Synthesis of 2,4-diaryl-3H-1-benzazepines

Article abstract of DOI:10.1055/s-2007-991095

Treatment of 2-fluoroaniline and some derivatives with aryl methyl ketones under acid catalysis gives the title compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991095

2868
LETTER
Synthesis of 2,4-Diaryl-3H-1-benzazepines
S
ynthesis of
Diary
e
lbenzazepin
i
es th Ramig,*a Shaan Alli,a Myra Cheng,a Richard Leung,a Rabail Razi,a Michelle Washington,a Linas V. Kudzmab
a
Department of Natural Sciences, Baruch College, 17 Lexington Ave., New York, NY 10010, USA
Fax +1(646)6606201; E-mail: keith_ramig@baruch.cuny.edu
Baxter Anesthesia and Critical Care, 95 Spring St., New Providence, NJ 07974, USA
b
Received 27 August 2007
The best conditions are heating equimolar amounts of 2-
fluoroaniline and the aryl methyl ketone, and a catalytic
amount of PTSA, at reflux for at least 20 hours in xylene,
with azeotropic removal of the water byproduct
(Table 1).6
Abstract: Treatment of 2-fluoroaniline and some derivatives with
aryl methyl ketones under acid catalysis gives the title compounds.
Key words: amines, annulations, bicyclic compounds, hetero-
cycles, ketones
With extensive 1H NMR and 13C NMR experiments per-
formed both on benzazepine 2 and some of its deuterated
analogues (prepared as above from deuterated starting
materials), we were able to unequivocally assign an atom
to each signal. In particular, we have observed a NOE be-
tween the H atoms on C atoms 5 and 6. This proves that
the benzazepine is the 3H-isomer, rather than the other
possibility, the 5H-isomer.
One of us recently disclosed1 an intriguing side reaction
that occurred during a synthesis of substituted indoles.
Heating a solution of 2-fluoroaniline, acetophenone, and
a catalytic amount of p-toluenesulfonic acid (PTSA) at
reflux for four hours gave the imine 1 as expected
(Scheme 1). However, when the reaction time was in-
creased, the major product was surprisingly the benz-
azepine 2. We are aware of one similar process, reported
by Brooke and Matthews,2 who employed aromatic
amines in which all the carbon atoms were fluorinated.
The purpose of their study was not to demonstrate a gen-
eral method for benzazepine synthesis – they gave only
two very low-yielding examples – but was to report the
reaction as an oddity, and speculate on the mechanism of
benzazepine formation. We reveal here that this reaction
can produce a variety of 2,4-diaryl-3H-1-benzazepines in
synthetically useful yields. Due to the beneficial pharma-
cological properties of certain molecules containing the 1-
benzazepine moiety,3,4 a short synthetic route is desir-
able.5
Thus far we have been unable to extend the scope beyond
aryl methyl ketones and 2-fluoroaniline. When either
propiophenone or 4-methyl-2-pentanone was treated with
2-fluoroaniline under the conditions of Table 1, only the
corresponding imines were seen. The same holds true for
treatment of either 2-chloroaniline or 2-methoxyaniline
with acetophenone.
Table 1 Synthesis of Diarylbenzazepines
Ar
Ar
NH2
N
Ar
PTSA
+
O
Me
xylene
reflux
F
2a–e
Entry
Compd
2
Ar
Phenyl
Yield (%)
Ph
Ph
Me
1
2
3
4
5
6
74
53
65
70
65
80
O
NH2
F
N
reflux
16 h
Me
PTSA
2a
4-Methoxyphenyl
3-Methoxyphenyl
4-Methylphenyl
F
toluene
2b
reflux, 4 h
1
2c
Ph
Ph
N
1
9
6
2d
4-(Trifluoromethyl)phenyl
2-Naphthyl
3
5
2e
2
Scheme 1
There is little correlation between yield and the electronic
characteristics of the aryl group of the aryl methyl ketone.
However, there appears to be a steric effect because 2¢-
methylacetophenone afforded less than 20% yield of ben-
zazepine. In this case imine formation proceeded unevent-
fully, but the subsequent cyclization was not efficient.
Although the benzazepines incorporate two molecules of
the aryl ketone for every one of the 2-fluoroaniline, we
find that the yields are very low when a 2:1 molar ratio of
SYNLETT 2007, No. 18, pp 2868–2870
Advanced online publication: 12.10.2007
DOI: 10.1055/s-2007-991095; Art ID: S06107ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
7

LETTER
Synthesis of Diarylbenzazepines
2869
aryl ketone to 2-fluoroaniline is used in the reaction. The
extra amine may be needed to scavenge the proton that is
lost during the cyclization (see later). We attempted to
employ the 2:1 stoichiometry with inclusion of either
pyridine, N,N-(dimethylamino)pyridine, or 2,6-dimethyl-
aniline to scavenge the proton, but conversion to benz-
azepine in these cases was very low.
Acknowledgment
K.R. acknowledges financial support from the Professional Staff
Congress of the City University of New York. We are grateful to Dr.
Cliff Soll of the CUNY Mass Spectrometry Facility at Hunter
College for recording the high-resolution mass spectra.
References and Notes
Scheme 2 shows a possible mechanism. After acid-cata-
lyzed imine formation, further heating may cause an al-
dol-like condensation, giving 3. In support of this, we
have found that reaction between 2-fluoroaniline and 1,3-
diphenyl-2-butenone (the aldol product of acetophenone)
will give benzazepine 2 under these conditions. Com-
pound 3 may then isomerize to 4 via a series of three acid-
catalyzed proton migrations. Compound 4 could then lose
fluoride ion and cyclize to give cation 5. The key to suc-
cess of the reaction may be at this stage. The pair of aryl
groups provided by the ketones may be needed to stabilize
the cation 5, explaining why the reaction did not give
benzazepine when 4-methyl-2-pentanone was used (see
above). In order for the aryl groups to exert the maximum
effect, they should be co-planar with the rest of the conju-
gated system of cation 5. This could explain the failure of
both 2¢-methylacetophenone and propiophenone to give
useful yields of benzazepine (see above); in these cases,
the aryl groups of cation 5 cannot be co-planar with the
rest of the system.
(1) Kudzma, L. Synthesis 2003, 1661.
(2) Brooke, G. M.; Matthews, R. S. J. Fluorine Chem. 1988, 40,
109.
(3) Sudo, K.; Miyazaki, Y.; Kojima, N.; Kobayashi, M.; Suzuki,
H.; Shintani, M.; Shimizu, Y. Antiviral Res. 2005, 65, 125.
(4) Seto, M.; Miyamoto, N.; Aikawa, K.; Aramaki, Y.; Kanzaki,
N.; Iizawa, Y.; Baba, M.; Shiranishi, M. Bioorg. Med. Chem.
2005, 13, 363.
(5) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.; Gelbrich, T.;
Coles, S. J.; Hursthouse, M. B.; Sheldrake, P. W.; Whittall,
N.; Hii, K. K. Tetrahedron Lett. 2003, 44, 3675.
(6) Typical Procedure
A solution of 6.7 mmol of the 2-fluoroaniline, 6.7 mmol of
the aryl methyl ketone, and 40 mg of PTSA in 30 mL of
toluene or xylenes in a Dean–Stark apparatus was heated at
reflux until the initially formed imine was converted into
benzazepine, as judged by silica gel TLC. After cooling, the
solution was washed with 5% NaHCO3 solution and dried
over MgSO4. Removal of the solvent under reduced pressure
gave dark oil or solid, which was triturated with EtOAc–
hexanes to isolate a first crop of benzazepine. Additional
product can be obtained by taking a second crop, or
purification by silica gel chromatography, eluting with
EtOAc–hexanes. Analytically pure samples can be obtained
by recrystallization from EtOAc–hexanes.
2,4-Bis(4-methoxyphenyl)-3H-1-benzazepine (2a)
Mp 159–160 °C. 1H NMR (300 MHz, CDCl3): d = 7.86 (d, 2
H, J = 9 Hz), 7.56–7.15 (m, 4 H), 7.49 (d, 2 H, J = 9 Hz),
6.98 (s, 1 H), 6.91 (d, 2 H, J = 9 Hz), 6.85 (d, 2 H, J = 9 Hz),
3.82 (s, 3 H), 3.78 (s, 3 H), 3.32 (br s, 2 H). 13C NMR (75
MHz, CDCl3): d = 161.30, 159.43, 156.30, 146.88, 134.37,
132.63, 130.88, 130.45, 129.70, 128.08, 127.90, 126.61,
125.29, 123.53, 114.12, 113.84, 55.32, 55.31, 33.67. Anal.
Calcd for C24H21NO2 (355.43): C, 81.10; H, 5.96; N, 3.94.
Found: C, 80.95; H, 6.17; N, 3.78.
2,4-Bis(3-methoxyphenyl)-3H-1-benzazepine (2b)
Mp 109–110 °C. 1H NMR (300 MHz, CDCl3): d = 7.60–7.20
(m, 9 H), 7.08 (s, 1 H), 7.05–6.85 (m, 3 H), 3.79 (s, 3 H), 3.70
(s, 3 H), 3.36 (br s, 2 H). 13C NMR (75 MHz, CDCl3): d =
159.96, 159.79, 157.13, 146.90, 141.47, 139.72, 134.83,
130.52, 130.13, 129.76, 129.48, 127.96, 127.00, 126.84,
123.97, 120.48, 119.37, 117.02, 113.64, 112.53, 112.48,
55.28, 55.19, 34.36. HRMS (EI): m/z calcd for C24H22NO2
[M + H+]: 356.1645; found: 356.1644.
2,4-Bis(4-methylphenyl)-3H-1-benzazepine (2c)
Mp 147–149 °C. 1H NMR (300 MHz, CDCl3): d = 7.79 (d, 2
H, J = 6 Hz), 7.56 (dd, 1 H, J = 8, 1 Hz), 7.49–7.43 (m, 3 H),
7.37 (td, 1 H, J = 8, 2 Hz), 7.23–7.13 (m, 5 H), 7.05 (s, 1 H),
3.36 (br s, 2 H), 2.37 (s, 3 H), 2.34 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 157.04, 146.95, 140.32, 137.68, 137.12,
135.50, 134.84, 130.47, 129.68, 129.42, 129.21, 128.03,
127.94, 126.71, 126.69, 126.02, 123.69, 33.67, 21.29, 21.15.
HRMS (EI): m/z calcd for C24H22N [M + H+]: 324.1746;
found: 324.1749.
The penultimate step is proton loss to give benzazepine 6.
Presumably, this proton would be scavenged by the equiv-
alent of amine, which was produced earlier in the process.
Finally, benzazepine 6 may isomerize to benzazepine 2.
To conclude, we have found a one-pot preparation of the
benzazepine ring system using 2-fluoroaniline and aryl
methyl ketones. Efforts aimed at extending the scope to
other kinds of ketones are in progress.
Ar
Ar
CH3
N
F
N
F
2
NH2
F
Ar
H3C
–
1
3
Ar
Ar
Ar
N
F
HN
F
N
Ar
Ar
Ar
H2C
H2C
H2C
F
H
4
Ar
Ar
Ar
N
N
– F–
– H+
Ar
H
5
6
Ar
N
2,4-Bis(4-trifluoromethylphenyl)-3H-1-benzazepine (2d)
Mp 142–143 °C. 1H NMR (300 MHz, CDCl3): d = 7.95 (d, 2
H, J = 6 Hz), 7.64–7.25 (m, 10 H), 7.13 (s, 1 H), 3.39 (br s,
2 H). 19F NMR (300 MHz, CDCl3): d = –63.05 (s), –63.35
Ar
2
Scheme 2
Synlett 2007, No. 18, 2868–2870 © Thieme Stuttgart · New York

2870
K. Ramig et al.
LETTER
(s). 13C NMR (75 MHz, CDCl3): d = 155.45, 146.75, 143.08
(q, J = 3 Hz), 141.19 (q, J = 3 Hz), 133.06, 132.00 (q,
J = 129 Hz), 130.75, 130.07 (q, J = 129 Hz), 129.05, 128.81,
128.27, 128.17, 127.76, 127.05, 125.96 (q, J = 15 Hz),
125.65 (q, J = 15 Hz), 124.72, 124.11 (q, J = 1083 Hz),
123.96 (q, J = 1083 Hz), 33.60. Anal. Calcd for C24H15NF6
(431.37): C, 66.82; H, 3.50; N, 3.25. Found: C, 66.61; H,
3.82; N, 3.12.
2,4-Bis(2-naphthyl)-3H-1-benzazepine (2e)
Mp 177–179 °C. 1H NMR (300 MHz, DMSO-d6): d = 8.70
(s, 1 H), 8.49 (s, 1 H), 8.19–7.88 (m, 8 H), 7.72–7.32 (m, 9
H), 3.66 (br s, 2 H). 13C NMR (75 MHz, CDCl3): d = 157.08,
147.05, 137.12, 135.49, 134.87, 134.18, 133.50, 132.94,
130.64, 129.64, 128.93, 128.51, 128.28, 128.26, 128.21,
128.06, 127.65, 127.57, 127.35, 127.13, 127.09, 126.49,
126.30, 126.28, 125.86, 125.21, 124.91, 124.05, 33.88.
Anal. Calcd for C30H21N (395.49): C, 91.11; H, 5.35; N,
3.54. Found: C, 90.81; H, 5.54; N, 3.44.
Synlett 2007, No. 18, 2868–2870 © Thieme Stuttgart · New York

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