Organocatalytic activation of alkylacetic esters as enolate precursors to react with α,β-unsaturated imines

Article abstract of DOI:10.1021/ol4021805

Asymmetric functionalization of alkylacetic esters and their derivatives is traditionally achieved via preformed enolates with chiral auxiliaries. Catalytic versions of such transformations are attractive but challenging. A direct catalytic activation of simple alkylacetic esters via N-heterocyclic carbene organocatalysts to generate chiral enolate intermediates for highly enantioselective reactions is reported.

Full text of DOI:10.1021/ol4021805

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Organocatalytic Activation of Alkylacetic
Esters as Enolate Precursors to React
with r,β-Unsaturated Imines
Lin Hao, Shaojin Chen, Jianfeng Xu, Bhoopendra Tiwari, Zhenqian Fu, Tong Li,
Jieyan Lim, 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 August 1, 2013
ABSTRACT
Asymmetric functionalization of alkylacetic esters and their derivatives is traditionally achieved via preformed enolates with chiral auxiliaries.
Catalytic versions of such transformations are attractive but challenging. A direct catalytic activation of simple alkylacetic esters via
N-heterocyclic carbene organocatalysts to generate chiral enolate intermediates for highly enantioselective reactions is reported.
Carboxylic esters and their derivatives are readily avail-
able and inexpensive substrates widely used in pharma-
ceutical and fine chemical synthesis. The versatile reactions
based on ester enolates can rarely be missed while design-
ing synthetic strategies for both small and complex mole-
cules. Consequently, enormous efforts have been directed
for the generation of chiral ester enolates and their equiva-
lents for effective reactions. Traditionally, chiral enolates
are preformed with the assistance of chiral auxiliaries, as
represented by Evans oxazolidinones and their variants
(Scheme 1a).1 Catalytic approaches for asymmetric gen-
eration of enolate intermediates directly from esters are
attractive but remain challenging (Scheme 1b).2 In related
efforts, aldehydes and ketones are now routinely used as
enamine precursors (“enolate analogs”) by employing
amine organocatalysts.3 Ketenes, activatedbynucleophilic
organocatalysts suchaschiral DMAPderivatives,4 cincho-
na alkaloids,5 and N-heterocyclic carbenes,6 can also
behave as ester enolate precursors. Recently, R-functiona-
lized aldehydes7 and R,β-unsaturated aldehydes8 have also
been used as enolate precursors via NHC catalysis, as
pioneered by Bode,7b,8a Rovis,7c Scheidt,8c and Glorius.8b,9
Despite the impressive success, the (functionalized)-
aldehyde and ketene substrates in these approaches pose
(1) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127–2129. Reviews: (b) Velazquez, F.; Olivo, H. F. Curr. Org.
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Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org.
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r
10.1021/ol4021805
XXXX American Chemical Society

acids worked well.11c A switch to the likely more useful
simple alkylacetic esters was unsuccessful, presumably due
tothe relatively poor electrophilicity of the alkylacetic ester
(to react with the NHC catalyst) and/or the low acidity of
the ester R-CꢀH. We now have addressed this problem
and report that simple alkylacetic esters can behave as effec-
tive enolate precursors under asymmetric catalysis (Scheme 1b).
The choice of NHC with suitable nucleophilicity (as
carbenes) and proper electron-withdrawing ability (as
triazoliums) is crucial in order to achieve controlled ester
activations. The sterics of NHC catalysts and the strength
of the bases also play important roles.
Scheme 1. Generation of Chiral Enolates from Esters
Our initial study and condition optimization is summar-
ized in Table 1 using ester 1a with an R-ethyl substituent as
a model substrate. The conditions (e.g., entry 1; cat. A,
DIEA) used in our earlier work for R-aryl acetic ester
activation10a,b did not lead to ester enolate generations.
Instead, the ester substrate (1a) under the catalysis of NHC
underwent hydrolysis to the corresponding carboxylic
acid. This observation indicated that an initial addition
of NHC to ester 1a toform NHC-bound ester intermediate
I did occur (in the presence of NHC, more rapid hydrolysis
of esters was observed) (Scheme 1b). The failure of enolate
generation was likely due to the relatively low acidity of the
R-CꢀH of intermediate I. Addressing the acidity issue was
not trivial as increasing the strength of the bases could lead
to background reactions (e.g., base-catalyzed deprotona-
tion of ester 1a without involving NHC catalysts) and
profound hydrolysis of the ester substrate. Fortunately, we
a few intrinsic limitations such as instabilities, relatively
poor availabilities, and somewhat undesired synthetic
steps to prepare these substrates. Carboxylic esters and
acids may be superior substrates on certain aspects from
the perspective of practical applications. On the funda-
mental side, the challenging asymmetric catalytic activa-
tion of ester is expected to generate insightful knowledge
for catalyst and reaction designs.10
Very recently, Smith and co-workers creatively used
isothioureas as nucleophilic catalysts to activate in situ
formed carboxylic anhydrides as enolate intermediates for
intra- and intermolecular additions to electron-deficient
alkenes.11 Our laboratory disclosed that stable esters de-
rived from R-aryl acetic acids could be activated with NHC
catalysts to generate ester enolate intermediates.10,12 In our
earlier approach,10a,b the ester substrate was limited to
R-aryl acetic esters. In Smith’s elegant study, the anhydride
substrates derived from R-aryl, alkyl, and heteroacetic
(9) For reviews on NHC catalysis, see: (a) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606–5655. (b) Marion, N.; Diez-
Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000.
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2698. (d) Rovis, T. Chem. Lett. 2008, 37, 2–7. (e) Glorius, F.; Hirano, K.
Ernst Schering Found. Symp. Proc. 2008, 2, 159–181. (f) Arduengo, A. J.,
III; Iconaru, L. I. Dalton Trans. 2009, 6903–6914. (g) Phillips, E. M.;
Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55–66. (h) Moore,
J. L.; Rovis, T. Top. Curr. Chem. 2011, 291, 77–144. (i) Biju, A. T.; Kuhl,
N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182–1195. (j) Hirano, K.; Piel,
I.; Glorius, F. Chem. Lett. 2011, 40, 786–791. (k) Chiang, P.-C.; Bode,
J. W. TCI MAIL 2011, 149, 2–17. (l) Nair, V.; Menon, R. S.; Biju, A. T.;
Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011,
40, 5336–5346. (m) Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 44, 3–
11. (n) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314–
325. (o) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53–57. (p)
Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522. (q)
Douglas, J.; Churchill, G.; Smith, A. Synthesis 2012, 44, 2295–2309
and also see ref 7m.
(10) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi,
Y. R. Org. Lett. 2012, 14, 2154–2157. (b) Hao, L.; Chan, W. C.; Ganguly,
R.; Chi, Y. R. Synlett 2013, 24, 1197–1200. (c) Cheng, J.; Huang, Z.; Chi,
Y. R. Angew. Chem., Int. Ed. 2013, 52, 8592–8596. (d) Fu, Z.; Xu, J.;
Zhu, T.; Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 201310.1038/
nchem.1710.
(11) (a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.;
Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714–2720. (b) Simal, C.;
Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Angew. Chem., Int. Ed. 2012, 51,
3653–3657. (c) Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D.
Chem. Sci. 2012, 3, 2088–2093. Smith also reported creative work on
NHC-catalyzed carbonate activation and O- to C-acyl transfers; see: (d)
Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8, 3785–3788. For
a mechanistic study on isothiourea-catalyzed activation of anhydride,
see: (e) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.;
Smith, A. D. Chem. Sci. 201310.1039/c3sc51791h.
(7) For a review, see: (a) Rong, Z. Q.; Zhang, W.; Yang, G. Q.; You,
S. L. Curr. Org. Chem 2011, 15, 3077–3090. For selected examples, see:
(b) Chow, K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–8127.
(c) Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004,
126, 9518–9519. (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) Kawanaka,
Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 18028–
18029. (l) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I.
Org. Lett. 2009, 11, 3934–3937. (m) Phillips, E. M.; Wadamoto, M.;
Roth, H. S.; Ott, A. W.; Scheidt, K. A. Org. Lett. 2009, 11, 105–108. (n)
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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. (q) Jian, T. Y.; Sun,
L. H.; Ye, S. Chem. Commun. 2012, 48, 10907–10909. Also see: (r) He,
M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817–3820 and ref 2e.
(8) For selective protonations of enal β-carbons leading to NHC-
bound 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 of enal activations, 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.
(12) Lupton et al. reported elegant studies on NHC-catalyzed activa-
tion of R,β-unsaturated enol esters to generate R,β-unsaturated acyli-
midazoliums as electrophiles; see: (a) Ryan, S. J.; Candish, L.; Lupton,
D. W. J. Am. Chem. Soc. 2009, 131, 14176–14177. (b) Candish, L.;
Lupton, D. W. Org. Lett. 2010, 12, 4836–4839.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Identification of Suitable Conditionsa
Scheme 2. Mechanistic Studies
entry
NHC
base
yieldb (%)
drc
eed (%) (trans/cis)
1
A
A
A
B
C
D
E
F
G
G
DIEA
DBU
TBD
DBU
DBU
DBU
DBU
DBU
DBU
DBU
<1e
61
15f
<1e
92
2
6:1
extension of our ester activation approach to other reactions
(electrophiles) should be feasible.
3
10:1
4
The two diastereomers of product 3a were found to
undergo facile epimerizations to each other under the
catalytic conditions. The thermodynamically more stable
trans-isomer was obtained as the major product. For
example, subjecting a pure trans-isomer of 3a (or a diastereo-
meric mixture enriched with the cis-isomer) to the cat-
alytic condition14 led to an equilibrium of trans/cis-
isomers in around 7:1 ratio (Scheme 2, eq 1). In a separate
NHC-catalyzed reaction using deuterium-labeled ester 1b0
(95% D) as the substrate, the corresponding product 3b
was obtained with only 20% D retained (eq 2). The loss of
deuterium in the product (via H/D exchange with residual
water in the reaction likely as the proton source) was likely
due to epimerization of the lactam product 3b and/or
reversible interconversion between NHC-bound ester in-
termediate I and ester enolate intermediate II (Scheme 1b).
Due to the facile epimerization of the product, it remains
unknown which diastereomer (cis- or trans-3a) is formed
more rapidly. In addition, we found that the epimerization
process could readily occur in the presence (or absence) of
water or 4-nitrophenol. The reactions in the absence of
water were carried out in a glovebox using pretreated
anhydrous solvents and reagents. As an important note,
NHC-bound enolate intermediates generated from R-Cl-
aldehydes or enals in cycloadditions afforded syn-selective
lactam products, as reported by Ye7q and Bode.8a Studies
to elucidate the kinetic isotope effect (e.g., using substrates
1b and 1b0) were difficult because the reactions were very
fast (e.g., over 60% conversion for 2a in 15 min with the
formation of trans:cis-3a in 3:1 ratio). In the evaluation of
reaction scope, we chose 24 h as the reaction time to allow
equlibration of the products to reach a high dr (3:1 dr after
15 min vs 7:1 dr after 24 h).
5
6:1
5:1
6
54
97/87
7
<1e
16f
83
8
10:1
8:1
94/86
99/99
99/99
9
10
57g
8:1
a Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), THF (1.0 mL).
b Isolated yield (of combined diastereomers) based on 2a. In all cases
with DBU or TBD as the base (entries 2ꢀ10), the conversion of 1a was
over 90% as determined by 1H NMR analysis of unpurified reaction
mixtures; when DIEA was the base (entry 1), conversion of ester 1a was
50%. c Diastereomeric ratio of 3a, determined via 1H NMR analysis of
unpurified reaction mixtures. d ee of major/minor diastereomer of 3a,
determined via chiral-phase HPLC analysis; absolute configuration of
product was determined via X-ray of 3b (Scheme 3 and Supporting
Information; CCDC 896595 contains the supplementary crystallo-
graphic data). e No detectable formation of product as indicated via
TLC and crude 1H NMR analysis. f Estimated via 1H NMR analysis of
crude reaction mixture. g 20 mol % of NHC catalyst G was used. DIEA:
N,N-diisopropylethylamine, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene,
TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
later found that a use of DBU in THF was effective (Table 1,
entry 2). The use of stronger base (e.g., TBD, entry 3) led to
significant ester hydrolysis and the reaction product 3a was
obtained in low yield. Further studies with achiral triazolium
catalysts (AꢀC) showed that the catalysts structures could
affect the reaction outcomes (entries 2, 4, and 5), although
general correlations between NHC catalysts (steric and
electrophilic properties) and reaction outcomes remain un-
clear at this moment. Chiral catalysts were then examined
(entries 6ꢀ9), and triazolium precatalyst G, pioneered by the
Glorius group,13 was found to be optimal with regard to yield
and stereoselectivities (entry 9). Both diastereomers of 3a
were obtained with 99% ee, indicating exceptional enantio-
induction of the NHC catalysts for ester activations. Our
studies also showed that several other common solvents
(CH2Cl2, toluene, EtOAc, CH3CN) and inorganic bases
(e.g., Cs2CO3) could mediate these reactions with mod-
erate to good yields and excellent stereoselectivities (see the
Supporting Information). The fact that different solvents
and bases can work for this reaction suggests that future
Withthe optimized conditions(Table 1, entry 9) in hand,
the scope of the esters was examined (Scheme 3). Both
methyl- and ethyl-substituted acetic esters gave the corre-
sponding products with good yields, drs, and excellent ee’s
(3a and 3b). It is worth noting that the corresponding
2-propenal and 2-butenal (required for the preparation of
3a and 3b using literature approach in generating enolate
(13) (a) Piel, I.; Steinmetz, M.; Hirano, K.; Frohlich, R.; Grimme, S.;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 4983–4987.
(14) Significant decomposition of product 3a was observed when
only DBU was used in THF.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Examples of the Ester Substrate 1a
Scheme 4. Examples of the Imine Substrate 2a
a Reaction conditions: same as in entry 9, Table 1.
either enals or R-functionalized aldehydes). The use of
β-alkoxypropanoic acid ester could give lactam product 3i
with moderate yield, 14:1 dr, and 99% ee. The presence of
an amino group (as imide) at the R- or β-carbon of the
esters was also tolerated by switching to NHC precatalyst
D, albeit with low yields (3j and 3k). Ester substrates with
relatively bulky substituents (e.g., β,β-disubstituted pro-
panoic acid esters) reacted well using nonchiral NHC
precatalyst C (3l, 54% yield). When chiral NHC catalysts
were used, the reactivity of the bulky ester dropped
significantly (e.g., NHC G, <5% yield). The scope of the
R,β-unsaturated imines was also examined, as shown in
Scheme 4. In general, unsaturated imines with different
1,3-diaryl substituents all reacted well (3mꢀs, Scheme 4).
In summary, we have developed the first asymmetric
organocatalytic activation of simple alkylacetic esters as
ester enolate equivalents for highly enantioselective
reactions. In the arena of asymmetric catalysis, especially
organocatalysis, aldehydes, ketones, and ketenes (and their
derivatives) have been extensively evaluated. However, the
more readily available and inexpensive carboxylic acids
and esters are much less studied. We hope this work on
simple ester activation will lead to additional investigation
on esters for the development of mechanistically interest-
ing activation modes and practically useful chemical
transformations.
a Reaction conditions are the same as in entry 9, Table 1. b Reaction
_
conditions: chiral catalyst D (30 mol %), Me4NCl (100 mol %), 4 A MS
(25 mg), and 1,2-dichloroethane (1.0 mL). c Achiral NHC C was used.
intermediates from enals) have remained challenging sub-
strates in NHC-enolate chemistry,8 and very limited stud-
ies on these simple enals have been reported.8e The ester
with a longer alkyl chain containing a terminal bromo
substituent could also react well (3c). It should be noted
that under other approaches the presence of alkyl halides
is typically problematic. For example, under the typical
chiral auxiliary approach, alkyl bromides (relatively reac-
tive electrophiles) will undergo (undesired) reactions with
the enolates (e.g., lithium ammonium enolates) under
strong basic conditions.15 In enamine catalysis (for alde-
hydes and ketones), alkyl halides will normally lead to
amine catalyst deactivation.16 The alkylacetic esters with
various β-(hetero)aryl substituents were also excellent
substrates (3dꢀh). We then evaluated esters substituted
with heteroatom functional groups (which could not
be activated by NHC as enolate precursors using
Acknowledgment. We acknowledge the generous finan-
cial support from the Singapore National Research Foun-
dation (NRF), and Nanyang Technological University
(NTU). We thank Dr. Y. Li (NTU) and Dr. R. Ganguly
(NTU) for X-ray structures.
(15) Forareview, seeref1c. Forselected examples, see:(a)Wittenberger,
S. J.; McLaughlin, M. A. Tetrahedron Lett. 1999, 40, 7175–7178. (b)
Hilpert, H. Tetrahedron 2001, 57, 7675–7683. (c) Prashad, M.; Har, D.;
Chen, L. J.; Kim, H. Y.; Repic, O.; Blacklock, T. J. J. Org. Chem. 2002,
67, 6612–6617.
(16) For selected examples, see: (a) Sibi, M. P.; Zhang, R. Z.;
Manyem, S. J. Am. Chem. Soc. 2003, 125, 9306–9307. (b) Roudeau,
R.; Pardo, D. G.; Cossy, J. Tetrahedron 2006, 62, 2388–2394. (c) Metro,
T. X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72, 6556–6561. (d)
Kovackova, S.; Dracinsky, M.; Rejman, D. Tetrahedron 2011, 67, 1485–
1500. For an example of enamine catalyzed intramolecular R-alkylation
of aldehydes involving alkyl halides, see: (e) Vignola, N.; List, B. J. Am.
Chem. Soc. 2004, 126, 450–451.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX