Indium-catalyzed synthesis of keto esters from cyclic 1,3-diketones and alcohols and application to the synthesis of seratrodast

Article abstract of DOI:10.1002/asia.200900553

Esterification reactions from cyclic 1,3-diketones and alcohols are carried out in the presence of several Lewis acids. In particular, indium(III) triflate, In(OTf)₃, iron(III) triflate, Fe-(OTf)₃, copper(II) triflate, Cu(OTf)₂, and silver(I) triflate, AgOTf, show high catalytic activities. These reactions proceed through the carbon-carbon bond cleavage by a retro-aldol reaction and were found to be highly regioselective even in the presence of other functional groups. This type of reaction can also be applied to the preparation of the keto esters during the synthesis of seratrodast, which is an antiasthmatic and eicosanoid antagonist.

Full text of DOI:10.1002/asia.200900553

DOI: 10.1002/asia.200900553
Indium-Catalyzed Synthesis of Keto Esters from Cyclic 1,3-Diketones and
Alcohols and Application to the Synthesis of Seratrodast
Yoichiro Kuninobu,* Atsushi Kawata, Taihei Noborio, Syun-ichi Yamamoto,
Takashi Matsuki, Kazumi Takata, and Kazuhiko Takai*[a]
Abstract: Esterification reactions from
cyclic 1,3-diketones and alcohols are
carried out in the presence of several
catalytic activities. These reactions pro-
ceed through the carbon–carbon bond
cleavage by a retro-aldol reaction and
were found to be highly regioselective
even in the presence of other function-
al groups. This type of reaction can
also be applied to the preparation of
the keto esters during the synthesis of
seratrodast, which is an antiasthmatic
and eicosanoid antagonist.
Lewis acids. In particular, indium
triflate, In(OTf)3, iron(III) triflate, Fe-
(OTf)3, copper(II) triflate, Cu(OTf)2,
ACHTUNGTNER(NUNG III)
A
ACHTUNGTRENNUNG
Keywords: alcohols · esterification ·
indium · ketones · keto esters
A
ACHTUNGTRENNUNG
and silver(I) triflate, AgOTf, show high
Introduction
using InACTHGNUTRENNU(G OTf)3. Then, we describe an application of the pro-
posed method to the synthesis of the drug, seratrodast.
Esters are one of the most fundamental and important cate-
gories in organic chemistry. Many bioactive molecules and
functional materials contain ester groups. Therefore, many
strategies for the synthesis of esters have been developed.[1]
For example, condensation of alcohols and carboxylic
acids,[2,3] or acid anhydrides,[4] or acyl halides,[5] transesterifi-
cation,[6] ester-interchange reactions,[7] mercury-catalyzed re-
actions of carboxylic acids with alkynes,[8] metal-catalyzed
oxidative procedures starting from aldehydes,[9] and enzyme-
catalyzed methods[10] are well known. As an alternative syn-
thetic method, we recently reported the indium-catalyzed
synthesis of esters from 1,3-diketones and alcohols through
the nucleophilic attack of an alcohol to a carbonyl group of
a 1,3-diketone, and the carbon–carbon bond cleavage by a
retro-aldol reaction [Eq. (1)].[11–13] An investigation of the
Results and Discussion
Investigation of Several Catalysts
In the synthesis of esters from 1,3-dicarbonyl compounds
and alcohols, InACTHNUTRGNEUNG
(OTf)3 has a high catalytic activity.[11] Inves-
tigation of various Lewis acids showed that several metal
salts have catalytic activities (Table 1). In particular, Fe-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
catalysts for this synthesis revealed that iron
N
showed high catalytic activities. Interestingly, the esterifica-
tion occurred at the carbonyl group of the cyclopentanone
framework selectively. Considering the catalytic activities,
A
ACHTUNGTRENNUNG
AgOTf, also have high catalytic activities. In this paper, we
first investigate the scope and limitations of the substrates
we decided on indium triflate, InACHTUNRGTNEUNG(OTf)3, as the key catalyst.
Indium-Catalyzed Esterification of 2-Phenylethanol with
Several Cyclic 1,3-Diketones
[a] Dr. Y. Kuninobu, A. Kawata, T. Noborio, S.-i. Yamamoto, T. Matsuki,
K. Takata, Prof. Dr. K. Takai
First, we investigated the scope and limitations of various
1,3-dicarbonyl compounds using an indium catalyst. In the
reaction between 2-acetylcyclopentanone (1a) and 2-phenyl-
ethanol (2a), the yield of 2-phenylethyl 6-oxoheptanoate
(3a) was improved by adding a catalytic amount of 2,6-di-
tert-butylpyridine (Table 2, entry 1).[14] In this reaction, the
Division of Chemistry and Biochemistry
Graduate School of Natural Science and Technology
Okayama University
Tsushima, Kita-ku, Okayama 700-8530 (Japan)
Fax : (+81)86-251-8094
E-mail: kuninobu@cc.okayama-u.ac.jp
ktakai@cc.okayama-u.ac.jp
Chem. Asian J. 2010, 5, 941 – 945
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941

FULL PAPERS
Table 1. Catalytic activities of several catalysts.[a]
Table 2. Indium-catalyzed reaction of cyclic 1,3-dicarbonyl compound 1 with 2-phe-
nylethanol (2a).[a]
Entry 1,3-Dicarbonyl Product
compound
Yield [%][b]
Entry Catalyst
Yield [%][b]
Entry Catalyst
Yield [%][b]
3a
3b
3a
3b
1[c]
>99
[d]
1
2
3
4
5
6
Sc
Fe
Fe
G
77
51
96
67
2
3
4
3
3
3
7
8
9
10
11
12
Ni
Cu
Zn(OTf)2
In(OTf)3
Bi(OTf)3
Me3SiOTf
U
88
94
20
96
43
47
4
6
1
4
1
2
G
ACHTUNGTRENNUNG
[c]
(OTf)3
ACHTUNGTRENNUNG
0
FeCl3
ACHTUNGTRENNUNG
FeCl3·6H2O 54
AgOTf 93
ACHTUNGTRENNUNG
2
85
11
[a] 2a (1.2 equiv). [b] GC yield. [c] FeCl3 (3.0 mol%), AgOTf
(9.0 mol%). [d] NiCl2 (3.0 mol%), AgOTf (6.0 mol%).
3b
3
7
alcohol attacked the carbonyl group of the cyclopentanone
moiety with high selectivity, and 2-phenylethyl acetate (3b)
was not formed. The reaction of 2-acetylcyclohexanone (1b)
with 2-phenylethanol (2a) in the presence of a catalytic
3b
80
92
4
amount of indiumACHTUNGTRENNUNG(III) triflate under solvent-free conditions
at 808C for 24 h afforded 2-phenylethyl 7-oxooctanoate (3c)
and 2-phenylethyl acetate (3b) in 85% and 11% yields, re-
spectively (Table 2, entry 2). In contrast, esterification oc-
curred at the acetyl moiety using 2-acetylcyclododecanone
(1c) as a substrate (Table 2, entry 3). When 2-benzoylcyclo-
pentanone (1d) was employed as the substrate, the five-
membered ring opened, and only e-keto ester 3e was ob-
tained in 92% yield (Table 2, entry 4). 2-Benzoylcyclohexa-
none (1e) and 2-isobutyrylcyclohexanone (1 f) also pro-
duced the corresponding z-keto esters 3g and 3h in 72%
and 78% yields, respectively (Table 2, entries 5 and 6). A
cyclic 1,3-diketone, cyclohexane-1,3-dione (1g), also under-
0
5[d]
3 f
6
72
19
78
15
95
went the reaction in the presence of InACTHNUTRGENUG(N OTf)3, and yielded
d-keto ester 3j through a ring opening reaction in 95%
yield without any side products (Table 2, entry 7). In con-
trast to 1,3-diketones, b-keto esters and 1,3-diesters did not
undergo the esterification reaction.
7
[a] 2a (1.2 equiv). [b] Yield of isolated product. [c] 2,6-Di-tert-butylpyridine
(5.0 mol%) was used as an additive. [d] 2a (1.5 equiv), In(OTf)3 (5.0 mol%).
AHCTUNGTRENNUNG
Indium-Catalyzed Esterification of Several Alcohols with 2-
Acetylcyclopentanone
Next, the scope of several alcohols was investigated using
InACHTUNGTRENNUNG(OTf)3 (Table 3). A secondary alcohol 2b yielded acetate
3k in 45% yield. By adding 2,6-di-tert-butylpyridine as an
additive, the reaction proceeded more cleanly, and improved
the yield of 3k to 60% (Table 3, entry 1). In the following
investigations, it was found that the addition of a catalytic
amount of 2,6-di-tert-butylpyridine was effective to obtain
the keto esters 3 in good to excellent yields. Allyl alcohol
(2c) afforded the corresponding allyl ester 3l in 78% yield
(Table 3, entry 2). Alcohols with carbon–carbon double and
triple bonds provided the corresponding e-keto esters, 3m–
3o in 84%–91% yields without isomerization of the olefin
and acetylene moieties (Table 3, entries 3–5). The corre-
sponding e-keto esters, 3p–3s were afforded from alcohols
that bear bromo, ether, ester, and nitrile groups in good to
excellent yields without affecting the functional groups
(Table 3, entries 6–9). All reactions occurred only at the car-
bonyl group of the cyclopentanone framework, and single
Abstract in Japanese:
942
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 941 – 945

Application of Keto Esters for the Synthesis of Seratrodast
Table 3. Indium-catalyzed reaction of 2-acetylcyclopentanone (1a) with
several alcohol 2.[a]
Proposed Mechanism
The proposed reaction mechanism is as follows (Scheme 1):
(1) coordination of the cyclic 1,3-dicarbonyl compound to a
metal center (Lewis acid); (2) nucleophilic attack of an alco-
hol on the carbonyl group of the cyclic 1,3-dicarbonyl com-
pound; (3) carbon–carbon bond cleavage through a retro
aldol-type reaction (ring-opening reaction); (4) the formed
enolate is quenched by a proton to give the keto ester and
regenerate the metal catalyst. In this reaction, step (3) is im-
portant because it leads to the formation of esters, and char-
acterizes the reactivity of the reaction.
Entry
1
Alcohol
Yield [%][b]
3k
60
2[c]
3
3l
78
84
3m
4
5
3n
3o
88
91
6
7
3p
3q
97
93
8
3r
3s
64
84
9[c]
[a] 2 (1.2 equiv). [b] Yield of isolated product. [c] 2 (1.5 equiv).
products were formed selectively. However, neither a terti-
ary alcohol, 1-adamanthanol, nor phenol gave the corre-
sponding esters.
Scheme 1. Proposed mechanism for the formation of keto esters.
Compounds that have both primary and secondary alco-
hols, such as sugars, are well known. Treatment of 1,3-dike-
tone 1a with a 1:1 mixture of primary and secondary alco-
Synthesis of Seratrodast
hols 2a and 2b in the presence of In
lectively produced ester 3a in 85% yield [Eq. (2)].
(OTf)3 as a catalyst, se-
Indium-catalyzed synthesis of esters can be applied to the
synthesis of seratrodast, which is an antiasthmatic and eico-
sanoid antagonist (Scheme 2).[15] Treatment of cyclic 1,3-di-
ketone 1e with ethanol (2k) in the presence of indium tri-
flate, InACTHNUTRGNEUNG
(OTf)3, provided z-keto ester 8 in 85% yield.[16] The
following procedures have already been reported.[15a] Car-
boxylic acid 10 was yielded in 84% yield by the reduction of
The reaction could be applied to the synthesis of keto
amide and keto carboxylic acid [Eqs. (3) and (4)]. The treat-
ment of 2-acetylcyclopentanone (1a) with morpholine (4) or
water (6) gave the corresponding e-keto amide 5 and e-keto
carboxylic acid 7 in 54% and 94% yields, respectively
[Eqs. (3) and (4)]. In these reactions, neither N-acetylmor-
pholine nor acetic acid was formed.
Scheme 2. Synthesis of seratrodast (13).
Chem. Asian J. 2010, 5, 941 – 945
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www.chemasianj.org
943

Y. Kuninobu, K. Takai et al.
FULL PAPERS
2-Phenylethyl 6-oxo-6-phenylhexanoate (3e). IR (nujol): n˜ =1744, 1693,
z-keto ester 8 with sodium borohydride and hydrolysis of
the formed alcohol 9. After the condensation of alcohol 10
with 2,3,5-trimethylbenzene-1,4-diol (11) in the presence of
a boron trifluoride–diethyl ether complex followed by oxida-
tion of 12, seratrodast (13) was obtained in 61% yield.
1169, 972, 907, 737 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.66–1.79 (m,
;
4H), 2.35 (t, J=7.0 Hz, 2H), 2.92–2.98 (m, 4H), 4.29 (t, J=7.0 Hz, 2H),
7.20–7.22 (m, 3H), 7.27–7.30 (m, 2H), 7.46 (t, J=7.6 Hz, 2H) , 7.56 (t,
J=7.6 Hz, 1H), 7.94 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=
23.4, 24.4, 33.9, 37.9, 64.6, 126.4, 127.8, 128.3, 128.4, 128.7, 132.8, 136.8,
173.1, 199.5 ppm; HRMS (ESI): m/z (%) calcd for C20H22O3Na: 333.1467
[M+Na]+; found: 333.1476.
2-Phenylethyl 7-oxo-7-phenylheptanoate (3g). IR (nujol): n˜ =1728, 1092,
Conclusions
976, 899, 775, 755, 687 cmÀ1 1H NMR (CDCl3, 400 MHz): d=1.34–1.42
;
(m, 2H), 1.61–1.69 (m, 2H), 2.31 (t, J=7.5 Hz, 2H), 2.90–2.98 (m, 4H),
4.29 (t, J=7.0 Hz, 2H), 7.20–7.24 (m, 3H), 7.26–7.31 (m, 2H) 7.46 (t, J=
7.3 Hz, 2H) , 7.56 (t, J=7.3 Hz, 1H), 7.95 ppm (m, 2H); 13C NMR
(CDCl3, 100 MHz): d=23.8, 24.7, 28.7, 34.0, 35.0, 38.2, 64.6, 126.4, 127.9,
128.4, 128.5, 128.8, 132.8, 136.9, 137.7, 173.5, 200.0 ppm; HRMS (ESI): m/
z (%) calcd for C20H22O3Na: 347.1623 [M+Na]+; found: 347.1633.
We have succeeded in the Lewis acid-catalyzed synthesis of
esters by regioselective reactions between 1,3-dicarbonyl
compounds and alcohols. In particular, indium triflate, iron
triflate, copper triflate, and silver triflate were effective to
promote the reaction efficiently. The reaction proceeded
well in the presence of several functional groups, such as
olefins, acetylenes, halides, ethers, esters, and nitriles. The
reaction could also be applied to the synthesis of a drug, ser-
atrodast. We hope that this reaction will become a powerful
tool in synthetic organic chemistry.
2-Phenylethyl 8-methyl-7-oxononanoate (3h). IR (nujol): n˜ =1740, 1717,
1169, 999, 748 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.08 (d, J=6.9 Hz,
;
6H), 1.23–1.30 (m, 2H), 1.51–1.63 (m, 4H), 2.28 (t, J=7.5 Hz, 2H), 2.42
(t, J=7.3 Hz, 2H), 2.54–2.61 (m, 1H), 2.93 (t, J=7.0 Hz, 2H), 4.28 (t, J=
7.0 Hz, 2H), 7.21–7.24 (m, 3H), 7.28–7.32 ppm (m, 2H); 13C NMR
(CDCl3, 100 MHz): d=18.2, 23.3, 24.7, 28.7, 34.1, 35.1, 40.0, 40.8, 64.7,
126.5, 128.5, 128.9, 137.8, 173.6, 214.7 ppm; HRMS (ESI): m/z (%) calcd
for C20H22O3Na: 313.1780 [M+Na]+; found: 313.1789.
1-Methyl-3-phenylpropyl 6-oxoheptanoate (3k). IR (nujol): n˜ =1736,
1175, 1130, 1082, 1051, 962, 746, 698 cmÀ1 1H NMR (400 MHz, CDCl3):
;
Experimental Section
d=1.24 (d, J=6.3 Hz, 3H), 1.55–1.70 (m, 4H), 1.74–1.86 (m, 1H), 1.86–
1.99 (m, 1H), 2.13 (s, 3H), 2.29 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.9 Hz,
2H), 2.54–2.72 (m, 2H), 4.94 (tq, J=6.3 and 6.6 Hz, 1H), 7.11–7.22 (m,
3H), 7.28 ppm (t, J=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=20.0,
23.2, 24.5, 29.9, 31.8, 34.3, 37.6, 43.2, 70.4, 125.9, 128.3, 128.4, 141.5, 173.0,
208.5 ppm; HRMS (ESI): m/z (%) calcd for C16H22O3Na: 299.1623
[M+Na]+; found: 299.1629.
General
All reactions were carried out under an argon atmosphere. 1,3-Diketones,
alcohols, an amine, and InACHTNUGTRNEUNG(OTf)3 were purchased from Wako Pure Chem-
ical Industries, Tokyo Kasei Kogyo Co. and Aldrich Co., and used as re-
ceived.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded using a
JEOL JNM-LA400 spectrometer. Proton chemical shifts are reported rel-
ative to Me4Si (CDCl3) at d=0.00 ppm or residual solvent peak (CDCl3
at d=7.26 ppm). Carbon chemical shifts are reported relative to CDCl3
at d=77.00 ppm. IR spectra were recorded on a Nicolet Protꢁgꢁ 460.
HR-MS spectra were measured using a Waters LCT (ESI-TOF MS) mass
spectrometer.
Allyl 6-oxoheptanoate (3l). IR (nujol): n˜ =1744, 1724, 1144, 984,
930 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.51–1.75 (m, 4H), 2.13 (s,
;
3H), 2.34 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.6 Hz, 2H), 4.56 (d, J=5.7 Hz,
2H), 5.26 (dd, J=10.5 and 17.4 Hz, 2H), 5.81–6.01 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=23.2, 24.3, 29.9, 34.0, 43.2, 65.0, 118.2,
132.2, 173.0, 208.5 ppm; HRMS (ESI): m/z (%) calcd for C10H16O3Na:
207.0997 [M+Na]+; found: 207.0990.
Structures of esters 3b, 3 f, and 3i, and carboxylic acid 7 were determined
10-Undecenyl 6-oxoheptanoate (3m). IR (nujol): n˜ =2361, 2341, 1740,
1
by comparison with the H and 13C NMR spectra taken from the Aldrich
1722, 1171, 1146, 1084, 964, 908, 735 cmÀ1 1H NMR (400 MHz, CDCl3):
;
database. The structures of 3a,[11] 3j,[11] 8,[17] 10,[15a] and 13[15a] were deter-
mined by comparison with the data already reported.
d=1.16–1.42 (m, 14H), 1.50–1.66 (m, 4H), 2.02 (q, J=6.9 Hz, 2H), 2.12
(s, 3H), 2.30, (t, J=6.9 Hz, 2H), 2.44 (t, J=6.6 Hz, 2H), 4.04 (t, J=
6.6 Hz, 2H), 4.94 (dd, J=10.2 and 17.1 Hz, 2H), 5.71–5.88 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=23.2, 24.4, 25.9, 28.6, 28.9, 29.0, 29.2,
29.3, 29.4, 29.8, 33.8, 34.0, 43.2, 64.5, 114.1, 139.2, 173.5, 208.5 ppm;
HRMS (ESI): m/z (%) calcd for C18H32O3Na: 319.2249 [M+Na]+; found:
319.2236.
Synthesis
Keto ester 3a.
A
mixture of 2-acetylcyclopentanone (1a, 31.5 mg,
(OTf)3
0.250 mmol), 2-phenylethanol (2a, 36.6 mg, 0.300 mmol), InAHCTUNGTRENNUNG
(4.2 mg, 0.0075 mmol), and 2,6-di-tert-butylpyridine (2.4 mg, 0.013 mmol)
was stirred at 808C for 24 h. The product was isolated by column chroma-
tography on silica gel to give 3a (62.1 mg, 0.250 mmol, >99%).
9-Dodecynyl 6-oxoheptanoate (3n). IR (nujol): n˜ =2359, 2341, 1738,
1720, 1238, 1173, 1146, 1082 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.09
;
(t, J=6.6 Hz, 3H), 1.21–1.39 (m, 8H), 1.39–1.52 (m, 2H), 1.52–1.69 (m,
6H), 2.05–2.21 (m, 7H), 2.24–2.35 (m, 2H), 2.39–2.50 (m, 2H), 4.03 ppm
(t, J=5.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=12.4, 14.3, 18.6, 23.1,
24.4, 25.8, 28.6, 28.7, 28.95, 29.02, 29.1, 29.8, 34.0, 43.2, 64.5, 79.4, 81.6,
173.4, 208.5 ppm; HRMS (ESI): m/z (%) calcd for C19H32O3Na: 331.2249
[M+Na]+; found: 331.2247.
2-Phenylethyl 7-oxooctanoate (3c). IR (nujol): n˜ =1740, 1165, 910,
737 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.22–1.32 (m, 2H), 1.52–1.63
;
(m, 4H), 2.13 (s, 3H), 2.28 (t, J=7.5 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H),
2.93 (t, J=7.0 Hz, 2H), 4.29 (t, J=7.0 Hz, 2H), 7.20–7.25 (m, 3H), 7.28–
7.32 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=23.2, 24.5, 28.4, 29.7,
33.9, 35.0, 64.6, 76.7, 126.4, 128.3, 128.7, 137.7, 173.3, 208.7 ppm; HRMS
(ESI): m/z (%) calcd for C16H22O3Na: 285.1467 [M+Na]+; found:
285.1470.
2-Decynyl 6-oxoheptanoate (3o). IR (nujol): n˜ =1746, 1722, 1148, 1082,
966 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.86 (t, J=6.8 Hz, 3H), 1.19–
;
1.40 (m, 8H), 1.49 (quint, J=6.6 Hz, 2H), 1.55–1.68 (m, 4H), 2.12 (s,
3H), 2.15–2.25 (m, 2H), 2.34 (t, J=6.9 Hz, 2H), 2.43 (t, J=6.9 Hz, 2H),
4.64 ppm (t, J=2.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=14.0, 18.7,
22.6, 23.1, 24.2, 28.4, 28.7, 28.8, 29.8, 31.7, 33.8, 43.2, 52.7, 73.9, 87.7,
172.7, 208.4 ppm; HRMS (ESI): m/z (%) calcd for C17H28O3Na: 303.1936
[M+Na]+; found: 303.1935.
2-Phenylethyl 13-oxotetradecanoate (3d). IR (nujol): n˜ =1744, 1720,
1165 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.22–1.32 (m, 10H), 1.51–
;
1.62 (m, 4H), 2.13 (s, 3H), 2.28 (t, J=7.5 Hz, 2H), 2.41 (t, J=7.4 Hz,
2H), 2.94 (t, J=7.0 Hz, 2H), 4.29 (t, J=7.0 Hz, 2H), 7.20–7.24 (m, 3H),
7.28–7.32 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=23.9, 24.9, 29.1,
29.20, 29.23, 29.38, 29.40, 29.42, 29.5, 29.8, 34.3, 35.2, 43.8, 64.7, 126.5,
128.5, 129.0, 137.9, 173.8, 209.3 ppm; HRMS (ESI): m/z (%) calcd for
C22H34O3Na: 369.2406 [M+Na]+; found: 369.2407.
6-Bromohexyl 6-oxoheptanoate (3p). IR (nujol): n˜ =2361, 2341, 1740,
1
1169, 1080, 972, 644, 563 cmÀ1; H NMR (400 MHz, CDCl3): d=1.27–1.39
944
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Chem. Asian J. 2010, 5, 941 – 945

Application of Keto Esters for the Synthesis of Seratrodast
(m, 2H), 1.39–1.50 (m, 2H), 1.50–1.66 (m, 6H), 1.84 (quint, J=7.2 Hz,
2H), 2.10 (s, 3H), 2.28 (t, J=6.9 Hz, 2H), 2.42 (t, J=6.6 Hz, 2H), 3.38 (t,
J=6.9 Hz, 2H), 4.03 ppm (t, J=6.9 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=23.1, 24.3, 25.1, 27.7, 28.4, 29.8, 32.5, 33.6, 34.0, 43.2, 64.1,
173.3, 208.4 ppm; HRMS (ESI): m/z (%) calcd for C16H22O3Na: 329.0728
[M+Na]+; found: 329.0720.
Chem. 1998, 63, 2342–2347; d) K. Ishihara, A. Hasegawa, H. Yama-
moto, Angew. Chem. 2001, 113, 4201–4203; Angew. Chem. Int. Ed.
2001, 40, 4077–4079; e) A. Orita, C. Tanahashi, A. Kakuda, J.
Otera, J. Org. Chem. 2001, 66, 8926–8934; f) K. Mikami, Y. Mikami,
H. Matsuzawa, Y. Matsumoto, J. Nishikido, F. Yamamoto, H. Naka-
jima, Tetrahedron 2002, 58, 4015–4021.
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37, 8053–8056; b) T. Oriyama, Y. Hori, K. Imai, T. Hosoya, Y.
Sasaki, Tetrahedron Lett. 1996, 37, 8543–8546.
3-Benzyloxypropyl 6-oxoheptanoate (3q). IR (nujol): n˜ =1742, 1724,
698 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=1.53–1.65 (m, 4H), 1.93
(quint, J=6.3 Hz, 2H), 2.12 (s, 3H), 2.28 (t, J=6.9 Hz, 2H), 2.43 (t, J=
6.6 Hz, 2H), 3.54 (t, J=6.3 Hz, 2H), 4.18 (t, J=6.6 Hz, 2H), 4.50 (s, 2H),
7.24–7.39 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=23.1, 24.3, 29.0,
29.8, 34.0, 43.2, 61.6, 66.6, 72.9, 126.7, 127.6, 128.3, 138.3, 173.3,
208.4 ppm; HRMS (ESI): m/z (%) calcd for C17H24O4Na: 315.1572
([M+Na])+; found: 315.1580.
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5311; b) T. Hanamoto, Y. Sugimoto, Y. Yokoyama, J. Inanaga, J.
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[8] a) P. F. Hudrlik, A. M. Hudrlik, J. Org. Chem. 1973, 38, 4254–4258;
b) T. Mitsudo, Y. Hori, Y. Yamakawa, Y. Watanabe, Tetrahedron
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2-Acetoxyethyl 6-oxoheptanoate (3r). IR (nujol): n˜ =2359, 2341, 1747,
1717, 1232, 1146, 1067, 962, 723, 667 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d=1.53–1.67 (m, 4H), 2.06 (s, 3H), 2.12 (s, 3H), 2.29–2.37 (m, 2H), 2.39–
2.48 (m, 2H), 4.25 ppm (s, 4H); 13C NMR (100 MHz, CDCl3): d=20.8,
23.0, 24.2, 29.8, 33.8, 43.2, 62.0, 62.1, 170.7, 173.1, 208.4 ppm; HRMS
(ESI): m/z (%) calcd for C11H18O5Na: 253.1052 [M+Na]+; found:
253.1047.
2-Cyanoethyl 6-oxoheptanoate (3 s). IR (nujol): n˜ =1746, 1703, 1497,
1236, 1205, 1146, 1088, 1055, 1032, 845, 748, 698 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=1.49–1.69 (m, 4H), 2.07 (s, 3H), 2.31 (t, J=
6.9 Hz, 2H), 2.40 (t, J=6.6 Hz, 2H), 2.66 (t, J=6.3 Hz, 2H), 4.21 ppm (t,
J=6.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=17.8, 22.8, 24.0, 30.0,
33.4, 42.9, 58.4, 116.7, 172.5, 208.2 ppm; HRMS (ESI): m/z (%) calcd for
C10H15NO3Na: 220.0950 [M+Na]+; found: 220.0947.
1-(4-Morpholinyl)heptane-1,6-dione (5). IR (nujol): n˜ =3503, 2341, 1713,
[10] a) G. Kirchner, M. P. Scollar, A. M. Klibanov, J. Am. Chem. Soc.
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[12] This reactivity is quite different from the reported result that
1636, 1234, 1115, 1034, 964, 845 cmÀ1 1H NMR (400 MHz, CDCl3): d=
;
1.50–1.67 (m, 4H), 2.09 (s, 3H), 2.27 (t, J=6.9 Hz, 2H), 2.42 (t, J=
6.6 Hz, 2H), 3.34–3.48 (m, 2H), 3.49–3.59 (m, 2H), 3.59–3.70 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=23.3, 24.5, 29.8, 32.7, 41.8, 43.3,
45.8, 66.5, 66.8, 171.2, 208.6 ppm; HRMS (ESI): m/z (%) calcd for
C11H19NO3Na: 236.1263 [M+Na]+; found: 236.1273.
ytterbiumACTHNUTRGNE(UNG III) triflate provides a b-keto enol ether through the nu-
cleophilic attack of an alcohol on a 1,3-diketone followed by dehy-
dration. See: M. Curini, F. Epifano, S. Genovese, Tetrahedron Lett.
2006, 47, 4697–4700.
Acknowledgements
[13] There have been many reports on indium triflate-catalyzed transfor-
mations. For examples, see: a) T.-P. Loh, Q.-Y. Hu, K.-T. Tan, H.-S.
Cheng, Org. Lett. 2001, 3, 2669–2672; b) T.-P. Loh, C.-L. K. Lee, K.-
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5264–5271.
[14] Addition of 2,6-di-tert-butylpyridine was effective to improve the
yields of keto esters although only for 2-acetylcyclopentanone (1a).
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Financial support from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology of Japan is gratefully acknowledged.
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the reaction of 6-(ethoxycarbonyl)hexanoic acid with thionyl chlo-
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with benzene in the presence of a stoichiometric amount of AlCl3.
See: Ref. 15b.
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Received: October 13, 2009
Published online: March 16, 2010
Chem. Asian J. 2010, 5, 941 – 945
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
945