Enantioselective synthesis of 3,3-disubstituted oxindoles through pd-catalyzed cyanoamidation

Article abstract of DOI:10.1021/ol801168j

(Chemical Equation Presented) The first enantioselective cyanoamidation of olefins provides quick access to a variety of 3,3-disubstituted oxindoles. The combination of Pd(dba)2, an optically active phosphoramidite, and N,N-dimethylpropylene urea (DMPU) i

Full text of DOI:10.1021/ol801168j

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3303-3306
Enantioselective Synthesis of
3,3-Disubstituted Oxindoles through
Pd-Catalyzed Cyanoamidation
Yoshizumi Yasui, Haruhi Kamisaki, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received May 22, 2008
ABSTRACT
The first enantioselective cyanoamidation of olefins provides quick access to a variety of 3,3-disubstituted oxindoles. The combination of
Pd(dba)2, an optically active phosphoramidite, and N,N-dimethylpropylene urea (DMPU) in decalin were found to be the best conditions.
Developing convenient synthetic methods for 3,3-disubsti-
tuted oxindoles may contribute to biological and pharma-
cological studies due to their frequent occurrence as sub-
structures or synthetic intermediates of biologically active
molecules.1 Recent efforts have been focused on enantiose-
lective construction of oxindoles which have a quaternary
stereocenter at the 3-position.2–9 Reported methods can be
categorized in three groups according to the synthetic
strategies (Figure 1). Retrosynthetic disconnection at position
a corresponds to the enantioselective Heck reaction pioneered
by Overman2 and the domino Heck/cyanation reaction which
was published recently by Zhu.3 The same disconnection
provides arylation reactions reported by Hartwig and oth-
ers.4,5 Disconnection at b meets O-to-C acyl migration,6
allylic alkylation,7 and cycloaddition8 strategies.9 Motivated
by our interest in transition-metal-catalyzed reactions of
formamide derivatives,10–12 we planned to develop an
(1) For a review, see: (a) Galliford, C. V.; Sheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 8748. For recent examples, see: (b) Kolackowski, M.;
Nowak, M.; Pawlowski, M.; Bojarski, A. J. J. Med. Chem. 2006, 49, 6732.
(c) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.; Ohta, T.;
Williams, R. M.; Tsukamoto, S. Angew. Chem., Int. Ed. 2007, 46, 2254.
(d) Uddin, M. K.; Reignier, S. G.; Coulter, T.; Montalbetti, C.; Gra˚na¨s, C.;
Butcher, S.; Krog-Jensen, C.; Felding, J. Bioorg. Med. Chem. Lett. 2007,
17, 2854. (e) Stevens, F. C.; Bloomquist, W. E.; Borel, A. G.; Cohen, M. L.;
Droste, C. A.; Heiman, M. L.; Kriauciunas, A.; Shall, D. J.; Tinsley, F. C.;
Jesudason, C. D. Bioorg. Med. Chem. Lett. 2007, 17, 6270.
(6) (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921.
(b) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,
13368.
(7) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
(8) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am.Chem. Soc. 2007,
129, 3086.
(9) Lipase-catalyzed desymmetrization of 3,3-bis(hydroxymethyl)oxin-
dole has also been reported; see: Akai, S.; Tsujino, T.; Akiyama, E.;
Tanimoto, K.; Naka, T.; Kita, Y. J. Org. Chem. 2004, 69, 2478.
(10) For addition of cyanoformamides to alkynes and alkenes, see: (a)
Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org. Lett. 2006,
8, 2711. (b) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Yanada,
(2) (a) Dounay, 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. For recent studies, see: (b) McDermott, M. C.; Stephenson, G. R.;
Walkington, A. J Synlett 2007, 51, and references cited therein
(3) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961
(4) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402
(5) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.-x.; Bernardinelli, G. Angew.
.
.
R.; Takemoto, Y. Tetrahedron 2007, 63, 2978.
.
(11) For amide synthesis through coupling of chloroformamides and
alkylboranes, see: Yasui, Y.; Tsuchida, S.; Miyabe, H.; Takemoto, Y. J.
Chem., Int. Ed. 2007, 46, 8484
.
Org. Chem. 2007, 72, 5898.
10.1021/ol801168j CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society

Table 1. Studies of Optically Active Ligands
entry ligand (mol %) time (h) yield (%)a ee (%) config
1
2
3
4
5
6
7
8
9
L1 (4)
L2 (4)
L3 (4)
L4 (4)
L5 (4)
L6 (8)
L7 (4)
L7 (8)
L8 (8)
L9 (8)
0.25
0.5
24
24
24
24
26
6
quant
98
9
7
0
(R)
(R)
26
4
80
65
(70)
(87)
(16)
(28)
(32)
0
16
46
64
69
16
44
(S)
(S)
(S)
(S)
(S)
(S)
60
Figure 1. Strategies for enantioselective synthesis of 3,3-disubsti-
tuted oxindoles.
96
quant
97
0.5
0.5
10
a The values in parentheses shows the recovered yield of compound 1.
enantioselective intramolecular cyanoamidation of alkenyl
cyanoformamides, which allows disconnection at position
c. Our strategy will have several advantages over existing
methods: (i) avoiding the use of halogens or their equivalents
(vs disconnection a), (ii) realizing simultaneous formation
of the lactam ring and a quaternary stereocenter (vs discon-
nection b), (iii) allowing use of neutral reaction conditions,
and (iv) exploring the less studied utility of cyanoformamides
in transition-metal-catalyzed reactions.13,14
Cyanoamidation is an attractive transformation that allows
introduction of two carbonyl equivalents to vicinal positions
of C-C multiple bonds with high atom economy. We
previously found that cyanoformamides add to intramolecular
triple and double bonds to give a variety of functionalized
lactams in the presence of a palladium catalyst.10,15 Herein
we report the first enantioselective cyanoamidation of olefins.
From preliminary experiments on screening achiral phos-
phorus ligands, it was found that monophosphorus ligands
give higher conversion than bisphosphorus ligands. Based
on this observation, we started this project by exploring
optically active monophosphorus ligands. Therefore, cyano-
formamide 1 was treated with Pd(dba)2 (2 mol %) and
ligands (4-8 mol %) in xylene at 130 °C (Table 1).16 When
4 mol % of MeO-MOP (L1)17 was used, the reaction finished
in 15 min to give oxindole 2 quantitatively, but the
enantioselectivity was poor (9% ee) (entry 1). NMDPP (L2)18
showed a similar result (entry 2). Taking advantage of simple
preparation, derivatives of phosphonic acids and phosphinic
acids were tested.19 Phosphonite L320 and phosphonic
diamide L421 promoted the reaction only slightly and did
not show any stereoselectivity (entries 3 and 4). However,
when the reaction was performed in the presence of phos-
phoramidite L5,22 oxindole (S)-2 was obtained in 80% yield
and 16% ee (entry 5). Based on this result, we started to
examine the effect of substituents on phosphoramidites.
Change of the dimethylamino group to a diisopropylamino
group improved the selectivity to 46% ee (entry 6).23
Moreover, use of bis[(R)-1-phenylethyl]amine derivative
(12) For rhodium-catalyzed hydroamidation, see: Kobayashi, Y.; Ka-
misaki, H.; Yanada, K.; Yanada, R.; Takemoto, Y. Tetrahedron Lett. 2005,
46, 7549
.
(13) No report exists for transition-metal-catalyzed reaction of cyano-
formamides except ref 10
.
(14) For general reactivity of cyanoformamides, see: (a) Oku, A.; Inoue,
J.; Ueda, H.; Mashio, F Bull. Chem. Soc. Jpn. 1977, 50, 549, and references
cited therein. (b) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.;
Penrose, A. J.; Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.; Wright,
(16) Cyanoformamides were synthesized from corresponding anilines.
See the Supporting Information for details.
(17) Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
(18) Morrison, J. D.; Burnett, R. E.; Agular, A. M.; Morrow, C. J.;
Phillips, C. J. Am. Chem. Soc. 1971, 93, 1301.
(19) For a review of using phosphonic acid and phosphinic acid
derivatives as a ligand for transition metal-catalyzed reactions, see: Ansell,
J.; Wills, M. Chem. Soc. ReV. 2002, 31, 259.
D. E. J. Med. Chem. 1986, 29, 538
.
(15) Related transition-metal-catalyzed insertion reactions has been
reported. Carbocyanation: (a) Nakao, Y.; Hirata, Y.; Tanaka, M.; Hiyama,
T. Angew. Chem., Int. Ed. 2008, 47, 385, and references cited therein.
Cyanoesterification: (b) Nakao, Y.; Hirata, Y.; Hiyama, T. J. Am. Chem.
Soc. 2006, 128, 7420. (c) Nishihara, Y.; Inoue, Y.; Izawa, S.; Miyasaka,
M.; Tanemura, K.; Nakajima, K.; Takagi, K Tetrahedron 2006, 62, 9872.
Bis(alkoxycarbonylation): (d) Liang, B.; Liu, J.; Gao, Y.-X.; Wongkhan,
K.; Shu, D.-X.; Lan, Y.; Li, A.; Batsanov, A. S.; Howard, J. A. H.; Marder,
T. B.; Chen, J.-H.; Yang, Z Organometallics 2007, 26, 4756, and references
cited therein. (e) Aratani, T.; Tahara, K.; Takeuchi, S.; Ukaji, Y.; Inomata,
(20) Tani, K.; Yamagata, T.; Nagata, K. Acta Crystallogr. 1994, C50,
1274.
(21) Alexakis, A.; Mutti, S.; Normant, J. F. J. Am. Chem. Soc. 1991,
113, 6332.
(22) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 699.
(23) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. 1996, 35, 2374.
K. Chem. Lett. 2007, 36, 1328
.
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Org. Lett., Vol. 10, No. 15, 2008

L724 led to 60% yield and 64% ee (entry 7). Finally, by
increasing the amount of L7 from 4 mol % to 8 mol %,
96% yield and 69% ee was achieved (entry 8). Reactions in
the presence of L8 and L9 provided higher yields but lower
selectivities (entries 9 and 10).
The effect of solvent and additives was examined for the
reaction catalyzed by Pd(dba)2 (2 mol %) and L7 (8 mol %)
(Table 2). When N-methyl-2-pyrrolidone (NMP) was used
followed by methoxycarbonylation and reductive cyclization
gave pyrroloindole 4. Comparison of the optical rotation of
4 with that reported in the literature showed that oxindole 2
has the S-configuration.26
A variety of 3,3-disubstituted oxindoles were synthesized
through enantioselective cyanoamidation (Table 3). N-
Table 3. Enantioselective Intramolecular Cyanoamidation
Table 2. Effect of Solvent and Additive
entry solvent additive T (°C) time (h) yielda (%) ee (%)
1
2
3
4
5
6
xylene
NMP
decalin
decalin NMP
decalin NMP
decalin DMPU
130
130
130
130
100
100
6
0.25
24
7
24
24
96
97
83 (10)
quant
85 (15)
quant
69
56
74
78
80
81
a The values in parentheses show the recovered yield of compound 1.
as solvent, to our surprise, the reaction was complete in 15
min at 130 °C, but the selectivity dropped to 56% ee (entry
2). On the other hand, the reaction in decalin provided poor
conversion but higher selectivity (entry 3). Therefore, we
planned to add polar additives such as NMP to the reaction
in decalin. When 100 mol % of NMP was added, oxindole
(S)-2 was obtained quantitatively and the selectivity reached
78% ee. It was possible to reduce the reaction temperature
to 100 °C when polar additives were present. At the end,
the best conditions were determined to be the addition of
N,N-dimethylpropylene urea (DMPU) in decalin at 100 °C,
which gave quantitative yield and 81% ee (entry 6).
The absolute configuration of the major enantiomer of
oxindole 2 obtained from the reaction using L7 was
determined by converting 2 to known pyrroloindole 4
(Scheme 1). Selective reduction of the cyano group25
a The values in parentheses show the recovered yield of starting
materials. b Pd(dba)2 (5 mol %) and L7 (20 mol %) were used. c Pd(dba)2
(5 mol %) and L7 (10 mol %) were used.
Scheme 1. Determination of Absolute Configuration
Methylcyanoformamide 5 underwent cyclization in 88%
yield and 75% ee (entry 1). The substituent on the vinyl
group can accommodate a simple alkyl group as well as a
(24) Badalassi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
Feringa, B. L. Tetrahedron Lett. 1998, 39, 7795.
(25) (a) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z.
Tetrahedron Lett. 1969, 4555. (b) Heinzman, S. W.; Ganem, B. J. Am.
Chem. Soc. 1982, 104, 6801.
(26) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043.
Org. Lett., Vol. 10, No. 15, 2008
3305

siloxymethyl group (entries 2 and 3). Especially, resulting
oxindole 10, which has distinct functional groups on both
side chains, seems to be a promising synthetic intermediate
for more complicated derivatives. The reaction has high
tolerance toward substitutions on the aromatic ring. Cyano-
formamides which have a methyl or chloro substituent on
the aromatic ring gave the corresponding lactams in high
yield and good selectivity (entries 4 and 5). A strange
behavior was observed when methoxy-substituted cyanofor-
mamide 15 was subjected to the reaction. Using 2 mol % of
Pd(dba)2 and 8 mol % of L7 led to incomplete reaction after
24 h (entry 6). However, by increasing the palladium catalyst
to 5 mol % and the ligand to 20 mol %, the desired oxindole
16 was obtained in 94% and 78% ee (entry 7). Dimethoxy
derivative 17 also required an increased amount of catalyst,
but the reaction proceeded smoothly (entry 8). Unfortunately,
cyclization of cyanoformamide 19 which has a methyl
substituent ortho to the propenyl group did not go to
completion, even with high catalyst loading (entry 9).
Though there is not much information for the reaction
mechanism, we believe that the reaction proceeds through
oxidative addition of the CO-CN bond to palladium(0),
followed by amidopalladation and reductive elimination
(Figure 2).27 We propose that the oxidative addition into the
CO-CN bond forms intermediate C prior to the insertion.
Other pathways through five coordinated complex E or
cationic complex F, which are frequently proposed in
enantioselective Heck reactions,28 are unlikely since the
reaction was catalyzed effectively by large unidentate ligands
and not by bidentate ligands.
Figure 2. Plausible mechanism for cyanoamidation.
conditions may meet further applications in pharmacological
and biological studies.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (B) (Y.T.) and for
Young Scientists (Start-up) (Y.Y.), Scientific Research on
Priority Areas: Creation of Biologically Functional Mol-
ecules, and “Targeted Proteins Research Program” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan, and 21st Century COE Program “Knowledge
Information Infrastructure for Genome Science”.
In conclusion, the synthesis of 3,3-disubstituted oxindoles
through enantioselective cyanoamidation has been developed.
A suitable combination of optically active ligand and Lewis
basic additives enables excellent yield and good to high
enantioselectivity. Broad substrate scope and neutral reaction
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) The corresponding pathway through cyanopalladation was excluded
through previous studies; see ref 10b.
(28) For similar discussion on enantioselective Heck reaction, see:
Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
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