Synthesis of 3-alkyl-2,5-dimethylfuran derivatives by indirect alkylation of 2,5-dimethylfuran with aliphatic nitrocompounds

Article abstract of DOI:10.1055/s-2001-17714

The preparation of 3-alkyl-2,5-dimethylfuranes via indirect alkylation of 2,5-dimethylfuran is reported. Thus, primary nitroalkanes react with cis-3-hexen-2,5-dione giving a tandem Michael addition/elimination of nitrous acid, followed by chemoselective hydrogenation of the C=C double bond of the obtained enones. The Paal-Knorr reaction, performed with p-toluenesulfonic acid in diethyl ether, completes the formation of the title compounds. In this context the nitroalkane can be considered as an alkyl cation synthon.

Full text of DOI:10.1055/s-2001-17714

PAPER
2003
Synthesis of 3-Alkyl-2,5-dimethylfuran Derivatives by Indirect Alkylation of
2,5-Dimethylfuran with Aliphatic Nitrocompounds
Indirect
A
lkylatio
o
n of 2,5-Dim
b
ethylfuran w
e
ith Alipha
r
tic Nitro
t
c
ompou
o
nds Ballini,* Giovanna Bosica, Dennis Fiorini, Guido Giarlo
Dipartimento di Scienze Chimiche dell'Università, Via S. Agostino 1, 62032 Camerino (MC), Italy
Fax +39(737)637345; E-mail: ballini@camserv.unicam.it
Received 20 June 2001; revised 27 July 2001
Abstract: The preparation of 3-alkyl-2,5-dimethylfuranes via indi-
rect alkylation of 2,5-dimethylfuran is reported. Thus, primary ni-
O
1
troalkanes react with cis-3-hexen-2,5-dione giving a tandem
Michael addition/elimination of nitrous acid, followed by chemose-
lective hydrogenation of the C=C double bond of the obtained
enones. The Paal–Knorr reaction, performed with p-toluenesulfonic
acid in diethyl ether, completes the formation of the title com-
pounds. In this context the nitroalkane can be considered as an alkyl
cation synthon.
Magnesium
monoperoxyphtalate
95%, Ref. 8
NO2
O
O
3
R
Key words: furan, nitroalkanes, Michael reaction, heterocycliza-
(-HNO2)
tion
O
R
DBU
CH3CN
r.t.
4
2
O
H2, 10% Pd/C
45 psi
65-93% from 2
By far the most heavily exploited of monocyclic heteroat-
omic system is the furan ring. Furans and their derivatives
are very useful as starting materials in the production of
industrially important compounds.1 It is also well-known
that furans are used in acid-catalyzed hydrolysis, auto-ox-
idation, Diels–Alder reaction, photocyclization, hydroge-
nation, substitution and so on.1,2
O
R
TsOH
Et2O
O
O
R
60-94%
In particular, polysubstituted furans play an important role
in organic chemistry due to their presence as key structur-
al units in many natural products3 and in important phar-
maceuticals.4 For this reason, the syntheses of
polysubstituted furans, especially the 2,3,5-trisubstituted
ones, which are reported to be of particular interest,5 con-
tinue to attract the interest of many synthetic chemists,
Herein, we wish to report a new procedure for the prepa-
ration of 3-alkyl-2,5-dimethylfuran by the indirect alkyla-
tion of 2,5-dimethylfuran.
6
5
Scheme
yield) from 2,5-dimethylfuran (1).9 The reaction of the di-
enone 2 with primary nitroalkanes 3, in acetonitrile with
DBU as base, proceeded in a tandem process, in which a
Michael addition was immediately followed by elimina-
tion of nitrous acid, thus giving the corresponding conju-
gated enone derivatives
4 in good yields. The
Nitroalkanes are well known as useful nucleophilic mole-
cules and often they can be employed as alkyl anion syn-
thons.6 Recently, we have reported a new methodology
through which, starting from unsaturated 1,4-diester and
nitroalkanes, the nitro group may simultaneously behave
both as an electron-withdrawing group and leaving group7
and this behavior has been applied for the preparation of
different targets.8 Following these results, we planned to
prepare the title compounds using 2,5-dimethylfuran and
nitroalkanes (Scheme).
chemoselective hydrogenation of the C=C double bond of
compounds 4 produced 3-alkylhexan-2,5-diones 5, which
were then converted to the title compounds 6 (Tables 1–
3).
The acid-catalyzed synthesis of furans from 1,4-diketones
has been known for more than a century,10 however, the
heterocyclization of the hexane-2,5-dione required the
continuous removal of the produced furan,11 or harsh re-
action conditions.12 After investigation of the most pow-
erful conditions for conversion of the 3-alkylated hexane-
2,5-diones 5 into the furan derivatives 6, we found that
this cyclization can be easily accomplished using half
equivalent of p-toluenesulfonic acid in refluxing diethyl
ether (Scheme).
It is well known that the oxidative cleavage of furans al-
lows the formation of conjugated 2-en-1,4-diones, thus,
cis-3-hexen-2,5-dione (2) can be easily obtained (97%
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
1437-210X,E;2001,0,13,2003,2006,ftx,en;Z06501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
In conclusion, the present methodology represents an al-
ternative procedure for the title compounds. Moreover, it
is important to point out that other functionalities, such as

2004
R. Ballini et al.
PAPER
Table 1 1,4-Dicarbonyl Derivatives 5 and 3-Alkyl-2,5-dimethyl-
furans 6 Prepared
nitroalkanes 3 as an (indirect) alkylating species of an ar-
omatic ring is the first report in which they are used as
alkyl cation synthons a (Figure).
Products
R
Yield (%)a Yield (%)a
5, 6
of 5
from 2
of 6 (reaction
time, h)
NO2
CH2
a
b
c
d
e
f
CH3(CH2)3
88
90
70
85
78 (8)
R
R
a
MeO2C(CH2)2
MeO2C(CH2)10
CH3(CH2)8
95 (25)
85 (7)
3
Figure
94 (10)
88 (14)
77 (8)
We believe that this procedure represents a progressive
evolution of the practical utilization of functionalized ni-
troalkanes as strategic tools in organic synthesis, not only
as a synthetic equivalent of carbanions6 but, now, also as
a synthetic equivalent of carbocations.
MeO2C(CH2)2CH(t-Bu)CH2 80
HOCH2(CH2)4
CH3(CH2)9
CH3CO(CH2)2
Ph
75
90
80
74
60
g
h
i
86 (12)
60 (12)
75 (14)
90 (15)
1H NMR spectra were recorded in CDCl3 at 200 MHz on a Varian
Gemini instrument; J values are given in Hz. IR spectra were re-
corded with a Perkin Elmer 257 spectrophotometer. Mass spectra
were determined on a capillary GC/MS operating in the split mode
with He carrier gas and fitted with a mass-selective detector (MDS).
The reactions were monitored by TLC, or GC performed on a Carlo
Erba Fractovap 4160 using a capillary column of Duran Glass, sta-
tionary phase OV1. Microanalyses were performed using a Fisons
model EA 1108. The products were purified by flash chromatogra-
phy on Merck silica gel with EtOAc–petroleum ether as eluent.
j
PhCH2
a Isolated yield.
ester, keto, hydroxyl and aromatic rings (6i,j), which are
difficult to introduce onto furans by other means,1,2,5 can
be easily introduced by simply choosing the appropriate
starting nitroalkane. Additionally, this new exploitation of
Table 2 Spectroscopic Data for 1,4-Dicarbonyl Derivatives 5a–j
Product
5a
IR(film) 1H NMR (CDCl3) (ppm), J (Hz)
MS: m/z (%)
(cm–1)
1712
0.88 (t, 3 H, J = 7.0), 1.20–1.30 (m, 6 H), 1.50–1.60 (m, 2 H), 2.14 (s, 3 H), 2.24 (s, 141, 127, 114, 100, 85, 71, 59,
3 H), 2.43 (d, 1 H, J = 14.5), 2.90 (d, 1 H, J = 10.0), 3.00–3.10 (m, 1 H) 55, 43 (100)
5b
1710
1705
1.50–1.60 (m, 4 H), 2.15 (s, 3 H), 2.25 (s, 3 H), 2.32 (t, 2 H, J = 6.7), 2.45 (d, 1 H, 214 (M+), 196, 181, 172, 157,
J = 14.3), 2.92 (d, 1 H, J = 9.8), 3.00–3.10 (m, 1 H), 3.67 (s, 3 H) 137, 114, 97 (100), 71, 43
5c
1712
1706
1.20–1.30 (m, 20 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 2.30 (t, 2 H, J = 7.4), 2.42 (d, 1 H, 326 (M+), 308, 269, 114, 97, 71,
J = 14.4), 2.90 (d, 1 H, J = 9.9), 3.00–3.10 (m, 1 H), 3.68 (s,3H) 43 (100)
5d
1712
0.88 (t, 3 H, J = 6.5), 1.20–1.40 (m, 18 H), 2.14 (s, 3 H), 2.24 (s, 3 H), 2.42 (d, 1 H, 254 (M+), 239, 221, 211, 197,
J = 14.4), 2.90 (d, 1 H, J = 10.0), 3.00–3.10 (m, 1 H)
169, 141, 128, 114, 85, 71, 43
(100)
5ea
5f
1712
1708
0.85 (s, 9 H), 1.20–1.70 (m, 7 H), 2.15 (s, 3 H), 2.25 (s, 3 H), 2.40 (t, 2 H, J = 13.8), 298 (M+), 280, 241, 114, 97, 71,
2.46 (d, 1 H, J = 14.2), 2.91 (d, 1 H, J = 9.4), 3.00–3.10 (m, 1 H), 3.67 (s, 3H) 57, 43 (100)
3410
1708
1.20–1.60 (m, 10 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 2.41 (d, 1 H, J = 14.0), 2.89 (d, 1 214 (M+), 196, 171, 157, 139,
H, J = 10.0), 2.90–3.00 (m, 1 H), 3.64 (t, 2 H, J = 6.5) 128, 114, 71, 43 (100)
5g
5h
5i
1712
1715
1708
1710
0.88 (t, 3 H, J = 6.5), 1.20–1.30 (m, 20 H), 2.14 (s, 3 H), 2.24 (s, 3 H), 2.42 (d, 1 H, 268 (M+), 250, 225, 211, 183,
J = 14.4), 2.90 (d, 1 H, J = 9.6), 3.00–3.10 (m, 1 H) 141, 128, 114 (100), 85, 71, 43
1.40–1.60 (m, 4 H), 2.13 (s, 3 H), 2.14 (s, 3 H), 2.24 (s, 3 H), 2.42 (t, 2 H, J = 4.7), 180, 155, 141, 128, 123, 114,
2.48 (d, 1 H, J = 14.0), 2.90 (d, 1 H, J = 9.9), 2.90–3.10 (m, 1 H) 95, 85, 71 (100), 43
2.08 (s, 3 H), 2.13 (s, 3 H), 2.30–2.60 (m, 2 H), 2.80–3.30 (m, 2 H), 3.20–3.40 (m, 204, 186, 171, 161, 147 (100),
1 H), 7.10–7.70 (m, 5 H) 91, 71, 43
5j
1.60–1.80 (m, 1 H), 1.80–2.00 (m, 1 H), 2.15 (s, 3 H), 2.24 (s, 3 H), 2.40–2.60 (m, 200, 185, 175, 129, 114 (100),
3 H), 2.90–3.20 (m, 2 H), 7.10–7.40 (m, 5 H) 91, 77, 71, 43
a Diastereomeric mixture.
Synthesis 2001, No. 13, 2003–2006 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Indirect Alkylation of 2,5-Dimethylfuran with Aliphatic Nitrocompounds
2005
Table 3 Spectroscopic Data for 3-Alkyl-2,5-dimethylfuranes 6a–j
1H NMR (CDCl3) ppm, J (Hz) 13C NMR (CDCl3) ppm
Product IR
MS: m/z (%)
(film)
(cm–1)
–
6a
6b
6c
0.89 (t, 3 H, J = 7.8), 1.20–1.40 (m, 6 149.44, 145.12, 119.71, 107.95, 31.35, 29.01,
H), 2.15 (s, 3 H), 2.22 (s, 3 H), 2.24 (t, 25.25, 22.45, 14.02, 11.92, 11.70
2 H, J = 8.8), 5.78 (s, 1 H)
166 (M+), 151, 137, 123,
109 (100), 95, 43
1708
1708
1.80 (m, 2 H, J = 14.0), 2.15 (s, 3 H), 174.56, 149.71, 145.94, 118.87, 107.68, 51.95, 196 (M+), 181, 165, 147,
2.21 (s, 3 H), 2.20–2.30 (m, 4 H), 3.65 33.77, 25.77, 24.48, 13.92, 11.77
(s, 3 H), 5.75 (s, 1 H)
135, 122, 109 (100), 103,
95, 43
1.20–1.40 (m, 18 H), 2.15 (s, 3 H),
2.21 (s, 3 H), 2.20–2.40 (m, 4 H), 3.67 34.60, 34.05, 30.18, 29.96, 29.91, 29.77, 29.72, 235, 221, 207, 193, 179,
174.84, 149.37, 145.41, 120.22, 107.88, 51.92, 308 (M+), 293, 277, 249,
(s, 3 H), 5.77 (s, 1 H)
29.54, 25.44, 25.30, 25.19, 13.94, 11.81
165, 151, 123, 110 (100),
95, 59
6d
6e
6f
–
0.88 (t, 3 H, J = 6.5), 1.20–1.30 (m, 16 149.37, 145.40, 120.24, 107.88, 32.39, 30.94,
H), 2.16 (s, 3 H), 2.21 (s, 3 H), 2.24 (t, 30.12, 29.98, 29.80, 25.31, 23.17, 14.59, 13.94, 179, 165, 151, 137, 123,
2 H, J = 7.4), 5.77 (s, 1 H) 11.81 110 (100), 95, 43
236 (M+), 221, 207, 193,
1708
3368
–
0.88 (s, 9 H), 1.20–1.40 (m, 5 H), 2.16 175.10, 149.59, 145.34, 120.20, 107.73, 51.97, 280 (M+), 265, 249, 223,
(s, 3 H), 2.22 (s, 3 H), 2.30–2.40 (m, 4 34.57, 33.56, 32.47, 28.31, 28.15, 27.05, 25.80, 123, 109 (100), 95, 57, 43
H), 3.67 (s, 3 H), 5.78 (s, 1 H)
13.93, 11.88
1.30–1.40 (m, 8 H), 2.15 (s, 3 H), 2.21 149.45, 145.45, 120.05, 107.83, 63.50, 33.23,
(s, 3 H), 2.25 (t, 2 H, J = 7.0), 3.64 (t, 30.88, 29.52, 26.08, 25.23, 13.96, 11.83
2 H, J = 6.5), 5.77 (s, 1 H)
196 (M+), 181, 165, 123,
109 (100), 95, 85, 71, 43
6g
6h
6i
0.88 (t, 3 H, J = 6.3), 1.20–1.40 (m, 18 149.37, 145.39, 120.24, 107.89, 32.41, 30.96,
H), 2.15 (s, 3 H), 2.22 (s, 3 H), 2.25 (t, 30.14, 30.00, 29.84, 29.79, 25.32, 23.19, 14.61, 193, 179, 165, 151, 123,
2 H, J = 7.2), 5.75 (s, 1 H) 13.94, 11.81 110 (100), 95, 43
250 (M+), 235, 221, 207,
1718
–
1.76 (m, 2 H), 2.12 (s, 3 H), 2.15 (s, 3 209.43, 149.72, 145.85, 119.09, 107.67, 43.31, 180 (M+), 162, 147, 137,
H), 2.21 (s, 3 H), 2.28 (t, 2 H, J = 7.3), 30.39, 24.77, 24.50, 13.92, 11.78
2.41 (t, 2 H, J = 13.0), 5.75 (s, 1 H)
122 (100), 109, 95, 71, 57,
43
2.20 (s, 3 H), 2.22 (s, 3 H), 3.64 (s, 2 149.35, 149.32, 145.65, 141.15, 128.37, 128.35, 186 ( M+ 100), 171, 153,
H), 5.71 (s, 1 H), 7.10–7.30 (m, 5 H) 128.33, 125.89, 118.30, 107.80, 31.21, 29.72,
13.48
143, 128, 109, 95, 91, 77,
57, 43
6j
–
2.05 (s, 3 H), 2.25 (s, 3 H), 2.50–2.70 149.57, 145.91, 142.51, 128.99, 128.77, 126.35, 200 (M+), 109 (100), 91, 77,
(m, 2 H), 2.70–2.90 (m, 2 H), 5.81 (s, 119.28, 118.87, 107.78, 37.36, 27.59, 14.00, 43
1 H), 7.20–7.40 (m, 5 H) 11.67
Acknowledgement
Saturated 1,4-Dicarbonyl Derivatives (5); General Procedure
To a solution of nitroalkane 3 (15 mmol) and cis-3-hexen-2,5-dione
(2, 1.68 g, 15 mmol), in CH3CN (100 mL), DBU (2.28 g, 15 mmol)
was added at r.t. The solution was then stirred for 6 h and evaporat-
ed. The crude residue was dissolved in CH2Cl2, washed with 2 N
HCl (2 20 mL), dried (Na2SO4), passed through a bed of Celite
and evaporated. To the obtained product 4, EtOAc (150 mL) and
10% Pd/C (0.3 g) were added and the suspension was hydrogenated
(40 psi) at r.t. for 6 h. The catalyst was removed by filtration through
a Celite pad and washed with EtOAc (3 20 mL). After evapora-
tion of the solvent, the crude product was purified by flash chroma-
tography (EtOAc–petroleum ether) giving the pure product 5.
This work was carried out in the framework of the National Project
'Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni'
supported by Ministero dell'Università e della Ricerca Scientifica e
Tecnologica, Rome-Italy and by Fondazione della Cassa di Rispar-
mio della Provincia di Macerata-Italy.
References
(1) Bosshard, P.; Eugster, C. H. In Advances in Heterocyclic
Chemistry, Vol. 7; Katritzky, A. R.; Boulton, A. J., Eds.;
Academic Press: New York, 1966, 377–488.
(2) (a) Livingstone, R. In Rodd’s Chemistry of Carbon
Compounds, Part A, Vol. IV; Coffey, S., Ed.; Elsevier:
Amsterdam, 1973, 83–217. (b) Dean, F. M. In Advances in
Hetrocyclic Chemistry, Part I, Vol. 30; Katritzky, A. R., Ed.;
Academic Press: New York, 1982, 167–238. (c) Acheson,
R. M. An Introduction to the Chemistry of Heterocyclic
Compounds; Wiley: Toronto, 1976.
3-Alkyl-2,5-dimethylfuran Derivatives (6); General Procedure
p-Toluensulfonic acid (0.43 g, 2.5 mmol) was added to a solution of
3-alkylatedhexane-2,5-dione 5 (5 mmol) in Et2O (40 mL). The so-
lution was refluxed for the appropriate time (see Table 1), then
washed with H2O (2 10 mL), dried (Na2SO4), evaporated and pu-
rified by flash chromatography.
(3) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
Synthesis 2001, No. 13, 2003–2006 ISSN 0039-7881 © Thieme Stuttgart · New York

2006
R. Ballini et al.
PAPER
Org. Chem. 1999, 64, 2954. (d) Ballini, R.; Bosica, G.;
Masè, A.; Petrini, M. Eur. J. Org. Chem. 2000, 2927, and
references cited therein.
(4) Nakanishi, K. Natural Products Chemistry; Kodansha Ltd:
Tokyo, 1974.
(5) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo,
T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54,
1955. (b) Aurrecoechea, J. M.; Pèrez, E.; Solay, M. J. Org.
Chem. 2001, 66, 564.
(6) Rosini, G.; Ballini, R. Synthesis 1988, 833.
(7) Ballini, R.; Rinaldi, A. Tetrahedron Lett. 1994, 35, 9247.
(8) (a) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213.
(b) Ballini, R.; Bosica, G.; Petrelli, L.; Petrini, M. Synthesis
1999, 1236. (c) Ballini, R.; Marcantoni, E.; Perella, S. J.
(9) Dominguez, C.; Czàky, A. G.; Plumet, J. Tetrahedron Lett.
1990, 31, 7669.
(10) Friedrichsen, W. In Furans and their Benzo Derivatives,
Vol. 2; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Elsevier Science Ltd: Oxford, 1996, 352.
(11) Scott, L. T.; Naples, J. O. Synthesis 1973, 209.
(12) Traynelis, V. J.; Hergenrother, W. I.; Hanson, H. T.;
Valicenti, J. A. J. Org. Chem. 1964, 29, 123.
Synthesis 2001, No. 13, 2003–2006 ISSN 0039-7881 © Thieme Stuttgart · New York