The first example of the cascade assembly of a spirocyclopropane structure: direct transformation of benzylidenemalononitriles and N,N′-dialkylbarbituric acids into substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles

Article abstract of DOI:10.1016/j.tetlet.2009.11.065

The direct formation of substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles in 75-95% yields from benzylidenemalononitriles and N,N′-dialkylbarbituric acids is described.

Full text of DOI:10.1016/j.tetlet.2009.11.065

Tetrahedron Letters 51 (2010) 428–431
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first example of the cascade assembly of a spirocyclopropane
structure: direct transformation of benzylidenemalononitriles and
N,N0-dialkylbarbituric acids into substituted 2-aryl-4,6,8-trioxo-5,7-
diazaspiro[2.5]octane-1,1-dicarbonitriles
a
a
b
Michail N. Elinson a, , Anatolii N. Vereshchagin , Nikita O. Stepanov , Tatiana A. Zaimovskaya ,
*
Valentina M. Merkulova a, Gennady I. Nikishin a
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia
b A. V. Topchiev Institute of Petrochemical Synthesis, Leninsky Prospect 29, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2009
Revised 3 November 2009
Accepted 13 November 2009
Available online 1 December 2009
The direct formation of substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles in
75–95% yields from benzylidenemalononitriles and N,N0-dialkylbarbituric acids is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Key words:
Benzylidenemalononitriles
Barbituric acids
Cyclopropane formation
5,7-Diazaspiro[2.5]octane
The discovery of new synthetic methodologies to facilitate the
preparation of organic compounds is a pivotal focal point of re-
search activity in the field of modern organic, bioorganic and
medicinal chemistry.1 The cyclopropyl group is a vital structural
unit in many synthetic and naturally occurring compounds, exhib-
iting a wide spectrum of biological properties ranging from en-
zyme inhibition to herbicidal, antibiotic, antitumor and antiviral
activities.2–4 Thus, the prevalence of cyclopropane-containing
compounds possessing biological activity, whether isolated from
natural sources or rationally designed pharmaceutical agents, has
inspired chemists to find novel and diverse approaches to their
synthesis.
On the other hand, barbiturates (derivatives of barbituric acid)
are a class of drugs that act as central nervous system depressants,
and by virtue of this, they produce a wide spectrum of effects, from
mild sedation to anaesthesia and are also effective as anxiolytics
and as anticonvulsants. They have additional pharmacological po-
tential as analeptics, immunomodulating and anti-AIDS agents,
and also as anticancer remedies.5 Spirobarbiturates are a class of
compounds with interesting pharmacological and physiological
activity.6
Thus, the 5,7-diazaspiro[2.5]octane system appears to be of the
interest because it incorporates spiro-connected cyclopropane and
hexahydropyrimidine-2,4,6-trione heterocyclic ring which in com-
bination may be promising with respect to biological responses.
Although methods for cyclopropane synthesis are numerous,
they can be classified into two main groups: (1) intramolecular
cyclization, and (2) interaction of two different molecules (addition
of carbenes to olefins or Michael initiated ring closure (MIRC) are
the best known examples of this type).2,4 MIRC plays an important
role in organic chemistry and many synthetic examples are de-
scribed in the literature.7
The well-known MIRC to substituted cyclopropanes involves
the addition of halogeno-substituted CH-acid anions (A), generated
by the action of a base on the corresponding CH-acid (AH), to con-
jugated activated olefins followed by cyclization with elimination
of the halide anion8 (Scheme 1).
R1
2
R
R1
R2
_
X
Y
X
Y
X
Y
CHalXY
+
C
C
_
-
Hal
A
X = COOR
Y = COOR, CN, C(O)NR2
Hal = Br, I
* Corresponding author. Tel.: +7 499 137 38 42; fax: +7 499 135 53 28.
E-mail address: elinson@ioc.ac.ru (M.N. Elinson).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.065

M. N. Elinson et al. / Tetrahedron Letters 51 (2010) 428–431
429
Table 1
R1
2
R
Influence of EtONa amount on the yield of 3aa,11
1
CN
CN
XHal
R
R
CN
CN
NC
NC
CN
CN
+
C
C
2
_
3
Entry
EtONa (equiv)
Yield of 3ab (%)
B
R OH,
1
2
3
4
5
0.5
1.0
1.2
1.5
2.0
59
71
95
83
67
Hal = I, Br
X=I, Br,
O
N
a
O
10 mmol of 1a, 10 mmol of 2a, 20 ml of EtOH, 0.5–2.0 mmol of EtONa, 10 mmol
of bromine, 3 h.
b
Scheme 2.
Isolated yield.
Cascade reactions have been utilized as powerful methods to
construct molecular complexity from readily available starting
materials by combining two or more reactions into a single trans-
formation.9 As such, cascade reactions are of increasing importance
in modern organic chemistry. This is not only due to the need for
more efficient and less labour-intense methodologies for the syn-
thesis of organic compounds, but also the consequence of the
increasing importance of environmental considerations in
chemistry.
Recently, we reported a new strategy to cyclopropanes: the di-
rect cascade transformation of benzylidenemalononitriles and
malononitrile into 1,1,2,2-tetracyanocyclopropanes (Scheme 2).10
In this reaction halogenation of the CH-acid was followed by a Mi-
chael addition step, thus an abbreviation for this type of cyclopro-
pane formation reaction should be MHIRC—Michael Halogenation
Initiated Ring Closure reaction.
In the present study, we report our results on the direct ‘one-
pot’ cascade transformation of benzylidenemalononitriles and
N,N0-dialkylbarbituric acids into 2-aryl-5,7-dimethyl-4,6,8-trioxo-
5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles (Scheme 3, Tables 1
and 2), which is to our knowledge, the first example of the cascade
assembly of the spirocyclopropane structure.
First, to evaluate the synthetic potential of the proposed proce-
dure and to optimize the conditions, the transformation of benzy-
lidenemalononitrile 1a and N,N0-dimethylbarbituric acid 2a into
5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitrile 3a was studied (Table 1).
Table 2
Direct transformation of substituted benzylidenemalononitriles 1a–i and N,N0-
dialkylbarbituric acids 2a,b into substituted 2-aryl-4,6,8-trioxo-5,7-diaza-spir-
o[2.5]octane-1,1-dicarbonitriles 3a–ka,11
R1
Benzylidene-
malononitrile
R2
Barbituricacid
Product,
yieldb (%)
H
1a
1b
1c
1d
1e
1f
1g
1h
1a
1b
1i
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
3a, 95
3b, 93
3c, 81
3d, 80
3e, 85
3f, 83
3g, 87
3h, 95
3i, 75
3j, 77
3k, 81
4-Me
2-MeO
4-t-Bu
2-Cl
3-Cl
3-Br
4-NO2
H
4-Me
4-Cl
Et
Et
a
10 mmol of benzylidenemalononitrile, 10 mmol of barbituric acid, 20 ml of
EtOH, 12 mmol of EtONa, 10 mmol of bromine, 3 h.
b
Isolated yield.
turic acids 2a,b were transformed into the corresponding substi-
tuted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles
3a–k in 75–95% yields (Table 2).
Taking into consideration the data obtained and our previous
results on the transformation of benzylidenemalononitriles and
malononitrile into substituted tetracyanocyclopropanes,10 the fol-
lowing mechanism is proposed (Scheme 4).
Excellent conversions of the starting compounds and a 95%
yield of 5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3a were ob-
tained when the reaction was carried out in ethanol in the pres-
ence of 1.2 equivalents of EtONa and bromine (Table 1, entry 3).
Increasing quantity of EtONa led to a decrease of the reaction yield,
which may result from undesired base-induced oligomerization of
the starting benzylidenemalononitile.12
Under the optimal conditions, that is, bromine as the active hal-
ogen compound, 1.2 equiv of EtONa as base, and ethanol as solvent,
substituted benzylidenemalononitriles 1a–i and N,N0-dialkylbarbi-
The first step involves Michael addition of N,N0-dimethylbarbi-
turic acids 2a,b to the benzylidenemalononitriles 1a–i in the pres-
ence of the base to give anion B. Next, bromination of anion B leads
to substituted 2-aryl-1-bromo-2-(1,3-dialkyl-2,4,6-trioxohexahy-
dropyrimidin-5-yl)ethane-1,1-dicarbonitrile 4. Cyclization of
4
to substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,
1-dicarbonitrile 3 takes place in accordance with the earlier re-
ported data (Scheme 4).10,13 It should be mentioned that the final
step of the mechanism (Scheme 4) is similar to that for the
R1
O
O
R2
O
R2
O
CN
R2
Br2
NC
NC
R1
N
N
N
+
EtONa/EtOH
CN
N
R2
O
O
1a-i
2a,b
a R2 = Me, b R2 = Et
3a-k
a R1 = H, b R1 = 4-Me, c R1 = 2-MeO,
d R1 = 4-t-Bu, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 3-Br, h R1 = 4-NO2, i R1 = 4-Cl
a R1 = H, R2 = Me; b R1 =4-Me, R2 = Me; c R1 = 2-MeO, R2 = Me;
d R1 = 4 - t-Bu, R2 = Me; e R1 = 2-Cl, R2 = Me; f R1 = 3-Cl, R2 = Me;
g R1 = 3-Br, R2 = Me; h R1 = 4-NO2, R2 = Me; i R1 = H, R2 = Et;
j R1 = 4-Me, R2 = Et; k R1 = 4-Cl, R2 = Et
Scheme 3.

430
M. N. Elinson et al. / Tetrahedron Letters 51 (2010) 428–431
O
R2
O
R2
N
N
O
_
R2
O
R2
O
CN
O
B, -BH
EtOH
R1
N
N
CN
+
_
CN
R1
CN
Br2
1
B
O
R1
R2
O
R2
N
N
O
R2
O
O
-HBr
NC
NC
N
EtOH
CN
Br
R1
N
R2
O
CN
4
Scheme 4.
2. (a) Yanovskaya, L. A.; Dombrovsky, V. A.; Khusid, A. K. Tsiklopropani
s
R1
R1
funktsionalnimi gruppami. Sintez i primenenie. (Cyclopropanes with Functional
Groups. Synthesis and Application), Nauka, Moscow, 1980.; (b) Tsuji, T.; Nishida,
S. The Chemistry of the Cyclopropyl Group; Wiley and Sons: New York, 1987; (c)
Boche, G.; Walbirsky, H. M. Cyclopropane Derived Intermediates; John Wiley and
Sons: New York, 1990; (d) Rappoport, Z. The Chemistry of the Cyclopropyl Group;
Wiley and Sons: New York, 1996.
Br2
EtOH
CN
CN
CN
NC
NC
NC
CN CN
R1 = Me, Et, n-Pr
3. (a) Graham, D. W.; Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning,
L. F.; Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem. 1987, 30, 1074–1090; (b)
Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511–519; (c) Baba, Y.; Saha, G.;
Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem.
2001, 66, 81–88; (d) Boger, D. L.; Hughes, T. V.; Hedrick, M. P. J. Org. Chem. 2001,
66, 2207–2216; (e) Yoshida, S.; Rosen, T. C.; Sloan, M. J.; Meyer, O. G. J.; Ye, S.;
Haufe, G.; Kirk, K. L. Bioorg. Med. Chem. 2004, 12, 2645–2652; (f) Yamaguchi, K.;
Kazuta, Y.; Hirano, K.; Yamada, S.; Matsuda, A.; Shuto, S. Bioorg. Med. Chem.
2008, 16, 8875–8881.
4. For reviews see: (a) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251–2253; (b)
Donaldson, W. A. Tetrahedron 2001, 57, 8589–8627; (c) Reissig, H. U.; Zimmer,
R. Chem. Rev. 2003, 10. pp 1151–1150; (d) Brandt, W.; Thiemann, T. Chem. Rev.
2003, 103, 1625–1647.
Scheme 5.
synthesis of 3-substituted tetracyanocyclopropanes as reported by
Mariella and Roth.13 This method includes bromination of 2-alkyl-
substituted 1,1,3,3-tetracyanopropanes in ethanol followed by
cyclization and formation of 3-alkyl substituted 1,1,2,2-tetracy-
ano-substituted cyclopropanes (Scheme 5).13
5. (a) Brunton, L. L.; Lazo, J. S.; Lazo, P.; Keith, L. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, 2006; (b) Johns,
M. W. Drugs 1975, 9, 448–478; (c) Naguib, F. N. M.; Levesque, D. L.; Wang, E.-C.;
Panzica, P. P.; El Kouni, M. H. Biochem. Pharmacol. 1993, 46, 1273–1278; (d)
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V.; Menta, E.; Oliva, A.; Zimmermann, G. Biol. Chem. 2001, 382, 1277–1285; (e)
Maquoi, E.; Sounni, N. E.; Devy, L.; Oliver, F.; Frankenne, F.; Krell, H.-W.; Grams,
F.; Foidart, J. M.; Noel, A. Clin. Cancer Res. 2004, 10, 4038–4047; (f) Uhlmann, C.;
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H. Int. J. Pharm. 1992, 83, 39–45; (c) Galati, E. M.; Monforte, M. T.; Miceli, N.;
Raneri, E. Farmaco 2001, 56, 459–461; (d) Singh, P.; Paul, K. J. Heterocycl. Chem.
2006, 43, 607–612; (e) Lomlin, L.; Einsiedel, J.; Heinemann, F. W.; Meyer, K.;
Gmeiner, P. J. Org. Chem. 2008, 73, 3608–3611.
7. (a) Little, R. D.; Dawson, J. R. J. Am. Chem. Soc. 1978, 100, 4607–4609; (b) Little,
R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609–2612; For reviews, see: (c)
Verhé, R.; De Kimpe, N. ‘Synthesis and Reactivity of Electrophilic
Cyclopropanes’. In ‘The Chemistry of the Cyclopropyl Group’; Rappoport, Z., Ed.;
Springer: New York, 1987; pp 445–564. Chapter 9; (d) Zwanenburg, B.; De
Kimpe, N.; Methods of Organic Chemistry (Houben-Weyl), Vol. E.17A
(Carbocyclic Three-Membered Ring Compounds), Ed. de Meijere, A.; Thieme
Verlag, Stuttgart, 1997. Chapters 1.1.1 and 1.1.3, pp 29–40 and pp 45–105.; (e)
Caine, D. Tetrahedron 2001, 57, 2643–2684; (f) Lebel, H.; Marcoux, J. F.;
Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 1015–1036.
Thus, a new type of cascade ‘one-pot’ reaction for the direct for-
mation of spirocyclopropanes from benzylidenemalononitriles and
N,N0-dialkylbarbituric acids has been reported. The action of bro-
mine on equimolar amounts of benzylidenemalononitrile and
N,N0-dialkylbarbituric acid in basic ethanol solution results in the
formation
of
substituted
2-aryl-4,6,8-trioxo-5,7-diazaspi-
ro[2.5]octane-1,1-dicarbonitriles in 75–95% yields.
The procedure utilises inexpensive reagents, is easily carried
out and the work up is not complicated. 2-Aryl-4,6,8-trioxo-5,7-
diazaspiro[2.5]octane-1,1-dicarbonitriles crystallized directly from
the reaction mixture, and consequently, the products were isolated
by the filtration and washing with warm water.
The 5,7-diazaspiro[2.5]octane system appears to be of interest
because it incorporates a cyclopropane unit and a hexahydropyr-
imidine-2,4,6-trione heterocyclic ring which are promising with
respect to biological responses.
Acknowledgements
8. Bonavent, G.; Causse, M.; Guittard, M.; Fraisse-Julien, R. Bull. Soc. Chim. Fr. 1964,
2462–2471.
9. For reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Padwa, A.
Pure Appl. Chem. 2003, 75, 47–62; (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P.
G. Angew. Chem. 2006, 45, 7134–7186.
The authors gratefully acknowledge the financial support of the
Russian Foundation for Basic Research (Project No. 09-03-00003).
10. Elinson, M. N.; Feducovich, S. K.; Stepanov, N. O.; Vereshchagin, A. N.; Nikishin,
References and notes
G. I. Tetrahedron 2008, 64, 708–713.
11. General procedure. To a 10 mL ethanol solution of benzylidenemalononitrile 1
(10 mmol) and barbituric acid 2 (10 mmol) in a 50 ml beaker, 0.82 g (12 mmol) of
sodium ethoxide in 10 mL of ethanol was added over 1 min. Then 10 mmol
1. (a) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324–337; (b) Nefzi, A.;
Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449–472.

M. N. Elinson et al. / Tetrahedron Letters 51 (2010) 428–431
431
(0.51 mL) of bromine was added over1 min without external cooling. Themixture
was magnetically stirred at room temperature for 3 h. After which the solid phase
was filtered, washed with warm water and dried in a desiccator over P2O5 to
afford pure 3. 5,7-Dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitrile 3a, mp 259–260 °C; 1H NMR (300 MHz, DMSO-d6): d 7.44–7.50 (m,
2H), 7.32–7.40 (m, 3H), 4.36 (s, 1H), 3.28 (s, 3H), 3.12 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): d 162.93, 160.50, 150.88, 129.20, 128.61, 128.21, 128.16, 112.37,
110.82, 43.88, 41.29, 29.02, 28.55, 23.50; MS (EI, 70 eV): m/z (%) 308 (23) [M+],
281 (16), 251 (45), 194 (88), 166 (100), 139 (66); IR (KBr, cm-1) 2252, 1704, 1456,
1444, 1424, 1392, 1300, 752; Anal. Calcd for C16H12N4O3: C, 62.33; H, 3.92; N,
18.17. Found: C, 62.21; H, 4.05; N, 18.03.2-(2-Methoxyphenyl)-5,7-dimethyl-
4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3c, mp 229–230 °C; 1H
NMR (300 MHz, DMSO-d6): d 7.36–7.42 (m, 2H), 6.96–7.08 (m, 2H), 4.01 (s, 1H),
3.73 (s, 3H), 3.30 (s, 3H), 3.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d 163.12,
160.48, 156.80, 150.70, 130.26, 130.07, 120.28, 116.11, 112.41, 110.98, 110.86,
55.59, 41.01, 40.79, 29.07, 28.54, 23.63; MS (EI, 70 eV): m/z (%) 338 (26) [M+], 307
(70), 273 (34), 243 (16), 224 (56), 181 (100); IR (KBr, cmꢀ1) 2252, 1704, 1684,
1460, 1444, 1424, 1388, 768; Anal. Calcd for C17H14N4O4: C, 60.35; H, 4.17; N,
16.56. Found: C, 60.23; H, 4.31; N, 16.48.2-(3-Bromophenyl)-5,7-dimethyl-4,6,8-
trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3g mp 217–219 °C; 1H NMR
(300 MHz, DMSO-d6): d 7.77–7.79 (m, 1H), 7.50–7.57 (m, 2H), 7.35 (t, 1H,
J = 7.9 Hz), 4.39 (s, 1H), 3.28 (s, 3H), 3.12 (s, 3H); 13C NMR (75 MHz, DMSO-d6): d
162.70, 160.58, 150.89, 132.05, 131.35, 131.09, 130.23, 128.28, 121.17, 112.12,
110.64, 42.44, 41.24, 29.01, 28.56, 23.60; MS (EI, 70 eV): m/z (%) 388 (11) [81Br,
M+], 386 (11) [79Br, M+], 361 (8), 359 (8), 331 (8), 329 (8), 307 (28), 274 (21), 272
(20), 193 (100); IR (KBr, cmꢀ1) 2252, 1708, 1680, 1460, 1424, 1388, 1300, 752;
Anal. Calcd for C16H11BrN4O3: C, 49.63; H, 2.86; Br, 20.64; N, 14.47. Found: C,
49.47; H, 3.01; Br, 20.59; N, 14.29.5,7-Diethyl-4,6,8-trioxo-2-phenyl-5,7-
diazaspiro[2.5]octane-1,1-dicarbonitrile 3i, mp 186–188 °C; 1H NMR (300 MHz,
DMSO-d6): d 7.36–7.46 (m, 3H), 7.22–7.32 (m, 2H), 4.29 (s, 1H), 4.10 (q, J = 7.0 Hz,
2H), 3.95 (dq, J1 = 7.1 Hz, J2 = 1.3 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, DMSO-d6): d 162.49, 160.13, 149.91, 129.09, 128.67,
128.19, 128.07, 112.41, 110.86, 43.84, 41.41, 38.67, 37.55, 23.47, 12.63, 12.53;
MS (EI, 70 eV): m/z (%); 237 (6, M+ꢀO@C–N(Et)–C@O), 194 (96), 166 (100), 139
(58), 70 (78), 56 (62); IR (KBr, cmꢀ1) 2252, 1704, 1684, 1456, 1444, 1408, 1380,
1316; Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found: C, 64.20; H,
4.88; N, 16.52.
12. (a) Freeman, F. Chem. Rev. 1969, 69, 591–624; (b) Fatiadi, A. J. Synthesis 1978,
165–204.
13. Mariella, R. P.; Roth, A. J. J. Org. Chem. 1957, 22, 1130–1133.