A novel and efficient macrolactonization of ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride (MNBA)

Article abstract of DOI:10.1016/S0040-4039(02)01819-1

A variety of lactones were prepared in high yields at room temperature from the corresponding ω-hydroxycarboxylic acids using 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction also occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods were successfully applied to the synthesis of erythro-aleuritic acid lactone and the efficiency of the cyclizations is compared to those of other reported mixed anhydride methods.

Full text of DOI:10.1016/S0040-4039(02)01819-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7535–7539
A novel and efficient macrolactonization of v-hydroxycarboxylic
acids using 2-methyl-6-nitrobenzoic anhydride (MNBA)
Isamu Shiina,* Mari Kubota and Ryoutarou Ibuka
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601,
Japan
Received 11 July 2002; revised 5 August 2002; accepted 23 August 2002
Abstract—A variety of lactones were prepared in high yields at room temperature from the corresponding v-hydroxycarboxylic
acids using 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction also occurs with
triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular
condensation reaction. These methods were successfully applied to the synthesis of erythro-aleuritic acid lactone and the efficiency
of the cyclizations is compared to those of other reported mixed anhydride methods. © 2002 Elsevier Science Ltd. All rights
reserved.
The macrocyclic framework is one of the most basic
structures for natural and unnatural useful organic
molecules. Recently, several effective CꢀC bond form-
ing reactions such as transition metal-promoted cou-
pling and olefin metathesis have been widely studied for
producing cyclic compounds.1,2 However, macrolac-
tonization is still the most popular method for produc-
ing cyclic compounds including carboxylic ester
moieties since there are some effective methods for
constructing the ester linkage.3
boxylic esters are produced in excellent yields with
higher chemoselectivities compared with those obtained
by the Yamaguchi esterification method.5 The reaction
of nearly equal amounts of carboxylic acids and alco-
hols smoothly proceeds at room temperature, therefore,
it is assumed that the MNBA method might be success-
fully applied to the intramolecular reaction for produc-
ing the macrocyclic compounds under mild conditions.
We would now like to report a novel and efficient
lactonization of v-hydroxycarboxylic acids using
MNBA, an effective condensation reagent, by the pro-
motion of DMAP or 4-(dimethylamino)pyridine 1-
oxide (DMAPO).
In a previous communication, we developed a new
condensation reaction (Scheme 1) for the synthesis of
carboxylic esters from nearly equimolar amounts of
carboxylic acids and alcohols using 2-methyl-6-
nitrobenzoic anhydride (MNBA) with triethylamine in
the presence of 4-(dimethylamino)pyridine (DMAP).4
This protocol is quite effective and the desired car-
First, 15-hydroxypentadecanoic acid is employed as a
model substrate for optimizing the reaction conditions
(see Table 1). When a solution of 15-hydroxypentade-
canoic acid in dichloromethane was slowly added to the
reaction mixture of MNBA (1.0 equiv.), triethylamine
(2.2 equiv.) and 10 mol% DMAP in dichloromethane
for over a 15 h period at room temperature, the corre-
sponding monomeric lactone was obtained in 65% yield
accompanied by 6% diolide and 1% triolide (entry 1).
Though the yield of the desired 15-pentadecanolide
increased to 84 or 86% using 20 or 30 mol% DMAP,
respectively, under the same reaction conditions, the
ratio of monomer to dimer and trimer was not satisfac-
tory, as shown in entry 2 or 3. Furthermore, employing
an excess amount of triethylamine decreased the ratio
to some extent (entry 4). On the other hand, better
selectivity was observed when a slight excess amount of
Scheme 1. Efficient esterification using MNBA.
* Corresponding author. Fax: (+81)-3-3260-5609; e-mail: shiina@
ch.kagu.sut.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01819-1

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I. Shiina et al. / Tetrahedron Letters 43 (2002) 7535–7539
Table 1. Isolated yields of 15-pentadecanolide and product-selectivities
Entry
x
y
z
Yield (%)
Dimer
Selectivitya
Monomer
Trimer
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.2
1.2
2.2
2.2
2.2
3.3
2.2
0
0.1
0.2
0.3
0.2
0.2
2.4
65
84
86
82
88
92
6
5
3
6
3
1
1
10.1
16.8
26.3
11.3
32.1
96.0
Trace
Trace
1
Trace
Trace
a Ratios of yields of monomer to that of dimer and trimer.
ature by adding a solution of v-hydroxycarboxylic
acids to mixture of MNBA and DMAP in
MNBA was used (entry 5). Therefore, we finally used a
stoichiometric amount of DMAP (2.4 equiv.) to
MNBA (1.2 equiv.) in the absence of triethylamine, and
the desired monomeric lactone was produced in high
yield with an excellent selectivity (entry 6). In this case,
DMAP does not only work as an activator for the
dehydration condensation but also as a base to generate
the corresponding 2-methyl-6-nitrobenzoyl pyridinium
salt.
a
dichloromethane. Each concentration in Table 2 shows
the molar amounts of v-hydroxycarboxylic acids to the
total volume of the dichloromethane solvent. Although
a small amount of diolide formed in the case of using
12-hydroxyundecanoic acid as shown in entry 1, from
14- to 17-membered ring macrolactones were obtained
in high yields and the undesired dimers and trimers
were scarcely produced (entries 3–5 and 7). Since the
reaction rate was not sufficiently fast when a secondary
v-hydroxycarboxylic acid was employed for the reac-
tion, an excess amount of reagents were required to
Table 2 shows the yields of the several macrolactones
synthesized by the present method using MNBA and
DMAP. All reactions were carried out at room temper-
Table 2. Isolated yields of a variety of macrolactones
Entry
R
n
Conc. (mM)
Time (h)
Yield (%)
Dimer
Monomer
Trimer
1a
2b
3a
4a
5a
6c
7a
H
C16H13
10
10
11
12
13
13
14
1.0
2.0
1.0
1.0
1.8
1.8
1.8
15
15
15
15
15
12
15
88
86
75
89
92
91
92
5
1
1
1
Trace
Trace
Trace
Trace
0
H
H
H
H
H
Trace
1
3
Trace
Trace
a 2.4 equiv. DMAP and 1.2 equiv. MNBA were used.
b 3.5 equiv. DMAP and 1.3 equiv. MNBA were used.
c 2.4 equiv. PPY and 1.2 equiv. MNBA were used.

I. Shiina et al. / Tetrahedron Letters 43 (2002) 7535–7539
7537
Finally, we applied the present protocol to the synthesis
of a functionalized macrocyclic molecule (Scheme 3).
The seco acid 1 having benzylidene acetal was prepared
from commercially available erythro-aleuritic acid (ery-
thro-9,10,16-trihydroxyhexadecanoic acid)8 by treating
with PhCH(OMe)2 and TsOH. Macrolactonization of
the seco acid 1 was then tried using MNBA with an
excess amount of DMAP (Method A), and the corre-
sponding monomeric lactone 2 was obtained in 90%
yield with excellent product-selectivity. When PPY was
used for the reaction under the same reaction condi-
tions, 2 was also obtained in 87% yield. Furthermore, it
was found that the reaction using MNBA with triethyl-
amine and a catalytic amount of DMAPO (Method B)
cleanly took place to produce the desired monomeric
lactone 2 in 90% yield. Successive facile deprotection of
2 with AcOH/H2O produced the erythro-aleuritic acid
lactone.9
Scheme 2. Efficient macrolactonization using MNBA with
triethylamine and a catalytic amount of DMAPO.
produce the excellent product-selectivity (entry 2). It is
also noted that these reactions could be performed by
the promotion of other derivatives of DMAP such as
4-pyrrolidinopyridine (PPY, see entry 6).
In order to compare the efficiency of our new protocols
with other mixed anhydride methods, the macrolac-
tonization of 1 was further examined. These data are
summarized in Table 3. Although the MNBA methods
(A and B) provided excellent results at room tempera-
ture as mentioned above (entries 1 and 2), the desired
lactone 2 was obtained in moderate yield with lower
selectivity by the Yamaguchi protocol at the same
temperature (entry 3). The yield increased to 70% when
the reaction was carried out at refluxing temperature in
Next, we tried to investigate other activators for the
present reaction to improve the efficiency for producing
the desired compounds with
a higher ratio of
monomers to dimers. After screening several basic com-
pounds including inorganic solid bases, it was proved
that substituted pyridine 1-oxides are quite effective
catalysts for the reaction forming large ring-size lac-
tones with triethylamine in the presence of MNBA
(Scheme 2). For example, the desired 15-pentadecano-
lide and 16-hexadecanolide were obtained in 91 and
92% yields, respectively, accompanied by only a trace
and 1% of the corresponding dimers when 20 mol%
DMAPO was employed as a catalyst for the reactions
with triethylamine (2.2 equiv.) at room temperature.
4-Pyrrolidinopyridine 1-oxide (PPYO), a derivative of
DMAPO, was also proved to be effective for the
macrolactonization and the desired 15-pentadecanolide
was produced in good yield (95%) from 15-hydroxypen-
tadecanoic acid at room temperature. As far as we
know, the present method is the first successful example
utilizing pyridine 1-oxides for the effective synthesis of
macrolactones.6,7
Scheme 3. Synthesis of protected erythro-aleuritic acid lac-
tone 2 using MNBA.
Table 3. Isolated yields of the protected erythro-aleuritic acid lactone 2 and product-selectivities obtained by several mixed
anhydride methods
Entry
Method
Yield (%)
Dimer
Selectivitye
Monomer
Trimer
1
2
3
4
MNBA, DMAPa
MNBA, DMAPOb
Yamaguchic
90
90
52
70
2
2
5
9
Trace
Trace
1
1
45.8
45.0
8.2
Yamaguchid
6.7
a Method A: A solution of 1 (0.380 mmol) in dichloromethane (84.6 mL) was slowly added to a solution of reagents in dichloromethane (135.8
mL) over a 16.5 h period at rt.
b Method B: A solution of 1 (0.360 mmol) in dichloromethane (108.0 mL) was slowly added to a solution of reagents in dichloromethane (151.0
mL) over a 16 h period at rt.
c A solution of MA derived from 1 (0.360 mmol) in toluene (36.0 mL) was slowly added to a solution of DMAP (2.16 mmol) in toluene (180.0
mL) over a 9 h period at rt.5a
d A solution of MA derived from 1 (0.360 mmol) in toluene (36.0 mL) was slowly added to a solution of DMAP (2.16 mmol) in toluene (180.0
mL) over a 9 h period at reflux temperature.5a
e Ratios of yields of monomer to that of dimer and trimer.

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I. Shiina et al. / Tetrahedron Letters 43 (2002) 7535–7539
toluene according to the original procedure, but the
product-selectivity is not sufficient for producing 2 with
high purity (entry 4). The Lewis acid-mediated macro-
lactonization of 1 via MA generated in situ from (4-
trifluoromethyl)benzoic anhydride (TFBA)10 using 5
mol% Cl2Ti(OTf)2, Hf(OTf)4 or 20 mol% Sc(OTf)3 was
not so effective, therefore, 2 was produced in moderate
yield (24, 40 or 60%) with lower product-selectivity (8.6,
7.9 or 13.1).11–13
References
1. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235–1246 and references cited therein.
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371–388 and references cited therein.
3. Mulzer, J. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6,
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4. Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002,
286–287.
Two typical experimental procedures are described for
the reaction of protected erythro-aleuritic acid 1.8
Method A: To a solution of MNBA14 (157.8 mg, 0.456
mmol) and DMAP (111.4 mg, 0.912 mmol) in
dichloromethane (135.8 mL) at room temperature was
slowly added a solution of 1 (149.2 mg, 0.380 mmol) in
dichloromethane (84.6 mL) with a mechanically driven
syringe over a 16.5 h period. After addition of the
solution, the reaction mixture was additionally stirred
for 1 h at room temperature. The reaction mixture was
concentrated to ca. 20 mL by evaporation of the sol-
vent under reduced pressure and then saturated
aqueous sodium hydrogencarbonate was added at 0°C.
Usual work up and purification of the mixture by TLC
on silica gel afforded 128.2 mg (90%) of protected
erythro-aleuritic acid lactone 2, 4.4 mg (1.5%) of diolide
and 1.8 mg (0.4%) of triolide.
5. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
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6. An effective phosphorylation was developed in 1985
using these substituted pyridine 1-oxides as promoters
with condensation reagents. See: (a) Efimov, V. A.;
Chakhmakhcheva, O. G.; Ovchinnikov, Yu. A. Nucleic
Acids Res. 1985, 13, 3651–3666; (b) Efimov, V. A.;
Chakhmakhcheva, O. G. Biochimie 1985, 67, 791–795; (c)
Efimov, V. A.; Chakhmakhcheva, O. G. Chem. Scr. 1986,
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Method B: To a solution of MNBA (148.7 mg, 0.432
mmol), triethylamine (80.1 mg, 0.792 mmol) and
DMAPO15 (9.9 mg, 0.072 mmol) in dichloromethane
(151.0 mL) at room temperature was slowly added a
solution of
1
(141.3 mg, 0.360 mmol) in
7. For the synthesis of arylsulphanilides, see: (a) Savelova,
V. A.; Solomoichenko, T. N.; Litvinenko, L. M. Zh. Org.
Khim. 1972, 8, 1011–1018; (b) Savelova, V. A.;
Belousova, I. A.; Litvinenko, L. M.; Yakovets, A. A.
Dokl. Akad. Nauk SSSR 1984, 274, 1393–1398. Polymer-
supported DMAPO was employed for the synthesis of
phenyl benzoate from phenol with benzoyl chloride. See:
(c) Zitsmanis, A.; Klyavinsh, M.; Skuyinsh, A.; Jakob-
sone, I. React. Polym. 1989, 11, 227–236.
dichloromethane (108.0 mL) with a mechanically driven
syringe over a 16 h period. After addition of the
solution, the reaction mixture was additionally stirred
for 1 h at room temperature. Same treatment of the
reaction mixture as mentioned above afforded 120.8 mg
(90%) of 2, 4.9 mg (1.8%) of diolide and 0.7 mg (0.2%)
of triolide.
Thus, we developed a new and convenient method for
the synthesis of a variety of macrolactones with high
product-selectivities via mixed anhydrides generated
from v-hydroxycarboxylic acids and MNBA using
basic catalysts. One of the features of the present
protocol is the very simple procedure for giving the
desired products, that is, slowly adding v-hydroxycar-
boxylic acids to the mixture of MNBA and the pro-
moters at room temperature produces the desired
macrolactones in excellent yields with high purity.16
Other applications of the present protocol for the syn-
theses of useful complex molecules are now in progress.
8. erythro-Aleuritic acid was purchased from Tokyo Kasei
Kogyo Co., Ltd (TCI).
9. Subramanian, G. B. V.; Mehrotra, A.; Mehrotra, K.
Chem. Ind. 1985, 3, 379–380.
10. (a) Mukaiyama, T.; Shiina, I.; Miyashita, M. Chem. Lett.
1992, 625–628; (b) Miyashita, M.; Shiina, I.; Miyoshi, S.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1993, 66, 1516–
1527. See also: (c) Mukaiyama, T.; Miyashita, M.; Shiina,
I. Chem. Lett. 1992, 1747–1757; (d) Mukaiyama, T.;
Izumi, J.; Miyashita, M.; Shiina, I. Chem. Lett. 1993,
907–910; (e) Miyashita, M.; Shiina, I.; Mukaiyama, T.
Chem. Lett. 1993, 1053–1054; (f) Miyashita, M.; Shiina,
I.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1994, 67, 210–
215; (g) Shiina, I.; Miyashita, M.; Nagai, M.;
Mukaiyama, T. Heterocycles 1995, 40, 141–148.
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Acknowledgements
12. (a) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.;
Mukaiyama, T. Chem. Lett. 1998, 831–832; (b) Shiina, I.;
Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000, 52,
1105–1123.
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.

I. Shiina et al. / Tetrahedron Letters 43 (2002) 7535–7539
7539
13. (a) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto,
H. J. Am. Chem. Soc. 1995, 117, 4413–4414, 6639; (b)
Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H.
J. Org. Chem. 1996, 61, 4560–4567.
pure MNBA (81%) as a white solid: mp 178–180°C; IR
(KBr): 1820 cm−1 1H NMR (CDCl3): l 8.06 (2H, d,
J=8.1 Hz), 7.64 (2H, d, J=7.6 Hz), 7.53 (2H, dd, J=7.6,
8.1 Hz), 2.57 (6H, s). Anal: calcd for C16H12N2O7: C,
55.82; H, 3.51; N, 8.14. Found: C, 55.81; H, 3.39; N,
8.07%.
;
14. MNBA was synthesized from 2-methyl-6-nitrobenzoic
acid. 2-Methyl-6-nitrobenzoic acid was purchased from
Tokyo Kasei Kogyo Co., Ltd (TCI). A solution of 2-
methyl-6-nitrobenzoic acid (5.00 g, 27.6 mmol) and thio-
nyl chloride (20.1 mL, 276 mmol) in dichloromethane (50
mL) was stirred for 15 h at room temperature. The
solvent and thionyl chloride were distillated under
reduced pressure at 50°C and then dichloromethane (40
mL), 2-methyl-6-nitrobenzoic acid (5.00 g, 27.6 mmol)
and pyridine (2.40 mL, 30.4 mmol) were successively
added at 0°C. After the reaction mixture had been stirred
for 24 h at room temperature, cooled water was added at
0°C. The mixture was extracted with dichloromethane,
and the organic layer was washed with saturated aqueous
copper(II) sulfate, saturated aqueous sodium hydrogen-
carbonate, cold water and brine, dried over sodium sul-
fate. Filtration of the mixture and evaporation of the
solvent under reduced pressure produced 8.80 g of the
crude MNBA. First recrystallization of the crude product
from dichloromethane (ca. 90 mL) at 0°C gave 7.70 g of
15. (a) DMAPO was prepared according to the procedure for
the synthesis of its derivatives. See: Ife, R. J.; Dyke, C.
A.; Keeling, D. J.; Meenan, E.; Meeson, M. L.; Parsons,
M. E.; Price, C. A.; Theobald, C. J.; Underwood, A. H.
J. Med. Chem. 1989, 32, 1970–1977; (b) Concerning the
purification, we followed the modified method of:
Mukaiyama, S.; Inanaga, J.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1981, 54, 2221–2222.
16. For example, the conventional Yamaguchi method
requires a stepwise operation,5a namely, v-hydroxycar-
boxylic acids are first treated with 2,4,6-trichlorobenzoyl
chloride and triethylamine to generate the corresponding
mixed anhydrides. After filtration of the mixture under
an inert gas to remove the triethylammonium chloride
formed, the filtrate containing mixed anhydrides is slowly
added to the solution of an excess amount of DMAP in
a suitable solvent at reflux temperature.