Synthesis of spirocyclic 4,5,5a,6,7,8-hexahydro-1H-pyrazolo[3,4-e] indolizine derivatives

Article abstract of DOI:10.1070/MC2005v015n03ABEH002073

The condensation of 3-methyl-1-phenyl-5-pyrrolidinopyrazole-4- carboxaldehyde with N,N-dimethylbarbituric acid or Meldrum's acid followed by cyclization of the Kn?venagel product by in a 'tert-amino effect' reaction resulted in the heterocyclic spiroderiv

Full text of DOI:10.1070/MC2005v015n03ABEH002073

,
2005, 15(3), 119–120
Synthesis of spirocyclic 4,5,5a,6,7,8-hexahydro-1H-pyrazolo[3,4-e]indolizine
derivatives
Oleg S. Eltsov, Elisaveta V. D’yachenko, Tatiana V. Glukhareva and Yury Yu. Morzherin*
Department of Technology of Organic Synthesis, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.
Fax: +7 3432 74 5483; e-mail: morjerine@htf.ustu.ru
DOI: 10.1070/MC2005v015n03ABEH002073
The condensation of 3-methyl-1-phenyl-5-pyrrolidinopyrazole-4-carboxaldehyde with N,N-dimethylbarbituric acid or Meldrum’s
acid followed by cyclization of the Knövenagel product by in a ‘tert-amino effect’ reaction resulted in the heterocyclic spiro-
derivatives of pyrazolo[3,4-e]indolizine.
Due primarily to their biological activities,1–3 fused pyrazoles are
of current interest. These ring systems are usually synthesised by
labile compound and is easily deformylated: on heating in
solvents such as DMF, toluene, or ethanol pyrazole 4¶ was
formed. The structures of compounds were confirmed by N
4
multi-step pathways. The tert-amino effect provides a powerful
approach to ring systems containing a spiro moiety.5 Here, we
report an application of the tert-amino effect to the preparation
of spirocyclic ring systems containing the 4,5,5a,6,7,8-hexa-
hydro-1H-pyrazolo[3,4-e]indolizine nucleus.
,6
microanalysis, mass spectrometry, IR and H NMR spectroscopy.
1
Thus, the tert-amino effect may offer a powerful approach to
the synthesis of complex ring systems including spirocyclic
derivatives, and we present the first examples of the application
of pyrazolecarboxaldehyde to the synthesis of spiro derivatives
of fused pyrazoles.
Spirocyclic derivatives 3a,b were obtained in two steps starting
†
from pyrazolecarboxaldehyde 1. The reaction of aldehyde 1
with Meldrum’s acid or 1,3-dimethylbarbituric acid in the presence
of piperidine as a catalyst afforded Knövenagel products 2a,b,
which underwent rearrangement upon heating to afford spiro
References
1
R. R. Ranatunge, D. S. Garvey, D. R. Janero, L. G. Letts, A. M. Martino,
M. G. Murty, S. K. Richardson, D. V. Young and I. S. Zemetseva,
Bioorg. Med. Chem., 2004, 12, 1357.
‡
derivatives of indolizine 3a,b (Scheme 1). In contrast to the
reaction of ortho-(N,N-dialkylamino)benzaldehydes with cyclic
7
,8
active methylene compounds, vinyl derivatives 2a,b were
2 J. A. Townes, A. Golebiowski, M. P. Clark, M. J. Laufersweiler, T. A. Brugel,
M. Sabat, R. G. Bookland, S. K. Laughlin, J. C. VanRens, B. De, L. C. Hsieh,
S. C. Xu, M. J. Janusz and R. L. Walter, Bioorg. Med. Chem. Lett., 2004,
§
isolated in good yields. Note that aldehyde 1 is a thermally
Y
X
1
4, 4945.
X
O
3 J.-M. Mussinu, S. Ruiu, A. C. Mulè, A. Pau, M. A. M. Carai, G. Loriga,
G. Murineddu and G. A. Pinna, Bioorg. Med. Chem., 2003, 11, 251.
O
Me
‡
Me
O
H
A solution of vinyl derivative 2a or 2b (0.72 mmol) in BuOH (10 ml)
was heated at 100 °C for 3 h and then filtered through charcoal. The
solvent was evaporated and the residue was recrystallised from ethyl
acetate; compound 3 was filtered off and dried.
i
N
N
N
N
N
Y
X
N
2',2',3-Trimethyl-1-phenyl-4,5,5a,6,7,8-hexahydro-1H-spiro(pyrazolo-
X
O
O
[
3,4-e]indolizine-5,5'-[1,3]dioxane)-4',6'-dione 3a. Yield 86%, mp 188 °C.
1
2
H NMR ([ H ]DMSO) d: 7.50–7.47 (m, 2H, HAr), 7.44–7.40 (m, 2H,
6
HAr), 7.28–7.24 (m, 1H, HAr), 4.03–4.00 (m, 1H, CH), 3.21–3.14 (m,
H, CH), 3.04–3.01 (m, 1H, CH), 2.78–2.74 (dd, 1H, CH, J' 8.01 Hz,
1
1
2a,b
J'' 2.56 Hz), 2.50–2.49 (m, 1H, CH), 2.12 (s, 3H, Me), 1.84–1.75 (m,
2
ii
10H, 2Me, 2CH2). 13C NMR ([ H ]DMSO) d: 170.15 (dd, CO, J 3.8
6
and 0.8 Hz), 166.00 (ddd, CO, J 7.6, 7.4 and 3.8 Hz), 145.56 [qdd, C(3),
i
X
Y
O
J 7.2, 2.3 and 2.9 Hz], 143.50 [br. s, C(9a)], 139.71 (tm, C , J 8.6 Hz),
i
X
1
28.89 (dd, C , J 162.3 and 7.2 Hz), 126.22 (dt, C , J 163.9 and 7.2 Hz),
Me
Me
o
p
1
23.12 (ddd, C , J 163.3, 7.2 and 7.2 Hz), 105.22 (qq, O–C–O, J 4.6 and
m
O
4.6 Hz), 96.30 [m, C(3a)], 67.91 [dm, C(5a), J 158.4 Hz], 49.72 [ddm,
C(8), J 140.7 and 144.4 Hz], 46.38 [ddd, C(5), J 2.0, 5.3 and 4.4 Hz],
29.54 (qq, Me, J 128.4 and 2.8 Hz), 27.81 [dd, C(4), J 131.2 and 131.8 Hz],
N
N
N
N
N
N
2
7.27 (qq, Me, J 126.9 and 3.1 Hz), 27.03 [ddm, C(7), J 134.5 and
1
33.6 Hz], 22.95 [ddm, C(6), J 134.7 and 128.4 Hz], 12.09 (q, Me,
J 127.0 Hz). MS, m/z: 381 (M , 100%). Found (%): C, 65.98; H, 6.17;
+
N, 10.96. Calc. for C H N O (%): C, 66.13; H, 6.08; N, 11.02.
21
23
3
4
4
3a,b
1',3',3-Trimethyl-1-phenyl-4,5,5a,6,7,8-hexahydro-1H-spiro(pyrazolo-
a X = O, Y = CMe2
b X = NMe, Y = CO
[
3,4-e]indolizine-5,5'-pyrimidine)-2',4',6'-trione 3b. Yield 78%, mp 224 °C.
1
2
H NMR ([ H ]DMSO) d: 7.49 (d, 2H, H , J 7.35 Hz), 7.43–7.39 (dd,
6
Ar
2
H, H , J' 7.51 Hz, J'' 8.26 Hz), 7.24 (m, 1H, HAr), 3.97–3.94 (dd, 1H,
Scheme 1 Reagents and conditions: i, DMF, 25 °C, 24 h; ii, BuOH,
Ar
100 °C, 3 h.
CH, J' 4.82 Hz, J'' 3.20 Hz), 3.24 (s, 3H, NMe), 3.20–3.10 (dd, 1H,
CH, J' 8.62 Hz, J'' 6.22 Hz), 3.09 (s, 3H, NMe), 3.02–2.93 (dd, 2H, CH2,
J' 15.79 Hz, J'' 4.6 Hz), 2.75–2.74 (m, 1H, CH), 2.20–2.11 (m, 1H, CH ),
2.08 (s, 3H, Me), 1.82–1.58 (m, 3H, CH , CH). C NMR ([ H ]DMSO)
d: 171.28 (br. s, CO), 168.66 (br. s, CO), 151.00 (hept, CO, J 2.6 Hz),
145.25 [qm, C(3), J 7.3 Hz], 143.66 [br. s, C(9a)], 139.85 (tm, Ci,
J 7.2 Hz), 128.85 (dd, C , J 162.7 and 7.5 Hz), 125.97 (dt, C , 163.8 and
†
Pyrrolidine (0.83 ml, 0.70 mg, 9.88 mmol) and potassium carbonate
2
13
2
(
1
(
1.38 g, 9.88 mmol) were added to a solution of 5-chloro-3-methyl-
-phenyl-1H-pyrazole-4-carboxaldehyde (2.49 g, 9.49 mmol) in DMF
8.0 ml). The reaction mixture was refluxed at 150 °C for 20 h. The
2
6
completion of the reaction was judged from TLC. Then the reaction
mixture was cooled to ~20 °C, water (75 ml) was added, and the product
was filtered off and dried.
o
p
7.3 Hz), 122.85 (ddd, C , J 162.1, 7.0 and 7.8 Hz), 97.66 [m, C(3a)],
o
66.87 [dm, C(5a), J 157.0 Hz], 49.82 [ddm, C(8), J 142.2 and 140.2 Hz],
48.12 [br. s, C(5)], 29.03 [dd, C(4), J 132.5 and 135.7 Hz], 28.09 (q,
NMe, J 142.3 Hz), 26.75 [ddm, C(7), J 127.6 and 125.7 Hz], 26.65 (q,
NMe, J 141.7 Hz), 23.27 [ddm, C(6), J 141.5 and 133.0 Hz], 12.08 (q,
Me, J 126.9 Hz). MS, m/z: 393 (M , 100%). Found (%): C, 64.12; H,
6.02; N, 18.15. Calc. for C H N O (%): C, 64.11; H, 5.89; N, 17.80.
3
-Methyl-1-phenyl-5-pyrrolidino-1H-pyrazole-4-carboxaldehyde 1.
1
2
Yield 75%, mp 224 °C. H NMR ([ H ]DMSO) d: 9.86 (s, 1H, CHO),
6
7
1
6
.35–7.47 (m, 5H, HAr), 3.23–3.20 (m, 4H, CH ), 2.29 (s, 3H, Me),
2
+
+
.70–1.75 (m, 4H, 2CH ). MS, m/z: 255 (M ). Found (%): C, 70.66; H,
2
.88; N, 17.15. Calc for C H N O (%): C, 70.56; H, 6.71; N, 16.46.
15
17
3
21 23
5
3
Mendeleev Commun. 2005 119

,
2005, 15(3), 119–120
4
5
W. Verboom and D. N. Reinhoudt, Recl. Trav. Chim. Pays-Bas., 1990,
09, 311.
T. V. Glukhareva, E. V. D’yachenko and Yu. Yu. Morzherin, Khim.
Geterotsikl. Soedin., 2002, 1610 [Chem. Heterocycl. Compd. (Engl.
Transl.), 2002, 38, 1426].
6 O. Elias, L. Karolyhazy, G. Horvath, V. Harmat and P. Matyus, J. Mol.
Struct. (Theochem.), 2003, 666–667, 625.
7 E. V. D’yachenko, T. V. Glukhareva and Yu. Yu. Morzherin, Khim.
Geterotsikl. Soedin., 2003, 1737 [Chem. Heterocycl. Compd. (Engl.
Transl.), 2003, 39, 1532].
1
8
E. V. D’yachenko, T. V. Glukhareva, E. F. Nikolaenko, A. V. Tkachev
and Yu. Yu. Morzherin, Izv. Akad. Nauk, Ser. Khim., 2004, 1191 (Russ.
Chem. Bull., Int. Ed., 2004, 53, 1240).
§
To a solution of aldehyde 1 (1.15 g, 4.53 mmol) in DMF (3 ml)
methylene compounds (4.75 mmol) were added at room temperature.
The reaction mixture was stirred for 24 h. After the addition of 20 ml of
water, the precipitate was filtered off and the product was crystallised
from ethanol.
2
,2-Dimethyl-5-(3-methyl-1-phenyl-5-pyrrolidino-1H-pyrazol-4-yl-
1
methylene)[1,3]dioxane-4,6-dione 2a. Yield 70%, mp 204 °C. H NMR
2
(
(
[ H ]DMSO) d: 8.39 (s, 1H, CH), 7.51–7.39 (m, 5H, HAr), 3.14–3.11
6
dd, 4H, 2CH , J' 7.3 Hz, J'' 8.2 Hz), 2.29 (s, 3H, Me), 2.11 (t, 4H, 2CH ,
J 6.4 Hz), 1.86 (s, 3H, Me), 1.74 (s, 3H, Me). C NMR ([ H ]DMSO)
2
2
1
3
2
6
d: 163.35 (d, CO, J 6.3 Hz), 159.99 (d, CO, J 10.3 Hz), 151.91 [q, C(3),
J 5.1 Hz], 150.50 [q, C(5), J 6.7 Hz], 147.90 (d, CH=, J 153.6 Hz),
1
39.70 (tm, C , J 9.2 Hz), 129.03 (dd, C , J 163.1 and 11.4 Hz), 128.20
i
o
(
dt, C , J 163.1 and 6.1 Hz), 125.98 (ddd, C , J 163.3, 6.1 and 11.4 Hz),
p
m
107.17 (d, C=, J 2.8 Hz), 103.97 (hept, O–C–O, J 4.6 Hz), 103.37 [d,
C(4), J 2.7 Hz], 51.85 (tm, 2NCH , J 139.4 Hz), 26.84 (qq, 2Me, J 128.4
2
and 3.2 Hz), 25.09 (tm, 2CH , J 131.7 Hz), 14.24 (q, Me, J 127.8 Hz).
2
+
MS, m/z: 381 (M , 100%). Found (%): C, 66.25; H, 6.07; N, 11.25. Calc.
for C H N O (%): C, 66.13; H, 6.08; N, 11.02.
21
23
3
4
1
,3-Dimethyl-5-(3-methyl-1-phenyl-5-pyrrolidino-1H-pyrazol-4-yl-
1
methylene)pyrimidine-2,4,6-trione 2b. Yield 68%, mp 254 °C. H NMR
2
(
[ H ]DMSO) d: 8.29 (s, 1H, CH), 7.51–7.37 (m, 5H, HAr), 3.27 (s, 3H,
6
Received: 20th October 2004; Com. 04/2398
NMe), 3.20 (s, 3H, NMe), 3.09–2.93 (m, 4H, 2CH ), 2.22 (s, 3H, Me),
2
1
1
1
1
1
.82–1.78 (m, 4H, 2CH2). 13C NMR ([ H ]DMSO) d: 162.60 (CO),
2
¶
3-Methyl-1-phenyl-5-pyrrolidino-1H-pyrazole 4: oil. 1H NMR
6
6
2
59.42 (CO), 152.34 (CO), 151.47 [C(3)], 150.66 [C(5)], 146.28 (CH=),
39.99 (C ), 129.04 (C ), 127.97 (C ), 125.71 (C ), 108.61 [C(4)],
07.02 (C=), 52.02 (NCH ), 28.10 (NMe), 27.74 (NMe), 25.15 (CH ),
([ H ]DMSO) d: 7.53–7.51 (m, 2H, HAr), 7.46–4.42 (m, 2H, HAr),
7.30–7.27 (m, 1H, HAr), 5.58 (s, 1H, Hpyr), 2.98–2.87 (m, 4H, 2CH ),
i
o
p
o
2
+
2.11 (s, 1H, Me), 1.75–1.85 (m, 4H, 2CH ). MS, m/z: 227 (M , 100%).
2
2
2
+
3.26 (Me). MS, m/z: 393 (M , 100%). Found (%): C, 64.25; H, 5.78;
Found (%): C, 74.21; H, 7.88; N, 18.20. Calc. for C H N (%): C,
1
4
17
3
N, 18.02. Calc. for C H N O (%): C, 64.11; H, 5.89; N, 17.80.
73.98; H, 7.54; N, 18.49.
21
23
5
3
1
20 Mendeleev Commun. 2005