Technical Field

The present invention relates to a process for the preparation of cyclobutenone derivatives.

Technological Background

Functionalized cyclobutenone derivatives are valuable intermediates for the production of various compounds such as pharmaceutical and agrochemical agents.

One example of such functionalized cyclobutenone derivatives is 3-acetoxy-2-cyclobuten-1-one (also known as triketene).

Triketene is a side product in the diketene production and is typically obtained by distillation from the distillation residue obtained in the diketene production. The distillation residue from the diketene production, which is also referred to as triketene resin, typically comprises 10% diketene, 30% triketene and 60% undefined compounds. The production of triketene by distillation of triketene resin is disclosed in CH 596 132. However, this method suffers inter alia from the drawback that only triketene and no other functionalized cyclobutenone derivatives can be obtained.

Hence, there is a need for a process with which various cyclobutenone derivatives are accessible. Furthermore, there is an ongoing need for optimized processes for the synthesis of cyclobutenone derivatives.

An object of the present invention is to provide an excellent process for the synthesis of cyclobutenone derivatives. A further object of the present invention is to provide a process which provides various cyclobutenone derivatives. Summary of the invention

In one aspect, the present invention provides a process for the preparation of a compound of formula (1) wherein

Y is O or NH,

R is -C(O)-R ¹ or -S(0) ₂ -R ¹ , and

R ¹ is selected from optionally substituted linear or branched C1-12 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted aryl, -NR ⁵ R ⁶ , -OR ⁷ , and halogen, wherein R ⁵ , R ⁶ , and R ⁷ are each independently selected from H, optionally substituted linear or branched C1-12 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, and optionally substituted aryl; the process comprising reacting a compound of formula (2)

A ⁺ wherein A+ is an ammonium group of formula (3) wherein R ² , R ³ , and R ⁴ are each independently selected from H, optionally substituted linear or branched C1-12 alkyl, and optionally substituted C3-8 cycloalkyl, with a compound of formula (4), (5), (6), or (7) wherein X is selected from F, Cl, Br, or I, wherein the process excludes reacting 3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt with trimethylacetyl chloride.

Detailed description of the invention

In the following, the invention will be explained in more detail.

According to the present invention, the term “linear or branched C1-12 alkyl” refers to a straight- chained or branched saturated hydrocarbon group having 1 to 12 carbon atoms, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Likewise, the term “linear or branched C1-6 alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms (i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms) including methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2- methylpropyl, 1 ,1-dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethyl propyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1 -methylpropyl and 1-ethyl-2-methylpropyl.

According to the present invention, the term “C3-8 cycloalkyl” refers to monocyclic saturated hydrocarbon groups having 3 to 8 carbon ring members (i.e. 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms) including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Likewise, the term “C3-6 cycloalkyl” refers to monocyclic saturated hydrocarbon radicals having 3 to 6 carbon ring members (i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms) including cyclopropyl, cyclobutyl, cyclopentyl, and cyclo hexyl.

According to the present invention, the term “C3-8 cycloalkenyl” refers to monocyclic alkene hydrocarbon groups having 3 to 8 carbon ring members (i.e. 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms) that include at least one carbon-carbon double bond in the ring of carbon atoms. Exemplary “C3-8 cycloalkenyl” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1 ,3- cyclohexadienyl, 1 ,4-cyclohexadienyl, 1 ,5-cyclooctadienyl, cis-cyclooctenyl, and trans-cyclooctenyl.

According to the present invention, the term “aryl” refers to refers to both single-ring aromatic hydrocarbyl groups and polycyclic aromatic ring systems. The polycyclic rings may have two or more rings in which two carbons are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is an aromatic hydrocarbyl group, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles, and/or heteroaryls. Preferred aryl groups are those containing six to twelve carbon atoms. Especially preferred is an aryl group having six carbons, ten carbons or twelve carbons. Suitable aryl groups include phenyl, biphenyl, triphenyl, triphenylene, tetraphenylene, naphthalene, anthracene, phenalene, phenanthrene, fluorene, pyrene, chrysene, perylene, and azulene, preferably phenyl, biphenyl, triphenyl, triphenylene, fluorene, and naphthalene.

It is to be understood that the linear or branched C1-12 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl and aryl may optionally be further substituted. Exemplary substituents include hydroxy, oxo (=O), linear or branched C1-12 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, a carboxy group, halogen, and aryl.

According to the present invention, the term “halogen” refers to fluorine, chlorine, bromine and iodine.

It is to be understood that the term “tolyl” includes o-tolyl, m-tolyl, and p-tolyl.

As outlined above, subject of the present invention is a process for the preparation of a compound of formula (1) wherein

Y is O or NH,

R is -C(O)-R ¹ or -S(0) ₂ -R ¹ , and

R ¹ is selected from optionally substituted linear or branched C1-12 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted aryl, -NR ⁵ R ⁶ , -OR ⁷ , and halogen, wherein R ⁵ , R ⁶ , and R ⁷ are each independently selected from H, optionally substituted linear or branched C1-12 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, and optionally substituted aryl; the process comprising reacting a compound of formula (2) wherein A+ is an ammonium group of formula (3) wherein R ² , R ³ , and R ⁴ are each independently selected from H, optionally substituted linear or branched C1-12 alkyl, and optionally substituted C3-8 cycloalkyl, with a compound of formula (4), (5), (6), or (7) wherein X is selected from F, Cl, Br, or I, wherein the process excludes reacting 3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt with trimethylacetyl chloride.

The inventive process provides an excellent route for the preparation of compounds of formula (1). Particularly, it has been surprisingly found that the inventive process is atom efficient and produces low amounts of waste. Furthermore, with the inventive process for the preparation of compounds of formula (1) various cyclobutenone derivatives are accessible. Reacting a compound of formula (2) also has the advantage that different reactions are possible and cyclobutenone derivatives of formula (1) are accessible. Moreover, the inventors surprisingly found that with the inventive process for the preparation of compounds of formula (1), various cyclobutenone derivatives are obtainable without the use of a catalyst.

In one embodiment, R ¹ is selected from optionally substituted linear or branched Ci-e alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, phenyl, benzyl, tolyl, - NR ⁵ R ⁶ , -OR ⁷ , and halogen. In one embodiment, R ¹ is selected from optionally substituted linear or branched C1-6 alkyl, optionally substituted C3-6 cycloalkyl, phenyl benzyl, tolyl, -NR ⁵ R ⁶ , -OR ⁷ , and halogen.

In one embodiment, R ¹ is selected from methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tolyl, and benzyl.

Preferably, R ¹ is methyl, tert-butyl, phenyl, tolyl, or benzyl.

In one embodiment, R is -C(O)-R ¹ and R ¹ is selected from -NR ⁵ R ⁶ , -OR ⁷ , and halogen, Preferably, R ⁵ is H and R ⁶ and R ⁷ are optionally substituted C3-8 cycloalkenyl, More preferably, R ⁵ is H and R ⁶ and R ⁷ are 3-oxo-cyclobuten-1-yl. Preferably, halogen is Cl or Br, more preferably Cl.

In one embodiment, R is -C(O)-R ¹ and R ¹ is -OR ⁷ . In one embodiment, R is -C(O)-R ¹ and R ¹ is - OR ⁷ and R ⁷ is 3-oxo-cyclobuten-1-yl or methyl.

In one embodiment, R is -C(O)-R ¹ and R ¹ is-NR ⁵ R ⁶ . In one embodiment, R is -C(O)-R ¹ and R ¹ is- NR ⁵ R ⁶ and R ⁵ is H and R ⁶ is 3-oxo-cyclobuten-1-yl. In one embodiment, in the ammonium group of formula (3), R ² is H, and R ³ and R ⁴ are each independently selected from optionally substituted linear or branched C1-12 alkyl, and optionally substituted C3-8 cycloalkyl.

Preferably, R ² is H, and R ³ and R ⁴ are cyclohexyl.

Preferably, the compound of formula (2) is 3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt, depicted by the following formula:

In one embodiment, the compound of formula (4) is selected from the group consisting of acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, butyryl bromide, isobutyryl chloride, isobutyryl bromide, trimethylacetyl chloride, trimethylacetyl bromide, tertbutylacetyl chloride, tert-butylacetyl bromide, benzoyl chloride, benzoyl bromide, phosgene, methyl chloroform ate, ethyl chloroformate, propyl chloroformate, 1 -methylethyl chloroform ate, butyl chloroform ate, 1 -methylpropyl chloroform ate, 2-methylpropyl chloroform ate, 1 ,1 -dimethylethyl chloroform ate, pentyl chloroform ate, 1 -methylbutyl chloroformate, 2-methylbutyl chloroform ate, 3- methylbutyl chloroform ate, 2,2-dimethylpropyl chloroform ate, 1 -ethylpropyl chloroform ate, 1 ,1- dimethylpropyl chloroform ate, 1 ,2-dimethylpropyl chloroformate, hexyl chloroform ate, 1- methylpentyl chloroformate, 2-methylpentyl chloroformate, 3-methylpentyl chloroform ate, 4- methylpentyl chloroformate, 1 ,1 -dimethylbutyl chloroform ate, 1 ,2-dimethylbutyl chloroform ate, 1 ,3- dimethylbutyl chloroform ate, 2,2-dimethylbutyl chloroform ate, 2,3-dimethylbutyl chloroform ate, 3,3-dimethylbutyl chloroformate, 1-ethylbutyl chloroform ate, 2-ethylbutyl chloroformate, 1 ,1 ,2- trimethyl propyl chloroform ate, 1 ,2,2-trimethylpropyl chloroform ate, 1 -ethyl-1 -methylpropyl chloroform ate, 1-ethyl-2-methylpropyl chloroform ate, cyclopropyl chloroformate, cyclobutyl chloroform ate, cyclopentyl chloroformate, cyclohexyl chloroform ate, cycloheptyl chloroformate, cyclooctyl chloroform ate, cyclopropenyl chloroformate, cyclobutenyl chloroform ate, 3-oxo- cyclobuten-1-yl chloroform ate, cyclopentenyl chloroform ate, cyclohexenyl chloroform ate, cycloheptenyl chloroform ate, 1 ,3-cyclohexadienyl chloroform ate, 1 ,4-cyclohexadienyl chloroform ate, 1 ,5-cyclooctadienyl chloroform ate, cis-cyclooctenyl chloroformate, trans-cyclooctenyl chloroformate, phenyl chloroformate, benzyl chloroform ate, methyl bromoformate, ethyl bromoformate, propyl bromoformate, 1 -methylethyl bromoformate, butyl bromoformate, 1 -methylpropyl bromoformate, 2- methylpropyl bromoformate, 1 ,1 -dimethylethyl bromoformate, pentyl bromoformate, 1-methylbutyl bromoformate, 2-methylbutyl bromoformate, 3-methylbutyl bromoformate, 2,2-dimethylpropyl bromoformate, 1 -ethylpropyl bromoformate, 1 ,1 -dimethylpropyl bromoformate, 1 ,2-dimethylpropyl bromoformate, hexyl bromoformate, 1 -methylpentyl bromoformate, 2-methylpentyl bromoformate, 3- methylpentyl bromoformate, 4-methylpentyl bromoformate, 1 ,1 -dimethylbutyl bromoformate, 1 ,2- dimethylbutyl bromoformate, 1 ,3-dimethylbutyl bromoformate, 2,2-dimethylbutyl bromoformate, 2,3- dimethylbutyl bromoformate, 3,3-dimethylbutyl bromoformate, 1 -ethylbutyl bromoformate, 2- ethylbutyl bromoformate, 1 ,1 ,2-trimethyl propyl bromoformate, 1 ,2,2-trimethylpropyl bromoformate, 1-ethyl-1 -methylpropyl bromoformate, 1-ethyl-2-methylpropyl bromoformate, cyclopropyl bromoformate, cyclobutyl bromoformate, cyclopentyl bromoformate, cyclohexyl bromoformate, cycloheptyl bromoformate, cyclooctyl bromoformate, cyclopropenyl bromoformate, cyclobutenyl bromoformate, 3-oxo-cyclobuten-1-yl bromoformate, cyclopentenyl bromoformate, cyclohexenyl bromoformate, cycloheptenyl bromoformate, 1 ,3-cyclohexadienyl bromoformate, 1 ,4- cyclohexadienyl bromoformate, 1 ,5-cyclooctadienyl bromoformate, cis-cyclooctenyl bromoformate, trans-cyclooctenyl bromoformate, phenyl bromoformate, and benzyl bromoformate.

Preferably, the compound of formula (4) is selected from the group consisting of acetyl chloride, acetyl bromide, trimethylacetyl chloride, trimethylacetyl bromide, benzoyl chloride, benzoyl bromide, phosgene, 3-oxo-cyclobuten-1-yl chloroform ate, 3-oxo-cyclobuten-1-yl bromoformate, cyclohexenyl chloroform ate, cyclohexenyl bromoformate, phenyl chloroformate, phenyl bromoformate, benzyl chloroform ate, and benzyl bromoformate.

In one embodiment, the compound of formula (4) is selected from the group consisting of acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, trimethylacetyl chloride, tertbutylacetyl chloride, benzoyl chloride, phosgene, 3-oxo-cyclobuten-1-yl chloroform ate, cyclohexenyl chloroform ate, phenyl chloroform ate, and benzyl chloroformate.

Preferably, the compound of formula (4) is selected from the group consisting of acetyl chloride, trimethylacetyl chloride, benzoyl chloride, phosgene, and 3-oxo-cyclobuten-1-yl chloroform ate.

In one embodiment, the compound of formula (4) is selected from the group consisting of acetyl bromide, propionyl bromide, butyryl bromide, isobutyryl bromide, trimethylacetyl bromide, tertbutylacetyl bromide, benzoyl bromide, phosgene, 3-oxo-cyclobuten-1-yl bromoformate, cyclohexenyl bromoformate, phenyl bromoformate, and benzyl bromoformate. Preferably, the compound of formula (4) is selected from the group consisting of acetyl bromide, trimethylacetyl bromide, benzoyl bromide, phosgene, and 3-oxo-cyclobuten-1-yl bromoformate.

The inventive process does not encompass reacting 3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt as the compound of formula (2) with trimethylacetyl chloride (compound of formula (4)) to obtain 3-oxocyclobut-1-en-1-yl pivalate (compound of formula (1)).

In one embodiment, the compound of formula (5) is selected from the group consisting of triphosgene, acetic anhydride, propanoic anhydride, butyric anhydride, isobutyric anhydride, trimethylacetic anhydride, benzoic anhydride and cyclopropanecarboxylic acid anhydride. Preferably, the compound of formula (5) is acetic anhydride.

In one embodiment, the compound of formula (6) is selected from the group consisting of methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, 1 -propanesulfonyl chloride, 1 -propanesulfonyl bromide, 2-propanesulfonyl chloride, 3- propanesulfonyl bromide, butanesulfonyl chloride, butanesulfonyl bromide, butane-2-sulfonyl chloride, butane-2-sulfonyl bromide, 2-methyl-2-propanesulfonyl chloride, 2-methyl-2- propanesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl bromide, toluenesulfonyl chloride, and toluenesulfonyl bromide.

Preferably, toluenesulfonyl chloride is p-toluenesulfonyl chloride. Preferably, toluenesulfonyl bromide is p-toluenesulfonyl bromide.

In one embodiment, the compound of formula (6) is selected from the group consisting of methanesulfonyl chloride, ethanesulfonyl chloride, 1 -propanesulfonyl chloride, 2-propanesulfonyl chloride, butanesulfonyl chloride, butane-2-sulfonyl chloride, 2-methyl-2-propanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride.

In one embodiment, the compound of formula (6) is selected from the group consisting of methanesulfonyl bromide, ethanesulfonyl bromide, 1 -propanesulfonyl bromide, 2-propanesulfonyl bromide, butanesulfonyl bromide, butane-2-sulfonyl bromide, 2-methyl-2-propanesulfonyl bromide, benzenesulfonyl bromide, and toluenesulfonyl bromide.

In one embodiment, the compound of formula (7) is selected from the group consisting of urea, methyl carbamate, ethyl carbamate, propyl carbamate, 1 -methylethyl carbamate, butyl carbamate, 1 -methylpropyl carbamate, 2-methylpropyl carbamate, 1 ,1 -dimethylethyl carbamate, pentyl carbamate, 1 -methylbutyl carbamate, 2-methylbutyl carbamate, 3-methylbutyl carbamate, 2,2- dimethylpropyl carbamate, 1 -ethylpropyl carbamate, 1 ,1 -dimethylpropyl carbamate, 1 ,2- dimethylpropyl carbamate, hexyl carbamate, 1 -methylpentyl carbamate, 2-methylpentyl carbamate, 3-methylpentyl carbamate, 4-methylpentyl carbamate, 1 ,1 -dimethylbutyl carbamate, 1 ,2- dimethylbutyl carbamate, 1 ,3-dimethylbutyl carbamate, 2,2-dimethylbutyl carbamate, 2,3- dimethylbutyl carbamate, 3,3-dimethylbutyl carbamate, 1 -ethylbutyl carbamate, 2-ethylbutyl carbamate, 1 ,1 ,2-trimethyl propyl carbamate, 1 ,2,2-trimethylpropyl carbamate, 1-ethyl-1- methylpropyl carbamate, 1-ethyl-2-methylpropyl carbamate, cyclopropyl carbamate, cyclobutyl carbamate, cyclopentyl carbamate, cyclohexyl carbamate, cycloheptyl carbamate, cyclooctyl carbamate, cyclopropenyl carbamate, cyclobutenyl carbamate, 3-oxo-cyclobuten-1-yl carbamate, cyclopentenyl carbamate, cyclohexenyl carbamate, cycloheptenyl carbamate, 1 ,3-cyclohexadienyl carbamate, 1 ,4-cyclohexadienyl carbamate, 1 ,5-cyclooctadienyl carbamate, cis-cyclooctenyl carbamate, trans-cyclooctenyl carbamate, phenyl carbamate, and benzyl carbamate.

In one embodiment, the compound of formula (7) is selected from the group consisting of urea, methyl carbamate, ethyl carbamate, propyl carbamate, 1 -methylethyl carbamate, butyl carbamate, 1 -methylpropyl carbamate, 2-methylpropyl carbamate, 1 ,1 -dimethylethyl carbamate, hexyl carbamate, cyclopropyl carbamate, cyclobutyl carbamate, cyclopentyl carbamate, cyclohexyl carbamate, cyclobutenyl carbamate, 3-oxo-cyclobuten-1-yl carbamate, cyclopentenyl carbamate, cyclohexenyl carbamate, phenyl carbamate, and benzyl carbamate.

Preferably, the compound of formula (7) is selected from the group consisting of urea, 1 ,1- dimethylethyl carbamate, 3-oxo-cyclobuten-1-yl carbamate, cyclohexenyl carbamate, phenyl carbamate, and benzyl carbamate.

In one embodiment, X is selected from Cl and Br. Preferably X is Cl.

An exemplary reaction of the compound of formula (2) with a compound of formula (4) is shown in the following: In one embodiment, the compound of formula (2) is reacted with the compound of formula (4), R ¹ is methyl or phenyl, X is Cl, and R ² is H, and R ³ and R ⁴ are cyclohexyl.

An exemplary reaction of the compound of formula (2) with a compound of formula (5) is shown in the following:

In one embodiment, the compound of formula (2) is reacted with the compound of formula (5), R ¹ is methyl, tert-butyl or phenyl, and R ² is H, and R ³ and R ⁴ are cyclohexyl.

An exemplary reaction of the compound of formula (2) with a compound of formula (6) is shown in the following:

In one embodiment, the compound of formula (2) is reacted with the compound of formula (6), R ¹ is methyl, tert-butyl, phenyl, tolyl, or benzyl, X is Cl, and R ² is H, and R ³ and R ⁴ are cyclohexyl.

In one embodiment, the compound of formula (2) is reacted with a compound selected from

In one embodiment, the compound of formula (1) is selected from

In one embodiment, the compound of formula (2) is reacted with the compound of formula (4), (5), (6), or (7) in the presence of a solvent. In one embodiment, the solvent is selected from methyl tertbutyl ether (MTBE), dichloromethane (CH2CI2), deuterated dichloromethane (CD2CI2), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate.

In one embodiment, the compound of formula (2) is reacted with the compound of formula (4), (5), (6), or (7) at a temperature of from -10°C to 50°C. Preferably, the compound of formula (2) is reacted with the compound of formula (4), (5), (6), or (7) at a temperature of from 0°C to 30°C.

In one embodiment, the compound of formula (2) is reacted with the compound of formula (4), (5), (6), or (7) for at least 30 minutes, preferably for at least 1 h., such as at least 1 .5 h, at least 2 h, at least 2.5 h or at least 3 h.

In one embodiment, the compound of formula (2) is added dropwise to the compound of formula (4), (5), (6), or (7).

In one embodiment, the compound of formula (2) is contacted with trifluoroacetic acid (TFA) prior to reacting with the compound of formula (4), (5), (6), or (7).

It will be obvious for a person skilled in the art that these embodiments and items only depict examples of a plurality of possibilities. Hence, the embodiments shown here should not be understood to form a limitation of these features and configurations. Any possible combination and configuration of the described features can be chosen according to the scope of the invention.

The present invention will be further illustrated by the following examples.

Examples

Example 1 : The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt, 20.04 g) was suspended in methyl tert-butyl ether (140.04 g) at room temperature (r.t.) under inert atmosphere (Nitrogen) and the obtained suspension was cooled with vigorous stirring on an ice bath. A solution of acetyl chloride (5.98 g) in methyl tert-butyl ether (10.50 g) was added dropwise and the obtained orange suspension was stirred at 0 °C for 2 h and 4 h at r.t. (until the precipitate in suspension became white). Filtration and washing of the precipitate with methyl tert-butyl ether (50.4 g) afforded 3- oxocyclobut-1-en-1-yl acetate as an orange in solution in methyl tert-butyl ether. A small sample was concentrated under reduced pressure at r.t. to measure a NMR-spectra. ¹ H-NMR: (400 MHz, CDCh) ppm 5.46 (s, 1 H), 3.31 (m, 2H), 2.26 (s, 3H).

Example 2:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt, 1.01 g), CH2CI2 (10.08 g), acetic anhydride (0.58 g) and triethylamine (0.46 g) were stirred in a vial at r.t for 24 h. The mixture was filtered and the filtrate was concentrated under vacuum.

Example 3:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 1.00 g) was suspended in CH2CI2 (10.21 g). Methanesulfonyl chloride (0.65 g) and triethylamine (0.47 g) were added to the suspension. The orange-brownish suspension was stirred at room temperature (r.t.) for 24 h. The suspension was filtered. The filtrated was concentrated under vacuum. 1H-NMR: (400 MHz, CDCh) ppm 5.35 (s, 1 H), 3.37 (m, 3H), 3.22 (m, 2H). Example 4:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 1.06 g) was suspended in CH2CI2 (10.04 g). Triphosgene (1.21 g) was added at 0°C and stirred for 2 h at 0°C and 2 h at r.t. The suspension was filtered and concentrated. The mono- and disubstituted product was obtained as pale yellow solution (1.36 g). ¹ H-NMR: (400 MHz, CDCh) ppm 5.19 (s, 1 H), 3.43 (m, 2H).

Example 5:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 10.00 g) was suspended in CH2CI2 (134 g), placed into the phosgene reactor and cooled to 5 °C. Phosgene (1.0 eq.) was dosed over 1 h at 5 °C. The resulting mixture was stirred for 12 h at 5 °C and warmed up to 20 °C and further stirred for 6 h at 20 °C. MeOH (50 g) was dosed at 20 °C for 1 h to quench the reaction. The reaction mixture was concentrated to dryness and the suspension was washed with CH2CI2.

The filtrated was concentrated under vacuum to obtain methyl (3-oxocyclobut-1-en-1-yl) carbonate. Example 6:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 10.00 g) was suspended in CH2CI2 (134 g), placed into the phosgene reactor and cooled to 5 °C. Phosgene (0.5 eq.) was dosed over 1 h at 5 °C. The resulting mixture was stirred for 12 h at 5 °C and warmed up to 20 °C and further stirred for 6 h at 20 °C. MeOH (50 g) was dosed at 20 °C for 1 h to quench the reaction. The reaction mixture was concentrated to dryness and the suspension was washed with CH2CI2. The filtrated was concentrated under vacuum to obtain the product. Example 7:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 1.00 g) was suspended in methyl tert-butyl ether (10 g) at 0 °C. Trifluoroacetic acid (1.1 eq.) was added to the suspension and further stirred at 0 °C for 2 h. The suspension was filtered and the filtrate was mixed with urea (0.5 eq.) at 0 °C. The mixture was heated up to r.t over night. The reaction mixture was concentrated under vacuum to obtain 1 ,3-bis(3-oxocyclobut-1-en-1-yl)urea.

Example 8:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 1.00 g) was suspended in methyl tert-butyl ether (10 g) at 0 °C. Trifluoroacetic acid (1.1 eq.) was added to the suspension and further stirred at 0 °C for 2 h. The suspension was filtered and the filtrate was mixed with tert butyl carbamate (1 eq.) at 0 °C. The mixture was heated up to r.t over night. The reaction mixture was concentrated under vacuum to obtain tert-butyl (3-oxocyclobut-1-en-1-yl)carbamate. Example 9:

The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 1.03 g) was suspended in CH2CI2 (10.22 g). Phenyl chloroformate (0.59 g) was added at 0 °C and stirred for 2 h at 0 °C and 4 h at r.t. The suspension was filtered and concentrated to obtain 3-oxocyclobut-1-en-1-yl phenyl carbonate (0.73 g, 93.9%). ¹ H-NMR: (400 MHz, CDCh) ppm 7.35 (m, 2H), 7.24 (m, 1 H), 7.16 (m, 2H), 5.50 (s, 1 H), 3.39 (d, 2H).

Example 10: The Dion salt (3-hydroxy-2-cyclobuten-1-one dicyclohexylammonium salt; 10.00 g) was suspended in CH2CI2 (134 g), placed into the phosgene reactor and cooled to 5 °C. Phosgene (1 .0 eq.) was dosed over 1 h at 5 °C. The resulting mixture was stirred for 12 h at 5 °C and warmed up to 20 °C and further stirred for 6 h at 20 °C. The reaction mixture was concentrated to dryness and the suspension was washed with CH2CI2. The filtrated was concentrated under vacuum to obtain 3- oxocyclobut-1-en-1-yl carbonochloridate.