A carbon tetrachloride-free synthesis of N-phenyltrifluoroacetimidoyl chloride

Article abstract of DOI:10.1016/j.carres.2017.08.004

N-Phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is a reagent widely used for the preparation of glycosyl N-phenyltrifluoroacetimidates. However, the most commonly applied method requires carbon tetrachloride, a hepatotoxic reagent that has been phased ou

Full text of DOI:10.1016/j.carres.2017.08.004

Accepted Manuscript
A carbon tetrachloride-free synthesis of N-phenyltrifluoroacetimidoyl chloride
Dylan G.M. Smith, Spencer J. Williams
PII:
S0008-6215(17)30524-4
10.1016/j.carres.2017.08.004
CAR 7429
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 28 July 2017
Revised Date: 9 August 2017
Accepted Date: 9 August 2017
Please cite this article as: D.G.M. Smith, S.J. Williams, A carbon tetrachloride-free synthesis of N-
phenyltrifluoroacetimidoyl chloride, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.08.004.
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Graphical abstract
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Note
A carbon tetrachloride-free synthesis of N-phenyltrifluoroacetimidoyl
chloride
Dylan G.M. Smith, Spencer J. Williams*
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of
Melbourne, Parkville, Victoria, 3010, Australia
Keywords
Glycosylation; imidoyl chloride; green chemistry
Abstract
N-Phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is a reagent widely used for the
preparation of glycosyl N-phenyltrifluoroacetimidates. However, the most commonly applied
method requires carbon tetrachloride, a hepatotoxic reagent that has been phased out under
the Montreal Protocol. We report a new synthesis of N-phenyltrifluoroacetimidoyl chloride
(PTFAI-Cl) using dichlorotriphenylphosphane and triethylamine.
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Glycosyl N-phenyltrifluoroacetimidates (PTFAI; Figure 1a) are a powerful class of glycosyl
donors [1]. Since their first disclosure in 2001 [2], these glycosyl donors have rapidly risen to
become a mainstay of carbohydrate chemistry. The two main benefits of PFTAI donors over
the more commonly-applied trichloroacetimidates (TCAs) are (1) their greater stability,
particularly for 2-deoxy sugars, and (2) the lower nucleophilicity of the released N-
phenyltrifluoroacetamide versus trichloroacetamide. Thus, for example, PFTAI donors allow
the high yielding glycosylation of the amide of asparagine, whereas for TCAI donors the
trichloroacetamide by-product competes, lowering yields [3]. As well, comparison of a panel
of deoxysugar PFTAI and TCAI donors led to the conclusion that the former were more
stable, which led to higher yields of the glycosides [4].
Fig. 1. a) Preparation of glycosyl N-phenyltrifluoroacetimidates (PFTAIs) using N-
phenyltrifluoroacetimidoyl chloride (PTFAI-Cl). b) Prior approach to the synthesis of
PFTAI-Cl using carbon tetrachloride [5]. c) This work.
Glycosyl PFTAIs are formed by the reaction of sugar hemiacetals with N-
phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) in the presence of a base (Figure 1a). The
most common approach for synthesis of PTFAI-Cl involves refluxing aniline with
trifluoroacetic acid, triphenylphosphine, and triethylamine in carbon tetrachloride, followed
by distillation [5]. However, carbon tetrachloride is subject to the Montreal Protocol on
Substances that Deplete the Ozone Layer, and has a tropospheric lifetime estimate of 35 years
[6]. As a class I ozone-depleting substance, the phase-out target for carbon tetrachloride was
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1996. Moreover carbon tetrachloride is a potent hepatotoxin [7]. PTFAI-Cl is commercially
available; it is not known whether the commercial synthesis utilizes carbon tetrachloride.
Accordingly, we sought to develop a carbon tetrachloride-free synthesis of PTFAI-Cl.
Several carbon tetrachloride-free syntheses of PFTAI-Cl have been reported. An early
approach to imidoyl chlorides involved treatment of amides with PCl5; however, the yields
were relatively low and were complicated by the formation of diazadiphosphetidines [8]. An
approach involving POCl3 required specialized equipment and high temperature [9]. A patent
report discloses a synthesis of PTFAI-Cl by treatment of N-phenyltrifluoroacetamide with
(PhO)2POCl/Et3N [10].
The existing approach using TFA/Ph3P/Et3N/CCl4 may be considered a variant of the
Appel reaction, and likely proceeds via a [Ph3PCl]+[CCl3]– intermediate [11]. Therefore we
explored the use of other halogen donor compounds. Attempts to convert N-
phenyltrifluoroacetamide to PTFAI-Cl using Cl3CCN/Ph3P [12, 13] or thionyl chloride [14]
using the literature methods were unsuccessful. Our preferred method, reported below,
involves the treatment of N-phenyltrifluoroacetamide with Ph3PCl2/Et3N [11]. PFTAI-Cl is
relatively stable and can be purified by flash chromatography and is sufficient for use in
standard protocols for preparation of glycosyl PFTAIs. We also note that various benzyl and
allyl PFTAI derivatives are of utility in the acid-catalyzed etherifications [15-17], and this
new approach should support the environmentally-friendly synthesis of these reagents.
Experimental
Note: Like carbon tetrachloride, dichlorotriphenylphosphorane (Ph3PCl2) is classified as an
IARC Group 2B substance (possibly carcinogenic to humans).
N-Phenyl-2,2,2-trifluoroacetimidoyl chloride (PFTAI-Cl)
N-Phenyltrifluoroacetamide [18] (4.00 g, 21.2 mmol) and dichlorotriphenylphosphorane
(17.6 g, 52.9 mmol) were suspended in MeCN (80 ml) and Et3N (7.67 ml, 55.0 mmol) was
added. The suspension was refluxed for 3 h and then cooled to 0 °C. The precipitated solids
(Et3N.HCl and Ph3PO) were removed by filtration and the filtrate concentrated under reduced
pressure. The residue was dissolved in minimal CHCl3 and triturated with hexanes. The
precipitate was removed by filtration and the filtrate concentrated under reduced pressure.
The residue was purified by flash chromatography (Et2O/hexanes 1:4) afford the chloride as a
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colourless liquid (2.68 g, 61%). 1H NMR (500 MHz, CDCl3) δ 7.48–7.40 (m, 2H), 7.34–7.28
(m, 1H), 7.13–7.07 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 143.6, 132.1 (q, J 277.1), 129.3,
127.6, 120.8, 117.0 (q, J 43.0); IR (acetone) 1506, 1260, 1093, 1055, 1012, 795, 693; HRMS
(Orbitrap) calcd for C8H5ClF3N [M+H]+ 208.0135, found 208.0136.
Acknowledgements
We thank the Australian Research Council for funding.
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Highlights
•
N-Phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is used in the synthesis of glycosyl
N-phenyltrifluoroacetimidates.
•
•
A new synthesis of N-phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is reported.
The method avoids the use of ozone-depleting and hepatotoxic carbon tetrachloride.
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