Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for the Synthesis of Substituted Bicyclic Cyclopentanes

Article

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX −XXX

Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for

the Synthesis of Substituted Bicyclic Cyclopentanes

Evan C. Bornowski,^†Elsa M. Hinds,^†Derick R. White,^†Yusuke Nakamura, and John P. Wolfe*

Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States

S

* Supporting Information

ABSTRACT: Palladium-catalyzed alkene difunctionalization reactions between alkenes bearing tethered aryl or alkenyl triﬂates

and enolate nucleophiles are described. The transformations form two C−C bonds, a ring, and up to two stereocenters while

producing substituted cyclopentane derivatives that contain appended carbonyl functionality. Products are formed with up to

>20:1 diastereoselectivity, and the formation of sterically congested bonds between quaternary carbon atoms is feasible.

KEYWORDS: palladium, cross-coupling, alkene difunctionalization, stereoselective

catalyzed reactions, including C-arylation⁶and allylic alkyla-

INTRODUCTION

Late transition metal-catalyzed alkene difunctionalization

■

tion.⁷In addition, cyclopentane derivatives bearing malonate,

ester, or ketone groups have previously shown utility as synthetic

reactions are powerful methods that have demonstrated utility

intermediates.^8,9In this article we describe a set of new alkene

for the construction of a range of heterocycles and carbo-

difunctionalization reactions of malonates,¹⁰esters, and ketones

that provide substituted cyclopentane derivatives in moderate to

good yields with high levels of diastereoselectivity.

cycles.^1,2We have recently reported a new class of alkene

difunctionalization reactions of alkenes tethered to aryl or

alkenyl triﬂates with amine,³alcohol,⁴or indole⁵nucleophiles.

As shown in Scheme 1, these reactions aﬀord substituted

RESULTS AND DISCUSSION

■

Transformations of Malonate Nucleophiles. In order to

probe the feasibility of alkene difunctionalization reactions

involving enolate nucleophiles, we initially examined the

coupling of diethyl malonate with 2-allylphenyl triﬂate (5a).

We began our studies using conditions we had previously

developed for similar reactions of alcohol or amine nucleophiles

and were pleased to ﬁnd that these conditions provided

satisfactory results in this transformation. The desired product

6a was formed in 93% isolated yield on a 0.2 mmol scale, 84%

isolated yield on a 1.0 mmol scale, and 88% yield on a 1.5 g scale

(eq 4).

Scheme 1. Prior Studies

cyclopentane derivatives in good yields with high diastereose-

lectivity. For example, the Pd/BrettPhos-catalyzed coupling of

1a with morpholine aﬀorded 2 in 76% yield with >20:1 dr

(Scheme 1, eq 1). Similarly, treatment of 1a with 3-phenyl-

propanol (Scheme 1, eq 2) or indole (Scheme 1, eq 3) provided

3 and 4, respectively, in good yields with >20:1 diastereose-

lectivity under appropriate conditions.

In order to further explore the scope of this general class of

transformations, we elected to examine the use of stabilized

carbanions as nucleophiles for alkene difunctionalization. We

were cautiously optimistic about the chances for success at the

outset of these studies, as enolates and related compounds have

previously been employed as nucleophiles in a range of other Pd-

Given the successful outcome of this initial reaction, we

elected not to pursue further optimization of conditions but

instead decided to explore the scope of this transformation

(Scheme 2). Reactions between diethyl malonate and terminal

alkene substrates (5a−d) proceeded in good yield under our

standard reaction conditions, and substrate 5d was converted to

6d with >20:1 dr. In contrast, internal alkene substrates 5e−h

Special Issue: Honoring 25 Years of the Buchwald-Hartwig

Amination

Received: May 31, 2019

A

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a b c

, ,

excellent yields in most cases examined (Scheme 3). The

reactions were eﬀective with substrates derived from both six-

Scheme 2. Reactions of Aryl Triﬂates with Malonates

Scheme 3. Reactions of Alkenyl Triﬂates Bearing Terminal

a b c

, ,

Alkenes with Malonates

a

Conditions: 1.0 equiv of 5, 1.2 equiv of diethyl malonate, 1.4 equiv

of LiO^tBu, 4 mol % Pd(OAc)₂, 6 mol % BrettPhos, toluene (0.1 M),

95 °C, 16 h. Reactions were conducted on a 0.1−0.25 mmol scale.

Conditions: 1.0 equiv of 1, 1.2 equiv of diethyl malonate, 1.4 equiv

of LiO^tBu, 4 mol % Pd(OAc)₂, 6 mol % BrettPhos, toluene (0.1 M),

95 °C, 16 h. Reactions were conducted on a 0.1−0.25 mmol scale.

b

Diastereomeric ratios were determined by ¹H NMR analysis.

b

Diastereomeric ratios were determined by ¹H NMR analysis.

Diastereomeric ratios were identical for crude reaction mixtures and

isolated compounds unless otherwise noted. Yields are average

isolated yields of two or more experiments. The reaction was

Diastereomeric ratios were identical for crude reaction mixtures and

isolated compounds unless otherwise noted. Yields are average

isolated yields of two or more experiments. The reaction was

conducted using RuPhos as the ligand.

c

d

conducted using (BrettPhos)Pd(allyl)(Cl) in place of Pd(OAc)₂.

e

The reaction was conducted using 2.2 equiv of LiO^tBu and 3.6 equiv

of diethyl malonate, a substrate concentration of 0.8 M, and a reaction

temperature of 65 °C.

and ﬁve-membered-ring ketones. Products bearing fused

heterocyclic rings (7b, 7c) were formed in good yields with

high dr, and the presence of a substituent on the carbon bearing

the allyl group (7e, 7g) was tolerated. The reaction between

substrate 1f and diethyl 2-allylmalonate provided 7f, with the

formation of a bond between two quaternary carbon atoms, in

63% yield with 19:1 dr, although use of the smaller RuPhos

ligand was needed to obtain acceptable results.

Eﬀorts to couple alkenyl triﬂates bearing internal alkenes

failed to provide satisfactory results either under these

conditions (Scheme 4, entry 1) or under the reoptimized

conditions that were modestly eﬀective with aryl triﬂates.

Therefore, we elected to examine the inﬂuence of the precatalyst

and ligand structure on the reaction between diethyl malonate

and 1l. As shown in Scheme 4, use of other biaryl phosphines,¹²

including CPhos, RuPhos, and SPhos that are less sterically

hindered than BrettPhos, provided improved results (45−48%

yield). However, use of the wide-bite-angle ligand Dpe-Phos

aﬀorded the desired product in 65% yield when LiHMDS was

employed as the base. We then examined Pd(acac)₂as a

precatalyst, as we previously observed increased eﬃciency in

other transformations when this precatalyst was used.¹³The

were less reactive and suﬀered from competing base-mediated

isomerization of the alkene and/or cleavage of the triﬂate to give

the corresponding phenoxide. However, these problems could

be alleviated to some extent through use of increased amounts of

diethyl malonate (3.6 equiv) and lithium tert-butoxide (2.2

equiv) combined with a lower reaction temperature of 65 °C.

Under these modiﬁed conditions, products 6e−h were obtained

with >20:1 dr, albeit in modest isolated yields (33−46%).¹¹The

diminished reactivity of the internal alkene substrates is

presumably due to their increased steric bulk, which decreases

the facility by which the alkene is bound to palladium. Substrate

5i, which contains a methyl group at the internal alkene carbon

was transformed to 6i in only 14% yield because of competing,

and somewhat surprising, 5-endo Heck-type cyclization of the

substrate.

We subsequently turned our attention to cyclic alkenyl triﬂate

substrates, which can be prepared from the corresponding cyclic

ketones in two steps (Pd-catalyzed enolate allylation followed by

formation of the enol triﬂate). Transformations of cyclic alkenyl

triﬂates bearing pendent terminal alkenes proceeded in good to

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Scheme 4. Optimization of the Reaction Between 1l and

Diethyl Malonate

Scheme 5. Reactions of Alkenyl Triﬂates Bearing Internal

Alkenes with Malonates

a

a b c

, ,

a

Conditions: 1.0 equiv of 1l, 2.0 equiv of diethyl malonate, 4 mol %

Pd, 6 mol % ligand, 2.2 equiv of LiOtBu, toluene (0.8 M), 95 °C, 14

b

h. Isolated yields (averages of two or more experiments).

c

Diastereomeric ratios were determined by ¹H NMR analysis.

d

e

LiHMDS was used as the base instead of LiOtBu. The yield was

1

determined by H NMR analysis of the crude reaction mixture using

phenanthrene as an internal standard.

combination of Pd(acac)₂with SPhos provided the best results,

aﬀording 7p in 79% yield with >20:1 dr.

We then examined the use of these newly optimized

conditions with a number of diﬀerent internal alkene substrates

(Scheme 5). The transformations proceed in moderate to good

yields with generally high (>20:1) diastereoselectivity. A

substituent (R ≠ H) on the carbon bearing the tethered alkene

was tolerated and in some instances provided a signiﬁcant

increase in yield. For example, the coupling of 1l (R = CO₂Et)

with diethyl malonate proceeded to give 7p in 79% yield,

whereas the analogous substrate 1m (R = H) was converted to

7q in only 21% yield. Not surprisingly, use of di-tert-butyl

malonate as the nucleophile provided results similar to those

obtained with diethyl malonate. Transformations involving

diethyl 2-benzylmalonate also provided the desired products 7j,

7n, and 7s with >20:1 dr, although a higher reaction temperature

(110 °C) was required and the chemical yields were lower than

those obtained with the unsubstituted diethyl malonate

nucleophile.

a

Conditions: 1.0 equiv of 1, 3.6 equiv of diethyl malonate, 2.2 equiv

of LiO^tBu, 4 mol % Pd(acac)₂, 6 mol % SPhos, toluene (0.8 M), 95

°C, 14 h. Reactions were conducted on a 0.2 mmol scale.

b

Diastereomeric ratios were determined by ¹H NMR analysis.

Diastereomeric ratios were identical for crude reaction mixtures and

isolated compounds unless otherwise noted. Yields are average

isolated yields of two or more experiments. The reaction was

conducted in xylenes solvent at 110 °C.

c

d

In prior studies involving amine or alcohol nucleophiles, we

found that acyclic alkenyl triﬂates are also viable substrates in

related alkene difunctionalization reactions.^3b,4Thus, we brieﬂy

examined the reactivity of two acyclic substrates with diethyl

malonate. As shown in eq 5, the coupling of 8 with diethyl

malonate proceeded smoothly under the standard conditions to

aﬀord spirocycle 9 in 82% yield with >20:1 dr. However, when

gem-diester substrate 10 was treated with di-tert-butyl malonate

under analogous conditions, we obtained a 4:1 mixture of 11 and

12 in 53% yield (eq 6). A preliminary screen of several other

phosphine ligands, including X-Phos, Dpe-Phos, and P(2-

furyl)₃, provided similar mixtures of 11 and 12 (in ratios ranging

from 2:1 to 1:2.5) in good yields (up to 90% for the mixture).

Future studies will be directed toward improving the

regioselectivity in these transformations.

nucleophiles. For example, the reaction between 1a and ethyl

acetoacetate aﬀorded 13a in 83% yield as a 1:1 mixture of

stereoisomers epimeric at the stereocenter adjacent to the

carbonyl group (Scheme 6, eq 7). Use of triethyl phosphonoa-

In addition to symmetrical malonate esters, these trans-

formations are also eﬀective with other stabilized carbanion

C

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a b c

, ,

Scheme 6. Reactions of Other Doubly Activated Nucleophiles

Scheme 7. Reactions of Ester Nucleophiles

a

Conditions: 1.0 equiv of triﬂate substrate, 1.2 equiv of ester, 2.2

equiv of LiHMDS, 4 mol % Pd(OAc)₂, 6 mol % BrettPhos, toluene

(0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1−0.25 mmol

b

1

scale. Diastereomeric ratios were determined by H NMR analysis.

Diastereomeric ratios were identical for crude reaction mixtures and

cetate as the nucleophile combined with LiHMDS as the base

provided 13b in 55% yield on a 1.85 mmol scale (Scheme 6, eq

8). However, reactions involving other activated nucleophiles

were more challenging. Ethyl cyanoacetate was much less

reactive than diethyl malonate, and only small amounts of the

desired product were formed under standard conditions.

Nonetheless, after some experimentation we were able to

produce 13c in 50% yield by using (BrettPhos)Pd(allyl)Cl as the

precatalyst¹⁴along with Cs₂CO₃as the base (Scheme 6, eq 9).

These conditions were also eﬀective for the coupling of 2-

allylphenyl triﬂate 5a with ethyl cyanoacetate to aﬀord 14a in

47% yield (Scheme 6, eq 10). Eﬀorts to employ 2,4-

pentanedione (acac) as the nucleophile provided only trace

amounts of product, possibly because of inhibition of catalysis

by the action of acac as a ligand for Pd. In contrast, 5a was

successfully coupled with 2-acetyltetralone under modiﬁed

conditions in which an excess of LiHMDS (2.6 equiv) was

employed as the base. In this case the alkylation occurred on the

methyl group rather than the carbon between the carbonyls,

presumably via the dianion derived from 2-acetyltetralone, to

aﬀord 14b in 40% yield (Scheme 6, eq 11).¹⁵The modest yield

results from competing arylation⁶of the methyl ketone with 2-

allylphenyl triﬂate rather than alkene difunctionalization.

Although these other nucleophiles proved to be viable with

terminal alkene substrates, eﬀorts to couple them with internal

alkene derivatives have thus far been unsuccessful.

c

isolated compounds unless otherwise noted. Yields are average

isolated yields of two or more experiments. RuPhos was used in

d

place of BrettPhos as the ligand.

In contrast, much better results were obtained with more highly

substituted esters. For example, sterically hindered methyl

isobutyrate was coupled with terminal alkene substrates 5a and

1a to aﬀord 15b and 15g, respectively, in high yields. This

hindered ester was also successfully coupled with substrates

bearing a methyl group on the internal alkene carbon (1d, 1f, 5i,

and 5j) when RuPhos was used as the ligand for Pd. These

reactions aﬀorded 15h, 15i, 15d, and 15c in 52%, 50%, 24%, and

23% yield, respectively. Although the yields in these particular

transformations are modest, the reactions do eﬀect the

formation of a C−C bond between two quaternary carbon

atoms, and products 15h and 15i¹⁶were formed with high

diastereoselectivity (11:1 dr and >20:1 dr, respectively). Acyclic

alkenyl triﬂate 16 was also successfully coupled with methyl

isobutyrate using the Pd(OAc)₂/RuPhos catalyst to aﬀord 17 in

52% yield with >20:1 dr (eq 12). Reactions of 5a and 1a with

Transformations of Ketone or Ester Nucleophiles.

Given the successful transformations of malonates and related

nucleophiles, we sought to further expand the scope of this

method by employing other carbonyl-containing nucleophiles.

We surveyed the reactivity of a few aryl and alkenyl triﬂate

substrates toward several diﬀerent esters. Eﬀorts to employ

acetate esters gave poor results, as represented by the formation

of 15a in only 24% yield (Scheme 7). The main side reaction in

this case is identical to that observed with 2-acetyltetralone:

competing α-arylation of the ester with the aryl triﬂate substrate.

methyl 2-phenylacetate aﬀorded 15e and 15f, respectively, in

moderate to good yields, but 15f was obtained as a 2:1 mixture of

diastereomers epimeric at the stereocenter adjacent to the ester.

The coupling of 1a or 5a with several diﬀerent ketones also

proceeded smoothly (Scheme 8), and this series of reactions

exhibited the same general trends that were observed with ester

nucleophiles. Low to moderate yields were obtained with methyl

ketones (18a, 24%; 18h, 52%), and in the case of 2,2-

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a b c

, ,

alkene, the mechanism of these transformations is probably

similar to those of related reactions of amine, alcohol, and indole

nucleophiles.³⁻⁵As illustrated in Scheme 9, the reactions are

Scheme 8. Reactions of Ketone Nucleophiles

Scheme 9. Mechanism and Relative Stereochemistry

likely initiated by oxidative addition of the aryl or alkenyl triﬂate

to a Pd(0) complex generated by ligation and reduction of the

Pd(II) precatalyst. After oxidative addition, the alkene in

intermediate 19 is poised to bind to the Pd(II) center, which

activates it for attack by the exogenous nucleophile in

intermediate 20. This intermediate then undergoes anti-

carbopalladation to provide 21, which is transformed to the

desired product with regeneration of the Pd(0) catalyst through

reductive elimination. The observed major product stereo-

chemistry is consistent with carbopalladation through a chairlike

conformation in which nonbonding interactions are minimized.

Although control of the relative stereochemistry of the

substituents on the bicyclic ring system is generally quite high,

we currently are unable to control the relative stereochemistry of

stereocenters adjacent to the carbonyl of the nucleophilic

component. For products such as 15f and 18i−k, which contain

an acidic proton at the carbonyl α-stereocenter, the poor

stereocontrol is easily ascribed to epimerization under the

strongly basic reaction conditions. However, the poor selectivity

in the formation of 18l, which does not contain an epimerizable

α-stereocenter, reveals a second problem in stereocontrol. In

this case the 1:1 dr must result from inherently low relative face

selectivity when the enolate approaches intermediate 20

(Scheme 9).

a

Conditions: 1.0 equiv of triﬂate substrate, 1.2 equiv of ketone, 1.4

equiv of LiHMDS, 4 mol % Pd(OAc)₂, 6 mol % BrettPhos, toluene

(0.1 M), 95 °C, 16 h. Reactions were conducted on a 0.1−0.25 mmol

b

1

scale. Diastereomeric ratios were determined by H NMR analysis.

Diastereomeric ratios were identical for crude reaction mixtures and

isolated compounds unless otherwise noted. Yields are average

isolated yields of two or more experiments. The reaction was

conducted with 2.6 equiv of the ketone.

c

d

diphenylacetone, reaction selectively occurred at the less

hindered carbon rather than through the more highly

substituted thermodynamic enolate. However, reactions of

several other ketones, including α-phenylacetophenone, α-

tetralone, 6-methoxy-α-tetralone, and cyclohexanone, pro-

ceeded smoothly. In all cases examined, products were

generated with essentially complete control of the relative

stereochemistry around the bicyclic ring system. Products 18i,

18j, and 18k, which contain a base-epimerizable stereocenter,

were formed as essentially 1:1 mixtures of diastereomers

epimeric at the carbonyl-bearing stereocenter. However, the

reaction of 2-methyl-α-tetralone to produce 18l, which lacks a

base-epimerizable proton, also proceeded with 1:1 dr.

Interestingly, cyclohexanone underwent selective monoalkyla-

tion (using 2.6 equiv of cyclohexanone) to provide 18c and 18i;

bisalkylation products were not observed. This is likely due to

the use of excess cyclohexanone, along with the fact that the

thermodynamic enolates derived from products 18c and 18i are

sterically encumbered. These hindered enolates should react

much more slowly than the enolate of cyclohexanone itself, and

the less-substituted “kinetic” enolates of the monoalkylated

cyclohexanone products should be present at relatively low

concentration under these conditions.

SUMMARY AND CONCLUSION

■

We have developed a series of new alkene difunctionalization

reactions between alkenes bearing pendent aryl or alkenyl

triﬂates and enolate nucleophiles derived from esters, ketones,

and malonates. The reactions of terminal alkene substrates are

reasonably general, and the transformations involving internal

alkenes provide moderate yields when malonate nucleophiles

are used. The reactions generate a ring and two C−C bonds and

provide products that contain up to three stereocenters with

high diastereoselectivity in most cases examined. The product

stereochemistry implicates a mechanism involving anti-

carbopalladation of the alkene, which occurs with high

diastereoselectivity. The transformations aﬀord several diﬀerent

fused-bicyclic products, including heterocycles, although

reactions that generate simple monocyclic cyclopentane

derivatives are currently limited in scope because of the

formation of regioisomeric cyclobutene products. Future studies

will be directed toward stereocontrol in reactions of prochiral

enolates, regiocontrol in reactions of acyclic alkenyl triﬂates, and

investigation of other carbon-centered nucleophiles.

Mechanism and Stereochemical Model. On the basis of

the stereochemical outcome of transformations involving

internal alkenes, in which products result from anti addition of

the nucleophile and the aryl or alkenyl group to the pendent

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then transferred to a separatory funnel. The layers were

separated, and the aqueous layer was extracted with diethyl

ether (3 × 20 mL). The combined organic layers were washed

with brine, dried over MgSO₄, ﬁltered, and concentrated in

vacuo to yield a yellow oil. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 → 90:10

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

2.52 g (57% yield) of the title compound as a yellow semisolid

(mp 57−58 °C). ¹H NMR (500 MHz, CDCl₃): δ 7.28 (d, J =

18.1 Hz, 4H), 7.25−7.11 (m, 3H), 6.91 (s, 1H), 6.82 (d, J = 8.0

Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 6.44−6.34 (m, 1H), 4.89 (s,

1H), 3.58 (d, J = 6.5 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃): δ

154.0, 137.1, 131.5, 130.5, 128.5 (two peaks), 127.9 (two

peaks), 127.3, 126.2, 121.0, 115.8, 34.1. IR (ﬁlm): 3531.5,

1591.7 cm⁻¹. HRMS (ESI⁻TOF) m/z: [M − H]⁻calcd for

C₁₅H₁₄O 209.0966; found 209.0972.

2-Cinnamylphenyl Triﬂuoromethanesulfonate (5e). A

ﬂame-dried ﬂask equipped with a stir bar was cooled under a

stream of nitrogen and charged with 2-cinnamylphenol (S1)

(0.934 g, 4.45 mmol, 1.0 equiv) and dichloromethane (20 mL,

0.2 M). Pyridine (0.72 mL, 8.9 mmol, 2.0 equiv) was added, and

the reaction mixture was cooled to 0 °C. Triﬂuoromethane-

sulfonic anhydride (1.5 mL, 8.9 mmol, 2.0 equiv) was added,

and the ice bath was removed. The reaction mixture was stirred

for 15 h at rt, and the purple mixture was ﬁltered through a pad of

Celite, eluting with ethyl acetate. The purple ﬁltrate was

concentrated in vacuo to yield a purple oil. The crude material

was puriﬁed via column chromatography on silica gel using 98:2

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

1.18 g (78% yield) of the title compound as a colorless oil. ¹H

NMR (500 MHz, CDCl₃): δ 7.46−7.13 (m, 9H), 6.51 (d, J =

15.8 Hz, 1H), 6.35−6.22 (m, 1H), 3.65 (d, J = 6.8 Hz, 2H). ¹³C

NMR (126 MHz, CDCl₃): δ 147.9, 137.0, 133.1, 132.7, 131.4,

128.5, 128.2, 127.4, 126.2, 126.1, 121.4, 118.5 (q, J_C−F= 319

Hz), 33.2, 29.7. IR (ﬁlm): 1595.3 cm⁻¹. HRMS (ESI⁺TOF) m/

z: [M + H]⁺calcd for C₁₆H₁₃F₃O₃S 342.0538; found 342.0538.

2-Cinnamyl-4-ﬂuorophenol (S2). The title compound was

synthesized via a procedure similar to that described above for

the preparation of S1, except using 4-ﬂuorophenol (2.9 g, 17.86

mmol, 1.0 equiv), cinnamyl chloride (2.5 mL, 17.86 mmol, 1.0

equiv), and sodium hydride (60% in mineral oil, 1.428 g, 35.7

mmol, 2.0 equiv). The crude material was puriﬁed via column

chromatography on silica gel using 95:5 → 90:10 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 2.617 g (64%

yield) of the title compound as a yellow solid (mp 51−52 °C).

¹H NMR (500 MHz, CDCl₃): δ 7.41−7.16 (m, 5H), 6.90 (d, J =

9.0 Hz, 1H), 6.83 (d, J = 13.6 Hz, 1H), 6.75 (d, J = 13.4 Hz, 1H),

6.51 (d, J = 15.9 Hz, 1H), 6.35 (d, J = 15.9 Hz, 1H), 4.78 (s, 1H),

3.54 (d, J = 6.6 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 158.1,

156.2, 149.8 (d, J = 2.5 Hz), 136.9, 132.0, 128.6, 127.4 (d, J = 7.5

Hz), 127.0, 126.2, 116.6 (d, J = 31 Hz), 116.5 (d, J = 18 Hz),

113.9 (d, J = 23 Hz), 34.0. IR (ﬁlm): 3411.7, 1619.3 cm⁻¹.

HRMS (ESI⁻TOF) m/z: [M − H]⁻calcd for C₁₅H₁₃FO

227.0872; found 227.0878.

EXPERIMENTAL SECTION

■

General Considerations. All of the reactions were carried

out under a nitrogen atmosphere in ﬂame-dried glassware. All of

the reagents, palladium precatalysts, and ligands were purchased

from commercial sources and used without further puriﬁcation

unless otherwise noted. Substrates 1a−e,^3b1f,⁴1g,⁴5a,^3a5c,^3a

5d,^3b8,^3b10,^3b16,^3b(BrettPhos)Pd(allyl)(Cl),¹³N-(2-

pyridyl)triﬂimide,¹⁷4-tert-butyl-2-allylphenol,¹⁸and allyl 1-

methyl-2-oxocyclohexane-1-carboxylate¹⁹were prepared by

previously published methods. Alkenyl triﬂate starting materials

were stored in a freezer under nitrogen. Bulk quantities of

cesium carbonate, lithium tert-butoxide, and lithium hexame-

thyldisilazide were stored in a nitrogen-ﬁlled glovebox, and small

amounts were removed and used within a few days, during which

time they were stored in a desiccator. Toluene, tetrahydrofuran

(THF), dichloromethane (DCM), and diethyl ether were

puriﬁed using a GlassContour solvent puriﬁcation system.

Anhydrous dioxane was purchased from Sigma-Aldrich and used

without further puriﬁcation. Structural and stereochemical

assignments were made on the basis of 2-D COSY and

NOESY experiments. Ratios of diastereomers were determined

by ¹H NMR analysis. Yields refer to isolated yields of

1

compounds estimated to be ≥95% pure as determined by H

NMR analysis, unless otherwise noted. The yields reported in

the Experimental Section describe the results of single

experiments, whereas the yields reported in Schemes 2−8 and

eqs 4−12 are average yields of two or more experiments. Thus,

the yields reported in the Experimental Section may diﬀer from

those shown in Schemes 2−8 and eqs 4−12.

Preparation and Characterization of Substrates. 2-

Allyl-4-(tert-butyl)phenyl Triﬂuoromethanesulfonate (5b). A

ﬂame-dried ﬂask equipped with a stir bar was cooled under a

stream of nitrogen and charged with 2-allyl-4-tert-butylphenol

(0.231 g, 1.21 mmol, 1.0 equiv) and dichloromethane (1.3 mL, 1

M). Pyridine (0.117 mL, 1.48 mmol, 1.2 equiv) was added, and

the reaction mixture was cooled to 0 °C. Triﬂuoromethane-

sulfonic anhydride (0.225 mL, 1.34 mmol, 1.1 equiv) was added,

and the ice bath was removed. The reaction mixture was stirred

for 15 h at room temperature (rt) and then quenched with

ammonium chloride. The resulting mixture was extracted with

DCM (×3), and the organic layer was dried with MgSO₄and

concentrated in vacuo to yield a brown oil. The crude material

was puriﬁed via column chromatography on silica gel using 99:1

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

0.334 g (85% yield) of the title compound as a colorless oil. ¹H

NMR (500 MHz, CDCl₃): δ 7.32−7.25 (m, 2H), 7.19−7.14 (m,

1H), 5.98−5.87 (m, 1H), 5.18−5.09 (m, 2H), 3.47 (d, J = 6.6

Hz, 2H), 1.31 (s, 9H). ¹³C NMR (126 MHz, CDCl₃): δ 151.5,

145.7, 134.9, 131.9, 128.3, 125.1, 120.7, 118.5 (q, J_C−F= 321 Hz)

117.2, 77.2, 34.7, 34.3, 31.2. IR (ﬁlm): 2967, 1491 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + H]⁺calcd for C₁₄H₁₇F₃O₃S 323.0850;

found 323.0565.

2-Cinnamylphenol (S1). A ﬂame-dried two-neck ﬂask

equipped with a stir bar and a condenser was cooled under a

stream of nitrogen and charged with phenol (2.0 g, 21.2 mmol,

1.0 equiv) and diethyl ether (22 mL, 0.1 M). Sodium hydride

(60% in mineral oil, 1.7 g, 42.4 mmol, 2.0 equiv) was added, and

the reaction mixture was stirred at rt for 30 min. Cinnamyl

chloride was added, and the reaction mixture was heated to 37

°C with stirring for 6 h. The reaction mixture was cooled to rt

and transferred to an Erlenmeyer ﬂask containing aqueous HCl

(0.1 M, 75 mL). The resulting mixture was stirred brieﬂy and

2-Cinnamyl-4-ﬂuorophenyl Triﬂuoromethanesulfonate

(5f). The title compound was synthesized via a procedure

similar to that described above for the preparation of 2-

cinnamylphenyl triﬂuoromethanesulfonate (5e), except using 2-

cinnamyl-4-ﬂuorophenol (S2) (0.79 g, 3.47 mmol, 1.0 equiv),

triﬂuoromethanesulfonic anhydride (1.16 mL, 6.94 mmol, 2.0

equiv), and pyridine (0.56 mL, 6.94 mmol, 2.0 equiv). The crude

material was puriﬁed via column chromatography on silica gel

using 100:1 → 98:2 hexanes/ethyl acetate as the eluent. This

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procedure aﬀorded 0.8474 g (68% yield) of the title compound

as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.52−7.22 (m,

6H), 7.15 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.60 (d, J = 15.8 Hz,

1H), 6.31 (dd, J = 15.8, 7.0 Hz, 1H), 3.69 (d, J = 7.0 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃): δ 162.6, 160.6, 143.5 (d, J = 4

Hz), 136.8, 135.9 (d, J = 8 Hz), 133.5, 127.7, 126.3, 125.1, 123.1

(d, J = 9 Hz), 118.7 (q, J = 319 Hz), 117.9 (d, J = 24 Hz), 115.0

(d, J = 24 Hz), 33.3. IR (ﬁlm): 1592.3 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₁₆H₁₂F₄O₃S 361.0522; found

361.0516.

2-Cinnamyl-4-methoxyphenol (S3). The title compound

was synthesized via a procedure similar to that described above

for the preparation of S1, except using 4-methoxyphenol (1.9 g,

14.4 mmol, 1.0 equiv), cinnamyl chloride (2.0 mL, 14.4 mmol,

1.0 equiv), and sodium hydride (60% in mineral oil, 1.15 g, 28.8

mmol, 2.0 equiv). The crude material was puriﬁed via column

chromatography on silica gel using 95:5 → 90:10 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 1.516 g (44%

yield) of the title compound as an orange solid (mp 74−76 °C).

¹H NMR (500 MHz, CDCl₃): δ 7.46−7.10 (m, 5H), 6.83−6.61

(m, 3H), 6.50 (d, J = 15.9 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H),

4.59 (s, 1H), 3.76 (s, 3H), 3.54 (d, J = 6.3 Hz, 2H). ¹³C NMR

(126 MHz, CDCl₃): δ 153.8, 137.0, 131.6, 128.6 (two peaks),

128.5, 127.7, 126.8, 126.2, 116.5, 116.0, 112.6, 55.7, 34.3. IR

(ﬁlm): 3384.8, 1598.5 cm⁻¹. HRMS (ESI⁻TOF) m/z: [M −

H]⁻calcd for C₁₆H₁₆O₂239.1072; found 239.1078.

similar to that described above for the preparation of 5e, except

using 2-cinnamyl-4-methylphenol (S4) (1.02 g, 4.46 mmol, 1.0

equiv), triﬂuoromethanesulfonic anhydride (1.5 mL, 8.93 mmol,

2.0 equiv), and pyridine (0.72 mL, 8.93 mmol, 2.0 equiv). The

crude material was puriﬁed via column chromatography on silica

gel using 100:0 → 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 1.20 g (76% yield) of the title compound as a

colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.38 (d, J = 7.0 Hz,

2H), 7.32 (t, J = 7.6 Hz, 2H), 7.28−7.20 (m, 1H), 7.20−7.13

(m, 2H), 7.10 (dd, J = 8.4, 2.2 Hz, 1H), 6.51 (d, J = 15.7 Hz,

1H), 6.35−6.21 (m, 1H), 3.61 (dd, J = 7.0, 1.5 Hz, 2H), 2.35 (s,

3H). ¹³C NMR (126 MHz, CDCl₃): δ 145.8, 138.5, 137.1,

132.6, 132.5, 131.9, 128.7, 128.5, 128.4, 127.4, 126.3, 118.6 (q,

J_C−F= 321 Hz), 121.1, 33.2, 20.9. IR (ﬁlm): 3028.5, 2924.4,

1599.3, 1490.7, 1417.7 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

NH₄]⁺calcd for C₁₇H₁₅F₃O₃S 374.1038; found 374.1032.

4-(tert-Butyl)-2-(2-methylallyl)phenyl Triﬂuoromethane-

sulfonate (5i). A ﬂame-dried thick-walled sealable glass pressure

ﬂask equipped with a stir bar was cooled under a stream of

nitrogen and charged with 1-(tert-butyl)-4-[(2-methylallyl)-

oxy]benzene (5.33g, 26 mmol) and dimethylformamide (5 mL,

5.2 M). The solution was heated to 200 °C for 12 h and then

cooled to rt, and ethyl acetate (20 mL) was added. The mixture

was transferred to a separatory funnel, washed with water (3 ×

20 mL), dried with anhydrous MgSO₄, and concentrated in

vacuo to yield a brown oil. The crude material was puriﬁed via

column chromatography on silica gel using 80:20 hexanes/

dichloromethane as the eluent. This procedure aﬀorded 4.05 g

(76% yield) of 4-(tert-butyl)-2-(2-methylallyl)phenol as a

colorless oil with ca. 3% side product resulting from isomer-

ization of the alkene. ¹H NMR (401 MHz, CDCl₃): δ 7.14 (dd, J

= 8.4, 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 8.4 Hz,

1H), 4.97 (s, 1H), 4.90 (s, 1H), 4.83 (s, 1H), 3.36 (s, 2H), 1.74

(s, 3H), 1.28 (s, 9H).

A ﬂame-dried ﬂask equipped with a stir bar was cooled under a

stream of nitrogen and charged with 4-(tert-butyl)-2-(2-

methylallyl)phenol (1.4 g, 6.85 mmol, 1.0 equiv) and dichloro-

methane (7 mL, 1 M). Pyridine (1.4 mL, 8.22 mmol, 1.2 equiv)

was added, and the mixture was cooled to 0 °C. Triﬂuor-

omethanesulfonic anhydride (0.7 mL, 8.22 mmol, 1.2 equiv)

was added, and the ice bath was removed. The reaction mixture

was stirred at rt for 15 h and then quenched with saturated

aqueous ammonium chloride (10 mL). The resulting mixture

was transferred to a separatory funnel and extracted with

dichloromethane (3 × 10 mL), and the organic layers were

combined, dried with anhydrous MgSO₄, and concentrated in

vacuo to yield a brown oil. The crude material was puriﬁed via

column chromatography on silica gel using 99:1 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 2.06 g (89% yield)

of the title compound as a colorless oil that contained ca. 6% side

product resulting from alkene isomerization. The data shown are

for the major isomer. ¹H NMR (500 MHz, CDCl₃): δ 7.32−7.27

(m, 2H), 7.20−7.14 (m, 1H), 4.89 (s, 1H), 4.66 (s, 1H), 3.40 (s,

2H), 1.72 (s, 3H), 1.31 (s, 9H). ¹³C NMR (126 MHz, CDCl₃): δ

151.34, 146.09, 142.74, 131.42, 128.76, 125.07, 120.58, 118.5

(q, J_C−F= 321 Hz), 113.05, 38.29, 34.63, 31.23, 22.22. IR (ﬁlm):

2951, 2700, 1480, 1415, 1208, 729 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₁₅H₁₉F₃O₃S 337.1080; found

337.1077.

2-Cinnamyl-4-methoxyphenyl Triﬂuoromethanesulfonate

(5g). The title compound was synthesized via a procedure

similar to that described above for the preparation of 5e, except

using 2-cinnamyl-4-methoxyphenol (S3) (1.0 g, 4.17 mmol, 1.0

equiv), triﬂuoromethanesulfonic anhydride (1.4 mL, 8.33 mmol,

2.0 equiv), and pyridine (0.67 mL, 8.33 mmol, 2.0 equiv). The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 1.18 g (76% yield) of the title compound as a

1

colorless oil. H NMR (500 MHz, CDCl₃): δ 7.44−7.13 (m,

6H), 6.87 (s, 1H), 6.79 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 15.8 Hz,

1H), 6.34−6.18 (m, 1H), 3.80 (s, 3H), 3.60 (d, J = 6.9 Hz, 2H).

¹³C NMR (126 MHz, CDCl₃): δ 159.0, 141.3, 137.0, 134.4,

132.8, 128.5, 127.4, 126.2, 126.0, 122.4, 118.7 (q, J_C−F= 305

Hz), 116.3, 112.8, 55.7, 33.5. IR (ﬁlm): 1587.1 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + NH₄]⁺calcd for C₁₇H₁₅F₃O₄S

390.0987; found 390.0981.

2-Cinnamyl-4-methylphenol (S4). The title compound was

synthesized via a procedure similar to that described above for

the preparation of S1, except using 4-methylphenol (2.3 mL,

22.0 mmol, 1.0 equiv), cinnamyl chloride (3.0 mL, 22.0 mmol,

1.0 equiv), and sodium hydride (60% in mineral oil, 1.80 g, 44.0

mmol, 2.0 equiv). The crude material was puriﬁed via column

chromatography on silica gel using 95:5 → 90:10 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 2.68 g (54% yield)

1

of the title compound as a yellow wax. H NMR (500 MHz,

CDCl₃): δ 7.44−7.14 (m, 5H), 7.04−6.88 (m, 2H), 6.72 (d, J =

8.0 Hz, 1H), 6.56−6.46 (m, 1H), 6.44−6.33 (m, 1H), 4.75 (s,

1H), 3.54 (dd, J = 6.5, 1.4 Hz, 2H), 2.28 (s, 3H). ¹³C NMR (126

MHz, CDCl₃): δ 151.7, 137.1, 131.4, 131.0, 130.2, 128.5, 128.2,

128.1, 127.3, 126.2, 125.4, 115.6, 34.1, 20.5. IR (ﬁlm): 3214.4,

2750.3, 1495.7, 1405.2, 1275.7 cm⁻¹. HRMS (Electron Impact

Ionization TOF) m/z: [M + H]⁺calcd for C₁₆H₁₆O 224.1201;

found 224.1201.

Ethyl 1-Cinnamyl-2-oxocyclopentane-1-carboxylate (S5).

A ﬂame-dried ﬂask equipped with a stir bar was cooled under a

stream of nitrogen and charged with sodium hydride (60% in

mineral oil, 0.534 g, 13.35 mmol, 0.89 equiv) and THF (6 mL).

2-Cinnamyl-4-methylphenyl Triﬂuoromethanesulfonate

(5h). The title compound was synthesized via a procedure

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The mixture was cooled to 0 °C, and a solution of ethyl 2-

oxocyclopentane-1-carboxylate (1.9 mL, 15 mmol, 1 equiv) in

THF (10 mL) was added dropwise over the course of 90 min.

The reaction mixture was warmed to rt and stirred for 90 min,

and then a solution of cinnamyl bromide (2.6 mL, 17.25 mmol,

1.15 equiv) in THF (5 mL) was added. The mixture was stirred

at rt for 16 h and then quenched with saturated aqueous

ammonium chloride (20 mL). The resulting mixture was

transferred to a separatory funnel. The layers were separated,

and the aqueous layer was extracted with ethyl acetate (3 × 20

mL). The combined organic layers were washed with brine (1 ×

20 mL), dried over Na₂SO₄, ﬁltered, and concentrated in vacuo

to aﬀord a yellow oil. The crude material was puriﬁed via column

chromatography on silica gel using 90:10 hexanes/ethyl acetate

as the eluent. This procedure aﬀorded 1.84 g (45% yield) of the

title compound as a colorless oil. ¹H NMR (500 MHz, CDCl₃):

δ 7.40−7.25 (m, 4H), 7.21 (d, J = 14.2 Hz, 1H), 6.45 (d, J = 15.8

Hz, 1H), 6.16−6.01 (m, 1H), 4.25−4.10 (m, 2H), 2.89−2.73

(m, 1H), 2.59−2.37 (m, 3H), 2.31−2.16 (m, 1H), 2.04 (d, J =

14.0 Hz, 2H), 1.90 (d, J = 17.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H).

¹³C NMR (126 MHz, CDCl₃): δ 214.6, 170.9, 137.0, 134.1,

128.5, 127.4, 126.2, 124.5, 61.5, 60.2, 38.1, 37.0, 32.3, 19.6, 14.1.

IR (ﬁlm): 1750.4, 1719.9, 1448.4 cm⁻¹. HRMS (ESI⁺TOF) m/

z: [M + H]⁺calcd for C₁₇H₂₀O₃272.1413; found 273.1485.

Ethyl 1-Cinnamyl-2-{[(triﬂuoromethyl)sulfonyl]oxy}-

cyclopent-2-ene-1-carboxylate (1l). A ﬂame-dried ﬂask

equipped with a stir bar was cooled under a stream of nitrogen

and charged with THF (10 mL) and diisopropylamine (1.0 mL,

7.29 mmol, 1.7 equiv). The mixture was cooled to 0 °C, and n-

BuLi (2.5 M in hexanes, 2.9 mL, 7.29 mmol, 1.7 equiv) was

added dropwise. The resulting mixture was stirred at 0 °C for 30

min and then cooled to −78 °C, and a solution of ethyl 1-

cinnamyl-2-oxocyclopentane-1-carboxylate (S5) (1.17 g, 4.29

mmol, 1 equiv) in THF (10 mL) was added dropwise over the

course of 90 min. The reaction mixture was stirred at −78 °C for

2.5 h, and then N-(2-pyridyl)triﬂamide (2.61 g, 7.29 mmol, 1.7

equiv) in THF (5 mL) was added. The mixture was warmed to

rt, stirred for 16 h, and quenched with water (20 mL), and the

resulting mixture was transferred to a separatory funnel. The

layers were separated, and the aqueous layer was extracted with

ethyl acetate (3 × 20 mL). The combined organic layers were

washed with brine (1 × 20 mL), dried over Na₂SO₄, ﬁltered, and

concentrated in vacuo to aﬀord a yellow oil. The crude material

was puriﬁed via column chromatography on silica gel using 98:2

→ 95:5 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 1.18 g (68% yield) of the title compound as a yellow oil.

¹H NMR (500 MHz, CDCl₃): δ 7.42−7.14 (m, 5H), 6.50 (d, J =

15.7 Hz, 1H), 6.14−6.00 (m, 1H), 5.80 (s, 1H), 4.32−4.11 (m,

2H), 2.78 (d, J = 8.0 Hz, 1H), 2.63 (d, J = 14.1 Hz, 1H), 2.48 (d,

J = 9.3 Hz, 2H), 2.35 (d, J = 5.5 Hz, 1H), 2.15−1.93 (m, 1H),

1.29 (t, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 172.5,

pyrrolidine (0.33 mL, 4 mmol, 0.2 equiv) were added, and the

mixture was then heated to 45 °C with stirring for 16 h. The

reaction mixture was quenched with cold saturated aqueous

ammonium chloride (20 mL) and transferred to a separatory

funnel. The layers were separated, and the aqueous layer was

extracted with diethyl ether (3 × 20 mL). The combined organic

layers were washed with brine (1 × 20 mL), dried over Na₂SO₄,

ﬁltered, and concentrated in vacuo to aﬀord a yellow oil. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 3.38 g (83% yield) of the title compound as a

1

colorless oil. H NMR (500 MHz, CDCl₃): δ 7.39−7.13 (m,

5H), 6.43 (d, J = 15.6 Hz, 1H), 6.24−6.08 (m, 1H), 2.65 (d, J =

10.0 Hz, 1H), 2.41−2.16 (m, 4H), 2.11 (d, J = 8.8 Hz, 1H), 2.01

(s, 1H), 1.81 (dddt, J = 14.7, 8.5, 4.3, 2.3 Hz, 1H), 1.63 (s, 1H).

¹³C NMR (126 MHz, CDCl₃): δ 220.4, 137.4, 131.8, 128.5,

127.6, 127.1, 126.0, 49.0, 38.2, 33.1, 29.0, 20.7. IR (ﬁlm):

1732.7, 1597.2 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₁₄H₁₆O 201.1280; found 201.1274.

5-Cinnamylcyclopent-1-en-1-yl Triﬂuoromethanesulfo-

nate (1m). A ﬂame-dried ﬂask equipped with a stir bar was

cooled under a stream of nitrogen and charged with THF (20

mL) and diisopropylamine (1.05 mL, 7.5 mmol, 1.5 equiv). The

mixture was cooled to 0 °C, and n-BuLi (2.5 M in hexanes, 3.0

mL, 7.5 mmol, 1.5 equiv) was added dropwise. The resulting

solution was stirred at 0 °C for 30 min and then cooled to −78

°C, and a solution of 2-cinnamylcyclopentan-1-one (S6) (1.0 g,

5.0 mmol, 1 equiv) in THF (20 mL) was added dropwise over

the course of 70 min. The reaction mixture was stirred for 2 h at

−78 °C, and then a solution of N-(2-pyridyl)triﬂamide (2.61 g,

7.29 mmol, 1.2 equiv) in THF (10 mL) was added. The resulting

mixture was warmed to −41 °C in an CH₃CN/dry ice bath and

stirred for 2 h. The reaction mixture was quenched with water

(20 mL) and transferred to a separatory funnel. The layers were

separated, and the aqueous layer was extracted with ethyl acetate

(3 × 20 mL). The combined organic layers were washed with

brine (1 × 20 mL), dried over Na₂SO₄, ﬁltered, and

concentrated in vacuo to aﬀord a yellow oil. The crude material

was puriﬁed via column chromatography on silica gel using

100:0 → 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 0.8675 g (52% yield) of the title compound

as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.35 (d, J =

18.6 Hz, 4H), 7.26 (s, 1H), 6.49 (d, J = 15.8 Hz, 1H), 6.18 (d, J =

15.7 Hz, 1H), 5.71 (s, 1H), 3.04 (s, 1H), 2.57 (ddt, J = 11.1, 5.8,

2.9 Hz, 1H), 2.45−2.26 (m, 3H), 2.20 (s, 1H), 1.80 (d, J = 6.2

Hz, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 151.3, 137.3, 132.6,

128.5, 127.2, 126.3, 126.1, 121.1 (q, J_C−F= 315 Hz), 117.4, 43.0,

35.7, 26.7, 26.6. IR (ﬁlm): 1656.6, 1495.7 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₁₅H₁₅F₃O₃S 333.0772; found

333.0767.

Ethyl 1-Cinnamyl-2-oxocyclohexane-1-carboxylate (S7).

The title compound was synthesized via a procedure similar to

that described above for the preparation of S5, except using ethyl

2-oxocyclohexane-1-carboxylate (3.2 mL, 20 mmol, 1 equiv),

cinnamyl bromide (3.4 mL, 23.0 mmol, 1.15 equiv), and sodium

hydride (0.712 g, 17.8 mmol, 0.89 equiv). The crude material

was puriﬁed via column chromatography on silica gel using 95:5

→ 90:10 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 3.58 g (63% yield) of the title compound as a yellow oil.

¹H NMR (500 MHz, CDCl₃): δ 7.39−7.12 (m, 5H), 6.37 (d, J =

15.8 Hz, 1H), 6.24−6.09 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.73

(tdd, J = 11.5, 7.1, 1.4 Hz, 1H), 2.56−2.41 (m, 3H), 2.01 (ddt, J

= 9.2, 6.2, 3.1 Hz, 1H), 1.81−1.57 (m, 4H), 1.57−1.49 (m, 1H),

147.9, 137.0, 134.5, 128.5, 127.5, 126.2, 123.6, 121.6 (q, J_C−F

=

375 Hz), 118.3, 61.6, 57.6, 38.0, 31.2, 26.2, 14.0. IR (ﬁlm):

1728.6, 1602.5, 1422.8 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₁₈H₁₉F₃O₅S 405.0984; found 405.0978.

2-Cinnamylcyclopentan-1-one (S6). A ﬂame-dried ﬂask

equipped with a stir bar was cooled under a stream of nitrogen

and charged with palladium allyl chloride dimer (0.146 g, 0.4

mmol, 0.02 equiv), dppf (0.665 g, 1.2 mmol, 0.06 mmol), and

methanol (80 mL). The mixture was stirred at rt for 60 min, and

then cinnamyl alcohol (2.8 mL, 22 mmol, 1.1 equiv) was added

to the orange mixture. The resulting mixture was stirred at rt for

30 min. Cyclopentanone (2.1 mL, 20 mmol, 1 equiv) and

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1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 207.6,

171.5, 137.2, 133.2, 128.4, 127.2, 126.1, 125.1, 61.3, 41.2, 38.6,

36.1, 27.9, 27.5, 22.5, 14.2. IR (ﬁlm): 1709.8 (two overlapping

peaks), 1597.9, 1495.7 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₁₈H₂₂O₃287.1647; found 287.1642.

similar to that described above for the preparation of ethyl 1-

cinnamyl-2-oxocyclopentane-1-carboxylate (S5), except using

ethyl 2-oxocyclohexane-1-carboxylate (3.4 mL, 21.1 mmol, 1

equiv), crotyl bromide (2.5 mL, 24.3 mmol, 1.15 equiv), and

sodium hydride (0.75 g, 18.8 mmol, 0.89 equiv). The crude

material was puriﬁed via column chromatography on silica gel

using 98:2 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 2.26 g (48% yield) of the title compound as a brown oil.

¹H NMR (500 MHz, CDCl₃): δ 5.54−5.22 (m, 2H), 4.26−4.04

(m, 2H), 2.60−2.28 (m, 4H), 2.28−2.13 (m, 1H), 1.96 (ddd, J =

14.1, 5.2, 2.9 Hz, 1H), 1.81−1.51 (m, 6H), 1.42 (d, J = 16.2 Hz,

1H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ

207.7, 171.6, 128.8, 125.6, 61.1, 41.1, 38.0, 35.7, 27.5, 22.5, 22.4,

17.9, 14.1. IR (ﬁlm): 1710.4 (two overlapping peaks), 1438.0

cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₁₃H₂₀O₃

225.1491; found 225.1485.

(E)-Ethyl 1-(But-2-en-1-yl)-2-{[(triﬂuoromethyl)sulfonyl]-

oxy}cyclohex-2-ene-1-carboxylate (1j). The title compound

was synthesized via a procedure similar to that described above

for the preparation of 1l, except using ethyl 1-(but-2-en-1-yl)-2-

oxocyclohexane-1-carboxylate (S9) (0.98 g, 4.46 mmol, 1

equiv), LDA (7.6 mmol, 1.7 equiv), and N-(2-pyridyl)triﬂamide

(2.66 g, 7.6 mmol, 1.7 equiv). The crude material was puriﬁed

via column chromatography on silica gel using 100:0 → 98:2

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

0.623 g (40% yield) of the title compound as a colorless oil. ¹H

NMR (500 MHz, CDCl₃): δ 5.86 (s, 1H), 5.57−5.45 (m, 1H),

5.28 (d, J = 15.0 Hz, 1H), 4.15 (d, J = 16.3 Hz, 2H), 2.47 (s, 2H),

2.29−2.08 (m, 3H), 1.63 (d, J = 15.5 Hz, 6H), 1.27 (t, J = 7.1 Hz,

3H). ¹³C NMR (126 MHz, CDCl₃): δ 172.8, 148.2, 130.2,

124.5, 120.0, 118.3 (q, J_C−F= 318 Hz), 61.5, 50.3, 38.3, 32.0,

31.9, 24.4, 18.7, 13.9. IR (ﬁlm): 1731.2, 1677.4, 1414.4 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₁₄H₁₉F₃O₅S

357.0984; found 357.0978.

( )-Cinnamyl 1-Methyl-2-oxocyclohexane-1-carboxylate

(S10). A ﬂame-dried ﬂask equipped with a stir bar was cooled

under a stream of nitrogen and charged with allyl 1-methyl-2-

oxocyclohexane-1-carboxylate (1.169 g, 5.97 mmol, 1 equiv),

Grubbs II catalyst (0.203 g, 0.239 mmol, 0.04 equiv), and copper

iodide (68.1 mg, 0.358 mmol, 0.06 equiv). The ﬂask was

evacuated and backﬁlled with nitrogen, and then diethyl ether

(30 mL, 0.2 M) and styrene (2.05 mL, 17.9 mmol, 3.0 equiv)

were added to the mixture. The septum was replaced with a

condenser, and the mixture was heated to 40 °C with stirring for

15 h. The reaction mixture was cooled to rt and concentrated in

vacuo to yield a purple-colored crude product, which was

puriﬁed via column chromatography on silica gel using 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

0.904 g (63% yield) of the title compound as a colorless oil. ¹H

NMR (500 MHz, CDCl₃): δ 7.42−7.21 (m, 5H), 6.71−6.58 (m,

1H), 6.31−6.18 (m, 1H), 4.87−4.72 (m, 2H), 2.57−2.41 (m,

2H), 2.09−1.95 (m, 1H), 1.83 (m, 1H), 1.78−1.58 (m, 2H),

1.54−1.42 (m, 1H), 1.32 (s, 3H), 1.04 (m, 1H). ¹³C NMR (126

MHz, CDCl₃): δ 208.2, 172.9, 136.0, 134.8, 134.0, 128.6, 126.7,

122.4, 65.8, 57.2, 40.7, 38.2, 27.5, 22.6, 21.3. IR (ﬁlm): 2935.8,

2867.1, 1709.7 (the two carbonyls are incidentally equivalent),

1495.5, 1449.5 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd

for C₁₇H₂₀O₃Na 295.1305; found 295.1305.

Ethyl 1-Cinnamyl-2-{[(triﬂuoromethyl)sulfonyl]oxy}-

cyclohex-2-ene-1-carboxylate (1h). The title compound was

synthesized via a procedure similar to that described above for

the preparation of ethyl 1-cinnamyl-2-{[(triﬂuoromethyl)-

sulfonyl]oxy}cyclopent-2-ene-1-carboxylate (1l), except using

ethyl 1-cinnamyl-2-oxocyclohexane-1-carboxylate (S7) (1.13 g,

4.0 mmol, 1 equiv), lithium diisopropylamide (LDA) (6.73

mmol, 1.7 equiv), and N-(2-pyridyl)triﬂamide (2.409 g, 6.73

mmol, 1.7 equiv). The crude material was puriﬁed via column

chromatography on silica gel using 100:0 → 98:2 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 1.06 g (64% yield)

1

of the title compound as a colorless oil. H NMR (500 MHz,

CDCl₃): δ 7.46−7.12 (m, 5H), 6.49 (d, J = 15.7 Hz, 1H), 6.12 (t,

J = 15.4 Hz, 1H), 5.92 (s, 1H), 4.36−4.11 (m, 2H), 2.82−2.64

(m, 2H), 2.38−2.10 (m, 3H), 1.82−1.53 (m, 3H), 1.31 (t, J =

7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 172.6, 148.1,

137.0, 134.5, 128.5, 127.5, 126.2, 123.8, 120.3, 118.3 (q, J_C−F

=

318 Hz), 61.8, 50.5, 38.7, 32.3, 24.4, 18.6, 14.0. IR (ﬁlm):

1730.3, 1677.1 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₁₉H₂₁F₃O₅S 419.1140; found 419.1135.

2-Cinnamylcyclohexan-1-one (S8). The title compound was

synthesized via a procedure similar to that described above for

the preparation of 2-cinnamylcyclopentan-1-one (S6), except

using cyclohexanone (2.1 mL, 20 mmol, 1 equiv), cinnamyl

alcohol (2.8 mL, 2.2 mmol, 1.1 equiv), palladium allyl chloride

dimer (0.146 g, 0.4 mmol, 0.02 equiv), dppf (0.665 g, 1.2 mmol,

0.06 mmol), and pyrrolidine (0.33 mL, 4.0 mmol, 0.2 equiv).

The crude material was puriﬁed via column chromatography on

silica gel using 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 2.74 g (63% yield) of the title compound as a

yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 7.44−7.23 (m, 4H),

7.19 (s, 1H), 6.39 (d, J = 15.8 Hz, 1H), 6.20 (t, J = 15.2 Hz, 1H),

2.73−2.60 (m, 1H), 2.43 (d, J = 15.8 Hz, 2H), 2.32 (d, J = 19.2

Hz, 1H), 2.25−2.00 (m, 3H), 1.88 (s, 1H), 1.67 (s, 2H), 1.41 (d,

J = 12.4 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 212.4, 137.5,

131.6, 128.5, 128.4, 128.3, 127.0, 126.0, 50.7, 42.1, 33.6, 27.9,

25.0. IR (ﬁlm): 1705.24, 1597.9 cm⁻¹. HRMS (ESI⁺TOF) m/z:

[M + H]⁺calcd for C₁₅H₁₈O 215.1436; found 215.1430.

6-Cinnamylcyclohex-1-en-1-yl Triﬂuoromethanesulfonate

(1i). The title compound was synthesized via a similar procedure

to 5-cinnamylcyclopent-1-en-1-yl triﬂuoromethanesulfonate

(1m), except using 2-cinnamylcyclohexan-1-one (S8) (0.544

g, 2.54 mmol, 1 equiv), LDA (3.82 mmol, 1.5 equiv), and N-(2-

pyridyl)triﬂamide (1.09 g, 3.05 mmol, 1.2 equiv). The crude

material was puriﬁed via column chromatography on silica gel

using 100:0 → 98:2 → 95:5 hexanes/ethyl acetate as the eluent.

This procedure aﬀorded 0.660 g (75% yield) of the title

1

compound as a colorless oil. H NMR (500 MHz, CDCl₃): δ

7.43−7.13 (m, 5H), 6.45 (d, J = 15.6 Hz, 1H), 6.23−6.04 (m,

1H), 5.83 (s, 1H), 2.62 (d, J = 10.1 Hz, 2H), 2.40−2.26 (m, 1H),

2.18 (s, 2H), 1.88 (s, 1H), 1.62 (dd, J = 49.8, 6.2 Hz, 3H). ¹³C

NMR (126 MHz, CDCl₃): δ 151.7, 137.3, 132.7, 128.5, 127.2,

126.7, 126.1, 119.5, 118.5 (q, J_C−F= 319 Hz), 37.6, 35.1, 27.8,

24.3, 19.0. IR (ﬁlm): 1680.2, 1494.3 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + NH₄]⁺calcd for C₁₆H₁₇F₃O₃S 364.1194; found

364.1189.

2-Cinnamyl-2-methylcyclohexan-1-one (S11). A ﬂame-

dried Schlenk ﬂask equipped with a stir bar was cooled under

a stream of nitrogen and charged with palladium acetate (27.8

mg, 0.124 mmol, 0.10 equiv) and triphenylphosphine (0.812 g,

3.10 mmol, 2.5 equiv). The ﬂask was evacuated and backﬁlled

Ethyl 1-(But-2-en-1-yl)-2-oxocyclohexane-1-carboxylate

(S9). The title compound was synthesized via a procedure

I

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Article

with nitrogen, and then tetrahydrofuran (25 mL, 0.1 M) and

cinnamyl 1-methyl-2-oxocyclohexane-1-carboxylate (S10)

(0.337 g, 1.24 mmol, 1.0 equiv) were added. The septum was

replaced with a condenser, and the reaction mixture was heated

to 30 °C with stirring for 15 h. The mixture was then cooled to rt,

diluted with diethyl ether, ﬁltered through a pad of silica gel, and

concentrated in vacuo to yield a yellow oil. The crude material

was puriﬁed via column chromatography on silica gel using 98:2

→ 95:5 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 33.9 mg (12% yield) of the title compound as a

lithium tert-butoxide (0.44 mmol, 2.2 equiv). The vial was

purged with nitrogen and charged with toluene (0.8 M) and the

appropriate malonate derivative (0.6 mmol, 3.6 equiv). The vial

was capped and heated to the appropriate temperature with

stirring until the starting material was consumed. The mixture

was cooled to rt, charged with phenanthrene (1 equiv; NMR

internal standard), diluted with dichloromethane (1 mL), and

quenched with saturated ammonium chloride (1 mL). The

aqueous layer was extracted with dichloromethane (3 × 1 mL),

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. The

crude product was puriﬁed via ﬂash chromatography on silica gel

to aﬀord the desired product.

Diethyl 2-(2,3-Dihydro-1H-inden-2-yl)malonate (6a). The

title compound was prepared from 2-allylphenyl triﬂate (53.5

mg, 0.2 mmol) and diethyl malonate (37 μL, 0.24 mmol) using

General Procedure A. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 51.7 mg (93%

yield) of the title compound as a colorless solid (mp 33−35 °C).

¹H NMR (500 MHz, CDCl₃): δ 7.22−7.15 (m, 2H), 7.16−7.13

(m, 2H), 4.22 (qd, J = 7.1, 2.7 Hz, 4H), 3.45 (d, J = 9.3 Hz, 1H),

3.25−3.03 (m, 3H), 2.83−2.69 (m, 2H), 1.28 (t, J = 7.1 Hz,

6H). ¹³C NMR (126 MHz, CDCl₃): δ 168.8, 142.1, 126.4,

124.4, 61.4, 56.8, 39.0, 37.3, 14.1. IR (ﬁlm): 2980, 2840, 1744,

1727, 1476 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₆H₂₀O₄277.1362; found 277.1434.

The title compound was prepared on a larger scale from 2-

allylphenyl triﬂate (267 mg, 1.0 mmol) and diethyl malonate

(183 μL, 1.2 mmol) using General Procedure A. The crude

material was puriﬁed via column chromatography on silica gel

using 95:5 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 232 mg (84% yield) of the title compound as a white

solid (mp 33−35 °C). The characterization data were identical

to those listed above.

The title compound was also prepared on an even larger scale

from 2-allylphenyl triﬂate (1.50 g, 5.63 mmol) and diethyl

malonate (1.03 mL, 6.76 mmol) using General Procedure A.

The crude material was puriﬁed via column chromatography on

silica gel using 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 1.36 g (88% yield) of the title compound as a

white solid (mp 33−35 °C). The characterization data were

identical to those listed above.

( )-Diethyl 2-[5-(tert-Butyl)-2,3-dihydro-1H-inden-2-yl]-

malonate (6b). The title compound was prepared from 2-

allyl-4-tert-butylphenyl triﬂate (64.5 mg, 0.2 mmol) and diethyl

malonate (37 μL, 0.24 mmol) using General Procedure A. The

crude material was puriﬁed via column chromatography on silica

gel using 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 48.3 mg (77% yield) of the title compound

as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.24 (s, 1H),

7.20 (dd, J = 7.9, 1.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 4.28−

4.16 (m, 4H), 3.46 (d, J = 8.9 Hz, 1H), 3.23−3.08 (m, 3H),

2.86−2.66 (m, 2H), 1.32 (s, 9H), 1.31−1.27 (m, 6H). ¹³C NMR

(126 MHz, CDCl₃): δ 168.9, 149.7, 142.1, 139.3, 124.0, 123.7,

121.4, 61.4, 57.1, 39.4, 37.6, 37.0, 34.7, 31.68, 14.3. IR (ﬁlm):

1748, 1729, 1467 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺

calcd for C₂₀H₂₈O₄333.199; found 333.206.

( )-Diethyl 2-(5-Fluoro-2,3-dihydro-1H-inden-2-yl)-

malonate (6c). The title compound was prepared from 2-

allyl-4-ﬂuorophenyl triﬂate (56.8 mg, 0.2 mmol) and diethyl

malonate (37 μL, 0.24 mmol) using General Procedure A. The

crude material was puriﬁed via column chromatography on silica

gel using 95:5 hexanes/ethyl acetate as the eluent. This

1

colorless oil. H NMR (500 MHz, CDCl₃): δ 7.36−7.25 (m,

5H), 7.19 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 15.7 Hz, 1H), 6.18−

6.06 (m, 1H), 2.47 (d, J = 15.0 Hz, 4H), 1.91−1.68 (m, 4H),

1.68−1.56 (m, 1H), 1.13 (s, 3H). ¹³C NMR (126 MHz,

CDCl₃): δ 215.4, 137.4, 133.0, 128.4, 127.1, 126.0, 125.7, 48.9,

38.8, 38.6, 29.7, 27.4, 22.9, 21.1. IR (ﬁlm): 3026.3, 2931.9,

2863.5, 1704.1, 1598.2, 1495.1 cm⁻¹. HRMS (ESI⁺TOF) m/z:

[M + H]⁺calcd for C₁₆H₂₁O 229.1587; found 229.1586.

6-Cinnamyl-6-methylcyclohex-1-en-1-yl Triﬂuorometha-

nesulfonate (1k). The title compound was synthesized via a

procedure similar to that described above for the preparation of

1l, except using 2-cinnamyl-2-methylcyclohexan-1-one (S11)

(1.13 g, 4.0 mmol, 1 equiv), LDA (6.73 mmol, 1.7 equiv), and N-

(2-pyridyl)triﬂamide (2.409 g, 6.73 mmol, 1.7 equiv). The crude

material was puriﬁed via column chromatography on silica gel

using 100:0 → 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 1.06 g (64%) of the title compound as a

1

colorless oil. H NMR (500 MHz, CDCl₃): δ 7.45−7.13 (m,

5H), 6.43 (d, J = 15.7 Hz, 1H), 6.14 (ddd, J = 15.4, 8.1, 7.0 Hz,

1H), 5.76 (t, J = 4.1 Hz, 1H), 2.46 (ddd, J = 13.9, 7.0, 1.4 Hz,

1H), 2.31 (ddd, J = 13.9, 8.1, 1.2 Hz, 1H), 2.17 (ddd, J = 9.6, 5.7,

3.9 Hz, 2H), 1.82 (td, J = 9.6, 4.6 Hz, 1H), 1.73−1.58 (m, 2H),

1.59−1.48 (m, 1H), 1.20 (s, 3H). ¹³C NMR (126 MHz,

CDCl₃): δ 154.8, 137.3, 133.6, 128.5, 127.2, 126.1, 125.1, 118.4

(q, J_C−F= 313 Hz), 117.3, 42.0, 38.7, 35.4, 24.7, 24.5, 18.2. IR

(ﬁlm): 3027.8, 2938.4, 1495.6, 1457.0, 1410.0 cm⁻¹. HRMS

(Electron Impact Ionization TOF) m/z: [M]⁺calcd for

C₁₇H₁₉F₃O₃S 360.1007; found 360.1024.

Preparation and Characterization of Products. General

Procedure A: Pd-Catalyzed Alkene Dialkylation Reactions on

Terminal Alkene Substrates. A ﬂame-dried 4 mL vial equipped

with a stir bar was cooled under a stream of nitrogen and charged

with Pd(OAc)₂(0.008 mmol, 0.04 equiv), BrettPhos (0.012

mmol, 0.06 equiv), and lithium tert-butoxide (0.28 mmol, 1.4

equiv). The aryl or alkenyl triﬂate (0.2 mmol, 1.0 equiv) was

weighed in a separate 1 dram vial and diluted with toluene (1

mL, 0.2 M). This mixture was added to the reaction vessel, and

the appropriate nucleophile (0.24 mmol, 1.2 equiv) was added.

Toluene (1 mL, 0.2 M) was used to rinse the 1 dram vial, and the

solution was transferred to the reaction vessel. The vial was

ﬂushed with nitrogen, capped, and heated to 95 °C with stirring

overnight until the starting material was consumed. The mixture

was then cooled to rt and quenched with saturated aqueous

ammonium chloride (1 mL). The aqueous layer was extracted

with ethyl acetate (3 × 1 mL), dried over MgSO₄, ﬁltered, and

concentrated in vacuo. The crude product was puriﬁed via ﬂash

chromatography on silica gel to aﬀord the desired product.

General Procedure B: Pd-Catalyzed Alkene Dialkylation

Reactions on Internal Alkene Substrates. A ﬂame-dried 4 mL

vial equipped with a stir bar and was cooled under a stream of

nitrogen and charged with the appropriate triﬂate (0.2 mmol, 1.0

equiv), the appropriate palladium precatalyst (0.008 mmol, 0.04

equiv), the appropriate ligand (0.012 mmol, 0.06 equiv), and

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DOI: 10.1021/acs.oprd.9b00248

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1

procedure aﬀorded 46.5 mg (79% yield) of the title compound

as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.09 (dd, J =

8.3, 5.2 Hz, 1H), 6.89−6.83 (m, 1H), 6.82 (td, J = 8.9, 2.4 Hz,

1H), 4.25−4.16 (m, 4H), 3.44 (d, J = 9.1 Hz, 1H), 3.24−3.04

(m, 3H), 2.86−2.65 (m, 2H), 1.27 (t, J = 7.2 Hz, 6H). ¹³C NMR

(126 MHz, CDCl₃): δ 168.8, 163.2, 161.2, 144.2 (d, J = 8.2 Hz),

137.4 (d, J = 2.5 Hz), 125.1 (d, J = 8.8 Hz), 113.2 (d, J = 22.6

Hz), 111.4 (d, J = 21.9 Hz), 61.6, 56.8, 39.7, 37.5, 37.5, 36.6,

14.2. IR (ﬁlm): 2982, 1745, 1727, 1614, 1599, 1483 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₁₆H₁₉FO₄

295.1267; found 295.134.

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

C₆D₆): δ 7.16−6.94 (m, 5H), 6.69 (dd, J = 9.0, 2.4 Hz, 1H), 6.60

(t, J = 8.7 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.13 (d, J = 8.4 Hz,

1H), 3.95−3.76 (m, 2H), 3.65 (dd, J = 10.8, 7.1 Hz, 1H), 3.61−

3.46 (m, 2H), 3.29−3.17 (m, 2H), 2.80 (dd, J = 15.1, 8.0 Hz,

1H), 0.84 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz, 3H). ¹³C NMR

(126 MHz, C₆D₆): δ 168.0 (d, J = 34 Hz), 163.5, 161.5, 144.1 (d,

J = 9 Hz), 143.1, 141.3 (d, J = 1 Hz), 128.8, 127.9, 126.7, 126.0,

113.5 (d, J = 25 Hz), 111.1 (d, J = 23 Hz), 60.8 (d, J = 14 Hz),

54.5, 54.1, 49.2, 35.8 (two peaks), 13.7, 13.4. IR (ﬁlm): 1728.0,

1600.2, 1483.7 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₂₂H₂₃FO₄371.1659; found 371.1653.

( )-(1S,2R)-Diethyl 2-(1-Methyl-2,3-dihydro-1H-inden-2-

yl)malonate (6d). The title compound was prepared from 2-

(but-3-en-2-yl)phenyl triﬂate (56.0 mg, 0.2 mmol) and diethyl

malonate (37 μL, 0.24 mmol) using General Procedure A,

except with (BrettPhos)Pd(allyl)(Cl) (8.6 mg, 0.04 equiv) in

place of Pd(OAc)₂. The crude material was puriﬁed via column

chromatography on silica gel using 95:5 hexanes/ethyl acetate as

the eluent. This procedure aﬀorded 43.1 mg (75% yield) of the

title compound as a colorless oil. The compound was obtained

( )-(1S,2S)-Diethyl 2-(5-Methoxy-1-phenyl-2,3-dihydro-

1H-inden-2-yl)malonate (6g). The title compound was

prepared from 2-cinnamyl-4-methoxyphenyl triﬂuoromethane-

sulfonate (81.6 mg, 0.23 mmol), diethyl malonate (0.1 mL, 0.6

mmol), palladium acetate (1.8 mg, 0.008 mmol, 0.04 equiv), and

BrettPhos (6.4 mg, 0.012 mmol, 0.06 equiv) at a reaction

temperature of 65 °C for 5 h using General Procedure B. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 29.2 mg (35% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

as a >20:1 mixture of diastereomers as judged by H NMR

1

analysis. The data shown are for the major isomer. H NMR

(401 MHz, CDCl₃): δ 7.23−7.10 (m, 4H), 4.24−4.15 (m, 4H)

3.51 (d, J = 8.2 Hz, 1H), 3.24 (dd, J = 16.1, 8.1 Hz, 1H), 3.08 (p,

J = 6.8 Hz, 1H), 2.81 (dd, J = 16.1, 7.3 Hz, 1H), 2.69 (p, J = 8.0

Hz, 1H), 1.32−1.22 (m, 9H). ¹³C NMR (176 MHz, CDCl₃): δ

169.1, 168.8, 147.0, 141.4, 126.7, 126.66, 124.5, 123.6, 61.51,

61.45, 55.6, 46.9, 43.4, 35.8, 19.8, 14.3, 14.2. IR (ﬁlm): 1741,

1728, 1464 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H⁺]⁺calcd for

C₁₇H₂₂O₄291.1518; found 291.1591.

1

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

C₆D₆): δ 7.19 (d, J = 7.2 Hz, 2H), 7.10 (s, 3H), 7.01 (s, 1H),

6.69 (d, J = 19.9 Hz, 2H), 6.61 (d, J = 10.3 Hz, 1H), 4.26 (d, J =

8.5 Hz, 1H), 3.97−3.78 (m, 2H), 3.76−3.53 (m, 3H), 3.49−

3.36 (m, 1H), 3.30 (s, 3H), 3.04−2.87 (m, 1H), 0.84 (t, J = 7.1

Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, C₆D₆): δ

168.2, 167.2, 159.5, 143.9, 143.4, 137.8, 128.8, 128.3, 127.9,

127.8, 126.5, 125.6, 113.0, 109.5, 60.7, 54.8, 54.6, 54.3, 49.4,

36.1, 13.7. IR (ﬁlm): 1727.7, 1608.5, 1588.8 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₂₃H₂₆O₅383.1859; found

383.1853.

( )-(1S,2S)-Diethyl 2-(5-Methyl-1-phenyl-2,3-dihydro-1H-

inden-2-yl)malonate (6h). The title compound was prepared

from 2-cinnamyl-4-methylphenyl triﬂuoromethanesulfonate

(5h) (81.6 mg, 0.23 mmol) and diethyl malonate (0.1 mL, 0.6

mmol) using General Procedure B. The crude material was

puriﬁed via column chromatography on silica gel using 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

29.2 mg (35% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

isomer. ¹H NMR (500 MHz, C₆D₆): δ 7.23−7.14 (m, 1H), 7.09

(dd, J = 15.1, 7.6 Hz, 3H), 7.04−6.97 (m, 1H), 6.87 (s, 1H), 6.78

(d, J = 7.7 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 4.28 (d, J = 8.7 Hz,

1H), 3.96−3.78 (m, 2H), 3.73−3.53 (m, 3H), 3.44 (dd, J = 15.7,

7.9 Hz, 1H), 3.37−3.25 (m, 1H), 2.97 (dd, J = 15.7, 8.7 Hz, 1H),

2.11 (s, 3H), 0.84 (t, J = 7.2 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H).

¹³C NMR (126 MHz, C₆D₆): δ 168.2, 167.9, 143.7, 142.9, 142.1,

136.2, 128.9, 128.3, 127.5, 126.5, 124.9, 124.7, 60.7, 60.6, 54.8,

54.7, 49.2, 35.9, 20.9, 13.7, 13.6. IR (ﬁlm): 2980.6, 1728.9,

1602.0, 1493.5, 1453.4 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₂₃H₂₆O₄367.1909; found 367.1904.

(1S,2S)-Diethyl 2-(1-Phenyl-2,3-dihydro-1H-inden-2-yl)-

malonate (6e). The title compound was prepared from 2-

cinnamylphenyl triﬂuoromethanesulfonate (75.2 mg, 0.22

mmol), diethyl malonate (0.1 mL, 0.6 mmol), Pd(OAc)₂(1.8

mg, 0.008 mmol, 0.04 equiv), and BrettPhos (6.4 mg, 0.012

mmol, 0.06 equiv) at a reaction temperature of 65 °C for 5 h

using General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 98:2 → 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

39.8 mg (51% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

1

isomer. H NMR (500 MHz, benzene-d₆): δ 7.22−6.97 (m,

7H), 6.93 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 4.27 (d, J

= 9.0 Hz, 1H), 3.92−3.79 (m, 2H), 3.73−3.52 (m, 3H), 3.45

(dd, J = 15.7, 7.9 Hz, 1H), 3.32−3.22 (m, 1H), 2.96 (dd, J =

15.8, 8.9 Hz, 1H), 0.83 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz,

3H). ¹³C NMR (126 MHz, benzene-d₆): δ 168.1, 167.9, 145.9,

143.4, 142.0, 127.8, 127.7, 127.6, 127.5, 126.6, 124.9, 124.2,

60.7, 60.6, 55.0 (two peaks), 48.9, 36.0, 13.7, 13.4. IR (ﬁlm):

1730.5, 1601.2 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₂₂H₂₄O₄353.1753; found 353.1747.

( )-(1S,2S)-Diethyl 2-(5-Fluoro-1-phenyl-2,3-dihydro-1H-

inden-2-yl)malonate (6f). The title compound was prepared

from 2-cinnamyl-4-ﬂuorophenyl triﬂuoromethanesulfonate

(64.7 mg, 0.18 mmol), diethyl malonate (0.1 mL, 0.6 mmol),

palladium acetate (1.8 mg, 0.008 mmol, 0.04 equiv), and

BrettPhos (6.4 mg, 0.012 mmol, 0.06 equiv) at a reaction

temperature of 65 °C for 5 h using General Procedure B. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 31.0 mg (47% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

Diethyl 2-[5-(tert-Butyl)-2-methyl-2,3-dihydro-1H-inden-

2-yl]malonate (6i). The title compound was prepared from 4-

tert-butyl-2-(2-methylallyl)phenyl triﬂate (67.3 mg, 0.2 mmol)

and diethyl malonate (37 μL, 0.24 mmol) using General

Procedure A. The crude material was puriﬁed via column

chromatography on silica gel using 99:1 hexanes/ethyl acetate as

K

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

the eluent. This procedure aﬀorded 9.7 mg (14% yield) of the

title compound as a colorless oil. ¹H NMR (401 MHz, CDCl₃):

δ 7.21−7.15 (m, 2H), 7.12−7.06 (m, 2H), 4.25−4.12 (m, 4H),

3.56 (s, 1H), 3.24−3.12 (m, 2H), 2.86−2.74 (m, 2H), 1.30 (s,

9H), 1.29−1.24 (m, 9H). ¹³C NMR (100 MHz, CDCl₃): δ

168.53, 149.43, 141.54, 138.71, 124.11, 123.37, 121.54, 61.01,

60.38, 45.55, 44.97, 44.44, 34.49, 31.55, 24.41, 14.08. IR (ﬁlm):

2955, 1721, 1727, 1033 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₂₁H₃₀O₄347.2217; found 347.2220.

HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for C₂₀H₃₁NO₆

404.2044; found 404.2044.

( )-(6S,7aR)-Diethyl 2-(2,3,5,6,7,7a-Hexahydro-1H-

cyclopenta[c]pyridin-6-yl)malonate (S12). In order to conﬁrm

the connectivity and stereochemistry of 7c, the Boc group was

cleaved by addition of triﬂuoroacetic acid (3 drops) to a solution

of 7c in dichloromethane; the resulting solution was stirred for 1

h at rt. The solvent and excess triﬂuoroacetic acid were removed

under reduced pressure, and the product was washed with

NaHCO₃and brine and dried with MgSO₄. This procedure

aﬀorded 34.3 mg (89% yield) of the title compound as a

colorless oil. This material was judged to be a >20:1 mixture of

diastereomers by ¹H NMR analysis. The data shown are for the

major isomer. ¹H NMR (400 MHz, CDCl₃): δ 5.38 (s, 1H), 4.18

(q, J = 7.1 Hz, 4H), 3.37−3.29 (m, 2H), 3.18 (d, J = 9.5 Hz, 1H),

2.73−2.59 (m, 2H), 2.40 (br s, 1H), 2.33−2.23 (m, 1H), 2.11−

1.97 (m, 2H), 1.49−1.37 (m, 1H), 1.26 (t, J = 7.1 Hz, 6H), 0.88

(q, J = 11.3 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 168.9,

168.8, 141.8, 116.8, 61.4, 57.5, 48.3, 44.5, 40.4, 36.9, 35.7, 35.0,

14.2. IR (ﬁlm): 2983, 1782, 1730, 1148 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₁₅H₂₃NO₄282.1700; found

282.1706.

( )-(2S,3aR)-Diethyl 2-(2-Methyl-2,3,3a,4,5,6-hexahydro-

1H-inden-2-yl)malonate (7d). The title compound was

prepared from 6-(2-methylallyl)cyclohex-1-en-1-yl triﬂate

(54.1 mg, 0.2 mmol) and diethyl malonate (37 μL, 0.24

mmol) using General Procedure A. The crude material was

puriﬁed via column chromatography on silica gel using 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

55.6 mg (94% yield) of the title compound as a colorless oil. The

compound was obtained as a 9:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

isomer. ¹H NMR (500 MHz, CDCl₃): δ 5.35 (s, 1H), 4.17 (q, J

= 7.1 Hz, 4H), 3.32 (s, 1H), 2.48 (d, J = 17.0 Hz, 1H), 2.39 (br s,

1H), 2.28 (d, J = 17.0 Hz, 1H), 2.02−1.90 (m, 3H), 1.87−1.73

(m, 2H), 1.45 (tddd, J = 13.4, 10.3, 7.5, 2.9 Hz, 1H), 1.28−1.21

(m, 10H), 1.03−0.92 (m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ

168.8, 143.1, 118.1, 61.7, 61.3, 61.04, 61.03, 45.9, 44.1, 41.6,

38.7, 38.6, 29.0, 28.9, 25.3, 24.9, 22.6, 22.5, 14.3. IR (ﬁlm): 1753,

1729 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for

C₁₇H₂₆O₄317.1723; found 317.1729.

( )-(2S,3aS)-Diethyl 2-(3a-Allyl-1,2,3,3a,4,5-hexahydro-

pentalen-2-yl)malonate (7e). The title compound was

prepared from 5,5-diallylcyclopent-1-en-1-yl triﬂate (60 mg,

0.2 mmol) and diethyl malonate (37 μL, 0.24 mmol) using

General Procedure A. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 56.6 mg (92%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (700 MHz, CDCl₃): δ 5.79 (dddd, J = 16.9, 10.1, 7.9, 6.6

Hz, 1H), 5.22 (s, 1H), 5.05 (d, J = 17.0 Hz, 1H), 5.02 (d, J = 10.1

Hz, 1H), 4.22−4.12 (m, 4H), 3.25 (d, J = 10.3 Hz, 1H), 3.09 (qt,

J = 10.3, 6.4 Hz, 1H), 2.63−2.50 (m, 2H), 2.42−2.36 (m, 2H),

2.12 (dd, J = 13.8, 6.6 Hz, 1H), 2.07 (dd, J = 13.8, 8.0 Hz, 1H),

1.98−1.92 (m, 2H), 1.56 (dt, J = 12.4, 9.5 Hz, 1H), 1.25 (td, J =

7.1, 4.4 Hz, 6H), 1.03 (dd, J = 12.0, 10.5 Hz, 1H). ¹³C NMR

(176 MHz, CDCl₃): δ 168.9, 168.8, 153.9, 136.1, 119.1, 116.9,

61.41, 61.37, 59.3, 58.2, 41.5, 40.3, 39.9, 36.9, 36.1, 28.2, 14.3. IR

(ﬁlm): 1732, 1150 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺

calcd for C₁₈H₂₆O₄307.1904; found 307.1909.

( )-(2S,3aR)-Diethyl 2-(2,3,3a,4,5,6-Hexahydro-1H-inden-

2-yl)malonate (7a). The title compound was prepared from 6-

allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and diethyl

malonate (37 μL, 0.24 mmol) using General Procedure A. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 45.4 mg (84% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

CDCl₃): δ 5.37 (s, 1H), 4.19 (qd, J = 7.1, 3.1 Hz, 4H), 3.17 (d, J

= 9.9 Hz, 1H), 2.70−2.52 (m, 2H), 2.22 (br s, 1H), 2.11−2.01

(m, 1H), 2.03−1.91 (m, 4H), 1.77 (ddd, J = 12.3, 6.0, 3.2 Hz,

1H), 1.43 (m, 1H), 1.26 (td, J = 7.1, 1.9 Hz, 6H), 0.99 (m, 1H),

0.88 (q, J = 11.5 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ

169.1, 169.0, 142.8, 118.1, 61.4, 57.8, 41.0, 38.6, 37.1, 35.3, 28.9,

25.3, 22.5, 14.3. IR (ﬁlm): 1730, 1029 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₁₆H₂₄O₄281.1675; found 281.1747.

(

) - ( 6 S , 7 a R ) - D i e t h y l 2 - ( 1 , 3 , 5 , 6 , 7 , 7 a -

Hexahydrocyclopenta[c]pyran-6-yl)malonate (7b). The title

compound was prepared from 3-allyl-3,6-dihydro-2H-pyran-4-yl

triﬂate (54.4 mg, 0.2 mmol) and diethyl malonate (37 μL, 0.24

mmol) using General Procedure A. The crude material was

puriﬁed via column chromatography on silica gel using 95:5 →

90:10 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 53.6 mg (95% yield) of the title compound as a

colorless oil. The compound was obtained as a >20:1 mixture of

diastereomers as judged by ¹H NMR analysis. The data shown

are for the major isomer. ¹H NMR (500 MHz, CDCl₃): δ 5.40

(s, 1H), 4.25−4.09 (m, 6H), 4.09−3.99 (m, 1H), 3.19 (d, J = 9.2

Hz, 1H), 3.03 (t, J = 10.2 Hz, 1H), 2.75−2.63 (m, 2H), 2.56 (br

s, 1H), 2.11−1.96 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.87 (q, J =

11.5 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃): δ 168.8, 140.8,

116.8, 69.3, 65.1, 61.5, 57.4, 39.8, 37.1, 34.7, 34.0, 14.3. IR

(ﬁlm): 1750, 1727, 1461 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₁₅H₂₂O₅305.1359; found 305.1362.

( )-(6S,7aR)-Diethyl 2-[2-(tert-Butoxycarbonyl)-

2,3,5,6,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-yl]-

malonate (7c). The title compound was prepared from tert-

butyl 3-allyl-4-{[(triﬂuoromethyl)sulfonyl]oxy}-3,6-dihydro-

pyridine-1(2H)-carboxylate (67.1 mg, 0.2 mmol) and diethyl

malonate (37 μL, 0.24 mmol) using General Procedure A. The

crude material was puriﬁed via column chromatography on silica

gel using 25:75 hexanes/dichloromethane as the eluent. This

procedure aﬀorded 52.3 mg (76% yield) of the title compound

as a colorless oil. The characterization data are for a mixture of

rotamers; broadening was due to slow interconversion on the

NMR time scale. ¹H NMR (500 MHz, C₆D₆): δ 5.09 (s, 1H),

4.57−4.15 (m, 2H), 4.11−3.82 (br m, 4H), 3.43−3.37 (m, 1H),

3.18−3.15 (m, 1H), 2.81−2.53 (m, 2H), 2.25 (br s, 1H), 2.21−

2.12 (m, 1H), 2.07−1.95 (br m, 1H), 1.94−1.81 (m, 1H), 1.55−

1.38 (m, 9H), 1.04−0.90 (m, 6H), 0.86−0.74 (m, 1H). ¹³C

NMR (100 MHz, CDCl₃): δ 168.7, 79.7, 61.5, 57.3, 40.2, 37.5,

35.1, 34.8, 28.6, 28.4, 14.2. IR (ﬁlm): 1751, 1729, 1693 cm⁻¹.

L

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

( )-(2S,3aR)-Diethyl 2-Allyl-2-(2-methyl-1,2,3,3a,4,5-hex-

ahydropentalen-2-yl)malonate (7f). The title compound was

prepared from (methylallyl)cyclopent-1-en-1-yl triﬂate (54.0

mg, 0.2 mmol) and diethyl allylmalonate (48 μL, 0.24 mmol)

using General Procedure A, except with RuPhos (5.6 mg, 0.012

mmol) as the ligand. The crude material was puriﬁed via column

chromatography on silica gel using 95:5 hexanes/ethyl acetate as

the eluent. This procedure aﬀorded 40.8 mg (63% yield) of the

title compound as a colorless oil. The compound was obtained

1.22 (m, 1H), 1.12 (td, J = 13.1, 3.8 Hz, 1H), 1.01−0.91 (m,

3H), 0.84 (dt, J = 17.9, 7.1 Hz, 3H), 0.70 (t, J = 7.1 Hz, 3H). ¹³C

NMR (126 MHz, C₆D₆): δ 175.1, 167.9, 167.6, 144.5, 143.3,

129.4, 129.3, 127.5, 126.3, 123.8, 60.8, 60.6, 54.2, 53.5, 53.4,

44.6, 41.9, 33.0, 24.5, 19.2, 13.9, 13.7, 13.3. IR (ﬁlm): 1724.1,

1605.6, 1446.6 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₂₅H₃₂O₆429.2277; found 429.2272.

( )-(1R,2S,3aR)-Diethyl 2-(1-Phenyl-2,3,3a,4,5,6-hexahy-

dro-1H-inden-2-yl)malonate (7i). The title compound was

prepared from 6-cinnamylcyclohex-1-en-1-yl triﬂuoromethane-

sulfonate (1i) (69.0 mg, 0.20 mmol), diethyl malonate (0.1 mL,

0.6 mmol), Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv), and

SPhos (4.9 mg, 0.012 mmol, 0.06 equiv) at 95 °C for 14 h using

General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 98:2 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 54.1 mg (76%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.32−7.21 (m, 2H), 7.21−7.11 (m,

3H), 5.23 (p, J = 2.9 Hz, 1H), 4.15 (p, J = 7.0 Hz, 2H), 3.82 (dq,

J = 10.7, 7.1 Hz, 1H), 3.63 (dq, J = 10.8, 7.2 Hz, 1H), 3.40 (dt, J =

9.6, 2.6 Hz, 1H), 3.34 (d, J = 8.1 Hz, 1H), 2.78−2.66 (m, 1H),

2.58−2.45 (m, 1H), 2.31 (dt, J = 12.0, 6.1 Hz, 1H), 2.09−1.88

(m, 3H), 1.79 (dt, J = 12.7, 3.9 Hz, 1H), 1.51−1.38 (m, 1H),

1.24 (t, J = 7.1 Hz, 3H), 1.16−0.95 (m, 5H). ¹³C NMR (126

MHz, CDCl₃): δ 168.6, 168.3, 147.6, 145.2, 128.2, 128.1, 126.1,

120.3, 61.2, 61.0, 55.5, 53.1, 46.4, 41.3, 37.5, 28.8, 25.1, 22.2,

14.1, 13.7. IR (ﬁlm): 1730.9, 1601.5 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₂₂H₂₈O₄357.2066; found 357.2060.

( )-(1S,2S,3aS)-Diethyl 2-Benzyl-2-[3a-(ethoxycarbonyl-1-

phenyl-2,3,3a,4,5,6-hexahydro-1H-inden-2-yl]malonate (7j).

The title compound was prepared from 1h (85.4 mg, 0.20

mmol), diethyl 2-benzylmalonate (0.1 mL, 0.43 mmol),

Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv), and SPhos (4.9

mg, 0.012 mmol, 0.06 equiv) for 14 h using General Procedure

B, except with xylenes as the solvent at 110 °C. The crude

material was puriﬁed via column chromatography on silica gel

using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 53.3 mg (51% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

as a 19:1 mixture of diastereomers as judged by H NMR

analysis. NOTE: The alkene was observed to isomerize in

CDCl₃to a 4:1 mixture of regioisomers. The data shown are for

the major isomer. ¹H NMR (401 MHz, CDCl₃): δ 5.90 (ddt, J =

17.1, 10.1, 7.1 Hz, 1H), 5.22 (s, 1H), 5.14−4.92 (m, 2H), 4.15

(m, 4H), 3.12−2.95 (br m, 1H), 2.82−2.38 (m, 5H), 2.10 (dtd, J

= 12.0, 6.8, 1.2 Hz, 1H), 1.98 (ddd, J = 17.4, 4.5, 2.3 Hz, 1H),

1.83−1.60 (m, 2H), 1.50−1.33 (m, 1H), 1.24 (q, J = 7.3 Hz,

6H), 1.15 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 170.83,

170.79, 152.5, 135.2, 118.0, 117.5, 110.0, 65.5, 60.7, 51.9, 49.4,

43.2, 37.7, 37.3, 37.0, 32.4, 26.5, 14.1. IR (ﬁlm): 1741, 1723,

1206 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for

C₁₉H₂₈O₄343.199; found 343.188.

( )-(1R,2S,3aR)-Diethyl 3a-(Ethoxycarbonyl)-1,2,3,3a,4,5-

hexahydropentalen-2-yl)malonate (7g). The title compound

was prepared from ethyl 1-allyl-2-{[(triﬂuoromethyl)sulfonyl]-

oxy}cyclopent-2-ene-1-carboxylate (69.9 mg, 0.213 mmol),

diethyl malonate (36 μL, 0.24 mmol), Pd(OAc)₂(1.8 mg,

0.008 mmol, 0.04 equiv), and BrettPhos (4.9 mg, 0.012 mmol,

0.06 equiv) at 95 °C for 14 h using General Procedure B. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 → 95:5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 48.2 mg (67% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

CDCl₃): δ 5.44 (s, 1H), 4.22−4.09 (m, 6H), 3.27 (d, J = 9.7 Hz,

1H), 3.17 (qd, J = 10.3, 5.0 Hz, 1H), 2.80 (dt, J = 14.9, 8.0 Hz,

1H), 2.66−2.53 (m, 1H), 2.46 (m, 4H), 2.04 (dd, J = 16.4, 6.0

Hz, 1H), 1.75 (dt, J = 12.8, 9.6 Hz, 1H), 1.27−1.23 (m, 9H). ¹³C

NMR (126 MHz, CDCl₃): δ 175.6, 168.5, 168.5, 149.6, 122.9,

65.5, 61.3, 60.7, 60.6, 57.6, 40.8, 40.6, 37.6, 36.9, 36.8, 28.8, 14.2,

14.1. IR (ﬁlm): 2980.3, 2933.2, 2855.3, 1724.2, 1446.3 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₈H₂₆O₆Na

361.1622; found 361.1617.

1

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

CDCl₃): δ 7.38−7.21 (m, 4H), 7.16−7.08 (m, 3H), 7.04 (dd, J =

7.1, 2.4 Hz, 2H), 5.43 (d, J = 2.5 Hz, 1H), 4.15 (dd, J = 29.8, 7.1

Hz, 2H), 4.03−3.84 (m, 2H), 3.70 (s, 2H), 3.10 (d, J = 13.9 Hz,

1H), 3.01 (d, J = 14.1 Hz, 1H), 2.83 (dd, J = 12.6, 6.2 Hz, 1H),

2.27 (dt, J = 12.7, 3.5 Hz, 1H), 2.18−1.90 (m, 2H), 1.73−1.46

(m, 2H), 1.25 (dt, J = 14.2, 8.3 Hz, 5H), 1.11 (t, J = 7.1 Hz, 3H),

0.97 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.7 Hz, 3H). ¹³C NMR (126

MHz, CDCl₃): δ 175.9, 170.0, 169.9, 144.9, 144.5, 137.0, 130.2,

128.6, 128.0, 127.8, 126.6, 123.4, 62.2, 60.9, 60.8, 52.4, 51.8,

48.2, 40.9, 40.4, 33.6, 31.6, 24.5, 22.6, 18.9, 14.1, 13.9, 13.7. IR

(ﬁlm): 1720.8, 1601.5, 1495.7 cm⁻¹. HRMS (ESI⁺TOF) m/z:

[M + H]⁺calcd for C₃₂H₃₈O₆519.2747; found 519.2741.

( )-(1R,2S,3aS)-Diethyl 2-[3a-(Ethoxycarbonyl)-1-methyl-

2,3,3a,4,5,6-hexahydro-1H-inden-2-yl]malonate (7k). The

title compound was prepared from (E)-ethyl 1-(but-2-en-1-

yl)-2-{[(triﬂuoromethyl)sulfonyl]oxy}cyclohex-2-ene-1-car-

boxylate (1j) (73.5 mg, 0.21 mmol), diethyl malonate (0.1 mL,

0.6 mmol), Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv), and

SPhos (4.9 mg, 0.012 mmol, 0.06 equiv) at 95 °C for 14 h using

General Procedure B. The crude material was puriﬁed via

( )-(1S,2S,3aS)-Diethyl 2-[3a-(Ethoxycarbonyl)-1-phenyl-

2,3,3a,4,5,6-hexahydro-1H-inden-2-yl]malonate (7h). The

title compound was prepared from ethyl 1-cinnamyl-2-

{[(triﬂuoromethyl)sulfonyl]oxy}cyclohex-2-ene-1-carboxylate

(1h) (83.0 mg, 0.20 mmol), diethyl malonate (0.1 mL, 0.6

mmol), Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv), and SPhos

(4.9 mg, 0.012 mmol, 0.06 equiv) at 95 °C for 14 h using

General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 → 90:10

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

62.5 mg (73% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

isomer. ¹H NMR (500 MHz, C₆D₆): δ 7.64 (d, J = 7.6 Hz, 2H),

7.21−7.09 (m, 2H), 7.02 (t, J = 7.3 Hz, 1H), 5.33 (q, J = 3.2 Hz,

1H), 4.06−3.78 (m, 4H), 3.59 (dq, J = 10.5, 7.0 Hz, 1H), 3.49

(d, J = 6.9 Hz, 1H), 3.44 (dq, J = 10.8, 7.2 Hz, 1H), 3.14−2.95

(m, 2H), 2.37 (dt, J = 12.6, 3.5 Hz, 1H), 1.94−1.82 (m, 1H),

1.73 (dtd, J = 18.3, 7.4, 3.8 Hz, 1H), 1.61−1.38 (m, 3H), 1.37−

M

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

column chromatography on silica gel using 98:2 → 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

40.1 mg (52% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

isomer. ¹H NMR (500 MHz, CDCl₃): δ 5.54 (q, J = 3.1 Hz, 1H),

4.17 (ddt, J = 11.1, 7.6, 4.4 Hz, 6H), 3.39−3.30 (m, 1H), 3.26 (d,

J = 6.0 Hz, 1H), 2.44−2.31 (m, 2H), 2.23 (dt, J = 12.5, 3.4 Hz,

1H), 2.18−2.07 (m, 1H), 1.98 (ddq, J = 14.6, 7.1, 3.5 Hz, 2H),

1.76−1.59 (m, 2H), 1.53 (ddd, J = 13.9, 6.9, 3.5 Hz, 1H), 1.26 (t,

J = 7.1 Hz, 9H), 1.12 (d, J = 6.7 Hz, 3H). ¹³C NMR (126 MHz,

CDCl₃): δ 175.5, 169.0, 168.4, 141.8, 114.8, 114.4, 61.3, 61.1

(two peaks), 60.6, 54.8, 51.0, 49.7, 37.9, 31.7, 24.2, 19.6, 16.3,

14.1, 14.0. IR (ﬁlm): 1725.2 (two peaks), 1446.7 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₀H₃₀O₆367.2121;

found 367.2115.

( )-(1S,2S,3aS)-Di-tert-butyl 2-[3a-(Ethoxycarbonyl)-1-

phenyl-2,3,3a,4,5,6-hexahydro-1H-inden-2-yl]malonate (7l).

The title compound was prepared from 1h (83.6 mg, 0.20

mmol) and di-tert-butyl malonate (0.1 mL, 0.4 mmol) using

General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 64.1 mg (66%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.44−7.35 (m, 2H), 7.27 (t, J = 7.4

Hz, 2H), 7.22−7.13 (m, 1H), 5.44 (q, J = 3.2 Hz, 1H), 4.20 (q, J

= 7.2 Hz, 2H), 3.53 (dt, J = 11.0, 2.9 Hz, 1H), 3.20 (d, J = 5.8 Hz,

1H), 2.67 (dd, J = 12.2, 5.5 Hz, 1H), 2.63−2.49 (m, 1H), 2.34

(dt, J = 12.4, 3.3 Hz, 1H), 2.11 (ddd, J = 14.1, 7.2, 3.4 Hz, 1H),

2.03 (dq, J = 11.2, 3.8 Hz, 1H), 1.77−1.56 (m, 3H), 1.47 (m,

11H), 1.39−1.22 (m, 11H). ¹³C NMR (126 MHz, CDCl₃): δ

176.0, 167.8, 167.7, 144.4, 143.2, 128.9, 128.2, 126.3, 123.8,

81.5, 81.3, 60.8, 55.1, 53.4, 52.9, 44.2, 40.8, 33.3, 28.0, 27.7, 24.5,

19.1, 14.3. IR (ﬁlm): 2977.9, 2934.0, 1722.4 (two peaks),

1496.0, 1453.7 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₂₉H₄₀O₆485.2903; found 485.2898.

( )-(1R,2S,3aR)-Di-tert-butyl 2-(1-Phenyl-2,3,3a,4,5,6-hex-

ahydro-1H-inden-2-yl)malonate (7m). The title compound

was prepared from 1i (73.1 mg, 0.21 mmol) and di-tert-butyl

malonate (0.1 mL, 0.4 mmol) using General Procedure B. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 53.9 mg (62% yield) of the title compound

as a white solid (mp 79−81 °C). The compound was obtained as

a >20:1 mixture of diastereomers as judged by ¹H NMR analysis.

The data shown are for the major isomer. ¹H NMR (500 MHz,

CDCl₃): δ 7.32−7.10 (m, 5H), 5.26 (m, 1H), 3.43 (dt, J = 9.2,

2.4 Hz, 1H), 3.19 (d, J = 7.0 Hz, 1H), 2.69−2.56 (m, 1H), 2.56−

2.43 (m, 1H), 2.31 (dt, J = 12.2, 6.3 Hz, 1H), 2.09−1.92 (m,

3H), 1.78 (dt, J = 13.0, 3.7 Hz, 1H), 1.47 (d, J = 1.2 Hz, 9H),

1.26 (s, 9H), 1.22−1.10 (m, 2H), 1.07 (dt, J = 12.6, 2.6 Hz, 1H).

¹³C NMR (126 MHz, CDCl₃): δ 168.0, 167.96, 147.7, 145.5,

128.3, 128.0, 126.0, 120.0, 81.4, 81.2, 56.8, 53.1, 46.1, 41.1, 36.8,

29.0, 28.0, 27.7, 25.1, 22.3. IR (ﬁlm): 2977.9, 2929.2, 1720.2

(two peaks), 1601.8, 1477.5, 1452.7 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₂₆H₃₆O₄413.2692; found 413.2686.

( )-(1R,2S,3aR)-Diethyl 2-Benzyl-2-(1-phenyl-2,3,3a,4,5,6-

hexahydro-1H-inden-2-yl)malonate (7n). The title compound

was prepared from 1i (57.6 mg, 0.17 mmol) and diethyl 2-

benzylmalonate (0.1 mL, 0.43 mmol) using General Procedure

B, except that the reaction was run in xylenes at 110 °C. The

crude material was puriﬁed via column chromatography on silica

gel using 98:2 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 39.0 mg (51% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

mixture of diastereomers as judged by H NMR analysis. The

1

data shown are for the major isomer. H NMR (500 MHz,

CDCl₃): δ 7.41−7.06 (m, 9H), 6.95 (dd, J = 6.6, 3.0 Hz, 1H),

5.27 (q, J = 2.7 Hz, 1H), 4.05−3.87 (m, 3H), 3.88−3.76 (m,

1H), 3.70−3.61 (m, 1H), 3.20−3.14 (m, 2H), 3.09 (d, J = 14.0

Hz, 1H), 2.94 (dt, J = 10.6, 7.2 Hz, 1H), 2.40 (dt, J = 12.2, 7.2

Hz, 1H), 2.04 (ddt, J = 12.4, 5.3, 3.4 Hz, 1H), 1.98−1.85 (m,

1H), 1.74 (ddd, J = 12.2, 6.1, 2.9 Hz, 1H), 1.52−1.34 (m, 2H),

1.32−1.18 (m, 1H), 1.19−1.04 (m, 4H), 1.02 (q, J = 7.0 Hz,

3H). ¹³C NMR (126 MHz, CDCl₃): δ 170.4, 148.1, 147.5,

136.9, 130.2, 128.3, 127.8, 126.5, 119.2, 62.8, 60.8, 54.7, 51.9,

50.3, 40.5, 39.9, 36.0, 34.6, 29.2, 25.08, 22.1, 13.9. IR (ﬁlm):

3027.9, 2979.3, 2929.1, 2854.1, 1725.4, 1602.4, 1495.3 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₉H₃₅O₄

447.2530; found 447.2530.

( )-(1R,2S,3aR)-Diethyl 2-(3a-Methyl-1-phenyl-

2,3,3a,4,5,6-hexahydro-1H-inden-2-yl)malonate (7o). The

title compound was prepared from 6-cinnamyl-6-methylcyclo-

hex-1-en-1-yl triﬂuoromethanesulfonate (1k) (44.6 mg, 0.12

mmol) and diethyl malonate (0.1 mL, 0.43 mmol) using General

Procedure B. The crude material was puriﬁed via column

chromatography on silica gel using 98:2 → 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 28.4 mg (62%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.30−7.11 (m, 5H), 5.19 (td, J =

3.6, 2.1 Hz, 1H), 4.24−4.07 (m, 2H), 3.77 (dq, J = 10.8, 7.1 Hz,

1H), 3.58 (dq, J = 10.8, 7.2 Hz, 1H), 3.47 (dq, J = 9.0, 2.8 Hz,

1H), 3.35 (d, J = 8.1 Hz, 1H), 2.98 (dddd, J = 11.9, 10.1, 8.1, 5.8

Hz, 1H), 2.11−1.90 (m, 3H), 1.82−1.60 (m, 3H), 1.38−1.15

(m, 8H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃):

δ 168.6, 168.3, 150.4, 144.3, 128.3, 128.2, 126.1, 120.6, 61.1,

61.0, 55.7, 53.5, 45.7, 43.6, 40.2, 36.8, 25.5, 24.5, 18.1, 14.1, 13.7.

IR (ﬁlm): 2977.3, 2933.5, 1731.4, 1492.9, 1452.0 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₃H₃₁O₄371.2217;

found 371.2217.

( )-(1S,2S,3aS)-Diethyl 2-[3a-(Ethoxycarbonyl)-1-phenyl-

1,2,3,3a,4,5-hexahydropentalen-2-yl]malonate (7p). The

title compound was prepared from ethyl 1-cinnamyl-2-

{[(triﬂuoromethyl)sulfonyl]oxy}cyclopent-2-ene-1-carboxylate

(1l) (70.9 mg, 0.18 mmol), diethyl malonate (0.1 mL, 0.6

mmol), Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv), and SPhos

(4.9 mg, 0.012 mmol, 0.06 equiv) at 95 °C for 14 h using

General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 → 90:10

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

53.8 mg (72% yield) of the title compound as a yellow oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

1

isomer. H NMR (500 MHz, CDCl₃): δ 7.32−7.08 (m, 4H),

5.58 (dt, J = 3.5, 1.7 Hz, 1H), 4.27−4.01 (m, 4H), 4.01−3.90

(m, 1H), 3.90−3.77 (m, 1H), 3.66−3.57 (m, 1H), 3.48 (d, J =

7.3 Hz, 1H), 3.24 (ddt, J = 8.8, 7.1, 1.8 Hz, 1H), 3.01−2.87 (m,

1H), 2.77 (dd, J = 12.1, 6.3 Hz, 1H), 2.52 (ddd, J = 15.8, 8.7, 3.4

Hz, 1H), 2.33 (dd, J = 12.6, 6.5 Hz, 1H), 1.93−1.78 (m, 1H),

1.45 (t, J = 11.7 Hz, 1H), 1.23 (ddt, J = 25.1, 10.9, 7.2 Hz, 7H),

1.15−1.01 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 175.8,

168.2, 166.6, 153.3, 142.8, 128.3, 127.7, 126.3, 125.9, 64.9, 61.5,

N

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

61.4, 60.7, 55.1, 54.3, 50.2, 47.1, 41.7, 39.5, 37.1, 29.7, 14.1. IR

(ﬁlm): 1725.0 (two peaks), 1597.5 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₂₄H₃₀O₆415.2121; found 415.2115.

( )-(1R,2S,3aR)-Diethyl 2-(1-Phenyl-1,2,3,3a,4,5-hexahy-

dropentalen-2-yl)malonate (7q). The title compound was

prepared from 5-cinnamylcyclopent-1-en-1-yl triﬂuorometha-

nesulfonate (1m) (62.4 mg, 0.19 mmol), diethyl malonate (0.1

mL, 0.6 mmol), Pd(acac)₂(2.4 mg, 0.008 mmol, 0.04 equiv),

and SPhos (4.9 mg, 0.012 mmol, 0.06 equiv) at 95 °C for 14 h

using General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 98:2 → 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

18.8 mg (30% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

3.61 (m, 1H), 3.52 (dt, J = 10.3, 7.2 Hz, 1H), 3.19 (s, 2H), 3.02−

2.81 (m, 2H), 2.52 (ddd, J = 15.6, 8.8, 3.3 Hz, 1H), 2.30 (dd, J =

12.7, 6.8 Hz, 1H), 1.84 (dt, J = 12.7, 9.4 Hz, 1H), 1.62−1.49 (m,

1H), 1.17 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.89 (t, J =

7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 176.2, 170.3,

170.2, 153.8, 143.7, 136.6, 130.2, 128.2, 127.9, 127.5, 126.7,

125.9, 124.4, 64.0, 63.0, 61.0, 60.8, 60.6, 52.4, 46.0, 40.6, 39.6,

37.9, 37.2, 14.0 (two peaks), 13.5. IR (ﬁlm): 2980.3, 1719.6,

1602.1, 1495.9, 1454.1 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M +

H]⁺calcd for C₃₁H₃₆O₆505.2590; found 505.2585.

( )-(5S,7R)-Diethyl 2-(9-Methylene-1-oxaspiro[4.4]nonan-

7-yl)malonate (9). The title compound was prepared from 1-(2-

allyltetrahydrofuran-2-yl)vinyl triﬂate (57.3 mg, 0.2 mmol) and

diethyl malonate (37 μL, 0.24 mmol) using General Procedure

A. The crude material was puriﬁed via column chromatography

on silica gel using 95:5 → 90:10 hexanes/ethyl acetate as the

eluent. This procedure aﬀorded 49.0 mg (82% yield) of the title

compound as a colorless oil. The compound was obtained as a

>20:1 mixture of diastereomers as judged by ¹H NMR analysis.

The data shown are for the major isomer. ¹H NMR (500 MHz,

C₆D₆): δ 4.96 (s, 1H), 4.88 (s, 1H), 4.07−3.84 (m, 4H), 3.75−

3.59 (m, 2H), 3.31−3.18 (m, 1H), 3.23−3.09 (m, 1H), 2.89

(dd, J = 16.4, 7.8 Hz, 1H), 2.29 (dd, J = 12.9, 6.5 Hz, 1H), 2.16

(ddt, J = 16.3, 9.5, 2.6 Hz, 1H), 1.87−1.76 (m, 1H), 1.71−1.52

(m, 3H), 1.46 (dd, J = 12.9, 10.7 Hz, 1H), 0.91 (t, J = 7.1 Hz,

6H). ¹³C NMR (126 MHz, C₆D₆): δ 168.12, 168.09, 154.1,

106.3, 88.0, 66.3, 60.63, 60.62, 57.0, 43.8, 36.8, 35.7, 34.4, 26.0,

13.7. IR (ﬁlm): 1749, 1728, 1445, 1025 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₁₆H₂₄O₅297.1624; found

297.1697.

( )-Diethyl 4-(1,3-Di-tert-butoxy-1,3-dioxopropan-2-yl)-2-

methylenecyclopentane-1,1-dicarboxylate (11) and ( )-Di-

ethyl 3-(3-(tert-Butoxy)-2-(tert-butoxycarbonyl)-3-oxoprop-

yl)-2-methylenecyclobutane-1,1-dicarboxylate (12). The

title compounds were prepared from diethyl 2-allyl-2-(1-

{[(triﬂuoromethyl)sulfonyl]oxy}vinyl)malonate (37.3 mg, 0.1

mmol) and di-tert-butyl malonate (26.7 μL, 0.12 mmol) using

General Procedure A, except that XPhos (6 mol %) was used as

the ligand, 1,4-dioxane was used as the solvent, and the reaction

was conducted for 1 h. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 33.4 mg (76%

combined yield) of 11 and 12 in a 1:2.5 regioisomeric mixture as

determined by ¹H NMR analysis. The characterization data are

for the mixture. ¹H NMR (500 MHz, CDCl₃): δ 5.35−5.3 (ddd,

J = 12.4, 2.9, 1.3 Hz, 1.4H), 5.25 (t, J = 2.0 Hz, 0.43H), 5.14 (dd,

J = 2.4, 1.2 Hz, 1H), 4.30−4.15 (m, J = 14.2, 7.2, 5.9, 3.2 Hz,

5.7H), 3.16 (t, J = 7.6 Hz, 1H), 3.09−2.95 (m, 1.4H), 2.75−2.55

(m, 2.3H), 2.31−2.18 (m, 1.4H), 2.15 (ddd, J = 13.9, 7.8, 6.1 Hz,

1H), 2.09−2.00 (m, 0.8H), 1.94 (ddd, J = 13.9, 9.4, 7.4 Hz, 1H),

1.50−1.41 (m, 26H), 1.25 (td, J = 7.2, 6.1 Hz, 9.7H). ¹³C NMR

(126 MHz, CDCl₃): δ 169.6, 169.1, 168.7, 168.6, 147.8, 146.5,

112.8, 110.6, 81.75, 81.73, 81.72, 61.84, 61.78, 61.76, 61.7, 59.3,

58.6, 51.8, 40.0, 38.5, 36.9, 32.9, 32.1, 29.8, 28.1, 19.0, 14.19,

14.14, 14.12.

1

isomer. H NMR (500 MHz, CDCl₃): δ 7.33−7.22 (m, 3H),

7.22−7.10 (m, 3H), 5.25 (tt, J = 3.2, 1.7 Hz, 1H), 4.23−4.05 (m,

2H), 3.98−3.84 (m, 1H), 3.84−3.71 (m, 1H), 3.47 (dd, J = 21.1,

8.3 Hz, 2H), 3.20 (d, J = 6.6 Hz, 1H), 3.10−2.97 (m, 1H), 2.59

(ddd, J = 7.0, 3.4, 1.7 Hz, 1H), 2.49 (dd, J = 9.7, 6.2 Hz, 1H),

2.29 (dt, J = 12.3, 6.4 Hz, 1H), 2.15 (dt, J = 13.2, 6.9 Hz, 2H),

1.24 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H). ¹³C NMR (126

MHz, CDCl₃): δ 168.5, 168.4, 155.7, 144.6, 128.3, 127.6, 126.2,

120.2, 61.2, 61.1, 55.7, 52.3, 51.5, 47.2, 37.2, 36.7, 32.1, 14.1,

13.7. IR (ﬁlm): 2932.7, 2849.4, 1730.9, 1600.8, 1495.7, 1452.3

cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₁H₂₆O₄

343.1909; found 343.1904.

( )-(1S,2S,3aS)-Di-tert-butyl 2-[3a-(Ethoxycarbonyl)-1-

phenyl-1,2,3,3a,4,5-hexahydropentalen-2-yl]malonate (7r).

The title compound was prepared from 1l (80.8 mg, 0.2

mmol) and di-tert-butyl malonate (0.1 mL, 0.4 mmol) using

General Procedure B. The crude material was puriﬁed via

column chromatography on silica gel using 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 54.5 mg (58%

yield) of the title compound as a pale-yellow oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.29−7.21 (m, 4H), 7.16 (td, J =

3.5, 2.8 Hz, 1H), 5.63−5.55 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H),

3.64 (d, J = 8.4 Hz, 1H), 3.33 (dd, J = 6.8, 1.5 Hz, 1H), 3.20−

3.08 (m, 1H), 2.94 (t, J = 8.5 Hz, 1H), 2.79 (dd, J = 12.3, 6.5 Hz,

1H), 2.53 (ddd, J = 15.7, 9.0, 2.8 Hz, 1H), 2.35 (dd, J = 12.6, 6.5

Hz, 1H), 1.95−1.81 (m, 1H), 1.56−1.40 (m, 10H), 1.31 (d, J =

1.6 Hz, 9H), 1.17 (td, J = 7.1, 1.5 Hz, 3H). ¹³C NMR (126 MHz,

CDCl₃): δ 175.9, 167.8, 167.7, 153.3, 143.0, 128.3, 127.7, 126.2,

125.7, 81.6, 81.5, 64.8, 60.6, 56.9, 49.9, 47.0, 39.4, 39.1, 37.1,

28.0, 27.7, 14.1. IR (ﬁlm): 2977.8, 2933.2, 1721.1 (the carbonyl

peaks are incidentally equivalent), 1596.3, 1497.0, 1454.5 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₈H₃₈O₆

471.2747; found 471.2741.

( )-(1S,2S,3aS)-Diethyl 2-Benzyl-2-[3a-(ethoxycarbonyl)-

1-phenyl-1,2,3,3a,4,5-hexahydro pentalen-2-yl]malonate

(7s). The title compound was prepared from 1l (89.2 mg, 0.22

mmol) and diethyl 2-benzylmalonate (0.1 mL, 0.43 mmol)

using General Procedure B, except that the reaction was run in

xylenes at 110 °C. The crude material was puriﬁed via column

chromatography on silica gel using 98:2 → 95:5 hexanes/ethyl

acetate as the eluent. This procedure aﬀorded 45.4 mg (41%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.30−7.02 (m, 10H), 5.54 (dt, J =

3.2, 1.5 Hz, 1H), 4.14−3.96 (m, 3H), 3.98−3.82 (m, 3H), 3.73−

( )-(2S,3aR)-Ethyl 2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-

yl)-3-oxobutanoate (13a). The title compound was prepared

from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and

ethyl acetoacetate (31 μL, 0.24 mmol) using General Procedure

A. The crude material was puriﬁed via column chromatography

on silica gel using 99:1 → 95:5 hexanes/ethyl acetate as the

eluent. This procedure aﬀorded 40.5 mg (81% yield) of the title

compound. The compound was obtained as a 1:1 mixture of

O

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

diastereomers epimeric at the stereocenter between the carbonyl

groups, as judged by ¹H NMR analysis. The data shown are for

the mixture. ¹H NMR (401 MHz, CDCl₃): δ 5.35 (s, 0.5H), 5.32

(s, 0.5H), 4.28−4.10 (m, 2H), 3.25 (dd, J = 10.1, 8.2 Hz, 1H),

2.75−2.50 (m, 2H), 2.22 (d, J = 3.1 Hz, 4H), 2.10−1.71 (m,

6H), 1.51−1.34 (m, 1H), 1.29−1.25 (m, 3H), 1.05−0.89 (m,

1H), 0.88−0.71 (m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ

203.1, 202.9, 169.33, 169.28, 142.7, 142.5, 118.3, 118.2, 66.4,

66.2, 61.4, 41.1, 40.8, 38.6, 38.59, 36.9, 35.2, 35.2, 29.3, 29.0,

28.9, 25.30, 25.29, 22.5, 22.4, 14.3. IR (ﬁlm): 1735, 1710 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₅H₂₂O₃

273.1569; found 273.1461.

as the base, and dioxane (2 mL, 0.1 M) as the solvent. The crude

material was puriﬁed via column chromatography on silica gel

using 95:5 hexanes/ethyl acetate as the eluent. This procedure

aﬀorded 22.0 mg (47% yield) of the title compound as a

colorless oil. The compound was obtained as a 1:1 mixture of

diastereomers epimeric at the CN-bearing stereocenter, as

judged by ¹H NMR analysis. The data shown are for the mixture.

¹H NMR (500 MHz, CDCl₃): δ 7.25−7.15 (m, 4H), 4.28 (q, J =

7.2 Hz, 2H), 3.64 (dd, J = 6.8, 1.7 Hz, 1H), 3.25−3.08 (m, 3H),

2.99 (dd, J = 15.5, 7.4 Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H),

1.34 (t, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 165.59,

140.95, 140.93, 126.91, 126.87, 124.54, 124.46, 115.72, 62.85,

42.08, 42.04, 39.96, 37.07, 36.56, 14.02. IR (ﬁlm): 2908, 2242,

1737, 1460, 743 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺

calcd for C₁₄H₁₅NO₂247.1441; found 247.1445.

( )-(2S,3aR)-Ethyl 2-(Diethoxyphosphoryl)-2-(2,3,3a,4,5,6-

hexahydro-1H-inden-2-yl)acetate (13b). The title compound

was prepared from 6-allylcyclohex-1-en-1-yl triﬂate (500 mg,

1.85 mmol), and triethyl phosphonoacetate (440 μL, 2.22

mmol) using General Procedure A, except with lithium

hexamethyldisilazide (774 mg, 4.625 mmol) as the base. The

crude material was puriﬁed via column chromatography on silica

gel using 50:50 → 15:85 hexanes/ethyl acetate as the eluent.

This procedure aﬀorded 332 mg (52% yield) of the title

compound as a yellow oil. The compound was obtained as a 1:1

mixture of diastereomers epimeric at the stereocenter adjacent

( )-2-[2-(2,3-Dihydro-1H-inden-2-yl)acetyl]-3,4-dihydro-

naphthalen-1(2H)-one (14b). The title compound was

prepared from 2-allylphenyl triﬂate (53.5 mg, 0.2 mmol) and

2-acetyl-1-tetralone (45.2 mg, 0.24 mmol) using General

Procedure A, except with LiHMDS (87.0 mg, 0.52 mmol) as

the base and xylenes (2 mL) as the solvent at a reaction

temperature of 130 °C. The crude material was puriﬁed via

column chromatography on silica gel using 65:35 hexanes/

dichloromethane as the eluent. This procedure aﬀorded 24.5 mg

(40% yield) of the title compound as a yellow solid (mp 77−80

°C) that contained ca. 5% inseparable impurities. ¹H NMR (401

MHz, CDCl₃): δ 7.95−7.91 (m, 1H), 7.37 (td, J = 7.4, 1.5 Hz,

1H), 7.33−7.26 (m, 1H), 7.20−7.14 (m, 3H), 7.14−7.08 (m,

2H), 3.15 (dd, J = 15.6, 7.7 Hz, 2H), 3.01−2.91 (m, 1H), 2.85−

2.79 (m, 2H), 2.73−2.61 (m, 4H), 2.58 (dd, J = 8.3, 6.3 Hz, 2H).

¹³C NMR (100 MHz, CDCl₃): δ 194.95, 177.67, 142.75, 140.82,

131.88, 131.30, 127.51, 126.85, 126.26, 125.90, 124.50, 106.06,

41.46, 39.10, 36.22, 28.28, 22.52. IR (ﬁlm): 3062, 2926, 2833,

1712, 1666, 1586, 1554, 1294 cm⁻¹. HRMS (ESI⁺TOF) m/z:

[M + Na]⁺calcd for C₂₁H₂₀O₂327.1356; found 327.1360.

tert-Butyl 2-(2,3-Dihydro-1H-inden-2-yl)acetate (15a).

The title compound was prepared from 2-allylphenyl triﬂate

(266.5 mg, 1 mmol) and tert-butyl acetate (165 μL, 1.4 mmol)

using General Procedure A, except with LiHMDS (368 mg, 2.2

mmol) as the base. The crude material was puriﬁed via column

chromatography on silica gel using 95:5 hexanes/ethyl acetate as

the eluent to aﬀord a mixture of the desired product and a side

product resulting from C-arylation of the ester. In order to

separate these compounds, the material was further reacted with

0.5 g of AD-mix-α in a 1:1 solution of tert-butyl alcohol and

water (1.6 mL:1.6 mL) for 12 h at rt to oxidize the alkene in the

undesired product. The oxidation reaction mixture was then

quenched with sodium sulﬁte and stirred at rt for 30 min. The

aqueous layer was extracted with ethyl acetate (3 × 5 mL), dried

with MgSO₄, and concentrated in vacuo. The crude material was

puriﬁed via column chromatography on silica gel using 80:20

hexanes/dichloromethane. This procedure aﬀorded 24.5 mg

1

to the ester group, as judged by H NMR analysis. The data

shown are for the mixture. ¹H NMR (401 MHz, CDCl₃): δ 5.39

(s, 0.5H), 5.35 (s, 0.5H), 4.35−3.98 (m, 6H), 2.84−2.54 (m,

2.5H), 2.35−2.09 (m, 2H), 2.07−1.86 (m, 4H), 1.85−1.71 (m,

1H), 1.50−1.37 (m, 1H), 1.41−1.14 (m, 9H), 1.14−0.73 (m,

2.5H). ¹³C NMR (126 MHz, CDCl₃): δ 169.21, 169.06, 142.83,

142.20, 117.97, 62.46, 61.21, 52.14, 51.09, 41.32, 40.64, 39.63,

39.51, 39.42, 36.28, 36.24, 36.15, 36.11, 35.92, 35.79, 35.43,

28.65, 28.58, 25.19, 25.14, 22.32, 22.30, 16.40, 16.36, 14.17. IR

(ﬁlm): 1731 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₇H₂₉O₅P 345.1753; found 345.1825.

( )-(2S,3aR)-Ethyl 2-Cyano-2-(2,3,3a,4,5,6-hexahydro-1H-

inden-2-yl)acetate (13c). The title compound was prepared

from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and

ethyl cyanoacetate (26 μL, 0.24 mmol) using General Procedure

A, except with Pd(allyl)BrettPhosCl (8.6 mg, 0.012 mmol) as

the catalyst, additional BrettPhos (6.4 mg, 0.012 mmol), cesium

carbonate (91.2 mg, 0.28 mmol) as the base, and 1,4 dioxane (2

mL, 0.1 M) as the solvent. The crude material was puriﬁed via

column chromatography on silica gel using 65:35 → 50:50

hexanes/dichloromethane as the eluent. This procedure

aﬀorded 22.8 mg (50% yield) of the title compound as a

colorless oil. The compound was obtained as a 1:1 mixture of

diastereomers epimeric at the CN-bearing stereocenter, as

judged by ¹H NMR analysis. The data shown are for the mixture.

¹H NMR (401 MHz, CDCl₃): δ 5.43 (s, 1H), 4.26 (q, J = 7.1 Hz,

2H), 3.48 (dd, J = 11.3, 6.5 Hz, 1H), 2.69−2.50 (m, 2H), 2.35−

1.91 (m, 6H), 1.85−1.71 (m, 1H), 1.51−1.34 (m, 1H), 1.32 (t, J

= 7.1 Hz, 3H), 1.16−0.97 (m, 2H). ¹³C NMR (126 MHz,

CDCl₃): δ 166.0, 141.3, 141.1, 119.32, 119.27, 115.9, 62.8,

42.70, 42.65, 41.1, 41.0, 38.5, 37.9, 37.7, 34.8, 34.0, 28.7, 25.2,

22.3, 14.2. IR (ﬁlm): 2248, 1743, 1453 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₁₄H₁₉NO₂234.1416; found

234.1493.

1

(24% yield) of the title compound as a colorless oil. H NMR

(401 MHz, CDCl₃): δ 7.22−7.16 (m, 2H), 7.16−7.10 (m, 2H),

3.12 (dd, J = 15.5, 7.8 Hz, 2H), 2.85 (p, J = 7.6 Hz, 1H), 2.64

(dd, J = 15.5, 7.4 Hz, 2H), 2.41 (d, J = 7.5 Hz, 1H), 1.47 (s, 9H).

¹³C NMR (126 MHz, CDCl₃): δ 172.27, 142.80, 126.20, 124.44,

80.22, 41.41, 38.92, 36.34, 28.13. IR (ﬁlm): 2969, 2921, 1724,

1480 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for

C₁₅H₂₀O₂255.1356; found 255.1360.

( )-Ethyl 2-Cyano-2-(2,3-dihydro-1H-inden-2-yl)acetate

(14a). The title compound was prepared from 2-allylphenyl

triﬂate (53.3 mg, 0.2 mmol) and ethyl cyanoacetate (26 μL, 0.24

mmol) using General Procedure A, except with Pd(allyl)-

BrettPhosCl (8.6 mg, 0.012 mmol) as the catalyst, additional

BrettPhos (6.4 mg, 0.012 mmol), Cs₂CO₃(91.2 mg, 0.28 mmol)

Methyl 2-(2,3-Dihydro-1H-inden-2-yl)-2-methylpropa-

noate (15b). The title compound was prepared from 2-

P

DOI: 10.1021/acs.oprd.9b00248

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Organic Process Research & Development

Article

allylphenyl triﬂate (53.3 mg, 0.2 mmol) and methyl isobutyrate

(28 μL, 0.24 mmol) using General Procedure A, except with

LiHMDS (73.6 mg, 0.44 mmol) as the base. The crude material

was puriﬁed via column chromatography on silica gel using 95:5

hexanes/ethyl acetate as the eluent. This procedure aﬀorded

37.1 mg (85% yield) of the title compound as a colorless oil.¹H

NMR (500 MHz, CDCl₃): δ 7.20−7.15 (m, 2H), 7.14−7.10 (m,

2H), 3.68 (s, 3H), 2.96−2.86 (m, 2H), 2.85−2.74 (m, 3H), 1.23

(s, 6H). ¹³C NMR (126 MHz, CDCl₃): δ 178.11, 142.89,

126.33, 124.45, 77.41, 77.16, 76.91, 51.85, 47.83, 44.52, 34.56,

23.09. IR (ﬁlm): 1726 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺

calcd for C₁₄H₁₈O₂219.3180; found 219.1380.

HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₈H₁₈O₂

289.1199; found 289.1203.

( )-(2S,3aR)-Methyl 2-(2,3,3a,4,5,6-Hexahydro-1H-inden-

2-yl)-2-phenylacetate (15f). The title compound was prepared

from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and

methyl 2-phenylacetate (35 μL, 0.24 mmol) using General

Procedure A, except with LiHMDS (73.6 mg, 0.44 mmol) as the

base. The crude material was puriﬁed via column chromatog-

raphy on silica gel using 80:20 → 65:35 hexanes/dichloro-

methane as the eluent. This procedure aﬀorded 29.2 mg (54%

yield) of the title compound as a colorless oil. The compound

was obtained as a 2:1 mixture of diastereomers epimeric at the

1

stereocenter α to the carbonyl group, as judged by H NMR

( )-Methyl 2-(5-Fluoro-2-methyl-2,3-dihydro-1H-inden-2-

yl)-2-methylpropanoate (15c). The title compound was

prepared from 4-ﬂuoro-2-(2-methylallyl)phenyl triﬂate (56.8

mg, 0.2 mmol) and methyl isobutyrate (28 μL, 0.24 mmol)

using General Procedure A, except with LiHMDS (73.6 mg, 0.44

mmol) as the base and RuPhos (5.6 mg, 0.012 mmol) as the

ligand. The crude material was puriﬁed via column chromatog-

raphy on silica gel using 80:20 hexanes/dichloromethane as the

eluent. This procedure aﬀorded 11.5 mg (23% yield) of the title

1

analysis. The data shown are for the mixture. H NMR (500

MHz, CDCl₃): δ 7.38−7.30 (m, 4H), 7.30−7.24 (m, 1H), 5.40

(m, 0.67H), 5.30 (s, 0.34H), 3.66 (s, 3H), 3.29 (d, J = 10.6 Hz,

1H), 2.84−2.61 (m, 1.67H), 2.28 (br s, 0.33H), 2.24−2.09 (m,

1.35H), 2.05−1.94 (m, 3H), 1.92−1.83 (m, 0.67H), 1.83−1.70

(m, 1.34H), 1.66−1.55 (m, 1H), 1.51−1.34 (m, 1H), 1.09−0.86

(m, 1.34H), 0.67 (q, J = 11.6 Hz, 0.67H). ¹³C NMR (126 MHz,

CDCl₃): δ 174.15, 143.38, 143.06, 138.54, 128.51, 128.19,

128.14, 127.25, 127.22, 117.78, 117.75, 58.17, 57.91, 51.86,

51.83, 41.21, 40.88, 40.82, 40.74, 39.42, 38.66, 35.92, 35.01,

28.91, 28.83, 25.19, 25.17, 22.38, 22.35. IR (ﬁlm): 2914, 2833,

1731, 1430 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₈H₂₂O₂271.1693; found 271.1695.

( )-(2S,3aR)-Methyl 2-(2,3,3a,4,5,6-Hexahydro-1H-inden-

2-yl)-2-methylpropanoate (15g). The title compound was

prepared from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2

mmol) and methyl isobutyrate (28 μL, 0.24 mmol) using

General Procedure A, except with LiHMDS (73.6 mg, 0.44

mmol) as the base. The crude material was puriﬁed via column

chromatography on silica gel using 80:20 → 65:35 hexanes/

dichloromethane as the eluent. This procedure aﬀorded 39.1 mg

(88% yield) of the title compound as a colorless oil. The

compound was obtained as a >20:1 mixture of diastereomers as

judged by ¹H NMR analysis. The data shown are for the major

isomer. ¹H NMR (500 MHz, CDCl₃): δ 5.34 (s, 1H), 3.65 (s,

3H), 2.38−2.12 (m, 3H), 2.09−1.90 (m, 4H), 1.87−1.70 (m,

2H), 1.50−1.36 (m, 1H), 1.13 (s, 3H), 1.12 (s, 3H), 1.06−0.95

(m, 1H), 0.94−0.83 (m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ

178.47, 143.62, 117.60, 77.41, 77.16, 76.91, 51.72, 45.66, 44.10,

41.42, 35.44, 31.85, 28.98, 25.39, 22.74, 22.61, 22.57. IR (ﬁlm):

1730, 1151 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₄H₂₂O₂223.1693; found 223.1682.

1

compound as a colorless oil. H NMR (401 MHz, CDCl₃): δ

7.08 (dd, J = 8.2, 5.3 Hz, 1H), 6.90−6.75 (m, 2H), 3.65 (s, 3H),

3.23 (dd, J = 25.1, 16.1 Hz, 2H), 2.48 (dd, J = 16.0, 11.5 Hz, 2H),

1.25 (s, 6H), 1.03 (s, 3H). ¹³C NMR (176 MHz, CDCl₃): δ

177.52, 162.65, 161.27, 144.36 (d, J = 8.0 Hz), 137.55, 125.58

(d, J = 8.7 Hz), 112.94 (d, J = 22.2 Hz), 111.71 (d, J = 21.8 Hz),

51.51, 48.95, 47.81, 47.56, 42.50, 42.49, 41.50, 29.69, 23.75,

22.09, 22.07, 19.01. IR (ﬁlm): 2929, 1723, 1141 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₅H₁₉FO₂273.1369;

found 273.1267.

( )-Methyl 2-[5-(tert-Butyl)-2-methyl-2,3-dihydro-1H-

inden-2-yl]-2-methylpropanoate (15d). The title compound

was prepared from 4-tert-butyl-2-(2-methylallyl)phenyl triﬂate

(67.3 mg, 0.2 mmol) and methyl isobutyrate (28 μL, 0.24

mmol) using General Procedure A, except with LiHMDS (73.6

mg, 0.44 mmol) as the base and RuPhos (5.6 mg, 0.012 mmol)

as the ligand. The crude material was puriﬁed via column

chromatography on silica gel using 99:1 hexanes/ethyl acetate as

the eluent. This procedure aﬀorded 13.7 mg (24% yield) of the

title compound as a colorless oil. ¹H NMR (401 MHz, CDCl₃):

δ 7.22−7.15 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H),

3.31−3.20 (m, 2H), 2.54−2.43 (m, 2H), 1.31 (s, 9H), 1.26 (s,

6H), 1.04 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 177.71,

149.22, 142.08, 139.24, 124.23, 123.15, 121.69, 51.44, 48.47,

47.61, 42.47, 41.89, 34.49, 31.59, 23.94, 22.14. IR (ﬁlm): 2952,

1728, 1144 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for

C₁₉H₂₈O₂306.2428; found 306.2436.

( )-Methyl 2-(2,3-Dihydro-1H-inden-2-yl)-2-phenylace-

tate (15e). The title compound was prepared from 2-allylphenyl

triﬂate (53.3 mg, 0.2 mmol) and methyl 2-phenylacetate (35 μL,

0.24 mmol) using General Procedure A, except with LiHMDS

(73.6 mg, 0.44 mmol) as the base. The crude material was

puriﬁed via column chromatography on silica gel using 80:20 →

65:35 hexanes/dichloromethane as the eluent. This procedure

aﬀorded 45.8 mg (86% yield) of the title compound as a white

solid (mp 70−71 °C). ¹H NMR (400 MHz, CDCl₃): δ 7.41−

7.28 (m, 4H), 7.24−7.19 (m, 1H), 7.18−7.06 (m, 3H), 3.70 (s,

3H), 3.56 (d, J = 10.5 Hz, 1H), 3.34−3.15 (m, 2H), 2.84−2.66

(m, 2H), 2.50 (dd, J = 15.7, 7.6 Hz, 1H). ¹³C NMR (100 MHz,

CDCl₃): δ 174.03, 142.53, 142.33, 138.30, 128.70, 128.28,

127.45, 126.32, 126.29, 124.48, 124.34, 56.98, 51.96, 42.92,

38.19, 37.06. IR (ﬁlm): 2941, 1725, 1577, 1451, 1433 cm⁻¹.

( )-(2S,3aR)-Methyl 2-Methyl-2-(2-methyl-2,3,3a,4,5,6-

hexahydro-1H-inden-2-yl)propanoate (15h). The title com-

pound was prepared from 6-(2-methylallyl)cyclohex-1-en-1-yl

triﬂate (56.9 mg, 0.2 mmol) and methyl isobutyrate (28 μL, 0.24

mmol) using General Procedure A, except with LiHMDS (73.6

mg, 0.44 mmol) as the base and RuPhos (5.6 mg, 0.012 mmol)

as the ligand. The crude material was puriﬁed via column

chromatography on silica gel using 95:5 hexanes/ethyl acetate as

the eluent. This procedure aﬀorded 24.7 mg (52% yield) of the

title compound as a colorless oil. The compound was obtained

1

as an 11:1 mixture of diastereomers as judged by H NMR

1

analysis. The data shown are for the major isomer. H NMR

(401 MHz, CDCl₃): δ 5.32 (s, 1H), 3.63 (s, 3H), 2.65−2.54 (m,

1H), 2.38 (br s, 1H), 2.05−1.88 (m, 4H), 1.82−1.72 (m, 1H),

1.52 (dd, J = 12.1, 7.0 Hz, 1H), 1.48−1.37 (m, 1H), 1.33 (t, J =

12.1 Hz, 1H), 1.14 (s, 6H), 1.01 (s, 3H), 1.00−0.94 (m, 1H).

¹³C NMR (126 MHz, CDCl₃): δ 177.90, 143.91, 117.22, 51.28,

47.96, 45.16, 42.34, 40.66, 38.95, 29.04, 25.17, 24.87, 22.47,

Q

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

21.61, 21.58. IR (ﬁlm): 1922, 1726, 1432, 1135 cm⁻¹. HRMS

(ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₉H₂₈O₂306.2428;

found 306.2436.

mg (24% yield) of the title compound as a colorless oil. ¹H NMR

(401 MHz, CDCl₃): δ 7.34−7.27 (m, 4H), 7.26−7.19 (m, 6H),

7.14−7.05 (m, 4H), 5.10 (s, 1H), 3.08 (dd, J = 15.6, 7.8 Hz, 2H),

2.90 (dt, J = 14.9, 7.5 Hz, 1H), 2.74 (d, J = 7.1 Hz, 2H), 2.46 (dd,

J = 15.5, 7.3 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 207.95,

142.79, 138.35, 129.01, 128.78, 127.30, 126.28, 124.48, 64.35,

48.73, 39.07, 35.10. IR (ﬁlm): 3020, 2902, 2833, 1713, 1492,

903 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for

C₂₄H₂₂O 349.1563; found 349.1566.

( )-(2S,3aR)-Methyl 2-Methyl-2-(2-methyl-1,2,3,3a,4,5-

hexahydropentalen-2-yl)propanoate (15i). The title com-

pound was prepared from 5-(2-methylallyl)cyclopent-1-en-1-yl

triﬂate (54.0 mg, 0.2 mmol) and methyl isobutyrate (28 μL, 0.24

mmol) using General Procedure A, except with LiHMDS (73.6

mg, 0.44 mmol) as the base and RuPhos (5.6 mg, 0.012 mmol)

as the ligand. The crude material was puriﬁed via column

chromatography on silica gel using 95:5 hexanes/ethyl acetate as

the eluent. This procedure aﬀorded 22.2 mg (50% yield) of the

title compound as a colorless oil. The compound was obtained

( )-2-(2,3-Dihydro-1H-inden-2-yl)-1,2-diphenylethan-1-

one (18b). The title compound was prepared from 2-allylphenyl

triﬂate (53.3 mg, 0.2 mmol) and deoxybenzoin (47.1 mg, 0.24

mmol) using General Procedure A, except with LiHMDS (73.6

mg, 0.44 mmol) as the base. The crude material was puriﬁed via

column chromatography on silica gel using 80:20 hexanes/

dichloromethane as the eluent. This procedure aﬀorded 50.1 mg

1

as a >20:1 mixture of diastereomers as judged by H NMR

analysis. The data shown are for the major isomer. NMR spectra

were acquired in C₆D₆, as some (ca. 5%) isomerization of the

alkene occurred when the spectra were acquired in CDCl₃. ¹H

NMR (401 MHz, C₆D₆): δ 5.24 (s, 1H), 3.31 (s, 3H), 2.95 (br s,

1H), 2.80−2.67 (m, 1H), 2.66−2.53 (m, 1H), 2.51−2.38 (m,

1H), 2.11−2.05 (m, 1H), 1.84−1.74 (m, 1H), 1.52−1.29 (m,

4H), 1.14 (s, 6H), 1.03 (s, 3H). ¹³C NMR (126 MHz, C₆D₆): δ

176.54, 152.91, 117.81, 52.08, 50.53, 49.78, 48.01, 41.82, 37.24,

34.74, 32.35, 25.21, 21.47, 21.43. IR (ﬁlm): 2943, 2839, 1726,

1132 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₄H₂₂O₂223.1693; found 223.1690.

( )-(1S,4R)-Methyl 2-Methyl-2-(1-methyl-3-methylene-4-

phenylcyclopent-1-yl)propanoate (17). The title compound

was prepared from 5-methyl-3-phenylhexa-1,5-dien-2-yl triﬂate

(64.1 mg, 0.2 mmol) and methyl isobutyrate (28 μL, 0.24

mmol) using General Procedure A, except with LiHMDS (73.6

mg, 0.44 mmol) as the base and RuPhos (5.6 mg, 0.012 mmol)

as the ligand. The crude material was puriﬁed via column

chromatography on silica gel using 80:20 hexanes/dichloro-

methane as the eluent. This procedure aﬀorded 28 mg (52%

yield) of the title compound as a colorless oil. The compound

was obtained as a >20:1 mixture of diastereomers as judged by

¹H NMR analysis. The data shown are for the major isomer. ¹H

NMR (500 MHz, CDCl₃): δ 7.33−7.27 (m, 2H), 7.23−7.17 (m,

3H), 5.00 (s, 1H), 4.59 (s, 1H), 3.79−3.70 (m, 1H), 3.67 (s,

3H), 2.83 (d, J = 16.4 Hz, 1H), 2.21 (d, J = 16.3 Hz, 1H), 2.03−

1.94 (m, 1H), 1.92−1.84 (m, 1H), 1.23 (s, 3H), 1.22 (s, 3H),

1.06 (s, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 177.64, 155.32,

145.32, 128.35, 128.14, 126.05, 108.75, 51.39, 48.86, 47.74,

45.59, 44.87, 43.20, 22.23, 21.63, 21.60. IR (ﬁlm): 2968, 1726,

1142 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₈H₂₄O₂273.1849; found 273.1847.

3-(2,3-Dihydro-1H-inden-2-yl)-1,1-diphenylpropan-2-one

(18a). The title compound was prepared from 2-allylphenyl

triﬂate (533 mg, 2.0 mmol) and 1,1-diphenylacetone (505 mg,

2.4 mmol) using General Procedure A, except with LiHMDS

(736 mg, 4.4 mmol) as the base. The crude material was puriﬁed

via column chromatography on silica gel using 99:1 hexanes/

ethyl acetate as the eluent to aﬀord a mixture of the desired

product and a side product resulting from C-arylation of the

ester. In order to separate these compounds, the material was

further reacted with 1.2 g of AD-mix-α in a 1:1 solution of tert-

butyl alcohol and water (4 mL:4 mL) for 12 h at rt to oxidize the

alkene in the undesired product. The oxidation reaction mixture

was then quenched with sodium sulﬁte and stirred at rt for 30

min. The aqueous layer was extracted with ethyl acetate (3 × 8

mL), dried with MgSO₄, and concentrated in vacuo. The crude

material was puriﬁed via column chromatography on silica gel

using 99:1 hexanes/ethyl acetate. This procedure aﬀorded 158

1

(81% yield) of the title compound as a colorless oil. H NMR

(401 MHz, CDCl₃): δ 8.01−7.95 (m, 2H), 7.52−7.45 (m, 1H),

7.43−7.36 (m, 4H), 7.35−7.28 (m, 2H), 7.26−7.20 (m, 1H),

7.18−7.08 (m, 4H), 4.57 (d, J = 10.7 Hz, 1H), 3.53−3.37 (m,

1H), 3.27 (dd, J = 15.8, 7.7 Hz, 1H), 2.77−2.54 (m, 3H). ¹³

C

NMR (126 MHz, CDCl₃): δ 199.76, 142.91, 142.54, 138.59,

137.06, 132.94, 128.97, 128.65, 128.59, 128.55, 127.27, 126.27,

126.24, 124.54, 124.37, 58.86, 43.16, 38.65, 37.04. IR (ﬁlm):

3026, 2938, 2836, 1675, 1596, 698 cm⁻¹. HRMS (ESI⁺TOF)

m/z: [M + H]⁺calcd for C₂₃H₂₀O 313.1587; found 313.1592.

( )-2-(2,3-Dihydro-1H-inden-2-yl)cyclohexan-1-one (18c).

The title compound was prepared from 2-allylphenyl triﬂate

(53.3 mg, 0.2 mmol) and cyclohexanone (50 μL, 0.48 mmol)

using General Procedure A, except with LiHMDS (73.6 mg, 0.44

mmol) as the base. The crude material was puriﬁed via column

chromatography on silica gel using 65:35 hexanes/dichloro-

methane as the eluent. The product was further puriﬁed via

column chromatography on silica gel using 99:1 hexanes/ethyl

acetate. This procedure aﬀorded 30.5 mg (71% yield) of the title

1

compound as a white solid (mp 67−69 °C). H NMR (500

MHz, CDCl₃): δ 7.21−7.15 (m, 2H), 7.15−7.10 (m, 2H), 3.24

(dd, J = 15.9, 7.9 Hz, 1H), 3.03 (dd, J = 15.3, 7.9 Hz, 1H), 2.76

(p, J = 8.5 Hz, 1H), 2.64 (dd, J = 15.4, 9.2 Hz, 1H), 2.55 (dd, J =

15.9, 8.9 Hz, 1H), 2.49−2.39 (m, 2H), 2.39−2.30 (m, 1H),

2.19−2.11 (m, 1H), 2.09−2.00 (m, 1H), 1.95−1.87 (m, 1H),

1.80−1.64 (m, 2H), 1.60−1.48 (m, 1H). ¹³C NMR (100 MHz,

CDCl₃): δ 213.08, 143.51, 142.67, 126.14, 126.00, 124.29,

124.13, 56.25, 42.23, 39.38, 38.22, 36.64, 32.17, 28.24, 24.64. IR

(ﬁlm): 2931, 2857, 1704, 744 cm⁻¹. HRMS (ESI⁺TOF) m/z:

[M + H]⁺calcd for C₁₅H₁₈O 215.1430; found 215.1432.

2-(2,3-Dihydro-1H-inden-2-yl)-2-methyl-1-phenylpropan-

1-one (18d). The title compound was prepared from 2-

allylphenyl triﬂate (53.3 mg, 0.2 mmol) and phenyl isopropyl

ketone (36 μL, 0.24 mmol) using General Procedure A, except

with LiHMDS (73.6 mg, 0.44 mmol) as the base. The crude

material was puriﬁed via column chromatography on silica gel

using 90:10 → 80:20 hexanes/dichloromethane as the eluent.

This procedure aﬀorded 35.5 mg (67% yield) of the title

1

compound as a colorless oil. H NMR (500 MHz, CDCl₃): δ

7.72−7.66 (m, 2H), 7.51−7.45 (m, 1H), 7.44−7.38 (m, 2H),

7.21−7.16 (m, 2H), 7.15−7.11 (m, 2H), 3.24−3.13 (m, 1H),

2.99−2.78 (m, 4H), 1.37 (s, 6H). ¹³C NMR (100 MHz,

CDCl₃): δ 209.32, 142.62, 139.58, 130.65, 128.12, 127.43,

126.25, 124.33, 49.99, 46.61, 34.30, 22.93. IR (ﬁlm): 2914,

1669, 1593, 956, 740 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺

calcd for C₁₉H₂₀O 265.1587; found 265.1592.

R

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

( )-2-(2,3-Dihydro-1H-inden-2-yl)-6-methoxy-3,4-dihy-

dronaphthalen-1(2H)-one (18e). The title compound was

prepared from 2-allylphenyl triﬂate (53.3 mg, 0.2 mmol) and 6-

methoxy-1-tetralone (42.3 mg, 0.24 mmol) using General

Procedure A, except with LiHMDS (73.6 mg, 0.44 mmol) as the

base. The crude material was puriﬁed via column chromatog-

raphy on silica gel using 65:35 → 50:50 hexanes/dichloro-

methane as the eluent. This procedure aﬀorded 42.1 mg (72%

from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and

acetophenone (28 μL, 0.24 mmol) using General Procedure A,

except with LiHMDS (73.6 mg, 0.44 mmol) as the base. The

crude material was puriﬁed via column chromatography on silica

gel using 99.5:0.5 hexanes/ethyl acetate as the eluent. This

procedure aﬀorded 25.0 mg (52% yield) of the title compound

as a colorless oil. The compound was obtained as a >20:1

1

mixture of diastereomers as judged by H NMR analysis. The

1

yield) of the title compound as a colorless oil. H NMR (500

data shown are for the major isomer. H NMR (700 MHz,

MHz, CDCl₃): δ 8.04 (d, J = 8.7 Hz, 1H), 7.23−7.17 (m, 2H),

7.15−7.11 (m, 2H), 6.84 (dd, J = 8.8, 2.5 Hz, 1H), 6.71−6.67

(m, 1H), 3.85 (s, 3H), 3.18 (dd, J = 15.7, 7.9 Hz, 1H), 3.15−2.91

(m, 4H), 2.87 (dd, J = 15.7, 8.4 Hz, 1H), 2.74 (dd, J = 15.0, 8.2

Hz, 1H), 2.62 (ddd, J = 9.8, 7.4, 4.1 Hz, 1H), 2.24−2.17 (m,

1H), 2.02−1.92 (m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ

198.64, 163.38, 146.16, 143.53, 142.78, 129.87, 126.34, 126.19,

126.09, 124.28, 124.16, 113.15, 112.39, 55.41, 51.94, 38.75,

37.81, 36.74, 28.45, 26.21. IR (ﬁlm): 2963, 2832, 1660, 1601,

1251, 742 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₂₀H₂₀O₂293.1536; found 293.1541.

( )-(2S,3aR)-2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-yl)-2-

methyl-1-phenylpropan-1-one (18f). The title compound was

prepared from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2

mmol) and phenyl isopropyl ketone (36 μL, 0.24 mmol) using

General Procedure A, except with LiHMDS (73.6 mg, 0.44

mmol) as the base. The crude material was puriﬁed via column

chromatography on silica gel using 50:50 hexanes/dichloro-

methane as the eluent under high pressure. This procedure

aﬀorded 28.4 mg (53% yield) of the title compound as a

colorless oil. The compound was obtained as a >20:1 mixture of

diastereomers as judged by ¹H NMR analysis. The data shown

are for the major isomer. ¹H NMR (500 MHz, CDCl₃): δ 7.63−

7.59 (m, 2H), 7.46−7.42 (m, 1H), 7.41−7.35 (m, 2H), 5.35 (s,

1H), 2.63−2.53 (m, 1H), 2.33−2.25 (m, 1H), 2.21−2.13 (m,

1H), 2.08−1.90 (m, 4H), 1.86−1.73 (m, 2H), 1.42 (m, 1H),

1.27 (s, 3H), 1.23 (s, 3H), 1.07−0.90 (m, 2H). ¹³C NMR (126

MHz, CDCl₃): δ 209.74, 143.29, 139.83, 130.43, 128.01, 127.34,

117.60, 49.61, 44.55, 41.15, 35.16, 31.72, 28.81, 25.22, 23.03,

22.38. IR (ﬁlm): 2925, 2837, 1673, 958 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + H]⁺calcd for C₁₉H₂₄O 269.1900; found

269.1905.

( )-2-(2,3-Dihydro-1H-inden-2-yl)-3,4-dihydronaphtha-

len-1(2H)-one (18g). The title compound was prepared from 2-

allylphenyl triﬂate (53.3 mg, 0.2 mmol) and 1-tetralone (32 μL,

0.24 mmol) using General Procedure A, except with LiHMDS

(73.6 mg, 0.44 mmol) as the base. The crude material was

puriﬁed via column chromatography on silica gel using 80:20

hexanes/dichloromethane as the eluent. This procedure

aﬀorded 37.8 mg (72% yield) of the title compound as a white

solid (mp 61−63 °C). ¹H NMR (500 MHz, CDCl₃): δ 8.08 (dd,

J = 7.9, 1.4 Hz, 1H), 7.49 (td, J = 7.5, 1.5 Hz, 1H), 7.37−7.32 (m,

1H), 7.29−7.25 (m, 1H), 7.25−7.20 (m, 2H), 7.18−7.13 (m,

2H), 3.22 (dd, J = 15.7, 8.0 Hz, 1H), 3.18−2.97 (m, 4H), 2.89

(dd, J = 15.8, 8.5 Hz, 1H), 2.78 (dd, J = 15.2, 8.4 Hz, 1H), 2.69

(ddd, J = 10.1, 7.6, 4.2 Hz, 1H), 2.30−2.22 (m, 1H), 2.08−1.97

(m, 1H). ¹³C NMR (126 MHz, CDCl₃): δ 199.93, 143.76,

143.47, 142.74, 133.21, 132.72, 128.71, 127.46, 126.64, 126.26,

126.16, 124.32, 124.21, 52.32, 38.72, 37.83, 36.73, 28.12, 26.25.

IR (ﬁlm): 3009, 2877, 1671, 1597, 734 cm⁻¹. HRMS (ESI⁺

TOF) m/z: [M + Na]⁺calcd for C₁₉H₁₈O 285.1250; found

285.1255.

CDCl₃): δ 7.95 (d, J = 7.7 Hz, 2H), 7.58−7.53 (m, 1H), 7.49−

7.43 (m, 2H), 5.37 (s, 1H), 3.06−2.94 (m, 2H), 2.73−2.64 (m,

1H), 2.56−2.47 (m, 1H), 2.23 (br s, 1H), 2.16−2.09 (m, 1H),

2.06−1.94 (m, 3H), 1.93−1.86 (m, 1H), 1.82−1.74 (m, 1H),

1.49−1.40 (m, 1H), 1.05−0.96 (m, 1H), 0.84 (q, J = 11.4 Hz,

1H). ¹³C NMR (176 MHz, CDCl₃): δ 200.22, 143.91, 137.35,

133.03, 128.69, 128.22, 117.73, 45.15, 41.34, 40.73, 37.19,

33.57, 29.15, 25.39, 22.62. IR (ﬁlm): 1682, 1448 cm⁻¹. HRMS

(ES) m/z: [M]⁺calcd for C₁₇H₂₀O 240.1514; found 240.1517.

( )-(2S,3aR)-2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-yl)-

cyclohexan-1-one (18i). The title compound was prepared

from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2 mmol) and

cyclohexanone (50 μL, 0.48 mmol) using General Procedure A,

except with LiHMDS (73.6 mg, 0.44 mmol) as the base. The

crude material was puriﬁed via column chromatography on silica

gel using 80:20 hexanes/dichloromethane as the eluent. This

procedure aﬀorded 29.5 mg (68% yield) of the title compound

as a colorless oil. The compound was obtained as a 1:1 mixture

of diastereomers epimeric at the stereocenter α to the carbonyl

group, as judged by ¹H NMR analysis. The data shown are for

1

the mixture. H NMR (500 MHz, CDCl₃): δ 5.38−5.30 (m,

1H), 2.75−2.66 (m, 0.5H), 2.56−2.47 (m, 0.5H), 2.41−2.33

(m, 1H), 2.33−2.12 (m, 4H), 2.13−2.06 (m, 1H), 2.06−1.91

(m, 5H), 1.90−1.69 (m, 4H), 1.69−1.59 (m, 1H), 1.57−1.37

(m, 2H), 1.02−0.92 (m, 1H), 0.76−0.64 (m, 1H). ¹³C NMR

(100 MHz, CDCl₃): δ 213.62, 213.49, 144.03, 143.49, 117.41,

117.06, 57.36, 56.70, 42.09, 41.90, 41.47, 40.87, 39.04, 38.06,

36.80, 36.63, 36.24, 34.37, 32.21, 32.13, 28.93, 28.80, 28.32,

28.28, 25.25, 25.20, 24.56, 24.11, 22.42. IR (ﬁlm): 2920, 2853,

1709, 1447 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for

C₁₅H₂₂O 219.1743; found 219.1747.

( )-(2S,3aR)-2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-yl)-

1,2-diphenylethan-1-one (18j). The title compound was

prepared from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg, 0.2

mmol) and deoxybenzoin (47.1 mg, 0.24 mmol) using General

Procedure A, except with LiHMDS (73.6 mg, 0.44 mmol) as the

base. The crude material was puriﬁed via column chromatog-

raphy on silica gel using 99:1 hexanes/ethyl acetate as the eluent.

The material was further puriﬁed via column chromatography

on silica gel using 90:10 → 80:20 hexanes/dichloromethane as

the eluent. This procedure aﬀorded 45.4 mg (72% yield) of the

title compound as a viscous, colorless oil. The compound was

obtained as a 1:1 mixture of diastereomers epimeric at the

1

stereocenter α to the carbonyl group, as judged by H NMR

1

analysis. The data shown are for the mixture. H NMR (500

MHz, CDCl₃): δ 8.02−7.94 (m, 2H), 7.53−7.47 (m, 1H),

7.45−7.33 (m, 4H), 7.33−7.26 (m, 2H), 7.25−7.19 (m, 1H),

5.34 (s, 1H), 4.39−4.29 (m, 1H), 2.98−2.84 (m, 1H), 2.84−

2.73 (m, 0.5H), 2.30 (br s, 0.5H), 2.24−2.13 (m, 1H), 2.05−

1.73 (m, 5H), 1.66−1.55 (m, 1H), 1.50−1.38 (m, 1H), 1.04−

0.92 (m, 1H), 0.89−0.73 (m, 1H). ¹³C NMR (100 MHz,

CDCl₃): δ 200.18, 199.77, 143.95, 143.37, 138.83, 138.80,

137.24, 137.05, 132.81, 132.78, 128.76, 128.73, 128.60, 128.51,

128.49, 128.46, 128.35, 127.01, 117.58, 117.48, 60.37, 59.63,

( )-(2S,3aR)-2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-yl)-1-

phenylethan-1-one (18h). The title compound was prepared

S

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

41.36, 41.08, 41.00, 40.58, 39.80, 38.93, 36.45, 34.99, 28.97,

25.22, 22.38. IR (ﬁlm): 2914, 2847, 1678, 1596, 659 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd for C₂₃H₂₄O

317.1900; found 317.1906.

AUTHOR INFORMATION

Corresponding Author

*E-mail: jpwolfe@umich.edu.

ORCID

■

( )-(2S,3aR)-2-(2,3,3a,4,5,6-Hexahydro-1H-inden-2-yl)-

3,4-dihydronaphthalen-1(2H)-one (18k). The title compound

was prepared from 6-allylcyclohex-1-en-1-yl triﬂate (54.1 mg,

0.2 mmol) and 1-tetralone (32 μL, 0.24 mmol) using General

Procedure A, except with LiHMDS (73.6 mg, 0.44 mmol) as the

base. The crude material was puriﬁed via column chromatog-

raphy on silica gel using 80:20 hexanes/dichloromethane as the

eluent. This procedure aﬀorded 42.1 mg (79% yield) of the title

compound as a colorless oil. The compound was obtained as a

1:1 mixture of diastereomers epimeric at the stereocenter α to

John P. Wolfe: 0000-0002-7538-6273

Author Contributions

^†E.C.B., E.M.H., and D.R.W. contributed equally to this work.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

The authors thank the NIH NIGMS (GM 124030) for ﬁnancial

support of this work. E.M.H. was partially supported by a

University of Michigan Rackham Dissertation Fellowship.

1

the carbonyl group, as judged by H NMR analysis. The data

shown are for the mixture. ¹H NMR (500 MHz, CDCl₃): δ 8.0−

7.98 (m, 1H), 7.47−7.42 (m, 1H), 7.32−7.27 (m, 1H), 7.25−

7.20 (m, 1H), 5.37 (s, 1H), 3.11−3.02 (m, 1H), 3.00−2.88 (m,

1H), 2.68−2.54 (m, 1H), 2.50−2.35 (m, 2H), 2.28−2.17 (m,

2H), 2.17−2.08 (m, 1H), 2.08−1.92 (m, 5H), 1.84−1.73 (m,

1H), 1.50−1.37 (m, 1H), 1.08−0.82 (m, 2H). ¹³C NMR (126

MHz, CDCl₃): δ 200.29, 143.83, 143.71, 143.69, 143.47, 133.03,

132.99, 132.71, 132.67, 128.64, 128.61, 127.43, 127.39, 126.51,

117.61, 117.32, 52.62, 52.09, 41.43, 41.08, 38.76, 38.01, 36.25,

36.10, 35.60, 34.27, 28.90, 28.80, 27.95, 27.41, 26.31, 26.01,

25.27, 25.23, 22.44. IR (ﬁlm): 2934, 2869, 1675, 1598 cm⁻¹.

HRMS (ESI⁺TOF) m/z: [M + Na]⁺calcd for C₁₉H₂₂O

289.1563; found 289.1569.

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■

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1

by H NMR analysis. The data shown are for the mixture. H

NMR (401 MHz, CDCl₃): δ 8.06−7.99 (m, 1H), 7.48−7.41 (m,

1H), 7.33−7.26 (m, 1H), 7.23−7.18 (m, 1H), 5.35 (s, 1H),

3.12−2.98 (m, 1H), 2.97−2.87 (m, 1H), 2.56−2.36 (m, 1.5H),

2.25−2.12 (m, 2H), 2.10−2.04 (m, 1H), 2.03−1.84 (m, 5H),

1.82−1.72 (m, 1H), 1.71−1.63 (m, 0.5H), 1.49−1.33 (m, 1H),

1.13 (s, 1.5H), 1.12 (s, 1.5H), 1.08−0.94 (m, 2H). ¹³C NMR

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126.57, 117.49, 117.43, 46.25, 46.02, 41.23, 41.15, 40.74, 40.62,

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25.26, 25.22, 22.43, 22.39, 18.75. IR (ﬁlm): 2926, 2856, 1680,

1600, 1222, 747 cm⁻¹. HRMS (ESI⁺TOF) m/z: [M + H]⁺calcd

for C₂₀H₂₄O 281.1900; found 281.1902.

ASSOCIATED CONTENT

■

S

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.oprd.9b00248.

Description of stereochemical assignments and copies of

¹H and ¹³C NMR spectra for all new compounds (PDF)

T

DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

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DOI: 10.1021/acs.oprd.9b00248

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for the Synthesis of Substituted Bicyclic Cyclopentanes

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