Catalytic nucleophilic acyl substitution of anhydrides by amphoteric vanadyl triflate

Article abstract of DOI:10.1021/ol016684c

Figure presented Among four vanadyl species examined, vanadyl triflate was the most efficient catalyst to facilitate nucleophilic acyl substitution of anhydrides with a myriad array of alcohols, amines, and thiols in high yields and high chemoselectivity. By using mixed-anhydride technique, one can achieve oleate and peptide syntheses. In marked contrast to common metal Inflates, the amphoteric character of the V=O unit in vanadyl species was proven to be responsible for the catalytic profile in this process.

Full text of DOI:10.1021/ol016684c

ORGANIC
LETTERS
2
001
Vol. 3, No. 23
729-3732
Catalytic Nucleophilic Acyl Substitution
of Anhydrides by Amphoteric Vanadyl
Triflate
3
Chien-Tien Chen,* Jen-Huang Kuo, Chun-Hsin Li, N. B. Barhate, Sang-Wen Hon,
Tai-Wei Li, Shi-Deh Chao, Chia-Cheng Liu, Ying-Chieh Li, I-Hsin Chang,
Jin-Sheng Lin, Chin-Jing Liu, and Y-Chen Chou
Department of Chemistry, National Taiwan Normal UniVersity, Taipei, Taiwan, R.O.C.
chefV043@scc.ntnu.edu.tw
Received September 3, 2001
ABSTRACT
Among four vanadyl species examined, vanadyl triflate was the most efficient catalyst to facilitate nucleophilic acyl substitution of anhydrides
with a myriad array of alcohols, amines, and thiols in high yields and high chemoselectivity. By using mixed-anhydride technique, one can
achieve oleate and peptide syntheses. In marked contrast to common metal triflates, the amphoteric character of the VdO unit in vanadyl
species was proven to be responsible for the catalytic profile in this process.
The acylations of alcohols, amines, and thiols are important
and commonly used transformations in organic synthesis.
acylation of alcohols with anhydrides. However, only a few
of them have been studied with more complete anhydride
1
5
,7
In these reactions, acid halides or anhydrides are often
scope, and substrates bearing acid-sensitive groups, such
2
10
employed as the acyl source in basic media or in the
as acetonide and allylic, might not be fully compatible. In
3
4
presence of Lewis base or acid catalysts. For the past five
addition, their actual role in the catalytic pathway was not
fully understood. Notably, the preparation of metal triflates
often require direct mixing of metal oxides with excess of
hot triflic acid. The incomplete removal of triflic acid from
the metal triflates might limit the overall efficiency of the
process. In this context, new mild and neutral catalysts, which
can achieve general nucleophilic acyl substitution of anhy-
drides with protic nucleophiles, remain in great demand.
The synthetic utility of vanadium-containing compounds
has been widely explored and utilized. Among them,
oxovanadium(IV) (vanadyl) compounds were normally treated
5
years, trimethylsilyl (TMS) and metal triflates such as
indium, scandium, copper, and most recently bismuth
triflate have been found to be effective in catalyzing the
6
7
8
9
(
1) Green, T. W. ProtectiVe Groups in Organic Synthesis; John Wiley
Sons: New York, 1991.
2) Larock, R. C. In ComprehensiVe Organic Transformations; VCH
Publisher Inc.: New York, 1989; p 980.
3) For leading references, see: (a) H o¨ fle, G.; Steglich, W.; Vorbr u¨ ggen,
&
(
(
H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (b) Vedejs, E.; Bennett, N.
S.; Conn, L. M.; Diver, S. T.; Gingvas, M.; Lin, S.; Oliver, P. A.; Peterson,
M. J. J. Org. Chem. 1993, 58, 7286. (c) Verkade, J. G.; Ilankumaran, P.
J. Org. Chem. 1999, 64, 9063.
V
11
(4) (a) Baker, R. H.; Bordwell, F. G. Organic Syntheses; Wiley: New
as precatalysts of the corresponding V species. However,
synthetic transformations that are directly catalyzed by
York, 1955; Collect. Vol. III, p 141. (b) Iqbal, J.; Srivastava, R. R. J. Org.
Chem. 1992, 57, 2001. (c) Chandrasekhar, S.; Ramachander, T.; Takhi, M.
Tetrahedron Lett. 1998, 39, 3263.
1
1a,12
vanadyl species were relatively unexplored.
Notably,
(5) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J.
Togni in 1990 reported the uses of camphor-derived vanadyl
Org. Chem. 1998, 63, 2342.
(
(
6) Chauhan, K. K.; Frost, C. G.; Love, I.; Waite, D. Synlett 1999, 1743.
7) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
(9) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. Angew. Chem., Int.
Ed. 2000, 39, 2877.
(10) Jarowicki, K.; Kocienski, P. Contemp. Org. Synth. 1997, 454.
1
996, 61, 4560.
8) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1999, 40, 2611.
(
1
0.1021/ol016684c CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/20/2001

bis(1,3-diketonato) complexes as Lewis acid catalysts for
asymmetric Diels-Alder reactions between Danishefsky
dienes and aldehydes.13 Although a concerted pathway was
suggested in the report, the potential amphoteric character
of the VdO unit (i.e., V-O ) to facilitate a stepwise, push-
pull type mechanism was overlooked. Namely, the (partial)
positively charged V in VdO is Lewis acidic enough to
activate the carbonyl oxygen of an aldehyde. In the mean-
time, the (partial) negatively charged O in VdO serves as a
Lewis base to activate an enol silane with concomitant
removal of its silyl group. The proposal was somewhat
Table 1. Catalytic Acylations of 2-Phenylethanol with Various
Anhydrides in the Presence of Various Vanadyl Species
+
-
supported by a facile conversion of V(O)(salen)
2
to VCl
2
-
14
(salen) under the action of SOCl . Therefore, we sought
2 2
to examine if a vanadyl species can similarly react with an
anhydride to establish a fast equilibrium with its anhydride
adduct (Scheme 1). Under such circumstances, a protic
Scheme 1. Proposed Equilibrium between an Amphoteric
Vanadyl Species and an Anhydride in the Catalytic Acylation of
an Alcohol
a
Isolated yields. b Acetylacetonate. c Five mol % catalyst was used. The
d
trihydrate was used. e CH3CN was used as solvent. Catalyst was recovered
from aqueous layer and reused for five consecutive runs. Diphenethyl ester
f
g
was isolated in 16%.
nucleophile (e.g., an alcohol) may add to one of the two
alkanoates in the adduct with a concomitant elimination of
an alkanoic acid to regenerate the vanadyl species (i.e., a
catalytic nucleophilic acyl substitution of an anhydride). We
herein disclose our realization of this catalytic process.
Four different vanadyl species were first tested in mediat-
ing the acetylation of 2-phenylethanol, Table 1. Initial trials
supporting the mechanistic role of the VdO unit in the
1
6
vanadyl catalysts. In addition, there is no need of chro-
matographic purification with the acetylation protocol since
the remaining acetic anhydride and vanadyl triflate can be
readily removed by direct aqueous wash. More importantly,
2
V(O)(OTf) is fully compatible with water. It can be
recovered from the concentrate of the aqueous layer and
reused for at least five consecutive runs with similar catalytic
activity.
Beside acetic anhydride, the catalytic system is amenable
to acyclic and cyclic, aliphatic, and aromatic anhydrides,
Table 1. In general, the more hindered the anhydride, the
with 5 mol % of vanadyl acetylacetonate (VO(acac)
2
) and
vanadyl sulfate were effective to complete the acetylation
at ambient temperature in the presence of 1.5 equiv of Ac
in 5 and 24 h, respectively.
2
O
Vanadyl chloride and triflate, which were prepared from
vanadyl sulfate and suitable barium salts,15 were found to
be much more reactive. Acetylation using 1 mol % of V(O)-
2 2 2 2 2
Cl and V(O)(OTf) with 1.5 equiv of Ac O in CH Cl were
slower the acylation rate (i.e., CH
3
> i-Pr > t-Bu; entries 4,
7
, and 8). Acylation with an aromatic anhydride (e.g., R )
Ph, entry 10) is up to 50 times slower than those with
aliphatic anhydrides (entries 4 and 6-8). Acylation with di-
tert-butyl dicarbonate also proceeds well and with a rate
similar to that of benzoylation (entry 9). Cyclic anhydrides
such as succinic and phthalic anhydride are the least reactive.
Acylations took 2-4 days (entries 11 and 12).
With the optimal catalyst-vanadyl triflate in hands, nu-
cleophilic acyl substitutions of both acetic and pivalic
anhydride (representing two steric extremes) with protic
nucleophiles (e.g., alcohols, amines, and thiols) of varying
steric and electronic demands were examined. In almost all
complete in 7.5 and 0.5 h, respectively, leading to phenethyl
acetate in g94% yields. It should be noted that the corre-
sponding VCl and V(OTf) are catalytically inactive,
3 3
(
11) For a general review, see: (a) Hirao, T. Chem. ReV. 1997, 97, 2707.
(
b) For oxidative couplings, see: Hwang, D. R.; Chen, C. P.; Uang, B. J.
J. Chem. Soc. Chem. Commun. 1999, 1207. (c) Hon, S.-W.; Li, C.-H.; Kuo,
J.-H.; Barhate, N. B.; Liu, Y.-H.; Wang, Y.; Chen, C.-T. Org. Lett. 2001,
3
, 869. (d) For vicinal dialkylation of cyclic enones, see: Hirao, T.; Takada,
T.; Sakurai, H. Org. Lett. 2000, 2, 3659.
12) For recent applications, see: (a) Belokon, Y. N.; North, M.; Parsons,
(
T. Org. Lett. 2000, 2, 1617. (b) Ishii, Y.; Matsunaka, K.; Sakaguchi, S. J.
Am. Chem. Soc. 2000, 122, 7390.
(13) Togni, A. Organometallics 1990, 9, 3106.
(
14) Schmidt, H.; Bashirpoor, M.; Rehder, D.J. Chem. Soc., Dalton Trans.
1
996, 3865.
15) See Supporting Information.
(16) V(O)Cl3 is moisture-sensitive but was found to be catalytically active
(100% yield, 1.5 h).
(
3730
Org. Lett., Vol. 3, No. 23, 2001

cases except in the pivalations of cinnamyl alcohol (85%)
and (-)-menthol (84%), the chemical yields of acylation
were g95%, Table 2. In general, acetylations proceed much
The acylation protocol is tolerant to protic nucleophiles
bearing functional groups such as alkene, ester, lactone,
ketone, imide, acetonide, and lactol (entries 1-9, Table 3).
Table 2. Vanadyl Triflate-Catalyzed Acetylation and Pivalation
of Alcohols, Amines, and Thiols
Table 3. Acetylation and/or Pivalation of Functionalized
Substrates
a
A total of 1.5 equiv of anhydride was used unless otherwise stated.
b
c
Isolated yields and characterized spectroscopically. The data in paren-
d
theses correspond to pivalations. A total of 2 equiv of anhydride was used.
e
A total of 3 equiv of anhydride was used. f THF was used as solvent.
g
Toluene was used as solvent.
faster than the corresponding pivalations. Acylations went
smoothly with primary, secondary, and acid-sensitive allylic
and benzylic alcohols. No trace of allylic7 or pinacol
,17
18
a
A total of 1.5 equiv of anhydride was used unless otherwise stated.
b
c
rearrangement byproducts was observed in the case of
cinnamyl alcohol and 10,11-dihydroxy-dibenzosuberane
entries 2 and 5). Tertiary alcohols such as tert-butyl alcohol
and trityl alcohol are inactive. Nevertheless, the correspond-
ing tert-butanethiol is fairly reactive (entry 10). Aromatic
alcohols, amines, and thiols (e.g., 2-hydroxy, 2-amino, and
-thio-naphthalenes) are amenable to acylations in essentially
quantitative yields (entries 6-8).
Isolated yields and characterized spectroscopically. The data in paren-
theses correspond to pivalations. A total of 2 equiv of anhydride was used.
d
e
f
g
A total of 3 equiv of anhydride was used. Carried out at -5 °C. No
(
solvent was used. h Asterisk signifies the reactive site. For effective
i
j
monoacylation, 0.95 equiv of anhydride was used. Diacetylated product
was isolated in 10% yield.
19
2
Their acylations proceeded smoothly in 75-100% yields.
Side reactions such as oxidation (dehydrogenation) and
dehydration were not observed in the case of R-hydroxy,
4
b
(
17) A mixture of products was obtained under usual conditions (acid
chloride/pyridine). For its effective acetylation mediated by TMSOTf, lower
reaction temperature (-10 °C in ethyl acetate) was required (ref 5).
(19) (a) Aniline has failed to produce acetanilide in Cp*2Sm(thf)2-
mediated acetylation. (b) Ishii, Y.; Takeno, M.; Kawasaki, Y.; Muromachi,
A.; Nishiyama, Y.; Sakaguchi, S. J. Org. Chem. 1996, 61, 3088.
(18) Conventional procedure (acid chloride/pyridine) led to only pinacol
rearrangement product.
Org. Lett., Vol. 3, No. 23, 2001
3731

R-amino esters (entries 2 and 3), â-hydroxy esters and
ketones (entries 4 and 5). No trace of the glycosidic C-O
cleavage was observed in the acetylation of diacetone-D-
glucose (entry 7) at -5 °C, although 22% of acetylation at
the primary hydroxy group with concomitant migration of
the acetonide unit could not be prevented.15
Scheme 2. Acylations with Mixed-Anhydride Approaches in
Oleate and Dipeptide Syntheses
The high catalytic efficacy of vanadyl triflate was further
demonstrated in the peracetylations of polyhydroxyl mol-
ecules such as uridine, lactose, and cyclodextrin (21 OH
groups!). In all cases, reactions went to completion in acetic
acid or in neat acetic anhydride, albeit with longer reaction
20
time (2.5-4 days). By taking advantage of the differential
reactivity between nucleophiles, we were able to carry out
chemoselective acylation of 3-hydroxymethyl-2-naphthol. Its
primary hydroxyl group was acylated with complete chemo-
To support the mechanistic proposal in Scheme 1, vanadyl
triflate was first heated in refluxing trifluoroacetic anhydride
21
selectivity and in g95% yields (entry 10). Acetylation of
tert-leucinol at the sterically hindered amino moiety was
moderately selective. The corresponding N-acetylated product
was furnished in 60% yield. Nevertheless, the analogous
(R′ ) CF ) for 12 h and then concentrated. The resultant
3
adduct was treated with a stoichiometric amount of 2-phen-
ylethanol (R ) Ph(CH ) ) in CH Cl for 3 h. The corre-
2
2
2
2
sponding 2-phenethyl trifluoroacetate was isolated in 87%
2
2
15
N-pivalation proceeded with complete selectivity (97%).
yield.
Since benzoic anhydride23 is the least reactive acyclic
anhydride, one may carry out acylation directly with fatty
acid in the presence of benzoic anhydride. By this protocol,
the in-situ-generated mixed anhydride acts as the real
acylation reagent. As an example, 1-phenethyl-3-buten-1-
ol was treated with a mixture of oleic acid and benzoic
In conclusion, we have unraveled the amphoteric catalytic
behavior of vanadyl triflate in nucleophilic acyl substitutions
with various anhydrides. It can be readily prepared and
represents a new type of water-tolerant metal triflate.24 The
acylation protocol allows for chemoselective acylation and
tolerates many structural and substrate variations. Mixed-
anhydride technique allows for acylations with commercially
unavailable anhydrides. Investigations toward solution and
solid-state peptide syntheses by this catalytic process are
underway.
7
2 2
anhydride (1.1 equiv) in CH Cl with 5 mol % of vanadyl
triflate for 2 h. The resultant oleate was produced smoothly
in 82% yield, Scheme 2. More importantly, the mixed-
anhydride technique can be applied to dipeptide synthesis,
as illustrated in the direct coupling of Fmoc-L-leucine and
methyl L-tert-leucinate in 94% yield.
Acknowledgment. We are grateful to the National
Science Council of the Republic of China for generous
support of this research. We thank reviewers and Professor
Alois F u¨ rstner for enlightening suggestions on this work.
(
20) Pivalations did not work properly because of the poor solubility of
these substrates in pivalic anhydride.
21) (a) Further stirring with excess of acetic and pivalic anhydride (10
(
equiv) for another 18 and 72 h (50 °C) furnished the corresponding
diacetylated and dipivalated products in 87% and 89% yields, respectively.
Supporting Information Available: Representative ex-
1
13
perimental procedures, spectral data, and H and C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
b) In DMAP catalyzed acylation in pyridine, reversed chem-selectivity
was observed in this case as a result of the more acidic nature of phenolic
OH.
(
22) By using the pivalic anhydride/pyridine protocol, the desired product
was isolated in only 20% yield.
23) It was found that amines, thiols, and primary and aromatic alcohols
OL016684C
(
are amenable to benzoylations. Benzoylations of secondary alcohols are
rather limited and require harsher reaction conditions. So far, the only
workable substrate is as shown in entry 1, Table 3, which underwent
benzoylation at 50 °C in 52% yield.
(24) For an elegant survey of other water-tolerant metal salts, see:
Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120,
8287.
3732
Org. Lett., Vol. 3, No. 23, 2001