WO2017163263A1

WO2017163263A1 - Indole derivatives, preparation and use thereof

Info

Publication number: WO2017163263A1
Application number: PCT/IN2017/050102
Authority: WO
Inventors: Arumugam Sudalai; Pragati Kishore PRASAD; Rupali Gundappa KALSHETTI; Rambabu REDDI
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2016-03-22
Filing date: 2017-03-21
Publication date: 2017-09-28
Anticipated expiration: 2018-09-22

Abstract

The present invention provides novel indole derivatives of formula (I), I Wherein, R, R1 and R2 is independently selected from halo, nitro, methoxy, alkyl, thiomethyl, alkyl, aryl, substituted aryl, cyano, cycloalkyl, -COO, amide; and X is selected from N or S; a one pot, room temperature process for the preparation of novel indole derivatives of formula (I) with high yields and use of compounds of formula I for the synthesis of anti-diabetic drugs.

Description

INDOLE DERIVATIVES, PREPARATION AND USE THEREOF

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:

The present invention relates to novel indole derivatives, its preparation and use thereof. BACKGROUND AND PRIOR ART OF THE INVENTION:

Indole is one of the most popular heterocyclic scaffolds in nature. The challenging molecular architectures of polycyclic, naturally occurring indolyl compounds constitute a continuous stimulus for development in organic synthesis. The field had a formidable boom across the new millennium when catalysis started revolutionizing the chemistry of indole, providing always more sustainable solutions to the selective functionalization of this pharmacophore.

However, in nature, it is common to encounter indolyl-containing species featuring specific interatomic connections that would be difficult to be obtained via "conventional" indole reactivity. In this direction, the availability of efficient synthetic methodologies for the treatment of "electrophilic" indoles will allow to significantly improve the current synthetic portfolio for indole manipulation.

Amines are commonly used as starting substrates for the synthesis of indoles. An amine at position 3 may be diazotized with N2C1 and then reacted to form an azide, but such an amine is not known, though amine at position 2 or 5 is known.

WO 2001081306 A2 provides a method of making a compound of formula (II):

an intermediate in the synthesis of a compound of formula (X) ; wherein R2 is R20, - OR20, -SR20, -NR20R20', -C(O)OR20, or -C(O)R20; R3, R4, R5, R6 and R7 are each individually H, halogen, R, -OR, -SR, -NRR', -C(0)R, -C(0)OR, -S(0)R or - S(0)2R; provided that at least one of R4 and R5 is not H; each R, RIO and R20 is individually alkyl, alkenyl, alkynyl, aryl or heterocyclic radical; and each R' and R20' is individually H, alkyl, alkenyl, alkynyl, aryl or heterocyclic radical.

Book Titled, "Nitrogenation Strategy for the Synthesis of N-containing Compounds" edited by Ning Jiao published by springer reports the following reaction Scheme:

Scheme: A

US 6984657 B 1 discloses a compo ,

wherein: R¹ is hydrogen, halo, methyl, ethyl or methoxy; R² is hydrogen, halo, methyl, ethyl or methoxy; R³ is a halo group, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, trifluoromethyl, nitro, cyano, trifluoromethoxy, C(0)R⁷, or S(0)_nR⁷ where n is 0, 1 or 2 and R⁷ is an alkyl group; R⁴ is a halo, trifluoromethyl, methylthio, methoxy, trifluoromethoxy or lower alkyl, lower alkenyl or lower alkynyl or COR⁸ where R⁸ is lower alkyl; R⁶ is hydrogen, halo, lower alkyl, lower alkenyl, lower alkynyl or COR⁹ where R⁹ is lower alkyl; provided that when R¹ is hydrogen, halo or methoxy, R² is hydrogen, halo, methyl, ethyl or methoxy, R⁵ and R⁶ are both hydrogen, and one of R³ or R⁴ is not halo or trifluoromethyl; or a pharmaceutically acceptable salt or prodrug thereof. These compounds have useful activity for the treatment of inflammatory disease, specifically in antagonizing an MCP-1 mediated effect in a warm-blooded animal such as a human being.

US 20090181960 Al discloses a compound or a pharmaceutically acceptable salt thereof,

Wherein, L represents lower alkylene, lower alkenylene,— O-lower alkylene, lower alkylene-0— or a bond, in which each of the groups may be substituted by aryl(s);

represents an aryl, cycloalkyl or heterocyclic group ;Raaa, which is the same or different, represents hydrogen, lower alkyl, halogen, cyano, lower alkenyl, halogen- substituted lower alkyl, lower alkyl-0— , cyano lower alkyl-0— , halogen-substituted lower alkyl-0— , aryl, heteroaryl, aryl-0— , heteroaryl-0— , aryl lower alkyl, acyl- O— , acyl, heteroaryl lower alkyl-0— , lower alkylthio, lower alkylsulfonyl, oxo, nitro, amino, mono-lower alkylamino, di-lower alkylamino, acylamino or arylamino, in which the aryl, the heteroaryl, and the aryl and the heteroaryl moieties of each of the aryl-0— , heteroaryl-0— , heteroaryl lower alkyl-0— , aryl lower alkyl and arylamino in the Raaa may be substituted by lower alkyl(s), lower alkyl-O-(s), halogen(s) or halogen-substituted lower alkyl(s);R^ul, R²²², R³³³, R⁴⁴⁴, R⁵⁵⁵ and R⁶⁶⁶ represent hydrogen or an appropriate substituent, in which at least one of the R¹¹¹, R²²², R³³³, R⁴⁴⁴, R⁵⁵⁵ and R⁶⁶⁶ represents carboxy, carboxy-substituted lower alkyl or carboxy-substituted lower alkenyl, and any adjacent two groups of R³³³, R⁴⁴⁴, R⁵⁵⁵ and R⁶⁶⁶ together may form a lower alkylene dioxy group ;a double line of a solid line and a dotted line represents a single bond or a double bond; and p represents an integer of

1 to 15.

Article titled, "A facile approach to spirocyclic 2-azido indolines via azidation of indoles with eerie ammonium nitrate" by Jing Li et. al in Org. Biomol. Chem., 2014,12, 9769-9772 reports a process for azidation of indoles with NaN₃ and eerie ammonium nitrate (CAN) to obtain spirocyclic 2-azido indolines in good yields and moderate diastereoselectivities.

Scheme: B

Article titled, "Radical Azidonation of Aldehydes" by L. Marinescu, J. Thinggaard, I. B. Thomsen, M. Bols in J. Org. Chem. , 2003, 68 (24), pp 9453-9455 reports Aliphatic and aromatic aldehydes can be converted to acyl azides by treatment with iodine azide. If the reaction is performed at reflux, Curtius rearrangement occurs and carbamoyl azides are obtained directly from the aldehyde in good yield.

0 2 eq. I N, °

U — Jl 3 eq NaN _;, 2 eq. l CI -^H MeCN , 25°C , 2.5 h R N₃ MeCN , 0°C , ~ 1 0 m in

Scheme: C

Article titled, "Regiospecific Azidoiodination of Alkenes with Sodium Periodate,

Potassium Iodide, and Sodium Azide: A High- Yield Synthesis of β-Iodoazides" by P.

V. Chouthaiwale, P. U. Karabal, G. Suryavanshi, A. Sudalai in Synthesis, 2010, 3879-

3882 reports the combination of sodium periodate, potassium iodide, and sodium azide is an efficient, simple, and inexpensive reagent system for azidoiodination of alkenes. The regiospecific 1,2-azidoiodination proceeds in an anti-Markovnikov fashion to produce β-iodoazides in excellent yields.

1 eq. KI . 3 eq. NaN,

1 eq. N al0₄ ^" I

R ^¾

AcOH , 25°C , 2 h ^ JL N

"³ : Ar, a kyl

Scheme: D

From activity point of view, indolyl C-3 guanidines are known to bind with a putative 13 receptor (a 3rd imidazoline binding site distinct from two imidazoline receptors II and 12) in pancreatic β-cells and thereby regulate insulin secretion (Fig. A).

27 28 29

rapalexln A

Fig. A: Biologically active indolyl C-3 guanidines.

Therefore, it is the need to develop novel indole derivatives which can be used for the synthesis of anti-diabetic drugs.

OBJECTS OF THE INVENTION:

The main object of the present invention is to provide novel indole derivatives.

Another object of the present invention is to provide a process for the preparation of novel indole derivatives.

Yet another object of the present invention is to provide novel indole derivatives which can be used for the synthesis of anti-diabetic drugs.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides novel indole derivatives, preparation and use thereof. In an embodiment the present invention provides novel indole derivatives of formula

(I),

I

Wherein, R, R¹ and R² is independently selected from halo, nitro, methoxy, alkyl, thiomethyl, alkyl, aryl, substituted aryl, cyano, cycloalkyl, -COO, amide; and X is selected from N or S. In another embodiment the present invention provides a one pot, single step room temperature process for the preparation of novel indole derivatives of formula (I) with more than 85% yield.

In a preferred embodiment the present invention provides a process for the synthesis of compounds of formula Ia-n comprising the steps of:

a. Adding and Et₃N to a solution of indole compounds of formula Ila-n to obtain a mixture;

b. Adding NaN₃ to the mixture of step (a) to obtain the reaction mixture;

c. Quenching, extracting the reaction mixture of step (b) followed by purification to obtain 3-azidoindole derivatives of formula Ia-n.

In yet another embodiment, the present invention provides a process for the reduction of indoles of formula I comprising the steps of:

a. Adding Pd/C to a solution of indoles (I) to obtain the reaction mixture;

b. Extracting and purifying the reaction mixture of step (a) to afford 3 -amino indoles (IV).

In still another embodiment, the present invention provides a process for synthesis of trizolecompound of formula (VI),

from indole compound of formula (la),

and compound of formula (V),

comprising the steps of:

a. Adding phenylacetylene (V) to a solution of CuS0₄.5H₂0 and Na ascorbate in 'BuOH: H₂0 followed by the addition of azido indole la to obtain the reaction mixture;

b. Extracting and purifying the reaction mixture of step (a) to give pure triazole

VI.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In view of above, the present invention provides novel indole derivatives, preparation and use thereof.

In an embodiment the present invention rovides indole derivatives of formula (I),

I

Wherein, R, R^xand R² is independently selected from halo, nitro, methoxy, alkyl, thiomethyl, alkyl, aryl, substituted aryl, cyano, cycloalkyl, -COO, amide;andX is selected from N or S.

In another embodiment the present invention provides a one pot, room temperature, transition metal-free process for the preparation of novel indole derivatives of formula I with more than 85% yield.

In a preferred embodiment the present invention provides a process for the synthesis of compounds of formula Ia-n comprising the steps of: d. Adding I₂ and Et₃N to a solution of indole compounds of formula Ila-n to obtain a mixture;

e. Adding NaN₃ to the mixture of step (a) to obtain the reaction mixture;

f. Quenching, extracting the reaction mixture of step (b) followed by purification to obtain 3-azidoindole derivatives of formula Ia-n.

The above process is shown below in Scheme 1:

Ila-n la-n

Scheme: 1

c. Adding Pd/C to a solution of indoles (I) to obtain the reaction mixture;

d. Extracting and purifying the reaction mixture of step (a) to afford 3 -amino indoles (IV).

The above process is shown below in Scheme 2:

IV

Scheme: 2

from indole compound of formula (Ia),

and compound of formula (V),

comprising the steps of:

a. Adding phenylacetylene (V) to a solution of CuS0₄.5H₂0 and Na ascorbate in 'BuOH: H₂0 followed by the addition of azido indole (Ia) to obtain the reaction mixture;

b. Extracting and purifying the reaction mixture of step (a) to give pure triazole VI.

The above process is shown below in Scheme 3:

Scheme: 3 aspect, compound of formula Ia-n is selected from the following

3-Azido- lH-indole (Ia);

3-Azido-5-methyl-lH-indole (lb);

3-Azido-5-methoxy- lH-indole (Ic);

3-Azido-5-bromo-lH-indole (Id); 3-Azido-5-chloro-lH-indole (Ie);

3-Azido-5-nitro-lH- indole (If);

3-Azido- lH-indol-5-yl acetate (Ig);

3-Azido-2-methyl-lH-indole (Hi);

3-Azido-4-bromo-lH- indole (Ii);

3-Azido-2-phenyl- lH-indole (Ij);

Ethyl 3-azido-lH-indole-2-carboxylate (Ik);

3 -Azido- 1 -methyl- lH-indole (II);

1- Benzylindoline-2,3-dione (Im);

3-azido-5-nitro-lH-indazole (In).

In another aspect, compound of formula Ila-n is selected from the following

lH-indole (Da);

5-methyl- lH-indole (lib);

5-methoxy-lH- indole (lie);

5-bromo- lH-indole (IId);

5-chloro- lH- indole (He);

5-nitro- lH-indole (IK);

lH-indol-5-yl acetate (Ilg);

2- methyl- lH-indole (Ilh);

4-bromo- lH-indole (IIi);

2-phenyl-lH-indole (Ilj);

Ethyl- lH-indole-2-carboxylate (Ilk);

1 -methyl- lH-indole (III) ;

1 -Benzylindole(IIm) ;

5-nitro- lH-indazole (Iln).

In another aspect, the present invention provides compound of formula I which is used for the synthesis of anti-diabetic drugs selected from Rapalexin A. The cited prior art WO 2001081306 A2 provides a method of making a compound of formula:

and its use further to obtain morpholino ester compound, which can acts as an ester type prodrug which is highly bioavailable upon oral administration.

But, the present invention provides novel compounds of formula I, its preparation and use for the synthesis of synthesis of anti-diabetic drugs. Examples: Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Example: 1

General experimental procedure for the preparation of compounds Ia-n:

To a stirred solution of indole compounds Ila-n (3 mmol) in dry DMSO (25 mL) at 0 °C was added I₂ (3 mmol) and Et₃N (3 mmol) dropwise. After 5 min, NaN₃ (3.6 mmol) was added portionwise. The reaction mixture was then stirred at 25 °C under an inert atmosphere for 6-8 h. After completion of the reaction (as monitored by TLC), it was quenched with H₂0 (20 mL) at 0 °C. It was then extracted with EtOAc (3 x 50 mL) followed by washing with brine (3 x 50 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. Concentration of organic solvent under reduced pressure gave the crude product, which was further purified by column chromatography over silica gel using Pet. ethenEtOAc (9:1) as eluent to obtain 3- azidoindole derivatives Ia-n in high purity.

Example 2

3-Azido-lH-indole (la)

Yield: 94% (0.445 g); yellow colored solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax764, 825, 1025, 1468, 1657, 2127, 2254, 3424; ¾ NMR (400 MHz, DMSO- ): δ 7.09-7. 14 (m, 1H), 7. 15-7.21 (m, 1H), 7.42 (t, = 8.6 Hz, 2H), 7.54 (s, 1H), 11.45 (br. s., 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 88.7, 1 12.1, 1 17.9, 1 19.8, 122.2, 124.7, 126.1, 135.4; MALDI-MS: calcd for C₈H₆NaN₄ ⁺ [M + Na⁺] 181.0485, found 181.0478.

Example 3

3-Azido-5-methyl-lH-indole (lb)

Yield: 95% (0.490 g); orange colored solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax767, 821 , 1024, 1468, 1654, 2123, 2252, 3426; ¾ NMR (400 MHz, DMSO-d₆): δ 2.24 (s, 3H), 6.88 (s, 1H), 7. 12-7.18 (m, 1H), 7.37 (d, = 6.8 Hz, 1H), 7.40-7.45 (m, 1H), 10.95 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 21.5, 92.4, 109.2, 123.7, 123.9, 124.1, 127.3, 131.8, 142.8; MALDI-MS: calcd for C₉H₈N₄Na⁺ [M + Na⁺ ] 195.0641 , found 195.0644.

Example 4

3- Azido-5-methoxy-lH- indole (Ic)

Yield: 92% (0.520 g); colorless solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax762, 824, 1026, 1206, 1490, 1658, 1737, 2125, 2251 , 3425; ^lH NMR (200 MHz, DMSO- ): δ 3.43 (s, 3H), 6.76-6.89 (m, 2H), 7.26-7.38 (m, 1H), 7.48 (d, = 2.7 Hz, 1H), 11.31 (br. s., 1H); ¹³C NMR (50 MHz, DMSO-d₆): δ 55.3, 88.3, 99.1, 1 12.7, 113.0, 125.1, 126.4, 130.4, 154.1 ; MALDI-MS: calcd for C₉H₈N₄ONa⁺ [M + Na⁺ ] 211.0590, found 211.0588.

Example 5 3-Azido-5-bromo-lH-indole (Id)

Yield: 96% (0.680 g); red colored solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax624, 760, 822, 1028, 1248, 1659, 2123, 2250, 3438; ^lH NMR (200 MHz, DMSO- ): δ 7.29 (dd, J = 8.6, 1.9 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.54 (d, / = 1.8 Hz, 1H), 11.68 (br. s., 1H); ¹³C NMR (50 MHz, DMSO-d₆): δ 87.8, 1 12.4, 1 14.2, 120.1, 124.8, 126.5, 127.9, 134.1 ; MALDI-MS: calcd for C₈H₅N₄BrNa⁺ [M + Na⁺ ] 258.9590, found 258.9592.

Example 6

3-Azido-5-chloro-lH-indole (Ie)

Yield: 91% (0.525 g); yellow colored solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): v_max624, 760, 822, 1027, 1659, 2124, 2250, 3438; ^lH NMR (400 MHz, DMSO- d₆): δ 7.16-7.21 (m, 1H), 7.40 (s, 1H), 7.46 (d, = 8.2 Hz, 1H), 7.59-7.71 (m, 1H), 11.69 (br. s., 1H); ¹³C NMR (50 MHz, DMSC fc): δ 88.0, 1 13.8, 1 17.0, 122.3, 124.6, 126.7, 127.2, 133.9; MALDI-MS: calcd for C₈H₅ClN₄Na⁺ [M + Na⁺ ] 215.0095, found 215.0097. Example 7

3-Azido-5-nitro-lH-indole (If)

Yield: 89% (0.540 g); red colored solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax763, 825, 1025, 1338, 1531, 1658, 1733, 2127, 2254, 3424; ¾ NMR (400 MHz, DMSC fc) δ 7.60-7.67 (m, 1H), 7.87 (d, = 1.4 Hz, 1H), 8.03-8.12 (m, 1H), 8.28-8.38 (m, 1H), 12.21 (br. s., 1H); ¹³C NMR (100 MHz, DMSC fc): δ 91.0, 1 13.0, 115.0, 117.5, 125.7, 129.1, 138.6, 141.4; MALDI-MS: calcd for C₈H₅N5C>2Na⁺ [M + Na⁺] 226.0335, found 226.0336.

Example 8

3-Azido-lH-indol-5-yl acetate (Ig)

Yield: 90% (0.582 g); colorless solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax766, 823, 1021, 1650, 1733, 2121, 2252, 3429; ^lH NMR (200 MHz, DMSO-d₆): δ 2.32 (s, 3H), 6.98 (s, 1H), 7.12 (m, 2H), 7.44 (d, = 2.6 Hz, 1H); ¹³C NMR (50 MHz, DMSC fc): δ 21.1, 91.2, 109.3, 1 1 1.5, 1 19.1, 123.8, 126.9, 135.6, 145.2, 169.2; MALDI-MS: calcd for CioH₈N₄0₂Na ⁺ [M + Na⁺ ] 239.0539, found 239.0537.

Example 9

3-Azido-2-methvl-lH-indole (Ih)

Yield: 88% (0.455 g); colorless solid; mp: 30 °C (decomposes); IR (DMSO-d₆, cm^"1): Vmax761 , 822, 1021, 1463, 1651, 2125, 2251, 3427; ^lH NMR (200 MHz, DMSO-d₆): δ 2.28 (s, 3H), 7.12-7.26 (m, 2H), 7.37-7.56 (m, 2H); ¹³C NMR (100 MHz, DMSO- d₆): δ 20.3, 91.7, 109.5, 123.3, 123.6, 124.5, 127.1, 131.6, 142.1 ; MALDI-MS: calcd for C₉H₈N₄Na ⁺ [M + Na⁺ ] 195.0641, found 195.0640.

Example 10:

3-Azido-4-bromo-lH-indole (Ii):

Yield: 81% (195 mg), colorless solid, mp: 60 °C decomposed; ¾ NMR (200 MHz, DMSO-4) δ 1 1.85 (br. s., 1H), 7.66 (d, = 2.7 Hz, 1H), 7.48 (d, = 8.1 Hz, 1H), 7.27 (d, = 6.8 Hz, 1H), 6.99 - 7.11 (m, 1H); ¹³C NMR (50 MHz, DMSO-d₆) δ 136.7, 127.6, 124.4, 123.2, 122.3, 112.3, 112.1, 87.7; HRMS (ESI): [M+H]⁺ calcd for [C₈H₅BrN₄+H]⁺: 236.9776; found: 236.9771.

Example 11:

3-Azido-2- henyl-lH-indole (Ij):

Yield: 87% (210 mg), brown solid, mp: 60°C decomposed; ¾ NMR (200 MHz, DMSO- ) δ 1 1.87 (s, 1H), 7.85-7.93 (m, 2H), 7.51-7.60 (m, 2H), 7.41-7.48 (m, 3H), 7.09-7.27 (m, 2H);¹³C NMR (50 MHz, DMSC fc) δ 134.7, 133.4, 130.3, 127.9, 127.5, 126.9, 122.2, 119.5, 117.6, 111.1, 86.8, 38.7; HRMS (ESI): [M+H]⁺ calcd for [Ci₄HioN₄+H]⁺: 235.0984; found: 235.0986.

Example 12:

Eth l 3-azido-lH-indole-2-carboxylate (Ik):

Yield: 89% (216 mg), colorless solid, mp: 60°C decomposed; ^lH NMR (400 MHz, MeOH-d₄) δ 7.93 (d, = 8.2 Hz, 1H), 7.85 (d, = 8.7 Hz, 1H), 7.71 (t, = 7.8 Hz, 1H), 7.46-7.61 (m, 1H), 4.77 (q, = 7.0 Hz, 2H), 1.78 (t, = 7.1 Hz, 3H);¹³C NMR (100 MHz, MeOH-d₄) δ 161.9, 137.5, 128.8, 127.4, 125.6, 122.5, 121.7, 1 14.1, 97.8, 62.3, 40.0, 15.1 ; HRMS (ESI): [M+H]⁺ calcd for [CiiHioN₄0₂+H]⁺: 231.0882; found: 231.0885.

Example 13:

3-Azido-l-methyl-lH-indole (II):

Yield: 54% (93 mg), colorless oil ; *H NMR (200 MHz, DMSO-d₆) δ 7.34-7.62 (m, 3H), 7.06-7.30 (m, 2H), 3.77 (s, 3H);¹³C NMR (50 MHz, DMSO-d₆) δ 135.54, 128.2, 126.0, 121.8, 119.5, 117.8, 109.9, 87.0, 39.9, 39.1, 38.7, 38.3, 32.8; HRMS (ESI):

[M+H]⁺ calcd for [C₉H₈N₄+H]⁺: 173.0827; found: 173.0831.

Example 14:

l-Benzylindoline-2,3-dione (Im):

Yield: 60% (142 mg), orange solid, mp. 135-136 °C; ¾ NMR (200 MHz,CDCl₃) δ 7.60-7.66 (m, 1H), 7.44-7.55 (m, 1H), 7.31-7.38 (m, 5H), 7.12 (d, = 8.2 Hz, 1H), 6.78 (d, = 8.0 Hz, 1H), 4.95 (s, 2H);¹³C NMR (100 MHz, CDC1₃) δ 183.2, 158.3, 150.7, 138.3, 134.5, 129.1, 128.2, 127.4, 125.4, 123.9, 117.7, 110.9, 44.1; HRMS (ESI): [M+H]⁺ calcd for [Ci5HnN0₂+H]⁺: 238.0868; found: 238.0872.

Example 15:

3-azido-5-nitro- lH-indazole (In) :

Yield: 60% (135 mg), colorless solid, mp: 60 °C decomposed; ¾ NMR (400 MHz, DMSO-4) δ 8.46 (d, = 1.8 Hz, 1H), 8.25 (dd, = 9.2, 1.8 Hz, 1H), 7.77 (d, = 9.2 Hz, 1H);¹³C NMR (100 MHz, DMSC fc) δ 142.9, 142.3, 123.7, 122.3, 121.5, 117.1, 112.2; HRMS (ESI): [M+H]⁺ calcd for [C₇H₄N₆0₂H+]⁺: 205.0474; found: 205.0469. Example 16:

Procedure for the reduction of azido indoles:

To a stirred solution of azido indoles If and Ij (1 mmol) in degassed MeOH (6 mL), was added Pd/C (10 wt %) at 25 °C and the reaction mixture was then stirred at 25 °C under H₂ (1 atm) atmosphere for 5 h. After completion of the reaction (as monitored by TLC), the reaction mixture was filtered over celite bed, washed with methanol (25 mL). Concentration of organic solvent under reduced pressure gave the crude product, which was purified by column chromatography over silica gel using pet. ether /EtOAc (7:3) as eluent to afford 3-amino indoles IVf and IVj in high purity.

Example 17:

5-nitro-lH-indol-3-amine (IVf):

Yield: 92% (200 mg), brown sticky gum; ¾ NMR (200 MHz, CDC1₃) δ 10.83-11.03 (m, 1H), 7.56 (br. s., 1H), 7.40-7.50 (m, 1H), 7.28 (br. s., 1H), 7.09 (br. s., 1H), 6.35- 6.45 (m, 2H);¹³C NMR (50 MHz, CDCI3) δ 133.6, 126.7, 125.5, 122.9, 114.2, 112.3, 111.2, 100.1, 38.6; HRMS (ESI): [M+H]⁺ calcd for [C₈H₈N30₂H+]⁺: 178.0617; found: 178.0620.

Example 18:

2-phenyl-lH-indol-3-amine (IVj):

Yield: 92% (198 mg), gum; ¾ NMR (400 MHz, DMSO-d₆) δ 6.69 (t, = 7.6 Hz, 1H), 6.93-7.03 (m, 2H), 7.27-7.39 (m, 2H), 7.46 (t, = 7.6 Hz, 3H), 7.64-7.70 (m, 2H), 11.18 (s, 1H);¹³C NMR (100 MHz, DMSC fc) δ 136.1, 134.4, 133.1, 128.8, 128.7, 128.2, 127.3, 121.2, 119.2, 118.5, 111.1, 110.8; HRMS (ESI): [M+H]⁺ calcd for [Ci₄Hi₂N₂+H]⁺: 209.1079 ; found: 209.1084.

Example 19:

Procedure for synthesis of trizole from azido indole:

To a stirred solution of CuS0₄.5H₂0 (5 mol %), Na ascorbate (20 mol %) in T3uOH: H₂0 (1: 1), was added phenylacetylene (V) (1 mmol) followed by the addition of azido indole (la) (1 mmol) at 25 °C. The reaction mixture was then stirred at room temperature in open air for 6 h. After completion of the reaction (6 h), the reaction mixture was concentrated under reduced pressure to remove ¾uOH. The aqueous layer was then extracted with EtOAc (3 x 20 mL) followed by washing with brine (3 x 20 mL) and the combined organic layers were dried over anhydrous Na₂S0₄. Concentration of EtOAc under reduced pressure gave the crude product which was purified by column chromatography with pet. ether: ethyl acetate (7:3) as eluent to give pure triazole VI in 78% yield.

Example 20:

3-(4-phenyl-lH-l,2,3-triazol-l-yl)-lH-indole (VI): Yield: 92% (245 mg), amber colored gum; ¾ NMR (400 MHz, CDC1₃) δ 8.28 (br. s., 2H), 8.02 (d, = 7.8 Hz, IH), 7.65 (d, = 8.2 Hz, IH), 7.37-7.48 (m, 4H), 7.24-7.34 (m, 4H), 7.10-7.21 (m, 3H), 6.80 (d, = 1.8 Hz, IH); ¹³C NMR (100 MHz, CDCI3) δ 136.5, 136.1, 133.2, 129.5, 125.4, 122.9, 121.4, 121.4, 120.8, 119.9, 119.9, 111.5, 110.5, 99.4; HRMS (ESI): [M+H]⁺ calcd for [Ci₆Hi₂N₄H+]⁺: 261.1140; found: 261.1146.

Example 21:

Rapalexin A (29)

IR (KBr, cm-¹! _max: 3399, 2072, 1592, 1508, 1280, 1100, 1075, 774, 729.

*H NMR (500 MHz, CDCI3) δ 7.94 (IH, s), 7.27 (IH, s), 7.16 (IH, dd, J = 8, 8 Hz), 7.07

(IH, d, J = 3 Hz), 6.94 (IH, d, J = 8 Hz), 6.57 (IH, d, J = 8 Hz), 3.98 (3H, s).

Advantages of the invention:

a. Novel compounds which is used for synthesis of anti-diabetic drugs b. Novel azido indoles which can be used for the synthesis of biologically active molecules like RapalaxinA, Rapalexin B, Isocyalexin A, etc. having anti- carcinogenic properties.

c. A one pot, room temperature metal free synthesis process.

Claims

The claims:

1. Compound of formula I,

Wherein, R, R^xand R² is independently selected from halo, nitro, methoxy, alkyl, thiomethyl, alkyl, aryl, substituted aryl, cyano, cycloalkyl, -COO, amide; and

X is selected from N or S .

The compound of formula I as claimed in claim 1, wherein said compound of formula I is selected from the following:

3-Azido- lH-indole (la);

3-Azido-5-methyl-lH-indole (lb);

3-Azido-5-methoxy- lH-indole (Ic);

3-Azido-5-bromo-lH- indole (Id);

3-Azido-5-chloro-lH-indole (Ie);

3-Azido-5-nitro-lH- indole (If);

3-Azido- lH-indol-5-yl acetate (Ig);

3-Azido-2-methyl-lH-indole (Hi);

3-Azido-4-bromo-lH- indole (Ii);

3-Azido-2-phenyl- lH-indole (Ij);

Ethyl 3-azido-lH-indole-2-carboxylate (Ik);

3 -Azido- 1 -methyl- lH-indole (II);

l-Benzylindoline-2,3-dione (Im);

3 - azido- 5 -nitro- 1 H-indazole (In) .

A one-pot process for the synthesis of compound of formula I as claimed in claim 1, wherein said process comprises the steps of:

a. adding 12 and Et3N to a solution of compounds of formula II,

Wherein, R, R^xand R² is independently selected from halo, nitro, methoxy, alkyl, thiomethyl, alkyl, aryl, substituted aryl, cyano, cycloalkyl, -COO, amide;

to obtain a mixture;

b. adding NaN3 to the mixture of step (a) to obtain the reaction mixture; c. quenching, extracting the reaction mixture of step (b) followed by purification to obtain compounds of formula I.

4. The process as claimed in claim 1, wherein the yield of compounds of formula I is more than 85%.

5. A process for the synthesis of compound IV,

IV

from compounds of formula I as claimed in claim 1, wherein said process comprises the steps of:

a. Adding Pd/C to a solution of compound of formula I to obtain the reaction mixture;

b. Extracting and purifying the reaction mixture of step (a) to afford

compound of formula IV.

6. A process for the synthesis of compound of formula VI,

from compound of formula la,

is.

claimed in claim 1, wherein said process comprises the steps of:

a. Adding phenylacetylene to a solution of CuS0₄.5H₂0 and Na ascorbate in ¾uOH: H₂0 followed by the addition of azido indole of formula la to obtain the reaction mixture;

b. Extracting and purifying the reaction mixture of step (a) to give pure compound of formula VI.