Highly Selective Acylation of Alcohols Using Enol Esters Catalyzed by Iminophosphoranes

Article abstract of DOI:10.1021/jo990928d

The iminophosphorane bases PhCH₂N=P(MeNCH₂CH₂)₃N and PhCH₂N=P(NMe₂)₃ catalyze the acylation of primary alcohols with enol esters in excellent yields and in high selectivity. It was found that acid labile groups such as acetal and epoxide survive under the reaction conditions. Groups such as TBS and disulfide, which undergo cleavage in the presence of Ac₂O and the Lewis acid Sc(OTf)₃, are also unaffected. Diene, conjugated acetylene, oxazoline, nitro, and benzodioxane groups are also compatible with our catalyst/reagent system. Because secondary alcohols do not react under our conditions, our methodology is attractive for the selective acylation of primary alcohols. Polymer-supported iminophosphorane catalysts are also shown to be useful in these reactions, thus opening the possibility of wider applications.

Full text of DOI:10.1021/jo990928d

J . Org. Chem. 1999, 64, 9063-9066
9063
High ly Selective Acyla tion of Alcoh ols Usin g En ol Ester s
Ca ta lyzed by Im in op h osp h or a n es
Palanichamy Ilankumaran and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received J une 8, 1999
2 2 2 3 2 2 3
The iminophosphorane bases PhCH NdP(MeNCH CH ) N and PhCH NdP(NMe ) catalyze the
acylation of primary alcohols with enol esters in excellent yields and in high selectivity. It was
found that acid labile groups such as acetal and epoxide survive under the reaction conditions.
Groups such as TBS and disulfide, which undergo cleavage in the presence of Ac
2
O and the Lewis
acid Sc(OTf) , are also unaffected. Diene, conjugated acetylene, oxazoline, nitro, and benzodioxane
3
groups are also compatible with our catalyst/reagent system. Because secondary alcohols do not
react under our conditions, our methodology is attractive for the selective acylation of primary
alcohols. Polymer-supported iminophosphorane catalysts are also shown to be useful in these
reactions, thus opening the possibility of wider applications.
In tr od u ction
the aforementioned catalysts are effective, the acidic
conditions in Lewis acid acylations lead to cleavage of
sensitive functional groups such as acetals, TBDMS,
The acyl group serves as an important protecting group
for alcohols because of its stability toward a variety of
reagents. Selective protection of an hydroxyl group is
dienes, and epoxides. The somewhat basic catalyst PBu
3
1
suffers from poor air stability and flammability, and very
basic catalyst systems lack the ability to select between
primary and secondary hydroxyl groups. This selectivity
is often needed in the synthesis of complex polyhydroxy
natural products.
often needed in the synthesis of complex natural products
and hence a variety of methods have been developed to
effect this conversion. Anhydrides are found to be ver-
satile acylating agents in the presence of bases such as
pyridine or triethylamine. 4-(Dimethylamino)pyridine,
however, was the first efficient basic catalyst used to
accelerate the acylation of alcohols by acetic anhydride
as the acylating agent.2 More recently a variety of
catalysts have been developed for this purpose, including
Due to the aforementioned problems associated with
anhydride/catalyst combinations, attention was turned
toward other acylating agents. Transesterification with
16
esters as acylating agents is an alternate possibility for
mild alcohol acylation, but because of the reversibility
of the reaction, high conversions cannot be achieved.
However, this problem can be solved by using enol esters
as acylating agents, since the resultant enolate is con-
verted to an aldehyde or ketone that is unable to
participate in the reverse reaction. Such reactions are
3
4
5
the Lewis acidic catalysts Sc(OTf)
3
, TiCl(OTf)
3
, TMSCl,
6
7
8
9
Sc(NTf
2
)
3
,
CoCl
2
,
Sn(OTf)
2
,
TiCl
4
/AgClO
4
,
and
1
0
TMSOTf; the exceedingly strong proazaphosphatrane
base 1a 11 and PBu
base system MgBr
-acetylthiazolidine/NaH and AcCl/hindered amine )
have also been used for alcohol acylation. Even though
,
12
and the combination Lewis acid/
3
1
3
2
3
/R N. Other acylating agents (e.g.,
1
4
15
3
17
16,18
catalyzed by simple acids, enzymes,
Sm‚thf19 and [ClBu
2
-
and organo-
metallic compounds such as Cp*
Although these organometallic catalysts
are better than simple acids for this reaction, Schlenk
tube techniques are required for Cp* Sm‚thf, and the
2
2
0
2 2
SnOSnBu Cl] .
*
Corresponding author. Phone: (515) 294-5023; fax: (515) 294-
105; email: jverkade@iastate.edu.
1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
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Ser. Khim. 1967, 176, 97. (b) Steglich, W.; Hofle, G. Angew. Chem.,
Int. Ed. Engl. 1969, 8, 981. (c) Hofle, G.; Steglich, W. Synthesis 1972,
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4, 2069. (e) Shimizu, T.; Kobayashi, R.; Ohmori, H.; Nakata, T. Synlett
995, 650.
0
2
(
Lewis acidity of tin halides, which can complex with
amino groups (see later), further justify the search for
new catalysts for this important reaction.
(
6
3
1
Polymers are becoming increasingly important in
21
synthesis. Thus, they can be used as supports for solid-
(
3) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J . Am.
Chem. Soc. 1995, 117, 4413. Idem. J . Org. Chem. 1996, 61, 4560.
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(
1
997, 27, 277.
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Org. Chem. 1972, 37, 3551. (c) Kita, Y.; Maeda, H.; Takahashi, F.;
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(8) Mukaiyama, T.; Shiina, I.; Miyashira, M. Chem. Lett. 1992, 625.
(9) Miyashita, M.; Shiina, I.; Mukaiyama, T. Bull. Chem. Soc. J pn.
1
993, 66, 1516.
10) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A.
J . Org. Chem. 1998, 63, 2342.
(
(11) D’Sa, B.; Verkade, J . G. J . Org. Chem. 1996, 61, 2963.
(
12) (a) Vedejs, E.; Diver, S. T. J . Am. Chem. Soc. 1993, 115, 3358.
(19) (a) Tashiro, D.; Kawasaki, Y.; Sakaguchi, S.; Ishii, Y. J . Org.
Chem. 1997, 62, 8141. (b) Takeno, M.; Kawasaki, Y.; Muromachi, Y.;
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(20) Orita, A.; Mitsutome, A.; Otera, J . J . Org. Chem. 1998, 63,
2420.
(
b) Vedejs, E.; Bennet, N. S.; Conn, L. M.; Diver, S. T.; Gingras, M.;
Lin, S.; Oliver, P. A.; Paterson, M. J . J . Org. Chem. 1993, 58, 7268.
(
(
13) Vedejs, E.; Daugulis, O. J . Org. Chem. 1996, 62, 5702.
14) Yamada, S. J . Org. Chem. 1992, 57, 1591.
1
0.1021/jo990928d CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

9
064 J . Org. Chem., Vol. 64, No. 25, 1999
Ilankumaran and Verkade
Sch em e 2
Sch em e 1
Ta ble 1. Acyla tion of Alcoh ols Usin g Vin yl Aceta te
Ca ta lyzed by 2b
phase synthesis,21a-c for catalysts,21d or for quenching
2
1e
reagents in solution-phase synthesis.
Highly basic
2
2
23
organic polymers and inorganic solids have also been
attractive because of their ability to catalyze a variety of
reactions.
Phosphorus-based nonionic bases of the proazaphos-
phatrane class have recently been shown to be very useful
in organic synthesis as stoichiometric bases and as
catalysts.24 Recently we reported the acylation of hin-
dered alcohols using anhydrides or enol esters in the
1
1
presence of proazaphosphatrane 1a as a catalyst.
Though catalyst 1a was very efficient for acylating
hindered alcohols, it induced desulfurization and de-
silylation in some substrates. Moreover 1a does not effect
selective acylation of primary alcohols in the presence of
secondary alcohols. These problems are attributable to
the very reactive trivalent aminophosphine moiety in 1a ,
and we therefore decided to use a modification of this
catalyst system which was obtained by converting it to
a less basic but stable iminophosphorane 1b. This
synthesis was achieved by the procedure in Scheme 1
which we reported earlier.25 Acyclic derivative 2b in
Scheme 1, derived from hexamethyl phosphorus triamide
2
a , was prepared by the same procedure,25 and both 1a
and 2a were evaluated as catalysts for the acylation of
primary alcohols using enol esters as acylating agents.
Resu lts a n d Discu ssion
Benzyl alcohol 3 was examined as a model substrate
by treating it with vinyl acetate 4a in THF in the
presence of 10 mol % of 1b. After 6 h, benzyl alcohol was
quantitatively converted into benzyl acetate 5a . Simi-
larly, when 2b was used as the catalyst, the product was
obtained in 99% yield in 8.5 h (Scheme 2). Since 2b
appeared to be as effective as 1b and is cheaper to
synthesize, we decided to pursue the use of catalyst 2b
as the catalyst for further acylations. Benzyl alcohol was
then treated with vinyl benzoate 4b and vinyl acrylate
(
21) (a) Lam, K. S.; Lebl, M.; Krchnak, V. Chem. Rev. 1997, 97,
11. (b) Najzi, A.; Ostresh, J . M.; Houghten, R. A. Ibid. 1997, 97, 449.
c) Gravert, D. J .; J anda, K. D. Ibid. 1997, 97, 489. (d) Kobayashi, S.;
4
(
Nagayama, S. J . Am. Chem. Soc. 1996, 118, 8977. (e) Xu, W.; Mohan,
R.; Morrissey, M. Bioorg. Med. Chem. Lett. 1998, 8, 1089 and references
therein.
4
c in the presence of 2b (10 mol %) to afford the
corresponding esters 5b and 5c in 94% and 87% yields,
respectively (Scheme 2).
(
22) (a) Schwesinger, R. Chimia 1985, 39, 296. (b) Idem. Nachr.
Chem. Tech. Lab 1990, 38, 1214.
23) Subba Rao, Y. V.; De Vos, D. E.; J acobs, P. A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2661 and references therein.
24) (a) For the chemistry of nonionic superbases of the proaza-
To test the selectivity of catalyst 2b in acylation
reactions, alcohols with a variety of functional groups
were chosen as substrates, and the results are sum-
marized in Table 1. Cinnamyl alcohol 6 and phenethyl
alcohol 8 reacted equally well giving the corresponding
acetates 7 and 9 in excellent yields. When geraniol 10
was treated under the same reaction conditions, geranyl
acetate 11 was isolated in 94% yield. On the other hand,
others have reported that when 10 was subjected to
(
(
phosphatrane type, see: Tang, J . S.; Verkade, J . G. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 2, 896. (b) Tang, J . S.; Verkade, J . G. J . Org.
Chem. 1994, 59, 7793. (c) D’Sa, B. A.; Verkade, J . G. J . Am. Chem.
Soc. 1996, 118, 10168. (d) Tang, J . S.; Verkade, J . G. J . Org. Chem.
1
996, 61, 8570. (e) D’Sa, B. A.; McLeod, D.; Verkade, J . G. J . Org.
Chem. 1997, 62, 5057. (f) Arumugam, S.; Verkade, J . G. J . Org. Chem.
997, 62, 4827. (g) Arumugam, S.; McLeod, D.; Verkade, J . G. J . Org.
1
Chem. 1998, 63, 3677. (h) D’Sa, B. A.; Kisanga, P.; Verkade, J . G. J .
Org. Chem. 1998, 63, 3691. (i) Kisanga, P.; D’Sa, B. A.; Verkade, J . G.
J . Org. Chem. 1998, 63, 10057.
Sc(OTf)
3 2
/Ac O conditions, multiple products were ob-
(25) Tang, J . G.; Verkade, J . G. J . Am. Chem. Soc. 1993, 115, 1660.
tained,20 clearly demonstrating that our conditions are

Selective Acylation of Alcohols Using Enol Esters
J . Org. Chem., Vol. 64, No. 25, 1999 9065
Sch em e 3
Sch em e 4
milder and more efficient. To further assess the efficacy
of 2b in the presence of sensitive functional groups,
alcohols with acid-labile functional groups were em-
ployed. Thus, when acid-sensitive alcohol 12 was treated
with vinyl acetate in the presence of 2b, the correspond-
ing acetate 13 was obtained in excellent yield. Acid-labile
epoxy alcohol 14 underwent clean acylation with vinyl
acetate to give the epoxy acetate 15 in 99% yield. This
cleavage of the TBS group. Such selectivity has been
2
0
reported only for the catalyst [ClBu
2
SnOSnBu
2
Cl]
2
.
To
compare our catalytic system with the important re-
agents Cp* Sm‚thf and [ClBu SnOSnBu Cl] , an oxazo-
2
2
2
2
line with a hydroxyl group and a nitro group (24) was
selected as a substrate. When 24 was treated with 2b
and vinyl acetate, the corresponding acetate 25 was
obtained in 74% yield. By contrast, our use of [ClBu2-
SnOSnBu Cl] did not provide an appreciable amount of
selectivity cannot be achieved using Cp* Sm‚thf since
2
2
2
low-oxidation-state samarium reagents are known to
reduce epoxides in a few minutes.26 The 2b-catalyzed
reaction also illustrates the mildness of our catalytic
conditions. To explore further the selectivity toward acid-
sensitive substrates, alcohol 16 containing an acetonide
group was found to give the corresponding acetate 17 in
acetate 25, probably because of the reaction of the Lewis
acidic catalyst with the basic oxazoline moiety. Cp* Sm‚
2
thf also may not be a suitable catalyst for substrate 24
because it is known that low-oxidation-state samarium
reagents reduce the nitro group.27
Protection of a primary alcohol in the presence of a
secondary alcohol is useful in natural product synthesis.
2
excellent yield. On the other hand, the TMSOTf/Ac O
system decomposes the acetonide group in a similar
substrate.10 Functional groups such as a conjugated
terminal acetylene also survives under our reaction
conditions as is seen from the acylation of substrate 18.
To compare the selectivity of our reagent system with
10
10
This can be achieved by Sc(OTf)
3 2 2
/Ac O, TMSOTf/Ac O,
20
[
ClBu SnOSnBu Cl] /enol ester, and AcCl/hindered
2
2
2
15
amine. When the secondary alcohol 26 was subjected
to our the reaction conditions, only a trace of acylated
product was obtained (reaction 1). Thus in a mixture of
benzyl alcohol 3 and 1-phenylethanol 26 in the presence
of 2b and vinyl acetate, only the benzyl alcohol reacted,
providing 5 in 99% yield while the secondary acetate 27
formed in <5% yield (reaction 2). This selectivity was
further confirmed by subjecting diol 28, containing a
primary and secondary alcohol in the same molecule, to
catalytic acylation with 2b. In this case the monoacetate
weaker bases such as PBu
3
, the disulfide-containing diol
2
0 was treated with vinyl acetate and 2b. The corre-
sponding diacetate 21 was obtained in almost quantita-
tive yield. When the same substrate was treated with
PBu
3
or Sc(OTf)
3
in the presence of Ac
2
O, the disulfide
bond underwent cleavage to give AcOCH
2
CH
2
SAc.20 In
the synthesis of complex natural products, orthogonal
stability of protecting groups plays an important role in
achieving the target molecule. To determine the stability
of other hydroxyl-protecting groups under our reaction
conditions, a molecule with a free hydroxyl group and a
silyl-protected hydroxyl group was chosen as the sub-
strate. Thus when the mono-TBS-protected 1,4-butane-
diol 22 was reacted with vinyl acetate in the presence of
2
9 was isolated in 86% yield along with a <5% yield of
the diacetate 30. This reaction clearly demonstrates the
utility of our catalyst in selecting for primary alcohols.
(
26) (a) Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1
987, 28, 4437. (b) Matsukawa, M.; Tabuchi, T.; Inanaga, J .; Yamagu-
chi, M. Chem. Lett. 1987, 2101.
2
b, the corresponding acetate 23 was obtained without
(27) Zhang, Y.; Lin, R. Synth. Commun. 1987, 17, 329.

9
066 J . Org. Chem., Vol. 64, No. 25, 1999
Ilankumaran and Verkade
Ta ble 2. Acyla tion of Som e Rep r esen ta tive Alcoh ols
Usin g Vin yl Aceta te Ca ta lyzed by 33
[ClBu
SnOSnBu
Cl]
) were not affected by our procedure.
2
2
2
Selective protection of primary hydroxyl groups in the
presence of secondary hydroxyl groups makes our pro-
cedure attractive for the synthesis of complex natural
products. The use of polymer-supported catalysts 33 and
34 in this procedure is potentially attractive in industrial
applications. The use of these new basic catalysts, and
in particular polymers 33 and 34, in other transforma-
tions such as Michael addition are underway.
substrate
product
time (h)
yield (%)
99
3
3
6
5
5
7
11
13
15
17
21
25
8
21
5.5
25
4
a
99
99
88
97
99
94
97
87
1
1
1
1
2
2
0
2
4
6
0
4
11
21
14
14
Exp er im en ta l Section
a
Compound 34 was used as a catalyst.
Gen er a l P r oced u r e for th e Ester ifica tion of Alcoh ols
w ith En ol Ester s. To a stirred solution of 1b or 2b (10 mol
%) and 1 mmol of alcohol in THF (0.5 mL) was added enol
After establishing these applications of our iminophos-
ester (5 mmol) at room temperature. The mixture was stirred
at room temperature for the time given in Table 1, and the
solvent and excess enol ester were evaporated in vacuo. The
residue was purified by column chromatography on a small
pad of silica gel using 0-20% ethyl acetate in hexane as eluent.
When polymer-supported catalyst was employed, the polymer
was filtered after the completion of the reaction and washed
with ether. The solvent was then evaporated in vacuo, and
the residue was purified by column chromatography on a small
pad of silica gel using 0-20% ethyl acetate in hexane as eluent.
phoranes as homogeneous catalysts for acylation, we
attached 1b and 2b to a Merrifield resin to test their
properties in heterogeneous form and to take advantage
of the ease of their separation from reaction mixtures.
The synthesis of the polymer-supported reagents was
accomplished by first converting the chloromethylated
resin 31 into azidomethylated resin 32 (Scheme 4). The
azide resin was then treated with 1a or 2a to give the
polymer-supported catalysts 33 and 34. The solid state
Syn th esis of 1b. To a stirred solution of 10 mmol of 1a
3
1
P NMR spectrum of 33 shows a peak at 18 ppm which
11
(
prepared according to our previously reported method ) in
we assign to the formation of product. For evaluating
polymer-supported catalysts, we reacted benzyl alcohol
with vinyl acetate in their presence. We found that the
bicyclic derivative 33 was faster acting than the acyclic
derivative 34, and the results of acylation reactions
catalyzed by 33 are summarized in Table 2. It may be
benzene (10 mL) under argon atmosphere at room temperature
was added benzyl azide (10 mmol) and stirred overnight.
Benzene was evaporated under reduced pressure and the
residue triturated with dry hexanes to give a fine powder
1
31
which was found to be very pure by H and P spectroscopy.
1
H NMR (C
6 6
D ): 7.63 (d, J ) 8 Hz, 2H), 7.17-7.31 (m, 3H),
5
2
6
.26 (s, 2H), 2.68 (d, J ) 8 Hz, 9H), 2.46 (t, J ) 8 Hz, 6H),
.26 (s, 6H). C NMR (CD
4.7, 126.3, 128.2, 128.4, 140.4. P NMR (C
3
1
noted, however, that the solution-phase P NMR spec-
13
3
CN): 34.7 (d, J ) 3 Hz), 49.2, 51.2,
31
3
1
trum of 1b reveals δ P at 37.8.
6
6
D ): 37.84. LRMS
+
As seen from Table 2, 33 is as effective as its homo-
geneous acyclic counterpart 2b. In testing the reusability
of catalyst 33, benzyl alcohol was taken as an acylation
substrate for vinyl acetate. We found that the catalyst
(EI mode): 321 (M ), 258, 216, 175, 116. HRMS: calcd for
P ) 321.20824; measured ) 321.20809.
16 28 5
C H N
Syn th esis of 2b. This can be made using an alternate two-
step procedure reported earlier.28 To a stirred solution of 11
mmol of 2a (Aldrich) in benzene (10 mL) under argon atmo-
sphere at room temperature was added benzyl azide (10 mmol)
and stirred overnight. Benzene was evaporated under reduced
pressure, and the residue was distilled under reduced pressure
3
3 can be used three times without significant loss of
product yield. After three cycles, however, the catalyst
beads became a fine powder which was more difficult to
isolate.
1
to give 2b. (bp 160 °C/8 mm).
8 Hz, 2H), 7.33 (t, J ) 8 Hz, 2H), 7.12-7.18 (m, 1H), 4.62 (d,
J ) 24 Hz, 2H), 3.38 (d, J ) 12 Hz, 6H). 13C NMR (CD
CN):
δ 36.9 (d, J ) 3 Hz), 47.9, 125.2, 126.7, 127.6. P NMR
): δ 24.16.
H NMR (C D ): δ 7.78 (d, J )
6
6
In conclusion we have shown that the highly basic
iminophosphoranes 1b and 2b (which are made by a
simple procedure) catalyze the acylation of sensitive
alcohols using enol esters. The selectivities in this reac-
tion are better than those in published procedures; the
yields are generally excellent and product purity is better
3
3
1
6 6
(C D
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and mass spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
than 95% according to H NMR spectroscopy. Sensitive
functional groups such as TBDMS, diene, disulfide, and
J O990928D
acetonide (which were not stable under Ac
conditions) and groups such as epoxide, nitro, and ox-
azoline (which are not compatible with Cp* Sm‚thf and
2
O/Lewis acid
(28) Zal’tsman, I. S.; Koidan, G. N.; Kurdryavtsev, A. A.; March-
2
enko, A. P.; Pinchuk, A. M. Zh. Obshch. Khim. 1989, 59, 2135.