Hetero-Diels-Alder reaction of photochemically generated α-hydroxy-o-quinodimethanes with trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2012.05.082

Hetero-Diels-Alder reaction of α-hydroxy-o-quinodimethanes photochemically generated from o-tolualdehydes with trifluoromethyl ketones gave a mixture of hemiacetals and hydroxyaldehydes in fairly good yields. Their subsequent oxidation with PCC provided 1-isochromanones as formal oxidative [4+2] cycloaddition products. In contrast, similar reaction of aromatic ketones such as o-methylbenzophenone, 1-indanone, and α-tetralone gave exclusively the corresponding ketones having (trifluoromethyl)methylol groups at the o-position.

Full text of DOI:10.1016/j.tetlet.2012.05.082

Tetrahedron Letters 53 (2012) 3974–3976
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hetero-Diels–Alder reaction of photochemically generated
a-hydroxy-o-quinodimethanes with trifluoromethyl ketones
⇑
Ken Takaki , Toshifumi Fujii, Hosei Yonemitsu, Makoto Fujiwara, Kimihiro Komeyama, Hiroto Yoshida
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Kagamiyama, Higashi-Hiroshima 739-8527, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Hetero-Diels–Alder reaction of a-hydroxy-o-quinodimethanes photochemically generated from o-tolual-
Received 16 March 2012
Revised 12 May 2012
Accepted 18 May 2012
Available online 24 May 2012
dehydes with trifluoromethyl ketones gave a mixture of hemiacetals and hydroxyaldehydes in fairly good
yields. Their subsequent oxidation with PCC provided 1-isochromanones as formal oxidative [4+2] cyclo-
addition products. In contrast, similar reaction of aromatic ketones such as o-methylbenzophenone, 1-
indanone, and
a-tetralone gave exclusively the corresponding ketones having (trifluoromethyl)methylol
groups at the o-position.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Photoreaction
a-Hydroxy-o-quinodimethanes
Hetero-Diels–Alder reaction
o-Tolualdehydes
Trifluoromethyl ketones
O
O
O
o-Quinodimethanes (oQDMs) have been well known as reactive
dienes in Diels–Alder reaction, and they are generated by various
methods such as thermolysis of benzocyclobutenes and
benzo-fused heterocyclic compounds, and 1,4-elimination of
R3
2
R2
O
H
R1
R1
R3
R2
1
3
a,a a-hydro-
’-substituted o-xylenes.1 Photochemical generation of
hν
oxidation
xy-o-quinodimethanes (HoQDMs) from o-tolualdehydes is also a
convenient and attractive approach to elaborate benzocyclohexane
derivatives via Diels–Alder reaction.2 On the other hand, hetero-
Diels–Alder reaction of oQDMs with ketones and imines to yield
isochromans and tetrahydroisoquinolines has been little explored,
wherein most of the reaction used benzocyclobutene precursors
having 1-silyloxy and 1-alkoxy substituents.3,4 The similar reaction
of HoQDM would be more difficult than that of oQDM, because by-
products derived from HoQDM and o-tolualdehyde precursors
could be formed. In fact, only one example has been reported,
but the products were isolated as a mixture.5
With these results in mind, we designed oxidative hetero-
Diels–Alder reaction of o-tolualdehydes 1 with ketones 2 to yield
1-isochromanones 3 (Scheme 1). Generation of HoQDM A by irra-
diation of 1 and its trapping with 2 would yield an equilibrium
mixture of hemiacetal B and hydroxyaldehyde C. If the mixture
could be efficiently oxidized to 3,6 the overall transformation could
be regarded as a formal oxidative [4+2] cycloaddition. Herein we
would like to report these results.
OH
OH
O
2
O
H
R1
R1
R1
R3
R2
R2 OH
R3
A
B
C
Scheme 1. Oxidative hetero-Diels–Alder reaction of o-tolualdehydes.
After screening of various trapping reagents for HoQDM, it was
found that trifluoromethyl ketones acted as good dienophiles.7
Thus, when a solution of mesitaldehyde (1a) and phenyl trifluoro-
methyl ketone (2a) (1.1 equiv) in MeCN was irradiated by Hg lamp
for 3 h, an inseparable mixture of hemiacetal B and hydroxyalde-
hyde C was obtained, which was subsequently treated with PCC in
DCM in the presence of molecular sieves to give only 1-isochroma-
none 3a in 75% yield. The results using various o-tolualdehyde deriv-
atives 1 and trifluoromethyl ketones 2 are summarized in Table 1.8
The reactions of 2,4-dimethylbenzaldehyde (1b) and o-tolualde-
hyde (1c) with the ketone 2a gave the 1-isochromanones 3b and
3c in 57% and 68% yields, respectively, (entries 2 and 3). Similarly
the expected product 3d was obtained from 4-fluoro-2-methyl-
benzaldehyde (1d) (entry 4). o-Benzyl- and o-heptylbenzaldehyde
⇑
Corresponding author.
E-mail address: ktakaki@hiroshima-u.ac.jp (K. Takaki).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.082

K. Takaki et al. / Tetrahedron Letters 53 (2012) 3974–3976
3975
Table 1
Photochemical synthesis of 1-isochromanones by hetero-Diels–Alder reaction followed by PCC oxidationa
O
i) hν,
O
O
MeCN, rt
H
3
O
R1
F3C R3
R1
+
R
ii) PCC, MS 4Å,
DCM, rt, 2-5 h
CF3
R2
R2
1
2
3
Entry
1
Aldehyde 1
Ketone 2
Timeb (h)
Product 3
Yieldc (%) (dr)
O
O
O
H
F3C Ph
O
O
3
75
57
68
54
Ph
2a
CF3
1a
3a
O
O
H
2
3
4
2a
2a
2a
6
Ph
CF3
1b
O
3b
O
O
H
12
4
Ph
CF3
1c
3c
O
O
H
O
Ph
F
F
CF3
1d
O
3d
O
H
O
Ph
5
6
2a
2a
17
6
44 (63/37)
61 (53/47)
CF3
1e
3e
Ph
O
Ph
O
O
H
Ph
CF3
1f n-Hex
3f n-Hex
O
O
F3C
O
7
8
1a
24
8
30
39
CF3
2bd
3g
O
O
Ph
Ph
F3C
O
O
1a
1a
2cd
CF3
3h
O
O
n-Bu
F3C
9
9
36
n-Bu
CF3
2dd
3i
a
b
c
Reaction conditions: (i) 2 (1.1 equiv), anhydrous MeCN (0.1 M), high-pressure Hg lamp (100 w); (ii) PCC (1.1 equiv), DCM (0.3 M).
Irradiation time.
Isolated yield.
d
2 Equiv of 2b–2d were used.
(1e) and (1f) participated the reaction to yield 3e and 3f in 44% and
61% yields with diastereomer ratios of 63/37 and 53/47, respec-
tively, (entries 5 and 6). Trifluoromethyl ketones other than 2a could
be used in this transformation. Thus, the reaction of mesitaldehyde
(1a) with 1,1,1-trifluoroacetone (2b) and benzyl trifluoromethyl ke-
tone (2c) gave the corresponding products 3g and 3h in 30% and 39%
yields, respectively, (entries 7 and 8). 3-Hexynyl-1-isochromanone
3i was also prepared in 36% yield from 1a and 1-trifluoroacetyl-1-
hexyne (2d) by the standard procedure (entry 9). However, when
the reaction mixture formed by irradiation of 1a with 2d was re-
duced with NaBH4, diol 4i was obtained in 60% yield (Eq. 1). Thus,
low yield of 3i may be caused by the oxidation step to yield uniden-
tified by-products.
i) hν,
OH
OH
CF3
4i 60%
MeCN, rt
1a + 2d
ð1Þ
n-Bu
ii) NaBH4,
MeOH, rt, 2h
Next, hetero-Diels–Alder reaction of 2-methylbenzophenone
(5) with trifluoromethyl ketones 2 was investigated (Table 2).8 In
contrast with the reaction of o-tolualdehydes 1, irradiation of 5
together with phenyl trifluoromethyl ketone (2a) gave directly
o-(hydroxyethyl)benzophenone 6a in 65% yield, wherein a corre-
sponding ketal was not detected (entry 1). Similar results were
obtained using various trapping reagents 2. The difference
between 1 and 5 would be attributed to the equilibrium of the

3976
K. Takaki et al. / Tetrahedron Letters 53 (2012) 3974–3976
Table 2
OH
OH
Photochemical reaction of o-methylbenzophenone (5) with trifluoromethyl ketones
h
ν
2a
2a
O
1g
9a
vs.
CF3
Ph
9b
A' OMe
OMe
O
h
ν
,
O
O
MeCN, rt
Ph
Ph
R
+
O
H
•
O
H
F3C
R
OH
• CF3
1g
2a*
+
5
2
HO
OH
CF3
Ph
6
CF3
MeO
Ph
D
C'
OMe
E
Entry
Ketone
Time (h)
Product 6
Yieldb (%)
Scheme 2. Reaction process by hetero-Diels–Alder reaction versus radial coupling.
2
R
1
2
3
2ac
2b
2c
Ph
Me
CH2Ph
11
21
8
6a
6b
6c
65
53
61
In summary, formal oxidative [4+2] cycloaddition of o-tolualde-
hydes with trifluoromethyl ketones to yield 1-isochromanones has
been achieved through hetero-Diels–Alder reaction of the
n-Bu
Ph
4
2d
14
6d
74
5
6
2e
2f
48
48
6e
6f
73
46
photochemically generated
a-hydroxy-o-quinodimethanes and
CF3
subsequent oxidation with PCC. On the other hand, o-methylben-
zophenone and benzocycloalkan-1-ones reacted with the trapping
reagents under irradiation to yield o-substituted ketones
exclusively.
a
b
c
Reaction conditions: 2 (2.0 equiv), anhydrous MeCN (0.1 M).
Isolated yield.
1.5 Equiv of 2a were used.
hetero-Diels–Alder products, that is, ketals could shift to hydroxy-
ketones exclusively. Moreover, the products 6 may be converted to
the other HoQDM by further irradiation, because they have
carbonyl and o-methylene groups. However, no photoreaction of
the isolated 6a was observed in the presence of the representative
trapping reagents such as N-phenylmaleimide and dimethyl
acetylenedicarboxylate.1
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.082.
References and notes
The photoreaction of o-methylacetophenone with 2a was found
to take place by GC monitoring, but isolation of the expected prod-
ucts failed because of many by-products. Surprisingly, 1-indanone
1. For reviews, see: (a) Segura, J. L.; Martín, N. Chem. Rev 1999, 99, 3199–3246; (b)
Charlton, J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873–2889.
2. (a) Nicolaou, K. C.; Gray, D. L. F. J. Am. Chem. Soc. 2004, 126, 607–612; (b)
Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613–627.
3. (a) Benda, K.; Regenhardt, W.; Schaumann, E.; Adiwidjaja, G. Eur. J. Org. Chem.
2009, 1016–1021; (b) Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2000, 39, 1937–1940; (c) Craig, D.; Robson, M. J.; Shaw, S. J.
Synlett 1998, 1381–1383; (d) Chino, K.; Tanaka, T.; Endo, T. Synth. Commun.
1996, 26, 2145–2154; (e) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1976,
98, 6755–6757.
(7a) and
a-tetralone (7b) gave the hydroxyketones 8a and 8b in
38% and 32% yields with diastereomer ratios of 52/48 and 50/50,
respectively, (Eq. 2). Although the yield and stereoselectivity were
low, the results would demonstrate unprecedented generation of
the HoQDM from benzocycloalkan-1-ones.
4. Palladium-catalyzed generation of an equivalent to oQDM and its reaction with
ketones and imines have been recently reported; see: (a) Ueno, S.; Ohtsubo, M.;
Kuwano, R. Org. Lett. 2010, 12, 4332–4334; (b) Ueno, S.; Ohtsubo, M.; Kuwano,
R. J. Am. Chem. Soc. 2009, 131, 12904–12905.
5. Griesbeck, A. G.; Stadtmüller, S. Chem. Ber. 1993, 126, 2149–2150.
6. DDQ oxidation of trimethylsilylhemiacetal to ester has been known; see: Ref.
3b.
7. Irradiation of mesitaldehyde (1a) in the presence of other ketones such as
acetophenone, phenyl trichloromethyl ketone, phenylglyoxal, and ethyl
benzoylformate resulted in the quantitative recovery of the both starting
materials or decomposition of the trapping reagents.
O
O
h
ν
, MeCN
+
2a
n
n
rt, 96h
Ph
ð2Þ
HO
CF3
7a: n = 1
7b: n = 2
8a 38% (dr = 52/48)
8b 32% (dr = 50/50)
8. General procedure for the reaction listed in Tables 1 and 2. A pyrex test tube
When o-(methoxymethyl)benzaldehyde (1g) was irradiated to-
gether with 2a under standard conditions, 4-isochromanol 9a was
directly formed in 55% yield as a mixture of two diastereomers (60/
40) (Eq. 3).9 However, hemiacetal 9b, regioisomer of 9a, and
hydroxyaldehyde C’ were not obtained. Regioselectivity in the
hetero-Diels–Alder reaction of HoQDM A’ generated from 1g was
reversed probably by the methoxy substituent (Scheme 2). More
importantly, formation of 9a would rule out an alternative reaction
process, which includes hydrogen abstraction from 1g by photo-
excited ketone 2a⁄10and subsequent coupling of the resulting two
radicals D and E, because this process should provide 9b via C’,
instead of 9a.
containing o-tolualdehydes
1
(1.0 mmol), trifluoromethyl ketones
2
(1.1 mmol), and CH3CN (10 mL) was purged with nitrogen and irradiated at
room temperature by high-pressure Hg lamp (100 W) with monitoring by GC
and TLC. After the reaction being completed, the solvent was evaporated to
leave a solid or viscous oil. Then, this mixture and pyridinium chlorochromate
(237 mg, 1.1 mmol) were dissolved in dichloromethane (3 mL). After addition
of molecular sieves 4 Å (100 mg), the mixture was stirred for 2–5 h at room
temperature. The reaction mixture was passed through celite, evaporated in
vacuo, and chromatographed on silica gel using hexane-EtOAc (10/1) eluent to
give the 1-isochromanones 3. The reactions of 5 and 7 were carried out
similarly, but the products 6 and 8 were isolated without the oxidation.
9. Although stereochemistry of 9a could not be determined, its regiochemistry
was distinguishable from that of 9b, because 9a was recovered unchanged on
treatment with NaBH4.
10. Kamijo, S.; Hoshikawa, T.; Inoue, M. Tetrahedron Lett. 2011, 52, 2885–2888.
OH
O
O
CF3
Ph
O
h
ν
, MeCN
rt, 2h
H
+
Ph CF3
ð3Þ
OMe
OMe
2a
9a
55% (60/40)
1g