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Tetrahedron xxx (2014) 1e8

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Tetrahedron

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Reactions of selected 3-bromoisothiazole-5-carbonitriles with thesecondary dialkylamines pyrrolidine and morpholine

Andreas S. Kalogirou, Panayiotis A. Koutentis *

Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus

a r t i c l e i n f o

Article history:Received 17 December 2013Received in revised form 28 January 2014Accepted 3 June 2014Available online xxx

Dedicated to the memory of Professor SandyMcKillop who sadly passed away on 20thAug. 2013

Keywords:HeterocyclesIsothiazolesNucleophilic aromatic substitutionHeteroaromatic chemistrySulfur heterocycles

* Corresponding author. E-mail address: koutenti@

http://dx.doi.org/10.1016/j.tet.2014.06.0120040-4020/� 2014 Elsevier Ltd. All rights reserved.

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a b s t r a c t

Readily available 3-bromoisothiazole-5-carbonitriles bearing various C-4 substituents [H, CO2R C^N andhalogen (Cl or Br)], react with either pyrrolidine or morpholine to give, in most cases, the 3-amino-substituted derivatives in high yields. The reaction of 3-bromoisothiazole-4,5-dicarbonitrile, however,varied with the nucleophilicity of the dialkylamine: pyrrolidine led to cleavage of the isothiazole ring togive 2-[di(pyrrolidin-1-yl)methylene]malononitrile while morpholine led to the expected 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile. By comparison, 3-chloroisothiazole-4,5-dicarbonitrile reacted withpyrrolidine to give surprisingly, 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile as the majorproduct, while with morpholine the major product was the expected 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile. The mechanisms of the transformations are discussed, together with rationalization forthe formation of side products. Furthermore, the hydrolytic decarboxylation of methyl and ethyl esters of3-dialkylaminoisothiazoles using both conventional heating and microwave irradiation is reported.

� 2014 Elsevier Ltd. All rights reserved.

Fig. 1. Selected important commercial isothiazoles.

1. Introduction

Isothiazoles (1,2-thiazoles) are isomers of the more commonlyknown thiazoles and their synthesis, chemistry, and applicationshave been extensively reviewed.1 Unlike thiazoles, which areprevalent in nature, there are only a few isothiazole-containingnatural products; e.g., the phytotoxins brassilexin2 and sinalexin,3

the prostaglandin release inhibitor pronqodine A,4 and the cyto-toxin aulosirazole.5 Nevertheless, many isothiazoles exhibit usefulbiological properties that find uses in either medicinal (e.g., anti-cancer,6 cathepsin C inhibitors,7 antirhinoviral and enteroviral ac-tivity,8 and mitostatic behavior9) or agrochemical (e.g., asinsecticides, fungicides, and acaricides)10 sciences. Other iso-thiazoles have industrial applications, e.g., as corrosion inhibitors,11

dyes,12 and wood preservatives.13 Important commercial iso-thiazoles include the antibacterial drug Sulfasomizole,14 the artifi-cial sweetener Saccharin,15 the novel fungicide Isotianil (Stout�),10c

and methylchloroisothiazolone (MCIT) a major component of theKathon preservatives with antibacterial and antifungal effects(Fig. 1). The antipsychotic pharmaceutical drugs ziprasidone16 andperospirone17 also contain a benzoisothiazole moiety. Isothiazoles

ucy.ac.cy (P.A. Koutentis).

, A. S.; Koutentis, P. A., Tetrah

are also useful synthetic intermediates (e.g., Woodward’s synthesisof colchicine).18

A group of important isothiazole scaffolds are haloisothiazole-carbonitriles.19 In particular, 3,5-dichloroisothiazole-5-carbonitrile(1),19d is a versatile scaffold for a wide range of (het)arylsubstituted derivatives19f,g,20 and its derivatives have applications

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Table 1Reaction of 3-bromoisothiazole-5-carbonitriles 5aee with either morpholine orpyrrolidine in PhMe heated at reflux

Entries 5 (R1) R2NH (equiv) Time (h) Yields 6 (%)

1 5a (H) Morpholine (2) 48 a

2 5a (H) Morpholine (8) 1 6a (11)3 5a (H) Pyrrolidine (2) 0.75 6ba

4 5b (Br) Morpholine (2) 48 a

5 5b (Br) Morpholine (8) 24 6c(70)6 5b (Br) Morpholine (16) 3 6c (67)7 5b (Br) Pyrrolidine (2) 2 6d (55)8 5b (Br) Pyrrolidine (8) 0.5 6d (54)

A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e82

as fungicides,10c insecticides,21 herbicides,22 and cathepsin C in-hibitors.7 Moreover 3,4-dichloroisothiazole-5-carbonitrile (2),19h isa precursor to various isothiazole herbicides including the rice blastfungicide Isotianil,10c while 3-chloroisothiazole-4,5-dicarbonitrile(3)19a is also a precursor to various potent biocides.23

Several routes to isothiazolecarbonitriles have been repor-ted.19d,h,i,24 Recently, we described the efficient conversion of (4-chloro-5H-1,2,3-dithiazolylidene)acetonitriles 4 into 3-bromoisothiazole-5-carbonitriles 5 on treatment with gaseousHBr19a,b,25 (Scheme 1).

9 5c (CO2Me) Morpholine (2) 24 6e (98)10 5c (CO2Me) Morpholine (2) 0.5b 6e (89)11 5c (CO2Me) Morpholine (8) 1 6e (99)12 5c (CO2Me) Pyrrolidine (2) 0.17 6f (86)13 5d (CO2Et) Morpholine (2) 14 6g (99)14 5d (CO2Et) Pyrrolidine (2) 0.08 6h (92)15 5e (CN) Morpholine (2) 30 6i (59)16 5e (CN) Morpholine (8) 1.5 6i (81)17 5e (CN) Pyrrolidine (2) 1.5 6j (11)c

a Complicated mixture, trace of 6.b Microwave, 150 �C, 60 PSI, 250 W.c Colorless product also observed (see Table 2).

Scheme 1. Route to 3-bromoisothiazole-5-carbonitriles 5 via (dithiazolylidene)aceto-nitriles 4.

Since we had a number of 3-bromoisothiazole-5-carbonitrilesavailable, we compared their reactivity towards the cyclic second-ary amines pyrrolidine andmorpholine. The results of our study aredescribed herein.

2. Results and discussion

2.1. Reactions of isothiazoles with cyclic secondary amines

To the best of our knowledge, the only reported examples ofnucleophilic aromatic substitution on 3-haloisothiazole-5-carbonitriles are the reactions of 3-chloro- or 3-bromoisothiazole-4,5-dicarbonitriles 3 and 5e with morpholine toafford 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile (6i).19a,b

Having developed synthetic routes to the 3-bromoisothiazole-5-carbonitriles 5aee, we investigated their reactions with the cyclicsecondary amine morpholine and the more nucleophilic pyrroli-dine (Table 1).

The reactions of morpholine or pyrrolidine (2 and 8 equiv) with4-unsubstituted 3-bromoisothiazole-5-carbonitrile (5a) gavecomplex reaction mixtures containing only traces of the expected3-(morpholin-4-yl)- and 3-(pyrrolidin-1-yl)isothiazole-5-carbonitriles 6a and 6b, respectively, and some elemental sulfur(by TLC) that supported cleavage of the isothiazole ring. Worthy ofnote was that highly electrophilic isothiazoles bearing leavinggroups at C-3 were known to suffer ring opening via nucleophilicattack at either C-5 or at S-1,19f,26 however, in this case we wereunable to isolate any carbon containing products originating fromcleavage of the isothiazole. By comparison with the remainingisothiazoles, the 4-unsubstituted 3-bromoisothiazole-5-carbonitrile (5a) was the least reactive toward nucleophilic aro-matic substitution.

3,4-Dibromoisothiazole-5-carbonitrile (5b) treated with eithermorpholine or pyrrolidine underwent regioselective nucleophilicsubstitution at C-3 to give the 3-(morpholin-4-yl)- and 3-(pyrroli-din-1-yl)-4-bromoisothiazole-5-carbonitriles 6c and 6d in yields ashigh as 70% (entry 5) and 55% (entry 7), respectively, depending onthe equivalents of amine used. However, the reaction of thedibromoisothiazole 5b with 2 equiv of morpholine at ca. 110 �C

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failed to go to completion even after 2 days, while increasing theequivalents of morpholine to 8 and 16 led to significant reductionsin reaction time (24 and 3 h, respectively) and gave the expected 4-bromo-3-(morpholin-4-yl)isothiazole-5-carbonitrile (6c) in67e70% yields (entries 5 and 6). No trace of other products wasseen in the reaction mixture, and attempts to reduce the reactiontime by using microwave irradiation (150 �C, 60 PSI, 250 W) gavemainly degradation when either 2 or 8 equiv of amine were used.

The C-3 regioselectivity of the nucleophilic substitution reactionwas confirmed by protodehalogenating 4-bromo-3-(morpholin-4-yl)isothiazole-5-carbonitrile (6c) using In powder (5 equiv) inHCO2H at ca. 10 �C19f to give 3-(morpholin-4-yl)isothiazole-5-carbonitrile (6a) in 37% yield (Scheme 2). Protodebromination us-ing Zn powder (5 equiv) in HCO2H at ca. 10 �C19f for 1 day was tooaggressive and gave lower yields (23%). Additional efforts to pro-todebrominate via a palladium catalyzed silane-mediated proto-dehalogenation using polymethylhydrosiloxane (5 equiv),Pd(Ph3P)2Cl2 (5 mol %), and Et3N (2 equiv) in dioxane at ca.100 �C,27

or via hydrogenation with Pd/C (10 mol %) in EtOH at ca. 20 �Cunder 44 PSI of H2(g) gave mainly recovered starting material,while an attempted lithium/halogen exchangewith n-BuLi (�78 �C,THF) followed by quenching with MeOH led to degradation of thestarting material.

Scheme 2. Protodebromination of 4-bromoisothiazole 6c.

During protodehalogenation with either In or Zn powder, theformation of hydrogen sulfide was detected (Dr€ager detector),which indicated reductive cleavage of the isothiazole ring and

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A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e8 3

provided a possible explanation for the low product yields. In-terestingly, subjecting 3-bromoisothiazole-5-carbonitrile (5a) tosimilar reaction conditions also led to its gradual degradation.

Methyl and ethyl 3-bromo-5-cyanoisothiazole-4-carboxylates5c and 5d, bearing three very different functional groups, reactedchemoselectively with either morpholine or pyrrolidine to give thecorresponding 3-(morpholin-4-yl)- and 3-(pyrrolidin-1-yl)-5-cya-noisothiazole-4-carboxylates 6eeh in excellent yields (86e99%)(Table 1, entries 9e14). The reaction time with morpholine wasconsiderably longer than with the more nucleophilic pyrrolidine,however, by increasing the equivalents of morpholine (from 2 to8 equiv, Table 1 entry 11) or by using microwave irradiation (150 �C,60 PSI, 250 W, Table 1 entry 10) the reaction time was significantlyreduced (from 1 day to 1 h or less), without a significant loss inproduct yield.

Unexpected behavior was, however, observed with 3-bromoisothiazole-4,5-dicarbonitrile (5e). Bromoisothiazole 5e reac-ted as expected with either 2 or 8 equiv of morpholine to give 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile (6i) in 59 and 81%yields, respectively (Table 1, entries 15 and 16).19b Treatment of 3-bromoisothiazole-4,5-dicarbonitrile (5e) with pyrrolidine (2 equiv),however, gave 3-(pyrrolidin-1-yl)isothiazole-4,5-dicarbonitrile (6j)in only 11% yield (entry 17) together with 2-[di(pyrrolidin-1-yl)methylene]malononitrile (7) in 32% yield (Table 2, entry 1), whichmust arise from cleavage of the isothiazole ring. The structuralidentity of the ylidenemalononitrile 728 was supported by an in-dependent synthesis from tetracyanoethylene (TCNE) and pyrroli-dine (4 equiv), which in toluene at ca. 80 �C for 1 h gave an identicalproduct in 79% yield. Similar syntheses of diamine-ylidene malo-nonitriles from TCNE and dialkylamines have been reported.29

Table 2Reaction of 3-haloisothiazole-4,5-dicarbonitriles 5e and 3 with pyrrolidine in PhMe

Entry 5e or 3 (Hal) Pyrrolidine (equiv) Temp (�C) Time (h) Yields (%)

6j 8 7

1 5e (Br) 2 110 1.5 11 0 322 5e (Br) 8 110 0.08 0 0 853 5e (Br) 2 0 1 0 0 354 5e (Br) 8 0 0.08 0 0 585 5e (Br) 2 �30 24 0 0 766 5e (Br) 8 �30 0.17 0 0 747 3 (Cl) 2 110 0.5 37 24 88 3 (Cl) 2 80 1 7 68 169 3 (Cl) 2 20 48a 2 39 410 3 (Cl) 8 20 0.17 0 71 2811 3 (Cl) 2 0 2 0 55 2612 3 (Cl) 8 0 0.08 0 80 1813 3 (Cl) 8 �30 0.08 0 78 16

a Recovered starting material 8%.

Interestingly, when excess pyrrolidine (8 equiv) was used, the 3-bromoisothiazole-4,5-dicarbonitrile (5e) was consumed in 5 minand only the ylidenemalononitrile 7was isolated in 85% yield (Table2, entry 2). Reducing the reaction temperature to as low as �30 �Calso led only to the formation of the ylidene 7 (Table 2, entries 3e6).

The formation of the ylidenemalononitrile 7 prompted an in-vestigation of the reaction of readily available 3-chloroisothiazole-4,5-dicarbonitrile (3) with pyrrolidine (Table 2, entries 7e13). When3-chloroisothiazole-4,5-dicarbonitrile (3) was reacted with pyrroli-dine (2 equiv) at ca. 80 �C, three products were identified, 3-(pyr-rolidin-1-yl)isothiazole-4,5-dicarbonitrile (6j), 2-[di(pyrrolidin-1-

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yl)methylene]malononitrile (7), and the unexpected 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile (8) that was also themajor product, resulting from the displacement of the 5-cyanogroup by pyrrolidine. Clearly, in this case the highly activated iso-thiazole bearing two carbonitrile groups was sufficiently electro-philic at C-5 to allow displacement of cyanide at C-5 by the stronglynucleophilic pyrrolidine. The displacement of cyanide from iso-thiazoles,30a pyridines,30b and arenes30c,d by amine nucleophiles isknown. Lowering the temperature to ca. 20 �C led to longer reactiontimes and an overall lower yield of the three products (Table 2, entry9), while increasing the equivalents of pyrrolidine from 2 to 8 led tofaster reaction times and isolation of only 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile (8) and 2-[di(pyrrolidin-1-yl)methyl-ene]malononitrile (7) in 71 and 28% yields, respectively (Table 2,entry 10). Lowering the temperature further to ca. 0 �C with 2 equivof amine again led to a longer reaction time and drop in yield (Table2, entry 11). However, using 8 equiv of amine led to a fast reaction(5 min) and the highest yield of the 5-(pyrrolidin-1-yl)isothiazole 8(80%), which could not be improved further by lowering the tem-perature to ca. �30 �C (Table 2, entries 12 and 13). Similar resultswere not obtained from reactions of 3-chloro- or 3-bromoisothiazole-4,5-dicarbonitriles 3 and 5e with morpholine(2 equiv) at ca. 20 �C that gave only low yields of 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile (6i). Nevertheless, we note that the 3-chloro- and 3-bromoisothiazole-4,5-dicarbonitriles 3 and 5e reactwith an excess ofmorpholine (8 equiv) in benzene or toluene heatedat reflux to give the 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitriles in 8019a and 81% (Table 1, entry 16), respectively.

2.2. Mechanistic rationale

Based on these results, we tentatively believe the 5-dialkylaminoisothiazole 8 to be the kinetic product and the 3-dialkylaminoisothiazole 6j to be the thermodynamic product.This is not surprising as the isothiazole 5-position is stronglyelectrophilic, activated by both nitriles and the isothiazole ringnitrogen. As such, pyrrolidine, which compared to morpholine isa stronger nucleophile,31 is expected to preferentially attack the C-5position at lower temperatures (kinetic control). On the other hand,displacement of the halogen at C-3 by a dialkylamine can lead togreater enthalpy gain, based on the bonds broken and formed (CeXand NeH broken and CeN andHeX formed), but should suffer froma higher activation energy as the C-3 position is less electrophilic.Thus, the C-3 substitution product was observed at higher tem-peratures (thermodynamic control). In the case of the 3-bromoiso-thiazole 5e as the startingmaterial, the bond enthalpy of the CAreBr(351 kJ/mol)32 bond is smaller that of a CAreCl (406 kJ/mol)32 bond,therefore the activation energy for the C-3 displacement should belower resulting in only the 3-dialkylaminoisothiazole 6j and nodisplacement of cyanide at C-5 (Scheme 3).

The origins of the ylidenemalononitrile 7 were also in-vestigated: treating either the 3- or the 5-(pyrrolidin-1-yl)iso-thiazoles 6j and 8with pyrrolidine (2 equiv) in toluene heated to ca.110 �C for 1 day indicated that both compounds were relativelystable to the amine with only a small trace of the ylidene 7 detectedby TLC. Nevertheless, adding a large excess of pyrrolidine (20 equiv)led to the complete consumption of the starting isothiazoles andformation of the ylidene 7 in 70 and 65% yields, respectively(Scheme 4).

Our studies on the treatment of 3- or the 5-pyrrolidinoisothiazoles 6j and 8 with pyrrolidine, showed thatthese isothiazoles are sufficiently stable under mild reaction con-ditions and cannot therefore be the source of ylidene 7 observed inthe reaction of 3 or 5e with pyrrolidine (Table 2). As such, underthese mild conditions, the ylidene 7 must form via an alternativeroute: two possibilities can be proposed; the first (Scheme 5, Route

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Scheme 3. Rationale for the formation of 3- and 5-dialkylaminoisthiazoles 10 and 11.

Scheme 4. Treatment of (pyrrolidin-1-yl)isothiazoles 6j and 8 with excess pyrrolidine.

N

Scheme 5. Mechanistic rationale for the formation of ylidene 7.

A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e84

A), involves direct attack at the isothiazole sulfur to give a ringopened 2-(dialkylaminothio)ethene-1,1,2-tricarbonitrile 12, whichcan undergo subsequent attack by additional dialkylamine to givefirst the 2-dialkylaminoethene-1,1,2-tricarbonitrile 13 and then theobserved 2-(diaminomethylene)malononitrile 14. The second route(Scheme 5, Route B), involves direct attack at the isothiazole C-5position to give the ring opened species 15, which subsequentlyloses HX and elemental sulfur, presumably via a sulfur chain ex-tension mechanism,33 to give the common intermediate 2-dialkylaminoethene-1,1,2-tricarbonitrile 13, which then gives theobserved product 14. Tentatively, we propose Route A to be themore probable, since this requires immediate cleavage of the CeX

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bond and our results show that the formation of ylidene 14 isstrongly favored when the C-3 halogen is bromine rather thanchlorine (DH0 of CeBr is 351 kJ/mol vs 406 kJ/mol for CeCl).32 Alsoworthy of note, is that the proposed intermediate 2-(dia-lkylaminothio)ethene-1,1,2-tricarbonitrile 12 can also act asa source of the 3-(dialkylamino)isothiazoles 6, since nucleophilicaddition onto the geminal nitrile can be followed by an intra-molecular cyclization onto the sulfur atom. In a similar way, in-termediate 15 could be the source of the isothiazole 8 if the thiolcyclizes onto the b-position eliminating cyanide.

2.3. Hydrolysis and protodecarboxylation of isothiazole-4-carboxylates

Disappointingly, the nucleophilic displacement of the C-3 hal-ogen of isothiazole 5a by either morpholine or pyrrolidine gaveonly low yields of the corresponding 4-unsubstituted isothiazoles6a and 6b (Table 1, entries 1e3). Fortunately, an alternative route tothese compounds was discovered while investigating the chemis-try of the analogous 3-(morpholin-4-yl)- and 3-(pyrrolidin-1-yl)isothiazole-4-carboxylates 6eeh (Table 1).

When methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6e) was treated with excess morpholine (4 equiv) intoluene at ca. 110 �C for 1 day, we expected to isolate the corre-sponding carboxamide, but obtained only unreacted isothiazole 6e.When polar aprotic solvents DMSO or DMF were used and the re-action mixtures were heated at ca. 100 �C for 2 days, we observedthe formation of 4-unsubstituted isothiazole 6a in 51 and 73% yield,respectively, resulting from an in situ saponification andprotodecarboxylation.

After a brief partial optimization of this reaction that involvedscreening bases (NaOH, pyridine, Et3N), solvents (DMF, DMSO,DMA, EtOH, and PhMe), and reaction temperatures (20e100 �C) wefound that the highest yields (up to 92%) were obtained byreplacing the cyclic secondary amine with Et3N (5 equiv) and per-forming the reaction in DMF at ca. 100 �C. These conditions, how-ever, worked less well with 3-(pyrrolidin-1-yl)isothiazole 6f, whichgave the desired product 6b in only a moderate yield (45%) after 3days reaction time. Furthermore, the analogous reactions of theethyl ester analogs 6g and 6h under the same conditions gavemainly unreacted starting material. Fortunately, heating the re-actions in a microwave reactor at ca. 150 �C at 45 PSI (250 W) for1 h, gave the desired products in excellent yields (Scheme 6). Undermicrowave irradiation, the methyl esters 6e and 6f underwentrapid (0.5 h) and quantitative hydrolytic protodecarboxylation(Scheme 6). Despite these successes, attempts to proto-decarboxylate the starting haloesters 5c and 5d using these con-ditions led only to degradation of the starting isothiazoles.

Decarboxylations of carboxylic acids by heating in DMF havebeen reported.34 However, the hydrolysis of esters in DMF underbasic conditions is known to occur only in the presence of hardnucleophiles like hydroxide or alkoxides,35 or salts like LiCl, LiBr,and LiI,36 and very rarely in the presence of amine bases.37 In ourcase, we presume that water in the solvent in the presence of theamine base led to the formation of sufficient catalytic hydroxide tohydrolyze the ester. To support this hypothesis we reacted the ester6ewith tetramethylammonium hydroxide (10 mol %) in DMF at ca.100 �C, and after 2 days obtained the isothiazole 6a in 81% yield.Since DMF is unstable in the presence of hydroxide,38 we also in-vestigated the use of the more stable DMA and at ca. 100 �C after 1.5days obtained 6a in a near quantitative 97% yield. By using micro-wave irradiation, and heating the mixture to ca. 150 �C, the reactiontime was reduced to only 0.5 h, albeit with a drop in yield (80%).This protocol worked well with all the other analogs 6feh (Scheme6). Using a lower temperature in the microwave (140 �C) for ethylester analog 6f led to a longer reaction time of 3 h and an identical

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Scheme 6. Hydrolytic protodecarboxylation of isothiazole-4-carboxylates.

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yield of 6a of 81%. Interestingly, while the use of tetramethy-lammonium hydroxide to effect the hydrolysis of esters has beenreported,39 to the best of our knowledge, no catalytic methods havebeen reported.

3. Conclusions

Nucleophilic substitution reactions of a range of 3-bromoisothiazole-5-carbonitriles with morpholine and pyrroli-dine are reported. 3-Amino-4-carboxylate derivatives were ob-tained in near-quantitative yields, with 4-bromo and 4-cyanosubstituents giving medium yields, while 4-unsubstituted 3-bromoisothiazole-5-carbonitrile (5a) reacted poorly to givemainly degradation. Reductive protodebromination of the 4-bromoisothiazole 6c using In/HCO2H also afforded the 4-unsubstituted isothiazole 6a. Treatment of 3-chloroisothiazole-4,5-dicarbonitrile with pyrrolidine gave a mixture of 3-(pyrrolidin-1-yl)isothiazole 6j (thermodynamic product), 3-chloro-5-(pyrroli-din-1-yl)isothiazole 8 (kinetic product), and ylidene-malononitrile7. The origins of ylidenemalononitrile 7 were investigated anda mechanism was proposed for the formation of all products. Fi-nally, hydrolytic decarboxylation of methyl and ethyl esters of 3-aminoisothiazoles, using either Et3N (5 equiv) in DMF or Me4NOH(10 mol %) in DMA, under microwave heating, afforded the other-wise difficult to access 4eunsubstituted 3-aminoisothiazole-5-carbonitriles 6a and 6b.

4. Experimental

4.1. General procedures

All chemicals were commercially available except those whosesynthesis is described. DMF was dried by azeotropically removingwater with benzene and then distilling under vacuum over driedmolecular sieves 4 �A and then kept under an argon atmosphere ina desiccator. Anhydrous Na2SO4 was used for drying organic ex-tracts and all volatiles were removed under reduced pressure. Allreaction mixtures and column eluents were monitored by TLC us-ing commercial glass backed thin layer chromatography (TLC)plates (Merck Kieselgel 60F254).40 The plates were observed underUV light at 254 and 365 nm. The technique of dry flash chroma-tography was used throughout for all non-TLC scale chromato-graphic separations using Merck Silica Gel 60 (less than 0.063 mm).A CEM Discover Microwave Reactor was used for microwave ex-periments. Melting points were determined using a TA InstrumentsDSC Q1000 with samples hermetically sealed in aluminum pansunder an argon atmosphere; using heating rates of 5 �C/min (DSCmp listed by onset and peak values). Solvents used for re-crystallization are indicated after the melting point. UV spectrawere obtained using a PerkineElmer Lambda-25 UV/vis spectro-photometer and inflections are identified by the abbreviation ‘inf’.IR spectra were recorded on a Shimadzu FTIR-NIR Prestige-21

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spectrometer with Pike Miracle Ge ATR accessory and strong, me-dium, and weak peaks are represented by s, m, and w, respectively.1H and 13C NMR spectra were recorded on a Bruker Avance 500machine (at 500 and 125 MHz, respectively). Deuterated solventswere used for homonuclear lock and the signals are referenced tothe deuterated solvent peaks. CH assignments are made based onDEPT 135 spectroscopy. Low resolution (EI) mass spectra wererecorded on a Shimadzu Q2010 GCeMS with direct inlet probe.MALDI TOF mass spectra were recorded on a Bruker Autoflex IIISmartbeam instrument, while ESIeAPCIþ mass spectra wererecorded on a Model 6110 Quadrupole MSD, Agilent Technologies.

4.2. Reactions of 3-haloisothiazoles with morpholine orpyrrolidine

4.2.1. 3-(Morpholin-4-yl)isothiazole-5-carbonitrile (6a) (typicalprocedure). To a stirred solution of 3-bromoisothiazole-5-carbonitrile (5a) (38 mg, 0.20 mmol) in dry toluene (2 mL) wasadded morpholine (140 mL, 1.60 mmol) and the mixture was heatedat ca. 110 �C until the starting material was consumed (TLC). Thereaction mixture was then cooled to ca. 20 �C, adsorbed onto silica,and chromatographed (DCM) to give the title compound 6a (4.3 mg,11%) as colorless needles, mp (DSC) onset: 144.9 �C, peak max:147.3 �C (from c-hexane); Rf 0.33 (DCM); (found: C, 49.25; H, 4.53;N, 21.50. C8H9N3OS requires C, 49.21; H, 4.65; N, 21.52%); lmax(DCM)/nm 340 (log 3 3.08); nmax/cm�1 3109w (Ar CH), 2986w,2970w, 2907w, 2882w and 2853w (CH2), 2237w and 2222w(C^N), 1545s, 1462m, 1445m, 1433m, 1308m, 1275m, 1265s,1231m, 1211w, 1186m, 1119s, 1066w, 999m, 926w, 872s, 853m,841m, 818s; dH (500 MHz; CDCl3) 7.05 (1H, s, H-4), 3.81 (4H, t, J4.8 Hz, CH2O), 3.46 (4H, t, J 4.9 Hz, CH2N); dC (125MHz; CDCl3) 166.9(s), 133.0 (s), 117.9 (d, C-4), 111.2 (s, C^N), 66.2 (t, CH2O), 47.4 (t,CH2N); m/z (MALDI-TOF) 196 (MHþ, 100%), 195 (Mþ, 87).

4.2.2. 4-Bromo-3-(morpholin-4-yl)isothiazole-5-carbonitrile(6c). Similar treatment of 3,4-dibromoisothiazole-5-carbonitrile(5b) (53.5 mg, 0.20 mmol) with morpholine (140 mL, 1.60 mmol)gave on chromatography (n-hexane/DCM, 2:8) the title compound6c (38.5 mg, 70%) as colorless plates, mp (DSC) onset: 112.0 �C, peakmax: 113.1 �C (from c-hexane); Rf 0.52 (n-hexane/DCM, 2:8);(found: C, 35.20; H, 3.03; N, 15.28. C8H8BrN3OS requires C, 35.05; H,2.94; N, 15.33%); lmax (DCM)/nm 254 inf (log 33.48), 331 (3.37);nmax/cm�1 2970w, 2961w, 2930w, 2874w and 2845w (CH2), 2232m(C^N), 1503s, 1431s 1375m, 1352w, 1335w, 1306w, 1275s, 1265s,1213w, 1159w, 1146w, 1111s, 1065m, 1028m, 926m, 889s, 853s,841m, 789m; dH(500 MHz; CDCl3) 3.84 (4H, t, J 4.8 Hz, CH2O), 3.45(4H, t, J 4.7 Hz, CH2N); dC (125 MHz; CDCl3) 165.25 (s), 132.6 (s),110.2 (s), 109.5 (s), 66.3 (t, CH2O), 49.45 (t, CH2N);m/z (MALDI-TOF)274 (Mþþ1, 100%), 272 (Mþ�1, 98), 194 (Mþ�Br, 51).

4.2.3. 4-Bromo-3-(pyrrolidin-1-yl)isothiazole-5-carbonitrile(6d). Similar treatment of 3,4-dibromoisothiazole-5-carbonitrile

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A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e86

(5b) (54 mg, 0.20 mmol) with pyrrolidine (24 mL, 0.40 mmol) gaveon chromatography (n-hexane/DCM, 1:1) the title compound 6d(28.5 mg, 55%) as colorless plates, mp (DSC) onset: 84.5 �C, peakmax: 85.1 �C (from n-hexane/0 �C); Rf 0.67 (n-hexane/DCM, 1:1);(found: C, 37.30; H, 2.99; N, 16.18. C8H8BrN3S requires C, 37.22; H,3.12; N, 16.28%); lmax (DCM)/nm 255 inf (log 34.13), 366 (4.01);nmax/cm�1 2976w, 2967w and 2876w (CH2), 2226m (C^N), 1526s,1468m, 1452s, 1360w, 1348m, 1314w, 1247w, 1231w, 1177w, 1153m,1138w, 1099m, 1032w, 932w, 916w, 893s, 854m, 839w, 797w; dH(500 MHz; CDCl3) 3.74 (4H, m, CH2N), 1.97 (4H, m, CH2);dC(125 MHz; CDCl3) 161.8 (s), 131.8 (s), 110.8 (s), 104.3 (s), 49.85 (t,CH2N), 25.7 (t, CH2); m/z (MALDI-TOF) 258 (Mþþ1, 94%), 256(Mþ�1, 100), 178 (Mþ�Br, 53), 133 (17).

4.2.4. Methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate(6e). Similar treatment of methyl 3-bromo-5-cyanoisothiazole-4-carboxylate (5c) (49.5 mg, 0.20 mmol) with morpholine(140 mL, 1.60 mmol) gave on chromatography (n-hexane/t-BuOMe, 1:1) the title compound 6e (50 mg, 99%) as yellow plates,mp (DSC) onset: 114.0 �C, peak max: 115.4 �C (from c-hexane); Rf0.52 (n-hexane/t-BuOMe, 1:1); (found: C, 47.42; H, 4.27; N, 16.48.C10H11N3O3S requires C, 47.42; H, 4.38; N, 16.59%); lmax (DCM)/nm 238 (log 34.09), 360 (3.31); nmax/cm�1 2968w, 2905w, 2874wand 2857w (CH2 and CH3), 2231w (C^N), 1726s (C]O), 1512s,1464m, 1437m, 1425m, 1371w, 1356m, 1335w, 1315w, 1294m,1261s, 1219w, 1200m, 1171w, 1159w, 1142m, 1113s, 1072m, 1024s,966m, 933m, 916m, 872w, 860s, 845m, 814m, 789m, 773m; dH(500 MHz; CDCl3) 3.98 (3H, s, CH3), 3.84 (4H, t, J 4.7 Hz, CH2O),3.37 (4H, t, J 4.8 Hz, CH2N); dC (125 MHz; CDCl3) 167.2 (s), 160.25(s), 139.55 (s), 124.1 (s), 110.0 (s, C^N), 66.4 (t, CH2O), 52.9 (q,CH3), 50.3 (t, CH2N); m/z (MALDI-TOF) 254 (MHþ, 100%), 253 (Mþ,42).

4.2.5. Methyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate(6f). Similar treatment of methyl 3-bromo-5-cyanoisothiazole-4-carboxylate (5c) (49.5 mg, 0.20 mmol) with pyrrolidine (24 mL,0.40 mmol) gave on chromatography (n-hexane/DCM, 1:1) the titlecompound 6f (41mg, 86%) as yellow plates, mp (DSC) onset: 69.9 �C,peak max: 70.5 �C (from c-hexane); Rf 0.43 (n-hexane/DCM, 1:1);(found: C, 50.68; H, 4.60; N,17.62. C10H11N3O2S requires C, 50.62; H,4.67; N, 17.71%); lmax (DCM)/nm 239 (log 34.08), 382 (3.73); nmax/cm�1 2984w, 2953w, 2940w, 2886w and 2868w (CH2 and CH3),2230w (C^N), 1721s (C]O), 1533s, 1487m, 1479m, 1470m, 1456m,1445m, 1435m, 1371m, 1352m, 1328m, 1287s, 1242m, 1231w,1196m, 1172w, 1140s, 1105m, 1034m, 989m, 972m, 918m, 883m,862m, 824m, 781s, 764m; dH (500 MHz; CDCl3) 3.97 (3H, s, CH3),3.46 (4H, m, CH2N), 1.96 (4H, m, CH2); dC (125MHz; CDCl3) 163.1 (s),161.1 (s), 136.9 (s), 122.0 (s), 110.3 (s, C^N), 52.9 (q, CH3), 50.3 (t,CH2N), 25.7 (t, CH2); m/z (MALDI-TOF) 239 (MHþþ1, 11%), 238(MHþ, 100), 237 (Mþ, 41).

4.2.6. Ethyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate(6g). Similar treatment of ethyl 3-bromo-5-cyanoisothiazole-4-carboxylate (5d) (52 mg, 0.20 mmol) with morpholine (35 mL,0.40 mmol) gave on chromatography (DCM) the title compound 6g(53 mg, 99%) as yellow needles, mp (DSC) onset: 73.4 �C, peak max:74.0 �C (from n-pentane/0 �C); Rf 0.50 (DCM); (found: C, 49.33; H,4.73; N, 15.66. C11H13N3O3S requires C, 49.43; H, 4.90; N, 15.72%);lmax (DCM)/nm 237 (log 3 4.13), 358 (3.37); nmax/cm�1 2992w,2962w, 2904w and 2878w (CH2 and CH3), 2232w (C^N), 1721s(C]O), 1501s, 1452m,1437m,1427s, 1385m,1375m,1368m,1352w,1341m, 1311m, 1292s, 1271s, 1261s, 1171m, 1151s, 1119s, 1101m,1068m, 1030s, 1005m, 949m, 932m, 887w, 864s, 814m, 793m,787m; dH (500MHz; CDCl3) 4.43 (2H, q, J 7.2 Hz, CH2O), 3.84 (4H, t, J4.7 Hz, CH2O), 3.37 (4H, t, J 4.8 Hz, CH2N), 1.44 (3H, t, J 7.2 Hz, CH3);dC (125MHz; CDCl3) 167.1 (s),159.9 (s),139.45 (s),124.2 (s),110.1 (s),

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66.4 (t, CH2O), 62.55 (t, CH2O), 50.2 (t, CH2N), 13.9 (q, CH3); m/z(MALDI-TOF) 268 (MHþ, 100%), 267 (Mþ, 41).

4.2.7. Ethyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate(6h). Similar treatment of ethyl 3-bromo-5-cyanoisothiazole-4-carboxylate (5d) (52 mg, 0.20 mmol) with pyrrolidine (24 mL,0.40 mmol) gave on chromatography (n-hexane/DCM, 1:1) the titlecompound 6h (46 mg, 92%) as yellow needles, mp (DSC) onset:54.0 �C, peak max: 54.7 �C (from n-pentane/0 �C); Rf 0.46 (n-hex-ane/DCM, 1:1); (found: C, 52.71; H, 5.09; N, 16.63. C11H13N3O2Srequires C, 52.57; H, 5.21; N, 16.72%); lmax (DCM)/nm 240 (log 3

4.02), 383 (3.37); nmax/cm�1 2988w, 2938w, 2909w and 2857w(CH2 and CH3), 2226w (C^N), 1713s (C]O), 1522s, 1477m, 1460m,1391w, 1373m, 1350w, 1327w, 1300w, 1279m, 1246m, 1200w,1169m, 1142m, 1123w, 1105m, 1043w, 1011m, 962w, 932m, 920m,901m, 866m, 827w, 816w, 787m, 777m; dH (500 MHz; CDCl3) 4.43(2H, q, J 7.1 Hz, CH2O), 3.47 (4H, m, CH2N), 1.96 (4H, m, CH2), 1.44(3H, t, J 7.1 Hz, CH3); dC (125 MHz; CDCl3) 163.0 (s), 160.7 (s), 136.7(s), 122.2 (s), 110.4 (s), 62.5 (t, CH2O), 50.2 (t, CH2N), 25.7 (t, CH2),14.0 (q, CH3);m/z (ESIeAPCI positive) 253 (MHþþ1,15%), 252 (MHþ,100).

4.2.8. 3-(Morpholin-4-yl)isothiazole-4,5-dicarbonitrile (6i). Similartreatment of 3-bromoisothiazole-4,5-dicarbonitrile (5e) (43 mg,0.20 mmol) with morpholine (140 mL, 1.60 mmol) gave on chro-matography (n-hexane/t-BuOMe, 1:1) the title compound 6i(35.5 mg, 81%) as yellow plates, mp (DSC) onset: 180.1 �C, peakmax: 181.9 �C (from c-hexane) (lit.,19a 185e187 �C); Rf 0.67 (n-hexane/t-BuOMe, 1:1); nmax/cm�1 2978w, 2928w, 2899w, 2884wand 2862w (CH2 and CH3), 2224s (C^N), 1514s, 1464m, 1443s,1375m, 1302m, 1279m, 1261m, 1234w, 1219w, 1175w, 1119s, 1069w,1038w, 1020w, 1003w, 953m, 935w, 897w, 874m, 862m, 841w,800w; dH (500MHz; CDCl3) 3.83 (4H, t, J 4.7 Hz, CH2O), 3.68 (4H, t, J4.7 Hz, CH2N); dC (125 MHz; CDCl3) 165.35 (s), 142.7 (s), 111.4 (s),108.3 (s), 102.9 (s), 66.1 (t, CH2O), 48.0 (t, CH2N); identical to anauthentic sample.19a,b

4.3. Reaction of 3-chloroisothiazole-4,5-dicarbonitrile (3)with pyrrolidine (Table 2, entry 7)

To a stirred solution of 3-chloroisothiazole-4,5-dicarbonitrile (3)(34 mg, 0.20 mmol) in dry toluene (2 mL) was added pyrrolidine(24 mL, 0.40 mmol) and the mixture was heated at ca. 110 �C untilthe starting material was consumed (TLC). The reaction mixturewas then cooled to ca. 20 �C, adsorbed onto silica, and chromato-graphed (n-hexane/DCM, 1:1) to give 3-(pyrrolidin-1-yl)isothiazole-4,5-dicarbonitrile (6j) (15 mg, 37%) as yellow needles, mp (DSC)onset: 173.0 �C, peak max: 173.9 �C (from c-hexane); Rf 0.36 (n-hexane/DCM, 1:1); (found: C, 53.03; H, 3.83; N, 27.36. C9H8N4Srequires C, 52.92; H, 3.95; N, 27.43%); lmax (DCM)/nm 242 (log 3

4.28), 405 (3.51); nmax/cm�1 2970w, 2924w, 2874w and 2851w(CH2), 2232w and 2221w (C^N), 1541s, 1481m, 1462m, 1454m,1350m, 1323w, 1238w, 1225w, 1200w, 1179w, 1155w, 1130w, 1111w,1038w, 964w, 912w, 872w, 858m, 816w; dH (500 MHz; CDCl3) 3.73(4H, m, CH2N), 2.03 (4H, m, CH2); dC (125 MHz; CDCl3) 162.4 (s),141.8 (s), 112.1 (s, C^N), 108.7 (s, C^N), 100.3 (s), 49.1 (t, CH2N),25.6 (t, CH2); m/z (MALDI-TOF) 205 (MHþ, 70%), 204 (Mþ, 100).Further elution (n-hexane/DCM, 1:1) gave 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile (8) (10.3 mg, 24%) as colorless needles,mp (DSC) onset: 94.2 �C, peakmax: 95.2 �C (from c-hexane); Rf 0.30(n-hexane/DCM, 1:1); (found: C, 45.12; H, 3.84; N, 19.65. C8H8ClN3Srequires C, 44.97; H, 3.77; N, 19.66%); lmax (DCM)/nm 279 (log 3

3.89); nmax/cm�1 2994w, 2968w, 2934w and 2872w (CH2), 2208m(C^N),1566s,1557m,1481s,1452m,1368m,1333m,1292m,1258w,1233w, 1184w, 1155w, 1045m, 1016m, 995m, 984m, 912w, 864w,856w, 808w, 779m; dH (500 MHz; CDCl3) 3.59 (4H, br s, CH2N), 2.12

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A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e8 7

(4H, m, CH2); dC (125MHz; CDCl3) 174.7 (s),149.7 (s),114.4 (s, C^N),83.95 (s), 51.35 (t, CH2N), 25.75 (t, CH2); m/z (MALDI-TOF) 216(MHþþ2, 17%), 214 (MHþ, 30), 153 (87), 133 (100). A final elution (t-BuOMe) gave 2-[di(pyrrolidin-1-yl)methylene]malononitrile (7)(3.5 mg, 8%) as colorless needles, mp (DSC) onset: 169.3 �C, peakmax: 169.4 �C (from 1,2-DCE/c-hexane) (lit.,28 168e169 �C); Rf 0.25(t-BuOMe); nmax/cm�1 2986w, 2965w, 2891w and 2876w (CH2),2197s and 2172s (C^N), 1518s, 1481s, 1456s, 1364w,1350m,1329m,1298w, 1244w, 1236w, 1180m, 1126m, 1030w, 978w, 964w, 920m,878m, 837w; dH(500 MHz; CDCl3) 3.49 (8H, m, CH2N), 1.98 (8H, m,CH2); dC(125 MHz; CDCl3) 162.3 [s, C]C(CN)2], 119.5 (s, C^N), 50.8(t, CH2N), 37.1 [s, C(CN)2], 25.6 (t, CH2); identical to an authenticsample.28

4.3.1. Reaction of 3-(pyrrolidin-1-yl)isothiazole-4,5-dicarbonitrile(6j) with pyrrolidine (Scheme 4). To a stirred solution of 3-(pyrro-lidin-1-yl)isothiazole-4,5-dicarbonitrile (6j) (20.5 mg, 0.10 mmol)in dry toluene (1 mL) was added pyrrolidine (167 mL, 2.00 mmol)and the mixture was stirred at ca. 110 �C until the starting materialwas consumed (TLC). The reaction mixture was then cooled to ca.20 �C, adsorbed onto silica, and chromatographed (t-BuOMe) togive 2-[di(pyrrolidin-1-yl)methylene]malononitrile (7) (15 mg,70%) as colorless needles, mp (DSC) onset: 169.3 �C, peak max:169.4 �C (from DCE/c-hexane) (lit.,28 168e169 �C); Rf 0.25 (t-BuOMe), identical to that described above.

4.3.2. Reaction of 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile (8) with pyrrolidine (Scheme 4). To a stirred solutionof 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile (8)(21.5 mg, 0.10 mmol) in dry toluene (1 mL) was added pyrrolidine(167 mL, 2.00 mmol) and the mixture was stirred at ca. 110 �C untilthe starting material was consumed (TLC). The reaction mixturewas then cooled to ca. 20 �C, adsorbed onto silica, and chromato-graphed (t-BuOMe) to give 2-[di(pyrrolidin-1-yl)methylene]malo-nonitrile (7) (14 mg, 65%) as colorless needles, mp (DSC) onset:169.3 �C, peak max: 169.4 �C (from DCE/c-hexane) (lit.,28

168e169 �C); Rf 0.25 (t-BuOMe), identical to that described above.

4.4. Protodebromination of 4-bromo-3-(morpholin-4-yl)iso-thiazole-5-carbonitrile (6c)

To a stirred solution of 4-bromo-3-(morpholin-4-yl)isothiazole-5-carbonitrile (6c) (27 mg, 0.10 mmol) in HCO2H (1 mL), cooled toca.10 �Cwas added In dust (57mg, 0.50mmol) and themixturewasstirred at this temperature until the starting material was con-sumed (TLC, 1 day). The mixture was then filtered through Celite�

and the filtrate extracted with DCM (3�20 mL) and water (10 mL).The combined organic phase was dried (Na2SO4), filtered and thevolatiles removed in vacuo to afford 3-(morpholin-4-yl)isothiazole-5-carbonitrile (6a) (7.3 mg, 37%) as colorless needles, mp (DSC)onset: 144.9 �C, peak max: 147.3 �C (from c-hexane); Rf 0.33 (DCM),identical to that described above.

4.5. Hydrolytic decarboxylations of 3-dialkylamino-5-cyanoisothiazole-4-carboxylates

4.5.1. Reaction of methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6e) with Et3N (typical procedure). To a stirred solu-tion of methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6e) (51 mg, 0.20 mmol) in DMF (1.0 mL) at ca. 20 �Cwas added Et3N (139 mL, 1.00 mmol) and the mixture was heated atca. 100 �C until the starting material was consumed (TLC). The re-action mixture was then cooled to ca. 20 �C and extracted with t-BuOMe (3�20 mL). The combined organic extracts were thenwashed with water (20 mL), dried (Na2SO4), filtered, adsorbed ontosilica, and chromatographed (DCM) to give 3-(morpholin-4-yl)

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isothiazole-5-carbonitrile (6a) (36 mg, 92%) as colorless needles,mp (DSC) onset: 144.9 �C, peak max: 147.3 �C (from c-hexane); Rf0.33 (DCM), identical to that described above.

4.5.2. Reaction of ethyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6g) with Et3N using microwave irradiation (typicalprocedure). To a stirred solution of ethyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6g) (27 mg, 0.10 mmol) in DMF(0.50 mL) at ca. 20 �C was added Et3N (70 mL, 0.50 mmol) and themixture was stirred at ca. 150 �C under microwave irradiation(45 PSI, 250W) until the startingmaterial was consumed (TLC). Thereaction mixture was then cooled to ca. 20 �C and extracted with t-BuOMe (3�20 mL). The combined organic extracts were thenwashed with water (20 mL), dried (Na2SO4), filtered, adsorbed ontosilica, and chromatographed (DCM) to give 3-(morpholin-4-yl)isothiazole-5-carbonitrile (6a) (19.5 mg, 100%) as colorless needles,mp (DSC) onset: 144.9 �C, peak max: 147.3 �C (from c-hexane); Rf0.33 (DCM), identical to that described above.

4.5.3. Reaction of methyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6f) with Et3N using microwave irradiation. Similartreatment of methyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6f) (24 mg, 0.10 mmol) in DMF (0.50 mL) with Et3N(70 mL, 0.50 mmol) gave on chromatography (n-hexane/DCM, 1:1)3-(pyrrolidin-1-yl)isothiazole-5-carbonitrile (6b) (18 mg, 100%) ascolorless plates, mp (DSC) onset: 112.7 �C, peak max: 113.3 �C (fromn-hexane/0 �C); Rf 0.26 (n-hexane/DCM, 1:1); (found: C, 53.63; H,5.12; N, 23.32. C8H9N3S requires C, 53.61; H, 5.06; N, 23.44%); lmax(DCM)/nm 360 (log 3 3.40); nmax/cm�1 3082w (Ar CH), 2965w,2943w and 2872w (CH2), 2241w and 2224w (C^N), 1560s, 1557s,1474s, 1458m,1383w,1350m,1292w,1246w,1238w,1227w,1196w,1179w, 1165w, 1134w, 1061w, 1027w, 968w, 912w, 880m, 864w,837m, 818m, 731w; dH (500MHz; CDCl3) 6.83 (1H, s, H-4), 3.48 (4H,m, CH2N), 2.02 (4H, m, CH2); dC (125MHz; CDCl3) 164.2 (s), 131.9 (s),117.5 (d, C-4), 111.6 (s, C^N), 48.3 (t, CH2N), 25.6 (t, CH2); m/z(ESIeAPCI positive) 181 (MHþþ1, 11%), 180 (MHþ, 100).

4.5.4. Reaction of ethyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6h) with Et3N using microwave irradiation. Similartreatment of ethyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6h) (25 mg, 0.10 mmol) in DMF (0.50 mL) with Et3N(70 mL, 0.50 mmol) gave on chromatography (n-hexane/DCM, 1:1)3-(pyrrolidin-1-yl)isothiazole-5-carbonitrile (6b) (15.4 mg, 86%) ascolorless plates, mp (DSC) onset: 112.7 �C, peak max: 113.3 �C (fromn-hexane/0 �C); Rf 0.26 (n-hexane/DCM, 1:1), identical to that de-scribed above.

4.5.5. Reaction of methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6e) with Me4NOH (typical procedure). To a stirred so-lution of methyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6e) (51 mg, 0.20 mmol) in DMA (1.0 mL) at ca. 20 �Cwas added Me4NOH∙5H2O (3.6 mg, 0.02 mmol) and the mixturewas heated at ca. 100 �C until the starting material was consumed(TLC). The reaction mixture was then cooled to ca. 20 �C andextracted with t-BuOMe (3�20 mL). The combined organic extractswere then washed with water (20 mL), dried (Na2SO4), filtered,adsorbed onto silica, and chromatographed (DCM) to give 3-(morpholin-4-yl)isothiazole-5-carbonitrile (6a) (38 mg, 97%) ascolorless needles, mp (DSC) onset: 144.9 �C, peak max: 147.3 �C(from c-hexane); Rf 0.33 (DCM), identical to that described above.

4.5.6. Reaction of ethyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6g) with Me4NOH using microwave irradiation (typicalprocedure). To a stirred solution of ethyl 5-cyano-3-(morpholin-4-yl)isothiazole-4-carboxylate (6g) (54 mg, 0.20 mmol) in DMA(1.0 mL) at ca. 20 �C was addedMe4NOH$5H2O (3.6 mg, 0.02 mmol)

edron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.012

A.S. Kalogirou, P.A. Koutentis / Tetrahedron xxx (2014) 1e88

and the mixture was stirred at ca. 150 �C under microwave irradi-ation (45 PSI, 250 W) until the starting material was consumed(TLC). The reaction mixture was then cooled to ca. 20 �C andextracted with t-BuOMe (3�20 mL). The combined organic extractswere then washed with water (20 mL), dried (Na2SO4), filtered,adsorbed onto silica, and chromatographed (DCM) to give 3-(morpholin-4-yl)isothiazole-5-carbonitrile (6a) (31.6 mg, 81%) ascolorless needles, mp (DSC) onset: 144.9 �C, peak max: 147.3 �C(from c-hexane); Rf 0.33 (DCM), identical to that described above.

4.5.7. Reaction of methyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6f) with Me4NOH using microwave irradiation. Similartreatment of methyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6f) (48 mg, 0.20 mmol) in DMA (1.0 mL) withMe4NOH$5H2O (3.6 mg, 0.02 mmol) gave on chromatography (n-hexane/DCM, 1:1) 3-(pyrrolidin-1-yl)isothiazole-5-carbonitrile(6b) (29 mg, 81%) as colorless plates, mp (DSC) onset: 112.7 �C,peak max: 113.3 �C (from n-hexane/0 �C); Rf 0.26 (n-hexane/DCM,1:1), identical to that described above.

4.5.8. Reaction of ethyl 5-cyano-3-(pyrrolidin-1-yl)isothiazole-4-carboxylate (6h) with Me4NOH using microwave irradi-ation. Similar treatment of ethyl 5-cyano-3-(pyrrolidin-1-yl)iso-thiazole-4-carboxylate (6h) (50 mg, 0.20 mmol) in DMA (1.0 mL)with Me4NOH$5H2O (3.6 mg, 0.02 mmol) gave on chromatography(n-hexane/DCM, 1:1) 3-(pyrrolidin-1-yl)isothiazole-5-carbonitrile(6b) (28.5 mg, 79%) as colorless plates, mp (DSC) onset: 112.7 �C,peak max: 113.3 �C (from n-hexane/0 �C); Rf 0.26 (n-hexane/DCM,1:1), identical to that described above.

Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2014.06.012.

References and notes

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