Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. preparative and stereochemical aspects

Article

pubs.acs.org/joc

Catalytic, Enantioselective, Intramolecular Carbosulfenylation

of Oleﬁns. Preparative and Stereochemical Aspects

Scott E. Denmark* and Alex Jaunet

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States

S

* Supporting Information

ABSTRACT: The ﬁrst catalytic, enantioselective, intramolecular

carbosulfenylation of isolated alkenes with aromatic nucleophiles

is described. The combination of N-phenylsulfenylphthalimide, a

chiral selenophosphoramide derived from BINAM, and ethane-

sulfonic acid as a cocatalytic Brønsted acid induced an eﬃcient

and selective cyclofunctionalization of various alkenes (aliphatic

and aromatic) tethered to a 3,4-methylenedioxyphenyl ring. Under these conditions, 6-phenylthio-5,6,7,8-tetrahydronaphthalenes

are formed diastereospeciﬁcally in good yields (50−92%) and high enantioselectivities (71:29−97:3 er). E-Alkenes reacted much

more rapidly and with much higher selectivity than Z-alkenes, whereas electron-rich alkenes reacted more rapidly but with

comparable selectivity to electron-neutral alkenes and electron-deﬁcient alkenes. The Brønsted acid played a critical role in

eﬀecting reproducible enantioselectivity. A model for the origin of enantioselectivity and the dependence of rate and selectivity

on alkene structure is proposed along with a rationale for the site selectivity in reactions with monoactivated arene nucleophiles.

Scheme 1

INTRODUCTION AND BACKGROUND

■

1. Sulfenofunctionalization. The reaction of sulfur(II)

electrophiles with alkenes¹to aﬀord sulfenofunctionalized

products has been thoroughly studied since the 1960s primarily

in the context of investigating the chemistry of thiiranium ions.²

These reactive intermediates can be generated by a variety of

diﬀerent sulfenylating reagents such as dimethyl(methylthio)-

sulfonium tetraﬂuoroborate,^2dmethyl(bismethylthio)sulfonium

hexachloroantimonate, sulfenyl halides,^2e,3sulfenate esters,⁴

sulfenylamides, and disulﬁdes. A wide range of nucleophiles,

such as enol ethers, silyl ketene acetals, allylsilanes, aromatic

rings, organometallic agents (aluminum, zinc), carboxylic acids,

alcohols, amines, nitriles, and thiols have been employed in

sulfenofunctionalization reactions following the general process

illustrated in Scheme 1.^2dFor many such processes, the chloro-

sulfenylation product is generated ﬁrst followed by generation

of the thiiranium ion with a Lewis acid in the presence of the

pronucleophile.

Alternatively, intramolecular captures (sulfenocyclization

reactions) can be eﬀected with sulfenylating agents to form

carbocycles and heterocycles (Scheme 2). Warren and co-

workers⁵have extensively investigated the preparative and

mechanistic features of sulfenyl migration reactions from

thiiranium ions generated by neighboring group participation

of the sulfur moiety for the synthesis of oxygen- and nitrogen-

containing⁶heterocycles. In addition, sulfenium-initiated cycliza-

tions have also been successful with polyoleﬁns⁷and electron-

rich arenes.⁸

1.1. Enantioselective Sulfenofunctionalization. Several

examples of nucleophilic opening of chiral thiiranium ions

are on record. These species are generated by anchimerically

assisted ionization of enantiomerically enriched hydroxy sulﬁdes

formed from asymmetric dihydroxylation of alkenes.⁹These

enantiomerically enriched thiiranium ions have been captured

by nitriles, sulfonamides, silyl enol ethers, and substituted

benzene rings. Intramolecular capture has also been developed.¹⁰

However, only two reports of direct, enantioselective methyl-

sulfenylation reactions have been reported, both employing

stoichiometric reagents (Scheme 3).¹¹

1.2. Lewis Base Catalysis of Sulfenofunctionalization. As

part of a broadly based program to apply the concept of Lewis

base activation of Lewis acids¹²to the reactions of main group

Received: October 24, 2013

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Scheme 2

Scheme 5

Scheme 3

In continuation of these studies, we sought to expand the

scope of the asymmetric sulfenofunctionalization to include

carbocyclizations with aromatic nucleophiles. Although such

transformations are known (as mentioned above), no examples

of catalytic, enantioselective cyclizations are on record. Thus,

we initiated a program to evaluate (1) the diversity of sub-

stituent patterns on the alkene tether, (2) the nucleophilicity of

the aromatic residue needed for eﬀective cyclization, (3) the

reactivity of the thiiranium ions generated under catalytic

conditions compared to those generated stoichiometrically, and

(4) the dependence of enantioselectivity on the alkene structure.

The results of these studies along with some unexpected insights

into the role of the Brønsted acid coactivator are described

herein.¹⁹

elements, we have investigated the chemistry of selenium(II)¹³

and sulfur(II)¹⁴electrophiles. From extensive preparative and

mechanistic studies, we have discovered that the functionaliza-

tion of isolated alkenes with both N-phenylselenosuccinimide

and N-phenylsulfenophthalimide is susceptible to catalysis by

Lewis bases (Scheme 4).

RESULTS

■

1. Synthesis of the Alkene Substrates. As the point of

entry, we chose to evaluate electron-rich methylenedioxy-

benzenes to capture the intermediate thiiranium ions given

the success of sulfenocarbocyclizations with these species.^8,20

To study the scope of the carbosulfenylation with variously

substituted alkenes required a general and ﬂexible synthesis

of geometrically deﬁned oleﬁns. Of the many methods to

synthesize trans-disubstituted carbon−carbon double bonds,

initial attempts focused on the Schlosser modiﬁcation of the

Wittig oleﬁnation reaction.²¹Thus, 5-(3-oxopropyl)-1,3-benzo-

dioxolane 1²²was combined with the ethylidenetriphenyl-

phosphorane under standard Wittig−Schlosser oleﬁnation

conditions to aﬀord the alkene 2 in 60% yield as a 96:4 E/Z

mixture (Table 1, entry 1). Initial optimization of the carbo-

sulfenocyclization reaction was carried out with this E/Z

mixture of isomers 2a. However, the 4% of Z-alkene produced

when R²= Me and the low yielding reaction when R²= i-butyl

and Ph (entries 2 and 3) stimulated the search for an alternative

preparation of these substrates.²³

Scheme 4

The next strategy for the preparation of geometrically

deﬁned (3,4-methylenedioxyphenyl) alkenes employed the

Warren modiﬁcation of the Horner−Wittig reaction.²⁴Thus,

addition of methyl ester 3²⁵to a solution of ethyldiphenylphos-

phine oxide and n-BuLi aﬀorded β-keto diphenylphosphine

oxide 4 (Scheme 6). Both diastereomeric alcohols anti- and

syn-5 could be selectively prepared by the reduction of 4 under

appropriate reaction conditions.²⁶Treatment of ketone 4 with

However, whereas the intermediate seleniranium ions are not

conﬁgurationally stable, the corresponding thiiranium ions are

stable^15aand can be captured stereospeciﬁcally with a variety of

heteroatom nucleophiles.^15bThese insights led to the develop-

ment of the ﬁrst, catalytic, enantioselective sulfenofunctionaliza-

tion of isolated alkenes (Scheme 5).^14,16−18

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A third strategy was employed for the synthesis of various

(3,4-methylenedioxyphenyl)-derived alkenes through a B-alkyl

Suzuki−Miyaura cross-coupling reaction.²⁷In view of the

ready availability of styrenes and vinyl iodides, this reaction was

envisaged to provide access to aliphatic and aromatic sub-

stituted (3,4-methylenedioxyphenyl)-derived alkenes (Table 2).

The initial conditions for the cross-coupling reaction

between styrene 8a and (E)-(2-iodoethenyl)benzene (10b)

employed PdCl₂(dppf) (5 mol %), Cs₂CO₃(2.0 equiv), Ph₃As

(10 mol %), and H₂O (15.0 equiv) in DMF/THF for 15 h at

room temperature (Table 2, entry 1).²⁸Three products were

isolated from this reaction: cross-coupling product 2b, alkene

hydroboration product 9, and starting alkene 8a formed from

β-elimination of 9 during the cross-coupling. By extending the

reaction time to 24 h, no hydroboration product 9 was observed

by ¹H NMR spectroscopic analysis and the cross-coupling

product 2b was isolated in 43% yield (Table 1, entry 2). Despite

extensive optimization of the reaction conditions (solvent,

temperature, base, and ligands), none of the modiﬁcations

completely suppressed of the formation of the β-elimination

product 8a. Decreasing the amount of H₂O increased the

amount of 8a (entry 3), but increasing the amount of both

PdCl₂(dppf) and Ph₃As slightly improved the formation of the

desired alkene 2b (entry 4). The absence of the Ph₃PAs slightly

favored the formation of alkene 8a (entry 5). Removing water

slowed the cross-coupling reaction and aﬀorded only alkylbor-

ane 9 (entry 6). Changing the base to either CsF or NaOMe

also caused the cross-coupling reaction to fail (entries 7 and 8).

Modiﬁcation of the palladium source to Pd(OAc)₂, as reported

by Fu,²⁹did not improve the coupling (entry 9).

Table 1. Wittig−Schlosser Oleﬁnation

a

b

entry

R¹

product

R²

E/Z

yield, %

1

2

Et

PhCH₂

2a

2b

Me

Ph

96:4

60

42

>99:1

a

E/Z selectivity was determined by ¹H NMR spectroscopic analysis of

b

the puriﬁed product. Yield of isolated, puriﬁed products.

Scheme 6

Although still far from optimal, the conditions in entry 2

were employed in the cross-coupling of (E)-1-iodoheptene

(10n) to aﬀord the target alkene (E)-2n in 20% yield (Table 3,

entry 1). Despite the use of diﬀerent bases to activate the

alkyl-9-BBN derivative, it is clear that other activators for the

cross-coupling reactions needed to be evaluated. For example,

thallium salts (TlOH, Tl₂CO₃, TlOEt) have been used to

enhance the rate of Suzuki−Miyaura cross-coupling reactions

between vinylboronic acids and vinyl halides^30,31as well as

between alkylboranes and vinyl halides.³²When the conditions

recommended by Danishefsky [PdCl₂(dppf) (20 mol %), Ph₃As

(20 mol %), TlOEt (3.0 equiv), H₂O (5.0 equiv), THF, rt]

(Table 3, entry 2) were employed, the cross-coupling product

(E)-2n was formed in a gratifying 71% yield.

Reoptimization of certain experimental variables was next

conducted. The ﬁrst series of experiments evaluated the loading

of the palladium catalyst. Lowering the palladium loading to

10 mol % aﬀorded an identical yield of 70% (entry 3), but with

5 mol %, the yield of (E)-2n dropped to 58% (entry 4). The

amount of TlOEt was next investigated. Two equivalents of

TlOEt aﬀorded a comparable yield of 2c; however, lowering the

amount of the salt to 1.5 equiv aﬀorded (E)-2n in 66% yield

(entries 5 and 6). Moreover, the use of Pd(PPh₃)₄produced

(E)-2n in only 20% yield (entry 7).

LiBH₄and CeCl₃aﬀorded a (separable) mixture of β-hydroxy

diphenylphosphine oxide diastereoisomers 5 in a 75:25 anti/syn

ratio, whereas reduction of 4 with BH₃·py and TiCl₄furnished

diastereoisomers 5 in a 20:80 anti/syn ratio. Finally, β-hydroxy

phosphine oxides 5 were transformed into the corresponding

alkenes 2 in good yields (74−76%, Scheme 6).

To access the trisubstituted alkenes, β-hydroxy phosphine

oxide 4 was ﬁrst alkylated with MeI and KOt-Bu and the gem-

dimethylated product 6 was subsequently reduced with NaBH₄

to aﬀord β-hydroxy phosphine oxide 7 (Scheme 7). β-Hydroxy

phosphine oxide 7 was converted into trisubstituted alkene 2c

in good yield (72%), upon treatment with KH.

Scheme 7

From these optimization studies, the best conditions were

identiﬁed as PdCl₂(dppf) (10 mol %), Ph₃As (20 mol %),

TlOEt (2.0 equiv), H₂O (5.0 equiv), THF, rt, 12 h. However,

in several cases, the use of TlOEt did not aﬀord superior yields

compared with the previous protocol using Cs₂CO₃. Consid-

ering the high cost and toxicity of TlOEt, aryl-substituted

alkenyl iodides 2e, 2h, 2j, and 2s were cross-coupled using

the initial reaction conditions (B: (PdCl₂(dppf) (5 mol %),

Ph₃As (10 mol %), Cs₂CO₃(2.0 equiv), H₂O (15.0 equiv),

C

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Table 2. Optimization of Suzuki Cross−Coupling Reaction

a

ratio, %

entry

Pd source (mol %)

ligand (mol %)

base (equiv)

H₂O, equiv

solvent

time, h

temp, °C

8

9

2b

1

2

3

4

5

6

7

8

9

PdCl₂(dppf) (5)

PdCl₂(dppf) (15)

PdCl₂(dppf) (5)

PdCl₂(dppf) (3)

PdCl₂(dppf) (50)

Ph₃As (10)

Ph₃As (30)

Cs₂CO₃(2.0)

NaOMe (2.0)

CsF (4.0)

15.0

10.0

15.0

DMF/THF

THF

15

24

12

24

12

22

66

82

22

25

35

88

30

55

25

50

b

65

12

70

45

Ph₃As (10)

Cy₃P (8)

100

50

49.0

0.8

CH₃CN

Pd(OAc)₂(4)

K₃PO₄(2.0)

THF

50

a

b

1

Ratio determined by H NMR spectroscopic analysis. (E)-2b was isolated in 43% yield.

a

Table 3. Eﬀect of Thallium Ethoxide in the Suzuki−Miyaura Cross-Coupling of 9

b

entry

Pd source (mol %)

AsPh₃, mol %

TlOEt, equiv

H₂O, equiv

(E)-2n, yield, %

d

1

2

3

4

5

6

7

PdCl₂(dppf) (5)

PdCl₂(dppf) (20)

PdCl₂(dppf) (10)

PdCl₂(dppf) (5)

PdCl₂(dppf) (10)

Pd(PPh₃)₄(10)

10

20

c

15

5.0

20

3.0

2.0

1.5

71

70

58

70

66

5.0

2.0

825.0

20

a

b

c

d

Reaction carried out in THF at 22 °C for 12 h. Yield of isolated, puriﬁed product. Cs₂CO₃(2.0 equiv) was used instead of TlOEt. Starting

alkene 8a was recovered (37%).

THF/DMF, rt, 12 h). A wide variety of alkyl- and aryl-

substituted alkenyl iodides coupled in acceptable yields (60−

70%) (Table 4). The electronic character of the aryl substituent

of the alkenyl iodides did not aﬀect the yield of reaction, as

both electron-deﬁcient and electron-rich aryl residues aﬀorded

the trans-alkenes in acceptable yields (64−70%) (entries 1−6).

However, substitution in the 2-position of the benzene ring

aﬀorded the alkene 2i in lower yield (entry 7). In contrast,

alkyl-substituted alkenyl iodides furnished trans-alkenes 2k−2p

in good yields (entries 9−14). Finally, 10b and 10n coupled

with (3-methoxyphenyl)- (8b) and (4-methoxyphenyl)alkyl-

boranes (8c) in good yields (entries 15−18).

2. Optimization of the Sulfenocarbocyclization.

2.1. Initial Survey of Cyclization Conditions. A recent

disclosure from these laboratories described the development

of a catalytic, enantioselective sulfenoetheriﬁcation of unac-

tivated double bonds using N-phenylsulfenylphthalimide 13,

MsOH (to help activate 13), and a chiral selenophosphoramide

as the Lewis base.¹⁴In view of these studies and the known

conﬁgurational stability of the intermediate thiiranium species

at −20 °C,¹⁵the initial conditions for the sulfenocarbo-

cyclization of alkene 2a employed MsOH (1.0 equiv), 13

(1.0 equiv), and Lewis base (10 mol %) in CH₂Cl₂at −20 °C.

The initial success of these reaction conditions led to the

following optimization of the Lewis base structure. However, as

will become apparent in subsequent sections, the role of MsOH

in these reactions was quite diﬀerent from the sulfenoetheriﬁ-

cations and required a signiﬁcant amount or reoptimization.

Moreover, careful investigation of the uncatalyzed reaction

revealed a remarkable autocatalytic process that had heretofore

gone unnoticed.

2.2. Survey of Chiral Lewis Bases. With a method for

eﬀecting the racemic, intramolecular sulfenocarbocyclization in

hand, a number of chiral phosphoramides were tested to

develop an asymmetric variant of the reaction. The initial

survey of Lewis bases was carried out with E/Z mixtures of the

starting material 2a (Table 5). As was observed in the

sulfenoetheriﬁcation reaction, 1,1′-binaphthalene-2,2′-diamine

(BINAM)-derived thio- and selenophosphoramides proved to

be eﬃcient and selective chiral Lewis base catalysts.¹⁴In early

studies, various modiﬁcations of the BINAM backbone and the

internal nitrogen substituents were evaluated. Thio- and

selenophosphoramides derived from the parent 2,2′-dimethyl-

amino-1,1′-binaphthyl were the most selective to evaluate the

various Lewis base catalysts with initial reactions conditions

of MsOH (1.0 equiv), 13 (1.0 equiv), and phosphoramide (R)-

15a (10 mol %). The trans/cis ratio of the diastereomeric

products 14a was determined by ¹H NMR spectroscopic

analysis of the puriﬁed material, and the enantiomeric com-

position of the products was determined by chiral stationary

phase, supercritical ﬂuid chromatographic (CSP-SFC) analysis

(Table 5).

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a

Table 4. Substrate Scope of the B-Alkyl Suzuki−Miyaura Cross-Coupling Reaction

b

entry

conditions

R¹

R²

R³

R⁴

iodide

product

yield, %

1

2

A

B

A

B

A

B

A

B

−OCH₂O−

C₆H₅

4-CH₃C₆H₄

4-NC-C₆H₄

4-CH₃OC₆H₄

2-naphthyl

4-CF₃C₆H₄

2-CH₃C₆H₄

C₆H₅

H

10b

10d

10e

10f

(E)-2b

(E)-2d

(E)-2e

(E)-2f

71

60

61

70

64

47

80

82

62

56

70

73

69

68

75

54

70

3

H

4

H

5

H

10g

10h

10i

(E)-2g

(E)-2h

(E)-2i

6

H

7

H

8

CH₃

H

10j

(E)-2j

9

cyclopropyl

cyclopentyl

cyclohexyl

n-C₅H₁₁

10k

10l

(E)-2k

(E)-2l

10

11

12

13

14

15

16

17

18

H

10m

10n

10o

10p

10b

10n

10b

10n

(E)-2m

(E)-2n

(E)-2o

(E)-2p

(E)-11b

(E)-11n

(E)-12b

(E)-12n

H

Cl(CH₂)₃

(CH₃)₂CHCH₂

C₆H₅

H

CH₃O

H

n-C₅H₁₁

H

CH₃O

C₆H₅

H

n-C₅H₁₁

H

a

Conditions A: PdCl₂(dppf) (10 mol %), AsPh₃(20 mol %), TlOEt (2.0 equiv), H₂O (5.0 equiv), THF, 22 °C, 12 h. Conditions B: PdCl₂(dppf)

b

(5 mol %), AsPh₃(10 mol %), Cs₂CO₃(2.0 equiv) H₂O (15.0 equiv), THF/DMF, 22 °C, 24 h. Yield of analytically pure products.

Chiral Lewis base (R)-15a aﬀorded cyclized products 14a

with high diastereospeciﬁcity (trans/cis, 62:38) and reasonable

enantioselectivity for the major product, trans-14a (Table 5

entry 1). However, the minor cis-14a was produced in racemic

form. The corresponding thiophosphoramide catalyst (R)-15b

still aﬀorded excellent diastereospeciﬁcity (trans/cis, 96:4), but

signiﬁcantly lower enantioselectivity was obtained for trans-14a.

Nevertheless, (R)-15b delivered the ﬁrst nonracemic sample of

cis-14a (entry 2). Altering the external nitrogen substituent to a

piperidine (catalyst (R)-16a) aﬀorded excellent diastereo-

speciﬁcity but did not improve the selectivity of trans-14a and

cis-14a (entry 3). Once again, the corresponding thiophosphor-

amide catalyst (R)-16b provided excellent diastereospeciﬁcity;

however, the enantiomeric composition of trans-14a was lower

compared with that formed from the selenophosphoramide

catalyst (R)-16a (cf. entries 3 and 4). On the other hand, the

enantiomeric ratio of cis-14a was slightly improved.

In general, thiophosphoramide catalysts (i.e., (R)-15b, (R)-

16b) aﬀorded lower enantioselectivity for trans-14a than the

corresponding selenophosphoramides (i.e., (R)-15a, (R)-16).

For these reasons, the thiophosphoramide catalysts were not

further evaluated, and the investigation focused on the sub-

stituents on the external nitrogen. Increasing the size of the ring

to the azepane catalyst (R)-17a led to excellent diastereo-

speciﬁcity (trans/cis, 96:4) and higher enantioselectivity for

trans-14a but to cis-14a in racemic form (entry 5). A further

increase in the size of the ring to produce the azocane catalyst

(R)-18a still achieved excellent diastereospeciﬁcity but slightly

reduced enantioselectivity in the formation of trans-14a (entry 6).

As was observed with the previous catalysts, cis-14a was obtained

with moderate enantioselectivity.

aﬀorded excellent diastereospeciﬁcity and reasonable enantio-

selectivity for trans-14a (entry 7). As with the cyclic secondary

amine-based catalysts, this catalyst produced cis-14a with poor

enantioselection (entry 7). The corresponding thiophosphor-

amide catalyst (R)-19b aﬀorded excellent diastereospeciﬁcity

but lower enantioselectivity compared to selenophosphoramide

catalysts (R)-19a for trans-14a. Evaluation of other catalysts

prepared from branched secondary amines allowed the

identiﬁcation of the diisobutyl-derived catalyst (S)-20a, which

aﬀorded excellent diastereospeciﬁcity and enantioselectivity for

trans-14a (entry 9). Further extension to the diisoamylamine-

derived catalyst (S)-21a aﬀorded results similar to the azepane

catalyst (R)-17a for trans-14a and a slight improvement for cis-

14a (entry 10).

Continuing the survey of chiral Lewis bases for this cycliza-

tion led to the evaluation of selenophosphoramides derived

from linear dialkylamines. Catalysts (R)-22a and (S)-23a

bearing diethylamino and dibutylamino substituents aﬀorded

excellent diastereospeciﬁcity and enantioselectivities for trans-

14a but lower enantioselectivities than (S)-19a bearing a

diisobutylamino group. The ethyl(butyl)amino-derived catalyst

(S)-24a furnished excellent diastereospeciﬁcity and enantiomeric

ratio for trans-14a, as well (entry 13). Finally, phenyl(methyl)-

amine-derived catalyst (R)-25a aﬀorded moderate and poor

enantioselectivity for trans- and cis-14a, respectively (entry 14).

In the ﬁnal phase of optimization, the loading of catalyst

(S)-20a was evaluated. Lowering the catalyst loading to 5 and

7.5 mol % led to decreases in the enantioselection for trans-14a

(entries 15 and 16), whereas increasing the loading to 15 mol %

did not improve the enantioselectivity (entry 17). At this

point, the reaction conditions in Table 5, entry 9, were deemed

suﬃcient to explore the generality of this transformation with

respect to other substrates.

The next evaluation of external nitrogen substituents focused

on the use of acyclic, branched, secondary amines. For example,

diisopropylamino-substituted selenophosphoramide (R)-19a

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The Journal of Organic Chemistry

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a

Table 5. Survey of Chiral Lewis Bases to Sulfenocarbocyclization of 2a

a

b

Reaction conditions: 2a (0.12 mmol), 13 (0.12 mmol), MsOH (0.12 mmol), CH₂Cl₂(0.2 M), −20 °C. All reactions were completed in 24 h. E/Z

c

ratio of the starting material was determined by ¹H NMR spectroscopic analysis. The trans/cis ratios of the cyclization products were determined by

d

¹H NMR spectroscopic analysis. Enantiomeric ratio was determined by CSP-SFC analysis.

2.3. Brønsted Acid Eﬀect. 2.3.1. An Unexpected Compli-

cation. With the various reaction parameters established for

the catalytic, asymmetric sulfenocarbocyclization of (E)-2a, an

evaluation of the substrate scope was next undertaken. Good

enantioselectivities were obtained with E-aryl-substituted

alkenes, on a 0.1 mmol scale (>89:11 er, Table 6). Eﬀectively,

the same enantioselectivity was obtained with electron-rich and

electron-neutral aromatic substrates (phenyl (E)-2b, (entry 1);

4-tolyl (E)-2d, (entry 2), and 4-methoxyphenyl (E)-2f (entry 3)).

Surprisingly, however, upon scaling the reactions to 1.0 mmol, the

enantioselectivity decreased. Clearly, not all the critical reaction

parameters had been properly optimized. Because of the early

success of the conditions adapted from sulfenoetheriﬁcation, the

amount of the Brønsted acid employed was not evaluated, making

it the prime suspect for the lack of reproducibility.

Several modiﬁcations relating to the Brønsted acid were

explored. First, the rate of the addition of MsOH was reduced

from 6.5 to 0.7 μL/s, but lower enantiomeric ratios were still

observed on a 1.0 mmol scale. Second, a solution of MsOH

in CH₂Cl₂(0.2 M) was prepared and precooled to −70 °C

before slow addition (0.7 μL/s) into the reaction mixture.

Unfortunately, MsOH (mp 19 °C) crystallized in the precooled

solution. Thus, an alternative Brønsted acid with similar a

pK_avalue but a lower melting point was sought. Fortunately,

ethanesulfonic acid (EtSO₃H), which possesses a melting point

of −18 °C and a pK_avalue of −1.68 in H₂O,³³is commercially

available.

a

Table 6. Initial Survey of Reaction Scope

b

er on 0.1 mmol

er on 1.0 mmol

entry

aryl

C₆H₅

substrate

scale

1

2

3

2b

2d

2f

92:8

93:7

89:11

87:13

89:11

87:13

4-CH₃C₆H₄

4-CH₃OC₆H₄

a

All reactions were complete within 24 h. Conversion was determined

b

by ¹H NMR spectroscopic analysis. The enantiomeric ratio was

determined by CSP-SFC analysis.

2.3.2. Optimization of the Brønsted Acid. Extensive

optimization of the loading and delivery (neat vs solution) of

the Brønsted acid cocatalyst revealed that 0.75 equiv of EtSO₃H

gave reproducible results and restored the original enantiose-

lectivity for the cyclization. Detailed studies on the protonation

state of the catalyst, (S)-20a, the sulfenylating agent, 13, the

structure, and concentration of the catalytically active species

revealed the remarkable behavior of EtSO₃H in these reactions

F

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and are the subject of a forthcoming manuscript. For the

purposes of the preparative component of this study, the use of

0.75 equiv of EtSO₃H delivered neat solved the problem of

reproducibility.

2.3.3. Optimization of the Catalyst Loading. Identiﬁcation

of the appropriate conditions for the cyclization reaction led to

a reoptimization of the catalyst loading with alkene (E)-2d.

With 0.75 equiv of EtSO₃H and 10 mol % of catalyst (S)-20a,

cyclization aﬀorded excellent enantioselection (Table 7, entry 1),

and the better conversion obtained with the use 0.75 equiv of

EtSO₃H.

3. Sulfenocarbocyclization with (3,4-Methylenedioxy-

phenyl)-Derived Alkenes. 3.1. Alkyl Substituents. At this

point, the exploration of the generality of this transformation

with other substrates was investigated. Gratifyingly, application

of the optimized conditions to a large variety of E-alkyl- and

aryl-substituted alkenes aﬀorded the cyclized products in

moderate to excellent yields (50−92%) with good to excellent

enantioselectivities and as single (trans) diastereomers. For

example, under these conditions, E-methyl-substituted alkene

(E)-2a formed trans-14a in excellent yield and enantioselectiv-

ity (Table 8, entry 1). In contrast, the corresponding isomer

(Z)-2a led to cis-14a as a nearly racemic mixture (52:48 er,

entry 2) but in excellent yield (91%). E-Alkenes 2n−2p lacking

substitution at the allylic position furnished the cyclized

products trans-14n−trans-14p in moderate yields but very

good enantiomeric ratios (entries 3−5). Cyclopropyl substrate

(E)-2k bearing branching at the allylic position led to a good

yield and enantioselectivity (entry 6), whereas common

cycloalkyls (ﬁve- and six-membered) gave lower yields and

enantioselectivities (entries 7 and 8). If the alkene contained a

tert-butyl substituent, no cyclization occurred.³⁴Cyclization of

substrates 2c and (E)-2j containing geminally disubstituted

alkenes allowed formation of quaternary carbon centers albeit

with moderate enantiomeric ratios but good yields (entries 9

and 10). Interestingly, byproducts 26 and 27 resulting from the

proton-initiated cyclization reaction were formed in 2−8% yield

with these trisubstituted alkenes (Figure 1).

Table 7. Eﬀect of Catalyst Loading on the

a

Enantioselectivity

b

c

entry

EtSO₃H, equiv

(S)-20a, equiv

conv, %

er

1

2

3

4

0.75

0.5

0.10

0.05

0.02

0.10

82

60

36

80

93:7

88:12

83:17

93:7

a

Reaction conditions: (E)-2d (0.5 mmol), 13 (0.5 mmol), CH₂Cl₂

b

(0.2 M) at −20 °C for 10 h. Conversion was determined by ¹H NMR

spectroscopic analysis of the crude product. The enantiomeric ratio

c

was determined by CSP-SFC analysis.

slightly higher than with 1.0 equiv of EtSO₃H. Lowering the

loading of (S)-20a to 5 and 2 mol % aﬀorded enantiomeric ratios

of 88:12 and 83:17, respectively (entries 2 and 3). In addition to

the erosion of enantioselection, the rate of the reactions with

5 and 2 mol % of Lewis base (S)-20a was slower, aﬀording

only 60 and 36% conversion to product trans-14d. The use of

0.5 equiv of EtSO₃H and 10 mol % of (S)-20a produced

identical enantioselection (entry 4), compared to 0.75 equiv of

EtSO₃H, with 80% conversion after 10 h (entry 4). The best

conditions for the sulfenocarbocyclization were deﬁned in regard

to the enantioselectivity achieved with 10 mol % of (S)-20a

Figure 1. Products of unexpected side reactions.

3.2. Aryl Substituents. The next stage of the investigation

focused on the scope of E-aryl-substituted alkenes that could

participate in the cyclization (Table 9). Substrates (E)-2b,

(E)-2d, and (E)-2f bearing no substituents or electron-donating

Table 8. Cyclization with Alkyl-Substituted Alkenes

a

bc

,

entry

substrate

R¹

R²

product

time, days

temp, °C

yield, %

er

1

2

(E)-2a

(Z)-2a

(E)-2n

(E)-2o

(E)-2p

(E)-2k

(E)-2l

(E)-2m

2c

H

CH₃

H

trans-14a

cis-14a

3

1

3

6

3

1

2

−20

0

92

91

73

63

77

88

97:3

CH₃

H

52:48

96:4

3

n-C₅H₁₁

(CH₂)₃Cl

i-Bu

trans-14n

trans-14o

trans-14p

trans-14k

trans-14l

trans-14m

14c

−20

20

4

H

93:7

5

H

−20

0

96:4

6

H

cyclopropyl

cyclopentyl

cyclohexyl

CH₃

95:5

d

7

H

50

82:18

85:15

80:20

71:29

e

8

H

0

70

f

9

CH₃

−20

90

g

10

(E)-2j

CH₃

C₆H₅

trans-14j

82

a

b

c

Yields of analytically pure products. The enantiomeric ratio was determined by CSP-SFC analysis. The absolute conﬁgurations of the products

were assigned by comparison of their CD spectra with trans-14d. Unreacted starting material was recovered (15%). Unreacted starting material

was recovered (16%). An 8% yield of 26 was isolated. A 2% yield of 27 was isolated.

d

e

f

g

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Table 9. Cyclization of Aryl-Substituted Alkenes

a

bc

,

entry

substrate

aryl

product

time, days

temp, °C

yield, %

er

1

2

3

4

5

6

7

(E)-2b

(E)-2d

(E)-2f

(E)-2i

(E)-2g

(E)-2e

(E)-2h

Ph

trans-14b

trans-14d

trans-14f

trans-14i

trans-14g

trans-14e

trans-14h

2

−20

20

90

86

94:6

92:8

89:11

92:8

4-CH₃C₆H₄

4-CH₃OC₆H₄

2-CH₃C₆H₄

2-naphthyl

2

1

d

3.5

2

82

e

61

4-NC-C₆H₄

6

83

85

4-CF₃C₆H₄

3

20

a

b

c

Yields of analytically pure products. The enantiomeric ratio was determined by CSP-SFC analysis. The absolute conﬁgurations of the products

d

e

were assigned by comparison of their CD spectra with trans-14d. A 4% yield of 28 was isolated from earlier, unoptimized experiments. Unreacted

starting material was recovered (36%).

Table 10. Cyclization with Monomethoxyphenyl-Substituted Substrates

a

b

c

Yields of analytically pure products. The enantiomeric ratio was determined by CSP-SFC analysis. The absolute conﬁgurations of the products

were assigned by comparison of their CD spectra with trans-14d .

substituents aﬀorded cyclization products in good yields and

enantioselectivities (entries 1−3). However, substrate (E)-2i

bearing a methyl group in the ortho position reacted slowly,

but with good enantioselectivity (entry 4). Interestingly, 28, the

product of proton-initiated isomerization of the double bond,

was obtained in 4% yield (Figure 1). Substrate (E)-2g bearing

a 2-naphthyl substituent aﬀorded good selectivity but in lower

yield (entry 5). Finally, alkenes (E)-2e and (E)-2h bearing

electron-deﬁcient aromatic groups furnished nearly identical

enantioselectivities in very slow reactions (entries 6 and 7).

4. Sulfenocarbocyclization with Methoxyphenyl De-

rivatives. The ﬁnal exploration of substrate scope was carried

out with less nucleophilic aryl groups. The position of the

electron-donating substituent on the aromatic ring had a major

impact on the reactivity and site selectivity of the sulfeno-

carbocyclization. Substrates bearing a methoxy group in the

3-position with respect to the tethered alkene aﬀorded a mixture

of cyclized products 29−33, with both n-pentyl ((E)-11n)

and phenyl ((E)-11b) substituents (Table 10). With (E)-11n,

a 3:1 ratio of 30/31 was produced in good yields and

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enantioselectivities (entry 1). However, substrate (E)-11b

bearing a phenyl substituent aﬀorded a 1:1 ratio of 31/32, but

good enantioselectivity was still achieved for both constitutional

isomers (entry 2). For substrate (E)-12b with the activating

group in the 4-position, a good yield of 33 was obtained, albeit

with moderate enantioselectivity (entry 3). Interestingly, having

the activating group in the 4-position of the phenyl ring did not

lead to cyclization with the corresponding n-pentyl-substituted

alkene (E)-12n.³⁵

5. Stereochemical Assignment. Most of the sulfeno-

carbocyclization took place with high enantioselectivity. The

relative conﬁguration of tetrahydronaphthalenes was conﬁrmed

by correlation of the ¹H NMR chemical shifts of HC(3)

with known products trans-2a and cis-2a (Figure 2). All of the

trans-products displayed diastereotopic methylene protons on

C(3) of the tetrahydronaphthalene that split in two distinct

chemical shift around 1.80−1.92 and 2.08−2.18 ppm. On the

other hand, in the syn-product, the chemical shift of the

methylene protons on C(3) appeared around 2.00 and

2.06 ppm. Furthermore, the absolute conﬁguration of the

(−)-trans-14d was determined to be (1R,2R) by X-ray cry-

stallographic analysis of the derived sulfone trans-34 (obtained

by m-CPBA oxidation of the parent sulﬁde) (Scheme 8).³⁶

1. Synthesis of the Alkene Substrates. In a view of the

ready availability of (E)-2-iodostyrene and other vinyl iodides, a

general synthesis of alkyl- and aryl-substituted oleﬁns was

undertaken using the B-alkyl Suzuki−Miyaura cross-coupling

reaction. Since the ﬁrst report of cross-coupling between B-alkyl-

9-BBN derivatives and aromatic or alkenyl halide in 1989,³⁷

detailed accounts of the reaction conditions of the B-alkyl

Suzuki−Miyaura reaction have been reported.³⁸The most

commonly used conditions for the Suzuki−Miyaura reaction

between alkylborane derivatives and iodoalkenyl or styrenyl

iodides employs PdCl₂(dppf), Ph₃As, and Cs₂CO₃, with the

borane partner prepared by hydroboration of the corresponding

oleﬁn. Initial attempts to eﬀect cross-coupling between in situ

generated B-alkyl borane 9 and (E)-(2-iodoethenyl)benzene

(10) employed these standard conditions (PdCl₂(dppf)

(2 mol %), AsPh₃(10 mol %), Cs₂CO₃(2.0 equiv), and

water (15.0 equiv)) and aﬀorded two products, 2b, and

β-hydride elimination product 8a.³⁹No further optimization

could be achieved by adjusting these reaction parameters.

Ultimately, success was achieved by the use of thallium bases as

has been described by others previously.⁴⁰Kishi et al. ﬁrst

reported the use of TlOH for the cross-coupling reaction

between sp²centers. Subsequently, Roush,^31aChamberlain,^31b

and Marko⁴⁰

generated TlOH, and Tl₂CO₃) to improve the eﬃciency of

Suzuki cross-coupling reactions. Marko commented that a likely

́

employed various thallium salts (TlOEt, in situ

́

reason for the performance of thallium salts is the precipitation

of the thallium halide by combination with palladium(II) species

(ArylPd(dppf)X). This process would then form a highly

reactive, cationic palladium(II) species (ArylPd(dppf)⁺) that

would undergo rapid transmetalation with alkenyl-B(catechol)-

OTl⁻followed by rapid reductive elimination. After screening

the conditions described by Danishefsky et al. (using TlOEt),

it was possible to reduce the amount of PdCl₂(dppf) to

10 mol % and TlOEt to 2.0 equiv without adversely aﬀecting

the yield and the reaction time of the cross-coupling. Under

these newly developed conditions, a wide range of

(E)-(2-iodoethenyl)benzenes and vinyl iodides were coupled.

Interestingly, the cross-coupling of electron-poor (E)-(2-iodo-

ethenyl)benzene derivatives aﬀorded comparable yields

using either activator Cs₂CO₃or TlOEt. This behavior may

result from the greater electrophilicity of the palladium(II)

species (Pd(dppf)(styrene)⁺) with electron-deﬁcient styrenyl

moieties.

Figure 2. Conﬁgurations of trans-2a and cis-2a.

The negative Cotton eﬀect in the CD spectra of the products

allowed an unambiguous assignment of the absolute conﬁg-

urations of the major enantiomer of the cyclization products by

in comparison with trans-14d.

Scheme 8

2. Sulfenocarbocyclization of 3,4-Methylenedioxy-

phenyl Derivatives. The sulfenocarbocyclization of E-alkenes

catalyzed by (S)-20a aﬀorded the cyclized products in good to

excellent yields (Tables 8−10). The exclusive formation of

trans- and cis-1,2-disubstituted-1,2,3,4-tetrahydronaphthalenes

from E- and Z-oleﬁns, respectively, is in accordance with the

anticipated diastereospeciﬁcity characteristic of other seleno-¹³

and thiofunctionalizations.¹⁵

2.1. Eﬀect of the Oleﬁn Conﬁguration on Enantioselec-

tivity and Rate. Both the enantioselectivity and the rate of the

reaction were highly dependent on the substitution and conﬁgura-

tion of the alkene, whereas the formation of the catalytically active

species is independent of the alkene. To enter the catalytic cycle,

sulfenylating agent 13 is activated by protonation with EtSO₃H

(Figure 3, step a), whereupon the sulfenyl group is transferred to

the Lewis base to generate the catalytically active sulfenylating

agent 35 (step b). Approach of 35 onto the alkene leads to the

formation of thiiranium ion i (step c), which upon subsequent

intra- or intermolecular nucleophilic capture (step d) delivers the

DISCUSSION

■

Our primary objective in this work was to develop a catalytic,

asymmetric carbosulfenylation of oleﬁns as a method to

prepare enantioenriched 1-alkyl- or 1-aryl-2-thiophenyl-1,2,3,4-

tetrahydronaphthalenes. Moreover, given the striking divergence

in behavior of these cyclizations compared to the sulfenocyclo-

etheriﬁcations reported previously,¹⁴a second goal focused on a

more reﬁned understanding of the role of the Brønsted acid in

these reactions.

I

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corresponding enantioenriched thioether (step e). The dramatic

diﬀerence in reactivity and selectivity among the various alkenes

(and in particular between E- and Z-alkenes)⁴¹must arise from

either the rate of formation of the thiiranium ion i (step c) or the

intramolecular trapping of that ion (step d).

replaced with the diisobutylamino group of catalyst (S)-20a;

(2) all of the atoms of the (S)-17a backbone are ﬁxed, and the

diisobutylamino group was minimized with molecular mechan-

ics; and (3) an S-phenyl group was attached to the selenium

atom and again minimized with molecular mechanics. Model 1

illustrates the destabilizing steric interaction between the

S-phenyl group and the diisobutylamino group of the active

species 35, causing the phenylsulfenyl group to point toward

the binaphthyl subunit (models 2 and 3). The energy proﬁle

for the C−S−Se−P dihedral angle is very ﬂat with two minima

at 121 and 83°. For our purposes, this angle is assumed to

be close to 120° as seen in [(Me₂N)₃P−Se]₂²⁺[(BiCl₄)₂]_nⁿ⁻, in

which the P−Se−Se−P dihedral angle is 112°.⁴³

The next step in rationalizing the stereochemical course of the

reaction involves the approach of the alkene onto 35. Several

factors inﬂuence this approach such that the orbital interactions are

maximized and the destabilizing steric interactions are minimized.

To maximize orbital overlap between the HOMO of the alkene

and the LUMO of the electrophile, the bonding π-electrons of the

alkene must approach the sulfur atom in i along the trajectory of

the S−Se σ*-orbital.⁴⁴Two, limiting transition state geometries are

considered for the thiiranium ion formation: the spiro and the

planar approaches (Figure 5). By analogy with the epoxidation of

alkenes with dioxiranes and peracids,⁴⁵a spiro transition state is

favored over the planar transition state due to stabilizing interaction

of a sulfur lone pair with π*-orbital of the alkene in the former.

Figure 3. Proposed catalytic cycle for sulfenofunctionalization.

Our interest in a detailed mechanistic understanding of this

reactionespecially the structure of the catalytically active

species 35led to numerous attempts at crystallization of

various salts which have been unsuccessful to date. Computa-

tional studies to determine the conformation of the putative

catalytic species 35 and develop a better understanding of the

transition state structure for the formation of thiiranium ion i

are ongoing. However, a single-crystal X-ray diﬀraction analysis

of Lewis base catalyst (S)-17a⁴²could be obtained from which

working models can be proposed to explain the origin of the

enantioselectivity with related Lewis base (S)-20a.

The solid-state structure of (S)-17a revealed the pseudo-

equatorial positions of the N-methyl groups of the azepine ring

relative to the 1,3,2-diazaphosphephine ring. Moreover, the

plane deﬁned by the C(1)−N−C(6) atoms of the azepine ring

is nearly coincident with the PSe unit (−8.77°) and thus the

ring carbons occupy space near the PSe unit (Figure 4).

The models employed in the discussion below are derived

from the crystallographic coordinates of catalyst (S)-17a with

the following modiﬁcations: (1) the azepino group of (S)-17a is

Figure 5. Spiro and planar transition states for the thiiranium ion

formation.

Taken together, these two factors allow the formulation of

six limiting transition structures TS-A−TS-F to rationalize the

enantioselectivity of the reaction. In the case of Z-alkenes,

models TS-A−TS-C explain the lower reactivity as well as

the poor enantioselectivity of the thiiranium ion formation

(Figure 6). In model TS-A, the Z-alkene approaches i on the

Si−Re face,⁴⁶with the alkene substituents facing down (Si−Re

(d)). This arrangement suﬀers from destabilizing steric interactions

between the binaphthyl moiety of 35 and the substituents on the

alkene. It is important to note that same argument can be made if

Figure 4. X-ray crystallographic structure of (S)-17a and proposed models for the geometry of the catalytically active species i.

J

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Figure 6. Proposed rationale for the unselective formation of thiiranium ions from Z-alkenes.

Figure 7. Proposed rationale for the selective formation of thiiranium ions from E-alkenes.

the alkene approaches 35 on the Re−Si face with the substituent

of the alkene down (Re−Si (d), not shown). In models TS-B and

TS-C, the alkene approaches 35 on the Si−Re and Re−Si faces,

respectively, with the alkene substituents facing up (u). In these

transition structures, destabilizing interactions between the

S-phenyl group and the R¹/R²substituents of the alkene would

K

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reduce the rate of the formation of the thiiranium ion. As none

of these arrangements is devoid of nonbonding interactions, the

formation of two thiiranium ion enantiomers cis-i and ent-cis-i will

occur at similar rates which, after cyclization, aﬀord tetralin

enantiomers cis-14 and ent-cis-14 with equal facility.

The presence of a chlorine atom on the alkyl chain ((E)-2o)

decreased the rate of the reaction while maintaining a high

level of enantioselectivity.⁴⁷The low cyclization rate could be

explained by protonation of the chlorine atom or interception

of the thiiranium species with the pendant chlorine atom.

However, the latter explanation can be ruled out because this

would change the relative conﬁguration of the product.⁴⁸

Protonation of the chlorine atom, which has been proposed in

an acid-catalyzed Friedel−Crafts alkylation,⁴⁹would reduce the

concentration of Brønsted acid in the solution. Lowering the

concentration of the acid would shift the equilibrium protona-

tion of the sulfenylating agent to the left (step a, Figure 3) and

lower the overall rate of the reaction.

The electronic properties of the alkenes also inﬂuenced the

outcome of cyclization. For example, trisubstituted alkenes

were more reactive than disubstituted E-alkenes, although the

enantioselectivities were lower. These results reﬂect the

inﬂuence played by the substituent in cis position of the alkyl

chain, bearing the veratryl ring, on the approach of the alkene

to 35. The greater rate of reaction coupled with the lower

enantioselectivity is puzzling. Given the additional steric con-

tributions from a cis substituent, these results imply that several

competing transition states are lower in energy than those for

disubstituted alkenes. This outcome may arise from earlier

transition states which result from greater electron density in

the trisubstituted alkene. Alternatively, reactions of these

substrates may be highly asynchronous or involve discrete

carbocations. Although all of the sulfenocarbocyclizations were

highly diastereospeciﬁc, it is conceivable that the reaction of

(E)-2j proceeded through a stepwise process via formation of

a tertiary carbocation ii. However, as only one diastereomer

was observed, capture of the carbocation must be faster than

rotation of bond a (k¹≫ k²) to form iii (Scheme 9).

In the case of E-alkenes, model TS-D illustrates the approach

of the Si−Si face of the alkene to the active species 35 in which

destabilizing interactions between the R²substituent of the alkene

and the binaphthyl rings of 35 would disfavor this approach

(Figure 7). The same argument is also valid when R¹and R²

substituents are interchanged. The two models TS-E and TS-F

depict the approach of the Re−Re face of the alkene to 35 in

which no repulsive steric interactions occur between the R¹or R²

substituents of the alkene and the binaphthyl rings of 35. In

addition, the approach of the Re−Re face of the alkene may

prefer TS-E because the bulkier substituent (R¹) does not

encounter steric repulsions with the N-methyl group of the Lewis

base. As a consequence of reaction via transition states TS-E and

TS-F, a single thiiranium ion trans-i is formed which after ring

closure aﬀords tetralin trans-14. Comparison of models TS-E and

TS-F with models TS-B and TS-C illustrates why the formation

of the thiiranium ion is faster for E-alkenes than for Z-alkenes.

2.2. Reaction of Alkyl-Substituted Alkenes. Unactivated

E-alkenes bearing linear, β-branched, and alicyclic substituents

aﬀorded excellent levels of enantioselectivity and reacted with

similar rates. The length of the alkyl chain on the alkene did not

inﬂuence the rate or enantioselectivity of the reaction, substrates

with longer carbon chains ((E)-2n−(E)-2p) led to moderate

yields, and substrate (E)-2a bearing a methyl group gave

excellent yield. The lower enantioselectivity of the sulfeno-

carbocyclization observed for alkenes bearing branched

substituents (E)-2l and (E)-2m implies that neither TS-E nor

TS-F can accommodate larger groups on each end of the alkene.

The alkene approach via TS-D may become competitive, but

more likely an alternative transition structure that can

accommodate at least one large group leading to the minor

enantiomer can be considered. For example, TS-G in which the

S−Se bond is rotated at a diﬀerent minimum may lead to an

increase in the formation of the ent-trans-14 (Figure 8).

Scheme 9

In addition to the Lewis base catalyzed sulfenocarbocycliza-

tion reaction of trisubstituted alkenes, the formation of non-

sulfur-containing 1,1-disubstituted-1,2,3,4-tetrahydronaphthalenes

26 and 27 was also observed in certain cases resulting from a

proton-initiated intramolecular Friedel−Crafts reaction.

2.3. Reaction of Aryl-Substituted Alkenes. In the case of

E-alkenes bearing neutral or electron-donating aryl substituents

((E)-2b, (E)-2d, (E)-2f) with Hammett’s values 0 > σ_p> −0.2,⁵⁰

very good enantioselectivities were achieved. These selectivities

were slightly lower than alkenes bearing linear or β-branched

Figure 8. Proposed rationale for thiiranium ion formation from branched

E-alkenes.

L

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substituents most likely because of diﬀerent steric demands.

Likewise E-alkenes bearing electron-donating aryl substituents

with Hammett values σ_p< −0.2 led to a slight decrease of

enantioselectivity compared to neutral aryl-substituted alkenes.

As was observed with trisubstituted alkenes, increasing the

electronic density of the double bond led to faster cyclization.

Both of these observations are explained by analogy to the

behavior of the trisubstituted alkenes above.

Scheme 11

Sterically hindered, aryl-substituted alkenes ((E)-2i and

(E)-2g)) cyclized with lower enantioselectivities. This outcome

was attributed to the congestion around 35 that renders

the approach of the alkene diﬃcult (models TS-E and TS-F).

The lower reactivity of alkene (E)-2i allowed for a competing

pathway to appear involving migration of the double bond

along the alkyl chain into conjugation with the veratryl group.

Protonation of the alkene presumably led to formation of a

benzylic carbocation iv that could undergo a 1,4-hydride shift⁵¹

to produce a more stable benzylic carbocation v, potentially

through the bridging transition state structure vi.⁵²Subsequent

deprotonation aﬀorded E-alkene 28 that did not cyclize

(Scheme 10).

ratio obtained for 29 was identical to that obtained for trans-

14n. For the phenyl-substituted alkene (E)-11b, the cyclization

led to the formation of constitutional isomers 31 and 32 in a 1:1

ratio.

Interestingly, substrate (E)-12n containing a 4-methoxy-

substituted aryl ring bearing the alkyl-substituted alkene did

not cyclize. This outcome is ascribed to the decreased electron

density on the C(3) and C(5) positions of the 4-methoxy-

substituted aryl group (σ_p= −0.115). However, phenyl-substituted

alkene (E)-12b aﬀorded 1,2,3,4-tetrahydronaphthalene 33. The

formation of products 31, 32, and 33 is likely attributed to the

presence of the phenyl substituent on the alkene, which through

charge stabilization can enhance the electrophilic character of

the benzylic carbon of the thiiranium ion.

Scheme 10

Cyclizations with the electron-rich veratryl group occurred

exclusively at the C(6) position which ﬁnds ample precedent

in intramolecular cationic cyclization reactions such as

N-acyliminium ion closures and Friedel−Crafts reactions.⁵⁴

To explain the diﬀerence in the site selectivity for the

sulfenocarbocyclization reaction between the methylenedioxy

and the methoxy activating groups, computational studies were

performed using density functional theory (B3LYP/6-31G*)

with substrates 36 and 37 to simplify calculations (Figure 9).

The very slow cyclization (even at room temperature) of

E-styrenes bearing electron-withdrawing substituents ((E)-2e

and (E)-2h) could be ascribed to a number of factors. In

addition to the electron-deﬁcient nature of the alkene, which

would slow the formation of the thiiranium species, the presence

of the cyano group in substrate (E)-2e might serve as a buﬀer

for the Brønsted acid coactivator. Ineﬃcient protonation of the

sulfenylating agent 13 (Figure 3, step b) would lead to slow

reaction.

Comparison of alkyl-substituted and aryl-substituted alkenes

allowed the identiﬁcation of some trends: (1) increasing the

electron density of the alkenes (with electron-rich aryl or

trisubstituted alkenes) aﬀorded faster sulfenocarbocyclization

but with slightly lower enantioselectivity; (2) small aliphatic

rings have identical selectivity as linear alkyl-substituted alkenes;

(3) increasing the size of the allylic substituent or the steric

bulk of aryl-substituted alkene decreased both the rate and

the enantioselectivity of the reaction; and (4) electron-deﬁcient

aryl-substituted alkenes reacted slowly without aﬀecting the

enantioselectivity.

2.4. Inﬂuence of the Nucleophilic Activator on the Aryl

Group. The position of the electron-donating substituent on the

nucleophilic aryl group inﬂuenced the rate of product formation.

Substrate (E)-11n containing a 3-methoxy-substituted aryl ring

attached to an alkyl-substituted alkene reacted to aﬀord two

constitutional isomers 29 and 30 in a 3:1 ratio (Scheme 11).

In previous studies, cationic ring closures with m-anisole

occurred at both C(2) and C(4) positions.⁵³The enantiomeric

Figure 9. Electrostatic charge (natural charge values) and local

energies of HOMO orbitals for models 36 and 37.

Computational studies of simpliﬁed model 36 showed

localization of the HOMO orbital at the C(5) position of the

aromatic group and not at the C(3) position. In the case of 37,

similar calculations showed HOMO populations at both C(3)

and C(5) positions of the nucleophilic ring. Comparison of the

electrostatic (and natural) charges between models 36 and 37

showed in both cases that the C(3) position of the aryl group

exhibits higher negative charge than the C(5) position, which if

the reaction were purely charge-controlled would indicate a

M

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

11.5 (C(1)); ³¹P NMR (202 MHz, CDCl₃) δ 31.25; IR (KBr) 2922

(s), 2853 (s), 2850 (s), 1737 (m), 1703 (w), 1498 (s), 1485 (w), 1462

(s), 1403 (m), 1376 (s), 1363 (s), 1346 (m), 1325 (m), 1240 (s),

1185 (s), 1119 (s), 1094 (s), 1035 (s), 996 (m), 928 (s); MS (ES⁺)

408.1 (20), 407.1 (100); TLC R_f0.54 (EtOAc/pentane, 4:1). Anal.

Calcd for C₂₄H₂₃O₄P (406.41): C, 70.93; H, 5.70; P, 7.62%. Found: C,

70.65; H, 5.67;P, 7.76%.

higher nucleophilic character at C(3) for alkene substrates 36

and 37. However, the experimental results do not align with

these charges densities. Calculations of the HOMO orbital

occupancies support the experimental data. Thus, the

calculations suggest that the sulfenocarbocyclization is under

FMO control rather than electrostatic control despite the

formation of a charged thiiranium ion intermediate.

CONCLUSION

■

In conclusion, the ﬁrst catalytic, asymmetric carbosulfenylation

of oleﬁns has been accomplished by using a cocatalytic system

of a Brønsted acid (EtSO₃H) and a chiral Lewis base (S)-20a.

This method enables eﬃcient access to enantioenriched trans-

tetrahydronaphthalenes with complete diastereospeciﬁcity,

generally high enantiomeric ratios, and a broad substrate scope

with E-oleﬁns. Oleﬁns bearing α-substituted alkyl groups (cyclic

or branched) and electron-poor oleﬁns tend to give lower

enantioselectivities due to the higher temperature required.

E-Oleﬁns reacted slowly and with very poor enantioselectivity.

Formation of quaternary centers was achieved in moderate

enantioselectivity. Further investigations aimed at expanding the

scope of the reaction (diﬀerent ring sizes and heterocycles) along

with mechanistic studies on the origins of the enantioselectivity are

in progress. Studies on the role of the Brønsted acid and resting

state of the catalyst are the subjects of a forthcoming manuscript.

Preparation of anti-2-Diphenylphosphinoyl-5-(3′,4′-methylene-

55

dioxyphenyl)pentan-3-ol (anti-5) and syn-2-Diphenylphosphinoyl-

5-(3′,4′-methylenedioxyphenyl)pentan-3-ol (syn-5). Dried CeCl₃

(788.0 mg, 3.2 mmol) was suspended in THF (30 mL) and stirred for

2 h at room temperature. A solution of ketone 4 (1.0 g, 2.5 mmol) in

THF (25 mL) was added, and the reaction mixture was stirred for 12 h

and then cooled at −70 °C. LiBH₄(1 M in THF, 7.4 mL) was slowly

added, and the reaction mixture was vigorously stirred for 3 h at

−70 °C. The reaction was quenched by slow addition of saturated

NH₄Cl (20 mL) at 0 °C. The aqueous phase was extracted with Et₂O

(3 × 20 mL). A diluted solution of HCl (10% in H₂O, 5 mL) was

added into the aqueous phase and extracted again with Et₂O (20 mL).

The combined organic layers were washed with brine (60 mL), dried

over MgSO₄, ﬁltered through glass wool, and then concentrated

in vacuo (20−23 °C, 10 mmHg). Puriﬁcation via ﬂash column

chromatography (Teledyne Isco Combiﬂash R_f75, Silicycle SiO₂, 25 g,

15−40 μm mesh, gradient: 35 to 50% EtOAc in hexane over 70 min,

30 mL/min) to aﬀord syn-5 as pale white oil (230 mg, 23%) that

crystallized upon standing and anti-5 as white solid (690 mg, 69%).

EXPERIMENTAL PROCEDURES

■

Preparation of Cyclization Substrates. Phosphine Oxide Route.

1

Data for anti-5: mp 118−122 °C; H NMR (500 MHz, CDCl₃) δ

7.82−7.73 (m, 4 H, HC(b) and HC(f)), 7.58−7.55 (m, 2 H, HC(d)),

7.52−7.48 (m, 4 H, HC(c) and HC(e)), 6.95 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.64 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.60 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 5.91 (s, 2 H, OCH₂O), 4.71 (s, 1 H, OH), 3.88

(q, J = 7.5 Hz, 1 H, HC(3)), 2.82−2.76 (m, 1 H, HC(5)), 2.74−2.69

(m, 1 H, HC(2)), 2.61−2.55 (m, 1 H, HC(5)), 1.90−1.83 (m, 1 H,

HC(4)), 1.77−1.70 (m, 1H, HC(4)), 1.04 (d, J = 17.5, 7.5 Hz,

HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 147.7 (C(3′)), 145.7

(C(4′)), 136.1 (C(1′)), 132.5 (d, J = 95.5 Hz, C(a)), 132.3 (d, J =

2.6 Hz, C(d)), 132.2 (d, J = 2.6 Hz, C(d)), 132.1 (d, J = 9.0 Hz, C(e)),

131.2 (d, J = 9.0 Hz, C(c)), 130.5 (d, J = 95.5 Hz, C(a)), 129.1 (d, J =

11.4 Hz, C(f)), 128.7 (d, J = 11.4 Hz, C(b)), 121.4 (C(2′)), 109.2

(C(6′)), 108.3 (C(5′)), 100.9 (OCH₂O), 71.6 (C(3)), 38.4 (d, J =

68.8 Hz, C(2)), 37.1 (C(4)), 31.5 (C(5)), 11.9 (C(1)); ³¹P NMR

(202 MHz, CDCl₃) δ 41.76; IR (KBr) 3303 (br s), 2926 (m), 2878

(m), 1503 (s), 1487 (s), 1434 (s), 1313 (w), 1243 (s), 1115 (s), 1035

(s), 994 (w), 928 (m); MS (EI⁺, 70 eV) 408.1 (15.4), 259.1 (15.7),

230.0 (12.4), 229.0 (11.1), 203.0 (14.9), 202.0 (100.0), 201.0 (72.4),

188.1 (13.5), 135.0 (29.3), 77.1 (33.7), 57.1 (13.9), 51.1 (14.9);

HRMS calcd for C₂₄H₂₅O₄P⁺408.1491, found 408.1499; TLC R_f0.34

Preparation of 2-Diphenylphosphinoyl-5(3′,4′-methylenedioxy-

phenyl)pentan-3-one (4). n-BuLi (2.5 M in hexanes, 32.7 mL, 81.8

mmol) was added dropwise to a stirred solution of diphenylethyl-

phosphine oxide (19.0 g, 82.6 mmol) in THF (300 mL) at 0 °C. After

30 min, the red solution was cooled to −70 °C and a solution of

methyl-3-(3′,4′-methylenedioxyphenyl)propanoate 3 (8.6 g, 41.3

mmol) in THF (80 mL) was added dropwise over 30 min, with a

syringe. After complete addition, the reaction mixture was slowly

warmed to room temperature and stirred for 12 h. The reaction

was quenched with saturated aq NH₄Cl (90 mL), and the aqueous

phase was extracted with Et₂O (3 × 50 mL). The combined organic

layers were washed with brine (120 mL) then dried over MgSO₄,

ﬁltered through glass wool, and concentrated in vacuo (20−23 °C,

10 mmHg). The product was ﬁrst puriﬁed by ﬂash column chromato-

graphy on silica gel (SiO₂, 25 g, 30 mm Ø, pentane/EtOAc, 4:1) to

aﬀord a mixture of 4 and diphenylethylphosphine oxide (14.76 g).

Puriﬁcation of the mixture via recrystallization from pentane/CH₂Cl₂

(85:15 v/v) (200 mL) gave 4 as white solid 8.5 g for the ﬁrst crop and

3.9 g for the second crop (pentane/CH₂Cl₂(85:15 v/v) (90 mL))

(74%). Data for 4: mp 149−151 °C (pentane/CH₂Cl₂(85:15 v/v));

¹H NMR (500 MHz, CDCl₃) δ 7.82−7.74 (m, 4 H, HC(b) and

1

(EtOAc/pentane, 7:3) [KMnO₄]. Data for syn-5: mp 56−58 °C; H

NMR (500 MHz, CDCl₃) δ 7.80−7.74 (m, 4 H, HC(b) and HC(f)),

7.55−7.46 (m, 6 H, HC(c), HC(d), H(e)), 6.66 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.62 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.56 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 5.91 (d, J = 2.5 Hz, 2 H, OCH₂O), 4.25 (s, 1 H, OH),

4.11−4.06 (m, 1 H, HC(3)), 2.69−2.63 (m, 1 H, HC(5)), 2.54−2.48

(m, 1 H, HC(5)), 2.32 (dq, J = 7.5, 7.5 Hz, 1 H, HC(2)), 2.03−1.96

(m, 1 H, HC(4)), 1.63−1.56 (m, 1 H, HC(4)), 1.21 (dd, J = 17.0, 7.5

Hz, 3 H, HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 147.7 (C(3′)),

145.8 (C(4′)), 135.6 (C(1′)), 132.2 (d, J = 2.8 Hz, C(d)), 132.0 (d,

J = 2.8 Hz, C(d)), 131.9 (d, J = 94.4 Hz, C(a)), 131.4 (d, J = 94.4 Hz,

C(a)), 131.0 (d, J = 11.5 Hz, C(b)), 130.9 (d, J = 11.5 Hz, C(f)),

HC(f)), 7.58−7.55 (m, 2 H, HC(d)), 7.51−7.48 (m, 4 H, HC(c) and

HC(e)), 6.67 (d, J = 7.5 Hz, 1 H, HC(5′)), 6.56 (d, J = 1.5 Hz, 1 H,

HC(2′)), 6.53 (dd, J = 7.5, 1.5 Hz, 1 H, HC(6′)), 5.91 (s, 2 H,

OCH₂O), 3.66 (d, J = 14.0, 7.0 Hz, 1 H, HC(2)), 2.84 (t, J = 7.5 Hz,

2 H, HC(5)), 2.66 (t, J = 7.5 Hz, 2 H, HC(4)), 1.37 (dd, J = 16.0,

7.0 Hz, 3 H, HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 206.8 (CO),

147.6 (C(3′)), 145.9 (C(4′)), 134.8 (C(1′)), 132.4 (d, J = 2.8,

C(d)), 131.6 (d, J = 9.3, C(b)), 131.5 (d, J = 9.3, C(f)), 131.2 (d,

J = 98.6, C(a)), 131.0 (d, J = 98.6, C(a)), 129.0 (d, J = 6.3, C(c)),

128.9 (d, J = 6.3, C(e)), 121.4 (C(6′)), 109.2 (C(2′)), 108.3 (C(5′)),

101.0 (OCH₂O), 50.7 (d, J = 56.8, C(2)), 45.0 (C(5)), 29.4 (C(4)),

N

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

129.1 (d, J = 4.1 Hz, C(c)), 129.0 (d, J = 4.1 Hz, C(e)), 121.3 (C(6′)),

109.0 (C(2′)), 108.3 (C(5′)), 100.9 (OCH₂O), 68.5 (C(3)), 36.8 (d,

J = 12.5 Hz, C(4)), 36.1 (d, J = 70.1 Hz, C(2)), 32.1 (C(5)), 5.9

(C(1)); ³¹P NMR (202 MHz, CDCl₃) δ 41.69; IR (KBr) 3425 (br s),

3059 (m), 2926 (s), 2885 (s), 1712 (s), 1608 (m), 1590 (m), 1503

(s), 1486 (s), 1451 (m), 1434 (m), 1361 (m), 1337 (m), 1234 (s),

1160 (s), 1115 (m), 1035 (m), 924 (s); MS (EI⁺, 70 eV) 408.2 (16.1),

259.1 (12.3), 231.2 (10.0), 230.1 (13.7), 229.1 (12.2), 203.1 (15.6),

202.0 (100.0), 201.0 (64.0), 191.1 (9.7), 188.1 (20.2), 155.1 (10.8),

135.0 (25.9), 91.1 (11.1), 77.1 (28.6), 71.1 (37.9), 69.1 (12.4), 57.1

(25.7), 55.1 (20.4), 51.0 (12.5); HRMS calcd for C₂₄H₂₅O₄P⁺

408.14905, found 408.14850; TLC R_f0.42 (EtOAc/pentane, 7:3)

[KMnO₄].

135.0 (C(1′)), 132.4 (d, J = 15.0 Hz, C(b,f)), 132.3 (d, J = 2.8 Hz,

C(d)), 130.7 (d, J = 95.5 Hz, C(a)), 128.7 (d, J = 14.6 Hz, C(c,e)),

121.5 (C(2′)), 109.3 (C(6′)), 108.3 (C(5′)), 100.9 (OCH₂O), 53.2

(d, J = 57.5 Hz, C(2)), 42.9 (C(5)), 29.8 (C(4)), 21.4 (C(1)); ³¹P

NMR (202 MHz, CDCl₃) δ 34.61; IR (KBr) 3060 (w), 2970 (w),

2922 (w), 1699 (s), 1606 (w), 1592 (w), 1505 (m), 1490 (m), 1482

(m), 1439 (s), 1417 (m), 1370 (m), 1297 (w), 1241 (s), 1177 (s),

1116 (s), 1099 (s), 1039 (s), 996 (m), 928 (s); MS (TOF ES⁺) 422.1

(25.0), 421.1 (16.1, M+H⁺); HRMS calcd for C₂₅H₂₆O₄P⁺421.1569,

found 421.1574; TLC R_f0.49 (pentane/EtOAc, 3:7). Anal. Calcd for

C₂₅H₂₅O₄P (420.44): C, 71.42; H, 5.99; P, 7.37%. Found: C, 71.29; H,

6.02; P, 7.49%.

Preparation of 2-Methyl-2-diphenylphosphinoyl-5-(3′,4′-

methylenedioxyphenyl)pentan-3-ol (7). Sodium borohydride (675

mg, 17.8 mmol) was added portion wise to a solution of ketone 6

(2.50 g, 5.95 mmol) in CH₂Cl₂/MeOH (1:1 v/v, 100 mL) at room

temperature and stirred for 4 h. The reaction was quenched with

saturated aq NH₄Cl (30 mL) at 0 °C. The aqueous phase was extracted

with Et₂O (3 × 55 mL), and the combined organic layers were

successively washed with brine (100 mL), dried over MgSO₄, ﬁltered

through glass wool, and then concentrated in vacuo (20−23 °C,

10 mmHg). The product 7 was obtained as a white solid (2.51 g, 99%).

The crude material was used without further puriﬁcation. Recrystalliza-

tion of an aliquot (400 mg) from CH₂Cl₂20%/Et₂O 80% (v/v) (5 mL)

gave an analytical sample of 7 (380 mg). Data for 7: mp 123−125 °C

Preparation of syn-2-Diphenylphosphinoyl-5-(3′,4′-methylenedi-

oxyphenyl)pentan-3-ol (syn-5) and anti-2-Diphenylphosphinoyl-5-

(3′,4′-methylenedioxyphenyl)pentan-3-ol (anti-5). Titanium tetra-

chloride (0.7 mL, 6.4 mmol) was added to a solution of ketone 4

(2.0 g, 4.92 mmol) in CH₂Cl₂(30 mL) at −30 °C. The reaction

turned immediately red. After 1 h, the reaction mixture was cooled to

−70 °C and BH₃·py (1 M, 8.4 mL, 9.84 mmol) was slowly added and

the reaction mixture was stirred for 3 h and then warmed to room

temperature. The reaction was quenched with slow addition of dilute

HCl (10% in H₂O, 20 mL) at 0 °C. The aqueous phase was extracted

with CH₂Cl₂(3 × 30 mL), and the combined organic layers were

washed with brine (80 mL), dried over MgSO₄, ﬁltered through

glass wool, and then concentrated in vacuo (20−23 °C, 10 mmHg).

Puriﬁcation via ﬂash column chromatography (Teledyne Isco

Combiﬂash R_f75, Silicycle silica gel, 25 g, 15−40 μm mesh, gradient:

35 to 50% EtOAc in hexane over 70 min, 30 mL/min) to aﬀord syn-5

as pale white oil (1.4 g, 72%) that crystallized upon standing, and anti-

5 as white solid (343 mg, 17%). Characterizations were in accordance

with the previously described compounds for anti-5 and syn-5.

1

(CH₂Cl₂/Et₂O); H NMR (500 MHz, CDCl₃) δ 8.03−8.00 (m, 2 H,

HC(d)), 7.97−7.94 (m, 2 H, HC(e)), 7.60−7.50 (m, 6 H, HC(d),

HC(c) and HC(f)), 6.70 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.66 (d, J = 1.0

Hz, 1 H, HC(2′)), 6.62 (dd, J = 8.0, 1.0 Hz, 1 H, HC(6′)), 5.92 (s, 2 H,

OCH₂O), 5.46 (s, 1 H, OH), 3.86 (dt, J = 11.0, 1.5 Hz, 1 H, HC(3)),

2.88 (ddd, J = 14.0, 10.5, 4.5 Hz, 1 H, HC(5)), 2.48 (ddd, J = 14.0, 9.5,

6.5 Hz, 1 H, HC(5)), 1.72−1.64 (m, 1 H, HC(4)), 1.58−1.52 (m, 1 H,

HC(4)), 1.26 (d, J = 16.0 Hz, 3 H, HC(1)), 1.08 (d, J = 17.0 Hz, 3 H,

HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 147.6 (C(3′)), 145.7

(C(4′)), 136.5 (C(1′)), 132.4 (d, J = 8.1 Hz, C(c)), 132.3 (d, J = 8.1

Hz, C(e)), 132.2 (d, J = 2.6 Hz, C(d)), 131.1 (d, J = 2.5 Hz, C(d)),

130.4 (d, J = 89.1 Hz, C(a)), 128.8 (d, J = 10.8 Hz, C(b)), 128.7 (d, J =

10.8 Hz, C(f)), 121.4 (C(6′)), 109.2 (C(2′)), 108.3 (C(5′)), 100.9

(OCH₂O), 73.8 (C(3)), 40.5 (d, J = 68.7 Hz, C(2)), 32.5 (C(4,5), 21.4

(C(1)), 16.3 (C(1)); ³¹P NMR (202 MHz, CDCl₃) δ 44.8; IR (KBr)

3306 (bm), 3056 (w), 2966 (m), 2927 (m), 2879 (m), 1609 (w), 1592

(w), 1501 (m), 1488 (s), 1437 (s), 1241 (s), 1168 (s), 1146 (s), 1110

(s), 1093 (s), 1037 (m), 998 (w), 929 (s); MS (TOF ES⁺) 457.1 (4.0),

425.2 (3.5), 424.2 (23.2), 423.2 (100, M+2H⁺), 403.1 (3.5); HRMS

calcd for C₂₅H₂₈O₄P⁺423.1725, found 423.1715; TLC R_f0.47 (EtOAc/

pentane, 7:3) [KMnO₄].

General Procedure 1. An oven-dried, 50 mL, two-necked, round-

bottomed ﬂask was charged with KH (1.5 equiv) in a glovebox and

capped with a septum and a stopper. Outside of the glovebox,

a solution of the requisite β-hydroxy diphenylphosphine oxide

(1.0 equiv) in DMF (30 mL) at room temperature then the reaction

mixture was heated at 50 °C. After 30 min, the homogeneous orange

solution was allowed to cool to room temperature, and the reaction

was quenched with H₂O (50 mL). The aqueous phase was extracted

with pentane (3 × 20 mL). HCl (1 M, 30 mL) was added to the

aqueous solution. The aqueous phase was extracted with pentane

(2 × 15 mL). The combined organic layers were washed with brine

(60 mL), dried over MgSO₄, ﬁltered through glass wool, and then

concentrated in vacuo (20−23 °C, 10 mmHg). The product oleﬁns

were puriﬁed by ﬂash column chromatography on silica gel (SiO₂,

15 g, 20 mm Ø, pentane/Et₂O, 98:2) followed by distillation.

Preparation of 2-Methyl-2-diphenylphosphinoyl-5-(3′,4′-

methylenedioxyphenyl)pentan-3-one (6). A solution of KOt-Bu

(435 mg, 3.9 mmol) in THF (20 mL) was added at 0 °C via syringe,

into a solution of ketone 4 (1.5 g, 3.7 mmol) in THF (50 mL). The

homogeneous mixture was then vigorously stirred for 1 h followed by

slow addition of MeI (460.0 μL, 7.4 mmol). After complete addition,

the reaction mixture was warmed to room temperature and stirred for

12 h. The reaction was quenched with dilute HCl (10% in H₂O,

20 mL). The aqueous phase was extracted with Et₂O (3 × 20 mL),

and the combined organic layers were washed with brine (60 mL),

dried over Na₂SO₄, ﬁltered through glass wool, and then concentrated

in vacuo (20−23 °C, 10 mmHg). Puriﬁcation via by ﬂash column

chromatography (SiO₂, 20 g, 25 mm Ø, EtOAc/pentane, 7:3) aﬀorded

6 as white solid (1.36 g, 87%). Recrystallization from hot Et₂O

provided 1.31 g of analytically pure 6. Data for 6: mp 108−110 °C

(Et₂O); ¹H NMR (500 MHz, CDCl₃) δ 7.84−7.80 (m,

4 H, HC(b) and HC(f)), 7.58−7.54 (m, 2 H, HC(d)), 7.50−7.46

(m, 4 H, HC(c) and HC(e)), 6.67 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.56

(d, J = 1.5 Hz, 1 H, HC(2′)), 6.54 (dd, J = 8.0, 1.5 Hz, 1 H, HC(6′)),

5.90 (s, 2 H, OCH₂O), 2.91 (t, J = 7.5 Hz, 2 H, HC(5)), 2.62 (t, J =

7.5 Hz, 2 H, HC(4)), 1.45 (d, J = 15.0 Hz, 6 H, HC(1)); ¹³C NMR

(125 MHz, CDCl₃) δ 210.3 (CO), 147.6 (C(3′)), 145.9 (C(4′)),

O

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1247 (s), 1188 (w), 1094 (w), 1042 (s), 938 (s), 855 (m), 806 (s);

MS (EI⁺, 70 eV) 205.2 (2.6), 204.2 (17.4), 204.1 (17.4), 136.1 (9.1),

135.1 (100.0), 105.0 (3.7), 79.1 (2.8), 77.1 (11.1), 51.0 (5.7); HRMS

+

calcd for C₁₃H₁₆O₂204.1150, found 204.1155; TLC R_f0.35

(pentane) [KMnO₄]. Anal. Calcd for C₁₃H₁₆O₂(204.26): C, 76.44;

H, 7.90%. Found: C, 76.41; H, 7.65%.

Preparation of (E)-5-(3′,4′-Methylenedioxyphenyl)pent-2-ene

((E)-2a). Following General Procedure 1, oven-dried 50 mL KH

(160 mg, 3.97 mmol) and alcohol anti-5 (1.08 mg, 2.6 mmol) were

reacted to give (E)-2a (372 mg, 74%) as colorless liquid after puriﬁ-

cation by distillation. Data for (E)-2a: bp 45 °C at 3.2 × 10⁻⁵mmHg;

¹H NMR (500 MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H, HC(5′)),

Preparation of Cyclization Substrates. Suzuki Coupling

Route. Preparation of Cyclization Substrates (please refer to

footnote 56 for the safe handling and disposal of thallium and

arsenic containing compounds). General Procedure 3. To an oven-

dried, 20 mL, two-necked, round-bottomed ﬂask charged with the

requisite alkene (1.0 equiv) was added dropwise a solution of 9-BBN

(solution in THF, 1.5 equiv) at room temperature with stirring.

In a separate ﬂask, the requisite vinyl iodide (1.2 equiv) was added at

room temperature to a mixture of PdCl₂(dppf) (0.1 equiv), AsPh₃

(0.2 equiv), and THF. After 2 h, TlOEt (2.0 equiv) and H₂O (5.0

equiv) were sequentially added dropwise to the alkylborane solution.

Immediately, the solution turned gray. The reaction mixture was

allowed to stir for 2 min, then the alkylborane solution was transferred

via cannula into the orange suspension of the vinyl iodide,

Pd(dppf)Cl₂, and AsPh₃at room temperature whereupon the reaction

mixture turned pale green.⁵⁶^aThe ﬂask containing the borane solution

was rinsed with THF (2 mL) and was transferred via cannula into

the reaction solution. The reaction ﬂask was wrapped in aluminum

foil to exclude light. After being stirred for 12 h, the contents of the

6.70 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.65 (dd, J = 8.0, 1.0 Hz, 1 H,

HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.49−5.47 (m, 2 H, HC(2) and

HC(3)), 2.61 (t, J = 7.5 Hz, 2 H, HC(5)), 2.30−2.26 (m, 2 H,

HC(4)), 1.67 (d, J = 3.5 Hz, 3 H, HC(1)); ¹³C NMR (125 MHz,

CDCl₃) δ 147.6 (C(3′)), 145.7 (C(4′)), 136.3 (C(1′)), 130.6 (C(3)),

125.7 (C(2)), 121.3 (C(6′)), 109.2 (C(2′)), 108.3 (C(5′)), 100.9

(OCH₂O), 36.0 (C(5)), 35.0 (C(4)), 18.1 (C(1)); IR (neat) 3017

(m), 2912 (s), 2857 (s), 2766 (w), 1608 (w), 1503 (w), 1486 (s),

1441 (s), 1358 (m), 1243 (s), 1035 (s), 966 (s), 938 (s), 855 (m), 806

(s); MS (EI⁺, 70 eV) 191.1 (3.0), 190.1 (22.2), 136.1 (8.3), 135.0

(100.0), 105.0 (4.2), 79.1 (3.5), 77.1 (11.4), 55.1 (2.4), 51.0 (6.4);

+

HRMS calcd for C₁₂H₁₄O₂190.0988, found 190.0994; TLC R_f0.71

(pentane) [KMnO₄]. Anal. Calcd for C₁₂H₁₄O₂(190.24): C, 75.76; H,

7.42%. Found: C, 76.15; H, 7.58%.

ﬂask were poured into H₂O (30 mL).⁵⁶The aqueous phase was

b

extracted with Et₂O (3 × 15 mL). Then, the combined organic extracts

were stirred with H₂O₂(30% aq, 4.0 equiv) at room temperature for

20 min whereupon the mixture turned a cloudy yellow. Saturated

aq Na₂SO₃solution (10 mL) was added dropwise to quench any

remaining H₂O₂(a slight warming of the solution was noted),

prompting the mixture to become clear and orange. Starch-iodide paper

was used to conﬁrm that no H₂O₂remained. The organic phase was

successively washed with H₂O (20 mL), brine (60 mL), then dried

Preparation of (Z)-5(3′,4′-Methylenedioxyphenyl)pent-2-ene

((Z)-2a). Following General Procedure 1, KH (134 mg, 3.35 mmol)

and alcohol syn-5 (913 mg, 2.23 mmol) were reacted to give (Z)-2a

(2 mg, 76%) as colorless liquid after puriﬁcation by distillation. Data

over MgSO₄, ﬁltered through glass wool,⁵⁶and concentrated in vacuo

c

1

for (Z)-2a: bp 40 °C at 3.2 × 10⁻⁵mmHg; H NMR (500 MHz,

(20−23 °C, 10 mmHg). The crude products were puriﬁed by ﬂash

d

CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.72 (d, J = 1.0 Hz, 1 H,

HC(2′)), 6.67 (dd, J = 8.0, 1.0 Hz, 1 H, HC(6′)), 5.94 (s, 2 H,

OCH₂O), 5.53−5.41 (m, 2 H, HC(2) and HC(3)), 2.61 (t, J = 7.5 Hz,

2 H, HC(5)), 2.34 (dt, J = 7.5, 7.5 Hz, 2 H, HC(4)), 1.60 (d, J = 6.5

Hz, 3 H, HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 147.7 (C(3′)),

145.7 (C(4′)), 136.3 (C(1′)), 129.7 (C(3)), 124.8 (C(2)), 121.4

(C(6′)), 109.1 (C(2′)), 108.3 (C(5′)), 100.9 (OCH₂O), 35.7 (C(5)),

29.3 (C(4)), 13.0 (C(1)); IR (neat) 3010 (s), 2926 (s), 2773 (m),

1608 (w), 1503 (s), 1486 (s), 1441 (s), 1358 (m), 1247 (s), 1039 (s),

935 (s), 858 (m), 810 (s); MS (EI⁺, 70 eV) 191.1 (2.0), 190.1 (14.9),

136.1 (8.2), 135.1 (100.0), 105.0 (4.8), 79.1 (3.7), 78.1 (2.4), 77.1

column chromatography on silica gel⁵⁶followed by distillation or

recrystallization as necessary.

General Procedure 4. To an oven-dried, 20 mL, two-necked,

round-bottomed ﬂask charged with the requisite alkene (1.0 equiv)

was added dropwise a solution of 9-BBN (solution in THF, 1.5 equiv)

at room temperature with stirring. In a separate ﬂask, the requisite

vinyl iodide (1.2 equiv) was added at room temperature to a mixture

PdCl₂(dppf) (0.05 equiv), AsPh₃(0.1 equiv), Cs₂CO₃(2.0 equiv),

and DMF. After 2 h, H₂O (15.0 equiv) and alkylborane solution

were sequentially added dropwise to the Pd(dppf)Cl₂solution. After

stirring for 24 h at room temperature, the contents of the ﬂask were

poured into H₂O (50 mL). The aqueous phase was extracted with

Et₂O (3 × 15 mL). Then, the combined organic layers were stirred

with H₂O₂(30% aq) at room temperature for 20 min to oxidize

AsPh₃residues. The organic phase were successively washed with H₂O

(20 mL), brine (60 mL), then dried over MgSO₄, ﬁltered through

glass wool, and concentrated in vacuo (20−23 °C, 10 mmHg). The

crude products were puriﬁed by ﬂash column chromatography on

silica gel.

+

(14.9), 63.1 (2.3), 51.0 (8.6); HRMS calcd for C₁₂H₁₄O₂190.0994,

found 190.0997; TLC R_f0.71 (pentane) [KMnO₄]. Anal. Calcd

for C₁₂H₁₄O₂(190.24): C, 75.76; H, 7.42%. Found: C, 75.73; H,

7.39%.

Preparation of 2-Methyl-5(3′,4′-methylenedioxyphenyl)pent-2-ene

(2c). Following General Procedure 1, oven-dried 50 mL KH (108 mg,

2.7 mmol) and alcohol 7 (760 mg, 1.8 mmol) were reacted to give 2c

(293 mg, 72%) as colorless liquid after puriﬁcation by distillation. Data

for 2c: bp 50 °C at 3.2 × 10⁻⁵mmHg; ¹H NMR (500 MHz, CDCl₃) δ

6.75 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.72 (d, J = 1.0 Hz, 1 H, HC(2′)),

6.66 (dd, J = 8.0, 1.0 Hz, 1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.18

(tq, J = 7.0, 1.5 Hz, 1 H, HC(3)), 2.57 (t, J = 8.0 Hz, 2 H, HC(5)),

2.27 (dt, J = 7.5, 7.5 Hz, 2 H, HC(4)), 1.72 (s, 3 H, HC(1a)), 1.60 (s,

3 H, HC(1b)); ¹³C NMR (125 MHz, CDCl₃) δ 147.6 (C(3′)),

145.7 (C(4′)), 136.5 (C(1′)), 132.4 (C(2)), 123.8 (C(3)),

121.3 (C(6′)), 109.1 (C(2′)), 108.3 (C(5′)), 100.9 (OCH₂O), 36.1

(C(5)), 30.6 (C(4)), 25.9 (C(1a)), 17.9 (C(1b)); IR (neat) 2961 (s),

2912 (s), 2773 (w), 1608 (w), 1503 (s), 1486 (s), 1441 (s), 1379 (m),

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-phenylbut-

1-ene ((E)-2b). Following General Procedure 3, oleﬁn 8a (149 mg,

1.0 mmol), 9-BBN (0.345 M in THF, 4.4 mL, 1.5 mmol), TlOEt

(142 μL, 2.0 mmol), and H₂O (91 μL, 5.0 mmol) were reacted

with PdCl₂(dppf) (73.5 mg, 0.1 mmol), AsPh₃(61.2 mg, 0.4 mmol),

(E)-(2-iodovinyl)benzene 10b (277.6 mg, 1.2 mmol), and THF

(4 mL). The product was puriﬁed by ﬂash column chromatography

(SiO₂, 30 g, 40 mm Ø, hexane/Et₂O, 98:2) to aﬀord 183 mg of (E)-2b

as orange oil. Puriﬁcation by distillation aﬀorded 179 mg (71%) of

P

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analytically pure (E)-2b as slightly orange oil. Data for (E)-2b: bp

mp 105−106 °C (hexane); ¹H NMR (500 MHz, CDCl₃) δ 7.58

(d, J = 8.0 Hz, 2 H, HC(c)), 7.41 (d, J = 8.0 Hz, 2H, HC(b)), 6.74

(d, J = 7.5 Hz, 1 H, HC(5′)), 6.72 (s, 1H, HC(2′)), 6.70 (d, J = 7.5,

1.0 Hz, 1 H, HC(6′)), 6.45−6.36 (m, 2 H, HC(1) and HC(2)), 5.95

(s, 2 H, OCH₂O), 2.75 (t, J = 7.5 Hz, 2 H, HC(4)), 2.51 (dt, J =

7.0, 7.0 Hz, 2 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 147.9

(C(3′)), 146.0 (C(4′)), 142.4 (C(a)), 135.3 (C(1)), 134.3 (C(1′)),

132.6 (C(c)), 129.4 (C(2)), 126.7 (C(b)), 121.4 (C(6′)), 119.3 (CN),

110.4 (C(d)), 109.1 (C(2′)), 108.4 (C(5′)), 101.0 (OCH₂O),

35.4 (C(4)), 35.3 (C(3)); IR (KBr) 3026 (w), 2990 (w), 2909 (w),

2880 (w), 2775 (w), 2223 (m), 1645 (w), 1645 (w), 1603 (s), 1500

(s), 1486 (s), 1452 (m), 1440 (s), 1411 (m), 1351 (m), 1251 (s), 1229

(s), 1185 m), 1100 (m), 1029 (s), 974 (s), 956 (s), 920 (s), 873 (s),

859 (s), 802 (s); MS (TOF ES⁺) 324 0 (20.0), 323.0 (100.0), 278.1

(10.0); HRMS calcd for C₁₈H₁₆O₂⁺278.1181, found 278.1174; TLC R_f

0.37 (hexane/Et₂O, 80:20) [KMnO₄]. Anal. Calcd for C₁₈H₁₅NO₂

(277.32): C, 77.96; H, 5.45; N, 5.05%. Found: C, 77.88; H, 5.51; N,

4.98%.

1

120 °C at 3.0 × 10⁻⁵mmHg; H NMR (500 MHz, CDCl₃) δ 7.36−

7.29 (m, 4 H, HC(b) and HC(c)), 7.22 (dt, J = 7.0, 1.5 Hz, 1 H,

HC(d)), 6.76 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.74 (d, J = 1.0 Hz, 1 H,

HC(2′)), 6.68 (dd, J = 8.0, 1.0 Hz, 1 H, HC(6′)), 6.42 (d, J = 16.0 Hz,

1 H, HC(1)), 6.26 (dt, J = 16.0, 6.5 Hz, 1 H, HC(2)), 5.94 (s, 2 H,

OCH₂O), 2.73 (t, J = 7.5 Hz, 2 H, HC(4)), 2.50 (dtd, J = 7.5, 7.5,

1.0 Hz, 2 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 147.8 (C(3′)),

145.9 (C(4′)), 137.9 (C(a)), 135.8 (C(1′)), 130.7 (C(d)), 130.1

(C(1)), 128.7 (C(c)), 127.2 (C(2)), 126.2 (C(b)), 121.4 (C(6′)),

109.1 (C(2′)), 108.4 (C(5′)), 100.9 (OCH₂O), 35.9 (C(4)), 35.3

(C(3)); IR (neat) 3060 (w), 3024 (m), 2931 (m), 2902 (m), 2845

(m), 1607 (w), 1596 (w), 1499 (s), 1487 (s), 1447 (s), 1366 (m), 1242

(s), 1200 (s), 1117 (m), 1101 (m), 1036 (s), 962 (s), 923 (s), 868 (s),

804 (s), 757 (s), 737 (s), 687 (s); MS (EI⁺, 70 eV) 252.1 (45.0), 136.1

(11.5), 135.1 (100.0), 117.1 (9.0), 115.1 (8.8); HRMS calcd for

+

C₁₇H₁₆O₂252.1150, found 252.1142; TLC R_f0.49 (hexane/Et₂O,

96:4) [KMnO₄].

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(4-methyl-

phenyl)but-1-ene ((E)-2d). Following General Procedure 3, oleﬁn 8a

(149 mg, 1.0 mmol), 9-BBN (0.345 M in THF, 4.4 mL, 1.5 mmol),

TlOEt (142 μL, 2.0 mmol), and H₂O (91 μL, 5.0 mmol) were reacted

with PdCl₂(dppf) (73.5 mg, 0.10 mmol), AsPh₃(61.6 mg, 0.20 mmol),

(E)-1-(2-iodovinyl)-4-methylbenzene 10d (292 mg, 1.2 mmol), and

THF (4 mL). Puriﬁcation by ﬂash column chromatography (SiO₂,

24 g, 40 mm Ø, hexanes/Et₂O, 96:4) aﬀorded (E)-2d (166 mg, 62%)

as white solid. Recrystallization from hot hexane provided 160 mg

(60%) of analytically pure (E)-2d. Data for (E)-2d: mp 67−68 °C

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(4-methoxy-

phenyl)but-1-ene ((E)-2f). Following General Procedure 4, oleﬁn 8a

(222.0 mg, 1.5 mmol) in THF (2 mL), 9-BBN (0.577 M in THF,

3.9 mL, 2.25 mmol), and H₂O (0.41 mL, 22.5 mmol) were reacted with

PdCl₂(dppf) (54.8 mg, 74.9 μmol), AsPh₃(45.8 mg, 149.8 μmol),

Cs₂CO₃(976.4 mg, 3.0 mmol), (E)-1-(2-iodovinyl)-4-methoxybenzene

10f (458.6 mg, 1.8 mmol), and DMF (4 mL). Puriﬁcation by ﬂash

column chromatography (SiO₂, 35 g, 30 mm Ø, hexanes/Et₂O, 95:5)

aﬀorded (E)-2e (180 mg, 43%) as white solid, along with starting

material 8a (22 mg, 10%). Recrystallization of (E)-2e from hot hexane

provided 170 mg (40%) of (E)-2e. Data for (E)-2f: mp 92−93 °C

1

(hexane); H NMR (500 MHz, CDCl₃) δ 7.27 (d, J = 8.0 Hz, 2 H,

HC(b)), 7.14 (d, J = 8.0 Hz, 2 H, HC(c)), 6.77 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.75 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.70 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 6.41 (d, J = 16.0 Hz, 1 H, HC(1)), 6.22 (dt, J = 15.5,

6.5 Hz, 1 H, HC(2)), 5.96 (s, 2 H, OCH₂O), 2.74 (t, J = 8.0 Hz, 2 H,

HC(4)), 2.51 (dt, J = 7.5, 7.5 Hz, 2H, HC(3)), 2.36 (s, 3 H, HC(1));

¹³C NMR (125 MHz, CDCl₃) δ 147.8 (C(3′)), 145.9 (C(4′)), 136.9

(C(d)), 135.9 (C(a)), 135.1 (C(1′)), 130.5 (C(2)), 129.4 (C(b)),

129.0 (C(1)), 126.1 (C(c)), 121.4 (C(6′)), 109.2 (C(2′)), 108.4

(C(5′)), 101.0 (OCH₂O), 35.9 (C(4)), 35.4 (C(3)), 21.4 (C(e)); IR

(KBr) 3022 (w), 2929 (m), 2897 (m), 2852 (w), 2783 (w), 1607 (w),

1498 (s), 1486 (s), 1442 (s), 1355 (m), 1243 (s), 1189 (s), 1122 (m),

1100 (s), 1037 (s), 970 (s), 936 (s), 924 (s), 859 (s), 810 (s), 800 (s),

768 (s); MS (TOF ES⁺) 364.4 (50.0), 341.3 (72.0), 282.3 (100.0),

1

(hexane); H NMR (500 MHz, CDCl₃) δ 7.30 (d, J = 9.0 Hz, 2 H,

HC(b)), 6.87 (d, J = 8.0 Hz, 2 H, HC(c)), 6.77 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.75 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.69 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 6.39 (d, J = 16.0 Hz, 1 H, HC(1)), 6.12 (dt, J = 16.0,

7.0 Hz, 1 H, HC(2)), 5.95 (s, 2 H, OCH₂O), 3.83 (s, 3 H, OCH₃),

2.73 (t, J = 7.5 Hz, 2 H, HC(4)), 2.51 (dt, J = 7.5, 7.5 Hz, 2 H,

HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 159.0 (C(d)), 147.8 (C(3′)),

145.8 (C(4′)), 136.0 (C(1′)), 130.8 (C(a)), 130.0 (C(1)), 127.9

(C(2)), 127.3 (C(b)), 121.4 (C(6′)), 114.15 (C(c)), 109.1 (C(2′)),

108.4 (C(5′)), 101.0 (OCH₂O), 55.5 (OCH₃), 36.1 (C(4)), 35.4

(C(3)); IR (KBr) 3014 (m), 2961 (m), 2937 (w), 2913 (w), 2840 (m),

1597 (s), 1569 (s), 1506 (s), 1464 (s), 1410 (s), 1415 (s), 1369 (w),

1300 (s), 1247 (s), 1177 (s), 1112 (s), 1025 (s), 982 (s), 958 (s), 817

(s), 800 (s), 750 (s); MS (EI⁺, 70 eV) 282.1 (16.9), 267.1 (5.4), 266.1

(27.0), 265.1 (6.2), 235.1 (6.2), 151.0 (6.0), 148.0 (11.2), 147.1

(100.0), 135.0 (23.8), 121.0 (7.8), 115.0 (6.6); HRMS calcd for

+

267.1 (65.0), 175.1 (80.0), 145.1 (91.5); HRMS calcd for C₁₈H₁₉O₂

267.1385, found 267.1382; TLC R_f0.51 (hexane/Et₂O, 96:4)

[KMnO₄]. Anal. Calcd for C₁₈H₁₈O₂(266.33): C, 81.17; H, 6.81%.

Found: C, 81.42; H, 6.68%.

+

C₁₈H₁₈O₃282.12560, found 282.12578; TLC R_f0.29 (hexane/Et₂O,

95:5) [KMnO₄]. Anal. Calcd for C₁₈H₁₈O₃(282.12): C, 76.57; H,

6.43%. Found: C, 76.67; H, 6.51%.

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(4-cyano-

phenyl)but-1-ene ((E)-2e). Following General Procedure 4, oleﬁn 8a

(222.0 mg, 1.5 mmol) in THF (2 mL), 9-BBN (0.577 M in THF,

3.9 mL, 2.25 mmol), and H₂O (0.41 mL, 22.5 mmol) were reacted

with PdCl₂(dppf) (54.8 mg, 74.9 μmol), AsPh₃(45.8 mg, 149.8 μmol),

Cs₂CO₃(976.4 mg, 3.0 mmol), (E)-4-(2-iodovinyl)benzonitrile 10e

(458.6 mg, 1.8 mmol), and DMF (4 mL). Puriﬁcation by ﬂash

column chromatography (SiO₂, 27 g, 30 mm Ø, hexanes/Et₂O, 80:20)

aﬀorded (E)-2e (262 mg, 63%) as white solid, along with starting

material 8a (26 mg 12%). Recrystallization of (E)-2e from hot hexane

provided 253 mg (16%) of analytically pure (E)-2e. Data for (E)-2e:

Following General Procedure 3, oleﬁn 8a (149 mg, 2.0 mmol),

9-BBN (0.345 M in THF, 4.4 mL, 1.5 mmol), TlOEt (142 μL,

2.0 mmol), and H₂O (91 μL, 5.0 mmol) were reacted with PdCl₂(dppf)

(73.5 mg, 0.1 mmol), Ph₃As (61.6 mg, 0.2 mmol), and (E)-1-(2-

iodovinyl)-4-methoxybenzene 10f (313.8 mg, 1.2 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, 25 g, 40 mm Ø, hexanes/Et₂O,

95:5) aﬀorded (E)-2f (160 mg, 64%) as pale yellow solid.

Recrystallization from hot hexane provided 172 mg (61%) of analytically

pure (E)-2f. Spectroscopic data matched those of the product from the

previous procedure.

Q

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The Journal of Organic Chemistry

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1614 (s), 1500 (s), 1488 (s), 1438 (s), 1413 (s), 1320 (s), 1329 (s),

1168 (s), 1124 (s), 1108 (s), 1063 (s), 1041 (s), 1015 (s), 972 (s), 954

(s), 936 (s), 922 (s), 861 (s), 806 (s); MS (EI⁺, 70 eV) 320.1 (32.4),

227.0 (5.9), 191.1 (5.8), 165.0 (6.9), 159.0 (5.8), 152.0 (24.6), 149.0

(12.6), 147.0 (5.0), 137.0 (5.6), 136.0 (61.6), 135.0 (100.0), 131.0

(5.4), 116.0 (7.8), 115.0 (12.1), 105.0 (20.6), 91.0 (7.8), 79.1 (9.1),

78.1 (6.2), 77.1 (51.4); HRMS calcd for C₁₈H₁₅F₃O₂⁺320.1024, found

320.1021; TLC R_f0.53 (hexane/Et₂O, 95:5) [KMnO₄]. Anal. Calcd

for C₁₈H₁₅F₃O₂(320.31): C, 67.50; H, 4.72; F, 17.79%. Found: C,

67.59; H, 4.65; F, 17.23%.

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(2-

naphthalenyl)but-1-ene ((E)-2g). Following General Procedure 3,

oleﬁn 8a (149 mg, 1.0 mmol), 9-BBN (0.345 M in THF, 4.4 mL, 1.5

mmol), TlOEt (142.4 μL, 2.0 mmol), and H₂O (91.0 μL, 5.0 mmol)

were reacted with PdCl₂(dppf) (73.5 mg, 0.1 mmol), AsPh₃(61.6 mg,

0.2 mmol), (E)-2-(2-iodovinyl)naphthalene 10g (313.8 mg, 1.2 mmol),

and THF (4 mL). Puriﬁcation by ﬂash column chromatography (SiO₂,

26 g, 40 mm Ø, hexanes/Et₂O, 96:4) aﬀorded (E)-2g (217 mg, 72%) as

pale green solid. Recrystallization from hot hexane provided 212 mg

(70%) of analytically pure (E)-2g. Data for (E)-2g: mp 96−98 °C

(hexane); ¹H NMR (500 MHz, CDCl₃) δ 7.83−7.79 (m, 3 H, HC(c)

and H(f) and H(g)), 7.70 (s, 1 H, HC(j)), 7.60 (dd, J = 8.5, 1.0 Hz,

1 H, HC(h)), 7.50−7.43 (m, 2 H, HC(b), HC(e)), 6.79 (d, J = 8.0 Hz,

1 H, HC(5′)), 6.78 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.72 (dd, J = 8.0,

1.0 Hz, 1 H, HC(6′)), 6.61 (d, J = 16.0 Hz, 1 H, HC(1)), 6.40 (dt, J =

16.0, 7.0 Hz, 1 H, HC(2)), 5.97 (s, 2 H, OCH₂O), 2.79 (t, J = 8.0 Hz,

2 H, HC(4)), 2.51 (dt, J = 8.0, 8.0 Hz, 2 H, HC(3)); ¹³C NMR

(125 MHz, CDCl₃) δ 147.8 (C(3′)), 145.9 (C(4′)), 135.8 (C(1′)),

135.4 (C(i)), 133.9 (C(a)), 133.0 (C(d)), 130.8 (C(2)), 130.5 (C(1)),

128.3 (C(c)), 128.1 (C(g)), 127.9 (C(f)), 126.4 (C(e)), 125.8 (C(j)),

125.7 (C(b)), 123.8 (C(h)), 121.5 (C(6′)), 109.1 (C(2′)), 108.4

(C(5′)), 101.0 (OCH₂O), 35.9 (C(4)), 35.5 (C(3)); IR (KBr) 3051

(m), 3018 (w), 2994 (w), 2917 (m), 2856 (m), 2795 w), 1624 (w),

1605 (w), 1496 (s), 1486 (s), 1440 (s), 1359 (s), 1247 (s), 1187 (s),

1122 (s), 1098 (s), 1041 (s), 960 (s), 924 (s), 867 (s), 814 (s), 780 (s),

766 (s), 738 (s); MS (EI⁺, 70 eV) 381.3 (6.1), 365.3 (7.1), 340.2

(15.1), 326.2 (17.3), 325.2 (71.8), 303.2 (7.2), 302.2 (24.8), 287.2

(6.3), 279.2 (7.5), 266.1 (15.6), 239.1 (9.7), 231.1 (14.6), 191.1

(17.3), 168.1 (5.9), 167.1 (58.8), 166.1 (5.9), 165.1 (13.2), 152.1

(9.2), 147.1 (7.4), 141.0 (6.0), 136.0 (10.7), 135.0 (100.0), 127.1 (7.5),

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(2-methyl-

phenyl)but-1-ene ((E)-2i). Following General Procedure 4, oleﬁn 8a

(222 mg, 1.5 mmol) in THF (2 mL), 9-BBN (0.577 M in THF,

3.9 mL, 1.5 mmol), and H₂O (405 μL, 22.5 mmol) were reacted with

PdCl₂(dppf) (54.8 mg, 74.9 μmol), AsPh₃(45.9 mg, 149.8 μmol),

Cs₂CO₃(976.4 g, 3.0 mmol), (E)-1-(2-iodovinyl)-2-methylbenzene

10i (603.5 mg, 2.0 mmol), and DMF (4 mL). Puriﬁcation by ﬂash

column chromatography (SiO₂, 30 g, 30 mm Ø, hexanes/Et₂O, 98:2)

aﬀorded (E)-2i (194 mg, 49%) as pale yellow solid along with 8a

(19 mg, 9%). Recrystallization of (E)-2i from hot hexane provided

346 mg (47%) of analytically pure (E)-2i. Data for (E)-2i: mp 38−

1

40 °C (hexane); H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 8.0 Hz,

2 H, HC(b)), 7.18−7.14 (m, 3 H, HC(c), HC(d), HC(e)), 6.77 (d,

J = 8.0 Hz, 1 H, HC(5′)), 6.75 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.70 (dd,

J = 8.0, 1.0 Hz, 1 H, HC(6′)), 6.60 (d, J = 15.5 Hz, 1 H, HC(1)), 6.11

(dt, J = 15.5, 7.0 Hz, 1 H, HC(2)), 5.95 (s, 2 H, OCH₂O), 2.75 (t, J =

8.0 Hz, 2 H, HC(4)), 2.54 (dt, J = 7.0, 7.0 Hz, 2 H, HC(3)), 2.33 (s,

3 H, HC(1)); ¹³C NMR (125 MHz, CDCl₃) δ 147.9 (C(3′)), 146.8

(C(4′)), 137.2 (C(a)), 135.9 (C(f)), 135.2 (C(1′)), 131.4 (C(2)),

130.4 (C(d)), 128.9 (C(1)), 127.1 (C(c)), 126.3 (C(e)), 125.9

(C(b)), 121.5 (C(6′)), 109.2 (C(2′)), 108.4 (C(5′)), 101.0

(OCH₂O), 36.0 (C(4)), 35.5 (C(3)), 19.9 (C(g)); IR (KBr) 3017

(w), 2922 (m), 2891 (m), 2776 (w), 1607 (w), 1502 (s), 1487 (s),

1441 (s), 1362 (w), 1242 (s), 1186 (m), 1096 (w), 1037 (s), 964 (m),

936 (m), 925 (m), 807 (m), 745 (s); MS (EI⁺, 70 eV) 267.1 (2.7),

266.1 (13.7), 136.0 (8.2), 135.0 (100.0), 131.1 (12.8), 116.0 (4.2),

115.0 (4.6), 105.0 (2.7), 91.0 (4.1), 77.0 (8.5), 51.0 (3.9); HRMS

+

121.1 (6.4), 105.1 (8.8); HRMS calcd for C₂₁H₁₈O₂302.1307,

found 302.1304; TLC R_f0.42 (hexane/Et₂O, 96:4) [KMnO₄]. Anal.

Calcd for C₂₁H₁₈O₂(302.37): C, 83.42; H, 6.00%. Found: C, 83.52; H,

6.24%.

+

calcd for C₁₈H₁₈O₂266.13068, found 266.12971; TLC R_f0.52

(hexane/Et₂O, 96:4) [KMnO₄]. Anal. Calcd for C₁₈H₁₈O₂(266.33):

C, 81.17; H, 6.81%. Found: C, 80.90; H, 6.73%.

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-(4-triﬂuoro-

phenyl)but-1-ene ((E)-2h). Following General Procedure 4, oleﬁn 8a

(250 mg, 1.7 mmol) in THF (2 mL), 9-BBN (0.577 M in THF,

4.4 mL, 2.5 mmol), and H₂O (455 μL, 25.2 mmol) were reacted with

PdCl₂(dppf) (61.7 mg, 84.4 μmol), AsPh₃(51.7 mg, 168.7 μmol),

Cs₂CO₃(1.1 g, 3.4 mmol), (E)-1-(2-iodovinyl)-4-(triﬂuoromethyl)-

benzene 10h (603.5 mg, 2.0 mmol), and DMF (4 mL). Puriﬁcation

by ﬂash column chromatography (SiO₂, 30 g, 30 mm Ø, hexanes/

Et₂O, 95:5) aﬀorded (E)-2h (357 mg, 66%) as pale yellow solid along

with 8a (25 mg, 10%). Recrystallization of (E)-2h from hot hexane

provided 346 mg (64%) of analytically pure (E)-2h. Data for (E)-2h:

Preparation of (E)-5-(3′,4′-Methylenedioxyphenyl)-2-phenylpent-

2-ene ((E)-2j). Following General Procedure 4, oleﬁn 8a (500 mg,

3.4 mmol) in THF (2 mL), 9-BBN (0.577 M in THF, 8.8 mL,

5.1 mmol), and H₂O (911 μL, 50.6 mmol) were reacted with

PdCl₂(dppf) (123.5 mg, 168.7 μmol), AsPh₃(103.3 mg, 337.5 μmol),

Cs₂CO₃(2.2 g, 6.7 mmol), (E)-(1-iodoprop-1-en-2-yl)benzene 10j

(988.4 mg, 4.0 mmol), and DMF (8 mL). Puriﬁcation by ﬂash column

chromatography (SiO₂, 30 g, 50 mm Ø, hexane/Et₂O, 98:2) aﬀorded

733 mg of (E)-2j as pale yellow oil along with 8a (45 mg, 9%). The

product was puriﬁed by distillation to aﬀord (E)-2j (719 mg, 80%) as

1

mp 53−54 °C (hexane); H NMR (500 MHz, CDCl₃) δ 7.56 (d, J =

8.0 Hz, 2 H, HC(b)), 7.43 (d, J = 8.0, 2 H, HC(c)), 6.77 (d, J =

8.0 Hz, 1 H, HC(5′)), 6.74 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.69 (dd, J =

8.0, 1.0 Hz, 1 H, HC(6′)), 6.46 (d, J = 16.0 Hz, 1 H, HC(1)), 6.39 (dt,

J = 15.5, 8.0 Hz, 1 H, HC(2)), 5.96 (s, 2 H, OCH₂O), 2.75 (t, J =

8.0 Hz, 2 H, HC(4)), 2.54 (dt, J = 7.5, 7.5 Hz, 2 H, HC(3)); ¹³C

NMR (125 MHz, CDCl₃) δ 147.9 (C(3′)), 146.0 (C(4′)), 141.4

(C(a)), 135.5 (C(1′)), 132.9 (C(2)), 129.5 (C(1)), 129.0 (q, J = 32.6

Hz, C(d)), 126.3 (C(b)), 125.7 (q, J = 3.8 Hz, C(c)), 124.4 (d, J =

250.0 Hz, CF₃), 121.4 (C(6′)), 109.1 (C(2′)), 108.4 (C(5′)), 101.0

(OCH₂O), 35.6 (C(4)), 35.3 (C(3)); ¹⁹F NMR (376 MHz, CDCl₃) δ

−62.8; IR (KBr) 3010 (w), 2929 (w), 2876 (m), 2779 (w), 1652 (m),

1

colorless oil. Data for (E)-2j: bp 125 °C at 2.7 × 10⁻⁵mmHg; H

NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 8.0 Hz, 2 H, HC(b)), 7.32 (d,

J = 8.0, 2 H, HC(c)), 7.23 (dt, J = 7.0, 1.0 Hz, 1 H, HC(d)), 6.75 (d,

J = 8.0 Hz, 1 H, HC(5′)), 6.74 (d, J = 1.5 Hz, 1 H, HC(2′)), 6.68 (dd,

J = 8.0, 1.5 Hz, 1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.80 (dt, J = 7.0,

1.5 Hz, 1 H, HC(3)), 2.70 (t, J = 8.0 Hz, 2 H, HC(5)), 2.49 (dt, J =

7.5, 7.5 Hz, 2 H, HC(4)), 2.00 (s, 3 H, HC(1)); ¹³C NMR (125 MHz,

R

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The Journal of Organic Chemistry

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CDCl₃) δ 147.8 (C(3′)), 145.8 (C(4′)), 144.1 (C(a)), 136.1 (C(1′)),

135.7 (C(2)), 128.4 (C(c)), 127.5 (C(3)), 126.8 (C(d)), 125.9

(C(b)), 121.4 (C(6′)), 109.2 (C(2′)), 108.3 (C(5′)), 101.0

(OCH₂O), 35.8 (C(5)), 31.2 (C(4)), 16.1 (C(1)); IR (neat) 3056

(w), 3030 (w), 2918 (m), 2889 (m), 1600 (w), 1501 (s), 1487 (s),

1440 (s), 1359 (w), 1242 (s), 1189 (m), 1097 (w), 1038 (s), 935 (s),

854 (m), 807 (m), 755 (s), 694 (s); MS (TOF ES⁺) 323.0 (96.2),

1186 (m), 1121 (m), 1097 (m), 1039 (s), 966 (m), 938 (s), 856 (m),

805 (s); MS (TOF ES⁺) 339.2 (14.9), 322.0 (100.0), 243.1 (28.6),

187.1 (18.7), 161.1 (15.1), 135.0 (28.6); HRMS calcd for C₁₆H₂₁O₂

245.1542, found 245.1544; TLC R_f0.67 (hexane/Et₂O, 96:4)

[KMnO₄]. Anal. Calcd for C₁₆H₂₀O₂(244.33): C, 78.65; H, 8.25%.

Found: C, 78.91; H, 8.16%.

+

265.1 (100.0), 145.1 (63.2); HRMS calcd for C₁₈H₁₉O₂267.1385,

found 267.1393; TLC R_f0.49 (hexane/Et₂O, 96:4) [KMnO₄]. Anal.

Calcd for C₁₈H₁₈O₂(266.33): C, 81.17; H, 6.81%. Found: C, 81.01;

H, 6.75%.

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-cyclohexyl-

but-2-ene ((E)-2m). Following General Procedure 3, oleﬁn 8a (296

mg, 2.00 mmol), 9-BBN (0.345 M in THF, 8.7 mL, 3.00 mmol),

TlOEt (283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were

reacted with PdCl₂(dppf) (146.3 mg, 0.2 mmol), AsPh₃(122.5 mg,

0.4 mmol), (E)-(2-iodovinyl)cyclohexane 10m (567 mg, 2.40 mmol),

and THF (9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂,

25 g, 40 mm Ø, hexanes/diethyl ether, 98:2) aﬀorded 300 mg (58%)

of (E)-2m as colorless oil. Distillation provided 289 mg (56%) of

analytically pure (E)-2m. Data for (E)-2m: bp 70 °C at 2.4 × 10⁻⁵

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-cyclopropyl-

but-2-ene ((E)-2k). Following General Procedure 3, oleﬁn 8a (296 mg,

2.0 mmol), 9-BBN (0.321 M in THF, 9.4 mL, 3.0 mmol), TlOEt

(283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted

with PdCl₂(dppf) (146.4 mg, 0.2 mmol), AsPh₃(122.5 mg, 0.4 mmol),

(E)-(2-iodovinyl)cyclopropyl 10k (465.6 mg, 2.4 mmol), and THF

(9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂, 25 g,

40 mm Ø, hexanes/diethyl ether, 98:2) aﬀorded (E)-2k (370 mg,

85%) as colorless oil. Distillation provided 355 mg (82%) of

analytically pure (E)-2k. Data for (E)-2k: bp 65 °C at 3 × 10⁻⁵

1

mmHg; H NMR (500 MHz, CDCl₃) δ 6.74 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.70 (d, J = 1.5 Hz, 1 H, HC(2′)), 6.64 (dd, J = 7.5, 1.5 Hz,

1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.42−5.40 (m, 2 H, HC(1) and

HC(2)), 2.60 (t, J = 7.5 Hz, 2 H, HC(4)), 2.28−2.25 (m, 1H, HC(a)),

1.95−1.89 (m, 2 H, HC(3)), 1.75−1.65 (m, 5 H, HC(b) and HC(c)

and HC(d)), 1.32−1.21 (m, 2 H, HC(c)), 1.21−1.14 (m, 2 H,

HC(d)), 1.10−1.03 (m, 2 H, HC(b)); ¹³C NMR (125 MHz, CDCl₃)

δ 147.6 (C(3′)), 145.7 (C(4′)), 137.5 (C(1′)), 136.4 (C(1)), 126.8

(C(2)), 121.4 (C(6′)), 109.2 (C(2′)), 108.2 (C(5′)), 100.9

(OCH₂O), 40.9 (C(a)), 36.0 (C(4)), 35.1 (C(3)), 33.4 (C(b)),

26.5 (C(d)), 26.4 (C(c)); IR (neat) 2921 (m), 2850 m), 1503 (m),

1488 (s), 1442 (m), 1360 (w), 1242 (s), 1186 (m), 1096 (w), 1039

(s), 967 (m), 938 (m), 855 (w), 805 (m); MS (TOF ES⁺) 338.3

(28.9), 300.2 (27.8), 275.2 (22.2), 271.2 (55.1), 259.2 (77.2), 257.2

(56.4), 175.1 (19.4), 161.1 (28.1), 135.0 (100.0); HRMS calcd for

1

mmHg; H NMR (500 MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.70 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.65 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.56 (dt, J = 15.0, 6.5 Hz, 1 H,

HC(2), 5.03 (dd, J = 15.0, 8.5 Hz, 1 H, HC(1)), 2.61 (t, J = 8.0 Hz,

2 H, HC(4)), 2.27 (dt, J = 7.5, 7.5 Hz, 2 H, HC(3)), 1.40−1.33 (m,

1 H, HC(a)), 0.70−0.67 (m, 2 H, HC(b trans), 0.35−0.32 (m, 2 H,

HC(b cis)); ¹³C NMR (125 MHz, CDCl₃) δ 147.6 (C(3′)),

145.7 (C(4′)), 136.3 (C(1′)), 134.7 (C(1)), 127.3 (C(2)), 121.3

(C(6′)), 109.1 (C(2′)), 108.3 (C(5′)), 100.9 (OCH₂O), 36.1

(C(4)), 34.9 (C(3)), 13.7 (C(a)), 6.5 (C(b)); IR (neat) 3078 (w),

3009 (w), 2925 (m), 2772 (w), 1609 (w), 1503 (s), 1487 (s), 1441

(s), 1364 (m), 1242 (s), 1186 (s), 1097 (m), 1037 (s), 962 (s),

935 (s), 855 (s), 808 (s); MS (EI⁺)216.1 (17.8), 136.0 (9.1), 135.0

(24.1), 81.1 (7.7), 77.1 (14.4), 51.0 (7.6); HRMS calcd for

+

C₁₇H₂₂O₂259.1698, found 259.1706; TLC R_f0.67 (hexane/Et₂O,

96:4) [KMnO₄]. Anal. Calcd for C₁₇H₂₂O₂(258.36): C, 79.03; H,

8.58%. Found: C, 79.24; H, 8.46%.

+

C₁₄H₁₆O₂216.1150, found 216.1152; TLC R_f0.63 (hexane/Et₂O,

96:4) [KMnO₄].

Preparation of (E)-1-(3′,4′-Methylenedioxyphenyl)non-3-ene ((E)-

2n). Following General Procedure 3, oleﬁn 8a (296 mg, 2.0 mmol),

9-BBN (0.312 M in THF, 9.4 mL, 3.0 mmol), TlOEt (283.3 μL,

4.00 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted with

PdCl₂(dppf) (146.4 mg, 0.2 mmol), AsPh₃(122.5 mg, 0.4 mmol),

(E)-1-iodoheptene 10n (537.8 mg, 2.4 mmol), and THF (9 mL).

Puriﬁcation by ﬂash column chromatography (SiO₂, 32 g, 40 mm Ø,

hexanes/diethyl ether, 97:3) aﬀorded (E)-2n (360 mg, 73%) as

colorless oil. Distillation provided 345 mg (68%) of analytically pure

(E)-2n. Data for (E)-2n: bp 75 °C at 3 × 10⁻⁵mmHg; ¹H NMR (500

MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H, HC(5′)), 6.70 (d, J = 1.5 Hz,

1 H, HC(2′)), 6.65 (dd, J = 8.0, 1.5 Hz, 1 H, HC(6′)), 5.94 (s, 2 H,

OCH₂O), 5.46−5.44 (m, 2 H, HC(3) and HC(4)), 2.62 (t, J = 8.0 Hz,

2 H, HC(1)), 2.28 (dt, J = 7.0, 7.0 Hz, 2 H, HC(2)), 2.00 (dt, J = 7.0,

7.0 Hz, 2 H, HC(5)), 1.36−1.26 (m, 6 H, HC(6) and HC(7) and

HC(8)), 1.92 (t, J = 7.5 Hz, 3 H, HC(9)); ¹³C NMR (125 MHz,

CDCl₃) δ 147.7 (C(3′)), 145.7 (C(4′)), 136.3 (C(1′)), 131.5 (C(3)),

129.4 (C(4)), 121.4 (C(6′)), 109.2 (C(2′)), 108.3 (C(5′)), 100.9

(OCH₂O), 36.1 (C(1)), 35.0 (C(2)), 32.8 (C(5)), 31.6 (C(7)), 29.5

(C6)), 22.8 (C(8)), 14.3 (C(9)); IR (neat) 2957 (m), 2922 (m), 2862

(m), 1609(w), 1503 (s), 1488 (s), 1443 (s), 1359 (m), 1243 (s), 1185

(m), 1095 (m), 1040 (s), 966 (m), 938 (s), 856 (m), 804 (s); MS

(TOF ES⁺) 343.3 (58.7), 341.2 (100.0), 245.3 (50.1), 231.1 (28.2),

Preparation of (E)-4-(3′,4′-Methylenedioxyphenyl)-1-cyclopentyl-

but-2-ene ((E)-2l). Following General Procedure 3, oleﬁn 8a (296 mg,

2.0 mmol), 9-BBN (0.321 M in THF, 9.4 mL, 3.0 mmol), TlOEt

(283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted

with PdCl₂(dppf) (146.4 mg, 0.2 mmol), AsPh₃(122.5 mg, 0.4 mmol),

(E)-(2-iodovinyl)cyclopentane 10l (532.9 mg, 2.4 mmol), and THF

(9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂, 30 g,

40 mm Ø, hexanes/diethyl ether, 98:2) aﬀorded 310 mg (63%) of

(E)-2l as colorless oil. Distillation provided 303 mg (62%) of

analytically pure (E)-2l. Data for (E)-2l: bp 50 °C at 2.4 × 10⁻⁵

1

mmHg; H NMR (500 MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.70 (d, J = 1.5 Hz, 1 H, HC(2′)), 6.64 (dd, J = 8.0, 1.5 Hz,

1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.44−5.42 (m, 2 H, HC(1) and

HC(2)), 2.61 (t, J = 7.5 Hz, 2 H, HC(4)), 2.43−2.36 (m, 1 H, HC(a)),

2.29−2.25 (m, 2 H, HC(3)), 1.79−1.73 (m, 2 H, HC(b)), 1.69−1.61

(m, 2H, HC(c)), 1.60−1.51 (m, 2 H, HC(c)), 1.30−1.23 (m, 2H,

HC(b)); ¹³C NMR (125 MHz, CDCl₃) δ 147.6 (C(3′)), 145.7

(C(4′)), 136.3 (C(1′)), 136.1 (C(1)), 127.4 (C(2)), 121.4 (C(6′)),

109.2 (C(2′)), 108.2 (C(5′)), 100.9 (OCH₂O), 43.5 (C(a)), 36.2

(C(4)), 35.0 (C(3)), 33.4 (C(b)), 25.3 (C(c)); IR (neat) 2949 (m),

2866 (m), 1609 (w), 1503 (s), 1488 (s), 1441 (s), 1362 (m), 1242 (s),

+

135.0 (53.0); HRMS calcd for C₁₆H₂₃O₂247.1698, found 247.1697;

S

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

TLC R_f0.69 (hexane/Et₂O, 96:4) [KMnO₄]. Anal. Calcd for C₁₆H₂₂O₂

(246.35): C, 78.01; H, 9.00%. Found: C, 78.31; H, 8.98%.

Preparation of (E)-4-(3′-Methoxyphenyl)-1-phenylbut-1-ene ((E)-

11b). Following General Procedure 4, 3-methoxystyrene 8b (500.0

mg, 3.7 mmol) in THF (4 mL), 9-BBN (0.577 M in THF, 9.7 mL,

5.6 mmol), and H₂O (1.0 mL, 55.9 mmol) were reacted with

PdCl₂(dppf) (136.3 mg, 0.19 mmol), Ph₃As (114.1 mg, 0.37 mmol),

Cs₂CO₃(2.4 g, 7.45 mmol), (E)-(2-iodovinyl)benzene 10b (1.03 mg,

4.47 mmol), and DMF (6 mL). Puriﬁcation by ﬂash column

chromatography (SiO₂, 32 g, 40 mm Ø, hexanes/diethyl ether, 98:2)

aﬀorded (E)-11b (621 mg, 70%) as colorless oil along with starting

material 8b (70 mg, 14%). Distillation of (E)-11b provided 607 mg

(68%) of analytically pure (E)-11b. Data for (E)-11b: bp 100 °C at

Preparation of (E)-7-(3′,4′-Methylenedioxyphenyl)-1-chlorohept-

4-ene ((E)-2o). Following General Procedure 3, oleﬁn 8a (296 mg,

2.0 mmol), 9-BBN (0.321 M in THF, 9.4 mL, 3.0 mmol), TlOEt

(283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted

with PdCl₂(dppf) (146.4 mg, 0.2 mmol), Ph₃As (122.5 mg, 0.4 mmol),

(E)-5-chloro-1-iodopent-1-ene 10o (553.1 mg, 2.4 mmol), and THF

(9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂, 30 g,

40 mm Ø, hexanes/diethyl ether, 98:2) aﬀorded (E)-2o (378 mg,

75%) as colorless oil. Distillation provided 368 mg (73%) of

analytically pure (E)-2o. Data for (E)-2o: bp 65 °C at 3.0 × 10⁻⁵

1

2.4 × 10⁻⁵mmHg; H NMR (500 MHz, CDCl₃) δ 7.37−7.21 (m,

mmHg; H NMR (500 MHz, CDCl₃) δ 6.73 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.67 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.62 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 5.92 (s, 2 H, OCH₂O), 5.48 (dt, J = 14.0, 6.5 Hz, 1 H,

HC(3)), 5.36 (dt, J = 14.0, 6.5 Hz, 1 H, HC(4)), 3.48 (t, J = 6.5 Hz,

2 H, HC(7)), 2.59 (t, J = 8.0 Hz, 2 H, HC(1)), 2.27 (dt, J = 7.5,

7.5 Hz, 2 H, HC(2)), 2.13 (dt, J = 7.0, 7.0 Hz, 2 H, HC(5)), 1.80

(dq, J = 7.0, 7.0 Hz, 2 H, HC(6)); ¹³C NMR (125 MHz, CDCl₃) δ

147.7 (C(3′)), 145.8 (C(4′)), 136.0 (C(1′)), 131.1 (C(3)), 129.2

(C(4)), 121.4 (C(6′)), 109.1 (C(2′)), 108.3 (C(5′)), 101.0

(OCH₂O), 44.6 (C(7)), 35.9 (C(1)), 34.9 (C(2)), 32.4 (C(6)),

29.8 (C(5)); IR (neat) 2857 (w), 2930 (m), 2849 (w), 2780 (w),

1607 (w), 1503 (s), 1488 (s), 1441 (s), 1357 (w), 1243 (s), 1187 (m),

1097 (w), 1039 ((s), 969 (m), 937 (s), 858 (s), 808 (s), 723 (m); MS

(TOF ES⁺) 359.1 (55.7), 338.3 (38.9), 309.1 (55.7), 267.1 (39.4),

251.1 (59.4), 239.0 (21.4), 219.0 (100.0), 217.2 (26.3), 149.0 (21.3),

6 H, HC(b) and HC(c) and HC(d) and HC(5′)), 6.85 (d, J = 8.0,

1 H, HC(6′)), 6.81−6.77 (m, 2 H, HC(2′), HC(4′)), 6.45 (d, J =

16.0 Hz, 1 H, HC(1)), 6.29 (dd, J = 16.0, 7.0 Hz, 1 H, HC(2)), 3.83

(s, 3 H, OCH₃), 2.80 (t, J = 8.0 Hz, 2 H, HC(4)), 2.56 (dt, J = 8.0, 8.0

Hz, 2H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 160.1 (C(3′)),

143.7 (C(a)), 138.1 (C(1′)), 130.8 (C(2)), 130.3 (C(1)), 129.6

(C(5′)), 128.7 (C(c)), 127.2 (C(d)), 126.3 (C(b)), 121.2 (C(6′)),

114.6 (C(3′)), 55.4 (OCH₃), 36.2 (C(4)), 34.9 (C(3)); IR (neat)

3022 (m), 2935 (m), 2832 (m), 1596 (s), 1581 (s), 1488 (s), 1452

(s), 1435 (s), 1259 (s), 1150 (s), 1043 (s), 963 (s), 910 (m), 872 (s),

777 (s), 735 (s), 691 (s); MS (TOF ES⁺) 341.2 (42.5), 323.0 (65.1),

282.3 (28.3), 278.1 (32.1), 239.1 (39.6), 237.1 (90.6), 161.1 (100.0),

131.1 (17.8), 121.1 (13.5); HRMScalcd for C₁₇H₁₉O⁺239.1436,

found 239.1438; TLC R_f0.47 (hexane/Et₂O, 96:4) [KMnO₄]. Anal.

Calcd for C₁₇H₁₈O (238.32): C, 85.67; H, 7.61%. Found: C, 85.49;

H, 7.39%.

+

135.0 (30.3); HRMS calcd for C₁₄H₁₆ClO₂251.0839, found

251.0846; TLC R_f0.50 (hexane/Et₂O, 96:4) [KMnO₄]. Anal. Calcd

for C₁₄H₁₇ClO₂(252.74): C, 66.53; H, 6.78%. Found: C, 66.45; H,

7.07%.

Preparation of (E)-1-(3′-Methoxyphenyl)non-3-ene ((E)-11n).

Following General Procedure 3, 3-methoxystyrene 8b (268.8 mg,

2.0 mmol), 9-BBN (0.321 M in THF, 9.4 mL, 3.0 mmol), TlOEt

(283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted

with PdCl₂(dppf) (146.4 mg, 0.2 mmol), Ph₃As (122.5 mg,

0.4 mmol), (E)-1-iodoheptene 10n (538 mg, 2.4 mmol), and THF

(9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂, 30 g,

40 mm Ø, hexanes/diethyl ether, 97:3) aﬀorded (E)-11n (365 mg

(77%) as colorless oil. Distillation provided 357 mg (75%) of

analytically pure (E)-11n. Data for (E)-11n: bp 60 °C at 2.6 × 10⁻⁵

mmHg; ¹H NMR (500 MHz, CDCl₃) δ 7.21 (ddd, J = 7.5, 7.5,

1.0 Hz, 1H, HC(5′)), 6.81−6.74 (m, 3 H, HC(2′) and HC(4′) and

HC(6′)), 5.47−5.45 (m, 2 H, HC(3) and HC(4)), 3.82 (s, 3 H,

OCH₃), 2.67 (t, J = 7.5 Hz, 2 H, HC(1)), 2.34−2.30 (m, 2 H,

HC(2)), 2.01−1.97 (m, 2 H, HC(5)), 1.38−1.24 (m, 6 H, HC(6)

and HC(7) and HC(8)), 0.90 (t, J = 7.0 Hz, 3 H, HC(9)); ¹³C NMR

(125 MHz, CDCl₃) δ 159.9 (C(3′)), 144.0 (C(1′)), 131.4 (C(4′)),

129.4 (C(3′)), 129.3 (C(5′)), 121.1 (C(6′)), 114.6 (C(2′)), 111.3

(C(4′)), 55.3 (OCH₃), 36.4 (C(1)), 34.3 (C(2)), 32.6 (C(5)), 31.5

(C(7)), 29.4 (C(6)), 22.6 (C(8)), 14.1 (C(9)); IR (neat) 2957 (m),

2924 (s), 2853 (m), 1602 (s), 1585 (s), 1488 (s), 1467 (m), 1454 (s),

1435 (m), 1259 (s), 1164 (m), 1151 (s), 1045 (s), 968 (s), 869 (s),

775 (s), 694 (s); MS (TOF ES⁺) 231.2 (5.5), 122.0 (8.8), 121.0

(100.0), 91.0 (3.2), 78.1 (4.6), 77.1 (3.9); HRMS calcd for C₁₆H₂₄O⁺

232.1827, found 232.1821; TLC R_f0.67 (hexane/Et₂O, 96:4)

[KMnO₄].

Preparation of (E)-1-(3′,4′-Methylenedioxyphenyl)-6-methylhept-

3-ene ((E)-2p). Following General Procedure 3, oleﬁn 8a (296 mg,

2.00 mmol), 9-BBN (0.321 M in THF, 9.4 mL, 3.0 mmol), TlOEt

(283.3 μL, 4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted

with PdCl₂(dppf) (146.3 mg, 0.2 mmol), Ph₃As (122.5 mg, 0.4 mmol),

(E)-1-iodo-4-methyl-1-pentene 10p (504.1 mg, 2.4 mmol), and THF

(9 mL). Puriﬁcation by ﬂash column chromatography (SiO₂, 28 g,

40 mm Ø, hexanes/diethyl ether, 98:2) aﬀorded (E)-2p (333 mg,

71%) as colorless oil. Distillation provided 321 mg (69%) of

analytically pure (E)-2p. Data for (E)-2p: bp 40 °C at 3.0 × 10⁻⁵

1

mmHg; H NMR (500 MHz, CDCl₃) δ 6.75 (d, J = 8.0 Hz, 1 H,

HC(5′)), 6.70 (d, J = 1.0 Hz, 1 H, HC(2′)), 6.65 (dd, J = 8.0, 1.0 Hz,

1 H, HC(6′)), 5.94 (s, 2 H, OCH₂O), 5.44−5.42 (m, 2 H, HC(3) and

HC(4)), 2.16 (t, J = 8.0 Hz, 2 H, HC(1)), 2.31−2.28 (m, 2 H,

HC(2)), 1.90−1.87 (m, 2 H, HC(5)), 1.64−1.55 (m, 1 H, HC(6)),

0.88 (dd, J = 6.5, 1.5 Hz, 6 H, HC(7)); ¹³C NMR (125 MHz, CDCl₃)

δ 147.6 (C(3′)), 145.7 (C(4′)), 136.3 (C(1′)), 130.5 (C(3)), 130.1

(C(4)), 121.4 (C(6′)), 109.2 (C(2′)), 108.2 (C(5′)), 100.9

(OCH₂O), 42.2 (C(5)), 36.2 (C(1)), 35.0 (C(2)), 28.7 (C(6)),

22.5 (C(7)); IR (neat) 2949 (s), 2929 (m), 2901 (m), 2872 (m), 1608

(w), 1502 (s), 1488 (s), 1442 (s), 1365 (w), 1243 (s), 1187 (m), 1096

(s), 1039 (s), 966 (m), 940 (s); MS (EI⁺, 70 eV) 233.1 (2.8), 232

(15.4), 136.0 (8.9), 135.0 (100.0), 105.0 (2.5), 77.0 (6.2); HRMS

calcd for C₁₅H₂₀O₂⁺232.1463, found 232.1468; TLC R_f0.67 (hexane/

Et₂O, 96:4) [KMnO₄].

T

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Preparation of (S)-4-(Diisobutylamino)-3,5-dimethyl-4,5-dihy-

dro-3H-dinaphtho[2,1-d:1′,2′-f ][1,3,2]diazaphosphepine-4-selenide

((S)-20a). To a ﬂame-dried, 100 mL Schlenk ﬂask equipped with a

magnetic stir bar and septum were added N,N′-dimethyl-1,1′-

binaphthalene-2,2′-diamine (37) (2.00 g, 6.40 mmol), Et₃N (2.23

mL, 16.0 mmol, 2.50 equiv), and THF (64.0 mL) via syringe. The

homogeneous mixture was cooled to 0 °C. PCl₃(1.68 mL, 19.2 mmol,

3.00 equiv) was added dropwise via syringe whereupon a colorless

precipitate formed immediately. The reaction mixture was stirred at

0 °C for 1.5 h, then was allowed to warm to room temperature and

was stirred for another 3 h. The volatiles were removed under high

vacuum (room temperature, 0.5 mmHg), and Et₂O (20.0 mL) was

added via syringe, then the mixture was stirred for 5 min. The

supernatant was cannula ﬁltered into a tared, ﬂame-dried, argon ﬁlled,

200 mL Schlenk ﬂask equipped with a rubber septum. The remaining

precipitate in the reaction ﬂask was washed with Et₂O (20 mL) and

was ﬁltered into the receiver Schlenk ﬂask. The volatiles were removed

under high vacuum (room temperature, 0.5 mmHg) to aﬀord a light

yellow solid. The solid was redissolved with Et₂O (20 mL), and the

volatiles were again removed under high vacuum (room temperature,

1.0 mmHg) to aﬀord a white solid. The solid was then dried for 3 h at

reduced pressure (45 °C, 0.50 mmHg) to give a white foam (2.34 g).

CH₂Cl₂(60.0 mL) was added via syringe, and the mixture was cooled

to 0 °C. Et₃N (0.74 mL, 5.30 mmol, 1.2 equiv) and diisobutylamine

(1.23 mL, 7.10 mmol, 1.1 equiv) were added via syringe, and the

reaction mixture was allowed to warm to room temperature and then

stirred for 14 h. Powdered selenium (1.46 g, 18.6 mmol, 2.9 equiv)

was added, and the mixture was stirred for 50 h and then ﬁltered

through a pad of Celite (12 g, 70 mm Ø). The pad was washed with

EtOAc (100 mL), and the ﬁltrate was concentrated in vacuo (40 °C,

10 mmHg). Puriﬁcation via ﬂash column chromatography (SiO₂, 55 g,

50 mm Ø, hexane/Et₂O 4:1) aﬀorded (S)-20a (2.55 g, 73%) as slightly

orange solid. Recrystallization from hot pentane provided (2.35 g,

Preparation of (E)-4-(4′-Methoxyphenyl)-1-phenylbut-1-ene ((E)-

12b). Following General Procedure 4, 4-methoxystyrene 8c (500.0

mg, 3.72 mmol) in THF (4 mL), 9-BBN (0.577 M in THF, 9.7 mL,

5.6 mmol), and H₂O (1.0 mL, 55.9 mmol) were reacted with

PdCl₂(dppf) (136.3 mg, 0.19 mmol), Ph₃As (114.1 mg, 0.37 mmol),

Cs₂CO₃(2.42 g, 7.45 mmol), (E)-(2-iodovinyl)benzene 10b (1.03 mg,

4.47 mmol), and DMF (6 mL). Puriﬁcation by ﬂash column

chromatography (SiO₂, 32 g, 40 mm Ø, hexanes/Et₂O, 97:3) aﬀorded

(E)-12b (506 mg, 57%) as white solid along with starting material 8c

(60 mg, 12%). Recrystallization from hot hexane provided 480 mg

(54%) of analytically pure (E)-12b. Data for (E)-12b: mp 75−77 °C

1

(hexane); H NMR (500 MHz, CDCl₃) δ 7.37 (d, J = 7.5 Hz, 2 H,

HC(b)), 7.33 (t, J = 8.0, 2 H, HC(c)), 7.23 (d, J = 7.5 Hz, 1 H,

HC(d)), 7.17 (d, J = 8.5 Hz, 1 H, HC(2′)), 6.89 (d, J = 8.5 Hz, 1 H,

HC(3′)), 6.45 (d, J = 15.5 Hz, 1 H, HC(1)), 6.29 (dt, J = 15.5, 7.0 Hz,

1H, HC(2)), 3.83 (s, 3 H, OCH₃), 2.79 (t, J = 8.0 Hz, 2 H, HC(4)),

2.54 (dt, J = 8.0, 8.0 Hz, 2 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃)

δ 158.1 (C(4′)), 138.0 (C(a)), 134.1 (C(1′)), 130.5 (C(2)), 130.3

(C(1)), 129.6 (C(2′)), 128.7 (C(c)), 127.2 (C(d)), 126.2 (C(b)),

114.0 (C(3′)), 55.5 (OCH₃), 35.4 (C(4)), 35.2 (C(3)); IR (KBr)

3030 (w), 3009 (w), 2935 (m), 2909 (w), 2836 (w), 1650 (w), 1609

(m), 1598 (w), 1507 (w), 1507 (s), 1465 (m), 1445 (m), 1441 (m),

1299 (m), 1237 (s), 1179 (s), 1151 (s), 1033(s), 985 (s), 977 (s), 828

(s), 809 (s), 740 (s); MS (EI⁺, 70 eV) 238.2 (7.6), 136.1 (9.0), 135.1

(100.0), 122.1 (8.2), 121.1 (95.5), 77.1 (8.8); HRMS calcd for

C₁₇H₁₈O⁺238.1358, found 238.1354; TLC R_f0.47 (hexane/Et₂O,

96:4) [KMnO₄]. Anal. Calcd for C₁₇H₁₈O (238.32): C, 85.67; H,

7.61%. Found: C, 85.77; H, 7.66%.

1

67%). Data for (S)-20a: mp 118−120 °C (pentane); H NMR (500

MHz, CDCl₃) δ 7.98 (d, J = 9.0 Hz, 1 H, HC(4)), 7.92 (d, J = 9.0 Hz,

1 H, HC(4′)), 7.90 (d, J = 8.5 Hz, 1 H, HC(6)), 7.86 (d, J = 8.0 Hz,

1 H, HC(6′)), 7.67 (d, J = 9.0 Hz, 1 H, HC(3′)), 7.66 (dd, J = 9.0, 1.0

Hz, 1 H, HC(3)), 7.43 (dt, J = 7.5, 1.0 Hz, 1 H, HC(7)), 7.36 (t, J =

7.5 Hz, 1 H, HC(7′)), 7.28 (d, J = 8.0 Hz, 1 H, HC(8)), 7.24 (dt, J =

8.5, 1.0 Hz, 1 H, HC(9)), 7.12 (dt, J = 8.0, 1.0 Hz, 1 H, HC(8′)), 7.04

(d, J = 9.0 Hz, 1 H, HC(9′)), 3.21 (d, J = 13.5 Hz, 3 H, HC(11′)),

3.18−3.11 (m, 2 H, HC(12)), 2.96 (d, J = 13.5 Hz, 3 H, H₃C(11)),

2.81 (dt, J = 14.0, 6.0 Hz, 2 H, HC(12′)), 1.96−1.87 (m, 2 H, HC(13,

13′)), 0.86 (d, J = 6.5 Hz, 6 H, HC(14′)), 0.84 (d, J = 6.5 Hz, 6 H,

HC(14)); ¹³C NMR (125 MHz, CDCl₃) δ 143.4 (d, J = 5.0 Hz,

C(2′)), 142.3 (C(2)), 132.7 (C(10)), 132.5 (C(10′)), 131.5 (C(5′)),

131.3 (C(5)), 129.5 (C(4)), 128.7 (C(4′)), 128.3 (C(9)), 128.2

(C(6′), 128.0 (C(6)), 127.5 (C(1,1′)), 127.3 (C(9′)), 126.3 (C(8)),

125.9 (C(8′)), 125.5 (C(7)), 124.9 (C(7′)), 124.6 (C(3′)), 122.6

(C(3)), 55.1 (C(12, 12′)), 39.3 (d, J = 11.3 Hz, C(11′)), 36.1 (d, J =

5.0 Hz, C(11)), 27.2 (C(13, 13′)), 21.0 (C(14′)), 20.9 (C(14′)); ³¹P

NMR (202 MHz, CDCl₃) δ 95.39; IR (KBr) 3052 (w), 2954 (s), 2864

(s), 2801 (w), 1618 (w), 1590 (m), 1503 (s), 1465 (s), 1386 (m),

1365 (m), 1327 (s), 1271 (s), 1261 (s), 1157 (m), 1115 (s), 1087 (s),

1007 (s), 955 (m), 935 (s), 876 (m), 810 (s), 747 (s); MS (EI⁺,

70 eV) 422.1 (5.6), 421.1 (18.7), 419.1 (9.5), 342.1 (23.5), 341.1

(100.0), 312.1 (6.4), 282.2 (5.2), 281.1 (18.4), 215.1 (6.3), 128.1

(15.5), 57.1 (7.6); HRMS calcd for C₃₀H₃₆N₃PSe⁺549.1812, found

Preparation of (E)-1-(4′-Methoxyphenyl)non-3-ene ((E)-12n).

Following General Procedure 3, oleﬁn 45 (276 mg, 2.0 mmol),

9-BBN (0.345 M in THF, 8.7 mL, 3.0 mmol), TlOEt (283.3 μL,

4.0 mmol), and H₂O (180.0 μL, 10.0 mmol) were reacted with

PdCl₂(dppf) (146.3 mg, 0.2 mmol), Ph₃As (122.5 mg, 0.4 mmol),

(E)-1-iodoheptene 10n (537.8 mg, 2.4 mmol), and THF (9 mL).

Puriﬁcation by ﬂash column chromatography (SiO₂, 28 g, 40 mm Ø,

hexanes/diethyl ether, 98:2) aﬀorded (E)-12n (331 mg, 70%) as

colorless oil. Data for (E)-12n; ¹H NMR (500 MHz, CDCl₃) δ 7.10 (d,

J = 8.5 Hz, 2 H, HC(3′)), 6.83 (d, J = 8.5 Hz, 2 H, HC(2′)), 5.47−5.37

(m, 2 H, HC(3) and HC(4)), 3.79 (s, 3 H, OCH₃), 2.61 (t, J = 8.0 Hz,

2 H, HC(1)), 2.31−2.22 (m, 2 H, HC(2)), 2.00−1.92 (m, 2 H,

HC(5)), 1.38−1.19 (m, 6 H, HC(6) and HC(7) and HC(8)), 0.89 (t,

J = 7.0 Hz, 3 H, HC(9)); ¹³C NMR (125 MHz, CDCl₃) δ 157.6

(C(4′)), 134.3 (C(1′)), 131.1 (C(3)), 129.3 (C(2′)), 129.3 (C(4)),

113.6 (C(3′)), 55.22 (OCH₃), 35.2 (C(1)), 34.7 (C(2)), 32.5 (C(5)),

31.4 (C(7)), 29.2 (C6)), 22.6 (C(8)), 14.1 (C(9)); IR (neat) 2954 (s),

2919 (s), 2850 (m), 1611 (w), 1510 (s), 1462 (w), 1438 (w), 1299 (w),

1243 (s), 1174 (m), 1039 (m), 966 (w), 820 (w); MS (EI⁺, 70 eV)

233.2 (3.5), 232.2 (24.5), 122.1 (12.7), 121.0 (100.0), 91.1 (14.1), 86.0

(3.0), 84.9 (4.6), 84.0 (5.1), 82.9 (7.1), 78.0 (12.8), 77.0 (12.9); HRMS

calcd for C₁₆H₂₄O⁺232.1827, found 232.1826; TLC R_f0.68 (hexane/

Et₂O, 96:4) [KMnO₄].

24

549.1809; TLC R_f0.61 (hexanes/Et₂O, 4:1) [CAM]; [α]_D+187.5

(c = 1.67, EtOH); SFC (S)-37, t_R12.8 min (99.8%); (R)-37, t_R15.6

min (0.8%) (Chiralpak OJ, 5% MeOH in CO₂, 2 mL/min, 220 nm,

40 °C).⁵⁷Anal. Calcd for C₃₀H₃₆N₃PSe (549.56): C, 65.68; H, 6.61%;

N, 7.66; P, 5.65; Se, 14.39%. Found: C, 65.75; H, 6.69%; N, 7.42; P,

5.52; Se, 14.46%.

Sulfenocarbocyclizations with (S)-20a. General Procedure 8. An

oven-dried, 10 mL, two-necked, round-bottomed ﬂask under nitrogen

was charged with N-phenylthiophthalimide 13 (256 mg, 1.00 mmol,

1.0 equiv), 20a (54.9 mg, 0.10 mmol, 0.1 equiv), and oleﬁn (1.00

mmol) in CH₂Cl₂. The ﬂask was placed into isopropyl alcohol bath

and cooled at the requisite temperature via cryocool. A solution of

U

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

EtSO₃H (1 M in CH₂Cl₂) was added over 20 s, and the mixture was

allowed to stir for the speciﬁed time. The reaction was quenched while

cold by addition of Et₃N (1.6 mL). The resultant mixture was poured

into H₂O (20 mL), and the aqueous phase was extracted with Et₂O

(3 × 10 mL). The combined organic layers were washed with brine

(50 mL), dried over MgSO₄, ﬁltered through glass wool, and then

concentrated in vacuo (20−23 °C, 10 mmHg). The thioether products

were puriﬁed by ﬂash column chromatography followed by distillation

or recrystallization.

145.9 (C(8)), 135.5 (C(12)), 134.6 (C(5)), 131.5 (C(13)), 129.1

(C(14)), 127.8 (C(10)), 126.8 (C(15)), 108.5 (C(9)), 108.5 (C(6)),

100.8 (OCH₂O), 48.9 (C(2)), 36.9 (C(1)), 29.3 (C(4)), 24.9 (C(3)),

18.9 (C(11)); IR (KBr) 2961 (m), 2898 (m), 1580 (w), 1500 (s),

1479 (s), 1434 (w), 1375 (w), 1247 (s), 1219 (s), 1087 (w), 1039 (s),

941 (m), 928 (m), 893 (w), 862 (m), 737 (m), 688 (m); MS (EI⁺, 70

eV) 299.1 (14.4), 298.1 (68.5), 231.2 (35.6), 189.1 (100.0), 188.1

(24.8), 174.1 (11.2), 173.1 (26.7), 162.1 (34.9), 159.1 (37.9), 135.1

(20.7), 131.1 (31.6), 128.1 (10.8), 116.1 (15.2), 115.1 (30.0), 107.1

(12.6), 103.1 (12.1), 91.1 (27.6), 78.1 (12.6), 77.1 (18.8), 65.1 (14.6),

57.1 (23.6), 55.1 (12.0), 51.1 (11.6); HRMS calcd for C₁₈H₁₈O₂S⁺

298.1028, found 298.1034; TLC R_f0.42 (hexanes/Et₂O, 96:4)

[KMnO₄]; SFC cis-14a, t_R112.6 min (52%); cis-14a, t_R214.1 min

(48%) (Chiralpak OJ, 5% MeOH in CO₂, 2.0 mL/min, 220 nm,

40 °C). Anal. Calcd for C₁₈H₁₈O₂S (298.40); Calcd: C, 72.45; H,

6.08%. Found: C, 72.43; H, 6.03%.

Preparation of (5R,6R)-5-Methyl-6-(phenylthio)-5,6,7,8-tetra-

hydronaphtho[2,3-d]-1,3-dioxole (trans-14a). Following General

Procedure 8, (E)-2a (190 mg, 1.0 mmol), 13 (256 mg, 1.0 mmol),

(S)-20a (54.8 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were reacted

with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol) at

−20 °C for 72 h. Puriﬁcation by ﬂash column chromatography (SiO₂,

32 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14a (277 mg, 93%)

as a white solid. Recrystallization from hot pentane provided 273 mg

(92%) of analytically pure trans-14a. Data for trans-14a: mp 46−48 °C

1

(pentane); H NMR (500 MHz, CDCl₃) δ 7.46 (dd, J = 8.0, 1.0 Hz,

Preparation of ((5R,6R)-5-Phenyl-6-(phenylthio)-5,6,7,8-tetra-

hydronaphtho[2,3-d]-1,3-dioxole (trans-14b). Following General

Procedure 8, (E)-2b (252.3 mg, 1.0 mmol), 13 (256 mg, 1.0 mmol),

(S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were reacted

with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol) at

−20 °C for 48 h. Puriﬁcation by ﬂash column chromatography (SiO₂,

30 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14b (328 mg, 91%)

as a pale yellow solid. Recrystallization form hot pentane provided

324 mg (90%) of analytically pure trans-14b. Data for trans-14b: mp

2 H, HC(13)), 7.34 (t, J = 8.0 Hz, 2 H, HC(14)), 7.27 (tt, J = 8.5,

1.5 Hz, 1 H, HC(15)), 6.64 (s, 1 H, HC(6)), 6.58 (s, 1 H, HC(9)),

5.91 (s, 2 H, OCH₂O), 3.43−3.40 (m, 1 H, HC(2)), 2.97−2.91 (m,

2 H, HC(1) and HC(4)), 2.66 (ddd, J = 16.5, 5.5, 5.5 Hz, 1 H,

HC(4)), 2.23−2.16 (m, 1 H, HC (3)), 1.91−1.85 (m, 1 H, HC(3)),

1.42 (d, J = 7.0 Hz, 3 H, HC(11)); ¹³C NMR (125 MHz, CDCl₃) δ

146.0 (C(7)), 145.9 (C(8)), 135.4 (C(12)), 132.6 (C(5)), 131.9

(C(13)), 129.0 (C(14)), 128.2 (C(10)), 126.9 (C(15)), 108.8 (C(9)),

108.6 (C(6)), 100.7 (OCH₂O), 49.9 (C(2)), 38.3 (C(1)), 26.6

(C(4)), 24.8 (C(3)), 24.1 (C(11)); IR (KBr) 3052 (w), 2961 (m),

2926 (m), 2885 (m), 2766 (w), 1580 (m), 1500 (s), 1479 (s), 1438

(m), 1379 (m), 1233 (s), 1184 (m), 1087 (w), 1035 (s), 938 (s), 858

(m), 740 (s); MS (EI⁺, 70 eV) 299.1 (14.2), 298.1 (69.8), 190.1

(13.2), 189.1 (100.0), 188.1 (75.1), 174.0 (18.0), 173.0 (43.8), 162.1

(26.5), 159.1 (34.4), 131.1 (22.0), 116.1 (12.2), 115.0 (26.2), 103.1

(7.3), 91.1 (10.9), 85.0 (31.7), 83.0 (48.7), 65.1 (8.1); HRMS calcd

for C₁₈H₁₈O₂S⁺298.1028, found 298.1032; TLC R_f0.44 (hexanes/

Et₂O, 96:4) [KMnO₄]; [α]_D²⁵−18.7 (c = 0.53, EtOH); SFC (5S,6S)-

14a, t_R11.7 min (3%); (5R,6R)-14a, t_R15.2 min (97%) (Chiralpak OJ,

5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for

C₁₈H₁₈O₂S (298.40): C, 72.45; H, 6.08%. Found: C, 72.59; H, 5.90%.

1

54−56 °C (pentane); H NMR (500 MHz, CDCl₃) δ 7.42 (d, J =

7.5 Hz, 2 H, HC(16)), 7.34−7.22 (m, 6 H, HC(13) and HC(14) and

HC(17) and HC(18)), 7.07 (d, J = 7.5 Hz, 2 H, HC(12)), 6.66 (s, 1 H,

HC(6)), 6.32 (s, 1 H, C(9)), 5.90 (d, J = 2.5 Hz, 2 H, OCH₂O), 4.13

(d, J = 5.0 Hz, 1 H, HC(1)), 3.68−3.65 (m, 1 H, HC(2)), 3.00 (ddd,

J = 16.0, 8.0, 5.5 Hz, 1 H, HC(4)), 2.81 (ddd, J = 17.0, 6.0, 6.0 Hz, 1 H,

HC(4)), 2.20−2.14 (m, 1 H, HC(3)), 2.19−2.12 (m, 1 H, HC(3));

¹³C NMR (125 MHz, CDCl₃) δ 146.4 (C(7)), 146.2 (C(8)), 145.5

(C(11)), 135.1 (C(15)), 132.4 (C(16)), 129.5 (C(5)), 129.4 (C(10)),

129.1 (C(12)), 129.0 (C(13)), 128.5 (C(17)), 127.2 (C(18)), 126.7

(C(14)), 110.4 (C(9)), 108.3 (C(6)), 100.8 (OCH₂O), 51.5 (C(2)),

50.4 (C(1)), 26.8 (C(4)), 24.9 (C(3)); IR (KBr) 3052 (w), 3017 (w),

2919 (m), 2885 (m), 1580 (w), 1500 (m), 1479 (s), 1448 (m), 1434

(m), 1382 (w), 1236 (s), 1170 (w), 1039 (s), 938 (m), 869 (m), 740

(m), 699 (m); MS (EI⁺, 70 eV) 361.1 (18.7), 360.0 (71.7), 252.1

(16.6), 251.1 (91.6), 250.0 (100.0), 224.0 (20.2), 223.0 (29.6), 205.1

(19.0), 194.0 (15.6), 193.1 (10.4), 191.1 (19.0), 189.0 (13.2), 178.0

(13.9), 173.0 (13.6), 166.1 (17.0), 165.0 (35.2), 160.0 (9.5), 159.0

(15.7), 152.0 (8.4), 143.0 (7.3), 135.0 (18.3), 115.0 (28.6), 109.0

(11.8); HRMS calcd for C₂₃H₂₀O₂S⁺360.1164, found 360.1178;

Preparation of trans-5-Methyl-6-(phenylthio)-5,6,7,8-tetrahydro-

naphtho[2,3-d]-1,3-dioxole (cis-14a). Following General Procedure

8, (Z)-2a (190 mg, 1.0 mmol), 13 (256.0 mg, 1.0 mmol), (S)-20a

(54.8 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were reacted with a

solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol) at 0 °C for

72 h. Puriﬁcation by ﬂash column chromatography (SiO₂, 32 g, 30 mm

Ø, hexane/Et₂O, 96:4) aﬀorded of cis-14a (275 mg, 92%) as a white

solid. Recrystallization from hot pentane provided 271 mg (91%) of

analytically pure cis-14a. Data for cis-14a: mp 76−78 °C (pentane);

¹H NMR (500 MHz, CDCl₃) δ 7.46 (dd, J = 7.5 Hz, 2 H, HC(13)),

7.33 (t, J = 7.5 Hz, 2 H, HC(14)), 7.26 (t, J = 7.6 Hz, 1 H, HC(15)),

6.58 (s, 1 H, HC(6)), 6.56 (s, 1 H, HC(9)), 5.90 (s, 2 H, OCH₂O),

3.69−3.65 (m, 1 H, HC(2)), 3.10−3.04 (m, 1 H, HC(1)), 2.89 (ddd,

J = 17.0, 5.5, 5.5 Hz, 1 H, HC(4)), 2.80 (ddd, J = 17.0, 8.5, 8.5 Hz,

1 H, HC(4)), 2.05−2.00 (m, 2 H, HC (3)), 1.33 (d, J = 7.0 Hz,

3 H, HC(11)); ¹³C NMR (125 MHz, CDCl₃) δ 146.1 (C(7)),

25

TLC R_f0.40 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D−33.0 (c =

0.65, EtOH); SFC (5R,6R)-14b, t_R14.0 min (94%); (5S,6S)-14b,

t_R17.2 min (6%) (Chiralpak OJ, 5% MeOH in CO₂, 2.0 mL/min,

220 nm, 40 °C).

Preparation of (6R)-5,5-Dimethyl-6-(phenylthio)-5,6,7,8-tetra-

hydronaphtho[2,3-d]-1,3-dioxole ((R)-14c) and 5,5-Dimethyl-5,6,7,-

8-tetrahydronaphtho[2,3-d]-1,3-dioxole (26). Following General

Procedure 8, a 10 mL Schlenk ﬂask was charged with 4c (204.3 mg,

V

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1.0 mmol), 13 (256.0 mg, 1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol),

and CH₂Cl₂(4.5 mL) and reacted with a solution of EtSO₃H (1 M in

CH₂Cl₂, 0.5 mL, 0.5 mmol) at −20 °C for 24 h. Puriﬁcation by ﬂash

column chromatography (SiO₂, 32 g, 30 mm Ø, hexane/Et₂O, 96:4)

aﬀorded (R)-14c (284 mg, 91%) as a white solid along with 26

(20 mg, 10%) as colorless oil. Distillation provided 281 mg (90%) of

analytically pure (R)-14c. Data for (R)-14c: bp 130 °C at 2.2 × 10⁻⁵

2.35 (s, 3 H, HC(15)), 2.20−2.14 (m, 1 H, HC(3)), 1.87−1.81 (m,

1 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 146.4 (C(7)), 146.1

(C(8)), 142.5 (C(14)), 136.2 (C(11)), 135.1 (C(16)), 132.3 (C(17)),

129.8 (C(5)), 129.4 (C(10)), 129.2 (C(13)), 129.0 (C(18)), 128.9

(C(12)), 127.0 (C(19)), 110.3 (C(9)), 108.2 (C(6)), 100.8

(OCH₂O), 51.4 (C(2)), 50.0 (C(1)), 26.8 (C(4)), 24.9 (C(3)),

21.2 (C(15)); IR (KBr) 3003 (w), 2919 (m), 2885 (m), 1580 (w),

1500 (s), 1479 (s), 1434 (m), 1382 (w), 1236 (s), 1174 (w), 1035 (s),

938 (m), 869 (w), 806 (w), 740 (m), 692 (m); MS (EI⁺, 70 eV)

375.1 (21.2), 374.1 (75.9), 326.2 (26.2), 266.1 (19.0), 265.1 (100.0),

264.1 (90.0), 249.0 (9.3), 237.0 (9.8), 224.0 (9.8), 223.0 (58.2),

191.1 (10.8), 189.0 (11.0), 179.0 (9.8), 178.0 (10.7), 173.0 (17.7),

165.0 (21.8), 159.0 (96.4), 159.0 (15.7), 143.0 (11.4), 135.0

(14.0), 115.0 (23.2), 109.0 (10.9), 105.1 (66.4); HRMS calcd for

C₂₄H₂₂O₂S⁺374.1341, found 374.1336; TLC R_f0.35 (hexanes/

Et₂O, 96:4) [KMnO₄]; [α]_D²⁵−28.4 (c = 0.59, EtOH); SFC (5S,6S)-

14d, t_R12.7 min (6%); (5R,6R)-14d, t_R14.1 min (94%) (Chiralpak

AD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd

for C₂₄H₂₂O₂S (374.50): C, 76.97; H, 5.92%. Found: C, 76.79;

H, 6.03%.

1

mmHg; H NMR (500 MHz, CDCl₃) δ 7.47 (t, J = 8.0, 1.5 Hz, 2 H,

HC(14)), 7.33 (t, J = 7.5 Hz, 2 H, HC(15)), 7.25 (t, J = 7.0 Hz, 1 H,

HC(16)), 6.85 (s, 1 H, HC(6)), 6.51 (s, 1 H, C(9)), 5.91 (s, 2 H,

OCH₂O), 3.43 (dd, J = 10.5, 3.0 Hz, 1 H, HC(2)), 2.86 (ddd, J = 16.5,

5.5, 5.0 Hz, 1 H, HC(4)), 2.71 (ddd J = 16.0, 10.0, 1.0 Hz, 1 H,

HC(4)), 2.21−2.15 (m, 1 H, HC(3)), 2.06−1.98 (m, 1 H, HC(3)),

1.56 (s, 3 H, HC(12)), 1.40 (m, 3 H, HC(11)); ¹³C NMR (125 MHz,

CDCl₃) δ 146.3 (C(7)), 145.7 (C(8)), 138.1 (C(12)), 136.6 (C(5)),

131.6 (C(14)), 129.1 (C(15)), 128.0 (C(10)), 126.7 (C(16)), 108.3

(C(9)), 106.6 (C(6)), 100.8 (OCH₂O), 57.8 (C(2)), 38.9 (C(1)),

30.8 (C(11)), 29.5 (C(4)), 27.7 (C(12)), 26.6 (C(3)); IR (neat) 3066

(m), 2961 (s), 2891 (s), 2766 (m), 1625 (w), 1580 (s), 1503 (s), 1434

(s), 1368 (s), 1333 (s), 1302 (s), 1240 (s), 1191 (s), 1160 (s), 1115

(s), 1087 (s), 1049 (s), 1021 (s), 938 (s), 914 (s), 893 (s); MS (EI⁺,

70 eV) 313.0 (10.0), 312.0 (46.5), 204.1 (13.6), 203.1(100.0), 202.1

(13.7), 188.0 (21.3), 187.0 (29.6), 176.0 (20.6), 173.0 (23.1), 161.0

(10.4), 145.1 (10.2), 131.0 (10.4), 129.0 (9.5), 128.0 (8.3), 115.0

(11.2), 103.0 (6.5), 77.1 (6.6); HRMS calcd for C₁₉H₂₀O₂S⁺312.1184,

25

found 312.1190; TLC R_f0.42 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D

−10.72 (c = 0.63, EtOH); SFC (5S)-14c, t_R14.7 min (20%); (6R)-

14c, t_R16.5 min (80%) (Chiralpak AD, 1−5% MeOH over 40 min in

CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for C₁₉H₂₀O₂S

(312.12): C, 73.04; H, 6.45%. Found: C, 73.24; H, 6.57%. Data for

26:^54k¹H NMR (500 MHz, CDCl₃) δ 6.83 (s, 1 H, HC(6)), 6.53 (s,

1 H, C(9)), 5.90 (s, 2 H, OCH₂O), 2.69 (t, J = 6.5 Hz, 2 H, HC(4)),

1.82−1.77 (m, 2 H, HC(3)), 1.66−1.64 (m, 2 H, HC(2)), 1.27 (s,

6 H, HC(11) and HC(12)); ¹³C NMR (125 MHz, CDCl₃) δ 145.9

(C(7)), 145.2 (C(8)), 139.0 (C(5)), 129.3 (C(10)), 108.6 (C(9)),

106.6 (C(6)), 100.6 (OCH₂O), 39.4 (C(2)), 34.1 (C(1)), 32.1

(C(11) and C(12)), 31.0 (C(4)), 20.0 (C(3)); IR (neat) 2947 (s),

2926 (s), 2766 (w), 1621 (w), 1500 (s), 1483 (s), 1371 (s), 1333 (w),

1233 (s), 1191 (m), 1108 (m), 1039 (s), 1011 (w), 931 (m), 865 (m),

844 (m), 740 (w); MS (EI⁺, 70 eV) 204.1 (29.0), 190.1 (12.5), 189.1

(100.0), 160.1 (29.6), 176.0 (20.6), 173.0 (23.1), 160.1 (5.7), 159.1

(23.2), 131.1 (15.0), 115.0 (9.3), 91.1 (6.8), 84.0 (6.8); HRMS calcd

Preparation of ((5R,6R)-5-(4-Cyanophenyl)-6-(phenylthio)-5,6,7,-

8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14e). Following

General Procedure 8, (E)-2e (277.3 mg, 1.0 mmol, 1.0 equiv), 13

(256 mg, 1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂

(4.25 mL) were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂,

0.75 mL, 0.75 mmol) at room temperature for 96 h. Puriﬁcation by

ﬂash column chromatography (SiO₂, 30 g, 30 mm Ø, hexane/Et₂O,

80:20) aﬀord trans-14e (324 mg, 84%) as a white solid. Recrystalli-

zation from hot pentane provided 320 mg (83%) of analytically

pure trans-14e. Data for trans-14e: mp 64−66 °C (pentane); ¹H NMR

(500 MHz, CDCl₃) δ 7.55 (d, J = 8.0 Hz, 2 H, HC(13)), 7.37−7.35

(m, 2 H, HC(17) and HC(23)), 7.41−7.25 (m, 3 H, HC(18) and

HC(19) and HC(20)), 7.13 (d, J = 8.0 Hz, 2 H, HC(12)), 6.63 (s,

1 H, HC(6)), 6.17 (s, 1 H, C(9)), 5.88 (s, 2 H, OCH₂O), 4.11 (d, J =

5.5 Hz, 1 H, HC(1)), 3.52−3.49 (m, 1 H, HC(2)), 2.97 (ddd, J = 17.0,

14.0, 6.0 Hz, 1 H, HC(4)), 2.79 (ddd, 1H, J = 17.0, 6.5, 6.5 Hz, 1 H,

HC(4)), 2.13−2.07 (m, 1 H, HC(3)), 1.88−1.82 (m, 1 H, HC(3));

¹³C NMR (125 MHz, CDCl₃) δ 151.0 (C(7)), 146.9 (C(8)), 146.5

+

for C₁₃H₁₆O₂204.1150, found 204.1154; TLC R_f0.52 (hexanes/

Et₂O, 96:4) [KMnO₄].

(C(16)), 134.5 (C(17,21)), 132.9 (C(13)), 132.4 (C(12), 129.7

(C(10)), 129.3 (C(18,20)), 128.4 (C(5)), 127.7 (C(19)), 119.1

(C(15)), 110.7 (C(14)), 110.0 (C(9)), 108.6 (C(6)), 101.1 (OCH₂O),

51.8 (C(2)), 50.9 (C(1)), 27.3 (C(4)), 25.8 (C(3)); IR (KBr) 3059

(w), 2968 (w), 2926 (w), 2885 (w), 2216 (m), 1604 (w), 1580 (w),

1500 (s), 1476 (s), 1434 (m), 1382 (m), 1236 (s), 1035 (s), 938 (m),

820 (m), 740 (m); MS (EI⁺, 70 eV) 385.2 (22.9), 381.3 (18.4), 340.3

(17.6), 326.2 (24.7), 325.2 (100), 276.2 (30.4), 275.1 (33.4), 269.2

(14.2), 239.2 (14.6), 231.2 (34.4), 191.2 (48.8), 190.1 (16.6), 175.1

(12.8), 160.1 (14.1), 141.1 (12.4), 135.1 (29.8), 121.0 (12.8), 115.1

(22.3), 107.1 (18.8), 91.1 (22.0), 77.1 (19.2), 69.1 (14.0), 57.1 (48.1),

55.1 (22.0); HRMS calcd for C₂₄H₁₉NO₂S⁺385.1137, found 385.1129;

TLC R_f0.38 (hexanes/Et₂O, 80:20) [KMnO₄]; [α]_D²⁵−19.9 (c = 0.58,

EtOH); SFC (5S,6S)-14e, t_R23.9 min (89%); (5R,6R)-14e, t_R27.6 min

(11%) (Chiralpak OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm,

40 °C). Anal. Calcd for C₂₄H₁₉NO₂S (385.48): C, 74.78; H, 4.97%; N,

3.63%. Found: C, 74.50; H, 4.69%; N, 3.60%.

Preparation of ((5R,6R)-5-(4-Methylphenyl)-6-(phenylthio)-5,6,7,-

8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14d). Following

General Procedure 8, 10 mL of (E)-2d (266.3 mg, 1.0 mmol), 13

(256 mg, 1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol, 0.1 equiv), and

CH₂Cl₂(4.25 mL) was reacted with a solution of EtSO₃H (1 M in

CH₂Cl₂, 0.75 mL, 0.75 mmol) at −20 °C for 48 h. Puriﬁcation by ﬂash

column chromatography (SiO₂, 30 g, 30 mm Ø, hexane/Et₂O, 96:4)

aﬀord trans-14d (327 mg, 87%) as a white solid. Recrystallization from

hot pentane provided 322 mg (86%) of analytically pure trans-14d.

1

Data for trans-14d: mp 72−74 °C (pentane); H NMR (500 MHz,

CDCl₃) δ 7.43 (d, J = 7.0 Hz, 2 H, HC(17), 7.32 (t, J = 7.5 Hz, 2 H,

HC(18)), 7.27 (t, J = 7.5 Hz, 1 H, HC(19)), 7.11 (d, J = 7.5 Hz, 2 H,

HC(13)), 6.96 (d, J = 7.5 Hz, 2 H, HC(12)), 6.65 (s, 1 H, HC(6)),

6.33 (s, 1 H, C(9)), 5.89 (s, 2 H, OCH₂O), 4.09 (d, J = 4.5 Hz, 1 H,

HC(1)), 3.67−3.64 (m, 1 H, HC(2)), 2.99 (ddd, J = 16.0, 8.0, 5.5 Hz,

1 H, HC(4)), 2.80 (ddd, 1H, J = 16.0, 6.0, 6.0 Hz, 1 H, HC(4)),

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H(C-aryl)), 7.32−7.20 (m, 5 H, HC(23) and HC(24) and HC(25)

and H(C-aryl)), 6.69 (s, 1 H, HC(6)), 6.33 (s, 1 H, C(9)), 5.89 (s, 2 H,

OCH₂O), 4.27 (d, J = 5.5 Hz, 1 H, HC(1)), 3.78−3.73 (m, 1 H,

HC(2)), 3.03 (ddd, J = 18.0, 8.0, 6.5 Hz, 1 H, HC(4)), 2.86 (ddd, J =

17.0, 6.0, 5.5 Hz, 1 H, HC(4)), 2.25−2.18 (m, 1 H, HC(3)), 1.91−

1.85 (m, 1 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 146.6 (C(7)),

146.3 (C(8)), 142.9 (C(11)), 135.1 (C(21)), 133.5 (C-aryl), 132.6

(C(22,26)), 132.5 (C-aryl), 129.7 (C(5)), 129.5 (C(10)), 129.1

(C(23,25)), 128.4 (C(aryl)), 128.3 (C(aryl)), 128.0 (C(aryl)), 127.8

(C(aryl)), 127.3 (C(aryl), 127.0 (C(24)), 126.3 (C(aryl)), 125.9

(C(aryl)), 110.5 (C(9)), 108.4 (C(6)), 101.0 (OCH₂O), 51.5 (C(2)),

50.8 (C(1)), 27.2 (C(4)), 25.5 (C(3)); IR (KBr) 3045 (w), 2968 (w),

2919 (m), 2885 (m), 1597 (w), 1580 (w), 1500 (s), 1479 (s), 1438

(m), 1382 (w), 1236 (s), 1170 (w), 1115 (m), 1035 (s), 938 (m), 855

(w), 817 (m), 796 (w), 744 (s), 692 (m); MS (EI⁺, 70 eV) 446.2

(66.5), 325.2 (58.7), 310.4 (12.6), 295.3 (34.6), 279.3 (30.9), 259.3

(18.2), 247.2 (17.8), 239.2 (54.4), 231.2 (100.0), 227.2 (21.0), 215.2

(17.1), 205.2 (15.7), 191.2 (93.0), 175.2 (28.9), 159.1 (24.4), 149.1

(27.1), 143.1 (25.5), 141.1 (33.5), 133.1 (21.2), 128.1 (25.7), 121.1

(32.4), 115.1 (38.3), 109.1 (30.5), 107.1 (44.4), 105.1 (46.2); HRMS

calcd forC₂₇H₂₂O₂S⁺410.1341, found 410.1343; TLC R_f0.36

Preparation of ((5R,6R)-5-(4-Methoxyphenyl)-6-(phenylthio)-5,6,-

7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14f). Following

General Procedure 8, a 10 mL Schlenk ﬂask was charged with

(E)-2f (282.3 mg, 1.0 mmol), 13 (256.0 mg, 1.0 mmol), (S)-20a

(54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) and reacted with a

solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol) at −20 °C

for 24 h. Puriﬁcation by ﬂash column chromatography (SiO₂, 32 g,

30 mm Ø, hexane/Et₂O, 90:10) aﬀorded trans-14f (340 mg, 87%) as a

white solid. Recrystallization from hot pentane provided 336 mg

(86%) of analytically pure trans-14f. Data for trans-14f: mp 104−

106 °C (pentane); ¹H NMR (500 MHz, CDCl₃) δ 7.42−7.41 (m, 2 H,

HC(17) and HC(21)), 7.33−7.28 (m, 2 H, HC(18) and HC(20)),

7.26 (tt, J = 7.0, 2.0 Hz, 1 H, HC(19)), 6.97 (d, J = 7.5 Hz, 2 H,

HC(13)), 6.84 (d, J = 7.5 Hz, 2 H, HC(12)), 6.64 (s, 1 H, HC(6)),

6.32 (s, 1 H, C(9)), 5.86 (s, 2 H, OCH₂O), 4.06 (d, J = 5.0 Hz, 1 H,

HC(1)), 3.81 (s, 3 H, HC(15)), 3.63−3.60 (m, 1 H, HC(2)), 2.98

(ddd, J = 16.0, 9.0, 6.0 Hz, 1 H, HC(4)), 2.79 (ddd, J = 17.0, 5.5, 5.5

Hz, 1 H, HC(4)), 2.19−2.13 (m, 1 H, HC(3)), 1.88−1.81 (m, 1 H,

HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 158.4 (C(14)), 146.4 (C(7)),

146.2 (C(8)), 137.7 (C(11)), 135.3 (C(16)), 132.4 (C(17,20)), 130.1

(C(13)), 130.0 (C(5)), 129.4 (C(10)), 129.1 (C(18,20)), 127.2

(C(19)), 113.9 (C(12)), 110.4 (C(9)), 108.3 (C(6)), 100.9

(OCH₂O), 55.5 (C(15)), 51.7 (C(2)), 49.7 (C(1)), 27.0 (C(4)),

25.0 (C(3)); IR (KBr) 2919 (m), 2829 (m), 1608 (m), 1580 (m), 1507

(s), 1479 (s), 1434 (m), 1389 (w), 1299 (w), 1240 (s), 1039 (m), 941

(w), 869 (w), 817 (m), 740 (m); MS (EI⁺, 70 eV) 390.2 (17.0), 381.5

(16.5), 340.3 (20.3), 326.2 (26.2), 325.2 (100.0), 295.4 (12.0), 281.2

(23.0), 280.2 (20.2), 269.3 (15.0), 231.2 (43.9), 223.1 (16.0), 191.2

(58.7), 175.2 (14.2), 159.1 (14.1), 149.2 (16.1), 143.1 (11.5), 141.1

(20.0), 135.1 (40.6), 133.1 (12.1), 128.1 (14.8), 127.1 (13.6), 121.1

(32.2), 115.1 (28.0), 57.0 (60.0); HRMS calcd for C₂₄H₂₂O₃S⁺

390.1290, found 390.1297; TLC R_f0.36 (hexanes/Et₂O, 90:10)

25

(hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D−19.2 (c = 0.54, EtOH);

SFC (5S,6S)-14g, t_R23.4 min (11%); (5R,6R)-14g, t_R23.5 min (89%)

(Chiralpak OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C).

Anal. Calcd for C₂₇H₂₂O₂S (410.13): C, 78.99; H, 5.40%. Found: C,

78.98; H, 5.48%.

Preparation of ((5R,6R)-5-(4-Triﬂuoromethylphenyl)-6-(phenyl-

thio)-5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14h).

Following General Procedure 8, (E)-2h (320.3 mg, 1.0 mmol), 13

(256.0 mg, 1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂

(4.25 mL) were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂,

0.75 mL, 0.75 mmol) at 22 °C for 72 h. Puriﬁcation by ﬂash column

chromatography (SiO₂, 30 g, 32 mm Ø, hexane/Et₂O, 96:4) aﬀord

trans-14h (368 mg, 86%) as a white solid. Recrystallization from

hot pentane provided 364 mg (85%) of analytically pure trans-14h.

25

[KMnO₄]; [α]_D−25.9 (c = 0.54, EtOH); SFC (5R,6R)-14f, t_R

23.7 min (92%); (5S,6S)-14f, t_R42.7 min (8%) (Chiralpak OJ, 5%

MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for

C₂₄H₂₂O₃S (390.13): C, 73.82; H, 5.68%. Found: C, 73.89; H, 5.60%.

1

Data for trans-14h: mp 98−100 °C (pentane); H NMR (500 MHz,

CDCl₃) δ 7.54 (d, J = 8.0 Hz, 2 H, HC(13)), 7.39 (t, J = 7.0 Hz, 2 H,

HC(17), 7.31 (t, J = 6.5 Hz, 2 H, HC(18)), 7.23 (t, J = 7.5 Hz, 1 H,

HC(19)), 7.16 (d, J = 8.0 Hz, 2 H, HC(12)), 6.66 (s, 1 H, HC(6)),

6.23 (s, 1 H, C(9)), 5.90 (s, 2 H, OCH₂O), 4.16 (d, J = 5.5 Hz, 1 H,

HC(1)), 3.60−3.57 (m, 1 H, HC(2)), 3.00 (ddd, J = 16.5, 8.0, 6.0 Hz,

1 H, HC(4)), 2.82 (ddd, 1H, J = 17.0, 6.0, 6.0 Hz, 1 H, HC(4)), 2.18−

2.11 (m, 1 H, HC(3)), 1.90−1.84 (m, 1 H, HC(3)); ¹³C NMR

(125 MHz, CDCl₃) δ 149.5 (C(11)), 146.7 (C(7)), 146.3 (C(8)),

134.6 (C(16)), 132.6 (C(18)), 129.6 (C(10)), 129.5 (C(12)), 129.1

(C(17)), 129.0 (q, J = 32.0 Hz, (C(14)), 128.8 (C(5)), 127.5

(C(19)), 125.4 (q, J = 3.9 Hz, C(13)), 124.3 (q, J = 272.0 Hz, C(15)),

110.1 (C(9)), 108.4 (C(6)), 101.0 (OCH₂O), 51.6 (C(2)), 50.6

(C(1)), 27.1 (C(4)), 25.5 (C(3)); IR (KBr) 2927 (w), 2891 (w),

1608 (w), 1580 (w), 1503 (s), 1479 (s), 1437 (m), 1381 (w), 1301

(w), 1238 (s), 1171 (m), 1032 (s), 937 (m), 906 (w), 818 (m); MS

(EI⁺, 70 eV) 429.2 (22.9), 428.2 (84.1), 325.2 (17.9), 319.1 (17.2),

318.1 (100.0), 291.1 (9.2), 289.2 (9.5), 260.1 (9.2), 233.1 (12.0), 223.1

(47.5), 191.1 (10.3), 189.1 (11.4), 165.0 (20.0), 161.1 (11.6), 160.1

(36.1), 159.1 (30.9), 115.1 (16.3); HRMS calcd for C₂₄H₁₉F₃O₂S⁺

428.1058, found 428.1050; TLC R_f0.29 (hexanes/Et₂O, 96:4)

Preparation of ((5R,6R)-5-(2-Naphthyl)-6-(phenylthio)-5,6,7,8-

tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14g). Following Gen-

eral Procedure 8, (E)-2g (302 mg, 1.0 mmol, 1.0 equiv), 13 (256 mg,

1.0 mmol, 1.0 equiv), (S)-20a (55 mg, 0.1 mmol, 0.1 equiv), and

CH₂Cl₂(4.25 mL) were reacted with a solution of EtSO₃H (1 M in

CH₂Cl₂, 0.75 mL, 0.75 mmol) at −20 °C for 48 h. Puriﬁcation by ﬂash

column chromatography (SiO₂, 30 g, 30 mm Ø, hexane/Et₂O, 96:4)

aﬀorded trans-14g (254 mg, 62%) as a white solid along with unreacted

(E)-2g (109 mg, 36%). Recrystallization from hot pentane provided

250 mg (61%) of analytically pure trans-14g. Data for trans-14g: mp

25

[KMnO₄]; [α]_D−18.5 (c = 0.55, EtOH); SFC (5R,6R)-14h, t_R

6.4 min (92%); (5S,6S)-14h, t_R9.8 min (8%) (Chiralpak OJ, 5% MeOH

in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for C₂₄H₂₂F₃O₂S

(428.11): C, 67.28; H, 4.47%. Found: C, 67.92; H, 4.35%.

1

92−94 °C (pentane); H NMR (500 MHz, CDCl₃) δ 7.83−7.77 (m,

2 H, H(C-aryl)), 7.50−7.42 (m, 5 H, HC(22) and HC(26) and

X

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Article

Preparation of ((5R,6R)-5-Methyl-5-phenyl-6-(phenylthio)-5,6,7,-

8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14j) and 5-Methyl-

5-phenyl-5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (27). Fol-

lowing General Procedure 8, a 10 mL Schlenk ﬂask was charged

with (E)-2j (266 mg, 1.0 mmol, 1.0 equiv), 13 (256 mg, 1.0 mmol,

1.0 equiv), (S)-20 (55 mg, 0.1 mmol, 0.1 equiv), and CH₂Cl₂(4.25

mL) reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 48 h. Puriﬁcation by ﬂash column chromato-

graphy (SiO₂, 30 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14j

(318 mg, 85%) as a white solid along with 27 (5 mg, 2%) as colorless

oil. Recrystallization from hot pentane provided 310 mg of analytically

pure trans-14j. Data for trans-14j: mp 90−92 °C (pentane); ¹H NMR

(500 MHz, CDCl₃) δ 7.33−7.19 (m, 10 H, HC(13) and HC(14),

and HC(15) and HC(17) and HC(18) and HC(19)), 6.59 (s, 1 H,

HC(6)), 6.34 (s, 1 H, C(9)), 5.89 (s, 2 H, OCH₂O), 3.68 (dd, J = 9.0,

4.5 Hz, 1 H, HC(2)), 2.97 (ddd, J = 17.0, 5.5, 5.5 Hz, 1 H, HC(4)),

2.86 (ddd, J = 16.0, 8.0, 8.0 Hz, 1 H, HC(4)), 2.13−2.07 (m, 2 H,

HC(3)), 1.84 (s, 3 H, HC(11)); ¹³C NMR (125 MHz, CDCl₃) δ 148.6

(C(12)), 146.1(C(7)), 146.0 (C(8)), 137.4 (C(5)), 136.2 (C(16),

132.2 (C(17)), 128.9 (C(14)), 128.7 (C(10)), 128.0 (C(13) and

C(18)), 126.8 (C(15), 126.3 (C(19)), 109.2 (C(9)), 107.9 (C(6)),

100.8 (OCH₂O), 60.2 (C(2)), 47.7 (C(1)), 29.3 (C(4)), 26.8 (C(3)),

25.7 (C(11)); IR (KBr) 3045 (w), 2968 (m), 2933 (m), 2885 (m),

1580 (w), 1500 (m), 1483 (s), 1438 (m), 1368 (m), 1330 (w), 1229

(s), 1115 (w), 1035 (s), 935 (m), 858 (m), 752 (m), 737 (m), 699 (s);

MS (EI⁺, 70 eV) 375.1 (16.9), 374.1 (55.4), 266.1 (23.0), 265.1

(100.0), 264.1 (16.3), 249.1 (12.5), 237.1 (14.0), 224.0 (10.7), 223.0

(70.1), 205.1 (12.0), 1919.1 (17.7), 189.0 (12.5), 187.0 (11.0), 178.0

(12.7), 173.0 (107), 165.0 (24.9), 135.0 (13.0), 129.0 (10.5), 120.9

(19.6), 118.9 (22.1), 115.0 (15.7), 110.0 (12.4), 109.0 (13.8), 105.0

(32.6), 101.0 (9.5); HRMS calcd for C₂₄H₂₂O₂S⁺374.1341, found

Preparation of ((5R,6R)-5-(2-Methylphenyl)-6-(phenylthio)-5,6,7,-

8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14i) and (E)-1-(3′,4′-

Methylenedioxyphenyl)-4-(2-methylphenyl)but-1-ene (28). Follow-

ing General Procedure 8, (E)-2i (266.3 mg, 1.00 mmol), 13 (256.0

mg, 1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 86 h. Puriﬁcation by ﬂash column

chromatography (SiO₂, 95 g, 40 mm Ø, hexane/Et₂O, 96:4) aﬀorded

trans-14i (323 mg, 86%) as a white solid. Recrystallization of trans-

14i from hot pentane provided 308 mg (82%) of analytically pure

trans-14i. Isomerized starting material 28 was isolated from earlier

unoptimized experiments. Data for trans-14i: mp 56−58 °C

(pentane); ¹H NMR (500 MHz, CDCl₃) δ 7.45−7.43 (m, 2 H,

HC(19) and HC(23)), 7.32−7.25 (m, 3 H, HC(20) and HC(21) and

HC(22)), 7.18 (d, J = 6.5 Hz, 1 H, HC(14)), 7.12 (d, J = 7.5 Hz,

1.5 H, HC(15)), 7.08 (dt, J = 7.5, 1.5 Hz, 1 H, HC(16)), 6.76 (d, J =

7.5 Hz, 1 H, HC(17)), 6.66 (s, 1 H, HC(6)), 6.28 (s, 1 H, C(9)), 5.90

(s, 2 H, OCH₂O), 4.36 (d, J = 4.5 Hz, 1 H, HC(1)), 3.58−3.55 (m,

1 H, HC(2)), 3.06 (ddd, J = 16.5, 11.5, 5.5 Hz, 1 H, HC(4)), 2.80

(ddd, J = 16.5, 5.5, 5.5 Hz, 1 H, HC(4)), 2.31 (s, 3 H, HC(13)), 2.18−

2.11 (m, 1 H, HC(3)), 1.87−1.80 (m, 1 H, HC(3)); ¹³C NMR

(125 MHz, CDCl₃) δ 146.4 (C(7)), 146.3 (C(8)), 143.6 (C(14)),

136.2 (C(18)), 135.1 (C(12)), 133.2 (C(19,23)), 130.5 (C(14)),

130.0 (C(5)), 129.6 (C(17)), 129.5 (C(10)), 129.0 (C(20, 22)),

127.4 (C(21)), 126.5 (C(15)), 126.0 (C(16)), 110.1 (C(9)), 108.2

(C(6)), 100.8 (OCH₂O), 50.4 (C(2)), 46.6 (C(1)), 26.5 (C(4)), 24.5

(C(3)), 19.6 (C(13)); IR (KBr) 3059 (m), 3015 (m), 2924 (s), 2770

(w), 1583 (m), 1504 (s), 1485 (s), 1454 (s), 1385 (s), 1348 (m), 1305

(w), 1283 (w), 1236 (s), 1176 (m), 1088 (w), 1038 (s), 941 (s), 907

(m), 868 (m), 823 (m), 741 (s); MS (EI⁺, 70 eV) 374.1 (32.2), 325.2

(25.5), 265.1 (41.9), 264.1 (33.9), 239.1 (14.8), 223.1 (28.9), 220.2

(28.9), 206.2 (21.1), 205.2 (71.9), 192.1 (15.5), 191.1 (100.0), 175.1

(16.6), 165.1 (17.3), 149.0 (43.8), 145.1 (16.6), 135.1 (86.3), 131.1

(16.1), 129.1 (17.1), 128.1 (15.4), 121.1 (27.4), 115.1 (28.3), 111.1

(13.1), 109.1 (12.2), 107.1 (36.4), 105.1 (44.9); HRMS calcd for

C₂₄H₂₂O₂S⁺374.1341, found 374.1334; TLC R_f0.37 (hexanes/Et₂O,

25

374.1343; TLC R_f0.37 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D+72.9

(c = 0.48, EtOH); SFC (5R,6R)-14j, t_R15.5 min (71%); (5S,6S)-14j, t_R

21.5 min (29%) (Chiralpak OD, 5% MeOH in CO₂, 2.0 mL/min,

220 nm, 40 °C). Anal. Calcd for C₂₄H₂₂O₂S (374.13): C, 76.97; H,

25

96:4) [KMnO₄]; [α]_D−40.1 (c = 0.43, EtOH); SFC (5S,6S)-14i,

t_R10.2 min (8%); (5R,6R)-14i, t_R11.5 min (92%) (Chiralpak AD, 5%

MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for

C₂₄H₂₂O₂S (374.13): C, 76.97; H, 5.92%. Found: C, 77.26; H, 5.77%.

1

5.92%. Found: C, 76.91; H, 5.85%. Data for 27: H NMR (500 MHz,

CDCl₃) δ 7.27 (t, J = 7.5 Hz, 2 H, HC(14)), 7.17 (t, J = 7.5 Hz, 1 H,

HC(15)), 7.16 (d, J = 7.5 Hz, 2 H, HC(13)), 6.60 (s, 1 H, HC(6)),

6.46 (s, 1 H, C(9)), 5.89 (d, J = 10.0 Hz, 2 H, OCH₂O), 2.77 (t, J = 6.5

Hz, 2 H, HC(4)), 2.02 (ddd, J = 13.5, 8.5, 3.0 Hz, 1 H, HC(2)), 1.86

(ddd, J = 12.5, 9.0, 3.0 Hz, 1 H, HC(2)), 1.79−1.72 (m, 1 H, HC(3)),

1.70 (s, 3 H, HC(11)), 1.68−1.62 (m, 1 H, HC(3)); ¹³C NMR (125

MHz, CDCl₃) δ 151.6 (C(12)), 145.9 (C(7)), 145.7 (C(8)), 137.4

(C(5)), 130.4 (C(10)), 127.9 (C(14), 127.5 (C(13)), 125.6 (C(15)),

108.9 (C(9)), 108.3 (C(6)), 100.7 (OCH₂O), 43.1 (C(1)), 41.6

(C(2)), 30.6 (C(4)), 30.1 (C(3)), 15.8 (C(11)); IR (neat) 2926 (m),

1500 (m), 1479 (s), 1441 (w), 1372 (w), 1226 (s), 1163 (w), 1039

(m), 931 (w), 827 (w), 754 (w), 695 (w); MS (EI⁺, 70 eV) 267.1

(10.8), 266.1 (56.8), 252.0 (17.8), 251.1 (100.0), 189.0 (16.9), 115.1

1

Data for 28: H NMR (500 MHz, CDCl₃) δ 7.17−7.08 (m, 4 H,

HC(b) and HC(c) and HC(d) and HC(e)), 6.70 (d, J = 7.0 Hz, 1 H,

HC(5′)), 6.62 (s, 1 H, HC(2′)), 6.59 (d, J = 7.0 Hz, 1 H, C(6′)), 6.44

(d, J = 11.5 Hz, 1 H, HC(1)), 5.90 (s, 2 H, OCH₂O), 5.72 (dt, J =

11.5, 7.0 Hz, 1 H, HC(2)), 2.63 (t, J = 8.0 Hz, 2 H, HC(4)), 2.48 (dt,

J = 7.0, 7.0 Hz, 2 H, HC(3)), 2.21 (s, 3 H, HC(g)); ¹³C NMR (125

MHz, CDCl₃) δ 147.6 (C(3′)), 145.7 (C(4′)), 136.7 (C(a)), 136.4

(C(f)), 135.7 (C(1′)), 131.6 (C(2)), 129.9 (C(aryl), 129.1 (C(1)),

128.8 (C(aryl), 127.0 (C(aryl), 125.4 (C(b)), 121.3 (C(6′)), 109.1

(C(2′)), 108.2 (C(5′)), 100.9 (OCH₂O), 35.8 (C(3)), 30.5 (C(4)),

20.0 (C(g)); IR (KBr) 3017 (w), 2919 (m), 1601(w), 1500 (m), 1486

(s), 1441 (m), 1361 (w), 1243 (s), 1184 (w), 1094 (s), 1039 (w), 962

(w), 935 (m), 858 (w), 806 (w), 744 (m); MS (EI⁺, 70 eV) 266.1

(22.9), 149.0 (5.6), 136.0 (9.0), 135.0 (100.0), 131.1 (10.3), 120.9

(5.8), 118.9 (6.8), 115.0 (5.2); HRMS calcd for C₁₈H₁₈O₂⁺266.1307,

found 266.1315; TLC R_f0.60 (hexanes/Et₂O, 96:4) [KMnO₄].

+

(7.4), 91.1 (22.7), 86.0 (15.3), 84.0 (24.0); HRMS calcd for C₁₈H₁₈O₂

266.1307, found 266.1303; TLC R_f0.58 (hexanes/Et₂O, 96:4)

[KMnO₄].

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The Journal of Organic Chemistry

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129.0 (C(18)), 128.2 (C(10)), 126.8 (C(19)), 110.4 (C(9)), 108.8

(C(6)), 100.7 (OCH₂O), 49.6 (C(1)), 47.7 (C(11)), 46.9 (C(2)),

32.9 (C(15)), 30.9 (C(12)), 25.0 (C(13)), 24.9 (C(14)), 24.4 (C(4)),

22.6 (C(3)); IR (KBr) 2926 (m), 2864 (m), 1500 (s), 1479 (s), 1455

(m), 1434 (w), 1375 (w), 1347 (w), 1229 (s), 1181 (m), 1118 (w),

1035 (s), 935 (m), 851 (w); MS (EI⁺, 70 eV) 325.1 (10.1), 352.1

(36.8), 284.0 (6.7), 283.0 (43.2), 243.1 (7.9), 242.1 (8.4), 175.0

(20.5), 174.0 (100.0), 173.0 (63.3), 161.0 (16.0), 145.1 (6.7), 144.0

(10.0), 143.0 (8.6), 135.0 (8.3), 119.9 (5.6), 117.0 (9.5), 116.0 (16.0),

115.0 (35.3), 110.0 (12.9), 109.0 (9.4), 103.0 (5.0); HRMS calcd for

C₂₂H₂₄O₂S⁺352.1497, found 352.1491; TLC R_f0.52 (hexanes/Et₂O,

Preparation of ((5R,6R)-5-Cyclopropyl-6-(phenylthio)-5,6,7,8-

tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14k). Following Gen-

eral Procedure 8, (E)-2k (216.3 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 72 h. Puriﬁcation by ﬂash column

chromatography (SiO₂, 30 g, 25 mm Ø, hexane/Et₂O, 96:4) to aﬀord

trans-14k (292 mg, 90%) as colorless oil. Recrystallization from hot

pentane provided 285 mg (88%) of analytically pure trans-14k. Data

25

96:4) [KMnO₄]; [α]_D+11.8 (c = 0.19, EtOH); SFC (5S,6S)-14l, t_R

9.6 min (18%); (5R,6R)-14l, t_R11.3 min (82%) (Chiralpak OD, 5%

MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for

C₂₂H₂₄O₂S (352.49): C, 74.59; H, 6.86%. Found: C, 74.72; H, 6.50%.

1

for trans-14k: mp 25 °C (pentane); H NMR (500 MHz, CDCl₃)

δ 7.43 (dd, J = 7.5, 1.0, 2 H, HC(15)), 7.32 (t, J = 7.5 Hz, 2 H,

HC(16)), 7.25 (tt, J = 7.5, 1.0 Hz, 1 H, HC(17)), 6.68 (s, 1 H,

HC(6)), 6.61 (s, 1 H, C(9)), 5.92 (s, 2 H, OCH₂O), 3.85 (q, J =

2.0 Hz, 1 H, HC(2)), 3.04 (ddd, J = 17.5, 12.0, 6.0 Hz, 1 H HC(4)),

2.68 (ddd, J = 17.0, 6.0, 1.5 Hz, 1 H, HC(4)), 2.34−2.27 (m, 1 H,

HC(3)), 2.03 (d, J = 9.0 Hz, 1 H, HC(1)), 2.02−1.97 (m, 1 H,

HC(3)), 0.99−0.92 (m, 1 H, HC(11)), 0.65−0.60 (m, 1 H, HC(12)),

0.56−0.50 (m, 1 H, HC(13)), 0.48−0.44 (m, 1 H, HC(12)), 0.29−

0.22 (m, 1 H, HC(13)); ¹³C NMR (125 MHz, CDCl₃) δ 146.4

(C(7)), 145.7 (C(8)), 135.6 (C(14)), 131.7 (C(15)), 139.5 (C(5)),

129.0 (C(16)), 128.1 (C(10)), 126.8 (C(17)), 109.4 (C(9)), 108.7

(C(6)), 100.8 (OCH₂O), 48.3 (C(1,2)), 25.2 (C(4)), 23.2 (C(3)),

19.9 (C(11)), 6.2 (C(12)), 4.0 (C(13)); IR (neat) 3066 (s), 2996 (s),

2919 (s), 2766 (s), 1580 (s), 1503 (s), 1379 (s), 1344 (s), 1271 (s),

1229 (s), 1181 (s), 1125 (m), 1046 (s), 1021 (s), 983 (s), 938 (s),

737 (s); MS (EI⁺, 70 eV) 324.9 (12.2), 324.0 (54.6), 215.0 (30.2),

214.0 (36.0), 185.0 (13.3), 175.0 (12.7), 174.0 (100.0), 173.0 (39.3),

161.0 (13.1), 160.1 (9.6), 143.0 (9.2), 128.0 (11.1), 116.0 (11.7),

115.0 (33.2), 85.9 (28.5), 83.9 (44.0); HRMS calcd for C₂₀H₂₀O₂S⁺

324.1184, found 324.1181; TLC R_f0.29 (hexanes/Et₂O, 96:4)

Preparation of ((5R,6R)-5-Cyclohexyl-6-(phenylthio)-5,6,7,8-

tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14m). Following Gen-

eral Procedure 8, (E)-2m (258.4 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at 0 °C for 72 h. Puriﬁcation by ﬂash column chromato-

graphy (SiO₂, 40 g, 50 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14m

(264 mg, 72%) as a white solid along with unreacted (E)-2m (41 mg,

16%). Recrystallization from hot pentane provided 257 mg of analyti-

cally pure trans-14m. Data for trans-14m: mp 90−92 °C (pentane);

¹H NMR (500 MHz, CDCl₃) δ 7.43 (dd, J = 8.0, 1.5 Hz, 2 H,

HC(18)), 7.32 (t, J = 8.0 Hz, 2 H, HC(19)), 7.22 (dt, 1H, J = 7.0, 1.0

Hz, 1 H, HC(20)), 6.59 (s, 1 H, HC(6)), 6.55 (s, 1 H, C(9)), 5.92

(dd, J = 7.0, 1.5 Hz, 2 H, OCH₂O), 3.82 (dt, J = 7.0, 4.0 Hz, 1 H,

HC(2)), 2.91 (ddd, J = 17.0, 10.0, 7.0 Hz, 1 H, HC(4)), 2.70 (ddd,

1H, J = 17.0, 10.0, 4.0 Hz, 1 H, HC(4)), 2.59 (dd, J = 4.0, 2.0 Hz, 1 H,

HC(1)), 2.20−2.13 (m, 1 H, HC(3)), 1.89−1.84 (m, 1 H, HC(3)),

1.79−1.71 (m, 3 H, HC(14) and HC(15) and HC(16)), 1.67−1.63

(m, 1 H, HC(12)), 1.62−1.59 (m, 1 H, HC(13)), 1.59−1.43 (m, 1 H,

HC(11)), 1.22−1.12 (m, 3 H, HC(13), and HC(14) and HC(15)),

1.08−1.00 (m, 2H, HC(12) and HC(16)); ¹³C NMR (125 MHz,

CDCl₃) δ 146.1 (C(7)), 145.2 (C(8)), 136.0 (C(17)), 131.9 (C(18)),

130.1 (C(5)), 129.2 (C(10)), 129.0 (C(19)), 126.9 (C(20)), 110.6

(C(9)), 108.5 (C(6)), 100.7 (OCH₂O), 49.7 (C(1)), 45.5 (C(2)),

44.3 (C(11)), 32.2 (C(12)), 31.1 (C(16)), 27.0 (C(13)), 26.9

(C(15)), 26.6 (C(14)), 2.55 (C(4)), 24.3 (C(3)); IR (KBr) 2919 (s),

2843 (m), 1580 (w), 1500 (m), 1479 (s), 1444 (m), 1375 (w), 1347

(w), 1236 (s), 1036 (s), 935 (m), 865 (m), 737 (m), 688 (m); MS

(EI⁺, 70 eV) 366.1 (31.9), 284.1 (10.2), 283.1 (51.0), 191.1 (8.5),

175.1 (18.5), 174.1 (100.0), 173.0 (53.4), 161.0 (9.8), 144.0 (10.2),

135.0 (10.6), 116.0 (16.2), 115.0 (28.6); HRMS calcd for C₂₃H₂₆O₂S⁺

366.1654, found 366.1659; TLC R_f0.52 (hexanes/Et₂O, 96:4)

25

[KMnO₄]; [α]_D−23.9 (c = 0.53, EtOH); SFC (5S,6S)-14k, t_R9.6

min (5%); (5R,6R)-14k, t_R11.3 min (95%) (Chiralpak OD, 5%

MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C).

Preparation of ((5R,6R)-5-Cyclopentyl-6-(phenylthio)-5,6,7,8-

tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14l). Following Gen-

eral Procedure 8, (E)-2l (244.4 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at 0 °C for 72 h. Puriﬁcation by ﬂash column chromato-

graphy (SiO₂, 30 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14l

(183 mg, 52%) as a white solid along with unreacted (E)-2l (37 mg,

15%). Recrystallization from hot pentane provided 180 mg (50%)

of analytically pure trans-14l. Data for trans-14l: mp 102−104 °C

25

[KMnO₄]; [α]_D−1.29 (c = 0.21, EtOH); SFC (5S,6S)-14m, t_R

11.0 min (15%); (5R,6R)-14m, t_R12.8 min (85%) (Chiralpak OD, 5%

MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd for

C₂₂H₂₄O₂S (366.53): C, 75.37; H, 7.15%. Found: C, 75.40; H, 7.11%.

1

(pentane); H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 7.0 Hz, 2 H,

HC(17)), 7.29 (t, J = 7.0 Hz, 2 H, HC(18)), 7.22 (tt, J = 7.0,

1.5 Hz, 1 H, HC(19)), 6.58 (s, 1 H, HC(6)), 6.55 (s, 1 H, C(9)),

5.89 (dd, J = 4.5, 1.5 Hz, 2 H, OCH₂O), 3.82−3.80 (m, 1 H, HC(2)),

2.97 (ddd, J = 18.0, 11.0, 7.5 Hz, 1 H, HC(4)), 2.70 (ddd, J = 18.0, 7.0,

2.0 Hz, 1 H, HC(4)), 2.56 (d, J = 9.0 Hz, 1 H, HC(1)), 2.26−2.19 (m,

1 H, HC(3)), 1.91−1.76 (m, 3 H, HC(3) and HC(11) and HC(13)),

1.68−1.62 (m, 3 H, HC(13) and HC(14) and HC(15)), 1.58−1.51

(m, 1 H, HC(12)), 1.48−1.37 (m, 1 H, HC(14)), 1.31−1.17 (m, 3 H,

HC(12), and HC(15)); ¹³C NMR (125 MHz, CDCl₃) δ 146.2

(C(7)), 145.1 (C(8)), 136.0 (C(16)), 131.7 (C(17)), 131.1 (C(5)),

Z

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Preparation of ((5R,6R)-5-Pentyl-6-(phenylthio)-5,6,7,8-tetra-

hydronaphtho[2,3-d]-1,3-dioxole (trans-14n). Following General

Procedure 8, (E)-2n (246.3 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 72 h. Puriﬁcation by ﬂash column

chromatography (SiO₂, 32 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded

of trans-14n (266 mg, 76%) as colorless oil. Distillation provided

259 mg of analytically pure trans-14n. Data for trans-14n: bp 140 °C at

(13.0), 128.1 (13.1), 117.1 (13.1), 116.1 (23.1), 115.1 (58.9), 109.0

(13.0), 103.1 (14.6), 91.1 (10.9), 77.1 (12.8), 65.1 (11.0); HRMS

calcd for C₂₀H₂₁ClO₂S⁺360.0951, found 360.0941; TLC R_f0.21

(hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D²⁵+16.03 (c = 0.51, EtOH); SFC

(5S,6S)-14o, t_R12.1 min (6%); (5R,6R)-14o, t_R14.6 min (94%)

(Chiralpak OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal.

Calcd for C₂₀H₂₁ClO₂S (360.90): C, 66.56; H, 5.87%. Found: C, 66.61;

H, 5.90%.

1

5.5 × 10⁻⁵mmHg; H NMR (500 MHz, CDCl₃) δ 7.45 (dd, J = 7.5,

1.0 Hz, 2 H, HC(17)), 7.33 (t, J = 7.5 Hz, 2 H, HC(18)), 7.26 (tt, J =

7.0, 1.0 Hz, 1 H, HC(19)), 6.58 (s, 2 H, HC(6) and HC(9)), 5.91 (s,

2 H, OCH₂O), 3.673−3.65 (m, 1 H, HC(2)), 2.97 (ddd, J = 17.0,

10.5, 6.0 Hz, 1 H, HC(4)), 2.80 (dt, J = 8.0, 4.5 Hz, 1 H, HC(1)), 2.64

(ddd, J = 17.0, 6.0, 3.5 Hz, 1 H, HC(4)), 2.15 (dddd, J = 11.0, 6.5, 3.5

Hz, 1 H, HC(3)), 1.91−1.85 (m, 1 H, HC(3)), 1.72−1.59 (m, 2 H,

HC (11)), 1.41−1.22 (m, 6 H, HC(12) and HC(13) and HC(14)),

0.90 (t, J = 7.0 Hz, 3 H, HC(15)); ¹³C NMR (125 MHz, CDCl₃) δ

146.0 (C(7)), 145.8 (C(8)), 135.6 (C(16)), 132.0 (C(17)), 131.8

(C(5)), 129.0 (C(18)), 128.3 (C(10)), 126.9 (C(19)), 109.3 (C(6)),

108.6 (C(9)), 100.7 (OCH₂O), 46.6 (C(2)), 43.6 (C(1)), 38.1

(C(11)), 32.0 (C(13)), 27.1 (C(12)), 25.6 (C(4)), 23.4 (C(3)), 22.7

(C(14)), 14.2 (C(15)); IR (neat) 3052 (m), 2926 (s), 2857 (m), 2766

(m), 2666 (w), 2613 (w), 1621 (w), 1583 (s), 1503 (s), 1483 (s),

1469 (s), 1451 (s), 1441 (s), 1379 (s), 1233 (s), 1118 (s), 1087 (s),

1035 (s), 938 (s), 903 (s), 858 (m); MS (EI⁺, 70 eV) 299.1 (14.2),

298.1 (69.8), 190.1 (13.2), 189.1 (100.0), 188.1 (75.1), 174.0 (18.0),

173.0 (43.8), 162.1 (26.5), 159.1 (34.4), 131.1 (22.0), 116.1 (12.2),

115.0 (26.2), 103.1 (7.3), 91.1 (10.9), 85.0 (31.7), 83.0 (48.7), 65.1

(8.1); HRMS calcd for C₂₂H₂₆O₂S⁺354.1650, found 354.1654; TLC

Preparation of ((5R,6R)-5-(2-Methylpropyl)-6-(phenylthio)-

5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14p). Follow-

ing General Procedure 8, a 10 mL Schlenk ﬂask was charged with

(E)-2p (232.3 mg, 1.0 mmol), 13 (256.0 mg, 1.0 mmol), (S)-20a

(54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were reacted with a

solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol) at −20 °C

for 72 h. Puriﬁcation by ﬂash column chromatography (SiO₂, 32 g,

30 mm Ø, hexane/Et₂O, 96:4) aﬀorded trans-14p (269 mg, 79%) as

colorless oil. Distillation provided 262 mg (77%) of analytically pure

1

trans-14p. Data for trans-14p: bp >135 °C at 1.5 × 10⁻⁵mmHg; H

NMR (500 MHz, CDCl₃) δ 7.43 (dd, J = 8.0, 1.5, 2 H, HC(16)), 7.34

(t, J = 7.0 Hz, 2 H, HC(17)), 7.24 (tt, J = 7.0, 1.5 Hz, 1 H, HC(18)),

6.56 (s, 1 H, HC(6)), 6.51 (s, 1 H, C(9)), 5.88 (s, 2 H, OCH₂O),

3.64−3.62 (m, 1 H, HC(2)), 3.00 (ddd, J = 17.5, 9.5, 6.5 Hz, 1 H,

HC(4)), 2.84 (dd, J = 9.0, 4.5 Hz, 1 H, HC(1)), 2.61 (ddd, J = 17.0,

6.0, 1.5 Hz, 1 H, HC(4)), 2.14−2.07 (m, 1 H, HC(3)), 1.90−1.86 (m,

1 H, HC(3)), 1.71−1.63 (m, 1 H, HC(12)), 1.52 (ddd, J = 14.0, 9.5,

5.0 Hz, 1 H, HC(11)), 1.37 (ddd, J = 14.0, 9.0, 5.0 Hz, 1 H, HC(11)),

0.90 (d, J = 6.5 Hz, 3 H, HC(14)); ¹³C NMR (125 MHz, CDCl₃) δ

146.0 (C(7)), 145.9 (C(8)), 135.5 (C(15)), 132.3 (C(16)), 132.1

(C(5)), 129.0 (C(17)), 128.0 (C(10)), 127.1 (C(18)), 109.4 (C(9)),

108.7 (C(6)), 100.7 (OCH₂O), 48.4 (C(11)), 46.6 (C(2)), 41.2

(C(1)), 25.7 (C(12)), 24.9 (C(4)), 23.6 (C(14)), 22.3 (C(3)), 22.0

(C(13)); IR (neat) 2917 (s), 2850 (s), 1580 (w), 1503 (s), 1483 (s),

1451 (s), 1377 (s), 1240 (s), 1216 (s), 1181 (m), 1122 (w), 1043 (s),

945 (m), 858 (m), 692 (s); MS (EI⁺, 70 eV) 341.1 (20.6), 340.2

(83.8), 283.1 (19.1), 231.2 (63.9), 230.2 (48.2), 187.1 (12.3), 175.1

(44.3), 174.1 (100.0), 173.1 (75.0), 161.1 (50.0), 159.1 (12.6), 145.1

(15.4), 144.1 (13.8), 135.1 (13.0), 131.0 (19.2), 128.1 (10.2), 117.1

(13.5), 116.1 (23.8), 115.1 (49.3), 109.0 (13.7), 103.1 (14.4), 91.1

(12.9), 77.1 (11.6), 65.1 (10.5), 57.1 (11.2); HRMS calcd for

C₂₁H₂₄O₂S⁺340.1497, found 340.1493; TLC R_f0.47 (hexanes/

Et₂O, 96:4) [KMnO₄]; [α]_D²⁵+17.16 (c = 0.61, EtOH); SFC (5R,6S)-

14p, t_R6.4 min (96%); (5S,6S)-14p, t_R6.9 min (4%) (Chiralpak

OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal. Calcd

for C₂₁H₂₄O₂S (340.48): C, 74.08; H, 7.10%. Found: C, 74.33; H,

7.31%.

25

R_f0.52 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D+12.8 (c = 0.76,

EtOH); SFC (5S,6S)-14n, t_R9.2 min (4%); (5R,6R)-14n, t_R10.3 min

(96%) (Chiralpak OD, 4% MeOH in CO₂, 2.0 mL/min, 220 nm,

40 °C).

Preparation of ((5R,6R)-5-(3-Chloropropyl)-6-(phenylthio)-

5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-14o). Follow-

ing General Procedure 8, (E)-2o (253.7 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20 (54.9 mg, 0.1 mmol), and CH₂Cl₂

(4.25 mL) were reacted with a solution of EtSO₃H (1 M in

CH₂Cl₂, 0.75 mL, 0.75 mmol) at room temperature for 6 days.

Puriﬁcation by ﬂash column chromatography (SiO₂, 32 g, 30 mm Ø,

hexane/Et₂O, 96:4) aﬀorded trans-14o (235 mg, 65%) as colorless oil.

Distillation provided 227 mg of analytically pure trans-14o. Data for

1

trans-14o: bp 135 °C at 3.2 × 10⁻⁵mmHg; H NMR (500 MHz,

CDCl₃) δ 7.45 (t, J = 7.5 Hz, 2 H, HC(15)), 7.34 (t, J = 7.5 Hz, 2 H,

HC(16)), 7.28 (t, J = 7.0 Hz, 1 H, HC(17)), 6.58 (s, 2 H, HC(6) and

C(9)), 5.92 (d, J = 2.5 Hz, 2 H, OCH₂O), 3.59−3.56 (m, 1 H,

HC(2)), 3.55−3.45 (m, 2 H, HC(13)), 2.95 (ddd, J = 16.5, 10.5,

5.0 Hz, 1 H, HC(4)), 2.85−2.82 (m, 1 H, HC (1)), 2.65 (ddd, J =

10.5, 5.5, 5.5 Hz, 1 H, HC(4)), 2.16 (dddd, J = 13.5, 10.0, 5.5, 3.0 Hz,

1 H, HC(3)), 1.92−1.76 (m, 5 H, HC(3) and HC(11) and HC(12));

¹³C NMR (125 MHz, CDCl₃) δ 146.2 (C(7)), 146.0 (C(8)), 135.1

(C(14)), 132.6 (C(16)), 130.8 (C(5)), 129.1 (C(15)), 128.6 (C(10)),

127.2 (C(17)), 109.1 (C(9)), 108.7 (C(6)), 100.8 (OCH₂O), 46.9

(C(2)), 45.0 (C(13)), 42.9 (C(1)), 34.8 (C(11)), 30.2 (C(12)), 25.9

(C(4)), 24.0 (C(3)); IR (neat) 3044 (m), 2911 (s), 2761 (m), 1581 (s),

1501 (s), 1484 (s), 1466 (s), 1431 (s), 1378 (s), 1290 (s), 1237 (s),

1030 (s), 933 (s), 902 (s), 858 (s), 823 (s); MS (EI⁺, 70 eV) 360.1

(63.8), 283.2 (13.6), 253.1 (30.6), 252.1 (28.7), 251.1 (92.5), 250.1

(47.2), 188.1 (19.0), 187.2 (13.8), 175.1 (18.4), 174.1 (89.9), 173.1

(100.0), 161.1 (24.9), 145.1 (17.7), 144.1 (14.8), 131.0 (18.2), 129.1

Preparation of (1R,2R)-6-Methoxy-1-pentyl-2-(phenylthio)-

1,2,3,4-tetrahydronaphthalene (29) and (1R,2R)-8-Methoxy-1-pen-

tyl-2-(phenylthio)-1,2,3,4-tetrahydronaphthalene (30). Following

General Procedure 8, (E)-11n (232.3 mg, 1.0 mmol), 13 (256.0 mg,

AA

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were

reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 72 h. Puriﬁcation by ﬂash column chromato-

graphy (SiO₂, 32 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded 29

(210 mg, 62%) as colorless oil along with 30 (73 mg, 21%) as a white

solid. Distillation provided 204 mg (60%) of analytically pure 29.

Recrystallization of 30 from hot pentane provided 68 mg (20%) of

analytically pure 30. Data for 29: bp 140 °C at 1.5 × 10⁻⁵mmHg; ¹H

NMR (500 MHz, CDCl₃) δ 7.46 (dd, J = 7.5, 1.5 Hz, 2 H, HC(17)),

7.33 (tt, J = 7.5, 1.5 Hz, 2 H, HC(18)), 7.27 (tt, J = 7.0, 1.0 Hz, 1 H,

HC(19)), 7.04 (d, J = 8.5 Hz, 1 H, HC(9)), 6.76 (dd, J = 8.5, 2.5 Hz,

1 H, HC(8)), 6.66 (d, J = 2.5 Hz, 1 H, HC(6)), 3.81 (s, 3 H, OCH₃),

3.71−3.69 (m, 1 H, HC(2)), 3.06 (ddd, J = 17.0, 11.0, 5.5 Hz, 1 H,

HC(4)), 2.89−2.86 (m, 1 H, HC(1)), 2.72 (ddd, J = 17.5, 6.0, 4.0 Hz,

1H, HC(4)), 2.19 (dddd, J = 14.0, 9.0, 6.0, 3.0 Hz, 1 H, HC(3)), 1.94−

1.88 (m, 1 H, HC(3)), 1.74−1.62 (m, 2 H, HC(11)), 1.42−1.24 (m,

6 H, H(12) and HC(13), and HC(14)), 0.90 (t, J = 7.0 Hz, 3 H,

HC(15)); ¹³C NMR (125 MHz, CDCl₃) δ 157.7 (C(7)), 136.5

(C(5)), 135.6 (C(16)), 132.0 (C(17)), 131.1 (C(10)), 130.7 (C(9)),

129.0 (C(18)), 126.9 (C(19)), 113.2 (C(6)), 112.4 (C(8)), 55.2

(OCH₃), 46.8 (C(2)), 42.7 (C(1)), 38.0 (C(11)), 32.00 (C(13)), 27.0

(C(12)), 25.8 (C(4)), 23.4 (C(3)), 22.7 (C(14)), 14.2 (C(15)); IR

(neat) 3052 (s), 2919 (s), 2843 (s), 1608 (s), 1580 (s), 1500 (s), 1455

(s), 1434 (s), 1375 (m), 1320 (m), 1254 (s), 1233 (s), 1157 (m), 1125

(s), 1087 (m), 1039 (s), 896 (m), 844 (m), 813 (m), 740 (s); MS (EI⁺,

70 eV) 340.1 (20.5), 269.2 (23.0), 231.1 (100.0), 191.2 (47.8), 161.1

(24.5), 160.1 (36.1), 159.1 (30.2), 147.1 (31.4), 135.1 (48.5), 121.1

(24.7), 115.1 (19.2), 107.1 (26.8), 91.1 (25.00), 77.1 (19.5), 57.1

(37.7), 55.1 (22.8); HRMS calcd for C₂₂H₂₈OS⁺340.1861, found

340.1856; TLC R_f0.38 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D²⁵+14.5

(c = 0.54, EtOH); SFC (1R,2R)-29, t_R8.8 min (96%); (1S,2S)-29, t_R

13.7 min (4%) (Chiralpak OJ, 5% MeOH in CO₂, 2.0 mL/min, 220

nm, 40 °C). Anal. Calcd for C₂₂H₂₈OS (340.19): C, 77.60; H, 8.29%.

Found: C, 77.89; H, 8.42%. Data for 30: mp 72−74 °C (pentane); ¹H

NMR (500 MHz, CDCl₃) δ 7.45 (dd, J = 7.5 Hz, 2 H, HC(17)), 7.32

(t, J = 7.5 Hz, 2 H, HC(18), 7.25 (t, J = 7.0, 1.0 Hz, 1 H, HC(19)),

7.13 (t, J = 8.0 Hz, 1 H, HC(7)), 6.74 (d, J = 8.5, 1 H, HC(6)), 6.71 (d,

J = 8.5 Hz, 1 H, HC(8)), 3.82 (s, 3 H, OCH₃), 3.79 (s, 1 H, HC(2)),

3.22 (d, J = 6.0 Hz, 1 H, HC(1)), 3.10 (ddd, J = 17.5, 11.5, 6.0 Hz, 1 H,

HC(4)), 2.72 (dd, J = 17.5, 4.5 Hz, 1 H, HC(4)), 2.20−2.13 (m, 1 H,

HC(3)), 1.90−1.87 (m, 1 H, HC(3)), 1.79−1.68 (m, 1 H, HC(11)),

1.50−1.23 (m, 7 H, HC(11) and (HC(12) and HC(13), and HC(14)),

0.91 (t, J = 7.0 Hz, 3 H, HC(15)); ¹³C NMR (125 MHz, CDCl₃) δ

157.6 (C(9)), 136.4 (C(16)), 136.1 (C(5)), 131.8 (C(17)), 128.9

(C(18)), 128.1 (C(10)), 126.70 (C(19)), 126.4 (C(7)), 121.66

(C(6)), 107.7 (C(8)), 55.3 (OCH₃), 45.6 (C(2)), 37.6 (C(1)), 35.6

(C(11)), 31.7 (C(13)), 27.6 (C(12)), 24.9 (C(4)), 22.7 (C(14)), 22.0

(C(3)), 14.2 (C(15)); IR (KBr) 2940 (m), 2912 (s), 2843 (m), 1580

(s), 1465 (s), 1451 (s), 1438 (m), 1337 (m), 1250 (s), 1084 (s), 1066

(s), 765 (m), 737 (m); MS (EI⁺, 70 eV) 341.1 (12.6), 340.2 (47.4),

269.1 (34.7), 231.2 (42.7), 230.2 (11.9), 174.1 (13.9), 161.1 (50.4),

160.1 (31.8), 159.1 (69.0), 148.0 (12.1), 147.1 (100.0), 145.1 (13.3),

144.0 (17.2), 135.1 (11.6), 129.1 (14.2), 128.1 (14.9), 127.0 (10.3),

121.1 (10.3), 115.1 (24.0), 109.0 (10.8), 91.1 (14.7), 85.9 (52.3), 84.0

(79.4), 58.1 (9.6); HRMS calcd for C₂₂H₂₈OS⁺340.1861, found

340.1865; TLC R_f0.54 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D²⁵+13.6

(c = 0.61, EtOH); SFC (1R,2R)-30, t_R5.8 min (91%); (1S,2S)-30, t_R

8.9 min (9%) (Chiralpak OJ, 5% MeOH in CO₂, 2.0 mL/min, 220 nm,

40 °C). Anal. Calcd for C₂₂H₂₈OS (340.19): C, 77.60; H, 8.29%.

Found: C, 77.43; H, 8.22%.

Preparation of (1R,2R)-6-Methoxy-1-phenyl-2-(phenylthio)-1,2,-

3,4-tetrahydronaphthalene (31) and (1R,2R)-8-Methoxy-1-phenyl-

2-(phenylthio)-1,2,3,4-tetrahydronaphthalene (32). Following

General Procedure 8, (E)-11b (238.3 mg, 1.0 mmol), 13 (256.0 mg,

1.0 mmol), (S)-20a (54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL)

were reacted with a solution of EtSO₃H (1 M in CH₂Cl₂, 0.75 mL,

0.75 mmol) at −20 °C for 72 h. Puriﬁcation by ﬂash column

chromatography (SiO₂, 32 g, 30 mm Ø, hexane/Et₂O, 96:4) aﬀorded

31 (160 mg, 46%) as colorless oil along with 32 (161 mg, 46%) as a

white solid. Distillation provided 156 mg (45%) of analytically pure

31. Recrystallization of 32 from hot pentane provided 156 mg (45%)

of analytically pure 32. Data for 31: bp 135 °C at 1.6 × 10⁻⁵mmHg;

¹H NMR (500 MHz, CDCl₃) δ 7.49 (dd, J = 8.5, 1.5 Hz, 2 H,

HC(16)), 7.35 (t, J = 9.0 Hz, 2 H HC(17), 7.30−7.22 (m, 4 H, HC(7)

and HC(13) and HC(18)), 7.18 (tt, J = 7.0, 1.0 Hz, 1 H, HC(14)),

6.99 (d, J = 7.0 Hz, 2 H, HC(12)), 6.88 (d, J = 7.5 Hz, 1 H, HC(6)),

6.70 (d, J = 8.0 Hz, 1 H, HC(8)), 4.55 (s, 1 H, HC(1)), 3.81−3.79 (m,

1 H, HC(2)), 3.57 (s, 3 H, OCH₃), 3.19 (ddd, J = 17.5, 12.5, 6.0 Hz,

1 H, HC(4)), 2.85 (ddd, J = 17.0, 5.5, 2.0 Hz, 1H, HC(4)), 2.11−2.03

(m, 1 H, HC(3)), 1.83−1.77 (m, 1 H, HC(3)); ¹³C NMR (125 MHz,

CDCl₃) δ 158.1 (C(9)), 146.0 (C(11), 137.7 (C(10)), 135.8 (C(15)),

132.1 (C(16)), 129.2 (C(12), 128.3 (C(17)), 128.2 (C(13)), 127.4

(C(7)), 127.1 (C(18)), 126.2 (C(14)), 125.7 (C(5)), 121.3 (C(6)),

108.3 (C(7)), 55.7 (OCH₃), 50.8 (C(2)), 44.0 (C(1)), 25.1 (C(4)),

21.6 (C(3)); IR (neat) 3052 (w), 3017 (w), 2926 (m), 2829 (w),

1583 (s), 1465 (s), 1434 (m), 1337 (w), 1254 (s), 1222 (w), 1091 (s),

1066 (m), 1021 (w), 955 (w), 817 (w), 768 (m), 737 (s), 699 (s); MS

(EI⁺, 70 eV) 346.0 (12.4), 346.0 (43.1), 238.0 (18.9), 237.1 (98.4),

236.0 (29.3), 179.0 (12.1), 178.0 (13.6), 165.0 (13.7), 159.0 (27.4),

145.0 (21.7), 144.0 (11.0); 129.0 (11.8), 121 (16.5), 115.0 (19.4),

109.0 (10.8), 91.0 (100.0), 65.1 (10.3); HRMS calcd for C₂₃H₂₂OS⁺

346.1391, found 346.1384; TLC R_f0.38 (hexanes/Et₂O, 96:4)

25

[KMnO₄]; [α]_D−84.3 (c = 0.55, EtOH); SFC (1R,2R)-31, t_R12.3

min (90%); (1S,2S)-31, t_R13.8 min (10%) (Chiralpak OD, 5% MeOH

in CO₂, 2.0 mL/min, 220 nm, 40 °C). Data for 32: mp 77−79 °C

1

(pentane); H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 7.5 Hz, 2 H,

HC(16)), 7.32−7.19 (m, 6 H, HC(13) and HC(14) and HC(17) and

HC(18)), 7.03 (d, J = 7.5 Hz, 1 H, HC(12)), 6.76 (d, J = 8.5 Hz, 1 H,

HC(9)), 6.71 (d, J = 2.5 Hz, 1 H, HC(6)), 6.66 (dd, J = 8.5, 2.5 Hz,

1 H, HC(8)), 4.16 (d, J = 5.5 Hz, 1 H, HC(1)), 3.77 (s, 3 H, OCH₃),

3.67 (ddd, J = 8.5, 5.5, 3.0 Hz, 1 H, HC(2)), 3.05 (ddd, J = 16.5, 8.5,

5.5 Hz, 1 H, HC(4)), 2.86 (ddd, J = 17.0, 6.0, 6.0 Hz, 1 H, HC(4)),

2.21−2.15 (m, 1 H, HC(3)), 1.89−1.83 (m, 1 H, HC(3)); ¹³C NMR

(125 MHz, CDCl₃) δ 158.2 (C(7)), 145.9 (C(11), 137.5 (C(10)),

135.2 (C(15)), 132.5 (C(16)), 132.1 (C(9), 129.2 (C(5,12)), 129.1

(C(17)), 128.5 (C(13)), 127.2 (C(18)), 125.7 (C(14)), 113.1 (C(6)),

113.0 (C(8)), 55.4 (OCH₃), 51.8 (C(2)), 49.9 (C(1)), 27.3 (C(4)),

25.3 (C(3)); IR (KBr) 3052 (m), 3017 (m), 2926 (s), 2829 (m), 1608

(s), 1583 (s), 1503 (s), 1451 (s), 1434 (s), 1323 (s), 1250 (s), 1236

(s), 1219 (s), 1153 (s), 1122 (s), 1108 (m), 1087 (m), 1035 (s),

928 (m), 893 (m), 858 (m), 820 (m), 792 (s), 696 (s); MS (EI⁺,

70 eV) 246.3 (15.0), 243.5 (14.5), 237.2 (26.8), 231.12 (100.0),

191.2 (86.0), 175.2 (17.7), 159.1 (17.2), 149.1 (42.0), 145.1 (14.8),

135.1(99.9), 129.1 (13.3), 121.0 (43.0), 115.1 (19.3), 111.1 (12.4),

107.1 (53.5), 105.1 (22.2), 95.1 (20.9), 91.1 (37.8), 81.1 (16.2), 77.1

(23.8), 69.1 (20.8), 67.1 (14.7), 65.1 (11.7), 57.1 (65.4), 55.1 (38.4);

HRMS calcd for C₂₃H₂₂OS⁺346.1391, found 346.1383; TLC R_f

AB

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

0.32 (hexanes/Et₂O, 96:4) [KMnO₄]; [α]_D²⁵−55.0 (c = 0.48, EtOH);

SFC (1R,2R)-32, t_R13.6 min (94%); (1S,2S)-32, t_R16.1 min (6%)

(Chiralpak OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm,

40 °C). Anal. Calcd for C₂₃H₂₂OS (346.14): C, 79.73; H, 6.40%.

Found: C, 80.01; H, 6.03%.

98%) as white solid. Recrystallization from pentane/CH₂Cl₂(60:10)

(v/v) (14 mL) provided 130 mg (94%) of analytically pure trans-34.

Data for trans-34: mp 138−140 °C (pentane/CH₂Cl₂); ¹H NMR (500

MHz, CDCl₃) δ 7.82 (d, J = 7.5 Hz, 2 H, HC(17)), 7.62 (t, J = 7.5 Hz,

1 H, HC(19)), 7.49 (t, J = 8.0, 2 H, HC(18)), 6.98 (d, J = 8.0 Hz, 2 H,

HC(13)), 6.77 (d, J = 8.0 Hz, 2 H, HC(12)), 6.58 (s, 1 H, HC(6)),

6.31 (s, 1 H, HC(9)), 5.87 (d, J = 2.5 Hz, 2 H, OCH₂O), 4.54 (d, J =

4.5 Hz, 1 H, HC(1)), 3.57−3.54 (m, 1 H, HC(2)), 3.03 (ddd, J = 16.0,

8.0, 5.5, 1 H, HC(4)), 2.81 (ddd, J = 17.0, 6.0, 6.0 Hz, 1 H, HC(4)),

2.28 (s, 3 H, HC(14)), 2.29−2.23 (m, 1 H, HC(3)), 2.19−2.12 (m,

1 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 146.4 (C(7,8)),

141.6 (C(11)), 138.7 (C(16)), 136.5 (C(14)), 133.5 (C(19)), 129.4

(C(13)), 129.1 (C(10,18)), 128.9 (C(5)), 128.7 (C(17)), 128.5

(C(12)), 109.8 (C(9)), 108.0 (C(6)), 100.9 (OCH₂O), 67.1 (C(2)),

43.6 (C(1)), 26.7 (C(4)), 21.1 (C(15)), 20.5 (C(3)); IR (KBr) 3445

(bm), 2968 (m), 2912 (m), 2878 (m), 1698 (s), 1573 (w), 1503 (m),

1483 (s), 1444 (m), 1302 (s), 1261 (s), 1240 (s), 1143 (s), 1084 (m),

1035 (m), 938 (w), 848 (w), 810 (w), 747 (s). MS (EI⁺, 70 eV) 325.5

(21.7), 265.1 (21.1), 264.1 (1000), 231.1 (37.6), 191.1 (60.5), 158.0

(21.0), 156.0 (63.3), 141.0 (21.6), 139.0 (64.1), 135.1 (37.3), 115.0

(19.7), 11.0 (35.6), 107.0 (24.4), 105.1 (30.6); HRMS calcd

C₂₄H₂₃O₄S⁺407.1317, found 407.1316; TLC R_f0.37 (hexanes/

Preparation of (1R,2R)-7-Methoxy-1-phenyl-2-(phenylthio)-1,2,-

3,4-tetrahydronaphthalene (33). Following General Procedure 8,

(E)-12b (238.3 mg, 1.0 mmol), 13 (256.0 mg, 1.0 mmol), (S)-20a

(54.9 mg, 0.1 mmol), and CH₂Cl₂(4.25 mL) were reacted with a

solution of EtSO₃H in CH₂Cl₂(1 M in CH₂Cl₂, 0.75 mL, 0.75 mmol)

at 0 °C for 36 h. Puriﬁcation by ﬂash column chromatography (SiO₂,

26 g, 30 mm Ø, hexane/Et₂O, 96:4) to aﬀorded 33 (298 mg, 86%)

as a white solid. Recrystallization from hot pentane provided 294 mg

(85%) of analytically pure 33. Data for 33: mp 92−94 °C (pentane);

¹H NMR (500 MHz, CDCl₃) δ 7.43 (dd, J = 8.0, 2.0 Hz, 2 H,

HC(16)), 7.34−7.21 (m, 6 H, HC(13) and HC(14) and HC(17) and

HC(18)), 7.11 (d, J = 8.5 Hz, 1 H, HC(6)), 7.05 (d, J = 6.5 Hz, 2 H,

HC(12)), 6.78 (dt, J = 8.5, 2.5 Hz, 1 H, HC(7)), 6.39 (d, J = 2.0 Hz,

1 H, HC(9)), 4.18 (d, J = 5.0 Hz, 1 H, HC(1)), 3.68 (s, 3 H, OCH₃),

3.70−3.66 (m, 1 H, HC(2)), 3.06−3.00 (m, 1 H, HC(4)), 2.84 (ddd,

J = 17.0, 6.0, 6.0 Hz, 1 H, HC(4)), 2.23−2.16 (m, 1 H, HC(3)), 1.90−

1.86 (m, 1 H, HC(3)); ¹³C NMR (125 MHz, CDCl₃) δ 158.0 (C(8)),

145.5 (C(11), 138.0 (C(15)), 135.2 (C(5)), 132.5 (C(16)), 129.9

(C(6), 129.2 (C(17), 129.1 C(12)), 128.6 (C(10)), 128.5 (C(13)),

127.2 (C(18)), 126.7 (C(14)), 115.5 (C(9)), 113.2 (C(7)), 55.4

(OCH₃), 51.6 (C(2)), 50.8 (C(1)), 26.1 (C(4)), 25.4 (C(3)); IR

(KBr) 3045(w), 3017 (w), 2926 (m), 2829 (w), 1608 (m), 1580 (m),

1500 (s), 1451 (m), 1434 (m), 1268 (s), 1250 (s), 1157 (s), 1111 (w),

1035 (m), 876 (w), 813 (m), 740 (s), 696 (s); MS (EI⁺, 70 eV) 347.0

(14.2), 346.0 (55.5), 238.1 (13.1), 237.1 (78.2), 236.1 (93.2), 235.0

(10.6), 210.0 (11.1), 209.0 (18.1), 179.0 (16.7), 178.0 (15.7), 165.0

(15.3), 159.0 (24.9), 145.0 (28.8), 129.0 (10.2), 121.0 (16.7), 115.0

(15.4), 109.0 (9.3), 91.0 (100.0), 77.0 (9.0), 65.1 (9.7); HRMS calcd

for C₂₃H₂₂OS⁺346.1391, found 346.1386; TLC R_f0.33 (hexanes/

Et₂O, 96:4) [KMnO₄]; [α]_D²⁵−29.3 (c = 0.53, EtOH); SFC (1R,2R)-

33, t_R12.0 min (84%); (1S,2S)-33, t_R15.7 min (16%) (Chiralpak

OD, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal.

Calcd for C₂₃H₂₂OS (346.14): C, 79.73; H, 6.40%. Found: C, 79.66;

H, 6.28%.

25

Et₂O, 50:50) [KMnO₄]; [α]_D−30.3 (c = 0.52, EtOH); SFC

(1R,2R)-34, t_R14.0 min (92%); (1S,2S)-34, t_R17.7 min (8%)

(Chiralpak OJ, 5% MeOH in CO₂, 2.0 mL/min, 220 nm, 40 °C). Anal.

Calcd for C₂₄H₂₂O₄S (406.12): C, 70.91; H, 5.46%. Found: C, 70.85;

H, 5.38%.

ASSOCIATED CONTENT

* Supporting Information

■

S

Optimization experiments, X-ray coordinates for (S)-17a and

trans-34, and copies of ¹H and ¹³C NMR spectra. This material

is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: sdenmark@illinois.edu. Tel: (217) 333-0066. Fax:

(217) 333-3984.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Mr. W.-T. Timothy Chang and Mr. Larry M. Wolf are thanked

for providing helpful preparative and computational advice. Mr.

David J.-P. Kornﬁlt is thanked for providing the X-ray crystal

structure of (S)-17a, and Mr. Hyung-Min Chi is thanked for

additional technical assistance. We are grateful to the National

Institutes of Health for generous ﬁnancial support (R01

GM85235).

REFERENCES

■

(1) de la Mare, P. B. D.; Bolton, R. In Electrophilic Additions to

Unsaturated Systems, 2nd ed.; de la Mare, P. B. D., Bolton, R., Eds.;

Elsevier: Amsterdam, 1982; Vol. 9, pp 198−246.

(2) (a) Schmid, G. H. Supplement A: The Chemistry of Double-Bonded

Functional Groups, Part 1; John Wiley & Sons: London, 1989; Vol. 2,

pp 679−731. (b) Schmid, G. H.; Garratt, D. G. The Chemistry of

Double-Bonded Functional Groups, Part 2; John Wiley & Sons: London,

1977; pp 725−912. (c) Lucchini, V.; Modena, G.; Pasquato, L. Gazz.

Chim. Ital. 1997, 127, 177−188. (d) Rayner, C. M. In Organosulfur

Chemistry: Synthetic Aspects, Page, P., Ed.; Academic Press: London,

1995; pp 89−131. (e) Modena, G.; Pasquato, L.; Lucchini, V.

Phosphorus, Sulfur Silicon Relat. Elem 1994, 95−96, 265−282.

(f) Capozzi, G.; Modena, G.; Pasquato, L. In The Chemistry of

Sulphenic Acids and Their Derivatives; Patai, S., Ed.; John Wiley & Sons

Ltd.: West Sussex, UK, 1990; pp 403−516. (g) Harring, S. R.;

Preparation of ((5R,6R)-5-(4-Methylphenyl)-6-(phenylsulfonyl)-

5,6,7,8-tetrahydronaphtho[2,3-d]-1,3-dioxole (trans-34). To a sol-

ution of trans-14d (128.0 mg, 0.34 mmol) in CH₂Cl₂(6 mL) was

added m-CPBA (177 mg, 1.02 mmol) at room temperature After

being stirred for 2 h, the contents of the ﬂask were poured in H₂O

(30 mL). The aqueous phase was extracted with CH₂Cl₂(3 × 10 mL).

The combined organic layers were successively washed with saturated

aq Na₂SO₃(10 mL), brine (40 mL), then dried over MgSO₄and

ﬁltered through glass wool, and then concentrated in vacuo (20−

23 °C, 10 mmHg). Puriﬁcation by ﬂash column chromatography

(SiO₂, 15 g, 25 mm Ø, hexane/Et₂O, 1:1) aﬀorded trans-34 (135 mg,

AC

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Edstrom, E. D.; Livinghouse, T. Adv. Heterocycl. Nat. Prod. Synth. 1992,

2, 299−376. (h) Capozzi, G.; Modena, G. In Organic Sulfur Chemistry:

Theoretical and Experimental Advances, Bernardi, F., Csizmadia, I. G.,

Mangini, A., Eds.; Elsevier: Amsterdam, 1985; Vol. 19, pp 246−298.

(i) Mueller, W. H. Angew. Chem., Int. Ed. Engl. 1969, 8, 482−492.

(3) (a) Drabowicz, J.; Lyzwa, P.; Mikolajczyk, M. In The Chemistry of

Sulphenic Acids and Their Derivatives; Patai, S., Ed.; John Wiley & Sons

Ltd.: West Sussex, UK, 1990; pp 187−220. (b) Drabowicz, J.;

Kielbasinski, P.; Mikolajczyk, M. In The Chemistry of Sulphenic Acids

and Their Derivatives; Patai, S., Ed. John Wiley & Sons Ltd.: West

Sussex, UK, 1990; pp 221−292.

(19) For a preliminary communication of these studies, see:

Denmark, S. E.; Jaunet, A. J. Am. Chem. Soc. 2013, 135, 6419−6422.

(20) The methylenedioxy substituent is less donating than a single 4-

methoxy group and roughly equivalent to 3,4-dimethoxy substituents.

(a) McDaniel, D. H.; Brown, H. C. J. Org. Chem. 1968, 23, 420−427.

(b) Hammett, L. P. Physical Organic Chemistry; McGraw-Hill: New

York, 1940; p 188.

(21) (a) Schlosser, M.; Christmann, K. F. Liebigs Ann Chim. 1967,

708, 1−35. (b) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed.

Engl. 1966, 5, 126.

(22) Schobert, R.; Siegfried, S.; Gordon, G. J. J. Chem. Soc., Perkin

Trans. 1 2001, 2393−2397.

(23) The E/Z ratio varied from 96/4 to 64/36. The SFC anaylsis of

the cyclized products was also complicated by overlap of the trans and

cis diastereomers. The yields obtained for i-Bu and phenyl were 38%

(>99:1 E/Z) and 42% (>99:1), respectively.

(4) Hogg, D. R. In The Chemistry of Sulphenic Acids and Their

Derivatives; Patai, S., Ed.; John Wiley & Sons Ltd.: West Sussex, UK,

1990; pp 361−402.

(5) Fox, D. J.; House, D.; Warren, S. Angew. Chem., Int. Ed. 2002, 41,

2462−2482.

(6) Coldham, I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1993, 1637.

(7) (a) Moore, J. T.; Soldi, C.; Fettinger, J. C.; Shaw, J. T. Chem. Sci.

2013, 292−296. (b) Edstrom, E. D.; Livinghouse, T. J. Org. Chem.

1987, 52, 949−951. (c) Masaki, Y.; Hashimoto, K.; Sakuma, K.; Kaji,

K. Tetrahedron Lett. 1982, 1481−1484.

(24) (a) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,

2307−2325. (b) Buss, A. D.; Cruse, W. B.; Kennard, O.; Warren, S. J.

Chem. Soc., Perkin Trans. 1 1984, 243−247.

(25) Brown, T. H.; Blakemore, R. C.; Durant, G. J.; Emmet, J. C.;

Ganellin, C. R.; Parsons, M. E.; Rawlings, D. A.; Walker, T. F. Eur. J.

Med. Chem. 1988, 23, 53−62.

(8) Edstrom, E. D.; Livinghouse, T. J. Am. Chem. Soc. 1986, 108,

1334−1336.

(26) (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Sambri,

L. Chem.Eur. J. 1997, 3, 1941−1950. (b) Bartoli, G.; Bosco, M.;

Sambri, L.; Marcantoni, E. Tetrahedron Lett. 1996, 37, 7421−7424.

(27) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,

11014−11015.

(9) (a) Toshimitsu, A.; Hirosawa, C.; Tamao, K. Synlett 1996, 465−

467. (b) Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tamao, K. J. Chem.

Soc., Perkin Trans. 1 1994, 3465−3471. (c) Toshimitsu, A.; Hirosawa,

C.; Tamao, K. Tetrahedron 1994, 50, 8997−9008. (d) Toshimitsu, A.;

Hirosawa, C.; Tanimoto, S. Chem. Lett. 1992, 239−242. (e) Toshi-

mitsu, A.; Abe, H.; Hirosawa, C.; Tanimoto, S. J. Chem. Soc., Chem.

Commun. 1992, 284−285. (f) Toshimitsu, A.; Hirosawa, C.;

Tanimoto, S. Tetrahedron Lett. 1991, 32, 4317−4320.

(10) Branchaud, B. P.; Blanchette, H. S. Tetrahedron Lett. 2002, 43,

351−353.

(28) Kim, G.; Jung, S.-D.; Kim, W.-J. Org. Lett. 2001, 3, 2985−2987.

(29) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem.

̈

Soc. 2001, 123, 10099−10100.

(30) For Suzuki−Miyaura cross-coupling reaction between vinyl-

boronic acids and vinyl halides with TlOH, see: (a) Roush, W. R.;

Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411−7419. (b) Roush, W.

R.; Brown, B. B. J. Am. Chem. Soc. 1993, 115, 2268−2278. (c) Uenishi,

J.-I.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987,

109, 4756−4758.

(11) (a) Archer, N. J.; Rayner, C. M.; Bell, D.; Miller, D. Synlett 1994,

617−619. (b) Pasquato, L.; Modena, G. Chem. Commun. 1999, 1469−

1470.

(12) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,

(31) For Suzuki−Miyaura cross-coupling reaction between vinyl-

boronic acids and vinyl halides with TlOEt, see: (a) Frank, S. A.; Chen,

H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2,

2691−2694. (b) Humphrey, J. M.; Aggen, J. B.; Chamberlin, A. R. J.

Am. Chem. Soc. 1996, 118, 11759−11770.

(32) (a) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695−

2698. (b) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett.

1990, 31, 6509−6512. (c) Sato, M.; Miyaura, N.; Suzuki, A. Chem.

Lett. 1989, 1405−1408.

1560−1638.

(13) (a) Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem. Soc.

2010, 132, 15752−15765. (b) Denmark, S. E.; Collins, W. R. Org. Lett.

2007, 9, 3801−3804.

(14) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T. J. Am. Chem. Soc.

2011, 133, 15308−15311.

(15) (a) Denmark, S. E.; Collins, W. R.; Cullen, M. D. J. Am. Chem.

Soc. 2009, 131, 3490−3493. (b) Denmark, S. E.; Vogler, T. Chem.

Eur. J. 2009, 15, 11737−11745.

(33) MeSO₃H, pK_a(water) −1.91; EtSO₃H, pK_a(water) −1.68.

Tully, P. S. Sulfonic Acids. In Kirk-Othmer Encyclopedia of Chemical

Technology, 4th ed.; Kroschwitz, J. I., Ed.; Wiley: New York, 1997; Vol.

23, pp 194−21.

(16) Enantioselective sulfenylation of activated alkenes derived from

aldehydes, ketones, and amides has also been reported recently.

́

Aldehydes: (a) Zhao, G. L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova,

A. Angew. Chem., Int. Ed. 2008, 47, 8468−8472. (b) Marigo, M.;

Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem., Int. Ed.

2005, 44, 794−797. Ketones: (c) Lin, A.; Fang, L.; Zhu, X.; Zhu, C.;

Cheng, Y. Adv. Synth. Catal. 2011, 353, 545−549. (d) Polaske, N. W.;

Dukey, R.; Nichol, G. S.; Olenyuk, B. Tetrahedron: Asymmetry 2009,

20, 2742−2750. (e) Fang, L.; Lin, A.; Hu, H.; Zhu, C. Chem.Eur. J.

2009, 15, 7039−7043. (f) Sobhani, S.; Fielenbach, D.; Marigo, M.;

Wabnitz, T. C.; Jorgensen, K. J. Chem.Eur. J. 2005, 11, 5689−5694.

Indolones: (g) Han, Z.; Chen, W.; Dong, S.; Yang, C.; Liu, H.; Pan, Y.;

Yan, L.; Jiang, Z. Org. Lett. 2012, 14, 4670−4673. (h) Li, X.; Liu, C.;

Xue, X.-S.; Cheng, J.-P. Org. Lett. 2012, 14, 4374−4377. (i) Wang, C.;

Yang, X.; Loh, C. C. J.; Raabe, G.; Enders, D. Chem.Eur. J. 2012, 18,

11531−11535. (j) Cai, Y.; Li, J.; Chen, W.; Xie, M.; Liu, X.; Lin, L.;

Feng, X. Org. Lett. 2012, 14, 2726−2929.

(34) The reactions was run at room temperature in the presence of

tetrahydrothiophene (1.0 equiv), MsOH (1.0 equiv), 13 (1.0 equiv),

and (E)-1-(3′,4′-methylenedioxyphenyl)-5,5-dimethylhex-3-ene for 24

1

h. H NMR spectroscopic analysis of the reaction mixture did not

show the characteristic proton in α-position of the thiophenyl group,

around 3.40−3.80 ppm.

(35) The reactions was run at room temperature in the presence of

tetrahydrothiophene (1.0 equiv), MsOH (1.0 equiv), 13 (1.0 equiv),

and (E)-1-(4′-methoxyphenyl)non-3-ene for 24 h. ¹H NMR

spectroscopic analysis of the reaction mixture did not show the

characteristic proton in α-position of the thiophenyl group, around

3.40−3.80 ppm.

(36) The crystallographic coordinates of trans-34 have been

deposited with the Cambridge Crystallographic Data Centre;

deposition no. 913987. These data can be obtained free of charge

via from the Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; via www.ccdc.

cam.ac.uk/conts/retrieving.html or deposit@ccdc.cam.ac.uk.

(37) Miyaura, N.; Ishikawa, M.; Ishiyama, M.; Suzuki, A. Tetrahedron

Lett. 1986, 27, 6369−6372.

(17) For a recent report of catalytic, enantioselective oxysulfenylation

of unactivated alkenes under chiral Brønsted acid catalysis, see: Guan,

H.; Wang, H.; Huang, D.; Shi, Y. Tetrahedron 2012, 68, 2728−2735.

(18) For a recent report of catalytic desymmetrization of meso-

thiiranium ions, see: Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817−

824.

AD

dx.doi.org/10.1021/jo4023765 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Catalytic, enantioselective, intramolecular carbosulfenylation of olefins. preparative and stereochemical aspects

DOI: 10.1021/jo4023765

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