Syntheses of new carbonyl derivatives from α-halohetaryl ketones

Article abstract of DOI:10.1023/A:1015307813291

The Kroehnke reaction of 2ω-bromoacetylphenoxathiin and 2-ω-bromophenoxathiin 10,10-dioxide, through N-ylide and S-ylide intermediates, leading to the corresponding glyoxals, was described. The condensation reaction of 2-ω-bromoacetylphenoyathiin with aro

Full text of DOI:10.1023/A:1015307813291

Chemistry of Heterocyclic Compounds, Vol. 38, No. 2, 2002
SYNTHESES OF NEW CARBONYL
DERIVATIVES FROM
α-HALOHETARYL KETONES
D. Gavriliu1, T. Loloiu2, A. Nicolae1, G. Loloiu1, and O. Maior1
The Kröhnke reaction of 2ω-bromoacetylphenoxathiin and 2-ω-bromophenoxathiin 10,10-dioxide,
through N-ylide and S-ylide intermediates, leading to the corresponding glyoxals, was described. The
condensation reaction of 2-ω-bromoacetylphenoxathiin with aromatic o-hydroxy aldehydes and further
cyclization to new furan derivatives was also performed. The new compounds were characterized
through elemental analysis and spectral data (IR, 1H NMR and 13C NMR).
Keywords: 2-ω-bromoacetylphenoxathiin,
2-ω-bromophenoxathiin
10,10-dioxide,
glyoxals,
α-halohetaryl ketones, N-ylides, S-ylides, cyclization, Kröhnke reaction.
The continuous interest in phenoxathiin chemistry is not only due to the large variety of biological
activities but also to the diversified theoretical aspects concerning the reactivity of this polynuclear heterocyclic
system [1-4].
On the other hand, N-ylides and S-ylides are highly reactive compounds used as intermediates in the
synthesis of numerous heterocyclic systems [5-8].
This paper describes the synthesis of phenoxathiin carbonyl derivatives 1, 2 starting from
2-ω-bromoacetylphenoxathiin 3 and the corresponding 10,10-dioxide 4 (Schemes 1 and 2).
In the first step of the Kröhnke reaction, N-(phenoxathiin-2-carbonylmethyl)- or N-(phenoxathiin-10,10-
dioxide-2-carbonylmethyl)pyridinium halides 5-8 reacted with p-nitrosodimethylaniline, under basic conditions,
leading to the corresponding nitrones 9, 10. The pyridinium N-ylide intermediates were not isolated. In the
classical Kröhnke reaction, NaOH was used as base (mode A for 7); the use of triethylamine as catalyst
increases the reaction yield by 40% (mode B, Table 1). The analogous reactions of S-[(phenoxathiin-2-
carbonyl)methyl]tetrahydrothiophenium bromide (11), the corresponding 10,10-dioxide 12, and
dimethylsulfonium chloride 13 (triethylamine as a catalyst) through nonisolated S-ylide intermediates were also
carried out (modes C, D). The reaction yields are lower than in the case of N-ylide intermediates, showing the
comparatively lower reactivity of S-ylides (Table 1).
In the second step of the Kröhnke reaction, the obtained nitrones 9, 10 were hydrolyzed under acid
catalysis to the corresponding glyoxals 14, 15 having the same characteristics as previously reported in the
literature [9, 10].
New benzofuran derivatives 16-18 were obtained in very good yields by cyclocondensation of
2-ω-bromoacetylphenoxathiin (3) with 2-hydroxybenzaldehyde (19), 5-formyl-2-hydroxy-3-methoxybenzaldehyde
(20), and 1-formyl-2-hydroxynaphthalene (21) under K2CO3 catalysis in refluxing ethanol (Scheme 2).
__________________________________________________________________________________________
1
Faculty of Chemistry, Org. Chem. Dept., University of Bucharest, 90-92 Panduri Road, 76233,
Roumania; e-mail: gloloiu@chem.unibuc.ro. 2 Faculty of Pharmacy, Org. Chem. Dept., University of Medicine
and Pharmacy "Carol Davila", 6 Traian Vuia street, Bucharest, Roumania. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, 265-271, February, 2002. Original article submitted October 27, 2000.
242
0009-3122/02/3802-0242$27.00©2002 Plenum Publishing Corporation

Scheme 1
O
Z
O
Me2SO
HCl
O
Z
N
Me
Me
+
Z
1 Z = S; 2
Br2,
COCH2S
+
COMe
I2
N
COCH2
Z = SO2
_
_
Cl
X
13 Z = S
5 Z = S, X = Br
6 Z = SO2, X = Br
7 Z = S,
AcOH
Py
O
Z
X = I
8 Z = SO2, X = I
COCH2Br
3 Z = S; 4 Z = SO2
NMe2
ON
Et3N (D)
S
NaOH (A)
or
O
_
NMe2
ON
Br
5 '
2 '
+
4 '
3 '
Et3N (B)
Z
S
COCH21 '
11 Z = S; 12 Z = SO2
NMe2
Et3N (C)
ON
5
O
6
9
4
4 '
1 '
4a
5a
9a
O
Z
3 '
2 '
7
8
3
2
+
1
2 '
3 '
H2O/H
Me
Me
CH(OH)2
2
C
1 '
4 '
Z
10a
N
O
N
C
O
CH
10
1
6 ' 5 '
O
9 Z = S; 10 Z = SO2
14 Z = S; 15 Z = SO2

TABLE. Characteristics of the Synthesized Products 9-12, 16-18
Com-
Empirical
S, %
Name
Yield, %
*
mp, °C (solvent)
RT, min.
pound
formula
Calc.
8.19
Found
8.43
N-(Phenoxathiin-2-carbonylmethylene)-4'-(N,N-dimethyl-
amino)aniline N-oxide
C22H18N2O3S
C22H18N2O5S
C18H17BrO2S2
C18H17BrO4S2
120-121 (toluene–petr. ether)
171-173 (toluene–petr. ether)
144-146
3.7
2.4
4.0
2.3
9
2
N-(Phenoxathiin-10,10-dioxide-2-carbonylmethylene)-
7.57
15.63
14.50
7.24
15.34
14.68
*
10
11
12
4'-(N,N-dimethylamino)aniline N-oxide
S-(Phenoxathiin-2-carbonylmethyl)tetrahydrothiophenium
bromide
S-(Phenoxathiin-10,10-dioxide-2-carbonylmethyl)tetra-
95
86
188-189
hydrothiophenium bromide
2'-Benzo[b]furyl 2-phenoxathiinyl ketone
C21H12O3S
C23H16O5S
9.31
7.97
9.39
8.28
96.5
86.0
155-156 (ethanol)
188–189 (toluene)
7.2
5.6
16
17
2'-(5'-Formyl-7'-methoxy)benzo[b]furyl 2-phenoxathiinyl
ketone
2'-Naphto[1,2-b]furyl 2-phenoxathiinyl ketone
C25H16O3S
8.13
8.27
88.1
186-187 (toluene)
11.2
18
_______
* Yield, %: 30.8 – mode A, 83.3 – mode B, 65.4 – mode C, 42.5 – mode D.
*2 Yield, %: 85.6 – mode B, 66.8 – mode C.

1
The new compounds 9-12, 16-18 were characterized by elemental analyses, IR, UV, H NMR, and
13C NMR spectral data (Tables 2-4).
Scheme 2
CHO
4 '
O
3 'a
OH
3 '
2 '
5 '
6 '
19
7 'a
3 'a
C
O
S
O
K2CO3
7 '
1 '
CHO
OHC
16
4 '
CHO
OH
O
5 '
3 '
OMe
20
2 '
3
6 '
C
S
7 'a
O
7 '
K2CO3
1 '
OMe
O
17
CHO
5 '
4 '
3 'b
OH
6 '
7 '
O
3 'a
3 '
2 '
7 'a
21
8 '
K2CO3
C
9 'a
S
O
9 '
1 '
O
18
1
The H NMR and 13C NMR spectra (Table 3 and 4) are in perfect agreement with the suggested
1
structures of all the new compounds. The bidimensional connectivity experiments (1H–1H- and H–13C-COSY)
allowed more accurate assignments of aromatic and heteroaromatic H- and C-signals.
TABLE 2. IR and UV Spectra of the Synthesized Compounds 9-12, 16-18
Compound
IR, cm-1
9
10
11
12
16
17
18
1661 vs
νC−O−Cas 1262 s
1647 vs
1269 vs
1662 vs
1264 vs
1674 vs
1275 vs
1634 vs
1271 vs
1649 s
1267 vs
1635 s
1272 vs
νC=O
(phenox.)
νC–O–Csym 1063 s
1063 s
1080 s
1064 s
1080 m
1079 m
831 s
1081 m
(phenox.)
γ2CH
γ4CH
Others
818 m
736 m
1257 vs
829 m
753 s
1240 vs
818 m
750 s
2929 m
832 m
763 m
1309 vs
836 s
735 s
furan:
3128 w
(νCH)
745 vs
(γCH)
832 s
742 vs
furan:
3116 w
(νCH)
749 vs
(γCH)
746 s
1150 vs
(νO-CH3)
1699 vs
(νCHO)
furan:
(νN→O) (νN→O) (νCH2as
)
(νSO2as
1156 vs
(νSO2sym
2926 m
)
1603 s
(νC=N)
1603 s
2853 m
(νCH2sym
(νC=N)
1297 vs
)
)
3135 w
(νCH)
749(γCH)
(νSO2as
1155 vs
(νSO2sym
)
(νCH2as)
2858 m
)
(νCH2sym
)
λ, nm
235
280
318
451
218
291
323
469
222
270
212
226
277
314
226
284
316
222
272
318
363
264
288
_______
vs – very strong, s – strong, m – medium, w – weak.
245

TABLE 3. 1H NMR Data for Compounds 9-12, 16-18 (δ, ppm, J, Hz, DMSO-d6)
Atom
H(1)
H(3)
H(4)
9
10
11
12
16
17
18
7.89, d, J13 = 1.7
7.83, d, J34 = 8.6
7.18, d, J43 = 8.5
8.61, s
7.90, s
8.71, s
7.86-7.88, m, 3H
(+H(5'))
7.24, d, J43 = 8.4
7.97, s
7.91-7.93, m, 3H
(+H(10'))
7.25, d, J43 = 8.3
8.36, d, J34 = 8.6
7.71, d, J43 = 8.8
7.82, d, J34 = 8.8
7.24, d, J43 = 8.7
8.44, d, J34 = 8.8
7.84, d, J34 = 8.6
7.24, d J43 = 8.6
7.81, d
J
43 = 8.7
H(6)
7.64, bd, J67 = 8.3
7.94, bd
7.13, dd
7.10-7.14 m, 2H
7.13-7.16, m, 2H
J
67 = 7.7
J67 = 7.8 , J68 = 1.2
7.10-7.14, m, 2H
7.22-7.28, m, 2H
7.11-7.16, m, 2H
7.27-7.30 m, 2H
H(8)
H(7)
7.57, bt, J = 7.3
7.86, bd, J = 8.5
7.63,d, J89 = 7.8
7.14, bd, J89 = 7.7
7.92, t
7.21-7.28, m, 2H
7.23-7.28 m, 2H
7.28-7.31, m, 2H
J
78 = 7.8
J
76 = 7.7
H(9)
H(2')
8.11, d, J98 = 7.8
7.85, d, J3'2' = 8.8
8.19, d, J98 = 8.1
3.56-3.69
7.82, d, J3'2' = 9.3
6.75, d, J3'2' = 9.3
—
3.55-3.69, m, 4H
2.25-2.36, m, 4H
—
—
7.84, s
—
8.02, s
—
—
m, 4H
H(3')
H(6')
6.75, d, J3'2' = 8.8
2.24-2.37
m, 4H
8.55, s
—
—
7.39, bt. J6'5' = 7.6
6'7' = 7.4
8.50, d, J6'7' = 8.0
J
H(7')
—
—
—
—
7.57, td, J7'8' = 8.4
7.52, s
7.60, t, J7'8' = 7.3
J
7'6' = 7.4, J7'5' = 1.1
J7'6' = 7.9
Others
8.75, s (CH=N)
3.00, s (2CH3)
8.89, s (CH=N)
3.07, s (2CH3)
5.30, s (CH2)
5.72, s (CH2)
7.77, d, J7'8' = 8.5
10.02, s (CHO)
7.83, s (H(5'))
4.04, s (OCH3)
7.70, t, J8'7' = 7.3;
8'9' = 7.6, (H(8'))
8.09, d, 2H (H(9'), H(11'))
(H(8'))
J

TABLE 4. 13C NMR Data for Compounds 9-12, 16-18 (δ ppm, DMSO-d6)
Atom
C(1)
C(2)
C(3)
C(4)
C(4a)
C(5a)
C(6)
C(7)
C(8)
C(9)
9
10
11
12
16
17
18
127.08
134.50
128.75
117.83
154.38
150.40
117.79
127.02
126.59
128.55
118.18
119.49
181.41
122.89
110.85
152.14
110.85
122.89
—
123.42
134.36
134.36
119.70
153.32
150.48
119.26
135.33
126.08
123.08
124.32
124.44
185.06
122.99
110.83
152.26
110.83
122.99
—
128.75
130.91
129.23
117.91
155.54
149.97
117.51
127.13
125.86
127.84
118.11
119.85
190.0
42.71
28.22
28.22
42.71
—
124.20
131.01
134.25
120.52
154.47
150.45
119.72
135.57
126.40
123.15
124.66
124.83
197.05
42.81
28.32
28.32
42.81
—
128.12
133.49
129.94
117.86
154.66
150.43
117.86
127.11
125.66
128.72
118.83
119.90
181.33
155.30
117.11
128.60
124.17
112.30
126.84
151.15
128.15
133.05
129.98
117.84
154.77
150.30
117.84
127.08
125.65
128.59
118.07
119.86
192.16
152.40
117.51
120.89
133.05
107.46
146.05
147.91
128.16
133.70
129.97
117.87
154.60
150.50
117.87
127.14
128.61
128.61
118.36
119.90
180.72
153.87
116.6
124.07
127.56
125.74
130.32
127.88
122.71
(C(3'a))
130.17
(C(3'b))
112.80
(C(8'))
128.97
(C(9'))
150.96
(C(9'a))
C(9a)
C(10a)
CO
C(2')
C(3')
C(4')
C(5')
C(6')
C(7')
C(7'a)
Others
—
—
—
—
—
—
136.91
(C(1'))
125.56
(CH=N)
39.87
136.78
(C(1'))
125.66
(CH=N)
39.84
123.88
128.47
(C(3'a))
192.16
(CHO)
56.22
(C(3'a))
(CH3)
(CH3)
(OCH3)
EXPERIMENTAL
The IR spectra were recorded in KBr pellets on a FTS-135 Biorad instrument (Table 2), the UV spectra
on a Specord UV-vis C. Zeiss Jena apparatus (Table 1), and the NMR spectra (Tables 3 and 4) on a Jeol-
1
LAMBDA 400 (400 MHz for H and 100 MHz for 13C) spectrometer in DMSO-d6, using TMS as internal
standard. Melting points were determined on a Boetius apparatus and are uncorrected. The HPLC analysis were
performed on a Beckman liquid chromatograph, Gold-126 system equipped with a UV-Diode Array Gold-168
detector; stationary phase octylsilane (5 µm); 25 cm × 4.6 mm column. Detection was made at 270 nm, and the
mobile phase was methanol–water (80:20) at 1.5 ml/min.
The starting compounds 1-8, 13, 14 were obtained according to the literature [10-13]. The
characteristics of the products 9-12, 16-18 are given in Table 1.
Tetrahydrothiophenium Bromides 11, 12. A solution of tetrahydrothiophene (2 mmol) and α-bromo
ketone 3, 4 (2 mmol) in anhydrous toluene (15 ml) was refluxed for 5 h. The resulting solid was filtered after
24 h and washed with petroleum ether.
Nitrones 9, 10. A. To a cooled (-2°C) suspension of N-(phenoxathiin-2-carbonylmethyl)pyridinium
iodide (7) (33 mmol) in water (5ml), a solution of p-nitrosodimethylaniline (37 mmol) in ethanol (20 ml) was
added in small portions with stirring. To the reaction mixture an ice-cooled 1N solution of NaOH (4 ml) was
added dropwise and stirring was continued for 2 h at room temperature. The red precipitate was filtered off and
then washed with 3 ml ethanol.
247

B. To an ice-cooled suspension of pyridinium halide 5-8 (33 mmol) in ethanol (15 ml), a solution of
triethylamine (15 mmol) in ethanol (5 ml) was added dropwise for 15 min with stirring. A solution of
p-nitrosodimethylaniline (12 mmol) in 5 ml of ethanol was added to the reaction mixture and the stirring was
continued for another 2 h at room temperature. The red precipitate was filtered off. Using the same procedure,
nitrones 9, 10 were obtained starting from tetrahydrothiophenium bromides 11, 12 or from S-(phenoxathiin-2-
carbonylmethyl)dimethylsulfonium chloride (13).
Phenoxathiinyl Glyoxal Hydrates 14, 15. To a suspension of nitrone 9, 10 (15 mmol) in water (2 ml),
H2SO4 5N (5 ml) was added. The reaction mixture was maintained at room temperature for 6 h with stirring and
then was extracted with ether (3 × 10 ml). After the ether was removed by evaporation, the obtained solid was
recrystallized from 80% AcOH giving crystals of 2-(2'-phenoxathiinyl)glyoxal hydrate (14) (mp 132-134°C;
24% yield) and 2-(2'-phenoxathiinyl-10,10-dioxide)glyoxal hydrate (15) (mp 128.5-129.5°C; 35% yield).
Furan Derivatives 16-18. To 2-ω-bromoacetylphenoxathiine (3) (2.5 mmol) a solution of aldehydes
19-21 (2.5 mmol) in ethanol (20 ml) and anhydrous K2CO3 (3.5 g) were added. The reaction mixture was
refluxed for 90 min (16, 18) and 4 h respectively (17). After removing the solvent by vacuum distillation, water
was poured over the residue and the resulting solid was filtered off, washed with water, and dried.
REFERENCES
1.
2.
C. T. Supuran, A. Scozzafava, F. Briganti, G. Loloiu, and O. Maior, Eur. J. Med. Chem., 33, 821 (1998).
K. H. Komig, L. Kaul, M. Kuge, and M. Schuster, Liebigs Ann. Chem., 1115 (1987).
M. Vas Dort, R. Neubig, and R. E. Counsell, J. Med. Chem., 30, 1241 (1987).
G. Loloiu, C. Draghici, and T. Loloiu, O. Maior, Khim. Get. Soed., 999 (1998).
P. V. Litvinov, Zh. Org. Khim., 31, 1441 (1995).
3.
4.
5.
6.
D. B. Reusching and F. Kröhnke, Chem. Ber., 104, 209 (1971).
7.
R. G. Hiskey, T. Mizoguchi, and H. Igeta, J. Org. Chem., 31, 1185 (1966).
H. Nozaki, M. Takaku, and K. Kondo, Tetrahedron, 22, 2145 (1966).
A. Nicolae, D. Gavriliu, O. Maior, and C. Draghici, South. Braz. J. Chem., 6, No. 7, 33 (1998).
A. Nicolae, D. Gavriliu, and O. Maior, South. Braz. J. Chem., 6, No. 7, 47 (1998).
G. Vasiliu and O. Maior, Anal. Univ. Buc., 13, 103 (1964).
D. Gavriliu, S. Stoia, S. Florea, and O. Maior, Anal. Univ. Buc., 105 (1997).
O. Maior, D. Gavriliu, and S. Stoia, South. Braz. J. Chem., 3, No. 3, 79 (1995).
8.
9.
10.
11.
12.
13.
248