Photodecarboxylative addition of carboxylates to phthalimides: A concise access to biologically active 3-(alkyl and aryl)methylene-1H-isoindolin-1-ones

Article abstract of DOI:10.1016/j.tetlet.2012.07.142

A series of 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives were synthesized in a simple two-step procedure using a recently established photodecarboxylative addition of carboxylates to phthalimides as the key-step. Subsequent acid-catalyzed dehydration and deprotection furnished the desired target compounds with high E-selectivity. The reaction sequence was applied to the synthesis of the known bioactive phenylethylene derivative, AKS-186. Different analogues, including heteroatom-containing isosteres were also synthesized using this approach.

Full text of DOI:10.1016/j.tetlet.2012.07.142

Tetrahedron Letters 53 (2012) 5573–5577
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photodecarboxylative addition of carboxylates to phthalimides: a concise
access to biologically active 3-(alkyl and aryl)methylene-1H-isoindolin-1-ones
Fadi Hatoum a, Jana Engler a, Christina Zelmer b, Johannes Wißen b, Cherie Ann Motti c, Johann Lex d,
Michael Oelgemöller b,
⇑
a Dublin City University, School of Chemical Sciences, Glasnevin, Dublin 9, Ireland
b James Cook University, School of Pharmacy and Molecular Sciences, Center for Biodiscovery and Molecular Development of Therapeutics (BMDT), Townsville, QLD 4811, Australia
c Australian Institute of Marine Science (AIMS), Biomolecular Analysis Facility, Townsville, Queensland, Australia
d University of Cologne, Institute of Organic Chemistry, Greinstrasse 4, D-50939 Cologne, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives were synthesized in a simple two-
step procedure using a recently established photodecarboxylative addition of carboxylates to phthali-
mides as the key-step. Subsequent acid-catalyzed dehydration and deprotection furnished the desired
target compounds with high E-selectivity. The reaction sequence was applied to the synthesis of the
known bioactive phenylethylene derivative, AKS-186. Different analogues, including heteroatom-con-
taining isosteres were also synthesized using this approach.
Received 21 May 2012
Revised 21 June 2012
Accepted 11 July 2012
Available online 14 August 2012
Keywords:
Photodecarboxylation
Phthalimide
Ó 2012 Elsevier Ltd. All rights reserved.
Photoinduced electron transfer
Photochemistry
Photoaddition
Due to their broad biological activity,1 3-alkyl and 3-arylmeth-
ylene-2,3-dihydro-1H-isoindolin-1-ones (I) have attracted consid-
erable attention in synthetic organic chemistry.2–10 Among these
compounds, the E-phenylethylidene derivative II (AKS-186) has
been reported to inhibit thromboxane A2 analogue (U-46619)
induced vasoconstriction, which makes it an interesting target
compound (Fig. 1).1b,c
O
O
N
R1
N
R2
OH
The photodecarboxylative addition of alkyl carboxylates to
N-substituted phthalimides was established by us as a versatile
alternative to Grignard reactions.11,12 The approach uses readily
available, inexpensive, and stable potassium carboxylates as ‘alkyl-
ating agents’ and gives the corresponding 3-hydroxy-isoindolin-1-
ones in good to excellent yields. The methodology also allows for
easy scale-up and multi-gram alkylations have subsequently been
realized.13 Likewise, continuous photodecarboxylative additions
have been achieved in a microflow photoreactor.14 Subsequent
acid-catalyzed dehydration yields the desired 3-alkyl and 3-aryl-
methylene-2,3-dihydro-1H-isoindolin-1-ones in high yields.15 We
have consequently investigated this synthetic strategy for the
preparation of the bioactive phenylethylidene derivative AKS-186
and its isosteric analogues.16
R1, R2 = alkyl, aryl
I
II
(AKS-186)
Figure 1. 3-Alkyl and 3-arylmethylene-2,3-dihydro-1H-isoindol-1-ones.
Initially, 2-(4-acetoxybenzyl)isoindoline-1,3-dione (1)17 was
irradiated in the presence of three equivalents of different potas-
sium alkyl carboxylates 2a–h. Due to the low solubility of 1, all
photoreactions were performed in a 3:1 mixture of acetone and
water. After irradiations with UVB light for 2–10 h, the correspond-
ing addition products 3a–f were obtained in yields of 23–76%
(Scheme 1, Table 1).18 In line with earlier observations,11a a notice-
able drop in efficiency was observed for 4-phenylbutanoate (2c)
despite an extended reaction time of 10 h. With di- and trimethoxy
substituted carboxylates 2g and 2h, no reaction occurred even
after prolonged irradiation of 20 h and 1 was recovered in 69%
⇑
Corresponding author. Tel.: +61 7 4781 4543; fax: +61 7 4781 6078.
E-mail address: michael.oelgemoeller@jcu.edu.au (M. Oelgemöller).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.142

5574
F. Hatoum et al. / Tetrahedron Letters 53 (2012) 5573–5577
O
O
hν
300 nm
N
N
Ar
CO2K
n
acetone/H2O
(3:1)
2a-h
HO
Ar
O
n
OAc
OAc
1
3a-h
Scheme 1. Photodecarboxylative additions of 2a–h to 1.
Table 1
Product yields and experimental details for photodecarboxylative additions of 2a–h to 1
Entry
Ar
n
Time (h)
Conversion of 1a (%)
Yield of 3 (%)
a
b
c
Ph
Ph
Ph
1
2
3
5
2
10
95
52
69
43 (46b)
44 (85b)
23 (33b)
MeO
d
e
f
2
2
2
2
6
2
63
43 (68b)
76 (90b)
74 (78b)
—
OMe
84
OMe
OMe
2
95
OMe
OMe
g
20
(69c)
OMe
OMe
h
2
20
(89c)
—
a
b
c
Conversion determined by 1H NMR spectroscopic analysis of the crude mixture ( 3%).
Yield based on conversion.
Reisolated 1.
and 89% yields, respectively. For almost all transformations, non-
volatile alkylated arenes, that is, decarboxylation products of 2,
were detected in the crude product by TLC or 1H NMR spectro-
scopic analysis. During column chromatography these ‘simple’
decarboxylation products were eluted together with unreacted 1
and could thus not be obtained in pure form. However, their com-
petitive formation caused incomplete conversion rates due to con-
sumption of the corresponding carboxylates.
AKS-186, was furthermore determined by X-ray structure analysis
and is shown in Figure 2.19 The compound forms a dimer via
hydrogen bonding between the C–OH and the C@O group of inde-
pendent molecules, and crystallized as a racemate.
In order to produce isosteric analogues of 3-(aryl and
alkyl)methyleneisoindolin-1-ones, several heteroatom containing
carboxylates 4a–e were furthermore investigated (Scheme 2, Table
2).20 Irradiations in the presence of 1 and in aqueous acetone for
2–9 h furnished the corresponding addition products 5a–e in
moderate to good yields of 44–89%.21 With the exception of 4e,
conversions were again incomplete due to the competitive
For all photoproducts 3a–f, the characteristic singlet of the
newly formed C–OH group was detected around 92 ppm in the
13C NMR spectra. The structure of 3b, that is, the precursor to
Figure 2. Crystal structure of 3b (Schakal).

F. Hatoum et al. / Tetrahedron Letters 53 (2012) 5573–5577
5575
O
O
hν 300 nm
R
N
N
X
CO2K
acetone/H2O
(3:1)
4a-e
HO
O
X
R
OAc
OAc
5a-e
1
Scheme 2. Photodecarboxylative additions of 4a–e to 1.
Table 2
O
O
Product yields and experimental details for photodecarboxylative additions of 4a–e to
1
acetone, H2O,
N
N
Entry
R
X
Time (h)
Conversion of 1a (%)
Yield of 3 (%)
conc. HCl, Δ
a
b
c
d
e
Ph
Ph
Ph
Ph
H
S
O
NH
NAc
NAc
9
4
5
5
2
75
84
89
90
100
44 (59b)
55 (66b)
48 (54b)
55 (61b)
89
HO
Ar
n
n-1
OAc
Ar
OH
3a-f
7a-f
a
Conversion determined by 1H NMR spectroscopic analysis of the crude mixture
Scheme 4. Acid-catalyzed dehydration and deprotection of 3a–f.
( 3%).
b
Yield based on conversion.
Table 3
Product yields and E:Z ratios for the dehydrations/depro-
tection of 3a–f
formation of ‘simple’ decarboxylation products. The characteristic
stench of thioanisole was particularly noticeable when potassium
2-(phenylthio)acetate (4a) was used as starting material. In line
with previous reports,20a the decarboxylative addition of N-phe-
nylglycinate 4c was rather unselective with larger amounts of
undefined by-products, however, the desired photoproduct 5c
was still isolated in an acceptable yield of 48%. In contrast, the
amide-containing carboxylates 4d and 4e reacted smoothly. For
all compounds 5a–e the C–OH group was again observed between
89–93 ppm during 13C NMR spectroscopic analysis.
Entry
Yield of 7 (%)
E:Z ratioa
a
b
c
d
e
f
93
87
83
96
76
88
12:1
10:1
11:1
14:1
15:1
16:1
a
Determined by 1H NMR spectroscopic analysis ( 3%).
Irradiation of 1 in the presence of potassium L-3-phenyl lactate
O
O
6 for 2 h resulted in approximately 60% conversion. A complex
product mixture was obtained from which only the benzylated
product 3a could be isolated in 19% yield (Scheme 3). Its formation
can be explained by a subsequent loss of formaldehyde after the
initial photodecarboxylation.11a,22
acetone, H2O,
N
N
conc. HCl, Δ
HO
Acid hydrolysis of compounds 3a–f in a mixture of acetone,
water, and conc. HCl (10:7:3 vol %) conveniently allowed for dehy-
dration and deprotection in a single step (Scheme 4).23,24 The de-
sired methyleneisoindolin-1-ones 7a–f (including AKS-186; 7b)
were obtained in good to excellent yields of 76–96% (Table 3)
and with high E-selectivity (E:Z = P10:1), as confirmed by 1H
NMR spectroscopic analysis. The olefinic proton of the Z-isomer
was shifted downfield by the shielding effect of the isoindolin-1-
one ring, whereas no such effect was observed in the case of the
corresponding E-isomer.2a
X
X
R
R
OH
OAc
5a-e
8a-e
Scheme 5. Acid-catalyzed dehydration and deprotection of 5a–e.
Table 4
Product yields and E:Z ratios for the dehydrations/depro-
tection of 5a and 5b
Entry
Yield of 8 (%)
E:Z ratioa
When the same dehydration/deprotection procedure was ap-
plied to the heteroatom-containing hydroxy phthalimidines 5a–e,
only the sulfur and oxygen analogues furnished the desired prod-
ucts 8a and 8b in yields of 88% and 89% (Scheme 5, Table 4),
a
b
88
89
4:1
1:1
Determined by 1H NMR spectroscopic analysis ( 3%).
a
O
N
O
hν 300 nm
CO2K
Ph
N
OH
acetone/H2O
(3:1)
HO
Ph
O
6
OAc
OAc
3a
1
Scheme 3. Photobenzylation of 1 with 6.

5576
F. Hatoum et al. / Tetrahedron Letters 53 (2012) 5573–5577
OAc
OAc
O
O
3Sens., PETCO
2
X
CO2
n
N
N
+
R
X = CH2 , O, NAc
A
O
1
- CO2
3Sens., PETX
+
X
CO2
n
X = S , NH
R
X
C
R
3Sens., PETArene
n-1
OAc
R = Ar(OMe)2/3
BET
O
1. H+
B
- CO2
OAc
2. C-C
N
+
O
X
CO2
R
OAc
Ph
N
X
+
HO
n
CO2
R'
N
MeO
3, 5
OMe
Scheme 6. Mechanistic scenarios.
respectively.25 Their E:Z ratios were determined by 1H NMR spec-
troscopy and were found to be 4:1 (8a) and 1:1 (8b). Due to the
instability of the initially formed enamines 8c–e (or their imine
tautomers), all nitrogen-containing compounds 5c–e underwent
unselective decomposition reactions.26,27
(SmI2/R-X),35 addition of organometallic compounds (R-Mg-X or
R-Li),2,36 or alkylation with organic halides using lithium in liquid
ammonia (Li/NH3/R-X),37 require unstable reagents and harsh
reaction conditions that cannot be easily transferred to continuous
flow reactors.
Triplet sensitization by acetone and subsequent photoinduced
electron transfer (PET) to the triplet excited phthalimide have been
established as key steps of the photodecarboxylation (Scheme 6).28
The origin of the PET step depends on the nature of the carboxylate
employed.29,30 For compounds 2a–f, 4b, 4d, and 4e, the carboxylate
function acts as an electron donor thus generating an unstable car-
boxy radical (path A). Subsequent decarboxylation, protonation,
and C–C bond formation yields the observed hydroxy phthalimi-
dines. For the di- and trimethoxyphenyl propanoates 2g and 2h,
the electron-rich aryl moiety functions as an electron donor in-
stead (path B).31 Loss of carbon dioxide is not feasible for the
resulting aryl radical cation and a ‘non-productive’ back electron
transfer (BET) consequently occurs. These aryl groups thus behave
as ‘hole traps’.20d,32 Due to the low oxidation potentials of amines
and thioethers, the corresponding carboxylates 4a and 4c operate
via electron transfer from the heteroatom (path C).33 Successive
Acknowledgments
This research was financially supported by Science Foundation
Ireland (SFI, 07/RFP/CHEF817 and 06/RFP/CHO028) and James Cook
University (JCU-CRIG 2011). The authors thank Assoc-Prof. Bruce
Bowden and Dr. Murray Davies (JCU) for technical assistance.
References and notes
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5. Couty, S. C.; Liégault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511–2514.
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1338.
a-decarboxylation, protonation, and C–C bond formation again
give the observed addition products.
In conclusion, the photodecarboxylative addition of carboxyl-
ates to phthalimides was applied successfully to the synthesis of
novel and known 3-(alkyl and aryl)methyleneisoindolin-1-ones.
Among the compounds obtained was the bioactive phenylethyli-
dene derivative 7b (AKS-186). Isosteric analogues were likewise
prepared. The simple two-step procedure uses readily available
starting materials and gives moderate to high combined yields.
These features make the process interesting for a continuous
microflow production of 3-(alkyl and aryl)methyleneisoindolin-1-
ones in micro-structured devices, and this application is currently
being investigated.34 In contrast, alternative thermal alkylation
methods, for example, SmI2-mediated coupling of organic halides
8. Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361–7364.
9. Bubar, A.; Estey, P.; Lawson, M.; Eisler, S. J. Org. Chem. 2012, 77, 1572–1578.
10. Kobayashi, K.; Matsumoto, K.; Nakamura, D.; Fukamachi, S.; Konishi, H. Helv.
Chim. Acta 2010, 93, 1048–1051.
11. (a) Hatoum, F.; Gallagher, S.; Baragwanath, L.; Lex, J.; Oelgemöller, M.
Tetrahedron Lett. 2009, 50, 6335–6338; (b) Oelgemöller, M.; Cygon, P.; Lex, J.;
Griesbeck, A. G. Heterocycles 2003, 59, 669–684; (c) Griesbeck, A. G.; Gudipati,
M. S.; Hirt, J.; Lex, J.; Oelgemöller, M.; Schmickler, H.; Schouren, F. J. Org. Chem.
2000, 65, 7151–7157; (d) Griesbeck, A. G.; Oelgemöller, M.; Lex, J. Synlett 2000,
1455–1457; (e) Griesbeck, A. G.; Oelgemöller, M. Synlett 1999, 492–494.

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5577
12. For reviews, see: (a) McDermott, G.; Yoo, D. J.; Oelgemöller, M. Heterocycles
2005, 65, 2221–2257; (b) Oelgemöller, M.; Griesbeck, A. G. J. Photochem.
Photobiol. C: Photochem. Rev. 2002, 3, 109–127; (c) Griesbeck, A. G.; Kramer, W.;
Oelgemöller, M. Synlett 1999, 1169–1178; (d) Kramer, W.; Griesbeck, A. G.;
Nerowski, F.; Oelgemöller, M. J. Inf. Rec. 1998, 24, 81–85; (e) 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.
13. (a) Griesbeck, A. G.; Maptue, N.; Bondock, S.; Oelgemöller, M. Photochem.
Photobiol. Sci. 2003, 2, 450–451; (b) Griesbeck, A. G.; Kramer, W.; Oelgemöller,
M. Green Chem. 1999, 1, 205–207.
was isolated by vacuum filtration, washing with H2O (ca. 50 mL), and drying in
vacuo. In all other cases, the reaction mixture was extracted with EtOAc
(3 Â 25 mL). The combined organic layer was washed with saturated NaHCO3
(1 Â 25 mL) and brine (1 Â 25 mL), dried over MgSO4 and evaporated. The
products were obtained after column chromatography (eluent: n-hexane/
EtOAc = 1/1). Selected physical and spectral data for (E)-2-(4-hydroxybenzyl)-
3-(2-phenethylidene)isoindolin-1-one (E-7b): colorless solid, Rf (n-hexane/
EtOAc = 1/1) = 0.64, mp 187–190 °C. 1H NMR (400 MHz, acetone-d6):
d
(ppm) = 4.05 (d, J = 8.0 Hz, 2H, CH2), 5.00 (s, 2H, CH2), 5.80 (t, J = 8.0 Hz, 1H,
CH), 6.81 (d, J = 8.6 Hz, 2H, Harom), 7.17 (d, J = 8.6 Hz, 2H, Harom), 7.23 (m, 3H,
14. (a) Shvydkiv, O.; Nolan, K.; Oelgemöller, M. Beilstein. J. Org. Chem. 2011, 7,
1055–1063; (b) Shvydkiv, O.; Gallagher, S.; Nolan, K.; Oelgemöller, M. Org. Lett.
2010, 12, 5170–5173.
15. (a) Belluau, V.; Noeureuil, P.; Ratzke, E.; Skvortsov, A.; Gallagher, S.; Motti, C.
A.; Oelgemöller, M. Tetrahedron Lett. 2010, 51, 4738–4741; (b) Griesbeck, A. G.;
Warzecha, K.-D.; Neudörfl, J. M.; Görner, H. Synlett 2004, 2347–2350.
16. (a) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147–3176; (b) Lima, L. M.;
Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23–49; (c) Kier, L. B.; Hall, L. H. Chem.
Biodivers. 2004, 1, 138–151.
Harom), 7.30 (m, 2H, Harom), 7.63 (dd, J = 7.5, J = 1.1 Hz, 1H, Harom), 7.71 (dd,
J = 7.5, J = 1.1 Hz, 1H, Harom), 7.91 (d, J = 7.5 Hz, 1H, Harom), 8.08 (d, J = 7.5 Hz,
1H, Harom), 8.32 (s, 1H, OH). 13C NMR (100 MHz, acetone-d6): d (ppm) 34.2 (t,
1C, CH2), 43.4 (t, 1C, CH2), 96.0 (d, 1C, CH), 112.7 (d, 2C, CH), 116.9 (d, 1C, CH),
124.7 (d, 1C, CH), 125.3 (d, 1C, CH), 127.8 (d, 1C, CH), 129.8 (d, 2C, CH), 130.0 (d,
2C, CH), 130.1 (d, 2C, CH), 130.6 (d, 1C, CH), 133.8 (s, 1C, Cq), 136.6 (s, 1C, Cq),
137.2 (s, 1C, Cq), 141.7 (s, 1C, Cq), 156.0 (s, 1C, Cq), 167.1 (s, 1C, Cq), 171.6 (s,
1C, C@O). IR (ATR):
1237, 763, 737. HR–MS (ESI, positive ions): Calcd. [M+Na]+: 364.1308
23H19NO2 + Na+. Found [M+Na]+: 364.1306.
25. Selected physical and spectral data
m
(cmÀ1) = 3105, 3026, 2937, 1672, 1652, 1515, 1418, 1269,
17. Johansson, A.; Abrahamsson, M.; Magnuson, A.; Huang, P.; Mårtensson, J.;
Styring, S.; Hammarström, L.; Sun, L.; Åkermark, B. Inorg. Chem. 2003, 42, 7502–
7511.
C
for
2-(4-hydroxybenzyl)-3-
(phenoxymethylene)isoindolin-1-one (8b): colorless solid, Rf (mixture; n-
hexane/EtOAc = 1/1) = 0.60, mp (mixture) 175–177 °C. E-isomer (E-8b): 1H
NMR (400 MHz, acetone-d6): d (ppm) = 5.06 (s, 2H, CH2), 6.73 (d, J = 8.6 Hz, 1H,
18. General irradiation procedure: 2-(4-Acetoxybenzyl) isoindoline-1,3-dione (1,
450 mg, 1.5 mmol) was dissolved in acetone (45 mL).
A solution of the
potassium carboxylate (4.5 mmol) in H2O (15 mL) was added, and the
mixture was irradiated (Rayonet Photochemical Reactor RPR-200; k = 300
20 nm) at 15–20 °C in a Pyrex Schlenk tube (k P 300 nm) equipped with a cold
finger while purging with a slow stream of N2. The progress of the reaction was
followed by TLC analysis or by passing the leaving gas stream through a
saturated Ba(OH)2 solution. After 2–20 h of irradiation, most of the acetone
was evaporated and the mixture was extracted with CH2Cl2 (3 Â 50 mL). The
combined organic layers were washed with saturated NaHCO3 (30 mL) and
brine (30 mL), dried over MgSO4 and evaporated. The products were obtained
after column chromatography (SiO2; eluent: n-hexane/EtOAc = 1/1 or 1/3).
Harom), 7.11 (s, 1H, CH), 7.12 (m, 1H, Harom), 7.20 (m, 5H, Harom), 7.27 (d,
J = 8.6 Hz, 2H, Harom), 7.55 (dd, J = 7.5, J = 0.8 Hz, 1H, Harom), 7.61 (dd, J = 7.5,
J = 0.8 Hz, 1H, Harom), 7.66 (dd, J = 7.6, J = 1.3 Hz, 1H, Harom), 7.71 (dd, J = 7.6,
J = 1.3 Hz, 1H, Harom), 8.21 (s, 1H, OH). 13C NMR (100 MHz, acetone-d6): d
(ppm) = 43.9 (t, 1C, CH2), 116.6 (d, 2C, CH), 117.1 (d, 2C, CH), 120.6 (d, 1C, CH),
125.0 (s, 1C, Cq), 125.7 (d, 1C, CH), 129.6 (s, 1C, Cq), 130.1 (d, 2C, CH), 130.4 (s,
1C, Cq), 131.5 (d, 2C, CH), 133.3 (s, 1C, Cq), 135.9 (d, 1C, CH), 142.1 (d, 1C, CH),
148.5 (d, 1C, CH), 155.0 (d, 1C, CH), 158.5 (s, 1C, Cq), 162.8 (s, 1C, Cq), 167.9 (s,
1C, C@O). Z-isomer (Z-8b): 1H NMR (400 MHz, acetone-d6): d (ppm) = 5.27 (s, 2
H, CH2), 6.87 (d, J = 8.6 Hz, 1H, Harom), 7.14 (m, 2H, Harom), 7.20 (m, 2H, Harom),
7.42 (s, 1H, CH), 7.43 (m, 4H, Harom), 7.85 (d, J = 7.6 Hz, 1H, Harom), 7.90 (d,
J = 7.6 Hz, 1H, Harom), 7.99 (d, J = 7.6 Hz, 1H, Harom), 8.15 (d, J = 7.6 Hz, 1H,
Selected
physical
and
spectral
data
for
4-[(1-hydroxy-3-oxo-1-
phenethylisoindolin-2-yl)methyl] phenyl acetate (3b): colorless solid, Rf (n-
hexane/EtOAc = 1/1) = 0.44, mp 121–123 °C. 1H NMR (400 MHz, acetone-d6):
d (ppm) = 1.79 (m, 1H, CH2), 1.94 (m, 1H, CH2), 2.30 (s, 3H, CH3), 2.33 (m, 1H,
CH2), 2.43 (m, 1H, CH2), 4.57 (d, J = 15.3 Hz, 1H, NCH2), 4.92 (d, J = 15.3 Hz, 1H,
NCH2), 5.50 (s, 1 H, OH), 6.72 (d, J = 7.2 Hz, 2H, Harom), 7.13 (br m, 5H, Harom),
7.61 (dd, J = 7.2, J = 1.4 Hz, 1H, CH2), 7.66 (d, J = 7.2 Hz, 2H, Harom), 7.72 (dd,
J = 7.2, J = 1.4 Hz, 1H, Harom), 7.75 (d, J = 7.2 Hz, 1H, Harom), 7.80 (d, J = 7.2 Hz,
1H, Harom). 13C NMR (100 MHz, acetone-d6): d (ppm) = 21.7 (q, 1C, CH3), 31.6 (t,
1C, CH2), 40.7 (t, 1C, CH2), 42.6 (t, 1C, CH2), 92.5 (s, 1C, COH), 123.3 (d, 2C, CH),
123.7 (d, 1C, CH), 124.3 (d, 1C, CH), 127.3 (d, 1C, CH), 129.7 (d, 2C, CH), 129.8 (d,
2C, CH), 131.0 (d, 1C, CH), 131.4 (d, 2C, CH), 133.4 (s, 1C, Cq), 134.0 (d, 1C, CH),
138.5 (s, 1C, Cq), 142.5 (s, 1C, Cq), 149.1 (s, 1C, Cq), 151.9 (s, 1C, Cq), 168.8 (s,
H
arom), 8.40 (s, 1H, OH). 13C NMR (100 MHz, acetone-d6): d (ppm) = 46.0 (t, 1C,
CH2), 117.4 (d, 2C, CH), 118.1 (d, 2C, CH), 124.6 (d, 1C, CH), 125.3 (s, 1C, Cq),
126.3 (d, 1C, CH), 130.2 (d, 2C, CH), 130.3 (s, 1C, Cq), 131.0 (s, 1C, Cq), 131.6 (d,
2C, CH), 133.8 (s, 1C, Cq), 138.6 (d, 1C, CH), 142.2 (d, 1C, CH), 149.4 (d, 1, CH),
155.1 (d, 1C, CH), 158.8 (s, 1C, Cq), 166.7 (s, 1C, Cq), 171.7 (s, 1C, C@O). IR
(mixture; ATR):
m
(cmÀ1) = 3099, 3017, 2889, 1652, 1589, 1228, 1206, 1196,
1168, 1148, 820, 808. HR–MS (mixture; ESI, positive ions): Calcd. [M+Na]+:
366.1101 C22H17NO3+Na+. Found [M+Na]+: 366.1102.
26. (a) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enamines (The Chemistry of
Functional Groups); Rappoport, Z., Ed.; John Wiley & Sons: Chichester, 1994; pp
1049–1109. Ch. 19; (b) West, J. E. J. Chem. Educ. 1963, 40, 194–200.
27. Layer, R. W. Chem. Rev. 1963, 63, 489–510.
1C, C@O), 170.4 (s, 1C, C@O). IR (ATR): m
(cmÀ1) = 3282, 3051, 2955, 1760, 1670,
1402, 1218, 1196, 1088, 1077, 1034, 916. HR–MS (ESI, positive ions): Calcd.
28. (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; (c) 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.
29. (a) Hoffmann, N. J. Photochem. Photobiol. C: Photochem. Rev. 2008, 9, 43–60; (b)
Oelgemöller, M.; Bunte, J.-O.; Mattay, J. In Synthetic Organic Photochemistry;
Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker: New York, 2004; pp 267–295.
Ch. 10.
[M+Na]+: 424.1525 C25H23NO4 + Na+. Found [M+Na]+: 424.1524.
19. Crystal data for 3b (CCDC-882812): colorless prisms (from acetone), C25H23NO4,
FW = 401.44 g/mol, monoclinic, space group P21/n; a = 10.0460(3),
b = 14.2639(4), c = 15.2060(4) Å; b = 104.634(2)°; V = 2108.26(10) Å3; Z = 4;
dcalc = 1.265 g/cm3; R = 0.0395, Rw = 0.0796 for 3037 reflections having
F > 2r(F).
20. (a) Gallagher, S.; Hatoum, F.; Zientek, N.; Oelgemöller, M. Tetrahedron Lett.
2010, 51, 3639–3641; (b) Hatoum, F.; Gallagher, S.; Oelgemöller, M.
Tetrahedron Lett. 2009, 50, 6593–6596; (c) Kim, A. R.; Lee, K.-S.; Lee, C.-W.;
Yoo, D. J.; Hatoum, F.; Oelgemöller, M. Tetrahedron Lett. 2005, 46, 3395–3398;
(d) Griesbeck, A. G.; Oelgemöller, M. Synlett 2000, 71–72.
30. Warzecha, K.-D.; Görner, H.; Griesbeck, A. G. J. Phys. Chem. A 2006, 110, 3356–
3363.
31. The
oxidation
potentials
increase
in
the
order
Ar(OMe)2/
21. Selected
physical
and
spectral
data
for
4-{[1-hydroxy-3-oxo-1-
3 6 NR3 < SR2 < RCO2À 6 RCONR2 < OR2, see: (a) Pienta, N. J. In Photoinduced
Electron Transfer; Fox, M. A., Chanon, M., Eds.; Elsevier: Amsterdam, 1988; pp
421–486. Ch. 4.7; (b) Eberson, L. In Electron Transfer Reactions in Organic
Chemistry Reactivity and Structure-Concepts in Organic Chemistry; Hafner, K., Ed.;
Springer-Verlag: Berlin, 1987; Vol. 25, pp 39–66; (c) Siegerman, H. In Technique
of Electroorganic Synthesis Techniques of Chemistry; Weinberg, N. L., Ed.; J. Wiley
& Sons: New York, 1975; Vol. 5, pp 667–1056. Part 2; For reduction potentials
of phthalimides, see: (d) Oelgemöller, M.; Griesbeck, A. G.; Lex, J.; Haeuseler,
A.; Schmittel, M.; Niki, M.; Hesek, D.; Inoue, Y. Org. Lett. 2001, 3, 1593–1596; (e)
Oelgemöller, M.; Haeuseler, A.; Schmittel, M.; Griesbeck, A. G.; Lex, J.; Inoue, Y.
J. Chem. Soc., Perkin Trans. 2002, 2, 676–686.
(phenoxymethyl)isoindolin-2-yl]methyl}phenyl acetate (5b): colorless solid, Rf
(n-hexane/EtOAc = 1/1) = 0.46, mp 120–122 °C. 1H NMR (400 MHz, CDCl3): d
(ppm) = 2.24 (s, 3H, CH3), 3.67 (br s, 1H, OH), 3.99 (d, J = 9.6 Hz, 1H, CH2O), 4.21
(d, J = 9.6 Hz, 1H, CH2O), 4.61 (d, J = 15.4 Hz, 1H, NCH2), 4.70 (d, J = 15.4 Hz, 1H,
NCH2), 6.63 (dd, J = 7.6, J = 1.4 Hz, 2H, Harom), 6.91 (m, 3H, Harom), 7.19 (d,
J = 8.4 Hz, 2H, Harom), 7.38 (d, J = 8.4 Hz, 2H, Harom), 7.52 (dd, J = 7.6, J = 1.4 Hz,
1H, Harom), 7.57 (dd, J = 7.6, J = 1.4 Hz, 1H, Harom), 7.67 (d, J = 7.6 Hz, 1H, Harom),
7.81 (d, J = 7.6 Hz, 1H, Harom). 13C NMR (100 MHz, CDCl3): d (ppm) = 21.5 (q, 1C,
CH3), 42.2 (t, 1C, CH2), 70.2 (t, 1C, CH2), 89.5 (s, 1C, COH), 114.8 (d, 2C, CH),
121.9 (d, 2C, CH), 123.0 (d, 1C, CH), 123.9 (d, 1C, CH), 129.5 (d, 2C, CH), 129.8 (d,
2C, CH), 130.5 (d, 1C, CH), 131.4 (s, 1C, Cq), 132.8 (d, 1C, CH), 132.9 (d, 1C, CH),
136.1 (s, 1C, Cq), 145.5 (s, 1C, Cq), 150.1 (s, 1C, Cq), 157.9 (s, 1C, Cq), 168.3 (s,
32. Fox, M. A. Photoinduced Electron Transfer in Organic Systems Control of Back
Electron Transfer In Advances in Photochemistry; Volman, D. H., Hammond, G.
S., Gollnick, K., Eds.; John Wiley & Sons: Hoboken, NJ, 2007; Vol. 13,.
33. (a) Tan, S. B.; Shvydkiv, O.; Fiedler, J.; Hatoum, F.; Nolan, K.; Oelgemöller, M.
Synlett 2010, 2240–2243; (b) Baciocchi, E.; Del Giacco, T.; Elisei, F.; Lapi, A. J.
Org. Chem. 2006, 71, 853–860; (c) Bowers, P. R.; McLauchlan, K. A.; Sealy, R. C. J.
Chem. Soc., Perkin Trans. 2 1976, 915–921; (d) Davidson, R. S.; Harrison, K.;
Steiner, P. R. J. Chem. Soc. (C) 1971, 3480–3482; (e) Davidson, R. S.; Steiner, P. R.
J. Chem. Soc. (C) 1971, 1682–1689.
34. (a) Oelgemöller, M. Chem. Eng. Technol. 2012, 35, 1144–1152; (b) Oelgemöller,
M.; Shvydkiv, O. Molecules 2011, 16, 7522–7550; (c) Coyle, E. E.; Oelgemöller,
M. Photochem. Photobiol. Sci. 2008, 7, 1313–1322.
35. Farcas, S.; Namy, J.-L. Tetrahedron Lett. 2001, 42, 879–881.
36. Wittig, G.; Streib, H. Liebigs Ann. Chem. 1953, 584, 1–22.
1C, C@O), 169.8 (s, 1 C, C@O). IR (ATR): m
(cmÀ1) = 3213, 3060, 2916, 1761,
1668, 1435, 1403, 1234, 1196, 1168, 1067, 910. HR–MS (ESI, positive ions):
Calcd. [M+Na]+: 426.1312 C24H21NO5+Na+. Found [M + Na]+: 426.1302.
22. (a) Xu, M.; Lukeman, M.; Wan, P. J. Photochem. Photobiol., A: Chem. 2009, 204,
52–62; (b) Su, Z.; Mariano, P. S.; Faley, D. E.; Yoon, U. C.; Oh, S. W. J. Am. Chem.
Soc. 1998, 120, 10676–10686.
23. Griesbeck, A. G.; Oelgemöller, M.; Lex, J.; Haeuseler, A.; Schmittel, M. Eur. J. Org.
Chem. 2001, 1831–1843.
24. General procedure for dehydration/deprotection: Compounds 3 or 5 (100 mg)
were dissolved in acetone (10 mL), H2O (7 mL), and conc. HCl (3 mL). This
solution was refluxed for 5 h. After stirring overnight at room temperature,
H2O (50 ml) was added and most of the acetone was removed by rotary
evaporation. In most cases, the desired product precipitated on standing and
37. Flynn, G. A. J. Chem. Soc., Chem. Commun. 1980, 862–863.