A new synthetic method for methyl ketones from carboxylic acids using metallic strontium and methyl iodide

Article abstract of DOI:10.1246/cl.2007.28

Carboxylic acids reacted with metallic strontium and methyl iodide to give methyl ketones preferentially in moderate to good yields. Copyright

Full text of DOI:10.1246/cl.2007.28

28
Chemistry Letters Vol.36, No.1 (2007)
A New Synthetic Method for Methyl Ketones from Carboxylic Acids
Using Metallic Strontium and Methyl Iodide
Norikazu Miyoshi,Ã Tsuyoshi Matsuo, Masashi Asaoka, Aki Matsui, and Makoto Wada
Department of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,
1-1 Minamijosanjima, Tokushima 770-8502
(Received September 20, 2006; CL-061094; E-mail: miyoshi@ias.tokushima-u.ac.jp)
Table 1. Investigation of reaction conditions
Carboxylic acids reacted with metallic strontium and methyl
iodide to give methyl ketones preferentially in moderate to good
yields.
O
O
OH
Sr0, MeI
OH
THF
+
Ph
Ph
Ph
A
B
Entry Sr, MeI/equiv. THF/mL Total yield/%a A:B
Few studies on the preparation and reactivity of organo-
strontium compounds were found in the literature1–3 until the
current decade. We have been investigating synthetic reactions
using strontium compounds, and we reported the alkylation of
aldehydes or imines with alkyl iodides using metallic strontium.4
When we recently extended our investigation to include addition
reactions of esters, we found that dialkylation of esters with alkyl
iodides using strontium metal proceeded smoothly to afford the
corresponding adducts in good yields.5 When we attempted the
reaction with carboxylic acids instead of esters, the monoalkylat-
ed ketone, rather than the dialkylated alcohol, was obtained pref-
erentially (eq 1).
1
2
3
4
5
6
2.0
2.5
3.0
3.5
3.0
3.0
5
5
5
5
2.5
39
44
63
62
46
84
46:54
59:41
76:24
74:26
67:33
75:25
10
aIsolated yields.
Table 2. Investigation of several alkyl iodides
3.0 equiv. 3.0 equiv.
O
OH
O
Sr0,
RI
3.0 equiv. 3.0 equiv.
O
O
+
Sr0,
MeI
OH
THF (5 mL)
OH
+
Ph
OH
THF (10 mL)
R
Ph
Ph
R
(1)
Ph
R
Ph
A
B
Ph
A
B
Entry
R-
Total yield/%a
A:B
Total yield 63% (A:B = 76:24)
In the alkylation of esters using strontium, only the dialky-
1
2
3
4
Me
Et
n-Bu
i-Bu
84
48
41
22
75:25
73:27
73:27
77:23
lated adducts were produced in good yields; monoalkylated
ketones were not obtained. It is not usually easy to control the
over-addition of alkylating agents to carboxylic derivatives.
The preparation of monoalkylated ketones from carboxylic
acids is one of the important transformations in organic synthe-
sis. It is well known that the lithium carboxylates react with
alkyl- and aryl-lithium reagents to afford the ketones in good
yields.6 Although the early literature7 records a number of exam-
ples of ketones synthesis by reactions of the Grignard reagents to
carboxylic acids or metal carboxylates, this method has general-
ly been found less satisfactory than the corresponding reaction of
organolithium compounds.8 To our knowledge, there are no re-
ports of practical syntheses using ‘‘carboxylic acids’’ besides the
above and modified versions thereof, although there are a large
number of works using ‘‘carboxylic derivatives’’ such as acid
chlorides with organocuprates9 or organocadmiun reagents,10
and Weinreb’s amides11 with organolithium reagents, etc.12 This
prompted us to inverstigate monoalkylation of carboxylic acids
using strontium metal.
We examined the reaction using 3-phenylpropanoic acid
and methyl iodide under various conditions. Investigation of
the molar ratio of the methylating agents showed that 3 molar
equivalents of agents were required (Table 1, Entry 3). More-
over, we investigated the effects of varying the amount of
solvent, and it was found that dilute conditions (THF 10 mL)
resulted in an improvement in the yields (84%) with moderate
selectivity towards the monomethylated ketone rather than the
aIsolated yields.
dimethylated alcohol (75:25) (Entry 6).
Next we investigated the reactions of various alkyl iodides
using 3-phenylpropanoic acid. Alkyl iodides other than methyl
iodide were found to cause a reduction in the yield with similar
selectivities (Table 2).
The reaction was applied to various carboxylic acids, and
the results are summarized in the ‘‘Direct method’’ column in
Table 3. When aromatic or aliphatic carboxylic acids were used,
the reactions proceeded smoothly to afford the corresponding
products in good yields with moderate selectivities (Entries 1–
7). It is noted that carboxylic acids containing several functional
groups such as chloro, bromo, or olefin reacted to give the
corresponding adducts in good yields (Entries 3, 6, and 7).
Further investigation was carried out in order to obtain in-
creased selectivities. On the basis of the results obtained,13
a
reaction was developed in which the carboxylic acid was con-
verted into its sodium salt using sodium hydride, followed by
2 molar equiv. of strontium metal and 2 molar equiv. of methyl
iodide (in two separate portions) were added to the reaction mix-
ture. This resulted in a slightly decrease in the yield (69%), but
helped to prevent the over-addition of the methylating agent and
giving a dramatically improvement in high selectivities of 93:7
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
Table 3. Investigation of methyl ketones synthesis from various carboxylic acidsa or sodium saltsb
29
The direct methoda
Total yield/%c
Sodium salt’s methodb
Total yield/%c
Entry
RCOOH
A:B
A:B
1
2
3
4
5
6
7
PhCOOH
4-CH3C6H4COOH
4-ClC6H4COOH
Ph(CH2)2COOH
CH3(CH2)8COOH
CH2=CH(CH2)8COOH
Br(CH2)5COOH
76
83
84
84
84
83
77
76:24
81:19
80:20
75:25
77:23
73:27
80:20
59
76
75
69
64
53
50
93:7
88:12
92:8
93:7
84:16
92:8
94:6
b
c
aSee Ref. 14 for the reaction conditions. See Ref. 15 for the reaction conditions. Isolated yields.
(eq 2).16 The reaction was applied to various carboxylic acids
under these conditions, and the results are summarized in
Table 3 (sodium salt’s method). The reaction proceeded smooth-
ly to afford the monoalkylated adducts in moderate to good
yields with high selectivities.
5
6
7
8
9
N. Miyoshi, T. Matsuo, M. Wada, Eur. J. Org. Chem. 2005,
4253.
a) M. J. Jorgenson, Org. React. 1970, 18, 1. b) T. M. Bare, H. O.
House, Org. Synth. 1955, Coll. Vol. V, 775.
M. S. Kharasch, O. Reinmuth, Grignard Reactions of Nonmetallic
Substances, Prentice-Hall, Englewood Cliffs, NJ, 1954.
B. J. Wakefield, Organomagnesium Methods in Organic Synthe-
sis, Academic Press, UK, 1995.
O
0.9 equiv.
NaH
O
J. Cason, F. S. Prout, Org. Synth. 1955, Coll. Vol. III, 601.
Ph
OH
THF (10 mL)
Ph
ONa
10 G. H. Posner, C. E. Whitten, P. E. McFarland, J. Am. Chem. Soc.
1972, 94, 5106.
2.0 equiv. 1.0 equiv. x 2
MeI
11 S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815.
12 a) B. T. O’Neill, in Comprehensive Organic Synthesis, ed. by
B. M. Trost, I. Fleming, Pergamon, Oxford, 1991, Vol. 3,
p. 397. b) R. C. Larock, Comprehensive Organic Transforma-
tions, VCH, N. Y., 1989. References cited therein.
13 We also attempted to convert the carboxylic acid to lithium salt
using butyllithium for a similar reaction, but we obtained no good
result.
O
OH
Sr
+
(2)
Ph
Ph
A
B
Total yield 69% (A:B = 93:7)
In summary, a new method of synthesizing methyl ketones
from carboxylic acids was demonstrated. The reaction of sodium
carboxylates with 2.0 molar equivalents of methyl iodide and
metallic strontium took place smoothly to give the correspond-
ing methyl ketones with high selectivities. Further applications
of the practical method are now in progress.
14 A typical reaction procedure using carboxylic acid (the direct
method): Under an argon atmosphere, 3-phenylpropanoic acid
(153 mg, 1.02 mmol), THF (10 mL), and methyl iodide (445 mg,
3.13 mmol) were added successively to metallic strontium
(267 mg, 3.04 mmol) at room temperature. After stirring for
30 min, the reaction mixture was quenched with an aqueous
solution of 0.2 M hydrochloric acid (20 mL) (1 M = 1 mol
dmÀ3). The organic materials were extracted with diethyl ether
(30 mL Â 3), and the combined organic layers were washed suc-
cessively with 5% NaHSO3 (aq), 2 M NaOH (aq) and brine, and
dried over anhydrous Na2SO4. After evaporation of the solvent,
the residue was purified by thin layer chromatography on silica
gel (hexane:ethyl acetate = 8:1) to give the corresponding mono-
methylated product, 4-phenyl-2-butanone (95 mg, 63% yield) as
yellow oil and the corresponding dimethylated product, 4-phen-
yl-2-methyl-2-butanol (35 mg, 21% yield) as yellow oil.
15 A typical reaction procedure using sodium carboxylate (sodium
salt’s method): Under an argon atmosphere, 3-phenylpropanoic
acid (151 mg, 1.00 mmol) was added to a THF (10 mL) suspen-
sion of 60% sodium hydride (36 mg, 0.89 mmol) washed with
anhydrous hexane at room temperature. After stirring for
30 min, metallic strontium (184 mg, 2.10 mmol), methyl iodide
(162 mg, 1.14 mmol) and another portion of methyl iodide
(161 mg, 1.13 mmol) were added successively to the reaction mix-
ture at interval of 15 min at room temperature. After stirring
for 45 min, the reaction mixture was quenched with an aqueous
solution of 0.2 M hydrochloric acid (20 mL) (1 M = 1 mol dmÀ3),
followed by a work-up similar to that carried out in the previously
described reaction (direct method) to give the corresponding
monomethylated product (94 mg, 64% yield) as yellow oil and
the corresponding dimethylated product (8 mg, 5% yield) as
yellow oil.
This paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 80th birthday.
References and Notes
1
a) W. E. Lindsell, in Comprehensive Organometallic Chemistry,
ed. by G. Wilkinson, F. G. A. Stone, E. W. Abel, Pergamon
Press, Oxford, 1982, Vol. 1, Chap. 4, p. 155. b) W. E. Lindsell,
in Comprehensive Organometallic Chemistry II, ed. by E. W.
Abel, F. G. A. Stone, G. Wilkinson, Pergamon Press, Oxford,
1995, Vol. 1, Chap. 3, p. 57, and references cited therein. c) N.
Miyoshi, Product Class 8: Strontium Compounds in Houben-
Weyl: Methods of Molecular Transformation, Science of Synthe-
sis, ed. by H. Yamamoto, Thieme, Stuttgart, 2004, Vol. 7, p. 685.
Lindsell et al. reported that alkylstrontium halides reacted with
carbonyl compounds to afford the corresponding products in
low yields, with the exception of the reaction with benzophenone.
a) G. Gowenlock, W. E. Lindsell, B. Singh, J. Organomet. Chem.
1975, 101, C37. b) G. Gowenlock, W. E. Lindsell, B. Singh, J.
Chem. Soc., Dalton Trans. 1978, 657.
M. S. Sell, R. D. Rieke, Synth. Commun. 1995, 25, 4107. b) L. N.
Cherkasov, V. I. Panov, V. N. Cherkasov, Russ. J. Org. Chem.
1993, 29, 411. c) L. N. Cherkasov, S. I. Radchenko, Russ. J.
Org. Chem. 1994, 30, 456. d) L. N. Cherkasov, V. N. Cherkasov,
Russ. J. Org. Chem. 1995, 31, 267.
a) N. Miyoshi, K. Kamiura, H. Oka, A. Kita, R. Kuwata, D.
Ikehara, M. Wada, Bull. Chem. Soc. Jpn. 2004, 77, 341. b) N.
Miyoshi, D. Ikehara, T. Kohno, A. Matsui, M. Wada, Chem. Lett.
2005, 34, 760.
2
3
4
16 These selectivities seem to be influenced by the formation of met-
al alkoxy acetals intermediates, but the details are not yet clear.
Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.28