4
436
S. Niwayama et al. / Tetrahedron Letters 49 (2008) 4434–4436
6. Ozaki, E.; Uragaki, T.; Sakashita, K.; Sakimae, A. Chem. Lett. 1995, 539–540.
which also sometimes allowed isolation of a visible amount of the
corresponding diacid. Here the use of another slightly polar aprotic
solvent that is slightly miscible with water, acetonitrile, instead of
THF as a co-solvent helped accelerate the reaction time to some
extent, increasing the yield of the half-ester by about 10%. Earlier
we studied the influence of the co-solvent in this monohydrolysis
and found that a slightly polar aprotic solvent with a small degree
of miscibility with water appears to be an effective co-solvent. It
may also be possible that introduction of several bulky groups pro-
hibited adoption of a preferable conformation for this selectivity.
In summary, we have found highly practical conditions with
aqueous KOH or NaOH with THF or acetonitrile as a co-solvent at
7
.
Krapcho, A. P.; Jahngen, E. G. E., Jr.; Kashdan, D. S. Tetrahedron Lett. 1974, 15,
721–2723.
Niwayama, S. J. Org. Chem. 2000, 65, 5834–5836.
2
8
.
9. Typical procedures are as follows: Dimethyl malonate, 1, (159 mg, 1.20 mmol)
was dissolved in 2 mL of THF, and 20 mL of water was added. The reaction
mixture was cooled to 0 °C in an ice-water bath. To this mixture was added the
indicated equivalent of
a 0.25 M aqueous NaOH, KOH, or LiOH solution
dropwise with stirring. The reaction mixture was stirred for 30 min to one
hour, acidified with 1 M HCl at 0 °C to make the pH about 2, saturated with
1
3
2 4
NaCl, immediately extracted with ethyl acetate (X4), and dried over Na SO .
This extract was concentrated in vacuo and purified by silica gel column
chromatography with hexane–ethyl acetate (3:1) and then ethyl acetate as
typical eluents to afford monomethyl malonate.
10. Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498–500.
11. We are finding
a similar tendency in selective monohydrolysis of other
0
°C to selectively monohydrolyze a series of dialkyl malonates
symmetric or non-symmetric diesters. These results will be published in due
course.
and their derivatives. The yields here are among the highest
reported. All the half-esters prepared here showed excellent
purity and are quite stable over a long period of time. We also
found that the selectivity generally increases as the hydrophobicity
of the starting diesters increases.
12. We are investigating further mechanistic studies to detect potential
intermediates by physicochemical techniques.
13. Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron Lett. 2007, 48,
1
4
8757–8760.
1
4. The structures of all the half-esters reported here were determined by 1H NMR,
13
C
NMR, IR, and elemental analysis. The spectral data are as follows:
Monomethyl malonate (2):
Oil. 1H NMR (300 MHz, CDCl
) d = 3.39 (2H, s), 3.70 (3H, s), 11.19 (1H, br s); 13C
Acknowledgment
3
À1
NMR (75 MHz, CDCl
3
) d = 40.50, 52.50, 167.03, 171.46; IR (neat, cm ) 1741,
1
5
746, 2960–3185. Anal. Calcd for C
.34.
4 6 4
H O : C, 40.68; H, 5.12. Found: C, 40.51; H,
This work is supported by the National Science Foundation-
CAREER (CHE-0443265).
Monoethyl malonate (3a):
Oil. 1H NMR (300 MHz, CDCl
3
) d = 1.25 (3H, t, J = 7.2), 3.39 (2H, s), 4.19 (2H, q,
3
1
J = 7.2), 10.67 (1H, br s); C NMR (75 MHz, CDCl
166.69, 171.77; IR (neat, cm ) 1736, 1741, 2914-3182. Anal. Calcd for C H O :
C, 45.46; H, 6.10. Found: C, 45.83; H, 6.30.
3
) d = 13.84, 40.90, 61.85,
À1
Supplementary data
5
8 4
Supplementary data ( H and 13C NMR spectra for half-esters, 2,
1
Monopropyl malonate (4a):
Oil. 1H NMR (300 MHz, CDCl
3
) d = 0.93 (3H, t, J = 7.7), 1.66 (2H, m), 3.42 (2H, s),
13
3
4
.11 (2H, q, J = 7.2), 10.14 (1H, br s); C NMR (75 MHz, CDCl
3
) d = 10.13, 21.69,
40.89, 67.42, 166.81, 171.75; IR (neat, cm ) 1723, 1740, 2883–3181. Anal.
Calcd for C : C, 49.31; H, 6.90. Found: C, 49.43; H, 7.14.
Monomethyl methylmalonate (5a):
Oil. 1H NMR (300 MHz, CDCl
) d = 1.43 (3H, d, J = 7.2), 3.48 (1H, q, J = 7.2), 3.74
3H, s), 9.42 (1H, br s); 13C NMR (75 MHz, CDCl
) d = 13.08, 45.48, 52.39,
70.16, 175.38; IR (neat, cm ) 1721, 1739, 2956–3202. Anal. Calcd for C
À1
6 10 4
H O
References and notes
3
(
1
3
À1
5 8 4
H O :
1
.
For example, (a) Bulychev, A.; Bellettini, J. R.; O’Brien, M.; Crocker, P. J.;
Samama, J.-P.; Miller, M. J.; Mobashery, S. Tetrahedron 2000, 56, 5719–5728; (b)
Bihovsky, R.; Pendrak, I. Bioorg. Med. Chem. Lett. 1996, 6, 1541–1542; (c)
Horikawa, M.; Shirahama, H. Synlett 1996, 95–96; (d) Keum, G.; Hwang, C. H.;
Kang, S. B.; Kim, Y.; Lee, E. J. Am. Chem. Soc. 2005, 127, 10396–10399; (e) Kim,
H.-J.; Lindsey, J. J. Org. Chem. 2005, 70, 5475–5486; (f) Knoelker, H.-J.; Wolpert,
M. Tetrahedron Lett. 1997, 38, 533–536; (g) Marcaccini, S.; Pepino, R.; Pozo, M.
C.; Basurto, S.; Garcia-Valverde, M.; Torroba, T. Tetrahedron Lett. 2004, 45,
C, 45.46; H, 6.10. Found: C, 45.65; H, 5.94.
Monoethyl methylmalonate (6a):
Oil. 1H NMR (300 MHz, CDCl
) d = 1.22 (3H, t, J = 7.2), 1.40 (3H, d, J = 7.5), 3.44
3
13
(
3
1H, q, J = 7.2), 4.19 (2H, q, J = 7.2), 11.21 (1H, br s); C NMR (75 MHz, CDCl )
À1
d = 13.44, 13.90, 45.93, 61.69, 169.83, 176.00; IR(neat, cm ) 1722, 1735,
946–3200. Anal. Calcd for C : C, 49.31; H, 6.90. Found: C, 49.68; H, 6.75.
Monopropyl methylmalonate (7a):
Oil. 1H NMR (300 MHz, CDCl
) d = 0.92 (3H, t, J = 7.5), 1.43 (3H, d, J = 7.2), 1.65
2
6 10 4
H O
3
999–4001; (h) List, B.; Doehring, A.; Hechavarria Fonseca, M. T.; Job, A.; Rios
3
13
(
(
2H, m), 3.47 (1H, q, J = 7.2), 4.10 (2H, q, J = 7.2), 10.62 (1H, br s); C NMR
Torres, R. Tetrahedron 2006, 62, 476–482; (i) Balasubramanian, T.; Lindsey, J. S.
Tetrahedron 1999, 55, 6771–6784; (j) Hudson, R. D. A.; Osborne, S. A.;
Stephenson, G. R. Synlett 1996, 845–846; (k) Ashton, M. J.; Hills, S. J.;
Newton, C. G.; Taylor, J. B.; Tondu, S. C. D. Heterocycles 1989, 28, 1014–1035;
l) Williams, D. R.; Kammler, D. C.; Goundry, R. F. Heterocycles 2006, 67,
55–559.
(a) Strube, R.E. Organic Synthesis; Wiley: New York, NY, 1963; Collect. Vol. 4,
pp 417–419.; (b) Grakauskas, V.; Guest, A. M. J. Org. Chem. 1978, 43, 3485–
488; (c) Hutchinson, C. R.; Nakane, M.; Gollman, H.; Knutson, P.L. Organic
Synthesis; Wiley: New York, NY, 1990; Collect. Vol. 7, pp 323–326.
For example, (a) Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5897–5905; (b) Vecchi,
A.; Melone, G. J. J. Org. Chem. 1959, 24, 109–110; (c) Westermann, J.; Schneider,
M.; Platzek, J.; Petrov, O. Org. Process Res. Dev. 2007, 11, 200–205; (d) de
Meijere, A.; Ernst, K.; Zuck, B.; Brandl, M.; Kozhushkow, S. I.; Tamm, M.; Yufit,
D. S.; Howard, J. A. K.; Labahn, T. Eur. J. Org. Chem. 1999, 11, 3105–3115; (e) De
Kimpe, N.; Boeykens, M.; Tehrani, K. A. J. Org. Chem. 1994, 59, 8215–8219; (f)
Robertson, A.; Sandrock, W. F. J. Chem. Soc. 1933, 1617–1618; (g) Eaton, P. E.;
Nordari, N.; Tsanaktsidis, J.; Upadhyaya, S. P. Synthesis 1995, 501–502.
(a) Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. Tetrahedron Lett. 1989, 30,
75 MHz, CDCl
3
) d = 10.17, 13.51, 21.77, 45.94, 67.24, 169.93, 175.96; IR (neat,
À1
cm ) 1717, 1739, 2883–2971. Anal. Calcd for C
7 12 4
H O : C, 52.49; H, 7.55.
Found: C, 52.74; H, 7.49.
Monomethyl phenylmalonate (8a):
(
5
1
White solid; mp 92–93 °C; H NMR (300 MHz, CDCl
3
) d = 3.75 (3H, s), 4.65 (2H,
s), 7.35 (5H, m), 8.99 (1H, br s); 13C NMR (75 MHz, CDCl
) d = 53.06, 57.33,
2
.
.
3
À1
1
2
5
28.55, 128.77, 129.15, 131.96, 168.59, 173.24; IR (neat, cm ) 1717, 1740,
956–3212. Anal. Calcd for C10
.40.
10 4
H O : C, 61.85; H, 5.19. Found: C, 61.92; H,
3
Monoethyl phenylmalonate (9a):
White solid; mp 74 °C (lit. 76–77 °C);3a 1H NMR (300 MHz, CDCl
t, J = 7.2), 4.21 (2H, q, J = 7.2), 4.63 (1H, s), 7.37 (5H, m), 10.16 (1H, br s);
3
3
) d = 1.25 (3H,
13
C
3
NMR (75 MHz, CDCl ) d = 13.81, 57.51, 62.10, 128.39, 128.62, 129.13, 132.01,
À1
167.95, 173.84; IR (neat, cm
)
1717, 1737, 2941–3190. Anal. Calcd for
C
11
12 4
H O : C, 63.45; H, 5.81. Found: C, 63.30; H, 5.80.
Monopropyl phenylmalonate (10a):
Oil. 1H NMR (300 MHz, CDCl
) d = 0.87 (3H, t, J = 7.5), 1.64 (2H, m, J = 7.2), 4.12
3
2H, m), 4.64 (1H, s), 7.35 (5H, m), 10.02 (1H, br s); C NMR (75 MHz, CDCl )
3
13
(
4
.
.
d = 10.16, 21.74, 57.47, 67.72, 128.48, 128.73, 129.12, 132.21, 168.41, 173.07;
3
3
073–3076; (b) Junek, H.; Ziegler, E.; Herzog, U.; Kroboth, H. Synthesis 1976,
À1
IR (neat, cm ) 1717, 1736, 2881–3067. Anal. Calcd for C12
H
14
O
4
: C, 64.85; H,
32–334.
6.35. Found: C, 65.17; H, 6.61.
5
Duthaler, R. Helv. Chim. Acta 1983, 66, 1475–1492.