2
S. Dey et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
HO
O
OH
(a)
H3CO2C
H2O
NHTf
H3CO2C
NH3
Cl
N
H3CO
N
(b)
CH3
N
Tf
HO
HO
8
9
+
1
2
OH
10
(c)
HO
7
O
( )n
N
O
H
HO
Tf
3
(d)
N
N
Tf
N
Tf
+
Figure 1. Development of 3-benzazepin-1-ols
antagonists.
3 as GluN2B selective NMDA
13
12
11
Tf = SO2CF3
for the development of GluN2B selective NMDA antagonists. With
the aim of increasing the selectivity of 1 without losing GluN2B
affinity, the 3-benzazepine 2 with reduced conformational free-
dom was successfully developed as novel type of GluN2B antago-
nist.8,9 In order to analyze the contribution of the particular
structural elements of the 3-benzazepine 2 for receptor binding,
the synthesis and pharmacological evaluation of 3-benzazepin-1-
ols 3 lacking the phenolic 7-OH moiety was envisaged (Fig. 1).
In Scheme 1 the retrosynthesis of 3-benzazepines 3 is shown.
According to the plan, the phenylalkyl side chain should be intro-
duced as last step by alkylation or reductive alkylation of the sec-
ondary amine 4. The amino alcohol 4 will be obtained by
deprotection and reduction of ketone 5, which will be synthesized
by an intramolecular Friedel–Crafts acylation of a carboxylic acid.
The starting material for the intramolecular Friedel–Crafts acyla-
tion will be prepared by condensation of 2-phenylethanol (7) with
the protected glycine derivative 6. The glycine derivative 6 has to
be supplied with an appropriate protecting group (PG), which
allows condensation with 2-phenylethanol (7) and intramolecular
Friedel–Crafts acylation and, moreover, can be removed after
establishing the 3-benzazepine ring. Since it was shown that tosyl
and acyl protecting groups are not suitable for the synthesis of the
desired 3-benzazepines by intramolecular Friedel–Crafts acylation
in such a non-activated aromatic ring, the trifluoromethylsulfonyl
(triflyl) protecting group was selected.10
Scheme 2. Preparation of ketone 12; Reagents and reaction conditions: (a) Tf2O,
NEt3, CH2Cl2, ꢀ70 °C to rt, 70%. (b) PPh3, DIAD, THF, 0 °C to rt, 90%. (c) LiOH, THF/
H2O 7:3, rt, 95%. (d) P4O10 (8 equiv), CH2Cl2, 40 °C, 3 h, 67% (12).
At first the intramolecular Friedel–Crafts acylation of the car-
boxylic acid 11 was tried with different Lewis acids, such as SnCl4
and FeCl3.9 Unfortunately, these Lewis acids did not lead to the
desired ketone 12 (Table 1, entries 1 and 2).
Then, the cyclization of 11 was performed with P4O10 in CH2Cl2
as reported in the literature.10 At 0 °C the ketone 12 was obtained
in 70% yield, while the isoquinoline 13 was produced in 10% yield
(Table 1, entry 3). But a very fast and clean conversion was
observed upon reacting of the acid 11 with P4O10 in refluxing
CH2Cl2 leading to the ketone 12 in 67% yield and the isoquinoline
13 in 20% yield after 3 h (Table 1, entry 4). The isoquinoline side
product 13, which was formed by decarbonylation of acid 11,
was not mentioned in the report.10 The cyclization in boiling
CH2Cl2 was considered the standard procedure as the desired
ketone 12 was obtained in comparable yields within a short period
of time.
Removal of the triflyl protecting group of 12 was the next cru-
cial reaction step to obtain the 3-benzazepin-1-ols 3. The triflyl
group is known to be one of the strongest electron withdrawing
groups in organic chemistry. It was used for monoalkylation pur-
poses and, moreover, in few examples it served as protecting group
of amines.13 In this project, it was used to increase the NH-acidity
of sulfonamide 9 for the Mitsunobu reaction and as an electron
sink for the prevention of the undesired decarbonylation reaction,
which is induced by the electron donating properties of the N-
atom. Once its role has been fulfilled, it should be removed. In lit-
erature the reductive cleavage of the S-N bond of triflamide by
LiAlH4 was reported.14 Organic neutral super-electron donor medi-
ated S–N bond cleavage was also described in recent years.15 Base-
induced elimination of triflinate anion CF3SOꢀ2 represents a further
method to deprotect an amino moiety.16,17 But unfortunately most
of these methods lack direct practical implications and in some
cases led to undesired side product formation.17 Thus, the estab-
lishment of an efficient and mild deprotection method of the N-tri-
flyl group to afford the corresponding amine is of high importance
generally and in particular for this project.
In order to obtain tetrahydro-3-benzazepin-1-one, glycine ester
HCl (8.HCl), which was prepared by esterification of glycine with
methanol in the presence of SOCl2, was reacted with triflic anhy-
dride to afford the sulfonamide 9 in 70% yield.11 Mitsunobu reac-
tion12 of sulfonamide 9 with 2-phenylethanol (7) in the presence
of PPh3 and diisopropyl azodicarboxylate (DIAD) provided the ter-
tiary sulfonamide 10 in 90% yield. Hydrolysis of the ester 10 was
carried out with LiOH in a THF/H2O mixture providing the car-
boxylic acid 11 in 95% yield (Scheme 2).
HO
HO
( )n
NH
N
N
Ph
3
4
O
Table 1
O
Optimization of the intramolecular Friedel–Crafts acylation of 11
MeO
HN PG
Entry
Reagent
Conditions
Yield of 12
Yield of 13
PG
+
6
1
SnCl4, (F3CCO)2O
FeCl3, (F3CCO)2O
P4O10
CH2Cl2, ꢀ30 °C, 24 h
CH2Cl2, ꢀ30 °C, 24 h
CH2Cl2, 0 °C, 36 h
CH2Cl2, 40 °C, 3 h
—
—
70%
67%
—
—
10%
20%
2
OH
5
3a
4
P4O10
7
a
These reaction conditions are reported in literature giving 65% of the ketone
12.10
Scheme 1. Retrosynthesis of tetrahydro-3-benzazepin-1-ols 3.