Chemistry of hetero analogs of isoflavones 26. Synthesis of 2-alkyl derivatives of 3-(thiazol-2-yl)-and 3-(benzothiazol-2-yl)chromones

Article abstract of DOI:10.1007/s10593-008-0092-7

Treatment of substituted 2-(2,4-dihydroxyphenacyl)thiazole and 2-(2,4-dihydroxyphenacyl)benzothiazole with propionic and isobutyric anhydrides gives the substituted 2-ethyl-and 2-isopropyl-7-acyloxychromones. The use of pivaloyl chloride gives 1-pivaloylo

Full text of DOI:10.1007/s10593-008-0092-7

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
CHEMISTRY OF HETERO
ANALOGS OF ISOFLAVONES
26*. SYNTHESIS OF 2-ALKYL
DERIVATIVES OF 3-(THIAZOL-
2-YL)- AND 3-(BENZOTHIAZOL-
2-YL)CHROMONES
M. S. Frasinyuk1 and V. P. Khilya2
Treatment of substituted 2-(2,4-dihydroxyphenacyl)thiazole and 2-(2,4-dihydroxyphenacyl)benzo-
thiazole with propionic and isobutyric anhydrides gives the substituted 2-ethyl- and 2-isopropyl-
7-acyloxychromones. The use of pivaloyl chloride gives 1-pivaloyloxy-2-hetarylstyrene derivatives.
Keywords: 2-alkylchromones, acid anhydrides (chlorides), O-acylenols, hetero analogs of isoflavones.
Amongst frequently occurring natural compounds of plant origins an important place is occupied by the
class of flavonoids, one or another representatives of which occurs in virtually all kinds of plants [2]. Greater
attention has been focussed in recent times on the methods of synthesis and modification of both natural
isoflavonoids and their synthetic analogs and hetero analogs.
For the overwhelming majority of examples of synthesis of 2-alkylchromones the reaction of
2-hydroxydeoxybenzoins with acylating agents has been used, most frequently with acetic and trifluoroacetic
anhydride. Individual cases are known where derivatives of propionic acid and its homologs have been
employed in the synthesis of 2-alkylchromones [3-6]. Other synthetic routes are used extremely rarely, e.g. in
the rearrangement of α-methyl substituted chalcones to 2-methylisoflavones with Tl(NO3)3 [7, 8].
In the last decade an increased interest has occurred in the synthesis of 2-(ω-carboxyalkyl)isoflavones
which have found application in immunology thanks to the presence of the carboxyl group in the 2-alkyl chain
which can associate with proteins and change their stereochemical and electronic parameters [9-11].
We have found that reaction of 2-(2,4-dihydroxyphenacyl)-1-methylbenzimidazole with aliphatic acid
anhydrides (chlorides) gives exclusively 2-alkyl-3-(1-methylbenzimidazol-2-yl)chromones [1].
_______
* For Communication 25 see [1].
__________________________________________________________________________________________
1Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, Kiev
2
02094; e-mail: mfras@i.kiev.ua. Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail:
vkhilya@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 835-840,
June, 2008. Original article submitted December 16, 2007.
666
0009-3122/08/4406-0666©2008 Springer Science+Business Media, Inc.

Bearing in mind the fact that the structure of the reaction products of deoxybenzoins with carboxylic
acid derivatives depends to a marked extent on the activity of the methylene group in the starting deoxybenzoin
(number of free hydroxyl groups and substituents [12]) and on the acylation reagent used we have now studied
the interaction of the 2-(2,4-dihydroxy-5-ethylphenacyl)-4-methylthiazole (1a) [13] and 2-(2,4-dihydroxy-
5-ethylphenacyl)benzothiazole (1b) [14] with aliphatic acid anhydrides and chlorides.
Prolonged holding of compounds 1a,b with a marked excess of propionic or isobutyric anhydride in
pyridine gives the corresponding 7-acyloxy derivatives of 2-ethyl- or 2-isopropyl-3-hetarylchromones 2a,b or
1
3a,b respectively. The H NMR spectra of compounds 2, 3 show the absence of signals for the methylene and
hydroxyl groups and the appearance of signals for the protons of two residues of the acid used. The signals for
the methyl protons in the 2-isopropyl group in compounds 3a,b are seen as a doublet pointing to their
equivalence and to the absence of a chiral axis due to hindered rotation as was observed in the case of
isoflavones having bulky substituents in positions 2 and 3 [15, 16].
The use of pivaloyl chloride, both at room temperature and upon heating, did not give 2-tert-butyl-
3-hetarylchromones as was the case for the synthesis of 2-tert-butyl-3-(benzimidazol-2-yl)chromones [1]. The
1H NMR spectra of the compounds formed showed a one proton singlet at 6.78 and 6.90 ppm as well as signals
for three pivalic acid residues. With the preceding investigation of the acetylation of 2-hydroxydeoxybenzoins
[17, 18] and the structures of the starting compounds 1a,b in mind we can propose that the acylation involves
the phenol hydroxyls and also the methylene unit (type A) or enol hydroxyl (type B). We do not exclude that the
presence of the (benzo)thiazole ring can make possible an acylation to form an N-acyl-2-methylene-
2,3-dihydro(benzo)thiazole of type C.
CH3–nMen
O
(MenCH3–nCO)2O
n = 1, 2
CH3–nMen
N
O
O
HO
Et
OH
N
Py
Et
R
R
O
S
O
S
R1
R1
2,3 a,b
1a,b
1-3 a R = Me, R1 = H; b RR1 = CH=CH−CH=CH; 2a,b n = 1, 3a,b n = 2
A choice of route for the reaction could be made between A-C in this case on the basis of the 13C NMR
spectroscopic data for the synthesized compounds as well as for compounds 2, 3 (Table 1). It was found that
here the acylation occurs to give the acyl derivatives at the enol hydroxyl 4a,b as type B.
OR2
2 O
Et
OR2
OR2
2O
Et
R2
R
R
O
OR2
N
O
O
-t
C(O)Bu
Et
t- Bu
N
N
R
R
R
S
S
S
O
R1
R1
R1
B
C
A
4 a R = Me, R1 = H; b RR1 = CH=CH−CH=CH; 4a,b R2 = t-BuCO
667

668

Attempts to convert compounds 4a,b to 2-tert-butylchromone derivatives using base [17] were
unsuccessful, the reaction products proving to be the starting desoxybenzoins 1a,b.
Hence we have studied the reaction of 2-(5-ethyl-2,4-dihydroxyphenacyl)thiazole and an annelated
analog with aliphatic acid anhydrides (chlorides). The use of propionic or isobutyric acid anhydrides makes
possible the synthesis of substituted 2-ethyl- and 2-isopropyl-3-hetarylchromones. Introduction of the bulkier
pivaloyl chloride into the reaction leads to formation of 1-pivaloyloxy-2-((benzo)thiazol-2-yl)styrene.
EXPERIMENTAL
Monitoring of the reaction course and evaluation of the purity of the compounds obtained was carried
out by TLC on Silufol UV-254 and Merck plates. The eluents used were a mixture of chloroform and methanol
(9:1 and 95:5) or of hexane and ethyl acetate (1:2). 1H NMR and 13C NMR spectra were taken on a Varian VXR
300 instrument (300 and 75 MHz respectively) using CDCl3 and with TMS as internal standard.
Synthesis of compounds 2-4 a,b (General Method). A mixture of the starting ketone 1a,b (10 mmol)
the corresponding acid anhydride or chloride (50-60 mmol) and absolute pyridine (25 ml) was held for 48-72 h
at room temperature (the end of the reaction being judged by TLC). The reaction mixture was poured onto ice
and the precipitate after solidification was filtered off, dried, and crystallized from hexane.
3-(4-Methyl-1,3-thiazol-2-yl)-4-oxo-2,6-diethyl-4H-chromen-7-yl Propionate (2a). Yield 49%; mp
107-108ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.26, 1.32, 1.37 (9H, three t, J = 7.2, 1-CH2CH3, 6-CH2CH3, and
CH3CH2CO); 2.51 (3H, s, 4'-CH3); 2.63, 2.69 (4H, two q, J = 7.2, MeCH2CO and 6-CH2Me); 3.36 (2H, q,
J = 7.2, 2-CH2Me); 7.02 (1H, s, H-5'); 7.28 (1H, s, H-8); 8.15 (1H, s, H-5). Found, %: N 3.77; S 8.63.
C20H21NO4S. Calculated, %: N 3.52; S 8.68.
3-(1,3-Benzothiazol-2-yl)-4-oxo-2,6-diethyl-4H-chromen-7-yl Propionate (2b). Yield 54%; mp
151-153ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.28, 1.33, 1.43 (9H, three t, J = 7.2, 2-CH2CH3, 6-CH2CH3, and
CH3CH2CO); 2.68 (4H, m, MeCH2CO and 6-CH2Me); 3.44 (2H, q, J = 7.2, 2-CH2Me); 7.31 (1H, s, H-8); 7.40,
7.49 (2H, two m, H-4', H-7'); 7.98, 8.07 (2H, two m, H-5',6'); 8.21 (1H, s, H-5). Found, %: N 3.44; S 7.87.
C23H21NO4S. Calculated, %: N 3.45; S 7.73.
2-Isopropyl-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-6-ethyl-4H-chromen-7-yl 2-Methylpropionate (3a).
Yield 58%; mp 165-167ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.26 (3H, t, J = 7.2, 6-CH2CH3); 1.35, 1.38 (12H, two
d, J = 7.2, 2-CH(CH3)2 and (CH3)2CHO); 2.51 (3H, s, 4'-Me); 2.65 (2H, q, J = 7.2, 6-CH2Me); 2.90 (1H, m,
Me2CHCO); 4.26 (1H, m, 2-CHMe2); 7.04 (1H, s, H-5'); 7.28 (1H, s, H-8); 8.16 (1H, s, H-5). Found, %: N 3.51; S
8.03. C22H25NO4S. Calculated, %: N 3.40; S 8.23.
3-(1,3-Benzothiazol-2-yl)-2-isopropyl-4-oxo-6-ethyl-4H-chromen-7-yl 2-Methylpropionate (3b).
1
Yield 47%; mp 174-176ºC. H NMR spectrum, δ, ppm (J, Hz): 1.29 (3H, t, J = 7.2, 6-CH2CH3); 1.39 (12H, d,
J = 7.2, 2-CH(CH3)2 and (CH3)2CHCO); 2.67 (2H, q, J = 7.2, 6-CH2Me); 2.91 (1H, d, Me2CHCO); 4.27 (1H, m,
2-CHMe2); 7.32 (1H, s, H-8); 7.41, 7.50 (2H, two m, H-4', 7'); 7.97, 8.08 (2H, two m, H-5', 6'); 8.18 (1H, s,
H-5). Found, %: N 3.22; S 7.36. C25H25NO4S. Calculated, %: N 3.05; S 7.39.
1-{2,4-Bis[(2,2-dimethylpropanoyl)oxy]-5-ethylphenyl}-2-(4-methyl-1,3-thiazol-2-yl)ethenyl Piva-
1
late (4a). Yield 65%; mp 96-97ºC. H NMR spectrum, δ, ppm (J, Hz): 1.18 (3H, t, J = 7.2, 5'-CH2CH3); 1.32
(9H, s, 1-CCOO(CH3)3); 1.38 (18H, s, 2'-CCOO(CH3)3 and 4'-CCOO(CH3)3); 2.45 (3H, s, 4"-CH3); 2.55 (2H, q,
J = 7.2, 5'-CH2Me); 6.78 (1H, s, H-2); 6.86 (1H, s, H-3'), 6.88 (1H, s, H-5"); 7.35 (1H, s, H-6’). Found, %:
N 2.64; S 6.05. C29H39NO6S. Calculated, %: N 2.50; S 6.15.
2-(1,3-Benzothiazol-2-yl)-1-{2,4-bis[2,2-dimethylpropanoyl]oxy}-5-ethylphenyl}ethenyl Pivalate (4b).
1
Yield 72%; mp 163-164ºC. H NMR spectrum, δ, ppm (J, Hz): 1.20 (3H, t, J = 7.2, 5'-CH2CH3); 1.33 (9H, s,
669

1-CCOO(CH3)3) 1.38, 1.42 (18H, two s, 2'-CCOO(CH3)3 and 4'-CCOO(CH3)3); 2.54 (2H, q, J = 7.2, 5'-CH2Me);
6.90 (1H, s, H-2); 6.92 (1H, s, H-3'); 7.38 (1H, s, H-6’); 7.40, 7.49 (2H, two m, H-4", 7"); 8.01, 8.03 (2H, two
m, H-5", 6"). Found, %: N 2.48; S 5.67. C32H39NO6S. Calculated, %: N 2.63; S 5.50.
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