10.1002/chem.201800588
Chemistry - A European Journal
FULL PAPER
(1 x 50 mL), dried over MgSO4 and concentrated under reduced pressure
(minimum pressure 200 mbar) to yield the crude, volatile chloride 21 as a
yellow oil, of which 1H-NMR affirmed full conversion of 11. Additionally,
75% of the MTBE used could be reisolated. Finally, distillation through a
micro distillation apparatus at 0.8 mbar furnished the benzylic chloride 21
as a colourless liquid (24.78 g, 176.2 mmol, 88%) with a boiling range of
51-55 °C. As some precipitate remained in the aqueous phase from the
work up protocol (vide supra) further 2 N NaOH-solution (aq., 30 mL) was
added at 0 °C. The resulting clear solution was acidified to pH≤1 by
dropwise addition of 4 N HCl solution in water (70 mL) under vigorous
stirring. In the following, the resulting precipitate was collected by filtration
over a sintered funnel, washed with water (2 x 30 mL) and acetone (2 x
30 mL) and dried in high vacuum to furnish cyanuric acid as a colourless
fine powder (7.97 g, 61.8 mmol, 81%).
acid (IV with X = OH). Actually, the ability of TCT to be applied as
chlorination agent in amounts down to 34 mol% was unexpected.
It has been reported that the third chlorine atom of TCT is only
replaced by a nucleophile above 60-70 °C.[15] In the present case
substitution of all Cl-atoms on the triazine skeleton already occurs
at room temperature (see for instance Table 1, entry 5).
Surprisingly, reaction of chlorodimethoxytriazine (CDMT) as a
close analog to chlorodihydroxytriazine (intermediate IV with X =
OH, Cl) with substrate 12 does not provide benzylic chloride 22
under elsewise identical conditions (Scheme 5 B). Only in the
presence of para-toluene sulfonic acid (pTsOH) formation of 22
could be observed. These results suggest that Brønsted acid
cocatalysis via the plausible protonated triazine intermediate V
might play a crucial role.
Acknowledgements
Conclusions
We want to thank the German research foundation (DFG) and the
Fonds of the Chemical Industry (Liebig fellowship) for generous
support.
In summary, a powerful catalytic SN2-method for the conversion
of alcohols 1 into alkyl chlorides 2 relying on inexpensive TCT in
substoichiometric amounts (down to 34 mol%) has been
established. This substitution protocol creates a novel highly
efficient access to bioactive compounds, as exemplified by the
preparation of the pharmaceutical Rivastigmine in an enantio-
selective dehydroxychlorination/amination operation in one-pot.
In comparison to earlier procedures the (1) atom-economy, (2)
waste-balance and (3) cost-efficiency are improved significantly.
Due to formation of weakly acidic cyanuric acid as exclusive by-
product (instead of HCl) the presented method is in addition
distinguished by high levels of (4) functional group compatibility
and (5) stereoselectivity. In light of these advantages, the current
protocol is of high synthetic value and will find broad application
in both academia and industry. Ongoing efforts focus on the
application of FPyr and TCT in substoichiometric quantities in
other important substitution and dehydration reactions.
Keywords: homogenous catalysis • halogenation • nucleophilic
substitution • green chemistry • organocatalysis
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Experimental Section
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For an intriguing Brønsted acid catalyzed cyclodehydration protocol
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G. Huang, A. Orthaber, P. J. R. Sjꢀberg, S. Biswas, F. Himo, J. S. M.
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For general experimental conditions, detailed experimental procedures,
analytical data, 1H- and 13C-NMR-spectra see Supporting Information (SI).
The following procedure serves as a representative example.
Multigramscale Synthesis of rac-1-Chloro-1-phenylethane (21)
[6]
[7]
[8]
To a solution of 1-phenylethanol (11, 12.3 mL, 12.47 g, 100 mmol,
0.5 equiv) and FPyr (3.9 mL, 4.09 g, 40.0 mmol, 20 mol%) in acetone
(reagent-grade, 150 mL, [11] = 0.7 M) in a 500 mL one-necked round
bottom flask was added TCT (7.15 g, 38.0 mmol, 19 mol%) in one portion
at 40 °C. After 1 h of stirring at 40 °C, a solution of further starting material
11 (100 mmol, 0.5 equiv) in acetone (50 mL, 1 M)[24] and a second portion
of TCT (19 mol%) were added successively. The reaction suspension was
allowed to stir at 40 °C until TLC control confirmed full consumption of 11
after 4 h. Next, the reaction mixture was concentrated at the rotatory
evaporator (minimum pressure 100 mbar), which redelivered 85% of the
acetone. The residue was diluted with MTBE (100 mL) and 2 N NaOH
solution (aq., 110 mL) under cooling in an ice bath. The aqueous phase
was processed further as described below to isolate cyanuric acid. The
organic phase was successively washed with water (2 x 50 mL) and brine
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Dryzhakov J. Moran, Org. Biomol. Chem. 2014, 12, 5990-5994; b) M.
Dryzhakov, M. Hellal, E. Wolf, F. C. Falk, J. Moran, J. Am. Chem. Soc.
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