510
Vol. 57, No. 5
81 °C was collected to yield monoethyl malonate, 4, as a colorless oil. The
yield of monoethyl malonate, 4, was 87.073 g (82%).28) 1H-NMR (300 MHz,
CDCl3) d: 1.30 (3H, t, Jꢁ7.2 Hz), 3.44 (2H, s), 4.24 (2H, q, Jꢁ7.2 Hz),
10.21 (1H, br s). 13C-NMR (75 MHz, CDCl3) d: 13.78 (q), 40.88 (t), 61.80
(t), 166.64 (s), 171.76 (s). IR (neat) cmꢀ1: 1722, 1741, 2914—3182. Anal.
in due course.
In summary, we have examined conditions for a large scale
synthesis of monomethyl malonate and monoethyl malonate,
applying the selective monohydrolysis of symmetric diesters
we reported previously. Since this reaction is extremely green Calcd for C5H8O4: C, 45.46; H, 6.10. Found: C, 45.76; H, 6.20.
and practical, with mild and safe conditions, and requires
Acknowledgements This work is supported by the National Science
Foundation-CAREER (CHE-0443265).
only inexpensive reagents, its synthetic utility, particularly in
process chemistry, is expected.
References and Notes
Experimental
1) This work is the subject of U.S. and international patent applications.
The 1H-NMR at 300 MHz and 13C-NMR at 75 MHz spectra were
Niwayama S., U.S. 2009/0023945, WO 2008/150487.
measured as solutions in CDCl3 using tetramethylsilane (TMS) as an
2) Bulychev A., Bellettini J. R., O’Brien M., Crocker P. J., Samama J.-P.,
internal standard. The IR spectra were recorded on an FT-IR instrument. The
5 M KOH was titrated with 20 ml of 0.5 M oxalic acid.
Synthesis of Monomethyl Malonate, 2 In a 1 l-sized one-necked flask,
equipped with a magnetic stirrer, was placed 158.30 g (1.2 mol) of dimethyl
Miller M. J., Mobashery S., Tetrahedron, 56, 5719—5728 (2000).
3) Bihovsky R., Pendrak I., Bioorg. Med. Chem. Lett., 6, 1541—1542
(1996).
4) Horikawa M., Shirahama H., Synlett, 1, 95—96 (1996).
malonate, 1, and 10 ml of acetonitrile was added to dissolve this dimethyl
5) Keum G., Hwang C. H., Kang S. B., Kim Y., Lee E., J. Am. Chem.
malonate, 1. After the solution was stirred for one minute, the reaction
Soc., 127, 10396—10399 (2005).
mixture was cooled to 0 °C with an ice-water bath in a cold room maintained
at 0—4 °C. To this mixture, 100 ml of water was added and the mixture was
stirred for 30 min. To this reaction mixture was added 240 ml of 5 M aqueous
KOH (1.2 mol) solution dropwise with continuous stirring for a period of
6) Kim H.-J., Lindsey J., J. Org. Chem., 70, 5475—5486 (2005).
7) Knoelker H.-J., Wolpert M., Tetrahedron Lett., 38, 533—536 (1997).
8) Marcaccini S., Pepino R., Pozo M. C., Basurto S., Garcia-Valverde M.,
Torroba T., Tetrahedron Lett., 45, 3999—4001 (2004).
15 min with an addition funnel. When this addition was completed, the
9) List B., Doehring A., Hechavarria Fonseca M. T., Job A., Rios Torres
reaction mixture was stirred for one additional hour while covered with a
stopper and immersed in the ice-water bath in the cold room maintained at
R., Tetrahedron, 62, 476—482 (2006).
10) Balasubramanian T., Lindsey J. S., Tetrahedron, 55, 6771—6784
0—4 °C. The reaction was monitored by TLC using a staining solution
(1999).
prepared with bromocresol green (40 mg) dissolved in ethanol (100 ml, 200
proof).
The reaction mixture was acidified with 150 ml of 12 M aqueous HCl
solution in the ice-water bath, saturated with NaCl, and extracted with five
11) Hudson R. D. A., Osborne S. A., Stephenson G. R., Synlett, 1, 845—
846 (1996).
12) Ashton M. J., Hills S. J., Newton C. G., Taylor J. B., Tondu S. C. D.,
Heterocycles, 28, 1014—1035 (1989).
500 ml portions of ethyl acetate with a 1 l separatory funnel. The extract was
13) Williams D. R., Kammler D. C., Goundry R. F., Heterocycles, 67,
washed with 500 ml of a saturated aqueous NaCl solution. The ethyl acetate
555—559 (2006).
extract was dried over approximately 100 g of anhydrous sodium sulfate.
14) Strube R. E., “Organic Syntheses,” Collect. Vol. 4, Wiley, New York,
After the drying agent was removed by gravity filtration, the ethyl acetate
1963, pp. 417—419.
solution was concentrated by a rotary evaporator and distilled under a
15) Hutchinson C. R., Nakane M., Gollman H., Knutson P. L., “Organic
reduced pressure at 2.5 mmHg. The fraction showing a boiling point of
Syntheses,” Collect. Vol. 7, Wiley, New York, 1990, pp. 323—326.
91—92 °C was collected to yield monomethyl malonate, 2, as a colorless oil.
16) Grakauskas V., Guest A. M., J. Org. Chem., 43, 3485—3488 (1978).
The yield of monomethyl malonate, 2, was 114.77 g (81%).27) 1H-NMR
17) Rigo B., Fasseur D., Cauliez P., Couturier D., Tetrahedron Lett., 30,
3073—3076 (1989).
18) Junek H., Ziegler E., Herzog U., Kroboth H., Synthesis, 1976, 332—
(300 MHz, CDCl3) d: 3.47 (2H, s), 3.78 (3H, s), 10.88 (1H, br s). 13C-NMR
(75 MHz, CDCl3) d: 40.52 (t), 52.51 (q), 167.09 (s), 171.33 (s). IR (neat)
cmꢀ1: 1724, 1741, 2960—3185. Anal. Calcd for C4H6O4: C, 40.68; H, 5.12.
334 (1976).
Found: C, 40.29; H, 5.27.
Synthesis of Monoethyl Malonate, 4 In a 1 l-sized one-necked flask,
equipped with a magnetic stirrer, was placed 128.66 g (0.8 mol) of diethyl
19) Ozaki E., Uragaki T., Sakashita, K., Sakimae A., Chem. Lett., 1995,
539—540 (1995).
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malonate, 3, and 30 ml of acetonitrile was added to dissolve this diethyl
15, 2721—2723 (1974).
malonate, 3. After the solution was stirred for 1 min, the reaction mixture
21) Niwayama S., J. Org. Chem., 65, 5834—5836 (2000).
was cooled to 0 °C with an ice-water bath in a cold room maintained at
22) Niwayama S., Cho H., Lin C., Tetrahedron Lett., 49, 4434—4436
0—4 °C. To this mixture, 300 ml of water was added and the mixture was
(2008).
stirred for 30 min. To this reaction mixture was added 160 ml of 5 M aqueous
23) Niwayama S., Wang H., Hiraga Y., Clayton J. C., Tetrahedron Lett., 48,
KOH (0.8 mol) solution dropwise with continuous stirring for a period of
8508—8510 (2007).
15 min with an addition funnel. When this addition was completed, the
24) Niwayama S., Rimkus A., Bull. Chem. Soc. Jpn., 78, 498—500
reaction mixture was stirred for one additional hour while covered with a
(2005).
stopper and immersed in the ice-water bath in the cold room maintained at
25) Niwayama S., J. Synth. Org. Chem., Jpn., 66, 983—994 (2008).
0—4 °C. The reaction was monitored by TLC using a staining solution
26) Under comparable conditions on a 0.12 mol-scale with a reaction time
prepared with bromocresol green (40 mg) dissolved in ethanol (100 ml, 200
of 1 h, we have also obtained the half-esters of dimethyl methyl mal-
proof).
onate and diethyl methyl malonate in 90% and 83% yields, respec-
The reaction mixture was acidified with 120 ml of 12 M aqueous HCl
tively.
solution in the ice-water bath, saturated with NaCl, and extracted with five
27) Under the same pressure, 6.55 g (4%) of dimethyl malonate was col-
500 ml portions of ethyl acetate with a 1 l separatory funnel. The extract was
lected at 45 °C, and 1.31 g (1%) of malonic acid remained after the
washed with 500 ml of a saturated aqueous NaCl solution. The ethyl acetate
distillation.
extract was dried over approximately 100 g of anhydrous sodium sulfate.
28) Under the same pressure, 5.60 g (4%) of diethyl malonate was col-
After the drying agent was removed by gravity filtration, the ethyl acetate
lected at 43 °C, and 4.79 g (6%) of malonic acid remained after the
solution was concentrated by a rotary evaporator and distilled under a
distillation.
reduced pressure at 2.5 mmHg. The fraction showing a boiling point of 79—