Synthesis of allyl cyanamides and N-cyanoindoles via the palladium-catalyzed three-component coupling reaction

Article abstract of DOI:10.1021/ja0272742

The palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides, allyl methyl carbonate, and trimethylsilyl azide was conducted in the presence of Pd₂(dba)₃·CHCl₃ (2.5 mol %) and dppe (1,2-bis(diphenyl

Full text of DOI:10.1021/ja0272742

Published on Web 09/10/2002
Synthesis of Allyl Cyanamides and N-Cyanoindoles via the
Palladium-Catalyzed Three-Component Coupling Reaction
†
Shin Kamijo and Yoshinori Yamamoto*
Contribution from the Research Center for Sustainable Materials Engineering, Institute of
Multidisciplinary Research for AdVanced Materials, and Department of Chemistry, Graduate
School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received June 12, 2002
Abstract: The palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides, allyl
methyl carbonate, and trimethylsilyl azide was conducted in the presence of Pd
2
(dba)
3 3
‚CHCl (2.5 mol %)
and dppe (1,2-bis(diphenylphosphino)ethane) (10 mol %). Allyl aryl cyanamides with a wide variety of
functional groups were obtained in excellent yields. This palladium-catalyzed TCCR was further utilized for
the synthesis of N-cyanoindoles. The reaction of 2-alkynylisocyanobenzenes, allyl methyl carbonate, and
trimethylsilyl azide in the presence of Pd
higher temperatures afforded N-cyanoindoles in good to allowable yields. (η -Allyl)(η -cyanamido)palladium
complex, an analogue of the bis-π-allylpalladium complex, is a key intermediate in the TCCR, and a
2
(dba)
3
3
‚CHCl (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) at
3
3
3
3
π-allylpalladium mimic of the Curtius rearrangement is involved to generate the (η -allyl)(η -cyanamido)-
palladium intermediate.
follows:1,5 (i) alkylation of cyanamide under basic conditions,
Introduction
(
ii) cyanation of amines by using cyanogen bromide, and (iii)
Cyanamides have been attracting many chemists because of
their unique structure and reactivity. They have been used not
only as a building block for heterocyclic compounds in the fields
condensation of cyanamide with carbonyl compounds. Our
recent work has focused on the synthesis of allyl cyanamides
via the palladium-catalyzed three-component coupling reaction
(TCCR) of isocyanides, allyl carbonate, and trimethylsilyl azide
1
of organic chemistry but also as a ligand for various metals in
2
those of inorganic chemistry and material science. Some
6
3
(eq 1). We anticipated that this new palladium-catalyzed
cyanamides are found in natural products and are known to
4
transformation of the allyl cyanamides could be applied for the
synthesis of N-cyanoindoles by the proper design of the starting
isocyanides.
exhibit biological activities. Although cyanamides are one of
the important classes of chemicals, their synthetic routes are
quite limited. The major approaches to the cyanamides are as
*
To whom correspondence should be addressed. E-mail: yoshi@
yamamoto1.chem.tohoku.ac.jp.
†
Institute for Multidisciplinary Research for Advanced Materials.
(
1) Reviews for the preparations and the reactions of cyanamides, see: (a)
Lantzsch, R. In Methoden der Organischen Chemie (Houben-Weyl);
Hagemann, H., Ed.; Georg Thieme Verlag: Stuttgart, 1983; Vol. E4, pp
9
74-999. (b) Grundmann, C. In Methoden der Organischen Chemie
(
Houben-Weyl); Falbe, J., Ed.; Georg Thieme Verlag: Stuttgart, 1985; Vol.
E5, pp 1611-1658. (c) Sandler, S. R.; Karo, W. Organic Functional Group
Preparations; Academic: New York, 1972; Vol. 3, p 286-287 and Vol.
2
, p174-178.
(
2) (a) Miyasaka, H.; Cl e´ rac, R.; Campos-Fern a´ ndez, C. S.; Dunbar, K. R.
Inorg. Chem. 2001, 40, 1663-1671. (b) Letcher, R. J.; Zhang, W.;
Bensimon, C.; Crutchley, R. J. Inorg. Chim. Acta 1993, 210, 183-191.
(
c) Zhang, W.; Bensimon, C.; Crutchley, R. J. Inorg. Chem. 1993, 32,
5
3
1
808-5812. (d) Hollebone, B. R.; Nyholm, R. S. J. Chem. Soc. A 1971,
32-337. (e) Pomberio, A. J. L. Inorg. Chim. Acta 1992, 198-200, 179-
86.
(3) (a) Echavarren, A. M.; Tamayo, N.; Frutos, OÄ . D.; Garc ´ı a, A. Tetrahedron
1
997, 53, 16835-16846. (b) Kn o¨ lker, H.-J.; O’Sullivan, N. Tetrahedron
994, 50, 10893-10908. (c) Dmitrienko, G. I.; Nielsen, K. E.; Steingart,
1
C.; Ming, N. S.; Wilson, J. M.; Weeratunga, G. Tetrahedron Lett. 1990,
3
Great attention has been paid to the synthesis of indoles
because these structural frameworks are often seen in many
1, 3681-3684.
(
4) (a) Falgueyret, J.-P.; Oballa, R. M.; Okamoto, O.; Wesolowski, G.; Aubin,
Y.; Rydzewski, R. M.; Praist, P.; Reindeau, D.; Ridab, S. B.; Percival, M.
D. J. Med. Chem. 2001, 44, 94-104. (b) Atwal, K. S.; Grover, G. J.;
Ahmed, S. Z.; Sleph, P. G.; Dzwonczyk, S.; Baird, A.; Normandin, D. E.
J. Med. Chem. 1995, 38, 3236-3245. (c) Manley, P. W.; Quast, U. J. Med.
Chem. 1992, 35, 2327-2340. (d) Yanagisawa, I.; Hirata, Y.; Ishii, Y. J.
Med. Chem. 1984, 27, 849-857. (e) Shimada, K.; Fujisaki, H.; Oketani,
K.; Murakami, M.; Shoji, T.; Wakabayashi, T.; Ueda, K.; Ema, K.;
Hashimoto, K.; Tanaka, S. Chem. Pharm. Bull. 1984, 32, 4893-4906.
(5) Palladium-catalyzed synthesis of cyanamides, see: (a) Cerezo, S.; Cort e´ s,
J.; Moreno-Ma n˜ as, M.; Pleixats, R.; Roglans, A. Tetrahedron 1998, 54,
14869-14884. (b) Cerezo, S.; Cort e´ s, J.; L o´ pez-Romero, J.-M.; Moreno-
Ma n˜ as, M.; Parella, T.; Pleixats, R.; Roglans, A. Tetrahedron 1998, 54,
14885-14904.
(6) As a preliminary communication, see: Kamijo, S.; Jin, T.; Yamamoto, Y.
J. Am. Chem. Soc. 2001, 123, 9453-9454.
11940
9
J. AM. CHEM. SOC. 2002, 124, 11940-11945
10.1021/ja0272742 CCC: $22.00 © 2002 American Chemical Society

Synthesis of Allyl Cyanamides and N-Cyanoindoles
A R T I C L E S
Table 1. Palladium-Catalyzed Formation of Allyl Cyanamidesa
natural products which exhibit unique biological activities.
Although many methodologies have been developed for the
construction of indoles, a new catalytic procedure compatible
7
with a wide variety of functional groups is still needed. Recent
advances of transition metal chemistry in organic synthesis have
provided new catalytic methodologies for the synthesis of
8
indoles. Various approaches utilizing isocyanides as a precursor
of indole have been developed, and they are categorized under
the following three types: (i) lithiation of 2-alkylisocyanoben-
9,10
11
zenes, (ii) radical cyclization of 2-alkenylisocyanobenzenes,
and (iii) transition-metal-catalyzed12a,13c or -mediated12,13 reac-
tion of arylisocyanides. Although many useful procedures for
the synthesis of indoles from isocyanides have been reported,
the use of a stoichiometric amount of metal salts and organo-
metallics or even more is needed in most cases. To the best of
our knowledge, there have been no reports for the palladium-
catalyzed synthesis of indoles from isocyanides as a starting
1
3c
material. We now report a new strategy for the synthesis of
N-cyanoindoles (eq 2) together with a full account on the
formation of allyl cyanamides, via the palladium-catalyzed
TCCR of isocyanides, allyl carbonate, and trimethylsilyl azide.
(
7) Reviews for the indole chemistry, see: (a) D o¨ pp, H.; D o¨ pp, U.; Langer,
U.; Gerding, B. In Methoden der Organischen Chemie (Houben-Weyl);
1
Kreher, R., Ed.; Georg Thieme Verlag: Stuttgart, 1994; Vol. E6b , pp 546-
8
48 and Vol. E6b
2
. (b) Sundberg, R. J. Indoles; Academic: London, 1996.
(
c) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000; Chapter 3. (d) Chadwick, D. J.; Jones, R. A.;
Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry; Bird, C. W.,
Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 155-
3
76. (e) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry; Pergamon: Oxford, 2000; Chapter 4. (f) Joule, J. A. In Science
of Synthesis (Houben-Wyle Methods of Molecular Transformations);
Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2000; Vol. 10, pp
3
1
1
2
61-652. (g) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-
075. (h) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113-
126. (i) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27,
225-2249.
a
To a mixture of 1 (0.5 mmol), allyl methyl carbonate (1 mmol), and
TMSN3 (1 mmol) were added Pd2(dba)3‚CHCl3 (2.5 mol %) and dppe (10
mol %) in toluene (1 mL). The mixture was stirred at room temperature
for 10 min and then at the indicated temperature for the time shown in
Table 1. b Isolated yield. Pd(acac)2 (5 mol %) was used instead of
(
8) Recent reports on the palladium-catalyzed indole synthesis, see: (a) Takeda,
A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662-5663.
c
(
b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
14
d
1
6
1
20, 6621-6622. (c) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001,
6, 412-420. (d) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
998, 63, 7652-7662. (e) Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schultz, P.
Pd2(dba)3‚CHCl3.
The reaction of 1 (0.5 mmol) was conducted with
allyl methyl carbonate (2 mmol) and TMSN (2 mmol) under Pd (dba) ‚CHCl
3
2
3
3
(
5 mol %) and dppe (20 mol %) in toluene.
G. Org. Lett. 2001, 3, 3827-3830. (f) Mori, M.; Nakanishi, M.; Kajishima,
D.; Sato, Y. Org. Lett. 2001, 3, 1913-1916. (g) Back, T. G.; Bethell, R.
J.; Parvez, M.; Taylor, J. A. J. Org. Chem. 2001, 66, 8599-8605.
9) For anionic cyclizations, see: (a) Ito, Y.; Kobayashi, K.; Saegusa, T. J.
Am. Chem. Soc. 1977, 99, 3532-3534. (b) Ito, Y.; Kobayashi, K.; Seko,
N.; Saegusa, T. Bull. Chem. Soc. Jpn. 1984, 57, 73-84. (c) Haeflinger,
Knecht, H. Tetrahedron Lett. 1984, 25, 289-292.
Results and Discussion
(
The Palladium-Catalyzed Synthesis of Allyl Cyanamides.6
The results are summarized in Table 1. Allyl methyl carbonate
and trimethylsilyl azide were added to a solution of 4-methoxy-
(
10) For other methods, see: (a) Wojciechowski, K.; Mackosza, M. Tetrahedron
Lett. 1984, 25, 4793-4794. (b) Orita, A.; Fukudome, M.; Ohe, K.; Murai,
S. J. Org. Chem. 1994, 59, 477-481.
1
-isocyanobenzene 1a, Pd2(dba)3‚CHCl3 (2.5 mol %), and dppe
(
11) For radical cyclizations, see: (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am.
Chem. Soc. 1994, 116, 3127-3128. (b) Kobayashi, Y.; Fukuyama, T. J.
Heterocycl. Chem. 1998, 35, 1043-1055. (c) Shinada, T.; Miyachi, M.;
Itagaki, Y.; Naoki, H.; Yoshihara, K.; Nakajima, T. Tetrahedron Lett. 1996,
(10 mol %) in toluene. The mixture was stirred at room
temperature for 10 min and then heated at 60 °C for 1 h to
afford N-allyl-N-(4-methoxyphenyl)cyanamide 2a in 99% yield
3
7, 7099-7102. (d) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron
Lett. 1999, 40, 6325-6327. (e) Rainier, J. D.; Kennedy, A. R. J. Org. Chem.
000, 65, 6213-6216.
(
entry 1). Only a limited number of phosphine ligands, such as
2
(
12) Transition-metal-catalyzed or -mediated cyclizations, see: [Cu] (a) Ito, Y.;
Inubushi, Y.; Sugaya, T.; Konayashi, K.; Saegusa, T. Bull. Chem. Soc.
Jpn. 1978, 54, 1186-1188. (b) Ito, Y.; Kobayashi, K.; Saegusa, T. J. Org.
Chem. 1979, 44, 2030-2032. [Ru] (c) Jones, W. D.; Kosar, W. P. J. Am.
Chem. Soc. 1986, 108, 5640-5641. (d) Hsu, G. C.; Kosar, W. P.; Jones,
W. D. Organometallics 1994, 13, 385-396. [Cr, Mo] (e) Aumann, R.;
Heinen, H. Chem. Ber. 1986, 119, 2289-2307. (f) Aumann, R.; Heinen,
H.; Kr u¨ ger, C.; Tsay, Y.-H. Chem. Ber. 1986, 119, 3141-3149. (g)
Aumann, R.; Kuckert, E.; Heien, H. Angew. Chem., Int. Ed. Engl. 1985,
dppe, tri(2-furyl)phosphine, and dppp (1,3-bis(diphenylphos-
phino)propane), showed catalytic activity, whereas the use of
the other phosphine ligands, such as PPh3, (o-tolyl)3P, Bu3P,
n
and dppb (1,4-bis(diphenylphosphino)butane), did not give the
desired product. Among the palladium sources we tested, Pd2-
(dba)3‚CHCl3 showed the best catalytic activity. Pd(acac)2 was
2
4, 978-979.
3
also effective; however, Pd(OAc)2 and [(η -C3H5)PdCl]2 were
(
13) Palladium-mediated cyclization from isocyanides, see: (a) Onitsuka, K.;
Segawa, M.; Takahashi, S. Organometallics 1998, 17, 4335-4337. (b)
Onitsuka, K.; Yamamoto, M.; Suzuki, S.; Takahashi, S. Organometallics
ineffective. As for the solvent, less polar solvents such as toluene
and octane gave the desired product. Polar solvents such as CH3-
CN, THF, and 1,2-dichloroethane did not give the allyl
cyanamide 2a. In the absence of the palladium catalyst, no
reaction took place even after heating at 60 °C for 1 h.
2
002, 21, 581-583. During the preparation of the manuscript, the
palladium-catalyzed indole synthesis from some isocyanides was reported,
see: (c) Suzuki, S.; Yamamoto, M.; Onitsuka, K.; Takahashi, S. Presented
at the 81st Annual Meetings of the Chemical Society of Japan, Tokyo,
March 2002, Abstract 3G6-28.
J. AM. CHEM. SOC.
9
VOL. 124, NO. 40, 2002 11941

A R T I C L E S
Kamijo and Yamamoto
Table 2. Palladium-Catalyzed Formation of N-Cyanoindolesa
A wide applicability for the synthesis of allyl cyanamides 2
via the palladium-catalyzed three-component coupling reaction
is shown in Table 1. The reaction proceeds regardless of the
substitution pattern on the aromatic ring of isocyanides (entries
2
b
entry
isocyanide
R
indole
yield, %
1
2
3
4
5
6
1n
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3o
3p
3q
3r
3s
H
4-Me
4- Pr
4-MeO
4-MeS
4-Ph-NdN
4-F
4-Cl
4-Br
4-CF3
4-CO Me
4-NO2
4-CN
4-CH3CO
4-Me3SiCtC
5-Me
5-MeO
5-Cl
4n
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4o
4p
4q
4r
4s
59
68
77
69
67
45
56
54
47
65
53
34
30
37
58
65
57
47
59
45
61
62
63
i
1
-3). Representative protective groups for the alcohol, such
as silyl, acetyl, methoxylmethyl, and mesyl groups, can be
tolerated under the reaction conditions (entries 4-7). The
reactions of the isocyanobenzenes with electron-withdrawing
groups 1h-k proceeded even at 40 °C to give the corresponding
products 2h-k (entries 8-11). The results indicate that the
isocyanobenzenes with electron-withdrawing groups are more
reactive than those with electron-donating groups. The isocyano-
benzenes conjugated with vinyl 1l and alkynyl groups 1m-o
afforded the corresponding products 2l-o (entries 12-15). In
the case of ortho-alkynyl isocyanobenzenes, it is important to
run reactions at 40 °C to obtain the desired allyl cyanamides
as a sole product. Naphthyl isocyanide 1p also gave the
cyanamide 2p (entry 16). Even sterically hindered 2,6-disub-
stituted isocyanobenzenes 1q and 1r gave the corresponding
products 2q and 2r (entries 17 and 18). The reaction can be
applicable for the sterically congested isocyanides. The sub-
strates having two isonitrile groups in the same molecule 1s
and 1t also afforded the corresponding dicyanamides 2s and 2t
c
7
8
c
e
9
0
11
d
1
c
c
c
c
2
12
13
14
15
16
1
1
1
7
8
9
c
c
c
5-NO2
5-CH CO
5-Me3SiCtC
3-MeO
6-MeO
20
3t
3
4t
2
2
2
1
2
3
3u
3v
3w
4u
4v
4w
a
To a mixture of 1 (0.5 mmol), allyl methyl carbonate (1 mmol), and
TMSN3 (1 mmol) were added Pd2(dba)3‚CHCl3 (2.5 mol %) and (2-furyl)3P
10 mol %) in octane (1 mL), and the mixture was stirred at room
(
(entries 19 and 20). The reaction is applicable for the substrates
b
c
temperature for 10 min and then at 100 °C for 1 h. Isolated yield. THF
was used instead of octane. d Five equivalents of allyl methyl carbonate
and five equivalents of TMSN3 were used. e Allyl cyanamide was obtained
in ∼17% yield.
having plural reaction sites.
The structures of the products were determined by spectro-
scopic data and elemental analysis. Furthermore, the structure
of 2o was unambiguously confirmed by X-ray crystallographic
analysis (see Supporting Information). It is clear that the
obtained product 2o is an allyl cyanamide and not an allyl
carbodiimide.
(1,2-bis(diphenylphosphino)ethane), dppp (1,3-bis(diphenylphos-
phino)propane), and dppb (1,4-bis(diphenylphosphino)butane)
were ineffective. The reaction proceeded even without the
addition of a phosphine ligand, but the yield of the desired indole
was low. As for the palladium complexes, Pd (dba) ‚CHCl
The Palladium-Catalyzed Synthesis of N-Cyanoindoles. In
the course of the allyl cyanamide synthesis with 2-(trimethyl-
silylethynyl)-1-isocyanobenzene 1n, we found that the cyclized
product, 3-allyl-N-cyano-2-(trimethylsilyl)indole 4n, was ob-
tained as a very minor byproduct along with the desired allyl
cyanamide 2n. Further investigation revealed that the three-
component coupling reaction of the ortho-alkynylisocyanoben-
zenes 3a-y under the palladium catalyst at 100 °C gave the
N-cyanoindoles 4a-y in good to allowable yields (eq 2). It is
essential to carry out the reaction at 100 °C to obtain the desired
N-cyanoindole as a sole product.
2
3
3
showed the best catalytic activity. Pd(PPh ) and Pd(acac) also
3
4
2
showed catalytic activity, while the use of PdCl (PPh ) resulted
2
3 2
in the formation of complex mixtures. Less polar solvents such
as octane and toluene gave the desired product in good yields.
THF was also usable, although a slight decrease of the yield
was observed. Polar solvents such as 1,2-dichloroethane, CH3-
CN, and DMF afforded only small amounts of the indole 4n.
We carried out the reactions with the isocyanides which have
an electron-donating group at the position para to the isonitrile
group. The isocyanobenzenes having alkyl substituents such as
methyl 3a and isopropyl group 3b gave the corresponding
indoles 4a and 4b in good yields (entries 2 and 3). The reaction
of isocyanobenzenes having heteroatom containing electron-
donating substituents such as methoxy 3c, methylthio group 3d,
and phenylazo group 3e also proceeded smoothly to give the
corresponding indoles 4c-e in good yields (entries 4-6). We
next investigated the reactivity of isocyanides which have an
electron-withdrawing group at the position para to the isonitrile
group. The isocyanobenzenes having halogen 3f-h, trifluoro-
methyl group 3i, methoxycarbonyl group 3j, nitro group 3k,
cyano group 3l, and acetyl group 3m afforded the corresponding
indoles 4f-m in moderate yields (entries 7-14). In the case of
3i, the addition of 5 equiv of allyl methyl carbonate and 5 equiv
of trimethylsilyl azide was needed to obtain the desired indole
The results are summarized in Table 2. Allyl methyl carbonate
and trimethylsilyl azide were added to a solution of 2-(tri-
methylsilylethynyl)-1-isocyanobenzene 1n, Pd2(dba)3‚CHCl3
15
(2.5 mol %), and tri(2-furyl)phosphine (10 mol %) in octane.
The mixture was stirred at room temperature for 10 min and
then heated at 100 °C for 1 h. 3-Allyl-N-cyano-2-(trimethylsilyl)-
indole 4n was obtained in 59% yield (entry 1). Under these
conditions, the allyl cyanamide 2n was not obtained at all.
Among the phosphine ligand we tested, tri(2-furyl)phosphine
showed the best catalytic activity when combined with the Pd2-
(dba)3‚CHCl3 complex. Other monodentate phosphine ligands
such as PPh3, (o-tolyl)3P, and tri(p-fluorophenyl)phosphine were
also effective, whereas bidentate phosphine ligands such as dppe
16
(
14) It is difficult to separate the cyanamide 2d and dibenzylideneacetone derived
4i in high yield. The isocyanide 3o conjugated with the alkynyl
group at the position para to the isonitrile group also proceeded
2 3 3
from Pd (dba) ‚CHCl .
(
15) (a) Andersen, N. G.; Keay, B. A. Chem. ReV. 2001, 101, 997-1030. (b)
Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993,
5
8, 5434-5444. (c) Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.; Khalil,
(16) The reaction with 2 equiv of allyl methyl carbonate and 2 equiv of
F.; Chahdi, F. O. Organometallics 1998, 17, 2958-2964.
trimethylsilyl azide gave 4i only in 37% yield.
1
1942 J. AM. CHEM. SOC. VOL. 124, NO. 40, 2002
9

Synthesis of Allyl Cyanamides and N-Cyanoindoles
A R T I C L E S
Scheme 1. Proposed Mechanism for the Formation of Allyl
Cyanamides and N-Cyanoindoles
Figure 1. X-ray structure of 4z.
to give the corresponding indole 4o in 58% yield (entry 15).
We further carried out the reactions with the isocyanides which
have a substituent at the position para to the alkynyl group.
The isocyanobenzenes with electron-donating substituents such
as methyl 3p and methoxy group 3q gave the corresponding
indoles 4p and 4q in 65 and 57% yields, respectively (entries
followed by the 1,2-migration of π-allylpalladium moiety from
the carbon atom to the R-nitrogen atom in B would give the
1
9
palladium-carbodiimide complex C. It should be noted that
the conversion from B to C is a π-allylpalladium mimic of the
Curtius rearrangement. The palladium-carbodiimide complex
C could be in equilibrium with the palladium-cyanamide
complex D, or more probably could be represented as a
heteroatom containing bis-π-allylpalladium analogue E.20 The
allyl cyanamides 2 are formed as a final product after the
reductive elimination of Pd(0) from the intermediate D at lower
temperature (up to 40 °C), whereas at elevated temperature (100
°C), the N-cyanoindoles 4 are formed via the insertion of the
alkyne moiety into the Pd-N bond in intermediate D21 followed
by the reductive elimination of Pd(0).
16 and 17). The isocyanobenzene having chloro 3r, nitro group
3s, and acetyl group 3t also afforded the corresponding indoles
3r-t in moderate yields (entries 18-20). The isocyanobenzene
3u conjugated with the alkynyl group at the position para to
the trimethylsilylethynyl group gave the corresponding indole
u in 61% yield (entry 21). Even 3- and 6-substituted meth-
oxyisocyanobenzenes 3v and 3w gave the corresponding indoles
4
4
v and 4w in 62 and 63% yields, respectively (entries 22 and
23). It is clear that the indole forming reaction proceeds
smoothly irrespective of the substitution site and the electronic
nature of the substituents on aromatic ring. A wide variety of
functional groups are tolerated under the reaction conditions.
One of the key steps for the proposed mechanism is the
formation of π-allylpalladium carbodiimide complex C and its
isomerization to π-allylpalladium cyanamide complex D. To
obtain a strong support for this interesting isomerization, we
synthesized the allyl carbodiimide 5 and examined the
isomerization under the palladium catalyst (eq 4). As expected,
the allyl cyanamide 2a was obtained in 88% yield.23 When 5
We next examined the isocyanobenzenes having alkyl and
aryl groups at the end of the alkynyl substituent (eq 3). The
reactions were conducted in a sequential procedure. The
isocyanides were derived from the corresponding formanilides
and used without purification, because they were unstable at
2
2
1
7
room temperature and decomposed during the isolation step.
Both propyl 3x and p-methylphenyl substituted isocyanoben-
zenes 3y afforded the corresponding indoles 4x and 4y in
moderate yields.
The structures of the products were determined by spectro-
scopic data and elemental analysis. Furthermore, the structure
of 4z, which was obtained in a manner similar to those shown
in Table 2, was unambiguously confirmed by X-ray crystal-
lographic analysis (Figure 1).
A proposed mechanism is shown in Scheme 1. First, Pd(0)
reacts with allyl methyl carbonate and TMSN3 to give the
π-allylpalladium azide A;18 CO2 and TMSOMe would be
generated at this stage. The insertion of the isocyanide between
the Pd-N3 bond in the π-allylpalladium azide A would then
give the π-allylpalladium intermediate B. Elimination of N2
(
19) Stoichiometric reaction of palladium-azido complexes with isocyanides,
see: (a) Kim, Y.-J.; Kwak, Y.-S.; Lee, S.-W. J. Organomet. Chem. 2000,
6
03, 152-160. (b) Kim. Y.-J.; Kwak, Y.-S.; Joo, Y.-S.; Lee, S.-W. J. Chem.
Soc., Dalton Trans. 2002, 144-151. (c) Beck, W.; Burger, K.; Fehlhammer,
W. P. Chem. Ber. 1971, 104, 1816-1825.
(
20) For the chemistry on bis-π-allylpalladium, see: (a) Nakamura, H.; Iwama,
H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 6641-6647. (b)
Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 4242-4243. (c) Nakamura, H.; Shim, J.-G.; Yamamoto, Y. J. Am.
Chem. Soc. 1997, 119, 8113-8114. (d) Shim, J.-G.; Nakamura, H.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 8470-8474. (e) Yoshikawa, E.;
Radhakrishnan, K. V.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 729-
731. (f) Nakamura, H.; Aoyagi, K.; Shim, J.-G.; Yamamoto, Y. J. Am.
Chem. Soc. 2001, 123, 372-377. (g) Kamijo, S.; Jin, T.; Yamamoto, Y. J.
Am. Chem. Soc. 2001, 123, 9453-9454. (h) Szab o´ , K. J. Chem.-Eur. J.
2000, 6, 4413-4421. (i) Solin, N.; Narayan, S.; Szab o´ , K. J. Org. Lett.
2
001, 3, 909-912. (j) Wallner, O. A.; Szab o´ , K. J. Org. Lett. 2002, 4,
1
563-1566.
(21) Two palladium atoms might participate in this step.
(
22) Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925-932.
(
23) It is well known that a π-allylpalladium complex is formed by the oxidative
addition of Pd(0) to CH
2 2 2
dCHCH Y (Y: halide, OCO R, OAc, OP(O)-
(
17) These isocyanides were especially unstable in concentrated pure form. Thus,
careful handling is needed. See Experimental Section.
(OR) , NR , etc.). However, to the best of our knowledge, there is no report
2
2
for the oxidative addition of Pd(0) to allyl carbodiimide (Y: NdCdNR).
See: Tsuji, J. Transition Metal Reagents and Catalysts; Wiley: New York,
2000; Chapter 4.
(18) (a) Busetto, L.; Palazzi, A. Inorg. Chim. Acta 1975, 13, 233-238. (b) Shaw,
B. L.; Shaw, G. J. Chem. Soc. A 1971, 3533-3535.
J. AM. CHEM. SOC.
9
VOL. 124, NO. 40, 2002 11943

A R T I C L E S
Kamijo and Yamamoto
Scheme 2. Transformations of 4na
tetrabutylammonium fluoride (TBAF) at 50 °C. 3-Allylindole
6
d was obtained in 70% yield. Selective deprotection of the
cyano group was achieved by treatment with MeMgBr. 3-Allyl-
-(trimethylsilyl)indole 6e was obtained in 93% yield.27
2
Conclusions
A novel synthetic route to the allyl aryl cyanamides 2 and
N-cyanoindoles 4 has been developed. The allyl aryl cyanamides
are synthesized through the palladium-catalyzed three-compo-
nent coupling reaction (TCCR) between arylisocyanides 1, allyl
carbonate, and trimethylsilyl azide. N-Cyanoindoles are syn-
thesized by the use of the arylisocyanides 3, substituted by ortho-
alkynyl groups, at higher reaction temperatures under a modified
catalyst system. Mechanistically, a very interesting step is
involved in the three-component coupling reaction, that is to
say, a π-allylpalladium mimic of the Curtius rearrangement.
Perhaps one of the most useful and powerful aspects of the
present TCCR is that a wide range of functional groups are
tolerated at the p-, m-, and even o-positions of the aromatic
ring. Further manipulation of N-cyanoindoles can provide a wide
range of indole derivatives.
a
Reagents and Conditions: (a) HCl, CH3CN, 100 °C, 75%; (b) NBS,
CH3CN, 100 °C, 85%; (c) Pd(PPh3)4 (5 mol %), CuI (10 mol %), 1-pentyne,
Et3N, 78%; (d) TBAF, THF, 50 °C, 70%; (e) MeMgBr, THF, 0 °C to room
temperature, 93%.
was heated in toluene with 10 mol % dppe at 100 °C for 1 h,
no reaction took place, and 5 was recovered.24 Accordingly, it
is very probable that the π-allylpalladium complexes C-E
intervene in the catalytic cycle of the three-component coupling
process.
Experimental Section
Typical Procedure for the Palladium-Catalyzed Synthesis of Allyl
Cyanamides.6 To a toluene solution (1.0 mL) of 4-methoxy-1-
isocyanobenzene 1a (66.6 mg, 0.5 mmol), Pd
2
(dba)
3
‚CHCl
3
(13.0 mg,
0.0125 mmol), and dppe (20.0 mg, 0.05 mmol) were added allyl methyl
carbonate (0.11 mL, 1 mmol) and trimethylsilyl azide (0.13 mL, 1
mmol) under an argon atmosphere. The solution was stirred at room
temperature for 10 min and then at 60 °C for 1 h. The reaction mixture
was cooled to room temperature and filtered through a short Florisil
pad and concentrated. The residue was purified by column chroma-
tography (silica gel, hexane-ether 10/1 to 1/1) to afford N-allyl-N-(4-
methoxyphenyl)cyanamide 2a in 99% yield (93.3 mg).
Another interesting step in the proposed mechanism is that
the insertion of the alkyne moiety to the π-allylpalladium
intermediates C-E takes place in trans manner to afford the
N-cyanoindoles 4. To obtain detailed information for the unique
cyclization, we examined the reaction of the allyl cyanamide
Typical Procedure for the Palladium-Catalyzed Synthesis of
N-Cyanoindoles. To an octane solution (1.0 mL) of 2-(trimethylsilyl-
2
n at 100 °C under the palladium catalyst (eq 5). As expected,
ethynyl)-1-isocyanobenzene 1n (99.7 mg, 0.5 mmol), Pd
2
(dba)
3
‚CHCl
3
25
the N-cyanoindole 4n was obtained in 52% NMR yield. When
n was heated in the absence of the palladium catalyst in octane
(13.0 mg, 0.0125 mmol), and tri(2-furyl)phosphine (11.6 mg, 0.05
2
mmol) were added trimethylsilyl azide (0.13 mL, 1 mmol) and allyl
methyl carbonate (0.11 mL, 1 mmol) under an argon atmosphere. The
solution was stirred at room temperature for 10 min and then at 100
°C for 1 h. The reaction mixture was cooled to room temperature and
filtered through a short Florisil pad and concentrated. The residue was
purified by column chromatography (silica gel, hexane-ether 50/1 to
at 100 °C for 1 h, no reaction took place, and 2n was recovered
quantitatively. This result indicates the existence of an equi-
librium between the π-allylpalladium intermediates C-E and
the allyl cyanamide 2. High temperature is needed for the
insertion of the alkyne moiety to the Pd-N bond in the
π-allylpalladium intermediate D.
10/1) to afford 3-allyl-2-(trimethylsilyl)-N-cyanoindole 2n in 59% yield
(74.6 mg).
We also investigated further transformations of 3-allyl-2-
trimethylsilyl-N-cyanoindole 4n obtained through the three-
component coupling reaction (Scheme 2). Selective removal of
the trimethylsilyl group was achieved by treatment with
Typical Procedure for the Sequential Reaction. Synthesis of
3
-Allyl-2-propyl-N-cyanoindole (4x). A THF solution (2 mL) of 2-(1-
pentynyl)-1-formanilide (187.3 mg, 1 mmol) and Et N (0.42 mL, 3
mmol) was cooled at 0 °C; then phosphorus oxychloride (0.11 mL,
.2 mmol) was added dropwise. After the reaction was completed,
saturated NaHCO
3
2
6
hydrogen chloride. Complete protodesilylation was attained
in CH3CN at 100 °C to give the N-cyanoindole 6a in 75% yield.
The reaction with N-bromosuccinimide (NBS) in CH3CN at 100
1
3
aqueous solution (∼1 mL) was added at 0 °C to
quench the reaction, and the product was extracted with ether (∼10
8
d,26
°
C afforded the 2-bromoindole 6b in 85% yield.
The
mL). The extract was dried with Na SO , and the solvent was removed
2
4
treatment of the obtained 2-bromoindole with 1-pentyne under
a catalytic amount of Pd(PPh3)4 and CuI afforded the 2-alkynyl-
indole 6c in 78% yield. Both the trimethylsilyl group and the
cyano group could be removed all at once by the treatment with
under vacuum at 0 °C (ice bath). THF (0.5 mL) was added immediately
to dissolve 2-(1-pentynyl)-1-isocyanobenzene 3x, and the resulting
solution was kept at 0 °C. To a THF solution (0.5 mL) of Pd
2 3
(dba) ‚
CHCl (25.9 mg, 0.025 mmol) and tri(2-furyl)phosphine (23.3 mg, 0.1
3
mmol) was added a THF solution of 2-(1-pentynyl)-1-isocyanobenzene
3x under an argon atmosphere, and the mixture was stirred for 5 min
at room temperature. Trimethylsilyl azide (0.27 mL, 2 mmol) and allyl
(
24) Yamamoto, N.; Isobe, M. Chem. Lett. 1994, 2299-2302.
25) Palladium-catalyzed synthesis of 3-allylindoles, see: (a) Cacchi, S.; Fabrizi,
G.; Pace, P. J. Org. Chem. 1998, 63, 1001-1011. (b) Iritani, K.; Matsubara,
S.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1799-1802.
(
(
26) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org.
(27) Wu, Y.-q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. Org. Lett.
2000, 2, 795-797.
Chem. 2001, 66, 4525-4542.
11944 J. AM. CHEM. SOC.
9
VOL. 124, NO. 40, 2002

Synthesis of Allyl Cyanamides and N-Cyanoindoles
A R T I C L E S
methyl carbonate (0.23 mL, 2 mmol) were then added to the reaction
mixture, and the mixture was stirred at room temperature for 10 min
and at 100 °C for 1 h. The reaction mixture was cooled to room
temperature and filtered through a short Florisil pad and concentrated.
The residue was purified by column chromatography (silica gel,
hexane-ether 50/1 to 10/1) to afford 3-allyl-2-propyl-N-cyanoindole
measurements of X-ray crystallography, NMR spectra, mass
spectra, and elemental analyses.
Supporting Information Available: Characterization data and
H NMR spectra of compounds 2k, 2n, 2p, 2t, 4a-z, 5, 6a-e
1
(PDF) and X-ray crystallographic data for 2o, 4z (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
4
x in 52% yield (116.4 mg).
Acknowledgment. We thank faculties in the Instrumental
Analysis Center for Chemistry at Tohoku University for
JA0272742
J. AM. CHEM. SOC.
9
VOL. 124, NO. 40, 2002 11945