Synthesis of substituted 4-amino-2-benzazepin-3-ones via N-acyliminium ion cyclizations

Article abstract of DOI:10.1055/s-2005-918946

Two versatile syntheses of 1- and 1,2-disubstituted 2-benzazepinones are presented, using N-acyliminium ions as reactive intermediates. The methodology for 1-substitution is based on the synthesis of benzotriazole adducts, which are cyclized upon addition

Full text of DOI:10.1055/s-2005-918946

LETTER
2791
Synthesis of Substituted 4-Amino-2-benzazepin-3-ones via N-Acyliminium Ion
Cyclizations
Synthesis of
S
t
ubstitu
e
d
4-Amin
v
o-2-benzazep
e
in-3-ones n Ballet,a Zofia Urbanczyk-Lipkowska,b Dirk Tourwé*a
a
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
Fax +32(2)6293304; E-mail: datourwe@vub.ac.be
b
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 18 August 2005
azepin-ones 1, based on N-acyliminium ion cyclizations
(Scheme 1).
Abstract: Two versatile syntheses of 1- and 1,2-disubstituted 2-
benzazepinones are presented, using N-acyliminium ions as reac-
tive intermediates. The methodology for 1-substitution is based on
the synthesis of benzotriazole adducts, which are cyclized upon
addition of AlCl3. The simultaneous introduction of 1- and 2-sub-
stitions is realized by an N-acylation of an imine.
The synthesis of the 1-substituted benzazepinones 1 was
achieved through pathways A and B. Both synthetic
pathways are based on the formation of N-acyliminium
ion intermediates (2 and 3). Method A is based on the in-
tramolecular cyclization developed by Katritzky et al. for
the synthesis of substituted isoquinolines.3,4 A benzotriaz-
ole adduct serves an a precursor for the N-acyliminium
intermediate. Petrini and coworkers published a similar
strategy using benzenesulfonyl derivatives.5,6
Key words: 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one tem-
plate, N-acyliminium ions, Friedel–Crafts alkylation, benzotriazole
adducts
The tetrahydro-2-benzazepine skeleton is present in
several bioactive compounds such as ACE, NEP, farne-
syltransferase and factor Xa inhibitors, integrin and fibrin-
ogen receptor antagonists, and analgesics.1,2 Synthetic
methods that allow the introduction of a variety of sub-
stituents at different positions are therefore highly valu-
able in medicinal chemistry. The methods available,
however, do not allow an easy introduction of a sub-
stituent at the 1-position.2 We now report our results on
versatile synthetic methods for the preparation of 1- and
We prepared the benzotriazole adducts 5 (Scheme 2),
starting from the corresponding N-phthaloyl-phenylala-
nine amide 9a (R2 = H) or 9b (R2 = OMe),7 using benzo-
triazole (BtH) and an aldehyde in acid-catalyzed
conditions by azeotropic removal of water.8
The equilibrium shift towards the N-acyliminium ion 3 is
induced by the addition of a Lewis acid catalyst. The use
of SnCl4, SbCl5, TFMSA and Yb(OTf)3 resulted in the
complete conversion of 513 back into the starting material
9 (Table 1).
1,2-disubstituted
4-amino-1,2,4,5-tetrahydro-2-benz-
R2
R2
R2
Bt
NH
R3
R3
A
R3
R1
R1
NH
+
R1
N
N
R
N
R
R4 = H
–
R4
N
R
Bt
O
O
O
1
5
3
B
R2
R2
R3
R3
R1
N
+
R1
N
R4
Cl
R4
N
7
O
N
R
O
R
6
2
Scheme 1
SYNLETT 2005, No. 18, pp 2791–2795
0
3
.1
1
.2
0
0
5
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918946; Art ID: G26005ST
© Georg Thieme Verlag Stuttgart · New York

2792
S. Ballet et al.
LETTER
R2
R2
1 equiv R3CHO
1 equiv BtH
0.2 equiv p-TosOH
Bt
NH
R3
benzene, reflux,
overnight
NH2
Pht=N
Pht=N
O
O
R = H (4S) 9a
5
R = MeO (4R,S) 9b
R2
R2
R3
AlCl3
R3
N
NH
Pht=N
+
–
Bt
Pht=N
O
O
8
Figure 1
3
Scheme 2
In contrast to method A, no diastereoselectivity is ob-
served: the 1,2-disubstituted benzazepinones 10 are ob-
tained in a 1:1 to 2:1 ratio (Table 2). One stereoisomer of
10 (entry 2, Table 2) was obtained by crystallization, and
was shown by X-ray diffraction to be the trans isomer.
We could observe that this isomer was formed selectively
(1:10, cis/trans) when SbCl5 was used in excess, but with
yields <20% (Figure 2).
Table 1 Synthesis of 1-Substituted Benzazepinones 814,15,17
Entry
Substrate
R3
Yield of 8 (%)
1
2
3
4
5
9a
9a
9a
9b
9b
Ph
31
30
31
71
68
4-ClPh
4-BrPh
Ph
4-BrPh
3,8
We obtained compounds 8 (entry 1–3) using AlCl3
under reflux conditions in dichloromethane in yields vary-
ing around 30%. By activation of the aromatic ring of the
amino acid a much better yield was obtained (entries 4 and
5). The starting racemic amide for this entry was obtained
through phase-transfer catalysis using ethyl N-(diphenyl-
methylene)glycinate and 3-methoxybenzylbromide with
–
n-Bu4N+HSO4 as the catalyst.2c In all cases the cycliza-
tion of the acyliminium ions 3 resulted in only one stereo-
isomer. The X-ray diffraction structure of 9a indicated
that the cis isomer was obtained (Figure 1).
Figure 2
R2
R2
A direct way to 1,2-disubstituted benzazepinones 1 con-
sists of the N-acylation of an imine 7 (method B,
Scheme 3). This reaction yields an N-acyliminium ion af-
ter addition of SbCl5,9 which cyclizes to 10 after an over-
night reaction.
R3
R3
R4
SbCl5
N
N
+
Cl
R4
Pht=N
Pht=N
O
O
The use of SnCl4 and AgBF4 resulted in lower yields,
whereas other metal halides (TiCl4, SbCl5) led to the
hydrolysis of the N-acyliminium species 11.
7
11
R2 = H 12a (S)
R2 = OMe 12b (R,S)
R2
The reaction time for N-acylation was strongly dependent
on the R4 substituent: whereas the reaction with R4 =
benzyl or ethyl acetate required 45 minutes, the methyl
propanoate substituent (entry 6, Table 2) needed 5 hours,
probably due to increased steric hindrance. Literature
proposes that the N-acylation step is an equilibrium step
strongly dependent of the kind of imine used.10 Steric
hindrance might disfavor the N-acylated form.
R3
R4
N
Pht=N
O
10
Scheme 3
Synlett 2005, No. 18, 2791–2795 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 4-Amino-2-benzazepin-3-ones
2793
It was impossible to obtain yields higher then 10% (HPLC intermediate was observed on HPLC analysis, and after
quantification) for the 1-cyclohexyl analogue (entry 7). purification by flash chromatography satisfying yields
As apparent from Table 2, only non-enolizable aldehydes (69–75%) were obtained. When on the other hand Pht-
could be used to introduce a 1-substituent (R3). The use of pBr-Phe, Pht-pI-Phe or Pht-pCl-Phe were used, only the
a cyclohexanecarboxaldehyde (entry 7) led to the forma- hydrolyzed products were observed, due to a decreased
tion of enamide 13 which could not be cyclized success- reactivity of the aromatic ring.
fully (Scheme 4). Ring closure by protonation with
The selectivity for the formation of the cis isomer during
TFMSA11 did not result in the desired product.
the iminium ion cyclization of 3 is consistent with a pre-
viously reported example (R3 = COOCH3) for which the
Table 2 Synthesis of 1,2-Disubstituted Benzazepinones 1014,16,17
preferred transition state 14 was proposed (Scheme 3).2a
A major aspect in 14 is that it results in an equatorial dis-
position of the imino substituent when the aromatic ring
approaches from the top side.
Entry
Substrate
Yield of 10
(%, cis/trans)
R2
H
H
H
H
H
H
R3
R4
1
2
3
4
5
6
Ph
Bn
26 (1:1.2)
50 (1:1)
R3
H
Ph
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
R3
A
H
cis
4-ClPh
4-BrPh
4-PhPh
Ph
52 (1:1.4)
54 (1:1.2)
45 (1:1.2)
36 (1:1)
H
N
N
H
Pht=N
Pht=N
O
O
14
8
(S)-CH(CH3)
R3
R4
COOEt
H
R3
H
H
7
8
H
Chex
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
0
H
N
N
R4
Pht=N
Pht=N
OMe
OMe
OMe
OMe
Ph
75 (1:2)
70 (1:1.5)
69 (1:2)
71 (1:1.5)
O
O
16
15
9
4-ClPh
4-BrPh
4-PhPh
B
B
10
11
cis
trans
Scheme 5
When an R4 substituent is present, the N-acyliminium in-
termediate 11 does not exist in a single E configuration,
but as the E/Z mixture 15 and 16 (Scheme 5). Cyclization
then results in a diastereomeric mixture.
Upon work up of the reaction a partial hydrolysis of the
unreacted N-acyliminium ion intermediate 11 was ob-
served. Ganesan et al. reported a similar iminium ion hy-
drolysis in Pictet–Spengler reactions using metal chloride
Lewis acid catalysis.11 Metal triflates (M(OTf)n) were re-
ported to avoid this side reaction and to result in high
yields for the synthesis of tetrahydro-b-carboline ring sys-
tems. We investigated the use Yb(OTf)3, In(OTf)3 and
Sn(OTf)2 but unfortunately these catalysts were not effec-
tive, leading to no conversion to the ring-closed products
10 whatsoever.
In conclusion we have developed two versatile strategies
for the 1-substitution (pathway A) and 1,2-disubstitution
(pathway B) of 4-amino-1,2,4,5-tetrahydro-2-benza-
zepin-3-ones 1. Good yields are obtained, provided that
the aromatic ring has an activating substituent, which is in
agreement with other studies.12 The cis product is solely
formed using the benzotriazole pathway, whereas the
strategy through a N-acylation of an imine gave a dia-
stereomeric mixture.
As in method A, the reaction yields are much improved by
having an activating methoxy substituent (entries 8–11).
No side-product due to the hydrolysis of the acyliminium
c-Hex
c-Hex
SbCl5
N
N
Cl
R4
N
R4
+
Pht=N
R4
Pht=N
Pht=N
O
O
O
12
7 (entry 7)
13
Scheme 4
Synlett 2005, No. 18, 2791–2795 © Thieme Stuttgart · New York

2794
S. Ballet et al.
LETTER
(12) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen, J.
H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J.
Org. Chem. 2005, 70, 5519.
(13) General Procedure for the Preparation of Compounds 5
(Entries 1–3).
Acknowledgment
We thank the IWT (Institution for the Promotion of Innovation by
Science and Technology in Flanders) for the financial support.
N-Phthaloyl-(S)-phenylalanine amide 9a (0.5 g, 1.7 mmol),
benzotriazole (1 equiv, 0.202 g, 1.7 mmol) and p-TsOH (0.1
equiv, 32 mg, 0.17 mmol) were added to an oven-dried 100-
mL flask, and dissolved in dry benzene (15 mL). After
addition of the aldehyde (1 equiv, 1.7 mmol) the flask was
heated by means of an oil bath (105 °C) and the solution was
refluxed over night. After evaporation of the solvent,
trituration with Et2O gave compound 5 (entries 1–3) in
quantitative yields.
References
(1) Examples given: (a) ACE inhibitors: Flynn, G. A.; Giroux,
E. L.; Dage, R. C. J. Am. Chem. Soc. 1987, 109, 7914.
(b) NEP inhibitors: Warchawsky, A. M.; Flynn, G. A.;
Koehl, J. R.; Mehdi, S.; Vaz, R. J. Bioorg. Med. Chem. Lett.
1996, 6, 957. (c) Farnesyl transferase inhibitors: Le
Duguarher, T.; Ortuno, J.-C.; Shanks, D.; Guilbaud, N.;
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Tucker, G. C.; Casara, P. J. Bioorg. Med. Chem. Lett. 2004,
14, 767. (d) Factor Xa: Reiner, J. E.; Uong, T. H.; Semple,
J. E.; Tamura, S. Y. 219th ACS Med. Chem. Meeting, San
Francisco, 2000, Poster 192. (e) Integrin antagonists:
Miller, W. H.; Ali, F. E.; Bondinell, W. E.; Callahan, J. F.;
Calvo, R. R.; Eggleston, D. S.; Haltiwanger, R. C.; Huffman,
W. F.; Hwang, S.-M.; Jakas, D. R.; Keenan, R. M.; Koster,
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Wong, A. S.; Yellin, T. O.; Yuan, C. C. K. Bioorg. Med.
Chem. Lett. 1996, 6, 2481. (f) Fibrinogen receptor
antagonists: Keenan, R. M.; Callahan, J. F.; Samanen, J. M.;
Bondinell, W. E.; Calvo, R. R.; Chen, L.; DeBrosse, C.;
Eggleston, D. S.; Haltiwanger, R. C.; Hwang, S.-M.; Jakas,
D. R.; Ku, T. W.; Miller, W. H.; Newlander, K. A.; Nichols,
A.; Parker, M. F.; Southhall, L. S.; Uzinskas, I.; Vasko-
Moser, J. A.; Venslavsky, J. W.; Wong, A. S.; Huffman, W.
F. J. Med. Chem. 1999, 42, 545. (g) Analgesics: Sawa, Y.;
Takeshi, K.; Toru, M.; Mikio, H.; Hajime, F. Chem. Pharm.
Bull. 1975, 23, 1917.
(2) (a) Flynn, G. A.; Burkholder, T. P.; Huber, E. W.; Bey, P.
Bioorg. Med. Chem. Lett. 1991, 1, 309. (b) Van Rompaey,
K.; Van den Eynde, I.; De Kimpe, N.; Tourwé, D.
Tetrahedron 2003, 59, 4421. (c) Tourwé, D.; Verschueren,
K.; Frycia, A.; Davis, P.; Porreca, F.; Hruby, V. J.; Toth, G.;
Jaspers, H.; Verheyden, P.; Van Binst, G. Biopolymers 1995,
38, 1. (d) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org.
Chem. 2001, 5, 519. (e) Gámez-Montaño, R.; Chávez, M. I.;
Roussi, G.; Cruz-Almanza, R. Tetrahedron Lett. 2001, 42, 9.
(3) Katritzky, A. R.; Lan, X.; Zhang, Z. J. Heterocycl. Chem.
1993, 30, 381.
(4) Katritzky, A. R.; Mehta, S.; He, H.-Y. J. Org. Chem. 2001,
66, 148.
(5) Mecozzi, T.; Petrini, M.; Profeta, R. Tetrahedron:
Asymmetry 2003, 14, 1171.
(6) Marcantoni, E.; Mecozzi, T.; Petrini, M. J. Org. Chem. 2002,
67, 2989.
(14) General Procedure for the Preparation of Compounds 8
(Entries 1–5).
Benzotriazole adducts 5 (100 mg) were dissolved in dry
CH2Cl2 (10 mL). Then, 10 equiv of AlCl3 were added and
these mixtures were refluxed over a period varying between
3 h and 5 h. The reaction mixtures were cooled down to r.t.
after which H2O (10 mL) was added. The organic phase was
isolated and washed with brine (10 mL). After drying over
MgSO4 the solvent was removed in vacuo. Flash
chromatography (15% EtOAc in hexanes) or crystallization
(from EtOH) yielded compounds 8 (entries 1–5).
(15) General Procedure for the Preparation of Compounds
10 (Entries 1–7).
In an oven-dried 25-mL flask, Pht-Phe (150 mg, 0.5 mmol)
was dissolved in a,a-dichloromethyl methyl ether (5 mL)
and the reaction mixture was stirred at 60 °C (oil bath
temperature) over night. After evaporation the residue was
re-dissolved in dry benzene (10 mL) and evaporated (2
times). The resulting white solid was dissolved in dry
CH2Cl2 (5 mL) and cooled down to 0 °C by means of an ice
bath. The flask was filled with argon, the imine 7 (1.5 equiv)
was added, the reaction mixture was stirred during 45 min at
0 °C after which 1.2 equiv (0.6 mL, 0.60 mmol) of a 1 M
solution of SbCl5 in CH2Cl2 was added. Overnight reaction
at r.t. was followed by quenching with H2O (5 mL). Isolation
of the organic phase, evaporation and flash chromatography
yielded the benzazepinones 10 (entries 1–7).
(16) Analytical data of N-phthaloyl-(4S)-amino-1-phenyl-
1,2,4,5-tetrahydrobenzo[c]azepin-3-one (8, entry 1): white
solid, Rf = 0.70 (EtOAc), mp 222–224 °C. MS (ESP+): m/z
calcd for C24H19N2O3: 383.13. Found: 383 [M + H]+. HPLC:
tR = 21.2 (min). 1H NMR (250 MHz, CDCl3): d = 2.65 (dd,
J = 13.5 Hz, J = 3.0 Hz, 1 H), 3.19 (br s, 1 H), 3.71 (dd,
J = 13.0 Hz, J = 12.6 Hz, 1 H), 4.90 (dd, J = 12.5 Hz, J = 3.0
Hz, 1 H), 4.19 (m, 3 H), 4.86 (dd, J = 3.0 Hz, J = 14.0 Hz, 1
H), 5.65 (d, J = 6.5 Hz, 1 H), 7.21–7.40 (m, 9 H), 7.74 (m, 2
H), 7.85 (m, 2 H). 13C NMR (63 MHz, CDCl3): d = 34.6,
52.7, 123.9, 126.9, 128.0, 128.0, 129.0, 129.7, 130.0, 131.0,
132.9, 134.5, 136.8, 139.3, 141.1, 167.8, 172.0.
(17) Analytical data of N-phthaloyl[1-phenyl-(4S)-amino-3-oxo-
1,2,4,5-tetrahydrobenzo[c]azepin-2-yl]acetic acid ethyl
ester) (10, entry 2): white solid, Rf = 0.68 (EtOAc), mp 108–
110 °C. MS (ESP+): m/z calcd for C28H25N2O5: 468.17.
Found: 469 [M + H]+. HPLC: tR = 24.1 and 24.3 (min). 1H
NMR (250 MHz, CDCl3): d = 1.08 and 1.22 (t, J = 7.1 Hz, 3
H), 2.55 and 3.18 (dd, J = 17.0 Hz, J = 4.0 Hz, 1 H), 4.11 (q,
J = 7.1 Hz, 2 H), 3.62 and 4.25 (d, J = 17.0 Hz, 1 H), 4.32
(m, 1 H), 4.91 and 5.12 (d, J = 17.0 Hz, 1 H), 4.85 and 5.32
(dd, J = 12.0 Hz, J = 4.0 Hz, 1 H), 5.65 and 5.70 (s, 1 H),
7.15–7.50 (m, 9 H), 7.68–7.82 (m, 4 H). 13C NMR (63 MHz,
CDCl3): d = 14.2 and 14.6, 33.7 and 34.6, 53.1, 52.3 and
54.0, 61.7 and 61.8, 69.3 and 70.4, 123.8, 126.9, 128.0,
129.0, 129.5, 130.3, 131.9, 134.5, 136.0, 137.5, 139.6,
139.3, 141.5, 169.2, 169.5, 170.1.
(7) (a) N-Phthaloyl-(S)-phenylalanine was obtained following
the methodology described by: Casimir, J. R.; Guichard, G.;
Briand, J.-P. J. Org. Chem. 2002, 67, 3764. (b) The amides
9 were obtained by converting the phthaloyl-protected
amino acid into the acid chloride by treatment with a,a-
dichloromethyl methyl ether2a followed by the addition of aq
NH3.
(8) Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K.
Tetrahedron 2005, 61, 2555.
(9) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367.
(10) Bose, A. J.; Spiegelman, G.; Manhas, M. S. Tetrahedron
Lett. 1971, 34, 3167.
(11) Srinivasan, N.; Ganesan, A. Chem. Commun. 2003, 916.
Synlett 2005, No. 18, 2791–2795 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 4-Amino-2-benzazepin-3-ones
2795
(18) X-ray structure analysis of compounds 8 (entry 1) and 10
(entry 2). Suitable crystals were mounted on glass fibers.
Data collections were performed at 295 nm on a Nonius BV
MACH diffractometer with graphite monochromated CuKa
(l = 1.54178 Å). Both structures were solved with direct
methods using the SHELXS9719 and refined with
CCDC-279758 [10 (entry2)] contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; e-
mail: deposit@ccdc.cam.sc.uk).
SHELXL9720 software. Refinements were performed
anisotropically for all non-hydrogen atoms using the full-
matrix least-squares method. In general, hydrogen atoms
were assigned to idealized positions and were allowed to ride
with thermal parameters fixed at 1.2 Ueq of the parent atom.
The residual electron densities were of no chemical
(19) Sheldrick, G. M. SHELXS-97, Program for Crystal
Structure Solution; University of Göttingen: Göttingen,
Germany, 1997.
(20) Sheldrick, G. M. SHELXL-97, Program for Crystal
Structure Refinement; University of Göttingen: Göttingen,
Germany, 1997.
significance. Accordingly, CCDC-279757 [8 (entry 1)], and
Synlett 2005, No. 18, 2791–2795 © Thieme Stuttgart · New York