Zn-mediated asymmetric allylation of N-tert-butanesulfinyl ketimines: An efficient and practical access to chiral quaternary 3-aminooxindoles

Article abstract of DOI:10.1039/c2cc38600c

Room temperature zinc-mediated diastereoselective allylation or propargylation of isatin-derived N-tert-butanesulfinyl ketimines for synthesis of highly enantiomerically enriched tetrasubstituted 3-aminooxindoles is described.

Full text of DOI:10.1039/c2cc38600c

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Graphical Abstract
Zn-Mediated Asymmetric Allylation of N-tert-Butanesulfinyl
Ketimines: An Efficient and Practical Access to Chiral
Quaternary 3-Aminooxindoles
R4
R4
R2
Br
S
R3
R2
O
O
NH
HN
R3
R3
R1
O
R1
N
N
Tr
Diao Chen and Ming-Hua Xu*
S
Tr
O
N
up to 99% de
up to 99% ee
Zn
rt
R1
O
Room temperature zinc-mediated diastereoselective allylation
or propargylation of isatin-derived N-tert-butanesulfinyl
ketimines for synthesis of highly enantiomerically enriched
tetrasubstituted 3-aminooxindoles is described.
N
S
O
Tr
NH
HN
Br
R1
O
O
N
N
Tr
up to 99% de
Tr
99% ee

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Zn-Mediated Asymmetric Allylation of N-tert-Butanesulfinyl Ketimines:
An Efficient and Practical Access to Chiral Quaternary 3-
Aminooxindoles†
Diao Chen, and Ming-Hua Xu*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Room temperature zinc-mediated diastereoselective allylation
or propargylation of isatin-derived N-tert-butanesulfinyl
Table 1. Screening of reaction conditions for diastereoselective allylation
of isatin N-sulfinyl ketimines a
ketimines for synthesis of highly enantiomerically enriched
10 tetrasubstituted 3-aminooxindoles is described.
S
S
O
O
N
NH
N
3-Aminooxindoles construct the core skeletons of a large family
In or Zn
Br
of biologically active natural products and
a series of
O
N
O
solvent, rt
pharmaceutically important compounds.1 Consequently, the
development of efficient methods to synthesize these valuable
15 frameworks has been a topic of considerable interest in recent
years.1d,e Among them, intensive research efforts have focused on
the assembly of tetrasubstituted 3-aminooxindoles.2-6 Catalytic
asymmetric amination of 3-substitued oxindoles with
azodicarboxylates using chiral metal catalyst4 and organocatalyst5
20 for the highly stereoselective construction of these structures has
been successfully developed. However, these transformations still
suffer from some drawbacks, such as the facts that they generally
require a long reaction time (1–7 days), the starting 3-substitued
oxindoles are not readily available, and the final cleavage of
25 product N-N bond can not be easily accomplished. On the other
hand, asymmetric addition of carbon nucleophiles to isatin-
derived ketimines represents another straightforward route to
chiral quaternary 3-aminooxindoles, but only limited success has
been achieved due to often unsatisfactory results.6 Therefore, a
30 simple new method that provides efficient and direct access to
enantiopure quaternary 3-aminooxindoles with useful functional
groups remains highly desirable.
We have recently disclosed our success on α-allylation of various
unprotected racemic amino acid esters to afford nonnatural α,α-
35 disubstituted α-amino acids with great stereocontrol through an
efficient stereospecfic [2,3]-sigmatropic rearrangement process.7
In considering tetrasubstituted 3-aminooxindoles (cyclic α,α-
disubstituted α-amino acid derivatives), we also became
interested in stereoselectively installing an allyl functional group
40 to the quaternary carbon center to form chiral 3-allyl 3-
aminooxindoles. In our earlier work, efficient methods for the
highly diastereoselective synthesis of chiral homoallylic amines
by using N-tert-butanesulfinyl imine chemistry have been
developed,8 however, successful asymmetric allyl addition to
45 ketimines is far less explored8a,d and remains a significant
challenge.9 In 2009, Silvani described allylmagnesium bromide
addition to isatin-derived tert-butanesulfinyl ketimines to
R
R
1a, R = Me; 1b, R = PMB; 1c, R = Tr
3a-c
50
yieldc
(%)
ded
(%)
entry
1
2
3
4
5
6
7
R
M
In
Zn
Zn
Zn
In
Zn
Zn
Zn
In
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
solvent
additiveb
Me
sat. aq NaBr
THF
THF
HMPA
sat. aq NaBr
THF
78
28
39
-7
Me
Me
Me
PMB
PMB
PMB
PMB
Tr
Tr
Tr
Tr
Tr
80
89
85
80
80
88
90
62
58
62
92
90
73
56
80
48
80
In(OTf)3
In(OTf)3
In(OTf)3
74
54
37
-10
72
52
53
-16
83
89
97
90
97
94
97
THF
8
9
HMPA
sat. aq NaBr
THF
THF
DMF
DMSO
HMPA
THF
THF
THF
10
11
12
13
14
15e
16
17f
18g
Tr
Tr
Tr
Tr
HMPA
HMPA
HMPA
HMPA
Tr
THF
aThe reaction were performed with isatin N-sulfinyl ketimine 1 (0.06
mmol), Zn or In powder (3 equiv), allyl bromide (4 equiv) in 2 mL of dry
solvent at room temperature, unless otherwise noted. b1.3 equiv of
In(OTf)3 or 0.2 mL of HMPA was employed, if indicated. cIsolated yield.
55 dDetermined by LC-MS analysis. 0.1 mL of HMPA was employed. 2
e
f
equiv of Zn was employed. g4 equiv of Zn was employed.
synthesize 3-allyl 3-aminooxindoles, but both the yields (25-46%)
and diastereoselectivities (up to 78% de) were not ideal.6a Other
known examples of effective allylation of isatin ketimines,
60 however, led to racemic 3-allyl 3-aminooxindoles.2b,c Herein, we
report a highly practical approach that allows convenient
formation of a wide range of stereochemically defined 3-allyl 3-
aminooxindoles via Zn-mediated asymmetric allylation of isatin-
derived N-sulfinyl ketimines.
65 Initially, the reactions of simple allyl bromide (2) with a series of
N-protected isatin-derived N-sulfinyl ketimines under previously
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Page 3 of 4
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Table 2. Diastereoselective allylation of isatin ketimines.a,b,c,d
described mild conditions were carried out (Table 1). To our
delight, all the reactions proceeded smoothly at room temperature,
giving the desired product 3-allyl 3-aminooxindoles in goods
yields, albeit with low to moderate diastereoselectivities in most
cases (entries 1-14). It was found that Zn-mediated reactions
showed much better stereocontrol than In-mediated ones.
Surprisingly, unlike in the known cases of N-sulfinyl imines,8a the
addition of Lewis acid In(OTf)3 in THF led to sharp declines in
diastereoselectivities (entries 3, 7 and 11). In contrast, we were
R4
S
S
O
3
N
R4
VieNwHArRtRi2cle Online
O
Zn (3 equiv)
R2
Br
5
+
R1
R1
O
O
N
Tr
THF/HMPA (10:1)
rt, 0.2 - 4 h
N
R3
Tr
1
3
2
, R1 = H, 0.5 h, 75% yield, 97% de
, R = 4-Br, 1 h, 80% yield, 88% de
3c
1
3d
10 delighted to observe
significant increases in the
, R1 = 5-F, 0.5 h, 70% yield, 99% de
3f, R1 = 5-Cl, 0.5 h, 72% yield, 99% de
3g, R1 = 5-Br, 0.5 h, 90% yield, 99% de
3h, R1 = 5-Me, 0.5 h, 78% yield, 99% de
3i, R1 = 5-OMe, 0.5 h, 90% yield, 99% de
S
3e
O
NH
diastereoselectivities of the reactions in polar aprotic solvents
such as DMF, DMSO and HMPA in the presence of Zn powder
(entries 4, 8 and 12-14). Among isatin substrates bearing different
N-protecting groups, the reaction with N-Tr derivative (1c) in
15 HMPA afforded the best result of diastereoselectivity (97% ee)
(entry 14). In consideration of the carcinogenic potential of
HMPA, we attempted to reduce the amounts of HMPA.
Fortunately, the use of mixed solvent of THF and HMPA was
found also effective. Moreover, the two solvents in a 10:1 volume
20 ratio were essential to achieve the reaction with both high yield
and excellent diasteroselectivity (80% yield, 97% de) (entry 16).
In addition, the use of 3 equiv of zinc was determined to be the
best in terms of atom economy and efficiency (entries 16-18).
With the optimal reaction conditions identified, we then turned
25 our attention to the evaluation of substrate generality. A wide
range of N-trityl isatin ketimines bearing different substituents
were investigated. Gratifyingly, the reaction was found to be
general and efficient (Table 2). In all cases, it proceeded
smoothly to completion in 0.2-4 hours. Isatin imines containing
30 either electron-donating or electron-withdrawing groups at the C5
or C6 position could be successfully applied, affording
quaternary 3-allyl 3-aminooxindole products 3e-j in good yields
and with excellent diastereoselectivities (typically 99% de) at
room temperature. 4-Substituted substrate gave a slightly lower
35 diastereselectivity (3d, 88% de), probably due to the
conformational influence of the N-sulfinyl imine group by steric
interaction. Notably, the scope of the reaction was substantially
expanded with its compatibility with various substituted allyl
bromides. For example, treatment of N-sulfinyl imine 1c with
40 3,3-dimethylallyl bromide at room temperature resulted in
exceptionally fast formation of 3k and 3l in good yields with 96-
99% de. When a variety of 2- substituted ally bromides were
employed, again, the reactions occurred readily to furnish the
corresponding adducts 3n-p in equal high yields and
45 diastereoselectivities. More challenging (E)-1-bromo-2-butene
was also found an applicable substrate.10 Interestingly, two
stereoisomers (3m) were produced with a diastereomeric ratio of
77:23 in favor of (S, S) isomer with 99% ee.
R1
O
N
Tr
, R1 = 6-Br, 0.5 h, 86% yield, 98% de
3j
S
S
S
O
O
O
NH
NH
NH
F
O
O
O
N
N
Tr
N
Tr
Tr
3k, 0.2 h
85% yield, 96% de
3l
, 0.2 h
3m, 4 h
83% yield, 77:23 dr
99% de (major)
83% yield, 99% de
Ph
Np
S
S
S
O
O
O
NH
NH
NH
O
O
O
N
N
Tr
N
Tr
Tr
3p, 3 h
80% yield, 94% de
3n, 4 h
83% yield, 97% de
3o, 3 h
85% yield, 96% de
60
aReactions were performed in 0.06 mmol scale, with 3 equiv of Zn, 4
equiv of allyl bromide in 2 mL of dry THF and 0.2 mL of dry HMPA at
room temperature, unless otherwise noted. bIsolated yields. cde was
measured as enantiomeric excess for the oxidate derivative of product 3;
65 determined by chiral HPLC analysis. For 3o and 3p, the reactions were
carried out at 50OC.
d
S
S
O
O
NH
N
N
R
R
Zn (3 equiv)
+
O
O
Br
THF/HMPA (10:1)
rt, 10 min
N
Tr
Tr
4a
. R = H, 76% yield, 99% de
4b
. R = OMe, 82% yield, 98% de
Scheme 1 Diastereoselective propargylation of isatin ketimines
Conversion of the allylation/propargylation product to the
70 corresponding free amine could be easily accomplished under
acidic conditions. For example, upon treatment of TFA and
HCl/MeOH, both the trityl and sulfinyl groups of 3c were readily
removed to afford clean 3-allyl 3-aminooxindole (5).12 The
absolute configuration at C3-stereogenic center was determined
75 to be S by comparison of its optical rotation with that of the
known compound.12 Assuming an analogous reaction mechanism,
the same stereochemistry of the obtained 3-aminooxindoles 3 and
4 were assigned. For the product 3m with two stereogenic centers,
the absolute structure was determined by single-crystal X-ray
80 analysis13 (See Supplementary Information).
Encouraged by the above success on allylation, we reasoned that
50 the same isatin ketimines might undergo asymmetric
propargylation in a highly diastereoselective fashion to provide
equally valuable 3-propargyl 3-aminooxindoles if 3-bromo-1-
propyne instead of allyl bromide was employed under similar
conditions. In literature, asymmetric method to such compounds
55 is unprecedented.11 As expected, the propargylation proceeded to
completion very rapidly (within 10 min); accordingly, products
4a and 4b were formed in high yields with excellent
diastereoselectivities (98-99% de) (Scheme 1).
To rationalize the observed diastereofacial selectivity, an acyclic
transition state model is proposed (Figure 1). Because of the
strong metal cation coordination ability of HMPA, the allylzinc
2
| Journal Name, [year], [vol], 00–00
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Page 4 of 4
chelation to imine nitrogen or carbonyl oxygen is much less
temperature. The method provides easy access to a wide range of
favored in solution. As the uncoordinated N-sulfinyl group adopts
an approximate synperiplanar configuration, the bulky tert-butyl
group is positioned at the si-face of ketimine molecule (TS-1).
highly enantiomerically enriched 3-allyl or 3-propargyl
substituted 3-aminooxindoles under exceptionally mild
conditions. By taking advantage of the functional group
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5
Thus, the allylzinc reagent attacks preferentially from the 40 transformations, the rapid asymmetric construction of two
sterically unblocked re-face of the imine C=N bond, facilitating
(S)-amine formation.
important classes of spirocyclic aminooxindoles has been
established.
This work was generously supported by the NSFC (21021063).
LB
LB
Zn
S
LB
Zn LB
LB
LB
Notes and references
O
S
N
N
O
45 State key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai
201203, People’s Republic of China. E-mail: xumh@mail.shcnc.ac.cn;
Fax/Tel: +86 21 5080 7388.
† Electronic Supplementary Information (ESI) available: Experimental
50 procedures and spectral data for new compounds. See
DOI: 10.1039/b000000x/
O
O
R
R
N
N
PG
PG
TS- II
TS- I
favored
disfavored
Figure 1. Mechanistic proposals for stereocontrol
1
(a) N. J. White, J. Antimicrob. Chemother. 1992, 30, 571; (b) M. Ochi,
K. Kawasaki, H. Kataoka and Y. Uchio, Biochem. Biophys. Res.
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Zhou, Org. Biomol. Chem. 2012, 10, 3178.
O
S
S
N
O
NH
N
HN
R1
Br
2. Grubbs(II), DCM
R1
R1
1. NaH,
HCl/MeOH
> 90%
O
O
O
55
60
N
N
Tr
Tr
Tr
3c, R1 = H, 97% de
1 = H, 68% yield
, R1 = H, 97% ee
7a,
8a
R
R1 = 5-OMe, 99% de
3i,
7b, R1 = 5-OMe, 70% yield
8b, R1 = 5-OMe, 99% ee
2
O
S
S
N
O
NH
N
HN
Br
1. NaH,
HCl/MeOH
92%
O
O
O
2. Grubbs(II), DCM
50%
N
N
Tr
Tr
Tr
7c
8c, 98% ee
3m
, 77:23 dr, 99% ee
65 3 (a) X. Companyó, G. Valero, O. Pineda, T. Calvet, M. Font-Bardí, A.
Moyano and R. Rios, Org. Biomol. Chem. 2012, 10, 431; (b) H.
Zhang, S.-J. Zhang, Q.-Q. Zhou, L. Dong and Y.-C. Chen, Beilstein J.
Org. Chem. 2012, 8, 1241; (c) K. Shen, X. Liu, G. Wang, L. Lin and
X. Feng, Angew. Chem., Int. Ed. 2011, 50, 4684.
70 4 (a) P. Tolstoy, S. X. Y. Lee, C. Sparr and S. V. Ley. Org. Lett. 2012,
14, 4810; (b) S. Mouri, Z. Chen, H. Mitsunuma, M. Furutachi, S.
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Z. Yang, Z. Wang, S. Bai, K. Shen, D. Chen, X. Liu, L. Lin and X.
Feng, Chem-Eur. J. 2010, 16, 6632.
75 5 (a) F. Zhou, M. Ding, Y. L. Liu, C, H. Wang, C. B. Ji, Y. Y. Zhang
and J. Zhou, Adv. Synth. Catal. 2011, 353, 2945; (b) T. Bui, G. Torres,
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S
O
S
NH
HN
N
O
AgOAc
HCl/MeOH
O
O
O
NaBH3CN
70%
CH2Cl2, reflux
75%
N
Tr
N
N
Tr
Tr
, 99% de
4a
10
, 99% ee
9
10
Scheme 2 Facile synthesis of chiral spirocyclic oxindoles
Finally, the synthetic utility of this chemistry is demonstrated by
facile access to series of enantiopure spirocyclic
aminooxindoles (Scheme 2). A sequential treatment of the
a
15 addition products 3c, 3i with NaH/allyl bromide, followed by
Grubbs' catalyzed ring-closing metathesis, gave chiral spirocyclic
products 7a, 7b in good yields. After removal of the sulfinyl
group, the corresponding spirocyclic aminooxindoles were
obtained with no racemization detected. Similarly, by using 3m
20 as the substrate, spirocyclic product 8c bearing two contiguous
stereocenters on the 1,2,3,6-tetrahydropyridine ring was
conveniently produced. Remarkably, we found that the propargyl
adduct can also be applied to prepare specific spiro oxindoles
through intramolecular hydroamination strategy. Upon exposure
25 of 4a to AgOAc (15 mol%) in CH2Cl2, the cyclized product 9
was generated in 75% yield. Under acidic conditions in the
presence of NaBH3CN, the stereochemically defined spiro-
indolinone-pyrrolidine ring system was successfully constructed.
It is noteworthy that these chiral spirocyclic oxindole compounds
30 are valuable pharmacological components but usually difficult to
access.1e
80
85
90
Zhou, Chem. Commun. 2009, 6753.
6
(a) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti and A. Silvani, J.
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Ellman, Org. Lett. 2011, 13, 3912; (c) W. Yan, D. Wang, J. Feng, P.
Li and R. Wang, J. Org. Chem. 2012, 77, 3311; (d) Y.-L. Liu, F. Zhou,
J.-J. Cao, C.-B. Ji, M. Ding and J. Zhou, Org. Biomol. Chem. 2010, 8,
3847; (e) Q. X. Guo, Y. W. Liu, X. C. Li, L. Z. Zhong and Y. G. Peng,
J. Org. Chem. 2012, 77, 3589.
T, S. Zhu and M, H. Xu, Chem. Commun. 2012, 48, 7274.
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M. Liu, A. Shen, X.-W. Sun, F. Deng, M.-H. Xu and G.-Q. Lin, Chem.
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7
8
95 9 S. Kobayashi, Y. Mori, J. S. Fossey and M. Salter, Chem. Rev. 2011,
111, 2626.
10 With cinnamyl bromide, no reaction occured at rt.
11 For a non-asymmetric synthesis example, see ref 2c.
12 See the Supplementary Information for details.
100 13 CCDC 916093 (3m) contains the supplementary crystallographic data.
In summary, a highly practical asymmetric approach for the
efficient preparation of chiral tetrasubstituted 3-aminooxindoles
has been developed based on
a
simple Zn-mediated
35 diastereoselective allylation/propargylation process at room
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3