Facile synthesis of 7-10 membered rings by intramolecular condensation using dialkylcarbonate as solvent

Article abstract of DOI:10.1016/j.tetlet.2004.10.120

A convenient large-scalable synthesis of 1-benzazepines 19 as an important intermediate of CCR5 antagonist, oral HIV-1 therapy, was established. The anilination of o-halogenobenzaldehyde 9 with alkylamino-acid 16 gave o-formylaniline-acid 17. Compound 17

Full text of DOI:10.1016/j.tetlet.2004.10.120

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9335–9339
Facile synthesis of 7–10 membered rings by
intramolecular condensation using dialkylcarbonate as solvent
Tomomi Ikemoto,* Tatsuya Ito, Atsuko Nishiguchi and Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Pharmaceutical Company Limited, Jusohonmachi,
Yodogawa-ku, Osaka 532-8686, Japan
Received 5 October 2004;revised 21 October 2004;accepted 22 October 2004
Available online 6 November 2004
Abstract—A convenient large-scalable synthesis of 1-benzazepines 19 as an important intermediate of CCR5 antagonist, oral HIV-1
therapy, was established. The anilination of o-halogenobenzaldehyde 9 with alkylamino-acid 16 gave o-formylaniline-acid 17. Com-
pound 17 was esterified followed by the improved reaction using the combination of alcoholate and dialkyl carbonate in one-pot, to
easily produce 19. Namely, these new processes afforded the desired product 19 in only two steps from the starting materials, as
compared with the previous 10 steps. Moreover, these convenient methodologies were applied to other heterocycles to give 8–10
membered rings, such as 1-benzazocine, 1-benzazonine, and 1-benzazecine.
Ó 2004 Elsevier Ltd. All rights reserved.
In nature, there is a large amount of compounds con-
taining the nitrogen atom, which shows the various bio-
logical activities. These compounds and modified
products have popularly been utilized as a pharmacore
for therapeutic drugs.1 Therefore, it is very important
to develop convenient synthesis of heterocyclic products
for the timely supply of bulk for the patients. On the
other hand, 1-alkyl-2,3-dihydro-1-benzazepines 1 have
recently been found to be potent oral HIV-1 candidates,
as CCR5 antagonists,2–4 and these products were syn-
thesized by the condensation of carboxylic acid 2 and
aniline 3 (Scheme 1).2 In medicinal synthesis,2 b-oxo-
ester 5 was converted to 6 followed by alkylation,
arylation, or acylation, which was led to the important
intermediate product 2 (Scheme 2). However, this
approach involved several limitations from the stand-
point of large-scale preparation, for example, multi-
steps (12 steps) and repeated tedious chromatographic
methods. Hence, an efficient preparation of 1 on a large
scale was required to support toxicological evaluation.
For the preparation of 2,3-dihydro-1-benzazepines,
most reported syntheses have had the same strategy, in
that the Dieckmann type reaction was the key reaction.
There have been few reports based on other generation
R
N
Ts
N
CO2Me
CO2Et
R1
N
R1
N
Br
Br
CHO
CO2Me
4
7
previous method
CO2H
2
3
H
N
trial work
Ts
N
R2
R
H2N
R2
R3
O
N
Br
CO2Et
1
R3
O
5
Br
CO2Me
6 steps
8
Scheme 1.
H
N
Keywords: Dialkylcarbonate;Intramolecular Claisen type reaction;
7–10 Membered ring;CCR5 antagonist.
Br
CO2Me
6
2
*
Corresponding author. Tel.: +81 6 6300 6378;fax: +81 6 6300
6281;e-mail: ikemoto_tomomi@takeda.co.jp
Scheme 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.120

9336
T. Ikemoto et al. / Tetrahedron Letters 45(2004) 9335–9339
Table 1. Intramolecular condensation of 12 under various conditionsa
Me
N
12
Br
CO2R
13a; R= Et
13b; R= Me
14; R= H
Entry
12
Base
Solvent
Conditions
Yield (%)d
1
2
3
4
12b
12a
12a
12a
NaOMeb
NaOEtc
NaOEt
KOBut
(MeO)2CO
(EtO)2CO
EtOH
rt, 5.5h
rt, 4h
13b;83
13a;90
rt, 1h, then reflux, 1h
rt, 1h
13a;38, 14;11
13a;38, 14;31
THF
a General procedure: A mixture of substrate and base (1.2equiv) in solvent was stirred.
b NaOMe (28%) in MeOH was used.
c NaOEt (20%) in EtOH was used.
d NaOEt (20%) in EtOH was used.
(Scheme 5).5 Our retro-synthetic analysis of 2 as the key
intermediate compound is depicted in Scheme 2. We
have previously reported the convenient synthesis of
HCl
H
Me
N
CO2H
N
CO2H
Me
F
10
Na2CO3, aq.DMSO
86%
Br
2,3-dihydro-1-benzothiepin-4-carboxylate using the
CHO
Br
CHO
improved intramolecular Claisen type reaction of 4-(o-
formylphenylthio)butyrate with alcoholate in dialkyl-
carbonate.6 Therefore, 8 was recognized to be accessed
by the treatment of 4-(o-formylphenylalkylamino)buty-
rate 7 under the reported conditions. In this paper, we
announce the convenient and efficient synthesis of 8,
which led to 1, and the synthesis of 8–10 membered rings
having the possibility as the templates of new biological
compounds.
9a
11
Me
N
MeI or EtBr,
K2CO3
CO2R
Br
CHO
12a; R=Me
12b; R=Et
12
Scheme 3.
First, 4-(N-aryl-N-methylamino)butyric ester 12 was
chosen as a model substrate and allowed to react with
base in solvent (Table 1). Compound 12 was synthesized
as shown in Scheme 3. Aryl halide 9a was refluxed with
4-methylaminobutyric acid hydrochrolide 10 and
Na2CO3 in aqueous DMSO to give acid 11 in 86% yield,
although the use of DMF instead of aqueous DMSO as
a solvent produced a large amount of 5-bromo-2-
dimethylaminobenzaldehyde. When NaOH was used
as a base, the main product was 5-bromo-salicylalde-
hyde. The treatment of 11 with MeI or EtBr led to ester
12. The traditional conditions,7 such as the treatment of
12a with NaOEt in EtOH solution in EtOH as a solvent,
provided a mixture of 1-benzazepine 13a in 38% yield
and hydrolyzed 14 in 11% yield (entry 3). Changing to
THF as the solvent did not protect the hydrolysis (entry
4). Our conditions,6 which we discovered in the synthesis
of 2,3-dihydro-1-benzothiepines, were applied to this
reaction. Namely, 12a was reacted with 1.2equiv of
NaOEt in EtOH solution in diethyl carbonate instead
of ether or alcohol as a solvent at room temperature
for 4h. Surprisingly, the reaction gave the desired 13a
in 90% yield, and did not detect 14 (entry 2), while the
cyclization using t-butyl ester of 12 and t-BuOK gave
77% yield.5 The use of dimethyl carbonate as a solvent
in the case of 12b also showed the preparation of 13b
in 83% yield. Moreover, the treatment of acid 11 was
carried out with MeI and K2CO3 in DMF followed by
cyclization with the combination of NaOMe in dimeth-
ylcarbonate in one-pot, to give 13b in 86% yield.
Next, we explored the scope and limitation of the new
protocol of 1-alkyl-2,3-dihydro-1-benzazepines. A vari-
ety of o-formylaniline-acids 17 as precursor were pre-
pared by two methods, and the results are summarized
9
in Table 2. One result was that N-alkylamide 15 was
hydrolyzed with aqueous NaOH, followed by the neu-
tralization and anilination of o-halogenobenzaldehyde
9 in one-pot (method A). The hydrolysis of 15 gave
85–90% yield, as determined by 1H NMR. The other re-
sult was that the reductive alkylation of 4-aminobutyric
acid with 2-methoxybenzaldehyde catalyzed Pd–C under
a hydrogen atmosphere led to alkylamino-acid 16, which
was anilinated with 9 in one-pot (only N-benzyl type,
method B). The substrates having the bulky groups on
the nitrogen atom gave lower yields than that having
the straight alkyl group (entry 1 vs entries 2 and 3).
The electron-withdrawing groups in 9 increased the
yields (entry 6 vs entry 7).
The intramolecular condensations of 17 using new con-
ditions were carried out (Table 3). In the Claisen type
reactions of 1-benzazepines, the functional groups on
the aromatic ring did not affect the yields of 19 (entry
6 vs entry 7). The yields were affected by the substituted
groups on the nitrogen atom, and the reactions using
substrates having the branched groups, such as isopro-
pyl and cyclohexyl groups, gave lower yields (entry 1
vs entries 2 and 3). The treatment of 17e having the
benzyl type group smoothly proceeded the cyclization
to give 19e in 93% yield. The yield of cyclization using

T. Ikemoto et al. / Tetrahedron Letters 45(2004) 9335–9339
Table 2. Coupling reaction of 9 with 16 led from 15 or 18 in one-pota
9337
NH2(CH2)3CO2H (18)
(method B)
2-MeOPhCHO,
Pd-C, H2
1) NaOH
2) c.HCl
3) Na2CO3,
X
R1NH(CH2)3CO2H
16
O
N
R1
(method A)
15
R2
CHO
one-pot reaction
9b; R2=H, X=F
R1
9c; R2=NO2, X=Cl
N
CO2H
R2
CHO
17
Entry
Substrates
Method
Product 17
Yield (%)c
16
9
1
2
3
4
5
6
7
16a; R1 = n-Bu
16b; R1 = i-Pr
9a
9a
9a
9a
9a
9b
9c
A
A
A
A
B
17a; R1 = n-Bu, R2 = Br
17b; R1 = i-Pr, R2 = Br
84
22
3
16c; R1 = cyclohexyl
16d; R1 = allyl
17c; R1 = cyclohexyl, R2 = Br
17d; R1 = allyl, R2 = Br
50
70
78
92
16e; R1 = 2-MeOC6H4CH2
16f; R1 = Meb
16fb
17e; R1 = 2-MeOC6H4CH2, R2 = Br
17f; R1 = Me, R2 = H
17g; R1 = Me, R2 = NO2
A
A
a See Ref. 8 for general procedures (methods A and B).
b Compound 10 was used as reagent.
c Isolated yield.
Table 3. Intramolecular condensation of 17–19 in one-pot
R1
N
1) MeI, K2CO3, DMF
2) 28%NaOMe in MeOH, (MeO)2CO
17
1) EtBr, K2CO3, DMF
2) 20%NaOEt in EtOH, (EtO)2CO
or
R2
CO2R3
19
one-pot
Entry
Substrate
Product 19
Yield (%)a
1
2
3
4
5
6
7
17a
17b
17c
17d
17e
17f
17g
19a; R1 = n-Bu, R2 = Br, R3 = Me
19b; R1 = i-Pr, R2 = Br, R3 = Et
81
74
44
73
93
74
72
19c; R1 = cyclohexyl, R2 = Br, R3 = Et
19d; R1 = allyl, R2 = Br, R3 = Me
19e; R1 = 2-MeOC6H4CH2, R2 = Br, R3 = Et
19f; R1 = Me, R2 = H, R3 = Et
19g; R1 = Me, R2 = NO2, R3 = Et
General procedure: To a suspension of 17 (1.0g) K2CO3 (1.1equiv) and DMF (3mL) was added alkyl halide (1.2equiv) and stirred for 2h at room
temperature. Subsequently, dialkylcarbonate (6mL) and sodium alcoholate (2.4equiv) were added, and stirred for 0.5h at 50°C in one-pot.
a Isolated yield.
the combination of alcoholate and dialkylcarbonate
increased considerably, as compared with the case of
2,3-dihydro-1-benzothiepine (best yield was 71%).
dimethylcarbonate as a reagent of condensation also
provided 1-benzazonine 23e or 1-benzazecine 23f,
although there has been no report of the synthesis of
these heterocyclic compounds to the best of our knowl-
edge. The structures of 1-benzazonine and 1-benzazecine
Furthermore, the new methodologies for 1-benzazepines
were applied to other heterocyclic compounds contain-
ing a nitrogen atom, 8–10 membered rings (Scheme 4
and Table 4). Acid 22 was synthesized by methods A
and B. The treatments of 22a–d using our conditions
gave 1-benzazocines. The treatment of 22c or 22d was
converted to 23c or 23d in 78% and 76% yields, respec-
tively. Surprisingly, the combination of NaOMe and
1
were determined by H and 13C NMR to be single iso-
mers, respectively, however, the accurate configurations
were not clearly confirmed. Recently, the preparations
of some nitrogen-containing cyclic compounds by ring-
closing metathesis (RCM), such as benzazepine and
benzazocine, have been reported.10 However, it is diffi-
cult that RCM applies to a large-scale preparation

9338
T. Ikemoto et al. / Tetrahedron Letters 45(2004) 9335–9339
NH2
In conclusion, we have developed a facile and efficient
CO2H
n
synthesis of 1-benzazepines by the improved Claisen
type reaction of 4-(N-alkylamino-N-aryl)butyric ester
using the combination of alcoholate and dialkyl carbon-
ate. These processes afforded the target products by only
two steps from the starting materials. Moreover, these
convenient methodologies were applied to other hetero-
cycles to give 8–10 membered rings.
24
PhCHO,
method B
H2, Pd-C
9, Na2CO3
R1
N
CO2H
method A
n
n
21
NMe
H
O
20
1) MeI, K2CO3, DMF
R1
N
R1
N
2) 28%NaOMe in MeOH,
(MeO)2CO
CO2H
n
References and notes
n
R2
CHO
R2
CO2Me
22
1. Gadamasetti, K. G. Process Chemistry in the Pharmaceu-
tical Industry;Marcel Dekker: New York, 1999.
23
Scheme 4.
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Entry
Substrates
Acid 22, yield (%)b
8–10 Membered ring 23, yield (%)b
Me
N
Me
N
30%
CO2Me
CO2H
1a
37%
,
9b
O
N
CHO
Me
22a
23a
20a
Me
N
Me
N
40%
CO2Me
2a
20a, 9a
20a, 9c
CO2H
58%
Br
CHO22b
Br
23b
Me
Me
N
N
78%
CO2Me
CO2H
3
93%
61%
O2N
O2N
CHO
22c
23c
Bn
Bn
N
N
CO2H
4a
H2N(CH2)4CO2H (24a), 9a
76%
CO2Me
Br
Br
Br
Br
CHO
22d
22e
23d
Me
N
Me
N
CO2H
, 9a
5a
N
80%
18%
O
Me
CHO
20b
CO2Me
CO2Me
23e
Bn
N
Bn
N
CO2H
6
H2N(CH2)6CO2H (24b), 9a
27%
6%
Br
Br
CHO
22f
23f
See Ref. 8 for general procedures (methods A and B).
a The ester of 22 was isolated.
b Isolated yield.

T. Ikemoto et al. / Tetrahedron Letters 45(2004) 9335–9339
9339
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CHO
24
R=Me; 77%,
R
N
R=Et; 70%,
R= n-Pr; 60%
Br
CO2t-Bu
25
Scheme 5.
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with 2-methoxybenzaldehyde or benzaldehyde (2equiv),
1N NaOH (2equiv), and a catalytic amount of Pd–C
overnight at room temperature under the hydrogen
atmosphere followed by the neutralization with concn
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Tetrahedron