Further Insight into the Photochemical Behavior of Aromatic γ,δ-Epoxy Ketones: A New Approach for Synthesis of 4-Methyleneisochromanols

Article abstract of DOI:10.1055/s-0034-1378814

The photochemical behavior of methyl-substituted aromatic γ,δ-epoxy ketones was investigated by irradiation with a 500 W high-pressure mercury lamp in benzene which led to the formation of 4-methyleneisochromanols through δ-hydrogen abstraction-epoxy rear

Full text of DOI:10.1055/s-0034-1378814

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1997–2000
letter
1997
B. Li et al.
Letter
Synlett
Further Insight into the Photochemical Behavior of Aromatic
γ,δ-Epoxy Ketones: A New Approach for Synthesis of 4-Methy-
leneisochromanols
Bing Li
Chao Yang
Weitao Xia
Wujiong Xia*
State Key Lab of Urban Water Resource and Environment, the Academy of
Fundamental and Interdisciplinary Sciences, Harbin Institute of Technology,
Harbin 150080, P. R. of China
xiawj@hit.edu.cn
Received: 07.05.2015
Accepted after revision: 21.06.2015
Published online: 30.07.2015
oxy ketones have discovered that the type of photoinduced
ring opening of epoxides is alternative depending on the
substitution and the nature of reactive excited states of
substrates.2 Recently, we have developed a novel and effi-
cient way to prepare polysubstituted benzocyclobutanones
and indanones through the investigations on the photo-
chemistry of terminal and substituted aromatic γ,δ-epoxy
ketones in which the process involves the abstraction of γ-
hydrogen as the typical first step of Norrish type II reac-
tion3 and the Lewis acid free semipinacol rearrangement–
photocyclization cascade reaction (Scheme 1, a).4 Herein
we further investigated the photochemical behavior of sub-
stituted γ,δ-epoxy ketones in which the γ-hydrogen is re-
placed by a methyl group and found that 4-methyleneiso-
chromanol compounds were obtained via initial abstraction
of δ-hydrogen instead (Scheme 1, b). Such a conversion pro-
vides an easy and quick access to the synthesis of isochro-
DOI: 10.1055/s-0034-1378814; Art ID: st-2015-w0344-l
Abstract The photochemical behavior of methyl-substituted aromatic
γ,δ-epoxy ketones was investigated by irradiation with a 500 W high-
pressure mercury lamp in benzene which led to the formation of 4-
methyleneisochromanols through δ-hydrogen abstraction–epoxy rear-
rangement–1,5-biradical cyclization reactions.
Key words γ,δ-epoxy ketones, photochemical behavior, 4-methylene-
isochromanol, epoxy rearrangement, 1,5-biradical cyclization
Organic photochemical reactions play an important role
in building organic frameworks that are otherwise difficult
to make.1 Considerable research efforts have concentrated
on the development of new photochemical reactions.
Among them, photochemical studies on epoxides and ep-
a) previous work
O
H
R1
O
hν
R2
steps
R2
OH
R2
R1
R1
γ-H abstraction
O
O
OH
1
2
b) this work
H
O
O
OH
hν
steps
R3
R3
R3
δ-H abstraction
O
OH
O
Ar
Ar
Ar
4
3
γ-H unavailable
Scheme 1 Previous work and our further investigations.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1997–2000

1998
B. Li et al.
Letter
Synlett
manol derivatives,5 the versatile synthetic building blocks
of natural products6 which urges us to investigate this reac-
tion in detail.
Table 1 Optimization of Reaction Conditionsa
O
OH
hν
Our investigation was started from the synthesis of
methyl-substituted γ,δ-epoxy ketone 3a (R1 = Ph, R2 = H) us-
ing olefin 5a (R2 = H) as the starting material according to
the known straightforward steps (Scheme 2). The initial
photochemical study on 3a was conducted by irradiation
with a 500 W high-pressure mercury lamp in benenze for
40 minutes which led to a product of 4-methyleneisochro-
manol 4a in 52% yield (Scheme 3). The structure of 4a was
determined by its spectroscopic properties, in particular its
1D and 2D NMR spectra.
solvent
O
O
Ph
4a
Ph
3a
Entry Solvents
Gas Wavelength
(nm)
Conversionb Yield
(%)c
1
2
3
4
5
6
7
8
anhydrous benzene
N2
N2
air
N2
N2
N2
N2
N2
>280 (Pyrex) 100
354
63
anhydrous benzene
anhydrous benzene
normal benzene
0
0
52
52
56
55
0
>280 (Pyrex) 100d
>280 (Pyrex) 100
>280 (Pyrex) 100
>280 (Pyrex) 100
>280 (Pyrex) 100
>280 (Pyrex) 100
a
anhydrous acetone
anhydrous MeCN
R1-CHO
+
OH
Br
R2
R2
R1
O
anhydrous benzene, InCl3
5
6
anhydrous benzene,
BF3·OEt2
0
a Reactions were carried out with 3a (0.1 mmol) in 10 mL of solvent at r.t.
b
b Irradiated for 40 min.
c Isolated yields.
c
O
O
d Completed in 100 min.
R2
R2
R1
R1
3
7
action also could proceed under air but longer time was
needed (Table 1, entry 3).
Scheme 2 Synthesis of γ,δ-epoxy ketones 3. Reagents and conditions:
a) n-BuLi, THF, –70 °C; b) PCC, CH2Cl2; c) Oxone, MeCN, H2O, 18-crown-6,
acetone, NaHCO3, 0 °C.
With the optimized reaction conditions in hand, we
therefore prepared a series of methyl-substituted aromatic
γ,δ-epoxy ketones to investigate the scope of the reaction.7
As shown in Table 2, the reactions were completed within
30–50 minutes at room temperature to form the desired
products in moderate to good yields. The electron effect on
the pendent aryl group has no influence on the results of
the reactions, for example, when R1 was an electron-with-
drawing or an electron-donating group located at different
positions, the corresponding products were obtained in 45–
76% yield (Table 2, entries 2–9, 11) with the diastereoiso-
meric ratio ranging from 1:3 to 3.6. Even if the substrate
was highly electron deficient, the desired product also
could be prepared in 40% yield (Table 2, entry 10). When
the phenyl group adjacent to the epoxy ring was substitut-
ed with an electron-withdrawing group, such as F, the reac-
tion still goes smoothly to afford the corresponding prod-
ucts (Table 2, entries 13 and 14). It seems that it is neces-
sary for R1 to be an aryl group or conjugated group, for
example, the corresponding product was formed as the
phenyl group was replaced by a thiophene although the
yield is not good (Table 2, entry 12). However, the reaction
of 3o led to the diketone compound 8 in very low yield
along with other byproducts (Scheme 4, eq. 1) which might
result from the decomposition of the starting material. The
similar result was also observed on the reaction of the p-
methoxy phenyl ketone compound 3p whose lowest triplet
O
OH
hν
benzene
O
O
Ph
4a
Ph
3a
Scheme 3 Initial photochemical studies of 3a
Based upon the initial result, the optimization of reac-
tion conditions were then conducted by treatment of 3a
with different solvents and wavelengths, and results are
listed in Table 1. As it can be seen, the reaction proceeded in
anhydrous benzene using a 500 W high-pressure mercury
lamp as light source led to the best yield (Table 1, entry 1).
In contrast, no reaction was observed when 354 nm wave-
length was used which might be due to the difficulty in ex-
citation of the substrate at this wavelength. The complex
products were observed when Lewis acids such as InCl3,
BF3·OEt2 were employed in the reaction as additives (Table
1, entries 2, 7, and 8). Reactions conducted in other sol-
vents, such as acetone and acetonitrile, or undried benzene,
led to lower yields (Table 1, entries 4–6). In addition, the re-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1997–2000

1999
B. Li et al.
Letter
Synlett
state is known as π,π* failed to form the desired isochroma-
O
O
nol product but the diketone 9 in 18% yield (Scheme 4, eq.
2).
hν
(1)
O
O
benzene
Table 2 Scope of the Photorearrangement
<10%
O
3o
8
OH
O
O
hν
benzene
MeO
O
O
MeO
hν
R2
(2)
R2
R1
R1
O
benzene
O
3
4
18%
Ph
Ph
3p
9
Entry
Substrate
Time
(min)
Yield (%)a (dr)b
Scheme 4
1
2
3a R1 = Ph, R2 = H
40
30
40
40
40
40
40
40
40
40
40
40
50
50
4a 63 (1:3.1)
4b 60 (1:3.4)
4c 61 (1:3.5)
4d 70 (1:3)
3b R1 = 2-FC6H4, R2 = H
3c R1 = 3-FC6H4, R2 = H
3d R1 = 4-FC6H4, R2 = H
3e R1 = 3-ClC6H4, R2 = H
3f R1 = 4-ClC6H4, R2 = H
3g R1 = 3-MeC6H4, R2 = H
3h R1 = 4-MeC6H4, R2 = H
3i R1 = 4-F3CC6H4, R2 = H
3j R1 = 3-Cl-4-FC6H3, R2 = H
3k R1 = 4-t-BuC6H4, R2 = H
3l R1 = 2-thiophene, R2 = H,
3m R1 = Ph, R2 = 4-F
bonyl group of 3 to form the 1,2-biradical under UV light ir-
radiation via an n,π* triplet state, which was then trans-
formed to 1,5-biradical intermediate 11 after abstraction of
a δ-hydrogen of epoxy ring. Epoxy ring opening of 11 led to
forming of carbonyl group and the 1,4-biradical of 12,
which then afforded the 1,2-biradical intermediate 13 after
the abstraction of hydrogen. Final product 4 was obtained
from the formation of the C–C double bond and pyran ring.
In conclusion, the photochemical behavior of methyl-
substituted aromatic γ,δ-epoxy ketones in benzene solution
was investigated. This protocol provides an easy access to
isochromanol derivatives and highlights the application of
photochemistry in the realm of organic synthesis. We are
continuing to explore the scope of this transformation as
well as further mechanistic investigations.
3
4
5
4e 76 (1:3.3)
4f 54 (1:3)
6
7
4g 48 (1:3)
8
4h 57 (1:3)
9
4i 57 (1:3.6)
4j 40 (1:2.8)
4k 45 (1:3.5)
4l 20 (1:3.6)
4m 65 (1:3.3)
4n 32 (1:2.7)
10
11
12
13
14
3n R1 = 4-FC6H4, R2 = 4-F
a Isolated yields.
b The diastereomeric ratios are calculated from their 1H NMR spectra indi-
cating the ratio of between cis and trans products.
Acknowledgment
We are grateful for the financial supports from China NSFC (Nos.
21002018, 21072038 and 21472030), SKLUWRE (No. 2015DX01), the
Fundamental Research Funds for the Central Universities (Grant No.
HIT.BRETIV.201310) and HLJNSF (B201406).
Based upon the above results and previous work,4 the
reaction mechanism was accordingly proposed and depict-
ed in Scheme 5. A common step is the excitation of the car-
O
O
O
O
OH
hν
O
O
OH
ISC
R2
R2
R1
R1
R2
R2
abstraction of H
ISC
R1
R1
3
11
12
10
CH2
CH2
O
O
OH
O
OH
OH
R2
R2
R2
R1
R1
R1
14
4
13
Scheme 5 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1997–2000

2000
B. Li et al.
Letter
Synlett
Supporting Information
2361. (d) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew.
Chem. Int. Ed. 2004, 43, 1998. (e) Shi, L.; Meyer, K.; Greaney, M.
F. Angew. Chem. Int. Ed. 2010, 49, 9250.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378814.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(7) Typical Experimental Procedure for the γ,δ-Epoxy Ketone 3
and Isochromanol 4
To round-bottomed flask was added olefin 7 (0.2 mmol),
acetone (2 mL), H2O (1 mL), MeCN (1 mL), NaHCO3 (2 mmol), 18-
crown-6 (0.002 mmol), the mixture was cooled to 0 °C, and
Oxone (0.6 mmol) was dissolved in H2O and added slowly. After
addition, the reaction was stirred at the same temperature until
no starting material could be detected by TLC. The mixture was
extracted with CH2Cl2, the combined organic phase was washed
with sat. NaHCO3, brine, and dried over Na2SO4, then quickly
purified through a neutral Al2O3 gel column (PE–EtOAc) to give
3, which is unstable, refrigerated storage. The γ,δ-epoxy ketone
3 (0.1 mmol) in anhydrous benzene (10 mL) was treated with N2
for 10 min in darkness, and then irradiated by a 500 W high-
pressure mercury lamp with condensate until no starting mate-
rial could be detected by TLC. The solvent was removed in
vacuo, and the residue was purified by silica gel column chro-
matography (PE–EtOAc) to give the desired product 4.
References and Notes
(1) For reviews, see: (a) Griesbeck, A. G.; Hoffmann, N.; Warzecha,
K. Acc. Chem. Res. 2007, 40, 128. (b) Winkler, J. D.; Bowen, C. M.;
Liotta, F. Chem. Rev. 1995, 95, 2003. (c) Hoffmann, N. Pure Appl.
Chem. 2007, 79, 1949. (d) CRC Handbook of Organic Photochem-
istry and Photobiology; Griesbeck, A.; Oelgemöller, M.; Ghetti, F.,
Eds.; CRC Press: Boca Raton, 2011, 3rd ed.; and references cited
therein.
(2) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(3) For a general review of the Norrish type II reaction, see:
(a) Wagner, P.; Park, B. S. In Organic Photochemistry; Vol. 11;
Padwa, A., Ed.; Chap. 4; Marcel Dekker: New York, 1991.
(b) Wagner, J. P. CRC Handbook of Organic Photochemistry and
Photobiology; Horspool, W.; Lenci, F., Eds.; CRC Press: Boca
Raton, FL, 2004, 2nd ed. Chap. 58.
1-(4-tert-Butylphenyl)-4-methyleneisochroman-3-ol (4k)
Colorless oil. Yield 45%. 1H NMR (400 MHz, CDCl3): δ = 7.72 (d, 1
H, J = 7.8 Hz), 7.42 (d, 2 H, J = 7.3 Hz), 7.29 (d, 3 H, J = 7.1 Hz),
7.19 (t, 1 H, J = 7.4 Hz,), 6.79 (d, 1 H, J = 7.7 Hz), 6.07 (s, 0.77 H),
5.91 (s, 0.24 H), 5.85 (s, 0.78 H), 5.82 (s, 0.74 H), 5.79 (s, 0.22 H),
5.67 (d, 0.22 H, J = 7.8 Hz), 5.53 (s, 0.22 H), 5.35 (s, 0.77 H), 3.21
(d, 0.20 H, J = 7.7 Hz), 3.08 (s, 0.74 H), 1.35 (s, 9 H).13C NMR (100
MHz, CDCl3): δ = 151.4, 151.3, 141.6, 139.6, 138.1, 137.8, 137.0,
136.7, 131.5, 129.8, 128.5, 128.0, 127.4, 127.3, 126.6, 126.5,
125.5, 124.2, 123.9, 110.8, 107.7, 94.1, 93.9, 79.1, 73.2, 34.6,
31.4. ESI-HRMS: m/z calcd for C20H23O2+: 295.1698 [M + H]+;
found: 295.1696.
(4) Shao, Y.; Yang, C.; Gui, W.; Liu, Y.; Xia, W. Chem. Commun. 2012,
48, 3560.
(5) (a) Dijoux-Franca, M.-G.; Tchamo, D.; Cherel, B.; Cussac, M.;
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1997–2000