Organocatalytic asymmetric intermolecular dehydrogenative α-alkylation of aldehydes using molecular oxygen as oxidant

Article abstract of DOI:10.1021/ol202090a

An organocatalytic enantioselective intermolecular oxidative dehydrogenative α-alkylation of aldehydes via benzylic C-H bond activation has been developed. The asymmetric reaction is smoothly fulfilled by using simple and green molecular oxygen as the oxi

Full text of DOI:10.1021/ol202090a

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5212–5215
Organocatalytic Asymmetric
Intermolecular Dehydrogenative
r-Alkylation of Aldehydes Using
Molecular Oxygen as Oxidant
Bo Zhang,† Shi-Kai Xiang,† LiꢀHe Zhang,† Yuxin Cui,*,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China,
and Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department
of Chemistry, East China Normal University, Shanghai 200062, China
yxcui@bjmu.edu.cn; jiaoning@bjmu.edu.cn
Received August 2, 2011
ABSTRACT
An organocatalytic enantioselective intermolecular oxidative dehydrogenative R-alkylation of aldehydes via benzylic CꢀH bond activation has
been developed. The asymmetric reaction is smoothly fulfilled by using simple and green molecular oxygen as the oxidant. Two hydrogen
dissociations make this transformation more environmentally benign because of high atom efficiency.
In the past decade, organocatalysis has experienced
dramatic growth.1 The magical performance of organoca-
talysis encouraged chemists to discover more efficient
approaches for construction of optically active com-
pounds. Among them, the organocatalytic asymmetric
R-alkylation of carbonyl comounds, especially of aldehydes,
has long been a challenging task.2 Recently, the intra-
molecular R-alkylation of aldehydes has been disclosed by
List3 and others.4 In contrast, the organocatalytic enantio-
selective intermolecular R-alkylation of aldehydes has been
rarely reported. MacMillan and co-workers made a signifi-
cant contribution on the asymmetric intermolecular
R-alkylation of aldehydes via a radical process by their
organo-SOMO catalysis or merging photocatalysis and
† Peking University.
‡ East China Normal University.
(1) For recent reviews on organocatalysis, see: (a) Erkkila, A.;
€
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (b) Brazier,
J. B.; Tomkinson, N. C. O. In Asymmetric Organocatalysis; List, B., Ed.;
Springer-Verlag: Heidelberg, 2010; Vol. 291, pp 281ꢀ347. (c) Lelais, G.;
MacMillan, D. W. C. In Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007;
pp 95ꢀ120. (d) Gerald, L.; MacMillan, D. W. C. Aldrichim. Acta 2006,
39, 79. (e) Mac-Millan, D. W. C.; Lelais, G. In New Frontiers in
Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; John Wiley & Sons:
Hoboken, 2007; pp 313ꢀ358. (f) Mukherjee, S.; Yang, J. W.; Hoffmann,
S.; List, B. Chem. Rev. 2007, 107, 5471. (g) Pihko, P. M.; Majander, I.;
(3) (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (b) Fu,
A.; List, B.; Thiel, W. J. Org. Chem. 2006, 71, 320.
(4) (a) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886. (b) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem.,
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Int. Ed. 2008, 47, 7539. (c) Rios, R.; Sunden, H.; Vesely, J.; Zhao, G.-L.;
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Dziedzic, P.; Cordova, A. Adv. Synth. Catal. 2007, 349, 1028. (d)
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Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunden, H.; Dziedzic,
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Erkkila, A. In Asymmetric Organocatalysis; List, B., Ed.; Springer-Verlag:
P.; Cordova, A. Chem.;Eur. J. 2008, 14, 7867.
Heidelberg, 2010; Vol. 291, pp 29ꢀ75. (h) List, B. Acc. Chem. Res. 2004,
37, 548. (i) Tanaka, F.; Barbas, C. F. In Enantioselective Organocata-
lysis: Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, 2007; pp 19ꢀ55. (j) Kano, T.; Maruoka, K. Chem.
Commun 2008, 5465.
(2) For reviews on asymmetric alkylation of glycine derivatives by
phase-transfer catalysis, see: (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
103, 3013. (b) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679.
(5) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(b) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582. (c) Wilson, J. E.; Casarez, A. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11332. (d) Nagib,
D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
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r
10.1021/ol202090a
Published on Web 09/08/2011
2011 American Chemical Society

during the formation of the enamine.12 In 2009, Cozzi’s
group first realized the organocatalytic stereoselective
alkylation of aldehydes via benzylic CꢀH bond activation
using DDQ as the oxidant (b, Scheme 1).13
Scheme 1. Strategies for Enantioselective R-Alkylation of
Aldehydes
The utilization of molecular oxygen as an oxidant has
attracted considerable attention because of its readily
availability and its inexpensive and environmental benign
character.14,15 More recently, a nonasymmetric oxidative
R-alkylation of ketones with benzylic CꢀH bond activa-
tion using molecular oxygen as oxidant promoted by
Brønsted acid was reported by Klussmann et al.16 Con-
sidering that the free acid could be generated in the
enamine catalytic process,6,9 we envisioned that the en-
antioselective R-alkylation of aldehydes might be realiz-
able in a simple and green way using molecular oxygen as
the oxidant under enamine catalysis and acid catalysis
(c, Scheme 1). Herein, we describe an organocatalytic
asymmetric oxidative dehydrogenative R-alkylation of
aldehydes via benzylic CꢀH bond activation using mole-
cular oxygen as the oxidant.
To validate our hypothesis, we embarked on the inves-
tigation with the reaction of commercially available
xanthene 1a with hexanal 2a in the presence of catalyst A
in CH3NO2 under O2 (1.0 atm). Interestingly, the desired
product 3aa was obtained in 63% yield with 56% ee
(enantiomeric excess) (entry 1, Table 1). Encouraged by
this result, we screened a range of the MacMillan
catalysts1c,e BꢀE, under the same reaction conditions.
The results showed that catalyst B is an effective organo-
catalyst for this transformation, which gave 3aa in 81%
yield with 73% ee (entry 2, Table 1). When pyrrolidine
derivatives FꢀH (eitherthe freeamine ortheirsalts of TFA
and PhCOOH) were employed as the catalysts, the reac-
tions did not work or only gave traces of the desired
product 3aa (entries 6ꢀ8). Different reaction temperatures
were subsequently surveyed. When the reaction was per-
formed at ꢀ5 °C, the ee value was improved to 80% and
the yield to 76% (entry 9, Table 1). Lowering the reaction
temperature to ꢀ15 °C raised the ee value to 87% but
decreased the yield to 33% (entry 10). Different solvents
were then screened. The results indicate that the reactions
in CH3NO2 performed the best in terms of yield and ee
value (entries 11ꢀ16, Table 1). Gratifyingly, H2O as an
additive had a significant effect on this asymmetric R-
alkylation. When 10 equiv of H2O was employed, the
desired alkylation product 3aa was obtained in 71% yield
enamine catalysis.5 Another important SN1-type enantiose-
lective intermolecular R-alkylation of aldehydes, with a
stabilized carbocation generated from an alcohol with the
acid involved in the enamine catalysis,6,7 or by dissociation
of arylsulfonyl8 group (a, Scheme 1), has been developed by
Cozzi6 and Melchiorre.8 Our recent studies have also shown
the enantioselective tandem reduction and alkylation of
R,β-unsaturated aldehydes with a stabilized carbocation
generated in situ from loss of a hydroxyl group.9
On the other hand, a stabilized carbocation can be
produced from the benzylic CꢀH bond under different
oxidative conditions.10,11 Recently, Li and co-workers
have developed the cross-dehydrogenative coupling
(CDC reaction).11 However, the enantioselective R-alkyla-
tion of aldehydes with a potential electrophile via CꢀH
bond activation is more challenging, mainly because of the
stability of the produced carbocation and the potential side
reaction between the carbocation and the generated water
(6) (a) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009,
48, 1313. (b) Capdevila, M. G.; Benfatti, F.; Zoli, L.; Stenta, M.; Cozzi,
P. G. Chem.;Eur. J. 2010, 16, 11237. (c) Sinisi, R.; Vita, M. V.;
Gualandi, A.; Emer, E.; Cozzi, P. G. Chem. Eur. J. 2011, DOI:
10.1002/ chem.201100729.
(7) For an asymmetric SN1-type R-alkylation of cyclic ketones with a
potential carbocation by dissociation of hydroxy, see: Zhang, L.; Cui,
L.; Li, X.; Luo, S.; Cheng, J.-P. Chem.;Eur. J. 2010, 16, 2045.
(8) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2008, 47, 8707.
(9) Xiang, S.-K.; Zhang, B.; Zhang, L.-H.; Cui, Y.; Jiao, N. Chem.
Commun 2011, 47, 5007.
(10) (a) Xu, Y.-C.; Kohlman, D. T.; Liang, S. X.; Erikkson, C. Org.
Lett. 1999, 1, 1599. (b) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006,
45, 1949. (c) Tu, W.; Lei, L.; Floreancig, P. E. Angew. Chem., Int. Ed.
2008, 47, 4184. (d) Jeong, Y. J.; Kang, Y.; Han, A.-R.; Lee, Y.-M.;
Kotani, H.; Fukuzumi, S.; Nam, W. Angew. Chem., Int. Ed. 2008, 47,
7321. (e) Cheng, D.; Bao, W. Adv. Synth. Catal. 2008, 350, 1263.
(11) For some reviews on CDC reactions, see: (a) Li, C.-J. Acc. Chem.
Res. 2009, 42, 335. (b) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935. (c)
Scheuermann, C. Chem. Asian J. 2010, 5, 436.
(12) (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36,
66. (b) Minegishi, S.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2004,
126, 5174.
(13) (a) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 5919. For other asymmetric CDC reactions,
see: (b) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (c) Li, Z.; Macleod, P. D.;
Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590. (d) Shi, B.-F.; Maugel,
N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882. (e)
Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed. 2010,
49, 5558.
(14) For reviews, see: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400. (b) Punniyamurthy, T.; Velusamy, S.; Iqbal J. Chem. Rev. 2005,
105, 2329. (c) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39,
€
221. (d) Piera, J.; Backvall, J.-E. Angew. Chem., Int. Ed. 2008, 47, 3506.
(e) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854. (f)
Stoltz, B. M. Chem. Lett. 2004, 33, 362.
(15) For some of our recent work using dioxygen as an oxidant, see:
(a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 1. (b) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 7895. (c) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2010, 49, 4036. (d) Zhang, C.; Jiao, N. J. Am.
Chem. Soc. 2010, 132, 28. (e) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed.
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Chem., Int. Ed. 2010, 49, 1.
Org. Lett., Vol. 13, No. 19, 2011
5213

Table 1. Reaction of Xanthene 1a and Hexanal 2a in the
Presence of Different Conditionsa
Table 2. Reaction of Xanthene 1a, Thioxanthene 1b, and
10-Methyl-9,10-dihydroacridine 1c with Different Aldehydesa
entry
1
2(R)
temp (°C)
3
yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
1a C4H9
1a Me
2a
2b
2c
2d
2e
2f
ꢀ5
þ5
þ5
ꢀ5
þ5
þ5
þ5
þ5
þ5
ꢀ5
þ5
þ5
ꢀ5
þ5
3aa
3ab
3ac
3ad
3ae
3af
71
61
62
77
48
65
40
67
64
82
81
82
24
52
92
81
90
90
89
83
69
87
92
86
80
93
76
45
1a Et
1a C3H7
1a C5H11
1a C6H13
1a iPr
2g
2h
2i
3ag
3ah
3ai
1a allyl
1a benzyl
10d,e 1a p-MeO-benzyl 2j
11d,f 1a p-Me-benzyl 2k
12g 1a o-NO2-benzyl 2l
13d 1b C4H9
14h 1c C4H9
3aj
3ak
3al
entry
catalyst
solvent
temp (°C)
yieldb (%)
eec (%)
2a
2a
3ba
3ca
1
A
B
C
D
E
F
G
H
B
B
B
B
B
B
B
B
B
B
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DCM
5
5
63
56
73
2
81
a All reactions were carried out on the scale of 1 (0.2 mmol), 2
(0.6 mmol), catalyst B (0.04 mmol), and H2O (10 equiv) in 1 mL of dry
CH3NO2 at the appointed temperature under O2 (1 atm) for 4 days.
b Isolated yields. c The ee value was determined by chiral HPLC analysis.
d The commercial CH3NO2 (1 mL) was directly used. e Isolated yield
based on 51% conversion of xanthene. f Isolated yield based on 48%
conversion of xanthene. g Isolated yields based on 49% conversion of
xanthene. h The reaction was carried out in 1 mL of dry DCM with the
addition of 10 equiv of H2O.
3
5
trace
40
4
5
18
42
5
5
73
6
5
trace
nr
7
5
8
5
nr
9
ꢀ5
ꢀ15
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
5
76
80
87
82
83
10
11
12
13
14
15
16
17d
18e
33
21
DCE
29
67% yield with 87% ee value (entry 8). Moreover, this
method proved to be effective for a range of aldehydes
substituted with phenyl groups, leading to excellent ee
values (80ꢀ93%) (entries 9ꢀ12, Table 2). The reaction
using thioxanthene 1b and 10-methyl-9,10-dihydroacri-
dine 1c as the substrates could also execute this trans-
formation under these conditions but in moderate
enantiomeric excesses, respectively (entries 13 and 14,
Table 2). The absolute configuration of compound 3ai
was determined to be R by comparison of the elution order
of the products from a chiral phase HPLC column to those
reported in the literature.13
toluene
xylene
trace
nr
THF
nr
CH3CN
CH3NO2
CH3NO2
81
70
92
71
trace
a All reactions were carried out on the scale of 1a (0.2 mmol), 2a
(0.6 mmol), catalyst (0.04 mmol) in 1 mL of solvent at the appointed
temperature under O2 (1 atm) for 4 days. b Isolated yields; nr = no
reaction. c The ee value was determined by chiral HPLC analysis. d The
reaction was carried out in 1 mL of dry CH3NO2 and 10 equiv of H2O.
e The reaction was carried out under N2.
A plausible mechanism for the asymmetric transforma-
tion is illustrated in Scheme 2. We believe that the mechan-
ism includes two catalytic cycles: enamine catalysis and
acid catalysis. The enamine catalytic cycle involves con-
densation of the ammonium salt catalysts and the satu-
rated aldehydes 2 to generate iminium intermediates 4,
which are converted to the activated nucleophilic enamine
species 5 by deprotonation with the release of free acid
(HX). Subsequently, the nucleophilic enamine species 5
react with carbocations 8 to form new iminium intermedi-
ates 6. Finally, the products 3 are produced by hydrolysis
of 6 with formation of the ammonium salt catalysts to
complete the catalytic cycle. In the acid catalytic cycle, the
with 92% ee (entry 17, Table 1). The reaction under N2 did
not work (entry 18, Table 1).
With the optimized conditions in hand, the scope of this
transformation was then investigated (Table 2). A wide
range of aliphatic aldehydes smoothly underwent this
asymmetric transformation generating the desired alkyla-
tion products 3 in moderate to good yield (48ꢀ77%) with
excellent ee values (81ꢀ92%) (entries 1ꢀ6, Table 2). The
yields and ee values in the reaction of isovaleraldehyde 2g
were unsatisfactory, possibly due to steric hindrance in the
aldehyde (entry 7, Table 2). Aldehydes containing olefins
were tolerated in this transformation generating 3ah in
5214
Org. Lett., Vol. 13, No. 19, 2011

substrates 1 could be oxidized to peroxides 7 and/or 70 by a
radical pathway with O2.16,17 The peroxides 7 and/or 70
could then produce stabilized carbocations 816 catalyzed
by the free acid (HX) generated in the enamine catalysis or
by the ammonium salts serving as Brønsted acids.18 The
formed carbocations 8 immediately participate in the
enamine catalysis cycle to execute this transformation.
Further investigation showed that the isolated xanthene
peroxide 70 could directly react with 2a at 5 °C to produce
3aa in 83% yield with 89% ee (eq 1). This result indicates
that the peroxides 70 which could be generated from 7
under acidic conditions16,17 may be the key intermediates
of this transformation.
Scheme 2. Proposed Catalytic Cycles for the Enantioselective
Transformation
In summary, we have developed an organocatalytic
asymmetric intermolecular oxidative dehydrogenative R-
alkylation of aldehydes via benzylic CꢀH bond activation.
The asymmetric reaction is smoothly effected by using
simple and green dioxygen as the oxidant. Two hydrogen
dissociations make this transformation more environmen-
tally benign via high atom efficiency. Furthermore, that
the ammonium salt catalysts play dual roles not only as
enamine catalysts but also as acid catalysts, to broaden the
research into the areas of ammonium salt catalysis and the
cross-dehydrogenative coupling using dioxygen as the oxi-
dant. Further studies on the scope, the mechanism, and the
synthetic applications are ongoing in our laboratory.
(17) (a) Milas, N. A. Chem. Rev. 1932, 10, 295. (b) Rieche, A.; Hoeft,
E.; Schultze, H. Chem. Ber 1964, 97, 195. (c) Berkessel, A. Science of
Synthesis. Compounds with One Saturated CarbonꢀHeteroatom Bond.
Peroxides; Thieme: Stuttgart, 2009; Vol. 38, pp 9ꢀ141. (d) Davies, A. G.;
Foster, R. V.; Nery, R. J. Chem. Soc. 1954, 2204.
(18) (a) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006.
(b) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (c) Wiskur, S. L.; Fu, G. C. J.
Am. Chem. Soc. 2005, 127, 6176. (d) Nugent, B. M.; Yoder, R. A.;
Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. (e) Ishihara, K.;
Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127, 4168. (f)
Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am.
Chem. Soc. 2008, 130, 16858. (g) Wakasugi, K.; Misaki, T.; Yamada, K.;
Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249. (h) Akiyama, T.; Itoh, J.;
Fuchibea, K. Adv. Synth. Catal. 2006, 348, 999. (i) Huang, J.; Corey, E. J.
J. Org. Lett. 2004, 6, 5027. (j) Enders, D.; Narine, A. A.; Toulgoat, F.;
Bisschops, T. Angew. Chem., Int. Ed. 2008, 47, 5661.
Acknowledgment. Financial support from Peking Uni-
versity, the National Science Foundation of China
(20872003), and the National Basic Research Program of
China (973 Program 2009CB825300) is greatly appre-
ciated. We thank Guolin Wu in this group for reproducing
the results for 3ai and 3al.
Supporting Information Available. Experimental de-
tails, NMR spectra, and HPLC analysis of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5215