Primary 1,2-diamine catalysis (V): Efficient asymmetric aldol reactions of isatins with cyclohexanone

Article abstract of DOI:10.1055/s-0031-1290507

1,2-Diaminocyclohexane-hexanedioic acid has been demonstrated to catalyze the asymmetric aldol reactions of cycloketones and various isatin derivatives efficiently in MeOH-H. The corresponding products were obtained in good yields (70-90%) with high diastereoselectivity (up to 99:1 anti/syn) and enantioselectivity (up to 99% ee). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290507

LETTER
▌1031
letter
Primary 1,2-Diamine Catalysis (V): Efficient Asymmetric Aldol Reactions of
Isatins with Cyclohexanone
Asymmetric Aldol Reactions of Isatins with Cyclohexanone
Yi Liu, Pengchao Gao, Junfeng Wang, Qi Sun,* Zemei Ge, Runtao Li*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmeceutical Science, Peking University, Beijing 100191, P. R. of China
E-mail: lirt@mail.bjmu.edu.cn; E-Mail: sunqi@bjmu.edu.cn
Received: 04.01.2012; Accepted after revision: 06.02.2012
isatin derivatives as acceptors reacting with cyclic ketones
Abstract: 1,2-Diaminocyclohexane-hexanedioic acid has been
are also scant. Ricci’s group8 only reported one example
demonstrated to catalyze the asymmetric aldol reactions of cyclo-
of cyclohexanone reacting with isatin to afford the oxin-
dole in a anti/syn ratio of 98:2 with 80% ee during their in-
ketones and various isatin derivatives efficiently in MeOH–H2O.
The corresponding products were obtained in good yields (70–90%)
with high diastereoselectivity (up to 99:1 anti/syn) and enantio- vestigation of using chitosan (11) as the asymmetric aldol
reaction catalyst (reaction 1, Scheme 1). Singh’s group9
selectivity (up to 99% ee).
carried out the enantioselective synthesis of 3-substituted-
3-hydroxy-indolin-2-ones, which are quite promising in
the field of medicinal chemistry, with three isatin deriva-
tives as acceptors by using a primary–tertiary diamine–
Brønsted acid catalyst 12.
Key words: asymmetric aldol reaction, diaminocyclohexane, or-
ganocatalyst, isatin
The 3-substituted-3-hydroxyindolin-2-ones 1–5 are a
class of compounds (Figure 1) with an indole skeletal
structure, which are found in several biologically active
alkaloids and pharmacological agents.1 Owing to the sig-
nificance of this structural motif, numerous methodolo-
gies have been developed and continue to be explored for
the construction of this structure.2 Most methods involve
the use of expensive or toxic metal reagents as catalysts.
O
(1)
O
O
HO
catalyst 11 or 12
O
R1
R1
+
O
N
N
H
H
R1 = H, anti/syn = 98:2, 80% ee
Ricci's work
R1 = 5-H, 5-Cl, 5-Br, anti/syn: up to 1:99, up to 99% ee Singh's work
In light of the great progress made in organocatalytic
asymmetric aldol reaction, there has been an increasing
interest in applying this reaction for the synthesis of chiral
3-substituted-3-hydroxyindolin-2-ones in recent years.
For example, several efficient organocatalysts (Figure 2),
such as 6,3 7,4 8,5 9,6 10,7 have been reported. While non-
cyclic ketones and aldehydes as donors have been widely
investigated, to the best of our knowledge, there are only
two reports on the organocatalytic asymmetric aldol reac-
tion of cyclohexanone and isatins. Moreover, examples of
O
(2)
R1
HO
O
O
catalyst 13,
additive
X
+
R1
O
O
N
N
R2
R2
X
X = CH2 or O
1 = various substituents, anti/syn: up to 99:1, up to 99% ee in this study
R
Scheme 1 Aldol reactions of istans with various ketones or aldehydes
O
NH
Br
O
HO
HO
HO
R2
SMe
HN
O
R1
O
O
O
N
N
N
Br
H
H
H
convolutamydine A (1)
maremycin A (2)
S
O
O
MeO
NMe
H
n-Bu
HO
SMe
N
H
N
HO
H
N
O
Me
O
N
H
madinoline A (3)
CPC-1 (4)
dioxibrassinine (5)
Figure 1 Examples of biologically active 3-substituted-3-hydroxy indole-2-ones
SYNLETT 204012, 237, 1031–1034
Advanced online publication: 16.03.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290507; Art ID: ST-2012-W0005-L
© Georg Thieme Verlag Stuttgart · New York

1032
Y. Liu et al.
LETTER
Ph
Ph
O
O
O
O
O
S
N
NH HN
COOH
N
H
N
H
Ar
H
S
H2N
OH
⋅TFA
NH
6
7
8
9
S
Ar
N
NH
*
Me
H
O
NH2
HO
O
O
N
N
NH2
Ph
N
H
NH2
NH2
12
*
HO
11
OMe
10
13
Figure 2 Structures of some organocatalysts
Because catalytic, intermolecular ketone–ketone cross-
aldol reactions are still rare and represent a significant
challenge for the chemists,6 herein we report an efficient
asymmetric aldol reaction of cycloketones with various
isatin derivatives catalyzed by vicinal primary diamine
salts in good yields, excellent diastereoselectivities and
enantioselectivities.
Table 1 Optimization of the Reaction Conditions
O
O
O
HO
catalyst 13, additive
+
O
O
N
H
N
H
16a
14a
15a
In our previous studies, the simple and commercially
available chiral 1,2-diaminocyclohexane (13) was found
to be an effective organocatalyst in Michael addition reac-
tions. Reactions of γ-butenolides10 and cyclopentanone11
with chalcones provided products with up to 99% ee. This
catalyst was also found to be useful in the asymmetric al-
dol reactions of ketones and aromatic aldehydes.12 Based
on these results, we envisioned that the asymmetric aldol
reaction catalyzed by 13 could be extended for the prepa-
ration of chiral 3-substituted-3-hydroxyindolin-2-ones us-
ing cyclohexanone and isatins (reaction 2, Scheme 1).
anti/synb
Entry Solvent
13 and HAD Yield
(mol%)
ee
(%)a
(%)b
1
2
3
4
5
6
7
8
9
MeOH–H2O
MeOH
20
20
20
20
5
90
85
30
50
30
65
20:1
99:1
20:1
20:1
20:1
99:1
99:1
99:1
–
>99
90
68
72
95
96
96
97
–
DMF
MeCN
MeOH–H2O
MeOH–H2O
MeOH–H2O
MeOH–H2O
MeOH–H2O
10
20
20
20
Our initial reaction of isatin (14a) with cyclohexanone
(15a) was carried out using our previous optimized reac-
tion conditions for asymmetric aldol reaction12 [20 mol%
of chiral 1,2-diaminocyclohexane (13) and 20 mol% co-
catalyst hexanedioic acid (HDA), in a mixture of MeOH–
H2O (1:1) at r.t.; Table 1, entry 1]. To our surprise, the re-
action proceeded smoothly to provide the desired aldol
product 16a in high yield with excellent diastereoselectiv-
ity and enantioselectivity (yield: 90%; dr >20:1; ee
>99%). When single solvents were used instead of the co-
solvent MeOH–H2O, the corresponding yield and enantio-
selectivity decreased significantly (Table 1, entries 2–4).
Similarly, reducing the amount of catalyst or lowering the
reaction temperature also impacted the yields (Table 1,
entries 5–8). It is worth noting that only a trace amount of
product was detected in the absence of hexanedioic acid
(Table 1, entry 9), which indicated that the co-catalyst
plays an important role in this reaction.
43c
10d
tracee
a Isolated yields.
b Determined by chiral HPLC.
c Carrying the reaction at 0 °C.
d Carrying the reaction at –10 °C.
e Only catalyst 13.
stereo- and/or enantioselectivities (Table 2, entries 1–8).13
It appeared that the introduction of substituents on the
isatin could slightly decrease the yield and enantioselec-
tivities, but the property and the position of substituents
did not have a significant influence on the yields, diaste-
reoselectivities, and enantioselectivities. We found that
substituents such as 5-O2N (Table 2, entry 2, 72% yield;
anti/syn = 13:1; 87% ee), 6-Br (Table 2, entry 6, 82%
yield; anti/syn = 20:1; 90% ee), or Me at 1-N (Table 2, en-
try 7, 78% yield; anti/syn = 10:1; 83% ee) gave similar re-
sults. In addition to cyclohexanone (15a), we also
We further examined the generality of the reaction using
the optimized reaction conditions. As shown in Table 2,
various substituted isatins reacted with cyclohexanone
15a to afford the corresponding 3-cyclohexanone-3-
hydroxy-2-oxindoles in good to excellent yields and dia-
Synlett 2012, 23, 1031–1034
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Aldol Reactions of Isatins with Cyclohexanone
1033
examined tetrahydropyran-4-one (15b), acetone (15c), almost lost completely when acetone (15c) or cyclopen-
and cyclopentanone (15d) as donors. Tetrahydropyran-4- tanone (15d) was used (Table 2, entries 15 and 16). The
one (15b) was found to react with various substituted isat- configuration of compounds was determined by compar-
ins 14a–h and gave excellent results (Table 2, entries 9– ing our Chiralcel HPLC profile with Ricci’s result.8 Inter-
14), except with N-substituted isatins, which gave moder- estingly, the compounds obtained by our method were R,R
ate enantioselectivities (Table 2, entry 13, 51% ee and en- isomers, which are different from the S,R isomers report-
try 14, 50% ee). However, the enantioselectivity was ed.
Table 2 Aldol Reactions of Isatin and Various Ketones
O
R4
HO
O
13 (20 mol%),
O
R3
O
HDA (20 mol%)
R1
R1
O +
MeOH–H2O (1:1),
R4
r.t.
N
N
R3
R2
R2
14
15
16
R1, R2
R3, R4
Yield (%)a
anti/synb
ee (%)b
Entry
Product
1
2
14a H, H
14b 5-O2N, H
14c 5-MeO, H
14d 5-Cl, H
14e 6-Cl, H
14f 6-Br, H
14g H, Me
14h H, Bn
14a
15a -(CH2)3-
16a
16b
16c
90
72
70
73
75
82
78
85
80
68
76
81
72
78
87
83
20:1
13:1
20:1
15:1
20:1
20:1
10:1
99:1
20:1
20:1
20:1
20:1
10:1
10:1
–
99
87
77
72
91
90
83
77
87
82
83
71
51
50
<5
16
15a
3
15a
4
15a
16d
16e
5
15a
6
15a
16f
7
15a
16g
16h
16ic
16jc
16kc
16lc
16mc
16nc
16oc
16pc
8
15a
9
15b -CH2OCH2-
10
11
12
13
14
15
16
14c
15b
14d
15b
14f
15b
14g
15b
14h
15b
14a
15c H, H
15d -(CH2)2-
14a
2:1
a Isolated yields.
b Determined by chiral HPLC.
c Carrying the reaction at 0 °C in MeOH–H2O (10:1).
O
O
HO
H
HO
R
H
S
N
N
N
N
H
H
H
H
H
H
R
R
O
O
O
O
N
H
N
O
O
H
anti product
(major)
syn product
(minor)
NH
NH
TS1
favorable
TS2
sterically unfavorable
Scheme 2 Proposed mechanism for the reaction of cyclohexanone and isatin
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1031–1034

1034
Y. Liu et al.
LETTER
Similar to our previous hypothesis,12 we propose that both
the aldol donor (ketone) and the receptor (isatin) could be
activated simultaneously in this reaction system to form
transition states TS1 and TS2 (Scheme 2). It is obvious
that TS1 is sterically more stable than TS2, the size of the
cyclic six-membered enamine ring was crucial for this ste-
ric restriction. Therefore, the R,R isomer is formed as the
main product.
(n) Durbin, M. J.; Willis, M. C. Org. Lett. 2008, 10, 1413.
(o) Kumar, C. N. S. S. P.; Devi, C. L.; Rao, V. J.;
Palaniappan, S. Synlett 2008, 2023. (p) Jia, Y.-X.; Hillgren,
J. M.; Watson, E. L.; Marsden, S. P.; Kundig, E. P. Chem.
Commun. 2008, 34, 4040. (q) Trost, B. M.; O’Boyle, B. M.
Org. Lett. 2008, 10, 1369. (r) Lai, H.; Huang, Z.; Wu, Q.;
Qin, Y. J. Org. Chem. 2009, 74, 283. (s) Jia, Y.-X.; Kundig,
E. P. Angew. Chem. Int. Ed. 2009, 48, 1636. (t) Castaldi, M.
P.; Troast, D. M.; Porco, J. A. Org. Lett. 2009, 11, 3362.
(u) Tsuchikama, K.; Hashimoto, Y.; Endo, K.; Shibata, T.
Adv. Synth. Catal. 2009, 351, 2850. (v) Beaumont, S.; Pons,
V.; Retailleau, P.; Dodd, R. H.; Dauban, P. Angew. Chem.
Int. Ed. 2010, 49, 1634. (w) An, G.; Zhou, W.; Zhang, G.;
Sun, H.; Han, J.; Pan, Y. Org. Lett. 2010, 12, 4482.
(x) Urgaonkar, S.; Cortese, J. F.; Barker, R. H.; Cromwell,
M.; Serrano, A. E.; Wirth, D. F.; Clardy, J.; Mazitschek, R.
Org. Lett. 2010, 12, 3998. (y) Kothandaraman, P.; Rao, W.;
Foo, S. J.; Chan, P. W. H. Angew. Chem. Int. Ed. 2010, 49,
4619. (z) Zheng, K.; Yin, C.; Liu, X.; Lin, L.; Feng, X.
Angew. Chem. Int. Ed. 2011, 50, 2573.
In conclusion, we have developed an efficient asymmetric
aldol reaction of cycloketones and various isatin deriva-
tives using a simple and commercially available chiral
1,2-diaminocyclohexane as the catalyst and hexanedioic
acid as the co-catalyst. The corresponding 3-substituted-
3-hydroxyindolin-2-ones have R,R configuration and
were obtained in good to excellent yields (70–90%), dia-
stereoselectivity (up to 99:1 anti/syn) and enantioselectiv-
ity (up to 99% ee). A possible mechanism of the reaction
was proposed to proceed via the more stable TS1 interme-
diate leading to the anti product.
(3) (a) Corrêa, R. J.; Garden, S. J.; Angelici, G.; Tomasini, C.
Eur. J. Org. Chem. 2008, 736. (b) Angelici, G.; Corrêa, R. J.;
Garden, S. J.; Tomasini, C. Tetrahedron Lett. 2009, 50, 814.
(4) (a) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14, 8079. (b) Hara,
N.; Nakamura, S.; Shibata, N.; Toru, T. Adv. Synth. Catal.
2010, 352, 1621.
Acknowledgment
We are grateful for the financial support from the National Natural
Science Foundation of China (No. 20972005 and No. 20802004).
(5) Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao, Y. F.; Zhang,
J. M.; Xiao, W. J. Tetrahedron 2007, 63, 10437.
(6) Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.;
Malyshev, D. A.; Pluháčková, K.; Kočovský, P. Org. Lett.
2007, 9, 5473.
(7) Guo, Q.; Bhanushali, M.; Zhao, C. G. Angew. Chem. Int. Ed.
2010, 49, 9460.
References and Notes
(1) (a) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
(b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed.
2007, 46, 8748; Angew. Chem. 2007, 119, 8902. (c) Marti,
C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(d) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.;
Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36,
2783. (e) Zhang, H.-P.; Kamano, Y.; Ichihara, Y.; Kizu, H.;
Komiyama, K.; Itokawa, H.; Pettit, G. R. Tetrahedron 1995,
51, 5523. (f) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley,
S. Eur. J. Org. Chem. 2001, 66, 261. (g) Hayashi, M.; Rho,
M.-C.; Enomoto, A.; Fukami, A.; Kim, Y.-P.; Kikuchi, Y.;
Sunazuka, T.; Hirose, T.; Komiyama, K.; Ōmura, S. Proc.
Natl. Acad. Sci. U.S.A. 2002, 99, 14728. (h) Kitajima, M.;
Mori, I.; Arai, K.; Kogure, N.; Takayama, H. Tetrahedron
Lett. 2006, 47, 3199.
(8) Ricci, A.; Bernardi, L.; Gioia, C.; Vierucci, S.; Robitzer, M.;
Quignard, F. Chem. Commun. 2010, 46, 6288.
(9) (a) Raj, M.; Veerasamy, N.; Singh, V. Tetrahedron Lett.
2010, 51, 2157. (b) Popp, F. D.; Donigan, B. E. J. Pharm.
Sci. 1979, 68, 519. (c) Pajouhesh, H.; Parson, R.; Popp, F. D.
J. Pharm. Sci. 1983, 72, 318. (d) Joshi, K. C.; Dandia, A.;
Sanan, S. J. Fluorine Chem. 1989, 44, 59.
(10) Wang, J. F.; Qi, C.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Chem.
Commun. 2010, 46, 2124.
(11) Wang, J. F.; Wang, X.; Ge, Z. M.; Cheng, T. M.; Li, R. T.
Chem. Commun. 2010, 46, 1751.
(12) Liu, Y.; Wang, J. F.; Sun, Q.; Li, R. T. Tetrahedron Lett.
2011, 52, 3584.
(2) (a) Kamenecka, T. M.; Danishefsky, S. J. Chem. Eur. J.
2001, 7, 41. (b) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy,
M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A.
Angew. Chem. Int. Ed. 2003, 42, 1753. (c) Liao, Y.-J.; Wu,
Y.-L.; Chuang, C.-P. Tetrahedron 2003, 59, 3511.
(13) Typical Procedure To the mixed solvent (2 mL, MeOH–
H2O = 1:1) was added the corresponding isatin (0.2 mmol),
cyclohexanone (0.6 mmol), and catalyst 13 (0.04 mmol)
with equal amount of hexanedioic acid (0.04 mmol). The
mixture was stirred at r.t. for 14 h, then quenched with
additional H2O. The organic matter was extracted with
EtOAc, dried over Na2SO4, and the filtrate was concentrated
to get the crude product, which was further purified by a
silica gel chromatography.
(d) Barroso, S.; Blay, G.; Cardona, L.; Fernandez, I.; Garcia,
B.; Pedro, J. R. J. Org. Chem. 2004, 69, 6821. (e) Cleghorn,
L. A. T.; Cooper, I. R.; Fishwick, C. W. G.; Grigg, R.;
MacLachlan, W. S.; Rasparini, M.; Sridharan, V.
J. Organomet. Chem. 2003, 687, 483. (f) Schwaebisch, D.;
Tchabanenko, K.; Adlington, R. M.; Cowley, A. M.;
Baldwin, J. E. Chem. Commun. 2004, 22, 2552. (g) Luo, S.;
Mi, X.; Xu, H.; Wang, P. G.; Cheng, J.-P. J. Org. Chem.
2004, 69, 8413. (h) Hamashima, Y.; Suzuki, T.; Takano, H.;
Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127,
10164. (i) Toullec, P. Y.; Jagt, R. B. C.; De Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715.
(j) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru,
T.; Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488.
(k) May, J. P.; Patrick, B. O.; Perrin, D. M. Synlett 2006,
3403. (l) Yadav, J. S.; Reddy, B. V. S.; Reddy, C. S.;
Krishna, A. D. Tetrahedron Lett. 2007, 48, 2029. (m) Sano,
D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593.
3-Hydroxy-3-(2-oxocyclohexyl)indolin-2-one (16a)
Yield 90%; mp 159 °C; anti/syn = 20:1; 99% ee. 1H NMR
(400 MHz, DMSO-d6): δ = 10.16 (s, 1 H), 7.13–7.21 (m, 2
H), 6.75–6.87 (m, 2 H), 5.77 (s, 1 H), 3.07 (dd, J = 12.0, 4.0
Hz, 1 H), 2.53–2.58 (m, 1 H), 2.36–2.53 (m, 1 H), 2.27–2.34
(m, 1 H), 1.58–2.08 (m, 5 H), 1.43–1.50 (m, 1 H). 13C NMR
(100 MHz, DMSO-d6): δ = 209.8, 179.4, 144.1, 131.5,
129.3, 125.5, 121.5, 110.1, 74.6, 58.1, 42.1, 27.4, 27.3, 25.1.
HRMS: m/z calcd for C14H16NO3 [M + H+]: 246.11247;
found: 246.11184. The enantiomeric ratio was determined
by chiral HPLC with AD-H column (hexane–2-PrOH =
80:20, 1 mL/min).
Synlett 2012, 23, 1031–1034
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.