Synthesis of 1-mono- and 1,2-bisacylpyrazolidines and 1- arylsulfonylpyrazolines

Article abstract of DOI:10.1007/s11172-010-0257-2

Study of a reaction of 1,5-diazabicyclo[3.1.0]hexanes with acyl and sulfonyl chlorides in organic or aqueous organic media in the presence of inorganic bases resulted in development of new simple one-step methods for the preparation of 1-mono- and 1,2-bis

Full text of DOI:10.1007/s11172-010-0257-2

Russian Chemical Bulletin, International Edition, Vol. 59, No. 7, pp. 1419—1426, July, 2010
1419
Synthesis of 1ꢀmonoꢀ and 1,2ꢀbisacylpyrazolidines
and 1ꢀarylsulfоnylpyrazolines*
V. Yu. Petukhova, V. A. Maslennikov, V. V. Kuznetsov, N. N. Makhova, and S. A. Serkov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: pvyu@ioc.ac.ru
Study of a reaction of 1,5ꢀdiazabicyclo[3.1.0]hexanes with acyl and sulfоnyl chlorides in
organic or aqueous organic media in the presence of inorganic bases resulted in development of
new simple oneꢀstep methods for the preparation of 1ꢀmonoꢀ and 1,2ꢀbisacylpyrazolidines and
1ꢀarylsulfоnylpyrazolines.
Key words: 1,5ꢀdiazabicyclo[3.1.0]hexanes, ketenes, 1ꢀmonoacylpyrazolidines, 1,2ꢀbisꢀ
acylpyrazolidines, 1ꢀacylpyrazolines, 1ꢀarylsulfоnylpyrazolines, arenesulfоnyl chlorides, acyl
chlorides, mechanism.
It is known that compounds containing a pyrazolidine
ring possess a wide range of biological activity.2,3 In addiꢀ
tion, certain pyrazolidine derivatives are used as starting
compounds in the synthesis of important biologically acꢀ
tive substances, in particular, 1ꢀacylpyrazolidines are used
for the preparation of new TNFꢀαꢀinhibitors.4—6 The
known approaches to the synthesis of 1ꢀacylpyrazolidines
are based on the threeꢀ, fourꢀstep procedures,7—10 thereꢀ
fore, a search for new simple methods for obtaining comꢀ
pounds of this type remains an actual problem.
Earlier, we have developed an improved method for
the synthesis of 6ꢀsubstituted 1,5ꢀdiazabicyclo[3.1.0]ꢀ
hexanes 1, whose structure already contained a pyrazolꢀ
idine fragment.11,12 Compounds 1 were obtained in one
step from a carbonyl compound, 1,3ꢀdiaminopropane, and
sodium hypochlorite in water in virtually quantitative
yields. In the case of carbonyl compounds insoluble in water,
ButOCl was used as a chlorinating agent and organic solꢀ
vents (MeOH, CHCl3) as a reaction medium (Scheme 1).
Compounds 1 were chosen for the search of convenient
method for the preparation of pyrazolidine derivatives.
Recently,13 we have reported on the results of the reacꢀ
tion of 6ꢀunsubstituted, 6ꢀalkylꢀ and 6,6ꢀdialkylꢀsubstiꢀ
tuted 1,5ꢀdiazabicyclo[3.1.0]hexanes 1 with arylketenes,
which were generated in situ from arylacetyl chlorides and
Et3N. It was found that the synthesis of 1ꢀacylpyrazolꢀ
idines 2 is the main and predominant direction of this
reaction (Scheme 2). The reaction was carried out in anꢀ
hydrous organic solvents (diethyl ether, benzene) in the
flow of an inert gas. The following mechanism has been
suggested for the formation of 1ꢀacylpyrazolidines 2 in
this reaction. The first step of the reaction of arylketene
with 1,5ꢀdiazabicyclo[3.1.0]hexanes 1 gives zwitterionic
intermediates 3, which undergo the cleavage of С—N bond
of the threeꢀmembered ring to generate new zwitterionic
intermediates 4. The enolate ion in these intermediates,
being a strong base, combines with the НCl molecule from
Et3N•HCl, formed during obtaining arylketene, which
converts zwitterions 4 to salts 5, hydrolysis of the latter
under isolation conditions on a column with SiO2 leads to
1ꢀacylpyrazolidines 2. On the whole, this reaction can be conꢀ
sidered as the sequence of acylation and hydrolysis steps.
This approach to the synthesis of 1ꢀarylacetylpyrazolꢀ
idines 2 is a good supplement to the known methods, but
it requires anhydrous reaction medium. Proceeding from
the mechanism suggested, in order to prepare compounds
of pyrazolidine series it was logically to carry out the reacꢀ
tion of 1,5ꢀdiazabicyclo[3.1.0]hexanes 1 with acyl chloꢀ
rides 6 in aqueous organic medium in the presence of
a base. In fact, treatment of 1 with arylacetyl, benzoyl, and
other acyl chlorides 6 under conditions of the dichloꢀ
romethane—aqueous NaOH twoꢀphase system leads to
1,2ꢀbis(arylacetyl)ꢀ, 1,2ꢀbisaroylꢀ and a number of other
1,2ꢀbisacylpyrazolidines 7 in 53—94% yields (Scheme 3).
The formation of 1,2ꢀbisacylpyrazolidines 7 under these
Scheme 1
R1 = H, Alk, Ar
R
2 = H, Alk
* For preliminary communication, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1388—1394, July, 2010.
1066ꢀ5285/10/5907ꢀ1419 © 2010 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Petukhova et al.
Scheme 2
R1, R2 = H, Alk
3 = Ar; R4 = H, Alk, Ph
R
Scheme 3
R1 = R2 = Me (a)
1 = Pri, R2 = H (b)
R
Table 1. Starting 1,5ꢀdiazabicyclo[3.1.0]hexanes 1, acyl chloꢀ
rides 6, and yields of 1,2ꢀbisacylpyrazolidines 7 obtained
conditions proceeds, by all accounts, through the interꢀ
mediates 8, which after the С—N bond cleavage are conꢀ
verted to compounds 5 similar to compounds 5 in the
reaction of compounds 1 with arylketenes (see Scheme 2).
Since the reaction was carried out in water, the intermediꢀ
ates 5 were hydrolyzed to 1ꢀacylpyrazolidines 2, which
then were involved into the reaction with the second molꢀ
ecule of acyl chloride 6 to form the final products 7, with
1,2ꢀbisacylpyrazolidines 7 being the major products at any
ratio 1 : 6. The best yields were obtained for the ratio
1 : 6 = 1 : 2 (see Scheme 3). Table 1 summarizes the data
on the starting compounds and yields of 1,2ꢀdisubstituted
pyrazolidines 7 obtained.
Starting
compounds
R3
Product and its
yield (%)
in compounds 6 and 7
6a + 1а
6b + 1а
6c + 1а
6d + 1b
6e + 1a
6f + 1a
6g + 1b
6h + 1a
4ꢀFC6H4CH2
2ꢀFꢀ6ꢀClC6H3CH2
PhCH2
7a (53)
7b (91)
7c (65)
7d (90)
7e (84)
7f (64)
7g (84)
7h (94)
4ClC6H4
4ꢀMeOC6H4
4ꢀNO2C6H4
Ph
4ꢀClC6H4OC(Me)2
For the selective formation of 1ꢀarylacetylꢀ and 1ꢀaroꢀ
ylpyrazolidines 2, the reaction of two moles of 1,5ꢀdiꢀ
azabicyclo[3.1.0]hexanes 1 and one mole of arylacetyl
or benzoyl chlorides 6 in organic solvent (toluene) at
6i + 1a
6k + 1a
7i (72)
7k (75)
2ꢀClC6H4CH=CH

Acylpyrazolidines and arylsulfonylpyrazolines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1421
Table 2. Starting compounds and yields of 1ꢀmonoacylpyrꢀ
azolidines 2 obtained
–18÷–15 °C with subsequent treatment of the reaction
mixture with aqueous solution of sodium bicarbonate
turned out to be efficient. The final products were isolated
by column chromatography on SiO2. The yields of comꢀ
pounds 2 were 36—59% (Scheme 4, Table 2).
Starting
R3
Product and its
yield (%)
compounds
in compounds 6 and 2
6a + 1а
6d + 1b
6f + 1a
6h + 1a
6l + 1a
6m + 1a
6n + 1b
4ꢀFC6H4CH2
4ꢀClC6H4
4ꢀNO2C6H4
4ꢀClC6H4OC(Me)2
4ꢀClC6H4CH2
4ꢀBrC6H4CH2
2,4ꢀ(NO2)2C6H3
2a (52)
2d (59)
2f (42)
2h (36)
2l (41)
2m (45)
2n (37)
Scheme 4
tion on a column with SiO2 (analogous reactions are deꢀ
scribed in the literature14) (Scheme 6).
R1 = R2 = Me (a)
R1 = Pri, R2 = H (b)
The structures of 1ꢀacylꢀ (2) and 1,2ꢀbisacylpyrazolꢀ
idines (7) obtained were confirmed by a combination of
spectral characteristics, elemental analysis, and compariꢀ
son with the literature data.
Reagents and conditions: 1) toluene, –15 °С; 2) NaHCO3/H2O.
Isolation of the product of the reaction of 6ꢀisopropylꢀ
1,5ꢀdiazabicyclo[3.1.0]hexane 1b with 4ꢀchlorobenzoyl
chloride 6d by column chromatography on SiO2 gives,
together with desired 4ꢀchlorobenzoylpyrazolidine 2d,
1ꢀ(4ꢀchlorobenzoyl)ꢀ2ꢀ(2ꢀmethylpropenꢀ1ꢀyl)pyrazolꢀ
idine 9 in low yield (8%), whose formation confirms the
reaction mechanism suggested in Scheme 3. Apparently,
intermediate 5d in alkaline medium is transformed to prodꢀ
uct 9 with the double bond migration and elimination of
the HCl molecule (Scheme 5).
When products of the reaction of 6,6ꢀdimethylꢀ1,5ꢀ
diazabicyclo[3.1.0]hexane 1а with 2ꢀ(4ꢀchlorophenoxy)ꢀ
2ꢀmethylpropionyl chloride 6h under indicated conditions
were separated, the corresponding pyrazoline 10 was isoꢀ
lated along with monosubstituted pyrazolidine 2h, the forꢀ
mation of which can be explained by the oxidation of
pyrazolidine 2h with air oxygen in the process of its isolaꢀ
To sum up, this stage of the study resulted in the develꢀ
opment of simple twoꢀstep methods for obtaining 1ꢀacylꢀ
(2) and 1,2ꢀbisacylpyrazolidines (7), including in the first
step the synthesis of 1,5ꢀdiazabicyclo[3.1.0]hexanes 1 and
in the second step, their reaction with acyl chlorides 6.
For simplification of these procedures, a possibility of the
preparation of 1,2ꢀbisacylpyrazolidines 7 by a oneꢀpot reꢀ
action was studied, which excluded the isolation of comꢀ
pounds 1. As it was mentioned above, 1,5ꢀdiazabicycloꢀ
[3.1.0]hexanes 1 were obtained by the action of NaOCl on
a mixture of 1,3ꢀdiaminopropane and the corresponding
carbonyl compound in water at reduced temperature.11
For obtaining compounds 7 by the oneꢀpot reaction, we
carried out the synthesis of bicycle 1а without isolation
(TLC monitoring, iodometric titration). The reaction mixꢀ
Scheme 5
i. 1) Toluene, –15 °С; 2) NaHCO3/H2O.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Petukhova et al.
Scheme 6
the synthesis of various heterocyclic compounds, for exꢀ
ample, in obtaining 1,2,3ꢀtriazolꢀ4ꢀine.15
Scheme 8
Reagents and conditions: toluene, –15 °С.
Ar = 4ꢀMeC6H4(a), 4ꢀFC6H4 (b), 4ꢀBrC6H4 (c)
ture obtained was diluted with the equal volume of CH2Cl2,
followed by addition of calculated amount of NaOH, and,
on cooling, the corresponding acyl chloride. In fact, in all
the cases the desired compounds were obtained in preparꢀ
ative yields (Scheme 7). The yields were calculated on
1,3ꢀdiaminopropane.
Product
Yield (%)
12a
12b
12c
21.5 (13.2)
26.7 (16) 78.0 (54)
This process was also carried out under conditions of
the oneꢀpot reaction. It turned out that arylsulfоnylpyrꢀ
azolines 12a—c are formed in this case as well, but in
considerably lower yields than in the twoꢀstep version (see
Scheme 8, the numbers in parentheses).
Scheme 7
In conclusion, the studies performed resulted in the
development of simple and accessible methods for the
preparation of 1ꢀmonoꢀ and 1,2ꢀbisacylpyrazolidines and
1ꢀarylsulfоnylpyrazolines by the reaction of 1,5ꢀdiazaꢀ
bicyclo[3.1.0]hexanes with acyl chlorides and arenesulfꢀ
оnyl chlorides in preparative yields. It was shown that 1,2ꢀbisꢀ
acylpyrazolidines and 1ꢀarylsulfоnylpyrazolines can be
obtained by оneꢀpot reactions, that considerably simplifies
procedure for their synthesis.
Experimental
IR spectra were recorded on a URꢀ20 spectrometer in КВr
1
pellets, H NMR spectra were recorded on a Bruker WMꢀ250
(250 МHz), Bruker AMꢀ300 (300 МHz), and Bruker ACꢀ200
(200 МHz) spectrometers, 13С NMR spectra, on a Bruker
AMꢀ300 (75.5 МHz) spectrometer, chemical shifts are given
with respect to the signal of SiMe4. The reaction course and
purity of the products obtained were monitored by TLC on
Silufol UV254 plates with visualization under a UV lamp and
in I2 vapors. Melting points were determined on a Sanyo
GALLENKAMP instrument.
6,6ꢀDimethylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane (1а) (see Ref. 16),
6ꢀisopropylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane (1b) (see Ref. 12),
carboxylic acyl chlorides and arenesulfоnyl chlorides17—22 were
obtained according to the known procedures.
In order to broaden preparative application of the reꢀ
actions found under conditions of obtaining 1,2ꢀbisꢀ
acylpyrazolidines 7, a reaction of 6,6ꢀdimethylꢀ1,5ꢀdiꢀ
azabicyclo[3.1.0]hexane 1а with arenesulfоnyl chlorides
11 was studied. In this case, 1ꢀarylsulfоnylpyrazolines 12
were isolated as the reaction products in 13—78% yields
(Scheme 8). Probably, the formation of the desired 1,2ꢀbisꢀ
(arylsulfоnyl)pyrazolidines 13 occurs in the first step of
the reaction. However, in the presence of a strong base
(NaOH), elimination of arenesulfinic acid takes place with
the formation of pyrazoline derivative 12. Such an elimiꢀ
nation of arenesulfinic acids has been already observed in
Synthesis of 1ꢀacylpyrazolidines 2 (general procedure). A soꢀ
lution of the corresponding benzoyl or arylacetyl chloride 6
(2 mmol) in toluene (20 mL) was slowly added dropwise to a soꢀ
lution of the corresponding 1,5ꢀdiazabicyclo[3.1.0]hexane (1a

Acylpyrazolidines and arylsulfonylpyrazolines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1423
Table 3. Yields and some physicoꢀchemical characteristics of compounds synthesized
Comꢀ
pound
M.p./°Ca
Rf
Found (%)
Calculated
Molecular
formula
Yieldb
(%)
C
H
N
Cl (S)
—
c
1b
—
—
66.40 11.23 22.39
66.62 11.18 22.20
C7H14N2
98
2a
2d
2f
75—76 [76—77]13
140—141 [139—140]23
103—105 [106]7
—
—
—
0.47e
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
52
59
42
36.4
d
2h
—
58.22 6.10 10.63 13.00
58.10 6.38 10.42 13.19
C13H17ClN2O2
2l
2m
2n
105—106 [104—105]13
102—103 [102—103]13
119—120 (with decomp.)
[119—125]13 (with decomp.)
127—128
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
41
45
37
7а
7b
0.34f
0.36f
66.50 5.21
66.27 5.27
55.30 4.01
55.22 3.90
—
—
67.22 5.87
67.05 5.92
55.31 3.54 14.99
55.14 3.81 15.13
8.00 11.21
8.14 11.03
6.63 17.09
6.78 17.16
—
—
C19H18F2N2O2
53
111—112
C19H16Cl2F2N2O2
91
(72)
65
90
84
7с
7d
7e
79—80 [78—79]24
95—96 [92—93]4
112—114
—
—
0.41f
—
—
—
—
—
—
—
—
—
—
—
8.02
8.23
C19H20N2O4
(72)
64
7f
236—238
0.41f
C17H14N4O6
7g
7h
145—146 [146—147]25
155—157
—
0.67e
—
—
—
—
84
97
(74)
72
59.68 5.32
59.36 5.63
—
63.01 4.90
62.85 4.52
5.96 15.56
6.02 15.24
—
7.14 17.32
6.98 17.67
C23H26Cl2N2O4
7i
7k
202—204 [205—206]26
144—147
—
0.40f
—
—
—
C21H18Cl2N2O2
75
9
93—94
0.52e
0.73e
0.62e
0.65e
0.50e
63.76 6.52 10.79 13.18
63.51 6.47 10.58 13.39
58.69 5.23 10.27 13.10
58.54 5.67 10.50 13.29
53.30 5.71 12.76 (14.08)
53.55 5.39 12.49 (14.30)
47.80 4.09 12.59 (14.43)
47.36 3.97 12.27 (14.05)
C14H17ClN2O
C13H15ClN2O2
C10H12N2O2S
C9H9FN2O2S
C9H9BrN2O2S
8.5
8.5
10
56—58
12a
12b
12c
163—164
75—77
36.7
(16)
78
(54)
21.5
(13)
160—162
37.18 3.43
37.38 3.14
9.23 (11.53)
9.69 (11.09)
a The data from the present work. Literature data are given in square brackets.
b The yield of the product obtained by the oneꢀpot reaction is given in brackets.
c Boiling point is 70—71 °C (13 Torr), nD20 = 1.4600.
d Crystallizing oil.
e An ethyl acetate—hexane (1 : 1) solvent mixture was an eluent, visualization was performed under the UV light.
f Ethyl acetate was an eluent.
or 1b) (4 mmol) in anhydrous toluene (30 mL) under argon at
Compound 1а gave rise to 1ꢀ(4ꢀfluorophenylacetyl)pyrꢀ
azolidine (2a), 1ꢀ(4ꢀnitrobenzoyl)pyrazolidine (2f), 1ꢀ[2ꢀ(4ꢀchloroꢀ
phenoxy)ꢀ2ꢀmethylpropionyl]pyrazolidine (2h), 1ꢀ[2ꢀ(4ꢀchloroꢀ
phenoxy)ꢀ2ꢀmethylpropionyl]pyrazoline (10), 1ꢀ(4ꢀchloroꢀ
phenylacetyl)pyrazolidine (2l), and 1ꢀ(4ꢀbromophenylacetyl)ꢀ
pyrazolidine (2m).
Compound 1b gave rise to 1ꢀ(4ꢀchlorobenzoyl)pyrazolidꢀ
ine (2d), 1ꢀ(4ꢀchlorobenzoyl)ꢀ2ꢀ(2ꢀmethylpropenꢀ1ꢀyl)pyrazolꢀ
idine (9), 1ꢀ(2,4ꢀdinitrophenylacetyl)pyrazolidine (2n).
—
–15 –10 °С with constant and vigorous stirring. The reaction
mixture was kept at room temperature and vigorous stirring for
3 h, followed by addition of 20% aqueous NaHCO3 (30 mL).
The organic layer was separated, dried with MgSO4, the solvent
was evaporated in vacuo of a waterꢀjet pump. An oil obtained was
purified by column chromatography on SiO2 using hexane—ethyl
acetate (1 : 1 → 0 : 1) mixture as an eluent. The solvent was
evaporated in vacuo of a waterꢀjet pump.

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Petukhova et al.
Table 4. The IR spectral data
Comꢀ
pound
IR, ν/cm–1
1b
2h
—
668, 736, 796, 832, 892, 940, 972, 1008, 1092, 1124, 1156, 1240,1284, 1364, 1380,1488, 1596, 1628, 1640, 1720, 1736,
2890, 3250
7a
7b
7e
—
—
768, 844, 1008, 1052, 1088, 1112, 1172, 1256, 1308, 1360, 1420, 1440, 1460, 1512, 1548, 1576, 1608, 1640, 1668, 2360,
2840, 2892, 2936, 2972
7f
716, 732, 708, 720, 840, 860,912, 964, 1012, 1112, 1144, 1240, 1292, 1316, 1344, 1396, 1420, 1492, 1524, 1604, 1648,
1650
7h
492, 508, 526, 572, 594, 664, 704, 740, 832, 848, 896, 936, 964, 1008, 1088, 1108, 1164, 1236, 1280, 1304, 1360, 1388,
1440, 1468, 1492, 1524, 1580, 1592, 1656, 1688
7k
9
—
628, 696, 752, 836, 848, 892, 932, 972, 1012, 1088, 1116, 1132, 1184, 1216, 1256, 1280, 1308, 1328, 1420, 1452, 1472,
1488, 1508, 1564, 1608, 1680, 1704, 2324, 2896, 2980, 3060, 3240
10
668, 704, 760, 796, 832, 872, 932, 944, 972, 1008, 1020, 1088, 1104, 1124, 1156, 1204, 1240, 1280, 1332, 1368, 1384,
1404, 1432, 1448, 1472, 1492, 1544, 1600, 1628, 1884, 2992, 3064
12a
664, 708, 732, 800, 824, 840, 856, 928, 980, 1008, 1016, 1100, 1120, 1164, 1184, 1224, 1256, 1292, 1352, 1400, 1436,
1468, 1492, 1520, 1560, 1596, 1644, 1944, 2924, 3000, 3080
12b
12c
664, 712, 829, 840, 928, 980, 1012, 1088, 1144, 1176, 1236, 1292, 1336, 1356, 1360, 1408, 1496, 1592, 2964
704, 748, 820, 828, 840, 928, 980, 1008, 1068, 1080, 1096, 1168, 1176, 1232, 1256, 1280, 1292, 1336, 1356, 1392, 1436,
1468, 1572, 1596, 3000, 3084
Table 5. The 1Н and 13C NMR spectral data (CDCl3) for the compounds synthesized*
Comꢀ
pound
δ, J/Hz
1Н NMR
13С NMR
1b
0.68 (d, 6 H, Me, 3J = 6.3); 1.09 (m, 1 H, CHMe, 3J = 7.5);
1.49 (m, 1 H, Hax(3)); 1.55 (m, 1 H, Heq(3), 2J = –11.8);
1.70 (d, 1 H, CHCring, 3J = 7.5); 2.68 (m, 2 H, Hax(2), Hax(4),
18.01 (Me); 22.24 (CCH2C); 30.65 (CMe2);
51.58 (NCH2); 62.84 (Cring
)
2J = –12.0, 3J H
(3) = 8.7, 3JH
(3) = 11.3);
ax(2)(4),Heq
3.04 (m, 2 H, Heq(2), Heq(4), 3JH
ax(2)(4),Hax
(3) = 8.7)
eq(2)(4).Hax
2h
10.38 (s, 6 H, Mе); 1.65 (br.m, 2 H, CCH2C); 2.67 (br.m, 2 H,
HNCH2); 3.28 (br.m, 2 H, CONCH2); 4.63 (br.s, 1 H, NH);
6.56, 6.99 (both d, Ar, 3J = 8)
24.00 (Me); 31.25 (CCH2C); 45.19, 47.85
(NCH2); 80.22 (CMe); 118.40, 128.61 (C(2),
C(3), C(5), CAr(6)); 148.51 (CCl); 153.92
(CAr(1)); 170.82 (CO)
7a
7b
1.87 (q, 2 H, CCH2C, 2J = 18.0, 3J = 9.0); 2.67 (m, 2 H, NCH2);
3.63 (m, 4 H, CH2CO); 4.15 (m, 2 H, NCH2); 6.99—7.25 (m, 8 H, Ar)
2.12 (m, 2 H, CCH2C, 2J = 18.0, 3J = 9.0); 3.13 (m, 2 H, NCH2);
4.05 (m, 4 H, CH2CO); 4.38 (m, 2 H, NCH2); 7.02 (t, 2 H, Ar);
7.22 (d, 8 H, Ar)
—
—
7e
7f
2.09 (m, 2 H, CCH2C, 3J = 9.9); 3.48 (m, 2 H, NCH2); 3.77 (s, 6 H,
MeO); 3.99 (m, 2 H, NCH2); 6.82, 7.57 (both d, 8 H, Ar, 3J = 8.3)
24.99 (CCH2C); 47.34 (NCH2); 55.32 (OMe);
113.63 (CHAr); 126.06 (C(1)); 130.10
(CHAr); 161.98 (C(4)); 171.50 (CO)
2.209 (m, 2 H, CCH2C, 3J = 7.15); 3.79 (br.m, 4 H, NCH2); 7.80,
8.23 (both d, 8 H, Ar, 3J = 8.3)
24.29 (CH2); 39.92 (NCH2); 123.38, 129.06
(CHAr); 140.00 (CCO); 148.68 (CNO2);
169.00 (CO)
7h
1.61 (s, 12 H, Me); 1.92 (m, 2 H, CCH2C); 3.32 (m, 2 H, NCH2);
4.35 (m, 2 H, NCH2); 7.15, 7.49 (both d, 8 H, Ar, 3J = 8.1)
24.85 (CH3C); 25.14 (CH3C); 25.96 (CCH2C);
46.05 (NCH2); 80.47 (CMe2); 120.04 (CHAr);
127.05 (CiAr); 128.99 (CHAr); 153.40 (CCl);
170.0 (CO)
(to be continued)

Acylpyrazolidines and arylsulfonylpyrazolines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1425
Table 5 (continued)
Comꢀ
δ, J/Hz
pound
1Н NMR
13С NMR
7k
9
1.95 (m, 2 H, CCH2C); 3.45 (m, 2 H, NCH2); 4.25 (m, 2 H, NCH2);
—
6.93 (d, 2 H, CHCO, 2J = 14.0); 8.23 (d, 2 H, ArCH, 2J = 14.0);
7.23 (t, 2 H, Ar); 7.28 (t, 2 H, Ar); 7.39 (d, 2 H, Ar); 7.55 (d, 2 H, Ar)
1.44 (s, 3 H, Me); 1.48 (s, 3 H, Me); 2.01 (m, 2 H, CCH2C, 3J = 6.9,
16.73 (Me); 21.64 (Me); 23.70 (CCH2C); 43.28
3J = 7.3); 2.96 (m, 2 H, CH2NC=, 3J = 6.9); 3.73 (m, 2 H, CH2NCO, (CH2NCO); 56.24 (CH2C=N); 124.34
3J = 7.3); 5.57 (s, 1 H, CH=); 7.22, 7.64 (both d, 4 H, Ar, 3J = 8.3)
(CH2=CMe2); 127.36, 130.09 (CHAr);
133.25 (CH=C); 135.77 (CiAr); 154.00 (CCl);
168.30 (C=O)
10
1.68 (s, 6 H, Me); 2.53 (m, 2 H, CCH2C, 3J = 9.8); 3.57 (m, 2 H,
CH2N, 3J = 10.0); 6.76, 8.18 (both d, 4 H, Ar, 3J = 8.9); 7.98
(s, 1 H, CH=N)
25.02 (Me); 31.62 (CCH2C); 43.12 (NCH2);
80.58 (CMe2); 119.07 (CHAr); 126.05 (CAr(4));
128.92 (CHAr); 148.77 (C=N); 154.0 (CCl);
170.98 (C=O)
12a
12b
2.4 (s, 3 H, Me); 2.75 (t, 2 H, CCH2C, 3J = 8.8); 3.5 (t, 2 H, CH2N,
3J = 8.1); 7.0 (br.s, 1 H, CH=N); 7.35, 7.75 (both d, 4 H, Ar,
3J = 9.0)
2.77 (t, 2 H, CCH2C, 3J = 9.2, 3J = 9.8); 3.50 (t, 2 H, CH2N,
3J = 9.8); 7.02 (br.s, 1 H, CH=N); 7.22 (dd, 2 H, CAr(3), CAr(5),
3JР,H = 8.5, 3JH,F = 4.3); 7.90 (dd, 2 H, CAr(2), CAr(6), 3JH,H = 5.3,
3JH,F = 3.2)
21.5 (Me); 34.13 (CCH2C); 45.49 (CH2N);
128.77, 129.53 (CHAr); 131.06, 144.45
(CAr(4)); 150.21 (C=N)
34.24 (CCH2C); 46.60 (CH2N); 116.09, 116.54
(d, CAr(2), CAr(6), 3JC,F = 11.03); 130.65,
131.60 (dd, CAr(3), CAr(5), 2JC,F = 20.7); 150.32
(C=N); 163.22, 168.32 (d, CAr(4), JC,F = 96.6)
12s
2.77 (t, 2 H, CCH2C, 3J = 9.2, 3J = 9.9); 3.50 (t, 2 H, CH2N,
3J = 9.9); 7.02 (s, 1 H, CH=N); 7.71 (both d, 4 H, Ar, 3J = 7.9)
34.33 (CCH2C); 46.58 (CH2N); 128.82 (CAr(4));
130.33, 132.02 (CHAr); 133.35 (CAr(1));
150.46 (C=N)
* The 1Н and 13С NMR spectra of compound 7f were recorded in DMSOꢀd6.
Synthesis of 1,2ꢀbisacylpyrazolidines 7 and 1ꢀarylsulfоnylpyrꢀ
azolines 12 (general procedure). Dichloromethane (20 mL) and
the corresponding 1,5ꢀdiazabicyclo[3.1.0]hexane (1а or 1b)
(2 mmol) were added to a solution of NaOH (4 mmol) in water
(30 mL) at 0 °С (ice bath) with vigorous stirring, followed by
a dropwise adition over 5 min of a solution of the corresponding
acyl chloride 6 or arenesulfоnyl chloride 11 (4 mmol) in СН2Cl2
(10 mL). The reaction mixture was vigorously stirred for 1 h,
while the temperature rised to ambient. The organic layer was
separated, the aqueous layer was extracted with CH2Cl2 (2×20 mL).
A combined organic phase was dried with MgSO4, the solvent
was evaporated in vacuo of a waterꢀjet pump. The residue
obtained was dissolved in acetone (5—10 mL) and reprecipitatꢀ
ed with 10% aq. NaHCO3 (1ꢀarylsulfоnylpyrazolines were
reprecipitated with water), filtered off, washed with water,
and dried in air.
Compound 1а gave rise to 1,2ꢀbis(4ꢀfluorophenylacetyl)ꢀ
pyrazolidine (7а), 1,2ꢀbis[(2ꢀchloroꢀ6ꢀfluorophenyl)acetyl]ꢀ
pyrazolidine (7b), 1,2ꢀbis(phenylacetyl)pyrazolidine (7с), 1,2ꢀbisꢀ
(4ꢀmethoxybenzoyl)pyrazolidine (7е), 1,2ꢀbis(4ꢀnitrobenzoyl)ꢀ
pyrazolidine (7f), 1,2ꢀbis[2ꢀ(4ꢀchlorophenoxy)ꢀ2ꢀmethylpropioꢀ
nyl]pyrazolidine (7h), 2,3ꢀdihydroꢀ1Hꢀpyrazolo[1,2ꢀb]phthalꢀ
azineꢀ5,10ꢀdione (7i), 1,2ꢀbis[(2E)ꢀ3ꢀ(2ꢀchlorophenyl)propenꢀ
2ꢀyl]pyrazolidine (7k), 1ꢀ[(4ꢀmethylphenyl)sulfоnyl]pyrazoline
(12а), 1ꢀ[(4ꢀfluorophenyl)sulfоnyl]pyrazoline (12b), and 1ꢀ[(4ꢀ
bromophenyl)sulfоnyl]pyrazoline (12с).
Oneꢀpot synthesis of 1,2ꢀbisacylpyrazolidines 7 and 1ꢀarylꢀ
sulfоnylpyrazolines 12. Acetone (0.1 mol, 5.8 г, 7.3 mL) was
added to 1,3ꢀdiaminopropane (0.1 mol, 7.4 g, 8.4 mL) in water
(50 mL). The reaction mixture was stirred for 10 min, cooled to
—
0
–5 °С, followed by a dropwise addition of freshly prepared
aq. sodium hypochlorite (40 mL) containing active chlorine
(0.1 mol) and having residual alkalinity of 10—15%. The reacꢀ
tion mixture was kept for 1 h at 0—5 °С and 12 h at room temperꢀ
ature. The yield of 6,6ꢀdimethylꢀ1,5ꢀdiazabicyclo[3.1.0]hexane
1а (96—100%) was determined by iodometris titration with adꢀ
dition of Cu2+ salts. An aliquot of the solution containing 2 mmol
of 1а was taken. The рН of the aliquot taken was raised to 14
by addition of aq. NaOH. An equal volume of СН2Cl2 was
added and a solution of the corresponding acyl or sulfоnyl
chloride (4 mmol) in CH2Cl2 (10 mL) was added dropwise
over 5 min with vigorous stirring at 0 °С (ice bath). The reacꢀ
tion mixture was vigorously stirred for 1 h, while the temperaꢀ
ture rised to ambient. The organic layer was separated, the
aqueous was extracted with CH2Cl2 (2×20 mL). A combined
extract was dried with MgSO4, the solvent was evaporated
in vacuo of a waterꢀjet pump. The residue obtained was dissolved
in acetone (5—10 mL) and reprecipitated with 10% aq. NaHCO3
(1ꢀarylsulfоnylpyrazolines were reprecipitated with water),
filtered off, washed with water, and dried in air to obtain
1,2ꢀbis[(2ꢀchloroꢀ6ꢀfluorophenyl)acetyl]pyrazolidine (7b),
1,2ꢀbis(4ꢀmethoxybenzoyl)pyrazolidine (7е), 1,2ꢀbis[2ꢀmethꢀ
ylꢀ2ꢀ(4ꢀchlorophenoxy)propionyl]pyrazolidine (7h), 1ꢀ[(4ꢀmethꢀ
ylphenyl)sulfоnyl]pyrazoline (12а), 1ꢀ[(4ꢀfluorophenyl)sulfꢀ
Compound 1b gave rise to 1,2ꢀbis(4ꢀchlorobenzoyl)pyrꢀ
azolidine (7d) and 1,2ꢀbisbenzoylpyrazolidine (7g).

1426
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Petukhova et al.
оnyl]pyrazoline (12b), 1ꢀ[(4ꢀbromophenyl)sulfоnyl]pyrazolꢀ
ine (12с).
The yields, physicoꢀchemical and spectral characteristics of
compounds obtained are given in Tables 3—5.
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Received July 2, 2009;
in revised form February 16, 2010