3-Bromooxindoles as nucleophiles in asymmetric organocatalytic Mannich reactions with N-Ts-imines

Article abstract of DOI:10.1039/c2cc38475b

A direct asymmetric Mannich reaction of N-unprotected 3-bromooxindoles with N-Ts-imines catalyzed by bifunctional thiourea derived from 2-substituted cinchona alkaloid was developed. Products with vicinal chiral tertiary and brominated quaternary stereogenic centers were achieved in excellent diastereo- and enantioselectivity (up to 99:1 dr, 99% ee).

Full text of DOI:10.1039/c2cc38475b

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3-Bromooxindoles as Nucleophiles in Asymmetric Organocatalytic
Mannich Reactions with N-Ts-imines
Jianhao Li, Taiping Du, Gang Zhang* and Yungui Peng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
represent an important class of nitrogen-containing
50 heterocycles with potential synthetic utility and biological
activity.13
The direct asymmetric Mannich reaction of N-unprotected 3-
bromooxindoles with N-Ts-imines catalyzed by bifunctional
thiourea derived from 2-substituted cinchona alkaloid. The
products with vicinal chiral tertiary and brominates
10 quaternary stereogenic centers were achieved in excellent
diastereo- and enantioselectivity (up to 99:1 dr, 99% ee).
H
H
H
H
N
N
N
N
N
N
R1
R1
X
S
MeO
MeO
Oxindoles bearing a quaternary stereocenters at the C3 are
prevalent in biologically relevant alkaloid natural products
and pharmaceuticals.1 For this reason, the development of
15 methodologies to access various of chiral 3,3’-disubstituted
oxindoles derivatives has become a hot topic.2-5 Thus, great
efforts and achievements have been made in catalytic
asymmetric reactions to afford those chiral promising target
compounds involving 3-alkyl-3 or 3-aryloxindoles,4 3-
20 hydroxyoxindoles,5 and 3-halo 3,3’-disubstituted oxindoles6
which could be easily elaborated to other functional
derivatives and have exhibited potential use in the construct of
complex bioactive compounds. Amongst the chiral 3-halo
3,3’-disubstituted oxindoles, the 3-chloro-7,8 and 3-fluoro-9
25 analogues have been successfully accessed by asymmetric
reactions. However, to our knowledge, the chiral 3-bromo
3,3’-disubstituted oxindoles, which could have more potential
and be broadly used as versatile synthetic intermediates, have
no general asymmetric catalytic method to access.10
N
N
3b R1 = 4-CF3C6H4;
3c R1 = 4-NO2C6H4;
1
2
X = NH, R1 = 3,5-(CF3)2C6H3;
X = O, R1 = 3,5-(CF3)2C6H3;
3d R1 = 4-MeOC6H4;
3e R1 = CH2CF3
3a X = S, R1 = 3,5-(CF3)2C6H3;
R3
H
H
H
H
N
N
N
N
N
N
R1
R1
R2
S
S
MeO
R4
N
N
5e R4 = 4-FC6H4;
5f R4 = 4-ClC6H4;
5g R4 = Bn;
R
1 = 3,5-(CF3)2C6H3
5a R4 = Ph;
4a R2 = H, R3 = -CH=CH2;
4b R2 = OH, R3 = -CH=CH2; 5b R4 = 4-MeC6H4;
4c R2 = OiPr, R3 = -CH=CH2; 5c R4 = 4-EtC6H4;
5h R4
=
nBu;
5d R4 = 4-MeOC H ;
5i R4 = tBu
6 4
4d R2 = OMe, R3 = Et
Figure 1 Screened catalysts derived from cinchona alkaloids.
Herein, we report the first example of
a
highly
55 enantioselective direct asymmetric Mannich reaction of N-
unprotected 3-bromooxindoles with N-Ts-imines catalyzed by
bifunctional cinchona alkaloid catalysts, and further allow for
construction of chiral spiroaziridine oxindoles.
30
Racemic 3-bromooxindoles, with both eletrophilicity as
alkylating agents and nucleophilicity in the enolate tautomer,
were first reported by Hinman and Baumann.11 The
eletrophilicity of 3-bromooxindole and its derivatives has
been successfully realized.12 Stoltz group has exploited it in
The reaction of 6a with benzaldehyde N-Ts-imine 7a was
60 selected as a model reaction. We exploited bifunctional
cinchona alkaloid catalysts 1–5 (Figure 1) to concomitantly
activate the two reactive partners through the tertiary nitrogen
to deprotonate the 3-position proton of 3-bromooxindole and
the hydrogen bond donating ability to interact with nitrogen of
65 the imine. When the catalyst 3a was investigated at rt, initial
test had found the phenomena that the catalyst had been
deactivated during the reaction procedure, we ascribed this to
the electrophilic ability of 3-bromooxindole and with the
propensity to alkylate the tertiary nitrogen to form quaternary
70 ammonia salt to deactivate the catalyst. Thus the basicity of
the tertiary nitrogen must be exerted and its nucleophilicity
must be restrained by varying the reaction temperature and
solvent with the help of the different effect of the two factors
on them. After preliminary screening, we had delighted to find
75 that good reactivity (79% yield) and stereoselectivities (90:10
dr and 88% ee) were achieved when the reaction was
35 preparing
racemic
3,3’-disubstituted
oxindoles.12a
Subsequently, the enantioselective variant was achieved and
used in constructing the core structures of an important
biologically active alkaloid.12b In contrast, 3-bromooxindoles
have rarely been employed as nucleophiles. We hypothesized
40 that if racemic 3-bromooxindoles could be successfully
applied as nucleophilic partners in asymmetric Mannich
reactions with N-Ts-imines, then those densely functionalized
products with vicinal chiral tertiary and brominates quaternary
centers could be accessed. Those products could be further
45 transformed into chiral spiroaziridine oxindoles. The synthesis
of highly strained optical activity spiroaziridine oxindoles
remains a significant challenge, and until now, no report has
documented
a
success. Those spiroaziridine oxindoles
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Table 2 Asymmetric Mannich reaction of 3-bromooxindoles to N-Ts-
imines a
performed at low temperature (-40 °C) in DCM after 72 h
(Table 1, entry 3). By changing the catalyst into guanidine (1)
and urea (2), the yields and stereoselectivities decreased
greatly (Table 1, entries 1 and 2). The effect of the substituent
at the terminal aromatic ring of thiourea on the reaction was
further investigated. When 3a was changed into 3b, 3c, or 3d,
TsHN
Br
Br
Ar
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5e (10 mol %)
DCM, -40 oC, 72 h
O
ArC=NTs
5
O
N
R5
N
R
R
5
8a - 8v
R
6
7a - 7r
40
Yield/
%
91
(86) (95:5)
94
99
96
84
99
94
89
99
87
90
99
88
Table 1 Catalysts screened in asymmetric Mannich reaction of 3-
bromooxindole to N-Ts-imine a
Entry
1d
R
H
R5
Ar
Product
Drc
Ee/%c
b
96:4
94
(95)
82
82
90
82
75
87
92
93
94
94
91
98
-
H
Ph
8a
TsHN
Br
NTs
Br
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
o-FC6H4
m-FC6H4
p-FC6H4
94:6
96:4
97:3
93:7
92:8
93:7
99:1
83:17
97:3
99:1
78:22
97:3
-
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
Ph
O
Cat. (10 mol %)
O
DCM, -40 oC, 72 h
N
N
H
8a
6a
H
7a
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-MeC6H4
m-MeC6H4
p-MeC6H4
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
p-HOC6H4
Furan-2-yl
1-Naphthyl
Ph
Entry
1
2
3
4
5
6
7
8
Cat.
1
2
Yield/%b
Drc
Ee/%c
53
45
88
80
88
78
75
85
77
88
87
90
93
91
93
94
94
90
-
42
47
79
53
42
32
53
40
30
59
64
72
70
66
72
76
66
66
NR
66
85:15
84:16
90:10
89:11
90:10
95:5
86:14
84:16
93:7
94:6
92:8
93:7
95:5
93:7
94:6
96:4
96:4
95:5
-
3a
3b
3c
3d
3e
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
Trace
99
81
79:21
95:5
93
95
9
10
11
12
13
14
15
16
17
18
19
20
17
H
H
89
94:6
90
8q
18
19
20
21
22
H
5-F
5-Cl
5-Br
6-Cl
Me
H
H
H
H
Ph
64
89
90
93
75
92:8
99:1
99:1
99:1
95:5
79
95
95
96
99
8r
8s
8t
8u
8v
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
a
5g
5h
5i
Reaction conditions: 6 (0.1 mmol), 7 (0.15 mmol), 5e (0.01 mmol), c =
0.20 M, -40 °C, 72 h. Isolated yield. Determined by chiral HPLC
analysis. d Results of reaction magnified to 30 times are in parentheses.
b
c
88:12
90
10 a Reaction conditions: 6a (0.1 mmol), 7a (0.12 mmol), Cat. (0.01 mmol),
c = 0.20 M, -40 °C, 72 h. b Isolated yield. c Determined by chiral HPLC
analysis.
Having established the optimal reactive conditions, the
45 reaction was expanded to a wide variety of 3-bromooxindoles
6 and N-Ts-imines 7. The results are summarized in Table 2.
Generally, N-Ts-imines with electron donating substituents
gave better enantioselectivity than those with electron
withdrawing groups. The position of the substituent on the N-
50 Ts-imines phenyl group had a slight influence on the reaction.
N-Ts-imines with a meta substituent on the phenyl proceeded
smoothly to give the corresponding products with slightly
higher yields (Table 2, entries 3, 6, 9 and 12). Better
enantioselectivities were achieved when substituents were in
55 the para position of N-Ts-imines rather than in the meta or
ortho position (Table 2, entries 2–13). When the substituent in
the para position was –OH, no reaction occurred, which was
ascribed to the acidity of the –OH, which neutralized the
basicity of the tertiary nitrogen in the catalyst thus
60 deactivating it (Table 2, entry 14). Imines with heteroaromatic
and naphthalene substituents were also tested, and were
suitable for the asymmetric Mannich reactions. The furyl
imine showed slightly lower diastereoselectivity. Product 8o
was obtained in excellent yield (99%), good enantioselectivity
65 (93% ee), and with moderate diastereoselectivity (79:21 dr)
(Table 2, entry 15). Excellent stereoselectivities were
observed in product 8p (Table 2, entry 16). When the reaction
was scaled up to 30 times, the stereoselectivities kept the
same level (Table 2, entry 1). Distinct reactive performance
70 between the protected and unprotected 3-substituted oxindoles
has been documented.14 The same phenomenon was also
the yields of the reaction decreased gradually with slightly
fluctuated stereoselectivities (Table 1, entries 3–6). This may
15 be caused by the hydrogen bond donating ability of the
thiourea, which is associated and governed by the electronic
status of the aromatic substituent. When we introduced an
aliphatic trifluoroethyl into the terminal of thiourea (3e), no
better results were observed (Table 1, entry 7). On the base of
20 catalyst 3a, we changed the group of R2 to hydrogen (4a),
hydroxyl (4b), and isopropoxyl (4c), and we also changed the
group of R3 to ethyl (4d), but the performance of those
catalysts did not improve. When phenyl (R4 = Ph) was
introduced into the 2-position of the catalyst (5a), better
25 diastereoselectivity (93:7 dr vs 90:10 dr) and stereoselectivity
(90% ee vs 88% ee) were achieved with slightly lower yield
(72% vs 79%) (Table 1, entries 3 and 12). Encouraged by this
promising result, a series of other substituents on the 2-
position of the catalysts (5b–5i) were investigated
30 systematically (Table 1, entries 13–20). 5e was identified as
the best catalyst in steric control ability and had a 76% yield,
96:4 dr and 94% ee (Table 1, entry 16). Other bifunctional
catalysts were screened, but none performed better than
catalyst 5e (see ESI: Electronic Supplementary Information).
35 Reaction conditions were further optimized and the best result
was achieved when the concentration of 6a was 0.2 M and the
ratio of 7a to 6a was 1.5 : 1 in DCM at -40 °C (see ESI).
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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absolute
DOI: 10.1039/b000000x/
configuration
determinations
for
8u.
See
identified in this catalytic system. N-Me-protected 3-
bromooxindole resulted in lower yield and enantioselectivity
(Table 2, entry 18). Various halo-substituted 3-
bromooxindoles (6b–6e) were further investigated in the
asymmetric reactions with imine 7m. The desired products
(8s–8v) were achieved with good yields (75–93%), and
excellent stereoselectivities (95:5–99:1 dr; 95–99% ee) (Table
2, entries 19–22). Regrettably, this process didn’t
accommodate to aliphatic imines.
The absolute configuration of the major diastereomer of
product 8u was confirmed by X-ray analysis (See ESI).15 To
account for the stereochemical outcome, a transition state
model was proposed (Figure 2). The two reactive partners
were activated concurrently by the catalyst and the
1
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10
15 nucleophilic attack from both the Re-faces of the enolate
anion and the N-Ts-imine afford the observed products. Other
product configurations were deduced based on analogy.
4
5
(a) Q. Zhu and Y.-X. Lu, Angew. Chem. Int. Ed. 2010, 49, 7753; (b)
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R4
N
N
H
N
H
O
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N
H
H
S
Ts
OMe
N
R1
Br
N
Re
Ar
Ar = 4-MeOC6H4; R1 = 3,5-(CF3)2C6H3; R4 = 4-FC6H4
Figure 2 Proposed transition state model.
20
Attempt to transform the chiral Mannich products into the
corresponding spiroaziridine oxindoles.16 After a series of
tests and found that the target compound 9 could be achieved
successfully by an intramolecular SN2 reaction in 86% yield,
>99:1 dr and 93% ee in the presence of AgNO3 (1.2 equiv.)
25 and TEA (1.2 equiv.) at rt in toluene (1.0 mL) for 1 h (Scheme
1).
TsHN
Br
TsN
Ph
O
6
7
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Ph
O
AgNO3 (1.2 equiv.), TEA (1.2 equiv.)
toluene, rt
N
N
H
H
9: yield 86%
8a: 1 equiv.
95:5 dr; 95% ee
>99:1 dr; 93% ee
Scheme 1 Synthesis of chiral spiroaziridine oxindole
8
9
In conclusion, a series of bifunctional thiourea catalysts
30 first derived from cinchona alkaloid with substituents at 2-
position had been employed in the direct asymmetric Mannich
reaction of N-unprotected 3-bromooxindoles with N-Ts-imines.
The products bearing vicinal chiral tertiary and brominates
quaternary stereogenic centers were attainable in the catalysis
35 of 5e with excellent stereoselectivities (up to 99:1 dr, 99% ee)
for the first time. Thus, a novel general methodology to access
chiral spiroaziridine oxindoles was further developed.
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105
110
We are grateful for the National Science Foundation of
China (21172180) and Specialized Research Fund for the
40 Doctoral Program of Higher Education (20110182110006).
15 CCDC 885433 (8u) contains the supplementary crystallographic data
could be obtained free of charge from the Cambridge
Notes and references
a School of Chemistry and Chemical Engineering, Southwest University, 2
N. Tiansheng Road, Chongqing, 400715, (P. R. China). Fax: 8623-
68253157; Tel: 8623-68253157; E-mail: pengyungui@hotmail.com
45 † Electronic Supplementary Information (ESI) available: Catalysts
synthesis, spectroscopic data, enantioselectivities measurement, and
Crystallographic
www.ccdc.cam.ac.uk/datarequest/cif.
115 16 No spiroaziridine oxindole was observed in the Mannich reaction
procedure, even deal with the Mannich products with various bases.
Data
Centre
via
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