Gold/copper-catalyzed activation of the aci-form of nitromethane in the synthesis of methylene-bridged bis-1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/c1cc14926a

Activation of the aci-form of nitromethane using Lewis acids for the attack of carbon nucleophiles was studied. 1,3-Dicarbonyl compounds in the presence of catalytic amounts of AuCl₃ or Cu(OTf)₂ in nitromethane solvent could be converted into methylene-bridged bis-1,3-dicarbonyl compounds.

Full text of DOI:10.1039/c1cc14926a

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COMMUNICATION
Gold/copper-catalyzed activation of the aci-form of nitromethane in the
synthesis of methylene-bridged bis-1,3-dicarbonyl compoundsw
Rengarajan Balamurugan* and Seetharaman Manojveer
Received 9th August 2011, Accepted 22nd August 2011
DOI: 10.1039/c1cc14926a
Activation of the aci-form of nitromethane using Lewis acids for
the attack of carbon nucleophiles was studied. 1,3-Dicarbonyl
compounds in the presence of catalytic amounts of AuCl3 or
Cu(OTf)2 in nitromethane solvent could be converted into
methylene-bridged bis-1,3-dicarbonyl compounds.
the attack of water taking place in the classical Nef reaction
(Fig. 1).2,11 The aci-nitro alkane is generally involved in lower
acid concentrations.12 However, to the best of our knowledge,
direct activation of the aci-form of a nitroalkane by a Lewis
acid catalyst and attack by a carbon nucleophile on it is not
known. Nucleophilic attack of benzene at an aci-nitro form
generated from nitronate salt is known, however this makes
use of very strong acid HF as solvent.13
Due to the strong electron withdrawing nature of the nitro
group, nitroalkanes have become versatile building blocks in
the synthesis of a variety of useful molecular scaffolds and fine
chemicals.1 The conversion of nitroalkanes into ketones,
called the Nef reaction,2 is achieved by acidic hydrolysis of a
nitronate salt made by the basic treatment of an aliphatic nitro
compound. Hydrolysis take place at the stage of the protonated
aci-nitro (nitronic acid) form. In the nitro aci-nitro equilibrium,
the aci-form is the thermodynamically unfavorable tautomer.3
However, the aci-form has been the key intermediate in certain
reactions. Feuer and Nielsen have reported the first example of
a Nef reaction where 2-nitrooctane is directly converted into
2-octanone in acidic medium via nitronic acid formation.4
Edward and Tremaine have shown that Nef and Meyer reactions
of nitroalkanes happen due to the catalytic events that occur
after the nitronic acid formation.5 Acid-catalyzed nitronic acid
formation was achieved by Erden et al., making use of a
tropylium ion rather than a proton as the electrofuge from the
nitroalkane.6 Other ways of stabilizing nitronic acid are by
aryl substitution7 at the a-carbon of a nitroalkane and by
H-bonding.8 It is therefore evident that the stabilization of
nitronic acid is not trivial and hence the limited chemistry of
nitronic acids is not surprising.
Fig. 1
Methylene-bridged 1,3-dicarbonyl compounds are useful
materials and precursors of ligands employed in inorganic
chemistry.10b,14
The reaction of dibenzoylmethane was screened using
5-mol% of selected Lewis and Brønsted acids and the results
Table 1 Screening of different catalysts in the conversion of dibenzoyl-
methane into methylene-bridged bis-dibenzoylmethane
During our investigations on exploring the applications of
the combined use of oxo- and alkynophilicities of gold catalysts,9
we found that 1,3-dicarbonyl compounds, upon refluxing
with catalytic AuCl3 in nitromethane, gave methylene-bridged
bis-1,3-dicarbonyl compounds.10 It was envisaged that the
bridging methylene group should have come from the solvent
nitromethane. Furthermore, the reaction could have occurred
via the initial nucleophilic attack of the 1,3-dicarbonyl compound
at the carbon of the aci-nitro form activated by AuCl3, just like
Entry
Catalyst
Time (h)
Yielda,b
1
2
3
4
5
6
7
8
AuCl3
6
3
24
5
24
24
24
24
24
24
24
24
24
98
97
AuCl3/AgSbF6
AgOTf
Cu(OTf)2
InCl3
Sn(OTf)2
CuCl2
FeCl3
BF3OEt2
CuI
HCl
HOTf
none
No reaction
93
5 (94)
33 (63)
37 (61)
54 (45)
24 (25)
No reaction
10 (80)
6 (86)
9
10
11
12
13
School of Chemistry, University of Hyderabad, Gachibowli,
Hyderabad, India. E-mail: rbsc@uohyd.ernet.in;
Fax: 9140 2301 2460; Tel: 91 40 2313 4817
w Electronic supplementary information (ESI) available: Experimental
details and copies of the spectra. See DOI: 10.1039/c1cc14926a
No reaction
a
b
Isolated yield. Values in the parenthesis represent the percentage of
recovered unreacted starting material.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11143–11145 11143

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Table 2 The scope of the gold/copper-catalyzed methylene-bridged
bis-1,3-dicarbonyls formation
is cumbersome due to aldol-related side product formation.
The reactions could be scaled up. By the reaction of 1a on a 1g
scale when performed using Cu(OTf)2 and AuCl3, the product
2a was obtained in 93% and 95%, respectively, after 8 h.
Indole, a C-nucleophile, did not result in any product when it
was refluxed in nitromethane with either AuCl3 or Cu(OTf)2.
The ability of AuCl3 to hydrate alkynes17 could be taken as
an advantage to directly convert alkynones into methylene-
bridged bis-1,3-dicarbonyl compounds in one pot via the
formation of 1,3-dicarbonyl compound, using moist nitro-
methane as shown in the Scheme 1. This reaction did not take
place when Cu(OTf)2 was used as catalyst.
Yield (time in h)a
Starting
Entry material R1
R2
Ph
Product
AuCl3 Cu(OTf)2
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
2a
2b
2c
2d
2e
2f
98 (6)
84 (2)
93 (5)
75 (2)
4-MeO–C6H4 Ph
4-Br–C6H4 Ph
4-Me–C6H4 Ph
4-Cl–C6H4
4-I–C6H4
3-Br–C6H4
96 (2.5) 76 (5.5)
93 (4) 78 (4)
92 (2.5) 73 (3)
Ph
Ph
Ph
98 (3.5) 95 (2.5)
2g
88 (2)
95 (2)
85 (4)
80 (2)
86 (2.5)
79 (2)
51 (3)
42 (3)
4-Me–C6H4 4-I-C6H4 2h
9
Ph
Ph
Me
Me
Et
2i
2j
2k
10
11
1j
1k
Me
83 (2.5) complex
reaction
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1l
Ph
Ph
OEt
2l
88 (5)
94 (2)
93 (2.5) 89 (3)
88 (2.5) 77 (3)
96 (2)
93 (3.5) 86 (5.5)
94 (2) 90 (4)
91 (2.5) 83 (2)
89 (2) 86 (2)
98 (2.5) 76 (3)
90 (2.5) 80 (5)
65 (5)
70 (2.5) 35 (3)
no
reaction
82 (4.5)
87 (5)
1m
1n
1o
1p
1q
1r
OMe
OMe
OMe
OMe
2m
2n
2o
2p
2q
2r
4-Cl–C6H4
4-Br–C6H4
3-Br–C6H4
4-MeO–C6H4 OEt
4-Me–C6H4 OEt
Scheme 1 The gold-catalyzed one-pot conversion of alkynones into
98 (2.5)
methylene-bridged bis-1,3-dicarbonyl compounds.
A simple mechanism, as shown in Scheme 2, could be
envisaged, although the exact nature of the activated inter-
mediate is unclear.18 The enolic form of the 1,3-dicarbonyl
compound could attack the Lewis acid-activated aci-nitro-
methane to account for the first C–C bond formation. Inter-
mediate II, on elimination of H2O and HNO, as known in the
mechanism of Nef reaction,2 would give intermediate III. This
will undergo a fast Lewis acid-catalyzed Michael addition
of the 1,3-dicarbonyl compound to furnish 2. The involvement
of intermediate III was inferred by trapping it with benzyl
thiol, which was intentionally added to the reaction of 1a.16
In another experiment, the reaction of 1,1-dibenzoylethane
was studied under the present reaction conditions as the
transformation of intermediate II into III is not possible with
this system. However, with both AuCl3 and Cu(OTf)2, only
1-phenylpropane-1,2-dione19 was obtained in 25% and 30%,
respectively, after 50 h of reflux. The expected nucleophilic
attack on the Lewis acid-activated aci-nitromethane did not
happen, perhaps for the reason that enolization is completely
suppressed by the methyl substituent at the central carbon
1s
1t
4-Br–C6H4
OEt
2s
2t
4-MeO–C6H4 OMe
4-Me–C6H4 OMe
1-Naphthyl OMe
Me
Et
1u
1v
1w
1x
1y
2u
2v
2w
2x
2y
OEt
OMe
OEt
10 (4)
OEt
46 (4)
a
Isolated yield.
are summarized in Table 1. Among the Lewis acids screened,
AuCl3 and Cu(OTf)2 were found to be superior catalysts, with
the former being the best for the formation of methylene-
bridged bis-dibenzoylmethane in high yield in a shorter reaction
time. It is known that gold can catalyze condensation reactions
under neutral and mild conditions.15 Brønsted acids, HCl and
HOTf were found to be poorer catalysts. In a different set of
experiments, the reaction of dibenzoylmethane was examined
in different solvents taking 5 equivalents of nitromethane using
AuCl3 and Cu(OTf)2 catalysts.16 However, these conditions
were not good for the efficiency of the reaction. Perhaps a large
quantity of nitromethane is required to have its aci form in a
sufficient amount for the reaction to take place. The substrate
scope was examined with both AuCl3 and Cu(OTf)2 separately
with a variety of substrates. The substrates include aryl and
alkyl 1,3-diketones, b-ketoesters and 1,3-diester. The results
are summarized in Table 2.
Substrates containing substituents like, I, Br, Cl and OMe
on the aryl rings could be handled without any trouble.
Substrates with alkyl ketone moieties resulted in slightly lesser
yields of the product in the AuCl3-catalyzed reactions (entries
9–11, 23 and 24). Cu(OTf)2 was found to be less efficient in
these cases, resulting in poor yields of the desired products. It
is notable that preparing such compounds by a base-assisted
reaction between formaldehyde and 1,3-dicarbonyl compounds
Scheme 2 A tentative mechanism for the formation of methylene-
bridged bis-1,3-dicarbonyl compounds.
c
11144 Chem. Commun., 2011, 47, 11143–11145
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of the 1,3-dione.20 The possibility for the involvement of
formaldehyde formed by the Nef-type reaction initiated by
traces of water present in the solvent cannot be neglected. A Nash
test was carried out to check the formation of formaldehyde.21
The outcome indicated that some amount of formadehyde is
formed under the reaction condition. If this happened at all
under the reaction conditions, it is a new observation as there
is no literature precedent for the direct Lewis acid-catalyzed
Nef reaction on a nitroalkane.
9 (a) R. Balamurugan, R. B. Kothapalli and G. K. Thota, Eur. J.
Org. Chem., 2011, 1557; (b) R. Balamurugan and V. Gudla,
Org. Lett., 2009, 11, 3116; (c) R. Balamurugan and S. R. Koppolu,
Tetrahedron, 2009, 65, 8139.
10 For synthesis of methylene bridged 1,3-dicarbonyl compounds,
see: (a) J.-N. Tan, H. Li and Y. Gu, Green Chem., 2010, 12,
1772; (b) H. Li, Z. He, X. Guo, W. Li, X. Zhao and Z. Li, Org.
Lett., 2009, 11, 4176; (c) S. Xue, Q.-F. Zhou, L.-Z. Li and
Q.-X. Guo, Synlett, 2005, 2990; (d) Y.-S. Hon, T.-R. Hsu,
C.-Y. Chen, Y.-H. Lin, F.-J. Chang, C.-H. Hsieh and P.-H. Szu,
Tetrahedron, 2003, 59, 1509; (e) D.-R. Hwang and B.-J. Uang, Org.
Lett., 2002, 4, 463; (f) K. Maruyama, K. Kubo, Y. Toda,
K. Kawase, T. Mashino and A. Nishinaga, Tetrahedron Lett.,
1995, 36, 5609.
11 For gold-catalyzed nucleophilic addition to alkenes, see:
(a) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2000, 39, 3590;
(b) C.-G. Yang and C. He, J. Am. Chem. Soc., 2005, 127, 6966;
(c) X. Zhang and A. Corma, Chem. Commun., 2007, 3080; For
direct auration of acetone, see: (d) A. S. K. Hashmi, S. Schafer,
M. Wolfle, C. D. Gil, P. Fischer, A. Laguna, M. C. Blanco and
M. C. Gimeno, Angew. Chem., Int. Ed., 2007, 46, 6184.
12 R. B. Cundall and A. W. Locke, J. Chem. Soc. B, 1968, 98.
13 C. Berrier, R. Brahmi, H. Carreyre, J. M. Coustard and
J. C. Jacquesy, Tetrahedron Lett., 1989, 30, 5763.
A similar reaction with nitroethane as the solvent did not
take place with either AuCl3 or Cu(OTf)2. This may be due to
the famous ‘nitroalkane anomaly’ that the proton transfer
reactions of nitroalkanes show abnormal trends.22 Perhaps a
detailed theoretical study might give a better picture.
To summarize, the Lewis acid-activated aci-form of nitro-
methane might have been the key intermediate in the
formation of methylene-bridged bis-1,3-dicarbonyls. Theore-
tical and experimental studies on the Lewis acid activation of
the aci-form could expand the scope of nitroalkane chemistry.
The authors thank Department of Science and Technology
(DST), India for the financial support. SM is grateful to CSIR,
India for a fellowship.
14 (a) J. Guin, R. Frohlich and A. Studer, Angew. Chem., Int. Ed.,
2008, 47, 779; (b) R. Karvembu and K. Natarajan, Polyhedron,
2002, 21, 219; (c) A. Gogoll, C. Johansson, A. Axen and
H. Grennberg, Chem.–Eur. J., 2001, 7, 396; (d) A. M. Cuadro,
J. Elguero and P. Navarro, Chem. Pharm. Bull., 1985, 33, 2535.
15 (a) S. Komiya, T. Sone, Y. Usui, M. Hirano and A. Fukuoka, Gold
Bull., 1996, 29, 131; (b) A. S. K. Hashmi, Gold Bull., 2004,
37, 51.
Notes and references
1 For extensive reviews, see: (a) R. Ballini and M. Petrini, ARKIVOC,
2009, 195; (b) R. Ballini, A. Palmieri and L. Barboni, Chem.
Commun., 2008, 2975; (c) R. Ballini, M. Petrini and G. Rosini,
Molecules, 2008, 13, 319; (d) I. N. N. Namboothiri and N. Rastogi,
in Topics in Heterocyclic Chemistry, ed. A. Hassner, Springer-
Verlag, Berlin Heidelberg, 2008, vol. 12, p. 01; (e) R. Ballini,
A. Palmieri and P. Righi, Tetrahedron, 2007, 63, 12099;
(f) R. Ballini and A. Palmieri, Curr. Org. Chem., 2006, 10, 2145;
(g) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini,
Chem. Rev., 2005, 105, 933.
16 See supplementary information for details.
17 (a) N. Ghosh, S. Nayak and A. K. Sahoo, J. Org. Chem., 2011,
76, 500; (b) W. Wang, J. Jasinski, G. B. Hammond and B. Xu,
Angew. Chem., Int. Ed., 2010, 49, 7247; (c) W. Wang, B. Xu and
G. B. Hammond, J. Org. Chem., 2009, 74, 1640; (d) R. Casado,
M. Contel, M. Laguna, P. Romero and S. Sanz, J. Am. Chem. Soc.,
2003, 125, 11925; (e) Y. Fukuda and K. Utimoto, J. Org. Chem.,
1991, 56, 3729; (f) Y. Fukuda and K. Utimoto, Bull. Chem. Soc.
Jpn., 1991, 64, 2013.
2 For a concise review, see: R. Ballini and M. Petrini, Tetrahedron,
2004, 60, 1017.
3 (a) K. Lammertsma and P. V. Bharatam, J. Org. Chem., 2000,
65, 4662; (b) N. J. Harris and K. Lammertsma, J. Am. Chem. Soc.,
1996, 118, 8048; (c) K. Lammertsma and P. V. Bharatam, J. Am.
Chem. Soc., 1993, 115, 2348.
4 H. Feuer and A. T. Nielsen, J. Am. Chem. Soc., 1962, 84, 688.
5 (a) J. T. Edward and P. H. Tremaine, Can. J. Chem., 1971,
49, 3483; (b) J. T. Edward and P. H. Tremaine, Can. J. Chem.,
1971, 49, 3489; (c) J. T. Edward and P. H. Tremaine, Can. J.
Chem., 1971, 49, 3493.
6 I. Erden, J. R. Keeffe, F.-P. Xu and J.-B. Zheng, J. Am. Chem.
Soc., 1993, 115, 9834.
7 H. Bock, R. Dienelt, H. Schodel, Z. Havlas, E. Herdtweck and
W. A. Herrmann, Angew. Chem., Int. Ed. Engl., 1993, 32, 1758.
8 F.-A. Kang and C.-L. Yin, J. Org. Chem., 1996, 61, 5523.
18 For a mini review on gold-catalyzed reactions with characterized
intermediates, see: A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010,
49, 5232.
19 Y. Zhang, J. Jiao and R. A. Flowers, II, J. Org. Chem., 2006,
71, 4516.
20 C. L. Bickel and R. Morris, J. Am. Chem. Soc., 1951, 73, 1786 and
the references cited therein.
21 T. Nash, Biochem. J., 1953, 55, 416. The details of the Nash test are
described in the supplementary information.
22 (a) A. J. Kresge, Can. J. Chem., 1974, 52, 1897; For recent studies
on this issue, see: (b) K. Ando, Y. Shimazu, N. Seki and
H. Yamataka, J. Org. Chem., 2011, 76, 3937; (c) M. Sato,
Y. Kitamura, N. Yoshimura and H. Yamataka, J. Org. Chem.,
2009, 74, 1268; (d) T. Bug, T. Lemek and H. Mayr, J. Org. Chem.,
2004, 69, 7565; (e) J. Grinblat, M. Ben-Zion and S. Hoz, J. Am.
Chem. Soc., 2001, 123, 10738.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11143–11145 11145