Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines with Multi- Functionalized Dipolarophiles

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598 Current Organic Chemistry, 2014, 18, 598-614 Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines with Multi- functionalized Dipolarophiles

Ahmad S. Shawali*

Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt

Abstract: This review presents a survey of literature reports dealing with both site and peri-selectivities in cycloaddition reactions of nitrilimines with multifunctionalized dipolarophiles. The literature results covered in this review, during the period from 1970 to mid 2013, demonstrate that chemo-selectivity plays an important role in synthetic design.

Keywords: Chemoselectivity, heterocycles, hydrazonoyl halides, nitrilimines.

1. INTRODUCTION The dipolarophiles are compounds that have one or more double bonds such as –C=C-, -C=N-, C=O; C=S, C=Se or triple bonds The 1,3-dipolar cycloaddition reactions belong to the family of such as -CC- and CN bonds. Examples of such dipolarophiles thermally occurring pericyclic reactions and usually lead to five- are alkenes, alkynes, imines, enamines, nitriles and isothiocyanates. membered heterocyclic rings [1]. Each of such reactions involves the cycloaddition of a 1, 3-dipole to a given dipolarophile (Fig. 1). In general, cycloaddition reactions are important tools for The 1, 3-dipole is a system of three atoms over which 4 electrons synthesis in organic chemistry, since they proved vital to modern are distributed and it is of the general formula [X+=Y-Z-]. The dipo- synthesis of natural products and biologically active substances. For larophile is 2 electrons system such as an alkene. Such reactions example, 1,3-Dipolar cycloadditions of nitrilimines, derived from are usually classified on the basis of the number of electrons in the the base catalyzed dehydrohalogenation of hydrazonoyl halides, two reactants as (4 + 2) cycloaddition and on the basic size of the with different kinds of double and triple bonds have been exten- two reactants as (3+2)cycloadditions. sively used in the last few decades for synthesis of numerous five- membered N-heterocycles of effective biological importance [2-4]. For example, many pyrazolines, 1,3,4-oxadiazoles, 1,3,4- Y - Y + Z X Z X selenadiazoles, were prepared via cycloadditions of nitrilimines to compounds containing C=C, C=O and C=Se double bonds, respec- AB A B tively (Fig. 3). Also, various pyrazoles and 1,2,4-triazoles were Fig. (1). synthesized via cycloaddition of nitrilimines to CC and CN triple A 1,3-dipole is a system containing four electrons in three par- bonds, respectively [5] (Fig. 3). Furthermore, numerous 1,3,4- allel atomic p-orbitals in which the center atom has a formal posi- thiadiazole derivatives were synthesized via cycloaddition of ni- tive charge that compensates for the negative charge distributed trilimines to the C=S double bond in carbon disulfide, thioketones, over the two termini. Thus, 1,3-dipoles can react as both nucleo- aroyl isothiocyanate, thiosemicarbazides and thiourea [5, 6] (Fig. philes and electrophiles. In general, the dipoles are divided into two 3). All such reactions with unsymmetrical dipolarophiles were re- types namely the propargyl–allenyl-type dipoles and allyl-type ported to exhibit an interesting phenomenon namely regioselectivity dipoles. which is usually rationalized by Frontier Molecular Theory (FMO) [7]. Propargyl–allenyl-type dipoles are linear, whereas allyl-type dipoles are bent. The nitrilimines I, whose reactions will be covered R-C(Cl)=NNH-Ar here in, are of the propargyl-allenyl type dipoles (Fig. 2). TEA / PhH R + + i - iv N + _ Y - R-C = N-N-Ar N X Y Z Z X R iii N R' R' ii + - R R' Ar R-C = N-N-R' N R" R Y - Y - N X + I + R' N X Z X Z R" Ar N N N R" Propagyl - allenyl type Allyl type Ar Ar Fig. (2). X = O; S ; Se; N-R"' i = R'-CH=CH-R" ii = R'R"C = X *Address correspondence to this author at the Department of Chemistry, Faculty of iii = R' C C-R" iv = R'-C N Science, University of Cairo, Giza, Egypt; Tel: +25084164; E-mail: [email protected] Fig. (3).

1,3-Dipolar cycloadditions of nitrilimines to multifunctional di- Ar-C(Cl)=NNHAr polarophilic substrates having two or more different dipolarophilic TEA / PhH sites have been found to exhibit another interesting phenomenon + - namely chemoselectivity. The latter includes two types of selectiv- Ar-C = N-N-Ar' + NEt ities namely site- and peri-selectivities. These selectivities result 2 1 Ar from the competition of different dipolarophilic sites in acyclic and 2 cyclic polyfunctionalized molecules, respectively, for the nitrilimi- Ar N nes. Thus, site selectivity refers to the competition between two or Et2N N NEt2 more different dipolarophilic sites in acyclic molecule towards the N Ar' nitrilimine. The periselectivity is a special kind of site selectivity as N Ar it is observed in cycloadditions of a nitrilimine to a polyfunctional - Et NH Ar' Et2N 2 cyclic dipolarophile. Both types of these selectivities are due to the Ar different dipolarophilicities of the various unsaturated bonds. N N N Ar' Generally, both site- and peri-selectivities in cycloadditions of N N Ar' N nitrilimines can be rationalized in terms of Woodward-Hoffmann Ar Ar rule and Frontier Molecular Theory (FMO) [8, 9]. The former rule 3 Ar' Ar limits the total number of electrons in both reactants to be 6, 10, N CHO - Et NH 14...etc i.e. in thermal cycloaddition, the total number of electrons N 2 N should be equal to (4n + 2) where n is an integral number. Accord- Ar' Ar ing to the FMO theory, the feasible cycloaddition proceeds through 4 Ar N overlap of the orbitals with the largest orbital coefficients of the N Ar' Ar' N N LUMO of one reactant with the orbitals of the largest coefficients N Ar' N N of the HOMO of the second reactant, i.e. large with large and small Ar with small. Also, such selectivities can be rationalized in terms of 6 5 Ar' the principle of maximum gain in sigma bond energy of the two Ar = XC6H4; Ar' = YC6H4 sigma bonds formed during cycloaddition. X / Y : a, H / 4-NO2; b, H / H; c, H / 4-Cl; d, 4-NO2 / H Recently, the more accurate density functional theory (DFT) Scheme 1. has been applied in the mechanistic studies on 1, 3-dipolar cycloadditions [10], and the reactivity and selectivity of the cycloadditions The reactions of 2-alkoxy-1,3-butadienes with nitrilimines were have been predicted on the basis of electron densities derived from also found to be site selective. In 1976 it was shown that C,N- quantum mechanical calculations. In addition, some typical cy- diphenylnitrilimine adds to 2-methoxy-1,3-butadiene 7A at the cloadditions such as click reaction were also reported [11-13]. unsubstituted double bond to yield the corresponding 1,3-diphenyl- At present, although there are several review articles covering 5-(-methoxyvinyl)-2-pyrazoline 8Aa (Scheme 2) [28]. Later, it various aspects of the reactions of nitrilimines with many dipolaro- was shown that the site selectivity is controlled by the nature of the philic compounds [4-6] [14-26], there has been no survey hitherto alkoxy group and the type of the nitrilimine [29]. For example, covering the site- and peri-selectivities in such reactions. Because C,N-diarylnitrilimines were found to add at the vinyl group of 2- of this, the intention of the present review is to survey literature isopropoxy-1,3-butadiene 7B to give the corresponding 8Ba,d in reports on both the site- and peri-selectivities in cycloaddition reac- 88-90% yields whereas C-acetyl- and C-ethoxycabonyl-N- tions of nitrilimines with polyfunctionalized dipolarophles during phenylnitrilimines add at the alkoxyvinyl group to form 9Bb,c in the period from 1970 to mid 2013. The aim of such a coverage is to 64-74% yields. The latter cycloadducts eliminated R’OH upon shed light on the utility of such selectivities in synthetic design of standing to give the corresponding 10 (Scheme 2) [29]. Reactions various heterocyclic compounds. of 2-(t-butoxy)-1,3-butadiene 7C with diphenylnitrilimine and C- ethoxycarbonyl-N-arylnitrilimines behave differently toward as 2. SITE SELECTIVITY they yielded the corresponding 5-(-(t-butoxy)vinyl)-2-pyrazolines 2.1. Compounds with Two Dipolarophilic Sites 8Ca in 70% yield and 8Cc,e in 44-58% yields from addition to the unsubstituted double bond. Similar reaction of C-acetyl-N-phenyl 2.1.1. Competition Between two C=C Double Bonds nitrilimine with 7C yielded, however, 9Cb in 61% yield (Scheme Reaction of diarylnitrilimines 1 with N,N-diethyl-1,3- 2) [26]. butadienylamine 2 was reported to give a mixture of cycloadducts Reaction of 2-vinylcarbapenem 11 with nitrilimines derived depending on the reaction conditions. For example, reaction of 2 from hydrazonoyl chlorides 12 in the presence of triethylamine in with 1a in benzene at room temperature yielded 3a, 4a, 5a and 6a dichloromethane at room temperature yielded 2-(pyrazolin-5- in 31-21, 36-48, 12-14 and 17-10% yields, respectively (Scheme 1) yl)carbapenems as a mixture of the distereoisomers 13A and 13B in [27]. When the reaction was carried out at 80°C, the products iso- 47% and 23% yields. Such diastereomers were seperated by silica lated were only 5a and 6a in 40% and 42% yields, respectively. gel chromatography (Scheme 3) [30]. Similar reactions of 2 with each of the nitrilimines 1b-d at either The 1,3-dipolar cycloaddition of diarylnitrilimines each with room temperature or at 80°C were reported to yield only the corre- 6,6-diphenylpentafulvene 14 in toluene was reported to be site sponding products 5b-d and 6b-d in 53-24% and 20-18% yields, selective as it gave , in each case, a mixture of the two regioisomers respectively [27]. The finding that the yield of 4 > 3 and that of 5 > namely 1,3-diaryl-6-diphenylmethylene-3a,6a-dihydrocyclopenta[c] 6 indicates that in compounds 2 and 3, the less substituted C=C pyrazole 15 (70%) and 1,3-diaryl-4-diphenylmethylene-3a,6a- double bond is more sterically favourable and its conjugation with dihydrocyclopenta[c]pyrazole 16 (30%) via cycloaddition to the enamine C=C renders it more dipolarophilic than the more substi- less substituted C=C double bond [31] (Scheme 4). tuted C=C bond. 600 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

+ - cloaduct is more resonance stabilized than the pyrazoline derivative R-C(Cl)=NNHPh R-C = N-N-Ph that will result from cycloaddition to the C=C double bond. In addition, it indicates that the electron-donating diethylamino group at-

CH2 = C(OR')-CH=CH2 tached to the triple bond renders it more dipolarophilic than the enone double bond. 7 R CH CO-C(Cl)=NNHAr R 3

N + - Et2N-C C-CH=CH-COCH3 N N CH3CO-C = N-N-Ar - R'OH N OR' 17 Ph OR' H CCO CH=CH-COCH 8 R Ph 3 3 9 N N N NEt N 2 Ar = 4-XC H ; X : a, H, b, Br Ar 18 Ar 6 4 10 Scheme 5. R' : A, MeO; B, Me2CHO; C, t-BuO 2.1.3. Competition Between Acyclic C=C and C=N Double Bonds R / Ar: a, Ph / Ph; b, Ac / Ph; c, EtOOC / Ph; d, 4-O2NPh / Ph; e, EOOC / 4-MePh The 1,3-dipolar cycloaddition of nitrilimines to N-phenyl cin- namaldehyde imine 19 was reported to proceed site selectively as it Scheme 2. yielded, in each case, the corresponding 1,2,4-triazoline derivative OH 20 (Scheme 6) [33]. This result indicates that the dipolarophilicity of the C=N double bond in 3 is more than the C=C double bond.

R-C(Cl)=NNHR' + Et N R-C(X)=NNH-Ar 3 R Ph 12 O N dioxane N + - Ph-N=CH-CH=CH-Ph H 11 R-C = N- N-Ar N COOAr 19 N CH=CHPh OH Ar OH 20 R R / Ar : a, MeCO / 4-ClC H ; b, EtOOC / 4-O NC H ; c, Ph / 4-O NC H R 6 4 2 6 4 2 6 4 Scheme 6. O N N + N O N N Recently, it was reported that reactions of the enamine deriva- H N COOAr R' H tive 21 with nitrilimies, generated from the hydrazonoyl halides in COOAr R' dioxane in the presence of triethylamine, furnished site-selectively 13A 13B the cycloadducts 22 in 80 % yield (Scheme 7) [34]. This finding Ar = 4-O2NC6H4CH2- indicates that the enamine C=C double bond is more dipolarophilic than cyclic C=N double bond. R / R' : a, Ph / Ph; b, Me / Ph; c, Ph / F3CCH2 R-C(X)=NNH-Ph Scheme 3. i NNH + O Ar-C(Cl)=NNH-Ph - R-C = N-N-Ph + Me2N TEA N N Ph Ph Ar Ph 14 21 Ar N N N R + N NNH Ph Ar N O Ph 15Ph 16 N Ph Ph i = TEA / Dioxane Ph Ar : a, Ph; b, p-tolyl; c, p-anisyl; d, p-nitrophenyl N Ar = 4-O NC H 2 6 4 22 N Scheme 4. R : a, CH3CO; b, PhCH=CH- Ar 2.1.2. Competition Between C=C Double Bond and CC Triple Bond Scheme 7. Reaction of N-aryl-C-acetylnitrilimines with ynaminoketones 1,3-Dipolar cycloaddition of 2-arylidene-6,7-dihydro-5H- 17 was reported to be site-selective as well as regioselective be- thiazolo[3,2-a]pyrimidine-3(5H)-ones to diphenylnitrilimine, gen- cause it yielded the pyrazole derivatives 18 in 33–48% yields erated in situ by triethylamine dehydrochlorination of N-phenyl (Scheme 5) [32]. This finding seems to be due to the pyrazole cy- benzenecarbohydrazonoyl chloride at room temperature, was re- Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 601 ported to proceed regio- and site- selectively to yield the trihetero- double bond in 29 is more dipolarophilic than the exocyclic C=C cycle derivative 23 (Scheme 8) [35]. double bond [38].

Ph-C(Cl)=NNHPh R X i N + - N S Ar Ph-C = N-N-Ph + Ph-C(Cl)=NNHAr R N N X TEA 29 N Ph O Ph + - N Ph-C = N- N-Ar Ph N N N S Ar Ph X = CH O R = H; Me Ph 2; N N Ar N R / R' : a, Ph / Ph; b, Ph / 4-O2NPh i = TEA / Dioxane / rt 30 23 O Ar = XC6H4; Scheme 11. X : a, H; b, 4-Cl; c, 2,4-Cl ; d, 4-NO ; 2 2e, 4-Me; f, 4-F; g, 3,4,5-(MeO)3 2.1.5. Competition Between a C=C Double Bond and CN Bond Scheme 8. Results in several literature reports indicate that the CN bond 2.1.4. Competition Between Cumulated C=C and Cyclic C=N in ,-unsaturated nitriles is a much poorer dipoarophile than the Double Bonds C=C bond. For example, reaction of acrylonitrile 31 with various nitrilimines afforded site-selectively the corresponding 5-cyano-2- Literature reports indicate that dipolarophilic activity of cumu- pyrazoline derivatives 32 (Scheme 12) [39-43]. Such results indi- lated C=C bond is more than the cyclic C=N bond. For example, cate that the cyano group, being electron-withdrawing group, it reaction of diarylnitrilimines with 5-methylenepyrazoline deriva- increases the dipolarophilicity of the C=C double bond. The regio- tives 24 was found to be site selective as it yielded a mixture of the chemical assignment of the latter structure 32 was based on the 1H products 25 and 26 with the former being the major product. The NMR spectra which revealed a doublet signal at 4.8 and a triplet latter product 26 seems to result via in situ ring cleavage of the signal at 5.12 assignable to the H-4 and H-5 protons of 2- initially formed cycloadduct 25 (Scheme 9) [36]. pyrazoline moiety, respectively [43].

Ar-C(Cl)=NNHAr' R-C(X)=NNH-Ar Me Me Me Me Me R Me Ar' + - N Ar-C = N-N-Ar' + + N N N + - CH =CH-CN N 2 N R- C = N-N-Ar N 24 COAr" 25 31 N CN COAr" Ar Me Me Ar 32 Me Ar' R = Ar : a, Ph; b, 4-MePh N , Z = MeSO2-; MeS-; ClCH2- N Z Ar' : a, Ph; b, 4-O2NPh; c, Me N Me S NH Ar": a, Ph; b, 4-MePh; c, 4-ClPh 26 ; COAr" Ar N SO2 ; EtOOC - Scheme 9. S CO

Similarly, cycloaddition of nitrilimines to 4- Ar = 4-XC6H4 : X : a, H; b, Me; c, MeO; d, Cl methyleneisoxazoline derivatives 27 yielded the spirocycloadducts 28 indicating that it is also site selective as it occurred to the exo- Scheme 12. cyclic C=C rather than the endocyclic C=N bond (Scheme 10) [37]. Also, reaction of bis-nitrilimines with acrylonitrile 31 was reported to follow regio- and site-selective pathway similar to that Ph CH 2 R found for nitrilimines [44]. Thus, reaction of bis-nitrilimines with R-C(Cl)=NNHPh acrylonitrile 31 was found to give the bis-cycloadduct 33 (Scheme TEA N Ph N O R' 13) as the sole product in 51-73% yield. The structure assigned was +- N evidenced by 1H NMR data and was confirmed by conversion into R-C = N- N-Ph Ph 27 N 34 which was prepared by reaction of the same bis-nitrilimine with O R' 28 acrylamide 35 as outlined in (Scheme 13). In contrast to the foregoing regiochemical results, it was re- R / R' : a, Ph / Ph; b, MeOOC / Ph; c, Ph / 4-O2NPh ported that the cycloaddition of acrylonitrile 31 to the nitrilimine 37 Scheme 10. derived from the hydrazonoyl bromide 36 followed same site selec- Contrary to the foregoing reports, 1,3-dipolar cycloaddition of tivity but different regiochemical pathway as it yielded the 4- nitrilimines with 1,4-benzodiazepines 29 was reported to occur at cyanopyrazoline derivative 38 (Scheme 14) [45]. The assigned the C=N double bond to yield the cycloadduct 30 (Scheme 11) [38]. structure was confirmed by its conversion in the pyrazole and pyra- No rationalization was given to account for why the cyclic C=N zolo[3,4-d]pyridazine derivatives 39 and 40 upon its treatment with 602 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

Ar-NHN=C(Cl)-C(Cl)=NNHAr (Scheme 15) [40]. The physical properties of the latter were found to be different from that of 42. This finding was taken as an evi- dence for the site-selectivity leading to 42. - + + - 2 CH = CH-CN Ar-N-N = C-C = N-N-Ar 2 Reactions of nitrilimines with 2,3-disubstituted acrylonitriles 44 31 were reported to follow similar regio- and site-selectivities to yield the corresponding 1,3,4,5-tetrasubstituted 5-cyano-2-pyrazoline 2 CH2=CH-CONH2 NC CN derivatives 45 (Scheme 16) [46, 47]. The latter cycloadducts 45 35 were reported to be readily converted into the corresponding pyra- N N zole derivatives 46 upon refluxing them in sodium methoxide solu- N N CONH2 Ar H2NOC Ar tion (Scheme 16). The structures of the products 45 isolated have 33 1 H2SO4 been evidenced by IR and H NMR spectral data. For example, the N N 1 N N H NMR spectra of 45 revealed in each case a singlet signal in the Ar Ar 34 region 5.23 – 5.42. Their IR spectra showed no nitrile absorption Ar = XnC6H5-n ; X : a, H; b, Me; c, 4-Cl; d, 2,4-Cl2; e, 4-O2N similar to those reported for aliphatic nitriles activated by a neigh- bouring oxygen or nitrogen atom in the -position. Scheme 13. R-C(Cl)=NNH-Ph Het-CO-C(Br)=NNH-Het' 36 H CH2=CH-CN + - R Het-CO-C = N-N-Het' + - Het-C(CN(=CH-Ar' Ar' 37 R- C = N-N-Ph N N Het 44 N Het-CO CN Het NH 2 N 45 CN NH2NH2-H2O N Ph N N N 38 Het' 40 Het-CO Het' - HCN MeONa / MeOH EtONa / R Ar' EtOH N Het = N O 39 Het' Ph R = Ph; EtOOC; PhNHCO N Het' = Het Ar : a, Ph; b, 4-MePh; c, 4-ClPh; d, 2-thienyl; N N e, 2-furyl 46 N Ph H Me Scheme 14. S S N Het= Ar-CO-C(Br)=NNH-Ar' Ar ArCO R N N N + - R-CH=C(CN)2 Ar-CO-C = N-N-Ar' Scheme 16. 41 N N CN Similar reactions of 3-aryl-2-heteroaryl-acrylonitriles 44 with ArCO CN Ar' 42 bis- nitrilimines in benzene at reflux were reported to give exclu- RCOCH2CN sively the bis -cycloadducts namely 5,5’-dicyano-4,4’, 5,5’- EtONa / EtOH N tetrahydro[3,3’-bi-1H-pyrazole] 47 (Scheme 17) [48]. The struc- N R Ar = tures of the isolated cycloadducts were elucidated on the basis of Ar' 43 their spectral (IR, 1H NMR and 13C NMR) data. The formation of 47 and exclusion of its regio-isomer 49 was considered to be con- Ar' = 4-YC6H4; Y : a, H; b, Me R = 4-XC6H4; X: a, H; b, NO2 firmed by chemical transformation. For example, treatment of the Scheme 15. cycloadducts 47 with sodium ethoxide in refluxing ethanol resulted in elimination of hydrogen cyanide and the formation of the respec- ethanolic sodium ethoxide and hydrazine hydrate, respectively tive bis-3,3’-pyrazole derivatives 48 (Scheme 17) [48]. (Scheme 14) [45]. No rationalization was given, however, to account for this different regiochemical result. 2.1.6. Competition Between C=O and C=C Double Bonds Similar reaction of C-(2-naphthoyl)-N-arylnitrilimines with Reaction of diaryl nitrilimines, generated in situ by action of arylmethylene-malononitrile 41 in chloroform in the presence of triethylamine on the respective hydrazonoyl halides in benzene , triethylamine was reported to yield the respective 5-cyanopyrazole with 2,3,4,5-tetraphenylcyclopentadienone 50 proceeded via cy- derivatives 42 (Scheme 15) [35]. The assigned structures 42 were cloaddition to the C=O rather than the C=C bond and gave the elucidated on the basis of IR spectra which revealed a nitrile ab- spiro-cycloadducts 51 (Scheme 18) [49]. -1 1 sorption near 2220 cm and H NMR spectra which revealed the In contrast, similar reaction of diaryl nitrilimines with 4- absence of signals assignable to the 4-CH or 5-CH protons. Reac- methylene-2,6-di-t-butylcyclohexa-2,5-dienone 52 was reported to tion of the parent hydrazonoyl halide with phenacyl cyanide in proceed via cycloaddition to the exocyclic C=C double bond rather ethanol in the presence of sodium ethoxide was reported to give the than the C=O bond and yielded the spiro-cycloadducts 53 in 65% isomeric 1, 5-diphenyl-3-(2-naphthoyl)-4-cyanopyrazole 43 yield (Scheme 19) [50]. Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 603

Ar-NHN=C(Cl) - C(Cl) =N-NHAr Ph-C(Cl)=NNHR' TEA - ++ - Het-C(CN)=CHAr' O Ar-N - N=C - C= N-N-Ar 44 + - Het R Ph- C = N- N-R'Ar Ar' CN Het + CN Ar' H H Ar' N N 54 Het H Ar' N N H Ar Ar Het 49 NC CN Ph N N R' Ar N N Ar Ar' Ar' 47 Het O N O Het N N EtONa N R' - 2 HCN N N Ph N N Ar Ar 48 R R N S 56 55 Het = ; N N Scheme 20. Me Ar' : a, Ph; b, 4-ClPh; c, 4-O NPh Ar: a, Ph; b, 4-MePh; c, 4-ClPh RCO-C(X)=NNHPh 2 O O TEA Scheme 17. + - Ph NN Ph-C(Cl)=NNHAr N N Ph Ph Ph Ph + RCO-C = N-N-Ph Ph Ph N S Ph Ph S + 57 58 N - Ph + Ph- C = N- N-Ar Ph COR Ar N O R / X : a, Me / Cl; b, Ph / Br; c, EtO / Cl Ph Ph N Scheme 21. O 50 51 Ph Ar : a, Ph; b, p-tolyl O Et-C(Br)=NNH-Ar O TEA Scheme 18. N S Ph NS O + - i Ph-C(Cl)=NNHAr Ph + Et-C = N-N-Ar O Bu-t Ar N S t-Bu S Bu-t 59 60 N t-Bu + - i = Et3N / HCCl3 / heat Et + Ph- C = N- N-Ar Ar N Ar = 4-O2NC6H4 Et N N H 52 Et N Ar 53 Ph O Ar : a, Ph; b, p-O2NPh O NNHAr Ph NS Scheme 19. Ph NS

S 62 Reaction of N-aryl benzenecarbohydrazonoyl chlorides with 2- S 61 arylmethylene-3,4-dihydro-1-naphthalenones 54 in refluxing benzene in the presence of TEA afforded regioselectively the corre- Scheme 22. sponding spironaphthalene-2(1H),3’-[3H]pyrazol]-1-ones 55 and not the isomeric spiro[naphhalene-2(1H),4’-[4H]pyrazol]-1-ones 56 2.2. Compounds with Three Dipolarophilic Sites (Scheme 20) [51]. The results of various literature reports generally indicate that the reactivities of C=X dipolarophilic groups decrease in the order 2.1.7. Competition Between C=O and C=S Double Bonds C=S > C=N > C=C > C=O. Substitution and steric effects were Literature reports indicate that the dipolarophilicity of the C=S found to result in changes of such order as depicted below. is much more than that of the C=O bond. Thus, reaction of nitrilimines, generated in situ by action of triethylamine on the re- 2.2.1. Reaction with 4-arylmethylene-5(4H)-thiazolones spective hydrazonoyl halides in chloroform, with 1,3-diphenyl-2- Reactions of diarylnitrilimines with 4-arylmethylene-2-phenyl- thioxo-4-imidazolinone 57 proceeded via cycloaddition to the C=S 5(4H)-thiazolones 63 were reported to afford the spiro-pyrazolines rather than the C=O bond and gave the corresponding spiro- 64 (Scheme 23) [54]. The cycloaddition was site- and regio- cycloadducts 58 (Scheme 21) [52]. selective as the other regioisomer 65 was not produced. In the same manner, the reaction of nitrilimines with 3-phenyl- Reactions of diarylnitrilimines with 5-arylidene-2-arylimino-4- 2-thioxo-thiazol-4(5H)one 59 was reported to yield the spirothiadi- thiazolones 66 were reported to react with diarylnitrilimines in re- azoline derivative 60 rather than the spiro-oxadiazoline 61 or the fluxing toluene and yielded the corresponding pyrazole derivatives 1,3-adduct 62 (Scheme 22) [53]. 67 (Scheme 24) [55]. The formation of latter products was consid- 604 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

Ar' Ar-C(Cl)=NNH-Ph Similarly, 1,3-diphenyl-4-arylmethylenepyrazolin-5-ones 70 reacted with the nitrilimines derived from hydrazonoyl chlorides in H TEA N chloroform in the presence of triethylamine regioselectively and + - gave site-selectively a mixture of the stereoisomers of the respec- O Ph S + Ar-C = N-N-Ph tive spiropyrazolo[5.4’]pyrazolin-5’-ones namely 71A and 71B. The structures and stereochemistry of the latter cycloadduct were 63 assigned on the basis of spectroscopic data and chemical behaviour (Scheme 26) [57]. H H Ar' Ar' R' R-C(Cl)=NNHPh N Ph Ph Ph N Ph N N S N S N + - N Ar N + R|-C = N- N-Ph O Ph O Ph Ph O 70 65 64 Ar' : a, Ph; b, 4-MePh Ar : a, Ph; b, 4-MePh; c, 4-ClPh R' H R' Ar H R Scheme 23. Ar R N N + O Ar"-C(Cl)=NNHPh + N N O Ph N N N Ph N Ph O Ar N Ar N O Ph + - N N Ph Ar' 71A 71B S + Ar"-C = N- N-Ph Ar N S A" 66 N R : a, Ph; b, MeOOC; c, t-BuOOCR : a,Ph ; b, Me Ar' H Ar Scheme 26. 2.2.3. Reactions with 4-arylmethylene-5(4H)-oxazolones

Ph O Ph The reactions of nitrilimines with (Z)-4-arylmethylene-2- O phenyl-5(4H)-oxazolones 72 were studied by several groups of N Ar N Ar N N N investigators. Such reactions proved to be site-selective and regio- N H specific as they yielded one regioisomeric cycloadduct namely 73 A" - ArNCS A" N SH (Scheme 27) [58-61]. The site- and regio-selectivities of the iso- 67 Ar' Ar Ar' lated cycloadducts were confirmed by conversion of 73 into 74 by its reaction with ethyl aminoacetate and alternate synthesis of the Ar / Ar' / Ar" : a, Ph / Ph / Ph; b, Ph / 4-ClPh / Ph; latter 74 by reaction of ethyl 2-benzoylaminocinnamic acid deriva- c, 4-MePh / Ph / Ph; d, 4-MePh / Ph / 4-ClPh; tives 75 with diphenylnitrilimine (Scheme 27) [61]. e, 4-MePh / 4-ClPh / Ph Scheme 24. Ar Ph-C(Cl)=NNHPh N i ered to result via the cycloaddition of nitrilimine to the exocyclic Ph H + - enone C=C double bond to give the spirocycloadduct which under- O + Ph|-C = N- N-Ph went in situ ring cleavage followed by elimination of arylisocyanate. O 72 2.2.2. Reactions with 4-arylmethylene-5(4H)-pyrazolones Ar R' Ar Singh et al. [56] reported that reaction of N-phenyl benzenecar- Ph Ph H H Ph H bohydrazonoyl chloride with 4-arylmethylene-3-methyl-1- N ii N substituted-5-pyrazolones 68 in the presence of base catalyst O N O N yielded a mixture of two stereoisomeric spirocycloadducts namely N N O 69 and 69A (Scheme 25). EtOOC-H2C-HN O Ph Ph 74 73 Me + - Ph-C(Cl)=NNHPh Ph|-C = N- N-Ph Ar H

N Ar' + - PhOCHN CONHCH2COOEt N + Ph|-C = N- N-Ph 75 R O i = TEA / PhH ii = H2NCH2COOEt 68 Me Ar Ar = 4-XC6H4; X : a, MeO; b, Me; c, Cl; d, NO2 Me H H Ph Ar Ph N Scheme 27. N + N N N N N Similar reaction of the isomer E-72 with N-phenyl benzenecar- N R R O Ph bohydrazonoyl chloride exhibited the same site selectivity but it O Ph was reported, however, to give a mixture of the two stereoisomers 69 69A 76 and 77 (Scheme 28) [59, 60]. The formation of the latter prod- R : a, Ph; b, PhCH Ar : a, 4-MeOPh; b, 4-Me NPh 2 2 uct 77 was attributed to the known conversion of the labile E-72 Scheme 25. isomer to its stable Z-72 isomer in the presence of amines [62]. Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 605

H Ph Ar H Ph-C(Cl)=NNHPh Ph-C(Cl)=NNHPh H Ar H N i i Ph Ar N N Ar N + - + - Ph Ph-C = N-N-Ph + Ph-C = N-N-Ph + R O R O N Ph O O O O N O E-72 Z-72 O 80 81 Ph Ph - PhCN Ar H Ph Ph H N Ar N N N Ph N N N EtOH / H+ Ph EtOOC HOOC N R O R O N Ar = Ph N O O 76 77 Ph Ph Ar Ph 83 82 i = TEA / PhH R : a, Ph; b, 4-MePh Ar = a, Ph; b, 4-MePh; c, 4-MeOPh; d, 4-BrPh; e, 3-BrPh; f, 3-thienyl Ar = 4-XC6H4; X: a, MeO; b, Me; c, H; d, Cl; e, NO2 Scheme 30. Scheme 28. In other literature reports, it was indicated that the reaction of selective [66-69] as they yielded the corresponding 1,3,4,7,8-penta- Z-72 with nitrilimines followed different regiochemical pathway as substituted-1,2,6,8-tetrazaspiro[4,4]nona-2,6-dien-9-ones 85A-E it gave the other regioisomeric spirocycloadduct namely 78 (Scheme 31). The regiochemistry of the latter cycloadducts was (Scheme 29) [58, 60, 63, 65]. In some cases the nature of the sol- confirmed by the conversion of the cycloadducts 85C,D into 86 by vent and the temperature promoted the formation of the cycloadduct treatment with ethanolic sodium ethoxide and comparison of 86 78 and/or the pyrazoline derivatives 79 [63, 65]. The latter products with authentic samples of their regioisomers 87 prepared as de- 79 seem to result from ring cleavage of the former cycloadducts 78 picted in (Scheme 32) [68]. (Scheme 29) [63]. R" Ar-C(Cl)=NNHAr' Ar Ph N Ph-C(Cl)=NNHPh Ar H H O + - N Ar' i H N Ar N Ar-C = N-N-Ar' + R" O +- N N N Ph-C = N-N-Ph + N N Ph R' R N R O 84 O R O O R' 85 R Z-72 78 R / R' / R" : A, Me / Me / Ph; B, XC6H4 / Ph / YC6H4;

C, Ph / Ph / XC6H4; D, PhCH2 / Ph / XC6H4; Ph i = TEA / xylene/ rt E, XC6H4 / Me / YC6H4 H Ar / Ar' : Ph / Ph; Ph / XC H ; 2-furanyl / XC H ; XC H / YC H R : a, Ph; b, 4-MePh 6 4 6 4 6 4 6 4 Ar N Ar = 4-XC6H4; X: a, MeO; b, Me; c, H; d, Cl Scheme 31. HN N Ph EtONa / EtOH COOH ArCOCH CONHR + Ph-C(Cl)=NNH-Ph R O 2 79 Scheme 29. Ph Ar Ph CONHR 2.2.4. Reactions with 4-arylmethylene-5(4H)-isoxazolones N N CONHPh Ar The reaction of diphenylnitrilimine with 4-arylmethylene-3- N N phenylisoxazol-5(4H)-ones 80 was reported to proceed site- and 86 H Ph regio-selectively to give, in each case, a single product that was Ph Ar 87 Ph Ph identified as 1,3,5-triaryl-pyrazole-4-carboxylic acid 82 (Scheme EtONa / N 30) [64]. The latter products were assumed to be formed via elimi- EtOH N N nation of benzonitrile from the initially formed spirocycloadducts - PhCN N R O 81 under the reaction conditions. The assigned structure was con- Ph 85C,D firmed by comparison of the ethyl ester 83 (Ar = Ph) with an R / Ar: a, Ph / Ph; b, Ph / 4-MePh; c, Ph / 4-ClPh; d, PhCH2 / Ph; authentic sample of ethyl 1,3,5-triphenylpyrazole-4-carboxylate. e, PhCH2 / 4-MePh; f, PhCH2 / 4-ClPh The foregoing result indicates that the regiochemical pathway in this case is opposite to that followed in reactions of nitrilimines Scheme 32. with 4-arylmethylene-5(4H)-oxazolones outlined in the previous 2.2.6. Competition Between C=C, C=N and N=N Double Bonds section [61]. Cycloaddition of diphenylnitrilimine with the 1,2,3-triazole de- 2.2.5. 4-Arylmethylene-5(4H)-imidazolones rivative 88 was reported to be site selective as it afforded a mixture Reactions of nitrilimines with various 5-arylmethylene-2,3- of the two regioisomeric cycloadducts A and B via cycloaddition to disubstituted-imidazolin-5-ones 84A-E were reported to be site the acyclic C=N double bond which underwent elimination of a 606 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali triazole moiety and gave the 1,2,3-triazoles and 1,2,4-triazole de- R-C(X)=NNH-Ar R Ph rivatives 89 and 90, respectively (Scheme 33) [70, 71]. O Ph O N + - R R' N Ph-C(Cl)=NNH-Ph N S + R-C = N-N-Ar Ph S Ar Ph N N N + - N N + Ph-C = N- N-Ph 94 S 95 88 S R' R" Ph R' Ph R / X: a, Ph / Cl; b, PhCH=CH / Cl; c, MeCO / Cl; R R N d, EtOOC / Cl; e, PhCO / Br; f, 2-Naphthoyl / Br; N N N N + N N g, 2-thenoyl / Br N N N Ph N N Ph Scheme 35. R" H R" H 88 - Het-H In contrast to the foregoing report, reaction of diphenylni- Ph Ph trilimine with Z-5-phenylmethylene-3-phenyl-2-thioxo-4(5H)- N N N thiazolinone 96 was found to exhibit different site selectivity as it N + N give the spirocycloadducts 97, whose structure was confirmed by N X-Ray analysis (Scheme 36) [71, 73]. Very recently other nitrilimi- Ph Ph R" 89 R" 90 nes were reported to exhibit the same site selelctivity in their reactions with 96 to afford the corresponding cycloadducts 97 [74]. This R' R finding indicates that the C=S is more dipolarophilic than the exo- R" : a, Ar; b, ArCO Het-H = NH cyclic C=C bond. N N R-C(X)=NNH-Ar O Ph Scheme 33. O Ph S 2.3. Competition Between Exocyclic C=C, C=O and C=S Dou- + - Ph N Ar S + R-C = N-N-Ar ble Bonds Ph N S N 2.3.1. Reactions with 5-arylmethylene-2-thioxo-4-imidazolinone N 96 S R Reaction of the nitrilimines with 1,3-diphenyl-5- 97 phenylmethylene-2-thioxo-4-imidazolinone 91 was reported to give Ar = XC6H4 the spiro compounds 92 via cycloaddition of the nitrilimines to the R / X: a, Ph / H; b, PhCH=CH / H; c, 2-furyl / 4-NO2; exocyclic C=C double bond. The other regioisomeric products 93 d, 2-thienyl /4-NO2; e, MeCO / H; f, 2-Naphthoyl / H; were not produced (Scheme 34) [52]. This result indicates that the g, EtOOC . H; h, PhNHCO / H; i, 2-thenoyl / H C=S, while it is more dipolarophilic than the C=O double bond, it is less dipolarophilic than the enone moiety in 91 (Scheme 34). How- Scheme 36. ever, the regiochemistry of such cycloaddition reaction needs fur- Similarly, reaction of E-4-phenylmethylene-2-thioxo- ther investigation as product 93 seems to be the expected cycload- thiazolinones 98 with other nitrilimines in chloroform were found duct. to yield the corresponding spirocycloadducts 99 (Scheme 37) [71, RCO-C(X)=NNHPh 75]. Ph O R-C(X)=NNH-Ar Ph O + - O + RCO-C = N-N-Ph Ph N N S Ph Ph + - Ph N + R-C = N-N-Ar Ar N S S N 91 S Ph N 98 S R 99 N RCO N Ph COR Ar : Ph; 4-O2NPh O N N Ph O R: EtOOC; Ph; 2-Thenoyl;PhNHCO; PhCH=CH ; c, 2-Naphthoyl; H H Ph MeCO; 2-furyl; 2-thienyl; PhCO NN N Ph Ph Ph Ph N Ph Scheme 37. S 93 S 92 2.4. Competition Between C=C, CN and C=X Bonds R / X : a, Me / Cl; b, Ph / Br; c, EtO / Cl 2.4.1. Competition Between C=C, CN and C=O Bonds Scheme 34. Reaction of C-(2-naphthoyl)-N-aryl nitrilimines with ethyl 2- 2.3.2. Reactions with 5-arylmethylene-2-thioxo-4(5H)-thiazo- cyanocinnamate 100 and 2-cyanocinnamamide 101 in chloroform linones in the presence of triethylamine yielded the corresponding 5- Reactions of nitrilimines with 5-phenylmethylene-3-phenyl- substituted pyrazoles 102 and 103, respectively (Scheme 38) [40]. 4(5H)-thiazolinone 94 were reported to proceed site-selectively as This finding suggests that the dipolarophilicity of the C=C bond is they gave the spirocycloadducts 95 (Scheme 35) [72]. more than that of CN and C=O bonds. Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 607

Ar-CO-C(Br)=NNHAr' 2.4.3. Competition Between C=C, C=N and CN Bonds 100 (101) H -HBr Ar-CO The acyclic C=C double bond in 2-aryl-1-cyano-1-(thiazol-2- Ph yl)-ethylene derivatives 109 was reported to be more dipolarophilic - + PhCH=C(CN)COX than both the enodocyclic C=C double bond and the nitrile group as Ar-CO-C = N-N-Ar' N COX N its reaction with nitrilimines yielded only the cycloadduct 110 CN (Scheme 40) [47]. Heating the latter with ethanolic sodium ethoxide Ar' Ar = furnished the pyrazole derivatives 111 (Scheme 40) [47]. - HCN Reaction of diphenylnitrilimine with 2-aryl-1-cyano-1-(1- Ar' : Ph; 4-O NPh Ar-CO Ph 2 methylbenzimidazol-2-yl)ethylene 112 follows similar site selectiv- X : 100(102), EtO; 101(103), NH 2 N ity as it yielded the cycloadduct 113 via cycloaddition to the acyclic COX N C=C double bond (Scheme 41) [46]. This site-selectivity was confirmed by the formation of the pyrazole derivatives 114 upon heat- 102(103) Ar' ing the cycloadduct 113 with ethanolic sodium ethoxide (Scheme Scheme 38. 41) [46].

2.4.2. Competition Between C=C, CN and C=S Bonds Ph-C(Cl)=NNHPh Me TEA Me Only in one report it was indicated that the C=C is more dipo- N + - CN Ph-C = N- N-Ph N Ph larohilic than that of C=S and CN bond. Thus, cycloaddition of CN N-heteroaryl-C-heteroarylcarbonylnitrilimine to arylmethylene- N N 112 N N malononitrile 104 and 2-cyanocinnamic thioamide 105 were re- Ar ported to yield the pyrazoline derivatives 106 and 107, respectively Me Ar H (Scheme 39) [76]. Hydrazinolysis of the latter products gave the N Ph Ph 113 pyrazolo[3,4-d]pyridazine derivative 108 (Scheme 39). N EtONa / EtOH N N heat Het-CO-C(Br)=NNH-Het' Ar 114 -Br Ph ArCH=C(CN)CSNH + - Ar : Ph; 4-MePh; 4-MeOPh; 4-ClPh; 4-O2NPh 2 Ar-CH=C(CN)2 Het-CO-C = N-N-Het' Scheme 41. 105 104 CN CN Het-CO Het-CO 3. PERISELECTIVITY CSNH2 CN Ar Ar 3.1. Competition Between two Endocyclic C=C Double Bonds N N N H N N N H The cycloaddition of diphenylnitrilimine to each of the norbornadiene derivatives 115A-C in benzene was reported to be site- 107 Het' Het NH Het' 2 106 selective as it was found to proceed via attack preferentially the H2NNH2 H2NNH2 electron-poor tetra-substituted double bond to give dimethyl 1,3- N -HCSNH2 Ar - HCN diphenylpyrazole-4,5-dicarboxylates 116a in 80.5-99.4 % yield N (Scheme 42) [77]. In more recent report [78], other nitrlimines were Ph Het' 108 reported to react site selectively with 115A to give the correspond- Het = Het' = ing dimethyl 1,3-disubbstituted-pyrazole-4,5-dicarboxylates 116b-f O N in 73-82 % yield. The latter products 116a-f were considered to be H formed through in situ a retro Diels-Alder reaction of the initially Ar : a, Ph; b, 4-MeOPh; c, 4-Me NPh; d, 4-HOPh; e, piperonyl 2 formed cycloadducts. Such results were rationalized in term of Scheme 39. HOMO dipole-LUMO dipolaophile interaction [78]. R-C(Cl)=NNHR' S +- X X COOMe CN Ar-C = N- N-Ph S Ph R R CN COOMe + - N R N R-C = N- N-R' N N N 109 R' N Ph R' 115 COOMe S MeOOC H Ar R' R N 110 MeOOC R EtONa / EtOH N N X heat + N R' N Ar MeOOC 111 R' 116 R: Ph; 4-MePh X : A, O; B, CH ; C, Me C=C R' : Ph; 4-MePh; 4-ClPh; 2-thienyl; 2-furyl 2 2 R / R' : a, Ph / Ph; b, 4-O NPh / Ph; c, 4-ClPh / Ph; d, 4-ClPh / Me; Ar : Ph; EtOOC; PhNHCO 2 e, 5-O2N-3-furyl / Ph; f, 5-O2N-3-furyl / Me Scheme 40. Scheme 42. 608 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

Ar-C(Cl)=NNH-Ar' Me

Me + - Ar-C = N- N-Ar'

117 Ar' Ar N Me Me N N N Me Me Ar Ar' +

RO RO 118 119 a, Ar = Ar' = Ph; b, Ar = Ph; Ar' = 2-ClPh R = H; MeCO

Scheme 43.

The cycloaddition of diphenylnitrilimine to 3-hydroxyandrost- afforded the cycloadduct 125 (Scheme 45) [82]. Similar reaction of 5,11-diene 117 was also found to be site selective and yields a mix- diphenylnitrilimine with 2,3-dimethyl-2,5-diphenyl-2H-pyrrole ture of the two regioisomeric cycloadducts 118a and 119a in 1 : 1 124B was also periselective as it yielded a mixture of the two di- ratio (Scheme 43) [79]. Similar reaction of N-2-chloro- astereoisomers 126A and 126B (Scheme 45) [82]. phenylbenzonitrilimine with 117 gave a mixture of cycloadducts 118b and 119b in 1:5 ratio, respectively [80]. Such site-selectivity Ph-C(Cl)=NNH-Ph Me result indicates that cycloaddition occurs preferentially to the less substituted C=C double bond than the more substituted one. Me + - R = Ph R = Me Ph-C = N- N-Ph Ph N R 3.2. Competition Between Three Endocyclic C=C Double Bonds 124 Cycloaddition of diphenylnitrilimine to a polyfunctional cyclic Me Me dipolarophile such as tropone 120 can theoretically proceed through Me Me (6 + 4 ) pathway to give 121 and/ or (4 + 2 ) pathway to afford Me Ph Ph Ph Ph Ph one or more of the two cycloadducts 122 and/or 123. Practically Ph N Ph N N N N Ph when such a reaction was carried out, it afforded a mixture of the N Me Me + N N N cycloadducts 121, 122 and 123 in 5%, 37% and 5% yields, respec- Ph Ph Ph tively (Scheme 44) [79, 81]. This finding indicates that in such a 125 126A 126B reaction the competition between the various dipolarophilic sites in R : A, Me; B, Ph tropone is in favor of C2-C3 double bond more than other sites namely C4-C5 and C=O double bonds. Scheme 45. Also, the electrochemically generated diarylnitrilimines were Ph-C(Cl)=NNH-Ph reported to cycloadd to the C=N rather than the C=C bond of imi- dazole 127 to give the cycloadduct 128 which undergo in situ oxi- O +- dation to yield 129 as end products (Scheme 46) [83]. Ph-C = N- N-Ph Ar-C(Cl)=NNH-Ar' Ar

120 Ph N O O + - N N Ph O + Ar-C = N- N-Ar' N N H N N 127 Ar Ar' + + H H N N 128 N Ph N N Ph N Ph Ph N N N Ar' 121 122 123 129

Scheme 44. Ar = 4-Me2NPh; Ar' = 4-O2NPh

3.3. Competition Between Cyclic C=C and C=N Double Bonds Scheme 46. Reaction of diphenylnitrilimine with 2,2-dimethyl-3,5- Reaction of 5-amino-3-phenylpyrazole 130 with N-p-tolyl-C- diphenyl-2H-pyrrole 124A was reported to be periselective as it ethoxycarbonyl nitrilimine gave pyrazolo[3,4-c]pyrazole derivative Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 609

131 (Scheme 47) [84]. In contrast, similar reaction of diarylni- R N trilimines with 3,5-di-amino-4-arylazopyrazoles 132 was reported R-C(Cl)=NNH-Ar N to yield pyrazol[5,1-c][1,2,4]triazole derivatives 133 (Scheme 48) N Ar i N H [85, 86]. No rationalization was given to account for such different + - H peri- selectivities, however. R-C = N- N-Ar + Ar N N N COOEt 137 N EtOOC-C(Cl)=NNH-Ar Ph R Ph i = TEA / PhH / heat 138 N + - R / Ar : a, Ph / Ph; b, 4-ClPh / Ph; c, 4-BrPh / Ph; d, Ph / 4-O2NPh; EtOOC-C = N- N-Ar + N N N e, 4-ClPh / 4-O2NPh; f, EtOOC / Ph N NH N Ar 2 H NH2 H Scheme 50. 130 COOEt Reaction of diarylnitrilimines with 2-aminopyrazine 139 was Ph reported to occur at the enamino C=C double bond rather than the N imino double bond to give the corresponding pyrazolo[3,4- Ar = 4-MePh N N - NH3 d]pyrazine 140 in 35-60% yield via elimination of ammonia from N the initially formed cycloadducts (Scheme 51) [85, 89]. H Ar 131 Ar-C(Cl)=NNH-Ph Ar Scheme 47. H i N N + - Ar-C = N- N-Ph+ N Ph-C(Cl)=NNH-Ph H N Z N 2 N NH N H2N Z 2 NH 139 2 Ph + - i = TEA / PhH / heat NH2 Ph-C = N- N-Ph + HN HN N N Ph N NH2 Ar 132 N N Ph Ar : a, Ph; b, 4-ClPh H2N Z N - NH3 N N N 140 Ph N N Ph - NH3 Scheme 51. N Ph Similarly, the cycloaddition of diarylnitrilimines to 5- Z = Ar-N=N- 133 substituted –2-methyl-3(2H)-pyridazinones 141 was reported to Ar = 4-XC6H4; X : a, Cl; b, Me; c, MeO occur at the enone C=C double bond and proceed regioselectively Scheme 48. yielding in all cases examined the corresponding pyrazolo[3,4- d]pyridazinone derivatives 143 (Scheme 52) [90]. The other regioi- The cycloaddition of N-benzenesulfonylnitrilimine to 2- someric cycloadducts 144 were not formed. The structures of the aminopyridine 134 was reported to be periselective as it yielded isolated products 142 were based on NMR spectroscopy. The re- 1,2,4-triazolo[4,3-a]pyridine 136 via elimination of benzenesul- ported results indicate that the initially formed cycloadducts 142 fonamide from the initially formed cycloadduct 135 (Scheme 49) undergo in situ elimination of HX to give 143 as end products [87]. (Scheme 52).

Ph-C(Cl)=NNH-SO2Ph Ph-C(Cl)=NNH-Ph O O Ph H i i Me Me +- NH2 +- N N Ph-C = N- N-SO2Ph + Ph-C = N- N-Ph N SO2Ph + N NH2 N N N N X N X 134 N Ph i = TEA / PhH / heat Ph 141 135 142 i = TEA / PhH / heat

O N N Ph Ph O - PhSO2NH2 Me N N Me Ph N 136 N N N N N N Scheme 49. Ph 144 Ph 143 Unsubstituted pyrazine 137 reacted with diarylnitrilimines to produce the bicycloadducts 1,10,10a,10b-tetrahydrodi[1,2,4]tri- X = EtSO2; I; Cl; N azolo[4,3-a:3':4'-c]-pyrazines 138 via cycloaddition to the C=N double bonds (Scheme 50) [88]. Scheme 52. 610 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

Similar reaction of pyrimidines 145 with diarylnitrilimines was acid and furnished the aromatized compounds 155 and 156 in 57- reported to occur at the C=N double bond rather than the C=C dou- 68% yield, respectively (Scheme 56) [95]. ble bond and produced the corresponding 1, 8a-dihydro-1,2,4- triazolo[4,3-a]-pyrimidines 146 (Scheme 53) [88]. Ph-C(Cl)=N-NH-SO2Ph i Ar N N Ar-C(Cl)=NNH-Ar' N + - Ph-C = N- N-SO Ph i R N N 151 2 152 R N Ar' i i + - Ar-C = N- N-Ar' + H N N i = CH2Cl2 145 146 ii = CCl4 / heat i = TEA / PhH / heat H R / Ar / Ar': a, H / Ph / Ph; b, H / 4-ClPh / 4-O2NPh; N N c, Me / Ph / 4-O NPh; d, Ph / Ph / 4-O NPh; N SO2Ph Ph 2 2 153 e, Ph / EtOOC / Ph N H N Ph N ii PhSO ii - PhSO H -PhSO2H 2 154 Scheme 53. 2 Reaction of 3, 4-dihydro-6,7-diethoxyisoquinolines 147 with 2- oxo-N-aryl nitrilimines was reported to exhibit the same chemoselectivity as they furnished the cycloadducts 148 (Scheme 54) [92, 93]. N N N Ph R-C(Cl)=NNH-Ar N 155 N 156 N i Ph EtO +- Scheme 56. R-C = N- N-Ar + N EtO In contrast to the foregoing reports, it was indicated in an earlier 147 report [91], that reactions of C-ethoxycarbonyl-N-phenyl methane- hydrazonoyl bromide with quinoline and isoquinoline in ethanol at 30-40 °C yielded only the substitution products 157 and 158 in 60- N 70 % yield, respectively (Scheme 57). This result seems to indicate i = TEA / PhH / heat R that under such reaction conditions the nitrilimine is formed and R : Me; Ph; 2-naphthyl; 2-thienyl; EtOOC, MeOCO N N thus no cycloaddition occurred. Ar = XC6H4; X : a, H; b, 4-Me; 4-Cl Ar 148 EtOOC-C(Cl)=N-NH-Ar Scheme 54. i Also, it was recently reported that 6,7-dimethoxy-1-methyl-3,4- N N + - dihydro-isoquinoline 149 with nitrilimines derived from the corres- EtOOC-C = N- N-Ar ponding hydrazonoyl halides in ethanol in the presence of chitosan i i under microwave irradiation afforded the 1,3.4- triazolo[3,4- a]isoquinoline derivatives 150 in 72-73 % yield (Scheme 55) [94]. i = EtOH / 30-40 °C

MeCO-C(Cl)=NNH-Ar + - + - i Br N Br MeO N +- HN Ar COOEt MeCO-C = N- N-Ar + N HN N N EtOOC Ar = 4-O2NC6H4 MeO Ar 158 157 149 Me MeO Scheme 57.

N COMe Reaction of naphthyridinone 159 with diarylnitrilimines was i = TEA / PhH / heat MeO Me reported to proceed via cycloaddition to the enone double bond N N Ar = XC6H4; X : a, H; b, 4-Me; 4-Cl rather than the C=N double bond to give the pyrazolo[4,5- Ar 150 c][1,8]naphthyridines 160 (Scheme 58) [96]. This result may be due Scheme 55. to steric effect. Dehydrogenation of the latter with chloranil yielded Similar reaction of N-phenylsulfonyl nitrilimine with each of 161 [96]. quinoline 151 and isoquinoline 152 proceeded site-selectively as it Treatment of the furo[3,4-c]thieno[2,3-d]pyrazole derivative yielded 1-phenyl-3-phenylsulfonyl-3,3a-dihydro[1,2,4]triazolo[3,4- 162 with C-methoxycarbonylnitrilimines, generated in situ from the a]quinoline 153 and 3-phenyl-1-phenylsulfonyl-1,10b-dihy- corresponding hydrazonoyl chlorides in the presence of silver car- dro[1,2,4]triazolo[3,4-a]isoquinoline 154, respectively in 91-96 % bonate, was reported to furnish the tetra-heterocyclic cycloadducts yield (Scheme 56) [95]. When the latter products were refluxed in 163a and 164a and the pentacyclic product 165a in 12-20, 10-20 carbon tetrachloride, they underwent elimination of benzenesulfinic and 10 % yield, respectively (Scheme 59) [97]. Use of the benzyl Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 611

Ph-C(Cl)=N-NH-Ar Ar R'-C(Cl)=NNH-Ar' Ar i N N i H N + - + - Ph NH R'-C = N- N-Ar' Ph-C = N- N-Ar + H Ar R Ar N N N N Ar O O N HN 159 Me Me R' i = TEA / PhH / heat Ar 160 N N N NH Chloranil Ar 170 N Ph Ar R N Ar Ar' N HN N N O Me Ar : a, Ph; b, 4-ClPh; c, 4-BrPh 161 R / Ar : H / 4-MePh; H / Ph; O N / Ph Scheme 58. 2 Ar R' / Ar' : Ph / Ph; EtOOC / Ph; MeCO / Ph; 171 ROOC-C(Cl)=N-NH-Ar' EtOOC / 4-MePh Ar COOR Ar AcOAg Scheme 61. N N +- N N N ROOC-C = N- N-Ar' + + 3.4. Competition Between Cyclic C=N and C=O Double Bonds N S S The 1,3-dipolar cycloaddition reaction of nitrilimines to 3,4- O Ar' O O dihydro-4-methyl-5H-1,3,4-benzotriazepin-5-one led, with com- 163 O 162 plete regio- and peri-selectivity, to [1,2,4]triazolo[1,3,4]benzo- Ar COOR Ar triazepine 172 , the structures of which were assigned by spectral COOR N COOR methods and X-ray crystallographic analysis (Scheme 62) [100]. N N N N + O EtOOC-C(Cl)=NNH-Ar N Me S N N N TEA Ar' Ar' S N N O O Ar' + - O O N + 164 165 EtOOC-C = N- N-Ar R : a, Me; b, PhCH2 N H Ar = 4-O2NC6H4 Ar' = 4-XC6H4; X : a, Me; b, MeO; c, Cl; d, NO2 R O Me Scheme 59. N COOEt N analog with 162 gave only the corresponding cycloadducts 163b and 164b in 0.5-35 and 1-41 % yields, respectively (Scheme 59) N N H N [97]. 172 R Diphenyl nitrilimine was reported to react readily with equimo- Ar lar amounts of azaheptafulvene 166 to give a mixture of two Scheme 62. [8+4]cycloadducts 168 and 169 in high yield via the mechanism depicted in (Scheme 60) [98]. 3.5. Competition Between two Endocyclic C=N Double Bonds Reaction of ethyl N-arylhydrazonobromoacetates with 2,7- R Ph-C(Cl)=NNH-Ph Ph N dimethyl-4-phenyl-3H-1,5-benzodiazepine 173 in benzene in the N presence of TEA yielded the cycloadducts 174 (Scheme 63) [101]. + - Ph-C = N- N-Ph Ph N N R Reaction of the latter products 173 each with the same nitrilimine furnished regioselectively, in each case, a mixture of the two stereoisomeric cycloadducts 175A and 175B (Scheme 63). 166 Similar reaction of 176 with nitrilimines, derived from N- R R 167 arylbenzenecarbohydrazonoyl bromides, proceeded region- and Ph Ph N N peri-selectively to give the bis-cycloadducts 177 (Scheme 64) + [101]. N N N N 3.6. Competition Between C=O, C=S and Endocyclic C=N Ph 169 Ph 168 Double Bonds Reaction of equimolar quantities of 2,7-dimethyl-3-thioxo- Scheme 60. 3,4,5,6-tetrahydro-2H-[1,2,4]triazepin-5-one 178 and nitrilimines, Reaction of porphyrin 170 with various nitrilimines in dry ben- generated in situ from the appropriate hydrazonoyl halides precur- zene in the presence of triethylamine was reported to follow differ- sors in dry benzene in the presence of triethylamine at room tem- ent chemoselective pathway as it afforded the (6+4)cycloadduct perature in equimolar quantities was reported to yield, in each case, 171 (Scheme 61) [99]. two products namely 179 and 180 in 20-25% and 45-50 % yields, 612 Current Organic Chemistry, 2014, Vol. 18, No. 5 Ahmad S. Shawali

EtOOC-C(Br)=NNH-Ar EtOOC-C(Br)=NNH-Ar Me Me N TEA Me N i N + - + - + EtOOC-C = N- N-Ar + EtOOC-C = N- N-Ar S N Me N H O Ph 178 173 Me EtOOC N Me Me N Me N Ar N N Ar Ar N N N Me N N HN N N S H O S H O Me EtOOC N EtOOC 176 174 Ph ii EtOOC N EtOOC N Ar N N Ar Me Ar Me N N Me N Me Me Ar N N N NH + ii N HN N Me N Ph N Ph N + Ar S H O S N N Ar N EtOOC EtOOC Me O EtOOC N EtOOC N N COOEt 180 181 Ar N 175A 175B 179 + - i = TEA / PhH / rt ii = EtOOC-C = N- N-Ar Scheme 63. Ar = 4-XC6H4; X : a, Cl; b, Me; c, NO2 Ar-C(Br)=NNH-Ar' Me Scheme 65. N TEA - + Ph + Ar-C = N- N-Ar' N Ph-C(Cl)=NNH-Ph Ph N Me N N S Ar i N S Ar Ph +- 176 Ar N + Ph-C = N- N-Ph Ar' N N N N Me O i = TEA / Dioxane / rt 183 O 182 ii = TEA / Dioxane / heat / DPNI

Me N Ph N Ar' Ph Ph Ar N N N Ph Ph 177 + N N N H N Ar Scheme 64. ii Ar S N respectively (Scheme 65) [102]. The structures of the products were N S- confirmed by X-ray crystallography. When 1: 2 stoichiometry was O O used, the formation of the product 179 in 50 % yield was favoured [102]. Ph Ph Ph N NH 3.7. Competition Between C=O, Exocyclic C=C and Endocyclic N Ph N Ph C=N Double Bonds Ph N N N N Ph Ar N N When a mixture of 2-arylidene-6,7-dihydro-5H-thiazolo[3,2- + S Ph a]pyrimidin-3(5H)-ones and N-phenyl benzenecarbohydrazonoyl N N S Ph chloride was refluxed in dioxane in the presence of triethylamine O 185 O 184 (TEA), it yielded a mixture of the products 184 and 185 via the mechanism depicted in (Scheme 66) [103]. The suggested mecha- Scheme 66. nism was confirmed by the finding that reaction of the same hydrazonoyl chloride and heterocycle 182 in dioxane in the presence of the molecular structures of the reactants. The ready availability of triethylamine at room temperature, it gave the cycloadduct 183, the reactants together with the generally good yields of the products which upon treatment with DPNI in refluxing dioxane, afforded the make the reactions outlined above very attractive to synthetic chem- products 184 and 185 (Scheme 66) [103]. ists. In addition, there are reasons to believe that the chemoselectivity of some reactions reported need further refinement. CONCLUSION CONFLICT OF INTEREST From the previous literature survey, it is clear that chemoselectivity plays an important role in synthetic design. Literature The authors confirm that this article content has no conflict of data revealed that both site- and peri-selectivities are controlled by interest. Chemoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrilimines Current Organic Chemistry, 2014, Vol. 18, No. 5 613

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Received: August 30, 2013 Revised: November 11, 2013 Accepted: November 12, 2013