Asymmetric direct α-alkylation of 2-oxindoles with Michler's hydrol catalyzed by bis-cinchona alkaloid-Bronsted acid via an S N1-type pathway

Article abstract of DOI:10.1039/c3cc39012h

An enantioselective direct α-alkylation of 2-oxindoles with Michler's hydrol via an S_N1-type pathway in the non-covalent activation mode using the bis-cinchona alkaloid and Bronsted acid as a co-catalyst was developed and good to high yields and enantioselectivities were obtained. The Royal Society of Chemistry 2013.

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Asymmetric direct αꢀalkylation of 2ꢀoxindoles with Michlers Hydrol
catalyzed by bisꢀcinchona alkaloid/Brønsted acid via SN1ꢀtype pathway†
Tao Zhang,a,b Zhen Qiao,a,b Yan Wang, ,a,b Nengjun Zhong,a,b Li Liu,*a Dong Wang,a and YongꢀJun Chena
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
50 benign properties.[10] Therefore, the asymmetric alkylation
An enantioselective direct αꢀalkylation of 2ꢀoxindoles with
reaction utilizing carbocations directly generated from
alcohols is of great significance. On the other hand, the
oxindoles bearing a quaternary carbon stereocenter at 3ꢀ
position of the indole ring constitute a ubiquitous structural
55 motif in a variety of natural products and biologically active
drug candidates.[11]
Herein, we would like to report our preliminary results of
an enantioselective αꢀalkylation of 2ꢀoxindoles with Michlers
Hydrol promoted by a proper combination of bisꢀtertiary
60 amine and Brønsted acid (1:1) in the nonꢀcovalent mode.
Michlers Hydrol via SN1ꢀtype pathway in the nonꢀcovalent
activation mode using the bisꢀcinchona alkaloid and Brønsted
acid as the coꢀcatalyst was developed in good to high yields
10 and enantioselectivities.
Inspired by the works of Enders[1]
,
Rueping[2] and
Melchiorre[3], Cozzi and coꢀworkers introduced carbocations
to asymmetric organocatalysis in 2008,[4] when the promising
SN1ꢀtype reaction had seldom been used for stereoselective
15 tranformations. Only a few years passed, it has been becoming
a powerful and attractive tool in organic synthesis. Enamineꢀ
catalyzed asymmetric reaction of carbocations have
accomplished the αꢀalkylation of aldehydes and ketones.
However, there is no successful example of the
20 enantioselective direct αꢀalkylation of amides involving
carbocation. Among all the reported catalytic asymmetric
reactions involving carbocation, the majority is charactered by
the combination of a chiral enamine and a carbocation via the
covalent activation mode.[4ꢀ5] In contrast, there is only one
25 successful example[6] reported through nonꢀcovalent
mechanism,[7] which was promoted by the chiral phosphoric
acid.[8] Although the chiral tertiary amine bearing the thiourea
moiety was used as a catalyst in the alkylation of oxazolones
under the nonꢀcovalent catalysis, the attempts for efficient
30 asymmetric induction failed and only 13% ee was obtained.[9]
The poor enantioselectivity might be attributed to the
flexibility of nonꢀcovalent catalysis for stereocontrol and the
poor stability of the generated carbocation.
Bis(4ꢀdimethylaminoꢀphenyl)methanol
2
(Michlers
Hydrol), which can generate a stabilized carbocation under
acidic conditions,[12] was employed in the model reaction with
NꢀBocꢀ3ꢀbenzylꢀ2ꢀoxindole 1a. Initially, cinchona alkaloids,
65 3a (QD ) or 3b (DHQD) was used as the catalyst with benzoic
acid as coꢀcatalyst at room temperature to give the product 5a
in 55~58% yield. Unfortunatly, in both cases, the product was
a racemic mixture (Table 1, entries 1 and 2).
It was noteworthy that the biscinchona alkaloids could
70 provide
a
stronger interaction with substrates than
monocinchona alkaloids.[13] Therefore, the subsequent catalyst
screening focused on biscinchona alkaloids (3c~3g, Figure 1)
under the same reaction conditions. Compared with
pseudoenantiomer (DHQ)2PHAL (3c), (DHQD)2PHAL (3d)
75 showed better stereocontrol, with opposite configuration of
newly formed chiral center (entry 3 vs 4). When the linker
was changed to 2,5ꢀdiphenylpyrimidine (3e), the reaction
provided lower yield and the enantioselectivity sharply
decreased to 24% (entry 5). The stereoselectivity was even
80 reversed with the use of anthraceneꢀ9,10ꢀdione unit as a linker
(3f) (entry 6). Athough the reaction could proceed smoothly in
the presence of catalyst 3g with the phthalate linker, poor
asymmetric induction was observed (entry 7).
In general, if the alcohol was used as an electrophile to
35 undergo alkylation reaction, the hydroxy group of the alcohol
must be converted to the fuctional group with stronger leaving
5f]
ability[3,
However, the direct alkylation reaction with the
alcohol is a significant and attractive chemical transformation
owing to its green, atomꢀeconomical and environmentally
Subsequently, various acids were employed as coꢀcatalyst
85 in the 3dꢀcatalyzed reaction of 1a with 2 (Table 2). Among
the achiral organic and inorganic acids (entries 1 to 6), MsOH
displayed the best catalytic efficiency (85% yield and 76% ee)
(entry 4). For chiral Brønsted acid, in comparison with (S)ꢀ4b,
chiral phosphoric acid (S)ꢀ4a relatively matched with the
90 catalyst bisꢀcinchona alkaloid 3d (entries 7 and 9). However,
in the absence of 3d, single catalyst (S)ꢀ4a could offer very
poor result (entry 8, 7% ee). To our surprise, the same
enantioselectivity and value were deduced for both
40
a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail:
lliu@iccas.ac.cn; Fax: +86 10 6255 4449; Tel: +86 10 6255 4614
45 b Graduate School of Chinese Academy of Sciences, Beijing 100049,
China
† Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data, and chiral chromatographic analysis for
all new compounds. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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enantiomers of camphorsulfonic acid 4c (entries 10 and 11),
which seemed that the chirality of anion of acid did not
determine the transfer of stereochemistry during the catalysis.
to 85% yield and 82% ee (Table 3). For 3ꢀbenzylꢀ2ꢀoxindoles
bearing the functional group either at metaꢀ or paraꢀposition
on the aromatic ring of the benzyl group gave the
25 corresponding products (5bꢀi) in good to high yields and
enantioselectivities (entries 2ꢀ9). With Nꢀunprotected 3ꢀ
benzylꢀ2ꢀoxindole, the reaction provided racemic product with
65% yield.
Table 1. Catalyst Screening for the reaction of 1a with 2a
N
N
Table 2. Acid Screening for the reaction of 1a with 2a
Bn
N
Ph
Bn
3 + benzoic acid (20%)
O
O
O
SO3H
O
DCM, rt
N
O
O
O
HO
P
P
N
Boc
OH
OH
O
O
N
Boc
O
1a
5a
2
5
SO3H
Ph
Entry
Catalyst
Yield (%)b
Ee (%)c
(S)- 4b
(S)- 4a
(S)- 4c
(R)- 4c
30
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
58
55
69
79
57
69
83
rac
rac
ꢀ26 d
66
Entry
Brönsted acid
Yield of 5a (%)b Ee (%)c
1
2
3
4
5
6
HOAc
TFA
59
79
78
85
87
66
87
46
66
69
78
48
70
72
76
14
74
72
7
24
TsOH
MsOH
CF3SO3H
HNO3
(S)ꢀ4a
(S)ꢀ4a
(S)ꢀ4b
(S)ꢀ4c
(R)ꢀ4c
ꢀ5 d
40
3g
a Reaction conditions: 1a (0.11 mmol), 2 (0.1 mmol), 20 mol % of 3,
20 mol % of benzoic acid, 0.5 mL DCM. b Isolated yield. c Determined
by chiral HPLC analysis. d The opposite enantiomer was obtained.
7
8 d
9
rac
74
74
10
11
N
N
N
N
N
N
a Reaction performed at a 0.11 mmol scale 1a with 0.1 mmol of 2, 20 mol
% of (3d + acid) in DCM (0.5mL). b Isolated yield after FC. c
Determined by chiral HPLC analysis. d in absence of 3d.
OH
H
O
O
OH
H
H
H
H
H
H
O
O
O
O
N
N
N
N
O
3c
3a
3b
Table 3 Organocatalytic αꢀalkylation of 2ꢀoxindoles with alcohol
N
N
N
N
N
N
O
O
H
O
H
H
H
N
H
N
H
H
H
O
O
N
N
O
O
N
R
N
N
N
N
3d (20 mol%)
MsOH (20 mol%)
DCM (0.2M), rt
3d
O
R
3e
N
HO
N
N
O
Boc
N
N
O
H
O
H
N
O
O
H
H
N
O
O
O
O
1a-1j
5a-5j
H
H
2a
Boc
O
O
H
H
O
O
N
N
Entrya
R
Products Yield (%)b Ee (%)c
N
N
3g
3f
1
2
3
4
5
6
7
8
1a, Bn
5a
5b
5c
5d
5e
5f
85
63
71
62
64
71
64
63
73
58
76
82
76
76
80
73
70
72
70
76
Figure 1 Catalysts for the reaction of 1a with 2a
1b, 3ꢀMeOꢀC6H4CH2
1c, 3ꢀMeꢀC6H4CH2
1d, 3ꢀClꢀC6H4CH2
1e, 3ꢀFꢀC6H4CH2
1f, 4ꢀMeOꢀC6H4CH2
1g, 4ꢀMeꢀC6H4CH2
1h, 4ꢀBrꢀC6H4CH2
Various solvents were examined in the reaction of 1a with 2
in the presence of bisꢀcinchona alkaloid/Brønsted acid catalyst
10 (detailed results listed in supporting information). It was
found that in all cases the reaction could proceed smoothly in
good yields with resonable enantioselectivities. Even if the
reaction was proceeded in water, 37% ee of the product 5a
could be observed. The optimum conditions were selected as
15 the combination of 3d + MsOH (20 mol %, 3d/MsOH=1:1) in
DCM (0.2M) at room tempreture.
5g
5h
9
10
1i, 3,4ꢀOCH2OꢀC6H4CH2 5i
1j, nꢀPr
5j
a Reaction conditions: 0.11 mmol 1 with 0.1mmol 2, 20 mol % catalyst
(3d +MsOH) in DCM (0.5 mL) at room temperature for 2d. b Isolated
yield. c Determined by chiral HPLC analysis.
Under the optimum conditions various NꢀBocꢀ2ꢀoxindoles
with 3ꢀalkyl substituents (Table 3, 1aꢀj), including nꢀpropyl
It was proposed that the catalyst system of biscinchona
35 alkaloid with two tertiary amine moieties and an additional
(1j) and
benzyl (1a) groups, were employed in the
acid (1:1) simultaneously activates oxindoles both 1 and
alcohol
2
(Figure 2).[14] One tertiary amine moiety
20 asymmetric direct αꢀalkylation of 2ꢀoxindoles with Michlers
Hydrol (2), affording the corresponding products (5aꢀj) in up
2
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deprotonates the C3 methine proton of the 2ꢀoxindole leading
to the generation of the enolateꢀanion intermediate, and the
other tertiary amine moiety combined with acid interacts with
activated alcohol (2) to produce diarylmethine carbocation by
dehydration.
[4] P. G. Cozzi, F. Benfatti and L. Zoli, Angew. Chem., Int. Ed. 2009, 48,
1313ꢀ1316.
[5] For selected examples, see: a) J. O. Bauer, J. Stiller, E. Marquesꢀ
40 Lopez, K. Strohfeldt, M. Christmann and C. Strohmann, Chem.– Eur. J.
2010, 16, 12553ꢀ12558; b) M. G. Capdevila, F. Benfatti, L. Zoli, M.
Stenta and P. G. Cozzi, Chem.– Eur. J. 2010, 16, 11237ꢀ11241; c) M.
Ikeda, Y. Miyake and Y. Nishibayashi, Angew. Chem., Int. Ed. 2010, 49,
7289ꢀ7293; d) L. Zhang, L. Y. Cui, X. Li, J. Y. Li, S. Z. Luo and J. P.
45 Cheng, Chem.– Eur. J. 2010, 16, 2045ꢀ2049; e) L. Zhang, L. Y. Cui, X.
Li, J. Y. Li, S. Z. Luo and J. P. Cheng, Eur. J. Org. Chem. 2010, 4876ꢀ
4885; f) A. R. Brown, W. H. Kuo and E. N. Jacobsen, J. Am. Chem. Soc.
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and N. Jiao, Chem. Commun. 2011, 47, 5007ꢀ5009; h) K. Motoyama, M.
50 Ikeda, Y. Miyake and Y. Nishibayashi, Eur. J. Org. Chem. 2011, 2011,
2239ꢀ2246; i) G. Bergonzini, S. Vera and P. Melchiorre, Angew. Chem.,
Int. Ed. 2010, 49, 9685ꢀ9688; j) A. Gualandi, E. Emer, M. G. Capdevila
and P. G. Cozzi, Angew. Chem., Int. Ed. 2011, 50, 7842ꢀ7846; k) J. Stiller,
E. MarquesꢀLopez, R. P. Herrera, R. Froehlich, C. Strohmann and M.
55 Christmann, Org. Lett. 2011, 13, 70ꢀ73; l) B. Zhang, S.ꢀK. Xiang, L. H.
Zhang, Y. Cui and N. Jiao, Org. Lett. 2011, 13, 5212ꢀ5215; m) J. Xiao, K.
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Gualandi, D. Petruzziello, E. Emer and P. G. Cozzi, Chem. Commun.
2012, 48, 3614ꢀ3616.
5
chiral motif
R
R
N
R
NH
R
X
Base site
Acid site
Activating nucleophile
Activating alcohol
catalyst system
OMe
MeO
BocN
N
N
H
Ar
R
O
H
N
X
Ar
O
N
N
H
N
O
H
H
60 [6] a) M. Rueping, U. Uria, M.ꢀY. Lin and I. Atodiresei, J. Am. Chem.
Soc. 2011, 133, 3732ꢀ3735; An unsuccessful attempt: b) D. Wilcke, E.
Herdtweck and T. Bach, Synlett 2011, 2011, 1235ꢀ1238.
catalyst mechanism
Figure 2 Proposed catalytic system and activated mechanism
[7] J.ꢀF. Briere, S. Oudeyer, V. Dalla and V. Levacher, Chem. Soc. Rev.
2012, 41, 1696ꢀ1707.
The absolute configuration of the main enantiomer of 5a
was deduced as (R) by Vibrational Circular Dichroism (VCD)
10 spectroscopy analysis (see supporting information).[15] As
suggested by Corey and Noe,[13a, 16] the biscinchona alkaloid
catalyst could construct a chiral pocket, which was favorable
to firmly fix both of the formed carbocation and enolated 2ꢀ
oxindole, resulting in highly efficent stereocontrol in SN1ꢀtype
15 alkylation reaction. The approach of carbocation to the
enolate anion from Re face results in the formation of Rꢀ
stereoselective product 5a (Figure 2).
65 [8] a) C. Guo, J. Song, J.ꢀZ. Huang, P.ꢀH. Chen, S.ꢀW. Luo and L.ꢀZ.
Gong, Angew. Chem., Int. Ed. 2012, 51, 1046ꢀ1050; b) E. Aranzamendi,
N. Sotomayor and E. Lete, J. Org. Chem. 2012, 77, 2986ꢀ2991; c) Q. X.
Guo, Y. G. Peng, J. W. Zhang, L. Song, Z. Feng and L. Z. Gong, Org.
Lett. 2009, 11, 4620ꢀ4623.
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Vincentiis and P. G. Cozzi, Eur. J. Org. Chem. 2011, 2011, 647ꢀ666.
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Kempf and A. R. Ofial, Acc. Chem. Res. 2002, 36, 66ꢀ77.
In summary, we have firstly developed
a
novel
organocatalytic asymmetric αꢀalkylation of 2ꢀoxindoles with
20 Michlers alcohol via SN1ꢀtype reaction pathway, which was
catalyzed by the combination of chiral bisꢀcinchona alkaloid
and Brønsted acid (1:1). Good to high yields and
enantioselectivities were obtained. The investigation of
organocatalytic asymmetric αꢀalkylation of carbonyl
25 compounds with other alcohols is underway in our lab.
We thank the National Natural Science Foundation of
China, Ministry of Science and Technology (973 program
2010CB833305) and the Chinese Academy of Sciences for the
financial support.
[13] a) G. D. H. Dijkstra, R. M. Kellogg, H. Wynberg, J. S. Svendsen, I.
80 Marko and K. B. Sharpless, J. Am. Chem. Soc. 1989, 111, 8069ꢀ8076; b)
E. J. Corey and M. C. Noe, J. Am. Chem. Soc. 1996, 118, 11038ꢀ11053.
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3874ꢀ3877; b) S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru
and M. Shiro, Angew. Chem., Int. Ed. 2007, 46, 8666ꢀ8669.
85 [15] a) C. M. CerdaꢀGarcíaꢀRojas, H. A. GarcíaꢀGutiérrez, J. D.
HernándezꢀHernández, L. U. RománꢀMarín and P. JosephꢀNathan, J. Nat.
Prod. 2007, 70, 1167ꢀ1172; b) P. Mobian, C. Nicolas, E. Francotte, T.
Bu rgi and J. r. m. Lacour, J. Am. Chem. Soc. 2008, 130, 6507ꢀ6514.
[16] a) E. J. Corey and M. C. Noe, J. Am. Chem. Soc. 1993, 115, 12579ꢀ
90 12580; b) S.ꢀK. Tian and L. Deng, J. Am. Chem. Soc. 2001, 123, 6195ꢀ
6196.
30 Notes and references
[1] D. Enders, A. A. Narine, F. Toulgoat and T. Bisschops, Angew. Chem.,
Int. Ed. 2008, 47, 5661ꢀ5665.
[2] M. Rueping, B. J. Nachtsheim, S. A. Moreth and M. Bolte, Angew.
Chem., Int. Ed. 2008, 47, 593ꢀ596.
35 [3] R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli and P. Melchiorre,
Angew. Chem., Int. Ed. 2008, 47, 8707ꢀ8710.
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An enantioselective αꢀalkylation of 2ꢀoxindoles with an alcohol via SN1ꢀtype pathway in the
nonꢀcovalent mode using the bisꢀcinchona alkaloid and Brønsted acid as the coꢀcatalysts was
developed.