A concise route to novel 1-aryl and 1-pyridyl-2-azabicyclo[2.1.1]hexanes

Article abstract of DOI:10.1055/s-1999-2775

A number of novel 1-aryl and 1-pyridyl-2-azabicyclo[2.1.1]hexane derivatives were prepared by an intramolecular [2+2] photocycloaddition in the presence of acetophenone as the sensitizer. Substitution of the azabicyclo[2.1.1]hexane ring was accomplished by appropriate choice of the heteroaryl ketone and allylamine starting materials. Several aryl 9a-e, g and pyridyl analogs 9h-l were prepared by this method. The structures of 9a and 9i were verified by X-ray crystallography. Several of the photoproducts 9 were converted into the corresponding N-Me and N-H 2,4-methanonicotine analogs 4 by reduction or hydrolysis of the N-carboethoxy group.

Full text of DOI:10.1055/s-1999-2775

LETTER
1091
A Concise Route to Novel 1-Aryl and 1-Pyridyl-2-Azabicyclo[2.1.1]hexanes
David W. Piotrowski
E. I. du Pont de Nemours and Company, Agricultural Products, Stine-Haskell Research Center, P.O. Box 30, Elkton Road, Newark,
DE 19714, USA
Fax +1 (302) 451 0867; E-mail: david.w.piotrowski@usa.dupont.com
Received 3 November 1998
Abstract: A number of novel 1-aryl and 1-pyridyl-2-azabicyc-
lo[2.1.1]hexane derivatives were prepared by an intramolecular
[2+2] photocycloaddition in the presence of acetophenone as the
sensitizer. Substitution of the azabicyclo[2.1.1]hexane ring was ac-
complished by appropriate choice of the heteroaryl ketone and allyl-
amine starting materials. Several aryl 9a-e, g and pyridyl analogs
9h-l were prepared by this method. The structures of 9a and 9i were
verified by X-ray crystallography. Several of the photoproducts 9
were converted into the corresponding N-Me and N-H 2,4-metha-
nonicotine analogs 4 by reduction or hydrolysis of the N-carboeth-
oxy group.
Key words: intramolecular, [2+2], photocycloaddition, ene-car-
bamate, azabicyclohexane
Figure 1
A common strategy often utilized to find more potent,
more selective and less toxic biologically active mole-
cules relies on the synthesis of ring constrained analogs.
These conformationally restricted analogs, where the key
pharmacophoric elements are held rigidly with respect to
each other, often provide information about important
ligand-receptor interactions. The natural products nico-
tine (1) and epibatidine (2) display potent biological activ-
ity in mammals and invertebrate pests by modulation of
the nicotinic acetylcholine receptor (nAChR).1 However,
1 and 2 are highly toxic and lack receptor selectivity. For
these reasons, it was of interest to investigate a novel class
of rigid nicotine analogs based on the 2-azabicyclohexane
ring system. A key method for construction of bicy-
clo[2.1.1]hexanes utilizes an intramolecular photochemi-
Scheme 1
cal [2+2] cycloaddition.2,3 The work of Hammond and Liu
demonstrated that photocycloaddition of 1,5-hexadienes
in the presence of a sensitizer leads to exclusive formation
of bicyclo[2.1.1]hexanes.4 This methodology was exploit-
as benzene or ether was added to enhance the solubility of
ed by Clardy5a,b and Pirrung5c for the synthesis of 2,4-
the ketone. The imines 7 could be purified by distillation
methanoproline (3) and Liu in the synthesis of 1-phenyl-
under reduced pressure, however, the crude imines were
bicyclo[2.1.1]hexane.4c It was recognized that an exten-
sufficiently pure for further use. The E/Z configuration of
sion of the Clardy/Pirrung/Liu methodology would not
imines 7 ranged from 97:3-95:5 (R = H) to 93:7-78:22
only provide a concise entry into 1-heteroaryl-2-azabicy-
(R = Me), with purities of > 95% as determined by NMR
clohexanes 4 but also allow for the exploration of substi-
spectroscopy. Yields of 7 ranged from 77-97%.
tuted azabicyclic analogs by the appropriate choice of the
starting materials.6,7
A number of methods are known for conversion of imines
7 into ene-amides or ene-carbamates 8 by treatment with
acyl chlorides, chloroformates or anhydrides, usually in
the presence of a base.9 The carbamate moiety appeared
attractive since it could be cleaved to give a secondary
amine or it could be reduced with LiAlH4 to provide an N-
methylated product. A survey of carbamoylating reagents
(EtO2CCl, (tBOC)2O, (EtO2C)2O), solvents (1,2-dichloro-
The target azabicyclohexanes 4 were prepared in a few
steps starting from a substituted acetophenone or a het-
eroaryl ketone 5. The ketones 5 were prepared by addition
of a Grignard reagent to the Weinreb amide 6. The imines
7 were prepared by combination of a ketone 5 with 1.5
equivalents of allylamine in cyclohexane in the presence
of 3 Å molecular sieves.8 In some cases a co-solvent such
Synlett 1999, No. 07, 1091–1093 ISSN 0936-5214 © Thieme Stuttgart · New York

1092
D. W. Piotrowski
LETTER
ethane, toluene, cyclohexane) and conditions (0 °C - re-
flux, presence of base) revealed that the preferred reaction
conditions consisted of heating a toluene solution of imine
7 with a slight excess of diethyl pyrocarbonate under re-
flux for 24-48 hours until judged complete (TLC/NMR).
Yields ranged from 90-100%. Several of the ene-carba-
mates 8 were found to be somewhat unstable to silica gel
chromatography. The crude ene-carbamates 8a-f were
sufficiently pure (90-95%, NMR) to be used directly in
the photolysis step. In contrast, ene-amide 8g was pre-
pared in 94% yield by reaction of a toluene solution of
imine 7 with acetyl chloride in the presence of N,N-
diethylaniline9c and purified by silica gel chromatography
without incident.
Table 1 Photochemical [2+2] Cycloaddition of 8
All of the photocycloaddition reactions were carried out
on preparative scale (0.010-0.038mol). Typically, solu-
tions of the ene-carbamates 8 in benzene were subjected
to photolysis with a 450W Hanovia lamp in the presence
of acetophenone as the photosensitizer.10 The initial in-
vestigation was conducted on 8a resulting in a 52% yield
1
of the cycloaddition product 9a (Table 1).11 The H and
13C NMR data for 9a was consistent for the 2-azabicyc-
lo[2.1.1]hexane ring system. The structure of 9a was also
verified by X-ray crystallography. Several other aryl ana-
logs 9b-e were prepared under similar conditions in isolat-
ed, purified yields of 50-66%. However, hindered ene-
carbamate 8f was resistant to photocycloaddition under
these conditions returning only unreacted starting materi-
al. One example of a photocycloaddition with an ene-
amide was performed. Ene-amide 8g was subjected to
photolysis under the described conditions only to provide
a significant amount of polymeric material. In contrast,
photolysis in acetone provided 9g in 63% yield.
The synthesis of the 1-pyridyl-2-azabicyclohexanes 9
proved to be somewhat more difficult. In general, the py-
ridyl ene-carbamates 8h-l usually required some purifica-
tion. Chromatography of 8h, 8k, and 8l on silica gel
provided the ene-carbamates in 21-80% yield but also led
to recovery of a significant amount of the corresponding
ketone 5. The pyridyl analogs 9h, 9k and 9l were prepared
from purified ene-carbamates in 32-68% yield. However,
6-chloropyridyl analogs 9i and 9j, containing substitution
on the azabicyclohexane moiety, were prepared from
crude ene-carbamates.12 For these compounds the reac-
tion products were also accompanied by significant
amounts of polymeric material that had to be periodically
removed from the outside of the immersion well during
the course of the reaction. These factors partially account
for the lower yields of 9i and 9j (Table 1).
b
aunoptimized: chromatographically homogenous material. based on
c
crude starting ene-carbamate. based on purified starting ene-amide;
reaction was conducted in acetone. dbased on purified enecarbamate.
ebased on crude-starting ene-carbamate. fpurified ene-carbamate con-
tained 3-acetylpyridine.
The 2,4-methanonicotine analogs 4a,b,e,f were prepared
by reduction of the 2-azabicyclohexanes 9a,b,e,f with
LiAlH4 in THF.13 Alternatively, the carbamate moiety of
9a,e could be cleaved with aqueous base in methanol to
give the secondary amines 4c,d (Scheme 2). In general,
the 2,4-methanonicotines 4 were obtained and character-
ized as oils after purification by chromatography. They
could also be converted into stable, crystalline borane
complexes by treatment with borane in THF at 0 °C.14
Scheme 2
Synlett 1999, No. 07, 1091–1093 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Concise Route to Novel 1-Aryl and 1-Pyridyl-2-Azabicyclo[2.1.1]hexanes
1093
which was prepared from 2,4-methanoproline. See: Davies, J.
W.; Malpass, J. R.; Walker, M. P. J. Chem. Soc. Chem.
Commun. 1985, 686.
Analysis of the crystal structure data from compounds 9a,
9i and 4c (borane complex), as well as measurement of in-
ter-nitrogen distance in molecular models of 4b,15 suggest
that the azabicyclohexanes 4 fulfill the classical pharma-
cophore models for nicotinic agonists.16,17
(7) For the synthesis of 2-azabicyclohexanes via enone-alkene
photocycloaddition, see: (a) Tamura, Y.; Ishibashi, H.; Hirai,
M.; Kita, Y.; Ikeda, M. J. Org. Chem. 1975, 40, 2702. (b)
Schell, F. M.; Cook, P. M.; Hawkinson, S. W.; Cassady, R. E.;
Thiessen, W. E. J. Org. Chem. 1979, 44, 1380. (c) Swindell,
C. S.; Patel, B.; deSolms, S. J.; Springer, J. P. J. Org. Chem.
1987, 52, 2346.
Table 2 2,4-Methanonicotine analogs 4
(8) Govindan, C. K.; Taylor, G. J. Org. Chem. 1983, 48, 5348.
(9) (a) Lenz, G. R. Synthesis 1978, 489. (b) Lessor, R. A.; Ezell,
E. F. J. Org. Chem. 1990, 55, 1753. (c) Davies, D. T.; Goodall,
K.; Kapur, N.; O’Brien, M.; Parsons, A. F. Synth. Commun.
1997, 27, 3815.
(10) Typical procedure for 9a: A solution of crude imine 7a (6.4
g, 33.0 mmol) and diethyl pyrocarbonate (7.3 mL, 49.5 mmol)
in about 80 mL toluene was heated under reflux. After 24 h,
additional diethyl pyrocarbonate (2.0 mL, 13.6 mmol) was
added and the mixture was heated under reflux for an
additional 12 h. The solvent was removed in vacuo. The
residue was dissolved in toluene and concentrated (twice) to
provide the crude ene-carbamate 8a. A portion of the crude
ene-carbamate (6.0 g, 22.6 mmol) was dissolved in 300 mL
benzene (spectrophotometric grade) containing acetophenone
(0.6 mL, 2% v/v) and degassed with nitrogen for at least 30
minutes. Irradiation was performed at room temperature with
a medium pressure 450 W Hanovia Hg lamp in a water-cooled
Pyrex immersion apparatus. After 48 h, the solvent was
removed in vacuo and the residue was purified by
In summary, a concise synthesis of 1-aryl and 1-pyridyl-
2-azabicyclo[2.1.1]hexanes using a photosensitized [2+2]
cycloaddition was demonstrated on preparative scale. The
substitution on the azabicyclic ring was varied by proper
choice of the ketone and allylamine starting materials.
The carbamates 9 were converted into novel 2,4-metha-
nonicotine analogs 4.
chromatography on silica gel with 20% ethyl acetate/hexane
as eluent to afford 3.1 g (52%) of 9a as a white solid. mp 75.5-
77 °C (ether/hexanes); 1H NMR (300 MHz): d=7.29 (d, 2H,
J = 8.5, aryl), 7.21 (d, 2H, J = 8.5, aryl), 3.90 (q, 2H, J = 7.2,
CH2O), 3.60 (s, 2H, CH2N), 2.88-2.84 (m, 1H, CHbridgehead),
2.09-2.04 (m, 2H, 2 x CH), 1.92 (dd, 2H, J = 4.5, 1.8, 2 x CH),
0.97 (t, 3H, J = 7.2, CH3); 13C NMR (75.4 MHz): d=157.02
(C = O), 137.51, 132.80, 127.82 and 127.78 (CH aryl), 73.26
(1-C), 60.32 (CH2O), 52.67 (CH2N), 43.75 (CH2), 34.33
(HCbridgehead), 14.09 (CH3); MS (APCI+) 268.0 (MH+, 37Cl,
40); 266.0 (MH+, 35Cl, 100); IR: u=1687.4 cm–1 (C = O);
Anal. Calcd for C14H16ClNO2 (265.74): C, 63.28; H, 6.07; N,
5.27. Found: C, 63.29, H, 6.03, N, 5.14.
Acknowledgement
DuPont Agricultural Products. Thomas Stevenson and Thomas
Selby for helpful advice. James Rauh and Daniel Cordova for
biological evaluation of 4b. DuPont Ag Analytical Services for
NMR and MS results. Joseph Calabrese and Will Marshall for
X-ray crystallographic structure determinations of 9a, 9i and 4c.
(11) Significant improvement in isolated yield of 9a (87%) was
obtained when distilled ene-carbamate 8a was used.
(12) The estimated purity of ene-carbamates 8i and 8j was only
78% and 70%, respectively, by NMR spectroscopy.
(13) (a) Yang, N. C.; Lenz, G. R.; Shani, A. Tetrahedron Lett.
1966, 2941. (b) Cava, M. P. Mitchell, M. J.; DeJongh, D. C.;
Van Fossen, R. Y. Tetrahedron Lett. 1966, 2947.
(14) Stotter, P. L.; Friedman, M. D.; Dorsey, G. O.; Shiely, R. W.;
Williams, R. F.; Minter, D. E. Heterocycles 1987, 25, 251.
(15) Inter-nitrogen distance for compound 4b ranges from 4.32-
4.99 Å based on rotation of the bond connecting the pyridine
to the azabicyclic ring.
(16) (a) Beers, W. H.; Reich, E. Nature 1970, 228, 917. (b)
Sheridan, R. P.; Nilakantan, R.; Dixon, J. S. Venkataraghavan,
R. J. Med. Chem. 1986, 29, 899.
(17) Compound 4b was shown to activate acetylcholine receptors
in embryonic cockroach neuronal cells. This response to
application of 4b was blocked by the nAChR antagonist
mecamylamine. Thus, 4b appears to be a nAChR agonist.
References and Notes
(1) (a) Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem.
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(2) (a) Crimmins, M. T. Chem. Rev. 1988, 88, 1453. (b)
Crimmins, M. T. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter
2.3.
(3) For a new entry into the 2-azabicyclo[2.1.1]hexanes, see:
Stevens, C.; De Kimpe, N. J. Org. Chem. 1996, 61, 2174.
(4) (a) Liu, R. S. H.; Hammond, G. S. J. Am. Chem. Soc. 1964, 86,
1892. (b) Liu, R. S. H.; Hammond, G. S. J. Am. Chem. Soc.
1967, 89, 4936. (c) Yamada, C.; Pahk, M. J.; Liu, R. S. H. J.
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(5) (a) Hughes, P.; Clardy, J. J. Org. Chem. 1988, 53, 4793. (b)
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(6) The only other 1-substituted-2-azabicyclo[2.1.1]hexane that
has been reported is 1-methyl-2-azabicyclo[2.1.1]hexane,
Article Identifier:
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Synlett 1999, No. 07, 1091–1093 ISSN 0936-5214 © Thieme Stuttgart · New York