Ethylene glycol: A powerful catalyst-free medium for C-C bond-forming reactions

Article abstract of DOI:10.1002/asia.201200289

A good EG: Ethylene glycol (EG) is a catalyst-free medium that can promote the highly efficient Strecker reaction of α-CF₂H or α-CF₃ ketoimines and TMSCN. EG was used in several reactions, including the catalyst-free Morita-Baylis-Hi

Full text of DOI:10.1002/asia.201200289

DOI: 10.1002/asia.201200289
À
Ethylene Glycol: A Powerful Catalyst-Free Medium for C C Bond-Forming
Reactions
Yun-Lin Liu,[a] Xing-Ping Zeng,[a] and Jian Zhou*[a, b]
Over the past two decades, researches have revealed that
some organic solvents can promote certain reactions very ef-
ficiently in the absence of any catalyst.[1] For example, Ko-
bayashi and Hirabayashi reported an efficient N,N-dimethyl-
formamide (DMF)-mediated allylation of benzoylhydra-
zones by using allyltrichlorosilane.[1a] Huang and Rawal
found that using 2-butanol as the solvent promoted an effi-
cient hetero-Diels–Alder (HDA) reaction of unactivated ke-
tones.[1b] Ding and co-workers reported an acid-free HDA
reaction of Danishefsky’s diene with imines in MeOH,[1c]
whilst Olah and co-workers discovered a catalyst-free cyano-
silylation of aldehydes in DMF.[1d] However, there are only
limited examples of the catalyst-free construction of tetra-
substituted carbon centers.[1–2] Herein, we report a remark-
able catalyst-free Strecker reaction of a-CF2H or a-CF3 ke-
toimines with TMSCN (TMS=trimethylsilyl) in ethylene
glycol; this reaction is more efficient than that catalyzed by
an acid or base (Scheme 1).
Owing to the importance of the selective introduction of
a CF3 or CF2H group in modulating the properties of organ-
ic molecules for medicinal applications, much attention has
Scheme 1. A remarkable catalyst-free Strecker reaction.
been paid to the development of facile methods to prepare
difluoro- or trifluoromethyl analogues of important com-
pounds.[3] In this context, we are interested in the synthesis
of a-tetrasubstituted a-amino nitriles that contain a-CF2H
or a-CF3 groups; these groups are valuable for the synthesis
of the fluorinated Ca-tetrasubstituted a-amino acids and dia-
mines, which are interesting targets for medical studies.[4]
Although the Strecker reaction[5] has been intensively stud-
ied, only very few reports have been based on the reactions
between a-CF2H or a-CF3 ketoimines and TMSCN.[6]
During our efforts in this area, we noticed that the presence
of a-fluorine atoms significantly influenced the reactivity of
a-CF2H or a-CF3 ketoimines, which were both less reactive
than their non-fluorinated analogues, and that the a-CF2H
ketoimines were less reactive than their corresponding a-
CF3 analogues.[6c] In addition, whilst the reaction between
compound 1a and TMSCN worked well in the presence of
tertiary amines, such as DABCO (1,4-diazabicyclo-
AHCTUNGTREG[NNUN 2.2.2]octane), that of aliphatic ketoimine 1x ended in a com-
plex mixture of products under the same conditions
(Scheme 1), possibly because imine–enamine tautomeriza-
tion under basic conditions led to side-reactions. Very sur-
prisingly, both H-bond-donor catalysts, such as catalyst 4,
and specific acid catalysts, such as p-TsOH or oxalic acid,
failed to catalyze the reaction (Scheme 1), possibly because
the a-fluorine atom interfered with the activation of imines
by Brønsted acids.[6c] To expand the substrate scope to allow
the diverse synthesis of a-tetrasubstituted a-CF2H or a-CF3
a-amino nitriles, we deemed it necessary to identify a neutral
reaction medium for problematic substrates like 1x.
[a] Y.-L. Liu, X.-P. Zeng, Prof. Dr. J. Zhou
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes
Department of Chemistry
East China Normal University
3663N, Zhongshan Road, Shanghai 200062 (China)
Fax : (+86)21-62234560
E-mail: jzhou@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhou
We have developed a catalyst-free “one-pot” sequential
State Key Laboratory of Elemento-organic Chemistry
Nankai University
Tianjin 300071 (P. R. China)
À
Strecker reaction of isatin, p-methoxyaniline (PMP NH2),
and TMSCN in MeOH.[7a] The role of MeOH was believed
to activate isatin-derived ketoimines through H-bonding in-
teractions and to activate TMSCN to form the more-reac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200289.
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COMMUNICATION
tive HCN.[7a] Based on this analysis, we speculated that eth-
ylene glycol might be a more efficient catalyst-free reaction
medium for the following reasons (Scheme 2): As dual hy-
drogen-bond donors,[8] the electrophiles might be activated
more effectively in ethylene glycol through two H bonds
Table 1. Optimization of the reaction conditions.
Entry[a]
Solvent
1a (R=Ph)
Yield [%][b]
1r (R=c-Hexyl)
t [h]
t [h]
Yield [%][b]
1[c]
2
3
4
5
ethylene glycol
ethylene glycol
MeOH
24
7
48
48
48
97
97
90
88
5
24
24
72
72
72
20
85
63
45
13
nPrOH
iPrOH
6
24
73
72
46
7
8
9
10
11
12
13
14
24
48
48
48
48
48
24
48
94
93
19
10
4
78
87
88
72
72
72
72
72
72
72
72
80
56
15
glycerin
H2O
H2O/THF[d]
THF
7
trace
trace
19
CH3CN
DMF
DMSO
trace
Scheme 2. Possible activation modes in ethylene glycol.
[a] On a 0.25 mmol scale; [b] yield of isolated product; [c] at 258C;
[d] H2O/THF (1:1, v/v).
(Scheme 2, i) or enhanced H-bond activation (Scheme 2, ii)
that results from the Brønsted-acid-assisted Brønsted acid
catalysis, as proposed by Yamamoto, Rawal, and co-worker-
s.[8e,f] Because of the pervasive H-bond donors in ethylene
glycol, the interference of fluorine atoms with the H-bond
activation of fluorinated imines[6c] would no longer be
a problem. In addition, trimethylsilyl nucleophiles might be
activated more efficiently through the formation of hexa-
coordinate silicates (Scheme 2, iii).[9] Accordingly, both elec-
trophilic and nucleophilic reaction partners could be activat-
ed efficiently in ethylene glycol. Importantly, the reaction
medium in ethylene glycol is neutral and, therefore, friendly
towards substrates that are able to undergo tautomerization
under acidic or basic conditions.
With this hypothesis in mind, we first tried the Strecker
reaction of imine 1a and TMSCN in ethylene glycol at
258C. Indeed, the reaction worked well to give the desired
product (3a) in excellent yield (Table 1, entry 1). However,
for the less-reactive ketoimine (1r), the reaction proceeded
very slowly and, even after 24 hours, the desired product
(3r) was obtained in only 20% yield. Increasing the temper-
ature to 508C afforded product 3r in 85% yield after
24 hours (Table 1, entry 2).
To obtain more information about the role of ethylene
glycol, other alcoholic solvents were tried in the reaction be-
tween imine 1a and TMSCN at 508C. MeOH and n-PrOH,
as single H-bond donors, were about seven times less reac-
tive than ethylene glycol in promoting this reaction (Table 1,
entries 3 and 4 versus entry 2). Unsurprisingly, the reaction
proceeded very slowly in iPrOH (Table 1, entry 5) and pro-
pylene glycol, which contained an a-methyl group, was also
less reactive than ethylene glycol (Table 1, entry 6 versus
entry 2), possibly because the steric effect of the a-methyl
groups of both alcohols interfered the H-bond activation of
the imine. In addition, propane-1,3-diol, which could form
larger hydrogen-bonded rings, was about three times less ef-
fective than ethylene glycol (Table 1, entry 7). Unexpectedly,
glycerol was seven times less reactive than ethylene glycol
for this reaction (Table 1, entry 8). These results suggested
that ketoimines were activated more efficiently in ethylene
glycol than in other alcoholic solvents because TMSCN was
known to readily react with alcohols to form HCN.[5t] Re-
cently, Galletti, Giacomini, and co-workers reported a cata-
lyst-free Strecker reaction in water;[10a] therefore, we tried
water as the solvent, which gave product 3a in only 19%
yield after 2 days (Table 1, entry 9). To confirm whether this
result was due to the poor solubility of imine 1a in H2O, we
tried a mixed solvent system of water/THF (1:1, v/v) be-
cause imine 1a dissolved well in THF but failed to promote
the reaction, thus no improvement was observed (Table 1,
entries 10–11).
We also tried solvents that could only serve as a neutral
Lewis base to activate TMSCN, including CH3CN, DMF,
and dimethyl sulfoxide (DMSO). All of these solvents
turned out to be less efficient than ethylene glycol in pro-
moting the reaction (Table 1, entries 12–14 versus entry 5).
Most importantly, the reactions of significantly less-reac-
tive substrate 1r in all other protic solvents afforded product
3r in lower yield than that in ethylene glycol (Table 1,
entry 2 versus entries 3–10) over a much longer reaction
time. In addition, no reaction took place in CH3CN and
DMSO (Table 1, entries 12 and 14) and only 19% yield of
product 3r was obtained in DMF (Table 1, entry 13). These
results suggested that the mere Lewis-base activation of
TMSCN was inefficient in promoting the reaction of less-re-
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Ethylene Glycol: A Medium for C C Bond Formations
active ketoimines, which further supported our hypothesis
that both nucleophilic and electrophilic reaction partners
could be effectively activated in the catalyst-free environ-
ment in ethylene glycol.
Very impressively, the use of ethylene glycol as the sol-
vent allowed the preparation of products that were difficult
to prepare under base catalysis. For example, the use of
10 mol% DABCO as a catalyst only afforded compound 3q
in 15% yield after 4 days at 508C in toluene, whereas it
could be obtained in 60% yield in ethylene glycol. Similarly,
product 3q–3s and 3y–3z were obtained in good to high
yield.
The most noteworthy result was that products 3t–3x,
which were unable to be prepared under the catalysis of ter-
tiary amines or Brønsted acids (Scheme 1), could be synthe-
sized in reasonable yield. This result unambiguously demon-
strated the power of this neutral catalyst-free reaction envi-
ronment.
It should be noted that, whilst several catalyst-free Streck-
er reactions have been reported,[10] all of them are limited to
aldimines and relatively reactive ketoimines from acetone
and cyclic ketones. In sharp contrast, our method worked
well for the catalyst-free Strecker reaction of less-reactive
ketoimines, such as two representative nonfluorinated ketoi-
mines (1o and 1p) and a variety of a-CF2H or a-
CF3 ketoimines that had been shown to be less re-
active than their nonfluorinated analogues.[6c]
The substrate scope was then evaluated by running the re-
action in ethylene glycol at 508C with 2.0 equivalents of
TMSCN (Table 2). A variety of a-CF3 ketoimines (1a–1h)
worked very efficiently to afford their corresponding prod-
ucts (3a–3h) in excellent yield (Table 2, entries 1–8). To our
delight, less-reactive a-CF2H ketoimines 1j–1n also worked
well under these conditions to give their corresponding
products (3j–3n) in good yield (Table 2, entries 10–14). In
fact, for substrates 1a–1 f and 1j–1n, only 1.2 equivalents of
TMSCN were enough for obtaining good to excellent yields,
although the reaction time was obviously longer (for details,
see the Supporting Information). Two non-fluorinated ketoi-
mines (1o and 1p) also worked well under these conditions
to afford products 3o and 3p, respectively, in excellent
yield.
Table 2. Substrate scope.
Intrigued by the high efficiency of the Strecker
reaction in ethylene glycol, we further examined
whether the bifunctional Brønsted-acid/Lewis-base-
Entry[a]
1
R
R1
3
t [h]
Yield [%][b]
activation potency of ethylene glycol could be used
to develop a catalyst-free Morita–Baylis–Hillman
reaction.[11] Usually, the use of a Lewis base, such as
tertiary amines or phosphines as the catalyst, was
crucial for the MBH reaction, and a few examples
have demonstrated that the methoxide anion could
trigger this reaction.[11g,h] To the best of our knowl-
edge, no catalyst-free variant of this reaction has
been reported to date.
Initially, we tried the reaction between isatin and
acrolein[7b] in ethylene glycol and were pleased to
find that the reaction took place. However, the
poor solubility of isatin 5 in ethylene glycol retard-
ed the reaction (Table 3). Because THF could dis-
solve isatins well, and because no reaction took
place when using pure THF as the solvent, the
mixed solvent of ethylene glycol/THF (5:2, v/v) was
finally optimized for the reaction. At 508C, a variety
of different substituted isatins (5) could react with
acrolein to give their corresponding products (7) in
good yield. This reaction represented the first ex-
ample of the useful catalyst-free MBH reaction.[11]
A rare example of the catalyst-free Mukaiyama
aldol reaction[12] was also achieved by using ethyl-
ene glycol as the solvent. The reaction of isatins 5
and difluoroenoxysilane[13] (8) proceeded smoothly
in a mixed solvent of ethylene glycol/THF (5:2, v/v)
at 508C to give 3-difluoroalkyl-3-hydroxyoxindoles
(9)[7f,14] in good yield (Scheme 3). The catalyst-free
medium also enabled an unknown “one-pot” cata-
1
2
3
4
5
6
7
8
1a
Ph
p-MeOC6H4
m-MeOC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
2-thienyl
Me
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF2H
CF2H
CF2H
CF2H
CF2H
Me
3a
7
13
13
6
6
6
24
24
24
20
20
20
20
20
20
48
97
91
88
96
81
94
95
92
90
81
88
79
83
76
92
93
1b
1c
1d
1e
1 f
1g
1h
1i
3b
3c
3d
3e
3 f
3g
3h
3i
9
PhCH2CH2
Ph
10
11
12
13
14
15
16
1j
3j
1k
1l
1m
1n
1o
1p
p-MeC6H4
m-MeC6H4
p-ClC6H4
p-MeOC6H4
Ph
3k
3l
3m
3n
3o
3p
Ph
Ph
[a] On a 0.25 mmol scale; [b] yield of isolated product; [c] 3.0 equivalents of TMSCN. lyst-free reductive amination of aldehyde with
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Jian Zhou et al.
COMMUNICATION
Experimental Section
General Procedure for the Strecker
Reaction of Ketoimines (1) with
TMSCN (2)
Ketoimine
1
(0.25 mmol)
and
HOCH2CH2OH (0.50 mL), followed
by TMSCN (2; 67 mL, 0.50 mmol)
were added to a 5 mL reaction vial.
The resulting mixture was stirred at
508C until the complete consumption
of ketoimine 1 had been confirmed by
TLC analysis and then the mixture
was cooled to RT. The reaction mix-
ture was transferred into
a 50 mL
round-bottomed flask, followed by the
addition of silica gel (about 1.0 g). The
Scheme 3. Synthesis of 3-hydroxyindoles and PMP-amines in ethylene glycol.
solvent was carefully removed under
vacuum in the fume hood (be careful
Table 3. Substrate scope of the MBH reaction of istains 5.[a,b]
of HCN that can form from the reaction of excess TMSCN
with ethylene glycol). The residue was directly subjected to
column chromatography on silica gel (petroleum ether/EtOAc,
50:1–10:1) to afford the desired product (3). The general pro-
cedure for the other reactions is given in the Supporting Infor-
mation.
Acknowledgements
Financial support from the NSFC (20902025, 21172075), the
Innovation Program of SMEC (12ZZ046), the Shanghai Pu-
jiang Program (10J1403100), the Fundamental Research Funds
for the Central Universities (ECNU 11043), and the 973 pro-
gram (2011CB808600) are highly appreciated.
À
Keywords: C C coupling
homogeneous reactions · solvent effects · Strecker
reaction
·
ethylene glycol
·
[a] On a 0.25 mmol scale in ethylene glycol (1.0 mL) and THF (0.4 mL); [b] yield of
isolated product.
[1] a) S. Kobayashi, R. Hirabayashi, J. Am. Chem. Soc. 1999, 121, 6942–
6943; b) Y. Huang, V. H. Rawal, J. Am. Chem. Soc. 2002, 124, 9662–
9663; c) Y. Yuan, X. Li, K. Ding, Org. Lett. 2002, 4, 3309–3311;
d) G. K. S. Prakash, H. Vaghoo, C. Panja, V. Surampudi, R. Kulty-
shev, T. Mathew, G. A. Olah, Proc. Natl. Acad. Sci. USA 2007, 104,
3026–3030; e) R. Martꢁnez, D. J. Ramꢂn, M. Yus, Tetrahedron Lett.
2005, 46, 8471–8474; f) J. Wu, X. Sun, W. Sun, Org. Biomol. Chem.
2006, 4, 4231–4235; g) A. Shirakawa, S. Shimizu, Synlett 2007,
3160–3164; h) Y. Gu, J. Barrault, F. Jꢃrꢄme, Adv. Synth. Catal. 2008,
350, 2007–2012; i) F. He, P. Li, Y. Gu, G. Li, Green Chem. 2009, 11,
1767–1773; j) C. Mukhopadhyay, P. Das, R. J. Butcher, Org. Lett.
2011, 13, 4664–4667.
[2] The construction of tetrasubstituted carbon centers is often more
difficult; for reviews, see: a) M. Bella, T. Gasperi, Synthesis 2009,
1583–1614; b) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853–
2873; c) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5,
873–888.
[3] For reviews, see: a) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308–319;
b) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011, 111,
455–529; c) G. Valero, X. Companyꢂ, R. Rios, Chem. Eur. J. 2011,
17, 2018–2037; d) D. Cahard, X. Xu, S. Couve-Bonnaire, X. Panne-
coucke, Chem. Soc. Rev. 2010, 39, 558–568; e) N. Shibata, S. Mizuta,
H. Kawai, Tetrahedron: Asymmetry 2008, 19, 2633–2644; f) J. Hu,
W. Zhang, F. Wang, Chem. Commun. 2009, 7465–7478.
PMP NH2 by using the Hantzsch ester.[15] Both aromatic
and aliphatic aldehyde 10 readily afforded the desired prod-
ucts (13) in good yield at 508C in ethylene glycol without
any catalyst.
À
In summary, we have developed a general Strecker reac-
tion of a-CF2H or a-CF3 ketoimines. The use of ethylene
glycol as a neutral catalyst-free medium successfully circum-
vented the substrate restrictions that were associated with
the use of tertiary-amine catalysts. The power of this neutral
catalyst-free reaction medium presumably resulted from the
effective activation of both electrophilic- and nucleophilic
reaction partners through H-bonding interactions and
Lewis-base activation, respectively. This discovery further
contributed to an unprecedented catalyst-free MBH reac-
tion, a rare example of a catalyst-free Mukaiyama aldol re-
action, and a one-pot reductive amination of aldehydes by
using the Hantzsch ester. Experimental and theoretical in-
vestigations to elucidate the power of the catalyst-free
medium in ethylene glycol,[16–17] together with the scope and
limitations of this procedure, are now underway in our labo-
ratory.
[4] For reviews, see: a) X.-L. Qiu, F.-L. Qing, Eur. J. Org. Chem. 2011,
3261–3278; b) C. Czekelius, C. C. Tzschuche, Synthesis 2010, 543–
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Chem. Asian J. 0000, 00, 0 – 0
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À
Ethylene Glycol: A Medium for C C Bond Formations
566; c) N. C. Yoder, K. Kumar, Chem. Soc. Rev. 2002, 31, 335–341.
For examples, see: d) P. Bravo, S. Capelli, S. V. Meille, P. Seresini,
A. Volonterio, M. Zanda, Tetrahedron: Asymmetry 1996, 7, 2321–
2332; e) F. Huguenot, A. Billac, T. Brigaud, C. Portella, J. Org.
Chem. 2008, 73, 2564–2569; f) K. Ogu, S. Matsumoto, M. Akazome,
K. Ogura, Org. Lett. 2005, 7, 589–592; g) H. Wang, X. Zhao, Y. Li,
L. Lu, Org. Lett. 2006, 8, 1379–1381; h) M.-W. Chen, Y. Duan, Q.-
A. Chen, D.-S. Wang, C.-B. Yu, Y.-G. Zhou, Org. Lett. 2010, 12,
5075–5077.
D. J. Ramꢂn, M. Yus, Tetrahedron Lett. 2005, 46, 8471–8474; see
also ref. [1e].
[11] For reviews, see: a) V. Singh, S. Batra, Tetrahedron 2008, 64, 4511–
4574; b) V. Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109,
1–48; c) G.-N. Ma, J.-J. Jiang, M. Shi, Y. Wei, Chem. Commun.
2009, 5496–5514; for examples: d) X.-Y. Guan, Y. Wei, M. Shi,
Chem. Eur. J. 2010, 16, 13617–13621; e) F. Zhong, G.-Y. Chen, Y.
Lu, Org. Lett. 2011, 13, 82–85; f) V. K. Aggarwal, S. Y. Fulford,
G. C. Lloyd-Jones, Angew. Chem. 2005, 117, 1734–1736; Angew.
Chem. Int. Ed. 2005, 44, 1706–1708; g) S. Luo, X. Mi, H. Xu, P. G.
Wang, J.-P. Cheng, J. Org. Chem. 2004, 69, 8413–8422; h) E. Ciga-
nek, J. Org. Chem. 1995, 60, 4635–4637.
[12] For reviews, see: a) T. Mukaiyama, Angew. Chem. 2004, 116, 5708–
5733; Angew. Chem. Int. Ed. 2004, 43, 5590–5614; b) S. Adachi, T.
Harada, Eur. J. Org. Chem. 2009, 3661–3671; for a diol catalyzed
version, see: c) J. D. McGilvra, A. K. Unni, K. Modi, V. H. Rawal,
Angew. Chem. 2006, 118, 6276–6279; Angew. Chem. Int. Ed. 2006,
45, 6130–6133; Also see: d) P. Garcꢁa-Garcꢁa, F. Lay, P. Garcia-
Garcia, C. Rabalakos, B. List, Angew. Chem. 2009, 121, 4427–4430;
Angew. Chem. Int. Ed. 2009, 48, 4363–4366; e) L. Ratjen, P. Garcia-
Garcia, F. Lay, M. E. Beck, B. List, Angew. Chem. 2011, 123, 780–
784; Angew. Chem. Int. Ed. 2011, 50, 754–758; f) C. H. Cheon, H.
Yamamoto, Org. Lett. 2010, 12, 2476–2479; g) W. Zhuang, T. B.
Poulsen, K. A. Jørgensen, Org. Biomol. Chem. 2005, 3, 3284–3289.
[13] a) H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama, Chem.
Commun. 1999, 1323–1324; b) W. Kashikura, K. Mori, T. Akiyama,
Org. Lett. 2011, 13, 1860–1863; c) Y. Guo, J.-M. Shreeve, Chem.
Commun. 2007, 3583–3585; d) L. Chu, X. Zhang, F.-L. Qing, Org.
Lett. 2009, 11, 2197–2200; e) Z.-L. Yuan, Y. Wei, M. Shi, Tetrahe-
dron 2010, 66, 7361–7366; f) Z. Yuan, Y. Wei, M. Shi, Chin. J.
Chem. 2010, 28, 1709–1716.
[5] For reviews, see: a) J. Wang, X. Liu, X. Feng, Chem. Rev. 2011, 111,
6947–6983; b) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter,
Chem. Rev. 2011, 111, 2626–2704; c) P. Merino, E. Marquꢃ-Lꢂpez,
T. Tejero, R. P. Herrera, Tetrahedron 2009, 65, 1219–1234; d) S. J.
Connon, Angew. Chem. 2008, 120, 1194–1197; Angew. Chem. Int.
Ed. 2008, 47, 1176–1178; e) D. Enders, J. P. Shilvock, Chem. Soc.
Rev. 2000, 29, 359–373. for selected Lewis acid catalyzed examples:
f) S. Kobayashi, S. Nagayama, T. Busujima, Tetrahedron Lett. 1996,
37, 9221–9224; g) A. Heydari, P. Fatemi, A.-A. Alizadeh, Tetrahe-
dron Lett. 1998, 39, 3049–3050; h) H. Nogami, S. Matsunaga, M.
Kanai, M. Shibasaki, Tetrahedron Lett. 2001, 42, 279–283; i) J. S.
Fossey, C. J. Richards, Tetrahedron Lett. 2003, 44, 8773–8776; for or-
ganocatalytic examples, see: j) M. S. Sigman, E. N. Jacobsen, J. Am.
Chem. Soc. 1998, 120, 4901–4902; k) M. Rueping, E. Sugiono, S. A.
Moreth, Adv. Synth. Catal. 2007, 349, 759–764; l) S. C. Pan, J. Zhou,
B. List, Angew. Chem. 2007, 119, 618–620; Angew. Chem. Int. Ed.
2007, 46, 612–614; m) J. Huang, E. J. Corey, Org. Lett. 2004, 6,
5027–5029; n) T. Ooi, Y. Uematsu, K. Maruoka, J. Am. Chem. Soc.
2006, 128, 2548–2549. for selected examples on Strecker reaction of
ketoimines, see: o) S. Masumoto, H. Usuda, M. Suzuki, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 5634–5635; p) J. Wang,
X. Hu, J. Jiang, S. Gou, X. Huang, X. Liu, X. Feng, Angew. Chem.
2007, 119, 8620–8622; Angew. Chem. Int. Ed. 2007, 46, 8468–8470;
q) J. Wang, W. Wang, W. Li, X. Hu, K. Shen, C. Tan, X. Liu, X.
Feng, Chem. Eur. J. 2009, 15, 11642–11659; r) J. P. Abell, H. Yama-
moto, J. Am. Chem. Soc. 2009, 131, 15118–15119; s) G.-W. Zhang,
D.-H. Zheng, J. Nie, T. Wang, J.-A. Ma, Org. Biomol. Chem. 2010, 8,
1399–1405; t) K. Mai, G. Patil, J. Org. Chem. 1986, 51, 3545–3548.
[6] a) G. K. S. Prakash, C. Panja, C. Do, T. Mathew, G. A. Olah, Synlett
2007, 2395–2398; b) D. Enders, K. Gottfried, G. Raabe, Adv. Synth.
Catal. 2010, 352, 3147–3152; c) Y.-L. Liu, T.-D. Shi, F. Zhou, X.-L.
Zhao, X. Wang, J. Zhou, Org. Lett. 2011, 13, 3826–3829.
[14] For 3-hydroxyoxindoles, see: a) X. Liu, L. Lin, X. Feng, Acc. Chem.
Res. 2011, 44, 574–587; b) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth.
Catal. 2010, 352, 1381–1407; Also see: c) L. Liu, S. Zhang, F. Xue,
G. Lou, H. Zhang, S. Ma, W. Duan, W. Wang, Chem. Eur. J. 2011,
17, 7791–7795; d) L. Yin, M. Kanai, M. Shibasaki, Angew. Chem.
2011, 123, 7762–7765; Angew. Chem. Int. Ed. 2011, 50, 7620–7623;
e) K. Zheng, C. Yin, X. Liu, L. Lin, X. Feng, Angew. Chem. 2011,
123, 2621–2625; Angew. Chem. Int. Ed. 2011, 50, 2573–2577; f) K.
Aikawa, S. Mimura, Y. Numata, K. Mikami, Eur. J. Org. Chem.
2011, 62–65.
[15] For organocatalytic reductive-amination reactions using the
Hantzsch ester, see: a) S. Hoffmann, A. M. Seayad, B. List, Angew.
Chem. 2005, 117, 7590–7593; Angew. Chem. Int. Ed. 2005, 44, 7424–
7427; b) R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J.
Am. Chem. Soc. 2006, 128, 84–86; c) D. Menche, J. Hassfeld, J. Li,
G. Menche, A. Ritter, S. Rudolph, Org. Lett. 2006, 8, 741–744; for
a review, see: d) S.-L. You, Chem. Asian J. 2007, 2, 820–827.
[16] As suggested by one reviewer, we performed the following control
experiments to eliminate the possibility that ethylene glycol might
be oxidized during the reaction to produce the true catalytic species:
1) under a N2 atmosphere, the reaction between compounds 1a and
2 gave product 3a in 97% yield after 7 h, the same as that in air
(Table 1, entry 2); for the same reaction that was run in air at 508C,
GCMS analysis of the crude mixture failed to detect any possible
products that were derived from the oxidation of ethylene glycol;
2) even using 50 mol% of oxalic acid failed to catalyze this reaction
when using toluene as the solvent.
[7] a) Y.-L. Liu, F. Zhou, J.-J. Cao, C.-B. Ji, M. Ding, J. Zhou, Org.
Biomol. Chem. 2010, 8, 3847–3850; for our related work: b) Y.-L.
Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X. Zhang, C. Wang, J. Zhou,
J. Am. Chem. Soc. 2010, 132, 15176–15178; c) M. Ding, F. Zhou, Y.-
L. Liu, C.-H. Wang, X.-L. Zhao, J. Zhou, Chem. Sci. 2011, 2, 2035–
2039; d) Z.-Y. Cao, Y. Zhang, C.-B. Ji, J. Zhou, Org. Lett. 2011, 13,
6398–6401; e) Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding,
X.-L. Zhao, J. Zhou, Chem. Commun. 2009, 6753–6755; f) Y.-L.
Liu, J. Zhou, Chem. Commun. 2012, 48, 1919–1921.
[8] For Brønsted-acid catalysis, see: a) J. Seayad, B. List, Org. Biomol.
Chem. 2005, 3, 719–724; b) A. G. Doyle, E. N. Jacobsen, Chem. Rev.
2007, 107, 5713–5743; c) X. Yu, W. Wang, Chem. Asian J. 2008, 3,
516–532; d) Z. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38,
1187–1198; e) A. K. Unni, N. Takenaka, H. Yamamoto, V. H.
Rawal, J. Am. Chem. Soc. 2005, 127, 1336–1337; f) H. Yamamoto,
K. Futatsugi, Angew. Chem. 2005, 117, 1958–1977; Angew. Chem.
Int. Ed. 2005, 44, 1924–1942.
[17] As suggested by another reviewer, we tried other readily available
chiral diols as the solvent for the reaction between compounds 1a
and 2: (R)-3-chloropropane-1,2-diol and (R)-propylene glycol. Un-
fortunately, no enantioselectivity was observed for product 3a,
either when the reaction was carried out at 258C or 508C.
[9] For Lewis-base catalysis, see: a) J. Gawronski, N. Wascinska, J.
Gajewy, Chem. Rev. 2008, 108, 5227–5252; b) S. E. Denmark, G. L.
Beutner, Angew. Chem. 2008, 120, 1584–1663; Angew. Chem. Int.
Ed. 2008, 47, 1560–1638; c) S. Kobayashi, M. Sugiura, C. Ogawa,
Adv. Synth. Catal. 2004, 346, 1023–1034.
[10] For catalyst-free Strecker reactions, see: a) P. Galletti, M. Pori, D.
Giacomini, Eur. J. Org. Chem. 2011, 3896–3903; b) R. Martꢁnez,
Received: April 3, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ

COMMUNICATION
À
C C Coupling
Yun-Lin Liu, Xing-Ping Zeng,
Jian Zhou*
&&&& — &&&&
Ethylene Glycol: A Powerful Catalyst-
À
Free Medium for C C Bond-Forming
Reactions
A good EG: Ethylene glycol (EG) is
a catalyst-free medium that can pro-
mote the highly efficient Strecker reac-
tion of a-CF2H or a-CF3 ketoimines
and TMSCN. EG was used in several
reactions, including the catalyst-free
Morita–Baylis–Hillman reaction.
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www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!