A new synthesis of cyclobutanones: Highly selective carbonylation of titanacyclobutane complexes prepared by free radical alkylation [11]

Full text of DOI:10.1021/ja0158657

8872
J. Am. Chem. Soc. 2001, 123, 8872-8873
Scheme 1
A New Synthesis of Cyclobutanones: Highly
Selective Carbonylation of Titanacyclobutane
Complexes Prepared by Free Radical Alkylation
Charles A. G. Carter, Grace Greidanus, Jian-Xin Chen, and
Jeffrey M. Stryker*
Department of Chemistry, UniVersity of Alberta
Edmonton, Alberta, T6G 2G2 Canada
ReceiVed March 22, 2001
ReVised Manuscript ReceiVed July 18, 2001
under appropriate conditions, be controlled to incorporate a single
equivalent of CO, producing cyclobutanones exclusively.
As anticipated, permethyltitanacyclobutane complexes 1 un-
dergo the Bercaw carbonylation at low temperature under CO
pressure (-78 °C, 60 psi).9 Conducting the carbonylation at higher
temperature and low pressure, however, promotes the intramo-
lecular migration (II f IV) over the intermolecular carbonylation
(II f III) and leads to the formation of organic cyclobutanones
exclusively in high yield (Table 1).10,11 The organometallic product
of the reaction, (C5Me5)2Ti(CO)2,12 is recovered in high yield by
precipitation from the nonpolar reaction medium. The low yield
obtained for carbonylation of â-allyltitanacyclobutane complex
2e arises from the thermal instability of this compound above
room temperature.13
For synthetic applications, titanacyclobutane complexes 1 can
be prepared without isolation of the η3-allyltitanium intermediate,
using SmI2‚THF to mediate both the reductive allylation and
generation of the alkyl radical (eq 1). In contrast to the reactions
of isolated η3-allyltitanium complexes with unstabilized organic
radicals generated by using SmI2,4a the one-pot preparation does
Cyclobutanones and related carbocyclic four-membered ring
compounds constitute an important class of synthetic intermedi-
ates1 and polymer precursors.2 More recently, cyclobutane deriva-
tives have emerged as significant in terms of biological and
pharmaceutical activity.3
In this communication, we report general new methodology
for the synthesis of substituted cyclobutanones, based on the
highly selective mono-carbonylation of titanacyclobutane com-
plexes, a new reactivity pattern for metallacyclobutane complexes
of the early transition metals. In conjunction with the recent
development of titanacyclobutane synthesis by free radical
alkylation of η3-allyltitanium(III) complexes,4 this carbonylation
constitutes a convergent and stereoselective new approach to the
construction of cyclobutanones.
Carbonylation converts metallacyclopentane, metallacyclopen-
tene, and related early transition metal complexes into syntheti-
cally valuable five-membered ring compounds via the insertion
of one equivalent of carbon monoxide and subsequent reductive
elimination.5-7 In contrast, metallacyclobutane complexes of the
early transition metals instead undergo the Bercaw carbonylation,
incorporating two equiValents of carbon monoxide to give
cyclopentendiolate complexes (e.g., III, Scheme 1).8 Here we
report that the carbonylation of titanacyclobutane complexes can,
(6) Cyclopentenones, recent and leading references: (a) Ti: Hicks, F. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 7026. Sturla, S. J.; Buchwald,
S. L. J. Org. Chem. 1999, 64, 5547. Hicks, F. A.; Kablaoui, N. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 5881 and references therein. Cohen, S.
A.; Bercaw, J. E. Organometallics 1985, 4, 1006. Bristow, G. S.; Lappert,
M. F.; Martin, T. R.; Atwood, J. L.; Hunter, W. F. J. Chem. Soc., Dalton
Trans. 1984, 399. (b) Zr: Negishi, E.-i.; Holmes, S. J.; Tour, J. M.; Miller,
J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc.
1989, 111, 3336. Negishi, E.-i. In ComprehensiVe Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 1163. Buchwald,
S. L.; Lum, R. T.; Fisher, R. A.; Davis, W. M. J. Am. Chem. Soc. 1989, 111,
9113. Probert, G. D.; Whitby, R. J.; Coote, S. J. Tetrahedron Lett. 1995, 36,
4113, and references therein. Erker, G.; Engel, K.; Kruger, C.; Chiang, A.-P.
Chem. Ber. 1982, 115, 3311.
(7) γ-Lactones, leading references: Kablaoui, N. Hicks, F. A.; Buchwald,
S. L.; J. Am. Chem. Soc. 1997, 119, 4424. Crowe, W. E.; Vu, A. T. J. Am.
Chem. Soc. 1996, 118, 5508. Mashima, K.; Haraguchi, H.; Ohyoshi, A.; Sakai,
N.; Takaya, H. Organometallics 1991, 10, 2731.
(8) (a) See ref 5c and the following: Roddick, D. M.; Bercaw, J. E. Chem.
Ber. 1989, 122, 1579. (b) Brown-Wensley, K. A.; Buchwald, S. L.; Cannizzo,
L.; Clawson, L.; Ho, S.; Meinhardt, D.; Stille, J. R.; Straus, D.; Grubbs, R.
H. Pure Appl. Chem.1983, 55, 1733. (c) Dennehy, R. D.; Whitby, R. J. J.
Chem. Soc., Chem. Commun. 1990, 1060. (d) Petersen, J. L.; Egan, J. W., Jr.
Organometallics 1987, 6, 2007. (e) Beckhaus, R.; Wilbrandt, D.; Flatau, S.;
Bohmer, W.-H. J. Organomet. Chem. 1992, 423, 211. (f) Tjaden, E. B.;
Stryker, J. M. J. Am. Chem. Soc. 1993, 115, 2083.
(9) The synthesis of cyclopentenediolates and organic cyclopentanoid
derivatives is detailed in a separate account: Carter, C. A. G.; Casty, G. L.;
Stryker, J. M. Synlett 2001, 1046.
(10) Experimental procedures and complete characterization of all new
compounds are provided as Supporting Information.
(11) Two isolated instances of single carbonylation in early transition metal
metallacyclobutane complexes have been previously observed, both providing
complexed η2-cyclobutanone rather than the free organic. (a) Hf: Erker, G.;
Czisch, P.; Schlund, R.; Angermund, K.; Kruger, C. Angew. Chem., Int. Ed.
Engl. 1986, 25, 364. (b) Ta: Rietveld, M. H. P.; Hagen, H.; van de Water,
L.; Grove, D. M.; Kooijman, H.; Veldman, N.; Spek, A. L.; van Koten, G.
Organometallics 1997, 16, 168.
* Author for correspondence. Telephone: (780) 492-3891. E-mail:
jeff.stryker@ualberta.ca.
(1) Reviews: (a) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988,
27, 797. (b) Lee-Ruff, E. In AdVances in Strain in Organic Chemistry; Halton,
B., Ed.; JAI Press: Greenwich, CT, 1991; Vol. 1. (c) Nemoto, H.; Fukumoto,
K. Synlett 1997, 863. Recent and leading references: (d) Murakami, M.;
Tsuruta, T.; Ito, Y. Angew. Chem., Int. Ed. 2000, 39, 2484. (e) Brown, B.;
Hegedus, L. S. J. Org. Chem. 2000, 65, 1865. (f) Hegedus, L. S.; Ranslow,
P. B. Synthesis 2000, 953. (g) Riches, A. G.; Wernersbach, L. A.; Hegedus,
L. S. J. Org. Chem. 1998, 63, 4691. (h) Brown, R. C. D.; Keily, J.; Karim, R.
Tetrahedron Lett. 2000, 41, 3247. (i) Miyata, J.; Nemoto, H.; Ihara, M. J.
Org. Chem. 2000, 65, 504. (j) Johnston, D.; McCusker, C. F.; Muir, K.; Proctor,
D. J. J. Chem. Soc., Perkin Trans. 1 2000, 681. (k) Jiang, W.; Fuertes, M. J.
Wulff, W. D. Tetrahedron 2000, 56, 2183. (l) Weber, J.; Haslinger, U.; Brinker,
U. J. Org. Chem. 1999, 64, 6085. (m) Vinson, N. A.; Day, C. S.; Welker, M.
E.; Guzei, I.; Rheingold, A. L. Organometallics 1999, 18, 1824.
(2) Kniep, C. S.; Padius, A. B.; Hall, H. K., Jr. Tetrahedron 2000, 56,
4279, and references therein.
(3) (a) Cyclobut-A and related anti-viral compounds: Norbeck, D. W.;
Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham, H.; Herrin, T.; Plattner, J. J.;
Erisckson, J. Clement, J.; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh,
K.; Arnett, G.; Shannon, W.; Broder, S.; Mitsuya, H. J. Med. Chem. 1990,
33, 1281. Brown, B.; Hegedus, L. S. J. Org. Chem. 1998, 63, 8012 and
references therein. Frieden, M.; Giraud, M.; Rees, C. B.; Song, Q. L. J. Chem.
Soc., Perkin Trans. 1 1998, 2827. (b) Prasit, P. Rideneau, D. Ann. Rep. Med.
Chem. 1997, 32, 211. Friesen, R. W.; Dube, D.; Fortin, R.; Frenette, R.;
Prescott, S.; Cromlish, W.; Greig, G. M.; Kargman, S.; Wong, E.; Chan, C.
C.; Gordon, R.; Xu, L. J.; Rideneau, D. Bioorg. Med. Chem. Lett. 1996, 6,
2677. (c) Delincee, H.; PoolZobel, B. L. Radiat. Phys. Chem. 1998, 52, 39.
(4) (a) Casty, G. L.; Stryker, J. M. J. Am. Chem. Soc. 1995, 117, 7814. (b)
Ogoshi, S.; Stryker, J. M. J. Am. Chem. Soc. 1998, 120, 3514. (c) Carter, C.
A. G.; McDonald, R.; Stryker, J. M. Organometallics 1999, 18, 820. (d)
Greidanus, G.; McDonald, R.; Stryker, J. M., Organometallics 2001, 20, 2942.
(5) Cyclopentanones: (a) McDermott, J. X.; Wilson, M. E.; Whitesides,
G. M. J. Am. Chem. Soc. 1976, 98, 6529. (b) Grubbs, R. H.; Miyashita, A.;
Liu, M.; Burk, P. J. Am. Chem. Soc. 1978, 100, 2418. (c) Manriquez, J. M.;
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(12) Bercaw, J. E.; Marvich, R. H.; Bell, L. G.; Brintzinger, H. H. J. Am.
Chem. Soc. 1972, 94, 1219.
(13) The 3-allyl complex 2e decomposes by homolysis of the â-carbon-
carbon bond, an unprecedented pathway for titanacyclobutane decomposi-
tion: Greidanus, G.; Stryker, J. M. Manuscript in preparation.
10.1021/ja0158657 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 36, 2001 8873
Table 1. Carbonylation of Titanacyclobutanes to Give
substituted allyl complexes in the bis(2-N,N-dimethylaminoinde-
nyl)titanium series can be prepared in situ from allylic Grignard
or lithium reagents and alkylated without isolation (eq 2).15 More
importantly, the 2-methyl- and 3-benzyl-substituted titanacyclo-
butane complexes 5b-d are thermally more stable than the
corresponding bis(2-piperidinoindenyl)titanacyclobutane com-
plexes, which do not undergo clean carbonylation.16
Cyclobutanones10
In contrast to the carbonylations of bis(2-piperidinoindenyl)-
titanacyclobutane complexes, however, the corresponding bis(2-
N,N-dimethylaminoindenyl)titanacyclobutane complexes do not
directly liberate cyclobutanone under standard carbonylation
conditions. Although the crude reaction mixture contains the
expected byproduct, (2-N,N-dimethylaminoindenyl)2Ti(CO)2 7,
this complex is isolated in only about 50% yield.10 The rest of
the metal and all of the organic fragment are obtained in the
form of an as yet uncharacterized paramagnetic intermediate.
Release of the cyclobutanone is obtained upon air oxidation or
hydrolytic workup.10
Finally, in a preliminary investigation, we have established that
the cyclobutanone synthesis can be carried out in a single
operation starting from bis(2-N,N-dimethylaminoindenyl)titanium
chloride 6 (eq 3). As illustrated for cyclobutanones 4a and 4f,10
this as yet unoptimized one-pot procedure delivers only moderate
yields but avoids the isolation and manipulation of air- and
moisture-sensitive intermediates.
a Reaction conditions. A: 45 °C, 10 psig CO, pentane, 12 h; B: as
in A, but in toluene, 6 h; C: rt, 1 atm CO, THF, 5-15 min; then air;
D: 45 °C, 10 psig CO, THF, 15 min; then HCl; E: as in C, but with
HCl quench. b Isolated yield after purification by chromatography.
c Yield of volatile cyclobutanone determined by GC (calibrated against
2-butanone as internal standard). d Volatile cyclobutanone isolated and
purified as the 2,4-dinitrophenylhydrazone.
not require elevated temperatures.14 The titanacyclobutane com-
plexes thus formed can be carbonylated directly without isolation
or purification.10
The carbonylation of titanacyclobutane complexes can thus be
controlled to produce strained cyclobutanones rather than the
expected cyclopentenediolate complexes. Combined with the
regioselective radical alkylation of allyltitanium complexes, the
carbonylation provides a unique, convergent, three-component
strategy for the stereocontrolled synthesis of substituted cyclo-
butanones. Development of improved titanocene templates and
extension of titanacyclobutane synthesis to accommodate ad-
ditional substitution, richer functionality, and intramolecular
variants is currently under investigation.
Acknowledgment. Financial support from the NSERC of Canada and
the University of Alberta is gratefully acknowledged.
The synthesis of more highly substituted cyclobutanones
requires the use of alternative titanocene templates based on
2-N,N-dialkylaminoindenyl ligand systems.4c,d Titanacyclobutane
complexes 3 and 5 derived from 2-piperidinoindenyl4c and 2-N,N-
dimethylaminoindenyl4d titanocenes, respectively, undergo highly
selective carbonylation, providing trans-2,3-disubstituted cyclo-
butanones 4a-f exclusively in high yield (Table 1).10 Although
the carbonylation reaction proceeds cleanly in both systems, the
use of the 2-N,N-dimethylaminoindenyl system provides signifi-
cant advantages over the 2-piperidinoindenyl template. The
Supporting Information Available: Text providing full experimental
details and complete spectroscopic and analytical characterization for all
new compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0158657
(15) The use of SmI2‚THF for both allyl complex generation and subsequent
radical alkylation, analogous to the permethyltitanocene procedure (eq 1),
returns high yields for the unsubstituted allyl ligand and moderate yields for
the crotyl ligand, but fails for the cinnamyl ligand.
(16) 2-Methyltitanacyclobutanes decompose by â-hydride elimination from
the methyl substitutent;4c 3-benzyltitanacyclobutanes undergo slow homolytic
scission of the â-benzyl substituent at room temperature.13
(14) We tentatively attribute this observation to the intervention of an
unidentified Ti(III) species, which catalyzes the generation of unstabilized
radicals at a rate significantly greater than obtained from SmI2 alone, as
previously noted.4b