Scandium trifluoromethanesulfonate as an extremely active Lewis acid catalyst in acylation of alcohols with acid anhydrides and mixed anhydrides

Article abstract of DOI:10.1021/jo952237x

Scandium trifluoromethanesulfonate (triflate), which is commercially available, is a practical and useful Lewis acid catalyst for acylation of alcohols with acid anhydrides or the esterification of alcohols by carboxylic acids in the presence of p-nitrobenzoic anhydrides. The remarkably high catalytic activity of scandium triflate can be used for assisting the acylation by acid anhydrides of not only primary alcohols but also sterically-hindered secondary or tertiary alcohols. The method presented is especially effective for selective macrolactonization of ω-hydroxy carboxylic acids.

Full text of DOI:10.1021/jo952237x

4560
J . Org. Chem. 1996, 61, 4560-4567
Sca n d iu m Tr iflu or om eth a n esu lfon a te a s a n Extr em ely Active
Lew is Acid Ca ta lyst in Acyla tion of Alcoh ols w ith Acid An h yd r id es
a n d Mixed An h yd r id es†
Kazuaki Ishihara, Manabu Kubota, Hideki Kurihara, and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-01, J apan
Received December 19, 1995X
Scandium trifluoromethanesulfonate (triflate), which is commercially available, is a practical and
useful Lewis acid catalyst for acylation of alcohols with acid anhydrides or the esterification of
alcohols by carboxylic acids in the presence of p-nitrobenzoic anhydrides. The remarkably high
catalytic activity of scandium triflate can be used for assisting the acylation by acid anhydrides of
not only primary alcohols but also sterically-hindered secondary or tertiary alcohols. The method
presented is especially effective for selective macrolactonization of ω-hydroxy carboxylic acids.
In tr od u ction
catalysts (DMAP, Bu3P), and therefore, we have inves-
tigated the possibility of developing new classes of stable
acylation catalysts that are insensitive to protic sub-
stances like alcohols and carboxylic acids. Thus, we
reported in a preliminary paper that scandium triflate
catalyzes the acylation of alcohols with acid anhydrides
and that its catalytic activity is superior to DMAP and
Bu3P.9 Further, we found that this method is effective in
the selective benzoylation of aliphatic alcohols in the
presence of aromatic alcohols.
Recently, Mukaiyama et al. reported a viable method
for the preparation of carboxylic esters from free car-
boxylic acids and alcohols by combined use of p-(trifluo-
romethyl)benzoic anhydride and a catalytic amount of
active titanium(IV) salt together with chlorotrimethyl-
silane,10 and they applied the technique to the macro-
lactonization of ω-hydroxy carboxylic acids.11
Scandium triflate was found to be an extremely effec-
tive catalyst for this type of esterification. Specifically,
we have carried out an esterification of aliphatic car-
boxylic acids by alcohols via mixed anhydrides by the
combined use of p-nitrobenzoic anhydride and a catalytic
amount of scandium triflate.9 While it seemed to be
difficult to synthesize aromatic carboxylic acid esters via
mixed anhydrides in the preliminary study, this system
has been found to be useful for aromatic carboxylic acids.
Furthermore, we were able to develop an extremely
selective internal esterification of ω-hydroxy carboxylic
acids to give medium and large ring lactones through the
application of this procedure. Thus, this paper reports
a practical and very general approach to esters which is
based on the use of a stable Lewis acid catalyst for
acylation of alcohols with acid anhydrides or mixed
anhydrides.12
The acylation of alcohols by acid anhydrides or acyl
chlorides is routinely carried out in the presence of
tertiary amines. 4-(Dimethylamino)pyridine (DMAP)
and 4-pyrrolidinopyridine (PPY) are known to catalyze
this reaction and to increase the rate of acylation by a
factor of 104.1 Recently, Vedejs et al. reported tributyl-
phosphine as a similar catalyst for the acylation of
alcohols.2 Although the mechanism of tributylphosphine
catalysis is not yet clear,2,3 the remarkable catalytic
activity of these basic and nucleophilic catalysts can be
interpreted by assuming the formation of ion pair inter-
mediates such as N-acyl-4-(dimethylamino)pyridinium
carboxylates or chlorides. In addition to the above
catalysts, protic or Lewis acids are also known to catalyze
the acylation of alcohols with acid anhydrides. Never-
theless, there is still a great demand for acid catalysts
to generate esters under mild conditions.4-8 We theorized
that there must also be acid catalysts with an extremely
strong catalytic potential similar to that of the basic
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) Reviews: (a) Cherkasova, E. M.; Bogatkov, S. V.; Golovina, Z.
P. Russ. Chem. Rev. 1977, 46, 246. (b) Ho¨fle, G.; Steglich, V.;
Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (c) Scriven,
E. F. V. Chem. Soc. Rev. 1983, 12, 129. Kinetics: (d) Connors, K. A.;
Ebaka, C. J . J . Pharm. Sci. 1983, 72, 366. (e) Connors, K. A.; Lin, S.-
F. J . Pharm. Sci. 1981, 70, 235.
(2) (a) Vedejs, E.; Diver, S. T. J . Am. Chem. Soc. 1993, 115, 3358.
(b) Vedejs, E.; Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras, M.;
Lin, S.; Oliver, P. A.; Peterson, M. J . J . Org. Chem. 1993, 58, 7286.
(3) Although several attempts were made to define the structure of
the phosphine-activated acylating agent by Vedejs et al., the evidence
did not prove that the phosphonium carboxylate was the key inter-
mediate.
(4) Larock, R. C. Comprehensive Organic Transformations; VCH
Publishers, Inc.: New York, 1989; p 980.
(5) Recently, CoCl2-catalyzed acetylation of alcohols with acetic
anhydride was reported. Iqbal, J .; Srivastava, R. R. J . Org. Chem. 1992,
57, 2001.
Resu lts a n d Discu ssion
Sca n d iu m Tr ifla te-Ca ta lyzed Acyla tion of Alco-
(6) For references on the esterification of trimethylsilyl ethers via
acid anhydrides or mixed anhydrides using a catalytic amount of Lewis
acid, see: (a) Ganem, B.; Small, V. R., J r. J . Org. Chem. 1974, 39,
3728. (b) Mukaiyama, T.; Shiina, I.; Miyashita, M. Chem. Lett. 1992,
625. (c) Mukaiyama, T.; Miyashita, M.; Shiina, I. Chem. Lett. 1992,
1747. (d) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1993, 66, 1516.
h ols w ith Acid An h yd r id es. We first sought various
(9) For a preliminary communication: Ishihara, K.; Kubota, M.;
Kurihara, H.; Yamamoto, H. J . Am. Chem. Soc. 1995, 117, 4413, 6639
(corrections).
(10) Shiina, I.; Miyoshi, M.; Miyashita, M.; Mukaiyama, T. Chem.
Lett. 1994, 515.
(11) (p-CF3C6H4CO)2O, TMSCl, TiCl2(OTf)2: Shiina, I.; Mukaiyama,
T. Chem. Lett. 1994, 677.
(12) Mukaiyama et al. very recently developed an efficient esteri-
fication between free carboxylic acids and alcohols by the combined
use of octamethylcyclotetrasiloxane and a catalytic amount of titanium-
(IV) chloride tris(trifluoromethanesulfonate). Izumi, J .; Shiina, I.;
Mukaiyama, T. Chem. Lett. 1995, 141.
(7) TiCl4 + 2AgClO4, TMSO(CH2)nCO2TMS: Mukaiyama, T.; Izumi,
J .; Miyashita, M.; Shiina, I. Chem. Lett. 1993, 907.
(8) For references on the amidation reaction of weakly nucleophilic
amines via mixed anhydrides using a catalytic amount of Lewis acid,
see: (a) Miyashita, M.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1993,
1053. (b) Miyashita, M.; Shina, I.; Mukaiyama, T. Bull. Chem. Soc.
J pn. 1994, 67, 210. (c) Shiina, I.; Miyashita, M.; Nagai, M.; Mukaiyama,
T. Heterocycles 1995, 40, 141.
S0022-3263(95)02237-7 CCC: $12.00 © 1996 American Chemical Society

Acylation of Alcohols with Acid and Mixed Anhydrides
J . Org. Chem., Vol. 61, No. 14, 1996 4561
Ta ble 1. Solven t Effect on Sca n d iu m Tr ifla te-Ca ta lyzed
Acetyla tion of 2-Octa n ol w ith Acetic An h yd r id e
Ta ble 3. Th e Sc(OTf)3-Ca ta lyzed Acyla tion of Alcoh ols
w ith Acid An h yd r id es
condnsa and results T (°C),
entry
solvent
CH3CN
time (h), conversnb (%)
1
2
3
4
5
-20, 2, >95
23, 0.5, >95c
23, 1, >95c
23, 2, >95c
23, 23, 52c
CH3NO2
toluene or CCl4
CH2Cl2 or THF
CHCl3
a
b
A solution of 2-octanol (0.4 M) was used. The conversion was
determined by 1H NMR analysis of the crude product. c The
conversion was less than 5% yield in the reaction condition of 0
°C for 2 h.
Ta ble 2. Com p a r ison of Ca ta lysts in th e Acyla tion of
Men th ol w ith Acid An h yd r id es
acetylationa
conversnb (%)
benzoylationa
(reaction time (min))
catalyst
Sc(OTf)3
DMAP/Et3N (3 equiv)
DMAP
Bu3P
conversionb (%)
>95 (15)
75 (55)
>95
ca. 75c
23c
88c
a
b
An acetonitrile solution of 1 (0.25 M) was used. The conver-
sion was determined by 1H NMR analysis of the crude product.
c See ref 2a.
Lewis acids (1 mol %) which promote the model reaction
of sec-phenethyl alcohol (1 equiv) with acetic anhydride
(3 equiv) in dichloromethane. Among several stable
metal triflates screened, we found scandium triflate to
be quite effective:13 the reaction proceeded even at 0 °C
in the presence of scandium triflate, while it barely
proceeded in the presence of lanthanide triflate at 0 °C.
Although other Lewis acids such as Sc(OAc)3, ScCl3‚
6H2O, Sc(NO3)3‚4H2O, BF3‚Et2O, SnCl4, and TiCl4 were
also screened, scandium triflate proved the most effective
catalyst for the present reaction.
The effect of solvents in the acetylation of 2-octanol (1
equiv) with acetic anhydride (1.5 equiv) under the influ-
ence of 1 mol % of scandium triflate is shown in Table 1.
Under these conditions, the reaction proceeded faster in
acetonitrile than in other organic solvents. Interestingly,
the reaction was very slow in chloroform even at 23 °C.
Following this demonstration of the remarkable cata-
lytic activity of scandium triflate, three catalysts, DMAP,
Bu3P, and Sc(OTf)3, were compared for the acetylation
and benzoylation of menthol (1) under identical condi-
a
b
Additional amount (equiv) per mol of hydroxy group. Addi-
tional amount (mol %) per mol of hydroxy group. c An acetonitrile
solution of substrate (0.25 M) was used. Unless otherwise noted,
isolated yield by column chromatography on silica gel was
indicated. e Isolated yield of olefins, which are produced by the
elimination of acetoxy group, was indicated in parentheses. f 1.0
mol % of DMAP was used in place of Sc(OTf)3. Acetic anhydride
as a solvent was used in place of acetonitrile. Chemical yield of
primary acetates, which are produced by the 1,3-migration of
acetoxy group, was indicated in parentheses. It was determined
by 1H NMR analysis of the crude product.
d
g
h
tions. The results are summarized in Table 2. It was
noted that Sc(OTf)3 was not deactivated by the carboxylic
acid byproduct of acylation. Vedejs and Diver have
reported that the DMAP/Et3N acetylation is ca. 10-fold
faster than the Bu3P/Et3N reaction, and the acetylations
by both catalysts under amine-free conditions are some-
what slower than with Et3N present.2a In view of the
experimental results of Vedejs’ group and our own, we
might conclude that Sc(OTf)3 is the most effective acy-
lation catalyst.
(13) It was previously reported that scandium triflate is a good Lewis
acid catalyst for several reactions. Review: (a) Kobayashi, S. Synlett
1994, 689. Meerwein-Ponndorf-Verley-type reductions: (b) Castel-
lani, C. B.; Carugo, O.; Perotti, A.; Sacchi, D.; Invernizzi, A. G.; Vidari,
G. J . Mol. Catal. 1993, 85, 65. Aldol and Michael reactions: (c)
Kobayashi, S.; Hachiya, I.; Araki, M. Synlett 1993, 472. Diels-Alder
reaction: (d) Kobayashi, S.; Hachiya, I.; Ishitani, H. Tetrahedron Lett.
1993, 34, 3755. (e) Kobayashi, S.; Araki, M.; Hachiya, I. J . Org. Chem.
1994, 59, 3758. Allylation: (f) Hachiya, I.; Kobayashi, S. J . Org. Chem.
1993, 58, 6958. Friedel-Crafts acylation: (g) Kawada, A.; Mitamura,
S.; Kobayashi, S. Synlett 1994, 545. Reactions of imines: (h) Kobayashi,
S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya, I. Synlett 1995,
233.
To explore the generality and scope of the above
scandium triflate-catalyzed acylation, the reaction was

4562 J . Org. Chem., Vol. 61, No. 14, 1996
Ishihara et al.
Ta ble 4. Th e Sc(OTf)3-Ca ta lyzed Acyla tion of Men th ol
w ith Ca r boxylic Acid s
examined with various structurally diverse alcohols and
acid anhydrides. The results are summarized in Table
3. Scandium triflate is capable of acylating not only
primary alcohols, but also sterically-hindered secondary
or tertiary alcohols with various acid anhydrides. Sur-
prisingly, tertiary alcohols were easily acetylated under
very mild conditions. In the acetylation of 2-methyl-2-
undecanol, elimination byproducts were produced to-
gether with the desired acetate (Table 3, entry 7). When
the reaction was carried out in the presence of excess
acetic anhydride at as low a temperature as possible (-50
to -20 °C), the relative amount of acetylation increased
and the elimination products decreased (Table 3, entry
9).14 For more acid-sensitive substrates such as allylic
or benzylic tertiary alcohols, the reaction proceeded
successfully using acetic anhydride as a solvent at as low
a temperature as possible (-50 to -20 °C, Table 3,
entries 12-15). In most cases of DMAP-catalyzed acety-
lation of tertiary alcohols, it is necessary to use more than
10 mol % of DMAP and an excess of amine at conditions
of high concentration (Table 3, entry 9 vs entry 10).1
Although the acylation of menthol 1 with benzoic
anhydride in the presence of 1 mol % of scandium triflate
was relatively slow (Table 3, entry 6), the benzoylation
of various aromatic alcohols smoothly proceeded in the
presence of 2.5-5 mol % of scandium triflate at room
temperature (Table 3, entries 18-22). The present
reactions were very clean, and byproducts followed by
Fries rearrangement of aromatic esters were not observed
in a detectable amount.29
Sc(OTf)3 condition Aa
5b
6b
R1CO2H (equiv) (mol %)
(°C, h)
(% yield) (% yield)
AcOH (2.0)
AcOH (2.0)
AcOH (1.5)
EtCO2H (2.0)
EtCO2H (1.5)
10
5
1
5
1
0, 1
92
85
83
77
85
0
<1
5
0
4
0, 10
23, 8
0, 10
23, 8
a
b
See text. Isolated yield.
with our simple procedure was quite remarkable and the
inverse of that observed for DMAP-catalyzed benzoyla-
tion in the presence of triethylamine (eq 2). The change
in selectivities is attributed to the difference of nucleo-
philicities between aromatic and aliphatic alcohols under
each condition: aliphatic alcohol is more nucleophilic
under acidic conditions, but on the other hand aromatic
alcohol is more nucleophilic under basic conditions.
The highly catalytic system is especially attractive for
large-scale synthesis (menthol (20 mmol), Ac2O (30
mmol), CH3CN (20 mL), Sc(OTf)3 (0.002 mmol), room
temperature, 1 h, 99% acetate after chromatography).
Sca n d iu m Tr ifla te-Ca ta lyzed Ester ifica tion be-
tw een Alcoh ols a n d Ca r boxylic Acid s in th e P r es-
en ce of p-Nitr oben zoic An h yd r id e. Because the
acylation of menthol 1 with benzoic anhydride (Table 3,
entry 6) was relatively slow in comparison with the
acylation using other aliphatic carboxylic acid anhydrides
(Table 3, entries 3-5), we have developed a convenient
esterification between alcohols and carboxylic acids pro-
moted by a catalytic amount of Sc(OTf)3.
It is in general known that aromatic alcohols are
predominantly acylated in the presence of aliphatic
alcohols under basic or nucleophilic condition. Several
useful procedures for selective acylation of aromatic
alcohols have already been developed.15 To clarify which
reacts with acid anhydrides faster in the presence of
scandium triflate, aromatic alcohols or aliphatic alcohols,
we examined chemoselective benzoylation for a 1:1
mixture of phenol and 3-phenylpropanol (eq 1). Surpris-
The esterification of aliphtic carboxylic acids with
alcohols in the presence of an equimolar amount of
benzoic anhydride would proceed smoothly if the mixed
anhydride could be generated from the aliphatic carboxy-
lic acid and benzoic anhydride in the presence of a
catalytic amount of Sc(OTf)3.6-8,10,11,16 Actually, the cor-
responding esters were obtained in high yield with
excellent chemoselectivity from menthol 1 and carboxylic
acids by the following experimental procedure: after a
mixture of acetic acid or propanoic acid and benzoic
anhydride in acetonitrile was stirred in the presence of
1-10 mol % of Sc(OTf)3 at room temperature for 12 h,
menthol 1 was added to the solution precooled to 0 °C,
and the mixture was stirred under conditions A (see
Table 4).
The phenyl ring substituent effect of benzoic anhydride
was examined to find the most suitable anhydride
additive, and p-nitrobenzoic anhydride was found to give
good reactivity and high chemoselectivity (Table 5). In
the reaction using p-nitrobenzoic anhydride, nitromethane
was more effective than acetonitrile as a solvent with
respect to its solubility. p-(Trifluoromethyl)benzoic an-
hydride which was used by Mukaiyama et al. was also
ingly, 3-phenylpropyl benzoate was obtained in 91%
chemical yield and with 92% selectivity. The chemose-
lectivity for aliphatic alcohol which could be achieved
(14) It was ascertained by independent experiments that 3 and the
corresponding acetate gradually eliminated in the presence of Sc(OTf)3.
(15) (a) Orazi, O. O.; Corral, R. A.; Zinczuk, J . Rev. Latinoamer.
Quim. 1978, 9, 211. (b) Illi, V. O. Tetrahedron Lett. 1979, 20, 2431. (c)
Mukaiyama, T.; Pai, F.-C.; Onaka, M.; Narasaka, K. Chem. Lett. 1980,
563. (d) Paradisi, M. P.; Zecchini, G. P.; Torrini, I. Tetrahedron Lett.
1986, 27, 5029.
(16) For a reference on DMAP-promoted esterification of alcohols
with mixed anhydrides, see: Inanaga, J .; Hirata, K.; Saeki, T.; Katsuki,
T.; Yamaguchi, M. Bull. Chem. Soc. J pn. 1979, 52, 1989.

Acylation of Alcohols with Acid and Mixed Anhydrides
J . Org. Chem., Vol. 61, No. 14, 1996 4563
Ta ble 5. Sca n d iu m Tr ifla te-Ca ta lyzed Ester ifica tion
betw een 1 a n d P r op a n oic Acid
tertiary alcohols and carboxylic acids. It is noteworthy
that the esterification smoothly proceeded with not only
aliphatic carboxylic acids but also aromatic acids such
as 2,4,6-trimethylbenzoic acid. In addition, the benzoy-
lation of aromatic alcohols with benzoic acid, as well as
the reaction of alcohols with benzoic anhydride, was
much faster than that of aliphatic alcohols. The experi-
mental procedure is extremely simple and facile:
a
catalytic amount of Sc(OTf)3 is employed at room tem-
perature in a mixed solution of alcohols, carboxylic acids,
and p-nitrobenzoic anhydride to afford the desired esters
in high yield, and prior preparation of mixed anhydrides
is unnecessary.
(R2CO)2O
condns
(°C, h)
conversna
(%)
R2-
solvent
ratio 7b:8c
p-NO2C6H4
MeNO2
MeCN
23, 2
23, 3
23, 2
23, 2
23, 4
23, 2.5
0, 1
>95
71
>95
<5
>95
>95
>95
>95
>99:<1
>99:<1
>99:<1
High ly Selective Lacton ization Catalyzed by Scan -
d iu m Tr ifla te. Since natural products of the macrolide
type possess potent antibiotic, antitumoral, and other
types of interesting biochemical activity, their syntheses
have captured the imagination of many synthetic chem-
ists.17 Recent landmark achievements in the synthesis
of macrolides have necessitated the development of mild
and efficient methods for ring closure to macrocyclic
lactones from ω-hydroxy carboxylic acids11,18,19 or their
activated derivatives.7,16,18,20 A wide variety of methods
have already been developed, and most of them are
effective for preparation of 13- to 19-membered lac-
tones.7,11,16,19,20 However, a large quantity of diolides is
usually formed in the preparation of 8- to 12-membered
lactones. To our knowledge, there are no general meth-
ods for highly selective monolide synthesis; thus, consid-
erable effort continues to be expended in search of more
efficient techniques.
p-CF3C6H4
2,4,6-Cl3C6H2
Ph
t-Bu
Cl3C
88:12
85:15
62:38
25:75
F3C
0, 0.5
a
b
Isolated yield. 7 corresponds to 5 (R1 ) Et; see Table 4). c 8
corresponds to 5 (R1 ) R2; see Table 4).
Ta ble 6. Sca n d iu m Tr ifla te-Ca ta lyzed Ester ifica tion of
Alcoh ols w ith Ca r boxylic Acid s
Scandium triflate-catalyzed acylation was found to be
the method of choice for internal esterification of ω-hy-
droxy carboxylic acids to medium and large ring lactones.
This was based on the following considerations: (1)
Because lactone formation becomes relatively slow in
conversnb (%)
time
entry
R3OH
R1CO2H
EtCO2H
i-PrCO2H
EtCO2H
(h)
9
10
1
2
2
1
2
3
2
3
2
2
>95
>95
>95
89
>95
>95
0
0
0
0
<1
0
(17) Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer-Verlag: Berlin, 1990.
3
4c
5
EtCO2H
(18) For representative reviews, see: (a) Masamune, S.; Bates, G.
S.; Corcoran, J . W. Angew. Chem., Int. Ed. Engl. 1977, 16, 585. (b)
Nicolaou, K. C. Tetrahedron 1977, 33, 683. (c) Back, T. G. Tetrahedron
1977, 33, 3041. (d) Trost, B. M.; Fleming, I. In Comprehensive Organic
Synthesis; Benz, G., Ed; Pergamon Press: Oxford, 1991; Vol. 6, p 323.
(19) For representative references to lactonization of ω-hydroxy
carboxylic acids, see the following. 2,2′-Dipyridyl disulfide, Ph3P: (a)
Corey, E. J .; K. C. Nicolaou J . Am. Chem. Soc. 1974, 96, 5614. 2,2′-
Bis(4-tert-butyl-N-alkylimidazolyl) disulfide, Ph3P: (b) Corey, E. J .;
Brunelle, D. J . Tetrahedron Lett. 1976, 28, 3409. (c) 1-Alkyl-2-
halopyridinium salts, Et3N: (c) Mukaiyama, T.; Usui, M.; Saigo, K.
Chem. Lett. 1976, 49. DEAD, Ph3P: (d) Kurihara, T.; Nakajima, Y.;
Mitsunobu, O. Tetrahedron Lett. 1976, 28, 2455. Me2NCH(OCH2-
But)2: (e) Vorbru¨ggen, H.; Krolikiewicz, K. Angew. Chem., Int. Ed.
Engl. 1977, 16, 876. BF3‚Et2O, polystyrene: (f) Scott, L. Synthesis 1976,
738. Cyanuric chloride: (g) Venkataraman, K.; Wagle, D. R. Tetrahe-
dron Lett. 1980, 21, 1893. Bu2SnO: (h) Steliou, K.; Szczygielska-
Nowosielska, A.; Favre, A,; Poupart, M.-A.; Hanessian, S. J . Am. Chem.
Soc. 1980, 102, 7578. (i) Steliou, K.; Poupart, M.-A. J . Am. Chem. Soc.
1983, 105, 7130. N,N,N′,N′-Tetramethylchloroformamidinium chloride,
collidine: (j) Fujisawa, T.; Mori, T.; Fukumoto, K.; Sato, T. Chem. Lett.
1982, 1891. DCC, DMAP, DMAP‚HCl: (k) Boden, E. P.; Keck, G. E.
J . Org. Chem. 1985, 50, 2394. (Bu2ClSnOSnBu2OH)2, (Bu2(SCN)Sn-
OSnBu2OH)2: (l) Otera, J .; Yano, T.; Himeno, Y.; Nozaki, H. Tetra-
hedron Lett. 1986, 27, 4501. Zeolite molecular sieves: (m) Tatsumi,
T.; Sakashita, H.; Asano, K. J . Chem. Soc., Chem. Commun. 1993,
1264.
(20) For representative references to lactonization of activated
derivatives derived from ω-hydroxy carboxylic acids, see: 2-Pyridine
thioester, AgClO4 or AgBF4: (a) Gerlach, H.; Thalmann, A. Helv. Chem.
Acta 1974, 57, 2661. HO(CH2)nCOSR, Hg(OCOCF3)2: (b) Masamune,
S.; Kamata, S.; Schilling, W. J . Am. Chem. Soc. 1975, 97, 3515. TMSO-
(CH2)nCO2TMS, Pr2BOTf: (c) Taniguchi, N.; Kinoshita, H.; Inomata,
K.; Kotake, H. Chem. Lett. 1984, 1347. HO(CH2)nCO2Et, ZrO2 (hy-
drous): (d) Kuno, H.; Shibagaki, M.; Takahashi, K.; Honda, I.;
Matsushita, H. Chem. Lett. 1992, 571. HO(CH2)nCO2CH2CF3, Bu3Sn-
OMe: (e) White, J . D.; Green, N. J .; Fleming, F. F. Tetrahedron Lett.
1993, 34, 3515.
i-PrCO2H
(E)-MeCHdC-
MeCO2H
t-BuCO2H
EtCO2H
6
7
8
9
10
11e
12f
13f
3
2
>95
0
d
d
3
-
-
0
0
2
2
0
2,6-dimethylphenol i-PrCO2H
t-BuCO2H
3.5 >95
4
12.5
3.5 >95
0.8 >95
90
86
4
2
EtCO2H
PhCO2H
2,4,6-Me3-
C6H2CO2H
PhCO2H
PhCO2H
14f
1
16
1
1
>95
>95
89
0
0
0
15f PhOH
16f 2,6-dimethylphenol PhCO2H
Room temperature. b Isolated yield by column chromatography
a
on silica gel. c 1 equiv of p-nitrobenzoic anhydride was used.
d
Although the esterification did proceed, the acyloxy group of the
ester produced was gradually eliminated under the same condi-
tions. e 10 mol % of scandium triflate and 2.0 equiv of propanoic
acid were used. f 5 mol % of scandium triflate and 1.5 equiv of
carboxylic acid were used.
very effective in this system,6-8,10,11 but the materials
from which it is made are more expensive. 2,4,6-
Trichlorobenzoic anhydride which was used by Yamagu-
chi et al. was not effective at all.16
Several examples of the esterification of free alcohols
with free carboxylic acids under the best conditions
(additive: (p-NO2C6H4CO)2O (1.5 equiv), solvent: MeNO2)
are shown in Table 6. This method gave excellent results
for the reaction between various alcohols except for

4564 J . Org. Chem., Vol. 61, No. 14, 1996
Ishihara et al.
Ta ble 7. Selective La cton iza tion of ω-Hyd r oxy
Ca r boxylic Acid s
going from common to large ring sizes, slow addition of
ω-hydroxy carboxylic acid to the medium is required for
maintenance of high dilution.20a (2) The catalytic activity
of the esterification should be high, even under high
dilution. (3) The catalyst is required to activate both
carboxy and hydroxy groups in an ω-hydroxy carboxylic
acid and allow them to come near each other for selective
internal esterification. Our acylation catalyst, scandium
triflate, in Mukaiyama’s esterification system is charac-
terized by outstanding catalysis, and can coordinate with
both the mixed anhydride moiety and the hydroxy group
to give a possible reaction intermediate 11. It is not yet
clear whether other active intermediate species such as
scandium carboxylates are produced via interconversion
between scandium triflate and carboxylic anhydrides
under the conditions.
Sc(OTf)3
slow
reaction yieldc (%) yieldc (%)
n
(mol %) additiona (h) timeb (h) of lactone of diolide
5
6
7
8
9
10
11
12
13
14
15
20
20
20
20
20
10
10
10
10
10
10
15
15
15
15
15
15
6
15
15
9
5
5
5
5
5
0
0
5
5
0
0
>99
71
52
87
77
78
91
94
99
99
92
<1
<1
3
<5
2
2
3
<1
<1
<1
<1
9
a
Slow addition of a solution of ω-hydroxy carboxylic acid in THF
to a refluxing solution of Sc(OTf)3 and (p-NO2C6H4CO)2O in
b
acetonitrile. After addition of ω-hydroxy carboxylic acid, the
reaction mixture was stirred for the hours indicated at reflux.
c Isolated yield.
A series of ω-hydroxy carboxylic acids, HO(CH2)nCO2H
with n ) 5-15, was utilized in the cyclization studies.
These substrates were directly subjected to lactonization
by slow addition to a mixed solution of 10-20 mol % of
scandium triflate and 2 equiv of p-nitrobenzoic anhydride
in acetonitrile at reflux. The addition was conveniently
performed using a mechanically driven syringe. After
completion of the reaction the monomeric lactone and the
dimeric cyclic ester (diolide) were isolated. The identity
of each lactone was proved by comparison with authentic
sample. As indicated in Table 7, the desired lactones
were obtained in good to excellent yields in all cases of n
) 5-15. Surprisingly, few diolides or other oligomeric
esters were obtained. To the best of our knowledge, this
is the most selective monomeric lactonization method
available. It is particularly noteworthy that 8- to 12-
membered lactones were obtained in high yields, without
producing a large quantity of diolides. The powerful
efficiency of this system is demonstrated in comparison
with other typical systems as shown in Table 8.
films on NaCl plates unless otherwise noted. For thin layer
chromatography (TLC) analysis, Merck precoated TLC plates
(silica gel 60 GF254, 0.25 mm) were used. The products were
purified by preparative column chromatography on silica gel
E. Merck 9385. Microanalyses were carried out at the School
of Agriculture, Nagoya University.
Ether and tetrahydrofuran (THF) were purchased from
Aldrich Chemical Co. as “anhydrous” and stored over 4A
molecular sieves. Acetonitrile, nitromethane, and methylene
chloride were freshly distilled from calcium hydride. Scan-
dium trifluoromethanesulfonate purchased from Fluka was
used without further purification.
Typ ica l P r oced u r e for Acyla tion of Alcoh ols w ith Acid
An h yd r id es (Table 3, Entry 3). To a mixture of menthol (938
mg, 6 mmol) and acetic anhydride (849 µL, 9 mmol) in
acetonitrile (24 mL) was added dropwise an acetonitrile
solution (60 µL, 0.006 mmol, 0.1 M) of scandium triflate at
room temperature. After being stirred at room temperature
for 1 h, the solution was quenched with aqueous sodium
hydrogen carbonate, and the product was extracted with ether.
The organic layers were dried over magnesium sulfate, fil-
trated, and concentrated in vacuo to afford the crude product.
Further purification of (1S,3R,5S)-5-methyl-2-(1-methylethyl)-
cyclohexyl acetate23 was done by column chromatography on
silica gel (1.17 g, 98% isolated yield): 1H NMR (CDCl3, 300
MHz) δ 0.76 (d, J ) 7.0 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H), 0.90
(d, J ) 6.6 Hz, 3H), 0.84-1.14 (m, 3H), 1.30-1.60 (m, 2H),
1.79-1.93 (m, 2H), 1.93-2.04 (m, 2H), 2.03 (s, 3H), 4.67 (dt, J
) 4.4, 10.8 Hz, 1H).
Con clu sion
In summary, we have demonstrated that scandium
triflate, which is commercially available, is a practical
and useful Lewis acid catalyst for acylation of alcohols
with acid anhydrides and esterification between alcohols
and carboxylic acids in the presence of p-nitrobenzoic
anhydride because of its remarkable catalytic potential
and stability. The development of this method allows the
preparation of lactones in excellent yield with high
selectivity, regardless of ring size.
Other esters synthesized by essentially the same procedure
were the following.
3-P h en ylp r op yl a ceta te (Table 3, entry 1):21 1H NMR
(CDCl3, 300 MHz) δ 1.90-2.01 (m, 2H), 2.05 (s, 3H), 2.69 (t, J
) 7.4 Hz, 2H), 4.09 (t, J ) 6.5 Hz, 2H), 7.11-7.33 (m, 5H).
1-P h en ylet h yl a cet a t e (Table 3, entry 2):22 1H NMR
Exp er im en ta l Section
(21) Alexakis, A.; J achiet, D.; Normant, J . F. Tetrahedron 1986, 42,
5607.
(22) Mitsui, S.; Kudo, Y. Tetrahedron 1967, 23, 4271.
(23) Takahashi, K.; Shibagaki, M.; Matsushita, H. Bull. Chem. Soc.
J pn. 1989, 62, 2353.
Gen er a l P r oced u r es. The mass spectra were recorded
with a direct-inlet system operating at 20 eV. The high-
resolution mass spectra (HRMS) were conducted at Daikin
Industries, Ltd., J apan. IR spectra were measured as thin

Acylation of Alcohols with Acid and Mixed Anhydrides
J . Org. Chem., Vol. 61, No. 14, 1996 4565
Ta ble 8. Com p a r ison of Yield (%) in th e Selective La cton iza tion of ω-Hyd r oxy Ca r boxylic Acid s Usin g Typ ica l
Rea gen tsa
nb
reagents
5
6
7
8
9
10
11
12
13
14
15
acidic
Sc(OTf)3/(4-NO2C6H4CO)2O
TiCl2(OTf)2/TMSCl(4-CF3C6-
H4CO)2Od
>99 (<1) 71 (<1) 52 (3)
87 (<5) 77 (2)
78 (2)
91 (3)
94 (<1) 99 (<1) 99 (<1)
92 (<1)
56 (29) 83 (10) 80 (5)
89 (3)
46c
88 (10)
88 (2)
TiCl4-2AgClO4/(4-CF3C6H4CO)2Oe,f
Pr2BOTff,g
70 (0)
99 (0)
0 (50)
0 (40) 33 (47) 70 (23)
75 (7)
89 (4)
94
83 (17) 89
85
BF3‚Et2O/polystyreneh
41c
77c
77c
neutral
Bu3SnXi,j
0 (82)
45 (40) 60 (22)
8 (<1)
(82)
22
74 (17)
52 (0)
78
81 (14)
ZrO2 (hydrous)k,l
distannoxanem
Bu2SnOn
49 (51) 36 (38)
20
19
81
60 (15)
40 (17)
0 (20)
0 (14)
5
63(8)
o
Me2NCH(OCH2But)2
basic/nucleophilic
DMAP/Et3N/(2,4,6-Cl3C6H2CO)2Op
DMAP/DCC/DMAP‚HClq
cyanuric chloride/Et3Nr
Bu3P/DEADt
36 (23)
48 (20)
32 (32) 77 (11)
70
63 (32)
95 (trace) 96
68
85
40 (53)
89 (0)
0 (70)
13 (34)
1-methyl-2-chloropyridinium iodide/
61 (24) 69 (14)
84 (3)
Et3Nu
c
2,2′-(4-t-Bu-N-alkylimidazolyl)
disulfide/Ph3Pv
0 (93)
8 (41)
87c
90
83
2,2′-dipyridyl disulfide/Ph3Pw
71 (7)
47 (30) 66 (7)
68 (6)
80 (5)
85 (15)n
a
b
Isolated yield (%) of monomeric lactones is presented. Isolated yield (%) of diolides is presented in parentheses. HO(CH2)nCO2H.
c GLC yield (%). Reference 11. e Reference 7. f ω-(Trimethylsiloxy) carboxylates were used. Reference 20c. Reference 19f. Reference
d
g
h
i
j
k
l
20e. 1,1,2-Trifluoroethyl esters of ω-hydroxy carboxylic acids were used. Reference 20d. Ethyl esters of ω-hydroxy carboxylic acids
were used. Reference 19l. References 19h and 19i. o Reference 19e. Reference 16. Reference 19k. Reference 19g. Reference 19d.
m
n
p
q
r
s
Diethyyl azodicarboxylate (DEAD). Reference 19c. v Reference 19b. Reference 19a.
t
u
w
(CDCl3, 300 MHz) δ 1.53 (d, J ) 6.6 Hz, 3H), 2.07 (s, 3H),
5.88 (q, J ) 6.6 Hz, 1H), 7.26-7.41 (m, 5H).
) 2.2, 11.0 Hz, 2H), 7.66 (tt, J ) 2.2, 11.0 Hz, 1H), 8.20-8.29
(m, 2H).
o-P h en ylen e d iben zoa te (Table 3, entry 19):28,29 1H NMR
(CDCl3, 300 MHz) δ 7.36-7.45 (m, 8H), 7.54 (tt, J ) 1.4, 7.4
Hz, 2H), 8.06-8.11 (m, 4H).
(1S,3R,5S)-5-Meth yl-2-(1-m eth yleth yl)cycloh exyl p r o-
p a n oa te (Table 3, entry 4):24 1H NMR (CDCl3, 300 MHz) δ
0.76 (d, J ) 7.0 Hz, 3H), 0.81-1.10 (m, 3H), 0.89 (d, J ) 7.0
Hz, 3H), 0.90 (d, J ) 7.0 Hz, 3H), 1.14 (t, J ) 7.6 Hz, 3H),
1.25-1.44 (m, 1H), 1.44-1.56 (m, 1H), 1.61-1.74 (m, 2H),
1.75-2.05 (m, 2H), 2.30 (q, J ) 7.6 Hz, 2H), 4.68 (dt, J ) 4.4,
10.8 Hz, 1H).
(1S,3R,5S)-5-Meth yl-2-(1-m eth yleth yl)cycloh exyl 2,2-
d im eth ylp r op a n oa te (Table 3, entry 5):25 1H NMR (CDCl3,
300 MHz) δ 0.75 (d, J ) 7.0 Hz, 3H), 0.80-1.11 (m, 3H), 0.89
(d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H), 1.19 (s, 9H),
1.30-1.44 (m, 1H), 1.44-1.56 (m, 1H), 1.62-1.72 (m, 2H),
1.82-2.00 (m, 2H), 4.62 (dt, J ) 4.4, 10.8 Hz, 1H).
(1S,3R,5S)-5-Meth yl-2-(1-m eth yleth yl)cycloh exyl ben -
zoa te (Table 3, entry 6):26 1H NMR (CDCl3, 300 MHz) δ 0.80
(d, J ) 7.0 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H), 0.93 (d, J ) 6.6
Hz, 3H), 0.98-1.22 (m, 2H), 1.48-1.66 (m, 3H, CH), 1.68-
1.80 (m, 2H), 1.90-2.18 (m, 2H), 4.94 (dt, J ) 4.4, 11.0 Hz,
1H), 7.39-7.58 (m, 3H), 8.01-8.08 (m, 2H).
m -P h en ylen e d iben zoa te (Table 3, entry 20):29 1H NMR
(CDCl3, 300 MHz) δ 7.14-7.22 (m, 3H), 7.45-7.57 (m, 5H),
7.65 (tt, J ) 1.4, 7.4 Hz, 2H), 8.18-8.25 (m, 4H).
p-P h en ylen e d iben zoa te (Table 3, entry 21):29 1H NMR
(CDCl3, 300 MHz) δ 7.30 (s, 4H), 7.48-7.57 (m, 4H), 7.66 (tt,
J ) 1.4, 7.4 Hz, 2H), 8.18-8.25 (m, 4H).
2,2-Bis[p-(ben zoyloxy)p h en yl]p r op a n e (Table 3, entry
22):30 1H NMR (CDCl3, 300 MHz) δ 1.73 (s, 6H), 7.14 (dt, J )
3.5, 13.2 Hz, 4H), 7.32 (dt, J ) 3.5, 13.2 Hz, 4H), 7.44-7.58
(m, 4H), 7.64 (tt, J ) 2.0, 11.0 Hz, 2H), 8.12-8.26 (m, 4H).
P h en yl ben zoa te (in eq 3):31 1H NMR (CDCl3, 300 MHz) δ
7.11-7.24 (m, 3H), 7.32-7.49 (m, 4H), 7.57 (tt, J ) 1.4, 7.4
Hz, 1H), 8.10-8.18 (m, 2H).
3-P h en ylp r op yl ben zoa te (in eq 3):6d 1H NMR (CDCl3, 300
MHz) δ 2.03-2.17 (m, 2H), 2.80 (t, J ) 7.7 Hz, 2H), 4.34 (t, J
) 6.5 Hz, 2H), 7.16-7.36 (m, 5H), 7.40-7.50 (m, 2H), 7.57 (tt,
J ) 1.3, 7.4 Hz, 1H), 8.0-8.08 (m, 2H).
1,1-Dim eth yld eca n yl a ceta te (Table 3, entries 7-10): IR
(film) 2928, 1857, 1736 (CO2), 1468, 1385, 1368, 1258, 1140,
1115, 1019, 943 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J
) 6.6 Hz, 3H), 1.19-1.40 (br, 12 H), 1.42 (s, 6H), 1.68-1.78
(m, 2H), 1.96 (s, 3H); Anal. Calcd for C14H28O2: C, 73.63; H,
12.36. Found: C, 73.59; H, 12.39. 2-Methyl-2-undecene
(byproduct): 1H NMR (CDCl3, 300 MHz) δ 1.60 (s, 3H,
CdCMeCH3), 1.69 (d, J ) 1.2 Hz, 3H, CdCCH3Me), 5.06-5.16
(m, 1H, CH)C), other resonances could not be discerned.
2-Methyl-1-undecene (byproduct): 1H NMR (CDCl3, 300 MHz)
δ 1.71 (s, 3H, CH3CdC), 4.62-4.70 (m, 2H, H2CdC), other
resonances could not be discerned.
Typ ica l P r oced u r e for Acetyla tion of Acid -Sen sitive
Ter tia r y Alcoh ols (Table 3, Entry 13). To a solution of
3-methyl-1-dodecen-3-ol (198.4 mg, 1 mmol) in acetic anhy-
dride (4 mL) was added dropwise a cloudy acetonitrile solution
(200 µL, 0.02 mmol, 0.1 M) of scandium triflate at -45 °C.
After being stirred at the same temperature for 1 h, the
solution was carefully quenched with aqueous sodium hydro-
gen carbonate, and the product was extracted with ether. The
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo to crude product. Purification was done
by column chromatography on silica gel (eluent: hexane only-
hexane/ethyl acetate, 20:1) to give the mixture of 3-acetoxy-
1-Meth ylcycloh exyl a ceta te (Table 3, entry 11):5 1H NMR
(CDCl3, 300 MHz) δ 1.25-1.60 (m, 8H), 1.47 (s, 3H), 2.00 (s,
3H), 2.08-2.16 (m, 2H).
2,4,6-Tr im eth ylp h en yl ben zoa te (Table 3, entry 18):27 1
H
(27) Ray, K. B.; Weatherhead, R. H.; Pirinccioglu, N.; Williams, A.
J . Chem. Soc., Perkin Trans. 2 1994, 83.
(28) Do¨bner, O. Liebigs Ann. Chem. 1881, 210, 261.
(29) Hoefnagel, A. J .; van Bekkum, H. Appl. Catal. A 1993, 97, 87;
102, N16 (erratum).
(30) Sasaki, A.; Kimura, Y. Nippon Kagaku Kaishi 1994, 10, 939.
(31) Kanaoka, Y.; Tanizawa, K.; Sato, E.; Yonemitsu, O. Ban, Y.
Chem. Pharm. Bull. 1967, 15, 593.
NMR (CDCl3, 300 MHz) δ 2.15 (s, 6H), 2.30 (s, 3H), 6.92 (s, J
(24) Rupe, H. Liebigs Ann. Chem. 1903, 327, 157.
(25) Kunieda, N.; Suzuki, A.; Kinoshita, M. Bull. Chem. Soc. J pn.
1981, 54, 1143.
(26) Akiyama, F.; Tokura, N. Bull. Chem. Soc. J pn. 1968, 41, 2690.

4566 J . Org. Chem., Vol. 61, No. 14, 1996
Ishihara et al.
3-methyl-1-dodecene and 1-acetoxy-3-methyl-2-dodecene in
90% yield with the raio of 84:16. The ratio was determined
by 1H NMR analysis of the crude products: IR (film) 2855,
2728, 1740, 1645, 1368, 1466, 1248, 1173, 1019, 922 cm-1; 1H
NMR (CDCl3, 300 MHz) for 3-acetoxy-3-methyl-1-dodecene δ
0.88 (t, J ) 6.7 Hz, 3H), 1.26 (br, 16H), 1.52 (s, 3H), 2.01 (s,
3H), 5.10 (dd, J ) 0.9, 10.9 Hz, 2H), 5.13 (dd, J ) 0.9, 17.5
Hz, 1H), 5.97 (dd, J ) 10.9, 17.5 Hz, 1H); 1H NMR (CDCl3,
300 MHz) for 1-acetoxy-3-methyl-2-dodecene δ 2.06 (s, 3H),
4.57 (t, J ) 7.3 Hz, 2H), 5.33 (dt, J ) 1.0, 7.3 Hz, 1H), other
resonances could not be discerned for minor isomer. Anal.
Calcd for C15H27O2: C, 75.26; H, 11.37. Found: C, 75.28; H,
11.36.
(d, J ) 6.4 Hz, 3H), 0.81-1.10 (m, 3H), 1.15 (d, J ) 6.9 Hz,
3H), 1.16 (d, J ) 6.9 Hz, 3H), 1.32-1.59 (m, 2H), 1.62-1.74
(m, 2H), 1.82-2.02 (m, 2H), 2.51 (septet, J ) 6.9 Hz, 1H), 4.65
(dt, J ) 4.4, 10.9 Hz, 1H).
(1S,3R,5S)-5-Meth yl-2-(1-m eth yleth yl)cycloh exyl (E)-
2-m eth yl-2-bu ten oa te (Table 6, entry 6):6d 1H NMR (CDCl3,
300 MHz) δ 0.76 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H),
0.90 (d, J ) 6.5 Hz, 3H), 0.84-1.16 (m, 3H), 1.38-1.58 (m,
2H), 1.63-1.74 (m, 2H), 1.78 (dd, J ) 1.0, 7.1 Hz, 3H), 1.83 (t,
J ) 1.2 Hz, 3H), 1.85-1.94 (m, 1H), 1.98-2.08 (m, 1H), 4.73
(dt, J ) 4.2, 10.8 Hz, 1H), 6.83 (qq, J ) 1.2, 7.1 Hz, 1H).
2,6-Dim eth yp h en yl 2-m eth ylp r op a n oa te (Table 6, entry
9): IR (film) 2977, 1755, 1530, 1470, 1169, 1134, 1095, 1046,
1
Other acid-sensitive esters synthesized by essentially the
same procedure were the following.
770 cm-1; H NMR (CDCl3, 300 MHz) δ 1.36 (d, J ) 7.0 Hz,
6H), 2.14 (s, 6H), 2.87 (septet, J ) 7.0 Hz, 1H), 7.04 (s, 3H).
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.95;
H, 8.40.
Lin a lyl a ceta te (Table 3, entry 14):32 1H NMR (CDCl3, 300
MHz) δ 1.54 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 1.71-2.08 (m,
4H), 2.01 (s, 3H), 5.04-5.12 (m, 1H), 5.12 (dd, J ) 0.9, 11.0
Hz, 1H), 5.15 (dd, J ) 0.9, 17.5 Hz, 1H), 5.97 (dd, J ) 11.0,
17.5 Hz, 1H).
2,6-Dim eth ylp h en yl 2,2-d im eth ylp r op a n oa te (Table 6,
entry 10):39 1H NMR (CDCl3, 300 MHz) δ 1.41(s, 9H), 2.13 (s,
6H), 7.04 (s, 3H).
2,6-Bis(1,1-d im eth yleth yl)-4-m eth ylp h en yl p r op a n oa te
(Table 4, entry 11):40 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J
) 7.6 Hz, 3H), 1.32 (s, 18H), 2.31 (s, 3H), 2.64 (q, J ) 7.6 Hz,
2H), 7.11 (s, 2H).
r,r-Dim eth ylben zyl a ceta te (Table 3, entry 15):33 1H
NMR (CDCl3, 300 MHz) δ 1.77 (s, 6H), 2.04 (s, 3H), 7.20-
7.40 (m, 5H).
1-Eth n ylcycloh exyl a ceta te (Table 3, entry 16):34 1H NMR
(CDCl3, 300 MHz) δ 1.25-1.41 (m, 1H), 1.46-1.68 (m, 5H),
1.81-1.91 (m, 2H), 2.05 (s, 3H), 2.08-2.18 (m, 2H), 2.60 (s,
1H).
3-P h en ylp r op yl 2,4,6-tr im eth ylben zoa te (Table 6, entry
13): IR (film) 2955, 1725 (CO2), 1613, 1455, 1266, 1169, 1082,
853, 747 cm-1 1H NMR (CDCl3, 300 MHz) δ 2.01-2.13 (m,
;
2H), 2.29 (s, 3H), 2.31 (s, 6H), 2.71-2.79 (m, 2H), 4.33 (t, J )
6.6 Hz, 2H), 6.87 (s, 2H), 7.16-7.34 (m, 5H). Anal. Calcd for
C19H22O2: C, 80.82; H, 7.85. Found: C, 80.79; H, 7.82.
2,6-Dim eth ylp h en yl ben zoa te (Table 6, entry 16):27 1H
NMR (CDCl3, 300 MHz) δ 2.20 (s, 6H), 7.08-7.13 (m, 3H), 7.53
(tt, J ) 1.3, 7.5 Hz, 2H), 8.2-8.3 (m, 2H).
P r ep a r a tion of ω-Hyd r oxy Ca r boxylic Acid s. The
hydroxycarboxylic acids, HO(CH2)nCO2H with n ) 9, 11, 14,
and 15, are commercially available. The hydroxycarboxylic
acids, HO(CH2)nCO2H with n ) 5-8, 10, and 12, were obtained
by saponification of the corresponding lactones which in turn
were prepared by Baeyer-Villiger oxidation of commercially
available cycloalkanones. Purified samples of the intermediate
lactones also served as reference materials for comparison with
the products of hydroxy acid cyclization. 14-Hydroxytetrade-
canoic acid (n ) 13) was prepared by selective hydrolysis of
diethyl tetradecanedioate to monocarboxylic acid, subsequent
reduction to the primary alcohol, and hydrolysis of the remain-
ing ester unit.41
Typ ica l P r oced u r e for Ba eyer -Villiger Oxid a tion of
Cycloa lk a n on es. A mixture of cycloalkanone (5 mmol),
3-chloroperoxybenzoic acid (7.5 mmol), 2,6-di-tert-butyl-4-
methylphenol (200 mg), and 1,2-dichloroethane (15 mL) was
refluxed for 12-24 h in the dark. After being cooled to room
temperature, the mixture was treated with aqueous sodium
hydrogen sulfite and aqueous sodium hydrogen carbonate. The
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Purification was done by column
chromatography on silica gel (eluent: hexane-ethyl acetate
system) to give the desired lactone in good yield (50-90%).
Typ ica l P r oced u r e for Sa p on ifica tion of La cton es. A
mixture of the corresponding lactone (4 mmol), potassium
hydroxide (16 mmol), water (1 mL), and methanol (10 mL) was
stirred for 2-5 h and rotary evaporated to near dryness. Then
4 N HCl (30 mL) was added, and the mixture was extracted
with ethyl acetate twice, dried over Na2SO4, and concentrated
in vacuo. The crude products were separated by column
chromatography on silica gel eluting with hexane/ethyl acetate
2:1, ethyl acetate only, and then ethyl acetate/methanol/acetic
acid 125:25:1 to obtain ω-hydroxy carboxylic acid included
silica gel. Finally, the pure ω-hydroxy carboxylic acid was
2,6-Bis(1,1-d im et h ylet h yl)-4-m et h ylp h en yl a cet a t e
(Table 3, entry 17):35 1H NMR (CDCl3, 300 MHz) δ 1.34 (s,
18H), 2.32 (s, 3H), 2.35 (s, 3H), 7.12 (s, 2H).
P r ep a r a tion of p-Nitr oben zoic An h yd r id e.36 To the
mixture of p-nitrobenzoic acid (3.34 g, 20 mmol) and p-
nitrobenzoyl chloride (3.71 g, 20 mmol) in dichloromethane (50
mL) was added pyridine (2.02 mL, 25 mmol) dropwise at 0
°C. The reaction mixture was stirred for 15 h at room
temperature and then quenched with cold water (20 mL). After
usual workup, the crude product was purified by recrystalli-
zation from dichloromethane-hexane to afford p-nitrobenzoic
anhydride (5.71 g, 90% yield).
Typ ica l P r oced u r e for Ester ifica tion betw een Alco-
h ols a n d Ca r boxylic Acid s (Table 6). To a cloudy mixed
solution of alcohols (1 mmol), carboxylic acids (1.1 mmol), and
p-nitrobenzoic anhydride31 (474 mg, 1.5 mmol) in nitromethane
(4 mL) was added dropwise a cloudy solution (100 µL, 0.01
mmol, 0.1 M) of scandium triflate in acetonitrile at room
temperature. After being stirred at the same temperature
until alcohols were completely comsumed, the suspension was
quenched with aqueous sodium hydrogen carbonate, and the
product was extracted with ether. The organic layers were
dried over magnesium sulfate, filtered, and concentrated in
vacuo to crude product. Purification was done by column
chromatography on silica gel (eluent: hexane-ethyl acetate
system) to give the desired ester in good yield.
The physical properties and analytical data of the esters
thus obtained are listed below.
3-P h en ylp r op yl p r op a n oa te (Table 6, entry 1):37 1H NMR
(CDCl3, 300 MHz) δ 1.15 (t, J ) 7.5 Hz, 3H), 1.90-2.01 (m,
2H), 2.33 (q, J ) 7.5 Hz, 2H), 2.69 (t, J ) 7.8 Hz, 2H), 4.09 (t,
J ) 6.6 Hz, 2H), 7.10-7.35 (m, 5H).
3-P h en ylp r op yl 2-m eth ylp r op a n oa te (Table 6, entry 2):6d
1H NMR (CDCl3, 300 MHz) δ 1.18 (d, J ) 7.0 Hz, 6H), 1.90-
2.02 (m, J ) 7.0 Hz, 2H), 2.55 (septet, J ) 7.0 Hz, 1H), 2.69
(t, J ) 7.8 Hz, 2H), 4.09 (t, J ) 6.5 Hz, 2H), 7.11-7.34 (m,
5H).
(1S,3R,5S)-5-Meth yl-2-(1-m eth yleth yl)cycloh exyl 2-m e-
th ylp r op a n oa te (Table 6, entry 5):38 1H NMR (CDCl3, 300
MHz) δ 0.75 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 7.1 Hz, 3H), 0.90
(32) Ho¨fle, G.; Steglich, W. Synthesis 1972, 619.
(33) Burghardt, A.; Kulicki, Z.; Stec, Z.; Zawadiak, J . Pol. J . Appl.
Chem. 1993, 37, 243.
(34) Brittelli, D. R.; Boswell, G. A., J r. J . Org. Chem. 1981, 46, 312.
(35) Volod’kin, A.; Rasuleva, D.; Ershov, V. Izv. Akad. Nauk SSSR,
Ser. Khim. 1972, 178.
(36) Carpenter, F. H. J . Am. Chem. Soc. 1948, 70, 2964.
(37) Yamaguchi, M.; Tsukamoto, Y.; Minami, T. Chem. Lett. 1990,
1223.
(38) Ralitsch, M.; Ciccio, J .; Calzada, J . Rev. Latinoam. Quim. 1982,
13, 16.
(39) Takimoto, S.; Inanaga, J .; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. J pn. 1976, 49, 2335.
(40) Heathcock, C. H.; Young, S. D.; Hagen, J . P.; Pirrung, M. C.;
White, C. T.; VanDerveer, D. J . Org. Chem. 1980, 45, 3846.
(41) Ogawa, T.; Fang, C.-L.; Suemune, H.; Sakai, K. J . Chem. Soc.,
Chem. Commun. 1991, 1438.

Acylation of Alcohols with Acid and Mixed Anhydrides
J . Org. Chem., Vol. 61, No. 14, 1996 4567
obtained by filtration of silica gel after extraction into THF
(80 - >95% yield).
(CDCl3, 300 MHz) δ 1.20-1.47 (m, 10H), 1.48-1.60 (m, 2H),
1.60-1.80 (m, 4H), 2.33-2.41 (m, 2H), 4.20 (t, J ) 5.1 Hz, 2H).
1,13-Dioxa cyclotetr a d ocosa n e-2,14-d ion e (n ) 10):16,42
IR (CHCl3) 2930, 2857, 1723 (CO2), 1387, 1262, 1235, 1184,
Typ ica l P r oced u r e for Selective La cton iza tion of
ω-Hyd r oxy Ca r boxylic Acid s (Table 7). p-Nitrobenzoic an-
hydride (253 mg, 0.8 mmol) was dissolved in dry acetonitrile
(169 mL), and a cloudy solution of scandium triflate (0.8 mL,
0.08 mmol, 0.1 M) in acetonitrile was added to the solution at
room temperature under argon. A solution of ω-hydroxy
carboxylic acid (10 mL, 0.4 mmol, 0.04 M) in THF was added
slowly from a mechanically driven syringe over 15 h to the
mixed solution at reflux under argon, and the reaction mixture
was further stirred for 5 h at reflux. After being cooled to room
temperature, the solution was quenched with aqueous satu-
rated sodium hydrogen carbonate (4 mL). The resulting
mixture was concentrated under reduced pressure and ex-
tracted with ether twice. The organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Pu-
rification was done by column chromatography on silica gel
(eluent: hexane-ethyl acetate system) to give the desired
lactone in good yield. In some cases, diolide was afforded as
minor product.
1
1157, 1105, 1067 cm-1; H NMR (CDCl3, 300 MHz) δ 1.13-
1.44 (m, 24H), 1.55-1.71 (m, 8H), 2.31 (t, J ) 7.0 Hz, 4H),
4.11 (t, J ) 6.0 Hz, 4H); HRMS (FAB) for C22H41O4 [MH]+,
calcd 369.3005, found 369.2987.
12-Dod eca n olid e (n ) 11):42 IR (film) 2932, 2863, 1734
(CO2), 1339, 1252, 1142, 1096, 1051 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 1.25-1.49 (m, 14H), 1.61-1.73 (m, 4H), 2.32-
2.40 (m, 2H), 4.16 (t, J ) 5.3 Hz, 2H); MS (EI, 20 eV) m/ z (rel
intensity) 198 (100, M+), 180 (83, M+-18[H2O]), 162 (81), 138
(98, M+ - 60 [CH3CO2H]), 136 (79), 110 (60).
1,14-Dioxa cycloh exa cosa n e-2,15-d ion e (n ) 11):42 IR
(CHCl3) 2930, 2857, 1723 (CO2), 1466, 1387, 1182, 1107 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.22-1.43 (m, 28H), 1.55-1.69
(m, 8H), 2.31 (t, J ) 7.1 Hz, 4H), 4.10 (t, J ) 6.0 Hz, 4H); MS
(FD) m/ z 397 (MH+).
13-Tr id eca n olid e (n ) 12):42 IR (film) 2930, 2861, 1736
(CO2), 1460, 1385, 1347, 1242, 1208, 1169, 1105 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.15-1.50 (m, 16H), 1.59-1.72 (m, 4H),
2.34-2.41 (m, 2H), 4.15 (t, J ) 5.2 Hz, 2H).
The physical properties and analytical data of the lactones
thus are listed below.
6-Hexa n olid e (n ) 5):42,43 IR (film) 2936, 2865, 1732 (CO2),
1,15-Dioxa cycloocta cosa n e-2,16-d ion e (n ) 12):42 IR
(CHCl3) 2930, 2857, 1725 (CO2), 1466, 1266, 1238, 1179, 1109
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.10-1.45 (m, 32H), 1.55-
1.71 (m, 8H), 2.32 (t, J ) 7.0 Hz, 4H), 4.10 (t, J ) 6.0 Hz, 4H);
HRMS (FAB) for C26H49O4 [MH]+, calcd 425.3631, found
425.3613.
1476, 1439, 1393, 1348, 1327, 1293, 1169 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.60-1.94 (m, 6H), 2.60-2.65 (m, 2H),
4.23 (t, J ) 4.4 Hz, 2H).
7-Hep ta n olid e (n ) 6):42 IR (film) 2932, 2863, 1731 (CO2),
1453, 1354, 1298, 1235, 1130, 1096, 1076 cm-1 1H NMR
;
14-Tetr a d eca n olid e (n ) 13):42 IR (film) 2928, 2859, 1732
(CO2), 1458, 1348, 1142, 1109, 965 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.20-1.50 (m, 18H), 1.51-1.78 (m, 4H), 2.31-2.40 (m,
(CDCl3, 300 MHz) δ 1.51-1.70 (m, 4H), 1.73-1.94 (m, 4H),
2.55 (t, J ) 6.4 Hz, 2H), 4.35 (t, J ) 5.6 Hz, 2H).
1,9-Dioxa cycloh exa d eca n e-2,10-d ion e (n ) 6):42 IR
(CHCl3) 3021, 2940, 2863, 1725 (CO2), 1458, 1389, 1266, 1192,
1157, 1107 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.25-1.50 (m,
8H), 1.60-1.77 (m, 8H), 2.32-2.39 (m, 4H), 4.10 (t, J ) 5.3,
4H); MS (EI, 20 eV) m/ z (rel intensity) 256 (6, M+), 238 (77,
M+ - 18[H2O]), 142 (47), 129 (100), 127 (49), 126 (34), 124
(19).
2H), 4.14 (t, J ) 5.2 Hz, 2H); HRMS (CI) for C14
H27O2 [MH]+,
calcd 227.2011, found 227.1992.
1,16-Dioxa cyclotr ia con ta n e-2,17-d ion e (n ) 13):42 IR
(CHCl3) 2930, 2857, 1721 (CO2), 1466, 1179, 1109 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 1.15-1.43 (br, 36H), 1.44-1.70 (m,
8H), 2.31 (t, J ) 7.1 Hz, 4H), 4.09 (t, J ) 5.9 Hz, 4H); HRMS
(CI) for C28H53O4 [MH]+, calcd 453.3944, found 453.3971.
15-P en ta d eca n olid e (n ) 14):42 IR (film) 2930, 2859, 1736
(CO2), 1460, 1350, 1167, 1109, 1013, 758 cm-1; 1H NMR (CD-
Cl3, 300 MHz) δ 1.20-1.49 (m, 20H), 1.58-1.71 (m, 4H), 2.33
(t, J ) 6.6 Hz, 2H), 4.14 (t, J ) 5.3 Hz, 2H); MS (EI, 20 eV)
m/ z (rel intensity) 240 (83, M+), 222 (100, M+ - 18[H2O]), 180
(79, M+ - 60 [CH3CO2H]), 152 (37), 138 (49), 124 (54), 110 (70).
1,17-Dioxa cyclod otr ia con ta n e-2,18-d ion e (n ) 14):42,44
IR (CHCl3) 2930, 2857, 1721 (CO2), 1466, 1277, 1237, 1179,
1111, 1075 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.18-1.41 (m,
40H), 1.56-1.70 (m, 8H), 2.31 (t, J ) 7.0 Hz, 4H), 4.09 (t, J )
6.1 Hz, 4H); MS (EI, 20 eV) m/ z (rel intensity) 481 (72, M+),
463 (82, M+ - 18 [H2O]), 283 (52), 241 (100), 220 (65).
16-Hexa d eca n olid e (n ) 15):42 IR (film) 2928, 2857, 1736
(CO2), 1460, 1387, 1350, 1242, 1167, 1109, 1069 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.20-1.45 (m, 22H), 1.57-1.72 (m, 4H),
2.32 (t, J ) 6.6 Hz, 2H), 4.13 (t, J ) 5.6 Hz, 2H); MS (EI, 20
eV): m/ z (rel intensity) 254 (100, M+), 236 (92, M+ - 18 [H2O]),
208 (15), 194 (51, M+ - 60 [AcOH]), 192 (28), 166 (19), 152
(31), 138 (31), 124 (29), 110 (43).
8-Octa n olid e (n ) 7):16,42 IR (film) 2934, 2867, 1736 (CO2),
1460, 1375, 1356, 1331, 1271, 1238, 1144 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.35-1.55 (m, 4H), 1.56-1.87 (m, 6H),
2.29 (t, J ) 6.7 Hz, 2H), 4.29 (t, J ) 5.8 Hz, 2H).
1,10-Dioxa cyclooca ta d eca n e-2,11-d ion e (n ) 7):16,42 IR
(CDCl3) 2936, 2860, 1721 (CO2), 1460, 1387, 1275, 1237, 1156,
1103, 1063 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.20-1.45 (m,
12H), 1.52-1.74 (m, 8H), 2.32 (t, J ) 6.9 Hz, 4H), 4.13 (t, J )
5.7 Hz, 4H); MS (CI) m/ z 285 (MH+).
9-Non a n olid e (n ) 8):42 IR (film) 2957, 2870, 1732 (CO2),
1468, 1294, 1273, 1252, 1238, 1167, 1152, 1109 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.20-1.35 (m, 2H), 1.41-1.60 (m, 6H),
1.71-1.85 (m, 4H), 2.31-2.37 (m, 2H), 4.28 (t, J ) 5.3 Hz, 2H).
1,11-Dioxa cycloicosa n e-2,12-d ion e (n ) 8):42 IR (CHCl3)
2934, 2859, 1725 (CO2) cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.20-1.45 (m, 16H), 1.50-1.75 (m, 8H), 2.33 (t, J ) 6.7 Hz,
4H), 4.07-4.12 (m, 4H); MS (EI, 20 eV) m/ z (rel intensity)
312 (20, M+), 294 (82, M+ - 18 [H2O]), 138 (100).
10-Deca n olid e (n ) 9):42 IR (film) 1947, 1867, 1732 (CO2),
1466, 1449, 1381, 1354, 1248, 1183, 1157 cm-1 1H NMR
;
1,18-Dioxa cyclotetr a con ta n e-2,19-d ion e (n ) 15):42 IR
(CDCl3, 300 MHz) δ 1.20-1.60 (m, 10H), 1.68-1.81 (m, 4H),
2.10-2.18 (m, 2H), 4.18 (t, J ) 4.8 Hz, 2H); MS (EI, 20 eV)
m/ z (rel intensity) 170 (42, M+), 152 (66, M+ - 18 [H2O]), 127
(100), 113 (84), 110 (72, M+ - 60[AcOH]).
(CHCl3) 2928, 2857, 1717 (CO2), 1179, 1111 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.20-1.42 (m, 44H), 1.57-1.70 (m, 8H),
2.30 (t, J ) 7.2 Hz, 4H), 4.09 (t, J ) 6.1 Hz, 4H); MS (FD)
m/ z 509 (MH+).
1,12-Dioxacyclodocosan e-2,13-dion e (n ) 9):42 IR (CHCl3)
3021, 2932, 2857, 1721 (CO2), 1466, 1387, 1339, 1264, 1235,
1105 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.20-1.45 (m, 20H),
1.55-1.70 (m, 8H), 2.31 (t, J ) 6.9 Hz, 4H), 4.11 (t, J ) 5.8
Hz, 4H); MS (EI, 20 eV): m/ z (rel intensity) 340 (40, M+), 322
(100, M+ - 18 [H2O]), 281 (32), 257 (35), 213 (37), 171 (55),
152 (82), 110 (44).
Ack n ow led gm en t. We are especially indebted to
Daikin Industries, Ltd., for the HRMS analyses of
macrocyclic lactones. Support of this research by the
Ministry of Education, Science and Culture of the
J apanese Government is greatly appreciated. H.K. also
acknowledges a J SPS Fellowship for J apanese J unior
Scientists.
11-Un d eca n olid e (n ) 10):16,42 IR (film) 2932, 2865, 1736
(CO2), 1466, 1447, 1244, 1221, 1175, 1142, 1094 cm-1; 1H NMR
J O952237X
(42) Stoll, M.; Rouve´, A. Helv. Chim. Acta 1935, 18, 1087.
(43) Van Natta, F. J .; Hill, J . W.; Carothers, W. H. J . Am. Chem.
Soc. 1934, 56, 455.
(44) J aeger, D. A.; Ippoliti, J . T. J . Org. Chem. 1981, 46, 1964.