Three-component synthesis of cyclic enaminones via ketene cyclization

Article abstract of DOI:10.1021/ol200358h

Chemical equations presented. Cyclic six-membered enaminones were synthesized from three components (bromodiazoacetone, primary amine, and alkyne) in high yields via aza-Michael addition, Wolff rearrangement, and nucleophilic ketene cyclization.

Full text of DOI:10.1021/ol200358h

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2147–2149
Three-Component Synthesis of Cyclic
Enaminones via Ketene Cyclization
Hajime Seki and Gunda I. Georg*
Department of Chemistry and Department of Medicinal Chemistry, Institute for
Therapeutics Discovery and Development, College of Pharmacy, University of
Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
georg@umn.edu
Received February 7, 2011
ABSTRACT
Cyclic six-membered enaminones were synthesized from three components (bromodiazoacetone, primary amine, and alkyne) in high yields via
aza-Michael addition, Wolff rearrangement, and nucleophilic ketene cyclization.
Ketenes, first discovered by Staudinger in 1905, are
among the best studied intermediates in organic che-
mistry.1 Their versatile reactivity provides access to a
number of valuable structural motifs. Ketenes can be
readily prepared from several precursors including diazo-
ketones and acid halides, which further underscores their
value in synthetic organic chemistry.2
Reactions involving ketenes can be categorized into
two major types: cycloaddition reactions and nucleo-
philic additions to ketenes. The so-called Staudinger
reaction is a well-known example of a cycloaddition
reaction, where a ketene reacts with an imine or a
ketone to provide a β-lactam or β-lactone, respecti-
vely.3 Ketenes can also undergo cycloadditions with
alkenes or alkynes to form a CÀC bond at the sp center
of the ketene.4
(1) (a) Staudinger, H Chem. Ber. 1905, 38, 1735. (b) Tidewell, T. T.
Ketenes, 2nd ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2006.
(2) (a) Meier, H.; Zeller, K. P. Angew. Chem. 1975, 87, 52. (b) Kirmse,
W. Eur. J. Org. Chem. 2002, 2193. (c) Tidwell, T. T. Eur. J. Org. Chem.
2006, 563. (d) Staudinger, H. Chem. Ber. 1911, 44, 1619.
(3) For review: (a) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45,
159. (b) Georg, G. I.; Ravikumar, V. T. Stereocontrolled Ketene-Imine
Cycloaddition Reactions. In The Organic Chemistry of β-Lactams;
Georg, G. I., Ed.; Verlag Chemie: New York, 1993; p 295.
The other type of reaction, the nucleophilic addition
to a ketene,5 is exemplified by the ArndtÀEistert
homologation, where the acid functionality is homo-
logated via the formation of a diazo intermediate,
followed by a Wolff rearrangement, and subsequent
nucleophilic addition to the intermediate ketene.6 In
nucleophilic additions to electrophilic ketenes, most often
(4) (a) Lee, S. Y.; Kulkarni, S.; Burbaum, B. W.; Snider, B. B. J. Org.
Chem. 1988, 53, 1848. (b) Liebenskind, L. S. Tetrahedron 1989, 45, 3053.
(c) Moore, H. W.; Yerxa, B. R. Chemtracts 1992, 5, 273. (d) Snider, B. B.
Chem. Rev. 1988, 88, 793.
(5) Examples of CÀX bond forming ketene cyclizations: (a) Rahman,
S. S.; Wakefield, B. J.; Roberts, S. M.; Dowle, M. D. J. Chem. Soc.,
Chem Commun. 1989, 303. (b) Boeckman, R. K.; Pruitt, J. R. J. Am.
Chem. Soc. 1989, 111, 8286. (c) Vernier, J. M.; Hegedus, L. S.; Miller,
D. B. J. Org. Chem. 1992, 57, 6914. (d) Barton, D. H. R.; Quinkert, G. J.
Chem. Soc. 1960, 1. (e) Quinkert, G.; Kleiner, E.; Freitag, B. J.;
Glenneberg, J.; Billhardt, U. M.; Cech, F.; Schmieder, K. R.; Schudok,
€
C.; Steinmetzer, H. C.; Bats, J. W.; Zimmermann, G.; Durner, G.;
(6) (a) Bachmann, W. E.; Struve, W. S. Org. React. 1942, 38. (b)
Seikaly, H. R.; Tidwell, T. T. Tetrahedron 1986, 42, 2587. (c) Matthews,
J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D.
Enantiosel. Synth. β-Amino Acids 1997, 105.
(7) Nonorganometallic C-nucleophile addition to ketenes:
(a) Hickmott, P. W.; Giasuddin Ahmed, M.; Ahmed, S. A.; Wood,
S.; Kapon, M. J. Chem. Soc., Perkin Trans. 1985, 2559. (b) Hickmott,
P. W. S. Afr. J. Chem. 1989, 42, 17. (c) Yerxa, B. R.; Moore, H. W.
Tetrahedron Lett. 1992, 33, 7811. (d) Byeon, C.-H.; Hart, D. J.; Lai,
C.-S.; Unch, J. Synlett 2000, 119.
Rehm, D. Helv. Chim. Acta 1986, 69, 469. (f) Quinkert, G.; Billhardt,
U. M.; Jakob, H.; Fischer, G.; Glenneberg, J.; Nagler, P.; Autze, V.;
€
Heim, N.; Wacker, M.; Schwalbe, T.; Kurth, Y.; Bats, J. W.; Durner, G.;
Zimmermann, G.; Kessler, H. Helv. Chim. Acta 1987, 70, 771. (g)
Quinkert, G.; Nestler, H. P.; Schumacher, B.; Delgrosso, M.; Durner,
G.; Bats, J. W. Tetrahedron Lett. 1992, 33, 1977. (h) Dillon, J. L.; Gao,
Q.; Dillon, E. A.; Adams, N. Tetrahedron Lett. 1997, 38, 2231. (i) Coutts,
I. G. C.; Saint, R. E.; Saint, S. L.; Chambers-Asman, D. M. Synthesis
2001, 247. (j) Tojino, M.; Uenoyama, Y.; Fukuyama, T.; Ryu, I. Chem.
Commun. 2004, 2482.
r
10.1021/ol200358h
2011 American Chemical Society
Published on Web 04/01/2011

Scheme 1. Synthesis of Diazoketone 1
derived from three components: a primary amine, an
alkyne, and a bromodiazoacetone.10
Herein, we are communicating a new synthetic method
to obtain cyclic enaminones from amines and alkynes in
two steps. This disconnection enabled us to vary the
substituents on the enaminone structure in a convergent
fashion and to limit the use of diazomethane to the
preparation of the common diazoacetone intermediate
3a (Scheme 1). The enaminone reaction products are
well-known to be versatile intermediates for alkaloid
synthesis.11
To test our hypothesis, we first investigated the synthesis
of known diazoketone 1. We found that the desired
product could be readily synthesized by aza-Michael addi-
tion of benzylamino diazoacetone to ethyl propiolate in
ethanol (Scheme 1). Benzylamino diazoacetone (3a) was
prepared by the treatment of readily available bromodia-
zoacetone12 with an excess of benzylamine.
Figure 1. Two approaches for the synthesis of diazoketone 1.
water, alcohol, and amines are used whereas carbon nu-
cleophiles are used less frequently.7 Although organome-
tallic reagents such as RMgX and RLi have been explored
in reactions with ketenes, few methods are of significant
synthetic utility.8
Recently we reported a novel CÀC bond forming cycliza-
tion with a ketene tosynthesize six-membered enaminones,
under very mild conditions (Figure 1).9 In this cyclization,
a ketene is generated from diazoketone 1, employing a
silver-catalyzed Wolff rearrangement, which subsequently
reacts with a pendant vinylogous amide as a neutral
nucleophile to form six-membered enaminones such as 2a.
In our recently reported method, the diazoketone pre-
cursors were obtained from amino acids using diazo-
methane. Although the incorporation of chirality derived
from an amino acid into the enaminone is advantageous,
the use of diazomethane as well as the limited solubility of
amino acids in organic solvents diminishes the scale and
scope of this method. To address these issues, an alter-
native approach to synthesize the diazoketones was
sought. We envisioned that the diazoketones can be
Table 1. Synthesis of Amino Diazoketones
(8) For ketene reactions with organo lithium/magnesium reagents,
see: (a) Haener, R.; Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107,
5396. (b) Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. T. J. Am. Chem. Soc.
1985, 107, 5391. For reactions with other type of carbon nucleophiles,
see:(c) Rathke, M. W.; Sullivan, D. F. Tetrahedron Lett. 1973, 1297. (d)
Kita, Y.; Matsuda, S.; Kitagaki, S.; Tsuzuki, Y.; Akai, S. Synlett 1991,
401. (e) Negri, G.; Kascheres, C. J. Heterocycl. Chem. 2001, 38, 109.
(9) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512.
(10) A recent report of a three-component synthesis using a ketene:
Leon, F.; Rivera, D. G.; Wessjohann, L. A. J. Org. Chem. 2008, 73, 1762.
(11) (a) Comins, D. L.; Joseph, S. P. Adv. Nitrogen Heterocycl. 1996,
2, 251. (b) Joseph, S.; Comins, D. L. Curr. Opin. Drug Discovery Dev.
2002, 5, 870. (c) Comins, D. L.; O’Connor, S.; Al-awar, R. S. In
Comprehensive Heterocyclic Chemistry III; Alan, R. K., Christopher,
A. R., Eric, F. V. S., Richard, J. K. T., Eds.; Elsevier: Oxford, 2008; p 41.
(d) Turunen, B. J.; Georg, G. I. J. Am. Chem. Soc. 2006, 128, 8702. (e)
Niphakis, M. J.; Turunen, B. I.; Georg, G. I. J. Org. Chem. 2010, 75,
6793. (f) Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6019. (g)
Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 196.
a Reaction conditions: Bromodiazoacetone was treated with the
amine (4 equiv) in dichloroethane (0.25 M) at 50 °C. b Bromodiazoace-
tone was treated with tryptamine hydrochloride (2 equiv) in a 0.5 M
MeONa/MeOH solution (0.25 M) at 50 °C.
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Org. Lett., Vol. 13, No. 9, 2011

same fashion using bromodiazoacetone and alkyl amines.
A variety of primary alkyl amines (entry 1À6), as well as a
chiral amine (entry 7), and an amino acid derived amine
(entry 8) afforded the corresponding amino diazoketones
in good yields.
Scheme 2. Synthesis of an Enaminone Library via the Sequence
of aza-Michael Addition, Wolff Rearrangement, and Ketene
Cyclizationa
With amino diazoketones 3aÀ3h in hand, we carried out
the aza-Michael addition to the alkynes13 and subsequent
Wolff rearrangement in a one-flask procedure. In order to
obtain optimal yields, the use of two different solvents was
necessary. Ethanol was employed for the aza-Michael
addition, and dichloromethane for the Wolff rearrange-
ment. Using these reaction conditions, the enaminone
reaction products 2, 4, and 5À8 were obtained in good to
excellent yields (Scheme 2). In several instances, Ag2O was
found to be a better catalyst for the Wolff rearrangement
than PhCO2Ag.
In summary, we have discovered an efficient, conver-
gent synthesis of cyclic enaminones from bromodiazoa-
cetone, primary amines, and alkynes. Aza-Michael
addition, Wolff rearrangement, and nucleophilic ketene
cyclization were carried out sequencially in one flask,
providing facile access to an enaminone library. Explora-
tion of other C-nucleophiles in this methodology is
currently ongoing.
Acknowledgment. This work was supported by the Na-
tional Institutes of Health (GM081267) and the University
of Minnesota through the Vince and McKnight Endowed
Chairs. We thank Dr. Subhashree Francis (University of
Minnesota) for mass spectrometry assistance.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Bromodiazoacetone is currently commercially available or can
be prepared as described in the following references: (a) Pace, V;
Verniest, G.; Sinisterra, J.-V.; Alcantara, A. R.; De Kimpe, N. J. Org.
Chem. 2010, 75, 5760. (b) Padwa, A.; Austin, D. J.; Precode, L.; Zhi, L. J.
Org. Chem. 1993, 58, 1144.
a Reaction conditions: The amino diazoacetone was reacted with an
alkyne (1.2 equiv) in EtOH (0.2 M). Upon evaporation, the reaction
mixture was treated with the Ag catalyst (20 mol %, PhCO2Ag, under-
line: Ag2O) in dichloromethane (0.2 M) in the dark.
(13) The alkynes are commercially available with the exception of
1-phenylprop-2-yn-1-one, used for the synthesis of enaminones 6, which
was prepared using a reported method: Chassaing, S.; Kueny-Stotz, M.;
Isorez, G.; Brouillard, R. Eur. J. Org. Chem. 2007, 2438.
Encouraged by the successful synthesis of diazoketone 1,
amino diazoketones 3aÀ3h (Table 1) were prepared in the
Org. Lett., Vol. 13, No. 9, 2011
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