Dipolar cycloaddition route to diverse analogues of cocaine: The 6- and 7-substituted 3-phenyltropanes

Article abstract of DOI:10.1021/jo961957g

In our quest for an antagonist or partial agonist of cocaine, access to certain 6- and 7-substituted 3-phenyltropanes of type I was required. Starting from 3-hydroxy-1-methyl-4-phenylpyridinium iodide, we disclose a pyridinium betaine-based dipolar cycloaddition route to tropenones of type II. In turn, we show how this intermediate can be transformed to type I products either through the copper-catalyzed conjugate addition reaction of Grignard reagents to the enones 7-9 or by the copper(I)-catalyzed cross coupling reaction of the allylic acetates 15a and 16a with Grignard reagents.

Full text of DOI:10.1021/jo961957g

J . Org. Chem. 1997, 62, 503-509
503
Dip ola r Cycloa d d ition Rou te to Diver se An a logu es of Coca in e:
Th e 6- a n d 7-Su bstitu ted 3-P h en yltr op a n es
Alan P. Kozikowski,*,† Gian Luca Araldi,† and Richard G. Ball‡
Georgetown University Medical Center, Institute for Cognitive and Computational Sciences,
3970 Reservoir Road NW, Washington, DC 20007-2197, and Merck Sharp & Dohme Research
Laboratories, P.O. Box 2000, Rahway, New J ersey 07065
Received October 21, 1996X
In our quest for an antagonist or partial agonist of cocaine, access to certain 6- and 7-substituted
3-phenyltropanes of type I was required. Starting from 3-hydroxy-1-methyl-4-phenylpyridinium
iodide, we disclose a pyridinium betaine-based dipolar cycloaddition route to tropenones of type II.
In turn, we show how this intermediate can be transformed to type I products either through the
copper-catalyzed conjugate addition reaction of Grignard reagents to the enones 7-9 or by the
copper(I)-catalyzed cross coupling reaction of the allylic acetates 15a and 16a with Grignard
reagents.
In tr od u ction
(R)-Cocaine, a plant alkaloid purified from the leaves
of Erythroxylum coca, has long been recognized to be a
potent central nervous system stimulant.1 Its abuse is
one of the greatest concerns of the American public today,
and it is clear that immediate therapies are needed for
the treatment of individuals who have become addicted
to this powerful reinforcing drug.2 In order to discover
agents for use in the treatment of cocaine abuse, we
believe that it will be valuable to identify molecules that
can act as cocaine antagonists and cocaine partial ago-
nists. Previously, we have shown that cocaine’s C-2 ester
group can be replaced by alkyl and alkenyl groups with
no loss in activity,3 while other workers have shown that
replacement of the C-3 benzoate by phenyl leads to
compounds of higher potency (these phenyl-bearing
structures are often referred to as the Win series com-
pounds; see Figure 1).4 In order to more quickly identify
those structural changes that may lead to altered func-
tional activity, we required a versatile chemical approach
to diversely substituted 3-phenyltropanes of type I.
While previous synthetic methodologies have been di-
rected primarily to altering substituents about the three-
carbon bridge, no general strategy that allowed for
introduction of diverse functionality into the 6- and
7-positions of the 3-phenyltropane skeleton has been
available.5 We were particularly interested in gaining
access to the Win series compounds of type I bearing
substitution on the two-carbon bridge, for we had found
previously that methoxylation of pseudococaine’s 7-posi-
tion led to a compound capable of acting as a weak
F igu r e 1. Structures of cocaine-related molecules.
antagonist.6 Thus, in our quest for a cocaine antagonist
or partial agonist, it was deemed logical to examine the
structure-activity relationships of the higher potency
Win series compounds bearing additional substitution on
the two-carbon bridge.
Herein we disclose a pyridinium betaine-based dipolar
cycloaddition route7 to a tropenone of type II and show
how this intermediate can be transformed to type I
products.
† Georgetown University Medical Center.
‡ Merck Sharp & Dohme Research Laboratories.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Lounasmaa, M. Alkaloids 1988, 33, 1.
Resu lts a n d Discu ssion
(2) (a) Woolverton, W. L.; J ohnson, K. M. Trends Pharmacol. Sci.
1992, 13, 193. (b) Woolverton, W. L.; Kleven, M. S. NIDA Res. Monogr.
1988, 88, 160.
(3) Kozikowski, A. P.; Eddine Saiah, M. K.; J ohnson, K. M.;
Bergmann, J . S. J . Med. Chem. 1995, 38, 3086.
To carry out the dipolar cycloaddition chemistry, we
first required access to oxidopyridinium betaine 6. This
building block was, in fact, easily obtained as a crystal-
line, storable compound starting from 3-hydroxypyridine
(4) (a) Clarke, R. L.; Daum, S. J .; Gambino, A. J .; Aceto, M. D.; Pearl,
J .; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. J . Med. Chem. 1973,
16, 1260. (b) Carroll, F. I.; Gao, Y.; Rahman, M. A.; Abraham, P.;
Parham, K.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . J . Med. Chem.
1991, 34, 2719. (c) Carroll, F. I.; Lewin, A. H.; Boja, J . W.; Kuhar, M.
J . In Drug Design for Neuroscience; Kozikowski, A. P., Ed.; Raven
Press: New York, 1993; pp 149-166.
(6) Simoni, D.; Stoelwinder, J .; Kozikowski, A. P.; J ohnson, K. M.;
Bergmann, J . S.; Ball, R. G. J . Med. Chem. 1993, 36, 3975.
(7) Katritzky, A. R.; Dennis, N.; Chaillet, M.; Larrieu, C.; El
Mouhtadi, M. J . Chem. Soc., Perkin Trans. 1 1979, 408. Dennis, N.;
Katritzky, A. R.; Takeuchi, Y. Angew. Chem., Int. Ed. Engl. 1976, 15,
1.
(5) Kozikowski, A. P.; Simoni, D.; Manfredini, S.; Roberti, M.;
Stoelwinder, J . Tetrahedron Lett. 1996, 37, 5333.
S0022-3263(96)01957-3 CCC: $14.00 © 1997 American Chemical Society

504 J . Org. Chem., Vol. 62, No. 3, 1997
Kozikowski et al.
Sch em e 1
Sch em e 2
as outlined in Scheme 1. Comins8 has previously de-
scribed the synthesis of 3-benzyloxypyridine (2) by reac-
tion of 3-chloropyridine with the sodium salt of benzyl
alcohol in DMSO at 125 °C. In our hands, this reaction
proceeded in good yield (70%); however, the pyridine
derivative was apparently contaminated with some sulfur-
containing byproducts, for difficulty was experienced in
the subsequent hydrogenolysis step. Therefore, the
synthesis of the protected pyridine 2 was performed using
3-hydroxypyridine and benzyl chloride under phase-
transfer conditions. The addition of phenylmagnesium
bromide to the pyridine 2 was performed following the
Comins protocol but using soluble CuI‚2LiCl9 in place of
CuI/Me2S. The dihydropyridine intermediate was di-
rectly aromatized using o-chloranil to afford 3-(benzyl-
oxy)-4-phenylpyridine (3) in 75% yield. Hydrogenation
of compound 3 gave in quantitative yield the hydroxy-
pyridine 4, which was treated with MeI in acetone at
reflux. Finally, the resulting hydroxypyridinium salt 5
was stirred with Amberlite IRA 400 (OH-) ion-exchange
resin in methanol to afford the desired betaine 6 in
quantitative yield.
Ta ble 1. P r od u cts a n d Isola ted Yield s Obta in ed for th e
Rea ction of Beta in e 6 w ith Th r ee Rep r esen ta tive
Dip ola r op h iles
compda
X
Y
W
Z
yield (%)
7a
7b
7c
7d
CN
H
CN
H
H
H
CN
H
H
H
H
37
42
5
H
H
H
H
CN
16
8a
8b
8c
8d
SO2Ph
H
H
H
H
H
H
60
16
15
0
H
H
H
SO2Ph
H
H
SO2Ph
H
SO2Ph
9a
9b
9c
9d
CO2Et
H
CO2Et
H
H
H
H
CO2Et
H
H
H
H
CO2Et
33
26
20
12
H
H
H
a
See Scheme 1 for the structures of compounds 7-9.
istry. In addition, small amounts of the other two
regioisomeric products were isolated (7c, 7â-isomer, 5%,
and 7d , 7R-isomer, 16%, see Scheme 1 and Table 1).
Similar results were achieved upon using phenyl vinyl
sulfone as the dipolarophile and acetonitrile as solvent.
After 3 h at reflux, the resulting mixture contained 8a
as the major reaction product together with small amounts
of the isomers 8b and 8c. In this particular case, the
isomer 8d could not be detected (Table 1). The results
obtained using ethyl acrylate are also provided in Table
1. NMR assignments of all of the pure isomers were
The 1,3-dipolar cycloaddition of betaine 6 with acrylo-
nitrile proceeded readily at reflux temperature within 3
h. Two major adducts 7a and 7b were isolated. These
compounds are of a single regiochemistry and of either
6â (7a , 37% isolated yield) or 6R (7b, 42%) stereochem-
(8) Commins, D. L.; Stroud, E. D. J . Heterocycl. Chem. 1985, 22,
1419.
(9) Reetz, M. T.; Kindler, A. J . Organomet. Chem. 1995, 502, C5.

Cycloaddition Route to Analogues of Cocaine
J . Org. Chem., Vol. 62, No. 3, 1997 505
Sch em e 3
made through the use of COSY, DEPT, and HETCOR
experiments.
To investigate the general utility of these tropenone
intermediates to afford access to a wide variety of
3-phenyltropanes, we carried out further chemistry on
7a . For example, reaction of 7a with n-BuMgBr in the
presence of CuBr and Me3SiCl10 at -78 °C furnished the
conjugate addition product 10a in 88% yield (Scheme 2).
Attempts to effect this same reaction by use of higher
order organocuprates were unsuccessful. The ketone 10a
was reduced in turn with NaBH4 to afford predominantly
the 2R-alcohol 11a in 81% yield. Next, we treated this
alcohol with n-BuLi followed by phenyl thionochlorofor-
mate in THF11 at -78 °C to provide the thionocarbonate,
which was deoxygenated with n-Bu3SnH to the tropane
12a . Alternatively, the alcohol 11a could be dehydrated
with the Burgess reagent12 to provide the olefin 13a in
poor yield. Subsequent hydrogenation provided a readily
separable 6:4 mixture of 12a and 17a .
In the case of 7b, conjugate addition followed by NaBH4
reduction provided 11b as a crystalline solid. Unequivo-
cal structure proof was obtained from X-ray crystal-
lography. The ORTEP drawing of 11b is shown in Figure
2.13 This X-ray structure revealed the R stereochemistry
of the hydroxyl, phenyl, and cyano groups and the â
stereochemistry of the n-butyl group. Additionally, the
six-membered ring was found to adopt the boat confor-
mation.
While the sequence of reactions shown in Scheme 2
provides ready access to a new series of tropane deriva-
tives possessing substitution at the 6- or 7-positions,
together with R-stereochemistry at C-2 and C-3, we still
desired efficient access to those analogues possessing
cocaine-like, i.e., 2â,3â, stereochemistry. Thus, efforts
were made to epimerize ketone 10b so as to locate the
phenyl ring on the â face. Unfortunately, we were
unsuccessful in carrying out this transformation under
a number of conditions such as the use of DBU in
refluxing methanol. Quantum mechanical calculations
using the semiempirical AM1 method in the MOPAC 6.0
molecular-modeling package offered some rationale for
this result. The heat of formation of 10b was found to
be 20.33 kcal/mol, while the heat of formation of its C-3
F igu r e 2.
epimer is 16.15 kcal/mol. Thus, the R-phenyl isomer 10b
is more stable than its epimer by 4.18 kcal/mol based
upon this gas phase calculation. Further attempts to
effect the epimerization reaction were therefore aban-
doned.
After some experimentation, we were able to realize
our goal in another way. As shown in Scheme 3, the
ketone 7a undergoes exclusive 1,2-reduction using so-
dium borohydride/cerium chloride in methanol14 to pro-
vide the allylic alcohol 14 as a mixture of R- and
â-stereoisomers in a GC ratio of 85:15. These alcohols
were converted to their acetates 15a and 16a , and the
mixture was then separated by flash chromatography.
Both isomerically pure acetates were found to undergo
a copper(I)-catalyzed cross-coupling reaction15 using n-
BuMgBr as the nucleophile to afford the same olefin 13a
derived by an SN2′-type mechanism and having the
n-butyl group in the â orientation. Although SN2′ dis-
placement reactions by organocuprates generally proceed
with anti selectivity, reaction through a syn mechanism
has been observed in sterically hindered cases.15
The olefin 13a was subjected in turn to hydrogenation
over Pd/C to yield the desired 2â,3â isomer 17a together
(10) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025.
(11) Berkowitz, D. B.; Eggen, M. J .; Shen, Q.; Shoemaker, R. K. J .
Org. Chem. 1996, 61, 4666.
(12) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J . Org. Chem. 1973,
38, 26.
(13) The authors have deposited the atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK.
(14) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226.
(15) Tseng, C. C.; Paisley, S. D.; Goering, H. L. J . Org. Chem. 1986,
51, 2884.

506 J . Org. Chem., Vol. 62, No. 3, 1997
Kozikowski et al.
(100 mL), dried, and concentrated under reduced pressure. The
crude residue was purified by flash chromatography on silica
gel using EtOAc/hexane as eluent to afford the title compound
(5.8 g, 60%) as a yellow oil: Rf 0.6 (EtOAc/hexane 3/4); 1H NMR
(CDCl3) δ 5.11 (s, 2H), 7.18-7.29 (m, 2H), 7.30-7.47 (m, 5H),
8.23 (dd, 1H, J ) 1.5, 4.5 Hz), 8.39 (d, 1H, J ) 2.7 Hz); 13C
NMR (CDCl3) δ 70.26, 121.50, 123.81, 126.96, 127.49, 128.28,
128.70, 136.11, 138.31, 142.35, 154.85.
with the product 12a derived from â-face hydrogenation.
The GC ratio of 17a to 12a was 4:6, and these isomers
were separable by preparative layer chromatography.
This cuprate chemistry thus affords a higher yielding
route to olefin 13a than the dehydration method shown
in Scheme 2.
3-(Ben zyloxy)-4-p h en ylp yr id in e (3). To a solution of 2
(7.7 g, 42.0 mmol) in dry THF (200 mL) under N2 was added
CuI (0.80 g, 4.2 mmol) and LiCl (0.35 g, 8.3 mmol). The
mixture was cooled to -23 °C, and then PhOCOCl (5.74 mL,
46.0 mmol) was added dropwise and the mixture stirred at
-23 °C for 10 min. A 1 M solution of PhMgBr in THF (46
mL) was added dropwise. The mixture was stirred at -23 °C
for 15 min, allowed to warm to rt, and quenched with 20%
NH4Cl solution (120 mL). Ether (120 mL) was added, and the
organic layer was washed with 120-mL portions each of 20%
NH4Cl/NH4OH (1/1), water, 10% HCl, water, and brine. After
drying, the solution was concentrated to give the crude
dihydropyridine (18.0 g) as a viscous oil, which was used
directly in the next step.
Con clu sion
In conclusion, we have demonstrated a convenient
route for the synthesis of Win-type compounds by way
of a 3-phenyltropen-2-one using a pyridinium betaine-
based dipolar cycloaddition. The foregoing chemistry is
expected to be applicable to a range of other tropenones
derived from any of a number of other reactive dipolaro-
philes. In particular, in view of the encouraging results
achieved previously regarding the weak antagonist activ-
ity found for a 7-methoxylated analogue of pseudococaine,
we are now in an excellent position to rapidly explore
the effect of 6- and 7-substitution on the activity of the
higher potency Win-type compounds. The dipolar cy-
cloaddition strategy can thus be used to create a stereo-
defined library of tropane structures for biological assay.
Further modifications to the current chemical process
include the use of dipolarophiles bearing chiral auxiliary
groups to permit access to optically pure tropanes as well
as the attachment of the betaine to resin supports for
use in combinatorial chemistry approaches. These modi-
fications as well as results from biological assays will be
reported separately.16
To the crude dihydropyridine in toluene (180 mL) was added
dropwise o-chloranil (11.0 g, 46.2 mmol) in toluene (70 mL).
The mixture was stirred at rt for 15 h. An aqueous solution
of 10% NaOH (150 mL) was added, and the mixture was
stirred for 10 min at 25 °C. After ether (150 mL) was added
the organic layer was washed with 150-mL portions of 10%
NaOH and water and then extracted with 10% HCl. The
combined acid extracts were cooled, made basic with 25%
NaOH, and extracted with DCM (4 × 100 mL). The combined
organic layers were washed with brine (200 mL), dried, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel using EtOAc/
hexane as eluent to afford the title compound (8.1 g, 75%) as
1
Exp er im en ta l Section
a white solid: mp 75 °C; Rf 0.4 (EtOAc/hexane 1/1); H NMR
(CDCl3) δ 5.16 (s, 2H), 7.29 (d, 1H, J ) 4.8 Hz), 7.30-7.36 (m,
5H), 7.40-7.49 (m, 3H), 7.60-7.66 (m, 2H), 8.33 (d, 1H, J )
4.8 Hz), 8.41 (s, 1H).
Gen er a l Meth od s. Starting materials were obtained from
Aldrich Chemicals or from other commercial suppliers. Sol-
vents were purified as follows: diethyl ether was distilled from
phosphorus pentoxide; THF was freshly distilled under nitro-
gen from sodium benzophenone.
4-P h en yl-3-p yr id in ol (4). A mixture of 3 (4.5 g, 17.2
mmol) and 10% Pd/C (0.7 g) in MeOH (40 mL) was hydroge-
nated at 50 psi and rt for 3 h. After filtration through a pad
of Celite, the clear solution was concentrated under reduced
pressure to afford the title compound (2.98 g, 99%) as a white
solid: mp 168-170 °C (lit.8 mp 125-126 °C); Rf ) 0.35 (EtOAc/
n-hexane 1/1); 1H NMR (CDCl3) δ 5.33 (s, 1 H), 7.33 (d, 1H, J
) 4.8 Hz), 7.38-7.52 (m, 3H), 7.66-7.72 (m, 2H), 8.15 (d, 1H,
J ) 4.8 Hz), 8.48 (s, 1H); 13C NMR (CDCl3) δ 125.07, 128.57,
128.63, 128.98, 135.406, 137.06, 137.22, 139.86, 152.04.
3-H yd r oxy-1-m et h yl-4-p h en ylp yr id in iu m Iod id e (5).
To a solution of 4 (4.1 g, 24.0 mmol) in acetone (100 mL) was
added MeI (3.0 mL, 48.0 mmol). The mixture was refluxed
for 3 h and stirred at rt for 20 h. Ether (100 mL) was added,
and the precipitate was filtered off and washed with ether to
afford the title compound (6.8 g, 90%) as a pale yellow solid:
mp 175 °C; 1H NMR (DMSO-d6) δ 4.31 (s, 3 H), 7.53-7.61 (m,
3 H), 7.76-7.84 (m, 2 H), 8.07 (d, 1 H, J ) 6.0 Hz), 8.35 (s, 1
H), 8.53 (d, 1 H, J ) 6.0 Hz), 12.1 (br s, 1 H); 13C NMR (DMSO-
d6) δ 47.46, 127.40, 128.81, 129.42, 130.20, 133.34, 133.55,
135.24, 142.27, 155.00.
1H and 13C NMR spectra were obtained at 300 and 75.46
MHz, respectively. 1H chemical shifts (δ) are reported in ppm
downfield from internal TMS. 13C chemical shifts are referred
to CDCl3 (central peak, δ ) 77.0 ppm), benzene-d6 (central
peak, δ ) 128.0 ppm), or DMSO-d6 (central peak, δ ) 39.7
ppm). NMR assignments were made with the help of COSY,
DEPT, and HETCOR experiments. The subscript numbers
used to identify the tropane protons are defined according to
the following numbering scheme:
Melting points were determined in Pyrex capillaries with a
Thomas Hoover Unimelt apparatus and are uncorrected. Mass
spectra were measured in the EI mode at an ionization
potential of 70 eV. TLC was performed on Merck silica gel
60F254 glass plates; column chromatography was performed
using Merck silica gel (60-200 mesh).
3-(Ben zyloxy)p yr id in e (2). A mixture of 3-hydroxypyri-
dine (5.0 g, 0.053 mol), pulverized KOH (5.9 g, 0.11 mol), n-Bu4-
NBr (0.85 g, 0.0026 mol), and benzyl chloride (9.7 mL, 0.084
mol) in THF (150 mL) was stirred at reflux for 6 h. Water
(200 mL) was added and the organic phase extracted with 10%
HCl (2 × 100 mL). The combined aqueous phases were
basified with 25% NaOH and extracted with CH2Cl2 (2 × 150
mL). The combined organic phases were washed with brine
1-Meth yl-4-p h en yl-3-p yr id in iu m ola te (6). A mixture of
5 (4.03 g, 12.9 mmol) and Amberlite IRA-400 (OH-) resin (20
mL) in MeOH (70 mL) was stirred at rt for 1 h, and then the
resin was filtered off and washed several times with MeOH.
The resulting clear solution was concentrated under reduced
pressure to afford the crude title compound (2.21 g, 92%) as a
pale yellow solid that was used in the next step without further
1
purification: mp 154-157 °C; H NMR (DMSO-d6) δ 3.97 (s,
3 H), 7.30-7.52 (m, 5 H), 7.38 (d, 1 H, J ) 7.5 Hz), 8.04 (d, 1
H, J ) 8.1 Hz), 8.05 (s, 1 H).
8-Meth yl-2-oxo-3-p h en yl-8-a za bicyclo[3.2.1]oct-3-en e-
6-ca r bon itr ile a n d 8-Meth yl-2-oxo-3-p h en yl-8-a za bicyclo-
[3.2.1]oct-3-en e-7-ca r bon itr ile (7a -d ). To a solution of 6
(2.21 g, 11.9 mmol) in acrylonitrile (20 mL) was added a small
amount of hydroquinone. The mixture was refluxed under
nitrogen for 1 h and then concentrated under reduced pressure.
(16) For other recent synthetic work in the cocaine area, see:
Keverline, K. L.; Abraham, P.; Lewin, A. H.; Carroll, F. I. Tetrahedron
Lett. 1995, 36, 3099.

Cycloaddition Route to Analogues of Cocaine
J . Org. Chem., Vol. 62, No. 3, 1997 507
1
The four isomers 7a -d present in the crude mixture were
separated by flash chromatography on silica gel using EtOAc/
hexane as eluent. 7a (1.07 g, 37%): pale yellow solid; mp 129-
130 °C; Rf 0.6 (EtOAc/hexane 2/3); 1H NMR (CDCl3) δ 2.19
(dd, H7R, J 7R-7â ) 13.8 Hz, J 7R-6 ) 9.3 Hz), 2.62 (s, 3 H), 2.78
(ddd, H7â, J 7â-6 ) 3.3 Hz, J 7â-1 ) 7.5 Hz, J 7â-7R ) 13.8 Hz),
3.06 (dd, H6, J 6-7â ) 3.6 Hz, J 6-7R ) 9.0 Hz), 3.84 (d, H1, J 1-7â
) 7.5 Hz), 4.18 (d, H5, J 5-4 ) 5.4 Hz), 6.97 (d, H4, J 4-5 ) 5.4
Hz), 7.36 (br s, 5 H); 13C NMR (CDCl3) δ 30.37, 31.63, 36.03,
64.72, 70.16, 121.34, 128.15, 128.29, 128.69, 133.08, 138.771,
141.12, 196.40. 7b (1.23 g, 42%): pale yellow solid; mp 110-
112 °C; Rf 0.42 (EtOAc/n-hexane 4/1); 1H NMR (CDCl3) δ 2.00
(dd, H7R, J 7R-7â ) 13.8 Hz, J 7R-6 ) 5.7 Hz), 2.48 (s, 3 H), 2.88
(ddd, H7â, J 7â-6 ) 10.2 Hz, J 7â-7R ) 13.8 Hz, J 7â-1 ) 7.8 Hz),
3.45 (dt, H6, J 6-5 ) J 6-7R ) 5.7 Hz, J 6-7â ) 10.5 Hz), 3.75 (d,
H1, J 1-7â ) 7.5 Hz), 4.18 (t, H5, J 5-4 ) J 5-6 ) 5.4 Hz), 7.14 (d,
H4, J 4-5 ) 5.4 Hz), 7.3-7.5 (m, 5 H); 13C NMR (CDCl3) δ 29.93,
30.72, 36.83, 62.45, 70.67, 119.62, 128.26, 128.46, 128.66,
133.33, 139.84, 142.08, 195.99. 7c (0.15 g, 5%): pale yellow
wax; Rf 0.4 (EtOAc/n-hexane 2/3); 1H NMR (benzene-d6) δ 1.22
(dd, H6R, J 6R-6â ) 12.3 Hz, J 6R-7 ) 9.3 Hz), 1.84 (dt, H6â, J 6â-5
) J 6â-7 ) 6.3 Hz, J 6â-6R ) 12.3 Hz), 1.96 (s, 3 H), 1.9-2.0 (m,
H7), 2.88 (dd, H5, J 5-4 ) 5.4 Hz, J 5-6â ) 6.0 Hz), 3.75 (s, H1),
6.12 (d, H4, J 4-5 ) 5.4 Hz), 7.1-7.2 (m, 3 H), 7.3-7.4 (m, 2 H);
13C NMR (benzene-d6) δ 27.91, 34.59, 37.13, 61.43, 76.07,
116.64, 121.55, 128.91, 128.94, 134.57, 137.05, 146.21, 193.20.
0.70 (EtOAc/n-hexane 1/1); H NMR (CDCl3) δ 1.31 (t, 3 H, J
) 6.9 Hz), 1.99 (dd, H7R, J 7R-6 ) 9.9 Hz, J 7R-7â ) 14.1 Hz),
2.52 (s, 3 H), 2.90 (ddd, H7â, J 7â-6 ) 3.6 Hz, J 7â-1 ) 7.8 Hz,
7â-7R ) 13.8 Hz), 3.02 (dd, H6, J 6-7â ) 3.6 Hz, J 6-7R ) 9.3 Hz),
J
3.74 (d, H1, J 1-7â ) 7.5 Hz), 4.23 (q, 2 H, J ) 7.2 Hz), 4.25 (d,
H5, J 5-4 ) 5.4 Hz), 7.07 (d, H4, J 4-5 ) 5.4 Hz), 7.3-7.4 (m, 5
H); 13C NMR (CDCl3) δ 14.20, 27.84, 35.83, 47.52, 61.44, 63.61,
70.72, 128.23, 128.28, 133.95, 137.93, 143.61, 172.83, 197.86.
9b (26%): yellow oil; Rf 0.4 (EtOAc/hexane 1/1); 1H NMR
(CDCl3) δ 1.25 (t, 3 H, J ) 7.2 Hz), 2.11 (dd, H7R, J 7R-6 ) 6.0
Hz, J 7R-7â ) 14.4 Hz), 2.48 (s, 3 H), 2.64 (ddd, H7â, J 7â-1 ) 7.8
Hz, J 7â-6 ) 10.2 Hz, J 7â-7R ) 13.8 Hz), 3.60 (dt, H6, J 6-5
)
J 6-7R ) 5.7 Hz, J 6-7â ) 10.5 Hz), 3.70 (d, H1, J 1-7â ) 8.1 Hz),
4.20 (t, H5, J 5-4 ) J 5-6 ) 5.4 Hz), 6.98 (d, H4, J 4-5 ) 5.1 Hz),
7.34 (br s, 5 H). 9c (20%): pale yellow oil; Rf 0.6 (EtOAc/
hexane 1/1); 1H NMR (CDCl3) δ 1.30 (t, 3 H, J ) 7.2 Hz), 2.22
(dd, H6R, J 6R-7 ) 9.6 Hz, J 6R-6â ) 12.6 Hz), 2.80 (dt, H6â, J 6â-5
) J 6â-7 ) 6.3 Hz, J 6â-6R ) 12.6 Hz), 3.53 (dd, H7, J 7-6â ) 6.6
Hz, J 7-6R ) 9.3 Hz), 3.97 (t, H5, J 5-4 ) J 5-6â ) 5.7 Hz), 4.01 (s,
H1), 7.08 (d, H4, J 4-5 ) 5.4 Hz), 7.36 (br s, 5 H); 13C NMR
(CDCl3) δ 14.18, 32.45, 37.10, 43.39, 61.49, 61.65, 74.17, 128.20,
128.26, 129.87, 132.90, 134.03, 136.83, 146.61, 173.43, 195.92.
9d (12%): pale yellow oil; Rf 0.35 (EtOAc/hexane 1/1); 1H NMR
(CDCl3) δ 1.20 (t, 3 H, J ) 7.2 Hz), 2.30 (dd, H6R, J 6R-7 ) 3.9
Hz, J 6R-6â ) 12.3 Hz), 2.47 (s, 3 H), 2.52 (ddd, H6â, J 6â-5 ) 6.6
Hz, J 6â-7 ) 10.5 Hz, J 6â-6R ) 12.4 Hz), 3.64 (m, H7), 3.87 (t,
H5, J 5-4 ) J 5-6â ) 6.0 Hz), 3.95 (d, H1, J 1-7 ) 7.2 Hz), 4.07 (q,
2 H, J ) 7.2 Hz), 7.11 (d, H4, J 4-5 ) 5.7 Hz), 7.33 (br s, 5 H).
4â-Bu tyl-8-m eth yl-2-oxo-3r-p h en yl-8-a za bicyclo[3.2.1]-
octa n e-6-exo-ca r bon itr ile (10a ). To a cooled (-78 °C)
mixture of n-BuMgBr (1.05 mL, 1.01 mmol, 0.96 M in ether),
HMPA (0.35 mL, 2.01 mmol), and CuBr‚Me2S (8.6 mg, 0.04
mmol) was added dropwise a mixture of 7a (200 mg, 0.84
mmol) and Me3SiCl (0.21 mL, 1.68 mmol) in dry THF (10 mL).
After 1 h, the reaction was quenched with a 20% solution of
NH4OH (20 mL), and the mixture was extracted with EtOAc
(30 mL). The organic phase was washed with brine (30 mL),
dried, and concentrated under reduced pressure. The crude
mixture containing the silyl enol ether intermediate was
diluted with MeOH (5 mL), and potassium fluoride was added
(24 mg, 0.84 mmol). The resulting solution was stirred at rt
for 5 min and then concentrated under reduced pressure, and
the crude mixture was purified by flash chromatography on
silica gel using EtOAc/hexane as eluent to afford the title
compound (220 mg, 88%) as a wax: Rf 0.8 (EtOAc/hexane 1/1);
1H NMR (CD3OD) δ 0.82 (t, 3 H, J ) 7.2 Hz), 1.1-1.35 (m, 3
H), 1.37-1.1.5 (m, 4 H), 1.5-1.7 (m, H4), 2.31 (dd, H7R, J 7R-7ex
) 13.5 Hz, J 7R-6 ) 9.9 Hz), 2.57 (s, 3 H), 2.66 (dt, H7â, J 7â-7R
) 13.8 Hz, J 7â-6 ) J 7â-1 ) 7.2 Hz), 3.06 (dd, H6, J 6-7â ) 6.9
Hz, J 6-7R ) 9.6 Hz), 3.55 (d, H3, J 3-4 ) 8.7 Hz), 3.67 (s, H5),
3.76 (d, H1, J 1-7â ) 7.2 Hz), 6.95-7.10 (m, 2 H), 7.2-7.4 (m, 3
H); 13C NMR (benzene-d6) δ 14.35, 23.25, 29.16, 33.47, 33.50,
34.73, 40.74, 48.82, 56.82, 72.53, 73.08, 123.03, 127.64, 128.90,
130.42, 131.24, 138.19, 209.46; IR (film) 2955, 2234, 1723, 1453
7d (0.47 g, 16%): pale yellow solid; mp 117 °C, Rf 0.26 (EtOAc/
1
n-hexane 4/1); H NMR (benzene-d6) δ 1.42 (dd, H6R, J 6R-7
)
3.3 Hz, J 6R-6â ) 12.3 Hz), 1.64 (ddd, H6â, J 6â-6R ) 12.3 Hz,
J 6â-7 ) 10.5 Hz, J 6â-5 ) 5.7 Hz), 1.75 (s, 3 H), 2.52 (ddd, H7,
J 7-1 ) 7.2 Hz, J 7-6â ) 10.8 Hz, J 7-6R ) 3.3 Hz), 2.81 (t, H5,
J 5-4 ) J 5-6â ) 5.7 Hz), 3.44 (d, H1, J 1-7 ) 7.5 Hz), 6.28 (d, H4,
J 4-5 ) 5.4 Hz), 7.05-7.20 (m, 3 H), 7.43-7.58 (m, 2 H); 13C
NMR (CDCl3) δ 26.04, 33.91, 37.31, 61.35, 73.44, 119.13,
128.29, 128.31, 128.53, 133.59, 138.44, 146.08, 193.57.
8-Meth yl-2-oxo-3-p h en yl-8-a za bicyclo[3.2.1]oct-3-en -6-
yl P h en yl Su lfon e a n d 8-Meth yl-2-oxo-3-p h en yl-8-a za -
bicyclo[3.2.1]oct-3-en -7-yl P h en yl Su lfon e (8a -c). To a
solution of 6 (0.59 g, 3.17 mmol) in acetonitrile (20 mL) was
added phenyl vinyl sulfone (1.07 g, 6.34 mmol). The resulting
solution was refluxed under N2 for 1 h and then concentrated
under reduced pressure. The three isomers 8a -c present in
the crude mixture were separated by flash chromatography
on silica gel using EtOAc/hexane as eluent. 8a (0.64 g, 60%):
pale yellow solid; Rf ) 0.8 (EtOAc/hexane 1/1); 1H NMR
(CDCl3) δ 2.01 (dd, H7R, J 7R-7â ) 14.1 Hz, J 7R-6 ) 9.0 Hz), 2.49
(s, 3 H), 2.82 (ddd, H7â, J 7â-6 ) 4.5 Hz, J 7â-1 ) 7.5 Hz, J 7â-7R
) 14.1 Hz), 3.67 (dd, H6, J 6-7â ) 4.5 Hz, J 6-7R ) 9.0 Hz), 3.71
(d, H1, J 1-7â ) 7.5 Hz), 4.41 (d, H5, J 5-4 ) 5.4 Hz), 6.99 (d, H4,
J 4-5 ) 5.4 Hz), 7.34 (br s, 5 H), 7.55-7.63 (m, 2 H), 7.64-7.72
(m, 1 H), 7.91-7.98 (m, 2 H); 13C NMR (CDCl3) δ 27.76, 34.74,
61.00, 67.70, 70.29, 128.16, 128.29, 128.62, 128.66, 129.28,
133.28, 133.95, 138.29, 138.92, 141.08, 196.85. 8b (0.18 g,
16%): pale yellow foam; Rf 0.4 (EtOAc/n-hexane 4/1); 1H NMR
(CDCl3) δ 2.15 (dd, H7R, J 7R-7â ) 14.1 Hz, J 7R-6 ) 6.9 Hz), 2.46
(s, 3 H), 2.56 (ddd, H7â, J 7â-6 ) 9.6 Hz, J 7â-7R ) 13.8 Hz, J 7â-1
) 8.1 Hz), 3.73 (d, H1, J 1-7â ) 7.8 Hz), 4.15 (m, H6), 4.22 (t,
H5, J 5-4 ) J 5-6 ) 5.1 Hz), 7.20 (d, H4, J 4-5 ) 5.1 Hz), 7.32-
7.43 (m, 3 H), 7.47-7.53 (m, 2 H), 7.54-7.62 (m, 2 H), 7.64-
7.72 (m, 1 H), 7.87-7.94 (m, 2 H); 13C NMR (CDCl3) δ 27.16,
36.65, 62.07, 67.13, 71.10, 127.90, 128.13, 128.25, 128.62,
129.5, 134.01, 139.23, 139.77, 141.60, 196.38. 8c (0.16 g,
cm-1
.
4â-Bu tyl-8-m eth yl-2-oxo-3r-p h en yl-8-a za bicyclo[3.2.1]-
octa n e-6-en d o-ca r bon itr ile (10b). Using a procedure simi-
lar to that for 10a , 10b was obtained (95%) as a colorless oil:
1
Rf 0.6 (EtOAc/hexane 1/1); H NMR (benzene-d6) δ 0.72 (t, 3
H, J ) 6.9 Hz), 1.0-1.43 (m, 6 H), 1.55 (s, 3 H), 1.68-1.88 (m,
H7R and H7â), 2.23 (td, H4, J 4-3 ) J 4-1′ ) 9.3 Hz, J 4-1′′ ) 3.0
Hz), 2.35 (dt, H6, J 6-5 ) J 6-7R ) 6.3 Hz, J 6-7â ) 11.7 Hz), 2.85
(d, H5, J 5-6 ) 6.3 Hz), 2.97 (d, H1, J 1-7â ) 7.2 Hz), 3.44 (d, H3,
J 3-4 ) 9.6 Hz), 7.0-7.2 (m, 5 H); 13C NMR (CDCl3) δ 13.87,
22.42, 28.66, 29.45, 32.08, 33.95, 40.16, 40.54, 56.06, 68.30,
71.65, 120.29, 127.25, 128.58, 129.74, 136.78, 210.82; IR (film)
1
16%): pale yellow foam; Rf 0.2 (EtOAc/hexane 1/1); H NMR
(CDCl3) δ 2.20 (dd, H6R, J 6R-6â ) 13.2 Hz, J 6R-7 ) 9.0 Hz), 2.56
(s, 3 H), 2.80 (dt, H6â, J 6â-5 ) J 6â-7 ) 6.6 Hz, J 6â-6R ) 12.9
Hz), 3.53 (t, H7, J 7-6â ) J 7-6R ) 8.1 Hz), 3.9-4.2 (m, H5 and
H1), 7.03 (d, H4, J 4-5 ) 5.4 Hz), 7.32 (br s, 5 H), 7.55-7.63 (m,
2 H), 7.64-7.72 (m, 1 H), 7.92-7.99 (m, 2 H); 13C NMR (CDCl3)
δ 30.88, 36.60, 61.35, 64.40, 71.89, 128.15, 128.23, 128.33,
128.46, 129.46, 133.37, 134.05, 137.05, 138.63, 145.29, 193.61.
Eth yl 8-Meth yl-2-oxo-3-p h en yl-8-a za bicyclo[3.2.1]oct-
3-en e-6-ca r boxyla te a n d Eth yl 8-Meth yl-2-oxo-3-p h en yl-
8-a za bicyclo[3.2.1]oct-3-en e-7-ca r boxyla te (9a -d ). Using
a procedure similar to that for 7, 9 was obtained as a mixture
of four isomers separated by silica gel column chromatography
using EtOAc/hexane as eluent. 9a (33%): dark yellow oil; Rf
2956, 2930, 2235, 1724, 1462, 1105 cm-1
.
4â-Bu tyl-2-h yd r oxy-8-m eth yl-3r-p h en yl-8-a za bicyclo-
[3.2.1]octa n e-6-exo-ca r bon itr ile (11a ). To a solution of 10a
(0.55 g, 1.86 mmol) in EtOH (20 mL) was added portionwise
NaBH4 (0.21 g, 5.57 mmol). The resulting solution was stirred
at rt for 1 h and then concentrated, and the residue was diluted
with water (60 mL) and extracted with EtOAc (2 × 50 mL).
The combined organic phases were washed with brine (80 mL),
dried, and concentrated under reduced pressure. The crude
mixture containing the two hydroxy isomers was purified by

508 J . Org. Chem., Vol. 62, No. 3, 1997
Kozikowski et al.
flash chromatography on silica gel using EtOAc/hexane as
eluent. 2R-Isomer (0.45 g, 81%): white solid; Rf 0.8 (EtOAc/
hexane 1/1); 1H NMR (benzene-d6) δ 0.63 (d, OH, J OH-2 ) 3.0
Hz,), 0.72 (t, 3 H, J ) 6.9 Hz), 0.9-1.15 (m, 5 H), 1.16-1.30
(m, 1 H), 1.36 (dt, H4, J 4-3 ) 11.1 Hz, J 4-1′ ) J 4-1′′ ) 6.0 Hz),
1.84 (dt, H7â, J 7â-1 ) J 7â-6 ) 6.5 Hz, J 7â-7R ) 11.1 Hz), 2.27 (s,
3 H), 2.37 (dd, H6, J 6-7R ) 9.0 Hz, J 6-7â ) 7.1 Hz), 2.69 (dd,
128.35, 144.45; MS m/ z 282 (M+, 12), 239 (13), 225 (64), 172
(12), 107 (32), 42 (100). Anal. Calcd for C19H26N2: C, 80.80;
H, 9.28; N, 9.92. Found: C, 80.58; H, 9.49; N, 9.54.
2-Hyd r oxy-8-m eth yl-3-p h en yl-8-a za bicyclo[3.2.1]oct-3-
en e-6-exo-ca r bon itr ile (14a ). Enone 7a (200 mg, 0.84 mmol)
was dissolved in a solution of CeCl3‚7H2O (340 mg, 0.92 mmol)
in MeOH (2.3 mL), and then NaBH4 (32 mg, 0.84 mmol) was
added portionwise. This mixture was stirred at rt for 5 min
and then diluted with water (30 mL) and extracted with EtOAc
(2 × 30 mL). The combined organic phases were dried and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel using EtOAc/
hexane as eluent to obtain a mixture of the two alcohols (200
mg, 98%) as a white foam: Rf 0.8 (EtOAc/hexane 4/1). 2R-
H
7R, J 7R-7â ) 12.9 Hz, J 7R-6 ) 9.6 Hz), 2.74 (dd, H3, J 3-2 ) 4.5
Hz, J 3-4 ) 11.4 Hz), 3.11 (dd, H1, J 1-2 ) 8.4 Hz, J 1-7â ) 6.9
Hz), 3.29 (s, H5), 3.70 (ddd, H2, J 2-OH ) 3.0 Hz, J 2-1 ) 8.6 Hz,
J 2-3 ) 4.8 Hz), 6.85-6.98 (m, 2 H), 7.0-7.1 (m, 3 H); 13C NMR
(benzene-d6) δ 14.10, 22.99, 26.73, 28.89, 34.40, 34.56, 42.03,
45.47, 47.19, 66.08, 70.57, 71.91, 123.95, 127.00, 128.89,
129.80, 140.40; MS m/ z 298 (M+, 16), 255 (34), 245 (10), 177
(39), 135 (30), 107 (71), 42 (100); IR (film) 3466, 2932, 2231,
1451 cm-1. 2â-Isomer (0.05 g, 9%): colorless oil; Rf 0.6 (EtOAc/
hexane 1/1); 1H NMR (CDCl3) δ 0.74 (t, 3 H, J ) 7.2 Hz), 0.70-
0.95 (m, 1 H), 1.00-1.35 (m, 4 H), 1.37-1.70 (m, 3 H), 2.38
(dd, H7R, J 7R-6 ) 6.0 Hz, J 7R-7â ) 12.6 Hz), 2.44-2.60 (m, H3
and H7â), 2.59 (s, 3 H), 2.89 (dd, H6, J 6-7R ) 6.0 Hz, J 6-7â ) 9.6
Hz), 3.46 (br t, H1, J ) 4.8 Hz), 3.63 (s, H5), 4.27 (dd, H2, J 2-OH
) 3.0 Hz, J 2-3 ) 10.5 Hz), 7.1-7.4 (m, 5 H); 13C NMR (CDCl3)
δ 13.93, 22.53, 27.57, 27.86, 29.75, 30.49, 42.56, 46.45, 46.67,
67.78, 68.65, 70.82, 124.03, 127.02, 128.61, 128.82, 138.12; MS
m/ z 298 (M+, 14), 255 (43), 245 (4), 241 (52), 177 (12), 135
(27), 107 (24), 42 (100).
Isomer: 1H NMR (CDCl3) δ 1.83 (br s, OH), 2.32 (ddd, H7â
,
J 7â-6 ) 3.3 Hz, J 7â-1 ) 7.2 Hz, J 7â-7R ) 14.1 Hz), 2.66 (s, 3 H),
2.77 (dd, H7R, J 7R-6 ) 9.6 Hz, J 7R-7â ) 13.8 Hz), 3.02 (dd, H6,
J 6-7â ) 3.3 Hz, J 6-7R ) 9.6 Hz), 3.68 (br t, H1, J ) 6.0 Hz),
3.78 (d, H5, J 5-4 ) 5.4 Hz), 5.15 (d, H2, J 2-1 ) 5.1 Hz), 6.11 (d,
H4, J 4-5 ) 5.4 Hz), 7.24-7.40 (m, 5 H); MS m/ z 240 (M+, 4),
186 (2), 170 (28), 154 (3), 128 (30), 85 (4), 57 (100). 2â-
Isomer: 1H NMR (CDCl3) δ 1.70 (br s, OH), 1.95 (dd, H7R, J 7R-6
) 9.9 Hz, J 7R-7â ) 14.1 Hz), 2.55 (ddd, H7â, J 7â-6 ) 3.9 Hz,
J 7â-1 ) 8.1 Hz, J 7â-7R ) 14.1 Hz), 2.90 (dd, H6, J 6-7â ) 3.6 Hz,
J 6-7R ) 9.9 Hz), 3.68 (d, H1, J 1-7â ) 8.1 Hz), 3.91 (d, H5, J 5-4
) 6.0 Hz), 4.13 (s, H2), 6.33 (d, H4, J 4-5 ) 6.0 Hz), 7.24-7.45
(m, 5 H); MS m/ z 240 (M+, 2), 186 (4), 170 (30), 115 (2), 85
(3), 57 (100).
4â-Bu tyl-2r-h yd r oxy-8-m eth yl-3r-p h en yl-8-a za bicyclo-
[3.2.1]octa n e-6-en d o-ca r bon itr ile (11b). Using a procedure
similar to that for 11a , 11b was obtained (95%) as a white
solid: Rf 0.4 (EtOAc/hexane 1/1); 1H NMR (benzene-d6) δ 0.80
(t, 3 H, J ) 7.2 Hz), 0.90 (br s, OH), 1.0-1.4 (m, 6 H), 1.63
(ddd, H7â, J 7â-1 ) 7.5 Hz, J 7â-6 ) 12.0 Hz, J 7â-7R ) 13.5 Hz),
2-Acetoxy-8-m eth yl-3-p h en yl-8-a za bicyclo[3.2.1]oct-3-
en e-6-exo-ca r bon itr ile (15a a n d 16a ). To a solution of 14a
(200 mg, 0.83 mmol) in pyridine (2 mL) was added Ac2O (0.31
mL, 3.33 mmol). The resulting solution was stirred at rt for
15 h and then concentrated under reduced pressure, diluted
with EtOAc (30 mL), and washed with NH4Cl (2 × 20 mL).
Drying and concentration under reduced pressure afforded a
crude mixture of the two isomers, which were separated by
flash chromatography on silica gel using EtOAc/hexane as
eluent. Compound 15a (180 mg, 76%): white solid; mp 107-
109 °C; Rf 0.6 (EtOAc/hexane 1/1); 1H NMR (CDCl3) δ 1.91 (s,
1.74 (s, 3 H), 2.32-2.44 (m, H4), 2.54 (dt, H6, J 6-5 ) J 6-7R
)
6.3 Hz, J 6-7â ) 12.0 Hz), 2.76 (dd, H7R, J 7R-7â ) 13.5 Hz, J 7R-6
) 6.3 Hz), 2.81 (d, H5, J 5-6 ) 6.0 Hz), 2.90 (dd, H3, J 3-2 ) 5.4
Hz, J 3-4 ) 12.0 Hz), 2.97 (dd, H1, J 1-2 ) 8.2 Hz, J 1-7â ) 7.3
Hz), 3.89 (ddd, H2, J 2-OH ) 2.1 Hz, J 2-1 ) 8.1 Hz, J 2-3 ) 5.1
Hz), 6.98-7.20 (m, 5 H); 13C NMR (benzene-d6) δ 14.18, 23.0,
24.55, 28.6, 30.06, 34.57, 38.68, 41.03, 47.37, 65.31, 68.27,
70.16, 121.73, 127.0, 128.92, 130.19, 139.79; MS m/ z 298 (M+,
14), 255 (30), 241 (8), 177 (10), 137 (29), 82 (52), 42 (100).
2â-Bu tyl-8-m eth yl-3r-ph en yl-8-azabicyclo[3.2.1]octan e-
6-exo-ca r bon itr ile (12a ). To a solution of alcohol 11a (54
mg, 0.18 mmol) in THF (5 mL) at -78 °C was added n-BuLi
(0.072 mL, 0.18 mmol, 2.5 M in hexane), followed immediately
by phenyl thionochloroformate (0.038 mL, 0.27 mmol). After
1 h, the reaction was quenched with a saturated solution of
NaHCO3 (20 mL), and the mixture was extracted with ether
(2 × 20 mL). The collected organic phases were dried and
concentrated under reduced pressure, and the crude mixture
was purified by flash chromatography on silica gel using
EtOAc/hexane as eluent to afford the phenoxy(thiocarbonyl)-
oxy derivative (30 mg, 40%) as a colorless oil: Rf 0.8 (EtOAc/
hexane 1/4); 1H NMR (CDCl3) δ 0.83 (t, 3 H, J ) 6.6 Hz), 1.2-
1.5 (m, 6 H), 1.62-1.80 (m, H4), 2.25-2.50 (m, H7R and H7â),
3 H), 2.34 (ddd, H7â, J 7â-6 ) 3.0 Hz, J 7â-1 ) 6.9 Hz, J 7â-7R
)
13.8 Hz), 2.64 (dd, H7R, J 7R-6 ) 9.6 Hz, J 7R-7â ) 13.8 Hz), 2.70
(s, 3 H), 3.08 (dd, H6, J 6-7â ) 3.3 Hz, J 6-7R ) 9.6 Hz), 3.76 (t,
H1, J 1-2 ) J 1-7â ) 6.0 Hz), 3.81 (d, H5, J 5-4 ) 5.4 Hz), 6.25 (d,
H4, J 4-5 ) 5.4 Hz), 6.30 (d, H2, J 2-1 ) 5.1 Hz), 7.15-7.22 (m,
2 H), 7.27-7.36 (m, 3 H), 13C NMR (CDCl3) δ 20.86, 28.92,
33.61, 37.23, 60.73, 63.60, 69.37, 122.37, 125.62, 128.03,
128.32, 128.43, 136.41, 136.62, 170.49; MS m/ z 282 (M+, 5),
223 (10), 182 (7), 170 (100), 128 (9), 115 (9). Compound 16a
(50 mg, 21%): white solid; mp 134-137 °C; Rf 0.55 (EtOAc/
1
hexane 1/1); H NMR (CDCl3) δ 1.97 (s, 3 H), 2.03 (dd, H7R
,
J 7R-6 ) 9.3 Hz, J 7R-7â ) 13.8 Hz), 2.56 (ddd, H7â, J 7â-6 ) 3.3
Hz, J 7â-1 ) 7.5 Hz, J 7â-7R ) 13.8 Hz), 2.61 (s, 3 H), 2.88 (dd,
H6, J 6-7â ) 3.3 Hz, J 6-7R ) 9.3 Hz), 3.65 (d, H1, J 1-7â ) 7.5
Hz), 4.0 (d, H5, J 5-4 ) 5.4Hz), 5.42 (s, H2), 6.40 (d, H4, J 4-5
)
5.7 Hz), 7.24-7.57 (m, 5 H); 13C NMR (CDCl3) δ 20.93, 31.13,
32.30, 38.37, 62.84, 64.03, 68.86, 122.25, 125.56, 128.36,
128.62, 128.84, 134.23, 136.32, 170.53; MS m/ z 282 (M+, 3),
223 (4), 186 (3), 170 (100), 154 (5), 128 (40), 127 (3), 115 (3),
57 (76).
2.57 (s, 3 H), 2.77 (br t, H6, J ) 8.1 Hz), 3.07 (dd, H3, J 3-2
)
4.8 Hz, J 3-4 ) 10.8 Hz), 3.50 (br s, H5), 3.98 (br t, H1, J ) 6.6
Hz), 5.75 (dd, H2, J 2-3 ) 5.1 Hz, J 2-1 ) 8.7 Hz), 6.84 (d, 2 H,
J ) 7.8 Hz), 7.1-7.4 (m, 8 H); 13C NMR (CDCl3) δ 13.95, 22.62,
28.34, 28.64, 33.79, 34.12, 41.95, 44.55, 46.07, 64.15, 71.60,
76.58, 77.00, 77.42, 83.32, 121.67, 123.51, 126.62, 126.91,
128.29, 129.46, 129.76, 138.00, 153.05, 194.33.
2â-Bu t yl-8-m et h yl-3-p h en yl-8-a za b icyclo[3.2.1]oct -3-
en e-6-exo-ca r bon itr ile (13a ). To a suspension of CuCN (4.0
mg, 0.045 mmol) in dry ether (2 mL) at -7 °C was added
n-BuMgBr (0.45 mL, 1.0 M in ether). After 10 min, a solution
of 15a (60 mg, 0.22 mmol) in dry ether (3 mL) was added
dropwise. The resulting mixture was stirred at rt for 1.5 h
and diluted with ether (20 mL), and the organic phase was
washed with a saturated solution of NH4Cl (2 × 20 mL), dried,
and concentrated under reduced pressure. The crude mixture
was purified by flash chromatography on silica gel using
EtOAc/hexane as eluent to afford the title compound (48 mg,
A solution of the above derivative (20 mg, 0.046 mmol), Bu3-
SnH (0.02 mL, 0.069 mmol), and AIBN (1.5 mg, 0.01 mmol)
in toluene (2 mL) was purged with argon. The reaction flask
was placed in a preheated oil bath at 60 °C and then heated
from 60 to 90 °C over 15 min. After concentration under
reduced pressure, the crude residue was purified by flash
chromatography on silica gel using EtOAc/hexane as eluent
to afford the title compound (9 mg, 70%) as a colorless oil: Rf
0.80 (EtOAc/hexane 7/3); 1H NMR (CDCl3) δ 0.82 (t, 3 H, J )
6.6 Hz), 1.1-1.5 (m, 8 H), 2.03 (dd, H6R, J 6R-7 ) 9.3 Hz, J 6R-6â
) 12.9 Hz), 2.3-2.6 (m, 3 H), 2.49 (s, 3 H), 2.75 (t, H7, J ) 8.1
Hz), 3.41 (s, H1), 3.47 (br t, H5, J 5-4 ) 7.8 Hz), 7.1-7.3 (m, 5
H); 13C NMR (CDCl3) δ 13.93, 22.71, 28.94, 33.00, 34.02, 36.23,
39.08, 40.09, 42.05, 51.47, 60.82, 71.52, 123.99, 126.21, 127.89,
1
80%) as a colorless oil: Rf 0.7 (EtOAc/hexane 3/7); H NMR
(benzene-d6) δ 0.76 (t, 3 H, J ) 6.6 Hz), 1.0-1.4 (m, 5 H), 1.6-
1.7 (m, H2), 1.71 (dd, H6R, J 6R-7 ) 9.0 Hz, J 6R-6â ) 12.0 Hz),
2.0-2.12 (m, H6â), 2.21 (s, 3 H), 2.12-2.30 (m, H7), 2.90 (t, H5,
J 5-4 ) J 5-6â ) 5.4 Hz), 3.51 (s, H1), 5.58 (d, H4, J 4-5 ) 5.4 Hz),
7.04-7.20 (m, 5 H); 13C NMR (CDCl3) δ 13.94, 22.61, 30.17,

Cycloaddition Route to Analogues of Cocaine
J . Org. Chem., Vol. 62, No. 3, 1997 509
30.70, 31.85, 37.22, 41.94, 47.52, 62.16, 70.10, 123.62, 125.83,
127.52, 128.32, 128.47, 138.17, 139.39; MS m/ z 280 (M+, 3),
237 (2), 170 (9), 119 (100), 107 (17), 91 (14).
126.21, 127.58, 127.91, 128.26, 141.95; MS m/ z 282 (M+, 12),
239 (13), 225 (11), 172 (20), 107 (57), 42 (100). Anal. Calcd
for C19H26N2: C, 80.80; H, 9.28; N, 9.92. Found: C, 80.48; H,
9.03; N, 9.56.
2â-Bu tyl-8-m eth yl-3-p h en yl-8-a za bicyclo[3.2.1]octa n e-
6-exo-ca r bon itr ile (12a a n d 17a ). A mixture of 13a (80 mg,
0.30 mmol) and a catalytic amount of 10% Pd/C in MeOH (7
mL) was hydrogenated under 30 psi of H2 at 25 °C for 24 h.
Filtration through a pad of Celite and concentration under
reduced pressure afforded a mixture containing the two
isomers, which were separated by preparative thin-layer
chromatography on silica gel using EtOAc/hexane as eluent
to afford the title compounds. 12a (46 mg, 58%): colorless
oil. 17a (30 mg, 38%): colorless oil; Rf 0.85 (EtOAc/hexane
Ack n ow led gm en t. We are indebted to NIH/NIDA
(DA 10458) for support of this work. We wish to thank
Professor Shaomeng Wang for the quantum mechanical
calculations.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for the compounds 7b-d , 10b, 11b, 12a , 13a , 15a ,
16a , and 17a and 1H NMR spectra for the compounds 5, 6,
7a , and 11a are provided (24 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microform version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
7/3); H NMR (CDCl3) δ 0.75 (t, 3 H, J ) 7.2 Hz), 0.70-0.95
(m, 2 H), 1.04-1.30 (m, 3 H), 1.36-1.56 (m, 2 H), 1.66-1.76
(m, 1 H), 2.18 (dd, H6R, J 6R-7 ) 9.6 Hz, J 6R-6â ) 13.2 Hz), 2.12-
2.24 (m, 1 H), 2.48-2.59 (m, 1 H), 2.53 (s, 3 H), 2.82 (dt, H6â
,
)
J 6â-5 ) J 6â-7 ) 5.1 Hz, J 6â-6R ) 13.2 Hz), 2.99 (dd, H7, J 7-6â
5.7 Hz, J 7-6R ) 9.6 Hz), 3.44-3.54 (m, H5), 3.66 (s, H1), 7.05-
7.35 (m, 5 H); 13C NMR (CDCl3) δ 13.98, 22.60, 26.42, 29.60,
30.58, 32.21, 32.55, 36.53, 42.68, 45.91, 63.02, 71.28, 124.25,
J O961957G