Enantiopure 2-aryl-2-methyl cyclopentanones by an asymmetric chelation-controlled Heck reaction using aryl bromides: increased preparative scope and effect of ring size on reactivity and selectivity

Article abstract of DOI:10.1016/j.tetasy.2008.04.004

Quaternary 2-aryl-2-methyl cyclopentanones were obtained in 85-94% ee via Pd(0)-catalyzed chelation-controlled asymmetric arylation of a cyclopentenyl ether with aryl bromides and subsequent hydrolysis. Two new cyclohexenyl ethers were synthesized and evaluated as Heck substrates with both aryl iodides and bromides under different reaction conditions. Arylations of the six-membered vinyl ether 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine with aryl bromides were achieved with t-Bu₃P-promoted palladium catalysis using either classical or microwave heating. Isolated Heck products were also obtained in high diastereoselectivities (94-98% de).

Full text of DOI:10.1016/j.tetasy.2008.04.004

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1120–1126
Enantiopure 2-aryl-2-methyl cyclopentanones by an asymmetric
chelation-controlled Heck reaction using aryl bromides: increased
preparative scope and effect of ring size on reactivity and selectivity
Gopal K. Datta, Patrik Nordeman, Jakob Dackenberg, Peter Nilsson,
Anders Hallberg and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
Received 20 March 2008; accepted 7 April 2008
Abstract—Quaternary 2-aryl-2-methyl cyclopentanones were obtained in 85–94% ee via Pd(0)-catalyzed chelation-controlled asymmetric
arylation of a cyclopentenyl ether with aryl bromides and subsequent hydrolysis. Two new cyclohexenyl ethers were synthesized and eval-
uated as Heck substrates with both aryl iodides and bromides under different reaction conditions. Arylations of the six-membered vinyl
ether 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine with aryl bromides were achieved with t-Bu3P-promoted palladium cataly-
sis using either classical or microwave heating. Isolated Heck products were also obtained in high diastereoselectivities (94–98% de).
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The pioneering work by Hartwig et al. and Buchwald et al.
at the turn of the century spurred substantial research
around Pd(0)-catalyzed a-arylation of carbonyl com-
pounds.19,20 Today, this direct method ranks among one
of the most powerful methods in organic synthesis despite
the requirements for a strong base and inert reaction con-
ditions.20 In pivotal work, Buchwald et al. demonstrated
an enantioselective and direct a-arylation procedure of cyc-
lic ketones providing a chiral quaternary a-carbon center in
88–94% ee utilizing palladium(0) catalysis, an axially chiral
ligand, and NaOt-Bu as the base.20 An inconvenience with
this method was the requirement to block the non-alkyl-
ated a-carbon to avoid arylation at this position.
The palladium-catalyzed Heck reaction1–7 has become an
invaluable and unique tool for carbon–carbon bond forma-
tion8 in organic synthesis.9–11 With cyclic olefins, the ste-
reochemical outcome can be controlled by using either
chiral bidentate ligands12 or substrate-bound catalyst
directing groups.13,14 Although the enantioselective con-
struction of tetra-substituted carbon centers can be
achieved by the application of intramolecular Heck reac-
tions,15,16 the formation of quaternary carbons17 in high
stereopurity remains a challenge when using an intermolec-
ular approach.18
O
O
O
N
N
Pd(t-Bu3P)2
HCl (aq)
Ar-Br
+
Ar
Ar
1a
2a-i
3
(R)-4a-i
(85-94% ee)
Scheme 1.
*
Corresponding author. Tel.: +46 18 471 4667; fax: +46 18 471 4474; e-mail: mats@orgfarm.uu.se
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.004

G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
1121
We have previously reported the smooth generation of
quaternary aryl, methyl carbon centers at the 2-position
of cyclopentanone employing a chelation-controlled Heck
reaction21,22 with a catalyst-presenting (S)-1-methyl-2-pyr-
rolidine auxiliary.23,24 Herein, we report a highly diastereo-
selective25 Heck methodology for the construction of
quaternary carbons using a suitable palladium-catalyst,
aryl bromides, and tetra-substituted olefin 1a (Scheme 1).
Formed Heck products 3 were hydrolyzed to the corre-
sponding 2-aryl-2-methyl cyclopentanones 4 in high to
excellent enantiomeric purities. Six-membered, non-C2-
methyl substituted products 5 were also isolated in high
diastereomeric excess after the monoarylation of tri-substi-
tuted olefin 1c (Scheme 4).
without affecting the protected ketone (Scheme 2). The
reaction was repeated, and product 3c after cooling was di-
rectly hydrolyzed by the addition of 0.5 mL concd HCl to
produce 4c in 68% yield and 94% ee (Table 1, entry 3). This
successful protocol was applied with nine different aryl bro-
mides carrying both electron-withdrawing, electron-donat-
ing, and potentially palladium(II)-chelating substituents in
para-, meta-, and ortho positions. In all the cases, the ary-
lated products were hydrolyzed in situ, providing 2-aryl-2-
methyl cyclopentanones 4 in decent two-step one-pot yields
with good to excellent enantiomeric purities (85–94% ee)
(see Table 1). Electronic influences did not seem to affect
the enantioselectivity much. However, sterically congested
Table 1. Asymmetric arylation of 1a with aryl bromides and subsequent
hydrolysis
2. Results and discussion
Entry Aryl bromide
Time (h) Isolated yielda eeb (%)
2.1. Reactions with five-membered cyclic olefin 1a
1
10
10
62 (%) 4a
60 (%) 4b
92
91
2a
2b
Br
Br
N
In our previous studies, tetra-substituted vinyl ether 1a was
arylated with seven different aryl iodides and two reactive
aryl bromides employing standard Pd(OAc)2 as the precat-
alyst, furnishing 2-aryl-2-methyl cyclopentanones 4 in
moderate to good yields and with excellent enantioselectiv-
ities (90–98% ee).24 Unfortunately, the published procedure
using Pd(OAc)2 as a precatalyst was found to be limited to
activated aryl bromides. Based on the positive results using
sluggish aryl chlorides,23 and with the overall aim of devel-
oping a general aryl bromide protocol, we decided to eval-
uate the model reaction between 1a and 2c employing the
bulky 14-electron catalyst Pd(t-Bu3P)2.26 The Heck cou-
pling of olefin 1a (1.0 equiv, 0.15 mmol) with aryl bromide
2c (1.3 equiv) in the presence of LiCl (2.0 equiv), NaOAc
(1.2 equiv), K2CO3 (1.2 equiv), and 5.0 mol % of Pd(t-
Bu3P)2 in 2.2 mL of aqueous DMF (10% water) furnished
full conversion after 9 h of oil-bath heating at 100 °C
(Scheme 2). The LiCl, NaOAC, and K2CO3 combination
was crucial for obtaining full conversion22 keeping in mind
that the base effect27 in Pd-catalysis can play an important
role.
O
2
Ph
O
3
10
10
14
10
36
14
10
68 (%) 4c
64 (%) 4d
58 (%) 4e
54 (%) 4f
45 (%) 4g
60 (%) 4h
62 (%) 4i
94
93
90
89
85c
91
92
2c
Br
H
O
4
5
6
7
8
9
Br
2d
Br
2e
Br 2f
2g
Br
2h
Br
Me2N
The monoarylated Heck product 3c was obtained in excel-
Br 2i
1
lent diastereomeric purity according to H NMR and was
a The reactions were performed at 100 °C under air with 1a (0.15 mmol,
1.0 equiv) using 5.0 mol % of Pd(t-Bu3P)2. Ketones (R)-4 were obtained
after hydrolysis with concd HCl (aq). Isolated yields are the average of
three runs. Purity >95% by GC–MS.
isolated in 69% yield after silica chromatography in the
presence of Et3N. Lower catalyst loading did not produce
full conversion of the starting materials. Notably, com-
pound 3c has a free aldehyde functionality along with a
masked keto group, providing the opportunity to utilize
the reactive aldehyde group for further transformations
b Ee of (R)-4 by chiral HPLC (average of three runs).
c Additional 5.0 mol % of Pd(t-Bu3P)2 was added after 20 h.
Pd(t-Bu3P)2, LiCl
O
O
NaOAc, K2CO3
N
N
DMF-water (10:1)
p-CHO-Ph-Br
+
p-CHO-Ph
Classical heating
9 h, 100 oC
1a
2c
3c
(>91% de by 1H-NMR)
Yield = 69%
Scheme 2.

1122
G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
ortho-functionalized aryl bromide 2g furnished the lowest
enantiomeric excess. Due to the slow reaction with hin-
dered 2g, an extra portion of Pd(t-Bu3P)2 was added after
20 h to give complete conversion of 1a (Table 1, entry 7).
Furthermore, concomitant hydrolysis of 1a and dehalogen-
ation of 2g resulted in the somewhat low yield of 4g
(45%).28
O
O
N
N
Ar-Br, [Pd]
Ar
H
Condition A or B
1c
5a-e
Scheme 4.
A Heck reaction using 1c (1.0 equiv, 0.075 mmol), aryl
bromide 2j (2.0 equiv) in the presence of LiCl (2.0 equiv),
NaOAc (1.2 equiv), K2CO3 (1.2 equiv), 5.0 mol % of air-
stable Herrmann’s palladacycle, and 10.0 mol % [(t-Bu)3
PH]BF4 in 2.2 mL of aqueous DMF (10% water) under
controlled irradiation at 150 °C for 90 min (conditions A)
resulted in the full conversion of 1c. The C2-arylated vinyl
ether 5e showed excellent diastereopurity by GC–MS
(97%) and 1H NMR analysis, and was isolated in 42% yield
after silica chromatography in the presence of Et3N. In or-
der to show the preparative scope of this microwave meth-
od, conditions A were utilized with four additional aryl
bromides furnishing Heck products 5a–d with moderate
yields (34–38%) but with excellent diastereoselectivities
(94–98% de, Table 2). However, under the same conditions,
three other electron deficient aryl bromides were tried but
gave unimpressive results (4-Ac-Ph-Br, 25%; 4-CN-Ph-Br,
20%; 4-CHO-Ph-Br, 30%). Aiming to improve the yield
of the arylated product 5, we decided to investigate similar
coupling reactions with traditional heating and the more
active, but less thermostable 14-electron catalyst Pd(t-
Bu3P)2. A test reaction between 1c (1.0 equiv, 0.15 mmol)
and 2j (1.3 equiv) in the presence of LiCl (2.0 equiv), NaO-
Ac (1.2 equiv), K2CO3 (1.2 equiv), and 5.0 mol % of Pd(t-
Bu3P)2 in 2.2 mL of aqueous DMF (10% water) at
100 °C for 40 h (conditions B) resulted in a better yield of
5e (55%) and intact high diastereoselectivity. Based on this
positive outcome, all arylation reactions were performed
also under conditions B, furnishing improved yields in
two additional cases (Table 2, entries 3 and 4) although
no product formations were observed for electron deficient
aryl bromides.
2.2. Reactions with six-membered cyclic olefin 1c
In order to evaluate the general usefulness of the 1-methyl-
2-pyrrolidine moiety as a stereocontrolling arylpalladium
presenting group, we decided to synthesize 1-methyl-2-(S)-
(2-methyl-cyclohex-1-enyloxymethyl)-pyrrolidine 1b and
1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine 1c
and to investigate the appropriate Heck arylation reactions
using both aryl iodides and bromides. Vinyl ether 1b was
synthesized as described in the literature23 and 1c was syn-
thesized via a similar acid-catalyzed transacetalization–
elimination process in 68% isolated yield (Scheme 3 ).24
Unfortunately, tetra-substituted olefin 1b failed to partici-
pate in the arylations despite numerous attempts using dif-
ferent reaction conditions including both aryl bromides
and iodides as arylpalladium precursors. Hydrolysis of
1b, the release of palladium-catalyst poisoning (S)-1-
methyl-2-pyrrolidine-methanol,21,22,28 and homocoupling
of the arylating agents were the dominating processes,
quickly deteriorating the catalytic system and consuming
the starting materials. Next, tri-substituted vinyl ether 1c
was studied under similar arylation reactions using aryl
iodides as arylating agents and Pd(OAc)2 as the precatalyst
at 100 °C. Disappointingly, reactions were either slow or
non-yielding and biaryl formations were predominant.29
It has, however, been noted earlier that aryl iodides provide
low yields in the arylation of tri-substituted vinyl ethers.22
Due to the poor outcome of the reactions using aryl
iodides, we shifted our attention toward the use of aryl
bromides as substrates for the arylation of 1c.
Despite the use of an excess amount of 2 under both con-
ditions A and B, only trace amounts of diarylated product
could be detected. To some extent, the lower yields in the
arylations of tri-substituted cyclohexene vinyl ether 1c,32
compared to cyclopentene derivative 1a, can be explained
by the slow reaction kinetics, allowing concomitant hydro-
lysis of 1c to rival. The low reaction rates might be due to
the conformational flexibility of the six-membered ring and
the lack of ring strain release upon insertion. The results
High-density microwave processing of sealed reaction mix-
tures has the potential to speed-up chemistry development
by increasing reaction rates and providing high reaction
control.30,31 Hence, we decided to use this heating method
under inert conditions to quickly identify productive reac-
tion conditions by employing aryl bromides. In order to
improve the thermostability of the catalytic system, micro-
wave-stable Herrmann’s catalyst was used in combination
with the preligand [(t-Bu)3PH]BF4.
O
O
O
N
N
1) PTSA, HC(OMe)3
2)
H
H
OH
, HCl (g)
N
1b
1c (68%)
3) distillation
Scheme 3.

G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
Table 2. Diastereoselective arylation of 1c with aryl bromides
1123
23
,c
Entry
Aryl bromide
Condition
Time
Isolated yielda (%)
deb (%)
½aꢀD
Br
1
A
B
90 min
40 h
38
35
95
98
ꢁ31
2e
5a
2
3
4
5
A
B
90 min
40 h
38
36
98
98
ꢁ52
ꢁ54
ꢁ40
ꢁ50
Br 2f
5b
5c
5d
5e
A
B
90 min
52 h
34
46
94
98
2g
Br
A
B
90 min
40 h
37
40
96
94
2h
Br
A
B
90 min
40 h
42
55
97
98
Br 2j
a Condition A: the reactions were performed at 150 °C under microwave heating with 1c (0.075 mmol, 1.0 equiv) using 5.0 mol % of Herrmann’s
palladacycle and 10.0 mol % of [(t-Bu)3PH]BF4. Condition B: the reactions were performed at 100 °C using classical heating with 1c (0.15 mmol,
1.0 equiv) using 5.0 mol % Pd(t-Bu3P)2. Isolated yields are average of three runs. Purity >95% by GC–MS.
b De of (ꢁ) isomer of 5 by GC–MS (average of three runs) and 1H NMR.
c Specific rotation values are an average of three measurements.
are in agreement with the reported sluggish arylation of
account for the failure to arylate methyl substituted cyclo-
hexenyl ether 1b.
3,4-dihydro-2H-pyran using chiral P,N-ligands.33
The introduction of a metal-directing auxiliary22,25,34–36 to
afford both high stereocontrol24,25,37 and effective reactivity
enhancement in Heck couplings was justified by the reac-
tion outcome. In short, the coordination between the
amine and the palladium(II) center leads to the formation
of the arylated six-membered r-complex intermediate
(Scheme 5).35,38 With olefin 1a, the insertion preferentially
occurs from the Si-face due to the control of the chirally
defined (S)-pyrrolidine ring, providing the (R)-3 Heck
products. The recently published DFT calculations39 for
the arylation of 1a and measured specific rotation values24
strongly support this conclusion. The absolute configura-
tion of the aryl substituted carbon in six-membered vinyl
ethers 5 was assigned as (R) based on X-ray crystallogra-
phy analysis of the methyl ammonium salt of the five-mem-
bered analogue.40 Microwave irradiation probably
accelerates the arylation of 1c due to the higher reaction
temperature. Nevertheless, the high diastereopurities of
products 5a–e, which were obtained at 150 °C under micro-
wave heating, are impressive.41–43 Additional unfavorable
steric requirements for arylpalladium insertion probably
3. Conclusion
In conclusion, we have identified efficient reaction condi-
tions for diastereoselective Heck arylations of five- and
six-membered cyclic vinyl ethers with aryl bromides using
a chiral palladium(II)-presenting (S)-1-methyl-2-pyrroli-
dine auxiliary to control the stereochemistry. Arylated
products from the tetra-substituted cyclopentene vinyl
ether 1a were hydrolyzed to the corresponding 2-aryl-2-
methyl cyclopentanones, which were obtained in excellent
enantiomeric excess (85–94% ee). Despite slow reaction
rates and relatively low yields, arylation reactions
with the tri-substituted cyclohexene vinyl ether 1c were
highly diastereoselective (de >98%). Microwave-heating at
150 °C accelerated the arylations38,44 of the six-membered
vinyl ether, and the reaction times were reduced from 52
to 40 h to 90 min. We believe that the synthesis of 2-aryl-
2-methyl cyclopentanones from aryl bromides in 85–94%
ee using K2CO3 as a weak base may provide an attractive
alternative to direct a-arylation in the presence of strong
H
H
N
N
Br
Br
O
O
1a,c
2a-j
3 or 5
Pd
+
Pd
R
L
Ar
Ar
R
n
n
n = 1, 2
n = 1, 2
π−complex
R = Me, H
σ−complex
Scheme 5.

1124
G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
base.19,20,45 Continued studies to extend the chelation-con-
trolled methodology to include also open chain analogues
are currently ongoing in the laboratory.
tral data and optical rotations were in agreement with the
literature values.23,24
4.3. Synthesis of 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-
pyrrolidine 1c
4. Experimental
4.1. General
Cyclohexanone (152.8 mmol, 14.9 g) and trimethylortho-
formate (168.1 mmol, 17.8 g) were stirred with 4-toluene-
sulfonic acid monohydrate (0.764 mmol, 0.145 g) at 0 °C
for 40 min. The reaction mixture was allowed to warm to
room temperature and after another 40 min a distillation
was performed to remove methyl formate at 45 °C. (S)-
(ꢁ)-1-Methyl-2-pyrrolidine-methanol (50.9 mmol, 5.87 g)
was dissolved in 15 mL toluene and precipitated with
HCl (g). The slurry was transferred to the distillation resi-
due and heated at 100 °C for 26 h. The oil-bath tempera-
ture was raised to 130 °C to facilitate a slow distillation.
Toluene (15 mL), forming an azeotrope with methanol,
was added once a day during 4 days. The distillation was
stopped when GC–MS analysis of the residue showed com-
plete consumption of the amino alcohol. The addition of
sodium hydroxide (10 M, aq, 50 mL) and subsequent
extraction with diethyl ether provided a red brown crude
product after drying over K2CO3 and concentration. Puri-
fication on a silica column using 95:5 hexane/triethylamine
provided 1c in 68% isolated yield as a pale yellow colored
oil. 1H NMR (400 MHz, CDCl3, Me4Si) d 4.60 (t,
J = 3.6 Hz, 1H), 3.65 (dd, J = 5.3, 9.5 Hz, 1H), 3.53 (dd,
J = 5.9, 9.2 Hz, 1H), 3.08–3.04 (m, 1H), 2.52–2.45 (m,
1H), 2.41 (s, 3H), 2.26–2.19 (m, 1H), 2.07–2.01 (m, 4H),
1.98–1.90 (m, 1H), 1.78–1.54 (m, 7H); 13C NMR
(100 MHz, CDCl3, Me4Si) d 154.8, 93.7, 69.4, 64.4, 57.8,
41.7, 28.9, 27.8, 23.6, 23.0, 22.9, 22.8; GC–MS (70 eV)
m/z (relative intensity) 195 (M+, 1), 98 (5), 84 (100).
Elemental Anal. Calcd: C, 73.80; H, 10.84. Found: C,
74.10; H, 10.80.
All traditionally heated syntheses were performed at 100 °C
using a preheated metal block equipped with magnetic stir-
ring under an air atmosphere in vials fitted with Teflon-
lined screw caps. Microwave-assisted syntheses were
carried out at 150 °C in a Smith/EmrysTM Synthesizer sin-
gle-mode microwave cavity producing controlled irradia-
tion at 2450 MHz. The temperature of the reaction
mixture was measured by an on-line built-in IR sensor.
GC–MS analyses were performed with a CP-SIL 8 CB
Low Bleed (30 m ꢂ 0.25 mm) or a CP-SIL 5 CB Low Bleed
(30 m ꢂ 0.25 mm) capillary column using a 40–300 °C tem-
perature gradient and EI ionization. RP-LC–MS analyses
were performed using a Chromolith SpeedROD RP-18e
column (50 ꢂ 4.6 mm) and a quadrupole mass spectrome-
ter using a 4 mL/min CH3CN/H2O gradient (0.05%
HCOOH) and detection by UV (DAD) and MS (ESI+).
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively, using CDCl3 as a solvent. Chemical
shifts for 1H and 13C are referenced to TMS via the solvent
signals (1H, CHCl3 at 7.26 ppm; 13C, CDCl3 at 77.0 ppm).
HRMS experiments were performed for new compounds
on a 7-T hybrid linear ion trap (LTQ) FT mass spectrom-
eter modified with a nanoelectrospray ion source. Silica Gel
60 (0.040–0.063 mm, E. Merck, No. 9385) was used for col-
umn chromatography and Silica Gel 60 PF254 containing
gypsum (0.045 mm) was used for radial thin-layer chroma-
tography. Enantiomerical purities were analyzed by chiral
HPLC (Chiracel OD-H; 0.46 ꢂ 25 cm, PS = 5 lm or Rep-
rosil Chiral-NR/Reprosil Chiral NR-R; 4.6 ꢂ 250 mm,
PS = 8 lm, with degassed isohexane/2-propanol, flow rate
0.5 or 1.0 mL/min and detection at 220 nm). The chiral
HPLC column (Chiracel OD-H) was protected by a guard
column (Chiralcel OD 0.46 ꢂ 5 cm, PS = 10 lm). Optical
rotations were measured in CHCl3 (c 1, T = 23 °C). All
the isolated compounds were >95% pure as deduced by
GC–MS and all isolated yields were calculated as an aver-
age of three separate reactions.
4.4. Synthesis of {4-[1-(R)-methyl-2-(1-methyl-pyrrolidin-2-
(S)-ylmethoxy)-cyclopent-2-enyl]-formyl}-benzene 3c
The reactants were added to a reaction vial in the
following order: 2c (0.19 mmol, 0.024 g), enol ether 1a
(0.15 mmol, 0.029 g), Pd(t-Bu3P)2 (5.0 mol %, 0.004 g),
NaOAc (0.18 mmol, 0.015 g), LiCl (0.30 mmol, 0.013 g),
K2CO3 (0.18 mmol, 0.025 g), DMF (2 mL), and water
(0.2 mL). The tube was closed, and the contents were mag-
netically stirred and heated at 100 °C for 9 h in a preheated
metal block under an air atmosphere. The reaction was
interrupted when GC–MS analysis showed complete con-
version. After cooling, the reaction mixture was diluted
with diethyl ether and was washed five times with NaOH
(0.1 M, aq). The combined aqueous phases were addition-
ally extracted twice with diethyl ether. The ether phases
were combined and dried with K2CO3 (s). Concentration
and silica column chromatography (hexane/diethyl ether/
triethylamine, 1:1:0.05) yielded pure product 3c (69%) with
4.2. Materials
Bis(tri-t-butylphosphine)palladium(0), Pd(OAc)2, and tri-t-
butylphosphonium tetrafluoroborate were obtained from
Strem Chemicals. 2-Methylcyclopentanone, 2-methylcyclo-
hexanone, cyclohexanone, trimethyl orthoformate, (S)-(ꢁ)-
1-methyl-2-pyrrolidine-methanol, aryl iodides and all aryl
bromides were commercially available and used as ob-
tained. All other reagents obtained from commercial
sources were also used as received. Compounds 1c, 3c,
and 5a–e have not been reported and they were character-
ized according to the guideline. Vinyl ethers 3c and 5a–e
gradually decomposed in air, prohibiting elemental analy-
sis. Compounds 1a,b, 4a–i are known compounds.24 Spec-
1
de >91%. H NMR (400 MHz, CDCl3, Me4Si) d 9.97 (s,
1H), 7.82–7.77 (m, 2H), 7.50–7.46 (m, 2H), 4.65 (t,
J = 2.5 Hz, 1H), 3.82 (dd, J = 6.1, 9.5 Hz, 1H), 3.63 (dd,
J = 6.0, 9.5 Hz, 1H), 3.05–2.98 (m, 1H), 2.54–2.44 (m,
1H), 2.4 (s, 3H), 2.31–2.17 (m, 3H), 2.15–1.99 (m, 2H),
1.93–1.80 (m, 1H), 1.80–1.60 (m, 2H), 1.56–1.41 (m, 4H);

G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
1125
13C NMR (100 MHz, CDCl3, Me4Si) d 192.1, 162.8, 155.4,
134.2, 129.6, 126.8, 95.0, 73.3, 63.8, 57.7, 51.3, 41.7, 40.9,
29.0, 25.8, 25.0, 22.9; GC–MS (70 eV) m/z (relative inten-
sity) 299 (M+, 2), 98 (8), 84 (100). High resolution MS cal-
culated for C19H25NO2: [M+H]+ 300.1964, found 300.1957.
aqueous phases were additionally extracted twice with
CH2Cl2. The organic phases were combined and dried with
K2CO3(s). Concentration and purification of the crude
product using radial thin-layer chromatography (hexane/
diethyl ether/triethylamine, 86:10:4) furnished pure prod-
ucts 5. All the isolated products were >95% pure according
GC–MS.
4.5. General procedure for the Heck arylation of 1a with aryl
bromides under classical conditions with subsequent hydro-
lysis producing 4
4.6.3.
[2-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-
cyclohex-2-enyl]-naphthalene 5a. (Conditions A: 38%
yield and 98% de, conditions B: 35% yield and 95% de).
The reactants were added to a reaction vial in the following
order: aryl bromide
2 (0.19 mmol), enol ether 1a
1H NMR (400 MHz, CDCl3, Me4Si) d 1.34–1.69 (m, 4H),
1.70–1.85 (m, 3H), 2.03–2.12 (m, 1H), 2.15–2.30 (m, 3H),
2.32 (s, 3H), 2.38–2.52 (m, 1H), 2.80–3.04 (m, 1H), 3.51–
3.56 (m, 1H), 3.62–3.67 (m, 1H), 3.79–3.85 (m, 1H), 4.96
(t, J = 4.0 Hz, 1H), 7.33–7.36 (m, 1H), 7.39–7.46 (m, 2H),
7.75–7.81 (m, 4H); 13C NMR (100 MHz, CDCl3, Me4Si) d
19.6, 23.0, 24.1, 29.2, 32.9, 40.7, 44.5, 57.6, 64.4, 70.0,
97.1, 125.1, 125.7, 126.5, 126.9, 127.47, 127.55, 127.59,
132.1, 133.4, 142.0, 154.7; GC–MS (70 eV) m/z (relative
intensity) 321 (M+, 12), 141 (13), 115 (5), 98 (14), 84 (100);
(0.15 mmol, 0.029 g), Pd(t-Bu3P)2 (5.0 mol %, 0.004 g),
NaOAc (0.18 mmol, 0.015 g), LiCl (0.30 mmol, 0.013 g),
K2CO3 (0.18 mmol, 0.025 g), DMF (2 mL), and water
(0.2 mL). The tube was closed, and the contents were mag-
netically stirred and heated at 100 °C for 10–36 h in a pre-
heated metal block under an air atmosphere. The reaction
was interrupted when GC–MS analysis showed complete
conversion of 1a. After cooling, 0.5 mL HCl (aq, satd)
was added, and the mixture was stirred for 30 min. After
complete hydrolysis of 3 according to GC–MS analysis,
the reaction mixture was diluted with 10 mL 0.5 M HCl
and extracted five times with diethyl ether. The ether
phases were washed twice with NaOH (0.1 M, aq) and
dried with K2CO3(s). Concentration and silica column
chromatography afforded pure products 4.
High resolution MS calculated for C22H27NO: [M+H]+
23
322.2171, found 322.2166. ½aꢀD ¼ ꢁ31 (c 1, CHCl3).
4.6.4. [(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-cyclo-
hex-2-enyl]-benzene 5b. (Conditions A: 38% yield and
98% de, conditions B: 36% yield and 98% de).
4.6. General procedure for Heck arylation of 1c with aryl
bromides under conditions A and B producing 5
1H NMR (400 MHz, CDCl3, Me4Si) d 1.35–1.39 (m, 3H),
1.60–1.84 (m, 4H), 1.96–2.07 (m, 1H), 2.10–2.30 (m, 3H),
2.33 (s, 3H), 2.42–2.53 (m, 1H), 2.85–3.11 (m, 1H), 3.44–
3.53 (m, 1H), 3.53–3.70 (m, 1H), 3.75–3.83 (m, 1H), 4.90
(t, J = 4.2 Hz, 1H), 7.17–7.20 (m, 2H), 7.24–7.34 (m, 3H);
13C NMR (100 MHz, CDCl3, Me4Si) d 19.4, 22.9, 23.8,
29.0, 32.7, 41.5, 44.1, 57.4, 64.1, 69.8, 96.8, 125.8, 127.9,
128.1, 144.5, 154.8; GC–MS (70 eV) m/z (relative intensity)
271 (M+, 8), 115 (9), 98 (12), 84 (100); High resolution MS
4.6.1. Conditions A. A thick wall glass vial (0.5–2.0 mL)
with a Teflon coated stirring bar was charged with aryl bro-
mide 2 (0.15 mmol), vinyl ether 1c (0.075 mmol, 0.015 g),
Herrmann’s palladacycle (5.0 mol %, 0.002 g), [(t-
Bu)3PH]BF4 (10.0 mol %, 0.004 g), NaOAc (0.09 mmol,
0.0075 g), K2CO3 (0.09 mmol, 0.0125 g), and LiCl
(0.15 mmol, 0.0065 g). DMF/H2O (2 mL/0.2 mL) was
thereafter added followed by sealing the vial under nitro-
gen. The vial was heated to 150 °C under microwave irra-
diation for 90 min. After cooling, the reaction mixture
was diluted with CH2Cl2 and was washed five times with
NaOH (0.1 M, aq). The combined aqueous phases were
additionally extracted twice with CH2Cl2. The organic
phases were combined and dried with K2CO3(s). Concen-
tration and purification of the crude product using radial
thin-layer chromatography (hexane/diethyl ether/triethyl-
amine, 86:10:4) yielded pure products 5. All the isolated
products were >95% pure according to GC–MS.
calculated for C18H25NO: [M+H]+ 272.2014, found
23
272.2008. ½aꢀD ¼ ꢁ52 (c 1, CHCl3).
4.6.5. {2-[1-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-
cyclohex-2-enyl]-methyl}-benzene 5c. (Conditions A: 34%
yield and 94% de, conditions B: 46% yield and 98% de).
1H NMR (400 MHz, CDCl3, Me4Si) d 1.32–1.40 (m, 1H),
1.43–1.58 (m, 2H), 1.60–1.80 (m, 4H), 1.93–2.01 (m, 1H),
2.07–2.26 (m, 3H), 2.31 (s, 3H), 2.34 (s, 3H), 2.36–2.45
(m, 1H), 2.90–3.01 (m, 1H), 3.41–3.47 (m, 1H), 3.66–3.70
(m, 1H), 3.72–3.77 (m, 1H), 4.92 (t, J = 4.1 Hz, 1H),
7.05-7.15 (m, 4H). 13C NMR (100 MHz, CDCl3, Me4Si)
d 19.2, 19.4, 22.9, 23.9, 29.0, 30.5, 40.4, 41.4, 57.5, 64.0,
70.0, 96.9, 125.3, 125.7, 127.9, 130.1, 135.7, 142.2, 155.1;
GC–MS (70 eV) m/z (relative intensity) 285 (M+, 7), 115
(9), 98 (20), 84 (100). High resolution MS calculated for
4.6.2. Conditions B. The reactants were added to a reac-
tion vial in the following order: aryl bromide
2
(0.19 mmol), vinyl ether 1c (0.15 mmol, 0.029 g), Pd(t-
Bu3P)2 (5.0 mol %, 0.004 g), NaOAc (0.18 mmol, 0.015 g),
LiCl (0.30 mmol, 0.013 g), K2CO3 (0.18 mmol, 0.025 g),
DMF (2 mL), and water (0.2 mL). The tube was closed
and the contents were magnetically stirred and heated at
100 °C for 40–52 h in a preheated metal block under an
air atmosphere. The reaction was interrupted when GC–
MS analysis showed complete conversion of 1c. After cool-
ing, the reaction mixture was diluted with CH2Cl2 and then
washed five times with NaOH (0.1 M, aq). The combined
C19H27NO: [M+H]+ 286.2171, found 286.2177.
23
½aꢀD ¼ ꢁ54 (c 1, CHCl3).
4.6.6. {4-[1-(R)-2-(1-Methyl-pyrrolidine-2-(S)-ylmethoxy)-
cyclohex-2-enyl]-methyl}-benzene 5d. (Conditions A: 37%
yield and 96% de, conditions B: 40% yield and 94% de).

1126
G. K. Datta et al. / Tetrahedron: Asymmetry 19 (2008) 1120–1126
1H NMR (400 MHz, CDCl3, Me4Si) d 1.39–1.59 (m, 3H),
1.66–1.90 (m, 4H), 1.95–2.04 (m, 1H), 2.09–2.25 (m, 3H),
2.30 (s, 3H), 2.34 (s, 3H), 2.37–2.44 (m, 1H), 2.92–2.97
(m, 1H), 3.41–3.45 (m, 1H), 3.58–3.69 (m, 1H), 3.70–3.76
(m, 1H), 4.92 (t, J = 3.9 Hz, 1H), 7.04–7.15 (m, 4H); 13C
NMR (100 MHz, CDCl3, Me4Si) d 19.1, 21.0, 22.9, 23.9,
29.2, 32.8, 41.7, 43.5, 57.6, 64.0, 70.3, 95.7, 127.9, 128.6,
135.1, 141.5, 155.0; GC–MS (70 eV) m/z (relative intensity)
285 (M+, 8), 115 (5), 98 (12), 84 (100). High resolution MS
12. Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal.
2004, 346, 1533–1552.
13. Oestreich, M. Eur. J. Org. Chem. 2005, 783–792.
14. Oestreich, M. Top. Organomet. Chem. 2007, 24, 169–192.
15. de Meijere, A.; Bra¨se, S. J. Organomet. Chem. 1999, 576, 88–
110.
16. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–
2963.
17. Svennebring, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007,
72, 5851–5854.
calculated for C19H27NO: [M+H]+ 286.2171, found
18. Fuji, K. Chem. Rev. 1993, 93, 2037–2066.
19. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–
245.
23
286.2176. ½aꢀD ¼ ꢁ40 (c 1, CHCl3).
20. Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1261–1268.
21. Stadler, A.; von Schenck, H.; Vallin, K. S. A.; Larhed, M.;
Hallberg, A. Adv. Synth. Catal. 2004, 346, 1773–1781.
22. Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc.
2001, 123, 8217–8225.
23. Datta, G. K.; Larhed, M. Org. Biomol. Chem. 2008, 6, 674–
676.
24. Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc.
2003, 125, 3430–3431.
25. Buezo, N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc.
1998, 120, 7129–7130.
26. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176–4211.
27. Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.;
Skrydstrup, T. Angew. Chem., Int. Ed. 2006, 45, 3349–3353.
28. Larhed, M.; Andersson, C. M.; Hallberg, A. Tetrahedron
1994, 50, 285–304.
29. (Ph-I, 72 h, 30% 5b; 4-Tol-I, 90 h, 20% 5d and no product
with 4-CHO-Ph-I).
4.6.7. {3-[1-(R)-2-(1-methyl-pyrrolidine-2-(S)-ylmethoxy)-
cyclohex-2-enyl]-methyl}-benzene 5e. (Conditions A: 42%
yield and 97% de, conditions B: 55% yield and 98% de).
1H NMR (400 MHz, CDCl3, Me4Si) d 1.37–1.45 (m, 1H),
1.46–1.59 (m, 2H), 1.61–1.84 (m, 4H), 1.95–2.05 (m, 1H),
2.11–2.29 (m, 3H), 2.32 (s, 3H), 2.33 (s, 3H), 2.41–2.51
(m, 1H), 2.91–3.03 (m, 1H) 3.41–3.52 (m, 2H), 3.75–3.81
(m, 1H), 4.89 (t, J = 4.0 Hz, 1H), 6.96–7.00 (m, 3H),
7.13–7.17 (m, 1H); 13C NMR (100 MHz, CDCl3, Me4Si)
d 19.4, 21.5, 22.9, 23.9, 29.0, 32.8, 41.5, 44.0, 57.5, 64.1,
69.8, 96.8, 125.2, 126.5, 127.8, 129.0, 137.3, 144.4, 154.9;
GC–MS (70 eV) m/z (relative intensity) 285 (M+, 9), 115
(7), 98 (17), 84 (100); High resolution MS calculated for
C19H27NO:
[M+H]+ 286.2171, found 286.2172.
½aꢀD ¼ ꢁ50 (c 1, CHCl3).
23
30. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
31. Nilsson, P.; Olofsson, K.; Larhed, M. Top. Curr. Chem. 2006,
266, 103–144.
Acknowledgments
32. Acidic hydrolysis of 5 smoothly produced the 2-aryl-cyclo-
hexanone product but with competing racemization at the
C2-position.
33. Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.; Pfaltz,
A. J. Organomet. Chem. 1999, 576, 16–22.
34. Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.;
Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577–11585.
35. Andersson, C. M.; Larsson, J.; Hallberg, A. J. Org. Chem.
1990, 55, 5757–5761.
We gratefully acknowledge the financial support from the
Swedish Research Council and Knut and Alice Wallen-
berg’s Foundation. We also thank Dr. Kristofer Olofsson
for linguistic advice and Sandra Funning and Ashkan Far-
dost for technical support.
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