Modification of 1-Substituents in the 2-Azabicyclo[2.1.1]hexane Ring System; Approaches to Potential Nicotinic Acetylcholine Receptor Ligands from 2,4-Methanoproline Derivatives

Article abstract of DOI:10.1021/jo035199n

Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-positi

Full text of DOI:10.1021/jo035199n

Mod ifica tion of 1-Su bstitu en ts in th e 2-Aza bicyclo[2.1.1]h exa n e
Rin g System ; Ap p r oa ch es to P oten tia l Nicotin ic Acetylch olin e
Recep tor Liga n d s fr om 2,4-Meth a n op r olin e Der iva tives
J ohn R. Malpass,* Anup B. Patel, J ohn W. Davies, and Sarah Y. Fulford
Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom
jrm@le.ac.uk
Received August 15, 2003
Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the
2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a
wider range of functional groups attached to the 1-position via a methylene “spacer” (including the
â-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues
containing heterocyclic substituents and also to further homologation at the 1-position. Displace-
ments with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative)
require thermal activation but proceed without the rearrangement initially anticipated in such a
strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated;
nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with
concomitant decarboxylation).
In tr od u ction
cis-cyclobutene dicarboxylic anhydrides5 so that the
azabicyclic framework itself is now readily available.
Considerable recent effort has led to a significant
widening of the range of methods for functionalization
of the 2- and 5-/6-positions of the 2-azabicyclo[2.1.1]-
hexane ring system.3,5 In particular, Krow has recently
introduced attractive approaches to 5(6)-syn,anti-difunc-
tional derivatives3a and to control of lithiation at the 1-
and 3-positions of N-Boc-2-azabicyclo[2.1.1]hexane lead-
ing to aldehydes and esters.6 Other alternatives to the
carboxylic acid group at the 1-position include nitriles1
and pyridine derivatives,2d and hydride reduction of the
cyano group1 has been reported. However, we are not
aware of any reports of displacement reactions at the
1-methylene position apart from replacement of a tosyl
group by hydride in our own work (Scheme 1) in which
we examined formal dyotropic rearrangements of N-
chloro-derivatives of this strained ring system together
with study of the elevated nitrogen inversion barrier.7
The need to extend the range of functionalization at the
1-position is made more urgent by intense current
activity in the construction of analogues of epibatidine8
in the search for high affinity and high subtype selectivity
There has been substantial recent interest in the
2-azabicyclo[2.1.1]hexane ring system, which forms the
basis for the nonproteinogenic amino acid 2,4-methano-
proline.1 Early synthetic routes to the ring system were
based on photochemical intramolecular [2 + 2] cycload-
dition strategies,2 and there have been recent reports of
alternative approaches, from 2-azabicyclo[2.2.0]hexane
derivatives,3 3-halomethyl-1-aminocyclobutanes,1,4 and
* To whom correspondence should be addressed. Ph: + 44 116 252
2126. Fax: +44 116 252 3789.
(1) (a) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J .; J anzen, D. H.; Lemke,
P.; Clardy, J . J . Am. Chem. Soc. 1980, 102, 1409-1412. (b) See:
Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J . Org. Chem. 2002, 67,
6509-6513 for recent work and leading references.
(2) (a) Pirrung, M. C. Tetrahedron Lett. 1980, 21, 4577-4578. (b)
Hughes, P.; Martin, M.; Clardy, J . Tetrahedron Lett. 1980, 21, 4579-
4580. (c) Hughes, P.; Clardy, J . J . Org. Chem. 1988, 53, 4793-4796.
(d) Piotrowski, D. W. Synlett 1999, 1091-1093.
(5) Lescop, C.; Me´vellec, L.; Huet, F. J . Org. Chem. 2001, 66, 4187-
4193.
(6) (a) Krow, G. R.; Lin, G.; Rapolu, D.; Fang, Y.; Lester, W. S.;
Herzon, S. B.; Sonnet, P. E. J . Org. Chem. 2003, 68, 5292-5299. (b)
Krow, G. R.; Herzon, S. B.; Lin, G.; Qiu, F.; Sonnet, P. E. Org. Lett.
2002, 4, 3151-3154.
(7) Davies, J . W.; Malpass, J . R.; Walker, M. P. Chem. Commun.
1985, 686-687.
(8) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J .
C.; Pannell, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475-3478.
For leading references to epibatidine analogue synthesis, see: (b)
Carroll, F. I.; Lee, J . R.; Navarro, H. A.; Ma, W.; Brieaddy, L. E.;
Abraham, P.; Damaj, M. I., Martin, B. R. J . Med. Chem. 2002, 45,
4755-4761 and (c) Wei, Z.-L.; George, C.; Kozikowski, A. P. Tetrahe-
dron Lett. 2003, 44, 3847-3850.
(3) For leading references, see: (a) Krow, G. R.; Lin, G.; Yu, F.;
Sonnet, P. E. Org. Lett. 2003, 5, 2739-2741. (b) Krow, G. R.; Yuan, J .;
Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4, 1259-1262. (c) Krow, G. R.;
Lester, W. S.; Liu, N.; Yuan, J .; Hiller, A.; Duo, J .; Herzon, S. B.;
Nguyen, Y.; Cannon, K J . Org. Chem. 2001, 66, 1811-1817. (d) Krow,
G. R.; Lee, Y. B.; Lester, W. S.; Liu, N.; Yuan, J .; Duo, J .; Herzon, S.
B.; Nguyen, Y.; Zacharias, D. J . Org. Chem. 2001, 66, 1805-1810. (e)
Krow, G. R.; Lee, Y. B.; Lester, W. S.; Christian, H.; Shaw, D. A.; Yuan,
J . J . Org. Chem. 1998, 63, 8558-8560.
(4) (a) Rammeloo, T.; Stevens, C. V. Chem. Commun. 2002, 250-
251. (b) Stevens, C.; De Kimpe, N. J . Org. Chem. 1996, 61, 2174-
2178.
10.1021/jo035199n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2003
9348
J . Org. Chem. 2003, 68, 9348-9355

2-Azabicyclo[2.1.1]hexane Ring System
SCHEME 1a
a
Reagents: (a) 254 nm (cf. ref 2a); (b) LiAlH4/Et2O, reflux (94%); (c) TsCl/pyridine, 4 °C (86%); (d) LiAlH4/THF, reflux (92%); (e) H2/Pd
(100%).
SCHEME 2
at the nicotinic acetylcholine receptor (nAChR).9 We have
described epibatidine isomers10 and homologues based on
azabicyclic alternatives to the 7-azabicyclo[2.2.1]heptane
skeleton11 that have high affinity at the nicotinic acetyl-
choline receptor (nAChR), and modeling studies suggest
that attachment of a heterocyclic substituent separated
by one or more methylene spacers at the 1-position of
2-azabicyclo[2.1.1]hexane should also provide appropriate
N-N distances and orientation for effective interaction
at the receptor. Although Piotrowski has utilized the
photochemical route to produce 2-azabicyclo[2.1.1]hexane
derivatives having pyridine substituents directly at-
substitution process that involves participation by N-
alkoxycarbonyl protecting groups.
tached to the 1-position,2d we were anxious to widen the
range of potential nAChR agonists by extending the chain
length and the range of available attached heterocycles12
Discu ssion
at the 1-position. We here describe successful substitution
reactions at the 1-methylene position, opening the way
to the isolation of useful intermediates for further
elaboration. Manipulation of N-protecting groups is also
described together with a convenient refinement of the
Pirrung2a and Clardy and Hughes2b,c and includes our
Scheme 1 summarizes the preparation of 2 from
N-benzoyl N-allyldehydroalanine ethyl ester 1 using the
reliable photolytic approach originally established by
earlier conversion of the 1-ethoxycarbonyl group into
(9) For leading reviews and references to nAChR affinities, see: (a)
methyl via the tosylate 4a (by displacement using the
Astles, P. C.; Baker, S. R.; Boot, J . R.; Broad, L. M.; Dell, C. P.; Keenan,
sterically undemanding hydride ion).7 This proceeded
M. Curr. Drug Targets: CNS Neurol. Disord. 2002, 1, 337-348. (b)
efficiently to give 5 and hence the secondary amine 6 (via
hydrogenolysis), which provided the N-chloroamine with
sodium hypochlorite solution.7 We did not expect to be
able to achieve ready SN2 displacement of a leaving group
at the hindered (“pseudo-neopentyl”) 1-methylene group
in 4 using other, more sterically demanding nucleophiles.
Some possible substitution pathways from 4 are shown
in Scheme 2. Any thought of a “double displacement”
leading to substitution via neighboring group participa-
tion of the amino-nitrogen lone pair is unlikely on the
basis of the orientation of the lone pair and the strain in
intermediate 7 (although this strain could, in principle,
be released by C-N bond cleavage to 8 to yield 3-azabi-
cyclo[3.1.1]heptane isomers). We did not expect to achieve
useful SN1 substitution in view of the propensity of the
strained azabicyclo[2.1.1]hexane system for skeletal rear-
rangement or fragmentation.7 However, further consid-
eration is justified when the limited options for rear-
rangement of the primary carbocation 9 are considered.
The strained rearranged bridgehead cation 10 should be
intrinsically inaccessible; resonance stabilization by the
(almost orthogonal) nitrogen lone pair is clearly impos-
sible, and the electronegative nitrogen would further
destabilize the hypothetical cation 10.
Tønder, J . E.; Olesen, P. H. Curr. Med. Chem. 2001, 8, 651-674. (c)
Lloyd, G. K.; Williams, M. J . Pharmacol. Exp. Ther. 2000, 292, 461-
467. (d) Curtis, L.; Chiodini, F.; Spang, J . E.; Bertrand, S.; Patt, J . T.;
Westera, G.; Bertrand, D. Eur. J Pharmacol. 2000, 393, 155-163. (e)
Holladay, M. W.; Dart M. J .; Lynch, J . K. J . Med. Chem. 1997, 40,
4169-4194. (f) Tønder, J . E.; Hansen, J . B.; Begtrup, M.; Petterson,
I.; Rimvall, K.; Christensen, B.; Ehrbar, U.; Olesen, P. H. J . Med. Chem.
1999, 42, 4970-4980. For earlier work on the nAChR, see: (g)
Bencherif, M.; Schmitt, J . D.; Bhatti, B. S.; Crooks, P.; Caldwell, W.
S.; Lovette, M. E.; Fowler, K.; Reeves, L.; Lippiello, P. M. J . Pharmacol.
Exp. Ther. 1998, 284, 886-894. (h) Glennon, R. A.; Herndon, J . I.;
Dukat, M. Med. Chem. Res. 1994, 4, 461-473.
(10) (a) Cox, C. D.; Malpass, J . R.; Gordon, J .; Rosen, A. J . Chem.
Soc., Perkin Trans. 1 2001, 2372-2379. (b) Cox, C. D.; Malpass, J . R.
Tetrahedron 1999, 55, 11879-11888. (c) Malpass, J . R.; Cox, C. D.
Tetrahedron Lett. 1999, 40, 1419-1422.
(11) (a) Malpass, J . R.; Hemmings, D. A.; Wallis, A. L.; Fletcher, S.
R.; Patel, S. J . Chem. Soc., Perkin Trans. 1 2001, 1044-1050. (b)
Malpass, J . R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett. 1996,
22, 3911-3914. The papers under 10 and 11 provide leading references
to the work of others.
(12) Examples of alternative heterocycles incorporated into the
epibatidine framework and into analogues include the following. (a)
Methylisoxazole in epiboxidine: Badio, B.; Garraffo, H. M.; Plummer,
C. V.; Padgett, W. L.; Daly, J . W. Eur. J . Pharmacol. 1997, 321, 189-
194. (b) Isoxazoles: Silva, N. M.; Tributino, J . L. M.; Miranda, A. L.
P.; Barreiro, E. J .; Fraga, C. A. M. Eur. J . Med. Chem. 2002, 37, 163-
169. (c) Pyridazines: Che, D.; Wegge, T.; Stubbs, M.; Seitz, G.; Meier,
H.; Methfessel, C. J . Med. Chem. 2001, 44, 47-57. (d) Substituted
pyridines: ref 8b. Avalos, M.; Parker, M. J .; Maddox, F. N.; Carroll,
F. I.; Luetje, C. W. J . Pharmacol. Exp. Ther. 2002, 302, 1246-1252.
Carroll, F. I.; Lee, J . R.; Navarro, H. A.; Brieaddy, L. E.; Abraham, P.;
Damaj, M. I.; Martin, B. R. J . Med. Chem. 2001, 44, 4039-4041. (e)
6-Chloropyridazin-3-yl derivatives: Toma, L.; Quadrelli, P.; Bunnelle,
W. H.; Anderson, D. J .; Meyer, M. D.; Cignarelli, G.; Gelain, A.;
Barlocco, D. J . Med. Chem. 2002, 45, 4011-4017. (f) See also: Gohlke,
H.; Schwarz, S.; Gu¨ndisch, D.; Tilotta, M. C.; Weber. A.; Wegge, T.;
Seitz, G. J . Med. Chem. 2003, 46, 2031-2048 for recent work on 3D
QSAR analysis in the design of heterocyclic substituents for high
nAChR subtype selectivity in epibatidine analogues and homologues.
Initial scoping studies were carried out starting with
the readily available N-benzyl-protected alcohol 3a in
order to establish whether displacement reactions were
feasible. Conversion of 3a into the mesylate 11a (88%)
was followed by successful but slow displacement with
KCN in the presence of 18-crown-6 at 80 °C, giving the
J . Org. Chem, Vol. 68, No. 24, 2003 9349

Malpass et al.
SCHEME 3a
a
Reagents: (a) MsCl/CH2Cl2 (88%); (b) KCN, 18-crown-6, CH3CN, 80 °C, 48 h (65%); (c) as (b), 60 °C (78%); (d) (i) H+/H2O, (ii) SOCl2,
(iii) EtOH (32%); (e) (i) acetoxime, BuLi, (ii) concentrated HCl, 90 °C; (f) imidazole/NEt3/acetonitrile, 90 °C, 48 h (29%).
SCHEME 4a
a
Reagents: (a) H2/Pd (100%); (b) BnOCOCl, pH 7-8 (40%); (c) MsCl/CH2Cl2/NEt3 (80%); (d) KCN, 18-crown-6, CH3CN, 80 °C, 48 h
(78%); (e) NaN3, DMF (85%); (f) imidazole/BuLi/CH3CN (15b, 43%; 17, 6%;); (g) H2/Pd/C/MeOH, (Boc)2O (60%); (h) MsCl/CH2Cl2/NEt3
(88%); (i) as (f) (40%); (j) as (d) (55%); (k) TMSI, HBF4, CH2Cl2 (90%).
nitrile 12a in 63% yield (Scheme 3; yields are not
optimized). The use of mesylate proved slightly more
effective than the conversion via the tosylate 4a . Acid
hydrolysis/esterification of 12a gave the ester 13a . Con-
version into the methylisoxazole12a 14a was attempted
despite the potential for competing pathways based, for
example, on enolization of 13a , and a sample of 14a was
isolated in very low yield (as shown by signals at δ 5.96
and 2.26, corresponding to the lone isoxazole proton and
the methyl group, respectively). This is not a practical
preparative route but was our first example of a hetero-
cyclic derivative of the title ring system attached to the
1-position by a methylene “spacer”. The synthesis of a
second example was achieved by treatment of 11a with
imidazole in the presence of triethylamine, giving 15a
directly in 29% yield and demonstrating that the direct
displacement approach is also effective using a nitrogen
nucleophile. The conditions for the substitution reactions
are suggestive of SN2 reactivity (the methylene bridges
of the azabicyclic system clearly offer less steric hin-
drance than a normal neopentyl system), but we have
no further evidence, as yet, concerning the balance
between SN2 and SN1.
of photoadducts using the benzyloxycarbonyl (Cbz) group
were poor. We therefore chose to debenzylate 3a and
reprotect the secondary amine 3c with the Cbz (3b) and
Boc (3d ) groups.13
Scheme 4 shows the preparation of the N-protected
derivative 3b and conversion into the mesylate 11b
together with further substitution reactions. Nucleophilic
displacement on 11b using cyanide ion gave the nitrile
12b in 78% yield. An X-ray crystal determination con-
firmed the retention of the 2-azabicyclo[2.1.1]hexane core
of 12b. Spectroscopic comparisons and protonation stud-
ies within the N-Bn and N-Cbz series eliminated any
possibility of isomeric 3-azabicyclo[3.1.1]heptane deriva-
tives derived from the hypothetical intermediate 8.
Further chemical interconversions confirmed the absence
of rearrangement in both series; for example, reduction
of the cyanomethyl derivative 12a gave a primary amine
attached to the 1-position by a bismethylene chain.
Treatment of 11b with azide ion provided the azide 16b
(85% yield), and use of the imidazole anion gave 15b
together with a minor product that was identified as the
cyclic carbamate 17 (6% yield). The products 15b and 17
were also formed (27% and 36%, respectively) using
imidazole and triethylamine to displace the mesyl group.
Clearly the cyclic carbamate 17 is formed by NGP of the
benzyloxycarbonyl oxygen with loss of benzyl, and pre-
dictably, it was produced more efficiently under similar
reaction conditions via loss of tert-butyl from the N-Boc-
Having established the validity of the basic approach
in Scheme 3 in the N-benzyl-protected (a) series, we
explored the use of N-alkoxycarbonyl groups to pro-
tect the nitrogen, i.e., the (b) series shown in Scheme 4.
The use of N-alkoxycarbonyl instead of N-benzoyl in
the initial photochemical reaction has been used by
Piotrowski to produce 1-aryl and 1-pyridyl 2-azabicyclo-
[2.1.1]hexane derivatives,2d but in our hands the yields
(13) N-Boc- and N-Cbz derivatives of the parent 2-azabicyclo[2.1.1]-
hexane derivatives have been described.3a,6
9350 J . Org. Chem., Vol. 68, No. 24, 2003

2-Azabicyclo[2.1.1]hexane Ring System
SCHEME 5a
a
(a) SOBr2 (77%); (b) CBr4/PPh3 (80%); (c) Swern oxidation (90%); (d) (20) methoxymethylenetriphenylphosphorane; (e) (21)
methylenetriphenylphosphorane 63%.
protected derivative 3d . This observation raises the
possibility of wider involvement of the carbonyl of the
Cbz protecting group in other displacements in Scheme
4, although the fact that corresponding reactions in the
N-Bn and N-Cbz series require similar temperatures and
reaction times weakens the case for wider NGP by the
carbonyl group. More detailed kinetic investigations will
be required to clarify this issue. Nucleophilic attack at
the 1-methylene position of 17 by the imidazolyl anion
required more vigorous conditions than for the mesylate
11b but provided the N-deprotected compound 15c
directly (with concomitant decarboxylation) in good yield;
the identical secondary amino-compound 15c was also
formed by N-deprotection of 15b using TMSI. Similar
treatment of 17 with cyanide ion gave 12c. The value of
17 as a convenient direct source of N-deprotected 1-func-
tionalized derivatives of the 2-azabicyclo[2.1.1]hexane
ring system is under continuing study.
The potential for synthesis of a wider range of deriva-
tives of this ring system is illustrated in Scheme 5. The
bromo-derivative 18a was isolated from treatment of 3a
with thionyl bromide (77%) and 18b was accessible from
3b using CBr4/PPh3 (80%); these compounds will form
the basis for coupling chemistry. Swern oxidation of 3b
provided the aldehyde 19, which was converted into the
mixture of vinyl ethers 20 and the alkene 21 using
established Wittig methodology.14 The vinyl ethers 20 are
precursors of systems containing pendant heterocycles
including diazenes14 and were isolated in acceptable
purity, although they were not amenable to chromato-
graphic purification.16 Pyridyl derivatives 22 should be
accessible from the alkenes using reductive Heck chem-
istry15 and from halo-derivatives (e.g., 18) via coupling
reactions. These intermediates are currently forming the
basis for the synthesis of target compounds having a
wider range of nitrogen heterocycles attached to the
1-position by methylene chains of varying lengths. Such
derivatives should allow systematic investigation of the
effects of the key N-N distances (secondary N/hetero-
cyclic N) and orientation on nAChR subtype selectivity.
The recent interest in 2,4-methanoproline1 led us to
synthesize the novel homologue, the â-amino acid 23, by
hydrolysis of the 1-cyanomethyl derivative 12b. The
crude hydrochloride salt 23‚HCl was isolated directly in
good yield and ion-exchange chromatography provided
the crystalline amino acid 23. Derivatization and further
chemistry of 23 is under continuing study.
Con clu sion s
Nucleophilic substitution has been successfully dem-
onstrated (without rearrangement) at a methylene group
attached to the 1-position of the 2-azabicyclo[2.1.1]hexane
ring system and has led to the isolation of a broad
selection of novel substituted derivatives. The work has
demonstrated that a wide range of 1-substituted inter-
mediates having different chain lengths are accessible,
including heterocyclic derivatives that have significance
as potential ligands for the nAChR. The methodology will
also be applicable to precursors bearing substituents in
the azabicyclic core.
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 using tetramethylsi-
lane as internal standard. Routine mass spectra were mea-
sured using electrospray, and accurate mass measurements
were made using FAB. All reactions were performed in oven-
dried glassware under dry nitrogen (or argon where stated).
Commercially available solvents were purified and dried, when
necessary, prior to use. “Ether” refers to diethyl ether and
“petrol” to petroleum ether, bp 40-60 °C, unless indicated
otherwise.
Flash chromatography was carried out using silica gel (60)
unless stated otherwise. Thin-layer chromatography was
conducted on silica 60-254 plates. Chromatography solvents
were routinely saturated with ammonia gas for amine (and
N-protected amine) separations.
N-Ben zoyl-N-a llyld eh yd r oa la n in e Eth yl Ester , 1. Al-
lylamine (9.38 mL, 125 mmol) was added dropwise to a stirred
solution of ethyl pyruvate (13.7 g, 125 mmol) in toluene (150
mL), and stirring was continued for 3 h at room temperature.
The organic layer was separated, and the aqueous layer was
extracted with toluene (3 × 150 mL). The combined organic
layers were dried with MgSO4 and filtered. Distilled triethyl-
amine (19.5 mL, 140 mmol) was added under nitrogen,
(14) For typical procedures, see ref 12c. For the preparation of 20
we used potassium tert-butoxide in place of LDA.
(15) See refs 10b and 11 for typical reductive Heck procedures and
references to the work of other groups.
(16) The purity of 20 was estimated to be greater than 90% by NMR.
The spectra were complicated further owing to the presence not only
of cis/ trans isomers but also of slow rotation about the C-N bond.
Spectra of many N-alkoxycarbonylamines in this work showed the
effects of slow rotation (cf. ref 11).
J . Org. Chem, Vol. 68, No. 24, 2003 9351

Malpass et al.
followed by dropwise addition of benzoyl chloride (16.3 mL,
140 mmol) over 15 min. After the mixture stirred overnight,
the triethylamine hydrochloride was filtered off, and the
solvent was evaporated to give crude 1 (42.91 g). A sample
(18.36 g) was chromatographed (3:7 ether/petrol; Rf 0.19),
yielding 1 as a pale yellow oil (6.53 g, 47%). 1H NMR (250 MHz,
CDCl3): δ 1.17 (t, J ) 7.0 Hz, 3H), 4.07 (q, J ) 7.0 Hz, 2H),
4.31 (bd, J ) 6.0 Hz, 2H), 5.20 (ddt, J ) 10.0, 1.5, 1.0 Hz),
5.24 (ddt, J ) 17.0, 1.5, 1.5 Hz), 5.51 (bs, 1H), 5.92 (ddt, J )
17.0, 10.0, 6.0 Hz, 1H), 6.07 (bs, 1H), 7.26-7.52 (m, 5H). 13C
NMR (62.9 MHz, CDCl3): δ 13.8 (CH3), 51.8, 61.4, 117.8, 121.8
(CH2), 127.9, 130.0, 132.8 (CH), 135.6 (C), 140.6 (C), 163.7,
170.6 (C). νmax (CDCl3): 1702 1652, 1625, cm-1. m/z: 260.12865;
run off, and the aqueous layer was extracted with CH2Cl2 (6
× 50 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered, and evaporated under reduced
pressure. Chromatography (7:3 petrol/ether saturated with
NH3, Rf 0.17) gave 3b (0.884 g, 45%) as a colorless oil. 1H NMR
(250 MHz, CDCl3): δ 1.57 (dd, J ) 4.8, 1.8 Hz, 2H), 1.79 (m,
2H), 2.77-2.79 (m, 1H), 3.46 (s, 2H), 3.95 (d, J ) 7.0 Hz, 2H),
4.60 (bs, 1H), 5.14 (s, 2H), 7.26-7.38 (m, 5H). 13C NMR (62.9
MHz, CDCl3): δ 34.7 (CH), 42.1, 52.4, 61.9, 67.1 (CH2), 74.9
(C), 128.2, 128.4, 128.9 (CH), 137.0 (C), 156.0 (CdO). νmax
(CDCl3): 3420, 1684 cm-1. m/z: 248.12867; C14H18NO3 [MH+]
requires 248.12866.
(2-Aza bicyclo[2.1.1]h ex-1-yl)-m eth a n ol, 3c. Compound
3a (768 mg, 3.78 mmol) in dry methanol (20 mL) was
hydrogenated using 10% Pd/C (250 mg) at room temperature
for 24 h. Ammonia gas was bubbled through the solution,
which was filtered through Celite. The solid was washed with
methanol saturated with NH3 (100 mL), and the combined
methanol extracts were evaporated under reduced pressure
to yield 3c (427 mg, 100%) as a yellow oil. (Rf 0.10 in 6:4 ether/
methanol saturated with NH3). 1H NMR (250 MHz, CDCl3):
δ 1.53 (dd, J ) 4.4, 1.8 Hz, 2H), 1.86 (m, 2H), 2.79 (m, 1H),
3.05 (m, 2H), 3.74 (s, 2H). 13C NMR (62.9 MHz, CDCl3): δ 37.1
(CH), 39.8, 48.5, 62.2 (CH2), 70.6 (C). νmax (CDCl3): 3375, 1650,
1638 cm-1. m/z: 114.09181; C6H12NO [MH+] requires 114.09189.
C
15H18NO3 [MH+] requires 260.12867.
2-Ben zoyl-2-a za bicyclo[2.1.1]h exa n e-1-ca r boxylic Acid
Eth yl Ester , 2. These methods were based on the work of
Pirrung2a and Clardy.2b,c Compound
1
(1.0-1.5% in dry
benzene containing 0.2% acetophenone) was photolyzed in
quartz tubes in a Rayonet reactor (254 nm, 40 h) to give
crystalline 2, mp 105.5-106.5 °C, in 65% yield after chroma-
tography (1:1 ether/petrol). 1H NMR (250 MHz, CDCl3): δ 1.31
(t, J ) 7.0 Hz, 3H), 1.81 (dd, J ) 5.0, 2.0 Hz, 2H), 2.19 (m,
2H), 2.81 (m, 1H), 3.56 (bs, 2H), 4.28 (q, J ) 7.0 Hz, 2H), 7.36-
7.52, 7.71-7.79 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 14.4
(CH3), 35.7 (CH), 42.2, 55.5, 61.4 (CH2), 70.7 (C), 128.7, 128.8,
131.7 (CH), 135.0 (C), 168.8, 174.2 (CdO). νmax (CDCl3): 1733,
1652 cm-1. m/z: 260.12862; C15H18NO3 [MH+] requires
260.12867. Further crystallization from ether gave an analyti-
cal sample, mp 106.5-107 °C. Anal. Calcd for C15H17NO3: C,
68.48; H, 6.61; N, 5.40. Found: C, 68.42; H, 6.65; N, 5.43. X-ray
crystallographic data for 2 are recorded in Supporting Infor-
mation.
1-Hyd r oxym eth yl-2-a za bicyclo[2.1.1]h exa n e-2-ca r box-
ylic Acid ter t-Bu tyl Ester , 3d , fr om 3a . Compound 3a (60
mg, 0.295 mmol) was stirred in dry methanol (1 mL) with
(10%) Pd/C (250 mg) and Boc2O (45 mg, 0.206 mmol) at room
temperature for 24 h. The mixture was filtered through Celite,
and the solid was washed with ethyl acetate saturated with
NH3 (30 mL) and methanol saturated with NH3 (30 mL). The
combined organic layers were evaporated under reduced
pressure, and the product was chromatographed (7:3 petrol/
ether saturated with NH3, Rf 0.58) to give 3d (38 mg, 60%
yield) as a colorless oil. 1H NMR (250 MHz, CDCl3): δ 1.48 (s,
9H), 1.56 (dd, J ) 4.6, 1.8 Hz, 2H), 1.76 (m, 2H), 2.75 (m, 1H),
3.37 (s, 2H), 3.93 (d, J ) 7.0 Hz, 2H). 13C NMR (62.9 MHz,
CDCl3): δ 29.0 (CH3), 34.7 (CH), 42.2, 52.9, 62.2 (CH2), 74.6
(C), 80.3 (C), 156.2 (C). m/z: 214.14432; C11H20NO3 [MH+]
requires 214.14429.
Photolysis of a 1.5% solution of 1 in acetone (254 nm, 60h)
followed by filtration through silica (7:3 petrol/ether) gave
material, mp 106-107 °C, in ca. 40% yield; although the yield
was lower, this method was readily adaptable to production
of 2 on a multigram scale because yields were more consistent
and the chromatographic separation was simpler.
(2-Ben zyl-2-a za bicyclo[2.1.1]h ex-1-yl)m eth a n ol, 3a . The
ester 2 (2.32 g, 8.95 mmol) in dry THF (20 mL) was added
dropwise to a stirred suspension of LiAlH4 (1.358 g, 35.78
mmol) in dry THF (40 mL). The mixture was heated at 68 °C
for 36 h, cooled, and quenched with water-saturated ether. The
slurry was filtered through Celite, and the solvent was
removed under reduced pressure prior to chromatographic
purification. The less polar impurities were eluted with ether
and the product was then flushed off the column with 9:1 ether:
methanol (saturated with NH3, Rf 0.10) to give crystalline 3a
(1.75 g, 96%), mp 58-59 °C after recrystallization from petrol.
1H NMR (250 MHz, CDCl3): δ 1.62 (bs, 4H), 2.60 (bs OH), 2.66
(bs, 1H), 2.67 (bs, 2H), 3.69 (bs, 2H), 3.79 (bs, 2H), 7.20-7.44
(m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 37.2 (CH), 38.2 (CH2),
55.8 (CH2), 57.9 (CH2), 61.9 (CH2), 74.3 (C), 127.4, 128.8, 129.0
(CH), 139.8 (C). m/z: 204.13884; C13H18NO [MH+] requires
204.13885. Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89. Found: C, 77.06; H, 8.41; N, 6.88.
1-Hyd r oxym eth yl-2-a za bicyclo[2.1.1]h exa n e-2-ca r box-
ylic Acid Ben zyl Ester , 3b. Following the procedure of Cox,17
3c (0.908 g, 8.03 mmol) was dissolved in distilled water (10
mL) and cooled to 0 °C. Aqueous sodium hydroxide (12 M, 2.5
mL) was added dropwise, and when addition was halfway
through (pH 12), the simultaneous addition of benzyl chloro-
formate (2.97 mL, 20.81 mmol) was begun. Addition of the
sodium hydroxide was finished just after that of the benzyl
chloroformate, and stirring was continued at 0 °C for 15 min
and then at room temperature for 24 h. Distilled water (10
mL) was added to the reaction mixture. The organic layer was
Tolu en e-4-su lfon ic Acid (2-Ben zyl-2-a za bicyclo[2.1.1]-
h ex-1-ylm eth yl) Ester , 4a . A solution of the alcohol 3a (2.03
g; 10 mmol) in dry pyridine (50 mL) was cooled in an ice bath,
and tosyl chloride (3.81 g; 20 mmol) was added portionwise so
that the temperature did not exceed 10 °C. The mixture was
left overnight at 4 °C, poured into ice water, and basified with
aqueous NH3. The resulting yellowish solid was slurried and
filtered twice more with ice water (2 × 100 mL). The solid was
dried under vacuum to afford the tosylate 4a (3.08 g; 86%),
which was used without further purification. 1H NMR (250
MHz, CDCl3): δ 1.52 (m, 2H), 1.68 (m, 2H), 2.43 (s, 3H), 2.65
(m, 3H), 3.58 (bs, 2H), 4.18 (s, 2H), 7.2-7.3 (m, 7H), 7.75 (d,
J ) 8 Hz, 2H). 13C NMR (62.9 MHz, CDCl3): δ 22.0 (CH3),
37.2 (CH), 38.4, 56.9, 58.1, 69.8 (CH2), 70.9 (C), 127.2, 128.3,
128.6, 128.9, 130.2 (CH), 133.3, 139.9, 145.2 (C). νmax (CH2-
Cl2): 1598 cm-1. m/z: 358.14769; C20H24NO3S [MH+] requires
358.14764. X-ray crystallographic data for 4a are recorded in
Supporting Information.
2-Ben zyl-1-m eth yl-2-a za bicyclo[2.1.1]h exa n e, 5. A solu-
tion of 4a (3.00 g, 8.4 mmol) in dry THF (80 mL) was added
dropwise to a stirred suspension of LiAlH4 (1.60 g, 40 mmol)
in dry THF (120 mL) and heated overnight under reflux. After
careful decomposition of the excess LiAlH4 using water-
saturated ether, the mixture was filtered, dried with MgSO4,
and evaporated under vacuum to yield 5 as a pale yellow oil
(1.44 g, 91%). An analytical sample was obtained by chroma-
tography on alumina (ether). 1H NMR (90 MHz, CDCl3): δ
1.29 (s, 3H), 1.41-1.62 (m, 4H), 2.55 (brs, 1H), 2.59 (brs, 2H),
3.60 (s, 2H), 7.13-7.44 (m, 5H). 13C NMR (15 MHz, CDCl3): δ
17.7 (CH3), 36.6 (CH), 40.8, 56.0, 57.9 (CH2), 70.1 (C), 126.8,
(17) Cox, C. D. PhD Thesis, University of Leicester, 2000. We thank
Caroline Cox for
a synthesis of 18b and the corresponding iodo-
derivative. Details of coupling investigations will be reported in due
course. We also acknowledge her additional assistance with the
optimization of yields for compounds 2, 3a , and 4a .
9352 J . Org. Chem., Vol. 68, No. 24, 2003

2-Azabicyclo[2.1.1]hexane Ring System
128.4, 128.9 (CH), 140.6 (C). Anal. Found: C, 83.04; H, 9.17;
N, 7.36. C13H17N requires C, 83.37; H, 9.15; N, 7.48.
CDCl3): δ 1.68 (dd, J ) 4.6, 1.6 Hz, 2H), 1.79 (m, 2H), 2.70
(bs, 5H), 3.64 (s, 2H), 7.22-7.47 (m, 5H). 13C NMR (62.9 MHz,
CDCl3): δ 21.0 (CH2), 36.5 (CH), 39.4 (CH2), 55.9 (CH2), 57.9
(CH2), 68.4 (C), 117.4 (CN), 127.0, 128.3, 128.5 (CH), 139.2
(C). m/z: 213.13917; C14H17N2 [MH+] requires 213.13918.
1-Meth yl-2-a za bicyclo[2.1.1]h exa n e Hyd r och lor id e, 6‚
HCl, a n d P icr a te Sa lt of 6. A solution of 5 (0.48 g, 2.57 mmol)
in ethanol (15 mL) was hydrogenated over 10% Pd/C (0.14 g)
for 24 h. The reaction mixture was filtered through Celite, and
dry HCl gas was passed through the cooled filtrate. Removal
of solvent left a dark oil, which was dissolved in the minimum
of CH2Cl2 and treated with ether to precipitate the hydrochlo-
ride salt. This was filtered and dried under vacuum to afford
1-Cya n om et h yl-2-a za b icyclo[2.1.1]h exa n e-2-ca r b ox-
ylic Acid Ben zyl Ester , 12b. The mesylate 11b (350 mg, 1.08
mmol) in dry acetonitrile (5 mL) was reacted with KCN (280
mg, 4.30 mmol) and 18-crown-6 (4.4 mg, 0.165 mmol). After
48 h of heating at 60 °C and workup as described for 12a , the
solid product was chromatographed (7:3 petrol/ether saturated
with NH3, Rf 0.23) to give 12b (215 mg, 78%); a small sample
was recrystallized from ether for CHN analysis and X-ray
determinations, mp 86.5-88.0 °C. 1H NMR (250 MHz,
CDCl3): δ 1.51 (dd, J ) 4.7, 1.95 Hz, 2H), 1.92 (m, 2H), 2.72-
2.75 (m, 1H), 3.24 (s, 2H), 3.42 (s, 2H), 5.04 (s, 2H), 7.12-7.29
(m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 21.6 (CH2), 34.1 (CH),
42.9, 52.3, 66.5 (CH2), 68.2 (C), 117.2 (CN), 127.6, 127.9, 128.4
(CH), 136.3 (C), 155.8 (C). m/z: 257.12900; C15H17N2O2 [MH+]
requires 257.12905. Anal. Calcd for C15H16N2O2: C, 70.29; H,
6.29; N, 10.93. Found: C, 70.39; H, 6.54; N, 11.13. X-ray
crystallographic data for 12b are recorded in Supporting
Information.
1
6‚HCl, which was used without further purification. H NMR
(90 MHz, CDCl3): δ 1.70 (s, 3H), 1.83 (brs, 4H), 2.78 (brs (1H),
3.30-3.48 (m, 2H), 9.88 (brs, exch. 2 × NH). Solutions of the
free amine 6 were prepared as required by dissolution of the
salt in water and basification with 2 M aqueous NaOH. The
free amine was then extracted into ether (or an alternative
solvent such as a low-boiling chlorofluorocarbon) and dried by
passage through a short column of MgSO4. 1H NMR (90 MHz,
CDCl3): δ 1.70 (s, 3H), 1.83 (brs, 4H), 2.78 (brs, 1H), 3.30-
3.48 (m, 2H), 9.88 (brs, NH). The hydrochloride 6‚HCl was
hygroscopic, and a solution of 6 in ether was used to prepare
an analytical sample of 6 as the picrate salt. A solution of the
free amine was concentrated carefully under reduced pressure
and treated with a dry, saturated solution of picric acid in ether
until no further precipitate appeared. The supernatant was
removed from the precipitate, which was washed with a small
aliquot of cold, dry ether. The precipitate was recrystallized
from 80% ethanol/water, filtered, and dried under vacuum to
afford the picrate salt of 6 as a yellow crystalline solid, mp
(2-Aza bicyclo[2.1.1]h ex-1-yl)-a ceton itr ile, 12c. The car-
bamate 17 (20 mg, 0.144 mmol) was reacted with KCN (37
mg, 0.57 mmol) and 18-crown-6 (6 mg, 0.023 mmol) in dry
acetonitrile (3 mL) and heated at 80 °C for 168 h. After workup
as described for 12a , chromatography (9:1 ether/methanol
saturated with NH3, Rf 0.14) yielded 12c as a yellow oil (12
1
1
166-172 °C (dec). H NMR (250 MHz, CDCl3): δ 1.22 (bd, J
mg, 70%). H NMR (300 MHz, CDCl3): δ 1.40 (dd, J ) 4.38,
) 4 Hz, 2H), 1.38 (s, 3H), 1.55 (bd, 2H), 2.03 (brs, NH), 2.64
(m, 1H), 2.97 (brs, 2H). Anal. Found: C, 44.09; H, 4.32; N,
17.02. C12H14N4O7 requires C, 44.18; H, 4.33; N, 17.17.
1.77 Hz, 2H), 1.79 (m, 2H), 2.10 (bs, NH), 2.79 (m, 2H), 2.81
(m, 1H), 3.07 (s, 2H). 13C NMR (75.8 MHz, CDCl3): δ 22.0
(CH2), 37.2 (CH), 41.8, 49.3 (CH2), 64.9, 116.9 (C). m/z: 123
(MH+).
1-Meth a n esu lfon ic Acid (2-Ben zyl-2-a za bicyclo[2.1.1]-
h ex-1-ylm eth yl) Ester , 11a . Methanesulfonyl chloride (0.726
mL, 9.39 mmol) was added dropwise to a solution of the alcohol
3a (1.74 g, 8.53 mmol) in dry CH2Cl2 (15 mL) followed by dry
triethylamine (2.38 mL, 17.06 mmol). The reaction was heated
at 30 °C for 20 h, filtered to remove triethylamine hydrochlo-
ride, and washed with distilled water (2 × 25 mL) and finally
with saturated NaHCO3 (30 mL). The organic layer was dried
with anhydrous MgSO4, filtered, and evaporated under re-
duced pressure to yield 11a (2.10 g, 88%) as a brown oil, which
was used without further purification. (Rf 0.29 in ether
(2-Ben zyl-2-a za bicyclo[2.1.1]h ex-1-yl) Acetic Acid Eth -
yl Ester , 13a . The nitrile 12a (0.691 g, 3.25 mmol) was heated
in 8 N HCl (5 mL) at 90 °C for 96 h. After cooling and
evaporation to dryness under reduced pressure, thionyl chlo-
ride (4 mL, 54.37 mmol) was added. The mixture was heated
to 40 °C for 5 h and evaporated to dryness, and absolute
ethanol (5 mL) was added. The mixture was stirred at room
temperature for 15 min and evaporated to dryness, and the
solid remaining was dissolved in 1 N HCl (5 mL). After
washing with ethyl acetate (2 × 5 mL), the aqueous layer was
basified with ammonium hydroxide and extracted with CH2-
Cl2 (5 × 10 mL). The combined organic layers were dried with
anhydrous MgSO4 and filtered, and the solvent was removed
under reduced pressure. Chromatography (7:3 petrol/ether
saturated with NH3, Rf 0.43) gave 13a (0.296 g, 35%) as a
colorless oil. 1H NMR (250 MHz, CDCl3): δ 1.25 (t, J ) 7.0
Hz, 3H), 1.66 (dd, J ) 4.6, 1.6 Hz, 2H), 1.70 (m, 2H), 2.68 (s,
2H), 3.66 (s, 2H), 3.73 (m, 1H), 4.14 (q, J ) 7.0 Hz, 2H), 7.18-
7.45 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 14.2 (CH3), 36.4
(CH), 37.2 (CH2), 39.6 (CH2), 57.4 (CH2), 60.3 (CH2), 69.7 (C),
128.1, 128.2, 128.6 (CH), 140.0 (C), 171.1 (CdO). νmax
(CDCl3): 1732 cm-1. m/z: 260.16500; C16H22NO2 [MH+] re-
quires 260.16505.
1
saturated with NH3). H NMR (250 MHz, CDCl3): δ 1.61 (dd,
J ) 4.6, 1.4 Hz, 2H), 1.71 (m, 2H), 2.65 (s, 3H), 2.92 (s, 3H),
3.65 (s, 2H), 4.38 (s, 2H), 7.1-7.4 (m, 5H). 13C NMR (62.9 MHz,
CDCl3): δ 36.7 (CH), 37.4 (CH3), 38.1 (CH2), 56.4 (CH2), 57.6
(CH2), 68.4 (CH2), 70.8 (C), 126.9, 128.2, 128.5 (CH), 139.3 (C).
νmax (CDCl3): 3430, 1638, 1628 cm-1. m/z: 282.11639 (MH+);
C
14H20NO3S [MH+] requires 282.11644.
1-Met h a n esu lfon yloxym et h yl-2-a za b icyclo[2.1.1]h ex-
a n e-2-ca r boxylic Acid Ben zyl Ester , 11b. Compound 3b
(606 mg, 2.45 mmol) in CH2Cl2 (10 mL) was treated with
methanesulfonyl chloride (0.209 mL, 2.695 mmol) and dry
triethylamine (0.683 mL, 4.9 mmol) using the procedure for
11a and gave 11b (0.670 g, 81%) as a pale yellow oil (Rf 0.76
1
in 4:1 petrol/ether saturated with NH3). H NMR (250 MHz,
2-Ben zyl-1-(3-m et h ylisoxa zolyl-5-ylm et h yl)-2-a za b i-
cyclo[2.1.1]h exa n e, 14a . Butyllithium (1.57 M solution; 800
µL) was added to acetone oxime (13.2 mg, 0.18 mmol) in THF
(580 µL). The solution was heated at 60 °C for 5 min in a sealed
reacti-vial. A solution of the ester 13a (40 mg, 0.15 mmol) in
THF (240 mL) was injected, and the mixture was stirred at
60 °C for 45 min. Concentrated HCl (800 mL) was added, and
the solution was heated in the sealed reacti-vial at 100 °C for
3 h. After neutralization with aqueous NaHCO3 and extraction
with ethyl acetate (3 × 8 mL), the organic layers were
combined, dried over anhydrous MgSO4, and filtered, and the
solvent removed under reduced pressure to yield a brown oil,
which was chromatographed (7:3 ether/petrol, Rf 0.35) to give
CDCl3): δ 1.47 (dd, J ) 4.0, 1.7 Hz, 2H), 1.94 (m, 2H), 2.74
(m, 1H), 2.92 (s, 3H), 3.42 (s, 2H), 4.76 (s, 2H), 5.02 (s, 2H),
7.2-7.4 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 34.7 (CH),
37.3 (CH3), 41.5, 52.2, 66.6, 68.6 (CH2), 69.7 (C), 127.9, 128.0,
128.5 (CH), 136.3 (C), 155.6 (C). νmax (CDCl3): 1750, 1685, 1636
cm-1. m/z: 326.10622; C15H20NO5S [MH+] requires 326.10620.
(2-Ben zyl-2-a za bicyclo[2.1.1]h ex-1-yl)-a ceton itr ile, 12a .
Potassium cyanide (1.47 g, 22.51 mmol) and 18-crown-6 (0.238
g, 0.90 mmol) were added to a solution of mesylate 11a (1.58
g, 5.63 mmol) in dry acetonitrile (8 mL). The mixture was
heated at 60 °C for 72 h, cooled, triturated with ether, and
filtered, and the solvent was removed under reduced pressure.
Chromatography (4:1 petrol/ether saturated with NH3, Rf 0.77)
gave 12a (0.778 g, 65%) as a colorless oil. 1H NMR (250 MHz,
1
an impure sample of 14a (10 mg) as a colorless oil. H NMR
(250 MHz, CDCl3): δ 1.44-1.63 (m, 4H), 2.26 (s, 3H), 2.58-
J . Org. Chem, Vol. 68, No. 24, 2003 9353

Malpass et al.
2.63 (m, 3H), 3.10 (s, 2H), 3.68 (s, 2H), 5.96 (s, 1H), 7.2-7.4
(m, 5H). m/z: 269 (MH+). Yields from later attempts to produce
14a were low and variable, and alternative approaches to this
compound are under study.
HF-ether complex (29 µL, 0.38 mmol) was added, and stirring
was continued for a further 6 min. Water (200 µL) was added,
and the solvent was removed under reduced pressure. Ad-
ditional water (0.5 mL) was added, and the solution was
washed with petrol (2 × 2 mL). The aqueous solution was
neutralized with solid K2CO3 and extracted with CH2Cl2 (5 ×
5 mL). The organic layer was dried with anhydrous MgSO4
and filtered, and the solvent was removed under reduced
pressure. Chromatography (95:5 CH2Cl2/methanol saturated
with NH3, Rf 0.14) gave 15c (27 mg, 87%) as a yellow oil.
2-Ben zyl-1-im id a zol-1-ylm eth yl-2-a za bicyclo[2.1.1]h ex-
a n e, 15a . The mesylate 11a (100 mg, 0.355 mmol) was
dissolved in dry acetonitrile (3 mL), and imidazole (24 mg,
0.355 mmol; dried by azeotropic distillation with benzene prior
to use) was added, followed by dry triethylamine (54 µL, 0.39
mmol). After heating at 90 °C for 48 h, the mixture was cooled
and basified with gaseous NH3 before removal of the solvent
under reduced pressure. The crude product was purified by
flash chromatography (4:1 petrol/ether saturated with NH3,
1-Azid om eth yl-2-a za bicyclo[2.1.1]h exa n e-2-ca r boxyl-
ic Acid Ben zyl Ester , 16b, fr om 11b. Sodium azide (146 mg,
2.25 mmol) was added to a solution of 11b (183 mg, 0.56 mmol)
in dry DMF (4 mL), and the mixture was heated at 40 °C for
48 h. After washing with aqueous NH4Cl (2 × 5 mL) and
distilled water (2 × 4 mL), the organic layer was dried with
anhydrous MgSO4 and filtered, and the solvent was removed
under reduced pressure to yield 16b (130 mg, 85%) as a yellow
oil, which was not purified further (Rf 0.74 in ether saturated
1
Rf 0.45) to give 15a (26 mg, 29%) as a colorless oil. H NMR
(250 MHz, CDCl3): δ 1.49 (m, 2H), 1.60 (dd, J ) 4.6, 1.5 Hz,
2H), 2.63 (m, 1H), 2.69 (s, 2H), 3.74 (s, 2H), 4.19 (s, 2H), 6.95
(s, 1H), 7.06 (s, 1H), 7.26-7.40 (m, 5H), 7.50 (s, 1H). 13C NMR
(62.9 MHz, CDCl3): δ 36.0 (CH), 38.2 (CH2), 47.7 (CH2) 55.9
(CH2), 57.9 (CH2), 72.5 (C), 119.9, 127.1, 128.4, 128.5, 129.1
137.7 (CH), 139.2 (C). νmax (CDCl3): 1676 cm-1. m/z: 254.16572
(MH+); C16H20N3 [MH+] requires 254.16573.
A similar reaction using butyllithium instead of triethyl-
amine (following the procedure described below for 15b) gave
15a in improved yield (35%).
1
with NH3). H NMR (250 MHz, CDCl3): δ 1.51 (dd, J ) 4.6,
1.84 Hz, 2H), 1.93 (m, 2H), 2.76 (m, 1H), 3.48 (s, 2H), 4.02 (s,
2H), 5.13 (s, 2H), 7.27-7.37 (m, 5H). 13C NMR (62.9 MHz,
CDCl3): δ 34.2 (CH), 41.7, 51.6, 52.3, 66.4 (CH2), 72.2 (C),
127.7, 127.9, 128.7 (CH), 136.7 (C), 155.6 (C). νmax (CH2Cl2):
2090, 1690 cm-1. m/z: 273.13515; C14H17N4O2 [MH+] requires
273.13522.
Rea ction of Mesyla te 11b w ith Im id a zole; F or m a tion
of 1-Im id a zol-1-ylm et h yl-2-a za -b icyclo[2.1.1]h exa n e-2-
ca r boxylic Acid Ben zyl Ester , 15b a n d 17. Imidazole (199
mg, 2.92 mmol) was dried by azeotropic distillation with
benzene. Butyllithium (1.57 M in hexanes, 1.434 mL) in dry
acetonitrile (5 mL) was then added, and the mixture was
stirred for 15 min, forming a white precipitate. The mesylate
11b (733 mg, 2.25 mmol) in dry acetonitrile (8 mL) was added
dropwise, and the mixture was heated at 40 °C for 96 h. After
basification with gaseous NH3 and removal of solvent under
reduced pressure, the mixture was introduced onto silica and
washed with ether. Further elution (CH2Cl2) gave the cyclic
urethane 17 (19 mg, 6% yield), and elution with 5% methanol/
CH2Cl2 (saturated with NH3) gave the imidazole derivative 15b
(285 mg, 43%). 1H NMR (250 MHz, CDCl3): δ 1.46 (dd, J )
4.5, 1.7 Hz, 2H), 1.68 (m, 2H), 2.70 (m, 1H), 3.48 (s, 2H), 4.76
(s, 2H), 5.13 (s, 2H), 7.09 (bs, 2H), 7.25-7.33 (m, 5H), 7.55
(bs, 1H). 13C NMR (62.9 MHz, CDCl3): δ 33.8 (CH), 41.8, 47.7,
52.8, 66.7 (CH2), 73.0 (C), 127.2, 127.8, 128.1, 128.3, 128.5,
3-Oxa -5-a za -tr icyclo[5.1.1.01,5]n on a n -4-on e, 17, fr om 3d .
Methanesulfonyl chloride (0.340 mL, 4.39 mmol) was added
dropwise to 3d (0.891 g, 4.39 mmol) in dry CH2Cl2 (10 mL)
followed by dry triethylamine (1.16 mL, 8.36 mmol), and the
mixture was heated at 30 °C for 24 h. Triethylamine hydro-
chloride was filtered off and washed with dry CH2Cl2 (10 mL).
The organic extracts were washed with distilled water (2 ×
10 mL) and saturated NaHCO3 (20 mL), dried with anhydrous
MgSO4, and filtered, and the solvent was removed under
reduced pressure. Chromatography (7:3 petrol/ether saturated
with NH3, Rf 0.17) yielded 17 (0.509 g, 88%) as a cream solid,
mp 29.5-31.5 °C. 1H NMR (250 MHz, CDCl3): δ 1.62 (dd, J )
4.7, 1.8 Hz, 2H), 1.93 (m, 2H), 2.88-2.91 (m, 1H), 3.25 (s, 2H),
4.21 (s, 2H). 13C NMR (62.9 MHz, CDCl3): δ 40.1 (CH), 42.6,
47.0, 66.4 (CH2), 73.9 (C), 156.7 (C). νmax (CH2Cl2): 1745 cm-1
m/z: 140.07115; C7H10NO2 [MH+] requires 140.07109.
.
128.9 (CH), 136.6 (C), 156.4 (C). νmax (CH2Cl2): 1690 cm-1
.
2-Ben zyl-1-br om om eth yl-2-azabicyclo[2.1.1]h exan e, 18a.
Thionyl bromide (34 mg, 13µL, 164 mmol) was added to a
solution of 3a (28.0 mg, 138 mmol) in CDCl3 (1 mL) in an NMR
tube, which was shaken and left for 17 h. NH3(g) was bubbled
through the reaction mixture until the pH was alkaline, the
ammonium bromide salt was filtered off, and the solvent was
removed under reduced pressure. Chromatography (3:1 petrol/
ether Rf 0.29) gave 18a (28.3 mg, 106 mmol, 77%) as a colorless
oil. 1H NMR (250 MHz, CDCl3): δ 1.68 (bs, 4H), 2.63 (bs, 1H),
2.68 (bs, 2H), 3.63 (bs, 4H), 7.20-7.48 (m, 5H). 13C NMR (62.9
MHz, CDCl3): δ 35.9 (CH), 32.8, 39.2, 39.2, 55.6, 57.7 (CH2)
71.6 (C), 126.8, 128.2, 128.8 (CH), 139.5 (C). m/z: 266.05444
& 268.05252; C13H17N79Br [MH+] requires 266.05452.
m/z: 298.15555; [MH+] requires 298.15544.
In another experiment, dry imidazole (48 mg, 0.699 mmol)
in dry acetonitrile (4 mL) was added to 11b (175 mg, 0.538
mmol) in dry acetonitrile (5 mL), followed by dry triethylamine
(0.112 mL, 0.807 mmol). After heating at 60 °C for 96 h, the
mixture was worked up and chromatographed as above to give
the cyclic urethane 17 (27 mg, 36%) and 15b (69 mg, 0.232
mmol, 27%). An improved method and spectral data for 17 are
given below.
1-Im id a zol-1-ylm eth yl-2-a za bicyclo[2.1.1]h exa n e, 15c,
fr om 17. Compound 17 (34 mg, 0.24 mmol) in dry DMF (3
mL) was added to a solution of the imidazolyl anion [prepared
from imidazole (34 mg, 0.24 mmol) and butyllithium (1.57 M,
0.202 mL) in dry DMF (2 mL) as described in the previous
procedure]. The mixture was heated at 90 °C for 144 h and
chromatographed (9:1 CH2Cl2/methanol saturated with NH3)
to give some unchanged 17 and 15c (22 mg, 55% yield, 69%
conversion) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.48
(dd, J ) 4.4, 1.8 Hz, 2H), 1.75 (m, 2H), 2.85 (m, 1H), 3.10 (s,
2H), 4.38 (s, 2H), 6.87 (bs, 1H), 6.98 (bs, 1H), 7.55 (bs, 1H).
Shifts varied and showed broadening, possibly associated with
1-Br om om et h yl-2-a za b icyclo[2.1.1]h exa n e-2-ca r b ox-
ylic Acid Ben zyl Ester , 18b. Triphenylphosphine (212 mg,
0.81 mmol) was added to a solution of 3b (50 mg, 0.20 mmol)
in dry CH2Cl2 (5 mL) followed by slow addition of CBr4 (288
mg, 0.87 mmol). After heating at 25 °C for 10 min, the mixture
was stirred at room temperature for 24 h. The mixture was
filtered, and the solids were washed successively with dry CH2-
Cl2 (50 mL) and ether (20 mL). Chromatography (1:1 petrol/
ether saturated with NH3, Rf 0.23) gave 3b (50 mg, 80%) as a
yellow oil. 1H NMR (250 MHz, CDCl3): δ 1.50 (dd, J ) 4.7,
2.0 Hz, 2H), 1.90-194 (m, 2H), 2.65-2.68 (m, 1H), 3.44 (s, 2H),
4.05 (s, 2H), 5.06 (s, 2H), 7.24-7.26 (m, 5H). 13C NMR (62.9
MHz, CDCl3): δ 32.7 (CH2), 33.4 (H), 42.8, 53.2, 66.5 (CH2),
72.6 (C), 127.8, 127.9, 128.4 (CH), 136.7, 155.8 (C). νmax (CH2-
traces of moisture and slow rotation of the imidazole ring. 13
C
NMR (75.8 MHz, CDCl3): δ 37.0 (CH), 40.7, 48.7, 49.4 (CH2),
69.8 (C), 119.4, 129.2, 137.2 (CH). m/z: 163.11095; C9H13N3
[MH+] requires 163.11092.
1-Im id a zol-1-ylm eth yl-2-a za bicyclo[2.1.1]h exa n e, 15c,
fr om 15b. To 15b (57 mg, 0.19 mmol) in dry CH2Cl2 (1.5 mL)
was added TMSI (136 µL, 0.96 mmol). After 7 min of stirring,
Cl2): 1690 cm-1. m/z: 310.04427 and 312.04235; C14H17
NO279Br [MH+] requires 310.04422. Treatment of 3b with
-
9354 J . Org. Chem., Vol. 68, No. 24, 2003

2-Azabicyclo[2.1.1]hexane Ring System
SOBr2 following the procedure of Cox17 also produced 18, but
the method above was more successful.
5.48 (d, J ) 13.1 Hz, 1H), 5.91 (d, J ) 6.9 Hz, 1H), 6.39 (d, J
) 12.9 Hz, 1H), 6.50 (m, 1H), 7.17-7.31 (m, 5H, Ph). m/z: 273
(MH+).
1-F or m yl-2-a za bicyclo[2.1.1]h exa n e-2-ca r boxylic Acid
Ben zyl Ester , 19. DMSO (0.097 mL, 1.38 mmol) in dry CH2-
Cl2 was added dropwise to a solution of oxalyl chloride (0.060
mL, 0.69 mmol) in dry CH2Cl2 (5 mL) at -78 °C. The mixture
was stirred for 30 min at -78°C after completion of the
addition. A solution of 3b in dry CH2Cl2 (5 mL) was added
dropwise, and the mixture was stirred for a further 15 min at
-78°C. Triethylamine (0.230 mL, 1.65 mmol) in dry CH2Cl2
(5 mL) was added dropwise, and the reaction mixture was
warmed to room temperature with stirring for 90 min. CH2-
Cl2 (2 mL) was added, and the mixture was washed with water
(2 × 10 mL) and saturated aqueous NaHCO3 (5 × 15 mL).
The organic extracts were dried with anhydrous MgSO4 and
filtered, and the solvent removed under reduced pressure to
yield 19 (60 mg, 90%) as a pale yellow oil (Rf 0.82 in ether
1-Vin yl-2-a za b icyclo[2.1.1]h exa n e-2-ca r b oxylic Acid
Ben zyl Ester , 21. Potassium tert-butoxide (0.123 g, 1.09
mmol) was stirred in dry THF (2 mL) under argon at 0 °C.
Methyltriphenylphosphonium bromide (0.390 g, 1.09 mmol)
was added, followed by dry THF (2 mL). The bright yellow
mixture was stirred for 2 h at 0 °C under argon. A solution of
19 in dry THF (3 mL) was added at 0 °C, and the mixture
was stirred for 20 h under argon. The workup procedure
followed that described for 20, but the product was chromato-
graphed (1:1 petrol/ether saturated with NH3, Rf 0.59) to give
1
21 (0.16 g, 63%) as a yellow oil. H NMR (250 MHz, CDCl3):
δ 1.56 (dd, J ) 4.9, 3.1 Hz, 2H), 1.82 (m, 2H), 2.64 (m, 1H),
3.41 (s, 2H), 5.05 (m, 4H), 6.50 (m, 1H), 7.18-7.31 (m, 5H).
13C NMR (62.9 MHz, CDCl3): δ 30.0 (CH), 43.6, 52.2, 66.2
(CH2), 74.1 (C), 114.9 (CH2), 127.7, 128.1, 128.3 (CH), 135.5
(CH), 137.1 155.9 (C). νmax (CH2Cl2): 1690 cm-1. m/z: 243.12593;
C15H17NO2 [MH+] requires 243.12592.
1
saturated with NH3). H NMR (250 MHz, CDCl3): δ 1.65 (dd,
J ) 4.7, 1.95 Hz, 2H), 2.12 (m, 2H), 2.82 (m, 1H), 3.43 (s, 2H),
5.16 (s, 2H), 7.30-7.36 (m, 5H), 9.87 (s, 1H). 13C NMR (62.9
MHz, CDCl3): δ 35.0 (CH), 41.5, 52.3, 67.5, (CH2), 76.3 (C),
128.0, 128.2, 128.5 (CH), 136.1 (C), 194.0 (C). νmax (CH2Cl2):
1735, 1680 cm-1. m/z: 246.11302; C14H16NO3 [MH+] requires
246.11296.
(2-Aza bicyclo[2.1.1]h ex-1-yl)-a cetic Acid , 23. The nitrile
12b (40 mg, 0.156 mmol) was dissolved in 8 N HCl (8 mL),
and the mixture was heated to 90 °C for 72 h. The reaction
was monitored using mass spectroscopy, and when hydrolysis
was complete, the product was evaporated to dryness under
reduced pressure to give 23‚HCl as a white residue in
1-(2-Met h oxy-vin yl)-2-a za b icyclo[2.1.1]h exa n e-2-ca r -
boxylic Acid Ben zyl Ester , 20. Potassium tert-butoxide (143
mg, 1.28 mmol) was stirred in dry THF (2 mL) at 0 °C under
an argon atmosphere. (Methoxymethyl)triphenylphosphonium
chloride (437 mg, 1.28 mmol) was then added, followed by dry
THF (2 mL). The bright red mixture was stirred for 2 h at 0
°C under argon. Compound 19 in dry THF (4 mL) was added
at 0 °C, and the mixture was stirred for 20 h under argon.
Water-saturated ether (6 mL) was added at room temperature,
and the mixture was stirred for 10 min followed by more water
(4 mL) and stirring (10 min). The organic layer was separated,
and the aqueous layer was extracted with ether (5 × 10 mL).
The combined organic layers were washed with brine (5 mL),
dried with anhydrous MgSO4, and filtered, and the solvent
removed under reduced pressure to yield the mixture of cis
and trans stereoisomers 20 as an orange oil that still contained
some triphenylphosphine oxide. The crude product was un-
stable and was not purified by chromatography. 1H NMR (250
MHz, CDCl3): δ (both stereoisomers showed slow N-CO
rotation) 1.61 (dd, J ) 4.93, 3.10 Hz, 2H), 1.83 (m, 2H), 2.96
(m, 1H), 3.32 (s, 2H), 3.41 (s, 3H), 5.12 (m, 1H), 5.19 (m, 2H),
1
quantitative yield. H NMR (300 MHz, D2O): δ 1.60 (dd, J )
6.0, 2.0 Hz, 2H), 2.04 (m, 2H), 2.86 (m, 1H), 3.00 (s, 2H), 3.38
(s, 2H). 13C NMR (75.8 MHz, D2O): δ 34.5 (C7), 36.0 (C4), 39.9
(C5/6), 49.8 (C3), 69.6 (C1), 173.1 (CdO). A small amount of 23‚
HCl was passed down a Dowex ion exchange column to give a
sample of 23, which crystallized as fine needles (dec 42-45
°C). 1H NMR (300 MHz, D2O): δ 1.54 (dd, J ) 6.1, 2.3 Hz,
2H), 1.97 (m, 2H), 2.72 (m, 1H), 2.84 (s, 2H), 3.35 (s, 2H). m/z:
142.08680; C7H12NO2 [MH+] requires 142.08689.
Ack n ow led gm en t. We are grateful to Dr. J ohn
Fawcett for the X-ray determination and Dr. Graham
Eaton for mass spectra.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035199N
J . Org. Chem, Vol. 68, No. 24, 2003 9355