Studies with functionally substituted enamines: The reactivity of enaminals and enamino esters toward naphthoquinone, hydrazonoyl halides, aminoazoles and hippuric acid

Article abstract of DOI:10.1055/s-2005-921750

Whereas enamines 1a,b react with naphthoquinone (2) to yield the naphthofuranals 5a,b, enamine ester 1c react with 2 to yield benzoindole derivatives 7. Enamine 1b reacts with hydrazonoyl halides 8 to yield 3,4-disubstituted pyrazoles 12. On the other hand, the enaminal 1a failed to react with 8, while enamine ester 1c afforded hydrazone 16 on treatment with 8. The enamino ester 1b afforded triethyl 1,3,5-benzenetricarboxylates on refluxing in acetic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921750

PAPER
59
Studies with Functionally Substituted Enamines: The Reactivity of Enaminals
and Enamino Esters toward Naphthoquinone, Hydrazonoyl Halides,
Aminoazoles and Hippuric Acid
S
tudies
with Fun
a
l
bstitute
k
d Enaminesis AL-Saleh,a Saad Makhseed,*a Huwaida M. E. Hassaneen,b Mohamed Hilmy Elnagdib
a
Chemistry Department, Faculty of Science, University of Kuwait, P. O. Box 5969, Safat 13060, Kuwait
E-mail: smakhseed@kuc01.kuniv.edu.kw
Chemistry Department, Faculty of Science, Cairo University, Giza 12136, A. R. Egypt
E-mail: shelmy@access.com.eg
b
Received 18 May 2005; revised 12 July 2005
In contrast to the behavior of 1a,b, the enamino ester 1c
reacted with 2 to yield the dihydroxynaphthalene 6 which
could be cyclized to 1-phenylbenzo[g]indole 7 on reflux-
ing for a short period in acetic acid solution (Scheme 2).
Abstract: Whereas enamines 1a,b react with naphthoquinone (2) to
yield the naphthofuranals 5a,b, enamine ester 1c react with 2 to
yield benzoindole derivatives 7. Enamine 1b reacts with hydra-
zonoyl halides 8 to yield 3,4-disubstituted pyrazoles 12. On the oth-
er hand, the enaminal 1a failed to react with 8, while enamine ester The conversion of 6 into 7 finds parallels in the formation
1c afforded hydrazone 16 on treatment with 8. The enamino ester
of benzoindoles from reaction of 2 with enamines (Nen-
itzescu reaction7).
1b afforded triethyl 1,3,5-benzenetricarboxylates on refluxing in
acetic acid.
Key words: enaminals, enamino esters, hydrazonoyl halides, ami-
noazoles, enaminonitriles
In previous work from our laboratories we have explored
synthetic potentialities of enaminones,1–4 enaminonitriles5
and nitroenamines.6 In continuation of this work, we re-
port here our work aimed at exploring the chemistry of
enamino esters and enaminals. Thus, the enamines 1a,b
reacted readily with naphthoquinone (2) to yield the naph-
thofuranals 5a,b in good yields. It is believed that 1a adds
to 2 to yield 3 which hydrolyzes to 4 and then cyclized to
give 5. Possible direct cyclization of adduct 3 seems least
likely as this would then be an endo-trig cyclization to 5
Scheme 2
(Scheme 1).
While 1a failed to react with hydrazonoyl halides 8a–d
under a variety of conditions, 1b reacted readily to yield
products of condensation via dimethylamine hydrochlo-
ride elimination. It was thus assumed that 8 initially fur-
nishes nitrile imine 9 which then adds to 1b yielding either
10 or isomeric 11. Adduct 10 would aromatize into 12
while 11 would give 13. 1H NMR and 13C NMR spectra as
well as HMQC and HMBC measurements indicated that
1
the reaction products are 12a–c. Thus, H NMR and 13C
NMR spectroscopy indicated that pyrazole C-5 signal at
d = 133.83 is linked to pyrazole proton at d = 9.29 which
had a cross peak in HMBC carbonyl carbon of ester group
at d = 162.19. In addition treatment of 12a,b with hydra-
zine hydrate afforded the pyrazolo[3,4-d]pyridazin-4-
ones 14a,b.
On the other hand reaction of 1c with 8 to yield the
amidrazones 16a,b, formed most likely via initial alkyla-
tion of 1c yielding the intermediate amidrazone 15 that
hydrolyzed during work up of the reaction mixture or un-
der the reaction conditions to give 16a,b (Scheme 3).
Scheme 1
SYNTHESIS 2006, No. 1, pp 0059–0062
0
6
.
0
1
.2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-921750; Art ID: P06805SS
© Georg Thieme Verlag Stuttgart · New York
It is of value to indicate that the regiochemistry of addition
of 1b to 9 is similar to the regiochemistry of reaction of
enaminones, enaminonitriles and nitroenamines with 8.

60
B. AL-Saleh et al.
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Scheme 3
Attempts to react 1a,b with active methylenes in refluxing 3-amine (21b) with 1a. Similarly, two azolopyrimidino-
acetic acid resulted in formation of 17 and 18, respectively nes 22a,b were formed from reaction of 21a,b with 1b
(Figure 1). Compound 18 has also been recently obtained (Figure 2). Although 20a has been prepared earlier,8–10 we
on attempted acylation of 1b.
believe that our synthesis is more convenient.
All melting points are uncorrected. 1H NMR, 13C NMR, HMBC and
HMQC spectra were recorded on a Varian EM-390-400 MHz spec-
trometer in DMSO-d6 as solvent and TMS as internal standard;
chemical shifts are reported in d (ppm). Mass spectra were mea-
sured on MS 30 and MS 9 (AEI) spectrometers at 70 eV. Micro-
analyses were performed on LECO CHClNS-932 analyzer.
Compounds 5a,b; General Procedure
Figure 1 1,3,5-Benzenetricarboxlyic esters 17 and 18
To a stirred solution of 3-(dimethylamino)acrolein (1a; 1.0 g, 10
mmol) or 3-(dimethylamino)acrylic acid ethyl ester (1b; 1.43 g, 10
mmol) in AcOH (30 mL), was added naphthoquinone (2; 1.58 g, 10
mmol). Stirring was continued overnight at r.t. The mixture was
evaporated in vacuo and the solid product was collected by filtration
and crystallized from MeCN.
Refluxing 1a with hippuric acid afforded the pyranone 19.
The parent pyrazolo[1,5-a]pyrimidine (20a) and 1,2,4-tri-
azolo[5,1-a]pyrimidine (20b) were obtained in excellent
yields by reacting aminopyrazole 21a and 1,2,4-triazole-
5-Hydroxynaphtho[1,2-b]furan-3-carbaldehyde (5a)
Yield: 72%; mp 130 °C.
1H NMR (DMSO-d6): d = 7.00 (s, 1 H), 7.57 (t, 1 H, J = 8 Hz), 7.67
(t, 1 H, J = 8 Hz), 8.20 (d, 1 H, J = 8 Hz), 8.26 (d, 1 H, J = 8 Hz),
8.96 (s, 1 H), 9.76 (s, 1 H), 10.22 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 104.52, 114.66, 117.88, 120.28, 121.93,
124.35, 126.03, 128.50, 136.29, 145.62, 151.98, 161.02, 185.43.
MS: m/z = 212 (M+).
Figure 2 Compounds 19–22
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Studies with Functionally Substituted Enamines
61
Anal. Calcd for C13H8O3 (212.20): C, 73.58; H, 3.80. Found: C,
73.55; H, 3.78.
Anal. Calcd for C19H15ClN2O3 (354.79): C, 64.32; H, 4.26; Cl, 9.99;
N, 7.90. Found: C, 64.30; H, 4.22; Cl, 10.02; N, 7.85.
5-Hydroxynaphtho[1,2-b]furan-3-carboxylic Acid Ethyl Ester
(5b)
1-(4-Chlorophenyl)-1H-pyrazole-3,4-dicarboxylic Acid Diethyl
Ester (12c)
Yield: 79%; mp 182 °C.
Yield: 55%; mp 118 °C.
1H NMR (DMSO-d6): d = 1.38 (t, 3 H, J = 7.2 Hz), 4.36 (q, 2 H,
J = 7.2 Hz), 7.43 (s, 1 H), 7.56 (t, 1 H, J = 8 Hz), 7.68 (t, 1 H, J = 8
Hz), 8.18 (d, 1 H, J = 8 Hz), 8.24 (d, 1 H, J = 8 Hz), 8.76 (s, 1 H),
10.33 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 15.08, 61.31, 100.52, 105.84, 115.66,
120.28, 121.57, 124.32, 124.35, 126.03, 128.50, 136.29, 145.62,
151.72, 163.95.
1H NMR (DMSO-d6): d = 1.20–1.33 (m, 6 H), 4.27 (q, 2 H, J = 7.4
Hz), 4.36 (q, 2 H, J = 7.5 Hz), 7.35 (d, 2 H, J = 10 Hz, ArH), 7.98
(d, 2 H, J = 10 Hz, ArH), 9.20 (s, 1 H).
13C NMR (DMSO-d6): d = 15.19, 20.77, 61.97, 80.19, 116.31,
128.73, 129.76, 134.52, 139.86, 142.00, 144.12, 161.92, 189.2.
MS: m/z = 322 (M+).
Anal. Calcd for C15H15ClN2O4 (322.74): C, 55.82; H, 4.68; Cl,
10.98; N, 8.68. Found: C, 55.80; H, 4.66; Cl, 10.93; N, 8.60.
MS: m/z = 256 (M+).
Anal. Calcd for C15H12O4 (256.25): C, 70.31; H, 4.72. Found: C,
70.31; H, 4.70.
Compounds 14a,b; General Procedure
A mixture of the pyrazoles 12a,b (10 mmol) and hydrazine hydrate
(320 mg, 10 mmol) in absolute EtOH (20 mL) was refluxed for 1 h.
The mixture was left to cool and triturated with EtOH. The solid
product was collected by filtration and crystallized from DMF.
5-Hydroxy-1-phenyl-1H-benzo[g]indole-3-carboxylic Acid
Ethyl Ester (7)
To a stirred solution of 3-anilinoacrylic acid ethyl ester (1c; 1.91 g,
10 mmol) in AcOH (30 mL), was added naphthoquinone (2; 1.58 g,
10 mmol) and the mixture was refluxed for 1 h. The mixture was
evaporated in vacuo and the solid product was collected by filtration
and crystallized from MeCN; yield: 80%; mp 162 °C.
2-(4-Chlorophenyl)-7-(2-thienyl)-2,5-dihydropyrazolo[3,4-
d]pyridazin-4-one (14a)
Yield: 79%; mp 260 °C.
1H NMR (DMSO-d6): d = 1.15 (t, 3 H, J = 7.5 Hz), 4.11 (q, 2 H,
J = 7.5 Hz), 7.00–7.37 (m, 6 H), 7.89–9.22 (m, 5 H, ArH), 10.27 (s,
1 H, OH).
1H NMR (DMSO-d6): d = 7.26 (t, 1 H, J = 8 Hz), 7.71–7.72 (d, 3 H,
J = 8 Hz), 7.21 (d, 2 H, J = 8 Hz), 8.38–8.39 (d, 1 H), 9.63 (s, 1 H),
12.59 (s, 1 H, NH).
MS: m/z = 331 (M+).
MS: m/z = 328 (M+).
Anal. Calcd for C21H17NO3 (331.36): C, 76.12; H, 5.17; N, 4.23.
Found: C, 76.06; H, 5.13; N, 4.20.
Anal. Calcd for C15H9ClN4OS (328.78): C, 54.80; H, 2.76; Cl,
10.78; N, 17.04; S, 9.75. Found: C, 54.75; H, 2.73; Cl, 10.72; N,
17.00; S, 9.72.
Compounds 12a,b and 16a,b; General Procedure
To a hot solution of 1b (1.43 g, 10 mmol) or 1c (1.91 g, 10 mmol)
and the appropriate hydrazonoyl halide 8a–d (10 mmol) in EtOH
(30 mL) was added Et3N (1.01 g, 10 mmol). The mixture was re-
fluxed for 6 h and the solvent was evaporated under reduced pres-
sure. The crude product was collected and crystallized from a
suitable solvent.
2-(4-Chlorophenyl)-7-phenyl-2,5-dihydropyrazolo[3,4-d]py-
ridazin-4-one (14b)
Yield: 75%; mp 222 °C.
1H NMR (DMSO-d6): d = 7.48–7.65 (m, 6 H, ArH), 7.63 (t, 2 H,
J = 10 Hz ArH), 8.13 (d, 2 H, J = 8 Hz, ArH), 8.36 (d, 2 H, J = 8 Hz,
ArH), 9.60 (s, 1 H), 12.58 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 117.78, 121.64, 128.60, 128.96, 129.63,
1-(4-Chlorophenyl)-3-(2-thienylcarbonyl)-1H-pyrazole-4-car-
boxylic Acid Ethyl Ester (12a)
Yield: 60%; mp 126 °C.
129.92, 130.28, 130.92, 134.79, 139.67, 139.86, 146.22, 159.19.
MS: m/z = 322 (M+).
1H NMR (DMSO-d6): d = 1.15 (t, 3 H, J = 7.5 Hz), 4.18 (q, 2 H,
J = 7.5 Hz), 7.29 (t, 1 H, J = 6 Hz), 7.65 (d, 2 H, J = 6 Hz, ArH),
7.87 (d, 1 H, J = 8 Hz), 8.03 (d, 2 H, J = 7.2 Hz, ArH), 8.18 (d, 1 H,
J = 8 Hz), 9.29 (s, 1 H).
Anal. Calcd for C17H11ClN4O (322.75): C, 63.26; H, 3.44; Cl,
10.98; N, 17.36. Found: C, 63.22; H, 3.40; Cl, 10.96; N, 17.33.
2-Phenylamino-2-[phenylhydrazono]-1-phenylethanone (16a)
13C NMR (DMSO-d6): d = 14.88 (CH3), 61.51 (CH2), 116.83,
122.34, 130.10, 130.68, 133.31, 133.83, 137.82, 137.99, 138.34,
143.63, 151.22, 162.20 (CO), 181.21 (CO).
Yield: 66%; mp 159 °C.
1H NMR (DMSO-d6): d = 6.68 (d, 2 H, J = 8 Hz, ArH), 6.67–7.75
(m, 11 H, ArH), 7.9 (d, 2 H, J = 8 Hz, ArH), 8.05 (s, 1 H, NH), 10.01
(s, 1 H, NH).
MS: m/z = 360 (M+).
13C NMR (DMSO-d6): d = 114.8, 116.91, 120.49, 121.49, 123.28,
128.99, 130.17, 131.07, 133.93, 136.72, 138.65, 143.60, 145.96,
188.52 (CO).
Anal. Calcd for C17H13ClN2O3S (360.81): C, 56.59; H, 3.63; Cl,
9.83; N, 7.76; S, 8.89. Found: C, 56.55; H, 3.60; Cl, 9.81; N, 7.76;
S, 8.85.
MS: m/z = 315 (M+).
3-Benzoyl-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylic Acid
Ethyl Ester (12b)
Yield: 65%; mp 151 °C.
Anal. C20H17N3O (315.37): C, 76.17; H, 5.43; N, 13.32. Found: C,
76.14; H, 5.42; N, 13.30.
1H NMR (DMSO-d6): d = 1.16 (t, 3 H, J = 7.6 Hz), 4.23 (q, 2 H,
J = 7.6 Hz), 7.45–7.65 (m, 5 H, ArH), 8.13 (d, 2 H, J = 7.8 Hz,
ArH), 8.36 (d, 2 H, J = 8 Hz, ArH), 9.60 (s, 1 H).
2-Phenylamino-2-[(4-chlorophenyl)hydrazono]-(2-thienyl)eth-
anone (16b)
Yield: 64%; mp 172 °C.
1H NMR (DMSO-d6): d = 6.62 (d, 2 H, J = 7 Hz ArH), 6.79 (t, 1 H,
J = 6 Hz), 7.17 (t, 1 H, J = 6 Hz), 7.28 (t, 1 H, J = 6 Hz), 7.32–7.37
MS: m/z = 354 (M+).
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62
B. AL-Saleh et al.
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(m, 5 H, ArH), 8.05 (d, 2 H, J = 8 Hz, ArH), 8.09 (s, 1 H, NH), 10.13
MS: m/z = 119 (M+).
(s, 1 H, NH).
Anal. Calcd for C6H5N3 (119.12): C, 60.50; H, 4.23; N, 35.27.
Found: C, 60.48; H, 4.20; N, 35.25.
13C NMR (DMSO-d6): d = 116.77, 117.05, 120.61, 125.41, 128.84,
129.80, 130.10, 135.81, 137.07, 137.20, 140.44, 143.17, 144.02
178.77 (CO).
1,2,4-Triazolo[5,1-a]pyrimidine (20b)
Yield: 59%; mp 147–149 °C.
1H NMR (DMSO-d6): d = 7.38–7.41 (q, 1 H, J = 7.5 Hz), 8.70 (s, 1
H), 8.91 (d, 1 H, J = 8 Hz), 9.43 (d, 1 H, J = 8 Hz).
13C NMR (DMSO-d6): d = 125.50, 130.88, 138.07, 151.18, 158.84.
MS: m/z = 120 (M+).
MS: m/z = 355 (M+).
Anal. Calcd for C18H14ClN3OS (355.84): C, 60.76; H, 3.97; Cl,
9.96; N, 11.81; S, 9.01. Found: 60.77; H, 3.95; Cl, 9.92; N, 11.78;
S, 8.98.
Compounds 17 and 18; General Procedure
Anal. Calcd for C5H4N4 (120.11): C, 50.00; H, 3.36; N, 46.65.
Found: C, 49.99; H, 3.35; N, 46.65.
To a stirred solution of 3-(dimethylamino)acrolein (1a; 1.0 g, 10
mmol) or 3-(dimethylamino)acrylic acid ethyl ester (1b; 1.43 g, 10
mmol) in AcOH (30 mL) for 10 h. The solvent was removed and the
residual solid was crystallized from AcOH.
4H-Pyrazolo[1,5-a]pyrimidin-7-one (22a)
Yield: 60%; mp 340 °C.
1H NMR (DMSO-d6): d = 6.09 (d, 1 H, J = 8 Hz), 7.05 (d, 1 H, J = 8
Hz), 7.30 (d, 1 H, J = 8 Hz), 7.75 (d, 1 H, J = 8 Hz), 9.68 (s, 1 H,
NH).
13C NMR (DMSO-d6): d = 91.58, 105.51, 117.78, 129.83, 134.24,
164.53.
Benzene-1,3,5 tricarbaldehyde (17)
Yield: 60%; mp 160 °C.
1H NMR (DMSO-d6): d = 8.22 (s, 3H), 10.16 (s, 3H, 3CHO).
MS: m/z = 162 (M+).
Anal. Calcd for C9H6O3 (162.14): C, 66.67; H, 3.73. Found: C,
66.65; H, 3.70.
MS: m/z = 135 (M+).
Anal. Calcd for C6H5N3O (135.12): C, 53.33; H, 3.73; N, 31.10.
Found: C, 53.30; H, 3.72; N, 31.08.
Benzene-1,3,5-tricarboxylic Acid Triethyl Ester (18)
Yield: 70%; mp 140 °C.
1H NMR (DMSO-d6): d = 1.36 (t, 9 H, J = 7.5 Hz), 4.39–4.41 (q, 6
H, J = 7.5 Hz), 8.66 (s, 3 H).
4H-1,2,4-Triazolo[5,1-a]pyrimidin-7-one (22b)
Yield: 58%; mp 295 °C.
1H NMR (DMSO-d6): d = 5.84 (d, 1 H, J = 10 Hz), 7.45 (s, 1 H),
7.99 (d, 1 H, J = 8 Hz), 8.22 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 99.96, 142.18, 152.13, 152.90, 157.50.
MS: m/z = 136 (M+).
MS: m/z = 294 (M+).
Anal. Calcd for C15H18O6 (294.30): C, 61.22; H, 6.16. Found: C,
61.20; H, 6.14.
3-Benzoylamino-2H-pyran-2-one (19)
Anal. Calcd for C5H4N4O (136.11): C, 44.12; H, 2.96; N, 41.16.
Found: C, 44.11; H, 2.96; N, 41.14.
A solution of 1a (1.0 g, 10 mmol) and hippuric acid (1.79 g, 10
mmol) in anhyd Ac2O (45 mL) was refluxed for 4 h, left to cool, and
then poured into H2O. After complete decomposition of excess
Ac2O, the remaining oil was separated and triturated with EtOH.
The solid product, so formed was collected by filtration and crystal-
lized from EtOH; yield: 72%; mp 148 °C.
1H NMR (DMSO-d6): d = 6.54 (t, 1 H, J = 8 Hz), 7.52–7.64 (m, 3
H, ArH), 7.68 (d, 1 H, J = 8 Hz), 7.93–7.94 (d, 2 H, J = 8 Hz), 8.07
(d, 1 H, J = 8 Hz), 9.55 (s, 1 H, NH).
Acknowledgment
The support of the University of Kuwait received through research
grant No. SC06/03 and the facilities used from ANALAB and SAF
(GS 01/01, GS 02/01) are gratefully acknowledged.
13C NMR (DMSO-d6): d = 107.67, 126.17, 128.63, 129.05, 129.65,
133.24, 134.51, 148.26, 160.03, 166.89.
References
(1) AL-Shiekh, M. A.; Salah EL-Din, A. M.; Hafez, E. A.;
Elnagdi, M. H. J. Chem. Res., Synop. 2004, 174.
(2) AL-Saleh, B.; Behbehani, H.; El-Apasery, M. A.; Elnagdi,
M. H. J. Chem. Res., Synop. 2004, 575.
MS: m/z = 215 (M+).
Anal. Calcd for C12H9NO3 (215.20): C, 66.97; H, 4.22; N, 6.51.
Found: C, 66.95; H, 4.20; N, 6.49.
(3) AL-Saleh, B.; El-Apasery, M. A.; Elnagdi, M. H. J. Chem.
Res., Synop. 2004, 578.
(4) Almazroa, S.; Elnagdi, M. H.; Salah EL-Din, A. M. J.
Heterocycl. Chem. 2004, 41, 267.
(5) Ghozlan, S. A. S.; Abdelshafi, I. A.; Gaber, H.; Elnagdi, M.
H. J. Chem. Res., Synop. 2004, 789.
Compounds 20a,b and 22a,b; General Procedure
A mixture of 1a (1.0 g, 10 mmol) or 1b (1.43 g, 10 mmol) and het-
erocyclic amine 21a,b in EtOH (20 mL) was refluxed for 6 h. The
solvent was removed and the residual solid was crystallized from a
suitable solvent.
(6) Hassaneen, H. M. E.; Hassaneen, H. M.; Elnagdi, M. H. Z.
Naturforsch., B: Chem. Sci. 2004, 59, 1127.
(7) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longman:
London, 1998, 236.
(8) Khan, M. A.; Lynch, B. M. J. Heterocycl. Chem. 1970, 7,
247.
(9) Lynch, B. M.; Khan, M. A.; Sharma, S. C.; Teo, H. C. Can.
J. Chem. 1975, 53, 119.
(10) Kirkpatrick, W. E.; Okabe, T.; Hillyard, I. W.; Robins, R. K.;
Pyrazolo[1,5-a]pyrimidine (20a)
Yield: 65%; mp 105 °C.
1H NMR (DMSO-d6): d = 6.73 (d, 1 H, J = 8 Hz), 7.04 (t, 1 H, J = 8
Hz), 8.23 (d, 1 H, J = 8 Hz), 8.55 (d, 1 H, J = 7 Hz), 9.12 (d, 1 H,
J = 8 Hz).
13C NMR (DMSO-d6): d = 97.03, 109.42, 139.66, 145.76, 148.98,
150.75.
Drean, A. T.; Novinsom, T. J. Med. Chem. 1977, 20, 386.
Synthesis 2006, No. 1, 59–62 © Thieme Stuttgart · New York