4. DESCRIPTION
TITLE OF THE INVENTION:
A CHEAP AND SIMPLE PROCESS FOR THE PREPARATION OF « - DIAZO OXIME ETHERS
FIELD OF INVENTION
This invention relates to a process for the preparation of a-diazo oxime ethers. More particularly, this invention describes the synthesis of a-diazo oxime ethers exclusively with cis isomer of oxime ethers via diazo transfer reaction, employing sulfonyl azide as diazo source and a mixture of bases. This invention also relates to a one-pot process for the preparation of a-diazo oxime ethers from ketones via oxime ethers.
BACKGROUND OF THE INVENTION:
a-diazocarbonyl compounds have a long history of useful applications in organic synthesis. They are easily prepared from readily accessible precursors and undergo a wide variety of chemical transformations under very mild conditions, such as generation of carbenes, metal-complexed carbenoids and diazonium cations, which participate in useful chemical transformations including 1, 3-dipolar cycloadditions, cyclopropanation, X-H insertion reactions (X = C, O, N, P, etc.), phosphorous or sulfur ylide formation, and Pd catalyzed cross-coupling reactions, (a) Regitz. M.; Heydt, H. in 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 (Ed. A. Padwa), Wiley-Inter science, New York, 1984, 393; b) Kissane, M.; Maguire, A. N. Chem. Soc. Rev. 2010, 39, 845; c) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061; d) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137: e) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 109; f) Burke, S. D.; Grieco, P. A. Org. React. (N.Y.) 1979, 26. 361; g) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanation to Ylides, Wiley-lnterscience, New York, 1998)}.
One of the major routes for the synthesis of diazo compounds involves the base-assisted reaction of an active methylene group with a diazo transfer reagent. Several electron-deficient

sulfonyl azide derivatives have been identified as efficient diazo transfer reagents. Readily accessible /?-toluenesulfonyl azide has been the reagent employed most frequently. (Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733; Regitz, M. Synthesis 1972, 351).
With the objective to improve efficiency, ensure safety and to ease product purification from the sulfonamide by-product, several alternative reagents have been investigated over the years. The first diazo transfer reaction in active methylene compounds was reported by Regitz et al. using tosyl azide as nitrogen source. Until now, this protocol is considered as practical method. (Regitz, M. Synthesis 1972, 351).
Depending upon their stability and co-existing functional groups, diazo compounds can post a challenge with respect to their preparation and isolation. The a-diazo imines, the nitrogen analogues of a-diazocarbonyl compounds, remain largely unexplored due to their limited availability since they spontaneously undergo cyclization to produce 1,2,3-triazoles. {a) Gilchrist, T. L.; Gymer, G. E. Adv. Heterocycl. Chem. 1974, 16, 33; b) Romeiro, G. A.; Pereira, L. O. R.; de Souza, M. C. B. V.; Ferreira, V. F.; Cunha, A. C. Tetrahedron Lett. 1997, 38, 5103: c) Himbert, G.; Regitz, M. Chem. Ber. 1972, 105, 2963}. a-diazo oxime ethers are the precursors for large number of derivatives like ]M-alkoxy pyrroles, which are used as insecticides for crop protection (Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed. 2010, 49, 7963). The growing interest in the development of new methodologies for preparation of a-diazo oxime ethers is its probability of production in the industrial scales.
1. A standard procedure for the diazo transfer was described by Regitz et al. which provided the route for the synthesis of diazo carbonyl compounds from malonic ester, /?-keto esters and /i-diketones containing active methylene group. The method includes the reaction of active methylene group with tosyl azide in dry chloroform or ethanol using Triethylamine as base (Regitz, M.; Mass, G. Diazo compounds: properties and synthesis, Academic press, London, 1986, 65).
2. Emmanuvel et al. have synthesized the a-diazo oxime ethers from /?-oximino esters using 1, 8-diaza bicyclo undec-7-ene (DBU) as a base in acetonitrile as solvent at -20 °C

followed by the addition of 4-nitro benzenesulphonyl azide (Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed. 2010, 49, 7963). 3. Shimon Shatzmiller and Sorin Bercovici have reported the synthesis of a-diazo oxime ethers from oxime ether using w-butyllithium («-BuLi) as base and methanesulphonyl azide as diazo transfer reagent at -78 °C. (Shatzmiller, S.; Bercovici, S. Eur. J. of Org. Chem. Leibigs annalen der chemie, 1992, 8, 877).
Even though the above methods are widely used in the laboratory, they suffer from following setbacks.
A. Significant drawback for the synthesis of a-diazo oxime ethers is the use of 4-nitro
benzenesulfonyl chloride, which is very expensive and not affordable for scale up, which
limits its plausible scale up.
B. Another major drawback is the excessive formation of 4-nitro benzene sulfonamide as
by-product.
C. Another major drawback is the requirement of extreme low temperatures during reaction,
which also limits its preparation in the laboratories.
D. Yet another major drawback is the use of strong base such as w-BuLi or use of less
common and relatively expensive bases like 1, 8-diaza bicyclo undec-7-ene (DBU).
OBJECTS OF THE INVENTION
i. The main object of the invention is to provide simple, cheap and high yield preparation of
cis a-diazo oxime ethers, ii. Another object of the invention is the use of a mixture of simple bases for the
deprotonation of active methylene hydrogen present in oxime ethers instead of using
harsh bases like «-BuLi. iii. Another object of the invention is to use cheaper and readily available sulphonyl azides
for carrying out the diazo transfer reaction with oxime ethers, thereby reducing the cost of
bulk production of a-diazo oxime ethers as fine chemical in industries, iv. Another object of the invention is to develop a one-pot process for the preparation of
a-diazo oxime ethers from ketones via oxime ethers.

v. Another object of the invention is to carry out the reaction at the ambient temperature. vi. Another object of the invention is to reduce the time of reaction, which makes it more
profitable in the industrial scale up. vii. Yet another object of the invention is to synthesize cis a-diazo oxime ether stereo
specifically.
SUMMARY OF THE INVENTION
The present invention provides a method to carryout diazotization of oxime ethers using sulfonyl azide as the source of nitrogen in the presence of mixture of bases at temperature in the range of-20 °C to 60 °C for 15 min to 24 hours, followed by the conventional workup, solvent extraction and purification to obtain a-diazo oxime ethers. The present invention also provides a one-pot process to prepare oxime ethers from ketones followed by diazotization using sulfonyl azide in the presence of mixture of bases at temperature in the range of-20 °C to 60 °C for 15 min to 24 hours.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the simple and cheaper process for the production of cis a-diazo oxime ethers II from the cis : trans mixture of oxime ethers I via diazo transfer reaction using sulfonyl azide and a mixture of bases.
Accordingly, to a solution of cis : trans mixture of oxime ether I and sulfonyl azide (1 eq.) in solvent at room temperature varying from -20 °C to 60 °C. was added a mixture of bases such as KOH/Et3N, K2C03/Et3N, NaOH/Et3N, NaOH/Pyridine, etc. The resulting pale yellow solution was stirred for 15 min to 3 hours at the same temperature during which period the solution darkens in yellow colour. After the completion of the reaction as indicated by the TLC, the solvent was removed under reduced pressure and the residue was extracted with

organic solvent, washed with water, brine and dried over anhydrous Na2SC>4. The organic layer was concentrated under reduced pressure to get crude product and was purified by column chromatography to obtain pure et-diazo oxime ethers II.

*The substrates given in the table are illustrative only and should not be construed to limit the scope of present invention in any matter.
The present invention also provides a simple and cheap one-pot process for the production of cis a-diazo oxime ethers II from ketones III. This reaction involves formation of oxime ether I followed by diazo transfer reaction using sulfonyl azide and a mixture of bases.

1. In one embodiment of the invention, the mixture of bases was employed in 1-5 equivalent amounts, preferably around 3 equivalents.
2. In another embodiment, one of the bases is organic while the other is alkali metal base.
3. In another embodiment of the invention, a variety of cis : trans mixture of oxime ethers with electron withdrawing groups are converted to their corresponding a-diazo oxime ethers.
4. In another embodiment, the electron withdrawing group (EWG) can be -N02, -CN, -CF3, -COCH3, -CHO, -CONH2, etc.
5. In another embodiment, a variety of bases like NaOH, KOH and K2CO3 in combination with Triethylamine, Diisopropylamine, Diisopropylethylamine, DABCO, pyridine etc. were found to bring about this transformation and found that NaOH in combination with Triethylamine has shown excellent yields. Other bases exhibited moderate to good yields.
6. In another embodiment, the reaction time varies from 15 min to 3 hours.
7. In another embodiment, a variety of solvents like tetrahydrofuran. acetonitrile, 1, 4-Dioxane, ethylene dichloride and diethyl ether of which, the reaction in acetonitrile solvent resulted excellent yields. Other solvents resulted moderate to good yield.
8. In another embodiment, sulfonyl azides employed are 4-methyl benzenesulfonyl azide, benzenesulfonyl azide, methanesulfonyl azide, trifluoro methanesulfonyl azide, imidazole sulfonyl azide in the range of 1-3 equivalents.
9. In another embodiment, only cis a-diazo oxime ether was obtained irrespective of the cis : trans ratio in the oxime ether I.

10. In another embodiment, the cis : trans ratio of the oxime ether varies from 95:10 to 50:50.
11. In another embodiment, cis a-diazo oxime ether is directly prepared by one-pot process from ketones by treating them with alkoxyl amine in organic base and for 2-6 hours followed by adding inorganic base and diazo transfer reagent.
12. Yet in another embodiment, the reaction time for the one-pot process varies from 15 min -24h.
PREPARATION
The process of the present invention is described herein with reference to examples, which are

illustrative only and should not be construed to limit the scope of the present invention in any
matter.
Example 1: preparation of (Z)-ethyl-2-diazo-3-(methoxyimino) butanoate
To a solution of/?-oximino ethyl butanoate (leq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC, the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 65%. Example 2: Preparation of (Z)-methyl-2-diazo-5-ethoxy-3-(methoxyimino) pentanoate To a solution of/?-methoxyimino methyl ethoxy pentanoate (leq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC, the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 68%.
Example 3: Preparation of (Z)-methyl-3-cyclohexyl-2-diazo-5-ethoxy-3-(methoxyimino) propanoate
To a solution of/y-methoxyimino methyl cyclohexyl propanoate (1 eq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC. the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 79%.

Example 4: Preparation of (Z)-methyl-2-diazo-3-(methoxyimino)-3 phenyl propanoate
To a solution of y9-methoxyimino methyl phenyl propanoate (1 eq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic base (1-10 eq.)- The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC, the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 91%.
Example 5: Preparation of (Z)-ethyl-2-diazo-3-(methoxyimino)-4-phenyl butanoate To a solution of /?-methoxyimino phenyl butanoate (leq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic bas (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC, the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 75%.
Example 6: Preparation of (Z) - methyl-2-diazo-3-(methoxyimino)-5-phenyl pentanoate To a solution of/?-methoxyimino methyl phenyl pentanoate (leq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After the completion of the reaction as indicated by the TLC. the conventional workup was carried out with water and organic solvent. The separated organic phase was dried over anhydrous sodium sulphate. The dried organic phase was concentrated to give crude product. The crude was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed yield was 77%.
Example 7: Preparation of (Z)-methyl-2-diazo-3-(methoxyimino) hept-6-ynoate To a solution of /?-methoxyiminio methyl phenyl heptynoate (leq.) and sulfonyl azide (1-3 eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and

organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After
the completion of the reaction as indicated by the TLC, the conventional workup was carried
out with water and organic solvent. The separated organic phase was dried over anhydrous
sodium sulphate. The dried organic phase was concentrated to give crude product. The crude
was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed
yield was 76%.
Example 8: preparation of (Z)-ethyl-2-diazo-3-(methoxyimino)-3-(4-nitrophenyl)
propanoate
To a solution of/?-methoxyimino ethyl 4-nitrophenyl propanoate (leq.) and sulfonyl azide (1-3
eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and
organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After
the completion of the reaction as indicated by the TLC, the conventional workup was carried
out with water and organic solvent. The separated organic phase was dried over anhydrous
sodium sulphate. The dried organic phase was concentrated to give crude product. The crude
was purified by column chromatography using hexane : ethyl acetate (19:1) and the observed
yield was 87%.
Example 9: Preparation of (Z)-ethyl-2-diazo-3-(methoxyimino)-3-(4-methoxyphenyl)
propanoate
To a solution of/y-methoxyimino-4-methoxy phenyl propanoate (1 eq.) and sulfonyl azide (1-3
eq.) in solvent (5-10 ml/mM) at -20 °C to 60 °C was added inorganic base (1-3 eq.) and
organic base (1-10 eq.). The resulting yellow color solution was stirred for 30 min at RT. After
the completion of the reaction as indicated by the TLC, the conventional workup was carried
out with water and organic solvent. The separated organic phase was dried over anhydrous
sodium sulphate. The dried organic phase was concentrated to give crude product. The crude
was purified by column chromatography using hexane : ethyl acetate (19:1) and the
observed yield was 88%.
ADVANTAGES OF THE PRESENT METHOD:
i. The main advantage of the present process is that the cis ec-diazo oxime ethers can be synthesized with readily available sulfonyl azides replacing the expensive 4-nitro toluene

sulfonyl azide reducing the cost of production in the industrial scale up. ii. The reaction was carried out employing cheaper and commonly available base combination
such as NaOH/Et3N, KOH/Et3N, K2C03/Et3N, NaOH/DMAP,
NaOH/Diisopropylamine, NaOH/Pyridine, NaOH/Diisopropyl ethylamine. iii. The reaction was carried out at temperatures ranging from -20 °C to 60 °C and at higher
rates, which is noteworthy, as the earlier methods required very low temperatures like
-78 °C. iv. The workup and the purification of the diazo compounds is very simple and obtained
comparable yields ranging from excellent to moderate, v. Although, cis : trans mixture of oxime ethers was employed for diazo transfer reaction,
only cis a-diazo oxime ethers were obtained stereo specifically, vi. Another advantage of this present invention is one-pot process for the synthesis of cis
«-diazo oxime ethers from ketones, avoiding the workup procedure for the oxime ethers
reaction mixture, thereby saving the workup solvents as well as time.
5. CLAIMS WE CLAIM,
I. A cheap and simple process for the preparation of a-diazo oxime ethers II from oxime ethers via diazo transfer reaction, said process comprises treating sulfonyl azide of structure R2S02N3 wherein, R2 = -CF3, -CH3, -C6H5, 4-CH3C6H5 etc. with cis : /ram-mixture of oxime ether of structure I in the presence of mixture of bases in solvent at a temperature range of-20 °C to 60 °C for 15 min to 24 hours, evaporating the solvent and extracting with ethyl acetate and purifying the product to obtain pure cis a-diazo oxime ethers of the structure II.
2. A simple and cheap one-pot process for the production of cis a-diazo oxime ethers II from ketones III via imines I formed in situ. This reaction involves formation of oxime ether with alkoxyl amine hydrochloride in the presence of base as solvent followed by

diazo transfer reaction using sulfonyl azide and a mixture of bases at a temperature ranging from -20 °C to 60 °C.
3. A process as claimed in 1 and 2, the substituents R, R , R are selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, benzyl, allyl etc. and the EWG is selected from nitro, ester, amide, N-substituted amide, nitrile, ketone, aldehyde, trifluoro methyl etc.
4. A process as claimed in 1 and 2, wherein, sulfonyl azide has been employed as the source of nitrogen. The amount of sulfonyl azide may be in the range of 1-3 eq. to bring about quantitative conversion and the sulfonyl azide employed is one of the following, methanesulfonyl azide, trifluoro methanesulfonyl azide, benzenesulfonyl azide, toluenesulfonyl azide, imidazolesulfonyl azide, p-carboxy benzenesulfonyl azide (PCBSA), 2,4,6-triisopropyl benzenesulfonyl azide, /?-nitro benzenesulfonyl azide (PNBSA), />-acetamido benzenesulfonyl azide etc.
5. A process as claimed in I. wherein, any combination of the following bases were employed for the diazo transfer reaction. The bases include NaOH, KOH. LiOH, «Bu4N+OH", Et^N, pyridine, diisopropylamine, diisopropyl ethylamine, picolines, DMAP etc.
6. A process as claimed in I, wherein a cis : trans mixture of oxime ether gives only cis a-diazo oxime ethers stereo specifically. The cis : trans ratio varies from 0:100 to 100:0.
7. A process as claimed in I and 2, wherein the diazo transfer reaction is carried out in the temperature range of-20 "C to 60 "C and for the time period of 15 min to 24 hours.
8. A process as claimed in I. wherein, the solvent is independently chosen from tetrahydrofuran, acetonitrile. halogenated solvents, diethyl ether, 1, 4-dioxane etc.
9. A process as claimed in 1 and 2. wherein, the solvent used for workup is independently chosen from ethyl acetate, dichloroethane, chloroform, mixture of ethyl acetate and petroleum ether with the ratio varying from 1:99 to 50:50.
10. A process as claimed in 1 and 2, wherein, the crude is purified by chromatography or distillation and the yield of the cis a-diazo oxime ethers varies from 50% to 99%.