Palladium-catalyzed intramolecular cyanoamidation of alkynyl and alkenyl cyanoformamides

Article abstract of DOI:10.1021/ol060733+

The five- to seven-membered α-alkylidene lactams were prepared in 45-99% yield by the palladium-catalyzed cyanoamidation of alkynyl cyanoformamides. The reaction proceeded exclusively in a 5-exo mode, giving the corresponding (2)-alkenes as major products

Full text of DOI:10.1021/ol060733+

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2711-2713
Palladium-Catalyzed Intramolecular
Cyanoamidation of Alkynyl and Alkenyl
Cyanoformamides
Yusuke Kobayashi, Haruhi Kamisaki, Reiko Yanada, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received March 25, 2006
ABSTRACT
The five- to seven-membered
r-alkylidene lactams were prepared in 45−99% yield by the palladium-catalyzed cyanoamidation of alkynyl
cyanoformamides. The reaction proceeded exclusively in a 5-exo mode, giving the corresponding (Z)-alkenes as major products. The reaction
was also applied to 1,1-disubstituted alkenes to afford oxindoles bearing a quaternary carbon center.
Transition-metal-catalyzed carbonylative cyclization of un-
saturated amines with use of carbon monoxide is a powerful
tool for the synthesis of lactams and various heterocyclic
compounds.1 Recent progress in this research area has
demonstrated that these compounds can be synthesized
without carbon monoxide through the use of well-designed
substrates.2 Grigg et al. explored a palladium-catalyzed
cyclization-anion capture protocol for the synthesis of
R-alkylidene oxindoles from alkynyl carbamoyl chlorides
(Scheme 1, X ) Cl, R1 ) H).3a Kambe and co-workers
reported the palladium-catalyzed intramolecular thio- and
seleno-carbamoylation of appropriate alkynes (X ) SPh and
SePh).3b Recently, our group also reported the rhodium-
catalyzed intramolecular hydroamidation of alkynyl forma-
mides (X ) H) to afford R-alkylidene-γ-lactams.4 However,
these methods have not been applied to the synthesis of
tetrasubstituted alkene derivatives with all carbon substitu-
ents. This prompted us to investigate the transition-metal-
catalyzed intramolecular cyanoamidation of alkynes A into
lactams C (X ) CN). Such nitriles C obtained by this method
Scheme 1. Lactam Synthesis by Transition-Metal Catalysts
(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, 63, 1027. (f) Ma, S.; Wu, B.;
Jiang, X. J. Org. Chem. 2005, 70, 2588.
(2) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(3) (a) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000,
2239. (b) Toyofuku, M.; Fujiwara, S.; Shin-ike, T.; Kuniyasu, H.; Kambe,
N. J. Am. Chem. Soc. 2005, 127, 9706.
would be versatile building blocks in organic synthesis and
are seen in many natural products, pharmaceuticals, and
organic materials.5 Although direct activation of the C-C
single bond by transition metals (A f B) and subsequent
(4) Kobayashi, Y.; Kamisaki, H.; Yanada, K.; Yanada, R.; Takemoto,
Y. Tetrahedron Lett. 2005, 46, 7549.
10.1021/ol060733+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/06/2006

addition of the metal complex to the C-C unsaturated bond
(B f C) should be of great synthetic value because such a
reaction provides a simultaneous installation of two C-C
bonds onto the C-C triple bond with perfect atom economy,
only a few reports are available.6 We report here a concise
synthesis of R-alkylidene lactams by the palladium-catalyzed
intramolecular cyanoamidation of alkynyl cyanoformamides.
To the best of our knowledge, this is the first report of
transition-metal-catalyzed carbonylative cyclization using
C-C bond activation.7
in the presence of PPh3 (4 equiv) instead of Pd(PPh3)4, the
yield of 2a decreased to 39% (entry 3). Similarly, the use of
other phosphine ligands only resulted in unsatisfactory results
(entries 4 and 5). 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 2 and 6). When a polar
solvent such as DMF was used, both the chemical yield and
the Z/E ratio decreased (entry 7).
Having established the optimum reaction conditions, we
next investigated the cyanoamidation of several alkynyl
cyanoformanilides (1b,c) and alkynyl cyanoformamides
(1d-h) (Table 2). The palladium-catalyzed reaction of
formanilides 1b,c, which have different substituents such as
We first investigated the reaction conditions for the
intramolecular cyanoamidation of cyanoformamide 1a. Rep-
resentative results are summarized in Table 1. Although we
Table 1. Survey of Intramolecular Cyanoamidation of 1a
Table 2. Pd-Catalyzed Cyanoamidation of Alkynes 1b-h
entrya
catalyst
Rh4(CO)12
solvent
yield (%)
Z/E ratio
1
2
3
4
5
6d
7
toluene
toluene
toluene
toluene
toluene
xylene
DMF
0
97
39
0
17
97
71
-
73/27
b
-
b
Pd(PPh3)4
Pd(acac)2/4PPh3
Pd(acac)2/4PBun
Pd(acac)2/2dppbc
Pd(PPh3)4
3
69/31
21/79
Pd(PPh3)4
a All reactions were carried out with 1a (0.158 mmol) and catalyst (10
mol %) in solvent (1.5 mL) under an argon atmosphere. b In each case, a
trace amount of E-isomer was obtained. c dppb ) 1,4-bis(diphenylphos-
phino)butane. d Carried out at 130 °C.
carried out the reaction of 1a with Rh4(CO)12 at 130 °C,4
the desired product 2a could not be obtained (entry 1).
Likewise other metal complexes such as Ru3(CO)12, Pt-
(PPh3)4, Ni(PPh3)4, and RhCl(PPh3)3 were totally ineffective.
After further experiments on cyclization, we found that Pd-
(PPh3)4 was an effective catalyst for the cyanoamidation, and
the desired R-alkylidene lactams 2a were obtained in 97%
yield as a mixture of (E)- and (Z)-isomers (entry 2).8 In
contrast, when the reaction was performed with Pd(acac)2
(5) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597. (b) Greenham, N.
C.; Moratti, S. C.; Bradley, D. D. C.; Friend, R. H.; Holmes, A. B. Nature
1993, 365, 628.
(6) (a) Nozaki, K.; Sato, N.; Takaya, H. Bull. Chem. Soc. Jpn. 1996, 69,
1629. (b) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904. (c) Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi, K. Org. Lett. 2005,
7, 2639. Palladium- and nickel-catalyzed intramolecular cyanoboration of
alkynes, see; (d) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem.
Soc. 2003, 125, 6358.
(7) For a recent review on C-C bond activation, see: (a) Jun, C.-H.
Chem. Soc. ReV. 2004, 33, 610. For recent examples of C-CN bonds
activation, see: (b) Taw, F. L.; Mueller, A. H.; Bergman, R. G.; Brookhart,
M. J. Am. Chem. Soc. 2005, 125, 9808 and references therin.
(8) The stereochemistry of the products was determined by the NOE
experiments of their 1H NMR experiments, and it was already reported
that E/Z isomerization of sevaral R-alkylideneoxindoles easily occurs in
polar solvents, see: Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.;
McMahon, G.; Tang, C. J. Med. Chem. 1998, 41, 2588.
a All reactions were carried out under an argon atmosphere. b In each
case, a trace amount of E-isomer of 2b or 2c was detected. c Products were
obtained as a mixture of 2e (38%) and 3e (39%). d Products were obtained
as a mixture of 2f (68%) and 3f (31%).
2712
Org. Lett., Vol. 8, No. 13, 2006

Ph and CH2OTBS as an alkynyl side chain, proceeded slowly
even at 130 °C, and gave the corresponding oxindoles 2b
and 2c in respective yields of 45% and 57% (entries 1 and
2). In contrast to these results, the same reaction of acyclic
cyanoformamides 1d took place smoothly to furnish the
desired lactam 2d in 84% yield as a single isomer (entry 3).
In the case of cyanoformamide 1e having a phenyl group,
the corresponding cyclized adduct 2e and the isomerized
product 3e were obtained as a 1/1 mixture in a combined
yield of 77% (entry 4). The product 3e was probably derived
from 2e via 1,3-migration of the C4 proton.9 The reaction
of cyanoformamides 1f,g, which were easily prepared from
L-valine and L-proline, also occurred smoothly to provide
the lactam 2f and bicyclic lactam 2g in good yields (entries
5 and 6). In addition, the cyclization of R,R-disubstituted
amino acid derivative 1h similarly afforded 2h in 84% yield
(entry 7). These results suggest that the Pd-catalyzed
carbonylative cyclization of nonaromatic substrates 1d-h
proceeds exclusively in a 5-exo mode and that the substit-
uents have little effect on this cyclization.
Scheme 3. The Cyclization of 1,1-Disubstituted Alkenes 8a,b
examined (Scheme 3). The reaction of 8a proceeded cleanly
with perfect regioselectivity to afford the cyclized adduct
9a, which had a quaternary carbon center, in excellent yield.
The presence of a protecting group was not critical, since
N-H cyanoformamide 8b was similarly converted into its
lactam 9b in 68% yield.10 The obtained adduct 9b was a
key intermediate for the total synthesis of physostigmine,11
which possesses a core structure of pyrrolo[2,3-b]indole
alkaloids. Therefore, this cyclization may be a novel method
for the preparation of related alkaloids.12
We further examined the scope and limitations of the
palladium-catalyzed intramolecular cyanoamidation. For this
purpose, this protocol was next applied to the cyclization of
cyanoformamides 4 and 6 possessing alkyl chains of different
lengths (Scheme 2). As expected, cyanoformamide 4 was
In summary, we have developed a novel method for the
synthesis of five- to seven-membered R-alkylidene lactams
by the palladium-catalyzed intramolecular cyanoamidation
of alkynyl and alkenyl cyanoformamides. Further detailed
investigations into the synthetic and mechanistic aspects of
this cyclization are underway in this laboratory.
Scheme 2. Application to the Synthesis of Six- and
Seven-Membered Lactams
Acknowledgment. This work was supported by grants
from 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science” and Grant-in-Aid for
Scientific Research on Priority Areas 17035043 from The
Ministry of Education, Culture, Sports, Science and Technol-
ogy.
Supporting Information Available: Experimental pro-
cedure and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
successfully cyclized in the presence of 10 mol % of Pd-
(PPh3)4. The reaction regio- and stereoselectively gave six-
membered lactam 5 in 89% yield. The stereochemistry of 5
was determined by NOE experiment. Furthermore, by the
same treatment of 6 as 4, the corresponding seven-membered
lactam 7 was obtained in good yield as a single isomer.
To expand the utility of this reaction, the intramolecular
cyanoamidation of 1,1-disubstituted alkenes 8a,b was next
OL060733+
(10) In contrast to this result, the same reaction of the corresponding
alkynes led to a complex mixture.
(11) (a) Marales-R´ıos, M. S.; Buc`ıo, M. A.; Joseph-Nathan, P. Tetra-
hedron Lett. 1994, 35, 881. (b) Julian, P. L.; Pikl, J.; Boggess, D. J. Am.
Chem. Soc. 1934, 56, 1797. (c) Node, M.; Itoh, A.; Masaki, Y.; Fuji, K.
Heterocycles 1991, 32, 1705 and references therein.
(12) (a) Kawasaki, T.; Terashima, R.; Sakaguchi, K.; Sekiguchi, K.;
Sakamoto, M. Tetrahedron Lett. 1996, 37, 7525. (b) Kawasaki, T.; Ogawa,
A.; Takashima, Y.; Sakamoto, M. Tetrahedron Lett. 2003, 44, 1591. (c)
Kawasaki, T.; Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.; Sekiguchi,
H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70, 2957.
(9) Treatment of the isolated 2e under the same reaction conditions
afforded 3e in 38% yield along with recovery of the starting material 2e
(47%).
Org. Lett., Vol. 8, No. 13, 2006
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