Unexpected ring closure reaction of α,β-unsaturated ketones with aminoguanidine. Entry into 1,3,5-trisubstituted pyrazoles

Article abstract of DOI:10.1002/jhet.5570390220

Cyclizations of α,β-unsaturated ketones with aminoguanidine under neutral conditions were examined. In contrast to literature reports of 1,2,4-triazines as reaction products, formation of 5-aryl-4,5-dihydro-3-methyl-1H-pyrazole-1-carboximidamides and carb

Full text of DOI:10.1002/jhet.5570390220

Mar-Apr 2002
363
Unexpected Ring Closure Reaction of α,β-Unsaturated Ketones with
Aminoguanidine. Entry into 1,3,5-Trisubstituted Pyrazoles.
ˇ
Jan Sveˇtlík* and Ladislav Sallai
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University,
Odbojarov 10, SK-832 32 Bratislava, Slovak Republic
Received October 29, 2001
Cyclizations of α,β-unsaturated ketones with aminoguanidine under neutral conditions were exam-
ined. In contrast to literature reports of 1,2,4-triazines as reaction products, formation of 5-aryl-4,5-dihy-
dro-3-methyl-1H-pyrazole-1-carboximidamides and carboxamides was observed. An explanation based
on the Hard-Soft Acid-Base principle is presented and the probable causes of divergent reaction path-
ways are discussed.
J. Heterocyclic Chem., 39, 363 (2002).
4-(2-Hydroxyphenyl)but-3-en-2-one (1a) is a unique
α,β-unsaturated ketone, in that it contains an additional
reactive site in the phenolic functional group. The ability
of the hydroxyl group to undergo nucleophilic ring closure
onto a preformed heterocyclic core is a key point in our
syntheses of oxygen-bridged heterocycles. Based on
butenone 1a, we have previously prepared derivatives of
pyridine, pyrimidine, benzodiazepine, benzothiazepine,
thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b]thiazine,
pyrimido[2,1-b]thiazepine, and pyrido[2,3-d]pyrimidine
[1]. Some of these conformationally locked molecules
exhibit more complex structures arising from double-
bridging or further annelation [2,3].
Reactions of aminoguanidine with α,β-unsaturated
ketones 1 including bis(alkylidene)- or bis(arylidene)ace-
tone have been extensively studied in the past and thor-
oughly reviewed by Neunhoeffer [7-9]. The primary prod-
ucts in the synthetic pathway are amidinohydrazones 2
formed in acid media [10]. Upon heating they were con-
verted into 5,6-disubstituted 3-amino-4,5-dihydro-1,2,4-
triazines 3 which can eliminate the 5-alkyl or aralkyl group
when treated with a base to yield fully aromatized triazines
4 (Scheme 1) [7-9].
To avoid isolating a condensation intermediate 2 we per-
formed heterocyclization directly in the higher boiling sol-
vent (n-butanol) but under neutral conditions. Surprisingly,
In collaboration with DuPont, it was found that certain
pyrimidines bearing an O-bridge were active as inhibitors
of acetylcholine esterase with arthropodicide activity [4].
Thus, low-cost starting materials (acetone and salicylalde-
hyde), simple preparation, and multigram-scale access ren-
der enone 1a an attractive synthon for constructing novel
heterocyclic compounds of potentially interesting chemi-
cal and medical properties.
treatment of 1a with aminoguanidine hydrogencarbonate
gave an isomeric product whose spectral data were not com-
patible with the expected structure 3a (Scheme 2). In spite
of similar structural features, the compounds 3a and 5a
obtained here differ in the arrangement of the building units.
Namely, the observed long-range H,C-correlations from
selective INEPT spectra did not fit the triazine model 3a,
while they clearly proved the HOC H CHCH C(=)CH
6
4
2
3
Aminoguanidine is known to be an important bioactive
substance. It belongs to potent inhibitors of nitric oxide
synthase controlling the nitric oxide production in mam-
malian cells [5] and has become one of the promising
agents for the treatment of diabetic complications [6]. On
the other hand, due to its multifunctional nature,
aminoguanidine can serve as a valuable component in het-
erocyclic synthesis. Seeking more effective aminoguani-
dine mimics, we decided to incorporate the aminoguani-
dine unit into a heterocyclic structure by our above-men-
tioned method of condensation with 1a. We also present
herein a convenient synthetic route to highly functional-
ized 2-pyrazolines.
connectivity pattern. To complete the connectivity in the
whole molecule, it remained only to link the recognized
fragment to the aminoguanidine moiety. However, this
required considering different reacting centres of the
addends. Inspection of the literature revealed that condensa-
tion of aminoguanidine with ethyl acetoacetate [11] leading
to pyrazolone 6 and diaminopyrimidine 7 (Scheme 3) could
give us a lead for structure determination. According to
these findings, our preceding experience with butenone 1a,
and the obtained spectral data, we postulated 4,5-dihydro-
1H-pyrazole-1-carboximidamide 5a and 5,6-dihydro-2H-
pyrimidin-1-ylamine 5'a as acceptable alternatives of the
constitutional isomer 3a.

ˇ
364
J. Sveˇtlík and L. Sallai
Vol. 39
The results of the H,C-correlation nmr are compatible
with both structures. Thus, upon irradiation of the respec-
tive aliphatic protons the following interactions were deter-
Since we anticipated largely the formation of oxygen-
bridged pyrimidine 9 or a similar compound derived from
8, attempts have been made to detect them (Scheme 3).
However, in spite of our efforts, the hydroxyphenyl deriv-
ative 5a was the only detectable product.
mined: 4-H − C-3, C-1'; 5-H − C-3, C-1', C-6' and H of
a,b
Me − C-4 (numbering for 5a). Evidently, the last two of the
six detected polarization transfers cannot be referred to the
corresponding H,C-nuclei pairs in triazine 3a because only
In order to find additional support for the studied hete-
rocyclization, we employed two other arylidenes as a
starting material for the synthesis. However, under simi-
lar conditions 4-phenyl- and 4-(4-methylphenyl)but-3-
en-2-one (1b and 1c) gave rise to two types of products
having similar nmr spectral parameters. Remarkably, the
condensations with 1b and 1c were accompanied with evo-
lution of ammonia. The elemental composition of com-
pounds 10b,c, which crystallized from the reaction mix-
ture, indicated a substitution of an O atom for the NH
group when compared with the expected amidines 5b,c,
suggesting thus formation of amide analogues (Scheme 4).
The target pyrazoles 5b,c were isolated from the filtrates
upon further work-up. Interestingly, these amidines,
according to nmr analysis, were obtained as acetate salts
2
3
J
and J are observable. An additional support for 5a
CH
CH
1
and 5'a came from the resolution enhanced H nmr spec-
trum wherein a splitting between CH and 4-H protons
3
b
4
with J=1.0 Hz was found. Note that an analogous coupling
over five saturated bonds in 3a would be rather unusual.
Another important fact followed from the analysis of the
ABX system of the CH CH segment. The magnitudes of
2
the geminal and vicinal couplings closely resembled to
those reported for 1,3,5-trisubstituted 2-pyrazolines [12].
The mass spectrum of the product furnished a signifi-
cant proof of the amidine structure 5a. The prominent
peaks at m/z 201, 176 and 175 were produced by loss of
neutral molecules of NH and HN=C=NH and the HN=C-
3
NH radical from the molecular ion (m/z 218), the primary
.
2
(5b,c CH COOH). The solvate formation had to be the
3
cleavage modes being typical of N-substituted guanidines
result of a decomposition of ethyl acetate used as a crys-
tallization solvent. The obvious reason why only deriva-
tives 5b,c suffered hydrolysis into 10b,c lies in their solu-
bility in n-butanol whereas hydroxyphenylpyrazole 5a
[13]. In addition, the second most abundant peak at m/z
+
83, (C H N ) , was a clue that indicated a 3-methylpyra-
4
7 2
zolinium species.
It should be noted that there is another possible isomeric
structure 8 which may satisfy the nmr data (Scheme 3).
Nevertheless, the above fragmentation pattern, additional
chemical evidence of 5a via ring closure reactions [14] and
results from single-crystal X-ray diffraction for analogous
derivatives (see below) ruled out variant 8.

Mar-Apr 2002
Unexpected Ring Closure Reaction
365
EXPERIMENTAL
was insoluble and precipitated from the reaction mixture
and thus remained intact. Moreover, unlike compounds
5b,c, amidine 5a proved to be stable in solution.
Tolyl derivatives 5c and 10c turned out to be well crys-
tallizing compounds so that we could grow suitable sam-
ples for X-ray analysis. The X-ray molecular structures
represent the ultimate proof of the unusual products from
the well known reaction [7-9] and will be published else-
where [15].
The direction in which the observed heterocyclizations
proceed depends on the reaction conditions used. As to the
triazine pathway, open-chain amidinohydrazones 2 are
produced by a nucleophilic 1,2-addition while the carbonyl
group of the conjugated system 1 is attacked by the termi-
nal hydrazine nitrogen of the reactant. The reaction mode
of the key step under acid catalysis is controlled by proto-
nation, which occurs at the imine nitrogen as evidenced by
the X-ray structure of the aminoguanidine salt [16]. Due to
the extensive delocalization of the positive charge over the
guanidyl group in the monocation form [16,17], an inter-
vention via the former nitrogen atom of the aminoguani-
dine will hence be favored.
By contrast, a competitive 1,4-addition becomes opera-
tive in the first stage of our pyrazole route. Evidently, such
a Michael-type reaction has to involve an initial attack by
the aminoguanidine internal hydrazine nitrogen at the elec-
trophilic C-3 of enone 1. Our explanation in terms of the
HSAB concept relies on the assumption that the interven-
ing species should be actually a free aminoguanidine mol-
ecule, as the hydrogencarbonate salt liberates vigorously
The melting points (uncorrected) were determined with a Kofler
hot stage microscope. The ir spectra were recorded on a Nicolet
Impact 400 D spectrophotometer. The EI mass spectra were
obtained on a Jeol JMS D-100 instrument operating at 75 eV. Peak
matching with perfluorokerosene as the reference was utilized for
accurate mass measurements by hrms. The nmr spectra were mea-
1
13
sured on a Bruker AC-400 spectrometer with a dual H/ C probe
1
13
(400.136 MHz for H and 100.614 MHz for C) for 5a and Varian
VXR-300 (299.943/75.429 MHz) for 5b,c and 10b,c.
The butenones were prepared according to the literature: 1a
[20], 1b [21], 1c [22].
General Procedure for the Preparation of Pyrazolines 5a-c and
10b,c.
A suspension of butenone 1a-c (10 mmoles) and aminoguani-
dine hydrogencarbonate (1.36 g, 10 mmoles) in n-butanol (30 ml)
was refluxed under stirring for 3 hours. The precipitated product
5a was isolated by filtration, washed with n-butanol, and dried.
For 1b,c the reaction mixture (a solution formed after 2 hours)
was concentrated on a vacuum rotary evaporator, the syrupy
residue dissolved in ethyl acetate (10 ml) and left to stand at room
temperature. The crystallized products 10b,c were collected by
filtration. The pyrazolines 5b,c precipitated from the mother
liquors upon standing.
4,5-Dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-pyrazole-1-car-
boximidamide (5a).
This compound was obtained in 74 % yield (1.62 g), mp 249-
251° (DMF); ir (potassium bromide): 3447 (NH ), 3350-2450
(assoc. OH, NH , NH), 1670 (exo C=N), 1622 (C=N, NH bend),
2
2
2
1472 (CH bend), 1449 (CH bend), 1304, 862, 750 (o-C H -
2
3
6 4
-1 1
wag) cm ; H nmr (DMSO-d ): δ 2.12 (s, 3H, Me), 3.08 (dd, 1H,
6
J
J
J
=18.6 and J =4.2 Hz, 4-H ), 3.45 (ddd, 1H, J =18.6,
AB
BX
BX
AX a AB
CO when heated with 1 at the beginning of the reaction.
2
=11.8 and J
=1.0 Hz, 4-H ), 5.45 (dd, 1H, J =4.2 and
b AX
=11.8 Hz, 5-H), 5.70-7.20 (br, 4H, OH, NH , NH), 6.36 (dt,
BMe
Hence, the reaction conditions are practically basic and
typical of a conjugate addition. According to the recent
quantum chemical studies on the aminoguanidine free
2
1H, J=7.3 and 1.3 Hz, 5'-H), 6.43 (dd, 1H, J=8.1 and 1.2 Hz, 3'-
H), 6.93 (m, 1H, 6'-H). 6.94 (m, 1H, 4'-H); C nmr (DMSO-d ):
13
6
δ 15.0 (Me), 43.1 (CH ), 54.0 (CH), 114.0 (CH-3'), 118.9 (CH-
2
base, [18] the endiamine form, H NN=C(-NH )NH , was
2
2
2
5'), 125.8 (CH-6'/CH-4'), 127.0 (C-1'), 128.4 (CH-4'/CH-6'),
found to be the most stable tautomer in the gas phase.
Moreover, internal imine nitrogen bears the greatest nega-
tive charge [18] as calculated by the B3-LYP/6-31G(d)
method. With respect to the reported findings we presume
that this key hydrazine/imine nitrogen should become
more polarizable and would be therefore a somewhat
softer donor than the terminal one. This soft acid - soft
base interaction of the olefinic β-carbon, possessing usu-
ally the largest LUMO coefficient [19], and the mentioned
nitrogen will be a determining factor of the reaction.
However, in this case it would be useful to know the sol-
vent effects on the tautomer population in solution, that
may affect the energy difference between the endiamine
154.3 (C-2'), 155.9 (C-3), 162.1 (N-C=N); ms: m/z (relative
+
intensity) 219 (6), 218 (C H N O, M , 33), 201 (13), 177 (13),
11 14
4
176 (22), 175 (C
H N O, 37), 160 (11), 146 (13), 145
10 11 2
(C H O, 100), 135 (14), 125 (14), 120 (16), 118 (23), 91 (13),
10
9
83 (C H N , 80), 77 (13), 65 (10), 58 (31), 43 (22), 42 (31).
4
7 2
Anal. Calcd. for C H N O: C, 60.53; H, 6.47; N, 25.67.
11 14
4
Found: C, 60.71; H, 6.42; N, 25.39.
4,5-Dihydro-3-methyl-5-phenyl-1H-pyrazole-1-carboximi-
damide Acetate (5b).
Compound 5b was obtained in 14 % yield (0.28 g), mp 227-
229° (DMF); ir (potassium bromide): 3321 (NH , NH), 1667
2
-1
1
(C=N), 1590 (COO), 1407, 765 (C H -wag), 695 cm ; H nmr
6
5
(DMSO-d ): δ 1.60 (s 3H, Me of HOAc), 2.04 (s, 3H, Me), 2.76
6
(dd, 1H, J =18.3 and J =3.3 Hz, 4-H ), 3.64 (dd, 1H, J =18.3
AB
AX
a
AB
and imidiamide form H NNHC(=NH)NH (approximately
2
2
and J =11.7 Hz, 4-H ), 5.51 (dd, 1H, J =3.3 and J =11.7 Hz,
BX
b
AX
BX
5 kcal/mol in the gas phase [18]). Finally, the presented
heterocyclization is completed by attack of the terminal
hydrazine nitrogen at the carbonyl group in the initial
Michael adduct.
5-H), 7.14 (dd, 2H, J=7.0 and 1.1 Hz, H ), 7.30-7.40 (m, 3H, H ),
ar
ar
13
7.8-10.0 (br, 4H, NH ); C nmr (DMSO-d ): δ 15.5 (Me), 25.0
2
6
(Me of HOAc) 47.5 (CH ), 59.3 (CH), 125.3 (CH-2' + CH-6'),
2
127.9 (CH-4'), 128.9 (CH-3' + CH-5'), 140.4 (C-1'), 153.6 (C-3),

ˇ
366
J. Sveˇtlík and L. Sallai
Vol. 39
158.6 (N-C=N), 176.0 (CO of HOAc); ms: m/z (relative intensity)
Anal. Calcd. for C H N O: C, 66.34; H, 6.96; N, 19.37.
12 15 3
Found: C, 66.20; H, 7.02; N, 19.53.
+
202 (C H N , M , 5), 201 (3), 185 (C H N , 4), 184 (3), 162
11 14
4
11 11 3
(6), 161 (60), 160 (36), 159 (C H N , 49), 145 (5), 144 (7), 119
10 11
2
Acknowledgements.
(8), 115 (10), 104 (31), 93 (15), 91 (17), 83 (C H N , 100), 82
4
7 2
(13), 78 (18), 77 (24), 65 (8), 63 (6), 60 (22), 56 (16), 51 (18), 45
(35), 43 (55), 42 (42), 41 (16), 39 (15).
This work was supported by the Grant Agency of the Slovak
Republic (# 1/8215/01). The author wishes to thank Dr. V. Hanus
of the Heyrovsky Institute of Physical Chemistry, Prague, for
measuring the mass spectra.
Anal. Calcd. for C H N O : C, 59.53; H, 6.92; N, 21.36.
13 18
4 2
Found: C, 59.79; H, 7.09; N, 21.13.
4,5-Dihydro-3-methyl-5-phenyl-1H-pyrazole-1-carboxamide
(10b).
REFERENCES AND NOTES
Compound 10b was obtained in 37% yield (0.75 g), mp 194-
197° (dioxane-ethyl acetate); ir (potassium bromide): 3337 +
[ ] E-mail: svetlik@fpharm.uniba.sk
[1a] J. Svetlik, F. Turecek and V. Hanus, J. Chem. Soc., Perkin
Trans. I, 563 (1987); [b] J. Svetlik, F. Turecek and V. Hanus, J. Chem.
Soc., Perkin Trans. I, 2053 (1988); [c] J. Svetlik, V. Hanus and J. Bella,
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Chem. Soc., Perkin Trans. I, 1315 (1990); [e] J. Svetlik, V. Hanus and J.
Bella, J. Chem. Res. (S), 4 (1991).
3185 (NH ), 1655 (C=O), 1603 (C=N), 760 (C H -wag), 703
2
6 5
-1
1
cm ; H nmr (DMSO-d ): δ 2.06 (s, 3H, Me), 2.78 (dd, 1H,
6
J
J
=18.3 and J = 3.0 Hz, 4-H ), 3.67 (dd, 1H, J =18.3 and
AB
AX a AB
=11.8 Hz, 4-H ), 5.54 (dd, 1H, J =3.0 and J =11.8 Hz, 5-
BX
b
AX
BX
H), 7.15 (dd, 2H, J=7.2 and 1.2 Hz, H ), 7.29-7.41 (m, 3H, H ),
ar
ar
13
7.50-9.60 (br, 2H, NH ); C nmr (DMSO-d ): δ 15.5 (Me), 47.5
[2] J. Svetlik, T. Liptaj and F. Turecek, J. Heterocyclic Chem., 36,
209 (1999).
2
6
(CH ), 59.4 (CH), 125.3 (CH-2' + CH-6'), 128.0 (CH-4'), 128.9
2
[3] J. Svetlik and T. Liptaj, J. Heterocyclic Chem., 36, 1023
(1999).
(CH-3' + CH-5'), 140.3 (C-1'), 153.4 (C-3), 159.1 (CO); m/s: m/z
+
(relative intensity) 203 (C H N O, M , 22), 202 (7), 185
11 13
3
[4] S. F. McCann and B. L. Finkelstein, PCT Int. Appl. WO
9946,266 (1999); Chem. Abstr., 131, 214308d (1999).
[5] O. W. Griffith and S. S. Gross, in Methods in Nitric Oxide
Research, M. Feelisch and J. S. Stamler, eds., John Wiley & Sons,
Chichester, 1996, pp 187-208.
(C H N , 3), 184 (3), 161 (61), 160 (85), 159 (C H N , 70),
11 11
3
10 11 2
145 (7), 129 (7), 128 (7), 119 (9), 118 (9), 115 (9), 104 (43), 93
(8), 91 (10), 83 (C H N , 100), 82 (12), 78 (13), 77 (21), 65 (8),
4
7 2
63 (7), 51 (15), 43 (20), 42 (39), 39 (14).
Anal. Calcd. for C H N O: C, 65.01; H, 6.45; N, 20.67.
11 13
3
[6] R. Bucala, A. Cerami and H. Vlassara, Diabetes Rev., 3, 258
(1995).
Found: C, 64.83; H, 6.61; N, 20.54.
[7] H. Neunhoeffer and P. F. Wiley, in The Chemistry of
Heterocyclic Compounds, Vol. 33,
A. Weissberger and E. C. Taylor, eds., Wiley-Interscience, New York,
1978, pp 360 and 600.
4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-car-
boximidamide Acetate (5c).
Compound 5c was obtained in 20% yield (0.42 g), mp. 220-
[8] H. Neunhoeffer, in Comprehensive Heterocyclic Chemistry,
Vol. 3, Part 2B, A. R. Katritzky and C. W. Rees, eds., Pergamon Press,
Oxford, 1984, pp 432-435.
[9] H. Neunhoeffer, in Comprehensive Heterocyclic Chemistry II,
Vol. 6, A. R. Katritzky, C. W. Rees and E.F.V. Scriven, eds., Pergamon,
New York, 1996, p. 559.
[10] T. Nishimura, C. Yamazaki, H. Toku, S. Yoshii, K. Hasegawa,
M. Saito and D. Nagaki, Chem. Pharm. Bull., 22, 2444 (1974).
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Chem., 21, 1537 (1984).
[12] W. Bruegel, Handbook of NMR Spectral Parameters, Vol. 3,
Heyden, London, 1979, p 640.
[13] J. H. Beynon, J. A. Hopkinson and A. E. Williams, Org. Mass.
Spectrom., 1, 169 (1968).
[14] J. Svetlik and T. Liptaj, J. Heterocyclic Chem., in preparation.
[15] V. Kettmann and J. Svetlik, Acta Crystalogr., Sect. C, in
preparation.
221° (DMF); ir (potassium bromide): 3314 (NH , NH), 1666
2
-1
1
(C=N), 1589 (COO), 1407, 809 (p-C H -wag) cm ; H nmr
6
4
(DMSO-d ): δ 1.61 (s, 3H, Me of HOAc), 2.04 (s, 3H, Me), 2.28
6
(s, 3H, Me-Tol), 2.74 (dd, 1H, J =18.3 and J =3.5 Hz, 4-H ),
AB
AX
a
3.62 (dd, 1H, J =18.3 and J =11.3 Hz, 4-H ), 5.46 (dd, 1H,
AB
BX
b
J
=3.5 and J =11.3 Hz, 5-H), 7.04 (AA' part of AA'BB', 2H,
AX
BX
J=8.1 Hz, 3'-H + 5'-H), 7.18 (BB' part of AA'BB', 2H, J=8.1 Hz,
13
2'-H + 6'-H), 7.30-10.80 (br, 4H, NH ); C nmr (DMSO-d ):
2
6
δ 15.5 (Me), 20.6 (Me-Tol), 25.0 (Me of HOAc), 47.4 (CH ),
2
59.2 (CH), 125.2 (CH-2' + CH-6'), 129.4 (CH-3' + CH-5'), 137.2
+ 137.5 (C-1',C-4'), 153.6 (C-3), 158.4 (N-C=N), 176.0 (CO of
HOAc).
Anal. Calcd. for C H N O : C, 60.85; H, 7.29; N, 20.27.
14 20
4 2
Found: C, 60.99; H, 7.59; H, 20.02.
4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-car-
boxamide (10c).
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H. Elo, Z. Naturforsch., 51B, 1771 (1996).
Compound 10c was obtained in 26% yield (0.27 g), mp 198-
[17] M. Koskinen, I. Mutikainen, P. Tilus, E. Peltari, M. Korela
and H. Elo, Monatsh. Chem., 128, 767 (1997).
201° (dioxane); ir (potassium bromide): 3246 (NH ), 1673
2
-1
1
[18] J. T. Koskinen, M. Koskinen, I. Mutikainen, P. Tilus, B.
Mannfors and H. Elo, Z. Naturforsch., 52B, 1259 (1997).
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Gilman and A.H. Blatt, eds., John Wiley & Sons, New York, 1948, p 77.
[22] S. J. Kesten, M. J. Degnan, J. Hung, D. J. McNamara, D. F.
Ortwine, S. E. Uhlendorf and L. M. Werbel, J. Med. Chem., 35, 3429
(1992).
(C=O), 1597 (C=N), 814 (p-C H -wag) cm ; H nmr (DMSO-
6
4
d ): δ 2.05 (s, 3H, Me), 2.28 (s, 3H, Me-Tol), 2.75 (dd, 1H,
6
J
J
=18.3 and J =3.0 Hz, 4-H ), 3.64 (dd, 1H, J =18.3 and
AB
AX a AB
=11.7 Hz, 4-H ), 5.50 (dd, 1H, J =3.0 and J =11.7 Hz,
BX
b
AX
BX
5-H), 7.04 (AA' part of AA'BB', 2H, J=8.1 Hz, 3'-H + 5'-H), 7.18
(BB' part of AA'BB', 2H, J=8.1 Hz, 2'-H + 6'-H), 7.60-10.20 (br,
13
2H, NH ); C nmr (DMSO-d ): δ 15.5 (Me), 20.6 (Me-Tol),
2
6
47.5 (CH ), 59.2 (CH), 125.2 (CH-2' + CH-6'), 129.4 (CH-3' +
2
CH-5'), 137.3 (C-1' + C-4'), 153.4 (C-3), 159.1 (CO).