Organocatalytic asymmetric α-amination of unprotected 3-aryl and 3-aliphatic substituted oxindoles using di-tert-butyl azodicarboxylate

Article abstract of DOI:10.1002/adsc.201100379

The bifunctional quinine-derived thiourea catalyst 14 was found to catalyze the direct amination of unprotected 3-aryl and aliphatic substituted oxindoles with di-tert-butyl azodicarboxylate (DBAD) to construct a tetrasubstituted stereogenic carbon center at the C-3 position of oxindoles in good to excellent yield and enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201100379

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DOI: 10.1002/adsc.201100379
Organocatalytic Asymmetric a-Amination of Unprotected
3-Aryl and 3-Aliphatic Substituted Oxindoles using Di-tert-butyl
Azodicarboxylate
Feng Zhou,a Miao Ding,a Yun-Lin Liu,a Cui-Hong Wang,a Cong-Bin Ji,a
Yi-Yu Zhang,b and Jian Zhoua,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-21-6223-4560; phone: (+86)-21-6223-4560; e-mail: jzhou@chem.ecnu.edu.cn
College of Chemistry and Material Sciences, Sichuan Normal University, Chengdu, Sichuan 610066, Peopleꢀs Republic of
b
China
Received: May 13, 2011; Revised: July 7, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100379.
Abstract: The bifunctional quinine-derived thiourea
catalyst 14 was found to catalyze the direct amina-
tion of unprotected 3-aryl and aliphatic substituted
oxindoles with di-tert-butyl azodicarboxylate
(DBAD) to construct a tetrasubstituted stereogenic
carbon center at the C-3 position of oxindoles in
good to excellent yield and enantioselectivity.
a promising method for the synthesis of 3-substituted
3-aminooxindoles.[5] Because of its presence in some
natural bioactive products and pharmaceutically
active compounds such as the potent gastrin/CCK-B
receptor antagonist AG-041R[5f] and the vasopressin
VIb receptor antagonist SSR-149415,[5g,h] the catalytic
synthesis of enantioenriched 3-aminooxindoles is of
current interest.[3,6] The reaction of unprotected 3-sub-
stituted oxindole 1 with diisopropyl or diethyl azodi-
carboxylate (DIAD or DEAD) could afford the de-
sired products in excellent ee,[3a–d] but it was difficult
to convert the corresponding products to synthetically
useful 3-aminooxindoles.[7] In a previous study,[3b] we
found that adducts obtained from DIAD or DEAD
easily decomposed under all the reported conditions
À
Keywords: 3-aminooxindoles; asymmetric catalysis;
atom efficiency; organocatalysis; tetrasubstituted
stereogenic carbon centers
To prepare products in an atom-economical manner is to remove the alkoxycarbonyl group for further N N
very important in modern organic synthesis.[1] As far cleavage. The use of di-tert-butyl azodicarboxylate
as the catalytic asymmetric construction of tetrasub- (DBAD) as amination reagent was favourable for the
stituted carbon stereogenic centers is concerned,[2]
a
easy removal of the Boc group. However, since
number of the current methods are not sufficiently DBAD is less electrophilic than other azodicarboxy-
atom-efficient as judged by the principles of “ideal lates,[8] the reaction of unprotected 3-substituted oxin-
synthesis” to maximize products and minimize by- doles and DBAD has not been developed up to now.
products,[1b] although they are highly enantioselective.
An alternative method is to activate 3-substituted
Because of the known challenges such as the low re- oxindoles to react with DBAD. Helpfully, introducing
activity of precursors involved in the generation of an electron-withdrawing group to the nitrogen moiety
tetrasubstituted carbon centers, the use of activating was able to lower down the pKa value of 3-substituted
groups to make the substrates more reactive is a oxindoles. For example, N-acetyloxindole has a pKa
common strategy for reaction development. However, value of 13.0, much lower than that of oxindole
the introduction and removal of activating groups (18.2).[9] Accordingly, the more reactive N-Boc pro-
needs extra steps, consumes more time, labor and re- tected 3-substituted oxindole 2 was widely used for
agents, and generates more waste to get the desired the catalytic asymmetric synthesis of 3,3-disubstituted
products.[1]
oxindoles.[10] Based on this strategy, Shibasaki and co-
This dilemma can be exemplified by the catalytic workers developed a highly enantioselective amina-
asymmetric direct amination of 3-prochiral oxindoles tion of N-Boc-protected 3-alkyloxindoles using
using azodicarboxylate,[3,4] which recently emerged as DBAD, and applied it to the formal synthesis of AG-
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Scheme 1. Synthesis of N-Boc-protected oxindoles 2.
041R.[3e] Most recently, Barbas III et al. expanded the ing that the use of additives to improve both the
substrate scope to N-Boc-protected 3-aryloxindoles.[3f] enantioselectivity and reactivity is a fruitful method
Despite these achievements, there is still room for in asymmetric catalysis,[16] we tried different additives
further improvement. First, it would be more atom- to improve the reactivity. To our delight, we found
economical to use unprotected 3-substituted oxindole that the addition of powdered MS 5 ꢂ could obvious-
1 as the starting material, because it took three steps ly accelerate the reaction to finish the products within
to prepare N-Boc-oxindole 2 from isatin with the sac- three days, with only
a slight decrease in ee
rifice of one equivalent of (Boc)2O.[11a] The direct pro- (entry 14). The role of MS 5 ꢂ to accelerate the reac-
tection of 1 using (Boc)2O was problematic due to the tion is now under investigation.
competitive N- and O-selectivity (Scheme 1).[11] In ad-
The DBAD was found to be crucial for the high ee
dition, there are no available methods for the highly of this amination reaction. As shown in Scheme 2, the
enantioselective amination of both 3-aryl- and 3-alkyl- alkyl group R at azodicarboxylates 6 significantly in-
ACHTUNGTRENNUNGoxindoles using DBAD as yet. Accordingly, it is of fluenced the ee of product 7. DBAD, with bulkyl tert-
great interest to develop an enantioselective amina- butyl group, afforded the corresponding adduct 7a in
tion reaction of both unprotected 3-aliphatic and aryl- the highest ee. In contrast, DIAD or DEAD enabled
substituted oxindoles using DBAD. In our efforts in the reaction to be obviously faster but the desired
the synthesis of 3,3-disubstituted oxindoles for biolog- product 7b or 7c was obtained in much lower ee. The
ical evaluation,[3b,12] we started this research work, and absolute configuration of product 7b was assigned to
here we wish to report our results.
be S by comparing its HPLC performance with the lit-
The reaction of 3-phenyloxindole 1a and DBAD 6a erature report,[3a] and that of compound 7a was tenta-
was chosen for optimization, using THF as the solvent tively assigned by comparing the sign of its optical ro-
at À108C in the presence of 10 mol% chiral catalyst. tations to that of 7b.
We first focused on the use of bifunctional Brønsted
Then a variety of unprotected 3-aryloxindoles 1a–m
acid-base catalysts, with the base moiety[13] for depro- were examined using catalyst 14 and DCE as the sol-
tonative activation of oxindole and the acid moiety[14] vent, and the results were shown in Table 2. All the
to interact with DBAD. Hatakeyamaꢀs catalyst 8, with reactions were run on a 0.25-mmol scale at À108C
a phenol group as the Brønsted acid moiety, worked with the addition of powdered MS 5 ꢂ. Generally, the
well to afford the desired product in moderate yield electron-donating substituents had a positive influ-
and 56% ee (entry 1, Table 1). This result encouraged ence on the selectivity of the reaction, irrespectuive
us to try other bifunctional catalysts, and bifunctional of whether on the oxindole framework or on the
urea catalyst 14[15] turned out to be the most effective, phenyl ring at the C-3 position of oxindole, and the
which could promote the reaction in 82% yield with desired products were all obtained in excellent ee (en-
87% ee (entry 7). For comparison, Brønsted base cat- tries 2–5, 9, 10 and 13). The methoxy group on the C-
alysts 11 and 12 were also tried, but both proved to 5 position of the oxindole greatly slowed down the re-
be less enantioselective (entries 4 and 5). The solvent action so that 20 mol% of catalyst was used to ensure
effect was further examined using catalyst 14, and 1,2- a high yield of product 7l (entry 10). On the other
dichloroethane (DCE) was found to be the best, hand, the presence of electron-withdrawing groups on
which afforded the product 7a in up to 90% ee, but the phenyl group at C-3 position improved the reac-
the reactivity was unsatisfactory (entry 13). Consider- tivity but decreased the ee of the products 7h and 7i
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Organocatalytic Asymmetric a-Amination of Unprotected 3-Aryl and 3-Aliphatic Substituted Oxindoles
Table 1. Catalyst screening and solvent effect.
Entry[a]
Catalyst
Time [days]
Solvent
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
8
9
5
5
5
5
5
4
4
4
4
4
4
4
4
3
THF
THF
THF
THF
THF
THF
THF
toluene
CH2Cl2
acetone
CH3CN
Et2O
51
64
58
56
55
19
82
25
64
68
72
10
58
91
56
26
15
3
10
11
12
13
14
14
14
14
14
14
14
14
0
74[d]
87
71
89
81
60
46
90
88
9
10
11
12
13
14[e]
CH2ClCH2Cl
CH2ClCH2Cl
[a]
On a 0.1-mmol scale.
Isolated yield.
Determined by chiral HPLC analysis.
Opposite enantiomer.
Powdered MS 5ꢂ as the additive.
[b]
[c]
[d]
[e]
Scheme 2. Effect of the alkyl group R at azodicarboxylates 6.
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Table 2. Substrate scope of 3-aryloxindoles with catalyst 14.
Entry[a]
Substrate 1
Product 7
Time [days])
Yield [%][b]
ee[c] [%]
1
2
3
1a: R=R1 =H, Ar=Ph
7a
7d
7e
7f
7g
7h
7i
7j
7k
7l
3
5
5
5
5
3
3
5
5
5
2
2
5
91
67
83
88
75
83
89
74
65
81
61
86
97
88
94
90
93
95
82
83
87
91
95
84
81
96
1b: R=R1 =H, Ar=o-MeC6H4
1c: R=R1 =H, Ar=m-MeC6H4
1d: R=R1 =H, Ar=p-MeC6H4
1e: R=R1 =H, Ar=p-MeOC6H4
1f: R=R1 =H, Ar=p-ClC6H4
1g: R=R1 =H, Ar=p-BrC6H4
1h: R=R1 =H, Ar=2-naphthyl
1i: R=Me, R1 =H, Ar=Ph
1j: R=MeO, R1 =H, Ar=Ph
1k: R=F, R1 =H, Ar=Ph
4
5[d]
6
7
8
9
10[e]
11[e]
12[e]
13
7m
7n
7o
1l: R=Cl, R1 =H, Ar=Ph
1m: R=Me, R1 =Me, Ar=Ph
[a]
On a 0.25-mmol scale.
Isolated yield.
Determined by chiral HPLC analysis.
THF as the solvent without MS 5ꢂ.
20 mol% catalyst.
[b]
[c]
[d]
[e]
(entries 6 and 7). In the case of oxindoles 1k and 1l,
we found that the use of 20 mol% of catalyst could
improve the ee of the products 7m and 7n, which
were obtained in above 80% ee (entries 11 and 12).
An oxindole bearing a 2-naphthyl group at the C-3
position was also examined, and the corresponding
product 7j was obtained in 87% ee (entry 8).
The structure of the amination adduct 7m was fur-
ther confirmed by single-crystal X-ray diffraction
analysis (Figure 1).[17]
We were pleased to find that unprotected 3-alkylox-
indoles also worked well under these conditions. This
result was really interesting, because unprotected 3-
alk
that can be expected to be substantially higher than
18.2 (oxindole).[9] The reaction was run at 08C. 3- Figure 1. X-ray structure of amination adduct 7m.
Benzyloxindole worked well to give the desired prod-
ACHTUNGTRENNUNGyloxindoles were less reactive, with a pKa value
ACHTUNGTRENNUNG
uct 7p in 72% yield with 88% ee (entry 1, Table 3).
Electron-withdrawing substituents at the C-5 position ent aryl substituents on the C-3 benzyl group of oxin-
accelerated the reaction, so that products 7q and 7r dole 1 were also examined, and the corresponding
could be obtained in up to 90% ee with high yield, products 7u–y were all obtained in excellent ee (en-
using only 10 mol% of catalyst (entries 2 and 3). The tries 6–10). Interestingly, even 5-bromo-3-methyloxin-
5-bromo-substituted product 7s was obtained in 84% dole could afford the corresponding product 7z in
ee in the presence of 20 mol% catalyst 14 (entry 4). 85% ee, although 30 mol% of catalyst 14 was used
On the other hand, a methyl group on the C-5 posi- (entry 11).
tion obviously slowed the reaction, although the prod-
During the catalyst screening, we observed that the
uct 7t could be obtained in 95% ee (entry 5). Differ- pseudo-enantiomeric quinidine-derived bifunctional
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Organocatalytic Asymmetric a-Amination of Unprotected 3-Aryl and 3-Aliphatic Substituted Oxindoles
Table 3. Substrate scope of 3-alkyloxindoles with catalyst 14.
Entry[a]
R1
R
X
Product 7
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
H
F
Cl
Br
Me
H
H
H
H
H
Bn
Bn
Bn
Bn
20
10
10
20
20
20
20
30
20
20
30
7p
7q
7r
7s
7t
7u
7v
7w
7x
7y
7z
72
70
83
92
88
86
90
84
95
90
93
98
89
90
85
Bn
47 (86)[d]
67
p-ClC6H4CH2
p-CF3C6H4CH2
p-MeOC6H4CH2
o-FC6H4CH2
m-MeC6H4CH2
Me
80
56 (71)[d]
60
9
10
11
56 (88)[d]
60
Br
[a]
On a 0.25-mmol scale.
Isolated yield.
By chiral HPLC analysis.
[b]
[c]
[d]
Yield based on recovery of oxindole 1.
catalyst 13 could deliver the opposite enantiomer of chloroethane in the presence of MS 5ꢂ, the use of
product 7a in 74% ee when using THF as the solvent, 20 mol% catalyst 13 could afford the desired opposite
although at a much slower rate (entry 6, Table 1). enantiomers of product 7 in reasonable yields and ee
Under the optimized conditions, we further examined (Table 4). It also should be pointed out that the
the potency of catalyst 13 for the synthesis of the op- pseudo-enantiomeric catalyst 13 was less reactive and
posite enantiomers of products 7. To our delight, enantioselective than catalyst 14.
when the reaction was carried out at À108C in 1,2-di-
Table 4. Substrate scope of 3-alkyloxindoles with catalyst 13.
Entry[a]
R1
R2
R
Product 7
Yield[b] [%]
ee[c] [%]
1
2
3
4
H
H
H
Me
Me
Cl
H
H
H
H
Me
H
Ph
7a
7f
7i
7k
7o
7r
69
67
86
90
80
89
97
82
p-MeC6H4
p-BrC6H4
Ph
Ph
Bn
61
36 (62)[d]
5
76
71
6[e]
[a]
On a 0.25-mmol scale.
Isolated yield.
By chiral HPLC analysis, opposite enantiomer.
Yield based on recovery of oxindole 1.
08C.
[b]
[c]
[d]
[e]
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Scheme 3. Product elaboration.
References
The thus obtained amination adducts can be readily
transformed to the desired 3-amino-3-aryloxindoles.
For example, compounds 7a and 7o can be converted
to the corresponding aminooxindoles 15a and 15o in
good yield without loss of ee, after the removal of
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In summary, we have developed the first example
of highly enantioselective direct amination of both
unprotected 3-aryl- and 3-alkyloxindoles using
DBAD. Simple and easily available bifuntional cata-
lyst 14 was identified as a powerful catalyst for this
reaction. The use of unprotected 3-substituted oxin-
doles is very impressive because they can be easily ac-
cessed. The use of DBAD allows the facile transfor-
mation of amination adducts to synthetically useful 3-
aminooxindoles without loss of enantioselectivity. The
application of this method for the total synthesis of
related bioactive compounds is now in process in our
laboratory.
Experimental Section
To a 5-mL vial were added catalyst 14 (0.025 mmol), oxin-
dole 1 (0.25 mmol), 2.5 mL of anhydrous 1,2-dichloroethane
and MS 5ꢂ (250 mg). After the reaction mixture had been
stirred at À108C for half an hour, DBAD 6a (0.3 mmol) was
added. The resulting mixture was stirred at À108C until
almost full conversion of 1 by TLC analysis. The reaction
mixture was directly subjected to column chromatography
(5–10% EtOAc in DCM) to afford the desired product 7.
Acknowledgements
The financial support from the National Natural Science
Foundation of China (20902025), Shanghai Pujiang Program
(10J1403100), Shanghai talent grooming funding (2009015),
Specialized Research Fund for the Doctoral Program of
Higher Education (20090076120007) and the Fundamental
Research Funds for the Central Universities (East China
Normal University 11043) are highly appreciated.
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