Direct α-functionalization of simple aldehydes via oxidative N-heterocyclic carbene catalysis

Article abstract of DOI:10.1021/ol303035r

A direct α-functionalization of simple aldehydes under N-Heterocyclic Carbene (NHC) catalysis and direct generation of ester enolate equivalents from nonfunctionalized aldehydes are disclosed. The catalysis involves selective enolate generation from an oxidatively generated NHC-bounded ester intermediate as a key step. The ester enolate intermediates undergo stereoselective reactions with enones and trifluoromethyl ketones.

Full text of DOI:10.1021/ol303035r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct r‑Functionalization of Simple
Aldehydes via Oxidative N‑Heterocyclic
Carbene Catalysis
Junming Mo, Ruojie Yang, Xingkuan Chen, Bhoopendra Tiwari, 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 November 5, 2012
ABSTRACT
A direct R-functionalization of simple aldehydes under N-Heterocyclic Carbene (NHC) catalysis and direct generation of ester enolate equivalents
from nonfunctionalized aldehydes are disclosed. The catalysis involves selective enolate generation from an oxidatively generated NHC-bounded
ester intermediate as a key step. The ester enolate intermediates undergo stereoselective reactions with enones and trifluoromethyl ketones.
Aldehydes are unambiguously an important class of
basic building blocks in organic synthesis. In recent years,
the enantioselective direct R-functionalization of simple alde-
hydes could be realizedusingaminesasorganocatalystsvia
enamine catalytic pathways1 or SOMO activation catalysis.2
In another arena of organocatalysis, the development in
N-heterocyclic carbene (NHC) catalysis3 has offered im-
portant strategies for a set of impressive asymmetric
transformations. However, in the activation of simple
aldehydes for new carbonꢀcarbon bond formations, only
the aldehyde carbonyl carbon could be used (via Breslow
intermediates) as a reactive nucleophilic carbon under
NHC catalysis. To functionalize the aldehyde R-carbon
(via enolate intermediates), only indirect methods could
be used. These indirect methods were primarily based on
prefunctionalized aldehyde derivatives such as R-chloro
aldehydes, as reported by Bode;4 R-aryloxy acetalde-
hydes, reported by Scheidt;5 R-aroyloxy aldehydes,
reported by Smith;6 and R,β-unsaturated aldehydes,
as disclosed by Glorius, Bode, Scheidt, Nair, and our
group.7 Alternatively, by using ketene (especially R,R0-
disubstituted ketene) substrates, access to similar enolate
(1) For selected recent reviews on enamine catalytic R-functionaliza-
tion of simple aldehydes: (a) Notz, W.; Tanaka, F.; Barbas, C. F., III.
Acc. Chem. Res. 2004, 37, 580. (b) List, B. Acc. Chem. Res. 2004, 37, 548.
ꢀ
(c) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (d) Marigo, M.;
Jørgensen, K. A. Chem. Commun. 2006, 2001. (e) Paloma, C.; Mielgo,
A. Angew. Chem., Int. Ed. 2006, 45, 7876. (f) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (g) Moyano, A.;
Rios, R. Chem. Rev. 2011, 111, 4703.
(2) For selected examples and recent reviews on SOMO activation
catalysis: (a) Beeson, T. D.; Mastracchio, A.; Hong, J.; Ashton, K.;
Macmillan, D. W. C. Science 2007, 316, 582. (b) Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 1360 and ref 1g.
(3) For selected recent reviews on NHC catalysis: (a) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. (b) Zeitler, K. Angew.
Chem., Int. Ed. 2005, 44, 7506. (c) Enders, D.; Niemeier, O.; Henseler, A.
Chem. Rev. 2007, 107, 5606. (d) Marion, N.; Diez-Gonzalez, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (e) Nair, V.; Vellalath, S.;
Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (f) Rovis, T. Chem. Lett.
2008, 37, 2. (g) Arduengo, A. J., III; Iconaru, L. I. Dalton Trans. 2009,
6903. (h) Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Acta
2009, 42, 55. (i) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 291, 77. (j)
Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (k)
Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786. (l) Chiang,
P.-C.; Bode, J. W. TCI MAIL 2011, 149, 2. (m) Nair, V.; Menon, R. S.;
Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc.
Rev. 2011, 40, 5336. (n) Rong, Z. Q.; Zhang, W.; Yang, G. Q.; You, S.-L.
Curr. Org. Chem. 2011, 15, 3077. (o) Vora, H. U.; Rovis, T. Aldrichimica
Acta 2011, 44, 3. (p) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3, 53.
(q) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3512. (r) Grossmann,
A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314.
(4) For a selected example of NHC-catalyzed R-functionalization of
R-chloro aldehydes, see: He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem.
Soc. 2006, 128, 15088.
(5) For selected examples of NHC-catalyzed R-functionalization of
R-aryloxyacetaldehydes, see: (a) Maki, B. E.; Scheidt, K. A. Org. Lett.
2009, 11, 1651. (b) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am.
Chem. Soc. 2009, 131, 13028.
(6) For a selected example of NHC-catalyzed R-functionalization of
R-aroyloxy aldehydes, see: Ling, K. B.; Smith, A. D. Chem. Commun.
2011, 47, 373.
r
10.1021/ol303035r
XXXX American Chemical Society

intermediates via NHC catalysis was explored by the
groups of Smith and Ye.8 Despite the impressive progress,
the drawbacks of these otherwise very successful ap-
proaches include the relative instabilities of the substrates
and/or somewhat undesired synthetic efforts in preparing
these substrates. It has become clear that the employment
of simpler and more readily available substrates (e.g.,
simple alcohols, aldehydes, carboxylic acids, and esters)
will constitute a significant advancement in asymmetric
catalytic enolate chemistry. Here we report a direct
R-functionalization of simple aldehydes under oxidative
NHC catalysis and the direct generation of ester enolates
by using simple nonfunctionalized aldehydes as sub-
strates. Our work provides solutions that are comple-
mentary to the direct enamine catalysis approach and
indirect NHC catalysis methods for R-functionalization
of simple aldehydes. It is of special note that Rovis and
co-workers’s independent research on similar chemistry
just appeared online on the day of submission of our
manuscript.9
Table 1. Condition Optimizationa
entry
base
DBU
solvent
yield (%)b
drc
eed
1
2
THF
54
ꢀ
7:1
ꢀ
99
ꢀ
DIEA
THF
3
TEA
THF
ꢀ
ꢀ
ꢀ
4
DMAP
pyridine
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
<5
ꢀ
ꢀ
ꢀ
5
THF
ꢀ
ꢀ
6
THF
41
50
83
66
73
19
62
20:1
20:1
20:1
20:1
20:1
4:1
20:1
99
99
99
99
99
n.d.
99
7
THF
8e
9e
10e
11e
12e
THF
MeCN
CH2Cl2
DMF
toluene
a Reaction conditions: 0.1 mmol of 1a, 0.1 mmol of 2a, 0.1 mmol of B.
b Isolated yield based on 2a. c Diastereomeric ratio of 3a, determined via
1H NMR analysis of crude reaction mixture. d Enantiomeric excess of
3a, determined via chiral phase HPLC analysis; the absolute configura-
tion of the major diastereomer was assigned based on the X-ray structure
of 3i (see Supporting Information). e 0.25 mmol of 1a, 0.25 mmol of B.
Scheme 1. Direct R-Functionalization of Simple Aldehydes
aldehydes has also been studied by the groups of Scheidt
and others.10jꢀs The other key step is a selective deproto-
nation of II to form chiral enolate intermediate III. This
deprotonation step (II to III) should be feasible based on
our recent work on NHC-catalyzed activation of esters for
enolate formation.11 In contrast, the high reactivity of the
NHC-bounded ester intermediate (e.g., toward hydrolysis,
etc.)12 and potential competing reactions of the acyl anion
intermediate I (e.g., Stetter reactions)13 with electrophiles
have made the achievement of effective enolate chemistry
difficult.
We started by using aldehyde 1a and chalcone 2a as
model substrates and triazolium A4 as an NHC precatalyst
Our working hypothesis is illustrated in Scheme 1b. One
important stepisthe oxidation of Breslow intermediateI to
form NHC-bounded ester intermediate II. This process in
the oxidation of aldehydes to acids, esters, and amides as
the final products has been pioneered by several groups.10
The related NHC-catalyzed oxidation of R,β-unsaturated
(10) For examples of (self- or external) oxidation of nonenals under
NHC catalysis, see: (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 8126. (b) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 9518. (c) Zeitler, K. Org. Lett. 2006, 8, 637. (d)
Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (e) Noonan, C.;
Baragwanath, L.; Connon, S. J. Tetrahedron Lett. 2008, 49, 4003. (f)
Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891. (g) Yoshida, M.;
Katagiri, Y.; Zhu, W.-B.; Shishido, K. Org. Biomol. Chem. 2009, 7, 4062.
(h) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc.
2009, 131, 18028. (i) Xin, Y.-C.; Shi, S.-H.; Xie, D.-D.; Hui, X.-P.; Xu,
P.-F. Eur. J. Org. Chem. 2011, 6527. For examples of oxidation of enals
under NHC catalysis, see: (j) Maki, B. E.; Chan, A.; Phillips, E. M.;
Scheidt, K. A. Org. Lett. 2007, 9, 371. (k) De Sarkar, S.; Grimme, S.;
Studer, A. J. Am. Chem. Soc. 2010, 132, 1190. (l) De Sarkar, S.; Studer,
A. Angew. Chem., Int. Ed. 2010, 49, 9266. (m) Reddy, R. S.; Rosa, J. N.;
Veiros, L. F.; Caddick, S.; Gois, P. M. P. Org. Biomol. Chem. 2011, 9,
3126. (n) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080.
(7) For selected examples of NHC-catalyzed R-functionalization of
enals, see: (a) Glorius, F.; Burstein, C.; Tschan, S.; Xie, X. Synthesis
2006, 2418. (b) Bode, J. W.; He, M.; Struble, J. R. J. Am. Chem. Soc.
2006, 128, 8418. (c) Scheidt, K. A.; Phillips, E. M.; Wadamoto, M.;
Chan, A. Angew. Chem., Int. Ed. 2007, 46, 3107. (d) Fang, X.; Chen., X.;
Chi., Y. R. Org. Lett. 2011, 13, 4708. (e) Nair, V.; Paul, R. R.; Lakshmi,
K. C. S.; Menon, R. S.; Jose, A.; Sinu, C. R. Tetrahedron Lett. 2011, 52,
5992.
(8) For selected examples of NHC-catalyzed R-functionalization of
ketenes, see: (a) Zhang, Y. R.; He, L.; Wu, X.; Shao, P. L.; Ye, S. Org.
Lett. 2008, 10, 277. (b) Duguet, N.; Campbell, C. D.; Slavin, A. M. Z.;
Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108. (c) Huang, X.-L.; He, L.;
Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009, 48, 192.
(9) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem., Int. Ed. 2012,
51, 12330.
€
(o) Biswas, A.; De Sarkar, S.; Frohlich, R.; Studer, A. Org. Lett. 2011,
13, 4966. (p) Maji, B.; Vedachalan, S.; Ge, X.; Cai, S.; Liu, X.-W. J. Org.
Chem. 2011, 75, 3016. (q) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc.
2012, 134, 8810. (r) Biswas, A.; De Sarkar, S.; Tebben, L.; Studer, A.
Chem. Commun. 2012, 48, 5190. (s) Kravina, A. G.; Mahatthananchai,
J.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9443.
B
Org. Lett., Vol. XX, No. XX, XXXX

(Table 1). With DBU as the base, among the oxidants
examined,14 quinone B was found to be effective in giving
the enollactoneproduct3ainanencouraging yield, dr, and
ee (Table 1, entry 1). Weaker organic bases, such as DIEA,
TEA, DMAP, and pyridine, were not effective in promot-
ing this reaction (entries 2ꢀ5). In these cases, most alde-
hyde substrates remained unconsumed, as revealed by
TLC and NMR analysis. When inorganic base Cs2CO3
was used with THF as the solvent, a higher dr (20:1 dr,
entry 7) was obtained, compared to the reaction using
DBU as the base (entry 1). The low 50% yield (entry 7) was
mainly caused by the competing hydrolysis of intermediate
II (Scheme 1b). By increasing the amount of aldehyde
substrate to 2.5 equiv, an acceptable yield (83% isolated
yield) along with an excellent dr and ee was obtained (entry 8).
A brief evaluation of solvents showed that other common
solvents (e.g., CH3CN, CH2Cl2, toluene, DMF; entries
9ꢀ12) were also suitable for this oxidative enolate gen-
eration, suggesting that this chemistry might be further
developed for a large set of reactions.
reacted well, giving products in good yields, with an
excellent dr and ee. Aldehydes with R-aryl substituents,
or with R,R0-disubstituents, led to no formation of the
δ-lactone products; most of the aldehyde substrate and the
oxidant (B) remained unreacted using anhydrous THF as
the solvent.15 Chalcone substrates with different types of
(hetero)aryl substituents all reacted well (3a and 3hꢀo).
Enones with alkyl substituents led to no observable con-
versions. Asa special note, theδ-lactoneproductsobtained
in our studies could not be easily accessed using other
reported approaches. For example, the related asymmetric
enamine catalysis approach using aldehyde prenucleo-
philes worked well only with more reactive modified
enones as the electrophiles.16
Given the relatively broad conditions (e.g., solvents,
bases, etc.) available for this oxidative enolate generation
chemistry, it is possible to develop reactions using other
electrophiles. For example, trifluoromethyl aryl ketones
(eq 1, Scheme 2) could react with simple aldehydes (e.g., 1a)
to form the corresponding β-lactones (5a and 5b), albeit in
moderate yields and dr’s, under the conditions employed
in Table 2.7a
Table 2. Examples of Aldehydes and Chalconesa
Scheme 2. Reactions Using Trifluoromethyl Aryl Ketone as
Electrophile and MnO2 as Terminal Oxidanta
yield
3
R
Ar, Ar0
Ph, Ph
(%)b
drc
eed
3a
3b
3c
3d
3e
3f
Ph
H
83
78
81
88
84
84
80
91
95
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
10:1
99
99
99
99
99
99
99
99
99
Ph, Ph
Me
Ph, Ph
n-C3H7
n-C7H15
4-MeOC6H4
4-BrC6H4
Ph
Ph, Ph
Ph, Ph
Ph, Ph
3g
3h
3i
Ph, Ph
4-ClC6H4, Ph
4-ClC6H4,
4-ClC6H4
3-Py, Ph
Ph
a The relative configurations of β-lactones were assigned following
ref 7a.
3j
Ph
84
79
94
71
73
70
20:1
20:1
20:1
20:1
20:1
20:1
99
99
99
99
99
99
3k
3l
Ph
Ph, 2-furyl
Ph, 4-ClC6H4
4-MeC6H4, Ph
4-MeOC6H4, Ph
Ph, 4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
We also tried to develop protocols that could use more
readily available terminal oxidants that were cheaper than
3m
3n
3o
(13) For selected examples of acyl anion equivalents from aldehydes,
see: (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639. (b) Stetter,
H.; Hilboll, G.; Kuhlmann, H. Chem. Ber. 1979, 112, 84. (c) Stetter, H.;
Jonas, F. Chem. Ber. 1981, 114, 564. (d) Enders, D.; Breuer, K.; Runsink,
J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899. (e) Kerr, M. S.; Read de
Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (f) Hachisu, Y.;
Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432. (g) Kerr,
M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (h) Mattson, A. E.;
Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314. (i)
Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932. (j) DiRocco, D. A.; Rovis, T. J. Am. Chem.
Soc. 2011, 133, 10402. (k) Fang, X.-Q.; Chen, X.-K.; Lv, H.; Chi, Y. R.
Angew. Chem., Int. Ed. 2011, 50, 11782. (l) Liu, G.; Wilkerson, P. D.;
Toth, C. A.; Xu, H. Org. Lett. 2012, 14, 858.
a Reaction conditions same as those in Table 1, entry 8. b Isolated
yield based on 2. c Diastereomeric ratio of 3, determined via 1H NMR
analysis of crude reaction mixture. d Enantiomeric excess of 3, deter-
mined via chiral phase HPLC analysis.
With the optimized conditions in hand, the scope of the
aldehydes and enones were examined (Table 2). Several
representative aldehyde substrates were examined
(Table 2, 3aꢀg). Aldehydes with aryl (3a, 3f, and 3g) or
alkyl substituents (3bꢀe) at the aldehyde β-carbon all
(14) Quinone, TEMPO, acridine, and MnO2 are not effective oxi-
dants in the reaction.
(11) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y. R.
Org. Lett. 2012, 14, 2154.
(15) When the solvent was not dry enough, aldehyde was consumed
and acid was detected by TLC and crude 1H NMR.
(12) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860.
(16) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10, 2561.
Org. Lett., Vol. XX, No. XX, XXXX
C

quinone B (Aldrich price: $100 per 50 mg). We found that
by using a catalytic amount of B (10 mol %) in the presence
of MnO2 (Aldrich price: $160 per 1000 g) as an oxidant, the
oxidative enolate reaction could be realized to obtain the
δ-lactone products (in gram scale) with excellent yields and
selectivities (eq 2, Scheme 2). In the presence of MnO2
alone, nearly no detectable formation of the δ-lactone
product was observed (most of the aldehyde substrate
could be recovered). This result suggests that the role of
MnO2 is to oxidize the reduced form of B back to quinone
and thus a catalytic amount of B can be used. It is
important to note that the groups of Scheidt,10d,j Hui,10i
and Liu10p have used MnO2 as the oxidant under NHC
catalysis for the conversion of alcohols, aryl aldehydes,
and enals to esters.
terminal oxidants. Given the wide use of enolate and
enolate equivalents in organic synthesis, we expect this
new approach for catalytic generation of chiral enolate
intermediates from simple substrates to be broadly useful.
The versatile conditions for this chemistry will likely allow
for a set of other reactions to be developed.
Acknowledgment. We thank Singapore National Re-
search Foundation (NRF), Singapore Economic Devel-
opment Board (EDB), GlaxoSmithKline (GSK), and
Nanyang Technological University (NTU) for the gener-
ous financial support and Dr. Y. Li and Dr. R. Ganguly
(NTU) for the X-ray structure.
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.
In summary, we have developed the oxidative genera-
tion of enolates for R-functionalization of simple nonfunc-
tionalized aldehydes under NHC catalysis. The organic qui-
none oxidants can be made catalytic by using inexpensive
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX