Photodecarboxylative benzylations of phthalimides

Article abstract of DOI:10.1016/j.tetlet.2009.08.115

Photoadditions of phenylacetates to phthalimides give the corresponding benzylated hydroxyphthalimidines in moderate to high yields of 29-90%. With 2-phenylpropanoate, photoaddition affords a diastereoisomeric mixture in a de of 24% in favour of the like-diastereoisomer. l-3-Phenyl lactate and 2-oxo-3-phenylpropanoate both furnish the benzylated product through subsequent loss of formaldehyde and decarbonylation, respectively.

Full text of DOI:10.1016/j.tetlet.2009.08.115

Tetrahedron Letters 50 (2009) 6335–6338
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photodecarboxylative benzylations of phthalimides
Fadi Hatoum a, Sonia Gallagher a, Louise Baragwanath a, Johann Lex b, Michael Oelgemöller a,c,
*
a Dublin City University, School of Chemical Sciences, Glasnevin, Dublin 9, Ireland
b Universität zu Köln, Institut für Organische Chemie, Greinstrasse 4, D-50939 Köln, Germany
c James Cook University, School of Pharmacy and Molecular Sciences, Townsville, Queensland 4811, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2009
Revised 6 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Photoadditions of phenylacetates to phthalimides give the corresponding benzylated hydroxyphthalim-
idines in moderate to high yields of 29–90%. With 2-phenylpropanoate, photoaddition affords a
diastereoisomeric mixture in a de of 24% in favour of the like-diastereoisomer. L-3-Phenyl lactate and
2-oxo-3-phenylpropanoate both furnish the benzylated product through subsequent loss of formalde-
hyde and decarbonylation, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Photodecarboxylation
Benzylation
Phthalimides
Photochemistry
Photoinduced electron transfer
Due to their favourable photophysical and electrochemical
properties, phthalimides are superior substrates for photoinduced
electron transfer reactions.1 As an example, the photodecarboxyla-
that is, non-volatile toluene derivatives, were detected in small
amounts (<5%) in the crude 1H NMR spectra but no attempt was
made to isolate these by-products.
tive (PDC) addition of carboxylates,
a
-keto carboxylates and
A special case was the irradiation of branched 2-phenylpropan-
oate 2k with N-methylphthalimide 1 and a diastereoisomeric mix-
ture of unlike- and like-3k was obtained in 90% yield after just two
hours of irradiation. The diastereoisomeric ratio was determined
heteroatom-substituted carboxylates to phthalimides has been
established as a powerful alkylation method.2 Multi-gram scale
alkylations have furthermore, been realised using a 308 nm exci-
mer light source.3 Of these, the photodecarboxylative benzylation
has been applied to the synthesis of open analogues of aristolac-
tams (I; Fig. 1).4,5 Arylmethylene-isoindolin-1-ones (II) represent
an important class of pharmaceutically active compounds6 and,
as example, the 4-acetoxyphenylmethylene derivative III has been
shown to exhibit local anaesthetic activity superior to that of
procaine.7
We thus became interested in the photobenzylation of phthali-
mides as an easy access to novel arylmethylene-isoindolin-1-one
precursors. N-Methylphthalimide 1 was initially chosen as a model
compound for a detailed laboratory study. When 1 was irradiated
for 1–5 h in the presence of three equivalents of different potas-
sium phenyl acetates 2a–m in acetone-water (50:50), the corre-
sponding addition products 3a–m were obtained in moderate to
high yields of 29–90% (Scheme 1, Table 1).8 Likewise, vinyl acetate
2n gave the allylated product 3n in an acceptable yield of 26%. For
all compounds, the characteristic C–OH signals in the 13C NMR
spectra were found around 90 ppm. In some cases, the correspond-
ing ‘simple’ decarboxylation products (-CO2HM-H exchange),
R1
AcO
R4
R2
R1
NEt2
N
R3
N
N
R3
R2
O
O
O
aristolactams (I)
II
III
Figure 1. Examples of arylmethylene-isoindolin-1-ones.
R2
R1
O
HO
R1 R2
Ar
CH3
hν
N
CH3
+
N
Ar
CO2K
acetone/H2O
O
O
3a-m
1
2a-m
* Corresponding author. Tel.: +61 (0)7 4781 4543; fax: +61 (0)7 4781 6078.
E-mail address: michael.oelgemoeller@jcu.edu.au (M. Oelgemöller).
Scheme 1. Additions of phenylacetates 2a–m to 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.115

6336
F. Hatoum et al. / Tetrahedron Letters 50 (2009) 6335–6338
Table 1
n
O
(
)
HO
Ar
Product yields and experimental details for photodecarboxylative benzylations of 1
hν
n
(
)
Ar
Ph
R1
H
R2
H
h
1
3 (%)
80
+
N CH3
N
CH3
Ar
CO2K
acetone/H2O
n = 2, 3
a
O
O
1
4a-c
5a-c
b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
6
4
2
5
2
3
5
4
53
Scheme 2. Additions of 4a–c to 1.
OH
OMe
F
c
d
e
f
67/96a
78
the ‘simple’ decarboxylation product 2-ethylanisole was addition-
ally obtained in significant quantity (composition of the crude prod-
uct: 24% 1, 40% 5b, 36% 2-ethylanisole).
The structure of product 5a was confirmed by X-ray structure
analysis.10 Remarkably, two molecules of the same enantiomer of
5a form dimers, which are connected by hydrogen bonding. A pair
with the configuration S is depicted in Figure 3. The same number
of S,S and R,R dimers are found in the crystal. Hence, the compound
crystallised as a racemate and not as a conglomerate.
36
Cl
29/56b
50
Irradiation of 1 in the presence of either potassium L-3-phenyl
lactate 6 or sodium 2-oxo-3-phenylpropanoate 7 furnished the
benzylated product 3a in yields of 21% and 52%, respectively
(Scheme 3). Hence, decarboxylation is followed by the loss of form-
aldehyde11 or decarbonylation, that is, the loss of CO.12
The general protocol was furthermore applied to the glycine
derivative 8 and the benzylated products 9a and b were isolated
in yields of 60% and 63% after four hours and one hour of irradia-
tion (Scheme 4), respectively. Unlike alternative thermal additions
(e.g., Grignard reactions13), the ester group in the N-side chain was
tolerated and photoinduced-alkylation occurred regioselectively at
the imide chromophore.
OMe
OMe
OMe
g
h
i
Cl
Cl
53
Br
I
35
j
51
The mechanistic scenario for the photoinduced-benzylation is
illustrated in Scheme 5.14 Triplet sensitisation by acetone is
followed by a single electron transfer from the carboxylate to the
triplet-excited phthalimide (path A). Although the oxidation
potentials of carboxylates are relatively high (e.g., acetate:
EOx = 1.54 V in MeCN, 2.65 V in H2O vs SCE15) both, electron trans-
k
l
m
n
Ph
Ph
Ph
Vinyl
Me
Ph
Me
H
H
H
Me
H
2
90c
46
76
26
3.5
3.5
5
a
b
c
Yield based on a conversion of 70%.
Yield based on a conversion of 52%.
de of 24% in favour of the like-diastereoisomer.
fer via the excited 3p p* triplet state (E00 = 3.1 eV) or the higher
,
3n,p* state (E00 ꢀ 3.6 eV), are energetically feasible.16 Subsequent
decarboxylation of the carboxy radical yields the corresponding
benzylic radical.17 Protonation, intersystem crossing and C–C bond
formation result in the desired photoaddition products. For 3,4,5-
trimethoxyphenyl acetate 2g, electron transfer has been postulated
from the electron-rich aryl group instead (path B).4 Subsequent
for the crude product by integration of baseline-separated signals
in the 1H NMR and was found to be 1:1.6 (de of 24%) in favour of
the like-diastereoisomer. Pure fractions of each diastereoisomer
were collected by column chromatography and suitable crystals
for X-ray analysis were obtained by recrystallisation (Fig. 2).9 Inter-
estingly, both compounds formed dimers between different enan-
tiomeric forms via hydrogen bonding.
After five hours of irradiation, the photoreactions involving 3-
phenylpropionate (4a), 3-(2-methoxyphenyl)propionate (4b) and
4-phenylbutanoate (4c) furnished the corresponding addition prod-
ucts 5a–c in yields of 67%, 29% and 21% (Scheme 2), respectively. In
the case of 4b, an incomplete conversion of 62% was observed and
Figure 3. Crystal structure of 5a (dimer).
CO2K
Ph
O
HO
OH
6
Ph
hν
+
or
N
CH3
N
CH3
CO2Na
acetone/H2O
Ph
O
O
3a
O
7
1
Figure 2. Crystal structures of ul-3k and l-3k.
Scheme 3. Benzylations of 1 with 6 and 7.

F. Hatoum et al. / Tetrahedron Letters 50 (2009) 6335–6338
6337
Photochemistry and Photobiology; Horspool, W. M., Lenci, F., Eds., 2nd ed.; CRC
Press: Boca Raton, 2004; pp 1–19. Chapter 84; (c) Oelgemöller, M.; Griesbeck,
A. G. J. Photochem. Photobiol., C: Photochem. Rev. 2002, 3, 109–127; (d) Yoon, U.
C.; Mariano, P. S. Acc. Chem. Res. 2001, 34, 523–533; (e) Bartoschek, A.;
Griesbeck, A. G.; Oelgemöller, M. J. Inf. Rec. 2000, 26, 119–126; (f) Coyle, J. D. In
Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New
York, 1984; pp 259–284; (g) Mazzocchi, P. H. Org. Photochem. 1981, 5, 421–471;
(h) Kanaoka, Y. Acc. Chem. Res. 1978, 11, 407–413.
O
HO
Ar
hν
2a,b
+
N
N
acetone/H2O
CO2Me
CO2Me
O
8
O
9a,b
2. (a) Kim, A. R.; Lee, K.-S.; Lee, C.-W.; Yoo, D. J.; Hatoum, F.; Oelgemöller, M.
Tetrahedron Lett. 2005, 46, 3395–3398; (b) Oelgemöller, M.; Cygon, P.; Lex, J.;
Griesbeck, A. G. Heterocycles 2003, 59, 669–684; (c) Griesbeck, A. G.;
Oelgemöller, M. Synlett 2000, 71–72; (d) Griesbeck, A. G.; Oelgemöller, M.
Synlett 1999, 492–494.
3. Griesbeck, A. G.; Kramer, W.; Oelgemöller, M. Green Chem. 1999, 1,
205–207.
4. (a) Griesbeck, A. G.; Warzecha, K.-D.; Neudörfl, J. M.; Görner, H. Synlett 2004,
2347–2350; (b) Warzecha, K.-D.; Görner, H.; Griesbeck, A. G. J. Phys. Chem. A
2006, 110, 3356–3363.
Scheme 4. Additions of 2a and b to 8.
O
R1
R1 R2
Ar CO2
3Sens., PETCO
-
2
1
+
+
N
CH3
Ar
R2
- CO2
2
A
5. For aristolactams, see: (a) Kumar, V.; Poonam; Prasad, A. K.; Parmar, V. S. Nat.
Prod. Rep. 2003, 20, 565–583; (b) Couture, A.; Deniau, E.; Grandclaudon, P.;
Rybalko-Rosen, H.; Léonce, S.; Pfeiffer, B.; Renard, P. Bioorg. Med. Chem. Lett.
2002, 12, 3557–3559.
3Sens.,
PETAr
1. H+
2g
2. C-C
B
6. (a) Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Bioorg. Chem.
2007, 5, 1466–1471; (b) Csende, F.; Stáer, G. Curr. Org. Chem. 2005, 9, 1261–
1276; (c) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1999, 44, 529–
535; (d) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett. 1997, 53,
10313–10330; (e) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1993,
41, 2003–2006.
7. Marsili, A. Eur. Pat. EP0105131A1, 1983; Chem. Abstr. 1984, 101, 54922.
8. General irradiation procedure: N-Methylphthalimide (1.5 mmol) was dissolved
in acetone (50 mL). A solution of the potassium phenylacetate (4.5 mmol) in
water (50 mL) was added, and the mixture was irradiated (Rayonet
R2
R1
O
N
HO
Ar
CH3
MeO
MeO
1. - CO2
CO
2
CH3
+
N
2. H+, 3. C-C
OMe
3
Scheme 5. Mechanistic scenario.
Photochemical Reactor RPR-200; k = 300 20 nm) at 15–20 °C in
a Pyrex
Schlenk tube (k P 300 nm) while purging with a slow stream of nitrogen. The
progress of the reaction was monitored by TLC analysis or by passing the
departing gas stream through a saturated barium hydroxide solution until
precipitation of barium carbonate had ceased. Most of the acetone was
evaporated and the remaining solution was extracted with CH2Cl2 (3 Â 50 mL).
The combined organic layers were washed with 5% NaHCO3 and brine, dried
over MgSO4 and evaporated. The crude products were purified by column
chromatography (eluent:n-hexane/EtOAc = 1/1). In some cases, the pure
product precipitated during evaporation of acetone and was isolated by
vacuum filtration and drying in vacuo instead.Selected physical and spectral
data for 3-(4-hydroxybenzyl)-3-hydroxy-2-methy isoindolin-1-one 3c: yellow
solid, mp 145–148 °C. 1H NMR (400 MHz, acetone-d6): d = 3.08 (s, 3H, NCH3),
3.25 (d, 2J = 14.0 Hz, 1H, CH2), 3.43 (d, 2J = 14.0 Hz, 1H, CH2), 5.38 (s, 1H, OH),
6.56 (d, 3J = 8.4 Hz, 2H, Harom), 6.76 (d, 3J = 8.4 Hz, 2H, Harom), 7.44 (m, 1H,
Harom), 7.49 (m, 1H, Harom), 7.58 (m, 2H, Harom), 8.20 (s, 1H, OH). 13C NMR
(100 MHz, acetone-d6): d = 23.9, 42.2, 91.1, 115.3, 122.6, 123.6, 126.2, 129.4,
131.4, 131.8, 133.0, 148.3, 157.0, 166.7. HR-MS (ESI, positive ions): Calcd
[M+H]+: 270.11302 for C16H15NO3 + H+. Found [M+H]+: 270.11273.
loss of carbon dioxide, protonation and C-C bond formation like-
wise yields the observed addition product. For vinyl acetate 2n
both mechanistic pathways may operate in parallel.18
The efficiency of the PDC approach becomes apparent when
comparing the benzylation of phthalimides with either toluenes
or phenyl acetates, respectively. As reported by Kanaoka et al. pho-
toadditions through hydrogen abstraction give the corresponding
benzylated product in low yields and with poor selectivity and
conversions.19 In contrast, the PDC procedure developed rapidly
giving the desired benzylation products 3 in moderate to high
yields and purities. In addition, the photodecarboxylation protocol
utilises simple phenyl acetates 2. These starting materials are
easily accessible in large quantities and with broad structural
diversity, and are additionally stable in comparison to reagents
used in other thermal alkylation methods for example, SmI2-
mediated coupling of organic halides (SmI2/R–X),20 addition of
organometallic compounds (R–Mg–X or R–Li),13,21 or alkylation with
organic halides using lithium in liquid ammonia (Li/NH3/R–X),22
respectively.
9. Crystal data for ul-3k (CCDC 737177): colourless platelets (from acetone), mp
156–162 °C, C17H17NO2, FW = 267.32 g/mol, triclinic, space group P-1; a =
7.9053(4), b = 8.6707(4), c = 10.7456(5) Å;
88.757(2)°; V = 676.89(6) Å3; Z = 2; dcalc = 1.312 g/cm3; R = 0.0425, Rw = 0.0842
for 1945 reflections having F > 2 (F). Crystal data for l-3k (CCDC 737176):
a = 73.026(2), b = 74.305(2), c =
r
colourless prisms (from acetone), mp 146–152 °C, C17H17NO2, FW = 267.32 g/
mol, monoclinic, space group P21/c; a = 10.2136(4), b = 10.8771(5),
3
c = 13.3876(6) Å; b = 111.297(2)°; V = 1385.72(10) Å
;
Z = 4; dcalc = 1.281 g/
(F).
cm3; R = 0.0386, Rw = 0.0849 for 2253 reflections having F > 2
r
10. Crystal data for 5a (CCDC 737175): colourless prisms (from acetone), mp 65–70 °C,
C17H17NO2, FW = 267.32 g/mol, monoclinic, space group P21; a = 14.4399(3),
b = 28.1060(5), c = 13.4152(2) Å; b = 90.1030(10)°; V = 5444.52(17) Å3; Z = 16;
In conclusion, phenylacetates efficiently undergo photodecarb-
oxylative benzylations to phthalimides. The procedure offers a
versatile access to 3-arylmethylene-isoindolin-1-ones and this
application is currently under investigation. In addition, the
simple protocol is currently being transferred to ‘micro-photochem-
istry’, that is, photochemical transformations in micro-structured
devices.23
dcalc = 1.304 g/cm3; R = 0.0554, Rw = 0.1222 for 8287 reflections having F > 2
r(F).
11. (a) Su, Z.; Mariano, P. S.; Faley, D. E.; Yoon, U. C.; Oh, S. W. J. Am. Chem. Soc.
1998, 120, 10676–10686; (b) Xu, M.; Lukeman, M.; Wan, P. J. Photochem.
Photobiol., A: Chem. 2009, 204, 52–62.
12. Griesbeck, A. G.; Oelgemöller, M.; Lex, J. Synlett 2000, 1455–1457.
13. (a) Ang, W. S.; Halton, B. Aust. J. Chem. 1971, 24, 851–856; (b) Heidenbluth, K.;
Tönjes, H.; Scheffler, R. J. Prakt. Chem. 1965, 30, 204–217.
14. (a) Griesbeck, A. G.; Kramer, W.; Oelgemöller, M. Synlett 1999, 1169–1178; (b)
Kramer, W.; Griesbeck, A. G.; Nerowski, F.; Oelgemöller, M. J. Inf. Rec. 1998, 24,
81–85.
Acknowledgements
15. Eberson, L. In Electron Transfer Reactions in Organic Chemistry; Hafner, K., Ed.;
Reactivity and Structure—Concepts in Organic Chemistry; Springer: Berlin,
1987; Vol. 25.
16. (a) Görner, H.; Oelgemöller, M.; Griesbeck, A. G. J. Phys. Chem. A 2002, 106,
1458–1464; (b) Görner, H.; Griesbeck, A. G.; Heinrich, T.; Kramer, W.;
Oelgemöller, M. Chem. Eur. J. 2001, 7, 1530–1538.
17. The rate for CO2 loss is controlled by the stability of the corresponding alkyl
radical and is estimated to be in the range of 109–1010 sÀ1 for simple alkyl
acyloxy radicals, see: Metzger, J. O. In Houben-Weyl (Methoden der organischen
Chemie); Regitz, M., Giese, B., Eds.; C-Radikale; Thieme: Stuttgart, 1989; Vol.
E19a.
This research project was financially supported by Science
Foundation Ireland (SFI, 07/RFP/CHEF817 and 06/RFP/CHO028)
and Dublin City University (Research Career Start Award 2006).
The authors would like to thank Prof. J. Mattay and Dr. M. C. Letzel
(University of Bielefeld, Germany) for providing MS analyses.
References and notes
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18. Kurauchi, Y.; Ohga, K.; Nobuhara, H.; Morita, S. Bull. Chem. Soc. Jpn. 1985, 58,
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