Synthesis of a novel series of 4,4-disubstituted 2,3,4,7-tetrahydroazepines

Article abstract of DOI:10.1016/j.tetlet.2005.05.088

A general, simple and straightforward strategy for the synthesis of a novel series of 4,4-disubstituted 2,3,4,7-tetrahydroazepines is described. This route involves a one-pot Wittig olefination/N-allylation process on a five-membered hemi-aminal followed by a final ring closing metathesis reaction.

Full text of DOI:10.1016/j.tetlet.2005.05.088

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4847–4850
Synthesis of a novel series of 4,4-disubstituted
2,3,4,7-tetrahydroazepines
´ ´ ´
Mario Barberis, Pablo Garcıa-Losada, Sehila Pleite, Juan Ramon Rodrıguez,
*
´
Jose Francisco Soriano and Javier Mendiola
Lilly S.A., Avda de la Industria 30, Alcobendas-Madrid 28108, Spain
Received 13 April 2005; revised 12 May 2005; accepted 17 May 2005
Available online 4 June 2005
Abstract—A general, simple and straightforward strategy for the synthesis of a novel series of 4,4-disubstituted 2,3,4,7-tetra-
hydroazepines is described. This route involves a one-pot Wittig olefination/N-allylation process on a five-membered hemi-aminal
followed by a final ring closing metathesis reaction.
Ó 2005 Published by Elsevier Ltd.
Alkaloids represent a significant subset of all biologi-
cally active compounds,1 and so the development of
new general methods for their construction remains an
important goal in organic synthesis. Such is the case of
azepines, which in the past few years have been the sub-
ject of an increasing number of published synthetic
methods due to their biological activities. These N-con-
taining seven-membered rings have been readily ob-
tained in the past by condensation reactions or by
rearrangement of three-, five- and six-membered rings
following Beckmann and SchmidtÕs conditions.2 There
is ample precedent for the selective ring expansion of
mixtures of syn and anti oximes, under both harsh3
and weak4 acidic conditions. An alternative to these
routes is the very popular approach of ring closing
metathesis (RCM)5 that uses the ruthenium alkylidene
catalysts that have been developed by Grubbs and co-
workers.6 The application of this novel methodology
has continually increased over the last decade due to
the ease of synthesis by metathesis of carbo- or hetero-
cyclic seven-membered rings.7 Below, we present a novel
approach to this powerful tool in organic synthesis,
which widens its application to other acyclic di-olefins.
The work we describe here details our studies on the
synthesis of a novel series of 4,4-disubstituted 2,3,4,7-
tetrahydroazepines 1, involving, as key steps, a one-
pot Wittig reaction/N-allylation process followed by
final ring closing metathesis reaction (Fig. 1).
Alkylation reactions on analogous pyroglutamate
rings have been previously reported by our research
group.8 Applying this methodology we envisaged a sim-
ple and straightforward strategy starting from
R2
R2
R1
R2
R1
R1
O
N
N
N
Ts
Ts
Ts
1
Figure 1.
Keywords: Azepine; Metathesis; Pyrrolidinone; Wittig.
*
Corresponding author. Tel.: +34 91 623 36 65; fax: +34 91 663 34 11; e-mail: mendiola_javier@lilly.com
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.088

4848
M. Barberis et al. / Tetrahedron Letters 46 (2005) 4847–4850
N-tosylpyrrolidinone,9 which is easily obtained by reac-
tion of commercially available pyrrolidinone with tosyl
chloride. Substitution at C-3 was achieved in two differ-
ent ways depending on the nature of the R group. Thus,
to incorporate alkyl or benzyl groups a one-pot process
was carried out by reaction with LiHMDS as base and
R1–Br, and subsequent reaction with one additional
equivalent of base and R2–Br. When one of the alkyl
groups was a methyl, initial substitution with MeI was
more convenient as it could be easily controlled to pre-
vent disubstitution. Thus, treatment of N-tosylpyrrolid-
inone 2 with LiHMDS followed by slow addition of MeI
provided the monoalkylated pyrrolidinone 310 in 98%
yield (Scheme 1).
On the other hand, monoarylated pyrrolidinone 4 was
prepared albeit in low yield, employing Hartwig condi-
tions.11 Unfortunately, attempts to improve the re-
ported yield by changing the base, solvent, catalyst
and temperature failed. Treatment of 4 with LiHMDS
and R2–Br provided new tosylpyrrolidin-2-ones 5g,h
(Scheme 2).
Reduction of pyrrolidinones 5a–h to pyrrolidinols 6a–h
was conveniently carried out with Dibal-H, the best con-
ditions being those employing the reagent as a 1 M tol-
uene solution added to a THF solution of the lactam at
0 °C. When R1 and R2 were different, a mixture of diaste-
reomers was isolated, showing a complex 1H NMR
spectrum. No attempt was made to separate these iso-
mers, which were carried to the next step without further
purification.
R1
Olefination of pyrrolidinol12 6 was investigated next.
When 6a was reacted with methylene triphenylphospho-
rane, the Wittig product 7 was obtained in good yield.
Next, a one-pot process was attempted by combining
the olefination and following allylation reactions to re-
duce the total number of synthetic steps.13 Thus, once
olefination was complete as determined by LCMS, the
amino group was captured by treatment with 3 equiv
of allyl bromide. Compounds 8a–h were isolated in
41–73% yield, employing this one-pot methodology.
This is the first time that these two processes have been
combined in a single pot to afford a tertiary amine from
pyrrolidinol derivatives.
ii
i
O
N
40-80%
R1
R2
Ts
3-R1: Me,98%
O
N
O
N
Ts
Ts
2
5a-h
ii
60-70%
iii
16%
Finally, a metathesis reaction was applied as the ring
closure event. Reaction of 8a–h in refluxing dichloro-
methane in the presence of 10 mol % of 1,2-dimesityl-
pyrrolidin-2-yl-Ru@CHPh(Cl)2(PCy3) catalyst afforded
the corresponding 4,4-disubstituted 2,3,4,7-tetra-
hydroazepine14 1a–h in moderate to excellent yields.
This methodology allows the incorporation of a variety
of substituent types at the 4-position of the resulting
O
N
Ts
4
Scheme 1. Reagents and conditions: (i) LiHMDS, R1–Br, THF,
À78 °C; (ii) LiHMDS, R2–Br, THF, À78 °C; (iii) Ph–Br, Pd2dba3,
BINAP, LiHMDS, dioxane, 70 °C.
R2
R2
R1
R2
R1
R2
R1
R1
iii
i
iia, iib
O
OH
N
N
N
N
Ts
5a-h
Ts
Ts
Ts
8a-h
1a-h
6a-h
R1=Me, Bn
R1=R2=Bn
86%
R2=Me, Bn, Ph, allyl,
CH2CH=CHPh,
iia
Bn
CH2-p-Py
Bn
MesN
Cl
Ru
Cl
NMes
Ph
Ru*=
H
N
Ts
7
Cy3
Scheme 2. Reagents and conditions: (i) Dibal-H/toluene/1 M, THF, 0 °C; (ii) (a) Ph3PMeBr, t-BuOK, THF, 0 °C; (b) BrCH2CH@CH2, rt; (iii) 1,2-
dimesitylpyrrolidin-2-yl-Ru@CHPh(Cl)2(PCy3) (10 mol %), CH2Cl2, 50 °C.

M. Barberis et al. / Tetrahedron Letters 46 (2005) 4847–4850
4849
azepine derivative: methyl, benzyl, 4-pyridylmethyl,
cinnamyl, allyl and phenyl in combination with methyl
and benzyl groups. In all these cases, the metathesis
reaction worked in excellent yield (70–98%) except for
1f, which was isolated in only moderate yield (53%).
In this reaction, only the seven-membered ring metathe-
sis product was observed (no eight-membered ring was
detected) together with a secondary product formed by
reaction between the terminal olefin of 1f and the olefin
contained in the ruthenium Grubbs catalyst. This prod-
uct was isolated as 1e in 10% yield (Table 1).
The methodology here described constitutes a general,
versatile and straightforward route for the synthesis of
Table 1.
Entry
Pyrrolidinone
Reductiona (%)
92
Wittigb (%)
73
Metathesisc (%)
79
Azepine
Bn
Bn
Bn
Bn
1
O
N
Ts
N
Ts
1a
1b
5a
Bn
Me
Bn
Me
2
3
99
70
56
65
82
70
O
N
Ts
N
Ts
5b
Me
Me
Me
Me
O
N
Ts
N
Ts
1c
N
N
Me
Me
4
90
82
73
O
N
N
Ts
5d
Ts
1d
Ph
Ph
Me
Me
O
5
6
71
99
41
72
97
N
N
Ts
Ts
1e
5e
Me
Me
O
53d
N
N
Ts
Ts
5f
1f
Ph
Me
Me
Ph
7
8
90
75
65
67
98
73
O
N
Ts
5g
N
Ts
1g
Ph
Bn
Bn
Ph
O
N
Ts
5h
N
Ts
1h
a Dibal-H/toluene/1 M, THF, 0 °C.
b (i) Ph3PMeBr, t-BuOK, THF, 0 °C; (ii) BrCH2CH@CH2, rt.
c 1,2-Dimesitylpyrrolidin-2-yl-Ru@CHPh(Cl)2(PCy3) (10 mol %), CH2Cl2, 50 °C.
d 10% of 1e was isolated too.

4850
M. Barberis et al. / Tetrahedron Letters 46 (2005) 4847–4850
H. J. Am. Chem. Soc. 2002, 124, 14848; (c) Gurjar, M. K.;
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new 4,4-disubstituted azepines as novel heterocyclic
products. Substitution was achieved employing the
methodology described by our research group; the next
step involves a one-pot Wittig/N-allylation process fol-
lowed by ring closing metathesis reaction, affording a
concise and easy approach to the synthesis of 4,4-disub-
stituted azepine derivatives.
8. (a) Ezquerra, J.; Pedregal, C.; Rubio, A.; Escribano, A.;
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´
´
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We wish to thank Dr. Jesu´s Ezquerra, Dr. Ulf Tilstam,
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na Marıa Garcıa-Cerrada for her assistance, and we also
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Dr. Ivan Collado for helpful discussions.
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10% mol, 41 mg) was added to
a solution of 8c
(0.650 mmol, 200 mg) in CH2Cl2 (110 mL) and refluxed
for 10 h. The solvent was removed under reduced pressure
and purified by flash chromatography (silica gel column,
ethyl acetate–hexane 5:95). Compound 1c (127 mg, 70%
yield) was isolated as white solid. 1H NMR (300 MHz,
CDCl3) d 1.02 (s, 6H), 1.68 (t, J = 6.4 Hz, 2H), 2.40 (s,
3H), 3.32 (t, J = 6.1 Hz), 3.74 (d, J = 4.4 Hz), 5.51–5.39
(m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 7.7 Hz, 2H);
13C NMR (75 MHz, CDCl3) d 21.9, 29.6, 37.1, 38.7, 44.7,
45.4, 122.8, 127.6, 129.9, 135.8, 143.3, 143.5.
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