A novel synthesis of 2-azabicyclo[2.1.1]hexane from pyridine

Full text of DOI:10.1021/jo9808472

8558
J . Org. Chem. 1998, 63, 8558-8560
Sch em e 1
A Novel Syn th esis of
2-Aza bicyclo[2.1.1]h exa n e fr om P yr id in e
Grant R. Krow,* Yoon B. Lee, Walden S. Lester,
Hermona Christian, Donald A. Shaw, and J ing Yuan
Department of Chemistry, Temple University,
Philadelphia, Pennsylvania 19122
Received May 5, 1998
The reported synthesis of the parent 2-azabicyclo[2.1.1]-
hexane ring system 1, unsubstituted on the ring carbons,
is based upon the final ring closure of 1-(N-alkylamino)-
3-(chloromethyl)cyclobutanes 2 and requires 10 overall
synthetic steps.1 We desired a more convenient route,
which might offer further synthetic opportunities, to
prepare this small strained heterocyclic ring system.
Although other approaches to substituted 2-azabicyclo-
[2.1.1]hexane ring systems have been described, they are
not readily amenable to synthesis of the parent ring.2,3
Here, we report a new approach, which is convenient for
the preparation of useful quantities of the 2-azabicyclo-
[2.1.1]hexane ring system 1. The new method is based
upon previous observations that N-(alkoxycarbonyl)-2-
azabicyclo[2.2.n]alk-5-enes 3 (n ) 1, 2) undergo rear-
rangement to dibromides 4 upon addition of bromine to
the double bond.4,5
at -5 °C in dichloromethane afforded dibromide mixtures
in 61-78% isolated yield. The isomer ratio of unrear-
ranged dibromide 6a and rearranged dibromide 7a
obtained on gram-scale runs was 55:45 as determined by
1
comparison of the integrated H NMR resonance for H4
at δ 3.38 of dibromide 6a with that for H4 of dibromide
7a at δ 3.17. The ratio of isomers is kinetically deter-
mined, since the purified dibromides were stable at 25
°C in CDCl3.
The structure of the unrearranged dibromide 6a was
1
assigned on the basis of coupling patterns in the H NMR
spectrum. The absence of coupling between H-1 at δ 4.65
and H-6 at δ 4.55 is consistent with an endo orientation
for H-6 based upon the near 90° dihedral angle relation-
ship for H-1 and H-6. The couplings of H-5 at δ 4.91 with
H-6 (J ) 5.1 Hz) and with H-4 at δ 3.38 (J ) 7.8 Hz) are
consistent with a trans relationship for H-5 and H-6 and
a cis relationship for H-5 and H-4. The structure of the
rearranged dibromide 7a was also assigned by 1H NMR.
Protons H-1 at δ 4.56 and H-4 at δ 3.17 show four-bond
coupling (J ) 6.9 Hz). The equivalent H-3 protons
appear as a singlet at δ 3.56, and the equivalent H-5 and
H-6 protons appear as a singlet at δ 4.05; the absence of
vicinal coupling between H-1/H-4 and their adjacent
protons H-5/H-6 suggests dihedral angles close to 90°,
which is consistent with an arrangement for the two
bromine atoms in 7a anti to the nitrogen bridge. The
13C NMR spectrum of rearranged dibromide 7a showed
four lines for the five-ring carbon atoms and is consistent
with the molecular symmetry in which C-5 and C-6 are
equivalent. The desired 2-azabicyclo[2.1.1]hexane 8a
was synthesized uneventfully in 89% yield from rear-
ranged dibromide 7a by tributyltin hydride removal of
the bromine atoms.
The key synthetic intermediate, N-(ethoxycarbonyl)-
2-azabicyclo[2.2.0]hex-5-ene (5), has been synthesized
readily in multigram quantities in two steps from pyri-
dine.6 As shown in Scheme 1, bromination of alkene 5
(1) Stevens, C.; De Kimpe, N. J . Org. Chem. 1996, 61, 2174-2178.
(2) For syntheses of 1-substituted 2-azabicyclo[2.1.1]hexanes from
substituted cyclobutylamines, see: (a) Gaoni, Y. Org. Prop. Proced. Int.
1995, 27, 185. For photochemical ring closure of N-vinyl-N-allylamines
to give 1-substituted and 1,5-bridged 2-azabicyclo[2.1.1]hexanes, see:
(b) Hughes, P.; Clardy, J . J . Org. Chem. 1988, 53, 4793. (c) Hughes,
P.; Martin, M.; Clardy, J . Tetrahedron Lett. 1980, 21, 4579. (d) Pirrung,
M. C. Tetrahedron Lett. 1980, 21, 4577. (e) Tamura, Y.; Ishibashi, H.;
Hirai, M.; Kita, Y.; Ikeda, M. J . Org. Chem. 1975, 40, 2702.
(3) For synthesis of 1,4-dimethyl-2-aza-3-oxobicyclo[2.1.1]hexane,
see: Paquette, L. A.; Allen, G. R., J r.; Broadhurst. M. J . J . Am. Chem.
Soc. 1971, 93, 4503.
As shown in Scheme 2, addition of bromine to cycload-
duct 5 should be favored on the open exo face to afford
bromonium ion 9. The bridged ion 9 can be trapped by
regioselective attack of bromide ion from the C-5 endo
face remote from the N-ethoxycarbonyl substituent to
give unrearranged dibromide 6a . Competitively, par-
ticipation by nitrogen can lead to the formation of
aziridinium ion 10.7 Regioselective attack of bromide ion
on intermediate 10, at the C-1 position farthest from the
bromine at C-5, gives the rearranged dibromide 7a . No
other stereoisomeric dibromides, which might have been
formed by the alternative attack of bromide ion at C-6 of
(4) Raasch, M. S. J . Org. Chem. 1975, 40, 161.
(5) Krow, G. R.; Shaw, D. A.; J ovais, C. S.; Ramjit, H. G. Synth.
Commun. 1983, 575. (b) Krow, G. R.; Lee, Y. B.; Raghavachari, R.;
Szczepanski, S. W.; Alston, P. V. Tetrahedron 1991, 47, 8499. (c) Krow,
G. R.; Raghavachari, R.; Shaw, D. A.; Zacharias, D. E. Trends
Heterocycl. Chem. 1990, 1, 1.
(6) (a) Fowler, F. W. J . Org. Chem. 1972, 37, 1321. (b) Beecken, P.;
Bonfiglio, J . N.; Hasan, I.; Piwinski, J . J .; Weinstein, B.; Zollo, K. A.;
Fowler, F. W. J . Am. Chem. Soc. 1979, 101, 6677.
10.1021/jo9808472 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/28/1998

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8559
hexane/ether): 1H NMR δ 1.26 (3H, t, J ) 7.2 Hz), 3.38 (1H,
dddd, J ) 7.8, 7.2, 4.2, 2.7 Hz), 4.16 (2H, q, J ) 7.2 Hz), 4.28
(1H, dd, J ) 9.3, 7.2 Hz), 4.47 (1H, dd, J ) 9.3, 2.7 Hz), 4.55
(1H, d, J ) 5.1 Hz), 4.65 (1H, d, 4.2 Hz), 4.91 (1H, dd, J ) 7.8,
5.1 Hz); 13C NMR δ 14.5, 35.8, 51.3, 51.8, 52.1, 61.6, 67.6, 154.9;
HRMS m/z 311.9234, 313.9202, 315.9197, calcd for C8H1279/79,
79/81, 81/81Br2NO2, 311.9235, 313.9214, 315.9194. Dibromide
6a remained unchanged after 18 h at 70 °C. There also was
obtained 76 mg (39%) of rearranged dibromide 7a (Rf ) 0.23,
3:1 hexane/ether): 1H NMR δ 1.26 (3H, t, J ) 7.2 Hz), 3.17 (1H,
d, J ) 6.9 Hz), 3.56 (2H, s), 4.05 (2H, s), 4.15 (2H, q, J ) 7.2
Hz), 4.56 (1H, d, J ) 6.9 Hz); 13C NMR δ 14.6, 50.1, 50.7, 51.0,
61.9, 66.1, 154.9; HRMS m/z 311.9233, 313.9199, 315.9166, calcd
for C8H1279/79, 79/81, 81/81Br2NO2, 311.9234, 313.9214, 315.9193.
The roughly 5:4 ratio of dibromides 6a :7a was found to vary from
1:2 to 5:4, although all scale-up attempts have been near 55:45.
To facilitate scale-up, an alternative workup procedure, which
involves elimination of HBr from unrearranged dibromide 6a
and the possibility of thermal decomposition of the elimination
product formed,5 was developed for the isolation of dibromide
7a . A solution of bromine (2.09 g, 13 mmol) in CH2Cl2 (25 mL)
was added dropwise over 40 min to a cold (-5 °C) solution of
N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-ene (5)6 (2.0 g, 13
mmol) in CH2Cl2 (80 mL) under argon. Reaction and workup
as above provided 3.56 g of an oil that was dissolved in
diazabicycloundecane (DBU) (8 mL) and stirred at 65-70 °C for
4 h under argon. Water (25 mL) was added, and the solution
was extracted with ether (4 × 25 mL); the extract was dried
over sodium sulfate and filtered, and solvent was removed in
vacuo to provide after column chromatography 1.05 g (26%) of
rearranged dibromide 7a . After 30 d in CDCl3 at 25 °C,
dibromide 7a remained unchanged.
Sch em e 2
bromonium ion intermediate 9 or C-6 of aziridinium ion
10, were observed.
The rearrangement method has been extended to allow
the formation of the first 5-hydroxy-2-azabicyclo[2.1.1]-
hexane 8b (Scheme 1). The photocycloadduct 5 was
reacted with HOBr to afford in 70-80% yield a 7:3
mixture of unrearranged bromohydrin 6b and rearranged
bromohydrin 7b. The integrated intensity for H-5 of the
unrearranged bromohydrin 6b and the combined inte-
gration for the carbamate methyl groups were used to
calculate the isomer ratio. Tributyltin hydride removal
of the bromine atom from bromohydrin 7b afforded
N -(et h oxyca r bon yl)-5-a n t i-h yd r oxy-2-a za bicyclo-
[2.1.1]hexane (8b) in 63% yield. The herein described
rearrangement-reduction protocol using N-(alkoxycar-
bonyl)-1,2-dihydropyridine photocycloadduct 5 is short
and amenable to scale-up, and has the potential to
provide numerous functionalized derivatives of the novel
2-azabicyclo[2.1.1]hexane ring system.8
P r ep a r a tion of N-(Eth oxyca r bon yl)-2-a za bicyclo[2.1.1]-
h exa n e (8a ). The dibromide 7a (176 mg, 0.56 mmol) and 2,2′-
azobis(2-methylpropionitrile) (AIBN) were dissolved in benzene
(10 mL), tributyltin hydride (454 µL, 491 mg, 1.69 mmol) was
added, and the resulting solution was heated to 80 °C for 2 h.
The reaction mixture was cooled to room temperature, and the
benzene was removed in vacuo to give a residue that upon
chromatography (10:1 hexane/ether) gave 77 mg (89%) of
compound 8a (Rf ) 0.6, 1:1 hexane/ether): 1H NMR δ 1.23 (3H,
t, J ) 7.2 Hz), 1.34 (2H, dd, J ) 4.8, 1.8 Hz), 1.87, 2H, m), 2.80
Exp er im en ta l Section
(1H, m), 3.30 (2H, s), 4.11 (2H, q, J ) 7.2 Hz), 4.36 (1H, br); 13
C
N-(Ethoxycarbonyl)-2-azabicyclo[2.2.0]oct-5-ene (5) was pre-
pared according to the literature procedure for the N-(methoxy-
carbonyl) analogue.6a 1H NMR spectra were recorded at 300
MHz, and 13C NMR spectra were recorded at 75 MHz in CDCl3
solvent. High-resolution mass spectra were recorded at an
ionizing voltage of 70 eV. Flash column chromatography of
photoproduct 5 and dibromide 7a was performed using Acros
activated basic Al2O3 (50-200 µm) using 1:1 hexane/ether as
eluent. Other flash column chromatography was performed
using Fisher Davisil Grade 633 silica gel Type 60A (200-425
mesh); TLC was performed on silica gel GF 500 or 1000 µm
(Analtech, Inc.).
P r ep a r a tion of N-(Eth oxyca r bon yl)-5-en d o-6-exo-d ibr o-
m o-2-a za bicyclo[2.2.0]h exa n e (6a ) a n d N-(Eth oxyca r bo-
n yl)-5-a n ti-6-a n ti-d ibr om o-2-a za bicyclo[2.1.1]h exa n e (7a ).
A solution of bromine (113 mg, 0.71 mmol) in CH2Cl2 (3 mL)
was added dropwise to a cold (-5 °C) solution of N-(ethoxycar-
bonyl)-2-azabicyclo[2.2.0]hex-5-ene (5)6 (108 mg, 0.71 mmol) in
CH2Cl2 (10 mL) under argon, and the resulting solution was
stirred for 2 h. The temperature was then raised to room
temperature and stirred for an additional 16 h. The solution
was diluted with ether (25 mL), washed with 10% aqueous
sodium bisulfite (10 mL) and water (10 mL), dried over MgSO4,
and filtered, and solvent was removed in vacuo to provide an
oil, which upon column chromatography (4:1 hexane/ether) gave
96 mg (49%) of unrearranged dibromide 6a (Rf ) 0.30, 3:1
NMR δ 15.5, 39.2, 41.2, 49.7, 61.4, 157.0; HRMS m/z 155.0938,
calcd for C8H13NO2 155.0938.
P r ep a r a tion of N-(Eth oxyca r bon yl)-6-exo-br om o-5-en d o-
h yd r oxy-2-a za bicyclo[2.2.0]h exa n e (6b) a n d N-(Eth oxy-
car bon yl)-5-a n ti-br om o-6-a n ti-h ydr oxy-2-azabicyclo[2.1.1]-
h exa n e (7b). To the photoproduct 5 (2 g, 13 mmol) in DMSO
(60 mL) and H2O (30 mL) at -5 °C was added N-bromosuccin-
imide (6.97 g, 39 mmol) in small portions so that the temperature
never exceeded 0 °C.9 Upon completion of the addition, the
solution was stirred for 14 h, diluted with water (50 mL), and
extracted with ether (5 × 50 mL). The combined extracts were
washed with H2O (2 × 25 mL) and dried over MgSO4, solvent
was removed in vacuo, and flash silica gel chromatography of
the residue (2:1 ether/hexane) gave 1.72 g (53%) of unrearranged
bromohydrin 6b (Rf ) 0.57, 5:1 ether/hexane): 1H NMR δ 1.24
(3H, t, J ) 7.2 Hz), 3.29 (1H, dddd, J ) 7.8, 7.5, 4.8, 3.0 Hz),
3.49 (1H, b), 4.08 (1H, dd, J ) 9.3, 7.5 Hz), 4.12 (2H, q, J ) 7.2
Hz), 4.31 (1H, d, J ) 4.2 Hz), 4.35 (1H, d, J ) 4.8 Hz), 4.45 (1H,
dd, J ) 9.3, 3.0 Hz), 4.66 (1H, dd, J ) 7.8, 4.2 Hz); 13C NMR δ
14.6, 35.2, 47.2, 52.2, 61.5, 63.8, 75.2, 155.6; HRMS m/z
170.0818, calcd for C8H12NO3 - Br 170.0817. Also obtained was
0.57 g (17%) of rearranged bromohydrin 7b (Rf ) 0.43, 5:1 ether/
hexane): 1H NMR δ 1.25 (3H, t, J ) 7.2 Hz), 2.98 (1H, d, J )
7.2 Hz), 3.45 (1H, d, J ) 9.0 Hz), 3.52 (1H, d, J ) 9.0 Hz), 3.55
(1H, br), 4.06 (1H, d, J ) 7.5 Hz), 4.13 (2H, q, J ) 7.2 Hz), 4.24
(1H, d, J ) 7.5 Hz), 4.38 (1H, d, J ) 7.2 Hz); 13C NMR δ 14.6,
49.2, 49.9, 52.0, 61.7, 65.8, 84.9, 155.4; HRMS m/z 170.0803,
calcd for C8H12NO3 - Br 170.0817.
(7) (a) Begley, W. J .; Lowe, G.; Cheetham, A. K.; Newsam, J . M. J .
Chem. Soc., Perkin Trans. 1 1981, 2620. Addition of HOBr to an
N-alkyl-2-aza-3-oxobicyclo[2.2.0]hex-5-ene afforded only unrearranged
6-exo-bromo-5-endo-hydroxy addition product. (b) Krow, G. R.; Fan,
D. M. J . Org. Chem. 1974, 39, 2674.
(8) We note also that 2-azabicyclo[2.1.1]hexanes have been converted
to their corresponding 3-oxo derivatives (lactams). See ref 2b.
(9) Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. G. Synth.
Commun. 1984, 429.

8560 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
P r ep a r a tion of N-(Eth oxyca r bon yl)-5-a n ti-h yd r oxy-2-
a za bicyclo[2.1.1]h exa n e (8b). According to the procedure
described for the preparation of compound 8a , the bromohydrin
7b (73 mg, 0.29 mmol) was debrominated using tributyltin
hydride (118 µL, 127 mg, 0.44 mmol). Workup and column
chromatography (2:1 ether/hexane) gave 31 mg (63%) of the
alcohol 8b (Rf ) 0.36, 3:1 ether/hexane): 1H NMR δ 1.24 (3H, t,
J ) 7.2 Hz), 1.61 (1H, dd, J ) 7.5, 7.2 Hz), 2.65 (1H, d, J ) 7.2
Hz), 2.89 (1H, d, J ) 7.5 Hz), 3.35 (2H, s), 3.75 (1H, br), 4.07
(1H, d, J ) 7.2 Hz), 4.12 (2H, q, J ) 7.2 Hz), 4.15 (1H, dd, J )
7.2, 1.8 Hz); 13C NMR δ 14.6, 36.8, 43.9, 48.2, 61.1, 63.2, 81.1,
156.1; HRMS FAB m/z 172.0971, calcd for C8H14NO3 (MH+)
172.0974.
Ack n ow led gm en t. We thank Temple University for
a Grant-in-aid in support of this work and Professor
Steven Burke for helpful suggestions.
Su p p or tin g In for m a tion Ava ila ble: Alternate proce-
dures for reductive debromination of rearranged dibromides
7a and 7b using tris(trimethylsilyl)silane (TTMSS), 300 MHz
1H NMR spectra and 75 MHz 13C NMR spectra for compounds
6a ,b, 7a ,b, and 8a ,b (12 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O9808472