Efficient synthesis of polysubstituted isochromanones via a novel photochemical rearrangement

Article abstract of DOI:10.1039/c1cc14269k

A novel and convenient approach to the synthesis of polysubstituted isochromanones is described. Irradiation of 2-formyl phenylalkeno-derivatives with UV light in benzene solution afforded the corresponding products in up to 98% yield. The possible reaction mechanism is proposed and further supported by the isotopic experiments.

Full text of DOI:10.1039/c1cc14269k

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COMMUNICATION
Efficient synthesis of polysubstituted isochromanones via a novel
photochemical rearrangementw
Wujiong Xia,*ab Yutian Shao,a Weijun Guia and Chao Yanga
Received 15th July 2011, Accepted 1st September 2011
DOI: 10.1039/c1cc14269k
A novel and convenient approach to the synthesis of polysub-
stituted isochromanones is described. Irradiation of 2-formyl
phenylalkeno-derivatives with UV light in benzene solution
afforded the corresponding products in up to 98% yield. The
possible reaction mechanism is proposed and further supported
by the isotopic experiments.
groups of the photoproduct constructed in one step from a
simple cinnamic acid ester are versatile building blocks in
organic synthesis,6 which urged us to investigate this reaction
in detail.
Upon initial investigation of the reaction conditions, we
were encouraged to treat 1a with different wavelengths in
combination with different solvents (benzene, acetone, aceto-
nitrile, DMF and DMSO), and the results are listed in Table 1.
As can be seen, the reaction proceeds efficiently in all employed
solvents with 52–89% yield at high conversions. Finally,
screening of the conditions on GC showed that the reaction
conducted in benzene, using a 500 W high-pressure mercury
lamp as the light source through a Pyrex filter, produced the
highest yield which were then utilized as the reaction conditions
in further investigations.7
Organic photochemical reactions play an important role in the
context of green chemistry and/or total synthesis.1 The photon
involved in the procedure can be considered as the ideal clean
reagent for organic synthesis in contrast to toxic chemical
activators.2 Another big advantage of reactions in the excited
state is their application in the synthesis of polycyclic or highly
functionalized molecules which would be difficult to access
with standard chemistry reactions in the ground state.3 There-
fore, the field of organic photochemical reactions has received
considerable interest from both academia and industry.4 During
our continuous investigations on the photochemical synthesis of
furans or pyrans,5 we recently discovered a novel and efficient
route to the synthesis of polysubstituted isochromanones via
a unique photochemical rearrangement. In this paper, we
present what we have learned to date about this unusual and
interesting new reaction.
To explore the scope of this reaction, we prepared a variety
of 2-formyl phenylalkeno-derivatives (for preparations see
Supporting Informationw) and subjected them to the reaction
conditions, which uniformly afforded the desired photo-
product in good to excellent yields (63–98%; Table 2, entries
1–11). As can be seen, both simple alkyl cinnamate (entries 1
and 2) and bulky alkyl cinnamate (entries 3 and 4) provided
the desired products. The presence of substituents at the para
or meta position of the aldehyde group was tolerated for the
reaction independently of their electron-donating or electron-
withdrawing effect (entries 5, 6, 9, 10). Irradiation of (Z)-ethyl
3-(2-formylphenyl)acrylate also smoothly afforded the corres-
ponding photoproduct in high yield (entry 11).8 It is note-
worthy that the formation of photoproduct 2a was affected by
the substitutions on the double bond. When the acrylate was
tethered with an alkyl group at the b position, the reaction
proceeded efficiently (entries 7 and 8) and highest yield was
obtained (entry 7), whereas the one containing a methyl group
at the a position only afforded the isomerization product
Our preliminary studies focused on the UV irradiation of
ethyl 3-(2-formylphenyl)acrylate, a substrate that we expected
might undergo a formal retro-Claisen photorearrangement
leading to a pyran compound.5 Irradiation of (E)-ethyl 3-(2-
formylphenyl)acrylate (Scheme 1, 1a) in a benzene solution
through Pyrex with a 500 W high-pressure mercury lamp for
1.5 h, to our delight, led to a single product in 89% isolated
yield. Based on its spectroscopic properties, in particular its
1D and 2D 1H NMR spectra, this photoproduct was assigned
as the compound 2a (Scheme 1). The conversion of 1a to 2a
provides a quick and easy way to synthesise polysubstituted
isochromanones. In addition, the lactone and cyclopropanyl
a State Key Lab of Urban Water Resource and Environment,
the Academy of Fundamental and Interdisciplinary Sciences,
Harbin Institute of Technology, Harbin 150080.
E-mail: xiawj@hit.edu.cn; Fax: (+)-86-451-86403760
b State Key Lab of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
w Electronic supplementary information (ESI) available: experimental
procedures and 1H and 13C NMR spectra for all new compounds. See
DOI: 10.1039/c1cc14269k
Scheme 1 Initial photochemical studies of 1a in benzene.
c
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Table 1 Irradiation of 1a in different solvents
Entry
Conditionsa
Conv. (%)b
Yield (%)b
1
2
3
4
5
Benzene, r.t., 1.5 h
Acetone, r.t., 1.5 h
Acetonitrile, r.t., 1.5 h
DMF, r.t., 1.5 h
98
88
100
100
100
89c
53
68
74
52
Scheme 2 Isolation of the byproducts 3 and 5.
DMSO, r.t., 1.5 h
that the photochemical conversion of 1a to 2a most likely
proceeds from the (p, p*)1 excited state. To add credence to
our mechanistic hypothesis, we were fortunate enough to
obtain compound 3 and 5 as the byproducts in the case of
entries 1 and 3 (Table 2) with isolated yields of 23% and 17%,
respectively (Scheme 2). Such products were presumably
formed from the intermediate of 1,4-biradicals 4.
a
b
A 500 W high-pressure mercury lamp as the light source. Detected
c
using GC. Isolated yield after purification by chromatography on SiO2.
Table 2 Photochemical studies on 2-formyl phenylalkeno-derivatives
Entry Substrate
Product
Time (h) Yield (%)a
Throughout our investigations, a control experiment was
conducted by the irradiation of 1b in which an acetyl group
replaced the aldehyde group. As expected, no desired photo-
product was observed, which indicates that the hydrogen of
the aldehyde group plays a crucial role in the reaction.
To further support our mechanistic hypothesis, we performed
labeling studies using deuterated compound 6 as a substrate.
Irradiation of 6 under the same reaction conditions successfully
afforded the photoproduct 7. On the basis of NMR analysis, it
was shown that the deuterium atom shifted from the aldehyde
group to the cyclopropane (Scheme 3).
1
2
3
4
R1 = Me
2.5
5.0
4.0
8.0
68
89
71
74
R1 = Et
R1 = CH(CH3)2
R1 = menthyl
5
6
R2 = Cl
7.0
3.0
75
74
R2 = MeO
Accordingly, we propose a mechanism wherein the double
bond of 8 is excited to form the 1,2-biradicals 9 under UV light
irradiation (Scheme 4). Sequentially, the abstraction of the
hydrogen from aldehyde group affords the 1,4-biradical 10,
which is then transformed to the ketene intermediate 11 via the
cleavage of the double bond of the aromatic group. Finally,
rearrangement of the exocyclic double bonds occurs, regenerating
the aromatic ring and forming the lactone and cyclopropane
groups in one step, which leads to the final photoproduct 12.
In a dramatic demonstration of the synthetic potential of
the reaction, a solution of 500 mg of (E)-ethyl 3-(2-formyl-
phenyl)acrylate in 150 mL of benzene was irradiated to 100%
conversion to afford an 80% isolate yield of the corresponding
photoproduct.
7
8
R3 = Me
1.0
5.0
98
82
n
R3 = Bu
9
10
R4 = MeO
R4 = Cl
2.0
7.0
63
73
11
12
4.5
82
50.0
60.0
49
b
—
13
—
a
b
Isolated yields at complete conversions. Only the isomerization
product obtained.
Scheme 3 Deuterium-labeling experiments.
instead of the desired product (entry 13). The reaction conditions
were also tolerant of a, b-unsaturated ketones (entry 12).
Although longer a reaction time was involved, the desired
photoproduct was obtained in moderate yield.
The photoreaction is not prevented by the addition of
stilbene, and no [2+2]-cyclodimerization products were observed
during the reaction. Based on the above control experiment
results and associated with the behavior of the excited state of
cinnamic acid esters that exhibits ineffective dimerization
proceeds from the singlet excited state,9 it could be proposed
Scheme 4 Proposed reaction mechanism.
c
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In summary, we have reported a convenient approach to the
synthesis of polysubstituted isochromanones via a novel photo-
chemical reaction. The lactone and cyclopropane groups of the
photoproducts have potential applications in bioactive mole-
cules synthesis. We are continuing to explore the scope of this
transformation as well as further mechanistic investigations.
We are grateful for the financial supports from China NSFC
(Nos. 20802013, 21002018 and 21072038), HIT.NSRIF (Nos.
01107866 and 01107986) and Wenzhou Science and Technology
Program (No. G20100056).
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c
11100 Chem. Commun., 2011, 47, 11098–11100
This journal is The Royal Society of Chemistry 2011