N-METHYLACETAMIDE 1

N-Methylacetamide

Me NH

OMe

[79-16-3] C3H7NO (FW 73.09) InChI=1S/C3H7NO/c1-3(5)4-2/h1-2H3,(H,4,5) InChIKey=OHLUUHNLEMFGTQ-UHFFFAOYSA-N

(solvent and reagent) Alternate names: methylacetamide, monomethylacet-amide, acetylmethylamine, methyl acetamide, N-methyl acetamide, NMA Physical Data: mp 27-29 oC; bp 205 oC, 70-71 oC (2.5-3.0 torr); d 0.96 g/mL Solubility: organic solvent, substantial solubility in water Form Supplied in: colorless liquid or low-melting solid Preparative Methods: Although this compound is commercially available, for special needs it can be synthesized in a laboratory as follows. Gaseous methylamine is passed through hot glacial acetic acid to produce methylammonium acetate, which upon heating to 130 oC expels water to give NMA.1 Purification: Fractional distillation in vacuum, followed by two-fold fractional crystallization from its melt allows for removal of impurities, such as acetic acid, methylamine, and water. Anhydrous material can be obtained by vacuum distillation over CaO.2 As nucleophilic component in substitution reactions Non-catalyzed alkylation with activated electrophiles. As a secondary amide, N-methylacetamide can be efficiently allylated by activated electrophiles. Thus, allylation with crotyl bromide in the presence of sodium hydride afforded crotylamide 1 in high yield (eq 1). Radical cyclization of the latter provided γ-butyrolactam 2,3 a key intermediate in the total synthesis of (±)-isocynometrine (3)4 (eq 1). Electrophilic benzylation of NMA also proceeds smoothly, as was demonstrated in a multigram scale synthesis of amide 5, an important precursor for muscarinic receptor MI agonist 6 (eq 2).5 Electrophilic alkylation with less reactive alkylhalides (benzyl chloride, n-alkyl bromides) proceeds readily in the presence of tetrabutylammonium bromide (10 mol%), K2CO3 (4 equiv) and KOH (4 equiv) upon heating under microwave irradiation to 135-170 oC. The reaction is usually complete within 1-2 min and affords 84-90% yields of tertiary amides.6 Electrophilic alkylation of an in situ generated N-trimethylsilyl derivative of NMA

with alkyl halides bearing a chlorosilane moiety at α-position affords heterocyclic product 8 with oxazosilol-idine core (eq 3).7 In contrast, simple N-alkylation with TMSCH2I provided only poor yield.8

Reaction of 2-methoxy-3H-azepines 9 with NBS carried out in the presence of N-methylacetamide afforded 2-amino-2H-azepine derivatives 10 (eq 4).9

Me NH

OMe

(4)

10a: R = H, 53%10b: R = t-Bu, 77%

NBS/Et3NCH2Cl2, 10 hr

+

N OMe

R

N OMe

R

NMe

O

Me

9

Katritzky investigated alkylation of amides with 1-(hydroxymethyl)benzotriazole 11.10 It was demonstrated that reaction of NMA with 11 proceeded smoothly under acidic catalysis to afford tertiary amide 12 in good yield

N-METHYLACETAMIDE 2(eq 5).10 A three-component reaction between BtH (33), benzaldehyde, and NMA produced 1-hydroxyalkyl-benzotriazole 14 (eq 5).10

Lewis-acid mediated alkoxymethylation by dimethoxy-methane (15) was demonstrated by Danikiewicz.11 This reaction is applicable to a wide range of secondary amides, sulfonamides, phosphoramides, and imides. Methoxymethylamide 16 was obtained by this method with 95% conversion by GC; however, isolation by extraction afforded only 30% yield due to high solubility of this low molecular weight, polar compound in aqueous media (eq 6).

Bronsted acid-catalyzed condensation with phenylacet-aldehyde 17 was employed by Snider to assemble enamide 18, which underwent regio- and diastereo-specific [2 + 2]-photodimerization in solid state to give cyclobutane 19 (eq 7).12

Transition metal-catalyzed cross-coupling reactions. Buchwald reported Pd-catalyzed N-arylation of NMA and other secondary amides, which proceeded efficiently under mild conditions in the presence of diphosphine ligand Xantphos (eq 8).13 This methodology was successfully employed for the preparation of a series of 1,3,4-oxadiazolyl-substituted naphthyridines in SAR studies of potential HIV-1 integrase inhibitors (eq 9).14

A few other transition metal complexes have been shown to efficiently catalyze N-arylation of NMA. Thus, Buchwald demonstrated that this coupling proceeds smoothly in the presence of catalytic amounts of CuI and N,N’-dimethylethylenediamine (eq 10).15 This method-ology was employed by Diedrich for preparation of a Tröger’s base - bis-acetamide derivative 27 (eq 11).16 Furthermore, a combination of bishydrazone ligand 28 and copper iodide was employed for arylation of secondary amides (eq 12).17 Although most of the amides produced good yields of arylation products, NMA provided only marginal results. Wolf reported that the reaction between NMA and iodobenzene proceeds efficiently at 100 oC in NMP in the presence of 5 mol% of Cu2O and two equivalents of t-BuONa, affording amide 25 in 81% yield.18

N-METHYLACETAMIDE 3

Cu(II)-catalyzed alkynylation of N-methylacetamide with bromoalkyne 29 was demonstrated by Hsung.19 This reaction afforded the corresponding ynamide 30 in good yield (eq 13).

Ruthenium-catalyzed substitution of propargylic alcohols with various oxygen-, nitrogen-, and phosphorous-based nucleophiles was investigated.20 It was shown that the reaction proceeds via an allenylidene intermediate, which undergoes a regiospecific nucleophilic attack at γ-carbon. NMA can be employed in this transformation as a nucleophile, providing propargylamide 32 in good yield (eq 14).20

Acylations and carbonylations. Takemoto employed the copper(I)-catalyzed acylation of NMA with cinnamoyl chloride (33) to prepare α,β-unsaturated imide 34 (eq 15), a substrate for the asymmetric Michael addition reaction.21

Padwa reported acylation of NMA by acyl chloride 35, followed by oxidation with sodium periodate to afford sulfoxide 36 in high yield. An attempt to induce Pummerer rearrangement in the presence of trifluoro-acetic anhydride and triethylamine resulted in the formation of oxazolidone 37 in low yield (eq 16).22

Lithium aza-enolate of NMA underwent insertion of carbon monoxide in the presence of selenium to produce selenyllithium species 39. Subsequent electrophilic trapping of the latter with BuI afforded carbamo-selenolate 40 in good yield (eq 17).23

N-METHYLACETAMIDE 4Halogenations and sulfenylations. A simple and efficient protocol for N-chlorination of NMA and other secondary amides was reported by Giacomelli (eq 18).24 Thus, treatment of NMA with trichlorocyanuric acid (TCCA, 41) under mild conditions provided excellent yield of N-chloroamide 42.

Ding employed N-bromination of NMA with NBS to generate N-bromoacetamide 43. The latter was used to induce radical α-bromination of N-benzylcarboxamides 44 to afford species 45, which fragmented into benzald-ehyde and amide 46 (eq 19). Overall, transformation can be viewed as a method for removal of benzyl protection from an amide function, in which NMA serves as a catalyst.25

It was demonstrated that N-sulfenylbenzimidazole 47 can efficiently sulfenylate NMA to afford arylthioacetamide 48 (eq 20).26

Me NH

OMe

(20)

48, 60%

47

Me N

OMe

S

EtO2C

S

EtO2C

N

N

NaHTHF

+

As an N-H entity in additions across multiple bonds Hydroamidation of alkynes. Goossen investigated Ru-catalyzed regioselective addition of secondary amides to

alkynes en route to enamides.27 The reaction between NMA and 1-hexyne (49) afforded hexenylamide 50 in high yield and moderate diastereoselectivity (eq 21). A related metal oxide-catalyzed gas-phase reaction of ethyne was studied by Trofimov.28

Addition of NMA across the triple bond of phenyl-acetylene and tolane catalyzed by a phosphazene base, t-Bu-P4 (51), was reported by Kondo. This reaction is sluggish and requires harsh conditions; however, it provides good yields of mixtures of the E- and Z-enamides 52 (eq 22).29

Hydroamidation of allenes. Palladium-catalyzed amino-palladation of alkoxyallenes with various secondary amides was investigated by Hiemstra and Rutjes.30 N-Methylacetamide underwent this transformation affording the corresponding N,O-acetal 54 in low yield (eq 23).

Hydroamidation of alkenes. Rubin reported a base-mediated nucleophilic addition of NMA across the strained double bond of 3-methyl-3-phenylcyclopropene, generated in situ from a mixture of diastereomeric bromocyclopropanes 55 (eq 24). This formal substitution reaction proceeds efficiently in the presence of catalytic amounts of 18-crown-6 ether, and the diastereoselectivity of the nucleophilic attack in this case is governed by

N-METHYLACETAMIDE 5steric factors, providing trans-aminocyclopropane derivative 56 (eq 24).31

Amidacarbonylation of aldehydes. Beller demonstrated a very efficient Pd-catalyzed amidocarbonylation of the aldehydes, producing N-acetyl α-amino acids. It was shown that addition of substoichiometric amounts of LiBr and catalytic amounts of sulfuric acid significantly accelerated this reaction. Under the optimized reaction conditions, amidocarbonylation of isovaleric aldehyde (57) with NMA proceeded readily at 120 oC and 60 bar of CO pressure to give 58 in 88% yield (eq 25).32

As C-H entity in additions across multiple bonds Hydroalkylation of alkynes. Shibata demonstrated that cationic Ir(I)-BINAP undergoes a carbonyl-directed insertion into the sp3C-H bond of the N-methyl group in NMA to produce complex 59. The subsequent migratory insertion of tolane 60 followed by reductive elimination, afforded allylamine 61 in good yield (eq 26).33

As electrophilic reagent in the form of imidoyl chloride or chloroiminium salt Chandrasekaran reported a facile transformation of amides into the corresponding selenamides.34 The reaction begins with the formation of chloroiminium salt 62 upon treatment of NMA with (COCl)2 or POCl3. Subsequent work up with tetraethylammonium tetra-selenotugstate afforded selenoamide 63 in good yield (eq 27). The same group described preparation of thioamide

64 after treatment of chloroiminium salt 28 with benzyl-triethylammonium tetrathiomolybdate.35 An alternative synthesis of thioamide 64 was achieved by Fuchs who employed Lawesson’s reagent (yield 89%) or TMS2S (yield 77%) as the S-nucleophile source.36

Gataulin demonstrated that chloroiminium salt 62 generated in situ from NMA and PCl5 reacted readily with o-alkenylanilines 65 to afford high yields of amidines 66. The latter underwent intramolecular cycliz-ation into quinazoline 67 upon heating with polyphosph-oric acid (eq 28).37

Imidoyl chloride 68 generated in situ from NMA and oxalyl chloride in the presence of 2,6-lutidine was reacted with a series of pyridine-1-oxides.38 This protocol represents a convenient and efficient approach to diverse N-pyridine-2-yl acetamides 69 (eq 29).

N-METHYLACETAMIDE 6

Johansson used the reaction of imidoyl chloride 68 with arylhydrazides 70 to generate iminoalkylhydrazide species 71. The latter underwent cyclization upon reflux with sodium bicarbonate to furnish 1,2,4-triazoles 72 in moderate yield (eq 30).39

Teles reported an analogous transformation between chloroimidinium salt 62 and N-formyl-N-methylhydr-azine as an efficient route to 4H-1,2,4-triazolium salt 73 (eq 31).40

Transamidation. Bigg and Bertrand demonstrated a transamidation reaction of NMA promoted by AlCl3.41 In contrast to other analogous transformations, this method provides excellent yields for both secondary and primary amides. Thus, reaction of NMA with various amines afforded excellent yields of secondary and tertiary amides (74), respectively (eq 32). Enzymatic transamidation of non-activated amides in organic solvent was investigated by Khmelnitsky. Reaction of NMA (10 mM) with benzylamine (20 mM) in MTBE carried out at 45 oC in the presence of Candida Antarctica afforded N-benzylacetamide 74a with 53% conversion after 6 days.42

As a base in a form of an alkali metal salt. Guzzo reported the use of potassium salt of NMA to induce an intramolecular cyclization of sulfonium salt 75. The reaction produced a mixture of lactams 76 and 77 without any detectable epimerization. The concurrent partial removal of SEM protecting group had no consequences for the synthesis, since both esters 76 and 77 were converted to hydroxyacid 78 in the next step upon treatment with TFA (eq 33).43

N-METHYLACETAMIDE 7

N-Nitrosation. Selective N-nitrosation of NMA was carried out in the presence of nitrogen(IV) oxide supported on charcoal (N2O4/C) or on cross-linked poly-vinylpyrrolidone (PVP-N2O4).44 Ring expansion of oxadiborinanes. Paetzold investigated the reactivity of oxadiborinane 79 in the presence of NMA and other acetamides and formamides.45 The reaction proceeded with ring expansion, furnishing a six-membered cyclic species 80 in low yield (eq 34).

As a ligand for transition metal complexes. Gunnoe demonstrated that Ru(II)-tripyrazolylborate complex 81 readily inserts into the N-H bond of N-methylacetamide. Subsequent reductive elimination liberates benzene and produces amidate complex 82 (eq 35).46

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N-METHYLACETAMIDE 8

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Marina Rubina & Michael Rubin

The University of Kansas, Lawrence, KS, USA