Metal-catalyzed acyl transfer reactions of enol esters: Role of Y5(OiPr)13O and (thd)2Y(OiPr) as transesterification catalysts

Article abstract of DOI:10.1021/ol0057131

(equation presented) Primary and secondary alcohols react with vinyl or isopropenyl acetate at room temperature in the presence of catalytic amounts (0.05-1 mol percent) of Y₅(OⁱPr)₁₃O to give the corresponding esters. In selected cases, the yttrium catalyst promotes the selective O-acylation of amino alcohols without the formation of the amide. Enol esters also react with α-amino acid esters in the absence of a catalyst, at room temperature, to give the corresponding amides.

Full text of DOI:10.1021/ol0057131

ORGANIC
LETTERS
2
000
Vol. 2, No. 7
97-1000
Metal-Catalyzed Acyl Transfer Reactions
i
9
of Enol Esters: Role of Y (O Pr) O and
5
13
i
(
thd) Y(O Pr) as Transesterification
2
Catalysts
Mei-Huey Lin and T. V. RajanBabu*
Department of Chemistry, 100 West 18th AVenue, The Ohio State UniVersity,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received February 23, 2000
ABSTRACT
Primary and secondary alcohols react with vinyl or isopropenyl acetate at room temperature in the presence of catalytic amounts (0.05−1 mol
i
%
5
) of Y (O Pr)13O to give the corresponding esters. In selected cases, the yttrium catalyst promotes the selective O-acylation of amino alcohols
without the formation of the amide. Enol esters also react with r-amino acid esters in the absence of a catalyst, at room temperature, to give
the corresponding amides.
Esters and amides occupy a central role in synthetic organic
chemistry both as protecting groups and as key intermediates
in functional group transformations. New, highly efficient
and stereoselective methods for the synthesis of these
ubiquitous functional groups continue to evolve. In this
context, two of the most significant recent advances have
been in the use of better acyl transfer agent/catalyst combina-
kinds of alcohols (for example, primary vs secondary, or
1
a
1b
alcohol vs phenol) is the goal. Otera found that distan-
noxane reagent 1 is an excellent catalyst for the synthesis of
primary alcohol esters using vinyl esters as acylating agents.
Acylation of alcohols and amines using enol esters can also
1
c
2 2
be effected by Cp* Sm(thf) , even though the need for a
catalyst for a primary amide formation from amines and vinyl
1
1e
tions and the discovery of new protocols for effecting kinetic
esters is questionable. Exploratory studies in search of a
2
resolution of secondary alcohols. For the synthesis of esters
well-defined transition metal catalyst that could improve the
efficiency and selectivity of the known transesterification
processes using vinyl esters (eq 1) led us to yttrium
from alcohols and anhydrides, trimethylsilyl triflate appears
to be the catalyst of choice, if no selectivity between various
(1) (a) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A.
J. Org. Chem. 1998, 63, 2342 and references therein. (b) Orita, A.;
Mitsutome, A.; Otera, J. J. Org. Chem. 1998, 63, 2420. (c) Ishii, Y.; Takeno,
M.; Kawasaki, Y.; Muromachi, A.; Nishiyama, Y.; Sakaguchi, S. J. Org.
Chem. 1996, 61, 3088. (d) Ishihara, K.; Kubota, M.; Kurihara, H.;
Yamamoto, H. J. Org. Chem. 1996, 61, 4560. (e) Kabouche, Z.; Bruneau,
C.; Dixneuf, P. H. Tetrahedron Lett. 1991, 32, 5359. (f) Degueil-Castaing,
M.; De Jeso, B.; Drouillard, S.; Maillard, B. Tetrahedron Lett. 1987, 28,
3
alkoxides including the pentameric yttrium aggregate Y
5
-
i
i
i
(µ
5
-O)(µ
3
-O Pr)
4
2 4 5
(µ -(O Pr) (O Pr) , generally formulated as
9
53. (g) See also: Seebach, D.; Hungerb u¨ hler, E.; Naef, R.; Schnurrenberger,
P.; Weidmann, B.; Z u¨ ger, M. Synthesis 1982, 138.
2) (a) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813 and
(
T.; Arakawa, A.; Shibuya, S. J. Org. Chem. 1994, 59, 3506. (e) Evans, D.
A.; Anderson, J. C.; Taylor, M. K. Tetrahedron Lett. 1993, 34, 5563. (f)
Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.; Wong,
C.-H. J. Am. Chem. Soc. 1988, 110, 7200.
references therein. (b) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem.
Soc. 1997, 119, 1492 and references cited therin. (c) Kawabata, T.; Nagato,
M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (d) Yokomatsu,
1
0.1021/ol0057131 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/10/2000

i
4
Y
5
(O Pr)13O. A careful examination of the literature suggests
Primary alcohols react faster than secondary alcohols, while
tertiary alcohols are unreactive under these conditions. Vinyl
acetate (Table 1, entries 12, 13, and 14 and eqs 2, 5, and 7)
is an exceptionally fast acylating agent, and benzyl and
cinnamyl alcohols are converted into the corresponding
acetates with as little as 0.0005 equiv of complex 2 (substrate/
catalyst ratio ) 2000, entries 12 and 13). Such catalytic
efficiency for acyl transfer reactions is unprecedented. With
0.005 equiv of catalyst 2, the reaction between benzyl alcohol
and vinyl acetate is virtually over in about 5 min. The
recovery of the product in most cases involves evaporation
of the excess enol ester and distillation or simple filtration
through a column of silica gel.
that in several structurally characterized yttrium complexes
alkoxide ligands are particularly susceptible to exchange (a
necessary feature if high turnovers in transacylations is the
ultimate goal), while other chelating ligands such as â-di-
ketonates are more robust.3 The latter might provide a
stereochemically well-defined coordination environment for
our eventual goal of exploring stereospecific processes such
kinetic resolution and desymmetrization with these catalysts.
In scouting experiments, isopropenyl acetate was treated
with benzyl alcohol, 1-methylbenzyl alcohol (1-phenyletha-
nol), and cyclohexanol in the presence catalytic amounts of
d-f
i
i
5 2
Y (O)(O Pr)13 (2) and ( PrO)Y(thd) (thd ) 2,2,6,6-tetra-
methyl-3,5-heptanedionato) (3). The results are shown in
3d
In the reactions of cyclohexanol, we observed that iso-
propenyl acetate consistently gave cleaner reactions and
better conversions and yields as compared to vinyl acetate
(eq 2). This may be related to catalyst deterioration caused
Table 1 (entries 1-5). Typically the reaction is done in neat
enol ester with 0.5 mol % of the catalyst at room temperature.
by the acetaldehyde side product in the case of vinyl acetate,
especially when the acylation itself is sluggish.
Table 1. Transesterifications Catalyzed by Y Complexesa
When a mixture of benzyl alcohol and 1-methylbenzyl
alcohol was reacted with 10.8 equiv of vinyl acetate in the
presence of 0.24 mol % of 2, in 5 min 100% of the primary
alcohol and 25% of the secondary alcohol were esterified.
The selectivity can be improved dramatically (>24:1) when
isopropenyl benzoate (∼1 equiv in benzene) is used as the
acylating agent (eq 3). The catalyst also appears to have an
effect on the primary vs secondary selectivity. A marked
difference in acetylation of primary vs secondary hydroxyl
groups was noted when isopropenyl acetate (1 equiv) was
employed with catalyst 3 (selectivity 2.7:1 for 2 vs 8:1 for
3).
no.
alcohol
cat. S/C b
time (h)
convnc
A. Reactions with Isopropenyl Acetate
1
2
3
4
5
benzyl alcohol
1-phenylethanol
cyclohexanol
1-Ph-1,2-ethanediol
E-cinnamyl alcohol
2, 200
2, 118
2, 217
2, 100
2, 200
1
>99
>99
>95
>99
>99
1.5
1.5
1.5
0.16
Stoichiometric Reactions Using Catalyst 2
6
7
8
benzyl alcohol
1-phenylethanol
t-butanol
2, 50
2, 50
2, 50
7
27
96
89
73
0
Selectivity for a primary alcohol in 1,2-diols is good to
moderate. For example, in the acylation of 1-phenyl-1,2-
ethanediol, the diacetate is formed in competition with the
Stoichiometric Reactions Using Catalyst 3
9
0
1
benzyl alcohol
1-phenylethanol
t-butanol
3, 50
3, 50
3, 50
14
20
96
98
84
0
1
1
(
3) Other alkoxides investigated include Y(OCH2CH2NMe2)3, SmI3‚THF,
B. Reactions with Vinyl Acetate
i IV IV
Ti(O Pr)4, (N[(CH2CH(CH3)O)3]Ti Cl, (N[(CH2CH(CH3)O)3]Zr Cl, Zr-
1
1
1
2
3
4
E-cinnamyl alcohol
benzyl alcohol
benzyl alcohol
2, 2000
2, 2000
2, 200
48
24
0.08
72
96
92
n
n
i
(
)
O Pr)4, Hf(O C4H9)4, Nb(OC2H5)5, V(O)(O Pr)3, Ta(OC2H5)5, Eu(tfc)3 tfc
tris[3-(trifluoromethylhydroxymethylene)camphorato], Pr(tfc)3, Y(thd)3
(thd ) tris(2,2,6,6-tetramethyl-3,5-heptanedionato), La(thd)3, and Yb(thd)3.
The alkoxides were added at a 2 mol % loading level to a mixture (1:1) of
a
Entries 1-5 carried out in neat isopropenyl acetate (1 mL, 9.1 mmol/
1
-phenylethanol and isopropenyl acetate dissolved in 2 mL of benzene-d6,
mmol of substrate) at rt. Entries 12-14 carried out in neat vinyl acetate.
Entries 6-11 carried out with a 1:1 molar ratio of the reagents in benzene
and the reaction was followed by GC and NMR. For synthetic applications
of Y-alkoxides, see: (a) Anwander, R. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.;
VCH: New York, 1996; p 866. (b) Abiko, A.; Wang, G. J. Org. Chem.
b
c
(
2 mL/mmol) at rt. S/C ) substrate-to-catalyst ratio. Conversions were
determined by GC or NMR.
1
996, 61, 2264. (c) Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc.,
Chem. Commun. 1995, 1021. (d) McLain, S. J.; Drysdale, N. E. U.S. Patent
028667; McLain, S. J.; Drysdale, N. E. Polym. Prepr. (Am. Chem. Soc.,
5
Under these conditions, isopropenyl acetate gave essentially
quantitative yields of the esters. The reaction can also be
done with stoichiometric amounts of the reagents in a
hydrocarbon solvent if higher catalyst loading and longer
reaction times are employed (entries 6-11). Under these
conditions, thd complex 3 is also a very effective catalyst.
DiV. Polym. Chem.) 1992, 33, 463. (e) Ford, T. M.; McLain, S. J. U.S.
Patent 5208297; Chem. Abstr. 1993, 119, 140012. (f) Ford, T. M.; McLain,
S. J. U.S. Patent 5292859; Chem. Abstr. 1994, 121, 58221.
(
4) (a) Mazdiyasni, K. S.; Lynch, C. T.; Smith, J. S. U.S. Patent 3278571,
966; Chem. Abstr. 1966, 65, 20008b. (b) Poncelet, O.; Sartain, W. J.;
Hubert-Pfalzgraf, L. G.; Folting, K.; Caulton, K. G. Inorg. Chem. 1989,
8, 263. (c) Coan, P. S.; Hubert-Pfalzgraf, L. G.; Caulton, K. G. Inorg.
Chem. 1992, 31, 1262.
1
2
998
Org. Lett., Vol. 2, No. 7, 2000

neat isopropenyl acetate (9 equiv) at room temperature,
giving a quantitative yield of the expected amides (eq 8).5
Gratifyingly, no epimerization at the R-position occurs under
the reaction conditions (the ee’s of products determined by
chiral GC, under conditions where the limit of detection is
primary acetate if excess isopropenyl acetate is present (100%
diacetate with 1 mol % of catalyst 2 in 1.5 h, entry 4, Table
(
0.2%). Remarkably, there was little reaction in the presence
1
0
). With a stoichiometric amount of isopropenyl acetate and
.5 mol % of catalyst, approximately 7:1 selectivity for the
6
of 0.5 mol % of catalyst 2. This serendipitous observation
raises the prospects of unprecedented functional group
transformations, for example, selectiVe acylation of an
alcohol in the presence of an amine. We are just beginning
to address this issue, and a few such examples are shown
below. A very good yield (82%) of O-acylation can be
realized when benzyl 2-amino-2-deoxy-4,6-di-O-phenyl-
methyl-R-D-glucopyranoside (0.5 mmol) is treated with 2 mL
of isopropenyl acetate and 3 mol % of catalyst 2 at room
temperature for 2 h (eq 9). The corresponding allose
monoacetate can be achieved at 78% conversion (10 h).
Exquisite selectivity for the acylation of an equatorial
hydroxyl group was realized in the reaction of tert-butyl
cholate (eq 4).
derivative (-OH, axial) gave a mixture of N- and O-acyl
compounds, presumably via O f N acyl migration. Selective
O-acylation of 2-piperidinemethanol (eq 10) is another
example. Very little of the N-acyl derivative was formed in
both reactions.
Functional group compatibility of Lewis acidic Y-alkox-
ides is a potential concern in this chemistry. However,
3
quantitative acylation of relatively sensitive electrophilic
substrates such as cinnamyl alcohol (Table 1, entry 5), 2,3-
epoxygeraniol (eq 5), and 1,3-diphenylallyl alcohol (eq 6)
suggests that such fears maybe unfounded. Acylation of
phenols is relatively slow under these conditions. It is
therefore possible to achieve excellent selectivity for the
reaction at the benzyl hydroxyl group in the acylation of
3-hydroxybenzyl alcohol (eq 7) even in the presence of
excess of isopropenyl acetate. This chemoselectivity is the
1d
same as that observed with Sc(OTf)
2
.
A stoichiometric mixture of 1-phenylethanol, 1-phenyl-
ethylamine, and isopropenyl acetate (1 equiv of each) in
benzene quantitatively converts the alcohol (>49% of the
reaction mixture) to the acetate (eq 11). Less than 0.8% (GC)
Enol esters have been reported to react with primary
1e
amines in the absence of catalysts. It has also been reported
that R-amino esters (and secondary amines) are unreactive
without a catalyst (such as KCN) in the formation of a
peptide bond. We were therefore surprised to find that
phenylglycine and phenylalanine esters readily reacted with
(
5) Admittedly, the failed reactions were carried out with 1 M reagents
in ethyl acetate with stoichiometric amount of enol ester (ref 1e). In benzene
under these conditions 55% conversion was observed.
Org. Lett., Vol. 2, No. 7, 2000
999

of the reaction mixture is the N-acyl derivative. The only
the reaction can be carried out with no solvents and the
recovery of the products involves no more than a simple
filtration through silica gel or direct distillation from the
reaction flask. Selectivity between different kinds of hydroxyl
groups can be controlled by stoichiometry, by structure of
the vinyl ester, and, at least in one demonstrated case, by
the nature of the yttrium catalyst. Since functionalized vinyl
esters are readily available from Ru-catalyzed reactions of
amine-derived product in this mixture identified by GCMS
7
(
∼19% of the reaction mixture) and NMR is the corre-
sponding acetone imine which, upon aqueous workup, reverts
back to the amine.
As we explored the scope of this reaction, some limitations
have been uncovered. Tertiary alcohols are not acylated by
any of the reagents discussed. Formation of side products
and deterioration of primary products are observed if
prolonged reaction times are needed, especially when vinyl
acetate, which liberates acetaldehyde in the medium, is used
as the acyl transfer agent. A number of polyhydroxylic
compounds, especially carbohydrates (e.g., phenyl â-D-
glucopyranoside, D-arabino-1,4-lactone, 1,2-dideoxy-4,6-O-
benzylidene-D-arabinohexopyranose), gave a complex mix-
ture of products with no apparent selectivity with the two
vinyl esters tried. Secondary amines such as diisopropylamine
and pseudoephedrine also do not react under these acylation
conditions. Additional functional group compatibility of the
two reagents 2 and 3 must also await further studies.
In summary, a highly efficient method for the acylation
of primary and secondary alcohols using vinyl esters as
acylating agents in the presence of catalytic amounts of a
8
carboxylic acids and enol esters or acetylenes, a number of
other applications of this chemistry can be envisioned. We
are currently exploring the expanded scope of the metal-
catalyzed transesterification reactions.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-9706766) and U.S. EPA
Program for Technology for Sustainable Environment
(R826120-01-0). We thank Dr. Steve McLain (DuPont) for
providing samples of yttrium compounds.
Supporting Information Available: Experimental pro-
cedures for transformations described in Table 1 and eqs 2
and 4-11. This material is available free of charge via the
Internet at http://pubs.acs.org.
4b
readily available yttrium alkoxide is reported. In many cases
OL0057131
(
6) We have no satisfactory explanation for this unusual observation,
which is limited to R-amino acid esters. It is likely that the reaction of the
amino group with an enol ester is catalyzed by an acid and the Y-alkoxide
acts as a scavenger for acidic impurities.
(8) (a) Waller, F. J. Transvinylation catalysts for the production of higher
vinylic esters of vinyl acetate. In Catalysis of Organic Reactions; Kosak,
J. R., Johnson, T. A., Eds.; Marcel Dekker: New York, 1994; p 397. (b)
Ruppin, C.; Dixneuf, P. H. Tetrahedron Lett. 1986, 27, 6323. (c) Murray,
R. E. U.S. Patent 5430179, 1995; Chem. Abstr. 1995, 123, 313396. (d)
Mitsudo, T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. J. Org. Chem. 1987,
52, 2230. (e) Rotem, M.; Shvo, Y. Organometallics 1983, 2, 1689.
(
7) Identified by the following characteristic peaks: 1H NMR 1.38 (d, J
)
6.6 Hz, 3 H), 1.85 (s, 3H), 2.03 (s, 3 H), 4.55-4.62 (q, J ) 6.6 Hz, 1
13
H), 7.1-7.4 (m, aromatic); C NMR (inter alia 18.50, 24.49, 29.37, 59.16,
+•
+•
1
65.80); GCMS m/z 161 (M+•), 146 (M - CH3), 105 (M - C3H6N).
1000
Org. Lett., Vol. 2, No. 7, 2000