Direct synthesis of fused, bicyclic γ-butyrolactones via tandem reductive cyclization-carbonylation of tethered enals and enones

Full text of DOI:10.1021/ja9535874

J. Am. Chem. Soc. 1996, 118, 1557-1558
1557
Direct Synthesis of Fused, Bicyclic γ-Butyrolactones
via Tandem Reductive Cyclization-Carbonylation
of Tethered Enals and Enones
William E. Crowe* and An T. Vu
Figure 1. Diagnostic 1H NMR peaks for metallacycles 2b and 3b and
γ-butyrolactone 4b.
Department of Chemistry, Emory UniVersity
Atlanta, Georgia 30322
Scheme 1
ReceiVed October 25, 1995
γ-Butyrolactones are ubiquitous in Nature, occurring in about
10% or more of structurally elucidated natural products.1 An
attractive route to this ring system is the [2 + 2 + 1] approach
illustrated in Scheme 1A (X ) O). Although a similar approach
has been successfully employed for the construction of five-
membered-ring carbocycles,2 the application of this route to
heterocycle synthesis is not known. Herein we report the first
examples of this useful reaction.
Takaya has shown that 1-oxa-5-titanacyclopentanes, derived
from insertion of aldehydes into Cp*2Ti(CH2dCH2) (Cp* )
η5-C5Me5), react with CO to give stable carbonylated metalla-
cycles by insertion of CO into the Ti-C bond (Scheme 1B).3
No products arising from insertion into the stronger Ti-O bond
were observed. Takaya’s carbonylated metallacycles were
remarkably stable with respect to reductive elimination. Slow
decomposition was observed at 210 °C; ethylene and CO were
liberated, but no γ-butyrolactone products were detected.
In 1990, Whitby and Hewlett4 reported that δ,ꢀ-unsaturated
carbonyl compounds react with Cp2Ti(PMe3)25 to afford bicyclic
titanium oxametallacycles (eq 1). In their initial report, the
authors briefly described several metallacycle cleavage protocols
but noted that “unfortunately, ...conditions for new carbon-
carbon bond formation have not yet been found.” We6 and
Buchwald7 recently showed that, in the presence of 1 equiv of
an appropriate silane reagent, a titanium-catalyzed reaction is
possible. Reductive metallacycle cleavage, allowing for ca-
talysis, takes place via σ-bond metathesis followed by reductive
elimination as depicted in eq 2. This reaction sequence,
however, results in the formation of a C-H bond upon
metallacycle cleavage. To the best of our knowledge, carbon-
carbon bond forming reactions of these titanium oxametalla-
cycles still have not been reported. Surprisingly, carbonylation
does not appear to have been studied.
Table 1. Yield Summary for Tandem Reductive
Cyclization-Carbonylation Reactionsa
a Reaction conditions: (i) Cp2Ti(PMe3)2, pentane, 25 °C, 2 h; (ii)
CO (1 atm), pentane, 25 °C, 12 h; (iii) air (1 atm), pentane, 25 °C, 4
h. b Reaction yields, indicated by column heading, are for the overall
transformation carried out without isolation of organometallic inter-
mediates. All reported yields are for isolated products purified by
crystallization or column chromatography. c Reference 2. d Improved
yield. e Low yield is due to the high solubility of the product in pentane
hampering product crystallization. Reaction yield is much higher.
f Formed as a mixture of diastereomers (diastereomer ratios: 1.5:1 for
2c-4c; 2.3:1 for 2d-4d; 4.5:1 for 2f-4f; 1.8:1 for 2g-4g). g A
reasonably pure product could not be isolated from the reaction mixture
by crystallization.
Titanium metallacycles 2a-l were prepared by reacting
substrates 1a-l (Table 1) with Cp2Ti(PMe3)2 (eq 1). Upon
treatment of complexes 2a-i with CO (1 atm, 25 °C),
carbonylated metallacycles 3a-i were formed via insertion of
CO into the Ti-C bond (Table 1). As expected, the carbony-
lated metallacycles did not spontaneously undergo reductive
elimination at room temperature and could be isolated as purple,
(1) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
24, 94-110.
(2) See, for example: (a) Lee, B. Y.; Chung, Y. K.; Jeong, N.; Lee, Y.
S.; Hwang, S. H. J. Am. Chem. Soc. 1994, 116, 8793-8794. (b) Jamison,
T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc.
1994, 116, 5505-5506. (c) Berk, S. C.; Grossman, R. B.; Buchwald, S. L.
J. Am. Chem. Soc. 1994, 116, 8593-8601. (d) Bernardes, V.; Verdaguer,
X.; Kardos, N.; Riera, A.; Moyano, A.; Pericas, M. A.; Greene, A. E.
Tetrahedron Lett. 1994, 35, 575-578. (e) Krafft, M. E.; Scott, I. L.; Romero,
R. H.; Feibelmann, S.; Vanpelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199-
7207. (f) Schore, N. E. Org. React. (N.Y.) 1991, 40, 1-90. (g) Negishi, E.;
Swanson, D. R.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1987,
28, 917-920.
(4) Hewlett, D. F.; Whitby, R. J. J. Chem. Soc., Chem. Commun. 1990,
1684-1686.
(5) (a) Kool, L. B.; Rausch, M. D.; Alt, H. G.; Herberhold, M.; Thewalt,
U.; Wolf, B. Angew. Chem., Int. Ed. Engl. 1985, 24 , 394. (b) Binger, P.;
Mu¨ller, P.; Benn, R.; Rufinska, A.; Gabor, B.; Kru¨ger, C.; Betz, P. Chem.
Ber. 1989, 122, 1035.
(6) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787-
6788.
(7) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117,
6785-6786.
(3) Mashima, K.; Haraguchi, H.; Oyoshi, A.; Sakai, N.; Takaya, H.
Organometallics 1991, 10, 2731-2736.
0002-7863/96/1518-1557$12.00/0 © 1996 American Chemical Society

1558 J. Am. Chem. Soc., Vol. 118, No. 6, 1996
Communications to the Editor
Figure 2. ORTEP drawings of metallacycle 2f and its carbonylation product, 3f.
microcrystalline solids. The presence of a titanium acyl moiety
was supported by IR (νCdO ) 1618-1625 cm-1) and 13C NMR
(δCdO ) 289-290 ppm).8 Exclusive insertion of CO into the
Ti-C is suggested by 1H NMR. The widely separated,
diastereotopic protons (AMX pattern) for the TiCH2 moiety9
of the starting metallacycle are replaced by the slightly separated
signals (ABX pattern) for Ti(CdO)CH2 (Figure 1).
X-ray quality crystals of the major diastereomer of metalla-
cycle 2f (from pentane/heptane solution) and carbonylation
product 3f (from toluene solution) could be obtained by slow
solvent evaporation (1-3 weeks, 25 °C). Molecular structures,
established by single-crystal X-ray analysis, are shown in Figure
2. In 3f, the Ti-C8 bond distance of 2.218(3) Å and the Ti-
O1 bond distance of 1.850(2) Å are normal for single, covalent
bonds. The Ti‚‚‚O2 interatomic distance of 3.117 Å and the
Ti-C8-O1 bond angle of 128.3(2)° indicate an η1 bonding mode
for the Ti-acyl moiety.
Reductive elimination of γ-butyrolactones 4a-i from met-
allacycles 3a-i could be induced thermally or oxidatively or
upon treatment with a suitable Lewis acid. We found that
simply exposing the carbonylated metallacycles to air cleanly
and reproducibly gave γ-butyrolactone products in fair to good
yields. The entire reaction sequence of reductive cyclization,
carbonylation, and reductive elimination could also be carried
out directly without isolation of organometallic intermediates
(Table 1).10
Metallacycle 2j, obtained by reductive cyclization of internal
alkyne 1j, did not react with CO (1 atm) at ambient temperature.
Imine-derived metallacycles 2k and 2l (from 1j and 1l) also
failed to react with CO. In both cases starting metallacycle
could be recovered from the reaction mixture quantitatively.
The failure of 2j to react with CO may be attributable to the
increase strength of the Ti-Cvinyl (vs Ti-Calkyl) bond in the
metallacycle. The lack of reactivity of imine-derived metalla-
cycles may be related to the increased steric bulk resulting from
the replacement of a divalent oxygen with a trivalent nitrogen
in the metal coordination sphere.
Heating toluene solutions of metallacycles 2a-i with CO (1
atm) to 80 °C significantly accelerated the rate of carbonyl
insertion and reductive elimination. Carbonylation reactions
performed at elevated temperatures lead to direct formation of
γ-butyrolactone products in a single step.11 Heating of toluene
solutions of metallacycles 2j-l, however, did not lead to
carbonyl insertion. Although starting material was consumed,
neither carbonylated metallacycles nor five-membered-ring
heterocycles (from reductive elimination) could be detected in
these reaction mixtures.12
In summary, we have reported a titanium-mediated synthesis
of γ-butyrolactones which proceeds via the reaction sequence
of reductive coupling-carbonylation-reductive elimination.
Notable features of this new procedure are the mild reaction
conditions (ambient temperature and pressure) and the readily
available titanium reagent (prepared in one step from com-
mercially available Cp2TiCl2). The current procedure has been
successfully applied to the intramolecular coupling of aldehydes
or ketones to terminal olefins. We are currently attempting to
derive similar protocols for the conversion of the less reactive
metallacycles derived from imines or alkynes to corresponding
five-membered-ring heterocycles.13
Acknowledgment. Support of this work by the Emory University
Research Fund and the Petroleum Research Fund is gratefully
acknowledged. We thank Karl Hagen and Mark Semones for assistance
with X-ray crystallography.
(8) Although the carbonyl carbon resonance was not observable in stable
C6D6 solutions, it was observable in CDCl3. In CDCl3, the complexes
decomposed slightly during the course of data acquisition.
Supporting Information Available: Experimental procedures,
spectral data for all compounds, and listings of fractional atomic
coordinates and anisotropic thermal parameters for metallacycles 2f
and 3f (33 pages). This material is contained in many libraries on
microfiche, immediately follows this article in the microfilm version
of the journal, can be ordered from the ACS, and can be downloaded
from the Internet; see any current masthead page for ordering
information and Internet access instructions.
(9) (a) Widely separated, diastereotopic TiCH2 protons seems to be a
general characteristic of chiral titanocene metallacycles. For the monocyclic
1-oxa-5-titanacyclopentanes studied by Bercaw9b and Takaya,3 there are
an upfield signal at δ 0.3-0.4 and a downfield signal at δ 2.2-2.3. For
bicyclic 1-oxa-5-titanacyclopentanes 1a-l, there are an upfield signal at δ
0.82-1.11 and a downfield signal at δ 2.85-2.99. (b) Cohen, S. A.; Bercaw,
J. E. Organometallics 1985, 4, 1006-1014.
(10) To a solution of 330 mg (1 mmol) of Cp2Ti(PMe3)2 in 15 mL of
pentane was added directly 98 mg (1 mmol) of 5-hexenal 1a. After being
stirred for 2 h at room temperature, the reaction mixture was filtered through
a pad of Celite and rinsed with pentane to give a reddish solution of
metallacycle 2a. To this solution was introduced atmospheric pressure of
carbon monoxide via a balloon at room temperature for an additional 12 h.
The solution color changed from red to deep red-purple, indicating formation
of 3a. After 20 mL of ethyl ether was added, the reaction mixture was
exposed to air and stirred for 4 h, during which time it turned bright yellow
and a precipitate formed. The resulting yellow mixture was filtered through
a pad of silica gel, rinsed with 3:1 ether/pentane (2 × 40 mL). The filtrate
was concentrated under reduced pressure to give a yellow liquid residue,
which was chromatographed on silica gel using 5:1 hexanes/EtOAc as eluent
to give the lactone product as a colorless liquid. Yield: 76.0 mg (60.3%).
JA9535874
(11) The only identifiable titanium-derived byproduct observed in the
final reaction mixture was Cp2Ti(CO)2 (1H NMR (C6D6) δ 4.56; IR
(heptane) νCO ) 1895, 1974 cm-1).
(12) The only identifiable products observed in these reaction mixtures
were Cp2Ti(CO)2 and, in low yield, the acyclic aldehyde (from 2j) or imine
(from 2k,l) used to form the metallacycle substrate.
(13) Preliminary studies indicate that replacing CO with more Lewis basic
isonitriles results in a faster insertion followed by an unexpected rearrange-
ment: W. E. Crowe, A. T. Vu, manuscript in preparation.