Formation of five-membered carbocycles by intramolecular palladium-catalyzed ring opening of terf-cyclobutanols

Article abstract of DOI:10.1021/ol070985q

Equation Presented We report herein stereoselective formation of a functionalized five-membered carbocycle bearing a quaternary center by intramolecular palladium-catalyzed ring-opening of o-bromophenyl-tethered tert-cyclobutanols.

Full text of DOI:10.1021/ol070985q

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2693-2696
Formation of Five-Membered
Carbocycles by Intramolecular
Palladium-Catalyzed Ring Opening of
tert-Cyclobutanols
Manivannan Ethirajan, Heong-Sub Oh, and Jin Kun Cha*
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVenue,
Detroit, Michigan 48202
jcha@chem.wayne.edu
Received April 26, 2007
ABSTRACT
We report herein stereoselective formation of a functionalized five-membered carbocycle bearing a quaternary center by intramolecular palladium-
catalyzed ring-opening of o-bromophenyl-tethered tert-cyclobutanols.
Ring opening of small rings is accompanied by release of
ring strain. Strain-releasing fragmentation reactions can be
induced by various methods and have seen frequent applica-
tions in organic chemistry. As cyclopropanes and cyclobu-
tanes possess similar strain energies (27.4 and 26.4 kcal/
mol, respectively),1 both rings show comparable reactivity
toward transition metal-mediated ring cleavage.2 Syntheti-
cally useful transition metal-mediated ring-opening reactions
of cyclobutanols have recently been developed besides well-
known counterparts involving cyclopropanols.3-5 For ex-
ample, Uemura and co-workers reported palladium-catalyzed
C-C bond cleavage of tert-cyclobutanols, whereas â-carbon
elimination takes place at a less hindered primary alkyl
group.4 To our knowledge, no intramolecular variant has
appeared: we speculated that geometrical factors imposed
by an intramolecular process could be relied on to override
the typical regioselectivity of â-carbon elimination (ring
opening a) for the construction of quaternary centers (ring
opening b) (eq 1). We describe herein stereoselective for-
mation of a functionalized five-membered carbocycle bearing
a quaternary center by intramolecular palladium-catalyzed
ring opening of tert-cyclobutanols.
(1) Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
(2) It is interesting to note, however, that there is a marked difference in
their reactivity toward electrophiles; this disparity is attributed primarily to
bent bonds of cyclopropanes.
(3) For reviews, see: (a) Namyslo, J. C.; Kaufmann, D. E. Chem. ReV.
2003, 103, 1485. (b) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597. (c)
Muzart, J. Tetrahedron 2005, 61, 9423.
Ready access to the requisite cyclobutanones bearing three
contiguous stereocenters was found in coupling of 1-(cyclo-
hexenyl)cyclopropan-1-ol trimethylsilyl ether (1) and an
10.1021/ol070985q CCC: $37.00
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Scheme 1. Coupling of 1 and 2, Followed by Addition of a
Scheme 2. Pd-Mediated Annulation of 4a-c
Grignard Reagent
acetal in the presence of a Lewis acid (Scheme 1).6,7
Treatment of a mixture of TMS ether 1 and acetal 2 with
TiCl4 at -78 °C afforded spirobutanone 3 in 84% yield and
with moderate diastereoselectivity (∼3:1 admixed with trace
amounts of the third isomer). The major isomer 3 was
separated easily by silica gel chromatography. Addition of
the phenyl, methyl, or ethyl Grignard reagent (or the
corresponding ceriates) to 3 gave the respective cyclobutanols
4a-c as single isomers in 79-90% yield. Single-crystal
X-ray diffraction studies of 4a and 4c revealed that addition
of the Grignard reagent took place from the more hindered
side of the spirocyclobutanone, presumably due to chelation-
controlled approach.8
We next explored palladium-mediated ring opening of
4a-c (Scheme 2): the intermediacy of a Pd(II)-alcoholate
species was precluded due to the unexpected stereochemistry
of the tert-cyclobutanol moiety, whereas the aforementioned
Uemura protocol is likely to proceed via a Pd(II)-alcoholate
intermediate.4 Treatment of 4a with 5 mol % of Pd(OAc)2
and 10 mol % of Ph3P in the presence of Cs2CO3 in toluene
at 90 °C resulted in formation of the five-membered
carbocycle 5a (IR 1684 cm-1) in 69% yield. Similarly, 5b
and 5c were obtained in 67-70% yield. A priori, the
respective 7-membered annulation products 6a-c could
not be discounted, especially because both ring systems
(4) (a) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999,
121, 2645. (b) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121,
11010. (c) Nishimura, T.; Ohe, K.; Uemura, S. J. Org. Chem. 2001, 66,
1455. (d) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S. Chem.
Commun. 2002, 50. (e) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura,
S. J. Am. Chem. Soc. 2003, 125, 8862. (f) Nishimura, T.; Uemura, S. Synlett
2004, 201.
(5) Cf. (a) Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. J. Am. Chem.
Soc. 1996, 118, 8285. (b) Matsuda, T.; Makino, M.; Murakami, M. Angew.
Chem., Int. Engl. 2005, 44, 4608. (c) Murakami, M.; Ashida, S.; Matsuda,
T. J. Am. Chem. Soc. 2006, 128, 2166.
1
would also display similar splitting patterns in their H
NMR spectra. The unequivocal structural assignment of
5a-c vis-a`-vis 6a-c was secured by deuterium labeling
studies of 5a,b and also NaBH4 reduction of 5a, coupled
with analysis of the 1H NMR spectra of the resulting
compounds 7a,b and 8.
(6) (a) Oh, H.-S.; Lee, H. I.; Cha, J. K. Org. Lett. 2002, 4, 3707. (b) Oh,
H.-S.; Cha, J. K. Tetrahedron: Asymmetry 2003, 14, 2911.
(7) (a) Trost, B. M.; Brandi, A. J. Am. Chem. Soc. 1984, 106, 5041. (b)
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 6556. (c) Trost, B.
M.; Chen, D. W. C. J. Am. Chem. Soc. 1996, 118, 12541. For reviews, see:
(d) Trost, B. M. Top. Curr. Chem. 1986, 133, 3. (e) Salau¨n, J. Top. Curr.
Chem. 1988, 144, 1.
(8) We thank Dr. Mary Jane Heeg of our Department for single-crystal
X-ray analyses. The X-ray data have been deposited with the Cambridge
Structural Database: please refer to CSD nos. 239496 (4a), 239454 (4c),
232508 (19), 232507 (20), 230187 (21), and 232509 (22).
A brief screening of several ligands with 4a and Pd(OAc)2
showed no significant difference between monodentate and
bidentate ligands: Ph3P (69%); dppp (69% + 8% unreacted
4a); dppe (66% + 15% 4a); and rac-BINAP (64% + 6%
4a). Comparable yields were obtained with Pd(PPh3)4, but
Pd2(dba)3‚CHCl3 was ineffective regardless of ligands em-
ployed. With regard to base, Cs2CO3 proved to be superior
to K2CO3, Ag2CO3, or Et3N. To establish the necessity of
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Org. Lett., Vol. 9, No. 14, 2007

the free alcohol, 4d and 4e were prepared by standard
methods (Scheme 1). When 4d and 4e were subjected to
identical conditions, no annulation was observed, but the bulk
of starting material was recovered unreacted. Thus, base is
necessary for not only removal of HBr generated, but also
deprotonation of the cyclobutanol.
tert-cyclobutanols epimeric to 4a-c were also prepared
to examine the possible involvement of an Uemura-type
cyclic palladium alcoholate,4 although formation of an eight-
membered palladium species would seem unfavorable.
Addition of allylmagnesium bromide gave a 5:1 separable
mixture of 9 and 10 in 73% yield, whereas a 1:1 mixture
was obtained in 65% yield by means of an allylindium
reagent. After separation, 9 and 10 were reduced by diimide
to afford 11 and 12, respectively, in 90% yield (Scheme 3).
salient feature is atypical cleavage of the more substi-
tuted C-C bond of the cyclobutanol ring, which is prob-
ably due to favorable entropy of a five-membered ring
formation.
As was the case with related compounds,6 a straightfor-
ward entry to enantioselective synthesis was available by
utilizing a nonracemic C2-symmetric acetal in the coupling
reactions of 1 and 16 (Scheme 4). The stereochemistry of
Scheme 4. Enantioselective Pd-Mediated Annulation
Scheme 3. Comparison of Both Epimers in Pd-Mediated
Annulation
As expected, 11 yielded 13 uneventfully under previously
developed conditions. However, no annulation product was
isolated from the epimer 12. Instead, 14 and 15 were iso-
lated in low yields along with recovered 12. Whereas
full elucidation of the reaction mechanism awaits further
studies, these results suggest that formation of 5a-c and
13 arises from direct electrophilic attack at the cyclobutanol
ring by an arylpalladium(II) intermediate derived from
the coupling products 18-21 was secured by X-ray analysis.8
The observed, albeit modest, 1,3-diastereofacial selectivity
by the chiral C2-symmetric acetal is consistent with literature
precedents.11 The major isomers 18 and 20 were subjected
to stereoselective addition of the methyl Grignard reagent
and subsequent annulation to afford 23 and 26, respec-
tively. For additional characterization, 24 and 27 were
oxidative addition of a Pd(0) species to aryl bromide.9,10
A
(9) Cf. Siloxycyclopropanes are known to react with arylpalladium cation
complexes: (a) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1988, 110, 3296. (b) Fujimura, T.; Aoki, S.; Nakamura, E. J.
Org. Chem. 1991, 56, 2809.
(10) For related palladium-catalyzed ring expansion reactions, see: (a)
Larock, R. C.; Reddy, C. K. Org. Lett. 2000, 2, 3325. (b) Larock, R. C.;
Reddy, C. K. J. Org. Chem. 2002, 67, 2027. (c) Wei, L.-M.; Wei, L.-L.;
Pan, W.-B.; Wu, M.-J. Tetrahedron Lett. 2003, 44, 595.
Org. Lett., Vol. 9, No. 14, 2007
2695

obtained in good yield by hydrogenolysis of 23 and 26,
respectively.
stereoselective preparation of functionalized five-membered
carbocycles containing a quaternary center. It is interesting
to note that palladium(II)-catalyzed cleavage of the tethered
tert-cyclobutanol occurs at the more hindered C-C bond.
Also included are stereochemical requirements for the key
annulation reaction. A modified approach to medium-sized
carbocycles is currently under investigation.
Inasmuch as the stereochemistry of the minor coupling
products 19 and 21 was unequivocally established, they were
subjected to the identical sequence of transformations to gain
additional information on the scope. Addition of methyl-
magnesium chloride to 19 and 21 gave poor conversion, pre-
sumably due to competing enolization, but use of the ceriate
agent furnished the corresponding tert-cyclobutanols as a ca.
2:1 diastereomeric mixture in 55% and 89% yield, respec-
tively. None of these tert-cyclobutanols furnished the annu-
lation products. These control experiments indicate that the
cis-stereochemical relationship between the two side chains
involved is required for the cyclization reaction.12
Acknowledgment. We thank the National Institutes of
Health (GM35956) for generous financial support.
Supporting Information Available: Experimental details
and spectroscopic data for key intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, intramolecular palladium-catalyzed ring
opening of tert-cyclobutanols has been developed for the
OL070985Q
(12) Analogous results were also obtained with the minor cyclobutanone
product (structure not shown) from the coupling reaction of 1 and 2 (Scheme
1): no annulation products were obtained from a 3:1 inseparable mixture
of the two tert-cyclobutanols, which were prepared by addition of the methyl
Grignard reagent.
(11) See, inter alia: (a) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477. (b) Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089. (c) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc.
1992, 114, 10998.
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Org. Lett., Vol. 9, No. 14, 2007