Benzotriazole-mediated amidoalkylations of nitroalkanes, nitriles, alkynes and esters

Reactions of readily available and stable N-( α -amidoalkyl)benzotriazoles 1 (derived from a variety of aliphatic, aromatic or heterocyclic aldehydes) with diverse nitroalkanes, nitriles, alkynes and esters afforded N-( β -nitroalkyl)amides 4 (54 − 96%), N -( β -cyanoalkyl)amides 6 (58 − 88%), N -acylpropargylamines 11 (41 − 87%) and esters of β -N -acylamino acid s 13 (68 − 96%), respectively.


Introduction
Amidoalkylations have attracted attention in organic synthesis as a valuable alternative to the Mannich reaction 1 since they provide ready access to a wide variety of α-substituted amines. 2 Amidoalkylation of π-nucleophiles, including alkenes, allenes, alkynes and (hetero)aromatic systems, is a common step in the synthesis of nitrogen heterocycles, 2a,b alkaloids, 3 and other nitrogen-containing biologically active compounds.2b Intramolecular amidoalkylations have been applied to the synthesis of monocyclic, 4 bicyclic and polycyclic systems with stereocontrol. 5 Benzotriazole mediated amidoalkylations introduced in 1988, 6 offer advantages over previously reported methods as was already demonstrated for the amidoalkylation of (i) Grignards, 6 (ii) malonates and acetoacetates, 7 (iii) cyanide anion, 8 (iv) mercaptans and alcohols, 9 (v) electron-rich (hetero)aromatics, 10 and (vi) amines 11 (Scheme 1).

Synthesis of N-(β-nitroalkyl) amides
Nitronate salts act as carbon nucleophiles in the well-known Michael, 13 Henry, 14 Knoevenagel, 15 and nitro-Mannich reactions, 16 providing valuable derivatives in which the nitro group can be retained, reductively eliminated, or transformed to provide ketones, 17 amines, 18 oximes, 19 or nitriles. 20Therefore, methodologies to introduce the nitro group into a molecular framework along with other functionalities have gained momentum.
Formation of the nitroamides of type 4 is indicated by the loss of benzotriazole signals in 1 H and C 13 NMR.In the 13 C NMR spectra of the compounds 4, resonances arising from amide carbonyl and carbons adjacent to the nitro group are found in the regions of 166.3−178.2ppm and 86.0−97.0ppm, respectively and their structures were also confirmed by elemental analysis.

Scheme 3
Trials with different base-solvent couples disclosed that phenylacetonitrile treated with 1.2 molar equivalent of t-BuOK in DMSO followed by subsequent addition of α-(amidoalkyl)benzotriazole 1a solution in DMSO at 15 o C provided 58% of the amidomethylated product 6a.The significant acidity of the hydrogen linked to the nitrogen atom in 1 and anionexchange explains the bis-amide 8 byproduct.
Using these optimized conditions, potassio-derivatives of 5a−e (generated from primary or secondary nitriles) reacted with diverse 1 to give 10 examples of the expected monoamidoalkyation products 6 in yields 61% to 92% (Scheme 4 and Table 2).For β-amidoalkyl nitriles 6 containing two asymmetric carbon atoms, the reaction shows little stereoselectivity; in nearly all cases two stereoisomers were isolated in about 1:1 ratio.Assignment of the two stereoisomers as syn and anti was accomplished by utilizing the reasoning of Carlier et al on βhydroxy nitriles, 33 and our own recent results with β-aminoalkyl nitriles. 32The reaction of 1h with 5c under the same conditions provided the doubly amidoalkylated product 7 (46%) (Scheme 4, Table 2).
For designation of R 1 R 2 and R 3 in 6 and 7 see Table 2. 1,3-Benzo [1,3]dioxol-4-yl Novel structures of 6 and 7 were supported by their elemental analyses and spectral data.The 13 C NMR spectra of the amides show the absorption peak for the carbonyl group in the region of 168.4−166.8ppm and for the carbon directly attached to the amide nitrogen at 56.1−53.1 ppm.

Synthesis of N-acylpropargylamines
Propargylamines are important therapeutic agents: 34 inhibitors of monoamine oxidase B and aldehyde dehydrogenase enzymes 35 and potential antifungal agents. 36They are also precursors for allylic amines and other targets. 37Propargylamines were previously prepared by: (i) metalcatalyzed three-component coupling of aldehyde, alkyne, and secondary amine; 38 (ii) metalcatalyzed addition of alkynes to enamines; 39 (iii) TiCl 4 -mediated amination of propargylic esters; 40 (iv) transition metal promoted addition reaction of terminal alkynes to imines; 41 and (v) alkynylation of N-(α-aminoalkyl)benzotriazoles with lithium alkynides 42 or dialkynyldiethylaluminates 43 (Scheme 5).We now report the synthesis of N-acyl-α-propargylamines 11 (Scheme 6), which can serve as precursors for the corresponding α-propargylamines. 40 Scheme 5 2-Phenylacetylene 9a was treated with 1.2 equiv. of n-BuLi to give 10a in situ which on treatment with 1c,d at -78 o C in THF afforded 53% and 63% of 11a and 11b, respectively.The molar equiv. of lithium alkynide could be replaced by 1.9 equiv. of alkynylmagnesium bromide 10 (prepared by treating 9 with 1.65 equiv of EtMgBr) at rt affording the corresponding Nacylpropargylic amides 11c−g in 47−87% yields (Scheme 6 and Table 3).Structures 11c−g were characterized by NMR spectroscopy.The 1 H NMR of 11 showed the characteristic peak of NH as doublet in the region 6.20−6.41ppm and the peaks of the two acetylenic carbons appeared in the 13 C NMR spectra in the regions 83.7−88.7 ppm and 76.4−84.3ppm.For designation of R, R 1 and R 2 in 11 see Table 3.

Scheme 7
Reactions of lithium or potassium enolates, prepared in situ by treating the corresponding ester itself 12a−c with LDA in THF or t-BuOK in DMSO, with 1b−d provided β-(N-protectedamino)alkyl esters 13a−e in moderate to excellent yields (Scheme 8 and Table 4).
Previously malonates and acetoacetates 7 were reacted with 1 in the presence of anhydrous aluminum chloride and gave the amidoalkyated products of type 13 in moderate yields.The efficiency of the nucleophilic substitution of benzotriazole from compounds of type 1 is demonstrated by comparison of the electrophilic conditions.Ethyl benzoylacetate (12d), methyl and benzyl acetoacetate (12e,f), and ethyl malonate (12g), each reacted efficiently with 1 in the presence of 1.2 equiv.t-BuOK in DMSO at rt, to give the amidoalkylated derivatives 13f−h (84−96%) (Scheme 7 and Table 4).The 1 H NMR spectra of 13 showed that while 13c and 13d were diastereomeric mixtures 13a,b and 13e−g were single diastereomers.In the 13 C NMR spectra of 13 the characteristic signals of ester and amide carbonyls appeared at 172.6−173.2ppm and 167.2−169.2ppm.
For designation of R, R 1 , R 2 and R 3 in 13 see Table 4.In summary, we have developed convenient approaches for N-(β-nitroalkyl)-amides, N-(βcyanoalkyl) amides, N-acylpropargylamines and esters of β-N-acylamino acids by the amidoalkylation of nitroalkanes, nitriles, alkynes, and esters and β-keto esters with N-(αamidoalkyl)benzotriazoles.The adopted procedures are simple and applicable to the preparation of amidoalkylation products derived from formaldehyde, aliphatic, and (hetero) aromatic aldehydes.In all cases, the N-protected amine derivatives were produced in high yields that make the use of N-(α-amidoalkyl)benzotriazoles as N-acyliminium ion equivalents advantageous.

Experimental Section
General Procedures.All reactions were carried out under an atmosphere of nitrogen, unless otherwise specified.Glassware was routinely oven-dried at 160 o C for a minimum of 4 h and then connected to a vacuum line before assembling under a dry argon stream.Column chromatography was performed on silica gel 200−425 mesh.THF was distilled from sodiumbenzophenone ketyl and DMSO was dried over molecular sieves prior to use.N-(α-Amidoalkyl) benzotriazoles 1 were prepared according to literature procedures. 12

General procedure for the preparation of N-(β-nitroalkyl) amides 4a−l.
A mixture of nitroalkane (4 mmol) and potassium t-butoxide (0.45 g, 4 mmol) in DMSO (10 mL) was stirred at room temperature for 40 min.To the resulting solution N-(αamidoalkyl)benzotriazoles 1 (2 mmol) in DMSO (10 mL) was added dropwise and the mixture was stirred at room temperature for 8 hrs.The mixture was poured into water (40 mL), acidified with acetic acid, and then extracted with ethyl acetate (3x30 mL).The extracts were washed with water, dried over MgSO 4 and the solvent removed under reduced pressure.The residue was placed in a silica-gel column and eluted with hexanes/ EtOAc 5:1 to give 4.

General procedure for the preparation of N-(β-cyanoalkyl) amides 6a−g and 7
A mixture of nitrile 5 (2 mmol) and potassium t-butoxide (0.25 g, 2.2 mmol) in DMSO (10 mL) was stirred at room temperature for 1h.To the resulting solution of 1 0.645 g, 2 mmol) in DMSO (10 mL) was added dropwise, and the mixture was stirred at room temperature for 8 hrs.The mixture was quenched with water, and extracted with ethyl acetate (3x30 mL).The extracts were washed with water, dried over MgSO 4 and the solvent was removed under reduced pressure.The residue was placed in a silica-gel column and eluted with hexanes/EtOAc 5:1 to give the pure product.General procedure for the preparation of N-acylpropargylamines 11a−g Method A. To a solution of alkyne 9 (2 mmol) in dry THF (10 mL), n-BuLi (2.6 mL, 1.6 M in pentane, 4.2 mmol) was added at -78 o C. The solution was stirred at -78 o C for 1 h, and a solution of 1 (2 mmol) in THF (10 mL) was added.The reaction mixture was stirred for 10 h while the temperature was allowed to rise to 20 o C.After quenching with water (20 mL) and extraction with EtOAc (3x25 mL), the combined organic layers were washed with water, dried over MgSO 4 and the solvent was removed in vacuo.The resulted oil was subjected to column chromatography (eluent: ethyl acetate/ hexanes = 1: 10 then 1: 5) to give the pure product.Method B. To a solution of ethylmagnesium bromide ( 5 mmol ) (prepared in situ ) in THF (10 mL), alkyne 9 (2.7 mmol ) was added.The contents were heated under reflux until evolution of ethane was ceased then left to attain room temperature.A solution of 1 (1.5 mmol) in THF (10 mL) was added dropwise to Grignard solution and mixture was stirred for 1h.After quenching with water (20 mL) and extraction with EtOAc(4x25 mL), the combined organic layers were dried over MgSO 4 and solvent removed in vacuo.The resulted oil was subjected to column chromatography ( eluent: hexanes/EtOAc = 5:1) to give the pure product.