Enantioselective, palladium-catalyzed α-arylation of N-Boc-pyrrolidine

Article abstract of DOI:10.1021/ja0605265

This communication discloses the first instance of the enantioselective Pd-catalyzed α-arylation of N-Boc-pyrrolidine. The methodology relies on Beak's sparteine-mediated, enantioselective deprotonation of N-Boc-pyrrolidine to form the 2-pyrrolidinolithium specices in high enantiomeric ratio (er). Transmetalation of this intermediate with zinc chloride generates the stereochemically rigid, 2-pyrrolidinozinc reagent, which was readily coupled to a variety of functionalized aryl halides at room temperature using a catalyst generated from Pd(OAc)₂ and PtBu₃-HBF₄. A diverse array of 2-aryl-N-Boc-pyrrolidines was synthesized using this methodology, providing adducts consistently in a 96:4 er. A survey of the stoichiometry revealed that as little as 0.3 equiv of zinc could be used in the coupling reaction, and the 2-pyrrolidinozinc reagent was found to exhibit stereochemical stability up to 60 °C. The method allows for the most convergent and reliable preparation of a broad range of functionalized 2-aryl-N-Boc-pyrrolidines in high enantioselectivity, which is highlighted in this report by the enantioselective synthesis of (R)-nicotine. Copyright

Full text of DOI:10.1021/ja0605265

Published on Web 03/01/2006
Enantioselective, Palladium-Catalyzed r-Arylation of N-Boc-pyrrolidine
Kevin R. Campos,* Artis Klapars, Jacob H. Waldman, Peter G. Dormer, and Cheng-yi Chen
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
Received January 23, 2006; E-mail: kevin_campos@merck.com
Table 1. Enantioselective Arylation of N-Boc-pyrrolidinea
2-Arylpyrrolidines constitute an important structural motif in
biologically active compounds and effective chiral controllers in
asymmetric synthesis.1 Few methods exist for the synthesis of these
privileged structures, and all suffer from either long synthetic
sequences, low yields, lack of generality, or modest enantioselec-
tivity.2 We reasoned that the most direct method to access
enantioenriched 2-arylpyrrolidines would be the arylation of (R)-
2-lithio-N-Boc-pyrrolidine (2) obtained from (-)-sparteine-medi-
ated, enantioselective deprotonation of N-Boc-pyrrolidine (1).3
However, whereas the stereoselective capture of 2 with a variety
of electrophiles is well established,4 the enantioselective arylation
of 2 is unprecedented. Herein we report a general, enantioselective,
palladium-catalyzed arylation of 1 that proceeds via in situ generated
2-pyrrolidinozinc reagent 3. This convergent, one-pot synthesis of
2-aryl-N-Boc-pyrrolidines provides each adduct in a 96:4 enantio-
meric ratio (er), regardless of the coupling partner. This remarkable
feature clearly signals the high stereochemical fidelity of configu-
rationally stable 2-pyrrolidinometal (Li, ZnX, Pd) reagents during
each stage of the process.
Pd
source
ZnCl2
equiv
% yield
(er)
entry
ligand
1
2
3
4
5
6
7
8
-
PdCl2dppf
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.1
0.3
0.6
<5 (nd)
<5 (nd)
12 (96:4)
<5 (nd)
83 (96:4)
80 (96:4)
80 (96:4)
82 (96:4)
70 (96:4)
70 (96:4)
78 (96:4)
<5 (nd)
1,1′-di-(tBu2P)ferrocene
Cy3P-HBF4
tBu2PMe-HBF4
tBu3P-HBF4
Ru-phos
Q-phos
tBu3P-HBF4
tBu3P-HBF4
-
9
PdCl2
10
11
12
13
14
Pd(tBu3P)2
[PdBr(tBu3P)]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
tBu3P-HBF4
tBu3P-HBF4
tBu3P-HBF4
79 (96:4)
80 (96:4)
a Deprotonation was performed with 1.2 equiv of 1, 1.2 equiv of s-BuLi,
1.2 equiv of (-)-sparteine, in MTBE (0.4 M) at -70 °C. Coupling was
performed at RT overnight using 4 mol % Pd and 5 mol % ligand.
Enantiomeric excess was determined by CSP HPLC (Chiralcel AD-H).
which was established in the deprotonation step! The absolute
configuration of 4a was assigned by deprotection to 2-phenylpyr-
rolidine and comparison of the optical rotation to that reported in
the literature,15 confirming that the transmetalation/Negishi coupling
occurred with retention of configuration. In contrast to the dogma
that secondary alkyl ligands on Pd rapidly undergo â-hydride
elimination,16 products resulting from this pathway amounted to
<8%. For reasons of cost, availability, and practicality, we selected
t-Bu3P-HBF4 for further development.
The nature of the palladium source was found to have a profound
effect on the rate of the coupling reaction. In particular, Pd(OAc)2
provided a significantly faster reaction than all other palladium
sources.17 It is interesting to note that either a 1:1 or 2:1 ratio of
ligand-to-Pd provided competent in situ generated catalysts;
however, the preformed catalyst Pd[(Pt-Bu3)2]18 afforded only
∼80% conversion, whereas with [PdBr(Pt-Bu3)]219 the reaction went
to completion.
Because of the potential to form different organozinc species
(RZnCl, R2Zn, or R3ZnLi), an examination of the dependence of
yield and selectivity on the stoichiometry of ZnCl2 was undertaken.
We were delighted to find that the amount of ZnCl2 could be
reduced to as low as 0.33 equiv (with respect to 2) without
significant change in yield or enantioselectivity!
The enantioselective deprotonation/transmetalation/Negishi cou-
pling was found to be quite general, affording a diverse array of
2-arylpyrrolidines in good yield and 96:4 er (Table 2). Not only
were a variety of aryl bromides tolerated, but preliminary results
suggested that aryl chlorides were also suitable coupling partners
(entry 2, unoptimized). Phenyl triflate and phenyl tosylate were
unreactive under the standard conditions.
Although 2 would serve as the most logical intermediate to
introduce both the enantioselectivity and functionalization required
for an asymmetric arylation of 1, the stereochemical lability of 2
at temperatures above -60 °C5 and the lack of a general method
for the arylation of alkyllithium reagents have prohibited the
development of this transformation.6 Attempts to circumvent the
configurational instability of 2 via transmetalation with CuCN‚2LiCl
were moderately successful; however, the enantioselectivities were
variable and rarely more than 90%, which suggested that epimer-
ization of some intermediate was still occurring.7
Despite the documented configurational integrity of secondary
alkylzinc reagents,8 there have been no reports of the direct
metalation of 1 with organozinc reagents to produce 3.9 Alterna-
tively, 3 should be readily accessed by treatment of 2 with ZnCl2.
Moreover, 3 should be configurationally stable in a broad range of
temperatures and should undergo facile transmetalation with organo-
palladium species.10 If a suitable catalyst could be identified that
preserved the configurational identity through the coupling, this
process would constitute a direct, enantioselective arylation of 1.
To test this hypothesis, the enantioselective deprotonation of 1
was performed according to literature precedent,3 and the resulting
anion was treated with 1 equiv of ZnCl2. The presumed organozinc
reagent 3 was warmed to room temperature to provide a homoge-
neous solution, which was readily subdivided for screening with a
variety of palladium catalysts in the arylation with bromobenzene
(Table 1). Despite the failure of PdCl2(dppf), historically the catalyst
of choice for Negishi couplings,11 Pd catalysts derived from
Buchwald’s Ru-phos,12 Hartwig’s Q-phos,13 and Fu’s t-Bu3P-
HBF4 14 delivered arylated product 4a in good yield and a 96:4 er,
9
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J. AM. CHEM. SOC. 2006, 128, 3538-3539
10.1021/ja0605265 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. General Enantioselective Arylation of N-Boc-pyrrolidinea
conditions, which produced 2,5-diphenyl-N-Boc-pyrrolidine (5) as
a 96:4 diastereomeric ratio, and was isolated in 57% yield (eq 1).22
In conclusion, we have developed an unprecedented asymmetric
arylation of N-Boc-pyrrolidine that relies on a (-)-sparteine
mediated asymmetric deprotonation, followed by transmetalation
with as little as 0.33 equiv of ZnCl2 and subsequent Pd-catalyzed
Negishi coupling with aryl bromides. The method was applicable
to a host of aryl halides to provide a diverse array of 2-arylpyrro-
lidines in good yield and a 96:4 er, regardless of the nature of the
aryl bromide component. This sequence offers a number of
advantages over existing methods and represents the most conve-
nient and practical synthesis of enantiomerically enriched 2-arylpyr-
rolidines and 2,5-diarylpyrrolidines. The use of 3 in other reactions
and the application of the asymmetric deprotonation/transmetalation/
Negishi coupling to other substrates will be reported shortly.
Acknowledgment. We thank Professors Scott Denmark, Stephen
Buchwald, and Barry Trost for valuable discussions and Tom Novak
for high-resolution mass spectral data.
Supporting Information Available: Experimental details and full
characterization of key intermediates. This material is available free
of charge via the Internet at http://pubs.acs.org.
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a Deprotonation was performed with 1.2 equiv of 1, 1.2 equiv of s-BuLi,
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(22) s-BuLi/TMEDA produced 5 in lower d.r. (66:34) and yield (42%).
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