A new method for the lactonization of ω-hydroxy carboxylic acids with Di-2-thienyl carbonate by the promotion of DMAP and iodine

Article abstract of DOI:10.1246/cl.2005.72

Successive reactions of ω-hydroxycarboxylic acids with an equimolar amount of di-2-thienyl carbonate (2-DTC) in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) followed by an addition of 2-4 equimolar amounts of iodine afforded the corresponding lactones in good to high yields. Copyright

Full text of DOI:10.1246/cl.2005.72

72
Chemistry Letters Vol.34, No.1 (2005)
A New Method for the Lactonization of !-Hydroxy Carboxylic Acids
with Di-2-thienyl Carbonate by the Promotion of DMAP and Iodine
Yoshiaki Oohashi,y Kentarou Fukumoto,y and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received October 22, 2004; CL-041249)
Successive reactions of !-hydroxycarboxylic acids with
most effectively when the reaction was carried out in CH3CN
(Entry 5). The same result was obtained even when 0.05 equiv-
alents of DMAP were used (Entry 6). It is interesting to note that
the corresponding lactone was not detected in any cases even
when it was allowed to react under more concentrated conditions
(35 mM) for 9 h (Entry 7). This indicates that the lactonization is
not accelerated by DMAP alone, therefore, it was needed to use
the other activator so as to form a lactone in high yield.
an equimolar amount of di-2-thienyl carbonate (2-DTC) in the
presence of a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) followed by an addition of 2–4 equimolar amounts of
iodine afforded the corresponding lactones in good to high
yields.
Natural products having macrolide structure are important
therapeutic agents in clinical medicine because of their antibiot-
ic, antitumoral, and other various helpful biochemical activities.
Accordingly, to prepare macrolactones from !-hydroxycarbox-
ylic acids is also major concern in synthetic organic chemistry.
Several useful methods have therefore been reported; namely,
the use of DCC,1 2,4,6-trichlorobenzoyl chloride,2 2,20-dipyridyl
disulfide/Ph3P,3 1-methyl-2-chloropyridinium iodide/Et3N,4
DEAD/Ph3P,5 2-Me-6-NO2-benzoic anhydride (MNBA),6 4-
(trifluoromethyl)benzoic anhydride,7 4-nitrobenzoic anhydride/
Sc(OTf)3,8 etc.9
In our previous communication, a new esterification
method between nearly equimolar amounts of carboxylic acids
and alcohols with the use of di-2-thienyl carbonate (2-DTC) in
the presence of a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) was reported.10 This reaction proceeded via two-step
procedure, i.e., i) reaction of carboxylic acid with 2-DTC that
formed thienyl ester and ii) formation of ester from thus formed
thienyl ester with various alcohols (Scheme 1). It was revealed in
both steps then that a catalytic amount of DMAP worked as use-
ful activators although a long reaction time was required for the
completion of the second step. Recently, it was reported from
our laboratory that this esterification could be accelerated by fur-
ther addition of an equimolar amount of iodine and to improve
the reaction time and the yield.11 This result prompted us to
study 2-DTC-mediated macrolactonization of !-hydroxycar-
boxylic acids in the coexistence of iodine.
Table 1. Synthesis of 2-thienyl 12-hydroxydodecanoate 2 using
12-hydroxydodecanoic acid and 2-DTC in the presence of
DMAP
O
O
2-DTC (1.0 equiv.)
DMAP (equiv.)
HO
OH
HO
O
S
10
1
10
2
Solv. (18 mM) , rt
Entry Solvent DMAP/equiv. Time/min Yield/%
1
2
3
4
5
6
7
CH2Cl2
toluene
THF
0.1
0.1
0.1
0.1
0.1
0.05
0.05
60
90
120
120
15
81
73
59
49
97
95
96a
Et2O
CH3CN
CH3CN
CH3CN
15
9 h
aConcentration 35 mM.
Next, lactonization of 12-hydroxydodecanoic acid that uses
2-DTC in the presence of DMAP and iodine was examined
(Table 2). Acetonitrile then turned out to be the most suitable
solvent for the preparation of thienyl ester 2 as described above.
However, the corresponding lactone was obtained in low yield
when a solution of 12-hydroxydodecanoic acid, 2-DTC and
DMAP in CH3CN was diluted to 2 mM by further addition of
CH3CN and iodine at room temperature (Entry 1).
Therefore, thienyl ester 2 was prepared in CH3CN as men-
tioned and then the effect of further addition of a solvent in
the lactonization step under diluted concentration was examined.
After various solvents were screened, the desired lactone was
obtained in 47% yield by further addition of toluene (Entry 6).
It was found that this reaction proceeded more smoothly in a
mixed solvent of CH3CN and toluene.
In the first place, the synthesis of 2-thienyl 12-hydroxy do-
decanoate 2, an active ester intermediate, was examined by re-
acting 12-hydroxydodecanoic acid 1 with 2-DTC in the presence
of a catalytic amount of DMAP (Table 1). The formation of 2
was found to be influenced by the solvents and was obtained
O
It is also noted that the corresponding lactone was not de-
tected when the above reaction was carried out in the presence
of DMAP (2.05 equiv.) instead of iodine (Entry 7). This result
indicates that iodine works quite effectively in this lactonization
step.
With these results in mind, the amounts of iodine and sol-
vents were further examined in order to optimize the reaction
conditions (Table 3). Finally, it was found that the desired 12-do-
decanolide was obtained in 77% yield in the case when the reac-
O
O
S
S
O
O
O
2-DTC
+
+
O
O
S
S
R
R
O
O
R
OH
S
DMAP
O
DMAP or I2
R'
+ R'OH
R
O
S
Scheme 1. Esterification of carboxylic acidswith alcohols using
2-DTC promoted by DMAP and iodine.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.1 (2005)
73
Table 2. Lactonization of 12-hydroxydodecanoic acid by using
2-DTC promoted by DMAP and iodine
Table 4. Lactonization of various !-hydroxycarboxylic acids
by using 2-DTC promoted by DMAP and iodine
O
2-DTC
(1.0 equiv.)
2-DTC
(1.0 equiv.)
O
O
O
n
O
O
O
I
2 (2.0 equiv.)
Solv.
O
I
2 ( equiv.)
n
10
O
O
+
O
+
O
HO
OH
HO
OH
10
DMAP
(0.05 equiv.)
CH3CN, rt, 15 min.
DMAP
(0.05 equiv.)
CH3CN, rt, 15 min. 10 h
toluene
reflux
n
n
10
lactone
10
O
O
1
diolide
(1.0 equiv.)
(1.0 equiv.)
lactone
diolide
Yieldb/%
Yielda/% (ring size)
Entry
Solvent (2 mM)a
Time/h
Entry
n
I2/equiv.
lactone
diolide
lactone
diolide
1
2
CH3CN
CH3NO2
Et2O
24
24
8
8
8
28
25
N.D.
N.D.
<26
47
8.6
3
N.D.
trace
11
1
2
3
4
5
6
9
4
4
4
4
2
2
58 (12)
77 (13)
85 (14)
87 (15)
90 (16)
92 (17)
18
14
<8
<11
<6
<7
10
11
12
13
14
3c
4c
5c
6c
7c,d
THF
CH2Cl2
toluene
toluene
8
8
22
N.D.
N.D.
aIsolated yield.
A solution of 1 with 2-DTC in CH3CN (10 mL) was added
DMAP and diluted with solvent (78 mL), followed by addition
of iodine at room temperature. aValues in parentheses was
the concentration without consideration of a change of total
ence of a catalytic amount of DMAP and 2–4 equimolar amounts
of iodine.
c
volume owing to mix plural solvents. bIsolated yield. reflux.
This study was supported in part by a Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
dReaction was carried by using 2 equivalents of DMAP instead
of iodine.
References and Notes
Table 3. Lactonization of 12-hydroxydodecanoic acid by using
2-DTC promoted by DMAP and iodine in CH3CN–toluene
1
2
E. P. Boden and G. E. Keck, J. Org. Chem., 50, 2394 (1985).
J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, and M. Yamaguchi,
Bull. Chem. Soc. Jpn., 52, 1989 (1979).
2-DTC
(1.0 equiv.)
O
O
O
I2 ( equiv.)
O
3
4
5
E. J. Corey and K. C. Nicolaou, J. Am. Chem. Soc., 96, 5614 (1974).
T. Mukaiyama, M. Usui, and K. Saigo, Chem. Lett., 1976, 49.
T. Kurihara, Y. Nakajima, and O. Mitsunobu, Tetrahedron Lett.,
28, 2455 (1976).
10
O
HO
OH
+
O
10
DMAP
(0.05 equiv.)
(1.0 equiv.) CH3CN, rt, 15 min.
toluene
reflux
10
lactone
10
O
1
diolide
6
I. Shiina, M. Kubota, and R. Ibuka, Tetrahedron Lett., 43, 7535
(2002); I. Shiina, M. Kubota, H. Oshiumi, and M. Hashizume,
J. Org. Chem., 69, 1822 (2004).
I2
Concentration
/mMa
Yieldb/%
lactone diolide
Entry
Time/h
/equiv.
7
8
9
I. Shiina and T. Mukaiyama, Chem. Lett., 1994, 677; I. Shiina,
Tetrahedron, 60, 1587 (2004).
K. Ishihara, M. Kubota, H. Kurihara, and H. Yamamoto, J. Org.
Chem., 61, 4560 (1996).
K. Venkataraman and D. R. Wagle, Tetrahedron Lett., 21, 1893
(1980); E. J. Corey and D. J. Brunelle, Tetrahedron Lett., 28,
3409 (1976); K. Steliou, A. S.-Nowosielska, A. Favre, M. A.
Poupart, and S. Hanessian, J. Am. Chem. Soc., 102, 7578 (1980);
K. Steliou and M. A. Poupart, J. Am. Chem. Soc., 105, 7130
(1983); J. Otera, T. Yano, Y. Himeno, and H. Nozaki, Tetrahedron
Lett., 27, 4501 (1986); I. Shiina, Y. Fukuda, T. Ishii, H. Fujisawa,
and T. Mukaiyama, Chem. Lett., 1998, 831; I. Shiina, H. Fujisawa,
T. Ishii, and Y. Fukuda, Heterocycles, 52, 1105 (2000).
1
2
3
4
5
6
0.5
1
2
1
2
2
2
2
1
1
1
20
8
8
8
8
40
50
47
57
67
77
21
19
19
16
15
14
4
8
A solution of 1 with 2-DTC in CH3CN (10 mL) was added
DMAP and diluted with toluene (2 mM; 78 mL, 1 mM;
166 mL), followed by addition of iodine at room temperature.
aThe concentration without consideration of a change of total
b
volume owing to mix plural solvents. Isolated yield.
10 T. Mukaiyama, Y. Oohashi, and K. Fukumoto, Chem. Lett., 33, 552
(2004).
11 Y. Oohashi, K. Fukumoto, and T. Mukaiyama, Chem. Lett., 33, 968
(2004).
tion was carried in 1 mM solution of toluene in the presence of 4
equimolar amounts of iodine (Entry 6).12
12 A typical experimental procedure was as follows: to a mixture of
12-hydroxydodecanoic acid (38.1 mg, 0.176 mmol), and 2-DTC
(40.0 mg, 0.176 mmol) in CH3CN (10 mL) was added DMAP
(1.08 mg, 0.0088 mmol). After stirring for 15 min at room temper-
ature, the resultant solution was diluted by the addition of 166 mL
of toluene and treated with iodine (179 mg, 0.707 mmol). The reac-
tion mixture was stirred for 10 h at reflux temperature of toluene
and then 10% aqueous sodium thiosulfate was added and the sol-
vent was evaporated. The mixture was extracted with ethyl acetate,
and the organic layer was washed with water and brine, dried over
sodium sulfate. After filtration of the mixture and evaporation of
the solvent, the crude product was purified by preparative
thin layer chromatography to afford the corresponding lactone
(26.8 mg, 77%).
Results of the lactonization using various !-hydroxycarbox-
ylic acids are listed in Table 4. The corresponding macrolactones
were obtained in good to high yields along with a small amount
of diolide under the reaction conditions mentioned above. The
desired product was obtained in 58% yield when 11-hydroxyun-
decanoic acid was used (Entry 1). Fourteen to seventeen mem-
bered ring macrolactones were obtained in high yields when
the cyclization was carried out using the corresponding !-hy-
droxycarboxylic acids (Entries 3–6).
It is noted that a simple and effective method for the synthe-
sis of various macrolactones was established by using equimolar
amounts of !-hydroxycarboxylic acids and 2-DTC in the pres-
Published on the web (Advance View) December 11, 2004; DOI 10.1246/cl.2005.72