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. 2023 Sep 20;88(19):13584–13589. doi: 10.1021/acs.joc.3c01257

Synthesis of N-alkoxycarbonyl Pyrroles from O-Substituted Carbamates: A Synthetically Enabling Pyrrole Protection Strategy

Jodie L Hann †, Catherine L Lyall ‡, Gabriele Kociok-Köhn ‡, Simon E Lewis †,*
PMCID: PMC10563134  PMID: 37729493

Abstract

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The condensation of readily available O-substituted carbamates with 2,5-dimethoxytetrahydrofuran gives N-alkoxycarbonyl pyrroles in a single step and in good yield. By this method, several common amine protecting groups can be introduced on the pyrrole nitrogen. With the exception of N-Boc, N-alkoxycarbonyl groups have seen only minimal use for protection of the pyrrole nitrogen to date. Here, we show that N-alkoxycarbonyl protection can endow pyrrole with distinct reactivity in comparison with N-sulfonyl protection, for example, in a pyrrole acylation protocol employing carboxylic acids with a sulfonic acid anhydride activator.

Introduction

Pyrroles are commonplace in both natural products1,2 and drug substances.3 Accordingly, many methods have been reported for pyrrole synthesis4,5 and functionalization.6 The Clauson-Kaas pyrrole synthesis employs 2,5-dimethoxytetrahydrofuran 1 as a 1,4-dicarbonyl surrogate, which reacts with amines to afford pyrroles 2 as shown in Scheme 1a.7 Subsequently, this methodology has been expanded to encompass the reaction of nitrogen-containing reagents other than simple amines. For example, reaction of 1 with sulfonamides gives N-sulfonyl pyrroles 3 (Scheme 1b),8 reaction with amides gives N-acylpyrroles 4,9−11 and reaction with hydrazines and hydrazides gives N-aminopyrroles 5.12,13 The reaction of 1 with an O-substituted carbamate 6 to give an N-alkoxycarbonyl pyrrole 7 (Scheme 1c) has not previously been reported in the peer-reviewed literature to the best of our knowledge. In this letter, we report that such reactions proceed cleanly and in high yield to afford N-alkoxycarbonyl pyrroles.

Scheme 1. Pyrrole Synthesis Employing 2,5-Dimethoxytetrahydrofuran 1.

Scheme 1

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The electron-rich nature of pyrrole often necessitates the introduction of a protecting group to render oxidative degradation less facile. Protection at nitrogen may also be required to block N-deprotonation. In this context, N-sulfonyl pyrroles 3 have often been employed, as have N-acyl and N-aminopyrroles (4 and 5), along with protecting group strategies such as N- silylation, allylation, and benzylation.14 In contrast, N-alkoxycarbonyl substituents are underexploited as protecting groups for pyrroles. While many pyrroles have been prepared starting from N-Boc pyrrole, other N-alkoxycarbonyl pyrroles have scarcely been explored. Indeed, even simple compounds such as N-Fmoc pyrrole and N-Troc pyrrole are unreported to date. An N-alkoxycarbonyl substituent is expected to exert an electron-withdrawing effect on the pyrrole ring, thus enhancing stability. However, distinct reactivity from that of N-sulfonyl pyrroles may be expected. A computational study comparing these two classes of N-substituted pyrroles concluded that an N-alkoxycarbonyl pyrrole possesses a more electron-deficient nitrogen than the analogous N-sulfonylpyrrole; this is due in part to a degree of pyramidalization at nitrogen in the latter case.15

Results and Discussion

We began our study by applying the reported Clauson-Kaas conditions (reflux in acetic acid) to 1 and the simplest O-substituted carbamate (6, R = Me). Gratifyingly, we found that no modification of the original reaction conditions was required to afford the product 8 in good yield (Scheme 2). We then carried out the reaction with a range of O-substituted carbamates that correspond to well-known protecting groups. These starting materials are either commercially available or easily prepared (see Supporting Information). Passing the crude N-alkoxycarbonyl pyrrole products through a plug of silica, then drying under high vacuum to remove any residual 1, was sufficient to provide material of good purity.

Scheme 2. Synthesis of N-alkoxycarbonyl Pyrroles 8–13,

Scheme 2

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ORTEP representation of the X-ray structure of 13 (CCDC #2241194) shows ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Only one of two independent molecules in the unit cell is shown for clarity. Crystals of 13 were formed upon cooling to 0 °C for a prolonged period.

1.0 equiv of 1 used, as 11 was unstable upon prolonged drying.

We next sought to evaluate the usefulness of N-alkoxycarbonyl pyrroles in a representative synthetic transformation. We selected pyrrole acylation, as this process has been extensively studied and many synthetic methods have been reported.16−28 A key consideration is regioselectivity, with reported methods exhibiting differing selectivity for 2-acyl/3-acyl/diacyl products. Many methods employ carboxylic acid derivatives as reagents (acid chlorides, anhydrides, etc.). Knight et al. reported that N-tosylpyrroles could be effectively acylated using trifluoroacetic anhydride (TFAA) to activate carboxylic acids in situ.29 The reaction was proposed to proceed by formation of a mixed carboxylic acid anhydride, which acts as the acylating agent. An alternate proposal is that the mixed anhydride fragments to an acylium ion and that this is the actual acylating agent.30 We applied Knight’s conditions to N-alkoxycarbonyl pyrroles 8–13, using acetic acid in an attempt to form 2-acetyl pyrroles (Scheme 3).

Scheme 3. Acetylation of N-alkoxycarbonyl Pyrroles 8–13.

Scheme 3

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(a) 3.0 equiv AcOH, 10 equiv TFAA, CH2Cl2, rt. (b) 1.0 equiv AcOH, 10 equiv Tf2O, CH2Cl2, 0 °C to rt.

N-COOMe-pyrrole 8 gave the expected 2-acetyl derivative 14 in good yield. N-Cbz-pyrrole 9 also gave 2-acetyl derivative 15, but then underwent rapid N-deprotection under the reaction conditions, giving 2-acetylpyrrole 18 directly. Careful monitoring of the reaction allowed isolation of 15 in 69% yield. The newly installed acyl group in 15 and the TFA byproduct may both play a role in the Cbz cleavage since N-Cbz-pyrrole 9 itself remains unchanged upon prolonged exposure to TFA. N-Teoc-pyrrole 10 underwent both 2-acetylation and deprotection in one pot; in this case, no acylated intermediate was observable and only 2-acetylpyrrole 18 was isolated. N-Alloc-pyrrole 11 decomposed upon attempted acetylation; the instability of such alkene-containing substrates under the acidic reaction conditions has been previously noted.29 Finally, N-Fmoc-pyrrole 12 and N-Troc-pyrrole 13 both gave the corresponding 2-acetyl derivatives 16 and 17 in good yield. It is notable that in every case the only products were the 2-acetylated pyrroles, with none of the corresponding 3-acetyl isomers (or any diacetyl isomers) formed. Deprotection of 14, 16, and 17 was then attempted. Basic hydrolysis of 14 gave 2-acetylpyrrole 18 in good yield. Similarly, 2-acetyl-N-Fmoc-pyrrole 16 was cleanly deprotected to 18 under classical conditions31 (piperidine/CH2Cl2). Finally, 2-acetyl-N-Troc-pyrrole 17 also gave 18 cleanly upon treatment with zinc in acetic acid.32

TFAA-mediated acetylations of N-alkoxycarbonyl pyrroles (conditions (a); Scheme 3) required long reaction times (16–24 h). We reasoned the reaction time could be reduced through the use of alternative reaction conditions to generate a more reactive electrophile in situ. Specifically, use of trifluoromethanesulfonic anhydride (Tf2O) instead of TFAA could afford significant rate accelerations. This modified approach is expected to proceed via formation of a mixed carboxylic sulfonic anhydride.33 In the first instance, we employed this alternative activating agent with N-Fmoc-pyrrole 12 and N-Troc-pyrrole 13, since we judged these to be the most useful protecting groups in the context of pyrrole acylation (conditions (b); Scheme 3). In both cases, the acylated products were formed more quickly (<30 min) and with a modest yield increase. Another advantage of using Tf2O as the activator is that only one equivalent of the carboxylic acid was required.

Having demonstrated the applicability of these acylation conditions to N-alkoxycarbonyl pyrroles, we selected N-Troc-pyrrole 13 as a substrate to explore the scope of the acylation reaction (Scheme 4). This was due to the wide synthetic utility of the Troc group (due to its inertness to a wide variety of reaction conditions), as well as the ease of purification of the deprotected pyrrole 18 formed from 17 (simple filtration through a plug of celite). All the acylated N-Troc pyrroles in Scheme 4 formed in good yield within 1–3 h and could be cleanly deprotected to the corresponding N-H pyrroles also in good yield. In each case, once the starting material was consumed, the 2-acylated isomer was the sole product present (and the sole product isolated if the reaction was worked up at this point). Upon prolonged reaction (>18 h), a degree of isomerization to the 3-acylated isomer was observed for some substrates. No diacylation was ever observed, even when 3 equiv of acetic acid and a reaction time of 24 h were used.

Scheme 4. N-Troc-pyrrole Acylation and Deprotection.

Scheme 4

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ORTEP representations of the X-ray structures of 25 (CCDC #2241195) and 27 (CCDC #2241193) show ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Disorder in the CCl3 group and a phenyl ring of 25, and in the isobutyl group of 27, is omitted for clarity. Crystals 25 formed upon prolonged standing of a solution of 25 in CDCl3 and crystals 27 formed by diffusion of hexane vapor into a CH2Cl2 solution of 27.

The monoacylation of N-Troc-pyrrole 13 even in the presence of excess carboxylic acid is in contrast to the outcome with N-Fmoc pyrrole 12. When 3 equiv of acetic acid were used in the acetylation of 12, diacylated product 29 was isolated instead of 16 (Scheme 5). Compound 29 was unstable on silica and hence was characterized in crude form. Seemingly, the presence of both the N-alkoxycarbonyl group and the 2-acyl group in 16 render the pyrrole less reactive toward further acylation than the fluorenyl motif. In comparison, overacetylation of N-tosyl pyrrole 30 under the same reaction conditions (3 equiv AcOH/Tf2O) results in the introduction of a second acetyl group on the pyrrole ring (see Supporting Information Figures S198,S199).

Scheme 5. Overacetylation of N-Fmoc Pyrrole.

Scheme 5

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The exclusive formation of 2-acylated products from the N-alkoxycarbonyl pyrroles above is distinct from the outcome of some of the other acylation protocols reported for pyrroles with other N-substituents. Partial or total selectivity for 3-acylation has been achieved by various means.34,35 It is well established that 2-acylpyrroles may be isomerized to the corresponding 3-acyl isomers under Brønsted acid catalysis, with the ease of this process depending on factors including acid strength, acyl group, and N-substituent.36−38 The acylation methodology described here by us (scheme 4–5) results in the formation of a stoichiometric quantity of acid byproduct (either TFA or TfOH, depending on the activating agent used). However, isomerization to 3-acylated products occurs only very slowly, if at all (vide supra). As such, we reasoned the N-alkoxycarbonyl protecting group might particularly disfavor the isomerization. To determine if this is the case, we studied acylation of N-tosyl pyrrole 30 under the same reaction conditions (i.e., Tf2O as an activator), to allow comparison with N-alkoxycarbonyl pyrroles (Scheme 6).

Scheme 6. N-Ts-pyrrole Acylation and Deprotection.

Scheme 6

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ORTEP representation of the X-ray structure of 31 (CCDC #2241194) shows ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Crystals of 31 were formed by diffusion of hexane vapor into a CH2Cl2 solution of 31.

In each case shown, 3-acylated-N-tosylpyrroles were the only isomers isolated (Scheme 6). Identification of the products as the 3-acylated isomers was on the basis of x-ray crystallography (for 32) as well as the spectroscopic inequivalence of the deprotected products (34, 36) from their 2-acylated counterparts (26, 28) and diagnostic 2D-NMR data (see Supporting Information). The clean formation of these 3-acyl isomers from an N-sulfonyl substrate under these conditions shows that there is good regiocomplementarity between the N-alkoxycarbonyl pyrroles we have described here and the already-established N-sulfonyl pyrroles. We propose that under the strongly acidic conditions, initial 2-acylation of N-tosyl pyrrole 30 is followed by isomerization (as opposed to direct acylation at the 3-position). In support of this proposition, NMR reaction monitoring of the acetylation of 30 with AcOH/Tf2O allows the formation and disappearance of peaks corresponding to the 2-acyl isomer to be observed as the reaction progresses to the endpoint of 3-acyl product formation. The finding that N-alkoxycarbonyl pyrroles are much more resistant to this isomerization under the same conditions is in keeping with the computational prediction that N-alkoxycarbonyl pyrroles are more electron-poor15 and hence less readily protonated.

Conclusions

In conclusion, we have described a facile one-step synthesis of N-alkoxycarbonyl pyrroles, a class of compounds that have been scarcely exploited in synthesis to date (with the exception of N-Boc-pyrrole). We anticipate that this rapid access to pyrroles bearing previously unused protecting groups will lead to their utilization in diverse synthetic contexts. To showcase their potential utility, we have demonstrated the applicability of these N-alkoxycarbonyl pyrroles in a straightforward acylation protocol that employs electrophiles generated in situ from simple carboxylic acids upon activation with triflic anhydride. (Instability of N-Boc-protected pyrroles under acidic conditions would preclude their use in this process). We have further shown the outcome of the acylation to be regioselective depending on the protecting group used, with N-alkoxycarbonyl- and N-sulfonyl pyrroles giving regioisomeric products (after deprotection). We anticipate the versatility of the N-alkoxycarbonyl pyrrole formation may be further increased by the use of substituted variants of 1, as has been demonstrated for the original Clauson-Kaas process.7,39−49

Experimental Procedure

General Procedure for N-alkoxycarbonyl Pyrrole Synthesis

Carbamate (4 mmol, 1.0 equiv) and 1,4-dimethoxytetrahydrofuran (0.63 mL, 4.4 mmol, 1.1 equiv, mixture of cis and trans) were added to a flask and purged with nitrogen. AcOH (2.2 mL) was added, and the reaction was heated to reflux (110 °C) using a heating mantle. The reaction was monitored by TLC, and upon completion was cooled to ambient temperature. (Vanillin TLC stain used for non-UV active substrates). CH2Cl2 (50 mL) was added, then washed with saturated Na2CO3(aq) (50 mL × 2), then brine (50 mL). The organic layer was dried over MgSO4 and filtered, and then the filtrate was concentrated in vacuo. The crude product was purified by passage through a silica plug (elution with CH2Cl2), and any residual 1,4-dimethoxytetrahydrofuran starting material was removed under a vacuum.

General Procedure for Acylation Reactions Using TFAA

To a nitrogen-purged flask of N-alkoxycarbonyl pyrrole (1.0 equiv), and carboxylic acid (3.0 equiv) in dry dichloromethane (c = 0.44 M), trifluoroacetic anhydride (10 equiv) was added dropwise at ambient temperature. The reaction was monitored by TLC, and upon completion, the reaction was diluted with CH2Cl2 and washed with 1 M Na2CO3(aq). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (×2). The combined organic solutions were then washed with brine, dried over MgSO4, and filtered, then the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, EtOAc–Pet Ether).

General Procedure for Acylation Reactions Using Tf2O

To a nitrogen-purged flask of N-alkoxycarbonyl pyrrole (1 equiv), and carboxylic acid (1 equiv) in dry dichloromethane (c = 0.44 M), trifluoromethanesulfonic anhydride (10 equiv) was added dropwise at 0 °C. The reaction was stirred without further cooling and monitored by TLC, and upon completion, the reaction was diluted with CH2Cl2 and washed with 1 M Na2CO3 (aq). The organic layer was separated, and the aqueous layer extracted with CH2Cl2 (×2). The combined organic solutions were then washed with brine, dried over MgSO4, and filtered, then the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, EtOAc–Pet Ether).

General Procedure for N-Troc Deprotection

To zinc dust (1.72 mmol) and the N-Troc-protected product (0.44 mmol), CH2Cl2 (3.2 mL) and AcOH (0.66 mL) were added. The reaction was stirred at ambient temperature and monitored by TLC until consumption of the starting material. The reaction mixture was diluted with acetone (30 mL) and filtered through celite, then concentrated under a vacuum to obtain an analytically pure product.

General Procedure for N-Tosyl Deprotection

NaOH pellets (3 equiv) were crushed and added to a solution of N-Tosyl pyrrole product in (9:1) MeOH/H2O (0.81 M) and stirred overnight at ambient temperature. EtOAc was added, the phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated to dryness to obtain analytically pure product.

Acknowledgments

The authors thank EPSRC for a DTP PhD studentship to J.L.H. (EP/T518013/1). The authors acknowledge the Material and Chemical Characterization Facility (MC2) at the University of Bath (https://doi.org/10.15125/mx6j-3r54).

Data Availability Statement

The data underlying this study are available in the published article, in its Supporting Information, and openly available in the University of Bath Research Data Archive at https://doi.org/10.15125/BATH-01255

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c01257.

  • Additional experimental procedures, tabulated compound characterization data, NMR spectra, IR spectra, X-ray crystallographic data (PDF)

The authors declare no competing financial interest.

Supplementary Material

jo3c01257_si_001.pdf (6.3MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

jo3c01257_si_001.pdf (6.3MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article, in its Supporting Information, and openly available in the University of Bath Research Data Archive at https://doi.org/10.15125/BATH-01255

Articles from The Journal of Organic Chemistry are provided here courtesy of American Chemical Society

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