Amines palladium-catalyzed cross-coupling

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

The reaction sequence starts by anchoring 2,6-dichloropurine onto the sohd-phase PAT, -amine at the more reactive C6 position with exclusive regioselectivity. A multitude of PAL-amine resins 59 can be prepared ahead by reductive amination of commercial (4-formyl-3,5-dimethoxyphe-noxy)-methylpolystyrene. The N9 position of the purine (60) may be modified by Mitsunobu alkylation. The final derivatization step involves a palladium-catalyzed cross-coupling reaction in position 2. This reaction... 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

Several groups have utilized benzophenone imine as an ammonia equivalent in the palladium-catalyzed cross coupling. For example, Mullen and co-workers prepared a new thermotropic dye via the BINAP/Pd-coupling of the corresponding bromide, Eq. (130) [110]. Similarly, Basu reported the amination of a mixture of bromopyrene derivatives [111]. 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

J.P. Buchwald, S.L. A highly active catalyst for palladium-catalyzed cross-coupling reactions room-temperature Suzuki couplings and amination of unactivated aryl chlorides. J. Am. Chem. Soc. 1998, 120, 9722-9723. 

The generally accepted catalytic cycle for the Buchwald-Hartwig amination mirrors that of other palladium catalyzed cross-coupling reactions.10 11 irThere is an oxidative addition (A to B), followed by an exchange on palladium (B to C), and finally a reductive elimination (C to D and A). The main difference involves the exchange step. In a Suzuki, or Stille, reaction this step proceeds through a discrete transmetallation event, whereas... 

The Buchwald-Hartwig reaction has been widely used in organic chemistry for the palladium-catalyzed cross-coupling of amines with aryl halides. In particular, it has been used in conjunction with benzothiophenes for arylamination of the thiophene. The final diarylamine product below demonstrated anti-fungal activity against dermatophytes, yeasts, and the Aspergillus species. ... 

Aryl bromides are the most reactive aryl halide, and aryl chlorides are the next most reactive for this catalytic process. For reasons not well understood, aryl iodides tend to be less reactive toward palladium-catalyzed cross-couplings that form C-N bonds. " Aryl triflates also couple with amines, - and even the less-reactive aryl tosylates have been shown to couple with amines. " ... 

One of the most versatile and widely employed methods for the construction of aryl C—N bonds is the palladium-catalyzed cross coupling of amines with aryl halides and related electrophiles [4]. These reactions are believed to occur as shown in Scheme 1.1, with the coupling initiated by oxidative addition of the aryl halide to a Pd° complex. The resulting intermediate 1 is converted to a palladium(aryl)(amido) complex 2 through reaction with the amine substrate in the presence of base. Finally,... 

In 1993, Corriu et al. studied the synthesis of nitrogen-containing heterocycles from (Z)-3-(tribulylstannyl)allylamine, which was prepared by the reaction of Af-(trimethylsilyl)allylamine with 2 mol of ra-butyllithium followed by treatment with chlorotributyltin and subsequent hydrolysis. The unprotected (Z)-3-(tributylstannyl)allylamine underwent a palladium-catalyzed cross-coupling reaction with aromatic bromides affording a stereospecific preparation of substituted allylic amines with Z configuration of the carbon-carbon double bond. The reactions of o/t/zo-functionalized aryl bromides offer a one-step preparation of 7-membered nitrogen heterocycles in high yields (Scheme 4.18). 

Palladium-catalyzed cross coupling of resin bound iodopyridine with a boronic acid (Suzuki reaction) (12) or with an alkenyl-, alkynyl-, or arylstannane (Stille reaction) (13) was effected by treatment of resin 5 with 4 equivalents of the boronic acid or stannane, 8 equivalents of K2CO3 (Suzuki reaction only), and catalytic Pd(PPh3)4 in DMF at 50 C for 20 hours. (14) Best results were achieved by running each reaction twice, with an intermediate wash of the resin, in order to drive the reaction to conq>letion. The corresponding Pd-catalyzed amination (Buchwald reaction) (15) worked well in protocol development but the reaction failed with the 3 amines attenpted during actual library preparation. 

The palladium-catalyzed cross-coupling of vinyl halides with secondary amines leads to the formation of tertiary enamines (Scheme 3.114) [120]. The catalyst system was comprised of a soluble source of Pd(0) along with a bisphosphine hgand as well as a base to consume the acid generated in the reaction. Several secondary amines were successfully used along with a host of vinyl bromides to afford the enamines in moderate to good yields. Even the use of tetrasubstituted alkenes such as 2-bromo-3-methyl-2-butene participated in the N-vinylation reaction. 

Need a reliable method for the synthesis of an enamine Need a method for the preparation of enamides from vinyl halides Can vinylboronates be converted into enamines The palladium-catalyzed cross-coupling between vinyl bromides and secondary amines would be a reasonable approach [120] An assortment of copper-catalyzed reactions are known to promote this reaction [121, 123] Using copper compounds to promote the coupling of nitrogen nucleophiles with vinylboronates would be a good starting point [51, 125]... 

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