Synthesis of multisubstituted pyrroles by nickel-catalyzed arylative cyclizations of N -tosyl alkynamides†

The synthesis of multisubstituted pyrroles by the nickel-catalyzed reaction of N -tosyl alkynamides with arylboronic acids is reported. These reactions are triggered by alkyne arylnickelation, followed by cyclization of the resulting alkenylnickel species onto the amide. The reversible E / Z isomerization of the alkenylnickel species is critical for cyclization. This method was applied to the synthesis of pyrroles that are precursors to BODIPY derivatives and a biologically active compound.

Pyrroles are common heterocycles that appear in natural products, 1 pharmaceuticals, 2 dyes, 3 and organic materials. 4 Representative pyrrole-containing natural products include lamellarin D 5,6 and lycogarubin C, 7 whereas drugs that contain a pyrrole include sunitinib 8 and atorvastatin 9 (Figure 1). In view of their importance, numerous strategies to prepare pyrroles have been developed. 10,11

Figure 1
Representative pyrrole-containing natural products and drugs We 12 and others 13 have recently described nickel-catalyzed anticarbometallative cyclizations of alkynyl electrophiles that give various carbo-and heterocyclic products. Although these reactions utilized several types of electrophiles, 12,13 amides have yet to be described, which is perhaps unsurprising given their relatively low electrophilicity. Nevertheless, the successful use of amides could provide a versatile synthesis of multisubstituted pyrroles, as shown in Scheme 1. Nickel-catalyzed addition of an arylboronic acid to the Scheme 1 Proposed synthesis of pyrroles alkynamide 1 would give alkenylnickel species (E)-2. Although (E)-2 cannot cyclize onto the amide because of geometric constraints, reversible E/Z isomerization of (E)-2 would provide (Z)-2, which could now attack the amide to give nickel alkoxide 4. Incorporating an electron-withdrawing N-tosyl group into 1 was expected to increase the reactivity of the amide carbonyl to favor this nucleophilic addition. Protonation of 4, followed by elimination of water, would then provide a 2,3,4-trisubstituted pyrrole 3.
With an effective ligand identified, the scope of the alkynamide was surveyed in reactions with PhB(OH)2 (Table 2). Here, racemic L2 was used and satisfactory results were obtained using a reduced catalyst loading of 5 mol%.These experiments gave pyrroles 3aa-3ma in 46-99% yield. 14 Regarding the alkyne substituent, the reaction is compatible with a phenyl group (3aa), various para-(3ba This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins and 3ca), meta-(3da), and ortho-substituted phenyl groups (3ea), and a 2-thienyl group (3fa). Replacement of the benzoyl group of the amide with various para-substituted benzenes is also possible (3ga and 3ha 15 ). N-Acyl groups with alkyl substituents are also tolerated. For example, pyrroles containing methyl (3ia), n-butyl (3ja), cyclopropyl (3ka), or cyclohexyl (3la) groups were formed in 54- Table 2 Scope of alkynamides a a Reactions were conducted with 0.30 mmol of 1a-1m in TFE (3 mL). Yields are of isolated products. b An acyclic tetrasubstituted alkene was also isolated in 23% yield (see Supplementary Information). c Conducted at 120 °C.
92% yield, although for 3la, increasing the temperature to 120 °C was required for high conversion. The process is not limited to aromatic groups at the alkyne, as shown by the reaction of 1,3-enyne 1m to give pyrrole 3ma in 99% yield. However, a substrate containing a methyl group on the alkyne only gave a complex mixture of products. Furthermore, the N-tosyl group is important for reactivity, as N-aryl alkynamides failed to cyclize.
The cyclization of carbomethoxy-containing substrate 1n failed under the standard conditions, and led only to decomposition by cleavage of the methyl oxalyl group. However, changing the solvent to THF and increasing the catalyst loading to 20 mol% successfully gave pyrrole 3na in 35% yield, along with 3-pyrroline 5na in 38% yield (eqn 1). Increasing the temperature to 120 °C improved the yield of 3na to 73%, and none of 5na was observed (eqn 2).
To illustrate its utility, this methodology was applied to the preparation of pyrroles that have been used in the synthesis of 4,4difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives (Scheme 2). 3a,b,d Removal of the tosyl group from 3aa with KOH in MeOH/TFH (1:1) at 70 °C gave pyrrole 6 in >99% yield, which has previously been converted into BODIPY derivative 7. 16 Alternatively, treatment of 3aa with POCl3 in DMF at 100 °C in a microwave reactor resulted in formylation with concomitant removal of the tosyl group to give pyrrole 8, which has been used in the synthesis of BODIPY derivative 9. 16

Scheme 2 Synthesis of precursors to BODIPY derivatives
In a further application, removal of the tosyl group of 3ia with KOH was followed by immediate alkylation with n-hexyl bromide as described previously to give pyrrole 10 in 56% yield over two steps (Scheme 3). 17 Pyrrole 10 was previously converted in two steps into 11, a known inhibitor of bovine cyclooxygenase and 5lipoxygenase. 17 Scheme 3 Formal synthesis of bovine cyclooxygenase and 5-lipoxygenase inhibitor 11 In conclusion, we have developed a synthesis of diverse 2,3,4trisubstituted pyrroles by the nickel-catalyzed reaction of N-tosyl alkynamides with arylboronic acids. These reactions rely upon the reversible E/Z isomerization of alkenylnickel species as a key step to enable cyclization to take place. This method was applied to the synthesis of pyrroles that are precursors to BODIPY derivatives, as well as an inhibitor of bovine cyclooxygenase and 5-lipoxygenase.

Conflicts of interest
There are no conflicts to declare.