Epoxidation of alkenes using HOF·MeCN by a continuous flow process

Article abstract of DOI:10.1016/j.tetlet.2008.12.073

Continuous flow methodology is described which allows the in situ generation of the highly effective oxidising agent HOF·MeCN from fluorine and wet acetonitrile and immediate reaction with alkenes to afford epoxides in high yield. The HOF·MeCN continuous flow oxidising system provides an environmentally benign process that is suitable for large scale synthesis and is atom efficient, because the only by-product is hydrogen fluoride which, in principle, could be recycled to produce fluorine by electrolysis. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.12.073

Tetrahedron Letters 50 (2009) 1674–1676
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Tetrahedron Letters
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Epoxidation of alkenes using HOFÁMeCN by a continuous flow process
a,
Christopher B. McPake a, Christopher B. Murray b, , Graham Sandford
*
*
a Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
b AWE, Aldermaston, Reading, Berkshire RG7 4PR, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Continuous flow methodology is described which allows the in situ generation of the highly effective oxi-
dising agent HOFÁMeCN from fluorine and wet acetonitrile and immediate reaction with alkenes to afford
epoxides in high yield. The HOFÁMeCN continuous flow oxidising system provides an environmentally
benign process that is suitable for large scale synthesis and is atom efficient, because the only by-product
is hydrogen fluoride which, in principle, could be recycled to produce fluorine by electrolysis.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Received 20 October 2008
Revised 9 December 2008
Accepted 16 December 2008
Available online 24 December 2008
1. Introduction
hazardous for processes where heat transfer, agitation, selectivity
and tar formation are problematic. Consequently, the increased
In a series of publications, Rozen and co-workers demonstrated
that the HOFÁMeCN complex, formed by the reaction of elemental
fluorine with water in acetonitrile at 0 °C, is a uniquely effective
electrophilic oxygen transfer agent.1–3 A wide range of oxidation
reactions have been reported of, for example, amine, azide, sulfide,
alcohol, ketone and N-heterocyclic substrates. All the reactions
proceeded rapidly under very mild conditions to give the corre-
sponding oxidation products in high yields. A further benefit of this
oxidising system is that it is an environmentally benign process,
replacing, for instance, toxic heavy metal oxidants for many trans-
formations. It is also atom efficient, because the only by-product is
hydrogen fluoride which, in principle, could be recycled to produce
fluorine by electrolysis.
Rozen estimated that the HOFÁMeCN complex has a half life of a
few hours at 0 °C and thus the reagent must be produced when
required immediately at the point of use. This requires ‘batch’ reac-
tion of F2 with wet acetonitrile to form a highly oxidising solution
of HOF in acetonitrile. Furthermore, the resulting solution of
HOFÁMeCN and HF must be immediately analysed by titration to
determine the concentration of oxidant. A combination of these
factors could inhibit the development of this potentially very use-
ful and powerful reagent for anything other than small scale labo-
ratory synthesis and, indeed, applications in larger scale syntheses
have not been developed.
costsassociatedwithconductingsafescale-upof manyconventional
oxidation processes in highly concentrated oxidising media can be
prohibitive and so there is still a requirement for the development
of reagents and/or processes that will allow safe, efficient oxidation
to be performed on the laboratory and manufacturing scale.
In recent years, continuous flow microreactor devices4,5 have
been developed for a variety of synthetic procedures, usually with
corresponding increases in yield, selectivity, controllability and
safety. In conjunction with the possibility of arithmetic ‘scale-
out’, there are clear benefits over conventional batch process tech-
nology. A key feature of using microreactor channels as the
reaction ‘vessels’ is that the synthesis of large quantities of product
is achieved by the operation of multiple channels and/or microre-
actor devices in parallel, avoiding many of the difficulties associ-
ated with traditional scale-up. In particular, the usual safety and
chemistry issues associated with the decrease in efficiency of heat-
and mass-transfers on increasing scale are avoided. In this context,
we have demonstrated that gas/liquid reactions, particularly direct
fluorination of a variety of organic substrates, can be achieved
using continuous flow microreactor devices6–10 and the scale-out
of reactions involving the use of 30 channels in parallel has been
successfully achieved for gas/liquid processes.10
We sought to use our continuous flow microreactor techniques
for the development of effective oxidation methodology using
HOFÁMeCN, prepared in situ by direct fluorination. Such an
approach avoids many of the problems associated with using
HOFÁMeCN in batch processes and could be suitable for scale-out
beyond laboratory scale. We aimed to generate quantitatively the
HOFÁMeCN complex in situ in a microchannel and then react it
immediately with an organic substrate so that the problems of
concentration measurement, stability and storage would be
avoided, making the process amenable to general use for both lab-
oratory and manufacturing applications.
In addition, highly exothermic, rapid oxidation processes can
exhibitproblemswithreactioncontrolwhenreagentsareaddedinto
an excess of a highly oxidising medium. The scale-up of batch syn-
theses using unstable materials can be particularly difficult or even
* Corresponding authors. Tel.: +44 (0)118 982 4162; fax: +44 (0)118 982 5024
(C.B.M.), tel.: +44 (0)191 334 2039; fax: +44 (0)191 384 4737 (G.S.).
E-mail addresses: christopher.murray@awe.co.uk (C.B. Murray), graham.
sandford@ durham.ac.uk (G. Sandford).
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.073

C. B. McPake et al. / Tetrahedron Letters 50 (2009) 1674–1676
1675
Table 1
Epoxidation of alkenes using HOFÁMeCN in a continuous flow process
HOF.MeCN, DCM, r.t.
Alkene
Epoxide
Continuous flow reactor
Alkene
Epoxide
Yield (%)
98
C
10H21
C10H21
O
O
Ph
H
Ph
99
81
97
Ph
H
Ph
O
Ph
H
H
Ph
Ph
Ph
O
O
O
O
O
82
Figure 1. Single channel continuous flow reactor.
O
O
H
CO2Et
39a
63b
99
CO2Et
Ph
In this Letter, we describe epoxidation reactions of a small ser-
ies of alkenes where the HOFÁMeCN is generated in situ in a contin-
uous flow process using microreactor techniques to demonstrate
this proof of concept.
Ph
H
O
O
O
For all the reactions involving the generation and reaction of
HOFÁMeCN described below, we used our single-channel microre-
actor, shown in Figure 1, and this apparatus and its operation
had been described in detail previously.6,7 Briefly, fluorine gas,
diluted to 10% in nitrogen, was introduced into the microchannel
using a mass flow controller set at a prescribed flow rate, and
wet acetonitrile was added via a second inlet at a controlled rate
by syringe pump (Fig. 2). The alkene was found to react preferen-
tially with fluorine in the presence of HOFÁMeCN, thus conditions
for the complete reaction of fluorine with water had to be deter-
mined to prevent the production of fluorinated by-products.
Continuous flow epoxidation processes were carried out in
which HOFÁMeCN was generated in the microchannel and the
alkene (in 1:1 v:v MeCN/dichloromethane solution) was added,
via a T-piece connection at a controlled rate using a second syringe
pump. We found that a throughput of 2.0 mmol hÀ1 channelÀ1 of
HOFÁMeCN was possible, based on the recovery of epoxide, in a
0.5 mm diameter, 125 mm reactor path length with a further
300 mm path length after the T-piece for oxidation of the alkene.
Cooling of the microreactor and collection vessel was unnecessary
because reactions proceeded with high control under ambient con-
ditions with no reduction in yield. The product mixture flowed into
a collection vessel that contained aqueous sodium hydrogen
carbonate solution which quenched any excess HOF and HF
O
O
O
O
O
O
38
94
O
O
O
a
1 equiv HOFÁMeCN, NMR yield.
2 equiv HOFÁMeCN, NMR yield.
b
immediately, minimising the risk of HF exposure and demonstrat-
ing that the reaction occurred in the flow system itself. Extraction
of the aqueous solution with dichloromethane, drying and evapo-
ration gave the desired epoxide, typically in greater than 80% yield
without the need for any further purification.
A small series of alkenes was epoxidised in a similar manner
and these results are collated in Table 1. Epoxidation of various
mono-, di-, tri- and tetra-substituted alkenes demonstrates the
potential of this technique.
Figure 2. Gas/liquid continuous flow techniques.

1676
C. B. McPake et al. / Tetrahedron Letters 50 (2009) 1674–1676
Ethyl trans-cinnamate is known to be less reactive towards epox-
(50 mL). After purging the apparatus with nitrogen, the reaction
mixture was added to NaHCO3 solution (25 mL), extracted with
CH2Cl2 (3 Â 75 mL), dried (MgSO4) and filtered. The solvent was
removed under reduced pressure to yield 2-decyloxirane (0.36 g,
98%) as a yellow oil, with no further purification required; mmax
(cmÀ1) 2923 (sp3 C–H), 2854 (sp3 C–H), 1466, 916, 833 (C–O–C),
idation processes, and our results are consistent with this observa-
tion.11 Reaction with 2 equiv of HOFÁMeCN, performed by halving
the addition rate of the alkene solution, resulted in an increase in
yield of approximately 50% as measured by 1H NMR. Cyclooctadiene
could be transformed into the corresponding di-epoxide upon reac-
tion with an excess of in situ generated HOFÁMeCN reagent.
In conclusion, we have demonstrated that HOFÁMeCN can be
generated and reacted immediately in situ in a continuous flow
microreactor channel for the efficient oxidation of alkenes, remov-
ing the need to analyse the resulting, relatively unstable
HOFÁMeCN solution. This methodology, therefore, demonstrates
that HOFÁMeCN could be used for a number of continuous flow oxi-
dations in microchannels, and given the potential for scale-out of
microreactor systems, which we have already demonstrated for
direct fluorination processes, the use of HOFÁMeCN could be
applied readily to larger scale synthesis.12
3
722; dH (400 MHz, CDCl3) 0.86 (3H, t, JHH 6.4, –CH2CH3), 1.24
(15H, m, –CH2–), 1.47 (3H, m, –CH2–), 2.43 (1H, m, OCH2), 2.71
(1H, m, OCH2), 2.87 (1H, m, CHO); dC (100 MHz, CDCl3) 14.0 (s,
CH3), 22.6, 25.9, 29.3, 29.4, 29.5, 29.6, 31.9, 32.4, 32.5 (all s, CH2),
47.0 (s, OCH2), 52.3 (s, OCH); m/z (EI) 184 ([M]+, 2%), 169
([MÀCH3]+ 100%); as compared to literature data.13
Acknowledgement
We thank AWE for funding.
References and notes
2. Experimental
1. Rozen, S.; Bareket, Y.; Kol, M. Tetrahedron 1993, 49, 8169–8178.
2. Rozen, S. Pure Appl. Chem. 1999, 71, 481–487.
3. Rozen, S. Eur. J. Org. Chem. 2005, 2433–2447.
4. Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors. New Technology for Modern
Chemistry; Wiley-VCH: New York, 2000.
5. Haswell, S. J.; Middleton, R. J.; O’Sullivan, B.; Skelton, V.; Watts, P.; Styring, P.
Chem. Commun. 2001, 391–398.
6. Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999, 883–884.
7. Chambers, R. D.; Holling, D.; Spink, R. C. H.; Sandford, G. Lab Chip 2001, 1, 132–
137.
8. Chambers, R. D.; Holling, D.; Sandford, G. U.K. Patent Application 0210809.0,
2002.
Typical procedure. CAUTION: Although 10% v/v fluorine in nitro-
gen is relatively easy to handle, it is still a potent oxidising agent
and must be treated as such. Appropriate precautions must also
be taken with regard to HF handling, including the provision of cal-
cium gluconate antidote gel.
Fluorine (10% in N2) was passed at an indicated rate of
20.0 ml minÀ1 (equating to 3.3 mmol hÀ1) into the microreactor
channel via one inlet, and simultaneously, MeCN/H2O (4:1,
10 ml) was added via syringe pump into a second inlet at a rate
9. Chambers, R. D.; Holling, D.; Rees, A. J.; Sandford, G. J. Fluorine Chem. 2003, 119,
81.
of 9.90 ml hÀ1 (110.0 mmol hÀ1
) while dodec-1-ene (0.34 g,
10. Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.; Sandford, G. Lab
Chip 2005, 5, 191–198.
11. Rozen, S.; Kol, M. J. Org. Chem. 1990, 55, 5155–5159.
12. Murray, C. B.; Sandford, G. U.K. Patent Application 0816170.5, 2008.
13. Kiraz, C. I.; Altinis, M. L.; Jimenez, L. S. Synthesis 2007, 1, 92–96.
2.0 mmol) (in a 1:1 mixture of CH2Cl2/MeCN, 10 mL) was added
via syringe pump into a third inlet at a rate of 9.90 ml hÀ1. After
passage through the microreactor system, all reaction fluids were
collected in
a vessel containing dilute aq NaHCO3 solution