Synthesis of new 2-benzazepino[4,5-a ]naphthalene derivatives via 1,7-electrocyclisation of nonstabilised azomethine ylides

Article abstract of DOI:10.1055/s-0030-1258036

Novel 2-benzazepino[4,5-a]naphthalene derivatives were synthesised efficiently via 1,7-electrocyclisation of nonstabilised azomethine ylides derived from 1-aryl- or 1-alkenyl-naphthalene-2-carbaldehyde derivatives. In some cases, surprisingly, pyrrole derivatives were isolated. A mechanism for the formation of the pyrrole byproduct is proposed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258036

LETTER
2411
Synthesis of New 2-Benzazepino[4,5-a]naphthalene Derivatives
via 1,7-Electrocyclisation of Nonstabilised Azomethine Ylides
N
ew 2-Benzaze
i
pino[
4
b
,5-
a
]naphtha
o
lene
D
erivati
r
ves Novak, Zoltán Mucsi, Barbara Balázs, László Keresztély, Gábor Blaskó, Miklós Nyerges*
Servier Research Institute of Medicinal Chemistry, Záhony u. 7., 1031 Budapest, Hungary
Fax +36(1)8812011; E-mail: miklos.nyerges@hu.netgrs.com
Received 9 June 2010
method of De Koning21 in two steps starting from the cor-
responding a-tetralone 1 (Scheme 1).
Abstract: Novel 2-benzazepino[4,5-a]naphthalene derivatives
were synthesised efficiently via 1,7-electrocyclisation of nonstabi-
lised azomethine ylides derived from 1-aryl- or 1-alkenyl-naphtha-
lene-2-carbaldehyde derivatives. In some cases, surprisingly,
pyrrole derivatives were isolated. A mechanism for the formation of
the pyrrole byproduct is proposed.
Our initial studies applied the generation of nonstabilised
azomethine ylides16 4 by the decarboxylation method, in-
volving the condensation of N-monosubstituted a-amino
acids with 1-aryl-3,4-dihydro-naphthalene-2-carbalde-
hydes 3a and 3b. In the first set of experiments a mixture
of 3a or 3b and sarcosine was refluxed for three hours in
p-xylene, and after the workup the expected benzazepine
derivatives 6a and 6b were obtained in good yield. No re-
action occurred at lower temperature, for example, in re-
fluxing toluene, nor did the microwave irradiation
facilitate the reaction. The obtained products arise from a
1,7-electrocyclisation of the conjugated azomethine ylide
4 formed by the condensation of aldehydes 3 and sar-
cosine, to give the intermediate 5, followed by a [1,5]-
hydrogen shift, resulting in the rearomatisation of the ben-
zene ring (Scheme 2).
Key words: Azepines, electrocyclic reactions, heterocycles, tan-
dem reactions, ylides
A number of seven-membered heterocyclic rings form
part of the structures of a range of biologically active nat-
ural products and medicinally important compounds. Ow-
ing to this over the last few decades several new
methodologies have been developed for the construction
of such ring systems.1,2
For many years 1,3-dipoles have been used extensively
for the construction of five-membered heterocyclic rings
via their cycloadditions with suitable dipolarophiles3,4 and
by the 1,5-electrocyclisation reactions of a,b-unsaturated
1,3-dipoles.5,6 More recently, the electrocyclisation of
diene-conjugated 1,3-dipolar intermediates has provided
a powerful general synthetic route to seven-membered
heterocyclic ring systems.7–19 The investigation of such
reactions of azomethine ylides resulted in the develop-
ment of a new approach to azepine derivatives.20
The same reaction was observed with N-benzylglycine 8
and the electron-withdrawing or electron-donating nature
of the substituent of the participating aromatic ring did not
affect the reaction course.
We next chose to form the azomethine ylides from the 1-
aryl-3,4-dihydronaphthalene-2-carbaldehydes 3a and 3b
and some cyclic secondary a-amino acids, such as pipe-
colinic acid (10), proline (12), 1,2,3,4-tetrahydro-3-
isoquinolinecarboxylic acid (16), and 4-thiazolidinecar-
boxylic acid (14), allowing the formation of various new
penta- and hexacyclic ring systems 9a,b, 11a,b, 13a,b,
and 15a, respectively, in a single step, in good yields
(Scheme 3).22 The intermediacy of an azomethine ylide in
this processes was proved by trapping an ylide 4
As a continuation of these studies our aim was to show the
generality of these methods as useful tools for the annela-
tion of a benzazepine ring to different naphthalene deriv-
atives in a single step. In this paper we describe the
synthesis of some hitherto unknown 2-benzazepino[4,5-
a]naphthalene derivatives. The starting material 3,4-dihy-
dro-aryl-naphthalenes 3a and 3b were prepared by the
R
O
Br
CHO
CHO
i
ii
MeO
MeO
MeO
1
2
3a R = OMe
3b R = CO2Me (66%)
(75%)
Scheme 1 Reagents and conditions: i. DMF, PBr3; ii. ArB(OH)2, Pd(OAc)2, P(o-tolyl)3, Na2CO3.
SYNLETT 2010, No. 16, pp 2411–2414
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258036; Art ID: D14410ST
© Georg Thieme Verlag Stuttgart · New York

2412
T. Novak et al.
LETTER
R
R
CO2Me
Me
N
[1,7]
i
H
–
H
CHO
CH2
N+
H
O
N
CO2Me
Me
MeO
MeO
MeO
i
O
Ph
3a R = OMe
3b R = CO2Me
4
17
+
R
CHO
R
CO2Me
MeO
[1,5]
Me
N
Me
3b
N
Me
N
H
H
H
O
N
MeO
MeO
5
6a R = OMe (80%)
6b R = CO2Me (86%)
MeO
O
Ph
18
Scheme 2 Reagents and conditions: i. sarcosine, xylene, reflux.
Scheme 4 Reagents and conditions: i. N-phenylmaleimide, sarco-
sine, xylene, reflux, 61%.
(R = CO2Me) with N-phenylmaleimide to give the two
isomeric cycloadducts 17 and 18 (exo/endo ratio = 1:1)
which were separated by column chromatography and
characterised by NMR methods (Scheme 4).
the reaction mixture the ratio of the formed products was
reversed (ratio 2:1 in favour of 21a). In the presence of
DBN (a strong base) only the formation of 21a was ob-
served. Applying N-benzylglycine 8 instead of sarcosine
in the reaction with 19 the pyrrole derivative 21b was the
sole product isolated from the reaction mixture without
the presence of extra base. The reactions of 19 with cyclic
amino acids as well as naphthalene aldehyde with sar-
cosine or N-benzylglycine proceeded again only on the
normal 1,7-electrocyclisation pathway resulting in the
formation of the expected azepine derivatives, and no pyr-
role or other byproduct formation was observed
(Scheme 5).
We were also interested in determining the reactivity of
azomethine ylides derived from conjugated aldehyde 1923
in similar electrocyclisation processes. In the reaction of
19 with sarcosine under the same conditions which were
used in the previous experiments we obtained a byproduct
21a which was isolated in addition to the expected
azepine derivative 20 (ratio = 2:1 in favour of 20). In ad-
dition, the position of the double bond in the obtained
azepine derivative 20 was different to that in the previous
examples. By adding an excess of triethylamine base to
R
R
R
N
Bn
N
N
MeO
MeO
MeO
9a R = OMe (72%)
9b R = CO2Me (67%)
11a R = OMe (70%)
11b R = CO2Me (74%)
7a R = OMe (80%)
7b R = CO2Me (76%)
H
H
N
N
CO2H
i
i
CO2H
H
i
Ph
N
CO2H
8
12
10
S
R
CO2H
R
R
HN
NH
S
CO2H
14
16
N
N
i
i
CHO
MeO
MeO
MeO
3a R = OMe
3b R = CO2Me
13a R = OMe (94%)
13b R = CO2Me (85%)
15a R = CO2Me (68%)
Scheme 3 Reagents and conditions: i. xylene, reflux.
Synlett 2010, No. 16, 2411–2414 © Thieme Stuttgart · New York

LETTER
New 2-Benzazepino[4,5-a]naphthalene Derivatives
2413
MeO2C
MeO2C
N
N
MeO
MeO
23 (53%)
22 (51%)
iv
iii
MeO2C
CO2Me
CHO
R
MeO2C
N
Br
N
Me
i
ii
+
CHO
MeO
MeO
MeO
MeO
21a R = Me (22%)
21b R = Bn (88%)
2
19
20 (49 %)
v
MeO2C
CO2Me
Br
N
R
CHO
CHO
i
ii
MeO
MeO
MeO
24
25
26a R = Me (72%)
26b R = Bn (63%)
Scheme 5 Reagents and conditions: i. CH2=CHCO2Me, Pd(OAc)2, P(o-tolyl)3, Et3N, DMA,120 °C, 3 h (82%); ii. sarcosine (R = Me) or
N-benzylglycine (R = Bn), xylene, reflux; iii. 12, xylene, reflux; iv. 10, xylene, reflux; v. DDQ, CHCl3, 60 °C, 48 h (65%).
A possible mechanism for the pyrrole formation, drawn in conditions 29 could form an ammonium ylide 31, through
Scheme 6 was investigated by computational meth- a very strained intermediate 30, which possibly trans-
ods.24,25 After the expected 1,7-electrocyclisation of forms to cyclopropyl derivative 32 in a Stevens [1,2] rear-
azomethine ylide 27 followed by the 1,5-sigmatropic rear- rangement (route A).26–29 Alternative, 30 could undergo a
rangement of azepine intermediate 28 the formed 29 could ring-opening retro-Michael reaction, yielding a dihydro
be stabilised in two possible ways. The simple migration pyrrole derivative 33 (route B). Under the applied harsh
of one of the double bond resulting in the formation of the reaction conditions the formation of 21 is facilitated by
more stable azepine derivative 20 via a solvent-mediated the aromatisation of the pyrrole ring in both cases of 32
proton-transfer reaction, driven by the increasing olefinic- and 33 (Scheme 6).
ity value25 (33.3% → 54.7%) during the rearrangement.
In conclusion we have developed an easy protocol for the
On the other hand, competing with the previous route, 21 formation of new fused benzazepine and pyrrole deriva-
may form in two possible routes (A and B). Under basic tives from simple starting materials via the 8p-electro-
MeO2C
MeO2C
CO2Me
N
R
N
R
1. + H+
2. – H+
N+
[1,5]
[1,7]
20
19
139.3 kJ mol–1
36.0 kJ mol–1
–
(–32.3 kJ mol–1
)
MeO
MeO
MeO
(16.6 kJ mol–1
29
)
(0.0 kJ mol–1
)
(+143.0 kJ mol–1
)
(– 67.2
kJ mol–1
)
27
28
199.7 kJ mol–1
route B
MeO2C
MeO2C
–
R
N
route A
MeO
MeO2C
–
R
R
R
N+
N+
N
MeO2C
[1,2]
21
21
16.6 kJ mol–1
MeO
9.2 kJ mol–1
MeO
(–85.9 kJ mol–1
MeO
(242.2 kJ mol–1
)
(63.8 kJ mol–1
)
(203.9 kJ mol–1
)
(23.1 kJ mol–1
)
)
31
33
32
30
Scheme 6 The possible mechanisms for the formation 20 and 21. The computed Gibbs free energies (in kJ mol–1) of intermediates and tran-
sition states are indicated below the structures and the arrows, respectively.
Synlett 2010, No. 16, 2411–2414 © Thieme Stuttgart · New York

2414
T. Novak et al.
LETTER
(CH2), 57.8 (CH2), 55.4 (2 × CH3), 43.8 (CH3), 31.3 (CH2),
29.1 (CH2). IR (KBr): 2935, 1605, 1251 cm–1.
cyclisation process of nonstabilised azomethine ylides,
followed by a sigmatropic 1,5-hydrogen shift.
Compound 13b: 1H NMR (500 MHz, DMSO-d6): d = 8.06
(s, 1 H, H-12), 7.96 (d, 1 H, J = 8.0 Hz, H-14), 7.36 (d, 1 H,
J = 8.0 Hz, H-15), 6.84 (d, 1 H, J = 1.9 Hz, H-4), 6.76 (d, 1
H, J = 8.5 Hz, H-1), 6.70 (dd, 1 H, J = 1.9, 8.5 Hz, H-2), 4.45
(d, 1 H, J = 10.2 Hz, H-9), 4.32 (d, 1 H, J = 10.2 Hz, H-9),
4.31 (t, 1 H, J = 8.8 Hz, H-11a), 3.88 (s, 3 H, OMe), 3.75 (s,
3 H, OMe), 3.39 (d, 1 H, J = 15.0 Hz, H-7), 3.21 (d, 1 H, J =
15.0 Hz, H-7), 2.93 (m, 1 H, H-6), 2.89 (t, 1 H, J = 8.8 Hz,
H-11), 2.86 (m, 1 H, H-6), 2.70 (m, 2 H, H-5), 2.60 (t, 1 H,
J = 8.8 Hz, H-11). 13C NMR (125 MHz, DMSO-d6): d =
166.3 (q),158.8 (q), 143.4 (q), 140.0 (q), 139.0 (q), 138.3 (q),
132.9 (q), 131.8 (CH), 130.4 (CH), 128.9 (q), 128.7 (CH),
127.4 (q), 126.3 (CH), 114.2 (CH), 111.7 (CH), 70.9 (CH),
62.8 (CH2), 56.4 (CH2), 55.5 (CH3), 52.6 (CH3), 38.6 (CH2),
30.5 (CH2), 28.5 (CH2). IR (KBr): 2931, 1717, 1606, 1252,
1111 cm–1.
References and Notes
(1) Seven-membered Heterocyclic Rings and their Fused
Derivatives, In Comprehensive Heterocyclic Chemistry III,
Vol. 13; Newkome, G. R., Ed.; Elsevier Science: Oxford,
2008.
(2) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem.
2001, 5, 519.
(3) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products;
Padwa, A.; Pearson, W. H., Eds.; Wiley: New York, 2002.
(4) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45,
232.
(5) Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181.
(6) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
(7) Zecchi, G. Synthesis 1991, 181.
(8) Groundwater, P. W.; Nyerges, M. Advances in Heterocyclic
Chemistry, Vol. 73; Katritzky, A. R., Ed.; Academic Press:
New York, 1999, 97.
(9) Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2873.
(10) Tan, Y.; Hartmann, T.; Huch, V.; Dürr, H.; Valat, P.;
Wintgens, V.; Kossanyi, J. J. Org. Chem. 2001, 66, 1130.
(11) Friebolin, W.; Eberbach, W. Tetrahedron 2001, 57, 4349.
(12) Reinhard, R.; Glaser, M.; Neumann, R.; Maas, G. J. Org.
Chem. 1997, 62, 7744.
(13) Marx, K.; Eberbach, W. Tetrahedron 1997, 53, 14687.
(14) Knobloch, K.; Eberbach, W. Eur. J. Org. Chem. 2002, 2054.
(15) Ma, Y.; Weber, C.; Hartmann, T.; Dürr, H.; Krüger, C.;
Kossanyi, J. Synthesis 2001, 1812.
(16) Arany, A.; Bendell, D.; Groundwater, P. W.; Garnett, I.;
Nyerges, M. J. Chem. Soc., Perkin Trans. 1 1999, 2605.
(17) Nyerges, M.; Pintér, ; Virányi, A.; Bitter, I.; Tőke, L.
Tetrahedron Lett. 2005, 46, 377.
(18) Nyerges, M.; Virányi, A.; Tóth, J.; Blaskó, G.; Tőke, L.
Synthesis 2006, 1273.
(19) Tóth, J.; Dancsó, A.; Blaskó, G.; Tőke, L.; Groundwater,
P. W.; Nyerges, M. Tetrahedron 2006, 62, 5725.
(20) Nyerges, M.; Tóth, J.; Groundwater, P. W. Synlett 2008,
1269.
Compound 15a: 1H NMR (500 MHz, CDCl3): d = 8.14 (d, 1
H, J = 1.0 Hz, H-15), 7.96 (dd, 1 H, J = 8.0, 1.0 Hz, H-17),
7.36 (d, 1 H, J = 8.0 Hz, H-18), 7.20 (d, 1 H, J = 8.5 Hz, H-
13), 7.11 (m, 2 H, H-11 and H-12), 7.04 (d, 1 H, J = 8.5 Hz,
H-10), 6.87 (d, 1 H, J = 2.5 Hz, H-4), 6.81 (d, 1 H, J = 8.5
Hz, H-1), 6.68 (dd, 1 H, J = 2.5, 8.5 Hz, H-2), 3.90 (s, 3 H,
OMe), 3.88 (d, 1 H, J = 17.8 Hz, H-9), 3.83 (d, 1 H, J = 17.8
Hz, H-9), 3.74 (s, 3 H, OMe), 3.52 (t, 1 H, J = 13.0 Hz, H-
14), 3.19 (d, 1 H, J = 14.7 Hz, H-7), 3.15 (d, 1 H, J = 14.7
Hz, H-7), 3.15 (t, 1 H, J = 13.0 Hz, H-14a), 2.96 (d, 1 H, J =
13.0 Hz, H-14), 2.81 (m, 2 H, H-5), 2.66 (m, 1 H, H-6), 2.51
(m, 1 H, H-6). 13C NMR (125 MHz, CDCl3): d = 166.6 (q),
158.8 (q), 145.5 (q), 140.6 (q), 138.6 (q), 135.3 (q), 134.6
(q), 133.6 (q), 129.1 (CH), 128.8 (CH), 128.7 (q), 128.2
(CH), 127.0 (CH), 126.9 (q), 126.4 (2 × CH), 126.3 (CH),
126.1 (CH), 114.2 (CH), 111.6 (CH), 58.2 (CH), 57.1 (CH2),
56.7 (CH2), 55.6 (CH3), 52.7 (CH3), 32.7 (CH2), 32.6 (CH2),
28.8 (CH2). IR (KBr): 2928, 1717, 1606, 1251, 1109 cm–1.
Compound 21b: 1H NMR (500 MHz, CDCl3): d = 7.42 (d, 1
H, J = 8.4 Hz, H-9), 7.35 (t, 2 H, J = 8.4 Hz, Ph-3¢ and 5¢H),
7.29 (t, 1 H, J = 8.4 Hz, Ph-4¢H), 7.06 (d, 2 H, J = 8.4 Hz, Ph-
2¢ and 6¢H), 6.87 (d, 1 H, J = 3.6 Hz, H-6), 6.83 (dd, 1 H, J =
8.4, 3.6 Hz, H-8), 6.43 (s, 1 H, H-3), 5.19 (d, 1 H, J = 16.8
Hz, CH2Ph), 5.11 (d, 1 H, J = 16.8 Hz, CH2Ph), 4.31 (q, 1 H,
J = 7.6 Hz, CHCH3), 3.85 (s, 3 H, OMe), 3.51 (s, 3 H,
CO2Me), 2.86 (m, 2 H, H2-4), 2.68 (m, 2 H, H2-5), 1.50 (d,
3 H, J = 7.6 Hz, CHCH3). 13C NMR (125 MHz, CDCl3): d =
174.2 (q), 157.0 (q), 138.9 (q), 138.6 (q), 128.6 (2 × CH),
127.3 (2 × CH), 126.4 (CH), 125.8 (q), 125.2 (q), 124.9
(CH), 120.5 (q), 118.6 (q), 117.2 (CH), 114.6 (CH), 111.5
(CH), 55.3 (CH3), 52.1 (CH3), 50.7 (CH2), 36.9 (CH), 32.0
(CH2), 21.2 (CH2), 16.1 (CH3). IR (KBr): 2938, 1722, 1612,
1253, 1108 cm–1.
(21) Moleele, S. S.; Michael, J. P.; De Koning, C. B. Tetrahedron
2006, 62, 2831.
(22) Experimental Procedure for 1,7-Electrocyclisation
Reactions
The aldehyde (3 or 19, 1.0 mmol) was dissolved in xylene
(50 mL), and the corresponding amino acid (2.0 mmol) was
added. The reaction mixture was refluxed under Dean–Stark
conditions and further portions of the amino acid (1.0 mmol)
were added every 2 h until the starting aldehyde completely
disappeared (2–6 h) judged by TLC. All the solvent was
removed in vacuo, and the residue was purified by column
chromatography (eluent: heptane–EtOAc).
(23) Samanta, S.; Jana, R.; Ray, J. K. Tetrahedron Lett. 2009, 50,
6751.
(24) Computed at B3LYP/6-31G(d,p) level of theory by using
Gaussian 03 program. Frisch, M. J. Gaussian 03 6.0;
Gaussian Inc.: Pittsburg, 2003.
(25) Mucsi, Z.; Chass, G. A.; Viskolcz, B.; Csizmadia, I. G.
J. Phys. Chem. A 2009, 113, 7953.
(26) Stevens, T. S.; Creighton, E. M.; Gordon, A. B.; MacNicol,
M. J. Chem. Soc. 1928, 3193.
(27) Johnstone, R. A. W.; Stevens, T. S. J. Chem. Soc. 1955,
4487.
(28) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc.,
Perkin Trans. 1 1983, 1009.
(29) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62,
1043.
Selected Data of Representative Examples
Compound 6a: 1H NMR (400 MHz, CDCl3): d = 7.24 (d, 1
H, J = 8.0 Hz, H-13), 6.97 (d, 1 H, J = 8.4 Hz, H-1), 6.92 (d,
1 H, J = 2.0 Hz, H-10), 6.90 (dd, 1 H, J = 8.0, 2.0 Hz, H-12),
6.78 (d, 1 H, J = 2.8 Hz, H-4), 6.65 (d, 1 H, J = 8.4, 2.8 Hz,
H-2), 3.86 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 3.45 (br m, 1
H, H-5), 3.40 (br m, 1 H, H-5), 3.03 (br m, 1 H, H-7), 2.97
(br m, 2 H, H-7 and H-9), 2.76 (br m, 2 H, H-8 and H-9), 2.42
(br m, 1 H, H-8), 2.41 (s, 3 H, NMe). 13C NMR (100 MHz,
CDCl3): d = 158.3 (q), 138.5 (2 × q), 137.9 (q), 134.9 (q),
131.5 (q), 130.6 (q), 129.6 (CH), 127.7 (q), 127.1 (CH),
114.7 (CH), 113.8 (CH), 112.9 (CH), 110.8 (CH), 58.1
Synlett 2010, No. 16, 2411–2414 © Thieme Stuttgart · New York