Direct easy synthesis of ketones from carboxylic acids and chlorinated compounds

Full text of DOI:10.1021/jo9605962

6058
J . Org. Chem. 1996, 61, 6058-6059
Sch em e 1
Dir ect Ea sy Syn th esis of Keton es fr om
Ca r boxylic Acid s a n d Ch lor in a ted
Com p ou n d s†
Francisco Alonso, Emilio Lorenzo, and Miguel Yus*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received April 1, 1996
Ta ble 1. Rea ction of Ben zoic Acid w ith sec-Bu tyl
In tr od u ction
Ch lor id e: P r ep a r a tion of Bu sCOP h
Τhe reaction of organolithium compounds with carbon
dioxide is a standard procedure to prepare carboxylic
acids.1a In general, small amounts of a ketone are
obtained in this process as a byproduct. However, the
preparation of ketones1b from carboxylates and organo-
lithium compounds can be achieved only under prolonged
reflux,2 using sonication,3 or in the presence of cerium-
(III) chloride.4 Methodologies for ketone synthesis in-
volving other carboxylic acid derivatives of the type
RCOX and alkyllithium compounds give usually tertiary
alcohols as the main reaction products, and R-deproto-
nation is often a serious limitation.5,6 On the other hand,
we have recently discovered that the combination of an
arene-catalyzed lithiation7 with Barbier-type conditions8
(carrying out the lithiation process in the presence of an
electrophile) is a versatile methodology to prepare very
reactive lithium intermediates, useful species in synthetic
organic chemistry. Thus, for instance, unstable func-
tionalized organolithium compounds9,10 or polylithium
synthons11 can be prepared under very mild reaction
conditions. In this paper, we apply the mentioned
combination to prepare ketones directly from carboxylic
acids and chlorinated derivatives.
reaction conditions
carboxylate
entry
formation
T (°C)
time
methoda yield (%)b
1
2
3
4
5
6
7
8
9
BunLi
BunLi
BunLi
BunLi
BunLi
Li
Li
Li
Li
d
0f20 3 h
-78f20 2 h
0f20 2 h
A
A
A
B
C
57
18
47
0
70
70
61
49
48
97
0f20 3 h
0f20 3 h
0f20 3 h
0f20 3 h
0f20 10 min
0f20 2 h
0f20 10 min
D
Dc
Dc
E
10
Fc
a
A catalytic amount of naphthalene (1:0.1 molar ratio) was
always used unless noted. Method A: PhCO2Li + BusCl added
to Li + naphthalene. Method B: PhCO2Li added to the mixture
of BusCl + Li + naphthalene. Method C: PhCO2Li + BusCl added
to Li + DTBB. Method D: PhCO2Li added to Li, then successive
addition of naphthalene and BusCl. Method E: PhCO2Li added
to Li, then addition of BusCl. Method F: PhCO2H + BusCl added
b
c
to Li + naphthalene. GLC yield. Lithium excess was filtered
d
off before the final hydrolysis. No carboxylate formation prior
the lithiation step (see Method F).
and 7 and 8), arene catalyst (Table 1, entries 1, 5, and
9), filtration of the lithium excess before the final
hydrolysis (Table 1, entries 6 and 7), prior formation of
the corresponding carboxylate [with n-butyllithium (Table
1, entries 1-5) or lithium (Table 1, entries 6-9], or the
direct use of the carboxylic acid (Table 1, entry 10), as
well as different ways to perform the reaction (Table 1,
footnote a, methods A-F), we concluded that the best
results were obtained using method F, which involves
adding the mixture of benzoic acid and sec-butyl chloride
in THF to the dark green lithium suspension in THF
containing a ∼10% of naphthalene at temperatures
ranging between 0 and 20 °C for 10 min.
The reaction of different carboxylic acids 1 with
representative chlorinated derivatives 2 to give the
expected ketones 3, following the above-mentioned pro-
tocol, is shown in Scheme 1, and the corresponding
results are summarized in Table 2. In all reactions, a
portion of the starting carboxylic acid 1 remained unre-
acted, so the real yields are higher if corrected for
unreacted carboxylic acid (Table 2, footnote b).
We applied this methodology to the preparation of
trans-chalcone 3fd starting from cinnamic acid (1f) and
chlorobenzene (2d ) (Table 2, entry 11); using sorbic acid
(1e) and the chlorinated precursor 2d , the expected
unsaturated ketone 3eb was isolated in low yield, due
probably to a partial decomposition of this final reaction
product under the reductive reaction conditions. Finally,
we tried to prepare phorone (2,6-dimethylhepta-2,5-dien-
4-one) using the methodology shown in Scheme 1, by
reaction of 3-methylbut-2-enoic acid (1d ) with 2-methyl-
prop-1-enyl chloride (2e). However, instead of phorone,
we obtained isophorone (3d e) as the only reaction product
Resu lts a n d Discu ssion
We first studied the best reaction conditions to carry
out the transformation using benzoic acid (1a ) and sec-
butyl chloride (2b) as reagents (Scheme 1). After varying
several parameters such as the temperature (Table 1,
entries 1 and 2), reaction time (Table 1, entries 1 and 3,
† This paper is dedicated to Prof. Nino Fava on his 73rd birthday.
(1) (a) For a monography, see: Wakefield, B. J . Organolithium
Methods; Academic Press: London, 1988; p 89. (b) For a review, see:
Larock, R. C. Comprehensive Organic Transformations; VCH Publish-
ers: New York, 1989; p 685.
(2) Zadel, G.; Breitmaier, E. Angew. Chem., Int. Ed. Engl. 1992, 31,
1035.
(3) Aurell, M. J .; Einhorn, C.; Einhorn, J .; Luche, J . L. J . Org. Chem.
1995, 60, 8.
(4) Ahn, Y.; Cohen, T. Tetrahedron Lett. 1994, 35, 203.
(5) Reference 1a, p 76.
(6) Successful methodologies involving organolithium compounds
and N-methoxy-N-methylamides (see, for instance: Whipple, W. L.;
Reich, H. J . J . Org. Chem. 1991, 56, 2911 and references cited therein),
N-cycloiminum salts of amides (de las Heras, M. A.; Molina, A.;
Vazquez, J . J .; Garc´ıa-Navio, J . L.; Alvarez-Builla, J . J . Org. Chem.
1993, 58, 5862), or N-carbethoxypiperidine (Prakash, G. K.; York, C.;
Liao, Q.; Kotian, K.; Olah, G. A. Heterocycles 1995, 49, 79) have been
recently described.
(7) Yus, M.; Ramo´n, D. J . J . Chem. Soc., Chem. Commun. 1991, 398.
For a review, see: Yus, M. Chem. Soc. Rev., in press.
(8) For a monography on this topic, see: Blomberg, C. The Barbier
Reaction and Related One-Step Processes; Springer Verlag: Berlin,
1993.
(9) For a review, see: Na´jera, C.; Yus, M. Trends Org. Chem. 1991,
2, 155.
(10) For the last paper from our laboratory, see: Guijarro, A.;
Manchen˜o, B.; Ortiz, J .; Yus, M. Tetrahedron 1996, 52, 1643.
(11) For the last paper from our laboratory, see: Guijarro, A.; Yus,
M. Tetrahedron 1996, 52, 1797.
S0022-3263(96)00596-8 CCC: $12.00 © 1996 American Chemical Society

Notes
entry
J . Org. Chem., Vol. 61, No. 17, 1996 6059
Ta ble 2. P r ep a r a tion of Keton es 3 fr om Ca r boxylic Acid s 1 a n d Ch lor in a ted Der iva tives 2
producta
starting acid
starting chloride
1/2 molar ratio
time
no.
R
R′
yield (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1c
1c
1d
1e
1f
2a
2b
2c
2d
2a
2d
2a
2d
2e
2b
2d
1:1.2
1:1.2
1:2
1:1.2
1:2
1:2
1:2
1:2
1:2
15 min
10 min
25 min
1.5 h
3.5 h
2 h
40 min
2 h
1 h
3a a
3a b
3a c
3a d
3ba
3bd
3ca
3cd
3d e
3eb
3fd
Ph
Ph
Ph
Ph
Bun
Bus
But
Ph
50 (56)
75 (96)
32 (40)
63 (98)
31 (40)
41 (53)
62 (73)
53 (63)
20 (50)
15 (28)
45 (60)
Prn
Prn
c-C3H5
c-C3H5
c
Bun
Ph
Bun
Ph
c
10
11
1:2
1:2
6 h
2 h
MeCHdCHCHdCH
PhCHdCH
Bus
Ph
a
b
All products 3 were >96% pure (GLC and 300 MHz 1H NMR), except 3eb (92%). Isolated yield after column chromatography
(silica gel, hexane/diethyl ether) based on the starting carboxylic acid 1; in parentheses is the corresponding isolated yield based on the
consummed carboxylic acid 1. See text and Scheme 1.
c
13C NMR, and MS) with those of the corresponding commercially
in low yield (Table 2, entry 9). This easy isomerization,
available samples. For the rest of the compounds 3, physical
under basic conditions, is surprising considering that the
reported conditions for such process are far more drastic
and tedious (formation of the corresponding silyl enol
and spectroscopic data, as well as references, follow.
sec-Bu tyl P h en yl Keton e (3a b):20 Rf 0.66 (hexane/diethyl
ether 4:1); IR (film) 3040, 1597, 1687 cm-1; 1H NMR δ 0.82 (t, J
ether followed by heating at 220 °C in the presence of a
) 7.4 Hz, 3H), 1.09 (d, J ) 6.9 Hz, 3H), 1.35-1.44, 1.69-1.79
Pd(II) catalyst and final acidic hydrolysis).12
(2m, 2H), 3.32-3.41 (m, 1H), 7.33 (m, 2H), 7.43 (m, 1H), 7.86
From a mechanistic point of view, we think that the
initially in situ-generated lithium carboxylate reacts with
the alkyllithium, formed by a rapid naphthalene-cata-
lyzed lithiation of the starting chlorinated material, in a
Barbier-type process.
In conclusion, and taking into account the results
described in this paper, we consider that this methodol-
ogy represents an easy way to prepare ketones from
carboxylic acids and chlorinated materials (alkyl, alkenyl,
or phenyl chloride). In no cases were tertiary alcohols
detected as byproducts.
(m, 2H); 13C NMR δ 11.7, 16.7, 26.6, 42.0, 128.1, 128.5, 136.8,
142.7, 204.0; MS m/ z (relative intensity) 162 (M+, 8), 40 (100).
n -Bu tyl n -P r op yl Keton e (3ba ):21 Rf 0.71 (hexane/diethyl
1
ether 4:1); IR (film) 1713 cm-1; H NMR δ 0.91 (t, J ) 7.0 Hz,
6H), 1.25-1.37 (m, 2H), 1.52-1.63 (m, 4H), 2.35-2.42 (m, 4H);
13C NMR δ 13.6, 13.7, 17.2, 22.3, 25.9, 42.5, 44.6, 211.3; MS m/ z
(relative intensity) 128 (M+, 13), 43 (100).
n -Bu tyl Cyclop r op yl Keton e (3ca ):22 Rf 0.33 (hexane/
diethyl ether 9:1); IR (film) 1693 cm-1 1H NMR δ 0.82-0.87,
;
0.97-1.02 (2m, 4H), 0.92 (t, J ) 7.3 Hz, 3H), 1.27-1.44 (m, 2H),
1.55-1.64 (m, 2H), 1.88-1.97 (m, 1H), 2.52-2.56 (t, J ) 7.3 Hz,
2H); 13C NMR δ 10.5, 13.9, 20.3, 22.4, 26.2, 43.2, 211.3; MS m/ z
(relative intensity) 126 (M+, 8), 69 (100).
(E,E)-2-Meth yl-4,6-n on a d ien -4-on e (3eb):23 Rf 0.18 (hex-
ane/diethyl ether 9:1); IR (film) 1693, 1633 cm-1; 1H NMR δ 0.88
(t, J ) 7.3 Hz, 3H), 1.09 (d, J ) 7.0 Hz, 3H), 1.66-1.75, 1.76-
1.87 (2m, 2H), 2.03 (d, J ) 2.3 Hz, 3H), 2.60-2.71 (m, 1H), 6.12-
6.27, 7.14-7.27 (2m, 4H); 13C NMR δ 11.7, 16.2, 18.8, 26.3, 45.9,
126.4, 130.4, 140.2, 142.7, 204.3; MS m/ z (relative intensity)
152 (M+, 7), 95 (100).
Exp er im en ta l Section
Gen er a l. For general information, see ref 11h.
P r ep a r a tion of Com p ou n d s 3. Gen er a l P r oced u r e.
A
solution of the carboxylic acid 1 (2.5 mmol) and the chlorinated
compound 2 (3 or 5 mmol, see Table 2 for the molar ratio) in
THF (5 mL) was added dropwise to a previously prepared deep
green suspension of lithium powder (14 mmol) and naphthalene
(0.25 mmol) in THF (5 mL) at 0 °C and under argon. The
mixture was warmed to 20 °C and stirred for the time specified
in Table 2. The excess of lithium was filtered (the nonpyrophoric
residue was destroyed by standing the glass fritted funnel in
contact with the air moisture under a hood), and the filtrate was
hydrolyzed with a saturated solution of NaHCO3. The resulting
mixture was extracted with diethyl ether (3 × 20 mL). The
organic layer was dried over anhydrous Na2SO4 and the solvent
evaporated (15 mmHg). The residue was purified by column
chromatography (silica gel; hexane/diethyl ether) to yield prod-
ucts 3. Yields are included in Table 2. Compounds 3a a ,13 3a c,14
3a d ,15 3bd ,16 3cd ,17 3d e,18 and 3fd 19 were characterized by
comparison of their physical and spectroscopic data (IR, 1H and
Ack n ow led gm en t. This work was supported by
DGICYT (No. PB94-1514). E.L. thanks the Ministerio
de Educacio´n y Ciencia of Spain for an undergraduate
fellowship.
J O9605962
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