Unusual reaction of 2-(trifluoromethyl)-1,2-dihydro-3λ6-thieno- [2,3-c]chromen-3,3,4-triones with hydrazine as a new route to 3-hydrazinopyridazine derivatives

Article abstract of DOI:10.1021/jo0258406

Oxidation of 2-(trifluoromethyl)-1,2-dihydro-4H-thieno[2,3-c]chromen-4-ones 2 with H₂O₂ in AcOH gives 2-(trifluoromethyl)-1,2-dihydrothieno[2,3-c]chromen-3,3,4-triones 3, which are transformed into 3-hydrazinopyridazine derivatives 4 in high yields by treatment with hydrazine hydrate in ethanol.

Full text of DOI:10.1021/jo0258406

Un u su a l Rea ction of 2-(Tr iflu or om eth yl)-1,2-d ih yd r o-3λ6-th ien o-
[2,3-c]ch r om en -3,3,4-tr ion es w ith Hyd r a zin e a s a New Rou te to
3-Hyd r a zin op yr id a zin e Der iva tives
Vyacheslav Ya. Sosnovskikh,*,† Boris I. Usachev,† and Ivan I. Vorontsov‡
Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russian Federation, and
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
117813 Moscow, Russian Federation
vyacheslav.sosnovskikh@usu.ru
Received April 18, 2002
Oxidation of 2-(trifluoromethyl)-1,2-dihydro-4H-thieno[2,3-c]chromen-4-ones 2 with H2O2 in AcOH
gives 2-(trifluoromethyl)-1,2-dihydrothieno[2,3-c]chromen-3,3,4-triones 3, which are transformed
into 3-hydrazinopyridazine derivatives 4 in high yields by treatment with hydrazine hydrate in
ethanol.
In tr od u ction
Resu lts a n d Discu ssion
We found that dihydrothienocoumarins 2a -f 1 obtained
from ethyl mercaptoacetate and 2-trifluoromethylchro-
mones 1a -f were smoothly oxidized by treatment with
H2O2 in glacial acetic acid at 100 °C for 2 h and give
sulfones 3a -f in 48-83% yields. Nitro derivative 3g was
prepared in 94% yield by the nitration of sulfone 3a with
the nitrating mixture at ∼20 °C for 10 min. The reduction
of 3g with SnCl2 in boiling ethanol gave aminosulfone
3h in 66% yield (Scheme 1).
Recently1,2 we have described the reaction of 2-trifluo-
romethylchromones 1 with ethyl mercaptoacetate in the
presence of Et3N. The reaction turned out to consist of
several stages, including the redox stage, and affords
dihydrothienocoumarins 2, which can be considered as
useful intermediates for constructing highly functional-
ized biologically important products. In this work, we
report our results of the selective oxidation of sulfides 2
to sulfones 3 and the unusual transformation of sulfones
3 into 3-hydrazinopyridazines 4 under the action of
hydrazine hydrate. The latter reaction is undoubtedly of
interest since several derivatives of 3-hydrazinopy-
ridazine exhibit different types of biological activity as
chemotherapeutics, antiinflammatory agents, CNS de-
pressants and stimulants, and antihypertensives.3 In
particular, prizidilol, a compound combining vasodilator
and â-blocker functionalities in the same molecule,4,5 has
been synthesized from 3-hydrazino-6-(2-hydroxyphenyl)-
pyridazine, epichlorohydrin, and tert-butylamine.6a,b In
addition, 3-hydrazinopyridazines are widely used in the
synthesis of triazolo- and tetrazolopyridazines, which also
show interesting pharmaceutical activity and are poten-
tial medicinal agents.7-12
Compounds 3 are poorly soluble in alcohol but heating
their alcoholic suspension with a 5-fold excess of hydra-
zine hydrate results in the exothermic reaction during
which the solution first becomes homogeneous and a
crystalline product immediately precipitates from it. As
a rule, 1-2 min of boiling is enough to complete the
reaction. On the basis of the data of elemental analysis,
1
IR, NMR, and H and 13C spectroscopy, we established
that the reaction products of sulfones 3 with hydrazine
are 3-hydrazinopyridazine derivatives 4 (Scheme 2),
whose structure was further confirmed by the X-ray
diffraction study of crystals of the salt of pyridazine 4b
with HClO4 (cation 5b, see below).
This unexpected reaction occurs very readily and
purely affords in high yields (47-74%) pyridazines 4a -
c,f-h with both electron-donating (Me, MeO, NH2) and
electron-withdrawing (NO2) groups. However, sulfones
3d ,e bearing a substituent in the 9-position did not form
the corresponding pyridazines, which can be attributed
to repulsive steric interactions between the peri-substitu-
ent and the N2H4 molecule at the stage of nucleophilic
addition of N2H4 at the CdC bond of the R-pyrone ring.
Note that 4,4,4-trihalo-3-hydroxy-1-(2-hydroxyaryl)bu-
* To whom correspondence should be addressed.
† Ural State University.
‡ A. N. Nesmeyanov Institute of Organoelement Compounds.
(1) Sosnovskikh, V. Ya.; Usachev, B. I.; Sevenard, D. V.; Lork, E.;
Ro¨schenthaler, G.-V. Tetrahedron Lett. 2001, 5117.
(2) Sosnovskikh, V. Ya.; Usachev, B. I. Tetrahedron Lett. 2001, 5121.
(3) Pinza, M.; Pifferi, G. Farmaco 1994, 49, 683.
(4) Slater, R. A.; Howson, W.; Swayne, G. T. G.; Taylor, E. M.;
Reavill, D. R. J . Med. Chem. 1988, 31, 345.
(5) Prout, K.; Burns, K.; Roe, A. M. Acta Crystallogr. 1994, B50,
68.
(6) (a) Coates, W. J .; Roe, A. M.; Slater, R. A.; Taylor, E. M. U.S.
Patent, 4,053,601, 1977. (b) Burpitt, B. E.; Graham, M. J .; Roe, A. M.
European Patent, 0007930, 1978. (c) Levinson, S. H.; Mendelson, W.
L. U.S. Patent 4,152,517, 1979.
(7) Albright, J . D.; Moran, D. B.; Wright, W. B., J r.; Collins, J . B.;
Beer, B.; Lippa, A. S.; Greenblatt, E. N. J . Med. Chem. 1981, 24, 592.
(8) Sunder, S.; Peet, N. P. J . Heterocycl. Chem. 1980, 17, 1527.
(9) Katrusiak, A. A.; Bałoniak, S.; Katrusiak, A. S. Pol. J . Chem.
1996, 70, 1279.
(10) Bałoniak, S.; Katrusiak, A. Pol. J . Chem. 1994, 68, 683.
(11) Shams, N. A.; Kaddah, A. M.; Moustafa, A. H. Indian J . Chem.
1982, 21B, 317.
(12) Wasfy, A. A. F. Indian J . Chem. 1994, 33B, 1098.
10.1021/jo0258406 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/22/2002
6738
J . Org. Chem. 2002, 67, 6738-6742

A New Route to 3-Hydrazinopyridazine Derivatives
SCHEME 1
F IGURE 1.
minor component of the mixture obtained in the first
experiment. When this compound, the molecular formula
of which corresponds to the addition of 3 molecules of
N2H4 to sulfone 3g with elimination of 3 molecules of HF,
was boiled in alcohol in the presence of hydrazine hydrate
or ammonia, pyridazine 4g was formed, which finally
proves its intermediacy. As expected, the reaction did not
occur without a base additive.
SCHEME 2
Since crystals of the isolated intermediate were inap-
propriate for X-ray diffraction study, its structure was
established from the data of IR and 1H and 13C NMR
spectra. The IR spectrum of the intermediate contains
no absorption bands of the ketone or ester carbonyl group
(1670-1740 cm-1) but exhibits several bands in the
regions of 1520-1660 (νCdN, δNH, amide-I) and 3090-3400
cm-1 (νNH).13 The 1H NMR spectrum in DMSO-d6 exhibits
signals from 3 aromatic protons (δ 7.7-8.3 ppm) and from
5 aliphatic protons of two CH2 and one CH groups
forming AMX and AB spin systems in a region of 2.8-
4.8 ppm. One of the CH2 groups is in a weak field (4.18
ppm), which indicates that it is adjacent to two electron-
withdrawing groups as, for example, in the diketo form
of â-diketones.14 In addition, the spectrum contains
signals from 7 mobile protons, which appear as 3 two-
proton (4.5, 6.7, and 7.3 ppm) and 1 one-proton (9.6 ppm)
singlets and disappear when CD3CO2D is added. On the
basis of these data, we can propose two alternative
structures for the intermediate in the reaction of 3g with
N2H4: benzocyclononene 6g (closer in structure to initial
sulfone 3g) and dihydropyridazine 6g′ (closer in structure
to product 4g), among which we prefer the first one
(Figure 1).
The following facts favor structure 6g. First, the
chemical shifts of singlets from NH and NH2 protons,
which are in the composition of the hydrazino (-NHNH2)
and hydrazono (dNNH2) groups, agree well only with
structure 6g: the downfield one-proton and upfield two-
proton signals correspond to the CONHNH2 group, and
2 two-proton peaks at 6.7 and 7.3 ppm correspond to two
hydrazono groups. Structure 6g′ contains only two hy-
drazino groups, whose NH2 protons are usually more
shielded, and the NH protons, as well as phenolic
hydroxyl, in a solution of DMSO-d6 should appear in a
tan-1-ones obtained by reaction of the appropriate 2-hy-
droxyacetophenones with chloral or bromal react with
hydrazine at elevated temperatures to give 6-(2-hy-
droxyaryl)-3-pyridazinones in good yields.6c
The reaction of N2H4 with sulfone 3g is very helpful
in revealing the mechanism of the transformation 3 f
4. Under standard conditions, this reaction gave a
mixture of pyridazine 4g with an unknown product in a
ratio of 3:1, respectively. Since the minor product could
be one of the intermediates of the transformation we are
interested in, the reaction was studied in more detail. It
turned out that if the heating time was increased from 2
to 15 min, pure hydrazinopyridazine 4g was formed in
73% yield, while if the reaction is conducted at 0 °C for
20 min, the treatment of the homogeneous solution with
dilute AcOH resulted in the starting sulfone 3g contain-
ing 9% of the same unknown admixture. However, when
the reaction temperature was increased to 20 °C, after
30 min the individual substance of molecular formula
C12H15N7O6S was isolated from the reaction mixture,
which decomposes on heating above 200 °C to evolve SO2
(13) Mashima, M. Bull. Chem. Soc. J pn. 1962, 35, 332.
(14) Bassetti, M.; Cerichelli, G.; Floris, B. Tetrahedron 1988, 44,
2997.
1
and has an H NMR spectrum identical with that of the
J . Org. Chem, Vol. 67, No. 19, 2002 6739

Sosnovskikh et al.
SCHEME 3
lower field (∼8-10 ppm). Second, the aromatic proton
in the ortho position to oxygen is manifested in initial
sulfone 3g at 7.81 ppm, in the intermediate it appears
at 7.69 ppm, and in product 4g, in which the oxygen atom
is not involved in cycle formation, the aromatic proton
appears at 7.10 ppm. Since the considered proton in the
intermediate is deshielded by 0.6 ppm compared to the
similar proton in pyridazine 4g, we may conclude that
the oxygen atom is in the composition of the cycle and,
hence, the intermediate has structure 6g rather than 6g′.
Structures 6g′′ and 6g′′′, which differ from 6g only by
the localization of the carbonyl oxygen atom, were
rejected on the basis of the data of IR and 13C NMR
spectra (Figure 1).
resolved triplet of doublets of doublets, which allows it
to be presumably assigned to the C(7) atom. Thus,
1
analysis of the H and 13C NMR spectra of the intermedi-
ate favors structure 6g, which, in turn, suggests the
possible mechanism of formation of pyridazines 4 from
sulfones 3 (Scheme 3).
We believe that the reaction is started from the attack
of the keto group of sulfone 3 by the hydrazine molecule.
This interaction through the addition-elimination stages
leads to the replacement of the carbonyl oxygen atom of
the ester group, by the hydrazono group. At first sight,
this transformation seems quite unexpected; however,
this is directly confirmed in the literature. Bakre and
Merchant16 showed for several examples that the reaction
of hydrazine hydrate with coumarin derivatives bearing
the heterocyclic ring in 3- and 4-positions of the coumarin
system proceeds at the keto group and leads to the
corresponding hydrazones. The subsequent hydrazinoly-
sis and hydrolysis of the CF3 group to the CONHNH2
moiety as the E-A process, addition to the activated
double bond of the hydrazine molecule, and opening of
the bond common for the bicycle lead to the formation of
the benzocyclononene intermediate 6, which was isolated
in the case of sulfone 3g. The further transformation of
this intermediate is accompanied by the elimination of
SO2 to form the hydrazine derivative of â-aroylacrylic
acid, which undergoes intramolecular cyclization and
gives 3-hydrazinopyridazines 4 (Scheme 3). The capabil-
ity of the fluorine atoms of the CF3 group of substituting
under the action of ammonia and primary and secondary
amines has previously been observed for R-trifluoro-
methyl-R-fluoro-2-hydroxyacetophenone17 and for the
reaction of 2- and 4(5)-trifluoromethylimidazoles18,19 with
a 5% solution of NH4OH. The latter lead through difluo-
rodiazafulvenes to 2- and 4(5)-cyanoimidazoles.
Probably, the fragment of molecule 6g, which is fused
with the benzene ring, is close to the planar conformation,
and the C(3), S(4), C(5), and C(6) atoms take the chairlike
conformation in which the hydrazide group occupied the
equatorial position. The axial methine proton H(5) (X part
of the AMX spin system) is split on the axial and
equatorial protons of the C(6)H2 group (AM part of the
AMX spin system) with J XA ) 12.5 Hz and J XM ) 5.0 Hz,
respectively, the equatorial C(6)HH proton (δ ) 3.61
ppm) forms a doublet of doublets with J MA ) 14.2 Hz and
J MX ) 5.0 Hz, and the axial C(6)HH proton (δ ) 2.79
ppm) appears as a triplet with J ) 13.4 Hz due to the
close values of the vicinal (J AX ) 12.5 Hz) and geminal
(J AM ) 14.2 Hz) constants. Since the molecule contains
the chiral center, the protons of the C(3)H2 group are
diastereotopic and form the AB system with J AB ) 14.3
Hz. Note that the indicated values of spin-spin coupling
constants in 6g agree well with the values of vicinal and
geminal constants in cyclohexane.15
The 13C NMR spectrum recorded for a solution of the
1
intermediate in DMSO-d6 without H decoupling contains
a triplet of doublets, a triplet, and a doublet of doublets
of doublets in the region of aliphatic carbon atoms, which
makes it possible to assign unambiguously these signals
to the C(6), C(3), and C(5) atoms, respectively. Three most
downfield signals belong to the CdO, C(11a), and C(9)
atoms, which is confirmed by the character of its splitting.
The protonated C(11), C(10), and C(8) atoms are at
121.9-123.4 ppm, and the quaternary C(7a), C(7), and
C(2) atoms lie in a region of 129.2-134.5 ppm. Note that
the signal at 133.9 ppm looks like a noncompletely
X-r a y Diffr a ction Stu d y of P er ch lor a te 5b. Struc-
ture 5b consists of the flattened cation and anions
associated by hydrogen bonds (Figure 2). In the [C11H13
-
N4O]+ cation, the angle between the planes of the
aromatic cycles is 8.4°, and the hydrazine group is
coplanar to the plane of the pyridazine cycle. Flatten-
ing of the cation is favored by the formation of the
intramolecular O(1)-H(1O)‚‚‚N(1) hydrogen bond with
(16) Bakre, K. M.; Merchant, J . R. Indian J . Chem. 1981, 20B, 614.
(17) Dmowski, W. Synthesis 1983, 396.
(18) Kimoto, H.; Fujii, S. J . Org. Chem. 1982, 47, 2867.
(19) Matthews, D. P.; Whitten, J . P.; McCarthy, J . R. J . Org. Chem.
1986, 51, 3228.
(15) Gu¨nther, H. NMR Spectroscopy; George Thieme Verlag:
Stuttgart, Germany, 1973.
6740 J . Org. Chem., Vol. 67, No. 19, 2002

A New Route to 3-Hydrazinopyridazine Derivatives
F IGURE 2. General view of the dimer of 5b in the projection along the b axis. The labeling scheme of non-hydrogen atoms,
dimer cations, and some anions is shown. Hydrogen bonds in the crystal are presented by dotted lines.
) 8. The intensities of 3817 independent reflections (Rint
)
the following parameters: H‚‚‚N 1.88(4) Å, O-H 0.88(3)
Å, O‚‚‚N 2.653(2) Å, and O(1)-H(1O)‚‚‚N(1) 146(3)°.
According to the published data,20 the interatomic dis-
tances for the O-H‚‚‚N hydrogen bonds in analogous
fragments vary in the following characteristic ranges:
O‚‚‚N 2.471-2.668 Å (average 2.586 Å) and H‚‚‚N 1.354-
2.090 Å (average 1.732 Å). Therefore, the O-H‚‚‚N
hydrogen bond can be considered as relatively weak (for
further discussion see the Supporting Information).
In conclusion, the reaction described above has wide
applicability and represents a new route to synthesize
3-hydrazinopyridazines with 2-hydroxyaryl substituents.
Our approach makes it possible to obtain these com-
pounds from 2-hydroxyacetophenones and ethyl trifluo-
roacetate (starting substances for the synthesis of 2-tri-
fluoromethylchromones21) in four stages, whereas the
method for synthesis of similar pyridazines described in
the patent literature6a consists of seven stages and starts
from phenols and succinic anhydride via 6-(2-hydroxyaryl)-
3-pyridazinones.
0.04) were measured on a Bruker SMART 1K CCD diffracto-
meter, λ(Mo KR) ) 0.71073 Å, graphite monochromator, ω
scans (scan step in ω 0.3°, exposition time of the frame 30 s),
2θmax ) 60°, data completeness 99%. The intensities of all
reflections were obtained by the use of the SAINT Plus and
SADABS program packages (maximum and minimum trans-
mission coefficients 0.977 and 0.715).22,23 The structure was
solved by the direct method using the SHELXTL-9724 program
package. Non-hydrogen atoms were refined by the full-matrix
least-squares procedure on F2 in an anisotropic approximation.
The positions of hydrogen atoms were found by a difference
Fourier synthesis and refined isotropically. The hydrogen
atoms of the Me group were refined by using the riding model
with isotropic displacement parameters Uiso(H) ) 1.5Ueq(C),
where Ueq(C) were equivalent isotropic displacement param-
eters of corresponding C atoms. The final discrepancy factors
were as follows: R1 ) 0.059 (based on F for 2213 reflections
with I > 2σ(I)), wR2 ) 0.150 (calculated based on F2 for all
3817 reflections, used at the final stage of the refinement);
the total number of the parameters in the refinement was 230,
GOOF ) 0.882.
Gen er a l P r oced u r e for t h e Syn t h esis of Su lfon es
3a -f. A mixture of dihydrothienocoumarin 2 (0.022 mol), 33%
H2O2 (18 mL), and AcOH (60 mL) was heated on a water bath
for 2 h and then cooled to room temperature. The crystalline
product that precipitated was filtered off, washed with aqueous
acetic acid (1:1), and dried.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively; chemical shifts are given in δ ppm downfield from
tetramethylsilane as internal standard. IR spectra were
measured in Nujol. Elemental analyses were performed at the
Microanalysis Services of the Institute of Organic Synthesis,
Urals Branch of the Russian Academy of Sciences. Melting
points are uncorrected. The starting dihydrothienocoumarins
2a -f were prepared by reaction of the appropriate 2-trifluo-
romethylchromone 1a -f 21 and ethyl mercaptoacetate accord-
ing to the procedure described.1
Cr ysta llogr a p h ic Da ta for 5b (C11H13N4O‚ClO4). The
crystal system is monoclinic at 140 K; a ) 25.369(3) Å, b )
12.5402(15) Å, c ) 8.5014(11) Å, â ) 104.312(3)°, V ) 2620.6(5)
Å3, dcalc ) 1.605 g cm-3, µ ) 0.322 mm-1, space group C2/c, Z
2-(T r iflu o r o m e t h y l)-1,2-d ih y d r o -3λ6-t h ie n o [2,3-c]-
ch r om en -3,3,4-tr ion e (3a ): yield 64%; mp 244-246 °C; H
NMR (DMSO-d6) δ 3.87 (dd, 1H, J ) 19.0, 5.9 Hz), 4.11 (dd,
1H, J ) 19.0, 9.1 Hz), 5.23-5.33 (m, 1H), 7.55 (ddd, 1H, J )
7.9, 7.4, 0.9 Hz), 7.59 (dd, 1H, J ) 8.5, 0.9 Hz), 7.88 (ddd, 1H,
J ) 8.5, 7.4, 1.5 Hz), 8.05 (dd, 1H, J ) 7.9, 1.5 Hz); IR (Nujol)
1745 (CdO), 1630, 1615, 1570 cm-1. Anal. Calcd for C12H7-
F3O4S: C, 47.37; H, 2.32. Found: C, 47.53; H, 2.10.
1
(22) SMART and SAINT, Release 5.0, Area detector control and
integration software; Bruker AXS, Analitical X-ray Instruments:
Madison, WI, 1998.
(23) Sheldrick, G. M. SADABS, Program for exploiting the redun-
dancy of area-detector X-ray data; University of Go¨ttingen: Go¨ttingen,
Germany, 1999.
(20) Sosnovskikh, V. Ya.; Vorontsov, I. I.; Kutsenko, V. A. Russ.
Chem. Bull. 2001, 50, 1430.
(21) Whalley, W. B. J . Chem. Soc. 1951, 3235.
(24) Sheldrick, G. M. SHELXTL-97, Program for Solution and
Refinement of Crystal Structure; Bruker AXS Inc.: Madison, WI, 1997.
J . Org. Chem, Vol. 67, No. 19, 2002 6741

Sosnovskikh et al.
8-Met h yl-2-(t r iflu or om et h yl)-1,2-d ih yd r o-3λ6-t h ien o-
[2,3-c]ch r om en -3,3,4-tr ion e (3b): yield 83%; mp 282-283
°C; 1H NMR (DMSO-d6/CCl4) δ 2.46 (s, 3H), 3.70 (dd, 1H, J )
18.9, 5.7 Hz), 4.04 (dd, 1H, J ) 18.9, 9.2 Hz), 5.07-5.17 (m,
1H), 7.41 (d, 1H, J ) 8.5 Hz), 7.64 (ddq, 1H, J ) 8.5, 2.1, 0.5
Hz), 7.82 (br d, 1H, J ) 1.7 Hz); IR (Nujol) 1735 (CdO), 1630,
1580 cm-1. Anal. Calcd for C13H9F3O4S: C, 49.06; H, 2.85.
Found: C, 49.02; H, 2.80.
1H); IR (Nujol) 3370, 3240, 1640, 1620, 1590 cm-1. Anal. Calcd
for C10H9N5O3: C, 48.59; H, 3.67; N, 28.33. Found: C, 48.54;
H, 3.58; N, 28.25.
4-Am in o-2-(6-h ydr azin opyr idazin -3-yl)ph en ol (4h ): yield
47% as yellow crystals; mp 221-222 °C; 1H NMR (DMSO-d6)
δ 4.40 (br s, 2H), 4.54 (br s, 2H), 6.58 (dd, 1H, J ) 8.5, 2.5
Hz), 6.67 (d, 1H, J ) 8.5 Hz), 7.01 (d, 1H, J ) 2.5 Hz), 7.24 (d,
1H, J ) 9.6 Hz), 7.91 (d, 1H, J ) 9.6 Hz), 8.24 (s, 1H), 12.56
(s, 1H); IR (Nujol) 3450, 3370, 3350, 3210-3270, 1650, 1620,
1600, 1570, 1515 cm-1. Anal. Calcd for C10H11N5O: C, 55.29;
H, 5.10; N, 32.24. Found: C, 55.30; H, 5.14; N, 32.36.
2,7-Dih yd r a zon o-9-n itr o-4,4-d ioxo-4,5,6,7-tetr a h yd r o-
1,4-ben zoxa th ion in -5(3H)-ca r boh yd r a zid e (6g). Aqueous
30% N2H4‚H2O (2 mL) was added to a suspension of nitrosul-
fone 4g (0.50 g, 1.4 mmol) in 6 mL of ethanol cooled to 0 °C.
The obtained mixture was stirred at ∼20 °C for 30 min, and
the product that formed was filtered off then washed with
aqueous ethanol (1:1), ethanol, and chloroform to give com-
pound 6g (0.40 g, 73%) as colorless powder: mp 200-202 °C
dec. 1H NMR (DMSO-d6) δ 2.79 (t, 1H, J ) 13.4 Hz), 3.61 (dd,
1H, J ) 14.2, 5.0 Hz), 4.18 (AB-system, 2H, ∆δ ) 0.10, J )
14.3 Hz), 4.51 (br s, 2H), 4.78 (dd, 1H, J ) 12.5, 5.0 Hz), 6.72
(s, 2H), 7.28 (s, 2H), 7.69 (d, 1H, J ) 9.0 Hz), 8.14 (dd, 1H, J
) 9.0, 2.9 Hz), 8.31 (d, 1H, J ) 2.9 Hz), 9.57 (s, 1H); 13C NMR
7-Meth oxy-2-(tr iflu or om eth yl)-1,2-d ih yd r o-3λ6-th ien o-
[2,3-c]ch r om en -3,3,4-tr ion e (3c): yield 77%; mp 246-247
°C; 1H NMR (DMSO-d6/CCl4) δ 3.66 (dd, 1H, J ) 18.8, 5.9 Hz),
3.94 (s, 3H), 4.01 (dd, 1H, J ) 18.8, 9.2 Hz), 5.00-5.10 (m,
1H), 7.05 (dd, 1H, J ) 8.9, 2.4 Hz), 7.11 (d, 1H, J ) 2.4 Hz),
7.90 (d, 1H, J ) 8.9 Hz); IR (Nujol) 1730 (CdO), 1615, 1560
cm-1. Anal. Calcd for C13H9F3O5S: C, 46.71; H, 2.71. Found:
C, 46.97; H, 2.68.
Gen er a l P r oced u r e for th e Syn th esis of 3-Hyd r a zin o-
p yr id a zin es 4a -c,f-h . Hydrazine hydrate (30%, 10 mL) was
added to a suspension of sulfone 3 (4.7 mmol) in boiling ethanol
(20 mL). The mixture was boiled for 1-2 min in the case of
3a -c,h and for 15 min in the case of 3f,g. In most cases,
pyridazine 4 is crystallized almost immediately after the initial
sulfone 3 was dissolved in the reaction mixture. Then the
mixture was cooled to room temperature, and the product was
filtered off, washed with ethanol, and dried. In the case of 3h ,
the reaction mixture, before the isolation of pyridazine 4h , was
diluted with 40% ethanol (25 mL).
2-(6-Hydr azin opyr idazin -3-yl)ph en ol m on oh ydr ate (4a):
yield 72% as colorless needles from ethanol; mp 184-186 °C;
1H NMR (DMSO-d6/CCl4) δ 4.35 (br s, 2H), 6.83-6.88 (m, 2H),
7.19 (ddd, 1H, J ) 8.4, 7.4, 1.5 Hz), 7.24 (d, 1H, J ) 9.6 Hz),
7.73 (br d, 1H, J ) 7.9 Hz), 8.04 (d, 1H, J ) 9.6 Hz), 8.21 (br
s, 1H), 13.71 (br s, 1H); IR (Nujol) 3350, 3180-3300, 1645,
1610, 1590 cm-1. Anal. Calcd for C10H10N4O‚H2O: C, 54.54;
H, 5.49; N, 25.44. Found: C, 54.37; H, 5.25; N, 25.61.
2-(6-Hydr azin opyr idazin -3-yl)-5-m eth oxyph en ol m on o-
h yd r a te (4c): yield 67% as colorless crystals; mp 206-207 °C;
1H NMR (DMSO-d6/CCl4) δ 3.78 (s, 3H), 4.24 (br s, 2H), 6.40
(d, 1H, J ) 2.6 Hz), 6.43 (dd, 1H, J ) 8.6, 2.6 Hz), 7.20 (d, 1H,
J ) 9.7 Hz), 7.63 (d, 1H, J ) 8.6 Hz), 7.95 (d, 1H, J ) 9.7 Hz),
8.06 (br s, 1H), 14.06 (br s, 1H); IR (Nujol) 3420, 3210-3360,
1620, 1590, 1575 cm-1. Anal. Calcd for C11H12N4O2‚H2O: C,
52.79; H, 5.64; N, 22.39. Found: C, 52.41; H, 5.47; N, 22.31.
2-(6-Hyd r a zin op yr id a zin -3-yl)-1-n a p h th ol (4f): yield
61% as a colorless crystals; mp 222-223 °C dec; 1H NMR
(DMSO-d6) δ 4.46 (s, 2H), 7.32 (d, 1H, J ) 9.7 Hz), 7.44 (d,
1H, J ) 8.8 Hz), 7.50-7.56 (m, 2H), 7.86 (d, 1H, J ) 7.3 Hz),
7.95 (d, 1H, J ) 8.8 Hz), 8.31 (d, 1H, J ) 9.7 Hz), 8.32 (d, 1H,
J ) 7.3 Hz), 8.38 (s, 1H), 15.6 (br s, 1H); IR (Nujol) 3300, 3125,
1640, 1585, 1520 cm-1. Anal. Calcd for C14H12N4O: C, 66.66;
H, 4.79; N, 22.21. Found: C, 66.81; H, 4.84; N, 22.20.
2-(6-Hyd r a zin op yr id a zin -3-yl)-4-n itr op h en ol (4g): yield
73% as a colorless crystals; mp 280-282 °C dec; 1H NMR
(DMSO-d6) δ 4.60 (br s, 2H), 7.10 (d, 1H, J ) 9.1 Hz), 7.30 (d,
1H, J ) 9.6 Hz), 8.14 (dd, 1H, J ) 9.1, 2.8 Hz), 8.35 (d, 1H, J
) 9.6 Hz), 8.57 (br s, 1H), 8.71 (d, 1H, J ) 2.8 Hz), 15.1 (br s,
2
(DMSO-d6) δ 22.46 (td, C,6 1J ) 134.3, J ) 3.9 Hz), 54.88 (t,
2
2
C,3 1J ) 139.5 Hz), 61.36 (ddd, C,5 1J ) 145.5, J ) 6.4, J )
3.7 Hz), 121.91 (d, C,11 1J ) 168.4 Hz), 122.92 (dd, C8 or C,10
1J ) 169.6, J ) 4.6 Hz), 123.39 (dd, C10 or C,8 1J ) 171.1, J
) 5.4 Hz), 129.23 (br s, C7a), 133.89 (tdd, C,7 3J ∼ 7.2, 2J ∼
4.0, 2J ∼ 2.0 Hz), 134.45 (br s, C2), 143.36 (dt, C,9 3J ) 10.3, 2J
3
3
) 3.6 Hz), 157.13 (ddd, C,11a 3J ) 10.3, J ) 8.7, J ) 3.6 Hz),
3
2
160.25 (q, CdO, 2J ∼ J ∼ 4.0 Hz); IR (Nujol) 3400, 3360, 3225,
3
3090 (NH, NH2), 1660 (CdO), 1615, 1600, 1585, 1560, 1520
cm-1. Anal. Calcd for C12H15N7O6S: C, 37.40; H, 3.92; N, 25.44.
Found: C, 37.32; H, 3.91; N, 25.41.
Ack n ow led gm en t. This work was financially sup-
ported by the Russian Foundation for Basic Research
(grants 02-03-32706, 00-15-97359, 99-07-90133, and 00-
03-32807) and, in part, by the US Civilian Research and
Development Foundation (grant REC-005). The authors
are grateful to Dr. L. N. Bazhenova for carrying out
elemental analyses and Dr. M. I. Kodess for recording
the NMR spectra (Institute of Organic Synthesis, Urals
Branch of the Russian Academy of Sciences).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 3a , 3g, 3h , 4a , 4b, 4g, 4h , 6g, and a mixture of
4g + 6g; 13C NMR spectra for compound 6g (decoupling,
coupling); complete listing of IR and 1H NMR peaks and
elemental analyses of compounds 3d -h , 4b, and 5b and 13C
NMR peaks for 4b; and a discussion and X-ray data for
compound 5b. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0258406
6742 J . Org. Chem., Vol. 67, No. 19, 2002