Alkyl heteroaromatics as building blocks in organic synthesis: The reactivity of alkyl azoles toward electrophilic reagents

Article abstract of DOI:10.1515/znb-1999-0716

Oxazolone (1) couples with aromatic diazonium salts to yield the arylhydrazones (3a-c). Compound 3 reacts with aniline to give aryl hydrazone (5). Compound 5 was also obtained via converting 1 into the imidazolone (4) and subsequent treatment of 4 with aromatic diazonium salts. Compounds 1 and 12 reacted with arylidenemalononitrile (6) to yield compounds 8 and 14 respectively. Also compounds 1, 12 condensed with an aromatic aldehydes to yield 11 and 17. Compounds 11, 17 reacted further with one molecule of malononitrile to give compounds 8 and 14, respectively. Compound 20 which was generated in situ by heating phenacylthiocyanate (19) in acetic anhydride on treatment with hydrazine hydrate or phenyl hydrazine gives 21 and 22 respectively. Also 20 reacted with malononitrile or with ethyl cyanoacetate to give 23 and 24, respectively.

Full text of DOI:10.1515/znb-1999-0716

Alkyl Heteroaromatics as Building Blocks in Organic Synthesis:
The Reactivity of Alkyl Azoles toward Electrophilic Reagents
I. S. Abdel Hafiz3, A. A. Hassanien3, and A. M. Hussein13'*
a Department of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt
b Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
* Reprint requests to Dr. A. M. Hussein. Fax: 002 088 325436.
E-mail: haleem_m_h@hotmail.com
Z. Naturforsch. 54b, 923-928 (1999); received January 14, 1999
Oxazolone, Imidazolone, Oxazolopyridines, Pyridobenzoxazine, Thiazolone
Oxazolone (1) couples with aromatic diazonium salts to yield the arylhydrazones (3a-c).
Compound 3 reacts with aniline to give aryl hydrazone (5). Compound 5 was also obtained
via converting 1 into the imidazolone (4) and subsequent treatment of 4 with aromatic diazo-
nium salts. Compounds 1 and 12 reacted with arylidenemalononitrile (6) to yield compounds
8 and 14 respectively. Also compounds 1, 12 condensed with an aromatic aldehydes to yield
11 and 17. Compounds 11, 17 reacted further with one molecule of malononitrile to give
compounds 8 and 14, respectively. Compound 20 which was generated in situ by heating
phenacylthiocyanate (19) in acetic anhydride on treatment with hydrazine hydrate or phenyl
hydrazine gives 21 and 22 respectively. Also 20 reacted with malononitrile or with ethyl
cyanoacetate to give 23 and 24, respectively.
Alkyl functions in jr-deficient alkylheteroaro-
matics are reactive toward electrophiles under
mild conditions [1-3]. This reactivity has been
extensively utilized for the synthesis of otherwise
not readily obtainable heterocyclic derivatives
[4-6]. We investigated the reactivity of an alkyl
function in 2-methyl-4-benzylidene-2-oxazolin-5-
one (1) and 2-methyl-l,3-benzoxazin-3-one (12)
toward electrophilic reagents. Also work, aimed
at the exploration of the potential of thiazolone
as precursors for polyfunctionally substituted
heteroaromatics, is reported here. So, we have
found that the methyl function in 1 readily cou-
ples with aromatic diazonium salts in acetic acid
solution and in presence of ammonium acetate
to yield the corresponding arylhydrazones (3a-c).
Compound 3a reacted with aniline to give the
arylhydrazone (5). Compound 5 was also ob-
tained via converting 1 into the imidazolone (4),
utilizing a literature procedure [7], and subse-
quent treatment of 4 with aromatic diazonium
salts (c.f. Scheme 1).
Scheme
1
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924
I. S. Abdel Hafiz et al. • Alkyl Heteroaromatics as Buildilng Block in Organic Synthesis
Trials to couple 12 with aromatic diazonium active toward carbon electrophiles, to our knowl-
salts failed. This can be rationalized in terms of edge, this is the first reported reaction of methyl
the great instability of such a structure in aqueous azole derivatives with aryldiazonium salts. It is of
medium [8]. Although the alkyl function in hetero- a value to report that coupling took place only in
aromatic azoles has been previously shown to be acetic acid and in presence of ammonium acetate.
.0
CH2(CN)2
ArC HO,
CN
Ph'^^j------
ArY
^
CN
X NYCH°2
LC N ^ cn
6,8,a, Ar = Ph
, b, Ar = p-anesyl
,c, Ar = C 6H4CI-p
o
Ph"^j------
nh2^
^
^0
CN
CN
cr
Ar
Ar
10
Scheme 2
14
,b, Ar = p-anesyl
,c, Ar = C5H4CI-P
Scheme
3
16
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925
I. S. Abdel Hafiz et al. ■Alkyl Heteroaromatics as Buildilng Block in Organic Synthesis
PhCO CH 2 Br + K SC N
PhCO CH 2 SC N
18
19
AC2O
Ph.
>
ch3^ n ^ s
CH3y
V
C H 3 . . N
S
T
T
O
N-NHPh
n h 2-n
n -n h 2
°
0
d
S
/
\
c
21
22
20
Y T
Y T
0CN A . CONH2
CN
CO O Et
24
23
a = NH2 NH2 b = PhNHNH2 , c = CH 2 (CN)2 , d = CN CH 2 CO OEt
Scheme 4
In media like EtOH/NaOAc, pyridine or EtOH/
NaOH, no coupling was observed. We do believe
that the presence of acetic acid is essential to pro-
tonate the ring nitrogen and that the Zwitter ion
2 is the reactive species.
ethanolic solution. Also it reacted with phenyl hy-
drazine to give compound 22. The reaction of 20
with active methylene shows that 23 affords with
malononitrile in ethanolic triethylamine com-
pound and with ethyl cyanoacetate to yield 24.
Compound 1 reacted with arylidenemalononit-
rile (6) in acetic acid and in presence of sodium
acetate to yield 1:1 adducts. These may be formu-
lated as 8 or isomeric 10. Acyclic products (7) were
ruled out based on ‘H NMR which did not reveal
expected multiplets for protons linked to a sp3 car-
bon. Structure 8 is preferred over 10 as demon-
Experimental
Melting points (uncorrected) were measured on
a Gallenkamp apparatus. IR spectra of KBr discs
recorded on a FT IR-820 IPC infrared spectropho-
tometer Shimadzu (v, cm-1). 'H NMR spectra
were recorded for CDCI3 solution on a Varian T-
60 NMR spectrometer using Me4Si as an internal
strated by
NMR which revealed a dihydropyri-
reference. Mass spectra were recorded on
a
dine proton at 6 6.45. Isomeric 10 should show
these protons at much higher field (ca. 5.0 ppm).
Compound 8 was also obtained via reaction of 1
with an aromatic aldehyde to yield 11. Subsequent
reaction of 11 with one mole of malononitrile to
yielded 8.
GCMS-QP 1000 Ex spectrometer. Elemental
analysis were carried out at the microanalytical
laboratory, University of Cairo. Melting points,
percentage yields and analytical data of the com-
pounds are listed in Tables I and II.
Similarly, compound 12 was reacted with aryli-
denemalononitrile (6) in acetic acid and in pres-
ence of sodium acetate to yield 1:1 adducts. These
may be formulated as 14 or isomeric 16. Structure
14 is the main product based on spectral data.
Compound 14 was also obtained via reaction of 12
with the aromatic aldehyde to yield 17 and subse-
quent reaction of 17 with one mole of malononit-
rile to give 14.
Preparation o f aryl hydrazones 3a-c
A solution of diazotized amines (prepared from
0.01 mol of aromatic amines and appropriate
quantities of sodium nitrite and hydrochloric acid)
was added to 0.01 mol of methyloxazolinone (1 )
in 100 ml acetic acid and 4.0 g ammonium acetate.
The reaction mixture was stirred in an ice-bath for
3 h. The solid product was washed with water, fil-
tered off, and crystallized from the proper solvent.
Compound 20 was generated in situ by heating
phenacyl thiocyanate (19) in acetic anhydride for
a short period. This compound afforded com-
4-Benzylidene-3-methyl-2-imidazol-5-one 4
To a solution of 1 (0.01 mol) in pyridine (20 ml),
pound 21 on treatment with hydrazine hydrate in the appropriate amount of aniline (0.01 mol) was
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926
I. S. Abdel Hafiz et al. • Alkyl Heteroaromatics as Buildilng Block in Organic Synthesis
Table I. Yields, melting points, and elemental analysis of the new compounds.
Comp.
M.p.
[°C]
227
205
217
168
180
175
190
80
Solvent
Colour
Yield
[%]
50
65
Molecular
formula
(MS)
Calcd (Found) [%]
C
H
N
3a
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
red
brown
red
70.1
4.46
(4.6)
3.68
(3.7)
4.91
(5.0)
4.91
(5.2)
4.39
(4.5)
4.58
(4.7)
3.73
(3.9)
4.72
4.9
4.91
(5.2)
3.87
(4.0)
4.12
(4.3)
4.34
(4.4)
3.43
(4.6)
4.41
(4.5)
4.65
(4.8)
3.52
(3.7)
4.14
(4.2)
6.06
(6.2)
4.89
(5.0)
3.89
(4.0)
4.49
(4.6)
C17H13N3O2
(290)
14.43
(14.5)
12.90
(13.1)
13.77
13.9
(70.2)
62.67
(62.8)
70.08
(70.3)
75.4
3b
c 1vh 12n ?o 2ci
(325)
3c
62
Ci8H15N30 2
(304)
c 23h 18n 4o
(366)
C2]H13N30 2
(341)
C22H)7N30 3
(370)
c 12h 14n 5o 2ci
(375)
Ci8H13N 02
(276)
c 19h 15n o 3
(306)
5
brown
yellow
yellow
yellow
brown
yellow
buff
75
5.30
(75.7)
73.9
(5.5)
12.31
(12.5)
11.32
(11.6)
11.18
(11.3)
5.09
(5.2)
4.59
(4.7)
4.52
8a
65
(74.1)
71.15
(71.3)
67.11
(67.2)
78.74
(78.9)
74.75
(75.0)
69.78
(70.0)
72.38
(72.6)
69.56
(69.7)
65.23
(65.4)
77.10
(77.3)
73.11
(73.3)
67.72
(67.9)
60.26
(60.4)
52.99
(53.2)
66.00
(66.2)
58.94
(59.1)
61.13
(61.3)
8b
78
70
80
75
8c
11a
lib
11c
14a
14b
14c
17a
17b
17c
20
172
188
240
210
268
140
206
185
135
128
185
260
212
78
50
55
60
62
72
65
70
65
68
75
78
c 18h 12n o 2ci
(310)
(4.6)
13.33
(13.5)
12.17
(12.3)
12.01
(12.2)
5.62
brown
c 19h 13n 3o 2
(315)
yellow
yellow
buff
C2oH15N30 3
(344)
EtOH/
DMF
EtOH
c 19h 12n ,o 2ci
(350)
c 16h un o 2
(249)
c 17h 13n o 3
(279)
c 16h 10n o 2ci
(287)
c uh 9n o ,s
(219)
c „ h 15n 5s
(249)
(5.8)
5.01
EtOH
EtOH
EtOH
EtOH
EtOH
colourless
colourless
colourless
colourless
Yellow
colourless
Yellow
(5.3)
4.93
(5.1)
6.39
(6.4)
28.09
(28.3)
13.58
(13..7)
14.73
(14.9)
8.91
21
22
c 17h 15n 3o s
(3Ö9)
23
EtOH/
DMF
EtOH
c 14h „ n 3o 2s
(285)
24
c 16h 14n 2o 3s
(314)
(9.1)
added. The reaction mixture was refluxed for five
imidazolinone (4) in 100 ml acetic acid and 4.0 g
hours and then evaporated in vacuo. The remain- ammonium acetate. The reaction mixture was
ing product is poured on ice, acidified by hydro- stirred in ice-bath for 3 h. The solid product was
chloric acid. The solid product was collected by
filtration and crystallized from ethanol.
washed with water, filtered off, and crystallized
from ethanol.
Method (B): To a solution of 3a (0.01 mol) in
pyridine (20 ml), the appropriate amount of ani-
line (0.01 mol) was added. The reaction mixture
was refluxed for five hours and then evaporated
Preparation o f aryl hydrazone 5
Method (A): A solution of benzene diazonium
salt (prepared from 0.01 mol of aniline and the
appropriate quantities of sodium nitrite and hy- in vacuo. The remaining product was poured on
drochloric acid) was added (0.0 1 ) mol of methyl- ice/water, acidified by hydrochloric acid. The solid
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927
I. S. Abdel Hafiz et al. • Alkyl Heteroaromatics as Buildilng Block in Organic Synthesis
Table II. Spectroscopic data of new compounds.
Comp.
3a
IR [cm -1]
*H NMR
3306-3212 (NH2), 1689
(CO), 1631 (C=N)
4.65(s,lH,CH), 7.0-7.8 (m ,llH , Ar-H), 9.5 (s, 1H, NH)
3b
4.6 (s, 1H, CH), 7.0-7.6 (m, 10H, Ar-H), 9.5 (s, 1H, NH)
3330-3055 (NH), 1776
(CO), 1630 (C=N)
2.7 (s,3H, CH3), 4.6 (s, 1H, CH), 1.0-1.6 (m, 10H, Ar -H),
9.8 (s, 1H, NH)
3c
3240-3100 (NH), 1680 (CO)
4.6 (s, 1H, CH), 1.0-1.1 (m, 16H, Ar-H), 9.7 (s,lH, NH)
6.4 (s, 1H, 2H-pyridine), 7.3-7.55 (m, 12H, Ar-H ), 9.8 (s,
2H, NH2)
3.4 (s, 3H, CH3), 4.6 (s, 1H, CH), 6.6 (s, 1H, 2H-pyridine),
7.3-7.5 (m, 10H, Ar-H), 8.7 (d, 2H, NH2)
4.5 (s, 1H, CH), 5.6 (s, 1H, 2H-pyridine), 7.4-8.0 (m, 10H,
Ar-H), 12.2 (s, 2H, NH ,)
5
8a
3307-3120 (NH), 1690 (CO)
3360-3100 (NH2), 2210
(CN), 1700 (CO)
3340-3110 (NH2), 2214 (CN),
1672 (CO)
8b
8c
3454-3200 (NH2), 2212 (CN),
1701 (CO)
4.3 (s, 1H, CH), 6.3 (d, 1H, CH), 6.6 (d, 1H, CH), 1 2 -1 .9
(m, 10H, Ar-H)
.3.4 (s,3H,CH3), 4.33 (s, 1H, CH), 6.2 (d, 1H, CH), 6.6 (d,
1H, CH), 1.2-1.1 (m, 9H, Ar-H)
.4,4 (s, 1H, CH), 6.0 (d, 1H, CH), 6.4 (d, 1H, CH), 1.2-1.6
(m, 9H, Ar-H)
7.0 (s,lH, 2H-pyridine), 7.4-8.2 (m, 10H, Ar-H), 12.3 (s,2H,
NH2)
3.5 (s,3H, CH3), 7.0-7.1 (s, 1H, 2H-pyridine), 7.4-8.0 (m,
9H, Ar-H), 12.2 (s, 2H, NH2)
7.0-7.2 (s, 1H, 2H-pyridine), 7.4-8.2 (m, 9H, Ar-H), 12.3
(s,2H, N H ,)
11a
lib
11c
14a
14b
14c
17a
17b
17c
20
3060-3030 (Ar-CH), 1732 (CO)
3050-3030 (Ar-CH), 1725 (CO)
3050-3030 (Ar-CH), 1728 (CO)
3350-3180 (NH2), 2200 (CN),
1700 (CO)
3340-3170 (NH2), 2210 (CN),
1700 (CO)
3345-3155 (NH2), 1705 (CO)
6.3 (d, 1H, CH), 6.6 (d, 1H, CH), 1.2-1.9 (m, 9H, Ar-H)
3070-3008 (Ar-CH), 1762 (CO),
1640 (C=N)
3060-3000 (Ar-CH), 1750 (CO),
1634 (C=N)
3080-3000 (Ar-CH), 1782 (CO),
1645 (C=N)
2.9 (s, 3H, CH3), 6.4(d, 1H, CH), 6.8 (d, 1H, CH), 1.2-1.9
(m, 8H, Ar-H)
6.5 (d, 1H, CH), 6.9 (d, 1H, CH), 1.2-1.9 (m, 8H, Ar-H)
2.4 (s, 3H, CH3), 6.8 (s, 1H, thiazole-H), 7.4-7.8 (m, 5H,
Ar-H)
1660 (CO), 1670 (CO)
2.2 (s, 3H, CH3), 6.9 (s, 1H, thiazole-H), 7.4-8.0 (m, 9H,
Ar-H and NH2)
3359-3126(NH ,)
21
2.4 (s, 3H, CH,), 6.8 (s, 1H, thiazole-H), 72-7.9 (m, 10H,
Ar-H), 9.8 (s, 1H, NH)
3220 (NH), 1670 (CO)
22
2.2 (s, 3H, CH3), 6.8 (s, 1H, thiazole-H), 72-7.9 (m, 7H, Ar-
H and NH2)
1.2 (t, 3H, CH,), 2.4 (s, 3H, CH3), 4.2 (q, 2H, CH,), 7.1 (s,
1H, thiazole-H), 75-7.9 (m, 5H, Ar-H)
23
3415-3300 (NH2), 2221 (CN),
1703 (amidic CÖ0, 1691 (ring CO)
2204 (CN), 1720 (ester CO), 1678
(ring CO)
24
Reaction o f 1 and 12 with aromatic aldehydes.
General procedure
product was washed with water and crystallized
from ethanol.
To a solution of 1 or 12 (0.01 mol) in acetic acid
(50 ml), 4 g of sodium acetate and the appropriate
aromatic aldehyde (0,01 mol) were added. The re-
action mixture was refluxed for 5 h and then evap-
orated in vacuo. The remaining product was
poured on ice and neutralized by sodium carbon-
ate. The solid product was then collected by filtra-
tion and crystallized from ethanol.
Preparation of condensed pyridines 8a-c and
14a-c General procedure
To a solution of 1 or 12 (0.01 mol) in acetic acid
(50 ml), 4 g of sodium acetate and the appropriate
6a-c (0.01 mol) were added. The reaction mixture
was refluxed for 5 h and then evaporated in vacuo.
The remaining product was poured on ice and
neutralized by sodium carbonate. The solid pro-
duct was then collected by filtration and crystal-
lized from the proper solvent.
Preparation o f thiazolone 20
2
g of the thiocyanate derivative 19 (0.01 mol)
were dissolved in 20 ml acetic anhydride and
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928
I. S. Abdel Hafiz et al. ■Alkyl Heteroaromatics as Buildilng Block in Organic Synthesis
heated under reflux for 1 h, then left to stand and
poured on water. The solid product formed after
standing overnight was filtered off and recrystal-
lized from ethanol as colorless crystals.
temperature. The solid product was filtered off
and recrystallized from ethanol as yellow crystals.
Reaction o f 20 with active methylene.
General procedure
Equimolar amounts of 20 and malononitrile or
ethyl cyanoacetate in ethanol (30 ml) were treated
with little amount of triethylamine. The reaction
mixture was refluxed for 3 h and then left to over-
night at room temperature. The precipitate formed
was collected by filtration and recrystallized from
ethanol.
Preparation o f compounds 21 and 22.
General procedure
To a solution of 20 (0.01 mol) in ethanol (30 ml),
the hydrazine hydrate or phenyl hydrazine (0.01
mol) was added. The reaction mixture was re-
fluxed for 3h and then left to overnight at room
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