Nitroalkanes and ethyl glyoxalate as common precursors for the preparation of both β-keto esters and α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2004.07.141

β-Nitro acrylic esters, obtained by the reaction of nitroalkanes and ethyl glyoxalate, are the key building blocks for the immediate synthesis of both the title compounds. In fact, their treatment with titanium trichloride produce the direct conversion to the β-keto esters, while their reaction with sodium boron hydride gives the one-pot synthesis of α,β- unsaturated esters through formal substitution of the vinylic nitro group with an hydrogen.

Full text of DOI:10.1016/j.tetlet.2004.07.141

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7027–7029
Nitroalkanes and ethyl glyoxalate as common precursors for
the preparation of both b-keto esters and a,b-unsaturated esters
Roberto Ballini,* Dennis Fiorini and Alessandro Palmieri
`
Dipartimento di Scienze Chimiche dell’Universita di Camerino, Via S. Agostino 1, I-62032 Camerino, Italy
Received 22 June 2004; revised 28 July 2004; accepted 29 July 2004
Available online 14 August 2004
Abstract—b-Nitro acrylic esters, obtained by the reaction of nitroalkanes and ethyl glyoxalate, are the key building blocks for the
immediate synthesis of both the title compounds. In fact, their treatment with titanium trichloride produce the direct conversion
to the b-keto esters, while their reaction with sodium boron hydride gives the one-pot synthesis of a,b-unsaturated esters through
formal substitution of the vinylic nitro group with an hydrogen.
ꢀ 2004 Published by Elsevier Ltd.
Nitroalkanes have proved to be valuable intermediates.1
Both the activating effect of the nitro group and its facile
transformation into various functionalities have
extended the importance of nitro compounds in the
preparation of complex molecules.2 Peculiar to aliphatic
nitro compounds is the formation of new carbon–car-
bon single bond, via their nitronate form3 and, in spe-
cific cases, the creation of carbon–carbon double
bonds through the elimination of nitrous acid.4 On the
basis of these considerations, we have found that nitro-
alkanes, combined with ethyl glyoxalate, can be conven-
iently used as building blocks to produce b-keto esters
and a,b-unsaturated esters.
a,b-Unsaturated esters are useful chemical entities
which are accessible through condensation reactions
involving aldehydes, viz. (i) Knoevenagel condensation
of active methylene esters with aldehydes,10 (ii) conden-
sation of alkyl acetates with aldehydes followed by
dehydration,11 (iii) Reformatsky reaction with alde-
hydes followed by elimination of the ensuing hydroxy
esters,12 (iv) Wadsworth–Emmons olefination of carb-
onyl compounds.13
Thus, many procedures for the syntheses of both the
title compounds have been reported for a long time,
but there exist many drawbacks and disadvantages such
as the need of drastic conditions, poor yields and low
selectivity. In contrast to this, the procedures that we
wish to report here give the title compounds in a few
steps (Scheme 1), in good yields, and with the possibility
to preserve several other functionalities.
b-Keto esters are multicoupling reagents having an elec-
trophilic carbonyl and a nucleophilic carbon, which
makes them a valuable tool for the synthesis of complex
molecules. Moreover they are extensively used in the
agrochemical, pharmaceutical and dyestuff industries.5
Apart from the classical Claisen condensation6 and
related reactions,7 the most direct method for their syn-
thesis involves the condensation of aldehydes with ethyl
diazoacetate.8 The use of methyl 3-nitropropionate, as
precursor for the preparation of b-keto esters was also
previously reported by our group.9
The first step of the sequence is a nitroaldol (Henry)
reaction between the nitroalkane 1 and ethyl glyoxalate
2, performed under heterogeneous catalysis, using
Amberlyst A-21 as solid base.14 The reaction proceeds
at room temperature, in the presence of just a small
amount of solvent (ethyl glyoxalate is commercially
available as 50% solution in toluene) and gives the b-
nitro alcohols 3 in good yield (70–87%, Table 1). The
resulting derivatives 3 were dehydrated to the nitroalke-
nes 4 (as E isomers) by mesylation of the hydroxy group,
followed by basic elimination of methanesulfonic acid.15
The dehydration reaction is very fast (about 1.5h) and,
as reported in Table 1, the yields are good (65–94%)16
Keywords: a,b-Unsaturated esters; b-Keto esters; Nitroalkanes; Ethyl
glyoxalate; Tandem process.
*
Corresponding author. Tel.: +39 0737 402270; fax: +39 0737
402297; e-mail: roberto.ballini@unicam.it
0040-4039/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.07.141

7028
R. Ballini et al. / Tetrahedron Letters 45 (2004) 7027–7029
OEt
OEt
Amberlyst A-21
O
NO2
Ph
Ph
r.t.
Et3N, MeSO2Cl,
CH2Cl2, 0°C, 1.5 h
OH
COOEt
NO2
+
O
O
+
NO2
OEt
R
R
4e
7
70-87%
OEt
O
OH
3
Ph
71%
1
2
NO2
3e
O
Et3N, MeSO2Cl,
CH2Cl2, 0°C, 1.5 h,
NO2
65-94%
Scheme 2.
TiCl3, NH4OAc
DME-H2O, 5h
NO2
O
COOEt
R
COOEt
R
50-63%
4
5
H
NaBH4, EtOH
0˚ C to reflux
NaBH4, EtOH
0˚ C to reflux
R
OEt
R
OEt
71-91%
NO2
O
NO2
O
8
4
COOEt
R
6
-HNO2
71-91%
R
Scheme 1.
OEt
O
6
even in the presence of other functional groups such as
ketone, ketal, ester and heteroaromatic systems.
Scheme 3.
The dehydration of the nitroalcohol 3e (Scheme 2) pro-
vides the expected nitroalkene 4e, together with its iso-
mer 7, in a 1:1 ratio.
In fact, the sodium borohydride first acts as a reducing
agent, converting nitroalkenes 4 into nitroalkanes 8
then, under reflux, causes nitrous acid elimination, aided
by its behaviour as base and by the presence of an acidic
hydrogen in a-position to the carbonyl. The conversion
4 to 6 appears as a formal substitution of a vinylic nitro
group with a hydrogen.
b-Nitro acrylic esters 4 are key building blocks for the
immediate synthesis of both the title compounds. Thus,
treatment of a 1,2-dimethoxyethane (DME)/water solu-
tion of 4a–i (or 7) with titanium trichloride, in the pres-
ence of ammonium acetate,1e,17 gives the direct
conversion to the b-keto esters 5 in satisfactory yield
(50–63%).18 The method also tolerates several functio-
nalities such as esters, carbonyls, ketals and heteroaro-
matic structures. Finally, in order to verify the
possibility of forming the a,b-unsaturated esters 6, we
selected a representative number of nitroalkenes 4, as
their precursors, and found that this conversion can be
directly performed through a tandem Michael addi-
tion–elimination process promoted by NaBH4 in metha-
nol (Scheme 3).19
The conjugated esters 6 are obtained in high yield (71–
91%) with complete diastereoselectivity since just the
E-isomers are produced.
In conclusion, we reported two new, mild and conven-
ient approaches for the synthesis of the title compounds,
starting from aliphatic nitro compounds and ethyl gly-
oxalate as common precursors. It is important to point
out that the procedures tolerate different functionalities
such as ethers, acetals, heteroaromatic systems, ketones
and chiral protected alcohols.
Table 1. Compounds 3, 4, 5 and 6 prepared
Entry
R
Yield (%)a of 3 (reaction time, h)
Yield (%)a of 4
Yield (%)a of 5
Yield (%)a of 6
A
b
c
CH3CH2
75 (18)
70 (16)
76 (16)
71 (17)
82 (17)
79 (19)
77 (20)
85
87
86
91
71
70
69
55
61
59
60
63
56
58
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
C6H5CH2
85
91
d
e
f
(CH2)2CO2CH3
CH3CO(CH2)2
71
g
h
i
73 (19)
78 (20)
87
73
50
54
73b
CH2
O
CH3C(OCH2CH2O)(CH2)2
94c
76
S
j
80 (18)
OBn
k
l
AcO(CH2)3
C6H5
78 (19)
87 (21)
65
71c
71
87
a Yield of pure, isolated products.
b The compound 6h is obtained as the b,c-unsaturated ester.
c Obtained as a mixture of E/Z isomers (ratio 6:4 for 4j and 7.2:2.5 for 4l).

R. Ballini et al. / Tetrahedron Letters 45 (2004) 7027–7029
7029
Gal, M.; Heintz, M.; Troupel, M. J. Chem. Soc., Chem.
Commun. 1992, 50.
NO2
H
R
P(R1)3
R
8. Bandgar, B. P.; Pandit, S. S.; Sadavarte, V. S. Green
Chem. 2001, 3, 247, and references cited therein.
9. Ballini, R.; Bosica, G. J. Chem. Res. (S), 1993, 2901.
10. Cope, A. C.; Hoffman, C. M. J. Am. Chem. Soc. 1941, 63,
3456.
a
1
Figure 1.
These transformations are a further illustration of the
great versatility of the nitroalkanes in organic synthesis,
and it is important of note that in the synthetic sequence
for the preparation of the a,b-unsaturated esters 6 (1 + 2
to 6), nitro compounds 1 can be regarded as the syn-
thetic equivalents of ylids a (Wittig or Wittig–Horner
reagents, Fig. 1), but with the great advantage of the
easier availability of a large variety of nitroalkanes com-
pared with the availability of the ylids.
11. Galat, A. J. Am. Chem. Soc. 1946, 68, 376.
12. (a) Shriner, R. L. Org. React. 1947, 1, 1; (b) Hauser, C. R.;
Breslow, D. S. Org. Synth. Coll. 1955, 3, 408; (c) Rinehart,
K. L.; Perkins, E. G. Org. Synth. Coll. 1963, 4, 444.
13. (a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733; (b) Wadsworth, W. S. Org. React. 1977,
25, 73; (c) Wadsworth, W. S. Acc. Chem. Res. 1983, 16,
1411; (d) Marynoff, B. E.; Reitz, A. B. Chem. Rev. 1989,
89, 863.
14. Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52,
1677.
15. Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.
16. Although the synthesis of the nitroalkenes 4, by conden-
sation of 1 with 2, has been previously reported, Shin, C.;
Yonezawa, Y.; Narukawa, H.; Nanjo, K.; Yoshimura, J.
Bull. Chem. Soc. Jpn. 1972, 45, 3595 the method needs of a
large excess of nitroalkanes, and give moderate overall
yields.
Acknowledgements
This work was supported by the University of Came-
rino-Italy and by MIUR-Italy (Project ÔI1 Mezzo Acqu-
oso nelle Applicazioni Sintetiche dei Nitrocomposti
AlifaticiÕ).
17. Katoh, T.; Nishide, K.; Node, M.; Ogura, H. Heterocycles
1999, 50, 833.
References and notes
18. Sample procedure (Table 1, product 5e): To a stirred
solution of 1,2-dimethoxyethane, (21.5mL) and distilled
water (15.5mL) were added 15% TiCl3 solution (10.4mL,
12.13mmol) and ammonium acetate (5.627g, 73mmol) at
0ꢁC, and the resulting mixture was stirred at room
temperature for 1h. A solution of nitroalkene 4e (0.47g,
2mmol) in 2mL of 1,2-dimethoxyethane was added to the
reaction mixture at 0ꢁC and stirring was continued at
room temperature for an additional 5h. The reaction was
quenched with 2N HCl, then extracted with diclorometh-
ane (4 · 30mL) and dried over Na2SO4 dry. Finally the
organic solution was filtrated and concentrated under
vacuum to give the crude product that was purified by fast
flash chromatography (hexane–ethyl acetate) allowing
0.3g (71%) of the pure compound 5e: oil; IR (neat):
1. (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia
1979, 31, 1; (b) Rosini, G.; Ballini, R. Synthesis 1988, 833;
(c) Ballini, R. Synlett 1999, 1009; (d) Ono, N. The Nitro
Group in Organic Synthesis; Wiley-VCH: New York, 2001;
(e) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
2. (a) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573; (b)
Ballini, R. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19, p
117.
3. (a) Rosini, G. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2, p 321; (b)
Ballini, R.; Marziali, P.; Mozzicafreddo, A. J. Org. Chem.
1996, 61, 3209 and references cited therein.
m=1716, 1741cmÀ1 1H NMR (CDCl3): d = 1.27 (t, 3H,
;
4. See for example: (a) Seebach, D.; Hoekstra, M. S.;
Protschuk, G. Angew. Chem., Int. Ed. Engl. 1977, 16,
321; (b) Ono, N.; Yanai, T.; Hamamoto, I.; Kamimura,
A.; Kaji, A. J. Org. Chem. 1985, 50, 2806; (c) Ballini, R.;
Rinaldi, A. Tetrahedron Lett. 1994, 35, 9247; (d) Ballini,
R.; Bosica, G. Tetrahedron 1995, 51, 4213; (e) Ballini, R.;
Barboni, L.; Bosica, G. J. Org. Chem. 2000, 65, 6261; (f)
Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.; Petrini, M.
Org. Lett. 2001, 3, 1265; (g) Ballini, R.; Fiorini, D.; Gil,
M. V.; Palmieri, A. Tetrahedron Lett. 2003, 44, 9033.
5. (a) Benetti, S.; Romagnoli, R.; De Risi, C.; Spallato, G.;
Zanirato, V. Chem. Rev. 1995, 95, 1065; (b) Sartori, G.;
Bigi, F.; Canali, G.; Casnati, G.; Tao, X. J. Org. Chem.
1993, 58, 840; (c) Landi, J. J.; Garofano, L. M.; Ramig, K.
Tetrahedron Lett. 1993, 34, 277; (d) Smith, X.; Mazzola, E.
P.; Sims, J. J.; Midland, S. L.; Keen, N. T.; Burton, V.;
Staytan, M. M. Tetrahedron Lett. 1993, 34, 223; (e)
Brehm, L.; Johansen, J. S.; Larsen, P. K. J. Chem. Soc.,
Perkin Trans. 1 1992, 2059; (f) Zhang, J.; Curran, D. P. J.
Chem. Soc., Perkin Trans. 1 1991, 1137; (g) Willims, M.
A.; Hsiao, C. N.; Miller, M. J. J. Org. Chem. 1991, 56,
2690; (h) Curran, D. P.; Morgan, T. M.; Schwartz, C. E.;
Snider, B. B. J. Am. Chem. Soc. 1981, 113, 6607.
J = 7.3Hz), 3.45, (s, 2H), 3.84 (s, 2H), 4.17 (q, 2H,
J = 7.0Hz), 7.20–7.36 (m, 5H); 13C NMR (CDCl3):
d = 14.2, 48.4, 50.1, 61.5 127.4, 129.0, 129.7, 133.2,
167.4, 200.2; EI-MS (70 ev) m/z: 39, 41, 43, 55, 65, 69,
77, 87, 91 (100), 115, 118, 131, 206; Anal. Calcd for
C12H14O3 (206.24) C, 69.89; H, 6.84. Found C, 70.08; H,
7.01.
19. Sample procedure (Table 1, compound 6k): To an
ethanolic solution (14mL) of b-nitro acrylic ester 4k
(0.490g, 2mmol) maintained at 0ꢁC, was slowly added
NaBH4 (4.4mmol). The reaction mixture was first stirred
at 0ꢁC for 15min, then refluxed for 45min. The reaction
mixture was quenched with 1N HCl (12mL) and extracted
with CH2Cl2 (4 · 30mL). The combined organic layers
were dried on Na2SO4, evaporated and the crude product
purified by flash chromatography (hexane–ethyl acetate)
giving 0.284g (71%) of the pure compound 6k: oil; IR
(neat): m = 1243, 1722, 1739cmÀ1 1H NMR (CDCl3):
;
d = 1.21 (t, 3H, J = 7.0Hz), 1.77–1.93 (m, 2H), 2.00 (s,
3H), 2.24 (dq, 2H, J = 7.0, 1.5Hz), 4.06–4.20 (m, 4H), 5.80
(dt, 1H, J = 15.6, 1.5Hz), 6.90 (dt, 1H, J = 15.6, 7.0Hz);
13C NMR (CDCl3): d = 14.4, 21.0, 27.1, 28.7, 60.6, 63.6,
122.16, 147.7, 166.6, 171.1; EI-MS (70 ev) m/z: 29, 43, 55,
71 (100), 87, 113, 130, 158; Anal. Calcd for C10H16O4
(200.23) C, 59.99; H, 8.05. Found C, 60.21; H, 7.81.
6. Hauser, C. R.; Hudson, B. E., Jr. Org. React. 1947, 1, 266.
7. (a) Schaefer, J.; Bloomfield, J. Org. React. 1967, 15, 1; (b)
Rathe, M. Org. React. 1975, 22, 423; (c) Barhdadi, R.;