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Synlett 2023; 34(12): 1415-1418
DOI: 10.1055/a-1969-4095
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Synthesis and Reactivity of a Stable Prototropic Isomer of 2-Acetyl-3-methylpyrrole

Aleksandras Lotuzas
,
Anton El Khoury
,
Liubo Li 
,
Patrick G. Harran  ∗

Funding provided by the D. J. and J. M. Cram Endowment and a ­National Science Foundation Equipment Grant (CHE1048804).
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Dedicated to Professor Masahiro Murakami on the occasion of his retirement

Abstract

4-Isocyanobut-1-ene reacted rapidly with acetyl bromide to afford an unstable imidoyl bromide adduct. Subsequent in situ cyclization under Heck conditions generated a stable prototropic isomer of 2-acetyl-3-methylpyrrole. The reactivity of this molecule toward ­acids, bases, and oxidants was explored, and its conversion into an α-methylidene γ-lactam was demonstrated. In protonated form, the molecule functioned as a reactive dienophile in Diels–Alder reactions.


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Key words

isocyanides - imidoyl bromides - Heck cyclization - ­methylpyrrolylethanone - Diels–Alder reaction

During studies aimed at synthesizing the marine natural product portimine (1; Scheme [1]).[2] we sought to prepare 1-(4-methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2) as a precursor to the spirocyclic imine in 1. This cross-conjugated prototropic isomer of 2-acetyl-3-methylpyrrole[3] (3) had not been synthesized previously. Its 3-­alkylidene-1-pyrroline motif is present in lanopylin natural products, which Snider and Zhou had synthesized by using an elegant Staudinger cyclization.[4] We felt a similar approach to 2 might be viable, but that other options would be more concise. α-Imino ketones had been synthesized in high yields by treating alkyl isocyanides with acid halides (e.g., 6 → 7).[5a] Livinghouse and co-workers used the resultant imidoyl halides as acyl nitrilium ion precursors.[5b] For our purposes, we felt related α-bromo azenones might be suitable as Heck cyclization substrates.[5c]

Zoom Image
Scheme 1 1-(4-methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2) viewed as a portimine substructure and earlier methods influential in the current studies. See references 4 and 5.

But-3-en-1-ylformamide (8)[6] was dehydrated with ­POCl3/Et3N to afford but-3-enyl isocyanide (9)[7] (Scheme [2]). When purified 9 was treated with acetyl bromide (DCM, 25 °C), the imidoyl bromide 10 formed almost instantaneously. 1H NMR spectra of the crude product (Figure [1]) showed clean conversion into a single geometric isomer, tentatively assigned an E-configuration.[5b] Because this imidoyl bromide could not be isolated without loss to hydrolysis, attempts to synthesize the target compound 2 by Heck cyclization in situ were explored. The addition of a catalytic amount of Pd(OAc)2 to a crude solution of 10 in the presence of CsOPiv or Et3N gave the product 2 contaminated with significant amounts of pyrrole 3 (Table [1]), presumably formed by palladium-catalyzed isomerization of 2. Changing the basic additive to Ag2CO3 eliminated the formation of 3, but the reaction was sluggish and conversion was low (entry 3).

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Scheme 2 Concise synthesis of 2 by Heck cyclization of an imidoyl bromide generated in situ
Zoom Image
Figure 1 1H NMR spectra (500 MHz, CDCl3, 23 °C) of compounds 9, 10, and 2. The spectrum for 10 was recorded on the concentrated crude material. Data for 9 and 2 were collected from chromatographically purified material.

Table 1 Heck Cyclizations of Imidoyl Bromide 10 a

Entry

Base

Catalyst (10 mol%)

Results (2:3) b

1

CsOPiv

Pd(OAc)2

3.5:1

2

Et3N

Pd(OAc)2

1.4:1

3

Ag2CO3

Pd(OAc)2

Only 2(<10% yield)

4

Ag2CO3

Pd(PPh3)4

Only 2(20% yield)

5c

Ag2CO3

Pd(PPh3)4

Only 2(50% yield)

a Reaction conditions: 9 (0.62 mmol, 1.0 equiv), AcBr (1.1 equiv), DCM (1M), 23 °C; then catalyst (10 mol%), base (1.5 equiv), PhMe (0.1 M), 95 °C.

b Determined by integration of the 1H NMR spectra of the crude material. Yields are given for chromatographically purified products; see also reference 9

c A mixture of 10 in PhMe (2 M) was added to a preheated (90 °C) suspension of the catalyst and base in PhMe (0.1 M) over 15 min.

Replacing Pd(OAc)2 with Pd(PPh3)4 and conducting an inverse addition, wherein a 2 M toluene solution of 10 was added slowly (15 min) to a preheated toluene suspension of the catalyst and Ag2CO3, permitted the isolation of pure 2 in 56% yield following chromatography on silica gel (Table [1], entry 5)[8] Under these conditions, only trace amounts of the α-keto amide N-(but-3-en-1-yl)-2-oxopropanamide, derived from hydrolysis of 10, could be detected in the crude reaction mixture.[9]

Having established an access to gram quantities of heterocycle 2, we studied its ability to react as a dienophile in a Diels–Alder reaction and we examined methods for enolizing the molecule under basic conditions. When one equivalent of TFA was added to a 0.1 M solution of compound 2 in DCM containing one equivalent of 5-benzyloxy-2-methylpenta-1,3-diene,[10] the major product was the oxetane-containing dimer 11 (Scheme [3]; relative stereochemistry unassigned). Repeating the reaction without the diene present, and adding the TFA rapidly, gave a near-quantitative yield of 11. Interestingly, if a MeCN solution of 2 was added slowly to one equivalent of TFA in MeCN (0.1 M) at 25 °C and the resultant salt solution was treated with a MeCN solution of 5-benzyloxy-2-methylpenta-1,3-diene at 25 °C, the endo Diels–Alder product 12 was isolated in 74% yield (dr = 8:1). This result indicated that protonated 2 is highly reactive and, in the absence of a competent trap, is able to react with its own free base to afford 11.

Zoom Image
Scheme 3 Reactivity of compound 2. (a) Dropwise addition of a MeCN solution of 2 to a 0.1 M MeCN solution of TFA (1 equiv); then, dropwise addition of a MeCN solution of 5-benzyloxy-2-methylpenta-1,3-diene.[10] (b) Rapid addition of TFA (1 equiv) to a 0.1 M DCM solution of 2. (c) t-BuLi (1.59 M, 0.3 mL, 1.1 equiv), 2 (50.0 mg, 0.41 mmol, 1 equiv), THF (0.1 M), –78 °C, 2 h. (d) mCPBA (235 mg, 1.02 mmol, 1.2 equiv), 2 (105 mg, 852 mmol, 1 equiv), THF (0.1M), 23 °C, 3 h.

Treating heterocycle 2 with a kinetic base such as (i-Pr)2NLi, KHMDS, or LiTMP in THF at various temperatures for varying times did not produce a reactive enolate. Quenching with TMSCl or a simple electrophile (e.g., BnBr) returned the starting material. Quenching with CDCl3 or D3CCO2D gave limited deuterium incorporation. In contrast, alkyllithium reagents reacted rapidly and efficiently with 2, but not through deprotonation; instead, carbonyl-addition reactions were observed. Even tert-butyllithium added to 2 to give the tertiary alcohol 13 in high yield (Scheme [3]).

A peracid also added efficiently to ketone 2; when 2 was treated with mCPBA in THF at 25 °C, the Bayer–Villager product 14 formed in high yield. Notably, the same migratory regiochemistry was observed when the branched-alkyl or aryl ketone variants 15a–d were oxidized with mCPBA (Scheme [4]). In each case, the acyl imidate product 16 was formed with high selectivity. Upon aqueous workup, the imidates were hydrolyzed to give α-methylidene-γ-butyrolactam (17), which could be isolated by column chromato­graphy. Spectral data for 17 were identical to those reported previously.[11a] The two-step conversion of 9 into 17 compares favorably with prior syntheses of this building block.[11]

Zoom Image
Scheme 4 Bayer–Villiger reactions of alkanoyl methylidene pyrrolines with various degrees of substitution on the α-carbon. Reaction conditions: 15 (0.85 mmol, 1 equiv), mCPBA (1.2 equiv), THF (0.1 M), 23 °C. For syntheses of compounds 15a–d, see the Supplementary Information (SI).

In conclusion, we have developed a short scalable ­synthesis of 1-(4-methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2)[13] and its congeners 15a–d. The alkene group in protonated 2 functions effectively as a Diels–Alder dienophile. Moreover, the carbonyl group in 2 is a highly competent electrophile, as evidenced by the facile formation of derivatives 11, 13, and 14. Current efforts are focused on synthesizing a variant of 2 that can facilitate the total synthesis of portimine. More generally, compounds 15 might be useful in syntheses of elaborated 2,3-disubstituted pyrrolines and pyrroles, whereas acyl imidates 16 might serve as substrates for metal-catalyzed cross-coupling reactions. Studies along these lines are ongoing.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1969-4095.
  • Supporting Information

  • References and Notes

  • 1 Current address: L. Li, Chinese Academy of Sciences, 52 Sanlihe Rd., Xicheng District, Beijing 100864, P. R. of China; liuboli@iccas.ac.cn.
  • 4 Snider BB, Zhou J. J. Org. Chem. 2005; 70: 1087
    CrossrefPubMedSearch in Google Scholar
  • 6 Ricardo MG, Marrrero JF, Valdés O, Rivera DG, Wessjohann LA. Chem. Eur. J. 2019; 25: 769
    CrossrefPubMedSearch in Google Scholar
  • 7 CAUTION: This volatile substance has a strong unpleasant odor. Proper handling in a well-ventilated fume hood is essential. See SerlinkI.
  • 8 The pyrroline is volatile, so some yield is lost on concentrating. Care needs to be taken to lose as little material as possible. See SI.
  • 9 Various alkyl alkanoyl pyrrolines were synthesized by using this procedure. Bromoacetyl and trichloroacetyl congeners of 10 formed efficiently when 9 was treated with the corresponding acid halides, but these products failed to cyclize effectively under Heck conditions.
  • 10 Marcoux D, Bindschädler P, Speed AW. H, Chiu A, Pero JE, Borg GA, Evans DA. Org. Lett. 2011; 13: 3758
    CrossrefPubMedSearch in Google Scholar
  • 12 1-(4-Methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2); Typical Procedure A solution of 4-isocyanobut-1-ene (9; 1.09 g, 13.27 mmol) in DCM (13.3 mL, 1.0 M) was treated by dropwise addition of acetyl bromide (1.03 mL, 1.1 equiv) at 23 °C. The resulting mixture was stirred for 1 h and then concentrated under vacuum. The crude crimson oily product 10 was used immediately in the next step. A separate flame-dried flask was charged with Pd(PPh3)4 (1.53 g, 1.33 mmol) and Ag2CO3 (5.49 g, 19.9 mmol), then purged with argon (×3). The catalyst mixture was suspended in toluene (110 mL) and heated to 95 °C. The crude imidoyl bromide 10 was dissolved in toluene (20 mL), and the solution was added to the catalyst mixture over 20 min. The mixture was stirred for 10 min and then removed from the heating bath. The toluene mixture was purified by column chromatography [silica gel, Et2O–pentane (0% Et2O → 10% → 20%)]. The fractions were collected and concentrated under vacuum (250 mbar) at rt until 10 mL of solution remained. This was transferred to a vial and the solvent was further evaporated by using an argon line to avoid evaporating the product; this gave a volatile yellow oil with a pleasant, corn-like smell; yield: 920 mg (56%). 1H NMR (500 MHz, CDCl3): δ = 6.07 (td, J = 2.9, 0.5 Hz, 1 H), 5.45 (td, J = 2.7, 0.7 Hz, 1 H), 4.08 (m, 2 H), 2.71–2.67 (m, 2 H), 2.52 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 198.1, 168.2, 145.3, 114.1, 58.3, 30.6, 27.8. HRMS (ESI): m/z [M + H]+ calcd for C7H10NO: 124.0762; found: 124.0766.

Corresponding Author

Patrick G. Harran
Department of Chemistry and Biochemistry
University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569
USA   

Publication History

Received: 07 October 2022

Accepted after revision: 27 October 2022

Accepted Manuscript online:
27 October 2022

Article published online:
20 December 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

  • 1 Current address: L. Li, Chinese Academy of Sciences, 52 Sanlihe Rd., Xicheng District, Beijing 100864, P. R. of China; liuboli@iccas.ac.cn.
  • 4 Snider BB, Zhou J. J. Org. Chem. 2005; 70: 1087
    CrossrefPubMedSearch in Google Scholar
  • 6 Ricardo MG, Marrrero JF, Valdés O, Rivera DG, Wessjohann LA. Chem. Eur. J. 2019; 25: 769
    CrossrefPubMedSearch in Google Scholar
  • 7 CAUTION: This volatile substance has a strong unpleasant odor. Proper handling in a well-ventilated fume hood is essential. See SerlinkI.
  • 8 The pyrroline is volatile, so some yield is lost on concentrating. Care needs to be taken to lose as little material as possible. See SI.
  • 9 Various alkyl alkanoyl pyrrolines were synthesized by using this procedure. Bromoacetyl and trichloroacetyl congeners of 10 formed efficiently when 9 was treated with the corresponding acid halides, but these products failed to cyclize effectively under Heck conditions.
  • 10 Marcoux D, Bindschädler P, Speed AW. H, Chiu A, Pero JE, Borg GA, Evans DA. Org. Lett. 2011; 13: 3758
    CrossrefPubMedSearch in Google Scholar
  • 12 1-(4-Methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2); Typical Procedure A solution of 4-isocyanobut-1-ene (9; 1.09 g, 13.27 mmol) in DCM (13.3 mL, 1.0 M) was treated by dropwise addition of acetyl bromide (1.03 mL, 1.1 equiv) at 23 °C. The resulting mixture was stirred for 1 h and then concentrated under vacuum. The crude crimson oily product 10 was used immediately in the next step. A separate flame-dried flask was charged with Pd(PPh3)4 (1.53 g, 1.33 mmol) and Ag2CO3 (5.49 g, 19.9 mmol), then purged with argon (×3). The catalyst mixture was suspended in toluene (110 mL) and heated to 95 °C. The crude imidoyl bromide 10 was dissolved in toluene (20 mL), and the solution was added to the catalyst mixture over 20 min. The mixture was stirred for 10 min and then removed from the heating bath. The toluene mixture was purified by column chromatography [silica gel, Et2O–pentane (0% Et2O → 10% → 20%)]. The fractions were collected and concentrated under vacuum (250 mbar) at rt until 10 mL of solution remained. This was transferred to a vial and the solvent was further evaporated by using an argon line to avoid evaporating the product; this gave a volatile yellow oil with a pleasant, corn-like smell; yield: 920 mg (56%). 1H NMR (500 MHz, CDCl3): δ = 6.07 (td, J = 2.9, 0.5 Hz, 1 H), 5.45 (td, J = 2.7, 0.7 Hz, 1 H), 4.08 (m, 2 H), 2.71–2.67 (m, 2 H), 2.52 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 198.1, 168.2, 145.3, 114.1, 58.3, 30.6, 27.8. HRMS (ESI): m/z [M + H]+ calcd for C7H10NO: 124.0762; found: 124.0766.

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Zoom Image
Scheme 1 1-(4-methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2) viewed as a portimine substructure and earlier methods influential in the current studies. See references 4 and 5.
Zoom Image
Scheme 2 Concise synthesis of 2 by Heck cyclization of an imidoyl bromide generated in situ
Zoom Image
Figure 1 1H NMR spectra (500 MHz, CDCl3, 23 °C) of compounds 9, 10, and 2. The spectrum for 10 was recorded on the concentrated crude material. Data for 9 and 2 were collected from chromatographically purified material.
Zoom Image
Scheme 3 Reactivity of compound 2. (a) Dropwise addition of a MeCN solution of 2 to a 0.1 M MeCN solution of TFA (1 equiv); then, dropwise addition of a MeCN solution of 5-benzyloxy-2-methylpenta-1,3-diene.[10] (b) Rapid addition of TFA (1 equiv) to a 0.1 M DCM solution of 2. (c) t-BuLi (1.59 M, 0.3 mL, 1.1 equiv), 2 (50.0 mg, 0.41 mmol, 1 equiv), THF (0.1 M), –78 °C, 2 h. (d) mCPBA (235 mg, 1.02 mmol, 1.2 equiv), 2 (105 mg, 852 mmol, 1 equiv), THF (0.1M), 23 °C, 3 h.
Zoom Image
Scheme 4 Bayer–Villiger reactions of alkanoyl methylidene pyrrolines with various degrees of substitution on the α-carbon. Reaction conditions: 15 (0.85 mmol, 1 equiv), mCPBA (1.2 equiv), THF (0.1 M), 23 °C. For syntheses of compounds 15a–d, see the Supplementary Information (SI).