Expanding the scope of cinchona alkaloid-catalyzed enantioselective α-aminations of oxindoles: A versatile approach to optically active 3-amino-2-oxindole derivatives

Article abstract of DOI:10.1021/jo902039a

(Chemical Equation Presented) A cinchona alkaloid-catalyzed, highly enantioselective, α-amination of oxindoles has been developed. The reaction is general, operationally simple, and affords the desired products in high yields with good to excellent enanti

Full text of DOI:10.1021/jo902039a

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Expanding the Scope of Cinchona Alkaloid-Catalyzed Enantioselective
r-Aminations of Oxindoles: A Versatile Approach to Optically Active
3-Amino-2-oxindole Derivatives
Tommy Bui, Mar Borregan, and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology,
The Scripps Research Institute
carlos@scripps.edu
Received September 23, 2009
A cinchona alkaloid-catalyzed, highly enantioselective, R-amination of oxindoles has been devel-
oped. The reaction is general, operationally simple, and affords the desired products in high yields
with good to excellent enantioselectivity. Significantly, this study provides a general catalytic method
for the construction of a C-N bond at the C3 position of oxindoles as well as for the creation of a
nitrogen-containing, tetrasubstituted chiral center.
Introduction
few recent reports have described the synthesis of 3-hydroxy-
substituted oxindoles through the use of transition metal
catalysis; in general, catalytic procedures that allow access to
3-amino-substituted oxindoles are lacking.3-5 Although
Chen et al. have recently reported cinchona alkaloid-cata-
lyzed R-aminations of N-unprotected oxindoles, these reac-
tions are highly limited in scope, working efficiently only
with C3-benzyl-substituted oxindoles, and therefore, signifi-
cant opportunities exist to develop a broadly applicable
methodology.5 In this communication, we describe a general
organocatalytic approach to the creation of a nitrogen-
containing tetrasubstituted center at C3 through cinchona
alkaloid-catalyzed highly enantioselective electrophilic
R-amination of oxindoles (Figure 1). Unlike Chen’s method,
this catalytic procedure is general with respect to oxindoles
and aminating reagents. More importantly, we also detail in
this report various factors that affect the reactivity and the
enantioselectivity of oxindoles and their products, giving
insight into the chemistry itself and providing a basic under-
standing for further development of asymmetric transforma-
tions involving oxindoles as nucleophiles.
Oxindoles are important structural motifs found in a wide
array of natural and biological active molecules.1 Of parti-
cular interest are those that bear an oxygen or a nitrogen
atom at the C3 position. These compounds exhibit important
biological activities and are potential drug candi-
dates.2 Despite the biological relevance of these compounds,
catalytic methods for their syntheses are still limited. Only a
*To whom correspondence should be addressed. Phone: (858) 784-9098.
Fax: (858) 784-2883.
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(b) Rahman, A. U.; Basha, A. Indole Alkaloid; Harwood Academic Publishers:
Amsterdam, 1997.
(2) (a) Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.; Weiner, H.;
Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.;
Meanwell, N. A. J. Med. Chem. 2002, 45, 1487. (b) Suzuki, H.; Morita, H.;
Shiro, M.; Kobayashi, J. I. Tetrahedron 2004, 60, 2489. (c) Leugn, C.;
Tomaszewski, M.; Woo, S. (Astrazeneca AB, Sweden); U.S. Patent Appl. Publ.
(2007), CODEN: USXXCO US 2007185179 A1 20070809; patent written in
English, application US 2007-671153 20070205. Priority: US 2006-771119
20060207.
(3) Synthesis of 3-hydroxy-2-oxindoles using transition metal asymmetric
catalysis: (a) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.;
Minnaard, A. L. Org. Lett. 2006, 8, 2715. (b) Shintani, R.; Inoue, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353. (c) Ishimaru, T.; Shibata,
N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanesmasa, S. J. Am. Chem. Soc.
2006, 128, 16488. (d) Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 6946. (e) Grant, C. D.; Krische, M. J. Org. Lett.
2009, 7, 867. (f) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed.
2009, 48, 6313. (g) Lai, H.; Huang, Z.; Wu, Q.; Qin, Y. J. Org. Chem. 2009,
74, 283.
(4) Preparation of 3-hydroxy or 3-amino-2-oxindoles by preparative
HPLC separation of enantiomers: (a) Labroo, R. B.; Cohen, L. A. J. Org.
Chem. 1990, 55, 4901. (b) See ref 2c.
(5) During the preparation of this paper, a related cinchona alkaloid-
catalyzed R-amination of oxidoles was published online: Cheng, L.; Liu, Li.;
Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11, 3874.
DOI: 10.1021/jo902039a
r
Published on Web 11/04/2009
J. Org. Chem. 2009, 74, 8935–8938 8935
2009 American Chemical Society

Bui et al.
JOCFeatured Article
SCHEME 1
FIGURE 1. Synthesis of 3-amino-substituted oxindoles.
Over the past several years, electrophilic R-amination of
carbonyl compounds using azodicarboxylates as a nitrogen
source and amines or cinchona alkaloids as catalysts has
drawn significant interest.6 Carbonyl compounds such as
aldehydes, ketones, β-ketoesters, and derivatives thereof are
often employed as nucleophiles in these reactions.7-11 We
envisioned that the analogous transformation employing
oxindoles as nucleophiles could be developed. This process
would allow for the construction of a C-N bond at C3 in a
catalytic fashion with the generation of a tetrasubstituted
stereogenic center, a task that has not been accomplished to
date by either organocatalysis or Lewis acid catalysis.6,12
Success of the proposed transformation relies on deproto-
nating the C3 methine proton with a chiral amine base such
that the resulting enolate is reactive enough to overcome the
steric encumbrance at this position, while orchestrating the
enantioselectivity of the addition. Therefore, judicious
choice of chiral amine base in combination with finely tuned
acidity of the oxindole methine proton is key to the devel-
opment of this amination chemistry.13
Results and Discussion
Experimentally, the reaction of oxindole 1a with diethyl
azodicarboxylate was examined in the presence of commer-
cially available catalyst 2a (hydroquinine 1,4-phthalazine-
diyl diether (DHQ)2PHAL, 10 mol %) (Scheme 1, Table 1).
Gratifyingly, product 3a was obtained in moderate yield and
enantiomeric excess (ee) (entry 1).14 Both yield and ee were
improved notably when the reaction was performed at 4 °C
(entry 2). Nonetheless, the low enantioselectivity warranted
further optimization. A brief survey of other cinchona
alkaloid-derived catalysts was conducted (entries 2-7). Cat-
alyst 2b (hydroquinidine 1,4-phthalazinediyl diether
(DHQD)2PHAL) was the most effective among cinchona
alkaloids 2a and 2c-2f (entry 3 vs entry 2 and entries 4-7).
A subsequent solvent screen resulted in conditions in
which good yield and enantioselectivity were obtained when
the reaction was performed in diethyl ether (entry 12 vs
entries 8-11 and entry 13). Finally, lowering the reaction
temperature increased both yield and ee (entry 12 vs entry
14).15 Like temperature, solvent affected ee significantly. For
instance, with nonpolar solvents such as toluene, the reaction
proceeded with only moderate yield and ee (entry 9).16 In
contrast, with more polar solvents such as ethyl acetate,
diethyl ether, and dimethoxy ethane, notable improvement
in yields and ee’s was generally observed, although there was
no simple correlation between ee and solvent polarity (entry
9 vs entries 10, 12, and 13). A loose correlation between
solvent polarity and ee was noted in some cases (entry 9 vs
entries 8, 11, and 12).17 These results suggest that the polarity
of solvent is not the sole factor that influences ee. The
sensitivity of the amination reactions to solvent effects
manifested itself in changes in ee’s, yields, and perhaps
reaction rates. We believe these solvent effects suggest that
the reaction might involve a charged intermediate.
(6) Reviews on R-amination of carbonyl compounds: (a) Guillena, G.;
Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465. (b) Janey, J. M.
Angew. Chem., Int. Ed. 2005, 44, 4292. (c) Erdick, E. Tetrahedron 2004, 60,
8747.
(7) Amine-catalyzed R-amination of aldehydes and ketones: (a) Kumar-
agurbaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J. Am.
Chem. Soc. 2002, 124, 6254. (b) Bogevig, A.; Juhl, K.; Kumaragurbaran, N.;
Zhuang, W.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (c) List,
B. J. Am. Chem. Soc. 2002, 124, 5656. (d) Chowdari, N. S.; Barbas, C. F. III.
Org. Lett. 2005, 7, 867. (e) Vogt, H.; Vanderheiden, S.; Brase, S. Chem.
Commun. 2003, 2448. (f) Dahlin, N.; Bogevig, A.; Adolfson, H. Adv. Synth.
Catal. 2004, 346, 1101.
(8) Organocatalytic enantioselective R-amination of β-ketoesters and
derivatives thereof: (a) Pihko, P. M.; Pohjakallio, A. Synlett 2004, 12,
2115. (b) Saaby, S.; Bella, M.; Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126,
8120. (c) Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. (d) Terada, M.;
Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. (d) Liu, Y;
Melgar-Fernandez, R.; Juaristi, E. J. Org. Chem. 2007, 72, 1522.
(9) For related C-C bond-forming reactions involving oxindoles as
nucleophiles in organocatalysis, see: (a) Bui, T.; Syed, S.; Barbas, C. F.
III. J. Am. Chem. Soc. 2009, 131, 8756. (b) He, R.; Ding, C.; Maruoka, K.
Angew. Chem., Int. Ed. 2009, 48, 4559. (c) Chen, X.-H.; Wei, Q.; Luo, S.-W.;
Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819-13825.
(d) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.;
Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2009, 15, 7846. (e) Duffey,
T. A.; Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14. (f) Shaw, S. A.;
Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006,
128, 925. Leading references for C-C bond-forming reactions of oxindoles
involving transition metal catalysis: (g) Kato, Y.; Furutachi, M.; Chen, Z.;
Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
9168. (h) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477. (i) Doumay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich,
M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125,
6261. (j) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308.
(k) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 126, 4590. (l) Trost, B. M.;
Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548. (m) Lee, S.; Hartwig, J. F. J. Org.
Chem. 2001, 66, 3402. (n) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42,
3921. (o) Kozlowski, M. C.; Linton, E. C. J. Am. Chem. Soc. 2008, 130, 16162.
(10) Aldol and Mannich reactions involving oxindoles as nucleophiles:
(a) Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666. (b) Tian, X.; Jiang, K.; Peng, J.; Du,
W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583.
Next, the scope of the reaction with respect to oxindole
substrates was investigated. A major setback surfaced when
we discovered that enantioselectivity notably decreased as
(14) Without a protecting group on the nitrogen atom and under identical
conditions, 3a was obtained in 78% yield with 11% ee.
(15) At -38 °C, with catalyst 2b, product 3a was obtained in 25% yield
with 65% ee after 24 h reaction.
(16) The background reaction was significantly less in toluene than in
methylene chloride, and this might, in part, account for the better ee observed
in this solvent.
(11) For related cinchona alkaloid-catalyzed R-fluorination of oxindoles:
Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru,
T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 4157.
(12) These optically active oxindoles are usually obtained through resolu-
tion or preparative HPLC separation; see ref 4.
(13) We previously observed that the acidity of the C3 methine proton
could be affected greatly by changing the protecting group on the oxindole
nitrogen atom; see ref 9a.
(17) Dielectric constants and solvent polarity: (a) Abboud, J-L. M.; Taft,
R. W. J. Phys. Org. 1979, 83, 412. (b) Katritzky, A. R.; Fara, D. C.; Yang, H.;
Tamm, K. Chem. Rew. 2004, 104, 175.
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Bui et al.
JOCFeatured Article
TABLE 1. Optimization Studies
TABLE 2. Substituent Effects on Enantioselectivities
entry R1
R
temperature (°C) product yielda(%) eeb(%)
entry catalyst
solvent
temperature (°C) yielda(%) eeb(%)
1
2
Boc Me
Boc allyl
Boc Bn
Bn
Bn
Bn
-20
-20
-20
-20 to 4
rt
3a
4a
5a
3b
3b
3c
96
89
85
41
95
96
91
87
82
97
94
99
1c
2
3
4
5
6
7
8
9
2a
2a
2b
2c
2d
2e
2f
2b
2b
2b
2b
2b
2b
2b
THF
THF
THF
THF
THF
THF
THF
rt
4
70
86
84
87
95
77
62
80
76
81
90
86
83
96
29
49
81
60
73d
74
66d
2
3
4
4
4c
5
allyl
allyl
Bn
-20
4
4
6
rt
aIsolated yields. bDetermined by chiral HPLC analysis. cReaction
performed at -20 °C for 24 h, then warmed to 4 °C for 48 h.
CH2Cl2
toluene
EtOAc
MeCN
Et2O
4
4
4
4
4
4
-20
70
70
35
87
78
91
10
11
12
13
14
TABLE 3. Scope of R-Amination
(MeOCH2CH2)2O
Et2O
aIsolated yields. bDetermined by chiral HPLC analysis. cReaction run
for 13 h. dThe opposite enantiomer was obtained.
the steric bulk of the alkyl substituents at the C3 position
increased, especially with N-Boc-protected oxindoles. Spe-
cifically, ee dropped from 91 to 82% as the alkyl substituent
was changed from methyl to benzyl (Table 2, entries 1-3).18
Fortunately, this selectivity problem was circumvented by
changing the Boc group to a benzyl protecting group (entry 4).
This change of protecting groups on the nitrogen atom may
significantly attenuate the acidity of the methine proton at
C3, thereby minimizing the background reaction. This might
account for the enhanced ee and the attenuated reactivity
observed in the reaction described in entry 4 compared to
entry 2. Finally, the amination reaction proceeded smoothly
at room temperature to afford the desired product with
excellent yield and enantioselectivity (entry 5). More impor-
tantly, the yield and ee remained high with larger alkyl
substituents (entry 5 vs entry 6).
After having established the optimal reaction conditions,
we began to examine the scope of the R-amination reaction.
A wide variety of oxindoles bearing different alkyl substit-
uents were investigated (Table 3). Remarkably, the amina-
tion reaction tolerated various oxindole substrates and
afforded the desired products in good yields with good to
excellent ee (Table 3, entries 1-4). Even with a branched
allyl substituent, the yield and ee of the desired product
were still high (Table 3, entry 5). Synthetically, the allyl
groups in compounds 3b and 3e, for example, are useful
handles for further functional group manipulation. These
results showed the synthetic advantages of our method over
Chen’s, which works well only with C3-benzyl-substituted
oxindoles and requires the use of a rather uncommon
halogenated solvent instead of diethyl ether. The require-
ment of benzyl-substituted oxindoles in order to obtain
high ee in Chen’s method precludes its broad synthetic
utility. The synthetic advantages of the current procedure
entry
R
product
yielda(%)
eeb
1c
2
3
4
Me
allyl
benzyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
95
96
90
98
87
96
95
94
90
97
93
91
91
94
99
89
98
91
96
97
97
90
76
95
96
4-Br-benzyl
2-methylallyl
cinnamyl
homoallyl
-CH2CCSiMe3
-(CH2)3-Ph
Et
Me
2-methylallyl
4-Br-benzyl
5
6d
7
8
9d
10
11
12e
13c
3j
3k
3l
3m
aIsolated yields. bDetermined by chiral HPLC analysis. cN-Boc-
protected oxindole as a substrate and the reaction performed at -20 °C
for 24 h. dEt2O/THF (5/1) as solvent. eUse of di-tert-butyl azodicarbox-
ylate as an aminating reagent.
were illustrated further in the scope of the R-amination
reaction with other oxindole substrates having different
functionalities such as cinnamyl, homoallyl, and propargyl
groups. No decrease in ee was observed in these cases
(Table 3, entries 6-8). Moreover, oxindoles bearing satu-
rated, aliphatic alkyl substituents also provided the corre-
sponding products in good yields and ee’s (Table 3, entries 9
and 10). Surprisingly, with N-benzyl-protected oxindoles
having a methyl substituent at C3, the ee was lower than
with the reaction employing N-Boc-protected oxindoles
(Table 3, entry 11 vs entry 1). The yield and ee were high
when di-tert-butyl azodicarboxylate was used in place of
diethyl azodicarboxylate, thus broadening the scope of the
reaction with respect to electrophiles (Table 3, entry 12 vs
entry 5). Hydrazide 3l was deprotected readily under acidic
conditions.19 Again, unlike Chen’s procedure, which requires
(18) Attempts to solve this selectivity problem by changing the diethyl
azodicarboxylate reagent failed. Specifically, 39 and 63% ee were obtained
when dibenzyl azodicarboxylate and diisopropyl azodicarboxylate were
used, respectively.
(19) Use of di-tert-butyl azocarboxylate in Lewis acid catalyzed asym-
metric amination: (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342.
(b) Mashiko, T.; Kumagai, N.; Shibasaki, M. Org. Lett. 2008, 10, 2725.
J. Org. Chem. Vol. 74, No. 23, 2009 8937

Bui et al.
JOCFeatured Article
oxindoles as nucleophiles. These addition reactions are gen-
eral, broad in scope, and proceed under mild conditions to
afford the desired products in excellent yields with good to
excellent enantioselectivity. Significantly, these reactions
provide a unique, catalytic approach to the construction of
C-N bonds of oxindoles and also provide the first examples
of general, catalytic, asymmetric procedures that allow the
installation of a nitrogen atom at the C3 position. The
investigations of the scope of this chemistry in other asym-
metric transformations are underway, and the results will be
reported in the near future.
Experimental Section
FIGURE 2. X-ray structure of 3n (H atoms omitted for clarity).
General Procedure for r-Aminations of Boc-Protected Oxindoles
(Compound 3a). To a solution of oxindole 1a (54.6 mg, 0.2 mmol,
1 equiv) and cinchona alkaloid catalyst 2b (12.4 mg, 0.02 mmol,
0.1 equiv) in diethyl ether at -20 °C was added diethyl azodi-
carboxylate (40 μL, 0.22 mmol, 1.1 equiv). The resulting solu-
tion was stirred at -20 °C for 24 h. The reaction mixture was
first diluted with ethyl acetate and then quenched with a
saturated aqueous ammonium chloride solution. The aqueous
layer was separated and extracted with ethyl acetate (three
times). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude material was
purified by flash column chromatography (hexanes/ethyl
acetate) to afford 76 mg (96%) of 3a as a white solid:
1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J=11.9, 8.2 Hz, 2H),
7.31 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.02 (s, 1H),
4.33-4.26 (m, 2H), 4.01-3.94 (m, 2H, J=7.4 Hz), 1.65 (s, 9H),
1.55 (s, 3H), 1.34 (t, J =7.1 Hz, 3H), 1.00 (br t, J =7.3 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 175.9, 157.0, 154.0, 149.1,
138.2, 131.1, 128.7, 124.9, 123.6, 114.6, 84.3, 66.0, 62.9, 62.3,
28.0, 23.7, 14.4, 13.7; HRMS calcd for C20H27N3O7 (MHþ)
422.1922, found 422.1925; HPLC (Chiralpak AD, hexane/
i-PrOH = 90:10, flow rate = 1.00 mL/min, λ = 254 nm) tR =
9.68 min (minor enantiomer), tR=15.44 min (major enantiomer).
General Procedure for r-Aminations of Benzyl-Protected Oxi-
ndoles (Compound 3b). To a solution of oxindole 1b (52.7 mg,
0.2 mmol, 1 equiv) and cinchona alkaloid catalyst 2b (15.6 mg,
0.02 mmol, 0.1 equiv) in diethyl ether at rt was added diethyl
azodicarboxylate (46 μL, 0.24 mmol, 1.2 equiv). The resulting
solution was stirred at rt for 48 h and then directly purified by flash
column chromatography (hexanes/ethyl acetate, 3/1) to afford
83.1 mg (94%) of 3b as oil: 1H NMR (400 MHz, CDCl3) δ 7.76
(d, J=7.2 Hz, 1H), 7.39-7.25 (m, 5H), 7.15 (t, J=8.7 Hz, 1H), 7.05
(t, J=7.4 Hz, 1H), 6.96 (s, 1H), 6.66 (d, J=7.7 Hz, 1H), 5.26-5.16
(m, 1H), 5.05-4.99 (m, 2H), 4.89 (d, J=9.96 Hz, 1H), 4.76 (d, J=
15.7 Hz, 1H), 4.21-4.37 (m, 2H), 4.02-3.88 (m, 2H), 2.84-2.71
(m, 2H), 1.33 (t, J=7.1 Hz, 5H). 0.95 (t, J=6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 176.3, 157.1, 154.1, 142.5, 135.9, 130.0, 129.8,
128.6, 127.6, 127.5, 124.2, 123.1, 120.5, 120.4, 108.7, 68.7, 62.7,
62.7, 44.3, 40.4, 14.5, 14.0; HRMS calcd for C24H27N3O5 (MHþ)
438.2023, found 438.2019; HPLC (Chiralpak AD, hexane/i-PrOH=
90:10, flow rate=1 mL/min, λ=254 nm) tR=20.37 min (major
enantiomer), tR=31.87 min (minor enantiomer).
the use of diisopropyl azodicarboxylates, the flexibility of
our method in the choice of aminating reagents employed
provides yet another synthetic advantage in addition to the
aforementioned characteristics. Finally, oxindole 3m was
also obtained in high yield with excellent enantioselectiv-
ity.20
The absolute configuration at the newly created center was
determined to be S. This was established by X-ray dispersion
analysis of a sulfonamide derived from product 3l (Figure2).20,21
Although details of the reaction mechanism have not been
determined, our current hypothesis is that the R-amination
reaction involves the generation of zwitterionic enolate (i) from
the starting oxindole by deprotonation (Scheme 2). This species
may exist as a contact ion pair such that the cinchona alkaloid
catalyst relays its chirality to the reacting carbon center, thereby
creating an asymmetric environment around the nucleophile. A
subsequent C-N bond formation occurs and proceeds to
provide an intermediate (ii), which, upon protonation, leads to
the formation of the desired product and releases the catalyst
back into the cycle.
SCHEME 2
Conclusions
In summary, we have developed new cinchona alkaloid-
catalyzed enantioselective R-amination reactions involving
Acknowledgment. This study was supported by The
Skaggs Institute for Chemical Biology.
(20) Occasionally, N-Boc-protected oxindoles gave products with high ee.
However, they are not as general as N-benzyl-protected counterparts.
Compounds 3m and 3d were made in an attempt to obtain crystals for
X-ray analysis. Unfortunately, these compounds did not yield satisfactory
crystals.
Supporting Information Available: Experimental proce-
dures and compound characterization data as well as X-ray
data for 3n. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) See Supporting Information.
8938 J. Org. Chem. Vol. 74, No. 23, 2009