Enantioselective activation of stable carboxylate esters as enolate equivalents via N-heterocyclic carbene catalysts

Article abstract of DOI:10.1021/ol300676w

The first N-Heterocyclic Carbene (NHC) mediated activation of stable carboxylate esters to generate enolate intermediates is disclosed. The catalytically generated arylacetic ester enolates undergo enantioselective reactions with α,β-unsaturated imines.

Full text of DOI:10.1021/ol300676w

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2154–2157
Enantioselective Activation of Stable
Carboxylate Esters as Enolate
Equivalents via N-Heterocyclic
Carbene Catalysts
Lin Hao, Yu Du, Hui Lv, Xingkuan Chen, Huishen Jiang, Yaling Shao, and
Yonggui Robin Chi*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
robinchi@ntu.edu.sg
Received March 17, 2012
ABSTRACT
The first N-Heterocyclic Carbene (NHC) mediated activation of stable carboxylate esters to generate enolate intermediates is disclosed. The
catalytically generated arylacetic ester enolates undergo enantioselective reactions with R,β-unsaturated imines.
Asymmetricorganocatalytic generationofchiralenolate
equivalents is a powerful approach in organic synthesis.
Ketenes are one of the most studied classes of enolate
precursors. The asymmetric activation of ketenes has been
realized with nucleophilic catalysts, such as planar-chiral
DMAP derivatives,1 cinchona alkaloids,2 and chiral
N-heterocyclic carbenes (NHCs).3ꢀ6 A drawback of this
otherwise very successful approach lies in the relatively
unstable nature of ketenes (and their carboxyl chloride
precursors) that can pose operational challenges. With
NHCs7 as the catalysts, recently the chiral ester enolate
equivalents have also been generated from functionalized
aldehydes8 and enals.9 The overall process (the “forward”
pathway) starts from enals (or functional aldehydes), goes
(1) Reviews: (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. (b) Fu,
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(5) For a selected review of enolate generations using phase-transfer
catalysts, see: Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028.
(6) For a recent review on the related “chiral enol equivalents”
(enamine catalysis), see: Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471–5569.
(2) Reviews: (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
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Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592–600. (c) Gaunt,
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D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771–6803.
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A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108–1113. (b)
Concellon, C.; Duguet, N.; Smith, A. D. Adv. Synth. Catal. 2009, 351,
3001–3009. (c) Douglas, J.; Ling, K. B.; Concellon, C.; Churchill, G.;
Slawin, A. M. Z.; Smith, A. D. Eur. J. Org. Chem. 2010, 5863–5869. (d)
He, L.; Lv, H.; Zhang, Y.; Ye, S. J. Org. Chem. 2008, 73, 8101–8103. (e)
Zhang, Y. R.; He, L.; Wu, X.; Shao, P. L.; Ye, S. Org. Lett. 2008, 10,
277–280. (f) Huang, X. L.; He, L.; Shao, P. L.; Ye, S. Angew. Chem., Int.
Ed. 2009, 48, 192–195. (g) Jian, T. Y.; He, L.; Tang, C.; Ye, S. Angew.
Chem., Int. Ed. 2011, 50, 9104–9107. (h) Jian, T. Y.; Shao, P. L.; Ye, S.
Chem. Commun. 2011, 47, 2381–2383.
(7) For reviews on NHC catalysis: (a) Enders, D.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534–541. (b) Zeitler, K. Angew. Chem., Int. Ed.
2005, 44, 7506–7510. (c) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606–5655. (d) Marion, N.; Diez-Gonzalez, S.; Nolan,
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mica Acta 2009, 42, 55–66. (i) Moore, J. L.; Rovis, T. Top. Curr. Chem.
2011, 291, 77–144. (j) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res.
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2–17. (m) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.;
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(4) Smith reported an elegant activation of in situ formed anhydrides
using chiral isothiourea catalysts to generate enolate intermediates; see:
(a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith,
A. D. J. Am. Chem. Soc. 2011, 133, 2714–2720. (b) Morrill, L. C.; Lebl,
T.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci. 2012DOI: 10.1039/
C2SC20171B.
r
10.1021/ol300676w
Published on Web 04/09/2012
2012 American Chemical Society

through a few key intermediates such as enolates, and ends
up as carboxylic acid derivatives (Scheme 1a).9 As part of a
larger program to explore and understand the rich chemistry
enabled by NHC catalysis, we wondered whether the “back-
ward” pathways starting from stable carboxylic ester
substrates10 could be realized (Scheme 1a). Our design is
further illustrated in Scheme 1b. A stable ester (I) bearing a
good leaving group (OR0) may react with an NHC to form a
more reactive intermediate (II) with increased acidities of the
R C-H’s. The ester intermediate II subsequently undergoes a
deprotonation to generate enolate III as a key intermediate
that can react with electrophiles. In addition to intrinsic
scientific values provided with asymmetric catalytic activa-
tion of esters, we expect that the use of stable carboxylic
esters as substrates will offer synthetic advantages over the
previously employed ketenes and aldehydes in certain cases.
We started by first identifying suitable phenylacetic esters
(1) that could be activated by NHCs to react with R,β-
unsaturated imine 2a as a model substrate (Table 1). The
results briefed in Table 1 showed that chromatographically
stable esters with good leaving groups (electro-deficient
phenols) could behave as effective substrates (Table 1, entries
5ꢀ6). The use of excess base (200 mol % DIEA) was
Scheme 1. NHC-Mediated Activation of Stable Carboxylate
Esters To Generate Enolate Intermediates: A Working
Hypothesis
necessary to neutralize the acidic phenols released during
the ester activations. No DIEA-catalyzed background reac-
tion in the absence of NHC was observed (entry 7).
(8) For a review, see ref 7n; for selected examples, see: (a) Chow,
K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–8127. (b)
Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
9518–9519. (c) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am.
Chem. Soc. 2009, 131, 18028–18029. (d) Reynolds, N. T.; Rovis, T. J.
Am. Chem. Soc. 2005, 127, 16406–16407. (e) He, M.; Uc, G. J.; Bode,
J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. (f) Alcaide, B.;
Almendros, P.; Cabrero, G.; Ruiz, M. P. Chem. Commun. 2007, 4788–
4790. (g) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–
13799. (h) Li, G. Q.; Li, Y.; Dai, L. X.; You, S. L. Org. Lett. 2007, 9,
3519–3521. (i) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129,
13796–13797. (j) Du, D.; Li, L. X.; Wang, Z. W. J. Org. Chem. 2009, 74,
4379–4382. (k) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu,
I. Org. Lett. 2009, 11, 3934–3937. (l) Li, G. Q.; Dai, L. X.; You, S. L. Org.
Lett. 2009, 11, 1623–1625. (m) Phillips, E. M.; Wadamoto, M.; Roth,
H. S.; Ott, A. W.; Scheidt, K. A. Org. Lett. 2009, 11, 105–108. (n) Wang,
L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891–893. (o) Vora, H. U.;
Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860–2861. (p) Ling, K. B.;
Smith, A. D. Chem. Commun. 2011, 47, 373–375. Also see: (q) He, M.;
Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817–3820 and ref 7.
(9) For selective protonations of enal β-carbons leading to NHC-
bounded ester enolates for new CꢀC and carbonꢀheteroatom bond
formations, see: (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 8418–8420. (b) Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F.
Synthesis 2006, 2418–2439. (c) Phillips, E. M.; Wadamoto, M.; Chan, A.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 3107–3110.
(d) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 10098–10099. (e) Kaeobamrung, J.;
Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20661–20665. (f) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett. 2011, 13,
4708–4711. For relevant mechanistic studies in enal activation, see: (g)
Schrader, W. W.; Handayani, P. P.; Burstein, C.; Glorius, F. Chem.
Commun. 2007, 716–718. (h) Mahatthananchai, J.; Bode, J. W. Chem.
Sci. 2012, 3, 192–197. Enolate intermediates are also involved in other
NHC-mediated enal reactions, such as homoenolate-enolate cascades
and self-redox processes; see ref 7. Also see: (i) Zhao, Y. M.; Tam, Y.;
Wang, Y. J.; Li, Z.; Sun, J. Org. Lett. 2012, 14, 1398–1401. (j) Liu, G.;
Wilkerson, P. D.; Toth, C. A.; Xu, H. Org. Lett. 2012, 14, 858–861.
(10) For NHC-catalyzed transesterifications, see: (a) Grasa, G. A.;
Singh, R.; Nolan, S. P. Synthesis 2004, 971–985. For NHC-catalyzed
carboxyl transfer reactions involving carbonates activations, see: (b)
Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8, 3785–3788. (c)
Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131,
14176–14177. (d) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836–
4839. (e) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4,
3583–3586. (f) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth,
R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587–3590. (g) Sarkar, S. D.;
Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010, 132, 1190–1191.
Table 1. Identification of Suitable Ester Substrates and Conditions
entrya
ester (1)
yield (%)b
drc
1
2
3
4
5
6
7f
1a1
1a2
1a3
1a4
1a5
1a6
1a6
<1d
<1d
<1d
∼10e
81
N.D.
N.D.
N.D.
N.D.
10:1
11:1
N.D.
83
<1d
a Reaction condition: 1 (0.15 mmol), 2a (0.10 mmol), solvent (0.5 mL).
b Isolated yield (major diastereomer) based on 2a. c Diastereomeric ratio of
3a, determined via 1H NMR analysis of unpurified reaction mixtures. Rela-
tive configuration of the product was determined via X-ray of 3o (Scheme 3,
see Supporting Information). d No detectable formation of product as
1
indicated via TLC and crude H NMR analysis. e Estimated via crude 1H
NMR analysis. f In the absence of NHC A. N.D. = Not determined.
Org. Lett., Vol. 14, No. 8, 2012
2155

Mechanistically, the enolate key intermediate (III,
Scheme 1b) was likely formed through deprotonation
of the NHC-bounded activated ester intermediate
(II, Scheme 1b). We postulated that intermediate II
(Scheme 1b) was formed through a direct nucleophilic
addition of NHC to ester substrate I. Our studies (see
Supporting Information (SI)) suggested that a ketene
intermediate was unlikely to be involved in the reactions.11
One catalyst deactivation pathway was observed during
the reaction optimizations (eq 1), which further confirmed
the involvement of NHC in the catalytic activation of
esters to generate enolate intermediates (see SI).12
could not be prepared using either NHC7,13 or enamine14
catalysis.15 For example, ketenes from monoaryl acetyl
chlorides were ineffective substrates under NHC catalysis;
arylacetyl aldehydes in enamine catalysis pose special
challenges due to competing (and even dominated) self-
aldol reactions and easy R-carbon chiral center racemiza-
tion of the resulting aldehyde products.
Scheme 2. Scope of the Unsaturated Imine Substrate 2a
We next chose the readily available and chromatogra-
phically stable 4-nitro-phenol esters (e.g., 1a6) to develop
enantioselective reactions. With achiral precatalyst A,
increasing the reaction temperature led to a better yield
with similar dr. Triazolium-based chiral catalyst B was not
effective even at elevated temperatures. Fortunately, by
using a less bulky catalyst C, the product could be obtained
in 59% yield and 94:6 er at rt (Table 2, entry 5). Catalyst D
was less enantioselective than C (Table 2, entry 6). We next
sought to improve the reaction yield and found that the use
of tetraalkylammonium halides was beneficial for unclear
reasons (Table 2, entry 7). By using 1 equiv of Me4NCl
additive and an excess (5ꢀ10 equiv) of DIEA, the reaction
could also be efficiently carried out at 0 °C to give the
product with excellent yield, dr, and ee (Table 2, entry 8).
Table 2. Enantioselective Activation of Esters
a Reaction conditions (Table 2, entry 7).
temp
yield
(%)c
entrya
NHC
add.b
(°C)
drd
ere
The scope of the reaction with respect to the R,β-
unsaturated imine substrates (2) was then examined
1
2
3
4
5
6
7
8f
A
A
B
C
C
D
C
C
ꢀ
rt
70
70
70
rt
rt
rt
0
61
83
14
72
59
78
87
89
7:1
ꢀ
ꢀ
10:1
N.D.
12:1
12:1
10:1
20:1
20:1
ꢀ
(11) (a) Radt, C. W.; Ried, W. Angew. Chem., Int. Ed. 1963, 2, 397. (b)
Bekele, T.; Shah, M. H.; Wolfer, J.; Abraham, C. J.; Weatherwax, A.;
Lectka, T. J. Am. Chem. Soc. 2006, 128, 1810–1811. (c) Paull, D. H.;
Wolfer, J.; Grebinski, J. W.; Weatherwax, A.; Lectka, T. Chimia 2007,
61, 240–246. (d) Abraham, C. J.; Paill, D. H.; Bekele, T.; Scerba, M. T.;
Lectka, T.; Dudding, T. J. Am. Chem. Soc. 2008, 130, 17085–17094.
(12) A conclusive kinetic picture of the reaction (Table 1) is difficult
to obtain due to catalyst deactivation and other unidentified side
reactions. A preliminary single-point kinetic study suggested that only
one ester molecule was involved in the rate-determine step for the
formation of 3.
(13) (a) Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008,
10, 957–960. (b) Fang, X. Q.; Chen, X. K.; Chi, Y. R. Org. Lett. 2011, 13,
4708–4711. (c) Lv, H.; Mo, J. M.; Fang, X. Q.; Chi, Y. R. Org. Lett.
2011, 13, 5366–5369. For R,R-disubstituted ketenes reacted with
1-azadienes, see: ref 3h.
ꢀ
N.D.
86:14
94:6
84:16
94:6
96:4
ꢀ
ꢀ
ꢀ
Me4NCl
Me4NCl
a Reaction condition: 1a6 (0.15 mmol), 2a (0.10 mmol), solvent (0.5 mL).
b Additive (100 mol %; see SI). c Isolated yield (major diastereomer) based
on 2a. d Diasteromeric ratio of 3a determined via 1H NMR analysis of
unpurified reaction mixtures. e er of the major diastereomer (3a), determined
via chiral phase HPLC analysis; absolute configuration of product was
determined via X-ray of 3o (Scheme 3; see SI). f 10 equiv of DIEA were used.
N.D. = Not determined.
(14) Enamine catalysis approach (with nonarylacetyl aldehyde
substrates): (a) Han, B.; Li, J. L.; Ma, C.; Zhang, S. J.; Chen, Y. C.
Angew. Chem., Int. Ed. 2008, 47, 9971–9974. (b) Han, B.; He, Z. Q.; Li,
J. L.; Li, R.; Jiang, K.; Liu, T. Y.; Chen, Y. C. Angew. Chem., Int. Ed.
2009, 48, 5474–5477.
It is interesting to note that such formal [4 þ 2] products
(3) with a single aryl substituent at the lactam R-carbon
2156
Org. Lett., Vol. 14, No. 8, 2012

(Scheme 2). The rt condition in the presence of an ammo-
nium halide additive and 5 equiv of DIEA (a slight
modification of Table 2, entries 7ꢀ8) could generally give
products with good yields and stereoselectivities for most
substrates within 24 h. The imine substrates with electron-
withdrawing or -donating or heteroaryl groups at Ar1
substituents were all tolerated (Scheme 2, 3aꢀg). Similarly,
substitutions at Ar2 did not lead to significant changes in
reaction outcomes (Scheme 2, 3hꢀn).
Scheme 3. Scope of the Ester Substrate 1a
We next evaluated the effects of the arylacetic ester
substrates (Scheme 3). The Ar group of esters (1) with
electron-withdrawing bromo, chloro and electron-donat-
ing methoxyl or methyl substituents were all excellent
substrates, giving products with good to excellent dr’s
and er’s (Scheme 3, 3oꢀr). Sterically bulkier esters with
naphthyl substituents (3s, t) and heteroaryl substituted
esters (3u, v) gave products with relatively low er’s without
further extensive condition optimizations. We also at-
tempted to replace the Ar substituent of ester 1 with alkyl
units (e.g., PhCH2). Under conditions evaluated in this
work, no product such as 3 was obtained. The esters
underwent hydrolysis with the residual water present in
the reaction mixture with a prolonged reaction time. It
appears that a different set of conditions (base, NHC, etc.)
must be developed for these esters with relatively low
acidities of the R-CH’s. R,R-Disubstituted esters and the
related R,β-unsaturated ketones (such as chalcones) were
also not effective substrates under current conditions.
Insummary, we havedevelopedthe first NHC-catalyzed
activation of stable carboxylate esters to form enolate
intermediates. The catalytically generated NHC-bounded
ester enolate intermediates undergo enantioselective reac-
tions with R,β-unsaturated imines. The catalytic process
likely proceeds through a direct addition of NHC to the
ester substrate without involving a ketene intermediate.
We expect our studies to shed insightful light on the
fundamentally challenging process of catalytic activa-
tions of stable esters to generate chiral enolate equiv-
alents and possibly other important intermediates (e.g.,
homoenolates). The use of esters will also offer opera-
tionally simpler synthetic methods. Further studies with
a Reaction conditions: same as those in Scheme 2. b2.0 equiv of DIEA.
d
c10 equiv of DIEA, and reaction at 0 °C. 2.0 equiv of DIEA without
Me4NCl, and reaction at 60 °C in 1,2-dichloroethane.
respect to the activation of other esters and mechanistic
evaluations are in progress in our laboratory.
Acknowledgment. We are thankful for the generous
financial support from Singapore National Research
Foundation, Singapore Economic Development Board
(EDB), GlaxoSmithKline (GSK), and Nanyang Techno-
logical University (NTU) and for help from Dr. Y. Li and
Dr. R. Ganguly, Div. of Chemistry and Biological Chem-
istry, NTU, Singapore (X-ray structure).
Supporting Information Available. Experimental de-
tails. This material is available free of charge via Internet
at http://pubs.acs.org.
(15) After submission of this manuscript, Smith’s group reported a
chiral isothiourea-catalyzed transformation of carboxylic acids to simi-
lar products. Simal, C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew.
Chem., Int. Ed. 2012, 10.1002/anie.201109061.
The authors declare no competing financial interest.
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