Synthesis of thiophenyl substituted cyclohexa-2,4-dien-1-one and its photocleavage coupling reaction with amines

Article abstract of DOI:10.1016/S0960-894X(00)00291-2

Thiophenyl substituted cyclohexa-2,4-dien-1-ones were synthesized and photolyzed in the presence of various amines to afford the amides containing diene moeties via the ketene intermediate under visible light irradiation at 38°C. (C) 2000 Elsevier Science

Full text of DOI:10.1016/S0960-894X(00)00291-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1551±1553
Synthesis of Thiophenyl Substituted Cyclohexa-2,4-dien-1-one
and its Photocleavage Coupling Reaction with Amines
Tae Woo Kwon,a,* Young Mee Kim,a Suk Jin Song,a Yong Uk Kwonb
and Sung Kee Chungb
aDepartment of Chemistry, Kyungsung University, Pusan 608-736, South Korea
bDepartment of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea
Received 22 March 2000; accepted 6 May 2000
AbstractÐThiophenyl substituted cyclohexa-2,4-dien-1-ones were synthesized and photolyzed in the presence of various amines to
a€ord the amides containing diene moeties via the ketene intermediate under visible light irradiation at 38 ꢀC. # 2000 Elsevier
Science Ltd. All rights reserved.
Since the pioneering work by Barton et al. on the pho-
tochemistry of cyclohexadienones of the ortho-type, 1, it
has been known that the phenolic nucleus are readily
cleaved to produce cis-ketene, 2, under UV light.1 We
have been interested in the synthesis and utilities of
symmetrical bis-cyclohexadienones such as 3, in which
two units of the photo active molecules are linked
through varying lengths of carbon tether. These type of
compounds, in principle, can be employed as molecular
measuring rods, e.g., measurement of the distance between
nucleophilic functional groups present on a protein or
DNA fragment. We previously reported the synthesis of
several cyclohexa-2,4-dien-1-ones, 1 (R1=CH3, R2=
CH2SCH3, CH2SO2CH3 and CH2SPh, R3=CH3, R4=
CH3, CH2COOH and CH2P(O)(OCH3)2) and their pho-
tocleavage reactions using a conventional mercury
lamp.2 In the presence of a variety of amines the reaction
gave the amide products containing the diene moieties in
good yields. In order to have a ready access to the sym-
metrical bichromophoric cyclohexadienone compounds,
it was thought desirable to have a functional group at
the C-4 position, which is robust to the photolysis and
amenable to further synthetic manipulations. With this
objective in mind, we synthesized new cyclohexa-2,4-
dien-1-ones with the CH2SPh functional group at the
C-4 position, and investigated its photolytic cleavage
reaction.
Scheme 1 summarizes the preparation of disul®de 8.
Commercially available 2,6-dimethylphenol, 4 was reac-
ted with 38% aqueous HCHO in NaOH solution to
provide 5 in 64% yield. The product 5 was treated with
thionyl chloride (0ꢀC, diethylether) to give 6 in quantita-
tive yield (mp=99±100ꢀC, lit3 100.5 ꢀC). Reaction of 6
with thiophenol in the presence of KOH gave the sub-
stitution product 7 in 86.2% yield.4 The target compound
*Corresponding author. E-mail: twkwon@star.kyungsung.ac.kr
Scheme 1.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00291-2

1552
T. W. Kwon et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1551±1553
Table 1. Photolytic reactions of dienone 8.
Product No.
Aminesa
Reaction time
Products
R
Rfb
Yieldc (%)
10
11
12
Pyrrolidine
Piperidine
9
4
9
0.19d
0.41d
0.22d
66
51
72
Morpholine
13
14
15
16
NH2CH2CH2CH2CH3
NH2 CH2CH2CH2OH
NH2CH2CH(OCH3)
10
9
10
10
0.16e
0.29d
0.28d
0.31d
-NHCH2CH2CH2CH3
-NHCH2CH2CH2OH
-NHCH2CH(OCH3) 2
-NHC(CH3) 2CH2OH
69
46
70
39
2
NH2C(CH3) CH2OH
2
aThe amines were purchased from Aldrich and used without further puri®cation.
bTLC plates were prepared with E. Merck AB Darmstadt Silica gel 60 F254.
cIsolation yield after ¯ash column chromatography.
d85% Et2O/15% Hexane.
e50% Et2O/50% Hexane.
8 was prepared in 89.7% yield5 by treatment of N-chloro-
succinimide and dimethylsul®de in the presence of triethyl-
Acknowledgements
amine in CH2Cl2 at 78 ꢀC.6
We would like to dedicate this article to the memory of
Sir Derek H. R. Barton (Deceased March 16th, 1998).
This work was supported by the Non Directed Research
Fund, Korea Research Foundation (1998).
Upon photolysis in the presence of a variety of amines,
cyclohexa-2,4-dienone generates ketene intermediates,
which is captured by amines to furnish the corresponding
amide products. The mechanistic aspects of the dienone
cleavage reaction have already been well studied.7 Thus
we have examined the photolysis reaction of 8 in the
presence of various amines in ethanol for 4±10 hr below
40 ꢀC. In all cases, the respective amide products were
obtained as colorless oils in good to moderate yields.8
The nucleophilic amine traps the cis-ketene intermediate
9 to give two isomers of 10±16, and the results are
summarized in Table 1. Oxidation of 8 with m-chloro-
perbenzoic acid (MCPBA) gave the sulfone product 17
as a white solid which was quite stable under acidic
condition without light and could be puri®ed by silica gel
chromatography without any noticeable decomposition.
The sulfone 17 was very polar but slightly soluble in
absolute ethyl alcohol.9
References and Notes
1. (a) Barton, D. H. R.; Quinkert, G. J. Chem. Soc. 1960, 1, 1.
(b) Barton, D. H. R.; Quinkert, G. Proc. Chem. Soc. 1958,
197.
2. (a) Barton, D. H. R.; Kwon, T. W.; Taylor, D. K.;
Tajbakhsh, M. Bioorg. Med. Chem. 1995, 3, 79. (b) Barton, D.
H. R.; Chung, S. K.; Kwon, T. W. Tetrahedron Lett. 1996, 37,
3631. (c) Barton, D. H. R.; Chung, S. K.; Kim, Y. M.; Kwon,
T. W. Bioorg. Med. Chem. Lett. 1997, 7, 733.
3. Stein, G.; Bohmer, V.; Lotz, W.; Kammerer, H. Z. Nat-
urforsch. 1981, 36b, 231.
4. Compound 7; A white crystalline solid, mp=50±52 ꢀC. H
NMR (300 MHz, CDCl3) 7.4.1 (5H, m), 6.91 (2H, s), 4.60
(1H, br. s), 4.01 (2H, s) and 2.19 (6H, s) ppm. 13C NMR (75
MHz, CDCl3) 151.3, 136.8, 129.3, 129.0, 128.7, 128.4, 126.0,
123.0, 38.3 and 15.8 ppm. GC/MS 244(M+), 227, 215, 135,
115, 109, 91 and 77.
1
5. Compound 8; A pale yellow oil (89.7%). 1H NMR shows ca.
96% purity. Rf=0.4 (100% CHCl3), 1H NMR (300 MHz,
CDCl3) 7.40.23 (5H, SPh, m), 6.9 (1H,=CH, s), 5.80
(1H,=CH, s), 3.64 (2H, CH2SPh, s), 2.84 (1H, CHS, d, J=12.6
Hz), 2.59 (1H, CHS, d, J=12.6 Hz), 1.97 (3H, SCH3, s), 1.91
(3H,=CCH3, s), and 1.00 (3H, CCH3, s) ppm. 13C NMR (75
MHz, CDCl3) 204.0, 140.2, 140.1, 134.3, 131.6, 128.3, 127.0,
50.8, 44.2, 39.5, 25.2, 17.7, and 15.5 ppm. GC/MS 304(M+),
289, 243, 211, 135, 109, 91, and 61.
In conclusion the synthetic procedure presented here
can o€er a reasonable route to the symmetrical bichro-
mophoric cyclohexadienone compounds via the replace-
ment of the phenyl-thio group. Preparation of such
bichromophoric compounds and photolysis are currently
in progress, and the results will be communicated in due
course.
6. Katayama, S.; Watanabe, T.; Yamauchi, M. Chem. Pharm.
Bull. 1993, 41, 439.

T. W. Kwon et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1551±1553
1553
7. (a) Quinkert, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 1072. (b) Quinkert, G. Pure and Appl. Chem. 1973, 33,
285.
s), 5.56 (1H, d, J=9.9 Hz), 3.62 (2H, CH2SO2, s), 3.51 (4H,
NCH2, m), 3.30 (1H, CHCO, m), 3.14 (2H, CH2SPh, s), 3.08
(3H, SO2CH3, s), 2.05 (3H, s), 1.61.32 (6H, m, ring CH2), 1.05
(3H, d, J=6.8 Hz); IR(neat);3550 (CONH), 3215(SPh; C-H),
2910, 1635(CONH), 1420, 1310/1105(SO2) cm 1. HRMS; m/z
calcd for C22H31NOS2; [M+H]+, 390.2685. Found 390.2697.
9. Compound 17; A white crystalline solid, mp=169±171 ꢀC,
93.7%, Rf=0.46 (100% ethyl acetate), 1H NMR (300 MHz,
CDCl3) 7.8.7 (2H, SPh, m), 7.7.4 (3H, SPh, m), 6.69 (1H,=CH,
s), 6.06 (1H,=CH, s), 3.91 (2H, CH2SO2Ph, s), 3.90 (1H, d,
J=13.98 Hz, CHSO2CH3), 3.11 (1H, d, J=13.98Hz, CHSO2
CH3), 2.76 (3H, SO2CH3, s), 1.82 (3H, CH3-C=, s), and 0.99
(3H, CH3C, s) ppm. 13C NMR (75 MHz, CDCl3) 200.3(CˆO),
143.9, 139.6, 137.8, 134.0, 133.4, 129.6, 129.27, 128.67, 122.04,
62.37, 61.6, 53.5, 48.1, 42.9, 26.2 and 15.6 ppm. Anal. calcd for
C17H20O5S2:C, 55.41; H, 5.46; S, 17.40. Found: C, 55.56; H,
5.82; S, 17.85.
8. A representative photolysis experiment (Table 1, Product 11).
The solution of the dienone, 8 (0.5 g, 1.64 mmol) in 5 mL of
freshly distilled ethyl alcohol in the presence of piperidine
(0.167 g, 1.97 mmole, 1.2 equiv) in a cooling bath was irra-
diated at a distance of 2 cm with a tungsten lamp (220 W) while
maintaining the bath temperature below 40 ꢀC. The cleavage
reaction was monitored by TLC. The starting material com-
pletely disappeared after 4 h and the volatiles were removed in
vacuo. The crude product was diluted with CH2Cl2 (15 mL)
and extracted with distilled water (2Â10 mL). The organic layer
was dried over MgSO4, ®ltered and evaporated. After puri®ca-
tion by ¯ash column chromatography over silica gel (17:3/
Et2O:hexane), a clear oil, 1,1 was obtained (0.33 g, 0.84 mmol,
51%). 1H NMR (300 MHz, CDCl3) 7.52.20 (5H, m), 5.81 (1H,