Syntheses and reactions of α -benzotriazolylenamines: stable analogs of α -Chloroenamines

Synthetic routes to and utility of α-benzotriazolylenamines have been explored. α-Benzotriazolylenamines 3a-g, 4a-f and 5a,b were successfully synthesized (i) from N -( trans - buten-1-yl)- N -methylaniline (2) by reaction with 1-chloro-1 H -1,2,3-benzotriazole, followed by base induced elimination of HCl and (ii) from amides 1a-g using benzotriazole, POCl 3 and NEt 3 in CH 3 CN. The utility of 3a-g, 4a-f and 5a,b as stable alternatives to α-haloenamines was demonstrated by the successful reaction of N -[1-(2 H -1,2,3-benzotriazol-2-yl)-2-methylprop-1- enyl]- N -methylaniline (5a) with phenylethynylzinc chloride to form N -methyl- N -[2-methyl-1-(2-phenylethynyl)-1-propenyl]aniline (7).


Introduction
The chemistry of α-haloenamines has been investigated extensively since their initial discovery 70 years ago. 1 They are highly effective reagents for replacing an OH moiety with a halogen under mild conditions.2a,b,c α-Haloenamines have been utilized as coupling reagents 3a,b and as precursors for α-aminovinyl Grignard reagents.4a,b Furthermore, they are versatile synthetic intermediates in the preparation of functionalized amides, 5a,b enamines, 5a 2-amino-1-azirines, 6 cyclobutenones, 7 cyclobutanones, 8 azetidinones 9 and numerous other classes of compounds. 10lthough the synthesis of α-haloenamines is reasonably easy, these compounds, especially α-haloenamines with only one substituent at the 2-position, are unstable and require special handling and conditions for storage. 11ecently, α-triflyloxyenamines have been successfully synthesized and used in further transformations.12a-d Thus, there is an interest in enamines with leaving groups other than halogen in the α-position.The benzotriazolyl (Bt) moiety can behave similarly to halogen substituents, but benzotriazolyl derivatives are typically more stable and less reactive than their halogen analogs. 13N-(α-Aminoalkyl)benzotriazoles are well-recognized synthetic intermediates that have been used in further reactions with nucleophiles. 14In this context, our attention was drawn to the potential of α-benzotriazolylenamines.

Results and Discussion
Preparation of Amides 1a-g.Amides 1a-g were synthesized in good to excellent yields by a procedure similar to the reaction reported by Human and Mills. 16An attempt to make the amide from octanoic acid and carbazole failed, possibly due to the poor solubility of carbazole in the solvent system used.Amides 1a,b,c,f,g 17a-e (Table 1) have been previously described; their proton and carbon-13 NMR spectra and boiling and melting points were consistent with those reported in the literature and with the proposed structure.N-Ethyl-N-phenylhexanamide (1d) and N,N-diphenylhexanamide (1e) gave satisfactory elemental analyses and NMR spectra.
Preparation of enamine 2b.Syntheses of enamines formally derived from an aliphatic aldehyde unbranched in the 2-position and an N-alkylaniline are rare (for reviews on enamines see 18a,b ).
Elimination of dimethylammonium bromide, as used in the synthesis of N-methyl-N-vinylaniline 19 is limited by the isomerization which converts N-allyl-N-methylaniline into N-methyl-N-(1-propenyl)aniline. 20We synthesized enamine 2b by the reaction of BtH, butyraldehyde (1 equiv) and N-methylaniline (1 equiv). 21eparation of α-benzotriazolylenamines 3a-g, 4a-f and 5a,b.We have now explored and extended the reaction of BtH and POCl3 with an amide for the synthesis of αbenzotriazolylenamines.In a typical procedure, BtH (4 equiv), POCl3 (2 equiv), NEt3 (2 equiv) and the tertiary amide 1 (5 mmol) were sequentially added dropwise as solutions in CH3CN into a nitrogen-blanketed round-bottomed flask at rt (Scheme 2).Disappearance of the amide was monitored by TLC or GC.The reactions which afforded Bt-enamines 3a,c,d and 4a,c,d were performed over 14 h at rt, but refluxing was required for the synthesis of Bt-enamines 3g, 5a ( ) and 3b, 4b (10 d).The reaction was worked-up as described in the experimental section once no amide was left in the reaction mixture.
Structure elucidation of α -benzotriazolylenamines 3a-g, 4a-f and 5a,b.α -Benzotriazolylenamines 3a-g, 4a-f and 5a,b were all characterized by elemental analysis and by their 1 H and ) is evidence that the vinylic proton is attached to the same carbon of the double bond as the alkyl fragment derived from the acid portion of the amide.
When C2 has an attached proton as in Bt-enamines 3a-f, 4a-f and 5b, both α-Bt 1 -and α-Bt 2enamines could exist as either E or Z isomers.Stereochemistry of the Bt 1 compounds was assigned based on the fact that irradiation of the C7 proton of the Bt 1 moiety (δH 7.74 ppm) of N- positive NOE for the vinylic proton (δH 5.94 ppm), establishing a cisoid relationship between these two groups in this compound (Figure 1).For the Bt 1 isomers (Table 2), the vinylic proton consistently appeared at either δH ~6.0 ppm for the E or δH ~5.5 ppm corresponding to the Z isomer for each pair of products from an amide.Due to this consistency in the chemical shifts of the two isomers, and the fact that the stereochemistry of Bt-enamine 4e (δH 5.94 ppm) was confirmed as E by an NOE experiment, it was concluded that all such Bt 1 isomers with δH ~6.0 ppm 4a-e had E stereochemistry and those with δH ~5.5 ppm 3a-e had Z stereochemistry.Its NMR spectra were similar to those of Bt-enamine 3g, except for the expected differences between Bt 2 and Bt 1 compounds.
It is shown by NMR spectra of the pure samples that the Bt 1 isomeric pairs 3 and 4 did not interconvert under ambient conditions either neat or in solution.Additionally, Bt-enamines 3a-g, 4a-f and 5a did not decompose under acidic (POCl3) reaction conditions, basic (saturated aqueous K2CO3) work-up or silica gel column chromatography.a -Benzotriazolylenamines 3a and 5b, which were made by reaction of enamine 2b with BtCl, were stable to the basic reaction conditions (t-BuOK) and silica gel column chromatography.
Limitations to the Preparation of a -Benzotriazolylenamines 3 and 4 from Amides 1.Although the synthesis of α-benzotriazolylenamines tolerated alkyl (1a-e,g) and aryl (1f) groups as well as linear (1a,c-e) and branched (1b,g) groups on the acid portion of an amide, the amine portion of the amide had to be a tertiary aniline derivative.Thus, N-methyl-2-pyrrolidinone, N,Ndimethylpropionamide and 1-acetylpiperidine did not yield any a -benzotriazolylenamine.The use of other acetamides (N-methylacetanilide and N-phenylacetanilide) also failed to give any desired α-benzotriazolylenamine. Starting amide was recovered when CH2Cl2 or THF was used as solvent instead of CH3CN.

Conclusions
In conclusion, the earlier work in this group 15a,b on the synthesis of α-benzotriazolylenamines was further developed in order to ascertain the scope and limitations of these syntheses and to demonstrate the potential utility of α-benzotriazolylenamines as stable analogs to αchloroenamines.A variety of α-(benzotriazol-1-yl)enamines 3a-g, 4a-f and 5a were easily prepared as separated E and Z isomers, except for the mixture of Bt-enamines 3f/4f, in good overall yields from amides 1a-g by the action of BtH, POCl3 and NEt3.The amides 1a-g were readily synthesized in excellent purity from reactions of acids with aniline derivatives by the action of SOCl2 and pyridine.

Experimental Section
General Procedures.All melting points were measured on a hot-stage microscope and are uncorrected.NMR experiments were conducted with a Varian VXR-300 NMR spectrometer at 75 MHz for 13 C and 300 MHz for 1 H spectra.Samples were dissolved in CDCl 3 with the internal reference being TMS (δH = 0.00 ppm) for 1 H spectra and the solvent (δC = 77.0ppm) for 13 C spectra.Elemental analyses were performed on a Carlo Erba-1106 elemental analyzer.Prior to use, CH3CN was distilled from CaH2, Et2O and THF were distilled from Na/benzophenone and toluene was distilled from Na. Column chromatography was carried out using silica gel (230-400 mesh, Fisher).All other chemicals were obtained from commercial sources and were not further purified.Reactions were carried out under dry nitrogen with magnetic stirring.

Preparation of amides 1a-g
All amides were synthesized in good yields using the procedure of Human and Mills, which delivers pure compounds. 16Pyridine (20 or 50 mmol) was added to a Et2O solution of an aliphatic acid (1 equiv).After 5 min in an ice water bath, SOCl2 (1 equiv) was added dropwise to the reaction vessel.After 5 min, a mixture of pyridine (1 equiv) and aniline derivative (1 equiv) was then added dropwise to the reaction vessel.The ice bath was removed, and the mixture stirred for 2 h at rt. Successive washes with 2 N HCl(aq) (3 x 100 mL), 10% NaOH(aq) (3 x 50 mL) and brine (50 mL) gave, after reduced-pressure removal of volatiles, analytically pure product.

General procedure for the synthesis of α-Benzotriazolylenamines 3a-g, 4a-f and 5a
A pressure equalized dropping funnel was placed on a 250 mL round bottom flask containing a magnetic stirrer, BtH (20 mmol, 2.38 g) and a nitrogen inlet.Acetonitrile was added to the round bottom flask (10 mL) and to the dropping funnel (7 mL).The vessel was heated gently until the BtH dissolved, and then cooled to rt.Phosphorus oxychloride (10 mmol, 0.925 mL) was added to the dropping funnel, the contents of which were gently swirled and then added dropwise to the reaction vessel.The dropping funnel was rinsed with CH 3 CN (7 mL) and then filled with the same.Triethylamine (10 mmol, 1.01 g) was added to the dropping funnel, the contents of that were swirled and then added dropwise to the vessel.After 15 min a solution of amide 1 (5 mmol) in CH3CN (3 mL) was added in one portion, and the dropping funnel replaced with a waterjacketed condenser topped with a nitrogen inlet.Complete reaction, as determined by GC or TLC analysis, sometimes required refluxing.Volatile compounds were removed under reducedpressure using a rotary evaporator.The resulting oil was dissolved in CHCl3 (100 mL).
Saturated, aqueous K 2 CO 3 (200 mL) was added, and the mixture swirled.After 30 min the mixture was filtered through a medium sintered funnel under reduced pressure (water aspirator).
The layers were separated, and the aqueous layer extracted with CHCl3 (50 mL).The combined organic solutions were dried over anhydrous Na2SO4, filtered and had the solvent removed by rotary evaporation.The residue was purified by silica gel, flash column chromatography using a pentane/Et2O mixture as eluent.The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL).The combined organics were dried over anhydrous Na2SO4, filtered and had the volatiles removed by rotary evaporation.The title compound was obtained in 76% yield as a red oil by silica gel, flash column chromatography using pentane as eluent;

Table 1 .
Physical Properties for Compounds 1a-g