1,3-Dipolar cycloadditions of organic azides to ester or benzotriazolylcarbonyl activated acetylenic amides

Reactions of 3-lithiopropiolate 10 with isocyanates or diisocyanates gave mono-carbamoylpropiolates 11a,b and bis-carbamoylpropiolates 12a − d , in 40 − 76% yields. 1,3-Dipolar cycloadditions of benzyl azide ( 1a ) and mono-acetylenes 11a,b under thermal conditions gave mono-triazoles 13a,b in 83 and 84% yields, respectively. The structure of 13a was confirmed by X-ray crystallography. Microwave induced cycloadditions of mono-azide 1a with bis-carbamoylpropiolates 12a − d furnished the bis-triazoles 14a − d . Similar reactions of 3-(azidomethyl)-3-methyloxetane ( 15 ) with mono-acetylenes 11a,b or bis-acetylenes 12a,d produced the mono-and bis-triazoles 16a,b and 17a,b , respectively. Reactions of 1,4-bis(azidomethyl)benzene ( 1b ) with mono-acetylenes 11a,b gave the azido-triazoles 18a,b and microwave irradiation with simultaneous air-cooling gave bis-triazoles 19a,b . 1,3-Dipolar cycloaddition of benzotriazolylcarbonyl-substituted acetylene 4 and benzyl azide ( 1a ) proceeded smoothly under microwave irradiation or thermal conditions to give the corresponding triazole 20 , which on further treatment with a variety of amines gave the C -carbamoyl triazoles 21a − d in 54 − 91% yields.


Introduction
1,2,3-Triazoles possess therapeutic value, 1 are synthetic intermediates in the preparation of medicinal compounds, 2 and find numerous applications in the chemical industry. 3Triazoleoligomers have been considered as new, robust binder systems for high-energy explosive and propellant formulations. 4The design and synthesis of such compounds is presently in the initial stage of development, but it is already known that structural features such as the length of chains between the triazole cross-links and the substituents on the triazole ring significantly impact the mechanical properties of triazole-oligomers.
1,3-Dipolar cycloaddition of azides to alkynes is the optimum method for the preparation of 1,2,3-triazoles 3a,5 and copper (I) catalyzed reactions offer good regioselectivity.5f Cycloadditions are faster with electron-withdrawing substituents on the acetylene moiety, while their presence on the azide has the opposite effect.5d Previously utilized activating substituents on the alkyne include especially alkoxycarbonyl 6 and other electron-withdrawing groups such as carboxyl, acyl, cyano, aryl, haloalkyl, trimethylsilyl, phenylsulfonyl or phosphonate. 7Functionalities on the acetylene play an important role in the kinetics of 1,3-dipolar cycloaddition reactions; for example, while reactions with alkoxycarbonyl substituents are fast and require low reaction temperature, carbamoylacetylenes require high temperatures and reaction times of 24 h to one week.7e,8 The low reactivity of acetyleniccarboxamides towards 1,3-dipolar cycloaddition with azides has remained a problem for direct access to important 1,2,3-triazoles with a carbamoyl substituent; the preparation of these compounds has generally involved the use of easily available 1,2,3-triazole esters, 1a,9 -acids or -imines 10 as intermediates, followed by a functional group transformation to amide.
Synthesis of oligomers with 1,2,3-triazole subunits is an emerging area in macromolecular chemistry: with examples on the preparation of bis-triazoles or triazole-oligomers by the 1,3-dipolar cycloaddition of diacetylenes and diazides, 11a,b diacetylenes and monoazides, 11c diazides and monoacetylenes, 11d or tris-acetylenes and diazides.11e The reported examples commonly use ester substituents and mostly require long reaction times (1-5 days) and relatively high temperatures (80-100 o C). 11a In continuation of an ongoing program in our laboratories to develop strategies for lowtemperature synthesis of 1,2,3-triazoles 12 and oligo-and poly-triazoles as new high-energy explosive and propellant ingredients, we now report the 1,3-dipolar cycloadditions of organic azides to ester or benzotriazolylcarbonyl activated acetylenic carboxamides, under mild conditions.

Results and Discussion
Preparation of acetylenic carboxamides and preliminary experiments on triazole formation.A literature search for the preparation of acetylenic carboxamides revealed few reports; (i) reaction between methyl propiolate and an amine (conducted at -30 o C, for the desired 1,2-addition to predominate over 1,4-addition), 13a,b (ii) Ritter reaction between cyanoacetylene and an appropriate carbenium ion generated in the presence of concentrated sulfuric acid, 13c (iii) reaction of amines with either the N-hydroxysuccinimide ester or a mixed anhydride of propiolic acid.13d Methods (i) and (ii) give low to moderate yields or mixtures with products resulting from 1,4-addition, while method (iii) usually affords a 1:1 mixture of the required acetylenic amide with an amide formed from ethyl chloroformate.13d A general and mild procedure for the preparation of primary, secondary and tertiary amides from carboxylic acids via N-acylbenzotriazoles was recently reported by our group, 13e but this procedure was not previously tested with acetylenic acids.Since few methods for the preparation of acetylenic amides are available in the literature, we explored the N-acylbenzotriazole route.Interestingly, reaction of phenylpropiolic acid (2) with 1-(methylsulfonyl)-1H-benzotriazole (3) 13e furnished the N-propioloylbenzotriazole 4 in 50% yield.Reaction of 4 with morpholine (5) in THF at 25 o C for 12 h gave the corresponding acetylenic amide 6 in 53% yield.Under similar conditions, reaction of 4 with 1,4-diaminocyclohexane (7) gave the acetylenic diamide 8 in 65% yield (Scheme 1).
Our objective was to prepare the triazoles under mild conditions.Reactions of acetylenic amides 6, 8 with benzyl azide (1a) were attempted in refluxing acetone for 12 to 24 h but no triazole formation could be detected by TLC or 1 H NMR analyses and the starting materials were recovered (Scheme 1).Literature reports support the need of high temperatures (>100 o C) to effect the 1,3dipolar cycloadditions of acetylenic amides and organic azides.7e

Scheme 1
The presence of electron-withdrawing substituents on the acetylene facilitates the 1,3-dipolar cycloaddition with organic azides owing to the mechanism and energies of the HOMO-LUMO interactions involved to form the 1,2,3-triazole ring.5d,14 Alkoxycarbonyl has been the most widely used alkyne substituent and 1,3-dipolar cycloadditions of acetylenic esters and organic azides proceed under mild conditions (50−60 o C) to give the corresponding triazoles in good to excellent yields.3a The failure of 1,3-dipolar cycloaddition of benzyl azide (1a) with acetyleniccarboxamides 6, 8 in refluxing acetone and the requirement of higher reaction temperatures in the reported examples 7e,8 indicate that the degree of activation provided by the carbamoyl group is much lower than that available from an alkoxycarbonyl substituent.It was concluded that low temperature triazole formation cannot be realized by the presence of the carbamoyl group alone on the acetylene.Therefore, we decided to incorporate an ester group in the acetylenic amides to study their 1,3-dipolar cycloaddition with organic azides under mild conditions.Preparation of mono-and bis-carbamoylpropiolates.Treatment of ethyl propiolate (9) with n-BuLi at -78 o C and reaction of the resulting 3-lithiopropiolate 10 with phenyl isocyanate or p-tolyl isocyanate gave the carboxamido-substituted propiolates 11a and 11b in 76 and 64% yields, respectively. 15Using this procedure, we also prepared bis-carbamoylpropiolates 12a−d.Thus, reaction of the carbanion 10 with 1,4-phenylene diisocyanate, tolylene Preparation of mono-and bis-triazoles.The concept of increasing the activation of acetylenic amides by further substitution with an ester functionality was realized when 1,3-dipolar cycloadditions of benzyl azide (1a) with carbamoyl-substituted propiolates 11a or 11b proceeded smoothly in refluxing acetone to give the N-substituted 1,2,3-triazoles 13a and 13b as the major regioisomers in 83 and 84% yields, respectively.The successful preparation of triazoles 13a,b is the first example of low-temperature 1,3-dipolar cycloaddition of organic azides to ester activated acetylenic amides under thermal conditions (Scheme 3) (Table 1).
Microwave heating has emerged as a useful technique to promote a variety of chemical reactions. 16We recently reported our preliminary results on microwave induced 1,3-dipolar cycloadditions of acetylenic carboxamides and organic azides under mild conditions. 17Herein, we report the extension of this method to synthesize substituted mono-triazoles by the 1,3-dipolar cycloaddition of mono-azides with mono-acetylenes and bis-triazoles from mono-azides and diacetylenes or di-azides and mono-acetylenes, under microwave irradiation.Thus, microwave reaction of benzyl azide (1a) with bis-carbamoylpropiolate 12a at 100 o C and 120 W irradiation power for 1 h gave a regioisomeric mixture of bis-triazoles.The regioisomers were separated and characterized as bis-triazoles 14a′ and 14a′′ in 42 and 37% yields, respectively.Similar reactions of benzyl azide (1a) with bis-carbamoylpropiolates 12b, 12c or 12d gave the corresponding bistriazoles 14b, 14c or 14d as the major regioisomers in 41, 37 or 73% yields, respectively (Scheme 3) (Table 1).The corresponding minor isomers were present in the mixtures but were not isolated pure.
For identity of R, see Table 1.
Under similar conditions, microwave reactions of 3-(azidomethyl)-3-methyloxetane (15) with carbamoylpropiolates 11a or 11b at 55 o C and 120 W microwave irradiation power gave the triazoles 16a or 16b as the major regioisomers in 72 and 53% yields, respectively.Also, the reactions of 15 with bis-carbamoylpropiolates 12a or 12d furnished the bis-triazoles 17a and 17b as the major isomers in 43 and 42% yields, respectively (Scheme 4) (Table 1).Structures of all the isolated mono-and bis-triazoles were confirmed by NMR ( 1 H and 13 C) and elemental analysis or high resolution mass spectrometry.
11a,b 15 Scheme 4. For identity of R, see Table 1. a Isolated yields.
Next, we explored the preparation of bis-triazoles by 1,3-dipolar cycloadditions of di-azides and mono-acetylenes.Microwave reactions of di-azide 1b with carbamoylpropiolates 11a or 11b at 120 W irradiation power and 55 o C temperature for 30 min.resulted in 1,3-dipolar cycloaddition at only one of the azido moieties to give the regioisomeric mixtures of azido-triazoles that were isolated as 18a and 18a′ in 60 and 12% yields or 18b and 18b′ in 54 and 18% yields, respectively (Scheme 5) (Table 1).Triazole formation at the second azido moiety in di-azide 1b could not be induced even after repeated trials with different reaction conditions.Increasing the temperature or irradiation power to higher levels resulted in charring and decomposition.Interestingly, use of a new model microwave synthesizer equipped with simultaneous irradiation and external air-cooling system proved beneficial.The reaction of 1,4-bis(azidomethyl)benzene (1b) with 2 equiv of ethyl 4anilino-4-oxo-2-butynoate (11a) in toluene under continuous microwave irradiation (120 W) with simultaneous cooling at 75 o C for 1 h furnished a mixture of regioisomeric bis-triazoles; the major regioisomer 19a was isolated by column chromatography in pure form in 54% yield.Similarly, bistriazole 19b was isolated in 65% yield from the reaction of di-azide 1b and ethyl 4-oxo-4-(4toluidino)-2-butynoate (11b) by the simultaneous cooling and irradiation procedure (Scheme 5) (Table 1).Thus, using microwave irradiation we have developed new methods of preparation of substituted bis-triazoles by the 1,3-dipolar cycloadditions of mono-azides and bis-acetylenes or diazides and mono-acetylenes.Scheme 5.For identity of R, see Table 1.
The structure of 13a was confirmed by X-ray crystallography (Figure 1), which unambiguously showed that this is the 5-(phenylcarbamoyl) regioisomer.In the solid state the ester and amide groups are approximately coplanar with the triazole ring [angles between meanplanes = 7.7(2) and 10.5(2) o , respectively] and are held in place by an intramolecular hydrogen bond between the amide hydrogen and the ester carbonyl oxygen [ In contrast the plane of the phenyl ring of the benzyl substituent is approximately orthogonal to the triazole ring [79.1(2) o ].The benzylic protons adjacent to N-1 of the triazole ring in regioisomer 13a resonate at 6.2 ppm as a singlet. 1 H NMR spectra of regioisomers 13b, 18a and 18b also display the benzylic protons as singlets at 6.2 ppm and 13b, 18a and 18b were therefore assigned the 5-(phenylcarbamoyl) structures.In the 1 H NMR spectra of azido-triazoles 18a′ and 18b′, the benzylic proton singlet resonated at 5.8 ppm and regioisomers 18a′ and 18b′ were assigned the 4-(phenylcarbamoyl) structure.Two separate singlets at 6.2 and 5.8 ppm for benzylic protons in the bis-triazoles 14a′ and 19a suggest the unsymmetrical structures displayed with one triazole ring having a 5-(phenylcarbamoyl) and the other a 4-(phenylcarbamoyl) substituent.Similarly, a singlet at 6.2 ppm for four benzylic protons indicated a symmetrical structure with both the triazole rings having a 5-(phenylcarbamoyl) substituent in bis-triazoles 14b, 14c, 14d and 19b.The methylene protons adjacent to N-1 of the triazole ring in 16a and 16b resonated at 5.2 ppm as a singlet and these regioisomers were assigned the 5-(phenylcarbamoyl) structure.Similarly, a singlet for four methylene protons at 5.2 ppm in bis-triazoles 17a and 17b suggested a symmetrical 5-(phenylcarbamoyl) structure.

1,3-Dipolar cycloaddition of benzotriazolylcarbonyl activated acetylenes and organic azides.
The benzotriazolyl group has been used as a synthetic auxiliary in many chemical transformations. 18t was of interest to see whether the presence of a benzotriazolylcarbonyl group on the acetylene provides the required activation for 1,3-dipolar cycloaddition with an organic azide.Indeed, the thermal reaction of benzyl azide (1a) with N-propioloylbenzotriazole 4 in refluxing acetone for 18 h gave the benzotriazolylcarbonyl substituted 1,2,3-triazole 20 in 32% yield.Alternatively, the microwave reaction of benzyl azide (1a) with 4 at 120 W and 100 o C for 1 h provided 20 in an improved yield of 75%.Further treatment of 20 with amines 13e such as morpholine, p-chloroaniline, phenethylamine or benzylamine in dichloromethane at 25 o C for 12 h replaced the benzotriazolyl group to give the corresponding C-carbamoyl 1,2,3-triazoles 21a−d in 54-91% yields.This strategy demonstrates the utility of benzotriazolylcarbonyl group as an activating group for 1,3-dipolar cycloaddition of azides with alkynes and subsequent displacement of the benzotriazolyl group by the amine moiety to form the corresponding C-carbamoyl triazoles under mild conditions (Scheme 6).

Conclusions
In summary, we have introduced a convenient and general method for the preparation of substituted C-carbamoyl mono-and bis-triazoles by the 1,3-dipolar cycloaddition of a variety of organic azides with ester or benzotriazolylcarbonyl activated acetylenic amides under thermal or microwave reaction conditions.

Experimental Section
General Procedures.Melting points are uncorrected.All of the reactions under microwave irradiation were conducted in heavy-walled Pyrex tubes sealed with aluminum crimp caps fitted with a silicon septum.Microwave heating was carried out with a single mode cavity Discover Microwave Synthesizer (CEM Corporation, NC, USA), producing continuous irradiation at 2455 MHz and equipped with simultaneous external air-cooling system. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded in CDCl 3 (with TMS for 1 H and chloroform-d for 13 C as the internal reference) unless specified otherwise.

General procedure for triazole formation under thermal conditions
Substituted acetylene (1 mmol) and benzyl azide (1a) (1.2 mmol) were dissolved in acetone (20 mL) and the solution was refluxed for the specified time.The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica-gel using hexanes/ethyl acetate (4:1) as the eluent to give the pure triazoles.Using this procedure, acetylenic amides 6, 8 failed to give the corresponding triazoles on reaction with benzyl azide (1a) while the reaction of 1a

General procedure for triazole formation under microwave irradiation
A dried heavy-walled Pyrex tube containing a small stir bar was charged with mono-acetylene (1 mmol) and mono-azide (1.2 mmol) or bis-acetylene (1 mmol) and mono-azide (2.2 mmol) or monoacetylene (2 mmol) and di-azide (1.2 mmol).The tube containing the reaction mixture was sealed with an aluminum crimp cap fitted with a silicon septum and then it was exposed to microwave irradiation according to the conditions specified in Schemes 3 and 4. The build-up of pressure in the closed reaction vessel was carefully monitored and was found to be typically in the range 4−10 psi.After the irradiation, the reaction tube was cooled with high-pressure air through an inbuilt system in the instrument until the temperature had fallen below 40 o C (ca. 2 min.).The crude product was purified by column chromatography on silica-gel using hexanes/ethyl acetate (4:1) as the eluent to give the pure triazoles 14 and 16−20. Bis

X-Ray Crystallography
Data were collected with a Siemens SMART CCD area detector, using graphite monochromatized MoKα radiation (λ = 0.71073 Å).The structure was solved by direct methods using SHELXS 22 and refined on F 2 , using all data, by full-matrix least-squares procedures using SHELXTL. 23Hydrogen atoms were included in calculated positions, with isotropic displacement parameters 1.2 times the isotropic equivalent of their carrier carbons, except for the NH hydrogen which was found in a difference map and its position refined.