Nitroalkanes as a New, Convenient Source of 1-Acyl-2,5-dialkylbenzene Derivatives, in Two Steps

Full text of DOI:10.1021/jo0006324

J . Org. Chem. 2000, 65, 6261-6263
6261
simple and practical synthesis of 1-acyl-2,5-dialkylben-
zene derivatives in two steps.
Nitr oa lk a n es a s a New , Con ven ien t Sou r ce
of 1-Acyl-2,5-d ia lk ylben zen e Der iva tives, in
Tw o Step s
Resu lts a n d Discu ssion
Roberto Ballini,* Luciano Barboni, and Giovanna Bosica
The first step of our procedure was the double Michael
addition, in aqueous medium, of the nitroalkanes 1 to
the enones 2, followed by in situ intramolecular aldol
reaction of the adducts 3 (Scheme 1). The cyclohexanols
4 were obtained in 70-95% yield as a diastereomeric
mixture. After workup, the compounds 4 and a stoichio-
metric amount of TsOH were dissolved in toluene and
refluxed with a Dean-Stark apparatus, with the simul-
taneous injection of air. Thus, the aromatic compounds
7 were obtained directly in 50-80% yield. The conversion
of 4 to 7 proceeds initially through the elimination of both
water (compounds 5) and nitrous acid, leading to the
compounds 6, which convert, by air oxidation, to the
aromatic systems 7. The formation of the intermediates
5 and 6 was detected by GC-MS during the reaction.
It is important to point out that since the acetyl
derivatives 7 (R1 ) Me) can be easily converted into
phenols (Baeyer-Villiger rearrangement)9 or carboxylic
acids (haloform reaction),10 they are potential precursors
of 2,5-dialkylphenols and 2,5-dialkylbenzoic acids, both
important targets widely used for industrial11 and phar-
maceutical applications.12,13
Our procedure allows the preparation of aromatic
systems from open-chain compounds in satisfactory to
good yields (Table 1). Moreover, several advantages can
be seen in this approach, such as the preparation of
trisubstituted compounds in only two steps and the
avoidance of ortho-meta-para mixture formation com-
mon in conventional aromatic synthesis. In fact, our
method appears as a regiodefined synthesis of 1-acyl-2,5-
dialkylbenzenes very difficult to prepare by electrophilic
substitution of benzenes. These compounds were usually
prepared from 1,4-disubstituted benzenes, and while the
acylation of symmetric 1,4-dialkylbenzenes does not
present complications14 of regioselectivity, more prob-
lematic is the acylation of nonsymmetric 1,4-dialkylben-
zenes.15 Moreover, in our method the appropriate choice
Dipartimento di Scienze Chimiche dell’Universita`, Via S.
Agostino n. 1, 62032 Camerino, Italy
ballini@camserv.unicam.it
Received April 25, 2000
In tr od u ction
Nitroalkanes have proved to be valuable intermedi-
ates.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-carbon
single bonds, via the nitronate3 and, in specific cases, the
creation of carbon-carbon double bonds through the
elimination of nitrous acid.4 Recently, we disclosed that
nitroalkanes exhibit a remarkable reactivity in water,5
in particular their conjugate addition to electron-deficient
alkenes.5a,c On the basis of these considerations, we have
found that nitroalkanes can be conveniently used as
building blocks to produce aromatic systems.
Aromatization of acyclic precursors is undoubtedly a
useful reaction in the synthesis of highly substituted
aromatic rings,6 and although several methods to obtain
aromatic compounds are known,7 to the best of our
knowledge the use of nitroalkanes in the synthesis of
substituted benzenes has not been reported.8 The nu-
cleophilicity of nitroalkanes and the ability of the nitro-
functionality to act as a leaving group4 make possible a
(1) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
31, 1-18. (b) Rosini, G.; Ballini, R. Synthesis 1988, 833-847. (c) Ballini,
R. Synlett 1999, 1009-1018.
(2) (a) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573-1590. (b)
Ballini, R. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1997; Vol. 19, pp 117-184.
(3) (a) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 321-340. (b) Ballini,
R.; Marziali, P.; Mozzicafreddo, A. J . Org. Chem. 1996, 61, 3209-3211
and references cited therein.
(4) See for example: (a) Seebach, D.; Hoekstra, M. S.; Protschuk,
G. Angew. Chem., Int. Ed. Engl. 1977, 16, 321-322. (b) Ono, N.; Yanai,
T.; Hamamoto, I.; Kamimura, A.; Kaji, A. J . Org. Chem. 1985, 50,
2806-2807. (c) Kitahara, T.; Mori, K. Tetrahedron 1984, 40, 2935-
2944. (d) Yamashita, M.; Tamada, Y.; Iida, A.; Oshikawa, T. Synthesis
1990, 420-422. (e) Ballini, R.; Rinaldi, A. Tetrahedron Lett. 1994, 35,
9247-9250. (f) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213-
4222. (g) Kostova, K.; Hesse, M. Helv. Chim. Acta 1995, 78, 440-446.
(h) Vanelle, P.; Terme, T.; Maldonado, J .; Crozet, M. P.; Giraud, L.
Synlett 1998, 1067-1068. (h) Ka´lai, T.; J eko¨, M. J .; Hideg, K. Synthesis
1999, 973-980. (i) Areces, P.; Gil, M. V.; Higes, F. J .; Roma´n, E.;
Serrano, J . A. Tetrahedron Lett. 1998, 39, 8557-8560. (j) Fumoto, Y.;
Eguchi, T.; Uno, H.; Ono, N. J . Org. Chem. 1999, 64, 6518-6521.
(5) (a) Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 37, 8027-8030.
(b) Ballini, R.; Bosica, G. J . Org. Chem. 1997, 62, 425-427. (c) Ballini,
R.; Bosica, G. Eur. J . Org. Chem. 1998, 355-357. (d) Ballini, R.; Papa,
F.; Abate, C. Eur. J . Org. Chem. 1999, 87-90.
(9) (a) McKillop, A.; Tarbin, J . A. Tetrahedron 1987, 43, 1753-1758.
(b) Token, K.; Hirano, K.; Yokoyama, T.; Goto, K. Bull. Chem. Soc.
J pn. 1991, 64, 2766-2771. (c) Pande, C. S.; J ain, N. Synth. Commun.
1989, 19, 1271-1279. (d) Koch, S. S. C.; Chamberlin, A. R. Synth.
Commun. 1989, 19, 829-833. (e) Fringuelli, F.; Germani, R.; Pizzo,
F.; Savelli, G. Gazz. Chim. Ital. 1989, 119, 249. (f) Fermin, M. C.;
Bruno, J . W. Tetrahedron Lett. 1993, 34, 7545-7548.
(10) (a) Neudeck, H. M. Monatsh. Chem. 1996, 127, 185-200. (b)
Madler, M. M.; Klucik, J .; Soell, P. S.; Brown, C. W.; Liu, S.; Berlin,
K. D.; Benbrook, D. M.; Birckbichler, P. J .; Nelson, E. C. Org. Prep.
Proced. Int. 1998, 30, 230-234. (c) Kajigaeshi, S.; Nakagawa, T.;
Nagasaki, N.; Fujisaki, S. Synthesis 1985, 674-675.
(11) (a) Tsukise, B.; Sakamoto, H. J pn. Kokai Tokkyo Koho J P 11,-
130,712, 1999; Chem. Abstr. 1999, 131, 5091. (b) Ichikawa, K.; Ozaki,
H. J pn. Kokai Tokkyo Koho J P 09,110,757; Chem. Abstr. 1997, 127,
33979.
(12) Liao, Y.; Wang, B. Bioorg. Med. Chem. Lett. 1999, 1795-1800.
(13) Melnick, M.; Reich, S. H.; Lewis, K. K.; Mitchell, L. J ., J r.;
Nguyen, D.; Trippe, A. J .; Dawson, H.; Davies, J . F., II; Appelt, K.;
Wu, B.-W.; Musik, L.; Gehlhaar, D. K.; Webber, S.; Shetty, B.; Kosa,
M.; Kahil, D.; Andrada, D. J . Med. Chem. 1996, 39, 2795-2811.
(14) (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett.
1995, 36, 409-412. (b) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull.
Chem. Soc. J pn. 1995, 68, 2053-2056. (c) Kawada, A.; Mitamura, S.;
Kobayashi, S. J . Chem. Soc., Chem. Commun. 1996, 183-184.
(15) Taylor, E. P.; Watts, G. E. J . Chem. Soc. 1952, 1123-1127.
(6) Gordon, P. F. Chem. Soc. Rev. 1984, 441-488.
(7) Larock, R. C. Comprehensive Organic Transformations, 2nd Ed.;
Wiley-VCH: New York, 1999; pp 187-213.
(8) Only the formation of nitrobenzenes via reaction of pyrylium
salts with nitromethane has previously been reported: (a) Dimroth,
K. Angew. Chem. 1960, 72, 331-342. (b) Dimroth, K.; Wolf, K. H.
Newer Methods Prep. Org. Chem. 1964, 3, 357-423.
10.1021/jo0006324 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

6262 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
Sch em e 1a
was cooled with an ice bath and the conjugated enone 2 (0.42 g,
5 mmol) was added. After the resulting solution was stirred at
the appropriate temperature (rt or 60 °C, Table 1) for 24 h, the
aqueous medium was extracted with Et2O (3 × 15 mL) and the
organic phase was dried (MgSO4). After flash chromatography
purification, the diastereomeric mixture 4 was dissolved in 20
mL of toluene, TsOH (2 mmol) was added, and the reaction
mixture was refluxed for the appropriate time (3-15 h, Table
1) with a Dean-Stark apparatus, with the simultaneous injec-
tion of air. The solvent was then removed under reduced
pressure and the residue dissolved in EtOAc and water. After
separation of the organic layer, the aqueous solution was
extracted three times with EtOAc, and the combined organic
solvents were dried (Na2SO4) and removed under reduced
pressure. The crude product was chromatographed on silica gel
using EtOAc/n-hexane (49:1) as eluent.
Da ta for 1-(2,5-Dim eth ylp h en yl)-1-eth a n on e (7a ):18 yel-
low oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 2.35 (s, 3H), 2.46
(s, 3H), 2.55 (s, 3H), 7.11 (d, 3J (H,H) ) 7.8 Hz, 1H), 7.15 (dd,
3J (H,H) ) 7.8, 4J (H,H) ) 1.5 Hz, 1H), 7.47 (d, 4J (H,H) ) 1.5
Hz, 1H); IR (neat) ν ) 1682; MS (70 eV) m/z 148 [M+], 133 [M+
- CH3] (100). Anal. Calcd for C10H12O: C, 81.04; H, 8.16.
Found: C, 79.90; H, 8.24.
Da ta for 1-(5-Eth yl-2-m eth ylp h en yl)-1-eth a n on e (7b):19
a
Conditions: (a) K2CO3, water, rt to -60 °C, 24 h, 70-95%; (b)
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 1.23 (t, 3J (H,H)
PhMe, reflux, air, 3-15 h, -H2O; (c) -HNO2; (d) -H2, 50-80%
from 4.
3
) 7.6 Hz, 3H), 2.46 (s, 3H), 2.56 (s, 3H), 2.64 (q, J (H,H) ) 7.6
Hz, 2H), 7.13 (d, 3J (H,H) ) 7.6 Hz, 1H), 7.20 (br d, 3J (H,H) )
7.6 Hz, 1H), 7.48 (br s, 1H); 13C NMR (75.4 MHz, CDCl3, 20 °C)
δ ) 15.62, 21.11, 28.35, 29.60, 128.75, 131.02, 132.01, 135.43,
137.74, 141.63, 202.02; IR (neat) ν ) 1682; MS (70 eV) m/z 162
[M+], 147 [M+ - CH3] (100). Anal. Calcd for C11H14O: C, 81.44;
H, 8.70. Found: C, 81.58; H, 8.74.
Ta ble 1. Syn th esis of Ar om a tic Der iva tives 7
yield (%) of
4 from 1
yield (%) of
7 from 4
R
R1
a
b
c
d
e
f
Me
Et
n-Pr
n-Bu
n-C5H11
i-Pr
Me
Me
Me
Me
Me
Me
Me
Et
90a
85a
93a
95b
95b
75b
70b
77b
53c
55c
65c
72c
61c
50c
80d
50c
Da ta for 1-(2-Meth yl-5-p r op ylp h en yl)-1-eth a n on e (7c):
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 0.93 (t,
19
3J (H,H) ) 7.3 Hz, 3H), 1.63 (m, 2H), 2.47 (s, 3H), 2.57 (s, 3H),
2.58 (t, 3J (H,H) ) 7.3 Hz, 2H), 7.13 (d, 3J (H,H) ) 7.8 Hz, 1H),
3
4
7.18 (dd, J (H,H) ) 7.8, J (H,H) ) 1.7 Hz, 1H), 7.46 (d, 4J (H,H)
) 1.7 Hz, 1H); 13C NMR (75.4 MHz, CDCl3, 20 °C) δ ) 13.73,
21.11, 24.56, 29.57, 37.43, 129.33, 131.59, 131.91, 135.46, 137.65,
140.06, 202.01; IR (neat) ν ) 1683; MS (70 eV) m/z 176 [M+],
161 [M+ - CH3] (100). Anal. Calcd for C12H16O: C, 81.77; H,
9.15. Found: C, 81.68; H, 9.24.
g
h
Ph
Me
a
b
Reaction performed at rt. Reaction performed at 60 °C.
c Reaction time 15 h. c Reaction time 3 h.
Da ta for 1-(5-Bu tyl-2-m eth ylp h en yl)-1-eth a n on e (7d ):
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 0.94 (t, 3J (H,H)
) 7.2 Hz, 3H), 1.38 (m, 4H), 1.61 (m, 2H), 2.49 (s, 3H), 2.58 (s,
3H), 2.62 (t, 3J (H,H) ) 7.5 Hz, 2H), 7.14 (d, 3J (H,H) ) 7.8 Hz,
1H), 7.20 (dd, 3J (H,H) ) 7.8, 4J (H,H) ) 1.8 Hz, 1H), 7.49 (d,
4J (H,H) ) 1.8 Hz, 1H); 13C NMR (50 MHz, CDCl3, 20 °C) δ )
14.42, 21.61, 22.80, 30.07, 34.13, 35.59, 129.79, 132.06, 132.41,
135.90, 138.14, 140.77, 202.49; IR (neat) ν ) 1684; MS (70 eV)
m/z 190 [M+], 175 [M+ - CH3] (100). Anal. Calcd for C13H18O:
C, 82.05; H, 9.53. Found: C, 81.94; H, 9.64.
of the starting nitroalkane and/or the alkyl vinyl ketone
offers the opportunity to predict the relative positions of
the substituents. Finally, the reported synthesis permits
the insertion of several n-alkyl groups without the
isomerization problems typical of the classical Friedel-
Crafts alkylation. It should be noted that the synthesis
of substituted biphenyls (compound 7g) can also be
accomplished.
Da ta for 1-(2-Meth yl-5-p en tylp h en yl)-1-eth a n on e (7e):
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 0.88 (br t,
3J (H,H) ) 7.0 Hz, 3H), 1.31 (m, 4H), 1.60 (m, 2H), 2.48 (s, 3H),
Exp er im en ta l Section
All 1H NMR spectra were collected on a 300 MHz NMR
spectrometer in CDCl3 or DMSO-d6. 13C NMR were recorded at
75.4 or 50 MHz with CDCl3 or DMSO-d6 as reference. All mass
spectra were determined on a capillary GC/MS operating in the
split mode with helium carrier gas and fitted with a mass-
selective detector (MSD). The column used was a HP5 capillary
column, 30 m × 0.25 mm, with a 0.25 µm film thickness of 5%
phenylmethylsilicone gum. The temperature of 65 °C was
maintained for 3 min and then ramped at 15 °C min-1 to 300
°C. The products were purified by flash chromatography on
Merck silica gel (0.040-0.063 mm). The enones 2 were com-
mercially available; the nitroalkanes 1 (R ) Me, Et, n-Pr, n-Bu,
n-C5H11) were commercially available or prepared16,17 (R ) i-Pr,
Ph) by standard procedures.
3
3
2.56 (s, 3H), 2.59 (br t, J (H,H) ) 7.6 Hz, 2H), 7.12 (d, J (H,H)
) 7.8 Hz, 1H), 7.18 (dd, 3J (H,H) ) 7.8, 4J (H,H) ) 1.7 Hz, 1H),
7.45 (d, 4J (H,H) ) 1.7 Hz, 1H); 13C NMR (50 MHz, CDCl3, 20
°C) δ ) 14.53, 21.64, 23.03, 30.09, 31.68, 31.93, 35.87, 129.79,
132.06, 132.42, 135.92, 138.12, 140.81, 202.50; IR (neat) ν )
1688; MS (70 eV) m/z 204 [M+], 189 [M+ - CH3] (100). Anal.
Calcd for C14H20O: C, 82.30; H, 9.86. Found: C, 82.42; H, 9.94.
Da ta for 1-(5-isop r op yl-2-m eth ylp h en yl)-1-eth a n on e (7f):
19
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 1.25 (d,
3J (H,H) ) 7.0 Hz, 6H), 2.47 (s, 3H), 2.57 (s, 3H), 2.91 (m, 1H),
3
3
4
7.15 (d, J (H,H) ) 7.9 Hz, 1H), 7.24(dd, J (H,H) ) 7.9, J (H,H)
) 1.8 Hz, 1H) 7.50 (d, 4J (H,H) ) 1.8 Hz, 1H); 13C NMR (75.4
MHz, CDCl3, 20 °C) δ ) 21.10, 23.98 (×2), 29.63, 33.68, 127.35,
129.51, 132.01, 135.55, 137.79, 146.31, 202.10; IR (neat) ν )
1685; MS (70 eV) m/z 176 [M+], 161 [M+ - CH3] (100), 133 [M+
- CH3CO]. Anal. Calcd for C12H16O: C, 81.77; H, 9.15. Found:
C, 81.90; H, 9.24.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ar om a tic
Com p ou n d s 7a -h . Nitroalkane 1 (2 mmol) and K2CO3 (0.138
g, 1 mmol) were dissolved in H2O (10 mL), then the solution
(16) Ballini, R.; Bosica, G. J . Chem. Res., Synop. 1993, 371.
(17) Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D.
D.; Oliveto, E. P.; Graham, G. E. J . Am. Chem. Soc. 1956, 78, 1497-
1501.
(18) Dorofeenko, G. N.; Polishchuk, L. V. Zh. Obshch. Khim. 1962,
32, 364-367; Chem. Abstr. 1963, 58, 2397d.
(19) Taylor, E. P.; Watts, G. E. J . Chem. Soc. 1952, 1123-1127.

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6263
Da ta for 1-[4-Meth yl-1,1′-bip h en yl]-3-yleth a n on e (7g):
yellow oil; H NMR (300 MHz, CDCl3, 20 °C) δ ) 2.55 (s, 3H),
MHz, CDCl3, 20 °C) δ ) 8.40, 16.15, 20.93, 26.49, 35.27, 128.34,
130.15, 131.62, 135.05, 138.52, 140.44, 205.24; IR (neat) ν )
1684; MS (70 eV) m/z 176 [M+], 147 [M+ - C2H5] (100). Anal.
Calcd for C12H16O: C, 81.77; H, 9.15. Found: C, 81.66; H, 9.24.
1
2.62 (s, 3H), 7.30 (d, 3J (H,H) ) 8.0 Hz, 1H), 7.37 (m, 1H), 7.45
(br t, 3J (H,H) ) 7.7 Hz, 2H), 7.58 (m, 3H), 7.87 (d, 4J (H,H) )
2.1 Hz, 1H); 13C NMR (75.4 MHz, CDCl3, 20 °C) δ ) 21.21, 29.67,
126.99 (×2), 127.56, 127.98, 128.92 (×2), 128.99, 130.02, 132.53,
137.25, 138.18, 140.21, 201.79; IR (neat) ν ) 1691; MS (70 eV)
m/z 210 [M+], 195 [M+ - CH3] (100), 167 [M+ - CH3CO]. Anal.
Calcd for C15H14O: C, 85.68; H, 6.71. Found: C, 85.80; H, 6.64.
Da ta for 1-(2-Eth yl-5-m eth ylp h en yl)-1-p r op a n on e (7h ):
yellow oil; 1H NMR (300 MHz, CDCl3, 20 °C) δ ) 1.17 (t, 3J (H,H)
Ack n ow led gm en t. This research was carried out
in the framework of the National Project “Stereoselezi-
one in Sintesi Organica: Metodologie ed Applicazioni”
supported by the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica, Rome, and by the
University of Camerino.
3
) 7.4 Hz, 6H), 2.33 (s, 3H), 2.74 (q, J (H,H) ) 7.4 Hz, 2H), 2.87
3
3
(q, J (H,H) ) 7.4 Hz, 2H), 7.14 (d, J (H,H) ) 7.8 Hz, 1H), 7.18
(br d, 3J (H,H) ) 7.8 Hz, 1H), 7.31 (br s, 1H); 13C NMR (75.4
J O0006324