From conventional to microphotochemistry: Photodecarboxylation reactions involving phthalimides

Article abstract of DOI:10.1021/ol102184u

A series of acetone-sensitized photodecarboxylation reactions involving phthalimides have been investigated using conventional and microphotochemistry. Both, intra- and intermolecular transformations were compared. In all cases examined, the reactions performed in microreactors were superior in terms of conversions or isolated yields. These findings unambiguously prove the advantage of microphotochemistry over conventional photochemical techniques.

Full text of DOI:10.1021/ol102184u

ORGANIC
LETTERS
2
010
Vol. 12, No. 22
170-5173
From Conventional to Microphotochemistry:
Photodecarboxylation Reactions Involving
Phthalimides
5
†
†
†
,‡
Oksana Shvydkiv, Sonia Gallagher, Kieran Nolan, and Michael Oelgem o¨ ller*
Dublin City UniVersity, School of Chemical Sciences, Dublin 9, Ireland, and James
Cook UniVersity, School of Pharmacy and Molecular Sciences, TownsVille,
Queensland 4811, Australia
michael.oelgemoeller@jcu.edu.au
Received September 12, 2010
ABSTRACT
A series of acetone-sensitized photodecarboxylation reactions involving phthalimides have been investigated using conventional and
microphotochemistry. Both, intra- and intermolecular transformations were compared. In all cases examined, the reactions performed in
microreactors were superior in terms of conversions or isolated yields. These findings unambiguously prove the advantage of
microphotochemistry over conventional photochemical techniques.
3
4
Recently, microprocess engineering has revolutionized the
chemical process industry, and a number of synthetic transfor-
mations have been realized on micro- to pilot production scales.
ized scale allows online UV- or IR-monitoring; and (e)
microreactors can be operated in series or in parallel clusters
1
5
for scale-up or optimization studies.
The small size of these devices, in combination with favorable
heat and mass transport, makes them especially beneficial for
To evaluate the efficiency of microphotochemistry in
comparison to conventional laboratory photochemistry, we
have chosen five acetone-sensitized photodecarboxylation
(PDC) reactions of phthalimides as model systems. In
conventional reactors, the selected PDC reactions show high
1h
modern R&D processes. Likewise, microphotochemistry, i.e.,
photochemistry in microstructured reactors, has emerged as a
2
new photochemical synthesis tool. Microphotoreactors have a
6
number of advantages over conventional batch photoreactors.
quantum yields of up to 60%. The photochemistry of
(
a) The thin layers within the microchannel plates allow
phthalimides has been studied in detail over the last decades
and is thus well understood. Semitechnical scale reactions
7
extensive penetration of the solution by light; (b) the short
residence time within the reactors (flow-through) avoids un-
desired side reactions or decompositions; (c) the small scales
of selected transformations using a 308 nm excimer light
8
source have also been reported.
1d
reduce the amounts of waste and materials; (d) the miniatur-
All microreactions were studied in a commercially avail-
able reactor (dwell device, mikroglas) which was placed
under a UV panel (Luzchem) fitted with 5 UVB lamps
†
Dublin City University.
James Cook University.
‡
9
(
1) (a) Hartman, R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495. (b)
(Figure 1). The dwell reactor is made out of Foturan glass
Fukuyama, T.; Rahman, Md. T.; Sato, M.; Ryu, I. Synlett 2008, 151. (c)
Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5,
7
and has a total path length of 1.15 m (20 turns) on a 118
33. (d) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
McQuade, D. T. Chem. ReV. 2007, 107, 2300. (e) Watts, P.; Wiles, C. Chem.
(3) Lu, H.; Schmidt, M. A.; Jensen, K. F. Lab Chip 2001, 1, 22.
(4) Bentrup, U.; K u¨ pper, L.; Budde, U.; Lovis, K.; J a¨ hnisch, K. Chem.
Eng. Technol. 2006, 29, 1216.
Commun. 2007, 443. (f) Watts, P.; Wiles, C. Org. Biomol. Chem. 2007, 5,
7
27. (g) Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Chem.sEur. J. 2006,
12, 8434. (h) Rubin, A. E.; Tummala, S.; Both, D. A.; Wang, C. C.; Delaney,
(5) For examples of successful scale-ups, see: (a) Sugimoto, A.;
Fukuyama, T.; Sumino, Y.; Takagi, M.; Ryu, I. Tetrahedron 2009, 65, 1593.
(b) Werner, S.; Seliger, R.; Rauter, H.; Wissmann, F. EP-2065387A2, 2009.
(6) (a) Griesbeck, A. G.; Kramer, W.; Oelgem o¨ ller, M. Synlett 1999,
1169. (b) Kramer, W.; Griesbeck, A. G.; Nerowski, F.; Oelgem o¨ ller, M.
J. Inf. Rec. 1998, 24, 81.
E. J. Chem. ReV. 2006, 106, 2794. (i) J a¨ hnisch, K.; Hessel, V.; L o¨ we, H.;
Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406.
(
2) (a) Coyle, E. E.; Oelgem o¨ ller, M. Photochem. Photobiol. Sci. 2008,
7
, 1313. (b) Matsushita, Y.; Ichimura, T.; Ohba, N.; Kumada, S.; Sakeda,
K.; Suzuki, T.; Tanibata, H.; Murata, T. Pure Appl. Chem. 2007, 79, 1959.
1
0.1021/ol102184u  2010 American Chemical Society
Published on Web 10/14/2010

of the UVB lamps. Despite the relatively poor overlap of the
spectra, it should be noted that acetone functions as a sensitizer
10
as well as a cosolvent. Hence, it is available in large excess
amounts (cacetone ) 6.8 M).
The light penetration profile was calculated from the
adsorption spectra and the experimental conditions (Figure
11
3
). As indicated by vertical lines, the narrow microchannel
Figure 1. Experimental setup: microreactor (dwell device, mikro-
glas) under a UV exposure panel (Luzchem).
mm × 73 mm aperture. The reactor consisted of a (bottom)
serpentine reaction channel 0.5 × 2 mm (D × W) with an
internal volume of 1.68 mL, with a second (top), heat-
exchanging channel through which water is passed to control
the reactor temperature. The reaction mixture was pumped
through the reaction channel via a programmable syringe
pump and collected in a flask outside the irradiated area.
The results obtained with the dwell device were compared
to similar experiments in a conventional Rayonet chamber
reactor (RPR-200) equipped with either 16 or 5 UVB lamps.
The latter lamp arrangement allowed a direct comparison with
the chosen microreactor setup in terms of light power. A
Figure 3
. Light penetration profile for a 6.8 M acetone solution at
3
00 nm. The vertical broken line (a) represents the path length in
the dwell device and the dotted line (b) the effective path length in
the Schlenk flask.
9
standard Pyrex Schlenk flask (32 mm inner ø) equipped with
a coldfinger (24 mm ø) was used as the reaction vessel. Due to
the circular arrangement of the lamps around the flask, the
effective path length through the solution was thus 4 mm. A
maximum irradiation time of 1 h was set for this comparison
study.
(
0.5 mm) allows complete penetration of light at 300 nm. In
contrast, total adsorption is achieved within the Schlenk
vessel after ca. 1.5 mm, way below its effective path length
of 4 mm.
The R-photodecarboxylation (-CO H/-H exchange) of
2
phthaloyl amino acids was initially chosen as the model reaction.
This transformation has been developed as an efficient access
12
to R-deuterated primary amines. The reaction protocol was
applied to microphotochemistry using the irradiation of phtha-
loyl glycine 1 in dry acetone as an example (Scheme 1). The
effect of residence time on the conversion of the decarboxylation
(after a single run) was examined by alteration of the flow rate
(Table 1). As would be expected, conversion rates improved
for both reactor types with increasing reaction times, but the
microreactor gave better results overall. For example, N-
methylphthalimide 2 was obtained in 92% yield next to 8% of
unreacted starting material (1) after a residence time of 60 min.
Figure 2. UV spectra of acetone (in water) vs lamp power. The
(
8) (a) Sosnin, E. A.; Oppenl a¨ nder, T.; Tarasenko, V. F. J. Photochem.
broken vertical line represents the cutoff wavelength of Pyrex and
9
Photobiol. C: Photochem. ReV. 2006, 7, 145. (b) Griesbeck, A. G.; Maptue,
N.; Bondock, S.; Oelgem o¨ ller, M. Photochem. Photobiol. Sci. 2003, 2, 450.
Foturan glass at 300 nm.
(
2
c) Griesbeck, A. G.; Kramer, W.; Oelgem o¨ ller, M. Green Chem. 1999, 1,
05.
9) The transmission of both Foturane and Pyrex is approximately 30%
(
Figure 2 shows the adsorption spectrum of an acetone/water
mixture (1:1 vol %) in comparison with the emission spectrum
at 300 nm. The chosen Pyrex and Foturan glass prevents photodecompo-
sition, which is commonly observed for reactions in Quartz vessels.
7
(10) Direct excitation of phthalimide is also possible. Acetone sensitiza-
tion is, however, known to give higher selectivities. See, for example:
Griesbeck, A. G. Chimia 1998, 52, 272.
(
7) (a) McDermott, G.; Yoo, D. J.; Oelgem o¨ ller, M. Heterocycles 2005,
6
5, 2221. (b) Oelgem o¨ ller, M.; Griesbeck, A. G. CRC Handbook of Organic
(11) Braun, A. M.; Maurette, M.; Oliveros, E. Photochemical Technol-
ogy, Wiley: Chichester, 1991.
Photochemistry and Photobiology, 2nd ed.; Horspool, W. M.; Lenci, F.;
Eds.; CRC Press: Boca Raton, 2004,Ch. 84, p. 1. (c) Oelgem o¨ ller, M.;
Griesbeck, A. G. J. Photochem. Photobiol. C: Photochem. ReV. 2002, 3,
(12) (a) Oelgem o¨ ller, M.; Griesbeck, A. G.; Lex, J.; Haeuseler, A.;
Schmittel, M.; Niki, M.; Hesek, D.; Inoue, Y. Org. Lett. 2001, 3, 1593. (b)
Takahashi, Y.; Miyashi, T.; Yoon, U. C.; Oh, S. W.; Mancheno, M.; Su,
Z.; Falvey, D. F.; Mariano, P. S. J. Am. Chem. Soc. 1999, 121, 3926. (c)
Griesbeck, A. G.; Henz, A. Synlett 1994, 931. (d) Sato, Y.; Nakai, H.;
Mizoguchi, T.; Kawanishi, M.; Hatanaka, Y.; Kanaoka, Y. Chem. Pharm.
Bull. 1982, 30, 1262.
1
09. (d) Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 2001, 34, 523. (e)
Bartoschek, A.; Griesbeck, A. G.; Oelgem o¨ ller, M. J. Inf. Rec. 2000, 26,
19. (f) Coyle, J. D. Synthetic Organic Photochemistry; Horspool, W. M.,
1
Ed.; Plenum Press: New York, 1984; p 259. (g) Mazzocchi, P. H. Org.
Photochem. 1981, 5, 421.
Org. Lett., Vol. 12, No. 22, 2010
5171

photodecarboxylations, and the transformation of potassium
phthalimidomethylsulfanyl acetate 4 to the thiazolidine
derivative 6 was thus examined (Scheme 2). Following the
Scheme 1
.
R-Photodecarboxylation of Phthaloyl Glycine 1
14
general trend, the dwell device gave higher yields than the
Rayonet reactor (Table 2). After exposure for 60 min, the
isolated yields of 6 were 80% under flow-through (microre-
actor) and 72% (16 lamps) or 21% (5 lamps), respectively,
under batch conditions (Rayonet).
Photodecarboxylative additions of carboxylates to phthalim-
ides have been recently established as efficient alternatives to
15
Grignard additions. These versatile reactions use stable and
easily available carboxylates as alkylating agents. The photo-
decarboxylative benzylation of N-methylphthalimide 2 with
Table 1. Experimental Details of R-Decarboxylation of 1
a
conversion to 2 (%)
flow rate (mL/min) residence time (min) µ-reactor Rayonet
15d
phenylacetate 7 is known to proceed rapidly (Scheme 3).
0
0
0
0
0
.5
3.4
11
21
40
60
5
23
44
74
92
2
7
.15
.08
.042
.028
19
39
b
Scheme 3. Photodecarboxylative Additions Involving 2
59 (22 )
a
1
b
Determined by H NMR spectroscopy. With 5 UVB lamps.
In contrast, the larger Rayonet reactor gave lower conversions
of just 59% (16 lamps) and 22% (5 lamps), respectively, after
the same irradiation time.
Likewise, the photodecarboxylative cyclization of the
potassium salt of phthaloyl-γ-aminobutyric acid 3 to the
polycyclic product 5 was investigated (Scheme 2; Table 2).
When studied in the dwell device, the corresponding addition
product 9 was obtained in 83% and 97% after just 14 and 21
min, respectively, whereas complete conversion was obtained
after 40 min (Table 3). While the larger Rayonet chamber
13
Scheme 2. Photodecarboxylative Cyclizations of 3 and 4
Table 3. Experimental Details of PDC Addition of 7 and 8
residence
time
a
a
flow rate
conversion to 9 (%) conversion to 10 (%)
µ-reactor Rayonet µ-reactor Rayonet
(
mL/min) (min)
0
0
0
0
.12
14
21
40
60
83
97
46
93
4
34
2
20
44
.08
.042
.028
100
100
100
66
b
b
100 (29 )
100
86 (17 )
Table 2. Experimental Details of PDC-Cyclizations of 3 and 4
a
1
b
Determined by H NMR spectroscopy. With 5 UVB lamps.
a
a
flow rate residence time
yield of 5 (%)
µ-reactor Rayonet µ-reactor Rayonet
yield of 6 (%)
(
mL/min)
(min)
0
0
0
.08
21
40
60
b
33
69
77
46
53
39
70
80
36
59
reactor achieved complete conversion after 40 min as well, it
gave lower yields after shorter reaction times, in particular after
.042
.028
b
b
69 (19 )
72 (21 )
a
Isolated yields. With 5 UVB lamps.
(
14) (a) G o¨ rner, H.; Oelgem o¨ ller, M.; Griesbeck, A. G. J. Phys. Chem.
A 2002, 106, 1458. (b) Griesbeck, A. G.; Oelgem o¨ ller, M.; Lex, J.;
Haeuseler, A.; Schmittel, M. Eur. J. Org. Chem. 2001, 1831. (c) Yoon,
U. C.; Lee, C. W.; Oh, S. W.; Kim, H. J.; Lee, S. J. J. Photosci. 2000, 7,
Using the microreactor, 5 was isolated in a yield of 77%
after 60 min of irradiation. After an identical irradiation time,
the yields were again lower with 69% (16 lamps) and 19%
1
43. (d) Peters, K.; Peters, E.-M.; Griesbeck, A. G.; Oelgem o¨ ller, M. Z.
Kristallogr. - New Cryst. Struct. 1998, 213, 757.
(15) (a) Belluau, V.; Noeureuil, P.; Ratzke, E.; Skvortsov, A.; Gallagher,
S.; Motti, C. A.; Oelgem o¨ ller, M. Tetrahedron Lett. 2010, 51, 4738. (b)
Gallagher, S.; Hatoum, F.; Zientek, N.; Oelgem o¨ ller, M. Tetrahedron Lett.
2010, 51, 3639. (c) Hatoum, F.; Gallagher, S.; Oelgem o¨ ller, M. Tetrahedron
Lett. 2009, 50, 6593. (d) Hatoum, F.; Gallagher, S.; Baragwanath, L.; Lex,
J.; Oelgem o¨ ller, M. Tetrahedron Lett. 2009, 50, 6335. (e) Oelgem o¨ ller, M.;
Cygon, P.; Lex, J.; Griesbeck, A. G. Heterocycles 2003, 59, 669. (f)
Griesbeck, A. G.; Oelgem o¨ ller, M.; Lex, J. Synlett 2000, 1455. (g) Griesbeck,
A. G.; Oelgem o¨ ller, M. Synlett 2000, 71. (h) Griesbeck, A. G.; Oelgem o¨ ller,
M. Synlett 1999, 492. (i) Tan, S. B.; Shvydiv, O.; Fiedler, J.; Hatoum, F.;
Nolan, K.; Oelgem o¨ ller, M. Synlett 2010, 2240.
(5 lamps), respectively, in the Rayonet reactor. Sulfur atoms
in R-position to a carboxylate group are known to accelerate
(
13) (a) Griesbeck, A. G.; Heinrich, T.; Oelgem o¨ ller, M.; Molis, A.;
Lex, J. J. Am. Chem. Soc. 2002, 124, 10972. (b) Oelgem o¨ ller, M.; Griesbeck,
A. G.; Kramer, W.; Nerowski, F. J. Inf. Rec. 1998, 24, 87. (c) Griesbeck,
A. G.; Henz, A.; Kramer, W.; Lex, J.; Nerowski, F.; Oelgem o¨ ller, M.; Peters,
K.; Peters, E.-M. HelV. Chim. Acta 1997, 80, 912.
5172
Org. Lett., Vol. 12, No. 22, 2010

14 min. Furthermore, the yield dropped significantly to 29%
when irradiation was performed for 1 h with only 5 UVB lamps.
Likewise, the addition of potassium 2-(methylthio)acetate 8 to
14b,15g
2
was investigated.
In the microreactor, quantitative
conversion to 10 was accomplished after 60 min of irradia-
tion. The Rayonet reactor again performed worth and gave
conversions of 86% (16 lamps) and 17% (5 lamps) after the
same reaction time.
The photobenzylation of 2 with 7 was selected to study the
effect of the concentration on the efficiency of the addition
(
Table 4). To achieve this, the photoreaction was performed in
10
acetonitrile, i.e., under conditions of direct excitation of 2.
Figure 4. Space-time yields for all five acetone-sensitized pho-
todecarboxylation reactions (microreactor and Rayonet with 16
lamps, 21 min; Rayonet with 5 lamps, 60 min).
Table 4. Concentration Study for PDC Addition of 7 in MeCN
a
concentrations (mmol/L)
conversion to 9 (%)
2
7
µ-reactor
Rayonet
1
5
0
0
0
45
90
100
100
64
100
93
3
6
9
microreactions make them advantageous for pharmaceutical
research, where only small amounts of materials are required,
180
270
53
45
38
17
a
1
Determined by H NMR spectroscopy.
e.g., in biological screening. Due to the limited amounts of
chemicals and solvents consumed, microphotochemistry also
18,19
falls within the emerging area of Green Photochemistry.
It
The reaction time was furthermore set to 1 h, while the
concentrations of 2 and 7 were increased systematically. The
dwell device gave complete consumptions of 2 at concentra-
tions of 15 and 30 mmol/L, respectively. In contrast, the
batch reaction only showed total conversion at 15 mmol/L.
At higher concentrations of 2, the yields dropped gradually.
In all cases examined, the reactions performed in the
microreactor gave higher conversions or yields. This superiority
can be explained by the larger surface to volume ratio of the
dwell device in combination with the better light penetration
within the microreactor. These factors ultimately result in higher
space-time yields (STYs) for all five acetone-sensitized pho-
todecarboxylations (Figure 4). STYs depended on the reactor
geometry and were calculated for reactions with incomplete
is hoped that this technology will be rapidly adopted by the
chemical and pharmaceutical community.
5
b,20
Acknowledgment. This work was financially supported
by Science Foundation Ireland (SFI, 07/RFP/CHEF817), the
Environmental Protection Agency (EPA, 2008-ET-MS-2-S2),
and the Department of Environment, Heritage and Local
Government (DEHLG, 2008-S-ET-2). We also thank Dr.
Thomas Dietrich, Dr. Andreas Freitag (both Mikroglas
Chemtech), and Dr. J. C. Scaiano (Luzchem) for technical
advice and support.
Supporting Information Available: Experimental pro-
cedures and NMR spectra of all photoproducts. This material
is available free of charge via the Internet at http://pubs.acs.org.
16
conversions using the following equation
OL102184U
STY ) n/(V × t)
R
n ) amount of phthalimide converted
R
(17) Chin, P.; Barney, W. S.; Pindzola, B. A. Curr. Opin. Drug
DiscoVery DeV. 2009, 12, 848.
V ) reactor volume
(
18) (a) Lerou, J. J.; Tonkovich, A. L.; Silva, L.; Perry, S.; McDaniel,
t ) irradiation time
J. Chem. Eng. Sci. 2010, 65, 380. (b) Hessel, V.; Kralisch, D.; Krtschil, U.
Energy EnViron. Sci. 2008, 1, 467. (c) Kralisch, D.; Kreisel, G. Chem. Eng.
Sci. 2007, 62, 1094. (d) Haswell, S. J.; Watts, P. Green Chem. 2003, 5,
From direct comparison between the reactors, it is apparent
that the STYs are considerably higher in the microreactor
than in the Rayonet setup. Of all transformations studied,
the photobenzylation to 9 furnished the highest STY.
In conclusion, we have demonstrated that the chosen pho-
tochemical transformations of phthalimides proceed more
efficiently in a commercially available microreactor than in a
conventional Rayonet chamber reactor. The small scales of the
240
(
.
19) For further examples of “Green Photochemistry”, see: (a) Albini,
A.; Fagnoni, M. Green Chemical Reactions (NATO Science for Peace and
Security Series, Series C: EnVironmental Security); Tundo, P., Esposito,
V., Eds.; Springer: Dordrecht, 2008; pp 173. (b) Hoffmann, N. Pure Appl.
Chem. 2007, 79, 1949. (c) Oelgem o¨ ller, M.; Jung, C.; Mattay, J. Pure Appl.
Chem. 2007, 79, 1939. (d) Mattay, J. Chem. Unserer Zeit 2002, 36, 98
.
(20) (a) For a recently developed photochemical microreactor by Abbott
Laboratories, see: Vasudevan, A.; Villamil, C.; Trumball, J.; Olson, J.;
Sutherland, D.; Pan, J.; Djuric, S. Tetrahedron Lett. 2010, 51, 4007. (b)
For a recently described UV-LED microchip, see: Shvydkiv, O.; Yavorskyy,
A.; Nolan, K.; Youssef, A.; Riguet, E.; Hoffmann, N.; Oelgem o¨ ller, M.
Photochem. Photobiol. Sci. 2010, DOI: 10.1039/c0pp00223b.
(
16) Meyer, S.; Tietze, D.; Rau, S.; Sch a¨ fer, B.; Kreisel, G. J. Photochem.
Photobiol. A: Chem. 2007, 186, 248.
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5173