Molecular Editing of Pyrroles via a Skeletal Recasting Strategy

Heterocyclic scaffolds are commonly found in numerous biologically active molecules, therapeutic agents, and agrochemicals. To probe chemical space around heterocycles, many powerful molecular editing strategies have been devised. Versatile C–H functionalization strategies allow for peripheral modifications of heterocyclic motifs, often being specific and taking place at multiple sites. The past few years have seen the quick emergence of exciting “single-atom skeletal editing” strategies, through one-atom deletion or addition, enabling ring contraction/expansion and structural diversification, as well as scaffold hopping. The construction of heterocycles via deconstruction of simple heterocycles is unknown. Herein, we disclose a new molecular editing method which we name the skeletal recasting strategy. Specifically, by tapping on the 1,3-dipolar property of azoalkenes, we recast simple pyrroles to fully substituted pyrroles, through a simple phosphoric acid-promoted one-pot reaction consisting of dearomative deconstruction and rearomative reconstruction steps. The reaction allows for easy access to synthetically challenging tetra-substituted pyrroles which are otherwise difficult to synthesize. Furthermore, we construct N–N axial chirality on our pyrrole products, as well as accomplish a facile synthesis of the anticancer drug, Sutent. The potential application of this method to other heterocycles has also been demonstrated.


■ INTRODUCTION
Heterocyclic compounds are among the most significant structural scaffolds in medicinal chemistry and drug discovery, 1−4 consequently, their selective functionalization is of crucial importance.−11 For structural editing of heterocyclic compounds at different peripheral sites, multistep synthetic manipulations are usually required (Figure 1A).−26 In this tactic, the structures of heterocycles are synthetically "edited" through one-atom deletion or addition of the core molecular framework, to achieve desired transformations, thus offering powerful tools in drug discovery.In medicinal chemistry, maintaining the molecular core/skeleton of a lead compound would be ideal in the lead optimization process, which enables structural interrogation/modification in an efficient and productive manner.When the heterocyclic structures are concerned, the ability of maintaining the ring size while allowing synthetic manipulations to take place at various ring sites represents an ideal approach in molecular editing.Toward this end, we wondered if we could disrupt a simple heterocycle with a carefully chosen molecular perturbator, resulting in ring deconstruction to form an advanced intermediate, which will then incorporate the perturbator moieties and recast back to form the same type of heterocyclic ring with more structural complexity.We term this the skeletal recasting strategy (Figure 1C).
In our proof-of-concept study, we decided to focus on pyrrole and its derivatives.−33 In fact, pyrrole synthesis dates back to the 19th century, and the most well-known methods include the Knorr, 34−36 Paal−Knorr, 37,38 and Hantzsch 39 reactions, which are still being commonly practiced nowadays.−43 On the other hand, synthesis of such structurally encumbered scaffolds represents a major synthetic challenge, presenting a bottleneck in the development of    pyrrole-containing agrochemicals and pharmaceuticals.There are some reports on the synthesis of multisubstituted pyrroles; 44−53 nevertheless, the reported methods often require specific prefunctionalized substrates, being somewhat less general (Figure 2B).Therefore, we became interested in devising an efficient approach to access fully substituted pyrroles, aiming to use our proposed skeletal recasting strategy.
When the synthesis of complex pyrroles is concerned, simple pyrroles are arguably ideal starting materials, as they are cheap and readily accessible.The presence of a nitrogen atom makes multipositions of pyrrole nucleophilic, which in combination with the installation of different substituents on the pyrrole core will make synthetic manipulations more versatile.We reckon the key in our proposed skeletal recasting strategy is to introduce a suitable molecular perturbator, which will first trigger the pyrrole deconstruction via dearomatization and then reconstruct the pyrrole ring through rearomatization at a later stage.Consequently, we set the following criteria: (1) a dipole molecule that enables deconstruction/reconstruction sequence and ( 2) contains (at least) a nitrogen atom to facilitate reforming pyrrole ring.We reasoned that azoalkenes 54−59 may serve as a suitable molecular perturbator.In a recent study, we showed that azoalkenes could serve as a valuable CCN 1,3dipole due to a facile hydrazine-enamine tautomerization. 58In a projected reaction, we hypothesize that an acid-promoted nucleophilic attack of pyrrole on the azoalkene leads to dearomatization of the pyrrole ring.Subsequently, with the participation of azoalkene nitrogen, and an acid-promoted C−N bond cleavage, a rearomatization reaction may take place.Lastly, hydrolysis and elimination would yield a fully substituted pyrrole (Figure 2C).Herein, we introduce a new molecular editing strategy, termed skeletal recasting, for one-step facile synthesis of fully substituted pyrroles from simple pyrroles.

■ RESULTS AND DISCUSSION
To start our investigation, we chose 2,5-dimethyl-1H-pyrrole 1a and azoalkene 2a as model substrates and examined the potential skeletal recasting reaction (Table 1).To our delight, the projected reaction proceeded smoothly to yield recast pyrrole in the presence of acid catalysts (entries 1−5).Among all the acid catalysts examined, Cat. 5 gave the best results.Catalyst is essential for the reaction, without which no reaction was observed (entry 6).Varying equivalence of azoalkene 2a had no influence on the reaction (entries 7 and 8).A quick solvent screening revealed that chloroform was the solvent of choice (entries 9−13).When the catalyst loading was further lowered to 10 mol %, comparable results were obtained.Under the optimized reaction conditions, the recast tetra-substituted 3a was obtained in 90% yield (entry 14).
With the optimized reaction conditions in hand, we explored the scope of azoalkene substrates (Figure 3).The tolerance of the reaction to the ester moieties appended to the C�C double bond of azoalkenes was first evaluated.A broad range of esters, such as methyl (3b), ethyl (3a), i-propyl (3c), t-butyl (3d), ibutyl (3e), benzyl (3f), and allyl (3g) esters, were all found to be suitable, and the tetra-substituted pyrroles were obtained in good yields.Subsequently, the ester groups at the azoalkene Nterminal were varied, and benzyl ester (3h), p-methoxybenzyl ester (3i), and t-butyl ester (3j) all worked well.Both ester moieties in the azoalkene structure can be changed at the same time, and the results remained excellent (3k and 3l).In the reaction, the R 2 group in azoalkene substrates ends up at the C5position of pyrrole products, and modification of R 2 offers great flexibility in accessing diverse 5-substituted pyrrole scaffolds.Indeed, the alkyl chain lengths could be varied from methyl, ethyl, n-propyl, to n-butyl, meanwhile, different esters could be installed at the two ester sites of the azoalkene structures, and decent yields were constantly obtained (3m−3r).Interestingly, when azoalkenes with an alkyl substituent bearing a terminal C�C bond or a phenyl substituent were employed, and the corresponding pyrroles (3s and 3t) were obtained, such modifications not only add in great structural diversity to the pyrrole products but also make synthetic manipulations of the products more feasible.
Next, the applicability of this method to different pyrrole starting materials was evaluated (Figure 4).Our strategy starts with simple pyrrole substrates, which is highly practical, as these pyrroles are either commercially available or synthetically readily   and untouched siloxy moiety (3ah), and it seems that unusual stability of imine is due to the formation of the intramolecular hydrogen-bonding network.When unsymmetric pyrroles bearing an alkyl and an aryl group were reacted with azoalkene 2a, the recasting reaction took place smoothly to form desired products.Notably, the more sterically hindered aryl moieties in pyrrole substrates ended up at the 2-position of pyrrole products.The employment of aryl groups in pyrrole substrates is versatile, from simple phenyl to various substituted phenyls, regardless of the substitution pattern and electronic nature (3ai−3aq).In addition, styrene and biphenyl-containing pyrrole substrates were also found to be suitable (3ar and 3as).Moreover, the reaction was applicable to pyrrole starting materials containing a (substituted)-naphthyl, benzofuran, benzothiophene, or thiophene, and the tetra-substituted pyrroles were constantly obtained in good yields (3at−3ax).Interestingly, replacement of the hydrogen atom of pyrrole NH moiety with a cyclopropyl group (1y) or phenyl (1y′) group had little influence, and the same pyrrole product 3a was obtained.At last, when unsymmetric N-phenyl pyrroles bearing two different C2-and C5-alkyl substituents were utilized, the corresponding pyrrole products were obtained in good yields; it is notable that highly sterically hindered t-butyl could be employed (3az).
To further investigate the reaction scope, we turned our attention to the application of this methodology to biologically active molecules to demonstrate the potential of our method for the modification of drug-like molecules (Figure 5A).2,5-Disubstituted pyrroles derived from naproxen (anti-inflammatory), indomethacin (anti-inflammatory), and bezafibrate (hyperlipidaemia treatment) were subjected to the standard reaction conditions, skeletal recasting took place smoothly without touching ester and amide groups, and the corresponding tetra-substituted pyrrole derivatives (3ba−3bc) were formed in good yields.It is noteworthy that enantiomeric excess of 3ba remained >99% after the skeletal recasting process, indicating no enantiomeric erosion under our reaction conditions.Furthermore, the reaction scope with regard to trisubstituted and monosubstituted pyrroles, as well as pyrrole itself, was also examined.The utilization of trisubstituted pyrrole formed the desired recast product in good yield (3bd), while the reaction with monosubstituted pyrrole or pyrrole only led to the formation of a 1,4-addition product (3be′ and 3bf′), not the recast products (Figure 5B).
A series of experiments were conducted to shed light on the mechanism of this skeletal recasting reaction of simple pyrroles with azoalkenes (Figure 7).In our hypothesis, the deconstruction of a simple pyrrole substrate entails a dearomatization process to form an advanced intermediate and the detection of which would provide strong evidence to our mechanistic proposal.Accordingly, we mixed pyrrole 1a and azoalkene 2a in anhydrous chloroform with the introduction of 10 molar equivalence of 18 -labeled H 2 O and monitored the reaction progress with liquid chromatography−mass spectrometry (LC− MS).Within 5 min, two peaks with retention time of 9.177 and 9.374 min were observed, corresponding to advanced intermediate 3a′ (MS = 296.10observed) and the final pyrrole product 3a″ (MS = 299.05observed).After the overnight reaction, intermediate 3a′ disappeared and only 3a″ was observed, and high-resolution mass spectrometry (HRMS) of the latter was taken, confirming its presence ambiguously (Figure 7A).Another key point to be clarified in the mechanism is the fate of the pyrrole nitrogen atom.The fact that the newly recast pyrrole contains a hydrazine moiety clearly suggests the incorporation of azoalkene into the product and the departure of the nitrogen atom from the pyrrole starting material.Consequently, we performed the reaction using 15 N-labeled pyrrole (1d′) as the starting material.Indeed, the recast pyrrole product (3ad) did not contain a radio-labeled nitrogen (Figure 7B).With the above mechanistic studies, a plausible mechanism for the reaction is proposed (Figure 7C).Phosphoric acid promotes a Friedel−Crafts-type 1,4-addition of pyrrole to azoalkene, forming a dearomatized hydrazine intermediate (I).Subsequently, a tautomerization to enamine takes place, yielding intermediate II.Under the catalysis of phosphoric acid catalyst, another 1,4-addition occurs to provide the bicyclic intermediate III, which undergoes a crucial rearomatization, through the cleavage of the C−N bond at the original pyrrole nitrogen site, restoring aromaticity and furnishing a new pyrrole ring (V).Finally, an enamine-imine tautomerization, followed by a hydrolysis, leads to the formation of final product 3a.
The tetra-substituted pyrroles prepared using the skeletal recasting strategy are useful and interesting.−69 As an illustration, we carried out the asymmetric N-alkylation reaction of pyrrole 3t, using the Morita−Baylis−Hillman (MBH) carbonate 5a as the alkylating agent (Table 2).Cinchona alkaloids turned out to be good catalysts, promoting the reaction in an enantioselective manner (entries 1−3).Among all the alkaloids examined, quinidine was found to be the best, forming the desired alkylation product 6 in 70% yield with 70% ee.Subsequently, a quick solvent screening showed that dichloromethane was the most suitable solvent (entries 4−6).Lowering the reaction temperature further enhanced the enantioselectivity of the reaction.When the reaction was performed in dichloromethane at −20 °C, the desired product 6 bearing an N−N axial chirality was obtained in 80% yield and with 91% ee (entry 9).We next proceeded to perform the N−N bond cleavage and form the N-unprotected pyrrole products. 70When N-protected pyrrole products 3 were treated with azoalkene 2a, the N−N bond was cleaved, and the corresponding N-unprotected pyrroles 7 were obtained in high yields (7a−7d).It is noteworthy that the modified drug-like 3bc well tolerated the deprotection conditions, and the complex N-unprotected pyrrole 7e was obtained in good yield.The proposed mechanism of N−N bond cleavage is also illustrated.The reaction commences with a nucleophilic attack by the exocyclic nitrogen of pyrroles 3′ on the electrophilic carbon of azoalkene 2a, leading to the formation of intermediate I, which undergoes a N−N bond cleavage through an E1cB process to afford Nunprotected pyrrole 7 (Figure 8A).
To highlight the synthetic value of our tetra-substituted pyrrole products, we conducted a concise synthesis of Sutent, one of the best-selling anticancer drugs. 40As depicted in Figure 8B, the N-unprotected pyrrole 7a was subjected to a few trivial reactions, yielding aldehyde 8.At last, a simple amination, followed by a condensation, completed the synthesis of Sutent (10).
From a conceptual viewpoint, the skeletal recasting strategy we introduced herein for heterocycle editing should be generally applicable to other heterocyclic structures, provided these heterocycles may: (1) chemically interact with a judiciously selected/designed molecular perturbator (azoalkene in current study) and ( 2) be capable of incorporating extra structural moieties from perturbator to form a more complex heterocyclic structure.Indeed, when indolizine was treated with azoalkene 2a in the presence of phosphoric acid, a novel heterocycle 14 containing both pyrrole and pyridine moieties was formed.Similarly, when pyrrolo quinoline was subjected to our standard reaction conditions, deconstruction and reconstruction processes happened, and the recast product 15 bearing both pyrrole and quinoline substructures was obtained in good yield (Figure 8C).

■ CONCLUSIONS
In summary, we have developed an efficient synthesis of fully substituted pyrroles from simple pyrroles, enabled by the skeletal recasting strategy.By introducing an azoalkene as a molecular perturbator, a dearomatization of pyrrole starting materials takes place, which is followed by a rearomatization process incorporating structural moieties of the perturbator to form more complex pyrrole motifs.A broad range of tetrasubstituted pyrroles are conveniently prepared, and we also introduce N−N axial chirality to the products, as well as to complete a facile synthesis of the anticancer drug, Sutent.Conceptually, the skeletal recasting strategy has broad applicability to other heterocycles, thus may offer a powerful tool for molecular editing of heterocyclic structures.Currently, we are working toward extending this concept to heterocycle editing in a broader context, targeting the synthesis of complex heterocycles.Such strategies should find wide applications in medicinal chemistry, argochemistry, and materials sciences, and we anticipate that more exciting discoveries in the science of molecular editing are forthcoming.
Relevant data include reaction optimization, reaction procedure, product characterization, and NMR spectra (PDF) X-ray structure of compound 9 (CIF)

Figure 2 .
Figure 2. Reaction design.(A) Biologically active fully substituted pyrroles.(B) Known methods for the synthesis of fully substituted pyrroles.(C) Reaction design: skeletal recasting of simple pyrroles.

Figure 6 .
Figure 6.Skeletal recasting strategy for the synthesis of 13 C-labeled pyrroles.