Aryl diynes

Scheme 3.2.1. Central core templates pyran derivatives 1, 2, type I, and aryl diynes 3-7, type II.

The most potent compound of the aryl diyne series (type II) was furan derivative 9 with a Ki value of 7.5 nM. An approximately tenfold decrease of potency was observed when the 1,3-substitution pattern of the head groups of 9 was replaced by 1,4-substitution to give 24 with a K, value of 80 nM. Substitution of the 2,5-furan ring in 9 by the 3,4-thiophene ring gave 25, with a twentyfold loss of tryptase inhibition activity (K, =150 nM). Replacement of the furanyl diyne template with the 1,3-substituted phenyl diyne template 29 was well tolerated (K, = 9 nM), whereas 1,4-substituted head groups resulted in a fourfold loss of activity (27, Ki = 32 nM) compared with 29. Combination of a 1,2-substituted phenyldiyne... 

We have created efficient syntheses of remarkably potent and selective bifunctional tryptase inhibitors, which are also competitive and reversible, containing pyran moieties and hetero and non-hetero aryl diynes as scaffolds. Several modifications at the core templates and the linker moieties are well tolerated without significant loss of inhibition activity. In contrast with previous results published recently [32], it was also apparent from the aryl diyne inhibitors that the distance between the two terminal amino groups can be considerably less than 30 bonds in highly potent target compounds (e.g. 9 and 29 with 26 bonds each). The in-vitro potencies of the compounds were between 1 im for 26 and 1.3 nM for 15 with high selectivity against other serine proteases (trypsin, thrombin, and factor Xa, respectively) in... 

The transition metal-catalyzed [2+2+2] cycloaddition has been applied to the atroposelective biaryl synthesis. The first example is the chiral cobalt(I) complex-catalyzed [2+2+2] cycloaddition of aryl-diynes with nitriles to produce axially chiral arylpyridines [19a]. Subsequently, the enantioselective synthesis of axially chiral biaryl phosphine oxides has also been achieved (Scheme 21.16) [19b]. 

The terminal diyne 320 is prepared by coupling of the zinc acetylide 318 with /rfln.s-l-iodo-2-chloroethylenc (319), followed by elimination of HCI with sodium amide[231]. Similarly, terminal di- and triynes are prepared by using cw-l,2-dichloroethylene[232]. The 1-alkenyl or l-aryl-2-(perefluoroalkyl) acetylene 321 is prepared by the reaction of a zinc acetylide with halides[233]. 

A subsidiary approach involves nuclear modification of the arylsilanes so obtained. The requisite organometallics can be prepared from aryl halides, or by deprotonation of a suitably activated (c.g. methoxy-substituted) arene. A more specialized route involves cycloaddition between alkynylsilanes and diynes. 

Aryl- and alkenylcarbene complexes are known to react with alkynes through a [3C+2S+1C0] cycloaddition reaction to produce benzannulated compounds. This reaction, known as the Dotz reaction , is widely reviewed in Chap. Chromium-Templated Benzannulation Reactions , p. 123 of this book. However, simple alkyl-substituted carbene complexes react with excess of an alkyne (or with diynes) to produce a different benzannulated product which incorporates in its structure two molecules of the alkyne, a carbon monoxide ligand and the carbene carbon [128]. As referred to before, this [2S+2SH-1C+1C0] cycloaddition reaction can be carried out with diyne derivatives, showing these reactions give better yields than the corresponding intermolecular version (Scheme 80). 

Haloalkynes (R—C=C—X) react with ArSnBu3 and Cul to give R—C= C—Ar. Acetylene reacts with two equivalents of iodobenzene, in the presence of a palladium catalyst and Cul, to give 1,2-diphenylethyne. 1-Trialkylsilyl alkynes react with 1-haloalkynes, in the presence of a CuCl catalyst, to give diynes and with aryl triflates to give 1-aryl alkynes. Alkynes couple with alkyl halides in the presence of Sml2/Sm. Alkynes react with hypervalent iodine compounds " and with reactive alkanes such as adamantane in the presence of AIBN. ... 

In the case of unsymmetrical alkynes, the carboxylation yielded a mixture of regioisomers. But the reaction in the carbon atom having an alkyl substituent in the alkyne unit seemed to be more preferred than the one with an aryl substituent (Scheme 24).30 The carboxylation of conjugated diynes by Ni/PTMDA under electrolytic conditions took place predominantly at an internal carbon atom of the diyne unit to give 74 as a major product (Scheme 25)38 When Ni(cod)2/DBU was used as a catalyst, however, the carboxylation occurred exclusively at the terminal carbon (Scheme 26).31... 

Table 22.7 Enantioselective catalytic reductive coupling of 1,3-diynes with alkyl, aryl and heteroaryl a-ketoaldehydes.

Hashmi et al. investigated a number of different transition metals for their ability to catalyze reactions of terminal allenyl ketones of type 96. Whereas with Cu(I) [57, 58] the cycloisomerization known from Rh(I) and Ag(I) was observed (in fact the first observation that copper is also active for cycloisomerizations of allenes), with different sources of Pd(II) the dimer 97 was observed (Scheme 15.25). Under optimized conditions, 97 was the major product. Numerous substituents are tolerated, among them even groups that are known to react also in palladium-catalyzed reactions. Examples of these groups are aryl halides (including iodides ), terminal alkynes, 1,6-diynes, 1,6-enynes and other allenes such as allenylcarbinols. This che-moselectivity might be explained by the mild reaction conditions. 

The Pd-catalyzed electro-cleavage of the C—O bond of allyl aryl ether proceeds smoothly in a DMF-Bu4NBp4-(Mg)-(Stainless Steel) system, giving depro-tected products in 73 99% yield [437]. The sp-sp intermolecular coupling reaction with the Pd water-soluble catalyst prepared in situ from Pd(II) acetate and sul-fonated triphenylphosphine in an MeCN-H2O system yields diynes in 45 65% yields [438]. Similarly, the sp -sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indol and furan... 

This is the intramolecular version of the previous reactions, and the precursors of the Z2E fragment are the same (e.g. disilanes)54. The reaction, however, has been applied only to 1,6-diynes bearing two aryl (or heteroaryl) groups in positions 1 and 7, in the presence of a Ni-catalyst. 

Platinum complexes (continued) with aryls, thallium adducts, 3, 399 with bis(alkynyl), NLO properties, 12, 125 with bisalkynyl copper complexes, 2, 182-186 with bis(3,5-dichloro-2,4,6-trifluorophenyl), 8, 483 and C-F bond activation, 1, 743 in C-H bond alkenylations, 10, 225 in C-H bond electrophilic activation studies, 1, 707 with chromium, 5, 312 with copper, 2, 168 cyclometallated, for OLEDs, 12, 145 in diyne carbometallations, 10, 351-352 in ene-yne metathesis, 11, 273 in enyne skeletal reorganization, 11, 289 heteronuclear Pt isocyanides, 8, 431 inside metallodendrimers, 12, 400 kinetic studies, 1, 531 on metallodendrimer surfaces, 12, 391 mononuclear Pt(II) isocyanides, 8, 428 mononuclear Pt(0) isocyanides, 8, 424 overview, 8, 405-444 d -cP oxidative addition, PHIP, 1, 436 polynuclear Pt isocyanides, 8, 431 polynuclear Pt(0) isocyanides, 8, 425 Pt(I) isocyanides, 8, 425 Pt(IV) isocyanides, 8, 430... 

The diyne 66 undergoes an intramolecular dehydro Diels-Alder reaction in toluene under reflux to afford naphtho[2,3-c]chromene derivatives in reasonable yield (Scheme 20). The reaction is presumed to proceed via a [4+2]-cycloaddition of the alkyne to the aryl alkyne group to form the cyclic allene intermediate 67, which then isomerizes to the aromatic product <2003SL1524>. 

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