Synthesis of highly conjugated arylpropenylidene-1,3-diazin-2-ones via Paterno-Buechi reaction by photoreaction of 5-fluoro-1,3-dimethyluracil with 1-methoxynaphthalenes

Article abstract of DOI:10.1246/cl.2008.872

In contrast to photoreactions of 5-fluoro-1,3-dimethyluracil (5-FDMU) with various naphthalenes including 2-methoxynaphthalenes that proceeds in a manner to give ethenoquinazolines through 1,4-cycloaddition, UV-irradiation of a mixture of 5-FDMU and naphthalenes with a methoxy group at C-1 gave rise to the formation of novel cycloadducts, methyl 2-[(1E)-3-(5-fluoro-1,3-dimethyl-2-oxo- 1,3-dihydropyrimidin-4-ylidene)-prop-1-enyl]benzoates, derived from the novel aromatic Paterno-Buechi type cycloaddition, followed by a concomitant disruption of the initially formed oxetane moiety. Copyright

Full text of DOI:10.1246/cl.2008.872

872
Chemistry Letters Vol.37, No.8 (2008)
Synthesis of Highly Conjugated Arylpropenylidene-1,3-diazin-2-ones via Paterno–Bu¨chi Reaction
by Photoreaction of 5-Fluoro-1,3-dimethyluracil with 1-Methoxynaphthalenes
Koh-ichi Seki,ꢀ1 Kazuya Aizawa,2 Tatsuyuki Sugaoi,2 Masayuki Kimura,3 and Kazue Ohkuraꢀ2
1Central Institute of Isotope Science, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638
2Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293
3School of Pharmacy, Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kita-Adachigun, Saitama 362-0806
(Received May 22, 2008; CL-080520; E-mail: seki@ric.hokudai.ac.jp)
In contrast to photoreactions of 5-fluoro-1,3-dimethyluracil
(5-FDMU) with various naphthalenes including 2-methoxy-
naphthalenes that proceeds in a manner to give ethenoquinazo-
lines through 1,4-cycloaddition, UV-irradiation of a mixture of
5-FDMU and naphthalenes with a methoxy group at C-1 gave
rise to the formation of novel cycloadducts, methyl 2-[(1E)-3-
(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihydropyrimidin-4-ylidene)-
prop-1-enyl]benzoates, derived from the novel aromatic
vestigate the scope and limitations of the above photoreaction,
we decided to extend our work to the photoreaction of 5-FDMU
with naphthalenes having an electron-donating methoxy group
at C-1.
In the present paper, we describe our finding that, UV-irra-
diation of a mixture of 5-FDMU and 1-methoxynaphthalene
leads to the Paterno–Buchi type reaction yielding novel and
¨
highly conjugated propenylidene derivatives 1.
Paterno–Buchi type cycloaddition, followed by a concomitant
¨
disruption of the initially formed oxetane moiety.
A degassed solution of 5-FDMU and 1-methoxynaphthalene
in cyclohexane was irradiated externally with a 500-W
high-pressure mercury lamp in a Pyrex tube (ꢀ > 300 nm) for
10 h (Scheme 1). In contrast to the reaction with 2-methoxy-
naphthalene, whereby 1,4-cycloadducts are produced exclusive-
ly,7b the present reaction furnished the novel products, methyl
2-[(1E)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihydropyrimidin-
4-ylidene)prop-1-enyl]benzoate as a mixture of the 10E,30E iso-
mer 1a8 (24%) and the 10E,30Z stereoisomer 1b9 (14%), together
with the conventional regioisomeric 1,4-cycloadducts 2a10 and
2b11 in 5% and 4% yield respectively (yields are given based
on 47% of 5-FDMU consumed).
The photochemistry and photobiology of pyrimidine bases
in DNA have been studied extensively, owing to their diverse
reactivity based on both carbonyl groups and an olefinic double
bond. The formation of thymine–adenine photoadducts1 or of
pyrimidine–pyrimidine cyclobutane dimers and bipyrimidine
(6-4) photoadducts2 between adjacent pyrimidine bases plays
an important role in the direct induction of DNA damage. The
former two reactions result through [2 + 2]-addition of olefinic
double bonds while the (6-4) photoadducts derive from oxetane
or azetidine intermediates formed by photoaddition of the C4-
carbonyl of thymine or the C4-imino tautomer of cytosine3
across the C5–C6 double bond of the adjacent base. From a syn-
thetic view point, photochemical coupling reactions involving
C=C or C=O double bonds have attracted our attention, since
the chemical modification of nucleic bases has been recognized
as one of the most promising approaches for developing bioac-
tive substances such as anticancer and antiviral agents.4 In this
context, we have intensively studied the photochemical modifi-
cation of halogenated and non-halogenated pyrimidines that oc-
curs when they are irradiated in the presence of aromatic hydro-
carbons such as benzene and naphthalene derivatives. We have
thus successfully demonstrated that upon UV-irradiation pyrimi-
dine derivatives undergo a variety of photocycloaddition reac-
tions with benzene derivatives5 and naphthalenes,6 to give a
structurally diverse range of photoproducts. The cycloadditions
with aromatic hydrocarbons hitherto reported, however, are lim-
ited only to the couplings or substitutions on the C5=C6 double
bond of the pyrimidine ring. No cycloaddition involving the car-
bonyl group has yet been discovered although the occurrence of
The structural assignment of 1a was made on the basis of
detailed MS and the NMR spectroscopic studies.8
The stereochemistry of 1a was determined with the aid of
NOE experiments. Irradiation of the H-30 proton significantly af-
fected the H-10 vinyl proton, as well as N300–CH3. Also irradia-
tion at N300–CH3 showed enhancement of signal for H-30 vinyl
proton. On the other hand, the 1E,3Z isomer 1b showed no
NOE correlation for H-30–N300–CH3, while significant correla-
tion was observed between N300–CH3–H-20. These differences
in the NOE’s conclusively determined the stereochemistry of
1a as 1E,3E and 1b to be 1E,3Z, respectively. The formation
of 1 is rationally explained in terms of [2 + 2]-addition of
the uracil C4=O carbonyl group with the C-1=C-2 double
bond of the naphthalene ring, to give an oxetane intermediate
(Paterno–Buchi reaction). Subsequent ring opening of the highly
¨
O
OCH3
CH3
(> 300 nm)
hν
F
N
500 Wh.p. Hg-lamp
+
rt , cyclohexane , 10h
O
N
CH3
1
H3COOC
1COOCH3
the Paterno–Buchi type reaction would provide new possibilities
¨
2
2
O
1'
F
5
1'
3
3
N
2
for the photochemical modification of pyrimidine rings with ar-
omatic compounds. We have recently reported that UV-irradia-
tion of 5-FDMU with naphthalene and its derivatives substituted
with electron-withdrawing groups, or electron-donating methyl
or 2-methoxy groups, proceeded selectively by 1,2- and 1,4-
cycloaddition, to afford naphthocyclobutapyrimidines and eth-
enobenzoquinazolines (barrelene), respectively.7 In order to in-
CH3
3
3'
2'
2'
+
3'
+
1
N
CH3
10
9
O
CH3
5" F
CH3
O
5"
10aH
F
N
2"
R1
R2
N3"
1"
6"
6"
O
N
N1"
CH3
1b
2a; R1 = H, R2 = OCH3
2b; R1 = OCH3, R2 = H
CH3
1a
Scheme 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.8 (2008)
873
5
6
K. Seki, K. Ohkura, in CRC Handbook of Organic Photochem-
istry and Photobiology, 2nd ed., ed. by W. M. Horspool and F.
Lenci, CRC Press Inc., Boca Raton, 2003, pp. 105.1–105.16.
a) K. Ohkura, K. Seki, Photochem. Photobiol. 2002, 75, 579.
b) K. Ohkura, S. Uchiyama, K. Aizawa, K. Nishijima, K. Seki,
Heterocycles 2002, 57, 1403. c) K. Ohkura, T. Ishihara, Y.
Nakata, K. Seki, Heterocycles 2004, 62, 213.
R
O
CH3
F
N
hν
H3CO
1a−1d
O
N
OCH3
O
CH3
H3C
F
N
5-FDMU
O
N
CH3
R
7
8
a) K. Ohkura, T. Sugaoi, K. Nishijima, Y. Kuge, K. Seki,
Tetrahedron Lett. 2002, 43, 3113. b) K. Ohkura, T. Sugaoi,
T. Ishihara, K. Aizawa, K. Nishijima, Y. Kuge, K. Seki,
Heterocycles 2003, 61, 377. c) K. Ohkura, T. Sugaoi, K. Seki,
Heterocycles 2004, 67, 57. d) K. Ohkura, T. Ishihara, K.
Nishijima, J. M. Diakur, K. Seki, Chem. Pharm. Bull. 2005,
53, 258.
R = H, OCH3
Scheme 2.
strained oxetane moiety in the manner shown in Scheme 2
leads to cleavage of the naphthalene ring system as observed
in compounds 1a–1d.
Similar irradiation of equimolar amounts of 5-FDMU
and 1,5-dimethoxynaphthalene in benzene furnished methyl 2-
[(1E,3E)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihydropyrimidin-
4-ylidene)prop-1-enyl]-3-methoxybenzoate (1c)12 in high yield
(64%) together with small amounts of the 1E,3Z isomer 1d13
(9%) (at the stage where 44% of the 5-FDMU was consumed).
Although the precise factors responsible for the dramatically
different outcomes of cycloaddition between 5-FDMU and 1-
methoxy- or 2-methoxynaphthalene remain to be clarified, we
consider that the reactivity of the intermediate oxetane plays a
key role. In the former case, where the methoxy group is incor-
porated as a ketal function on the oxetane ring, we surmise that
the rearrangement leading to ring fission and formation of a
stable carbomethoxy function is favored energetically. With
the oxetane derived from 2-methoxynaphthalene, where there
is no such driving force, ring fission simply regenerates the
original 5-FDMU and 2-methoxynaphthalene components.
Thus, the present study demonstrates the first aromatic
Methyl 2-[(1E,3E)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihy-
dropyrimidin-4-ylidene)prop-1-enyl]benzoate (1a): 1H NMR
(C6D6): ꢁ 2.43 (3H, s, N100–CH3), 2.76 (3H, s, N300–CH3),
3.50 (3H, s, C1-COOCH3), 5.25 (1H, d, J ¼ 8:6 Hz, H-600),
5.38 (1H, d, J ¼ 11 Hz, H-30), 6.90 (1H, dd, J ¼ 7:4, 8.0 Hz,
H-5), 7.07 (1H, dd, J ¼ 7:4, 8.0 Hz, H-4), 7.73 (1H, d,
J ¼ 8:0 Hz, H-3), 7.82 (1H, dd, J ¼ 11, 15 Hz, H-20), 7.90
(1H, d, J ¼ 8:0 Hz, H-6), 7.92 (1H, dd, J ¼ 4:4, 15 Hz, H-
10). NOE: H-30 with N300–CH3 (14.1%), H-10 (6.4%), H-600 with
N100–CH3 (7.1%), H-20 with H-3 (2.5%), H-30 (2.0%), H-3 with
H-20 (3.2%), H-4 (5.8%), N100–CH3 with H-600 (3.3%).
13C NMR (C6D6): ꢁ 31.1 (N300–CH3), 35.3 (N100–CH3), 51.3
(OCH3), 103.1 (d, J ¼ 7:2 Hz, 30), 116.4 (d, J ¼ 39:4 Hz,
600), 125.8 (5), 126.0 (3), 127.2 (10), 127.6 (20), 130.9 (6),
131.8 (4), 140.3 (2), 143.3 (d, J ¼ 231:3 Hz, 500), 149.8 (200),
167.7 (C1-CO). FAB-MS m=z: 317 [M + H]þ. HRFABMS:
Calcd for C17H18N2O3F: 317.1301. Found: 317.1316. IR
ꢂmax (neat) cmꢁ1: 1719, 1670. UV ꢀmax (CHCl3) nm ("/
ꢁ1 cmꢁ1): 376 (21290).
Paterno–Buchi photocycloaddition involving 5-FDMU. Its reac-
¨
M
tion with naphthalene bearing a methoxy group at C-1 yields
highly conjugated (phenylpropenylidene)-1,3-diazin-2-ones. A
striking feature of this reaction, which entails oxetane formation
between an aromatic hydrocarbon moiety and a carbonyl group,
is that it leads to ring fission of the original aromatic nucleus.
Further studies on the scope and the limitation of the present
photoreaction are now in progress.
9
Methyl 2-[(1E,3Z)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihy-
dropyrimidin-4-ylidene)prop-1-enyl]benzoate (1b): 1H NMR
(C6D6): ꢁ 2.44 (3H, s, N100–CH3), 3.20 (3H, s, N300–CH3),
3.46 (3H, s C1-COOCH3), 5.25 (1H, d, J ¼ 6:9 Hz, H-600),
5.86 (1H, d, J ¼ 12 Hz, H-30), 6.94 (1H, dd, J ¼ 7:4, 8.0 Hz,
H-5), 7.12 (1H, dd, J ¼ 7:4, 8.0 Hz, H-4), 7.12 (1H, dd,
J ¼ 12, 15 Hz, H-20), 7.43 (1H, d, J ¼ 8:0 Hz, H-3), 7.71
(1H, d, J ¼ 15 Hz, H-10), 7.90 (1H, d, J ¼ 8:0 Hz,
H-6). NOE: H-30 with H-10 (20.4%), H-20 (5.4%), H-600 with
N100–CH3 (7.1%), H-20 with N300–CH3 (3.2%), H-3 (3.5%),
H-30 (1.2%). HRFABMS: Calcd for C17H18N2O3F:
317.1301. Found: 317.1296.
References and Notes
1
a) S. N. Bose, R. J. Davies, S. K. Sethi, J. A. McCloskey,
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10 4a-Fluoro-4a,5,10,10a-tetrahydro-9-methoxy-1,3-dimethyl-cis-
5,10-ethenobenzo[ f]quinazoline-2,4-dione (2a): Colorless
crystals, mp 149–151 ꢂC (hexane). HRFABMS: Calcd for
C17H18N2O3F: 317.1301. Found: 317.1328.
11 4a-Fluoro-4a,5,10,10a-tetrahydro-10-methoxy-1,3-dimethyl-
cis-5,10-ethenobenzo[ f]quinazoline-2,4-dione (2b): Colorless
crystals, mp 134–135 ꢂC (hexane). HRFABMS: Calcd for
C17H18N2O3F: 317.1301. Found: 317.1324.
2
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12 Methyl 2-[(1E,3E)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihy-
dropyrimidin-4-ylidene)prop-1-enyl]-3-methoxybenzoate (1c):
yellow oil. FABMS m=z: 347 [M + H]þ. HRFABMS: Calcd
for C18H20N2O4F: 347.1407. Found: 347.1390.
13 Methyl 2-[(1E,3Z)-3-(5-fluoro-1,3-dimethyl-2-oxo-1,3-dihy-
dropyrimidin-4-ylidene)prop-1-enyl]-3-methoxybenzoate (1d):
FABMS m=z: 347 [M + H]þ. HRFABMS: Calcd for
C18H20N2O4F: 347.1407. Found: 347.1394.
¨
2005, 571, 221. f) C. van der Wees, J. Jansen, H. Vrieling,
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3
4
Published on the web (Advance View) July 12, 2008; doi:10.1246/cl.2008.872