Letter pubs.acs.org/OrgLett
Dearomatization Strategy for the Synthesis of Arylated 2H‑Pyrroles and 2,3,5-Trisubstituted 1H‑Pyrroles Peter Polák and Tomás ̌ Tobrman* Department of Organic Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic S Supporting Information *
ABSTRACT: The first high-yielding route to arylated 2Hpyrroles was developed. The methodology utilizes 2,5disubstituted pyrroles that are metalated, and the aryl substituents are introduced by a palladium-catalyzed crosscoupling reaction. The prepared pyrroles can be rearranged to 2,3,5-trisubstituted pyrroles under acidic conditions. Attempts to convert the 2,3,5-trisubstituted pyrroles to 2,3,4,5-tetrasubstituted pyrroles by the dearomatization rearrangement strategy were unsuccessful.
H
Scheme 1. Preparation of 2-Aryl-2H-pyrroles by the Dearomative Strategies
eterocyclic compounds are interesting analogues of the parent carbocycles. The presence of heteroatoms significantly influences the properties of heterocycles leading to various applications. Pyrrole is an example of a five-membered heterocycle that is extensively studied because of its use in material1 and medicinal2 chemistry. The synthetic approaches to the substituted pyrroles can be divided into several groups depending on the structure of the starting compounds. The transition-metal-catalyzed3 and noncatalyzed cyclization reactions, represented by Paal−Knorr4 and Piloty−Robinson syntheses,5 are presumably the most important class of reactions used for the synthesis of substituted pyrroles. Other types of reactions rely on the transition-metal-catalyzed couplings6 of suitable pyrrole precursors. Specific approach to the synthesis of heterocycles is based on the transition-metal-catalyzed dearomatization strategy.7,8 The dearomatization strategy is preferred for the preparation of diversely substituted pyrroles. According to the literature records, the dearomatization of pyrroles is suitable for the preparation of fused pyrroles,9 spiro-pyrroles,10 and the introduction of the alkyl groups11 by the reaction of 1H-pyrroles with electrophilic templates in the presence of base and transition metal catalysis. A common feature of the above-mentioned methods is the introduction of various Csp3-substituents to position 2 of the pyrrole unit producing 2H-pyrroles as a final product or intermediate. It is quite surprising that the efficient introduction of aryl substituents to position 2 was solved only in an intramolecular coupling reaction of pyrroles 110d (Scheme 1). Alternatively, 2-aryl-2H-pyrroles can be accessed by transitionmetal-mediated cyclization,12 the aza-Nazarov reaction,13 radical substitution process,14 cyclization−oxidation strategy,15 and others.16 Unfortunately, the above-mentioned protocols have limited scope, or several steps are required to synthesize 2Hpyrroles. Recently, during our synthetic studies toward the regioselective synthesis of the heterocyclic compounds,17 we observed that the lithiated pyrroles 3 can be smoothly coupled with the aryl halides, furnishing arylated 2H-pyrroles 4 in high yields (Scheme 1). Herein, we report our results obtained during © 2017 American Chemical Society
the preparation of arylated 2H-pyrroles along with attempts at their conversion to the 2,3,5-trisubstituted pyrrole. The cross-coupling reaction of the metalated pyrrole 3a, easily preparable by the action of n-BuLi, with iodobenzene in dry cyclopentyl methyl ether (CpOMe) afforded 2H-pyrrole 4a in 89% isolated yield, 93% 1H NMR yield (Table 1, entry 1). This finding encouraged us to investigate the influence of the reaction conditions on the reaction course. It soon became clear that the reaction requires a palladium catalyst, and lowering the reaction temperature to 80 °C significantly decreased the yield of 4a to 58% (Table 1, entries 2 and 3). A similar effect was observed in the XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) and SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) ligands (Table 1, entries 4 and 5). The generation of metalated pyrrole by reaction of 3a with isopropylmagnesium chloride gave 4a in a 60% yield (Table 1, entry 6). The use of 1 Received: July 20, 2017 Published: August 14, 2017 4608
DOI: 10.1021/acs.orglett.7b02219 Org. Lett. 2017, 19, 4608−4611
Letter
Organic Letters Table 1. Optimization of the Reaction Conditions for the Cross-Coupling of 3a with Iodobenzene
entry
liganda
yieldb (%)
1 2 3 4 5 6 7 8 9
RuPhos d RuPhose XPhos SPhos RuPhosf RuPhosg RuPhosh RuPhosi
93 (89c) 0 58 36 69 60 39 32 94
Table 2. Preparation of 2-Aryl-2H-pyrroles 4 and 5 by Palladium-Catalyzed Cross-Coupling Reaction of Pyrroles 3a−c
a
Typical reaction conditions involve the reaction of aryl halides with m e t a l a t e d p y r r o l e 3 a , 5 m o l % o f P d ( DB A ) 2 [ b is (dibenzylideneacetone)palladium(0)], and 10 mol % of ligand in dry CpOMe at 100 °C. b1H NMR yield. cIsolated yield. dThe reaction was carried out without palladium catalyst. eThe reaction was carried out at 80 °C. fThe metalated pyrrole was prepared by the reaction with iPrMgCl. gCs2CO3 was used as a base. Other bases (K2CO3, Li2CO3, NaH) were ineffective. h1 mol % of Pd(DBA)2 and 2 mol % of RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) was used. iBromobenzene was used. a
mol % of the catalyst as well as cesium carbonate as the base gave a low yield of the product 4a (Table 1, entries 7 and 8). The bromobenzene showed reactivity similar to that of iodobenzene (Table 1, entry 9). Successfully developed conditions were applied to differently substituted pyrroles 3a−d and aryl halides (Table 2). The initial investigation of the structure−reactivity relationship involved 2,5-dimethylpyrrole (3a) that smoothly coupled with the bromobenzene bearing methoxy- and dimethylamino groups (Table 2, entries 1 and 2). Electron-withdrawing groups were also tolerated, although fluoro and trifluoromethyl groups were superior to nitrile and ester groups (Table 2, entries 3−6). The ortho-substituted iodobenzene gave 2H-pyrrole 4h in 93% isolated yield (Table 2, entry 7). 2-Bromothiophene and 1bromopyrene smoothly coupled, affording 2H-pyrroles 4i,j (Table 2, entries 8 and 9). Attempts to synthesize the 2Hpyrroles bearing alkenyl unit were unfruitful as observed in the reaction of 3a with (E)-1-bromohex-1-ene (Table 2, entry 10). An exclusive formation of 2H-pyrroles 5b,j was observed in the case of 2-phenyl-5-methylpyrrole 3b (Table 2, entries 1 and 9). The diethyl pyrrole-2,5-dicarboxylate (3c) was unreactive under test conditions, and the starting compound 3c was quantitatively recovered. On the other hand, the coupling reaction of lithiated 2,5diphenyl-1H-pyrrole (3d) turned out to be less effective, affording a mixture of corresponding 2H-pyrrole (15%) and a separable mixture of regioisomers 6a (20%) and 6b (20%) along with an unreactive starting compound 3d (30%) (Scheme 2). Increasing the reaction temperature to 130 °C resulted in a complete conversion of the starting compound 3d to a mixture of 6a (30%) and 6b (30%). The formation of 2H-pyrrole was not observed in this case, indicating that the presence of a palladium catalyst along with an increased reaction temperature facilitates the rearrangement reaction.
entry
Ar
X
4a (%)
5a (%)
1 2 3 4 5 6 7 8 9 10
4-MeOPh 4-Me2NPh 4-FPh 4-NCPh 4-EtOOCPh 3-CF3Ph 2-MeOPh 2-thienyl 1-pyrenyl (E)-1-hexenyl
Br Br Br Br I Br I Br Br Br
4b, 94 4c, 80 4d, 89 4e, 53 4f, 43 4g, 91 4h, 93 4i, 45 4j, 96 b
5b, 91
5j, 80
Isolated yield. bUnreacted starting 3c was recovered.
Scheme 2. Coupling Reaction of Lithiated Pyrrole 3d with 4Bromoanisole
Highly regioselective access to 2-aryl-2H-pyrroles 4 and 5 along with the spontaneous formation of 2,3,5-trisubstituted pyrroles 6a,b sparked out our interest in an extension of the developed procedure for 4 and 5 to the preparation of 2,3,5trisubstituted pyrroles 6 by the acidic rearrangement reaction (Table 3). Thus, easily available 2H-pyrrole 4a was treated with common organic acid in nonpolar solvents. Two equivalents of acetic acid (AcOH) was insufficient to induce the rearrangement of 4a to 7a in toluene at 80 °C (Table 3, entry 1). On the other hand, trifluoroacetic acid (TFA) furnished the pyrrole 7a in 63% isolated yield (Table 3, entry 2). Decreasing the reaction temperature or the employment of cyclopentyl methyl ether instead of toluene gave lower yields of 7a (Table 3, entries 3 and 4). The catalytic amount of the TFA resulted in a trace amount of 7a (Table 3, entry 5). N,N-Dimethylformamide (DMF) as an example of a polar solvent substantially increased the yield of 7a up to 82% isolated yield of 7a in the presence of 10 equiv of TFA (Table 3, entries 6−8). Trifluoromethanesulfonic acid (TfOH) gave a similar yield of 7a (Table 3, entry 9), but the TFA was the acid of choice due to its easier handling. The optimized reaction conditions (Table 3) were applied to the 2H-pyrroles 4 and 5 to evaluate the scope of the developed methodology (Figure 1). Both ortho- and para-substituted benzenes bearing methoxy groups 4b,h smoothly rearranged to pyrroles 7b,c, in yields similar to those of model substrate 4a. On 4609
DOI: 10.1021/acs.orglett.7b02219 Org. Lett. 2017, 19, 4608−4611
Letter
Organic Letters Table 3. Course of Acid-Catalyzed Rearrangement of Pyrrole 4a
a
entry
acid
solvent
equiv
yielda (%)
1 2 3 4 5 6 7 8 9
AcOH TFA TFA TFA TFA TFA TFA TFA TfOH
toluene toluene tolueneb CpOMe toluene DMF DMF DMF DMF
2.0 2.0 2.0 2.0 0.05 3.0 5.0 10.0 10.0
0 63 57 61
