Palladium(II)-catalyzed 1,4-oxidation of 2-aryl-1,3-cyclohexadienes. Application to the synthesis of (±)-epibatidine and analogues

Article abstract of DOI:10.1021/jo981668n

Palladium(II)-catalyzed 1,4-chloroacetoxylation of 2-aryl-1,3- cyclohexadienes 2a and 2b resulted in a highly regio- and stereoselective reaction to give cis-1-acetoxy-3-aryl-4-chloro-2-cyclohexenes 7a and 7b, respectively. The phenyl adduct 7a was subjected to the synthesis of exo- and endo-2-phenyl-7-azabicyclo[2.2.1]heptanes (exo-1a and endo-1a). Stereoselective allylic nucleophilic substitution of the chloro group in 7a by tosylamide with either retention or inversion and hydrolysis to give 9a and 14a, respectively, followed by hydrogenation, cyclization, and deprotection afforded the target molecules. Interestingly, stereoselective hydrogenation of intermediates 9a and 14a afforded the required 1,2-cis and 1,2-trans relationships, respectively, between the nitrogen and the phenyl group. In an analogous manner, 7b was transformed to exo-12b, which previously has been converted to epibatidine.

Full text of DOI:10.1021/jo981668n

836
J . Org. Chem. 1999, 64, 836-842
P a lla d iu m (II)-Ca ta lyzed 1,4-Oxid a tion of
2-Ar yl-1,3-cycloh exa d ien es. Ap p lica tion to th e Syn th esis of
(()-Ep iba tid in e a n d An a logu es
Andreas Palmgren,†,‡,§ Anna L. E. Larsson,† and J an-E. Ba¨ckvall*,†,‡,§
Department of Organic Chemistry, University of Uppsala, Box 531, SE-751 21 Uppsala, Sweden and
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
Paul Helquist*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received August 17, 1998
Palladium(II)-catalyzed 1,4-chloroacetoxylation of 2-aryl-1,3-cyclohexadienes 2a and 2b resulted
in a highly regio- and stereoselective reaction to give cis-1-acetoxy-3-aryl-4-chloro-2-cyclohexenes
7a and 7b, respectively. The phenyl adduct 7a was subjected to the synthesis of exo- and endo-2-
phenyl-7-azabicyclo[2.2.1]heptanes (exo-1a and endo-1a ). Stereoselective allylic nucleophilic sub-
stitution of the chloro group in 7a by tosylamide with either retention or inversion and hydrolysis
to give 9a and 14a , respectively, followed by hydrogenation, cyclization, and deprotection afforded
the target molecules. Interestingly, stereoselective hydrogenation of intermediates 9a and 14a
afforded the required 1,2-cis and 1,2-trans relationships, respectively, between the nitrogen and
the phenyl group. In an analogous manner, 7b was transformed to exo-12b, which previously has
been converted to epibatidine.
In tr od u ction
have previously reported on the transformation of 1,3-
cycloheptadienes to cis- and trans-4-amido-2-cyclohep-
tenol derivatives and subsequent cyclization to tropane
alkaloids.3c,d The corresponding sequence applied to 1,3-
cyclohexadienes would afford 7-azabicyclo[2.2.1]heptane
systems (1) according to Scheme 1.
Recently there has been a great interest in aryl-
substituted 7-azabicyclo[2.2.1]heptanes, mainly due to
the discovery of the alkaloid epibatidine (1b) which was
isolated and characterized in 1992 by Daly5 et al. Epi-
batidine has been shown to possess remarkable analgesic
properties (>200 times as active as morphine), and its
synthesis has attracted considerable attention.6,7 It was
therefore of interest to study the palladium(II)-catalyzed
1,4-oxidation of 2-aryl-1,3-cyclohexadienes. In this paper
we report on regio- and stereoselective 1,4-functionaliza-
tion of 2-aryl-1,3-cyclohexadienes (2) via palladium(II)-
catalyzed 1,4-chloroacetoxylation, and the application to
the synthesis of bicyclic systems 1.
Regio- and stereoselective 1,4-functionalization of con-
jugated dienes via palladium(II)-catalyzed 1,4-diacyloxy-
lation and 1,4-haloacyloxylation has developed into useful
synthetic methodology.1-4 In particular, 1,4-functional-
ization via palladium(II)-catalyzed 1,4-chloroacetoxyla-
tion has been frequently employed in regio- and stereo-
selective organic synthesis. The chloroacetoxylation of
conjugated dienes proceeds with high 1,4-syn selectivity
and, for substituted dienes, good diastereo- and regiose-
lectivity are often obtained. For example, cyclic 2-sub-
stituted dienes give exclusively 1-acetoxy 4-chloro 3-sub-
stituted 2-alkenes.2a,3b However, there are no examples
where 2-aryl substituted 1,3-dienes are employed. We
† University of Uppsala.
‡ Stockholm University.
§ Current address: Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
(1) (a) Ba¨ckvall, J . E. Palladium-Catalyzed 1,4-Additions to Conju-
gated Dienes. Review in Metal-catalyzed Cross Coupling Reactions;
Stang, P., Diederich, F., Eds.; VCH: Weinham, 1998; pp 339-382. (b)
Ba¨ckvall, J . E. In The Chemistry of Functional Groups: Polyenes and
Dienes; Patai S., Rappoport, Z., Eds.; Wiley: New York, 1996; pp 653-
682. (c) Harrington, P. J . In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, G. A., Wilkinson, G., Eds.; Pergamon: New York,
1995; Vol. 12 (Vol. Ed. Hegedus, L. S.), p 797. (d) Tsuji, J . Palladium
Reagents and Catalysts: Innovations in Organic Synthesis; Wiley:
Chichester, 1995.
Resu lts a n d Discu ssion
P r ep a r a tion of Sta r tin g Ma ter ia ls. Synthesis of the
2-phenyl-1,3-cyclohexadiene 2a was carried out according
(5) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J . C.;
Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475.
(6) Broka, C. Med. Chem. Res. 1994, 4, 449; this review describes
nine total syntheses until September 1994. For later work not covered
by this review, see ref 7 and (b) Ko, S. Y.; Lerpiniere, J .; Linney, I. D.;
Wrigglesworth, R. J . Chem. Soc., Chem. Commun. 1994, 1775. (c)
Senokuchi, K.; Nakai, H.; Kawamura, M.; Katsube, N.; Nonaka, S.;
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Keijsers, J .; Hams, B.; Kruse, C. G.; Scheeren, H. W. Tetrahedron Lett.
1994, 35, 1299. (e) Pandey, G.; Bagul, T. D.; Lakshmaiah, G. Tetra-
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Risi, C.; Pollini, G. P.; Romagnoli, R.; Zanirato, V. Tetrahedron Lett.
1994, 35, 9297. (g) Kotian, P. L.; Carroll, F. I. Synth. Commun. 1995,
25, 63. (h) Gonzales, J .; Koontz, J . I.; Hodges, L. M.; Nilsson, K. R.;
Neely, L. K.; Myers, W. H.; Sabat, M.; Harman, W. D. J . Am. Chem.
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1989, 54, 3374. (c) Schink H. E.; Pettersson, H.; Ba¨ckvall, J . E. J . Org.
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(4) Some selected examples where this methodology has been used
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10.1021/jo981668n CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

Pd(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes
J . Org. Chem., Vol. 64, No. 3, 1999 837
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
to a known procedure developed in this laboratory.8 The
synthesis of 2b is shown in Scheme 2 and starts from
5-bromo-3-methoxypryridine (3) and 2-cyclohexen-1-one.
Lithiation of 3 followed by 1,2-addition to 2-cyclohexen-
1-one afforded allylic alcohol 4. Treatment of 4 with
p-toluenesulfonic acid resulted in the rearranged allylic
alcohol 5. Reaction of 5 with methyl chloroformate gave
the corresponding allylic carbonate (6b) which upon
treatment with Pd(PPh3)4 resulted in a regioselective
elimination to give diene 2b.
St er eoselect ive Syn t h esis of Bicycles exo- a n d
en do-1. A. 1,4-Ch lor oacetoxylation . Palladium(II)-cata-
lyzed chloroacetoxylation of 2-phenyl-1,3-cyclohexadiene
(2a ) employing Pd(OAc)2, p-benzoquinone, LiCl, and
LiOAc in acetone-acetic acid3b,9 afforded chloroacetate
7a in 62% yield in a highly regio- and stereoselective
reaction. The corresponding chloroacetoxylation of the
methoxypyridyl diene 2b was less efficient and gave the
corresponding adduct 7b in only 30% yield (Scheme 3).
B. Syn th esis of exo-1a . To reach the exo-analogue
(1a ) the cis-chloroacetate 7a was transformed into the
cis-amidoacetate 8a by Pd(PPh3)4-catalyzed allylic sub-
stitution with NaNHTs in acetonitrile, in 79% yield
(Scheme 4). Acetate 8a was hydrolyzed, and the resulting
allylic alcohol 9a was subsequently hydrogenated em-
ploying 7% of Adam’s catalyst in ethanol. The hydroge-
nation proceeded with high stereoselectivity, and 10a was
isolated in 94% yield, as a single diastereomer. In this
way the cis stereochemistry, between the phenyl and the
tosylamido groups, required for the exo compound, was
created. The trans 1,4-relationship required for the
cyclization was achieved by inversion of the stereochem-
istry at C-1. Replacement of the hydroxyl group with
chloride, using thionyl chloride, gave 11a in 66% yield.
Cyclization in methanol employing K2CO3 as base gave
the N-tosyl-protected compound, exo-12a , in 95% yield.
Detosylation of 12a by sodium naphthhalenide10 afforded
the target molecule, exo-1a in 97% yield.
C. Syn th esis of en d o-1a . For the synthesis of com-
pound endo-12a a trans relationship between the nitro-
gen and the phenyl group is required. Hydrogenation of
allylic alcohol 9a from the â-face would produce epi-10a
with phenyl trans to nitrogen. It is known that a hydroxy
group can direct a metal-catalyzed hydrogenation to the
syn-face, presumably by coordination of the OH group to
the metal.11a-d However all attempts to obtain stereose-
lective hydrogenation via such a hydroxy-directed hy-
drogenation failed. We therefore tried another approach
(Scheme 5). The chloroacate 7a was transformed to the
(7) (a) Bai, D.; Xu, R.; Chu, G.; Zhu, X. J . Org. Chem. 1996, 61, 4600.
(b) Xu, R.; Chu, G.; Bai, D. Tetrahedron Lett. 1996, 37, 1463. (c)
Malpass, J . R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett. 1996,
37, 3911. (d) Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485.
(e) Sza´ntay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sza´ntay, C., J r.;
Temesva´ri-Major, E.; Blasko´, G. Tetrahedron 1996, 52, 11053. (f)
Zhang, C.; Trudell, M. L. J . Org. Chem. 1996, 61, 7189. (g) Albertini,
E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, P.; Zanirato, V.
Tetrahedron Lett. 1997, 38, 681. (h) Zhang, C.; Gyermek, L.; Trudell,
M. L. Tetrahedron Lett. 1997, 38, 5619. (i) Giblin, G. M. P.; J ones, C.
D.; Simpkins, N. S. Synlett 1997, 589. (j) Kosugi, H.; Abe, M.; Hatsuda,
R.; Uda, H.; Kato, M. J . Chem. Soc., Chem. Commun. 1997, 1857. (k)
Pandey, G.; Bagul, T. D.; Sahoo, A. K. J . Org. Chem. 1998, 63, 760. (l)
J ones, C. D.; Simpkins, N. S.; Giblin, G. M. P. Tetrahedron Lett. 1998,
39, 1023. (m) Sirisoma, N. S.; J ohnson, C. R. Tetrahedron Lett. 1998,
39, 2059. (n) Clive, D. L. J .; Yeh, V. S. C. Tetrahedron Lett. 1998, 39,
4789. (o) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. Tetrahedron
Lett. 1998, 39, 4513.
Sch em e 5
(8) Karlstro¨m, S.; Ro¨nn, M.; Thorarensen, A.; Ba¨ckvall, J . E. J . Org.
Chem. 1998, 63, 2517.
(9) Ba¨ckvall, J . E.; Granberg, K. L.; Hopkins, R. B. Acta Chem.
Scand. 1990, 44, 492.

838 J . Org. Chem., Vol. 64, No. 3, 1999
Palmgren and Larsson
Sch em e 6
decoupling, COSY, NOESY, and DEPT experiments. IR spec-
tra were obtained using a Perkin-Elmer 1600 FTIR, and the
samples were examined as KBr plates or as thin films on NaBr
plates. Peaks are reported in cm-1 with the following intensi-
ties: s (strong, 67-100%), m (medium, 40-66%), and w (weak,
20-40%). Melting points are uncorrected and were obtained
using a Bu¨chi capillary melting point apparatus. Elemental
analyses were performed by Analytische Laboratorien, Lindlar,
Germany. Diethyl ether, DME, and THF were distilled under
nitrogen from sodium benzophenone ketyl. Pyridine and
methylene chloride were distilled under nitrogen from calcium
hydride. p-Toluenesulfonamide monosodium salt13 (NaNHTs)
and tetrakis(triphenylphosphine)palladium14 were prepared
according to known procedures. Thin-layer chromatography
(TLC) was run on Merck precoated silica gel 60-F254 plates.
Progress of reaction was followed by TLC until judged complete
for all reactions. For flash chromatography, Merck silica gel
60 (230-400 mesh) was used. 2-Phenyl-1,3-cyclohexadiene
(2a )8 and compound 3b15 were prepared according to literature
procedures.
5-Br om o-2-m eth oxyp yr id in e (3b).15 Freshly cut sodium
(3.762 g, 163.5 mmol) was dissolved in methanol (40 mL)
followed by addition of 2,5-dibromopyridine (12.01 g, 50.71
mmol) in DMF (150 mL). The reaction mixture was stirred
for 1 h at 80 °C. Ether (400 mL) was added when the reaction
mixture had cooled to room temperature, and the solution was
washed with water (4 × 50 mL). The aqueous phase was made
basic to pH > 10 using KOH and extracted with ether (2 × 30
mL). The collected organic phases were dried (MgSO4). The
solvent was removed in vacuo, and the crude product was
separated on silica (ether:pentane 5:95) to yield the title
compound (9.05 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 8.20
(dd, J ) 2.5, 0.7 Hz, 1 H, PyH-6), 7.63 (dd, J ) 8.8, 2.6 Hz, 1
H,PyH-4), 6.66 (dd, J ) 8.8, 0.7 Hz, 1 H, PyH-3), 3.91 (s, 3 H,
CH3O); 13C NMR (CDCl3, 100.6 MHz) δ 163.0, 147.5, 141.0,
112.6, 111.7, 53.7.
trans-amidoacetate 13a in 80% yield by reaction with
NaNHTs in DMSO at 55 °C. Subsequent hydrolysis
afforded the trans amido alcohol 14a . Interestingly,
hydrogenation of 14a with Adams catalyst was highly
stereoselective and occurred syn to the NHTs group to
produce 15a with the desired trans relationship between
nitrogen and phenyl. Mesylation followed by K2CO3-
promoted cyclization afforded the N-tosyl-protected com-
pound endo-12a in 74% yield from 15a . The target
molecule, endo-1a , was obtained in 89% yield by removal
of the tosyl group.10
Syn th esis of (()-Ep iba tid in e (exo-1b). The same
strategy as for the synthesis of compound exo-1a was
employed for the synthesis of (()-epibatidine. The amido
acetate 8b was obtained from chloroacetate 7b in 71%
yield using the palladium-catalyzed allylic substitution
(Scheme 6). Hydrolysis of 8b gave amido alcohol 9b,
which was hydrogenated in a highly stereoselective
reaction to afford 10b in 93% yield. Subsequent inversion
of the alcohol by the use of thionyl chloride to give 11b
(65% yield) followed by cyclization gave the bicyclic
compound exo-12b (63% yield). The transformation of exo-
12b to epibatidine (exo-1b) in 53% yield (two steps) has
previously been described in the literature.12
Con clu sion
A stereoselective synthesis of epibatidine and aryl
analogues has been developed. The strategy relies on a
stereo- and regioselective functionalization of 2-aryl-1,3-
cyclohexadienes via the chloroacetoxylation approach1a
and subsequent stereoselective hydrogenation of the
double bond. With this approach both the exo and endo
compounds are accessible.
1-(2-Meth oxy-5-p yr id yl)-2-cycloh exen ol (4b). 5-Bromo-
2-methoxypyridine (7.57 g, 40.3 mmol) was dissolved in dry
ether (50 mL) and cooled to -78 °C. n-Butyllithium (30 mL,
1.56 M in hexanes) was added dropwise over 15 min, and the
reaction was stirred at -78 °C for 2 h. 2-Cyclohex-1-one (4.61
g, 48.0 mmol) was added via syringe over 10 min. The reaction
was stirred overnight while the temperature was slowly raised
to room temperature. Water (50 mL) was added followed by
extraction with ether (100 mL) and collection of the organic
Exp er im en ta l Section
1H and 13C NMR spectra were recorded in CDCl3 solutions
at 400 and 100.6 MHz, respectively. Chemical shifts are
1
reported in ppm with CDCl3 as internal standard (7.26 for H
and 77.00 ppm for 13C) or methanol (3.49 ppm for 1H or 49.00
ppm for 13C) and coupling constants (J ) are given in hertz.
Assignments of the NMR signals were done using 1H-homo-
(12) (a) Okabe, K.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 1432.
(b) Sestanj, K.; Melenski, E.; J irkovsky, I. Tetrahedron Lett. 1994, 35,
5417.
(13) Bottini, F.; Di Grazia, M.; Finocchiaro, P.; Fronczek, F. R.;
Mamo, A.; Pappalardo, S. J . Org. Chem. 1988, 53, 3521.
(14) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1990.
(10) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J . Org.
Chem. 1989, 54, 1548.
(11) (a) Thompson, H. W.; McPherson, E.; Lences, B. L. J . Org.
Chem. 1976, 41, 2903. (b) Stork, G.; Kahne, D. E. J . Am. Chem. Soc.
1983, 106, 1072. (c) Evans, D. A.; Morrissey, M. M. J . Am. Chem. Soc.
1984, 106, 3866. (d) Crabtree, R. H.; Davis, M. W. J . Org. Chem. 1986,
51, 2655.
(15) Testaferri, L.; Tiecco, M.; Tingoli, M.; Bartoli, D.; Massoli, A.
Tetrahedron 1985, 41, 1373.

Pd(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes
J . Org. Chem., Vol. 64, No. 3, 1999 839
phase. The aqueous phase was saturated with NH4Cl and
further extracted with ether (3 × 70 mL). The collected organic
phases were dried (MgSO4). The solvent was evaporated and
the crude product was directly used in the next step. 1H NMR
(CDCl3, 400 MHz) δ 8.20 (dt, J ) 2.5, 0.6 Hz, 1 H, PyH-6),
7.69 (dd, J ) 8.7, 2.6 Hz, 1 H, PyH-4), 6.69 (dm, J ) 8.7 Hz,
1 H, PyH-3), 6.01 (ddd, J ) 10.0, 4.0, 3.4 Hz, 1 H, olefinic CH),
5.72 (dt, J ) 10.0, 2.2 Hz, 1 H, olefinic CH), 3.90 (s, 3 H, CH3),
2.20 (br s, 1 H, OH), 1.99-2.17 (m, 2 H, allylic CH2), 1.88-
1.98 (m, 1 H, CH2), 1.70-1.85 (m, 2 H, CH2), 1.51-1.63 (m, 1
H, CH2); 13C NMR (CDCl3, 100.6 MHz) δ 163.2, 144.2, 136.5,
135.8, 131.6, 131.0, 110.1, 70.7, 53.3, 39.4, 24.9, 19.0.
3-(2-Meth xoy-5-p yr id yl)-2-cycloh exen ol (5b). Crude 4b
from the experiment described above was stirred with p-TsOH‚
H2O (156 mg, 0.820 mmol) in 1,4-dioxane:H2O 4:1 (80 mL) for
5 h at room temperature. Saturated Na2CO3(aq) (40 mL) was
added, and the mixture was extracted with ether (3 × 100 mL).
The collected organic phases were dried (MgSO4). The solvent
was removed in vacuo, and the crude product was purified on
silica (ether:pentane gradient 5:95 f 50:50) to yield the title
compound (7.52 g, 91% in two steps). 1H NMR (CDCl3, 400
MHz) δ 8.17 (dt, J ) 2.6, 0.6 Hz, 1 H, PyH-6), 7.60 (ddd, J )
8.7, 2.6, 0.5 Hz, 1 H, PyH-4), 6.68 (ddd, J ) 8.7, 0.8, 0.4 Hz, 1
H, PyH-3), 6.05 (dddm, J ) 3.7, 2.1, 1.7 Hz, 1 H, olefinic CH),
4.33-4.40 (m, 1 H, allylic CHOH), 3.84 (s, 3 H, CH3O), 3.2 (br
s, 1 H, OH), 2.39 (dddd, J ) 17.5, 6.9, 5.0, 2.0 Hz, 1 H, allylic
CH2), 2.29 (dm, J ) 17.5 Hz, 1 H, allylic CH2), 1.84-1.98 (m,
2 H, CH2), 1.58-1.79 (m, 2 H, CH2); 13C NMR (CDCl3, 100.6
MHz) δ 163.2 (C), 143.2 (CH), 136.1 (C), 135.6 (CH), 129.8 (C),
126.3 (CH), 110.1 (CH), 65.8 (CH), 53.3 (CH3), 31.3 (CH2), 26.9
(CH2), 19.3 (CH2).
3-(2-Meth oxy-5-p yr id yl)-2-cycloh exen yl Meth yl Ca r -
bon a te (6b). To a solution of compound 5b (1.48 g, 7.04 mmol)
and pyridine (1.67 g, 21.1 mmol) in CH2Cl2 (70 mL) was added
methyl chloroformate (1.99 g, 21.1 mmol) over 2 h at 0 °C.
The reaction was stirred for an additional 12 h at room
temperature. The reaction mixture was washed with water (2
× 100 mL). The organic phase was collected, dried (Na2SO4),
and concentrated. The crude product was purified on silica
(pentane:ether 70:30) to yield the title compound, 1.36 g (72%),
as a colorless oil which solidified in the freezer. 1H NMR
(CDCl3, 400 MHz) δ 8.20 (dd, J ) 2.6, 0.7 Hz, 1 H, PyH-6),
7.63 (dd, J ) 8.7, 2.6 Hz, 1 H, PyH-4), 6.70 (dd, J ) 8.7, 0.7
Hz, 1 H, PyH-3), 6.07 (ddd, J ) 4.0, 1.6, 1.1 Hz, 1 H, olefinic),
5.27-5.33 (m, 1 H, allylic CHO), 3.92 (s, 3 H, CH3OPy), 3.78
(s, 3 H, CH3O), 2.43-2.54 (m, 1 H, allylic CH2), 2.29-2.41 (m,
1 H, allylic CH2), 1.87-2.02 (m, 3 H, CH2), 1.74-1.87 (m, 1 H,
CH2); 13C NMR (CDCl3, 100.6 MHz) δ 163.8 (C), 155.4 (C),
143.7 (CH), 139.8 (C), 135.8 (CH), 129.6 (C), 120.8 (CH), 110.4
(CH), 72.4 (CH), 54.6 (CH3), 53.5 (CH3), 27.8 (CH2), 27.1 (CH2),
18.9 (CH2). Anal. Calcd C, 63.87; H, 6.51; N, 5.32; Found: C,
63.96; H, 6.57; N, 5.40.
dissolved in HOAc) were added simultaneously over 12 h to a
stirred solution of Pd(OAc)2 (0.144 g, 0.64 mmol), LiCl (0.086
g, 2.03 mmol), LiOAc‚2H2O (0.516 g, 5.07 mmol) and p-
benzoquinone (2.14 g, 20.1 mmol) in a mixture of HOAc (7.0
mL) and acetone (25 mL). After complete addition, the reaction
was stirred for another 14 h. The solvents were removed in
vacuo, and the residue was diluted with ether (40 mL) and
washed with water (2 × 30 mL). The organic layer was washed
with 2 M NaOH (3 × 30 mL) and then with water (2 × 30
mL) containing NaBH4 to remove all remaining p-benzo-
quinone. The organic phase was dried over Na2SO4 and
concentrated to give a yellow oil. The crude product was
purified by flash chromatography (pentane:ether 80:20) to yield
1
the title compound, 1.22 g (62%). H NMR (CDCl3, 400 MHz)
δ 7.48 (d, J ) 8.1 Hz, 2 H, aromatic), 7.39-7.32 (m, 3 H,
aromatic) 6.06 (d, J ) 2.3 Hz, 1 H, olefinic), 5.55-5.50 (m, 1
H, CHOAc), 5.03 (ddd, J ) 4.1, 3.1, 1.2 Hz, 1 H, CHCl), 2.37-
2.10 (m, 4 H, CH2) 2.13 (s, 3 H, OAc); 13C NMR (CDCl3, 100.6
MHz) δ 170.1 (C), 140.7 (C), 137.9 (C), 128.4 (CH), 128.2 (CH),
127.4 (CH), 126.0 (CH), 69.6 (CH), 54.8 (CH), 30.9 (CH2), 22.8
(CH2), 21.2 (CH3); IR (neat), 3057 (w), 2962 (w), 2909 (w), 2876
(w), 1731 (s), 1662 (w), 1496 (w), 1445 (m), 1374 (m), 1346 (w),
1311 (w), 1266 (s), 1240 (s), 1204 (w), 1084 (w), 1036 (s), 1027
(s), 1000 (w) cm-1
.
cis-1-Acetoxy-3-p h en yl-4-(p-tolu en esu lfon a m id o)-2-cy-
cloh exen e (8a ). To a stirred suspension of Pd(PPh3)4 (0.074
g, 0.064 mmol), NaNHTs (0.270 g, 1.40 mmol), and H2NTs
(0.099 g, 0.58 mmol) in CH3CN (3 mL) was added 7a (0.290 g,
1.15 mmol) dissolved in CH3CN (1 mL). The reaction was
stirred at room temperature for 8 h. The reaction mixture was
diluted with EtOAc (30 mL) and washed with brine containing
2% NaOH (3 × 30 mL) and then with water (1 × 30 mL). The
organic phase was dried over Na2SO4 and concentrated. The
crude product was purified by flash chromatography (pentane:
EtOAc 80:20) to give 0.352 g (79%) of 8a as white crystals,
Mp: 175-177 °C (EtOAc:pentane). 1H NMR (CDCl3, 400 MHz)
δ 7.52 (dm, J ) 8.2 Hz, 2 H, aromatic), 7.19-7.05 (m, 5 H,
aromatic), 6.98 (dm, J ) 8.6 Hz, 2 H, aromatic), 5.94 (d, 1 H,
J ) 3.0 Hz, CH olefinic) 5.35-5.32 (m, 1 H, CHOAc), 4.54 (d,
J ) 6.2 Hz, 1 H, NHTs), 4.25-4.21 (m, 1 H, CHNHTs), 2.43
(s, 3 H, CH3Ar), 2.23-2.21 (m, 1 H, CH2), 2.09 (s, 3 H, OAc),
2.05-1.97 (m, 1 H, CH2), 1.88-1.74 (m, 2 H, CH2); 13C NMR
(CDCl3, 100.6 MHz) δ 170.6 (C), 143.2 (C), 140.1 (C), 137.4
(C), 129.5 (CH), 129.2 (CH), 128.3 (CH), 127.9 (CH), 127.0
(CH), 126.3 (CH), 69.0 (CH), 49.1 (CH), 27.5 (CH2), 22.7 (CH2),
21.5 (CH3), 21.2 (CH3); IR (KBr), 3250 (s), 3062 (w), 2967 (m),
2937 (m), 2920 (m), 2872 (w), 2728 (w), 2360 (w), 2344 (w),
1732 (s), 1598 (w) cm-1. Anal. Calcd C, 65.43; H, 6.01; N, 3.63;
Found: C, 65.23; H, 6.15; N, 3.66.
cis-3-P h en yl-4-(p-tolu en esu lfon a m id o)-2-cycloh exen -
1-ol (9a ). To a solution of compound 8a (2.52 g, 6.53 mmol) in
MeOH-H2O (125 mL, 4:1), was added K2CO3 (1.80 g, 13.0
mmol), and the reaction was stirred overnight at room tem-
perature. The MeOH was evaporated, and the residue was
diluted with EtOAc (140 mL) and extracted with sat. NH4Cl
(2 × 100 mL). The organic phase was dried (Na2SO4), concen-
trated, and purified by flash chromatography (CH2Cl2:ether:
MeOH 50:50:0.5) to yield 2.086 g (94%) of white crystals. Mp:
155-156 °C (EtOAc/pentane). 1H NMR (CDCl3, 400 MHz) δ
7.50 (dm, J ) 8.4 Hz, 2 H, aromatic), 7.20-7.05 (m, 5 H,
aromatic), 6.99 (dm, J ) 8.0 Hz, 2 H, aromatic), 6.02 (d, J )
2.3 Hz, 1 H, olefinic CH), 4.88 (d, J ) 6.3 Hz, 1 H, NHTs),
4.30-4.25 (m, 1 H, allylic CHOH), 4.23-4.19 (m, 1 H,
CHNHTs), 2.42 (s, 3 H, CH3Ar), 2.19-2.12 (m, 1 H, CH2),
2.02-1.93 (m, 1 H, CH2), 1.78-1.63 (m, 2 H, CH2); 13C NMR
(CDCl3, 100.6 MHz) δ 143.0 (C), 138.1 (C), 138.0 (C), 133.4
(CH) 129.5 (CH), 128.3 (CH), 127.5 (CH), 126.9 (CH), 126.3
(CH), 66.9 (CH), 49.1 (CH), 27.9 (CH2), 26.4 (CH2), 21.5 (CH3);
IR (KBr), 3476 (s), 3191 (s), 3065 (w), 3029 (w), 2936 (w), 2868
(w), 1598 (w), 1494 (w), 1445 (m), 1404 (w), 1328 (s), 1315 (s),
1305 (s), 1289 (s), 1153 (s), 1085 (s), 1055 (s), 1030 (w), 1020
2-(2-Meth oxy-5-p yr id yl)-1,3-cycloh exa d ien e (2b). The
allylic methyl carbonate 6b (800 mg, 3.038 mmol) and Pd-
(PPh3)4 (105 mg, 0.091 mmol) were dissolved in THF (7 mL)
under argon. The reaction was stirred for 20 h at room
temperature and then quenched with sat. Na2CO3 (20 mL) and
extracted with ether (3 × 40 mL). The combined organic phases
were dried (K2CO3), evaporated, and purified on silica to give
512 mg (90%) of the title compound. The silica was first
deactivated with 2% Et3N in pentane, and this eluent was used
for the separation. About 0.5 mL of 0.02% BHT in pentane
was put in each fraction tube before the separation in order
1
to prevent polymerization. H NMR (CDCl3, 400 MHz) δ 8.18
(dd, J ) 2.5, 0.8 Hz, 1 H, PyH-6), 7.58 (dd, J ) 8.6, 2.5 Hz, 1
H, PyH-4), 6.70 (dd, J ) 8.6, 0.8 Hz, 1 H, PyH-3), 6.23 (dq, J
) 9.7, 1.8 Hz, 1 H, diene CH-3), 5.98-6.06 (two overlapping
m, 2 H, diene CH-4 and CH-1), 3.91 (s, 3 H, CH3O), 2.27-2.35
(m, 2 H, CH2-6), 2.16-2.24 (m, 2 H, CH2-5); 13C NMR (CDCl3,
100.6 MHz) δ 163.1 (C), 143.4 (CH), 135.8 (CH), 132.6 (C),
129.5 (C), 128.2 (CH), 125.0 (CH), 122.2 (CH), 110.3 (CH), 53.3
(CH3), 22.7 (CH2), 21.8 (CH2).
(m) 1005 (s) cm-1
.
cis-1-Acetoxy-4-ch lor o-3-ph en yl-2-cycloh exen e (7a). The
2-Phenyl-1,3-cyclohexa-diene (2a )8 (1.58 g, 10.0 mmol dis-
solved in 4.5 mL of acetone) and LiCl (0.771 g, 18.2 mmol
3r-P h en yl-4r-(p-tolu en esu lfon a m id o)cycloh exa n e-1r-
ol (10a ). The amidoalkenol 9a (2.02 g, 5.90 mmol) was

840 J . Org. Chem., Vol. 64, No. 3, 1999
Palmgren and Larsson
dissolved in ethanol, and PtO2 (0.101 g, 0.41 mmol) was added.
Hydrogen (1 atm) was applied, and the reaction was stirred
at room temperature for 48 h. The catalyst was removed by
filtration through Celite, and the solvent was evaporated. The
crude product was purified by flash chromatography (EtOAc:
pentane 60:40). White crystals were collected, 1.917 g (94%).
128.3 (CH), 127.0 (CH), 125.8 (CH), 62.8 (CH), 56.4 (CH), 48.0
(CH), 40.1 (CH2), 30.8 (CH2), 29.6 (CH2); IR (film), 3064 (w),
3027 (w), 2966 (s), 2927 (s), 2874 (m), 2253 (m), 1496 (w), 1202
(w), 1053 (w) cm-1
.
tr a n s-1-Acetoxy-3-p h en yl-4-(p-tolu en esu lfon a m id o)-2-
cycloh exen e (13a ). The chloroacetate 7a (1.43 g, 5.70 mmol)
was added to stirred solution of NaNHTs (1.65 g, 8.55 mmol)
and H2NTs (0.488 g, 2.85 mmol) in DMSO (25 mL). The
reaction mixture was heated at 55 °C for 24 h. After cooling,
the mixture was diluted with EtOAc (100 mL) and washed
with brine containing 2% NaOH (3 × 70 mL) and sat. NH4Cl
(75 mL). The organic phase was dried (Na2SO4) and concen-
trated. The residue was purified on silica (pentane:EtOAc
gradient 90:10 f 40:60) which afforded 1.76 g (80%) of white
1
Mp: 112 °C. H NMR (CDCl3, 400 MHz) δ 7.21 (dm, J ) 8.2
Hz, 2 H, aromatic), 7.17-7.10 (m, 3 H, aromatic), 7.02 (dm, J
) 8.0 Hz, 2 H,), 6.93 (dm, J ) 7.1 Hz, 2 H, aromatic), 4.45 (d,
J ) 4.7 Hz, 1 H, NHTs), 3.77-3.69 (m, 1 H, CHOH), 3.37-
3.34 (m, 1 H, CHNHTs), 2.87 (ddd, J ) 13.6, 3.1, 3.1 Hz, 1 H,
PhCH), 2.38 (s, 3 H, CH3Ar), 2.35-2.29 (m, 1 H, CH2CHNHTs),
2.07-2.02 (m, 1 H, CH2), 1.90-1.56 (m, 4 H, CH2); 13C NMR
(CDCl3, 100.6 MHz) δ 142.7 (C), 140.2 (C), 129.4 (CH), 127
(CH), 126.8 (CH), 70.2 (CH), 53.3 (CH), 44.1 (CH), 33.9 (CH2),
29.8 (CH2), 21.4 (CH3); IR (KBr), 3481(s), 3211(m), 2950 (w),
1598 (w). 1497 (w), 1472 (w), 1439 (w), 1315 (s), 1155 (s), 1092
1
crystals. mp: 135 °C (CH2Cl2:pentane); H NMR (CDCl3, 400
MHz) δ 7.52 (dm, J ) 8.2 Hz, 2 H, aromatic), 7.25-7.15 (m, 3
H, aromatic), 7.04-7.15 (m, 2 H, aromatic), 6.98 (dm, J ) 8.0
Hz, 2 H), 6.06 (d, J ) 4.4 Hz, 1 H, olefinic), 5.35 (app t. dd, J
) 8.1, 4.2, 4.2 Hz, 1 H, CHOAc), 4.36 (d, J ) 5.7 Hz, 1 H,
HNTs), 4.32-4.28 (m, 1 H, CHNHTs), 2.43 (s, 3 H, CH3Ar),
2.07-1.98 (m, 2 H, CH2), 2.00 (s, 3 H, OAc), 1.80-1.78 (m, 2
H, CH2); 13C NMR (CDCl3, 100.6 MHz) δ 170.5 (C), 143.2 (C),
141.4 (C), 137.6 (C), 136.9 (C), 129.5 (CH), 128.4 (CH), 128.1
(CH), 127.4 (olefinic), 127.1 (CH), 126.4 (CH), 66.9 (CH),
49.3 (CH), 26.1 (CH2), 23.3 (CH2), 21.5 (CH3), 21.1 (CH3); IR
(KBr), 3232 (s), 3019 (w), 2973 (w), 2940 (w), 2867 (w), 1741
(s), 1492 (w), 1450 (m), 1373 (s), 1329 (s), 1300 (w), 1289 (m),
1260 (s), 1200 (m), 1182 (m), 1155 (s), 1120 (m), 1089 (s), 1008
(m), 1047 (s), 1003 (s) cm-1
.
1r-Ch lor o-3â-p h en yl-4â-(p-tolu en esu lfon a m id o)cyclo-
h exa n e (11a ). To alcohol 10a (0.040 g, 0.11 mmol), dissolved
in CHCl3 (3 mL), was added thionyl chloride (0.5 mL). The
reaction was refluxed for 24 h. The solvent was evaporated,
the excess of thionyl chloride was evaporated together with
toluene (3 × 10 mL), and the crude product was purified by
flash chromatography (pentane:EtOAc 80:20) to give 0.028 g
(66%) of 11a . 1H NMR (CDCl3, 400 MHz) δ 7.22-7.12 (m, 5
H, aromatic), 7.06 (dm, J ) 8.2 Hz, 2 H, aromatic), 6.91 (dm,
J ) 7.0 Hz, 2 H, aromatic), 4.68-4.64 (m, 1 H, CHCl), 4.52 (d,
J ) 2.0 Hz, 1 H, NHTs), 3.44 (ddd, J ) 13.0, 3.6, 3.6 Hz, 1 H,
benzylic), 3.39-3.35 (m, 1 H, CHNHTs), 2.39 (s, 3 H, CH3Ar),
2.34-2.12 (m, 4 H, CH2), 1.90-1.82 (m, 2 H, CH2); 13C NMR
(CDCl3, 100.6 MHz) δ 142.8 (C), 140.1 (C), 135.6 (C), 129.4
(CH), 128.7 (CH), 127.0 (CH), 126.9 (CH), 126.8 (CH), 58.8
(CH), 54.0 (CH), 38.9 (CH), 32.0 (CH2), 27.5 (CH2), 25.4 (CH2),
21.7 (CH3Ar).
(s) cm-1
.
tr a n s-3-P h en yl-4-(p-tolu en esu lfon am ido)-2-cycloh exen -
1-ol (14a ). To a solution of 13a (0.590 g, 1.53 mmol) in MeOH:
H2O (13 mL, 4:1) was added K2CO3 (0.221 g, 1.60 mmol), and
the reaction was stirred overnight at room temperature. White
crystals were formed during the reaction which were filtered
off and collected. The methanol was evaporated, and the
remaining crude product was recrystallized from methanol/
H2O to give 0.473 g (90%) of white crystals. Mp: 190-192 °C
exo-2-P h en yl-7-N-tosyla za bicyclo[2.2.1]h ep ta n e (exo-
12a ). To a stirred solution of 11a (0.015 g, 0.040 mmol) in
methanol (3 mL) was added K2CO3 (11 mg, 0.080 mmol). The
reaction was stirred at 55 °C for 48 h. The solvent was
removed, and the residue was separated on silica (pentane:
1
(MeOH). H NMR (CDCl3, 400 MHz) δ 7.53 (dm, J ) 8.2 Hz,
2 H, aromatic), 7.15-7.22 (m, 3 H, aromatic), 7.04-7.13 (m, 2
H, aromatic), 6.97 (d, J ) 7.2 Hz, 2 H, aromatic), 6.07 (d, J )
4.1 Hz, 1 H, olefinic), 4.36-4.32 (m, 1 H, CHOH), 4.29-4.24
(m, 2 H, overlapping NHTs and CHNHTs), 2.44 (s, 3 H, CH3-
Ar), 2.14-1.98 (m, 3 H, CH2), 1.75-1.68 (m, 1 H, CH2); 13C
NMR (CDCl3, 100.6 MHz) δ 143.3 (C), 139.6 (C), 138.0 (C),
137.0 (C), 131.5 (CH), 129.1 (CH), 128.4 (CH), 127.9 (C), 127.1
(CH), 126.5 (CH), 64.7 (CH), 49.7 (CH), 27.0 (CH2), 26.1 (CH2),
21.5 (CH3); IR (KBr), 3518 (s), 3250 (s), 2966 (m), 2927 (m),
1598 (w), 1492 (w), 1438 (m), 1292 (m), 1251 (m), 1155 (s),
1
EtOAc 80:20) to give 0.013 g (95%) of a white solid. H NMR
(CDCl3, 400 MHz) δ 7.80 (d, J ) 8.2 Hz, 2 H, aromatic), 7.28
(d, J ) 8.4 Hz, 2 H, aromatic), 7.20-7.16 (m, 5 H, aromatic),
4.32 (dd, J ) 4.3, 3.6 Hz, 1 H, PhCHCH), 4.18 (d, J ) 3.1 Hz,
1 H, PhCHCH2CH), 2.81 (dd, J ) 9.0, 5.1 Hz, 1 H, benzylic),
2.43 (s, 3 H, CH3Ar), 1.99-1.86 (m, 4 H, CH2), 1.58-1.49 (m,
2 H, CH2); 13C NMR (CDCl3, 100.6 MHz) δ 144.9 (C), 143.4
(C), 137.8 (C), 129.4 (CH), 128.3 (CH), 127.6 (CH), 127.0 (CH),
126.3 (CH), 65.1 (PhCHCH2CH), 59.4 (PhCHCH), 41.5 (CH2),
30.1 (CH2), 29.1 (CH2), 21.5 (CH3); IR (CH2Cl2), 3055 (w), 2983
(w), 1492 (w), 1455 (w), 1338 (m), 1320 (m), 1304 (w), 1273
(m), 1258 (m), 1223 (w), 1200 (w), 1175 (w), 1152 (s), 1091 (s),
1055 (w), 1031 (w), 1009 (w) cm-1. Anal. Calcd C, 69.69; H,
6.46; N, 4.28; Found: C, 69.54; H, 6.55; N, 4.31.
1097 (m), 1015 (s) cm-1
.
3r-P h en yl-4â-(p-tolu en esu lfon a m id o)cycloh exa n e-1r-
ol (15a ). The amidoalkenol (0.587 g, 1.72 mmol) was dissolved
in ethanol (15 mL). PtO2 was added, and H2 (1 atm) was
introduced. The reaction was stirred at room temperature for
78 h. The catalyst was filtered off, and solvent was removed.
The crude product was purified on silica (pentane:EtOAc
gradient 90:10 f 20:80) to give 0.510 g (86%) of a white solid.
Mp: 185 °C (EtOAc:pentane). 1H NMR (CDCl3, 400 MHz) δ
7.30 (dm, J ) 8.2 Hz, 2 H, aromatic), 7.16-7.07 (m, 5 H,
aromatic), 6.84 (dm, J ) 7.0 Hz, 2 H, aromatic), 4.22 (d, J )
7.0 Hz, 2 H, NHTs) 3.75-3.67 (m, 1 H, CHOH), 3.07-2.99 (m,
1 H, CHNHTs), 2.49-2.40 (m, 1 H, benzylic), 2.42 (s, 3 H, CH3-
Ar), 2.09-2.01 (m, 2 H), 1.60-1.40 (m, 4 H); 13C NMR (CDCl3,
100.6 MHz) δ 142.9 (C), 140.7 (C), 136.5 (C), 129.4 (CH), 128.9
(CH), 69.5 (CH), 56.6 (CH), 48.3 (CH), 42.8 (CH2), 33.9 (CH2),
32.2 (CH2), 21.5 (CH3); IR (KBr), 3494 (s), 3236 (s), 3059 (m),
3031 (w), 2928 (s), 2852 (m), 1496 (m), 1452 (m), 1406 (m),
1309 (s), 1281 (s), 1248 (w), 1210 (w), 1189 (w), 1160 (s), 1078
(s), 1060 (s), 1019 (w) cm-1. Anal. Calcd C, 66.06; H, 6.71; N,
4.05; Found: C, 66.02; H, 6.78; N, 4.10.
exo-2-P h en yl-7-a za bicyclo[2.2.1]h ep ta n e (exo-1a ). So-
dium (0.110 g, 4.78 mmol) and naphthalene (0.780 g, 6.09
mmol) were dissolved in DME under nitrogen. The dark green
solution was stirred at room temperature for 2 h. A solution
of tosylamide exo-12a (0.142 g, 0.43 mmol) dissolved in DME
(5 mL) was cooled to -60 °C. The sodium naphthalene solution
was added dropwise to the tosylamide solution until a dark
green solution persisted. The reaction was quenched by
addition of sat. NaHCO3 (1 mL). Anhydrous K2CO3 (2.2 g) was
added, and the solution was stirred for 12 h. The mixture was
filtered, and the precipitate was rinsed with CH2Cl2:Et2O (1:
1). The organic layer was washed with 2 × 30 mL of 0.5 M
HCl (aq). The combined aqueous phase was washed with CH2-
Cl2 and Et2O. The aqueous phase was made alkali with 1 M
KOH (aq) and then extracted with 2 × 30 mL of CH2Cl2:Et2O
(1:1). The organic layer was dried (Na2SO4) and concentrated
1r-(Mesyloxy)-3r-p h en yl-4â-(p -t olu en esu lfon a m id o)-
cycloh exa n e (16a ). Methanesulfonyl chloride (0.040 g, 0.34
mmol) was added dropwise, at 0 °C, to a stirred solution of
Et3N (0.032 g, 0.32 mmol) and 15a in THF (3 mL). After
complete addition, the reaction was stirred for 12 h, 0 °C f
rt. The reaction was quenched with ice/water, and the mixture
1
to give 0.074 g (97%) of exo-1a . H NMR (CDCl3, 400 MHz) δ
7.30-7.28 (m, 4 H), 7.20-7.16 (m, 1 H), 3.78 (dd, J ) 4.4, 3.6
Hz, 1 H, PhCHCH), 3.62 (d, J ) 3.9 Hz, 1 H, PhCHCH2CH),
2.88 (dd, J ) 8.8, 5.4 Hz, 1 H, benzylic), 1.95-1.90 (m, 1 H),
1.76-1.43 (m, 6 H); 13C NMR (CDCl3, 100.6 MHz) δ 146.3 (C),

Pd(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes
J . Org. Chem., Vol. 64, No. 3, 1999 841
was extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine (20 mL), dried (Na2SO4), and
concentrated. The crude product was directly used in the next
step.
4.14 (m, 1 H, CHNHTs), 3.89 (s, 3 H, CH3O), 2.39 (s, 3 H,
CH3Ar), 2.04 (s, 3 H, OAc), 1.98-1.93 (m, 2 H), 1.82-1.64 (m,
2 H); 13C NMR (CDCl3, 100.6 MHz) δ 170.5 (C), 163.6 (C), 144.8
(CH), 143.3 (C), 137.33 (C), 137.27 (C), 136.0 (CH), 129.5 (CH),
128.7 (CH), 126.8 (CH), 126.8 (CH), 110.1 (CH), 68.7 (CH), 53.4
(CH3), 49.1 (CH), 27.5 (CH2), 22.6 (CH2), 24.1 (CH3), 21.1 (CH3);
en do-2-P h en yl-7-N-tosylazabicyclo[2.2.1]h eptan e (en do-
12a ). The crude mesylate 16a was dissolved in methanol (3
mL), and K2CO3 (0.047 g, 0.35 mmol) was added. The reaction
was heated at 55 °C for 48 h. The solvent was removed, and
the crude product was separated on silica (pentane:ether
80:20) to give 0.056 g (74%, based on 15a ) of a white solid.
1H NMR (CDCl3, 400 MHz) δ 7.86 (dm, J ) 8.2 Hz, 2 H,
aromatic), 7.22 (m, 1 H, aromatic), 7.16 (dm, J ) 7.8 Hz, 2 H,
aromatic), 4.35 (dd, J ) 4.4, 4.4 Hz, 1 H, PhCHCH), 4.28
(dd, J ) 4.8, 4.8 Hz, 1 H, PhCHCH2CH), 3.60 (ddd, J )
11.7, 5.5, 4.5 Hz, 1 H, benzylic), 2.43 (s, 3 H, CH3Ar), 2.29
(tdd, J ) 12.1, 5.2, 3.2 Hz, 1 H, PhCHCH2 exo), 1.86-1.76 (m,
1 H, CH2), 1.65 (dd, J ) 12.4, 5.6 Hz, 1 H, PhCHCH2 endo),
1.39-1.59 (m, 3 H, CH2); 13C NMR (CDCl3, 100.6 MHz) δ 143.4
(C), 139.3 (C), 137.9 (C), 129.4 (CH), 128.4 (CH), 128.0 (CH),
127.5 (CH), 126.5 (CH), 63.6 (CH), 60.4 (CH), 46.9 (CH), 34.6
(CH2), 30.6 (CH2), 23.8 (CH2), 21.5 (CH3); IR (CH2Cl2), 2956
(w), 2922 (w), 1598 (w), 1496 (w), 1471 (w), 1454 (w), 1401
(w), 1349 (s), 1319 (m), 1303 (m), 1153 (s), 1096 (s), 1052 (m),
IR (KBr) 1727, 1289, 1161 cm-1
.
cis-3-(2-Meth oxy-5-p yr id yl)-4-(p-tolu en esu lfon a m id o)-
2-cycloh exen -1-ol (9b). Compound 8b (0.350 g, 0.84 mmol)
was dissolved in a mixture of MeOH:water (4:1, 8 mL), K2-
CO3 was added, and the reaction was stirred overnight at room
temperature. The solvents were evaporated, and the residue
was purified on silica (EtOAc:pentane 4:1) to give 0.253 g (81%)
of white crystals. Mp: 158-159 °C (CHCl3:pentane). 1H NMR
(CDCl3, 400 MHz) δ 7.88 (d, J ) 2.3 Hz, 1 H, pyH-6), 7.51 (d,
J ) 8.2 Hz, 2 H, aromatic), 7.17-7.12 (m, 3 H, aromatic), 6.38
(d, J ) 8.7 Hz, 1 H, pyH-3), 5.93 (d, J ) 2.6 Hz, 1 H, olefinic),
5.22 (d, J ) 7.5 Hz, 1 H, NHTs), 4.27-4.22 (m, 1 H, allylic
CHOH), 4.16-4.13 (m, 1 H, CHNHTs), 3.90 (s, 3 H, CH3O),
2.42 (s, 3 H, CH3Ar), 2.07-1.93 (m, 2 H), 1.76-1.58 (m, 2 H).
13C NMR (CDCl3, 100.6 MHz) δ 163.6 (C), 144.8 (CH), 143.3
(CH), 137.4 (CH), 136.4 (CH), 135.3 (C), 133.13 (CH), 129.5
(CH), 127.3 (C), 126.8 (CH), 110.2 (CH), 66.7 (CH), 53.5 (CH3),
49.2 (CH), 27.9 (CH2), 26.4 (CH2), 21.5 (CH3); IR (KBr), 1330,
1041 (m) cm-1
.
1289 cm-1
.
en d o-2-P h en yl-7-a za b icyclo[2.2.1]h ep t a n e (en d o-1a ).
3r-(2-Meth oxy-5-p yr id yl)-4r-(p-tolu en esu lfon a m id o)-
cycloh exa n e-1r-ol (10b). The amidoalkenol 9b (0.050 g, 0.13
mmol) was dissolved in EtOH (5 mL). PtO2 was added, and
H2 (1 atm) was introduced. The reaction was stirred at room
temperature for 5 d, filtered through Celite, and the solvent
was removed. The crude product was purified by flash chro-
matography (EtOAc) to give 0.047 g (93%) of white crystals.
The deprotection was performed as described for compound
exo-12a to yield endo-1a (0.021 g, 89%). H NMR (CDCl3, 400
1
MHz) δ 7.30-7.28 (m, 2 H), 7.22-7.17 (m, 3 H), 3.78 (dd, J )
4.9, 4.4 Hz, 2 H), 3.40-3.36 (m, 1 H), 2.94 (broad s, 1 H), 2.12-
2.04 (m, 1 H), 1.70-1.55 (m, 2 H), 1.46-1.35 (m, 3 H); 13C
NMR (CDCl3, 100.6 MHz) δ 140.9 (C), 128.2 (CH), 128.0 (CH),
126.1 (CH), 61.5 (CH), 57.8 (CH), 47.5 (CH), 34.5 (CH2),
30.7 (CH2), 29.7 (CH2); IR (film), 3369 (m), 2959 (s), 2364 (w),
1736 (w), 1601 (m), 1497 (m), 1458 (m), 1376 (m), 1121 (w),
1
Mp: 223 °C (CHCl3:pentane). H NMR (CD3OD, 400 MHz) δ
7.75 (d, J ) 2.4 Hz, 1 H,pyH-6), 7.32-7.27 (m, 3 H, aromatic),
7.06 (d, J ) 8.1 Hz, 2 H, aromatic), 6.38 (d, J ) 8.5 Hz, 1 H,
pyH-3), 3.86 (s, 3 H, CH3O), 3.64-3.62 (m, 1 H, CHOH), 3.49
(dd, J ) 5.4, 2.5 Hz, 1 H, CHNHTs), 2.83-2.78 (m, 1 H, pyr-
CH) 2.38 (s, 3 H, CH3Ar), 1.89-1.77 (m, 4 H), 1.72-1.63 (m,
2 H); 13C NMR (CD3OD, 100.6 MHz) δ 164.2 (C), 146.3 (CH),
143.8 (C), 139.9 (CH), 139.6 (C), 131.6 (C); 130.3 (CH), 127.5
(CH), 111.0 (CH), 70.8 (CH), 54.8 (CH), 54.0 (CH3), 42.8 (CH),
35.0 (CH2), 32.0 (CH2), 29.6 (CH2), 21.4 (CH3); IR (KBr), 1338,
1290, 1157, 1093 cm-1. Anal. Calcd C, 60.62; H, 6.43; N, 7.44;
Found: C, 60.51; H, 6.49; N, 7.49.
914 (w) cm-1
.
cis-1-Acet oxy-4-ch lor o-3-(2-m et h oxy-5-p yr id yl)-2-cy-
cloh exen e (7b). To a suspension of Pd(OAc)2 (18 mg, 0.082
mmol), LiCl (14 mg, 0.326 mmol), p-benzoquinone (176 mg,
1.63 mmol), and LiOAc‚2H2O (42 mg, 0.408 mmol) in HOAc
(0.3 mL) and acetone (1.3 mL) were simultaneously added over
15 h (i) LiCl (55 mg, 1.30 mmol) in HOAc (0.5 mL) and acetone
(0.3 mL) and (ii) diene 2b (152 mg, 0.815 mmol) in acetone
(0.8 mL). The reaction was stirred for another 21 h. Ether (50
mL) was added followed by sat. Na2CO3 until the pH of the
aqueous phase was above 8. After extraction, the ether phase
was collected, and the aqueous phase was further extracted
with ether (3 × 50 mL). The combined organic phases were
washed with 2 M NaOH (3 × 40 mL) and brine (30 mL) and
dried over MgSO4. The solvent was removed in vacuo, and the
residue was separated on silica (ether:pentane 1:4) to yield
1r-Ch lor o-3â-(2-Me t h oxy-5-p yr id yl)-4â-(p -t olu e n e -
su lfon a m id o)cycloh exa n e (11b). To a stirred solution of 10b
was added thionyl chloride, and the reaction was refluxed for
8 h. After being cooled to room temperature, the reaction was
quenched with ice, diluted with sat. NaHCO3, and extracted
with CHCl3. The organic phase was dried (MgSO4), concen-
trated, and purified by flash chromatography (pentane:EtOAc
1
the title compound (69 mg, 30%). H NMR (CDCl3, 400 MHz)
1
1:1) to give 0.020 g (65%) of white crystals. H NMR (CDCl3,
δ 8.27 (dm, J ) 2.6 Hz, 1 H, PyH-6), 7.68 (dd, J ) 8.7, 2.6 Hz,
1 H, PyH-4), 6.73 (dd, J ) 8.7, 0.8 Hz, 1 H, PyH-3), 5.99 (dd,
J ) 2.6, 0.9 Hz, 1 H, olefinic CH), 5.47-5.54 (m, 1 H, CHO),
4.90-4.95 (m, 1 H, CHCl), 3.95 (s, 3 H, CH3O), 2.34 (ddd, J )
14.5, 6.9, 3.3 Hz, 1 H, CH2), 2.12 (s, 3 H, CH3C(O)), 1.89-2.29
(m, 3 H, CH2); 13C NMR (CDCl3, 100.6 MHz) δ 170.7 (C), 164.0
(C), 144.6 (CH), 137.9 (C), 136.4 (CH), 127.0 (CH), 126.9 (C),
110.6 (CH), 69.6 (CH), 54.6 (CH), 53.6 (CH3), 30.8 (CH2), 22.8
(CH2), 21.3 (CH3).
400 MHz) δ 7.72 (d, J ) 2.3 Hz, 1 H, pyrH-6), 7.32 (d, J )
8.24 Hz, 1 H, aromatic), 7.09-7.04 (m, 3 H, aromatic), 6.39
(d, J ) 8.5 Hz, 1 H, pyrH-3), 4.68-4.64 (two overlapping m, 2
H, CHCl and NHTs), 3.91 (s, 3 H, CH3O), 3.43-3.72 (m, 1 H,
CHNHTs), 3.35 (ddd, J ) 13.0, 3.4, 3.4 Hz, 1 H, pyr-CH), 2.40
(s, 3 H, CH3Ar), 2.24-1.85 (m, 6 H); 13C NMR (CDCl3, 100.6
MHz) δ 163.0 (C), 144.9 (CH), 143.2 (C), 137.6 (CH), 129.4
(CH), 128.5 (C), 126.7 (CH), 110.7 (CH), 58.4 (CH), 53.8 (CH),
53.3 (CH3), 36.4 (CH), 32.0 (CH2), 27.4 (CH2), 26.1 (CH2), 21.4
cis-1-Ace t oxy-3-(2-Me t h oxy-5-p yr id yl)-4-(p -t olu e n e -
su lfon a m id o)-2-cycloh exen e (8b). To a stirred suspension
of Pd(PPh3)4 (0.115 g, 0.1 mmol), NaNHTs (0.468 g, 2.4 mmol),
and H2NTs (0.171 g, 1.0 mmol) in CH3CN (4 mL), under argon,
was added 7b (0.569 g, 2.0 mmol) in CH3CN (4 mL). The
reaction was stirred at room temperature for 12 h. The reaction
mixture was diluted with EtOAc (70 mL) and washed with
brine containing 2% NaOH (3 × 50 mL). The combined organic
layer were dried (Na2SO4) and concentrated. The crude product
was purified by flash chromatography (pentane:EtOAc 2:1) to
(CH3); IR(film) 1320, 1294, 1156 cm-1
.
exo-2-(2-Meth oxy-5-p yr id yl)-7-N-tosyla za bicyclo[2.2.1]-
h ep ta n e (exo-12b). To a stirred solution of 11b (0.010 g, 0.027
mmol) in MeOH (2 mL) was added K2CO3 (0.018 g, 0.14 mmol).
The reaction was stirred at 55 °C for 7 d. The solvent was
evaporated, and the crude product was purified by flash
chromatography (pentane:EtOAc 60:40) to give 0.006 g (63%)
of white crystals. The NMR data was identical with the
compound described in the literature.12b
1
give 0.590 g (71%) of white sticky crystals. H NMR (CDCl3,
Ack n ow led gm en t. The Swedish Natural Science
Research Council, the Swedish Research Council for
Engineering Sciences, and Astra Pain Control AB are
gratefully acknowledged for financial support.
400 MHz) δ 7.84 (d, J ) 2.3 Hz, 1 H, pyH-6), 7.49 (d, J ) 8.2
Hz, 2 H, aromatic), 7.15-7.11 (m, 3 H, aromatic), 6.37 (d, J )
8.5 Hz, 1 H, pyH-3), 5.82 (d, J ) 2.6 Hz, 1 H, olefinic), 5.29-
5.25 (m, 1 H, CHOAc), 4.96 (d, J ) 7.3 Hz, 1 H, NHTs), 4.16-

842 J . Org. Chem., Vol. 64, No. 3, 1999
Palmgren and Larsson
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds exo-1a , endo-1a , 5b , 6b, 7a ,
7b , 8a , 8b , 9a , 9b , 10a , 10b , 11a , 11b , exo-12a , exo-12b ,
endo-12a , 13a , 14a , and 15a (40 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O981668N