An efficient method for the synthesis of substituted N-aryl lactams

Article history: Received October 21, 2014 Received in revised form January 29, 2015 Accepted 10 March 2015 Available online 16 March 2015 A quick, efficient, and one-pot method for the synthesis of substituted N-aryl lactams through the reaction of various kinds of corresponding substituted arenes with a variety of ω-azido alkanoic acids using trifluoromethanesulfonic acid (triflic acid) at room temperature, by insitu involvement of Friedel-Crafts reaction followed by intramolecular Schmidt rearrangement was developed, and afforded good to excellent yields. © 2015 Growing Science Ltd. All rights reserved.

Traditional synthesis of substituted N-aryl lactams involved through the direct coupling reaction of substituted aryl halides with cyclic amides catalyzed by a transition metal catalyst. 18So far significant improvements have been achieved in Pd-catalyzed amide arylation reactions 19 but the method remains hard to apply these reactions to a large and industrial scale syntheses due to high cost of Pd and the difficulty in removing Pd residues from the polar reaction products.An alternative method for aryl amidation involves Cu-catalyzed Goldberg reaction between cyclic amides and aryl iodides. 20his method is attractive from economic standpoint because Cu is much cheaper than Pd.Despite this advantage, the Goldberg reaction is not a popular reaction in organic chemistry due to the necessity to use temperatures as high as 210 o C, highly polar aprotic solvents, strong bases such as alkoxides and NaH, large amounts of the nucleophile and often large amounts of Cu catalysts.In recent years, several kinds of efficient ligands have been used to promote this reaction such as diamines. 21diimines, 22 aminoacids, 23 β-ketoesters, 24 and diols. 25Some of the other multi-step synthetic routes for the synthesis of substituted N-aryl lactams have also been reported. 26The majority of the above mentioned routes are associated with several drawbacks such as low reactivity, requirement of large amount of catalysts and ligands, costly, toxic and moisture sensitive nature of catalysts, harsh reaction conditions, tedious work-up, longer reaction times, generation of toxic byproducts and, sometimes, two or more steps.Therefore, there is continued interest in developing new, efficient, and safer protocols employing mild reaction conditions.Recently, we have reported an efficient method for the synthesis of substituted Naryl lactams from the corresponding arenas and ω-azido alkanoic acid chloride employing catalytic amount of EtAlCl2 and BF3OEt2 respectively. 27We report herein an efficient and mild protocol for the synthesis of substituted N-aryl lactams starting from their corresponding substituted arenes using a variety of ω-azido alkanoic acids mediated by triflic acid (trifluoromethanesulfonic acid) at room temperature.To the best of our knowledge, this is the first report for the efficient and mild one-pot synthesis of substituted N-aryl lactams from the corresponding substituted arenes using triflic acid, which is exploring new interesting chemistry (through cascade reactions of Friedel-Crafts reaction followed by Schmidt rearrangement) than the reported methods and thus exploring a novel synthetic route.

Results and Discussion
The ω-azido alkanoic acids 4, 5, 6 are key intermediates for this single-step coupling methodology and have been synthesized from their corresponding cyclic ketones 1, 2, 3 respectively, following the standard reported procedure (Scheme 1). 28Initially, a reaction of 1,2-dimethoxybenzene (7) with a 4azidobutanoic acid (5) (n = 1) using triflic acid in dry CH2Cl2 was tried at room temperature (entry 1) and the corresponding 1,2-dimethoxy N-aryl lactam product formation was indeed realized.a Products were characterized by IR, NMR and MS data, which were identical to previously reported values. 27oduct formation was further confirmed through the appearance of an amidic peak at ~1660 cm -1 in IR.The identification of the desired product was further confirmed through various spectroscopic and analytical techniques and was further confirmed through our reported authentic samples. 27This reaction was also tried in various dry organic solvents such as chloroform, acetonitrile, methanol, acetone, DMSO, DMF, CH2Cl2 etc. and thus found that dry CH2Cl2 is best among all in carrying out this transformation at room temperature.Then, we optimized the scope of this method through the reaction of a variety of 3,4,5-substituted arenes 7 containing electron releasing/electron withdrawing groups with different kinds of ω-azido alkanoic acids 4, 5, 6 (Scheme 2).Thus, a variety of N-aryl lactams were synthesised and characterized through the IR, NMR, and mass spectral data.It was further realized that the yields of the N-aryl lactam was depend upon the type of substitution on the aromatic ring of the corresponding arene used.Furthermore, by introducing an electron releasing group at aromatic nucleus of the arene led to increasing yield of the substituted N-aryl lactam and by introducing electron withdrawing groups led to decrease in yield as depicted in Table 1.
We proposed that triflate of ω-azido alkanoic acids will form intermediate II through the Friedel-Crafts acylation reaction, which on subsequent 1,2-shift (i.e.C-N) of aryl migration of intermediate III through the intramolecular Schmidt rearrangement led to the formation of the desired substituted N-aryl lactam I (Scheme 3, Pathway I).Furthermore, the acylated compound II may also form nitrene intermediate IV which on subsequent C-H insertion may form intermediate V, electronic rearrangement of V may led to the formation of the corresponding N-aryl lactam of general formula I (Scheme 3, Pathway II).

Scheme 3. Proposed mechanism of formation of substituted N-aryl lactams of general formula I
To further validate this methodology, a reaction of 1,2-dimethoxybenzene was tried with previously synthesized 4-bromobutanoic acid chloride employing triflic acid afforded the corresponding acylated bromo-product through the Friedel-Crafts reaction, which on treatment with NaN3 afforded the corresponding 4-azidoacylated compound III.Treatment of compound III with triflic acid afforded the corresponding N-aryl lactam through the Schmidt rearrangement (Scheme 4).The spectral data of the synthesized compound was correlated with the N-aryl lactam compound (Tab.1, entry 1) synthesized through the direct coupling method.

Conclusions
In conclusion, we have developed an efficient and novel method for the synthesis of substituted Naryl lactams through the reaction of corresponding arenes with ω-azido alkanoic acids employing triflic acid at room temperature.This is a new and one-pot method using catalytic amount of triflic acid which afforded high yields (62-98%) of the desired substituted N-aryl lactams in shortest reaction time (20-60 min.)and dominates over the reported procedures in respect of milder reaction conditions, high yields, and shorter reaction time.

Experimental
Chemicals were procured from Merck, Aldrich, and Fluka.Reactions were carried out under argon.IR spectra 4000-200 cm -1 were recorded on Bomem MB-104-FTIR spectrophotometer using neat technique, whereas NMRs were scanned on an AC-300F, NMR (300 MHz & 75MHz) instrument using CDCl3 and TMS as internal standard.Elemental analysis were conducted by means of a Carlo-Erba EA 1110-CNNO-S analyzer and agreed favorably with calculated values.

Typical experimental procedure for the synthesis of substituted N-aryl lactams:
An equimolar amount of substituted arene and the corresponding ω-azido alkanoic acid were taken in dry CH2Cl2 (25 ml), and stirred for 10 min.at room temperature.To this, 1/10 th molar amount (with respect to arene) of Lewis acid was added slowly in 2-3 small portions at room temperature.The reaction was continued until completion (cf Table 1) as confirmed by TLC.The reaction mixture was then poured into distilled water (50 ml) and extracted with dichloromethane.The organic layer was separated and dried over anhydrous sodium sulfate and then concentrated to afford the desired substituted N-aryl lactam compound.

Table 1 .
Conversion of various substituted arenes into substituted N-aryl lactams of general formula