Highly regio-and enantioselective synthesis of polysubstituted 2 H -pyrroles via pd-catalyzed intermolecular asymmetric allylic dearomatization of pyrroles

Article abstract of DOI:10.1021/ja5028138

A highly efficient synthesis of chiral polysubstituted 2H-pyrrole derivatives via a Pd-catalyzed intermolecular asymmetric allylic dearomatization reaction of pyrroles is presented. With the commercially available palladium precursor and chiral ligand, the polysubstituted 2H-pyrrole products containing a chiral quaternary carbon center were obtained with up to 97% ee and >95/5 regioselectivity.

Full text of DOI:10.1021/ja5028138

Communication
pubs.acs.org/JACS
Highly Regio- and Enantioselective Synthesis of Polysubstituted
2H‑Pyrroles via Pd-Catalyzed Intermolecular Asymmetric Allylic
Dearomatization of Pyrroles
Chun-Xiang Zhuo, Yong Zhou, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. of China
S
* Supporting Information
Scheme 1. Transition-Metal-Catalyzed Intermolecular
Asymmetric Dearomatization Reactions of Pyrroles
ABSTRACT: A highly efficient synthesis of chiral
polysubstituted 2H-pyrrole derivatives via a Pd-catalyzed
intermolecular asymmetric allylic dearomatization reaction
of pyrroles is presented. With the commercially available
palladium precursor and chiral ligand, the polysubstituted
2H-pyrrole products containing a chiral quaternary carbon
center were obtained with up to 97% ee and >95/5
regioselectivity.
s one of the most important electron-rich heterocycles, the
A
pyrrole moiety is embedded in numerous biologically
active natural products and pharmaceutical agents.1 However,
the documented enantioselective Friedel−Crafts type alkylation
reactions of pyrroles are much fewer than those of indoles,2
likely due to the regioselectivity issue caused by the similar
nucleophilicity between the 2- and 3-positions of pyrroles.3 In
this regard, rare examples were reported using electron-rich
pyrroles as C-nucleophiles in transition-metal-catalyzed allylic
alkylation reactions,4−6 although electron-deficient pyrroles
have been well demonstrated to be N-nucleophiles over the
past decade.7 In 2006, Bandini, Umani-Ronchi, and their co-
workers reported the first example of a Pd-catalyzed intra-
molecular asymmetric Friedel−Crafts type allylic alkylation
reaction of pyrroles.5a Later, Du and co-workers disclosed the
first Pd-catalyzed intermolecular asymmetric Friedel−Crafts
type allylic alkylation reaction of pyrroles with a novel olefin-
phosphine ligand.6a,b
In addition to the above elegant studies, pyrroles can also
serve as prochiral nucleophiles in catalytic asymmetric
dearomatization reactions, furnishing various highly function-
alized pyrrolines or pyrrolidines.8,9 Recently, we described
efficient syntheses of chiral spiro-2H-pyrroles via an Ir-catalyzed
intramolecular asymmetric allylic dearomatization reaction of
pyrroles.8 The dearomatization was achieved in excellent regio-
and enantioselective control due to the intramolecular design
which led to the reduction of the number of possible transition
states and ring-size directed reactivity. However, the reactivity
and selectivity toward an intermolecular reaction remain
unsettled problems. Notably, [4 + 3] cycloaddition and
hydrogenation reactions have been proven successful for the
intermolecular asymmetric dearomatization of pyrroles.10−12 In
2007, Reddy and Davies reported an elegant synthesis of chiral
tropanes via Rh-catalyzed [4 + 3] cycloaddition from simple
pyrroles (eq 1, Scheme 1).10a Soon after, Kuwano and co-
workers reported the Ru-catalyzed asymmetric hydrogenative
dearomatization of 2,3,5-trisubstituted pyrroles, providing a
straightforward route for the synthesis of 4,5-dihydropyrroles
and pyrrolidines (eq 2, Scheme 1).11 Very recently, Zhou, Fan,
and their co-workers presented an efficient asymmetric
construction of chiral 1-pyrrolines via Pd-catalyzed partial
hydrogenation of simple pyrroles (eq 3, Scheme 1).12 With a
Brønsted acid as an activator, chiral 2,5-disubstituted 1-
pyrrolines were obtained with excellent ee. Nevertheless, the
enantioselective intermolecular alkylative dearomatization of
pyrroles is rare and challenging due to the multiselectivity
issues including the chemoselectivity (C2 and N1), regiose-
lectivity (C2 and C4, C2 and C5), and enantioselectivity (eq 4,
Scheme 1). Herein, for the first time we report a highly regio-
and enantioselective synthesis of polysubstituted 2H-pyrroles
containing a chiral quaternary carbon center via a Pd-catalyzed
intermolecular asymmetric allylic dearomatization reaction of
multisubstituted pyrroles (eq 4, Scheme 1).
At the outset, 2,5-dimethyl-pyrrole (1a) and cinnamyl
carbonate (2a) were chosen as the model substrates to
Received: March 20, 2014
Published: April 23, 2014
© 2014 American Chemical Society
6590
dx.doi.org/10.1021/ja5028138 | J. Am. Chem. Soc. 2014, 136, 6590−6593

Journal of the American Chemical Society
Communication
a
investigate the reaction conditions. In the presence of 5 mol %
of [Pd(C3H5)Cl]2, 11 mol % of (R)-BINAP,13 and 1.0 equiv of
Cs2CO3, the reaction of 1a and 2a in dioxane for 4 h gave 2H-
pyrrole 3aa in 69% yield and 83% ee (entry 1, Table 1).
Scheme 2. Investigation of Chiral Ligands
a
Table 1. Investigation of Reaction Conditions
b
c
entry
base
solvent
dioxane
t (h)
yield (%)
ee (%)
1
Cs2CO3
K2CO3
Na2CO3
Li2CO3
K3PO4
Et3N
4
11
16
16
16
22
22
22
12
12
7
69
50
35
30
35
70
68
71
35
24
82
78
67
83
78
70
70
75
79
79
77
70
46
81
83
76
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
3
4
5
6
7
DBU
a
Reaction conditions: 5 mol % of [Pd(C3H5)Cl]2, 11 mol % of ligand,
8
−
0.2 mmol of 1a, 0.4 mmol of 2a, and 0.2 mmol of Cs2CO3 in 2.0 mL of
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
b
c
d
o-xylene at rt. Isolated yield. Determined by HPLC analysis.
10
11
12
13
DCE
Toluene was used as the solvent.
toluene
o-xylene
cyclohexane
a
7
Scheme 3. Reaction Substrate Scope: Pyrroles
12
a
Reaction conditions: 5 mol % of [Pd(C3H5)Cl]2, 11 mol % of (R)-
L1, 0.2 mmol of 1a, 0.4 mmol of 2a, and 0.2 mmol of base in 2.0 mL
b
c
of solvent at rt. Isolated yield. Determined by HPLC analysis.
Encouraged by these results, further optimization of the
reaction conditions was carried out. Various inorganic and
organic bases such as K3PO4, K2CO3, Na2CO3, Li2CO3, Et3N,
and DBU were screened (entries 2−7, Table 1), and Cs2CO3
was found to be the optimal base. Notably, the reaction also
occurred smoothly with slightly decreased ee in the absence of
an additional base (entry 8, Table 1). Next, investigation of
various solvents (entries 9−13, Table 1) led to the
identification of o-xylene as being ideal (78% yield, 83% ee,
entry 12, Table 1). Several commercially available chiral ligands
were then tested (Scheme 2).14 Surprisingly, the increase in the
steric hindrance of the aromatic substituents on the phosphine
led to the decreased ee of 3aa (L2−L3, Scheme 2). Then,
examination of biphenyl type axially chiral bisphosphine ligands
disclosed that (R)-segphos (L5) was the best choice for the
reaction process (L4−L9, Scheme 2). Interestingly, the same
steric effect of the chiral phosphine ligands was also observed in
the segphos series (L5−L6, Scheme 2). According to the
observations made in the optimization studies, the best
conditions were identified as the following: reaction of 1a
and 2a in o-xylene (0.1 M) with 5 mol % of [Pd(C3H5)Cl]2, 11
mol % of (R)-L5, and 1.0 equiv of Cs2CO3 at rt. Under these
conditions, 2H-pyrrole 3aa was obtained in 85% yield and 89%
ee (Scheme 2).
a
Reaction conditions: 5 mol % of [Pd(C3H5)Cl]2, 11 mol % of (R)-
L5, 0.2 mmol of 1, 0.4 mmol of 2a, and 0.2 mmol of Cs2CO3 in 2.0
1
mL o-xylene at rt. The ratio of 3/4 was determined by H NMR
analysis of the crude reaction mixture. b Isolated yield of 3 and 4. c Ee
d
of 3 was determined by HPLC analysis. Reaction conditions: 1 mol
% of [Pd(C3H5)Cl]2, 2.2 mol % of (R)-L5, 0.5 mmol of 1a, 1.0 mmol
of 2a, and 0.5 mmol of Cs2CO3 in 5.0 mL of o-xylene at rt for 5 h.
Methyl (1-phenylallyl) carbonate was used as the electrophile.
e
f
With the optimized reaction conditions in hands, various
pyrrole derivatives 1b−k were reacted with cinnamyl carbonate
(2a) to examine the generality of the dearomatization process
(Scheme 3). Notably, the reaction of methyl (1-phenylallyl)
carbonate and 1a under the optimized reaction conditions for
3.5 h gave product 3aa in 82% yield with 85% ee, which are
similar to the results with cinnamyl carbonate. These results
suggest that the reaction proceeds through the Pd-pi-allyl
Determined by GC analysis of the crude reaction mixture.
intermediate. When 2,3,5-trimethyl-pyrrole (1b) was used, the
reaction occurred smoothly in excellent regioselectivity (95/5)
and enantioselectivity (95% ee) to give 3ba. The excellent
regioselectivity favoring the attack at the more sterically
6591
dx.doi.org/10.1021/ja5028138 | J. Am. Chem. Soc. 2014, 136, 6590−6593

Journal of the American Chemical Society
Communication
hindered C2 of 1b might be attributed to the resonance and
stereoelectronic effects, which make C2 more nucleophilic.15
By switching the 3-methyl substituent to the n-butyl (1c),
cyclopropyl (1d), or phenyl (1e) group, the reaction also
proceeded smoothly to give the corresponding desired products
in excellent regio- and enantioselectivity (85−90% yield, 94/6
− >95/5 r.r., 91−95% ee, 3ca−3ea, Scheme 3). 3-Aryl 2,5-
dimethyl-pyrrole containing an electron-donating group (p-Me,
p-OMe; 1f−1g) or an electron-withdrawing group (p-F; 1h) on
the benzene ring led to the corresponding dearomatized
products in excellent regioselectivity (92/8−95/5), yields and
enantioselectivity (86−95% yield, 91−94% ee, 3fa−3ha,
Scheme 3). Interestingly, when 2,3-dimethyl-5-phenyl-pyrrole
(1i) was utilized, the reaction occurred smoothly in excellent
yield and ee with exclusive formation of 3ia (90% yield, 95% ee,
Scheme 3). Moreover, the steric bulky 2,3,4,5-tertmethyl-
pyrrole (1j) was well tolerated in the reaction (78% yield, 91%
ee, 3ja, Scheme 3). It is noteworthy that the 2,4,5-trimethyl-3-
phenyl pyrrole (1k) could also undergo the dearomatization
reaction with moderate regioselectivity and excellent enantio-
selectivity [3ka/4ka = 76/24, 93% ee (3ka), Scheme 3].
Gratifyingly, when the reaction was run with 1 mol % of
[Pd(C3H5)Cl]2 and 2.2 mol % of (R)-L5 on 0.5 mmol scale,
3aa was obtained with an excellent yield and ee (85% yield,
90% ee, Scheme 3). The structures of all the major
regioisomers (3) were confirmed unambiguously by 2D-
NOESY analysis.16
Cl, p-Br; 2d-f) could be well reacted to afford the dearomatized
products (3bd−bf) in good yields with excellent regio- and
enantioselectivity (71−78% yield, 93/7−95/5 r.r., 88−92% ee,
entries 4−6, Table 2). The reaction of 2-thienyl allylic
carbonate (2g) with 1b afforded product 3bg in 77% yield
with 97% ee (94/6 r.r., entry 7, Table 2). When crotyl
carbonate (2h) and allylic carbonate (2i) were used, the
reaction also proceeded smoothly in moderate yields with
excellent ee (57−67% yield, >95/5 r.r., 88−94% ee, entries 9−
10, Table 2). Notably, the reaction of 2g with 1b on the 1.6
mmol scale gave 3bg in 75% yield with 97% ee (entry 8, Table
2). The structure and stereochemistry of the product were
confirmed unambiguously by an X-ray crystallographic analysis
of a crystal of enantiopure 3bg. The absolute configuration was
determined as (R).
To test the practicality of the methodology, a gram-scale
synthesis of chiral 2H-pyrrole was carried out. The
intermolecular allylic dearomatization of 1i and 2a on the 3.8
mmol scale gave the desired product 3ia in 88% yield and 92%
ee (Scheme 4).
Scheme 4. A Gram-Scale Synthesis of 3ia
In addition, reactions of 1b with various substituted allylic
carbonates 2 were also carried out. The results are summarized
in Table 2. Reactions of allylic carbonates containing para-
methylphenyl and para-methoxyphenyl groups (2b−c) oc-
curred smoothly to give the desired products (3bb−bc) in
good yields with excellent enantioselectivity (74−84% yield,
93/7−94/6 r.r., 92−93% ee, entries 2−3, Table 2). Cinnamyl
carbonates containing an electron-withdrawing group (p-F, p-
To further demonstrate the synthetic utility of the newly
developed methodology, several transformations of the 2H-
pyrrole derivatives were carried out. The imine group could be
easily reduced with Dibal-H, affording chiral pyrroline 5 in 60%
yield and excellent diastereoselectivity (>95/5 dr, 88% ee, eq 1,
Scheme 5). Selective hydrogenation of the CC bond was
achieved when Pd/C was chosen as the catalyst, providing the
imine derivative 6 in 65% yield and 85% ee (eq 2, Scheme 5).17
No notable loss of the enantiomeric purity was observed in
both cases.
a
Table 2. Reaction Substrate Scope: Electrophiles
Scheme 5. Product Transformation
yield
b
c
d
entry
2, R5
2a, Ph
t (h)
3/4
product
(%)
ee (%)
1
2
3
4
5
6
7
4.5
5
95/5
94/6
93/7
93/7
93/7
95/5
94/6
94/6
>95/5
>95/5
3ba
3bb
3bc
3bd
3be
3bf
85
84
74
78
71
74
77
75
67
57
95
92
93
91
92
88
97
97
94
88
2b, 4-Me-C6H4
2c, 4-MeO-C6H4
2d, 4-F-C6H4
2e, 4-Cl-C6H4
2f, 4-Br-C6H4
2g, 2-thienyl
2g, 2-thienyl
2h, Me
In summary, we have developed a highly efficient synthesis of
enantioenriched polysubstituted 2H-pyrrole derivatives via the
first Pd-catalyzed intermolecular asymmetric allylic dearomati-
zation reaction of pyrroles. With the commercially available
palladium precursor and chiral ligand L5, the substituted 2H-
pyrrole products containing a chiral quaternary carbon center
were obtained with up to 97% ee under mild reaction
conditions. Interestingly, the reactions occurred smoothly and
good to excellent regioselectivities were obtained when the tri-
and tetra-substituted pyrrole derivatives were used. Moreover,
to the best of our knowledge, it is the first example involving
the multisubstituted pyrroles as prochiral nucleophiles in Pd-
catalyzed asymmetric allylic alkylation reactions. Further
applications of the highly enantioenriched 2H-pyrrole deriva-
tives and investigation of the reaction mechanism are currently
underway in our laboratory.
5
5
5
5
5
3bg
3bg
3bh
3bi
e
8
f
5.5
5
9
f
10
2i, H
5
a
Reaction conditions: 5 mol % of [Pd(C3H5)Cl]2, 11 mol % of (R)-
L5, 0.2 mmol of 1b, 0.4 mmol of 2, and 0.2 mmol of Cs2CO3 in 2.0
mL of o-xylene at rt. Determined by H NMR analysis of the crude
reaction mixture. Isolated yield of 3 and 4. Ee of 3 was determined
b
1
c
d
e
by HPLC analysis. The reaction was performed on 1.6 mmol scale.
f
The ratio of 3/4 was determined by GC analysis of the crude reaction
mixture.
6592
dx.doi.org/10.1021/ja5028138 | J. Am. Chem. Soc. 2014, 136, 6590−6593

Journal of the American Chemical Society
Communication
MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815. (d) Phipps,
R. J.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 1268. (e) Spangler, J.
E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6802. (f) Xiong, H.;
Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851.
(g) Wu, K.-J.; Dai, L.-X.; You, S.-L. Chem. Commun. 2013, 49, 8620.
(h) Zhang, X.; Han, L.; You, S.-L. Chem. Sci. 2014, 5, 1059.
(10) (a) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
10312. For an early study using a chiral auxiliary, see: (b) Davies, H.
M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thornley, C.; Kong,
N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
slyou@sioc.ac.cn
Notes
■
(11) Kuwano, R.; Kashiwabara, M.; Ohsumi, M.; Kusano, H. J. Am.
Chem. Soc. 2008, 130, 808.
(12) Wang, D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.; Fan,
H.-J.; Duan, Y. J. Am. Chem. Soc. 2011, 133, 8866.
The authors declare no competing financial interest.
(13) For reviews, see: (a) Noyori, R.; Takaya, H. Acc. Chem. Res.
1990, 23, 345. (b) Noyori, R. Adv. Synth. Catal. 2003, 345, 15.
(c) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev.
2005, 105, 1801. For selected examples using BINAP-type chiral
ligands in Pd-catalyzed AAA reactions, see: (d) Kuwano, R.; Ito, Y. J.
Am. Chem. Soc. 1999, 121, 3236. (e) Kuwano, R.; Nishio, R.; Ito, Y.
Org. Lett. 1999, 1, 837. (f) Braun, M.; Laicher, F.; Meier, T. Angew.
Chem., Int. Ed. 2000, 39, 3494. (g) Kuwano, R.; Uchida, K.; Ito, Y. Org.
Lett. 2003, 5, 2177. (h) Ogasawara, M.; Ngo, H. L.; Sakamoto, T.;
Takahashi, T.; Lin, W. Org. Lett. 2005, 7, 2881.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program 2010CB833300) and National Natural Science
Foundation of China (21025209, 21121062, 21332009) for
generous financial support. We also thank Prof. Qi-Lin Zhou,
Prof. Shou-Fei Zhu, and Prof. Zhaoguo Zhang for providing
chiral phosphine ligands and helpful discussions. This paper is
dedicated to Prof. Chengye Yuan on the occasion of his 90th
birthday.
(14) For a detailed investigation of other chiral ligands, see the
Supporting Information.
(15) Kirby, A. J. In Stereoelectronic Effects; Oxford University Press:
Oxford, 1996.
REFERENCES
■
(1) For reviews: (a) Furstner, A. Angew. Chem., Int. Ed. 2003, 42,
̈
3582. (b) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. (c) Fan, H.;
Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264.
(d) Thirumalairajan, S.; Pearce, B. M.; Thompson, A. Chem. Commun.
2010, 46, 1797. (e) Rane, R.; Sahu, N.; Shah, C.; Karpoormath, R.
Curr. Top. Med. Chem. 2014, 14, 253. Selected total synthesis of the
(16) For details, see the Supporting Information.
(17) The ee and relative configuration of product 5 were determined
by the corresponding acetyl protected derivative 7. For details, see the
Supporting Information.
pyrrole-containing natural products: (f) Furstner, A.; Radkowski, K.;
̈
Peters, H. Angew. Chem., Int. Ed. 2005, 44, 2777. (g) Duspara, P. A.;
Batey, R. A. Angew. Chem., Int. Ed. 2013, 52, 10862.
(2) For reviews: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550. (b) Bandini, M.; Melloni, A.;
Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199. (c) Poulsen, T. B.;
Jørgensen, K. A. Chem. Rev. 2008, 108, 2903. (d) You, S.-L.; Cai, Q.;
Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. (e) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9608. (f) Zeng, M.; You, S.-L.
Synlett 2010, 1289.
(3) (a) Fleming, I. In Frontier Orbitals and Organic Chemical
Reactions; Wiley: New York, 1976; p 58. (b) Saracoglu, N. Top.
Heterocycl. Chem. 2007, 11, 1.
(4) For reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 395. (b) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(c) Trost, B. M. Org. Process Res. Dev. 2012, 16, 185.
(5) (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.;
Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424. For a related Ir-
catalyzed reaction and mechanistic study, see: (b) Zhuo, C.-X.; Wu,
Q.-F; Zhao, Q.; Xu, Q.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135,
8169.
(6) (a) Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H. Org.
Lett. 2011, 13, 2164. (b) Liu, Y.; Cao, Z.; Du, H. J. Org. Chem. 2012,
77, 4479. For a PdCl2-catalyzed intermolecular alkylation of pyrroles,
see: (c) Yuan, F.-Q.; Gao, L.-X.; Han, F.-S. Chem. Commun. 2011, 47,
5289.
(7) Selected recent examples: (a) Trost, B. M.; Dong, G. J. Am.
Chem. Soc. 2006, 128, 6054. (b) Trost, B. M.; Dong, G. Org. Lett.
2007, 9, 2357. (c) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem.
Soc. 2010, 132, 15800. (d) Trost, B. M.; Osipov, M.; Dong, G. Org.
Lett. 2012, 14, 2254.
(8) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012, 3,
205.
(9) For a review on the catalytic asymmetric dearomatization
reaction, see: (a) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int.
Ed. 2012, 51, 12662. Selected recent examples: (b) Oguma, T.;
Katsuki, T. J. Am. Chem. Soc. 2012, 134, 20017. (c) Zhu, S.;
6593
dx.doi.org/10.1021/ja5028138 | J. Am. Chem. Soc. 2014, 136, 6590−6593