GB2569412A - Preparation of bimanes and chlorination of pyrazolinones - Google Patents

Abstract

A method of chlorinating a pyrazolinone in the 4 position, comprising: (a) providing a pyrazolinone having a structure I: (b) contacting the pyrazolinone with a solid chlorination agent for a period of time, said contacting in the absence of a solvent; thereby chlorinating said pyrazolinone in the 4 position, yielding a 4-chloropyrazolinone having a structure II: wherein R1 and R2 are independently any suitable substituent is provided. R1 and R2 may be independently selected from the group consisting of: hydrogen, branched alkyl groups; straight alkyl groups; alkene groups, alkyne group and nitrile. The solid chlorinating agent may be selected from the group trichloroisocyanuric acid (TCCA), tert-butyl hypochlorite and N-chlorosuccinimide (NCS). A method of preparing bimanes (1,5-diazabicyclo[3.3.0]octadienediones) from said 4-chloropyrazolinone is described. A method of brominating said bimanes to form mono-bromo bimane (compound 6, figure 6) is also described.

Description

PREPARATION OF BIMANES AND CHLORINATION OF PYRAZOLINONES

FIELD AND BACKGROUND OF THE INVENTION

The invention, in some embodiments, relates to the field of chemical synthesis and more particularly, but not exclusively, to methods for chlorination of pyrazolinone in the 4position to yield a 4-chloropyrazolinone and methods for preparing bimanes from pyrazolinones.

Bimanes are a family of heterocyclic chemical compounds that include the 1,5diazabicyclo [3.3.0] octadienedione scaffold:

Bimanes are not easy to synthesize and therefore underutilized. One well-known synthesis (see Kosower EM, Pazhenchevsky B in J Am Chem Soc 1980, 102, 4983-4993) includes a chlorination step of a pyrazolinone by bubbling chlorine gas (prepared in-situ) through the reaction mixture to yield a 4-chloropyrazolinone. As is well-known, chlorine gas is highly toxic, dangerous and difficult to handle. As a result, at the time of this writing, the cost of a typical bimane from commercial sources is in the order of $80 for 10 mg of material.

Additional relevant background can be found in:

A. E. Radkowsky and E. M. Kosower, J. Am. Chem. Soc., 1986, 108, 4527;

C. M. Lau, K. Thangaraj, G. Kumar, V. T. Ramakrishnan, E. D. Stevens, J. H. Boyer,

I. R. Politzer and T. G. Pavlopoulos, Heteroat. Chem., 1990, 1, 195;

S. E. Mansoor and D. L. Farrens, Biochemistry, 2004, 43, 9426;

J. Skj old-Jorgensen, J. Vind, A. Svendsen and M. J. Bjerrum, Eur. J. Lipid Sci. Technol. 2016, 118, 1644;

A. Sosa-Peinado andM. Gonzalez-Andrade, Biochemistry, 2005, 44, 15083;

G. M. Nicholas, P. Kovac, and C. A. Bewley, J. Am. Chem. Soc., 2002, 124, 3492;

I. Smirnova, V. Kasho, J. Sugihara and H. R. Kaback, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 8876;

A. Chaudhuri, Y. Venkatesh, K. K. Behara, and N. D. P. Singh, Org. Lett. 2017, 19, 1598;

I. Lapidot, D. Baranes, A. Pinhasov, G. Gellerman, A. Albeck, F. Grynszpan and S. E. Shatzmiller, Med. Chem., 2016, 12, 48;

P. J. Das, Y. Diskin-Posner, M. Firer, M. Montag and F. Grynszpan, Dalt. Trans., 2016, 45, 17123;

L. A. Carpino, J. Am. Chem. Soc, 1958, 80, 599;

L. De Luca, G. Giacomelli, G. Nieddu, Synlett, 2005, 2, 223;

J. Mintz and C. Walling, Org. Synth. Coll, 1973, 5, 148;

B. M. Trost, Science, 1991, 254, 1471; and

N. S. Kosower and E. M. Kosower, Methods Enzymol., 1987, 143, 76.

SUMMARY OF THE INVENTION

The invention, in some embodiments, relates to methods for chlorination of pyrazolinone in the 4 position to yield a 4-chloropyrazolinone. Thus prepared 4chloropyrazolinones may optionally be used as starting materials for preparation of bimanes.

According to an aspect of some embodiments of the teachings herein, there is provided a method of chlorinating a pyrazolinone in the 4 position, comprising:

a. providing a pyrazolinone, the pyrazolinone having a structure I:

b. contacting the pyrazolinone with a solid chlorination agent for a period of time, the contacting in the absence of a solvent;

thereby chlorinating the pyrazolinone in the 4 position, yielding a 4-chloropyrazolinone having a structure II:

wherein R1 and R2 are independently any suitable substituent.

In some embodiments, R1 and R2 are the same. In some embodiments, R1 and R2 are different. In some embodiments, R1 and R2 are independently selected from the group consisting of: hydrogen; branched alkyl groups; straight alkyl groups; Cl-CIO branched alkyl groups; Cl-CIO straight alkyl groups; alkene groups; alkyne groups; and -CN.

In some embodiments, the non-gaseous chlorination agent is a A-ch 1 orination agent. In some embodiments, the A'-chlorination agent is selected from the group consisting of trichloroisocyanuric acid (TCCA), tert-butyl hypochlorite and Λ-chlorosuccinimide (NCS).

In some embodiments, the pyrazolinone is solid and during the contacting both the pyrazolinone and the chlorination agent are solid. In some embodiments, the contacting comprises: mixing a powder of the solid pyrazolinone with a powder of the solid chlorination agent. In some embodiments, the contacting comprises: pulverizing the solid pyrazolinone with the solid chlorination agent. In some embodiments, the contacting comprises milling the solid pyrazolinone and the solid chlorination agent together.

In some embodiments, the contacting is at room temperature.

BRIEF DESCRIPTION OF THE FIGURES

Some embodiments of the invention are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments of the invention may be practiced.

The figures are for the purpose of illustrative discussion and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the invention. For the sake of clarity, some objects depicted in the figures are not to scale. In the Figures:

Figure 1 (prior art) shows a prior art preparation of bimanes including a step of of chlorination of a pyrazolinone by bubbling chlorine gas through a reaction mixture to yield a 4-chloropyrazolinone;

Figure 2 shows chlorination of a pyrazolinone (2) in the 4 position to yield a 4chloropyrazolinone (3) according to the teachings herein, followed by using the thus-prepared 4-chloropyrazolinone (3) as starting materials to yield a mixture of a syn-bimane (4) and an cW/'-bimane (5) (reaction mechanistic details and intermediates are not shown);

Figure 3 shows preparation of a mixture of a syn-bimane (4) and an cW/'-bimane (5) from a pyrazolinone;

Figure 4 depicts a hypothesized mechanism of some embodiments of the teachings herein;

Figure 5 depicts some embodiments of the teachings herein; and

Figure 6 shows the chemical structure of a brominated bimane prepared according to an embodiment of the teachings herein.

DESCRIPTION OF SOME EMBODIMENTS OF THE INVENTION

The invention, in some embodiments, relates to methods for chlorination of pyrazolinone in the 4 position to yield a 4-chloropyrazolinone. The thus-prepared 4chloropyrazolinone may optionally be used as a starting material for the preparation of a bimane. The invention, in some embodiments, relates to methods for preparing bimanes using pyrazolinones as a starting material.

The principles, uses and implementations of the teachings of the invention may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art is able to implement the teachings of the invention without undue effort or experimentation. In the figures, like reference numerals refer to like parts throughout. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. The invention is capable of other embodiments or of being practiced or carried out in various ways. The phraseology and terminology employed herein are for descriptive purpose and should not be regarded as limiting.

As discussed in the introduction, bimanes are not easy to prepare due to the requirement of a step of bubbling chlorine gas into a reaction mixture to prepare a 4chloropyrazolinone (see: PCT Patent Application US79/00685 published as WO 80/00565; US Patent 4,499,284; Kosower EM, Pazhenchevsky B, Hershkowitz E 1978, J Am Chem Soc 5 100, 6516-6518; Kosower EM, Bernstein J, Goldberg I, Pazhenchevsky B, Goldstein E 1979,

J Am Chem Soc 101, 1620-1621; and Kosower EM, Pazhenchevsky B 1980, J Am Chem Soc 102, 4983-4993).

Herein are disclosed methods for chlorination of pyrazolinone in the 4 position to yield a 4-chloropyrazolinone. Thus prepared 4-chloropyrazolinones may optionally be used 10 as starting materials for preparation of bimanes. Also disclosed are methods for preparing bimanes using pyrazolinones as a starting material.

According to the teachings herein there is provided a method of chlorinating a pyrazolinone in the 4 position, comprising:

a. providing a pyrazolinone in solution, the pyrazolinone having a structure I:

b. in the solution, reacting the pyrazolinone with a non-gaseous chlorination agent; thereby chlorinating the pyrazolinone in the 4 position, yielding a 4-chloropyrazolinone having a structure II:

wherein R1 and R2 are independently any suitable substituent.

As known in the art, the thus-prepared 4-chloropyrazolinones may then be reacted to eliminate Cl from the (4-position) and H (from the 1-position) yielding a pyrazolone that can rearrange into an azo-ketene derivative that reacts with a pyrazolone to yield a bimane.

In some embodiments, R1 and R2 are the same.

In some embodiments, R1 and R2 are different.

In some embodiments, R1 and R2 are independently selected from the group consisting of: hydrogen; branched alkyl groups; straight alkyl groups; Cl-CIO branched alkyl groups; Cl-CIO straight alkyl groups; alkene groups; alkyne groups; and -CN.

In some embodiments, the non-gaseous chlorination agent is a Λ-chlorination agent, that is to say, a chlorination agent used to halogenate nitrogen atoms by means of chlorinium ion (Cl⁺).

In some preferred embodiments, the A'-chlori nation agent is selected from the group consisting of trichloroisocyanuric acid, tert-butyl hypochlorite and TV-chlorosuccinimide. It has been found that chlorination agents used to chlorinate nitrogen atoms unexpectedly chlorinate the pyrazolinone having a structure I at the 4-position rather than at the expected nitrogen atom at the 1-position.

The solution is any suitable solution, comprising any suitable solvent or suitable combination of solvents. In some embodiments, the solvents making up the solution are immiscible with water. In some embodiments, the solution comprises at least one chlorinated solvent. In some embodiments, not less than 80% by weight of the solvents making up the solution are chlorinated solvents. In some embodiments, not less than 90% by weight of the solvents making up the solution are chlorinated solvents. In some embodiments, not less than 95% by weight of the solvents making up the solution are chlorinated solvents. Any suitable chlorinated solvent or combination of chlorinated solvents may be used. In some embodiments, at least one chlorinated solvent is selected from the group consisting of chloroform, di chloromethane (DCM) and carbon tetrachloride.

Experiments were performed in a solvent made up of 100% by weight dichloromethane and it was found that the dichloromethane solvent facilitated the separation of the product by selective solubility. Accordingly, in some preferred embodiments, not less than 80%, not less than 90% and even not less than 95% by weight of the solvents making up the solution is dichloromethane.

When the method is performed batchwise, the starting concentration of the pyrazolinone having structure I in the solution is any suitable concentration. In some embodiments, the concentration is not less than 0.1 M, not less than 0.2 M, not less than 0.3

M and even not less than 0.4 M. In some embodiments, the concentration is not more than 1 M, not more than 0.8 M, not more than 0.6 M and even not more than 0.5 M.

According to an aspect of some embodiments of the teachings herein there is also provided a method of preparing a bimane, comprising:

a. providing a pyrazolinone in a water-miscible solvent, the pyrazolinone having a structure I:

b. in the water-miscible solution, reacting the pyrazolinone with a non-gaseous chlorination agent while the pH of the water-miscible solution is not less than 8;

thereby yielding a bimane having a structure selected from the group consisting of structures 10 III (syri) and IV (anti)'.

wherein R1 and R2 are independently any suitable substituent.

It has been unexpectedly found that reacting a pyrazolinone having Structure I with a non-gaseous chlorination agent (e.g., NaOCl) while the pH of the water-miscible solution is 15 not less than 8 leads to one-pot direct preparation of the bimane products (structure III and IV).

In some embodiments, R1 and R2 are the same.

In some embodiments, R1 and R2 are different.

In some embodiments, R1 and R2 are independently selected from the group consisting of: hydrogen; branched alkyl groups; straight alkyl groups; Cl-CIO branched alkyl groups; Cl-CIO straight alkyl groups; alkene groups; alkyne groups; and -CN.

In some embodiments, the pH of the water-miscible solution is not less than 9.

In some embodiments, the non-gaseous chlorination agent is also a pH-regulating agent, that is to say, addition of the non-gaseous chlorination agent to water brings the pH of the resulting solution to a desired value, e.g., depending on the embodiment not less than 8 and even not less than 9. In some embodiments, the non-gaseous chlorination agent is a hypochlorite. In some embodiments, the non-gaseous chlorination agent is NaOCl.

Any suitable water-miscible solvent may be used in implementing the teachings herein.

In some embodiments, the water-miscible solvent comprises water. In some embodiments, the water-miscible solvent comprises not less than 10%, not less than 20%, not less than 30% and even not less than 40% water by volume. In some embodiments, the watermiscible solvent comprises not more than 80%, not more than 70%, not more than 60% and even not more than 50% water by volume.

In some embodiments, the water-miscible solvent comprises an alcohol, in some embodiments methanol. In some embodiments, the water-miscible solvent comprises not less than 10%, not less than 20%, not less than 30% and even not less than 40% alcohol by volume. In some embodiments, the water-miscible solvent comprises not more than 90%, not more than 80%, not more than 70% and even not more than 60% alcohol by volume.

Further embodiments

Without wishing to be held to any one theory, it is currently hypothesized that implementation of some embodiments of the teachings herein to prepare a 4chloropyrazolinone (II) are dependent on formation of a chlorenium ion (Cl⁺) that is formed by the chlorination agent that reacts with a tautomer of the corresponding pyrazolinone (I), see Figure 4. Accordingly, it is hypothesized that in some embodiments a chlorination agent is a chlorenium ion source, such as NaOCl discussed above.

In some embodiments, a pyrazolinone (I) is reacted with a hypochlorite derivative other than sodium hypochlorite. In some embodiments, the hypochlorite derivative is soluble in organic solvents, for example tert-butyl hypochlorite. tert-Butyl hypochlorite is soluble in organic solvents, is easily prepared by reacting tert-butyl alcohol with NaOCl and is considered to be a chlorenium ion source. In some such embodiments, the hypochlorite derivative is added to a solution of the pyrazolinone (I) in an organic solvent such as dichloromethane or CC14, in some embodiments while the solution is maintained at a temperature of not more than 20°C, not more than 10°C, not more than 5°C and even not more than 2°C, for example, at 0°C. In some preferred embodiments, the addition is under an inert atmosphere, for example nitrogen or argon. After a sufficient reaction time (typically a few hours, e.g., 8-12 hours, typically at room temperature) the analogous 4chloropyrazolinone (II) is prepared.

Additional chlorination agents that are chlorenium ion sources include Nchlorosuccinimide (NCS), l,3-dichloro-5,5-dimethylhydantoin (DCDMH) and trichloroisocyanuric acid (TCCA). Preferably, such solid chlorination agents are added to a solution of a pyrazolinone (I) in a suitable organic solvent (e.g., dichloromethane, CC1₄), in some embodiments while the solution is maintained at a temperature of not more than 20°C, not more than 10°C, not more than 5°C and even not more than 2°C, for example, at 0°C. In some preferred embodiments, the addition is under an inert atmosphere, for example nitrogen or argon. After a sufficient reaction time (typically a few hours, e.g. 8-12 hours, typically at room temperature) the analogous 4-chloropyrazolinone (II) is prepared.

In some embodiments, trichlorocyanuric acid (TCCA) is a preferred chlorinating agent as it has been found that under some conditions using TCCA leads to a relatively high yield of 4-chloropyrazolinone (II) and also TCCA has intrinsic atom economy (see Figure 5) which allows the use of just 1/3 equivalent of TCCA relative to pyrazolinone (I).

Subsequently to the reaction time, if required, materials that are not soluble in the solvent (e.g., reaction products such as the dechlorinated chlorination reagents for example succinimide from NCS, dimethylhydantoin from DCDMH and cyanuric acid from TCCA that are not soluble in the reaction solvent, such as CC1₄ or DCM) are separated from the solution, for example by filtration and subsequently the 4-chloropyrazolinone (II) is optionally isolated from the solution in the usual way.

Alternatively, the 4-chloropyrazolinone (II) is not isolated and instead a suitable reagent such as K₂CO₃ · 1.5 H₂O is added to yield the desired bimane (see Figures 2 and 5) in about 75% yield of the desired syn bimane (III) and about 20% yield of the anti bimane (IV) in a convenient one pot process. The scalability of this process has been demonstrated by performing the reaction with 0.5 gr and 2 gr of a pyrazolinone (I) with similar overall yield in both cases. The yield of a typical embodiment according to the teachings herein is significantly higher than reported in the art for the two steps, typically 50.3%.

Solventless reactions

It has surprisingly been found that it is possible to chlorinate a pyrazolinone (I) with a chlorination agent (such as TCCA) to yield a 4-chloropyrazolinone (II) without any solvent.

Thus, according to an aspect of some embodiments of the teachings herein there is provided a method of preparing a 4-chloropyrazolinone (II) by contacting a pyrazolinone (I) with a solid chlorination agent for a period of time, wherein the contacting is in the absence of a solvent. Preferably, the contacting is done in a reaction vessel.

The molar ratio of pyrazolinone to chlorination agent is any suitable molar ratio. In some preferred embodiments, the molar ratio is between 0.8:1 and 1:0.8 pyrazolinone to chlorination agent.

In some embodiments, the pyrazolinone (I) is a solid and during the contacting both the pyrazolinone (I) and the chlorination agent are solid. In some embodiments the contacting comprises mixing a solid pyrazolinone (I) powder with a solid chlorination agent powder. In some embodiments the contacting comprises pulverzing the pyrazolinone (I) and the chlorination agent together (for example, using a mortar and pestle or ball-mill). In some embodiments, the chlorination agent is TCCA. It is important to note that typically in embodiments where the pyrazolinone and the chlorination agent are solids, the 4chloropyrazolinone product is a liquid. In some such embodiments, at least some of the liquid

4.chloropyrazolinone product is removed during the period of time (in which there is the chlorinating of the pyrazolinone). In some embodiments, during the period of time (in which there is the chlorinating of the pyrazolinone), a slurry is formed of the solid pyrazolinone and solid chlorination agent in the liquid 4-chloropyrazolinone product.

In some embodiments, the contacting is at room temperature. As detailed in the experimental section below, a pyrazolinone (I) was contacted with solid TCCA at room temperature for 15 minutes, giving a 69% yield of the corresponding 4-chloropyrazolinone (II). The chlorination of the pyrazolinone has been found to be exothermic so that typically, as the reaction progresses, the actual temperature is higher than the starting temperature (e.g., room temperature). In some embodiments, the reaction mixture (the pyrazolinone with chlorination agent) is actively cooled, e.g., the reaction vessel is cooled.

It is known that organic solvents make up the majority of the waste produced during organic syntheses. It is often preferred to use a benign solvent like water or no solvent at all, even at the expense of a lower yield in order to reduce the amount of waste. Accordingly, such solventless embodiments may be considered advantageous.

A bimane (III, IV) may be prepared from the resulting 4-chloropyrazolinone (II) as described above by reaction with K₂CO₃ · 1.5 H₂O, see Figure 5. However, since the 4chloropyrazolinone (II) is liquid at room temperature it has been surprisingly found that the preparation of a bimane can be performed without the use of any solvent. In the experimental section below, an exemplary such embodiment yielded a syn bimane (III) in 73% yield. This solvent-free synthesis of bimane is very convenient, quick (in some embodiments ending in less than 5 min) and the resulting bimane mixture can be easily separated from the K₂CO₃ reagent by solubilizing the bimanes from the reaction mixture with a suitable solvent such dichloromethane. Thus, according to an aspect of some embodiments of the teachings herein there is provided a method of preparing a bimane by contacting a 4-chloropyrazolinone (II) with K₂CO₃ · 1.5 H₂O for a period of time, wherein the contacting is in the absence of a solvent. In some embodiments, the 4-chloropyrazolinone (II) is a liquid and during the contacting the K₂CO₃ · 1.5 H₂O is immersed in, and preferably mixed with, the 4chloropyrazolinone (II). In some embodiments, the contacting is at room temperature. In some embodiments, subsequent to the period of time, the bimane product is dissolved in a solvent that does not dissolve the remaining K₂CO₃, thereby separating the bimane from the K₂CO₃.

In some embodiments, the above-two solventless steps: a) chlorinating a pyrazolinone (I) with a chlorination agent to yield a 4-chloropyrazolinone (II) without a solvent; and b) preparing a bimane by contacting a 4-chloropyrazolinone (II) with K₂CO₃ · 1.5 H₂O without a solvent are carried out consecutively, in some preferred embodiments in the same reaction container (vessel), for example, by adding solid potassium carbonate to the vessel in which the pyrazolinone (I) was chlorinated, wherein the adding of the solid potassium carbonate is preferably without intervening isolation and/or purification of the 4-chloropyrazolinone (II). In some such embodiments, the yield of syn bimane (III) is 38% relative to the starring pyrazolinone (I).

It is important to note that in some embodiments, both solvent-free reactions are exothermic so suitable care, handling and procedures are preferably followed.

Bromination of bimanes (IIP

One known use of a syn bimane (III) is as the basis for a fluorescent probe. Typically, for use as a fluoresecent prove the bimane (III) is converted to an akylating agent such as monobromo bimane (e.g., compound 6 in Figure 6). Conveniently, the fluorescence of a compound such as 6 is weak but strong fluoresence is again observed when the Br atom is replaced with a thiol nucleophile.

Bromination of a syn bimane (III) at the β-alkyl H site is achieved via the reaction of the bimane with liquid bromine. Herein is disclosed that such bromination is advantageously performed by reaction with solid N-bromosuccinimide (NBS). Such a reaction proceeds smoothly at room temperature over a period of 12 hour, affording the desired brominated product (as depicted in Figure 6) in yields comparable to the obtained by bromination with liquid bromine. Thus, according to an aspect of some embodiments of the teachings herein there is provided a method of brominating a syn-bimane (III) by contacting a a syn bimane (III) with solid N-bromosuccinimide (NBS) for a period of time, wherein the contacting is in the absence of a solvent, to yield a brominated syn bimane.

EXPERIMENTAL

Devices

The identity of some prepared compounds was confirmed using NMR spectra (¹H and ¹³C) that were recorded using a Bruker Avance-III 400 MHz spectrometer, equipped with a 5 mm BBFO SmartProbe. All measurements were done at 20°C, unless noted otherwise. Ή and ¹³C NMR chemical shifts are reported in ppm relative to tetramethylsilane. ¹H NMR chemical shifts are referenced to the residual hydrogen signal of the deuterated solvent, and the ¹³C NMR chemical shifts are referenced to the ¹³C signal(s) of the deuterated solvent. Abbreviations used in the description of NMR data are as follows: Ar, aryl; br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

Materials

Except where explicitly noted, all required chemical compounds and reagents were purchased from well-known commercial suppliers, e.g., Sigma-Aldrich (St. Eouis, MO, USA) and BioEab Etd. (Jerusalem, Israel).

Example 1 (Prior Art): Preparation of 9.10-dioxa-(Me,Me)bimane

The prior art preparation of 9,10-dioxa-(Me,Me)bimane substantially as reported in Kosower EM, Pazhenchevsky B in J Am Chem Soc 1980, 102, 4983-4993 was repeated, see Figure 1.

a. Preparation of 3,4-dimethyl-2-pyrazolin-5-one (2)

200g ethyl 2-methylacetoacetate (1, CAS 609-14-3) in absolute ethanol was maintained at 50°C with a small molar excess of hydrazine hydrate (CAS 10217-52-4) for 1 hour to obtain 3,4-dimethyl-2-pyrazolin-5-one (2). Yield of product was 30%.

b. Preparation of 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) by chlorination of 3,4dimethyl-2-pyrazolin-5-one (2) using chlorine gas

3.4- Dimethyl-2-pyrazolin-5-one (2, 137.8 g, 1.23 mol) was mixed with di chloromethane (DCM, 1200 mL). Chlorine gas (Cl₂, generated in situ) was bubbled through the resulting mixture while stirring until all the solid had dissolved and the resulting solution had a yellow-green color. Excess chlorine gas was removed from the mixture in the usual way by streaming nitrogen therethrough. Solvent was removed from the mixture using a standard rotary evaporator at 40°C, and the resulting oily residue was dissolved in benzene : petroleum ether (1:1, 300 mL) at room temperature. The solution was cooled to 0°C to yield a white precipitate 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3, 131.7 g, 73.1% yield).

c. Preparation of 9,10-dioxa-(Me,Me)bimane (4) from 3,4-dimethyl-4-chloro-2-pyrazolin-5one (3)

3.4- Dimethyl-4-chloro-2-pyrazolin-5-one (3, 70 g, 0.48 mol) dissolved in di chloromethane (500 mL) was added to a vigorously-stirred mixture of potassium carbonate hydrate (K₂CO₃ · 1.5 H₂O, 150 g), potassium carbonate (K₂CO₃, 50 g), and di chloromethane (250 mL) cooled in an ice bath. The mixture was removed from the ice bath after 1 hour and stirring continued at room temperature.

After additional stirring for 18 hours at room temperature, the mixture was filtered through a thick bed of Celite® (diatomaceous earth) to yield a filtrate. The solvent was removed from the filtrate using a standard rotary evaporator at about 40°C, yielding a yellow solid residue. The residue was dissolved in a minimum volume of boiling acetonitrile. The resulting acetonitrile solution was cooled to room temperature, yielding precipitation of yellowish crystals of 9,10-dioxa-sy«-(Me,Me)bimane (4, 27.5 g). Further cooling of the filtrate to 0°C yielded, after recrystallization from acetonitrile, another 2.5 g of 9,10-dioxa.sj7/-(Me,Me)birriane (4).

After removal of solid 4, filtrates were evaporated and the residue was chromatographed on alumina using dichloromethane as eluent. The first material eluted is

9,IO-dioxa-a////-(Me,Me)bimane (5) followed by 9,IO-dioxa-.sj7/-(Me,Me)bimane (4, 1.60 g). The overall yield of 9,IO-dioxa-.sj7/-(Me, Me)bimane (4) was 69%.

Example 2: Preparation of 9.10-dioxa-(Me,Me)bimane

9,10-dioxa-s}77-(Me,Me)bimanes having structures III and IV were prepared according to an embodiment of the teachings herein, using 3,4-dimethyl-4-chloro-2pyrazolin-5-one (3) as a starting material, according to an embodiment of the teachings herein.

a. Preparation of 3,4-dimethyl-2-pyrazoline-5-one (2)

Ethyl 2-methylacetoacetate (1, 26 mL, 184 mmol. 90% purity, CAS 609-14-3) was placed in a round-bottom flask and heated to 50°C with stirring. Hydrazine hydrate (13 mL, 210-250 mmol, 80% purity in water, CAS 10217-52-4) in 100 mL of absolute ethanol was added dropwise to the ethyl 2-methylacetoacetate over a period of about 2 minutes. After all of the hydrazine hydrate solution was added, the resulting reaction mixture was then stirred at 50°C for 1 hour, during which a white precipitate formed. After the 1 hour, the precipitate was isolated from the reaction mixture by filtration (vacuum filtration through Whatman filter paper 42), and washed several times with absolute ethanol to remove any hydrazine hydrate. The resulting white solid was dried overnight at room temperature under vacuum to remove solvent.

Additional 3,4-dimethyl-2-pyrazoline-5-one (2) was prepared by treatment of the filtrate containing unreacted ethyl 2-methylacetoacetate (1) with a second portion of hydrazine hydrate, and isolated substantially as described above.

The product was confirmed to be compound 2 using NMR: 'H NMR (CD₃OD, 400 MHz) δ 1.80 (s, 3H),2.11(s, 3H) ppm; ¹³C NMR (CD₃OD, 100 MHz) δ 5.9, 10.4, 99.2, 143.3, 164.4 ppm.

The total yield of compound 2 was 5.98 g (29% yield). Purity of the product was confirmed by the presence of a single spot on TLC.

bl. Preparation of 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) by chlorination of 3,4dimethyl-2-pyrazolin-5-one (2) using trichloroisocyanuric acid

3,4-dimethyl-2-pyrazoline-5-one (2, 0.5 g, 4.45 mmol) as prepared above was dissolved in 10 mL of di chloromethane. The solution was cooled to 0°C.

Trichloroisocyanuric acid (0.34 g, 1.48 mmol, CAS 87-90-1) as a chlorination agent (CHL in Figure 2) was slowly added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at room temperature. After stirring for 12 hours, a solid precipitate of cyanuric acid was observed. The cyanuric acid precipitate was removed by filtration (vacuum filtration through Whatman filter paper 42) to yield a filtrate. The solvent was removed from the filtrate using a standard rotary evaporator at 40°C, yielding a product.

The product was confirmed to be the desired 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) using NMR: Tf NMR (CDC1₃, 400 MHz) δ 1.68 (s, 3H),2.12 (s, 3H) ppm; ¹³C NMR (CDCh, 100 MHz) δ 12.7, 21.8, 60.1, 159.9, 174.0 ppm.

The total yield of the desired compound 3 was 0.54 mg (82% yield). Purity of the product was confirmed by the presence of a single spot on TLC.

b2. Preparation of 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) by chlorination of 3,4dimethyl-2-pyrazolin-5-one (2) using tert-butyl hypochlorite

3,4-dimethyl-2-pyrazoline-5-one (2, 0.49 g, 4.37 mmol) as prepared above was dissolved in 8 mL of carbon tetrachloride under nitrogen. The solution was cooled to 0°C.

tert-butyl hypochlorite (0.49 mL, 4.37 mmol, CAS 507-40-4) as a chlorination agent was slowly added to the solution in a dropwise fashion. After all the tert-butyl hypochlorite was added, the solution was stirred at room temperature for another 8 hours.

After the 8 hours, the solvent was removed from the solution using a standard rotary evaporator at 40°C, yielding a product.

The product was confirmed to be the desired 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) using NMR: Ή NMR (CDCh, 400 MHz) δ 1.68 (s, 3H),2.12 (s, 3H) ppm; ¹³C NMR (CDCL, 100 MHz) δ 12.7, 21.8, 60.1, 159.9, 174.0 ppm.

The total yield of the desired compound 3 was 0.60 mg (93% yield). Purity of the product was confirmed by the presence of a single spot on TLC.

b3. Preparation of 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) by chlorination of 3,4dimethyl-2-pyrazolin-5-one (2) using N-chlorosuccinimide

3,4-dimethyl-2-pyrazoline-5-one (2, 0.5 g, 4.45 mmol) as prepared above was dissolved in 10 mL of di chloromethane. The solution was cooled to 0°C.

A-chlorosuccinimide (0.59 g, 4.45 mmol, CAS 128-09-6) as a chlorination agent was added to the solution over a period of about 1 minute. After all the A-chlorosuccinimide was added, the solution was stirred at room temperature for another 12 hours.

After the 12 hours, the solvent was removed from the solution using a standard rotary evaporator at 40°C.

The resulting residue was dissolved in carbon tetrachloride, and filtered (vacuum filtration through Whatman filter paper 42) to remove solid succinimide and yielding a filtrate.

The solvent was removed from the filtrate using a standard rotary evaporator at about 40°C yielding a product.

The product was confirmed to be the desired 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) using NMR: Ή NMR (CDCh, 400 MHz) δ 1.68 (s, 3H),2.12 (s, 3H) ppm; ¹³C NMR (CDCh, 100 MHz) δ 12.7, 21.8, 60.1, 159.9, 174.0 ppm.

The total yield of compound 3 was 0.52 mg (80% yield). Purity of the product was confirmed by the presence of a single spot on TLC.

c. Preparation of 9,10-dioxa-(Me,Me)bimane (4) from 3,4-dimethyl-4-chloro-2-pyrazolin-5one (3)

3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3, 0.45 g, 3.09), as prepared above according to any one of bl, b2 or b3, was dissolved in 20 mL di chloromethane. This solution was added dropwise to a solution of potassium carbonate (3.4 g, 24.6 mmol, CAS 584-08-7) in 20 mL di chloromethane at 0°C over a period of about 10 minutes. To the resulting combined solution were added few drops of water from a faucet. The resulting reaction mixture was stirred at room temperature for 72 hours.

After the 72 hours, the solid potassium carbonate was removed from the reaction mixture by filtration (vacuum filtration through Whatman filter paper 42) to yield a filtrate.

The solvent was removed from the filtrate using a standard rotary evaporator at about 40°C yielding a crude yellow residue.

The crude product was purified by silica gel column chromatography (pore size 60 A, 230-400 mesh particle size) using a di chloromethane: hexane (1:1) eluent.

Two different bimane products were isolated.

The majority bimane product was confirmed to be 9,10-dioxa-s>77-(Me,Me)bimane (4, structure III) using NMR: Ή NMR (CDC1₃, 400 MHz) δ 1.82 (s, 3H), 2.30 (s, 3H) ppm. The total yield of compound 4 was 0.22 g (74% yield).

Also isolated was 9,10-dioxa-anri-(Me,Me)bimane (5, structure IV. 0.07 g, 23.6% yield).

Example 3: Preparation of 9J0-dioxa-svn-(Me,Me)bimane (4)

A 9,10-dioxa-(Me,Me)-bimane having structure III was prepared according to an embodiment of the teachings herein.

A solution of 3,4-dimethyl-2-pyrazoline-5-one (2, 50 mg, as prepared in 2a above) in 4 mL methanol and 2 mL 3% NaOCl as a chlorination agent and basification agent in water (a commercial lemon-scented bleach solution devoid of detergent (Solo Bleach brand name having a pH of 12.6) was stirred at room temperature for 72 hours.

After the 72 hours, the solvent was removed from the solution using a standard rotary evaporator at about 40°C yielding a crude yellow residue.

The crude product was purified by silica gel column chromatography (pore size 60 A, 230-400 mesh particle size) using a dichloromethane/hexane (1:1) eluent.

The purified product was confirmed to be the desired 9,10-dioxa-sj«-(Me,Me)bimane (4) using NMR: Ή NMR (CDCh, 400 MHz) δ 1.82 (s, 3H), 2.30 (s, 3H) ppm.

Example 4 (Prior Art): Methylbromination of 9.IO-dioxa-.vi7/-('methyl. methyl ((methyl, methyl) bimane (4) to yield 9.10-dioxa-xi77-(bromorn ethyl. methyl)(m ethyl. methyl) bimane.

The prior art preparation of 9,10-dioxa-sj«-(bromomethyl, methyl)(m ethyl, methyl)bimane (4) substantially as reported in Kosower EM, Pazhenchevsky B in J Am Chem Soc 1980, 102, 4983-4993 was repeated.

Bromine (0.79 g, 4.9 mmol) in 15 mL di chloromethane was added dropwise to a solution of 9,10-dioxa-syn-(methyl,methyl)bimane (4, 1.0 g, 5.2 mmol) in 10 ml di chloromethane in a round-bottom flask protected from light over a period of 15 minutes. The reaction was maintained at room temperature with continuous stirring. Progress of the reaction was monitored in the usual way using thin-layer chromatography. It is important to note that thin-layer chromatography (TLC) was found to be useful for monitoring the course of the reaction: the not-fluorescent methylbrominated product becomes fluorescent and detectable on TLC after some time on the TLC plate, presumably as a result of light-induced debromination.

After 1 hour, when the TLC indicated that the reaction was complete, the product was purified by chromatography. The product was confirmed to be 9,10-dioxa-sjn-(bromomethyl, methyl)(methyl, methyl)bimane (0.35 g , 50% yield) using 'H NMR (CDC1₃, 400 MHz) δ 1.82 (s, 3 H), 1.87 (s, 3 H), 2.44 (s, 3 H), 4.32 (s, 2 H) ppm.

Example 5: Preparation of 9.10-dioxa-vyn-ibromom ethyl. methyl ((methyl, methyl) bimane by methylbromination of 9.10-dioxa-5yn-(methyl. methyllfmethyl. methyl) bimane (4)

9,10-dioxa-xyn-(methyl,methyl)bimane (4, 0.5 g, 2.6 mmol) was dissolved in 50 mL acetonitrile. The reaction mixture was cooled to 0°C.

Recrystallized N-bromosuccinimide (CAS Nr. 128-08-5, 0.46 g, 2.6 mmol) was slowly (pinchwise) added to the cooled solution over a period of 30 minutes. After addition of the Λ-bromosuccinimide was complete, the solution was maintained at room temperature with continuous stirring for 12 hours.

At the end of the 12 hours, the solvent was evaporated using a rotary evaporator in the usual way. The residue was purified using flash column chromatography with a hexane/ethyl acetate (1:1) eluent. The product was determined to be 9,10-dioxa-sjn-(bromomethyl, methyl)(methyl, methyl)bimane (0.35 g, 50 % yield) using 'H NMR (CDC1₃, 400 MHz) δ 1.82 (s, 3 H), 1.87 (s, 3 H), 2.44 (s, 3 H), 4.32 (s, 2 H) ppm.

Example 6: Preparation of 3.4-dimethyl-4-chloro-2-pyrazolin-5-one by chlorination of 3.4dimethyl-2-pyrazolin-5-one using tert-butyl hypochlorite

3,4-dimethyl-2-pyrazoline-5-one (0.49 g, 4.37 mmol) was dissolved in 8 mL of carbon tetrachloride under a nitrogen atmosphere. The solution was cooled to 0°C.

tert-butyl hypochlorite (0.49 mL, 4.37 mmol, CAS 507-40-4) was added to the solution dropwise. After the addition of the tert-butyl hypochlorite was complete, the solution was maintained at room temperature with continuous stirring for 8 hours.

At the end of the 8 hours, the solvent was removed from the solution using a rotary evaporator in the usual way under reduced pressure at 40°C. The product was determined to be 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (0.60, 93% yield) using NMR and mass spectrometry: Ή NMR (CDC13, 400 MHz) δ 1.68 (s, 3H), 2.12 (s, 3H) ppm; ¹³C NMR (CDC13, 100 MHz) d 12.6, 21.7, 60.0, 159.9, 173.8 ppm. ESI-MS m/z C₅H₈C1N₂O - Calcd.: 147.0325 [MH⁺] found: 147.0352.

Example 7: Preparation of 3.4-dimethyl-4-chloro-2-pyrazolin-5-one by chlorination of 3.4dimethyl-2-pyrazolin-5-one using N-chlorosuccinimide

3,4-dimethyl-2-pyrazoline-5-one (0.5 g, 4.45 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to 0 °C.

N-chlorosuccinimide (0.59 g, 4.45 mmol, CAS 128-09-6) was added to the solution over a period of 30 min. After the addition of the t N-chlorosuccinimide was complete, the solution was maintained at room temperature with continuous stirring for 12 hours.

At the end of the 12 hours, the solvent was removed from the solution using a rotory evaporator in the usual way under reduced pressure at 40°C. The resulting residue was dissolved in carbon tetrachloride, filtered to remove solid succinimide and yielding a filtrate.

The carbon tetrachloride was removed from the filtrate using a rotary evaporator in the usual way under reduced pressure at 40 °C yielding 0.52 g of the product 2 (80% yield). NMR: Ή NMR (CDC13, 400 MHz) δ 1.68 (s, 3H), 2.12 (s, 3H) ppm; ¹³C NMR (CDC13, 100 MHz) δ 12.6, 21.7, 60.0, 159.9, 173.8 ppm.

Example 8: Preparation of 3.4-dimethyl-4-chloro-2-pyrazolin-5-one by chlorination of 3.4dimethyl-2-pyrazolin-5-one using L3-dichloro-5.5-dimethylhydantoin

3,4-dimethyl-2-pyrazoline-5-one ( 0.5 g, 4.45 mmol) was dissolved in 10 mL of carbon tetrachloride. The solution was cooled to 0°C.

1.3- Dichloro-5,5-dimethylhydantoin (0.44 g, 2.22 mmol, CAS 118-52-5) was slowly added to the solution over a period of 30 min. The solution was stirred at room temperature for 12 hours.

At the end of the 12 hours, a solid precipitate was observed. The precipitate was removed from the solution by filtration yielding a filtrate.

The solvent was removed from the filtrate using a rotary evaporator in the usual way under reduced pressure at 40°C, yielding 0.50 g the product 3,4-dimethyl-4-chloro-2pyrazolin-5-one (76% yield). NMR: Ή NMR (CDCh, 400 MHz) δ 1.68 (s, 3H), 2.12 (s, 3H) ppm; ¹³C NMR (CDCh, 100 MHz) δ 12.6, 21.7, 60.0, 159.8, 173.9 ppm.

Example 9: Preparation of 3.4-dimethyl-4-chloro-2-pyrazolin-5-one by chlorination of 3.4dimethyl-2-pyrazolin-5-one using trichloroisocvanuric acid

3.4- dimethyl-2-pyrazoline-5-one (0.5 g, 4.45 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to 0 °C.

Trichloroisocyanuric acid (0.34 g, 1.48 mmol, CAS 87-90-1) was slowly added to the solution over a period of 30 min. The solution was stirred at room temperature for 12 hours.

At the end of the 12 hours, a solid precipitate of cyanuric acid was observed. The cyanuric acid precipitate was removed by filtration yielding a filtrate. The solvent was removed from the filtrate using a rotary evaporator in the usual way under reduced pressure at 40°C, yielding 0.54 g the product(82% yield). NMR: Ή NMR (CDCh, 400 MHz) δ 1.68 (s, 3H), 2.12 (s, 3H) ppm; ¹³C NMR (CDCh, 100 MHz) δ 12.6, 21.7, 60.0, 159.9, 173.8 ppm.

Example 10: Preparation of 3.4-dimethyl-4-chloro-2-pyrazolin-5-one by chlorination of 3.4dimethyl-2-pyrazolin-5-one using trichloroisocvanuric acid without solvent

3.4- dimethyl-2-pyrazoline-5-one (0.2 g, 1.78 mmol) was manually finely ground in a mortar and pestle.

Trichloroisocyanuric acid (0.14 g, 0.59 mmol, CAS 87-90-1) was added to the fine powder in the mortar and grinding with the pestle was resumed.

The progress of the solventless reaction between the 3,4-dimethyl-2-pyrazoline-5-one (2) and the trichloroisocyanuric acid was monitored by TLC (Ethyl acetate / Hexane, 1:1). The reaction reached completion after 15 minutes of grinding.

The resulting powder was transferred to a vial and dichloromethane (10 mL) was added. The resulting mixture was filtered to remove the trichloroisocyanuric acid which is insoluble in dichloromethane, yielding a filtrate.

The solvent was removed from the filtrate using a rotary evaporator in the usual way under reduced pressure at 40°C, yielding 0.18 g 3,4-dimethyl-4-chloro-2-pyrazolin-5-one (3) (69% yield). NMR: Ή NMR (CDC13, 400 MHz) δ 1.68 (s, 3H), 2,12 (s, 3H) ppm; ¹³C NMR (CDCh, 100 MHz) δ 12.6, 21.7, 60.0, 159.8, 173.9 ppm; ESI-MS m/z C₅H₈C1N₂O Calcd: 147.0325 [MH⁺], found: 147.0352.

Example 11: Preparation of 9.10-dioxa-syn-(Me.Me)bimane without solvent

3.4- dimethyl-4-chloro-2-pyrazolin-5-one (0.2 g, 1.36 mmol) in a pre-heated mortar was melted and K₂CO₃ 1.5 H₂O (0.945 mg, 5.71 mmol) was added and pestle milled.

The progress of the reaction was monitored by TLC (DCM/ethylacetate, 2.5:7.5). The reaction reached completion after 15 minutes of stirring.

Five consecutive times, 15 ml dichloromethane was added each time to the mortar and poured into a flask, yielding a total 75 ml solution.

The solvent was removed from the solution using a rotary evaporator in the usual way under reduced pressure at 40°C, yielding a brown residue.

The residue was purified in the usual way by column chromatography eluting with hexane/ethyl acetate (1:3). The desired 9,10-dioxa-syn-(Me,Me)bimane was isolated (0.096 g, 73% yield). NMR: Ή NMR (CDCh, 400 MHz) δ 1.80 (s, 3H), 2.29 (s, 3H) ppm; ESI-MS m/z Ci₀Hi₃N₂O₂ Calcd: 193.0977 [MH⁺] found: 193.0992.

Example 12: Preparation of monobromo bimane by bromination of 9.10-dioxa-svn(Me.Me)bimane using N-bromosuccinimide

9,10-dioxa-syn-(Me,Me)bimane (0.5 g, 2.6 mmol) was dissolved in 50 mL acetonitrile. The solution was cooled to 0°C.

Recrystallized N-bromosuccinimide (0.46 g, 2.6 mmol, CAS. 128-08-5) was slowly added (pinchwise) to the cooled solution over a period of 30 minutes. After the addition of Nbromosuccinimide was complete, the reaction mixture was stirred at room temperature for 12 hours.

At the end of the 12 hours, the solvent was removed from the filtrate using a rotary evaporator in the usual way under reduced pressure at 40°C. The resulting brown residue was purified in the usual way using flash chromatography eluted with hexane/ethyl acetate (1:1) to isolate the resulting product (0.35 g, 50% yield). NMR: Ή NMR (CDC1₃, 400 MHz) δ 1.84 (s, 3 H), 1.89 (s, 3 H), 2.45 (s, 3 H), 4.32 (s, 2 H) ppm; ¹³C NMR (CDC13, 100 MHz) δ 6.9, 11.5, 17.8, 113.2, 115.4, 144.2, 146.0, 159.8, 160.7 ppm. ESI-MS m/z CmHnBr N₂O₂ Calcd: 271.0082 [MH⁺] found: 271.0067.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. In case of conflict, the specification, including definitions, takes precedence.

As used herein, the terms “comprising”, “including”, having and grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. As used herein, the indefinite articles a and an mean at least one or one or more unless the context clearly dictates otherwise.

As used herein, when a numerical value is preceded by the term about, the term about is intended to indicate +/-10%.

As used herein, a phrase in the form “A and/or B” means a selection from the group consisting of (A), (B) or (A and B). As used herein, a phrase in the form “at least one of A, B and C” means a selection from the group consisting of (A), (B), (C), (A and B), (A and C), (B and C) or (A and B and C).

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments 5 thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the scope of the appended claims.

Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the invention.

Section headings are used herein to ease understanding of the specification and should not be construed as necessarily limiting.

Claims (11)

1. A method of chlorinating a pyrazolinone in the 4 position, comprising:

a. providing a pyrazolinone, said pyrazolinone having a structure I:

b. contacting said pyrazolinone with a solid chlorination agent for a period of time, said contacting in the absence of a solvent;

thereby chlorinating said pyrazolinone in the 4 position, yielding a 4-chloropyrazolinone having a structure II:

wherein R1 and R2 are independently any suitable substituent.

2. The method of claim 1, wherein R1 and R2 are the same.

3. The method of claim 1, wherein R1 and R2 are different.

4. The method of any one of claims 1 to 3, wherein R1 and R2 are independently selected from the group consisting of hydrogen; branched alkyl groups; straight alkyl groups; Cl-CIO branched alkyl groups; Cl-CIO straight alkyl groups; alkene groups; alkyne groups; and -CN.

5. The method of any one of claims 1 to 4, wherein said non-gaseous chlorination agent is a A'-chlorination agent.

6. The method of claim 5, wherein said A-chlori nation agent is selected from the group consisting of trichloroisocyanuric acid (TCCA), tert-butyl hypochlorite and Nchlorosuccinimide (NCS).

7. The method of any one of claims 1 to 6, wherein said pyrazolinone is solid and during said contacting both said pyrazolinone and said chlorination agent are solid.

8. The method of claim 7, said contacting comprising: mixing a powder of said solid pyrazolinone with a powder of said solid chlorination agent.

9. The method of any one of claims 7 to 8, said contacting comprising: pulverizing said solid pyrazolinone with said solid chlorination agent.

10. The method of any one of claims 7 to 8, said contacting comprising milling said solid pyrazolinone and said solid chlorination agent together.

11. The method of any one of claims 1 to 10, said contacting being at room temperature