C-formylation of some 2(3H)-benzazolones and 2H-1,4-benzoxazin-3(4H)-one

Article abstract of DOI:10.1135/cccc19970494

The C-formylation of 1,3-dimethyl-2(3H)-benzimidazolone and 4-methyl-2H-1,4-benzoxazin-3(4H)-one was performed using 1,1-dichloromethyl methyl ether at the Friedel-Crafts reaction conditions. The formylation of 3-methyl-2(3H)-benzoxa-and -thiazolone at the 6-position was carried out by modified Duffs method with hexamethylenetetramine in trifluoroacetic acid.

Full text of DOI:10.1135/cccc19970494

494
Petrov, Kalcheva, Antonova:
C-FORMYLATION OF SOME 2(3H)-BENZAZOLONES AND
2H-1,4-BENZOXAZIN-3(4H)-ONE
1
Ognyan I. PETROV , Veneta B. KALCHEVA and Antonina Ts. ANTONOVA
Department of Chemistry, Sofia University, James Bourchier Ave. 1, 1126 Sofia, Bulgaria;
e-mail: 1 opetrov@chem.uni-sofia.bg
Received July 23, 1996
Accepted November 1, 1996
The C-formylation of 1,3-dimethyl-2(3H)-benzimidazolone and 4-methyl-2H-1,4-benzoxazin-3(4H)-
one was performed using 1,1-dichloromethyl methyl ether at the Friedel–Crafts reaction conditions.
The formylation of 3-methyl-2(3H)-benzoxa- and -thiazolone at the 6-position was carried out by
modified Duff’s method with hexamethylenetetramine in trifluoroacetic acid.
Key words: Formylation; Benzoheterocycles.
6-Acyl-2(3H)-benzoxa-, -thiazolones and 7-acyl-2H-1,4-benzoxazin-3(4H)-ones have
particularly interesting CNS, analgesic and normolipemic activity1,2. While the acyl-
ation of 2(3H)-benzimidazolones and 2H-1,4-benzoxazine-3(4H)-ones is performed
with routine Friedel–Crafts methods3, the acylation of 2(3H)-benzoxa-, -thiazolones
was found to be more difficult and occurs under irregular conditions4,5. This is the case
of the C-formylation reaction of 3-methyl-2(3H)-benzoxazolone in polyphosphoric acid
and hexamethylenetetramine in which certain problems arise related to the yields and
purity of the resulting 6-formyl derivatives.
In the present communication we report our results from the development of im-
proved alternative methods for the synthesis of C-formyl derivatives of 2(3H)-benza-
zolones and 2H-1,4-benzoxazin-3(4H)-one. The importance of the resulting compounds is
related to their use as starting materials for the preparation of DOPA-analogs, and a
series of compounds with expected analgesic, antipyretic and psychotropic activity6.
The conversion of 1,3-dimethyl-2(3H)-benzimidazolone (1a) and 4-methyl-2H-1,4-
benzoxazin-3(4H)-one (1b) to the corresponding 1,3-dimethyl-2-oxo-2,3-dihydro-1H-
benzimidazole-5-carbaldehyde (2a) or 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-
6-carbaldehyde (2b) was realized by a method using 1,1-dichloromethyl methyl ether in
the presence of aluminium chloride (Scheme 1).
This method, however, was not successful for the formylation of 3-methyl-2(3H)-
benzoxa-, -thiazolones 1c and 1d. The problem was successfully resolved by the appli-
cation of a modification of the Duff’s method, namely formylation with hexamethylene
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495
tetramine in trifluoroacetic acid (TFA) according to Scheme 1. The formylated deriva-
tives 2c and 2d were obtained in good yields and sufficiently pure.
CH
N
3
OHC
O
Cl CHOCH
2
3
Y
AlCl
3
X
CH
N
3
2a, 2b
O
Y
X
CH
1a-1d
3
N
O
(CH ) N
2 6
4
Y
CF COOH
3
OHC
X
2c, 2d
X
Y
1, 2
N-CH bond
a
b
c
d
3
O
O
S
-CH -
2
bond
bond
SCHEME 1
The same method was applied to 4-methyl-2H-1,4-benzoxazin-3(4H)-one in order to
investigate its effect on the yield of formylated material. The reaction gave both the 6-
and 7-substituted isomers 2b and 2e in equal amounts. The latter was proved by com-
parison of its physical properties and spectral data with those of a pure sample syn-
thesized via an independent route starting with the hydrolysis of 3-methyl-2-oxo-2,3-
dihydrobenzoxazole-6-carbaldehyde (2c) yielding 3-hydroxy-4-methylaminobenzalde-
hyde (3). The closure to the oxazinone cycle was realized with chloroacetyl chloride in
conditions of phase-transfer catalysis (Scheme 2).
CH
O
NHCH
OH
3
3
aq. NaOH
OHC
N
OHC
O
2c
3
CH
N
3
O
ClCH COCl
2
NaHCO , TEBA-Cl
3
OHC
O
2e
SCHEME 2
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Petrov, Kalcheva, Antonova:
EXPERIMENTAL
Melting points were determined on a Boetius hot-stage microscope and are uncorrected. IR spectra
1
(chloroform solutions) were recorded on a Specord 71 spectrometer. H NMR spectra (CDCl3 solu-
tions; δ, ppm; J, Hz) were recorded on a Bruker AC 250 with tetramethylsilane as internal standard.
TLC was performed on silica gel 60 F254 (Merck) plates with solvent system toluene–ethylacetate–
chloroform (3 : 1 : 1).
1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (2a)
To a suspension of AlCl3 (3.33 g, 25 mmol) in dichloromethane (40 ml) was added nitromethane (2 ml)
and a clear solution was obtained. 1,3-Dimethyl-2(3H)-benzimidazolone (1a; 1.63 g, 10 mmol) was
added and the resulting solution is stirred and cooled with an ice bath. Dichloromethyl methyl ether
(1.16 ml, 13 mmol) dissolved in dichloromethane (10 ml) was added dropwise during a 30 min
period, and mixture was stirred at room temperature for an additional 1.5 h and then poured into an
ice–water mixture (100 ml). The organic layer was separated and the aqueous layer was extracted
with dichloromethane. The combined organic phases were washed with 3 M HCl and water, and ex-
tracted with 18% aqueous NaHSO3 (15 ml). The aqueous layer was treated with 30% sodium hy-
droxide to destroy the bisulfite adduct and the formylated material precipitated from the solution. The
solid material was separated with filtration, washed with water and dried. Yield 1.15 g (60%); m.p.
1
153–155 °C (50% ethanol), lit.7 gives 151–151.5 °C. IR spectrum: 1 690, 1 715 cm–1 (CO). H NMR spec-
trum: 3.48 s, 6 H; 7.09 d, 1 H, J = 8; 7.54 d, 1 H, J = 1.4; 7.66 dd, 1 H, J = 1.4 and J = 8; 9.96 s, 1 H.
4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (2b)
This compound was synthesized by analogy of compound 2a from the compound 1b. Yield 40%;
1
m.p. 144–146 °C (ethanol). IR spectrum: 1 690 cm–1 (CO). H NMR spectrum: 3.43 s, 3 H; 4.73 s,
2 H; 7.12 d, 1 H, J = 8.3; 7.52–7.57 m, 2 H; 9.92 s, 1 H. For C10H9NO3 (191.2) calculated: 62.82% C,
4.74% H, 7.33% N; found: 62.97% C, 4.68% H, 7.30% N.
3-Methyl-2-oxo-2,3-dihydrobenzoxazole-6-carbaldehyde (2c)
A mixture of 3-methyl-2(3H)-benzoxazolone (1c, 1.49 g, 10 mmol), hexamethylenetetramine (2.80 g,
20 mmol), and trifluoroacetic acid (15 ml) was heated at reflux for 20 h. The products were concen-
trated and combined with ice–water (60 ml). The resultant mixture was stirred for 30 min, made
basic with sodium carbonate, and the solid separated was filtered, washed with water and dried. The
formylated derivative was purified by the formation of the corresponding bisulfite adduct in full ana-
logy with the synthesis of compound 2a. Yield 1.2 g (68%); m.p. 145–146 °C (ethanol), lit.4 145–146 °C. IR spec-
trum: 1 700, 1 780 cm–1 (CO). 1H NMR spectrum: 3.48 s, 3 H; 7.12 d, 1 H, J = 8.0; 7.72 d, 1 H, J = 1.3;
7.78 dd, 1 H, J = 1.3 and 8.0; 9.95 s, 1 H.
3-Methyl-2-oxo-2,3-dihydrobenzothiazole-6-carbaldehyde (2d)
This compound was synthesized by analogy of compound 2c from the compound 1d. Yield 76%; m.p.
1
130–131 °C (ethanol). IR spectrum: 1 690 cm–1 (CO). H NMR spectrum: 3.52 s, 3 H; 7.19 d, 1 H, J =
8.0; 7.87 dd, 1 H, J = 1.5, J = 8.3; 7.98 d, 1 H, J = 1.5; 9.96 s, 1 H. For C9H7NO2S (193.3) calculated:
55.93% C, 3.65% H, 7.25% N; found: 56.21% C, 3.78% H, 7.03% N.
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3-Hydroxy-4-methylaminobenzaldehyde (3)
A mixture of compound 2c (1.77 g, 10 mmol) and a 10% aqueous NaOH (20 ml) was refluxed for 4 h.
After cooling, the solution was acidified with concentrated hydrochloric acid. Aminophenol was libe-
rated from its hydrochloride by slow addition of saturated sodium carbonate solution until a white
precipitate formed. The precipitated product was isolated by suction and washed with water. M.p.
156–158 °C (water), lit.8 167–168 °C (water).
4-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde (2e)
To a stirred solution of the 3-hydroxy-4-methylaminobenzaldehyde (3; 1.51 g, 10 mmol) and benzyl-
triethylammonium chloride (TEBA-Cl; 2.28 g, 10 mmol) in chloroform (25 ml) was added finely
powdered sodium hydrogen carbonate (3.36 g, 40 mmol). The resultant mixture is cooled in an ice
bath, then a solution of chloroacetyl chloride (1.36 g, 12 mmol) in chloroform (5 ml) was added
dropwise. After the addition was completed, the mixture was stirred at 0–5 °C for 1 h, then heated
at 55 °C for 8 h. The solvent was removed and water (40 ml) was added. The crude product was
isolated by suction, washed with water, and recrystallized from ethanol. Yield 1.1 g (58%); m.p.
1
153–155 °C (ethanol). IR spectrum: 1 690 cm–1 (CO); H NMR spectrum: 3.42 s, 3 H; 4.69 s, 2 H;
7.11 d, 1 H, J = 8.2; 7.50 d, 1 H, J = 1.8; 7.60 dd, 1 H, J = 1.8 and 8.2; 9.96 s, 1 H. For C10H9NO3
(191.2) calculated: 62.82% C, 4.74% H, 7.33% N; found: 62.91% C, 4.77% H, 7.15% N.
We wish to thank our colleagues Dr V. Benin from Cornell University (Ithaca, New York) and Dr L.
Nechev from Vanderbild University (Nashville, Tennessee) for NMR spectra.
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