Hafnium inspired activation of highly hindered anhydrides in the acylation of alcohols and polyols

Article abstract of DOI:10.1016/j.tetlet.2018.02.009

A novel and highly efficient method for activating highly hindered acid anhydrides towards the acylation of alcohols and carbohydrate-derived polyols has been developed. This new method relies on the capacity of the hafnium triflate catalyst Hf(OTf)₂ to activate highly hindered acid anhydrides, and to direct the acylation reaction. This new acylation protocol is mild and proceed at room temperature with low catalyst loading. The method is versatile and has been extended to different alcohol substrates with different steric encumbrance as well as carbohydrate-derived polyols to afford the corresponding ester products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.02.009

Accepted Manuscript
Hafnium Inspired Activation of Highly Hindered Anhydrides in the Acylation
of Alcohols and Polyols
Enoch Mensah, Aaron Day, Raven Thomas
PII:
S0040-4039(18)30167-9
https://doi.org/10.1016/j.tetlet.2018.02.009
TETL 49694
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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27 December 2017
1 February 2018
4 February 2018
Please cite this article as: Mensah, E., Day, A., Thomas, R., Hafnium Inspired Activation of Highly Hindered
Anhydrides in the Acylation of Alcohols and Polyols, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.02.009
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Hafnium Inspired Activation of Highly
Hindered Anhydrides in the Acylation of
Alcohols and Polyols
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Enoch Mensah,* Aaron Day and Raven Thomas

1
Tetrahedron Letters
Hafnium Inspired Activation of Highly Hindered Anhydrides in the Acylation of
Alcohols and Polyols
Enoch Mensah,* Aaron Day and Raven Thomas
School of Natural Sciences, Indiana University Southeast, 4201 Grant Line Road, New Albany, IN, 47150, U.S.A.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and highly efficient method for activating highly hindered acid anhydrides towards the
acylation of alcohols and carbohydrate-derived polyols has been developed. This new method
relies on the capacity of the hafnium triflate catalyst, Hf(OTf)2 to activate highly hindered acid
anhydrides, and to direct the acylation reaction. This new acylation protocol is mild and proceed
at room temperature with low catalyst loading. The method is versatile and has been extended to
different alcohol substrates with different steric encumbrance as well as carbohydrate-derived
polyols to afford the corresponding ester products in good to excellent yields.
Available online
Keywords:
Acylation
Isobutyric anhydride
Pivalic anhydride
Hafnium triflate
Pivalation
2009 Elsevier Ltd. All rights reserved.
triflate,30 trimethylsilyl triflate,31
copper triflate,32 cerium
triflate,34
1. Introduction
triflate,33
silver
Acylation of hydroxyl groups to the corresponding esters
bis(benzonitrile)palladium(II)bistriflate,35
and their subsequent deprotections has been widely utilized and
remain popular in numerous organic synthetic protocols. 1-3 Some
of the notable methods to protect hydroxyl groups employ the use
of acetic anhydride and DMAP in pyridine.4 While this reaction
protocol works well, long reaction times coupled the noxious
nature of pyridine has necessitated the need for other alternative
acylation methods to complement the existing hydroxyl
protection protocols.1
terakis(acetonitrile)copper(I)triflate,36 montmorillonite K-10,37
sulfamic acid,38 molecular sieves,39 hafnium(IV) and
zirconium(IV) salts.40-41
While all these methods provide useful alternatives in
protecting hydroxyl groups to the corresponding acetate esters,
the extension of these protocols in activating hindered acid
anhydrides are rarely reported. This becomes particularly crucial
during long synthetic reaction sequence involving the
manipulation of hydroxyl groups in various reaction media,
where the usual ease of removal of the acetyl protecting group is
undesirable, and therefore necessitating the use of a relatively
more hindered and robust hydroxyl protecting groups.
Recently, hafnium triflate by virtue of its high stability in
air, ease of handling and commercial availability has been
utilized in many Lewis acid mediated organic synthetic
transformations.42 For example, Kobayashi research group in the
past few years reported the development of a new protocol in the
Friedel-Crafts acylation of arenes,43-44 Fries rearrangement of
acyloxybenzenes,45 as well as C-acylation of phenol and
naphthol derivatives,46 all inspired by hafnium triflate in
catalytic quantities.
Some of the notable acylation methods that utilizes acetic
anhydride, acetic acid, acetyl chloride or other carboxylic acids
as the acylating agent to protect hydroxyl groups include the use
of
magnesium
perchlorate,5
lithium
perchlorate,6-7
cobalt(II)chloride,8
iron(III)chloride,11
chlorotrimethylsilane,9 zinc chloride,10
magnesium
tantalum(V)chloride,14
bromide,12
vanadyl
ruthenium(III)chloride,13
acetate,15 N-bromosuccinamide (NBS),16 3-nitrobenzene boronic
acid,17 silica gel supported sodium hydrogen sulfate,18 sodium
acetate trihydrate,2 dried sodium bicarbonate,19 bromine,20
iodine,21-22 tributylphosphine,23-24 p-toluene sulfonic acid,25
alumina,26 indium triflate,27-28 scandium triflate,29 bismuth
———
* Corresponding author.
In utilizing hafnium triflate in natural product synthesis, the
Zhu research group reported the development of hafnium triflate
inspired thioacetalization reactions of carbonyl compounds,47
Email address: mensahe@ius.edu
a

2
Upon treatment of the alcohols with isobutyric anhydride using
strategy which was employed as one of the key steps in the
synthesis of (-)-rhazinilam and (-)-leucomidine B.48 In recent
years, Movassaghi et al employed hafnium inspired addition
reactions of imine derivatives as one of its key steps in the total
synthesis of (+)-gliocladin B from N-protected L-tryptophan and
sarcosine methylester.49
1 mol% of the catalyst, the acylation reactions proceeded
smoothly with shorter reaction times affording the corresponding
esters 6 – 15 in good to excellent yields (Table 2). Of particular
note is the use of 2,4-dinitrophenol as a substrate, although quite
deactivated and less nucleophilic, the acylation reaction still
proceeded, affording the corresponding ester 8 in good yields
(Table 2).
As a result of the excellent catalytic activity and versatility
of hafnium triflate in many organic transformation reactions, we
envisioned that this catalyst could potentially be effective in
activating hindered acid anhydrides towards the masking of
hydroxyl groups with more robust protecting groups.
Table 2
Acylation of alcohols with isobutyric anhydride catalyzed by Hf(OTf)4.a
To the best of our knowledge, the use of this catalyst in
activating hindered acid anhydrides in the protection of hydroxyl
groups has not been studied. We report herein a new method that
utilizes hafnium triflate as catalyst in the acylation of alcohols
and polyols using hindered acid anhydrides.
2. Results and Discussion
Preliminary studies to investigate the effectiveness of hafnium
triflate in activating hindered acid anhydrides began using benzyl
alcohol 1 as the starting substrate. An acetic anhydride 2 and a
relatively more hindered isobutyric anhydride 3 were used as the
acylating agents in a bid to study their relative rates of acylation
at different catalyst loading. (Table 1).
Table 1
Hafnium triflate catalyzed acylation of benzyl alcohol.a
a Reactions were conducted in dried CH2Cl2 (2.5M).
Encouraged by these results, the efficacy of this catalyst was
again investigated when more hindered alcohols such as
diphenylmethanol and adamantanol were employed as substrates.
Remarkably, in both cases, the hindered alcohols were converted
to their corresponding esters 11 and 15 in short reaction times
and in great yields (Table 2).
Entry
Acylating
Agent
Catalyst loading
Time
(min)
1
1
1
1
1
15
45
Product
Yield
(%)b
95
93
96
95
95
97
82
(mol %)
10
7
1
2
3
4
5
6
7
2
2
2
2
2
3
3
4
4
4
4
4
5
5
5
2
1
1
In our quest to test the scope of this catalyst, the protocol was
extended to the acylation of poly-hydroxyl systems using
carbohydrate-derived polyols as substrate (Table 3).
0.5
a Reactions were conducted on 0.5 mmol scale with benzyl alcohol in dried
CH2Cl2 (2.5M). b Isolated yield.
Table 3
Acylation of carbohydrate-derived polyols catalyzed by Hf(OTf)4.a
Conversion of benzyl alcohol 1 to the corresponding ester 4
using acetic anhydride 2 as the acylating agent proceeded
smoothly and rapidly even at 1 mol% catalyst loading to afford
the benzyl acetate in excellent yields (Table 1, entry 1-5). This
encouraging results prompted us to investigate the efficacy of
this catalyst in activating a relatively more hindered acid
anhydride such as isobutyric anhydride towards the protection of
hydroxyl groups.
Upon treatment of benzyl alcohol 1 with isobutyric anhydride 3,
to our amazement, the acylation reaction proceeded to
completion within 15 minutes at 1 mol% catalyst loading,
affording the corresponding ester 5 in excellent yield (Table 1,
entry 6). Further reduction in the catalyst loading resulted in a
sluggish reaction rate and reduced isolated yield (Table 1, entry
7). These results were significant because it demonstrate the
capacity of hafnium triflate to activate not only simple acid
anhydrides such as acetic anhydride but also a relatively more
hindered acid anhydrides as well.
a Reactions were conducted in dried CH2Cl2 (2.5M). 2 equiv. of isobutyric
anhydride were used per hydroxyl group.
To investigate the generality and scope of this method, the new
acylation protocol was extended to a wide variety of different
alcohols using isobutyric anhydride 3 as the acylating agent
(Table 2).

3
Acylation reaction of each of the polyols with isobutyric
anhydride using 1 mol% of the catalyst, resulted in a facile
transformation to the fully acylated sugars 16 – 21 in good to
excellent yields (Table 3).
4
TfOH
I mol%
-
20min
86
a Reactions were conducted in dried CH2Cl2 (2.5M).
b 2,6-Di-tertbutylpyridine
As a result of the use of pivaloyl group as a robust hydroxyl
protecting group in organic synthesis in recent years,50-51 we
again proceeded to test the limits of this protocol, by
investigating the efficacy of the catalyst to activate a relatively
more hindered acid anhydride such as pivalic anhydride in the
acylation of polyols (Table 4).
Upon treatment of benzyl alcohol 1 with isobutyric anhydride
3 in the absence of a catalyst, there were no significant formation
of the benzyl ester 5 even after stirring the reaction mixture for 5
hours (Table 5, entry 1). In the presence of 1 mol% catalyst
loading, the acylation reaction was rapid, affording the ester 5 in
excellent yield (Table 5, entry 2). This result may suggest the
significant role of the catalyst in the observed transformation.
Table 4
Pivalation of carbohydrate-derived polyols catalyzed by Hf(OTf)4.a
To rule out the potential of any in situ generated triflic acid
contributing to the observed catalytic transformations, another
control experiment was performed in the presence of an acid
scavenger 2,6-di-tertbutyl pyridine. Interestingly, the acylation
reaction was relatively sluggish forming the corresponding ester
in 2.5hrs (Table 5, entry 3). These results prompted us to run
another control experiment with triflic acid as the catalyst. In this
instance, the acylation reaction proceeded to afford the ester 5 in
good yields (Table 5, entry 4).
The results of this control experiments lead us to probe the limits
of this protocol by running two additional acylation experiments
using a substrate that is prone to elimination such as t-butanol
and with isobutyric anhydride as the acylating agent. Using 1
mol% hafnium triflate, elimination product was primarily
isolated in this instance. Similar result was observed with 1
mol% triflic acid. These results may suggest the high sensitivity
of this protocol to acid-sensitive substrates.
Overall, while these results indicates the high capacity of
hafnium triflate in activating hindered acid anhydrides in the
acylation of alcohols and polyols, we cannot rule out the
likelihood of an acid induced side reaction pathway in the
observed catalysis. Such dual catalytic pathway has also been
reported by the Cloninger group with indium triflate27 and by
Dumeunier and Marko with scandium triflate.52
a Reactions were conducted in dried CH2Cl2 (2.5M). 2 equiv. of pivalic
anhydride were used per hydroxyl group.
At 1 mol% catalyst loading, the pivalation reactions were very
sluggish with low percent conversions. However, upon
increasing the catalyst loading to 2.5 mol%, remarkably, in all
cases, the hafnium triflate was able to activate the pivalic
anhydride, resulting in a smooth transformation of the polyols to
the corresponding pivalate esters 22 – 27 in good to excellent
yields (Table 4).
Conclusion
In summary, a new method of activating hindered acid
anhydrides towards the acylation of alcohols and polyols inspired
by hafnium triflate has been developed. This method is simple,
versatile and highly efficient and requires low catalyst loading at
room temperature.
The observed excellent activity of the catalyst also prompted
us to investigate the tolerance of this protocol to other commonly
used hydroxyl protecting groups. The methoxy group (Table 3,
product 17 and Table 4, product 23) as well as p-methoxyphenyl
group (PMP) (Table 3, product 20 and Table 4, product 26) both
survived this acylation protocol to afford the respective esters in
good to excellent yields.
Acknowledgements
We thank 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.
As a result of the excellent transformations observed, the
origin of the observed catalytic activity was also investigated by
performing a number of control experiments using benzyl alcohol
1 and isobutyric anhydride 3 as model substrates (Table 5).
Supplementary Data
Supplementary information (experimental procedures and
spectral data) associated with this article is available.
Table 5
Control experiments with isobutyric anhydride as the acylating agent.a
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5
Highlights


A highly efficient method for activating highly hindered acid anhydrides has been developed.
The method relies on the capacity of the hafnium species to activate hindered acid anhydrides to protect hydroxyl
groups.

The method has wide substrate scope to afford ester products in good to excellent yields.