Photodecarboxylative benzylations of phthalimide in pH 7 buffer: A simple access to 3-arylmethyleneisoindolin-1-ones

Article abstract of DOI:10.1016/j.tetlet.2010.07.017

Photoadditions of phenylacetates to phthalimide in pH 7 buffer solution give the corresponding benzylated-hydroxyphthalimidines in moderate to high yields of up to 94%. In a micro-structured reactor, higher conversions and purities are achieved. With branched phenylacetates, photoaddition affords diastereoisomeric mixtures with low to moderate de values. Subsequent acid-catalyzed dehydration furnishes the corresponding 3- arylmethyleneisoindolin-1-ones in good to excellent yields and with high E-selectivities. Irradiation of the parent 3-phenylmethyleneisoindolin-1-one under oxidative conditions only leads to cis/trans-isomerization.

Full text of DOI:10.1016/j.tetlet.2010.07.017

Tetrahedron Letters 51 (2010) 4738–4741
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photodecarboxylative benzylations of phthalimide in pH 7 buffer: a simple
access to 3-arylmethyleneisoindolin-1-ones
Vincent Belluau a, Pierre Noeureuil b, Elfrun Ratzke a, Aleksei Skvortsov a, Sonia Gallagher b,
Cherri Ann Motti c, Michael Oelgemöller a,
*
a James Cook University, School of Pharmacy and Molecular Sciences, Townsville, Queensland 4811, Australia
b Dublin City University, School of Chemical Sciences, Glasnevin, Dublin 9, Ireland
c Australian Institute of Marine Science (AIMS), Biomolecular Analysis Facility, Townsville, Queensland 4810, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Photoadditions of phenylacetates to phthalimide in pH 7 buffer solution give the corresponding benzy-
lated-hydroxyphthalimidines in moderate to high yields of up to 94%. In a micro-structured reactor,
higher conversions and purities are achieved. With branched phenylacetates, photoaddition affords dia-
stereoisomeric mixtures with low to moderate de values. Subsequent acid-catalyzed dehydration fur-
nishes the corresponding 3-arylmethyleneisoindolin-1-ones in good to excellent yields and with high
E-selectivities. Irradiation of the parent 3-phenylmethyleneisoindolin-1-one under oxidative conditions
only leads to cis/trans-isomerization.
Received 25 May 2010
Revised 21 June 2010
Accepted 2 July 2010
Available online 8 July 2010
Keywords:
Photodecarboxylation
Benzylation
Ó 2010 Elsevier Ltd. All rights reserved.
Phthalimide
Photochemistry
Micro-photochemistry
Isoindolinones
Arylmethyleneisoindolin-1-ones (I; Fig. 1) and the structurally
related aristolactams (II) incorporating the free NH-group repre-
sent important classes of pharmaceutically active compounds.1,2
Consequently, a large number of synthetic pathways to these tar-
get compounds have been reported.3–9 An alternative approach
incorporating a photochemical key-step to N-alkylated derivatives
of I has been developed by Griesbeck and co-workers.10
R2
R3
R1
R2
R1
NH
NH
The key-step in the latter approach is the photodecarboxylative
(PDC) addition of carboxylates to phthalimides, which represents a
versatile alkylation method.11,12 Multi-gram scale photoreactions
O
O
I
aristolactams (II)
have also been realized using a 308 nm excimer light source.13
A
Figure 1. General structure of arylmethyleneisoindolin-1-ones and aristolactams.
major drawback of the original PDC procedure is the necessity of
N-substituents due to an increase in pH during irradiation (final
pH ca. 9–10). With ‘free’ phthalimide the initially formed benzylat-
ed-hydroxyphthalimidines are therefore obtained as their potas-
sium salts and cannot be isolated easily. Early attempts to
convert directly these salts to arylmethyleneisoindolin-1-ones (I)
by an acidic work-up and subsequent extraction furnished com-
plex mixtures with unreacted starting materials. Since the acidity
of phthalimide (pKa = 8.3) differs significantly from that of com-
mon carboxylic acids (pKa = 5–6), we therefore applied a mixture
of acetone and pH 7 buffer solution for the irradiations instead
O
HO
Ar
hν
+
NH
NH
Ar
CO2K
acetone/pH 7
O
O
3a-p
1
2a-p
Scheme 1. Additions of phenylacetates 2a–p to phthalimide (1).
(Scheme 1).14 When phthalimide (1) was irradiated for 2–5 h
(k = 300 25 nm) using this mixture in the presence of three equiv-
alents of phenylacetates 2a–p, the desired addition products 3a–p
were isolated in yields of up to 94% (Table 1).15
* Corresponding author. Tel.: +61 (0)7 4781 4543; fax: +61 (0)7 4781 6078.
E-mail address: michael.oelgemoeller@jcu.edu.au (M. Oelgemöller).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.017

V. Belluau et al. / Tetrahedron Letters 51 (2010) 4738–4741
4739
Table 1
Product yields for photodecarboxylative benzylations of 1
Product
Ar
Ph
Conversiona (%)
100
Time (h)
3
Yield (%)
92
3a
3b
3c
100
100
3
3
92
85
OMe
OAc
F
3d
3e
3f
100
100
100
100
2
3
3
3
92
80
86
76
Cl
Br
3g
3h
3i
100
100
3
3
92
93
Figure 2. Micro-reactor (dwell device, mikroglas) under a UV exposure panel
(Luzchem). A 5 Euro-cent coin is used to illustrate the size of the reactor.
OAc
(Scheme 2). Complete conversions were achieved after 2 h and
4 h of irradiation. In both cases, two complete sets of signals were
observed in the NMR spectra which were assigned to the individual
diastereoisomers. The diastereoisomeric ratios (de) were deter-
mined by integration of baseline separated signals in the 1H NMR
spectra. Stereoselectivities were low with 13% for 5a and moderate
with 33% for 5b (Table 2), respectively. An assignment of the dia-
stereoisomers was not possible.
The arylmethyleneisoindolin-1-ones 6a–p were easily available
in moderate to high yields of 41–97% via acid-catalyzed dehydra-
tion in dichloromethane (Scheme 3; Table 3).18 In almost all cases,
high E-selectivities were obtained as confirmed by 1H NMR spec-
troscopy. The olefinic proton of the Z-isomer is strongly influenced
by the shielding effect of the aromatic ring, whereas no such effect
was observed in the case of the E-isomer.3a Under the standard
hydrolysis conditions, the acetoxy-substituted derivatives 6d, i,
and k underwent partial hydrolysis of the ester group (ca. 30%).
Thus, complete hydrolysis to the corresponding phenolic com-
pounds was enforced by heating the irradiation products 3d, i,
3j
100
15b
3
3
91
AcO
I
3k
10 (67)c
3l
79b
100
5
3
36 (46)c
90
Cl
3m
Cl
OMe
3n
3o
100b
100
3
3
93
54
OMe
O
O
OMe
OMe
3p
100b
2
94
OMe
Conversion determined by 1H NMR spectroscopy of the crude reaction mixture.
Larger amounts of ‘simple’ PDC product detected.
Yield based on conversion.
a
b
c
O
NH
The progress of the reaction was easily monitored by TLC anal-
R
ysis or by passing the departing nitrogen stream through a satu-
rated barium hydroxide solution until the precipitation of barium
carbonate stopped. In most cases, the photoproduct 3 simply pre-
cipitated upon concentration of acetone, and could be isolated by
filtration. All compounds 3 showed characteristic singlets for
the C–OH group at around 90 ppm in their 13C NMR spectra. In iso-
lated cases the corresponding ‘simple’ decarboxylation products
(–CO2HM–H exchange), that is, toluene derivatives, or dibenzyls
(Ar-CH2CH2-Ar) were detected by NMR in the crude products, but
no attempt was made to isolate these compounds. Total consump-
tion of phenylacetate due to these competing side reactions may,
however, explain the incomplete conversion rates for products
3k and 3l.
+
Ph
CO2K
4a,b
O
1
hν
acetone/pH 7
R
R
HO
HO
Ph
Ph
+
NH
NH
O
-5a,b
O
-5a,b
u
l
The easy reaction protocol was also applied to ‘micro-photo-
chemistry’, that is, photochemical reactions in micro-reactors.16
The syntheses of 3b and 3e were used as the model reactions. A
commercially available micro-reactor (dwell device, mikroglas),
which was placed under a UV panel (Luzchem) fitted with five
UVB lamps, was chosen (Fig. 2).17 Using a residence time of 2 h, im-
proved yields of 97% (3b) and 98% (3e) were achieved. The thin
layer within the micro-channel plate (0.5 mm) obviously favors a
better penetration of the solution by light.
Scheme 2. Additions of branched phenylacetates 4 to phthalimide (1).
Table 2
Product yields and de ratios for photodecarboxylative additions of 4 to 1
Product
R
Time (h)
dea (%)
Yield (%)
5a
5b
Me
Et
2
4
13
33
97
94
a
de ratios were determined by 1H NMR spectroscopy of the crude reaction
The PDC reactions involving branched carboxylates 4a and 4b
resulted in like- and unlike-mixtures of 5a and 5b in high yields
mixture.

4740
V. Belluau et al. / Tetrahedron Letters 51 (2010) 4738–4741
Ar
Ar
HO
Ar
cat. H2SO4
CH2Cl2
NH
NH
NH
hν
NH
NH
O
3a-p
O
O
Z-6a-p
E-6a-p
B
O
O
Scheme 3. Acid-catalyzed dehydration of 3a–p.
E-6a
Z-6a
hν
A
Table 3
Product yields and E:Z ratios for dehydrations of 6a–p
Product
Yield (%)
E:Za
H
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
88
80
91
70b
90
90
87
82
60b
63
23b
41
97
90
70
94
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
3:1
[O]
NH
NH
O
O
8
Scheme 5. Attempted electrocyclic ring-closure of 6a.
O
R
3Sens., PETCO
-
2
>10:1
>10:1
7:1
1
+
+
NH
R
Ar
CO2
Ar
- CO2
2, 4
2a-m, 4
A
Determined by 1H NMR spectroscopy.
After dehydration and hydrolysis (see text).
a
3Sens.,
PETAr
2n-p
1. H+
b
- CO2
B
2. C-C
and k in a mixture of acetone, water, and concd HCl (40:28:12)
instead.19
R
O
HO
Following the initial dehydration procedure,18 the branched
photoproducts 5a and 5b were likewise converted into the corre-
sponding arylmethyleneisoindolin-1-ones 7a and 7b in 88% and
89%, respectively (Scheme 4). In both cases, high E-selectivities of
>10:1 were again observed.3a
Ar
R"
CO
2
+
NH
NH
3, 5
R'O
OR'
Scheme 6. Mechanistic scenario.
An attempt was made to convert 6a into the parent aristolactam
8 via an oxidative electrocyclization, as proposed by Griesbeck and
co-workers (Scheme 5, path A).10a This photochemical reaction is
widely observed for stilbenes, and proceeds easily in the presence
of traces of a mild oxidant.20 In contrast, irradiations of air-satu-
rated benzene solutions of 6a at 254 or 300 nm for 4 h only gave
cis/trans-isomerizations (Scheme 5, path B). In both cases, 1H
NMR spectroscopic analysis of the crude product showed an iso-
meric ratio of approximately 1:1. Obviously, the geometry of the
isoindolinone-ring prevents the necessary close proximity of the
‘inner’ carbon atoms for successful electrocyclization.21
The mechanism of the photodecarboxylative addition is illus-
trated in Scheme 6.22 The reaction is initiated by triplet-sensitiza-
tion of acetone. Subsequent electron transfer from the carboxylate
to the triplet-excited phthalimide yields an unstable carboxy radi-
cal which undergoes rapid decarboxylation to its corresponding
benzyl radical (path A). Protonation by water and C–C bond forma-
tion furnishes the observed photoaddition products.23 The mecha-
nistic scenario differs slightly for the di- and tri-alkoxyphenyl
acetates 2n–p, respectively. For these compounds electron transfer
from the electron-rich aryl moiety has been proposed instead (path
B).10 Decarboxylation, protonation, and C–C bond formation again
give the desired addition products.
The developed reaction cascade is remarkably efficient and
gives the desired 3-arylmethyleneisoindolin-1-ones in a simple
two-step procedure in good to high yields and excellent purities.
In addition, all the starting materials are stable and readily avail-
able in large quantities. In contrast to most thermal syntheses,3–9
the reaction protocols also completely avoid transition metal cata-
lysts or other sensitive reagents. An alternative photochemical ac-
cess to compounds 3a and 3c, starting from the phthalimide anion
and toluene derivatives, has been reported by Suau and co-work-
ers.24 However, this photoaddition suffers from low selectivity if
other potent hydrogen donor sites are present as, for example, in
4-methoxytoluene.
In conclusion, phthalimide readily undergoes photobenzyla-
tions with a range of phenylacetates at pH 7. Using a commercially
available micro-reactor, higher yields could be obtained, thus
unambiguously proving the concept of ‘micro-photochemistry’.
Subsequent acid-catalyzed dehydration opens a short pathway to
important 3-arylmethyleneisoindolin-1-ones with high E-selectiv-
ity. The free NH-group allows easy incorporation of a variety of
substituents and this application is currently being investigated.
Ar
R
R
R
Ar
NH
HO
Ar
cat. H2SO4
CH2Cl2
NH
NH
O
5a,b
O
O
Z-7a,b
E-7a,b
Scheme 4. Acid-catalyzed dehydration of 5a and 5b.

V. Belluau et al. / Tetrahedron Letters 51 (2010) 4738–4741
4741
the 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 layer was washed with saturated NH4Cl (1 Â 50 mL) and
brine (1 Â 50 mL), dried over MgSO4, and evaporated. The crude products were
purified by column chromatography (eluent: n-hexane/EtOAc = 1:1). In most
cases, the pure product precipitated during evaporation of acetone and was
isolated by vacuum filtration and dryied in vacuo instead. Selected physical
and spectral data for 3-(3,4-dimethoxybenzyl)-3-hydroxy-isoindolin-1-one 3n:
colorless solid, mp 170 °C. Rf (SiO2, n-hexane/EtOAc = 1:1): 0.13. 1H NMR
Acknowledgments
This research project was supported financially by the Science
Foundation Ireland (SFI, 07/RFP/CHEF817 and 06/RFP/CHO028),
the Environmental Protection Agency (EPA) and the Department
of Environment, Heritage and Local Government (DEHLG, 2008-
ET-MS-2-S2), and James Cook University (Startup Funding). The
authors would like to thank Assoc. Prof. Bruce Bowden (JCU), Dr.
Murray Davies (JCU), and Dr. Thomas Dietrich (mikroglas chem-
tech) for technical advice and support.
(300 MHz, acetone-d6):
d
(ppm) = 3.28 (d, 2J = 13.5 Hz, 1H, CH2), 3.36 (d,
2J = 13.5 Hz, 1H, CH2), 3.58 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 5.32 (s, 1H, OH),
6.64 (m, 3H, Harom), 7.43 (m, 2H, Harom), 7.60 (m, 2H, Harom), 7.81 (s, 1H, NH).
13C NMR (75 MHz, acetone-d6): d (ppm) = 45.3, 55.9, 56.0, 88.9, 112.1, 115.6,
123.4, 123.8, 123.9, 129.2, 129.8, 132.6, 133.2, 149.2, 149.6, 149.8, 168.5. IR
(KBr):
m = 3329, 2948, 2833, 1686, 1514, 1467, 1421, 1263, 1236, 1140, 1023,
767, 701 cmÀ1. HR-MS (ESI, negative mode): Calcd [MÀH]+: 298.1085 for
References and notes
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17H17NO4 À H+. Found [MÀH]+: 298.1088. HR-MS (ESI, positive mode): Calcd
[M+Na]+: 322.1050 for C17H17NO4 + Na+. Found [M+Na]+: 322.1053.
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18. General dehydration procedure: Compound 3 (1–2 mmol) was dissolved in
CH2Cl2 (30 mL). The reaction mixture was cooled in an ice-bath (0 °C) and 3–5
drops of concd H2SO4 were added. The reaction mixture turned yellow
instantly and precipitation occurred. After stirring overnight at room
temperature, H2O (ca. 30 mL) was added, and most of the CH2Cl2 was
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evaporation and was isolated by vacuum filtration, washing with H2O (ca.
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Selected physical and spectral data for (E)-3-(4-methoxybenzylidene)isoindolin-
1-one E-6c: yellow solid, mp 196 °C. Rf (SiO2, n-hexane/EtOAc = 1:1): 0.55. 1H
NMR (300 MHz, CDCl3): d (ppm) = 3.86 (s, 3H, OCH3), 6.52 (s, 1H, CHolef), 6.76
(m, 2H, Harom), 7.38 (m, 2H, Harom), 7.50 (ddd, 3J = 7.6, 3J = 7.6, 4J = 1.0 Hz, 1H,
H
arom), 7.63 (ddd, 3J = 7.6, 3J = 7.6, 4J = 1.2 Hz, 1H, Harom), 7.77 (dd, 3J = 7.6,
4J = 1.0 Hz, 1H, Harom), 7.88 (dd, 3J = 7.6, 4J = 1.2 Hz, 1H, CHarom), 7.99 (s, 1H,
NH). 13C NMR (75 MHz, CDCl3): d (ppm) = 31.1, 106.0, 115.0, 119.8, 123.7,
127.7, 129.1, 129.9, 131.9, 132.3, 138.5, 159.4, 165.2, 169.0. IR (KBr):
m = 3416,
1702, 1602, 1513, 1300, 1252, 1179, 1031, 849, 820 cmÀ1. HR-MS (ESI, negative
mode): Calcd [MÀH]+: 250.0874 for C16H13NO2ÀH+. Found [MÀH]+: 250.0866.
HR-MS (ESI, positive mode): Calcd [M+H]+: 252.1019 for C16H13NO2 + H+.
Found [M+H]+: 252.1022. Calcd [M+Na]+: 274.0838 for C16H13NO2 + Na+. Found
[M+Na]+: 274.0830.
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isoindolin-1-one moiety.
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1458–1464; (b) Görner, H.; Griesbeck, A. G.; Heinrich, T.; Kramer, W.;
Oelgemöller, M. Chem. Eur. J. 2001, 7, 1530–1538.
23. The mechanism mirrors that of related cyclization reactions, see: (a)
Oelgemöller, M.; Griesbeck, A. G.; Kramer, W.; Nerowski, F. J. Inf. Rec. 1998,
24, 87–94; (b) Griesbeck, A. G.; Henz, A.; Kramer, W.; Lex, J.; Nerowski, F.;
Oelgemöller, M.; Peters, K.; Peters, E.-M. Helv. Chim. Acta 1997, 80, 912–933.
24. Sánchez-Sánchez, C.; Pérez-Inestrosa, E.; García-Segura, R.; Suau, R.
Tetrahedron 2002, 58, 7267–7274.
14. Irradiations in pH 7/acetone mixtures were also successfully used for PDC-
cyclizations involving phthaloyl peptides, see: (a) Griesbeck, A. G.; Heinrich, T.;
Oelgemöller, M.; Molis, A.; Heidtmann, A. Helv. Chim. Acta 2002, 85, 4561–
4578; (b) Griesbeck, A. G.; Heinrich, T.; Oelgemöller, M.; Molis, A.; Lex, J. J. Am.
Chem. Soc. 2002, 124, 10972–10973.
15. General irradiation procedure: Phthalimide (1.5 mmol) was dissolved in acetone
(50 mL). A solution of the potassium phenylacetate (4.5 mmol) in pH 7 buffer
(FixanalÒ
,
50 mL) was added, and the mixture was irradiated (Rayonet
Photochemical Reactor RPR-200; k = 300 20 nm) at 15–20 °C in Pyrex
a
Schlenk tube (k ꢀ 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