Reactions of β-aroylacrylic acids with N-nucleophiles

Article abstract of DOI:10.1007/s11172-006-0068-7

Reactions of NH₂OH·HCl with β-aroylacrylic acids proceed ambiguously: a nucleophile attacks either the carbonyl group or the C=C bond. In the latter case, the resulting α-hydroxylamino derivative converts into enamine, probably via dehydration

Full text of DOI:10.1007/s11172-006-0068-7

1982
Russian Chemical Bulletin, International Edition, Vol. 54, No. 8, pp. 1982—1986, August, 2005
Brief Communications
Reactions of βꢀaroylacrylic acids with Nꢀnucleophiles
R. Dj. Khachikyan,a N. V. Karamyan,aꢀ H. A. Panosyan,b and M. H. Injikyana
aInstitute of Organic Chemistry, National Academy of Sciences,
167ꢀA ul. Z. Sarkavag, 375091 Yerevan, Republic of Armenia.
Fax: (374 1) 28 3511. Eꢀmail: Nara7777@mail.ru
bMolecular Structure Research Center,
Yerevan, Republic of Armenia
Reactions of NH2OH•HCl with βꢀaroylacrylic acids proceed ambiguously: a nucleophile
attacks either the carbonyl group or the C=C bond. In the latter case, the resulting αꢀhydroxylꢀ
amino derivative converts into enamine, probably via dehydration followed by isomerization.
Addition of 1,2,4ꢀtriazole to the C=C bond of βꢀ(pꢀtoluyl)acrylic acid followed by refluxing of
their adduct with 60% NH2NH2•H2O gave a dihydropyridazinone derivative.
Key words: βꢀaroylacrylic acids, hydroxylamine hydrochloride, carbonyl group, double
bond, enamine, oxime, triazole.
Scheme 1
A large number of studies devoted to reactions of
βꢀaroylacrylic acids with nucleophiles have been pubꢀ
lished to date. It is known1—8 that in reactions with water
and NH, SH, CH, and PH acids, a nucleophile attacks
the Cα atom to form αꢀsubstituted βꢀaroylpropionic acꢀ
ids. Quantumꢀchemical9 and experimental data are in
agreement. It should be noted that βꢀaroylacrylic acids
form salts with heterocyclic amines, thiourea, and thioꢀ
semicarbazide.10,11
We studied reactions of βꢀaroylacrylic acids 1 with
hydroxylamine; the expected products were either
oximes 2, which undergo subsequent cyclization into
isoxazole or oxazinone derivatives, or βꢀaroylꢀαꢀhydroxylꢀ
aminopropionic acids 3 (Scheme 1).
However, the reaction of βꢀ(pꢀtoluyl)acrylic acid (1a)
with NH2OH•HCl in aqueous methanol gave no oxime
2a or products of its subsequent transformations; instead,
a 1 : 3 mixture of αꢀaminoꢀβꢀ(pꢀtoluyl)acrylic acid (4)
and its methyl ester 5a was unexpectedly obtained in 70%
yield (Scheme 2).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1923—1927, August, 2005.
1066ꢀ5285/05/5408ꢀ1982 © 2005 Springer Science+Business Media, Inc.

βꢀAroylacrylic acids and Nꢀnucleophiles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
1983
Scheme 2
acids 1b—d. In all the cases, the corresponding oximes
2b—d were obtained as the major reaction products in 71,
45, and 50% yields, respectively (Scheme 4). Minor meꢀ
thyl αꢀaminoꢀβꢀaroylacrylates 5b—d were obtained in 19,
21, and 15.5% yields, respectively.
With βꢀ(pꢀtoluyl)acrylic acid (1a) as an example, we
found that the reaction pathway is decisively influenced
by the solvent nature. For instance, the reaction in acetoꢀ
nitrile or benzene rather than methanol gave the correꢀ
sponding oxime 2a as the only product (Scheme 5).
Scheme 5
Apparently, the reaction involves addition of NH2OH
to the double bond to form compound 3a, its dehydraꢀ
tion, and isomerization of the resulting imine into enꢀ
amine 4 (Scheme 3).
Scheme 3
Thus, the reactions of NH2OH•HCl with βꢀaroylꢀ
acrylic acids can follow alternative pathways, with an atꢀ
tack of the nucleophile on either the carbonyl group or
the C=C bond.
It is known12—14 that reactions of βꢀaroylacrylic acids
with hydrazines yield pyrazolinecarboxylic acids; dihydroꢀ
pyridazinone derivatives cannot be obtained with the use
of NH2NH2•H2O. Recently,15 we found that the imidꢀ
azolyl protection of the C=C bond in βꢀaroylacrylic acids
allows the synthesis of 2,3ꢀdihydropyridazinꢀ3ꢀone deꢀ
rivatives.
To verify the possibility of employing imidazole for
the synthesis of oxazinone derivatives from βꢀaroylacrylic
acids, we studied the reaction of adduct 6 (syntheꢀ
sized from imidazole and βꢀ(pꢀtoluyl)acrylic acid) with
NH2OH. However, the only product was αꢀaminoꢀβꢀ
(pꢀtoluyl)acrylic acid (4); i.e., in contrast to the reactions
with hydrazine, the attack by the nucleophile is preceded
by elimination of imidazole (Scheme 6).
The reaction of methyl βꢀ(pꢀtoluyl)acrylate with
hydroxylamine in the presence and in the absence of Et3N
afforded ester 5a in 58 and 61% yields, respectively.
The structures of compounds 4 and 5a were deterꢀ
mined by 1H NMR spectroscopy and confirmed by
2D NOESY NMR spectroscopy: the presence of a cross
peak between the orthoꢀprotons of the aromatic ring and
the H atom at the C=C bond unambiguously indicates
that the nucleophile attacks the αꢀposition relative to the
carboxyl group.
A different pattern was observed with βꢀbenzoylꢀ,
βꢀ(pꢀchlorobenzoyl)ꢀ, and βꢀ(pꢀbromobenzoyl)acrylic
Scheme 6
Scheme 4
1, 2, 5: Ar = Ph (b), pꢀClC6H4 (c), pꢀBrC6H4 (d)

1984
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Khachikyan et al.
In continuation of the previous investigations, here
we studied reactions of hydrazine hydrate with adducts of
βꢀaroylacrylic acids with some other amines. It was demꢀ
onstrated that 1,2,4ꢀtriazole behaves like imidazole; its
adduct with βꢀ(pꢀtoluyl)acrylic acid 7 in the presence of
hydrazine hydrate undergoes cyclization followed by
elimination of the triazole to give the corresponding
dihydropyridazinone 8 15 (Scheme 7).
acid (9, 10)16 occurs in a different way: elimination of the
amine precedes cyclization to give 3ꢀ(pꢀtolyl)pyrazolineꢀ
5ꢀcarboxylic acid (11)15 (Scheme 8).
Experimental
1
H NMR spectra were recorded on a Mercuryꢀ300 Varian
instrument. A mass spectrum was recorded on an MXꢀ1321
instrument (direct inlet probe, ionizing voltage 70 eV).
Reaction of βꢀ(pꢀtoluyl)acrylic acid (1a) with NH2OH•HCl.
Aqueous NH2OH•HCl (8.34 g, 0.12 mol) was added to a satuꢀ
rated solution of acid 1a (1.9 g, 0.01 mol) in MeOH. The reacꢀ
tion mixture was refluxed in a water bath for 30 h and then
treated with water. The precipitate was filtered off, washed with
water, and treated with 1 M KOH. The alkaline solution was
acidified with dilute HCl. The precipitate that formed was filꢀ
tered off, washed with water, dried in vacuo, and refluxed in
CHCl3 for purification. The yield of αꢀaminoꢀβꢀ(pꢀtoluyl)acrylic
acid (4) was 0.43 g (23%), m.p. 189—190 °C. Found (%):
C, 64.91; H, 5.43; N, 6.92. C11H11NO3. Calculated (%):
C, 64.39; H, 5.37; N, 6.83. 1H NMR (DMSOꢀd6—CCl4 (1 : 3)),
two isomers 4 and 4´ (60 : 40), δ: 4, 2.41 (s, 3 H, Me); 4.15 (br.s,
3 H, COOH + NH2); 7.26 (d, 2 H, pꢀC6H4, J = 8.1 Hz); 7.39 (s,
1 H, =CH); 7.75 (d, 2 H, pꢀC6H4, J = 8.1 Hz); 4´, 2.42 (s, 3 H,
Me); 4.15 (br.s, 3 H, COOH + NH2); 7.01 (s, 1 H, =CH); 7.29,
7.73 (both d, 2 H each, pꢀC6H4, J = 8.1 Hz).
Scheme 7
The precipitate that did not dissolve in KOH was filtered off,
washed with water, dried in vacuo, and refluxed in CHCl3 for
purification to give methyl αꢀaminoꢀβꢀ(pꢀtoluyl)acrylate (5a)
(0.89 g, 47%), m.p. 111—112 °C. Found (%): C, 64.43; H, 5.90;
N, 6.32. C12H13NO3. Calculated (%): C, 64.39; H, 5.93; N, 6.39.
1H NMR (DMSOꢀd6—CCl4 (1 : 3)), two isomers 5a and 5a´
(40 : 60), δ: 5a, 2.40 (s, 3 H, Me); 3.10 (br.s, 2 H, NH2); 3.96 (s,
3 H, OMe); 7.09 (s, 1 H, =CH); 7.29, 7.74 (both d, 2 H each,
pꢀC6H4, J = 8.2 Hz); 5a´, 2.40 (s, 3 H, Me); 3.10 (br.s, 2 H,
NH2); 3.97 (s, 3 H, OMe); 7.27 (d, 2 H, pꢀC6H4, J = 8.2 Hz);
7.53 (s, 1 H, =CH); 7.76 (d, 2 H, pꢀC6H4, J = 8.2 Hz). MS (EI,
70 eV), m/z (Irel (%)): 219 [M]+ (132).
We found that the reactions of hydrazine hydrate with
pyrrolidine and piperidine adducts of βꢀ(pꢀtoluyl)acrylic
Reaction of methyl βꢀ(pꢀtoluyl)acrylate with NH2OH•HCl.
Aqueous NH2OH•HCl (8.34 g, 0.12 mol) was added to a satuꢀ
rated solution of methyl βꢀ(pꢀtoluyl)acrylate (2.04 g, 0.01 mol)
in MeOH. The reaction mixture was refluxed in a water bath for
30 h and then treated with water. The precipitate was filtered
off, washed with water, dried in vacuo, and recrystallized from
MeOH to give ester 5a (1.34 g, 61%), m.p. 111—112 °C. Its
1H NMR spectrum agrees with the data given above.
Scheme 8
Under analogous conditions but in the presence of an
equimolar (with respect to NH2OH•HCl) amount of Et3N, the
yield of ester 5a was 1.27 g (58%), m.p. 112—113 °C. Its 1H NMR
spectrum agrees with the data given above.
Reactions of βꢀaroylacrylic acids 1b—d (Ar = Ph, pꢀClC6H4,
and pꢀBrC6H4) with NH2OH•HCl were carried out as described
for acid 1a. The waterꢀinsoluble precipitate was filtered off to
give methyl αꢀaminoꢀβꢀaroylacrylates 5b—d (Ar = Ph, pꢀClC6H4,
and pꢀBrC6H4). Acidification of the alkaline solution gave
βꢀaroylacrylic acid oximes 2b—d (Ar = Ph, pꢀClC6H4, and
pꢀBrC6H4) (Tables 1, 2).
βꢀ(pꢀToluyl)acrylic acid oxime (2a). Aqueous NH2OH•HCl
(8.34 g, 0.12 mol) was added to a saturated solution of
βꢀ(pꢀtoluyl)acrylic acid (1.9 g, 0.01 mol) in MeCN. The
n = 4 (9), 5 (10)

βꢀAroylacrylic acids and Nꢀnucleophiles
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
1985
Table 1. Physicochemical parameters and elemental analysis data for compounds 2b—d and 5b—d
Comꢀ
pound
Аr
Yield
(%)
M.p.
/°С
Found
Calculated
Molecular
formula
(%)
С
Н
Cl
—
Br
—
N
2b
2c
2d
5b
5c
5d
Ph
71
199—200
196—197
208—209
32—33
62.64
62.83
53.32
53.22
44.51
44.44
64.48
64.39
55.02
55.11
46.31
46.48
4.89
4.71
3.49
7.45
7.33
6.33
6.21
5.27
5.18
6.76
6.83
5.93
5.85
4.92
4.82
C10H9NO3
pꢀClС6Н4
pꢀBrС6Н4
Ph
45
15.69
15.74
—
—
С10H8ClNO3
С10H8BrNO3
С11H11NO3
3.55
2.88
2.96
5.41
5.36
4.27
4.18
3.64
3.58
56
29.62
29.69
—
19
—
pꢀClС6Н4
pꢀBrС6Н4
21
169—170
132—133
14.71
14.82
—
—
С11H10ClNO3
С11H10BrNO3
15.5
28.16
28.29
Table 2. 1H NMR spectra (DMSOꢀd6—CCl4) of compounds
2b—d and 5b—d
=CHCOOH, J = 16.4 Hz); 7.11, 7.47 (both d, 2 H each, pꢀC6H4,
J = 8.1 Hz); 7.90 (d, 1 H, =CHC(NOH), J = 16.4 Hz); 12.0
(br.s, 2 H, COOH + NOH).
Reaction of αꢀ(imidazolꢀ1ꢀyl)ꢀβꢀ(pꢀtoluyl)propionic acid (6)
with NH2OH•HCl. Aqueous NH2OH•HCl (2.65 g, 0.038 mol)
was added to a saturated solution of acid 6 (0.82 g, 0.0032 mol)
in MeOH. The reaction mixture was refluxed in a water bath for
30 h and then treated with water. The precipitate was filtered
off, washed with water, and dried in vacuo. To remove impuriꢀ
ties, the precipitate was recrystallized from EtOH. The yield of
acid 4 was 0.45 g (68.6%).
Reaction of βꢀ(pꢀtoluyl)acrylic acid (1a) with 1,2,4ꢀtriazole.
A mixture of acid 1a (1.9 g, 0.01 mol) and 1,2,4ꢀtriazole (0.69 g,
0.01 mol) in aqueous KOH (0.56 g, 0.01 mol) was allowed to
stand at room temperature for 3 days. The reaction mixture was
acidified with dilute HCl and the precipitate that formed was
filtered off, washed with water, and dried in vacuo. To remove
impurities, the precipitate was refluxed in ether and dried in vacuo
to give βꢀ(pꢀtoluyl)ꢀαꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)propionic acid (7) (1.9 g,
73%), m.p. 203 °C. Found (%): C, 60.39; H, 5.10; N, 16.13.
Comꢀ
pound
δ (J/Hz)
2b
2c
2d
5.96 (d, 1 H, =СHСООH, J = 16.4); 7.38—7.55
(m, 5 H, Ph); 7.84 (d, 1 H, =СHС(NОH), J = 16.4);
12.0 (br.s, 2 H, СООH + NОH)
5.90 (d, 1 H, =СHСООH, J = 16.4); 7.83 (d, 1 H,
=СHС(NОH), J = 16.4); 7.30—7.60 (m, 4 H,
pꢀС6H4); 11.95 (br.s, 2 H, СООH + NОH)
5.96 (d, 1 H, =СHСООH, J = 16.4); 7.84 (d,
1 H, =СHС(NОH), J = 16.4); 7.38 (d, 2 H,
pꢀС6H4, J = 16.4); 7.55 (d, 2 H, pꢀС6H4,
J = 8.5); 12.0 (br.s, 2 H, СООH + NОH)
3.00 (br.s, 2 H, NH2); 3.97 (s, 3 H, ОMe);
7.31 (s, 1 H, =СH); 7.66—7.84 (m, 5 H, Ph)
3.00 (br.s, 2 H, NH2); 3.98 (s, 3 H, ОMe);
7.62 (s, 1 H, =СH); 7.69—7.86 (m, 5 H, Ph)
3.00 (br.s, 2 H, NH2); 3.97 (s, 3 H, ОMe);
7.31 (s, 1 H, =СH); 7.66, 7.84 (both d, 2 H each,
pꢀС6H4, J = 8.6)
3.00 (br.s, 2 H, NH2); 3.98 (s, 3 H, ОMe);
7.62 (s, 1 H, =СH); 7.69, 7.86 (both d, 2 H each,
pꢀС6H4, J = 8.6)
3.00 (br.s, 2 H, NH2); 3.97 (s, 3 H, ОMe);
7.31 (s, 1 H, =СH); 7.66, 7.84 (both d, 2 H each,
pꢀС6H4, J = 8.6)
5b
5b´
5c
C
13H13N3O3. Calculated (%): C, 60.23; H, 5.02; N, 16.22.
1H NMR (DMSOꢀd6—CCl4 (1 : 3)), δ: 2.43 (s, 3 H, Me); 3.88
(m, 2 H, CH2); 5.73 (t, 1 H, N=CH, J = 6.5 Hz); 7.27 (d, 2 H,
3.5 pꢀC6H4, J = 8.0 Hz); 7.73 (s, 1 H, N=CH); 7.87 (d, 2 H,
2.6 pꢀC6H4, J = 8.0 Hz); 8.47 (s, 1 H, N=CH); 12.7 (br.s,
1 H, COOH).
5c´
5d
6ꢀTolylꢀ2,3ꢀdihydropyridazinꢀ3ꢀone (8). A mixture of acid 7
(0.6 g, 0.0023 mol) and 60% NH2NH2•H2O (4 mL) was reꢀ
fluxed for 4 h. The precipitate that formed was filtered off,
washed with EtOH, and dried in vacuo to give compound 8
(0.24 g, 50.5%). Its physicochemical constants were identical
with our previous data.15
5d´
3.00 (br.s, 2 H, NH2); 3.98 (s, 3 H, ОMe);
7.62 (s, 1 H, =СH); 7.69, 7.86 (both d, 2 H each,
pꢀС6H4, J = 8.6)
Reactions of adducts 9 and 10 with NH2NH2•H2O. A mixꢀ
ture of compound 9 or 10 (0.005 mol) in EtOH and 60%
NH2NH2•H2O (4 mL) was refluxed for 2 h. The precipitate that
formed was filtered off, washed with EtOH, and dried in vacuo
to give pyrazolinecarboxylic acid 11 in 45 and 48% yields, reꢀ
spectively. Its physicochemical constants were identical with
our previous data.15
alkaline solution was acidified and treated as described
above. The yield of oxime 2a was 1.4 g (68%), m.p. 204 °C.
Found (%): C, 64.47; H, 5.26; N, 6.95. C11H11NO3. Calꢀ
culated (%): C, 64.39; H, 5.37; N, 6.83. 1H NMR
(DMSOꢀd6—CCl4 (1 : 3)), δ: 2.35 (s, 1 H, Me); 5.98 (d, 1 H,

1986
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Khachikyan et al.
10. R. Dj. Khachikyan, S. Yu. Kotikyan, and S. G. Agbalyan,
Khim. Zh. Armen. [Armenian Chem. J.], 1999, 52, 90.
11. N. P. Churkina, N. P. Gambaryan, D. A. Bochvar, and
S. G. Agbalyan, Khim. Zh. Armen. [Armenian Chem. J.], 1977,
30, 370.
12. R. Dj. Khachikyan, G. V. Grigoryan, and S. G. Agbalyan,
Khim. Zh. Armen. [Armenian Chem. J.], 1986, 39, 452.
13. R. Dj. Khachikyan, G. V. Grigoryan, and S. G. Agbalyan,
Khim. Zh. Armen. [Armenian Chem. J.], 1986, 39, 373.
14. E. A. Soliman, Rev. Roum. Chem., 1978, 23, 1597.
15. R. A. Khachatryan, R. Dj. Khachikyan, N. V. Karamyan,
H. A. Panosyan, and M. H. Injikyan, Khim. Geterotsikl.
Soedin., 2004, 541 [Chem. Heterocycl. Compd., 2004 (Engl.
Transl.)].
References
1. R. A. Raphael, Nature, 1947, 160, 261.
2. A. N. Nesmeyanov, M. I. Rybinskaya, and A. N. Rybin,
Usp. Khim., 1967, 36, 1089 [Russ. Chem. Rev., 1967, 36 (Engl.
Transl.)].
3. M. M. Frazer and R. A. Raphael, J. Chem. Soc., 1950, 2245.
4. R. C. Moreau and P. Loiseau, Compt. Rend. Acad. Sci.,
1976, 283, 589.
5. N. H. Cromwel, P. L. Greger, and K. E. Cook, J. Am. Chem.
Soc., 1956, 78, 4412.
6. M. T. Bogert and J. J. Ritter, J. Am. Chem. Soc., 1925,
47, 526.
7. E. P. Kohler and H. Engelbrecht, J. Am. Chem. Soc., 1919,
41, 764.
16. J. Lehmann and A. Gossen, Arch. Pharm., 1988, 321, 443.
8. J. Bougault, Ann. Chim. Phys., 1908, 15, 491.
9. G. V. Grigoryan and S. G. Agbalyan, Khim. Geterotsikl.
Soedin., 1979, 348 [Chem. Heterocycl. Compd., 1979 (Engl.
Transl.)].
Received March 12, 2004;
in revised form June 15, 2005