Synthesis of 5-(2-chloroalkyl)-2,2-dimethyl-1,3-dioxane-4,6-diones

Article abstract of DOI:10.1081/SCC-120014984

A method has been worked out to synthetize hitherto unknown 5-(2-chloroalkyl) Meldrum's acids 4 starting from easily accessible 2-chlorocarboxylic acid chlorides 1 in a two-step reaction. Reactions of dihaloethane and Meldrum's acid in the presence of potassium carbonate and the usefulness of compounds 4 are also presented.

Full text of DOI:10.1081/SCC-120014984

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SYNTHESIS OF 5-(2-CHLOROALKYL)- 2,2-DIMETHYL-1,3-
DIOXANE-4,6-DIONES
György Tóth a , Tivadar Tamás a & Ildikó Borbély a
a Chemical Research Department, Biogal Pharmaceutical Works Ltd., Pallagi ut 13.,
Debrecen, H-4042, Hungary
Published online: 16 Aug 2006.
To cite this article: Gyrgy Tth , Tivadar Tams & Ildik Borbly (2002) SYNTHESIS OF 5-(2-CHLOROALKYL)- 2,2-DIMETHYL-1,3-
DIOXANE-4,6-DIONES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:23, 3659-3665, DOI: 10.1081/SCC-120014984
To link to this article: http://dx.doi.org/10.1081/SCC-120014984
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 23, pp. 3659–3665, 2002
SYNTHESIS OF 5-(2-CHLOROALKYL)-
2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONES
*
Gyorgy Toth, TivadarTama s,
and Ildiko Borbely
Chemical Research Department, Biogal Pharmaceutical
Works Ltd., Pallagi ut 13., H-4042 Debrecen, Hungary
ABSTRACT
A method has been worked out to synthetize hitherto unknown
5-(2-chloroalkyl) Meldrum’s acids 4 starting from easily
accessible 2-chlorocarboxylic acid chlorides 1 in a two-step
reaction. Reactions of dihaloethane and Meldrum’s acid in
the presence of potassium carbonate and the usefulness of
compounds 4 are also presented.
Key Words: Meldrum’s acid; Acylation; Reduction
2,2-Dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid)
2 and its
derivatives are very useful building blocks in synthetic organic chemistry.[1,2]
A lot of 5-mono- and 5,5-disubstituted derivatives of Meldrum’s acid have
been synthetized but 5-(2-chloroalkyl) Meldrum’s acids 4 have not been
known in the literature up to the present. Alkylation of Meldrum’s acid 2
with alkyl halogenides in the presence of a base results in the formation of
5,5-disubstituted Meldrum’s acids independently of the molecular ratios of
the reactants in most cases.[1,2] Owing to the willingness of Meldrum’s acid 2
*Corresponding author. E-mail: gyorgy.toth@biogal.hu
3659
DOI: 10.1081/SCC-120014984
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3660
TOTH, TAMAS, AND BORBELY
for the disubstitution, spiro compounds (like 5) form in a reaction of
Meldrum’s acid 2 with a,o-haloalkanes in the presence of a base.[3,4]
One of our starting points to synthetize 5-(2-chloroalkyl) Meldrum’s
acid 4 was that carboxylic chlorides and Meldrum’s acid 2 give 5-acyl
Meldrum’s acids in the presence of pyridine.[5] The other was that 5-acyl
Meldrum’s acids can be reduced to 5-alkyl Meldrum’s acids with sodium
cyanoborohydride.[6]
In our work we managed to apply the known method[5] without any
change to prepare 5-(2-haloacyl) Meldrum’s acids 3 and 7 (Scheme 1). The
crude products 3 and 7 did not prove stable enough so the crude acyl
compounds were subjected to reduction immediately after they were
formed and isolated. One of the chloro compounds and one of the bromo
compounds were purified by crystallization. Pure 3a and 7b were obtained as
1
sufficiently stable products. H NMR spectra showed that crude 3 and 7
contain a lot of impurity. It may happen that 3 and 7 are decomposed
considerably in the course of the reaction, isolation and storage.
We found that sodium borohydride was better to use for the reduction
of 5-haloacyl Meldrum’s acids 3 and 7 than sodium cyanoborohydride
proposed by Nutaitis et al.[6] for the reduction of 5-acyl Meldrum’s acids.
Using sodium borohydride we obtained better yield than by using sodium
cyanoborohydride and the former is safer than other compound. The yield
based on crude 3 changed between 56–64%. Chloroalkyl compounds 4 are
quite stable at acidic pH but in the presence of weak bases they transform
quickly to spiro derivatives 5 both in organic and aqueous medium.
The reaction was accomplished in both cases with potassium carbonate.
Scheme 1.

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5-(2-CHLOROALKYL)-2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONES
3661
Very good yield was obtained in acetonitrile. Compounds 5 prepared in this
manner have good quality. There is no need to crystallize the isolated
products. In the case of a reaction brought about in a sodium carbonate,
water, dichloromethane system the results are lower than in the case of the
method mentioned above. Crude, dried 4c was crystallized in ethyl acetate,
hexane with success. The temperature did not exceed 30ꢀC. 4c transformed
into 5c when we tried to crystallize it in 50% acetone at 45ꢀC.
5-(2-Bromoalkyl) Meldrum’s acids 8 failed to isolate because the ring
closure took place in acidic medium, too. As a result of the reduction of 7a
spiro compound 5a was obtained as the main product and 11 as the minor
component.
Scheme 2.
There are several methods[7–10] to synthetize 5. Our method is an
additional possibility to prepare 5. A reaction sequence is shown in
Scheme 2 for the further illustration of the usefulness of compounds 4.
The reactions were carried out easily with good yields. Compounds 9 and
10 can be starting materials for some other valuable products.
We found that 1,2-dibromoethane with Meldrum’s acid 2 in the
presence of potassium carbonate resulted in the formation of hitherto
unknown compound 11 (Scheme 3). This compound was also isolated in
6% yield as an accompanying impurity of 5a in the course of the reduction
step. The yield of 5a was 80% from 7a. Compound 11 formed also from the
Scheme 3.

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3662
TOTH, TAMAS, AND BORBELY
prepared 5a or 4a in the presence of Meldrum’s acid by means of potassium
carbonate in dimethylformamide. 1-Bromo-2-chloroethane also gave 11.
Danishefsky and Singh[10] accomplished a reaction between 5a and dimethyl
sodiomalonate and they obtained 12. The above observations proved that
2 and 1,2-dihaloethane gave 11 via 5a.
EXPERIMENTAL
Melting points are uncorrected and were determined on a Kofler
instrument. 1H NMR spectra were recorded on a Bruker instrument
WP-200 SY spectrometer. IR spectra were obtained in KBr on a Perkin
Elmer FT-IR instrument. Elemental analyses were performed on a Carlo
Erba EA 1108 apparatus. Chemicals were purchased from Aldrich and
E. Merck and were used without further purification.
General Procedure for the Synthesis of 5-(2-Haloacyl)
Meldrum’s Acids 3, 7
Meldrum’s acid 2 (14.4 g, 0.1 mol) was dissolved in a mixture of
dichloromethane (80 mL) and pyridine (15.8 g, 0.2 mol). 2-Haloacyl halides
1, 6 (0.1 mol) were added dropwise at ꢁ5–0ꢀC for an hour. The reaction
mixture was stirred at 0ꢀC and 20–25ꢀC for an hour, respectively. The
reaction mixture was poured onto a mixture of ice–water (100 g) and 17%
hydrochloric acid (70 mL). The precipitate was filtered off and dried. The
oily product was isolated by extraction. After drying the organic phase the
solution was evaporated to constant weight under reduced pressure in a
bath of 25ꢀC. The products were used generally to the further step without
purification except 3a and 7b.
5-(2-Chloroacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 3a: The crude
product (20.5 g, 93%) was obtained as a brown crystalline mass and it was
purified by dissolving in acetone and precipitating with water then crystal-
lizing in ether. M.p. 81–83ꢀC. IR (KBr) ꢀco (cmꢁ1): 1739; 1H NMR (CDCl3/
TMS), ꢁ (ppm): 1.79 (s, 6H), 4.91 (s, 2H), 15.6 (br. s, 1H). Anal. calcd for
C8H9ClO5 (%): C, 43.56; H, 4.11. Found: C, 43.74; H, 4.17.
5-(2-Bromopropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 7b: The crude
product was obtained as a reddish brown oil which crystallized at 5ꢀC in
two days. The crude product was crystallized twice from acetone and water
in such a way that the acetonic solution of the product was treated with
charcoal at r.t. then ice–water was added to the solution. M.p. 70–72ꢀC.
IR: 1737; 1H NMR (CDCl3): ꢁ (ppm) 1.73 (s, 6H), 1.88 (d, 3H), 6.15 (q, 1H),

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5-(2-CHLOROALKYL)-2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONES
3663
15.6 (s, 1H); Anal. calcd for C9H11BrO5: C, 38.73; H, 3.97. Found: C, 38.91;
H, 3.86.
General Procedure for the Synthesis of 5-(2-Chloroalkyl)
Meldrum’s Acids 4
5-(2-chloroacyl) Meldrum’s acid 3 (0.05 mol) was dissolved in acetic
acid (75 mL). Sodium borohydride (2.84g, 0.075 mol) was added at r.t. for
half an hour. The reaction mixture was stirred at r.t. for half an hour then
poured onto a mixture of ice (180 g) and 36% HCl (18 mL). The precipitate
was filtered off, washed with water, dried, then crystallized. If it
was necessary, an additional amount of the product could be obtained by
the extraction of the aqueous mother liquor with dichloromethane.
5-(2-Chloroethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 4a: The crude
material was dissolved in acetone at r.t., treated with charcoal and water
was added to the acetonic solution. The solid was filtered off, washed with
cold aqueous acetone. 5.8 g (56.1%) of the product was obtained. M.p.
114–116ꢀC. IR: 1794, 1748. H NMR (CDCl3): 1.78 (s, 3H), 1.86 (s, 3H)
1
2.54(q, 2H), 3.90 (q, 3H). Anal. calcd for C H11ClO4: C, 46.50; H, 5.37.
8
Found: C, 46.60; H, 5.25.
5-(2-Chloropropyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 4b: The crude
product was dissolved in acetone at r.t., treated with charcoal, cooled to
ꢁ20ꢀC. 7.1 g (64%) of the compound was obtained. M.p. 132–134. IR: 1791,
1
1741. H NMR (CDCl3): 1.64(d, 3H), 1.80 (s, 3H), 1.88 (s, 3H), 2.30 (m,
1H), 2.54(m, 1H), 3.95 (dd, 1H), 4.60 (m, 1H). Anal. calcd for C 9H13ClO4:
C, 48.99; H, 5.94. Found: C, 48.77; H, 6.02.
5-(2-Chlorobutyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 4c: The crude
product was dissolved in ethyl acetate at r.t., treated with charcoal. The
solution was evaporated (bath temperature <30ꢀC) to a small volume
under reduced pressure and n-hexane added to it. The product: 6.6 g
(56%). M.p. 108–109ꢀC. IR: 1786, 1742. H NMR (CDCl3): 1.10 (t, 3H),
1
1.81 (s, 3H), 1.88 (s, 3H), 1.78-1.92 (m, 2H), 2.31 (m, 1H), 2.52 (m, 1H), 4.00
(dd, 1H), 4.40 (m, 1H). Anal. calcd for C10H15ClO4: C, 51.18; H, 6.44.
Found: C, 51.43; H, 6.48.
General Procedure for the Synthesis of 5,7-Dioxaspiro[2.5]octane
Derivatives 5
5-(Chloroalkyl) Meldrum’s acid 4 (10 mmol) was dissolved in
acetonitrile (20 mL). Potassium carbonate (1.4g, 10 mmol) was added and

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3664
TOTH, TAMAS, AND BORBELY
the mixture was stirred at r.t. for half an hour. The inorganic salt was
filtered off, the filtrate was treated with charcoal and evaporated to dryness
under reduced pressure.
6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione 5a: According to the
general procedure the product was obtained in 82% yield and it melted at
66–67ꢀC. In the literature[11] 63.5–64.5ꢀC is given. H NMR spectrum is
1
identical with the data of the literature.[11] This compound was also obtained
in 80% yield by the reduction of 7a. Having accomplished the reduction,
the reaction mixture was poured onto acidic ice–water. A small amount
of the precipitate formed, which was filtered off. It proved 11. The mother
liquor was extracted with dichloromethane to give 5a.
1,6,6-Trimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione 5b: Yield: 94%.
M.p. 47–49ꢀC. IR: 1740. H NMR (CDCl3): 1.40 (d, 3H), 1.80 (s, 6H),
1
1.93 (m, 1H), 2.27 (m, 2H). Anal. calcd for C9H12O4: C, 58.69; H, 6.57.
Found: C, 58.58; H, 6.60.
1-Ethyl-6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione 5c: Yield: 95%;
oil. IR (film on KBr pellet): 1742. 1H NMR (CDCl3): 1.06 (t, 3H), 1.76 (m, 2H),
1.79 (s, 3H), 1.82 (s, 3H), 1.93 (m, 1H), 2.20 (m, 2H). Anal. calcd for
C10H14O4: C, 60.59; H, 7.12. Found: C, 60.41; H, 7.04.
Conversion of 4 to 9 and 10: 5-(2-Chloropropyl) Meldrum’s acid 4b
(8.83 g, 0.04mol) and ethanolic hydrochloric acid (0.8 N, 50 mL) was
refluxed for 3 h. A small sample was evaporated to dryness under reduced
pressure. An oil was obtained, which was proved to be diethyl-2-chloro-
propylmalonate 9b (1H NMR (CDCl3): 1.30 (t, 6H), 1.58 (d, 3H), 2.18 (m,
1H), 2.40 (m, 1H), 3.72 (q, 1H), 4.07 (m, 1H), 4.22 (m, 4H). Anal. calcd
for C10H17ClO4: C, 50.74; H, 7.24. Found: C, 50.89; H, 7.11.) After cool-
ing K2CO3 (12.2 g, 0.088 mol) was added to the reaction mixture gradually
and the mixture was refluxed for an hour then cooled. The inorganic salt
was filtered off. The filtrate was treated with charcoal then evaporated
to dryness under reduced pressure. The residue was dissolved in acetone
(25 mL), the insoluble solid was filtered off. The acetonic filtrate was
evaporated to dryness. Diethyl 2-methylcyclopropane-1,1-dicarboxylate
10b was obtained as an oil. Yield: 7.7 g (96.1%). IR: 1734. 1H NMR
(CDCl3): 1.16 (d, 3H), 1.35 (m, 6H), 1.42 (t, 2H), 1.94 (m, 1H), 4.25
(m, 4H). 10b was also identified by the hydrolysis of its ester groups
with a solution of NaOH in aqueous ethanol. 2-Methylcyclopropane-1,1-
dicarboxylic acid was obtained in 70% yield. It melted at 112–113ꢀC
(lit.[12] m.p. 113.5ꢀC). IR: 1716. 1H NMR (CDCl3): 1.40 (d, 3H), 1.89
(m, 1H), 2.08 (m, 1H), 2.32 (m, 1H), 11.28 (br s, 2H). Anal. calcd for
C6H8O4: C, 50.00; H, 5.59. Found: C, 50.00; H, 5.53. Diethyl cyclopro-
pane-1,1-dicarboxylate 10a was obtained in 84% yield in a similar manner
as 10b.

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5-(2-CHLOROALKYL)-2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONES
3665
5,50-Ethylenebis-(2,2-dimethyl-1,3-dioxane-4,6-dione) 11: A mixture of
Meldrum’s acid 2 (2.88 g, 20 mmol) and K2CO3 (6.92 g, 25 mmol) in DMF
(20 mL) was stirred at r.t. for 15 min. 1,2-Dibromoethane (4.51 g, 24 mmol)
was added and the reaction mixture was stirred at r.t. for 3 days. The mixture
was poured onto ice–water (40 g) and acidified with 17% HCl (pH: 3). The
product was filtered off, washed with water and acetone twice. The product:
1.95 g (62%). M.p.: 175–177ꢀC. IR: 1772, 1739. H NMR (DMSO): 1.66 (s,
1
6H), 1.80 (s, 6H), 2.14 (m, 4H), 4.48 (m, 2H). Anal. calcd for C14H18O8: C,
53.50; H, 5.77. Found: C, 53.77; H, 5.75. Compound 11 was also produced
starting from 4a or 5a. A mixture of Meldrum’s acid 2 (0.72 g, 5 mmol) and
K2CO3 (1.38 g, 10 mmol) in DMF (5 mL) was stirred at r.t. for 15 min. 5-(2-
Chloroethyl) Meldrum’s acid 4a (1.03 g, 5 mmol) or 6,6-dimethyl-5,7-
dioxaspiro[2.5]octane-4,8-dione 5a (0.85 g, 5 mmol) was added. The reaction
mixture was stirred at r.t. for 3 days then poured onto ice-water (20 g) and
acidified with 17% HCl (pH: 3). The product was filtered off, washed with
water and acetone twice. The yields were 1.12 g (71.3%) and 1.16 g (73.8%),
respectively. Products obtained from the three different starting materials
1
were identical with each other on the basis of their m.p., H NMR and IR
spectra.
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2. Chen, B.-C. Heterocycles 1991, 32, 529.
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5. Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087.
6. Nutaitis, C.F.; Schultz, R.A.; Obaza, J.; Smith, F.X. J. Org. Chem.
1980, 45, 4606.
7. Swoboda, G.; Eitel, A.; Swoboda, J.; Wessely, F. Monatsh. Chem.
1964, 95, 1355.
8. Izquierdo, M.L.; Arenal, I.; Bernabe, M.; Fernandez Alvarez, E.
Tetrahedron 1985, 41, 215.
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11. Singh, R.K.; Danishefsky, S.J. Org. Chem. 1975, 40, 2969.
12. Heilborn, I.; Bunbury, H.M. Dictionary of Organic Compounds;
London, 1946; Vol. 2, 670.
Received in the UK September 11, 2001

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