Synthesis of a cytisine/epibatidine hybrid: A radical approach

Article abstract of DOI:10.1016/j.tet.2010.09.079

With the aim of developing a new ligand of neuronal nicotinic receptors (nAChRs), ionic, and radical routes to the synthesis of a cytisine/epibatidine hybrid were studied. The key step of the convergent synthesis was an unprecedented intramolecular coupling between a primary radical and a pyridine heterocycle. The target compound '6,11-diaza' was formed with its '4,11-diaza' regioisomer ('6,11″/'4,11″: 70/30). Both compounds exhibited a nanomolar affinity at the α₄β₂ nAChR subtype, slightly better for the unexpected regioisomer [K_i (nM) target compound and its regioisomer: 3.5 and 0.5 nM, respectively].

Full text of DOI:10.1016/j.tet.2010.09.079

Tetrahedron 66 (2010) 9231e9241
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of a cytisine/epibatidine hybrid: a radical approach
,
Nicolas Houllier a, Marie-Claire Lasne a, Ronan Bureau b, Pierre Lestage c, Jacques Rouden a
*
a
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR 6507 CNRS, ENSICAEN-Universite de Caen Basse-Normandie, Institut Normand de Chimie Moleculaire,
ꢀ
ꢀ
ꢀ
Medicinale et Macromoleculaire (INC3M) FR 3038 CNRS, 6 Boulevard du Marechal Juin, 14050 Caen, France
b
ꢀ
ꢀ
Centre d’Etudes et de Recherche sur le Medicament de Normandie, INC3M FR 3038, CNRS, Universite de Caen Basse-Normandie, Boulevard Becquerel, 14032 Caen, France
c Institut de Recherche Servier, 125 Chemin de Ronde, F-78290 Croissy sur Seine, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2010
Received in revised form 9 September 2010
Accepted 15 September 2010
Available online 29 September 2010
With the aim of developing a new ligand of neuronal nicotinic receptors (nAChRs), ionic, and radical
routes to the synthesis of a cytisine/epibatidine hybrid were studied. The key step of the convergent
synthesis was an unprecedented intramolecular coupling between a primary radical and a pyridine
heterocycle. The target compound ‘6,11-diaza’ was formed with its ‘4,11-diaza’ regioisomer (‘6,1100/’4,1100:
70/30). Both compounds exhibited a nanomolar affinity at the a4b2 nAChR subtype, slightly better for the
unexpected regioisomer [Ki (nM) target compound and its regioisomer: 3.5 and 0.5 nM, respectively].
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cytisine
Nicotinic receptors
Radical
Cyclization
Piperidine
Pyridine
1. Introduction
the Ecuadorian frog Epipedobates tricolor, has a higher affinity than
(ꢀ)-cytisine toward a4b2 nAChRs and a powerful analgesic activity.
(ꢀ)-Cytisine1 and (ꢀ)-epibatidine2 (Fig. 1) are two natural
products known for their high affinity and selectivity at the a4b2
However, it is extremely toxic and therefore has limited therapeutic
potential. Both ligands have attracted interest as lead candidates for
the synthesis of analogues aimed at identifying structures with
improved pharmacological profiles,6 such as varenicline7 launched
in 2006 for smoking cessation treatment (Fig. 1).
nicotinic acetylcholine receptors (nAChRs),3
a subtype pre-
dominant in the central nervous system.4 (ꢀ)-Cytisine,5 extracted
from the seeds of Leguminosae plants, such as Laburnum Anagyr-
oides is commonly used as a reference for the binding affinity
evaluation of new nAChRs ligands. (ꢀ)-Epibatidine, isolated from
As a part of our continuing interest in finding selective ligands
for in vivo imaging,8 we envisaged the synthesis of the tricyclic
compound 1, which combines a 3-chloropyridyl unit and a rigid 11-
aza-tricyclo[7.3.1.02,3]tridecane skeleton, two important structural
features of the natural products epibatidine, and cytisine, re-
spectively (Fig. 1). The recent syntheses9 of pyridines analogues I of
(ꢀ)-cytisine, for which no biological data were reported, prompted
us to describe our approaches to compound 1.
The preparations of the four pyrido 11- azabicyclo[3.3.1]non-
anes I relied on the formation of the C1eC2 bond using Heck cy-
clization protocols. This approach, using the described conditions,
was not suitable for the preparation of compound 1 and the syn-
thesis of the starting material would require additional steps.
A few years ago, we described a formal synthesis of cytisine,10
based on a retrosynthetic strategy often used to access to cytisine
derivatives.11 The short convergent synthetic scheme (Scheme 1)
involved the formation the CeN bond of ring B via a straightfor-
ward intramolecular nucleophilic displacement of a leaving group
on piperidine ring A by the pyridine nitrogen of ring C in compound
Fig. 1. (ꢀ)-Cytisine, (ꢀ)-epibatidine and the target hybrid compound 1.
* Corresponding author. E-mail address: rouden@ensicaen.fr (J. Rouden).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.079

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N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
V. Our synthetic plan for tricyclic compound 1 relied on a more
challenging approach by creating the C7eC8 bond of ring B from
precursor W, similar to V.
1
HN
2
1
HN
A
2
A
C
B
C
B
N
5 Cl
7
7
8
N
8
O
Cytisine
1
a, b or c
LG
N
Y
8
8
A
A
1
1
2
N
2
7
PG
PG
C
C
7 N
5
V
X
N
Cl
W
OMe
M
CO2Et
M
X
C
N
C
A
N
7 N
5
Cl
OMe
Br
Scheme 2. Reagents and conditions. (i) X¼H, Y¼B(OH)2: Pd(OAc)2, dppf, CsF, DME,
80 ꢁC, 5 h; 4: 86%; (ii) X¼Cl, Y¼Sn(n-Bu)3: Pd2(dba)3, P(o-Tol)3, CuI, dioxane, 130 ꢁC,
16 h; 6: 72%; (iii) 4-methoxybenzyl chloride, KI, MeCN, 80 ꢁC; 8: 98%; 10: 98%; (iv)
NaBH3CN, AcOH, EtOH, 20 ꢁC, 3 h; 9: cis 45%, trans 15%; 11 cis 33%; (v) LiAlH4, Et2O, 1 h,
ꢀ20 ꢁCe0 ꢁC; 12: 89%; 14: 92%; (vi) 13a: MsCl, NEt3, CH2Cl2, 0 ꢁC to room temperature,
16 h, 76%; 13b: SOCl2, CH2Cl2, 40 ꢁC, 3 h 71%; 13c: TsCl, NEt3 then LiBr, acetone, reflux,
18 h, 40%; 13d: ClPO(OPh)2, NEt3, THF, 20 ꢁC, 16 h, 86%; 13e: PPh3, imidazole, I2, CH2Cl2,
35 ꢁC, 2 h, 78%; 15: PPh3, imidazole, I2, CH2Cl2, 35 ꢁC, 2 h, 81%.
Scheme 1. PG¼protecting group; LG¼leaving group. Route a: X¼metal, Y¼leaving
group. Route b: X¼Cl, Y¼metal. Route c: X¼H, Y¼I.
We described hereafter our studies on the ionic (a, X metal, Y
leaving group, b, X chlorine, Y metal) and the radical (c, X H, Y io-
dine) routes. This latter approach allowed us to prepare 1 with
a regioisomer and to evaluate the affinity of both regioisomers at
the nicotinic receptors.
2.2. Cyclization: the ionic approach
The first route to target 1 involved the formation of an anion in
-position of the pyridine nitrogen (C7 of the target, Scheme 3),
2. Results and discussion
2.1. Synthesis of precursors
a
which could displace a leaving group (LG) in compounds 13aee.
Several attempts of regioselective metalation of the 6-position of
the pyridine ring using n-BuLi in conjunction with lithium 2-dime-
thylaminoethanoate, according to a method described by Fort and
Gros,18 failed. The lowsolubility of the substrates and the presence of
an additional nitrogen function19 could explain these unsuccessful
results. Knowing that activation of the pyridine rings via their oxides
Efforts toward the synthesis of 1 started with the preparation of
bipyridines 4 and 6 (Scheme 2). A Suzuki coupling12 between 6-
chloropyridin-3-yl boronic acid 213 and ethyl 5-bromonicotinate 3
under optimized conditions afforded 4 in 86% yield. Whereas bo-
ronic acid 5 and ester 3 under the same conditions failed to give
pure 6, the Stille coupling11d,14,15 of 3 with the stannyl derivative 7
delivered bipyridine 6 in 72% yield. For a selective reduction of ring
A, the bipyridines were transformed quantitatively into their 4-
methoxybenzyl pyridinium iodides 8 and 10. Only one pyridine ring
in compounds 4 and 6 reacted due to steric congestion around the
nitrogen center of the other pyridine moiety.16 Treatment of salts 8
and 10 with sodium cyanoborohydride in acetic acid and ethanol at
room temperature led to piperidine esters 9 and 11, respectively as
a mixture of cis and trans isomers (molar ratio cis/trans: 3/1). The
structure of these compounds was unambiguously assigned by 1H
NMR spectroscopy, the coupling constants of protons in a piperi-
dine ring being well-known.17 Particularly, the signal of the axial H4
proton at 1.56 ppm appeared as a quartet (J¼12.6 Hz) suggesting
two vicinal axialeaxial interactions with the adjacent protons H3
and H5, therefore the cis equatorial arrangement of the sub-
stituents. In the other isomer, the H4ax proton showed two large
coupling constants (13.6 and 9.3 Hz) and a smaller one (4.4 Hz) (see
Experimental section) in good agreement with the expected mul-
tiplicity of a proton coupled with axial and equatorial vicinal pro-
tons. The cis isomers of 9 and 11, having the required configuration
for the cyclization, were isolated in 45 and 33%, respectively. Re-
duction of the ester group followed by the transformation of the
alcohols 12 and 14 into compounds bearing a good leaving group
(mesylate 13a, halides 13b,c, 13e, 15, phosphate 13d) was
straightforward (Scheme 2).
may facilitate the lithiation at the
a-position of the nitrogen
atom,20,21 the compound 20 bearing a carbobenzyloxy group (Cbz)
less prone tooxidation thana 4-methoxybenzyl(PMB) was prepared
(Scheme 4).22 Its precursor 19 was obtained directly from 1523
(Scheme 4). Reaction of the N-oxide 20 with LDA (2 or 3 or 5 equiv
ꢀ78 ꢁC in THF) afforded complex mixtures after hydrolysis.
LG
CH2
8
1
N
2
PMB
X = Cl
LG = I
X = H
7
5
X
N
Cl
LG
N
LG = leaving group
M
CH2
CH2
N
N
PMB
PMB
Li
from 13
Cl
N
Cl
Cl
from 15
X = H
SNAr
PMB
N
7
N
Cl
8
16
Scheme 3. Ionic routes to the nitrogen-protected target 1 as 16.

N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
9233
radical on a pyridine nucleus has received less attention.42 Fused
heteroaromatic ring systems were successfully prepared by intra-
molecular reaction of primary alkyl radicals generated from 1-
(iodoalkyl)pyridinium iodides,43 or from 2-aminopyridinyl alkyl
xanthates.44 A selective reaction of tertiary alkyl radicals at the 2-
position ofa 3-substituted pyridine ringwas observed in anapproach
to the synthesis of spongidines.45
Scheme 4. Conditions and reagents: (i) CbzCl or MeOCOCl, CH2Cl2, 20 ꢁC; 17: 82%; 18:
90%; 19: 69%. (ii) TFAA, urea/hydroxide peroxide complex, dichloroethane, 80 ꢁC, 24 h,
20: 85%.
At this point, we envisaged a ‘reversed ionic strategy’ with an
aromatic nucleophilic substitution (SNAr) involving a 2,6-dichlor-
opyridine andacarbanionin the C8 positionofpiperidine(Scheme 3).
To our knowledge, intramolecular couplings of an alkyl group to
a pyridine have not been reported. Halogen-lithium exchange of io-
dide 15 was carried out using t-BuLi24e26 (ꢀ78 ꢁC to room temper-
ature for 16 h). Whatever the electrophile (H2O or D2O) used to
quench the reaction mixture, t-BuLi in diethyl ether afforded a mix-
ture of methyl and monochloro compounds 22a and 22b, re-
spectively in a 12/88 M ratio (Scheme 5). In THF, reduction of the
carbonechlorine bond was not observed, compound 22a being the
sole product of the reaction. Attempts to trap the intermediate by
Bu3SnCl or D2O failed. Moreover, the use of an excess of t-BuLi
(4 equiv instead of 2.2 equiv ꢀ78 ꢁC, 30 min then D2O), afforded the
deutero pyridine 22c.
Scheme 6. (i) Radical initiator, (acid), solvent, T ꢁC, time, see Tables 1 and 2. (ii) 9 N
HCl, 100 ꢁC, 16 h.
The benzyloxycarbonyl and 4-methoxybenzyl protecting groups
being prone to hydrogen abstraction, compound 18 bearing
a methoxycarbonyl was prepared (Scheme 4). Investigation of the
reactivity of iodide 18 in the presence of radical initiators was un-
dertaken (Table 1). Initially, we studied the reaction of tri-n-
butylstannane/azobisisobutyronitrile46 (AIBN) in the presence of
BF3$Et2O.47 In benzene (entry 1) or in dichloroethane (DCE) (entry
2) and under conditions (syringe pump techniques) that minimize
the effective hydride concentration in the reaction medium,48 the
reactions were slow and incomplete. 6-exo Cyclization afforded
a mixture of the expected compound 24 and of its regioisomer 25
Scheme 5. Conditions and reagents: (i) RLi, THF or Mg/i-PrMgCl (1 or 2 equiv) then
D2O or Mg, i-PrMgCl, Fe(acac)3, THF/NMP27,28 or Zn, 1,2-dibromoethane (18 mol %) and
TMSCl (24 mol %)29 then Pd2dba3/PPh3, THF;30,31 (ii) H2O or D2O.
Scheme 5 summarized the different attempts of nucleophilic
attack of the pyridine ring of 15 by an in situ generated Grignard
reagent or by an organozinc derivative. In all these reactions, the
compound 22a was quantitatively formed whatever the quenching
reagent used (H2O, D2O).
(attack at the
a and g positions of the pyridine, respectively), beside
the reduced compound 26 (Scheme 6). No 5-exo cyclization was
observed. A radical translocation (intramolecular 1,5-hydrogen-
transfer)49,50 could explain the formation of compound 26. The
selectivity toward the formation of 24 versus 25 was higher in
benzene (molar ratio: 74/22) compared to DCE (24/25 M ratio: 57/
34) (entries 1 and 2). Reaction of 18 with triethylborane, known to
initiate radical reaction of iodides,51 in the presence of oxygen (or
air) in hexane/dichloromethane or in THF (entries 3 and 4) at room
temperature afforded compound 26 as the major or the sole
product with a poor conversion (47e57%). Benzoyl peroxide
(2 equiv)46,52 was tested in chlorobenzene (0.046 M) at 120 ꢁC.
After 60 h, starting material was recovered with an inseparable
mixture (data not shown). Dilauroyl peroxide (DLP), able to initiate
CeC bond formation and cyclization reactions when used with
iodides,46,53 was allowed to react with substrate 18 for 18 h at 80 ꢁC.
The tricyclic derivative 24, its regioisomer 25, and the reduced
compound 26 were formed in a 42/17/41 M ratio (entry 5). The use
of 2 equiv of DLP instead of 1.5 improved the conversion to the
benefit of the reduced compound 26 (entry 6). No reaction occurred
(data not shown) when DLP was used in conjunction with a Lewis
acid (BF3$Et2O) and UV irradiation at room temperature. Finally,
Finally, compound 19 was treated by activated zinc and the re-
action mixture quenched with D2O. Exclusive formation of com-
pound 23 with no deuterium incorporation in the final product
suggested a rapid protonation prior to the hydrolysis step.
2.3. Cyclization: the radical approach
To overcome the encountered difficulties, we decided to test
radical conditions to form the C7eC8 bondfrom iodide 18 (Scheme 6).
Intermolecular reaction of nucleophilic alkyl radicals with pro-
tonated aromatic heterocycles is well-known.32e34 The substitution
occurred exclusively at the
a and g positions of the protonated ni-
trogen. The regiochemistry of the reaction was strongly affected by
the nature of the solvent.35 The high values of the rate constants
compared to those measured for benzene derivatives make the ho-
molytic alkylation of protonated nitrogen heterocycles a syntheti-
cally useful transformation.36 Whereas the intramolecular reaction
of pyridyl radicals37e39 with alkenes (or alkynes or arenes), or that of
alkenyl or aryl radicals with pyridines (or related heterocycles)40,41
have been widely studied, the radical cyclization of a primary

9234
N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
reaction of 3 equiv of DLP in the presence of BF3$Et2O was
attempted at 80 ꢁC in DCE. Although the conversion was poor (22%),
no side-product 26 was formed, and the tricyclic compounds 24/25
were obtained in a 68/32 M ratio (Table 1, entry 7).
formation of 25. However, reversibility of the addition of the radical
cannot be excluded.33 As compound 27 could be a ligand of nAChRs,
no effort was made to obtain selectively 24 or 25.
Attempts to remove the carbomethoxy group of 24 with tri-
methylsilyl iodide,57 or with trichloroborane58 failed. However,
heating 24 with HCl (9 N) at 100 ꢁC for 16 h afforded the target
compound 1 in 80% yield. The same method was used to prepare
the compounds 27 and 28 in 70e82% yields from their protected
derivatives 25 and 26, respectively.
Table 1
Screening of reagents and conditions for the radical cyclization of iodide 18
Entry
Initiator (equiv)a
Solvent
Conv (%)
Productsb (%)
24
25
26
1
2
3
Bu3SnH (3), AIBN (1),
BF3$Et2O (1)
PhH
72
74
47
74
22
4
9
2.4. Binding assays
Bu3SnH (5), AIBN (2)
BF3$Et2O (1)
DCEf
57
32
34
11
Binding assays were carried out to measure binding affinities (Ki
values)of thethreecompounds 1, 27, 28intheirracemic formsata4b2
and a7 rat nicotinic receptor subtypes. Binding affinity for a4b2 and
for a7 nAChRs were measured by competition studies, respectively
,d
BEt3 (4), airc
Hexane
DCMf (1/1)
THF
57
,d
4
5
6
7
BEt3 (4), airc
DLPe (1.5)
DLPe (2)
57
48
75
22
0
42
33
68
0
17
20
32
100
41
47
0
DCEf
DCEf
with [3H]cytisine5a and [125I]-
a-bungarotoxin in adult Wistar rat
DLPe (3),
DCEf
brain membranes.59 The results are summarized in Table 3.
BF3$Et2O (1)
a
Table 3
The reactions were carried out at 80 ꢁC for 10e20 h after slow addition of the
Affinities of the synthesized compounds at nAChRs
initiator.
b
Determined by 1H NMR spectroscopy. Compounds 24, 25, 26 were separated by
Ligandsa Ki (nM)
a4b2
a7
flash chromatography (cyclohexane/EtOAc from 8:2 to 7:3). Order of elution: 26, 24,
25.
(ꢀ)-Cytisine
Varenicline
(ꢂ)-1
1.06 (lit.b 0.177)
>10.000 (lit.c 42007)
0.2 (lit.c 3227)
710
170
>10.000
c
0.9 (lit.b 0.067)
Reaction carried out at 20 ꢁC.
BEt3 was added at once.
DLP: dilauroyl peroxide.
DCE: dichloroethane, DCM: dichloromethane.
d
3.5
0.5
890
e
(ꢂ)-27
f
(ꢂ)-28
a
Binding affinities (Ki) were expressed as geometric means from four separate
This result encouraged us to test other Lewis (indium chloride,54
ytterbium triflate,55 BF3$Et2O, entries 1e3) or Brønsted acids (TFA,
entry 4) with an excess of DLP (10 equiv). Table 2 summarizes the
results. The reactions were clean and led exclusively to compounds
24 and 25 with no trace of reduced product 26. BF3$Et2O and TFA
gave the highest conversions and selectivities. Increasing the tem-
perature (entry 5) increased the conversion but led to unidentified
side products. A good compromise between the reaction conditions
(DLP, 10 equiv, BF3$Et2O, 1 equiv, in DCE at 80 ꢁC, entry 10 in bold)
allowed the formation of the tricyclic compounds 24 and 25 in a 67/
33 ratio, which were isolated in 37 and 15%, respectively.
experiments and measured by competition studies, respectively with [3H]cytisine5a
and [125I]-
a
-bungarotoxin in adult Wistar rat brain.
b
[3H]nicotine.
c
[
125I]-
a-bungarotoxin.
Biological evaluation (Table 3) revealed that compound 27 has
a remarquable affinity at a4b2 nAChRs, higher than (ꢀ)-cytisine and
varenicline under the same conditions of measurements. As a ra-
cemic mixture, compound 1 exhibits a nanomolar affinity for the
same receptor subtype although slightly lower than that of enan-
tiopur (ꢀ)-cytisine.
The selectivity of the tricyclic ligands (ꢂ)-1 and (ꢂ)-27 at a4b2
versus the a7 subtype receptors (ratio: 200e240) is higher than that
of varenicline but lower than (ꢀ)-cytisine. It is worthy of note the
high selectivity (>11,000) of the uncyclized compound 28 at a4b2
versus a7 nAChRs.
Table 2
Optimization of the radical cyclization of iodide 5
Entry Acida (equiv) Solventb Temp (ꢁC) Timec (h) Convd (%) Productsd (%)
24
25
2.5. Molecular modeling
1
2
3
4
5
6
7
8
InCl3 (1)
Yb(OTf)3 (1) DCE
BF3$Et2O (2) DCE
TFA (2)
TFA (2)
BF3$Et2O (1) PhH
BF3$Et2O (1) PhCl
BF3$Et2O (1) DCE,
BF3$Et2O (1) DCE
BF3$Et2O (1) DCE
BF3$Et2O (1) DCE
DCE
80
80
80
80
100
80
145
60
80
80
120
16
16
20
16
50
16
32
20
22
16
20
76
74
88
94
86
60
51
46
77
82
86
75
73
66
80
71
60
84
78
66
67
77
25
27
34
20
29
40
16
22
34
33
23
In order to understand the observed affinities of the synthesized
compounds 1 and 27, the molecular modeling of these compounds
were compared with those of (ꢀ)-cytisine and epibatidine (see
Experimental section). The analysis highlighted the key molecular
determinants (potential pharmacophore) of high affinity: (A) one
hydrophobic group (chlorine or/and aromatic ring), (B) one hy-
drogen bond acceptor (HBA) (sp2 nitrogen or carbonyl moiety), and
(C) one positive ionizable group (amine functions), present in all
previous models of nAChR pharmacophore.60 In our model, the
distances between the central points for each feature were (AeB)
DCE
DCE
9e
10
11
a
Dilauroyl peroxide (10 equiv).
DCE: dichloroethane.
b
c
Total reaction time.
d
e
Determined by 1H NMR spectroscopy.
20 Equiv of dilauroyl peroxide.
2.65 A; (AeC) 6.95 A; (BeC) 5.3 A. The distance BeC between the
ꢁ
ꢁ
ꢁ
polar characteristics compares well with that reported (average
60
ꢁ
value of 4.7 A with a standard error of 0.52). However, the dis-
The regioselectivity of radical attack at the
a
and
g
positions of
tances AeB and AeC are higher than those calculated, respectively
60
ꢁ
ꢁ
protonated pyridine was slightly lower in our case (molar ratio 24/
25: 67/33 in DCE and 60/40 in benzene at 80 ꢁC) compared to that
reported by Minisci in the intermolecular reactions of n-butyl
1.4 A (standard error: 0.20) and 6 A (standard error: 0.54).
Fig.
2
shows the mapping between (þ)-epibatidine and
(ꢀ)-cytisine in their stable conformations, close to X-rays data. The
radicals with protonated pyridine (
a
/g
: 75/25 in benzene at 80 ꢁC).
common volume between the two structures, after their align-
Calculations56 of the heat of formations of 24 and 25 revealed ꢀ59.6
and ꢀ61.2 kcal/mol, respectively, which would suggest preferential
ments, was 113 A . The superimposition between (ꢀ)-cytisine and
3
ꢁ
(ꢀ)-epibatidine led to the same potential pharmacophore.

N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
9235
the correct alignment of the nitrogen lone pair of pyridine (Fig. 4)
associated to the potential hydrogen bond formed into the receptor.
Moreover, a perfect superimposition of 27 to the most stable
conformation of (ꢀ)-epibatidine (three for the fit value) was ob-
3
ꢁ
served (common volume of 116 A in this case). For 27, only the
chlorine atom is able to fit the hydrophobic feature (blue sphere,
Fig. 4). From this model we can predict a decrease in affinity for
a non-chlorinated analogue of 27 but a slightly lower or no effect
for the non-chlorinated derivative of 1 (the aromatic ring is able to
fit the hydrophobic features, Fig. 3). As noted previously those non-
chlorinated compounds have been synthesized but their affinities
toward nicotinic receptors are not available.9,61 The flexibility of the
alignment toward the three characteristics of the pharmacophore
could explain the fact that the chlorine atom of epibatidine seems
to make a minor contribution toward the affinity for nicotinic
receptors.62
Fig. 2. Superimposition between (ꢀ)-cytisine (red) (relative energy: 0.23 kcal/mol)
and (þ)-epibatidine (green) (relative energy: 0.19 kcal/mol).
3. Conclusions
The mappings of 1 and 27 to the potential pharmacophore were
evaluated (Figs. 3 and 4). The observed fit value [2.95 (maximum
value: 3), relative energy of 0.36 kcal/mol] compared to that of li-
gand 1 (2.71, relative energy of 6.9 kcal/mol) correlates well with
the binding data. The higher fit value for 27 is mainly related with
In a search for new nAChRs ligands with high affinity and se-
lectivity, we envisaged structure 1, an analogue of cytisine and
epibatidine. Compound 1 was synthesized in eight steps using an
original radical cyclization as the key step. Although the formation
of six-membered rings via radical cyclizations is less common
compared to the five-membered rings, it still has an important role
in synthesis63 and the reaction described in this paper illustrates
the superiority of this approach compared to the ionic methodol-
ogies, notably for making constrained bridged structures. This
radical cyclization afforded two tricyclic regioisomers. The evalu-
ation of their in vitro affinity revealed excellent binding affinities
and selectivities at a4b2 nAChRs compared to a7 subtypes, slightly
better for the unexpected regioisomer. Molecular modeling of 1 and
27 has shown a good match of the hybrid structures with the
pharmacophore designed from (ꢀ)-cytisine and epibatidine. This
could explain the high affinities observed for these new ligands.
Work is now in progress to improve the selectivity of the reaction
and to develop an asymmetric version of the synthesis.
4. Experimental section
4.1. General
Fig. 3. Superimposition between 1 and the potential pharmacophore.
Dichloromethane, acetonitrile, ether, and toluene were dried
with a PURESOLVÔ apparatus (Innovative Technology Inc.). THF
was dried and distilled from sodium benzophenone ketyl. Hexane,
1,2-dichloroethane, benzene, and chlorobenzene were distilled
ꢁ
from calcium hydride and stored over molecular sieves 4 A. Dii-
sopropylamine, triethylamine, 2,2,6,6-tetramethylpiperidine,
chlorotrimethylsilane, and 1,2-dibromoethane were distilled from
calcium hydride. Triisopropylborate and benzaldehyde were dis-
tilled from calcium chloride. Dimethylaminoethanol was distilled
from sodium hydroxide. Organolithium solutions (n-butyllithium,
tert-butyllithium, sec-butyllithium and methyllithium, ALFA
AESAR) were titrated with N-benzylbenzamide64 before use. Thin
layer chromatography (TLC) was performed on Merck 60F254 silica
gel plates and visualized with a UV lamp (254 nm). Flash chro-
matography was performed with silica gel SI 60 (0.040e0.063 mm,
€
Merck). Melting points were obtained using a Kofler bench appa-
ratus (uncorrected). Infrared spectra (IR) were recorded with an
FT-IR PerkineElmer 684 spectrometer. Mass and high resolution
mass spectra (HRMS) were obtained on a Waters-Micromass Q-Tof
micro instrument. 1H NMR spectra were recorded on a Brucker
Avance DPX-250 at 250.1 MHz. Data are reported as follows:
chemical shift in ppm from tetramethylsilane as an internal stan-
dard, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, dd¼doublet of doublet, m¼multiplet or overlap of non
Fig. 4. Fitting 27 toward the pharmacophore.

9236
N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
equivalent resonances). 13C NMR spectra were recorded on
a Brucker Avance DPX-250 at 62.9 MHz. Chemical shift are repor-
ted in ppm from tetramethylsilane with the solvent as an internal
(1H, s), 8.80 (1H, d, J¼2.5 Hz), 8.75 (1H, dd, J¼8.3, 2.5 Hz), 7.64 (2H,
d, J¼8.7 Hz), 7.52 (1H, d, J¼8.3 Hz), 6.94 (1H, d, J¼8.7 Hz), 6.34 (2H,
s), 4.51 (2H, q, J¼7.1 Hz), 3.81 (3H, s), 1.60 (H2O), 1.45 (3H, t,
J¼7.1 Hz); 13C NMR (CDCl3) dC 161.3, 160.9, 154.1, 148.5, 146.4, 143.0,
142.5, 138.8, 137.2, 132.1, 131.0, 127.6, 125.5, 123.2, 115.3, 65.2, 63.9,
55.6, 14.4; HRMS (EI) calcd for C21H21ClN2O3 383.1162, found
383.1176.
indicator (CDCl3
d 77.0 ppm). 2-Chloro-5-pyridylboronic acid
2,13b,65 ethyl-5-bromonicotinate66 3, 2,6-dichloro-3-pyridylbor-
onic acid 5,65 and 2,6-dichloro-3-tributylstannyl-pyridine 767 were
prepared according to described procedures.
4.1.1. 60-Chloro-[3,30]bipyridinyl-5-carboxylic acid ethyl ester (4). 2-
Chloro-5-pyridylboronic acid 2 (500 mg, 3.18 mmol, 1.3 equiv),
ethyl-5-bromonicotinate 3 (603 mg, 2.45 mmol, 1 equiv), Pd(OAc)2
(27 mg, 0.12 mmol, 5 mol %), dppf68 (90 mg, 0.16 mmol, 6.6 mol %),
and CsF (930 mg, 6.12 mmol, 2.5 equiv) in DME (15 mL), previously
degassed, were placed in a Schlenk tube. The mixture was heated to
80 ꢁC for 5 h. After evaporation of the volatile compounds, the
residue was dissolved in CH2Cl2. The organic layer was washed with
a NH4OH solution. The aqueous layer was extracted with CH2Cl2
(two times). The combined organic layers were dried (MgSO4) and
concentrated to afford the crude product, which was purified by
column chromatography on silica gel (heptane/EtOAc, 7:3) to give
compound 4 as a white solid (533 mg, 83%). Mp 160e162 ꢁC; IR
4.1.4. cis and trans 60-Chloro-1-(4-methoxy-benzyl)-1,2,3,4,5,6-hex-
ahydro-[3,30]bipyridinyl-5-carboxylic acid ethyl ester (cis-9) and
(trans-9). To compound 8 (900 mg, 1.76 mmol, 1 equiv) in ethanol
(50 mL) cooled to 0 ꢁC were added acetic acid (25 mL) then sodium
cyanoborohydride (1.11 g, 17.62 mmol, 10 equiv) portionwise. The
reddish mixture was stirred at 0 ꢁC for 1 h then at room tempera-
ture for 2 h. The solvent was evaporated, then a diluted NH4OH
solution and EtOAc were added to the residue. Extraction with
EtOAc (three times), drying (MgSO4), and evaporation of the vola-
tile compounds afforded an oil. Both diastereoisomers were sepa-
rated by flash chromatography (heptane/EtOAc, 7:3) (410 mg,
overall yield: 60%).
(KBr, cmꢀ1
)
nmax 1719, 1445, 1299, 1251, 1022; 1H NMR (CDCl3) dH
4.1.4.1. Isomer trans-9. White solid (102 mg, 15%); mp
9.26 (1H, d, J¼1.9 Hz), 8.97 (1H, d, J¼2.3 Hz), 8.65 (1H, dd, J¼2.3,
1.9 Hz), 8.45 (1H, d, J¼2.5 Hz), 7.90 (1H, dd, J¼8.3, 2.5 Hz), 7.48 (1H,
d, J¼8.3 Hz), 4.45 (2H, q, J¼7.1 Hz), 1.43 (3H, t, J¼7.1 Hz); 13C NMR
(CDCl3) dC 164.9, 152.0, 151.5, 150.6, 148.1, 137.4, 135.4, 132.3, 131.7,
126.8, 124.9, 62.0, 14.4; HRMS (EI) calcd for C13H12ClN2O2 263.0563,
found 263.0575.
88e90 ꢁC; Rf 0.35 (heptane/EtOAc, 7:3); IR (KBr, cmꢀ1
) nmax 2932,
1727, 1610, 1509, 1451, 1235, 1181, 1029; 1H NMR (CDCl3) dH 8.33
(1H, d, J¼2.4 Hz), 7.60 (1H, dd, J¼8.2, 2.4 Hz), 7.22 (1H, d, J¼8.2 Hz),
7.19 (2H, d, J¼8.6 Hz), 6.82 (2H, d, J¼8.6 Hz), 4.14 (2H, q, J¼7.1 Hz),
3.77 (3H, s), 3.54 (d, 1H, J¼13.1 Hz), 3.40 (d, 1H, J¼13.1 Hz),
3.20e3.10 (1H, m), 3.05e2.95 (1H, m), 2.80e2.70 (1H, m),
2.70e2.60 (1H, m), 2.45e2.40 (1H, m), 2.35e2.30 (1H, m),
2.25e2.20 (1H, m), 1.67 (1H, ddd, J¼13.6, 9.3 and 4.4 Hz), 1.21 (3H, t,
J¼7.1 Hz,); 13C NMR (CDCl3) dC 173.6, 158.8, 149.3, 149.2, 138.5, 138.1,
130.1, 129.9, 123.9, 113.6, 62.4, 60.6, 58.9, 55.3, 54.5, 39.2, 36.0, 32.3,
14.2; HRMS (EI) calcd for C21H26ClN2O3 389.1632, found 389.1643
(Fig. 5).
4.1.2. 20,60-Dichloro-[3,30]bipyridinyl-5-carboxylic acid ethyl ester
(6). Suzuki coupling. Same procedure as for synthesis of compound
4. Boronic acid 5 (1.08 g, 5.65 mmol, 1.3 equiv) and ethyl-5-bro-
monicotinate 3 (1.07 g, 4.35 mmol, 1 equiv) afforded bipyridine 6 as
a white solid (371 mg, 29%) after purification by column chroma-
tography on silica gel (pentane/EtOAc, 8:2).
Stille coupling. To a degassed solution of the stannyl derivative 7
(2.0 g, 4.58 mmol, 1.3 equiv) and ethyl-5-bromonicotinate 3
(866 mg, 3.52 mmol, 1 equiv) in dioxane (35 mL) were added CuI
(64 mg, 0.33 mmol, 9.5 mol %), tri(o-tolyl)phosphine (222 mg,
0.77 mmol, 22 mol %) and Pd2(dba)3 (161 mg, 0.18 mmol, 5 mol %).
The reaction mixture was heated to 130 ꢁC for 24 h. The aqueous
layer was extracted with CH2Cl2 (three times). The combined or-
ganic extracts were dried (MgSO4) and concentrated to afford an
oil, which was purified by flash chromatography on silica gel
(pentane/EtOAc, 8:2) to affordꢀb1ipyridine 6 as a white solid (750 mg,
72%). Mp 186 ꢁC; IR (KBr, cm
) nmax 3052, 1711, 1433, 1309, 1251,
1024; 1H NMR (CDCl3) dH 9.19 (1H, d, J¼2.1 Hz), 8.77 (1H, d,
J¼2.1 Hz), 8.32 (1H, t, J¼2.1 Hz), 7.62 (1H, d, J¼8.0 Hz), 7.35 (1H, d,
J¼8.0 Hz), 4.37 (2H, q, J¼7.1 Hz), 1.35 (3H, t, J¼7.1 Hz); 13C NMR
(CDCl3) dC 164.8, 153.1, 150.7, 150.5, 148.9, 141.8, 137.7, 132.2, 131.4,
126.2, 123.6, 61.9, 14.4; HRMS (EI) calcd for C13H11N2O2Cl2 297.0198,
found 297.0202.
Fig. 5. 1H NMR signals of compound trans-9 in the range 1.5e3.2 ppm.
4.1.3. 60-Chloro-5-ethoxycarbonyl-1-(4-methoxy-benzyl)-[3,30]bipyr-
idinyl-1-ium iodide (8). To a suspension of bipyridine 4 (500 mg,
1.91 mmol, 1 equiv), potassium iodide (317 mg, 1.91 mmol, 1 equiv)
in anhydrous acetonitrile (25 mL) was added 1-chloromethyl-4-
methoxybenzene (0.25 mL, 1.81 mmol, 0.95 equiv). The mixture
was stirred at 80 ꢁC for 5 h and the solvent was evaporated. The
crude product was dissolved in a mixture of CH2Cl2/water (1:1). The
aqueous layer was extracted with CH2Cl2 (three times). The com-
bined organic layers were dried (MgSO4) and concentrated to afford
an oil. Precipitation from Et2O, gave the pyridinium salt 8 as an
orange solid (955 mg, 98%). This hygroscopic compound decom-
4.1.4.2. Isomer cis-9. Colorless oil, (308 mg, 45%); Rf 0.20
(heptane/EtOAc, 7:3); IR (NaCl, cmꢀ1
) nmax 2936, 1727, 1611, 1511,
1459, 1248, 1179, 1032; 1H NMR (CDCl3) dH 8.21 (1H, d, J¼2.5 Hz),
7.46 (1H, dd, J¼8.3, 2.5 Hz), 7.22 (1H, d, J¼8.3 Hz), 7.20 (2H, d,
J¼8.6 Hz), 6.83 (2H, d, J¼8.6 Hz), 4.10 (2H, q, J¼7.1 Hz), 3.77 (3H, s),
3.56 and 3.50 (AB, 2H, J¼13.1 Hz), 2.91 (1H, d, J¼11.1 Hz),
2.80e2.70 (2H, m), 2.68e2.65 (1H, m), 2.10 (1H, d, J¼12.6 Hz), 1.97
(1H, t, J¼11.4 Hz), 1.95 (1H, t, J¼10.9 Hz), 1.56 (1H, q, J¼12.6 Hz),
1.21 (3H, t, J¼7.1 Hz); 13C NMR (CDCl3) dC 173.5, 158.9, 149.7, 148.9,
137.8, 137.5, 130.3, 129.5, 124.1, 113.7, 62.3, 60.7, 59.4, 55.3, 54.7,
42.1, 39.0, 33.9, 14.2; HRMS (EI) calcd for C21H26ClN2O3 389.1632,
found 389.1649 (Fig. 6).
posed upon heating. IR (KBr, cmꢀ1
1168, 1112, 1029; 1H NMR (CDCl3) dH 10.29 (1H, s), 9.18 (1H, s), 8.97
) nmax 1724, 1512, 1464, 1255,

N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
9237
4.1.7. cis [60-Chloro-1-(4-methoxy-benzyl)-1,2,3,4,5,6-hexahydro-
[3,30]bipyridinyl-5yl]-methanol (12). To compound cis-9 (150 mg,
0.39 mmol, 1 equiv) in dry diethyl ether (5 mL), cooled to 0 ꢁC,
LiAlH4 (59 mg, 1.54 mmol, 4 equiv) was added in 3 portions. The
mixture was stirred at 0 ꢁC for 1.5 h. Water (60
(60 L) and water (120 L) were successively and cautiously added.
mL), then NaOH 15%
m
m
The mixture was stirred for 2 h at room temperature, filtered on
Celite and washed with dichloromethane. The filtrate was dried
then concentrated under vacuum. The residue (115 mg) was puri-
fied by column chromatography on silica gel (CH2Cl2/MeOH, 95:5)
to afford alcohol 12 as a colorless oil (120 mg, 89%). IR (NaCl, cmꢀ1
)
nmax 3382, 2929, 1611, 1511, 1460, 1248, 1058, 1029; 1H NMR (CDCl3)
dH 8.20 (1H, d, J¼2.3 Hz), 7.45 (1H, dd, J¼8.2, 2.3 Hz), 7.21 (1H, d,
J¼8.2 Hz), 7.19 (2H, d, J¼8.6 Hz), 6.83 (2H, d, J¼8.6 Hz), 3.77 (3H, s),
3.54e3.47 (4H, m), 3.07 (1H, d, J¼10.9 Hz), 2.95e2.84 (2H, m), 2.37
(1H, br s), 2.02e1.95 (2H, m), 1.91 (1H, t, J¼10.9 Hz), 1.74 (1H, t,
J¼11.0 Hz), 1.14 (1H, q, J¼12.2 Hz,); 13C NMR (CDCl3) dC 158.9, 149.6,
148.8, 138.5, 137.7, 130.5, 129.4, 124.1, 113.8, 65.9, 62.6, 60.0, 56.4,
55.3, 39.4, 39.2, 34.5; HRMS (EI) calcd for C19H24ClN2O2 347.1526,
found 347.1520.
Fig. 6. 1H NMR signals of compound cis-9 in the range 1.5e2.2 ppm.
4.1.5. 20,60-Dichloro-5-ethoxycarbonyl-1-(4-methoxy-benzyl)-[3,30]
bipyridinyl-1-ium iodide (10). To a suspension of compound 6
(1.536 g, 5.22 mmol,1 equiv), potassium iodide (0.866 g, 5.22 mmol,
1 equiv) in anhydrous acetonitrile (30 mL) was added 1-chlor-
omethyl-4-methoxybenzene (0.67 mL, 4.96 mmol, 0.95 equiv). The
clear (upon heating) solution was heated to 80 ꢁC for 5 h, then
concentrated. The residue was dissolved in a mixture dichloro-
methane/water (1:1). The aqueous layer was extracted with
dichloromethane (three times). The combined organic extracts
were dried (MgSO4) and concentrated to afford an oil, which after
precipitation from Et2O, gave the pyridinium salt 10 as an orange
solid (2.78 g, 98%). This hygroscopic compound decomposed upon
4.1.8. cis Methanesulfonic acid 60-chloro-1-(4-methoxy-benzyl)-5–
1,2,3,4,5,6-hexahydro-[3,30]bipyridinyl-5-yl methyl ester (13a). To
a cold solution of compound 12 (70 mg, 0.20 mmol, 1 equiv) in
dried CH2Cl2 (5 mL) were added at 0 ꢁC methanesulfonyl chloride
(0.02 mL, 0.30 mmol, 1.5 equiv), then Et3N (0.04 mL, 0.30 mmol,
1.5 equiv). The mixture was stirred at 0 ꢁC for 30 min and 16 h at
room temperature. It was then diluted with brine, extracted with
CH2Cl2 (three times). The combined organic layers were dried
(MgSO4), filtered, and concentrated to give the crude product,
which was purified by flash chromatography (heptane/EtOAc, 2:8)
to afford compound 13a as a colorless oil (65 mg, 76%). IR (NaCl,
heating. IR (KBr, cmꢀ1
)
nmax 3007, 1731, 1513, 1421, 1251, 1164, 1138,
cmꢀ1 nmax 2937, 1612, 1516, 1461, 1350, 1254, 1173, 1104; 1H NMR
)
1022; 1H NMR (CDCl3) dH 9.64 (1H, s), 9.32 (1H, s), 8.98 (1H, s), 8.80
(1H, d, J¼8.0 Hz), 7.63 (2H, d, J¼8.6 Hz), 7.47 (1H, d, J¼8.0 Hz), 6.94
(2H, d, J¼8.6 Hz), 6.29 (2H, s), 4.48 (2H, q, J¼7.1 Hz), 3.80 (3H, s),
1.43 (3H, t, J¼7.1 Hz); 13C NMR (CDCl3) dC 161.4, 160.8, 152.5, 148.2,
146.1,143.7,143.3,136.4, 132.2, 130.4, 127.3, 124.5,122.7,115.4,114.4,
65.4, 63.9, 55.6, 14.3; HRMS (EI) calcd for C21H19Cl2N2O3 417.0773,
found 417.0779.
(CDCl3) dH 8.21 (1H, d, J¼2.5 Hz), 7.45 (1H, dd, J¼8.2, 2.5 Hz), 7.23
(1H, d, J¼2.5 Hz), 7.18 (2H, d, J¼8.6 Hz), 6.84 (2H, d, J¼8.6 Hz), 4.09
(2H, dd, J¼6.4, 1.7 Hz), 3.79 (3H, s), 3.53 and 3.49 (AB, 2H,
J¼13.0 Hz), 3.04 (1H, d, J¼9.3 Hz), 2.98 (3H, s), 3.00e2.90 (2H, m),
2.25e2.15 (1H, m), 2.00e1.90 (2H, m), 1.81 (1H, t, J¼11.1 Hz), 1.23
(1H, q, J¼13.3 Hz); 13C NMR (CDCl3) dC 159.0, 149.8, 148.8, 137.8,
137.5, 130.3, 129.5, 124.2, 113.8, 71.9, 62.4, 59.6, 55.5, 55.3, 39.3, 37.4,
36.4, 34.1; HRMS (EI) calcd for C20H26ClN2O4S 425.1302, found
425.1321.
4.1.6. 20,60-Dichloro-1-(4-methoxy-benzyl)-1,2,3,4,5,6-hexahydro-
[3,30]bipyridinyl-5-carboxylic acid ethyl ester (11). To a cold solution
of compound 10 (700 mg, 1.28 mmol,1 equiv) in EtOH (25 mL) were
added acetic acid (15 mL) then sodium cyanoborohydride (807 mg,
12.84 mmol,10 equiv) portionwise. The reddish mixture was stirred
at 0 ꢁC for 1 h and at room temperature for 2 h. The reaction
mixture was concentrated and the residue was dissolved in EtOAc/
H2O (1/1), basified with diluted NH4OH, extracted with EtOAc
(three times), dried (MgSO4), and evaporated to give a yellow oil.
Flash chromatography (pentane/EtOAc, 9:1) afforded a first frac-
tion, which contained an inseparable mixture of ester trans-11 and
a partially reduced compound (mixture 119 mg, 22%). The ester cis-
11 was eluted in the second fraction (178 mg, 33%).
4.1.9. 2-Chloro-5-(cis-5-(chloromethyl)-1-(4-methoxybenzyl)piper-
idin-3-yl)pyridine (13b). Compound 12 (100 mg, 0.29 mmol,
1 equiv) and thionyl chloride (0.10 mL, 1.44 mmol, 5 equiv) in dry
CH2Cl2 (5 mL) were stirred at 40 ꢁC for 3 h. After cooling to room
temperature, the reaction was quenched by addition of a saturated
aqueous NaHCO3 solution (10 mL). The mixture was extracted with
CH2Cl2 (three times). The combined organic layers were dried
(MgSO4), filtered, and concentrated. Chromatography on silica gel
(CH2Cl2/MeOH, 98:2) afforded compound 13b as a colorless oil
(75 mg, 71%). IR (NaCl, cmꢀ1
) nmax 2935, 1611, 1510, 1458, 1246,
1103; 1H NMR (CDCl3) dH 8.23 (1H, d, J¼2.4 Hz,), 7.47 (1H, dd, J¼2.4,
8.2 Hz), 7.24 (1H, d, J¼8.2 Hz), 7.21 (2H, d, J¼8.4 Hz), 6.85 (2H, d,
J¼8.4 Hz), 3.79 (3H, s), 3.55 and 3.51 (AB, 2H, J¼13.0 Hz), 3.44 (2H,
d, J¼6.0 Hz), 3.10 (1H, d, J¼11.1 Hz), 3.00e2.90 (2H, m,), 2.25e2.10
(1H, m), 2.05e2.00 (1H, m), 1.94 (1H, t, J¼11.0 Hz), 1.81 (1H, t,
J¼11.0 Hz), 1.24 (1H, q, J¼12.6 Hz); 13C NMR (CDCl3) dC 159.1, 149.9,
149.1, 138.2, 137.7, 130.6, 130.5, 124.3, 114.0, 62.6, 59.9, 57.0, 55.5,
48.1, 39.6, 38.9, 35.9; HRMS (EI) calcd for C19H23Cl2N2O 365.1187,
found 365.1183.
4.1.6.1. Isomer cis-11. Yellow oil; Rf¼0.10 (pentane/EtOAc, 9:1);
IR (NaCl, cmꢀ1
) nmax 2936, 1726, 1611, 1510, 1425, 1244, 1176, 1032;
1H NMR (CDCl3) dH 7.53 (1H, d, J¼8.1 Hz), 7.22 (1H, d, J¼8.1 Hz), 7.21
(2H, d, J¼8.5 Hz), 6.85 (2H, d, J¼8.5 Hz), 4.11 (2H, q, J¼7.1 Hz), 3.79
(3H, s), 3.57 and 3.52 (AB, 2H J¼13.0 Hz), 3.30 (1H, tt, J¼12.1,
3.5 Hz,), 3.20 (1H, d, J¼11.6 Hz), 2.98 (1H, d, J¼11.1 Hz), 2.80 (1H, tt,
J¼11.5, 4.0 Hz), 2.19 (1H, d, J¼13.1 Hz), 2.12 (1H, t, J¼11.6 Hz), 1.90
(1H, t, J¼11.1 Hz), 1.53 (1H, q, J¼12.6 Hz), 1.21 (3H, t, J¼7.1 Hz); 13C
NMR (CDCl3) dC 173.6, 158.9, 150.1, 148.1, 138.5, 136.2, 130.3, 129.6,
123.3, 113.8, 62.2, 60.8, 57.9, 55.4, 54.9, 42.0, 37.6, 32.8, 14.3; HRMS
(EI) calcd for C21H25Cl2N2O3 423.1242, found 423.1126.
4.1.10. 2-Chloro-5-(cis-5-(bromomethyl)-1-(4-methoxybenzyl)piper-
idin-3-yl)pyridine (13c). To alcohol 12 (110 mg, 0.32 mmol, 1 equiv)
and triethylamine (0.07 mL, 0.48 mmol, 1.5 equiv) in dry

9238
N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
dichloromethane (5 mL) cooled to 0 ꢁC, tosyl chloride (91 mg,
0.48 mmol, 1.5 equiv) was added. After stirring for 20 h at room
temperature, brine and a saturated aqueous NaHCO3 solution were
added. Extraction with CH2CI2 (three times), drying (MgSO4), and
concentration afforded the tosylate. A mixture of this tosylate and
LiBr (78 mg, 0.90 mmol, 2.8 equiv) in dry acetone (5 mL) was
refluxed for 18 h. After filtration, acetone was removed under
vacuum. The crude product dissolved in CH2Cl2 was washed with
water, dried (MgSO4), and concentrated. Purification by flash
chromatography (CH2Cl2/MeOH, 98:2) led to bromide 13c as a col-
was stirred at 0 ꢁC for 1.5 h. Water (110
water (220 L) were cautiously added. The mixture was stirred for
mL), NaOH (15%, 110 mL) then
m
2 h at room temperature, filtered on Celite then washed with
CH2Cl2. The filtrate was dried (MgSO4) and concentrated under
vacuum. The crude product was purified by column chromatogra-
phy on silica gel (EtOAc, 100%) to give alcohol 14 as a colorless oil
(329 mg, 92%). IR (NaCl, cmꢀ1
) nmax 3359, 2925, 1611, 1548, 1511,
1426, 1247, 1177, 1056, 1032; 1H NMR (CDCl3) dH 7.51 (1H, d,
J¼8.1 Hz), 7.22 (2H, d, J¼8.5 Hz), 7.20 (1H, d, J¼8.1 Hz), 6.84 (2H, d,
J¼8.5 Hz), 4.80 (1H, br s), 3.78 (3H, s), 3.47e3.57 (4H, m), 3.32 (1H
tt, J¼12.0, 3.5 Hz,), 3.12 (1H, d, J¼11.0 Hz), 3.02 (1H, d, J¼10.5 Hz),
2.01e2.04 (1H, m), 1.97 (1H, d, J¼12.6 Hz), 1.87 (1H, t, J¼11.0 Hz),
1.79 (1H, t, J¼11.0 Hz), 1.12 (1H, q, J¼12.6 Hz); 13C NMR (CDCl3) dC
158.9, 150.1, 147.8, 138.5, 136.7, 130.5, 129.2, 123.2, 113.7, 65.8, 62.3,
58.2, 56.3, 55.3, 38.9, 37.9, 33.3; HRMS (EI) calcd for C19H23Cl2N2O2
381.1137, found 381.1128.
orless oil (42 mg, 40%). IR (NaCl, cmꢀ1
) nmax 2931, 1611, 1510, 1458,
1247, 1103; 1H NMR (CDCl3) dH 8.23 (1H, d, J¼2.5 Hz), 7.47 (1H, dd,
J¼8.2, 2.5 Hz), 7.24 (d, J¼8.2 Hz, 1H), 7.20 (d, J¼8.4 Hz, 2H), 6.85 (d,
J¼8.4 Hz, 2H), 3.80 (s, 3H), 3.55 and 3.50 (AB, J¼13.0 Hz, 2H), 3.30
(d, J¼6.0 Hz, 2H), 3.10 (d,12.0 Hz,1H), 2.95e2.85 (m, 2H), 2.20e2.00
(m, 2H), 1.93 (t, J¼11.7 Hz, 1H), 1.78 (t, J¼10.8 Hz, 1H), 1.30e1.20 (m,
1H); 13C NMR (CDCl3) dC 158.9,149.7,148.9,138.0,137.5,130.3,129.7,
124.1, 113.8, 62.4, 59.7, 57.8, 55.4, 39.5, 38.5, 36.8, 36.7; HRMS (EI)
calcd for C19H23BrClN2O 409.0682, found 409.0683.
4.1.14. cis-2,6-Dichloro-3-(5-(iodomethyl)-1-(4-methoxybenzyl)pi-
peridin-3-yl)pyridine (15). To triphenylphosphine (160 mg,
0.61 mmol, 1.2 equiv) in dichloromethane (30 mL) were sequen-
tially added imidazole (41 mg, 0.61 mmol, 1.2 equiv) then iodine
(155 mg, 0.61 mmol, 1.2 equiv). The mixture was stirred until
complete dissolution of iodine. Alcohol 14 (194 mg, 0.51 mmol,
1 equiv) was added dropwise. The reaction mixture was heated to
35 ꢁC for 2 h, then quenched with a saturated NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2 (three times). The com-
bined organic layers were dried (MgSO4) and concentrated to give
an oil, which was purified by column chromatography on silica gel
(pentane/EtOAc, 9:1) to afford compound 15 as a yellow oil
4.1.11. cis Phosphoric acid 60-chloro-1-(4-methoxy-benzyl)-1,2,3,4,5,6-
hexahydro-[3,30]bipyridinyl-5-ylmethyl ester diphenyl ether (13d). To
an ice-cooled solution of alcohol 12c (82 mg, 0.24 mmol,1 equiv) and
triethylamine (0.07 mL, 0.48 mmol, 2 equiv) in dry THF (3 mL) was
added chlorodiphenylphosphate (0.07 mL, 0.35 mmol, 1.5 equiv)
dropwise. The solution was stirred at room temperature for 16 h and
a saturated ammonium chloride solution was added. The aqueous
layer was extracted with CH2Cl2 (three times) and the combined
organic extracts were dried (MgSO4) and concentrated under vac-
uum. The crude product was purified by silica gel chromatography
(CH2Cl2/MeOH, 97:3) to give pure phosphate 13d as a colorless oil
(202 mg, 81%); IR (NaCl, cmꢀ1
) nmax 2930, 1611, 1547, 1510, 1424,
1244,1169,1034; 1H NMR (CDCl3) dH 7.51 (1H, d, J¼8.0 Hz), 7.22 (3H,
d, J¼8.5 Hz), 6.86 (2H, d, J¼8.5 Hz), 3.80 (3H, s), 3.58 and 3.53 (AB,
2H, J¼13.1 Hz), 3.33 (1H, tt, J¼11.6, 3.0 Hz), 3.15e3.10 (1H, m), 3.10
(2H, d, J¼6.5 Hz,), 2.96 (1H, d, J¼11.1 Hz), 2.15e2.05 (1H, m), 2.0e1.9
(1H), 1.87 (1H, t, J¼11.0 Hz), 1.77 (1H, t, J¼11.0 Hz), 1.12 (1H, q,
J¼12.1 Hz); 13C NMR (CDCl3) dC 159.0, 150.2, 148.0, 138.4, 136.2,
130.5, 130.3, 123.3, 113.8, 62.1, 59.4, 58.0, 55.4, 38.0, 37.9, 37.4, 10.5;
HRMS (EI) calcd for C19H22Cl2N2OI 491.0154, found 491.0155.
(120 mg, 86%). IR (NaCl, cmꢀ1
) nmax 2949, 1642, 1612, 1510, 1488,
1245,1188; 1H NMR (CDCl3) dH 8.22 (s, 1H), 7.50e7.20 (m, 14H), 6.89
(d, J¼8.2 Hz, 2H), 4.12 (t, J¼6.3 Hz, 2H), 3.79 (s, 3H), 3.48 (s, 2H),
3.00e2.80 (m, 3H), 2.19e2.17 (m, 1H), 1.95e1.80 (m, 2H), 1.75 (t,
J¼11.1 Hz,1H),1.16 (q, J¼12.2 Hz,1H); 13C NMR (CDCl3) dC 159.1,150.7,
150.6,149.9,148.9,138.0,137.6,130.5,130.0,125.7,124.2,120.3,120.2,
113.9, 71.6, 62.5, 59.8, 55.6, 55.5, 39.3, 37.4, 33.9; HRMS (EI) calcd for
C31H33ClN2O5P 579.1816, found 579.1799.
4.1.15. cis
60-Chloro-5-methanesulfonyloxymethyl-1,2,3,4,5,6-hex-
4.1.12. 2-Chloro-5-[(cis-5-(iodomethyl)-1-(4-methoxybenzyl)piper-
idin-3-yl)]pyridine (13e). To triphenylphosphine (161 mg, 0.61
mmol, 1.2 equiv) in dichloromethane (30 mL) were sequentially
added imidazole (42 mg, 0.61 mmol,1.2 equiv) then iodine (156 mg,
0.61 mmol, 1.2 equiv). The mixture was stirred until complete
dissolution of iodine. Alcohol 12 (178 mg, 0.51 mmol, 1 equiv) was
added dropwise. The mixture was heated to 35 ꢁC for 2 h then
quenched with a saturated NaHCO3 solution. The aqueous layer
was extracted with CH2Cl2 (three times). The combined organic
layers were dried (MgSO4) and concentrated to give an oil. The
crude product was purified by column chromatography on silica
gel (pentane/EtOAc, 8:2) to afford compound 13e as yellow oil
ahydro-[3,30]bipyridinyl-1-carboxylic acid benzyl ester (17). To
compound 13a (560 mg, 1.32 mmol, 1 equiv) in CH2Cl2 (15 mL) at
room temperature was added benzyl chloroformate (0.20 mL,
1.42 mmol, 1.1 equiv). The mixture was stirred for 16 h at room
temperature. Water was added and the mixture extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4) and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (pentane/EtOAc, 5:5) to give mesylate
17 as a colorless oil (474 mg, 82%). IR (NaCl, cmꢀ1
) nmax 2935, 1694,
1456, 1353, 1254, 1173, 1103; 1H NMR (CDCl3) dH 8.26 (1H, s), 7.50
(1H, d, J¼8.2 Hz), 7.36e7.31 (5H, m), 7.29 (1H, d, J¼8.2 Hz), 5.16 (2H,
s), 4.50e4.20 (2H, m), 4.20e4.10 (2H, m), 3.07 (3H, s), 2.80e2.60
(3H, m), 2.13e2.04 (2H, m), 1.50e1.40 (1H, m); 13C NMR (CDCl3) dC
155.1, 150.3, 148.7, 137.3, 136.4, 136.3, 128.7, 128.3, 128.1, 124.4, 70.7,
67.6, 49.8, 46.2, 39.2, 37.6, 34.0, 29.8; HRMS (EI) calcd for
C20H24ClN2O5S 439.1094, found 439.1077.
(182 mg, 78%). IR (NaCl, cmꢀ1
) nmax 2932, 1611, 1510, 1456, 1244,
1102; 1H NMR (CDCl3) dH 8.23 (d, J¼2.4 Hz, 1H), 7.47 (dd, J¼8.3,
2.4 Hz, 1H), 7.26e7.18 (m, 3H), 6.85 (d, J¼8.7 Hz, 2H), 3.80 (s, 3H),
3.55 and 3.50 (AB, J¼13.0 Hz, 2H), 3.15e3.10 (m, 1H), 3.09 (d,
J¼6.2 Hz, 2H), 2.95e2.85 (m, 2H), 2.05 (d, J¼12.8 Hz,1H), 2.00e1.85
(m, 2H), 1.73 (t, J¼10.8 Hz, 1H), 1.21 (q, J¼11.9 Hz, 1H); 13C NMR
(CDCl3) dC 158.9, 149.7, 148.9, 137.9, 137.5, 130.3, 129.7, 124.1, 113.8,
62.2, 59.7, 59.2, 55.4, 39.5, 38.6, 38.3, 10.4; HRMS (EI) calcd for
C19H23ClIN2O 457.0544, found 457.0528.
4.1.16. cis 60-Chloro-5-iodomethyl-1,2,3,4,5,6-hexahydro-[3,30]bipyr-
idinyl-1-carboxylic acid methyl ester (18). To iodo compound 13e
(800 mg, 1.76 mmol, 1 equiv) in dry CH2Cl2 (50 mL) at room tem-
perature was added methylchloroformate (0.34 mL, 4.39 mmol,
2.5 equiv). The mixture was stirred for 16 h at room temperature
then quenched with a saturated NaHCO3 solution. The aqueous
layer was extracted with CH2Cl2 (three times). The combined or-
ganic extracts were dried (MgSO4) and concentrated to give an
orange oil. The crude product was purified by column
4.1.13. cis [20,60-Dichloro-1-(4-methoxybenzyl)-1,2,3,4,5,6-hexahy-
dro-[3,30]bipyridin-5yl]-methanol (14). Compound cis-11 (400 mg,
0.94 mmol, 1 equiv) in dry Et2O(5 mL) was cooled to 0 ꢁC. LiAlH4
(108 mg, 2.83 mmol, 3 equiv) was added in 3 portions. The mixture

N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
9239
chromatography on silica gel (pentane/EtOAc, 8:2) to give com-
pound 18 as a colorless oil (623 mg, 90%); IR (NaCl, cmꢀ1
nmax 2951,
130.4, 129.9, 123.2, 113.7, 62.4, 61.2, 58.3, 55.4, 39.2, 38.4, 31.1, 19.6;
HRMS (EI) calcd for C19H23Cl2N2O 365.1187, found 365.1187.
)
1692, 1442, 1255, 1189, 1102; 1H NMR (CDCl3) dH 8.26 (1H, d,
J¼2.4 Hz), 7.52 (1H, dd, J¼8.3, 2.4 Hz), 7.29 (1H, d, J¼8.3 Hz),
4.40e4.10 (2H, m), 3.71 (3H, s), 3.11 (2H, d, J¼6.1 Hz), 2.90e2.60
(2H, m), 2.49 (1H, t, J¼12.1 Hz), 2.17 (1H, d, J¼14.5 Hz), 1.80e1.70
(1H, m), 1.38 (1H, q, J¼12.1 Hz); 13C NMR (CDCl3) dC 155.5, 150.0,
148.6, 137.3, 136.3, 124.2, 52.9, 49.6, 49.5, 39.2, 38.5, 37.7, 8.6; HRMS
(EI) calcd for C13H17ClIN2O2 395.0028, found 395.0023.
4.1.20. cis 20,60-Dichloro-5-methyl-1,2,3,4,5,6-hexahydro-[3,30]bipyr-
idinyl-1-carboxylic acid benzyl ester (23). Zn dust (27 mg,
0.416 mmol, 6 equiv) and 1,2-dibromoethane (1 mL, 0.012 mmol,
18% mol) were added to THF (0.1 mL) in a Schlenck tube. The
mixture was heated to 60 ꢁC for 2 min then cooled to room tem-
perature before adding TMSCl (2 mL, 0.016 mmol, 24 mol %). The
mixture was stirred at room temperature for 15 min. Compound 19
(35 mg, 0.069 mmol, 1 equiv) in THF (0.4 mL) was added then the
mixture was heated to 60 ꢁC for 1.5 h. After cooling, the reaction
was quenched with D2O. The aqueous layer was extracted with
CH2Cl2 and the combined organic extracts were dried (MgSO4),
concentrated to give compound 23 as a colorless oil (25 mg, 78%),
4.1.17. cis 20,60-Dichloro-5-iodomethyl-1,2,3,4,5,6-hexahydro-[3,30]
bipyridinyl-1-carboxylic acid benzyl ester (19). To compound 15
(82 mg, 0.17 mmol, 1 equiv) in CH2Cl2 (6 mL) was added benzyl
chloroformate (0.03 mL, 0.20 mmol, 1.2 equiv) at room tempera-
ture. The reaction mixture was stirred for 48 h at room temperature
then treated with water. The aqueous layer was extracted with
CH2Cl2 and the combined organic extracts were dried (MgSO4).
Evaporation of the volatile compounds then purification of the
residue by flash chromatography on silica gel (pentane/EtOAc, 8:2)
afforded compound 19 as a colorless oil (59 mg, 69%); IR (NaCl,
which was characterized without purification. IR (NaCl, cmꢀ1
) nmax
2925, 1694, 1547, 1422, 1253, 1210, 1134; 1H NMR (CDCl3) dH 7.53
(1H, d, J¼8.1 Hz), 7.40e7.30 (5H, m), 7.27 (1H, d, J¼8.1 Hz), 5.21 and
5.15 (2H, AB, J¼12.3 Hz), 4.40e4.15 (2H, m), 3.20e3.10 (1H, m), 2.61
(1H, t, J¼12.3 Hz), 2.45e2.30 (1H, m), 2.02 (1H, d, J¼12.1 Hz),
1.90e1.80 (1H, m), 1.35e1.20 (1H, m), 0.99 (3H, d, J¼6.3 Hz); 13C
NMR (CDCl3) dC 155.1, 150.3, 148.3, 138.1, 136.7, 135.4, 128.6, 128.2,
128.1,123.3, 67.4, 51.1, 48.7, 38.9, 31.2, 29.8, 18.9; HRMS (EI) calcd for
C19H21N2O2Cl2 379.0980, found 379.0974.
cmꢀ1 nmax 2923, 1693, 1547, 1421, 1254, 1211, 1143; 1H NMR (CDCl3)
)
dH 7.54 (1H, d, J¼8.1 Hz), 7.40e7.30 (5H, m), 7.29 (1H, d, J¼8.1 Hz),
5.20 and 5.16 (2H, AB, J¼12.3 Hz), 4.45e4.30 (2H, m), 3.20e3.10 (3H,
m), 2.65 (1H, t, J¼12.3 Hz), 2.60e2.50 (1H, m), 2.18 (1H, d,
J¼12.5 Hz), 1.85e1.75 (1H, m), 1.50e1.30 (1H, m), 0.90e0.80 (1H,
m); 13C NMR (CDCl3) dC 155.0, 150.2, 148.6, 138.1, 136.4, 134.7, 128.6,
128.3, 128.1, 123.4, 67.6, 49.8, 48.7, 38.3, 37.3, 29.8, 8.80; HRMS (EI)
calcd for C19H20N2O2Cl2I 504.9947, found 504.9948.
4.2. Radical cyclization of iodide 18
To a solution of iodo compound 18 (290 mg, 0.735 mmol,1 equiv)
in 1,2-dichloroethane (11 mL) was added BF3$Et2O (0.186 mL,
1.47 mmol, 2 equiv). Under argon, dilauroyl peroxide (DLP) (293 mg,
7.35 mmol,10 equiv) in 1,2-dichloroethane (40 mL) was added slowly
to the refluxing solution using a syringe pump (0.12 mmol of DLP per
hour) over 61 h. The mixture was refluxed for 10 h then cooled to
room temperature. Hydrochloric acid (3 N) and ammonia were suc-
cessively added, followed by brine. The aqueous layer was extracted
with CH2Cl2 (three times). The combined organic extracts were dried
(MgSO4) and concentrated to give an oil, which was purified by flash
chromatography (cyclohexane/EtOAc 9/1, from 8:2 to 7:3).
4.1.18. cis 60-Chloro-5-methanesulfonyloxymethyl-10-oxy-1,2,3,4,5,6-
hexahydro-[3,30]bipyridinyl-1-carboxylic
acid
benzyl
ester
(20). Pyridine derivative 17 (135 mg, 0.31 mmol, 1 equiv) was
dissolved in 1,2-dichloroethane (15 mL). Urea peroxide (61 mg,
0.65 mmol, 2.1 equiv) was added followed by trifluoroacetic an-
hydride (0.09 mL, 0.65 mmol, 2 equiv). The mixture was heated to
80 ꢁC for 5 h. After cooling to room temperature, the mixture was
quenched with aqueous Na2S2O3 solution, stirred for 15 min then
extracted with CH2Cl2. The organic extracts were washed with
a saturated NaHCO3 solution, dried (MgSO4), and concentrated
under vacuum. The crude product was purified by flash chroma-
tography on silica gel (CH2Cl2/MeOH, 98:2) to afford compound 20
4.2.1. 5-Chloro-11-methoxycarbonyl-6,11-diaza-tricyclo[7.3.1.02,7]tri-
deca-2(7),3,5-triene (24). Orange oil (573 mg, 37%); Rf 0.2 (cyclo-
as a yellow oil (120 mg, 85%); IR (NaCl, cmꢀ1
)
nmax 2934, 1692, 1432,
hexane/EtOAc, 7:3); IR (NaCl, cmꢀ1
) nmax 2921, 2860, 1693, 1567,
1352, 1262, 1171; 1H NMR (CDCl3) dH 8.26 (1H, s), 7.44 (1H, d,
J¼8.6 Hz), 7.40e7.30 (5H, m), 7.07 (1H, d, J¼8.6 Hz), 5.15 (2H, s),
4.50e4.30 (2H, m), 4.20e4.10 (2H, m), 3.02 (3H, s), 2.80e2.50 (3H,
m), 2.10 (2H, d, J¼11.5 Hz), 1.44 (1H, q, J¼12.5 Hz); 13C NMR (CDCl3)
dC 155.0, 140.4, 139.6, 139.2, 136.3, 128.6, 128.3, 128.1, 127.0, 125.2,
70.5, 67.7, 49.3, 46.0, 38.9, 37.5, 35.8, 33.4; HRMS (EI) calcd for
C20H24ClN2O6S 455.1044, found 455.1035.
1437, 1231, 1126; 1H NMR (CDCl3) dH 7.35 (1H, d, J¼8.1 Hz), 7.07 (1H,
d, J¼8.1 Hz), 4.31 and 4.04 (1H, d, J¼12.6 Hz, two rotamers), 4.16
and 3.87 (1H, d, J¼12.6 Hz, two rotamers), 3.51 and 3.37 (3H, s, two
rotamers), 3.15e2.90 (5H, m), 2.35e2.20 (1H, m), 2.00e1.85 (2H,
m); 13C NMR (CDCl3) dC 158.5 and 158.0 (two rotamers), 156.5,
149.0, 138.9, and 138.5 (two rotamers), 132.6, 121.8, and 121.4 (two
rotamers), 52.8 and 52.6 (two rotamers), 51.1, 50.5, and 50.3 (two
rotamers), 37.0, 33.8, 29.4, 27.7; HRMS (EI) calcd for C13H16ClN2O2Cl
267.0900, found 267.0887.
4.1.19. cis 20,60-Dichloro-5-methyl-1-(4-methoxy-benzyl)-1,2,3,4,5,6-
hexahydro-[3,30]bipyridinyl (22a). To compound 15 (28 mg,
0.073 mmol, 1 equiv) in dry THF (3 mL) cooled to ꢀ78 ꢁC was added
a solution of t-BuLi in pentane (1.5 M, 0.10 mL, 0.146 mmol, 2 equiv).
The mixture was stirred for 1 h at ꢀ78 ꢁC then quenched with
water. The reaction mixture was extracted with CH2Cl2 (three
times) and the combined organic layers were dried (MgSO4) then
evaporated. The crude product was purified by flash chromatog-
raphy (pentane/EtOAc, 9:1) to afford compound 22a as a colorless
4.2.2. 5-Chloro-11-methoxycarbonyl-4,11-diaza-tricyclo[7.3.1.02,7
trideca-2,4,6-triene (25). Colorless oil (29 mg, 15%); Rf 0.15 (cyclo-
hexane/EtOAc, 7:3); IR (NaCl, cmꢀ1
nmax 2924, 2856, 1696, 1587,
]
)
1443, 1232, 1127; 1H NMR (CDCl3) dH 8.12 (1H, s), 7.07 (1H, s),
4.40e3.85 (2H, m), 3.52 and 3.36 (3H, s, two rotamers), 3.20e2.85
(5H, m), 2.31 (1H, s), 2.05e1.95 (1H, m), 1.95e1.80 (1H, m); 13C NMR
(CDCl3) dC 157.0 and 156.6 (two rotamers), 149.9, 149.2, 148.9, 133.6,
123.2, 52.8, and 52.6 (two rotamers), 51.1, 50.9, 37.0, 33.3, 29.5, 27.0;
HRMS (EI) calcd for C13H16ClN2O2 267.0900, found 267.0897.
oil (16 mg, 63%); IR (NaCl, cmꢀ1
) nmax 2927, 1612, 1547, 1510, 1424,
1246, 1168, 1035; 1H NMR (CDCl3) dH 7.51 (1H, d, J¼8.0 Hz), 7.22 (2H,
d, J¼8.5 Hz), 7.21 (1H, d, J¼8.0 Hz), 6.85 (2H, d, J¼8.5 Hz), 3.80 (s,
3H), 3.54 and 3.50 (AB, 2H, J¼13.1 Hz), 3.30 (1H, tt, J¼12.0, 3.6 Hz,),
3.00 (1H, d, J¼10.6 Hz), 2.98 (1H, d, J¼11.0 Hz), 2.0e1.9 (2H, m), 1.82
(1H, t, J¼11.1 Hz),1.62 (1H, t, J¼10.6 Hz), 0.99 (1H, q, J¼12.1 Hz), 0.91
(3H, d, J¼6.5 Hz); 13C NMR (CDCl3) dC 158.9, 150.2, 147.7, 138.5, 137.1,
4.2.3. cis
idinyl-1-carboxylic acid methyl ester (26). Yellow oil; Rf 0.5 (cyclo-
20-Chloro-5-methyl-3,4,5,6-tetrahydro-2H-[3,30]bipyr-
hexane/EtOAc, 7:3); IR (NaCl, cmꢀ1
) nmax 2954, 1694, 1450, 1254,
1200, 1101; 1H NMR (CDCl3) dH 8.25 (1H, d, J¼2.5 Hz), 7.49 (1H, dd,

9240
N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
J¼8.2, 2.5 Hz), 7.27 (1H, d, J¼8.2 Hz), 4.30e4.10 (2H, m), 3.70 (3H, s),
2.80e2.60 (2H, m), 2.35 (1H, t, J¼12.1 Hz), 1.98 (1H, d, J¼14.3 Hz),
1.80e1.70 (1H, m), 1.25 (1H, q, J¼12.1 Hz), 0.95 (3H, d, J¼6.6 Hz); 13C
NMR (CDCl3) dC 155.8, 149.9, 148.7, 137.5, 137.3, 124.2, 52.8, 50.9,
49.8, 40.2, 40.0, 31.3, 18.9; HRMS (EI) calcd for C13H18ClN2O2
269.1057, found 269.1068.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.09.079.
References and notes
4.3. Deprotection of the secondary amine. General procedure
1. Ing, H. R. J. Chem. Soc. 1932, 2195e2203 and 2778e2780.
2. (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, 3475e3478; (b) Badio, B.; Daly, J. W. Mol.
Pharmacol. 1994, 45, 563e569.
3. Schmitt, J. D. Curr. Med. Chem. 2000, 7, 749e800.
4. Daly, J. W. Cell. Mol. Neurobiol. 2005, 25, 513e552.
A mixture of carbamate (0.10 mmol) in hydrochloric acid (9 N,
3 mL) was refluxed for 16 h. The mixture was cooled to room
temperature, then a NH4OH solution was added (pH¼14). The re-
action mixture was concentrated under vacuum. The residue was
triturated with CH2Cl2 and filtrated. The filtrate was evaporated.
The crude product was purified by flash chromatography (CH2Cl2/
MeOH, 94:6 and 1% NH4OH 28%).
5. (a) Pabreza, L. A.; Dhawan, S.; Kellar, K. J. Mol. Pharmacol. 1991, 39, 9e12; (b)
Hall, M.; Zerbe, L.; Leonard, S.; Freedman, R. Brain Res. 1993, 600, 127e133; (c)
Anderson, D. J.; Arneric, S. P. Eur. J. Pharmacol. 1994, 253, 261e267.
6. i.e., (a) Coe, J. W.; Vetelino, M. G.; Bashore, C. G.; Wirtz, M. C.; Brooks, P. R.;
Arnold, E. P.; Lebel, L. A.; Fox, C. B.; Sands, S. B.; Davis, T. I.; Schulz, D. W.;
Rollema, H.; Tingley, F. D.; O’Neill, B. T. Bioorg. Med. Chem. Lett. 2005, 15,
2974e2979; (b) Bashore, C. G.; Vetelino, M. G.; Wirtz, M. C.; Brooks, P. R.; Frost,
H. N.; McDermott, R. E.; Whritenour, D. C.; Ragan, J. A.; Rutherford, J. L.;
Makowski, T. W.; Brenek, S. J.; Coe, J. W. Org. Lett. 2006, 8, 5947e5950; (c)
Yohannes, D.; Procko, K.; Lebel, L. A.; Fox, C. B.; O’Neill, B. T. Bioorg. Med. Chem.
Lett. 2008, 18, 2316e2319; (d) Kozikowski, A. P.; Chellapan, S. K.; Xiao, Y. X.;
Bajjuri, K. M.; Yuan, H. B.; Kellar, K. J.; Petukhov, P. A. ChemMedChem 2007, 2,
1157e1161 and references therein; (e) Fitch, R. W.; Kaneko, Y.; Klaperski, P.;
4.3.1. 5-Chloro-6,11-diaza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene
(1). Carbamate 24 afforded compound 1 as an orange oil (14 mg,
70%); IR (NaCl, cmꢀ1 nmax 2923, 2853, 1569, 1438, 1259, 1125; 1H
)
NMR (CDCl3) dH 7.29 (1H, d, J¼8.0 Hz), 7.09 (1H, d, J¼8.0 Hz), 3.16 (1H,
dd, J¼9.0, 6.9 Hz), 3.10e2.85 (5H, m), 2.80e2.70 (1H, m), 2.30e2.15
(2H, m), 2.05e1.95 (1H, m), 1.90e1.80 (1H, m); 13C NMR (CDCl3) dC
159.6,148.8,138.6,133.8,129.2,121.7, 37.5, 37.4, 32.0, 29.8, 29.3, 22.8;
HRMS (EI) calcd for C11H14ClN2 209.0846, found 209.0840.
€
Daly, J. W.; Seitz, G.; Gundisch, D. Bioorg. Med. Chem. Lett. 2005, 15, 1221e1224.
7. Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold, E. P.; Huang, J.;
Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.; Shrikhande, A.; Heym, J. H.;
Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.;
Schulz, D. W.; Tingley, F. D.; O'Neill, B. T. J. Med. Chem. 2005, 48, 3474e3477.
4.3.2. 5-Chloro-4,11-diaza-tricyclo[7.3.1.02,7]trideca-2,4,6-triene
ꢂ
8. (a) Marriere, E.; Rouden, J.; Tadino, V.; Lasne, M.-C. Org. Lett. 2000, 2,
1121e1124; (b) Roger, G.; Lagnel, B.; Rouden, J.; Besret, L.; Valette, H.; Demphel,
(27). Carbamate 25 afforded compound 27 as an oil (15 mg, 72%);
IR (NaCl, cmꢀ1 nmax 2923, 2853, 1586, 1464, 1261, 1111; 1H NMR
)
S.; Gopisetti, J. M.; Coulon, C.; Ottaviani, M.; Wrenn, L. A.; Letchworth, S. R.;
ꢀ
Bohme, G. A.; Benavides, J.; Lasne, M.-C.; Bottlaender, M.; Dolle, F. Bioorg. Med.
(CDCl3) dH 8.04 (1H, s), 7.12 (1H, s), 3.10e2.85 (6H, m), 2.80e2.70
(2H, m), 2.15e2.00 (2H, m), 1.90e1.80 (1H, m); 13C NMR (CDCl3) dC
151.1, 149.0, 148.8, 135.1, 123.1, 37.6, 33.9, 32.1, 29.8, 29.5, 22.8;
HRMS (EI) calcd for C11H13ClN2 208.0767, found 208.0767.
Chem. 2003, 11, 5333e5343.
9. (a) Allen, M.P.; Coe, J.W.; Liras, S.; O’Donnell, C.J.; O’Neill, B.T. U.S. Patent. Appl.
U.S. 020,830, 2005; CAN 2005, 142, 176859; (b) Allen, M.P.; Coe, J.W.; Liras, S.;
O’Donnell, C.J.; O’Neill, B.T. PCT Int. Appl. WO 2005/007655; CAN 2005, 142,
74119; (c) Demers, S.; Stevenson, H.; Candler, J.; Bashore, C. G.; Arnold, E. P.;
O’Neill, B. T.; Coe, J. W. Tetrahedron Lett. 2008, 49, 3368e3371.
10. Nshimyumukiza, P.; Cahard, D.; Rouden, J.; Lasne, M.-C.; Plaquevent, J.-C. Tet-
rahedron Lett. 2001, 42, 7787e7790.
11. (a) Van Tamelen, E. E.; Baran, J. S. J. Am. Chem. Soc. 1958, 80, 4659e4670 and
references therein; (b) O’Neill, B. T.; Yohannes, D.; Bundesmann, M. W.; Arnold,
E. P. Org. Lett. 2000, 2, 4201e4204; (c) Danieli, B.; Lesma, G.; Passarella, D.;
Sacchetti, A.; Silvani, A.; Virdis, A. Org. Lett. 2004, 6, 493e496; (d) Honda, T.;
Takahashi, R.; Namiki, H. J. Org. Chem. 2005, 70, 499e504; (e) cf. for a review:
Stead, D.; O’Brien, P. Tetrahedron 2007, 63, 1885e1897.
4.3.3. cis-2-Chloro-5-(5-methylpiperidin-3-yl)pyridine (28). Car-
bamate 26 (27 mg, 0.10 mmol, 1 equiv) afforded compound 28 as an
oil (18 mg, 86%); IR (NaCl, cmꢀ1
) nmax 2951, 2922, 1583, 1563, 1455,
1263, 1103; 1H NMR (CDCl3) dH 8.22 (1H d, J¼2.4 Hz), 7.46 (1H, dd,
J¼8.2, 2.4 Hz), 7.23 (1H, d, J¼8.2 Hz), 3.12 (1H, d, J¼12.2 Hz), 3.06
(1H, d, J¼12.5 Hz), 2.72 (1H, t, J¼11.8 Hz), 2.51 (1H, t, J¼11.8 Hz),
2.25e2.15 (2H, m), 1.94 (1H, d, J¼12.9 Hz), 1.70e1.60 (1H, m),
1.30e1.20 (1H, m), 0.89 (3H, d, J¼6.7 Hz); 13C NMR (CDCl3) dC 149.4,
148.8, 138.7, 137.4, 124.1, 53.9, 53.1, 41.3, 40.6, 32.6, 19.5; HRMS (EI)
calcd for C11H15ClN2 210.0924, found 210.0917.
12. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483.
13. (a) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002,
58, 2885e2890; (b) Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B.
J. Org. Chem. 2002, 67, 7541e7543.
14. Yamamoto, Y.; Azuma, Y.; Mitoh, H. Synthesis 1986, 564e565.
15. Heller, M.; Schubert, U. S. J. Org. Chem. 2002, 67, 8269e8272.
16. (a) Plaquevent, J. C.; Chichaoui, I. Bull. Soc. Chim. Fr. 1996, 133, 369e379; (b)
Kang, C.-Q.; Cheng, Y.-Q.; Guo, H.-Q.; Qiu, X.-P.; Gao, L.-X. Tetrahedron: Asym-
metry 2005, 16, 2141e2147.
4.4. Molecular modeling
3D conformations of (ꢀ)-cytisine69 were retrieved from CSD.70 X-
ray data are only available for 3-hydroxy epibatidine71 and the initial
conformations for both enantiomers were retrieved from the same
file. Then, the first conformations associated to (ꢀ)- and (þ)-epi-
batidines were generated by replacing the hydroxyl group by a hy-
drogen. The conformational space of each derivativewas summarized
by the algorithm CAESAR.72 Mapping between the derivatives was
based on the definition of common chemical features (key in-
teractions sites), an analysis carried out with the Catalyst software.73
Default values were considered excepted a minimum distance of
17. Abraham, R. J.; Aboitiz, N.; Merret, J.; Sherborne, B.; Whitcombe, I. J. Chem. Soc.,
Perkin Trans. 2 2000, 2382e2392.
18. (a) Choppin, S.; Gros, P.; Fort, Y. Org. Lett. 2000, 2, 803e805; (b) Fort, Y.; Gros, P.;
Rodriguez, A. L. Tetrahedron: Asymmetry 2001, 12, 2631e2635; (c) Gros, P.;
Choppin, S.; Mathieu, J.; Fort, Y. J. Org. Chem. 2002, 67, 234e237; (d) Gros, P.;
Choppin, S.; Fort, Y. J. Org. Chem. 2003, 68, 2243e2247; (e) Gros, P. C.; Fort, Y.
Eur. J. Org. Chem. 2009, 4199e4209.
19. An attempt of metallation of 2-chloro-3,30-bipyridine using LiDMAE-n-BuLi
complex in hexane or toluene and trapping the potential intermediate with
chlorotrimethylsilane or benzaldehyde failed.
20. Abramovitch, R. A.; Saha, M.; Smith, E. M. J. Am. Chem. Soc. 1967, 89, 1537e1538.
ꢀ
21. (a) Mongin, O.; Rocca, P.; Thomas-dit-Dumont, L.; Trecourt, F.; Marsais, F.;
ꢀ
Godard, A.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1 1995, 2503e2508; (b)
ꢀ
ꢀ
Trecourt, F.; Gervais, B.; Mongin, O.; Le Gal, C.; Mongin, F.; Queguiner, G. J. Org.
Chem. 1998, 63, 2892e2897.
ꢁ
ꢁ
1 A instead of 3 A (size of the structures) between the features.
22. Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Lett. 2000, 41, 2299e2302.
23. Howarth, N. M.; Malpass, J. R.; Smith, C. R. Tetrahedron 1998, 54, 10899e10914.
24. Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem.1999, 64, 2184e2185.
25. Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc. 1987, 109,
2442e2448.
26. Merrill, R. E.; Negishi, E. J. Org. Chem. 1974, 39, 3452e3453.
27. For a review on iron-catalyzed reactions: Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217e6254.
Acknowledgements
This work was supported by the CNRS, the Ministery of Educa-
tion and Research, the Region Basse Normandie, the interregional
network PUNCH’Orga and the European Union (FEDER funding).
The authors gratefully acknowledge CNRS/Region Basse Normandie
for NH’s fellowship.
28. (a) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856e13863; (b) Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006, 8, 1771e1773;

N. Houllier et al. / Tetrahedron 66 (2010) 9231e9241
9241
€
(c) Vandromme, L.; Rei
2049e2055.
b
ig, H. U.; Groper, S.; Rabe, J. Eur. J. Org. Chem. 2008,
51. (a) Liu, J.-Y.; Jang, Y.-J.; Lin, W.-W.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2003, 68,
4030e4038 and references therein; (b) Ollivier, C.; Renaud, P. Chem. Rev. 2001,
101, 3415e3434; (c) Godineau, E.; Schafer, C.; Landais, Y. Org. Lett. 2006, 8,
4871e4874.
52. RajanBabu, T. V.; Gagosz, F. Encyclopedia of Reagents for Organic Synthesis;
€
29. Erdik, E. Tetrahedron 1987, 43, 2203e2212.
30. For an example of intramolecular Negishi coupling (Csp3eCsp2 bond forma-
tion), see: Nolasco, L.; Gonzalez, M. P.; Caggiano, L.; Jackson, F. W. J. Org. Chem.
2009, 74, 8280e8289.
Wiley: New York, NY, 2005.
31. For Negishi couplings of 2-chloropyridine or 2-chloroquinoline, see: (a) Sase, S.;
Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org. Chem. 2008, 73,
53. Charrier, N. Encyclopedia of Reagents for Organic Synthesis; Wiley: New York, NY,
2007.
54. Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002, 124, 906e907.
55. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W.-L. Chem. Rev. 2002, 102,
2227e2302.
€
7380e7382; (b) Lutzen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292e2297.
32. Harrowven, D. C.; Sutton, B. J. Prog. Heterocycl. Chem. 2005, 16, Chapter 2 27e53.
33. (a) Minisci, F.; Galli, R.; Cerere, M.; Malatesta, V.; Caronna, T. Tetrahedron Lett.
1968, 9, 5609e5612; (b) Minisci, F. Synthesis 1973, 1e24; (c) Minisci, F.; Citterio,
A.; Vismara, E. Tetrahedron 1985, 41, 4157e4170; (d) Minisci, F.; Mondelli, R.;
Gardini, G. P.; Porta, O. Tetrahedron 1972, 28, 2403e2413.
56. Calculations were performed using PC-SPARTAN-Pro, semi-empirical AM1
method.
57. (a) Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442e446;
(b) Kende, A. S.; Luzzio, M. J.; Mendoza, J. S. J. Org. Chem. 1990, 55, 918e924.
58. Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988, 53, 4074e4081.
59. Marks, M. J.; Stitzel, J. A.; Romm, E.; Wehner, J. M.; Collins, A. C. Mol. Pharmacol.
1986, 30, 427e436.
34. Barton, D. H. R.; Garcia, B.; Togo, H.; Zard, S. Z. Tetrahedron Lett. 1986, 27,
1327e1330.
35. Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M.; Giordano, C.
J. Org. Chem. 1987, 52, 730e736.
36. Citterio, A.; Minisci, F.; Porta, O.; Sesana, G. J. Am. Chem. Soc. 1977, 99,
7960e7968.
37. (a) Maiti, S.; Achari, B.; Mukhopadhyay, R.; Banerjee, A. K. J. Chem. Soc., Perkin
Trans. 1 2002, 1769e1773; (b) Maiti, S.; Drew, M. G. B.; Mukhopadhyay, R.;
Achari, B.; Banerjee, A. K. Synthesis 2005, 3067e3078.
60. Nicolotti, O.; Pellegrini-Calace, M.; Carrieri, A.; Altomare, C.; Centeno, N. B.;
Sanz, F.; Carotti, A. J. Comput. Aided Mol. Des. 2001, 15, 859e872.
61. Karig, G.; Large, J. M.; Sharples, C. G. V.; Sutherland, A.; Gallagher, T.; Wonna-
cott, S. Bioorg. Med. Chem. Lett. 2003, 13, 2825e2828.
62. Carroll, F. I.; Yokota, Y.; Ma, W.; Lee, J. R.; Brieaddy, L. E.; Burgess, J. P.; Navarro,
H. A.; Damaj, M. I.; Martin, B. R. Biorg. Med. Chem. 2008, 16, 746e754.
63. See i.e., (a) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron
2004, 60, 6239e6278; (b) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.
Tetrahedron 2005, 61, 10603e10642; (c) Kaoudi, T.; Miranda, L. D.; Zard, S. Z.
Org. Lett. 2001, 3, 3125e3127; (d) Lynch, M.; Hehir, S.; Kavanagh, P.; Leech, D.;
O’Shaughnessy, J.; Carty, M. P.; Aldabbagh, F. Chem.dEur. J. 2007, 13,
3218e3226; (e) Quirante, J.; Escolano, C.; Diaba, F.; Bonjoch, J. Heterocycles
1999, 50, 731e738; (f) Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996,
61, 7873e7881; (g) Boivin, J.; Pothier, J.; Zard, S. Z. Tetrahedron Lett. 1999, 40,
3701e3704; (h) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91,
1237e1286; (i) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.;
Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565e7581.
ꢀ
ꢀ~
38. Sanchez, A.; Nunez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron Lett. 2006, 47,
8343e8346.
39. Baker, S. R.; Cases, M.; Keenan, M.; Lewis, R. A.; Tan, P. Tetrahedron Lett. 2003,
44, 2995e2999.
40. Da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38,
137e140 and 141e144.
41. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron Lett. 2001, 42,
9061e9064; (b) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol. Chem.
2003, 1, 4047e4057; (c) Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998,
39, 5875e5876.
42. Doll, M. K. H. J. Org. Chem. 1999, 64, 1372e1374.
43. (a) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31, 3495e3496; (b)
Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47, 4077e4088; (c) Park, Y.-T.;
Song, N. W.; Hwang, C.-G.; Kim, K.-W.; Kim, D. J. Am. Chem. Soc. 1997, 119,
10677e10683.
64. Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem. 1997, 542, 281e283.
65. Voisin, A. S.; Bouillon, A.; Lancelot, J.-C.; Rault, S. Tetrahedron 2005, 61,1417e1421.
66. Isomura, S.; Wirsching, P.; Janda, K. D. J. Org. Chem. 2001, 66, 4115e4121.
67. i.e., for Suzuki reaction of boronic acid 5 and Stille coupling of tributylstanyl
derivative 7 with aryl iodides: Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett.
1993, 34, 2127e2130.
ꢀ
44. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671e3674.
45. Gonzalez, M. A.; Molina-Navarro, S. J. Org. Chem. 2007, 72, 7462e7465.
46. Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford University: Oxford, 2003.
47. For a review on the use of Lewis acids in radical reactions: Renaud, P.; Gerster,
M. Angew. Chem., Int. Ed. 1998, 37, 2562e2579.
68. Dppf: 1,10-Bis(diphenylphosphino)ferrocene
69. Freer, A.; Robins, D. J.; Sheldrake, G. N. Acta Crystallogr., Sect. C 1987, 43,
1119e1122.
48. Bennasar, M.-L.; Zulaica, E.; Ramirez, A.; Bosch, J. J. Org. Chem. 1996, 61,
1239e1251.
70. Allen, F. H. Acta Crystallogr. 2002, B58, 380e388.
49. (a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. J. Am. Chem. Soc. 1988, 110,
5900e5902; (b) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115, 6051e6059.
50. (a) Xu, W.; Zhang, X. M.; Mariano, P. S. J. Am. Chem. Soc. 1991, 113, 8863e8878;
(b) Parsons, P. J.; Caddick, S. Tetrahedron 1994, 50, 13523e13532; (c) Wardrop,
D. J.; Zhang, W. Org. Lett. 2001, 3, 2353e2356; (d) Curran, D. P.; Fairweather, N. J.
Org. Chem. 2003, 68, 2972e2974.
71. Wei, Z. L.; Xiao, Y.; George, C.; Kellar, K. J.; Kozikowski, A. P. Org. Biomol. Chem.
2003, 1, 3878e3881.
72. Li, J.; Ehlers, T.; Sutter, J.; Varma-OBrien, S.; Kirchmair, J. J. Chem. Inf. Model.
2007, 47, 1923e1932.
73. Barnum, D.; Greene, J.; Smellie, A.; Sprague, O. J. Chem. Inf. Comput. Sci. 1996, 36,
563e571.