A simple one-pot, multi-component synthesis of cyano-functionalized bis-β-diketones

Article abstract of DOI:10.1016/j.tetlet.2013.03.044

Mild, multi-component Knoevenagel condensation/Michael addition reactions of dibenzoylmethane (Hdbm) and methylene-active cyano molecules with formalin in ethanol gave cyano methylene-bridged bis-diketones. The syntheses of 1,1,5,5-tetrabenzoyl-3,3-dicyan

Full text of DOI:10.1016/j.tetlet.2013.03.044

Tetrahedron Letters 54 (2013) 2661–2664
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple one-pot, multi-component synthesis of cyano-functionalized
bis-b-diketones
⇑
Aron Urbatsch, William J. Gee, Glen B. Deacon, Stuart R. Batten
Monash University, School of Chemistry, Clayton, VIC 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Mild, multi-component Knoevenagel condensation/Michael addition reactions of dibenzoylmethane
(Hdbm) and methylene-active cyano molecules with formalin in ethanol gave cyano methylene-bridged
bis-diketones. The syntheses of 1,1,5,5-tetrabenzoyl-3,3-dicyanopentane (1) and 1,1,7,7-tetrabenzoyl-
3,5-dicyano-3,5-dimethoxycarbonyl-heptane (4) are reported. Increasing the reaction time with the
reagents for 1 led to the formation of the ester (2,2-dicyano-4-benzoylbutyl) benzoate (2). The isolation
of 2,2-dicyano-4,4-dipivaloyl-1-butanol (3a), the tert-butyl analogue of a proposed intermediate in the
formation of 2, provides evidence for a possible reaction pathway. Methylene-bis(dibenzoylmethane)
(mdbm) was obtained in good yield from the reaction between Hdbm and formalin, by the addition of
the base triethylamine. The X-ray crystal structures of 1–4 and mdbm were determined using synchro-
tron radiation.
Received 2 January 2013
Revised 24 February 2013
Accepted 8 March 2013
Available online 16 March 2013
Keywords:
Knoevenagel condensation
Michael addition
b-Diketones
Cyano/nitrile group
Crystal structure
Ó 2013 Elsevier Ltd. All rights reserved.
The installation of dicyano groups onto organic scaffolds re-
mains an interesting topic as a result of the varied avenues of fur-
ther modification such groups allow.1 Of further interest are a
number of biologically relevant molecules that contain polycyano
functionalities, which have been shown to possess either fungi-
cidal,2 arthropodicidal,3 antimicrobial4 or insecticidal5 properties.
The evaluation of antiviral6 and antimitotic7 properties of some
species is a parallel focus.
Malononitrile and related species are a convenient source of
dicyano groups and exhibit reactivity towards a range of sub-
strates, including alkyl halides and aldehydes, as well as self-reac-
tivity by di- and tri-merization.8 The reactivity of malononitrile
with b-diketones in the presence of formaldehyde has been largely
used to impart aromatic functionalities9 and for cycloaddition.10
Retention of dicyano functionality is unusual for such reactions,
which usually replace the methylene hydrogen atoms by a double
bond.11 This probably results from the reactivity of dinitrile moie-
ties towards ketone-containing species.12
Here we report our progress in synthesizing such ligands with
the facile one-pot synthesis and characterization of three quater-
nary dicyano moieties, including a bis-b-diketone species bearing
cyano functionalities. In a simple one-pot reaction, dibenzoylme-
thane [Hdbm or dipivaloylmethane (Hdpm)] and a CH2-acidic cya-
no compound such as malononitrile [CH2(CN)2, mn] or methyl
cyanoacetate [CH2(CN)(CO2Me), mca] were reacted with formalin
in boiling ethanol. In the absence of the cyano compound, we ob-
tained the well-known methylenebis(dibenzoylmethane) (mdbm),
for which we have determined the crystal structure for the first
time. Catalyst-free domino reactions involving formaldehyde and
1,3-dicarbonyl compounds are well established in the synthesis
of organic compounds.15
Dibenzoylmethane (Hdbm), formalin and malononitrile
[CH2(CN)2], in a 2:2:1 stoichiometric ratio, yielded 1,1,5,5-tetra-
benzoyl-3,3-dicyanopentane (1) within 2 h of heating. It was found
to crystallize from the reaction solution upon cooling in a yield of
37%. A longer reaction time, independent of an excess of Hdbm and
formalin, resulted in colourless (2,2-dicyano-4-benzoylbutyl) ben-
zoate (2) being precipitated from the boiling solution, its insolubil-
ity in ethanol preventing further reaction (Schemes 1 and 2).
To prepare 1, two formaldehyde molecules were condensed to
form two methylene bridges, which link the central dicyano meth-
ane moiety to the two outer dibenzoylmethane groups. Product 2
is formally composed of one equivalent of Hdbm and malononitri-
le, and 2 equiv of formaldehyde. This reaction was repeated and
monitored by 1H NMR spectroscopy at 30 min intervals (performed
on the crystallized products obtained upon cooling). The spectra
revealed that the majority of 1 was formed within 1.5 h. Its
Our interest in cyano-functionalized b-diketones is derived
from our recent studies with small cyano anions13 and on lantha-
noid dibenzoylmethanide cluster chemistry.14 The ability to syn-
thesize ligands that contain bidentate metal binding groups (e.g.,
b-diketones), yet retain a reactive cyano-functionality may allow
the synthesis of porous coordination polymers (CPs) possessing
the ability to impart selective cyanation of substrates.
⇑
Corresponding author. Tel.: +61 3 9905 4606; fax: +61 3 9905 4597.
E-mail address: stuart.batten@monash.edu (S.R. Batten).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.044

2662
A. Urbatsch et al. / Tetrahedron Letters 54 (2013) 2661–2664
Scheme 1. Condensation products.
Figure 1. X-ray crystal structures of compounds 1–4 and mdbm; carbon, oxygen
and nitrogen atoms are depicted in grey, red and blue, respectively. All hydrogen
atoms and lattice solvent molecules were omitted for clarity. Thermal ellipsoids are
shown at 50% probability.
was reported earlier and its synthesis is similar, and proceeds
without the addition of base.18 A 1:1 reaction of Hacac/CH2O in
ethylene glycol at 60 °C for 5.5 hours afforded a 2:2 Hacac/formal-
dehyde pyran heterocycle in 42% yield.19 This heterocycle is the
product of the initially formed 3,5-diacetylheptane-2,6-dione,
analogous to mdbm. Its subsequent reaction with a further form-
aldehyde molecule followed by intramolecular cyclization gives
1,10,100-[(5RS,6RS)-6-hydroxy-6-methyl-3,4,5,6-tetrahydro-2H-pyr-
an-3,3,5-triyl]-triethanone.19 The linear 3:2 Hacac/formaldehyde
3,5,5,7-tetraacetylnonane-2,8-dione has also been isolated.20 It
was obtained after three days of stirring of the reactants (in a 3:2
molar ratio) in ethanol at room temperature.
Scheme 2. Proposed reaction path for the formation of compounds 1 and 2.
concentration in the crystallized samples was then found to de-
crease and that of 2 increase, until, after 4 h, 2 was the main prod-
uct, 1 and mdbm also being detectable. After 15 h, 2 was found to
precipitate exclusively (66% yield) and with high purity. Each of the
isolated crystalline products 1–4 and mdbm is shown in Figure 1.
A crystallographic summary is given in Table 1.
The addition of triethylamine to a hot solution of Hdbm and for-
malin in ethanol led to the exclusive precipitation of methylene-
bis(dibenzoylmethane) (mdbm) within minutes, which could be
collected by filtration in high purity and yield. The triethylamine
prevents the formation of the mixed products described above
and greatly accelerates the formation of mdbm. It and other bis-
diketones have also been synthesized by Claisen-condensations,
the reaction between bis(acyl chlorides) and diketo alkali salts,16
and the iron-catalysed oxidative reactions of 1,3-dicarbonyl com-
pounds and N,N-dimethylaniline.17 It has also been found that
the formation of bis-b-diketones occurs at room temperature with
the addition of a different base (e.g., piperidine).16b The acetylace-
tone (Hacac) analogue of mdbm, 3,5-diacetylheptane-2,6-dione,
Formation of 1 occurs by the condensation reaction of 2 equiv of
Hdbm and formaldehyde with one equivalent of malononitrile
(Scheme 2). Continued heating of 1 in the presence of water prob-
ably instigates fragmentation of 1 into product 3 (3a being the iso-
lated tert-butyl analogue, see below) and Hdbm.
The intramolecular cyclization in which the hydroxyl arm of the
intermediate species 3 attacks the carbonyl group, affords a cyclic
six-membered pyran intermediate (Scheme 2) (see above for the
analogous acacH/CH2O species19). This is followed by a rearrange-
ment with concomitant decyclization, affording the thermody-
namically favoured benzoate ester 2 (Scheme 2). The related 4,4-
diacetylheptanedinitrile was obtained previously from a reaction
of acrylonitrile, a Michael-acceptor, with acacH, in a 2:1 mole ratio,
under basic conditions.21 In this case, both protons of the diketo-
backbone carbon atom were replaced by the Michael-acceptor,
acrylonitrile.
1H and 13C NMR spectroscopy, microanalyses and mass spec-
trometry measurements confirmed the composition of products 1
and 2. The characteristic methylene and backbone proton

A. Urbatsch et al. / Tetrahedron Letters 54 (2013) 2661–2664
2663
Table 1
Crystallographic data for compounds 1–4 and mdbm
1
2
3a
4
mdbm
Chemical formula
Formula mass
Crystal system
Space group
a (Å)
C
38H32N2O5
C20H16N2O3
332.35
C16H24N2O3
292.37
Monoclinic
P21/n
15.149(3)
6.2870(13)
17.798(4)
90
105.70(3)
90
1631.8(6)
100(2)
4
C41H34N2O8
682.70
C31H24O4
460.50
596.66
Triclinic
P1
Triclinic
Triclinic
Triclinic
ꢀ
ꢀ
ꢀ
ꢀ
P1
P1
P1
10.4150(5)
10.6451(4)
14.6761(6)
82.271(2)
81.506(2)
80.132(2)
1575.48(12)
123(1)
7.3407(4)
10.9839(7)
11.2795(6)
73.916(2)
82.005(2)
72.542(2)
832.05(8)
123(1)
5.7910(12)
11.958(2)
26.661(5)
78.34(3)
86.70(3)
78.11(3)
1769.1(6)
100(2)
11.253(2)
12.634(3)
17.590(4)
95.01(3)
98.49(3)
104.45(3)
2375.0(8)
100(2)
b (Å)
c (Å)
a
(°)
b (°)
(°)
c
Unit cell volume (Å3)
Temperature (K)
Z
2
2
2
4
Reflections observed
Unique reflections
Rint
19789
7096
0.0352
0.0478
0.1159
0.0774
0.1301
1.053
11250
3726
0.0180
0.0472
0.1342
0.0611
0.1690
0.602
25244
3739
28000
7401
39605
10095
0.0787
0.0517
0.1306
0.0647
0.1400
1.064
0.0354
0.0694
0.1872
0.0787
0.1958
1.084
0.0280
0.0459
0.1204
0.0521
0.1261
0.980
Final R1 values (I >2
r
(I))
r
Final wR(F2) values (I >2
Final R1 values (all data)
(I))
Final wR(F2) values (all data)
Goodness of fit on F2
resonances, and their different shifts and splitting patterns allow
easy distinction between the compounds. Compound 2 has a un-
ique –COO–CH2–C(CN)2– singlet resonance at 5.00 ppm, and the
diketo-backbone –(CO)2–CH–CH2– triplet protons of 1 and mdbm
are at 6.04 ppm and 5.74 ppm, respectively. The striking absence of
a vibrational nitrile stretching band (usually around 2250 cmꢀ1) in
the infrared spectra of both 1 and 2 is likely due to the electron-
withdrawing groups attached to the carbon atom binding both ni-
triles, which is known to result in very weak or absent bands.22
However, this characteristic nitrile stretching feature was detected
of the methylene protons in mca compared with malononitrile.
Thus, an excess of mca compared with Hdbm is required for the
reaction to proceed. The crystal structures of all the compounds re-
veal that they exist exclusively as the keto form in the solid state,
and that the diketo carbon backbone has a tetrahedral stereochem-
istry in all cases (Fig. 1).
In conclusion, the fast and simple one-pot reaction of a dike-
tone, formalin and methylene-active compounds such as malono-
nitrile or methyl cyanoacetate leads to the formation of cyano-
functionalized methylene-bridged bis-diketones 1 and 4. The out-
come of the reaction is highly dependent on the stoichiometry
and reaction times. The precipitation of an insoluble ester 2 from
the boiling reaction solution was observed. Product 2 is considered
to result from an intramolecular cyclization/ring-opening process.
Evidence for the intermediate species is provided by the isolation
of a trapped tert-butyl-analogue 3a. These species offer great
promise as ligands in porous coordination polymers which may
show cyanation activity, as well as a novel means of grafting cyano
groups onto organic scaffolds.
by Raman spectroscopy at 2250 cmꢀ1
.
We reasoned that increasing the steric bulk of the diketone
would inhibit the intramolecular cyclization/ring-opening path-
way (Scheme 2), hence 2,2,6,6-tetramethyl-heptane-3,5-dione
(dipivaloylmethane, Hdpm) was substituted for Hdbm. This re-
sulted in the formation of 2,2-dicyano-4,4-dipivaloyl-1-butanol
(3a), the tert-butyl analogue of the intermediate 3 shown in the
rectangle in Scheme 2. This demonstrated that the inclusion of a
bulky tert-butyl group does prevent the attack on the nearest car-
bonyl group by the intermediate alcohol (Scheme 2). This result is
important, as it highlights a means of controlling the location of
the labile ester in a product derived from the use of unsymmetrical
diketone starting materials. Ester 2 can thus be regarded as a pro-
tected alcohol. Its deprotection offers a handle for further modifi-
cation that may be used in the synthesis of complex dicyano-
containing species such as fused 6,7,5-tricarbocyclic systems.23
A reaction involving methyl cyanoacetate (mca), another active
methylene compound, in an excess relative to Hdbm, promotes the
formation of 1,1,7,7-tetrabenzoyl-3,5-dicyano-3,5-dimethoxycar-
bonylheptane (4) when reacted with formalin. Two equiv of Hdbm
and mca reacted with three equivalents of formaldehyde. This
demonstrates that exchanging the electron-withdrawing group
positioned adjacent to the cyano group does not inhibit the overall
reactivity. An excess of mca and formalin was required, as reac-
tions performed analogously to those that led to the isolation of
compounds 1 and 2 yielded only Hdbm after refluxing for 15 h in
ethanol.
Acknowledgments
The authors gratefully acknowledge the Australian Research
Council for financial support. Part of this research was undertaken
on the MX1/MX2 beamlines at the Australian Synchrotron, Victo-
ria, Australia.
Supplementary data
CCDC 916898 (1), 916899 (2), 916900 (3), 916901 (4) and
916902 (mdbm) contain the supplementary crystallographic data.
These data can be obtained free of charge via http://www.ccdc.ca-
m.ac.uk/conts/retrieving.html, or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.044.
The insolubility of the synthesized compounds involving Hdbm
in ethanol is highly advantageous for the separation of the prod-
ucts from the reaction solutions. All the compounds precipitated
either upon cooling (1, 4 and mdbm) or directly from the boiling
solution (2). The formation of the 2:3:2 product 4 instead of the
2:2:1 products (1 and 3a) is a result of the slightly changed acidity
References and notes
1. Bagby, M. O.; Smith, C. R., Jr.; Wolff, I. A. J. Org. Chem. 1969, 34, 2732–2735.
2. Harkin, S. A.; Slight, P. J.; Hudec, J. Eur. Pat. Appl. EP 219154 A2 19870422,
1987; Chem. Abstr. 1987, 107, 154229.

2664
A. Urbatsch et al. / Tetrahedron Letters 54 (2013) 2661–2664
3. Holyoke, C. W., Jr. PCT Int. Appl., WO 9711057 A1 19970327, 1997; Chem. Abstr.
1997, 126, 305586.
4. Sheverdov, V. P.; Ershov, O. V.; Nasakin, O. E.; Chernushkin, A. N. Pharm. Chem. J.
2009, 43, 659–660.
5. Rauh, J. J.; Holyoke, C. W.; Kleier, D. A.; Presnail, J. K.; Benner, E. A.; Cordova, D.;
Howard, M. H.; Hosie, A. M.; Buckingham, S. D.; Baylis, H. A.; Sattelle, D. B.
Invert. Neurosci. 1997, 3, 261–268.
6. Nasakin, O. E.; Lukin, P. M.; Sheverdov, V. P.; Lyshchikov, A. N. Khim.-Farm. Zh.
1998, 32, 21–23.
Commun. 2012, 48, 124–126; (d) Chesman, A. S. R.; Yang, M.; Spiccia, N. D.;
Deacon, G. B.; Batten, S. R.; Mudring, A.-V. Chem. Eur. J. 2012, 18, 9580–9589.
14. (a) Andrews, P. C.; Gee, W. J.; Junk, P. C.; MacLellan, J. G. Inorg. Chem. 2010, 49,
5016–5024; (b) Andrews, P. C.; Gee, W. J.; Junk, P. C.; MacLellan, J. G. Dalton
Trans. 2011, 40, 12169–12179; (c) Gee, W. J.; Hierold, J.; MacLellan, J. G.;
Andrews, P. C.; Lupton, D. W.; Junk, P. C. Eur. J. Inorg. Chem. 2011, 2011, 3755–
3760; (d) Andrews, P. C.; Deacon, G. B.; Gee, W. J.; Junk, P. C.; Urbatsch, A. Eur. J.
Inorg. Chem. 2012, 2012, 3273–3282; (e) Andrews, P. C.; Gee, W. J.; Junk, P. C.;
Massi, M. New J. Chem. 2013, 37, 35–48.
7. Dominguez, J. N.; Zapata, A. J.; Lobo, G. M.; Blanca, I. Pharmazie 1995, 50, 337–
341.
8. Freeman, F. Chem. Rev. 1969, 69, 591–624.
15. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Gu, Y.; De Sousa, R.; Frapper,
G.; Bachmann, C.; Barrault, J.; Jerome, F. Green Chem. 2009, 11, 1968–1972; (c)
Capdevila, E.; Rayo, J.; Carrion, F.; Jove, I.; Borrell, J. I.; Teixido, J. Afinidad 2003,
60, 317–337; (d) Lieby-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J.
QSAR Comb. Sci. 2006, 25, 432–438.
16. (a) Martin, D. F.; Shamma, M.; Fernelius, W. C. J. Am. Chem. Soc. 1958, 80, 4891–
4895; (b) Martin, D. F.; Shamma, M.; Fernelius, W. C. J. Am. Chem. Soc. 1958, 80,
5851–5856.
9. (a) Bischoff, C.; Schroeder, E.; Gruendemann, E. J. Prakt. Chem. 1982, 324, 519–
525; (b) Kadutskii, A. P.; Kozlov, N. G.; Bondarev, S. L. Russ. J. Org. Chem. 2006,
42, 1383–1387.
10. (a) Sowellim, S. Z. A.; El-Taweel, F. M. A.; Elagamey, A. A. Egypt. J. Chem. 1995,
38, 511–522; (b) El-Taweel, F. M. A. A. J. Heterocycl. Chem. 2005, 42, 943–946;
(c) Coia, N.; Bouyssi, D.; Balme, G. Eur. J. Org. Chem. 2007, 3158–3165; (d)
Jensen, A. A.; Erichsen, M. N.; Nielsen, C. W.; Stensboel, T. B.; Kehler, J.; Bunch,
L. J. Med. Chem. 2009, 52, 912–915.
17. Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Lett. 2009, 11, 4176–4179.
18. Burton, S.; Fronczek, F. R.; Maverick, A. W. Acta Crystallogr., Sect. E 2007, 63,
o3108.
11. (a) Mohareb, R. M.; Abdel-Sayed, N. I.; Sherif, S. M. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 119–129; (b) Kozlov, N. G.; Kadutskii, A. P. Russ. J. Org.
Chem. 2002, 38, 129–133.
19. (a) Aarna, A.; Köösel, A.; Kiisler, K. Finn. Chem. Lett. 1975, 3–4, 102–104; (b)
Burton, S.; Fronczek, F. R.; Maverick, A. W. Acta Crystallogr., Sect. E 2007, 63,
o2661–o2662.
12. Paine, J. B., III; Woodward, R. B.; Dolphin, D. J. Org. Chem. 1976, 41, 2826–
2835.
13. (a) Batten, S. R.; Murray, K. S. Coord. Chem. Rev. 2003, 246, 103–130; (b) Turner,
D. R.; Chesman, A. S. R.; Murray, K. S.; Deacon, G. B.; Batten, S. R. Chem.
Commun. 2011, 47, 10189–10210; (c) Chesman, A. S. R.; Yang, M.; Mallick, B.;
Ross, T. M.; Gass, I. A.; Deacon, G. B.; Batten, S. R.; Mudring, A.-V. Chem.
20. Guo, Z.; Hua, Y.; Tong, H.; Wei, X. J. Chem. Crystallogr. 2011, 41, 1501–1504.
21. Wang, G.-W.; Zhang, J.; Zhuang, L.-H.; Wu, W.-Y.; Wang, J.-T. Acta Crystallogr.,
Sect. E. 2009, 65, o15.
22. Kitson, R. E.; Griffith, N. E. Anal. Chem. 1952, 24, 334–337.
23. Rodriguez, J. R.; Rumbo, A.; Castedo, L.; Mascarenas, J. L. J. Org. Chem. 1999, 64,
966–970.