High stereoselectivity in chelation-controlled intermolecular Heck reactions with aryl chlorides, vinyl chlorides and vinyl triflates

Article abstract of DOI:10.1039/b719131f

Highly stereoselective chelation-controlled Pd(0)-catalyzed β-arylations and β-vinylations of a five-membered chiral, pyrrolidine-based vinyl ether were achieved using aryl- and vinyl chlorides as substrates, yielding quaternary 2-aryl/vinyl-2-methyl cyclopentanones in 89-96% ee under neutral reaction conditions. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b719131f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
High stereoselectivity in chelation-controlled intermolecular Heck reactions
with aryl chlorides, vinyl chlorides and vinyl triflates†
Gopal K. Datta and Mats Larhed*
Received 11th December 2007, Accepted 14th December 2007
First published as an Advance Article on the web 8th January 2008
DOI: 10.1039/b719131f
Highly stereoselective chelation-controlled Pd(0)-catalyzed
b-arylations and b-vinylations of a five-membered chiral,
pyrrolidine-based vinyl ether were achieved using aryl- and
vinyl chlorides as substrates, yielding quaternary 2-aryl/vinyl-
2-methyl cyclopentanones in 89–96% ee under neutral reac-
tion conditions.
The Heck vinylic substitution reaction is a mild palladium-
catalyzed reaction which has found a wide range of applications
in organic synthesis.1,2 As a unique carbon–carbon bond forming
process,3 this arylation/vinylation of an olefin holds even greater
Scheme 1
synthetic potential provided that the stereochemical outcome can
be fully dictated. With cyclic olefins, control of the stereochemistry
can be achieved either by employing a homogeneous catalytic
system with chiral bidentate ligands4 or, alternatively, by relying
on substrate-bound, removable, catalyst directing groups.5 On the
other side, the use of rarely commercially available organic triflates
or expensive iodides has proven essential, limiting the applicability
of this methodology. Less reactive aryl- and vinyl chlorides are,
however, both more easily accessible and less expensive alternative
organopalladium precursors. In the case of achiral Heck reactions,
noteworthy advances with aryl chlorides have been described by
the groups of Milstein6, Fu7 and Beller8, among others.9 To the
best of our knowledge, neither intra- nor intermolecular Heck
reactions with high chiral control have been reported utilizing
organic chlorides as substrates. In this paper we establish that
in the presence of highly active Pd(t-Bu3P)2 catalyst9 and using
standard neutral reaction conditions,2 the Heck reaction with
tetrasubstituted vinyl ether 1a and organic chlorides 2a–k can
indeed be achieved in excellent diastereoselectivities, furnishing
the 2,2-difunctionalized cyclopentanone products 4a–k in 89–96%
ee after hydrolysis (Scheme 1).
The use of alkenes carrying a metal-coordinating amino group
has been reported by several groups, including ours, as a fruitful
strategy to overcome the reluctance of substituted alkenes to par-
ticipate in intermolecular Heck reactions and to control the stere-
oselectivity of the process.5,10,11 Vinyl ethers 1a,b were prepared
as previously described12 and vinyl ethers 1c,d were synthesized
via a similar acid-catalyzed transacetalization–elimination process
(Scheme 2). Despite extensive chromatography, 1c was obtained
in only 90% purity (1c : 1d = 90 : 10). In order to evaluate aryl
chlorides as coupling partners in asymmetric transformations, we
decided to investigate 1a–d as olefins equipped with a strongly
Scheme 2
Pd(II)-coordinating (S)-N-methylpyrrolidine catalyst directing
group13 suitable for selective arylations at elevated temperatures. In
an earlier report, vinyl ether 1a was arylated with 7 different aryl
iodides and 2 different aryl bromides, yielding 2-aryl-2-methyl-
cyclopentanones 4 in 45–78% yields and 90–98% ee.12
A first coupling of 1a (1.0 equiv) with aryl chloride 2b (1.3 equiv)
using standard neutral reaction conditions 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), gave
full conversion after 18 h of oil-bath heating at 100 ◦C. The
formed b-arylated Heck product 3b was isolated in 51% yield after
careful flash chromatography in the presence of Et3N, showing
1
an excellent diastereomeric purity by H NMR (Scheme 3). The
synthesis of 3b was repeated and after complete conversion of 1a
based on GC-MS, a convenient acidic hydrolysis directly provided
the enantiomerically enriched 2-methyl-2-tolyl cyclopentanone 4b
in 57% yield and 91% ee as determined by chiral HPLC. Lower
catalyst loadings of 1.5 mol% and 3.0 mol% in the model reaction
between 1a and 2b resulted in incomplete conversion of starting
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry,
BMC, Uppsala, Box 574, SE-751 23, Sweden. E-mail: mats@orgfarm.uu.se;
Fax: +46 18 4714474; Tel: +46 18 4714667
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b719131f
Scheme 3
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Table 1 Stereoselective arylation of 1a with aryl chlorides and subsequent
hydrolysis
Table 2 Microwave-accelerated arylation of 1a with aryl chlorides and
subsequent hydrolysis
Entry Aryl chloride
1
Time
2a 9 h
Isolated yielda eeb
[a]2D3
Entry
1
Aryl chloride
Time
1.5 h
Isolated yielda
eeb
68 (%) 4a
94 (%) +39◦
2b
2d
2f
50 (%) 4b
84 (%)
2
3
4
1 h
1 h
1 h
54 (%) 4d
62 (%) 4f
63 (%) 4g
88 (%)
85 (%)
89 (%)
2
3
2b 18 h
2c 20 h
57 (%) 4b
55 (%) 4c
91 (%) +86◦
90 (%) +58◦
2g
4
5
2d 11 h
60 (%) 4d
59 (%) 4e
94 (%) +52◦
91 (%) +79◦
a The reactions were performed at 140 ◦C under air with 1a (0.15 mmol) as
the yield determining substrate using standard neutral conditions. Ketones
were obtained after hydrolysis with concentrated HCl (aq). Isolated yields
are average of three runs. Purity >95% by GC-MS. b Ee of (+) isomer of 4
by chiral HPLC (average of three runs).
2e
2f
12 h
8 h
6
7
8
9
69 (%) 4f
67 (%) 4g
60 (%) 4h
65 (%) 4i
93 (%) +12◦
92 (%) +12◦
96 (%) +46◦
92 (%) +44◦
2g 8 h
2h 8 h
Table 3 Stereoselective vinylation of 1a with vinyl chlorides/triflates and
subsequent hydrolysis
Entry Vinyl-Cl/OTf
1
Time Isolated yielda eeb
[a]2D3
2i
8 h
2j
2k 18 h
2l 22 h
2m 24 h
15 h
60 (%) 4j
61 (%) 4k
58 (%) 4j
59 (%) 4k
90 (%) +11◦
90 (%) +15◦
89 (%) +10◦
90 (%) +15◦
a The reactions were performed at 100 ◦C under air with 1a (0.15 mmol) as
the yield determining substrate using standard neutral conditions. Ketones
were obtained after hydrolysis with concentrated HCl (aq). Isolated yields
are average of three runs. Purity >95% by GC-MS. b Ee of (+) isomer of 4
by chiral HPLC (average of three runs).
2
3
4
materials. To demonstrate the scope and applicability of this two-
step, one-pot methodology, eight additional reactions were carried
out with 1a. Decent yields and excellent enantiomeric purities (90–
96% ee) were obtained for (+)-(R)-4a–i, including electron-rich,
electron-poor, and ortho-functionalized aryl chlorides after 8–20 h
of oil-bath heating (Table 1, entries 1–9). Competing hydrolysis
of 1a explains the somewhat moderate yields of 4a–i. A test
arylation of 1b provided only a small amount of epimeric product.
Unfortunately, both olefins 1c and 1d failed to participate in useful
arylation reactions under the same standard neutral conditions for
24 h at 100 ◦C and 120 ◦C.
In order to accelerate the reaction rate, selected experiments
were also carried out in sealed vessels under controlled microwave
irradiation using the identical neutral reaction conditions as in
the classical protocol but at higher temperature (Table 2).14 Full
conversion of 1a and similar yields as with classic heating could
be obtained with the investigated ◦four aryl chlorides after only
1–1.5 h of irradiation time at 140 C. Disappointingly, with this
high temperature methodology the enantioselectivities of isolated
quaternary ketones 4b,d,f,g were reduced to 84–89%.
a The reactions were performed at 100 ◦C under air with 1a (0.15 mmol) as
the yield determining substrate using standard neutral conditions. Ketones
were obtained after hydrolysis with concentrated HCl (aq). Isolated yields
are average of three runs. Purity >95% by GC-MS. b Ee of (+) isomer of 4
by chiral HPLC (average of three runs).
2j,k employing identical standard neutral reaction conditions as
in Table 1. As evident from Table 3, comparable yields (58–
61%) and very high enantioselectivities (89–90% ee) of isolated
2-methyl-2-vinyl ketones 4j,k were, regardless of the choice of
leaving group, realized after HCl-mediated hydrolysis. Analogous
vinylation reactions with cyclohexene derivatives 1c–d did not lead
to any product.
After the successful use of vinyl triflates in stereoselective
vinylations of 1a, we decided to investigate readily available aryl
triflates under identical standard neutral reaction conditions.
However, no arylation of 1a was observed using 4-CN-phenyl
(2n), phenyl, 1-naphthyl and 4-tolyl triflates. To understand the
reactivity pattern of aryl triflates with 1a, we further investigated
cationic reaction conditions16 employing 2n as the arylating agent
in the absence of a halide additive (Scheme 4). Interestingly,
arylation of 1a (1.0 equiv) with aryl triflate 2n (2.0 equiv) using
cationic reaction conditions in the presence of Et3N (4.0 equiv),
6.0 mol% of Pd(OAc)2 and 12.0 mol% of PPh3 in 2.0 mL of DMF
was productive. The arylation of 1a was monitored by GC-MS
analysis and after complete consumption of 1a the Heck product
Pioneering research by the Overman15 and Shibasaki4 groups
has proven that vinyl triflates can be useful in intramolecular asym-
metric Heck reactions to produce tetra-substituted carbon-centers.
Thus to further explore the reactivity scope of 1a, we decided to
study two vinyl chlorides (2j,k) and two vinyl triflates (2l,m) as
cyclic and acyclic coupling partners (Table 3). Surprisingly, vinyl
triflates 2l,m were more sluggish than the corresponding chlorides
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the reaction times were reduced from many hours down to 1–
1.5 hour. The scope of the protocol was further increased to
include vinyl triflates under neutral reaction conditions and one
aryl triflate carrying a strongly electron-withdrawing para-cyano
substituent under cationic conditions. We believe that this method
should provide an attractive complement to direct Pd(0)-catalyzed
a-arylation protocols,20–22 particularly when the use of organic
chlorides and mild reaction conditions are of importance.
We thank the Swedish Research Council, Knut and Alice
Wallenberg’s Foundation, Prof. Anders Hallberg, Dr Gunnar
Lindberg, Dr Alexander Stadler, Dr Peter Nilsson and Dr
Kristofer Olofsson.
Scheme 4
3i was hydrolysed to 4i in 63% yield and 88% ee. The rate of the
reaction with 1a and 2n under cationic conditions (Scheme 4) was
slower compared to the arylation rate using 4-CN-phenyl chloride
(2i) under standard neutral conditions (Table 1, entry 9). Phenyl, 1-
naphthyl and 4-tolyl triflates did not produce the desired arylation
under the same cationic conditions.
Notes and references
In the substrate controlled arylation/vinylation of 1a using 2a–
m and LiCl addition, the reaction route proceeding via the neutral
p-complex as depicted in Scheme 1 appears reasonable. This
chelation-controlled Heck pathway was previously suggested for
the reaction of 1a with aryl iodides12 and the only differences com-
prise the initial involvement of a T-shaped oxidative addition inter-
mediate using the t-Bu3P ligand,17 instead of the tetra-substituted
16-electron square planar palladium complex produced with less
bulky ligands. Recently published DFT calculations18 predict
chelation-controlled Si-face insertion of the neutral intermediate
PhPdCl complex into the 1a vinyl ether double bond, furnishing
R-configuration of the new quaternary center. This theoretical
result was fully supported by optical rotation measurements of
isolated ketone products 4 (Table 1).12 An explanation for the lack
of reactivity in the coupling between 1a and phenyl, 1-naphthyl
and 4-tolyl triflates could be the generation of a stable, chelated
r- or p-complex due to strong Pd(II)–N coordination.13 The low
Heck-reactivity of six-membered, tetra-substituted olefins 1c–d
was perhaps not surprising in the light of the reported slow
arylation rate of dihydropyran using chiral P, N-ligands.19
In summary, highly stereoselective Pd(0)-catalyzed b-arylation
and b-vinylation of a fully substituted cyclopentenyl vinyl ether
has been achieved by employing a chiral, pyrrolidine-based
and substrate-bound palladium(II)-directing group under neutral
reaction conditions. This presents the first case of aryl- and vinyl
chlorides being successfully utilized in asymmetric Heck reactions.
Formed Heck arylation products were hydrolysed and isolated as
the corresponding quaternary 2-aryl-2-methyl cyclopentanones in
good to moderate two-step yields with excellent stereoselectivities
(90–96% ee). Moreover, with high-density microwave-heating,
1 I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009–
3066.
2 J. P. Knowles and A. Whiting, Org. Biomol. Chem., 2007, 5, 31–44.
3 Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004.
4 M. Shibasaki, E. M. Vogl and T. Ohshima, Adv. Synth. Catal., 2004,
346, 1533–1552.
5 M. Oestreich, Eur. J. Org. Chem., 2005, 783–792.
6 Y. Ben-David, M. Portnoy, M. Gozin and D. Milstein, Organometallics,
1992, 11, 1995–1996.
7 A. F. Littke and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 6989–7000.
8 Transition Metals for Organic Synthesis, ed. M. Beller, A. Zapf and
T. H. Riermeier, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1, pp.
271–305.
9 A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176–4211.
10 P. Nilsson, M. Larhed and A. Hallberg, J. Am. Chem. Soc., 2001, 123,
8217–8225.
11 N. D. Buezo, J. C. de la Rosa, J. Priego, I. Alonso and J. C. Carretero,
Chem.–Eur. J., 2001, 7, 3890–3900.
12 P. Nilsson, M. Larhed and A. Hallberg, J. Am. Chem. Soc., 2003, 125,
3430–3431.
13 A. Stadler, H. von Schenck, K. S. A. Vallin, M. Larhed and A. Hallberg,
Adv. Synth. Catal., 2004, 346, 1773–1781.
14 M. Larhed, C. Moberg and A. Hallberg, Acc. Chem. Res., 2002, 35,
717–727.
15 A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945–2963.
16 W. Cabri, I. Candiani, A. Bedeschi, S. Penco and R. Santi, J. Org.
Chem., 1992, 57, 1481–1486.
17 J. P. Stambuli, C. D. Incarvito, M. Buehl and J. F. Hartwig, J. Am.
Chem. Soc., 2004, 126, 1184–1194.
18 W.-Y. Lu, M. Li, W. Shen, X.-L. Luo, Q.-L. Zhai and H. Huang, Acta
Chim. Sinica, 2006, 64, 1367–1372.
19 O. Loiseleur, M. Hayashi, M. Keenan, N. Schmees and A. Pfaltz,
J. Organomet. Chem., 1999, 576, 16–22.
20 D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36, 234–245.
21 J. Huang, E. Bunel and M. M. Faul, Org. Lett., 2007, 9, 4343–4346.
22 T. Hamada, A. Chieffi, J. Ahman and S. L. Buchwald, J. Am. Chem.
Soc., 2002, 124, 1261–1268.
676 | Org. Biomol. Chem., 2008, 6, 674–676
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