Synthesis of 3-iodoindoles by electrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines

[reaction: see text] A wide variety of N-alkyl-3-iodoindoles are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization by I(2)(). Alkyl-, aryl-, and vinylic-substituted alkynes all undergo iodocyclization in excellent yields.     

MeOTf-catalyzed formal [4 + 2] annulations of styrene oxides with alkynes leading to polysubstituted naphthalenes through sequential electrophilic cyclization/ring expansion

MeOTf-catalyzed formal [4 + 2] annulation of styrene oxides with alkynes to afford polysubstituted naphthalenes has been realized, which undergoes sequential electrophilic cyclization/ring expansion. A range of substrates were tolerated in the formation of naphthalene derivatives with high regioselectivity in satisfactory yields. The reaction could also be carried out on gram scale.     

Synthesis of naphthalenes and 2-naphthols by the electrophilic cyclization of alkynes

[reactions: see text] A wide variety of substituted naphthalenes are readily prepared regioselectively under mild reaction conditions by the 6-endo-dig electrophilic cyclization of appropriate arene-containing propargylic alcohols by ICl, I2, Br2, NBS, and PhSeBr. 3-Iodo-2-naphthols have also been prepared in excellent yields by the cyclization of analogous 1-aryl-3-alkyn-2-ones. This methodology readily accommodates various functional groups and has been successfully extended to the synthesis of substituted carbazoles and dibenzothiophenes.     

Synthesis of regioselectively functionalized benzo[b]thiophenes by combined ortho-lithiation-halocyclization strategies

An efficient synthesis of 3-halo-7-oxygen-functionalized benzo[b]thiophenes bearing different substituents at C-2 has been developed from N,N-diethyl O-3-halophenylcarbamates. The key steps are an ortho-lithiation reaction, which gives rise to 3-halo-2-sulfanylphenol derivatives, and a electrophilic cyclization. The subsequent functionalization of the prepared halobenzothiophenes allows the access of a wide variety of 2,3,7-regioselectively functionalized benzo[b]thiophenes in good overall yields.     

Synthesis of 3-iodoindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization

[reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields.     

Base-free NIS promoted electrophilic cyclization of alkynes: an efficient synthesis of iodo substituted pyrano[4,3-b]quinolines

A simple and mild procedure for the synthesis of iodo substituted 1H-pyrano[4,3-b]quinolines has been achieved using NIS reagent in the absence of base from 2-alkynylquinoline-3-carboxaldehydes via intramolecular electrophilic cyclization onto alkynes in good to excellent yields in a short duration of time. The reactions proceeded smoothly in a normal solvent in aerobic atmosphere at room temperature. The presence of substituent at either quinoline or alkyne moieties did not show effect on reaction rate of cyclization. The palladium-catalyzed transformations of iodo group to C-C bond are also discussed.     

Electrophilic cyclization of 3-alkynyl-4-chalcogen-2-H-chromenes: synthesis of 3-halo-chalcogenophene[3,2-c]chromene derivatives

An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electrophilic cyclization reaction of 3-alkynyl-4-chalcogen-2H-chromene using I₂, PhSeBr, and BuTeBr₃ as electrophilic sources. The cyclization reaction proceeded cleanly under mild reaction conditions, and 3-halochalcogen-chromenes were formed in good yields. In addition, the obtained 3-iodo-chalcogenophene-chromenes were readily transformed to more complex products using a metal-halogen exchange reaction with n-BuLi and trapping the lithium-intermediate formed with aldehyde, furnishing the desired secondary alcohol in good yield. Conversely, using the palladium catalyzed cross-coupling reactions with terminal alkynes and boronic acid, we were able to obtain the Sonogashira and Suzuki type products in good yields.     

A new approach to desketoraloxifene analogs from oxygen-bearing 3-iodobenzo[b]thiophenes prepared via iodocyclization

A formal total synthesis of the benzothiophene selective estrogen receptor modulator (SERM) desketoraloxifene and analogs has been accomplished from alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I₂. This approach affords oxygen-bearing 3-iodobenzo[b]thiophenes in excellent yields, which are easily further elaborated using a two-step approach involving Suzuki-Miyaura and Mitsunobu coupling reactions.     

Mechanistic details of metal-free cyclization reaction of organophosphorus oxide with alkynes mediated by 2,6-lutidine and Tf2O

Theoretical investigations have elucidated the mechanism of metal-free electrophilic phosphinative cyclization of alkynes reaction reported by Miura and coworkers. Two competitive mechanisms I and II were explored without or with 2,6-lutidine. Both of I and II involve transformation of P(V) to P(III), electrophilic addition, ring opening and cyclization/cyclization, hydrogen-transfer, and oxidation. The rate-determining step of mechanism I and competitive less-step II is electrophilic [2 + 1] cycloaddition and electrophilic addition via single C P bond formation with activation barrier of 13.5 and 10.6 kcal/mol, respectively. Our calculation results suggested that the cumulative effect of the isomer of 2,6-lutidine and Tf₂O as well as TfO⁻ affects the title reaction to some extent, and simultaneously activates key reaction sites and reverses the polarities of them via the formation of abundant noncovalent interactions to decrease activation barriers of TSs. In addition, the effects of two series substituents on reactivity of phosphine oxide were investigated. Therefore, our study will serve as useful guidance for more efficient metal-free synthesis of organophosphorus compounds mediated by pyridine reagents.     

Regioselective synthesis of substituted pyrroles: efficient palladium-catalyzed cyclization of internal alkynes and 2-amino-3-iodoacrylate derivatives

The first efficient and regioselective palladium-catalyzed cyclization of internal alkynes and 2-amino-3-iodoacrylates to give moderate to excellent yields of highly functionalized pyrroles has been developed. This approach is applicable to a range of alkynes and affords the deacylated pyrrole under reaction conditions for most substrates. [reaction: see text]     

Palladium‐Catalyzed Carbonylative [3+2+1] Annulation of N‐Aryl‐Pyridine‐2‐Amines with Internal Alkynes by CH Activation: Facile Synthesis of 2‐Quinolinones

We describe here a novel procedure for the synthesis of highly substituted 2‐quinolinones. By this newly developed approach, 2‐quinolinone derivatives were prepared in moderate to good yields by carbonylative cyclization of N‐aryl‐pyridine‐2‐amines and internal alkynes by C?H activation. Remarkably, [Mo(CO)₆] was applied as a solid CO source and the reaction proceeded in an atom economic manner.     

Totally chemo- and regioselective cobalt(I)-mediated formal intermolecular cyclotrimerization of alkynes

[reaction: see text] The first examples of totally chemo- and regioselective formal intermolecular cobalt(I)-catalyzed [2 + 2 + 2] cyclizations of three different alkynes are reported. The use of disposable silylated tethers in the sequence cyclization followed by the displacement of the silicon group led to polysubstituted arenes as a unique cycloadduct in high yields.     

Synthesis of 2,3-disubstituted benzo[b]thiophenes via palladium-catalyzed coupling and electrophilic cyclization of terminal acetylenes

2,3-Disubstituted benzo[b]thiophenes have been prepared in excellent yields via coupling of terminal acetylenes with commercially available o-iodothioanisole in the presence of a palladium catalyst and subsequent electrophilic cyclization of the resulting o-(1-alkynyl)thioanisole derivatives. I(2), Br(2), NBS, p-O(2)NC(6)H(4)SCl, and PhSeCl have been utilized as electrophiles. Aryl-, vinyl-, and alkyl-substituted terminal acetylenes undergo this coupling and cyclization to produce excellent yields of benzo[b]thiophenes. (Trimethylsilyl)acetylene also undergoes this coupling/cyclization process with I(2), NBS, and the sulfur and selenium electrophiles to afford the corresponding 2-(trimethylsilyl)benzo[b]thiophenes. However, cyclization of the silyl-containing thioanisole using Br(2) affords 2,3-dibromobenzo[b]thiophene.     

Electrophilic cyclization of (Z)-selenoenynes: synthesis and reactivity of 3-iodoselenophenes

We present here our results of the electrophilic cyclization reaction of (Z)-selenoenynes with different electrophiles such as I(2), ICl, PhSeBr, and PhSeCl. The cyclization reaction proceeded cleanly under mild reaction conditions, and 3-substituted selenophenes were formed in moderate to excellent yields. We observed that the nature of solvent and structure of (Z)-selenoenyne were important to the cyclization reaction. In addition, the obtained 3-iodoselenophenes were readily transformed to more complex products using a metal-halogen exchange reaction with n-BuLi and trapping the intermediate formed with aldehydes, furnishing the desired secondary alcohols in good yields. Conversely, using the palladium or copper catalyzed cross-coupling reactions with terminal alkynes or alkyl alcohols, we were able to convert 3-iodoselenophene to Sonogashira or Ullmann type products, respectively, in good yields.     

Electrophilic cyclization of o-acetoxy- and o-benzyloxyalkynylpyridines: an easy entry into 2,3-disubstituted furopyridines

[reaction: see text] 2,3-Disubstituted furo[3,2-b]pyridines, 2,3-disubstituted furo[2,3-b]pyridines, and 2,3-disubstituted furo[2,3-c]pyridines are readily prepared under mild conditions via the palladium-catalyzed cross-coupling of 1-alkynes with o-iodoacetoxy- or o-iodobenzyloxypyridines, followed by electrophilic cyclization by I(2) or by PdCl(2) under a balloon of carbon monoxide.     

A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina

A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina has been developed. β-Aminoalkynes are generated in good yields. The reaction can be extended to include a cyclization, which affords 2-substituted benzo[b]furans. The chemoselectivity of the reaction indicates that terminal alkynes are much more reactive than enolizable ketones under the reaction conditions.     

Rh(I)-catalyzed coupling cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes: one-pot synthesis of fluorinated quinolines

[reaction: see text]. Rh(I) complexes were found to catalyze the coupling cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes to afford 2-trifluoromethylated quinolines in good yields. Various alkynes were applied to this cyclization coupling with regioselectivity.     

Cobalt‐Catalyzed Cyclization of N‐Methoxy Benzamides with Alkynes using an Internal Oxidant through C−H/N−O Bond Activation

The cyclization of substituted N‐methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group‐substituted benzamides, as well as ester‐ and alcohol‐substituted alkynes. The cobalt complex [Co^IIICp*(OR)₂] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1‐chloro and 1‐bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl₃ or PBr₃.     

Parallel synthesis of a multi-substituted benzo[b]furan library

The solution-phase parallel synthesis of a 121-member library of multi-substituted benzo[ b]furans is described. 2,3,5-Trisubstituted benzo[ b]furans have been prepared by the palladium-catalyzed substitution of 3-iodobenzofurans by Suzuki-Miyaura, carbonylative Suzuki, Sonogashira, Heck, and carboalkoxylation chemistry. The 3-iodobenzofurans are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with ICl.     

Synthesis of Biphenylenes and Their Higher Homologues by Cyclization of Aryne Derivatives

This investigation demonstrates that a series of biphenylenes can be easily prepared from their corresponding halobiphenyls by the cyclization of in situ generated 2′,3′‐didehydro‐2‐lithiobiphenyls at low temperature. Two remarkable advantages of this synthetic method include 1) the lack of any need for transition‐metal catalysts or reagents in the cyclization, and 2) the ability to obtain C1‐functionalized products by treating the reaction intermediate 1‐lithiobiphenylene with an electrophilic reagent. π‐Extended derivatives, such as benzobiphenylenes, dibenzobiphenylene, linear/angular [3]phenylenes, and biphenyleno[2,3‐b ]biphenylenes, were synthesized similarly using suitable biaryls or teraryls.