Synthesis of 1-phenyl- and 1-pyridyl-3-pyridoazepines by reductive cyclization of diarylacetonitriles

Article abstract of DOI:10.1016/j.tet.2009.02.075

Several pyrido[2,3-d]azepines and pyrido[3,4-d]azepines, novel aza analogs of the pharmacologically relevant 1-aryl-3-benzazepines, were synthesized by assembling the azepine ring by reductive cyclization of (2-methoxyvinyl)pyridinyl(aryl)acetonitrile derivatives, which were easily derived from contiguously substituted bromo(2-methoxyvinyl)pyridines and the corresponding arylacetonitriles.

Full text of DOI:10.1016/j.tet.2009.02.075

Tetrahedron 65 (2009) 3653–3658
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Synthesis of 1-phenyl- and 1-pyridyl-3-pyridoazepines by reductive
cyclization of diarylacetonitriles
*
´
M. Carmen de la Fuente, Domingo Domınguez
´
´
Departamento de Qu´ımica Organica y Unidad Asociada al CSIC, Facultad de Quımica, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Several pyrido[2,3-d]azepines and pyrido[3,4-d]azepines, novel aza analogs of the pharmacologically
relevant 1-aryl-3-benzazepines, were synthesized by assembling the azepine ring by reductive cycliza-
tion of (2-methoxyvinyl)pyridinyl(aryl)acetonitrile derivatives, which were easily derived from conti-
guously substituted bromo(2-methoxyvinyl)pyridines and the corresponding arylacetonitriles.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 January 2009
Received in revised form 26 February 2009
Accepted 27 February 2009
Available online 5 March 2009
Keywords:
Pyrido[2,3-d]azepines
Pyrido[3,4-d]azepines
Aza-1-aryl-3-benzazepines
Reductive cyclization
Diarylacetonitriles
1. Introduction
In this work we investigated the synthesis of two new series of
analogs in which the fused benzene ring is replaced by a fused
The neurotransmitter dopamine (DA) is involved in various
physiological and pathological processes, including brain functions
such as motion, emotion, and cognition. DA antagonists are used for
treating schizophrenia, mania, delirium, and Huntington’s disease,
and DA agonists for treating Parkinson’s disease and neuroendo-
crine disorders.1 However, the limitations of current DA agonists
and antagonists maintain interest in the search for novel analogs,
especially with regard to the improvement of selectivity for par-
ticular DA receptor subtypes. The prototype D1-selective antagonist,
SCH 23390,2 is a 1-aryl-3-benzazepine, a family that, if conforma-
tionally restricted derivatives are counted, now includes the ago-
nists SKF 38393,3 SKF 82526 (fenoldopam),4 and SKF 82958,5 and
the antagonist SCH 39166.6 In all these compounds the 1-aryl
moiety is essential for affinity and selectivity for D1-like receptors.7
pyridine, namely the 1-phenyl-3-pyridoazepines and 1-pyridyl-3-
pyridoazepines (Fig. 1). Although 5H-pyrido[2,3-d]azepines8 and
5H-pyrido[3,4-d]azepines9 have appeared in the literature, as have
1-pyridyl-3-benzazepines,10 compounds incorporating the 1-aryl-
3-pyridoazepine scaffold have not previously been reported.
InaccordancewiththeretrosyntheticanalysisshowninScheme1,
we planned to prepare the target 1-aryl-3-pyridoazepines by
coupling bromo(2-methoxyvinyl)pyridines and arylacetonitriles,
followed by ring closure. Since pyridine is
p-deficient, and the
resonance effect of the N atom results in the
a
and positions
g
bearing a partial positive charge that makes them prone to
nucleophilic attack, we envisaged that bromopyridines 3a and
3c could be linked directly to the arylacetonitrile by an SNAr
reaction (addition–elimination) following base-induced forma-
tion of the corresponding anion (Scheme 2).11 In the case of
bromopyridine 3b, it was hoped that palladium-catalyzed ary-
lation of phenylacetonitrile12 would achieve the coupling. For
ring closing, a variety of methods would be tried.
N
NR
N
NR
N
OMe
OMe
1-phenyl-3-pyridoazepine 1-pyridyl-3-pyridoazepine
N
NH
N
N
Br
Ar
Figure 1. Aza analogs of 1-phenyl-3-benzazepines.
CN
+
Ar
Ar
* Corresponding author. Tel.: þ34 981563100; fax: þ34 981595012.
CN
E-mail addresses: mcarmen.delafuente@usc.es (M.C. de la Fuente), domi-
Scheme 1. Retrosynthetic analysis of pyridoazepines.
´
ngo.dominguez@usc.es (D. Domınguez).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.075

3654
M.C. de la Fuente, D. Dom´ınguez / Tetrahedron 65 (2009) 3653–3658
OMe
CN
4a
Z
Y
Ph
CN
X
1. LDA, THF
2. DMF
Z
Y
t
CHO
Br
Ph
KO Bu, toluene
Z
Y
OMe
CH3OCH2PPh3Cl
Z
Y
5aa, 43%
X
Br
t
5ca, 61%
KO Bu, THF
X
X
Br
(for 3b)
4a
CN
Ph
2a
2b
2c
3a, 87%
3b, 45%
3c, 86%
1a, X = N, Y = CH, Z = CH
1b, X = CH, Y = N, Z = CH
1c, X = CH, Y = CH, Z = N
t
KO Bu,
Pd(Ph3P)4
DME
N
Br
6, 50%
Scheme 2. Synthesis of diarylacetonitriles 5aa and 5ca.
2. Results and discussion
to 9-phenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (11aa) in
39% isolated yield (Scheme 3). By contrast, under the same con-
ditions the isomeric nitrile 5ca unexpectedly afforded cyclo-
pentane 8 as the major product, no doubt due to aldehyde
formation followed by intramolecular nucleophilic attack by the
2.1. Synthesis of 1-phenyl-3-pyridoazepines
To prepare bromo(2-methoxyvinyl)pyridines 3a–c from bro-
mopyridines 1a–c, bromopyridine carbaldehydes 2a–c were first
prepared by lithiation of 1a–c followed by formylation with DMF.13
The homologations of the aldehydes were then achieved by Wittig
reactions with methoxymethyl triphenylphosphonium chloride
and KOtBu. This afforded good yields of 3a and 3c as mixtures of E
and Z isomers (Scheme 2), but only about half as much of the 3-
bromo derivative 3b (although in this case the E and Z isomers were
separated; the combined yield of the geometrically pure vinyl
ethers was 45%). Nitriles 5aa and 5ca were obtained as planned,
though in moderate yield, by SNAr displacements on bromopyr-
idines 3a and 3c with phenylacetonitrile (4a) by heating in toluene
at 80 ꢀC in the presence of KOtBu. However, palladium-catalyzed
coupling of 3b to phenylacetonitrile did not afford their isomer 5ba,
but compound 6, probably as the result of a competitive conjugated
nucleophilic attack by the phenylacetonitrile anion on the
methoxy-substituted vinylic carbon, followed by elimination of
methanol and isomerization of the double bond to the more
substituted alkene.
For the cyclization of nitriles 5aa and 5ca we first considered
their reduction to the corresponding amines 7, followed by in situ
acid catalyzed intramolecular condensation with the aldehyde
obtained by hydrolysis of the vinyl ether and further reduction of
the resulting imine. This kind of one-pot reductive cyclization has
been used in the synthesis of 3-benzazepines from nitro acetals.10
In our case, reduction of the nitrile group of 5aa by treatment
with a large excess of Zn and CoCl2 in 6 M HCl14 gave direct access
a
-carbon of the nitrile. This undesired behavior probably takes
place through an -chloroenamine, which is formed by initial
a
protonation of the nitrile and further addition of HCl to form an
intermediate imidoyl chloride,15 a process that seems not occur in
the case of 5aa because the protonation of the nitrile might be
inhibited by electrostatic repulsion from the nearby protonated
pyridine nitrogen.16
To prevent undesired formation of 8, a two-step procedure was
employed in which the aminoethyl derivatives 7 were isolated
before their reductive cyclization. Reduction of nitriles 5aa and 5ca
with LAH/AlCl3 in diethylether gave only poor yields, but yields of
more than 60% were obtained by sequential treatment with DIBAL-
H and NaBH4.17 The resulting amines, 7aa and 7ca, were then
subjected to reductive cyclization using Zn in 6 M HCl, which
afforded the desired pyrido[2,3-d]azepine 11aa and pyrido[3,4-
d]azepine 11ca in yields of over 50% after chromatographic purifi-
cation (32% and 33%, respectively, from 5). A three-step approach in
which the vinyl ethers 5aa and 5ca were converted into the cor-
responding dimethyl acetals 9, which were then reduced to amines
10 before reductive cyclization of the latter, failed to improve on the
two-step procedure, affording pyridoazepines 11aa and 11ca in 33%
and 27% overall yields, respectively.
The originally envisaged route to 9-phenylpyrido[3,4-d]azepine
(11ba) having being blocked by the failure of the attempted prep-
aration of key intermediate 5ba from 3b, we decided to try coupling
of 4a to the pyridine ring of 2b before homologation of its aldehyde
OMe
OMe
CN
Z
Cl2SO
N
Z
OMe
CN
(for 5ca)
OH
MeOH
Zn, CoCl2, HCl
X
X
CN
Ph
Ph
80%
Ph
9aa, 98%
5aa, X = N, Z = CH
8
9ca, 59%
5ca, X = CH, Z = N
1. DiBAL-H, CH2Cl2
NaBH4, CoCl2
MeOH
Zn, CoCl2, HCl
39%
2. NaBH4, MeOH,
(for 5aa)
THF
OMe
OMe
Z
Z
Z
X
Zn, HCl
Zn, HCl
OMe
NH2
NH
11aa, 47%
11ca, 77%
11aa, 51%
11ca, 52%
X
NH2
X
Ph
Ph
Ph
11aa
10aa, 71%
10ca, 60%
7aa, 63%
7ca, 63%
11ca
Scheme 3. Synthesis of 1-phenyl-3-pyridoazepines 11aa and 11ca.

M.C. de la Fuente, D. Dom´ınguez / Tetrahedron 65 (2009) 3653–3658
3655
CH(OEt)2
CHO
Br
CH(OEt)2
Br
CH(OEt)2
CN
PhCH2CN
Pd(Ph3P)4
KO Bu, DME
EtOH
TfOH
1. DIBAL-H
2. NaBH4
N
N
N
N
NH2
Ph
14, 53%
t
Ph
13, 48%
2b
12, 89%
CHO
NH
N
N
NHCbz
CbzCl
Et3N
CH(OEt)2
NHCbz
Ph
16, 0%
Ph
11ba
TFA/H2O
N
CH2Cl2
Ph
HO
H
H
OH
NCbz
15, 40%
1
NCbz
+
N
4
N
Ph
H
Ph
H
17a, 50%
17b, 32%
CHO
CH(OEt)2
N
Phthalic
O
O
TFA/H2O
+
anhydride
N
N
N
14
N
N
o-xylene
Ph
Ph
O
Ph
O
18, 21%
19, 30%
Scheme 4. The abandoned route to pyridoazepine 11ba.
group. Accordingly, the aldehyde 2b was protected as diethylacetal
12 by treatment with ethanol in the presence of triflic acid,18 and
the arylated nitrile 13 was obtained in 48% unoptimized yield by
palladium-catalyzed couplingof 12 to phenylacetonitrile (Scheme 4).
The rest of the synthesis of pyridoazepine 11ba called for nitrile
reduction, followed by protection of the amino group prior to hy-
drolysis of the acetal and one-carbon homologation. Sequential
reduction of nitrile 13 provided amine 14, which was subsequently
protected with benzylchloroformate as carbamate 15, but attemp-
ted cleavage of the acetal to the required aldehyde 16 led instead to
tetrahydro-2,6-naphthyridine 17, which was obtained in 82% yield
as a separable mixture of the cis and trans stereoisomers 17a (50%)
and 17b (32%).19 No interconversion between 17a and 17b was
observed in CDCl3 solution after 4 days. When isomer 17a was
treated with (methoxymethylene)(triphenyl)phosphorane in THF
in the presence of KOtBu or n-BuLi as base, a 7:3 mixture of 17a and
17b was obtained but no reaction with the small amount of free
aldehyde 16 mediating this isomerization was observed. When
a 3:2 mixture of the two stereoisomers was treated in the same
way, only an approximately 1:1 mixture of 17a and 17b was
obtained after 18 h. To avoid the formation of these undesired cyclic
hemiaminals, we tried a different amine protector, refluxing 14
with phthalic anhydride in o-xylene to obtain a 30% yield of
phthalimide 19 together with 4-phenyl-2,6-naphthyridine (18,
produced in 21% yield by hydrolysis of the acetal followed by
condensation with the unprotected amino group and aromatiza-
tion). Unfortunately, attempts to hydrolyze the acetal group of 19
afforded only complex mixtures of products, and we made no
further attempt to synthesize 11ba.
2.2. Synthesis of 1-pyridyl-3-pyridoazepines
The protocols developed for 11aa and 11ca syntheses were ex-
tended to 1-pyridyl-3-pyridoazepines by coupling bromopyridines
3a and 3c to commercially available pyridylacetonitriles 4b–4d and
subjecting the resulting nitriles to reductive cyclization (Scheme 5).
Treatment of 2-bromo-3-[(E,Z)-2-methoxyvinyl]pyridine (3a)
with 2-pyridylacetonitrile (4b) and NaH in THF at 80 ꢀC provided
nitrile 5ab in 46% yield as mixture of E and Z isomers (Table 1, entry
1). Likewise, treatment with 3-pyridylacetonitrile (4c) and KOtBu in
toluene gave a 72% yield of 5ac, and in this case the mixture was
separated chromatographically (Entry 2). Nitriles 5ad, 5cc and 5cd
were prepared similarly in yields ranging from 44% to 71% (Table 1,
entries 3–5).20
OMe
Z1
X1 Br
OMe
OMe
3a, X1 = N, Z1 = CH
3c, X1 = CH, Z1 = N
Z1
Z1
Z1
Base
NH
solvent
[H]
CN
X1
X1
X1
+
NH2
(Table 1)
(Table 2)
X2
X2
Y2
CN
X2
Y2
X2
Y2
Y2
Z2
Z2
11
Z2
Z2
20
5
4b, X2 = N, Y2 = CH, Z2 = CH
4c, X2 = CH, Y2 = N, Z2 = CH
4d, X2 = CH, Y2 = CH, Z2 = N
Scheme 5. Synthesis of 1-pyridyl-3-pyridoazepines 11.

3656
M.C. de la Fuente, D. Dom´ınguez / Tetrahedron 65 (2009) 3653–3658
Table 1
treated with potassium tert-butoxide (2.03 g, 17.18 mmol). After
Preparation of diarylacetonitriles 5
stirring for 30 min a solution of aldehyde 2a (2 g, 10.75 mmol) in
THF (11 mL) was added. The mixture was further stirred at rt for
2 h, quenched with cold water, and extracted twice with ethyl ac-
etate. The organic layers were combined, washed with water,
evaporated under reduced pressure, and purified by flash chro-
matography (SiO2, 1:9 EtOAc/hexane) to give colorless oil 3a
(2.04 g, 87%) as a (1:1) mixture of (E) and (Z) isomers. IR (neat)
Entry Bromopyridinea Nitrile Conditions
5a (% yield)
5ab (46%)
E:Z ratiob
1
2
3a
3a
4b
4c
NaH, THF, 80 ꢀC, 22 h
1:1.8
KOtBu, toluene, 80 ꢀC, 21 h (E)-5ac (27%), 1:1.7
(Z)-5ac (45%)
3
4
5
3a
3c
3c
4d
4c
4d
NaH, dioxane, 120 ꢀC, 22 h 5ad (44%)
KOtBu, toluene, 80 ꢀC, 20 h 5cc (71%)
NaH, dioxane, 120 ꢀC, 20 h 5cd (51%)
1:1.8
1:1
1:1.8
1644, 1635, 1571, 1549, 1457, 1477 cmꢁ1. 1H NMR
d
8.29 (dd, J¼7.8,
a
As mixtures of E and Z isomers, except for 5ac, which was chromatographically
separated.
1.9 Hz, 1H), 8.10 (dd, J¼4.6, 1.9 Hz, 1H), 8.07 (dd, J¼4.6, 1.9 Hz, 1H),
7.56 (dd, J¼7.8, 1.9 Hz, 1H), 7.16 (dd, J¼7.8, 4.6 Hz, 1H), 7.13 (dd,
J¼7.8, 4.6 Hz,1H), 6.97 (d, J¼12.9 Hz,1H), 6.31 (d, J¼7.2 Hz,1H), 5.95
(d, J¼12.9 Hz, 1H), 5.51 (d, J¼7.2 Hz, 1H), 3.78 (s, 3H, OMe), 3.72 (s,
b
Determined by 1H NMR.
Table 2
3H, OMe). 13C NMR/DEPT
d 151.4 (CH), 150.8 (CH), 146.1 (CH), 145.9
Reduction and cyclization of diarylacetonitriles 5
(CH), 141.8 (C), 141.5 (C), 137.5 (CH), 133.4 (C), 132.6 (CH), 132.5 (C),
122.4 (CH), 122.2 (CH), 101.9 (CH), 101.6 (CH), 60.9 (OMe), 56.4
(OMe). MS (CI) (m/z): 244 [(Mþ2)þC2Hþ5 , 4], 242 (MþC2H5þ, 5), 216
[(Mþ2)þHþ, 33], 214 (MþHþ, 35). HRMS (ESI) calcd for C8H9BrNO
[(MþH)þ] 213.9868, found 213.9850.
Entry
Starting
nitrilea
Conditions
Product
(% yield)
1
2
3
4
5
6
7
8
9
10
5ab
5ab
5ab
(Z)-5ac
5ad
5ad
5ad
5cc
Zn (51–127 equiv), CoCl2 (7–16 equiv), 6 M HCl
LAH (10 equiv), AlCl3 (10 equiv)
(1) DIBAL-H (7 equiv); (2) NaBH4 (42 equiv)
Zn (42 equiv), CoCl2 (10 equiv), 6 M HCl
Zn (104 equiv), CoCl2 (26 equiv), 6 M HCl
LAH (6 equiv), AlCl3 (6 equiv)
(1) DIBAL-H (7 equiv); (2) NaBH4 (42 equiv)
Zn (64 equiv), CoCl2 (8 equiv), 6 M HCl
Zn (70 equiv), CoCl2 (24 equiv), 6 M HCl
LAH (10 equiv), AlCl3 (10 equiv)
d
d
d
11ac (45%)
11ad (25%)
20ad (70%)
20ad (79%)
11cc (41%)
d
3.3. General procedure for arylation of arylacetonitriles 4
3.3.1. Method A. {3-[(E,Z)-2-Methoxyvinyl]pyridin-2-
yl}(phenyl)acetonitrile (5aa)
To a mixture of 2-bromo-3-[(E,Z)-2-methoxyvinyl]pyridine (3a)
(479 mg, 2.24 mmol) and potassium tert-butoxide (1.058 g,
8.95 mmol) in toluene (16 mL) was added phenylacetonitrile
(540 m
L, 4.45 mmol). The mixture was heated at 80 ꢀC for 4 h. A
saturated NH4Cl aq solution was added (15 mL) and the mixture
was extracted with CH2Cl2, washed with brine, dried with Na2SO4,
filtered, and the solvent evaporated. Purification by flash chroma-
tography (SiO2, 1:9 EtOAc/hexane) afforded oil 5aa (241 mg, 43%) as
a (1:1.4) mixture of (E) and (Z) isomers. IR (NaCl) 2245 (CN), 2185
5cd
5cd
20cd (16%)
a
As mixtures of E and Z isomers, unless otherwise indicated.
The direct reductive cyclization of (Z)-5ac, 5ad, and 5cc (Zn,
CoCl2, 6 M HCl) afforded the corresponding azepines in modest
isolated yields (Table 2, entries 4, 5, and 8). However, Zn/CoCl2
treatment of nitriles 5ab and 5cd led to decomposition (entries 1
and 9), as did reduction of 5ab with LAH/AlCl3 or DIBAL-H/NaBH4
(entries 2 and 3); while treatment of 5ad and 5cd with LAH/AlCl3 or
DIBAL-H/NaBH4 afforded enamines (20ad and 20cd) that under
subsequent acid treatment yielded only intractable mixtures
(entries 6, 7, and 10).
In conclusion, we have synthesized previously unreported 1-aryl-
3-pyridoazepines from bromopyridines by reductive cyclization of
(2-methoxyvinyl)pyridinyl(aryl)acetonitriles, which were easily de-
rived from contiguously substituted bromo(2-methoxyvinyl)pyr-
idines and the corresponding arylacetonitriles. The developed
synthetic procedure allows a rapid entry to some pyrido[2,3-d]aze-
pines and pyrido[3,4-d]azepines with phenyl and pyridinyl sub-
stituents at the azepine ring, although in the pyridinyl substituted
series the final cyclization could not be achieved for all the targeted
compounds.
(CN), 1644, 1563, 1494, 1453 cmꢁ1. 1H NMR
d
8.49 (dd, J¼4.8, 1.6 Hz,
0.4H), 8.46 (dd, J¼4.7, 1.7 Hz, 0.6H), 8.14 (dd, J¼7.9, 1.7 Hz, 0.6H),
7.58 (dd, J¼7.9, 1.7 Hz, 0.4H), 7.42–7.28 (m, 5H), 7.27–7.18 (m, 1H),
6.81 (d, J¼12.7 Hz, 0.4H), 6.25 (d, J¼7.1 Hz, 0.6H), 5.73 (d, J¼12.7 Hz,
0.4H), 5.57 (s, 0.6H), 5.56 (s, 0.4H), 5.19 (d, J¼7.1 Hz, 0.6H), 3.74 (s,
1.8H), 3.52 (s, 1.2H). 13C NMR/DEPT
d 151.9 (CH), 151.2 (C), 150.7 (C),
150.6 (CH), 147.2 (CH), 146.9 (CH), 137.8 (CH), 134.6 (C), 134.3 (CH),
130.6 (C), 129.4 (C), 129.0 (CH), 128.9 (CH), 128.2 (CH), 128.0 (CH),
127.6 (CH), 123.5 (CH), 123.0 (CH), 119.1 (CN), 118.8 (CN), 99.2 (CH),
98.9 (CH), 60.8 (OMe), 56.6 (OMe), 43.2 (CH), 42.8 (CH). MS (CI) (m/z):
279 (MþC2Hþ5 ,11), 251 (MþHþ,100), 235 (8), 224 (11), 219 (7). HRMS
(CI) calcd for C16H15N2O [(MþH)þ] 251.1178, found 251.1187.
3.3.2. Method B. {3-[(E,Z)-2-Methoxyvinyl]pyridin-2-yl}
(pyridin-2-yl)acetonitrile (5ab)
3. Experimental
A solution of 2-bromo-3-[(E,Z)-2-methoxyvinyl]pyridine (3a)
(415 mg, 1.94 mmol) in THF (8 mL) was treated with NaH (388 mg,
3.1. General procedures
9.7 mmol) followed by 2-(pyridin-2-yl)acetonitrile (4b) (428 mL,
1H and 13C NMR spectra were recorded in CDCl3 at 250.13 and
62.89 MHz, respectively, using TMS as internal reference. All air-
sensitive reactions were run under dried deoxygenated argon, in
oven-dried glassware, with magnetic stirring; reagents were added
by syringe through septa. All solvents for air or moisture-sensitive
reactions were dried by standard procedures. All new compounds
were chromatographically pure and both identity and homogeneity
were provided by HRMS and by 1H and 13C NMR spectroscopy. All
chemicals were purchased from Aldrich.
3.97 mmol). The mixture was heated at 80 ꢀC for 22 h. NH4Cl aq so-
lutionwas added(10 mL) andthemixturewas extracted with CH2Cl2,
washed with brine, dried, filtered, and the solvent evaporated. The
residue was purified by flash chromatography (SiO2, 98:2 CH2Cl2/
MeOH) to afford oil 5ab(224 mg, 46%) as(1:1.8) mixture of(E) and(Z)
isomers. IR (neat) 2185, 2165 (CN), 1638, 1589 cmꢁ1. 1H NMR
d 8.56–
8.54 (m, 1H), 8.47–8.42 (m, 1H), 8.17 (dd, J¼8.0, 1.5 Hz, 0.65H), 7.77–
7.53 (m, 1.35H), 7.52–7.46 (m, 1H), 7.28–7.17 (m, 2H), 6.87 (d,
J¼12.7 Hz, 0.35H), 6.28 (d, J¼7.1 Hz, 0.65H), 6.03 (d, J¼12.7 Hz,
0.35H), 5.75 (s,1H), 5.45 (d, J¼7.1 Hz, 0.65H), 3.75 (s,1.95H, OMe) 3.69
3.2. Typical procedure for vinylation of bromopyridines 2
(s, 1.05H, OMe). 13C NMR/DEPT
d 154.7 (C), 154.5 (C), 152.0 (C), 150.7
(CH), 150.0 (C), 149.4 (CH), 147.2 (CH), 146.8 (CH), 137.7 (CH), 137.3
(CH), 133.9 (CH), 131.2 (C), 129.9 (C), 123.6 (CH), 123.1 (CH), 123.0 (C),
122.9 (CH),122.5 (CH),120.1 (CH),118.5 (C),113.2 (CH), 99.3 (CH), 99.0
(CH), 60.8 (OMe), 56.5 (OMe), 46.0 (CH), 45.8 (CH). MS (CI) (m/z): 252
3.2.1. 2-Bromo-3-[(E,Z)-2-methoxyvinyl]pyridine (3a)
A suspension of (methoxymethyl)triphenylphosphonium chlo-
ride (4.95 g, 14 mmol) in dry THF (20 mL) under Ar at 0 ꢀC was

M.C. de la Fuente, D. Dom´ınguez / Tetrahedron 65 (2009) 3653–3658
3657
(MþHþ, 23), 241 (91), 225 (83), 221 (100), 183 (67). HRMS (CI) calcd
for C15H14N3O [(MþH)þ] 252.1137, found 252.1136.
1H). 13C NMR/DEPT
d
153.9 (C), 148.0 (CH), 139.4 (CH), 134.8 (C),
130.2 (C), 128.9 (2ꢂCH), 128.1 (CH), 127.8 (2ꢂCH), 123.1 (CH), 119.3
(C), 104.9 (CH), 55.0 (OMe), 53.6 (OMe), 42.1 (CH), 36.0 (CH2). MS
(CI) (m/z) 311 (MþC2Hþ5 , 22), 283 (MþHþ, 88), 251 (100), 224 (45),
219 (14), 75 (35). HRMS (ESI) Calcd for C17H19N2O2 [(MþH)þ]
283.1440, found 283.1440.
3.4. General procedure for the two-step reductive cyclization
3.4.1. (2-{3-[(E,Z)-2-methoxyvinyl]pyridin-2-yl}-2-
phenylethyl)amine (7aa)
A solution of diisobutylaluminium hydride in hexane (1.7 M,
3.5.2. {2-[3-(2,2-Dimethoxyethyl)pyridin-2-yl]-2-
122
mL, 0.21 mmol) was added to a solution of 5aa (25 mg,
phenylethyl}amine (10aa)
0.1 mmol) in CH2Cl2 (2 mL) at 0 ꢀC and stirred for 30 min. Then the
mixture was added to a suspension of sodium borohydride
(157 mg, 4.1 mmol) in THF (1 mL) and methanol (2 mL) at 0 ꢀC and
stirred at rt for 30 min. Saturated aqueous ammonium chloride
(10 mL) was added and stirring continued for 30 min, aqueous 10%
NaOH (10 mL) was added, and the mixture was extracted with
CH2Cl2. The combined organic layers were washed with water and
brine, dried, concentrated in vacuo, and purified by flash chroma-
tography (SiO2, 9:1 CH2Cl2/MeOH) to afford oil 7aa (16 mg, 63%) as
a (1:2.5) mixture of (E) and (Z) isomers. IR (NaCl) 3359 (NH2), 1642,
To a solution of 9aa (200 mg, 0.71 mmol) and CoCl2 (95 mg,
0.71 mmol) in 2.5 mL of methanol at 0 ꢀC, NaBH4 (67 mg,1.77 mmol)
was added in small portions (caution: vigorous reaction with hy-
drogen evolution). The immediate formation of a black precipitate
was observed, and the mixture was stirred for an additional 1 h. 10%
aqueous HCl was added until pH 3–4 and, after stirring for 2 min, the
pH was adjusted to 10 with 4 M NaOH, andthemixturewas extracted
with Cl3CH. The combined organic layers were dried, filtered, and
concentrated to give a residue, which was purified by flash chro-
matography (SiO2, 95:5 CH2Cl2/MeOH) to afford 10aa (144 mg, 71%)
1562, 1492, 1396 cmꢁ1. 1H NMR
d
8.47 (dd, J¼4.8, 1.7 Hz, 0.3H), 8.43
as an oil. IR (neat) 3366, 3303, 1673, 1572, 1492 cmꢁ1. 1H NMR
d 8.38
(dd, J¼4.7, 1.7 Hz, 0.7H), 8.14 (dd, J¼7.9, 1.7 Hz, 0.7H), 7.50 (dd, J¼7.7,
1.7 Hz, 0.3H), 7.37–7.07 (m, 6H), 6.72 (d, J¼12.8 Hz, 0.3H), 6.14 (d,
J¼7.1 Hz, 0.7H), 5.78 (d, J¼12.8 Hz, 0.3H), 5.24 (d, J¼7.1 Hz, 0.7H),
4.37–4.29 (m, 1H), 3.68 (s, 2.1H, OMe), 3.66–3.53 (m, 1H), 3.59 (s,
(dd, J¼4.7, 1.5 Hz, 1H), 7.34 (dd, J¼7.7, 1.6 Hz, 1H), 7.12–6.94 (m, 6H),
4.23 (dd, J¼8.3, 5.6 Hz,1H), 3.92 (dd, J¼6.4, 4.6 Hz,1H), 3.47–3.39 (m,
1H), 3.10–3.01 (m, 1H), 3.03 (s, 6H, 2ꢂOMe), 2.75 (dd, J¼14.4, 6.4 Hz,
1H), 2.57 (dd, J¼14.4, 4.6 Hz, 1H), 1.77 (br s, 2H, NH2). 13C NMR/DEPT
0.9H, OMe), 3.27–3.20 (m,1H), 2.21 (br s, 2H). 13C NMR/DEPT
d
157.3
d
159.4 (C), 146.7 (CH), 141.8 (C), 138.5 (CH), 131.4 (C), 128.2 (2ꢂCH),
(C), 150.5 (CH), 149.4 (CH), 146.3 (CH), 145.9 (CH), 142.0 (C), 141.8
(C), 136.9 (CH), 133.1 (C), 131.7 (CH), 130.6 (C), 128.5 (CH), 128.4
(CH), 128.3 (CH), 126.5 (CH), 126.4 (CH), 121.6 (CH), 121.5 (C), 121.2
(CH), 100.7 (CH),100.2 (CH), 60.6 (OMe), 56.3 (OMe), 52.9 (CH), 52.5
(CH), 47.3 (CH2), 47.2 (CH2). MS (CI) (m/z): 255 (MþHþ, 100), 238
(43), 226 (82), 209 (26), 194 (34), 180 (8). HRMS (CI) calcd for
C16H19N2O [(MþH)þ] 255.1497, found 255.1497.
128.1 (2ꢂCH), 126.2 (CH), 121.1 (CH), 104.2 (CH), 53.9 (OMe), 53.2
(OMe), 52.3 (CH), 47.3 (CH2), 35.3 (CH2). MS (CI) (m/z): 315 (MþC2Hþ5 ,
13), 287 (MþHþ, 100), 255 (70), 240 (31), 223 (12). HRMS (ESI) calcd
for C17H23N2O2 [(MþH)þ] 287.1750, found 287.1740.
3.5.3. 9-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (11aa)
Zn dust (165 mg, 2.5 mmol) was added to a solution of 10aa
(40 mg, 0.14 mmol) in 2 M HCl (1 mL) and the mixture was heated
at 90 ꢀC for 2 h. After addition of 2 M NaOH until pH 9–11, the
mixture was extracted with Cl3CH, the organic layer was dried,
concentrated in vacuo, and purified by flash chromatography (SiO2,
9:1 CH2Cl2/MeOH) to afford 11aa (15 mg, 47%) as an oil.
3.4.2. 9-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (11aa)
Zn dust (200 mg, 3.06 mmol) was added to a solution of 7aa
(20 mg, 0.079 mmol) in 2 M HCl (0.7 mL) and the mixture was
heated at 90 ꢀC. After 30 min, additional quantities of 2 M HCl
(0.7 mL) and Zn (200 mg, 3.06 mmol) were added and heating was
continued for 30 min. After addition of 2 M NaOH until pH 9–11,
the mixture was extracted with Cl3CH, the organic layer was dried,
concentrated in vacuo, and purified by flash chromatography
(SiO2, 9:1 CH2Cl2/MeOH) to afford 11aa (9 mg, 51%) as an oil. IR
3.6. General procedure for the one-pot reductive cyclization
3.6.1. 9-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (11aa)
Zn dust (200 mg, 3.06 mmol) and CoCl2 (50 mg, 0.39 mmol)
were added to a solution of 5aa (20 mg, 0.08 mmol) in 6 M HCl
(0.7 mL) and the mixture was heated at 90 ꢀC. After 20 min, addi-
tional quantities of 6 M HCl (0.7 mL), Zn dust (200 mg, 3.06 mmol),
and CoCl2 (50 mg, 0.39 mmol) were added and heating was con-
tinued for 20 min. After addition of 2 M NaOH until pH 9–11, the
mixture was extracted with Cl3CH, the organic layer was dried,
concentrated in vacuo, and purified by flash chromatography (SiO2,
9:1 CH2Cl2/MeOH) to afford 11aa (7 mg, 39%) as an oil.
(NaCl) 3230,1600, 1583, 1571,1494 cmꢁ1. 1H NMR
d
8.40 (dd, J¼4.9,
1.7 Hz, 1H), 7.44 (dd, J¼7.5, 1.7 Hz, 1H), 7.40–7.18 (m, 3H), 7.14–7.05
(m, 3H), 4.55 (dd, J¼5.8, 2.2 Hz, 1H), 3.75 (dd, J¼14.4, 5.8 Hz, 1H),
3.32 (dd, J¼14.4, 2.2 Hz, 1H), 3.19–3.09 (m, 1H), 2.95–2.79 (m, 2H),
2.70–2.59 (m, 1H), 2.07 (br s, 1H). 13C NMR/DEPT
d 162.4 (C), 146.5
(CH), 140.0 (C), 137.8 (CH), 136.9 (C), 128.4 (2ꢂCH), 127.6 (2ꢂCH),
125.9 (CH), 121.4 (CH), 56.5 (CH), 50.5 (CH2), 47.6 (CH2), 38.0 (CH2).
MS (EI) (m/z): 224 (Mþ, 21), 196 (100), 180 (55), 167 (19), 152 (13),
133 (20). HRMS (EI) calcd for C15H16N2 224.1313, found 224.1307.
Acknowledgements
3.5. General procedure for the three-step reductive
cyclization
Support of this work by the Spanish Ministry of Education and
Science in collaboration with the European Regional Development
Fund (through Project CTQ2005-02338), by the Spanish Ministry of
Science and Innovation (through Project CTQ2008-03253), by the
Xunta de Galicia (through Projects PGIDITO6PXIC209067PN and
2007/XA084), and by Johnson & Johnson Pharmaceutical Research
and Development is gratefully acknowledged. M. C. de la Fuente
also thanks Xunta de Galicia for a Parga Pondal contract.
3.5.1. [3-(2,2-Dimethoxyethyl)pyridin-2-yl](phenyl)
acetonitrile (9aa)
To a stirred solution of 5aa (212 mg, 0.848 mmol) in methanol
(2 mL) at rt, Cl2SO (187 mL, 2.5 mmol) was added. After stirring for
10 h, 2 M NaOH aqueous solution was added until pH 9–11 and the
mixture was extracted with CH2Cl2, dried, filtered, and the solvent
evaporated to afford 9aa (234 mg, 98%) as an oil. IR (NaCl) 2250
(CN), 1659, 1632, 1350 cmꢁ1. 1H NMR
d
8.55 (dd, J¼4.7, 1.7 Hz, 1H),
Supplementary data
7.54 (dd, J¼7.8, 1.7 Hz, 1H), 7.38–7.25 (m, 5H), 7.21 (dd, J¼7.8, 4.8 Hz,
1H), 5.79 (s, 1H), 4.26 (dd, J¼6.5, 4.4 Hz, 1H), 3.30 (s, 3H, OMe), 3.29
(s, 3H, OMe), 2.94 (dd, J¼14.3, 6.5 Hz, 1H), 2.78 (dd, J¼14.3, 4.4 Hz,
Experimental procedures and characterization data for all
reported compounds, and copies of the 1H NMR and 13C NMR/DEPT

3658
M.C. de la Fuente, D. Dom´ınguez / Tetrahedron 65 (2009) 3653–3658
11. (a) Loupy, A.; Philippon, N.; Pigeon, P.; Galons, H. Heterocycles 1991, 32, 1947–
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spectra for all new compounds are provided. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2009.02.075.
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19. Relative configurations were assigned on the basis of NOE experiments on the
major isomer 17a, which upon irradiation of H-3
b (3.72 ppm) showed en-
hancements of 1% in the H-1 signal (6.45 ppm) and 8% in that of H-4
b
b
(4.22 ppm), thus establishing the relative configuration of H-1 and H-4 as cis.
20. The missing combination (reaction of 3c with 4b) was not attempted.
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