The convenient and useful esterification of bulky tertiary alcohols using strontium compounds

Article abstract of DOI:10.1246/cl.2012.35

Various esters reacted with metallic strontium and alkyl iodides to give dialkylated products, followed by adding acid chlorides or acid anhydrides to afford the corresponding bulky tert-alcohol esters in good yields.

Full text of DOI:10.1246/cl.2012.35

doi:10.1246/cl.2012.35
Published on the web December 24, 2011
35
The Convenient and Useful Esterification of Bulky Tertiary Alcohols
Using Strontium Compounds
Norikazu Miyoshi,* Masashi Asaoka, Yasuaki Miyazaki, Takahiro Tajima, Makoto Kikuchi, and Makoto Wada
Department of Chemistry, Faculty of Integrated Arts and Sciences, University of Tokushima,
1-1 Minami-Josanjima, Tokushima 770-8502
(Received October 9, 2011; CL-110826; E-mail: miyoshi@ias.tokushima-u.ac.jp)
Various esters reacted with metallic strontium and alkyl
iodides to give dialkylated products, followed by adding acid
chlorides or acid anhydrides to afford the corresponding bulky
tert-alcohol esters in good yields.
1.0 equiv Sr0
2.5 equiv MeI
O
O
O
Ph
ð2Þ
Ph
Cl
THF, r.t., 60 min
Ph
55% based on
0.5 equiv amount of acid chloride
Few studies on the preparation and reactivity of organo-
strontium compounds have been found in the literature1-3
outside our study. We have been investigating synthetic
reactions using strontium compounds and have reported that
the alkylation of aldehydes or imines with alkyl iodides4 and
dialkylation of esters with alkyl iodides5 proceeded smoothly
using metallic strontium to afford the corresponding adducts
in good yields. When we recently extended our investigation
to include the addition reaction of carboxylic acids, we
found that carboxylic acids reacted with metallic strontium
and alkyl iodides to give monoalkylated ketones preferen-
tially, in moderate-to-good yields.6 In addition, the new
alkylation method at the p-position of the aromatic ring of
benzoic acid was demonstrated.7 In the reaction of 3-phenyl-
propionyl chloride instead of carboxylic acid with methyl
iodide, the dimethylated product was obtained in 68%
yields, and the unexpected ester, 3-methyl-1-phenylbutan-
3-yl 3-phenylpropionate, was detected in a trace amount
(eq 1).
Next, in order to increase the yields, we attempted a reaction
of strontium bulky tert-alkoxide produced by strontium-medi-
ated dialkylation into ester with carboxylic acid chloride.
Investigating the molar ratio and adding methods of each agent
using methyl benzoate and isobutyl iodide, it was found that 2.5
molar equivalents of isobutyl iodide was added to the THF
suspension of methyl benzoate and 2.5 molar equivalents of
metallic strontium. This was followed by adding benzoyl
chloride as follows; 1.2 molar equivalents of benzoyl chloride
was added, successively 0.8 molar equivalents of benzoyl
chloride was added after 15 min. The crude products were
purified by chromatography on silica gel to give the correspond-
ing ester D in 86% yield (Scheme 1).
Although a good yield was obtained from the ester D, a
new problem has arisen. In the reaction of ester A, not only the
desired alkoxide B but also the undesired alkoxide C were
produced. Furthermore these reacted with acid chloride to derive
ester D and E in equal amounts which was difficult to separate.
In order to purify the crude products, the mixture was treated
with 2 mol L¹1 NaOH(aq) to hydrolyze with only ester E and to
2.5 equiv Sr0
2.5 equiv MeI
OH
O
ð1Þ
Ph
THF, r.t., 60 min
Ph
Cl
OSrI
O
2.5 equiv Sr0
2.5 equiv i-BuI
68%
O
Ph
Ph
OMe
+
ISrOMe
THF, r.t., 30 min
O
Ph
trace
A
C
Ph
B
O
We thus further investigated this unexpected ester. Ester-
ification of alcohols is one of the most fundamental and
important reactions in organic synthesis. However, the prepara-
tion of bulky secondary or tertiary alcohol esters is known to be
difficult compared with that of primary alcohol esters. Although
there are various reports for the synthesis of bulky alcohol
esters,8,9 it is still difficult to prepare these bulky alcohol esters
in good yield. This difficulty is due to the reaction which
requires long reaction time with a large excess amount of
either carboxylic acids or alcohols.9 This prompted us to
try esterification of bulky tert-alcohols with carboxylic acid
derivatives using strontium metal.
1.2 equiv +
0.8 equiv
PhCOCl
O
Ph
O
+
Ph
Ph
OMe
r.t., 60 min
E
D
O
2 molL−1
NaOH(aq)
O
Ph
O
+
Ph
Ph
ONa
r.t., 120 min
We first examined the reaction using 3-phenylpropionyl
chloride and methyl iodide under various conditions. As
shown at eq 2, tert-alcohol ester was obtained in a 55%
yield.
F
D
Scheme 1. Formation of ester and removement of coproducts.
© 2012 The Chemical Society of Japan www.csj.jp/journals/chem-lett/
Chem. Lett. 2012, 41, 35-36

36
Table 1. Investigation of the reaction of methyl benzoate with
various alkyl iodides using various acid chlorides
When the strontium-mediated reaction was compared with
the reaction using alkyllithium or Grignard reagent under similar
reaction conditions at Entry 4 in Table 1, reactions proceeded
slowly to obtain the corresponding esters in only 22% or 12%
yields, and dialkylated alcohols preferentially, respectively.10
In summary, various esters reacted with metallic strontium
and alkyl iodides to give dialkylated products, followed by
adding acid chlorides or acid anhydrides during a short reaction
time to afford the corresponding bulky tert-alcohol esters in
good yields. For more practical methods, more increasing yields
and further applications are now in progress.
2.5 equiv Sr0 1.2 equiv + 0.8 equiv
O
2.5 equiv R1I
R2COCl
O
Ph
OMe
r.t., 60 min
THF, r.t., 30 min
O
R2
2 molL−1 NaOH(aq)
r.t., 120 min
R1
Ph
R1
Entry
R1
R2
Yield/%a
1
2
3
4
5
6
i-Bu
i-Bu
i-Bu
n-Bub
Et
Ph
t-Bu
PhCH2CH2
Ph
Ph
Ph
90
88
17
87
95
92
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas “Advance Molecular Transformation
of Carbon Resources” from MEXT, Japan.
Me
References and Notes
b
aIsolated yields. Using 3.0 equiv of Sr and n-BuI.
1
a) N. A. Bell, Beryllium in Comprehensive Organmetallic Chem-
istry, ed. by G. Wilkinson, F. G. A. Stone, E. W. Abel, Pergamon
Press, Oxford, 1982, Vol. 1, Chap. 3, p. 121. doi:10.1016/B978-
008046518-0.00003-9; W. E. Lindsell, Magnesium, Calcium,
Strontium and Barium in Comprehensive Organmetallic Chemistry,
ed. by G. Wilkinson, F. G. A. Stone, E. W. Abel, Pergamon
Press, Oxford, 1982, Vol. 1, Chap. 4, p. 155 doi:10.1016/B978-
008046518-0.00004-0. b) W. E. Lindsell, Magnesium, Calcium,
Strontium and Barium 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.
doi:10.1016/B978-008046519-7.00003-4. c) N. Miyoshi, in Prod-
uct 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.
Table 2. Investigation of the reaction using acid anhydrides
2.5 equiv Sr0
2.5 equiv i-BuI
1.2 equiv + 0.8 equiv
(R1CO)2O
O
O
Ph
OMe
THF, r.t., 30 min
r.t., 60 min
O
R1
2 molL−1 NaOH(aq)
r.t., 120 min
Ph
Entry
R1
Yield/%a
1
2
3
Ph
Me
PhCH2CH2
81
76c
60
c
2
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)
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J. Chem. Soc., Dalton Trans. 1978, 657.
b
aIsolated yields. Using 3.0 equiv of Sr and i-BuI. Hydrolysis
b
was not performed.
3
4
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afford only ester D in 90% yield. Because the bulky tert-alcohol
esters are more stable under basic conditions rather than methyl
benzoate.
The reaction was applied to methyl benzoate with various
alkyl iodides using various acid chlorides, and proceeded
smoothly to afford the bulky tert-alcohol esters in good yields,
which were summarized in Table 1.10 Among them, using 3-
phenylpropionyl chloride, the yield was decreased (Entry 3).
Next, we tried to change the acylating agent from acid
chlorides to acid anhydrides as shown in Table 2. The strontium
alkoxide B was reacted with 3-phenylpropionic anhydride
instead of 3-phenylpropionyl chloride to give the corresponding
ester in moderate to good yield (Entry 3).
5
6
7
8
N. Miyoshi, T. Matsuo, M. Mori, A. Matsui, M. Kikuchi, M. Wada,
M. Hayashi, Chem. Lett. 2009, 38, 996.
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Mukaiyama has reported the new SN2 type esterification via
inversion of tert-alcohols. T. Shintou, W. Kikuchi, T. Mukaiyama,
Bull. Chem. Soc. Jpn. 2003, 76, 1645, and references cited therein.
Furthermore, the reaction of methyl 3-phenylpropionate
having an ¡-proton as a starting ester with methyl iodide and
benzoyl chloride as an acylating agent also proceeded smoothly
obtaining the corresponding adduct in good yield (eq 3).
1.2 equiv +
0.8 equiv
PhCOCl
3.0 equiv Sr0
3.0 equiv MeI
O
O
Ph
OMe
r.t., 60 min
THF, r.t., 30 min
9
O
Ph
2 molL−1 NaOH(aq)
r.t., 120 min
ð3Þ
Ph
10 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
88%
Chem. Lett. 2012, 41, 35-36
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/