SCHEME 1. Syn th etic Rou te to
C(9),C(10)-Su bstitu ted Ca m p h or s 1(X/Y)
SCHEME 2. Syn th etic P r oblem s in P r ep a r in g
1(X/Y) fr om 1(Br /Br )
l(X/H) (X ) halogen) to the corresponding bridgehead
2-methylenenorborn-1-yl triflate 5(X),12 followed by
(2) a second electrophile-promoted (N-halosuccinimide)
Wagner-Meerwein rearrangement of the triflate-derived
methylenenorbornanol 6(X) to yield the corresponding
C(9),C(10)-disubstituted camphor 1(X/Y) (X and Y are
halogens in such previously communicated cases).12
In this paper we provide insight into the scope and
limitations of this synthetic method, extending it to other
derivatives, including some interesting new disubstituted
C(9)-halogen, C(10)-O, S, or Se camphor derivatives.
Although enantiopure C(10)- and C(9)-substituted
camphors are now accessible,1b,9,11h the preparation of
enantiopure C(9),C(10)-disubstituted camphors presents
some serious difficulties.9,13 In fact, the only readily
accessible one, 9,10-dibromocamphor 1(Br /Br ), has been
used to date as the only disposable enantiopure synthetic
intermediate to other C(9),C(10)-disubstituted camphors
(via nucleophilic substitution of the bromine groups).9
This identically C(9),C(10)-disubstituted camphor (X )
Y ) Br) was prepared by an interesting selective camphor-
bromination technique developed by Money et al. during
the late 70’s.13 Unfortunately, this route to 1(Br /Br )
takes place with a very low overall yield (31% from
3-endo-9-dibromocamphor),13b,14 and it cannot be ex-
tended to other halogens. In addition, there are two
serious problems in the conversion of 1(Br /Br ) to other
C(9),C(10)-disubstituted camphors 1(X/Y): (a) the similar
and low reactivity of both bromomethyl groups (actually
neopentyl-like bromides)9c of 1(Br /Br ) toward nucleo-
philic substitution and (b) the possibility of a Grob-like
fragmentation in the rigid â-halosubstituted ketone 1(Br /
Br ) under nucleophilic treatment.15 The latter problem
is resolved by protecting the carbonyl group9c (Scheme
2).
Problem a (Scheme 2) could be avoided by employing
the double Wagner-Meerwein strategy in Scheme 1 for
the preparation of 9,10-dihalocamphor with different
halogens at the neopentyl-like positions. This strategy,
however, does not circumvent the Grob-like fragmenta-
tion problem.
To simplify the synthetic access to the desired various
C(9),C(10)-disubstituted camphors 1(X/Y), we were in-
terested in studying the scope of the electrophilic-
promoted Wagner-Meerwein rearrangement of camphor-
derived alcohols 6(X) (Scheme 1) with electrophiles other
than the N-halosuccinimides [NCS, NBS, and N-iodo-
succinimide (NIS)] previously used.12 The previously re-
ported Wagner-Meerwein rearrangement of simple (non-
heteroatomically substituted) camphor- and fenchone-
derived 2-methylenenorbornan-1-ols with several com-
mercial O-, S-, Se-, and C-electrophiles, such as m-CPBA,
p-nitrobenzenesulfenyl chloride, benzeneselenyl chloride,
and N,N-dimethylmethaniminium iodide (Eschenmoser’s
salt),11h led us to investigate the reactivity of the bromo-
(10) Some interesting examples of such Wagner-Meerwein-
rearrangement application are: (a) Garc´ıa Mart´ınez, A.; Os´ıo Barcina,
J .; Rodr´ıguez Herrero, M. E.; Iglesias de Dios, M.; Teso Vilar, E.;
Subramanian, L. R. Tetrahedron Lett. 1994, 35, 7285. (b) Garc´ıa
Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya Cerero, S.;
Gonza´lez-Fleitas de Diego, J . M. Tetrahedron: Asymmetry 1994, 5,
1599. (c) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; Mart´ınez Ruiz, P.; Garc´ıa AÄ lvarez, P. P. Tetrahedron:
Asymmetry 1997, 8, 849. (d) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa
Fraile, A.; Herrera Ferna´ndez, A.; de la Moya Cerero, S.; Moreno
J ime´nez, F. Tetrahedron 1998, 54, 4697. (e) Garc´ıa Mart´ınez, A.; Teso
Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B.
Tetrahedron: Asymmetry 2001, 12, 189. (f) Garc´ıa Mart´ınez, A.; Teso
Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; de Oro Osuna, S.;
Lora Maroto, B. Tetrahedron Lett. 2001, 42, 7795. (g) Garc´ıa Mart´ınez,
A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Lora Maroto,
B. Eur. J . Org. Chem. 2002, 781. (h) Garc´ıa Mart´ınez, A.; Teso Vilar,
A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B.
Tetrahedron: Asymmetry 2002, 13, 1837. (i) Garc´ıa Mart´ınez, A.; Teso
Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B.
Eur. J . Org. Chem. 2002, 3731. (j) Garc´ıa Mart´ınez, A.; Teso Vilar, E.;
Moreno J ime´nez, F.; AÄ lvarez Garc´ıa, A. M.; Pinilla Rodr´ıguez, P.
Tetrahedron: Asymmetry 2002, 13, 2635. (k) Garc´ıa Mart´ınez, A.; Teso
Vilar, E.; Garc´ıa Fraile, A.; Mart´ınez Ruiz, P. Tetrahedron 2003, 59,
1565. (l) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2003, 14,
1959.
(11) (a) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2000, 11,
3059. (b) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2000, 11,
4437. (c) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; Lora Maroto, B. Tetrahedron Lett. 2001, 42, 5017.
(d) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2001, 42, 7795.
(e) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2001, 12, 3325.
(f) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Lora Maroto, B. Tetrahedron Lett. 2002, 43, 1183. (g) Garc´ıa
Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.;
Lora Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17. (h) Garc´ıa
Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya Cerero, S.;
Lora Maroto, B. J . Org. Chem. 2003, 14, 1607.
(14) Actually, the low yield in obtaining 1(Br /Br ) can be resolved
by preparing it directly from the nowadays commercial intermediate
3,9,10-tribromocamphor.
(12) Garc´ıa Mart´ınez, A.; Teso Vilar, A.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; D´ıaz Morillo, C.; Pe´rez Morillo, R. Synlett 2004, 134.
(13) (a) Eck, C. R.; Mills, R. W.; Money, T. J . Chem. Soc., Perkin
Trans. 1 1975, 251. (b) Dadson, W. M.; Lam, M.; Money, T.; Piper, S.
E. Can. J . Chem. 1983, 61, 343.
(15) As a review see: (a) Becker, K. B.; Grob., C. A. In The Chemistry
of the Double-bonded Functional Groups; Patai, A. S., Ed.; Inter-
science: New York, 1977; Part II Supplement. As an example, see:
(b) Levitt, M. S.; Newton, R. F.; Roberts, S. M.; Willets, A. J . J . Chem.
Soc., Chem. Commun. 1990, 8, 619.
J . Org. Chem, Vol. 69, No. 21, 2004 7349