Radical promoted Magner-Meerwein-type rearrangement of epoxides in camphoric systems using a Ti(III) radical source

Full text of DOI:10.1021/jo051338k

SCHEME 1
Radical Promoted Wagner-Meerwein-Type
Rearrangement of Epoxides in Camphoric
Systems Using a Ti(III) Radical Source
Samaresh Jana, Chandrani Guin, and
Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for
the Cultivation of Science, Jadavpur, Kolkata 700032, India
ocscr@mahendra.iacs.res.in
Received June 29, 2005
A radical based Wagner-Meerwein-type rearrangement has
been observed in camphoric systems. The radical was
generated from the epoxide using Cp2TiCl as the radical
source. The radical initiator Cp2TiCl was prepared in situ
from commercially available Cp2TiCl2 and Zn dust in THF
under argon.
The tremendous growth in free radical cyclization
reactions in recent years proves their significance as a
powerful tool in modern synthetic chemistry leading to
the complex carbocyclic as well as heterocyclic natural
products.1 Epoxides are vastly used as building blocks
for organic synthesis due to their ready availability and
facile substitution reactions with predictable stereochem-
istry.2 In continuation of our study3 toward the synthesis
of natural products through radical cyclization of
epoxides using a Ti(III) species as the radical initiator,
we noticed a Wagner-Meerwein-type molecular re-
arrangement in camphoric systems promoted by a free
radical4 generated from an epoxide. The radical initiator
titanocene(III) chloride (Cp2TiCl) was generated5 in situ
from commercially available Cp2TiCl2 and Zn dust in
THF under argon.
In relation to our efforts for the synthesis of spirocyclic
natural compounds,3c we intended to prepare the spiro-
ethers 7 by radical cyclization of the epoxides 4 using
titanocene(III) chloride (Cp2TiCl) as the radical initiator
as depicted in Scheme 1.
Thus, commercially available camphor 1 on treatment
with vinylmagnesium bromide following the standard
procedure6 afforded compound 2 as an inseparable mix-
ture of two isomers, endo-vinyl and exo-vinyl adducts, in
a ratio of 1.4:1 (GC, detector-FID, column: OB17, column
temperature: 100 °C) along with a trace of unreacted
camphor. Since there was not any distinguishable peak
for the isomers of the crude 2, the ratio could not be
(1) For a general review and books, see: (a) Giese, B. Radicals in
Organic Synthesis: Formation of C-C Bonds; Pergamon Press: Oxford,
1986. (b) Curran, D. P. Synthesis 1988, 417 and 489. (c) Methoden der
Organischen Chemie; Regitz, M., Giese, B., Eds.; Houben-Weyl; Georg
Thieme Verlag: Stuttgart, 1989; band E19a, C.-Radikale, teil 1+2. (d)
Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmeihack, M. F., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, pp 715 and 779. (e) Motherwell, W. B.; Crich, D. Free Radical
Chain Reactions in Organic Synthesis; Academic Press: New York,
1992. (f) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic
Chemistry; Wiley: New York, 1995.
(2) (a) Rao, A. S.; Panikar, S. K.; Kirtane, J. G. Tetrahedron 1983,
39, 2323. (b) Smith, J. G. Synthesis 1984, 629. (c) Chini, M.; Crotti,
P.; Flippin, L. A.; Gardelhi, C.; Giovani, E.; Macchi, F.; Pineschi, M.
J. Org. Chem. 1993, 58, 1221 and references therein.
(3) (a) Mandal, P. K.; Maiti, G.; Roy, S. C. J. Org. Chem. 1998, 63,
2829. (b) Roy, S. C.; Rana, K. K.; Guin, C. J. Org. Chem. 2002, 67,
3242. (c) Rana, K. K.; Guin, C.; Roy, S. C. Ind. J. Chem. 2001, 40B,
925.
1
determined from the H NMR spectra. It is noteworthy
that the energy difference between these two isomers is
about 2.5 kcal/mol (MOPAC, AM1) and endo-vinyl adduct
is more favored than the exo one. The formation of endo
adduct is preferred probably due to the easier approach
of the vinyl moiety from the less hindered endo-face
compared to the exo-face where two methyl groups as well
as the bridge restrict the approach of the vinyl moiety.7
This was further confirmed when the crude 2 was
subjected to epoxidation with mCPBA to furnish 3 in 86%
(5) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116,
986 and references therein.
(6) Srikrishna, A.; Yelamaggad, C. V.; Kumar, P. P. J. Chem. Soc.,
Perkin Trans. 1 1999, 2877.
(4) For free radical Wagner-Meerwein, see: (a) Berson, J. A.; Olsen,
C. J.; Walia, J. S. J. Am. Chem. Soc. 1962, 84, 3337. (b) Prilezhaeva,
E. N.; Azovskaya, V. A.; Petukhova, N. P. Zh. Org. Khim. 1968, 4, 621.
10.1021/jo051338k CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/02/2005
8252
J. Org. Chem. 2005, 70, 8252-8254

SCHEME 2
SCHEME 3
radical rearrangement process, epoxides 9a and 11a were
also subjected separately to the radical cyclization reac-
tion with Cp2TiCl in THF under identical reaction
conditions and furnished the rearranged products 10a
(72%) and 12a (71%), respectively (Scheme 3).
The compounds 6a, 6b, 10a, and 12a were isolated as
viscous liquids. Although the structures of the rearranged
products were in good agreement with the NMR and
analytical data, the structural connectivity and relative
stereochemistry was finally established using X-ray
analysis of the 3,5-dinitrobenzoate ester derivative 13
(Figure 1) (colorless crystals, mp 104-106 °C) prepared
from the alcohol 10a.
yield as a mixture of two isomers in a ratio of 1.4:1
(Scheme 1). It is well established8 that during the
epoxidation of allylic alcohols the incoming oxygen from
the peroxy acid undergoes syn-addition with respect to
the OH group due to the hydrogen bonding between the
OH group and the peroxy acid in the transition state.
Therefore, each isomer of 2 furnished only one corre-
sponding isomer of the epoxide. It is obvious that the
major endo-vinyl adduct afforded the endo-epoxide 3a
and the minor exo-vinyl adduct afforded the exo-epoxide
3b, respectively. The isomers 3a and 3b were separated
by column chromatography in 50 and 36% yields, respec-
tively.
The isomers 3a and 3b on separate treatment with
propargyl bromide in the presence of NaH did not afford
the epoxy ethers 4a and 4b, but rather furnished the
rearranged epoxides 5a and 5b, respectively, in good
yields (Scheme 2) by Payne’s rearrangement.9 The pure
epoxide 5a on treatment with Cp2TiCl in THF under
argon at room temperature underwent a radical based
Wagner-Meerwein-type ring rearrangement to furnish
6a as the only isolated product in 72% yield.
No trace of the radical cyclization product 8a was
detected. Similarly, the pure epoxide 5b on treatment
FIGURE 1. X-ray of 13.
The proposed mechanism of the ring rearrangement
is depicted in Scheme 4.
The last step of the reaction may not be a H-atom loss,
but is a Ti(III) trapping of the radical followed by
â-elimination.10
In support of the radical-promoted molecular re-
arrangement, two separate experiments were done with
the epoxide 9a under the same reaction conditions as
described for the rearrangement reaction (i) without zinc
dust and (ii) with ZnCl2 in the absence of Cp2TiCl2. In
both cases, no rearrangement was found to get 10a, only
the unreacted starting material was isolated in quantita-
tive yield. This observation proved that Cp2TiCl2 or ZnCl2
(generated in situ in the reaction mixture from zinc dust
and Cp2TiCl2) did not take part in any cationic rear-
rangement to obtain the rearranged product 10a.
with Cp2TiCl under identical reaction conditions fur-
nished solely the rearranged product 6b in 75% yield.
To observe any influence of the O-alkyl group on the
(7) (a) Ruggles, E. L.; Maleczka, R. E., Jr. Org. Lett. 2002, 4, 3899.
(b) Hung, S.-C.; Wen, Y.-F.; Chang, J.-W.; Liao, C.-C.; Uang, B.-J. J.
Org. Chem. 2002, 67, 1308.
(8) (a) March, J. Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structures, 4th ed.; Wiley & Sons: New York, 2000; pp
820 and references therein. (b) Adam, W.; Bach, B. D.; Dmitrenko, O.;
Saha Moller, C. R. J. Org. Chem. 2000, 65, 6715.
J. Org. Chem, Vol. 70, No. 20, 2005 8253

1654, 1456, 1388, 1369, 1261 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.03 (s, 3H), 1.08 (s, 3H), 1.21-1.89 (m, 7H), 2.45 (t, J ) 2.4
Hz, 1H), 3.59 (dd, J ) 9.6, 8.4 Hz, 1H), 3.83 (dd, J ) 9.6, 2.4 Hz,
1H), 4.14-4.30 (m, 3H), 4.72 (s, 1H), 4.85 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 24.9, 26.3, 29.7, 31.2, 38.5, 43.7, 47.1, 57.1, 58.9,
71.4, 72.2, 75.1, 80.0, 100.4, 165.4; Anal. Calcd for C15H22O2: C,
76.88; H, 9.46. Found: C, 76.26; H, 9.50.
SCHEME 4
(1S)-1-(2,2-Dimethyl-3-methylenebicyclo[2.2.1]hept-1-
yl)-2-(prop-2-ynyloxy)ethanol (6b): colorless oil; 75% yield,
IR (neat) ν 3477, 3307, 2958, 2875, 2115, 1652, 1461, 1361 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.99 (s, 3H), 1.07 (s, 3H), 1.09-
2.00 (m, 7H), 2.44 (t, J ) 2.4 Hz, 1H), 3.46 (t, J ) 9.0 Hz, 1H),
3.78 (dd, J ) 9.3, 2.6 Hz, 1H), 4.16 (dd, J ) 8.7, 2.5 Hz, 1H),
4.19 (d, J ) 2.4 Hz, 2H), 4.65 (s, 1H), 4.74 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 23.94, 25.8, 29.1, 29.8, 37.2, 43.1, 46.9, 55.7, 58.3,
70.4, 72.0, 74.5, 79.4, 99.3, 165.7; Anal. Calcd for C15H22O2: C,
76.88; H, 9.46. Found: C, 76.16; H, 9.26.
(1R)-2-(Benzyloxy)-1-(2,2-dimethyl-3-methylenebicyclo-
[2.2.1]hept-1-yl)ethanol (10a): colorless oil; 74% yield; IR
(neat) ν 3444, 3064, 3030, 2950, 2871, 1722, 1651, 1494, 1454,
1386, 1361, 1315, 1274, 1201 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.02 (s, 3H), 1.07 (s, 3H), 1.20-1.85 (m, 7H), 3.57 (dd, J ) 9.4,
8.4 Hz, 1H), 3.73 (dd, J ) 9.6, 2.7 Hz, 1H), 4.18 (dd, J ) 8.4, 2.5
Hz, 1H), 4.60 (d, J ) 2.9 Hz, 2H), 4.69 (s,1H), 4.82 (s, 1H), 7.25-
7.48 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3) δ 24.9, 26.3, 29.7,
31.1, 38.5, 43.7, 47.1, 57.0, 71.5, 72.5, 73.7, 100.3, 128.1, 128.5,
130.0, 130.1, 133.5, 138.5, 165.5; Anal. Calcd for C19H26O2: C,
79.68; H, 9.15. Found C, 79.58; H, 9.16.
In conclusion, a radical-induced Wagner-Meerwein-
type rearrangement has been observed in camphoric
systems. The radical was generated from the epoxide
using titanocene(III) chloride as the radical initiator.
Experimental Section
Preparation of (1R)-1-(2,2-Dimethyl-3-methylenebicyclo-
[2.2.1]hept-1-yl)-2-(prop-2-ynyloxy)ethanol (6a) by Radical
Rearrangement of the Epoxide 5a. Representative Pro-
cedure. A solution of Cp2TiCl2 (225 mg, 0.9 mmol) in THF (5
mL) (dried over Na) was stirred with activated zinc dust (195
mg, 2.99 mmol) for 1 h under argon (activated zinc dust was
prepared by washing 20 g of commercially available zinc dust
with 60 mL of 4 N HCl, thorough washing with water until the
washings became neutral, and finally washing with dry acetone
and then drying in vacuo). The resulting green solution was then
added dropwise to a stirred solution of the epoxide 5a (100 mg,
0.43 mmol) in dry THF (12 mL) at room temperature under
argon. It was stirred for an additional 1 h and decomposed with
saturated sodium dihydrogen phosphate (10 mL). After removal
of most of the THF under reduced pressure, the crude material
obtained was purified by column chromatography over silica gel
(5% ethyl acetate in light petroleum) to furnish 6a (72 mg, 72%)
as a colorless liquid. IR (neat) ν 3463, 3307, 2931, 2873, 1739,
(1R)-1-(2,2-Dimethyl-3-methylenebicyclo[2.2.1]hept-1-
yl)-2-methoxyethanol (12a): colorless liquid; 71% yield; IR
(neat) ν 3465, 2956, 2927, 2879, 1651, 1458, 1361, 1195, 1124
cm-1 1H NMR (300 MHz, CDCl3) δ 1.03 (s, 3H), 1.08 (s, 3H),
;
1.16-1.88 (m, 7H), 2.35 (brs, OH), 3.42 (s, 3H), 3.47 (dd, J )
9.6, 8.6 Hz, 1H), 3.63 (dd, J ) 9.7, 2.6 Hz, 1H), 4.14 (dd, J )
8.5, 2.5 Hz, 1H), 4.71 (s, 1H), 4.85 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 24.9, 26.3, 29.6, 31.1, 38.4, 43.7, 47.1, 57.0, 59.4, 71.3,
74.8, 100.3, 165.4; Anal. Calcd for C13H22O2: C, 74.24; H, 10.54.
Found: C, 74.18; H, 10.55.
Acknowledgment. S.J. and C.G. thank CSIR, New
Delhi, for awarding research fellowships.
Supporting Information Available: General experimen-
tal details and spectral and analytical data of compounds 3a,
3b, 5a, 5b, 6a, 6b, 9a, 10a, 11a, 12a, and 13. Copies of 1H
NMR spectra of 3a, 3b, 5a, 5b, 6a, 6b, 10a, and 12a. Copies
of 13C NMR spectra of 6a, 6b, 10a, and 12a. X-ray crystal-
lographic data for 13 (CIF) and copy of the X-ray of 13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) (a) Payne, G. B. J. Org. Chem. 1962, 27, 3819. (b) Inoue, S.;
Asami, M.; Honda, K.; Shrestha, K. S.; Takahashi, M.; Yoshino, T.
Synlett 1998, 679.
(10) (a) Nakai, K.; Kamoshita, M.; Doi, T.; Yamada, H.; Takahashi,
T. Tetrahedron Lett. 2001, 42, 7855. (b) Barrero, A. F.; Oltra, J. E.;
Cuerva, J. M.; Rosales, A. J. Org. Chem. 2002, 67, 2566.
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