Unusual cyclopropanation of 9-bromocamphor derivatives: A novel formal C(1)-C(7) bond cleavage of camphor

Article abstract of DOI:10.1021/ol051141e

(Chemical Equation Presented) An unusual cyclopropanation of 9-bromocamphor derivatives 1 to a 7-spiro-cyclopropyl camphor derivative 3 was effected by the action of potassium tert-butoxide (or sodium hydride) in warm DMSO. The exo-hydroxy group and a non

Full text of DOI:10.1021/ol051141e

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3107-3110
Unusual Cyclopropanation of
9-Bromocamphor Derivatives: A Novel
Formal C(1)
Camphor
−C(7) Bond Cleavage of
Wei-Dong Z. Li*,†,‡ and Yu-Rong Yang†
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, China, and State Key Laboratory of Elemento-organic Chemistry,
Nankai UniVersity, Tianjin 300071, China
liwd@lzu.edu.cn, wdli@nankai.edu.cn
Received May 16, 2005
ABSTRACT
An unusual cyclopropanation of 9-bromocamphor derivatives 1 to a 7-spiro-cyclopropyl camphor derivative 3 was effected by the action of
potassium tert-butoxide (or sodium hydride) in warm DMSO. The exo-hydroxy group and a non-hydrogen endo-substituent at C(2) have proven
to be essential structural elements, and the solvent DMSO has proven to be the sole effective reaction medium. Tricyclic compound 3 undergoes
a facile tandem Wagner
−Meerwein rearrangement−cyclopropyl ring-opening under mild acidic conditions, leading to norbornenyl derivative 12
and subsequent Meinwald rearrangement of bicyclic epoxide 13 to a formal C(1)−C(7) bond cleavage product 14.
The uniqueness of the bicyclic structure of camphor is illu-
strated by a wide variety of intriguing structural transforma-
tions that frequently involve fascinating rearrangement
processes.1 Studies on these transformations have produced
much chemical knowledge on theoretical and mechanistic
aspects of organic chemistry in the past century and offered
synthetically useful chiral building blocks from readily
available natural camphor.1 We report in this Letter an
unusual cyclopropanation of C(2) endo-alkylated 9-bro-
mocamphor derivative 1 to a tricyclic 7-spiro-cyclopropyl
camphor 3 by the action of potassium tert-butoxide (or
sodium hydride) in warm DMSO.
As shown in Scheme 1, upon treatment of a warmed (70
°C) DMSO solution of C(2) endo-alkylated 9-bromocamphor
derivative 1, prepared from 9-bromocamphor (2)2 by an
endo-selective carbonyl addition with an organocerium
reagent,3 with potassium tert-butoxide (t-BuOK) or sodium
hydride (NaH) under a nitrogen atmosphere, a rapid and clean
transformation took place as judged by TLC. A formal
dehydrobrominative product was isolated in generally good
to excellent yield and characterized spectroscopically and
* Fax/Phone: 0086-(0)22-23494613.
† Lanzhou University.
(2) Prepared from natural D-camphor in three steps according to: Cachia,
P.; Darby, N.; Eck, C. R.; Money, T. J. Chem. Soc., Perkin Trans. 1 1976,
359.
(3) Dimitrov, V.; Brabantov, S.; Simova, S.; Kostova, K. Tetrahedron
Lett. 1994, 35, 6713.
‡ Nankai University.
(1) For extensive reviews, see: (a) Money, T. Nat. Prod. Rep. 1985,
253. (b) Money, T. In Studies in Natural Products Chemistry; Rahman, A.
U., Ed.; Elsevier: New York, 1989; Vol. 4, pp 625-697.
10.1021/ol051141e CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/11/2005

C(1)-C(2) cleavage6 and intramolecular cyclopropanation
pathway was also detected along with the major spiro-
cyclopropanation product 3b.
Scheme 1. Unusual Cyclopropanation of 1
The unusual tricyclic structure of 7-spiro-cyclopropyl
camphor derivative 3a was confirmed unequivocally by
hydrogenolysis of the cyclopropane ring over Adams’
catalyst in glacial acetic acid (Scheme 2), to a camphor
derivative 4, which is identical spectroscopically with an
authentic sample7 prepared from D-camphor by an endo-
selective methylation. Furthermore, an alternative synthesis
of 3a was achieved8 from spiro-cyclopropyl cyclopentadiene
derivative 5 via Diels-Alder adduct 69 and endo-methylated
tosylate 7 as depicted in Scheme 2.
by further chemical transformations (Schemes 2 and 3) as
an unusual 7-spiro-cyclopropyl camphor derivative 3.4 A
small amount (<10%) of nucleophilic substitution product
Scheme 2 Alternative Synthesis and Hydrogenolysis of 3a
To further probe the structural requirements for this
interesting γ-eliminative cyclopropanation reaction,10 analo-
gous compounds 8-11 derived from the corresponding
bromocamphor derivatives were subjected to the same
reaction conditions (Scheme 1). Intriguingly, exo-hydroxy
derivative 8,11 an analogue of 1 with R ) H, decomposed
gradually at 80-100 °C. C(2)-Alkylated 8-bromocamphor
derivative 912 did not undergo similar cyclopropanation, and
no dehydrobromination product could be detected even at
refluxing temperature (180 °C). The methyl ether 10 and
isomeric endo-hydroxyl derivative 1113 of 1a have been
proven experimentally to be inert substrates.
(i.e., 3a′, as a mixture of diastereomers) by methylsulfinyl
carbanion was also obtained.5 In the case of 1b (R ) Ph), a
bicyclic product 3b′ (ca. 20%) corresponding to an anionic
Scheme 3. Chemical Transformations of Tricyclic Alcohol 3
On the basis of the above facts, it appears that the free
exo-hydroxy group and a non-hydrogen (carbogenic) endo-
(4) See Supporting Information for experimental details and data.
(5) A substantial amount (up to 40%) of this product was produced when
a DMSO solution of the methylsulfinyl carbanion was preformed at 70-
80 °C for 1 h prior to the addition of 9-bromocamphor alcohol 1.
(6) For a relevant process involving a possible radical pathway, see:
Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Org. Lett. 2003, 5, 2691.
(7) See Supporting Information for comparison.
(8) This synthetic work will be detailed elsewhere.
(9) For an alternative preparation, see: Fo¨hlisch, B.; Bakr, D. A.; Fischer,
P. J. Org. Chem. 2002, 67, 3682.
(10) Nickon, A.; Werstiuk, N. H. J. Am. Chem. Soc. 1967, 89, 3914,
3915, and 3917.
(11) Prepared from 2 by stereoselective reduction with NaBH4 in ethanol
or LAH in ether.4
(12) Prepared from the corresponding 8-bromocamphor similarly to endo-
selective addition of organocerium reagent.4
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Org. Lett., Vol. 7, No. 14, 2005

substituent at C(2) are essential structural elements for
effecting this unusual γ-eliminative cyclopropanation. Re-
markably, the sole effective solvent14 has proven to be
anhydrous DMSO in combination with the use of strong
bases (i.e., t-BuOK or NaH) capable of generating methyl-
sulfinyl carbanion.15 No cyclic ether or other dehydrobro-
mination products were obtained from 9-bromocamphor
derivatives 1 or 8 and 8-bromo derivative 9 by reaction with
Pb(OAc)4.16 It is thus evident that this unusual cyclopropa-
nation is anionic in character.17
The unusual cyclopropanation of 1 may be attributed to
remarkable proximity and stereoelectronic effects in which
the LUMO electron of the exo-alkoxy anion invades the σ*
orbital of the C-H bond of C(8)-CH3 (intramolecular
C8-to-O proton transfer)18 and subsequent intramolecular
nucleophilic displacement of C(9)-Br (γ-eliminative cyclo-
propanation) as depicted in Figure 1 (cf. arrows in the
This unprecedented remote alkoxy anion-induced intramo-
lecular cyclization may manifest the transition state arrange-
ment of an enzymelike reaction in which unusual reactivity
is achieved by directing reacting groups in close proximity.21
The determinative role of DMSO as the sole effective
solvent may be attributed to its unique aprotic character22
by generating a solvation-free alkoxy anion or participating
in the intramolecular proton abstraction by forming a
transient adduct with the alkoxy anion.23 These mechanistic
rationales will be further interpreted with the assistance of
theoretical caculations19 based on a force-field model (or
DFT) in the future.
In view of the general interest in the chemistry of the
nonclassical carbocations of camphor derivatives in recent
history,24 we found that the tricyclic spiro-cyclopropyl
camphor derivative 3 underwent a facile tandem Wagner-
Meerwein (WM) rearrangement-cyclopropyl ring-opening
sequence under mild acidic conditions leading to the nor-
bornenyl derivative 12 via a spiro-cyclopropyl cationic
intermediate i generated from acid-mediated WM rearrange-
ment of 3. A variety of heteronucleophilic groupings (X)
can be attached to the norbornenyl ring system as shown
(Scheme 3). Stereoselective epoxidation with m-CPBA
furnished the exo-epoxide 13 (mp 56-57 °C)25 in good yield.
Bicyclic epoxide 13 underwent Meinwald-type rearrange-
ment26 by the action of mild Lewis acid (i.e., ZnBr2) or protic
acid to give a cyclohexene derivative 14 smoothly, a formal
C(1)-C(7) cleavage product of camphor skeleton,1 via
apparently an intermediary cationic intermediate ii that
resulted from epoxy ring-opening-initiated WM rearrange-
ment. Firm evidence for this pathway is provided by the
production of bicyclic diol 15 (mp 135-136 °C) under the
acidolysis conditions after a hydrolytic workup, whose
structure was verified by a single-crystal X-ray diffraction
analysis.27 Norbornyl alcohol 15′ was also obtained along
with 14 under various acidic conditions. The product 14 may
Figure 1. Orbital interaction diagram of cyclopropanation of 1.
brackets). The significance of the C(2) endo-alkyl substituent
in 1, exemplified by the intriguing reactivity difference of 1
vs 8, may be a result of the delicate geometrical changes in
this rigid bicyclic structure, which affects notably the ground
and the corresponding transition state energetics.19 Relevant
examples are depicted in Figure 2 where subtle ring-structure
(17) It is not possible that a carbene species (via R-elimination) is
involved in view of the inertness of compounds 8-11.
(18) For examples involving through-space intramolecular H-transfer and
theoretical accounts (below), see: (a) Menger, F. M.; Chow, J. F.;
Kaiserman, H.; Vasquez, P. C. J. Am. Chem. Soc. 1983, 105, 4996. (b)
Menger, F. M. Acc. Chem. Res. 1985, 18, 128.
(19) Dorigo, A. E.; Houk, K. N. J. Org. Chem. 1988, 53, 1650 and
references therein.
(20) Cf.: Hobbs, P. D.; Magnus, P. D. J. Am. Chem. Soc. 1976, 98,
4594.
Figure 2. Intramolecular H-transfer of alkoxy radical.19
(21) For research accounts on this topic, see: (a) Houk, K. N.; Tucker,
J. A.; Dorigo, A. E. Acc. Chem. Res. 1990, 23, 107. (b) Menger, F. M.
Acc. Chem. Res. 1993, 26, 206.
(22) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry,
2nd ed.; Wiley-VCH: New York, 1988; pp 213-233.
(23) Cf.: Kwart, H.; Brechbiel, M. J. Am. Chem. Soc. 1981, 103, 4650.
(24) For reviews, see: (a) Olah, G. A.; Prakash, G. K. S.; Saunders, M.
Acc. Chem. Res. 1983, 16, 440. (b) Olah, G. A. J. Org. Chem. 2005, 70,
2413.
variations render the intramolecular hydrogen abstraction of
alkoxy radical intermediates, leading to a cyclic ether product
(yield in parentheses) induced by the action of Pb(OAc)4.19,20
(13) Prepared selectively from 9-bromocamphor (1) via a C(2) spiro-
epoxide by LAH reduction.4
(14) Other solvents such as t-BuOH, THF, DMF, and HMPA were not
effective.
(15) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 866.
(b) Greenwald, R.; Chaykovsky, M.; Corey, E. J. J. Org. Chem. 1963, 28,
1128. (c) Arguello, J. E.; Penenory, A. B.; Rossi, R. A. J. Org. Chem.
1999, 64, 6115. Aqueous or weaker bases cannot effect this transformation.
(16) Partch, R. E. J. Org. Chem. 1963, 28, 276.
(25) X-ray crystallographic data of 13: C16H19BrO, FW 307.22, ortho-
rhombic, space group P212121, a ) 8.9507(8) Å, b ) 25.614(2) Å, c )
30.160(3) Å, Z ) 20, dcalcd ) 1.476 g/cm3, R1 (I > 2σ(I)) ) 0.0427, wR2
(all data) ) 0.0628. See Supporting Information for more details.
(26) (a) Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc.
1963, 85, 582. (b) Niwayama, S.; Kobayashi, S.; Ohno, M. J. Am. Chem.
Soc. 1994, 116, 3290.
Org. Lett., Vol. 7, No. 14, 2005
3109

be of synthetic value as a novel type of natural camphor-
derived chiral synthon in organic synthesis1 in which a
heteroatomic group X and alkyl group R were incorporated.
Among the above transformations, the interesting tandem
WM rearrangement-cyclopropyl ring-opening of 3 deserves
further comment here. As shown in Scheme 4, exo-hydroxy
favorable pinacol-type H-shift pathway due to the presence
of a strong cation-stabilizing methoxy group.
The above facts may imply that formation of a highly
symmetric nonclassical mesomeric cation species iv is
favorable because of charge delocalization into the spiro-
cyclopropyl ring system and is nonreactive toward nucleo-
philic attack. The incorporation of a carbogenic substituent
at C(2) (i.e., Me) would destabilize this compact cationic
structure and thus induce the subsequent nucleophilic reac-
tions (cf. 18 f 19 and 3 f 12). Interestingly, the carbogenic
endo-substituent at C(2) is not only essential for the unusual
γ-eliminative cyclopropanation of 1 but also determinative
for the skeletal rearrangement of the spiro-cyclopropyl
camphor derivative 3, which is another example of the
manifestation of the delicate relationship between chemical
structure and reactivity in the unique camphor series.1
In summary, an unusual γ-eliminative cyclopropanation
reaction of C(2)-alkylated camphor derivative 1 to 3 was
discovered and rationalized using remarkable proximity and
angular effects, which may be of value in understanding some
relevant enzyme-catalyzed cyclopropanation reactions such
as the presqualene synthesis.28 Some intriguing skeletal
transformations of spiro-cyclopropyl camphor derivatives 3
were investigated that add some new knowledge in the rich
chemistry of camphor and relevant nonclassical cations. The
formal cleavage of the C(1)-C(7) bond of camphor deriva-
tives and a resulting novel type chiral synthon (i.e., 14) may
be useful in organic synthesis.
Scheme 4
camphor derivatives 16 derived from 10-hydroxy spiro-
cyclopropyl camphor (6) were found to be inert toward the
anticipated skeletal rearrangement under similar acidolysis
conditions. Acetylation product 17 was obtained solely from
the reaction mixture with the cyclopropane ring intact.
Although the C(2)-endo-methylated derivative 18 underwent
WM rearrangement with the promotion of acid, tricyclic
aldehyde 19 (mixture of epimers) was the sole isolable
product instead of the anticipated norbornenyl product 20,
apparently produced via a cationic species iii through a more
Acknowledgment. We thank the National Natural Sci-
ence Foundation (Distinguished Youth Fund 29925204 and
QT 20021001) for financial support. The Cheung Kong
Scholars program and the Outstanding Scholars program of
Nankai University are gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of spectra for compounds
1, 3, 4, and 8-19 and CIF files for compounds 13 and 15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) X-ray crystallographic data of 15: C11H19BrO2, FW 263.17,
orthorhombic, space group P212121, a ) 7.2349(15) Å, b ) 7.3055(15) Å,
c ) 44.210(9) Å, Z ) 8, dcalcd ) 1.496 g/cm3, R1 (I > 2σ(I)) ) 0.0647,
wR2 (all data) ) 0.1490. See Supporting Information for more details.
OL051141E
(28) For a review, see: Julia, M. Y. Chem. Soc. ReV. 1991, 20, 129.
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