Intramolecular cyanoamidation of unsaturated cyanoformamides catalyzed by palladium: an efficient synthesis of multi-functionalized lactams

Article abstract of DOI:10.1016/j.tet.2007.01.060

The Pd(0)-catalyzed intramolecular cyanoamidation of several unsaturated cyanoformamides with alkenyl, allenyl, and alkynyl groups was investigated. In the cases of alkynyl and 1,1-disubstituted alkenyl cyanoformamides, the Pd(0)-catalyzed C-CN activation and subsequent insertion reaction proceeded smoothly and gave the corresponding lactams bearing a cyano group at the β-position in good yields. The mechanism of the reaction was also discussed.

Full text of DOI:10.1016/j.tet.2007.01.060

Tetrahedron 63 (2007) 2978–2989
Intramolecular cyanoamidation of unsaturated
cyanoformamides catalyzed by palladium: an efficient
synthesis of multi-functionalized lactams
Yusuke Kobayashi,a Haruhi Kamisaki,a Hiroshi Takeda,a Yoshizumi Yasui,a
Reiko Yanadab and Yoshiji Takemotoa,
*
aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
bFaculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
Received 28 December 2006; revised 25 January 2007; accepted 29 January 2007
Available online 31 January 2007
Abstract—The Pd(0)-catalyzed intramolecular cyanoamidation of several unsaturated cyanoformamides with alkenyl, allenyl, and alkynyl
groups was investigated. In the cases of alkynyl and 1,1-disubstituted alkenyl cyanoformamides, the Pd(0)-catalyzed C–CN activation and
subsequent insertion reaction proceeded smoothly and gave the corresponding lactams bearing a cyano group at the b-position in good yields.
The mechanism of the reaction was also discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cyanoformamides10 as well as other several unsaturated
cyanoformamides.
Transition-metal-catalyzed carbonylative cyclization of un-
saturated amines using carbon monoxide is a powerful tool
for the synthesis of lactams and various heterocyclic com-
pounds.1 Especially, the cyclocarbonylation–esterification
represents an efficient and versatile approach to the one-
step synthesis of functionalized lactams (Eq. 1).2 Recently,
through the use of well-designed substrates, several efficient
methods for the carbonylative cyclization without the use of
toxic carbon monoxide have been explored.3–5 These
methods, however, have not been applied to the synthesis
of a-alkylidene lactams bearing a cyano group at the
b-position. This prompted us to investigate the transition-
metal-catalyzed cyclocarbonylation–cyanation of unsatu-
rated cyanoformamides A into functionalized lactams C
(Eq. 2). Such multi-functionalized lactams C obtained by
this method would be versatile building blocks in organic
synthesis and are seen in many natural products.6 Although
direct activation of unstrained C–C single bond by transition
metals and subsequent addition of the metal complex to C–C
unsaturated bond should be of great synthetic value because
such a reaction provides a simultaneous installation of two
C–C bonds with perfect atom economy, only a few reports
are available.7–9 We report here the details of the palla-
dium-catalyzed intramolecular cyanoamidation of alkynyl
MeO2C
IPd
H
H
PdI2
CO
MeOH
+
(1)
(2)
CO
O
O
NH
R
N
N
R
R
CN
R1
R1
R 1
CN
CN
M
R2
R2
R3
Ln
R2
R3
M
( )n
( )n
( )n
O
cyanation
R3
cyclocarbonylation
O
N
N
O
N
R4
R4
A
R4
B
C
2. Results and discussion
We first examined the several methods to prepare the requi-
site unsaturated cyanoformamides (Scheme 1). Although the
chemistry of acyl cyanides has been well investigated,11
there are not so many reports concerning the preparations12
and the reactions13 of cyanoformamides. Using carbonyl
cyanide generated in situ according to the literature,12 the
primary and secondary unsaturated amines were converted
to the corresponding cyanoformamides in moderate to
good yield (Method A). This method, however, is not suit-
able for the large scale preparation of cyanoformamide
due to the production of toxic hydrogen cyanide. Then, we
* Corresponding author. Tel.: +81 75 753 4528; fax: +81 75 753 4569;
e-mail: takemoto@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.060

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2979
next investigated alternative method (Method B) and found
that the reaction of the corresponding chlorocarbamates
with KCN in the presence of 18-crown-6 provided the aimed
compounds in good yield. Furthermore, it was revealed that
the unsaturated cyanoformamides could be prepared from the
primary unsaturated alcohol and cyanoformamide under
the Mitsunobu conditions albeit in low yield (Method C).
could be obtained in moderate yields by using the appropri-
ate combination of Pd(II) and phosphine ligands such as
PPh3 and dppb (entries 3–5). After further experiments on
the cyclization, we found that Pd(PPh3)4 was an effective
catalyst for the cyanoamidation, and the oxindole 2a was
obtained in 97% yield as a mixture of (E)- and (Z)-isomer
(entry 6). We next examined the effect of the solvent on
the chemical yield. Among the solvents examined, toluene
and xylene gave good results in terms of chemical yield
and the ratio of Z/E isomers (entries 6 and 7). When a polar
solvent such as DMF was used, both the chemical yield and
the Z/E ratio decreased (entry 8).
Method A
R1
R1
CN
O
R2
R3
R2
R3
NC
CN
ether, rt
NH
R4
N
O
R4
To clarify the mechanism of production of (E)-2a, we carried
out the isomerization experiment (Scheme 2). Although no
isomerization occurred only by heating the isolated (Z)-iso-
mer in toluene, the slow isomerization from (Z)-2a to (E)-2a
was observed when (Z)-2a was subjected to the reaction con-
dition (Z/E¼91/9). In addition, (Z)-2a easily isomerized to
(E)-2a in DMF (100 ꢀC, 1 h, Z/E¼34/66). These results
are consistent with the ratio in Table 1 and suggest that the
reaction proceeds stereoselectively to afford (Z)-2a, which
then isomerizes to (E)-isomer in the presence of Pd(PPh3)4
and polar solvent.14
33-86%
Method B
R1
R1
Cl
R1
CN
KCN
R2
R2
R3
R2
R3
triphosgene
18-crown-6
t
CH2Cl2
−78 °C to rt
MeCN/Bu OH
60 °C
R3
NH
R4
N
O
N
O
R4
R4
68-95%
Method C
R1
R1
CN
O
PPh3, DIAD
THF, 60 °C
( )n
( )n
OH
+
HN
R2
CN
N
O
n
R2
10-38%
Bu
Pd(PPh3)4
(10 mol%)
CN
O
(Z)-2a
Scheme 1. Preparation of the unsaturated cyanoformamide.
toluene
100 °C, 3 h
N
Bn
We next investigated the reaction conditions for the intramo-
lecular cyanoamidation of cyanoformanilide 1a prepared as
described above. Representative results are summarized in
Table 1. Although we carried out the reaction of 1a with
Rh4(CO)12 at 130 ꢀC according to the previous report,5 the
desired product 2a could not be obtained. Likewise other
metal complexes such as Ru3(CO)12, Pt(PPh3)4, Ni(PPh3)4,
and RhCl(PPh3)3 were totally ineffective for the desired
reaction. Although the reaction did not proceed at all using
Pd(dba)2 or Pd(acac)2 without phosphine ligands (entries 1
and 2), we found that the desired a-alkylidene lactams 2a
Z/E = 91/9
NC
n
Bu
(Z)-2a
O
DMF
N
100 °C, 1 h
Bn
Z/E = 34/66
Scheme 2. Isomerization experiments of (Z)-2a.
Having established the optimum reaction conditions, we
next investigated the cyanoamidation of several alkynyl cy-
anoformanilides 1b–e and alkynyl cyanoformamides 1f–k
(Table 2). The palladium-catalyzed cyclization of formani-
lides 1b–c, which have different alkyl substituents such as
n-C10H21 and t-Bu, occurred to give the corresponding ox-
indoles in good yields (entries 1 and 2). The reaction of 1d,e
having Ph and CH2OTBS as an alkynyl side chain proceeded
slowly even at 130 ꢀC, and gave the corresponding oxindoles
2d and 2e in moderate yields (entries 3 and 4). In contrast to
these results, the same reaction of acyclic cyanoformamide
1f took place smoothly to furnish the desired lactam 2f in
84% yield as a single isomer (entry 5). The reaction of cya-
noformamide 1g, which was easily prepared from a-amino
acid derivative, also occurred cleanly to provide the mono-
substituted lactam 2g in 67% yield. The reaction of L-valine
and L-proline derivatives 1h–j provided the disubstituted lac-
tam 2h and bicyclic lactams 2i,j in good yields (entries 7–9).
Furthermore, the cyclization of a,a-disubstituted amino acid
derivative 1k afforded the desired product 2k without any
troubles (entry 10). In this way, the Pd-catalyzed carbonyla-
tive cyclization of non-aromatic substrates 1f–k proceeds
exclusively in a 5-exo mode with (Z)-selectivity, which
Table 1. Survey of the intramolecular cyanoamidation of 1aa
n
n
Bu
Bu
CN
O
catalyst (10 mol %)
solvent, 100 °C, 3 h
CN
N
O
N
Bn
Bn
1a
2a
Entry
Catalyst
Solvent
Yieldb (%)
Z/E Ratio
1
2
3
4
5
6
7e
8
Pd(dba)2
Pd(acac)2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
DMF
0
0
0
39
45
97
97
71
—
—
Pd(acac)2/4PnBu3
Pd(acac)2/4PPh3
Pd(acac)2/2dppbd
Pd(PPh3)4
—
c
c
73/27
69/31
21/79
Pd(PPh3)4
Pd(PPh3)4
a
All reactions were carried out under Ar.
Isolated yield.
A trace amount of (E)-isomer was obtained.
1,4-Bis(diphenylphosphino)butane.
The reaction was carried out at 130 ꢀC.
b
c
d
e

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Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
Table 2. Pd-catalyzed cyanoamidation of alkynes 1b–ka
Entry
Substrates
Time (h)
Products
Yieldb (%) Entry
Substrates
Time (h)
Products
Yield (%)
Me
Me
O
n
CN
O
n
C10H21
C10H21
CN
O
CN
CN
1
3
98c
6
3
67
N
Me
N
N
Bn
O
N
Bn
TBDPSO
1g
Me
TBDPSO
2g
1b
2b
t
n
t
n
Bu
Bu
Bu
CN
Bu
CN
CN
O
CN
MeO
MeO
2
3
4
3
8
88d
7
8
4
1
68
77
O
N
Bn
O
N
O
N
Bn
N
Me
1c
1h
2c
Me
2h
n
Ph
Ph
CN
Bu
n
Bu
CN
O
CN
O
MeO
MeO
45e
CN
N
O
N
Bn
N
O
N
N
Bn
1i
2d
1d
2i
n
TBSO
n
Bu
Bu
CN
O
OTBS
CN
O
TBSO
CN
TBSO
8
1
57e
9
1
4
82
84
CN
N
O
N
O
N
1e
Bn
2e
1j
Bn
2j
Me
Ph
Me
CN
Ph
CN
CN
O
MeO
MeO
CN
5
84
10
O
N
Bn
O
N
O
N
Bn
N
Me
1f
1k
Me
2f
2k
a
All reactions were carried out using 10 mol % of Pd(PPh3)4 in xylene at 130 ꢀC.
Isolated yield.
Z/E Ratio was 64/36.
Z/E Ratio was 86/14.
Z/E Ratio was >90/10.
b
c
d
e
Ph
means that the substituents have little effect on this
cyclization.
Ph
CN
CN
Pd(PPh3)4 (10 mol %)
N
Bn
O
N
Bn
xylene, 130 °C, 1 h
89%
O
We further examined the scope and limitations of the palla-
dium-catalyzed intramolecular cyanoamidation. For this
purpose, this protocol was applied to the cyclization of cya-
noformamides 3, 5, and 7 possessing alkyl chains of differ-
ent lengths (Scheme 3). As expected, cyanoformamide 3
was successfully cyclized in the presence of 10 mol % of
Pd(PPh3)4. The reaction gave the desired six-membered
lactam 4 regio- and stereoselectively in 89% yield. Further-
more, by the same treatment of 5 as 3, the corresponding
seven-membered lactam 6 was obtained in good yield as
a single isomer. This method could be also applied to the
synthesis of b-lactam, while the chemical yield of 8 was
somewhat low due to the poor reactivity of the substrate
and the instability of the product. The stereochemistry of
all products was determined to be Z by NOE experiments.
3
4
Ph
Ph
Pd(PPh3)4 (10 mol %)
CN
O
CN
N
Bn
xylene, 130 °C, 1 h
79%
N
Bn
O
5
6
Bn
N
Bn
Pd(PPh3)4 (10 mol %)
N
Me
xylene, 130 °C, 10 h
23%
O
Me
O
CN
NC
8
7
Scheme 3. Application to the synthesis of four-, six-, and seven-membered
lactams.
To expand the utility of this reaction, we next investigated
the intramolecular cyanoamidation of various unsaturated
cyanoformamides (Eqs. 3–6). As reported in our preliminary
communication,10 the reaction of 1,1-disubstituted alkenes
9a,b proceeded cleanly with perfect regioselectivity to
afford the cyclized adducts 10a,b, which had a quaternary
carbon center, in excellent yield. The presence of a protecting
group was not critical, since N–H cyanoformamide 9c was
similarly transformed into its lactam 10c in 68% yield (Eq.
3). Unexpectedly, the reaction of monosubstituted alkene
9d did not afford the desired product 10d and six-membered

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2981
Pd(PPh3)4
(10 mol %)
lactam 11, whose structure was identical with the authentic
CN
O
Me
2-quinolinol, was obtained in high yield as the single product
(Eq. 4). On the other hand, in the case of trisubstituted alkene
9e, the reaction did occur in exo mode, giving Heck-type
adduct 12 in 18% yield, but not the desired product 10e,
together with 59% yield of the starting material (Eq. 5).
Finally, we applied this reaction to the allenyl cyanoform-
amides 9f under the same reaction conditions (Eq. 6). In
fact, the desired cyanide 10f was obtained only in 15% yield
along with 24% of the six-membered lactam 13. In all cases
except for the 1,1-disubstituted alkenes 9a–c, the products
derived from elimination of HCN were obtained (Eqs. 4–6).
LDA, MeI
10a
O
(7)
xylene
130 °C, 18 h
THF
N
Bn
N
Bn
−78 °C to rt
12 h, 6%
10e
12
reductive
elimination
(R3 = H)
10
Ln
Pd(0)
Pd CN
H
9
R3
+
12
R3
R1
CN
oxidative
addition
R1
CN
Ln
Pd
Ln
Pd
Although it was revealed that this reaction could not be ap-
plied tovarious unsaturated cyanoformamides, weconsidered
these results would be useful for the mechanistic study on the
intramolecular cyanoamidation, in short, the elimination of
HCNwouldoccurviab-hydrideeliminationfromthe reaction
intermediate. Alternative possibility of direct elimination
from 10 can be ruled out based on the following experiment
(Eq. 7). When 10e, prepared from 10a, was treated with the
same reaction conditions as the Pd(0)-catalyzed cyclization,
the production of 12 was not observed at all.15 Taking into ac-
count these results, a plausible mechanism of the intramolec-
ular cyanoamidation is shown in Scheme 4. The reaction
would be initiated by the oxidative addition of the C–CN
bond of 9 to Pd(0) giving the Pd(II) complex 14.
O
N
O
N
-elimination
R2
R2
cyanopalladation
(R3 = Me)
15
carbopalladation
16
R1
R3
Ln
Pd
CN
O
N
(R1 H)
R2
14
Scheme 4. A plausible mechanism of the Pd(0)-catalyzed intramolecular
cyanoamidation of 9.
palladium(II) cyano complex,16 which lead to the low yield
of the Heck-type adduct. Alternative possibility of the inser-
tion process via cyanopalladation can be ruled out17 from the
results that cyanoamidation product 10e was not detected at
all in Eq. 5 as well as in the results of Eq. 7. Further detailed
mechanistic aspects are under investigations.
CN
Pd(PPh3)4
(10 mol %)
(3)
O
COCN
xylene
130 °C, 3 h
Finally, application of this method to the synthesis of eser-
methole18 20 was examined (Scheme 5) by using the cy-
clized adduct 10b bearing both a quaternary carbon center
and a b-cyano group. Hydrolysis of nitrile 10b into amide
17 with hydrogen peroxide was followed by the reductive
cyclization with LiAlH4 to give the tricyclic product 18,
which possesses a core structure of pyrrolo[2,3-b]indole al-
kaloids. The functionalization of the aromatic ring of 18 was
accomplished by the two-step sequence: methoxycarbonyla-
tion and bromination with NBS (N-bromosuccinimide) to
give 19 in good yield. The successive treatment with sodium
methoxide in the presence of cuprous iodide19 and LiAlH4
afforded the desired esermethole 20. Consequently, it has
been shown that the intramolecular cyanoamidation of 1,1-
disubstituted alkenyl cyanoformamides would be a novel
method for the preparation of related alkaloids.20,21
N
R
N
R
9a (R = Bn)
9b (R = Me)
9c (R = H)
10a, 100%
10b, 99%
10c, 68%
CN
O
Pd(PPh3)4
(10 mol %)
COCN
(4)
(5)
N
H
xylene
130 °C, 4 h
N
H
O
N
H
9d
11, 96%
10d
CN
O
Pd(PPh3)4
(10 mol %)
xylene
130 °C, 18 h
O
O
COCN
N
Bn
N
Bn
9e
N
Bn
12, 18%
10e
NC
i
i
Pr
Pr
i
Pd(PPh3)4
(10 mol %)
Pr
Me
Me
CONH2
O
+
(6)
a
b
c,d
COCN
NH
xylene
130 °C, 8 h
10b
N
Bn
N
Bn
O
N
Bn
10f, 15%
N
Me
17
N H
Me
9f
13, 24%
18
Me
Me
Br
MeO
e,f
N
H
N
CO2Me
Me
N
N H
Me
esermethole (20)
The subsequent insertion of the alkene moiety of 14 into the
Pd–CN bond via carbopalladation should afford the inter-
mediate 15, which would produce cyanoamidation product
10 and Pd(0) catalyst in the case of the substrates without
b-proton (R3¼H). In contrast, from the substrates bearing
a b-proton (R3¼CH3), b-hydride elimination proceeds
predominantly to provide the alkene 12 and inactive
Me
19
Scheme 5. Application to the synthesis of esermethole (20). Reagents and
conditions: (a) 30% H2O2, 1 N NaOH, MeOH, 0 ꢀC, 5 h, 77%; (b) LiAlH4,
THF, reflux, 2 h, 57%; (c) ClCO2Me, Et3N, DMAP, CH2Cl2, 0 ꢀC, 2 h, 78%;
(d) N-bromosuccinimide, DMF, 0 ꢀC, 2 h, 92%; (e) CuI, NaOMe, MeOH/
DMF, 120 ꢀC, 2 h, 70%; (f) LiAlH4, THF, reflux, 2 h, 96%.

2982
Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
In summary, we have developed a novel method for the syn-
thesis of four- to seven-membered functionalized lactams by
the palladium-catalyzed intramolecular cyanoamidation of
alkynyl and alkenyl cyanoformamides. Further detailed
investigations of another type of cyclization and further
applications of the obtained products are underway in this
laboratory.
silica gel with hexane/EtOAc (10/1) to give 9a (502 mg,
81%).
3.3.2. General procedure for Method B. To a solution
of N-benzyl-2-isopropenylaniline (3.20 g, 14.6 mmol) in
CH2Cl2 (30 mL) was added pyridine (1.77 mL, 21.9 mmol)
followed by triphosgene (1.51 g, 5.10 mmol) at ꢁ78 ꢀC. The
reaction mixture was warmed up to room temperature,
diluted with CHCl3, and washed with 1 N HCl and brine.
The organic phase was dried over MgSO4, filtered, and con-
centrated under reduced pressure to give the crude chloro-
carbamate. To a solution of the crude chlorocarbamate in
a mixture of 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 and addition of water,
the aqueous solution was extracted with CHCl3 (three
times). The organic phase was dried over MgSO4 and con-
centrated under reduced pressure. The obtained residue
was purified by column chromatography on silica gel with
hexane/EtOAc (95/5) to give 9a (3.83 g, 95%).
3. Experimental
3.1. General
Nominal (LRMS) and exact mass (HRMS) spectra were re-
corded on a JEOL JMS-01SG-2 or JMS-HX/HX 110A mass
1
spectrometer. H and 13C NMR spectra were registered on
JEOL JNM-LA500 using TMS as an internal standard
(s¼singlet, d¼doublet, dd¼double doublet, ddd¼doublet
of double doublets, t¼triplet, q¼quartet, m¼multiplet, br¼
broad). Optical rotations were measured in CHCl3 with a
JASCO DIP-360 digital polarimeter unless otherwise noted.
For column chromatography, Kanto Silica gel 60 (spherical,
63–210 mm) was employed and preparative thin-layer chro-
matography (PTLC) was carried out using Silica gel 60
(Merck).
3.3.3. General procedure for Method C. N-Benzylcyano-
formamide was prepared according to Method A.
To a solution of benzylamine (1.00 g, 9.34 mmol) in ether
(10 mL) was added an ether solution of carbonyl cyanide
(15 mL), as described above, at room temperature and the re-
action mixture was stirred at the same temperature for 2 h.
The organic solution was washed with saturated aqueous
NaOH and brine, dried over MgSO4, and concentrated under
reduced pressure. The obtained residue was purified by re-
crystallization from hexane/AcOEt to give N-benzylcyano-
formamide (1.28 g, 86%) as a yellow solid.
3.2. Materials
Unless otherwise noted, materials were purchased from
Tokyo Kasei Co., Aldrich Inc., and other commercial
suppliers and were used without purification. TCNEO
(¼tetracyanoethyleneoxide) was prepared according to the
literature procedure.12a
3.3. General procedure for the preparation
of unsaturated cyanoformamides (Methods A–C)
3.3.3.1. N-Benzylcyanoformamide. Yellow solid; mp
70–72 ꢀC (hexane/EtOAc); 1H NMR (CDCl3, 500 Hz)
d 4.39 (d, 2H, J¼6.1 Hz), 7.23 (d, 2H, J¼6.7 Hz), 7.33–
7.36 (m, 3H), 7.53 (br, 1H); 13C NMR (CDCl3, 126 Hz)
d 44.1, 111.3, 127.9, 128.2, 128.9, 135.1, 143.2; IR
(CHCl3) 2237, 1709, 1520 cmꢁ1; MS (EI+) 160 (M+, 100).
Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49.
Found: C, 67.55; H, 5.10; N, 17.63.
Cyanoformamides 1a–e10 were prepared according to our
preliminary report. Cyanoformamides 1g–k and 9a–f were
prepared from the corresponding unsaturated amines by us-
ing Method A or Method B. Cyanoformamides 1f, 3, 5 and 7
were prepared from the corresponding alkynol by using
Method C.
3.3.1. General procedure for Method A. Carbonyl cyanide
was prepared according to the reported paper.12a
To a solution of 3-pentyn-1-ol (500 mg, 5.95 mmol), N-ben-
zylcyanoformamide (1.05 g, 6.55 mmol), and triphenyl-
phosphine (1.87 g, 7.14 mmol) in THF (20 mL) was added
diisopropyl azodicarboxylate (3.90 mL, 40% solution in tol-
uene) and the reaction mixture was stirred at 60 ꢀC for 2 h.
After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure. The obtained resi-
due was purified by column chromatography on silica gel
with hexane/EtOAc (5/1) to give 1f (517 mg, 38%).
To a suspension of TCNEO (5.00 g, 34.7 mmol) in ether
(20 mL) was added Me2S (2.59 mL, 34.0 mmol) at 0 ꢀC. Af-
ter stirred at 0 ꢀC for 1 h, the mixture was filtered with ether
(15 mL) to give the carbonyl cyanide solution (w1.0 M) in
ether, which was used for the following reaction without
further purification. This material is stable for a few months
in a refrigerator.
3.3.3.2. N-Benzyl-N-[2-(hex-1-ynyl)phenyl]cyanoform-
amide (1a). Colorless oil; 1H NMR (CDCl3, 500 Hz)
d 0.96 (m, 3H), 1.46 (m, 2H), 1.57 (m, 2H), 2.40 (t, 2H,
J¼7.2 Hz), 4.49 (d, 1H, J¼14.0 Hz), 5.31 (d, 1H, J¼
14.0 Hz), 6.86 (d, 1H, J¼7.9 Hz), 7.16–7.36 (m, 7H), 7.51
(dd, 1H, J¼1.4, 7.8 Hz); 13C NMR (CDCl3, 126 Hz)
d 13.4, 19.1, 21.9, 30.4, 52.0, 75.7, 97.9, 110.8, 124.4,
128.3, 128.6, 129.4, 129.5, 129.8, 133.5, 134.5, 139.1,
145.3; IR (CHCl3): 2232.2, 1680.7 cmꢁ1; MS (EI+) m/z
To a solution of N-benzyl-2-isopropenylaniline3b (500 mg,
2.24 mmol) in ether (2.5 mL) was added an ether solution
of carbonyl cyanide (3.5 mL), as described above, at room
temperature and the reaction mixture was stirred at the
same temperature for 4 h. The organic solution was washed
with saturated aqueous NaOH solution and brine, dried over
MgSO4, and concentrated under reduced pressure. The ob-
tained residue was purified by column chromatography on

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2983
(relative intensity) 316 (M+, 25), 184 (100). HRMS (EI+)
C21H20N2O: (M+) 316.1576. Found: 316.1569.
3.3.3.8. N-(1-tert-Butyldiphenylsilyloxyhex-4-yn-2-yl)-
N-methylcyanoformamide (1g). White solid; mp 82–
1
84 ꢀC; H NMR (CDCl3, 500 Hz, mixture of the rotamers)
3.3.3.3. N-Benzyl-N-[2-(dodec-1-ynyl)phenyl]cyano-
formamide (1b). Yellow oil; H NMR (CDCl3, 500 Hz)
d 1.06 (s, 9H), 1.73 (s, 3H), 2.30–2.43 (m, 2H), 2.80 (s,
2H), 3.22 (s, 1H), 3.58–3.78 (m, 2H), 4.41–4.53 (m, 1H),
7.38–7.46 (m, 6H), 7.61–7.64 (m, 4H); 13C NMR (CDCl3,
126 Hz, mixture of the rotamers) d 3.3, 14.0, 18.4, 18.9,
19.0, 19.2, 22.6, 26.6, 26.7, 26.8, 31.5, 32.6, 55.6, 60.6,
62.2, 62.7, 72.7, 73.5, 78.6, 79.9, 110.7, 110.8, 127.9,
128.0, 130.06, 130.08, 130.11, 130.15, 132.38, 132.41,
132.6, 132.7, 135.52, 135.56, 135.59, 145.8, 146.2; IR
(CHCl3) 2236, 1674 cmꢁ1; MS (EI+) m/z (relative intensity)
361 (Mꢁt-Bu, 100). Anal. Calcd for C25H31N2O2Si: C,
71.73; H, 7.22; N, 6.69. Found: C, 71.73; H, 7.25; N, 6.68.
1
d 0.87 (t, 1H, J¼7.0 Hz), 1.27–1.31 (m, 12H), 1.42 (m, 2H),
1.59 (m, 2H), 2.39 (t, 1H, J¼7.2 Hz), 4.49 (d, 1H, J¼
14.0 Hz), 5.32 (d, 1H, J¼14.3 Hz), 6.86 (d, 1H, J¼7.9 Hz),
7.18 (m, 2H), 7.22 (m, 1H), 7.27 (m, 3H), 7.35 (m, 1H), 7.51
(dd, 1H, J¼7.8, 1.4 Hz); 13C NMR (CDCl3, 126 Hz) d 14.0,
19.4, 22.6, 28.4, 28.9, 29.0, 29.2, 29.4, 29.5, 31.8, 52.0, 75.7,
98.0, 110.8, 124.4, 128.3, 128.5, 128.6, 129.5, 129.8, 133.5,
134.6, 139.1, 145.3; IR (CHCl3) 2231, 1682 cmꢁ1; MS (CI+)
m/z (relative intensity) 401 (MH+, 100). HRMS (CI+)
C27H33N2O: (MH+) 401.2593. Found: 401.2602.
3.3.3.9. N-((3S,4S)-4-Methoxy-2-methyl-6-phenylhex-
5-yn-3-yl)-N-methylcyanoformamide (1h). Colorless oil;
1H NMR (CDCl3, 500 Hz) d 0.82–0.95 (m, 6H), 0.96–1.08
(m, 3H), 1.40 (m, 2H), 1.50 (m, 2H), 2.14–2.37 (m, 3H),
2.97–3.24 (m, 3H), 3.35 (m, 3H), 3.69 (dd, 1H, J¼
10.4 Hz, 3.7 Hz), 4.17–4.36 (m, 1H); 13C NMR (CDCl3,
126 Hz, mixture of the rotamers) d 13.4, 18.2, 19.0, 19.1,
19.6, 19.9, 21.8, 21.9, 25.2, 25.7, 29.9, 30.3, 30.5, 56.8,
57.0, 69.4, 70.9, 71.7, 75.0, 88.8, 90.6, 110.8, 110.9,
146.4, 147.2; IR (CHCl3) 2360, 1670 cmꢁ1; MS (EI+) m/z
(relative intensity) 264 (M+, 1), 207 (21), 44 (100). HRMS
(EI+) C15H24N2O2: (M+) 264.1838. Found: 264.1846.
3.3.3.4. N-Benzyl-N-[2-(3,3-dimethylbut-1-ynyl)phe-
nyl]cyanoformamide (1c). Yellow oil; H NMR (CDCl3,
1
500 Hz) d 1.30 (s, 9H), 4.50 (d, 1H, J¼14.3 Hz), 5.28 (d,
1H, J¼14.3 Hz), 6.88 (dd, 1H, J¼8.1, 1.1 Hz), 7.17 (m,
2H), 7.22 (dd, 1H, J¼7.8, 7.8 Hz), 7.27 (m, 1H), 7.33 (dd,
1H, J¼7.6, 7.6 Hz), 7.49 (d, 1H, J¼7.6 Hz); 13C NMR
(CDCl3, 126 Hz) d 28.0, 30.5, 52.0, 74.4, 105.8, 110.9,
124.4, 128.3, 128.6, 129.1, 129.4, 129.7, 133.1, 134.4, 139.2,
145.4; IR (CHCl3) 2360, 2235, 1680 cmꢁ1; MS (EI+) m/z
(relative intensity) 316 (M+, 12). HRMS (EI+) C21H20N2O:
(M+) 316.1576. Found: 316.1580.
3.3.3.5. N-Benzyl-N-[2-(2-phenylethynyl)phenyl]cyano-
formamide (1d). Red oil; 1H NMR (CDCl3, 500 Hz) d 4.63
(d, 1H, J¼14.3 Hz), 5.29 (d, 1H, J¼14.3 Hz), 6.95 (d, 1H,
J¼7.9 Hz), 7.21 (m, 6H), 7.35 (m, 4H), 7.48 (m, 2H), 7.59
(dd, 1H, J¼1.5, 7.6 Hz); 13C NMR (CDCl3, 126 Hz)
d 52.1, 84.1, 95.9, 110.7, 121.8, 123.5, 128.3, 128.4,
128.5, 129.0, 129.3, 129.4, 129.9, 131.6, 133.1, 134.1,
3.3.3.10. 2-[(S)-2-((S)-1-Methoxyhept-2-ynyl)pyrroli-
din-1-yl]-2-oxoacetonitrile (1i). Colorless oil; [a]2D0 ꢁ139
1
(c 1.03, CHCl3); H NMR (CDCl3, 500 Hz, mixture of the
rotamers) d 0.85 (m, 3H), 1.33–1.45 (m, 4H), 1.77–1.86
(m, 1H), 2.02–2.27 (m, 5H), 3.26–3.33 (m, 3H), 3.34–3.78
(m, 2H), 4.09 (m, 1H), 4.23–4.45 (m, 1H); 13C NMR
(CDCl3, 126 Hz, mixture of the rotamers) d 13.3, 18.08,
18.16, 21.6, 21.7, 22.2, 23.7, 25.8, 26.7, 30.2, 30.4, 46.6,
49.6, 56.6, 56.7, 61.3, 62.6, 69.8, 73.5, 75.0, 75.5, 88.2,
89.8, 111.1, 111.3, 142.7, 142.9; IR (CHCl3) 2935, 2231,
1661, 1413 cmꢁ1; MS (FAB+) m/z (relative intensity) 249
(MH+, 100). Anal. Calcd for C14H20N2O2: C, 67.71; H,
8.12; N, 11.28. Found: C, 67.42; H, 8.02; N, 11.25.
138.9, 145.2; IR (CHCl3) 2220, 1680, 1496, 1394 cmꢁ1
;
MS (EI+) m/z (relative intensity) 336 (M+, 22), 91 (100).
HRMS (EI+) C23H16N2O: (M+) 336.1263. Found: 336.1257.
3.3.3.6. N-Benzyl-N-{2-[3-(tert-butyldimethylsilyloxy)-
prop-1-ynyl]phenyl}cyanoformamide (1e). Colorless oil;
1H NMR (CDCl3, 500 Hz) d 0.01 (s, 6H), 0.78 (s, 9H),
4.30 (d, 1H, J¼14.3 Hz), 4.35 (s, 2H), 5.21 (d, 1H,
J¼14.0 Hz), 6.69 (d, 1H, J¼7.9 Hz), 7.00 (m, 2H), 7.11
(m, 4H), 7.22 (t, 1H, J¼7.6 Hz), 7.41 (d, 1H, J¼7.6 Hz);
13C NMR (CDCl3, 126 Hz) d 5.3, 18.2, 25.7, 51.9, 52.0,
79.5, 94.8, 110.6, 123.2, 128.4, 128.7, 129.4, 129.5, 129.9,
130.0, 133.8, 134.5, 139.0, 145.1; IR (CHCl3) 2232,
1680 cmꢁ1; MS (FAB+) m/z (relative intensity) 405 (M+,
4), 91 (100). HRMS (FAB+) C24H28N2OSi: (MH+)
405.1998. Found: 405.1983.
3.3.3.11. 2-[(S)-2-((R)-1-tert-Butyldimethylsilyloxy-
hept-2-ynyl)pyrrolidin-1-yl]-2-oxoacetonitrile (1j). Color-
1
less oil; [a]2D4 ꢁ106 (c 0.81, CHCl3); H NMR (CDCl3,
500 Hz) d ꢁ0.07 to 0.15 (m, 6H), 0.74–0.96 (m, 12H),
1.26–1.54 (m, 4H), 1.79 (m, 1H), 1.99–2.19 (m, 4H), 2.31
(m, 1H), 3.23–3.90 (m, 2H), 3.96–4.28 (m, 1H), 4.40–5.03
(m, 1H); 13C NMR (CDCl3, 126 Hz, mixture of rotamers)
d ꢁ5.5, ꢁ5.4, ꢁ5.1, ꢁ5.0, 13.3, 17.7, 17.8, 18.0, 18.1, 21.6,
21.7, 22.4, 23.9, 25.4, 25.5, 26.3, 30.1, 30.3, 46.9, 49.8,
61.2, 62.7, 64.1, 65.4, 77.9, 78.3, 86.6, 88.1, 110.9, 111.3,
142.6; IR (CHCl3) 2360, 2232, 1672 cmꢁ1; MS (EI+)
m/z (relative intensity) 291 (Mꢁt-Bu, 57), 225 (48), 73
(100). Anal. Calcd for C19H32N2O2Si: C, 65.47; H, 9.25; N,
8.04. Found: C, 65.46; H, 9.10; N, 8.00.
3.3.3.7.
N-Benzyl-N-(pent-3-ynyl)cyanoformamide
(1f). White solid; mp 63–65 ꢀC; 1H NMR (CDCl3,
500 Hz) d 1.80 (m, 3H), 2.43 (m, 2H), 3.43 (t, 1H,
J¼6.9 Hz), 3.62 (t, 1H, J¼6.4 Hz), 4.65 (s, 1H), 4.90 (s,
1H), 7.21–7.46 (m, 5H); 13C NMR (CDCl3, 126 Hz, mixture
of the rotamers) d 3.4, 17.0, 18.7, 43.9, 46.8, 47.7, 53.2, 74.0,
75.0, 78.1, 80.5, 110.6, 110.7, 127.7, 128.3, 128.4, 128.7,
128.8, 128.9, 129.0, 129.2, 134.0, 134.4, 144.8, 145.6; IR
(CHCl3) 2232, 1684 cmꢁ1; MS (FAB+) m/z (relative inten-
sity) 227 (M+, 41), 91 (100). HRMS (FAB+) C14H14N2O:
(MH+) 227.1184. Found: 227.1190.
3.3.3.12. N-(3-Methoxy-2-methyl-5-phenylpent-4-yn-
2-yl)-N-methylcyanoformamide (1k). Colorless oil; 1H
NMR (CDCl3, 500 Hz) d 1.58 (s, 3H), 1.59 (s, 3H), 3.34
(s, 3H), 3.45 (s, 3H), 5.08 (s, 1H), 7.33 (m, 3H), 7.44 (m,
2H); 13C NMR (CDCl3, 126 Hz) d 22.0, 22.3, 35.6, 57.4,
64.3, 73.9, 84.9, 87.3, 111.4, 122.2, 128.4, 128.7, 131.8,

2984
Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
145.6; IR (CHCl3) 2360, 2229.3, 1672 cmꢁ1; MS (EI+) m/z
(relative intensity) 270 (M+, 1), 186 (42), 145 (100). Anal.
Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found:
C, 71.33; H, 6.75; N, 10.23.
3.3.3.18.
N-[2-(Prop-1-en-2-yl)phenyl]cyanoform-
amide (9c). Colorless oil; 1H NMR (CDCl3, 500 Hz)
d 2.11 (s, 3H), 5.07 (m, 1H), 5.49 (m, 1H), 7.24 (m, 2H),
7.31 (m, 1H), 8.10 (d, 1H, J¼8.2 Hz), 8.31 (br, 1H); 13C
NMR (CDCl3, 126 Hz) d 24.3, 111.6, 118.1, 121.7, 121.8,
126.3, 128.1, 131.4, 134.5, 140.4, 141.6; IR (CHCl3) 3361,
1708, 1522 cmꢁ1; MS (EI+) m/z (relative intensity) 186
(M+, 13), 117 (100). HRMS (EI+) C11H10N2O: (M+)
186.0793. Found: 186.0796.
3.3.3.13. N-Benzyl-N-(5-phenylpent-4-ynyl)cyanoform-
amide (3). Colorless oil; H NMR (CDCl3, 500 Hz) d 1.82
1
(m, 1H), 1.92 (m, 1H), 2.42 (t, 1H, J¼6.9 Hz), 2.49 (t, 1H,
J¼6.7 Hz), 3.49 (m, 1H), 3.68 (m, 1H), 4.64 (s, 1H), 4.80
(s, 1H), 7.23–7.40 (m, 10H); 13C NMR (CDCl3, 126 Hz,
mixture of the rotamers) d 16.6, 16.8, 25.4, 27.1, 44.0,
47.0, 48.0, 52.8, 81.9, 82.3, 87.2, 88.0, 110.6, 110.8,
123.2, 123.3, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 128.8,
129.0, 129.2, 131.5, 131.6, 134.0, 134.6, 144.9, 145.4; IR
(CHCl3) 2231, 1677, 1429 cmꢁ1; MS (EI+) m/z (relative
intensity) 302 (M+, 8), 211 (47), 91 (100). HRMS (EI+)
C20H18N2O: (M+) 302.1419. Found: 302.1416.
3.3.3.19. N-Benzyl-N-[2-(but-2-en-2-yl)phenyl]cyano-
formamide (9e). Colorless oil; H NMR (CDCl3, 500 Hz)
1
d 1.55–2.03 (m, 6H), 3.99–4.11 (m, 1H), 5.42–5.56 (m,
1H), 5.58–5.77 (m, 1H), 6.76 (m, 1H), 7.10–7.30 (m, 7H),
7.37–7.44 (m, 1H); 13C NMR (CDCl3, 126 Hz, major peaks
of the rotamers) d 14.1, 17.1, 51.9, 111.0, 127.6, 128.1,
128.3, 128.7, 129.3, 130.2, 130.6, 131.6, 133.2, 134.7, 135.0,
144.2, 145.5; IR (CHCl3): 2360, 1678 cmꢁ1; MS (FAB+) m/z
(relative intensity) 291 (M+, 100). HRMS (FAB+)
C19H19N2O: (MH+) 291.1497. Found: 291.1505.
3.3.3.14. N-Benzyl-N-(6-phenylhex-5-ynyl)cyanoform-
amide (5). Colorless oil; H NMR (CDCl3, 500 Hz) d 1.51
1
(m, 1H), 1.58 (m, 1H), 1.66 (m, 1H), 1.77 (m, 1H), 2.37 (t,
1H, J¼6.9 Hz), 2.41 (t, 1H, J¼6.9 Hz), 3.33 (m, 1H), 3.50
(m, 1H), 4.58 (s, 1H), 4.71 (s, 1H), 7.20–7.39 (m, 10H);
13C NMR (CDCl3, 126 Hz, mixture of the rotamers)
d 18.6, 25.1, 25.4, 27.1, 44.1, 47.6, 47.7, 52.2, 81.2, 81.4,
88.6, 88.9, 110.6, 110.8, 123.5, 123.6, 127.4, 127.6, 128.0,
128.1, 128.2, 128.6, 128.8, 129.0, 131.4, 134.5, 144.7,
3.3.3.20. N-Benzyl-N-[2-(2-methylhexa-3,4-dien-3-yl)-
phenyl]cyanoformamide (9f). Colorless oil; 1H NMR
(CDCl3, 500 Hz) d 1.08 (d, 1H, J¼6.7 Hz), 1.12 (d, 2H,
J¼7.0 Hz), 1.18 (d, 3H, J¼6.6 Hz), 1.74 (d, 1H, J¼
7.3 Hz), 1.80 (d, 2H, J¼7.0 Hz), 2.80 (m, 1H), 3.97 (m,
1H), 5.43–5.61 (m, 2H), 6.61–6.68 (m, 1H), 7.09–7.14 (m,
3H), 7.24–7.31 (m, 3H), 7.40–7.49 (m, 2H); 13C NMR
(CDCl3, 126 Hz, mixture of the rotamers) d 14.3, 21.7,
21.9, 22.4, 22.8, 30.1, 30.2, 51.5, 51.6, 89.5, 89.7, 107.1,
107.4, 110.8, 111.0, 127.5, 128.3, 128.4, 128.7, 128.9, 129.1,
129.4, 129.5, 130.3, 130.4, 131.5, 131.6, 134.8, 134.9, 135.6,
135.8, 136.4, 136.5, 146.0, 146.1, 203.8, 203.9; IR (CHCl3)
2222, 1680 cmꢁ1; MS (FAB+) m/z (relative intensity) 331
(MH+, 14), 91 (100). HRMS C22H23N2O: (MH+) 331.1810.
Found: 331.1812.
145.1; IR (CHCl3) 2232, 1675 cmꢁ1
;
MS (EI+)
m/z (relative intensity) 316 (M+, 9), 225 (20), 91 (100).
HRMS (EI+) C21H20N2O: (M+) 316.1576. Found: 316.1567.
3.3.3.15.
N-Benzyl-N-(but-2-ynyl)cyanoformamide
1
(7). Colorless oil; H NMR (CDCl3, 500 Hz) d 1.84 (s,
3H), 4.06 (s, 1H), 4.18 (s, 1H), 4.71 (s, 1H), 4.88 (s, 1H),
7.27–7.40 (m, 5H); 13C NMR (CDCl3, 126 Hz, mixture of
the rotamers) d 3.4, 33.5, 38.0, 47.3, 51.3, 70.9, 71.0, 82.0,
83.0, 110.2, 110.5, 128.0, 128.5, 128.7, 128.8, 129.0,
129.2, 133.6, 134.1, 144.3, 144.6; IR (CHCl3) 2360, 2236,
1678 cmꢁ1; MS (EI+) m/z (relative intensity) 212 (M+, 13),
91 (100). HRMS (EI+) C13H12N2O: (M+) 212.0950. Found:
212.0956.
3.4. General procedure for the palladium-catalyzed
intramolecular cyanoamidation
Under an argon atmosphere, a solution of 1a (50.0 mg,
0.158 mmol) and Pd(PPh3)4 (18.2 mg, 10 mol %) in toluene
(1.6 mL) was stirred at 100 ꢀC for 2 h. Purification by col-
umn chromatograph on silica gel (AcOEt/hexane¼1/10 to
1/3 as eluant) gave the products (Z)-2a (35.3 mg, 71%)
and (E)-2a (12.9 mg, 26%) as yellow solids.
3.3.3.16. N-Benzyl-N-[2-(prop-1-en-2-yl)phenyl]cyano-
formamide (9a). Colorless oil; H NMR (CDCl3, 500 Hz)
1
d 2.11 (s, 3H), 4.09 (d, 1H, J¼14.3 Hz), 5.08 (s, 1H), 5.34
(s, 1H), 5.50 (d, 1H, J¼14.0 Hz), 6.75 (d, 1H, J¼7.9 Hz),
7.15 (m, 1H), 7.18 (m, 1H), 7.28 (m, 3H), 7.38 (m, 2H);
13C NMR (CDCl3, 126 Hz) d 23.5, 52.2, 110.8, 118.2,
128.3, 128.4, 128.7, 129.3, 130.2, 130.3, 130.5, 134.5,
3.4.1. 2-(1-Benzyl-2-oxoindolin-3-ylidene)hexanenitrile
1
(2a). Compound (Z)-2a: yellow solid; mp 123–124 ꢀC; H
134.8, 141.9, 142.2, 145.4; IR (CHCl3) 2231, 1677 cmꢁ1
;
NMR (CDCl3, 500 Hz) d 1.00 (m, 3H), 1.53 (m, 2H), 1.81
(m, 2H), 2.83 (t, 2H, J¼7.2 Hz), 4.95 (s, 2H), 6.77 (d, 1H,
J¼7.9 Hz), 7.04 (dd, 1H, J¼7.6, 7.6 Hz), 7.26–7.34 (m,
6H), 7.52 (d, 1H, J¼7.6 Hz); 13C NMR (CDCl3, 126 Hz)
d 13.7, 22.4, 29.3, 32.5, 43.8, 109.8, 117.4, 119.8, 120.6,
122.7, 125.4, 127.6, 127.9, 128.9, 132.1, 135.4, 136.7,
143.8, 164.6; IR (CHCl3) 2210, 1713, 1606, 1467, 1379,
1354 cmꢁ1; MS (EI+) m/z (relative intensity) 316 (M+, 12),
91 (100). Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37;
N, 8.85. Found: C, 79.94; H, 6.33; N, 8.86.
MS (EI+) m/z (relative intensity) 276 (M+, 1), 184 (64),
130 (100). HRMS (EI+) C18H16N2O: (M+) 276.1263. Found:
276.1267.
3.3.3.17. N-Methyl-N-[2-(prop-1-en-2-yl)phenyl]cyano-
formamide (9b). Colorless oil; H NMR (CDCl3, 500 Hz)
1
d 2.08 (s, 3H), 3.27 (s, 3H), 5.03 (s, 1H), 5.32 (s, 1H), 7.25
(m, 1H), 7.39 (m, 2H), 7.46 (m, 1H); 13C NMR (CDCl3,
126 Hz) d 23.4, 36.6, 110.8, 118.0, 128.6, 128.9, 130.2,
130.3, 136.8, 141.6, 142.3, 145.2; IR (CHCl3) 2232,
1690 cmꢁ1; MS (EI+) m/z (relative intensity) 200 (M+,
0.2). HRMS (EI+) C12H12N2O: (M+) 200.0950. Found
200.0959.
Compound (E)-2a: yellow solid; mp 102–103 ꢀC; 1H NMR
(CDCl3, 500 Hz) d 1.03 (m, 3H), 1.51 (m, 2H), 1.68 (m, 2H),
3.23 (m, 2H), 4.92 (s, 2H), 6.72 (d, 1H, J¼7.9 Hz), 7.07 (dd,

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2985
1H, J¼7.8, 7.8 Hz), 7.26–7.34 (m, 6H), 8.23 (d, 1H,
J¼7.6 Hz); 13C NMR (CDCl3, 126 Hz) d 13.7, 22.3, 29.3,
30.4, 43.5, 109.2, 118.1, 120.2, 121.4, 122.9, 123.8, 127.3,
127.8, 128.9, 131.9, 135.3, 135.4, 142.9, 166.0. Anal. Calcd
for C21H20N2O: C, 9.72; H, 6.37; N, 8.85. Found: C, 79.42;
H, 6.26; N, 8.83.
91 (100). HRMS (EI+) C23H16N2O: (M+) 336.1263. Found:
336.1266.
3.4.5. 2-(1-Benzyl-2-oxoindolin-3-ylidene)-3-tert-butyl-
dimethylsilyloxypropanenitrile (2e). Compound (Z)-2e:
colorless oil; H NMR (CDCl3, 500 Hz) d 0.20 (s, 6H),
1
0.95 (s, 9H), 4.77 (s, 2H), 4.95 (s, 2H), 6.76 (d, 1H,
J¼7.9 Hz), 7.05 (t, 1H, J¼7.3 Hz), 7.30 (m, 6H), 7.46 (d,
1H, J¼7.6 Hz); 13C NMR (CDCl3, 126 Hz) d ꢁ5.3, 18.2,
25.7, 43.8, 61.3, 109.7, 115.8, 118.6, 120.1, 122.8, 126.8,
127.5, 127.9, 128.9, 132.8, 135.3, 137.5, 143.9, 164.3; IR
(CHCl3) 2232, 1680 cmꢁ1; MS (FAB+) m/z (relative inten-
sity) 405 (M+, 14), 91 (100). HRMS (FAB+) C24H28N2OSi:
(MH+) 405.1998. Found: 405.2002.
3.4.2. 2-(1-Benzyl-2-oxoindolin-3-ylidene)dodecane-
nitrile (2b). Compound (Z)-2b: yellow solid; mp 92–94 ꢀC;
1H NMR (CDCl3, 500 Hz) d 0.88 (t, 3H, J¼6.6 Hz), 1.26–
1.32 (m, 10H), 1.37 (m, 2H), 1.49 (m, 2H), 1.82 (m, 2H),
2.82 (m, 2H), 4.94 (s, 2H), 6.76 (d, 1H, J¼7.9 Hz), 7.04
(dd, 1H, J¼7.6 Hz), 7.25–7.33 (m, 6H), 7.52 (d, 1H,
J¼7.6 Hz); 13C NMR (CDCl3, 126 Hz) d 14.1, 22.6, 27.3,
29.2, 29.3, 29.4, 29.5, 31.8, 32.7, 43.8, 109.7, 117.4, 119.9,
120.6, 122.7, 125.4, 127.6, 127.9, 128.9, 132.1, 135.4,
136.7, 143.8, 164.5; IR (CHCl3) 1714 cmꢁ1; MS (EI+) m/z
(relative intensity) 400 (M+, 17), 91 (100). Anal. Calcd for
C27H32N2O: C, 80.96; H, 8.05; N, 6.99. Found: C, 81.10;
H, 8.02; N, 7.11.
3.4.6. 2-(1-Benzyl-2-oxopyrrolidin-3-ylidene)propane-
nitrile (2f). Colorless oil; 1H NMR (CDCl3, 500 Hz)
d 2.04 (s, 3H), 2.78 (t, 2H, J¼4.7 Hz), 3.35 (t, 2H,
J¼6.1 Hz), 4.57 (s, 2H), 7.22–7.36 (m, 5H); 13C NMR
(CDCl3, 126 Hz) d 18.8, 23.8, 42.8, 47.2, 108.9, 117.2,
127.9, 128.4, 128.7, 135.6, 146.3, 163.9; IR (CHCl3) 2218,
1692 cmꢁ1; MS (EI+) m/z (relative intensity) 226 (M+, 72),
91 (100). Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24;
N, 12.38. Found: C, 74.04; H, 6.24; N, 12.12.
1
Compound (E)-2b: yellow oil; H NMR (CDCl3, 500 Hz)
d 0.88 (t, 3H, J¼6.6 Hz), 1.27–1.32 (m, 10H), 1.36 (m,
2H), 1.44 (m, 2H), 1.74 (m, 2H), 3.21 (m, 2H), 4.92 (s, 2H),
6.72 (d, 1H, J¼7.6 Hz), 7.07 (dd, 1H, J¼7.6 Hz), 7.25–7.33
(m, 6H), 8.22 (d, 1H, J¼7.3 Hz); 13C NMR (CDCl3, 126 Hz)
d 14.0, 22.6, 28.4, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 31.8,
43.5, 109.2, 118.1, 120.2, 121.5, 122.9, 123.8, 127.3, 127.8,
128.9, 131.9, 135.3, 135.4, 143.0, 166.0; IR (CHCl3)
1702 cmꢁ1; MS (EI+) m/z (relative intensity) 400 (M+, 17),
91 (100). Anal. Calcd for C27H32N2O: C, 80.96; H, 8.05;
N, 6.99. Found: C, 81.03; H, 8.05; N, 6.70.
3.4.7. 2-[5-(tert-Butyldiphenylsilyloxymethyl)-1-methyl-
2-oxopyrrolidin-3-ylidene]propanenitrile (2g). Yellow
1
solid; mp 157–162 ꢀC; H NMR (CDCl3, 500 Hz) d 1.00
(s, 9H), 1.97 (s, 3H), 2.61 (m, 1H), 2.77 (m, 1H), 2.81 (s,
3H), 3.61 (d, 1H, J¼8.9 Hz), 3.73 (m, 1H), 7.35–7.43 (m,
6H), 7.55–7.58 (m, 4H); 13C NMR (CDCl3, 126 Hz)
d 18.7, 19.0, 26.5, 28.0, 28.4, 57.7, 63.0, 107.5, 117.2, 127.9,
130.0, 130.1, 132.4, 132.7, 135.4, 135.5, 146.3, 164.5; MS
(EI+) m/z (relative intensity) 361 (Mꢁt-Bu, 100). Anal.
Calcd for C25H30N2O2Si: C, 71.73; H, 7.22; N, 6.69. Found:
C, 71.46; H, 7.15; N, 6.65.
3.4.3. 2-(1-Benzyl-2-oxoindolin-3-ylidene)-3,3-dimethyl-
butanenitrile (2c). Compound (Z)-2c: orange solid; mp
210–212 ꢀC; 1H NMR (CDCl3, 500 Hz) d 1.57 (s, 9H),
4.97 (s, 2H), 6.78 (d, 1H, J¼7.9 Hz), 7.05 (dd, 1H, J¼7.8,
7.8 Hz), 7.26–7.35 (m, 6H), 7.78 (d, 1H, J¼7.9 Hz); 13C
NMR (CDCl3, 126 Hz) d 28.8, 34.9, 43.9, 109.7, 116.6,
119.1, 122.0, 127.6, 127.8, 128.8, 129.4, 130.7, 132.1, 135.4,
137.4, 144.1, 165.4; IR (CHCl3) 2360, 1714 cmꢁ1; MS
(EI+) m/z (relative intensity) 316 (M+, 23). Anal. Calcd for
C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.47;
H, 6.43; N, 8.73.
3.4.8. 2-[(4S,5S)-5-Isopropyl-4-methoxy-1-methyl-2-oxo-
pyrrolidin-3-ylidene]-2-phenylacetonitrile (2h). Color-
1
less oil; [a]2D0 ꢁ0.24 (c 0.81, CHCl3); H NMR (CDCl3,
500 Hz) d 0.85 (d, 3H, J¼7.0 Hz), 0.94 (t, 3H, J¼7.3 Hz),
1.09 (d, 3H, J¼7.3 Hz), 1.38 (m, 2H), 1.63 (m, 2H), 2.12
(m, 1H), 2.49 (m, 2H), 3.02 (s, 3H), 3.46 (s, 2H), 3.65 (dd,
1H, J¼7.0, 2.1 Hz), 4.58 (d, 1H, J¼7.0 Hz); 13C NMR
(CDCl3, 126 Hz) d 13.7, 16.7, 20.6, 22.2, 28.7, 29.8, 30.6,
31.2, 58.7, 65.3, 78.8, 116.7, 117.4, 144.0, 163.9; IR
(CHCl3) 2360, 1692 cmꢁ1; MS (EI+) m/z (relative intensity)
264 (M+, 7), 98 (100). HRMS (EI+) C15H24N2O2: (M+)
264.1838. Found: 264.1840.
1
Compound (E)-2c: orange oil; H NMR (CDCl3, 500 Hz)
d 1.59 (s, 9H), 4.93 (s, 2H), 6.71 (d, 1H, J¼7.6 Hz), 7.06
(dd, 1H, J¼7.8, 7.8 Hz), 7.27–7.34 (m, 6H), 8.45 (d, 1H,
J¼7.9 Hz); 13C NMR (CDCl3, 126 Hz) d 29.1, 36.1, 43.7,
109.0, 118.0, 121.1, 122.8, 124.8, 127.3, 127.8, 128.9, 131.3,
131.8, 135.5, 143.3, 144.1, 164.5; IR (CHCl3) 1707 cmꢁ1
;
3.4.9. 2-((1S,7aS)-Tetrahydro-1-methoxy-3-oxo-1H-pyr-
rolizin-2(5H)-ylidene)hexanenitrile (2i). Colorless oil;
MS (EI+) m/z (relative intensity) 316 (M+, 25). HRMS
1
(EI+) C21H20N2O: (M+) 316.1576. Found: 316.1569.
[a]2D0 +37.7 (c 1.12, CHCl3); H NMR (CDCl3, 500 Hz)
d 0.94 (m, 3H), 1.37 (m, 3H), 1.65 (m, 2H), 2.13 (m, 3H),
2.45 (m, 2H), 3.24 (m, 1H), 3.41 (m, 3H), 3.71 (m, 2H),
4.36 (s, 1H); 13C NMR (CDCl3, 126 Hz) d 13.6, 22.1, 25.5,
29.4, 30.4, 31.4, 41.9, 56.3, 64.6, 79.5, 116.0, 120.8, 146.8,
164.0; IR (CHCl3) 1693 cmꢁ1; MS (EI+) m/z (relative inten-
sity) 248 (M+, 12), 109 (100). HRMS (EI+) C14H20N2O2:
(M+) 248.1525. Found: 248.1530.
3.4.4. 2-(1-Benzyl-2-oxoindolin-3-ylidene)-2-phenylaceto-
nitrile (2d). Compound (Z)-2d: red solid; mp 170–172 ꢀC;
1H NMR (CDCl3, 500 Hz) d 4.99 (s, 2H), 6.72 (t, 2H,
J¼7.3 Hz), 6.86 (m, 1H), 7.21 (m, 1H), 7.30 (m, 1H),
7.32–7.40 (m, 4H), 7.51–7.58 (m, 3H), 7.60 (m, 2H); 13C
NMR (CDCl3, 126 Hz) d 43.9, 109.7, 117.0, 117.1, 120.0,
122.3, 124.8, 127.6, 127.9, 128.8, 129.5, 130.8, 132.9, 135.3,
137.3, 144.1, 164.9; IR (CHCl3) 2212, 1713, 1603, 1469,
1353 cmꢁ1; MS (EI+) m/z (relative intensity) 336 (M+, 28),
3.4.10. 2-((1R,7aS)-Tetrahydro-1-tert-butyldimethylsilyl-
oxy-3-oxo-1H-pyrrolizin-2(5H)-ylidene)hexanenitrile

2986
Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
(2j). White solid; [a]D20 +46.1 (c 0.70, CHCl3); mp 113–
3.4.16. 2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetonitrile
(10b). Colorless oil; H NMR (CDCl3, 500 Hz) d 1.49 (s,
1
1
115 ꢀC; H NMR (CDCl3, 500 Hz) d ꢁ0.01 (s, 3H), 0.00
(s, 3H), 0.75 (s, 9H), 1.12 (m, 1H), 1.21 (m, 2H), 1.46 (m,
2H), 1.86 (m, 1H), 1.93 (m, 1H), 2.03 (m, 1H), 2.28 (t,
2H, J¼7.8 Hz), 3.06 (m, 1H), 3.41 (m, 1H), 3.56 (m, 1H),
4.55 (s, 1H); 13C NMR (CDCl3, 126 Hz) d ꢁ5.0, ꢁ4.0,
13.7, 17.7, 22.3, 25.2, 25.5, 29.5, 29.8, 31.2, 42.0, 68.0,
3H), 2.59 (d, 1H, J¼16.8 Hz), 2.83 (d, 1H, J¼16.8 Hz),
3.22 (s, 3H), 6.92 (d, 1H, J¼7.6 Hz), 7.12 (dd, 1H, J¼7.6,
7.6 Hz), 7.33 (dd, 1H, J¼7.6, 7.6 Hz), 7.45 (d, 1H,
J¼7.3 Hz); 13C NMR (CDCl3, 126 Hz) d 21.7, 25.6, 26.0,
44.4, 108.3, 116.3, 122.6, 122.7, 128.8, 130.6, 142.4,
177.1; IR (CHCl3) 1716 cmꢁ1; MS (EI+) m/z (relative inten-
sity) 200 (M+, 44), 160 (100). HRMS (EI+) C12H12N2O:
(M+) 200.0950. Found: 200.0952.
72.3, 116.2, 120.0, 149.2, 164.1; IR (CHCl3) 1693 cmꢁ1
;
MS (EI+) m/z (relative intensity) 348 (M+, 1), 291 (55), 69
(100). Anal. Calcd for C19H32N2O2Si: C, 65.47; H, 9.25;
N, 8.04. Found: C, 65.37; H, 9.35; N, 7.91.
3.4.17. 2-(3-Methyl-2-oxoindolin-3-yl)acetonitrile (10c).
Yellow oil; H NMR (CDCl3, 500 Hz) d 1.56 (s, 3H), 2.64
1
3.4.11. 2-(4-Methoxy-1,5,5-trimethyl-2-oxopyrrolidin-3-
ylidene)-2-phenylacetonitrile (2k). Pale yellow solid; mp
172–178 ꢀC; 1H NMR (CDCl3, 500 Hz) d 1.24 (s, 3H),
1.30 (s, 3H), 2.92 (s, 3H), 3.12 (s, 3H), 4.21 (s, 1H), 7.47
(m, 3H), 7.56 (m, 2H); 13C NMR (CDCl3, 126 Hz) d 19.9,
24.6, 25.5, 58.0, 62.1, 82.0, 116.2, 118.9, 128.8, 128.9,
130.1, 133.3, 145.2, 163.0; IR (CHCl3) 1690 cmꢁ1; MS
(EI+) m/z (relative intensity) 270 (M+, 100), 199 (55), 143
(54). Anal Calcd for C16H18N2O2: C, 71.09; H, 6.71; N,
10.36. Found: C, 69.78; H, 6.65; N, 10.02.
(d, 1H, J¼16.8 Hz), 2.85 (d, 1H, J¼16.5 Hz), 7.00 (d, 1H, J¼
7.6 Hz), 7.12 (t, 1H, J¼7.6 Hz), 7.30 (t, 1H, J¼7.8 Hz), 7.45
(d, 1H, J¼7.3 Hz), 9.15 (br, 1H); 13C NMR (CDCl3, 126 Hz)
d 22.1, 26.1, 45.3, 110.6, 116.5, 123.2, 123.4, 129.2, 131.4,
139.9, 180.2; IR (CHCl3) 3208, 1719 cmꢁ1; MS (EI+) m/z
(relative intensity) 186 (M+, 62), 145 (100), 128 (95).
HRMS (EI+) C11H10N2O: (M+) 186.0793. Found: 186.0790.
3.4.18. 2-Quinolinol (11). 1H NMR (CDCl3, 500 Hz) d 6.73
(d, 1H, J¼9.5 Hz), 7.22 (dd, 1H, J¼7.5, 7.5 Hz), 7.50–7.52
(m, 2H), 7.56 (m, 1H), 7.83 (d, 1H, J¼9.5 Hz), 12.7 (br, 1H);
13C NMR (CDCl3, 126 Hz) d 116.3, 119.9, 121.3, 122.7,
127.7, 130.6, 138.6, 141.1, 164.8.
3.4.12. (Z)-2-(1-Benzyl-2-oxopiperidin-3-ylidene)-2-phe-
nylacetonitrile (4). Yellow oil; H NMR (CDCl3, 500 Hz)
1
d 1.79 (dd, 2H, J¼12.1, 5.7 Hz), 2.63 (m, 2H), 3.33 (m,
2H), 4.74 (s, 2H), 7.26–7.44 (m, 10H); 13C NMR (CDCl3,
126 Hz) d 22.3, 28.2, 46.8, 51.0, 118.5, 118.8, 127.7,
128.5, 128.7, 128.8, 129.0, 129.4, 134.4, 136.5, 144.7,
3.4.19. 1-Benzyl-3-methyl-3-vinylindolin-2-one (12). Col-
orless oil; 1H NMR (CDCl3, 500 Hz) d 1.56 (s, 3H), 4.87 (d,
1H, J¼15.6 Hz), 4.95 (d, 1H, J¼15.6 Hz), 5.18 (m, 2H),
6.02 (dd, 1H, J¼17.4, 10.4 Hz), 6.73 (d, 1H, J¼7.6 Hz),
7.04 (dd, 1H, J¼7.6, 7.6 Hz), 7.15 (d, 1H, J¼7.9 Hz), 7.19
(dd, 1H, J¼6.5, 6.5 Hz), 7.25 (m, 3H), 7.30 (m, 2H); 13C
NMR (CDCl3, 126 Hz) d 22.6, 43.6, 51.2, 109.3, 115.4,
122.6, 123.9, 127.1, 127.6, 128.0, 132.8, 136.0, 138.2, 142.1,
178.9; IR (CHCl3) 1712, 1610, 1489, 1351, 1180 cmꢁ1; MS
(EI+) m/z (relative intensity) 263 (M+, 71), 91 (100). HRMS
(EI+) C18H17NO: (M+) 263.1310. Found: 263.1303.
161.6; IR (CHCl3) 3013, 1645, 1599, 1490, 1450 cmꢁ1
;
MS (EI+) m/z (relative intensity) 302 (M+, 29), 91 (100).
HRMS (EI+) C20H18N2O: (M+) 302.1419. Found:
302.1424.
3.4.13. (Z)-2-(1-Benzyl-2-oxoazepan-3-ylidene)-2-phe-
1
nylacetonitrile (6). Colorless crystal; mp 142–143 ꢀC; H
NMR (CDCl3, 500 Hz) d 1.55 (m, 2H), 1.71 (m, 2H), 2.49
(m, 2H), 3.32 (m, 2H), 4.72 (s, 2H), 7.30–7.44 (m, 10H);
13C NMR (CDCl3, 126 Hz) d 26.1, 27.1, 28.5, 47.3, 50.0,
113.8, 117.4, 127.8, 128.4, 128.6, 128.8, 129.0, 129.3,
132.2, 136.7, 156.3, 169.6; IR (CHCl3) 1641 cmꢁ1; MS
(EI+) m/z (relative intensity) 316 (M+, 18), 91 (100).
HRMS (EI+) C21H20N2O: (M+) 316.1576. Found: 316.1582.
3.4.20. 2-(1-Benzyl-3-isopropyl-2-oxoindolin-3-yl)but-2-
enenitrile (10f). Colorless oil; H NMR (CDCl3, 500 Hz)
1
d 0.94 (d, 3H, J¼6.9 Hz), 0.96 (d, 1H, J¼6.9 Hz), 1.29 (d,
3H, J¼7.6 Hz), 2.83 (m, 1H), 4.85 (d, 1H, J¼15.3 Hz), 4.96
(d, 1H, J¼15.3 Hz), 6.59 (q, 1H, J¼7.3 Hz), 6.84 (d, 1H, J¼
7.6 Hz), 7.06(dd, 1H, J¼7.6, 7.6 Hz), 7.23–7.27 (m, 4H), 7.32
(dd, 1H, J¼7.5, 7.5 Hz), 7.36 (m, 1H); 13C NMR (CDCl3,
126 Hz)d15.4,16.7,17.4,35.9,44.2,56.1,109.2,116.8, 119.5,
122.9, 124.3, 127.9, 128.7, 128.8, 129.6, 135.6, 142.9, 148.1,
175.8; MS (EI+) m/z (relative intensity) 330 (M+, 9), 91 (100).
HRMS (EI+) C22H22N2O: (M+) 330.1732. Found: 330.1734.
3.4.14. (Z)-2-(1-Benzyl-2-oxoazetidin-3-ylidene)propane-
nitrile (8). Colorless oil; 1H NMR (CDCl3, 500 Hz) d 1.93
(s, 3H), 3.72 (s, 3H), 4.54 (s, 3H), 7.25 (m, 1H), 7.34–7.40
(m, 4H); 13C NMR (CDCl3, 126 Hz) d 17.1, 46.4, 47.0,
104.0, 115.4, 128.2, 128.4, 129.1, 134.5, 151.8, 159.2; MS
(EI+) m/z (relative intensity) 212 (M+, 12), 91 (100).
HRMS (M+) C13H12N2O: (M+) 212.0950. Found:
212.0946.
3.4.21. 1-Benzyl-4-isopropyl-3-vinylquinolin-2(1H)-one
(13). Colorless oil; H NMR (CDCl3, 500 Hz) d 1.54 (d,
1
3.4.15. 2-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)aceto-
nitrile (10a). Yellow oil; 1H NMR (CDCl3, 500 Hz) d 1.57
(s, 3H), 2.64 (d, 1H, J¼16.5 Hz), 2.90 (d, 1H, J¼16.5 Hz),
4.93 (s, 2H), 6.78 (d, 1H, J¼7.6 Hz), 7.09 (t, 1H,
J¼7.6 Hz), 7.27 (m, 6H), 7.47 (m, 1H); 13C NMR (CDCl3,
126 Hz) d 22.4, 26.2, 43.8, 44.8, 109.7, 116.6, 123.1,
123.2, 127.1, 127.8, 128.9, 129.2, 130.9, 135.3, 141.8,
177.7; IR (CHCl3) 1714 cmꢁ1; MS (EI+) m/z (relative inten-
sity) 276 (M+, 19), 236 (23), 91 (100). HRMS (EI+)
C18H16N2O: (M+) 276.1263. Found: 276.1261.
6H, J¼7.3 Hz), 3.94 (m, 1H), 5.56 (m, 2H), 5.64 (m, 2H),
6.85 (m, 1H), 7.17 (dd, 1H, J¼7.8, 7.8 Hz), 7.22–7.30 (m,
5H), 7.36 (dd, 1H, J¼7.6, 7.6 Hz), 8.07 (d, 1H, J¼7.9 Hz);
MS (EI+) m/z (relative intensity) 303 (M+, 49), 212 (100).
HRMS (EI+) C21H21NO: (M+) 303.1626. Found: 303.1623.
3.5. Mechanistic study
To a solution of diisopropylamine (234 mg, 2.31 mmol) in
THF (5.0 mL), n-BuLi (1.6 M in hexane, 1.44 mL) was

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2987
added at ꢁ78 ꢀC. The reaction mixture was allowed to warm
up to 0 ꢀC, stirred for additional 15 min, and cooled again to
ꢁ78 ꢀC. A solution of 10a (580 mg, 2.10 mmol) in THF
(5.0 mL) was added slowly to the mixture. After being stirred
for 30 min, the mixture was quenched with MeI (0.39 mL,
6.30 mmol) and warmed up to room temperature (approx.
12 h). After successive addition of Et2O and a saturated
NH4Cl solution, the organic layer was separated and the
aqueous layer was extracted twice with ether. The combined
organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The re-
maining product was purified by chromatography with hex-
ane/EtOAc (3/1) to give 10e (35.6 mg, 6%) as colorless oil.
(s, 3H), 1.79 (m, 1H), 2.02 (m, 1H), 2.15 (br, 1H), 2.75
(m, 1H), 2.83 (s, 3H), 3.05 (m, 1H), 4.49 (s, 1H), 6.32 (d,
1H, J¼7.6 Hz), 6.63 (dd, 1H, J¼7.3, 7.3 Hz), 7.01 (d, 1H,
J¼7.3 Hz), 7.06 (dd, 1H, J¼7.6, 7.6 Hz); 13C NMR
(CDCl3, 126 Hz) d 26.2, 31.7, 42.7, 46.1, 52.1, 92.3,
105.0, 116.8, 122.5, 127.8, 135.7, 151.0; MS (EI+) 188 m/z
(relative intensity) (M+, 100). HRMS (EI+) C12H16N2:
(M+) 188.1313. Found: 188.1309.
To a solution of 18 (38.0 mg, 0.202 mmol), Et3N (40.8 mg,
0.404 mmol), and DMAP (1 mol %) in CH2Cl2 (2.0 mL)
was added ClCO2Me (23 mL, 0.303 mmol) at 0 ꢀC and the
reaction mixture was stirred at the same temperature for
2 h. The reaction mixture was diluted with CH2Cl2 and
washed with saturated aqueous NaHCO3 and brine. The
organic phase was dried over MgSO4 and concentrated un-
der reduced pressure. The obtained residue was purified by
column chromatography on silica gel with hexane/EtOAc
(10/1) to give carbamate18i (39.1 mg, 78%).
3.5.1. 2-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)propane-
nitrile (10e). Colorless oil; 1H NMR (CDCl3, 500 Hz)
d 0.93 (d, 3H, J¼7.0 Hz), 1.63 (m, 3H), 3.24 (q, 1H,
J¼7.0 Hz), 4.91 (m, 2H), 6.81 (d, 1H, J¼7.6 Hz), 7.11
(dd, 1H, J¼7.6, 7.3 Hz), 7.23–7.35 (m, 6H), 7.60 (d, 1H,
J¼7.3 Hz); 13C NMR (CDCl3, 126 Hz) d 13.6, 23.1, 33.0,
44.0, 49.0, 109.5, 120.7, 123.4, 123.7, 127.3, 127.9, 128.8,
128.9, 129.0, 129.3, 135.5, 142.5, 177.5; IR (CHCl3) 2244,
1712 cmꢁ1; MS (EI+) m/z (relative intensity) 290 (M+, 25),
236 (53), 91 (100). HRMS (EI+) C19H18N2O: (EI+)
290.1419. Found: 290.1418.
N-Bromosuccinimide (14.3 mg, 0.080 mmol) was added to
a solution of carbamate (18.0 mg, 0.073 mmol) in DMF
(0.7 mL) at 0 ꢀC. The mixture was stirred for 2 h at 0 ꢀC. Af-
ter addition of water, the aqueous solution was extracted
with ether. The combined organic extracts were washed
with brine, dried over Na2SO4, filtered, and evaporated. Pu-
rification by silica gel column chromatography with hexane/
AcOEt (8/1) provided 19 (21.8 mg, 92%) as a colorless oil.
3.6. Synthesis of esermethole (20)
To a solution of nitrile 10b (100 mg, 0.499 mmol) in MeOH
(5.0 mL), a solution of aqueous 30% hydrogen peroxide
(2.0 mL) and 1 M NaOH (2.5 mL) was added at 0 ꢀC. The
mixture was stirred at room temperature for 5 h. After add-
ing saturated aqueous Na2SO3, the mixture was evaporated
under reduced pressure. The residue was purified by recrys-
tallization from AcOEt to give amide 17 (84.0 mg, 77%) as
white solid.
3.6.3. Methyl 5-bromo-3,3a,8,8a-tetrahydro-3a,8-di-
methylpyrrolo[2,3-b]indole-1(2H)-carboxylate (19). 1H
NMR (CDCl3, 500 Hz) d 1.40 (s, 3H), 1.92 (m, 1H), 2.07
(m, 1H), 2.85–2.95 (m, 3H), 3.11 (m, 1H), 3.72–3.86 (m,
4H), 5.09–5.21 (m, 1H), 6.24 (d, 1H, J¼8.2 Hz), 7.07 (s,
1H), 7.18 (d, 1H, J¼10.0 Hz); MS (EI+) m/z (relative inten-
sity) 326 (83), 324 (84), 222 (100). HRMS (EI+)
C14H17BrN2O2: (M+) 324.0473. Found: 324.0469.
3.6.1. 2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetamide (17).
1H NMR (CDCl3, 500 Hz) d 1.46 (s, 3H), 2.69 (d, 1H,
J¼15.0 Hz), 2.81 (d, 1H, J¼15.0 Hz), 3.25 (s, 3H), 5.22 (br,
1H), 6.42 (br, 1H), 6.87 (d, 1H, J¼7.6 Hz), 7.09 (dd, 1H, J¼
7.5, 7.5 Hz), 7.27 (m, 1H), 7.29 (m, 1H); 13C NMR (CDCl3,
126 Hz) d 23.4, 26.4, 43.4, 45.9, 108.4, 122.7, 123.0, 128.3,
To a suspension of 19 (20.0 mg, 0.062 mmol) and CuI
(11.6 mg, 0.062 mmol) in DMF (0.3 mL) was added a so-
dium methoxide solution (0.3 mL, 0.61 mmol) prepared
from a lump of sodium (141 mg, 6.13 mmol) and absolute
MeOH (3.0 mL). After the resulting mixture was stirred at
120 ꢀC for 2 h, the reaction mixture was cooled and the in-
soluble materials were filtered off. The filtrate was concen-
trated in vacuo and H2O was added to the residue. The
aqueous layer was extracted with ether and the extract
was washed with brine and dried over MgSO4, and con-
centrated under reduced pressure. The obtained residue
was purified by column chromatography on silica gel with
hexane/AcOEt (5/1) to give methyl 3,3a,8,8a-tetrahydro-5-
methoxy-3a,8-dimethylpyrrolo[2,3-b]indole-1(2H)-carboxy-
late18i (11.9 mg, 70%).
133.3, 142.8, 171.3, 180.7; IR (CHCl3) 1693, 1612 cmꢁ1
;
MS (EI+) m/z (relative intensity) 218 (M+, 54), 160 (100).
HRMS (M+) C12H14N2O2: (M+) 218.1055. Found: 218.1052.
To a solution of amide 17 (80.0 mg, 0.367 mmol) in THF
(3.0 mL) was added LiAlH4 (189 mg, 4.99 mmol) at room
temperature and the reaction mixture was heated under re-
flux for 2 h. After cooling to 0 ꢀC, the reaction mixture
was treated with a mixture of THF and H2O (10/1) and di-
luted with AcOEt. The mixture was filtered through a pad
of Celite. The filtrate was concentrated under reduced pres-
sure to give a residue, which was diluted with AcOEt. The
organic solution was washed with saturated aqueous
Na2CO3 and brine, dried over MgSO4, and concentrated un-
der reduced pressure. The obtained residue was purified by
column chromatography on silica gel with CHCl3/MeOH
(9/1) to give pyrrolo[2,3-b]indole 18 (39.3 mg, 57%).
To a solution of methyl 3,3a,8,8a-tetrahydro-5-methoxy-3a,8-
dimethylpyrrolo[2,3-b]indole-1(2H)-carboxylate (11.0 mg,
0.039 mmol) in THF (1.0 mL) was added LiAlH4 (15.0 mg,
0.39 mmol) at room temperature and the reaction mixture
was heated under reflux for 2 h. After cooling to 0 ꢀC, the
reaction mixture was treated with a mixture of THF and
H2O (10/1) and diluted with AcOEt. The mixture was fil-
tered through a pad of Celite. The filtrate was concentrated
under reduced pressure to give a residue, which was diluted
3.6.2. 1,2,3,3a,8,8a-Hexahydro-3a,8-dimethylpyr-
rolo[2,3-b]indole (18). H NMR (CDCl3, 500 Hz) d 1.43
1

2988
Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
9. (a) Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi, K. Org. Lett.
2005, 7, 2639; (b) Nishihara, Y.; Inoue, Y.; Izawa, S.;
Miyasaka, M.; Tanemura, K.; Nakajima, K.; Takagi, K.
Tetrahedron 2006, 62, 9872.
10. Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org.
Lett. 2006, 8, 2711.
with AcOEt. The organic solution was washed with satu-
rated aqueous Na2CO3 and brine, dried over MgSO4, and
concentrated under reduced pressure. The obtained residue
was purified by column chromatography on silica gel with
CHCl3/MeOH (10/1) to give esermethole (20) (8.9 mg,
96%).
11. Hunig, S.; Schaller, R. Angew. Chem., Int. Ed. Engl. 1982,
21, 36.
3.6.4. Esermethole (20). 1H NMR (CDCl3, 500 Hz) d 1.43
(s, 3H), 1.95 (dd, 1H, J¼7.5, 5.3 Hz), 2.53 (s, 3H), 2.64
(m, 1H), 2.72 (m, 1H), 2.89 (s, 3H), 3.75 (s, 3H), 4.06 (s,
1H), 6.36 (d, 1H, J¼8.2 Hz), 6.65 (m, 2H); 13C NMR
(CDCl3, 126 Hz) d 27.4, 37.9, 38.1, 40.8, 52.8, 53.2, 56.0,
98.3, 107.5, 109.9, 112.3, 138.3, 146.6, 153.1; MS (EI+)
m/z (relative intensity) 232 (M+, 100). HRMS (EI+)
C14H20N2O: (M+) 232.1576. Found: 232.1579.
12. (a) Linn, W. J.; Webster, O. W.; Benson, R. E. J. Am. Chem. Soc.
1965, 87, 3651; (b) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall,
S. M.; Penrose, A. J.; Ramsden, C. A.; Summers, A. J. H.;
Walker, J. L.; Wrigh, D. E. J. Med. Chem. 1986, 29, 538.
13. Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2113.
14. The stereochemistry of the products was determined by the
NOE experiments, and it was already reported that E/Z isomer-
ization of several a-alkylideneoxindoles easily occurs in polar
solvents, see: J. Med. Chem. 1998, 41, 2588.
Acknowledgements
15. The same treatment of 10e in the presence of 9a did not pro-
duce 12 either, and 10a was obtained in 95% yield along
with recovery of 10e (94%).
16. (a) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Org. Chem.
2003, 3513; (b) Dobbs, K. D.; Marshall, W. J.; Grushin, V. V.
J. Am. Chem. Soc. 2007, 129, 30.
This work supported by grants from 21st Century COE Pro-
gram ‘Knowledge Information Infrastructure for Genome
Science’ and Grant-in-Aid for Scientific Research on Prior-
ity Areas 17035043 from The Ministry of Education,
Culture, Sports, Science and Technology and the Japan So-
ciety for the Promotion of Science (JSPS). Y.K. is grateful
for Research Fellowship from JSPS for Young Scientists.
17. This conclusion is consistent with the precedent reports. See
Ref. 9b and references therein.
18. (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.—Eur. J. 2007,
13, 961; (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314; (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006,
128, 4590; (d) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani,
A. Org. Lett. 2006, 8, 83; (e) Huang, A.; Kodanko, J. J.;
Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043; (f)
Rege, P. D.; Johnson, F. J. Org. Chem. 2003, 68, 6133; (g)
Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363; (h)
Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett.
2001, 42, 1049; (i) Kawahara, M.; Nishida, A.; Nakagawa,
M. Org. Lett. 2000, 2, 675; (j) Nakagawa, M.; Kawahara, M.
Org. Lett. 2000, 2, 953; (k) Elazab, A. S.; Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 2757; (l) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6500; (m) Node, M.; Hao, X.; Nishide, K.; Fuji, K. Chem.
Pharm. Bull. 1996, 44, 715; (n) Pei, X.-F.; Yu, Q.-S.; Lu,
B.-Y.; Greig, N. H.; Brossi, A. Heterocycles 1996, 42, 229;
(o) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. Tetrahedron:
Asymmetry 1994, 5, 363; (p) Ashimori, A.; Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58, 6949;
(q) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc.
1992, 114, 5566; (r) Lee, T. B. K.; Wong, G. S. K. J. Org.
Chem. 1991, 56, 872; (s) Takano, S.; Moriya, M.;
Ogasawara, K. J. Org. Chem. 1991, 56, 5982; (t) Node, M.;
Itoh, A.; Masaki, Y.; Fuji, K. Heterocycles 1991, 32, 1705;
(u) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K. Hetero-
cycles 1990, 31, 411; (v) Takano, S.; Moriya, M.; Iwabuchi,
Y.; Ogasawara, K. Chem. Lett. 1990, 109.
References and notes
1. For recent reviews, see: (a) El Ali, B.; Alper, H. Synlett 2000,
161; (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127 and references therein; For recent examples, see: (c)
ꢀ
Costa, M.; Ca, N. D.; Gabriele, B.; Massera, C.; Salerno, G.;
Soliani, M. J. Org. Chem. 2004, 69, 4607; (d) Dong, C.;
Alper, H. Tetrahedron: Asymmetry 2004, 15, 35; (e) Granito,
C.; Troisi, L.; Ronzini, L. Heterocycles 2004, 69, 5011; (f)
Ma, S.; Wu, B.; Jiang, X. J. Org. Chem. 2005, 70, 2588;
Goering, B. K. Ph.D. Dissertation, Cornell University, 1995.
2. (a) Gabriele, B.; Salerno, G.; Velti, L.; Costa, M.; Massera, C.
Eur. J. Org. Chem. 2001, 4607; (b) Negishi, E.; Coperet, C.;
Ma, S.; Liou, S.; Liu, F. Chem. Rev. 1996, 96, 365.
3. (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000,
2239; (b) Anwar, U.; Fielding, M. R.; Grigg, R.; Sridharan, V.;
Urch, C. J. J. Organomet. Chem. 2006, 691, 1476.
4. Toyofuku, M.; Fujiwara, S.; Shin-ike, T.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2005, 127, 9706.
5. Kobayashi, Y.; Kamisaki, H.; Yanada, K.; Yanada, R.;
Takemoto, Y. Tetrahedron Lett. 2005, 46, 7549.
ꢁ
6. (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597; (b) Suarez-
Castillo, O. R.; Sanchez-Zavala, M.; Melendez-Rodriguez,
ꢁ
ꢁ
M.; Castelan-Duarte, L. E.; Merales-Rıos, M. S.; Joseph-
Nathan, P. Tetrahedron 2006, 62, 3040.
7. Nozaki, K.; Sato, N.; Takaya, H. Bull. Chem. Soc. Jpn. 1996,
69, 1629.
19. Kikugawa, Y.; Miyake, Y.; Kawase, M. Chem. Pharm. Bull.
1981, 29, 1231.
8. (a) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904; (b) Nakao, Y.; Yukawa, T.; Hirata, Y.; Oda, S.; Satoh, J.;
Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7116; (c) Nakao, Y.;
Hirata, Y.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7420; (d)
Nakao, Y.; Kanyiva, K.; Oda, S.; Hiyama, T. J. Am. Chem. Soc.
2006, 128, 8146; (e) Nakao, Y.; Yada, A.; Satoh, J.; Ebata, S.;
Oda, S.; Hiyama, T. Chem. Lett. 2006, 35, 790; (f) Nakao, Y.;
Oda, S.; Yada, A.; Hiyama, T. Tetrahedron 2006, 62, 7567.
20. For reviews, see: (a) Anthoni, U.; Christophersen, C.; Nielsen,
P. H. Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1999; Vol. 13,
p 163; (b) Takano, S.; Ogasawara, K. The Alkaloids; Brossi,
A., Ed.; Academic: San Diego, CA, 1989; Vol. 36, p 225.
21. For recent synthesis, see: (a) Santos, P. F.; Srinivasan, N.;
Almeida, P.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005,

Y. Kobayashi et al. / Tetrahedron 63 (2007) 2978–2989
2989
ꢁ
61, 9147; (b) Morales-Rıos, M. S.; Rivera-Becerril, E.; Joseph-
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5482; (f) Kawasaki, T.; Ogawa, A.; Takashima, Y.;
Sakamoto, M. Tetrahedron Lett. 2003, 44, 1591; (g) Fuji, K.;
Kawabata, T.; Ohmori, T.; Shang, M.; Node, M. Heterocycles
1998, 47, 951; (h) Sun, W. Y.; Sun, Y.; Tang, Y. C.; Hu, J. Q.
Synlett 1993, 337.
Nathan, P. Tetrahedron: Asymmetry 2005, 16, 2493; (c) Fuchs,
J. R.; Funk, R. L. Org. Lett. 2005, 7, 677; (d) Kawasaki, T.;
Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.; Sekiguchi,
H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70,
2957; (e) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;