Fluorination reactions in microreactors

Article abstract of DOI:10.1039/b803695k

The DAST-mediated conversion of a range of alcohols to the corresponding fluorides in a microstructured device is described. This safe, practical fluorination method will facilitate reactions currently challenging on large scale. The Royal Society of Chem

Full text of DOI:10.1039/b803695k

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Fluorination reactions in microreactors
Tomas Gustafsson, Ryan Gilmour and Peter H. Seeberger*
Received (in Cambridge, UK) 4th March 2008, Accepted 1st April 2008
First published as an Advance Article on the web 29th April 2008
DOI: 10.1039/b803695k
The DAST-mediated conversion of a range of alcohols to the
corresponding fluorides in a microstructured device is described.
This safe, practical fluorination method will facilitate reactions
currently challenging on large scale.
incorporation of a 75 psi HPLC back pressure regulator
allowed the solvent to be super-heated to 70 1C resulting in
shortened reaction times.10 For economic reasons it was
deemed prudent to use exactly 1 equivalent of DAST in the
deoxyfluorination of alcohols and exactly 2 equivalents in the
case of carbonyl-containing substrates. A residence time of
16 min was found to be optimal while 8 min residence time
resulted in lower conversions as did 32 min (presumably due to
product degradation).
Fluorinated organic compounds are emerging with increasing
frequency as pharmaceutically active substances from the drug
discovery process1,2 owing to their unique physical and bio-
chemical properties.3,4 While organofluorine compounds are
relatively rare in nature,5 fluorine-containing molecules fea-
ture prominently in the agrochemical and pharmaceutical
repertoire owing to their enhanced metabolic stability. In
2005 alone, half of the top ten pharmaceuticals contained
fluorine;6 a number that is expected to increase further.
Among the numerous commercially available nucleophilic
fluorinating reagents, DAST (diethylaminosulfur trifluoride)
is perhaps the most widely utilised.7 However, the use of
DAST in large scale deoxyfluorination reactions is limited
by its propensity to detonate at temperatures above 90 1C. The
procurement of fluorinated intermediates and final products is
thus hampered by safety concerns. Prompted by the need to
find a safe, scalable method that allows for large quantities of
fluorinated molecules to be prepared, we developed a micro-
reactor-based deoxyfluorination method. Microreactors hold
advantages when tackling hazardous reactions as heat transfer
is more efficient in microstructured reaction vessels to control
thermal runaway. Super-heating of solvents to accelerate
reactions, and excellent mixing are further advantages. Ex-
plosive, highly toxic and corrosive reagents, intermediates or
by-products (in this case HF) can be quenched in situ. Only
small amounts of material are required to optimise reactions
due to the small reactor volumes. Still, scale-up is simple under
the flow-through regime. Reactions generally considered to be
unattractive due to safety concerns are made more accessible
using microreactors.8,9
Having established general deoxyfluorination conditions,
preliminary experiments focused on the conversion of a range
of benzylic and secondary alcohols to the corresponding
fluorides (Table 1). Both electron rich and electron deficient
benzylic alcohols were processed to the corresponding fluor-
ides (entries 1 and 2, respectively) in good yield.11,12 The
naphthalene derivative (entry 3) reacted cleanly to give the
desired product albeit in lower yield.13 More complex second-
ary alcohols such as menthol and dihydrocholesterol were also
tolerated (entries 4 and 5 respectively).14–16
Glycosyl fluorides are potent glycosylating agents that are
typically prepared by treating the corresponding lactols with
DAST. As part of an overall programme directed at simplify-
ing oligosaccharide assembly17 we explored whether glycosy-
lating agents could be prepared in continuous flow. 2,3,4,6-
Acetylated and benzylated glucoses undergo smooth conver-
sion to the corresponding glycosyl fluorides18–20 in excellent
yield and do not require further purification prior to use
(Table 2). Based on our interest in preparing ‘activated’
synthetic intermediates that may be used directly in subse-
quent transformations, we examined the conversion of a
family of carboxylic acids to the corresponding acid fluorides
(Table 3).21 Substituted benzoic acids such as the 4-methoxy-
and the 3,4-dimethyl- derivatives (entries 1 and 2) were
quantitatively transformed to the desired acyl fluorides.22
Similarly, aliphatic acids (entries 3, 4 and 5)23 were converted
to the expected products in excellent yield. Finally, the halogen
exchange process (entry 6) was examined whereby an acid
chloride was converted to the corresponding acid fluoride in
high yield.24
Herein, we describe the development of a general method
for the deoxyfluorination of a range of substrates, including
alcohols, lactols, aldehydes and carboxylic acids, in a micro-
structured device (Fig. 1).10 Pertinent features of this method
include short reaction times (16 min), elevated temperature
(70 1C) and in situ quenching of excess DAST and HF.
In order to establish general deoxyfluorination conditions,
exploratory reactions were performed in toluene, dichloro-
methane and tetrahydrofuran. Dichloromethane was quickly
identified as being the solvent of choice. Furthermore, the
To assess the scope of this method, the conversion of
aldehydes and ketones to the corresponding gem-
Swiss Federal Institute of Technology (ETH) Zurich, Laboratorium
fur Organische Chemie, HCI F 315, CH-8093 Zurich, Switzerland.
¨
E-mail: seeberger@org.chem.ethz.ch; Fax: +41 44 633 12 35;
Tel: +41 44 633 21 03
Fig.
1 Overview of the microreactor-based DAST fluorination
process.
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Table 1 DAST fluorination of selected benzylic and secondary
alcoholsa
Table 3 Synthesis of a variety of acid fluoridesa
Entry
1
Substrate
Fluoride
Yield (%)
Quant.b
Entry
1
Alcohol
Fluoride
Yield (%)
66
2
95
2
70
3
4
5
Quant.b
93
3
4
55
81
70b
6
80
5
61c
a
b
For experimental details see Table 1. No purification required.
quantitative.27 The conversion of ketones to the corresponding
difluorides was less efficient (entry 6) and was not investigated
further.28 This finding may be attributed to the lower reactivity
a
Reaction conditions: Solutions of the alcohol and DAST (both 0.2
mol dmÀ3 in CH2Cl2) were simultaneously injected into a 16 cm3 Syrris
FRX microreactor and heated to 70 1C (retention time: 16 min). The
outlet solution was subsequently mixed with a 10% aqueous solution
of NaHCO3. The product was extracted with ethyl acetate, washed
with a saturated aqueous solution of NaHCO3 and concentrated in
vacuo. Purification by flash column chromatography on silica gel
Table 4 Conversion of carbonyl groups to the corresponding di-
fluormethylenes
Entry
1
Substrate
Fluoride
Yield (%)
Quant.b
b
furnished the desired fluorides. The product was isolated as a 6 : 1
mixture of diastereoisomers as determined by 1H and 19F NMR
c
spectroscopy. The product was isolated as a 5 : 1 mixture of
1
diastereoisomers as determined by H and 19F NMR spectroscopy.
2
3
4
89
84
87
difluoromethylene adducts was explored and proved to be
general for aldehydes (summarised in Table 4). The bulky
ortho-substituted aldehyde (entry 1) was smoothly converted
to the desired product in quantitative yield. Furthermore,
electron rich (entries 2 and 3) and electron deficient (entry 4)
aldehydes were transformed into the desired gem-difluoro-
methylene derivatives25,26 in consistently high yield. Conver-
sion of a straight-chain aliphatic aldehyde (entry 5) was also
5
6
Quant.b
40c
Table 2 Facile preparation of glycosyl fluoridesa
Entry
1
Lactol
Fluoride
Yield (%)
89
a
Experimental details are the same as those described in Table 1 with
the exception that a 0.4 dmÀ3 solution of DAST in CH2Cl2 was
2
Quant.b
b
c
used. No purification required. 40% conversion determined by
1H NMR spectroscopy.
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of ketones towards DAST, a reaction that typically requires
elevated temperatures.29
before the heated reactor and the quench reagent (a saturated
aqueous solution of NaHCO3) was introduced directly after the
back pressure regulator. For further information visit http://www.
syrris.com.
In summary, we report a safe, practical and general method
for deoxyfluorination of a range of substrates in a microstruc-
tured device. This synthetic method illustrates the utility of
microreactors for modern synthetic organic chemistry.
We thank the Swiss Federal Institute of Technology (ETH)
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¨
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