The development of N-aryl trifluoroacetimidate-based benzyl and allyl protecting group reagents

Article abstract of DOI:10.1016/j.tetlet.2013.09.014

An exploration of the role of para-substituents on the balance between stability and reactivity of N-phenyl trifluoroacetimidates prompted the discovery of new reagents for the addition of allyl and benzyl protecting groups, namely O-allyl and O-benzyl N-

Full text of DOI:10.1016/j.tetlet.2013.09.014

Tetrahedron Letters 54 (2013) 6983–6985
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The development of N-aryl trifluoroacetimidate-based benzyl
and allyl protecting group reagents q
Sinele B. Tsabedze a, Daniel E. K. Kabotso b, Nicola L. B. Pohl a,b,
⇑
a Department of Chemistry, Hach Hall, Iowa State University, Ames, IA 50011, USA
b Department of Chemistry, Simon Hall, Indiana University, Bloomington, IN 47405, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An exploration of the role of para-substituents on the balance between stability and reactivity of N-phe-
nyl trifluoroacetimidates prompted the discovery of new reagents for the addition of allyl and benzyl pro-
tecting groups, namely O-allyl and O-benzyl N-(p-nitrophenyl)trifluoroimidates. These compounds are
stable and crystalline at ambient temperature, making them ideal alternatives to existing benzylating
and allylating reagents used under acidic conditions.
Received 10 August 2013
Revised 29 August 2013
Accepted 4 September 2013
Available online 11 September 2013
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Trifluoroacetimidate
Benzylation
Allylation
Protecting groups
Introduction
this reagent usually requires in situ preparation due to its high
reactivity. In the realm of glycosylation chemistry, several analogs
The development of protecting group chemistries has allowed
the synthesis of increasingly complex structures with dense func-
tional group patterns, especially in the realm of carbohydrate syn-
thesis.1 Amongst the hydroxyl protecting groups, much effort has
been focused on allyl and benzyl groups.2 Unfortunately, the intro-
duction of these protecting groups often involves employment of
harsh acidic/basic conditions that can be problematic when other
fragile groups are present in the compound being protected.2h Ben-
zylation is one of the more common permanent protecting groups
employed in oligosaccharide synthesis owing to its stability under
both the acidic and basic conditions employed in typical glycosyl-
ation/deprotection reactions. A popular benzylating protocol uses
benzyl bromide in the presence of sodium hydride and catalytic
tetrabutylammonium iodide (TBAI).2i The utility of this reaction
is limited when there are already base sensitive functional groups
in the substrate such as the acetyl groups. For neutral conditions,
benzylation in the presence of silver oxide2h can be successful,
but the need for freshly prepared silver oxide to make this reaction
reliable complicates the procedure. To employ acidic rather than
basic conditions, benzyl trichloroacetimidate2j has been used, but
of N-aryl trifluoroacetimidates have been used as glycosyl donors
to circumvent the high reactivity of trichloroacetimidates.3 The
advantage of using these donors as opposed to the widely used tri-
chloroacetimidate donors is that they are more stable and still very
efficient and can thus be used in conditions where the less stable
trichloroacetimidates fail.3,4 Given these precedents, we decided
to explore the possibility of modulating the reactivity of N-phenyl
trifluoroacetimidates to find a balance between the stability and
reactivity of this leaving group for use in reagents designed for
benzylation and allylation reactions. Herein we report structure/
function studies with these N-phenyl trifluoroacetimidates and
the discovery of a leaving group that provides stable and crystal-
line reagents for the facile addition of benzyl and allyl groups un-
der acidic conditions.
Methods
To find a more stable acetimidate, a systematic method to
investigate the effect of changing a para-substituent on the
X
1 X = NO2 (90%)
2 X = Cl (87%)
3 X = H (89%)
q
This is an open-access article distributed under the terms of the Creative
N
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
4 X = OMe (90%)
MeO
CF3
⇑
Corresponding author. Tel.: +1 812 855 0298; fax: +1 812 855 8300.
E-mail address: npohl@indiana.edu (N.L.B. Pohl).
Figure 1. Synthesis yields of para-substituted O-methyl N-aryl triflouroace-
timidates.
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.014

6984
S. B. Tsabedze et al. / Tetrahedron Letters 54 (2013) 6983–6985
N-phenyl group on the stability of the acetimidate under acidic
conditions was sought. To start the study, a variety of N-phenyl tri-
fluoracetimidates were made attached to methanol rather than
benzyl for simplicity in the analysis by 1H NMR (Fig. 1). Methyl
2,2,2-trifluoro-N-aryl acetimidates were synthesized by reacting
methyl alcohol with N-aryl trifluoroacetimidoyl chlorides5 under
basic conditions. Several bases such as NaOMe, NaH, and K2CO3
were tested for their viability in this synthesis; K2CO3 was ulti-
mately chosen for its ease of use while maintaining excellent
(85–90%) yields.
After synthesis and subsequent purification of each compound
1–4, a sample of 40 lmol of acetimidate was treated to 2% trifluo-
roacetic acid in DMSO-d6 and allowed to react over the course of at
least 120 min. Recordings of the reaction were taken by 1H NMR
every 5 min to determine which donor maintained the integrity
of its structure the longest. The rate of transformation was quanti-
fied as the percent acetimidate peak divided by the total amount of
aromatic peaks (starting material and product aromatic peaks). The
difference between the aromatic peaks of the imidate and the de-
graded product is very distinct, making it very easy to quantify the
rate of transformation (see Fig. 2).
Figure 3. An example of a graph showing the % imidate aromatic peaks by 1H NMR
over time for compound 4. Additional graphs are available in the Supplementary
data.
Results and discussion
The percent imidate peak was plotted against time to get expo-
nential graphs resembling Figure 3 below. From such graphs, the
comparative rates of degradation were obtained. A comparison of
nitro-substituted acetimidate 1 to the other analogs showed
marked stability under acidic conditions. Compound 1 formed nee-
dle-like light yellow crystals at ambient temperature.
NO2
NO2
K2CO3 , ROH, 1 h
N
N
F3C
OR
F3C
Cl
Given the superior stability of nitro-substituted N-phenyl triflu-
oroacetimidate, presumably because of the inductive effect of the
electron-withdrawing group making nitrogen less basic, we next
tested its reactivity as a leaving group in the context of a benzyla-
tion reaction. Obviously, to be a successful leaving group, the
substituted N-phenyl trifluoracetimidate could not be too stable
and thereby require harsh conditions for its transfer to a hydroxyl
as a protecting group. A benzylating agent using the unsubstituted
N-phenyl trifluoroacetimidoyl had already been reported,2d but
this reagent, like its trichloroacetimidate counterpart,2e,k is also
5 R = Bn
6 R = All
Figure 4. Synthesis of benzyl and allyl N-(nitrophenyl) trifluoroacetimidates.
not particularly stable and therefore requires in situ preparation
or stringent storage conditions. Prompted by the superior stability
of nitro derivatives in the simple methanol study above, benzyl
derivative 5 was synthesized in excellent (>90%) yield (Fig. 4).
Interestingly, the reagent was crystalline and proved to be stable
at ambient temperature for at least 10 days—properties that could
make it more viable for commercial production than benzyl
trichloroacetimidate.
NO2
NO2
acid
An initial trial reaction showed that the new nitro-derivative 1
could indeed serve as a benzylation reagent. Given this promising
initial data, allyl version 6 was also made. The reaction also pro-
ceeded in excellent yield to provide a crystalline product. These
two new reagents were then used in reactions to protect alcohols
7 and 8, representative of deactivated and activated carbohydrate
hydroxyls, to form the known products 9,6a 10,6b and 11,6c and
the new product 12. The benzylation and allylation reactions were
first tried with Zn(OTf)2 and Yb(OTf)2. Though successful, the yields
in these conditions were not satisfactory (ꢀ60%) compared to later
reactions with TMSOTf (Table 1). All reactions were complete with-
in 1 h compared to longer traditional methods and the yields were
improved compared to using the less stable trichloroacetimidates.
N
HN
F3C
O
F3C
OMe
Conclusion
After comparative monitoring of the rates of reaction associated
with different para-substituents on N-aryl trifluoroacetimidates,
the nitro-substitution was found to provide a perfect balance be-
tween stability and reactivity to aid in the development of a new
reagent for the addition of benzyl and allyl protecting groups.
These benzylating and allylating reagents are crystalline and stable
Figure 2. 1H NMR depicting the change in structure of acetimidate 1 under acidic
conditions.

S. B. Tsabedze et al. / Tetrahedron Letters 54 (2013) 6983–6985
6985
Table 1
Supplementary data
Reactions of 1.2 equivalents O-allyl and O-benzyl N-(nitrophenyl)trifluoroimidates
with different alcohols using catalytic amounts of TMSOTf as a promoter
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
09.014.
Alcohol
Imidate
Product
Yield (%)
OH
O
OBn
O
AcO
AcO
AcO
AcO
5
83
OAc
OAc
OAc
OAc
References and notes
OAc
OAc
7
9
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at ambient temperatures for days, thereby simplifying their use,
and react with alcohols in high yields with catalytic amounts of
TMSOTf comparable to the less stable allyl and benzyl trichloroace-
timidate reagents. These new reagents should thereby provide
attractive alternatives to the standard trichloroacetimidate re-
agents for acid-catalyzed additions of benzyl and allyl protecting
groups.
Acknowledgements
This work was supported in part by the US National Science
Foundation (CHE-0911123/1261046) and the Joan and Marvin Car-
mack fund.