Sonogashira reaction indoles

The Sonogashira reaction frequently serves as a platform for the construction of indoles, and we will explore this application in Chapter 3, but it also is a valuable method for the preparation of alkynyl pyrroles. 

The palladium-catalyzed Sonogashira reaction between l-(2-propynyl)-l//-indole 1460 and l-iodo-2-(2-phenylethy-nyl)benzene 1461 was successful in producing 17/-indole 1462 in excellent yield (Scheme 279) <2005JOC6647>. Treatment of indole 1462 with a strong base produced 12-phenyl-7//-indeno[l, 2 4,5]pyrido[l,2- ]indole 1463 in... 

Sonogashira reactions allow easy access to arenes with an alkynyl snbstitnent ortho to nitrogen, for example from ortho-iodo- and -bromo-nitrobenzenes, or ortho-iodo- and -bromo-A -acyl- (or N-sulfonyl)-arylamines, or even by conpUng acetylenes with 2-iodoaniUne itself.Conversion of orf/20-alkynyl-nitrobenzenes and -arylamines into indoles can be achieved in several ways, for example alkoxides add to the triple bond and form nitro-acetals, nitro-gronp rednction then acetal hydrolysis bringing ring closure. ... 

This process is commonly known as the Sonogashira reaction and has proven extraordinarily useful for the synthesis of a wide variety of aryl alkynes or enynes. When neighboring functionality exists, Pd and Cu salts are well known to effect cyclization to the corresponding hetero- or carbocycle. Thus, the reaction of terminal alkynes and aryl or vinylic halides bearing neighboring functionality often leads directly to heterocycles or carbocycles, providing a particularly useful synthesis of benzofurans and indoles. 

A new, water soluble palladium catalyst was used in the Sonogashira reaction (Pd(OAc)2 triphenylphosphine-trisulfonate sodium salt) [131], and several groups adapted the Sonogashira coupling and subsequent cyclization to the solid-phase synthesis of indoles. Bedeschi and coworkers used this method to prepare a series of 2-substituted-5-indolecarboxylic acids [132], CoUini and Ellingboe extended the technique to l,2,3-trisubstituted-6-indolecarboxylic acids [133]. Zhang and... 

In the first of three widely used indole syntheses involving Pd-catalyzed alkyne conpling with o-haloanilines, this chapter covers the Yamanaka-Sakamoto-Sonogashira reaction. This two-step process features an initial Sonogashira reaction with a terminal alkyne [1] followed by a facile indohzation, which was first uncovered by Yamanaka, Sakamoto, and coworkers (Scheme 1, equations 1 ) [2-9], The intermediate C-3 palladium species can undergo carbonylation with CO to give indole-3-carboxylates (equation 4) [7,9]. For reviews, see Sakamoto, Kondo, and Yamanaka [10] and Heravi and Sadjadi [11]. 

The Larock indole synthesis is the internal alkyne version of the Yamanaka-Sakamoto-Sonogashira indole synthesis presented in Chapter 75. Also known as the Larock heter-oannulation, it affords 2,3-disubstituted indoles, in contrast to 2-snbstituted indoles from the Sonogashira reaction (Scheme 1, eqnations 1-3) [1-12], Like the Sonogashira, the Larock reaction has been of enormous utility in indole synthesis. With unsymmetrical alkynes, the regiochemistry is such that the more bulky group (e.g., t-butyl relative to... 

In 2006, Lu and co-workers developed a practical and economical one-pot process for the synthesis of 2,3-disubstituted indoles. " This palladium-catalyzed domino indolization procedure allows rapid access to a variety of 2,3-disubstituted indoles regiospecifically under fairly mild conditions (Scheme 2.91). The reaction consisted of a palladium-catalyzed Sonogashira reaction and organopalladium-mediated amidopalladation. 

The metal-catalysed cyclization of o-alkynyl anilines to indoles and o-alkynylphenols to benzofurans has been studied (Scheme 6.19). It is a useful method because the starting materials are readily available by Sonogashira reactions (Section 2.8). Cyclization followed by protonolysis of the t -intermediate 6.51 gives the heterocycle. As protonolysis regenerates a palladium(II) species, no added oxidant is required. In some cases, protonolysis is slow, and the reaction must be carried out in acidic conditions. ... 

In terms of synthetic planning, it must be noted that a transition-metal catalyst is not required for this cyclization. o-Alkynylamines can be cyclized to indoles under basic conditions, especially if the nitrogen atom has an electron-withdrawing substituent to lower the pKa. Just such a base-catalysed cyclization was employed in a synthesis of goniomitine (Scheme 6.20), after a Sonogashira reaction was employed to synthesize the substrate. Similarly, benzofurans are easily prepared by base catalysed cyclization as in a synthesis of Ailanthoidol (Scheme 2.115). The transition-metal catalysed cyclization is of particular importance when... 

A.J. McCarroU, T.D. Bradshaw, A.D. WestweU, C.S. Matthews, M.F.G. Stevens, Quinols as novel therapeutic agents. 7.Synthesis of antitumor 4-[l-(arylsulfonyl-lH-indol-2-yl)]-4-hydroxycydohexa-2,5-dien-l-onesby Sonogashira reactions,]. Med. Chem. 50 (2007) 1707-1710. 

Kaspar and Ackermann also reported that the process could be performed as a three-component system, featuring in situ generation of the key o-alkynylhaloarenes via the incorporation of a tandem Sonogashira reaction [35]. Related chemistries have been reported for the synthesis of 2-aminoindoles from ynamide-based substrates [36], A-aminoindoles from hydrazine-based nucleophiles [37], and N-unsubstituted indoles via the use of ammonia as the coupling partner [38,39],... 

In domino Sonogashira processes, the second step is usually an amination or a hy-droxylation to give y-lactones, furans, or indoles however, there is also the possibility of performing a Heck reaction as a second step. 

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

The indole compound was described by Flynn et al. [73] and is prepared in a similar manner as the thiophene 103 and furan 108. One method involved a similar synthesis as described in Scheme 25, using the relevant starting material. However, an alternative synthesis involved a one-pot, room-temperature synthesis, Scheme 27. The o-iodotrifluoroacetanilide 110 was coupled to the alkyne 111 under Sonogashira conditions in MeCN. K2CO3 and the aryliodo compound 107 was added and the reaction stirred to produce the protected product 112 with a 77% yield. Deprotection to the corresponding phenol 113 was performed using AICI3. 

The cyclization of oalkynylanilines to indoles, which usually does not require palladium, has been described in Section 3.4. In view of their extensive research with this transformation, this reaction is often referred to as the Sakamoto-Yamanaka indole synthesis [211, 214-216, 220, 230, 231]. Although the cyclization of o-alkynylanilines, which are often obtained by the Sonogashira coupling (Section 3.4), is usually accomplished with base, Kundu used Pd(OAc)2 to effect the conversion of 348 to 349 [308]. 

In conclusion, the fantastically diverse chemistry of indole has been significantly enriched by palladium-catalyzed reactions. The accessibility of all of the possible halogenated indoles and several indolyl triflates has resulted in a wealth of synthetic applications as witnessed by the length of this chapter. In addition to the standard Pd-catalyzed reactions such as Negishi, Suzuki, Heck, Stille and Sonogashira, which have had great success in indole chemistry, oxidative coupling and cyclization are powerful routes to a variety of carbazoles, carbolines, indolocarbazoles, and other fused indoles. 

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