Synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed intramolecular cyanoamidation

Article abstract of DOI:10.1016/j.tet.2010.01.073

The cyanoamidation of olefins was achieved. When N-(2-vinylphenyl)cyanoformamides were treated with palladium catalyst, intramolecular cyanoamidation took place to give corresponding 3,3-disubstituted oxindoles. P(t-Bu)₃ showed a remarkable eff

Full text of DOI:10.1016/j.tet.2010.01.073

Tetrahedron 66 (2010) 1980–1989
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed
intramolecular cyanoamidation
,
Yoshizumi Yasui a, Haruhi Kamisaki b, Takayuki Ishida b, Yoshiji Takemoto b
*
a World Premier International Research Center, Advanced Institute for Materials Research, Tohoku University, Aoba, Sendai 980-8578, Japan
b Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyanoamidation of olefins was achieved. When N-(2-vinylphenyl)cyanoformamides were treated
with palladium catalyst, intramolecular cyanoamidation took place to give corresponding 3,3-di-
substituted oxindoles. P(t-Bu)3 showed a remarkable effect on this reaction. When it was used with
Pd(dba)2, the reaction was completed in 15 min at 100 ꢀC for many substrates. Furthermore, the enan-
tioselective cyanoamidation was accomplished with Pd(dba)2 and an optically active phosphoramidite to
provide optically active 3,3-disubstituted oxindoles. Manipulation of the resulting oxindoles has been
studied.
Received 6 January 2010
Received in revised form
19 January 2010
Accepted 20 January 2010
Available online 25 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have been interested in developing lactam formation
through intramolecular insertion of carbamoyl transition-metal
Compounds possessing the 3,3-disubstituted oxindole sub-
structure have received considerable pharmacological attention,
and have frequently been used as synthetic intermediates for in-
dole alkaloid synthesis.1 To obtain optically active 3,3-disubstituted
oxindoles, various classes of enantioselective methodologies have
been applied. These can be classified on the basis of retrosynthetic
disconnection (Fig. 1). Formation of the bond between C(3) and the
benzene ring (path a), represents an enantioselective Heck reaction
pioneered by Overman et al.2 Recently, this strategy has been ex-
panded to an arylpalladation–cyanation cascade.3 Alternatively, the
same bond was constructed through palladium-catalyzed enan-
complexes (Fig. 2).13 The catalytic process starts with the oxidative
addition of formamide derivatives to low valent transition-metal
species to generate carbamoyl complex A. This complex undergoes
ring closure via amidometalation. Either reductive elimination or
b-hydride elimination leads to the final product. The advantages of
our strategy are: (i) providing access to highly functionalized and
substituted lactams, (ii) in a single step, (iii) from readily available
starting materials, and (iv) under neutral conditions.
In line with this reaction design, several lactam forming
methods were developed (Fig. 3). Alkylidene lactams were syn-
thesized from alkynyl formamides through rhodium-catalyzed
tioselective intramolecular a
-arylation of acetanilide derivatives.4
R
The strategies starting from 3-monosubstituted oxindole (path b)
have also been extensively studied; namely, optically active pyri-
dine-catalyzed acyl migrations,5 palladium- or molybdenum-cata-
lyzed allylations,6 palladium-catalyzed trimethylenemethane
[3þ2]-cycloadditions,7 cinchona-alkaloid-catalyzed enantiose-
lective aldol-type reactions,8 palladium-catalyzed enantioselective
arylations and vinylations,9 organocatalytic Mannich reactions,10
and enantioselective Claisen rearrangements.11,12 In this project, we
studied the synthesis of optically active 3,3-disubstituted oxindoles
by bond formation between an amide carbonyl and C(3) (path c),
which has not been explored previously.
X
N
R
R'"
O
N
R"
O
R"
a
b
Heck
reaction
alkylation, etc
R b
R'
c
O
a
N
R"
arylation
this work
a
c
R
X
N
R
R'
CN
O
N
O
R"
R"
* Corresponding author. Tel.: þ81 75 753 4528; fax: þ81 75 753 4569.
E-mail address: takemoto@pharm.kyoto-u.ac.jp (Y. Takemoto).
Figure 1. Enantioselective synthesis of 3,3-disubstituted oxindoles.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.073

Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
1981
R2
R2
X
Table 1
Pd-catalyzed intramolecular cyanoamidation of olefins
oxidative
addition
X
LnM
CN
catalyst
xylene, 130 oC
N
O
N
O
CN
O
O
R1
R1
A
N
Bn
N
Bn
cyanoformamide
carbamoyl transition
metal complexes
1a
2a
insertion
Entry
Catalyst (mol %)
Time (h)
Yielda (%)
R2
Ln
1
2
3
Pd(PPh3)4 (10)
Pd(PPh3)4 (2)
0.25
6
2
0.25
69
24
98
quant
97
M X
reductive elimination
Pd(dba)2 (2), PPh3 (4)
Pd(dba)2 (2), P(t-Bu)3 (4)c
Pd(dba)2 (2), P(t-Bu)3 (4)c
Pd(dba)2 (2), P(2-furyl)3 (4)
Pd(dba)2 (2), P(OPh)3 (4)
Pd(dba)2 (2),
functionalized
lactams
O
N
4b
5d
6
98
or
β-hydride elimination
74 (16)
66 (33)
58 (42)
16 (63)
1
R
7
8
24
24
Figure 2. Synthesis of lactams through carbamoyl transition-metal complexes.
(t-BuO)2PN(i-Pr)2 (4)
Pd(dba)2 (2), BINAP (2)
Pd(dba)2 (2), dppb (4)
Pd(dba)2 (2), dppp (4)
Pd(dba)2 (2), dppf (4)
9
24
24
24
24
6 (91)
R2
R2
10
11
12
44 (45)
11 (78)
78 (21)
H
Rh-catalyzed
H
hydroamidation
ref. 14
O
a
The values in parentheses show the yield of recovered starting materials.
Reaction was performed at 100 ꢀC.
N
O
N
b
c
R1
R1
P(t-Bu)3 was generated from HBF4$P(t-Bu)3 and Et3N in situ.26
Reaction was performed at 80 ꢀC.
R2
d
R2
CN
O
Pd-catalyzed
reaction conditions to these investigated for the intramolecular
cyanoamidation of alkynes,15 gave the desired 3-cyanomethyl-3-
methyloxindole 2a in quantitative yield after 15 min (entry 1).
When the catalyst loading was reduced to 2 mol %, the reaction
took 6 h to reach completion (entry 2). Interest in the reactivity
profile of the ligand prompted us to test a variety of phosphine and
phosphorus ligands in combination with 2 mol % Pd(dba)2. As
CN
cyanoamidation
ref. 15
N
N
O
R1
R1
R2
R2
Pd-catalyzed
Cl
Heck-type reaction
O
ref. 16
N
O
N
R1
R1
Table 2
R2
Synthesis of 3,3-disubstituted oxindoles
R2
R2
Pd-catalyzed
CN
R2
N
CN
cyanoamidation
this work
Pd(dba)2 (2 mol %)
O
CN
P(t-Bu)3 (4 mol %)
R3
R3
O
N
O
N
CN
O
xylene, 100 oC
15 min
R1
R1
N
1
R1
R
Figure 3. Transition-metal-catalyzed lactam formations studied in our group.
1b−i
2b−i
hydroamidation14 and palladium-catalyzed cyanoamidation.15
Replacement of the alkyne with an alkene led to the formation of
Entry
Substrate
Yield (%)
R1
R2
R3
a
,
a
-disubstituted lactams:
reaction proceeded from alkenyl chloroformamides to give
lactams.16 As part of these studies, the reaction of alkenyl cyano-
formamides with palladium catalyst was found to give -cyano-
methyl lactams. This reaction was applied to the synthesis of 3,3-
disubstituted oxindoles and other -disubstituted lactams and
a
palladium-catalyzed Heck-type
1
2
3
1b
1c
1d
1e
1e
1f
Bn
Bn
Bn
Bn
Bn
Me
Me
n-Pr
i-Pr
Ph
CH2OTBS
CH2OTBS
CH2CH2OTBS
Me
H
H
H
H
H
H
H
96
90
quant
74
90
a
-vinyl
4a
5b
6
a
98
94
a,a
7
1g
was expanded to enantioselective transformation. Details of this
intramolecular cyanoamidation of alkenes are described herein.17
During the period when we were studying cyanoamidation,
other carbocyanation reactions were developed extensively.18
Nishihara’s group and Hiyama’s group reported cyanoesterification
of norbornenes and allenes.19,20 Hiyama also achieved a series of
carbocyanation reactions through C–CN bond activation of aryl,21
alkynyl,22 allyl,23 and alkyl21b cyanides. Recently, intramolecular
enantioselective arylcyanation has been achieved.24
CN
8
9
1h
1i
97
86
N
Bn
O
CN
Cl
N
Bn
O
2. Results and discussion
MeO
MeO
CN
2.1. Pd-catalyzed intramolecular cyanoamidation of olefins
10
1j
97
N
Bn
O
Cyanoformamide 1a25 derived from commercially available
2-isopropenylaniline was treated with palladium catalyst in xylene
at 130 ꢀC (Table 1). Treatment of 10 mol % Pd(PPh3)4, under similar
a
The reaction was allowed to run for 60 h and 12% of 1e was recovered.
The reaction was performed at 130 ꢀC for 6 h.
b

1982
Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
a result, it was found that the catalyst generated from P(t-Bu)3 was
extremely reactive. The cyanoformamide 1a was converted to
oxindole 2a in 98% yield after 15 min even at 100 ꢀC (entry 4).
Further decrease of the temperature to 80 ꢀC led to incomplete
conversion (entry 5). In contrast to those relatively strongly do-
nating monophosphorus ligands, such as PPh3 and P(t-Bu)3, the
conditions using weaker donating ligands (entries 6–8) and
bisphosphorus ligands (entries 9–12) resulted in poor conversion.
A variety of oxindoles were synthesized using 2 mol % Pd(dba)2
and 4 mol % P(t-Bu)3 at 100 ꢀC (Table 2). Most of the cyanoforma-
mides were converted to the corresponding oxindoles in 15 min.
The substituent R2 on the vinyl group did not affect the reaction
significantly, so a variety of oxindoles possessing different types of
side chains has been made available (entries 1–7). An exception was
the reaction of cyanoformamide 1e that required higher tempera-
ture and longer reaction time (entries 4 and 5). In particular, among
the products, oxindoles 2e and 2f with two distinct functionalized
side chains, namely cyanomethyl and silyloxyalkyl, possess high
utility as synthetic intermediates for natural and synthetic targets.
Indeed, a compound related to oxindole 2f was used as a key in-
termediate for synthetic studies on vincorine by our group.27 This
reaction also tolerated substitution on the aromatic ring, which is
considered to be crucial for medicinal studies (entries 8–10).
At present, the substituent on the amide nitrogen is limited to
alkyl groups due to the low stability of the corresponding primary
cyanoformamides and difficulty in the synthesis of other de-
rivatives. However, it is worth noting that a methyl group on
oxindole nitrogen is known to be cleaved under oxidative condi-
tions.28 Thus, oxindoles not substituted on the amide nitrogen are
available through cyanoamidation of N-methyl cyanoformamides
followed by sequential demethylation (Scheme 1).29
7). Obviously, the Pd(dba)2–P(t-Bu)3 system (conditions B) was not
effective for all the compounds in Table 3. We hypothesize that this
system generates reactive but unstable catalytic species with short
lifetimes, which are sensitive to neighboring heteroatoms (for 5) or
are not sufficiently stable to promote the cyclization of the sub-
strates that require large conformational changes (for 7, 9, and 11).
Nevertheless, this intramolecular cyanoamidation strategy is not
limited to 3,3-disubstituted oxindoles but is also effective for the
synthesis of other a,a-disubstituted lactam.
2.2. Enantioselective synthesis of 3,3-disubstituted oxindoles
Next, we studied the enantioselective version of this intra-
molecular cyanoamidation (Table 4). We started the investigation
with optically active monophosphorus ligands according to the re-
sults shown in Table 1. Initial attempts were made with well-known
phosphine derivatives such as NMDPP (L1)31 and MOP (L2)32 with
2 mol % Pd(dba)2 in xylene at 130 ꢀC (entries 1 and 2). As expected,
these electron rich ligands promoted the reaction efficiently to give
oxindole 2a in quantitative yields after 15 min, but only slight
enantioselectivity was observed. Phosphonite L333 and phosphonic
diamide L434 promoted the reaction poorly, and no enantiose-
lectivity was detected (entries 3 and 4). However, the reaction with
phosphoramidite L535 synthesized from BINOL and dimethylamine
gave (S)-oxindole 2a in 80% isolated yield and 16% ee (entry 5). It was
found that the size of the amino group significantly affected the
enantioselectivity. The selectivity increased from 16 to 26% ee when
dimethylamine was changed to morpholine (entry 6).36 Phosphor-
amidite L736 derived from bulkier diisopropylamine gave 46% ee, and
finally phosphoramidite L837 with the bis[(R)-1-phenylethyl]amino
group resulted in 69% ee with 96% isolated yield (entries 7 and 8).
Changing the configuration of BINOL from R to S gave (R)-2a as
a major product with lower selectivity and yield (entry 10). Phos-
phoramidites L9,37 L11,38 L12,39 and L1340 derived from dimethyl
BINOL, biphenol, spirobiindane diol, and TADDOL, respectively, un-
expectedly resulted in higher reactivity than L8 but poorer selec-
tivity (entries 9, 11–13). Bisphosphorus ligands L14, L15,41 and L1642
gave poor conversion and selectivity (entries 14–16). The effects
Me
1) NaBH4, Boc2O
N
CN
Boc
CoCl2 6H2O
2) MeI, NaH
O
O
N
N
76%
Me
Me
2g
3
Me
N
BzOOBz
80oC, 20 h
Boc
O
then NH3
rt, 18 h
Me
Ph
N
H
O
O
OMe
P
Ph
61%
4
Ph2P
N
O
Me
PPh
2
P
Scheme 1. Oxidative demethylation of the cyclized product.29
NMe2
L1
L2
L3
L4
R2
O
This intramolecular cyanoamidation was not limited to oxindole
formation (Table 3). When pyridine derivative 5 was treated with
10 mol % Pd(PPh3)4 (conditions A), azaoxindole 6 was isolated in
97% yield after 1 h (entry 1). Conditions B using P(t-Bu)3 un-
expectedly did not enable this transformation; cyclized product 6
was obtained in only 7% yield even after 24 h, and 71% of the
starting material was recovered (entry 2). It is apparent that under
both conditions cyanoformamide 5 reacted more slowly than 1a.
This difference likely comes from the presence of the nitrogen at-
tached closely to the reaction site. Although such nitrogen atoms
are known to promote some transition-metal-catalyzed reactions
by functioning as a directing group,30 negative effects showed up in
the case of 5. All the substrates tested had a rigid aromatic frame-
work that brings the two reaction sites close. Next, N-butenyl
cyanoformamide 7 with a flexible framework was tested. As a re-
Ph
N
Ph
N
O
O
P
NR1
P
P
2
O
O
R2
O
Ph
Ph
L5 (NR12 = NMe2)
L8 (R2 = H)
L10
L9 (R2 = Me)
L6 (NR1
=
)
N
O
2
L7 (NR12 = NiPr2)
Ph Ph
Ph
O
Ph
O
P
O
O
P
N
N
P
NMe2
O
O
O
O
Ph
Ph
Ph Ph
L13
L11
L12
OAc
sult, 7 gave the corresponding cyanomethyl-g-lactam 8 in 95% yield
PPh2
PPh2
O
O
by treatment of 10 mol % Pd(PPh3)4 (entry 3). The catalyst gener-
ated with P(t-Bu)3 gave no product (entry 4). Furthermore, six-
membered lactam 10 and seven-membered lactam 12 were
obtained from the reaction with 10 mol % Pd(PPh3)4 (entries 5 and
PPh2
PPh2
Fe
PPh2
PPh2
L14
L15
L16

Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
1983
Table 3
Synthesis of a,a-disubstituted lactams through intramolecular cyanoamidation
CN
conditions
xylene
CN
O
O
N
Bn
N
Bn
Entry
Substrate
Product
Conditionsa
Time (h)
Yield (%)
Recovery of SM (%)
CN
1
2
A
B
1
24
97
7
d
O
CN
71
N
Bn
N
N
N
Bn
O
6
5
CN
3
4
A
B
0.25
24
95
0
d
O
CN
O
89
N
Bn
N
Bn
8
7
CN
O
CN
5
6
A
B
24
24
45
0
38
92
N
O
N
Bn
9
10
Bn
7
8
A
B
10
24
quant
0
d
CN
O
94
CN
N
N
Bn
O
Bn
11
12
a
Conditions A: Pd(PPh3)4 (10 mol %) at 130 ꢀC; Conditions B: Pd(dba)2 (2 mol %), P(t-Bu)3 (4 mol %), at 100 ꢀC.
of solvents and additives were examined with using 2 mol %
Pd(dba)2 and 8 mol % phosphoramidite L8 (Table 5). When polar N-
methyl-2-pyrrolidone (NMP) was used as the solvent, the reaction
rate was markedly increased so that it reached completion in
15 min, but the selectivity dropped to 56% ee (entry 2). The reaction
in less-polar decalin gave better selectivity but poorer conversion
(entry 3). To achieve good selectivity and conversion, a polar ad-
ditive was employed in the reaction in decalin. Addition of
100 mol % of NMP resulted in completion of the reaction in 2 h to
give quantitative yield and 78% ee (entry 4). The amount of NMP
was reduced to 8 mol % and 2 mol % but the effect remained com-
parable (entries 5 and 6). Next, the reaction temperature was
reduced to 100 ꢀC in the hope of enhancing the stereoselectivity.
However, the reaction was not completed in 24 h even with
100 mol % of NMP (entry 7). The more donating 1,3-dimethyl-2-
imidazolidinone (DMI) was found to bring the reaction to
completion (entry 8), and at the end, addition of N,N-dimethyl-
propylene urea (DMPU) gave quantitative yield and 81% ee (entry
9). It is worth noting that other Lewis bases, such as 4-(N,N-dime-
thylamino)pyridine (DMAP) or hexamethylphosphorus triamide
(HMPT) had no activation effect at all. Several possibilities for the
effects of additive can be suggested: for example, (i) accelerating
formation of the reactive complex from Pd(dba)2 and phosphor-
amidite, and (ii) stabilizing the coordinatively unsaturated species
during the catalytic cycle. Additionally, we wish to propose other
roles by noting the structural similarity of the effective additives
and the reaction product: both have an amide or a urea function-
ality. After reductive elimination, the product must be cleaved from
the palladium complex to induce the next catalytic cycle. However,
the cyanomethyl oxindole should complex tightly to palladium,
particularly in nonpolar solvents. Lewis base additives may promote
this decomplexation.43
Table 4
Intramolecular enantioselective cyanoamidation of olefins
Pd(dba)2 (2 mol %)
CN
ligand
CN
O
O
xylene, 130oC
N
N
Bn
Bn
1a
(S)-2a
Entry
Ligand (mol %)
Time (h)
Yielda (%)
ee (%)
1
2
3
4
5
6
7
8
L1 (4)
L2 (4)
L3 (4)
L4 (4)
L5 (4)
L6 (4)
L7 (4)
L8 (8)
L9 (8)
L10 (8)
L11 (8)
L12 (8)
L13 (2)
L14 (2)
L15 (2)
L16 (2)
0.25
0.25
24
24
24
8
24
6
0.25
24
0.25
0.25
3
24
48
48
98
7 (R)
9 (R)
0
quant
26 (70)
4 (87)
80
97
65
96
quant
76
93
97
0
16 (S)
26 (S)
46 (S)
69 (S)
16 (S)
25 (R)
15 (S)
44 (S)
32 (S)
0
9
10
11
12
13
14
15
16
95
6 (91)
33 (58)
51 (38)
5 (S)
31 (S)
Optically active 3,3-disubstituted oxindoles were synthesized
under the conditions determined (Table 6). The substituent R2 on
the vinyl group did not affect the reaction rate and yield in these
a
The values in parentheses show the yield of recovered starting materials.

1984
Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
Table 5
Effect of solvent and additive
Pd(dba)2 (2 mol %)
CN
L8 (8 mol %)
CN
O
additive, solvent
N
N
Bn
O
Bn
1a
(S)-2a
Entry
Solvent
Additive (mol %)
Temp (ꢀC)
Time (h)
Yield (%)
eea (%)
Recovery of SM (%)
1
2
3
4
5
6
7
8
9
Xylene
NMP
d
130
130
130
130
130
130
100
100
100
6
0.25
24
2
3
3
24
24
24
96
97
83
quant
98
97
85
97
quant
69
56
74
78
76
76
80
79
81
d
d
10
d
d
d
15
d
d
d
Decalin
Decalin
Decalin
Decalin
Decalin
Decalin
Decalin
d
NMP (100)
NMP (8)
NMP (2)
NMP (100)
DMI (100)
DMPU (100)
a
The major enantiomer was the S-isomer in all reactions.
enantioselective reactions but did affect their stereoselectivity
(entries 1–5). An increase in bulkiness (Me<n-Pr<CH2OTBS<i-
PrzPh) resulted in a decrease in selectivity. N-Methyl cyano-
formamide 1g gave slightly lower selectivity than 1a (entry 6).
Substitution on the aromatic ring did not affect enantioselectivity
but unexpectedly changed the reactivity. An increased amount of
catalyst was required to complete the reaction of 1j and 1k that
have methoxy groups (entries 9, 10). The reaction of cyanoforma-
mide 1l with a substituent close to the vinyl group was not com-
pleted even with an increased amount of catalyst (entry 11).
The conditions described were applied to the cyclization of al-
iphatic cyanoformamide 7 without modification (Scheme 2). Un-
fortunately, the starting material was not consumed completely
after 24 h even at 130 ꢀC, and its selectivity was only 27% ee. Better
Table 6
Synthesis of optically active 3,3-disubstituted oxindoles
R2
R2
Pd(dba)2 (2 mol %)
CN
L8 (8 mol %)
R3
R3
O
CN
O
DMPU (100 mol %)
conditions for enantioselective access to
are being explored.
a
,a
-disubstituted lactams
N
decalin,100 oC, 24 h
N
R1
R1
Pd(dba)2 (2 mol %)
Entry
Substrate
Yield (%)
ee (%)
CN
L8 (8 mol %)
R1
R2
R3
CN
O
DMPU (100 mol %)
N
Bn
8
decalin, 130 oC, 24 h
N
1
2
3
4
5
6
1a
1b
1c
1d
1e
1g
Bn
Me
n-Pr
i-Pr
Ph
CH2-OTBS
Me
H
H
H
H
H
H
quant
quant
96
quant
72
81
72
60
61
68
75
O
Bn
Bn
Bn
Bn
Me
Bn
15%, 27% ee
SM recovery 64%
7
Scheme 2. Enantioselective cyclization of cyanoformamide 7.
88
2.3. Mechanistic considerations
CN
O
7
1h
94
74
82
82
N
Bn
Although not much information is available on the reaction
mechanism, we believe that the reaction proceeds through oxida-
tive addition of the CO–CN bond to palladium(0), followed by
amidopalladation and reductive elimination (Fig. 4). The alternative
cyanopalladation pathway (C/E), which may give the same final
product, has been excluded by previous studies.15 We propose that
the oxidative addition of the CO–CN bond forms the four-co-
ordinate intermediate C prior to insertion. Other pathways through
the five-coordinate complex F or cationic complex G are unlikely,
because the reaction is catalyzed effectively by large unidentate
ligands and not by bidentate ligands. There are clear contrasts in
terms of effective ligands between this reaction and other related
enantioselective 3,3-disubstituted oxindole and indoline forma-
tions starting from allyl amine derivatives H. These reactions pro-
ceed efficiently in the presence of optically active bidentate ligands.
For example, the palladium-catalyzed enantioselective Heck re-
action studied by Overman et al. gave the best result with BINAP,
and the reaction pathway containing a five-coordinate complex and
a cationic complex like F and G were proposed.2b More recently,
enantioselective arylation–cyanation reactions3 and nickel cata-
lyzed enantioselective intramolecular cyanoarylations24a have been
reported to give the best result with optically active bidentate
ligands.
CN
8
1i
quant
Cl
N
Bn
O
MeO
MeO
9a
1j
91
CN
N
O
Bn
MeO
10a
1k
94
44
78
86
CN
O
N
Bn
11b
1l
CN
O
N
Bn
a
Pd(dba)2 (5 mol %) and L8 (20 mol %) was used.
Pd(dba)2 (5 mol %) and L8 (10 mol %) was used.
b

Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
1985
R
OTBS
CN
OH
R
1) DMSO, ClC(O)C(O)Cl
CN
CN
O
cyanoamidation
Et3N
TBAF
CN
O
O
O
N
2) Pin nick Oxidation
3) MeI, Cs2CO3
N
Me
N
Me
N
R'
A
B
R'
2f
13
98%
70%
PdLn
O
H
N
O
OMe
CN
Pd
NaBH4, CoCl2 6H2O
then KOH
R
CN
O
R
O
CN
Pd
amidopalladation
N
N
Me
Ln
48%
O
Me
N
L
14
15
N
R'
O
C
D
R'
CN
Scheme 3. Synthesis of spirolactam 15.
cyanopalladation
R
On the other hand, pyrroloindole 17 can also be formed in
simple steps from oxindole 2a (Scheme 4). Again the selective re-
duction of the cyano group was achieved by CoCl2$6H2O and
NaBH4. Subsequent methoxycarbonylation gave carbonate 16. This
compound was reductively cyclized to give pyrroloindole 17.45
Comparison of the optical rotation of 17 with that reported in the
literature showed that oxindole 2a has the S-configuration.46
Ln
Pd
N
R'
O
E
R
R
R
CN
Pd
L
L
L
X
+Pd
O
−CN
1) NaBH4
L
NHCO2Me
N
R'
N
R'
N
R'
CN
CoCl2 6H2O
O
Y
F
G
H
O
O
2) ClCO2Me, Et3N
DMAP
Y = O or H2
X = I or CN
N
N
Bn
Bn
53%
(S)-2a (81% ee)
16
Figure 4. Plausible mechanism.
LiAlH4
THF, reflux
43%
N
H
Me
2.4. Synthetic manipulations of 3,3-disubstituted oxindoles
N
Bn
17
−
68 (c 0.20, CH2Cl2)
With the highly substituted oxindoles in hand, we studied
synthetic manipulations of this class of compounds with the
aim of providing drug-like structural motifs and realizing effi-
cient access to natural products. Our approach illustrated in
Figure 5 takes advantage of the presence of the cyano group
incorporated by the cyanoamidation. Connection between the
cyano group and substituent R2 on the quaternary carbon gives
spirooxindole A. On the other hand, ring formation between
the cyano group and the amide carbonyl provides fused indo-
line derivatives B with quaternary stereocenters at the ring
junctions.
α 26
[ ]
D
α 28
Lit.46 [ ]
−
82 (c 0.20, CH2Cl2)
D
Scheme 4. Synthesis of pyrroloindole 17.
3. Conclusions
The palladium-catalyzed intramolecular cyanoamidation of
olefins was reported and shown to be an efficient strategy toward
the synthesis of 3,3-disubstituted oxindoles as well as other a,a-
disubstituted lactams. Electron rich phosphine ligands were found
to promote this reaction smoothly. In particular, the catalyst gen-
erated from Pd(dba)2 and P(t-Bu)3 gave desired oxindoles in 15 min
at 100 ꢀC. On the other hand, Pd(PPh3)4 provided better results for
the synthesis of other a,a-disubstituted lactams. Efforts to expand
a
R3
O
this reaction to enantioselective conversions resulted in the finding
that a catalytic amount of Pd(dba)2 and the phosphoramidite de-
rived from (R)-BINOL and bis[(R)-1-phenylethyl]amine gave high
yields and high enantioselectivity. The addition of DMPU was
crucial to achieve the best results. This progress enables quick ac-
cess to a variety of oxindoles and related compounds in a conve-
nient manner.
a
b
N
R2
R1
A
B
CN
O
R3
R2
N
R1
b
R3
N
R1
4. Experimental section
4.1. General
Figure 5. Strategy for the access to higher-ordered structures.
The first example is the synthesis of spirolactam 15 (Scheme 3).
Starting from oxindole 2f, removal of the TBS group followed by
sequential oxidation and methylation gave cyanoester 14. This
compound was cyclized through selective reduction of the cyano
group by CoCl2$6H2O and NaBH4, followed by treatment with
KOH.44 Two distinct amides (N-methyl and N–H) in spirolactam 15
provide easy further manipulations.
Unless otherwise noted, all reactions were performed under
argon. Pd(PPh3)4 was prepared by using the reported protocol.47
Pd(dba)2 was purchased from Tokyo Chemical Industry Co., Ltd.
N,N0-Dimethyl propylene urea (DMPU) was distilled from CaH2. L8
and other optically active phosphoramidite ligands were prepared
according to the literature procedure.48 Silica gel column chroma-
tography was performed with Kanto silica gel 60 (particle size,

1986
Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
63–210
m
m). Proton nuclear magnetic resonance (1H NMR) spectra
Pd(dba)2 (4.16 mg, 0.00724 mmol), P(t-Bu3)$HBF4 (4.20 mg,
were recorded on a JEOL JNM-LA 500 at 500 MHz or a JEOL JNM-AL
400 at 400 MHz. Chemical shifts are reported relative to Me4Si (
0.00). Multiplicity is indicated by one or more of the following: s
(singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br
(broad). Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a JEOL JNM-LA 500 at 126 MHz or a JEOL JNM-AL
0.0145 mmol), and Et3N (5.08 mL, 0.0362 mmol) in xylene (3.6 mL)
d
was stirred at 100 ꢀC for 0.25 h. The mixture was subjected directly
to silica gel column chromatography (hexane/EtOAc¼10/0/8/2) to
give the oxindole 2a (98.4 mg, 98%).
4.3.3. Enantioselective cyanoamidation (Table 5, entry 9). A solution
of cyanoformamide 1a (100 mg, 0.362 mmol), L8 (15.6 mg,
0.0290 mmol), DMPU (0.043 mL, 0.36 mmol), and Pd(dba)2 (4.2 mg,
0.0072 mmol) in decalin (3.6 mL) was stirred at 100 ꢀC for 24 h. The
mixture was subjected directly to silica gel column chromatography
(hexane/EtOAc¼10/0/8/2) to give the oxindole 2a (99.4 mg,
quant). HPLC [Chiralcel OD-H, hexane/2-propanol¼90/10, 1.0 mL/
400 at 100 MHz. Chemical shifts are reported relative to CDCl3 (d
77.0). Infrared spectra were recorded on a FT/IR-4100 (JASCO)
equipped with an attenuated total reflection (ATR) attachment or
on a FT/IR-410 (JASCO) as a thin film on NaCl plate (thin film) or as
a KBr pellet (KBr) or as a CHCl3 solution (CHCl3). Optical rotations
were measured with a JASCO DIP-360 digital polarimeter. Enan-
tiomer ratios were determined by chiral HPLC using a Shimadzu
SPD-10A with Daicel Chemical Industries, LTD. Chiralpak AD-H
(0.46 cmꢁ25 cm), Chiralpak OJ-H (0.46 cmꢁ25 cm), Chiralpak OD-
H (0.46 cmꢁ25 cm), or Chiralpak AS-H (0.46 cmꢁ25 cm).
min,
17.5 min]; [
l
¼210 nm, retention times: (minor) 14.3 min, (major)
a
]
D
26 26.9 (c 0.90, CHCl3, 81% ee).
4.3.4. Oxindole 2b. Colorless oil; 1H NMR (500 MHz, CDCl3,
d) 7.42
(dd, 1H, J1¼0.9 Hz, J2¼7.6 Hz), 7.33–7.25 (m, 5H), 7.23 (dd, 1H,
J1¼J2¼7.6 Hz), 7.10 (ddd, 1H, J1¼0.9 Hz, J2¼J3¼7.6 Hz), 6.78 (d, 1H,
J¼7.6 Hz), 4.96 (d, 1H, J¼15.6 Hz), 4.90 (d, 1H, J¼15.6 Hz), 2.87 (d,
1H, J¼16.8 Hz), 2.65 (d, 1H, J¼16.8 Hz), 2.02 (ddd, 1H, J1¼5.2 Hz,
J2¼10.7 Hz, J3¼13.1 Hz), 1.98 (ddd, 1H, J1¼5.2 Hz, J2¼10.7 Hz,
J3¼13.1 Hz), 1.08 (m, 1H), 0.90 (m, 1H), 0.82 (dd, 3H, J1¼J2¼7.3 Hz);
4.2. Preparation of cyanoformamides49
4.2.1. Cyanoformamide 1a. To a solution of N-benzyl-2-(prop-1-en-
2-yl)aniline (3.20 g, 14.6 mmol) in CH2Cl2 (30 mL) was added pyr-
idine (1.77 mL, 21.9 mmol) followed by triphosgene (1.51 g,
5.10 mmol) at ꢂ78 ꢀC. The reaction mixture was warmed to room
temperature, diluted with CHCl3, and washed with 1 M HCl and
brine. The organic phase was dried over MgSO4, filtered, and con-
centrated under reduced pressure to give the crude chlor-
oformamide. To a solution of this crude chloroformamide in MeCN
(25 mL) and t-BuOH (5.0 mL) were added 18-crown-6 (392 mg,
1.46 mmol) and KCN (1.43 g, 21.9 mmol), and the resulting mixture
was stirred at 60 ꢀC for 2 h. After removal of the solvents, water was
added, and the mixture was extracted with CHCl3. The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue obtained was purified by silica
gel column chromatography (hexane/EtOAc¼95/5) to give oxindole
1a (3.83 g, 95% over two steps) as a colorless oil: 1H NMR (500 MHz,
13C NMR (126 MHz, CDCl3,
d) 177.4, 142.8, 135.6, 129.5, 129.2, 129.0,
128.0, 127.5, 123.44, 123.41, 116.7, 109.8, 49.3, 44.2, 38.7, 26.3, 17.6,
14.0; IR (thin film) 1712 cmꢂ1; MS (EI) m/z¼304 (Mþ); HPLC
[Chiralcel OD-H, hexane/2-propanol¼90/10,1.0 mL/min, ¼210 nm,
l
26
retention times: (minor) 10.5 min, (major) 13.1 min]; [
a
]
26.7 (c
D
0.78, CHCl3, 72% ee).
4.3.5. Oxindole 2c. Colorless oil; 1H NMR (500 MHz, CDCl3,
d) 7.37
(dd, 1H, J1¼0.9, J2¼7.7 Hz), 7.33–7.25 (m, 5H), 7.24 (ddd, 1H,
J1¼1.2 Hz, J2¼J3¼7.7 Hz), 7.08 (ddd, 1H, J1¼0.9 Hz, J2¼J3¼7.7 Hz),
6.78 (d,1H, J¼7.6 Hz), 4.98 (d,1H, J¼15.5 Hz), 4.88 (d,1H, J¼15.5 Hz),
2.98 (d, 1H, J¼16.4 Hz), 2.74 (d, 1H, J¼16.4 Hz), 2.44–2.31 (m, 1H),
0.97 (d, 3H, J¼7.1 Hz), 0.92 (d, 3H, J¼7.1 Hz); 13C NMR (126 MHz,
CDCl3,
7.31–7.25 (m, 3H), 7.19 (dd, 1H, J1¼J2¼7.6 Hz), 7.15–7.13 (m, 2H),
6.75 (d, 1H, J¼7.6 Hz), 6.66 (d, J¼7.7 Hz), 5.50 (d, 1H, J¼14.3 Hz),
5.35 (s, 1H), 5.26 (s), 5.08 (s, 1H), 4.96
(s), 4.09 (d, 1H, J¼14.3 Hz),
2.12 (s, 3H), 2.05 ) 145.7, 142.4,
(s); 13C NMR (126 MHz, CDCl3,
142.2, 135.1, 134.8, 130.7, 130.6, 130.5, 130.0 , 129.5, 129.3 , 129.1
128.9, 128.6, 128.5, 118.4, 116.8 , 111.0, 52.4, 23.7; IR (CHCl3) 2231,
d
) 7.40 (dd, 1H, J1¼J2¼7.6 Hz), 7.37 (dd, 1H, J1¼1.5, J2¼7.6 Hz),
CDCl3, d) 176.9, 143.0, 135.4, 129.0, 128.9, 128.8, 127.7, 127.3, 123.5,
122.9,116.6,109.4, 52.1, 43.9, 34.4, 23.9,17.1,16.8; IR (thin film) 2360,
1711 cmꢂ1; MS (EI) m/z¼304 (Mþ). Anal. Calcd for C20H20N2O: C,
78.92; H, 6.62; N, 9.20. Found: C, 78.66; H, 6.52; N, 9.24; HPLC
*
*
*
*
d
[Chiralcel OD-H, hexane/2-propanol¼90/10,1.0 mL/min,
l
¼210 nm,
*
*
*
,
retention times: (minor) 12.0 min, (major) 16.0 min, 60% ee].
*
1677 cmꢂ1; MS (EI) m/z¼276 (Mþ). Anal. Calcd for C18H16N2O: C,
78.24; H, 5.84; N, 10.14. Found: C, 78.35; H, 5.91; N, 10.02. (*denotes
peaks of minor rotamer).
4.3.6. Oxindole 2d. Colorless oil; 1H NMR (500 MHz, CDCl3,
d) 7.41
(d, 1H, J¼7.7 Hz), 7.28–7.13 (m, 11H), 7.07 (ddd, 1H, J1¼1.0,
J2¼J3¼7.7 Hz), 6.75 (d, 1H, J¼7.7 Hz), 4.82 (d, 1H, J¼15.9 Hz), 4.86
(d, 1H, J¼15.9 Hz), 3.33 (d, 1H, J¼16.5 Hz), 3.05 (d, 1H, J¼16.5 Hz);
4.3. General procedure for Pd-catalyzed cyanoamidation
13C NMR (126 MHz, CDCl3,
d) 176.0, 142.7, 136.7, 135.1, 129.6, 129.0,
128.9, 128.4, 127.8, 127.1, 126.7, 125.2, 123.4, 116.4, 110.1, 52.7, 44.1,
26.1; IR (ATR) 2353, 1716 cmꢂ1; MS (EI) m/z¼338 (Mþ). Anal. Calcd
for C23H18N2O: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.43; H, 5.49;
N, 8.01; HPLC [Chiralcel OD-H, hexane/2-propanol¼70/30, 1.0 mL/
4.3.1. Conditions using 10 mol % Pd(PPh3)4 (Table 1, entry 1). A so-
lution of cyanoformamide 1a (100 mg, 0.362 mmol) and Pd(PPh3)4
(41.8 mg, 0.0362 mmol) in xylene (3.6 mL) was stirred at 130 ꢀC for
0.25 h. The mixture was subjected directly to silica gel column
chromatography (hexane/EtOAc¼10/0/8/2) to give the oxindole
min,
l
¼210 nm, retention times: (minor) 9.3 min, (major) 13.4 min,
2a (98.2 mg, 98%) as a colorless oil; 1H NMR (500 MHz, CDCl3,
d)
61% ee].
7.48 (d, 1H, J¼7.6 Hz), 7.34–7.25 (m, 5H), 7.23 (dd, 1H, J1¼J2¼7.6 Hz),
7.09 (dd, 1H, J1¼J2¼7.6 Hz), 6.78 (d, 1H, J¼7.6 Hz), 4.95 (d, 1H,
J¼16.5 Hz), 4.92 (d, 1H, J¼16.5 Hz), 2.91 (d, 1H, J¼16.8 Hz), 2.64 (d,
4.3.7. Oxindole 2e. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 7.53
(d, 1H, J¼7.7 Hz), 7.38–7.32 (m, 5H), 7.28 (dd, 1H, J1¼J2¼7.7 Hz), 7.14
(dd,1H, J1¼J2¼7.7 Hz), 6.81 (d, 1H, J¼7.7 Hz), 5.02 (d, 1H, J¼16.7 Hz),
4.98 (d, 1H, J¼16.7 Hz), 4.07 (d, 1H, J¼9.5 Hz), 3.93 (d, 1H, J¼9.5 Hz),
3.10 (d, 1H, J¼16.5 Hz), 2.86 (d, 1H, J¼16.5 Hz), 0.87 (s, 9H), 0.06 (s,
1H, J¼16.8 Hz), 1.57 (s, 3H); 13C NMR (126 MHz, CDCl3,
d) 177.9,
142.0, 135.5, 131.2, 129.3, 129.1, 128.0, 127.4, 123.5, 123.4, 116.8,
109.9, 45.1, 44.1, 26.4, 22.6; IR (CHCl3) 1714 cmꢂ1; MS (EI) m/z¼276
(Mþ). Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found:
C, 78.18; H, 6.06; N, 10.12.
3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3,
d) 175.7, 143.1, 135.4,
129.4, 129.0, 128.5, 127.9, 127.3, 124.3, 123.1, 116.6, 109.7, 66.8, 51.2,
44.1, 25.7, 21.8, 18.2, ꢂ5.5, ꢂ5.7; IR (thin film) 2353, 1716 cmꢂ1; MS
(EI) m/z¼406 (Mþ). Anal. Calcd for C24H30N2O2Si: C, 70.90; H, 7.44;
N, 6.89. Found: C, 70.61; H, 7.46; N, 6.78; HPLC [Chiralcel OD-H,
4.3.2. Conditions using 2 mol % Pd(dba)2 and 4 mol % P(t-Bu3) (Table
1, entry 4). A solution of cyanoformamide 1a (100 mg, 0.362 mmol),

Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
1987
hexane/2-propanol¼90/10,1.0 mL/min,
l
¼210 nm, retention times:
hexane/2-propanol¼90/10,1.0 mL/min,
(minor) 16.7 min, (major) 19.1 min]; [a]
26 13.7 (c 1.11, CHCl3, 78% ee).
D
l
¼210 nm, retention times:
26
(minor) 6.7 min, (major) 8.2 min]; [
a
]
ꢂ5.2 (c 0.83, CHCl3, 68% ee).
D
4.3.8. Oxindole 2f. Colorless oil; 1H NMR (400 MHz, CDCl3,
d
); 7.43
4.3.14. Oxindole 2l. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 7.24–
(d, 1H, J¼7.8 Hz), 7.36 (dd, 1H, J1¼J2¼7.8 Hz), 7.13 (dd, 1H,
J1¼J2¼7.8 Hz), 6.89 (d, 1H, J¼7.8 Hz), 3.51–3.39 (m, 2H), 3.22 (s, 3H),
2.92 (d, 1H, J¼16.6 Hz), 2.58 (d, 1H, J¼16.6 Hz), 2.32–2.25 (m, 1H),
2.20–2.15 (m, 1H), 0.77 (s, 9H), ꢂ0.12 (s, 3H), ꢂ0.13 (s, 3H); 13C NMR
7.17 (m, 5H), 7.03 (dd, 1H, J1¼J2¼7.8 Hz), 6.77 (d, 1H, J¼7.8 Hz), 6.54
(d,1H, J¼7.8 Hz), 4.91 (d,1H, J¼15.8 Hz), 4.84 (d,1H, J¼15.8 Hz), 2.98
(d, 1H, J¼16.8 Hz), 2.91 (d, 1H, J¼16.8 Hz), 2.34 (s, 3H), 1.50 (s, 3H);
13C NMR (100 MHz, CDCl3,
d) 178.0, 142.8, 135.5, 134.6, 129.1, 129.0,
(100 MHz, CDCl3,
d
) 177.1, 143.8, 129.4, 128.9, 123.9, 123.1, 116.9,
127.9, 127.3, 125.9, 116.30, 116.29, 107.9, 46.8, 44.1, 24.7, 21.6, 18.4; IR
(thin film) 1713 cmꢂ1; MS (EI) m/z¼290 (Mþ). Anal. Calcd for
C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.32; H, 6.39; N,
9.53; HPLC [Chiralcel OD-H, hexane/2-propanol¼90/10,1.0 mL/min,
108.8, 59.2, 47.5, 37.9, 26.8, 26.6, 25.9, 18.3, ꢂ5.64; IR (CHCl3) 2251,
1719 cmꢂ1
;
MS (FAB) m/z¼345 (MþHþ). Anal. Calcd for
C19H28N2O2Si: C, 66.24; H, 8.19; N, 8.13. Found: C, 65.91; H, 8.19; N,
8.04.
l
¼210 nm, retention times: (minor) 15.1 min, (major) 19.6 min];
26
[a
]
ꢂ37.5 (c 0.88, CHCl3, 86% ee).
D
4.3.9. Oxindole 2g. Colorless oil; 1H NMR (500 MHz, CDCl3,
d) 7.48
(d, 1H, J¼8.0 Hz), 7.36 (dd, 1H, J1¼J2¼8.0 Hz), 7.14 (dd, 1H,
J1¼J2¼8.0 Hz), 6.92 (d, 1H, J¼8.0 Hz), 3.25 (s, 3H), 2.85 (d, 1H,
J¼16.4 Hz), 2.58 (d, 1H, J¼16.4 Hz), 1.53 (s, 3H); 13C NMR (126 MHz,
4.3.15. Lactam 6. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 8.25 (dd,
1H, J1¼1.7 Hz, J2¼5.3 Hz), 7.73 (dd,1H, J1¼1.7 Hz, J2¼7.3 Hz), 7.44–7.42
(m, 2H), 7.32–7.24 (m, 3H), 7.02 (dd,1H, J1¼5.3 Hz, J2¼7.3 Hz), 5.01 (s,
2H), 2.89 (d, 1H, J¼16.6 Hz), 2.53 (d, 1H, J¼16.6 Hz), 1.55 (s, 3H); 13C
CDCl3, d) 177.7, 142.9, 131.2, 129.3, 123.4, 123.3, 116.8, 108.8, 44.9,
26.6, 26.3, 22.2; IR (thin film) 1715 cmꢂ1; MS (EI) m/z¼200 (Mþ).
Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
71.70; H, 6.08; N, 13.85; HPLC [Chiralcel AD-H, hexane/2-prop-
NMR (100 MHz, CDCl3, d) 177.0,155.6,148.2,136.2,131.0,128.6,128.2,
127.7,125.2,118.8,116.3, 44.3, 42.8, 25.6, 21.7; IR (ATR) 1722 cmꢂ1; MS
(EI) m/z¼277 (Mþ). Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N,
15.15. Found: C, 73.78; H, 5.67; N, 15.02.
anol¼90/10, 1.0 mL/min,
l
¼210 nm, retention times: (minor)
26
8.4 min, (major) 9.6 min]; [
a
]
63.6 (c 0.93, CHCl3, 75% ee).
D
4.3.16. Lactam 8. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 7.35–7.27
4.3.10. Oxindole 2h. Colorless oil; 1H NMR (400 MHz, CDCl3,
d)
(m, 3H), 7.22–7.21 (m, 2H), 4.49 (d, 1H, J¼14.6 Hz), 4.43 (d, 1H,
J¼14.6 Hz), 3.24–3.21 (m, 2H), 2.61 (d, 1H, J¼16.8 Hz), 2.57 (d,
1H, J¼16.8 Hz), 2.12 (ddd, 1H, J1¼J2¼8.2 Hz, J3¼13.1 Hz), 1.96 (ddd, 1H,
J1¼5.2 Hz, J2¼6.4 Hz, J3¼13.1 Hz), 1.29 (s, 3H); 13C NMR (100 MHz,
7.32–7.23 (m, 6H), 7.01 (d, 1H, J¼7.8 Hz), 6.66 (d, 1H, J¼7.8 Hz), 4.91
(s, 2H), 2.88 (d, 1H, J¼16.5 Hz), 2.63 (d, 1H, J¼16.5 Hz), 2.32 (s, 3H),
1.56 (s, 3H); 13C NMR (100 MHz, CDCl3,
d) 177.8, 139.6, 135.6, 133.1,
131.2, 129.5, 129.0, 127.9, 127.3, 124.1, 116.8, 109.6, 45.0, 44.0, 26.3,
22.6, 21.1; IR (thin film) 1712 cmꢂ1; MS (EI) m/z¼290 (Mþ). Anal.
Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.55; H,
6.41; N, 9.53; HPLC [Chiralcel OD-H, hexane/2-propanol¼90/10,
CDCl3, d) 175.3,135.8,128.7,127.9,127.6,117.3, 46.7, 42.7, 42.5, 30.7, 26.2,
22.1; IR (thin film) 1689 cmꢂ1; MS (EI) m/z¼228 (Mþ). Anal. Calcd for
C14H16N2O: C, 73.66; H, 7.06; N,12.27. Found: C, 73.47; H, 7.22; N,11.99.
1.0 mL/min,
l
¼210 nm, retention times: (minor) 11.4 min, (major)
4.3.17. Lactam 10. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 7.39–
26
15.1 min]; [
a
]
D
22.9 (c 1.38, CHCl3, 74% ee).
7.25 (m, 8H), 7.09 (d,1H, J¼7.6 Hz), 4.86 (d,1H, J¼14.6 Hz), 4.74 (d,1H,
J¼14.6 Hz), 4.48 (d,1H, J¼16.3 Hz), 4.41 (d,1H, J¼16.3 Hz), 3.28 (d,1H,
J¼16.4 Hz), 2.96 (d, 1H, J¼16.4 Hz), 1.57 (s, 3H); 13C NMR (100 MHz,
4.3.11. Oxindole 2i. Colorless solid; mp 96.5–97.2 ꢀC; 1H NMR
(400 MHz, CDCl3,
d
) 7.39 (d, 1H, J¼7.8 Hz), 7.37–7.28 (m, 5H), 7.08
CDCl3, d) 170.6, 136.5, 136.2, 130.1, 128.9, 128.3, 127.9, 127.8, 127.5,
(dd, 1H, J1¼1.7 Hz, J2¼7.8 Hz), 6.78 (d, 1H, J¼1.7 Hz), 4.90 (s, 2H),
125.9,124.9,117.6, 50.8, 49.2, 44.6, 27.4, 26.2; IR (thin film) 2248,1642
cmꢂ1; MS (EI) m/z¼290 (Mþ). Anal. Calcd for C19H18N2O: C, 78.59; H,
6.25; N, 9.65. Found: C, 78.72; H, 6.24; N, 9.63.
2.89 (d, 1H, J¼16.6 Hz), 2.63 (d, 1H, J¼16.6 Hz), 1.57 (s, 3H); 13C NMR
(100 MHz, CDCl3, d) 177.9, 143.3, 135.3, 135.0, 129.5, 129.3, 128.3,
127.4, 124.4, 123.5, 116.5, 110.6, 44.9, 44.2, 26.4, 22.6; IR (KBr)
1680 cmꢂ1; MS (EI) m/z¼310 (Mþ). Anal. Calcd for C18H15ClN2O: C,
69.57; H, 4.86; N, 9.01. Found: C, 69.58; H, 5.10; N, 9.14; HPLC
4.3.18. Lactam 12. Colorless oil; 1H NMR (400 MHz, CDCl3,
d) 7.57–
6.88 (m, 13H), 5.12 (d, 1H, J¼15.8 Hz), 5.02 (d, 1H, J¼15.8 Hz), 3.41
[Chiralcel OD-H, hexane/2-propanol¼90/10,1.0 mL/min,
l
¼210 nm,
(d, 1H, J¼16.1 Hz), 3.24 (d, 1H, J¼16.1 Hz), 2.45
*
(d, J¼16.1 Hz), 2.34
*
retention times: (minor) 16.7 min, (major) 22.4 min]; [
0.17, CHCl3, 82% ee).
a]
26 12.2 (c
(d, J¼16.1 Hz), 2.02
171.4, 170.2 , 140.1, 139.9
135.6, 135.0 , 130.7, 130.3
128.9 , 128.6, 128.5 , 127.2, 126.8
123.1 , 122.5, 119.1, 117.0 , 54.6 , 54.2, 49.0, 48.2
*
(s), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3,
d
)
D
*
*
, 139.4, 138.7
*
, 137.4
*
, 137.3, 136.5, 136.4
, 129.2 , 129.1, 129.0,
, 126.2, 126.0 , 124.1,
, 28.1, 24.1 , 24.0 ,
*
,
*
*
, 130.2, 130.0, 129.5
*
*
4.3.12. Oxindole 2j. Colorless oil; 1H NMR (400 MHz, CDCl3,
d
) 7.35–
*
*
*
, 126.6, 126.5
*
*
7.27 (m, 5H), 7.07 (s, 1H), 6.36 (s, 1H), 4.92 (s, 2H), 3.87 (s, 3H), 3.74
*
*
*
*
*
*
(s, 3H), 2.89 (d, 1H, J¼16.6 Hz), 2.61 (d, 1H, J¼16.6 Hz), 1.56 (s, 3H);
20.3; IR (thin film) 1648, 2360 cmꢂ1; MS (EI) m/z¼352 (Mþ). Anal.
Calcd for C24H20N2O: C, 81.79; H, 5.72; N, 7.95. Found: C, 81.54; H,
5.63; N, 7.83. (*denotes peaks of minor atropisomer).
13C NMR (100 MHz, CDCl3,
d) 178.3, 150.4, 146.0, 135.7, 129.18,
129.17, 128.1, 127.4, 121.9, 117.0, 108.3, 96.1, 57.0, 56.4, 45.3, 44.2,
26.7, 22.7; IR (thin film) 1710 cmꢂ1; MS (EI) m/z¼336 (Mþ). Anal.
Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.18; H,
6.03; N, 8.27; HPLC [Chiralcel AS-H, hexane/2-propanol¼90/10,
4.4. Synthesis of spirolactam 15
1.0 mL/min,
47.3 min]; [
l
¼210 nm, retention times: (minor) 40.2 min, (major)
4.4.1. Alcohol 13. To a solution of compound 2f (148 mg, 430
in THF (15 mL) was added 1 M TBAF solution in THF (970
970
mol) at 0 ꢀC. After stirring at the same temperature for 30 min,
mmol)
a
]
26 36.4 (c 0.98, CHCl3, 82% ee).
mL,
D
m
4.3.13. Oxindole 2k. Colorless oil; 1H NMR (400 MHz, CDCl3,
d)
water was added, and the mixture was extracted with EtOAc. The
combined extracts were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (CHCl3/MeOH¼9/1/
6/4) to give 13 (96.8 mg, 98%) as a white solid; mp 85.5–85.9 ꢀC; 1H
7.33–7.26 (m, 5H), 7.08 (d, 1H, J¼2.5 Hz), 6.74 (dd, 1H, J1¼2.5 Hz,
J2¼8.5 Hz), 6.67 (d, 1H, J¼8.5 Hz), 4.90 (s, 2H), 3.77 (s, 3H), 2.89 (d,
1H, J¼16.6 Hz), 2.65 (d, 1H, J¼16.6 Hz), 1.56 (s, 3H); 13C NMR
(100 MHz, CDCl3, d) 177.6, 156.7, 135.6, 135.3, 132.5, 129.1, 128.0,
127.4, 116.7, 113.7, 110.7, 110.4, 55.9, 45.4, 44.1, 26.4, 22.6; IR (thin
NMR (400 MHz, CDCl3,
J1¼7.8 Hz, J2¼7.5 Hz), 7.16 (dd, 1H, J1¼7.6 Hz, J2¼7.5 Hz), 6.93 (d, 1H,
d
); 7.46 (d, 1H, J¼7.3 Hz), 7.39 (dd, 1H,
film) 1712 cmꢂ1; MS (EI) m/z¼306 (Mþ); HPLC [Chiralcel AD-H,

1988
Y. Yasui et al. / Tetrahedron 66 (2010) 1980–1989
J¼7.8 Hz), 3.68–3.61 (m,1H), 3.50–3.42 (m,1H), 3.25 (s, 3H), 2.95 (d,
1H, J¼16.6 Hz), 2.62 (d, 1H, J¼16.6 Hz), 2.37–2.31 (m, 1H), 2.24–2.18
stirring was continued at room temperature for 2 h. After adding
2 M HCl at 0 ꢀC and neutralizing with saturated aqueous NaHCO3,
the mixture was extracted with EtOAc. The combined organic ex-
tracts were washed with saturated aqueous potassium sodium
tartrate, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. To a solution of the residue in pyridine (10 mL) was
added 4-(N,N-dimethylamino)pyridine (12.5 mg, 0.102 mmol) and
methylchloroformate (0.40 mL, 5.1 mmol) at 0 ꢀC. After stirring at
room temperature overnight, saturated aqueous NH4Cl was added,
and the mixture was extracted with EtOAc. The combined organic
extracts were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue obtained was purified by silica gel
column chromatography (hexane/EtOAc¼9/1/7/3) to give carba-
mate 16 (182 mg, 53% over two steps) as a colorless oil: 1H NMR
(m, 1H), 1.72 (br, 1H); 13C NMR (100 MHz, CDCl3,
d); 177.9, 143.5,
129.7, 129.1, 123.7, 123.6, 116.6, 109.1, 59.0, 47.6, 38.1, 26.8, 26.1; IR
(CHCl3) 3347, 2251, 1707, 1613 cmꢂ1; MS (FAB) m/z¼231 (MþHþ).
Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C,
67.64; H, 6.22; N, 12.00.
4.4.2. Ester 14. To a solution of oxalyl chloride (177 mg, 1.39 mmol)
in CH2Cl2 (2 mL) was added DMSO (191 mg, 2.44 mmol) in CH2Cl2
(2 mL) at ꢂ78 ꢀC. After stirring for 10 min, a solution of 13 (112 mg,
0.487 mmol) in CH2Cl2 (2 mL) was added at the same temperature.
After stirring for 15 min, Et3N (680 ml, 4.88 mmol) was added, and
the reaction mixture was warmed to room temperature. After
stirring for 30 min, the reaction mixture was quenched with 1 M
HCl and brine. The mixture was extracted with CHCl3. The com-
bined organic extracts were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was dissolved in t-BuOH
(6 mL) and 2-methyl-2-butene (3 mL). To this solution was added
NaClO2 (385 mg, 3.41 mmol) in NaH2PO4 buffer solution (1 mM in
water, 3.5 mL). After stirring for 30 min, organic solvents were
concentrated under reduced pressure. The obtained residue was
diluted with water and then washed with hexane. The aqueous
layer was acidified with 1 M HCl to pH2 and extracted with CHCl3.
Combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. To the
residue was added CH3CN (1.5 mL), Cs2CO3 (170 mg, 0.522 mmol)
(400 MHz, CDCl3,
d
) 7.33–7.20 (m, 6H), 7.15 (ddd, 1H, J1¼1.2 Hz,
J2¼J3¼7.8 Hz), 7.04 (ddd, 1H, J1¼1.2 Hz, J2¼J3¼7.8 Hz), 6.74 (d, 1H,
J¼7.8 Hz), 4.95 (d, 1H, J¼15.8 Hz), 4.87 (d, 1H, J¼15.8 Hz), 4.85 (br,
1H), 3.58 (s, 3H), 3.02–2.91 (m, 2H), 2.21–2.14 (m,1H), 2.10–2.03 (m,
1H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3,
d) 180.7, 157.0, 142.2,
136.1, 133.5, 129.0, 128.2, 127.8, 127.4, 123.0, 122.9, 109.4, 52.0, 47.1,
43.8, 37.7, 37.5, 24.4; IR (CHCl3) 1708,1611 cmꢂ1; MS (FAB) m/z¼339
(MþHþ).
4.5.2. Pyrroloindole 17. To solution of carbamate 16 (52.1 mg,
0.154 mmol) in THF was added LiAlH4 (36.5 mg, 0.770 mmol) at
0 ꢀC. After stirring at room temperature for 1.5 h and at reflux for
10 min, Na2SO4$10H2O was added at 0 ꢀC. After stirring for 1 h at
room temperature, the inorganic solid was removed by filtration.
The filtrate was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue obtained was purified by silica gel
column chromatography (CHCl3/MeOH¼95/5) to give pyrro-
and MeI (54.4 mL, 0.873 mmol) at room temperature. After stirring
for 11 h, the reaction mixture was diluted with CHCl3 and filtered
through a Celite pad. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel column chro-
matography (hexane/EtOAc¼9/1/6/4) to give 14 (87.9 mg, 70%
loindole 17 (18.3 mg, 43%) as a colorless oil. Spectra were identical
26
to those reported previously46; [
a]
ꢂ68 (c 0.20, CH2Cl2).
D
over three steps) as a colorless oil: 1H NMR (400 MHz, CDCl3,
d);
7.44 (d, 1H, J¼7.6 Hz), 7.38 (dd, 1H, J1¼J2¼7.8 Hz), 7.12 (dd, 1H,
J1¼7.6 Hz, J2¼7.5 Hz), 6.93 (d, 1H, J¼7.8 Hz), 3.53 (s, 3H), 3.28 (s, 3H),
3.13–2.96 (m, 3H), 2.62 (d, 1H, J¼16.6 Hz); 13C NMR (100 MHz,
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific
Research B (Y.T.) and for Young Scientists B (Y.Y.), Scientific Research
on Priority Areas: Creation of Biologically Functional Molecules,
and ‘Targeted Proteins Research Program’ from the Ministry of
Education, Culture, Sports, Science and Technology of Japan, and
the 21st Century COE Program ‘Knowledge Information In-
frastructure for Genome Science’.
CDCl3, d); 176.4, 169.5, 143.9, 129.9, 128.5, 123.4, 116.1, 109.0, 52.1,
46.1, 39.2, 26.8, 25.9; IR (CHCl3) 2341, 1715 cmꢂ1; HRMS (MþHþ)
calcd for C14H15N2O3: 259.1083. Found: 259.1082.
4.4.3. Lactam 15. To a solution of 14 (18.1 mg, 70.2
CoCl2$6H2O (33.3 mg, 140 mol) in MeOH (3 mL) was added
NaBH4 (20.8 mg, 550 mol) in five portions over 2 h. After stir-
mmol) and
m
m
ring for 15 min, 10% w/v KOH in MeOH solution (1 mL) was
added. After stirring for 3 h, 1 M HCl and brine were added, and
the mixture was extracted with CHCl3. The combined extracts
were washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(CHCl3/MeOH¼97/3/95/5) to give 15 (7.8 mg, 48%); mp 198.9–
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.073.
References and notes
199.2 ꢀC; 1H NMR (400 MHz, CDCl3,
d); 7.34 (dd, 1H, J1¼7.8 Hz,
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J2¼7.6 Hz), 6.91 (d, 1H, J¼7.6 Hz), 6.39 (br, 1H), 3.75–3.69 (m, 1H),
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