- Email: [email protected]
Five-Membered Ring Systems
CHAPTER 5.5
Five-Membered Ring Systems: With N and S Atoms Yong-Jin Wu Bristol Myers Squibb Research and Development, Wallingford, CT, United States E-mail: [email protected].
5.5.1 INTRODUCTION This review chapter focuses on the syntheses and reactions of these fivemembered heterocyclic ring systems containing nitrogen and sulfur (reported during 2017). The importance of these p-rich heterocycles in medicinal chemistry and natural products is also covered.
5.5.2 THIAZOLES 5.5.2.1 Synthesis of Thiazoles The Hantzsch reaction discovered in 1889 is still one of the most reliable routes to thiazoles. However, the classic Hantzsch reaction produces one equivalent (eq.) of hydrogen halide, which can bring about significant loss of optical purity with substrates susceptible to epimerization under original Hantzsch conditions (refluxing ethanol). The racemization issue can be overcome by performing the Hantzsch thiazole synthesis using the twostep procedure. For example, cyclocondensation of thioamide 1 with ethyl 3-bromo-2-oxopropanoate under basic conditions provides the hydroxythiazoline intermediate, which undergoes dehydration using trifluoroacetic anhydride (TFAA) and pyridine followed by triethylamine to form the monothiazole 2. This thiazole is incorporated into the polyazole peptide antibiotic goadsporin (17AG(E)3069). The Hantzsch condensation of brominated trithiazolylpyridine 3 with N-Cbz/OTBDMS-bis-protected thioamide 4 assembles the last thiazole moiety of
Progress in Heterocyclic Chemistry, Volume 30 Copyright © 2018 Elsevier Ltd. ISSN 0959-6380, https://doi.org/10.1016/B978-0-08-102788-2.00009-X All rights reserved.
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the heterocyclic core of the D-series GE2270 (17BJOC1407). The first condensation step is carried out in the presence of molecular sieves instead of KHCO3 to afford a thiazoline intermediate, which is immediately dehydrated at low temperature using TFAA to furnish the tetra(thiazole) 5 with a high diastereoisomeric ratio (91:9) and high enantiomeric purity (>99%).
A cascade cyclization of (Cbz)Ala/Cys(Trt) amide 6 followed by oxidation of resulting oxazoline/thiazoline 7 generates the oxazole/thiazole 8 in one-pot, thus avoiding isolation and purification of the intermediate 7 (17JOC9585). Lower yields are obtained with other cyclodehydrating conditions such as TiCl4, diethylaminosulfur trifluoride, and TsCl due to the formation of a complex reaction mixture. The yield increases to 18% when the reaction is performed under Kelly’s thiazoline formation conditions (Tf2O/PPh3O, 78 C; 03JOC9506) and elevating temperature to 20 C further improves the yield (28%). Finally, switching the additive to Ph2SO and using pyridine as the base at 78 C generates the desired bis(azole) in 62% yield after MnO2 oxidation. The optimized conditions also work well for the synthesis of both monothiazole (e.g., 9 and 10) and bis-thiazole analogs (e.g., 13a/b).
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A chemoselective route to fully substituted thiazoles and 2,3-dihydrothiazoles 17 and 18 features a [4þ1] heterocyclization of a-(Nhydroxy/aryl)imino-b-oxodithioesters 15a/b with in situ generated Cucarbenoids of diazocarbonyl compounds 16 (17JOC10846). The dithioesters 15a/b are readily prepared from b-oxodithioesters 14 with nitrous acid/ nitrosoarenes.
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Reaction of thiourea or thioamide 22 with 4-bromo3-ethoxycrotonate in neat hexafluoroisopropanol (HFIP) affords thiazole 24 in excellent yields. HFIP is the optimal solvent, which possesses unique properties including high hydrogen bonding donor ability, low nucleophilicity, high ionizing power, and the ability to solvate water. Using HFIP as the solvent, there is no need for work-up and silica gel chromatography purification, the desired thiazoles are obtained simply by filtration followed by recrystallization, and HFIP can be recovered simply by distillation (17RSCA32647).
A one-pot, three-component reaction of n-BuNH2, CS2, and nitroepoxide 25 provides easy access to the functionalized thiazole-2(3H)thione 28 (17OL6748). Higher yields are generally obtained from nitroepoxides bearing an electron-withdrawing group on the phenyl ring. The reaction cascade starts by the addition of amine to CS2 to give the dithiocarbamic acid 29, which opens epoxide 25, intramolecular hemiaminalization and subsequent dehydration furnish 28. Interestingly, when water is used as the solvent instead of tetrahydrofuran (THF), no dehydration occurs, and thiazolidine-2-thione 27 is obtained as a mixture of diastereomers. A one-pot, two-step procedure for the synthesis of thiazole-2(3H)thione 31 from 30 is also developed. In situ oxidation of 30 with t-BuOOH in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by addition of CS2 and n-BuNH2 affords 31. This methodology has been extended to the S-alkyl dithiocarbamate 32, which reacts with nitroepoxide 25 to give 2-alkylthio thiazole 34 via the epoxide opening intermediate 33.
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The whole family of bromothiazoles is prepared in moderate to good yields under bromine-free conditions (17JOC5947). 2-Bromothiazole 36 is derived from the readily available 2-aminothiazole 35. The amino group is first converted to a diazonium salt, which is converted to the bromide 36 using a mixture of NaBr/CuSO4. 2,5-Dibromothiazole 37 is made from 2-aminothiazole in two steps. Bromination of 2-aminothiazole 35 using NBromosuccinimide (NBS) gives 2-amino-5-bromothiazole 38 in 56% yield. Due to its instability, this amine is subjected to Sandmeyer reaction within hours to give 2,5-dibromothiazole 37. 5-Bromothiazole 39 is derived from 2-amino-5-bromothiazole 38 through deamination via diazotization. 2,4-Dibromothiazole 41 is prepared from 2,4-thiazolidinedione 40 by means of simultaneous aromatization and bromination. This transformation is well executed with a mixture of P2O5 and Bu4NBr. 4-Bromothiazole 42 is produced via debromination of 2,4-dibromothiazole 41, which can be carried out with n-BuLi or Grignard reagents in 70% yields. An
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operationally simple procedure utilizes NaBH4 in CH3N under reflux, which results in 2,4-dibromothiazole 42. While the NBS bromination of 2-bromothiazole 36 is ineffective, the 2,4-dibromothiazole 41 undergoes smooth bromination with NBS in HOAc to give the perbrominated analog 43. Apparently, the second bromo group of 2,4-dibromothiazole provides sufficient electron density for electrophilic aromatic bromination via NBS. Further bromination of 2,5-dibromothiazole 37 using NBS also fails, a finding consistent with the lower reactivity of the 4-position in relation to either of the thiazole a-positions. 4,5-Dibromothiazole 46 is synthesized from tribromothiazole 43 upon treatment with n-BuLi in hexanes. Under these conditions, lithiumhalogen exchange initially occurs at the 5-position but slowly interconverts to the desired 2-lithium derivative via the halogen dance reaction. Apparently, the reduced reactivity of n-BuLi in hexanes reduces the rate of the overall reaction and provides sufficient time for the halogen dance to generate the thermodynamic product 45.
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5.5.2.2 Synthesis of Thiazolines Thiazolines are prepared from alkenes and thioamides using a simple onepot procedure (17OL930). This methodology takes advantage of the in situ generated bromine equivalent by oxidation of LiBr with urea$hydrogen peroxide in the presence of TFA, thus obviating the use of corrosive bromine. Under these conditions, alkenes are converted to the dibromides, which are exposed to thioamides and NaHCO3 to give thiazolines in moderate to good yields. The 5-substituted thiazoline 50 is the major product from styrene derivative 47, while the aliphatic alkene 52 furnishes the 4-substituted thiazoline 56 as the predominant product. With respect to aliphatic olefins, the more electrophilic primary CeBr bond of intermediate 53 is involved in the reaction thioamides, whereas the secondary benzylic CeBr bond of 48 is the more electrophilic site for the styrene substrates, thus resulting in the reversed regioselectivity. Thiazoline 57 is converted to b-aminothiol 58 and thiazole 59, respectively, under hydrolysis and oxidation conditions.
H
2-Amino-2-thiazoline 65 is prepared by means of intramolecular dehydrative cyclization of b-hydroxy thiourea 63, available from isothiocyanate 62 and amino alcohol 60 (17S2845). The Vilsmeier reagent 61 activates the hydroxyl group of 63 to form intermediate 64, which undergoes cyclization to give 65. Selective activation of primary alcohols in the presence of secondary alcohols is also possible. For example, treatment of diol 66 with phenyl isothiocyanate under the optimized conditions forms thiazoline 67 in high regioselectivity.
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Thiazoline derivatives 69 are made from thioamides 22 or thiourea and ethyl (E)-4-bromobut-2-enoate 68 via SN2 substitution of the bromide followed by an intramolecular Michael addition (17RSC32647). A similar strategy has been developed for the synthesis of thiazoles (vide supra). Again, the use of polar and strong hydrogen bonding HFIP as a solvent is critical for this reaction.
A series of imidazothiazolines 72 is made in a highly regio- and stereoselective manner through an intermolecular sulfenoamination reaction of thiol 70 with alkene 71 (17OL6204). Reactions with styrene derivatives afford the fused thiazolines (e.g., 73) with only nitrogen addition to the benzylic position and sulfur to the terminal carbon. The 1,2-disubstituted aliphatic alkenes also work with good diastereoselectivity. Interestingly, exotic tetracyclic structures (e.g., 76) could also be formed from the corresponding olefins. In general, the regioselectivity of aliphatic alkenes can be controlled by steric factors, as the more steric hindered olefins show reversed regioselectivity (e.g., 77). The regioselectivity of cyclic sulfenoamination depends on the halogenation sources. For example, treatment of 2-thiolbenzoimidazole 79 with styrene using Selectfluor as the halogen source forms 83 as the sole product. When bromine is used as the halogen source, the other regioisomer 84 is produced with great selectivity. In combination, these two sulfenoamination processes provide highly regiodivergent approaches for this class of heterocycles.
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5.5.2.3 Synthesis of Benzothiazoles 2-Phenylbenzothiazole derivative 89 is prepared from benzylthiol 85 and 2-bromo or 2-iodoaniline 86 via Fe(II)-catalyzed sulfur directed C(sp3)eH bond amination/CeS cross-coupling reaction (17CC2737). In this case the benzyl C(sp3)eH bond of the presumed intermediate 88 undergoes direct amination to give benzothiazole 89. A variety of functional groups are well tolerated under these conditions.
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2-Arylnaphthothiazoles 92 and 2-arylbenzothiazoles 94 are derived from primary arylamines, aromatic aldehydes, and elemental sulfur through oxidative annulation and CeH functionalization under transition metalfree conditions (17OL4576). NH4I and KI serve as the catalysts, while Dimethyl sulfoxide (DMSO) and oxygen are used as the oxidants.
5.5.2.4 Reactions of Thiazoles and Fused Derivatives a-Allylation of thiazolines 95 can be mediated by a Pd/Xantphos catalyst system under mild reaction conditions (17OL126). Mechanistic investigations suggest an initial allylation of the imine nitrogen followed by a Pdcatalyzed formal aza-Claisen rearrangement.
A metal-free photo-oxidative intermolecular CeH/CeH coupling reaction of thiazoles 100 with triethyl methanetricarboxylate is carried out with a catalytic amount of molecular iodine (17OL1610). In this transformation, molecular oxygen in the air serves as a terminal oxidant to regenerate molecular iodine. The 2- and 5-phenyl thiazoles undergo regioselective cross-dehydrogenative coupling reactions at C5 and C2 to give 102 and 103, respectively.
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5-N-Arylamino-4-methylthiazoles 108 are synthesized from 4-methylthiazole 105 in three steps: direct Pd-catalyzed CeH arylations at C2; bromination at C5; and the Pd-catalyzed BuchwaldeHartwig amination. Compounds 108 are used for the studies of photophysical properties (17OM2552).
A copper-catalyzed three-component coupling reaction of benzothiazole 109, Se powder, and aryl iodide provides a straightforward synthesis of 2-arylselanyl thiazole 110 (17JOC250). This reaction does not require any ligand, and a broad range of functional groups are well tolerated.
The Co(II)-catalyzed decarboxylative cross-coupling reaction of (hetero)aryl carboxylic acid 111 with benzothiazole has been investigated (17OL5589). When the decarboxylative cross-coupling of benzothiazole with 3-methylbenzothiophene-2-carboxylic acid in the presence of catalytic amounts of CoBr2 with Ag2CO3 as the oxidant, significant amount of the symmetric biheteroaryl 2,20 -bis(benzothiazole) is generated from the oxidative homocoupling reaction of benzothiazole. To minimize the formation of the homocoupling product, an extra ligand is added to the reaction mixture to control the Ag-mediated decarboxylation and the
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Co-promoted cross-coupling reaction. The N-heterocyclic carbene ligand, 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene (IPr), serves to promote the decarboxylative CeH functionalization and inhibit the formation of bis(benzothiazole). Among various solvents examined, 2-fluorobenzotrifluoride is optimal. Under these optimized conditions, the decarboxylative cross-coupling of benzothiazole with 3-methylbenzothiophene-2-carboxylic acid furnishes the desired product 113 in 82% yield. This reaction represents a first example of metal-catalyzed decarboxylative CeH heteroarylation of benzo-fused heterocycles.
Treatment of benzothiazole 114 with alkyl diacyl peroxide 115 or alkyl tert-butyl perester 117 in the presence of Fe(OTf)3 brings about CeH alkylation to give 2-alkyl benzothiazole 116 (17OL46). Notably, the reaction conditions are compatible with a broad range of functional groups such as alkene, ester, and ketone. In addition, the methodology is not sensitive to steric effects as tertiary alkyl groups such as admantanyl are incorporated into benzothiazoles.
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CeH arylation and heteroarylation of the thiazole moiety have been developed for the synthesis of dimer, triad, and polymeric materials (17JOC10139). Reaction of one eq. of fused thiazole 118 with 0.5 eq. of 2,5- dibromothiophene provides 56% yield of triad 120. Interestingly, increasing the amount of 2,5-dibromothiophene to 0.75 eq. increases the yield to 75%, while further increasing the amount of dibromide to 4 eq. decreases the yield, but still gives the desired triad 120 in 47% yield. This type of compounds shows broad optical absorption and low reduction potentials, and these materials could be used as organic semiconductors for applications in organic fieldeeffect transistors and as nonfullerene acceptors.
A general CeH functionalization approach to the synthesis of diverse thiazolyl-C-D1,2-glycosides features a Pd(OAc)2/CuI-catalyzed direct cross-coupling of thiazoles/benzothiazoles with 1-iodoglycals (17OL3608). The proposed reaction pathway involves the initial coordination between copper and nitrogen/oxygen on the substrate, which assists the deprotonation of C2 hydrogen on the thiazole by t-BuOLi. The resulting lithium salt of the thiazole undergoes lithiumecopper exchange to afford the organocopper species. Transmetalation with the palladium-mediated oxidative adduct from 1-iodoglycal followed by reductive elimination results in the thiazolyl C-glycoside 124. This protocol may be useful in the preparation of biologically important compounds.
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A visible light-induced radical difluoromethylation of benzothiazole2-thiol 125 with difluoromethyltriphenylphosphonium triflate 126 affords difluoromethyl thioether 127 in good yield (17JOC7373). The key reaction features include the use of a readily available CF2H radical source, mild reaction conditions, and excellent chemoselective thioldifluoromethylation.
5.5.2.5 New Thiazole-Containing Natural Products Biakamides AeD were isolated from an Indonesian marine sponge with a constructed bioassay using PANC-1 human pancreatic cancer cells (17JOC1705). These compounds exhibit selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions. Studies on the alkaloids from Peganum harmala seeds led to two rare thiazole derivatives, peganumal A/B (17JNP551). (þ)-Meyeniins AeC are novel
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hexahydroimidazo[1,5-c]thiazole derivatives from the tubers of Lepidium meyenii (17JAFC1887). The biological properties of these compounds provide support for using maca as healthy nutritional supplements or functional foods to prevent cancer.
5.5.2.6 Biologically Active Thiazoles and Isothiazoles GLPG1690 is a first-in-class autotaxin inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis (17JMC3580). PF-05089771 is the first subtype selective Nav1.7 inhibitor clinical candidate which binds to a site in the voltage-sensing domain (17JMC7029). Ruzasvir is currently in early clinical evaluations as part of an all-oral direct-acting antiviral regimen for the treatment of chronic HCV infection (17JMC290). Tropifexor (LJN452), a potent nonbile acid farnesoid X receptor agonist, is undergoing phase II trials for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (17JMC9960). Compound 128 is a phenylpropanoic acid GPR120 agonist as a development candidate for type II diabetes (17ACSMCL947).
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5.5.3 ISOTHIAZOLES 5-Alkylthio-substituted isothiazoles 130 are prepared from b-ketodithioesters 129 upon exposure to ammonia (17TL2512). This protocol is operationally simple, but the yields are very moderate.
5.5.4 THIADIAZOLES An oxidative NeS bond formation reaction has been developed for 1,2,4-thiadiazole synthesis using molecular iodine as the sole oxidant (17JOC5898). The reaction conditions are mild, and no transition metals are required. A variety of imidoyl and guanyl thiourea substrates are converted to 5-amino and 3,5-diamino-substituted 1,2,4-thiadiazole derivatives, respectively, in good yields.
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The N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives 135 and 137 are synthesized in good yields through the molecular iodinecatalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via NeS bond formation at room temperature (17JOC5310).
4,5-Functionalized 1,2,3-thiadiazoles 139 are readily available from 2-cyanothioacetamides 138 and benzenesulfonyl azide in the absence of any transition metal (17JOC4056). Under diazo transfer conditions in the presence of a base in an aprotic solvent, 2-cyanothioacetamide 138 serves as CeCeS building block to produce 5-amino-4-cyano-1,2,3-thiadiazole 139 exclusively. Presumably, addition of carbanion 140 to benzenesulfonyl azide generates the triazenyl anion 141, which undergoes 1,4-prototropic shift to give carbanion 142. Elimination of PhSO2NH2 leads to intermediate 143, and subsequent cyclization affords thiadiazole 139.
Rh-Catalyzed intramolecular transannulation reaction of alkynyl thiadiazoles generates a wide range of fused thiophenes, including those fused with lactams, lactones, or cyclic ethers (17JOC1437). A plausible reaction pathway starts with a reversible ringechain tautomerization of thiadiazole moiety in alkynyl thiadiazoles 144 to give the alkynyl-substituted a-diazo thiocarbonyl 146. Exposure to the Rh(I) catalyst affords the a-thiavinyl Rh
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carbenoid 147 together with the release of nitrogen gas. Intramolecular reaction of the Rh carbenoid with the triple bond affords the zwitterionic intermediate 148, which cyclizes to give intermediate 149. Elimination of the Rh species furnishes 145.
The intramolecular Rh-catalyzed transannulation approach has been extended to cyanothiadiazole substrates 150 to provide bicyclic isothiazoles 151 (17JOC10574).
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Five-Membered Ring Systems: With N and S Atoms Yong-Jin Wu Bristol Myers Squibb Research and Development, Wallingford, CT, United States E-mail: [email protected].
5.5.1 INTRODUCTION This review chapter focuses on the syntheses and reactions of these fivemembered heterocyclic ring systems containing nitrogen and sulfur (reported during 2017). The importance of these p-rich heterocycles in medicinal chemistry and natural products is also covered.
5.5.2 THIAZOLES 5.5.2.1 Synthesis of Thiazoles The Hantzsch reaction discovered in 1889 is still one of the most reliable routes to thiazoles. However, the classic Hantzsch reaction produces one equivalent (eq.) of hydrogen halide, which can bring about significant loss of optical purity with substrates susceptible to epimerization under original Hantzsch conditions (refluxing ethanol). The racemization issue can be overcome by performing the Hantzsch thiazole synthesis using the twostep procedure. For example, cyclocondensation of thioamide 1 with ethyl 3-bromo-2-oxopropanoate under basic conditions provides the hydroxythiazoline intermediate, which undergoes dehydration using trifluoroacetic anhydride (TFAA) and pyridine followed by triethylamine to form the monothiazole 2. This thiazole is incorporated into the polyazole peptide antibiotic goadsporin (17AG(E)3069). The Hantzsch condensation of brominated trithiazolylpyridine 3 with N-Cbz/OTBDMS-bis-protected thioamide 4 assembles the last thiazole moiety of
Progress in Heterocyclic Chemistry, Volume 30 Copyright © 2018 Elsevier Ltd. ISSN 0959-6380, https://doi.org/10.1016/B978-0-08-102788-2.00009-X All rights reserved.
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the heterocyclic core of the D-series GE2270 (17BJOC1407). The first condensation step is carried out in the presence of molecular sieves instead of KHCO3 to afford a thiazoline intermediate, which is immediately dehydrated at low temperature using TFAA to furnish the tetra(thiazole) 5 with a high diastereoisomeric ratio (91:9) and high enantiomeric purity (>99%).
A cascade cyclization of (Cbz)Ala/Cys(Trt) amide 6 followed by oxidation of resulting oxazoline/thiazoline 7 generates the oxazole/thiazole 8 in one-pot, thus avoiding isolation and purification of the intermediate 7 (17JOC9585). Lower yields are obtained with other cyclodehydrating conditions such as TiCl4, diethylaminosulfur trifluoride, and TsCl due to the formation of a complex reaction mixture. The yield increases to 18% when the reaction is performed under Kelly’s thiazoline formation conditions (Tf2O/PPh3O, 78 C; 03JOC9506) and elevating temperature to 20 C further improves the yield (28%). Finally, switching the additive to Ph2SO and using pyridine as the base at 78 C generates the desired bis(azole) in 62% yield after MnO2 oxidation. The optimized conditions also work well for the synthesis of both monothiazole (e.g., 9 and 10) and bis-thiazole analogs (e.g., 13a/b).
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A chemoselective route to fully substituted thiazoles and 2,3-dihydrothiazoles 17 and 18 features a [4þ1] heterocyclization of a-(Nhydroxy/aryl)imino-b-oxodithioesters 15a/b with in situ generated Cucarbenoids of diazocarbonyl compounds 16 (17JOC10846). The dithioesters 15a/b are readily prepared from b-oxodithioesters 14 with nitrous acid/ nitrosoarenes.
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Reaction of thiourea or thioamide 22 with 4-bromo3-ethoxycrotonate in neat hexafluoroisopropanol (HFIP) affords thiazole 24 in excellent yields. HFIP is the optimal solvent, which possesses unique properties including high hydrogen bonding donor ability, low nucleophilicity, high ionizing power, and the ability to solvate water. Using HFIP as the solvent, there is no need for work-up and silica gel chromatography purification, the desired thiazoles are obtained simply by filtration followed by recrystallization, and HFIP can be recovered simply by distillation (17RSCA32647).
A one-pot, three-component reaction of n-BuNH2, CS2, and nitroepoxide 25 provides easy access to the functionalized thiazole-2(3H)thione 28 (17OL6748). Higher yields are generally obtained from nitroepoxides bearing an electron-withdrawing group on the phenyl ring. The reaction cascade starts by the addition of amine to CS2 to give the dithiocarbamic acid 29, which opens epoxide 25, intramolecular hemiaminalization and subsequent dehydration furnish 28. Interestingly, when water is used as the solvent instead of tetrahydrofuran (THF), no dehydration occurs, and thiazolidine-2-thione 27 is obtained as a mixture of diastereomers. A one-pot, two-step procedure for the synthesis of thiazole-2(3H)thione 31 from 30 is also developed. In situ oxidation of 30 with t-BuOOH in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by addition of CS2 and n-BuNH2 affords 31. This methodology has been extended to the S-alkyl dithiocarbamate 32, which reacts with nitroepoxide 25 to give 2-alkylthio thiazole 34 via the epoxide opening intermediate 33.
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The whole family of bromothiazoles is prepared in moderate to good yields under bromine-free conditions (17JOC5947). 2-Bromothiazole 36 is derived from the readily available 2-aminothiazole 35. The amino group is first converted to a diazonium salt, which is converted to the bromide 36 using a mixture of NaBr/CuSO4. 2,5-Dibromothiazole 37 is made from 2-aminothiazole in two steps. Bromination of 2-aminothiazole 35 using NBromosuccinimide (NBS) gives 2-amino-5-bromothiazole 38 in 56% yield. Due to its instability, this amine is subjected to Sandmeyer reaction within hours to give 2,5-dibromothiazole 37. 5-Bromothiazole 39 is derived from 2-amino-5-bromothiazole 38 through deamination via diazotization. 2,4-Dibromothiazole 41 is prepared from 2,4-thiazolidinedione 40 by means of simultaneous aromatization and bromination. This transformation is well executed with a mixture of P2O5 and Bu4NBr. 4-Bromothiazole 42 is produced via debromination of 2,4-dibromothiazole 41, which can be carried out with n-BuLi or Grignard reagents in 70% yields. An
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operationally simple procedure utilizes NaBH4 in CH3N under reflux, which results in 2,4-dibromothiazole 42. While the NBS bromination of 2-bromothiazole 36 is ineffective, the 2,4-dibromothiazole 41 undergoes smooth bromination with NBS in HOAc to give the perbrominated analog 43. Apparently, the second bromo group of 2,4-dibromothiazole provides sufficient electron density for electrophilic aromatic bromination via NBS. Further bromination of 2,5-dibromothiazole 37 using NBS also fails, a finding consistent with the lower reactivity of the 4-position in relation to either of the thiazole a-positions. 4,5-Dibromothiazole 46 is synthesized from tribromothiazole 43 upon treatment with n-BuLi in hexanes. Under these conditions, lithiumhalogen exchange initially occurs at the 5-position but slowly interconverts to the desired 2-lithium derivative via the halogen dance reaction. Apparently, the reduced reactivity of n-BuLi in hexanes reduces the rate of the overall reaction and provides sufficient time for the halogen dance to generate the thermodynamic product 45.
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5.5.2.2 Synthesis of Thiazolines Thiazolines are prepared from alkenes and thioamides using a simple onepot procedure (17OL930). This methodology takes advantage of the in situ generated bromine equivalent by oxidation of LiBr with urea$hydrogen peroxide in the presence of TFA, thus obviating the use of corrosive bromine. Under these conditions, alkenes are converted to the dibromides, which are exposed to thioamides and NaHCO3 to give thiazolines in moderate to good yields. The 5-substituted thiazoline 50 is the major product from styrene derivative 47, while the aliphatic alkene 52 furnishes the 4-substituted thiazoline 56 as the predominant product. With respect to aliphatic olefins, the more electrophilic primary CeBr bond of intermediate 53 is involved in the reaction thioamides, whereas the secondary benzylic CeBr bond of 48 is the more electrophilic site for the styrene substrates, thus resulting in the reversed regioselectivity. Thiazoline 57 is converted to b-aminothiol 58 and thiazole 59, respectively, under hydrolysis and oxidation conditions.
H
2-Amino-2-thiazoline 65 is prepared by means of intramolecular dehydrative cyclization of b-hydroxy thiourea 63, available from isothiocyanate 62 and amino alcohol 60 (17S2845). The Vilsmeier reagent 61 activates the hydroxyl group of 63 to form intermediate 64, which undergoes cyclization to give 65. Selective activation of primary alcohols in the presence of secondary alcohols is also possible. For example, treatment of diol 66 with phenyl isothiocyanate under the optimized conditions forms thiazoline 67 in high regioselectivity.
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Thiazoline derivatives 69 are made from thioamides 22 or thiourea and ethyl (E)-4-bromobut-2-enoate 68 via SN2 substitution of the bromide followed by an intramolecular Michael addition (17RSC32647). A similar strategy has been developed for the synthesis of thiazoles (vide supra). Again, the use of polar and strong hydrogen bonding HFIP as a solvent is critical for this reaction.
A series of imidazothiazolines 72 is made in a highly regio- and stereoselective manner through an intermolecular sulfenoamination reaction of thiol 70 with alkene 71 (17OL6204). Reactions with styrene derivatives afford the fused thiazolines (e.g., 73) with only nitrogen addition to the benzylic position and sulfur to the terminal carbon. The 1,2-disubstituted aliphatic alkenes also work with good diastereoselectivity. Interestingly, exotic tetracyclic structures (e.g., 76) could also be formed from the corresponding olefins. In general, the regioselectivity of aliphatic alkenes can be controlled by steric factors, as the more steric hindered olefins show reversed regioselectivity (e.g., 77). The regioselectivity of cyclic sulfenoamination depends on the halogenation sources. For example, treatment of 2-thiolbenzoimidazole 79 with styrene using Selectfluor as the halogen source forms 83 as the sole product. When bromine is used as the halogen source, the other regioisomer 84 is produced with great selectivity. In combination, these two sulfenoamination processes provide highly regiodivergent approaches for this class of heterocycles.
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5.5.2.3 Synthesis of Benzothiazoles 2-Phenylbenzothiazole derivative 89 is prepared from benzylthiol 85 and 2-bromo or 2-iodoaniline 86 via Fe(II)-catalyzed sulfur directed C(sp3)eH bond amination/CeS cross-coupling reaction (17CC2737). In this case the benzyl C(sp3)eH bond of the presumed intermediate 88 undergoes direct amination to give benzothiazole 89. A variety of functional groups are well tolerated under these conditions.
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2-Arylnaphthothiazoles 92 and 2-arylbenzothiazoles 94 are derived from primary arylamines, aromatic aldehydes, and elemental sulfur through oxidative annulation and CeH functionalization under transition metalfree conditions (17OL4576). NH4I and KI serve as the catalysts, while Dimethyl sulfoxide (DMSO) and oxygen are used as the oxidants.
5.5.2.4 Reactions of Thiazoles and Fused Derivatives a-Allylation of thiazolines 95 can be mediated by a Pd/Xantphos catalyst system under mild reaction conditions (17OL126). Mechanistic investigations suggest an initial allylation of the imine nitrogen followed by a Pdcatalyzed formal aza-Claisen rearrangement.
A metal-free photo-oxidative intermolecular CeH/CeH coupling reaction of thiazoles 100 with triethyl methanetricarboxylate is carried out with a catalytic amount of molecular iodine (17OL1610). In this transformation, molecular oxygen in the air serves as a terminal oxidant to regenerate molecular iodine. The 2- and 5-phenyl thiazoles undergo regioselective cross-dehydrogenative coupling reactions at C5 and C2 to give 102 and 103, respectively.
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5-N-Arylamino-4-methylthiazoles 108 are synthesized from 4-methylthiazole 105 in three steps: direct Pd-catalyzed CeH arylations at C2; bromination at C5; and the Pd-catalyzed BuchwaldeHartwig amination. Compounds 108 are used for the studies of photophysical properties (17OM2552).
A copper-catalyzed three-component coupling reaction of benzothiazole 109, Se powder, and aryl iodide provides a straightforward synthesis of 2-arylselanyl thiazole 110 (17JOC250). This reaction does not require any ligand, and a broad range of functional groups are well tolerated.
The Co(II)-catalyzed decarboxylative cross-coupling reaction of (hetero)aryl carboxylic acid 111 with benzothiazole has been investigated (17OL5589). When the decarboxylative cross-coupling of benzothiazole with 3-methylbenzothiophene-2-carboxylic acid in the presence of catalytic amounts of CoBr2 with Ag2CO3 as the oxidant, significant amount of the symmetric biheteroaryl 2,20 -bis(benzothiazole) is generated from the oxidative homocoupling reaction of benzothiazole. To minimize the formation of the homocoupling product, an extra ligand is added to the reaction mixture to control the Ag-mediated decarboxylation and the
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Co-promoted cross-coupling reaction. The N-heterocyclic carbene ligand, 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene (IPr), serves to promote the decarboxylative CeH functionalization and inhibit the formation of bis(benzothiazole). Among various solvents examined, 2-fluorobenzotrifluoride is optimal. Under these optimized conditions, the decarboxylative cross-coupling of benzothiazole with 3-methylbenzothiophene-2-carboxylic acid furnishes the desired product 113 in 82% yield. This reaction represents a first example of metal-catalyzed decarboxylative CeH heteroarylation of benzo-fused heterocycles.
Treatment of benzothiazole 114 with alkyl diacyl peroxide 115 or alkyl tert-butyl perester 117 in the presence of Fe(OTf)3 brings about CeH alkylation to give 2-alkyl benzothiazole 116 (17OL46). Notably, the reaction conditions are compatible with a broad range of functional groups such as alkene, ester, and ketone. In addition, the methodology is not sensitive to steric effects as tertiary alkyl groups such as admantanyl are incorporated into benzothiazoles.
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CeH arylation and heteroarylation of the thiazole moiety have been developed for the synthesis of dimer, triad, and polymeric materials (17JOC10139). Reaction of one eq. of fused thiazole 118 with 0.5 eq. of 2,5- dibromothiophene provides 56% yield of triad 120. Interestingly, increasing the amount of 2,5-dibromothiophene to 0.75 eq. increases the yield to 75%, while further increasing the amount of dibromide to 4 eq. decreases the yield, but still gives the desired triad 120 in 47% yield. This type of compounds shows broad optical absorption and low reduction potentials, and these materials could be used as organic semiconductors for applications in organic fieldeeffect transistors and as nonfullerene acceptors.
A general CeH functionalization approach to the synthesis of diverse thiazolyl-C-D1,2-glycosides features a Pd(OAc)2/CuI-catalyzed direct cross-coupling of thiazoles/benzothiazoles with 1-iodoglycals (17OL3608). The proposed reaction pathway involves the initial coordination between copper and nitrogen/oxygen on the substrate, which assists the deprotonation of C2 hydrogen on the thiazole by t-BuOLi. The resulting lithium salt of the thiazole undergoes lithiumecopper exchange to afford the organocopper species. Transmetalation with the palladium-mediated oxidative adduct from 1-iodoglycal followed by reductive elimination results in the thiazolyl C-glycoside 124. This protocol may be useful in the preparation of biologically important compounds.
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A visible light-induced radical difluoromethylation of benzothiazole2-thiol 125 with difluoromethyltriphenylphosphonium triflate 126 affords difluoromethyl thioether 127 in good yield (17JOC7373). The key reaction features include the use of a readily available CF2H radical source, mild reaction conditions, and excellent chemoselective thioldifluoromethylation.
5.5.2.5 New Thiazole-Containing Natural Products Biakamides AeD were isolated from an Indonesian marine sponge with a constructed bioassay using PANC-1 human pancreatic cancer cells (17JOC1705). These compounds exhibit selective antiproliferative activities against PANC-1 cells cultured under glucose-deficient conditions. Studies on the alkaloids from Peganum harmala seeds led to two rare thiazole derivatives, peganumal A/B (17JNP551). (þ)-Meyeniins AeC are novel
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hexahydroimidazo[1,5-c]thiazole derivatives from the tubers of Lepidium meyenii (17JAFC1887). The biological properties of these compounds provide support for using maca as healthy nutritional supplements or functional foods to prevent cancer.
5.5.2.6 Biologically Active Thiazoles and Isothiazoles GLPG1690 is a first-in-class autotaxin inhibitor undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis (17JMC3580). PF-05089771 is the first subtype selective Nav1.7 inhibitor clinical candidate which binds to a site in the voltage-sensing domain (17JMC7029). Ruzasvir is currently in early clinical evaluations as part of an all-oral direct-acting antiviral regimen for the treatment of chronic HCV infection (17JMC290). Tropifexor (LJN452), a potent nonbile acid farnesoid X receptor agonist, is undergoing phase II trials for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (17JMC9960). Compound 128 is a phenylpropanoic acid GPR120 agonist as a development candidate for type II diabetes (17ACSMCL947).
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5.5.3 ISOTHIAZOLES 5-Alkylthio-substituted isothiazoles 130 are prepared from b-ketodithioesters 129 upon exposure to ammonia (17TL2512). This protocol is operationally simple, but the yields are very moderate.
5.5.4 THIADIAZOLES An oxidative NeS bond formation reaction has been developed for 1,2,4-thiadiazole synthesis using molecular iodine as the sole oxidant (17JOC5898). The reaction conditions are mild, and no transition metals are required. A variety of imidoyl and guanyl thiourea substrates are converted to 5-amino and 3,5-diamino-substituted 1,2,4-thiadiazole derivatives, respectively, in good yields.
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The N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives 135 and 137 are synthesized in good yields through the molecular iodinecatalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via NeS bond formation at room temperature (17JOC5310).
4,5-Functionalized 1,2,3-thiadiazoles 139 are readily available from 2-cyanothioacetamides 138 and benzenesulfonyl azide in the absence of any transition metal (17JOC4056). Under diazo transfer conditions in the presence of a base in an aprotic solvent, 2-cyanothioacetamide 138 serves as CeCeS building block to produce 5-amino-4-cyano-1,2,3-thiadiazole 139 exclusively. Presumably, addition of carbanion 140 to benzenesulfonyl azide generates the triazenyl anion 141, which undergoes 1,4-prototropic shift to give carbanion 142. Elimination of PhSO2NH2 leads to intermediate 143, and subsequent cyclization affords thiadiazole 139.
Rh-Catalyzed intramolecular transannulation reaction of alkynyl thiadiazoles generates a wide range of fused thiophenes, including those fused with lactams, lactones, or cyclic ethers (17JOC1437). A plausible reaction pathway starts with a reversible ringechain tautomerization of thiadiazole moiety in alkynyl thiadiazoles 144 to give the alkynyl-substituted a-diazo thiocarbonyl 146. Exposure to the Rh(I) catalyst affords the a-thiavinyl Rh
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carbenoid 147 together with the release of nitrogen gas. Intramolecular reaction of the Rh carbenoid with the triple bond affords the zwitterionic intermediate 148, which cyclizes to give intermediate 149. Elimination of the Rh species furnishes 145.
The intramolecular Rh-catalyzed transannulation approach has been extended to cyanothiadiazole substrates 150 to provide bicyclic isothiazoles 151 (17JOC10574).
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