Multi-step synthesis of benzopyranones via a key step involving reaction of the intermediate compound with phenyltrimethylammonium tribromide

Article abstract of DOI:10.1002/jhet.5570390404

Base catalysed condensation of a substituted 2-hydroxyacetophenone with acetic anhydride and sodium acetate followed by cyclization of the intermediate with acid gave substituted 3-acetyl-2-methyl-4H-1-benzopyran-4-ones. These were then brominated with phenyltrimethylammonium tribromide (PTT) to yield the desired 3-(2-bromoacetyl)benzopyran-4-ones. The latter compound on treatment with primary and secondary aryl or alkyl amines, gave the corresponding benzopyran-4-one derivatives.

Full text of DOI:10.1002/jhet.5570390404

Jul-Aug 2002
Multi-step Synthesis of Benzopyranones via a
Key Step Involving Reaction of the Intermediate
Compound with Phenyltrimethylammonium Tribromide
627
*
T. Javed and S.S. Kahlon
Medicinal and Pharmaceutical Research Group, James Starley Building,
Coventry University, Priory Street, Coventry, CV1 5FB, UK
Received August 13, 2001
Base catalysed condensation of a substituted 2-hydroxyacetophenone with acetic anhydride and sodium
acetate followed by cyclization of the intermediate with acid gave substituted 3-acetyl-2-methyl-4H-1-
benzopyran-4-ones. These were then brominated with phenyltrimethylammonium tribromide (PTT) to yield
the desired 3-(2-bromoacetyl)benzopyran-4-ones. The latter compound on treatment with primary and
secondary aryl or alkyl amines, gave the corresponding benzopyran-4-one derivatives.
J. Heterocyclic Chem., 39, 627 (2002).
The benzopyran-4-ones incorporating the chromones,
previously effective in other unrelated bromination
reactions [14,15]. We became interested in this reagent and
extended its use for the type of reactions reported herein.
Surprisingly, to the best of our knowledge, this reagent has
not been reported in the literature for the bromination of
3-acetylbenzopyran-4-ones and interestingly led to
improved yields (72-83%) of the 3-(2-bromoacetyl)-
benzopyran-4-ones (3a-b). The brominated chromones
were then treated with a range of primary and secondary
alkyl or aryl amines in ethanol to furnish the desired novel
chromanones and their naturally occurring analogues
flavones are ubiquitous in nature and have been found to
play an important role in a number of biological processes
[1,2]. In humans, naturally occurring chromones and
flavones have shown biological effects [3,4,5]. Flavonoids
and isoflavonoids have been described as a gold mine for
metabolic engineering [6]. There has been recent interest
of flavones as health promoting components of the human
diet [7], for example, genistein and daidzein have been
reported to be active against a variety of diseases [8,9].
The major precursors of chromones are 2-hydroxy-
acetophenones and phenols. A wide variety of chromones
[2] have been prepared by the claisen condensation
reaction of a 2-hydroxyacetophenone and an ester to give
the 1,3-diketone, which on subsequent cyclization with
acid affords the desired chromone. An alternative source
of 1,3-diketone is readily available via the o-acylation of a
2-hydroxyacetophenone.
Our investigation into a new series of analogues is based
on the synthesis, chemistry and pharmacological activity
of a variety of benzopyran-4-one derivatives, which have
been known to have a wide variety of pharmacological
activities [9,10]. This prompted us to modify this ring and
explore new activities associated with this nucleus. Thus,
we have developed a route that can be utilized to prepare
the benzopyran ring system commencing from 2-hydroxy-
acetophenones (1a-b, Scheme 1) containing either the
fluoro or a hydroxy functional group that via the
Baker-Venkataraman rearrangement [5,11] afforded the
desired chromones (2a-b) possessing the acetyl group at
position 3 of the pyran ring.
These types of systems have been reported to undergo
bromination with bromine in chloroform at the α-position
of the carbonyl group in yields of 65-75% [12,13].
However, in our hands, despite repeated attempts, yields
were low (30-42%) after purification. We thus turned our
attention towards the use of a more selective and quantita-
tive method of bromination and found that
phenyltrimethylammonium tribromide had been

628
T. Javed and S. S. Kahlon
Vol. 39
benzopyran-4-ones (4a-f) in high yields (70-84%). Results
on the biological effects on blood pressure and cardiac
rhythm disturbances, in experimental animals, is currently
under study in our pharmacology laboratory.
In conclusion, our synthesis of a series of benzopyran-4-
one heterocycles [16-20] has been accomplished in three
steps from relatively simple, inexpensive and
commercially available starting materials in an efficient
manner. The synthesis compares very favorably with other
methods [21] reported for similar ring systems and has
demonstrated further the utility of phenyltrimethyl-
ammonium tribromide in target synthesis. However, in
addition, we have successively adopted this robust
procedure for the synthesis of a variety of other hetero-
cycles containing different heteroatoms, which will be
reported in due course. The flexibility of the approach
described herein is thus noteworthy.
EXPERIMENTAL
1
H-NMR spectra were recorded on a Bruker 250 MHz
instrument in an appropriate deuterated solvent (CDCl DMSO,
3 ,
Acetone) with tetramethylsilane as the internal standard. Mass
spectra were recorded on a Varian Saturn 3 GC/MS spectrometer.

Jul-Aug 2002
Multi-step Synthesis of Benzopyranones via a Key Step
629
Infra red spectra were recorded on a Nicolet 205 FT-IR
spectrometer. Thin layer chromatography (TLC) was carried out
Anal. Calcd. for C H O (218.21): C, 66.05; H, 4.62. Found
12 10 4
C, 66.11; H, 4.63.
on F
silica gel plates. Solvent system used was 9:1 Toluene:
254
3-(2-Bromoacetyl)-7-fluoro-2-methyl-4H-1-benzopyran-4-one
(3a).
Ethanol. Microanalysis were preformed on an elemental analyzer
Perkin-Elmer 2400 CHN.
This compound was obtained by treatment of 2a with
phenyltrimethylammonium tribromide in THF to give 3a as light
brown crystals (ethanol), mp 132°; ir: (potassium bromide): 1690
General Procedure for the Preparation of 3-Acetyl-5-hydroxy
(or 7-fluoro)-2-methyl-4H-1-benzopyran-4-ones (2a-b).
-1
An appropriately substituted 2,6-dihydroxyacetophenone
(1a-b) (5 g, 37 mmol) and sodium acetate (5 g, 60.1 mmol) was
refluxed in 30 ml acetic anhydride. The reaction was monitored
by thin layer chromatography with toluene:EtOH (9:1, v/v) and
was thus observed to undergo completion within 8 hours. The
resulting mixture was then poured into ice:water (50:50, v/v) and
the aqueous layer was then removed and the solid or oil so
obtained was then washed with water (50 ml). Cyclisation of this
intermediate was achieved by boiling with 60 ml of cHCl:EtOH
(2:1, v/v). On cooling, the solid so obtained was washed with
water and recrystallized from ethanol to give the title compound,
4.98 g (70%) as dark yellow crystals.
(C=O of γ-pyrone), 1648 (C=O), 668 (C-Br), 3462 (OH) cm .
1
H-nmr (CDCl /DMSO): δ 2.49 (s, 3H, CH ), 4.71 (COCH Br),
3
3
2
7.4 (m, 1H, Ar), 7.5 (m, 1H, Ar), 8.2 (m, 1H, Ar) ; ms: m/z: 299,
+
301 (M ).
Anal. Calcd. for C H O BrF (301.10): C, 48.03; H, 3.02.
12
9 4
Found C, 47.91; H, 3.01.
3-(2-Bromoacetyl)-5-hydroxy-2-methyl-4H-1-benzopyran-4-one
(3b).
This compound was obtained by treatment of 2b with
phenyltrimethylammonium tribromide in THF to give 3b as light
brown crystals (ethanol), mp 257°; ir: (potassium bromide): 1696
(C=O of γ-pyrone), 1647 (C=O), 668, 705 (C-Br), 3462 (OH)
General Procedure for the Preparation of 3-(2-Bromoacetyl)-5-
hydroxy (or 7-fluoro)-2-methyl-4H-1-benzopyran-4-ones (3a-b).
-1
1
cm . H-nmr (CDCl /acetone-d /DMSO): δ 2.57 (s, 3H, CH ),
3
6
3
4.62 (COCH Br), 6.80, (d, 1H, Ar, J = 8.8 Hz, H-8,), 6.86 (d, 1H,
2
To a solution of 3-acetyl-5-hydroxy-2-methyl-4H-1-benzo-
pyran-4-one (2a-b) (4.98 g, 22.3 mmol) in anhydrous tetrahydro-
furan (25 ml) was added phenyltrimethylammonium tribromide
(8.62 g, 22.3 mmol) in portions over a period of 10 minutes. The
reaction mixture was stirred at room temperature for 6 hours and
poured into water (60 ml). THF was removed under reduced
pressure and the brown solid so obtained was filtered and
recrystallized from ethanol to give the title compound 5.2 g
(83%) as light brown crystals.
Ar, J = 8.8 Hz, H-6), 7.54 (t, 1H, Ar), 12.17 (s, 1H, OH); ms: m/z:
297, 299 (M )
+
Anal. Calcd. for C H O Br (297.10): C, 46.51; H, 3.05.
12
9 4
Found C, 46.40; H, 3.04.
3-[2-(5-Chloropyridin-2-ylamino)-acetyl]-7-fluoro-2-methyl-
4H-1-benzopyran-4-one (4a).
This compound was obtained by condensation of 3a with
2-amino-5-chloropyridine in ethanol to give 4a as dark orange
crystals (ethanol), mp 221°; ir: (potassium bromide): 1652, 1618
General Procedure for the Preparation of 2-Methyl-4H-1-
benzopyran-4-one Derivatives (4a-f).
-1 1
(C=O), 3390 (NH), 1252 (C-F) cm . H-nmr (CDCl /DMSO): δ
3
2.57 (s, 3H,CH ), 3.6 (s, 2H, CH ), 3.5-3.6 (s, 1H, NH), 7.2-7.5
3
2
The appropriately substituted 3-(2-bromoacetyl)-2-methyl-
4H-1-benzopyran-4-one (3a-b) (1.0 g, 3.36 mmol) was added to
the substituted amine (0.48 g, 5.2 mmol) in ethanol (20 ml). The
reaction mixture was refluxed for 2 hours and then cooled. The
solid, which separated, was recrystallized from ethanol solvent to
furnish the desired compounds.
(m, 2H, Ar, H-3 of pyridine and H-8 of benzo), 7.6 (d, 1H, Ar,
H-5 of benzo J = 8.8 Hz ), 7.9 (d, 1H, Ar, H-4 of pyridine J = 8.0
Hz), 8.3 (d, 1H, Ar, H-6 of benzo J = 8.8 Hz ), 8.55 (s, 1H, Ar,
+
H-6 of pyridine); ms: m/z: 345 (M ).
Anal. Calcd.C
H N O FCl (346.74): C, 58.88; H, 3.49; N,
17 12 2 3
8.08. Found C, 58.71; H, 3.48; N, 8.05.
3-Acetyl-7-fluoro-2-methyl-4H-1-benzopyran-4-one (2a).
7-Fluoro-2-methyl-3-[2-(3,4,5-trimethoxyphenylamino)-acetyl]-
4H-1-benzopyran-4-one (4b).
This compound was obtained by condensation of 4-fluoro-2-
hydroxyacetophenone (1a) with acetic anhydride to give 2a as
dark brown crystals (ethanol), mp 155°; ir: (potassium bromide):
This compound was obtained by condensation of 3a with 3,4,5
trimethoxyaniline in ethanol to give 4b as cream crystals
(ethanol), mp 210°; ir: (potassium bromide): 1666, 1610 (C=O),
-1
1
1690 (C=O of γ-pyrone), 1650 (C=O) cm . H-nmr (CDCl ): δ
3
-1
1
2.5 (s, 3H, CH ), 2.6 (s, 3H, COCH ), 7.0-7.3 (m, 2H Ar), 8.0-8.2
3426 (NH), 1256 (C-F) cm . H-nmr (CDCl ): δ 2.63 (s, 3H,
3
3
3
+
(m, 1H, Ar); ms: m/z: 221 (M ).
Anal. Calcd. for C O F (220.19): C, 65.45; H, 4.12.
CH ), 3.89 (s, 9H, OCH ), 3.96 (s, 2H, CH ), 3.7-3.9 (s, 1H,
3 3 2
H
NH), 6.55 (s, 2H, Ar H-2, H-5 of trimethoxy benzo), 6.9-7.1
(m, 2H, Ar, H-5,8 of benzo), 8.24 (m, 1H, Ar, H-6 of benzo); ms:
12 10
4
Found C, 65.53; H, 4.13.
+
m/z: 400 (M ).
3-Acetyl-5-hydroxy-2-methyl-4H-1-benzopyran-4-one (2b).
Anal. Calcd.C
H NO F (401.36): C, 62.84; H, 5.02; N, 3.49.
21 20 6
Found C, 62.90; H, 5.03; N, 3.50.
This compound was obtained by condensation of 2,6-
dihydroxyacetophenone (1b) with acetic anhydride to give 2b as
dark yellow crystals (ethanol), mp 117°; ir: (potassium bromide):
3-[2-(5-Chloropyridin-2-ylamino)-acetyl]-5-hydroxy-2-methyl-
4H-1-benzopyran-4-one (4c).
-1
1694 (C=O of γ-pyrone), 1646 (C=O), 3427 (broad OH) cm .
1
This compound was obtained by condensation of 3b with
2-amino-5-chloropyridine in ethanol to give 4c as dark orange
crystals (ethanol), mp 216°; ir: (potassium bromide): 1648, 1607
H-nmr (CDCl ): δ 2.50 (s, 3H, CH ), 2.60 (s, 3H, COCH ), 6.80
3
3
3
(d, 1H, Ar, J = 8.8 Hz), 6.85 (d, 1H, Ar, J = 8.8 Hz), 7.52 (t, 1H,
+
Ar), 12.50 (s, 1H, OH); ms: m/z: 218 (M ).

630
T. Javed and S. S. Kahlon
Vol. 39
-1
1
Acknowledgments.
(C=O), 3440 (OH) 3200 (NH) cm . H-nmr (CDCl /acetone
3
d /DMSO): δ 2.58 (s, 3H, CH ), 3.6 (s, 2H, CH ), 3.5 (s, 1H,
6
3
2
One of us (TJ) would like to thank the Royal Society of
Chemistry and Coventry University for the new initiative pump
priming research award and the postgraduate award (MSc) to
S.S.K., respectively. We also would like to acknowledge
Mr. J. C. Bickerton, analytical services technician, for his
assistance with chemical analyses.
NH), 6.77 (d, 1H, Ar, J = 8.0 Hz, H-4 of pyridine) 6.97 (d, 1H,
Ar, J = 8.0 Hz, H-5 of pyridine), 7.58- 7.68 (m, 2H, Ar, H-2, H-3
of benzo), 8.34 (s 1H, Ar, H-6 of pyridine), 8.61 (d, 1H, Ar, J =
+
8.8 Hz, H-1 of benzo), 12.65 (s, 1H, OH); ms: m/z: 344 (M ).
Anal. Calcd C
H N O Cl (344.74): C, 59.22; H, 3.80; N,
17 13 2 4
8.12. Found C, 59.27; H, 3.81; N, 8.14.
5-Hydroxy-2-methyl-3-[2-(3,4,5-trimethoxyphenylamino)-
REFERENCES AND NOTES
acetyl]-4H-1-benzopyran-4-one (4d).
[*] Author to whom correspondence should be addressed:
E-mail apx157@cov.ac.uk; fax +44 (024) 76838702.
[1] L. W. McGarry and M. R. Detty, J. Org. Chem., 55, 4349 (1990).
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[3] V. Codey, E. Middelon, J. P. Jr., Harborne, Flavanoids in
Biology and Medicine; Biochemical Structure Activity-Relationships,
Alan R. Liss, New York (1986).
This compound was obtained by condensation of 3b with 3,4,5
trimethoxyaniline in ethanol to give 4d as cream crystals
(ethanol), mp 181°; ir: (potassium bromide): 1666, 1610 (C=O),
-1
1
3440 (OH), 3390 (NH), 2850 (O-CH ) cm . H-nmr (DMSO):
3
δ 2.64 (s, 3H, CH ), 3.89 (s, 9H, OCH ), 3.95 (s, 2H, CH ),
3
3
2
3.8-3.9 (s, 1H, NH), 6.55 (s ,2H, Ar, H-2, H-5 of trimethoxy
benzo), 6.71 (d, 1H, Ar, J = 8.8 Hz, H-8 of benzo), 6.76 (d, 1H,
Ar, J = 8.8 Hz, H-6 of benzo), 7.48-7.5 (t, 1H, Ar, H-7 of benzo),
[4] T. M. Romney-Alexander, Heterocycles, 26,1899 (1987).
[5] W. Baker, J. Chem. Soc. 1381 (1933).
+
13.1 (s, 1H, OH) ; ms: m/z: 398 (M )
Anal. Calcd C
Found C, 63.27; H, 5.30; N, 3.50.
H NO (399.40): C, 63.15; H, 5.30; N, 3.50.
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21 21 4
[7] A. K. Srivastava, Trends in Pharm. Sci., 19, 205 (1998).
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I. Hajimohamadreza, Trends in Pharm. Sci., 20, 35 (1999).
4-[2-(5-Hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-2-oxoethyl-
amino]benzoic Acid (4e).
[9]
S. P. Sachchar, N. N. Tripath and A. K. Singh, Indian
This compound was obtained by condensation of 3b with
4-aminobenzoic acid in ethanol to give 4e as light grey
crystals (ethanol), mp 179°; ir: (potassium bromide): 1670,
J. Chem., 26B., 493 (1987).
[10] T. C. Hwang and D. N. Sheppard, Trends in Pharm. Sci., 20,
448 (1999).
-1
1
1610 (C=O), 3440 (broad OH), 3300 (NH) cm . H-nmr
(CDCl /DMSO): δ 2.64 (s, 3H, CH ), 3.48 (s, 2H, CH ),
[11a] H. S. Mahal and K. Venkataraman, Curr. Sci., 4, 214 (1933);
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Chem., 65, 583 (2000).
3
3
2
3.4-3.5 (s, 1H, NH), 6.67 (d, 2H, Ar, J = 7.9, Hz H-3, H-5 of
benzoic), 6.83 (d, 1H, Ar, H-2, H-6 of benzo J = 8.8 Hz), 7.52
(d, 1H, Ar, J = 8.8 Hz, H-8 of benzo), 7.56 (d, 1H, Ar, J = 8.8
Hz, H-6 of benzo), 8.12 (t, 1H, Ar, H-7 of benzo), 13.1 (s, 1H,
+
OH) ; ms: m/z: 352 (M ).
Anal. Calcd C
H NO (353.30): C, 65.59; H, 4.28; N, 3.96.
19 15 6
Found C, 65.51; H, 4.27; N, 3.95.
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5-Hydroxy-2-methyl-3-(2-morpholin-4-yl-acetyl)-4H-1-
benzopyran-4-one (4f).
This compound was obtained by condensation of 3b with
morpholine in ethanol to give 4f as dark yellow crystals
(ethanol), mp 165°; ir: (potassium bromide): 1647, 1608 (C=O),
3448 (broad OH), 3446 (NH); ms: m/z: (CDCl ): δ 2.63 (s, 3H,
3
CH ), 2.61- 2.76 (m, 8H, Ar of morpholino) 3.73 (s, 2H, CH ),
3
2
3.6-3.7 (s, 1H, NH), 6.64 (d, 1H, Ar, J = 8.8 Hz, H-8 of benzo),
6.67 (d, 1H, Ar, J = 8.8 Hz, H-6 of benzo), 7.54-7.57 (t, 1H, Ar,
H-7 of benzo), 12.43 (s, 1H, OH); ms: m/z: 314 (M ).
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their Benzo Derivatives: Synthesis in Comprehensive Heterocyclic
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pp 351-468.
+
Anal. Calcd C
H NO (315.32): C, 64.74; H, 5.43; N, 4.44.
17 17 5
Found C, 64.89; H, 5.44; N, 4.45.