Nickel-catalyzed rearrangement of 1-acyl-2-vinylcyclopropanes. A mild synthesis of substituted dihydrofurans

Article abstract of DOI:10.1021/ol052700k

Mild Ni(0)-catalyzed rearrangements of 1-acyl-2-vinylcyclopropanes have been developed. The room-temperature isomerizations afford dihydrofuran products in yields regularly greater than 90%. A highly substituted, stereochemically defined cyclopropane was

Full text of DOI:10.1021/ol052700k

ORGANIC
LETTERS
2006
Vol. 8, No. 4
573-576
Nickel-Catalyzed Rearrangement of
1-Acyl-2-vinylcyclopropanes. A Mild
Synthesis of Substituted Dihydrofurans
Roy K. Bowman and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received November 7, 2005
ABSTRACT
Mild Ni(0)-catalyzed rearrangements of 1-acyl-2-vinylcyclopropanes have been developed. The room-temperature isomerizations afford dihydrofuran
products in yields regularly greater than 90%. A highly substituted, stereochemically defined cyclopropane was employed in the rearrangement
to evaluate the reaction mechanism. Product analysis indicates that the overall reaction proceeds with retention of configuration at the vinyl-
bearing stereogenic center.
Increasingly sophisticated technologies are available for the
stereoselective synthesis of functionalized cyclopropanes.1
Simplified routes to such structures suggest that cyclopropyl
ketones might serve as readily accessed precursors to
dihydrofurans via [1,3]-transposition. The utility of such a
reaction rests in part on the ability of the rearrangement
product to undergo subsequent oxidative or reductive ma-
nipulation, leading to useful aromatic or saturated five-
membered oxygenated heterocycles.
development has received less attention than that of the all-
carbon variant (Y ) CR2).3
In this paper, we describe a strategy for performing mild
rearrangements of 1-acyl-2-vinyl cyclopropanes to the de-
rived dihydrofurans (1 f 2); the approach relies on the
documented propensity of low-valent metal complexes to
initiate productive π-allyl complex formation with suitably
activated vinyl cyclopropanes.4
The generalized rearrangement expressed in Scheme 1 (Y
) O) is a recognized entry into dihydrofurans,2 but its
Scheme 1. Rearrangement of Vinyl- and Acylcyclopropanes
to Cyclopentenes and Dihydrofurans
(1) (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 977-1050. (b) Kunz, R. K.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 3240-3241. (c) Risatti, C. A.; Taylor, R. E. Angew.
Chem., Int. Ed. 2004, 43, 6671-6672. (d) Papageorgiou, C. D.; de Dios,
M. A. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 4641-
4644. (e) Liao, W.-W.; Li, K.; Tang, Y. J. Am. Chem. Soc. 2003, 125,
13030-13031.
(2) (a) Wenkert, E.; Alonso, M. E.; Buckwalter, B. L.; Chou, K. J. J.
Am. Chem. Soc. 1977, 99, 4778-4782. (b) Davies, H. M. L.; Ahmed, G.;
Calvo, R. L.; Churchill, M. R.; Churchill, D. G. J. Org. Chem. 1998, 63,
2641-2645. (c) Yadav, V. K.; Balamurugan, R. Org. Lett. 2001, 3, 2717-
2719. (d) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645-
9660.
10.1021/ol052700k CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/19/2006

The rearrangement of vinyl cyclopropyl ketone 1a (X )
Me; R1 ) R2 ) R3 ) H) to dihydrofuran 2a may be catalyzed
under forcing conditions (g100 °C) with Cu(I) or Rh(I).5,6
The success of these preliminary studies and our continuing
interest in heterocycle synthesis from three-membered rings7
led us to consider methods that would effect this transforma-
tion under mild conditions. Initially, we chose to examine
several mechanistically distinct approaches (Scheme 2).
In the event, all three strategies proved adequate for
isomerization to dihydrofuran. Lewis acid catalysis was
observed with several metal salts; Cu(OTf)2 facilitated
complete conversion of cyclopropane 1a to dihydrofuran 2a
at ambient temperature with a catalyst loading of 10 mol %
(4 h).10 Pd(0) and Ni(0) catalysts were also effective, with
the latter typically providing >95% conversion in less than
1 h, while Pd(0) catalysts required several hours to reach
completion. The combination of BINOL/PPh3 provided 2a
but showed incomplete conversion even over extended
reaction times (74% conversion, THF, 25 °C, 17 h). Of the
methods examined, the use of Ni(0) was most efficient in
terms of catalyst loading and reaction time and was selected
for further exploration.
Scheme 2. Strategies for 1-Acyl-2-vinylcyclopropane
Rearrangement (See Text)
The application of the LnNi system to a group of diverse
vinyl cyclopropyl ketones resulted in an efficient rearrange-
ment protocol (Table 1). Cyclopropanes made from deriva-
tives of alkyl acetoacetates (entries 1-3) underwent smooth
isomerization at ambient temperature. The reactions were
complete in 10 min and required only 2 mol % of Ni(COD)2.
2,2’-Bipyridyl proved the most effective ligand for these
substrates. Low conversion was observed in the absence of
a ligand. As reported previously,6 the substrate containing
the geminal ester moiety (entry 4) does not isomerize to 2
even with a higher catalyst loading and longer reaction time.
Substitution at the keto-arm was successful as well (entries
5-8), with substrates containing alkene, aryl, cyano, and
acetal functional groups undergoing efficient rearrangement.
We were able to reduce catalyst loading to 1 mol %
Ni(COD)2 by changing the supporting ligand from 2,2’-
bipyridyl to triphenylphosphine. This extended the reaction
time to 1 h; however, dihydrofurans 2e-h were all isolated
in >95% yield. We observed incomplete conversion using
(Ph3P)2Ni(COD) for substrates 1-3. The two metal-ligand
systems could be interchanged based on the exact (to date
undefined) requirements of the substrate.
Structural changes to the alkene were also tolerated.
Disubstitution of the vinyl group was tolerated employing 2
mol % (Ph3P)2Ni(COD) (entry 9). While trisubstitution of
the olefin was initially unsuccessful using the (Ph3P)2Ni-
(COD) catalyst system, switching to 2,2’-bipyridyl as the
ligand led to higher yields. It was necessary to increase the
catalyst loading to 5 mol % and the reaction time to 4.5 h
(entry 10); however, this protocol successfully afforded
dihydrofuran 2j in 80% yield.
Under Lewis acid catalysis (A), chelation to the geminal
acyl groups would act to weaken the cyclopropane bond
leading to ring opening.8 In the limiting case, this would
result in an allyl cation/enolate zwitterion that could undergo
internal quenching to give product. Our second option (B)
was to use transition metals capable of triggering π-allyl
chemistry. In this scenario, association of the alkene followed
by π-allyl formation by ring opening of the cyclopropane
would result in an (allyl)metal species with a pendant
enolate.4a,d A third option (C) was use of a Lewis base in
conjunction with a Brønsted acid. Under these conditions
the Brønsted acid would activate the pendant carbonyl in
the same manner as a Lewis acid, then attack of the Lewis
base would open the cyclopropane in a “pull-push” fashion.9
Attempted asymmetric catalysis of this rearrangement
using scalemic catalysts in no case led to product enantio-
enrichment. The retention of chirality through an inversion-
inversion mechanism is the normal reaction mode for
stabilized anions11,12 and we hypothesized that this mecha-
nism was operative.
(3) For example: Zuo, G.; Louie, J. Angew. Chem., Int. Ed. 2004, 43,
2277-2279.
(4) (a) Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982,
23, 2871-2874. (b) Burgess, K. Tetrahedron Lett. 1985, 26, 3049-3052.
(c) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1985, 26, 3825-
3828. (d) Yamamoto, K.; Ishida, T.; Tsuji, J. Chem. Lett. 1987, 1157-
1158. (e) Hirio, K.; Arinaga, Y.; Ogino, T. Chem. Lett. 1992, 2329-2332.
(5) Vardapetyan, A. A.; Khachatryan, D. S.; Panosyan, G. A.; Morlyan,
N. M. J. Org. Chem. USSR 1986, 22, 2034-2037.
(6) Dzhemilev, U. M.; Khusnutdinov, R. I.; Shchadneva, N. A.; Tolstikov,
G. A. Bull. Acad. Sci. USSR, DiV. Chem. Sci. 1990, 39, 1447-1450.
(7) (a) Pohlhaus, P. D.; Bowman, R. K.; Johnson, J. S. J. Am. Chem.
Soc. 2004, 126, 2294-2295. (b) Pohlhaus, P. D.; Johnson, J. S. J. Org.
Chem. 2005, 70, 1057-1059.
(10) Other promoters tested, THF, 25 °C (GC yield, time): TiCl4(THF)2
(21%, 4 h), SnCl2 (<3%, 4 h), AlCl3 (<3%, 4 h), ZnCl2 (<3%, 4 h), MgCl2
(<3%, 4 h), Sn(OTf)2 (55%, 4 h), Mg(OTf)2 (<3%, 4 h), Zn(OTf)2 (<3%,
4 h), La(OTf)3 (24%, 4 h), TiF4 (<3%, 4 h), ZrCl4 (48%, 4 h), DMAP/
BINOL (<3%, 17 h), P(OPh)3/BINOL (<3%, 17 h), PPh3 (19%, 18 h),
quinuclidine (14%, 18 h).
(11) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257-276.
(12) Hayashi, T.; Yamane, M.; Ohno, A. J. Org. Chem. 1997, 62, 204-
207.
(8) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023-
3026.
(9) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094-
12095.
574
Org. Lett., Vol. 8, No. 4, 2006

Table 1. Rearrangement of Acyl Cyclopropanes to Dihydrofurans
To gain greater insight into the mechanism and to
implement the overall reaction strategy in a more complex
system, we evaluated the rearrangement of vinyl cyclo-
propane 7. This particular cyclopropane includes a vicinal
substituent that can be used as a stereochemical marker to
evaluate the fate of the neighboring vinyl-bearing stereogenic
center.
propane synthesis that enables downstream Ni-catalyzed
rearrangement: reaction of crotonaldehyde with sulfonium
ylide 3 catalyzed by indoline-2-carboxylic acid (S)-4 afforded
trisubstituted cyclopropane 5 selectively according to the
MacMillan protocol (Scheme 3).1b Wittig olefination of the
cyclopropyl aldehyde led to vinylcyclopropane 6. Acylation
of the derived enolate (LDA, benzoyl chloride) gave the
geminal diketone 7 in 47% yield (88% ee). Exposure to 5
mol % of (Ph3P)2Ni(COD) afforded dihydrofuran 8 in 94%
The use of 7 also provided us the opportunity to implement
newly developed enantioselective technology for cyclo-
Org. Lett., Vol. 8, No. 4, 2006
575

The observed stereochemical outcome is consistent with a
double-inversion mechanism.
Scheme 3. Synthesis of Enantioenriched Vinylcyclopropane
and Test for Chirality Transfer
We have successfully realized ring opening of vinyl
cyclopropyl ketones substituted geminally with electron
withdrawing groups at ambient temperature under mild
reaction conditions to afford dihydrofuran products. This
method is noteworthy for low catalyst loadings and short
reaction times and is tolerant of both functional and structural
changes made to the cyclopropane. Work is underway to
extend this method to the formation of other heterocycles,
and experimentation to intercept putative intermediates to
further probe the reaction mechanism is ongoing.
Acknowledgment. This work was supported by a NSF
CAREER grant (CHE-0239363). Additional support from
3M, Eli Lilly, Amgen, and GSK is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
yield (88% ee), as a single diastereomer with the methyl and
vinyl substituents disposed trans on the five-membered ring.
OL052700K
576
Org. Lett., Vol. 8, No. 4, 2006