Facile preparation and purification of mono tert-butyl malonate

Article abstract of DOI:10.1080/00397910500334405

Reaction of Meldrum's acid with tert-BuOH gives tert-BuO ₂CCH₂CO₂H, which can be easily purified via its corresponding crystalline ammonium salt and subsequent acidification. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500334405

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Facile Preparation and Purification of Mono
tert‐Butyl Malonate
Vitali I. Tararov a , Andrei Korostylev a , Gerd König b & Armin Börner a c
a Leibniz‐Institut für Organische Katalyse e.V. , Rostock, Germany
b Ratiopharm GmbH , Ulm, Germany
c Institut für Chemie der Universität Rostock , Rostock, Germany
Published online: 15 Aug 2006.
To cite this article: Vitali I. Tararov , Andrei Korostylev , Gerd König & Armin Börner (2006)
Facile Preparation and Purification of Mono tert‐Butyl Malonate, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:2, 187-191, DOI:
10.1080/00397910500334405
To link to this article: http://dx.doi.org/10.1080/00397910500334405
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Synthetic Communicationsw, 36: 187–191, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500334405
Facile Preparation and Purification of
Mono tert-Butyl Malonate
Vitali I. Tararov and Andrei Korostylev
Leibniz-Institut fu¨r Organische Katalyse e.V., Rostock, Germany
¨
Gerd Konig
Ratiopharm GmbH, Ulm, Germany
¨
Armin Borner
Leibniz-Institut fu¨r Organische Katalyse e.V., Rostock, Germany and
¨
Institut fu¨r Chemie der Universitat Rostock, Rostock, Germany
Abstract: Reaction of Meldrum’s acid with tert-BuOH gives tert-BuO2CCH2CO2H,
which can be easily purified via its corresponding crystalline ammonium salt and
subsequent acidification.
Keywords: Half esterification, malonic acid monoesters, tert-butyl ester
INTRODUCTION
Malonic acid monoesters proved to be very important reagents for two carbon
atom elongation of aldehydes and carboxylic acids, giving expediently
a,b-unsaturated esters[1] or b-ketoesters.[2] Unfortunately, only lower mono-
esters or their salts are available at costs reasonable for preparative work, for
example, EtO2CCH2CO2H, EtO2CCH2CO2K, and MeO2CCH2CO2K. In
contrast the price of tert-BuO2CCH2CO2H, which is required for the simul-
taneous introduction of bulky tert-Bu protective group in the products, is
extremely high.
Received in Poland June 14, 2005
¨
¨
Address correspondence to Armin Borner, Leibniz-Institut fur Organische Katalyse
e.V., A.-Einsteinstr. 29a, Rostock 18059, Germany. Fax: þ40 (0) 381 1281 5000;
E-mail: armin.boerner@ifok-rostock.de
187

188
V. I. Tararov et al.
In our current work we were forced to find a simple and cheap method for
preparation of mono tert-butyl malonate that could be easily upscaled in a
chemical laboratory. A literature survey revealed that Meldrum’s acid reacts
with alcohols[3] and phenols,[4] respectively, forming malonic acid monoesters.
As soon as Meldrum’s acid is available at a reasonable price it represents an
extremely valuable starting material for preparation of tert-BuO2CCH2CO2H.
It is rather surprising that the reaction of Meldrum’s acid with tert-BuOH
has not been detailed up to now.
RESULTS AND DISCUSSION
We found that refluxing Meldrum’s acid (1) in tert-BuOH for 5 h resulted in
nearly quantitative conversion of 1 and formation of tert-BuO2CCH2CO2H (2)
(Scheme 1). The side product 3 was formed in a small concentration in
comparison to 2 in a ratio of 4 : 96.
The purity of the raw product 2 might be sufficient for most synthetic
purposes. Nevertheless, we attempted to purify monoester 2. Unfortunately
vacuum distillation caused decomposition presumably by the mechanism
given in Ref. 4. We were pleased to see that monoester 2 forms the highly
crystalline and slightly hygroscopic ammonium salt 4, which can be
purified by simple washing with Et2O. Pure product 2 was isolated from the
salt by acidification and extraction. After this procedure the overall yield of
mono tert-butyl malonate 2 was 82% based on initial Meldrum’s acid 1.
The structure of the side product 3 was confirmed by the comparison of
NMR data measured with an independently prepared compound.[5] The coin-
cidence in chemical shifts was within +0.01 ppm. The compound is stable in
refluxing tert-BuOH. Its formation in the reaction of Meldrum’s acid with
hydroxy compounds has been never reported before. We observed also the
Scheme 1.

Mono tert-Butyl Malonate
189
formation of product 3 in the reaction of Meldrum’s acid with i-PrOH under
the conditions given in Ref. 3. During distillation of the crude mixture it
comes into the distillate. The formation can be easily rationalized on the
basis of the given mechanism of the alcoholysis of Meldrum’s acid,[6]
which includes enolization of Meldrum’s acid followed by the cleavage of
the acetonide 5 under the formation of carboxyketene 7 via hemiacetal 6
(Scheme 2). Acetone reacts with enol 5 to afford the Knoevenagel type
adduct 3.
In addition, we found that in the competitive reaction of Meldrum’s acid
with tert-BuOH–EtOH (equimolar mixture) the ratio of corresponding esters
was 1 : 3.8. For comparison, the competitive reaction of acetylketene with
tert-BuOH–n-BuOH gives corresponding acetoacetate in a ratio of 1 : 8.2.[7]
An alternative to our reported method of the preparation of tert-
BuO2CCH2CO2H (2) could be the saponification of tert-BuO2CCH2CO2Et[8]
or tert-BuO2CCH2CO2Me.[9] The price of these asymmetrical esters is rather
high; therefore our new methodology seems to be superior.
EXPERIMENTAL
O-tert-Butylmalonic Acid Ammonium Salt (4)
A mixture of Meldrum’s acid (1) (50 g, 0.347 mol) and tert-BuOH (100 mL)
was gently refluxed for 5 h with a CaCl2 tube on the head of the reflux
condenser. After cooling the excess of tert-BuOH and acetone was removed
under reduced pressure. The residue was dissolved in absolute EtOH
(ca. 200 mL), the solution cooled in an ice bath, and aqueous ammonia
solution (26 mL, 25%, 0.348 mol) added. The volatiles were evaporated
Scheme 2.

190
V. I. Tararov et al.
until a solid residue was formed. This was triturated with ether (200 mL),
filtered, and washed with the same volume of ether. Drying on air afforded
53.9 g (87.6%) of ammonium salt 4, mp 93–978C. In CD3OD H-D
exchange in the CH2-group was observed. 1H NMR (CD3OD), d 1.49
(tert-Bu); 3.09–3.31 (residual CH2 and CHD), 5.19 (H2O, DOH). 13C NMR
(CD3OD), d 29.19 (Me), 47–48 (m, residual CHD), 82.6 (Me3C), 171.5 and
175.3 (COO). Anal. calcd. for C7H15NO4: C, 47.45; H, 8.53; N, 7.90.
Found: C, 47.01; H, 8.50; N, 8.03.
tert-Butyl Malonate (2)
A mixture of ammonium salt 4 (50 g) and ether (300 mL) was cooled in an ice
bath, and an aqueous HCl solution (100 mL, ca. 9%) was slowly added. After
30 min the organic layer was separated and washed with brine (3 ꢀ 100 ml).
The ether solution was dried over Na2SO4 and evaporated. The residue was
dried in high vacuum under constant pressure. Yield 42.6 g (94.3%).
1H NMR (CDCl3), d 1.49 (s, 9H, Me3), 3.36 (s, 2H, CH2) 11.59 (broad s,
1H, COOH). 13C NMR (CDCl3), d 28.11 (Me), 42.32 (CH2), 83.12 (Me3C),
166.43 and 172.47 (COO). Anal. calcd. for C7H12O4: C, 52.49; H, 7.55.
Found: C, 51.81; H, 7.35.
5-Isopropylidene-2,2-dimethyl[1,3]dioxane-4,6-dione (3)
This compound was prepared according to Ref. 5 in a yield of 69%.
1
Mp 70–728C (Ref. 5: mp 68–718C). H NMR (CDCl3), d 1.73 (s, 6H,
2Me), 2.52 (s, 6H, 2Me). 13C NMR (CDCl3), d 27.02 (Me), 27.39 (Me),
103.77 (O–C–O), 116.22 (C55), 161.37 (C55), 177.59 (COO).
ACKNOWLEDGMENT
We thank K. Mevius for skilled technical assistance. Financial support from
Ratiopharm GmbH is gratefully acknowledged.
REFERENCES
1. Jones, G. The Knoevenagel condensation. Org. React. 1967, 15, 204–599.
2. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. C-Acylierung unter praktisch neutralen
Bedingungen. Angew. Chem. 1979, 91, 76–77.
3. Brooks, D. W.; de Lee, N. C.; Peevey, R. Remote substituent effects in microbial
reductions of 3-ketoglutarate and 3-ketoadipate esters. Tetrahedron Lett. 1984,
25, 4623–4626.

Mono tert-Butyl Malonate
191
4. Junek, H.; Ziegler, E.; Herzog, U.; Kroboth, H. Eine einfache Synthese von
¨
Malonsaure—mono- und -bis-phenylestern. Synthesis 1976, 332–334.
5. Vogt, P. F.; Molino, B. F.; Robichaud, A. J. A Regiospecific synthesis of
3,3,6-trimethylindan-1-one. Synth. Commun. 2001, 31, 679–684.
6. Sato, M.; Ban, H.; Kaneko, C. An efficient method for generation of a-oxoketenes:
Cycloreversion of enolized Meldrum’s acid derivatives. Tetrahedron Lett. 1997, 38,
6689–6692.
7. Birney, D. M.; Xu, X.; Ham, S.; Huang, X. Chemoselectivity in the reaction of
acetylketene and acetimidoylketene: Confirmation of theoretical predictions.
J. Org. Chem. 1997, 62, 7114–7120.
8. Saito, Y.; Watanabe, T.; Hashimoto, H.; Yoshimura, J. Synthesis of N0-(p-glycosyl-
oxycinnamoyl)spermidines. Carbohydr. Res. 1987, 169, 171–188.
9. Koskinen, A. M. P.; Munoz, L. Intramolecular cyclopropanation: Stereospecific
synthesis of (E)- and (Z)-1-aminocyclopropane-1-carboxylic acids. J. Org. Chem.
1993, 58, 879–886.