Radical reactions are among the most fundamental in
organic synthesis,8 and the recent progress is largely due to
the use of efficient radical chain mediators such as tributyltin
hydride and the related group 14 reagents.9 In this paper we
report that typical radical chain reactions, which use tribu-
tyltin hydride and tris(trimethylsilyl)silane (TTMSS), can be
successfully carried out using microreactors in a continuous
flow system.10 Interestingly, we found that the reactions using
tin hydride and quickly decomposing radical initiators
proceed within a very short period of time, in comparison
with a conventional batch system.
2). Conventional wisdom dictated that the decomposition
timing of AIBN would prevent achievement of such a short
reaction time. This working hypothesis led us to change the
radical initiator to V-65, which decomposes more rapidly
than AIBN (Figure 1). The change of the radical initiator to
As a model reaction, we carried out a standard radical
reduction of organic halides, using tributyltin hydride as a
radical mediator. For this reaction, we used a CPC CYTOS
Lab System-M equipped with a mixer having a 100 µm
channel width and residence time unit with 4.5 mL inner
volume (Microreactor A). The results are summarized in
Table 1. When a toluene solution of 1-bromododecane (1a)
Figure 1. Ten hours half-life decomposition temperature.12
V-65 (10 mol %) worked quite well, and as a result, we
achieved a 98% yield with a 1 min residence time (entry 3).
Using a smaller amount of V-65 (2 mol %), 2a was obtained
in 92% yield along with 8% unreacted 1a (entry 5).
Subsequently, we found that the use of 2 mol % of V-70,11
which decomposes more rapidly than V-65, achieved a
complete reaction (entry 6). For comparison, we checked
the batch reaction; the reaction of a 5 mL solution of 1a
(0.05 M) with 2 mol % of V-65 using a test tube (15 mm
i.d.) for 1 min resulted in a lower conversion (2a: 69%; 1a:
31%). We assume that higher thermal efficiency inherent to
tiny reaction channels would ensure efficient reaction in the
microreactors.
Table 1. Microflow Radical Reaction of 1-Bromododecane
with Tributyltin Hydridea
concn,
M
residence
time, min
yield of
2a (1a),c %
entry
radical initiator
To study the generality of the high-speed radical reaction
using Microreactor A, we examined the reduction of a variety
of organic bromides and iodides (Table 2). In most cases,
V-70 was used for radical reactions of organic bromides and
iodides, which were complete in 1 min. Aryl radical
cyclization starting from 1g also worked satisfactorily (entry
10). We also tested two other types of microreactors: a
microreactor system with a larger volume residence time unit
(Microreactor B: CYTOS Lab System-L, 100 µm channel
width, inner volume 15 mL) and a microreactor system with
a different micromixer (Microreactor C: MiChS-R mixer
with 200 µm channel size connected with a stainless-steel
tube reactor (1000 µm i.d. × 1 m)), both of which worked
well (entries 2, 5, 6, and 7).
1
2
3
4
5
6
AIBN, 10 mol %
AIBN, 10 mol %
V-65, 10 mol %
V-65, 5 mol %
V-65, 2 mol %
V-70, 2 mol %
0.05
0.05
0.05
0.05
0.05
0.05
8.5
1.0
1.0
1.0
1.0
1.0
96% (4%)
74% (25%)
98% (2%)
94% (4%)
92% (8%)
98% (trace)
a Flow rate: 0.27 mL/min each for entry 1 and 2.3 mL/min each for
entries 2-6. For details, see the Supporting Information. b CYTOS Lab
System-M (micromixer: 100 µm channel width; residence time unit: 4.5
mL inner volume). c GC yield with n-decane as an internal standard.
was mixed with a toluene solution of tributyltin hydride (1.2
equiv) and AIBN (10 mol %) ([RBr] ) 0.05 M, on mixing)
at 80 °C with a residence time of 8.5 min (flow rate: 0.27
mL/min), the reaction was almost complete, and a 96% yield
of n-dodecane (2a), the expected reduced product, was
obtained (entry 1). When the radical reaction of 1a with
tributyltin hydride and AIBN was carried out using a
shortened residence time, such as 1 min, the reaction resulted
in a 74% yield of 2a with the recovery of 25% of 1a (entry
Encouraged by successful execution of typical radical
reduction and cyclization of organic bromides and iodides
using microreactors, we then studied the radical reaction of
alkyl chlorides 1i and 1j, which are known to be less efficient
(11) (a) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. Tetrahedron Lett. 1997, 38, 3549. (b) Kita, Y.; Gotanda, K.;
Sano, A.; Oka, M.; Murata, K.; Suemura, M.; Matsugi, M. Tetrahedron
Lett. 1997, 38, 8345.
(7) Sugimoto, A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I.
Tetrahedron Lett. 2006, 47, 6197.
(8) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2001; Vols. 1 and 2.
(9) Chatgilialoglu, C. Organosilanes in Radical Chemistry; John Wiley
& Sons Ltd.: Chichester, UK, 2004.
(10) For radical polymerization using a microflow system, see: (a)
Iwasaki, T.; Yoshida, J. Macromolecules 2005, 38, 1159. (b) Iwasaki, T.;
Kawano, N.; Yoshida, J. Org. Process Res. DeV. 2006, 10, 1126.
(12) Taken from Azo Polymerization Initiators (third edition), which is
available from Wako Pure Chemical Industries, Ltd. For reviews on radical
initiators, see: (a) Kita, Y.; Matsugi, M. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001;
Vol. 1, pp 1-10. (b) Moad, G.; Solomon, D. H. The Chemistry of Free
Radical Polimerization; Pergamon: Oxford, UK, 1995; pp 43-144. (c)
Sheppard, C. S.; Kamath, V. R. Polym. Eng. Sci. 1979, 19, 597.
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Org. Lett., Vol. 10, No. 4, 2008