Nucleophilic carbenes in organic synthesis. Construction of functionalized hydroindolones via a novel reaction pathway of dimethoxycarbene

Full text of DOI:10.1021/ja962784f

12848
J. Am. Chem. Soc. 1996, 118, 12848-12849
dialkoxy-∆3-1,3,4-oxadiazolines (2) as a mild alternative method
into these species.7
Vinyl isocyanates have recently been shown to be versatile
“1,4-dipole” equivalents in various [2 + 4] and [1 + 4]
cyclization protocols,8 and it was envisioned that dimethoxy-
Nucleophilic Carbenes in Organic Synthesis.
Construction of Functionalized Hydroindolones Wia
a Novel Reaction Pathway of Dimethoxycarbene
James H. Rigby,* Alexandre Cavezza, and Gulzar Ahmed
Department of Chemistry, Wayne State UniVersity
Detroit, Michigan 48202-3489
ReceiVed August 9, 1996
So-called nucleophilic carbenes are intriguing reactive inter-
mediates that have attracted considerable attention in recent
years due, in large measure, to their unusual reaction charac-
teristics, which have been attributed to resonance stabilization
of the singlet state by donor substituents.1 It is noteworthy that,
in spite of their attractive reactivity profiles, these species have
rarely been employed in synthetic applications.1 In this paper
we report a novel reaction pathway between dimethoxycarbene
and isocyanates that efficiently delivers structurally elaborate
hydroindolone products.
carbene, in combination with these substrates, could provide a
new method for rapidly accessing highly functionalized pyr-
rolinone derivatives. To date, however, all reported reactions
between nucleophilic carbenes and isocyanates have afforded
only hydantoin-type products that have been produced by the
addition of two isocyanate molecules to one equivalent of
carbene.5,7
The [1 + n] cycloaddition represents an appealing method
for ring construction that has been effectively deployed in a
number of contexts,2 and dimethoxycarbene (1), a typical
nucleophilic carbene,1g offers the potential for serving as a novel
example of a carbonyl 1,1-dipole equivalent, which are currently
relatively rare species.3,4 Typically these reactive intermediates
have been generated by thermolysis of norbornadienone acetals5
or by photolysis/thermolysis of dimethoxydiazirines.1g,6 More
recently, Warkentin has introduced the thermolysis of 2,2-
We now report that vinyl isocyanates react with dimethoxy-
carbene through an entirely different reaction channel to afford
2:1 adducts in which one isocyanate combines with two carbene
units in a carbocyclization event. Thus heating 1-isocyanato-
cyclohexene with excess carbene precursor 2 (3 equiv) in
refluxing xylene afforded functionalized hydroindolone 3a9 in
good yield accompanied by only a trace of the dimethoxyhy-
dantoin (4). The presence of the nitrogen substituent in 3a is
noteworthy. It is presumed that addition of the second equiva-
lent of carbene occurs Via a fast NH insertion subsequent to
ring formation, since the 1:1 adduct 3b9 can be isolated in low
yield when only a stoichiometric amount of 2 is employed in
the reaction.
Structurally elaborate vinyl isocyanates have been found to
be useful reaction partners in this new [1 + 4] process. For
example, substituted systems such as 5 and 7 afford quite good
yields of hydroindolone products 6 and 8, respectively. The
results in eq 3 are particularly noteworthy in that the Curtius
rearrangement of the acyl azide intermediate as well as the
cycloaddition can be performed in one operation by directly
heating a mixture of acyl azide 7 and carbene precursor 2. The
successful reaction of acyl azide 7 also demonstrates that
quaternary carbon centers can be generated with facility using
this methodology. Acyclic isocyanates are also viable partners
in this reaction process (eq 4). From these results, it is clear
that the cyclization of dimethoxycarbene and vinyl isocyanates
(1) (a) Pole, D. L.; Sharma, P. K.; Warkentin, J. Can. J. Chem. 1996,
74, 1335. (b) de Meijere, A.; Kozhushkov, S. I.; Yufit, D. S.; Boese, R.;
Haumann, T.; Pole, D. L.; Sharma, P. K.; Warkentin, J. Justus Liebigs Ann.
Chem. 1996, 601. (c) Pole, D. L.; Warkentin, J. Justus Liebigs Ann. Chem.
1995, 1907. (d) Arduengo, A. J., III; Dias, H. V. R.; Dixon, D. A.; Harlow,
R. L.; Klooster, W. T.; Koetzle, T. F. J. Am. Chem. Soc. 1994, 116, 6812.
(e) Win, W. W.; Kao, M.; Eiermann, M.; McNamara, J. J.; Wudl, F.; Pole,
D. L.; Kassam, K.; Warkentin, J. J. Org. Chem. 1994, 59, 5871. (f) Moss,
R. A. Acc. Chem. Res. 1989, 22, 15. (g) Moss, R. A.; Wlostowski, M.;
Shen, S.; Krogh-Jespersen, K.; Matro, A. J. Am. Chem. Soc. 1988, 110,
4443.
(2) For some recent examples, see: (a) Pearson, W. H.; Bergmeier, S.
C.; Degan, S.; Lin, K.-C.; Poon, Y.-F.; Schkeryantz, J. M.; Williams, J. P.
J. Org. Chem. 1990, 55, 5719. (b) Padwa, A.; Norman, B. H. Tetrahedron
Lett. 1988, 29, 3041. (c) Ba¨ckvall, J. E.; Renko, Z. D.; Bystro¨m, S. E. Ibid.
1987, 28, 4199. (d) Pearson, W. H.; Celebuski, J. E.; Poon, Y.-F.; Dixon,
B. R.; Glans, J. H. Ibid. 1986, 27, 6301.
(3) For examples of other 1,1-dipole equivalents, see: (a) (Sulfur ylides)
Trost, B. M.; Melvin, L. S. Sulfur Ylides, Emerging Synthetic Intermediates;
Academic Press: New York, 1975. (b) (Alkylidene carbenes) Krageloh,
K.; Anderson, G. H.; Stang, P. J. J. Am. Chem. Soc. 1984, 106, 6015. (c)
(Carbon monoxide) Sigman, M. S.; Kerr, C. E.; Eaton, B. E. J. Am. Chem.
Soc. 1993, 115, 7545. (d) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV.
1996, 96, 177. (e) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996,
35, 1050.
(4) Isocyanides are also useful 1,1-dipole equivalents: (a) Rigby, J. H.;
Qabar, M. J. Am. Chem. Soc. 1991, 113, 8975. (b) Curran, D. P.; Liu, H.
Ibid. 1991, 113, 2127. (c) Morel, G.; Marchand, E.; Foucaud, A.; Toupet,
L. J. Org. Chem. 1990, 55, 1721. (d) VanWagenen, B. C.; Cardellina, J. H.
Tetrahedron Lett. 1989, 30, 3605. (e) Morel, G.; Marchand, E.; Foucaud,
A.; Toupet, L. J. Org. Chem. 1989, 54, 1185. (f) Westling, M.; Livinghouse,
T. J. Am. Chem. Soc. 1987, 109, 590. (g) Westling, M.; Smith, R.;
Livinghouse, T. J. Org. Chem. 1986, 51, 1159.
(7) (a) Couture, P.; Terlouw, J. K.; Warkentin, J. J. Am. Chem. Soc.
1996, 118, 4214. (b) Kassam, K.; Pole, D. L.; El-Saidi, M.; Warkentin, J.
Ibid. 1994, 116, 1161. (c) El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey,
T.; Warkentin, J. Ibid. 1992, 114, 8751.
(5) (a) Hoffmann, R. W.; Steinbach, K.; Dittrich, B. Chem. Ber. 1973,
106, 2174. (b) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1971, 10,
529. (c) Lemal, D. M.; Gosselink, E. P.; McGregor, S. D. J. Am. Chem.
Soc. 1966, 88, 582.
(6) (a) Ge, C.-S.; Jefferson, E. A.; Moss, R. A. Tetrahedron Lett. 1993,
34, 7549. (b) Moss, R. A.; Shen, S.; Wlostowski, M. Ibid. 1988, 29, 6417.
(c) Moss, R. A.; Fan, H.; Hadel, L. M.; Shen, S.; Wlostowska, J.;
Wlostowski, M.; Krogh-Jespersen, K. Ibid. 1987, 28, 4779.
(8) (a) Rigby, J. H.; Qabar, M.; Ahmed, G.; Hughes, R. C. Tetrahedron
1993, 49, 10219. (b) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5852.
(c) Rigby, J. H.; Holsworth, D. D.; James, K. Ibid. 1989, 54, 4019. (d)
Rigby, J. H.; Balasubramanian, N. Ibid. 1989, 54, 224.
(9) This compound exhibited spectral (1H NMR, 13C NMR, IR, MS)
and analytical (combustion analysis and/or HRMS) data in complete accord
with the assigned structure.
S0002-7863(96)02784-9 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 50, 1996 12849
synthesis of the Amaryllidaceae alkaloid, tazettine,10 or the
related mesembrine alkaloids (eq 7).11 Palladium-mediated
is a general process with significant potential for organic
synthesis applications.
coupling12 between the readily available vinyl triflate 15 (from
the corresponding â-ketoester13 ) and the arylstannane 169 (from
the known bromide14 ) afforded ester 179 in high yield. Routine
ester saponification and Curtius rearrangement of the corre-
sponding acyl azide gave the vinyl isocyanate intermediate,
which upon heating in the presence of excess oxadiazoline 2
afforded the hydroindolone 189 in 45% overall yield (58% for
the cycloaddition step). It is noteworthy that efforts to effect a
similar transformation using a wide range of insertion reactions,
including isocyanide cyclization,4a failed, demonstrating that
dimethoxycarbene-based [1 + 4] cyclization is an advance over
existing technology in this area. With compound 18 in hand,
routes to a number of alkaloid targets can be envisioned, and
these are being pursued at this time.
Interestingly, the mixed N/O-substituted carbene species
derived from oxadiazoline 117a initially provided a complex
mixture of products when heated for an extended period at 100
°C with the parent cyclohexenyl isocyanate in toluene. How-
ever, performing the same reaction in refluxing xylene resulted
in a mixture of products from which hydroindolones 12 and 13
could be isolated in modest yields (eq 5). It is noteworthy that
both of these adducts arise from 1:1 addition processes. This
observation is in contrast to the reaction pathway typically
followed by dimethoxycarbene as described above.
Acknowledgment. The authors thank the National Science Founda-
tion for their generous support of this work.
Supporting Information Available: Typical experimental proce-
dures and complete spectroscopic data for all new compounds (12
pages). See any current masthead page for ordering and Internet access
instructions.
JA962784F
The synthetic utility of the hydroindolones isolated from these
reactions is critically dependent on the ability to selectively
manipulate one of the two quite similar dimethoxy acetal
functions present in the products. Preferential removal of the
nitrogen substitution without jeopardizing the protected isatin-
like carbonyl function is particularly desirable. This can be
achieved in high yield as outlined in eq 6.
To illustrate the utility of dimethoxycarbene-based [1 + 4]
cyclization in complex synthesis, rapid entry has been achieved
into an advanced intermediate that could be employed in the
(10) (a) Hendrickson, J. B.; Bogard, T. L.; Fisch, M. E. J. Am. Chem.
Soc. 1970, 92, 5538. (b) Tsuda, Y.; Ukai, A.; Isobe, K. Tetrahedron Lett.
1972, 31, 3153. (c) Danishefsky, S.; Morris, J.; Mullen, G.; Gammill, R. J.
Am. Chem. Soc. 1980, 102, 2838. (d) Abelman, M. M.; Overman, L. E.:
Tran, V. D. Ibid. 1990, 112, 6959. (e) Pearson, W. H.; Postich, M. J. J.
Org. Chem. 1994, 59, 5662.
(11) Stevens, R. V. In The Total Synthesis of Natural Products; Apsimon,
J., Ed.; Wiley: New York, 1977; Vol. 3, pp 443-53.
(12) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Roth, G. P. Tetrahedron Lett. 1991, 32, 4243.
(13) Pariza, R. J.; Kuo, F.; Fuchs, P. L. Synth. Commun. 1983, 13, 243.
(14) Alexander, B. H.; Gertler, S. I.; Oda, T. A.; Brown, R. T.; Ihndris,
R. W.; Beroza, M. J. Org. Chem. 1960, 25, 626.