C. Wiles et al. / Tetrahedron Letters 48 (2007) 7362–7365
7363
O
In pursuit of an atom efficient technique for the protec-
tion of carbonyl moieties, we investigated the continu-
ous flow synthesis of 1,3-dithianes and 1,3-dithiolanes,
proposing that careful optimization of the reaction
conditions would allow the synthesis and isolation of
analytically pure products, by simply removing the reac-
tion solvent.
H
S
S
H
3
Flow
2
A-15 1
B
A
HS
SH
4
Figure 2. Schematic illustrating the continuous flow synthesis of 2-
phenyl-1,3-dithiane 2.
To manipulate reactants and products within the flow
reactor, the pumping mechanism selected was electroos-
motic flow (EOF) as compared to pressure-driven (PD)
flow, EOF generates minimal back-pressure; a particu-
larly important feature for packed-bed reactors. EOF
therefore enables reaction systems to be scaled without
being limited by the reactor’s pressure tolerance, a
frequently encountered problem in PD systems. The
technique also enables precise control over flow rate,
as it is not limited by an incremental stepper motor, thus
affording pulse-free flow. In addition, the absence of
mechanical pump drivers reduces the footprint of the
set-up, which simply consists of a power supply. Again,
automation of the system enables remote operation of
the reactors, reducing greatly the amount of valuable
fume cupboard space required to perform such reac-
tions. While EOF has predominantly been employed
as a pumping mechanism within miniaturized reaction
systems for the manipulation of nl quantities of mate-
rial,12 we recently reported its use within a flow reactor
of millimeter dimensions, enabling access to flow rates in
Figure 3. Gas chromatograms illustrating the difference between an
optimized and an unoptimized system for the synthesis of 2-phenyl-
1,3-dithiane 2, under continuous flow.
the range of 0.1–500.0 ll minÀ1
.
13
As Figure 1 illustrates, the reaction set-up employed
herein consists of a borosilicate glass capillary (3.0 mm
(i.d.) · 30.0 mm (length)), packed with A-15 1 (0.055 g,
0.231 mmol) attached to borosilicate glass reagent reser-
voirs via two rubber septa (No. 9, Suba Seal). To per-
sis by GC–MS whereby the percentage conversion of
carbonyl compound to product is determined. Once
optimized (Fig. 3), the reactor is operated continuously
for 1 h, after which the reaction products are removed
from reservoir B, concentrated in vacuo and the crude
product dissolved in CDCl3 prior to additional purity
evaluation by NMR spectroscopy.
form
a reaction, the packed-bed is filled with
anhydrous MeCN (to form a complete electrical circuit)
and a solution containing the reactants is then placed in
reservoir A along with an aliquot of solvent in reservoir
B. Platinum electrodes (0.5 mm (o.d.) · 2.5 cm (length))
are placed in each reservoir and the reaction mixture
pumped through the packed-bed by application of a
positive voltage (50–200 V cmÀ1) to reservoir A; the
reaction products are subsequently collected in reservoir
B (0 V cmÀ1) (Fig. 2). Unless otherwise stated optimiza-
tion reactions are performed for 10 min, prior to analy-
Using the set-up illustrated in Figures 1 and 2, the reac-
tor’s performance was assessed using the synthesis of 2-
phenyl-1,3-dithiane 2 as a model reaction. Employing an
applied field of 200 V cmÀ1, a pre-mixed solution of
benzaldehyde 3 and 1,3-propanedithiol 4 (1.0 M, 1:1 in
MeCN) was pumped through the packed-bed at a flow
rate of 63.7 ll minÀ1 (residence time = 75.4 s) and the
reaction products evaluated every 10 min, off-line by
GC–MS (Fig. 3). Typical reaction data from the optimi-
zation process afforded quantitative conversion of benz-
aldehyde 3 to 2-phenyl-1,3-dithiane 2 (99.992%). In
A (+)
B ( )
addition, the reaction reproducibility (5.0 · 10À3
%
Reagent
Reservoir
Suba Seals
(No. 9)
RSD) obtained over 2.5 h confirms effective recycle of
the acid catalyst, generating 9.42 mmol of product 2
with 0.231 mmol of catalyst; representing a turnover of
41 times, so far.
Pt Electrode
(2.5 cm x 0.5 mm)
Having established the ability to perform a model thio-
acetalization under continuous flow conditions, the
next step was to evaluate the generality of the tech-
nique, firstly investigating the protection of an array of
substituted aldehydes as the respective 1,3-dithiane. As
Borosilicate Glass Capillary
(3 mm x 30 mm)
Figure 1. Schematic illustrating the reaction set-up used for the
continuous flow synthesis of 1,3-dithianes and 1,3-dithiolanes.