Highly enantioselective partial hydrogenation of simple pyrroles: A facile access to chiral 1-pyrrolines

Article abstract of DOI:10.1021/ja203190t

A highly enantioselective Pd-catalyzed partial hydrogenation of simple 2,5-disubstituted pyrroles with a Bronsted acid as an activator has been successfully developed, providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee.

Full text of DOI:10.1021/ja203190t

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Highly Enantioselective Partial Hydrogenation of Simple Pyrroles:
A Facile Access to Chiral 1-Pyrrolines
Duo-Sheng Wang,† Zhi-Shi Ye,† Qing-An Chen,† Yong-Gui Zhou,*,†,‡ Chang-Bin Yu,†
Hong-Jun Fan,*,† and Ying Duan†
†State Key Laboratory of Catalysis and State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian 116023, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S Supporting Information
b
Table 1. Optimization of Asymmetric Hydrogenation of 1aa
ABSTRACT: A highly enantioselective Pd-catalyzed partial
hydrogenation of simple 2,5-disubstituted pyrroles with a
Brønsted acid as an activator has been successfully devel-
oped, providing chiral 2,5-disubstituted 1-pyrrolines with up
to 92% ee.
he asymmetric hydrogenation of aromatic compounds offers
straightforward access to chiral molecules with cyclic skele-
T
tons and has received much attention over the past decades.1
Some bicyclic heteroaromatic substrates have been successfully hydro-
genated because of their relatively low aromaticity (quinolines,
isoquinolines, quinoxalines, indoles, and benzofurans).2ꢀ6 This
process is much more difficult for single-ring heteroaromatic
compounds, although hitherto, special activated pyridines7 and
furans6 have been successfully hydrogenated, and a single elegant
example of asymmetric hydrogenation of N-Boc-protected pyr-
roles using a chiral Ru catalyst was reported by Kuwano and co-
workers.8 To the best of our knowledge, no report on the
asymmetric hydrogenation of simple pyrroles has appeared,
despite its potential usefulness.9 Thus, the exploration of a new
strategy for hydrogenation of simple pyrroles is urgently needed
and of great significance.
a Conditions: 1a (0.25 mmol), Pd(OCOCF3)2 (2 mol %), (R)-BINAP
or other ligand (2.4 mol %), Acid (x eq), solvent (3 mL), 60 °C,
Very recently, we disclosed the Brønsted acid-activated asym-
metric hydrogenation of simple indoles5h,i using a homogeneous
palladium catalyst.10,11 As part of our ongoing effort to develop
new strategies for asymmetric hydrogenation of heteroaromatic
compounds and considering the similarity of pyrroles and
indoles, we envisioned that electron-enriched pyrroles could be
protonated in the presence of strong Brønsted acids, which
would destroy their aromaticity thus be suitable for facilitating
hydrogenation. Herein we report the results of our preliminary
investigation of asymmetric hydrogenation of simple 2,5-disub-
stituted pyrroles, wherein partially hydrogenated 1-pyrrolines
were obtained with up to 92% ee.
c
16ꢀ24 h. b Isolated yields. Determined by HPLC. d (R)-MeOBiPhep
was used as the ligand. e (R)-SynPhos was used as the ligand. f (R)-C4-
TunePhos was used as the ligand.
ethylsulfonic acid (EtSO3H) as the activator. When the reaction
was carried out at 60 °C, it proceeded smoothly, affording the
unexpected product 5-methyl-2-phenyl-1-pyrroline (2a) in 70%
yield with 71% ee; no pyrrolidine was detected in the reaction
mixture (Table 1, entry 1). It is noteworthy that this is the first
example of asymmetric hydrogenation of a pyrrole to obtain a
Initially, 2-methyl-5-phenylpyrrole (1a) was selected as a
model substrate for optimization of the reaction conditions.
Pd(OCOCF3)2/(R)-BINAP was employed as the catalyst with
Received: April 7, 2011
Published: May 17, 2011
r
2011 American Chemical Society
8866
dx.doi.org/10.1021/ja203190t J. Am. Chem. Soc. 2011, 133, 8866–8869
|

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Table 2. Asymmetric Hydrogenation of 2,5-Disubstituted
Pyrroles 1a
Scheme 1. Process of Pyrrole Hydrogenation
entry
R in 2
Ar in 2
Ph
yield (%)b
ee (%)c
1
2
Me
Et
80 (2a)
77 (2b)
87 (2c)
91 (2d)
80 (2e)
83 (2f)
90 (2g)
65 (2h)
88 (2i)
51 (2j)
79 (2k)
82 (2l)
73 (2m)
73 (2n)
79 (2a)
92 (R)
80 (þ)
81 (þ)
85 (þ)
86 (þ)
86 (þ)
80 (þ)
81 (þ)
84 (þ)
85 (þ)
89 (þ)
86 (þ)
88 (þ)
90 (þ)
91 (R)
Ph
3
n-Pr
n-pentyl
i-Bu
c-C6H11CH2
Bn
Ph
4
Ph
5
Ph
Scheme 2. Possible Pathways for Hydrogenation
6
Ph
7
Ph
8
Me
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-CF3C6H4
4-FC6H4
3,5-F2C6H3
1-naphthyl
Ph
9
Me
10
11
12
13
14
15d
Me
Me
Me
Me
Me
Me
a Conditions: 1 (0.25 mmol), Pd(OCOCF3)2 (2 mol %), (R)-C4-
TunePhos (2.4 mol %), EtSO3H (0.375 mmol), solvent (3 mL), 60
°C, 16ꢀ24 h. b Isolated yields. c Determined by HPLC. d 1a (3.0 mmol),
EtSO3H (4.5 mmol), solvent (24 mL), 40 h.
Table 2, entry 11 vs 8). Ortho-substituted aryl substrates showed
higher enantioselectivity than para-substituted ones (Table 2,
entry 10 vs 8). 1-Naphthyl-substituted pyrrole gave 90% ee (Table 2,
entry 14). Notably, a hydrogenation experiment on a 3 mmol
scale was also carried out with 1a, and identical 91% enantios-
electivity with full conversion were obtained (Table 2, entry 15).
A possible mechanism (Scheme 1) was proposed as follows:
Simple unprotected pyrrole reacts with a strong Brønsted acid to
form the iminium salt by protonation of carbonꢀcarbon double
bond, and the aromaticity of pyrrole is destroyed. The in situ-formed
iminium salt is hydrogenated to give the intermediate enamine,
and in the presence of acid, the enamine isomerizes to the more
stable imine, which survives under the current catalytic system.12
The pyrrole can be protonated at both the 3- and 4-positions
in the presence of a strong Brønsted acid (Scheme 2). Density
functional theory calculations at the B3LYP/cc-pVTZ(-f)//
B3LYP/6-31G** level were carried out to give further insight
into the selectivity. The computed bond length alternation
suggests that the CdN bond in intermediate II is better
conjugated with the phenyl group (Figure 1). As a result, II is
more stable than I by 1.4 kcal/mol (ΔG° in CH2Cl2), and the
positive charge in II is also more delocalized. Palladium hydride
species were observed in palladium-catalyzed hydrogenation
reactions, strongly suggesting that it could be the true active
catalyst, and the rate-determining step for the hydrogenation is
most probably the hydride transfer from the catalyst to the
substrate. Thus, the observed selectivity is understandable. The
CdN bond in I is more facile for the hydride transfer because its
carbon atom is more positively charged than that in II. To further
validate this proposal, we studied the hydride transfer reaction
from ((R)-BINAP)Pd(H)(OCOCF3) to I and II. Indeed, the
calculations showed that the hydride transfer barrier for I is
27.7 kcal/mol relative to 1a, which is lower than that for II by
1.8 kcal/mol. Therefore, the theoretical studies suggest that the
pathway in Scheme 2 is reasonable and that IV is not formed for
kinetic reasons.
chiral 1-pyrroline. Encouraged by this promising result, we
conducted further investigation of the effect of the reaction
medium (Table 1, entries 2ꢀ6), and a mixed solvent of toluene
and 1,1,1-trifluoroethanol with a ratio of 2/1 (PhMe/TFE = 2/1)
gave the best result in terms of both yield and enantioselectivity
(86% ee; Table 1, entry 6). When the amount of acid was
increased to 1.5 equiv, the ee was improved slightly (87% ee;
Table 1, entry 7). Subsequently, different acids were screened;
the results showed that a strong Brønsted acid was necessary,
whereas weak acids were invalid and left the starting material
unchanged (Table 1, entries 7ꢀ9 vs 10). Finally, examination of
various ligands showed that (R)-C4-TunePhos was the best
choice regarding enantioselectivity (92% ee; Table 1, entry
13). Therefore, the optimal conditions were established as Pd-
(OCOCF3)2/(R)-C4-TunePhos, EtSO3H (1.5 equiv), H2 (600
psi), PhMe/TFE (2:1), 60 °C.
A series of 2-alkyl-5-aryl-disubstituted pyrrole derivatives were
then subjected to hydrogenation under the above optimized
conditions, and the results are summarized in Table 2. In general,
moderate to good yields and high enantioselectivities were
obtained (Table 2, entries 1ꢀ14). The length and steric property
of the alkyl chain showed a remarkable influence on the
enantioselectivity. It was found that longer chains resulted in
decreased ee values, whereas ones with higher steric demand
displayed better results (Table 2, entries 1ꢀ6). A benzyl group
could also be tolerated in this system with high yield and good
enantioselectivity (80% ee; Table 2, entry 7). Substrates with aryl
substituents having different electronic and steric properties were
also examined (Table 2, entries 8ꢀ14). It was found that aryl
substituents with an electron-withdrawing group gave higher ee
values than those with electron-donating groups (89 vs 81% ee;
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dx.doi.org/10.1021/ja203190t |J. Am. Chem. Soc. 2011, 133, 8866–8869

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Chemical Physics (K2010F1) is acknowledged. The authors
thank Prof. Xumu Zhang for helpful discussions.
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Figure 1. (left) Optimized bond lengths (in Å) and charges (in
parentheses) for intermediates I and II. (right) Structure of the
transition state for hydride transfer with I (bond lengths in Å).
Scheme 3. Derivatization of Hydrogenated Product 2a
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Notably, chiral 1-pyrrolines and related compounds are ubi-
quitous building blocks in many biologically active compounds.13
The asymmetric hydrogenation of simple pyrroles developed
here offers a facile access to these molecules. Furthermore, the
derivatization of the hydrogenated products can be conveniently
realized utilizing imine chemistry.
As illustrated in Scheme 3, reduction of 2a with DIBAL-H
afforded cis-2-methyl-5-phenylpyrrolidine (3) in quantitative
yield without loss of optical purity. In the presence of trifluor-
oacetic anhydride, 2a isomerized to 2-pyrroline 4 with a trifluor-
oacetyl group on the nitrogen atom. The enantiomeric excess
was preserved, and a yield of 88% was obtained.
In summary, a highly enantioselective Pd-catalyzed partial
hydrogenation of simple 2,5-disubstituted pyrroles using a
Brønsted acid as an activator has been successfully developed,
providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee.
Further studies will be directed toward the extension of this
strategy to other heteroaromatics and its synthetic application.
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’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization data for the prepared compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(9) For heterogenous hydrogenation of a pyrrole modified with a
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’ AUTHOR INFORMATION
Corresponding Author
ygzhou@dicp.ac.cn; fanhj@dicp.ac.cn
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asymmetric hydrogenation, see: (a) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G.
Org. Lett. 2005, 7, 3235. (b) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006,
1189. (c) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729.
(d) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org.
Lett. 2008, 10, 2071. (e) Yu, C.-B.; Wang, D.-W.; Zhou, Y.-G. J. Org. Chem.
2009, 74, 5633. (f) Chen, M.-W.; Duan, Y.; Chen, Q.-A.; Wang, D.-S.; Yu,
C.-B.; Zhou, Y.-G. Org. Lett. 2010, 12, 5075. (g) Zhou, X.-Y.; Bao, M.;
’ ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation
of China (21032003 and 20921092), the National Basic Research
Program of China (2010CB833300), and Dalian Institute of
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COMMUNICATION
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Herein, the obtained products were N-alkylimines, and they were not
further hydrogenated to pyrrolidines, in accord with that result. Theo-
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