A synthesis of highly functionalized pyrido[2,1-d][1,2,5]triazepines

Article abstract of DOI:10.1055/s-0031-1290354

A synthesis of functionalized 1-(alkylamino)-4-aryl-2,3-dihydro-2- phenylpyrido[2,1-d][1,2,5]triazepines from the sequential reaction between pyridinium ylides, alkyl isocyanides, and 1-[chloro(aryl)methylene]-2- phenylhydrazines in CH₂Cl₂

Full text of DOI:10.1055/s-0031-1290354

LETTER
557
A Synthesis of Highly Functionalized Pyrido[2,1-d][1,2,5]triazepines
A
Synth
s
H
ig
s
hly Func
a
tionalize
d
Pyrido[
Y
2,1-
d
][1,2,5]triaze
a
pines vari,* Gholamhossein Khalili, Fatemeh Sadeghizadeh
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: yavarisa@modares.ac.ir
Received 19 October 2011
Since no asymmetric center is present in 4, this heterotop-
icity may be attributed to atropisomerism resulted from
slow rotation around the C–CO2Et single bond in these
compounds. Such a rotation is hindered due to the pres-
ence of peri interaction between CO2Et group and the C–
H bond of the pyridine moiety (Figure 1), which is expect-
ed to be more congested compared to similar interaction
in naphthalene derivatives such as 5.16 Hindered com-
pounds such as 5 adopt a twisted conformation (i.e., the
RCO plane is not coplanar with the naphthalene ring) and
may thus exist as a pair of conformational enantiomers.
When R is not a prochiral group, the process will be de-
tectable only in the presence of a chiral solvating agent.
Thus, an enantiomerization barrier of about 8 kcal/mol
Abstract: A synthesis of functionalized 1-(alkylamino)-4-aryl-2,3-
dihydro-2-phenylpyrido[2,1-d][1,2,5]triazepines from the sequen-
tial reaction between pyridinium ylides, alkyl isocyanides, and 1-
[chloro(aryl)methylene]-2-phenylhydrazines in CH2Cl2, in good
yields, is described.
Keywords: pyrido[2,1-d][1,2,5]triazepine, hydrazonoyl chloride,
alkyl isocyanide, pyridinium ylide, MCR
Heterocyclic compounds have a special place among nat-
ural products and synthetic compounds. More specifical-
ly, nitrogen heterocycles are abundant in nature existing
in many natural products such as vitamins, hormones, an-
tibiotics, and alkaloids.1 As useful reaction intermediates,
the heterocyclic compounds have found widespread ap-
plication in organic synhhesis,2–4 and some of them are ac-
tive drugs with important application in pharmacology.5–7
1
has been reported for 5.16 The H NMR spectra of com-
pounds 4a and 4f in 1,2-dichlorobenzene did not show no-
Table 1 Synthesis of Functionalized 1-(Alkylamino)-4-aryl-2,3-di-
hydro-2-phenylpyrido[2,1-d][1,2,5]triazepines 4
In particular, seven-membered rings exhibit important
bioactivities.8 For this reason, different derivatives of tri-
azepines have attracted a great deal of attention as starting
materials in the synthesis of fused heterocyclic systems
with potential pharmacological activities.9–11 Fused het-
erocyclic ring systems are important scaffolds in medici-
nal chemistry. Fused triazepines with a bridgehead
nitrogen atom in the molecule exhibit interesting biologi-
cal properties.12–14
R1
R2HN
Ph
NH
Ar
R1
Cl
N
+
N
Et3N
H
–
C
R2
+
+
N
+
N
N
Ph
Ar
N
Br–
CO2Et
EtO2C
1
2
3
4
Entry 1–4 R1
R2
Ar
Ph
Yield of4
(%)
Herein, we report a one-pot synthesis of functionalized 1-
(alkylamino)-4-aryl-2,3-dihydro-2-phenylpyrido[2,1-d]-
[1,2,5]triazepines 4 from the reaction between ethoxycar-
bonylpyridinium bromides 1, alkyl isocyanides 2, and 1-
[chloro(aryl)methylene]-2-phenylhydrazines 3 in CH2Cl2,
in good yields (Table 1).15
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
H
t-Bu
t-Bu
t-Bu
77
72
p-tolyl
4-ClC6H4 76
p-tolyl 81
4-ClC6H4 75
Me t-Bu
Me t-Bu
The structures of compounds 4a–h were deduced from
their IR, 1H NMR, and 13C NMR spectra. For example, the
1H NMR spectrum of 4a exhibited three singlets for the
tert-butyl (d = 1.21 ppm) and NH (d = 9.59 and 10.32
ppm) protons, along with multiplets for the aryl groups.
H
H
H
1,1,3,3-tetramethylbutyl Ph
75
73
g
h
1,1,3,3-tetramethylbutyl p-tolyl
1
The H-decoupled 13C NMR spectrum of 4a showed 21
distinct resonances that confirms the proposed structure.
The NMR spectra of 4b–h are similar to those for 4a ex-
cept for the aryl moieties, which exhibited characteristic
resonances in appropriate regions of the spectra.
1,1,3,3-tetramethylbutyl 4-ClC6H4 80
OEt
O
R1
H
O
Ar
H
The CH2O protons of the ester moieties in 4a–h, as well
as the Me2C and CH2 protons in 4f–h, are diastereotopic.
N
NH
Ph
R1
N
R2HN
SYNLETT 2012, 23, 557–558
x
x
.
x
x
.
2
0
1
2
5
4
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1290354; Art ID: D56311ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

558
I. Yavari et al.
LETTER
R2
R2
+
N
+
N
Cl–
N
Ph
C
R1
C
R1
R1
HN
Et3N
3
2
N
1
N+
_
N
HBr
–
–
Ar
CO2Et
EtO2C
CO2Et
8
7
6
R2HN
R2N
Ph
Ph
1
imine–enamine
tautomerism
R1
R
N
N
[1,3]-H-shift
4
N
N
N
N
– HCl
Ar
Ar
EtO2C
EtO2C
9
10
Scheme 1
(7) Katritzky, A. R.; Fan, W.-Q.; Greenhill, J. V. J. Org. Chem.
1991, 56, 1299.
(8) Gupta, M.; Paul, S.; Gupta, R. Eur. J. Med. Chem. 2011, 631.
(9) Deam, M. L. Synthesis 1981, 322.
(10) Reddy, G. S.; Kumar, P. A.; Anand, R. V.; Mukkanti, K.;
Reddy, P. P. Synlett 2009, 1463.
(11) Demydchuk, B. A.; Brovarets, V. S.; Chernega, A. N.;
Rusanov, E. B.; Drach, B. S. Synthesis 2006, 2323.
(12) Birkett, P. R.; Chapleo, C. B.; Mackenzie, G. Synthesis
1991, 822.
ticeable broadening, even at 110 °C, the highest
temperature investigated. Thus, the conformational race-
mization barriers for compounds 4 are expected to be
higher than 16 kcal/mol.
A mechanistic rationalization for the reaction is given in
Scheme 1. The initial event is the formation of nitrogen
ylide 6, which is attacked by alkyl isocyanide to afford the
diionic intermediate 7. This intermediate undergoes a nu-
cleophilic substitution reaction with hydrazonoyl chloride
3 to generate 8, which affords 9 by intramoleculare cy-
clization reaction. Intermediate 9 is converted into 4 by
imine–enamine tautomerism and [1,3]-H shift.
(13) Raboisson, P.; Norberg, B.; Casimir, J. R.; Bourguignon,
J.-J. Synlett 2002, 519.
(14) Zaleska, B.; Trzewik, B.; Grochowski, J.; Serda, P. Synthesis
2003, 2559.
(15) General Procedure for the Synthesis of Compound 4
To a suspension of 1 (1 mmol) and isocyanide 2 (1 mmol) in
CH2Cl2 (4 mL) was added Et3N (2 mmol) at r.t. After stirring
for 20 h at r.t., hydrazonoyl chloride 3 (1 mmol) was added
to the solution and stirred for 10 h. Subsequently, the solvent
was evaporated, and the crude product was washed with
EtOAc. The solid mixture was dissolved in CH2Cl2 (5 mL)
and washed with two 3 mL portions of H2O, then dried
(Na2SO4), and evaporated under reduced pressure.
Selected Spectroscopic Data for Compound 4a
Pale yellow powder, mp 148–150 °C, yield 0.34 g, 90%. IR
(KBr): nmax = 3419 (NH), 1658, 1548, 1442 cm–1. 1H NMR
(500 MHz, CDCl3): d = 1.08 (3 H, t, 3J = 7.1 Hz, Me), 1.21
(9 H, s, CMe3), 4.14–4.15 (2 H, m, CH2O), 6.91 (1 H, t,
3J = 7.4 Hz, CH), 7.25–7.30 (4 H, m, 4 CH), 7.35–7.38 (2 H,
m, 2 CH), 7.60–7.62 (2 H, d, 3J = 7.7 Hz, 2 CH), 7.79 (1 H,
t, 3J = 6.4 Hz, CH), 7.93 (1 H, t, 3J = 6.4 Hz, CH), 8.48 (1 H,
t, 3J = 8.1 Hz, CH), 8.73 (1 H, d, 3J = 6.4 Hz, CH), 8.85 (1 H,
d, 3J = 6.4 Hz, CH), 9.59 (1 H, br s, NH), 10.32 (1 H, br s,
NH) ppm. 13C NMR (125.7 MHz, CDCl3): d = 13.9 (Me),
29.9 (CMe3), 54.7 (C), 60.3 (CH2O), 105.4 (C), 113.8 (2
CH), 121.0 (2 CH), 124.9 (C), 126.9 (CH), 127.1 (CH),
128.5 (CH), 128.7 (2 CH), 128.9 (2 CH), 130.9 (C), 135.0
(C), 143.8 (CH), 147.2 (CH), 147.5 (C), 148.3 (CH), 153.2
(C), 164.2 (C=O) ppm. MS: m/z (%) = 442 (4) [M+], 411
(75), 355 (77), 290 (28), 77 (100). Anal. Calcd (%) for
C27H30N4O2 (442.24): C, 73.28; H, 6.83; N, 12.66. Found
(%): C, 72.84; H, 6.51; N, 12.92.
In summary, we report a tandem transformation involving
ethoxycarbonylpyridinium bromides, hydrazonoyl chlo-
rides, and alkyl isocyanides, which affords a new route to
the synthesis of functionalized ethyl 1-(alkylamino)-4-
aryl-2,3-dihydro-2-phenylpyrido[2,1-d][1,2,5]triazepine-
5-carboxylates. Due to the presence of transformable
functionalities in these products they are potentially valu-
able for further synthetic manipulations.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) Dewick, P. M. Medicinal Natural Products, 2nd ed.; John
Wiley and Sons: Chichester, 2002.
(2) Tietze, L. F.; Brasche, C.; Gericke, K. M. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(3) Serratosa, F.; Xicart, J. Organic Chemistry in Action: The
Design of Organic Synthesis; Elsevier: New York, 1996.
(4) Smith, W. A.; Bochkov, A. F.; Caple, R. Organic Synthesis:
The Science behind the Art; RSC: Cambridge / U.K., 1998.
(5) Basile, A. S.; Gammal, S. H.; Jones, E. A.; Skolnick, P.
J. Neurochem. 1989, 53, 1057.
(6) Bellantuono, C.; Reggi, G.; Tognoni, G.; Grattini, S. Drugs
1980, 19, 195.
(16) Gasparrini, F.; Lunnazi, L.; Misiti, D.; Villani, C. Acc.
Chem. Res. 1995, 28, 163.
Synlett 2012, 23, 557–558
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
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