Aryl-substituted propargyl alcohol

A rhenium catalyst is quite valuable for the direct allylation of cr-aryl-substituted propargyl alcohols with 10 (Equation (58)).220 Benzyl alcohols are efficiently allylated with allylchlorodimethylsilane under catalysis by InCl3.221... 

Coordination of the C-C triple bond of an aryl-substituted propargyl alcohol with an electron-dehcient Ru(II) center caused 1,2-migration of the aryl group to the sp carbon center (Scheme 8.38) [60]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

Aryl furans were prepared in moderate yields by Rh-catalyzed regioselective hydroformylation of substituted propargylic alcohols followed by cyclization, and an example is shown below <06ASC545>. 

Fig. 10.24. Asymmetric carbonyl group reduction with Alpine-Borane (preparation Figure 3.27 for the "parachute-like" notation of the 9-BBN part of this reagent see Figure 3.21). The hydrogen atom that is in the cis-position to the boron atom (which applies to both ft- and /T-H) and that after removal of the reducing agent leaves behind a tri- instead of a disubstituted C=C double bond (which applies to ft-, but not / -H) is transferred as a hydride equivalent. In regard to the reduction product depicted in the top row, the designation S of the configuration relates to the aryl-substituted and R to the Rtert-substituted propargylic alcohol.

Fig. 10.25. Asymmetric carbonyl group reduction with diisopinocampheylchloroborane [Brown s chloroborane, (IPC)2BCL]. Concerning the reduction product depicted in the top row, the designation 5 of the configuration relates to the aryl-substituted and R to the Rttrt-substituted propargylic alcohol.

In comparison to conductive heating in an oil bath under comparable conditions, dielectric heating furnished higher yields in the model reaction at shorter reaction times. Whereas electron deficient (hetero)aryl halides are rapidly coupled and isomerized with triethylamine as a base, for electro neutral and electron rich aryl halides DBU has to be applied to achieve comparable reaction times and yields. Most remarkably the alkyl substituted propargyl alcohol 15 with R = "Pr can be successfully transformed giving rise to the enone 16f in moderate isolated yield. 

The carbolithiation- N C aryl migration sequence was performed in TH F, with and without the addition of DMPU, followed by the carbamate cleavage leading to highly substituted propargyl alcohols 47. When the enyne 48 was treated with n-BuLi in toluene without the addition of DMPU, allene products were observed after the protonation step (Scheme 10.16). The addition of (—)-sparteine and carrying out the reaction at —78 °C led to the product 49 as a racemic mixture or at best with moderate enantiomeric excess. 

The Cu(I)-catalyzed cyclization for the formation of ethyl ( )-tetrahydro-4-methylene-2-phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(a-substituted N-tosyIaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4-hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>. 

The propargyl alcohols react with trivalent phosphorus halides to give allenic phosphorus esters as described in Scheme 3 and Table VI. In the case of aryl-substituted alkynols or highly hindered t-propargyl alcohols which contain no free acetylenic —H, thionyl halides or phosphorus trihalides yield bromo- or chloroallenes [74d], Thionyl chloride also reacts in a similar fashion with a wide variety of unhindered secondary alcohols (structure XV) to give a mixture of the chloroallene and chloroalkyne [74a-d]. 

MUller reports a four component, one-pot synthesis of pyridines <02TL6907>. For example, aryl halide 15 and propargylic alcohol 16 were combined in the presence of copper and palladium to afford enone 17. The addition of cyclic enamine 18 led to Michael addition and the subsequent cyclocondensation was achieved by adding ammonium chloride and acetic acid (19—>20). Other multicomponent approaches to substituted pyridines have been reports by Litvinov <02RCBIE362>, Elkholy <02SC3493> and Veronese <02T9709>. 

The addition of vinyl and aryl Grignard reagents to propargyl alcohols followed by reaction with a nitrile provides access to furans and butenolides in a one-pot procedure. These reactions are believed to involve a magnesium-chelate intermediate. Highly substituted furans can be prepared with control over the substitution pattern by the judicious choice of substrates and reagents (Scheme 26) <2000TL17>. 

As a consequence of the mild reaction conditions in the sequence to 3-halo furans 55 the palladium catalyst should be still intact to trigger another Pd-catalyzed coupling in the sense of a sequentially Pd-catalyzed process [31]. As a consequence, a sequential Sonogashira-deprotection-addition-cyclocondensation-Suzuki reaction, where the same catalyst system is applied in two consecutive significantly different cross-coupling reactions in the same reaction vessel should be feasible. Therefore, upon consecutive reactions of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, Nal and PTSA, and finally, addition of 1.05 equiv of boronic acids 60 and sodium carbonate, the substituted 3-aryl furans 61 can be obtained in decent yields (Scheme 35). 

Following the same rationale, the Cl sequence can also be applied to the synthesis of seven-membered heteroazepines. Thus, upon CIR of electron-deficient (hetero) aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of orf/io-phenylene diamines 50 or ortho-zmmo thiophenols 52, 2,4-di(hetero)aryl substituted 2,3-dihydro benzo[b][l,4]diazepines 90 or di(hetero)aryl substituted 2,3-dihydro benzo[h][l,4]thiazepines 91 can be obtained in a consecutive three-component reaction in moderate to good yields (Scheme 49) [242, 243]. 

The novel heliannane-type sesquiterpenoid (-)-heliannuol E was synthesized in the laboratory of K. Shishido. Interest in the total synthesis of this natural product was not only spurred by its irregular terpenoid structure and significant biological activity but the need to establish the absolute stereochemistry at the C2 and C4 stereocenters. The Sonogashira reaction was utilized to prepare the 3-arylpropargyl alcohol by coupling of a heavily substituted aryl iodide with an unprotected propargyl alcohol in quantitative yield. 

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

The Pd-catalyzed coupling of 2-halo-, and 2,6-dihaloquinoxalines (217) with propargyl alcohol was reported [110]. This process worked well for the simple alkyl-, and a range of aryl-alkynes, resulting in the corresponding 2-substituted quinoxalines. 

---