The preparation of 2-arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3- ones

Article abstract of DOI:10.1081/SCC-120037905

An efficient and versatile two-step synthesis of 2-arylmethylidene-8- methyl-8-azabicyclo[3.2.1]octane-3-ones, via mono aldol condensation of tropinone with a variety of aryl aldehydes followed by pTsOH-catalyzed dehydration, is described.

Full text of DOI:10.1081/SCC-120037905

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The Preparation of
2‐Arylmethylidene‐8‐methyl‐8‐azabicyclo[3.2.1]octan‐3‐
Guangrong Zheng a , Linda P. Dwoskin a & Peter A. Crooks a
a College of Pharmacy , University of Kentucky , Lexington, Kentucky, 40536‐0082, USA
Published online: 20 Aug 2006.
To cite this article: Guangrong Zheng , Linda P. Dwoskin & Peter A. Crooks (2004) The Preparation of
2‐Arylmethylidene‐8‐methyl‐8‐azabicyclo[3.2.1]octan‐3‐ones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:11, 1931-1942, DOI: 10.1081/SCC-120037905
To link to this article: http://dx.doi.org/10.1081/SCC-120037905
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 1931–1942, 2004
The Preparation of 2-Arylmethylidene-
8-methyl-8-azabicyclo[3.2.1]octan-3-ones
*
Guangrong Zheng, Linda P. Dwoskin, and Peter A. Crooks
College of Pharmacy, University of Kentucky,
Lexington, Kentucky, USA
ABSTRACT
An efficient and versatile two-step synthesis of 2-arylmethylidene-
8-methyl-8-azabicyclo[3.2.1]octane-3-ones, via mono aldol condensation
of tropinone with a variety of aryl aldehydes followed by pTsOH-
catalyzed dehydration, is described.
Key Words: Tropane analogs; Aldol condensation; CNS agents; THF.
INTRODUCTION
The tropane ring system is present in the natural products cocaine,
atropine, and hyoscine, and in a number of other compounds that display inter-
esting pharmacological properties. In recent years, numerous tropane analogs
*
Correspondence: Peter A. Crooks, College of Pharmacy, University of Kentucky,
Lexington, KY 40536-0082, USA; E-mail: pcrooks@uky.edu.
1931
DOI: 10.1081/SCC-120037905
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1932
Zheng, Dwoskin, and Crooks
have been synthesized and evaluated as inhibitors of dopamine, serotonin, and
norepinephrine transporters in an effort to probe the topology of the cocaine
binding site on these biogenic amine transporters.[1] As part of a drug discov-
ery program aimed at the development of therapeutic agents for treating cen-
tral nervous system disorders, we were interested in the preparation of a series
of 2-arylmethylidene-8-methyl-8-azabicyclo-[3.2.1]octane-3-ones.
There have been several attempts to prepare 2-arylmethylidene-8-methyl-
8-azabicyclo[3.2.1]octane-3-ones from tropinone by aldol condensation.[2–5]
However, the mono aldol condensation reaction was generally either
unsuccessful,[2–4] or afforded very low yields of product.[5] Lounasmaa and
Johansson reported that they could obtain 2-benzylidene-8-methyl-8-azabicy-
clo[3.2.1]octane-3-one from tropinone and benzaldehyde if the condensation
conditions were controlled carefully and the reaction was terminated at an
early stage.[5] However, the product yield was only 15%. We have observed
that analytical monitoring of the base-catalyzed (NaOH) condensation of tro-
pinone with benzaldehyde, even in the presence of a large excess of tropinone,
indicates that the major product is 2,4-dibenzylidene-8-methyl-8-azabi-
cyclo[3.2.1]octane-3-one. Thus, the second aldol condensation and dehydration
appears to be much faster than the first condensation and dehydration. In
addition to the low yield of 2-benzylidene-8-methyl-8-azabicyclo[3.2.1]-
octane-3-one, we have found it very difficult to separate the mono-substituted
aldol product from the di-substituted product. We now describe a new and
efficient two-step procedure for the synthesis of a series of 2-arylmethyl-
idene-8-methyl-8-azabicyclo[3.2.1]octane-3-ones (3).
The mono aldol condensation of cyclic ketones with aryl aldehydes has
been achieved in the presence of strong bases,[6,7] and the resulting
b-hydoxyketone product can then be easily dehydrated to the corresponding
a, b-unsaturated ketone. Thus, we found that when tropinone was lithiated
with lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide
(LHMDS), the resulting lithium enolate could be condensed with an appro-
priate aryl aldehyde to afford the corresponding b-hydroxyketone with high
regioselectivity, affording mainly the expected exo-anti-isomer (2) (see
Sch. 1). Attempted purification of the aldol product by silica gel column
chromatography resulted in a significant loss of material and the recovery
of tropinone and the starting aryl aldehyde, due to an on-column retro-
aldol reaction. We have observed that this retro-aldol condensation also
occurs in organic solvents under either basic or neutral conditions, which
is in agreement with other reports.[7] In the presence of NaOH in methanol,
2a was slowly transformed into 2E, 4E-dibenzylidenetropinone (4) as a result
of the further reaction of 2a with the benzaldehyde generated from retro-
aldol decomposition of 2a, followed by dehydration (Sch. 2). Under the
same conditions, 2a was reacted with pyridine-3-carboxaldehyde to rapidly

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2-Arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones
1933
Scheme 1. Two-step synthesis of 2-arylmethylidene-8-methyl-8-azabicyclo[3.2.1]-
octane-3-ones (3) from tropinone (1).
form compound 5. This procedure represents a versatile strategy for the
synthesis of both symmetrical and unsymmetrical 2,4-disubstituted aldol
condensation products of tropinone.
Without further purification, compounds 2a–2m could be dehydrated
directly under acidic conditions utilizing pTsOH in refluxing toluene, which
proved to be the best dehydration reagent amongst all other reagents tested,
including HCl/THF, H3PO4, and SOCl2/Py. Under these conditions, inter-
mediates 2a–2j were transformed exclusively into their corresponding
2E-arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octane-3-ones 3a–3j (Sch. 1).
In the case of the acid-sensitive compounds 2k–2m, optimized conditions
were used, which are provided in Table 1. All products obtained were purified
by flash column chromatography on silica gel, and all dehydration reactions
Scheme 2. Formation of symmetrical and unsymmetrical 2E, 4E-diarylmethylidene-
8-methyl-8-azabicyclo[3.2.1]octane-3-ones 4 and 5, respectively, from 2a.

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Zheng, Dwoskin, and Crooks
Table 1. Dehydration conditions and yields of compounds 3a–3m.
Dehydration
conditions
Isolated yield
(%) (two steps)
Compound 3
Ar
3a
Reflux, 6 hr
Reflux, 6 hr
Reflux, 6 hr
84
3b
3c
47
35
3d
Reflux, 6 hr
25
3e
3f
Reflux, 6 hr
Reflux, 6 hr
85
89
3g
3h
Reflux, 6 hr
Reflux, 6 hr
69
57
3i
3j
Reflux, 6 hr
Reflux, 6 hr
51
62
3k
3l
658C, 0.5 hr
658C, 1 hr
rt, 0.5 hr
33
60
27
3m
provided only 2E-double bond products. The stereochemical assignment of
the double bond geometry in compound 3 was supported by nuclear overhau-
ser and exchange spectroscopy (NOESY), which showed proton interactions
between the phenyl protons and the C-1 proton, but no proton interactions
between the alkene proton and the C-1 proton (Sch. 1, 3b).

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2-Arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones
EXPERIMENTAL
1935
Reagents and chemicals were purchased from Aldrich, Fisher, Lancaster,
and Acros. Flash column chromatography was carried out using ICN Silic-
˚
Tech 32–63, 60 A silica gel. Melting points were determined with a
Fisher-Johns melting point apparatus and are uncorrected. 1H-NMR and
13C-NMR spectra were recorded on a Varian 300 MHz instrument and are
reported in ppm relative to TMS as internal standard. Mass spectra were
recorded on an Agilent 6890 GC incorporating an Agilent 7683 autosampler
and an Agilent 5973 MSD (Agilent Technologies, Wilmington, DE) inter-
faced to a Hewlett-Packard KAYAK XM600 computer (Hewlett-Packard
Co., Palo Alto, CA) with MSD Productivity ChemStation Software (Rev.
C.00.01) (Agilent Technologies, Palo Alto, CA) for analysis and data proces-
sing. An HP-5MS GC column (30 m ꢀ 0.25 mm I.D. ꢀ 0.25 mm film thick-
ness) (Agilent Co., Wilmington, DE) was utilized for analyses, with ultra
pure helium as carrier gas at a flow rate of 1.0 mL/min and an average
velocity of 38 cm/sec in constant flow mode. The temperature at the injection
port, MS interface, electron impact source, and mass filter was set constant at
2808C, 2808C, 2308C, and 1508C, respectively. The oven temperature was
initially set at 1208C and increased to 1608C at the rate of 108C/min; after
holding at 1608C for 1 min, the oven temperature was increased to 2758C
at the rate of 608C/min and held at this temperature for 10 min, to elute poss-
ible high boiling point interfering impurities. The MS analyzer was set in the
scan mode. High resolution electron impact ionization mass spectra were
recorded at 70 eV on a JEOL JMS-700T MStation (magnetic sector instru-
ment) at a resolution of greater than 10,000. Samples were introduced
via heatable direct probe inlet. perfluorokerosene (pfk) was used to produce
reference masses.
General Procedure for the Synthesis of 2E-Arylidene-
8-methyl-8-azabicyclo[3.2.1]-octan-3-ones (3)
LDA (5.5 mmol, 2.75 mL, 2.0 M solution in heptane/THF/ethylbenzene)
was added slowly via a syringe to a solution of tropinone (696 mg, 5.0 mmol)
in dry THF (10 mL) at 2788C under a nitrogen atmosphere. The resulting
solution was stirred for 2 hr at 2788C. The appropriate aryl aldehyde
(5.25 mmol) in THF (5 mL) was then added. The reaction mixture was con-
tinuously stirred at 2788C for 4 hr and then quenched by addition of saturated
aqueous NH4Cl (25 mL) and the reaction mixture was allowed to warm up to
ambient temperature. The organic layer was separated, and the aqueous layer
was extracted with ethylacetate (3 ꢀ 30 mL). The combined organic extracts

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Zheng, Dwoskin, and Crooks
were dried over anhydrous Na2SO4, filtered and evaporated to dryness under
reduced pressure to afford crude product 2. Without further purification, 2 was
.
used directly in the next step. pTsOH H2O (1.14 g, 6.0 mmol; for 2j,
2.2 equiv. of pTsOH were used) was added in portions to a solution of com-
pound 2 in toluene (40 mL) and the reaction mixture was either stirred at ambi-
ent temperature, heated at 658C with stirring, or refluxed under a nitrogen
atmosphere (see Table 1 for detail), then cooled to room temperature. The
toluene layer was discarded and the residual oil was washed with diethyl
ether to remove unreacted aryl aldehyde. The residual oil was then dissolved
in a mixture of saturated aqueous K2CO3 (30 mL) and CHCl3 (30 mL). The
organic layer was separated, and the aqueous layer was extracted with
CHCl3 (30 mL). The combined organic extracts were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue was
subjected to flash column silica gel chromatography, eluting with CH2Cl2/
MeOH (30 : 1) to afford compound 3 in high purity.
2E-Benzylidene-8-methyl-8-azabicyclo[3.2.1]-octan-3-one (3a). Com-
pound 3a was prepared in 84% yield as a brown oil. 1H NMR (CDCl3): d 7.53
(s, 1H, C55CH), 7.30–7.47 (m, 5H, PhH), 4.31 (d, J ¼ 6.9 Hz, 1H, CH-1),
3.54 (t, J ¼ 6.0 Hz, 1H, CH-4), 2.88 (ddd, J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5),
2.41 (s, 3H, N-CH3), 2.22–2.55 (m, 3H, CH-4, CH-6, and CH-7), 1.91
(m, 1H, CH-6), 1.73 (m, 1H, CH-7); 13C NMR (CDCl3): 199.43 (C55O),
139.69 (C-2), 134.88 (Ph-1-C), 134.30 (55CH), 130.22 (Ph-3-C and
Ph-5-C), 128.87 (Ph-4-C), 128.61 (Ph-2-C and Ph-6-C), 61.11 (C-1), 59.00
(C-5), 44.87 (C-4), 37.56 (N-CH3), 30.59 (C-6), 29.12 (C-7); GC:
tR ¼ 10.18 min, purity .99% (Only one peak was observed.); MS m/z (inten-
sity %): 226 (15), 199 (100), 185 (23), 171 (77), 156 (7), 141 (8), 128 (19), 115
(23), 94 (60), 82 (17), 42 (19); EI-HRMS: C15H17NO calcd. for 227.1305 (obs.
227.1314).
2E-(4-Methoxybenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3b). Compound 3b was prepared in 47% yield as a pale yellow solid. M.p.
1
79–808C; H NMR (CDCl3): 7.46 (s, 1H, C55CH), 7.31 (d, 2H, Ph-2-H and
Ph-6-H), 6.93 (d, 2H, Ph-3-H and Ph-5-H), 4.32 (d, J ¼ 6.6 Hz, 1H, CH-1),
3.84 (s, 3H, OCH3), 3.53 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.87 (ddd, J ¼ 18.6,
5.7, 1.8 Hz, 1H, CH-5), 2.42 (s, 3H, N-CH3), 2.24–2.56 (m, 3H, CH-4,
CH-6, and CH-7), 1.91 (m, 1H, CH-6), 1.74 (m, 1H, CH-7); 13C NMR
(CDCl3): 199.05 (C55O), 160.21 (Ph-4-C), 137.82 (C-2), 134.48 (55CH),
132.09, (Ph-2-C and Ph-6-C), 127.38 (Ph-1-C), 114.16 (Ph-3-C and Ph-5-
C), 61.21 (C-1), 58.87 (C-5), 55.53 (OCH3), 44.66 (C-4), 37.51 (N-CH3),
30.63 (C-6), 29.14 (C-7); GC: tR ¼ 11.36 min, purity .99% (Only one
peak was observed.); MS m/z: 256 (5), 242 (0.7), 214 (12), 229 (100), 201
(60), 186 (9), 170 (7), 145 (11), 128 (8), 115 (14), 94 (66), 82 (17), 42 (23);
EI-HRMS: C16H19NO2 calcd. for 257.1410 (obs. 257.1414).

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2-Arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones
1937
2E-(2-Methoxybenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
1
(3c). Compound 3c was prepared in 35% yield as a brown oil. H NMR
(CDCl3): 7.66 (s, 1H, C55CH), 7.34 (m, 1H, Ph-4-H), 7.14 (dd, J ¼ 7.5,
1.5 Hz, 1H, Ph-6-H), 6.96 (dt, J ¼ 0.6, 7.5 Hz, 1H, Ph-5-H), 6.91 (dd,
J ¼ 8.4, 0.9 Hz, 1H, Ph-3-H), 4.18 (d, J ¼ 6.9 Hz, 1H, CH-1), 3.83 (s, 3H,
OCH3), 3.53 (t, J ¼ 6.0 Hz, 1H, CH-4), 2.87 (ddd, J ¼ 18.6, 5.7, 1.8 Hz,
1H, CH-5), 2.41 (s, 3H, N-CH3), 2.20–2.48 (m, 3H, CH-4, CH-6, and CH-
7), 1.90 (m, 1H, CH-6), 1.71 (m, 1H, CH-7); 13C NMR (CDCl3): 199.54
(C55O), 158.42 (Ph-2-C), 139.29 (C-2), 130.50 (55CH), 130.45 (Ph-4-C),
130.39 (Ph-6-C), 123.95 (Ph-1-C), 120.08 (Ph-5-C), 110.80 (Ph-3-C), 61.21
(C-1), 58.96 (C-5), 55.58 (OCH3), 44.60 (C-4), 37.07 (N-CH3), 30.60 (C-6),
29.17 (C-7); GC: tR ¼ 10.96 min, purity .99% (Only one peak was
observed.); MS m/z: 256 (6), 242 (1), 229 (100), 214 (16), 201 (54), 186
(12), 170 (12), 145 (8), 131 (12), 115 (24), 94 (70), 82 (36), 42 (36); EI-
HRMS: C16H19NO2 calcd. for 257.1410 (obs. 257.1413).
2E-(2,4-Dimethoxybenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-
3-one (3d). Compound 3d was prepared in 25% yield as a semisolid. 1H NMR
(CDCl3): 7.68 (s, 1H, C55CH), 7.10 (d, J ¼ 8.4 Hz, 1H, Ph-6-H), 6.51 (dd,
J ¼ 8.4, 2.4 Hz, 1H, Ph-5-H), 6.46 (d, J ¼ 2.4 Hz, 1H, Ph-3-H), 4.21
(d, J ¼ 6.9 Hz, 1H, CH-1), 3.84 (s, 3H, 4-OCH3), 3.82 (s, 3H, 2-OCH3),
3.53 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.87 (ddd, J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5),
2.42 (s, 3H, N-CH3), 2.21–2.50 (m, 3H, CH-4, CH-6, and CH-7),
1.91 (m, 1H, CH-6), 1.71 (m, 1H, CH-7); 13C NMR (CDCl3): 199.27
(C55O), 161.96 (Ph-4-C), 160.05 (Ph-2-C), 137.53 (C-2), 131.48 (55CH),
130.62 (Ph-6-C), 116.91 (Ph-1-C), 104.40 (Ph-5-C), 98.56 (Ph-3-C), 61.36
(C-1), 58.89 (C-5), 55.70 (OCH3), 55.67 (OCH3), 44.39 (C-4), 37.01
(N-CH3), 30.80 (C-6), 29.29 (C-7); GC: tR ¼ 12.28 min, purity .99%
(Only one peak was observed.); MS m/z: 287 (2), 259 (100), 244 (9), 231
(54), 216 (13), 200 (14), 187 (7), 175 (6), 161 (6), 149 (6), 115 (14), 94 (71),
82 (19), 42 (24); EI-HRMS: C17H21NO3 calcd. for 287.1516 (obs. 287.1509).
2E-(4-Fluorobenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3e). Compound 3e was prepared in 85% yield as a pale yellow solid. M.p.
76–778C; 1H NMR (CDCl3): 7.46 (s, 1H, C55CH), 7.28–7.35 (m, 2H,
Ph-2-H, and Ph-6-H), 7.06–7.20 (m, 2H, Ph-3-H, and Ph-5-H), 4.25
(d, J ¼ 6.9 Hz, 1H, CH-1), 3.54 (t, J ¼ 6.0 Hz, 1H, CH-4), 2.87 (ddd,
J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5), 2.41 (s, 3H, N-CH3), 2.24–2.54 (m, 3H,
CH-4, CH-6, and CH-7), 1.89 (m, 1H, CH-6), 1.73 (m, 1H, CH-7); 13C
NMR (CDCl3): 199.15 (C55O), (164.49, 161.18) (C–F), 139.52 (C-2),
133.06 (55CH), (132.12, 132.00) (Ph-2-C and Ph-6-C), (131.00, 130.95)
(Ph-1-C), (115.95, 115.66) (Ph-3-C and Ph-5-C), 61.09 (C-1), 58.99 (C-5),
44.87 (C-4), 37.58 (N-CH3), 30.45 (C-6), 29.07 (C-7); GC: tR ¼ 10.19 min,
purity .99% (Only one peak was observed.); MS m/z: 244 (16), 230 (1),

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Zheng, Dwoskin, and Crooks
217 (100), 202 (21), 189 (82), 173 (5), 159 (7), 146 (18), 133 (29), 94 (88), 82
(34), 42 (41); EI-HRMS: C15H16FNO calcd. for 245.1210 (obs. 245.1220).
2E-(3-Fluorobenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
1
(3f). Compound 3f was prepared in 89% yield as a brown oil. H NMR
(CDCl3): 7.43 (s, 1H, C55CH), 7.37 (dt, J ¼ 6.0, 7.8 Hz, 1H, Ph-5-H), 7.09
(dd, J ¼ 7.8, 0.6 Hz, 1H, Ph-6-H), 6.99–7.07 (m, 2H, Ph-2-H and Ph-4-H),
4.26 (d, J ¼ 7.2 Hz, 1H, CH-1), 3.54 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.88 (ddd,
J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5), 2.42 (s, 3H, N-CH3), 2.24–2.54 (m, 3H,
CH-4, CH-6, and CH-7), 1.89 (m, 1H, CH-6), 1.73 (m, 1H, CH-7); 13C
NMR (CDCl3): 199.16 (C55O), (164.25, 160.99) (C–F), 140.69 (C-2),
(137.07, 136.97) (Ph-1-C), (132.62, 132.59) (55CH), (130.24, 130.12) (Ph-
5-C), (125.96, 125.93) (Ph-6-C), (116.85, 116.56) (Ph-4-C), (115.92,
115.65) (Ph-2-C), 61.12 (C-1), 59.07 (C-5), 44.99 (C-4), 37.64 (N-CH3),
30.39 (C-6), 29.04 (C-7); GC: tR ¼ 10.07 min, purity .99% (Only one
peak was observed.); MS m/z: 244 (16), 230 (1.4), 217 (100), 202 (28), 189
(86), 173 (6), 159 (8), 146 (21), 133 (26), 94 (89), 82 (34), 42 (40);
EI-HRMS: C15H16FNO calcd. for 245.1210 (obs. 245.1208).
2E-(4-Nitrobenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3g). Compound 3g was prepared in 69% yield as a pale yellow solid. M.p.
1
176–1788C; H NMR (CDCl3): 8.27 (d, J ¼ 8.7 Hz, 2H, Ph-2-H and Ph-
6-H), 7.47 (d, J ¼ 8.7 Hz, 2H, Ph-3-H and Ph-5-H), 7.46 (s, 1H, C55CH),
4.20 (d, J ¼ 7.2 Hz, 1H, CH-1), 3.57 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.90 (ddd,
J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5), 2.42 (s, 3H, N-CH3), 2.26–2.56 (m, 3H,
CH-4, CH-6, and CH-7), 1.90 (m, 1H, CH-6), 1.76 (m, 1H, CH-7); 13C
NMR (CDCl3): 198.90 (C55O), 147.47 (C-NO2), 142.58 (C-2), 141.49 (Ph-
1-C), 130.83 (55CH), 130.63 (Ph-2-C and Ph-6-C), 123.85 (Ph-3-C and
Ph-5-C), 61.18 (C-1), 59.15 (C-5), 45.18 (C-4), 37.75 (N-CH3), 30.20 (C-6),
28.94 (C-7); GC: tR ¼ 12.25 min, purity .99% (Only one peak was
observed.); MS m/z: 271 (29), 255 (3), 244 (74), 229 (33), 216 (100), 197
(8), 183 (9), 169 (17), 153 (9), 141 (11), 128 (12), 115 (19), 94 (84), 82
(43), 42 (53); EI-HRMS: C15H16N2O3 calcd. for 272.1155 (obs. 272.1159).
2E-(2-Naphthylmethylene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3h). Compound 3h was prepared in 57% yield as a pale yellow solid. M.p.
1
87–888C; H NMR (CDCl3): 7.82–7.88 (m, 3H, Np-4, 5 and 8-H), 7.79
(s, 1H, Np-1-H), 7.67 (s, 1H, C55CH), 7.48–7.54 (m, 2H, Np-4 and 5-H),
7.43 (dd, J ¼ 8.7, 1.8 Hz, 1H, Np-3-H), 4.40 (d, J ¼ 7.2 Hz, 1H, CH-1),
3.54 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.90 (ddd, J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5),
2.41 (s, 3H, N-CH3), 2.26–2.64 (m, 3H, CH-4, CH-6, and CH-7), 2.00
(m, 1H, CH-6), 1.75 (m, 1H, CH-7); 13C NMR (CDCl3): 199.27 (C55O),
139.87 (C-2), 134.37, 133.15, 133.05, 132.38, 130.09, 128.45, 128.20,
127.76, 127.32, 127.02, 126.64, 61.21 (C-1), 58.99 (C-5), 44.83 (C-4),
37.49 (N-CH3), 30.60 (C-6), 29.11 (C-7); GC: tR ¼ 13.24 min, purity

ORDER
REPRINTS
2-Arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones
1939
.99% (Only one peak was observed.); MS m/z: 277 (4), 262 (0.7), 249 (100),
234 (10), 221 (81), 205 (7), 192 (15), 178 (23), 165 (26), 152 (19), 139 (6), 115
(7), 94 (64), 82 (19), 42 (23); EI-HRMS: C19H19NO calcd. for 277.1461 (obs.
277.1463).
2E-(4-Phenylbenzylidene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3i). Compound 3i was prepared in 51% yield as a pale yellow solid. M.p.
101–1038C; 1H NMR (CDCl3): 7.59–7.67 (m, 4H, Ar-H), 7.56 (s, 1H,
C55CH), 7.36–7.50 (m, 5H, Ar-H), 4.37 (d, J ¼ 6.9 Hz, 1H, CH-1), 3.55
(t, J ¼ 6.3 Hz, 1H, CH-4), 2.90 (ddd, J ¼ 18.6, 5.7, 2.1 Hz, 1H, CH-5), 2.44
(s, 3H, N-CH3), 2.26–2.58 (m, 3H, CH-4, CH-6, and CH-7), 1.95 (m, 1H,
CH-6), 1.74 (m, 1H, CH-7); 13C NMR (CDCl3): 199.54 (C55O), 141.67
(C-2), 140.29, 139.62, 134.07 (55CH), 133.84, 130.85, 129.01, 127.87,
127.29, 127.17, 61.27 (C-1), 59.01 (C-5), 44.81 (C-4), 37.55 (N-CH3),
30.66 (C-6), 29.17 (C-7); GC: tR ¼ 15.75 min, purity .99% (Only one
peak was observed.); MS m/z: 302 (7), 275 (100), 260 (11), 247 (89), 215
(4), 202 (13), 189(13), 178 (14), 165 (13), 152 (13), 94 (75), 82 (20), 42
(26); EI-HRMS: C21H21NO calcd. for 303.1618 (obs. 303.1614).
2E-(3-Pyridylmethylene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
1
(3j). Compound 3j was prepared in 62% yield as a brown oil. H NMR
(CDCl3): 8.60 (s, 1H, Py-2-H), 8.59 (dd, J ¼ 5.1, 1.2 Hz, Py-6-H), 7.64 (dt,
J ¼ 7.8, 2.1 Hz, 1H, Py-4-H), 7.43 (s, 1H, 55CH), 7.36 (dd, J ¼ 7.8, 5.1 Hz,
1H, Py-5-H), 4.23 (d, J ¼ 6.9 Hz, 1H, CH-1), 3.55 (t, J ¼ 6.0 Hz, 1H,
CH-4), 2.88 (ddd, J ¼ 18.6, 5.7, 1.8 Hz, 1H, CH-5), 2.42 (s, 3H, N-CH3),
2.22–2.57 (m, 3H, CH-4, CH-6, and CH-7), 1.90 (m, 1H, CH-6), 1.74
(m, 1H, CH-7); 13C NMR (CDCl3): 198.84 (C55O), 150.56 (Py-2-C),
149.41 (Py-6-C), 141.54 (C-2), 137.00 (Py-4-C), 130.72 (Py-3-C), 129.83
(55CH), 123.43 (Py-5-C), 61.09 (C-1), 59.02 (C-5), 45.02 (C-4), 37.66 (N-
CH3), 30.28 (C-6), 28.89 (C-7); GC: tR ¼ 10.50 min, purity .99% (Only
one peak was observed.); MS m/z: 227 (20), 213 (2), 200 (100), 185 (27),
172 (91), 156 (11), 144 (12), 130 (18), 117 (11), 104 (7), 94 (87), 82 (38),
42 (40); EI-HRMS: C14H16N2O calcd. for 228.1255 (obs. 227.1259).
2E-(2-Furylmethylene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
(3k). Compound 3k was prepared in 33% yield as a pale yellow solid. M.p.
73–748C; 1H NMR (CDCl3): 7.57 (d, J ¼ 1.8 Hz, 1H, furan-5-H), 7.21 (s, 1H,
C55CH), 6.65 (d, J ¼ 3.3 Hz, 1H, furan-3-H), 6.50 (dd, J ¼ 3.3, 1.8 Hz,
1H, thiophene-4-H), 4.77 (d, J ¼ 6.6 Hz, 1H, CH-1), 3.53 (t, J ¼ 6.0 Hz,
1H, CH-4), 2.87 (ddd, J ¼ 18.9, 5.7, 1.8 Hz, 1H, CH-5), 2.48 (s, 3H,
N-CH3), 2.23–2.52 (m, 3H, CH-4, CH-6, and CH-7), 1.78 (m, 1H, CH-6),
1.66 (m, 1H, CH-7); 13C NMR (CDCl3): 198.67 (C55O), 151.63 (furan-2-
C), 145.10 (furan-5-C), 136.27 (C-2), 120.52 (55CH), 117.47 (furan-4-C),
112.43 (furan-3-C), 61.67 (C-1), 58.83 (C-5), 44.74 (C-4), 37.83 (N-CH3),
30.60 (C-6), 29.07 (C-7); GC: tR ¼ 9.66 min, purity .99% (Only one peak

ORDER
REPRINTS
1940
Zheng, Dwoskin, and Crooks
was observed.); MS m/z: 217 (3), 202 (0.4), 189 (100), 174 (11), 161 (96), 148
(14), 132 (39), 94 (18), 82 (16), 42 (26); EI-HRMS: C13H15NO2 calcd. for
217.1097 (obs. 217.1095).
2E-(2-Thienylmethylene)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one
1
(3l). Compound 3l was prepared in 60% yield as a brown oil. H NMR
(CDCl3): 7.66 (d, J ¼ 0.6 Hz, 1H, C55CH), 7.51 (dt, J ¼ 4.8, 0.9 Hz, 1H, thio-
phene-3-H), 7.28 (dt, J ¼ 3.9, 0.9 Hz, 1H, thiophene-5-H), 7.11 (dd, J ¼ 4.8,
3.9 Hz, 1H, thiophene-4-H), 4.55 (d, J ¼ 6.6 Hz, 1H, CH-1), 3.53
(t, J ¼ 6.6 Hz, 1H, CH-4), 2.88 (ddd, J ¼ 18.9, 5.7, 1.5 Hz, 1H, CH-5), 2.47
(s, 3H, N-CH3), 2.25–2.55 (m, 3H, CH-4, CH-6, and CH-7), 1.79 (m, 1H,
CH-6), 1.66 (m, 1H, CH-7); 13C NMR (CDCl3): 198.26 (C55O), 137.74 (C-
2), 136.65 (thiophene-2-C), 133.43 (55CH), 130.10 (thiophene-5-C), 127.86
(thiophene-4-C), 127.02 (thiophene-3-C), 61.68 (C-1), 58.63 (C-5), 44.52
(C-4), 37.77 (N-CH3), 30.20 (C-6), 29.08 (C-7); GC: tR ¼ 10.44 min, purity
.99% (Only one peak was observed.); MS m/z: 233 (3), 218 (0.5), 205
(100), 190 (12), 177 (86), 162 (6), 150 (9), 134 (10), 121 (14), 108 (8), 94
(47), 82 (23), 42 (35); EI-HRMS: C13H15NOS calcd. for 233.0869 (obs.
233.0878).
2E-(N-Methylpyrrole-2-methylene)-8-methyl-8-azabicyclo[3.2.1]-octan-
3-one (3m). Compound 3m was prepared in 27% yield as a dark brown oil. 1H
NMR (CDCl3): 7.48 (s, 1H, C55CH), 6.83 (dd, J ¼ 2.4, 1.5 Hz, 1H, pyrrole-
5-H), 6.43 (dd, J ¼ 4.2, 1.2 Hz, 1H, pyrrole-3-H), 6.24 (dd, J ¼ 3.9, 2.7 Hz,
1H, pyrrole-4-H), 4.37 (d, J ¼ 6.6 Hz, 1H, CH-1), 3.70 (s, 3H, pyrrole-N-
CH3), 3.52 (t, J ¼ 6.3 Hz, 1H, CH-4), 2.87 (ddd, J ¼ 18.9, 5.7, 1.5 Hz, 1H,
CH-5), 2.44 (s, 3H, N-CH3), 2.21–2.50 (m, 3H, CH-4, CH-6, and CH-7),
1.81 (m, 1H, CH-6), 1.66 (m, 1H, CH-7); 13C NMR (CDCl3): 197.72
(C55O), 134.41 (C-2), 128.23 (pyrrole-2-C), 126.91 (55CH), 122.02 (pyr-
role-5-C), 114.83 (pyrrole-4-C), 109.35 (pyrrole-3-C), 61.61 (C-1), 58.64
(C-5), 44.40 (C-4), 37.74 (N-CH3), 34.58 (pyrrole-N-CH3), 30.04 (C-6),
28.94 (C-7); GC: tR ¼ 10.56 min, purity .99% (Only one peak was
observed.); MS m/z: 230 (6), 215 (0.4), 202 (100), 187 (4), 173 (88), 159
(10), 144 (8), 130 (10), 118 (17), 104 (7), 94 (23), 82 (9), 42 (21); EI-HRMS:
C14H18N2O calcd. for 230.1414 (obs. 230.1423).
2E-(3-Pyridylmethylene)-4E-benzylidene-8-methyl-8-azabicyclo[3.2.1]-
octan-3-one (5). A mixture of 2a (491 mg, 2.0 mmol) (recrystallized from
EtOAc/hexanes to remove unreacted benzaldehyde), pyridine-3-carboxalde-
hyde (257 mg, 2.4 mmol) and NaOH (40 mg, 1 mmol) in 2 mL MeOH was stir-
red for 4 hr at room temperature. The filtered solid was recrystallized from
1
EtOH to afford 5 as a yellow solid in 60% yield. M.p. 152–1538C; H
NMR (CDCl3): 8.67 (dd, J ¼ 1.8 Hz, 1H, Py-2-H), 8.60 (dd, J ¼ 5.1,
1.5 Hz, 1H, Py-6-H), 7.85 (s, 1H, C55CH), 7.76 (s, 1H, C55CH), 7.69 (dt,
J ¼ 7.8, 1.8 Hz, 1H, Py-4-H), 7.35–7.50 (m, 6H, PhH, Py-5-H), 4.41

ORDER
REPRINTS
2-Arylmethylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-ones
1941
(d, J ¼ 6.3 Hz, 1H, CH-1), 4.33 (d, J ¼ 6.0 Hz, 1H, CH-5), 2.53–2.70 (m, 2H,
CH-6, CH-7), 2.32 (s, 3H, N-CH3), 1.95–2.10 (m, 2H, CH-6, CH-7); 13C
NMR (CDCl3): 199.43 (C55O), 150.82, 149.50, 140.54, 138.18, 137.09,
134.98, 132.23, 131.09, 130.39, 129.12, 128.68, 123.50, 61.15 (C-1), 61.12
(C-5), 36.23 (N-CH3), 30.50 (C-6), 30.38 (C-7); GC: tR ¼ 16.69 min, purity
.99% (Only one peak was observed.); MS m/z: 316 (13), 288 (100), 273
(3), 260 (33), 244 (4), 230 (3), 217 (5), 183 (15), 168 (5), 136 (7), 115 (10),
89 (6), 82 (7), 42 (13); EI-HRMS: C21H20N2O calcd. for 316.1570 (obs.
316.1565).
ACKNOWLEDGMENTS
This research was supported by National Institute of Health grants
DA13519 and DA00399. High resolution mass spectral determinations were
carried out at the University of Kentucky Mass Spectrometry Facility.
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Received in the USA Janurary 3, 2004

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