A new synthetic method for para alkylation of benzoic acids using metallic strontium and alkyl iodide

Article abstract of DOI:10.1246/cl.2009.996

Aromatic carboxylic acids reacted with metallic strontium and alkyl iodides to give para alkylated products preferentially in moderate to good yields. Copyright

Full text of DOI:10.1246/cl.2009.996

996
Chemistry Letters Vol.38, No.10 (2009)
A New Synthetic Method for Para Alkylation of Benzoic Acids
Using Metallic Strontium and Alkyl Iodide
Norikazu Miyoshi,ꢀ1 Tsuyoshi Matsuo,1 Mariko Mori,1 Aki Matsui,1 Makoto Kikuchi,1
Makoto Wada,1 and Masahiko Hayashi2
1Department of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,
1-1 Minamijosanjima, Tokushima 770-8502
2Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501
(Received August 6, 2009; CL-090733; E-mail: miyoshi@ias.tokushima-u.ac.jp)
Aromatic carboxylic acids reacted with metallic strontium
and alkyl iodides to give para alkylated products preferentially
in moderate to good yields.
para alkylation proceeded by simple operation and without pre-
paring sterically hindered esters or using a special sterically
bulky catalyst. However, in this case, the reaction allowed only
to using tert-butyl iodide or isopropyl iodide. Here we wish re-
port the selective para alkylation of aromatic carboxylic acids
by using several alkyl iodides and metallic strontium.
Few studies of the preparation and reactivity of organostron-
tium compounds have been found in the literature1–3 until the cur-
rent decade. We have been investigating synthetic reactions us-
ing strontium compounds, and we have reported that the alkyla-
tion of aldehydes or imines with alkyl iodides,4 and dialkylation
of esters with alkyl iodides5 proceeds smoothly using metallic
strontium to afford the corresponding adducts in good yields.
When we recently extended our investigation to include the addi-
tion reaction of carboxylic acids, we found that carboxylic acids
reacted with metallic strontium and alkyl iodides to give mono-
alkylated ketones preferentially in moderate to good yields.6 In
the reaction of benzoic acid with n-butyl iodide, the monoalky-
lated ketone was obtained in 37% yield and the unexpected 4-n-
butylbenzoic acid was detected in a trace amount (eq 1).
Initially, we examined the reaction using benzoic acid and
n-butyl iodide under various conditions. It was found that best
result was obtained using 3.0 equivalents of metallic strontium
and 2.0 equivalents of n-butyl iodide to benzoic acid. It was
noted that higher yield was achieved by a unique addition se-
quence of n-butyl iodide as follows; first, 1.2 equivalents of n-
butyl iodide were added, then 0.8 (0:2 ꢃ 4) equivalents of n-bu-
tyl iodide were added in four aliquots at 15 min intervals, succes-
sively. A mixture of the 1,6-adduct A and the oxidative aroma-
tization product, para alkylated compound B, were obtained in
moderate to good yield, although it was difficult to separate
the reaction mixtures. In order to purify the crude products,
the mixture was successively oxidized using 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) to afford 4-n-butylbenzoic acid
B in moderate good yield. Moreover, we examined other oxi-
dants instead of DDQ, because the 1,6-adduct A was unstable
and gradually decomposed and was not always converted using
DDQ into the para alkylated adduct B completely. As shown in
Table 1, the oxidation with palladium–carbon proceeded
smoothly to give the para alkylated adduct B, but the decompo-
sition of 1,6-adduct A also occurred slightly. The use of activat-
ed carbon, DarcoÒ KB (Aldrich Inc.) as an oxidant,10 gave the
improvement in the yield (67%) (Entry 5). However, the yields
are less satisfactory for synthetic methods. It was suggested that
DarcoÒ KB absorbed products slightly to decrease the yield. We
tried to use another activated carbon (Tokyo Chemical Industry
Co., Ltd.),10 which was less absorbent than DarcoÒ KB. Using
TCI activated carbon, the oxidation proceeded smoothly to in-
crease the yields (75%) (Entry 7).
Next we investigated several alkyl iodides using benzoic
acid, which are summarized in Table 2. As described above,
we have already reported that the reaction of ethyl benzoate with
tert-butyl iodide proceeds smoothly to afford ethyl 4-tert-butyl-
benzoate.4 However, in that case, the reaction only proceeds us-
ing tert-butyl iodide or isopropyl iodide, which seems to produce
the stable nucleophilic radicals.2 In this reaction, not only tert- or
sec-alkyl iodide but also primary alkyl iodide reacted to give the
corresponding products in moderate to good yields. Especially,
isobutylation is significant (Entry 2), because isobutyllithium
is not commercial available and it is difficult to prepare isobuty-
lating agent, as ꢀ-hydride elimination occurs. Moreover, the re-
action has the advantages of using unmodified benzoic acid
without special protection or activation as reported before.
3.0 equiv Sr0, 3.0 equiv n-BuI
PhCOOH
ð1Þ
THF, r.t., 30 min
O
O
+
OH
Bu-n
n-Bu
37%
trace
In this reaction, alkylation of the carboxyl group of benzoic
acid and at the para position of the aromatic ring of benzoic acid
occurred competitively. We were interested in the para alkylated
product because this alkylation reaction is unusual under these
conditions. The selective functionalization of an aromatic nu-
cleus has become increasingly important in synthetic organic
chemistry. There are only a few reports of the ortho or para al-
kylation of nucleophilic addition to an aromatic nucleus with
simple carbonyl and carboxyl functionalities. Tomioka and
Koga reported ortho alkylation by using the conjugate addition
of organolithiums to sterically hindered 2,6-di-tert-butyl-4-me-
thoxyphenyl naphthalenecarboxylate.7 Hattori and Miyano re-
ported that the para alkylation of benzoate with butyllithium pro-
ceeded using also a particularly sterically bulky ester of benzoic
acid.8 Yamamoto and Maruoka reported that the para alkylation
of benzaldehyde with butyllithium took place using a special
sterically bulky aluminum catalyst.9 On the other hand, we have
already reported that the reaction of ethyl benzoate with tert-bu-
tyl iodide and metallic strontium proceeded smoothly at ꢁ20 ꢂC
for 36 h to afford ethyl 4-tert-butylbenzoate as the sole product
in 55% yield.4 The yield was still moderate, but this reaction
has the advantages over other methodology in that the selective
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.10 (2009)
997
Table 1. Investigation of reaction conditions
3.0 equiv Sr0, 1.2 equiv n-BuI
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas ‘‘Advance Molecular Transformation
of Carbon Resources’’ from MEXT, Japan.
0.2 equiv n-BuI x 4 times
15 min interval
PhCOOH
THF(5 mL), r.t., 15 min
O
References and Notes
O
1
a) N. A. Bell, Beryllium, and W. E. Lindsell, Magnesium, Calcium,
Strontium and Barium in Comprehensive Organometallic Chemistry,
ed. by G. Wilkinson, F. G. A. Stone, E. W. Abel, Pergamon Press,
Oxford, 1982, Vol. 1, Chap. 3 and 4, p. 121 and p. 155, respectively.
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 Synthesis, ed. by H.
Yamamoto, Thieme, Stuttgart, 2004, Vol. 7, p. 685.
+
OH
OH
n-Bu
n-Bu
A
B
O
catalyst, O2
OH
solvent, overnight
n-Bu
B
Entry
Catalyst
Solvent
Temp/ꢂC
Yield/%a
2
Lindsell et al. reported that alkylstrontium halides reacted with carbon-
yl compounds to afford the corresponding products in low yields, with
the exception of the reaction with benzophenone. a) B. G. Gowenlock,
W. E. Lindsell, B. Singh, J. Organomet. Chem. 1975, 101, C37. b)
B. G. Gowenlock, W. E. Lindsell, B. Singh, J. Chem. Soc., Dalton
Trans. 1978, 657.
1
2
3
4
5
6
7
5% Pd/C
5% Pd/C
AcOH
AcOH
AcOH
Toluene
AcOH
AcOH
AcOH
55
80
55
80
80
100
80
45
57
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
TCI-ACc
—
b
58
67
64
75
3
4
a) 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.
aYields were determined by 1H NMR spectra. bNot complete-
ly oxidized. cAs TCI-AC (TCI activated carbon), see Ref. 10.
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.
N. Miyoshi, T. Matsuo, M. Wada, Eur. J. Org. Chem. 2005, 4253.
N. Miyoshi, T. Matsuo, M. Asaoka, A. Matsui, M. Wada, Chem. Lett.
2007, 36, 28.
Table 2. Investigation of several alkyl iodides
3.0 equiv Sr0, 1.2 equiv RI
0.2 equiv RI x 4 times
5
6
PhCOOH
THF(5 mL), r.t., 15 min
15 min interval
7
8
K. Tomioka, M. Shindo, K. Koga, Tetrahedron Lett. 1990, 31, 1739.
T. Hattori, N. Koite, T. Satoh, S. Miyano, Tetrahedron Lett. 1995, 36,
4821.
O
O
OH
OH
+
9
K. Maruoka, M. Ito, H. Yamamoto, J. Am. Chem. Soc. 1995, 117, 9091.
10 a) Y. Kawashita, N. Nakamichi, H. Kawabata, M. Hayashi, Org. Lett.
2003, 5, 3713. b) N. Nakamichi, H. Kawabata, M. Hayashi, J. Org.
Chem. 2003, 68, 8272. TCI activated carbon is commercial available
from Tokyo Chemical Industry Co., Ltd (TCI C2194).
R
R
O
Activated cabon (TCI), O2
OH
AcOH, 80 °C, overnight
11 A typical reaction procedure is as follows: Under an argon atmosphere,
benzoic acid (122 mg, 1.00 mmol) and THF (5 mL) were added to a
vessel with small pieces of metallic strontium (269 mg, 3.09 mmol)
cut with a chisel, and n-butyl iodide (213 mg, 1.16 mmol) and addition-
al n-butyl iodide (142 mg, 0.77 mmol) in four portions at 15 min inter-
vals were added successively to the reaction mixture at room temper-
ature. After stirring 15 min, the reaction mixture was quenched with
1 M HCl aq (20 mL) (1 M = 1 mol dmꢁ3). The organic materials were
extracted with diethyl ether (15 mL ꢃ 3), and the combined organic
layers were washed successively with 5% NaHSO3 aq and brine.
The organic layer was washed with 2 M NaOH (15 mL ꢃ 3) aq. The
combined aqueous extracts were acidified with 3 M HCl aq. The result-
ing cloudy suspension was extracted with diethyl ether (15 mL ꢃ 3).
These organic extracts were combined and dried over anhydrous
Na2SO4. After evaporation of the solvent, acetic acid (5 mL) and
TCI activated carbon (ca. 80 mg) was added to the residue, and the re-
action mixture was allowed to stand at 80 ꢂC for 14 h under an oxygen
atmosphere and then filtered through a short pad of Celite. The Celite
was washed with diethyl ether and the solvent was removed on a rotary
evaporator. The residue was dissolved in ether, and the organic layer
was washed with 2 M NaOH aq (15 mL ꢃ 3). The combined aqueous
extracts were acidified with 3 M HCl aq. The resulting cloudy suspen-
sion was extracted with diethyl ether (15 mL ꢃ 3). These organic ex-
tracts were combined and dried over anhydrous Na2SO4. After evapo-
ration of the solvent, 4-n-butylbenzoic acid (134 mg, 75%) was ob-
tained as a white crystal.
R
Entry
R-
Yield/%a
1
2
3
4
5
n-Bu
i-Bu
i-Pr
s-Bu
t-Bu
75
74
80b
83b
68
aIsolated yields. As reaction conditions in detail, see Ref. 11.
bAlkyl iodide was added in 5 aliquots (total 2.5 equiv to acid).
In summary, a new alkylation method at the para position of
the aromatic ring of benzoic acid was demonstrated. Aromatic
carboxylic acids reacted with metallic strontium and alkyl io-
dides to give para alkylated products predominantly in moderate
to good yields. The para alkylation of benzoic acid is a unique
characteristic in organostrontium chemistry. We found dialkyla-
tion of esters5 and monoalkylation of carboxylic acid.6 In this
time, we found that only the change of additional procedure in-
hibited 1,2-addition at carbonyl group of benzoic acid to proceed
1,6-addition (para alkylation) of benzoic acid predominantly.
Further applications are now progress.
Published on the web (Advance View) September 19, 2009; doi:10.1246/cl.2009.996