A hetero pauson-khand reaction of ketenimines: A new synthetic method for γ-exomethylene-α,β-unsaturated γ-lactams

Article abstract of DOI:10.3987/COM-09-S(S)62

A novel ketenimine Pauson-Khand reaction has been described for the first time. C,C,N-Triarylketenimines reacted with alkyne-dicobalthexacarbonyl complexes upon heating in toluene in the presence of dimethyl sulfoxide as a promoter to afford γ-lactams, 5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones, in good yields.

Full text of DOI:10.3987/COM-09-S(S)62

HETEROCYCLES, Vol. 80, No. 1, 2010
207
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 207 - 211. © The Japan Institute of Heterocyclic Chemistry
Received, 21st July, 2009, Accepted, 18th August, 2009, Published online, 20th August, 2009
DOI: 10.3987/COM-09-S(S)62
A HETERO PAUSON–KHAND REACTION OF KETENIMINES: A NEW
SYNTHETIC METHOD FOR ꢀ-EXOMETHYLENE-ꢁ,ꢂ-UNSATURATED
ꢀ-LACTAMS†
Takao Saito,* Katsuya Sugizaki, Hiroyuki Osada, Noriki Kutsumura, and
Takashi Otani
Department of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
tsaito@rs.kagu.tus.ac.jp
Abstract – A novel ketenimine Pauson–Khand reaction has been described for
the first time. C,C,N-Triarylketenimines reacted with alkyne–ꢀ
dicobalthexacarbonyl complexes upon heating in toluene in the presence of
dimethyl sulfoxide as promoter to afford ꢀ-lactams,
5-(diphenylmethylene)-1H-pyrrol-2(5H)-ones, in good yields.
a
The Pauson–Khand reaction, formally a cobalt-mediated three-component [2 + 2 + 1] cocyclization of an
alkyne, an alkene and carbon monoxide, constitutes one of the most useful, convergent and
atom-economical methods for the synthesis of a cyclopentenone.1-4 Since the first publications in the early
70s,1 many advances in this method and its related processes have been made, involving discovery or
improvement of promoters to effect the reaction, the Pauson–Khand type reaction mediated by other
metals, the allenic or electron-deficient alkenic Pauson–Khand type reaction, and the catalytic variant as
well as the asymmetric version.2-4 A hetero Pauson–Khand type reaction has also been developed in
which a hetero-alkene ꢃ-component such as a carbonyl (ketone and aldehyde) or an imine is used instead
of an alkene or alkyne partner to give a ꢀ-butyrolactone5 or a ꢀ-butyrolactam.6 Recently, a
heterocumulenic Pauson–Khand type reaction was reported from our laboratory in which
alkyne-carbodiimides were used as an alkyne-hetero-alkene partner to give [2 + 2 + 1] cyclocarbonylation
products, pyrrolo- or indolo-fused ꢀ-lactams.7-9 Mukai et al. applied a catalytic version of this
carbodiimide Pauson–Khand reaction for synthesis of hexahydropyrrolo[2,3-b]indole alkaloids.10
The
† This paper is dedicated to Professor Dr. Akira Suzuki on occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 1, 2010
synthetic utility of such heterocumulenic Pauson–Khand type cyclocarbonylation has also been enhanced
by the synthesis of poly-substituted maleimides, in which the reaction involved the ruthenium-catalyzed
intermolecular [2 + 2 + 1] cocyclization of isocyanates, alkynes, and carbon monoxide.11
Alkyne-isothiocyanates have also been used successfully in the heterocumulenic Pauson–Khand type
method leading to indolo-ꢀ-thiolactones (thieno[2,3-b]indol-2-ones).12 A ketenimine is now our target
molecule for evaluating the heterocumulene-mediated [2 + 2 + 1] cocyclization reaction. We herein report
the first example of the ketenimine Pauson–Khand reaction.
We took a fundamental protocol using Co2(CO)8 for the intermolecular Pauson–Khand reaction among a
ketenimine (1),13 an alkyne (2), and CO. In a model reaction between ketenimine 1a and the preformed
methyl propiolate-Co2(CO)6 complex 3a (Scheme 1), the desired ketenimine Pauson–Khand reaction did
not proceed in the absence of a promoter even after refluxing in toluene for 8 h (Table 1, entry 1).
Therefore, in order to find an efficient promoter for accelerating the ketenimine Pauson–Khand reaction,
the reactions in the presence of promoters such as P(OPh)3, N-methylmorpholine oxide (NMO), (CH2)5S,
CH3CN, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) were examined (entries 2-7).
Among the promoters tested, DMSO3,14 was found to most effectively accelerate the Pauson–Khand
reaction for producing 5-(diphenylmethylene)-2-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate
methyl ester (4a)15,16 in a fair yield (50%, entry 7).
Table 1. Screening of promoters
Ph
Ph
Co2(CO)6
CO2Me
C
Ph N
C
+
Entry
Promoter Time / h Yield of 4a / %
1a
1
none
8
8
4
2
2
2
2
0
0
3a
Co2(CO)8
2
P(OPh)3
NMO
CO2Me
3a)
trace
11
O
2a
Ph
Ph
promoter
(5 equiv)
MeO2C
4
(CH2)5S
MeCN
DMF
N
5
19
toluene
115 ºC
Ph
6
25
4a
7
DMSO
50
Scheme 1. Efficiency of promoters in a model
P-K reaction between 1a and 3a.
a) In the presence of MS4A.
With the optimal promoter (DMSO) and conditions identified, the scope of the reaction with respect to
both substrates, ketenimine (1) and alkyne-complex (3), bearing a variety of substituents (R1, R2, and R3)
was then examined (Scheme 2). The results are shown in Table 2. Thermally stable
C,C,N-triarylketenimines 1a-d were found to be good components in the Pauson–Khand reaction with the
cobalt-alkyne complex 3a-d having a variety of substituents to give the desired ꢀ-methylene-ꢀ-lactams
4a-m in moderate to good yields (entries 1-13). In contrast, the reaction of ketenimine 1e (R2 = H) with

HETEROCYCLES, Vol. 80, No. 1, 2010
209
3a failed, and the product 4n was not detected (entry 14). This is probably due to the thermal instability
of ketenimine 1e and its cobalt complex, which readily isomerize and/or polymerize under the employed
conditions.13
O
R2
Co2(CO)6
DMSO (5 equiv)
R1
R2
R3
R1
N C C
+
N
R3
toluene,115 ºC, 2 h
Ph
1a R1 = Ph, R2 = Ph
1b R1 = p-Tol, R2 = Ph
3a R3 = CO2Me
3b R3 = Ph
Ph
1c R1 = p-ClPh, R2 = Ph
1d R1 = p-MeOPh, R2 = Ph
1e R1 = Ph, R2 = H
3c R3 = CH2CH2OH
3d R3 = n-Hex
4a-m
Scheme 2. Scope of the ketenimine Pauson–Khand reaction to give ꢀ-lactams 4.
Table 2. Scope of the ketenimine Pauson–Khand reaction to give ꢀ-lactams 4 bearing a variety of substituents.
Entry Ketenimine Alkyne-complex R1
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
R3
Product
4a
Yield / %
50
1
2
1a
1b
1c
1a
1b
1c
1d
1a
1b
1c
1a
1b
1c
1e
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3d
3d
3d
3a
Ph
CO2Me
CO2Me
CO2Me
Ph
p-Tol
p-ClPh
Ph
4b
4c
45
3
43
4
4d
4e
69
5
p-Tol
p-ClPh
p-MeOPh
Ph
Ph
45
6
Ph
4f
46
7
Ph
4g
77
8
CH2CH2OH
CH2CH2OH
CH2CH2OH
n-Hex
n-Hex
n-Hex
CO2Me
4h
4i
50
9
p-Tol
p-ClPh
Ph
46
10
11
12
13
14
4j
53
4k
4l
53
p-Tol
p-ClPh
Ph
47
4m
4n
43
0
In summary, the ketenimine Pauson–Khand reaction was realized yielding ꢀ-methylene-ꢀ-lactams, though
usable ketenimines were limited to thermally tolerant triarylketenimines.
REFERENCES AND NOTES
1. (a) I. U. Khand, G. R. Knox, P. L. Pauson, and W. E. Watts, J. Chem. Soc., Chem. Commun., 1971,
36; (b) I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, and M. I. Foreman, J. Chem. Soc.,

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Perkin Trans. 1, 1973, 977; (c) P. L. Pauson, Tetrahedron, 1985, 41, 5855.
2. For discussions on the [2 + 2 + 1] reaction: N. Jeong, ‘Transition Metals for Organic Synthesis,’ ed.
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Christie, J. Chem. Soc., Perkin Trans. 1, 2000, 1657.
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J. Adrio, and J. C. Carretero, Synlett, 2005, 26 (electron-deficient alkenic); (g) M. Rodrîguez Rivero,
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and H.-G. Schmalz, Angew. Chem. Int. Ed., 1998, 37, 911; (i) H.-W. Frühauf, Chem. Rev., 1997, 97,
523; (j) S. Laschat, A. Becheanu, T. Bell, and A. Baro, Synlett, 2005, 2547.
5. For oxa-PK, Ti: (a) N. M. Kablaoui, F. A. Hicks, and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118,
5818 (catalytic); (b) W. E. Crowe and A. T. Vu, J. Am. Chem. Soc., 1996, 118, 1557; (c) S. K.
Mandal, R. Amin, and W. E. Crowe, J. Am. Chem. Soc., 2001, 123, 6457ꢀ(catalytic, asymmetric). Ru:
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(catalytic); (e) N. Chatani, M. Tobisu, T. Asaumi, Y. Fukumoto, and S. Murai, J. Am. Chem. Soc.,
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Chem., 2004, 69, 8506 (allenic); (h) J. Adrio and J. C. Carretero, J. Am. Chem. Soc., 2007, 129, 778
(Mo(CO)3DMF3). Ni: (i) S. Ogoshi, M. Oka, and H. Kurosawa, J. Am. Chem. Soc., 2004, 126, 11802.
6. For aza-PK, Ru: (a) A. Göbel and W. Imhof, Chem. Commun., 2001, 593; (b) N. Chatani, T.
Morimoto, A. Kamitani, Y. Fukumoto, and S. Murai, J. Organomet. Chem., 1999, 579, 177. Fe: (c) H.
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8. T. Saito, K. Sugizaki, T. Otani, and T. Suyama, Org. Lett., 2007, 9, 1239 (Rh, catalytic).
9. Before our first report on the heterocumulenic Pauson–Khand type reaction appeared, only two

HETEROCYCLES, Vol. 80, No. 1, 2010
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examples of such heterocumulenic [2 + 2 + 1] cocyclization had been reported. These involved the
intermolecular reaction of diphenylcarbodiimide or phenyl isocyanate with diphenylacetylene and
Fe(CO)5 or Ni(cod)2, which indeed afforded a hetero Pauson–Khand type product: (a) Y. Ohshiro, K.
Kinugasa, T. Minami, and T. Agawa, J. Org. Chem., 1970, 35, 2136; (b) H. Hoberg and B.W. Oster,
J. Organomet. Chem., 1982, 234, C35.
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Yoshida, N. Miyakoshi, and C. Mukai, J. Org. Chem., 2007, 72, 6878.
11. T. Kondo, M. Nomura, Y. Ura, K. Wada, and T. Mitsudo, J. Am. Chem. Soc., 2006, 128, 14816. See
also ref. 9b.
12. T. Saito, H. Nihei, T. Otani, T. Suyama, N. Furukawa, and M. Saito, Chem. Commun., 2008, 172.
13. (a) M. Shimizu, Y. Gama, T. Takagi, M. Shibakami, and I. Shibuya, Synthesis, 2000, 517; (b) G. R.
Krow, Angew. Chem., Int. Ed. Engl., 1971, 10, 435; (c) R. Aumann, Angew. Chem. Int. Ed., 1988, 27,
1456; (d) D. G. McCarthy and A. F. Hegarty, J. Chem. Soc., Perkin Trans. 2, 1980, 579.
14. Y. K. Chung, B. Y. Lee, N. Jeong, M. Hudecek, and P. L. Pauson, Organometallics, 1993, 12, 220.
15. A mixture of the dicobaltoctacarbonyl (622 mg, 1.82 mmol) and methyl propiolate (2a, 153 mg, 1.82
mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. Removal of the solvent and
column chromatography of the residue on silica gel (hexane/EtOAc (3:1)) afforded quantitatively the
dicobalthexacarbonyl-methyl propiolate complex (3a) as an oil. A mixture of 3aꢀ ꢀ112 mg, 0.303
mmol), C,C,N-triphenylketenimine (1a,13 97.8 mg, 0.363 mmol) and DMSO (0.11 mL, 1.52 mmol) in
toluene (5 mL) was heated at 115 ˚C for 2 hours. The reaction mixture was evaporated and the
residue was chromatographed on silica gel, eluting with hexane/ EtOAc (3:1), to give the P—K
product 4a (57.8 mg, 50%).
16. Methyl 5-(diphenylmethylene)-2-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (4a): Yellow
solid, mp 149.0-151.0 °C; 1H-NMR (300 MHz, CDCl3) ꢀ: 7.82 (s, 1H), 7.24-7.47 (m, 5H), 6.83-7.01
13
(m, 10H), 3.89 (s, 3H); C-NMR (76 MHz, CDCl3) ꢀ: 166.8 (CO), 162.7 (CO), 146.4 (CH), 140.0
(C), 137.5 (C), 137.0 (C), 135.8 (C), 135.3 (C), 132.0 (2CH), 131.1 (2CH), 129.5 (CH), 128.7 (CH),
128.4 (2CH), 128.0 (2CH), 127.3 (2CH), 127.0 (2CH), 126.3 (CH), 122.6 (C), 52.2 (CH3).; IR (KBr):
1754, 1686, 1560, 1346, 1190, 1064, 740, 688 cm-1. HRMS-ESI (m/z): Calcd for C25H19NO3: [M]+
381.1365. Found: 381.1358.
17. The structure 4 was determined spectroscopically (IR, 1H- and 13C-NMR). Particularly, the observed
13
prominent C-NMR chemical shift values are in good agreement with those calculated for the
structure 4 rather than those for the other possible chemo- and regio-isomers. The structure 4 was
further supported by the fact that in the HMBC measurement, the correlation between the olefinic
proton and the carbons (3JH-C , enamino ꢀ-carbon, two carbonyl carbons) was observed.