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ChemInform Abstract: Copper(I)-Catalyzed Synthesis of 2,5-Disubstituted Furans and Thiophenes from Haloalkynes or 1,3-Diynes.
Abstract
A regioselective synthesis of 2,5-disubstituted furans using copper(I) catalyst from haloalkynes in a one-pot procedure has been reported. This chemistry proceeds through the hydration reaction of 1,3-diynes, which can be readily prepared from the coupling reaction of haloalkynes in the presence of CuI. The procedure also can be used for the facile synthesis of 2,5-disubstituted thiophenes.
... Although similar reaction products would also be expected when using metal-based catalysts [146], the works carried out by different authors have shown the preferential formation of furan derivatives as the result of the formal double addition of the water O-H bonds to the diyne. This was evidenced for the first time by Jiang and colleagues in 2012, with the synthesis of the 2,5-diaryl-substituted furans 105 (Scheme 55) [154]. The hydration process is catalyzed by a CuI, in conjunction with 1,10-phenanthroline and KOH, in dimethyl sulfoxide (DMSO) at 70 • C. A reaction pathway involving the initial formation of the ketone intermediate R by single hydration of the diyne, followed by a Cu(I)-catalyzed cyclization, was proposed by the authors (see Scheme 55). ...
... In 2012, Jiang and colleagues described the synthesis of different 2,5-diaryl-substituted thiophenes 121 by reacting aromatic bromoalkynes with sodium sufide hydrate, i.e., Na 2 S·9H 2 O, in the presence of CuI and the 1,10-phenanthroline ligand (Scheme 68) [154]. Compounds 121 are the result of the formal double hydrothiolation of the corresponding 1,3diynes, generated in situ by copper-catalyzed homocoupling of the starting bromoalkynes. ...
Metal-catalyzed hydrofunctionalization reactions of alkynes, i.e., the addition of Y–H units (Y = heteroatom or carbon) across the carbon–carbon triple bond, have attracted enormous attention for decades since they allow the straightforward and atom-economic access to a wide variety of functionalized olefins and, in its intramolecular version, to relevant heterocyclic and carbocyclic compounds. Despite conjugated 1,3-diynes being considered key building blocks in synthetic organic chemistry, this particular class of alkynes has been much less employed in hydrofunctionalization reactions when compared to terminal or internal monoynes. The presence of two C≡C bonds in conjugated 1,3-diynes adds to the classical regio- and stereocontrol issues associated with the alkyne hydrofunctionalization processes’ other problems, such as the possibility to undergo 1,2-, 3,4-, or 1,4-monoadditions as well as double addition reactions, thus increasing the number of potential products that can be formed. In this review article, metal-catalyzed hydrofunctionalization reactions of these challenging substrates are comprehensively discussed.
... 383,384 Conjugated 1,3-diynes can be converted to 2,5-disubstituted furans using a simple and cheap copper(I) catalyst 519, which constitutes an alternative to reactions catalysed by much more expensive Au(I) complexes. 308,312,388 The formation of furans can occur directly from haloalkynes 1018a-n and 1019a-n via preliminary Glaser coupling to 1,3-diynes 1a-d, 27c, 37t, 230d, 258a, 258g-h, 265a, 500b, 1020a-b or direct hydration of diynes 60e, 655a, 1020c-e, followed by cyclisation. As a base, KOH was Scheme 183 Hydration/cyclisation of diynals 1002a-g to primary lactol derivatives 1003 catalysed by PtCl 2 1000. ...
... The mechanism of this transformation was previously described for the analgous hydration process (Scheme 187). 388 The synthesis of 3-halosubstituted thiophenes 1066 from simple aryl or alkyl-functionalised conjugated buta-1,3-diynes 1a, 1d, 13a, 27c, 65b, 208b, 258g, 258o, 617, 842b-c, 1028, and 1054a-b was described by Kesharwani et al. They proposed a two-step procedure yielding 3-chloro, 3-bromo and 3-iodothiophenes 1066 based on hydrothiolation reaction of 1,4-diaryl or 1,4-dialkyl-substituted diynes with methyl disulfide 1062 in the presence of NaBH 4 212 as a hydrogen source and, electrophilic cyclisation of the obtained sulfanyl modified enynes 1063 with natrium halides 1064a-c (NaCl, NaBr, NaI) in the presence of CuSO 4 Á5H 2 O 1065 (Scheme 196). ...
This review highlights the hydroelementation reactions of conjugated and separated diynes, which depending on the process conditions, catalytic system, as well as the type of reagents, leads to the formation of various products: enynes, dienes, allenes, polymers, or cyclic compounds. The presence of two triple bonds in the diyne structure makes these compounds important reagents but selective product formation is often difficult owing to problems associated with maintaining appropriate reaction regio- and stereoselectivity. Herein we review this topic to gain knowledge on the reactivity of diynes and to systematise the range of information relating to their use in hydroelementation reactions. The review is divided according to the addition of the E-H (E = Mg, B, Al, Si, Ge, Sn, N, P, O, S, Se, Te) bond to the triple bond(s) in the diyne, as well as to the type of the reagent used, and the product formed. Not only are the hydroelementation reactions comprehensively discussed, but the synthetic potential of the obtained products is also presented. The majority of published research is included within this review, illustrating the potential as well as limitations of these processes, with the intent to showcase the power of these transformations and the obtained products in synthesis and materials chemistry.
... 13 Polyynes have drawn the attention of biochemists due to their natural occurrence 14 and the attention of material scientists 15 and organic chemists since they are precursors of various compounds. 16,17 Regarding the latter, 1,3-diynes have found many uses in the organic synthesis of heterocycles, for example, 3,5-disubstituted pyrazoles 18 and 2,5-disubstituted furans, 19 and several protocols for their synthesis have been developed. 20,21 In materials chemistry, polyynes are potentially useful as conducting molecular wires 22 and have interesting optical properties. ...
The substituent effect (SE) is one of the most important topics in organic chemistry and related fields, and Hammett constants (σ) are commonly used to describe it. The results of the computational studies carried out for Y-R-X systems (reaction sites Y = NO2, O-; substituents X = NO2, CN, Cl, H, OH, NH2; spacers R = polyene, polyyne, acene with n = 1-5 repeatable units) show that the substituent properties depend significantly on n, the type of R, and Y. Results of the analysis of the substituent effect stabilization energy and geometrical parameters of the Y-R-X systems reveal that (i) the SE strength and its inductive and resonance components decay with the increase in spacer length, its weakening depends on the Y and R type; quantitative relations describing decay are presented; (ii) the ratio between inductive and resonance effect strength changes with n and depends on Y; (iii) differences in the substituents' properties are examples of reverse SE; (iv) in general, structural parameters are mutually well correlated as well as with the SE descriptors; (v) due to the strong O- resonance effect, the changes in π-electron delocalization within R are well correlated with the SE strength only for Y = O- systems.
... Jiang et al. investigated a one-pot procedure for the construction of 2,5-disubstituted thiophenes from bromoalkynes and sodium sulfide. Products were obtained in good to excellent yields using CuI and 1,10-phen as the catalyst system (Scheme 34) [44]. Lee et al. prepared 2,5-diaryl-substituted thiophenes from aryl propiolic acids and sodium sulfide through copper-catalyzed decarboxylative coupling followed by sulfur heterocyclization. ...
An efficient and environmentally-friendly protocol for the synthesis of 2- (arylamino)thiazoles has been investigated. The two-step, three-component reaction of aryl ketones, N-bromosuccinimide, and thiourea derivatives was performed using [bmim][BF4] ionic liquid as a solvent in one pot and gave products in good to excellent yields. Furthermore, the ionic liquid could be reused up to the 5th time without a considerable decrease in the reaction yield. Thirteen thiazoles were obtained in high yields (78-89%) under mild conditions (ambient temperature and relatively short reaction time) and their structures were confirmed by NMR data.
... These moieties have been widely applied as intermediate building blocks in organic transformations such as in the synthesis of natural products [10,11], pharmaceuticals [12][13][14][15] and heterocyclic compounds [16][17][18][19]. As already discussed that buta-1,3-diynes have been utilized for the construction of carbocycles such as benzene [20] and naphthalene [21,22], nitrogen containing 5/6-membered heterocycles such as pyrrole [23], pyrazole [24], triazole [25], naphthtriazoles [26], benzo[a]phenanthridine [27], benzoquinolines [24], oxygen based heterocycles such as furan [28], pyrone [29], selenium and sulphur containing heterocycles selenothiophenes [30] and thiophenes [31]. ...
... These moieties have been widely applied as intermediate building blocks in organic transformations such as in the synthesis of natural products [10,11], pharmaceuticals [12][13][14][15] and heterocyclic compounds [16][17][18][19]. As already discussed that buta-1,3-diynes have been utilized for the construction of carbocycles such as benzene [20] and naphthalene [21,22], nitrogen containing 5/6-membered heterocycles such as pyrrole [23], pyrazole [24], triazole [25], naphthtriazoles [26], benzo[a]phenanthridine [27], benzoquinolines [24], oxygen based heterocycles such as furan [28], pyrone [29], selenium and sulphur containing heterocycles selenothiophenes [30] and thiophenes [31]. ...
An efficient method for the synthesis of buta-1,3-diynes have been developed via copper(I) catalyzed homocoupling reaction of terminal acetylenes in presence of CuI and tetramethylethylenediamine (TMEDA) at 100 ºC for 3.0 h under solvent-free conditions. This efficient methodology allowed the homocoupling of five terminal alkynes in moderate to excellent yields.
... The starting materials were obtained from reactions between various 1-halopolyynes and amines (Scheme 236E) [427]. Thiophenes derivatives were provided in high yields using a combination of copper iodide and 1,10-phen catalyst (Scheme 237A) [428]. Irudayanathan et al. synthesized symmetric 2,5-diaryl-thiophenes from the corresponding arylacetylenen carboxylic acids and Na 2 S.9H 2 O via a sequence of CuI-catalyzed decarboxylative coupling to form 1,3-diynes and sulfur-triggered heterocyclization. ...
This chapter summarizes recent progress in the synthesis of furans, pyrroles, and thiophenes
... The formation of highly substituted furans from (1-alkynyl)-2-alkene-1-ones through tandem cycloisomerization and indole addition steps [215] and from haloalkynes or 1,3-diynes [216] in presence of Cu II or Cu I salts were also reported in the literature. The activity of copper salts extends to hydroamination reactions as reported by Buchwald and Shi [217]. ...
The review describes the state of the art in hydration reactions of alkynes by direct or indirect catalysis of first row transition metal complexes, covering mostly the literature of the last decade in which many examples based on these metal ions have been reported. Previously limited to few cases, catalytic metal ions of the fourth period allow for the regioselective conversion of terminal and internal alkynes with different electronic properties or even sterically hindered into the corresponding ketones. The substrate scope includes aromatic, heteroaromatic and aliphatic alkynes under reaction conditions compatible with various functional groups, in moderately acidic conditions, as for iron catalysts, or even in absence of Brønsted acids, as for cobalt and copper salts. The mechanism of activation of the triple bond varies largely depending on the metal ion and includes attack of proton under combined acid catalysis (Lewis acid-Brønsted acid) or intermediacy of π-alkyne or σ-acetylide late transition metal-complexes. The use of 3d metal complexes as alternatives to conventional noble metal catalysts for water addition reactions of alkynes entails significant implications on cost and environmental issues. Selected examples of applications in cascade and multi step reactions involving acid sensitive organic compounds are also described.
... Transition metal-catalyzed heterocyclization of 1,3-diynes has also received considerable attention in the last decades. In 2012, Jiang reported a regioselective synthesis of Scheme 8 Synthesis of tricyclic 2,3-disubstituted naphtho [2,1-b] thiophene-4,5-diones 32 symmetrical 2,5-disubstituted thiophenes 51 from the coupling reaction of haloalkynes 50 in the presence of CuI in high yield (Scheme 14) [26]. ...
Thiophene-based analogs have been fascinated by a growing number of scientists as a potential class of biologically active compounds. Furthermore, they play a vital role for medicinal chemists to improve advanced compounds with a variety of biological effects. The current review envisioned to highlight some recent and particularly remarkable examples of the synthesis of thiophene derivatives by heterocyclization of various substrates from 2012 on.
Graphic abstract
... Jiang et al. investigated a one-pot procedure for the construction of 2,5-disubstituted thiophenes from bromoalkynes and sodium sulfide. Products were obtained in good to excellent yields using CuI and 1,10-phen as the catalyst system (Scheme 34) [44]. Lee et al. prepared 2,5-diaryl-substituted thiophenes from aryl propiolic acids and sodium sulfide through copper-catalyzed decarboxylative coupling followed by sulfur heterocyclization. ...
Thiophene derivatives are aromatic five-membered ring compounds made up of one Sulphur as heteroatom. These compounds are present in a large number of natural and unnatural compounds with valuable bioactivities. Many of them have a wide range of applications in medicinal chemistry such as antimicrobial, anticancer, antiparasitic, anti-inflammatory, and antihypertensive activities. Some of them are famous drugs in the market nowadays such as Cefoxitin, Cephalothin, Cephaloridine, Temocillin, tinoridine, tiaprofenic acid, tenoxicam, suproprofen and Raltitrexed. The use of thiophenes derivatives also has been found in other fields. The application of thiophenes in organic materials thank to their electronic properties has been reported. In organic synthesis, thiophenes also have drawn attention of chemists because of their values as intermediates. The employment of thiophene derivatives in agrochemicals, flavors, and dyes has also been found. Due to diverse applications, the synthesis of thiophene derivatives has attracted a lot of attention. Numerous known synthetic methods such as Gewald and Fiesselmann methods have been modified and improved. Furthermore, a large number of novel synthetic approaches to the synthesis of thiophenes have been developed. This review will focus on considerable studies on the synthesis of thiophenes which date back from 2012. In this review, we discussed recent achievement in the synthesis of thiophene derivatives. Some established methods have been modified and improved, while other novel methods have been discovered. Diverse catalysts were employed for these transformations. In some syntheses, reaction mechanisms were also displayed. Many methods for the synthesis of thiophenes have been developed recently. In the near future, more imaginative approaches for the synthesis of thiophenes will be investigated to improve the efficiency and versatility or to use environmentally friendly and economical procedures. Application to natural product synthesis and drug synthesis is probably the next challenge in the field.
... 2,5-Diarylfuran derivatives 44 were obtained through microwave-assisted reaction (4-5 min.) of 1,4-diaryl-2-butyne-1,4-diones 43 with formic acid using Pd/C as a catalyst in poly(ethylene glycol)-200 (PEG-200) (Scheme 14) [74]. Scheme 16. ...
The present study provides an overview of the chemistry and biological importance of the cationic chalcophene derivatives (furans, thiophenes & selenophenes). The summarized literature survey includes synthetic methods, reactivity, and biological activities of aryl/hetarylchalcophenes that have been reported mainly from 2001 to 2019 focusing on monochalcophenes. A discussion demonstrating the proposed mechanisms of some interesting synthetic routes and linking structure features to biological activities is presented. These classes of compounds including cationic chalcophenes possess anti proliferative, antimicrobial, and antiprotozoal activities. This review highlights recent advances for arylchalcophene derivatives and may contribute to the design and structure optimization of new chalcophene derivatives in the future.
... 2,5-Diarylfuran derivatives 44 were obtained through microwave-assisted reaction (4-5 min.) of 1,4-diaryl-2-butyne-1,4-diones 43 with formic acid using Pd/C as a catalyst in poly(ethylene glycol)-200 (PEG-200) (Scheme 14) [74]. Scheme 16. ...
The present study provides an overview of the chemistry and biological importance of the cationic chalcophene derivatives (furans, thiophenes & selenophenes). The summarized literature survey includes synthetic methods, reactivity, and biological activities of aryl/hetarylchalcophenes that have been reported mainly from 2001 to 2019 focusing on monochalcophenes. A discussion demonstrating the proposed mechanisms of some interested synthetic routes and linking structure features to biological activities is presented. These classes of compounds including cationic chalcophenes possess anti-proliferative, antimicrobial, antiprotozoal activities. This review highlights recent advances for arylchalcophene derivatives and may contribute to the design and structure optimization of new chalcophene derivatives in the future.
... The transformation of diynes into furan 6 was carried out under simple gold-catalyzed conditions as shown in Scheme 2. Conversions to other heterocycles, such as thiophene and pyridine, can be readily achieved based on similar known methods. [52][53][54][55][56][57][58] One very important application of cycloalkyne is the copper-free azide-alkyne cycloaddition, which has received tremendous attentions in recent years as a bio-compatible labelling strategy under mild conditions. [59][60][61][62][63][64][65] The success of this strategy relies on the ring strain of the cycloalkyne. ...
A gold-catalyzed oxidative coupling of alkynes was developed as an efficient approach for the synthesis of challenging cyclic conjugated diynes (CCD). Compared to the classical copper-promoted oxidative coupling reaction of alkynes, this gold-catalyzed process exhibits a faster reaction rate due to the rapid reductive elimination from the Au(III) intermediate. This unique reactivity thus allowed a challenging diyne macrocyclization to take place in high efficiency. Condition screening revealed a [(n-Bu)4N]+[Cl-Au-Cl]- salt as the optimal pre-catalyst. Macrocycles with ring size between 13 to 28 atoms were prepared in moderate to good yields, which highlighted the broad substrate scope of this new strategy. Furthermore, the synthetic utilities of the cyclic conjugated diynes for copper-free click chemistry have been demonstrated, which showcased the potential application of this strategy in biological systems.
Thiophene, as an important sulfur‐containing heterocyclic, is widely used in pharmaceuticals, functional materials, and natural products. Furthermore, thiophene is of great interest to synthetic chemists due to its diverse reactivities. Over the past few decades, many synthetic strategies are developed for functionalized thiophenes. Several reviews have been reported. However, there is no review on thiophene synthesis summarized based on the sulfur sources. The current review envisioned to summary the synthesis methods for thiophene with the respect of sulfur sources and give support for choose the appropriate tools to obtain thiophene substrates.
Transition metal‐catalyzed C−H functionalization of diverse arenes with alkyne units has attracted enormous attention for decades since they provide straightforward access to various functionalization/annulations, which are commonly present in bioactive compounds and natural products. Recently, conjugated alkynes (1,3‐diynes) have been utilized as key coupling partner in many C−H activation reactions due to their versatile characteristic properties. The presence of two C≡C bonds in conjugated 1,3‐diyne brings the new diversity in synthetic transformations, such as chemo‐, regioselective pathways, mono‐bis functionalizations, cascade annulations, etc. Herein, we summarized the latest developments in the realm of transition‐metal‐catalyzed C−H functionalizations of diverse arenes with 1,3‐diynes. Moreover, we highlighted the diverse transformations, conditions, mechanisms and applications of the corresponding reaction in detail. Transition metal‐catalyzed C−H functionalizations with alkynes have become very familiar in organic synthesis. However, the alkyne surrogate, such as 1,3‐diynes in the C−H activation field is still in the early stage. This review summarizes the recent advances of transition metal‐catalyzed direct C−H annulation/alkenylation of arenes with 1,3‐diyne precursors and their notable applications in organic synthesis.
The catalytic activity of a series of [(AuCl)2(μ-PP)] (PP = 1,1'-bis(phosphino)metallocene ligands) compounds in the presence of Na[BArF24] (BArF24 = tetrakis(3,5-bis(trifluoromethyl)phenyl borate)) was examined in the formation of disubstituted furans from pyridine-N-oxide and terminal alkynes. The products of these reactions were typically the 2,5-disubstituted furans, but in the case of using 2-ethynylpyridene, the 2,4-disubstituted furan formed. The catalytic efficiency was dependent upon both the nature of the terminal alkyne and the 1,1'-bis(phosphino)metallocene ligands. During the course of this study, two new compounds, [(AuCl)2(μ-dppr)] and [(AuCl)2(μ-dppo)] (dppr = 1,1'-bis(diphenylphosphino)ruthenocene; dppo = 1,1'-bis(diphenylphosphino)osmocene), were prepared and characterized by NMR. X-ray crystal structures of both compounds were determined and the oxidative electrochemistry of these new compounds was examined.
In this work, we report the use of rongalite in PEG-400 as a general, reusable, efficient, inexpensive and environmentally benign reductive system for elemental chalcogens and its use for the...
Novel di- and tetra-substituted calix[4]arene derivatives bearing diacetylene moieties at the lower rim of macrocycle were synthesized via the Mitsunobu and Williamson reactions. The dealkylation of diacetylene moieties of calix[4]arene was for the first time discovered in the DMSO—hydrazine hydrate system. An important role in the dealkylation of diacetylene moieties is played by neighboring unsubstituted OH groups at the macrocycle. Blocking of OH groups with butyl substituents and elongation of the linker between the butadiynyl fragments and the macrocyclic platform significantly reduce the affinity of macrocycle to reductive cleavage. The unique reactivity of calix[4]arene in its reaction with hydrazine hydrate was demonstrated in comparison with a model conjugate of diacetylene with 4-tert-butylphenol. The reductive cleavage may proceed via the formation of pyrazole derivative of calix[4]arene. Pyrazole derivatives were the most reactive ones in the reaction with hydrazine hydrate among the studied isostructural calixarenes containing an active α-arylmethyleneoxy moiety. Results of performed quantum chemical calculations allowed us to propose a scheme for the reductive cleavage of oxymethylene derivatives of pyrazole with hydrazine hydrate.
Herein, a straightforward method for the synthesis of 2,5-disubstituted selenophenes via [2+2+1] cyclization of easily accessible terminal alkynes and elemental selenium has been developed. This reaction features high atom- and step-economy, excellent regioselectivity, good functional group tolerance and the use of stable and non-toxic selenium as a selenium source. A series of control experiments suggests that the reaction might undergo Glaser coupling reaction of two molecules of alkynes, followed by insertion of H2Se and subsequent cyclization. Moreover, the newly formed products can be further converted to diverse conjugated selenophene-based derivatives, demonstrating their potential applications in organic synthesis and materials science.
Cu complexes supported on metal‐organic frameworks (MOFs) with N1,N1,N2,N2‐tetramethylethylenediamine (TMEDA) were prepared via post‐synthetic modification, and proved to be highly efficient for Glaser heterocoupling reactions. Compared with some referential catalysts, which were prepared by using a series of copper salts and Cu0 nanoparticles as the copper sources, the newly designed MIL‐101‐NH‐TMEDA⋅CuClx exhibited highest catalytic activity and selectivity in the model Glaser heterocoupling reaction. Much lower activity was observed with the homogeneous counterpart, TMEDA⋅CuCl4. Intriguingly, the Glaser heterocoupling reactions over MIL‐101‐NH‐TMEDA⋅CuClx catalyst can be conducted without adding external ligands, base, or acid, which are always necessary in the previously reported systems. The dense catalytic active sites in the MOF channels and the adsorption properties of the MOF were conjectured to be partially responsible for the observed high catalytic activity, which may allow the formation of a unique internal environment in the three‐dimensional porous framework that significantly boosted progress of the reactions. The X‐ray photoelectron spectroscopy (XPS) results showed also that the catalytically active copper species changed from CuII to CuI after catalytic use. MOF catalysis: For the first time, MOFs were applied to catalyze the Glaser heterocoupling reaction, and they exhibited higher catalytic activity than a homogeneous catalyst under the same conditions.
This chapter describes the synthetic methods for the formation of four‐, five‐, and six‐membered heterocyclic compounds via the cycloaddition reactions starting from alkynes. Topics discussed in this chapter include several examples of four‐membered heterocycle formation; the construction of five‐membered heterocycles such as pyrroles, furans, thiophenes, and their benzo‐fused compounds of indoles, benzo[ b ]furans, benzo[ b ]thiophenes, and benzo[ b ]selenophenes; the synthesis of six‐membered heterocycles of pyridines, 2‐pyridone, and their benzo‐fused compounds of quinolones, isoquinolines, quinolinones, and isoquinolonones. The synthesis of 2‐pyrones, coumarins, isocoumarins, and chromones and the different sized heterocycles containing two heteroatoms are also described.
In this article, a direct synthetic method for alkyl 5‐arylthiophene‐2‐thiocarboxylates was reported. Treatment of alkyl 2‐aroyl‐1‐chlorocyclopropanecarboxylates with excess amount of Lawesson's reagent readily afforded alkyl 5‐arylthiophene‐2‐thiocarboxylates in good to excellent yields under mild conditions. This cycloisomerization reaction process would be initiated by a ring‐opening of the strained cyclopropane.
Herein a regioselective addition/annulation strategy of ferrocenyl (Fc) thioamides with alkynes to construct thienylferrocene (ThienylFc) structures, involving a rhodium-catalyzed C–H activation, an unusual C2-selective addition of 1,3-diyne, and an unexpected intramolecular sulfur-transfer rearrangement process is described. In this protocol, thioamide not only serves as a directing group to activate the ortho-C–H bond of the ferrocene, but also as a sulfur source to form the thiophene ring. The resulting carboxylic ester group after sulfur transfer can act as a linkage to construct extended π-conjugated ferrocenes (OCTFc) with luminescent properties. ThienylFc displays effective fluorescence quenching due to the photoinduced electron transfer (PET) from the Fc unit to the excited luminophore, which turns out to be a promising type of redox molecular switch. OCTFc exhibit relatively strong emission owing to their intramolecular charge transfer (ICT) characteristics. The ring-fused strategy is herein employed for the first time to construct luminescent materials based on ferrocenes, which provides inspiration for the development of novel organic optoelectronic materials, such as electroluminescent materials based on ferrocenes.
We propose a new method for assembling the imidazo[2,1-b][1,3]thiazole system, based on the reaction of (2Z)-1,3-diaryl-4-bromobut-2-en-1-one derivatives with 2-aminothiazoles. The outcome of this reaction depends on the structure of the starting bromo ketone: when electron-withdrawing substituents are present in the structure of the ketone, a competing reaction occurs, which leads to the formation of 2,5-diarylfurans. Screening for antitumor activity has been performed in the case of 1-phenyl-2-(6-phenyl-5,6-dihydroimidazo[2,1-b]- thiazol-6-yl)ethanone and this compound has shown moderate ability to suppress the growth of kidney cancer cells, with a weaker effect on the cell lines of prostate cancer, colon cancer, and leukemia.
The trithiocarbonate anion (CS32-) was generated in situ from CS2 and KOH in DMSO by a simple method and used as a novel synthetic equivalent of the S2-synthon for the synthesis of 2,5-disubstituted thiophenes from 1,3-butadiynes. Additionally, this system was employed for the metal-free synthesis of 2-substituted benzo[b]thiophenes from 2-haloalkynyl (hetero)arenes. These compounds were obtained from a cheap and readily available sulfur source in moderate to good yields, with good functional group tolerance.
Cu catalysts have been widely utilized in organic transformations because of their economical and viable nature. This chapter describes the applications of Cu catalysts to synthesize several types of symmetrical 1,3‐diynes, biaryls, and bi‐alkenyl systems via homocoupling reactions of terminal alkynes, aryls, and alkenyls, respectively.
This chapter focuses on the advances in the synthetic methods of thiophenes and their benzo derivatives. The references cover the literature of the period 2007–2019. The first part of the chapter includes the construction of thiophene ring involving the formation of one bond, two bonds, three bonds, and four bonds of the thiophene nucleus. The synthetic methods using other heterocyclic compounds as the starting material are presented in the second section. Thiophene syntheses through direct functionalization of the thiophene ring are introduced in the third section. Syntheses of benzo[b]thiophenes and benzo[c]thiophenes via annelation reaction of thiophenes are included in the last part.
A facile ruthenium‐catalyzed regio‐ and stereoselective hydroboration of symmetrical, aromatic 1,3‐diynes with pinacolborane towards 2‐boryl‐1,4‐diaryl‐buta‐1‐en‐3‐ynes and their further transformation into potassium trifluoroborate salts is presented. The reaction proceeded efficiently for 1,4‐diphenylbutadiynes with various substituents on the phenyl rings and heterocyclic 1,4‐di(thiophen‐3‐yl)buta‐1,3‐diyne. The resulting products were isolated and fully characterized ( ¹ H, ¹³ C, ¹¹ B and 1D NOESY NMR, IR, GC‐MS, HRMS or elemental analysis). Moreover, the crystal structure of an enynyl boronate was determined, proving the addition of boryl moiety at the internal carbon in the diyne, according to the anti‐Markovnikov rule. The results presented here are the first examples of selective catalytic monohydroboration of conjugated diynes. The products obtained due to the presence of the boryl group and the unsaturated bonds are potential synthons in the synthesis of natural compounds or active pharmaceutical ingredients (API). The model Suzuki coupling of 2‐boryl‐1,4‐diphenyl‐buta‐1‐en‐3‐ynes with iodobenzene was carried out to illustrate the utility of the resulting compounds.
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Herein we report a protocol for novel palladium‐catalyzed cross‐coupling reactions of sustainably produced primary furfuryl alcohols with arylboronic acids to deliver 5‐arylfurfuryl alcohols and 2,5‐diaryl furans. Hammett plot analysis suggested that the reaction mechanism involved aromatization‐driven cleavage of the carbon−carbon bond of a furan oxonium ion intermediate. This protocol provides a simple, practical way to transform 5‐hydroxymethylfurfural into useful compounds.
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Synthesis of thiophene aldehydes from easily available cyclopropyl ethanol derivatives and potassium sulfide has been developed. This novel one-pot procedure achieves double C-S bonds formation via cleavage of C-C bonds....
This review attempts to cover the use of 5-endo-dig cyclizations, “favored” as defined by Baldwin's rules, in the synthesis of heterocyclic and carbocyclic ring systems, ranging from furans, pyrroles, thiophenes, and their benzo-derivatives to cyclopentenes, indenes, and some more complex derivatives along with partly saturated examples. While some key contributions published prior to the turn of the millennium are included, the review consists predominantly of papers, which appeared after the year 2000. Despite that the original versions of Baldwin's rules were focused on nucleophile-driven processes, much of the considerable progress made in this area during this period has featured electrophile-driven cyclizations, often in a catalytic mode, the latter feature imbuing clear environmental advantages to many of these transformations. Hence, many examples have, as a key step, the attack of a nucleophilic center onto an activated alkyne, occasionally an allene, although these may be undetected intermediates in some cases. This defines the 5-endo-dig status of a particular transformation; because of the large volume of such contributions, this means that much closely related and useful methodology has had to be omitted. Brief sections on theoretical aspects and a summary of previously published reviews are also included.
A practical synthetic route to 1,3‐diynes from terminal alkyl alkynes through copper‐catalyzed oxidative coupling is developed. The remarkable features of this oxidative coupling including the base‐ and ligand‐free construct of C−C bond, mild reaction conditions, as well as wide substrate scope that is particularly compatible with some terminal alkyl alkynes. A practical synthetic route to 1,3‐diynes from terminal alkyl alkynes through copper‐catalyzed oxidative coupling is developed. The remarkable features of this oxidative coupling including the base‐ and ligand‐free construct of C−C bond, mild reaction conditions, as well as wide substrate scope that is particularly compatible with some terminal alkyl alkynes.
A new synthetic route of 2‐nitrothiophenes was described through a tetra‐n‐butylammonium fluoride‐promoted or diisopropylethylamine‐promoted tandem Henry reaction and nucleophilic substitution of nitromethane with 3‐thiocyanatopropenals, which were conveniently prepared by the replacement reaction of 3‐chloropropenals with potassium thiocyanate under a mild acidic condition.
Copper‐catalyzed amidation of alkynyl bromides can be carried out in water for the first time, which is made possible by a micellar catalysis strategy using rosin‐based surfactant APGS‐550‐M. The surfactant can be easily prepared from natural abundant biomass, resin acids. Studies as to substrate scope and reaction aqueous medium recycling showcase the ease and sustainability of this technology. The synthesis of ynamides in water was achieved by a micellar catalysis strategy using rosin‐based surfactant APGS‐550‐M, which can be easily prepared from natural abundant biomass.
A novel, atom economical, and transition-metal-free strategy for the synthesis of thiophenes from substituted buta-1-enes with potassium sulfide has been presented. The reaction achieves double C-S bond formations via cleavage of multiple C-H bonds and provides an efficient approach to access various functionalized thiophenes. Moreover, the strategy can also be used for the synthesis of thiophenes from 1,4-diaryl-1,3-dienes. Mechanistically, DMSO plays a role of oxidant and S3•- in situ generated from K2S is involved.
A novel one-pot protocol was developed for the synthesis of unsymmetrical 1,3-butadiynes. The procedure is based on two sequential reactions: deprotection of R─C≡C─C≡C─C(Me)2OH derivatives in a retro-Favorskii reaction to furnish a terminal1,3-butadiyne compound, which reacted with aryl iodides in a Sonogashira-type cross-coupling reaction catalyzed by Pd(PPh3)4 and CuI, using TBAOH as activator and toluene as solventunder reflux for 10min. We also studied in situ thiocyclizationof 1,3-butadiynes, leadingto unsymmetrical 2,5-diarylthiophenes. The principal features of this method are operational simplicity, good substrate scope, very fastreaction, and highyields.
Phenyl‐ and thien‐2‐yl‐[2, 2′‐bithiophen]‐5‐yl)(thiophen‐2‐yl)methanones were synthesized by the condensation of 2‐thienyldithioester with the corresponding methyl ketones followed by cyclization with 2‐bromoacetylthiophene. Also, condensation of 2‐thienyldithioester with methyl ketones followed by treatment with methyl iodide gave β‐thien‐2‐yl‐β‐methylthio‐α,β‐unsaturated ketones, which reacted with the Simmons‐Smith reagent to give corresponding 4‐phenyl‐ and thien‐2‐yl‐2,2′‐bithiophenes. The optoelectronic properties of these bithiophene derivatives were studied by UV‐Vis absorption, fluorescence spectroscopy and cyclic voltammetry. The lowest‐energy conformations of these new compounds in the ground and first excited states, the electronic origins of their UV‐Vis absorption and fluorescence emission bands, and related frontier molecular orbital (FMO) properties were elucidated by density functional theory (DFT) and time‐dependent density functional theory (TD‐DFT) calculations. Furthermore, these aryl‐substituted bithiophenes were treated with anhydrous ferric chloride to undergo oxidative polymerization, and the fluorescence properties of the resulting polymeric products are also reported herein. The synthesis and optoelectronic properties of phenyl‐ and thien‐2‐yl‐[2, 2′‐bithiophen]‐5‐yl)(thiophen‐2‐yl)methanones and 4‐phenyl‐ and thien‐2‐yl‐2,2′‐bithiophenes and some FeCl3‐derived polymeric products are described. The electronic origins of their UV‐Vis absorption and fluorescence emission bands, and related FMO (frontier molecular orbital) properties were also elucidated by DFT (density functional theory) and TD‐DFT calculations.
The first member of S-heterocycloarenes was synthesized from an easily prepared phenanthrylene ethynylene macrocycle through diyne cyclocondensation and a Scholl reaction. The solution-processed thin film of this S-heterocycloarene behaved as a p-type semiconductor.
A novel one-pot tandem process involving Knoevenagel condensation, Michael addition, selective amidation, and Paal–Knorr cyclization to diverse functionalized 3-hydroxy-2-furanyl-acrylamides from simple 2-oxoaldehydes and aroylacetonitriles was presented. Attempts were also made to expand the scope of the reaction to different 2-heteroarylfurans. The packing diagram of the molecules viewed down along the α-axis of the unit cell showed a characteristic intramolecular classical O–H···O hydrogen bond between hydroxyl and carbonyl O atoms leading to self-associated (Z)-2-furanyl-acrylamides.
The three‐component reaction for the synthesis of 2‐arylthiophenes has been developed. Easily available arylacetaldehydes, 1,3‐dicarbonyls, and elemental sulfur were directly assembled through cascade condensation/ annulation under base conditions. The present protocol provides a facile entry to 2,3,5‐trisubstituted thiophenes with moderate to excellent yields and good functional group tolerance.
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Acceptor-substituted 5,5″-terthiophenes were synthesized by a consecutive pseudo-five-component Sonogashira alkynylation-Fiesselmann cyclocondensation synthesis generating diethyl terthiophene-5,5″-dicarboxylates and terthiophene-5,5″-dinitrile. The diethyl terthiophene-5,5″-dicarboxylates were directly reacted with a variety of amines to give 5,5″-biscarboxamide substituted terthiophenes in moderate to excellent yields (62-99%). The electrochemical and photophysical properties of these novel diacceptor-substituted terthiophenes were examined by cyclic voltammetry as well as by absorption and emission spectroscopy. All synthesized 5,5″-diacceptor-substituted terthiophenes possess reversible oxidation potentials between 300 und 1550 mV. The compounds are blue luminescent and the emission maxima appear between 461 and 476 nm with fluorescence quantum yields between 0.14 and 0.33.
Macrocyclic precursor featuring highly reactive propargylic moieties was prepared via Williamson etherification with good 54-65 % yields. Organometallic methodology paired with protective metal insertion served as the foundation for better DBTAA exploitation through copper(I)-mediated coupling. Glaser-Hay and Eglinton coupling conditions were applied to the direct synthesis of the cyclic strapped ligand and its corresponding dimer in 44 % and 30 % yields respectively. Mechanistic insight into cyclic dimer formation is discussed with emphasis on the kinetic effective molarities which reveal that the working concentration regime profoundly affects the final product`s distribution. Both macrocyclic zinc(II) precursor and the corresponding inherently chiral strapped ligand are structurally characterized by single-crystal x-ray diffraction. Strapped enantiomers communicate in a solid state through the inherently chiral π-surfaces and display preferential self-recognition, leading to both homochiral MM and PP stereoisomers with pronounced helicity.
Described herein is a convenient and highly selective synthesis of alkynylated isoquinolines and biisoquinolines from various aryl ketone O-pivaloyloxime derivatives and 1,3-diynes via rhodium-catalyzed C-H bond activation. In this transformations, alkynylated isoquinolines, 3,4'- and 3,3'-biisoquinolines could be obtained respectively through changing the reaction conditions. Mechanistic investigation revealed that the C-H activation of aryl ketone O-pivaloyloxime was the key step to this reaction.
A facile one-pot synthesis of butadiyne bridged bipyrroles could be achieved from 2-iodopyrroles and trimethylsilylacetylene via a modified Sonogashira coupling and in-situ aerial oxidative coupling of the acetylenic pyrroles in 31-72% yields, depending upon the substituents on pyrrole. The acetylene bridged diacids obtained from hydrolysis of the corresponding ester derivatives were highly stable, unlike most of the reported oligopyrrolic diacids. This protocol could be easily extended towards the synthesis of butadiyne bridged bisporphyrin.
We report the binding properties of 18- and 24-membered cyclic oligopeptides developed from a novel furan amino acid, 5-(aminomethyl)-2-furancarboxylic acid, to G-quadruplex. Comparative analysis of the binding data of these ligands with G-quadruplex and double-strand DNA shows that 24-membered cyclic peptides are highly selective for telomeric G-quadruplex structures and thus can be used as a scaffold to target quadruplex structures at the genomic level.
An intriguing, facile, and efficient oxidation and cyclization of alkynes catalyzed by Pd(OAc)(2) in a fluorous biphasic system of N,N-dimethylacetamide (DMA) and perfluorodecalin directly with molecular oxygen is described, which opens an efficient access to tetrasubstituted furans. Under the optimized conditions, intermolecular reaction between diverse alkynes provides the corresponding mixture of regioisomers with appreciable selectivity. Intramolecular oxidation and cyclization of alkynes are also successfully demonstrated. The reaction proceeds efficiently under mild conditions with atmospheric oxygen as the sole oxidant.
2,5-Disubstituted furans were synthesized by one-flask Heck arylation/oxidation sequences. The starting materials are 2-substituted 2,3-dihydrofurans, conveniently available by RCM/isomerization sequences, and arenediazonium salts. These react in ligand-free Heck reactions to afford 2,5-disub-stituted 2,5-dihydrofurans, which are oxidized to the corresponding furans without isolation or intermediate workup. The oxidation is conveniently achieved with chloranil or DDQ, depending on the substrate.
Furans and pyrroles were prepared via the gold(I)-catalyzed alkyne hydration of diynes. The use of [Au(IPr)OH] as precatalyst in a silver-free protocol permits low catalyst loadings and in situ generation of the active cationic gold species. A detailed computational study confirmed the experimental results and supports the proposed mechanism.
A mild, general, and efficient method for the synthesis of 2-monosubstituted and 2,5-disubstituted furans via the CuI-catalyzed cycloisomerization of alkynyl ketones was developed. It was demonstrated that furans containing both acid- and base-labile groups could be easily synthesized using this methodology. A plausible mechanism for this transformation is proposed.
The aim of this review is to highlight the utility of a
remarkable triad of 2-silyloxy diene synthons derived from furan, pyrrole
and thiophene in organic synthesis. These heterocycles, in reacting with a
number of carbonyl-related compounds (aldehydes, imines,
heteroatom-stabilized carbenium ions), act as vinylogous nucleophile
modules giving rise to a myriad of functionality-rich aldol-type
constructs. These, in turn, represent invaluable synthetic platforms onto
which a limitless number of functional elements and chosen chirality may be
introduced. Eleven syntheses, amongst the most appealing of
1991–1999, have been chosen to illustrate the potentiality of
silyloxy diene chemistry.
The rhodium-catalysed carbonylative addition of arylboronic acids to propargylic alcohols yields gamma-hydroxy enones that are readily cyclised through a dehydration step to the corresponding furan analogues. The transformation was improved thanks to the screening of the reaction conditions and consequent improvements were obtained from the use of dicarbonylrhodium iodide [Rh(CO)2I]2 as catalyst precursor. The generalisation of the reaction was then further investigated by employing variously substituted arylboronic acids and propargylic alcohols.
Mononuclear complexes of the type [(p-cymene)RuX(CO)(PR3)][OTf] (R=Ph, Cy; X=Cl, OTf) promote the direct catalytic propargylation of furan with propargyl alcohols. These precursors are generated in situ from [(p-cymene)RuCl(OTf)(PR3)1 by activation of the propargylic alcohol, leading to the carbonyl ligand formation via allenylidene and alkenyl-hydroxycarbene intermediates. The generation of the catalytically active species requires a short initial thermal activation to induce decoordination of the p-cymene ligand. The in situ generated catalyst has been applied to catalytic transformations of alkynes and propargylic alcohols: propargylation of furans, propargyl ether synthesis from internal and terminal propargylic alcohols with propargyl, homopropargyl and allyl alcohols, selective dimerization of phenylacetylene into E-enyne, and propargyl alcohol rearrangement into alpha,beta-unsaturated aldehydes and ketones via the Meyer-Schuster rearrangement. The propargylation of propargylic alcohols containing internal C C bonds suggests an activation via the Nicholas-type intermediate, the metal-stabilized propargyl cation.
The Rh-catalyzed reaction of propargylic alcohols with aldehydes being an -S-Me functionality gives γ-hydroxy-α,β-enones which undergo dehydrative cyclization to di- and trisubstituted furan structures.
Flash vacuum pyrolyses (FVP) of benzoic 2-methyl-3-furoic anhydride (12) and benzoic 3-methyl-2-furoic anhydride (13) at 550 °C and ca. 10(-2) Torr both give methylenecyclobutenone (16) and 1-buten-3-yne (17) as the main products. A mechanism involving generation of furan analogues of α-oxo-o-quinodimethane, 10 and 11, from FVP of 12 and 13, respectively, followed by elimination of a CO molecule to give the respective carbenes 34 and 36 is proposed. Carbenes 34 and 36 are interconvertible via a cyclopropene intermediate 35. A ring contraction from 36 will give 16, whereas a ring-opening of 34 followed by elimination of a CO molecule then leads to 17. The proposed mechanism is supported by substituent- and deuterium-labeling study on FVP of the derivatives of 12.
The effects of furan and maleimide substitution on the dynamic reversibility of their Diels-Alder reactivity have been investigated computationally and by (1)H NMR spectroscopy. Furan and furan derivatives bearing methoxy, methyl, or formyl groups at their 2- or 3-positions were investigated with maleimide and maleimide derivatives bearing N-methyl, N-allyl, and N-phenyl substituents. Computational predictions indicate that electronic and regiochemical effects of furan substitution significantly influence their Diels-Alder reactivity with maleimide, with reaction free energies of exo adduct formation ranging from ΔG = -9.4 to 0.9 kcal/mol and transition state barriers to exo adduct formation ranging from ΔG(‡) = 18.9 to 25.6 kcal/mol. Much less variation was observed for the reactivity of N-substituted maleimide derivatives and furan, with reaction and transition state free energies each falling within a range of 1.1 kcal/mol. Dynamic exchange experiments monitored by (1)H NMR spectroscopy support computational predictions. The results indicate the reactivity and reversibility of furan-maleimide cycloadditions can be tuned significantly through the addition of appropriate substituents and have implications in the use of furan and maleimide derivatives in the construction of thermally responsive organic materials.
2,4-Disubstituted furans are prepared by treating 2,3-dibromo-1-phenylsulfonyl-1-propene (DBP, 2) with 1,3-diketones under basic conditions. The furan-forming step involves a deacetylation, and the selectivity of this process depends upon the steric demand of the R group. The substituent in position 4 is elaborated by reaction of sulfonyl carbanions with alkyl halides, acyl halides, and aldehydes. Oxidative or reductive desulfonylation produces the 2,4-disubstituted furans in 60-92% yield. This strategy has been used to prepare rabdoketone A (12) and the naturally occurring nematotoxic furoic acid 13.
An efficient and experimentally rapid protocol for the synthesis of hitherto unreported 2,3-dicarboalkoxy-4-aroyl/heteroaroyl/alkanoyl thiophenes has been developed via 1-2 (C-S) and 3-4 (C-C) bond connections promoted by 4-dimethylaminopyridine (DMAP). Optimally, the reaction takes only 3-5 min when β-oxodithioester and dialkyl acetylenedicarboxylate are stirred in DCM at room temperature in the presence of DMAP. This method allows a clean and general synthesis of previously inaccessible and synthetically demanding thiophenes containing the ferrocenyl group. The speed, experimental ease, and high yields of this process are improvements over existing methods to access this important substructure.
Ring the changes: The first example of an intramolecular aza-Piancatelli rearrangement is reported. Dysprosium(III) trifluoromethanesulfonate efficiently catalyzes the synthesis of functionalized azaspirocycles in a trans-selective manner by a 4π electrocyclization of elaborated furylcarbinols (see scheme; Tf=trifluoromethanesulfonyl).
The reactions proceed under extremely mild conditions and tolerate various functional groups.
The catalytic activity of [CpRu(L)(2)(MeCN)]PF(6) (L = 2-diphenylphosphinopyridine with bulky groups at C-6) for anti-Markovnikov hydration of terminal alkynes to aldehydes is retained when one heterocyclic ligand L is replaced by L' = PPh(3). Equal amounts of CpRuCl(PPh(3))(2) (1) and phosphane L in acetone solution equilibrate to a mixture of 1, CpRuCl(L)(PPh(3)) (2), and CpRuCl(L)(2) (3), which acts as highly active in situ catalyst for preparative anti-Markovnikov hydration of alkynes in water-rich media (2 mol % [Ru], 60 °C, 3-18 h in 4:1 (v/v) acetone/water). Reactions were completed in <15 min at 160 °C.
Three peri-substituted trisulfide-2-oxides are prepared by treatment of 1,8-naphthalene dithiols with thionyl chloride and pyridine. The 1,2,3-trithiane-2-oxide ring adopts a sofa conformation in the solid state, with a pseudoaxial oxygen and evidence of ring strain (peri-interaction). Heating the trisulfide-2-oxides in the presence of a diene results in formal sulfur monoxide (SO) transfer to form unsaturated cyclic sulfoxides, along with a recyclable 1,8-naphthalene disulfide. The presence of o-methoxy or o-tert-butyl substituents on the naphthalene ring lowers the temperature and increases the rate at which SO transfer occurs. Trapping experiments and kinetic studies are consistent with the generation of triplet SO, followed by in situ trapping by diene. Transfer of SO also occurs upon irradiation at room temperature, but yields of sulfoxide are lower. Dehydration of the sulfoxides under Pummerer conditions gives thiophenes, including the naturally occurring thioperillene. Two dienes form thiophenes directly under the SO transfer conditions. The methodology is applied in a formal synthesis of the antiplatelet medication Plavix.
Highly substituted lactone- and ester-containing furans have been prepared by the efficient palladium-catalyzed intramolecular cyclocarbonylation or intermolecular carboalkoxylation, respectively, of hydroxyl-containing 3-iodofurans, readily prepared by the iodocyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of various diols.
The easily accessible haloalkynes can be converted to (Z)-2-halo-1-iodoalkenes in high yields with excellent regio- and stereoselectivity. The method shows good functional group compatibility. The resulting products could find broad applications.
Symmetrical 1,3-diyne compounds can be easily synthesized via a transition-metal-free homocoupling reaction of 1-haloalkynes without base and oxidant. The method shows excellent functional group compatibility and high yields.
The Fe(ClO(4))(3)-catalyzed intramolecular rearrangement/cyclization/oxidation reaction sequence for the synthesis of alpha-carbonyl furan derivatives from electron-deficient alkynes and 2-yn-1-ols is reported.
A new silver-catalyzed highly regio- and stereoselective difunctionalization reaction of simple terminal alkynes was reported in which the (Z)-beta-haloenol acetate derivatives were formed efficiently. The resulting products were versatile intermediates in organic synthesis.
A novel highly efficient regiodivergent Au-catalyzed cycloisomerization of allenyl and homopropargylic ketones into synthetically valuable 2- and 3-silylfurans has been designed with the aid of DFT calculations. This cascade transformation features 1,2-Si or 1,2-H migrations in a common Au-carbene intermediate. Both experimental and computational results clearly indicate that the 1,2-Si migration is kinetically favored over the 1,2-shifts of H, alkyl, and aryl groups in the beta-Si-substituted Au-carbenes. In addition, experimental results on the Au(I)-catalyzed cycloisomerization of homopropargylic ketones demonstrated that counterion and solvent effects could reverse the above migratory preference. The DFT calculations provided a rationale for this 1,2-migration regiodivergency. Thus, in the case of Ph(3)PAuSbF(6), DFT-simulated reaction proceeds through the initial propargyl-allenyl isomerization followed by the cyclization into the Au-carbene intermediate with the exclusive formation of 1,2-Si migration products and solvent effects cannot affect this regioselectivity. However, in the case of a TfO(-) counterion, reaction occurs via the initial 5-endo-dig cyclization to give a cyclic furyl-Au intermediate. In the case of nonpolar solvents, subsequent ipso-protiodeauration of the latter is kinetically more favorable than the generation of the common Au-carbene intermediate and leads to the formation of formal 1,2-H migration products. In contrast, when polar solvent is employed in this DFT-simulated reaction, beta-to-Au protonation of the furyl-Au species to give a Au-carbene intermediate competes with the ipso-protiodeauration. Subsequent dissociation of the triflate ligand in this carbene in polar media due to efficient solvation of charged intermediates facilitates formation of the 1,2-Si shift products. The above results of the DFT calculations were validated by the experimental data. The present study demonstrates that DFT calculations could efficiently support experimental results, providing guidance for rational design of new catalytic transformations.
A Au(I)-catalyzed hydroamination or hydration of 1,3-diynes to access 2,5-diamidopyrroles and 2,5-diamidofurans has been developed. This method can also be expanded to 2,5-disubstituted furans and 1,2,5-trisubstituted pyrroles including the formation of deuterated heterocycles and (18)O-labeled furans.
(Chemical Equation Presented) Side by side: Direct cis addition of bro-moalkynes 1 to various alkynes 2 was found to proceed in the presence of a PdII catalyst to give difunctionalized enyne products 3. The method is facile for the synthesis of bromo alkenynes. Further-more, an unusual mechanism is pro-posed.
A new approach to 3-nitro-2-substituted thiophenes has been developed. Exposure of commercially available 1,4-dithane-2,5-diol to nitroalkenes in the presence of 20% triethylamine results in a tandem Michael-intramolecular Henry reaction to form the corresponding tetrahydrothiophene. Subsequent microwave irradiation on acidic alumina in the presence of chloranil effects the solvent free dehydration and aromatization to form 3-nitro-2-substituted thiophenes cleanly and rapidly. A simple workup procedure removes the requirement for purification by chromatography in most cases.
A novel and reliable method for the direct construction of polysubstituted furans is reported. The key transformation involves Sn(II)- and Cu(I)-involved addition/oxidative cyclization of alkynoates and 1,3-dicarbonyl compounds in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone.
The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amino-3-alkyn-2-ols with a low catalyst loading (0.05-0.5 mol %) of (Ph(3)P)AuCl-AgNTf(2) or (Ph(3)P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles in excellent yields (85-98% yields). This method is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol % each of the Au and Ag catalysts.
Furans, pyrroles, and thiophenes are efficiently prepared by gold-catalyzed dehydrative cyclizations of readily available, heteroatom-substituted propargylic alcohols. The reactions are rapid, high-yielding, and procedurally simple, giving essentially pure aromatic heterocycles in minutes under open-flask conditions with catalyst loadings as low as 0.05 mol %.
A novel and efficient method for the regiospecific synthesis of polysubstituted furan aldehydes/ketones has been developed via a copper(I)-catalyzed rearrangement/dehydrogenation oxidation/carbene oxidation sequence of 1,5-enynes in situ formed from alkynols and diethyl but-2-ynedioate under atmospheric pressure. The domino reaction proceeds smoothly under mild conditions with commercially available catalysts and affords highly functionalized furans in moderate to good yields.
Step in time: 2,5-Disubstituted furans can be prepared from terminal alkynes in one pot using two successive catalytic reactions (see scheme; p-TSA = para-toluenesulfonic acid). First, a 1,3-dienyl alkyl ether is produced by the dimerization of a terminal alkyne and addition of an alcohol catalyzed by [RuCp*(NCMe)(3)][PF(6)]. Then, consecutive hydrolysis and cyclization catalyzed by CuCl(2) provides the 2,5-disubstituted furan.
A highly efficient [(NHC)Au(I)]-based (NHC = N-heterocyclic carbene) catalytic system for the hydration of an array of alkynes that operates under acid-free conditions and at very low catalyst loadings (typically 50-100 ppm and as low as 10 ppm) was developed. Terminal and internal alkynes possessing any combination of alkyl and aryl substituents (alkyl/H, aryl/H, alkyl/alkyl, alkyl/aryl, and aryl/aryl) were found suitable substrates in the present catalytic system.
It was demonstrated that alkynyl halides could serve as a source of Br+ and acetylide ions in the same transformation. This allowed for the efficient one-step preparation of alkynyl epoxides, important organic building blocks, from readily available starting materials.
A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subtypes, ER alpha or ER beta. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavior as ER ligands. An aldehyde enone conjugate addition approach and an enolate alkylation approach were developed to prepare the 1,4-dione systems that were precursors to the trisubstituted and tetrasubstituted systems, respectively. All of the diones were easily converted into the corresponding furans, but formation of the thiophenes and pyrroles from the more highly substituted 1,4-diones was problematical. Of the systems investigated, the tetrasubstituted furans proved to be most interesting. They were ER alpha binding- and potency-selective agents, with the triphenolic 3-alkyl-2,4,5-tris(4-hydroxyphenyl)furans (15a-d) displaying generally higher subtype binding selectivity than the bisphenolic analogues (15f-i). Binding selectivity for ER alpha was as high as 50-70-fold, and transcriptional activation studies showed that several members of this series were ER alpha selective agonists, with the best compound [3-ethyl-2,4,5-tris(4-hydroxyphenyl)furan, 15b] having full transcriptional activity on ER alpha while being inactive on ER beta. Comparative binding affinity analysis and molecular modeling were used to investigate the preferred binding mode adopted by the furan ligands, which appears to have the C(2) phenol mimicking the important role of the A-ring of estradiol. These ligands should be useful in studying the biological roles of both ER alpha and ER beta, and they might form the basis for the development of novel estrogen pharmaceuticals.
Several di- and triarylfuran derivatives were prepared in high yields from but-2-ene-1,4-diones/but-2-yne-1,4-diones using formic acid in the presence of a catalytic amount of palladium on carbon and in poly(ethylene glycol)-200 medium in a one-pot operation under microwave irradiation (1-5 min).
Heterocycles are especially important in chemical and pharmaceutical industries. It seems that industrial people have been using mostly the traditional and conventional transformations for the synthesis of heterocycles, perhaps because those reactions are reliable and robust and proceed generally at low cost. However, it is also true that some of those reactions are accompanied with waste byproducts. In this sense, transition-metal-catalyzed reactions minimize such waste and are in general environmentally friendly. Heterocycles having a complicated structure with many labile functional groups can be synthesized often from rather simple starting materials through sequential catalytic processes.
The cyclization of 2-(1-alkynyl)-2-alken-1-ones 1 proceeded very smoothly in the presence of alcohols 2 with a catalytic amount of Cu(I)Br in DMF at 80 degrees C, leading to the formation of highly substituted furans 3. The catalytic system reported herein is easy to handle, compared to the previously known system wherein the reaction between 1 and 2 needed to use moisture sensitive gold(III) chloride.
It is shown for the first time that N-sulfonyl amides can be efficiently prepared by an unconventional approach of the hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of copper catalyst and amine base under very mild conditions. The present route is quite general, and a wide range of alkynes and sulfonyl azides are readily coupled catalytically with water to furnish amides in high yields. A variety of labile functional groups are tolerated under the conditions, and the reaction is regioselective in that only terminal alkynes react while double or internal triple bonds are intact. The reaction can be readily scaled up and is also adaptable to a solid-phase procedure with high efficiency.
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[reaction: see text] Thionation of amides, 1,4-diketones, N-(2-oxoalkyl)amides, N,N'-acylhydrazines, and acyl-protected uridines with the use of a fluorous analogue of the Lawesson's reagent leads to thioamides, thiophenes, 1,3-thiazoles, 1,3,4-thiadiazoles, and acyl-protected 4-thiouridines. The isolation of the final products in high yields is achieved in most cases by a simple filtration (fluorous solid-phase extraction).
Computed enthalpies of formation for various Lewis acid complexes with representative unsaturated compounds (aldehydes, imines, alkynes, and alkenes) provide a means to evaluate the applicability of a particular catalyst in a catalytic reaction. As expected, main group Lewis acids such as BX3 show much stronger complexes with heteroatoms than with carbon-carbon multiple bonds (sigma-electrophilic Lewis acids). Gold(I) and copper(I) salts with non-nucleophilic anions increase the relative strength of coordination to the carbon-carbon multiple bonds (pi-electrophilic Lewis acids). As representative examples for the use of sigma-electrophilic Lewis acids in organic synthesis, the Lewis acid mediated allylation reactions of aldehydes and imines with allylic organometallic reagents which give the corresponding homoallyl alcohols and amines, respectively, are mentioned. The allylation method is applied for the synthesis of polycyclic ether marine natural products, such as hemibrevetoxin B, gambierol, and brevetoxin B. As representative examples for the use of pi-electrophilic Lewis acids in organic synthesis, the Zr-, Hf-, or Al-catalyzed trans-stereoselective hydro- and carbosilylation/stannylation of alkynes is mentioned. This method is extended to sigma-pi chelation controlled reduction and allylation of certain alkynylaldehydes. Gold- and copper-catalyzed benzannulation of ortho-alkynylaldehydes (and ketones) with alkynes (and alkenes) is discovered, which proceeds through the reverse electron demand Diels-Alder type [4+2] cycloaddition catalyzed by the pi-electrophilic Lewis acids. This reaction is applied for the short synthesis of (+)-ochromycinone. Palladium and platinum catalysts act as a sigma- and/or pi-electrophilic catalyst depending on substrates and reaction conditions.
An efficient methodology for the indirect anti-Markovnikov hydration of unsymmetrically substituted terminal and internal alkynes is based on TiCl4-catalyzed hydroamination reactions. Its application to ortho-alkynylhaloarenes, followed by a copper-catalyzed O-arylation, provides flexible access to substituted benzo[b]furans.
2-(methylthio)-1,4-diaryl-2-butene-1,4-dione (3) are prepared from readily available aryl methyl ketones in the presence of copper(II) oxide, iodine, and dimethyl sulfoxide. The success of the cross-coupling reaction of 4-chloroacetophenone with 2-acetylthiophene confirms a proposed self-sorting tandem reaction mechanism. Both Z- and E-isomers of compound 3 are readily converted into the corresponding 3-methylthio 2,5-diaryl furan 7 in good yield through a domino process involving the reduction of the double bond followed by the Paal-Knorr furan synthesis. Meanwhile, 4-bromo-3-methylthio 2,5-diaryl furan 10 is obtained either by the treatment of furan 7 with molecular bromine or by the treatment of diketone 3 with 30% hydrogen bromide in acetic acid solution in one pot. Removal of the methylthio group is accomplished by the treatment of 7 with Raney Ni in ethanol, which affords the diaryl-substituted furan 11 in excellent isolated yield. Selective reduction of the double bond of compound 3 leads to the formation of the saturated 1,4-diketone 13, which is easily converted to the corresponding 3-methylthio-2,5-diaryl-substituted pyrrole 14 and thiophene 15 via the Paal-Knorr cyclization reaction.
A review on the coinage metals as with Cu, Ag, and Au is given regarding its uses in the synthesis of heterocycles. In addition, a discussion with the mechanism of the C-C and C-X bond formation reactions will be provided so as to show the activation of substrates and possible reaction pathways. Then, a description on the use of coinage metals as a sole catalyst for the synthesis of heterocycles is also offered. However, only the reactions where a heterocyclic ring that is essentially generated will only be discussed. Specific topics to be discussed include: the cyclization of unsaturated C-C bonds with tethered nucleophiles; cycloaddition reactions; the cycloisomerization of enynes/diynes; the intramolecular friedel-crafts-type reactions; reactions of α-Diazocarbonyl compounds; aziridination of olefins; N/O-vinylation/arylation; and finally, the radical cyclization of haloalkenes and haloalkynes.