Oxidative ring-contraction of 3H-1-benzazepines to quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.10.094

When treated with SeO₂, 2,4-diphenyl-3H-1-benzazepine (1) is oxidized equally at C3 and C5, giving either products of rearrangement or fragmentation; in both cases quinoline derivatives are the primary products. When C3 is oxidized, electrocycl

Full text of DOI:10.1016/j.tetlet.2015.10.094

Tetrahedron Letters 56 (2015) 6886–6889
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative ring-contraction of 3H-1-benzazepines to quinoline
derivatives
a
b
b
b
c
Sasan Karimi a, , Shuai Ma , Keith Ramig , Edyta M. Greer , David J. Szalda , Gopal Subramaniam
⇑
a Department of Chemistry, Queensborough Community College of the City University of New York, 222-05 56th Ave., Bayside, NY 11364, USA
b Department of Natural Sciences, Baruch College of the City University of New York, 17 Lexington Ave., New York, NY 10010, USA
c Department of Chemistry and Biochemistry, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
When treated with SeO2, 2,4-diphenyl-3H-1-benzazepine (1) is oxidized equally at C3 and C5, giving
either products of rearrangement or fragmentation; in both cases quinoline derivatives are the primary
products. When C3 is oxidized, electrocyclization followed by ring-opening with phenyl migration gives
the major product phenyl(3-phenylquinolin-2-yl)methanone (6), whereas C5 oxidation produces
2,4-diphenylquinoline (2) and 1,2-bis(2,4-diphenylquinolin-3-yl)diselane (8). Oxidation of C5 in 1 also
results in formation of 2-(3,5-diphenylfuran-2-yl)aniline (7). On the other hand, 3-methyl-2,4-diphe-
nyl-3H-1-benzazepine (9) upon treatment with SeO2 gives primarily a product of oxidation of C3,
2,3-diphenylquinoline (5). Oxidation of C5 in (9) is a minor pathway, and gives both 3-methyl-2,4-
diphenylquinoline (10) and (3-methyl-2-phenylquinolin-4-yl)(phenyl)methanone (11). CO was detected
as a byproduct in both reactions. Although the ring-contraction reaction using SeO2 has been previously
noted, no mechanistic proofs have been firmly established. In this Letter, we provide evidence for the
ring-contraction of benzazepines to quinolines through a fragmentation path (loss of CO and acetic acid)
or through rearrangement.
Received 8 October 2015
Accepted 28 October 2015
Available online 29 October 2015
Keywords:
Rearrangement
Fragmentation
Electrocyclization
Oxidation
Selenium dioxide
Quinoline
Ó 2015 Elsevier Ltd. All rights reserved.
We have reported1 that treatment of 2,4-diphenyl-3H-1-ben-
zazepine (1) with two equiv of NBS, a catalytic amount of DBP,
and water gave 2,4-diphenylquinoline derivatives 2, 3, and 4
(Scheme 1). A mechanism was proposed that involved both free-
radical and ionic intermediates. Initial free-radical bromination of
C5 of benzazepine 1 led to ring-contraction and eventually, oxida-
tive loss of C5 in the form of carbon monoxide. Bromoquinolines 3
and 4 resulted from subsequent bromination of quinoline 2.
Reported here will be preliminary results of the oxidation of
benzazepine 1 and its 3-methylated derivative with selenium diox-
ide. We found one precedent in the literature where selenium
dioxide was used as a catalyst for the ring-contraction of cycloalka-
nones to cycloalkanecarboxylic acids.2 In that study, a full mecha-
nistic proof was lacking, as there were no intermediates detected
or isolated. We anticipated that the initial oxidation would occur
at the allylic C3, and would result in oxidative loss of this carbon
atom, giving an isomer of 2 as product. We will show below that
this is indeed the case for 3-methyl-1, but 1 itself gives primarily
the product of an oxidative rearrangement, rather than fragmenta-
tion. It is hoped that an understanding of the mechanisms will lead
to reaction conditions resulting in synthetically useful yields of the
quinoline products.
Treatment of benzazepine 1 with 1.7 equiv of selenium dioxide,
a small amount of KH2PO4, and water in dioxane solvent at
90 °C—conditions employed previously for allylic oxidation3—gave
a mixture of five oxidation products (Scheme 2). Surprisingly, the
product of oxidative loss of C3, namely 2,3-diphenylquinoline (5),
was isolated only in small amounts (2–3%). The 1H and 13C NMR
spectra of 5 were identical to those reported in the literature.4
The major product was phenyl(3-phenylquinolin-2-yl)methanone
(6), in which a deep-seated oxidative rearrangement had occurred.
Three more products—apparently the result of initial oxidation of
C5—were isolated in low yields: quinoline 2,1 furan 7, and
surprisingly the diselenide 8. The presence of an additional pro-
duct, carbon monoxide, was inferred by a positive test using a
detector we have employed previously.1 A brief optimization study
established that 1.7 equiv of SeO2 was the minimum amount
required for complete conversion of starting material. The
structures of quinoline 6, furan 7, and the diselenide 8 were all
established by X-ray crystallography (see SI for details).
Treatment of the 3-methylated derivative of benzazepine 1 (9)5
under the conditions of Scheme 2 with 3.5 equiv of SeO2 (the
amount that gave the best yield) and higher temperature
⇑
Corresponding author. Tel.: +1 (718)281 5485; fax: +1 (718)281 5078.
E-mail address: skarimi@qcc.cuny.edu (S. Karimi).
http://dx.doi.org/10.1016/j.tetlet.2015.10.094
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. Karimi et al. / Tetrahedron Letters 56 (2015) 6886–6889
6887
Br
1
2 NBS
DBP
Ph
3
2
N
Ph
N
Ph
N
Ph
N
+
+
+
CO
H2O
Br
Br
CHCl3
4
Ph
5
Ph
Ph
Ph
2, 72%
3, 12%
4, 8%
1
Scheme 1. Oxidative ring-contraction of a benzazepine reported previously.
O
NH2
O
1.7 SeO2
KH2PO4
1
Ph
3
2
N
N
Ph
Ph
N
Ph
+
+
2, 12% +
Ph
Ph
H2O
dioxane
4
Ph
5
Ph
7, 6%
5, trace
6, 38%
1
N
N
Ph Ph
Se
+
Se
8, 16%
Scheme 2. Oxidation of benzazepine 1 with excess SeO2.
Ph
Ph
(110 °C) also gave initial oxidation of C3, but in this case, a
fragmentation reaction resulted, giving quinoline 5 as the major
product (Scheme 3). The other characterized products were the
3-methylated quinoline 10 (the analogue of quinoline 2), com-
pounds 11 and 6. The 1H and 13C NMR spectra of 10 were identical
to those reported in the literature.6 The structure of 11 was con-
firmed by 1D and 2D NMR experiments. Also seen in the reaction
mixture was acetic acid, which presumably carried C3 of the
starting material in the form of the carbonyl carbon atom. The
presence of an additional product, carbon monoxide, was inferred
by a positive test using a detector we have employed previously.1
Schemes 2 and 3 show the contrast between the reactivity of
benzazepines 1 and 9. While both apparently undergo initial oxi-
dation primarily at C3, the methyl group of 9 changes the result
from rearrangement (1 ? 6) to fragmentation (9 ? 5 + CH3CO2H).
And, like the reaction from Scheme 1 employing NBS, both reac-
tions from the current work give products from initial oxidation
of C5 (2, 7, 8, 10, and 11). Scheme 4 shows possible mechanisms
for formation of quinolines 5 and 6, starting with C3 oxidation of
benzazepines 1 and 9.
Cyclopropanes like 13 and 14 would be highly sensitive to the
acidic conditions of the reaction mixture. Since 14 cannot give a
ketone analogous to 13, it is possible that the cyclopropane ring
undergoes acid-catalyzed rupture instead, giving cation 16. This
could be attacked by water, giving cation 17; a proton is then
transferred, giving intermediate 18. The driving force for aromati-
zation then causes ejection of acetic acid—detection of which we
have noted above—elemental selenium, and water. Loss of a proton
then finally yields the major product from benzazepine 9, quino-
line 5.
Formation of quinoline products 2, 10 and 11, furan 7, and dis-
elenide 8 requires initial oxidation of C5 of benzazepines 1 and 9,
which seems unlikely, as C5 is not allylic. Thus, it is postulated that
benzazepines 1 and 9 first partially isomerize to their 5H isomers
19 and 20, respectively (Scheme 5), by an acid-catalyzed
rearrangement we have documented for benzazepine 1.9 5H-ben-
zazepines 19 and 20 are then oxidized by selenous acid to
intermediates 21 and 22, as in Scheme 4 for 12. Electrocyclization
then gives cyclopropanes 23 and 24. These give quinolines 2 and
10 by a process analogous to 13 ? 5 in Scheme 4.
Selenium dioxide is first converted to the actual oxidant, sele-
nous acid, by initial reaction with water. Intermediate 12 is the
result of the well-documented allylic oxidation procedure.7 Elec-
trocyclization, which is a well-known process for analogous substi-
tuted benzazepines,1 then occurs to give cyclopropanes 13 or 14.
From here, product formation is determined by the presence of
the methyl group. Unlike cyclopropane 14, 13 has the option of
forming cyclopropanone 15 by loss of elemental selenium
(observed in the crude) and water. This kind of process involving
loss of selenium and water has been proposed for the last step in
the oxidation of ketones to 1,2-diketones.8 Cyclopropanone 15
can either rearrange in the manner indicated by the arrows, giving
ketone 6, or it can fragment with loss of carbon monoxide,1 giving
quinoline 5.
Production of 11 (4%) from 26 can be rationalized similar to that
of the rearrangement of 15 to 6. Surprisingly, we have also verified
formation of 6 (4%) from the oxidation of 9. This may involve
demethylation of intermediate 14 to 15 by SeO2 before converting
to 6. Oxidative demethylation in the presence of SeO2 has been
previously noted.10 Formation of the diselenide 8 (16%) and furan
7 (6%) could occur from the same intermediate 27. Before electro-
cyclization, attack of water on the selenium atom of 21 would
result in loss of Se(OH)2 and production of allylic alcohol 27. This
process is analogous to the last step of the well-known allylic oxi-
dation procedure.7 Protonation of the nitrogen atom of the imino
group followed by intramolecular attack of the hydroxyl group
would give tricycle 28, after transfer of a proton from the oxygen
atom to the nitrogen atom. Furan formation is completed by
3.5 SeO2
KH2PO4
Ph
CH3
Ph
N
N
N
N
Ph
Ph
+
CH3
Ph
Ph
6, 4%
+
CH3CO2H
+
+
CH3
H2O
dioxane
Ph
O
Ph
9
11
, 4%
10, 8%
5, 34%
Scheme 3. Oxidation of benzazepine 9 with excess SeO2.

6888
S. Karimi et al. / Tetrahedron Letters 56 (2015) 6886–6889
Ph
Ph
OSeOH
R
Ph
Ph
N
N
Ph
Ph
O
N
H2SeO3
N
N
OSeOH
H
OSeOH
CH3
R
or
Ph
Ph
1 (R=H)
(R=CH3)
12
14
13
9
Ph
Ph
Ph
Ph
Ph
6 (major)
N
N
O
H
Se
OH
-Se
Fate of 13:
or
O
-H2O
N
Ph
Ph
13
15
-CO
Ph
5 (minor)
H2O
Ph
H
N
Ph
Se
H
N
H
O
Ph
Ph
OSeOH
N
OSeOH
CH3
OH
Fate of 14:
OH2
CH3
Ph
CH3
Ph
16
14
17
Ph
Se
H
N
O
N
Ph
-CH3CO2H
-Se -H2O
OH2
-H
OH
CH3
Ph
5 (major)
Ph
18
Scheme 4. Mechanisms rationalizing the formation of products from 1 and 9, with initial oxidation of C3.
Ph
Ph
Ph
N
N
N
N
Ph
R
H2SeO3
R
R
R
Ph
Ph
Ph
HOSeO
HOSeO
21
Ph
H
H
(R=H)
24 (R=CH3)
1 (R=H)
9 (R=CH3)
19 (R=H)
(R=H)
22 (R=CH3)
23
20 (R=CH3)
N
N
Ph
CH3
N
N
O
Ph
Ph
R
Ph
R
-Se
Fate of
23
11
Or
24
and
:
-H2O
O
Ph
Ph
Se
OH
O
H
Ph
R
-CO
25 (R=H)
26 (R=CH3)
23
(R=H)
24 (R=CH3)
Ph
2 (R=H)
10
(R=CH3)
H
H
NH2
Ph
N
Ph
H
Ph
Ph
N
N
Furan 7
-H
-Se(OH)2
O
O
21
from
:
Ph
Ph
H
Ph
HOSeO
H2O
HO
27
H
H
Ph
7
28
21
N
N
Ph
SeOH
Ph
N
Ph OH
Se
H2O
N
Ph
SeO2
-CO
8
27
SeOH
H
OH
Ph
31
Ph
Ph
Ph
O
O
HO
H2O
25
29
30
Scheme 5. Mechanisms rationalizing formation of the minor products with initial oxidation of C5.
cleavage of a C–N bond, and loss of a proton. To make 8, interme-
diate 27 first undergoes electrocyclization to give 29 followed by
oxidation to 25. Further reaction with Se(OH)2 gives the reactive
intermediate 30 which aromatizes and loses CO to give 31. In the
presence of water, intermediate 31 undergoes disproportionation
to the diselenide 8.11
We have shown that SeO2 oxidation of benzazepines 1 and 9
provides quinoline derivatives by both rearrangement and

S. Karimi et al. / Tetrahedron Letters 56 (2015) 6886–6889
6889
fragmentation. Unlike our previously reported oxidation of 1 with
NBS, where initial oxidation of C3 followed by fragmentation was
the exclusive outcome, SeO2 gives products of both rearrangement
and fragmentation after first oxidation of either C3 or C5. The
major product, 2-benzoylated quinoline 6, is the result of C3
oxidation followed by rearrangement accompanied by phenyl
migration; C3 ends up as part of a carbonyl group in the quinoline
product. The presence of a methyl group at C3 in the starting mate-
rial again gives primarily initial C3 oxidation, followed this time by
expulsion of C3 in the form of acetic acid after ring-contraction,
resulting in quinoline 5 as the major product. Minor but apprecia-
ble amounts of quinolines derived from initial oxidation of C5 in
both benzazepines 1 and 9 are the result of isomerization of these
3H benzazepines to their less stable 5H forms, before oxidation
occurs.
financial support of this work. E.M.G. acknowledges support from
the donors of the Petroleum Research Fund of the American Chem-
ical Society.
Supplementary data
Supplementary data (X-ray crystal structure for 6 (Fig. S1), 7
(Fig. S2), 8 (Fig. S3), spectroscopic data (1H NMR, 13C NMR) for
compounds 6, 7, 8 and 11) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2015.10.094.
References and notes
1. Karimi, S.; Ramig, K.; Greer, E. M.; Szalda, D. J.; Berkowitz, W. F.; Prasad, P.;
Subramaniam, G. Tetrahedron 2013, 69, 147–151.
2. Payne, G. B.; Smith, C. W. J. Org. Chem. 1957, 22, 1680–1682.
3. (a) Cookson, R. C.; Isaacs, N. S.; Szelke, M. Tetrahedron 1964, 20, 717–722; (b)
Teuber, H. J.; Steinmetz, G. Chem. Ber. 1965, 98, 666–684.
Typical experimental procedure
In a typical experiment, benzazepines 1 or 9 (1 equiv), SeO2
(1.7 equiv for 1 and 3.5 equiv for 9), and catalytic amount of
KH2PO4 in water were dissolved in dioxane and heated (90–95 °C
for 1, 110 °C for 9) for 18 h. After cooling, elemental Se was filtered
and the yellow mixture was extracted with aqueous NaHCO3,
saturated brine, and dried over MgSO4. Rotary evaporation gave a
crude product which was purified by radial chromatography (silica
gel, 2% EtOAc/hexane). All new compounds were confirmed by
X-ray or detailed spectral data, and known compounds were
compared with the spectra of authentic compounds. See SI for
experimental details.
4. (a) Armesto, D.; Gallego, M. G.; Horspool, W. M. J. Chem. Soc., Perkin Trans. 1
1989, 1623–1626; (b) Chuang, T. H.; Yang, C. H.; Kao, P. C. Inorg. Chim. Acta
2009, 362, 5017–5022; (c) Xi, L.-Y.; Zhang, R.-Y.; Zhang, L.; Chen, S.-Y.; Yu, X.-Q.
Org. Biomol. Chem. 2015, 13, 3924–3930; (d) Ji, X.; Huang, H.; Li, Y.; Chen, H.;
Jiang, H. Angew. Chem., Int. Ed. 2012, 51, 7292–7296.
5. Ko, A.; Lam, A.; Li, J.; Greer, E. M.; Szalda, D. J.; Karimi, S.; Subramaniam, G.;
Ramig, K. Tetrahedron Lett. 2014, 55, 4386–4389.
6. (a) Hou, R. S.; Wu, J. L.; Cheng, H. T.; Xie, Y. T.; Chen, L. C. J. Chin. Chem. Soc.
2008, 55, 915–918; (b) Osborne, A. G.; Ahmet, M. T.; Miller, J. R.; Warmsley, J. F.
Spectrochim. Acta 1995, 51A, 237–246; (c) Barluenga, J.; Cuervo, H.; Fustero, S.;
Gotor, V. Synthesis 1987, 1, 82–84; (d) Zhang, Z.; Du, H. Org. Lett. 2015, 17,
2816–2819; (e) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120–1123;
(f) Zhang, X.; Liu, B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem. 2012, 77, 501–
510; (g) Martinez, R.; Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2007, 1599–1605.
7. For reviews, see (a) Rabjohn, N. Org. React. 1976, 24, 261; (b) Jerussi, R. A. Sel.
Org. Transform. 1970, 1, 301; (c) Trachtenberg, E. N. In Oxidation; Augustine, R.
L., Ed.; Marcel Dekker: NY, 1969; Vol. 1, pp 123–153.
Acknowledgements
8. Corey, E. J.; Schaefer, J. P. J. Am. Chem. Soc. 1960, 82, 918–929.
9. Ramig, K.; Greer, E. M.; Szalda, D. J.; Razi, R.; Mahir, F.; Pokeza, N.; Wong, W.;
Kaplan, B.; Lam, J.; Mannan, A.; Missak, C.; Mai, D.; Subramaniam, G.;
Berkowitz, W. F.; Prasad, P.; Karimi, S.; Lo, N. H.; Kudzma, L. V. Eur. J. Org.
Chem. 2010, 2363–2371.
We thank Dr. E. Fujita of Brookhaven National Laboratory for
the use of the Bruker Kappa Apex II diffractometer for X-ray data
collection, Emeritus Prof. William F. Berkowitz of Queens College,
CUNY for many helpful suggestions, and the Professional Staff
Congress of the City University of New York is acknowledged for
10. Achremowicz, L. Tetrahedron Lett. 1980, 21, 2433–2434.
11. Gancarz, R. A.; Kice, J. L. J. Org. Chem. 1981, 46, 4899–4906.