Asymmetric intramolecular Pauson-Khand reaction mediated by a remote sulfenyl or sulfinyl group

Article

pubs.acs.org/joc

Asymmetric Intramolecular Pauson−Khand Reaction Mediated by a

Remote Sulfenyl or Sulﬁnyl Group

Jose Luis García Ruano,* Esther Torrente, Alejandro Parra, Jose Aleman, and Ana M. Martín-Castro*

́

Departamento de Química Organ

Madrid, Spain

́ ́ ́

ica (Modulo 01), Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco 28049

S

* Supporting Information

ABSTRACT: In this work, we report the use of the

asymmetric intramolecular Pauson−Khand reactions of 4-

aryl-4-cyano-1,6-enynes for obtaining enantiomerically en-

riched bicyclo[3.3.0]octenones, and the inﬂuence of both the

quaternary stereocenter and the sulfur functions located at

ortho-position of the aryl group, on their stereoselectivity and

reactivity. The sulfenyl derivatives bearing substituted or

unsubstituted triple bonds and mono- and disubstituted alkene moieties aﬀord bicyclo[3.3.0]octenones in high yields with

complete diastereocontrol. These results are explained by assuming the association of the lone electron pair at sulfur to the Co−

alkyne complexes.

likely to be overcome by using a remote sulﬁnyl group as a

chiral auxiliary, easily removable without aﬀecting the

enantiomeric purity of the resulting adducts. In this context,

we have recently reported a stereodivergent synthesis of

enantiomerically enriched α,α-dialkyl phenylacetonitriles,¹⁰

which could be easily adapted to the preparation of compounds

I−III (equation c, Scheme 1). We reasoned that these

compounds could be appropriate models for studying the

inﬂuence of several factors on the PK reaction course. First, the

sulﬁnyl group of II is not directly bonded to the double bond,

and its distance to the triple bond suggests an eﬃcient

interaction with the Co−alkyne complex, aﬀording a seven- or

eight-membered intermediate cobaltocycle. Second, it should

be easily transformed into a sulfenyl group (compounds III),

which has proved to be highly eﬃcient in reactions involving

sulfur-coordination to metals.¹¹Finally, I−III have a quaternary

stereogenic center, which presumably would improve the

reactivity by a Thorpe−Ingold’s eﬀect,¹²but whose inﬂuence

on the stereoselectivity of the intramolecular PK reactions has

never been investigated, basically due to the diﬃculties inherent

to their preparation (in most of the studied cases the

quaternary carbon atom is bonded to two methyl or

alkoxycarbonyl groups). In this work we describe the synthesis

of substrates I−III and their behavior under the PK reaction

conditions (Scheme 2) in order to evaluate the inﬂuence of the

remote sulﬁnyl group (as well as its sulfenyl derivative) and the

quaternary stereocenter on the reactivity and diastereoselecitv-

ity.

INTRODUCTION

■

Over the last decades, the Pauson−Khand (PK) reaction has

developed into a powerful tool in organic synthesis.^1,2This

formal [2 + 2 + 1] cycloaddition of an alkene and an alkyne

with carbon monoxide, obtained typically from Co₂(CO)₈,

aﬀords cyclopentenone derivatives, which are useful scaﬀolds

for further synthetic transformations. The intramolecular

variant of the PK reaction is particularly interesting since it

produces two fused rings and three new carbon−carbon bonds

in one synthetic step, representing one of the best method-

ologies so far reported for the synthesis of bicyclo[3.3.0]-

octenones and bicyclo[4.3.0]nonenones from 1,6- and 1,7-

enynes, respectively.³This synthetic utility explains why the

asymmetric version of this cyclization, controlled by a chiral

fragment present at the substrate,⁴or by an external chiral

promoter⁵or ligand,⁶has been so extensively investigated.

However, the best stereoselectivities so far reported were

achieved by using chiral auxiliaries as the source of asymmetric

induction.⁷

In this context, the inﬂuence of the sulﬁnyl group directly

bonded to one of the reactive multiple bonds of the substrate

has been studied.^8,9Its eﬃciency is not too high when located

at the alkyne fragment due to regio and stereoselective

problems (equation a, Scheme 1),⁸but it aﬀords much better

results when the t-BuSO group is joined to the alkene moiety

(equation b, Scheme 1),⁹presumably due to the interaction of

the lone electron pair at sulfur with the Co−alkyne complex.

This is one of the best reported methods in the asymmetric PK

ﬁeld despite its moderate yields and limited scope from

structural (it is restricted to terminal alkynes and 2-substituted

sulﬁnylethylenes) and stereochemical viewpoint (it is only

useful for preparing bicycloalkenones with one stereogenic

center because the second one, bonded to the sulﬁnyl group,

disappears when the auxiliary is removed). The later problem is

Received: June 13, 2012

Published: July 17, 2012

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Scheme 1. Diﬀerent Approaches for the Application of the Sulﬁnyl Group to the PK Reaction

Scheme 2. Synthetic Proposal for Obtaining Bicyclo[3.3.0]Octenones from Enynes Bearing an All-Carbon Quaternary

Stereocenter and/or a Remote Sulﬁnyl or Sulfenyl Group

Scheme 3. Synthesis of the 1,6-Enynes Epimeric at C-4 (8−18) by Diastereodivergent Dialkylation of (S)-[2-(p-

Tolylsulﬁnyl)phenyl]acetonitrile (1)

Although the preparation of the two enynes epimeric at the

quaternary center could be achieved by inverting the sequence

of the steps 1 and 2 (introducing the allyl group before the

propargyl, or vice versa), this strategy would not be advisable

for terminal alkynes with acidic protons. Therefore, we

prepared both epimeric series of enynes following the sequence

depicted in Scheme 1 and taking advantage of the

RESULTS AND DISCUSSION

■

Synthesis and Reactivity of Sulﬁnyl Enynes II. The

synthesis of 4-[2-(p-tolylsulﬁnyl)phenyl]-1,6-enynes II (com-

pounds 8-18) was accomplished following the methodology for

stereoselective dialkylation of (S)-[2-(p-tolylsulﬁnyl)phenyl]

acetonitrile (1)¹⁰by using allyl and propargyl halides as

electrophiles (Scheme 3).

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diastereodivergent course of the second alkylating step

depending on the reaction conditions. It allows the use of the

presumably more reactive propargyl halides in the second

alkylation step, which had been reported to be more sensitive

to steric eﬀects.¹⁰

We ﬁrst prepared the alkenyl derivatives indicated in Table 1,

with mono- (2), di- (3−6), and trisubstituted (7) double

The reactions of 2−7 with propargyl bromide or 1-

bromobut-2-yne aﬀorded the 4-[2-(p-tolylsulﬁnyl)phenyl]-1,6-

enynes 8−18 as diastereomerically enriched mixtures of

epimers at the benzylic carbon (a, b) depending on the

experimental conditions (Table 2). The conﬁguration of the

predominant diastereoisomer in the obtained diastereomeric

mixtures was dependent on the reaction conditions. As it had

been previously demonstrated,¹⁰diastereoisomers a were

obtained preferentially in those reactions performed with

KHMDS/18-crown-6 ether, whereas epimers b were predom-

inant in those processes carried out with NaHMDS, which

required longer reaction times. In all the cases the stereocontrol

(d.r. values ranging between 80:20 and 90:10) as well as the

yields (68−94%) were high regardless of the nature of the

counterion.

Table 1. Monoalkylation Reaction of Nitrile 1 with Allyl

Bromides

entry

product

R¹

R²

yield (%)

d.r.

The behavior of the simplest and presumably more reactive

sulﬁnylenyne (8a) was evaluated under the diﬀerent exper-

imental conditions classically reported for the PK cyclo-

additions. When performed thermally in reﬂuxing acetonitrile,

the formation of the enyne−cobalt complex was detected by

TLC of the reaction mixture but led ﬁnally to decomposition

products. The addition of chemical promoters (Me₂S or

molecular sieves) aﬀorded the desired cycloadducts 19aA +

19aB, but better diastereoselectivity and yield were obtained by

performing the reaction with Co₂(CO)₈(1.2 equiv) in

anhydrous CH₂Cl₂at room temperature, in the presence of 8

equiv of N-methylmorpholine N-oxide (NMO) as an additive.

Under these conditions a 72:28 diastereomeric mixture of

sulﬁnyl bicyclo[3.3.0]octenones 19aA + 19aB was obtained in

79% yield after 5 min reaction time (Table 3, entry 1). This

result was not improved by lowering the temperature, but

longer reaction times were required for the reaction to reach

completion. Thus, a similar diastereomeric ratio of 70:30 was

1

2

3

4

5

6

2 + 2′

3 + 3′

4 + 4′

5 + 5′

6 + 6′

7 + 7′

H

77

72

78

72

75

71

50:50

Me

H

a

b

Me

H

50 :50

Ph

H

60:40

50:50

Ph

b

Me

50 :50

a

Obtained as a 80:20 mixture of E/Z isomers, coincident with the E/Z

ratio of the starting allyl bromide. Obtained as a 86:14 mixture of E/Z

isomers, coincident with the E/Z ratio of the starting allyl bromide.

b

bonds, by reaction of (S)-[2-(p-tolylsulﬁnyl)phenyl]acetonitrile

(1) with LiHMDS (1.1 equiv) in THF and allyl bromides (1.2

equiv), commercially available (entries 1, 2, 3 and 5) or easily

prepared following reported procedures (entries 4¹³and 6¹⁴).

After chromatographic puriﬁcation, the oleﬁns 2−7 were

obtained in 71−78% yields (Table 1) as almost equimolecular

epimeric mixtures at the tertiary benzylic carbon, which was not

unexpected from our previous results.¹⁰

Table 2. Quaternization of 2-Allyl-[2-(p-tolylsulﬁnyl)phenyl]acetonitriles 2−7 with Diﬀerent Propargyl Bromides

product

d.r.

yield (%)

substrate (R¹, R²)

reagent (R³)

yield (%)

d.r.

product

8a

80:20

87:13

89:11

90:10

80

69

87

79

76

80

94

83

80

2 + 2′ (H, H)

3 + 3′ (Me, H)

4 + 4′ (H, Me)

5 + 5′ (Ph, H)

6 + 6′ (H, Ph)

7 + 7′ (Me, Ph)

H

84

76

85

81

78

80

20:80

12:88

13:87

20:80

10:90

18:82

20:80

8b

9a

Me

H

9b

10a

11a

12a

13a

14a

15a

16a

17a

18a

10b

11b

12b

13b

14b

15b

Me

H

a

88:12

90:10

89:11

87:13

86:14

82:18

a

c

Me

H

Me

H

,

b

H

d

68

Me

a

b

Diastereoisomeric mixture that could not be separated by ﬂash column cromatography. A (77:9):14 mixture of three diastereoisomers was

obtained from the 86:14 mixture of the starting E/Z allyl derivative 7 + 7′. Probably minor Z enyne derived from 7′ could not be detected in the ¹H

c

NMR spectrum of the crude mixture. A (74:8):18 mixture of three diastereoisomers was obtained from an 82:18 mixture of the starting E/Z allyl

d

derivative 7 + 7′. Probably minor Z enyne derived from 7′ could not be detected in the ¹H NMR spectrum of the crude mixture. Isolated yield for

compound 18a.

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aﬀorded only one diastereomerically pure bicyclo[3.3.0]-

octenone in moderate to good yields. The reactivity of these

substrates was clearly lower, but the negative inﬂuence of the

phenyl group was even higher when it was an R¹substituent

(reaction of 16a required 3.5 h, whereas 14a and 15a required

12 h). As it was the case in the previous cases, the inﬂuence of

the R³group was negligible. Finally, the cycloaddition failed

with enynes 17a and 18a, both with trisubstituted double

bonds (Table 3, entries 10 and 11).

Table 3. Pauson−Khand reaction of Homochiral Sulﬁnyl

1,6-Enynes 8a−18a

The impossibility of obtaining good crystals from any of the

synthesized bicyclo[3.3.0]octenones prevented us from un-

equivocally assigning their absolute conﬁguration by X-ray

analysis. However, the relative conﬁguration of adducts aA and

aB was established by bidimensional ¹H NMR experiments (see

the Supporting Information) by assuming that the conﬁg-

uration of the benzylic carbon atom of the starting compounds

8a−18a is known (on the basis of the stereochemical behavior

of the quaternization reactions¹⁰) and that it is preserved during

the cycloadditions. The absolute conﬁguration [2R,3aS,(S)S]

was then assigned to the major cycloadducts aA and [2R,3aR,

(S)S] to the minor isomers aB, as depicted in Table 3.

substrate (R¹, R²,

R³)

yield

b

a

entry

time

product

d.r.

(%)

1

8a (H, H, H)

5 min

19aA + 19aB

20aA + 20aB

72:28

70:30

81:19

78:22

80:20

82:18

79

70

65

76

74

80

56

58

74

n.r.

2

9a (H, H, Me)

10a (Me, H, H)

11a (Me, H, Me)

3

10 min 21aA + 21aB

10 min 22aA + 22aB

4

c

5

12a (H, Me, H)

1.5 h

12 h

3.5 h

23aA + 23aB

24aA + 24aB

d

6

13a (H, Me, Me)

c

7

14a (Ph, H, H)

25aA + 25aB >98:<2

c

8

15a (Ph, H, Me)

26aA + 26aB >98:<2

d

9

16a (H, Ph, H)

27aA + 27aB >98:<2

10

11

17a (Me, Ph, H)

18a (Me, Ph, Me)

n.r.

We also performed a parallel study on the behavior of the

epimeric 1,6-enynes of the homochiral series b, which were

similarly treated under PK conditions (Scheme 4). Compounds

8b (R¹, R², R³= H) and 9b (R¹, R²= H, R³= Me) exhibited a

reactivity similar to that observed for their corresponding a

isomers but the stereoselectivity was practically nonexistent. A

similarly low selectivity was detected for compounds 10b (R¹=

Me, R², R³= H) and 11b (R¹, R³= Me, R²= H), but the

reaction rate was signiﬁcantly lower than that of the a isomers.

The rest of the 1,6-enynes, 12b−16b and 18b were recovered

unaltered after long reaction times under similar conditions.

The absolute conﬁguration of the products resulting from the

PK reaction of the enynes b (19bA−22bA and 19bB−22bB),

a

Diastereomeric ratio determined by integration of well-separated

b

1

signals of the H NMR spectra. Yield of the diastereomeric mixture.

c

90:10 mixture of epimers a + b (diastereomeric ratio aA:aB

corresponds to the adducts derived from major epimer a). 87:13

mixture of epimers a + b (diastereomeric ratio aA:aB corresponds to

the adducts derived from major epimer a).

d

obtained both at 0 °C (reaction time 60 min) and at −40 °C

(reaction time 4.5 h).

Next, the scope of this intramolecular PK cycloaddition was

surveyed with all the previously synthesized 1,6-enynes 8−18 of

the epimeric homochiral series denoted as a. The obtained

results are collected in Table 3. The reactions of 8a and 9a,

with no substituents on the oleﬁnic fragment, are those

proceeding more rapidly (reaction time 5 min), though with

moderate diastereoselectivities (d.r. values ca. 70:30), regardless

of the substitution pattern on the alkynyl chain (Table 3,

entries 1 and 2). A slight improvement in the stereoselectivity

(d.r. values ca. 80:20) and a decrease in the reactivity (10 min

were needed for the reaction to reach completion) were

detected for substrates 10a and 11a bearing a gem-disubstituted

terminal double bond (R¹= Me; Table 3, entries 3 and 4). The

level of the stereoselectivity was similar (d.r. values ca. 80:20),

but the reactivity was severely eroded (reaction times were 1.5

h) for 12a and 13a (R²= Me; Table 3, entries 5 and 6). In all

these cases the role of the substituent at the triple bond (R³)

proved to be scarcely relevant. A dramatic improvement in the

stereoselectivity was detected in the reactions of those

substrates with R¹or R²= Ph (Table 3, entries 7−9), which

1

as indicated in Scheme 4, was assigned by H NMR (see the

Supporting Information).

Synthesis and Reactivity of 1−6 Enynes I. Diﬀerences in

reactivity and stereoselectivity of the epimeric sulﬁnyl enynes II

should be due to the contribution of the two stereogenic

elements present in their structures. In order to know the

relative inﬂuence of each one, we decided to study the behavior

of the enynes I (compounds 28−30), with the stereogenic

quaternary center as the only stereogenic element, whose

inﬂuence had never been considered due to the diﬃculties

associated to the preparation of this type of substrates. Removal

of the sulﬁnyl group of compounds 8a, 10a and 12a was

performed with t-BuLi¹⁵in THF at −78 °C, aﬀording nitriles

28, 29 and 30 in high yields (Scheme 5).

When 28 was treated under the usual PK reaction conditions

[Co₂(CO)₈, NMO in CH₂Cl₂] at room temperature, it

aﬀorded, in only ﬁve minutes, a mixture of cycloadducts 31A

and 31B in high yield but with practically no stereoselectivity

Scheme 4. Pauson−Khand Reactions of Homochiral Sulﬁnyl 1,6-Enynes (Series b)

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Scheme 5. Synthesis and Pauson−Khand Reactions of 1,6-Enynes 28−30

Scheme 6. Synthesis of Racemic Sulfone 34 and Thioethers 36−38

(Scheme 5). By contrast, when starting from 29, the inﬂuence

of the quaternary center on the stereoselectivity was signiﬁcant,

and a 90:10 mixture of 32A and 32B was obtained after 30 min

of reaction. Compound 30 did not react under the PK

conditions, and therefore we did not prepare more desulﬁny-

lated enynes. The diﬀerent d.r. values obtained in these

reactions show that the inﬂuence of the quaternary benzylic

carbon atom depends on the nature of the substituents at the

allylic fragment.

Despite that the comparison of the results collected in Table

3 for substrate 12a (entry 5) with those depicted in Scheme 5

for desulﬁnylated enyne 30 could suggest a positive inﬂuence of

the sulﬁnyl group on the reactivity, it is not so clear if we

compare the results obtained for 10a (entry 3) and 29. For

substrates evolving more rapidly, 8a and 28, this eﬀect was

demonstrated by performing a competitive assay by treating 8a

(1.0 equiv) and 28 (1.0 equiv) with Co₂(CO)₈(1.3 equiv) in

anhydrous CH₂Cl₂at room temperature. Further addition of

NMO provided a 67:33 mixture of adducts (19aA + 19aB) and

(31A + 31B).

quaternization process of the benzylic carbon similar to that

used for preparing sulfoxides (Scheme 6). A similar procedure

starting from thioether 35 provided sulfenyl 1,6-enines with

mono- (36), di- (37), and trisubstituted (38 as mixture Z:E

85:15) double bonds.

Under PK conditions compound 34 exhibited a lower

reactivity than that of the corresponding sulﬁnyl derivatives (8a

or 8b) or the desulﬁnylated compound (28) and produced a

mixture of racemic cycloadducts 39A + 39B with practically no

stereocontrol (Scheme 7). Contrarily, under similar conditions

Scheme 7. Behavior of Racemic Sulfone 34 and Thioethers

36, 37, And 38 under PK Reaction Conditions

Synthesis and Reactivity of Sulfenyl (1,6)-Enynes III.

The low reactivity and stereoselectivity of the sulfoxides of the

series b with respect to those of the series a, under similar PK

conditions, indicates that both features are associated to the

relative conﬁguration of the enyne, suggesting the existence of

some interaction of the sulﬁnyl group with the metal in the

transition state,^6c−gwhich is only possible for compounds of

the series a. In order to unequivocally establish which of the

two basic centers, the lone electron pair at sulfur or the sulﬁnyl

oxygen atom, were involved in this interaction, we studied the

behavior of thioethers (which lack the oxygen atom) and

sulfones (without any lone electron pair at sulfur), the benzylic

carbon being the only stereogenic element in both compounds.

We ﬁrst prepared these compounds in their racemic form by

using the sequence indicated in Scheme 6. Racemic sulfonyl

1,6-enyne 34 was obtained from 33 (prepared by MPCBA

oxidation of its corresponding sulfoxide 1) following a two-step

thioether 36 reacted immediately in a completely stereo-

selective manner, only yielding one diastereoisomer 40A. A

similar behavior was observed for 37, which only aﬀorded

cycloadduct 41A in 5 min. The relative conﬁguration of racemic

adducts 39A, 39B, 40A and 41A was established from their ¹H

NMR spectra. By contrast, thioether 38 did not react under the

usual PK reaction conditions. The comparison of these results

with those obtained from the sulfoxides of similar structure 8a,

12a and 17a (Table 3) allowed us to conclude that the

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Scheme 8. Reduction of the Sulfoxides 8a, 8b, 12a, and 16a

thioethers react with complete stereoselectivity and their

reactivity is much higher. These results are indicative of an

important role of the lone electron pair at sulfur (more easily

available in thioethers) in the course of the PK reactions.

Consequently, the best strategy for obtaining the optically

pure bicyclo[3.3.0]octenones would consist ﬁrst in employing

the sulﬁnyl group for creating the quaternary stereogenic

carbon (Table 2), and then transforming compounds 8−18

into their corresponding thioethers, which would be ﬁnally

treated under PK reaction conditions to aﬀord the desired

adducts. In order to assess the feasibility of this strategy, we

chose three sulﬁnyl 1,6-enynes of the series a (8a, 12a, and

16a) and one of the series b (8b) as the substrates for the

reduction of the sulfur function. After several unsuccessful

trials, the reduction of the sulﬁnyl group was performed by

treatment with BF₃·OEt₂and NaI in anhydrous CH₃CN.¹⁶The

reactions were clean, but under these conditions, concomitant

sulﬁnyl reduction and cyano hydrolysis took place (Scheme

8).¹⁷The resulting sulfenyl carboxamides were obtained in

satisfactory yields (50−60%) taking into account that the

conversions were not complete (ca. 70%) and the unreacted

sulﬁnyl nitriles could be recovered. As expected, the amides

resulting from 8a and 8b are enantiomers [(R)-42 and (S)-42].

Enantiomeric ratio of the obtained (R)-43, measured with

chiral HPLC, is 88:12, in complete agreement with the same

d.r. of the mixture 12a and 12b used as the starting product.

Analogously, the reaction of a 77:23 mixture of 16a and 16b

yielded (R)-44 with 54% ee (Scheme 8).

completely stereoselective reactions of (R)-43 and (R)-44,

yielding 46 and 47, respectively (de >98%, Scheme 9),

contrasts with the slower (90 min) and less stereoselective

(d.r. 80:20) reaction of the sulﬁnyl precursors 12a (entry 5,

Table 3) and the much lower reactivity of 16a (3.5 h, entry 6,

Table 3). All these results demonstrate that the thioethers are

better substrates than the sulfoxides (regardless of their relative

conﬁguration) in the assayed PK reactions. The relative

conﬁguration of the newly created stereogenic carbon atoms

at adducts 45−47 was determined from their ¹H NMR spectra.

Bearing in mind that the previously established conﬁguration of

the benzylic carbon for substrates 42−44 had been previously

established, the absolute conﬁguration of the resulting adducts

(45−47) could, therefore, be assigned.

Mechanistic Proposal. Our mechanistic proposal account-

ing for the experimental results is depicted in Schemes 10 and

11. The alkyne−cobalt complex A may follow two alternative

pathways, dependent on the C−Co bond chosen by the oleﬁn

π-system to become inserted. In the approach B_exo, the aryl

containing the X group (H, STol, SOTol, SO₂Tol) occupies a

pseudoaxial placement far from the cobalt atoms and obviously

Scheme 10. Stereochemical Pathway Accounting for the

Stereoselectivity of the PK Reactions of Desulﬁnylated and

Sulfonyl Enynes

The sulfenyl carboxamides (R)-42 and (S)-42 evolved with a

complete control of the stereoselectivity only aﬀording one

bicyclo[3.3.0]octenone (45 and ent-45, respectively) in high

yields (Scheme 9), in contrast with the moderate or low

stereocontrol that had been observed in the evolution of their

sulﬁnyl precursors 8a (d.r. 72:28, entry 1, Table 3) and 8b (d.r.

56:44, Scheme 4). Analogously, the fast (5−10 min) and

Scheme 9. Pauson−Khand Reactions of Sulfenyl 1,6-Enynes

42−44

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Scheme 11. Stereochemical Pathway Accounting for the Stereoselectivity of the PK Reactions of Sulfenyl and Sulﬁnyl Enynes

cannot interact with the metal. The same is true for the B_endo

approach when X cannot interact with the metal, which is the

case when X = H, SO₂Tol (they lack the lone electron pairs)

and SOTol (epimers b, vide infra). In these cases, the oleﬁn

insertion in the suitable C−Co bond will produce the

intermediates C_exoand C_endo, which will evolve into the exo

and endo adducts, respectively, by reductive elimination and

decomplexation. Intermediates B_exoand B_endo(as well as C_exo

and C_endo) must be similar in energy when R¹= H (because of

the low magnitude of the interactions between the metal

complex and the Ar and CN groups), and very low

stereoselectivity should be expected. When R¹= Me, the steric

repulsion Ar/Me could become important and justify the

diﬀerences in the stereoselectivity observed for cyclization of 28

and 29 (Scheme 5) or 8a and 10a (Table 3). Even more

important will be the interaction Ar/Ph in compounds 14a and

15a, thus explaining their much higher stereoselectivity with

respect to 10a and 11a (Table 3). In all the cases, the reactivity

must decrease substantially when R¹and R²are not hydrogen,

due to their interactions with the metal complex in both exo

and endo approaches.

The behavior of the sulfoxides depends on their relative

conﬁguration. Epimers b cannot form B″_endo‑bbecause of the

strong steric repulsion of the tolyl group with the alkene

fragment (right, Scheme 11), and therefore they would evolve

according to the model depicted in Scheme 10, with low

reactivity and stereoselectivity. By contrast, epimers a could

form B″_endo‑a(right, Scheme 11), although the magnitude of its

stabilization with respect to B_exowould be less important than

that existing for thioethers due to the lower association ability

of the sulﬁnyl sulfur and the steric repulsion of the oxygen with

the alkene fragment. Therefore, both reactivity and stereo-

selectivity of epimers a are intermediate between those of

thioethers and desulﬁnylated compounds.

CONCLUSIONS

■

From the above results, we can conclude that a variety of

diﬀerently substituted bicyclo[3.3.0]octenones, bearing up to

three carbon stereocenters, two of which are quaternary in

some of the cases, has been synthesized in high yields with

good to excellent diastereocontrol from 1,6-enynes bearing

remote sulfenyl or sulﬁnyl functions. The stereoselectivity of

these Pauson−Khand reactions was markedly dependent on the

coexistence in the substrate of a quaternary stereogenic carbon

and a sulfur atom bearing a coordinating lone electron pair. The

presence of the chiral sulﬁnyl group has proved crucial for the

eﬃcient asymmetric generation of the benzylic quaternary

stereogenic carbons present at the starting 1,6-enynes.

Thioethers, obtained by reduction of the sulfoxides, are much

When X = STol, the sulfur atom can stabilize the endo

approach strongly by forming the B′_endointermediate (Scheme

11) from B_endo, by association of the lone electron pair at sulfur

with the Co, displacing a CO molecule. Intermediate B′_endo

must be much more stable than B_exo, which would explain the

higher reactivity and the exclusive formation of the endo

adducts in reactions from thioethers.

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+

(2C), 17.7, 17.6 ppm; MS (ESI+) m/z 310 [M + H] (100), 292

(17); HRMS (EI+) calcd. for C₁₉H₂₀NOS 310.1266, found 310.1269.

[2S,(S)S,4E], [2R,(S)S,4E], [2S,(S)S,4Z] and [2R,(S)S,4Z]-2-[2-(p-

Tolylsulﬁnyl)phenyl]-hex-4-enenitrile [(E)-4 + (E)-4′ + (Z)-4 +

(Z)-4′]. The diastereoisomeric mixture 4 + 4′ was obtained using

commercial 1-bromobut-2-ene (E/Z mixture of 80:20) as the

electrophile. The reaction mixture was stirred at rt for 15 min. The

crude 40:40:10:10 mixture of (E)-4 + (E)-4′ + (Z)-4 + (Z)-4′, which

could not be isolated diastereomerically pure, was puriﬁed by ﬂash

column chromatography using AcOEt−hexane (1:3) as the eluent.

Yield: 78% (241 mg, colorless oil); IR (ﬁlm) 3078, 2974, 2243, 1643,

1473, 1083, 1035, 758 cm⁻¹; ¹H NMR [diastereoisomeric (E)-4 + (E)-

4′ mixture (50:50)] δ 7.88−7.85 (m, 2H), 7.59−7.47 (m, 6H), 7.42

and 7.26 (AA′BB′ system, 4H), 7.40 and 7.26 (AA′BB′ system, 4H),

5.68−5.51 (m, 2H, 2CH), 5.46−5.29 (m, 2H, 2CH), 4.47−4.40 (m,

2H, 2CH), 2.63−2.41 (m, 2H, 2CH), 2.40−2.28 (m, 1H), 2.35 (s,

6H), 2.21−2.14 (m, 1H), 1.66 (d, J 6.4 Hz, 3H), 1.63 (d, J 7.0 Hz, 3H)

more eﬃcient for controlling the stereoselectivity (only one

diastereoisomer is obtained) and for increasing the reactivity.

EXPERIMENTAL SECTION

■

General Procedures. NMR spectra were registered (300 and 75

1

MHz for H and ¹³C NMR, respectively) in CDCl₃solutions. ¹³C

NMR spectra were acquired on a broad band decoupled mode.

Melting points were measured in open capillary tubes. Mass spectra

(MS) were determined by EI, FAB and ESI, as indicated in each case.

High resolution mass spectra (HRMS) were performed by using a

magnetic-sector mass analyzer (for FAB ionization mode) or time-of-

ﬂight (TOF) mass analyzer (for EI and ESI ionization modes), as

indicated for each compound. All reactions were carried out in

anhydrous solvents under argon atmosphere. Commercially available

anhydrous tetrahydrofuran (THF) and ethyl ether (Et₂O) were dried

over 4 Å molecular sieves. Analytical thin layer chromatography

(TLC) was performed using precoated aluminum-backed plates

(Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation

or KMnO₄dip. Flash column chromatography was performed using

silica gel (230−400 mesh). The enantiomeric excess (ee) of products

was determined by chiral stationary phase HPLC. Commercially

available Co₂(CO)₈and NMO were used without further puriﬁcation.

General Procedure for the Synthesis of 2-Allyl-2-[2-(p-

tolylsulﬁnyl)phenyl]acetonitriles (2−7). To a solution of (S)-2-

[2-(p-tolylsulﬁnyl)phenyl]acetonitrile (255.3 mg, 1 mmol) in anhy-

drous THF (10 mL) at rt under argon was added LHMDS (1 M in

THF) (1.2 mL, 1.2 mmol). The mixture was stirred at rt for 10 min,

and then 1.4 mmol of the corresponding allyl halide was added

dropwise. The reaction was monitored by TLC. Upon transformation

of the starting material, the reaction was hydrolyzed with saturated

aqueous NH₄Cl (5 mL). The mixture was extracted with Et₂O (3 × 5

mL), dried (Na₂SO₄), and the solvent was evaporated. The

diastereoisomeric mixture was puriﬁed by ﬂash column chromatog-

raphy using the eluent indicated in each case.

[2S,(S)S] and [2R,(S)S]-2-[2-(p-Tolylsulﬁnyl)phenyl]pent-4-

enenitrile (2 + 2′). The diastereoisomeric mixture 2 + 2′ was

obtained using allyl bromide as the electrophile. The reaction mixture

was stirred at rt for 10 min. The crude 50:50 mixture of 2 + 2′ was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (1:1)

as the eluent. Yield: 77% (227 mg, colorless oil); IR (ﬁlm) 3055, 2923,

2241, 1493, 1083, 1038, 759 cm⁻¹; ¹H NMR [diastereoisomeric

mixture (50:50)] δ 7.91−7.87 (m, 2H), 7.55−7.45 (m, 6H), 7.44 and

7.27 (AA′BB′ system, 4H), 7.42 and 7.26 (AA′BB′ system, 4H), 5.84−

5.66 (m, 2H, 2CH), 5.21−5.04 (m, 4H, 2CH₂), 4.52−4.44 (m, 2H,

2CH), 2.62−2.49 (m, 2H, 2CH), 2.44−2.30 (m, 1H), 2.23 (s, 6H),

2.25−2.16 (m, 1H) ppm; ¹³C NMR [diastereoisomeric mixture

(50:50)] δ 142.4, 142.2 (2C), 141.7, 140.8, 140.7, 134.9, 133.9, 132.1

(2C), 132.0, 131.8, 130.4 (2C), 130.3 (2C), 129.7, 129.5, 129.2, 128.8,

127.2, 126.3, 125.7 (2C), 125.3 (2C), 119.9, 119.7, 119.6, 119.4, 39.3,

39.2, 32.6, 32.2, 21.3 (2C) ppm; MS (ESI+) m/z 295 (100); HRMS

(EI+) calcd. for C₁₈H₁₈NOS [M + H]⁺295.1031, found 295.1033.

[2S,(S)S] and [2R,(S)S]-4-Methyl-2-[2-(p-tolylsulﬁnyl)phenyl]-

pent-4-enenitrile (3 + 3′). The diastereoisomeric mixture 3 + 3′ was

obtained using commercial 3-bromo-2-methylprop-1-ene as the

electrophile. The reaction mixture was stirred at rt for 10 min. The

crude 50:50 mixture of 3 + 3′ was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:2) as the eluent. Yield: 72%

(222 mg, colorless oil); IR (ﬁlm) 3078, 2922, 2241, 1650, 1492, 1083,

1035, 761 cm⁻¹; ¹H NMR [diastereoisomeric mixture (50:50)] δ

7.80−7.77 (m, 1H), 7.74−7.71 (m, 1H), 7.54−7.49 (m, 2H), 7.47−

7.38 (m, 2H), 7.37−7.26 (m, 2H), 7.24−7.04 (m, 8H), 6.28 (m, 2H,

2CH), 6.24 (m, 2H, 2CH), 4.64 (dd, J 5.4 and 9.9 Hz, 1H), 4.54 (dd, J

6.5 and 8.7 Hz, 1H), 2.62−2.55 (m, 2H, 2CH), 2.50−2.30 (m, 2H,

2CH), 2.26 (s, 6H), 1.81 (d, J 1.3 Hz, 3H), 1.76 (d, J 1.2 Hz, 3H)

ppm; ¹³C NMR [diastereoisomeric mixture (50:50)] δ 142.4, 142.3,

141.9, 141.7, 140.8, 140.7, 137.3, 137.1, 135.8, 134.2, 132.8, 132.4,

132.3, 132.1, 130.5 (2C), 130.3 (2C), 130.1, 130.0, 129.7, 129.6, 129.1,

128.8 (2C), 128.7, 128.5, 128.1 (2C), 128.0 (2C), 127.9, 126.6, 126.5,

126.1, 125.5 (2C), 125.4 (2C), 119.7, 119.5, 46.2, 46.0, 32.2, 31.5, 21.3

1

ppm; H NMR [representative signals for diastereoisomers (Z)-4 +

(Z)-4′] δ 5.77−5.53 (m, 4H), 4.50−4.30 (m, 2H, 2CH), 2.65−2.50

(m, 2H), 2.22−2.10 (m, 2H), 1.50 (d, J 6.8 Hz, 3H), 1.45 (d, J 6.8 Hz,

3H) ppm; ¹³C NMR [diastereoisomeric (E)-4 + (E)-4′ mixture

(50:50)] δ 142.5, 142.1, 142.0, 141.9. 135.1, 134.1, 131.9, 131.8 (2C),

130.8, 130.4, 130.3, 130.2 (2C), 130.1 (2C), 129.5, 129.3, 129.0, 128.7,

127.0, 126.1, 125.7 (2C), 125.6, 125.2, 124.7, 124.4, 119.8, 119.6, 38.3,

38.2, 33.8, 32.8, 21.3 (2C), 17.7 (2C) ppm; ¹³C NMR [representative

signals for diastereoisomers (Z)-4 + (Z)-4′] δ 142.7, 142.1, 135.3,

134.1, 132.1, 129.7, 129.5, 128.9, 128.7, 127.4, 126.1, 123.8, 123.5,

53.4, 32.6, 32.3, 30.8, 12.8 (2C) ppm; MS (FAB+) m/z 310 [M + H]⁺

(100), 292 (17); HRMS (EI+) calcd. for C₁₉H₂₀NOS [M + H]⁺

310.1266, found 310.1274.

[2S,(S)S] and [2R,(S)S]-4-Phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]-

pent-4-enenitrile (5 + 5′). The diastereoisomeric mixture 5 + 5′ was

obtained using commercial 3-bromo-2-phenylprop-1-ene as the

electrophile. The reaction mixture was stirred at rt for 30 min. The

crude 60:40 mixture of 5 + 5′ was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:3) as the eluent. Yield: 72%

(267 mg, colorless oil); IR (ﬁlm) 3050, 2922, 2241, 1639, 1473, 1083,

1035, 810 cm⁻¹; ¹H NMR [diastereoisomeric mixture (60:40)] δ

8.10−8.07 (m, 1H), 7.97−7.93 (m, 1H), 7.72−7.60 (m, 7H), 7.56−

7.42 (m, 9H), 7.40 and 7.28 (2 × AA′BB′ system, 8H), 5.55 (m, 1H),

5.54 (m, 1H), 5.41 (m, 1H), 5.38 (m, 1H), 4.65 (dd, J 6.9 and 8.8 Hz,

1H), 4.36 (dd, J 5.5 and 10.1 Hz, 1H), 3.26 (dd, J 5.3 and 14.1 Hz,

1H), 3.09 (dd, J 10.1 and 14.1 Hz, 1H), 3.08−2.97 (m, 2H), 2.41 (s,

3H), 2.40 (s, 3H) ppm; ¹³C NMR [diastereoisomeric mixture

(60:40)] δ 143.6, 143.2, 142.4, 142.2, 142.0, 141.6, 140.5, 140.4,

139.2, 138.9, 135.2, 133.2, 132.3, 131.7, 130.2 (2C), 130.1 129.8,

129.4, 129.1, 128.6 (2C), 128.4, 128.3, 128.2, 127.8, 127.7, 126.5 (2C),

126.4 (2C), 125.6 (3C), 125.2, 125.1 (2C), 119.3, 118.8, 117.1, 116.3,

41.8, 40.8, 32.3, 31.8, 21.3 (2C) ppm; MS (FAB+) m/z 372 [M + H]⁺

(100), 307 (26), 165 (32); HRMS (FAB+) calcd. for C₂₄H₂₂NOS [M

+ H]⁺372.1422, found 372.1428.

[2S,(S)S,4E] and [2R,(S)S,4E]-5-Phenyl-2-[2-(p-tolylsulﬁnyl)-

phenyl]pent-4-enenitrile (6 + 6′). The diastereoisomeric mixture

6 + 6′ was obtained using commercial cinnamyl bromide as the

electrophile. The reaction mixture was stirred at rt for 30 min. The

crude 50:50 mixture of 6 + 6′ was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:3) as the eluent. Yield: 75%

(278 mg, colorless oil); IR (ﬁlm) 3049, 2930, 2241, 1639, 1473, 1083,

1035, 750 cm⁻¹; ¹H NMR [diastereoisomeric mixture (50:50)] δ

7.86−7.80 (m, 2H), 7.54−7.47 (m, 5H), 7.43−7.36 (m, 3H), 7.29−

7.17 (m, 16H), 6.43 (d, J 15.4 Hz, 1H), 6.30 (d, J 15.7 Hz, 1H), 6.16−

6.00 (m, 2H, 2CH), 4.57−4.49 (m, 2H, 2CH), 3.19−3.16 (m, 1H),

2.73−2.64 (m, 1H), 2.62−2.50 (m, 1H), 2.44−2.36 (m, 1H), 2.34 (s,

3H), 2.33 (s, 3H) ppm; ¹³C NMR [diastereoisomeric mixture

(50:50)] δ 142.2, 142.1, 136.4, 136.3, 135.8, 135.7, 135.0, 134.9,

134.6, 134.0, 132.2, 132.1, 130.4 (2C), 130.3 (2C), 130.0, 129.7, 129.5,

129.2, 128.9, 128.7, 128.6, 128.5, 128.4, 127.9, 127.8, 127.4, 126.6,

126.5, 126.4 (2C), 126.3 (2C), 125.9, 125.7 (2C), 125.4 (2C), 123.3,

123.0, 122.4, 121.8, 38.7 (2C), 33.2, 32.6, 21.4 (2C) ppm; MS (ESI+)

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m/z 372 [M + H]⁺(100), 65 (16); HRMS (FAB+) calcd. for

C₂₄H₂₂NOS [M + H]⁺372.1422, found 372.1426.

7.66 (m, 2H), 7.55−7.39 (m, 2H), 7.51 and 7.27 (sistema AA′BB′

system, 4H), 5.86−5.70 (m, 1H), 5.34−5.11 (m, 2H), 5.24−3.02 (m,

4H), 2.38 (s, 3H), 2.12 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR δ 144.9,

141.2, 140.7, 135.8, 131.8, 130.5, 130.3 (2C), 129.9 (2C), 128.7, 125.5

(2C), 121.6, 121.2, 77.3, 73.9, 47.5, 42.6, 31.5, 21.3 ppm.

[2S,(S)S,4E], [2R,(S)S,4E], [2S,(S)S,4Z] and [2R,(S)S,4Z]-4-

Methyl-5-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile

[(E)-7 + (E)-7′ + (Z)-7 + (Z)-7′]. The diastereoisomeric mixture 7 + 7′

was obtained using 3-bromo-2-methyl-1-phenylprop-1-ene¹²(E/Z

mixture of 86:14) as the electrophile. The reaction mixture was

stirred at rt for 30 min. The crude 42:42:8:8 mixture of (E)-7 + (E)-7′

+ (Z)-7 + (Z)-7′, which could not be isolated diastereomerically pure,

was puriﬁed by ﬂash column chromatography using AcOEt−hexane

(1:2) as the eluent. Yield: 71% (273 mg, white solid); IR (KBr) 3054,

[2R,(S)S] and [2S,(S)S]-2-(But-1-inyl)-2-[2-(p-tolylsulﬁnyl)-

phenyl]pent-4-enenitrile (9a + 9b). The diastereoisomeric mixture

9a + 9b was obtained using a 50:50 mixture of [2S,(S)S] and [2R,(S)

S]-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (2 + 2′) as the

substrate and 1-bromobut-2-ine as the electrophile, in the presence

of KHMDS/18-crown-6 ether. The reaction mixture was stirred for 60

min. The crude 87:13 mixture of 9a + 9b was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:3) as the eluent. Diaster-

3019, 2241, 1596, 1441, 1083, 1033, 753 cm⁻¹

;

¹H NMR

[diastereoisomeric (E)-7 + (E)-7′ mixture (50:50)] δ 7.88−7.79 (m,

2H), 7.61−7.56 (m, 2H), 7.54−7.48 (m, 3H), 7.43−7.35 (m, 4H),

7.31−7.15 (m, 15H), 6.34 (m, 1H), 6.32 (m, 1H), 4.71 (dd, J 5.4 and

9.9 Hz, 1H), 4.61 (dd, J 6.4 and 8.6 Hz, 1H), 2.69−2.64 (m, 2H,

2CH), 2.58−2.39 (m, 2H, 2CH), 2.32 (s, 6H), 1.86 (d, J 15.8 Hz,

3H), 1.85 (d, J 15.8 Hz, 3H) ppm; ¹H NMR [representative signals for

diastereoisomers (Z)-7 + (Z)-7′] δ 7.68−7.62 (m, 2H), 6.50 (m, 1H),

6.48 (m, 1H), 4.77 (dd, J 5.8 and 10.4 Hz, 1H), 4.57 (dd, J 7.1 and 9.1

Hz, 1H), 2.93−2.83 (m, 2H), 2.59−2.38 (m, 2H), 1.93 (d, J 10.4 Hz,

3H), 1.92 (d, J 10.2 Hz, 3H) ppm; ¹³C NMR [diastereoisomeric (E)-7

+ (E)-7′ mixture (50:50)] δ 142.4, 142.3, 141.9, 141.7, 140.8, 140.7,

137.3, 137.1, 135.8, 134.2, 132.8, 132.4, 132.3, 132.1, 130.4 (2C),

130.3 (2C), 130.1, 130.0, 129.8, 129.6, 129.5, 129.1, 128.3, 128.0 (3C),

128.7, 128.5, 128.1 (2C), 128.0 (2C), 127.9, 126.6, 126.5, 125.5, 125.4,

119.7, 119.5, 46.2, 46.0, 32.2, 31.5, 21.4, 21.3, 17.7, 17.6 ppm; ¹³C

NMR [representative signals for diastereoisomers (Z)-7 + (Z)-7′] δ

142.7, 141.8, 140.9, 137.4, 137.2, 135.9, 133.6, 132.9, 131.9, 130.7,

129.9, 129.1, 128.6, 128.2, 128.0, 126.7, 125.6, 125.3, 119.4, 37.9, 37.8,

30.8, 30.3, 23.6, 22.9 ppm; MS (FAB+) m/z 386 [M + H]⁺(100), 211

(30); HRMS (FAB+) calcd. for C₂₅H₂₄NOS [M + H]⁺386.1579,

found 386.1567.

General Procedure for the Synthesis of 2-Allyl-2-propargyl-

2-[2-(p-tolylsulﬁnyl)phenyl]acetonitriles (8−18). To a solution of

the corresponding 2-allyl-2-[2-(p-tolylsulﬁnyl)phenyl]acetonitrile

(0.13 mmol) and 18-crown-6 ether (42.0 mg, 0.16 mmol) in

anhydrous THF (1 mL) at −78 °C under argon was added

KHMDS (0.5 M in toluene) (0.320 mL, 0.16 mmol). The mixture

was stirred at −78 °C for 10 min, and then 0.14 mmol of the

corresponding propargyl bromide was added dropwise. The resulting

mixture was stirred at −78 °C. The reaction was monitored by TLC.

Upon transformation of the starting material, the reaction was

hydrolyzed with saturated aqueous NH₄Cl (5 mL). The mixture was

extracted with CH₂Cl₂(3 × 5 mL), dried (Na₂SO₄), and the solvent

was evaporated. The diastereoisomeric mixture was puriﬁed by ﬂash

column chromatography using as the eluent a mixture of AcOEt/

hexane as indicated in each case. The same experimental procedure

was employed when NHMDS was used as the base.

eoisomer [2R,(S)S]-9a (colorless oil): Yield 62% (28 mg); [α]²⁰

D

−149.5 (c 0.6, CHCl₃); IR (ﬁlm) 2921, 2236, 1641, 1453, 1082, 1044,

1

760 cm⁻¹; H NMR δ 7.72−7.64 (m, 2H), 7.55−7.38 (m, 2H), 7.54

and 7.27 (AA′BB′ system, 4H), 5.82−5.71 (m, 1H), 5.34−5.19 (m,

2H), 3.16−2.98 (m, 4H), 2.37 (s, 3H), 1.70 (t, J 2.4 Hz, 3H) ppm; ¹³C

NMR δ 144.9, 141.2, 141.1, 136.3, 131.7, 130.8, 130.1 (2C), 129.9

(2C), 128.6, 125.5 (2C), 121.7, 121.3, 81.6, 72.4, 48.0, 42.7, 32.2, 21.3,

3.4 ppm; MS (ESI+) m/z 348 [M + H]⁺(100); HRMS (ESI+) calcd.

for C₂₂H₂₂NOS [M + H]⁺348.1421, found 348.1416. Diaster-

eoisomer [2S,(S)S]-9b (colorless oil): Yield 7% (3 mg); [α]²⁰_D−63.7

1

(c 0.7, CHCl₃); H NMR δ 7.79−7.76 (m, 1H), 7.58−7.53 (m, 1H),

7.56 and 7.27 (AA′BB′ system, 4H), 7.52−7.42 (m, 2H), 5.73−5.59

(m, 1H), 5.25−5.19 (m, 2H), 3.17−3.01 (m, 4H), 2.38 (s, 3H), 1.78

(t, J 2.4 Hz, 3H) ppm; ¹³C NMR δ 145.7, 141.2, 141.1, 136.4, 131.7,

130.4, 130.1, 129.8 (3C), 127.5, 125.7 (2C), 122.2, 121.4, 81.5, 72.6,

45.7, 43.9, 29.0, 21.3, 3.5 ppm.

[2R,(S)S] and [2S,(S)S]-4-Methyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (10a + 10b). The diaster-

eoisomeric mixture 10a + 10b was obtained using a 50:50 mixture of

[2S,(S)S] and [2R,(S)S]-4-methyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (3 + 3′) as the substrate and propargyl bromide (80%

solution in toluene) as the electrophile, in the presence of KHMDS/

18-crown-6 ether. The reaction mixture was stirred for 30 min. The

crude 89:11 mixture of 10a + 10b was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:3) as the eluent. Diaster-

eoisomer [2R,(S)S]-10a (colorless oil): Yield 79% (36 mg); [α]²⁰

D

−132.5 (c 1.2, CHCl₃); IR (ﬁlm) 2955, 2236, 1528, 1472, 1083, 1047,

1

810, 756 cm⁻¹; H NMR δ 7.75−7.72 (m, 1H), 7.60−7.43 (m, 3H),

7.59 and 7.28 (AA′BB′ system, 4H), 5.01 (m, 1H), 4.86 (m, 1H),

3.31−3.13 (m, 2H), 3.21 and 3.05 (coupled AB system, J 2.3 and 14.6

Hz, 2H), 2.38 (s, 3H), 2.23 (t, J 2.3 Hz, 1H), 1.64 (m, 3H) ppm; ¹³C

NMR δ 144.5, 141.3, 140.8, 138.7, 136.1, 131.8, 130.4, 130.3, 130.0

(2C), 129.9, 125.6 (2C), 121.5, 118.0, 77.7, 73.9, 48.5, 46.7, 32.9, 23.5,

21.3 ppm; MS (FAB+) m/z 348 [M + H]⁺(100), 310 (32); HRMS

(FAB+) calcd. for C₂₂H₂₂NOS [M + H]⁺348.1422, found 348.1415.

Diastereoisomer [2S,(S)S]-10b (colorless oil): Yield 8% (3 mg);

[α]²⁰_D−120.7 (c 1.8, CHCl₃); ¹H NMR δ 7.81−7.78 (m, 1H), 7.73−

7.70 (m, 1H), 7.52−7.43 (m, 2H), 7.51 and 7.28 (AA′BB′ system,

4H), 4.96 (m, 1H), 4.93 (m, 1H), 3.28 and 3.08 (AB system, J 14.4

Hz, 2H), 3.26 and 3.05 (coupled AB system, J 2.5 and 16.0 Hz, 2H),

2.39 (s, 3H), 2.13 (t, J 2.5 Hz, 1H), 1.67 (m, 3H) ppm; ¹³C NMR δ

144.7, 141.4, 140.5, 138.7, 136.1, 131.8, 130.4, 130.3 (2C), 129.9,

129.4, 125.6 (2C), 121.6, 118.2, 77.6, 73.8, 48.6, 46.8, 33.0, 23.6, 21.3

ppm. MS (FAB+) m/z 348 [M + H]⁺(100), 310 (32); HRMS (FAB

+) calcd. for C₂₂H₂₂NOS [M + H]⁺348.1422, found 348.1412.

[2R,(S)S] and [2S,(S)S]-2-(2-But-1-inyl)-4-methyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (11a + 11b). The diaster-

eoisomeric mixture 11a + 11b was obtained using a 50:50 mixture of

[2S,(S)S] and [2R,(S)S]-4-methyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (3 + 3′) as the substrate and 1-bromobut-2-ine as the

electrophile, in the presence of KHMDS/18-crown-6 ether. The

reaction mixture was stirred for 60 min. The crude 90:10 mixture of

11a + 11b was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:3) as the eluent. Diastereoisomer [2R,(S)S]-11a

[2R,(S)S] and [2S,(S)S]-2-(Prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)-

phenyl]pent-4-enenitrile (8a + 8b). The diastereoisomeric mixture

8a + 8b was obtained using a 50:50 mixture of [2S,(S)S] and [2R,(S)

S]-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (2 + 2′) as the

substrate and propargyl bromide (80% solution in toluene) as the

electrophile, in the presence of KHMDS/18-crown-6 ether. The

reaction mixture was stirred for 60 min. The crude 80:20 mixture of 8a

+ 8b was puriﬁed by ﬂash column chromatography using AcOEt−

hexane (1:2) as the eluent. Diastereoisomer [2R,(S)S]-8a (yellow

solid): Yield 62% (27 mg); mp 85−87 °C (CH₂Cl₂−hexane); [α]²⁰

D

−160.3 (c 0.5, CHCl₃); IR (KBr) 3299, 2940, 2236, 1436, 1042, 1015,

1

759 cm⁻¹; H NMR δ 7.79−7.76 (m, 1H), 7.60−7.53 (m, 1H), 7.55

and 7.27 (AA′BB′ system, 4H), 7.51−7.44 (m, 2H), 5.73−5.59 (m,

1H), 5.29−5.21 (m, 2H), 3.24−3.13 (m, 3H), 3.06 (dd, J 7.6 and 14.1

Hz, 1H), 2.37 (s, 3H), 2.20 (t, J 2.5 Hz, 1H) ppm; ¹³C NMR δ 145.7,

141.3, 141.0, 135.9, 131.8, 130.4, 130.2, 130.1, 129.9 (2C), 127.4,

125.7 (2C), 121.8 (2C), 77.6, 73.9, 45.4, 44.0, 28.6, 21.3 ppm; MS

+

(FAB+) m/z 334 [M + H] (100); HRMS (FAB+) calcd. for

C₂₁H₂₀NOS [M + H]⁺334.1266, found 334.1270. Diastereoisomer

(colorless oil): Yield 71% (33 mg); [α]²⁰−88.2 (c 2.0, CHCl₃); IR

D

[2S,(S)S]-8b (yellow solid): Yield 18% (8 mg); mp 108−110 °C

(ﬁlm) 2920, 2236, 1645, 1471, 1082, 1047, 810, 754 cm⁻¹; ¹H NMR δ

7.78−7.71 (m, 2H), 7.52 and 7.27 (AA′BB′ system, 4H), 7.51−7.44

1

(CH₂Cl₂−hexane); [α]²⁰−145.9 (c 0.8, CHCl₃); H NMR δ 7.71−

D

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Article

(m, 2H), 4.93 (m, 1H), 4.91 (m, 1H), 3.25 and 3.05 (AB system, J

14.4 Hz, 2H), 3.18 and 3.08 (coupled AB system, J 2.5 and 12.8 Hz,

2H), 2.38 (s, 3H), 1.70 (t, J 2.5 Hz, 3H), 1.65 (m, 3H) ppm; ¹³C

NMR δ 144.5, 141.2 (2C), 138.9, 136.5, 131.7, 130.2, 130.1, 129.9

(2C), 129.3, 125.6 (2C), 121.9, 117.7, 81.6, 72.7, 49.0, 46.7, 33.6, 23.5,

21.3, 3.4 ppm; MS (FAB+) m/z 362 [M + H]⁺(100); HRMS (FAB+)

calcd. for C₂₃H₂₄NOS [M + H]⁺362.1601, found 362.1622.

Diastereoisomer [2S,(S)S]-11b (colorless oil): Yield 8% (4 mg);

[α]²⁰_D−132.5 (c 1.2, CHCl₃); ¹H NMR δ 7.75−7.72 (m, 1H), 7.61−

7.55 (m, 1H), 7.59 and 7.28 (AA′BB′ system, 4H), 7.49−7.43 (m,

2H), 4.98 (m, 1H), 4.84 (m, 1H), 3.20−3.06 (m, 2H), 3.18 and 3.02

(AB system, J 14.4 Hz, 2H), 2.38 (s, 3H), 1.79 (t, J 2.4 Hz, 3H), 1.63

(s, 3H) ppm; ¹³C NMR δ 146.1, 141.1, 141.0, 138.9, 137.1, 131.7,

130.1, 129.9, 129.8 (2C), 127.3, 125.7 (2C), 122.9, 117.7, 81.6, 72.9,

47.4, 44.9, 29.4, 23.6, 21.3, 3.6 ppm.

[2R,(S)S]-14a (data from a 90:10 mixture of 14a + 14b): IR (ﬁlm)

3058, 2854, 2236, 1718, 1447, 1083, 1029, 810, 755 cm⁻¹; ¹H NMR δ

7.67−7.62 (m, 2H), 7.50 and 7.26 (AA′BB′ system, 4H), 7.39−7.35

(m, 2H), 7.33−7.21 (m, 5H), 5.38 (m, 1H), 5.29 (m, 1H), 3.67 and

3.60 (AB system, J 14.8 Hz, 2H), 3.16 (coupled AB system, J 2.6 and

17.2 Hz, 2H), 2.38 (s, 3H), 2.06 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR δ

144.0, 142.9, 141.3, 140.6, 140.5, 136.3, 131.7, 130.2, 130.1, 129.9

(2C), 129.3, 128.4 (2C), 128.3, 127.8, 126.7 (2C), 125.6 (2C), 120.5,

77.8, 73.9, 49.7, 43.3, 32.4, 21.3 ppm; MS (FAB+) m/z 410 [M + H]⁺

(100); HRMS (FAB+) calcd. for C₂₇H₂₄NOS [M + H]⁺410.1579,

found 410.1578. Diastereoisomer [2S,(S)S]-14b (data from a 18:82

mixture of 14a + 14b): ¹H NMR δ 7.67−7.64 (m, 1H), 7.59 and 7.26

(AA′BB′ system, 4H), 7.38−7.20 (m, 8H), 5.31 (m, 1H), 5.22 (m,

1H), 3.66 and 3.64 (AB system, J 18.7 Hz, 2H), 2.99 (m, 2H), 2.35 (s,

3H), 2.19 (t, J 2.5 Hz, 1H) ppm; ¹³C NMR δ 145.9, 142.1, 141.1,

140.9, 140.8, 136.1, 131.4, 130.2, 130.1, 129.9 (2C), 128.4 (2C), 127.8,

126.7, 126.5 (2C), 125.5 (2C), 122.2, 120.6, 78.0, 74.0, 45.2, 44.8,

28.4, 21.3 ppm; MS (FAB+) m/z 410 [M + H]⁺(100), 372 (90);

HRMS (FAB+) calcd. for C₂₇H₂₄NOS [M + H]⁺410.1579, found

410.1566.

[2R,(S)S,4E] and [2S,(S)S,4E]-2-(Prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]hex-4-enenitrile (12a + 12b). The diaster-

eoisomeric mixture 12a + 12b was obtained using a 40:40:10:10

mixture of [2S,(S)S,4E], [2R,(S)S,4E], [2S,(S)S,4Z] and [2R,(S)

S,4Z]-2-[2-(p-tolylsulﬁnyl)phenyl]-hex-4-enenitrile [(E)-4 + (E)-4′ +

(Z)-4 + (Z)-4′] as the substrate and propargyl bromide (80% solution

in toluene) as the electrophile, in the presence of KHMDS/18-crown-

6 ether. The reaction mixture was stirred for 30 min. The crude

mixture was puriﬁed by ﬂash column chromatography using AcOEt−

hexane (1:3) as the eluent. An 88:12 mixture of 12a + 12b was

obtained, whereas the products derived from (Z)-4 and (Z)-4′ could

not be isolated. Yield (12a + 12b mixture): 76% (34 mg, colorless oil);

[2R,(S)S,4E] and [2S,(S)S,4E]-2-(But-2-inyl)-4-phenyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (15a + 15b). The diaster-

eoisomeric mixture 15a + 15b was obtained using a 60:40 mixture of

[2S,(S)S] and [2R,(S)S]-4-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (5 + 5′) as the substrate and 1-bromobut-2-ine as the

electrophile, in the presence of KHMDS/18-crown-6 ether. The

reaction mixture was stirred for 2 h. The crude 89:11 mixture of 15a +

15b was puriﬁed by ﬂash column chromatography using AcOEt−

hexane (1:4) as the eluent. Yield (mixture 15a + 15b): 94% (51.6 mg,

white solid). Diastereoisomer [2R,(S)S]-15a (data from an 89:11

mixture of 15a + 15b): IR (KBr) 3019, 2962, 2236, 1718, 1450, 1082,

1

IR (ﬁlm) 2940, 2236, 1648, 1438, 1083, 1047, 810, 755 cm⁻¹; H

NMR (12a + 12b mixture) δ 7.70−7.66 (m, 4H), 7.51 and 7.27

(AA′BB′ system, 8H), 7.52−7.41 (m, 4H), 5.81−5.70 (m, 2H), 5.47−

5.37 (m, 2H), 3.30−3.18 (m, 4H), 3.17−3.02 (m, 4H), 2.37 (s, 6H),

2.06 (t, J 2.5 Hz, 1H), 1.65 (d, J 7.0 Hz, 3H), 1.59 (d, J 6.2 Hz, 3H)

ppm; ¹³C NMR (12a + 12b mixture) δ 144.9, 141.2, 140.8, 136.2,

132.7, 131.8, 130.3, 130.2, 129.9 (2C), 128.7, 125.5 (2C), 123.0, 121.5,

77.7, 77.6, 73.7, 47.9, 47.5, 41.8, 36.1, 31.4, 21.3 (2C), 18.0, 13.4 ppm;

MS (FAB+) m/z 348 [M + H]⁺(100), 310 (32); HRMS (FAB+)

calcd. for C₂₂H₂₂NOS [M + H]⁺348.1422, found 348.1418.

1

1029, 810, 755 cm⁻¹; H NMR δ 7.69−7.62 (m, 1H), 7.61−7.58 (m,

1H), 7.50 and 7.26 (AA′BB′ system, 4H), 7.39−7.20 (m, 7H), 5.38

(m, 1H), 5.29 (m, 1H), 3.63 and 3.58 (AB system, J 17.6 Hz, 2H),

3.09 (coupled AB system, J 2.3 and 16.8 Hz, 2H), 2.38 (s, 3H), 1.65 (t,

J 2.6 Hz, 3H) ppm; ¹³C NMR δ 144.2, 143.2, 141.2 (2C), 140.7, 136.8,

131.5 (2C), 129.9, 129.8 (2C), 129.4, 128.3 (2C), 127.7, 126.8 (2C),

125.8 (2C), 121.1, 119.8, 81.6, 72.9, 50.1, 44.4, 33.2, 21.2, 3.3 ppm;

MS (FAB+) m/z 424 [M + H]⁺(100), 307 (15); HRMS (FAB+)

calcd. for C₂₈H₂₆NOS [M + H]⁺424.1735, found 424.1735.

Diastereoisomer [2S,(S)S]-15b (data from a 20:80 mixture of 15a

+ 15b): ¹H NMR δ 7.68−7.61 (m, 1H), 7.60 and 7.26 (AA′BB′

system, 4H), 7.36−7.20 (m, 8H), 5.38 (s, 1H), 5.27 (s, 1H), 3.67−

3.60 (m, 2H), 2.99 (m, 2H), 2.37 (s, 3H), 1.75 (t, J 2.4 Hz, 3H) ppm;

¹³C NMR δ 146.0, 142.5, 141.2, 141.0, 140.8, 136.8, 131.3, 130.1,

[2R,(S)S,4E] and [2S,(S)S,4E]-2-(But-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]hex-4-enenitrile (13a + 13b). The diaster-

eoisomeric mixture 13a + 13b was obtained using a 40:40:10:10

mixture of [2S,(S)S,4E], [2R,(S)S,4E], [2S,(S)S,4Z] and [2R,(S)

S,4Z]-2-[2-(p-tolylsulﬁnyl)phenyl]-hex-4-enenitrile [(E)-4 + (E)-4′ +

(Z)-4 + (Z)-4′] as the substrate and 1-bromobut-2-ine as the

electrophile, in the presence of KHMDS/18-crown-6 ether. The

reaction mixture was stirred for 90 min. The crude mixture was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (1:3)

as the eluent. A 90:10 mixture of 13a + 13b was obtained, whereas the

products derived from (Z)-4 and (Z)-4′ could not be isolated. Yield

(13a + 13b mixture): 80% (37.5 mg, colorless oil); IR (ﬁlm) 3058,

2950, 2235, 1532, 1438, 1082, 1045, 812, 754 cm⁻¹; ¹H NMR (13a +

13b mixture) δ 7.74−7.69 (m, 2H), 7.66−7.64 (m, 2H), 7.53 and 7.27

(AA′BB′ system, 8H), 7.58−7.40 (m, 4H), 5.77−5.68 (m, 1H), 5.70−

5.58 (m, 1H), 5.46−5.39 (m, 1H), 5.40−5.25 (m, 1H), 3.26−2.92 (m,

4H), 2.38 (s, 6H), 1.76 (t, J 2.4 Hz, 1H), 1.69 (t, J 2.2 Hz, 1H), 1.65

(d, J 6.3 Hz, 3H) ppm; ¹³C NMR (13a + 13b mixture) δ 144.9, 141.2,

141.0, 136.6, 132.2, 131.6, 130.1, 130.0, 129.9 (3C), 128.6, 125.6,

125.5 (2C), 123.3, 121.9, 81.4, 72.5, 48.4, 47.8, 43.0, 41.8, 36.1, 32.0,

21.2 (2C), 17.9, 13.3, 3.5, 3.3 ppm; MS (FAB+) m/z 362 [M + H]⁺

(100), 338 (11); HRMS (FAB+) calcd. for C₂₃H₂₄NOS [M + H]⁺

362.1601, found 362.1573.

[2R,(S)S] and [2S,(S)S]-4-Phenyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (14a + 14b). The diaster-

eoisomeric mixture 14a + 14b was obtained using a 60:40 mixture of

[2S,(S)S] and [2R,(S)S]-4-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (5 + 5′) as the substrate and propargyl bromide (80%

solution in toluene) as the electrophile, in the presence of KHMDS/

18-crown-6 ether. The reaction mixture was stirred for 2 h. The crude

90:10 mixture of 14a + 14b was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:4) as the eluent. Yield

(mixture 14a + 14b): 94% (50 mg, colorless oil). Diastereoisomer

130.0, 129.8 (2C), 128.3 (2C), 127.7, 127.2, 126.6 (2C), 125.7 (2C),

122.6, 120.2, 81.6, 73.0, 45.7, 44.7, 29.1, 21.3, 3.5 ppm; MS (FAB+)

m/z 424 [M + H]⁺(100), 372 (40); HRMS (FAB+) calcd. for

C₂₈H₂₆NOS [M + H]⁺424.1735, found 424.1737.

[2R,(S)S,4E] and [2S,(S)S,4E]-5-Phenyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (16a + 16b). The diaster-

eoisomeric mixture 16a + 16b was obtained using a 60:40 mixture of

[2S,(S)S] and [2R,(S)S]-5-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (6 + 6′) as the substrate and propargyl bromide (80%

solution in toluene) as the electrophile, in the presence of KHMDS/

18-crown-6 ether. The reaction mixture was stirred for 30 min. The

crude 87:13 mixture of 16a + 16b was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:4) as the eluent. Yield

(mixture 16a + 16b): 83% (44.1 mg, yellow oil); IR (ﬁlm) 3030, 2860,

1

2236, 1718, 1596, 1447, 1083, 1029, 754 cm⁻¹; H NMR (16a + 16b

mixture) δ 7.80−7.76 (dd, J 3.4 and 5.9 Hz, 1H), 7.70−7.67 (m, 5H),

7.55−7.39 (m, 9H), 7.29−7.18 (m, 11H), 6.62 (d, J 15.7 Hz, 1H), 6.48

(d, J 15.7 Hz, 1H), 6.11 (m, 1H), 5.95 (m, 1H), 3.38−3.16 (m, 8H),

2.34 (s, 6H), 2.19 (t, J 2.6 Hz, 1H), 2.10 (t, J 2.6 Hz, 1H) ppm; ¹³C

NMR (16a + 16b mixture) δ 145.6, 144.9, 141.3 (2C), 140.9, 140.7,

136.4, 136.3, 136.2, 136.0, 135.9, 131.9, 131.8, 130.4 (2C), 130.1,

129.9 (3C), 128.7, 128.6, 128.5 (2C), 127.9, 127.8, 127.4, 126.5 (2C),

126.4 (2C), 125.8 (2C), 125.5 (2C), 121.9, 121.7, 121.3, 121.1, 77.6,

77.2, 74.1, 74.0, 48.0, 45.7, 43.3, 42.2, 31.6, 28.6, 21.3 (2C) ppm; MS

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Article

(FAB+) m/z 410 [M + H]⁺(100), 109 (12); HRMS (FAB+) calcd.

for C₂₇H₂₄NOS [M + H]⁺410.1573, found 410.1566.

131.1, 128.8 (2C), 128.3, 126.1 (2C), 121.0, 120.7, 77.9, 72.9, 46.6,

42.9, 30.3 ppm; MS (EI+) m/z 195 [M]⁺(18), 154 (81), 127 (100);

HRMS (EI+) calcd. for C₁₄H₁₃N 195.1048, found 195.1048.

[2R,(S)S,4E], [2S,(S)S,4E], and [2R,(S)S,4Z]-4-Methyl-5-phenyl-

2-(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile

(17a + 17b + 17c). The diastereoisomeric mixture 17a + 17b + 17c

was obtained using a 40:40:10:10 mixture of [2S,(S)S,4E], [2R,(S)

S,4E], [2S,(S)S,4Z], and [2R,(S)S,4Z]-4-methyl-5-phenyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile [(E)-7 + (E)-7′ + (Z)-7 + (Z)-

7′] as the substrate and propargyl bromide (80% solution in toluene)

as the electrophile, in the presence of KHMDS/18-crown-6 ether. The

reaction mixture was stirred for 2 h. The crude mixture was puriﬁed by

ﬂash column chromatography using AcOEt−hexane (1:3) as the

eluent. A 75:16:9 mixture of 17a + 17b + 17c was obtained. Yield (17a

+ 17b mixture): 80% (44 mg, colorless oil); IR (ﬁlm) 3019, 2854,

2236, 1718, 1596, 1447, 1083, 1029, 810, 754 cm⁻¹. ¹H NMR (17a +

17b mixture) δ 7.82 (dd, J 1.7 and 7.6 Hz, 1H), 7.70 (dd, J 2.1 and 7.3

Hz, 1H), 7.50 and 7.25 (AA′BB′ system, 4H), 7.51−7.38 (m, 2H),

7.26−7.21 (m, 2H), 7.13−7.08 (m, 3H), 6.60 (m, 1H), 6.49 (m, 1H),

3.60 and 3.25 (AB system, J 14.4 Hz, 2H), 3.38 and 3.22 (AB system, J

16.5 Hz, 2H), 3.34 (coupled AB system, J 2.5 and 17.1 Hz, 2H), 2.99−

2.96 (m, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.13 (t, J 2.5 Hz, 1H), 1.92

(t, J 2.4 Hz, 1H), 1.77 (m, 3H), 1.67 (m, 3H) ppm; ¹³C NMR (17a +

17b mixture) δ 144.6, 141.4, 140.9, 137.3, 136.4, 132.5, 131.9, 131.6,

130.5, 130.3, 130.0 (2C), 129.5, 128.9 (2C), 128.0 (2C), 126.6, 125.6

(2C), 121.4, 121.3, 77.9, 77.6, 74.0, 73.7, 49.8, 48.2, 49.6, 41.5, 32.8,

30.8, 21.3 (2C), 19.1, 19.0 ppm; MS (FAB+) m/z 424 [M + H]⁺

(100), 307 (22); HRMS (FAB+) calcd. for C₂₈H₂₆NOS [M + H]⁺

424.1735, found 424.1747. Diastereoisomer [2R,(S)S,4Z]-17c (data

from a diastereoisomeric mixture 17a + 17b + 17c): ¹H NMR δ 7.85−

7.82 (m, 1H), 7.83−7.81 (m, 1H), 7.62 and 7.19 (AA′BB′ system,

4H), 7.57−7.42 (m, 3H), 7.34−7.21 (m, 4H), 6.40 (m, 1H), 3.37 and

3.20 (AB system, J 13.9 Hz, 2H), 3.27−3.25 (m, 2H), 2.38 (s, 3H),

2.26 (t, J 2.4 Hz, 1H), 1.78 (s, 3H) ppm.

(R,E)-2-Phenyl-2-(prop-2-yn-1-yl)hex-4-enenitrile (29). To a

solution of 50 mg (0.15 mmol) of [2R,(S)S]-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (10a) in anhydrous THF (1.5

mL) at −78 °C under argon was added t-BuLi (1.7 M in hexanes)

(0.13 mL, 0.23 mmol). The mixture was stirred at −78 °C for 30 min.

The reaction was hydrolyzed with saturated aqueous NH₄Cl (1.0 mL).

The organic layer was dried (Na₂SO₄), and the solvent was

evaporated. The residue was puriﬁed by ﬂash column chromatography

using AcOEt−hexane (1:6) as the eluent. Yield: 65% (19.1 mg,

1

colorless oil); [α]²⁰+8.0 (c 0.7, CHCl₃); H NMR δ 7.29−7.21 (m,

D

5H), 4.80 (dt, J 12.1, 3.0 Hz, 1H), 4.71 (d, J 6.1 Hz, 1H), 2.85−2.81

(m, 2H), 2.85−2.81 (m, 2H), 2.70−2.56 (m, 2H), 2.07 (t, J 3.0 Hz,

1H), 1.50 (d, J 9.0 Hz, 3H) ppm; ¹³C NMR δ 139.8, 139.5, 128.8,

128.3, 126.2, 117.1, 116.2. 78.2, 72.9, 48.8, 46.1, 31.3, 23.6 ppm.

HRMS (EI+) calcd. for C₁₅H₁₅N 209.1204, found 209.1197.

(R,E)-2-Phenyl-2-(prop-2-yn-1-yl)hex-4-enenitrile (30). To a

solution of 50 mg (0.15 mmol) of [2R,(S)S]-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (12a) in anhydrous THF (1.5

mL) at −78 °C under argon was added t-BuLi (1.7 M in hexanes)

(0.13 mL, 0.23 mmol). The mixture was stirred at −78 °C for 30 min.

The reaction was hydrolyzed with saturated aqueous NH₄Cl (1.0 mL).

The organic layer was dried (Na₂SO₄), and the solvent was

evaporated. The residue was puriﬁed by ﬂash column chromatography

using AcOEt−hexane (1:6) as the eluent. Yield: 58% (18.2 mg,

colorless oil); [α]²⁰_D+9.7 (c 0.42, CHCl₃); ¹H NMR δ 7.40−7.19 (m,

5H), 5.60−5.71 (m, 1H), 5.29−5.20 (m, 1H), 2.82−2.75 (m, 2H),

2.04 (t, J 3.0 Hz, 1H), 1.58 (t, J 6.1 Hz, 3H) ppm; ¹³C NMR δ 139.4,

128.8 (2C), 128.3, 126.2, 121.6, 117.1, 78.2, 72.9, 46.5, 31.3, 29.7, 23.6

ppm.

( )-2-(Prop-2-inyl)-2-[2-(p-tolylsulfonyl)phenyl]pent-4-ene-

nitrile (34). It was prepared from 2-[2-(p-tolylsulfonyl)phenyl]-

acetonitrile (33) by successive allylation and propargylation reactions,

using allyl bromide and propargyl bromide as the electrophiles,

respectively. Overall yield (two steps): 64% (133.8 mg, colorless oil);

¹H NMR δ 7.94 (dd, J 1.1 and 8.0 Hz, 1H), 7.88 (dd, J 1.4 and 8.0 Hz,

1H), 7.80 and 7.33 (AA′BB′ system, 4H), 7.58 (dt, J 1.4 and 7.5 Hz,

1H), 7.44 (dt, J 1.2 and 8.0 Hz, 1H), 5.72−5.62 (m, 1H), 5.28−5.15

(m, 2H), 3.63 (dd, J 2.6 and 17.2 Hz, 1H), 3.46 (dd, J 6.5 and 14.1 Hz,

1H), 3.32 (dd, J 2.6 and 17.2 Hz, 1H), 3.10 (dd, J 6.5 and 14.1 Hz,

1H), 2.43 (s, 3H), 2.00 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR δ 144.5,

140.3, 138.8, 135.8, 133.6, 132.9, 131.8, 131.5, 129.8 (2C), 128.9,

127.7 (2C), 121.5, 120.8, 78.5, 72.9, 49.3, 42.4, 29.2, 21.6 ppm; MS

(ESI+) m/z 350 [M + H]⁺(100), 312 (30); HRMS (FAB+) calcd. for

C₂₁H₂₀NO₂S [M + H]⁺350.1209, found 350.1193.

2-[2-(p-Tolylsulfenyl)phenyl]acetonitrile (35). To a solution of

4-methylbenzenethiol (890 mg, 3.6 mmol) in anhydrous DMF (5.0

mL) at rt was added 2-iodophenylacetonitrile (874 mg, 3.6 mmol),

potassium carbonate (506 mg, 3.6 mmol) and Cu(0) (228 mg, 3.6

mmol). The mixture was stirred at reﬂux for 18 h. The reaction was

monitored by TLC. Upon transformation of the substrate, the mixture

was cooled at rt and ﬁltered through a Celite pad. The solution was

washed with aqueous 1 N HCl (5.0 mL). The aqueous layer was

extracted with AcOEt (4 × 5 mL), dried (Na₂SO₄), and the solvent

was evaporated. The residue was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:6) as the eluent. Yield:

54% (464 mg, yellow oil); ¹H NMR δ 7.69−7.66 (m, 1H), 7.52−7.39

(m, 3H), 7.38−7.28 (m, 4H), 3.99 (s, 2H), 2.46 (s, 3H) ppm; ¹³C

NMR δ 137.5, 134.5, 133.2, 131.4, 130.2 (2C), 129.8 (2C), 129.0,

128.9, 128.5, 128.3, 117.4, 22.2, 20.9 ppm; MS (EI+) m/z [M⁺] 239

(100), 197 (87); HRMS (ESI+) calcd. for C₁₅H₁₃NS 239.0769, found

239.0779.

[2R,(S)S,4E], [2S,(S)S,4E], and [2R,(S)S,4Z]-2-(But-2-inyl)-4-

methyl-5-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]hex-4-enenitrile

(18a + 18b + 18c). The diastereoisomeric mixture 18a + 18b + 19c

was obtained using a 40:40:10:10 mixture of [2S,(S)S,4E], [2R,(S)

S,4E], [2S,(S)S,4Z], and [2R,(S)S,4Z]-4-methyl-5-phenyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile [(E)-7 + (E)-7′ + (Z)-7 + (Z)-

7′] as the substrate and 1-bromobut-2-ine as the electrophile, in the

presence of KHMDS/18-crown-6 ether. The reaction mixture was

stirred for 2 h. The crude 72:16:12 mixture of 18a + 18b + 18c was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (1:3)

as the eluent. Diastereoisomer [2R,(S)S,4E]-18a (colorless oil): Yield

68% (38.6 mg); [α]²⁰−70.1 (c 1.6, CHCl₃); IR (ﬁlm) 3058, 2854,

D

1

2236, 1689, 1447, 1082, 1027, 810, 755 cm⁻¹; H NMR δ 7.78−7.71

(m, 2H), 7.52 and 7.11 (AA′BB′ system, 4H), 7.49−7.44 (m, 2H),

7.29−7.11 (m, 5H), 6.48 (m, 1H), 3.36 and 3.20 (AB system, J 14.4

Hz, 2H), 3.26 (coupled AB system, J 2.5 and 14.5 Hz, 2H), 2.38 (s,

3H), 1.77−1.76 (m, 3H), 1.71 (t, J 2.5 Hz, 3H) ppm; ¹³C NMR δ

144.7, 141.3, 141.2, 137.4, 136.8, 132.2, 131.9, 131.7, 130.2, 130.0,

129.9 (2C), 129.4, 128.9 (2C), 127.9 (2C), 126.5, 125.7 (2C), 121.9,

81.7, 72.9, 50.1, 49.8, 33.5, 21.3, 19.2, 3.4 ppm; MS (FAB+) m/z 438

[M + H]⁺(100); HRMS (FAB+) calcd. for C₂₉H₂₈NOS [M + H]⁺

438.1892, found 438.1881. Diastereoisomers [2S,(S)S,4E]-18b and

1

[2R,(S)S,4Z]-18c: H NMR (signiﬁcative signals from a diastereoiso-

meric mixture 18a + 18b + 18c) δ 7.69−7.65 (m, 1H), 6.58 (m, 1H),

6.36 (m, 1H), 2.24 (t, J 2.3 Hz, 3H), 1.98 (t, J 2.4 Hz, 3H) ppm.

(R)-2-Phenyl-2-(prop-2-inyl)-pent-4-enenitrile (28). To a

solution of 50 mg (0.15 mmol) of [2R,(S)S]-2-(prop-2-inyl)-2-[2-

(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (8a) in anhydrous THF (1.5

mL) at −78 °C under argon was added t-BuLi (1.7 M in hexanes)

(0.13 mL, 0.23 mmol). The mixture was stirred at −78 °C for 30 min.

The reaction was hydrolyzed with saturated aqueous NH₄Cl (1.0 mL).

The organic layer was dried (Na₂SO₄), and the solvent was

evaporated. The residue was puriﬁed by ﬂash column chromatography

using AcOEt−hexane (1:6) as the eluent. Yield: 62% (18.1 mg,

colorless oil); [α]²⁰_D+11.5 (c 0.7, CHCl₃); ¹H NMR δ 7.49−7.34 (m,

5H), 5.74−5.60 (m, 1H), 5.24−5.20 (m, 1H), 5.18−5.15 (m, 1H),

2.92−2.73 (m, 4H), 2.13 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR δ 137.0,

( )-2-[2-(p-Tolylsulfenyl)phenyl]pent-4-enenitrile. It was pre-

pared by following the general procedure described for allylation. Allyl

bromide was used as the electrophile and 35 as the substrate. The

reaction mixture was stirred at rt for 30 min. The crude product was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (1:6)

as the eluent. Yield: 76% (27.6 mg, yellow oil); ¹H NMR δ 7.75−7.69

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(m, 1H), 7.47−7.44 (m, 3H), 7.40−7.26 (m, 4H), 7.85 (m, 1H),

5.37−5.24 (m, 2H), 4.70 (dd, J 6.9 and 7.7 Hz, 1H), 3.49 (dd, J 6.9

and 14.3 Hz, 1H), 3.06 (dd, J 7.7 and 14.3 Hz, 1H), 2.45 (s, 3H) ppm;

¹³C NMR δ 137.5, 136.6, 134.8, 132.5, 131.4, 131.3, 130.5 (2C), 130.2

(2C), 128.5, 128.4, 128.3, 120.3, 119.8, 38.9, 35.0, 21.0 ppm; MS (EI

+) m/z [M]⁺279 (22), 211 (100); HRMS (ESI+) calcd. for C₁₈H₁₇NS

279.1082, found 279.1095.

(2C), 129.5, 128.9 (2C), 128.0 (2C), 126.6, 125.6 (2C), 121.4, 121.3,

77.9, 77.6, 74.0, 73.7, 49.8, 48.2, 49.6, 41.5, 32.8, 30.8, 20.2, 20.1, 19.1,

18.9 ppm.

General Procedure for the Synthesis of 2-Allyl-2-propargyl-

2-[2-(p-tolylsulfenyl)phenyl]acetamides (42−44). To a solution

of corresponding 2-allyl-2-propargyl-2-[2-(p-tolylsulﬁnyl)phenyl]-

acetonitrile (0.18 mmol, 1.0 equiv) in anhydrous CH₃CN (3.0 mL)

at rt under argon was dropwise added BF₃·OEt₂(0.23 mmol, 1.3

equiv). The mixture was stirred at rt for 30 min, and then NaI (0.19

mmol, 1.1 equiv) was added. The resulting mixture was stirred at rt for

4.5 h. The reaction was monitored by TLC. Upon transformation of

the starting material, the reaction was hydrolyzed with saturated

aqueous NaHSO₃(2.0 mL) and washed with saturated aqueous

NaHCO₃(3 × 3.0 mL). The mixture was extracted with CH₂Cl₂(3 ×

5 mL), dried (Na₂SO₄), and the solvent was evaporated. The residue

was puriﬁed by ﬂash column chromatography using AcOEt−hexane

(1:3) as the eluent.

( )-2-[2-(p-Tolylsulfenyl)phenyl]hex-4-enenitrile. It was pre-

pared by following the general procedure described for allylation.

Commercial 1-bromobut-2-ene (80:20 mixture of E/Z) was used as

the electrophile and 35 as the substrate. The reaction mixture was

stirred at rt for 30 min. The crude product was puriﬁed by ﬂash

column chromatography using AcOEt−hexane (1:6) as the eluent.

1

Yield: 64% (24.4 mg, yellow oil); H NMR δ 7.66−7.64 (m, 1H),

7.41−7.38 (m, 3H), 7.34−7.25 (m, 4H), 5.72−5.58 (m, 2H), 5.59 (dd,

J 6.3 and 7.9 Hz, 1H), 3.30 (dd, J 6.7 and 14.3 Hz, 1H), 2.93 (dd, J 7.6

and 14.3 Hz, 1H), 2.41 (s, 3H), 1.71 (d, J 7.6 Hz, 3H) ppm; ¹³C NMR

δ 137.4, 137.3, 136.9, 133.6, 130.5, 130.4 (2C), 130.3 (2C), 129.6,

128.8, 128.4, 127.0, 125.1, 120.6, 37.9, 35.6, 21.0, 17.9 ppm; MS (EI+)

m/z [M]⁺293 (15), 211 (100); HRMS (ESI+) calcd. for C₁₉H₁₉NS

293.1238, found 293.1225.

(R)-2-(Prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]pent-4-en-

amide [(R)-42]. It was obtained using [2R,(S)S]-2-(prop-2-inyl)-2-[2-

(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (8a) as the substrate. Yield:

56% (33.7 mg, white solid); mp 109−111 °C (CH₂Cl₂−hexane); IR

(KBr) 2115, 1669, 1492, 1368, 807 cm⁻¹; [α]²⁰−13.7 (c 1.0,

( )-2-(Prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]pent-4-ene-

nitrile [( )-36]. It was prepared by following the general procedure

described for propargylation. ( )-2-[2-(p-Tolylsulfenyl)phenyl]pent-

4-enenitrile was used as the substrate and propargyl bromide (80%

solution in toluene) as the electrophile, in the presence of LiHMDS

(1.0 M in THF). The reaction mixture was stirred at rt for 30 min. The

crude ( )-36 was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:6) as the eluent. Yield: 62% (25.5 mg, yellow oil);

¹H NMR δ 7.43−7.40 (m, 1H), 7.38−7.31 (m, 3H), 7.30−7.23 (m,

4H), 5.88 (m, 1H), 5.42−5.26 (m, 2H), 3.60−3.39 (m, 3H), 3.21−

3.11 (m, 1H), 2.46 (s, 3H), 2.22 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR δ

137.4, 136.1, 135.6, 134.7, 132.3, 131.5, 130.9 (2C), 130.2 (2C), 129.3,

129.1, 127.5, 126.5, 120.5, 78.4, 72.8, 47.7, 41.2, 27.6, 21.0 ppm; MS

(EI+) m/z [M]⁺317 (24), 236 (100); HRMS (ESI+) calcd. for

C₂₁H₁₉NS 317.1238, found 317.1235.

D

1

CHCl₃); H NMR δ 7.50 (dd, J 1.5 and 8.0 Hz, 1H), 7.32 (dt, J 1.5

and 7.7 Hz, 1H), 7.27−7.18 (m, 2H), 7.12 and 7.07 (AA′BB′ system,

4H), 5.74−5.54 (m, 1H), 5.32 (br s, 2H), 5.25−5.18 (m, 1H), 5.15−

5.11 (m, 1H), 3.26−3.16 (m, 1H), 3.15 (coupled AB system, J 2.3 and

17.3 Hz, 2H), 2.82 (dd, J 7.0 and 13.6 Hz, 1H), 2.30 (s, 3H), 1.92 (t, J

2.7 Hz, 1H) ppm; ¹³C NMR δ 175.6, 141.1, 136.8, 136.7, 135.4, 132.9,

130.5 (2C), 129.9 (3C), 128.9, 128.5, 127.1, 119.1, 80.9, 71.6, 53.6,

40.5, 25.2, 21.0 ppm; MS (ESI+) m/z 336 [M + H]⁺(20), 319 (100),

292 (55); HRMS (ESI+) calcd. for C₂₁H₂₂NOS [M + H]⁺336.1423,

found 336.1416.

(S)-2-(Prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]pent-4-en-

amide [(S)-42]. It was obtained using [2S,(S)S]-2-(prop-2-inyl)-2-[2-

(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (8b) as the substrate. Yield:

58% (34.9 mg, white solid); [α]²⁰+7.7 (c 0.9, CHCl₃); HPLC

D

enantiomer (R)-42 t_R= 19.5 min and enantiomer (S)-42 t_R= 26.9 min

in Daicel CHIRALPAK OD column [eluent hexane/i-PrOH (90:10)];

ﬂow = 1 mL/min]; ee = 96% for (S)-42.

( )-2-(Prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]hex-4-eneni-

trile [( )-37]. It was prepared by following the general procedure

described for propargylation. ( )-2-[2-(p-Tolylsulfenyl)phenyl]hex-4-

enenitrile was used as the substrate and propargyl bromide (80%

solution in toluene) as the electrophile, in the presence of LiHMDS

(1.0 M in THF). The reaction mixture was stirred at rt for 30 min. The

crude ( )-37 was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:6) as the eluent. Yield: 51% (21.8 mg, yellow oil);

¹H NMR δ 7.64−7.58 (m, 1H), 7.30−7.21 (m, 4H), 7.16−7.09 (m,

3H), 5.65 (m, 1H), 5.34 (m, 1H), 3.41−3.28 (m, 2H), 3.19−3.12 (m,

1H), 3.01−2.89 (m, 1H), 2.36 (s, 3H), 2.07 (t, J 2.5 Hz, 1H), 1.65 (d,

J 6.4 Hz, 3H) ppm; ¹³C NMR δ 137.3, 136.5, 135.6, 134.8, 132.6,

131.7 (2C), 131.6, 130.1 (2C), 129.3, 128.9, 127.4, 123.9, 121.5, 78.5,

72.6, 47.7, 40.2, 27.4, 21.0, 18.0 ppm; MS (EI+) m/z [M + H]⁺331

(23), 211 (100); HRMS (ESI+) calcd. for C₂₂H₂₁NS [M + H]⁺

331.1425, found 331.1429.

(2R,4E)-2-(Prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]hex-4-

enamide (43). It was obtained using a diastereoisomeric 88:12

mixture of [2R,(S)S,4E] and [2S,(S)S,4E]-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]hex-4-enenitrile (12a + 12b) as the substrate, with

1

a conversion of 70%. Yield: 52% (32.5 mg, colorless oil); ee 76%; H

NMR δ 7.57−7.49 (m, 1H), 7.34−7.25 (m, 2H), 7.23−7.17 (m, 1H),

7.12 and 7.06 (AA′BB′ system, 4H), 5.64 (m, 1H), 5.36−5.29 (m,

3H), 3.23−3.02 (m, 3H), 2.76 (dd, J 6.4 and 13.5 Hz, 1H), 2.30 (s,

3H), 1.90 (t, J 2.6 Hz, 1H), 1.66 (d, J 6.4 Hz, 3H) ppm; ¹³C NMR δ

175.8, 141.3, 136.8, 135.3, 133.4, 130.5 (2C), 129.9 (2C), 129.8, 129.0,

128.5, 128.4, 127.1, 125.2, 81.2, 71.4, 53.4, 39.4, 25.1, 21.0, 18.1 ppm;

MS (ESI) m/z [M − H]⁻348 [M − H]⁻(100), 109 (13); HRMS

(ESI) calcd. for C₂₂H₂₄NOS [M − H]⁻348.1416, found 348.1403.

(2R,4E)-5-Phenyl-2-(prop-2-inyl)-2-[2-(p-tolylsulfenyl)-

phenyl]pent-4-enamide (44). It was obtained using a diastereoiso-

meric 77:23 mixture of [2R,(S)S,4E] and [2S,(S)S,4E]-5-phenyl-2-

(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (16a +

16b) as the substrate, with a conversion of 70%. A 30% of unreacted

16a + 16b was recovered. Yield: 48% (33.3 mg, yellow oil); ¹H NMR

(data from a 44 + 16 mixture) δ 7.56−7.44 (m, 2H), 7.37−7.19 (m,

7H), 7.14 and 7.07 (AA′BB′ system, 4H), 6.53 (d, J 15.7 Hz, 1H), 6.01

(m, 1H), 5.37 (br s, 2H), 3.37−3.13 (m, 3H), 3.02 (dd, J 7.1 and 13.7

Hz, 1H), 2.30 (s, 3H), 1.96 (t, J 2.6 Hz, 1H) ppm; ¹³C NMR (data

from a 44 + 16 mixture) δ 176.4, 141.3, 136.9, 136.4, 136.0, 135.4,

133.9, 133.3, 130.5 (2C), 130.4, 129.9 (2C), 128.7 (2C), 127.5 (2C),

125.8 (2C), 125.5, 121.7, 81.0, 71.8, 54.1, 39.6, 25.6, 21.0 ppm; MS

(FAB+) m/z 410 [M + H]⁺(100), 109 (10); HRMS (FAB+) calcd.

for C₂₇H₂₄NOS [M + H]⁺410.1573, found 410.1573.

(

)-(E/Z)4-Methyl-5-phenyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulfenyl)phenyl]pent-4-enenitrile [( )-38]. It was prepared

by following the general procedure described for propargylation. A

mixture 86:14 ( )-(E/Z)-4-methyl-5-phenyl-2-(2-(p-tolylsulfenyl)-

phenyl)pent-4-enenitrile was used as the substrate and propargyl

bromide (80% solution in toluene) as the electrophile, in the presence

of LiHMDS (1.0 M in THF). The reaction mixture was stirred at rt for

30 min. The crude ( )-38 was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:6) as the eluent. Yield:

51% (27.0 mg, yellow oil); ¹H NMR (86:14 E/Z mixture) δ 7.82 (dd, J

1.7 and 7.6 Hz, 1H), 7.70 (dd, J 2.1 and 7.3 Hz, 1H), 7.50 and 7.25

(AA′BB′ system, 4H), 7.51−7.38 (m, 2H), 7.26−7.21 (m, 2H), 7.13−

7.08 (m, 3H), 6.61 (m, 1H), 6.47 (m, 1H), 3.60 and 3.25 (AB system,

J 14.4 Hz, 2H), 3.38 and 3.22 (AB system, J 16.5 Hz, 2H), 3.34

(coupled AB system, J 2.5 and 17.1 Hz, 2H), 2.99−2.96 (m, 2H), 2.24

(s, 3H), 2.22 (s, 3H), 2.13 (t, J 2.5 Hz, 1H), 1.92 (t, J 2.4 Hz, 1H),

1.74 (m, 3H), 1.63 (m, 3H) ppm; ¹³C NMR (E/Z mixture) δ 144.5,

141.2, 140.9, 137.3, 136.4, 132.5, 131.9, 131.6, 130.5, 130.3, 130.0

General Procedure for Pauson−Khand Reaction. To a

solution of [Co₂(CO)₈] (60 mg, 0.21 mmol) in anhydrous CH₂Cl₂

(1.0 mL) at rt was added a solution of the corresponding 1,6-enyne

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(0.17 mmol) in anhydrous CH₂Cl₂(0.5 mL). The mixture was stirred

at rt for 1.5 h, and then N-methylmorpholine N-oxide (NMO) (160

mg, 1.3 mmol) was added dropwise onto the freshly prepared cobalt

complex solution. The resulting mixture was stirred at rt. The reaction

was monitored by TLC. Upon transformation of the complex, the

mixture was ﬁltered through a Celite pad, and the solvent was

evaporated. The diastereoisomeric mixture was puriﬁed by ﬂash

column chromatography using as the eluent a mixture of AcOEt/

hexane as indicated in each case.

[2R,3aS,(S)S] and [2R,3aR,(S)S]-5-Oxo-2-[2-(p-tolylsulﬁnyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile (19aA

+ 19aB). The diastereoisomeric mixture 19aA + 19aB was obtained

using [2R,(S)S]-2-(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-

enenitrile (8a) as the substrate. The reaction mixture was stirred for

5 min. The crude 72:28 mixture of 19aA + 19aB was puriﬁed by ﬂash

column chromatography using AcOEt−hexane (1:1) as the eluent.

Yield (19aA + 19aB mixture): 79% (48.5 mg, white solid); IR (KBr)

3058, 2972, 2231, 1704, 1631, 1083, 1030, 755 cm⁻¹; ¹H NMR (19aA

+ 19aB mixture) δ 7.66−7.60 (m, 6H), 7.50−7.41 (m, 2H), 7.48 and

7.30 (AA′BB′ system, 8H), 6.07 (m, 1H), 6.02 (m, 1H), 4.41 and 3.33

(AB system, J 19.0 Hz, 2H), 4.11 and 3.64 (AB system, J 20.0 Hz, 2H),

3.69−3.55 (m, 1H), 3.41−3.30 (m, 2H), 3.05 (dd, J 6.3 and 11.6 Hz,

1H), 2.82 (dd, J 6.3 and 17.7 Hz, 1H), 2.71 (dd, J 6.8 and 17.8 Hz,

1H), 2.39 (s, 6H), 2.34−2.26 (m, 1H), 2.30 (dd, J 3.3 and 17.7 Hz,

1H), 2.18 (dd, J 12.1 and 12.2 Hz, 1H) ppm; ¹³C NMR (19aA + 19aB

mixture) δ 207.9, 207.8, 182.1, 181.9, 146.6, 146.4, 141.5, 141.4, 140.0,

139.8, 138.4, 138.3, 137.6, 132.2, 132.1, 131.2, 130.7 (2C), 130.4,

130.0 (4C), 129.9, 126.7, 125.6, 125.2, 125.0 (4C), 124.2, 124.0, 46.4,

44.6, 44.2, 44.0, 42.7, 42.6, 42.0, 41.5, 21.3 (2C) ppm; MS (ESI+) m/z

362 [M + H]⁺, 327 (33); HRMS (ESI+) calcd. for C₂₂H₂₀NO₂S

362.1218 [M + H]⁺, found 362.1209.

[2S,3aR,(S)S] and [2S,3aS,(S)S]-5-Oxo-2-[2-(p-tolylsulﬁnyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile

(19bA + 19bB). The diastereoisomeric mixture 19bA + 19bB was

obtained using [2S,(S)S]-2-(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]-

pent-4-enenitrile (8b) as the substrate. The reaction mixture was

stirred for 5 min. The crude 56:44 mixture of 19bA + 19bB was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (1:1)

as the eluent. Yield (19bA + 19bB mixture): 75% (46.0 mg).

Diastereoisomer [2S,3aR,(S)S]-19bA (colorless oil): [α]²⁰_D−16.1 (c

1.0, CHCl₃); IR (ﬁlm) 3058, 2972, 2231, 1704, 1631, 1083, 1030, 755

cm⁻¹; ¹H NMR δ 7.82−7.79 (m, 1H), 7.65−7.62 (m, 1H), 7.55−7.49

(m, 2H), 7.44 and 7.29 (AA′BB′ system, 4H), 6.09 (m, 1H), 3.77 and

3.50 (AB system, J 19.0 Hz, 2H), 3.67−3.60 (m, 1H), 3.25 (dd, J 6.9

and 12.3 Hz, 1H), 2.78 (dd, J 6.3 and 17.8 Hz, 1H), 2.39 (s, 3H), 2.21

(dd, J 3.2 and 17.8 Hz, 1H), 2.04 (dd, J 12.1 and 12.2 Hz, 1H) ppm;

¹³C NMR δ 208.0, 181.7, 145.0, 141.8, 140.5, 137.1, 132.3, 130.6,

7.67−7.61 (m, 6H), 7.50−7.40 (m, 6H), 7.31−7.26 (m, 4H), 4.30 and

3.20 (AB system, J 18.9 Hz, 2H), 4.05 and 3.55 (AB system, J 18.2 Hz,

2H), 3.55−3.40 (m, 1H), 3.36 (dd, J 6.7 and 13.0 Hz, 1H), 3.20−3.10

(m, 1H), 3.01 (dd, J 5.9 and 11.5 Hz, 1H), 2.83 (dd, J 6.1 and 18.0 Hz,

1H), 2.76 (dd, J 6.1 and 17.9 Hz, 1H), 2.39 (s, 6H), 2.27 (dd, J 2.9 and

17.9 Hz, 1H), 2.24 (dd, J 3.0 and 17.9 Hz, 1H), 2.10 (dd, J 12.3 and

12.4 Hz, 1H), 2.09 (dd, J 12.8 and 12.9 Hz, 1H), 1.76 (s, 3H), 1.70 (s,

3H) ppm; ¹³C NMR (20aA + 20aB mixture) δ 208.0, 207.9, 174.3,

174.1, 146.7, 146.5, 141.4, 141.3, 140.2, 139.9, 138.8, 137.8, 134.4

(2C), 132.2, 132.1, 131.2, 130.6, 130.3, 129.9 (2C), 129.8 (2C), 125.6,

125.2 (2C), 125.1 (2C), 124.7, 124.2, 46.4, 43.9, 43.7, 42.8, 42.3, 42.2,

42.0, 41.7, 41.2, 40.7, 21.3 (2C), 8.6, 8.5 ppm; MS (ESI+) m/z 376 [M

+ H]⁺(100), 364 (62); HRMS (ESI+) calcd. for C₂₃H₂₂NO₂S [M +

H]⁺376.1365, found 376.1373.

[2S,3aR,(S)S] and [2S,3aS,(S)S]-6-Methyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (20bA + 20bB). The diastereoisomeric mixture 20bA +

20bB was obtained using [2S,(S)S]-2-(but-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (9b) as the substrate. The

reaction mixture was stirred for 5 min. The crude 51:49 mixture of

20bA + 20bB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (2:1) as the eluent. Yield (20bA + 20bB mixture):

66% (42.0 mg). Diastereoisomer [2S,3aR,(S)S]-20bA (colorless oil):

[α]²⁰_D−91.3 (c 1.6, CHCl₃); IR (ﬁlm) 2921, 2851, 2231, 1708, 1669,

1

1456, 1082, 1035, 760 cm⁻¹; H NMR δ 7.83−7.80 (m, 1H), 7.67−

7.64 (m, 1H), 7.54−7.50 (m, 2H), 7.42 and 7.28 (AA′BB′ system,

4H), 3.56 and 3.39 (AB system, J 18.6 Hz, 2H), 3.56−3.42 (m, 1H),

3.21 (dd, J 6.5 and 11.9 Hz, 1H), 2.79 (dd, J 6.3 and 18.0 Hz, 1H),

2.39 (s, 3H), 2.16 (dd, J 3.0 and 18.0 Hz, 1H), 1.93 (dd, J 12.2 and

12.3 Hz, 1H), 1.76 (s, 3H) ppm; ¹³C NMR δ 208.2, 174.3, 144.2,

140.8, 140.6, 137.3, 134.4, 132.2, 130.5, 130.3, 130.1 (2C), 126.8,

125.8 (2C), 123.3, 48.1, 46.1, 43.0, 41.2, 41.0, 21.3, 8.6 ppm; MS (ESI

+) m/z 376 [M + H]⁺(100); HRMS (ESI+) calcd. for C₂₃H₂₂NO₂S

[M + H]⁺376.1365, found 376.1378. Diastereoisomer [2S,3aS,(S)S]-

20bB (colorless oil): [α]²⁰_D−142.2 (c 0.5, CHCl₃); ¹H NMR δ 7.72−

7.68 (m, 1H), 7.66 and 7.31 (AA′BB′ system, 4H), 7.50−7.46 (m,

2H), 7.44−7.40 (m, 1H), 3.64 and 3.45 (AB system, J 17.4 Hz, 2H),

3.12 (m, 1H), 3.03−2.98 (m, 1H), 2.76−2.59 (m, 2H), 2.40 (s, 3H),

2.26 (dd, J 3.1 and 17.8 Hz, 1H), 1.86 (s, 3H) ppm; ¹³C NMR δ 208.3,

172.7, 146.4, 141.4, 140.1, 137.8, 135.1, 131.9, 130.9, 130.1 (2C),

125.7, 125.6 (2C), 124.4, 56.7, 46.1, 45.3, 42.2, 41.2, 39.1, 21.3, 8.9

ppm.

[2R,3aS,(S)S] and [2R,3aR,(S)S]-3a-Methyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (21aA + 21aB). The diastereoisomeric mixture 21aA +

21aB was obtained using [2R,(S)S]-4-methyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (10a) as the substrate. The

reaction mixture was stirred for 45 min. The crude 81:19 mixture of

21aA + 21aB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (2:1) as the eluent. Yield (21aA + 21aB mixture):

65% (41.4 mg, colorless oil); IR (ﬁlm) 2969, 2927, 2231, 1709, 1634,

1456, 1083, 1035, 812, 756 cm⁻¹; ¹H NMR (21aA + 21aB mixture) δ

7.66−7.58 (m, 2H), 7.59 and 7.31 (AA′BB′ system, 8H), 7.56−7.43

(m, 6H), 6.08 (m, 1H), 5.90 (m, 1H), 4.39 and 3.60 (AB system, J

18.6 Hz, 2H), 4.23 and 3.54 (AB system, J 15.9 Hz, 2H), 3.10 (d, J

14.2 Hz, 1H), 2.91 (d, J 12.7 Hz, 1H), 2.57 and 2.46 (AB system, J

17.4 Hz, 2H), 2.61−2.44 (m, 4H), 2.39 (s, 6H), 1.68 (s, 3H), 1.65 (s,

3H), 1.27−1.21 (m, 2H) ppm; ¹³C NMR (21aA + 21aB mixture) δ

207.7, 207.6, 185.8, 184.5, 146.5, 146.2, 141.5, 141.4, 140.2, 139.9,

139.4, 138.2, 132.0, 131.9, 131.0, 130.8, 130.7, 130.6, 130.2 (4C),

125.9, 125.7, 125.4, 125.3, 125.2 (4C), 124.3, 53.4, 52.4, 52.2, 50.6,

49.1, 48.7, 47.7, 45.0, 44.1, 42.8, 42.3, 27.8, 26.1, 21.3 (2C) ppm; MS

(ESI+) m/z 376 [M + H]⁺(100); HRMS (ESI+) calcd. for

C₂₃H₂₂NO₂S [M + H]⁺376.1365, found 376.1379.

130.5, 130.1 (2C), 126.8, 126.5, 125.9 (2C), 123.2, 48.0, 45.8, 45.4,

42.1, 41.8, 21.3 ppm; MS (ESI+) m/z 362 [M + H]⁺; HRMS (ESI+)

calcd. for C₂₂H₂₀NO₂S [M + H]⁺362.1218, found 362.1209.

Diastereoisomer [2S,3aS,(S)S]-19bB (colorless oil): [α]²⁰−101.7

D

1

(c 0.6, CHCl₃); H NMR δ 7.71−7.68 (m, 1H), 7.49−7.33 (m, 3H),

7.63 and 7.31 (AA′BB′ system, 4H), 6.20 (m, 1H), 3.76 and 3.50 (AB

system, J 17.6 Hz, 2H), 3.45−3.39 (m, 1H), 3.19−3.09 (m, 1H),

2.76−2.68 (m, 2H), 2.40 (s, 3H), 2.32 (dd, J 3.2 and 17.5 Hz, 1H)

ppm; ¹³C NMR δ 208.1, 180.5, 146.4, 141.9, 140.1, 137.5, 132.0,

131.0, 130.9, 130.0 (2C), 127.3, 125.5, 125.4 (2C), 124.1, 45.8, 45.4,

43.5, 43.1, 40.1, 21.3 ppm; MS (ESI+) m/z 362 [M + H]⁺(100);

HRMS (ESI+) calcd. for para C₂₂H₂₀NO₂S [M + H]⁺362.1218, found

362.1208.

[2R,3aS,(S)S] and [2R,3aR,(S)S]-6-Methyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (20aA + 20aB). The diastereoisomeric mixture 20aA +

20aB was obtained using [2R,(S)S]-2-(but-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (9a) as the substrate. The

reaction mixture was stirred for 5 min. The crude 70:30 mixture of

20aA + 20aB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:1) as the eluent. Yield (20aA + 20aB mixture):

70% (44.6 mg, colorless oil); IR (ﬁlm) 2921, 2851, 2231, 1708, 1669,

[2S,3aR,(S)S] and [2S,3aS,(S)S]-3a-Methyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (21bA + 21bB). The diastereoisomeric mixture 21bA +

21bB was obtained using [2S,(S)S]-4-methyl-2-(prop-2-inyl)-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (10b) as the substrate. The

reaction mixture was stirred for 45 min. The crude 56:44 mixture of

1

1456, 1082, 1035, 760 cm⁻¹; H NMR (20aA + 20aB mixture) δ

6595

dx.doi.org/10.1021/jo3011039 | J. Org. Chem. 2012, 77, 6583−6599

The Journal of Organic Chemistry

Article

21bA + 21bB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (2:1) as the eluent. Yield (21bA + 21bB mixture):

68% (43.3 mg, colorless oil); IR (ﬁlm) 2969, 2927, 2231, 1709, 1634,

1456, 1083, 1035, 812, 756 cm⁻¹; ¹H NMR (21bA + 21bB mixture) δ

7.81−7.78 (m, 1H), 7.71−7.68 (m, 1H), 7.64−7.61 (m, 3H), 7.54−

7.45 (m, 4H), 7.42−7.38 (m, 3H), 7.32−7.28 (m, 4H), 6.19 (m, 1H),

6.09 (m, 1H), 3.77 and 3.50 (AB system, J 18.6 Hz, 2H), 3.74 and 3.49

(AB system, J 17.5 Hz, 2H), 3.45 and 3.25 (AB system, J 7.1 Hz, 2H),

3.17 and 3.12 (AB system, J 8.8 Hz, 2H), 2.82−2.68 (m, 4H), 2.40 (s,

6H), 2.16 (s, 6H), 2.03 (m, 1H) ppm; MS (ESI+) m/z 376 [M + H]⁺

(100); HRMS (ESI+) calcd. for C₂₃H₂₂NO₂S [M + H]⁺376.1365,

found 376.1368.

[2R,3aS,(S)S] and [2R,3aR,(S)S]-3a,6-Dimethyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (22aA + 22aB). The diastereoisomeric mixture 22aA +

22aB was obtained using [2R,(S)S]-2-(2-but-1-inyl)-4-methyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (11a) as the substrate. The

reaction mixture was stirred for 45 min. The crude 78:22 mixture of

22aA + 22aB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:1) as the eluent. Yield (22aA + 22aB mixture):

76% (50.3 mg). Diastereoisomer [2R,3aS,(S)S]-22aA (colorless oil):

[α]²⁰_D−153.4 (c 1.0, CHCl₃); IR (ﬁlm) 2966, 2930, 2231, 1709, 1634,

1456, 1082, 1030, 812, 755 cm⁻¹; ¹H NMR δ 7.67−7.58 (m, 1H), 7.60

and 7.31 (AA′BB′ system, 4H), 7.52−7.41 (m, 3H), 4.28 and 3.50 (AB

system, J 18.2 Hz, 2H), 2.90 and 2.46 (AB system, J 12.6 Hz, 2H), 2.58

and 2.44 (AB system, J 17.3 Hz, 2H), 2.40 (s, 3H), 1.65 (s, 3H), 1.61

(s, 3H) ppm; ¹³C NMR δ 207.8, 176.9, 146.3, 141.4, 140.3, 139.7,

133.8, 132.0, 130.8, 130.5, 130.0 (3C), 125.6, 125.3 (2C), 51.8, 49.3,

48.4, 44.5, 41.8, 26.2, 21.3, 8.6 ppm; MS (ESI+) m/z 390 [M + H]⁺

(100), 229 (18); HRMS (ESI+) calcd. for C₂₄H₂₄NO₂S [M + H]⁺

h. The crude 80:20 mixture of 23aA + 23aB was puriﬁed by ﬂash

column chromatography using AcOEt−hexane (3:1) as the eluent.

The products derived from 12b were not detected in the crude

mixture. Diastereoisomer [2R,3aS,4S,(S)S]-23aA: Yield 59% (37.6

mg, white solid); mp 144−146 °C (CH₂Cl₂−hexane); [α]²⁰−216.1

D

(c 1.1, CHCl₃); IR (KBr) 2971, 2851, 2231, 1708, 1669, 1459, 1083,

1

1035, 811, 762 cm⁻¹; H NMR δ 7.66−7.61 (m, 1H), 7.62 and 7.31

(AA′BB′ system, 4H), 7.51−7.43 (m, 3H), 6.03 (m, 1H), 4.41 and

3.31 (AB system, J 19.3 Hz, 2H), 3.28−3.23 (m, 1H), 3.10 (dd, J 6.5

and 11.7 Hz, 1H), 2.38 (s, 3H), 2.38−2.36 (m, 1H), 2.21 (dd, J 11.9

and 12.0 Hz, 1H), 1.36 (d, J 7.4 Hz, 1H) ppm; ¹³C NMR δ 210.1,

179.7, 146.5, 141.5 (2C), 140.1, 137.7, 132.3, 130.8, 130.5, 130.1 (2C),

125.7, 125.3 (2C), 124.0, 52.9, 48.8, 46.5, 42.7, 42.3, 21.4, 13.6 ppm;

MS (FAB+) m/z 376 [M + H]⁺(100), 358 (12), 327 (14), 283 (38);

HRMS (FAB+) calcd. for C₂₃H₂₂NO₂S [M + H]⁺376.1371, found

376.1372. Diastereoisomer [2R,3aR,4R,(S)S]-23aB: Yield 15% (9.6

mg, colorless oil); [α]²⁰_D−84.1 (c 1.0, CHCl₃); ¹H NMR δ 7.68−7.60

(m, 1H), 7.64 and 7.31 (AA′BB′ system, 4H), 7.55−7.44 (m, 3H),

6.08 (m, 1H), 4.07 and 3.65 (AB system, J 18.4 Hz, 2H), 3.39 (dd, J

7.0 and 13.6 Hz, 1H), 2.96−2.88 (m, 1H), 2.39 (s, 3H), 2.34 (dq, J 3.8

and 7.5 Hz, 1H), 2.25 (dd, J 12.5 and 13.6 Hz, 1H), 1.30 (d, J 7.5 Hz,

1H) ppm; ¹³C NMR δ 209.8, 179.3, 146.7, 141.5 (2C), 139.9, 138.3,

132.2, 131.3, 130.8, 130.0 (2C), 125.9, 125.3 (2C), 124.4, 52.5, 49.6,

44.6, 44.3, 41.7, 21.3, 13.6 ppm; MS (ESI+) m/z 376 [M + H]⁺(100),

358 (12), 327 (14), 283 (38); HRMS (ESI+) calcd. for C₂₃H₂₂NO₂S

[M + H]⁺376.1371, found 376.1375.

[2R,3aS,4S,(S)S] and [2R,3aR,4R,(S)S]-4,6-Dimethyl-5-oxo-2-

[2-(p-tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-

carbonitrile (24aA + 24aB). The diastereoisomeric mixture 24aA +

24aB was obtained using a 87:13 mixture of [2R,(S)S,4E] and [2S,(S)

S,4E]-2-(but-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]hex-4-enenitrile (13a

+ 13b) as the substrate. The reaction mixture was stirred for 1.5 h. The

crude 82:18 mixture of 24aA + 24aB was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (2:1) as the eluent. The

products derived from 13b were not detected in the crude mixture.

Yield (24aA + 24aB mixture): 80% (52.9 mg). Diastereoisomer

[2R,3aS,4S,(S)S]-24aA (data from a 90:10 24aA + 24aB mixture): IR

(ﬁlm) 2921, 2851, 2231, 1704, 1650, 1459, 1083, 1030, 811, 755 cm⁻¹;

¹H NMR δ 7.68−7.63 (m, 1H), 7.63 and 7.31 (AA′BB′ system, 4H),

390.1522, found 390.1518. Diastereoisomer [2R,3aR,(S)S]-22aB

1

(colorless oil): [α]²⁰−40.8 (c 1.0, CHCl₃); H NMR δ 7.70 (dd, J

D

6.9 and 2.2 Hz, 1H), 7.62−7.56 (m, 1H), 7.61 and 7.31 (AA′BB′

system, 4H), 7.54−7.44 (m, 2H), 4.18 and 3.43 (AB system, J 15.9 Hz,

2H), 3.12 and 2.50 (AB system, J 14.2 Hz, 2H), 2.40 (s, 3H), 1.83 (s,

3H), 1.64 and 1.23 (AB system, J 13.2 Hz, 2H), 1.18 (s, 3H) ppm; ¹³C

NMR δ 207.9, 176.6, 146.7, 141.4, 140.4, 138.5, 133.7, 131.9, 131.0,

130.6, 130.0 (2C), 125.3 (3C), 124.7, 51.4, 47.9, 47.0, 45.2, 41.3, 27.8,

21.3, 8.7 ppm; MS (ESI+) m/z 390 [M + H]⁺(100), 229 (18); HRMS

(ESI+) calcd. for C₂₄H₂₄NO₂S [M + H]⁺390.1522, found 390.1540.

[2S,3aR,(S)S] and [2S,3aS,(S)S]-3a,6-Dimethyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (22bA + 22bB). The diastereoisomeric mixture 22bA +

22bB was obtained using [2S,(S)S]-2-(2-but-1-inyl)-4-methyl-2-[2-(p-

tolylsulﬁnyl)phenyl]pent-4-enenitrile (11b) as the substrate. The

reaction mixture was stirred for 45 min. The crude 50:50 mixture of

22bA + 22bB was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:1) as the eluent. Yield (22bA + 22bB mixture):

74% (48.9 mg). Diastereoisomer [2S,3aR,(S)S]-22bA (colorless oil):

[α]²⁰_D−94.9 (c 2.5, CHCl₃); IR (ﬁlm) 2966, 2930, 2231, 1709, 1634,

7.51−7.44 (m, 3H), 4.30 and 3.20 (AB system, J 18.9 Hz, 2H), 3.14−

3.03 (m, 2H), 2.40 (s, 3H), 2.34−2.24 (m, 1H), 2.13 (dd, J 11.3 and

11.4 Hz, 1H), 1.35 (d, J 7.3 Hz, 1H) ppm; ¹³C NMR δ 210.2, 172.0,

146.5, 141.6, 140.2, 137.8, 133.6, 132.2, 130.7, 130.4, 130.0 (2C),

125.6, 125.1 (2C), 124.2, 50.9, 47.9, 46.5, 42.4, 41.5, 21.3, 13.8, 8.8

ppm; MS (ESI+) m/z 390 [M + H]⁺(100); HRMS (ESI+) calcd. for

C₂₄H₂₄NO₂S [M + H]⁺390.1522, found 390.1523. Diastereoisomer

[2R,3aR,4R,(S)S]-24aB (colorless oil): [α]²⁰−40.8 (c 1.0, CHCl₃);

D

¹H NMR δ 7.68−7.64 (m, 1H), 7.65 and 7.31 (AA′BB′ system, 4H),

7.54−7.43 (m, 3H), 4.02 and 3.52 (AB system, J 18.0 Hz, 2H), 3.38

(dd, J 6.7 and 13.4 Hz, 1H), 2.83−2.72 (m, 1H), 2.40 (s, 3H), 2.27

(dq, J 3.3 and 7.4 Hz, 1H), 2.15 (dd, J 12.4 and 13.4 Hz, 1H), 1.30 (d,

J 7.4 Hz, 1H) ppm; ¹³C NMR δ 209.9, 171.6, 146.7, 141.2, 140.0,

138.6, 133.7, 132.1, 131.2, 130.7, 130.1, 129.9 (2C), 125.3 (2C), 124.3,

50.8, 48.7, 44.2, 43.6, 42.0, 21.3, 13.9, 8.9 ppm; MS (ESI+) m/z 390

[M + H]⁺(100); HRMS (ESI+) calcd. for C₂₄H₂₄NO₂S [M + H]⁺

390.1522, found 390.1525.

1

1456, 1082, 1030, 812, 755 cm⁻¹; H NMR δ 7.62−7.59 (m, 1H),

7.56−7.50 (m, 1H), 7.54 and 7.22 (AA′BB′ system, 4H), 7.48−7.29

(m, 2H), 3.50−3.44 (m, 2H) 3.36 and 2.58 (AB system, J 13.9 Hz,

2H), 2.57−2.48 (m, 2H), 2.38 (s, 3H), 1.87 (s, 3H) 1.20 (s, 3H) ppm;

¹³C NMR δ 208.3, 175.1, 146.8, 141.3, 140.2, 138.5, 133.9, 132.2,

130.7, 130.6, 129.9 (2C), 125.0 (2C), 124.9, 124.5, 52.8, 52.3, 46.5,

[2R,3aR,(S)S]-5-Oxo-3a-phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]-

1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile (25aA). The

diastereoisomer 25aA was obtained using a 90:10 mixture of [2R,

(S)S] and [2S,(S)S]-4-phenyl-2-(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)-

phenyl]pent-4-enenitrile (14a + 14b) as the substrate. The reaction

mixture was stirred for 12 h. The crude >98:<2 mixture of 25aA +

25aB was puriﬁed by ﬂash column chromatography using AcOEt−

hexane (2:1) as the eluent. The products derived from 14b were not

detected in the crude mixture. Yield (25aA): 56% (41.6 mg, colorless

oil); [α]²⁰_D−133.2 (c 0.8, CHCl₃); IR (ﬁlm) 3019, 2936, 2236, 1709,

45.8, 36.5, 29.4, 21.3, 8.7 ppm. Diastereoisomer [2S,3aS,(S)S]-22bB

1

(colorless oil): [α]²⁰−168.3 (c 2.0, CHCl₃); H NMR δ 7.62−7.59

D

(m, 1H), 7.56 and 7.25 (AA′BB′ system, 4H), 7.50−7.39 (m, 3H),

3.51 and 3.45 (AB system, J 14.2 Hz, 2H), 3.39 and 2.61 (AB system, J

13.9 Hz, 2H), 2.58 and 2.52 (AB system, J 17.3 Hz, 2H), 2.34 (s, 3H),

1.83 (s, 3H), 1.16 (s, 3H) ppm; ¹³C NMR δ 208.3, 175.1, 146.8, 141.3,

140.2, 138.5, 133.9, 132.2, 130.7, 130.6, 129.9 (2C), 125.0 (2C), 124.9,

124.5, 53.1, 52.3, 46.5, 45.4, 36.5, 30.8, 21.3, 8.5 ppm.

[2R,3aS,4S,(S)S] and [2R,3aR,4R,(S)S]-4-Methyl-5-oxo-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (23aA + 23aB). The diastereoisomeric mixture 23aA +

23aB was obtained using a 90:10 mixture of [2R,(S)S,4E] and [2S,(S)

S,4E]-2-(prop-2-inyl)-2-[2-(p-tolylsulﬁnyl)phenyl]hex-4-enenitrile

(12a + 12b) as the substrate. The reaction mixture was stirred for 1.5

1

1640, 1492, 1083, 1035, 810, 755 cm⁻¹; H NMR δ 7.64−7.60 (m,

1H), 7.52 and 7.23 (AA′BB′ system, 4H), 7.47−7.40 (m, 5H), 7.36−

7.30 (m, 3H), 6.27 (m, 1H), 4.45 and 3.63 (AB system, J 18.4 Hz,

2H), 3.59 and 2.71 (AB system, J 12.7 Hz, 2H), 2.84 and 2.73 (AB

6596

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The Journal of Organic Chemistry

Article

system, J 17.5 Hz, 2H), 2.35 (s, 3H) ppm; ¹³C NMR δ 211.1, 181.8,

146.6, 142.1 (2C), 141.4, 139.9, 139.4, 132.0, 130.6, 129.9 (2C), 129.8

(2C), 128.9, 128.1, 126.2 (2C), 125.3 (2C), 125.1, 123.1, 58.1, 53.7,

48.5, 44.1, 42.9, 21.3 ppm; MS (ESI+) m/z 438 [M + H]⁺(100), 301

(12), 229 (13); HRMS (ESI+) calcd. for C₂₈H₂₄NO₂S [M + H]⁺

438.1522, found 438.1505.

32A + 32B was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (1:3) as the eluent. Yield (32A + 32B mixture): 72%

1

(29.0 mg); [α]²⁰−9.2 (c 0.1, CHCl₃); H NMR (32A) δ 7.32−7.25

D

(m, 5H), 6.11 (m, 1H), 5.92 (s, 1H), 3.68 and 3.22 (AB system, J 18.0

Hz, 2H), 3.22−3.57 (AB system, J 15.0 Hz, 2H), 2.04−1.97 (m, 1H),

1.48 (d, J 9.1 Hz, 3H) ppm; ¹³C NMR (32A) δ 208.3, 186.1, 140.6,

129.6, 128.3, 127.8, 123.9, 53.5, 50.7, 41.2, 30.6, 21.6, 13.1 ppm;

HRMS (mixture 32A + 32B) (ESI+) calcd. for C₁₆H₁₅NO 237.1154,

found 237.1158.

[2R,3aR,(S)S]-6-Methyl-5-oxo-3a-phenyl-2-[2-(p-

tolylsulﬁnyl)phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-car-

bonitrile (26aA). The diastereoisomer 26aA was obtained using a

90:10 mixture of [2R,(S)S,4E] and [2S,(S)S,4E]-2-(but-2-inyl)-4-

phenyl-2-[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (15a + 15b) as

the substrate. The reaction mixture was stirred for 12 h. The crude

>98:<2 mixture of 26aA + 26aB was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (2:1) as the eluent. The

products derived from 15b were not detected in the crude mixture.

[2R*,3aS*] and [2R*,3aR*]-5-Oxo-2-[2-(p-tolylsulfonyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile

[( )-39A + ( )-39B]. The diastereoisomeric mixture ( )-39A +

(

)-39B was obtained using ( )-2-(prop-2-inyl)-2-[2-(p-

tolylsulfonyl)phenyl]pent-4-enenitrile (34) as the substrate. The

reaction mixture was stirred for 20 min. The crude 56:44 mixture of

39A + 39B was puriﬁed by ﬂash column chromatography using

AcOEt−hexane (2:1) as the eluent. Yield (39A + 39B mixture): 75%

Yield (26aA): 58% (44.5 mg, colorless oil); [α]²⁰−64.2 (c 1.7,

D

CHCl₃); IR (ﬁlm) 3040, 2926, 2236, 1715, 1640, 1448, 1085, 1031,

812, 760 cm⁻¹; ¹H NMR δ 7.65−7.61 (m, 1H), 7.55 and 7.23 (AA′BB′

system, 4H), 7.45−7.35 (m, 5H), 7.34−7.30 (m, 3H), 4.34 and 3.52

(AB system, J 18.3 Hz, 2H), 3.55 and 2.64 (AB system, J 12.3 Hz, 2H),

2.83 and 2.74 (AB system, J 17.9 Hz, 2H), 2.35 (s, 3H), 1.84 (s, 3H)

ppm; ¹³C NMR δ 207.3, 174.1, 146.6, 142.8, 141.3, 140.1, 139.6,

136.7, 132.0, 130.8, 130.6, 129.8 (2C), 129.1 (2C), 127.9, 126.4 (2C),

125.4, 125.1 (2C), 123.3, 55.9, 52.9, 48.9, 44.4, 41.7, 21.3, 8.8 ppm;

MS (ESI+) m/z 452 [M + H]⁺(100), 301 (14), 229 (13); HRMS

(ESI+) calcd. for C₂₉H₂₆NO₂S [M + H]⁺452.1678, found 452.1662.

[2R,3aR,4R,(S)S]-5-Oxo-4-phenyl-2-[2-(p-tolylsulﬁnyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile

(27aA). The diastereoisomer 27aA was obtained using a 87:13

mixture of [2R,(S)S,4E] and [2S,(S)S,4E]-5-phenyl-2-(prop-2-inyl)-2-

[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (16a + 16b) as the

substrate. The reaction mixture was stirred for 3.5 h. The crude

>98:<2 mixture of 27aA + 27aB was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (2:1) as the eluent. The

products derived from 16b were not detected in the crude mixture.

1

(48.2 mg, white solid); H NMR (39A + 39B mixture) δ 7.96−7.84

(m, 2H), 7.94 and 7.34 (AA′BB′ system, 4H), 7.89 and 7.36 (AA′BB′

system, 4H), 7.68−7.63 (m, 3H), 7.60−7.51 (m, 2H), 7.48−7.40 (s,

1H), 6.07 (s, 1H), 5.96 (m, 1H), 4.47 and 3.30 (AB system, J 19.8 Hz,

2H), 3.88 and 3.68 (AB system, J 18.6 Hz, 2H), 3.65 (m, 1H), 3.47−

3.41 (m, 1H), 3.09 (dd, J 6.4 and 11.5 Hz, 1H), 2.79 (dd, J 6.4 and

17.9 Hz, 1H), 2.72 (dd, J 6.2 and 11.5 Hz, 1H), 2.45 (s, 3H), 2.43 (s,

3H), 2.72 (dd, J 11.4 and 13.2 Hz, 1H), 2.25 (dd, J 6.4 and 14.4 Hz,

1H), 2.30−2.16 (m, 2H) ppm; ¹³C NMR (39A + 39B mixture) δ

208.5, 208.4, 183.8, 182.8, 145.0, 144.8, 141.2, 140.8, 139.4, 138.6,

138.1, 137.3, 136.6, 134.0, 133.1, 132.6, 130.0 (2C), 129.9 (2C), 129.3,

129.2, 128.7, 128.2 (2C), 128.0 (2C), 127.4, 126.5, 125.8, 123.1, 123.0,

47.5, 46.0, 45.0, 44.5, 44.4, 44.3, 44.0, 42.7, 42.3, 41.5, 21.6 (2C) ppm;

MS (ESI+) m/z [M + H]⁺378 (100); HRMS (ESI+) calcd. for

C₂₂H₂₀NO₃S [M + H]⁺378.1158, found 378.1161.

(

)-[2R*,3aS*]-5-Oxo-2-[2-(p-tolylsulfenyl)phenyl]-

1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile (40A). It was

obtained using ( )-2-(prop-2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]pent-

4-enenitrile (36) as the substrate. The reaction mixture was stirred for

5 min. The crude ( )-40A was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:2) as the eluent. Yield:

Yield (27aA): 74% (54.9 mg, colorless oil); [α]²⁰−223.8 (c 1.2,

D

CHCl₃); IR (ﬁlm) 3019, 2936, 2236, 1709, 1640, 1492, 1083, 1035,

810, 755 cm⁻¹; ¹H NMR δ 7.68−7.63 (m, 1H), 7.62 and 7.31 (AA′BB′

system, 4H), 7.55−7.44 (m, 3H), 7.43−7.38 (m, 2H), 7.35−7.30 (m,

1H), 7.27−7.24 (m, 2H), 6.14 (m, 1H), 4.50 and 3.41 (AB system, J

19.2 Hz, 2H), 3.75 (m, 1H), 3.48 (d, J 3.9 Hz, 1H), 3.15 (dd, J 6.4 and

11.7 Hz, 1H), 2.40 (s, 3H), 2.41−2.33 (m, 1H) ppm; ¹³C NMR δ

207.3, 180.0, 146.5, 141.6, 140.0, 137.6, 137.2, 132.3, 130.8, 130.6,

130.1 (2C), 129.0 (2C), 128.4 (2C), 127.5, 125.7, 125.6, 125.1 (2C),

123.8, 60.2, 53.7, 46.4, 42.8, 42.5, 21.3 ppm; MS (ESI+) m/z 438 [M +

H]⁺(100); HRMS (ESI+) calcd. for C₂₈H₂₄NO₂S [M + H]⁺438.1522,

found 438.1504.

1

68% (39.8 mg, colorless oil); H NMR δ 7.54−7.48 (m, 1H), 7.30−

7.23 (m, 4H), 7.19−7.12 (m, 3H), 5.96 (s, 1H), 4.05 and 3.17 (AB

system, J 19.1 Hz, 2H), 3.65 (m, 1H), 3.55 (m, 1H), 3.20 (m, 1H),

2.90 (dd, J 12.0 and 18.6 Hz, 1H), 2.79 (dd, J 6.3 and 17.8 Hz, 1H),

2.35 (s, 3H) ppm; ¹³C NMR δ 183.8, 137.8, 137.6, 136.8, 134.1, 131.7,

131.4, 131.3 (2C), 130.4, 130.3 (2C), 129.4, 127.5, 126.9, 126.3, 48.4,

45.0, 42.9, 41.7, 41.2, 21.1 ppm; MS (EI+) m/z [M]⁺345 (67), 318

(100); HRMS (ESI+) calcd. for C₂₂H₁₉NOS 345.1187, found

345.1181.

[2R,3aS] and [2R,3aR]-5-Oxo-2-phenyl-1,2,3,3a,4,5-hexahy-

dropentalene-2-carbonitrile (31A + 31B). The diastereoisomeric

mixture 31A + 31B was obtained using (R)-2-phenyl-2-(prop-2-inyl)-

pent-4-enenitrile (28) as the substrate. The reaction mixture was

stirred for 5 min. The crude 56:44 mixture of 31A + 31B was puriﬁed

by ﬂash column chromatography using AcOEt−hexane (1:3) as the

eluent. Yield (31A + 31B mixture): 80% (33.4 mg); IR (ﬁlm) 2965,

(

)-[2R*,3aS*,4S*]-4-Methyl-5-oxo-2-[2-(p-tolylsulfenyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile (41A).

It was obtained using ( )-2-(prop-2-inyl)-2-[2-(p-tolylsulfenyl)-

phenyl]hex-4-enenitrile (37) as the substrate. The reaction mixture

was stirred for 5 min. The crude ( )-41A was puriﬁed by ﬂash column

chromatography using AcOEt−hexane (1:2) as the eluent. Yield: 70%

(42.7 mg, white solid); ¹H NMR δ 7.54−7.46 (m, 1H), 7.29−7.20 (m,

4H), 7.19−7.12 (m, 3H), 5.96 (s, 1H), 4.05 and 3.13 (AB system, J

19.7 Hz, 2H), 3.25−3.16 (m, 1H), 2.95 (m, 1H), 2.38−2.20 (m, 2H),

2.34 (s, 3H), 1.32 (d, J 7.1 Hz, 3H) ppm; ¹³C NMR δ 183.6, 137.8,

137.7, 136.5, 134.3, 131.7, 131.5, 131.4 (2C), 130.5, 130.3 (2C), 129.6,

127.8, 126.7, 125.3, 52.1, 48.6, 42.8, 41.6, 41.0, 21.0, 13.7 ppm; MS (EI

+) m/z [M]⁺359 (26), 332 (100); HRMS (ESI+) calcd. for

C₂₃H₂₁NOS 359.1344, found 359.1336.

1

2926, 2234, 1699, 1632, 1448, 1261, 1085, 1031, 872, 700 cm⁻¹; H

NMR (31A + 31B mixture) δ 7.51−7.46 (m, 2H), 7.45−7.41 (m, 4H),

7.40−7.31 (m, 4H), 6.11 (m, 1H), 6.04 (m, 1H), 3.68 and 3.45 (AB

system, J 20.0 Hz, 2H), 3.61−3.52 (m, 1H), 3.52 and 3.15 (AB system,

J 19.1 Hz, 2H), 3.30−3.20 (m, 1H), 2.92 (dd, J 6.8 and 12.4 Hz, 1H),

2.81−2.66 (m, 2H), 2.28−2.16 (m, 2H), 1.83 (t, J 12.6 Hz, 1H) ppm;

¹³C NMR (31A + 31B mixture) δ 208.5, 208.4, 183.2, 182.6, 139.8,

138.7, 129.6 (2C), 129.3 (2C), 128.5, 128.4, 126.8, 126.3, 125.7 (2C),

125.6 (2C), 123.5, 123.4, 48.4, 46.5, 46.0, 45.9, 45.4, 44.0, 42.7, 42.6,

41.6, 41.5 ppm; MS (ESI+) m/z 224 [M]⁺(100), 197 (20); HRMS

(ESI+) calcd. for C₁₅H₁₃NO [M + Na]⁺246.0889, found 246.0896.

[2R,3aS] and [2R,3aR]-3a-Methyl-5-oxo-2-phenyl-

1,2,3,3a,4,5-hexahydropentalene-2-carbonitrile (32A + 32B).

The diastereoisomeric mixture 32A + 32B was obtained using (R,E)-2-

phenyl-2-(prop-2-yn-1-yl)hex-4-enenitrile (29) as the substrate. The

reaction mixture was stirred for 5 min. The crude 90:10 mixture of

[2R,3aS]-5-Oxo-2-[2-(p-tolylsulfenyl)phenyl]-1,2,3,3a,4,5-

hexahydropentalene-2-carboxamide (45). The diastereoisomer

45 was obtained using (R)-2-(prop-2-inyl)-2-[2-(p-tolylsulfenyl)-

phenyl]pent-4-enamide [(R)-42] as the substrate. The reaction

mixture was stirred for 5 min. The crude >98:<2 mixture was puriﬁed

by ﬂash column chromatography using AcOEt−hexane (3:1) as the

eluent. Yield (45): 78% (42.3 mg, white solid); mp 144−146 °C

1

(CH₂Cl₂−hexane); [α]²⁰−160.1 (c 0.6, CHCl₃); H NMR δ 7.46−

D

7.44 (m, 1H), 7.26 and 7.13 (AA′BB′ system, 4H), 7.24−7.19 (m,

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The Journal of Organic Chemistry

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3H), 5.88 (s, 1H), 5.33 (br s, 1H), 5.18 (br s, 1H), 4.32 and 2.74 (AB

system, J 20.0 Hz, 2H), 3.47 (m, 1H), 2.76−2.73 (m, 2H), 2.35 (s,

3H), 2.16 (m, 1H), 2.09 (dd, J 12.2 and 12.3 Hz, 1H) ppm; ¹³C NMR

δ 210.1, 188.9 (2C), 142.1, 139.8, 138.5, 138.1, 133.0, 132.2 (2C),

130.9, 130.2 (2C), 128.6, 126.9, 126.4, 124.8, 43.8, 42.7, 42.0, 38.8,

21.1 ppm; MS (ESI+) m/z 364 [M + H]⁺(36), 319 (100); HRMS

(ESI+) calcd. for C₂₂H₂₂NO₂S [M + H]⁺364.1365, found 364.1378.

[2R*,3aS*,4S*]-4-Methyl-5-oxo-2-[2-(p-tolylsulfenyl)phenyl]-

1,2,3,3a,4,5-hexahydropentalene-2-carboxamide (46). The dia-

stereoisomer 46 was obtained using (2R,4E)-2-(prop-2-inyl)-2-[2-(p-

tolylsulfenyl)phenyl]hex-4-enamide (43) (76% ee) as the substrate.

The reaction mixture was stirred for 5 min. The crude >98:<2 mixture

was puriﬁed by ﬂash column chromatography using AcOEt−hexane

(2:1) as the eluent. Yield (46): 78% (50.1 mg, white solid); ¹H NMR

δ 7.47−7.45 (m, 1H), 7.26 and 7.13 (AA′BB′ system, 4H), 7.24−7.19

(m, 3H), 5.87 (m, 1H), 5.26 (br s, 1H), 5.21 (br s, 1H), 4.34 and 2.71

(AB system, J 18.6 Hz, 2H), 3.10 (m, 1H), 2.79 (dd, J 7.26 and 11.9

Hz, 1H), 2.36−2.30 (m, 1H), 2.35 (s, 3H), 2.12 (dd, J 12.3 and 15.4

Hz, 1H) ppm; ¹³C NMR δ 211.8, 186.6, 186.4, 142.1, 138.5, 138.0,

133.0, 132.2 (2C), 131.0, 130.2 (2C), 128.6, 126.9, 126.4, 123.8, 52.1,

49.2, 42.3, 38.7, 29.6, 21.1, 13.7 ppm; MS (ESI+) m/z 378 [M + H]⁺

(20), 333 (100); HRMS (ESI+) calcd. for C₂₃H₂₄NO₂S [M + H]⁺

378.1522, found 378.1508.

[2R*,3aS*,4R*]-5-Oxo-4-phenyl-2-[2-(p-tolylsulfenyl)-

phenyl]-1,2,3,3a,4,5-hexahydropentalene-2-carboxamide (47).

The diastereoisomer 47 was obtained using (2R,4E)-5-phenyl-2-(prop-

2-inyl)-2-[2-(p-tolylsulfenyl)phenyl]pent-4-enamide (44) as the sub-

strate (54% ee) [unpuriﬁed with a 30% of 5-phenyl-2-(prop-2-inyl)-2-

[2-(p-tolylsulﬁnyl)phenyl]pent-4-enenitrile (16)]. The reaction mix-

ture was stirred for 10 min. The crude >98:<2, along with 32aA, was

puriﬁed by ﬂash column chromatography using AcOEt−hexane (2:1)

as the eluent. Diastereoisomer [2R*,3aS*,4R*]-47 (data from a

70:30 47 + 27aA mixture): ¹H NMR δ 7.46−7.44 (m, 1H), 7.38−730

(m, 3H), 7.26 and 7.13 (AA′BB′ system, 4H), 7.28−7.24 (m, 3H),

7.23−7.18 (m, 2H), 6.05 (s, 1H), 5.34 (br s, 1H), 5.20 (br s, 1H), 4.05

and 3.15 (AB system, J 18.9 Hz, 2H), 3.42 (d, J 3.8 Hz, 1H), 3.36−

3.30 (m, 1H), 3.03 (dd, J 7.2 and 13.2 Hz, 1H), 2.33 (s, 3H), 2.22 (dd,

J 12.5 and 12.8 Hz, 1H) ppm; ¹³C NMR δ 208.5, 185.0, 180.1, 141.3,

138.4, 138.3, 138.0, 133.3, 132.1, 130.2, 130.0 (2C), 129.0 (2C), 128.7,

128.5 (2C), 127.1, 127.0, 126.0, 125.6, 124.1, 60.7, 54.8, 45.0, 41.4,

39.4, 21.1 ppm; MS (ESI+) m/z 440 [M + H]⁺(100); HRMS (ESI+)

calcd. for C₂₈H₂₆NO₂S [M + H]⁺440.1678, found 440.1655.

DEDICATION

■

In memory of Prof. Alessandro Degl'Innocenti.

REFERENCES

■

(1) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.

Soc. D.: Chem. Commun. 1971, 36a.

(2) Illustrative reviews on the Pauson−Khand reaction: (a) Pauson,

P. L. Tetrahedron 1985, 41, 5855. (b) Schore, N. E. Chem. Rev. 1988,

88, 1081. (c) Schore, N. E. Org. React. 1991, 40, 1. (d) Schore, N. E.

Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;

Pergamon: Oxford, 1991; Vol. 5, p 1037. (e) Schore, N. E.

Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G.

A., Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol. 12, p 703.

(f) Geis, O.; Schmalz, H.-G. Angew. Chem., Int. Ed. 1998, 37, 911.

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ASSOCIATED CONTENT

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* Supporting Information

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¹H and ¹³C NMR for 2-allyl-2-[2-(p-tolylsulﬁnyl)-

phenylacetonitriles 2, 4−7; 1,6-enynes 8−18, 28−30, 34,

36−38, 42−44; adducts 19−26, 31−32, 39−41, 45−47, and

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, M.; Achard, T.; Sola, J.;

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9−12 and bidimensional H NMR experiments of compounds

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23aA and 23aB. This material is available free of charge via the

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AUTHOR INFORMATION

■

(7) (a) Castro, J.; Sorensen, H.; Riera, A.; Morin, C.; Moyano, A.;

̈

Corresponding Author

*E-mail: joseluis.garcia.ruano@uam.es; martin.castro@uam.es.

Notes

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, M. A.; Greene, A. E. J. Am. Chem. Soc. 1990, 112, 9388.

, M. A.; Riera, A. J. Am. Chem.

quez, J.; Moyano, A.; Pericas

quez, J.;

̀

́

̀

,

́

The authors declare no competing ﬁnancial interest.

̀

ACKNOWLEDGMENTS

■

̀

Financial support of this work by the Ministerio de Ciencia y

́

Tecnologia (CTQ2009-12168), UAM-Comunidad de Madrid

̀

(CCG08UAM/PPQ-4235), and Comunidad de Madrid

(AVANCAT, S-2009-PPQ-1634) is gratefully acknowledged.

E.T. and J.A. thank Ministerio de Ciencia e Innovacion

predoctoral fellowship and a “Ramon y Cajal contract”,

respectively.

́

̀

́

for a

́

̀

Riera, A. J. Org. Chem. 2001, 66, 6400. (e) Montenegro, E.; Moyano,

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dx.doi.org/10.1021/jo3011039 | J. Org. Chem. 2012, 77, 6583−6599

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Asymmetric intramolecular Pauson-Khand reaction mediated by a remote sulfenyl or sulfinyl group

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