Studies of benzoxazines 16*. synthesis and reactivity of 2,4-substituted 4H-3,1-benzoxazines

Article abstract of DOI:10.1007/s10593-012-0928-z

A novel method has been developed for preparation of substituted 4H-3,1-benzoxazines via formation of tetrafluoroborates. The substitution of halogen in 2-(α-haloalkyl)-4,4-diphenyl-4H-3,1-benzoxazines by NH and SH nucleophiles was performed. The effect of electrophilic substitution in the annelated aromatic ring in a series of 2,4-substituted 4H-3,1-benzoxazines has been studied.

Full text of DOI:10.1007/s10593-012-0928-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 11, February, 2012 (Russian Original Vol. 47, No. 11, November, 2011)
STUDIES OF BENZOXAZINES
16*. SYNTHESIS AND REACTIVITY OF
2,4-SUBSTITUTED 4H-3,1-BENZOXAZINES
E. V. Gromachevskaya1***, V. G. Kul'nevich1**, and T. P. Kosulina1
A novel method has been developed for preparation of substituted 4H-3,1-benzoxazines via formation of
tetrafluoroborates. The substitution of halogen in 2-(-haloalkyl)-4,4-diphenyl-4H-3,1-benzoxazines by
NH and SH nucleophiles was performed. The effect of electrophilic substitution in the annelated
aromatic ring in a series of 2,4-substituted 4H-3,1-benzoxazines has been studied.
Keywords: 2-aminopyridines, 4H-3,1-benzoxazines, mass spectroscopic fragmentation, nucleophilic and
electrophilic substitution, synthesis.
o-Acylaminobenzyl alcohols which undergo heterocyclization in acid medium are usually used as
starting materials in the synthesis of 4H-3,1-benzoxazines [2, 3]. The mechanism of benzoxazine heterocycle
formation assumes generation in the starting aromatic substrate of a carbenium center in the ortho position to the
NHC(R)=O group, the oxygen atom of which can show nucleophilic properties [4].
We have developed synthetic methods for the synthesis of 2,4-substituted 4H-3,1-benzoxazines via
acylation of tertiary o-aminophenylcarbinols using carboxylic acids, their anhydrides, or acid chlorides in the
presence of mineral or Lewis acids through formation of the corresponding chlorides [5], perchlorates [6], or
hexahaloantimonates [7]. In this reaction the acylation of aminocarbinols and heterocyclization occur in
sequence [5-8]. The 4H-3,1-benzoxazines and their salts obtained by us reveal compounds showing
hypnosedative activity [9], plant growth regulator properties [10], and antidotal activity [11-14].
Extending investigations in this field we have studied the reaction of o-aminophenyldiethyl-
(diphenyl)carbinols 1a,b with the -haloalkanyl or furanyl acid chlorides or bromides 2a-g in the presence of
boron trifluoride etherate. As a result we have prepared the 4H-3,1-benzoxazine tetrafluoroborates 3a-g (Scheme
1) which were separated from the reaction medium by precipitation with ether. Thanks to their thermal stability
and explosion resistance the tetrafluoroborates are preferred to perchlorates for further use [15].
The products 3a-e,g were obtained as crystals in 60-75% yields (Table 1) and the salt 3f as a viscous, oily
liquid. IR spectra of the salts 3a-g show absorption bands at 2750-2220 cm-1 due to the presence of the quaternary
N+H group nitrogen, OCNH+ stretching bands at 1670-1640 cm-1, and for the BF4 anion at 1120-990 cm-1.
-
_______
*For Communication 15, see [1].
**Deceased.
***To whom correspondence should be addressed, e-mail: organics@kubstu.ru.
1Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University, 2
Moscovskaya St., Krasnodar 350072, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1691-1701, November, 2011.
Original article submitted October 26, 2010; revision submitted November 7, 2011.
0009-3122/12/4711-1405©2012 Springer Science+Business Media, Inc.
1405

1406

Scheme 1
–
+
R1CO . BF4 + BF2 Hal
R1COHal + 2BF3
2a–g
R
R
R
R
BF
–
4
R
R
O
5
8
+
–
–
6
7
R1CO . BF4
O
OH
OH
+
R1
R1
CH2Cl2
NH2
N
H
N
4a–g
3a–g
1a–b
1a, 3f, 4f R = Et; 1b, 3a–e,g, 4a–e,g R = Ph; 2–4 a R1 = CH2Cl, b R1 = CHCl2,
c R1 = CH(Br)CH2CH3, d R1 = 2-furyl, e R1 = 3-furyl, f,g R1 = 5-nitro-2-furyl;
2a,b,d–g Hal = Cl, c Hal = Br
The bases 4a-g were prepared by deprotonation of the corresponding salts 3a-g using 5% alkali solution.
Constants and spectroscopic parameters for the 4H-3,1-benzoxazines 4a,c,d,g agree with literature data
[6-8]. The spectroscopic properties and elemental analytical data for the novel compounds 4b,e,f are given in
Tables 2 and 3.
In the 4H-3,1-benzoxazines the heterocycle is annelated to the benzene ring and conjugatively bonded to
it via the azomethine bond therefore the C=N bond of the heterocycle shows little reactivity [6]. The literature
for 4H-3,1-benzoxazines records the occurrence of both opening of the heterocycle and also its transformation. The
first relates to hydrolysis to give a substituted o-hydroxymethylanilide [16] and the second to the formation of
3,4-dihydroquinazolines [17-19] and 1,4-dihydro-2H-3,1-benzoxazines [20] through the action of nucleophiles and
reducing agents. In the system NaNH2–NH3 the heterocycle in 2,4-diphenyl-4H-3,1-benzoxazine undergoes ring
contraction through an intermediate indole-2,3-oxide anion via an intramolecular Wittig rearrangement to form
3-hydroxy-2,3-diphenylindole [20].
TABLE 2. Physicochemical Characteristics of 4H-3,1-Benzoxazines
4b,e,f,h-n
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Rf*
Yield, %
С
H
N
4b
4e
4f
C21H15Cl2NO
C24H17NO2
C16H16N2O4
C25H25NOS
C25H26N2O
C26H26N2O
C25H26N2O
C28H30N2O
C27H22N2O
C28H24N2O
68.35
68.49
82.20
82.03
63.82
63.99
77.61
77.48
81.32
81.05
81.82
81.64
81.25
81.05
81.67
81.91
4.17
4.11
4.71
4.88
5.52
5.33
6.40
6.50
7.11
7.07
6.65
6.80
7.32
7.07
7.55
7.37
3.49
3.80
3.62
3.99
9.14
9.33
3.56
3.62
7.43
7.56
7.42
7.33
7.28
7.56
6.52
6.82
165-166
208
0.85
0.80
0.28
0.87
0.16
0.35
0.29
0.15
0.25
0.22
85.0
70.0
55.0
50.0
72.5
85.6
75.0
82.0
51.0
55.0
117-119
76-78
4h
4i
61-63
4j
161-162
92-94
4k
4l
112-114
135-138
83-85
4m
4n
83.32
83.05
83.44
83.14
5.25
5.68
5.63
5.98
7.02
7.17
6.70
6.93
_______
Eluents: benzene–acetone, 4:1 (compound 4b); benzene–ether, 4:1 (compounds
4e,h-k), and benzene (compounds 4f,l-n).
1407

TABLE 3. Spectroscopic Characteristics of 4H-3,1-Benzoxazines 4b,e,f,h-n
Com-
pound
IR spectrum,
1Н NMR spectrum, , ppm (J, Hz)
ν, cm-1
4b
4e
4f
1610 (C=N)
1625 (C=N)
6.72 (1Н, d, 3J7,8 = 6.5, Н-8); 7.00 (1Н, s, СНCl2); 7.22 (10Н, m, H 2Ph);
7.35 (2H, m, Н-5,7); 7.47 (1Н, dd, 3J6,5 = 6.5, 3J6,7 = 7.0, Н-6)
6.82 (1Н, m, Н-4'); 6.95 (4Н, m, H Ar); 7.00-7.20 (10Н, m, H 2Ph);
7.34 (1Н, dd, 3J4',5' = 1.9, 4J2',5' = 1.5, Н-5'); 7.90-7.95 (1Н, m, Н-2′)
1620 (C=N);
1550, 1330
(NO2)
0.80 (3Н, t, 3J = 7.0, СН3); 1.05 (3Н, t, 3J = 7.0, СН3);
1.65, 1.80, 2.05 and 2.23 (in all 4Н, four q, 3J = 7.0, 2СН2);
6.70-6.90 (4Н, m, H Ar); 7.11 (1Н, d, Н-3'); 7.30 (1Н, d, 3J3',4' = 3.0, Н-4')
4h
4i
1625 (C=N)
1620 (C=N)
1640 (C=N)
0.95-1.15 (7Н, m, (CH2)2CH3); 2.20 (2Н, t, 3J = 6.0, SСН2Pr);
3.26 (2Н, s, СН2S); 6.67-6.77 (4Н, m, H Ar); 7.00-7.25 (10Н, m, H 2Ph)
1.00 (6Н, t, 3J = 6.5, 2СН3); 2.52 (4Н, к, 3J = 6.5, N(СН2)2);
3.23 (2Н, s, NСН2); 6.56-6.64 (4Н, m, H Ar); 7.01-7.20 (10Н, m, H 2Ph)
4j
1.33-1.39 (6Н, m, (СН2)3 piperidine);
2.27 (4Н, t, 3J = 5.0, N(СН2)2 piperidine); 3.12 (2Н, s, СН2);
6.65-7.10 (4Н, m, H Ar); 7.15-7.45 (10Н, m, H 2Ph)
4k
4l
1615 (C=N);
3300 (NH)
0.98 (9Н, s, C(СН3)3); 2.50 (1Н, br. s, NН); 3.38 (2Н, s, СН2);
6.50-6.80 (4Н, m, H Ar); 7.00-7.30 (10Н, m, H 2Ph)
1630 (C=N)
0.65 (3Н, t, 3J = 6.0, СН3); 1.30-1.60 (6Н, m, (СН2)3 piperidine);
1.60-1.80 (2Н, m, СН2); 2.45-2.60 (4Н, m, N(СН2)2 piperidine);
3.10 (1Н, t, 3J = 6.5, СН); 6.63 (1Н, d, 3J7,8 = 7.0, Н-8);
7.00-7.20 (3Н, m, Н-7,6,5); 7.25-7.40 (10Н, m, H 2Ph)
4m
4n
1620 (C=N);
3410 (NH)
3.92 (2Н, d, 3J = 5.5, СН2); 5.20 (1Н, br. s, NН);
6.45-7.00 (9Н, m, H Ar, H NPh); 7.10-7.45 (10Н, m, H 2Ph)
1620 (C=N);
3400 (NH)
2.68 (3Н, s, СН3); 3.95 (1Н, br. s, NН); 4.23 (2Н, s, СН2);
6.45 (2Н, d, 3JAB = 8.0, H Ar); 6.80 (2Н, d, 3JAB = 8.0, H Ar);
6.90-7.10 (4Н, m, H Ar); 7.15-7.40 (10Н, m, H 2Ph)
One of the targets of our work was to study the chemical activity of substituted 4H-3,1-benzoxazines.
Introduction into their structures of novel functional groups in nucleophilic and electrophilic reactions can lead
to preparation of novel compounds with potential biological activity [3].
Scheme 2
Ph
Ph
O
HSC4H9
N
N
CH2SC4H9
4h
Ph
Ph
O
Ph
Ph
O
NHR1R2
K2CO3
EtOH
CHRNR1R2
N
CHRX
4i–l
4a,c
Ph
Ph
O
H2N
R3
H
H
H
A
B
NH2CH2CH(OH)Ph
R3
N
C
H2
N
H
4m–n
Oligomers
H
A
B
4 i–k R = H, i R1 = R2 = Et, j R1 + R2 = (CH2)5, k R1 = H, R2 = t-Bu, l R = Et,
R1 + R2 = (CH2)5, m R3 = H, n R3 = Me, a X = Cl, b X = Br
1408

The reaction of 2-(1-haloalkyl)-4H-3,1-benzoxazines 4a,c with mercaptan and with amines yields the
corresponding sulphur- and nitrogen-containing compounds 4h-n with retention of the benzoxazine system
(Scheme 2 and Tables 2 and 3). This reaction is carried out by refluxing in absolute alcohol with a 1.5-fold
excess of the nucleophilic reagent in the presence of K2CO3 [21].
It should be noted that the substitution reaction of the chlorine in benzoxazine 4a for the butylmercaptan
residue under the conditions described in method [21] forms the product 4h in the course of 18-20 h. Compound
4a under these conditions reacts with diethylamine, piperidine, and tert-butylamine and also the benzoxazine 4c
reacts with piperidine (6-7 h) forming the corresponding aminoalkyl-substituted benzoxazines 4i-l (Table 2).
Reaction occurs for benzoxazine 4a with aniline and 4-methylaniline but not with the weaker nucleophile
4-nitroaniline. Reaction with -phenylethanolamine is accompanied by formation of resinous materials,
probably through dehydration and then polymerization of the reaction product.
1
The products 4k,m,n contain a –CH2–NH– fragment and their H NMR spectra might be expected to
show a vicinal coupling constant for this fragment. However, because the 14N atomic nucleus has spin number 1
and thus possesses a quadrupole moment [22], the N–H proton signals are broadened. However, in the spectrum
of 4,4-diphenyl-2-(phenylaminomethyl)-4H-3,1-benzoxazine (4m) a doublet splitting of 3J = 5.5 Hz is observed
for the protons of the methylene group.
The spectrum of compound 4n shows characteristic signals for aromatic substituent protons as an A2B2
3
system with JAB = 8.0 Hz. The chemical shift of the methine proton of the side chain in the spectrum of
2-dichloromethyl-4,4-diphenyl-4H-3,1-benzoxazine (4b) to low field can be explained by the deshielding effect
of the substituent. The furan protons in the 1H NMR spectra of compounds 4e,f show a normal dependence [23].
The furan ring H-2' and H-5' proton signals' shift to low field in the spectrum of the 4,4-diphenyl-2-(3-furyl)-
4H-3,1-benzoxazine (4e) when compared with the H-4' signal is related to the electron-acceptor effect of the
furan ring oxygen atom (Table 3).
The IR spectra of benzoxazines 4b,e,f,h-n show stretching bands for a conjugated azomethine group at
1640-1610 cm-1 (Table 3) which also confirms their structure.
Reaction of 2-chloromethyl-4,4-diphenyl-4H-3,1-benzoxazine (4a) with 2-amino-5-chloropyridine
proceeds unexpectedly under conditions reported in method [21] to give the novel tetracyclic system 9-chloro-
12,12-diphenyl-5,12-dihydropyrido[1',2':1,2]imidazo[4,5-b]quinoline [24].
Reaction of benzoxazine 4a with 2-aminopyridine proceeds differently. Analogous conditions gave
colorless crystals of [2-(imidazo[1,2-a]pyridin-2-ylamino)phenyl]diphenylmethanol (5) whose structure was
identified by spectroscopic methods. Both nitrogen atoms of the reagent take part in the reaction of benzoxazine
4a with both 2-aminopyridine and 2-amino-5-chloropyridine. The reactions (~6 h) occur via the intermediate
states A, B, and C with cleavage of the benzoxazine ring [24]. Formation of the product 5 occurs via
deprotonation of the cation C (Scheme 3).
The IR spectrum of compound 5 (see Experimental) shows a band for the NH group stretching
vibrations at 3310 cm-1. The broad absorption at 3200-2850 cm-1 points to the presence in this compound of a
hydroxyl group which takes part in formation of a chelate structure [25]. Position of the OH group proton signal
in low field in the 1H NMR spectrum indicates its participation in the formation of hydrogen bonds [26].
The structure of compound 5 was also supported by the mass spectroscopic data showing the presence
of a molecular ion peak. Its initial fragmentation scheme involves loss of a water molecule to form ion 1
(Scheme 4) which, with the presence of proton donors [27], points to the existence of a hydroxyl group in the
studied structure. Ion 1 then eliminates a hydrogen atom, a phenyl radical, or a radical of mass 117 a.u. which
has a pyridoimidazole structure, to give cations 2−4.
Reaction of the 2,4-substituted 4H-3,1-benzoxazines 4a,c-g with electrophilic reagents has been studied
using bromination of 4,4-diethyl(diphenyl)-2-(5-nitro-2-furyl)-4H-3,1-benzoxazines 4f,g by bromine in acetic
acid at room temperature [28] (Scheme 5) to give the corresponding 6,8-dibromo benzoxazines 6a,b in 65% and
70% yield respectively. Their properties were identical to those reported by us previously [29] where
1409

Scheme 3
Ph
H2N
O
Ph
O
Ph
Ph
4a
H2N
+
+
+
N
N
N
N
H
Cl
Cl
H2N
B
A
N
Ph
Ph
OH
OH
Ph
H
Ph
H
N
N
N
N
+
HN
N
– HCl
Cl
5
C
these compounds were obtained as side products in the bromination of 4,4-diethyl(diphenyl)-2-(5-nitro-2-furyl)-
1,2-dihydro-4H-3,1-benzoxazines. Compounds 4d,e with unsubstituted furyl substituents in position 2 of the
heterocycle undergo tarring during this reaction.
Scheme 4
+
+
.
.
Ph
Ph
Ph
OH
N
Ph
– H2O
N
N
H
N
N
N
Ф1 (m/z 373)
5
M+ (m/z 391)
.
– H
.
– C7H5N2
.
– C6H5
Ph
Ph
Ph
Ph
+
+
N
N
+
N
N
N
N
Ф4 (m/z 256)
N
Ф3 (m/z 296)
Ф2 (m/z 372)
The 2-(1-haloalkyl)-4H-3,1-benzoxazines 4a,c were not brominated under the conditions reported.
Increasing the temperature of the reaction mixture to 70-80ºC causes destruction of the heterocycle with tarring.
The bromination of benzoxazine 4a in refluxing nitromethane led to formation of the yellow colored
compound 7 (Scheme 5) whose mass spectrum shows a specific group of molecular ion peaks (cluster): [M]+,
[M+2]+, [M+4]+, and [M+6]+. The peaks intensity distribution is characteristic for ions containing three bromine
atoms and is found to be in full agreement with additivity rules [30].
1410

The IR spectrum of compound 7 contains characteristic absorption peaks for the stretching vibrations of
1
conjugated =CH and C=C bonds and the aromatic nucleus [25, p. 87]. The H NMR spectrum also confirms a
presence of the aromatic protons and an absence of a signal for the methylene group protons. According to
1H NMR, IR, and mass spectrometric data the product 7 obtained is 1,3,6-tribromo-9-phenylacridine.
Scheme 5
R
R
O
Br
MeCOOH (0–5°C)
NO2
for 4f,g
N
O
Br2
Br
6a,b
4a,f,g
Br
Ph
Fe, MeNO2 (~100°C)
for 4a
Br
Br
N
7
6 a R = Et, b R = Ph
We have previously [5] reported the nitration of 2,4,4-trimethyl-4H-3,1-benzoxazinium chloride using a
nitration mixture in the cold to give the mononitration product in up to 67% yield with retention of a
heterocycle. Nitration of 2-chloromethyl-4,4-diphenyl-4H-3,1-benzoxazine (4a) under the same conditions gave
a low (15-20%) yield of the corresponding product 8 but with much tarring (Scheme 6). It is possibly related to
the C–H acidity of the methylene group ion in the starting benzoxazine 4a which enables a 1,3-prototropic shift
of the multiple bond to the exocyclic position and to subsequent oligomerization.
Scheme 6
Ph
Ph
O
Ph
Ph
O
O2N
HONO2/H2SO4
–H2O
N
CH2Cl
N
CH2Cl
4a
8
The IR spectrum of compound 8 has strong absorption peaks for the stretching vibrations of the
1
azomethine bond and the nitro group. From the H NMR spectrum, in which the vicinal aromatic protons H-8
and H-7 show doublet signals and the H-5 proton appears as a singlet, it follows that the heterocycle orients the
nitronium to position 6 of the annelated aromatic ring of benzoxazine 4a to give 2-chloromethyl-4,4-diphenyl-
6-nitro-4H-3,1-benzoxazine (8).
The experimental data obtained shows that the course of nucleophilic substitution of the halogen in
2-(-haloalkyl)-4H-3,1-benzoxazines by aliphatic and aromatic amines occurs as expected with retention of a
heterocycle. In the case of -aminopyridines the reaction occurs with participation of the pyridine nitrogen and
opening of the oxazine ring to give the substituted 2-aminophenylmethanol. Electrophilic substitution in the
annelated aromatic ring of benzoxazines depends on the substituent structure in the 2 position of the
heterocycle.
EXPERIMENTAL
IR spectra were recorded on a Specord IR-75 instrument at room temperature using vaseline oil.
1H NMR spectra were taken on a Bruker DRX-500 instrument (500 MHz) using DMSO-d6 (compound 4b),
1411

Tesla 60 (60 MHz) using CCl4 (compound 4e), CDCl3 (compounds 4h-j), or (CD3)2CO (compounds 4k,m,n), or
on Bruker AC-200 (200 MHz) using CDCl3 (compounds 4f,l). TMS was used as internal standard. Mass spectra
were recorded on a Varian CH-6 instrument with direct introduction, ionization chamber temperature 50-180ºC,
and ionization energy 70 eV. TLC was performed on Silufol UV-254 plates and revealed using iodine vapor.
The substituted o-aminobenzyl alcohols 1a,b were synthesized from methyl anthranilate using the
method [31].
2-(1-Bromopropyl)-4,4-diphenyl-4H-3,1-benzoxazinium Tetrafluoroborate (3c). o-Aminophenyl-
diphenylcarbinol (1b) (2.75 g, 10 mmol) was added portionwise with stirring to a mixture of -bromobutyric
acid bromide (4.56 g, 20 mmol) and boron trifluoride etherate (2.84 g, 20 mmol) in methylene chloride (10 ml)
cooled to 0ºC. The mixture became blue-green in color and a mild warming effect was observed. After 30 min
the mixture was heated to the solvent reflux temperature and stirred for 3 h. The reaction mixture was cooled
and the salt 3c was precipitated by addition of absolute ether. The precipitated crystals were filtered off, washed
with ether, and dried in air. Yield 3.2 g (65%).
The salts 3a,b,d-g were prepared similarly using the corresponding acid chlorides.
2-(1-Bromopropyl)-4,4-diphenyl-4H-3,1-benzoxazine (4c). A mixture of the salt 3c (0.89 g, 1.8
mmol) in 5% aqueous KOH solution (10 ml) was stirred on a boiling water bath for 10 min. The organic fraction
was extracted with ether and dried over anhydrous Na2SO4. Solvent was distilled off and the precipitate formed
was recrystallized from a 1:1 mixture of petroleum ether and carbon tetrachloride. Yield 0.54 g (80%).
Benzoxazine 4c properties agreed with those in the literature [8].
Benzoxazines 4a,b,d-g were prepared similarly.
2-Diethylaminomethyl-4,4-diphenyl-4H-3,1-benzoxazine (4i). A mixture of benzoxazine 4a (0.6 g,
1.8 mmol), diethylamine (0.31 ml, 3 mmol), and K2CO3 (0.3 g) in absolute alcohol (7 ml) was heated with
stirring on a boiling water bath to the solvent reflux temperature and refluxed for 6 h. At the end of the reaction
(TLC monitoring) the mixture was cooled and the precipitate was filtered off. The filtrate was evaporated and
the crude product obtained was recrystallized from alcohol. Yield 0.48 g.
Benzoxazines 4h,j-n, 5 were prepared similarly. The synthesis of 2-butylsulfanylmethyl-4,4-diphenyl-
4H-3,1-benzoxazine (4h) took 20 h.
2-(1-Piperidinopropyl)-4,4-diphenyl-4H-3,1-benzoxazine (4l) was prepared similarly to compound 4i
by substituting the bromine in benzoxazine 4c with a piperidine residue.
2-[(Imidazo[1,2-a]pyridin-2-ylamino)phenyl]diphenylmethanol (5) of weight 0.39 g was purified by
column chromatography using L 40/100 grade silica gel sorbent and benzene–acetone (1:2) as eluent. Column
diameter 3 cm, layer thickness 10 cm. The fraction with Rf 0.83 was separated. Yield 0.17 g (45%); mp 207-
209ºC. IR spectrum, , cm-1: 3310 (NH); 3200-2850 (OH); 1540 (C=N). 1H NMR spectrum (500 MHz, DMSO-d6),
, ppm (J, Hz): 6.45 (1H, d, 3J3',4' = 6.5, H-3'); 6.65 (1H, m, H-7); 6.75 (1H, m, H-6); 7.05-7.30 (14H, m, H 2Ph,
H-4',5',6', NH); 7.45 (1H, s, H-3); 7.63 (1H, d, 3J7,8 = 5.0, H-8); 8.25 (1H, d, 3J5,6 = 4.5, H-5); 8.57 (1H, s, OH).
Mass spectrum, m/z (Irel, %): 391 [M]+ (14), 373 (65), 372 (75), 296 (60), 256 (100), 187 (38), 148 (47), 118
(40), 105 (48), 78 (71), 77 (75). Found, %: C 79.25; H 5.72; N 10.33. C26H21N3O. Calculated, %: C 79.77;
H 5.41; N 10.73.
1,3,6-Tribromo-9-phenylacridine (7). A mixture of 2-chloromethyl-4H-3,1-benzoxazine (4a) (1.03 g,
3 mmol) and powdered reduced iron (0.5 g) in nitromethane (5 ml) was heated with stirring to the solvent reflux
temperature. Bromine (2.88 g, 0.9 ml, 18 mmol) was added gradually at this time and the reaction mixture was
stirred for 1.5 h under these conditions. At the end of the reaction (TLC monitoring) the inorganic fraction was
filtered off. Solvent was evaporated from the filtrate and the residue was then treated with aqueous Na2S2O3
solution, recrystallized from alcohol, and dried. Yield 0.37 g (25%), Rf 0.75 (benzene); mp 220ºC. IR spectrum,
, cm-1: 3070, 1580, 1570 (C=CH ar); 1610 (C=N).1H NMR spectrum (200 MHz, DMSO-d6), , ppm: 7.25-7.90
(8H, m, Ph, H-4,5,8); 7.90-8.40 (2H, m, H-2,7). Mass spectrum, m/z (Irel, %): 495 [M+6]+ (13), 493 [M+4]+ (42),
491 [M+2]+ (40), 489 [M]+ (13), 413 (30), 253 (55), 251 (31), 126 (100), 112 (40), 100 (17), 87 (10). Found, %:
C 46.75; H 2.34; N 2.70; Br 48.56. C19H10Br3N. Calculated, %: C 46.38; H 2.05; N 2.85; Br 48.72.
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2-Chloromethyl-6-nitro-4,4-diphenyl-4H-3,1-benzoxazine (8). A nitrating mixture (prepared earlier
from HNO3 (2.1 ml, d = 1.5) and H2SO4 (3 ml, d = 1.84) with cooling in an ice salt bath) was added gradually
over 30 min to a solution of the benzoxazine 4a (1.03 g, 3 mmol) (again with cooling). The mixture was allowed
to stand at room temperature for 24 h, poured into crushed ice, and neutralized with sodium bicarbonate
solution. The precipitate formed in the weakly alkaline medium was filtered off, washed with water, and dried in
air. The product obtained was chromatographed on a column (neutral alumina sorbent, benzene eluent)
collecting the fraction with Rf 0.29. Yield 0.2 g (18%); mp 137-139ºC (benzene). IR spectrum, , cm-1: 3160,
1
1590, 1570 (C=CH ar); 1620 (C=N); 1490, 1330 (NO2). H NMR spectrum (200 MHz, DMSO-d6), , ppm (J,
3
3
Hz): 4.32 (2H, d, CH2); 7.20-7.70 (10H, m, 2 Ph); 8.05 (1H, d, J8,7 = 8.7, H-8); 8.22 (1H, d, J7,8 = 8.7, H-7);
8.27 (1H, s, H-5). Found, %: C 66.71; H 3.85; Cl 9.45; N 7.28. C21H15ClN2O3. Calculated, %: C 66.58; H 3.99;
Cl 9.36; N 7.40.
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