Rhodium-catalyzed chemo-, regio-, and enantioselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates

Article abstract of DOI:10.1021/ol052041b

(Chemical Equation Presented) We have developed a cationic rhodium(I)/modified-BINAP complex-catalyzed chemoselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates leading to a wide range of 2-pyridones. This method was successfully applied to the

Full text of DOI:10.1021/ol052041b

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4737-4739
Rhodium-Catalyzed Chemo-, Regio-, and
Enantioselective [2 2]
Cycloaddition of Alkynes with
Isocyanates
+
2 +
Ken Tanaka,*,† Azusa Wada,† and Keiichi Noguchi‡
Department of Applied Chemistry, Graduate School of Engineering, and
Instrumentation Analysis Center, Tokyo UniVersity of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
tanaka-k@cc.tuat.ac.jp
Received August 24, 2005
ABSTRACT
We have developed a cationic rhodium(I)/modified-BINAP complex-catalyzed chemoselective [2
+
2
+
2] cycloaddition of alkynes with isocyanates
leading to a wide range of 2-pyridones. This method was successfully applied to the chemo-, regio-, and enantioselective synthesis of axially
chiral 2-pyridones from unsymmetrical -diynes, bearing an ortho-substituted phenyl at one terminal position, and alkyl isocyanates.
r,ω
Transiton-metal-catalyzed [2 + 2 + 2] cycloaddition of
alkynes with isocyanates is a valuable method to construct
substituted 2-pyridones.1 The pioneering work for such a
catalytic formation of 2-pyridones was first reported by
Yamazaki using Co catalysts2 and by Hoberg using Ni
catalysts.3 Vollhardt et al. developed Co-catalyzed partially
intramolecular cycloaddition utilizing 5-isocyanatoalkynes.2c
Takahashi et al. developed the selective preparation of
pyridones from two different internal alkynes and isocyanates
by formation of an azazirconacyclopentenone followed by
transmetalation with Ni(PPh3)2Cl2 using stoichiometric amounts
of Ni and Zr.4 Yamamoto, Itoh, and co-workers developed
Ru-catalyzed cycloaddition of 1,6-diynes with isocyanates.5
Recently, Louie et al. demonstrated that Ni(cod)2/SIPr [1,3-
bis-(2,6-diisopropylphenyl)imidazolin-2-ylidene] efficiently
catalyzes cycloaddition of alkynes with isocyanates at room
temperature.3d However, the substrate scope, the efficiency,
and the selectivity remain to be improved.
† Department of Applied Chemistry.
‡ Instrumentation Analysis Center.
(1) For a review, see: Varela, J. A.; Saa`, C. Chem. ReV. 2003, 103,
3787-3801.
Although rhodium complexes are effective catalysts for
cyclotrimerization of alkynes,6 the use of a neutral rhodium
complex catalyzes only cycloaddition of tetrolic acid methyl
ester with isocyanates in low yield.7 We recently reported
(2) (a) Hong, P.; Yamazaki, H. Synthesis 1977, 50-52. (b) Hong, P.;
Yamazaki, H. Tetrahedron Lett. 1977, 1333-1336. (c) Earl, R. A.;
Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786-4800. (d) Diversi, P.;
Ingrosso, G.; Lucherini, A.; Malquori, S. J. Mol. Catal. 1987, 40, 267-
280. (e) Bonaga, L. V. R.; Zhang, H.-C.; Gauthier, D. A.; Reddy, I.;
Maryanoff, B. E. Org. Lett. 2003, 5, 4537-4540. (f) Bonaga, L. V. R.;
Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.;
Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473-3485.
(3) (a) Hoberg, H.; Oster, B. W. Synthesis 1982, 324-325. (b) Hoberg,
H.; Oster, B. W. J. Organomet. Chem. 1982, 234, C35-C38. (c) Hoberg,
H.; Oster, B. W. J. Organomet. Chem. 1983, 252, 359-364. (d) Duong, H.
A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438-11439.
(4) (a) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.;
Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
5059-5067. (b) Li, Y.; Matsumura, H.; Yamanaka, M.; Takahashi, T.
Tetrahedron 2004, 60, 1393-1400.
(5) (a) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117-
2119. (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda,
S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605-613.
10.1021/ol052041b CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/22/2005

Rh(I)+/H8-BINAP8-catalyzed cross-cyclotrimerization of ter-
minal alkynes with dialkyl acetylenedicarboxylates.9 In this
paper, we describe Rh(I)+/modified-BINAP-catalyzed chemo-,
regio-, and enantioselective [2 + 2 + 2] cycloaddition of
alkynes with isocyanates.
(trimethylsilyl)acetylene (1c) furnished isomer 5 as a sole
product (entries 5 and 6).
Next, the cycloaddition of both terminal and internal R,ω-
diynes with isocyanates was investigated using 5% [Rh(cod)2]-
BF4/H8-BINAP at room temperature (Table 2). The reaction
We first investigated the cycloaddition of terminal alkynes
with isocyanates. After screening various rhodium(I) com-
plexes, we found that [Rh(cod)2]BF4/H8-BINAP catalyzed
this reaction at room temperature. Regioselectivity is highly
dependent on the alkynes used (Table 1). Although the
Table 2. Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of
Symmetrical R,ω-Diynes with Isocyanatesa
Table 1. Rhodium-Catalyzed Regioselective [2 + 2 + 2]
Cycloaddition of Terminal Monoynes with Isocyanates
entry
7
X
R1
2
R2
8
yieldb (%)
1
2
3
4
5
6
7
8c
9
7a C(CO2Me)2
7a C(CO2Me)2
7a C(CO2Me)2
7b C(CO2Me)2
7b C(CO2Me)2
7c NTs
7c NTs
7d CH2
7e CH2CH2
Me 2a Bn
Me 2b n-Bu 8ab
Me 2d Ph
8aa
99
90
87
84
81
93
80
64
85
98
65
48
8ad
8ba
8bc
8ca
H
H
2a Bn
2c Cy
Me 2a Bn
Me 2b n-Bu 8cb
H
2a Bn
8da
8ea
8fa
8ga
8ha
Me 2a Bn
yielda (%)
10
11
12
7f
CH2CH2
Et
H
H
2a Bn
2a Bn
2a Bn
entry
1
R1
2
R2
3
4
5
6
7g CH2CH2
7h CH2CH2CH2
1
2
3
4
5
6
1a 1-cyclohexenyl 2a Bn
47b
1b
1b
30
31
0
0
0
0
0
0
0
0
0
1a 1-cyclohexenyl 2b n-Bu 47b
0
<5
<5
65
a Isocyanates (1.1 equiv: R1 ) Me or Et, 2.0 equiv: R1 ) H) were
used. b Isolated yield. c BINAP was used as ligand.
1b n-C10H21
1b n-C10H21
1c Me3Si
2a Bn
2c Cy
2b n-Bu
2c Cy
31
31
0
1c Me3Si
0
48
of malonate-derived 1,6-diynes and diynes containing an
internal amino group with a variety of isocyanates afforded
the desired 2-pyridones in good yield (entries 1-7). 1,6-
Heptadiyne, having no tertiary center on the tether chain,
also reacted with an isocyanate to afford the expected
2-pyridone (entry 8). The formation of a six- or seven-
membered ring was also possible (entries 9-12). In general,
the reactions of internal R,ω-diynes proceeded in higher yield
than those of terminal R,ω-diynes, due to the lower reactivity
toward homo-cycloaddition.
The [2 + 2 + 2] cycloaddition of unsymmetrical R,ω-
diynes, bearing an ortho-substituted phenyl at one terminal
position, with alkyl isocyanates would install axial chirality
during the formation of pyridone rings.10 As shown in Table
3, the reaction of unsymmetrical 1,6-diynes using [Rh(cod)2]-
BF4/(R)-DTBM-Segphos11 furnished a sterically demanding
and axially chiral regioisomer as a sole product.12 The
reaction of 2-chlorophenyl-substituted 1,6-heptadiyne 9a with
various alkyl isocyanates furnished axially chiral 2-pyridones
a Isolated yield. b Isolated as a mixture of 3 and 4.
reaction of conjugated alkyne 1a furnished isomer 3 as a
major product (entries 1 and 2), the reaction of nonconjugated
alkyne 1b furnished isomers 3 and 4 as major products
(entries 3 and 4). On the other hand, the reaction of
(6) For rhodium-catalyzed cyclotrimerization of alkynes, see: (a) Mu¨ller,
E. Synthesis 1974, 761-774. (b) Grigg, R.; Scott, R.; Stevenson, P.
Tetrahedron Lett. 1982, 23, 2691-2692. (c) Grigg, R.; Scott, R.; Stevenson,
P. J. Chem. Soc., Perkin Trans. 1 1988, 1357-1364. (d) Magnus, P.; Witty,
D.; Stamford, A. Tetrahedron Lett. 1993, 34, 23-26. (e) Baidossi, W.;
Goren, N.; Blum, J. J. Mol. Catal. 1993, 85, 153-162. (f) Doyle, M. P.;
Shanklin, M. S. Organometallics 1994, 13, 1081-1088. (g) McDonald, F.
E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem. Soc. 1995, 117, 6605-
6606. (h) Kotha, S.; Brahmachary, E. Tetrahedron Lett. 1997, 38, 3561-
3564. (i) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426-
2430. (j) Grigg, R.; Sridharan, V.; Wang, J.; Xu, J. Tetrahedron 2000, 56,
8967-8976. (k) Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M.
Chem. Commun. 2000, 1965-1966. (l) McDonald, F. E.; Smolentsev, V.
Org. Lett. 2002, 4, 745-748. (m) Witulski, B.; Zimmermann, A. Synlett
2002, 1855-1859. (n) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed.
2002, 41, 3281-3284. (o) Nishiyama, H.; Niwa, E.; Inoue, T.; Ishima, Y.;
Aoki, K. Organometallics 2002, 21, 2572-2574. (p) Yan, H.; Beatty, A.
M.; Fehlner, T. P. Organometallics 2002, 21, 5029-5037. (q) Kinoshita,
H.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 7784-7785.
(7) Flynn, S. T.; Hasso-Henderson, S. E.; Parkins, A. W. J. Mol. Catal.
1985, 32, 101-105.
(10) For enantioselective synthesis of axially chiral compounds through
[2 + 2 + 2] cycloaddition, see: (a) Gutnov, A.; Heller, B.; Fischer, C.;
Drexler, H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew.
Chem., Int. Ed. 2004, 43, 3795-3797. (b) Shibata, T.; Fujimoto, T.; Yokota,
K.; Takagi, K. J. Am. Chem. Soc. 2004, 126, 8382-8383. (c) Tanaka, K.;
Nishida. G.; Wada, A.; Noguchi, K. Angew. Chem., Int. Ed. 2004, 43, 6510-
6512. (d) Tanaka, K.; Nishida, G.; Ogino, M.; Hirano, M.; Noguchi, K.
Org. Lett. 2005, 7, 3119-3121.
(8) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. Tetrahedron. Lett. 1991, 32, 7283-7286.
(9) (a) Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697-4699. (b)
Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M. Chem. Eur.
J. 2005, 11, 1145-1156.
(11) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264-267.
4738
Org. Lett., Vol. 7, No. 21, 2005

substituted 1,6-diynes were suitable substrates in this process.
Furthermore, the reaction of dipropargyl ether derivative 9c
and malonate-derived 1,6-diyne 9d also proceeded with high
enantioselectivity (entries 5 and 6). The absolute configu-
ration of (+)-10ab was determined to be R by the anomalous
dispersion method (Figure 1).
Table 3. Rhodium-Catalyzed Regio- and Enantioselective [2 +
2 + 2] Cycloaddition of Unsymmetrical R,ω-Diynes with
Isocyanates
The observed high regio- and enantioselectivity can be
explained by the selective formation of rhodium complex A
(Scheme 1). The unsymmetrical R,ω-diyne 9 and isocyanate
Scheme 1
yielda ee
entry
9
X
R1
2
R2
10
(%) (%)
1
2
3
4
5
6
9a CH2
9a CH2
9a CH2
9b CH2
Cl 2a Bn
Cl 2b n-Bu
Cl 2e n-C8H17 (+)-10ae
Br 2a Bn
Cl 2a Bn
(+)-10aa
(R)-(+)-10ab
81
79
75
83
58
89
87
88
90
85
91
92
2 react with rhodium to form complex A, which can furnish
(R)-10. Indeed, homo-[2 + 2 + 2] cycloaddition products
of 9 were generated other than the desired cross-[2 + 2 +
2] cycloaddition products 10.
In conclusion, we have developed a rhodium-catalyzed
chemo-, regio-, and enantioselective [2 + 2 + 2] cycload-
dition of alkynes with isocyanates leading to a wide range
of 2-pyridones, including enentioenriched axially chiral
2-pyridones. Additional synthetic and mechanistic studies of
this reaction are underway in our laboratory.
(+)-10ba
(+)-10ca
(+)-10da
9c
O
9d C(CO2Me)2 Cl 2a Bn
a Isolated yield.
in high yield with high enantioselectivity (entries 1-3). Not
only 2-chlorophenyl- but also 2-bromophenyl (9b, entry 4)-
Acknowledgment. This work was supported by Uehara
Memorial Fundation. We thank Takasago International Corp.
for the gift of H8-BINAP and DTBM-Segphos.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052041B
(12) The use of R,ω-diynes, bearing an ortho-halogenated phenyl at the
terminal position, is important. The reaction of an o-methyl- or trifluorom-
ethylphenyl-substituted R,ω-diyne furnished a mixture of regioisomers, and
an axially chiral regioisomer 10 was a minor product.
Figure 1. ORTEP diagram of (R)-(+)-10ab.
Org. Lett., Vol. 7, No. 21, 2005
4739