Photochemical synthesis of 6-substituted 12-oxo-6,12-dihydroazepino[2,1-b]quinazolines

Article abstract of DOI:10.1007/s10593-016-1951-2

[Figure not available: see fulltext.] A method for the synthesis of 6-substituted 12-oxo-6,12-dihydroazepino[2,1-b]quinazolines via a photoinitiated reaction of orthosubstituted aryl azides with sodium 2-aminobenzoate is proposed. Stepwise annulation of t

Full text of DOI:10.1007/s10593-016-1951-2

DOI 10.1007/s10593-016-1951-2
Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
Photochemical synthesis of 6-substituted
12-oxo-6,12-dihydroazepino[2,1-b]quinazolines
Andrei V. Budruev1*, Daria Yu. Dzhons1, Vladimir I. Faerman2,
Georgy K. Fukin3, Andrey S. Shavyrin3
1
Lobachevsky State University of Nizhny Novgorod, 23/5 Gagarina Ave., Nizhny Novgorod 603950, Russia;
е-mail: budruev@gmail.com
2
Chemistry Research Institute of Lobachevsky State University of Nizhny Novgorod, 23/5 Gagarina Ave.,
Nizhny Novgorod 603950, Russia; е-mail: nauka@ichem.unn.ru
3 G. A. Razuvaev Institute of Organometallic Chemistry of Russian Academy of Sciences, 49 Tropinina St., Nizhny Novgorod 603950,
Russia; е-mail: gera@iomc.ras.ru; andrey@iomc.ras.ru
Submitted May 20, 2016
Accepted after revision June 21, 2016
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(9), 694–699
A method for the synthesis of 6-substituted 12-oxo-6,12-dihydroazepino[2,1-b]quinazolines via a photoinitiated reaction of ortho-
substituted aryl azides with sodium 2-aminobenzoate is proposed. Stepwise annulation of the quinazoline system to the azepine ring
occurs during nucleophilic addition of an amine to a cyclic keteneimine generated by photolysis of an aryl azide and subsequent
intramolecular condensation of the intermediate product.
Keywords: aryl azides, 3Н-azepines, azepino[2,1-b]quinazoline, cyclic keteneimine, 1,2-didehydroazepine, quinazolinones,
photoinitiated cyclization.
Elucidation of the structure of 2-substituted 3H-aze-
pines, formed during thermolysis1 as well as photolysis2 of
phenyl azide in the presence of amines or other
nucleophiles, has initiated a series of studies aimed at
clarifying the nature and possible rearrangements of
intermediates of this reaction. At present, it is known with
the assistance of spectroscopic and quantum-chemical
methods, spin trapping technique, and sensitized photolysis
that the expansion of the benzene ring occurs in the singlet
excited state with sequential formation of an aryl nitrene A,
benzazirine B, and 1,2-didehydroazepine C (cyclic ketene-
imine)3,4 (Scheme 1). Reaction of these intermediates with
the substrate leads to the formation of a broad spectrum of
photolysis products.
the electrophilic center C-2 of the keteneimine moiety of
intermediate C 1H-azepine is produced, which rearranges
to a stable 2-substituted 3H-azepine (Scheme 1). Further
development of this synthetic approach was the work of
Lamara and Smalley5 devoted to photoinitiated cyclization
of an in situ generated intermediate C with a substituted
2-aminobenzoic acid to form the corresponding 12-oxo-
6,12-dihydroazepino[2,1-b]quinazoline. However, the
technique proposed by the authors is limited to substituted
2-azidobenzoic acids and proceeds with decarboxylation of
the ortho-carboxyl group that limits the number of
accessible azepino[2,1-b]quinazolines. Therefore, the aim
of our study was altering the method of synthesis of
azepino[2,1-b]quinazolines to expand the range of aryl
azides that participates in this photoinitiated cyclization
reaction, as well as investigating the generality of this
reaction.
From the standpoint of synthetic organic photochemistry,
the most interesting intermediate of the photolysis of aryl
azides 1 is keteneimine C. Upon nucleophilic addition at
Scheme 1
0009-3122/16/52(9)-0694©2016 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
Scheme 2
Table 1. Reaction conditions and yields of compounds 3
Photolysis/
cyclization
time
Photolysis/
cyclization
time
Azide
R1
R2
Product (yield, %)
Azide
R1
R2
Product (yield, %)
C(O)OMe
C(O)OMe
C(O)OEt
Н
Br
Н
3 h / 3 min
3 h / 10 h
3 h / 3 h
3а (30)
3b (30)
3c (10)
CN
Н
Н
3 h / 10 h
3 h / 10 h
3 h / 10 h
3 h / 10 h
3 h / 10 h
3f (7)
3g (–*)
3h (–*)
3i (–*)
3j (–*)
1a
1b
1c
1d
1e
1f
1g
1h
1i
OC(O)Me
C(O)ONa
C(O)OH
C(O)OH
Н
C(O)Oi-Pr
C(O)On-Bu
Н
3 h / 10 h
3 h / 10 h
3d (8)
Br
Н
Н
3e (traces)
1j
* Not detected.
In the method proposed by us, 2-aminobenzoic acid is
replaced by sodium 2-aminobenzoate (2). Such replace-
ment is needed due to the ability of amino acids to form
intramolecular salts which leads to loss of activity of the
amino group as a nucleophilic center. Amino acid salts have
a free amino group, and the nucleophile has maximum activity.
Methyl 2-azidobenzoate (1a) and the amine 2 were
selected as the model reactant system for testing our
hypothesis and optimizing synthesis conditions (Scheme 2).
According to HPLC data, photolysis of these compounds
proceeds with the formation of a product which was
identified on the basis of literature data as sodium 2-{[3-
(methoxycarbonyl)-3H-azepin-2-yl]amino}benzoate (4a). It
has been found that acidification of the reaction mixture
results in the formation of product 3a within 2–3 min.
Without the addition of acid the reaction takes 8–10 h at a
temperature of about 5°C to complete. Product 3a was
isolated by preparative column chromatography on silica
gel using CCl4–CH2Cl2 as the eluent. Its structure was
proved by X-ray structural analysis (Fig. 1) and confirmed
maximum yields of compound 3a are obtained by photolysis
in dioxane–water, 1:1 mixture, with a threefold molar excess
of amine 2.
Intermediate C reacts with sodium 2-aminobenzoate (2)
in an equimolar ratio. The need for an excess of amine 2 is
dictated by the short lifetime of intermediate C and the
bimolecular nature of its reaction. In order to increase the
probability of the reaction of intermediate C with amine 2,
concentration of the latter was increased.
The method of synthesis of heterocycle 3a was extended
to a group of ortho-substituted aryl azides 1 (Table 1).
When subjecting azides 1 to photolysis in the presence of
amines, it was found that the yields of azepino[2,1-b]-
quinazolines 3a–f were low, and the reaction was
accompanied by the formation of resinous photolysis
products that apparently arise from low photochemical
stability of the resulting intermediate 4. The second stage
of the reaction proceeds smoothly. However, whereas the
formation of compounds 3a takes 2–3 min and 3 h for
heterocycle 3c, maintaining the photolytic mixture in a
weakly acidic medium for 10 h is required to produce
compounds 3b,d–f, which is apparently due to decreased
nucleophilicity of the nitrogen atom of the azepine ring.
Photolysis of azido acids 1i,j as well as sodium
2-azidobenzoate (1h) and 2-azidophenyl acetate (1g) in the
presence of amine 2 does not lead to the formation of
products 3g–j. When amine 2 is replaced by 2-amino-
benzoic acid, i.e., under conditions similar to those
described,5 products 3g–j do not form as well. In this case,
a UV radiation source different from ours is used.
However, replacing the low pressure mercury arc lamp
BUF-15 (λmax 254 nm) by high pressure mercury arc lamp
DRK-120 (λmax 365 nm) as the irradiation source still did
not lead to the formation of products 3.
1
by mass spectrometry, H and 13C NMR spectroscopy, as
well as ge-COSY, ge-HSQC, ge-HMBC two-dimensional
experiments. The obtained spectral data confirm the
structure of azepino[2,1-b]quinazoline 3a. It was revealed
by the use of X-ray structural analysis that the photo-
initiated cyclization leads to the formation of a fully
unsaturated quinazoline ring of compound 3a.
It was found in the course of optimization of the reaction
conditions that replacement of the dioxane–water solvent
by ethanol does not alter the route of the reaction. Neither
2-ethoxy-3H-azepine-3-carboxylic acid methyl ester nor
2-oxo-2,3-dihydro-1H-azepine-3-carboxylic acid methyl
ester, products of nucleophilic addition of EtOH or water to
intermediate C, are formed during the photolysis. The
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Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
addition mechanism to form an intermediate product. Then,
annulation of the quinazoline ring to azepine ring takes
place upon intramolecular condensation of the intermediate
product. In contrast to the previously proposed photo-
chemical method, heterocyclization occurs without the loss
of the ortho-substituent of the aryl azide, thus greatly
expanding the spectrum of accessible 12-oxo-6,12-dihydro-
azepino[2,1-b]quinazolines.
Experimental
IR spectra were registered on a Shimadzu IR Prestige-21
spectrometer with the sample as a thin film or oil suspen-
sion. 1H and 13C NMR spectra (400 and 100 MHz, respectively)
were acquired on Varian 400 MR (compounds 1a–j) or
Bruker Avance III (compounds 3a–d,f) spectrometers in
CDCl3, with TMS as internal standard. Chemical shifts were
assigned relative to the signal of the solvent (7.26 ppm for
1H nuclei and 77.2 ppm for 13C nuclei) or relative to TMS.
Figure 1. Molecular structure of compound 3a with atoms
represented as thermal vibration ellipsoids of 50% probability.
Two-dimensional
homonuclear
correlation
COSY
experiments were registered using gradient pulses
(cosygpmfqf),8 heteronuclear correlation HSQC experi-
ments were registered using gradient pulses (hsqcetgp),
whereas heteronuclear correlation HMBC experiments
used gradient pulses optimized for small coupling constants
(hmbcgplpndqf). Mass spectra were recorded on a Thermo
Electron DSQ II mass spectrometer, EI ionization (70 eV),
direct sample injection. Monitoring of the conversion of the
azide and the buildup of the reaction products was
performed by HPLC on a Shimadzu LC-20AD apparatus
with a SPD-M20A detector, 20-μ loop (column: Discovery
C-18, 5 μ, d 3 mm, l 25 cm; elution gradient: ethanol (10%) –
2% phosphoric acid in water (10%) – water (80%) with a
linear decrease of the latter two components to 0% at 20 min,
then elution with ethanol to 45 min, flow 0.15 ml/min).
Photochemical reactions were carried out in a quartz
photoreactor with external irradiation by two low pressure
mercury arc lamps BUF-15 (7 mW/cm2 at 254 nm
wavelength), equipped with an aluminum reflector. A
fraction of the light source radiation is absorbed by the
reaction mixture. Solutions of aryl azides 1a–j and amine 2
in a mixture of 1,4-dioxane–water, 1:1, were irradiated
with vigorous stirring until complete decomposition of the
azide without the access of air oxygen at room temperature.
The optimum irradiation time with azide concentration of
5 mmol/l is 3 h.
Based on the literature data3-5 and our experimental
work, the proposed mechanism for the formation of
compounds 3 is shown in Scheme 2. Reaction routes of the
singlet nitrene A, which do not lead to the formation of
compounds 3, are not given in this scheme.
During the photoinitiation stage of the reaction, aryl
azide 1 decomposes with elimination of nitrogen and
formation of the aryl nitrene A in the singlet excited state.6
Then aryl nitrene A rearranges into benzazirine B and
further into a cyclic keteneimine C via sequential 4π-electro-
cyclic ring closure (4π-ERC) and 6π-electrocyclic ring
opening (6π-ERO). Then, 1H-azepine (1H) forms by
nucleophilic 1,2-addition of amine 2 to the intermediate C.
Of the four possible tautomeric forms this azepine form is
the least stable. After three consecutive sigmatropic [1,5]-
hydrogen shifts it tautomerizes into the most stable form,
azepine 3H (Schemes 2, 3).7
Lastly, during the dark stage of the reaction upon
acidification of the solution and conversion of the carboxy-
late anion of the intermediate 4 to the free carboxylic acid,
the amino group of the azepine ring attacks the carbon
atom of the carboxyl group according to 6-exo-trig
cyclization mechanism with elimination of a water
molecule and formation of azepino[2,1-b]quinazoline 3.
To conclude, the formation of 6-substituted 12-oxo-6,12-
dihydroazepino[2,1-b]quinazolines upon photolysis of
ortho-substituted aryl azides with sodium 2-aminobenzoate
was found to occur in two successive independent steps. In
the first step, a cyclic keteneimine generated in situ reacts
with the amino group of the substrate by nucleophilic
All solvents were purified before use according to
established routines.9
Synthesis of esters of 2-azidobenzoic acids 1a–f (General
method). Method I. Synthesis was performed following a
modified literature procedure.10 The corresponding
Scheme 3
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Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
2-azidobenzoic acid (15 mmol) was added to a mixture of
sept, J = 6.2, CH(CH3)2); 1.36 (6H, d, J = 6.3, CH(CH3)2).
13C NMR spectrum, δ, ppm: 165.4 (C=O); 144.6, 131.4,
127.6, 118.8 (C Ar); 68.7 (O–CH); 22.0 (CH(CH3)2).
Found, %: 58.33; H 5.48. C10H11N3O2. Calculated, %:
58.53; H 5.40.
SOCl2 (10 ml) and benzene (25 ml) with 2 drops of DMF,
and the mixture heated under reflux for 4 h. Then, the
excess solvent and SOCl2 were distilled off. The residue was
chilled in an ice bath to 0–5°С, dry methanol (10 ml) added,
and the mixture stirred for 1 h. After the completion of the
reaction, the excess methanol was evaporated under
reduced pressure. The residue was dissolved in CHCl3, the
solution filtered through silica gel, and the solvent
removed.
n-Butyl 2-azidobenzoate (1e) was obtained according
to method II. Yield 2.46 g (75%). Yellow oil. IR spectrum
(thin layer), ν, cm–1: 2127 (νas N3), 1724 (ν C=O), 1257 (νs
N3). 1H NMR spectrum, δ, ppm (J, Hz): 7.84 (1H, m, H Ar);
7.55–7.49 (1H, m, H Ar); 7.25–7.23 (1H, m, J = 8.1, H Ar);
7.20–7.15 (1H, m, H Ar); 4.32 (2H, t, J = 6.6, OCH2); 1.75
(2H, d, J = 6.9, CH2); 1.48 (2H, d, J = 7.5, CH2); 0.97 (3H,
d, J = 7.3, CH3). 13C NMR spectrum, δ, ppm: 165.6 (C=O);
140.1, 133.2, 131.8, 124.5, 123.3, 120.0 (C Ar); 65.3 (O–CH2);
30.9 (CH2); 19.4 (CH2); 13.9 (CH3). Found, %: C 60.31;
H 5.95. C11H13N3O2. Calculated, %: C 60.26; H 5.98.
2-Azidobenzonitrile (1f) was obtained according to
method II from 2-aminobenzonitrile. Yield 1.78 g (82%).
Yellow crystals. Mp 52°C (mp 54°C)12. IR spectrum (thin
layer), ν, cm–1: 2225 (ν CN), 2141, 2111 (νas N3), 1309 (νs
N3). 1H NMR spectrum, δ, ppm (J, Hz): 7.60 (2H, t,
J = 7.6, H Ar); 7.28–7.15 (2H, m, H Ar). 13C NMR
spectrum, δ, ppm: 143.5 (CN); 134.2, 134.0, 125.1, 118.9,
115.7, 104.3 (C Ar). Found, %: C 58.35; H 2.75. C7H4N4.
Calculated, %: C 58.33; H 2.80.
Method II. The corresponding amine (15 mmol) and
concd. HCl (15 ml) were added with stirring to water (15 ml).
The amine dissolves upon the addition of HCl, and in some
cases precipitates as crystalline hydrochloride. The solution
was chilled in an ice bath to 0–5°С, and a solution of NaNO2
(1.032 g, 15 mmol, 1.00 equiv) in water (10 ml) was added
in small portions with stirring. The resulting solution was
stirred with cooling for 40 min, then a solution of NaN3
(1.463 g, 22.5 mmol, 1.5 equiv) in water (10 ml) was added
in small portions with vigorous stirring, and stirring
continued for 30 min. The obtained azide was extracted
with CHCl3, the extract washed with aqueous NaCl, dried
over anhydrous Na2SO4, filtered through silica gel, and the
solvent removed.
Methyl 2-azidobenzoate (1a) was obtained according
to method I. Yield 2.26 g (85%). Yellow oil. IR spectrum
(thin layer), ν, cm–1: 2128 (νas N3), 1730 (ν C=O), 1303,
1257 (νs N3). 1H NMR spectrum, δ, ppm (J, Hz): 8.35 (1H, s,
H Ar); 6.32–6.18 (2H, m, H Ar); 5.93 (2H, ddd, J = 14.1,
J = 9.2, J = 5.5, H Ar); 3.84 (3H, s, OCH3). 13C NMR
spectrum, δ, ppm 168.8 (C=O); 164.4, 126.7, 125.4, 114.7
(С Ar); 52.8 (OCH3). Found, %: C 54.33; H 4.16. C8H7N3O2.
Calculated, %: C 54.24; H 3.98.
2-Azidophenol. 2-Aminophenol (2.05 g, 18.8 mmol)
was added to water (50 ml), then concd. HCl (5 ml) was
added with stirring. The solution was chilled in an ice bath
to 0–5°С, and a solution of NaNO2 (1.298 g, 1 equiv) in
water (5 ml) was added in small portions with stirring. The
resulting solution was stirred with cooling for 10 min, then
a solution of NaN3 (1.47 g, 1.2 equiv) in water (10 ml) was
added in small portions with vigorous stirring, and stirring
continued for 60 min at room temperature. The obtained
azide was extracted with CHCl3, the extract washed with
aqueous NaCl, dried over anhydrous Na2SO4, filtered
through silica gel, and the solvent removed. Yield 1.98 g
(78%). IR spectrum (thin layer), ν, cm–1: 3440 (ν OH),
Methyl 2-azido-5-bromobenzoate (1b) was obtained
according to method I. Yield 2.90 g (80%). Light-yellow
crystals. Mp 68–69°C (mp 68–70°C)11. IR spectrum (thin
layer), ν, cm–1: 2126, 2085 (νas N3), 1733 (ν C=O), 1248 (νs
1
N3). H NMR spectrum, δ, ppm (J, Hz): 7.98 (1H, d,
1
J = 2.3, H Ar); 7.62 (1H, dd, J = 8.6, J = 2.3, H Ar); 7.11
(1H, d, J = 8.6, H Ar); 3.91 (3H, s, OCH3). 13C NMR
spectrum, δ, ppm: 164.6 (C=O); 139.5, 136.7, 136.2, 134.8,
121.8, 117.5 (C Ar); 53.2 (OCH3). Found, %: C 36.97;
H 3.20. C8H6BrN3O2. Calculated, %: C 37.03; H 3.26.
2128, 2085, 1599 (νas N3), 1495, 1294 (νs N3). H NMR
spectrum, δ, ppm (J, Hz): 7.09–7.07 (1H, m, H Ar); 7.06–
7.03 (1H, m, H Ar); 6.94 (2H, td, J = 7.7, J = 1.5, H Ar);
6.93–6.91 (1H, m, H Ar). 13C NMR spectrum, δ, ppm:
147.2, 125.9, 121.2, 118.3 (C Ar).
Ethyl 2-azidobenzoate (1c) was synthesized according
to method II. Yield 2.12 g (74%). Yellow oil. IR spectrum
(thin layer), ν, cm–1: 2127 (νas N3), 1730 (ν C=O), 1256 (νs
2-Azidophenyl acetate (1g) was prepared analogously
to a published procedure.10 2-Azidophenol (1.35 g, 10 mmol)
was dissolved in 10% aqueous NaOH solution (8 ml).
Crushed ice (12 g) was added to the solution, then acetic
anhydride (1.5 g, 1.4 ml) was added dropwise with stirring.
The solution was stirred for an additional 5 min until the
formation of 2-azidophenylacetate was complete. The
obtained azide was extracted with CHCl3, the extract
washed with aqueous NaCl, dried over anhydrous Na2SO4,
filtered through silica gel, and the solvent removed. Yield
1.3 g (74%). Yellow-red crystals. Mp 49°C. IR spectrum
(thin layer), ν, cm–1: 2126, 2092 (νas N3), 1758 (ν C=O),
1
N3). H NMR spectrum, δ, ppm (J, Hz): 7.85 (1H, dd,
J = 7.8, J = 1.4, H Ar); 7.51 (1H, td, J = 8.1, J = 1.4, H Ar);
7.26–7.21 (1H, m, H Ar); 7.21–7.14 (1H, m, H Ar); 4.37
(2H, q, J = 7.1, OCH2); 1.39 (3H, t, J = 7.1, CH3). 13C
NMR spectrum, δ, ppm 165.6 (C=O); 140.2, 133.2, 131.8,
124.6, 123.2, 120.0 (C Ar); 61.8 (OCH2); 14.4 (CH3).
Found, %: C 56.44; H 4.88. C9H9N3O2. Calculated, %:
C 56.54; H 4.75.
Isopropyl 2-azidobenzoate (1d) was synthesized
according to method II. Yield 2.18 g (71%). Yellow oil. IR
spectrum (thin layer), cm–1: 2125 (νas N3), 1724 (ν C=O),
1259 (νs N3). 1H NMR spectrum, δ, ppm (J, Hz): 8.02 (2H,
d, J = 8.7, H Ar); 7.05 (2H, d, J = 8.7, H Ar); 5.24 (1H,
1
1297 (νs N3), 1200 (ν C–O). H NMR spectrum, δ, ppm
(J, Hz): 7.26 (1H, t, J = 7.6, H Ar); 7.20–7.11 (2H, m,
H Ar); 7.07 (1H, d, J = 8.1, H Ar); 2.33 (3H, s, CH3).
13C NMR spectrum, δ, ppm: 168.6 (C=O); 142.1, 132.5,
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Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
1
127.2, 125.6, 123.9, 120.1 (С Ar); 20.7 (CH3). Found, %:
C 53.98; H 4.35. C8H7N3O2. Calculated, %: C 54.24;
H 3.98.
(30%). Yellow crystals. Mp 90–91°C (decomp.). H NMR
spectrum, δ, ppm (J, Hz): 8.29–8.25 (1H, m, H Ar); 7.76–
7.70 (1H, m, J = 4.0, H Ar); 7.63–7.55 (2H, m, H Ar); 7.52–
7.44 (1H, m, H azepine); 6.64–6.58 (1H, m, H azepine);
6.36–6.30 (1H, m, H azepine); 3.89 (1H, s, H azepine);
3.83 (3H, s, OCH3). 13C NMR spectrum, δ, ppm: 167.5
(O–C=O); 160.6 (N–C=O); 150.9 (C–C=N); 136.9 (C=C-N);
135.2, 133.6, 127.9, 127.7, 127.5, 127.0, 122.2, 120.0,
118.5 (С azepine); 53.2 (C azepine); 51.9 (CH3). Mass
spectrum, m/z (Irel, %): 348 [M(81Br)]+ (15), 346 [M(79Br)]+
(16), 317 (17), 316 [M(81Br)–CH3OH]+ (96), 315 (22), 314
[M(79Br)–CH3OH]+ (100), 289 [M(81Br)–CH3OC(O)]+
(61), 288 (17), 287 [M(79Br)–CH3OC(O)]+ (62), 267 (37),
210 (21), 209 (53), 208 (30), 179 (28), 153 (16). Found, %:
C 51.87; H 3.24. C15H11BrN2O3. Calculated, %: C 51.90;
H 3.19.
2-Azido-5-bromobenzoic acid (1i) was obtained
analogously to a published method.11 Yield 78%. Colorless
needles. Mp 140°C (decomp.) IR spectrum (oil suspension),
ν, cm–1: 2144, 2119, 2085 (νas N3), 1697 (ν C=O), 1301 (νs
1
N3). H NMR spectrum, δ, ppm (J, Hz): 8.21 (1H, d,
J = 2.4, H Ar); 7.70 (1H, dd, J = 8.6, J = 2.4, H Ar); 7.16
(1H, d, J = 8.6, H Ar). 13C NMR spectrum, δ, ppm: 167.2
(C=O); 137.3, 136.0, 122.3, 121.4, 117.9 (С Ar). Found,
%: C 34.78; H 1.87. C7H4BrN3O2. Calculated, %: C 34.74;
H 1.67.
2-Azidobenzoic acid (1j) was obtained according to a
published method.14 Yield 1.57 g (65%). Colorless needles.
Mp 144°C (decomp.) (mp 144°C14). IR spectrum (oil
suspension), ν, cm–1: 2131, 2110, 2081 (νas N3), 1692 (ν
12-Oxo-6,12-dihydroazepino[2,1-b]quinazoline-6-carb-
oxylic acid ethyl ester (3c). Yield 3.4 mg (10%). Yellow
crystals. Mp 85°C (decomp.). H NMR spectrum, δ, ppm
1
C=O), 1267 (νs N3). H NMR spectrum, δ, ppm (J, Hz):
1
10.65 (1H, s, COOH); 8.11 (1H, dd, J = 7.9, J = 1.5, H Ar);
7.66–7.56 (1H, m, H Ar); 7.31–7.21 (2H, m, H Ar).
13C NMR spectrum, δ, ppm: 168.8 (C=O); 140.4, 134.6,
133.4, 125.1, 120.9, 119.7 (С Ar). Found, %: C 51.53;
H 3.07. C7H5N3O2. Calculated, %: C 51.54; H 3.09.
(J, Hz): 8.30 (1H, dd, J = 8.1, J = 1.0, H Ar), 7.75–7.69
(1H, m, H Ar); 7.66 (1H, d, J = 9.4, H azepine); 7.60 (1H, d,
J = 8.0, H Ar); 7.50–7.44 (1H, m, H Ar); 6.38–6.26 (3H, m,
H azepine); 4.39–4.28 (2H, m, OCH2); 4.44–4.39 (1H, m,
H azepine); 1.32 (3H, t, J = 7.1, CH3). 13C NMR spectrum, δ,
ppm: 168.3 (O–C=O); 160.8 (N–C=O); 151.9 (C–C=N);
147.6 (C=C–N); 134.6, 128.1, 127.2, 126.9, 126.5, 125.7,
120.4, 119.9 (C azepine); 61.8 (CH2); 51.8 (C azepine); 14.2
(CH3). Mass spectrum, m/z (Irel, %): 282 [M]+ (10), 236
[M–EtOH]+ (33), 210 (34), 209 [M–EtOC(O)]+ (100), 182
(11), 181 (14), 179 (8), 154 (11), 121 (11), 119 (9). Found,
%: C 67.87; H 5.12. C16H14N2O3. Calculated, %: C 68.07;
H 5.00.
Synthesis of 6-substituted 12-oxo-6,12-dihydroazepino-
[2,1-b]quinozalines 3a–d,f (General method). The
corresponding azide 1a–d,f (0.12 mmol) and sodium
2-azidobenzoate (1h) (58.7 mg, 0.37 mmol) were dissolved
in 1,4-dioxane–water 1:1 mixture (23 ml), and the solution
irradiated (2 × BUF-15, 254 nm, 7 mW/cm2) with vigorous
stirring (magnetic stirring) until complete decomposition of
the azide (3 h, monitoring by HPLC). The solvent was
removed under reduced pressure. The residue was
dissolved in water and acidified with 2% H3PO4. The
solution was stirred for about 3 min (compound 3a), 3 h
(compound 3с), and for 10 h (compounds 3b,d–f) at 5°С.
The obtained product was extracted with CCl4, the extract
washed with aqueous Na2CO3 followed by water, dried
over anhydrous Na2SO4, and purified by column
chromatography on silica gel with CCl4–CH2Cl2, 2:1, as
eluent.
12-Oxo-6,12-dihydroazepino[2,1-b]quinazoline-6-carb-
oxylic acid isopropyl ester (3d). Yield 2.8 mg (8%).
Yellow crystals. Mp 130–132°C. H NMR spectrum, δ,
1
ppm (J, Hz): 8.31–8.27 (1H, m, H Ar); 7.75–7.69 (1H, m,
H Ar); 7.65 (1H, d, J = 9.4, H azepine); 7.58 (1H, d,
J = 8.1, H Ar); 7.51–7.43 (1H, m, H Ar); 6.40 (1H, dd,
J = 9.5, J = 6.0, H azepine); 6.34 (1H, dd, J = 9.4, J = 4.8,
H azepine); 6.29–6.24 (1H, m, H azepine); 5.25 (1H, sept,
J = 6.3, OCH); 4.20–4.14 (1H, m, H azepine); 1.33 (3H, d,
J = 6.2, CH3); 1.28 (3H, d, J = 6.3, CH3). 13C NMR
spectrum, δ, ppm: 167.9 (O–C=O); 160.9 (N–C=O); 152.1
(C–C=N); 147.8 (C=C–N); 134.7, 128.4, 127.4, 127.3,
127.1 (С Ar); 126.6, 125.7, 120.6, 120.1 (С azepine); 69.6
(OCH); 51.7 (С azepine); 21.9; 21.8 (CH3). Mass spectrum,
m/z (Irel, %): 296 [M]+ (17), 236 [M–i-PrOH]+ (8), 211 (5),
210 (38), 209 [M–i-PrOC(O)]+ (100), 182 (7), 181 (9), 154
(6), 127 (5), 43 (7). Found, %: C 68.82; H 5.60. C17H16N2O3.
Calculated, %: C 68.91; H 5.44.
12-Oxo-6,12-dihydroazepino[2,1-b]quinazoline-6-carbo-
nitrile (3f). Yield 2 mg (7%). Yellow crystals. Mp 125°C
(decomp.). H NMR spectrum, δ, ppm (J, Hz): 8.99–8.95
(1H, m, H Ar); 8.43 (1H, d, J = 11.3, H Ar); 7.98–7.95 (1H,
m, H Ar); 7.94–7.87 (2H, m, H azepine); 7.80–7.68 (1H,
m, H Ar); 7.61–7.45 (2H, m, H azepine); 6.85 (1H, t, J = 7.1,
H azepine). 13C NMR spectrum, δ, ppm: 158.5 (N–C=O);
147.9 (C–C=N); 142.4 (C=C–N); 136.1; 135.2; 131.4;
128.1; 127.6 (С Ar); 127.0; 119.6; 116.8; 114.8; 110.6
12-Oxo-6,12-dihydroazepino[2,1-b]quinazoline-6-carb-
oxylic acid methyl ester (3a). Yield 9.6 mg (30%).
Yellow crystals. Mp 121–123°C (decomp.). 1H NMR
spectrum, δ, ppm (J, Hz): 8.32–8.26 (1H, m, H-1); 7.75–
7.69 (1H, m, H-3); 7.66 (1H, d, J = 9.4, H-10); 7.61 (1H, d,
J = 8.1, H-4); 7.47 (1H, t, J = 7.5, H-2); 6.43–6.37 (1H, m,
H-7); 6.37–6.31 (1H, m, H-9); 6.27 (1H, ddd, J = 9.5,
J = 4.7, J = 0.6, H-8); 4.28 (1H, d, J = 5.1, 6-CH); 3.85
(3H, s, CH3). 13C NMR spectrum, δ, ppm 168.9 (O–C=O);
160.8 (N–C=O); 152.0 (C-5a); 147.7 (C-4a); 134.7 (C-3);
128.0 (C-7); 127.5 (C-4); 127.4 (C-2); 127.2 (C-1); 126.7
(C-10); 126.0 (C-8); 120.5 (C-9); 120.1 (C-12a); 52.9
(OCH3); 51.9 (C-6). Mass spectrum, m/z (Irel, %): 268 [M]+
(21), 237 (19), 236 [M–CH3OH]+ (100), 210 (18), 209
[M–CH3OC(O)]+ (74), 208 (12), 182 (16), 181 (23), 180
(16), 179 (11). Found, %: C 66.82; H 4.80. C15H12N2O3.
Calculated, %: C 67.16; H 4.51.
1
8-Bromo-12-oxo-6,12-dihydroazepino[2,1-b]quinazo-
line-6-carboxylic acid methyl ester (3b). Yield 12.5 mg
698

Chemistry of Heterocyclic Compounds 2016, 52(9), 694–699
Applications; Bräse, S.: Banert, K., Eds.; John Wiley & Sons,
(C azepine); 29.9 (C azepine). Mass spectrum, m/z (Irel, %):
235 [M]+ (100), 234 (20), 221 (59), 207 [M–CO]+ (32), 206
(46), 193 (22), 179 (17), 130 (29), 102 (24), 90 (26). Found, %:
C 71.34; H 4.05. C14H9N3O. Calculated, %: C 71.48; H 3.86.
X-ray structural studies of compound 3а. Crystals of
compound 3а (M 268.27) obtained by recrystallization
from CCl4 at 5°С are orthorhombic; spatial symmetry
group Pbca; a 8.193(4), b 10.371(6), c 29.085(14) Å; α = β =
γ = 90°; V 2471(2) Å3; Z 8; dcalc 1.442 mg·m–3; μ 0.103 cm–1;
F(000) 1120; 2.80° < Θ < 27.99°. Intensities of 28199
reflections (2977 independent reflections, Rint 0.0545) were
measured on a Bruker D8 Quest diffractometer (graphite
monochromator, λ(MoKα) 0.71073 Å, temperature 100 K).
Absorption correction was performed by the method
implemented in SADABS.15 The structure was solved with
the direct method and refined against F2 by the least-
squares technique with anisotropic thermahlklparameters for
all non-hydrogen atoms. H atom positions were calculated
geometrically and refined according to the "rider" model.
The final probability factors were: R1 0.0409 (I > 2σ(I)),
wR2 0.1113 (refined against F2hkl for all independent
reflections), S(F2) 1.037, ρmax/min 0.385 / –0.245 e·Å–3. All
calculations were performed using the SHELXTL16
software package. The rendered representation of the
structure of compound 3a was obtained using the program
ORTEP-3.17 The full set of X-ray structural data was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 1481139).
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(g) Albini, A.; Fagnoni, M. In Photochemically-Generated Inter-
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6. Xue, J.; Luk, H. L.; Eswaran, S. V; Hadad, C. M.; Platz, M. S.
J. Phys. Chem. A 2012, 116, 5325.
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(b) Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1971, 10, 11.
(c) Jansen, H.; Slootweg, J. C.; Lammertsma, K. Beilstein J.
Org. Chem. 2011, 7, 1713. (d) Smalley, R. K. In Houben-Weyl-
Methods of Organic Chemistry, Vol. E9d, Schaumann, E., Ed.;
Thieme: Stuttgart, New York, 1998, p. 172. (e) Tückmantel, W.
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The authors are indebted to Yu. A. Grachev (Lobachevsky
State University of Nizhny Novgorod) for registration of
1H and 13C NMR spectra for compounds 1a–j.
11. 11. Das, J.; Patil, S. N.; Awasthi, R.; Narasimholu, C. P.;
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