CN and NH Bond Metathesis Reactions Mediated by Carbon Dioxide

DOI:10.1002/cssc.201500318 Full Papers C Nand N HBond Metathesis Reactions Mediated by CarbonÀ DioxideÀ Yehong Wang,[a] Jian Zhang,[a] Jing Liu,[a] Chaofeng Zhang,[a, b] Zhixin Zhang,[a] Jie Xu,*[a] Shutao Xu,[a] FangjunWang,[a] andFengWang*[a] Herein, we report CO2-mediated metathesis reactions between ditions. The experimental data and in situ NMR and attenuated amines and DMF to synthesize formamides. More than total reflectance IR spectroscopy measurements support the 20 amines, including primary,secondary,aromatic, and hetero- formation of the N-carbamic acid as an intermediate through cyclic amines,diamines, and amino acids, are converted to the the weak acid–base interaction between CO2 and the amine. corresponding formamideswith good-to-excellent conversions The metathesis reaction is driven by the formation of astable and selectivities under mild conditions. Thisstrategy employs carbamate, and areactionmechanism is proposed. CO2 as amediator to activate the amine under metal-free con- Introduction The selective N-formylation of amines to formamidesisasignif- different to previous ones that required activated formylation icant reaction in organic,medicinal, andbiological chemistry.[1] reagents,metal-containing catalysts, and strong additives. In Formic acid[2] or in situ-generated formic acid,[3] DMF,[4] alde- addition, the reaction can be performed in air ( 400 ppm CO 2 hydes,[5] and their derivatives have been used as formylation in the atmosphere) with comparableresults. Moreover,ithas reagents.However,the majority of examples require high tem- broad substrate compatibility. peratures, water-sensitive reagents, or complex workups and, thus, are unsuitable for use with fine chemicals, pharmaceuti- cals, and molecules bearing diverse functional groups, such as proteins and thiophenes. Reactions induced by weak acid–base interactions play akey [6] role in living systems and in the chemical industry. For exam- Results and Discussion ple, CO2 generated from cellular respiration is expired in part through the reversible formation of acarbamate between CO2 First, we optimized the reaction temperature and time. The and the amino groups of hemoglobin.[7] Furthermore, the reac- temperature dependence of the conversion of benzylamine in tions of primary and secondary amines with CO2 are used to DMF under 1bar of CO2 gas is summarized in Figure S1. The captureCO2through the formation of azwitterion first and onset temperature for the reaction has been reported to be then acarbamate.[8] Encouraged by these previous studies, we more than 80 8Coreven as high as 1508C.[10] In this study,the proposed the possibility of utilizing the weak interactions be- onset temperature ( 40 8C, defined as the 30%conversion tween CO and amines to functionalize N Hbonds. We report temperature) is clearly much lower.The conversion increased 2 À here the results on the N-formylation of amines mediated by with increasing reactiontemperature and reached 92%after CO through ametathesis reaction [Eq. (1)].Usually,C Nbond 4hat 1008C. The selectivity for N-benzylformamideisalso pre- 2 À activation requires metal catalysts.[9] This method is markedly sented in Figure S1. An increased reaction temperature of 608Corhigheroffered almost pure N-benzylformamide. The [a] Y. Wang, J. Zhang, J. Liu, C. Zhang, Z. Zhang, Prof. Dr.J.Xu, Dr.S.Xu, reactiondid not proceed under Ar gas. The reactioninair of- Dr.F.Wang, Prof. Dr.F.Wang fered comparable resultsin48h.In1973, Kraus reported that State Key Laboratory of Catalysis (SKLC) the formylation of aliphatic amines occurred in pure DMF.[11] Dalian National Laboratoryfor Clean Energy(DNL) Up to 100 hwas required to complete the reaction. Our study Dalian Institute of Chemical Physics (DICP) Chinese Academy of Sciences revealed that the reactionconducted by Kraus might be medi- 457 Zhongshan Road, Dalian 116023 (PR China) ated by the slow absorption of atmospheric CO2 into the reac- E-mail:[email protected] tion mixture. [email protected] The progress of the reaction as monitored by GC is dis- [b] C. Zhang played in Figure 1. The formylation of benzylamine was con- University of the Chinese Academy of Sciences No.19A Yuquan Road, Beijing 100049 (PR China) ducted in DMF at 1008Cunder 1bar of CO2.The conversion of Supporting Information for this article is available on the WWW under benzylamine increased significantly to 86%in2hand then http://dx.doi.org/10.1002/cssc.201500318. slowed down and reached 93%in8hand > 99%in24h. ChemSusChem 2015, 8,2066 –2072 2066 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Papers Figure 1. Time-on-stream profile of the formylation of benzylamine to benzylformamide. Reactionconditions: benzylamine (1.5 mmol), DMF (2 mL), 1bar CO2,100 8C. Through the whole reaction, the selectivity for N-benzylform- Figure 2. Relationship between amine conversion and pKa(N H) values. Reac- À amide was > 99%. tion conditions:amine (0.6 mmol), DMF (2 mL), 1bar CO2,1008C, 2h. Areaction with isotopically labelled [D7]DMF was conducted to clarify the reaction route (Figure S2).The molecular ion (M+) thumb, it helps to determine which kind of amine can be con- peak of N-benzylformamide(normal m/z=135) increased to verted by this method. m/z=136 (labeled), and the M+ peak of dimethylamine (m/z= We then studied the substrate scope (Table 1). Sterically un- 45) increased accordingly to m/z=51 (Figures S3 and S4). We hindered linear aliphatic amines with chains of up to 12 13 also used CO2 instead of CO2 in this reaction system.There carbon atoms were converted to the corresponding forma- was no increase for the molecular ion peak of N-benzylforma- mides with >99 %selectivity and >99 %conversion(1–5); mide and it remained at m/z= 135. However,ifthe Catom these resultsare better than those reported previously.[10,14] Ali- 13 + came from CO2,the M peak of N-benzylformamide should cyclic cyclohexylamineand cyclopentylamine wereconverted have an m/z value of 136. The resultsconfirm that (1) ameta- satisfactorily to the corresponding formamides(4and 5). No thesis reactionoccurs between the amine and DMF,(2) DMF is conversion was observed for dipropylamine and diethylamine the formylation reagent, and (3) CO2 is amediator,not areac- (6 and 7). However,ahydroxy-terminated amine (8)and piperi- tant. In someother studies, although CO2 wasadded and for- dine (9)achieved 23 %and >99%conversion,respectively, mamides were products,the real reaction involved the hydro- with > 99%formamide selectivity.These amines were different genationofCO2to formic acid, which functioned as the formy- at the terminal group. Steric as well as electronic and solvation [3h,i, 5a,12] lation reagent. In contrast, the CO2-mediated method effects might affect their activity.The two terminal hydroxy requires no metal catalystand no hydrogen. Moreover,itcan groups might form hydrogen bonds and, thus, expose more be used to prepare 13C-labeled formamides. space for the N Hbond activation. Piperidine, which could be À We then investigated the dependence of the initial amine viewed as amolecule in which the terminal groups are conversion (2 h) on the pKa(N H) values. The largerthe pKa(N H) bonded, achieved better results. In contrast, apiperidine for- À À value, the stronger the amine basicity.Aplot of pKa(N H) versus mamide was obtained with only 36%yield in aB(OCH2CF3)3– À conversion produces symmetric linear fits that intercept at the DMF system.[10] To show the practical application of the proce- maximum point of pKa(N H) = 9.9 (Figure 2). The left end point dure, agram-scale synthesis of dodecylamine(2.78 g) was per- À was determined by extending the left half line to y=0, which formed. The reaction offered 97 %isolated yield of dodecylfor- intercepted the x axis at pKa(N H) =8.6. The right end point was mamide (3). À determined by dipropylamine [pKa(N H) = 10.6].The experimen- Heterocyclic amines such as furfurylamine and 2-thiophene- À tal data showed that the metathesis reaction relies greatlyon methylamine were converted to formamides(10 and 11,re- the amine pKa(N H),and only amines within the pKa(N H) range spectively) with selectivities of > 99%. To the best of our À À 8.6–10.6were converted into formamides. This explains why knowledge,this methodrepresents arare example of the for- the reactions with aniline and some diamines weresluggish.[13] mylation of athiopheneamine because sulfur may poison The basicity of the amine affects the strength of the interaction most catalytic metal centers.Several benzylamines were con- between the Natom of the amine and the Catom of CO2: verted with excellent formamide selectivities (12–18). Aslight weak basicity [such as aniline, pKa(N H) <8.6] resultsinaninsta- substituent effect was evidenced by the lower conversion of À ble amine–CO2 adduct;strong basicity [pKa(N H) > 10.6] gener- the CF3-substituted benzylamine than for the F-substituted À ates an interaction that is too stable, and the CO2 is bound one. The less-nucleophilic aniline was inactive (19)because of strongly.The amines in Figure 2were selected after consider- its weak basicity (Figure 2). The formylation of the sterically un- ation of both the pKa(N H) and steric hindrance;therefore, some hindered hexane-1,6-diamine afforded 99%ofthe diforma- À amines fall out of this range. However,asasimple rule of mide (20). Aworse result than that for hexane-1,6-diamine was ChemSusChem 2015, 8,2066 –2072 www.chemsuschem.org 2067 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Papers methods remains ahot topic.[16] In this study,wetested the la- Table 1. Substrate scope of the reaction.[a] beling of protein amine groupswith DMF through metathesis Structure Compound Conversion Selectivity reactions. We added alittle water to promote solubility but [%] [%] sacrificed some activity.After the reaction, both unreacted ar- 1 n=3 >99 >99[b] ginine (m/z=175) and formylated arginine (m/z=203) were 2 n=5 >99 >99 detected by means of matrix-assisted laser desorption/ioniza- 3 n=11 > 99 >99 tion–time of flight (MALDI-TOF)/TOF MS (Figure 3A).

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