2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.04.160

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing

Full text of DOI:10.1016/j.tetlet.2006.04.160

Tetrahedron Letters 47 (2006) 5825–5828
2-Allyl-N-benzyl substituted a-naphthylamines
as building blocks in heterocyclic synthesis. New and
efficient syntheses of benz[e]naphtho[1,2-b]azepine
and naphtho[1,2-b]azepine derivatives
a
a,
a
*
´
´
Andres Felipe Yepez, Alirio Palma, Elena Stashenko,
Ali Bahsasb and Juan M. Amaro-Luisb
aLaboratorio de Sı´ntesis Orga´nica, Centro de Investigacio´n en Biomole´culas, Escuela de Quı´mica,
Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia
bLaboratorio de RMN, Grupo de Productos Naturales, Departamento de Quı´mica, Universidad de los Andes, Me´rida 5101, Venezuela
Received 26 September 2005; revised 14 April 2006; accepted 28 April 2006
Abstract—A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a–d) and 2-aryl-4-hydroxy-2,3,4,5-tetra-
hydronaphtho[1,2-b]azepine derivatives (6a–d) have been synthesized from N-allyl-N-benzyl substituted a-naphthylamines (1a–d)
by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel–Crafts alkylation and intramolecular dipolar 1,3-cyclo-
addition nitrone-olefin reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
During the last 50 years, dibenz[b,e]azepine and tetra-
hydro-1-benzazepine rings have attracted wide interest
as several derivatives of these heterocyclic units have
been found to possess useful pharmacological activi-
ties.1–8 This fact has fuelled research, which focuses
mainly in the development of methodologies for the
preparation of many derivatives of these heterocyclic
systems.9–15
dipolar 1,3-cycloaddition reactions22 as key steps in
the construction of several nitrogen-containing hetero-
cycles. In a more recent communication,23 we described
an expedient synthetic route to dihydrodibenz[b,e]aze-
pine derivatives, from the readily available N-allyl-
N-benzylanilines, through aromatic amino-Claisen
rearrangement and Friedel–Crafts alkylation, as main
transformations.
Although a large number of synthetic routes to di-
benz[b,e]azepine and tetrahydro-1-benzazepine deriva-
tives are described in the literature, there is very few
information about benz[e]naphtho[1,2-b]azepines9 and
tetrahydronaphtho[1,2-b]azepines,16–18 which may, in
part, be due to lack of general methods for the synthesis
of such derivatives.
To broaden the scope of our approach, and the utility
of intramolecular Friedel–Crafts alkylation and 1,3-di-
polar cycloaddition processes as appropriate method-
ologies to dihydrobenz[e]naphtho[1,2-b]azepines and
tetrahydronaphtho[1,2-b]azepines, we have been testing
the chemistry of several 2-ally-N-benzyl-a-naphthyl-
amines, the common key intermediate in the synthesis
of these heterocyclic systems, in both acidic and oxida-
tive conditions. The results of these studies are reported
in this letter.
Lately, our attention has been focused on studying both
the intramolecular Friedel–Crafts alkylation19–21 and
Synthesis of the 13-acetyl-7,12-dihydrobenz[e]naphtho-
[1,2-b]azepines (4a–d) is depicted in Scheme 1. The
starting N-allyl-N-benzyl substituted a-naphthylamines
(1a–d) were prepared in good yields (70–85%) from the
corresponding secondary aromatic amines and an excess
Keywords: Benz[e]naphtho[1,2-b]azepines; Tetrahydronaphtho[1,2-b]-
azepines; Amino-Claisen rearrangement; Intramolecular Friedel–Cra-
fts alkylation; Intramolecular dipolar 1,3-cycloaddition.
*
Corresponding author. Fax: +57 76 349069/358210; e-mail:
apalma@uis.edu.co
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.160

5826
A. F. Ye´pez et al. / Tetrahedron Letters 47 (2006) 5825–5828
R1
R
R1
R
R1
R
ii
i
N
N
H
N
O
1a-d
2a-d
3a-d
R
R
H
H
R = H, Me, Cl, R1 = H,
R1 = Me, R = H
R1
R1
iii
N
N
+
O
O
trans-4a,d
cis-4a-d
Scheme 1. Reagents and conditions: (i) BF3ÆOEt2 (1 equiv), 118–120 °C, 1–2 h; (ii) Ac2O, reflux, 3 h; (iii) PPA, 90 °C, 2 h.
(2 equiv) of allyl bromide, as an alkylating agent, in boil-
ing acetone in the presence of K2CO3. The key inter-
mediates (2a–d) were obtained in 61–88% yields by
aromatic amino-Claisen rearrangement of N-allyl deriv-
atives (1a–d) in the presence of equimolar amounts of
BF3ÆOEt2.24 The reaction was completed within 1–2 h
at 118–120 °C.
perature (0–25 °C).26 The reactions were completed
within 45–50 h, and the isolated products were the
cycloadducts (5a–d) in 30–66% yields.
Oxidation of (2a–d) is assumed to proceed via initial
generation of reactive nitrones as unstable intermedi-
ates, which in the reaction conditions undergo intra-
molecular dipolar cycloaddition-[3+2] with the double
bond of the allylic moiety to provide the cycloadducts
In the next step, we chose to use the N-acetylated 2-allyl-
a-naphthylamines, instead of non-protected 2-allylnaph-
thylamines, to avoid the potential sulfonation of the
naphthalene ring. Additionally, polyphosphoric acid
(PPA) was used as promoter of the intramolecular Fri-
edel–Crafts alkylation. Thus, N-acetylation of inter-
mediates (2a–d) with excess of acetic anhydride
(4 equiv) at reflux gave the corresponding N-acetyl
derivatives (3a–d) in quantitative yields, which in turn
were reacted with PPA at 90 °C to give the desired prod-
ucts (4a–d) in 34–64% yields.
1
(5a–d). The H and 13C NMR spectra of these com-
pounds were assigned unambiguously using a combina-
tion of heteronuclear (HETCOR) spectra and chemical
shifts.27 The data derived from these spectra and
NOESY experiments were used to identify the isolated
cycloadducts as the exo isomer.
Finally, the reductive cleavage of the N–O bond of the
exo-cycloadducts (5a–d) was carried out by simply heat-
ing the substrates with zinc powder in glacial acetic
acid.28 The reactions are typically completed within 5–
10 h, and gave, after basic workup to remove the excess
of acetic acid and column chromatographic purification,
the desired tetrahydronaphtho[1,2-b]azepines (6a–d) in
64–78% yields.
1
The structures of (4a–d) were confirmed by H NMR
and 13C NMR spectroscopy in CDCl3 solution, and
were fully assigned on the basis of COSY and HMQC
1
as well as HMBC experiments.25 Thus, the H NMR
spectra of 4a (R = R1 = H) and 4d (R = H, R1 = CH3)
indicate that these derivatives are formed as a mixture
of two stereoisomers, in a 6:1 and 8:1 ratio, with cis
and trans configurations relative to the spatial orienta-
tion of the ethyl group at C-7 with respect to the acetyl
moiety at the nitrogen atom in the central ring. These
isomers could be separated by recrystallization from
heptane–ethyl acetate. The spectra displayed two set of
signals for each of the diastereotopic 12-HAHB and 7-
H protons, as well as for 7-ethyl protons. In contrast,
1
The H NMR spectra of these compounds29 showed a
single resonance for 2-H, 4-H and 3-CH2 protons at
3.99–3.96, 3.96–3.92 and 2.31–2.22 ppm, respectively,
and distinctive resonances for each of the diastereotopic
5-HAHB protons at 3.36–3.29 and 3.19–3.14 ppm. These
data indicate that reductive cleavage of the N–O bond of
the exo-cycloadducts was stereospecific with the forma-
tion of only one stereoisomer. The relative spatial orien-
tation of subtituents at positions C-2 and C-4 was
determined by means of NOESY experiments on the
protons of the azepine ring. These experiments revealed
that the target compounds contain both the 2-phenyl
(aryl) and 4-hydroxy substituents on the same side of
the molecule, consequently the isomers were identified
as the cis-2-aryl-4-hydroxy-2,3,4,5-tetrahydronaph-
tho[1,2-b]azepines.
1
the H NMR spectra of 4b (R = Me, R1 = H) and 4c
(R = Cl, R1 = H) displayed only one set of signals for
the same protons, indicating that they are formed as un-
ique stereoisomers. The NOESY spectra revealed the cis
isomer as the major product, as indicated by the obser-
vation of a cross-peak between the methyl protons of the
ethyl substituent at 7-position with the methyl protons
of acetyl group at nitrogen atom.
In summary, this contribution represents an extension of
our studies dealing with the synthesis of heterocyclic
compounds having the dibenz[b,e]azepine and tetra-
hydro-1-benz-azepine cores in their structure. Further
studies will be carried out, in the near future, to test their
potential biological activities.
Synthesis of 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaph-
tho[1,2-b]azepines (6a–d) is depicted in Scheme 2. The
key intermediates (2a–d) were oxidized with hydrogen
peroxide (H2O2) in the presence of catalytic amounts
of sodium tungstate in acetone/H2O (9:1), at low tem-

A. F. Ye´pez et al. / Tetrahedron Letters 47 (2006) 5825–5828
5827
O
N
+
R1
R
R1
R
i
N
N
H
O-
R1
2a-d
5a-d
non-isolated nitrones
R
OH
ii
N
H
R1
6a-d
R
Scheme 2. Reagents and conditions: (i) H2O2/Na2WO4, acetone/H2O, 0–25 °C, 45–50 h; (ii) Zn/AcOH, 80–82 °C, 5–10 h.
18. He, Y.; Chang, H. M.; Lau, Y. K.; Cui, Y. X.; Wang, R.
J.; Mak, T. C. W.; Wong, H. N. C.; Lee, C. M. J. Chem.
Soc., Perkin Trans. 1 1990, 3359–3361.
19. Palma, A.; Silva, A. J.; Carrillo, C.; Kouznetsov, V.;
Stashenko, E.; Bahsas, A.; Amaro-Luis, J. Tetrahedron
2002, 58, 8719–8727.
Acknowledgements
We thank Colciencias for financial support (Grant No.
1102-05-13567).
20. Kouznetsov, V.; Palma, A.; Rozo, W.; Stashenko, E.;
Bahsas, A.; Amaro-Luis, J. Tetrahedron 2003, 59, 419–425.
21. Palma, A.; Jaimes-Barajas, J.; Kouznetsov, V. V.; Stash-
enko, E.; Bahsas, A.; Amaro-Luis, J. Lett. Org. Chem.
2004, 1, 261–263.
22. Varlamov, A.; Kouznetsov, V.; Zubkov, F.; Chernyshev,
A.; Shurupova, O.; Vargas, L.; Palma, A.; Rivero, J.;
Rosas, A. Synthesis 2002, 771–783.
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25. NMR data for cis isomer 4a: 1H NMR (400 MHz, CDCl3,
d): 1.15 (3H, t, J = 7.3, –CH2–CH3), 1.83 (3H, s,
CH3AC@O), 2.40 (2H, m, 7-CH2–), 4.28 (1H, d,
J = 17.2, 12-HB), 4.56 (1H, t, J = 8.0, 7-H), 6.33 (1H, d,
J = 17.2, 12-HA), 6.97 (1H, d, J = 7, 11-H), 7.05 (1H, t,
J = 7.0, 10-H), 7.10 (1H, t, J = 7.0, 9-H), 7.26 (1H, d,
J = 7, 8-H), 7.42 (1H, d, J = 8.4, 6-H), 7.47 (1H, td,
J = 8.0, 1.2, 3-H), 7.56 (1H, td, J = 8.0, 2.0, 2-H), 7.80
(1H, d, J = 8.4, 5-H), 7.84 (1H, d, J = 8.0, 1-H), 7.86 (1H,
d, J = 8.0, 4-H). 13C NMR (100 MHz, CDCl3, d): 12.6
(–CH2–CH3), 22.6 (CH3AC@O), 20.7 (7-CH2–), 42.6 (7-
C), 47.7 (12-C), 121.9 (1-C), 121.9 (6-C), 123.9 (8-C), 125.8
(3-C), 126.3 (10-C), 126.4 (9-C), 127.5 (2-C), 128.3 (11-C),
128.5 (5-C), 128.6 (4-C), 130.5 (4b-C), 133.0 (4a-C), 134.4
(6a-C), 134.8 (11a-C), 140.2 (7a-C), 141.3 (6b-C), 171.2
(C@O). NMR data for trans isomer 4a: 1H NMR
(400 MHz, CDCl3, d): 0.93 (3H, t, J = 7.2, –CH2–CH3),
1.83 (3H, s, CH3AC@O), 2.01 (2H, m, 7-CH2–), 3.83 (1H,
t, J = 8.0, 7-H), 4.18 (1H, d, J = 16.8, 12-HB), 6.20 (1H, d,
J = 16.8, 12-HA), 7.14 (1H, d, J = 6.8, 11-H), 7.16 (1H, t,
J = 7.0, 10-H), 7.18 (1H, t, J = 7.0, 9-H), 7.21 (1H, d,
J = 6.8, 8-H), 7.42 (1H, d, J = 8.4, 6-H), 7.51 (1H, td,
J = 8.0, 1.3, 3-H), 7.59 (1H, td, J = 8.4, 1.3, 2-H), 7.80
(1H, d, J = 8.4, 5-H), 7.84 (1H, d, J = 8.4, 1-H), 7.89 (1H,
d, J = 8.0, 4-H). 13C NMR (100 MHz, CDCl3, d): 13.2
(–CH2–CH3), 21.5 (CH3AC@O), 30.7 (7-CH2–), 46.7
(12-C), 55.8 (7-C), 121.2 (1-C), 125.6 (3-C), 126.1 (10-C),
126.3 (9-C), 127.2 (2-C), 127.8 (5-C), 128.1 (4-C), 128.2
(11-C), 128.7 (6-C), 129.7 (4b-C), 130.9 (8-C), 133.3
(4a-C), 134.8 (11a-C), 135.6 (6a-C), 137.9 (7a-C), 138.0
(6b-C), 170.6 (C@O).
4. Kondo, K.; Ogawa, H.; Shinohara, T.; Kurimura, M.;
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27. NMR data for cycloadduct 5a: 1H NMR (400 MHz,
CDCl3, d): 2.63 (1H, dd, J = 16.8, 2.0, 5-HB), 2.68 (2H, m,
17. El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am.
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5828
A. F. Ye´pez et al. / Tetrahedron Letters 47 (2006) 5825–5828
3-HAHB), 3.59 (1H, dd, J = 16.8, 5.6, 5-HA), 4.77 (1H, dd,
29. NMR data for compound 6a: 1H NMR (400 MHz,
CDCl3, d): 2.22 (2H, m, 3-HAHB), 3.14 (1H, dd,
J = 13.2, 1.6, 5-HB), 3.29 (1H, dd, J = 13.2, 10.0, 5-HA),
3.92 (1H, qd, J = 9.8, 2.2, 4-H), 3.99 (1H, dd, J = 13.4,
7.2, 2-H), 4.37 (1H, br s, O–H), 7.30 (1H, d, J = 8.4, 6-H),
7.37 (1H, m, 40-H), 7.39 (2H, m, 30-H), 7.41 (1H, m, 9-H),
7.41 (1H, m, 10-H), 7.41 (2H, m, 20-H), 7.46 (1H, dd,
J = 8.4, 1.6, 7-H), 7.59 (1H, d, J = 8.0, 11-H), 7.79 (1H,
dd, J = 7.6, 1.6, 8-H). 13C NMR (100 MHz, CDCl3, d):
44.5 (5-C), 47.4 (3-C), 61.1 (2-C), 69.9 (4-C), 119.9 (11-C),
121.6 (7-C), 124.2 (5a-C), 125.2 (10-C), 125.7 (9-C), 126.3
(11a-C), 126.6 (20-C), 127.9 (40-C), 128.7 (8-C), 129.1 (30-
C), 129.9 (6-C), 133.4 (7a-C), 144.1 (10-C), 144.6 (5b-C).
J = 8.0, 3.2, 2-H), 5.09 (1H, td, J = 5.2, 2.0, 4-H), 7.23
(1H, d, J = 8.4, 6-H), 7.36 (1H, t, J = 7.6, 40-H), 7.45 (2H,
t, J = 7.6, 30-H), 7.47 (1H, m, 9-H), 7.47 (1H, m, 10-H),
7.60 (2H, d, J = 7.6, 20-H), 7.65 (1H, d, J = 8.4, 7-H), 7.81
(1H, dd, J = 9.2, 3.4, 8-H), 8.26 (1H, dd, J = 9.6, 3.6, 11-
H). 13C NMR (100 MHz, CDCl3, d): 35.2 (5-C), 43.0 (3-
C), 74.4 (2-C), 75.4 (4-C), 120.9 (5a-C), 122.0 (11-C), 125.4
(7-C), 125.7 (9-C), 125.7 (10-C), 126.4 (20-C), 127.0 (40-C),
127.3 (6-C), 127.5 (11a-C), 127.7 (8-C), 128.6 (30-C), 132.5
(7a-C), 143.8 (10-C), 145.5 (5b-C).
28. Hoffmann, W. R.; Eichler, G.; Endesfelder, A. Liebigs
Ann. Chem. 1983, 2000–2007.