Novel Synthesis and Properties of 1,6-Methanocycloundeca[b]pyrimido[5,4-d]pyrrole-12,14-dione Derivatives: Autorecycling Oxidation of Some Amines and Alcohols

Article abstract of DOI:10.1021/jo035336g

Novel 1,6-methanocycloundeca[b]pyrimido[5,4-d]pyrrole-12,14-dione derivatives 6a,b and 7a-c were synthesized in moderate to good yields by the enamine alkylation and dehydrating condensation reactions of 11-chloro-3,8-methano [11] annulenone (8) with 6-amino-3-substituted uracil derivatives and subsequent elimination of HCl. The ¹H NMR spectra clarified that compounds 6a,b and 7a-c are aromatic molecules having a diatropic π-system, which is suggested by the chemical shifts of the bridge methylene protons and peripheral protons. The electrochemical reduction exhibited more positive reduction potentials as compared with those of the vinylogous compounds of cyclohepta-[b]pyrimido[5,4-d]pyrrole derivatives. In a search for the oxidizing function of 6a,b and 7a-c, compounds 6a and 7b were demonstrated to oxidize benzylamines, cyclohexylamine, and benzyl alcohol to give the corresponding carbonyl compounds in more than 100% yield under aerobic and photoirradiation conditions, while only benzylamine was oxidized under aerobic and thermal conditions at 100 °C. Thus, compounds 6a and 7b oxidize amines and alcohols in an autorecyling process, and the efficiency is higher under photoirradiation as compared with the thermal process, suggesting the oxidation reaction probably proceeds via electron transfer from amine and alcohol to the excited and ground states of compounds 6a and 7b.

Full text of DOI:10.1021/jo035336g

Novel Syn th esis a n d P r op er ties of
1,6-Meth a n ocyclou n d eca [b]p yr im id o[5,4-d ]p yr r ole-12,14-d ion e
Der iva tives: Au tor ecyclin g Oxid a tion of Som e Am in es a n d
Alcoh ols
Yuhki Mitsumoto and Makoto Nitta*
Department of Chemistry, School of Science and Engineering, Waseda University,
Shinjuku-ku, Tokyo 169-8555, J apan
nitta@waseda.jp
Received September 10, 2003
Novel 1,6-methanocycloundeca[b]pyrimido[5,4-d]pyrrole-12,14-dione derivatives 6a ,b and 7a -c were
synthesized in moderate to good yields by the enamine alkylation and dehydrating condensation
reactions of 11-chloro-3,8-methano[11]annulenone (8) with 6-amino-3-substituted uracil derivatives
1
and subsequent elimination of HCl. The H NMR spectra clarified that compounds 6a ,b and 7a -c
are aromatic molecules having a diatropic π-system, which is suggested by the chemical shifts of
the bridge methylene protons and peripheral protons. The electrochemical reduction exhibited more
positive reduction potentials as compared with those of the vinylogous compounds of cyclohepta-
[b]pyrimido[5,4-d]pyrrole derivatives. In a search for the oxidizing function of 6a ,b and 7a -c,
compounds 6a and 7b were demonstrated to oxidize benzylamines, cyclohexylamine, and benzyl
alcohol to give the corresponding carbonyl compounds in more than 100% yield under aerobic and
photoirradiation conditions, while only benzylamine was oxidized under aerobic and thermal
conditions at 100 °C. Thus, compounds 6a and 7b oxidize amines and alcohols in an autorecyling
process, and the efficiency is higher under photoirradiation as compared with the thermal process,
suggesting the oxidation reaction probably proceeds via electron transfer from amine and alcohol
to the excited and ground states of compounds 6a and 7b.
In tr od u ction
(2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione), in which
the nitrogen atom of the 5-deazaflavin 1a is replaced by
an oxygen atom, has also been synthesized and found to
possess strong ability to oxidize alcohols to the corre-
sponding carbonyl compounds.7 On the basis of the above
observations and our interest in exploiting the unique
reactivity afforded by the vinyliminophosphoranes8 and
related compounds,9 we have previously studied conve-
nient preparations of 7,9-disubstituted cyclohepta[b]-
pyrimido[5,4-d]pyrrole-8(7H),10(9H)-diones 2a ,b10 and
6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-
8(6H),10(9H)-diones 3a -c, which are structural isomers
of 5-deazaflavin 1a (Figure 1).11 Compounds 2 and 3 have
appreciable oxidizing ability toward some alcohols11 and
amines,12 and thus, structural modifications of the uracil-
annulated heteroazulenes such as 2 and 3 are an
interesting project in view of exploration of novel func-
tions. Much of the motivation for studying the properties
of organic molecules stems from manipulation of the
primary chemical structure. Strategies for raising or
The importance of fused pyrimidines, which are com-
mon sources for the development of new potential thera-
peutic agents,1,2 is well-known. Among these, flavins are
known to play an important role as cofactors in a wide
variety of biological redox reactions. Dehydrogenation
reactions represent a major family of processes mediated
by the subclass of flavoenzymes known as oxidases.
Included in this group are the oxidative transformations
of alcohols to carbonyl compounds, of amines to imines,
and of fatty acid esters to their R,â-unsaturated ana-
logues.3 In this context, 5-deazaflavin 1a has been studied
extensively in both enzymatic4 and model systems5,6 in
the hope of providing mechanistic insight into flavin-
catalyzed reactions. In addition, 5-deaza-10-oxaflavin 1b
* To whom correspondence should be addressed. Phone: +81-(0)3-
5286-3236. Fax: +81-(0)3-3208-2735.
(1) Brown, D. J . In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, pp
57-155.
(2) Wamhoff, H.; Dzenis, J .; Hirota, K. Adv. Heterocycl. Chem. 1992,
55, 129.
(7) Yoneda, F.; Hirayama, R.; Yamashita, M. Chem. Lett. 1980, 1157.
(8) (a) Nitta, M. Rev. Heteroat. Chem. 1993, 9, 87 and references
therein. (b) Nitta, M.; Iino, Y.; Mori, S.; Takayasu, T. J . Chem. Soc.,
Perkin Trans. 1 1995, 1001.
(9) (a) Nitta, M.; Akie, T.; Iino, Y. J . Org. Chem. 1994, 59, 1309. (b)
Nitta, M.; Kanda, H. Heterocycles 2002, 57, 491.
(3) Hamilton, G. A. In Progress in Bioorganic Chemistry; Kaiser, E.
T., Kezdy, F. J ., Eds.; Wiley: New York, 1971; Vol. 1, p 83.
(4) Walsh, C. Acc. Chem. Res. 1986, 19, 216 and references therein.
(5) Yoneda, F.; Tanaka, K. Med. Res. Rev. 1987, 4, 477-506 and
references therein.
(6) Yoneda, F.; Kokel, B. In Chemistry and Biochemistry of Fla-
voenzymes; Muller, F., Ed.; CRC: Boca Raton, FL, 1991; Vol. 1, pp
121-169 and references therein.
(10) Nitta, M.; Tajima, Y. J . Chem. Res., Synop. 1999, 372.
(11) Nitta, M.; Tajima, Y. Synthesis 2000, 651.
(12) Naya, S.; Iida, Y.; Nitta, M. Tetrahedron, in press.
10.1021/jo035336g CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004
1256
J . Org. Chem. 2004, 69, 1256-1261

Synthesis of Fused Pyrimidine Derivatives
The structures of new compounds 6a ,b and 7a -c are
confirmed on the basis of the 1H NMR spectra (sum-
marized in Table 2), 13C NMR spectra, IR, UV-vis, and
mass spectral data, and elemental analyses. As com-
pound 7c is unstable on TLC using SiO2 and Al2O3,
satisfactory analytical data are not obtained; however,
satisfactory high-resolution mass spectral data (FAB) are
obtained. We propose the pathways for the formation of
6a ,b and 7a -c as outlined in Scheme 1. The enamine
alkylation of 9a ,b and 10a -c to the C-2 position of 8
occurs regioselectively to give the intermediates 11 and
13, which undergo intramolecular dehydrating condensa-
tion to generate 12 and 14, respectively, followed by the
elimination of HCl to result in the formation of 6a ,b and
7a -c. Possible formation of alternative intermediates
such as 15 and 16, instead of 11 and 13, to give regio-
isomers of 6 and 7 is not detected (Figure 2). According
to the AM1 method,18 the energy levels and coefficients
of the LUMO of 8 and HOMOs of 9a and 10a are
calculated as summarized in Figure 2. The coefficient of
the LUMO of 8 is larger on C-2 as compared with C-11.
Thus, the C-5 (larger coefficient as compared with the
amino nitrogen) atom of 9 and 10 probably intervenes
in the enamine alkylation to the C-2 position of 8
preferentially to give the intermediates 11 and 13, and
not to C-11, giving the intermediates 15 and 16 (Figure
2). An alternative explanation for the regioselectivity may
be a steric hindrance of the chlorine atom to inhibit the
formation of 15 and 16. Thus, it is considered the
preferential regioselectivity of the reaction results in the
formation of 6a ,b and 7a -c.8a
F IGURE 1.
lowering the HOMO and LUMO levels include conjuga-
tion length control, as well as the introduction of an
electron-withdrawing or -donating group to the parent
molecular skeleton. On the basis of this concept, we have
embarked on an investigation of the synthesis of 11,13-
disubstituted 1,6-methanocycloundeca[b]pyrimido[5,4-d]-
pyrrole-12(11H),14(13H)-dione derivatives 6a ,b and
10,13-disubstituted 1,6-methanocycloundeca[b]pyrimido-
[5,4-d]pyrrole-12(10H),14(13H)-dione derivatives 7a -c
for the first time (Scheme 1), which are the vinylogous
compounds of 2 and 3, respectively, to involve the 1,6-
methano[11]annulene ring system instead of cyclohep-
tatriene.
As for methano-bridged heteroaromatic compounds
having 14 π-electrons (heteroazulene vinylogues), we
have previously reported the synthesis and spectroscopic
properties of 6,11- and 4,9-methanocyclopentacyclo-
undecene ring systems 4 and 5 as 1-azaazulene vin-
ylogues.13 Thus, we study here the synthesis, structural
characteristics, and electrochemical properties of 6a ,b
and 7a -c. Thermal and photoinduced autorecycling
oxidation of some amines and alcohols to give the
corresponding carbonyl compounds are studied as well.
We describe here the results in detail.
1
Sp ectr oscop ic P r op er ties. The H NMR spectra of
two series of 1,6-methanocycloundeca[b]pyrimido[5,4-d]-
pyrrole-12,14-dione derivatives 6a ,b and 7a -c resemble
each other, respectively, and they are noteworthy since
the chemical shifts of bridged annulene systems are quite
useful in determining such structural properties as
diatropicity and bond alternation.19 Unambiguous proton
1
assignment was successfully made by analyzing the H
and 2D 1H NMR spectra. The chemical shifts of the
bridge protons, peripheral protons, and selected coupling
constants are listed in Table 2. The chemical shifts of
the methylene protons of 6a ,b and 7a -c are found in
the shielding region (δ -1.37 to -0.31), and those of the
peripheral protons appear in the aromatic region (δ 7.27
to 10.24). In particular, the characteristic H2 signals
Resu lts a n d Discu ssion
1
appearing at around δ 10.0 in the H NMR spectra are
Syn th esis. Vogel et al. justifies viewing 3,8-methano-
[11]annulenone as a vinylogous compound of tropone on
the basis of their spectroscopic properties and basicities.14
As we have reacted 2-chlorotropone with 6-aminouracils
to give 2 and 3,10,11 our strategy for the preparation of
1,6-methanocycloundeca[b]pyrimido[5,4-d]pyrrole-12(11H),-
14(13H)-dione derivatives 6a ,b and related compounds
7a -c involves the reactions of 11-chloro-3,8-methano[11]-
annulenone (8)15 with 6-aminouracil derivatives 9a ,b16
and 10a -c.17
due to the anisotropy effect of the oxygen atom of the
pyrimidinedione moiety. Furthermore, the large geminal
coupling constants of the bridge methylene protons (J E,Z
) 11.6-12.1 Hz) support the absence of a norcaradiene
structure for 6a ,b and 7a -c. These findings indicate that
compounds 6a ,b and 7a -c all exist as diatropic molecules
(14) Vogel, E. 23rd Int. Congr. Pure Appl. Chem. 1971, 1, 275 and
references therein.
(15) Reisdorff, J .; Vogel, E. Angew. Chem., Int. Ed. Engl. 1972, 11,
218.
(16) Papesh, V.; Schroeder, E. F. J . Org. Chem. 1951, 16, 1879.
(17) (a) Nubel, G.; Pfleiderer, W. Chem. Ber. 1962, 95, 1605. (b)
Yoneda, F.; Shinozuka, K.; Tsukuda, K. J . Hetercycl. Chem. 1979, 16,
1365. (c) Yoneda, F.; Matsumoto, S.; Sakuma, Y. Chem. Pharm. Bull.
1975, 23, 2425.
The reaction of 8 with 9a ,b and 10a -c in AcOH at
60-80 °C afforded 6a ,b and 7a -c, as single products,
respectively (Scheme 1). Reaction conditions and the
yields of the products are summarized in Table 1.
(18) The calculations were carried out using the MOPAC Ver. 6.12
program.
(19) (a) Vogel, E. Chem. Soc. Spec. Publ. 1967, No. 21, 113. (b) Vogel,
E. Proc. Robert A. Welch Found. Conf. Chem. Res. 1968, 12, 215.
(13) Nitta, M.; Kanomata, N.; Tada, M. Tetrahedron Lett. 1990, 31,
1291. Kanomata, N.; Kamae, K.; Iino, Y.; Nitta, M. J . Org. Chem. 1992,
57, 5313.
J . Org. Chem, Vol. 69, No. 4, 2004 1257

Mitsumoto and Nitta
SCHEME 1 a
a
Reagents and conditions: (i) AcOH, 60 °C; (ii) AcOH, 80 °C.
TABLE 1. Resu lts for th e Rea ction s of 8 w ith 9a ,b a n d
those of 7b,c are reversible, under the conditions of the
CV measurements: the peak potentials of 6a ,b and 7a
and mean values of cathodic and anodic potentials for
7b,c are summarized in Table 4, together with those of
the reference compounds 2a and 3a .12 As expected, the
Ered values of 6a ,b and 7a -c are more positive than the
corresponding values of 2a and 3a , respectively, due to
the elongated π-conjugation of these compounds as
compared with the reference compounds.
10a -c
reaction
compda
reaction
time/h
product
(yield/%)
entry
temp/°C
1
2
3
4
5
9a
9b
10a
10b
10c
60
60
80
80
80
25
36
48
22
54
6a (55)
6b (60)
7a (89)
7b (62)
7c (93)
a
Two molar equivalent amounts of 9 and 10 relative to 8 are
Au tor ecyclin g Oxid a tion . Compounds 2a and 3a
undergo autorecycling oxidation toward some amines and
alcohols under aerobic and thermal or photoirradiation
conditions.11,12 In this context and in a search for the
oxidizing ability of 6 and 7, we examined the oxidation
of some amines and alcohols by using 6a and 7b under
aerobic and photoirradiation (RPR100, 350 nm lamps)
conditions. Although cyclohexanol was not oxidized by
either 6a or 7b, we found that both compounds 6a and
7b have oxidizing ability toward benzylamine, 1-phenyl-
ethylamine, cyclohexylamine, and benzyl alcohol to give
the corresponding carbonyl compounds. In the case of
amine, imine is produced at first; however, it reacts with
another amine to result in the formation of R1R2CdNs
CHR1R2 and NH3 (Scheme 2). Then the reaction mixture
was diluted with ether and filtered, and the filtrate was
treated with 2,4-dinitrophenylhydrazine in 6 N HCl to
give 2,4-dinitrophenylhydrazone of the carbonyl com-
pound. The results are summarized in Table 5, together
with those of the reference compound 3a . Direct irradia-
tion of amines and benzyl alcohol in the absence of 6a
and 7b (named “blank”) gives the corresponding carbonyl
compounds in low to modest yields. Thus, the yields are
calculated by subtraction of the blank yield from the total
yield of the carbonyl compound in the presence of 6a and
7b. More than 100% yields are obtained based on 6a and
7b, and thus, autorecycling oxidation clearly proceeds.
Although the Ered values of 6a and 7b are more positive
than those of reference compounds 2a and 3a , 6a and
7b are less efficient in the autorecycling oxidation reac-
tion (entries 1 and 5), as compared with 2a and 3a
(entries 9 and 10). This feature would be due to the
instability of 6a and 7b under the conditions of autore-
used for the reaction.
having an aromatic π-electron system. Structural char-
acteristics are also observed for two series, 6a ,b and
7a -c. The vicinal coupling constants of protons of the
aromatic perimeter of 6a suggest that the C-7-C-8-C-9
system exhibits bond alternation [J 7,8 (9.5) > J 8,9 (12.5)],
while no significant bond alternation is observed in the
cycloheptatriene moiety [J 2,3(9.3) ≈ J 3,4(9.0) ≈ J 4,5(9.5)]
(Table 2). This feature is similarly observed for com-
pound 6b. On the contrary, the C7-C-8-C-9 system of
compound 7a exhibits no significant bond alternation
[J 8,9(11.0) ) J 7,8(11.0)], and significant bond alternation
is observed in the cycloheptatriene moiety [J 2,3(7.9) < J 4,5
(9.1) < J 3,4 (10.0)]. A feature similar to that of 7a is
observed for 7b; however, π-electron delocalization of 7c
is much enhanced as compared with that of 7a ,b, and
significant bond alternation is not observed either in the
C-7-C-8-C-9 or the cycloheptatriene moiety. The 13C
NMR spectra of these compounds also agree well with
the delocalized aromatic π-system. The UV-vis spectral
data of compounds 6a ,b and 7a -c in CH3CN are sum-
marized in Table 3, together with those of the reference
compounds 2a 10 and 3a .11 The two series 6a ,b and 7a -c
resemble each other, respectively, and the longest wave-
length absorption maxima show red shifts by ca. 90 and
140 nm as compared with those of 2a and 3a , respec-
tively, suggesting the elongated π-conjugation of 6a ,b and
7a -c.
The reduction potentials of 6a ,b and 7a -c were
determined by cyclic voltammetry (CV) in CH3CN. The
reduction waves of 6a ,b and 7a are irreversible, while
1258 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Fused Pyrimidine Derivatives
TABLE 2. 1H NMR Sp ectr a l Da ta (600 MHz, CDCl3) of Com p ou n d s 6a ,b a n d 7a -c
compd
H-2
H-3
7.80 8.06 8.19
9.0 9.5
8.07 8.06 8.19
9.5 9.5
7.96 7.91 7.87
H-4
H-5
H-7
H-8
7.84 8.19
12.5
7.84 9.03
12.3
7.54 8.10
11.0
7.35 8.00
10.4
H-9
HE-15 HZ-15
remaining protons
6a
δH 10.20
8.04
9.5
7.87
9.5
7.90
11.0
7.87
11.5
8.05
11.2
-1.37
11.6
-0.73 3.58 (3H, s), 3.86 (3H, s)
J
9.3
6b
7a
7b
7c
δH 10.24
-1.33
-0.71 1.38 (3H, t, J ) 7.2 Hz), 1.50 (3H, t, J ) 6.9 Hz)
4.28 (2H, q, J ) 7.2 Hz), 4.52 (2H, q, J ) 6.9 Hz)
-0.34 3.51 (3H, s), 3.95 (3H, s)
J
δH
J
δH
J
δH
J
9.2
9.81
7.9
9.91
8.3
9.96
8.3
11.8
-0.47
12.0
10.0
9.1
7.98 7.90 7.82
-0.44
12.1
-0.31 3.57 (3H, s), 5.73 (1H, d, J ) 16.4 Hz)
5.82 (1H, d, J ) 16.4 Hz), 7.21-7.30 (5H, m)
9.8
8.01 7.92 7.84
8.3 7.9
7.8
7.27 7.7 2 -0. 54 -0.31 3.55 (3H, s), 7.36-7.65 (5H, m)
11.8 12.1
SCHEME 2
F IGURE 2. Energy levels and coefficients of the LUMO of 8
and HOMOs of 9a and 10a .
TABLE 5. Au tor ecyclin g Oxid a tion of Som e Am in es a n d
Alcoh ols by 6a a n d 7b u n d er P h otoir r a d ia tion
TABLE 3. UV-Vis Sp ectr a Da ta of Com p ou n d s 6a ,b a n d
7a -c, a n d Refer en ce Com p ou n d s 2a a n d 3a
entry
compda
amine or alcohol
yieldb,c/%
1
2
3
4
5
6
7
8
6a
6a
6a
6a
7b
7b
7b
7b
2a
3a
PhCH2NH2
4173
2533
576
11748
2028
1000
719
4455
20881
8573
compd
λ )
max(CH3CN)/nm (log ꢀ/dm3 mol-1 cm-1
PhCH(Me)NH2
cyclohexylamine
PhCH2OH
6a
6b
7a
7b
7c
2a
3a
235 (4.37), 293 (4.15), 365 (4.65), 469 (4.05), 528 (3.60)
236 (4.38), 294 (4.15), 366 (4.66), 471 (4.06), 528 (3.46)
249 (4.27), 336 (4.35), 574 (4.30)
248 (4.31), 334 (4.41), 368 (4.29), 574 (4.38)
246 (4.23), 335 (4.19), 574 (4.13)
PhCH2NH2
PhCH(Me)NH2
cyclohexylamine
PhCH2OH
PhCH2NH2
PhCH2NH2
245 (4.23), 298 (4.74), 360 (3.98), 437 (3.36)
243 (4.19), 298 (4.74), 359 (4.01), 432 (3.46)
9d
10e
a
TABLE 4. Red u ction P oten tia ls of 6a ,b a n d 7a -c a n d
Refer en ce Com p ou n d s 2a a n d 3a
CH3CN solution was irradiated by RPR-100, 350 nm lamps.
Isolated as 2,4-dinitrophenylhydrazone. c Based on 6a and 7b
b
used; the yield is calculated by subtraction of the blank yield from
a
a
a
a
compd
Ered
E
cathod, Eanod
compd
Ered
Ecathod, Eanod
the total yield of carbonyl compound in the presence of 6a and
d
7b. Reference 20. e Reference 12.
6a
6b
7a
7b
-1.03b
-1.17b
-1.02b
7c
2a
3a
-0.93c -0.98, -0.87
-1.62b
-1.39b
aspect of the photoinduced oxidation reaction, the fluo-
rescence spectra of 6a and 7b were studied; however, no
fluorescence spectra were observed.
-0.99c -1.09, -0.89
Volts vs Ag/AgNO3. Cathodic peak potentials. c Mean value
of the cathodic and anodic peaks.
a
b
On the other hand, compounds 6a and 7b were added
to benzylamine, cyclohexylamine, and benzyl alcohol, and
the mixtures were heated at 100 °C for 16 h under aerobic
conditions. The results after treatment of the reaction
mixture with 2,4-dinitrophenylhydrazine (vide supra) are
cycling oxidation reaction. In a previous study, the fluor-
escence spectrum of 7,9-dimethylcyclohepta[b]pyrimido-
[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate,
which has oxidizing ability toward some alcohols, is
quenched by addition of 1-phenylethanol, suggesting an
interaction of the singlet excited state of the compound
with the alcohol.21 Thus, in a search of the mechanistic
(20) Naya, S.; Nitta, M. Unpublished results.
(21) Naya, S.; Miyama, H.; Yasu, K.; Takayasu, T.; Nitta, M.
Tetrahedron 2003, 59, 1811.
J . Org. Chem, Vol. 69, No. 4, 2004 1259

Mitsumoto and Nitta
TABLE 6. Au tor ecyclin g Oxid a tion of Am in es a n d
former compound is oxidized under aerobic conditions to
regenerate 6a [or 7b]. To confirm the intermediacy of
reduced compounds 17 and 19 (Scheme 3) in the present
autorecycling oxidation reaction, independent reductions
of compounds 6a and 7b with NaBH4 were carried out.
Compounds 17 and 19 were detected by the 1H NMR
spectra of the reduction products; however, they are not
isolated in pure form and decompose gradually under
aerobic conditions. On the other hand, reduction of 6a
and 7b with NaBH4 in CD3OD in an NMR tube indicated
clean formation of 18 and 20. Compounds 18 and 20 are
unstable under aerobic conditions and could not be
isolated in pure form; however, satisfactory 1H NMR and
high-resolution mass spectral data were obtained. The
CD3OD solutions of 18 and 20 were stirred at room
temperature under aerobic conditions for 24 h; however,
18 and 20 were oxidized partially to regenerate 6a and
7b, and mainly decomposed to result in the formation of
unidentified materials. Consequently, it is shown that
the regeneration of 6a [or 7b] by oxidation of 17 [or 19]
is slow and ineffective to achieve an efficient autorecy-
cling oxidation. Furthermore, attempted detection of 17
[or 19] in the present oxidation reaction of amines and
benzyl alcohol was unsuccessful. Thus, path A seems to
be preferable.
Alcoh ols by 6a a n d 7b u n d er Aer obic Con d ition s a t 100
°C
entry compd amine or alcohol
solvent
DMF
DMF
yielda,b/%
1
2
3
4
5
6
6a
7b
6a
7b
6a
7b
PhCH2NH2
PhCH2NH2
cyclohexylamine DMF
cyclohexylamine DMF/H2O (1/1)
PhCH2OH
PhCH2OH
629
839
0
0
0
DMF
DMF/H2O (1/1)
0
a
Carbonyl compound is isolated as 2,4-dinitrophenylhydrazone.
b
Based on 6a and 7b used; the yield is calculated by subtraction
of the blank yield from the total yield of carbonyl compound in
the presence of 6a and 7b.
SCHEME 3
Con clu sion
Convenient synthesis of novel 1,6-methanocyclounde-
ca[b]pyrimido[5,4-d]pyrole-12,14-dione derivatives 6a ,b
and 7a -c was accomplished. The 1H NMR spectra
clarified that compounds 6a ,b and 7a -c are aromatic
molecules having a diatropic π-electron system. Com-
pounds 6a and 7b oxidize benzylic amines, cyclohexyl-
amine, and benzyl alcohol under aerobic and photoirra-
diation conditions to give the corresponding carbonyl
compounds in an autorecyling process. On the other
hand, compounds 6a and 7b oxidize benzylamine to lead
to carbonyl compounds under aerobic conditions at 100
°C in an autorecycling process. The oxidizing reaction of
6a and 7b is more effective under photoirradiation
conditions as compared with thermal conditions.
summarized in Table 6. Thermal reactions of amines and
benzyl alcohol in the absence of 6a and 7b (named
“blank”) also gave the corresponding carbonyl compounds
in low to modest yields. Thus, the yields in Table 6 are
calculated by subtraction of the blank yield from the yield
of of the carbonyl compound in the presence of 6a and
7b.
Compounds 6a and 7b oxidize benzylamine in more
than 100% yield (based on 6a and 7b used) (Table 6,
entries 1 and 2); however, both cyclohexylamine and
benzyl alcohol were not oxidized (Table 6, entries 3-6).
Furthermore, oxidizing properties of 6a and 7b seem to
be similar each other. Thus, the oxidizing reaction of 6a
and 7b is less effective under thermal conditions as
compared with photoirradiation.21 The postulated mecha-
nistic pathways for the oxidation of amines and benzyl
alcohol are depicted in Scheme 2. The electron transfer
from amines and benzyl alcohol to the excited triplet or
ground state (in the case of benzylamine under ther-
mal conditions) of 6a [or 7b] would occur to produce a
radical anion, 6a •- [or 7b•-], and R1R2CHXH•+. In the
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of 1,6-Meth a n o-
cyclou n d eca [b]p yr im id o[5,4-d ]p yr r ole-12(11H),14(13H)-
d ion e Der iva tives 6a ,b. A solution of 8 (2 mmol) and 9a ,b
(4 mmol) in AcOH (10 mL) was heated at 60 °C for the period
indicated in Table 1. After removal of the solvent, the residue
was neutralized with aqueous NaHCO3 and extracted with
CH2Cl2, and the extract was dried over Na2SO4. After evapora-
tion of the solvent, the residue was purified by TLC on SiO2
by using CH2Cl2-acetone (2/1) as a developer to give 6a and
6b.
Gen er a l P r oced u r e for th e Syn th esis of 1,6-Meth a n o-
cyclou n d eca [b]p yr im id o[5,4-d ]p yr r ole-12(10H),14(13H)-
d ion e Der iva tives 7a -c. A solution of 8 (1 mmol) and 10a -c
(2 mmol) in AcOH (10 mL) was heated at 80 °C. After removal
of the solvent, the residue was neutralized with aqueous
NaHCO3 and extracted with CH2Cl2, and the extract was
dried over Na2SO4. After evaporation of the solvent, the residue
was purified by column chromatography on SiO2 by using
CH2Cl2-acetone (2/1) as an eluent to give 7a -c. In the reaction
of 8 and 10a , 7a is soluble in water, and thus, after evaporation
of the AcOH, the residue was separated directly by column
chromatography to give 7a .
presence of oxygen, an electron transfer from 6a •- [or
•-
7b•-] to O2 may give the radical ion pair [R1R2CHXH•+O2
]
and 6a [or 7b]. Then a proton transfer from R1R2CHXH•+
to O2 may occur, followed by formation of products
•-
R1R2CHdX and H2O2 (path A).22
On the other hand, there is an alternative pathway
(path B), in which hydrogenated compound 17 [or 19]
(Scheme 3) in addition to the carbonyl compound or imine
are generated from 6a •- [or 7b•-] and R1R2CH2XH•+; the
(22) Fukuzumi, S.; Kuroda, S. Res. Chem. Intermed. 1999, 25, 789.
1260 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Fused Pyrimidine Derivatives
Cyclic Volta m m etr y of 1,6-Meth a n ocyclou n d eca [b]-
p yr im id o[5,4-d ]p yr ole-12,14-d ion e Der iva tives 6a ,b a n d
7a -c. The reduction potentials of 6a ,b and 7a -c were
determined by means of a CV-27 voltammetry controller (BAS
Co.). A three-electrode cell was used, consisting of a Pt working
and an Ag/AgNO3 reference electrode. Nitrogen was bubbled
through a CH3CN solution (4 mL) of each sample (1 mmol
dm-3) and Bu4NClO4 (100 mmol dm-3) to deaerate it. The
measurements were made at a scan rate of 0.1 V s-1, and the
voltammograms were recorded on an X-Y recorder. Im-
to give the 2,4-dinitrophenylhydrazone of the corresponding
carbonyl compound. The results are summarized in Table 5.
Gen er a l P r oced u r e for th e Au tor ecyclin g Oxid a tion
of Som e Alcoh ols a n d Am in es by 6a a n d 7b u n d er
Th er m a l a n d Aer obic Con d ition s. A solution of 6a (0.015
mmol) and 7b (0.015 mmol) and alcohol or amine (0.75 mmol)-
in DMF (1 mL) or DMF/H2O (2 mL) was heated at 100 °C
under aerobic conditions for 16 h. The reaction mixture was
diluted with ether and filtered, and the filtrate was treated
with 2,4-dinitrophenylhydrazine in 6% HCl to give 2,4-dini-
trophenylhydrazone of the corresponding carbonyl compound.
The results are summarized in Table 6.
mediately after the measurements, ferrocene (0.2 mmol dm-3
)
(E1/2 ) +0.083 V) was added as the internal standard, and
the observed peak potentials were corrected with reference to
this standard.
Ack n ow led gm en t. Financial support from a Wase-
da University Grant for Special Research Project and
21COE “Practical Nano-Chemistry” from MEXT, J apan,
is gratefully acknowledged. We thank the Materials
Characterization Central Laboratory, Waseda Univer-
sity, for technical assistance with the spectral data and
elemental analyses.
Red u ction of 6a a n d 7b w ith Na BH4 in CD3OD. A
solution of 6a (9 mg, 0.03 mmol) or 7b (11 mg, 0.03 mmol)
and NaBH4 (1.1 mg, 0.03 mmol) in CD3OD (0.75 mL) in an
NMR tube was shaken at rt for 5 min, and the 1H NMR spectra
of the solutions of 18 and 20 were recorded using Me4Si as
the internal standard. The reaction mixtures were shaken
under aerobic conditions for 24 h, and partial regeneration of
6a and 7b and decomposition were observed.
Gen er a l P r oced u r e for th e Au tor ecyclin g Oxid a tion
of Som e Alcoh ols a n d Am in es by 6a a n d 7b u n d er
P h otoir r a d ia tion a n d Aer obic Con d ition s. To a solution
of 6a (0.005 mmol) and 7b (0.005 mmol) in CH3CN (16 mL)
was added an alcohol or amine (2.5 mmol) in a Pyrex tube,
and the mixture was irradiated by RPR-100, 350 nm lamps
under aerobic conditions for 16 h. The reaction mixture was
concentrated in vacuo and diluted with ether and filtered. The
filtrate was treated with 2,4-dinitrophenylhydrazine in 6% HCl
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of 6a ,b and 7a -c, 1H-1H COSY spectra of 6a ,b
and 7a -c, UV-vis spectra of 6a ,b and 7a -c, and analytical
and spectroscopic data of 6a ,b, 7a -c, 18, and 20 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035336G
J . Org. Chem, Vol. 69, No. 4, 2004 1261