Ortho-alkynyl anilines and process for preparation thereof

Abstract

The present invention relates to novel ortho alkynyl anilines of formula (I) which are useful in synthesis of drug intermediates and natural products and process for preparation of these ortho alkynyl anilines of formula (I) via copper catalyzed Multi Component Reactions (MCR). ##STR00001##

Claims

1. A compound of formula (I) ##STR00011## wherein, R.sup.1 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and ester; R.sup.2 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), and substituted or unsubstituted aryl; R.sup.3 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), substituted or unsubstituted aryl, and alkoxy; R.sup.4 is selected from hydrogen, substituted or unsubstituted C.sub.1 to C.sub.7 alkyl, substituted or unsubstituted aryl, and alkoxy; and R.sup.3 and R.sup.4 jointly represent 1,3-dioxolyl.

2. The compound as claimed in claim 1, wherein said compound of formula (I) are selected from the group consisting of: i. Dibenzyl1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)phenyl)hydrazine-1,2-dicarboxylate; ii. Dibenzyl1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethoxyphenyl)hydrazine-1,2-dicarboxylate, iii. Dibenzyl1-(6-(3-ethoxy-3-oxoprop-1-yn-1-yl)benzo[d][1,3]dioxol-5-yl)hydrazine-1,2-dicarboxylate and iv. Dibenzyl1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethylphenyl) hydrazine-1,2-dicarboxylate.

3. A one-pot process for the preparation of a compound of formula (I) comprising the steps of: i. stirring a reaction mixture of (trimethylsilyl) aryl triflates with terminal alkyne and azodicarboxylate in the presence of a copper catalyst, cesium fluoride and solvent at a temperature in the range of 80 to 110 C. for a period ranging from 8 to 15 h to obtain a mixture; ii. cooling the mixture as obtained in step (i) at room temperature in the range of 20 to 30 C. followed by filtering and purifying to obtain compound of formula (I), wherein the compound of formula (I) is: ##STR00012## wherein, R.sup.1 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and ester; R.sup.2 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), and substituted or unsubstituted aryl; R.sup.3 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), substituted or unsubstituted aryl, and alkoxy; R.sup.4 is selected from hydrogen, substituted or unsubstituted C.sub.1 to C.sub.7 alkyl, substituted or unsubstituted aryl, and alkoxy; and R.sup.3 and R.sup.4 jointly represent 1,3-dioxolyl.

4. The process as claimed in claim 3, wherein said copper catalyst is a copper (I) salt selected from the group consisting of copper chloride, copper bromide, and copper iodide.

5. The process as claimed in claim 3, wherein the (trimethylsilyl) aryl triflates are selected from the group consisting of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, 6-(trimethylsilyl)benzo[d][1,3]dioxol-5-yl trifluoromethane-sulfonate, 4,5-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate.

6. The process as claimed in claim 3, wherein the terminal alkyne is selected from the group consisting of ethyl propiolate, methyl propiolate and butyl propiolate.

7. The process as claimed in claim 3, wherein said azodicarboxylate is selected from dibenzyl azodicarboxylate and dialkyl azodicarboxylate.

8. The process as claimed in claim 3, wherein said solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, toluene, acetonitrile, and dimethylformamide.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention provides a ortho-alkynyl anilines of formula (I) and a one-pot process for the preparation protected ortho-alkynyl anilines of formula (I) via multi component reaction of arynes.

(2) Present invention provides a ortho alkynyl anilines of formula (I)

(3) ##STR00006##
Wherein
R.sup.1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and ester;
R.sup.2 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), substituted or unsubstituted aryl.
R.sup.3 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), substituted or unsubstituted aryl, alkoxy.
R.sup.4 is selected from hydrogen, substituted or unsubstituted alkyl(C.sub.1 to C.sub.7), substituted or unsubstituted aryl, alkoxy.
R3 and R4 jointly represent 1,3-dioxolyl.

(4) The compounds of formula (I) are selected from the group consisting of dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)phenyl)hydrazine-1,2-dicarboxylate; dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethoxyphenyl)hydrazine-1,2-dicarboxylate, dibenzyl 1-(6-(3-ethoxy-3-oxoprop-1-yn-1-yl) benzo[d][1,3]dioxol-5-yl)hydrazine-1,2-dicarboxylate and dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethylphenyl) hydrazine-1,2-dicarboxylate.

(5) The present invention provides a one-pot process for synthesis of compounds of formula (I), wherein said process comprises stirring the reaction mixture of (trimethylsilyl) aryl triflates with terminal alkyne and azodicarboxylate in presence of copper catalyst, cesium fluoride and suitable solvent at temperature ranging from 80-110 C. for the period ranging from 8 to 15 h to obtain the desired product of formula (I) with yield >80%. (Scheme 1).

(6) (Trimethylsilyl) aryl triflates are selected from 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, 6-(trimethylsilyl)benzo[d][1,3]dioxol-5-yl trifluoromethane-sulfonate, 4,5-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate and the like.

(7) Terminal alkynes are selected from ethyl propiolate, methyl propiolate, butyl propiolate and the like.

(8) Azodicarboxylates are selected from dibenzyl azodicarboxylate, dialkyl azodicarboxylate and the like.

(9) Solvent used is selected from dichloromethane, tetrahydrofuran, ethyl acetate, toluene, acetonitrile, dimethylformamide and the like.

(10) In the process, arynes are generated in situ from 2-(trimethylsilyl) aryl triflates and cesium fluoride. The temperature of the reaction is maintained in the range of 80-110 C.

(11) The copper catalyst is selected from copper (I) salt such as copper halide, the solvent is selected from polar aprotic solvent such as DCM, THF, ethyl acetate, toluene, acetonitrile, DMF and the like.

(12) These ortho-alkynyl anilines of formula (I) are useful as intermediates for synthesis of compounds that can be used for synthesis of indoles, quinolinones, in drug synthesis and natural products.

(13) The present invention provides the use of o-alkynyl anilines of formula (I) for synthesis of 3,4-dihydroquinolinones (Scheme 2).

EXAMPLES

(14) The compounds of formula (I) are also useful for synthesis of drug intermediates and natural products like cartiolol, aripiprazole and NMDA antagonist.

(15) Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

(16) General Experimental Procedure for Preparation of O-Alkynyl Anilines

(17) Terminal alkynes (1.0 mmol), CuI (10-20 mg, 0.03 to 0.08 mmol) and CsF (0.365 g, 2.4 mmol) were charged to an oven-dried flask under the protection of nitrogen. Then the aryl triflates (1.2 mmol) were added by syringe with the mixture of CH.sub.3CN and aprotic solvents ranging from DCM, THF, ethyl acetate, toluene, acetonitrile, DMF and the like (3: 3 mL). The reaction mixture was stirred at 110 C. for 12 h and then cooled to room temperature 25 C. The suspension was filtered through a pad of cellite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column to provide the desired product.

Example 1

Synthesis of Dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl) phenyl) hydrazine-1,2-dicarboxylate

(18) ##STR00007##

(19) Yield: 80%; colorless liquid .sup.1H NMR (200 MHz, CDCl.sub.3): 1.22-1.29 (t, J=7.0 Hz, 3H), 4.08-4.20 (q, J=7.0 Hz 2H), 5.10-5.27 (S, 4H). 7.0-7.4 (m, 14H); .sup.13C NMR (50 MHz, CDCl.sub.3): 14.2, 63.0, 67.2, 83.0, 89.1, 105.5, 113.0, 118.3, 127.0, 128.5, 132.1, 136.6, 146.8, 152.3, 155.5, 157.2

Example 2

Synthesis of Dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethoxyphenyl)hydrazine-1,2-dicarboxylate

(20) ##STR00008##

(21) Yield: 85%; gummy liquid .sup.1H NMR (200 MHz, CDCl.sub.3): 1.24-1.28 (t, J=7.0 Hz, 3H), 3.9 (S, 6H), 4.10-4.24 (q, J=7.0 Hz 2H), 5.12-5.28 (S, 4H); .sup.13C NMR (50 MHz, CDCl.sub.3): 14, 58, 64, 68, 83, 88, 97, 100, 120, 128, 129, 137, 140, 150, 153, 156.

Example 3

Synthesis of dibenzyl 1-(6-(3-ethoxy-3-oxoprop-1-yn-1-yl) benzo[d][1,3]dioxol-5-yl)hydrazine-1,2-dicarboxylate

(22) ##STR00009##

(23) Yield: 82%; colorless liquid .sup.1H NMR (200 MHz, CDCl.sub.3): 1.26 (t, J=7.1 Hz, 3H), 4.20 (q, J=7.1 Hz 2H), 5.21 (s, 4H), 6.02 (s, 2H) 6.82-7.43 (m, 12H); .sup.13C NMR (50 MHz, CDCl.sub.3): 14.4, 62.1, 66.5, 84.0, 92.3, 99.1, 120.2, 126.5, 127.3, 128.9, 134.5, 149.6, 150.1, 152.1, 156.4.

Example 4

Synthesis of dibenzyl 1-(2-(3-ethoxy-3-oxoprop-1-yn-1-yl)-4,5-dimethylphenyl)hydrazine-1,2-dicarboxylate

(24) ##STR00010##

(25) Yield: 78%; colorless liquid .sup.1H NMR (200 MHz, CDCl.sub.3): 1.27 (t, J=7.2 Hz, 3H), 2.21 (s, 3H), 2.30 (s, 3H), 4.1-4.3 (q, J=7.2 Hz, 2H), 5.2 (S, 4H). 6.9-7.5 (m, 12H); .sup.13C NMR (50 MHz, CDCl.sub.3): 13.2, 18.2, 18.8, 62.1, 66.7, 82.0, 90.0, 102.0, 111.0, 127.1, 127.6, 128.9, 133.7, 152.0, 156.0, 157.2.

ADVANTAGES OF INVENTION

(26) 1. No use of activated systems, one step and cheap process. 2. MCR helps to increase efficiency of synthetic organic routes to make a feasible process by reducing reaction time and their side products. 3. The ortho alkynyl anilines are the key intermediate for substituted indoles; 3, 4-hydroquinolinones which are useful scaffold for synthesis of various drugs and natural products and other heterocycles.