1524 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
EM Science. Starting materials (Table 1, entries 1-3, 7, and 9)
were purchased from Aldrich and used without purification. The
starting materials of Table 1, entries 4-6 and 10, were prepared
according to the general procedure described below. Structural
confirmation of products was obtained by comparison to com-
mercially available authentic material.
Sch em e 1
21-Meth oxa lylp r ogester on e (3). A solution of 3-hydroxy-
pregna-3,5-dien-20-one-3-methyl ether (10 g, 30 mmol) in toluene
(40 mL) was treated with diethyl oxalate (5.75 g, 39.3 mmol)
followed by 25% NaOMe/MeOH (13.9 mL, 60.8 mmol). The
solution was stirred at 35 °C for 3 h and then quenched with
the addition of 1 N HCl. The organic layer was washed with
water and diluted with MeOH (40 mL). The precipitated product
was collected by filtration and dried under a stream of N2 to
give 21-methoxalylprogesterone as an off-white solid (10.2 g,
85%): 1H NMR (400 MHz, CDCl3) δ 0.80 (s, 3 H), 1.10 (m, 3 H),
1.30 (s, 3 H), 1.51 (m, 3 H), 1.74 (m, 2 H), 1.83 (m, 2 H), 1.88 (m,
1 H), 2.13 (m, 2 H), 2.34 (m, 3 H), 2.53 (m, 4 H), 2.68 (t, 1 H),
4.0 (s, 3 H), 5.84 (s, 1 H), 6.43 (s, 1 H); 13C NMR (CDCl3) δ 13.3,
17.24, 20.77, 22.25, 24.26, 31.76, 32.62, 33.78, 35.55, 38.18, 38.46,
45.64, 52.98, 53.51, 55.91, 60.92, 102.31, 123.78, 162.60, 165.63,
199.23, 203.39.
for optimum reaction, a base is required to buffer the
system to prevent the decomposition of the potassium
peroxymonosulfate which occurs at low pH (<5).9 If
conducted in the absence of base, the reaction stalls as
the pH drops during the Oxone addition.
An dr ost-4-en e-17-â-car boxylic Acid (4). A vigorously stirred
mixture of 21-methoxalylprogesterone (4.0 g, 1 mmol) and
NaHCO3 (8.4 g, 10 mmol) in acetone (100 mL) was cooled to 0
°C. The slurry was treated with a solution of Oxone (15.4 g, 2.5
mmol) in water (60 mL) over a period of 15 min. The slurry was
then warmed to 25 °C, and solid byproducts were removed by
filtration. The pH of the crude product solution was adjusted
between pH 4 and 5 with 1 N H2SO4. The product precipitated
after concentration and was collected by filtration. Purification
by recrystallization from a minimum volume of hot MeOH/H2O/
THF (80/20/10) gave the title compound (2.75 g, 87%) as a white
crystalline solid: 1H NMR (400 MHz, DMSO-d6) δ 0.67 (s, 3 H),
0.91 (m, 2 H), 1.10 (m, 2 H), 1.15 (s, 3 H), 1.24 (m, 2 H), 1.40 (m,
1 H), 1.60 (m, 6 H), 1.98 (m, 3 H), 2.20 (m, 3 H), 2.40 (m, 2 H),
5.63 (m, 1 H); 13C NMR (DMSO-d6) δ 13.46, 17.21, 20.79, 23.56,
24.35, 31.99, 32.32, 33.94, 35.39, 35.51, 37.94, 38.52, 43.36, 53.53,
54.81, 55.03, 123.53, 117.09, 174.94, 198.22.
Our preliminary results show this reaction to be
general to 1,3-dicarbonyl compounds and R-hydroxy
ketones as indicated by the examples in Table 1.10
Oxalate derivatives (entries 4-6) as well as simple
malonic esters (entry 1) can be employed in this reaction.
The reaction works equally well for aliphatic and aro-
matic 1,3-diketones. The simple symmetrical biaryl dike-
tone (entry 2) undergoes clean conversion to 2 equiv of
benzoic acid. The cyclic alkyl diketone (entry 3) produced
the dicarboxylic acid, albeit in low yield due to isolation
problems. The most interesting comparison is that of
entries 7 and 8, where it is apparent that activation of
the R-carbon by a simple hydroxyl group is sufficient for
oxidative cleavage. Conjugated diketones (entry 9) and
oxalates with alkyl substituents R to the carbonyl (entry
10) are not oxidatively cleaved.
Meth yl (2Z)-4-(1-Adam an tyl)-2-h ydr oxy-4-oxo-2-bu ten oate
(5). To a solution of 1-adamantyl methyl ketone (3.0 g, 16.83
mmol) in toluene (15 mL) was added diethyl oxalate (3.43 g, 25.2
mmol). After addition of a 25% NaOCH3 solution (7.7 mL, 33.7
mmol), the reaction was heated at 50 °C for 5 h. CH2Cl2 was
added and the solution washed with H2O. The organic layer was
dried over MgSO4 and concentrated to a white solid: 1H NMR
(400 MHz, CDCl3) δ 1.70-1.86 (m, 12H), 2.02 (m, 3H), 3.90 (s,
3H, OCH3), 6.52 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.83,
36.47, 38.38, 43.56, 53.07, 97.58, 162.84, 168.10, 207.99; HRMS
calcd for C15H20O4 265.1440, found 265.1448.
In summary, we have developed a novel method for
converting methyl ketones to carboxylic acids using
Oxone to oxidatively degrade 1,3-dicarbonyl compounds
and R-hydroxy ketones. This method compliments exist-
ing methodologies and is in general a milder alternative
to the haloform reaction.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under an
atmosphere of dry nitrogen. Solvents were used as provided from
Ack n ow led gm en t. We thank Peter G. M. Wuts for
his encouragement and support in preparing this
manuscript.
(8) Grega, K. C.; Ashford, S. W. U.S. Patent 60-159,272 1999.
(9) Zheng, T.; Richardson, D. E. Tetrahedron Lett. 1995, 36, 833-
836.
(10) The adamantyl oxalate derivative (entry 5) was the only new
compound prepared in this study.
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