molecules Review Recent Uses of N,,N-Dimethylformamide and N,N-Dimethylacetamide as Reagents JeanJean LeLe BrasBras andand JacquesJacques MuzartMuzart ** InstitutInstitut dede ChimieChimie MolMoléculaireéculaire dede Reims,Reims, CNRS—UniversitCNRS—Universitéé dede ReimsReims Champagne-Ardenne,Champagne-Ardenne, B.P.B.P. 1039, 1039, 51687 Reims CEDEX 2,2, France;France; [email protected]@univ-reims.fr ** Correspondence:Correspondence: [email protected];[email protected]; Tel.:Tel.:+33-3-26913237 +33-3-26913237 Academic Editor: Michal Szostak Academic Editor: Michal Szostak Received: 13 July 2018; Accepted: 31 JulyJuly 2018; Published: 3 August 2018 Abstract:Abstract: NN,,N-Dimethylformamide and N,,N-dimethylacetamide are multipurpose reagents whichwhich deliver their own H, C, N and O atoms for the synthesissynthesis of a variety of compounds under a number of differentdifferent experimentalexperimental conditions.conditions. The review mainly highlights the correspondingcorresponding literatureliterature published overover thethe lastlast years.years. Keywords: N,N-dimethylformamide; DMF; N,N-dimethylacetamide;-dimethylacetamide; DMAc; amination; amination; amidation; amidation; thioamidation; formylation;formylation; carbonylation;carbonylation; cyanation;cyanation; insertion;insertion; cyclizationcyclization 1. Introduction The organic, organic, organometallic organometallic and and bioorganic bioorganic transformations transformations are areextensively extensively carried carried out in out N,N in- Ndimethylformamide,N-dimethylformamide (DMF) (DMF) or N or,N-dimethylacetamideN,N-dimethylacetamide (DMAc). (DMAc). These These two twopolar polar solvents solvents are not are notonly only use usefor fortheir their dissolution dissolution properties, properties, but but also also as as multipurpose multipurpose reagents. reagents. They They participate participate in a number of processes andand serve as a source of variousvarious building blocks giving one or more of their own atoms (Scheme1 1).). O C HnC NMe2 H H C O n=0,1,2 O O C CH2 R N C Me O CN C O H NMe NMe 2 C Me n C R N n=1,2 R NMe n Me CH n=1,2 n O n=0,1,2 C C NMe2 R C O O NMe2 C C R R Scheme 1.1. Fragments from DMDM (R(R == H or Me) used in synthesis. In 2009, one of us reviewed the different roles of DMF, highlighting that DMF is much more than In 2009, one of us reviewed the different roles of DMF, highlighting that DMF is much more a solvent [1]. Subsequently, this topic has been documented by the teams of Jiao [2] and Sing [3]. For than a solvent [1]. Subsequently, this topic has been documented by the teams of Jiao [2] and Sing [3]. of a book devoted to solvents as reagents in organic synthesis, we wrote a chapter summarizing the Molecules 2018, 23, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Molecules 2018, 23, 1939; doi:10.3390/molecules23081939 www.mdpi.com/journal/molecules Molecules 2018, 23, 1939 2 of 31 Molecules 2018, 23, x FOR PEER REVIEW 2 of 29 Forreactions of a book consuming devoted DMF to solvents and DMAc as reagents as carbon, in organic hydrogen, synthesis, nitrogen we an wroted/or oxygen a chapter sources summarizing [4]. This thebook reactions chapter consumingtentatively DMFcovered and the DMAc literature as carbon, up to hydrogen,middle 2015. nitrogen The pres and/orent mini-review oxygen sources focuses [4]. Thison recent book chapterreactions tentatively which involve covered DM the (DM literature = DMF up or to DMAc) middle as 2015. a reagent The present although mini-review some key focuses older onpapers recent are reactions also included which for involve context. DM Processes (DM = DMF which orDMAc) necessitate as a the reagent prerequisite although synthesis some key of older DM papersderivatives are alsosuch included as the Vilsmeier-Haack for context. Processes reagents which [5] and necessitate DMF dimethyl the prerequisite acetal [6] are synthesis not surveyed, of DM derivativesbut a few suchreactions as the of Vilsmeier-Haack the present review reagents invo [5]lve and the DMF in-situ dimethyl formation acetal [of6] area Vilsmeier-type not surveyed, butintermediate a few reactions (Vilsmeier-type of the present reagents review involvehave been the in-situextensively formation used. of aSearch Vilsmeier-type on 26 June intermediate 2018 for (Vilsmeier-type“Vilsmeier” with reagents SciFinder have led been to 4379 extensively entries). used.Color Searchequations, on 26based June on 2018 literature for “Vilsmeier” proposals, with are SciFinderused to easily led to 4379visualize entries). the ColorDM equations,atom origin. based Wh onen literatureuncertainty proposals, is expressed are used by to easilythe authors visualize or thesuspected DM atom by us, origin. the atom When is typed uncertainty in italic. is expressedMechanistic by schemes the authors are not or suspectedreported, but by Scheme us, the atom2 [7– is35] typed summarizes in italic. different Mechanistic proposed schemes reactions are not of reported, DM with but the Scheme corresponding2[ 7–35] summarizes literature references, different proposedwhere DM reactions acts as either of DM a withnucleophilic the corresponding or electroph literatureilic reagent, references, or leads whereto neutral, DM ionic acts as or either radical a nucleophilicspecies. The or review electrophilic is divided reagent, in orSections leads to depending neutral, ionic on or the radical DM species. fragment(s) The review which is dividedis (are) inincorporated Sections depending into the reaction on the DM product. fragment(s) which is (are) incorporated into the reaction product. SchemeScheme 2.2. ReactionsReactions ofof DMDM ((RR= =H H or or Me Me).). 2.2.C C Fragment Fragment AerobicAerobic carbonylationcarbonylation underunder nickel/coppernickel/copper oror palladium/silverpalladium/silver synergistic catalysis occurredoccurred efficientlyefficiently using the the Me Me group group of of DMF DMF as as the the C Csour source,ce, affording affording cyclic cyclic carbonylated carbonylated compounds, compounds, via viathe thedirecting directing group-assist group-assisteded activation activation of ofa aC(sp C(sp2)–H2)–H or or C(sp C(sp3)-H3)-H bond bond (Equations (Equations (1) (1) and and (2) (2) [36], [36], EquationsEquations (3) and (4) [[37]).37]). Shifting from DMF to DMAc greatly decreased the yields (Equations (1) andand (3)).(3)). Molecules 2018, 23, x FOR PEER REVIEW 2 of 29 reactions consuming DMF and DMAc as carbon, hydrogen, nitrogen and/or oxygen sources [4]. This book chapter tentatively covered the literature up to middle 2015. The present mini-review focuses on recent reactions which involve DM (DM = DMF or DMAc) as a reagent although some key older papers are also included for context. Processes which necessitate the prerequisite synthesis of DM derivatives such as the Vilsmeier-Haack reagents [5] and DMF dimethyl acetal [6] are not surveyed, but a few reactions of the present review involve the in-situ formation of a Vilsmeier-type intermediate (Vilsmeier-type reagents have been extensively used. Search on 26 June 2018 for “Vilsmeier” with SciFinder led to 4379 entries). Color equations, based on literature proposals, are used to easily visualize the DM atom origin. When uncertainty is expressed by the authors or suspected by us, the atom is typed in italic. Mechanistic schemes are not reported, but Scheme 2 [7– 35] summarizes different proposed reactions of DM with the corresponding literature references, where DM acts as either a nucleophilic or electrophilic reagent, or leads to neutral, ionic or radical species. The review is divided in Sections depending on the DM fragment(s) which is (are) incorporated into the reaction product. Scheme 2. Reactions of DM (R = H or Me). 2. C Fragment Aerobic carbonylation under nickel/copper or palladium/silver synergistic catalysis occurred efficiently using the Me group of DMF as the C source, affording cyclic carbonylated compounds, via the directing group-assisted activation of a C(sp2)–H or C(sp3)-H bond (Equations (1) and (2) [36], EquationsMolecules 2018 (3), 23 and, 1939 (4) [37]). Shifting from DMF to DMAc greatly decreased the yields (Equations3 of (1) 31 and (3)). Molecules 2018, 23, x FOR PEER REVIEW 3 of 29 Molecules 2018, 23, x FOR PEER REVIEW 3 of 29 The Me group of DMF was also involved in the cyanation of the C(sp2)-H bond of arenes The MeMe group group of of DMF DMF was was also also involved involved in the in cyanation the cyanation of the C(spof the2)-H C(sp bond2)-H of arenesbond of catalyzed arenes catalyzed with an heterogeneous copper catalyst (Equation (5)) [38]. withcatalyzed an heterogeneous with an heterogeneous copper catalyst copper (Equation catalyst (5))(Equation [38]. (5)) [38]. 3. CH Fragment 3.CH CH Fragment Fragment Treatment of indole at 130 °C with suprastoichiometric amounts of CuI, t-BuOOH and AcOH in Treatment of indole at 130 °C◦ with suprastoichiometric amounts of CuI, t-BuOOH and AcOH in DMAcTreatment under air of indoleafforded at 130the correspondingC with suprastoichiometric C3-formylation amounts product of (Equation CuI, t-BuOOH (6)) [39]. and Such AcOH a DMAc under air afforded the corresponding C3-formylation product (Equation (6)) [39]. Such a inreaction DMAc also under occurred air afforded with N the-methylindole corresponding using C3-formylation CuI and CF3CO product2H in (EquationDMAc under (6)) oxygen [39]. Such [40]. a reaction also occurred with N-methylindole using CuI and CF3CO2H in DMAc under oxygen [40].