Rhodium carboxylate catalyzed decomposition of vinyldiazoacetates in the presence of heterodienes: Enantioselective synthesis of the 6-azabicyclo[3.2.2]nonane and 6-azabicyclo[3.2.2]nonanone ring systems

Article abstract of DOI:10.1021/jo025697g

Dirhodium tetracarboxylate catalyzed decomposition of vinyldiazoacetates in the presence of N-phenoxycarbonyl protected 1,2-dihydropyridines or 1-methyl-2-pyridones is a direct method for the construction of the 6-azabicyclo[3.2.2]nonane ring system. The [3 + 4] cycloaddition occurs by a tandem cyclopropanation/Cope rearrangement. Asymmetric induction is possible in these transformations either by using (S)-lactate methyl ester as a chiral auxiliary or dirhodium tetraprolinates as chiral catalysts.

Full text of DOI:10.1021/jo025697g

Rh od iu m Ca r boxyla te Ca ta lyzed Decom p osition of
Vin yld ia zoa ceta tes in th e P r esen ce of Heter od ien es:
En a n tioselective Syn th esis of th e 6-Aza bicyclo[3.2.2]n on a n e a n d
6-Aza bicyclo[3.2.2]n on a n on e Rin g System s
Huw M. L. Davies* and L. Mark Hodges
Department of Chemistry, University at Buffalo, The State University of New York,
Buffalo, New York 14260
hdavies@acsu.buffalo.edu
Received March 8, 2002
Dirhodium tetracarboxylate catalyzed decomposition of vinyldiazoacetates in the presence of
N-phenoxycarbonyl protected 1,2-dihydropyridines or 1-methyl-2-pyridones is a direct method for
the construction of the 6-azabicyclo[3.2.2]nonane ring system. The [3 + 4] cycloaddition occurs by
a tandem cyclopropanation/Cope rearrangement. Asymmetric induction is possible in these
transformations either by using (S)-lactate methyl ester as a chiral auxiliary or dirhodium
tetraprolinates as chiral catalysts.
The azabicyclic ring system is a common structural
unit in natural products and pharmaceutical agents.1 Due
to their inherent biological activity, there is a demand
for general synthetic methods for these systems. We have
previously reported that the rhodium-catalyzed decom-
position of vinyldiazoacetates in the presence of N-BOC
protected pyrroles is a very effective method for the
construction of tropanes.2 This is an example of a very
general method for the construction of seven-membered
rings by a [3 + 4] cycloaddition between rhodium-
stabilized vinylcarbenoids and dienes.3 Continuing with
our long-standing interest in the design of novel azabi-
cyclic structures as potential medications for cocaine
addiction,4 we report herein a study to apply the vinyl-
diazoacetate chemistry to the synthesis of 6-azabiyclo-
[3.2.2]nonadienes,5 higher homologues of tropanes. The
two central reactions that were examined were the
reaction of vinyldiazoacetates with 1-methyl-2-pyridone
(eq 1) and various 1,2-dihydropyridines (eq 2). In addition
to evaluating the regiochemical issues of the reaction, the
development of asymmetric strategies for the construc-
tion of the 6-azabiyclo[3.2.2]nonadienes was explored.
(1) For reviews on various azabicyclic systems: (a) 7-Azabicyclo-
[2.2.1]heptanes: Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
(b) 8-Azabicyclooctanes (tropanes): Lounasmaa, M.; Tamminen, T.
Alkaloids 1993, 44, 1. (c) Azabicyclo[2.2.2]nonanes: Mashkovsky, M.
D.; Yakhontov, L. N.; Kaminka, M. E.; Mikhlina, E. E. Prog. Drug Res.
1983, 27, 9. (d) 2-Azabicyclo[3.3.1]nonanes: Bosch, J .; Bonjoch, J .
Heterocycles 1980, 14, 505. (e) 3-Azabicyclo[3.3.1]nonanes: J eyaraman,
R.; Avila, S. Chem. Rev. 1981, 81, 149. For recent reports concerning
the biological utility of the 1- and 2-azabicyco[2.2.2]octane ring systems,
see: (f) Brown, G. R.; Clarke, D. S.; Foubister, A. J .; Freeman, S.;
Harrison, P. J .; J ohnson, M. C.; Mallion, K. B.; McCormick, J .;
McTaggert, F.; Reid, A. C.; Smith, G. J .; Taylor, M. J . J . Med. Chem.
1996, 39, 2971. (g) Portevin, B.; Benoist, A.; Re´mond, G.; Herve´, Y.;
Vincent, M.; Lepagnol, J .; De Nanteuil, G. J . Med. Chem. 1996, 39,
2379. (h) Swain, C. J .; Fong, T. M.; Haworth, K.; Owen, S. N.; Seward,
E. M.; Strader, C. D. Biorg. Med. Chem. Lett. 1995, 5, 1261.
(2) Davies, H. M. L.; Matasi, J . J .; Hodges, L. M.; Huby, N. J . S.;
Thornley, C.; Kong, N.; Houser, J . H. J . Org. Chem. 1997, 62, 1095.
(3) Davies, H. M. L. In Advances in Cycloaddition; Harmata, M.,
Ed.; J AI Press: Stamford, CT, 1998; Vol. 5, pp 119-164.
A potentially very attractive method for the synthesis
of the 6-azabiyclo[3.2.2]nonane structure would be the
reaction of vinyldiazoacetates with 2-pyridones. To ex-
plore the feasibility of such a reaction, the decomposition
of vinyldiazoacetates was carried out in the presence of
4 equiv of 1-methyl-2-pyridone (1). The unsubstituted
vinyldiazoacetate (2) gave only trace amounts of the
desired azabicyclic product 3 when rhodium octanoate
was used as the catalyst (eq 3). Use of the more electron
deficient chiral catalyst Rh2(S-TBSP)4 (4a ) improved the
reaction, producing 3 in 17% yield. Even though the
dirhodium tetraprolinates have resulted in high asym-
(4) (a) Davies, H. M. L.; Saikali, E.; Huby, N. J .; Gilliatt, V. J .;
Matasi, J . J .; Sexton, T.; Childers, S. R. J . Med. Chem. 1994, 37, 1262.
(b) Davies, H. M. L.; Kuhn, L. A.; Thornley, C.; Matasi, J . J .; Sexton,
T.;, Childers, S. R. J . Med. Chem. 1996, 39, 2554. (c) Davies, H. M. L.;
Ren, P.; Kong, N.; Sexton, T.; Childers, S. R. Biorg Med. Chem. Lett.
2001, 11, 487.
(5) For a preliminary account of this work, see: Davies, H. M. L.;
Hodges, L. M.; Thornley, C. T. Tetrahedron Lett. 1998, 39, 2707.
10.1021/jo025697g CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
J . Org. Chem. 2002, 67, 5683-5689
5683

Davies and Hodges
TABLE 1. Syn th esis of
6-Aza bicyclo[3.2.2]n on a d ien e-7-on es 9
TABLE 2. Syn th esis of 6-Aza bicyclon on a d ien es 13 a n d
14
yield, %
yield, de,
entry diazo
X
R1
catalyst
product 13
14
entry compd R1
Xc
catalyst
%
%
1
2
3
4
5
6
7
2
2
2
10
10
11
11
OMe
OMe
OMe
Et
H
H
H
H
H
Rh2(OOct)4
Rh2(OPiv)4
Rh2(TPA)4
Rh2(OOct)4
Rh2(OPiv)4
a
a
a
b
b
c
c
30
56
50
11
27
17
34
29
12
3
25
12
24
3
1
2
3
4
5
a
b
b
b
c
H
H
H
H
CH2CO2Et
(S)-CH(Me)CO2Et Rh2(OOct)4
(S)-CH(Me)CO2Et Rh2(S-TBSP)4
(S)-CH(Me)CO2Et Rh2(R-DOSP)4 32
78
Rh2(OOct)4
36
33
40
-
40
45
60
51
Et
Me (S)-CH(Me)CO2Et Rh2(S-TBSP)4
OMe OTBS Rh2(OOct)4
OMe OTBS Rh2(OPiv)4
metric induction in various [3 + 4] cycloadditions,3,6 in
this case the enantioselectivity for the formation of 3 was
only 10% ee. When the styryldiazoacetate 5 was used,
higher overall yields of the azabicyclo[3.2.2]nonanone
product 6 were obtained (eq 4). Use of Rh2(S-DOSP)4 (4b),
a related prolinate catalyst to Rh2(S-TBSP)4, again
resulted in enhanced overall yields of 6 (33%) compared
to Rh2(OOct)4. In this reaction an isomeric [4.3.0] bicyclic
product 7 was formed. The enantioselectivity in the
formation of 6 (60% ee) was considerably improved over
the result for 3.
served with the methyl ester-substituted vinyldiaz-
omethanes 2 and 5, the more electron deficient chiral
catalysts result in higher isolated yields of the azabicyclo-
[3.2.2]nonadienones 9. Despite the yield enhancement
rendered by using the R-hydroxyester auxiliary on the
vinylcarbenoids, asymmetric induction was only modest
(40-60% de). The use of the chiral auxiliary, terminal
vinyl substitution (8c), and prolinate catalysis resulted
in the best result, a 78% isolated yield of 9c in 51% de
(entry 5).
1,2-Dihydropyridines were expected to be even better
substrates than 1-methyl-2-pyridone in the cycloaddition
because the diene would be more electron-rich. The
cycloaddition chemistry of 1,2-dihydropyridines, however,
is complicated because both double bonds are accessible
for cyclopropanation by the vinylcarbenoid, leading to the
formation of two regioisomeric 6-azabicyclononadienes
(Table 2). The regioselectivity of the reaction and the
yields are affected by the functionality on the vinyldia-
zoacetate as well as the steric bulk of the catalyst. When
the unsubstituted methyl ester vinyldiazoacetate 2 is
decomposed by rhodium octanoate in the presence of
N-phenoxycarbonyl-1,2-dihydropyridine (12) both the
4-substituted (13a ) and 2-substituted (14a ) regioisomers
are formed in approximately equal amounts (entry 1,
Table 2). Both regioisomers have been identified and
1
assigned on the basis of H NMR and decoupling data.
When systematically more bulky catalysts are used such
as rhodium pivalate (Rh2(OPiv)4) or rhodium triphenyl-
acetate (Rh2(TPA)4), the predominant product is 13a ,
which results from cyclopropanation at the double bond
closer to the nitrogen. Similar results are obtained with
the vinyldiazoketone 10 and tert-butyldimethylsiloxy-
substituted vinyldiazoacetate 11.
Two additional approaches were ultimately discovered
that allowed highly regioselective cycloadditions to be
achieved. Terminal substitution on the vinyldiazoacetate
results in highly selective formation of the 4-substituted
6-azabicyclononadienes 13 (Table 3, entries 1,2). Selective
formation of 13 is also achieved when 3-methyldihydro-
pyridine 16 is used as the substrate (Table 3, entries
3-5).
As the use of â-hydroxyesters as chiral auxiliaries has
been reported to increase the yield and regioselectivity
in the reaction between vinyldiazoacetates and pyrroles,7
this strategy was applied to the reaction between vinyl-
diazoacetates and 2-pyridones (Table 1). Reaction of
either the glycolate (8a ) or lactate (8b) substituted
vinyldiazoacetate resulted in a modest 30-40% yield of
the desired azabicyclononadienones 9a and 9b. As ob-
Having developed appropriate systems that can gener-
ate selectively the 4-substituted 6-azabicyclononadienes
13, the potential for the asymmetric synthesis of 13 was
then explored by using chiral catalysis (Table 4). Rh2(S-
(6) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J . Am. Chem. Soc.
1996, 118, 10774.
(7) Davies, H. M. L.; Matasi, J . J .; Thornley, C. Tetrahedron Lett.
1995, 36, 7205.
5684 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of the 6-Azabicyclo[3.2.2]nonane Ring System
TABLE 3. Syn th esis of 6-Aza bicyclon on a d ien es 13 a n d
14
SCHEME 1
yield, %
entry
diazo
X
R1
R2
product
13
14
1
2
3
4
5
5
15
10
15
5
OMe
OMe
Et
OMe
OMe
Ph
Me
H
Me
Ph
H
H
Me
Me
Me
d
e
f
g
h
69
58
32
50
71
trace
3
0
0
0
alcohol to give 19. Demethylation via the TROC-deriva-
tive 20 followed by final N-acylation with each of the
Mosher acid chlorides gave Mosher amides 22-R and 22-
S. Note that the R-acid chloride gives the corresponding
S-amide due to changes in priority of the groups around
the chiral center.
DOSP)4 catalyzed decomposition of the unsubstituted
vinyldiazoacetate 2 in the presence of N-phenoxycarb-
onyl-1,2-dihydropyridine (12) gives an overall 32% yield
of 13a in 50-60% ee. As expected, a small amount (5%
yield) of the isomeric 6-azabicyclononadiene 14a was
formed. Repeating the reaction of 2 with the 3-methyl-
1,2-dihydropyridine 16 gave only a single isomer of the
azabicyclononane 13i in 30% yield and 58% ee. Reactions
with the substituted vinyldiazoacetates (entries 3-5)
were more efficient than the reactions with 2. Rh2(S-
TBSP)4 catalyzed decomposition of the styryldiazoacetate
5 in the presence of 12 was especially good as 13d was
formed in 68% yield and 82% ee. By a slight modification
of the reaction conditions, 13d could be isolated in an
enantiomerically pure form. Rh2(S-DOSP)4 reaction with
5 in a 3:1 hexanes/toluene mixture results in selective
crystallization (12%) of a racemic mixture of 13d during
the reaction process; workup of the remainder of the
reaction mixture results in isolation of 13d in >96% ee
(51% yield).
The absolute configuration of 13d was determined to
be 1S,5R by using the Mosher amide method developed
by Hoye.2,8 The azabicyclononadiene 13d (97% ee) was
first converted to the nitrogen-unsubstituted acetate
derivative 21, which was subsequently converted to each
of the Mosher (methoxyphenyltrifluoromethyl; MTPA)
amides (Scheme 1). This was accomplished first by
hydrogenation of the C(8)-C(9) double bond followed by
lithium aluminum hydride reduction of the phenoxycar-
bonyl group and subsequent acylation of the primary
1
Each amide was analyzed by H NMR (500 MHz) to
establish the absolute stereochemistry of the original
6-azabicyclononane (Figure 1, Table 5). Since the most
stable conformation of the Mosher amides derived from
secondary amines has the trifluoromethyl group in an
anti-periplanar relationship relative to the nitrogen, the
phenyl group on the amide shields one of four possible
quadrants of the molecule depending on the specific
rotamer and the absolute stereochemistry of the amide.
In the case of 22, the major rotamer (2.2 to 1) was
assigned to the anti rotamer since the phenyl group was
shielding the half of the molecule (carbons 1-3 and 9)
away from the C(4) substituent as determined by the
chemical shifts differences of the protons on that side of
the molecule (Figure 1). Furthermore, since the protons
on carbons 1-3 as well as the ortho protons on the C(2)-
phenyl substituent were being shielded by the phenyl
group of the S-Mosher amide (resulting in negative δS
- δR values), the absolute stereochemistry of 22 was
assigned as shown in Figure 1. Accordingly, the protons
on the C(4)-substituent for the minor syn-rotamer were
effectively shielded for the R-amide (positive δS - δR
values) as evidenced by the 1.7 ppm shift of the meth-
ylene protons next to the acetoxy group, again consistent
with the absolute stereochemistry shown in Figure 1.
TABLE 4. Asym m etr ic Syn th esis of Aza bicylon on a d ien e 13
entry
diazo
R1
R2
catalyst
solvent
toluene
toluene
toluene
toluene
hex-tol (3:1)
product
yield, %
ee, %
1
2
3
4
5
2
2
15
5
H
H
Me
Ph
Ph
H
Me
H
H
H
Rh2(S-DOSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-DOSP)4
a
i
e
d
d
32
30
48
68
63
50-60
58
65
82
80
5
J . Org. Chem, Vol. 67, No. 16, 2002 5685

Davies and Hodges
TABLE 5. 1H NMR Ch em ica l Sh ift Differ en ces (δS - δR) of Mosh er Am id es 22
rotamer
H(1)
H(2â)
H(3)
o-Ph (C2)
H(5)
H(7)
CH2OAc
CH2OAc
anti
syn
-0.14
-0.08
-1.10
0.00
-0.17
+0.20
-0.26
b
-0.31
b
+0.22a
-0.03a
+0.11a
+1.69a
+0.01
+0.02
a
b
Average of two diastereotopic proton resonances. Resonances not assigned.
F IGURE 2.
the auxiliary.2 When the glycolate or lactate auxiliaries
are used in tandem with catalyst 4, the azabicyclonona-
dienone can be isolated in 40% yield; the yield increases
to 78% when substitution is present on the vinyl portion
of the vinyldiazomethane.
Also formed in the reaction is the azabicyclo[4.3.0]-
nonandienone product (7). Spectral evidence of small
quantities (<10%) of azabicyclo[4.3.0]nonandienones were
seen in all the reactions with N-methyl-2-pyridone, but
except for 7, these minor products were not fully char-
acterized. This compound is presumably formed via a
zwitterionic intermediate (23) formed during the cyclo-
propanation step (Figure 2). Alkylation of the pyridone
ring followed by ring closure through the vinyl group
produces 7. The formation of side products due to the
intermediacy of zwitterionic intermediates has been
observed in other vinylcarbenoid reactions.9 Catalysts
with more electron withdrawing ligands such as 4,
needed to give reasonable yields of the desired [3.2.2]
product, help to stabilize these zwitterionic intermedi-
ates, increasing the yield of this reaction pathway.
Fortunately, this can be mitigated through the use of
R-hydroxyesters on the vinyldiazomethane, which is
known to minimize products resulting from zwitterionic
intermediates in the reaction between vinylcarbenoids
and pyrroles.2
In the case of the dihydropyridine ring system, the
double bond regioselectivity directly leads to the forma-
tion of each of the regioisomers (Figure 3). Attack at the
5,6 double bond as in 24 generates isomer 13 while attack
at the 3,4 double bond as in 25 generates isomer 14.
Bulky catalysts such as rhodium pivalate lead to a strong
preference for cyclopropanation on the double bond closer
to the nitrogen.5 In accordance with this mechanism, use
of the sterically robust prolinate catalysts leads to a high
selectivity for formation of isomers 13. It should be noted
that the considerable electronic difference between the
two catalysts does not seem to be a factor in the
regioselectivity of these reactions.
F IGURE 1. Structures of the anti (major) and syn rotamers
of the Mosher amides 22-S and 22-R. Quadrants of the
molecules shielded by the phenyl group of the amide are
highlighted in bold.
Discu ssion
The reaction of vinycarbenoids with dienes provides
an efficient route to seven-membered rings. For example,
tropolones, 7-oxabicyclooctanes, tropanes, and tremu-
lanes all have been prepared in high yields with this
methodology.3 Through the use of either the chiral
auxiliaries or the chiral prolinate catalysts, Rh2(S-
DOSP)4 or Rh2(S-TBSP)4, these compounds can also be
prepared asymmetrically. These reactions occur via a
concerted, asynchronous cyclopropanation of one double
bond of the diene followed by a stereoselective Cope
rearrangement.
The 1-methyl-2-pyridone system reacts with vinylcar-
benoids to form the 6-azabicyclononadienone ring system
(3, 6, and 9). Due to the electron deficient nature of this
diene, specialized reaction conditions are required to
produce reasonable yields of the product. In this case,
the electron deficient prolinate catalysts, Rh2(S-DOSP)4
and Rh2(S-TBSP)4, provide a more reactive carbenoid,
which can react more efficiently with the pyridone. As
observed in the pyrrole system, the presence of R-hy-
droxyesters delivers a significant increase in yield and
reaction selectivity. This effect is believed to be due to
interaction of the carbenoid with the ester carbonyl on
In most cases, the prolinate catalysts lead to modest
asymmetric induction in the resulting 6-azabicyclonona-
dienes with the phenyl-substituted derivative 13d show-
ing the best result with 82% ee at room temperature. A
(9) (a) Davies, H. M. L.; Ahmed, G.; Chruchill, M. R. J . Am. Chem.
Soc. 1996, 118, 10774. (b) Davies, H. M. L.; Clark, T. J .; Kimmer, G.
F. J . Org. Chem. 1991, 56, 6440. (c) Davies, H. M. L.; Clark, T. J .
Tetrahedron 1994, 50, 9883. (d) Davies, H. M. L.; Matasi, J . J .; Ahmed,
G. J . Org. Chem. 1996, 61, 2305.
(8) (a) Hoye, T. R.; Renner, M. K. J . Org. Chem. 1996, 61, 2056 and
references therein. (b) Rauk, A.; Tavares, D. F.; Khan, M. A.; Borkent,
A. J .; Olson, J . F. Can. J . Chem. 1983, 61, 2572.
5686 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of the 6-Azabicyclo[3.2.2]nonane Ring System
In summary, these studies demonstrate the versatility
of the [3 + 4] cycloaddition between rhodium-stabilized
vinylcarbenoids and dienes. The reaction of these vinyl-
carbenoids with 2-pyridones and 1,2-dihydropyridines is
a direct approach for the construction of 6-azabicyclo-
[3.2.2]nonanes. Current studies are directed toward
elaboration of these 6-azabicyclo[3.2.2]nonanes to novel
monoamine re-uptake inhibitors, and the synthetic and
biological results of these studies will be described in due
course.
Exp er im en ta l Section
1H NMR spectra were run at either 300, 400, or 500 MHz,
and 13C NMR spectra were run at either 75 or 125 MHz in
CDCl3 unless otherwise noted. Mass spectral determinations
were carried out at 70 eV. Hexanes, THF, and Et2O were dried
over and distilled from sodium metal with benzophenone as
the indicator. Acetonitrile, toluene, and methylene chloride
were dried over and distilled from CaH2. Column chromatog-
raphy was carried out on Merck silica gel 60 (230-400 mesh).
Commercially available reagents were used without additional
purification unless noted. Melting points are uncorrected. The
chiral rhodium prolinate catalysts 4a and 4b10,11 and vinyl-
diazomethanes 2, 5, 8a -c, 10, 11, and 15 were synthesized
by literature procedures.12 N-Phenoxycarbonyl-1,2-dihydro-
pyridine (12) and N-phenoxycarbonyl-3-methyl-1,2-dihydro-
pyridine (16)13 were prepared according to the literature
procedure and purified via recrystallization from either abso-
lute ethanol or methanol. Commercial 1-methyl-2-pyridone (1,
Aldrich) was vacuum distilled before use.
F IGURE 3.
Syn th esis of 6-Aza bicyclo[3.2.2]n on a -3,8-d ien -7-on es,
Typ ica l P r oced u r e. A solution of methyl 2-diazo-3-butenoate
(2, 705 mg, 5.59 mmol) in 30 mL of dry toluene was added
dropwise over 30 min to a solution of 1-methyl-2-pyridone (1,
2.49 g, 22.9 mmol, 4 equiv) and tetrakis[N-(4-n-dodecyl-
phenylsulfonyl)prolinato]dirhodium [Rh2(DOSP)4] (4b, 208 mg,
0.112 mmol, 2 mol %) in 40 mL of toluene at room temperature.
The reaction was stirred overnight, and the excess pyridone
was removed via Kugelrohr distillation (100 °C, 0.1 Torr). The
crude product was then chromatographed (EtOAc) to give
methyl (6-methyl-6-azabicyclo[3.2.2]nona-3,8-diene-7-one)-4-
carboxylate (3, 17%). For compounds 6, 7, and 8a -c, the
catalyst, chromatography solvent system, and yield are given
F IGURE 4.
1
in that order in parentheses. H NMR (3, 400 MHz, CDCl3) δ
6.73 (m, 1 H), 6.55 (dd, J ) 7.9, 6.7 Hz, 1 H), 6.16 (dd, J ) 7.9,
6.7 Hz, 1 H), 4.64 (d, J ) 6.1 Hz, 1 H), 3.78 (s, 3 H), 3.19 (br
s, 1 H), 2.97 (s, 3 H), 2.76 (ddd, J ) 20.4, 4.0, 3.6 Hz, 1 H),
2.35 (ddd, J ) 21.2, 3.6, 3.2 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 173.0, 166.2, 141.2, 134.0, 133.4, 127.9, 53.4, 52.1,
41.9, 32.7, 27.6; IR (neat) 1707, 1669, 1636 cm-1; MS m/z (rel
intensity) 207 (M+, 65), 148 (19), 91 (100). Anal. Calcd for
reasonable model to rationalize the asymmetric induction
is shown Figure 4. This model is an extension of the
predictive model that has been developed for the dirhod-
ium tetraprolinate transformations,10 in which the cata-
lyst behaves as a D2-symmetric complex and the chiral
influence can be simplified to two blocking groups as
illustrated in 26. In the case of the 1,2-dihydropyridine
12, only one carbon for each double bond is activated for
electrophilic attack. To form 13d , the initial C5-C6
double bond cyclopropanation would occur preferentially
on the C-5 carbon. A subsequent Cope rearrangement of
the divinylcyclopropane 27 would lead to the formation
of 13d with the observed absolute configuration (1S,5R).
The analogous reaction between carbenoids and pyrroles
shows a modest 51% ee in the resulting tropanes.2 In this
case since attack of the pyrrole ring by the carbenoid can
occur at either the electronically favored R-position or
sterically favored â-position, these competing orientations
of attack lead to opposite asymmetric induction.2
C
11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.49; H,
6.44; N, 6.57.
Meth yl (6-m eth yl-2r-p h en yl-6-a za bicyclo[3.2.2]n on a -
3,8-d ien e-7-on e)-4-ca r boxyla te [6] (4b, 2:1 EtOAc/hexanes,
33%): 1H NMR (500 MHz, CDCl3) δ 7.33-7.25 (m, 3 H), 7.16
(d, J ) 7.3 Hz, 2 H), 6.80 (m, 1 H), 6.63 (dd, J ) 7.3, 6.7 Hz,
1 H), 5.75 (dd, J ) 7.3, 7.3 Hz, 1 H), 4.71 (d, J ) 6.4 Hz, 1 H),
4.00 (dd, J ) 3.4, 3.1 Hz, 1 H), 3.81 (s, 3 H), 3.46 (m, 1 H),
3.01 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 172.4, 166.3, 143.6,
138.1, 134.3, 134.1, 128.6, 128.0, 127.5, 127.3, 53.5, 52.3, 50.2,
42.8, 33.2; IR (neat) 1708, 1640 cm-1. HRMS calcd for C17H17
NO3 283.1208; found 283.1213.
-
Meth yl 7-p h en yl-1-a za bicyclo[4.3.0]n on a -3,5-d ien e-2-
on e-5-ca r boxyla te [7] (4b, 2:1 EtOAc/hexanes, 14%): 1H
NMR (500 MHz, CDCl3) δ 7.35-7.31 (m, 2 H), 7.28 (t, 1 H),
(11) Pirrung, M. C.; Zhang, J . Tetrahedron Lett. 1992, 33, 5987.
(12) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463.
(13) Sundberg, R. J .; Bloom, J . D. J . Org. Chem. 1981, 46, 4836.
(10) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J . J . Am. Chem. Soc. 1996, 118, 6897 and references therein.
J . Org. Chem, Vol. 67, No. 16, 2002 5687

Davies and Hodges
7.18 (d, J ) 7.6 Hz, 2 H), 6.70 (d, J ) 1.5 Hz, 1 H), 6.38 (dd,
J ) 10.1, 1.8 Hz, 1 H), 5.99 (dd, J ) 9.8, 2.4 Hz, 1 H), 4.06-
3.97 (m, 3 H), 3.80 (s, 3 H), 2.64 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 163.8, 162.5, 146.0, 140.9, 136.2, 134.8, 129.0, 127.7,
127.6, 123.6, 70.4, 58.3, 51.9, 42.8, 34.8; IR (neat) 1718, 1669,
1616 cm-1; MS m/z (rel intensity) 283 (M+, 100), 251 (33), 224
(79), 115 (52). Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05;
N, 4.94. Found: C, 72.06; H, 6.12; N, 4.84.
(ddd, J ) 11.5, 4, 4 Hz, 1 H total), 2.80-2.71 (m, 2 H), 2.70-
2.60 (m, 3 H), 1.10 (m, 3 H); IR (neat) 1715, 1666, 1633 cm-1
;
MS m/e (rel intensity) 297 (M+, 80), 204 (39), 161 (13), 147
(100). Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71.
Found: C, 72.89; H, 6.49; N, 4.79. Mp ) 109-111 °C.
Meth yl (3-ter t-bu tyld im eth ylsiloxy-6-p h en oxyca r bon -
yl-6-a za bicyclo[3.2.2] n on a -2,8-d ien e)-2-ca r boxyla te [14c]
a n d m eth yl (3-ter t-bu tyld im eth ylsiloxy-6-p h en oxyca r -
b on yl-6-a za b icyclo[3.2.2]n on a -3,8-d ien e)-4-ca r b oxyla t e
[13c] (Rh2(OOct)4, 4:1 to 2:1 petroleum ether/Et2O) to give both
14c (24%) and 13c (17%).
1H NMR (14c, 2:1 ratio of rotamers, 400 MHz, CDCl3) δ 7.36
(m, 2 H), 7.20 (m, 1 H), 7.11 (d, J ) 9.2 Hz, 2 H), 6.61 (m, 1
H), 6.23 (m, 1 H), 4.84, 4.79 (br t, 1 H total), 4.02, 3.90 (d, J )
14.4 Hz, 1 H total), 3.75, 3.73 (s, 3 H total), 3.66 (m, 1 H),
3.46, 3.34 (dd, J ) 14.2, 4.6 Hz, 1 H total), 2.94, 2.91 (dd, J )
22.9. 6.0 Hz, 1 H total), 2.41, 2.36 (dd, J ) 22.9, 2.3 Hz, 1 H
total), 0.94, 0.93 (s, 9 H total), 0.18, 0.17 (s, 6 H total); IR (neat)
1720, 1609 cm-1; MS m/e (rel intensity) 429 (M+, 0.2), 372 (M+
- t-Bu, 100). Anal. Calcd for C23H31NO5Si: C, 64.31; H, 7.27;
N, 3.26. Found: C, 64.28; H, 7.33; N, 3.25.
Syn th esis of 6-Aza bicyclo[3.2.2]n on a d ien e Ca r boxy-
la tes [13, 14], Typ ica l P r oced u r e. A chilled solution of
freshly purified 2 (3.82 g, 30.3 mmol) in 50 mL of dry toluene
was added dropwise to a solution of 12 (7.61 g, 37.8 mmol,
1.25 equiv) and Rh2(OOct)4 (476 mg, 0.611 mmol, 2.0 mol %)
in 100 mL of toluene over 30 min. The reaction was stirred
for 1.5 h and then heated to reflux for 30 min. The reaction
mixture was allowed to cool to room temperature and the
mixture was concentrated under reduced pressure. The residue
was chromatographed (4:1 to 1:1 petroleum ether/Et2O) to give
methyl (6-phenoxycarbonyl-6-azabicyclo[3.2.2]nona-2,8-diene)-
2-carboxylate (14a , 2.59 g, 8.64 mmol, 29%) and methyl (6-
phenoxycarbonyl-6-azabicyclo[3.2.2]nona-3,8-diene)-4-carbox-
ylate (13a , 2.69 g, 8.98 mmol, 30%). For compounds 13b-i
and 14b-h , the catalyst used, chromatography solvent system,
and yield are given in that order in parentheses. In many
cases, the usually favored and more polar 4-carboxylate
isomers (13) exist as solids. The presence of rotamers caused
by the phenoxycarbonyl substituent complicates the 13C data
of 13 and 14 and these data are not reported. When the
reaction was carried out with [Rh2(S-DOSP)4] in toluene, 13a
was formed in 32% yield and 50-60% ee (determined by
HPLC: Chiralcel OD, 2.0% i-PrOH in hexane, 1.0 mL/min, λ
) 254 nm, tR ) 48.0 min, major; tR ) 51.1 min, minor).
1H NMR (13c, 3:2 ratio of rotamers, 500 MHz, CDCl3) δ 7.33
(t, J ) 7.9 Hz, 2 H), 7.16 (t, J ) 7.4 Hz, 2 H), 7.10 (m, 2 H),
6.62 (m, 1 H), 6.20 (m, 1 H), 5.67, 5.66 (d, J ) 7.0 Hz, 1 H
total), 3.78, 3.68 (d, J ) 11.6 Hz, 1 H total), 3.57, 3.42 (ddd, J
) 11.3, 4.6, 4.3 Hz, 1 H total), 3.71 (s, 3 H), 2.77 (br s, 1 H),
2.63, 2.59 (dd, J ) 11.6, 3.7 Hz, 1 H total), 2.50 (m, 1 H), 0.94
(s, 9 H), 0.19, 0.17 (s, 6 H total); IR (neat) 1716, 1615 cm-1
;
MS m/e (rel intensity) 429 (M+, 3), 372 (M+ - t-Bu, 100). Anal.
Calcd for C23H31NO5Si: C, 64.31; H, 7.27; N, 3.26. Found: C,
64.38; H, 7.33; N, 3.25.
Meth yl (4r-p h en yl-6-p h en oxyca r bon yl-6-a za bicyclo-
[3.2.2]n on a -2,8-d ien e)-2-ca r boxyla te [14d ] a n d m eth yl
(2r-p h en yl-6-p h en oxyca r bon yl-6-a za bicyclo[3.2.2]n on a -
3,8-d ien e)-4-ca r boxyla te [13d ] (Rh2(OPiv)4, 4:1 to 2:1 pe-
troleum ether/Et2O) to give both 14d (trace) and 13d (69%).
When the reaction was carried out with [Rh2(S-TBSP)4] in
toluene, 13d was formed in 68% yield and 82% ee (determined
by HPLC: Chiralcel OD, 10% i-PrOH in hexane, 1.0 mL/min,
λ ) 254 nm, tR ) 17.3 min, major; tR ) 21.5 min, minor).
1H NMR (14d , 2:1 ratio of rotamers, 500 MHz, CDCl3) δ
7.45-7.16 (m, 10 H), 6.94 (m, 1 H), 6.58 (m, 1 H), 5.77 (m, 1
H), 5.00, 4.94 (dd, J ) 5.5, 4.9 Hz, 1 H total), 4.25, 4.22 (dd, J
) 4.3, 4.0, 1 H total), 4.00, 3.90 (d, J ) 11.0 Hz, 1 H total),
3.85 (m, 1 H), 3.80, 3.79 (s, 3 H total), 3.57, 3.45 (dd, J ) 11.0,
1H NMR (14a , 9:5 ratio of rotamers, 500 MHz, CDCl3)14
δ
7.36 (m, 2 H), 7.19 (q, J ) 7.3 Hz, 1 H), 7.11 (d, J ) 8.0 Hz, 2
H), 6.84 (dd, J ) 3.4, 3.3 Hz, 1 H), 6.51 (m, 1 H), 6.24 (m, 1
H), 4.84, 4.78 (dd, J ) 5.5, 5.2 Hz, 1 H total), 3.98, 3.89 (dd, J
) 11.3, 1.5 Hz, 1 H total), 3.77 (s × 2, 3 H total), 3.73 (m, 1
H), 3.55, 3.42 (dd, J ) 11.3, 3.7 Hz, 1 H total), 2.96, 2.92 (ddd,
J ) 20.4, 4.6, 4.0 Hz, 1 H total), 2.46, 2.40 (ddd, J ) 20.1, 2.7,
2.4 Hz, 1 H total); IR (neat) 1712, 1638 cm-1; MS m/e (rel
intensity) 299 (M+, 85), 206 (74), 174 (100). Anal. Calcd for
C
17H17NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.09; H,
5.80; N, 4.56.
1H NMR (13a , 1:1 ratio of rotamers, 500 MHz, CDCl3) δ 7.33
(t, J ) 7.6 Hz, 2 H), 7.14 (m, 3 H), 6.81 (m, 1 H), 6.58 (m, 1 H),
6.19 (m, 1 H), 5.69, 5.67 (d, J ) 7.3 Hz, 1 H total), 3.82, 3.73
(d, J ) 12 Hz, 1 H total), 3.76, 3.75 (s, 3 H total), 3.68, 3.52
(ddd, J ) 11.6, 4.6, 4.6 Hz, 1 H total), 2.76-2.53 (m, 3 H); IR
(neat) 1715, 1638, 1591 cm-1; MS m/e (rel intensity) 299 (M+,
100), 206 (66). Anal. Calcd for C17H17NO4: C, 68.22; H, 5.72;
N, 4.68. Found: C, 68.28; H, 5.74; N, 4.63. Mp ) 96.5-99 °C.
2-P r opion yl-(6-ph en oxycar bon yl-6-azabicylo[3.2.2]n on a-
2,8-d ien e) [14b] and 4-p r op ion yl-(6-p h en oxyca r bon yl-6-
a za bicylo[3.2.2]n on a -3,8-d ien e) [13b] (Rh2(OOct)4, 4:1 pe-
troleum ether/Et2O to 1:1 petroleum ether/Et2O) to give both
14b (25%) and 13b (11%).
3.4 Hz, 1 H total); IR (neat) 1716 cm-1. HRMS Calcd for C23H21
NO4 375.1471, found 375.1492.
-
1H NMR (13d , 1:1 ratio of rotamers, 500 MHz, CDCl3) δ
7.37-7.27 (m, 5 H), 7.19 (t, J ) 7.3 Hz, 1 H), 7.14 (m, 4 H),
6.88 (m, 1 H), 6.64 (m, 1 H), 5.84 (m, 1 H), 5.77, 5.74 (d, J )
6.9 Hz, 1 H total), 4.04, 3.91 (d, J ) 11.6 Hz, 1 H total), 3.88,
3.86 (dd, J ) 3.4, 3.1 Hz, 1 H total), 3.79 (s, 3 H), 3.77, 3.62
(dd, J ) 11.9, 4.6 Hz, 1 H total), 3.00 (m, 1 H); IR (neat) 1718,
1642 cm-1; MS m/e (rel intensity) 375 (M+, 41), 250 (22), 225
(100). Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73.
Found: C, 73.69; H, 5.71; N, 3.75. Mp ) 137-139.5 °C.
Meth yl (2r-p h en yl-6-p h en oxyca r bon yl-6-a za bicyclo-
[3.2.2]n on a -3-en e)-4-ca r boxyla te [17]. A solution of 13d (3.1
g, 8.3 mmol, 97% ee (HPLC)) in 125 g of absolute ethanol was
prepared in a Parr hydrogenation flask. Wilkinson’s catalyst
(115 mg, 0.124 mmol, 1.5 mol %) was added, and the system
was flushed with hydrogen four times and pressurized to 50
psi. The mixture was agitated for 23 h after which no starting
1H NMR (14b, 2:1 ratio of rotamers, 500 MHz, CDCl3) δ 7.35
(m, 2 H), 7.19 (m, 1 H), 7.12 (m, 2 H), 6.71 (m, 1 H), 6.48 (m,
1 H), 6.25 (m, 1 H), 4.86, 4.81 (br t, 1 H total), 3.97 (br s, 1 H),
3.85, 3.76 (d, J ) 11.0 Hz, 1 H total), 3.54, 3.41 (dd, J ) 11.6,
3.7 Hz, 1 H total), 2.99, 2.96 (ddd, J ) 20.4, 4.6, 4.3 Hz, 1 H),
2.70 (m, 2 H), 2.54, 2.48 (d, J ) 20.1 Hz, 1 H total), 1.13 (m,
3 H); IR (neat) 1716, 1668, 1630 cm-1; MS m/e (rel intensity)
297 (M+, 80), 147 (100). Anal. Calcd for C18H19NO3: C, 72.71;
H, 6.44; N, 4.71. Found: C, 72.60; H, 6.47; N, 4.58.
1H NMR (13b, 3:2 ratio of rotamers, 500 MHz, CDCl3) δ 7.31
(m, 2 H), 7.15 (m, 1 H), 7.11, 7.08 (d, J ) 8.0 Hz, 2 H), 6.65
(m, 1 H), 6.52 (m, 1 H), 6.18 (m, 1 H), 5.85, 5.74 (d, J ) 7.0
Hz, 1 H total), 3.86, 3.75 (d, J ) 11.5 Hz, 1 H total), 3.65, 3.51
1
material was observed by H NMR. The solvent was removed
under reduced pressure and the crude product chromato-
graphed on silica gel with 2:1 petroleum ether/Et2O to give
the title compound as a white solid. Yield: 3.0 g (8.0 mmol,
97%). Mp ) 98.5-100 °C. 1H NMR (400 MHz, CDCl3, 3:2 ratio
of rotamers) δ 7.39-7.10 (m, 11 H), 5.38, 5.35 (br s, 1 H total),
4.05, 3.99 (ddd, J ) 12.4, 2, 2 Hz, 1 H total), 4.04 (br s, 1 H),
3.80, 3.61 (dd, J ) 12.4, 3.3 Hz, 1 H total), 3.79, 3.78 (s, 3 H
total), 2.33 (m, 1 H), 2.19 (m, 1 H), 2.07 (m, 1 H), 1.81 (m, 1
(14) The 1H NMR resonances corresponding to the major rotamer
are underlined.
5688 J . Org. Chem., Vol. 67, No. 16, 2002

Synthesis of the 6-Azabicyclo[3.2.2]nonane Ring System
H), 1.56 (m, 1 H); IR (neat) 1715 cm-1; MS m/e (rel intensity)
377 (M+, 8), 284 (100). Anal. Calcd for C23H23NO4: C, 73.19;
H, 6.14; N, 3.71. Found: C, 73.23; H, 6.17; N, 3.76.
H), 7.21 (d, J ) 7.6 Hz, 2 H), 5.75 (br s, 1 H), 4.89-4.72 (m, 4
H), 4.66, 4.64 (br s, 1 H total), 4.48 (m, 1 H), 3.91 (br d, J )
12.2 Hz, 1 H), 3.88 (br s, 1 H), 3.71, 3.59 (dd, J ) 12.0, 4.4 Hz,
1 H total), 2.25 (br d, J ) 17.4 Hz, 1 H), 2.11, 2.10 (s, 3 H
total), 2.10-1.98 (m, 1 H), 1.78 (m, 1 H), 1.47 (m, 1 H); IR
(neat) 1740, 1715, 1601 cm-1; MS m/e (rel intensity) 445 (M+,
4-(Hyd r oxym eth yl)-2r-p h en yl-6-m eth yl-6-a za bicyclo-
[3.2.2]n on a -3-en e [18] a n d 4-(Acetoxym eth yl)-2r-p h en yl-
6-m eth yl-6-a za bicyclo[3.2.2]n on a -3-en e [19]. A solution of
17 (2.17 g, 5.75 mmol) in 75 g of dry THF was prepared and
cooled to 0 °C. Lithium aluminum hydride (1.21 g, 31.9 mmol)
was added, and the mixture was stirred for 3 h. The reaction
was quenched at 0 °C by the slow addition of EtOAc (100 mL)
followed by stirring for 1.5 h. Brine (100 mL) was then added,
and the mixture was stirred for an additional 2 h. The mixture
was filtered and the cake washed with 50 mL each of EtOAc
and water, and the layers were separated in the filtrate. The
organic layer was washed twice with 50 mL of 5% aq KOH
followed by 100 mL of brine. The organic solution was dried
(MgSO4), and the solvent was evaporated to give ∼1.5 g of
crude product that contained the desired compound along with
the acetate ester (the desired product of the next reaction) from
base-promoted ester exchange with ethyl acetate during
workup. The crude material was chromatographed (5% Et3N
in Et2O followed by 5% Et3N in Et2O with 20% added methanol
to elute the alcohol) to give the acetate ester 19 (169 mg, 0.59
mmol, 10%) and the desired alcohol 18 (767 mg, 3.15 mmol,
55%).
1), 385 ((M - HOAc)+, 26), 181 (100). Anal. Calcd for C20H22
-
NO4Cl3: C, 53.77; H, 4.96; N, 3.14. Found: C, 53.51; H, 5.00;
N, 3.05.
4-(Acetoxym eth yl)-2r-p h en yl-6-a za bicyclo[3.2.2]n on a -
3-en e [21]. A 4-dram vial was charged with 20 (200 mg, 0.448
mmol), glacial HOAc (5.0 mL), and zinc powder (100 mesh,
500 mg). The mixture was stirred for 18 h at room tempera-
ture. The reaction was diluted with water (25 mL), filtered,
and neutralized with K2CO3(s) and 60 mL of NH4OH (aq) (final
pH 11). The aqueous mixture was extracted with CH2Cl2 (4 ×
25 mL) and dried (MgSO4), and the solvent was evaporated
under reduced pressure to give the crude product, which
contained approximately 10% starting material. The crude
mixture was chromatographed (Et2O, then 5% Et3N in Et2O,
followed by 5% Et3N in Et2O with 10% methanol). Yield 53
1
mg (0.20 mmol, 44%). H NMR (500 MHz, CDCl3) δ 7.33 (t, J
) 7.6 Hz, 2 H), 7.25-7.30 (m, 3 H), 5.78 (br s, 1 H), 4.61 (br s,
2 H), 3.90 (br s, 1 H), 3.35 (br d, J ) 4.9 Hz, 1 H), 3.31 (dd, J
) 11.6, 4.9 Hz, 1 H), 3.20 (br d, J ) 11.9 Hz, 1 H), 2.78 (br s,
1 H), 2.10 (s, 3 H), 2.07 (m, 1 H), 2.04 (m, 1 H), 1.84 (m, 1 H),
1.66 (m, 1 H), 1.55 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ
170.9, 143.9, 142.4, 130.6, 128.3, 127.9, 126.3, 68.5, 53.0, 49.4,
Characterization of 18: 1H NMR (500 MHz, CDCl3) δ 7.31
(m, 2 H), 7.21 (m, 3 H), 5.75 (br s, 1 H), 4.13 (s, 2 H), 3.83 (br
s, 1 H), 3.13 (dd, J ) 11.0, 6.1 Hz, 1 H), 3.06 (d, J ) 6.4 Hz, 1
H), 2.69 (d, J ) 11.0 Hz, 1 H), 2.41 (s, 3 H), 2.12 (m, 2 H), 1.76
(m, 1 H), 1.47 (m, 2 H); OH resonance not observed; 13C NMR
(125 MHz, CDCl3) δ 144.0, 143.5, 128.2, 127.9, 126.8, 126.3,
68.1, 56.8, 56.2, 53.4, 44.2, 37.0, 28.0, 18.6; IR (neat) 3400 (br)
cm-1; HRMS calcd for C16H21NO 243.1623, found 243.1633.
Characterization of 19: 1H NMR (500 MHz, CDCl3) δ 7.32
(t, J ) 7.6 Hz, 2 H), 7.23 (t, J ) 7.6 Hz, 1 H), 7.19 (d, J ) 7.6
Hz, 2 H), 5.83 (br s, 1 H), 4.59 (abq, J ) 12.5 Hz, 2 H), 3.83
(br s, 1 H), 3.20 (dd, J ) 10.7, 6.4 Hz, 1 H), 3.01 (d, J ) 6.7
Hz, 1 H), 2.61 (d, J ) 10.7 Hz, 1 H), 2.40 (s, 3 H), 2.11 (s, 3 H),
2.1 (m, 2 H), 1.76 (m, 1 H), 1.50 (m, 1 H), 1.44 (m, 1 H); 13C
NMR (125 MHz, CDCl3) δ 170.9, 142.9, 139.0, 130.5, 128.4,
127.9, 126.4, 69.3, 56.7, 56.5, 53.6, 44.1, 36.9, 28.7, 21.0, 18.6;
IR (neat) 1739 cm-1; HRMS calcd for C18H23NO2 285.1729,
found 285.1714.
47.1, 37.4, 27.9, 21.0, 18.5; IR (neat) 3346 (br), 1738 cm-1
HRMS calcd for C17H21NO2 271.1572, found 271.1554.
;
Con ver sion of 21 to Mosh er Am id es 22-R a n d 22-S
(Gen er a l P r oced u r e). A 1-dram vial was charged with 21
(15 mg, 0.056 mmol), DIEA (18 mg, 0.14 mmol), and 0.40 g of
CH2Cl2. The corresponding acid chloride (R-acid chloride for
the S-amide; the S-acid chloride for the R-amide; 18 µL, 0.096
mmol) was added by syringe. The vial was gently flushed with
Ar for 30 s and the reaction allowed to stand for ∼12 h at room
temperature. The reaction mixture was diluted with 5 mL of
CH2Cl2 and added to 10 mL of stirred NH4Cl (sat, aq). After
the solution was stirred for 30 min, the layers were separated,
and the aqueous layer was back-extracted with 5 mL of CH2-
Cl2. The organic extracts were combined, dried (MgSO4), and
filtered through a pad of silica gel in a 15-mL coarse-fritted
funnel. The solvent was evaporated under reduced pressure
and the crude amide 22 dissolved in CDCl3 and analyzed by
1H NMR (500 MHz). Assignments of proton resonances were
made with the assistance of COSY and nOe data.
4-(Acetoxym eth yl)-2r-p h en yl-6-(2,2,2-tr ich lor oeth oxy-
ca r bon yl)-6-a za bicyclo[3.2.2]n on a -3-en e [20]. A solution
of 19 (147 mg, 0.515 mmol) in 10 mL of dry toluene was
prepared. Anhydrous potassium carbonate (10 mg, 0.072
mmol) was added followed by 2,2,2-trichloroethyl chlorofor-
mate (0.15 mL, 1.0 mmol, 2 equiv). The reaction mixture was
heated to reflux for 10 h. The mixture was diluted with Et2O
and extracted with 2 × 50 mL of NaHCO3 (sat, aq) followed
by 50 mL of brine. The organic solution was dried (MgSO4)
and the solvent evaporated under reduced pressure to give an
oil. The crude material was chromatographed (2:1 petroleum
ether/Et2O) to give the title product as a yellow oil. Yield: 200
mg (0.448 mmol, 87%). This compound could also be prepared
in 70% yield from 18 first by acylation (1.2 equiv each of Ac2O
and DMAP in CH2Cl2) followed by demethylation of crude 19
Ack n ow led gm en t. This research was supported by
grants from the National Institute on Drug Abuse (DA-
06301, DA-06634). L.M.H. thanks the National Institute
of Drug Abuse (DA-05732) for a research fellowship.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
9a -c, 13e-i, and 14e, and proton NMR spectra for 6, 9a , 13i,
19, and 21. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
with excess 2,2,2-trichloroethyl chloroformate. H NMR (500
MHz, CDCl3, 1:1 ratio of rotamers) δ 7.35 (m, 2 H), 7.27 (m, 1
J O025697G
J . Org. Chem, Vol. 67, No. 16, 2002 5689