2,6-Dimethyl-4-nitrobenzoic anhydride (DMNBA): An effective coupling reagent for the synthesis of carboxylic esters and lactones

Article abstract of DOI:10.3987/COM-08-S(N)96

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2,6-dimethyl-4-nitrobenzoic anhydride with triethylamine by the promotion of 4-(dimethylamino)pyridine. The efficiency of the esterification is compared to those of other dehydrations using substituted benzoic anhydrides as coupling reagents. This method was successfully applied to the synthesis of threo-aleuritic acid lactone and the desired 17-membered ring compound was prepared in high yield at room temperature from the corresponding free trihydroxycarboxylic acid using 2,6-dimethyl-4-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine.

Full text of DOI:10.3987/COM-08-S(N)96

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1313 - 1328. © The Japan Institute of Heterocyclic Chemistry
Received, 5th April, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)96
2,6-DIMETHYL-4-NITROBENZOIC ANHYDRIDE (DMNBA): AN
EFFECTIVE COUPLING REAGENT FOR THE SYNTHESIS OF
CARBOXYLIC ESTERS AND LACTONES
Isamu Shiina* and Ryo Miyao
Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601 Japan. E-mail:
shiina@rs.kagu.tus.ac.jp
The authors dedicate this paper to Professor Ryoji Noyori on the celebration of
his 70th birthday.
Abstract – Various carboxylic esters are obtained at room temperature in
excellent yields with high chemoselectivities from nearly equimolar amounts of
carboxylic acids and alcohols using 2,6-dimethyl-4-nitrobenzoic anhydride with
triethylamine by the promotion of 4-(dimethylamino)pyridine. The efficiency of
the esterification is compared to those of other dehydrations using substituted
benzoic anhydrides as coupling reagents. This method was successfully applied
to the synthesis of threo-aleuritic acid lactone and the desired 17-membered ring
compound was prepared in high yield at room temperature from the
corresponding free trihydroxycarboxylic acid using 2,6-dimethyl-4-nitrobenzoic
anhydride in the presence of 4-(dimethylamino)pyridine.
INTRODUCTION
While numerous esterifications using Brφnsted and Lewis acid catalysts have been reported, a few
methods have actually been utilized for the effective preparation of carboxylic esters from equimolar
1
amounts of carboxylic acids and alcohols under mild conditions. Especially, it is required to develop
efficient reactions which proceed under basic conditions since acid-sensitive protective groups such as

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HETEROCYCLES, Vol. 76, No. 2, 2008
acetals or silyl ethers are sometimes needed for the total synthesis of complex molecules.
Recently, we reported several useful methods for the synthesis of carboxylic acid derivatives using
2-4
substituted benzoic anhydrides under acidic or basic conditions.
For example, nearly equimolar
amounts of carboxylic acids and alcohols react in the presence of 2-methyl-6-nitrobenzoic anhydride
(MNBA) with nucleophilic catalysts such as 4-(dimethylamino)pyridine (DMAP) or
4-(dimethylamino)pyridine N-oxide (DMAPO) to produce the corresponding carboxylic esters in high
3
yields (Scheme 1). The intermediary mixed-anhydride, which functions as a reactive acylating reagent
for alcohols to produce the desired carboxylic esters with high product-selectivities, was formed during
the initial part of the reaction using MNBA.
Scheme 1. Effective Synthesis of Carboxylic Esters Using MNBA
Furthermore, a convenient and powerful method for the synthesis of macrolactones with high
product-selectivities via mixed anhydrides generated from ω-hydroxycarboxylic acids and MNBA using
3
basic catalysts was established.
A variety of lactones are prepared in high yields at room temperature
from the corresponding ω-hydroxycarboxylic acids with use of MNBA in the presence of DMAP (Table
1). One of the features of the present protocol is the very simple procedure for producing the desired
products, that is, the addition of ω-hydroxycarboxylic acids to the mixture of MNBA and the promoters at
room temperature affords the desired macrolactones in excellent yields with high purity.

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Table 1. Effective Synthesis of Various Lactones Using MNBA
Scheme 2. Synthesis of Octalactin 8-Membered Ring Core Using MNBA

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HETEROCYCLES, Vol. 76, No. 2, 2008
The utility of the present protocol was also demonstrated by the syntheses of the 8-membered ring moiety
3e
of octalactins A and B (Scheme 2).
The cyclization reaction of the seco-acid was efficiently
accelerated by MNBA with DMAP to afford the desired lactone in high yield at room temperature, and
the corresponding diolide was not produced.
In this paper, the effect of the substituents on the aromatic ring of benzoic anhydrides in the present
esterification was fully evaluated and it was found that 2,6-dimethyl-4-nitrobenzoic anhydride (DMNBA),
a new coupling reagent, could be applied to the effective synthesis of carboxylic esters and lactones by
the combination with DMAP.
RESULTS AND DISCUSSION
Preparation of Substituted Benzoic Anhydrides. First, synthesis of several substituted benzoic
anhydrides possessing electron withdrawing groups is attempted (Scheme 3).
Scheme 3. Several Substituted Benzoic Anhydrides Related to MNBA
Scheme 4. Synthesis of Several Substituted Benzoic Anhydrides

HETEROCYCLES, Vol. 76, No. 2, 2008
1317
2-Nitrobenzoic anhydride (1), 3,4-dinitrobenzoic anhydride (2), 3,5-dinitrobenzoic anhydride (3) and
MNBA (4) were simply prepared from the corresponding commercially available nitro-substituted
benzoic acids 7, 8, 9, and 10 according to the conventional pathway via formation of nitro-substituted
benzoyl chloride as shown in Scheme 4.
5-7
Since 2,6-dimethyl-4-nitrobenzoic acid (11)
could not be obtained from the commercial source, we
tried to prepare 11 starting from 2,6-dimethylaniline (13) via Sandmeyer reaction as depicted in Scheme 5.
Treatment of 13 with tosyl chloride in pyridine afforded sulfonamide 14 and then nitration of 14 with
HNO /AcOH at reflux temperature produced the intermediate 15 in good yield. Deprotection of the
3
tosyl group was performed in the presence of sulfuric acid at 50 °C to produce the desired tri-substituted
aniline 16 in satisfactory yield. Sandmeyer reaction using KCN was applied to the diazonium species
17 generated from aniline 16 by the promotion of CuSO ·5H O produced the tri-substituted benzonitrile
2
4
18 in 41% yield (2 steps).
Scheme 5. Synthesis of the Intermediates of DMNBA
Although the attempted direct hydrolysis of nitrile 18 using sulfuric acid exclusively produced the
undesired primary benzamide 19 (Scheme 6), stepwise transformation via reduction of 18 and oxidation
of the intermediary aldehyde 20 was carried out and the target molecule 11 was obtained in nice yield.
Finally, the tri-substituted benzoic acid 11 was transformed to 2,6-dimethyl-4-nitrobenzoic anhydride
(DMNBA, 5) according to Scheme 4 as described above.
8
Next, 2,6-dimethyl-3,5-dinitrobenzoic acid (12) was prepared form the corresponding Grignard reagent
derived from 2-bromo-1,3-dimethylbenzene (21) as shown in Scheme 7. Generation of the Grignard
reagent from 21 and successive addition of the nucleophile to carbon dioxide smoothly proceeded to give
2,6-dimethylbenzoic acid (22) in 54% yield. Nitration of 22 with H SO /fuming HNO at high
2
4
3
temperature (140 °C) afforded the desired tetra-substituted benzoic acid (12) in good yield (81%).

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Scheme 6. Synthesis of 2,6-Dimethyl-4-nitrobenzoic Acid
According to Scheme 4 as described above, 2,6-dimethyl-3,5-dinitrobenzoic anhydride (DMDNBA, 6)
was successfully obtained.
Scheme 7. Synthesis of 2,6-Dimethyl-3,5-dinitrobenzoic Acid
Esterification Reaction Using Substituted Benzoic Anhydrides. The reaction of 1.1 molar amounts of
3-phenylpropanoic acid with a 1.0 molar amount of 3-phenylpropanol was initially examined in the
presence of 1.2 molar amounts of substituted benzoic anhydrides 1-6, 2.2 molar amounts of triethylamine
and 10 mol% of DMAP (Table 2). When 2-nitrobenzoic, 3,4-dinitrobenzoic or 3,5-dinitrobenzoic
anhydride (1, 2, or 3) was used as the dehydrating reagent, 3-phenylpropyl 3-phenylpropanoate (23) was
obtained in 70%, 65%, or 66% yield along with a small amount of 3-phenylpropyl benzoate (23'), an
undesirable carboxylic ester (Entries 1, 2 or 3). We then tried to introduce substituents on the 2- and
6-positions of the aromatic ring of the benzoic anhydride to provide a hindrance near the carboxyl group
(Entries 4-6); actually, only the desired carboxylic ester was obtained with perfect chemoselectivity when
using 2-methyl-6-nitrobenzoic anhydride (MNBA, 4) as shown in Entry 4. Furthermore, we found that
2,6-dimethyl-4-nitrobenzoic anhydride (DMNBA, 5) was also a quite effective coupling reagent for
providing the carboxylic ester with high chemoselectivity (23/23'=210/1) in the presence of a catalytic
amount of DMAP (Entry 5). On the other hand, 2,6-dimethyl-3,5-dinitrobenzoic anhydride (DMDNBA,
6), which possesses two electron withdrawing groups on the 3- and 5-positions, gave somewhat lower
chemical yield and chemoselectivity as shown in Entry 6.
Several examples of carboxylic esters obtained by the present method under the optimized conditions are
listed in Table 3.

HETEROCYCLES, Vol. 76, No. 2, 2008
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Table 2. Synthesis of Carboxylic Esters Using Substituted Benzoic Anhydrides 1-6
The reaction of aliphatic alcohol gave the desired carboxylic ester in high yield with nearly perfect
selectivity (Entry 1). This protocol is successfully applicable to several carboxylic acids including
aromatic and α,β-unsaturated carboxylic acids, and the corresponding carboxylic esters were obtained in
good to high yields under the mild reaction conditions (Entries 2 and 3). Furthermore, α,α-disubstituted
and α,α,α-trisubstituted acetic acid derivatives were also employed and the corresponding carboxylic
esters were obtained in excellent yields (Entries 4 and 5). Acceptable chemoselectivities were observed
for all cases except for the reaction of the pivalic acid with a primary alcohol as shown in Entry 5.
Furthermore, we compared our results with those obtained according to the Yamaguchi procedure using
9
2,4,6-trichlorobenzoyl chloride. These data are presented in the right column of Table 4 and the
compared data obtained by DMNBA are shown in the left column. We observed the formation of
significant amounts of the undesired alkyl 2,4,6-trichlorobenzoates (23"-26") in many cases (Entries 1
(29% of 23"), 2 (8% of 24"), 3 (12% of 25"), and 4 (6% of 26")), though our method gave almost
perfect chemoselectivities. It is noted that the maximum yield of the desired ester 23 is limited to ca.
70% by Yamaguchi method in Entry 1 since the reaction proceeded without high chemoselectivity.
One of features of the present protocol using DMNBA is the quite simple procedure for the synthesis of a

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HETEROCYCLES, Vol. 76, No. 2, 2008
Table 3. Synthesis of Various Carboxylic Esters Using DMNBA
variety of carboxylic esters. The Yamaguchi method usually requires a stepwise operation, namely,
carboxylic acids are treated with 2,4,6-trichlorobenzoyl chloride and triethylamine at first to generate the
corresponding mixed anhydrides. After filtration of the mixture under an inert gas to remove the formed
triethylammonium chloride, the filtrate containing mixed anhydrides is next used for the esterification of
alcohols with an excess amount of DMAP. On the other hand, by only mixing carboxylic acids,
alcohols, DMNBA, triethylamine and a catalytic amount of DMAP at room temperature, the desired
compounds are produced in excellent yields with high purity according to our convenient method.
Efficient Lactonization Using DMNBA with DMAP. The macrocyclic framework is one of the most
basic structures for useful natural and unnatural organic molecules. Recently, several effective C-C
bond forming reactions such as transition metal-promoted coupling and olefin metathesis have been
widely studied for producing cyclic compounds. However, macrolactonization is still the most popular
method for producing cyclic compounds including carboxylic ester moieties since there are some
effective methods for constructing the ester linkage.
Table 5 shows the yields of the 17-membered macrolactone synthesized by the present method using
3f
MNBA or DMNBA with DMAP. All reactions were carried out at room temperature by adding a
solution of trihydroxycarboxylic acid 28 to a mixture of the substituted benzoic anhydride with DMAP in
dichloromethane.

HETEROCYCLES, Vol. 76, No. 2, 2008
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Table 4. Experimental Results Comparing Two Esterification Methods
The concentration in the table shows the molar amounts of seco-acid to the total volume of the solvent.
Since threo-aleuritic acid (28) did not completely dissolve in the dichloromethane at room temperature,

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HETEROCYCLES, Vol. 76, No. 2, 2008
the starting seco-acid was dissolved in THF prior to use, which was then added to the reaction mixture
including MNBA or DMNBA with DMAP in dichloromethane over a 12 h period at room temperature.
It is noteworthy that the best yield of 29 was attained for the macrolactonization of 28 using DMNBA
with 2.4 molar amounts of DMAP (Entry 3). The difference between the yields for Entries 2 and 3
shows that DMNBA is superior to MNBA for the generation of the desired monomeric lactone 29 in this
cyclization.
Table 5. Cyclization Forming 17-Membered Lactone from Free threo-Aleuritic Acid Using MNBA
or DMNBA
The dihydroxylactone 29 prepared by the above-mentioned method was in turn converted to the
corresponding thiocarbonate 30 by treating with 1,1'-thiocarbonyldiimidazole (TCDI) and DMAP under
reflux in toluene. Finally, 30 was transformed into (9E)-isoambrettolide (31) using trimethyl phosphite
10
in 87% yield.
(9E)-Isoambrettolide is now a very attractive artificial substrate as an alternative musk
resource, therefore, it has been revealed that this pathway is extremely efficient for the preparation of the
artificial perfume ingredient via only three steps (83%, 91%, and 87% yields, respectively) starting from
commercially available threo-aleuritic acid (28).
CONCLUSIONS
We have developed a new reaction that produces carboxylic esters in high yields using DMNBA and
DMAP in the presence of tertiary amines. The DMNBA-promoted cyclization also provided the syn-

HETEROCYCLES, Vol. 76, No. 2, 2008
1323
Scheme 8. Synthesis of the Musk Component (9E)-Isoambrettolide
thetic intermediary lactone of (9E)-isoambrettolide directly from the unprotected threo-aleuritic acid. It
is notable that the experimental procedure is quite simple, and nearly pure carboxylic esters and lactones
are obtained by only mixing DMNBA, basic promoters, and substrates. Further studies of the reaction
using substituted benzoic anhydrides and other applications of the present protocol for the syntheses of
useful complex molecules are now in progress.
EXPERIMENTAL
General
All reactions were carried out under argon atmosphere in dried glassware. Dichloromethane was
distilled from diphosphorus pentoxide, then calcium hydride, and dried over MS 4A. Thin layer
1
chromatography was performed on Wakogel B5F. All melting points are uncorrected. H and
13
C
NMR spectra were recorded with tetramethylsilane (TMS) or chloroform (in chloroform-d) as internal
standard.
Starting materials
All reagents were purchased from Tokyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Inc., or Aldrich
Chemical Co., Inc. and used without further purification unless otherwise noted. 2-Nitrobenzoic
11 11
anhydride (1), 3,4-dinitrobenzoic anhydride (2), 3,5-dinitrobenzoic anhydride (3), DMNBA (5), and

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HETEROCYCLES, Vol. 76, No. 2, 2008
DMDNBA (6) were prepared from the corresponding substituted benzoic acids (7-9, 11, and 12), whereas
MNBA (4) was purchased from Tokyo Kasei Kogyo Co., Ltd. (TCI, M1439) or synthesized from
3c
5-7
2-methyl-6-nitrobenzoic acid (10).
2,6-dimethyl-4-nitrobenzoic acid (11)
and 2,6-dimethyl-
8
3,5-dinitrobenzoic acid (12) were synthesized according to the literature methods.
1
2-Nitrobenzoic anhydride (1). Mp 131-133 °C; H NMR (CDCl ) δ 8.06 (dd, J = 8.2, 1.2 Hz, 2H),
3
7.84 (dd, J = 7.6, 1.5 Hz, 2H), 7.79 (ddd, J = 7.6, 7.3, 1.2 Hz, 2H), 7.73 (dd, J = 8.2, 7.3, 1.5 Hz, 2H);
13
C NMR (CDCl ) δ 159.6, 147.2, 133.8, 132.8, 130.3, 126.1, 124.3; HR MS: calcd for C H N O Na
3 14 8 2 7
+
(M + Na ) 339.0229, found 339.0402.
1
3,4-Dinitrobenzoic anhydride (2). Mp 161-163 °C; H NMR (DMSO-d ) δ 8.56 (d, J = 1.5 Hz, 2H),
6
13
8.41 (dd, J = 8.5, 1.8 Hz, 2H), 8.31 (d, J = 8.5 Hz, 2H); C NMR (DMSO-d ) δ 164.1, 144.2, 141.6,
6
135.9, 135.1, 126.2, 126.1.
1
3,5-Dinitrobenzoic anhydride (3). Mp 215-221 °C; H NMR (DMSO-d ) δ 9.00 (dd, J = 2.1, 2.1 Hz,
6
13
2H), 8.88 (d, J = 2.1 Hz, 4H); C NMR (DMSO-d ) δ 164.0, 148.4, 134.1, 128.9, 122.1.
6
1
2-Methyl-6-nitrobenzoic anhydride (4). Mp 178-180 °C; H NMR (CDCl ): δ 8.06 (d, J = 8.1 Hz,
3
13
2H), 7.64 (d, J = 7.6 Hz, 2H), 7.53 (dd, J = 8.1, 7.6 Hz, 2H), 2.57 (6H, s); C NMR (CDCl ) δ 160.3,
3
145.1, 137.9, 136.6, 130.5, 127.5, 121.7, 19.1; Anal: calcd for C H N O : C, 55.82; H, 3.51; N, 8.14,
16 12 2 7
found: C, 55.81; H, 3.39; N, 8.07.
1
2,6-Dimethyl-4-nitrobenzoic anhydride (5). Mp 195-197 °C; H NMR (CDCl ) δ 7.96 (s, 4H), 2.53
3
13
(s, 12H); C NMR (CDCl ) δ 163.1, 148.6, 137.7, 136.8, 122.8, 19.9; HR MS: calcd for C H N O Na
3
18 16 2 7
+
(M + Na ) 395.0855, found 395.0346.
1
2,6-Dimethyl-3,5-dinitrobenzoic anhydride (6). H NMR (CDCl ) δ 8.60 (s, 2H), 2.68 (s, 12H).
3
Typical Experimental Procedure for the Esterification Reaction
A typical experimental procedure is described for the reaction of 3-phenylpropanoic acid with
3-phenylpropanol (Table 3, Entry 1): To a solution of triethylamine (44.5 mg, 0.440 mmol) in CH2Cl2
(1.5 mL) were added DMAP (2.4 mg, 0.020 mmol), DMNBA (89.4 mg, 0.240 mmol) and
3-phenylpropanoic acid (36.0 mg, 0.240 mmol). After having been stirred for 10 min, a solution of
3-phenylpropanol (26.8 mg, 0.197 mmol) in CH2Cl2 (1.5 mL) was added. The reaction mixture was
stirred for 1 h at rt and then saturated aqueous NH4Cl was added at 0 °C. The mixture was extracted
with CH2Cl2, 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 thin layer
chromatography to afford the corresponding ester 23 (48.8 mg, 92%) as a colorless oil.

HETEROCYCLES, Vol. 76, No. 2, 2008
1325
12
-1 1
3-Phenylpropyl 3-phenylpropanoate (23).
IR (neat) 1735 cm ; H NMR (CDCl ) δ 7.31-7.13
3
(10H, m), 4.08 (2H, t, J = 6.6 Hz), 2.95 (2H, t, J = 7.8 Hz), 2.62 (4H, m), 1.91 (2 H, m); Found: C, 80.35;
H, 7.77%. Calcd for C H O : C, 80.56: H, 7.51%.
18 20
2
12
-1
1
3-Phenylpropyl benzoate (24).
7.54-7.05 (8H, m), 4.27 (2H, t, J = 6 Hz), 2.77 (2H, t, J = 8 Hz), 2.23 (2H, m); Found: C, 79.69; H, 6.97%.
Calcd for C H O : C, 79.97; H, 6.71%.
IR (neat) 1718 cm ; H NMR (CCl ) δ 8.10-7.85 (2H, m),
4
16 16
2
13
-1 1
3-Phenylpropyl (E)-3-phenyl-2-propenoate (25).
IR (neat): 1712 cm ; H NMR (CDCl ) δ 7.68
3
(1H, d, J = 16.0 Hz), 7.54-7.50 (2H, m), 7.43-7.35 (3H, m), 7.32-7.17 (5H, m), 6.45 (1H, d, J = 16.0 Hz),
4.23 (2H, t, J = 6.4 Hz), 2.75 (2H, dd, J = 7.9, 7.4 Hz), 2.04 (2H, ddt, J = 7.9, 7.4, 6.4 Hz); HR MS: calcd
+
for C H O (M + H ) 267.1385, found 267.1376.
18 19
2
12
-1 1
3-Phenylpropyl cyclohexanecarboxylate (26).
4.00 (2H, t, J = 6.0 Hz), 2.65 (2H, t, J = 8.0 Hz), 2.40-1.05 (13H, m); Found: C, 77.89; H, 8.90%. Calcd
for C H O : C, 78.01; H, 9.00%.
IR (neat) 1732 cm ; H NMR (CCl ) δ 7.15 (5H, s),
4
16 22
2
12
-1 1
3-Phenylpropyl 2,2-dimethylpropanoate (27).
(5H, m), 4.12 (2H, t, J = 6.3 Hz), 2.74 (2H, t, J = 7.6 Hz), 2.03-1.97 (2H, m), 1.26 (9H, s); Found: C,
76.06; H, 9.21%. Calcd for C H O : C, 76.33; H, 9.15%.
IR (neat) 1728 cm ; H NMR (CDCl ) δ 7.34-7.21
3
14 20
2
Typical Experimental Procedure for the Synthesis of Lactone 29
An experimental procedure is described for the preparation of lactone 29 using DMNBA with DMAP
(Table 5, Entry 3): To a solution of DMNBA (179 mg, 0.481 mmol) and DMAP (117 mg, 0.958 mmol)
in CH2Cl2 (169 mL) at rt was slowly added a solution of threo-aleuritic acid (28) (122 mg, 0.401 mmol)
in THF (40 mL) with a mechanically driven syringe over a 12 h period. After the reaction mixture had
been stirred for 1 h at rt, saturated aqueous NaHCO3 was added at 0 °C. The mixture was extracted with
CH2Cl2, and the organic layer was washed with water and brine, and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude product was purified by thin layer
3f
chromatography to afford dihydroxylactone 29 (101 mg, 83%) as a white solid: Mp. 53.5-54.0 °C; IR
-1 1
(KBr): 3440, 3310, 1730 cm ; H NMR (CDCl ): δ 4.18-4.05 (m, 2H, 16-H), 3.50-3.41 (br m, 2H, 9-H,
3
10-H), 2.40 (br s, 2H, 9-OH, 10-OH), 2.31 (t, J = 6.8 Hz, 2H, 2-H), 1.70-1.22 (m, 22H, 3, 4, 5, 6, 7, 8, 11,
13
12, 13, 14, 15-H); C NMR (CDCl ): δ 174.0 (1), 74.1 (9 or 10), 73.4 (10 or 9), 64.2 (16), 34.6 (2), 32.5,
3
31.4, 28.6, 28.2, 28.1, 27.7, 27.6, 25.4, 25.0, 23.9, 23.1 (3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15); Anal: calcd
+
for C H O : C, 67.10; H, 10.56, found: C, 66.97; H, 10.54; HR MS: calcd for C H O (M + H )
16 30
4
16 31 4
287.2222, found 287.2223.
3f
threo-9,10-Thiocarbonyldioxyheptadecan-16-olide (30).
To a solution of dihydroxylactone 29 (80.2 mg, 0.280 mmol) in toluene (14 mL) were added TCDI (499

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HETEROCYCLES, Vol. 76, No. 2, 2008
mg, 2.80 mmol) and DMAP (3.4 mg, 0.028 mmol). After the reaction mixture had been stirred for 4 h
at 130 °C, it was cooled down to rt. The mixture was concentrated by evaporation of the solvent and
then the crude product was purified by thin layer chromatography to afford thiocarbonate 30 (83.8 mg,
-1 1
91%) as a white solid: Mp. 73-74 °C; IR (KBr): 1720, 1280, 1180 cm ; H NMR (CDCl ): δ 4.55-4.43
3
(m, 2H, 9-H, 10-H), 4.21-4.08 (m, 2H, 16-H), 2.42-2.25 (m, 2H, 2-H), 2.10-1.21 (m, 22H, 3, 4, 5, 6, 7, 8,
13
11, 12, 13, 14, 15-H); C NMR (CDCl ): δ 191.4 (CS), 173.7 (1), 86.1 (9), 86.1 (10), 63.9 (16), 34.4 (2),
3
32.4, 32.1, 28.7, 28.3, 27.9, 27.9, 27.1, 25.6, 25.0, 23.6, 23.2 (3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15); Anal:
calcd for C H O S: C, 62.16; H, 8.59, found: C, 62.05; H, 8.61; HR MS: calcd for C H O S (M +
17 28
4
17 29 4
+
H ) 329.1786, found 329.1791.
3f
(9E)-Isoambrettolide (31).
To thiocarbonate 30 (20.4 mg, 0.062 mmol) was added trimethyl phosphite (3 mL) at rt. After the
reaction mixture had been stirred for 25 h at 140 °C, it was cooled down to rt. The mixture was
concentrated by evaporation of the solvent and then the crude product was purified by thin layer
chromatography to afford (9E)-isoambrettolide (31) (13.7 mg, 87%) as a colorless oil: IR (neat): 1730
-1 1
cm ; H NMR (C D ): δ 5.42 (dddd, J = 15.4, 9.5, 3.5, 1.6 Hz, 1H, 9-H or 10-H), 5.32 (dddd, J = 15.4,
6
6
9.5, 3.8, 1.6 Hz, 1H, 10-H or 9-H), 4.08 (t, J = 5.4 Hz, 2H, 16-H), 2.19 (t, J = 7.0 Hz, 2H, 2-H), 2.12-1.97
(m, 4H, 8-H, 11-H), 1.62-1.50 (m, 2H, 3-H), 1.48-1.34 (m, 2H, 15-H), 1.42-1.13 (m, 14H, 4, 5, 6, 7, 12,
13
13, 14-H); C NMR (C D ): δ 172.9 (1), 131.4 (9 or 10), 130.8 (10 or 9), 64.0 (16), 34.9 (2), 32.2 (8 or
6
6
11), 31.8 (11 or 8), 29.2 (15), 29.9, 28.8, 28.3, 28.2, 28.1, 27.2, 27.1 (4, 5, 6, 7, 12, 13, 14), 25.3 (3); HR
+
MS: calcd for C H O (M + H ) 253.2167, found 253.2165.
16 29
2
ACKNOWLEDGEMENTS
This study was partially supported by a Research Grant from Tokyo Ohka Foundation for the Promotion
of Science and Technology.
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