Ruthenium-catalyzed [2 + 2 + 1] cocyclization of isocyanates, alkynes, and CO enables the rapid synthesis of polysubstituted maleimides

Article abstract of DOI:10.1021/ja066305g

Intermolecular [2 + 2 + 1] cocyclization of isocyanates, alkynes, and CO (1 atm) proceeded smoothly in the presence of a catalytic amount of Ru₃(CO)₁₂ (3.3 mol %) in mesitylene at 130 °C for 342 h to give a variety of polysubstituted maleimides in excellent yields with high selectivity. The reaction may involve an azaruthenacyclopentenone intermediate derived from oxidative cyclization of an isocyanate and an alkyne on an active ruthenium species. Copyright

Full text of DOI:10.1021/ja066305g

Published on Web 10/28/2006
Ruthenium-catalyzed [2 + 2 + 1] Cocyclization of Isocyanates, Alkynes, and
CO Enables the Rapid Synthesis of Polysubstituted Maleimides
Teruyuki Kondo,* Masato Nomura, Yasuyuki Ura, Kenji Wada, and Take-aki Mitsudo
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Nishikyo-ku, Kyoto 615-8510, Japan
Received August 30, 2006; E-mail: teruyuki@scl.kyoto-u.ac.jp
Scheme 1. Synthesis of Five-membered Carbonyl Compounds
The formal [2 + 2 + 1] cocyclization of alkenes, alkynes, and
via the [2 + 2 + 1] Cocyclization Reactions
CO by transition metal complexes, represented by cobalt complexes,
(known as the Pauson-Khand reaction) has been accepted as one
of the most powerful, convergent, and atom-economical methods
for the construction of cyclopentenones (path a in Scheme 1).1 Many
advances related to this method have recently been reported,
including the development of catalytic versions of this reaction.2
Allenes have also been used as an alkene partner in this cocycliza-
tion reaction to give 4- and/or 5-alkylidenecyclopentenones.3 A
carbonyl or imino moiety can also be used in place of a carbon-
carbon double bond to give γ-lactones4 or γ-lactams,5 respectively
(path b, Scheme 1). If heterocumulenic compounds such as
merization of 2a to hexa-n-propylbenzene, and the only product
carbodiimides and/or isocyanates can be used in the catalytic [2 +
detected by GLC was 3a. A higher CO pressure (over 5 atm)
2 + 1] cocyclization with alkynes and CO, it could lead to a new
drastically suppressed the reaction to result in a low yield of 3a.
Consequently, when the reaction of phenyl isocyanate (1a, 3.0
mmol) with 4-octyne (2a, 1.0 mmol) was carried out in the presence
of a catalytic amount of Ru3(CO)12 (0.033 mmol) in mesitylene
(3.0 mL) at 130 °C for 42 h under 1 atm of CO, the corresponding
maleimide, 1-phenyl-3,4-dipropylazoline-2,5-dione (3a), was ob-
tained in an isolated yield of 82%. Various substrates were subjected
to the present [2 + 2 + 1] cocyclization reaction under the optimum
approach for the construction of novel heterocyclic compounds, as
a heteroatomic variant of the Pauson-Khand reaction (path c,
Scheme 1).
However, such processes are strictly limited to very recent
examples of the Mo(CO)6-mediated6 and Co2(CO)8-catalyzed7
intramolecular cocyclization of alkynecarbodiimides with CO. Two
other examples of the intermolecular [2 + 2 + 1] cocyclization of
isocyanates, alkynes, and CO have required stoichiometric amounts
reaction conditions, and the results are summarized in eq 1.
8
of metal complexes such as Fe(CO)5 and Ni(cod)2 (cod ) 1,5-
cyclooctadiene).9 At the outset of our study on ruthenium-catalyzed
cocyclization reactions,10 we found a novel and rapid synthesis of
polysubstituted maleimides by the ruthenium-catalyzed inter-
molecular [2 + 2 + 1] cocyclization of isocyanates, alkynes, and
CO. A traditional industrial process for manufacturing maleimides
is the reaction of amines with maleic anhydride obtained by the
oxidation of benzene or C4-hydrocarbons, which gives only
unsubstituted and/or symmetrically substituted maleimides.11 The
present reaction offers a highly efficient method for preparing novel
unsymmetrically polysubstituted maleimides in excellent yields with
high selectivity, which are important building blocks in materials
science12 and biological chemstry.13
First, the effects of catalysts and the reaction conditions were
examined in the synthesis of maleimide 3a from the reaction of
phenyl isocyanate 1a with 4-octyne 2a under 1 atm of CO. Among
the transition metal complexes, Ru3(CO)12 showed the highest
catalytic activity. Ru(CO)3(PPh3)2, RuH2(CO)(PPh3)3, and RuHCl-
(CO)(PPh3)3 also showed some catalytic activity (3a, up to 28%),
while [RuCl2(CO)3]2, Cp*RuCl(cod) [Cp* ) pentamethylcyclopenta-
dienyl], and CpRuCl(cod) [Cp ) cyclopentadienyl] were totally
ineffective. No 3a was obtained with rhodium complexes, such as
RhCl(CO)(PPh3)2, Rh4(CO)12, Rh6(CO)16, and [Cp*Rh(CO)2]2.
Mesitylene is the best solvent. The reactions in toluene or decane
also gave 3a in moderate yield (40% and 38%, respectively);
however, no reaction occurred in diglyme, 1,4-dioxane, N,N-
dimethylacetamide, and propionitrile. The use of an excess (3 equiv)
amount of 1a relative to 2a completely suppressed the cyclotri-
Aryl-substituted alkynes such as diphenylacetylene (2b) and
1-phenyl-1-propyne (2c) are more reactive than 4-octyne (2a), and
the reactions with phenyl isocyanate (1a) were almost complete
within 3 h to give 3b and 3c in isolated yields of 98% and 97%,
respectively (vide infra). With terminal alkynes such as 1-octyne
and phenylacetylene, however, a trace amount of the desired
maleimides was obtained (<10%). We next examined the co-
cyclization of a variety of aryl and alkyl isocyanates with 1-phenyl-
1-propyne (2c) and CO. No significant effect was observed for
electron-donating (4-Me (1b) and 4-MeO (1c)) and electron-
withdrawing (4-Cl (1d), 4-CF3 (1e), and 4-Ph (1f)) substituents on
a phenyl ring in aryl isocyanate, while bulky alkyl isocyanates (1i
and 1j) required a longer reaction time for the complete conversion
of 2c.
9
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10.1021/ja066305g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
1,4-Phenylene diisocyanate (1k) can be used for the present
reaction, and the corresponding dimaleimides (3n and 3o) were
obtained in isolated yields of 71% and 44%, respectively (eq 2). A
slow addition of alkynes (2b and 2d) to diisocyanate (1k) is
essential. No reaction occurred by simple mixing of alkynes with
diisocyanates, which suggests that the higher coordination ability
of alkynes causes deactivation of the catalyst.
In conclusion, we have developed the first catalytic inter-
molecular [2 + 2 + 1] cocyclization of alkynes, isocyanates, and
CO. This process provides a rapid and atom-economical method
for the synthesis of a variety of unsymmetrically polysubstituted
maleimides in one step. Isolation of azaruthenacyclopentenones and
a DFT calculation for the process of CO insertion are currently
under investigation.
Acknowledgment. This work was supported in part by Grant-
in-Aid for Scientific Research (B), and the 21st century COE
program (COE for a United Approach to New Materials Science)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.K. acknowledges financial support from the
Japan Science and Technology Agency (Research for Promoting
Technological Seeds, JST). This research was partly conducted at
the Advanced Research Institute of Environmental Material Control
Engineering, Katsura-Int’tech Center, Graduate School of Engineer-
ing, Kyoto University. We gratefully acknowledge Dr. Markus
Waelchli (Bruker BioSpin Corporation) for performing 13C NMR
gated decoupling and Inadequate measurements of 3c.
The carbonyl carbon observed at a lower field as a quartet (170.6
ppm, 3J ) 4.67 Hz) is adjacent to a methyl-substituted sp2 carbon,
while another carbonyl group attached to a phenyl-substituted sp2
carbon appeared at a higher field as a singlet (169.6 ppm), as clearly
shown in a detailed NMR study (13C gated decoupling and
Inadequate (Incredible Natural Abundance Double Quantum Trans-
fer Experiment) measurements) with maleimide (3c). In addition,
the reaction of 1a with 2c was carried out in the presence of
Ru3(CO)12 catalyst under 1 atm of 13CO to give the corresponding
13C-labeled maleimides, 3c-13C. 13C NNE measurement of the
carbonyl regions of 3c-13C clearly showed that the carbonyl carbon
at a higher field (169.6 ppm) was mainly derived from external
13CO (see, Supporting Information).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Stru¨bing, D.; Beller, M. In Transition Metals for Organic Synthesis,
2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
2004; Vol. 1, Chapter 3.13, pp 619-632. For recent reviews, see (b)
Bon˜aga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795. (c) Gibson,
S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873.
(d) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022.
(2) (a) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800.
(b) Park, K. H.; Chung, Y. K. Synlett, 2005, 545. (c) Laschat, S.; Becheanu,
A.; Bell, T.; Baro, A. Synlett 2005, 2547.
(3) (a) Cao, H.; Van Omum, S. G.; Deschamps, J.; Flippen-Anderson, J.;
Laib, F.; Cook, J. M. J. Am. Chem. Soc. 2005, 127, 933. (b) Brummond,
K. M.; Curran, D. P.; Mitasev, B.; Fischer, S. J. Org. Chem. 2005, 70,
1745. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Yoshitani, K.; Hara, Y.;
Kitagaki, S. J. Org. Chem. 2005, 70, 7159. For recent reviews, see (d)
Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377. (e) Ma, S.
Chem. ReV. 2005, 105, 2829.
(4) (a) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557. (b)
Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 5818. (c) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 4424. (d) Chatani, N.; Morimoto, T.; Fukumoto,
Y.; Murai, S. J. Am. Chem. Soc. 1998, 120, 5335. (e) Chatani, N.; Tobisu,
M.; Asaumi, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1999, 121,
7160. (f) Tobisu, M.; Chatani, N.; Asaumi, T.; Amako, K.; Ie, Y.;
Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12663.
(5) Chatani, N.; Morimoto, T.; Kamitani, A.; Fukumoto, Y.; Murai, S. J.
Organomet. Chem. 1999, 579, 177.
(6) Saito, T.; Shiotani, M.; Otani, T.; Hasaba, S. Heterocycles 2003, 60, 1045.
(7) Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. Org. Lett. 2006, 8, 83.
(8) Ohshiro, Y.; Kinugasa, K.; Minami, T.; Agawa, T. J. Org. Chem. 1970,
35, 2136.
Considering the results obtained above, we postulated a mech-
anism for this newly developed intermolecular [2 + 2 + 1]
cocyclization of 1a, 2c, and CO, as shown in Scheme 2. The
reaction starts with the formation of azaruthenacyclopentenones I
(major) and II (minor) by the oxidative cyclization of 1a and 2c
on an active ruthenium center.9,14 For aryl-substituted alkynes, this
oxidative cyclization process is thought to proceed significantly
faster than with alkyl-substituted alkynes to preferably generate an
R-aryl-substituted azaruthenacyclopentenone of type I (vide supra).
A
13CO-labeling experiment also suggests the formation of aza-
ruthenacyclopentenones, I and II, and R-phenyl-substituted I is
more favorable than R-methyl-substituted II (the ratio of I and II
is estimated to be approximately 5 to 1 based on the 13C NNE
spectrum of 3c-13C; see Supporting Information). Next, the insertion
of CO into a Ru-C(sp2) bond rather than a Ru-N bond15
predominantly occurred to give azaruthenacyclohexenediones, III
and IV, followed by reductive elimination to give maleimides 3c
in an excellent yield with high selectivity and with the regeneration
of an active low-valent ruthenium species.
(9) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234, C35.
(10) (a) Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc.
1997, 119, 6187. (b) Suzuki, N.; Kondo, T.; Mitsudo, T. Organometallics
1998, 17, 766. (c) Kondo, T.; Nakamura, A.; Okada, T.; Suzuki, N.; Wada,
K.; Mitsudo, T. J. Am. Chem. Soc. 2000, 122, 6319. (d) Kondo, T.;
Kaneko, Y.; Taguchi, Y.; Nakamura, A.; Okada, T.; Shiotsuki, M.; Ura,
Y.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 6824. (e) Kondo,
T.; Taguchi, Y.; Kaneko, Y.; Niimi, M.; Mitsudo, T. Angew. Chem., Int.
Ed. 2004, 43, 5369.
Scheme 2. A Possible Mechanism of Ru-Catalyzed [2 + 2 + 1]
Cocyclization of 1a, 2c, and CO to 3c
(11) Weissermel, K.; Alpe, H.-J. In Industrial Organic Chemistry; 4th ed.;
Wiley-VCH: Weinheim, Germany, 2003; pp 368-375.
(12) (a) Pontrello, J. K.; Allen, M. J.; Underbakke, E. S.; Kiessling, L. L. J.
Am. Chem. Soc. 2005, 127, 14536. (b) Zhang, X.; Li, Z.-C.; Wang, Z.-
M.; Sun, H.-L.; He, Z.; Li, K.-B.; Wei, L. H.; Lin, S.; Du, F.-S.; Li, F.-
M. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 304.
(13) (a) Kalgutkar, A. S.; Crews, B. C.; Marnett, L. J. J. Med. Chem. 1996,
39, 1692. (b) Yang, W.; Auciello, O.; Butler, J. E.; Cai, W.; Carlisle, J.
A.; Gerbi, J. E.; Gruen, D. M.; Knickerbocker, T.; Lasseter, T. L.; Russell,
J. N., Jr.; Smith, L. M.; Hamers, R. J. Nat. Mater. 2002, 1, 253.
(14) (a) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1983, 252, 359. (b)
Stockis, A.; Hoffmann, R. J. Am. Chem. Soc. 1980, 102, 2952.
(15) (a) Hartwig, J. F.; Bergman, R. G.; Andersen, R. A. J. Am. Chem. Soc.
1991, 113, 6499. (b) Hanna, T. A.; Baranger, A. M.; Bergman, R. G. J.
Org. Chem. 1996, 61, 4532.
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