Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See sections 10 & rule 13)
1. TITLE OF THE INVENTION
A METHOD FOR SYNTHESIZING N-FORMYLATED AMINES USING CO2 AS A GREEN FEEDSTOCK
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
INDIAN INSTITUTE OF TECHNOLOGY ROORKEE IN Roorkee- 247667, Uttarakhand, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION

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

FIELD OF INVENTION:
[001] The present invention relates to the field of N-formylated amines. The present invention in particular relates to a method for synthesizing N-formylated amines using CO2 as a green feedstock.
DESCRIPTION OF THE RELATED ART:
[002] Carbon dioxide (CO2) plays a crucial role in organic synthesis, serving as both a versatile reagent and a sustainable alternative to more toxic or environmentally harmful chemicals. Its importance in organic chemistry has gained significant attention due to its abundance, low cost, and relatively benign nature. It is an excellent source of carbon for a wide range of reactions, particularly in the formation of C-N or C-S bonds, formamide, and methylamine. These reactions are key to the synthesis of various organic compounds, including pharmaceuticals, agrochemicals, and specialty materials. Furthermore, CO2 is increasingly recognized for its potential to contribute to green chemistry by offering environmentally friendly pathways. Classical approach for selective N-formylation of different organic motifs requires the use of hazardous formylating agents. To overcome the use of hazardous agents, CO2 is utilized with hydrides such as hydrosilane or hydroborane as reducing agents.
[003] Reference may be made to the following:
[004] Publication no. US198774751A relates to the amine nitrogen of an amino carboxylic acid is formylated by reacting the amino carboxylic acid with formamide. N-Formylation of amine carboxylic acids is affected by heating a suspension of amine carboxylic acid in formamide at 50-100 oC.
[005] Publication no. US200054012A relates to the N-hydroxylamine to an N-hydroxyformamide comprising reacting the N-hydroxylamine with 2,2,2-trifluoroethylformate in an optionally buffered solvent.
[006] The N-formylation of amines with CO2 requires a reductant through a 2e- reduction process to yield a formamide product. Modern catalysis demands the use of more affordable catalysts, and atom-efficient for alkylation procedures using green and renewable carbon sources. Recently N-formylation of amines requires high temperature, high catalyst loading, high pressure of CO2, and a long-time interval for the transformation. In addition to this, hydrosilane is required to carry out a 2e- reduction process to yield an N-formylated product. These transformations can be classified as homogeneous and heterogeneous catalysis, organo-catalysis, and solvent-promoted conditions.
[007] Thus traditional methods for N-formylation of amines often involve hazardous or non-renewable reagents such as formic acid, dimethyl sulfate, and paraformaldehyde. Conventional methods often lack selectivity or fail in the presence of sensitive functional groups.
[008] The use of bench-stable metal catalysts and readily available ligands is not much explored. N-formylation of amides, nitro compounds, using CO2 using hydroborane or hydrosilane is still a challenging task.
[009] However, to overcome these problems, there is a selective metal-ligand combination that transforms various organic motifs into the corresponding alkylated products.
[010] In order to overcome above listed prior art, the present invention aims to provide an efficient and selective method of synthesizing N-formylation amines using CO2 as the carbon source, catalyzed by a nickel-based system.
OBJECTS OF THE INVENTION:
[011] The principal object of the present invention is to provide an efficient and selective method for the N-formylation of amines using CO2 as the carbon source, catalyzed by a nickel-based system.
[012] Another object of the present invention is to provide a method that converts primary and secondary amines, nitrobenzene, and amide into valuable N-formylated derivatives.
[013] Yet another object of the present invention is to cost-effective and environmentally friendly methods for synthesizing APIs (active pharmaceutical ingredients), intermediates, and fine chemicals involving formylated amines.
[014] Still another object of the present invention is to provide a compliance friendly, sustainable alternative to outdated methods for Industries via adopting a greener practice.
SUMMARY OF THE INVENTION:
[015] The present invention relates to an efficient and selective method for the N-formylation of amines using CO2 as the carbon source, catalyzed by a nickel-based system. The Ni-catalyst demonstrated high activity under mild reaction conditions, offering a practical approach to access N-N-formylated amines, which are important motifs in pharmaceuticals and fine chemicals. The transformation proceeds via a reductive pathway in the presence of a suitable hydride donor, leading to high yields with excellent functional group tolerance. This protocol represents a promising advancement in CO2 fixation chemistry, highlighting the potential of nickel catalysts in sustainable amine functionalization.
[016] N-formylation of amines is the crucial component of the reaction, which is widely used to produce pharmaceuticals and key intermediates. A catalyst composed of 3d metal with a Nitrogen-based ligand was effective in the N-formylation of amine using CO2 as a readily available C1 source in the presence of trimethylammonia bornane.
BREIF DESCRIPTION OF THE INVENTION
[017] It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered for limiting of its scope, for the invention may admit to other equally effective embodiments.
[018] Fig.1 shows scope of N-formylation of amine.
[019] Fig.2 shows reaction condition.
[020] Fig. 3 shows 3,4-dihydroquinoline-1(2H)-carbaldehyde (2).
[021] Fig. 4 shows 2-oxoazepane-1-carbaldehyde (15):22.
DETAILED DESCRIPTION OF THE INVENTION:
[022] The present invention provides an efficient and selective method for the N-formylation of amines using CO2 as the carbon source, catalyzed by a nickel-based system. N-formylation of amine is optimized with CO2 using tetrahydroquinoline as a model substrate. We started the screening for the synthesis of N-formylation of amines using several Ni catalysts and DpePhos as a ligand and ended with a 28% of formylated product. Furthermore, a series of nitrogen and phosphine-based ligands were optimized and the best result was obtained using NiCl2.DME, and 4,4’-diMe-Bpy in combination with Me3N.BH3 as reducing agent in the presence of atmospheric CO2 ended with 98% of the formylated product. Screening of various polar and non-polar solvents (THF, toluene, 1,4-dioxane, DMF, etc.) shows that DMSO gave the best result for N-formylation of amines, while the other solvent resulted only in a trace amount of desired product. By cutting the time interval of the reaction to 6 h, it ended with a better result. The optimization of reaction condition is given in table 1.

Entry Deviation from the above Yields of 2 (%)
1 none 28
2 NiCl2 10
3 NiBr2 14
4 NiBr2.DME 9
5 Ni(acac)2 trace
6 NiBr2.diglyme trace
7 L2 instead of L1 32
8 L3 instead of L1 52
9 L4 instead of L1 58
10 L5 instead of L1 67
11 L6 instead of L1 75
12 L7 instead of L1 98
13 L8 instead of L1 69
14 toluene trace
15 THF 3
16b 6h 98(96)*
[023] Table 1. aReaction condition: a 1a (0.25 mmol), NiCl2.DME (0.0125 mmol), DPEphos (0.015 mmol), and Me3N.BH3 (0.75 mmol) in DMSO (1.0 mL) in a high-pressure tube under atmospheric CO2 at 80 °C in a preheated oil bath for 24 h. b 6 h, Isolated yield. L1= DPEphos, L2 = Xhenphos, L3 = RuPhos, L4 = CyJhonPhos, L5 = 2,9-dimethylphenanthroline, L6 = 4,4’-ditBu-Bpy, L7 = 4,4’-diMe-Bpy, L8 = 1,10-Phenanthroline.
[024] After having optimization condition in hand, it is extended to various sterically hindered substrate scopes under the standard catalytic condition. Amines containing cyclopropyl (3) and cyclohexyl (5) resulted in corresponding formylated products in a range of 73-93% isolated yield. Furthermore, disubstituted amine undergoes N-formylation to encounter the desired product (4) in 63% isolated yield.
[025] In the case of nitro derivatives, an N-formylated product is received via in-situ reduction of nitro to the amine group using 5.0 equiv. of PhSiH3, 8.0 bar of CO2 at 110 °C observed excellent yields up to 89% were obtained. Successively, starting with various nitro derivatives containing different functionalities such as p-methyl (7), p-methylenedioxy (8), m-trifluoromethyl (9), and m-acetyl (10) were obtained in a range of 66-87% isolated yield (Scheme 1). The success in N-formylation of amines and nitro derivatives expands the substrate scope to primary amides.
[026] The N-formylation of primary amides has been analyzed with a slight change in the reaction condition. To check the reactivity for various functional groups, the case of p-methoxy(11), p-acetyl(12), p-fluoro(13), nicotinamide(14), and caprolactam (15) is formed desired product up to 93% yield (Figure 1).
[027] Figure 1 shows the scope of N-formylation of amine. aReaction condition: a1a (0.25 mmol), NiCl2.DME (0.0125 mmol), 4,4’-diMe-Bpy (0.015 mmol), and Me3N.BH3 (0.75 mmol) in DMSO (1.0 mL) in a high-pressure tube under atmospheric CO2 (1.0 atm.) at 80 °C in a preheated oil bath for 6 h. b PhSiH3 (1.25 mmol), CO2 pressure (8.0 atm.), 110 °C, 24 h. Figure 2 shows reaction condition: a1a (0.25 mmol), NiCl2.DME (0.0125 mmol), 4,4’-diMe-Bpy (0.015 mmol), and Me3N.BH3 (0.75 mmol) in DMSO (1.0 mL) in a high-pressure tube under atmospheric CO2 (1.0 atm.) at 80 °C in a preheated oil bath for 6 h.
[028] Further, the reactivity of more challenging drug derivatives has been analyzed. Notably, the coupling of various late-stage functionalized molecules undergoes N-formylation in standard conditions. The late-stage derivatization of lepidine (16), citronellol (17), sesamol (18), oleic acid derivative (19), butamben (20), ibuprofen derivative (21), mequinol derivative (22), indomethacin derivative (23), and ciprofloxacin (24) are analyzed which was transformed into N-formylated product in almost quantitative yield.
[029] 3,4-dihydroquinoline-1(2H)-carbaldehyde (2):
[030] The title compound was isolated as a colorless liquid eluting with 10% ethyl acetate in hexane (96%, 38.0 mg). 1H NMR (500 MHz, CDCl3) d 8.72 (s, 1H), 7.19 – 6.97 (m, 4H), 3.77 – 3.71 (m, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.89 (dt, J = 12.9, 6.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) d 161.2, 137.3, 129.7, 129.0, 127.2, 124.7, 117.1, 40.4, 27.2, 22.4. (figure 3).
[031] 2-oxoazepane-1-carbaldehyde (15):22
[032] The title compound was isolated as a colorless liquid eluting with 25% ethyl acetate in hexane (52%, 19.0 mg) 1H NMR (500 MHz, CDCl3) d 9.32 (s, 1H), 3.74-3.70 (m, 2H), 2.63-2.60 (m, 2H), 1.75-1.71 (m, 4H), 1.61 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) d 178.1, 162.3, 40.3, 38.4, 29.6, 28.7, 23.6 (figure 4).
[033] The proposed catalytic system has high selectivity for mono N-formylated products and a broad substrate scope, enhancing its practical utility in synthetic and pharmaceutical chemistry. This enables the eco-friendly synthesis of N-formylated amines, which are crucial scaffolds in many active pharmaceutical ingredients such as antidepressants, and anticancer drugs.
[034] Thus this provides an approach for carbon capture and utilization by converting CO2 into valuable chemical products, applicable for preparing intermediate compounds in dye, perfume, and flavor industries.
[035] This method is helpful in developing functionalized amine-based agrochemicals like herbicides and growth regulators. This process uses non-precious Ni-catalyst and Nitrogen-based bench stable ligands to carry out N-formylation. Moreover, this process involves the reduction of CO2 to corresponding N-formylated products. Also, this provides the method to synthesize N-formylated drug derivatives, which have wide applications in medicinal chemistry.
[036] The invention utilizes CO2 for the synthesis of essential chemicals. The invention reduces the formation of unwanted side products.
[037] The use of 3d nonprecious metal for the synthesis of N-formylated amines. (Previously, Pt-metal, Pd-metal, and Ru-metal, expensive and air/moisture sensitive metals, are used for the synthesis of N-formylated amines).
[038] Me3N.BH3 is used which is a safe and cheap hydrogen source for the catalytic reduction of CO2 to the corresponding N-formylated product. (Previously high pressure of H2 gas and air/moisture sensitive H-source is used to carryout this transformation).
[039] This invention provides a novel method for the N-formylation of amines using a catalytic system that is efficient, mild, and broadly applicable.
[040] Numerous modifications and adaptations of the system of the present invention will be apparent to those skilled in the art, and thus it is intended by the appended claims to cover all such modifications and adaptations which fall within the true spirit and scope of this invention.
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, Claims:WE CLAIM:
1. A method for synthesizing N-formylated amines using CO2 as a green feedstock catalyzed by a nickel-based system includes following steps:
a) In a clean oven-dried 15 mL pressure tube, tetrahydroquinoline (0.25 mmol, 1.0 equiv.), NiCl2.DME (0.0125 mmol), 4,4’-diMe-Bpy (0.015 mmol), Me3N.BH3 (0.75 mmol, 3.0 equiv.) was added, followed by DMSO (1.0 mL) were added.
b) After pressurizing with atmospheric pressure, CO2 and the reaction mixture were heated at 80 °C for 6 h in a closed system.
c) The reaction mixture was cooled to room temperature, and 3.0 mL of ethyl acetate was added and concentrated in vacuo.
d) The product was purified through column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give the pure product.
e) In a clean oven-dried 15 mL pressure tube, Nitrobenzene (0.25 mmol, 1.0 equiv.), NiCl2.DME (0.0125 mmol), 4,4’-diMe-Bpy (0.015 mmol), and PhSiH3 (1.25 mmol, 5.0 equiv.) were added, followed by DMSO (1.0 mL) were added.
f) After pressurizing CO2 to 8.0 atm, the reaction mixture was heated at 110 °C for 24 h in a closed system.
g) The reaction mixture was cooled to room temperature, and 3.0 mL of ethyl acetate was added and concentrated in vacuo.
h) The product was purified through column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to give the pure product.
2. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction conditions were optimized using NiCl2.DME as a nonprecious catalyst for synthesis of N-formylated product.
3. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction is performed with other Ni-catalyst NiCl2, NiBr2, NiBr2.DME, Ni(acac)2, and NiBr2.diglyme.
4. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction conditions were optimized using 4,4’-diMe-Bpy as a bench stable N-ligand for synthesis of N-formylated product.
5. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction is performed with other N/P based ligand such as DPEphos, Xhenphos, RuPhos, CyJhonPhos, 2,9-dimethylphenanthroline, 4,4’-ditBu-Bpy, 4,4’-diMe-Bpy, and 1,10-Phenanthroline.
6. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction conditions were optimized using Me3N.BH3 for the synthesis of N-formylated products.
7. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction is performed with H-source NH3.BH3 and PhSiH3.
8. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction conditions were optimized using DMSO as a polar solvent for synthesis of N-formylated product.
9. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein the reaction is performed with another solvent toluene, THF, DMA, and DMF.
10. The method for synthesizing N-formylated amines using CO2 as a green feedstock, as claimed in claim 1, wherein both electron-donating and withdrawing functional groups substituted at different positions are well tolerated, such as trifluoromethyl, acetyl, methoxy, and fluoro.