Phenylpyrrole

Mucic acid (1260 g. or 6.0 moles) is added to 1210 g. (13.0 moles) of aniline which has previously been heated to 150°. The mixture is stirred and heated to reflux for 3 4 hours, after which it is distilled. The entire distillate is extracted with ether. The ethereal solution is washed with 10-20% aqueous hydrochloric acid, dilute sodium carbonate solution, and water, and then dried over calcium chloride. Distillation gives 360-430 g. (42-50%) of 1-phenylpyrrole boiling at 110-116°/9 mm. or 127-135°/30 mm. and melting at 55-60°. Two recrystallizations from a mixture of 3 parts ethanol and 1 part water gives a product melting at 60-61°. 

1-Benzylpyrrole (51 g.) is obtained from 214 g. (1.02 moles) of mucic acid and 218 g. (2.04 moles) of benzylamine by a similar procedure except that 300 ml. of glycerol is placed in the reaction mixture and the distillate (600 ml.) is acidified with hydrochloric acid before 

A mixture of 15 g. (0.1 mole) of isatin [Org. Syntheses Coll. Vol. 1, 327 (1941)], 22.5 g. (0.19 mole) of acetophenone, 120 ml. of absolute ethanol, and 60 ml. of 33% aqueous potassium hydroxide solution is refluxed for 6 hours. The ethanol and most of the excess acetophenone are then removed by heating in an evaporating dish. The residue is dissolved in water, the resulting solution is extracted with ether, filtered, and acidified slowly with dilute hydrochloric acid with cooling. After 12 hours standing, the precipitated solid is dissolved in sodium carbonate solution and diluted to 750 ml., 50 g. of sodium chloride is added, and the solution is allowed to stand for 36 hours. The precipitated material is removed by filtration, and the acid is precipitated by careful acidification of the filtrate with dilute hydrochloric acid. An excess of hydrochloric acid should be avoided. The acid is recrystallized twice from absolute ethanol with activated carbon treatment it consists of 16.5 g. (65%) of yellow needles, m.p. 208-209°. 

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Phenylpyridazin-4-oxime is transformed into 5-methyl-2-phenylpyrrole when treated with zinc in acetic acid. 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

Dihydro-2/7- 74 and -4//-l,2-oxazines and thiazines 75 are interrelated by prototropy, being enamines and imines, respectively. In the case of oxazines, the imine form 75 is favored, and there are several well established examples of this system, including the parent heterocycle 75 (X = O) [84MI2]. No tautomeric equilibrium between the 2H and 4H forms has been observed under normal conditions in solution or in the solid state. However, the formation of intermediate 2H isomers 77 was proposed both for the conversion of 3-phenyl-5,6-dihydro-4//-l,2-oxazine 76 (R = Ph, r = R = H) into 2-phenylpyrrole(89TL3471) under strong basic conditions and for thermal decomposition of cyclopentene-fused 1,2-oxazine 76... 

Silylated acetylenic alcohols such as 1500 cyclize on treatment with HMDS-Li to give, via 1501 and 1502, 2-phenylpyrrole 1503 [46] (Scheme 9.27 compare also the formation of 2-pyridyl-2-pyrrole 543 in Chapter 5). 

Two unique type Had syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with -BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 

The N-pyrrolylzinc chloride 53 undergoes Pd-catalyzed coupling with perfluoroalkyl iodides to afford the 2-substituted pyrroles 54 in good yield [52], Smaller amounts (15-20%) of 2-perfluoroalkanoyl pyrroles, which presumably arise by hydrolysis of the benzylic difluoromethylene group, are also formed. This reaction, which is performed in one pot, also affords 2-phenylpyrrole (75%) and 3-phenylpyrrole (5%) with iodobenzene. Some biphenyl (15%) is also formed. 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

Reaction of cyclohexanone oxime (59) with phenylacetylene in the presence of KOH/ DMSO afforded Z-[l-(2-phenylvinyl)]-3-phenyl-4,5,6,7-tetrahydroindole (60) (equation 25) °. Transformation of 0-vinylacetophenone oxime (61) in the system f-BuOK/THF has been studied. The reaction at 60-65 °C afforded 2,4-diphenylpyrrole (62) and oligomeric products instead of the desired 2-phenylpyrrole (equation 26) . ... 

The ring closure of aminoalkynes bearing a leaving group in the appropriate position might lead to the formation of pyrroles in an addition-elimination sequence. 2-Phcnylcthynyl-1 -amino-sec-butanol. for example, gave 4-ethyl-2-phenylpyrrole on treatment with palladium dichloride in acetonitrile in excellent yield (3.46.),57... 

Another type of ring contractions occurs when 2-phenylpyrimidines (117) are reduced in an aqueous alcoholic-acetate buffer. Whereas pyrimidines generally are reduced in a one-electron reduction to a dimer,1 2-phenylpyrimidines are reduced to 2-phenylpyrroles (118). The following scheme has been suggested173 [Eq. (86)]. 

In Section III,B it was pointed out that 2-phenylpyrimidines did not follow the general reduction path of pyrimidines but were reduced to 2-phenylpyrroles in a four-electron ring-contraction reaction.174 [Eq. (86)]. 

Furans react readily with benzynes, e.g. 2-acetoxyfuran yields (185). A-Methylpyrrole also reacts normally across the 2,5-positions, but pyrrole itself yields 2-phenylpyrrole,... 

Molecular orbital calculations have also been made for carbonyl derivatives of pyrrole 97,98 and for 2-phenylpyrrole."... 

Analogous conclusions have been drawn in studying the reaction of acetophenone oxime with acetylene (Scheme 2) leading to 2-phenylpyrrole (3) and 2-phenyl-1-vinylpyrrole (4) (78ZOR1733). 

As seen from Table II, the decrease in the DMSO content of mixtures with dioxane drastically reduces the yield of 2-phenyl-l-vinylpyrrole. Varying the DMSO concentration makes it possible to obtain selectively either 2-phenylpyrrole or its W-vinyl derivative. 

Effect of DMSO/Dioxane Mixture on Yield of 2-Phenylpyrrole (3) and 2-Phenyl-I-vinylpyrrole (4) ... 

Fig. 2. Effect of salt additives (0.2 mol per 1 mol of KOH) on the yield of 2-phenylpyrrole [89KGS291] 1, no additive 2, RbCl 3, CsF 4, CsjCOj. Reaction conditions see Fig. 1.

Rubidium chloride even slows the reaction, this is especially well seen within a time span of 1-3 hr after the start of the process (Fig. 2, curve 2). In this case the normal salt effect is likely to prevail over the effect of oximate ion pair separation due to substitution of the potassium cation by the rubidium cation. The addition of cesium carbonate during the first 1.5 hr does not much affect the rate of the formation of 2-phenylpyrrole. The accelerating effect of these additives becomes evident only 2 hr after the beginning of the reaction and gradually increases (5 hr later the yield gain of pyrrole is 7% as compared with a standard run, Fig. 2, curve 4) which seems to result from a slow rate of heterophase exchange process ... 

Fig. 3. Solvent effect on the yield of 2-phenylpyrrole [89KGS29I] I, DMSO 2, HMPA 3, l-methyl-2-pyrrolidone 4, sulfolane 5, PEG 6. tetramethyl urea. Catalyst KOH (0.5 mol/L), for other reaction conditions see Fig. 1.

Figure 3 presents kinetic curves for the formation of 2-phenylpyrrole (Scheme 2) at 96°C and atmospheric C2H2 pressure in various solvents such as DMSO, HMPA, l-methyl-2-pyrrolidone, sulfolane, polyethyleneglycol (PEG) with Mm = 1000, and tetramethylurea [89KGS770]. DMSO is confirmed to possess a specific catalytic effect in this reaction, which is much superior to that of HMPA, l-methyl-2-pyrrolidone, and tetramethylurea. According to their capability to catalyze the formation of 2-phenylpyrrole from acetophenone oxime and acetylene, the solvents under consideration are arranged in the following order DMSO > HMPA l-methyl-2-pyrrolidone > sulfolane > PEG > tetra-... 

Oximes of alkyl phenyl ketones were successfully involved in the reaction with acetylene (Scheme 5). In this way, previously unavailable 3-alkyl(phenyl)-2-phenylpyrroles (5) and previously unknown 3-alkyl-(phenyl)-2-phenyl-l-vinylpyrroles (6) (Table XIII) were prepared (78ZOR-2182). 

It was intended (85KGS1501) to find milder synthetic conditions for further simplifying the purification of 3-alkyl-2-phenylpyrroles (5,6) (Scheme 5). It was necessary to increase the DMSO content of the reaction mixture. So, when the synthesis was carried out under pressure in a 10-fold excess (of the total mass of reagents) of DMSO with an equimolar (with respect to ketoxime) amount of KOH, it was possible to decrease considerably the reaction temperature (to 50-60°) and prepare 3-alkyl-2-arylpyrroles (5) and their 1-vinyl derivatives (6) (which more readily undergo purification) in total yield up to 90%. 

Alkyl-2-phenylpyrrole are readily formed, according to Scheme 5, under atmospheric pressure as well (50-70°C, 5-10 hr, equimolar amount or slight excess of KOH relative to oxime, excess of DMSO). Table XV illustrates the effects of the reaction temperature and time as well as of the structure of ketoximes on the composition and the yield of end products. 

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