Reductive methylation/phosphorylation of 3,4-diazacyclopentadienone N-oxides with trimethyl phosphite

Article abstract of DOI:10.3987/com-03-s(p)65

Treatment of 2,5-diphenyl-3,4-diazacyclopentadienone 3-oxide and 3,4-dioxide with trimethyl phosphite results in N-deoxygenation and methylation and O-phosphorylation to produce dimethyl (1-methyl-3,5-diphenyl-4-pyrazolyl) phosphate.

Full text of DOI:10.3987/com-03-s(p)65

HETEROCYCLES, Vol. 62, 2004, pp. 847 - 849
Received, 25th September, 2003, Accepted, 31st October, 2003, Published online, 14th November, 2003
REDUCTIVE METHYLATION/PHOSPHORYLATION OF 3,4-
DIAZACYCLOPENTADIENONE N-OXIDES WITH TRIMETHYL
PHOSPHITE
Jeremiah P. Freeman* and Marc E. Guay
Department of Chemistry and Biochemistry, University of Notre Dame
Notre Dame, IN 46556, U.S.A.
Abstract - Treatment of 2,5-diphenyl-3,4-diazacyclopentadienone 3-oxide
and 3,4-dioxide with trimethyl phosphite results in N-deoxygenation and
methylation and O-phosphorylation to produce dimethyl (1-methyl-3,5-
diphenyl-4-pyrazolyl) phosphate.
The reversible relationship between 1,4-dihydroxypyrazoles and 3,4-diazacyclopentadienone 3-
1
oxides (2) is reminiscent of the hydroquinone-quinone couple. In an effort to find other
OH
O
[OX]
R
R
R
R
N N+
[RED]
N N
O–
OH
1
2
chemical analogies between the two systems, we examined the action of trimethyl phosphite on
2, R = Ph. Ramirez and co-workers had shown that benzoquinone is converted to dimethyl p-
2
methoxyphenyl phosphate by this reagent. On the other hand trisubstituted phosphorus has
3
traditionally been used for the deoxygenation of N-oxides.
(CH3O)2P O
O
O
+
(CH3O)3P
O
OCH3
Heating 2, R = Ph with trimethyl phosphite in boiling toluene produced dimethyl (1-methyl-3,5-
diphenyl-4-pyrazolyl)phosphate (3) as the major product. A minor side-product was 1-methyl-
3,5-diphenyl-4-hydroxypyrazole, probably formed by adventitious hydrolysis of 3; the same
material was obtained from 3 by treatment with aqueous base. The structure of phosphate (3)

1
was inferred from its MS spectrum, H NMR spectrum, and its ready hydrolysis to 1-methyl-3,5-
diphenyl-4-hydroxypyrazole.
O
OCH3
P
O
O
O
OCH3
Ph
Ph
Ph
Ph
Ph
Ph
or
(CH3O)3P
N N+
N+ N+
N N
O–
–O
O–
CH3
2
4
3
Phosphate (3) was also obtained when 2,5-diphenyl-3,4-diazacyclopentadienone 3,4-dioxide (4)
was heated with trimethyl phosphite. Again a small amount of the 4-hydroxypyrazole was
obtained and, in one experiment, a trace of 4-methoxy-3,5-diphenylpyrazole. Interestingly, the
two methylated hydroxypyrazoles could easily be distinguished by their MS spectra: the N-
+
methyl compound exhibited its principal peak at m/z 118 (PhC =NCH ), whereas the O-
3
methyl isomer had its principal peak at m/z 104 (PhC+=NH).
Thus the reaction of these N-oxides does not exactly parallel the quinone reaction, but appears
to begin with nitrogen deoxygenation to the diazadienone (5). Conversion of 5 to 3 then
parallels the quinone methylation. The difference observed here is probably related to the
O
OP+(OCH3)3
Ph
Ph
Ph
(CH3O)3P
(CH3O)3P
Ph
2 or 4
3
N N–
5a
N N
5
relatively weak N-O bond. The fact that the dioxide gives the same product supports the
suggestion that nitrogen deoxygenation occurs so that intermediate (5) is common to both
reactions. (It had previously been shown that 5 is reduced to 4-hydroxy-3,5-diphenylpyrazole by
triphenylphosphine; an intermediate analogous to 5a was suggested). In a somewhat related
5
investigation, 2-phenyl-3-phenyimino-3H-indole N-oxide (6) was found to be converted
principally to 1-diethylphosphoryl-2-phenyl-3-(N-ethyl-N-phenylamino)-1H- indole (8) by triethyl
phosphite, presumably by way of the deoxygenation product (7). Again reductive
alkylation/phosphorylation was observed in this related system.
C2H
Ph
5 N
NPh
Ph
NPh
Ph
(EtO)3P
Ph
N
N
N
P(OC2H5)2
O
O
7
8
6

EXPERIMENTAL
2,5-Diphenyl-3,4-diazacyclopentadienone
3,4-Dioxide
(4)
or
2,5-Diphenyl-3,4-
diazacyclopentadienone 3-Oxide (2) and Trimethyl Phosphite. A mixture of 5 g (0.02 mol) of
either 2 or 4 and 3 mL of trimethyl phosphite in 50 mL of toluene was heated under nitrogen
overnight at reflux. At this point the original red or orange color of the starting N-oxides had
faded and the solution was bright yellow. The solution was cooled and washed several times to
remove trimethyl phosphate, dried, and concentrated to a yellow oil. The oil was dissolved in
ether and washed with 10% sodium hydroxide solution and water. The dried ether solution was
subjected to GLC analysis, which revealed the presence of a trace of benzonitrile. The
remaining ether solution was chromatographed on silica.
Ether-hexane (3:1) eluted 1-methyl-3,5-diphenyl-4-hydroxypyrazole as a pale yellow solid (0.5
4
+
g), mp 175-177°C (lit., 175-177°C); MS spectrum, m/z: M 250 (52), 118 (100), 103 (40), 77
1
(38); H NMR (300 MHz, CDCl ), d: 3.60, s, 3 H; 7.33, m, 6 H; 7.80, m, 4 H.. It was identical to
3
an authentic sample. Acetylation with acetic anhydride produced 1-methyl-3,5-diphenyl-4-
4
4
acetoxypyrazole as a white solid, mp 108-110°C (lit., 109-111°C).
Further elution with ether-ethyl acetate produced several fractions containing a yellow oil that
was rechromatographed to give 3.7 g (54%) of dimethyl (1-methyl-3,5-diphenyl-4-pyrazolyl)-
+
phosphate as a pale yellow oil; MS spectrum, m/z: M , 358 (100), 118 (80), 103 (12), 77 (16);
1
H NMR (300 MHz, CDCl ), d: 3.28 (d, J = 11 Hz, 6 H, P-OCH ); 3.72 (s, 3 H, N-CH ); 7.48 (m,
3
6 H); 7.96 (m, 4 H).
3
3
A solution of 1.4 g of this phosphate in 10 mL of 10% NaOH was heated under reflux for an
hour. The solution was neutralized by addition of 10% HCl and extracted with ether. After drying,
the ether extracts were concentrated to yield a white solid, mp 175-176°C, identical to 1-methyl-
3,5-diphenyl-4-hydroxypyrazole.
In one experiment with 4, further elution of the column with ethyl acetate yielded a trace of a
white solid, mp 160-162°C, identical to an authentic sample of 4-methoxy-3,5-diphenylpyrazole
4
(lit., mp 161-163°C).
REFERENCES
1. D. L. Surbey, J. J. Gannon, and J. P. Freeman, J. Org. Chem., 1969, 34, 187.
2. F. Ramirez, E. H. Chen, and S. Dershowitz, J. Am. Chem. Soc., 1959, 81, 4338.
3. For example, see C. Grundmann and H.-D. Frommeld, J. Org. Chem., 1965, 30, 2077.
4. P. J. Fagen, E. E. Neidert, M. J. Nye, M. J. O’Hare, and W.-P. O’Hare, Can. J. Chem., 1979,
57.
5. S. Canaestrari, A. Mar’in, P. Sgarabotto, L. Righi, and L. Greci, J. Chem Soc., Perkin Trans.
2, 2000, 833.