N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

Article abstract of DOI:10.1016/j.tet.2009.09.013

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines,?followed by base-promoted cyclization (route a), o

Full text of DOI:10.1016/j.tet.2009.09.013

Tetrahedron 65 (2009) 9224–9232
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis
and reaction mechanisms
a
a,
a,
b
*
*
´
´
´
Elena Gomez , Jose Marco-Contelles , Elena Soriano , Marıa L. Jimeno
a Laboratorio de Radicales Libres y Qu´ımica Computacional (LRL/QC), IQOG (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain
b
´
Centro de Qu´ımica Organica ‘Lora Tamayo’ (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2009
Received in revised form 27 August 2009
Accepted 3 September 2009
Available online 9 September 2009
N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of
N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-
enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected,
N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b).
In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is
stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated
heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on
compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has
been carried out to explain the results observed in this work.
Keywords:
Epibatidine analogues
N-Arylmethyl-7-azabicyclo[2.2.1]heptanes
N-(Arylmethyl)cyclohex-3-enamines
Bromination
Ó 2009 Elsevier Ltd. All rights reserved.
Heterocyclization
Reaction mechanisms
1. Introduction
activity relationship studies have been reported. Thus, a great
attention has been paid to the synthesis and biological evaluation
Epibatidine (1)1 (Fig. 1), an alkaloid isolated from the skin of the
Ecuadorian poison frog Epipedobates tricolor,2 is a powerful anal-
gesic agent 200 times more potent than morphine, with high af-
finity for the nicotinic acetylcholine receptor (nAChR).3 Epibatidine
of epibatidine analogues,5b either heterocyclic6 or conformation-
ally constrained.7
In this context, Trudell and co-workers reported the synthesis
and biological evaluation of a series of N-arylalkyl- and N-aryl-7-
azabicyclo[2.2.1]heptanes,8 among which, two new nAChR agonists
(3 and 4; Fig. 2) have been identified. In the in vitro [3H]cytisine
binding assay, N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (4)
showed a potent affinity (Ki¼98 nM), and both compounds (3 and 4)
were found to elicit moderately potent nicotinic agonist activity in
strongly binds at a4b2 subtype nAChRs, showing a Ki value about
two orders of magnitude lower than nicotine (2)2 (Fig. 1). However,
the toxic effects associated with its low subtype selectivity have
hampered its clinical application.4
a4b2 subtype nACRs; in addition, and like epibatidine, these com-
N
Cl
H
N
pounds produced dose-dependent analgesic activity in the tail-flick
and hotplate tests. Conversely, compounds belonging to the N-aryl-
7-azabicyclo[2.2.1]heptane family showed low binding affinities,
probably due to the reduced basicity of the bridging nitrogen atom
of the 7-azabicyclo[2.2.1]heptane moiety.8 Consequently, com-
pounds bearing the N-arylalkyl-7-azabicyclo[2.2.1]heptane and the
N-aryl-7-azabicyclo[2.2.1]heptane skeleton are of interest, and have
been synthesized by N-alkylation of 7-azabicyclo[2.2.1]heptane (5)
with arylalkyl halides,8 and by palladium-bisimidazol-2-ylidene
complex catalyzed amination reactions on halogenated heteroaryl
derivatives, respectively.9 The synthesis of precursor 5 (Fig. 2) has
been described several times.10
N
Me
N
Nicotine (2)
Epibatidine (1)
Figure 1. Structure of epibatidine (1) and nicotine (2).
In the last years a number of methodologies have been
reported for the total synthesis of epibatidine and 7-azabicy-
clo[2.2.1]heptane derivatives.5a In the search for epibatidine-type
compounds devoid of secondary effects, a number of structure–
On the other hand, the synthesis of conformationally con-
strained epibatidine analogues has been approached by intra-
molecular reductive Heck reaction,6b,7a intramolecular SN2
* Corresponding authors. Tel.: þ34 91 5622900; fax: þ34 91 5644853 (E.S.).
E-mail addresses: iqoc21@iqog.csic.es (J. Marco-Contelles), esoriano@iqog.
csic.es (E. Soriano).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.013

E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
9225
R
H
R
N
X
N
R
N
Cl
N
N
X
N
Y
N
Br
(I)
8
5
(3) R= H
(4) R= Cl
(6) X= N, R= Cl
(7) X= CH, R= H
(X= N,CH; R= Cl, H;
Y= H, Br)
Figure 2. Structure of the target molecules (l), the reference products (3, 4, 6–8), and compound (5).
reactions,7b or by intramolecular 5-exo or 6-endo free radical cy-
Cl
route a
clizations from suitable 7-azanorbornene precursors.7c
NRBoc
TFA
NHBoc
N
We have recently described the synthesis of 7-substituted exo-
2-bromo-7-azabicyclo[2.2.1]heptane derivatives11,12 following
a potent method based on a four-step synthetic sequence, starting
from readily available cyclohex-3-enecarboxylic acid (9), Curtius
reaction, stereoselective bromination leading to major 7-trans-bu-
tyl (benzyl) 7-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (or
2,2,2-trifluoroacetamides), followed by NaH-mediated intra-
molecular cyclization (Scheme 1).12,13
NaH, DMF
65%
+
Cl
10
12
11
NHR
NHR
Br2,
Et4NBr
from
15
NHR
6 (5%)
+
Br
Br
Br
Br
Br
13
R
N
15
14 (66%)
Br
Curtius
Br2
NaH, DMF
Br
Cl
1,3-dichlorobenzene,
K2CO3, 130 ºC, 3 d
CO2H
(9)
NHR
N
NHR
R:
(R= BOC, CO2Bn, COCF3)
R
Y
Scheme 1.
N
Cl
X
N
X
Our current interest in the synthesis and biological evaluation of
new epibatidine analogues,14 prompted us to apply this strategy to
prepare epibatidine analogues of type I (N-arylmethyl-7-azabicy-
clo[2.2.1]heptanes) (Fig. 2). Here we are reporting the synthesis of
N-arylmethyl-7-azabicyclo[2.2.1]heptanes 4, 6–8 (Fig. 2). In addi-
tion, we include DFT-based studies aimed at explaining the ob-
served stereoselectivities during the bromination reactions, as well
as the mechanism of the heterocyclization.
6 X= Br (77%)
4 X= H
HSnBu3
(see Text)
8 X= N, Y=CH
16 X= CH, Y= N
+
Scheme 2.
route b
NRBoc
NRBoc
2. Results and discussion
Br2,
Et4NBr
+
12
2.1. Synthesis and reactivity
Br
Br
Br
Br
According to our plan, we selected the Boc-carbamate 10,12,13
and submitted it to N-alkylation with 2-chloro-5-(chloro-
methyl)pyridine (11) to give carbamate 12 in 65% yield (Scheme 2).
At this point two routes have been investigated in order to obtain
compound 6 (Fig. 2): (route a) Boc-deprotection on carbamate 12,
followed by bromination and ring closure (Scheme 2), and (route b)
bromination of compound 12 followed by Boc-deprotection and
heterocyclization (Scheme 3).
Cl
N
17 (93%)
18 (3%)
TFA
(from 17)
R:
14 (99%)
1,3-dichlorobenzene,
K2CO3, 130 ºC
Accordingly, and following route a, the reaction of compound
12 with trifluoroacetic acid followed by treatment of the crude
[(6-chloropyridin-3-yl)methyl]cyclohex-3-enamine (13), without
isolation, with bromine, under the usual conditions,13 gave (trans-3,cis-
4)-dibromo-N-[(6-chloropyridin-3-yl)methyl]cyclohexanamine (14)
(66% yield in two steps), and (cis-3,trans-4)-dibromo-N-[(6-chlor-
opyridin-3-yl)methyl]cyclohexanamine (15), not detected, that most
probably cyclized in situ once formed to give derivative 6 in 5% yield
(Scheme 2). In these mild bromination reaction conditions, the alter-
native partial rearrangement of the major dibrominated intermediate
14 to give compound 6 (see below) can be excluded. Very interestingly,
compound 6 was isolated in 77% yield by cyclization of (trans-3,cis-4)-
dibromocyclohexylamine 14 upon reaction with potassium carbonate
in 1,3-dichlorobenzene for 3 days at 130 ꢀC. In view of the 1,4-cis ar-
rangement between the nucleophile and the leaving group in
6 (77%)
Scheme 3.
compound 14 during the intramolecular SN2 reaction leading to
compound 6, this result was fortunate for our purposes, but surprising.
However, this reactivity has precedent in the work of Kapferer and
Vasella, who have shown that the base-catalyzed cyclization of trans-
3,cis-4-dibromocyclohexan-1-amine is possible, yielding 2-bromo-7-
tert-butoxy(carbonyl)-7-azabicyclo[2.2.1]heptane, upon N-carbonyla-
tion, in 62% yield.13 The authors suggested that under the forcing ex-
perimental conditions (K2CO3,1,3-dichlorobenzene,130 ꢀC) the diaxial
dibromide rearranged to the diequatorial, which cyclized to the aza-
norbornane derivative.13

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E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
Finally, treatment of bromide 6 with tributyltin hydride (slow
In conclusion, the bromination of compound 19 gave a mixture
of dibromides 20 and 21, where major 1,4-cis-dibromide 20 pre-
vailed. We must conclude that this seems to be a general reactivity
trend, as the bromination of related carbamate 23 afforded only
tert-butyl allyl[(trans-3,cis-4)-dibromocyclohexyl]carbamate (24),
easily transformed into secondary amine 2516,17 (Scheme 5) as
usual (see Supplementary data).
In this context, it is interesting to note that related precursors
substituted with a phenyl or aryl group at C2 give different ste-
reochemical outcome depending on the N-protecting group, pro-
viding major 1,4-cis18,19 and 1,4-trans-dibromides,20–22 from amine
and amide precursors, respectively. The reaction of N-methyl-
cyclohex-3-enamine with chlorine gives a 1:1 mixture of the two
trans-3,4-dichlorides,23 and the bromination of carbamate 10 af-
fords major 1,4-trans-dibromides.12,13
addition) gave a complex reaction mixture. In the GC/MS analysis of
the reaction crude we detected unreacted starting material 6 and
three new compounds (4/8/1615) (Scheme 2) in a 3:31:5 ratio. After
chromatography we were only able to isolate and characterize an
inseparable mixture of 4 and 8 in a 1:5.6 ratio (GC/MS). Alterna-
tively, the fast addition of HSnBu3, under otherwise identical re-
action conditions, gave a mixture of compounds 4 and 8, in a 1:1
ratio, as determined by GC/MS, and pure 7-[(6-chloropyridin-3-
yl)methyl]-7-azabicyclo[2.2.1]heptane (4) (37%). Product 4 was
known and showed spectroscopic data in good agreement with
those reported in the literature.8 The fact that the fast addition
provided higher yields and less side products was an unexpected
result but we have found no explanation for such outcome.
In conclusion, compounds 4 and 6 were obtained from carba-
mate 10 in four steps in 19%, and in three steps in 51% overall yield,
respectively. In this sequence we observed that the bromination
of N-[(6-chloropyridin-3-yl)methyl]cyclohex-3-enamine (13) gave
mainly (trans-3,cis-4)-dibromo-N-[(6-chloropyridin-3-yl)methyl]-
cyclohexanamine (14), whose base-mediated cyclization cleanly
occurred to give exo-2-bromo-7-[(6-chloropyridin-3-yl)methyl]-7-
azabicyclo[2.2.1]heptane (6) in good yield.
Next we tested route b in order to improve the process. Bro-
mination of carbamate 12 gave major 1,4-cis-dibromide 17 (93%),
accompanied by minor 1,4-trans-dibromo 18 (3%) derivative. Acid
hydrolysis of compound 17 quantitatively provided dibromide 14,
which smoothly cyclized to afford compound 6, in three steps, in
a 71% overall yield from carbamate 12 (Scheme 3). Thus, not only
the yield was higher than in route a (Scheme 2), but the bromi-
nation reaction still afforded major cis-1,4-isomer 17.
Thus, route b was used in further developments on this chem-
istry, and successfully applied for the synthesis of compound 7
(Fig. 2), bearing a N-benzyl moiety. Thus, starting from carbamate
10 NaH-mediated alkylation with benzyl bromide gave compound
19 in 75% yield,16 whose bromination gave a mixture of dibromides
20 and 21, where 1,4-cis-dibromide 20 prevailed (79% yield)
(Scheme 4). Next, acid hydrolysis, to give amine 22, followed by
base-mediated cyclization, provided compound 7 in 30% yield
(Scheme 4).
2.2. Computational chemistry: reaction mechanisms
To account for these experimental observations and get insights
into the reaction pathways, we have carried a series of DFT calcu-
lations. We have first examined the mechanism of the bromination
reaction. The results are used to discuss the factors that modulate
the observed stereochemical outcome favoring the formation of
major 1,4-cis-dibromides (Schemes 2–4). Next, a study on the
mechanism of the base-mediated heterocyclization of 1,4-cis-
dibromides is presented.
2.2.1. Computational analysis of the mechanism of the bromination
reactions. We have established that major 1,4-cis-dibromides (14,
17, and 20, Schemes 2–4) are obtained in the bromination reactions
of the corresponding cyclohex-3-enamine derivatives 12, 13, and
19, respectively, by using Br2/Et4NBr as brominating system. As
detailed above, under the same experimental conditions, related
precursors substituted with a phenyl or aryl group at C2 give dif-
ferent stereochemical outcome depending on the N-group, pro-
viding major 1,4-cis18,19 and 1,4-trans-dibromides,20–22 from amine
and amide precursors, respectively. Furthermore, the bromination
of a Boc-carbamate (NHBoc) or trifluoroacetamide (NHCOCF3)
affords major 1,4-trans-dibromides.12,13
According to these results, the stereoselectivity of the bromina-
tion would be dependent on the nature of the N-protecting group:
1,4-trans-dibromides (i.e., 3R,4S-dibromides) are predominantly
formed from amide and carbamate precursors [–NHCO(O)], while
1,4-cis-dibromides (i.e, 3S,4R-dibromides) result from other pre-
cursors, bearing bulky N-protecting groups (benzyl arylmethyl), and
lacking acidic proton. As proposed by Vasella and Kapferer,13 this
stereoselectivity points to a key role of the –NHR moiety, which may
act as hydrogen-bond donor and promote the nucleophilic attack by
anchimeric assistance. This assistance between the brominating
agent and the –NHR moiety can be envisioned to proceed by different
modes:13 (i) through the formation of H-bond with the nucleophilic
Brꢁ;24 (ii) H-bond with the Brꢁ3 formed;25 (iii) H-bond with
the leaving Brꢁ.26 These hypotheses have been explored by compu-
tational methods in order to formulate a consistent reaction
mechanism.
Bn
Boc
Bn
Boc
Boc
Bn
N
N
N
Br2,
NaH, BnBr,
DMF
Et4NBr
+
10
Br
Br
Br
Br
19 (75%)
21 (1.3 %)
20 (79%)
(from 20)
TFA
NHBn
Bn
N
K2CO3
Br
1,3-dichlorobenzene
130 ºC
Br
Br
22 (96%)
7 (31%)
In addition, it should be expected that the effective formation of
an H-bond, related with the pKa value, would induce an efficient
Scheme 4.
Br
NaH, DMF
H
N
NBoc
TFA
NBoc
Br2, Et4NBr
10
Br
Br
Br
25 (96%)
Br
24 (74%)
23 [68% (78%)]
Scheme 5.

E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
9227
bromination reaction. Hence, the estimation of theoretical de-
scriptors related with the pKa should provide insights into the
strength of the H-bond, and thus, into the anchimeric assistance
capability. Among others, the NPA charge has been shown to be an
effective descriptor for the determination of pKa.27 The more pos-
itive the NPA charge on the proton atom, the more acidic (i.e., lower
pKa) the compound is, and as a result, the higher the tendency to
bind one of the above-mentioned Br-species and promote the re-
action. To cover a wide pKa range, we have also considered the
bromination of cyclohexenes 12 (Scheme 2), 13 (Scheme 2), 19
(Scheme 4), 26,28 27,28 and 2812 (Scheme 6).
The calculations have shown that the H-bond inhibits the
bromination when it engages the nucleophilic Brꢁ [mode (i)]: the
Br–H electrostatic interaction stabilizes the bromide as anionic
entity, consequently interfering with the nucleophilic addition.
Similarly, the H-bond with Brꢁ3 [mode (ii)] promotes the Br2 re-
lease, which then forms a stable
p-complex with the alkene,
rather than adding to the unsaturated moiety. Regarding both
situations (i) and (ii) all our efforts to locate the pertinent tran-
sition structure, with or without explicit consideration of NEt4þ
group, were unsuccessful, and instead
p-complexes were found.
So, after discarding modes (i) and (ii), we have effectively located
an H-bonded transition structure driving concertedly to the
dibromide product following mode (iii), i.e., formation of H-bond
with the leaving Brꢁ. The ionization of the initially formed 1:1
O
Cl
H
N
alkene–Br2
p-complex to a bromocarbenium bromide ion pair by
Et4NBr,
Br2
HN
H
N
N
N
formation of an H-bond with the leaving Brꢁ, assists an easier Br–
Br bond breaking, which indeed promotes the rate-limiting
N
+
O
Cl
Br
O
Cl
Brꢁ backside nucleophilic attack on the
p
-complex.26a,29
Br
Br
29 (62%)
30 (12%)
Br
26
According to the proposed model, the stereoselectivity can be
rationalized as depicted in Scheme 7. For precursors lacking acidic
proton, such as compounds 12 or 19, the reaction would likely take
place through diaxial bromination of the preferred pseudoequato-
rial conformer, lower in energy than the pseudoaxial conformer due
to the steric hindrance, to yield preferentially the 1,4-cis-dibromides
according to the Fu¨rst–Plattner rule. On other hand, the presence of
the –NHR fragment favors the pseudoaxial disposition by H-bond
NHTs
NHTs
NHTs
Et4NBr,
Br2
Br
+
Br
Br
Br
31 (70%)
27
32 (20%)
O
O
NHR
NHR
+
NHR
Et4NBr,
Br2
R
formation with Br2 in the
p-complex, which induces the Br2 ioni-
zation. This complex would then be trapped by the nucleophilic Brꢁ,
leading to the 1,4-trans-dibromide.
Br
Br
N
ref. 12
Br
34 (30%)
Br
33 (59%)
Cl
28
A close inspection of the transition structures provides further
support for this different behavior. TStrans for 27 shows a stronger
H-bond (i.e., shorter bond) than TStrans for 13 (2.318 vs 2.481 Å)
Scheme 6.
δ
Br
δ
Br
Br
NRR'
Br
Br2/Et4NBr
R' = H
- Et4NBr
NRR'
NRR'
or R' = H,
Et4N, Br
TScis
high pKa
1,4-cis-dibromides
δ
δ
H
N
Br
Br
NHR
Br
R
NRR'
Br2/Et4NBr
R' = H
- Et4NBr
low pKa
Br
1,4-trans-dibromides
Cl
Et4N, Br
N
N
TStrans
12: R=
, R'=Boc
Cl
13: R=
, R'=H
19: R=Bn, R'=Boc
27: R=Ts, R'=H
O
Cl
O
N
O
26: R=
, R'=Boc
28: R=
, R'=H
N
Cl
Scheme 7.

9228
E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
hence inducing a higher ionization of the Br1–Br2 bond, and the
transition state is reached at a shorter Br1–Br2 bond length (3.567
vs 5.007 Å). The bromonium character is therefore achieved earlier
for sulfonamide 27 than for amine 13, promoting the backside
nucleophilic attack, as suggests the larger asynchronicity of the
Br–C forming bonds for 27.
We have taken into account the difference between transition
state free-energy for the formation of the 1,4-cis and 1,4-trans-
dibromide adducts in solution (DDG#(cisꢁtrans)), and compared it
with the experimental cis/trans ratio (Table 1).
Conversely, Vasella and Kapferer have reported that both isomers,
tert-butyl 3-cis,4-trans-dibromocyclohexylcarbamate (3R,4S-dia-
stereoisomer) and tert-butyl 3-trans,4-cis-dibromocyclohexyl-
carbamate (3S,4R-diastereoisomer), can be transformed intoa single
tert-butyl-exo-2-bromo-7-azabicyclo[2.2.1]heptane-7-carboxylate,
under the same basic conditions used by us.13 These authors have
assumed that at high temperature reaction (130 ꢀC) the diaxial
(3S,4R)-dibromide rearranges to the (3R,4S)-isomer that cyclizes to
the corresponding 7-azanorbornane,13 which is supported by pre-
vious results from our laboratory.12
Therefore, it may be supposed that dibromides 14 and 22 might
undergo a similar rearrangement, justifying the formation of such
reaction products 6 and 7 showing the exo-orientation of Br–C2.
That is, the high temperature should allow the rearrangement from
the 3S,4R-dibromide to the 3R,4S-isomer by passing through the
cis–trans isomerization transition state. The ensuing cyclization of
the 3R,4S-diastereomer should lead to the azabicyclic adducts 6 and
7. Alternatively, the direct cyclization from the 3S,4R-dibromide
would drive to the epimers 60 and 70, showing endo-orientation of
Br–C2. In order to account for the experimental observations, we
have carried out a computational analysis.
The isomerization of 1,4-cis to 1,4-trans (that is, 3S,4R-/3R,4S-
dibromide) proceeds through the transition structure TSisom where
the concerted bond forming/breaking at C3 and C4 takes place in
a nearly synchronous mode (Fig. 3). This step involves a rather high
free-energy barrier (27.03 kcal molꢁ1), probably as a result of the
steric distortion required to attain the transition state. However,
alternative stepwise pathways have not been found.
Table 1
Relationship between experimental cis/trans ratio of dibromide products and
computed results (NPA charges, energy differences between precursor conformers,
and relative activation barriers)
DDG#
(cisꢁtrans)
b
c
Precursor –NRR0
cis/trans NPA
ratio
D
E(eqꢁax)
charge (kcal molꢁ1
on Ha
)
(kcal molꢁ1
)
13
12
19
26
27
28
Secondary amine
66:5
Carbamate; R,R0sH 93:3
Carbamate; R,R0sH 79:1.3
0.4048 ꢁ1.04
ꢁ1.01
ꢁ7.32
ꢁ7.54
þ3.29
þ1.11
þ1.48
d
d
ꢁ2.12
ꢁ2.36
Amide; R¼H
Sulfonamide; R¼H 20:70
Carbamate; R¼H 30:59
12:62
0.4411 þ0.14
0.4392 þ0.92
0.4376 ꢁ0.22
a
On the pseudoaxial conformer.
b
Total energy difference between pseudoequatorial and pseudoaxial conformer
precursors in solution (
E(eqꢁax)¼EeqꢁEax).
D
c
Free-energy difference between transition states for the formation of the 1,4-cis
and 1,4-trans-dibromide adducts in solution (DDG#
¼
D
D
G#cisꢁ G#trans).
(cisꢁtrans)
The results depicted in Table 1 clearly support the proposed key
role of the acidic properties of the amine/amide proton and the
conformational equilibrium of the precursor (governed by the
bulkiness of the N-protecting groups) on the bromination stereo-
selectivity. Thus, the NPA charges on H plotted against experi-
mental cis/trans ratio indicate a noteworthy linear dependence
(R2¼0.997). Also, the conformational energy differences show
a correlation with the experimental results (R2¼0.790). Whereas
bulky protecting groups clearly favor a pseudoequatorial arrange-
ment, the presence of a single functionality reduces the energy
difference in relation to the pseudoaxial conformer.
With these results in hand, the computed energy differences
between the stereoisomeric transition structures show the expec-
ted trend (Table 1). That is, the presence of only one protecting
group and acidic proton reduces the preference for the pseudoe-
quatorial conformer in relation to the pseudoaxial conformer
Figure 3. Transition structure for the 1,4-cis/1,4-trans isomerization, TSisom, for 22.
Distances are shown in angstroms (Å).
The complete mechanistic scheme (isomerizationþcyclization)
to justify the stereochemistry shows some similarities with
a pathway proposed by Fletcher and co-workers to account for the
formation of the exo-7-benzyl-7-azabicyclo[2.2.1]heptan-2-ol from
the cis-(N-benzylamino)cyclohexane 1,2-epoxide. They suggested30
that the presence of a nucleophile in the reaction medium might
cause initial 1,2-diaxial ring opening of the epoxide (dibromide
isomerization), that after transannular displacement of this nucleo-
phile by the amino substituent (1,4-trans cyclization) would lead to
the azabicycle skeleton and regeneration of the nucleophile.
The calculations have revealed that the base-promoted hetero-
cyclization proceeds through a barrierless proton abstraction by
CO23ꢁ followed by the intramolecular nucleophilic attack of the
activated N to the C4 position.12
(
D
E(eqꢁax), Table 1), where the formation of H-bond promotes the
Br2 ionization in the -complex (26–28), which is then more easily
p
trapped kinetically by the nucleophilic entity to afford major 1,4-
trans-dibromides (DDG#(cisꢁtrans)>1 kcal molꢁ1). Otherwise, pre-
cursors lacking acidic proton (13) or bearing two protecting groups
(12, 19) undergo bromination of the favored, less congested,
pseudoequatorial conformer (
D
E(eqꢁax)¼ꢁ1 to ꢁ2.4 kcal molꢁ1),
yielding major 1,4-cis-dibromides (DDG#(cisꢁtrans)<ꢁ1 kcal molꢁ1).
In summary, the stereoselectivity would be governed by the
ability of the –NHR group to act as H-donor (pKa value) and to
provide anchimeric assistance, and also by the energy difference
between pseudoaxial and pseudoequatorial conformers of the
cyclohexene precursor. While these relationships are likely to fail to
provide quantitative accuracy, the proposed model should supply
reasonable results for qualitative purposes.
For the syn-nucleophilic attack, the free-energy barrier to reach
the transition structure, TS1,4cis (N–C¼2.687 Å for 14, 2.635 Å for
22), is high and almost the same for both dibromides: 32.51 for 14
and 32.16 kcal molꢁ1 for 22.
On the other hand, and as expected, the free-energy barrier to
reach the transition structure TS1,4trans (N–C¼2.632 Å for 14,
2.616 Å for 22) is about 25 kcal molꢁ1lower (6.68 Å for 14,
6.53 kcal molꢁ1 for 22) than that computed for the cyclization from
the cis isomer.
2.2.2. Computational analysis for the mechanism for the hetero-
cyclization reaction. The base-mediated cyclization of the 1,4-cis-
dibromides 14 and 22 to give the ring closure derivatives 6 and 7,
respectively (Schemes 2 and 4), was unexpected in view of
the precedent for unsuccessful cyclization of the related 3-trans,
4-cis-dichloro-N-methylcyclohexanamine (3S,4R stereoisomer).23
In summary, according to these results, the most favorable het-
erocyclization pathway should lead to 6 and 7 through a mechanism

E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
9229
where the rate-determining step is the 3S,4R-/3R,4S-dibromide
isomerization. This configurational change, nevertheless, requires
a relatively high temperature to succeed. Other steps, such as cy-
clization or ring conformational interconversion,31 are kinetically
more accessible.
real points. NOESY experiments were acquired with a mix time of
300 ms. Mass spectra were recorded on a GC/MS spectrometer with
an API-ES ionization source. Elemental analyses were performed at
CQO (CSIC, Spain). TLC was performed on silica F254 and detection
by UV light at 254 nm or by charring with either ninhydrin, ani-
saldehyde or phosphomolybdic/H2SO4 dyeing reagents. Where
anhydrous solvents were needed, they were purified following the
usual procedures. In particular, dry DMF was critical for the out-
come of the cyclization reaction, and was either distilled at reduced
pressure or bought from commercial sources. Column chromatog-
raphy was performed on silica gel 60 (230 mesh).
3. Conclusions
To sum up, in this manuscript we have reported two new
methods for the synthesis of epibatidine analogues bearing the N-
aryalkyl and the N-aryl-7-azabicyclo[2.2.1]heptane skeleton. Re-
garding the synthesis of N-arylalkyl-7-azabicyclo[2.2.1]heptanes
we have explored two synthetic alternatives. Route a is based on
the deprotection of N-protected, N-(arylmethyl)cyclohex-3-en-
amines, bromination of the resulting secondary cyclohex-3-en-
amines, followed by base-promoted cyclization, while route
b proceeds by bromination of N-protected, N-(arylmethyl)cyclo-
hex-3-enamines followed by deprotection and by base-mediated
cyclization. Overall, the last approach is more efficient, and has
been used for the synthesis of exo-2-bromo-7-azabicyclo[2.2.1]-
heptanes 6 and 7. In these processes we have observed that the
highly stereoselective bromination of precursors 13, 12, and 19,
leads to major trans-3-cis-4-dibromides 14, 17, and 20, whose base-
mediated heterocyclization on compound 14, or the two-step
deprotection plus base-promoted cyclization on intermediates 17
and 20, gave products 6 and 7 in good yield. Consequently, the
trans-3-cis-4-dibromide intermediates 14 and 22 cleanly afforded
the exo-2-bromo-7-azabicyclo[2.2.1]heptanes 6 and 7. Compound 4
was obtained by tributyltin hydride reduction of bromide 6.
Furthermore, mechanistic DFT-based studies have been carried
out on the bromination and heterocyclization reactions to explain
the observed results. The calculations have allowed us to propose
a reasonable pathway for the bromination by the Br2/NEt4Br system
to account for the stereochemical outcome. The stereoselectivity
can be rationalized by an anchimeric assistance of the NHR sub-
stituent. The presence of an acidic H gives rise to the effective
formation of an H-bond of the pseudoaxial conformer with Br2,
4.1.1. tert-Butyl (6-chloropyridin-3-yl)methyl(cyclohex-3-enyl)car-
bamate (12). To
a
solution of carbamate 1012,13 (908 mg,
4.60 mmol) in dry DMF (54 mL, 0.09 M), NaH (415 mg, 10.38 mmol,
2.2 equiv, 60% in oil) was added, and the mixture was stirred for
15 min at 0 ꢀC. Then, halide 11 (1.0 g, 6.02 mmol, 1.3 equiv) was
added and the mixture was stirred for 54 h at rt. Water was added,
and the mixture was extracted with ethyl ether (ꢂ4). The organic
phase was washed with brine, dried with MgSO4, filtered, and
evaporated. The crude was submitted to chromatography (10%
hexane/AcOEt) to give recovered unreacted starting material 10
(120 mg) and compound 12 [959 mg, 65% (74%)]: white solid; 71–
73 ꢀC; IR (KBr)
n ;
3035, 2977, 1691, 1588, 1567, 1461, 1415, 1164 cmꢁ1
1H NMR (CDCl3, 500 MHz)
d
8.26 (dd, J¼0.6, 2.6 Hz, 1H, H20), 7.63–
7.47 (m, 1H, H40), 7.26 (d, J¼8.1 Hz, 1H, H50), 5.64–5.52 (m, 2H, H3,
H4), 4.50–4.20 (m, 3H, CH2N, H1, invertomer I), 4.05–3.87 (m,
invertomer II), 2.26–1.95 (m, 4H, 2ꢂH2, 2ꢂH5), 1.74–1.56 (m, 2H,
2ꢂH6), 1.56–1.21 (m, 9H); 13C NMR (CDCl3, 125 MHz)
d 156.2, 155.4
(NCOO), 149.9 (C20, invertomer I), 148.4 (C60, C20, invertomer II),
138.2, 137.2 (C40), 135.0 (C30), 126.7 (2ꢂCH, C3, C4), 125.2, 124.0
(C50), 80.5 (C–O), 53.6, 52.0 (C1), 43.8 (CH2N), 30.0, 29.6 (C2 ), 28.5
[(CH3)3], 27.9, 27.6 (C6), 25.9 (C5
*
); MS (ES) m/z [Mþ1]þ *323.0/
325.0, [Mþ23]þ 345.0/347.0. Anal. Calcd for C17H23ClN2O2: C, 63.25;
H, 7.18; N, 8.68. Found: C, 62.96; H, 7.47; N, 8.76.
4.1.2. Acid hydrolysis and bromination of tert-butyl (6-chloropyridin-
3-yl)methyl(cyclohex-3-enyl)carbamate (12). To a solution of car-
bamate 12 (144 mg, 0.45 mmol) in dry CH2Cl2 (9 mL, 0.05 M) at rt,
under argon, trifluoroacetic acid (0.64 mL, 8.60 mmol, 19.3 equiv)
was added. The mixture was stirred for 3 h. Then, the solvent was
removed, and an aqueous saturated K2CO3 solution and CHCl3 (ꢂ4)
were added. The combined organic phase was dried over K2CO3,
filtered, and evaporated. The crude intermediate 13 (110 mg,
0.49 mmol) was submitted to bromination as follows. To a solution
of this amine in dry CH2Cl2 (6 mL, 0.08 M), Et4NBr (1.04 g,
4.93 mmol, 10.0 equiv) was added at rt under argon. After stirring
for 5 min, the mixture was cooled at ꢁ78 ꢀC, and bromine (0.1 mL,
1.95 mmol, 4.0 equiv) was added, the mixture was stirred at this
temperature for 20 min, and warmed at rt. Then, an aqueous sat-
urated Na2S2O5 solution was added, and extracted with AcOEt (ꢂ4);
the organic phase was dried over Na2SO4, and evaporated, giving
a crude that was purified by chromatography (10% hexane/AcOEt),
affording (trans-3,cis-4)-dibromo-N-[(6-chloropyridin-3-yl)methyl]-
cyclohexanamine (14) (125 mg, 66%) and exo-2-bromo-7-[(6-chloro-
pyridin-3-yl)methyl]-7-azabicyclo[2.2.1]heptane (6) (7.5 mg, 5%).
thus promoting the Br2 ionization in the 1:1
p-complex, which is
then more easily trapped by the nucleophile to yield cis-3-trans-4-
dibromides in a concerted mechanism; otherwise, the bromination
takes place on the preferred pseudoequatorial conformation of the
precursor, hence affording trans-3-cis-4-dibromides. On other
hand, our results suggest that the cyclization of the 1,4-cis-dibro-
mides proceeds by an initial, rate-determining, isomerization of the
diaxial conformer of the trans-3-cis-4-dibromide.
4. Experimental part
4.1. General methods
Melting points were determined on a microscope type appara-
tus, and are uncorrected. 1H NMR and 13C NMR spectra were
recorded at rt in CDCl3, at 300, 400 or 500 MHz and at 75, 100 or
125 MHz, respectively, using solvent peaks (CDCl3: 7.27 (D), 77.2
(C) ppm; D2O: 4.60 ppm) as internal reference. The assignment of
chemical shifts is based on standard NMR experiments (1H, 13C-
DEPT, 1H,1H-COSY, gHSQC, gHMBC). In the NMR spectra values with
Compound (14): white solid; 67–69 ꢀC; IR (KBr)
2918, 1585, 1568, 1428, 1108 cmꢁ1; 1H NMR (CDCl3, 500 MHz)
d
n
3450, 3280, 2956,
8.33
(
*
) can be interchanged. Values with (0) show the invertomers,
when distinguishable. For compounds 14, 17, 18, and 20 the con-
formation and relative configuration were determined at 55 ꢀC
from 1H,1H-COSY and NOESY spectra (see Supplementary data).
Two-dimensional [1H, 1H] NMR experiments (COSY and NOESY)
were carried out with the following parameters: a delay time of 1 s,
a spectral width of 3000 Hz in both dimensions, 4096 complex
points in t2 and 4 transients for each of 256 time increments, and
linear prediction to 512. The data were zero-filled to 4096ꢂ4096
(d, J¼2.2 Hz, 1H, H20), 7.68 (dd, J¼2.4, 8.3 Hz, 1H, H40), 7.29 (d,
J¼8.3 Hz, 1H, H50), 4.60 (td, J¼3.4, 3.7 Hz, 1H, H3), 4.50 (ddd, J¼3.6,
3.7, 3.9 Hz, 1H, H4), 3.82 (d, J¼2.2 Hz, 2H, CH2N), 3.06 (tt, J¼3.9,
10.4 Hz, 1H, H1), 2.46 (dddd, J¼3.7, 4.3, 12.0, 15.4 Hz, 1H, H5ax), 2.27
(ddd, J¼3.4, 10.4, 14.4 Hz, 1H, H2ax), 2.21 (ddd, J¼3.7, 3.9, 14.4 Hz,
1H, H2eq), 1.99 (m, 1H, H5eq), 1.78 (m, 1H, H6eq), 1.64 (m, 1H, H6ax),
1.33 (br s, 1H, NH); 13C NMR (CDCl3, 125 MHz)
d
150.2 (C60), 149.4
(C20), 138.9 (C40), 135.0 (C30), 124.2 (C50), 53.1 (C4), 52.6 (C3), 51.3

9230
E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
(C1), 47.6 (CH2N), 36.1 (C2), 28.6 (C5), 28.1 (C6); MS (ES) m/z
[Mþ1]þ 380.9/382.9/384.9. Anal. Calcd for C12H15Br2ClN2: C, 37.68;
H, 3.95; N, 7.32. Found: C, 37.84; H, 4.06; N, 7.31.Compound (6):
added until a persistent color was observed. The mixture was
washed with an aqueous saturated KF solution, and the organic
phase was dried over MgSO4, filtered, and evaporated. The crude was
purified by chromatography (CH2Cl2/0.5% CH2Cl2/CH3OH/1%
CH2Cl2/CH3OH) to give an unseparable mixture of 7-[(6-chloro-
pyridin-3-yl)methyl]-7-azabicyclo[2.2.1]heptane (4) and 8 (14.2 mg;
analysis by coupled GC/MS of the mixture showed two compounds
(8 and 4) in a 1:1 ratio, respectively), and pure 7-[(6-chloropyridin-3-
yl)methyl]-7-azabicyclo[2.2.1]heptane (4) (9.1 mg, 37%) {1H NMR
white solid; 154–156 ꢀC; IR (KBr)
1324, 1101 cmꢁ1 1H NMR (CDCl3, 300 MHz)
n
3044, 2967, 1586, 1567, 1458,
;
d
8.39 (br s, 1H, H20),
7.96 (dm, J¼8.1 Hz, 1H, H40), 7.32 (d, J¼8.1 Hz, 1H, H50), 3.94 (dd,
J¼3.3, 7.8 Hz, 1H, H2), 3.84 (d, J¼14.2 Hz, 1H, CH2), 3.52 (d,
J¼14.2 Hz, 1H, CH2), 3.44–3.34 (m, 2H, H1, H4), 2.30 (dm, J¼13.5 Hz,
1H, H3endo), 2.30 (dd, J¼7.8, 13.8 Hz, 1H, H3exo), 1.59–1.55 (m, 2H,
H5exo, H6exo), 1.49–1.45 (m, 2H, H5endo, H6endo); 13C NMR (CDCl3,
(CDCl3, 500 MHz)
d
8.34 (d, J¼2.3 Hz, 1H, H20), 7.87 (br s, 1H, H40),
75 MHz)
d
150.2 (C60), 149.3 (C20), 139.1 (C40), 134.5 (C30), 124.2
7.32 (d, J¼8.1 Hz, 1H, H50), 3.59 (br s, 2H, CH2N), 3.28 (br s, 2H, H1,
(C50), 67.2, 60.6 (C1, C4), 50.4 (C2), 48.2 (CH2N), 43.9 (C3), 26.0, 25.7
(C5, C6); MS (ES) m/z [Mþ1]þ 301.0/303.0. Anal. Calcd for
C12H14Br2BrClN2: C, 47.79; H, 4.68; N, 9.29. Found: C, 47.56; H, 4.51;
N, 9.24.
H4), 1.93–1.78 (m, 4H), 1.46–1.32 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d
149.8 (C20, C60), 139.7 (C40), 134.6 (C30), 124.3 (C50), 59.8 (C1, C4),
48.5 (CH2N), 28.4 (br, 4ꢂCH2); MS (ES) m/z [Mþ1]þ 223.3/225.3} that
showed spectroscopic data identical to those described by Trudell
and co-workers.8
4.1.3. exo-2-Bromo-7-[(6-chloropyridin-3-yl)methyl]-7-azabicy-
clo[2.2.1]heptane (6) from amine 14. To a solution of compound 14
(347 mg, 0.91 mmol) in 1,3-dichlorobenzene (40 mL, 0.023 M) at rt,
under argon, dry K2CO3 (129 mg, 0.93 mmol, 1.0 equiv) was added,
and the mixture was heated at 130 ꢀC for 3 days. Then, more K2CO3
(34 mg, 0.24 mmol, 0.27 equiv) was added, and after 7 h at the
same temperature the solvent was removed, and the crude sub-
mitted to chromatography (0.5%/1% CH2Cl2/MeOH) to give com-
pound 6 (211 mg, 77%).
4.1.5. Bromination of tert-butyl (6-chloropyridin-3-yl)methyl(cyclo-
hex-3-enyl)carbamate (12). Following the same method as de-
scribed for the bromination of amine 13 (see above), carbamate 12
(459 mg, 1.42 mmol) in dry CH2Cl2 (17 mL, 0.08 M) was reacted
with Et4NBr (3.00, 14.2 mmol, 10.0 equiv) and bromine (0.08 mL,
1.56 mmol, 1.1 equiv) for 2.5 h. Work-up and chromatography (10%
hexane/AcOEt) gave tert-butyl (6-chloropyridin-3-yl)methyl[(trans-
3,cis-4)-dibromocyclohexyl]carbamate (17) (639 mg, 93%), and
tert-butyl (6-chloropyridin-3-yl)methyl[(cis-3,trans-4)-dibromocy-
clohexyl]carbamate (18) (20 mg, 3%). Compound (17): white solid;
4.1.4. Reaction of exo-2-bromo-7-[(6-chloropyridin-3-yl)methyl]-7-
azabicyclo[2.2.1]heptane (6) with HSnBu3
87–89 ꢀC; IR (KBr)
1254, 1164 cmꢁ1
n
3086, 2975, 1735, 1694, 1586, 1568, 1462, 1367,
;
1H NMR (CDCl3, 300 MHz)
d
8.37–8.30 (m, 1H,
4.1.4.1. Slow addition of HSnBu3. To a deoxygenated solution of
product 6 (48.4 mg, 0.160 mmol) in dry toluene (8 mL, 0.02 M), under
argon, AIBN (3 mg) was added. Then, a solution of tributyltin hydride
(0.07 mL, 0.252 mmol, 1.57 equiv), AIBN (5 mg) in deoxygenated
toluene (1.6 mL) was slowly added in 6 h at 120 ꢀC. After the addition,
the reaction mixture was heated at the same temperature for 18 h.
Then, the mixture was cooled, and the solvent was removed. The
residue was dissolved in ethyl ether, treated with iodine, until per-
sistent color, washed with an aqueous saturated KF solution, and the
organic phase was dried with MgSO4, filtered, and evaporated. The
residue was submitted to chromatography (0.1% CH2Cl2/MeOH to
0.5% CH2Cl2/MeOH) giving recovered compound 6 (7.6 mg) and
a inseparable mixture of compounds (2-chloro-5,7,8,9,9a,10-hexa-
hydro-7,10-methanopyrrolo[1,2-g]-1,6-naphthyridine) (8) and 7-[(6-
chloropyridin-3-yl)methyl]-7-azabicyclo[2.2.1]heptane (4) (14.8 mg).
Analysis by coupled GC/MS of the mixture showed two compounds
(8 and 4) in a 5.6:1 ratio, respectively. Compound 8 (tR 26.99 min):
MS m/z 222 (34), 220 (100), 205 (76), 152 (77). Compound 4 (tR
26.04 min): MS m/z 224 (10), 222 (32), 193 (77), 166 (69), 126 (100).
H20), 7.68–7.55 (m, 1H, H40), 7.30 (d, J¼8.1 Hz, 1H, H50), 4.58 (q,
J¼2.6 Hz, 1H, H3), 4.49 (ddd, J¼2.6, 2.9, 3.5 Hz, 1H, H4), 4.50–4.35
(m, 2H, CH2N), 4.26 (br s, 1H, H1), 2.56–2.47 (m, 2H, H2ax, H5ax),
2.25–1.95 (m, 1H, H6ax), 1.80 (dm, J¼15.0 Hz, 1H, H2eq), 1.95–1.80
(m, 1H, H5eq), 1.57 (s, 1H, H6eq), 1.50 [br s, 9H, (CH3)3]; 13C NMR
(CDCl3, 75 MHz)
(C40), 134.4 (C30), 124.2 (C50), 81.0 (C–O), 52.6, 51.8 (C3, C4), 50.4
d
155.8 (NCOO), 150.3 (C60), 148.7 (C20), 138.3
(C1), 45.1 (CH2N), 32.8 (C5
*
), 28.6 [(CH3)3, C2 ], 25.2 (C6); MS (ES)
*
m/z [Mþ1]þ 481.0/483.0/485.0. Anal. Calcd for C17H23Br2ClN2O2: C,
42.31; H, 4.80; N, 5.80. Experimental: C, 42.60; H, 5.01; N, 5.80.
Compound (18): white solid; IR (KBr)
n 2931, 1691, 1460, 1366,
1164 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
8.26 (d, J¼2.1 Hz, 1H, H20),
7.59–7.46 (m, 1H, H40), 7.30 (d, J¼8.2 Hz,1H, H50), 4.50–4.18 (m, 2H,
CH2N), 4.18–3.94 (m, 2H, H1, H3), 3.88 (td, J¼4.4, 11.3 Hz, 1H, H4),
2.56–2.40 (m, 2H, H2eq, H5eq), 2.09 (q, J¼12.3 Hz, 1H, H2ax), 1.91 (q,
J¼12.7 Hz, 1H, H5ax), 1.78–1.50 (m, 2H, 2ꢂH6), 1.42 [br s, 9H,
(CH3)3]; 13C NMR (CDCl3, 75 MHz)
d
155.2 (NCOO), 150.5 (C60),
148.4 (C20), 137.4 (C40), 134.1 (C30), 124.4 (C50), 81.5 (C–O), 55.3
(C4), 54.2 (2ꢂCH, C1, C3), 44.6 (CH2N), 42.4 (C2), 36.4 (C5), 31.2
(C6), 28.5 [(CH3)3]; MS (ES) m/z [Mþ1]þ 481.0/483.0/485.0. Anal.
Calcd for C17H23Br2ClN2O2: C, 42.31; H, 4.80; N, 5.80. Found: C,
42.60; H, 4.91; N, 5.76.
A
y
Compounds 8þ4: (see text for discussion: assignments with
*
, ,
1
could be interchanged within each set of symbols) H NMR (CDCl3,
500 MHz)
d
8.34 (d, J¼1.7 Hz,1H, H20, 4), 7.88 (br s,1H, H40, 4), 7.33 (d,
J¼7.8 Hz, 1H, H3
*
, 8), 7.12 (d, J¼8.0 Hz, 1H, H4 , 8), 4.36 (d, J¼18.3 Hz,
*
1H, H5A, 8), 3.92 (d, J¼18.3 Hz, 1H, H5B, 8), 3.61 (br s, 2H, CH2N, 4),
3.51 (t, J¼4.4 Hz,1H, H7, 8), 3.30 (br s, 2H, H1, H4, 4), 3.22 (d, J¼4.9 Hz,
1H, H9aA, 8), 3.11 (d, J¼7.1 Hz, 1H, H10A, 8), 2.01–1.34 (m, 6H, 1; 8H,
4.1.6. Deprotection of tert-butyl (6-chloropyridin-3-yl)methyl[(trans-
3,cis-4)-dibromocyclohexyl]carbamate (17). To an argonized solu-
tion of carbamate 17 (122 mg, 0.25 mmol) in anhyd CH2Cl2 (6 mL,
0.04 M) TFA was added (0.36 mL, 4.89 mmol, 19.3 equiv). The
resulting solution was reacted at rt for 5 h, and then evaporated
under pressure. Then, K2CO3, aqueous saturated solution was
added, and extracted with CHCl3 (ꢂ5). The organic phases were
dried over K2CO3, thus obtaining the free amine 14 (96 mg, 99%).
4); 13C NMR (CDCl3, 125 MHz) 164.9 (8), 149.8 (C20, C60, 4), 147.7 (8),
d
139.8 (C40, 4), 136.6 (C3
121.8 (C4
*
, 8), 134.1 (C30, 4), 127.4 (8), 124.4 (C50, 4),
*
, 8), 64.7 (C7, 8), 61.6 (C9aA, 8), 59.9 (C1, C4, 4), 49.4 (C5, 8),
48.5 (CH2N, 4), 46.0 (C10A, 8), 39.4 (C8y, 8), 30.9 (C9y, 8), 27.0 (4C, 4),
26.6 (C11y, 8).
4.1.4.2. Fast addition of HSnBu3. To a deoxygenated solution of
bromide 6 (33.5 mg, 0.11 mmol) and AIBN (5 mg) in dry toluene
(2 mL, 0.45 M), HSnBu3 (0.04 mL, 0.14 mmol, 1.3 equiv) was added,
and the mixture was refluxed for 24 h. Then, the solvent was re-
moved, the residue was dissolved in ethyl ether and iodine was
4.1.7. tert-Butyl benzyl(cyclohex-3-enyl)carbamate (19). Following
the same method as described for the synthesis of carbamate 12
(see above), compound 10 (840 mg, 4.26 mmol) in dry DMF (36 mL,
0.19 M) was reacted with NaH (454 mg, 11.36 mmol, 2.67 equiv)
and benzyl bromide (1.24 mL, 10.22 mmol, 2.4 equiv) for 22 h at rt.

E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
9231
Work-up and chromatography (4% hexane/AcOEt) gave recovered
starting material (10) (57 mg) and compound 19 (916 mg [75%
(CH2N), 51.3 (C1), 36.5 (C2), 28.9 (C5), 28.4 (C6); MS (ES) m/z [Mþ1]þ
345.9/347.9/349.9. Anal. Calcd for C13H17Br2N: C, 44.99; H, 4.94; N,
4.04. Found: C, 44.70; H, 5.05; N, 4.26.
(80%)]): oil; IR (KBr)
n
3026, 2974, 1692, 1454, 1408, 1365,
7.40–7.19 (m, 5H, Ph), 5.58
1167 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
(s, 2H, H3, H4), 4.40 (br s, 3H, H1, CH2N), 2.12 (br s, 4H, 2ꢂH2,
4.1.10. 7-Benzyl-exo-2-bromo-7-azabicyclo[2.2.1]heptane (7). Following
the same method as described for the cyclization of amine 14 (see
above), compound 22 (117 mg, 0.34 mmol) in 1,3-dichlorobenzene
(18 mL, 0.02 M) was reacted with K2CO3 (49.1 mg, 0.36 mmol,
1.0 equiv) at 140 ꢀC for 2 days. Work-up and chromatography (12%
hexane/AcOEt) gave recovered starting material 38 (13 mg) and
2ꢂH5), 1.80–1.70 (m, 2H, 2ꢂH6), 1.40 (s, 9H, t-Bu); 13C NMR (CDCl3,
75 MHz)
d
156.0 (NCOO), 140.5 (Cipso, Ph), 128.3 (2ꢂCH, Ph), 126.7
(3ꢂCH, Ph), 126.6, 125.6 (C3, C4), 79.8 [OC(CH3)3], 52.3 (br, C1), 47.0
(CH2N), 29.0 (C2
*
), 28.5 [OC(CH3)3], 27.7 (C6), 26.1 (C5 ); MS (ES)
*
m/z [Mꢁ55]þ 232.1, [Mþ1]þ 288.0, [Mþ23]þ 310.0, [2Mþ23]þ
597.3. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C,
75.41; H, 8.52; N, 4.85.
compound 7 [28 mg, 31% (35%)]: oil; IR (film)
n 3026, 2965, 1452,
1233 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.56–7.46 (m, Ph), 7.38–
7.30 (m, Ph), 7.29–7.22 (m, Ph), 4.37–4.28 (m, H2, minor inver-
tomer), 3.93 (dd, J¼3.5, 7.8 Hz, H2, major invertomer), 3.87 (d,
J¼13.9 Hz, 1H, CH2N, major invertomer), 3.52 (d, J¼13.9 Hz, 1H,
CH2N, major invertomer), 3.62 (s, CH2N, minor invertomer), 3.50–
4.1.8. Bromination of tert-butyl benzyl(cyclohex-3-enyl)carbamate
(19). Following the same method as described for the bromination
of amine 13 (see above), to a solution of carbamate 19 (804 mg,
2.80 mmol) in 33 mL of anhyd DCM (0.09 M) under argon, Et4NBr
(5.891 g, 28.0 mmol, 10 equiv) was added. The solution was left
stirring at rt for some minutes. The temperature was then lowered
to ꢁ78 ꢀC and Br2 was added (0.16 mL, 3.08 mmol, 1.1 equiv). The
temperature was maintained for 3 h and then allowed to reach rt. A
saturated aqueous solution of Na2S2O5 was added until lack of color,
and the resulting solution was extracted with AcOEt (ꢂ4). The or-
ganic phases were dried over Na2SO4, and the solvents were
evaporated under reduced pressure. The crude thus obtained was
purified by chromatography (silica gel, 2%/4% hexane/AcOEt),
obtaining tert-butyl benzyl[(trans-3,cis-4)-dibromocyclohexyl]car-
bamate (20) (984 mg, 79%) and tert-butyl benzyl[(cis-3,trans-4)-
dibromocyclohexyl]carbamate (21) (16.8 mg, 1.3%). Compound (20):
3.44 (d, J¼4.3 Hz, H1
*
, major invertomer), 3.43–3.36 (d, J¼4.3 Hz,
H1 , H4
*
*
), 3.26 (t, J¼4.5 Hz, H4
*
, minor invertomer), 2.60–2.48,
2.36–2.26 (m, 1H), 2.08 (dd, J¼8.0, 13.8 Hz, 1H), 1.98–1.82 (m, 2H),
1.53–1.44 (m, 1H), 1.38–1.23 (m, 1H); 13C NMR (CDCl3, 100 MHz)
d
139.9 (Cipso), 128.6, 128.4, 128.3, 127.0 (5ꢂCH, Ph); 67.2 (C1
major invertomer), 64.5 (C1 , minor invertomer), 60.5 (C4 , minor
invertomer), 60.2 (C4 , major invertomer), 52.2 (CH2N), 51.5 (C2,
*
,
*
*
*
major invertomer), 50.8 (C2, minor invertomer), 44.1 (C3A, major
invertomer), 41.1 (C3A, minor invertomer), 27.9 (C5A, minor
invertomer), 26.0 (C5A, major invertomer), 25.7 (C6A, major
invertomer), 22.8 (C6A, minor invertomer); MS (ES) m/z [Mþ1]þ
266.0/268.0. Anal. Calcd for C13H16BrN: C, 58.66; H, 6.06; N, 5.26.
Found: C, 58.40; H, 6.22; N, 5.37.
white solid; 85–87 ꢀC; IR (KBr)
n
3056, 2976, 1676, 1366, 1241,
7.40–7.19 (m, 5H, Ph), 4.56
1160 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
4.2. Computational methods
(q, J¼2.7 Hz,1H, H3), 4.47 (ddd, J¼2.7, 3.0, 3.2 Hz,1H, H4), 4.51–4.34
(m, 2H, CH2N), 4.25 (br s, 1H, H1), 2.70–2.35 (m, 2H, H2ax, H5ax),
2.11 (m, 1H, H6ax), 2.05–1.75 (m, 2H, H2eq, H5eq), 1.50 [s, 10H,
All calculations were carried out with Gaussian98 and Gauss-
ian03 packages.32 All the minima and transition states were fully
optimized at the mPW1PW91 level,33 which has a similar form to
the B3LYP functional34 but has been proved more accurate.35 This
model uses the modified Perdew–Wang exchange functional that
has improved long-range behavior, has been reported to give better
results in some cases, usually for negatively charged species. The
standard 6-31G(d) basis set has been applied for all the atoms. To
get reliable energy values, single-point-energy calculations have
been carried out with the extended 6-311G(2d,p) basis set on the
optimized structures. Zero-point energies (ZPEs) and thermal
contributions to thermodynamic functions and activation param-
eters, as well as harmonic frequencies were computed at the same
level of theory on the optimized structures. Intrinsic reaction co-
ordinate, IRC, calculations36 at the optimization level of theory
were carried out on the transition structures to obtain the two
minima on the potential energy surface, PES, connected by each
transition state.
Solvent effects have been taken into account by the self-con-
sistent reaction field (SCRF) method using the so-called conductor
polarizable continuum model (CPCM)37 as implemented in Gauss-
ian03, in which the solvent is represented by an infinite dielectric
medium characterized by the relative dielectric constant of the
bulk. A relative permittivity of 8.93 and 2.8 was assumed to sim-
ulate DCM and 1,3-dichlorobenzene, respectively, as solvents.
Natural bond orbital (NBO) analyses38 have been performed by the
module NBO v.3.1 implemented in Gaussian03 to evaluate the NPA
charges and hyperconjugation effects on the optimized structures.
C(CH3)3, H6eq]; 13C NMR (CDCl3, 75 MHz)
d
155.7, 154.7 (NCOO),
139.8, 138.8 (Cipso, CH), 128.4 (2ꢂCH, Ph), 127.5, 127.0, 126.0 (3ꢂCH,
Ph), 80.2, 79.2 (C–O), 53.0 (b, C3 ), 52.1, 51.1 (C4 ), 50.2 (C1), 48.4,
*
*
47.5 (CH2N), 32.6, 31.7 (CH2), 28.6 (t-Bu), 27.6 (CH2), 24.9, 23.9
(CH2); MS (ES) m/z [Mꢁ55]þ 390.0/392.0/394.0, [Mþ23]þ 468.0/
470.0/472.0. Anal. Calcd for C18H25Br2NO2: C, 48.34; H, 5.63; N, 3.13.
Found: C, 48.48; H, 5.60; N, 3.36. Compound (21): oil; IR (KBr)
3026, 2968, 1689, 1452, 1164 cmꢁ1 1H NMR (CDCl3, 300 MHz)
7.39–7.11 (m, 5H, Ph), 4.70–4.15 (m, 2H, CH2N), 4.15–3.75 (m, 3H,
n
;
d
H1, H3, H4), 2.56–2.30 (m, 2H, H2eq, H5eq), 2.23–2.02 (m, 1H, H2ax),
1.97–1.77 (m, 1H, H5ax), 1.77–1.48 (m, 2H, 2ꢂH6), 1.41 (s, 9H, t-Bu);
13C NMR (CDCl3, 75 MHz)
d 155.4 (NCOO), 139.5 (Cipso, CH), 128.7
(2ꢂCH, Ph), 127.2, 126.8 (3ꢂCH, Ph), 80.7 (C–O), 55.8 (C1
*
), 54.8
(2ꢂCH, C3
*
, C4
), 47.8 (CH2N), 42.2 (C2A), 36.6 (C5A), 31.0 (C6A),
*
28.5 (t-Bu); MS (ES) m/z [Mꢁ55]þ 390.0/391.9/393.9, [Mþ23]þ
467.9/470.0/472.0. Anal. Calcd for C18H25Br2NO2: C, 48.34; H, 5.63;
N, 3.13. Found: C, 48.18; H, 5.67; N, 3.22.
4.1.9. (trans-3,cis-4)-N-Benzyl-3,4-dibromocyclohexanamine
(22). Following the same method as described for the acid hydro-
lysisof carbamate 17 (see above), compound 20 (199 mg, 0.45 mmol)
in dry CH2Cl2 (9 mL, 0.05 M) was reacted with TFA (0.64 mL,
8.62 mmol,19.3 equiv) at rt for 7 h. Work-up and chromatography as
usual gave amine 22 (149 mg, 96%): 34–35 ꢀC; IR (film)
2944, 1452, 1429, 1176 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
(m, 5H, Ph), 4.71–4.66 (m, Wtotalz19 Hz, 1H, H3), 4.59–4.53 (m,
n
3155, 3026,
7.35–7.24
d
W
totalz20 Hz, 1H, H4), 3.82 (d, J¼1.6 Hz, 2H, CH2N), 3.11 (tt, J¼4.0,
10.0 Hz, 1H, H1), 2.46 (ddt, J¼3.7, 11.5, 15.1 Hz, 1H, H5ax), 2.31 (ddd,
J¼3.4, 9.9, 14.4 Hz, 1H, H2ax), 2.20 (dm, J¼14.5 Hz, 1H, H2eq), 2.12–
2.03 (m, 1H, H5eq), 1.90–1.81 (m, 1H, H6ax), 1.80–1.68 (m, 1H, H6eq),
Acknowledgements
J.M.-C. thanks MEC (Spain) for a grant (SAF2006-08764-C02-
01), Comunidad de Madrid (S/SAL-0275-2006), Instituto de Salud
Carlos III [RED RENEVAS (RD06/0026/1002)].
1.43 (br s, 1H, NH); 13C NMR (CDCl3, 75 MHz)
d
140.6 (Cipso), 128.7
(2ꢂCH, Ph),128.3 (2ꢂCH, Ph),127.2 (CH, Ph), 53.6 (C4), 52.9 (C3), 51.4

9232
E. Go´mez et al. / Tetrahedron 65 (2009) 9224–9232
25. In the presence of added bromide salts, which in low polarity nonprotic
Supplementary data
solvents bind Br2 as a highly stable Brꢁ3 ion: Bakshi, P. K.; James, M. A.;
Cameron, T. S.; Knop, O. Can. J. Chem. 1996, 74, 559.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.09.013.
26. (a) Bellucci, G.; Chiappe, C.; Lo Moro, G. J. Org. Chem. 1997, 62, 3176; (b) Barili, P.
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