Synthesis of N-Acyl Pyrroles and Isoindoles from Oxime Ester Precursors via Transition-Metal-Catalyzed Iminocarboxylation

Abstract

We describe Pt(II)- and Fe(III)-catalyzed iminocarboxylations of oxime esters conjugated with 1,3-enyne and an ortho-alkynylarene moiety, followed by a spontaneous O→N acyl migration of the enol carboxylate intermediate to generate N-acyl pyrroles and isoindoles. The reaction scope for pyrrole synthesis is general, whereas the formation of isoindoles has a relatively narrow scope because of their instability.

Oxyamination[1] is a process whereby N,O-functionalities are added across the π-bonds of alkenes or alkynes, usually with catalysis by transition-metal complexes, such as those of copper,[2] iron,[3] gold,[4] platinum,[5] palladium,[6] rhodium,[7] iridium,[8] or osmium.[9] Compared with the oxyamination of alkenes, the corresponding reaction of alkynes is much less developed, although some insightful examples of transition-metal-catalyzed cyclization of alkyne-tethered oxime esters and oximes have been reported (Scheme [1]). Kitamura et al. employed a Pd(0)-catalyzed N–O bond cleavage with pentafluorobenzoyl oxime (Scheme [1a]).[10] The imino–Pd(II) complex undergoes a 5-exo-dig cyclization followed by capture of the vinyl-Pd(II) species with a hydride or an arylboronic acid to generate methylene isoindole frameworks. Li and co-workers reported that a Rh(III) complex can behave as a π-philic Lewis acid to induce 6-endo-iminorhodation instead of N–O bond cleavage. The resulting N-acetoxyisoquinolinium intermediate undergoes a thermal [3,3]-sigmatropic rearrangement to generate an isoquinoline derivative (Scheme [1b]).[11] Similarly, Zhang et al. reported a Ag-catalyzed reaction of aldoximes to generate an N-acetoxyisoquinolinium intermediate that underwent a [1,2]-acetoxy migration followed by hydrolysis to provide isoquinolin-(2H)-ones (Scheme [1c]).[12] Shin and co-workers explored Au(I)-catalyzed cyclization reactions of E/Z-isomeric oximes and found that the (E)-oximes underwent iminoauration followed by proton transfer to generate isoquinoline N-oxides,[13] whereas the corresponding (Z)-oxime isomers selectively underwent oxyauration followed by N–O bond cleavage and C–N bond formation mediated by an α-carbonyl Au carbenoid to provide isoindole derivatives.

To expand the 1,2-difunctionalization of alkynes by using metal carbenoids, we turned our attention to the reactivity of metal nitrenoids (Scheme [1d]). Cyclization of N-acyloxycarbamates and O-acylhydroxamates catalyzed by Pt(II) or Fe(III) complexes provided the initial amidocarboxylation products via metal–ketimido complexes (azaalkylidenes). The characteristic reactivity of the enol carboxylate in these products involved an O→N acyl migration, leading to acylpyrrole derivatives.[14]

We began our exploration with an oxime ester to screen the variables. Treatment of the oxime ester 1a with PtCl₂ under CO (1 atm) in toluene at 65 °C generated pyrrole 2a in 84% yield (Table [1], entry 1). Changing the solvent to dichloroethane gave a higher yield (entry 2). When PtCl₂ was replaced with an iron(III) or iron(II) catalyst, product 2a was also obtained, albeit in a slightly lower yield (entries 3–5). LiCl as a Lewis acid gave 2a in a moderate yield (50%). Whereas the gold(I) complex Au(PPh₃)Cl gave 2a in a moderate yield, the reaction with the gold(III) complex dichloro(2-pyridinecarboxylato)gold led to decomposition of the substrate (entries 7 and 8, respectively). Among the catalyst tried, AgOTf showed a unique reactivity, giving the pyridine product 2a′ through a 6-endo cyclization followed by a [3,3]-sigmatropic rearrangement (entry 9). The reaction with Pd(PPh₃)₄ provided a moderate yield of 2a (entry 10). Heating the substrate without a catalyst resulted in full recovery of the starting material, which ruled out a thermal N–O bond-cleavage pathway (entry 11).

Table 1 Optimization of the Conditions for Iminocarboxylation Followed by an O→N Acyl Group Migration

Entry	Catalyst	Solvent	Temp (°C)	Time (h)	Product	Yielda (%)
1	PtCl2/CO	toluene	65b	16	2a	84
2	PtCl2/CO	DCE	65	20	2a	87
3	FeCl3	MeCN	45	18	2a	78
4	Fe(acac)3	MeCN	65	16	2a	78
5	FeBr2	MeCN	45	24	2a	76
6	LiClc	toluene	105	5.5	2a	50
7	Au(PPh3)Cl	toluene	80	18	2a	63
8	Au(III)d	toluene	50	14	–e	–
9	AgOTf	CH2Cl2	60	12	2a′	65
10	Pd(PPh3)4	MeCN	75	3.5	2a	48
11	none	toluene	65	24	–f	–

^a Isolated yield.

^b At 100 °C, complete conversion occurred in 1 h.

^c 20 mol% loading.

^d Dichloro(2-pyridinecarboxylato)gold.

^e Decomposition.

^f No conversion.

The effect of the oxime ester geometry[13] on the reaction course was next examined with separately prepared (E)- and (Z)-oxime ester 1b and 1b′ (Scheme [2]). These oxime esters reacted smoothly and both gave the same product, 2b, in similar yields. We also examined the reactivity of aldoxime 1c and found that nitrile 2c′ was formed in preference to pyrrole 2c.[10]

With these reactivity profiles in hand, we further explored the generality with other substrates (Scheme [3]). Replacing the benzoyl group with an acetyl group gave a lower yield of 2d, whereas the introduction of various alkynyl substituents was well tolerated to generate 2a, 2b, 2f, and 2l under the reaction conditions. The size of the fused ring had a significant impact on the reactivity; the substrate with a five-membered ring provided product 2g in a much lower yield, whereas substrates with larger rings gave good yields of the products 2h and 2i. Tetralone derivatives gave pyrroles 2j and 2k in high yields. Substrates without a fused ring also reacted smoothly, even in presence of an ester group, to generate compounds 2n, 2o, and 2p. Acyl silanes 2l and 2q were generated from the corresponding alkynyl silanes with an iron catalyst, whereas PtCl₂/CO provided a desilylated product with reduced yield; the increased water contents (20 equiv) in the reaction promoted desilylation, providing aldehydes 2m and 2r and deacylated product 2m′.

Next, we turned our attention to the reaction of benzo-fused oximes (Scheme [4]).[15] Whereas the treatment of substrate 3a with PtCl₂/CO provided 4a in a good yield, the reaction with iron(III) catalysts gave much lower yields of the same product, With Au, Ag, and Pd catalysts, however, the reaction gave the isoquinoline 4a′ in moderate to low yields. Substrates with an aryl group or other alkyl group gave products 4b, 4d, and 4e in good to moderate yields. On the other hand, a substrate with an electron-donating group on the fused benzene ring resulted in decomposition, and product 4f was not obtained. Also, replacing the benzoyl group with an acetyl group led to decomposition, and product 4g was not obtained.

To gain insight into the acyl transfer, we carried out a crossover experiment using two different oxime esters (Scheme [5]). When a 1:1 mixture of 1d and 1o was treated with either a Fe(III) or a Pt(II) catalyst, four products (2d, 2o, 2a, and 2o′) were obtained, including the acyl-exchanged products, in various yields. Also, treatment of the oxime ester 1b with FeCl₃ catalyst and NaOAc (3 equiv) provided pyrrole products 2b and 2d with low conversions in a normal timeframe. These results suggest a bimolecular reaction mechanism for the acyl transfer.

For the Pt(II)- and Fe(III)-catalyzed iminocarboxylation of oxime esters, we propose two plausible mechanisms that are consistent with the observed experimental data (Scheme [6]). The first pathway involves an initial N–O bond cleavage of oxime ester 1/3 to form a metal–ketimido complex[16] (azaalkylidene) IN-1. The ketimido moiety in IN-1 interacts with the alkyne to induce concomitant C–N and C–O bond formation to generate IN-2/IN-3, which undergoes acyl transfer to generate 2/4. The acyl transfer probably involves the formation of an acylium ion, which is justified by the acyl group crossover experiments.

In the other pathway, the π-philic Lewis acid induces a 5-exo-dig cyclization to form IN-4, a resonance form of IN-5, that cyclizes to form IN-6. N–O bond cleavage from IN-6 to form IN-7 followed by its reassociation with the catalyst generates the same intermediate IN-3. Because π-philic Lewis acids induce 6-endo-dig cyclization, and both E/Z-isomers of the oxime ester show similar reaction profiles, we conclude that the first pathway proceeding through a ketimido complex (azaalkylidene) is more consistent with the experimental outcomes.

In conclusion, we have developed a unique protocol for the preparation of N-acyl pyrroles and isoindoles.[17] Treating oxime esters conjugated with a 1,3-enyne or alkynylarene moiety with a Pt(II) or Fe(III) catalyst induces iminocarboxylation to generate enol carboxylate products that undergo a spontaneous O→N acyl migration, leading to N-acyl pyrroles and isoindoles. Mechanistically, we believe that a metal–ketimido complex (azaalkylidene) is generated through initial N–O bond cleavage by the metal catalyst; this complex then undergoes concomitant C–N and C–O bond formation with the tethered alkyne, followed by spontaneous acyl migration to complete the catalytic process. The similar reactivity of both the (E)- and (Z)-isomers of the oxime ester is strong evidence that N–O bond cleavage precedes C–N bond formation. The reaction scope for pyrrole synthesis is general, as exemplified by the formation of a novel acylsilane-containing pyrrole, whereas the formation of isoindoles has a relatively narrow scope because of their instability.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The Mass Spectrometry Laboratory at UIUC is acknowledged.

• References and Notes

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• 17 N-Acylpyrroles 2a–r; General Procedure (Conditions A) A Schlenk tube was charged with a solution of the appropriate oxime ester 1 (0.15 mmol) in freshly distilled MeCN (2.5 mL). FeCl₃ (0.075 mmol, 5 mol%) was added, the tube was sealed, and the mixture was heated at 45 °C until the reaction was complete. The crude product was concentrated in vacuo and purified by chromatography (silica gel). Conditions B A Schlenk tube was charged with a solution of the appropriate oxime ester 1 (0.15 mmol) in freshly distilled toluene (3 mL). PtCl₂ (0.075 mmol, 5 mol %) was added, and CO was gradually bubbled into the solution for 10 min. The Schlenk tube was then carefully sealed and heated at 65–70 °C until the reaction was complete. The crude product was concentrated in vacuo and purified by chromatography (silica gel). 1-(2-Benzoyl-3-methyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)pentan-1-one (2a) Light-yellow solid; yield: 78% (Conditions A); 87% (Conditions B). ¹H NMR (500 MHz, CDCl₃): δ = 7.56 (d, J = 7.6 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 2 H), 2.85 (t, J = 6.2 Hz, 2 H), 2.53 (t, J = 7.5 Hz, 2 H), 2.49 (t, J = 6.2 Hz, 2 H), 2.10 (s, 3 H), 1.89–1.82 (m, 2 H), 1.82–1.74 (m, 2 H), 1.46 (p, J = 7.6 Hz, 2 H), 1.18 (h, J = 7.4 Hz, 2 H), 0.81 (t, J = 7.3 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 188.61, 171.65, 135.32, 133.61, 133.12, 130.56, 129.45, 129.13, 128.51, 120.47, 39.47, 26.52, 24.47, 23.41, 22.83, 22.36, 21.41, 13.88, 10.08. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₆NO₂: 324.1964; found: 324.1962.

Corresponding Author

Publication History

Received: 10 September 2022

Accepted after revision: 26 September 2022

Article published online:
03 November 2022

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• References and Notes

• 1a Donohoe TJ, Callens CK. A, Flores A, Lacy AR, Rathi AH. Chem. Eur. J. 2011; 17: 58
  CrossrefPubMedSearch in Google Scholar
• 1b Hemric BN. Org. Biomol. Chem. 2021; 19: 46
  CrossrefPubMedSearch in Google Scholar
• 2a Michaelis DJ, Shaffer CJ, Yoon TP. J. Am. Chem. Soc. 2007; 129: 1866
  CrossrefPubMedSearch in Google Scholar
• 2b Michaelis DJ, Ischay MA, Yoon TP. J. Am. Chem. Soc. 2008; 130: 6610
  CrossrefPubMedSearch in Google Scholar
• 2c Fuller PH, Kim J.-W, Chemler SR. J. Am. Chem. Soc. 2008; 130: 17638
  CrossrefPubMedSearch in Google Scholar
• 2d Hemric BN, Shen K, Wang Q. J. Am. Chem. Soc. 2016; 138: 5813
  CrossrefPubMedSearch in Google Scholar
• 2e Liu R.-H, Wei D, Han B, Yu W. ACS Catal. 2016; 6: 6525
  CrossrefSearch in Google Scholar
• 2f Wu F, Stewart S, Ariyarathna JP, Li W. ACS Catal. 2018; 8: 1921
  CrossrefSearch in Google Scholar
• 2g Hemric BN, Chen AW, Wang Q. ACS Catal. 2019; 9: 10070
  CrossrefPubMedSearch in Google Scholar
• 3a Williamson KS, Yoon TP. J. Am. Chem. Soc. 2010; 132: 4570
  CrossrefPubMedSearch in Google Scholar
• 3b Williamson KS, Yoon TP. J. Am. Chem. Soc. 2012; 134: 12370
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• 3c Liu G.-S, Zhang Y.-Q, Yuan Y.-A, Xu H. J. Am. Chem. Soc. 2013; 135: 3343
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• 3d Lu D.-F, Zhu C.-L, Jia Z.-X, Xu H. J. Am. Chem. Soc. 2014; 136: 13186
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• 3e Legnani L, Morandi B. Angew. Chem. Int. Ed. 2016; 55: 2248
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• 4a de Haro T, Nevado C. Angew. Chem. Int. Ed. 2011; 50: 906
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• 4b Shaikh AC, Ranade DS, Rajamohanan PR, Kulkarni PP, Patil NT. Angew. Chem. Int. Ed. 2017; 56: 757
  CrossrefPubMedSearch in Google Scholar
• 5 Muñiz K, Iglesias A, Fang Y. Chem. Commun. 2009; 5591
  CrossrefPubMed
• 6a Bäckvall JE, Bjoerkman EE. J. Org. Chem. 1980; 45: 2893
  CrossrefSearch in Google Scholar
• 6b Bäckvall JE, Bystroem SE. J. Org. Chem. 1982; 47: 1126
  CrossrefSearch in Google Scholar
• 6c Alexanian EJ, Lee C, Sorensen EJ. J. Am. Chem. Soc. 2005; 127: 7690
  CrossrefPubMedSearch in Google Scholar
• 6d Liu G, Stahl SS. J. Am. Chem. Soc. 2006; 128: 7179
  CrossrefPubMedSearch in Google Scholar
• 6e Desai LV, Sanford MS. Angew. Chem. Int. Ed. 2007; 46: 5737
  CrossrefPubMedSearch in Google Scholar
• 6f Shen H.-C, Wu Y.-F, Zhang Y, Fan L.-F, Han Z.-Y, Gong L.-Z. Angew. Chem. Int. Ed. 2018; 57: 2372
  CrossrefPubMedSearch in Google Scholar
• 7a Dequirez G, Ciesielski J, Retailleau P, Dauban P. Chem. Eur. J. 2014; 20: 8929
  CrossrefPubMedSearch in Google Scholar
• 7b Escudero J, Bellosta V, Cossy J. Angew. Chem. Int. Ed. 2018; 57: 574
  CrossrefPubMedSearch in Google Scholar
• 7c Thornton AR, Blakey SB. J. Am. Chem. Soc. 2008; 130: 5020
  CrossrefPubMedSearch in Google Scholar
• 7d Mace N, Thornton AR, Blakey SB. Angew. Chem. Int. Ed. 2013; 52: 5836
  CrossrefPubMedSearch in Google Scholar
• 7e Pan D, Wei Y, Shi M. Org. Lett. 2018; 20: 84
  CrossrefPubMedSearch in Google Scholar
• 8a Lei H, Conway JH. Jr, Cook CC, Rovis T. J. Am. Chem. Soc. 2019; 141: 11864
  CrossrefPubMedSearch in Google Scholar
• 8b Hong SY, Chang S. J. Am. Chem. Soc. 2019; 141: 10399
  CrossrefPubMedSearch in Google Scholar
• 8c Kim S, Kim D, Hong SY, Chang S. J. Am. Chem. Soc. 2021; 143: 3993
  CrossrefPubMedSearch in Google Scholar
• 9a Sharpless KB, Patrick DW, Truesdale LK, Biller SA. J. Am. Chem. Soc. 1975; 97: 2305
  CrossrefSearch in Google Scholar
• 9b Rudolph J, Sennhenn PC, Vlaar CP, Sharpless KB. Angew. Chem. Int. Ed. Engl. 1996; 35: 2810
  CrossrefSearch in Google Scholar
• 9c Bruncko M, Schlingloff G, Sharpless KB. Angew. Chem. Int. Ed. Engl. 1997; 36: 1483
  CrossrefSearch in Google Scholar
• 9d Donohoe TJ, Johnson PD, Cowley A, Keenan M. J. Am. Chem. Soc. 2002; 124: 12934
  CrossrefPubMedSearch in Google Scholar
• 9e Donohoe TJ, Chughtai MJ, Klauber DJ, Griffin D, Campbell AD. J. Am. Chem. Soc. 2006; 128: 2514
  CrossrefPubMedSearch in Google Scholar
• 10 Kitamura M, Moriyasu Y, Okauchi T. Synlett 2011; 643
  Thieme ConnectPubMed
• 11 Zhao P, Wang F, Han K, Li X. Org. Lett. 2012; 14: 3400
  CrossrefPubMedSearch in Google Scholar
• 12 Gao H, Zhang J. Adv. Synth. Catal. 2009; 351: 85
  CrossrefPubMedSearch in Google Scholar
• 13a Yeom H.-S, Lee Y, Lee J.-E, Shin S. Org. Biomol. Chem. 2009; 7: 4744
  CrossrefPubMedSearch in Google Scholar
• 13b Kim WS, Espinoza Castro VM, Abiad A, Ko M, Council A, Nguyen A, Marsalla L, Lee V, Tran T, Petit AS, de Lijser HJ. P. J. Org. Chem. 2021; 86: 693
  CrossrefPubMedSearch in Google Scholar

For examples of pyrrole synthesis from oxime derivatives, see:
• 14a Yoshida M, Kitamura M, Narasaka K. Bull. Chem. Soc. Jpn. 2003; 76: 2003
  CrossrefSearch in Google Scholar
• 14b Portela-Cubillo F, Scott JS, Walton JC. Chem. Commun. 2007; 4041
  CrossrefPubMed
• 14c Cai Y, Jalan A, Kubosumi AR, Castle SL. Org. Lett. 2015; 17: 488
  CrossrefPubMedSearch in Google Scholar
• 14d Yang H.-B, Selander N. Chem. Eur. J. 2017; 23: 1779
  CrossrefPubMedSearch in Google Scholar
• 15a Pino-Rios R, Solà M. J. Phys. Chem. A 2021; 125: 230
  CrossrefPubMedSearch in Google Scholar
• 15b Heugebaert TS. A, Roman BI, Stevens CV. Chem. Soc. Rev. 2012; 41: 5626
  CrossrefPubMedSearch in Google Scholar
• 15c Shields JE, Bornstein J. J. Am. Chem. Soc. 1969; 91: 5192
  CrossrefSearch in Google Scholar
• 16a Shimbayashi T, Okamoto K, Ohe K. Chem. Eur. J. 2017; 23: 16892
  CrossrefPubMedSearch in Google Scholar

For a review on reactions of metal nitrenoids with alkynes, see:
• 16b Ren M, Wang Y.-C, Ren S, Huang K, Liu J.-B, Qiu G. ChemCatChem 2022; 14: e202200008
  CrossrefSearch in Google Scholar
• 17 N-Acylpyrroles 2a–r; General Procedure (Conditions A) A Schlenk tube was charged with a solution of the appropriate oxime ester 1 (0.15 mmol) in freshly distilled MeCN (2.5 mL). FeCl₃ (0.075 mmol, 5 mol%) was added, the tube was sealed, and the mixture was heated at 45 °C until the reaction was complete. The crude product was concentrated in vacuo and purified by chromatography (silica gel). Conditions B A Schlenk tube was charged with a solution of the appropriate oxime ester 1 (0.15 mmol) in freshly distilled toluene (3 mL). PtCl₂ (0.075 mmol, 5 mol %) was added, and CO was gradually bubbled into the solution for 10 min. The Schlenk tube was then carefully sealed and heated at 65–70 °C until the reaction was complete. The crude product was concentrated in vacuo and purified by chromatography (silica gel). 1-(2-Benzoyl-3-methyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)pentan-1-one (2a) Light-yellow solid; yield: 78% (Conditions A); 87% (Conditions B). ¹H NMR (500 MHz, CDCl₃): δ = 7.56 (d, J = 7.6 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 2 H), 2.85 (t, J = 6.2 Hz, 2 H), 2.53 (t, J = 7.5 Hz, 2 H), 2.49 (t, J = 6.2 Hz, 2 H), 2.10 (s, 3 H), 1.89–1.82 (m, 2 H), 1.82–1.74 (m, 2 H), 1.46 (p, J = 7.6 Hz, 2 H), 1.18 (h, J = 7.4 Hz, 2 H), 0.81 (t, J = 7.3 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 188.61, 171.65, 135.32, 133.61, 133.12, 130.56, 129.45, 129.13, 128.51, 120.47, 39.47, 26.52, 24.47, 23.41, 22.83, 22.36, 21.41, 13.88, 10.08. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₆NO₂: 324.1964; found: 324.1962.

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