mode.13 Particularly noteworthy among these benefits is
the potential of continuous flow reactors to overcome
the traditional drawbacks of photochemistry.14 We thus
anticipated that the intermolecular trifluoroethylation reac-
tion might be significantly accelerated due to the enhanced
light penetration in the small channels of a flow reactor.
We decided to examine the photocatalytic addition
of trifluoroethyl iodide to styrenes in continuous mode
employing the setup depicted in Figure 1.
Table 2. Scope of the Trifluoroethylation
entry
product
yielda
1
6a: p-tert-Bu-C6H4-
6b: p-MeO-C6H4-
6c: p-AcO-C6H4
6d: p-(CbzNH)-C6H4
6e: p-Me2N-C6H4
6f: p-MeO2C-C6H4
6g: p-OHC-C6H4
6h: 2-Naphthyl
6i: p-HOCH2-C6H4
6j: p-MeS-C6H4
6k: 2-pyr-
83%b
76%
2
3
68%
4
65%b
74%
5
6
68%
7
73%b
56%b
53%b
59%b,c
64%
8
9
10
11
12
13
6l: Ar, R0 = Ph
6m: Ar, R0 = p-Br-Ph
51%
56%
a Yield of the isolated product. b Reaction run in a 1:1 MeCN/DMSO
mixture. c Product contaminated with 10% starting material according
to 1H NMR analysis.
Figure 1. Flow photoreactor setup. The small insert shows the
LED array used as a light source consisting of 48 high-power
LEDs (λmax = 465 nm) mounted on a water-cooled copper
block for efficient heat dissipation.
Photochemical reactions conducted with standard la-
boratory batch equipment can have several shortcomings.
Most notably, the reactive irradiation volume is limited as
light penetration through a medium decreases exponen-
tially with increasing path length (BeerꢀLambert law).
Consequently, photochemical reactions in batch mode
occur most efficiently in the vessel region nearest the light
source. This aspect can limit the application of photo-
chemical processes in preparative chemical synthesis.
In recent years, flow chemistry has received considerable
attention because of its advantages compared to batch
The self-made flow reactor photobox consists of a
single-channel syringe pump, a water-cooled array of 48
high-power light-emitting diodes (LEDs), and a mesoscale
glass microreactor with integrated tempering.15 The LED
assembly has a total radiant flux of approximately 37 W
and is placed 5 mm above the glass chip. These two
components are encased in a protective box lined with
silver glass mirrors for optimal reflectivity.
(13) For recent reviews on microreactors and flow chemistry, see: (a)
Yoshida, J.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4, 331. (b) Wiles,
C.; Watts, P. Chem. Commun. 2011, 47, 6512. (c) Wegner, J.; Ceylan, S.;
Kirschning, A. Chem. Commun. 2011, 47, 4583. (d) Webb, D.; Jamison,
T. F. Chem. Sci. 2010, 1, 675. For an essay on the merits of homogeneous
reactions in continuous flow reactors, see: (e) Valera, F. E.; Quaranta,
M.; Moran, A.; Blacker, J.; Armstrong, A.; Cabral, J. T.; Blackmond,
D. G. Angew. Chem., Int. Ed. 2010, 49, 2478. (f) Kopach, M. E.; Murray,
M. M.; Braden, T. M.; Kobierski, M. E.; Williams, O. L. Org. Process
Res. Dev. 2009, 13, 152–160. For two recent examples of the use of flow
reactors in chemical synthesis involving hazardous chemicals, see: (g)
Gutmann, B.; Roduit, J.-P.; Roberge, D.; Kappe, C. O. Angew. Chem.,
Int. Ed. 2010, 49, 7101–7105. (h) Palde, P. B.; Jamison, T. F. Angew.
Chem., Int. Ed. 2011, 50, 3525–3528.
In an initial experiment, irradiation of a solution of
p-methoxy-styrene in the flow reactor with residence time
tR = 30 min (flow rate = 0.267 mL minꢀ1) led to 65%
conversion, and the product was isolated in 47% yield
(66% brsm, Figure 2). Several reaction parameters were
varied, including residence time, light intensity, and con-
centration, as well as catalyst loading and the amount
of 1. However, conversions >65% could not be achieved,
leading to the recovery of starting material along with the
desired product in all cases. Significantly, a salient feature
of the flow experiments is that they required residence
times of only 30 min as compared to a reaction time of 24 h
in batch mode, illustrating the significant acceleration
enabled by the photobox system.
(14) For a review on recent advances in microflow photochemistry,
€
see: (a) Oelgemoller, M.; Shvydkiv, O. Molecules 2011, 16, 7522. For
selected recent examples of photochemical reactions run in continuous
flow mode, see: (b) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson,
C. R. J. Angew. Chem., Int. Ed. 2012, 51, 4144. (c) Nettekoven, M.;
€
Pullmann, B.; Martin, R. E.; Wechsler, D. Tetrahedron Lett. 2012, 53,
1363. (d) Shen, B.; Bedore, M. W.; Sniady, A.; Jamison, T. F. Chem.
Commun. 2012, 48, 7444. (e) Bou-Hamdan, F. R.; Seeberger, P. H. Chem.
Sci. 2012, 3, 1612. (f) Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi,
M.; Ryu, I. Tetrahedron 2009, 65, 1593. (g) Neumann, M.; Zeitler, K. Org.
Encouraged by these promising results, we decided
to revisit the intramolecular cobalt-catalyzed alkyl-Heck
cyclizations previously reported10 (Table 3). To our de-
light, the cyclizations were as efficient in flow as in
batch mode and nearly identical isolated yields were
ꢀ
Lett. 2012, 14, 2658. (h) Andrews, R. S.; Becker, J. J.; Gagne, M. R.
Angew. Chem., Int. Ed. 2012, 51, 4140. For a recent book chapter on
€
microphotochemistry, see: (i) Shvydkiv, O.; Oelgemoller, M. In CRC
Handbook of Organic Photochemistry and Photobiology, 3rd ed., Vol. 1;
€
Griesbeck, A., Oelgemoller, M., Ghetti, F., Eds.; CRC Press: 2012;
pp 49ꢀ72.
(15) See the Supporting Information for more details.
Org. Lett., Vol. XX, No. XX, XXXX
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