PL243696B1 - Method for preparation of 1- (N-acylamino) alkyltriarylphosphonium salts - Google Patents

Abstract

The subject of the application is a method for preparing 1-(N-acylamino)alkyltriarylphosphonium salts of the general formula 1, in which R1 is Me, Ph, t-Bu, BnO; R2 is H, Me, Et, Ph, i-Pr, 2-thienyl; R3 is H, Me or R1 and R3 together are (CH2)3; Ar is Ph, 3-C6H4Cl, 4-C6H4OMe; X is BF4, Br, which is that aldehydes of the general formula 2, in which R2 is H, Me, Et, Ph, i-Pr, 2-thienyl; amides, carbamates, or lactams of the general formula 3, wherein R1 is Me, Ph, t-Bu, BnO; R3 is H, Me or R1 and R3 together are (CH2)3 and triarylphosphonium salts of general formula 4, where Ar is Ph, 3-C6H4Cl, 4-C6H4OMe; X is BF4, Br is mixed in a molar ratio of 1:1:1, aldehyde of general formula 2: amide/carbamate/lactam of general formula 3: triarylphosphonium salt of general formula 4 or mixed with an excess of aldehyde 1.2:1:0 .9 in organic solvents such as CH3CN, CHCl3, CH2Cl2, THF or without the use of a solvent, the process is carried out at a temperature of 25° - 135°C, preferably at a temperature of 50°C, for 1 - 48 h, and then the crude salt 1-(N-acylamino)alkyltriarylphosphonium is precipitated with Et2O or hexane, then preferably recrystallized from CH3CN or CHCl3/Et2O, CH3CN/Et2O, CH2Cl2/Et2O systems.

Description

The subject of the invention is a method for preparing 1-(N-acylamino)alkyltriarylphosphonium salts of the general formula 1.

Phosphonium salts are used in chemistry as solvents (PlLs - phosphonium ionic liquids), interphase transfer catalysts, and as precursors of phosphorus ylides of particular importance in the synthesis of biologically active substances. In addition, they are used as additives to lubricants to prevent scratching the surface of various materials and polymers to improve quality, plasticity and antibacterial properties. Phosphonium salts also act as flame retardants, whose task is to limit the flammability or completely make materials, including polymers, flame retardant [M. Selva, A, Perosa, M. Noe Organophosphorous Chemistry, ed., J.C. Tebby, D. Loakes, D.W. Allen; the Royal Society of Chemistry, Cambridge, 2016, 132-169; F. R. Hartley The Chemistry of Organophosphorus Compounds, Vol. 3, Wiley, New York, 1994, 1-185; E. Bruchajzer, B. Frydrych, J. Szymańska Med. Pr. 2015, 66, 235-264].

A special type of phosphonium salts are 1-(N-acylamino)alkyltriarylphosphonium salts. The immediate vicinity of the N-acylamino group and the positively charged phosphonium group is responsible for their high reactivity in the α-amidoalkylation reaction - one of the most important organic synthesis reactions allowing the effective creation of new carbon-carbon or carbon-heteroatom bonds [A. Październiok-Holewa, J. Adamek, R. Mazurkiewicz, K. Zielińska Phosphorus, Sulfur, and Silicon 2013, 188, 205-212; R. Mazurkiewicz, A. Październiok-Holewa, J. Adamek, K. Zielińska Advances in Heterocyclic Chemistry 2014, 111, 43-94; J. Adamek, A. Węgrzyk, J. Kończewicz, K. Walczak, K. Erfurt Molecules 2018, 23, 2453].

Several methods for the synthesis of 1-(N-acylamino)alkyltriarylphosphonium salts have been described in the chemical literature. The simplest of them involve α-amidoalkylation of triphenylphosphine with N-(chloromethyl)amides, N-(bromomethyl)amides or N-(hydroxymethyl)amides [V.S. Brovarets, O.P. Lobanov, T.K. Vinogradova, B.S. Drach Zh. Obshch. Khim. 1984, 54, 288-301; L.F. Kasukhin, V.S. Brovarets, O.B. Smolii, V.V. Kurg, L,V. Budnik, B.S. Drach Zh. Obshch, Khim. 1991, 61, 2679-2684]. N-(alkoxymethyl)amides can also be used as an α-amidoalkylating agent. In 1972, the reaction of N-(alkoxymethyl)urea derivatives with triphenylphosphine was described, which was carried out in a methanolic solution of hydrogen chloride gas or a mixture of methanol with a concentrated aqueous solution of hydrogen bromide or hydrogen iodide (MeOH/HCl, MeOH/48%HBr, MeOH/57%HI) [ H Peterson, W. Reuther Justus Liebigs Arm. Chem 1972, 766, 58-72].

1-(N-acyIoamino)alkyltriphenylphosphonium salts were also obtained without using triphenylphosphine as a substrate. An example is the reaction of alkylation of methyl carbamate with hydroxymethyltriphenylphosphonium chloride in boiling toluene, with azeotropic removal of the water formed by side [A.W. Frank, G.L. Drake J. Org. Chem. 1977, 42, 4040-4045].

More complicated, multi-step methods for the synthesis of 1-(N-acylamino)alkyltriphenylphosphonium salts have also been described in the literature, such as thermal demethoxycarbonylation of N-acyl-α-triphenylphosphonioglycinates [J. Adamek, J. Mrowiec-Białoń, A. Październiok-Holewa, R. Mazurkiewicz Thermochim. Acta 2011, 512, 22-27] or reactions using 4-phosphorylidene-5(4H)-oxazolones [R. Mazurkiewicz, A. Październiok-Holewa, M. Grymel Tetrahedron Lett. 2008, 49, 1801-1803; R. Mazurkiewicz, A. Październiok-Holewa, S. Stecko, B. Orlińska Tetrahedron Lett. 2009, 50, 46064609].

The common feature of the syntheses described above, and at the same time their greatest disadvantage, is primarily the narrow range of applicability, limited in most cases to 1-(N-acylamino)methyltriphenylphosphonium salts (R ² = H, Ar = Ph), the need to use burdensome and aggressive reagents ( e.g. MeOH/HCl, MeOH/48%HBr), as well as complicated procedures for processing the post-reaction mixture.

The most important and at the same time the most general method for the synthesis of 1-N-acylamino)alkyltriarylphosphonium salts is based on the reaction of N-(1-alkoxyalkyl)amides with the appropriate triarylphosphonium bromides or tetrafluoroborates (ArsP.HX, where X = BF4 or Br) [R. Mazurkiewicz, J. Adamek, A. Październiok-Holewa, K. Zielińska, W. Simka, A. Gajos, K. Szymura J. Org. Chem. 2012, 77, 1952-1960; R. Mazurkiewicz, J. Adamek, A. Październiok-Holewa, T. Gorewoda, W. Simka; Polish patent no. 215676 of June 19, 2013; J. Adamek, R. Mazurkiewicz, A. Październiok-Holewa, K. Zielińska, W. Simka; Polish patent no. 221593 of June 29, 2016; J. Adamek, A. Węgrzyk, M. Krawczyk, K. Erfurt Tetrahedron 2018, 74, 2575-2583; J. Adamek, A. Węgrzyk, J. Kończewicz, K. Walczak, K. Erfurt; Molecules 2018, 23,

PL 243696 Β1

2453] . It allows the synthesis of a wide range of 1-(A/-acylamino)alkyltriarylphosphonium salts with very good yields, under mild conditions, without the need to use harmful or toxic reagents.

The greatest limitation of this method is difficult access to substrates, i.e. A/-(1-alkoxyalkylylamides, the synthesis of which is based on inefficient chemical processes such as alcoholysis of A/-(1-hydroxysalkyl)amides or A/-(1-halogenoalkyl)amides and condensation of aldehydes and amides in alcohol in an acidic medium [R.D. Haworth, D.H. Peacock, W.R. Smith, R. MacGillivray J. Chem. Soc. 1952, 2972-2980; H. Bóhme, K. Hartke, Chem. Ber., 1963, 96, 600-603; B.J. Ivanov, S.S. Krochina, lzv. Akad. Nauk SSSR. Ser. Chim, 1970, 2627] or efficient, but expensive and not very popular electrochemical reactions such as electrochemical decarboxylative α-alkoxylation of amino acid derivatives or electrochemical oxidation of amides, carbamates or lactams [R.P. Linstead, B.R. Shephard, B.C.L. Weedon J. Chem. Soc. 1951, 2854-2858; T. Shono Tetrahedron 1984, 40, 811-850; G. Kardassis, P. Brungs, E. Steckhan Tetrahedron 1998, 54, 3471-3478; T. Tajima, H. Kurihara, T. Fuchigami J. Am. Chem. Soc. 2007, 129, 6680-6681; R. Mazurkiewicz, J. Adamek, A. Październiok-Holewa, K. Zielińska, W. Simka, A. Gajos, K. Szymura J. Org. Chem. 2012, 77, 1952-1960; J. Adamek, R. Mazurkiewicz, A. Październiok-Holewa, A. Kuźnik, M. Grymel, K. Zielińska, W. Simka Tetrahedron 2014, 70, 5725-5729; J. Adamek, R. Mazurkiewicz, A. Październiok-Holewa, M. Grymel, A. Kuźnik, K. Zielińska J. Org. Chem. 2014 , 79, 2765-2770].

Therefore, a new strategy for the synthesis of 1-(A/-acylamino)alkyltriarylphosphonium salts was proposed, which involves the use of the condensation reaction of aldehydes with amides, carbamates or lactams in the presence of triarylphosphonium bromides or tetrafluoroborates as shown in the diagram:

o , ©or |JU + RCHO + HPAr ₃ X® ---► |k 1 © _n

R NH ³ R^N^PAr, Χθ •3 <3

RR

R ^! = Me, Ph, r-Bu, BnO

R* = H. Me, Et. Ph.D. /-Pr. 2-thienyl

R ³ = H Me or R ¹ and R ^J (together) = (CH ₂ ) ₃

Ar = Ph 3-Ο ₆ Η^Ί. 4 _{- C6H4OMe}

X = BF ₄ , Br

So far, no attempts to use this type of reaction to obtain 1-(N-acylamino)alkyltriarylphosphonium salts have been described in the literature.

A method for preparing 1-(N-acylamino)alkyltriarylphosphonium salts of the general formula 1, in which R ¹ is methyl, phenyl, tert-butyl, benzyloxy group; ^R2 is hydrogen, methyl, ethyl, phenyl, isopropyl, 2-thienyl; ^R3 represents hydrogen, methyl or ^R1 and ^R3 together represent the group (CH2)3, the group Ar represents phenyl, 3-chlorophenyl, 4-methoxyphenyl; X is the tetrafluoroborate anion, the bromide anion is that aldehydes of general formula 2, in which R ² is hydrogen, methyl, ethyl, phenyl, isopropyl, 2-thienyl; amides, carbamates, or lactams of the general formula 3, where R ¹ is methyl, phenyl, tert-butyl, benzyloxy; ^R3 is hydrogen, methyl or ^R1 and ^R3 together represent the (CH2)3 group and triarylphosphonium salts of the general formula 4, in which the Ar group is phenyl, 3-chlorophenyl, 4-methoxyphenyl; X is the tetrafluoroborate anion, the bromide anion is mixed in a molar ratio of 1:1:1, the aldehyde of the general formula 2: amide/carbamate/lactam of the general formula 3: triarylphosphonium salt of the general formula 4 or mixed with an excess of the aldehyde 1.2:1 :0.9 in organic solvents such as acetonitrile, chloroform, methylene chloride, tetrahydrofuran or without the use of a solvent, the process is carried out at temperatures from 25°C to 135°C, preferably at 50°C, for 1 h up to 48 h, then the crude 1-(N-acylamino)alkyltriarylphosphonium salt is precipitated using diethyl ether or hexane, then preferably recrystallized from acetonitrile or acetonitrile/diethyl ether, acetonitrile/diethyl ether, methylene chloride/diethyl ether systems.

The advantage of the solution according to the invention is very good yields, the reaction takes place in mild conditions and in a short time, most often 60 minutes. The production method is based on a different raw material base, which is easily available aldehydes and amides. The above method enables obtaining a rich library of structurally diverse compounds that are difficult or impossible to obtain using other methods. An additional advantage of the solution according to the invention is the possibility of using not only amides, including N-alkylamides, but also carbamates and lactams as substrates.

The invention is explained with examples 1-17, and the products of the performed exemplary syntheses are presented with formulas 1a-n:

Example 1

Propionaldehyde (71.7 μΙ, 58.1 mg, 1.0 mmol), acetamide (59.07 mg, 1 mmol), triphenylphosphonium tetrafluoroborate (350.1 mg, 1.0 mmol) and chloroform (CHCh) (0.7 ml). The test tube was closed and the whole thing was intensively mixed and heated at 50°C for 1 h. After this time, the formed phosphonium salt was precipitated with diethyl ether (Et2O) to obtain 386.3 mg of the expected product 1a with a yield of 86% in the form of a white solid with a melting point 185°C - 186°C.

Example 2

Propionaldehyde (86.0 μl, 69.7 mg, 1.2 mmol), acetamide (59.07 mg, 1.0 mmol) and triphenylphosphonium bromide (308.9 mg, 0.9 mmol) were introduced into a glass test tube with a threaded cap. ). The whole was heated at 70°C for 1 h. Acetonitrile (CH3CN) (0.7 ml) was introduced into the post-reaction mixture, and the resulting phosphonium salt was precipitated with diethyl ether (Et2O) to obtain 226.9 mg of the expected product 1b with a yield of 57% in the form of a white solid with a melting point of 171°C - 172°C.

Example 3

Proceeding as in example 1, with 71.7 μl (58.1 mg) of propionaldehyde after 1 hour of reaction at 50°C in tetrahydrofuran (THF) (0.7 ml) and filtering off the phosphonium salt precipitating during the reaction, 332 was obtained, 4 mg of the expected product 1a with a yield of 74% in the form of a white solid with a melting point of 185°C - 186°C.

Example 4

Proceeding as in example 1, 390.8 mg of propionaldehyde was obtained with 71.7 μl (58.1 mg) of propionaldehyde after 48 h of reaction at room temperature in acetonitrile (CH3CN) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O). the expected product 1a in 87% yield as a white solid with a melting point of 185°C - 186°C.

Example 5

Proceeding as in example 1 with 71.7 μl (58.1 mg) of propionaldehyde, 59.1 mg of acetamide and 343.3 mg of triphenylphosphonium bromide after 1 h of reaction at 50°C in methylene chloride (CH2Cl2) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 309.6 mg of the expected product 1b with a yield of 70% in the form of a white solid with a melting point of 171°C - 172°C

Example 6

Proceeding as in example 1 with 71.7 μl (58.1 mg) of propionaldehyde, 59.1 mg of acetamide and 453.4 mg of tris(3-chlorophenyl)]phosphonium tetrafluoroborate after 1 h of reaction at 50°C in chloroform ( CHCl3) (0.7 ml) and precipitation of the phosphonium salt with hexane obtained 392.3 mg of the expected product 1c with a yield of 71% in the form of a resin.

Example 7

Proceeding as in example 1 with 71.7 μl (58.1 mg) of propionaldehyde, 121.1 mg of benzamide and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 50°C in chloroform (CHCl3) (0.7 ml ) and precipitation of the phosphonium salt with diethyl ether (Et2O) were obtained

281.2 mg of the expected product 1d with a yield of 55% in the form of a white solid with a melting point of 198°C - 199°C.

Example 8

Proceeding as in example 1 with 71.7 μl (58.1 mg) of propionaldehyde, 101.2 mg of pivalamide and 343.3 mg of triphenylphosphonium bromide after 1 h of reaction at 100°C in chloroform (CHCl3) (0.7 ml ) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 377.8 mg of the expected product 1e with a yield of 78% in the form of a white solid with a melting point of 161°C - 163°C.

Example 9

Proceeding as in example 1 with 71.7 μΙ (58.1 mg) propionaldehyde, 76.0 μΙ (85.1 mg) butyrolactam and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 100°C chloroform (CHCl3) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 465.8 mg of the expected product 1f with a yield of 98% in the form of a white solid with a melting point of 186°C - 188°C.

Example 10

Proceeding as in example 1 with 71.7 μl (58.1 mg) of propionaldehyde, 151.2 mg of benzyl carbamate and 440.2 mg of tris(4-methoxyphenyl)phosphonium tetrafluoroborate after 2 h of reaction at 50°C in acetonitrile ( CH3CN) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 435.7 mg of the expected product 1g with a yield of 69% in the form of a white solid with a melting point of 114°C - 116°C.

Example 11

Proceeding as in example 1 with 102.1 μl (106.1 mg) of benzaldehyde, 151.2 mg of benzyl carbamate and 350.1 mg of triphenylphosphonium tetrafluoroborate after 3 h of reaction at 50°C in acetonitrile (CH3CN) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 465.6 mg of the expected product 1 h with a yield of 79% in the form of a white solid with a melting point of 177°C - 178°C.

Example 12

Proceeding as in Example 1 with 91.3 μl (72.1 mg) of isobutyraldehyde, 151.2 mg of benzyl carbamate and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 50°C in acetonitrile (CH3CN) (0, 7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) yielded 449.9 mg of the expected product I1 with a yield of 81% in the form of a resin.

Example 13

Proceeding as in example 1 with 55.9 μl (44.1 mg) of acetaldehyde, 59.1 mg of acetamide and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 50°C in acetonitrile (CH3CN) (0.7 ml ) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 396.0 mg of the expected product 1j with a yield of 91% in the form of a white solid with a melting point of 150°C -151°C.

Example 14

Proceeding as in example 1 with 93.5 μl (112.2 mg) of 2-thiophenecarboxaldehyde, 101.2 mg of pivalamide and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 100°C in acetonitrile (CH3CN) (0, 7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 441.8 mg of the expected product 1k with a yield of 81% in the form of a white solid with a melting point of 195°C - 197°C.

Example 15

Proceeding as in Example 1 with 30.3 mg of paraformaldehyde, 59.1 mg of acetamide and 343.3 mg of triphenylphosphonium bromide after 1 h of reaction at 135°C in chloroform (CHCl3) (0.7 ml) and precipitation of the phosphonium salt with ether diethyl (Et2O), 410.2 mg of the expected product 11 were obtained with a yield of 99% in the form of a white solid with a melting point of 250°C - 251°C.

Example 16

Proceeding as in example 1 with 30.3 mg of paraformaldehyde, 76.4 μl (73.1 mg) of N-methylacetamide and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 135°C in acetonitrile (CH3CN) (0, 7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 330.8 mg of the expected product 1m with a yield of 76% in the form of a white solid with a melting point of 189°C - 191°C.

Example 17

Proceeding as in example 1 with 30.3 mg of paraformaldehyde, 76.0 μl (85.1 mg) of butyrolactam and 350.1 mg of triphenylphosphonium tetrafluoroborate after 1 h of reaction at 135°C in acetonitrile (CH3CN) (0.7 ml) and precipitation of the phosphonium salt with diethyl ether (Et2O) obtained 407.0 mg of the expected product 1n with a yield of 91% in the form of a white solid with a melting point of 170°C - 172°C.

Claims (1)

1. A method for preparing 1(N-acyIoamino)alkyltriarylphosphonium salts of the general formula I, in which R ¹ is methyl, phenyl, tert-butyl, benzyloxy group; ^R2 is hydrogen, methyl, ethyl, phenyl, isopropyl, 2-thienyl; ^R3 is hydrogen, methyl or ^R1 and ^R3 together represent the group (CH2)3; the group Ar represents phenyl, 3-chlorophenyl, 4-methoxyphenyl; X is a tetrafluoroborate anion, a bromide anion characterized in that aldehydes of the general formula 2, in which R ² is hydrogen, methyl, ethyl, phenyl, isopropyl, 2-thienyl; amides, carbamates, or lactams of the general formula 3, where R ¹ is methyl, phenyl, tert-butyl, benzyloxy; ^R3 is hydrogen, methyl or ^R1 and ^R3 together represent the (CH2)3 group and triarylphosphonium salts of the general formula 4, in which the Ar group is phenyl, 3-chlorophenyl, 4-methoxyphenyl; X is the tetrafluoroborate anion, the bromide anion is mixed in a molar ratio of 1:1:1, the aldehyde of the general formula 2: amide/carbamate/lactam of the general formula 3: triarylphosphonium salt of the general formula 4 or mixed with an excess of aldehyde 1,2: 1:0.9 in organic solvents such as acetonitrile, chloroform, methylene chloride, tetrahydrofuran or without the use of a solvent, the process is carried out at a temperature from 25°C to 135°C, preferably at a temperature of 50°C, for a time from 1 h to 48 h, then the crude 1-(N-acylamino)alkyltriarylphosphonium salt is precipitated using diethyl ether or hexane, then preferably recrystallized from acetonitrile or acetonitrile/diethyl ether, acetonitrile/diethyl ether, methylene chloride/diethyl ether systems.