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catalysts
Article
Mild and Highly Efficient Copper(I) Inspired
Acylation of Alcohols and Polyols
Enoch A. Mensah * and Lindsey Earl
School of Natural Sciences, Indiana University Southeast, New Albany, IN 47150, USA; [email protected]
* Correspondence: [email protected]; Tel.: +1-812-941-2305
Academic Editor: Kei Manabe
Received: 23 December 2016; Accepted: 12 January 2017; Published: 18 January 2017
Abstract: A new and highly efficient method mediated by tetrakis(acetonitrile)copper(I) triflate for
activating both simple and highly hindered anhydrides in the acylation of alcohols and polyols is
described. This new acylation method is mild and mostly proceeds at room temperature with low
catalyst loading. The method is versatile and has been extended to a wide variety of different alcohol
substrates to afford the corresponding ester products in good to excellent yields.
Keywords: acylation; acetic anhydride; isobutyric anhydride; pivalic anhydride; polyols;
copper(I) species
1. Introduction
The masking of hydroxyl groups to prevent side reactions during long synthetic reaction sequences
continues to be of paramount importance in organic synthesis. These protection protocols usually
involves the transformation of the hydroxyl groups to their corresponding ester analogs.
While the use of acetic anhydride, pyridine, and DMAP remains popular in transforming hydroxyl
groups to the corresponding acetate esters [1], the noxious smell of pyridine as well as its high boiling
point, makes its removal relatively difficult and can potentially complicate product isolation in synthetic
protocols run on a small scale.
In an attempt to avoid the use of pyridine during the masking of hydroxyl groups, several
alternative methods have been reported in recent years. Some notable methods include the use of
I2 [2–4], Br2 [5] montmorillonite K-10 [6], FeCl3 [7], TiCl4 -AgClO4 [8], LiClO4 [9], CuSO4 ·5H2 O [10],
TMSOTf [11], Bu3 P in CH2 Cl2 [12,13], La(NO3 )3 ·6H2 O [14], HClO4 -SiO2 [15], molecular sieves [16],
NaHCO3 [17], Mg(NTf2 )2 [18], 3-nitrobenzeneboronic acid [19], alumina [20], NBS [21], TaCl5 [22],
VO(OAc)2 [23] and metal triflates such as Pd(PhCN)2 (OTf) [24], Cu(OTf)2 [25], Bi(OTf)2 [26],
In(OTf)2 [27,28], Sc(OTf)2 [29], Ce(OTf)2 [30], and CoCl2 [31,32].
While all these methods provide a viable alternative in the acetylation of alcohols, long reaction
times, high temperature requirements, and high catalyst loading required in some of these protocols
has necessitated the need for the development of a new method of protecting hydroxyl groups to
complement the existing methods.
In recent years, the use of copper(I) species as efficient catalysts in various cross-coupling reactions
in the formation of C–C, C–N, and C–O linkages during organic transformations, and in the synthesis
of natural products, has received considerable attention. Sharpless et al. as well as the Meldal research
group independently employed the use of copper(I) catalysis in the formation of a cyclic adduct
during azide-alkyne cycloaddition reactions [33,34]. In the synthesis of (−)-galbulimima alkaloid,
the Movassaghi research group reported the use of copper-inspired coupling of vinyl bromide and
oxazolidinone as one of its key intermediate steps [35]. A similar strategy was also employed in
the synthesis of himandrine alkaloid [36]. Bergman et al. also reported the use of copper catalyzed
Catalysts 2017, 7, 33; doi:10.3390/catal7010033
www.mdpi.com/journal/catalysts
Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts
2017, 7, 33
Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 2 of 10 2 of 10 2 of
10
2 of 10 2 of 10 2 of 10 2 of 10 2 of 10 catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline Catalysts 2017, 7, 33 2 of 10 Catalysts 2017, 7, 33 2 of 10 catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline [37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic Catalysts 2017, 7, 33 2 of 10 catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline [37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic amidation
reactions
as
one
of
its
key
strategies
in
the
synthesis
of
the
alkaloid
vasicoline
[37].
Again,
[37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline [37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic substitution protocol to access substituted indolines, a very important and common structural motif [37]. Again, Buchwald al. reported a Cu(I) substitution protocol to access substituted indolines, a very important and common structural motif catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline Buchwald
et
al. also
reported et aet domino
catalyzed
amidation/nucleophilic
substitution protocol
substitution protocol to access substituted indolines, a very important and common structural motif catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline [37]. Again, Buchwald al. also also Cu(I)
reported a domino domino Cu(I) catalyzed catalyzed amidation/nucleophilic amidation/nucleophilic substitution protocol to access substituted indolines, a very important and common structural motif catalyzed amidation reactions as one of its key strategies in the synthesis of the alkaloid vasicoline in many bioactive natural products [38]. substitution protocol to access substituted indolines, a very important and common structural motif in many bioactive natural products [38]. [37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic [37]. Again, Buchwald also reported and
a domino catalyzed amidation/nucleophilic to access
substituted
indolines,et a al. very
important
commonCu(I) structural
motif
in many bioactive
substitution protocol to access substituted indolines, a very important and common structural motif in many bioactive natural products [38]. in many bioactive natural products [38]. in many bioactive natural products [38]. [37]. Again, Buchwald et al. also reported a domino Cu(I) catalyzed amidation/nucleophilic In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use in many bioactive natural products [38]. In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use substitution protocol to access substituted indolines, a very important and common structural motif substitution protocol to access substituted indolines, a very important and common structural motif in many bioactive natural products [38]. natural
products
[38].
In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use substitution protocol to access substituted indolines, a very important and common structural motif of copper(I) species in activating both simple and hindered anhydrides towards the masking of In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use of copper(I) species in activating both simple and hindered anhydrides towards the masking of in many bioactive natural products [38]. in many bioactive natural products [38]. In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use of copper(I) species in activating both simple and hindered anhydrides towards the masking of copper(I) species in in activating both simple and hindered anhydrides towards the masking of In
spite
of
the
extensive
use
of copper-mediated
catalysis
in natural
product
synthesis,
the useof ofof of copper(I) species activating both simple and hindered anhydrides towards the masking in many bioactive natural products [38]. various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, of copper(I) species in activating both simple and hindered anhydrides towards the masking of various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use of copper(I) species in activating both simple and hindered anhydrides towards the masking of various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, copper(I)
species
in activating
simple and
hindered anhydrides towards
the
various
In spite of the extensive use of copper‐mediated catalysis in natural product synthesis, the use mild, and simple protocol both
that utilizes tetrakis(acetonitrile)copper(I) triflate as masking
a highly ofefficient various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate as a highly efficient of copper(I) species in in activating both simple and hindered anhydrides towards the masking of of mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate as as a a a highly efficient of copper(I) species activating both simple and hindered anhydrides towards the masking various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate highly efficient hydroxyl
groups
in
organic
synthesis
have
not
been
investigated.
We
herein
report
new,
mild,
and
of copper(I) species in activating both simple and hindered anhydrides triflate towards the masking of catalyst in the acylation of simple alcohols and polyols. mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) as a highly efficient catalyst in the acylation of simple alcohols and polyols. various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate as a highly catalyst in the acylation of simple alcohols and polyols. catalyst in the acylation of simple alcohols and polyols. catalyst in the acylation of simple alcohols and polyols. simple
protocol
that utilizes
tetrakis(acetonitrile)copper(I)
triflate as a highly
efficient
catalystefficient in the
various hydroxyl groups in organic synthesis have not been investigated. We herein report a new, catalyst in the acylation of simple alcohols and polyols. mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate as as a highly efficient mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate a highly efficient catalyst in the acylation of simple alcohols and polyols. acylation
of simple
alcohols
and
polyols.
2. Results and Discussion mild, and simple protocol that utilizes tetrakis(acetonitrile)copper(I) triflate as a highly efficient 2. Results and Discussion catalyst in the acylation of simple alcohols and polyols. 2. Results and Discussion 2. Results and Discussion catalyst in the acylation of simple alcohols and polyols. 2. Results and Discussion catalyst in the acylation of simple alcohols and polyols. 2. Results and Discussion After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as 2. Results and Discussion 2. Results
and
Discussion
After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as 2. Results and Discussion the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 2. Results and Discussion After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 2. Results and Discussion After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 After
an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as the
mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of model
substrate
and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 mol %
After an extensive preliminary study using a simple alcohol such as phenol 1 (1 equivalent) as phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. the model substrate and acetic anhydride (4 equivalents) as the acetylation agent, we found that 1 of tetrakis(acetonitrile)copper(I)
triflate was able to efficiently catalyze the transformation of phenol 1
This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at mol % of tetrakis(acetonitrile)copper(I) triflate was able to efficiently catalyze the transformation of to the
corresponding
phenyl acetate 2 in 3 min and in quantitative yield.
low catalyst loading was very significant and may suggest the high capacity of copper(I) species to This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at low catalyst loading was very significant and may suggest the high capacity of copper(I) species to phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. low catalyst loading was very significant and may suggest the high capacity of copper(I) species to phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at low catalyst loading was very significant and may suggest the high capacity of copper(I) species to phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. activate simple anhydrides the masking of hydroxyl groups. As a result of the excellent This
remarkable
and
rapidtowards transformation
of phenol
1 hydroxyl to its corresponding
phenyl
acetate
2excellent at low
low catalyst loading was very significant and may suggest the high capacity of copper(I) species to activate simple anhydrides towards the masking of groups. As a result of the This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at low catalyst loading was very significant and may suggest the high capacity of copper(I) species to activate simple anhydrides towards the masking of hydroxyl groups. As a of the excellent activate simple anhydrides towards the masking of of hydroxyl groups. As a result result of of the excellent activate simple anhydrides towards the masking hydroxyl groups. As a result the excellent This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was catalyst
loading
waswith very
significant
and
may
suggest
the
high
capacity
of copper(I)
species
to
activate
activate simple anhydrides towards the of groups. excellent initial results phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was low catalyst loading was very significant and may suggest the high capacity of copper(I) species to low catalyst loading was very significant and may suggest the high capacity of copper(I) species to activate simple anhydrides towards the masking masking of hydroxyl hydroxyl groups. As As a a result result of of the the excellent initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was initial results with phenol, the versatility and efficacy of of tetrakis(acetonitrile)copper(I) triflate was initial results with phenol, the versatility and efficacy tetrakis(acetonitrile)copper(I) triflate was low catalyst loading was very significant and may suggest the high capacity of copper(I) species to also explored using a variety of different alcohols as substrates and with acetic anhydride as the simple
anhydrides
towards
the
masking
of
hydroxyl
groups.
As
a
result
of
the
excellent
initial
results
initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was also explored using a variety of different alcohols as substrates and with acetic anhydride as the activate simple anhydrides towards the masking of hydroxyl groups. As a result of the excellent activate simple anhydrides towards the masking of hydroxyl groups. As a result of the excellent initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was also explored using a of different alcohols as substrates and with acetic anhydride as the also explored using a variety variety of of different alcohols as substrates and with acetic anhydride as as the also explored using a variety different alcohols as substrates and with acetic anhydride the activate simple anhydrides towards the masking of hydroxyl groups. As a result of the excellent acetylating agent (Table 1). with
phenol,
the versatility
and
efficacy
of
tetrakis(acetonitrile)copper(I)
triflate
was
also
explored
also explored using a variety of different alcohols as substrates and with acetic anhydride as the acetylating agent (Table 1). initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was initial results with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was also explored using a variety of different alcohols as substrates and with acetic anhydride as the acetylating agent (Table 1). acetylating agent (Table 1). acetylating agent (Table 1). initial results of
with phenol, the versatility and efficacy of tetrakis(acetonitrile)copper(I) triflate was using
aalso variety
different
as
substrates
and with
acetic
anhydride
as
the
acetylating
agent
acetylating agent (Table 1). also explored using a variety of of different alcohols as as substrates and with acetic anhydride as the explored using a alcohols
variety different alcohols substrates and with acetic anhydride as the acetylating agent (Table 1). Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3CN)
4OTf. also explored using a variety of different alcohols as substrates and with acetic anhydride as the Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3CN)
4OTf. (Table
1).
3
4
acetylating agent (Table 1). Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3
CN)
4
OTf. Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3
CN)
4
OTf. acetylating agent (Table 1). Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH3CN)4OTf. acetylating agent (Table 1). Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH3CN)4OTf. Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3CN)4OTf. TableTable 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
1.Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
Acetylation
of alcohols with acetic anhydride catalyzed by Cu(CH3 CN)
3CN)
OTf. 44OTf.
3CN)
4OTf. Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
3CN)
4OTf. Entry Entry Entry Entry Entry Entry Entry Entry Entry 1 1 1 1 1 Entry Entry
1 1
Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate
1 1 1 2 2 2 2 2 2 2
2 2 2 2 3 3 3 3 3
3 3 7 7 6 6 5 5 5 5 5 Product Product Product Product
5 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 5
5 5 5 6
3 3 3 4 4 4 4 4
4 4 4 4 4 5 Product Product Product Product Product Product Product Time (min) Yield (%) b b b b b b Time (min) Yield (%) Yield (%) Time (min) Time (min) Yield (%) Time (min) Yield (%) Time (min) Yield (%) Yield (%) b b Time (min) b b Time (min) Time (min) Yield (%) Yield (%) Time (min) Yield (%) Time (min)
Yield
3 98 (%)b b
3 98 3 3 98 98 3 98 3 98 3 3 3 3 20 20 20 20 20 20 20 20 20 20 20 30 30 30 30 30 30 30 98 98 98 98 91 91 91 91 91 91 91
91 91 91 91 94 94 94 9494 94 94 30 30 30 30 30 30 30 30 30 30 30 30 30 94 94 94 90 90 90 9090 90 90 90 90 90 45 45 45 45 45 45 45 45 45 45 45 89 3 of 10 89 3 of 10 8989 89 89 89 89 89 89 89 22 22 22 92 92 92
30 30 92 92 Catalysts 2017, 7, 33 3 of 10 phenol 1 to the corresponding phenyl acetate 2 in 3 min and in quantitative yield. Catalysts 2017, 7, 33 3 of 10 Catalysts 2017, 7, 33 3 of 10 Catalysts 2017, 7, 33 3 of 10 This remarkable and rapid transformation of phenol 1 to its corresponding phenyl acetate 2 at Catalysts 2017, 7, 33 3 of 10 Catalysts 2017, 7, 33 22 92 6 low catalyst loading was very significant and may suggest the high capacity of copper(I) species to 22 92 3 of 10 6 Catalysts 2017, 7, 33 3 of 10 Catalysts 2017, 7, 33 3 of 10 22 92 6 anhydrides towards the masking of hydroxyl 22 6 activate simple groups. As a result of the 92 excellent Catalysts 2017, 7, 33 3 of 10 Catalysts 2017, 7, 33 3 of 10 tetrakis(acetonitrile)copper(I) initial results with phenol, the versatility and efficacy of triflate 22 22 92 92 was 6 6 Catalysts 2017, 7, 33
3 of 10
22 anhydride 92 as the 6 using a variety of different alcohols as substrates 22 92 6 also explored and with acetic Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 3 of 10 22 92 3 of 10 6 22 92 6 acetylating agent (Table 1). 22 92 6 22 92 6 7 30 92 7 30 92 Table 1. Cont. 22 3CN)4OTf. 92 92 6 22 6 Table 1. Acetylation of alcohols with acetic anhydride catalyzed by Cu(CH
7 30 92 7 30 92 7 7 30 30 92 92 22 92 6 6 22 92 7 30 92 7 30 92 7 30 92 7 30 92 7 30 92 b b
7 30 92 Entry Substrate Product Time (min) Yield (%) Entry
Substrate
Product
Time
(min)
Yield
(%)
8 55 93 8 55 93 7 30 92 7 30 92 8 55 93 8 55 93 93 55 93 7 8 7 7 8 3055 92
30 92 30 92 1 8 3 55 98 93 8 55 93 8 55 93 8 55 93 8 55 93 8 55 93 9 60 83 9 60 83 8 55 93 8
55 55 93
8 93 9 60 83 9 60 83 2 20 91 9 9 60 60 83 83 8 8 55 93 55 93 9 60 83 9 60 83 9 60 83 9 60 83 9 60 83 9
60 60 83
9 83 30 94 3 10 60 87 9 83 9 60 83 10 60 87 10 60 87 10 60 87 9 9 10 10 60 87 60 83 60 83 60 87 10 60 87 10 60 87 30 60 90 87 60
87
10 4 10 10 60 87 10 60 87 10 60 87 10 60 87 10 60 87 11 45 90 11 45 90 11 45 90 11 45 90 10 60 87 10 60 87 45 89 5 11 45 45 90 90 11 11 11 45 45 90
11 45 90 90 11 45 90 11 45 90 11 45 90 11 45 90 12 35 90 11 45 12 35 90 11 45 90 12 35 90 12 35 90 90 12 12 3535 90
11 45 90 11 45 90 12 35 90 12 35 90 12 35 90 12 35 90 12 35 90 12 35 90 12 35 90 60 83 13 60 83 13 12 35 90 12 35 90 60 83 13 13 13 60 60 83
83 60 83 13 60 83 13 12 35 90 12 35 90 60 83 13 60 83 13 60 83 13 60 83 13 60 83 13 60 83 13 13 14 14 13 14 14 14 13 13 14 14 60 45 45 60 45 45 45 60 45 60 45 83 83 89 89
89 89 89 83 83 89 89 14 45 89 14 45 89 aaa Reactions were carried out using 4 equiv.
b
bb Isolated yield. of acetic anhydride per hydroxyl
group;
yield. 89 Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. 14 45 Isolated
14 45 89 aa Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. 14 45 bb Isolated yield. 89 14 45 89 a Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; b Isolated yield. a
b
14 45 3–8 in Isolated yield. 89 yields
Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; In all instances,
there were smooth conversion
to their corresponding esters
excellent
14 45 89 aa Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; bb Isolated yield. 2–7).
Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. and in short
reaction times (Table 1, Entries
aa Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; bb Isolated yield. Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. 14 45 14 encouraging results, the efficacy
45 bbof
89 With athese
of
the
Cu(I)catalyst
in
the
presence
highly89 hindered
a Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Isolated yield. alcohol substrates
was also explored. In this study, the acetylation reaction was Isolated yield. performed using
aa Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; bb Isolated yield. highly hindered alcohol substrates such as diphenyl methanol and adamantanol (Table 1, Entries 8–9).
Remarkably,
there was a facile transformation of these hindered alcohols to their corresponding
esters
a Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; b Isolated yield. a Reactions were carried out using 4 equiv. of acetic anhydride per hydroxyl group; b Isolated yield. 9 and 10 respectively in excellent yields.
In all instances, there were smooth conversion to their corresponding esters 3–8 in excellent yields and in short reaction times (Table 1, Entries 2–7). With these encouraging results, the efficacy of the Cu(I)catalyst in the presence of highly hindered alcohol substrates was also explored. In this study, the acetylation reaction was performed Catalysts 2017, 7, 33
4 of 10
using highly hindered alcohol substrates such as diphenyl methanol and adamantanol (Table 1, Entries 8–9). Remarkably, there was a facile transformation of these hindered alcohols to their corresponding esters 9 and 10 respectively in excellent yields. Since several acid labile hydroxyl-protecting groups are routinely employed in organic synthesis
duringSince several acid labile hydroxyl‐protecting groups are routinely employed in organic synthesis long synthetic reaction sequences, the efficacy of this new acetylation protocol was also
during long insynthetic reaction sequences, the efficacy of this new acetylation protocol also investigated
the presence
of other
acid labile
hydroxyl-protecting
groups. Using
the was acetonide
investigated in the presence of other acid labile hydroxyl‐protecting groups. Using the acetonide protected galactose as a substrate, remarkably, the acid labile acetonide group survived this new
protected galactose as a substrate, remarkably, the acid galactose
labile acetonide survived this new 1,
reaction
protocol,
affording
the corresponding
protected
ester 12group in excellent
yield
(Table
reaction protocol, affording the corresponding protected galactose ester 12 in excellent yield (Table 1, Entry 11).
Entry 11). In the synthesis
of oligosaccharides, functionalization of the monosaccharide units prior to their
In the synthesis of oligosaccharides, functionalization of the monosaccharide units prior to their assembly is usually crucial. One of the main synthetic strategies used to achieve this objective is to
assembly is usually crucial. One of the main synthetic strategies used to achieve this objective is to employ the use of acid labile benzylidine acetal as a protecting group. This acid labile benzylidine
employ the use of acid labile benzylidine acetal as a protecting group. This acid labile benzylidine acetal is routinely used to mask diols in a 1,2 and 1,3 configuration [39,40]. The tolerance of the acid
acetal is routinely used to mask diols in a 1,2 and 1,3 configuration [39,40]. The tolerance of the acid sensitive benzylidene acetal to this acetylation protocol was also investigated using a benzylidene
sensitive benzylidene acetal to this acetylation protocol was also investigated using a benzylidene acetal protected glucose diol as the substrate. Gratifyingly, the acid labile benzylidene acetal-protecting
acetal protected glucose diol as the substrate. Gratifyingly, the acid labile benzylidene acetal‐
group survived, affording the fully protected sugar 13 in excellent yield (Table 1, Entry 12).
protecting group survived, affording the fully protected sugar 13 in excellent yield (Table 1, Entry 12). To further explore the scope and generality of this acetylation protocol, the efficacy of the
To further explore the scope and generality of this acetylation protocol, the efficacy of the Cu(I) Cu(I) catalyst was also explored in the presence of a silyl- and trityl-protecting groups. Silyl- and
catalyst was also explored in the presence of a silyl‐ and trityl‐protecting groups. Silyl‐ and trityl‐
trityl-protecting
groups
among
most
common
hydroxyl-protecting
groups
usedin inorganic organic
protecting groups are are
among the the
most common hydroxyl‐protecting groups used synthesis.
When
silyl
and
trityl
protected
sugars
were
used
as
substrates,
again,
both
protecting
synthesis. When silyl and trityl protected sugars were used as substrates, again, both protecting groups
survived, affording fully acetylated sugars 14 and 15 respectively in excellent yields. (Table 1,
groups survived, affording fully acetylated sugars 14 and 15 respectively in excellent yields. (Table Entries
13 and 14). All these results may suggest that this new Cu(I)-inspired acetylation protocol is
1, Entries 13 and 14). All these results may suggest that this new Cu(I)‐inspired acetylation protocol not
only
highly efficient but also mild as well.
is not only highly efficient but also mild as well. InIn the formation of glycosidic linkages during the synthesis of polysaccharides, one of the initial the formation of glycosidic linkages during the synthesis of polysaccharides, one of the initial
steps
usually involve the acetylation of the polyhydroxyl monosaccharides. To probe the limits of this
steps usually involve the acetylation of the polyhydroxyl monosaccharides. To probe the limits of new
acetylation method, the versatility and efficacy of this protocol was again investigated by using
this new acetylation method, the versatility and efficacy of this protocol was again investigated by polyols
derived from both carbohydrates and non-carbohydrates as substrates (Scheme 1).
using polyols derived from both carbohydrates and non‐carbohydrates as substrates (Scheme 1). Scheme 1. Cu(CH
CN)4OTf catalyzed acetylation of polyols. Scheme
1. Cu(CH33CN)
4 OTf catalyzed acetylation of polyols.
Using L-rhamnose sugar as substrate, the acetylation reaction proceeded with ease and at room
temperature affording the fully acetylated sugar 16 in good yield (Scheme 1). With polyhydroxyl
myo-inositol as substrate, the acetylation reaction was quite sluggish; however, upon warming up the
reaction, the acetylation reaction proceeded smoothly to obtain the fully acetylated D-myo-inositol 17
in excellent yield (Scheme 1).
To To continue exploring the scope and limits of this this protocol, the Cu(I)‐catalyzed acetylation continue exploring the scope and limits of this protocol, the Cu(I)‐catalyzed acetylation reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. reaction was again performed using a disaccharide‐derived polyol such as as melibiose as substrate. To continue exploring the scope and limits of protocol, the Cu(I)‐catalyzed acetylation reaction was again performed using a disaccharide‐derived polyol such melibiose as substrate. in excellent yield (Scheme 1). reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, To continue exploring the scope and limits of this protocol, the Cu(I)‐catalyzed acetylation Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield reaction was again performed using a disaccharide‐derived polyol such as melibiose as substrate. there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield (Scheme 1). there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield (Scheme 1). (Scheme 1). there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield (Scheme 1). Although the reaction was also initially sluggish, upon warming the reaction to 50 °C, remarkably, (Scheme 1). (Scheme 1). (Scheme 1). (Scheme 1). As a result of the excellent versatility and efficacy of this catalyst, we again investigated the As result of the excellent versatility and efficacy of this catalyst, we again investigated the As a result of of the excellent versatility and efficacy of of this catalyst, we again investigated the (Scheme 1). As a result the excellent versatility and efficacy this catalyst, we again investigated the there was a facile transformation of the polyol to the fully acetylated disaccharide 18 in good yield As a a result of the excellent versatility and efficacy of this catalyst, we again investigated the As a result of the excellent versatility and efficacy of this catalyst, we again investigated the As a result of the excellent versatility and efficacy of this catalyst, we again investigated the As a result of the excellent versatility and efficacy of this catalyst, we again investigated the capacity of this catalyst in activating a relatively hindered acylating agent such as isobutyric capacity of this catalyst in activating a relatively hindered acylating agent such as isobutyric this catalyst in in activating a a relatively hindered agent such as as isobutyric As a of result of the excellent versatility efficacy of this acylating catalyst, we again investigated the capacity of this catalyst activating relatively hindered acylating agent such isobutyric (Scheme 1). capacity of this catalyst in activating a and relatively hindered acylating agent such as isobutyric capacity of this catalyst in activating a relatively hindered acylating agent such as isobutyric Catalysts capacity 2017,
7, 33
5 of 10
capacity of this this catalyst in activating activating a relatively relatively hindered acylating agent such as as isobutyric capacity of this catalyst in activating a and relatively hindered acylating such isobutyric anhydride in the acylation of alcohols (Table 2). anhydride in the acylation of alcohols (Table 2). anhydride in the acylation of alcohols (Table 2). capacity of catalyst in a hindered acylating agent such as isobutyric anhydride in the acylation of alcohols (Table 2). As a result of the excellent versatility efficacy of this catalyst, we agent again investigated the anhydride in the acylation of alcohols (Table 2). anhydride in the acylation of alcohols (Table 2). anhydride in the acylation of alcohols (Table 2). anhydride in the acylation of alcohols (Table 2). With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the With phenol as as the starting substrate and isobutyric anhydride as as the acylation the anhydride in the acylation of alcohols (Table 2). With phenol the starting substrate and isobutyric anhydride the acylation agent, the capacity of this catalyst in activating a relatively hindered acylating agent such as agent, isobutyric With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the With phenol as the the starting substrate and isobutyric anhydride as the the acylation agent, the the With phenol as the starting substrate and isobutyric anhydride as the acylation agent, acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl With phenol as starting substrate and isobutyric anhydride as acylation agent, the acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl anhydride in the acylation of alcohols (Table 2). acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl To continue
exploring the scope and limits of this protocol, the Cu(I)-catalyzed acetylation reaction
acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl isobutyrate 19 in excellent yield (Table 2, Entry Entry 1). This exciting results prompted us to again acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl isobutyrate 19 in excellent yield (Table 2, 1). This exciting results prompted us to again isobutyrate 19 19 in excellent yield (Table 2, 2, Entry 1). This exciting results prompted us us to again acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl isobutyrate in excellent yield (Table Entry 1). This exciting results prompted to again With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the isobutyrate 19 in excellent yield (Table 2, Entry 1). This exciting results prompted us to again isobutyrate 19 in excellent yield (Table 2, Entry 1). This exciting results prompted us to again was again
performed
using
a
disaccharide-derived
polyol
such
as
melibiose
as
substrate.
Although
isobutyrate 19 in excellent yield (Table 2, Entry 1). This exciting results prompted us to again isobutyrate 19 in excellent yield (Table 2, Entry 1). This exciting results prompted us to again investigate the scope of the catalyst using different alcohols with different steric encumbrance as investigate the scope of the catalyst using different alcohols with different steric encumbrance as investigate the scope of of the catalyst using alcohols with different steric encumbrance as as isobutyrate 19 in scope excellent yield (Table 2, different Entry 1). This exciting results prompted us to again investigate the the catalyst using different alcohols with different steric encumbrance acylation reaction again proceeded smoothly with only 1 mol % catalyst loading, affording the phenyl investigate the scope of the catalyst using different alcohols with different steric encumbrance as investigate the scope of the catalyst using different alcohols with different steric encumbrance as ◦ C,
the reaction
was
also
initially
sluggish,
upon
warming
the
reaction
to
50
remarkably,
there
was a
investigate the scope of the catalyst using different alcohols with different steric encumbrance as investigate the scope of the catalyst using different alcohols with different steric encumbrance as substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in investigate the of the catalyst using 2, different alcohols with different encumbrance as substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in isobutyrate 19 scope in excellent yield (Table Entry 1). This exciting results steric prompted us to again substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in facile transformation
of
the
polyol
to
the
fully
acetylated
disaccharide
18
in
good
yield
(Scheme
excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly investigate the scope of the catalyst using different alcohols with different steric encumbrance as 1).
excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the Aseven with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the a
result
of
the excellent versatility and efficacy of this catalyst, we again investigated the
excellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the substrate. In all cases, the acylation reaction afforded the corresponding acylated products 20–26 in even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). capacityexcellent yields (Table 2, Entries 2–8). Remarkably, the acylation reaction again proceeded smoothly of
this catalyst in activating a relatively hindered acylating agent such as isobutyric anhydride
corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). corresponding ester 27 in excellent yield (Table 2, Entry 9). even with a hindered substrate such as diphenyl methanol at 1 mol % catalyst loading, affording the 3CN)
Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
44OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. in the acylation
of
alcohols (Table 2).
Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
43OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. corresponding ester 27 in excellent yield (Table 2, Entry 9). Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)
4OTf. Table 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)4OTf. TableTable 2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
2. Acylation of alcohols with isobutyric anhydride catalyzed by Cu(CH
3CN)4OTf. 3 CN)4 OTf.
Entry Entry Entry Entry Entry Entry Entry Entry Entry Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate Substrate Entry
Substrate
Entry 1 1 1 1 1 1 1 1 1 1 Substrate Product Product Product Product Product Product Product Product Product Product
Product 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 33 3 3 3 3 (min) 15 15 15 15 15 15 15 15 15 15 15 180 180 180 180 180 180 180 180180 180 2 Yield Time Yield Time Yield Time Time Time Yield Time Yield Yield Time Yield b Time Yield b (min) (%)
b Time Yield (min) (%)
b b b b (min) (min) (%)
(min) (%)
(min) (%)
(%)
b b (min) (%)
(min) (%)
b Time Yield (%)
Time (min) (min)
Yield (%) b
180 30 30 30 30 30 30 30 30 30 30 30 30 3 (%)b 92 92 92 92 92 92 92 92 92 92
92 93 93 93 93 93 93 93 93 93 93
93 90 90 90 90 90
90 90 90 90 90 90 4 44 4 4 4 4 4 4 4 4 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 5 55 5 5 5 Catalysts 2017, 7, 33 5 Catalysts 2017, 7, 33 5 5 5 7 7 7 7 7 77 8 8 8 8 8 88 99 9 9 9 9 9 60 60 60 60 60 60 60 60 5 6 6 6 6 6 6 6 90 93 6 of 10 6 of 10 6 of 10 6 of 10 6 of 10 89 89 89
89 89 6 of 10 89 89 89 89 6 of 10 89 89 60 60 60 60 60
60 60 91 91 91 91 91
91 91 210 210210 210 210 210 210 88 88 88 8888 88 88 90 90 90 90 90 85 85 85
85 85 85 85 120 120 120120 120 90 90 90
90 90 90 90 90 90 93 93 93 93 93
93 93 93 93 93 90 90 90 90 90 90 90 90 90 90 60 60 60 OO O
O
O O
O
O
O
O
O
O O
O
120 120 2727
27
27 27
27
b Isolated yield.
b Isolated yield.
b Isolated yield.
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. 27
aa Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. bb Isolated yield.
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. a Reaction
b Isolated
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. Isolated yield.
was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group.
yield.
a Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. b Isolated yield.
a Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. b Isolated yield.
aa a
To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride To further study the generality, scope, and efficiency of this new method of acylating alcohols, the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride To further study the generality, scope, and efficiency of this new method of acylating alcohols, was also investigated using different and sterically diverse alcohols as substrates (Table 3). the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
33CN)
OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
CN)344CN)
OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH3CN)4OTf. 7 7 7 7 7 7 7 7 7 Catalysts 2017, 7, 33
8 8 8 8 8 8 8 8 8 210 210 210 210 210 210 210 210 210 88 88 88 88 88 88 88 88 88 90 90 90 90 90 90 90 90 90 85 85 85 85 85 85 85 85 85 6 of 10
With phenol as the starting substrate and isobutyric anhydride as the acylation agent, the acylation
O
O
reaction again proceeded smoothly with only 1 mol % catalyst
OOO
O
O
loading, affording the phenyl isobutyrate
O O
19 in excellent yield (Table 2, Entry
Oprompted us to again investigate the scope
O
OOOO
1). This exciting results
O
O
O
of the catalyst using
different
alcohols
with
different
steric
encumbrance as120 substrate.
In
all
9 120 90 9 120 90 9 120 90 9 120 90 cases, the
9 9 120 90 120 90 9 90 9 120 90 9 acylation reaction
afforded the corresponding acylated products 20–26120 in excellent90 yields (Table 2,
2727
27
Entries 2–8). Remarkably, the acylation reaction again
proceeded
smoothly even with a hindered
27
27
27
27
27
aa Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. bb Isolated yield.
27
aa Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. bb Isolated yield.
substrate such
as
diphenyl
methanol
at
1
mol
%
catalyst
loading,
affording
the corresponding
ester 27
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. Isolated yield.
aa Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. a Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. b Isolated yield.
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. Isolated yield.
bb Isolated yield.
Isolated yield.
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. a Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. b Isolated yield.
a
b
in excellent
yield (Table 2, Entry 9).
Reaction was carried out using 4 equiv. of isobutyric anhydride per hydroxyl group. Isolated yield.
To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further
study
the
generality,
scope,
and
efficiency
of
this
new
method
of
acylating
alcohols, the
To further study the generality, scope, and efficiency of this new method of acylating alcohols, To further study the generality, scope, and efficiency of this new method of acylating alcohols, the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride To further study the generality, scope, and efficiency of this new method of acylating alcohols, the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride capacitythe capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride of
Cu(I)
catalysts
to
activate
a
highly
hindered
acylating
agent
such
as
pivalic
anhydride
was
the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). the capacity of Cu(I) catalysts to activate a highly hindered acylating agent such as pivalic anhydride was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). also investigated
using different and sterically diverse alcohols as substrates (Table 3).
was also investigated using different and sterically diverse alcohols as substrates (Table 3). was also investigated using different and sterically diverse alcohols as substrates (Table 3). Table 3. Pivalation of alcohols catalyzed by Cu(CH
33CN)
44OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
CN)
OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
33CN)
44OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
CN)
OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
4OTf. Table 3. Pivalation of alcohols catalyzed by Cu(CH
3CN)
4OTf. Table
3. Pivalation
of alcohols catalyzed by Cu(CH33CN)
CN)
4 OTf.
Table 3. Pivalation of alcohols catalyzed by Cu(CH3CN)
4OTf. Entry Substrate Entry Substrate Entry Substrate Entry Substrate Entry Substrate Entry Substrate Entry Substrate Entry Substrate Entry
Substrate
Entry Substrate 1 1 1 1 1 1 11 1 1 22 2 2 2 2 3 2 2 2 2 3 3 33 3 3 3 3 3 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 Catalysts 2017, 7, 33 4 4 44 4 4 4 4 Catalysts 2017, 7, 33 4 Catalysts 2017, 7, 33 4 5 5 5 5 5 5 55 5 6 6 6 6 66 6 6 6 77 7 7 7 7 7 7 7 88 8 8 8 8 8 8 8 a
Product Product Product Product Product Product Product Product Product
Product 30 30 30 30 30 30 30 30 90 90 90 90 90 90 90 90 210210 210 210 210 210 210 210 210 210 90 90 90 90 90 90 90 30 30 30 30 30 30 30 30 93 93 93 93 93 93 93 93 60 60 60 60 60 60 60 60 7 of 10 7 of 10 7 of 10 7 of 10 7 of 10 7 of 10 90 90 90 90 90 90 90 90 7 of 10 90 7 of 10 90 90 90 90 90 90 90 90 90 86 86 86 86 86 86 86 86 86 30 Yield (%) b b Time (min) Yield (%) Time (min) Yield (%) Time (min) b b b b Time (min) Yield (%) Yield (%) b Time (min) Yield (%) Time (min) Yield (%) Time (min) b b
Time (min) Yield (%) Time
(min)
Yield
(%)
b Time (min) Yield (%) 30 30 30 60 60 60 60 60 60 90 90 90 90 93 93 90 93 93 93 93 60 60 60 93 93 93 50 50 50 50 86 86 86 86 210210 210 89 89 89 60 60 90 50 50 50 50 50 210 210 210 210 210 210 93 93 86 86 86 86 86 89 89 89 89 89 89 aa Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; bb Isolated yield. a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. Reaction
was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated
yield.
a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; Isolated yield. a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. a Reaction was carried out using 4 equiv. of pivalic anhydride per hydroxyl group; b Isolated yield. It was the was gratifying gratifying to to note note that, that, in in all all cases cases using using different different alcohol alcohol substrates, substrates, the pivalation pivalation It It was gratifying to note that, in all cases using different alcohol substrates, the pivalation It was gratifying to note that, in all cases using different alcohol substrates, the pivalation was gratifying gratifying to to note note that, that, in in all all cases cases using using different different alcohol alcohol substrates, substrates, the the pivalation pivalation reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to It It was reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to It was gratifying to note that, in all cases using different alcohol substrates, the pivalation It was gratifying to note that, in all cases using different alcohol substrates, the pivalation the corresponding pivalate esters 28–35 in good to excellent yield. the corresponding pivalate esters 28–35 in good to excellent yield. reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to the corresponding pivalate esters 28–35 in good to excellent yield. the corresponding pivalate esters 28–35 in good to excellent yield. the corresponding pivalate esters 28–35 in good to excellent yield. reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates to These results are noteworthy because it demonstrates the capacity of Cu(I) catalyst the corresponding pivalate esters 28–35 in good to excellent yield. These results are noteworthy because demonstrates the capacity of Cu(I) catalyst These results are noteworthy because it it it demonstrates the capacity of Cu(I) catalyst These results are noteworthy because demonstrates the capacity of Cu(I) catalyst These results are noteworthy because it demonstrates the capacity of Cu(I) catalyst the corresponding pivalate esters 28–35 in good to excellent yield. the corresponding pivalate esters 28–35 in good to excellent yield. tetrakis(acetonitrile)copper(I) triflate to activate both simple and highly hindered acid anhydrides tetrakis(acetonitrile)copper(I) triflate to activate both simple and highly hindered acid anhydrides These results are noteworthy because it demonstrates the capacity of Cu(I) catalyst tetrakis(acetonitrile)copper(I) triflate to activate both simple and highly hindered acid anhydrides tetrakis(acetonitrile)copper(I) triflate to activate both simple and highly hindered acid anhydrides tetrakis(acetonitrile)copper(I) triflate to to activate both simple and and highly highly hindered acid anhydrides These results results are are noteworthy noteworthy because it demonstrates the capacity capacity of Cu(I) catalyst These because it demonstrates the of Cu(I) catalyst towards the masking of hydroxyl groups. towards the masking of hydroxyl groups. tetrakis(acetonitrile)copper(I) triflate activate both simple hindered acid anhydrides towards the masking of hydroxyl groups. towards the masking of hydroxyl groups. Catalysts 2017, 7, 33
7 of 10
It was gratifying to note that, in all cases using different alcohol substrates, the pivalation
reaction proceeded with ease even with hindered substrates, transforming the alcohol substrates
to the corresponding pivalate esters 28–35 in good to excellent yield.
These results are noteworthy because it demonstrates the capacity of Cu(I) catalyst
tetrakis(acetonitrile)copper(I) triflate to activate both simple and highly hindered acid anhydrides
towards the masking of hydroxyl groups.
While this protocol resulted in the facile transformation of the alcohols to the corresponding
esters using different acylating agents, separating the fully acylated products from the excess
isobutyric anhydride or pivalic anhydride used became problematic. To circumvent this problem, the
methanolysis protocol reported by Otera et al. [26] was adopted and modified to decompose the excess
isobutyric anhydride and pivalic anhydride.
To explore the origin of the observed catalysis, a control experiment with phenol as the substrate
and acetic anhydride as the acylating agent was carried out in the absence of the Cu(I) catalyst. In this
control reaction, there were no appreciable conversion of the phenol to the corresponding ester 2 even
after stirring the reaction for 5 h. Similar results were also obtained when isobutyric anhydride and
pivalic anhydrides were used as the acylating agents.
The lack of observable product formation obtained with phenol and acetic anhydride in the
absence of the Cu(I) catalyst was in sharp contrast to the rapid acetylation of phenol in the presence
of the catalyst (Table 1, Entry 1). Similarly, the results obtained during acylation of phenol when
isobutyric anhydride and pivalic anhydride were used as the acylating agents in the presence of
the Cu(I) catalyst (Table 2, Entry 1 and Table 3, Entry 1) were also in sharp contrast to the lack of
product formation observed when the acylation reactions were carried out in the absence of the catalyst,
which may suggest the crucial role of tetrakis(acetonitrile)copper(I) triflate in activating both simple
and hindered anhydrides, thereby effecting the facile transformation of alcohols and polyols to their
corresponding esters.
To further explore the source of the observed catalysis and the influence of the triflate counter ion,
another control experiment was run with phenol as the substrate and acetic anhydride as the acylating
agent. With 1 mol % triflic acid as the catalyst, the reaction was completed within 5 min to afford the
phenyl acetate in a 90% yield. When the control experiment was repeated using a 1 mol % non-triflate
Cu(I) source—Cu(CH3 CN)4 BF4 —surprisingly, the acetylation reaction was very sluggish, proceeding
to completion in 6 h and affording the phenyl acetate in a 92% yield.
These results may suggest the crucial role of the triflate counter ion in the observed catalyzed
acylation reactions and may also suggest the likelihood of an ancillary side reaction due to
Bronsted catalysis.
3. Experimental Section
3.1. Materials and Methods
All other chemicals were obtained from commercial vendors and used without further purification.
All acylation reactions were performed in a dried and argon flushed round bottom flask.
The reaction’s progress was routinely monitored by analytical thin-layer chromatography (TLC)
using a pre-coated silica gel glass plates. The products were identified and analyzed using IR,
1 H NMR, and 13 C NMR. The 1 H NMR spectra were recorded on a Varian 600 MHz spectrometer
(Agilent Technologies, Santa Clara, CA, USA.).
The 13 C NMR spectra were recorded on a Varian 150 MHz spectrometer (Agilent Technologies,
Santa Clara, CA, USA.) using CDCl3 as reference solvent.
3.2. Typical Experimental Procedure for O-Acetylation of Alcohols with Acetic Anhydride
An oven-dried and argon flushed 10 mL round-bottom flask was charged with Phenol (47.1 mg,
0.50 mmol, 1.0 equiv.) and acetic anhydride (0.19 mL, 2.0 mmol, 4.0 equiv.). To this mixture,
Catalysts 2017, 7, 33
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tetrakis(acetonitrile)copper(I) triflate (1.9 mg, 0.005 mmol, 1 mol %) was added. The reaction mixture
was stirred at room temperature and monitored by TLC. When the reaction was complete, the excess
acetic anhydride was decomposed with saturated aqueous NaHCO3 (2 mL) and stirred for 45 min.
The resulting reaction mixture was directly introduced onto a short SiO2 column and purified by flash
column chromatography (6/1, hexanes/ethyl acetate) to afford the phenyl acetate as pale yellow oil.
3.3. Typical Experimental Procedure for O-Acylation of Alcohols with Isobutyric Anhydride
An oven-dried and argon flushed 10 mL round-bottom flask was charged with phenol (47.1 mg,
0.50 mmol, 1.0 equiv.) and isobutyric anhydride (0.3 mL, 2.0 mmol, 4.0 equiv.). To this mixture,
tetrakis(acetonitrile)copper(I) triflate (1.9 mg, 0.005 mmol, 1 mol %) was added. The reaction mixture
was stirred at room temperature and monitored by TLC. When the reaction was complete, methanol
(3 mL) was added and heated at 50 ◦ C for 3 h. The resulting reaction mixture was concentrated in
vacuo and purified by flash column chromatography (7/1, hexanes/ethyl acetate) to afford the phenyl
isobutyrate as a pale yellow oil.
4. Conclusions
In summary, a new, simple, and highly efficient method of masking hydroxyl group to
the corresponding esters mediated by tetrakis(acetonitrile)copper(I) triflate has been developed.
This acylation protocol is mild and versatile, and mostly proceeds at room temperature.
Supplementary Materials: The following are available online at www.mdpi.com/2073-4344/7/1/33/s1, Spectra
data and Table S1: Preliminary studies of Cu(CH3 CN)4 OTf catalyzed acetylation of phenol.
Acknowledgments: We gratefully acknowledge Indiana University Southeast for financial support. This research
is also supported by Indiana University Southeast Research Support Program as well as the Indiana University
Southeast Large Grant Program.
Author Contributions: Enoch Mensah conceived and designed the experiments. The experimental procedures
were performed by Lindsey Earl and Enoch Mensah.
Conflicts of Interest: The authors declare no conflict of interest.
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