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Synthesis 2022; 54(04): 1043-1054
DOI: 10.1055/a-1703-6448
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Cycloadditions – Established and Novel Trends – in Celebration of the 70th Anniversary of the Nobel Prize Awarded to Otto Diels and Kurt Alder

Ascending of Cycloaddition Strategy for N–O Heterocycles

Prasanjit Ghosh
,
Swati Lekha Mondal
,
Mahiuddin Baidya∗

P.G. acknowledges the Science and Engineering Research Board (SERB) for a NPDF (PDF/2017/000449) and S.M. also acknowledges the Council of Scientific and Industrial Research, India (CSIR) for a JRF. M.B. thanks the Indian Institute of Technology Madras (IIT-Madras) for Institute Research Development Award (IRDA) and funding support through IOE project grant.
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Abstract

The N–O heterocycles are biologically relevant scaffolds and versatile building blocks in contemporary organic synthesis. In this short review, we showcase the involvement and elevation of various cycloaddition strategies towards the production of the N–O heterocycles; 1,2-oxazines and 1,2-oxazinanes, 1,2-oxazepanes, and 1,2-oxazetidines. An overview of the advantages and challenges associated with these synthetic endeavors is provided.

1 Introduction

2 Six-Membered N–O Heterocycles (1,2-Oxazines and 1,2-Oxazinanes)

3 Seven-Membered N–O Heterocycles (1,2-Oxazepanes)

4 Four-Membered N–O Heterocycles (1,2-Oxazetidines)

5 Summary and Outlook


#

Key words

cycloaddition - nitroso Diels–Alder reaction - nitrones - oxazines - oxazetidines - oxazepane - cyclopropanes - cascade reaction
1

Introduction

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Prof. Mahiuddin Baidyawas born in 1983 (West Bengal, India) and received his Ph.D. from Ludwig-Maximilians-Universität München, Germany in 2009 under the supervision of Prof. Herbert Mayr. After post-doctoral studies with Prof. Hisashi Yamamoto at the University of Chicago, USA and the Molecular Catalyst Research Center, Chubu University, Japan, he joined at the department of Chemistry, Indian Institute of Technology, Madras in 2014. In 2018, he was promoted to Associate Professor. His current research interests focus on the development of novel concepts for transition-metal catalysis, organocatalysis, photo-redox catalysis, and synthesis of bioactive compounds. He serves as an Early Career Advisory Board (ECAB) member of ACS Catalysis journal and International Advisory Board Member of Chemistry – An Asian Journal. Dr. Prasanjit Ghosh (left), Ph.D. in organic chemistry from University of North Bengal, is a SERB-NPDF fellow and Swati Lekha Mondal (middle), M.Sc. from IIT-ISM Dhanbad, is a graduate student in his research group.

Nature has enriched itself with an abundance of heterocyclic cores that continuously inspire chemists to embrace novel synthetic strategies. In this respect, molecules containing an N–O linkage in a ring framework are significant.[1] A wide variety of heterocycles containing an N–O bond are available: oxaziridine (three-membered), 1,2-oxazetidine (four-membered), 1,2-oxazolidine (five-membered), 1,2-oxazine and 1,2-oxazinanes (six-membered), and 1,2-oxazepane (seven-membered), to name a few. Natural products such as indole alkaloids alsmaphorazine A and B, the securinega family of alkaloids, for instance phyllantidine, and various drug candidates, for example FR900482 and CH4987655, with promising bioactivities are all N–O heterocycles (Figure [1]).[2] These heterocycles also serve as high-value building blocks to fabricate various oxygen- and nitrogen-rich molecules. Among the diverse synthetic endeavors,[1] cycloaddition-type of reaction modality has received substantial attention, providing a step-economical approach for the modular construction of N–O heterocycles with high regio- and stereocontrol. In this review, we will critically highlight the versatility and diversity of the cycloaddition strategy leading to N–O heterocyclic frameworks. Reactions are classified based on types of cycloaddition process ([4+2], [3+3], [4+3], and [2+2]) and product categories with specific emphasis on stereoinduction and natural product synthesis. Strategic developments towards six-, seven-, and four-membered N–O heterocycles are considered here; five-membered N–O heterocycles are not included as recent reviews are available on this topic.[1e] Also, syntheses of N–O heterocycles that do not follow cycloaddition reaction modality, for example cascade reactions depicted in Scheme [1], are out with the scope of this review.[3]

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Scheme 1 Alternative synthesis of N–O heterocycles
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Figure 1 Biologically active compound containing N–O heterocycles

# 2

Six-Membered N–O Heterocycles (1,2-Oxazines and 1,2-Oxazinanes)

Among the wide variety of N-O bond containing heterocycles, the six- membered homologues, so called 1,2-oxazines and 1,2-oxazinanes are most popular. Strategically, they can be accessed through cycloaddition-type reactions with suitable synthons effective to deliver the N–O bond. In this direction, nitroso species and nitrones play pivotal roles owing to their ambiphilic reactivity. At present two types of cycloaddition reaction modalities, [4+2] and [3+3], also termed as formal [4+2], are largely explored.

2.1

[4+2] Cycloaddition

The development of [4+2]-cycloaddition reaction modality leading to 1,2-oxazine frameworks predominantly utilizes nitroso species. Generally, C-nitroso compounds such as cyanonitroso, acylnitroso, α-halonitroso, α-acetoxynitroso, arylnitroso, and pyridinonitroso have been exploited (Scheme [2]). The cycloaddition reaction of a substituted diene with nitroso species typically affords two regioisomers. One is called proximal where the main substituent is close to the oxygen center and other is termed as distal where the main substituent is close to the nitrogen center in the cycloadduct (Scheme [2]). However, the prediction of regioselectivity for this reaction is a cumbersome task and often rationalized with combined steric and electronic effects and the nature of the nitroso species.[4] [5]

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Scheme 2 Nitroso dienophiles and mode of [4+2] cycloaddition with dienes
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Scheme 3 HDA reaction between thebaine and an acylnitroso compound

Pioneering studies in the 1940s on [4+2]-cycloaddition reactions of nitroso species were attempted by Wichterle[6] and Arbuzov.[7] Their ground-breaking discovery was highlighted in 1973 by Kirby and Sweeny in the cycloaddition reaction of acylnitroso species in the presence of alkaloid thebaine (Scheme [3]).[8] Notably, acylnitroso species are highly reactive and must be generated in situ during the course of the reaction. One major challenge was to identify mild reaction conditions to enable the generation of acylnitroso species. In 2011, Marder, Shea, Whiting, and co-workers reported a mild CuCl2/2-ethyl-2-oxazoline ligand-based catalytic system for the oxidation of hydroxamic acids into acylnitroso species under an oxygen atmosphere, and this was used in an intermolecular [4+2] reaction in a one-pot fashion to give dihydro-1,2-oxazines in high yields.[9a] The solvents MeOH and CHCl3 showed a substantial effect on both the rate of reaction and the yields of cycloadducts (Scheme [4a]). The synthetic efficacy of the [4+2]-cycloaddition reaction modality of acylnitroso species is evident from the total synthesis of (–)-pumiliotoxin C developed by the Kibayashi­ group (Scheme [4b]).[9b]

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Scheme 4 [4+2] Cycloaddition of acylnitroso species with dienes
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Scheme 5 Cycloaddition reaction of nitrosoalkenes with enol ethers

The Denmark group reported a dehalogenative strategy to access nitrosoalkenes from α-chloro O-silyl oximes and demonstrated their intramolecular [4+2]-cycloaddition reaction with tethered enol ethers to obtain 1,2-oxazine-embedded tricyclic building blocks (Scheme [5a]).[10a] This reaction is an example of an inverse-electron-demand mode of reactivity. Palacios and co-workers further advanced this process in an intermolecular fashion using phosphonyl- and phosphinyl-substituted nitrosoalkenes in an aqueous medium (Scheme [5b]).[10b]

Yu, Liao, and co-workers introduced a zwitterionic nitroso species, generated in situ from α-halo-N-alkylhydroxamic acids under basic conditions, that smoothly reacted with an alkene in HFIP solvent to give 1,2-oxazinan-3-ones (Scheme [6]).[11] The choice of HFIP is critical to stabilize the reactive intermediates. The reaction scope is quite general; styrenes, strained alkenes, such as norbornene, and aromatic furan readily participated, albeit acyclic simple aliphatic alkenes exhibited diminished efficacy.

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Scheme 6 Cycloaddition reaction of in situ formed zwitterionic nitrosoalkenes

# 2.2

Enantioselective [4+2] Cycloaddition

An early breakthrough in the enantioselective [4+2] cycloaddition strategy with nitrosobenzene to access six-membered N–O heterocycles was accomplished by Inomata and co-workers who used a stoichiometric amount of Zn-tartaric acid complex as a chiral promoter (Scheme [7a]).[12] The diene was substituted with a hydroxy group for assistance through chelation with the chiral complex, however, the chiral induction remained unsatisfactory.

In 2004, the Yamamoto group used chelated monomeric nitroso derivatives (6-methyl-2-nitrosopyridines) with diverse dienes in the presence of a Lewis acid Cu(I) catalyst to obtain enantioenriched nitroso Diels–Alder adducts (Scheme [7b]).[13] In this catalytic strategy, the combination of chiral biphosphine ligand and sterically hindered nitroso coupling unit was crucial to realize product formation with excellent yields and enantioselectivities, albeit the substrate scope was limited.

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Scheme 7 Enantioselective [4+2] cycloaddition with nitrosoarenes

The Studer group broaden the scope of nitroso Diels–Alder reaction using [Cu(MeCN)4](PF6) catalyst in combination with Walphos-CF3 ligand (Scheme [7c]).[14] Notably, they showed the utility of this method by its use as a key step in the chiral synthesis of the natural products (–)-peracylated conduramine A-1 and (+)-trans-dihydronarciclasine.[15] [16]

Again in 2015, the Yamamoto group reported a stereoselective [4+2]-cycloaddition reaction with heteroaromatic nitroso compounds. The reaction was catalyzed with [Cu(MeCN)4](BF4)-(S)-DTBM-SEGPHOS complex to afford 3,6-dihydro-1,2-oxazine cycloadducts with excellent yields and enantioselectivities (Scheme [7d]).[17] This protocol was also employed in the formal synthesis of the alkaloid narciclasine. In 2017, the Wang and Feng groups also independently developed Cu-based catalysis for the enantioselective nitroso Diels–Alder reaction of 2-nitrosopyridines with various cyclic dienes and 1,3-diene-1-carbamates (Scheme [8]).[18] [19]

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Scheme 8 Enantioselective nitroso Diels–Alder reaction of 2-nitrosopyridines with a Cu complex

Masson and co-workers introduced chiral phosphoric acid [(S)-TRIP] to effect the enantioselective [4+2]-cycloaddition process of nitrosoarenes and diene carbamates, furnishing a broad array of cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-, and enantioselectivities (Scheme [9]).[20] Mechanistic studies indicated that the high azaphilicity of (S)-TRIP activates both the coupling partners with the formation of a hydrogen bonding network and thereby accelerates the reaction rate, which was also corroborated by DFT calculations. The Masson group also utilized N-arylhydroxylamines along with m-CPBA oxidant and successfully performed a similar [4+2] cycloaddition with (S)-TRIP catalyst (Scheme [9]).[21]

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Scheme 9 Chiral phosphoric acid catalyzed asymmetric [4+2] cycloaddition reaction of diene carbamates with nitroso species

In 2004, the Yamamoto group used a pyrrolidine-based tetrazole catalyst in a new enantioselective pathway to obtain the [4+2]-cycloadducts of nitrosoarenes (Scheme [10]).[22] The reaction is believed to follow a stepwise path consisting of O-nitroso aldol reaction with cross-dienamines generated from α,β-unsaturated ketones and subsequent intramolecular aza-Michael addition. Starting from the isolated cross-enamine, this reaction can be performed using a silyl binaphthol catalyst possessing tri(m-xylyl)silyl groups at the 3,3′-positions. However, in this case, the nitroso aldol step is N-selective which can be attributed to a hydrogen bond network between the hydroxy groups in the catalyst and the oxygen center of the nitrosoarene (Scheme [10]). In both cases, very high enantioselectivity was achieved.[23]

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Scheme 10 Enantioselective [4+2] cycloaddition of nitrosoarenes with cross-dienamine

In 2019, the Liu group reported the first example of a gold(I)-catalyzed nitroso-Povarov reaction between cyclopentadienes and nitrosoarenes that gave 1,2-oxazine-adorned tricyclic building units in good to excellent yields (Scheme [11a]).[24] This catalytic manifold involves the 1,4-addition of nitrosoarene to the gold–π-diene complex to furnish an allylgold nitrosonium intermediate and next intramolecular annulation facilitates the generation of C–C and C–O bonds. Surprisingly, treatment of haloarylnitroso derivatives with various acyclic 1,3-dienes afforded the oxidative nitroso-Povarov adducts in satisfactory yields under slightly modified reaction parameters (Scheme [11b]). Deuterium-labeling experiments showed that water and O2 are the main sources of the ketonic oxygen atom in the annulated product. In addition, the Liu group also highlighted the asymmetric version of this catalytic transformation with excellent enantioselectivity, albeit alkyl-substituted allenylene gave deleterious results.[25]

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Scheme 11 Au(I)-catalyzed nitroso-Povarov reaction and intramolecular annulation

# 2.3

[3+3] Cycloaddition (Formal [4+2] Cycloaddition)

The [3+3]-cycloaddition reaction pathway is also a renowned synthetic route to access 1,2-oxazine frameworks. Typically, in this approach the nitrone serves as a N–O synthon and strained cyclopropane-1,1-dicarboxylate diesters deliver a three-carbon unit.

The first example of this synthetic strategy was reported in 2003 by Kerr and co-workers. They used the Lewis acid catalyst Yb(OTf)3 to activate cyclopropane-1,1-carboxylate diesters and obtained 1,2-oxazinanes in high yields with excellent diastereoselectivity with a cis relationship between R1 and R2 in the 1,2-oxazinane core (Scheme [12a]).[26] The potential of this methodology was showcased through the construction of the bicyclo[3.3.1] core of the antitumor agent FR-900482 in decent yields.

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Scheme 12 Lewis acid catalyzed [3+3] cycloaddition of nitrones and cyclopropane-1,1-dicarboxylate diesters

In 2004, Kerr and co-workers then reported a multicomponent coupling involving aldehyde, hydroxylamine, and cyclopropane-1,1-dicarboxylate diesters for the same purpose (Scheme [12b]).[27] Notably, this [3+3] cycloaddition reaction was also effectively promoted by MgI2, however, the diastereoselectivity was compromised.[28] It was anticipated that the magnesium malonate intermediate is kinetically stable and fosters a long-lived acyclic intermediate that allows stereochemical leakage to the trans isomer (Scheme [12c]). In 2015, Nolin and co-workers also showed that another Lewis acid Ca(OTf)2 is also an effective catalyst without affecting the syn diastereoselectivity (Scheme [12d]).[29]

In 2005, Sibi and co-workers disclosed the asymmetric version of 1,2-oxazinane synthesis using the Lewis acid Ni(ClO4)2 in combination with a chiral bisoxazoline ligand (Scheme [13a]).[30] The protocol gave [3+3] cycloadducts with moderate diastereoselectivity and high enantioselectivity. In 2007, Tang and co-workers reported a more general synthesis using Ni(ClO4)2 and a sterically encumbered chiral trisoxazoline ligand (Scheme [13b]).[31]

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Scheme 13 Ni(II)-oxazoline ligand catalyzed asymmetric synthesis of 1,2-oxazinanes

Zhang and co-workers used the Sc(OTf)3/1,10-phenanthroline catalytic system to facilitate the [3+3] cycloaddition of nitrones with 1-(alk-1-ynyl)cyclopropyl ketones (Scheme [14]).[32]

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Scheme 14 Sc(OTf)3-catalyzed formal [3+3] cycloaddition of yne-ones with nitrones

Mattson and co-workers introduced a difluoroborane urea as an emerging hydrogen bonding catalyst to activate 1-nitrocyclopropane-1-carboxylates for [3+3]-cycloaddition reactions (Scheme [15]).[33] However, the methodology is strictly restricted to electron-rich 1-nitrocyclopropane-1-carboxylates as they easily rearranged to isoxazoline N-oxides.

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Scheme 15 Hydrogen-bonding-aided [3+3] cycloaddition
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Scheme 16 Synthesis of 1,2-oxazinanes via [3+3] cycloaddition of oxyallyl cation with nitrones

Archambeau and Cordier identified α-tosyloxy ketones as a transient electrophilic 3C synthon that reacts readily with nitrones in 2,2,2-trifluoroethanol (TFE) solvent to give stereodefined 1,2-oxazinane scaffolds (Scheme [16a]).[34] Here the oxyallyl cation is a proposed intermediate, generated from the α-tosyloxy ketone in the presence of the hydrogen bond donor TFE solvent. The use of cyclic ketonitrones with 2-(tosyloxy)pentan-3-one gave spirocyclic products as a single cis-diastereomer with excellent yields. When unsymmetrical cyclic ketonitrones were utilized the corresponding products were obtained, but an erosion of diastereoselectivity took place. This indicates a stepwise reaction pathway where iminium ion isomerization proceeds before the ring-closing sequence. In parallel, Rawal and co-workers reported a similar oxyallyl cation based strategy towards 1,2-oxazinanes (Scheme [16b]).[35] However, it requires an over stoichiometric amount of base, higher temperature, and longer reaction time. Through further investigation, Rawal and co-workers also showed that inexpensive p-nitrophenol can be used as a hydrogen bond donor catalyst in DCE solvent to promote the [3+3]-cycloaddition reactions with improved diastereoselectivity (Scheme [16c]).

In 2020, Banerjee and co-workers reported an advanced synthesis of functionalized 1,2-oxazines (Scheme [17]).[36] This transformation involves a Cloke–Wilson-type rearrangement of activated imines formed through the condensation of aryl-substituted cyclopropanecarbaldehydes and hydroxylamine in an open-air operation, delivering 5,6-dihydro-4H-1,2-oxazines in moderate to good yields. In the presence of the Lewis acid Cu(OTf)2, these products smoothly undergo [3+2] cycloaddition with donor-acceptor cyclopropanes to yield fused N–O heterocycles with good diastereoselective ratio.

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Scheme 17 Cloke–Wilson-type rearrangement of 1,2-oxazine frameworks
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Scheme 18 Pd-catalyzed [3+3] cycloaddition of nitrones with a TMM synthon

In 2006, Hayashi and Shintani explored the reaction of a nitrone with a silylated allylic acetate (precursor for trimethylenemethane, TMM) under Pd(0) catalysis (Scheme [18]).[37a] The reaction was initiated through formation of a TMM synthon by Pd(PPh3)4 and subsequent annulation which resulted in the 5-methylene-1,2-oxazinane in excellent yield. Hayashi and co-workers also examined the asymmetric [3+3] cycloaddition involving a TMM synthon employing a rationally designed chiral phosphoramidite ligand under ambient conditions; enantioenriched 1,2-oxazinane scaffolds were obtained with high stereoselectivity.[37b]

In 2011, the Doyle group introduced a dirhodium carboxylate catalyzed [3+3] cycloaddition of an enol diazoacetate, methyl 3-(tert-butyldimethylsiloxy)-2-diazobut-3-enoate, with acyclic nitrones for the rapid synthesis of rac-3,6-dihydro-2H-1,2-oxazines in excellent yields (Scheme [19]).[38] Furthermore, the [3+3] cycloaddition utilizing chiral (S)-N-phthaloylamino acid ligated dirhodium carboxylates [Rh2(S-PTA)4] gave the desired products with excellent enantioselectivities (Scheme [19]).[39]

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Scheme 19 Rh-catalyzed [3+3] cycloaddition of nitrones with vinylcarbene intermediates

In 2012, the Doyle group showcased a Cu-catalyzed cycloaddition reaction of nitrones with enol diazoacetates (Scheme [20a]).[39] Of note, this innovation also expanded the substrate scope limitation of the Rh(II) catalytic system.

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Scheme 20 Cu and Rh/Ag-catalyzed [3+3] cycloaddition reaction of enol diazoacetates with nitrones
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Scheme 21 Au(I)-catalyzed asymmetric tandem cyclization/[3+3] cycloaddition of 2-(alk-1-ynyl)alk-2-en-1-ones with nitrone

In 2013, the Doyle group developed an unprecedented Rh(II)/Ag(I)-catalyzed cascade enantioselective [3+3] cycloaddition of nitrones with a γ-phenyl-substituted enoldiazoacetate (Scheme [20b]).[40] This one-pot asymmetric transformation first involved in the formation of donor-acceptor cyclopropene by Rh(II)-catalyzed dinitrogen extrusion followed by chiral AgSbF6/(S)- t BuBox facilitated intramolecular cyclization of enoldiazoacetate, to deliver cis-disubstituted 3,6-dihydro-1,2-oxazines with high reaction efficiency and enantioselectivity. On a similar line, [Cu(MeCN)4](BF4) catalyst together with chiral bisoxazoline complexes were also effective in giving the chiral oxazines with high enantiomeric excess (Scheme [20c]).[41]

In notable work in 2009, Zhang and co-workers described a Au(I)-catalyzed intramolecular cycloisomerization of 2-(alk-1-ynyl)alk-2-en-1-ones to afford furyl–gold complexes which subsequently engaged in stepwise [3+3]-cycloaddition reactions with nitrones in a succinct synthesis of fused bicyclic 1,2-oxazine scaffolds in high yields and diastereoselectivity (Scheme [21]).[42] They also exploited two different types of chiral biphenyl-2,2′-bisphosphine ligands, (R)-C1-tunephos and (R)-MeO-dtbm-biphep, for the asymmetric gold(I)-catalyzed [3+3] annulative transformation. The protocol exhibited broad functional group tolerance and delivered optically active heterobicyclic furo[3,4-d][1,2]oxazines with excellent enantioselectivity.[43] In case of an alkyl group present at the terminal position of the alkyne, a reduction in both enantioselectivity and diastereoselectivity was observed. This issue was also overcome by introducing a structurally designed chiral sulfinamide monophosphine ligand (Ming-Phos) and AgNTf2 additive, allowing access to both the enantiomers of fused 1,2-oxazine heterocycles with excellent stereoselectivity (Scheme [21]).[44]

In this vein, the Hashmi group reported an elegant example of the Pt(II)-catalyzed intramolecular cyclization of alkyne-tethered anilines and subsequent formal [3+3] cycloaddition with diverse nitrones to give indole-fused dihydro-1,2-oxazines (Scheme [22]).[45] Mechanistically, the 2-(alk-1-ynyl)aniline undergoes 5-endo-dig cyclization in the presence of PtCl2 to afford an α,β-unsaturated carbene as a crucial intermediate for the [3+3]-cycloaddition process.

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Scheme 22 Pt(II)-catalyzed tandem intramolecular cyclization of 2-(alk-1-ynyl)anilines and [3+3] cycloaddition with nitrones

#
# 3

Seven-Membered N–O Heterocycles (1,2-Oxazepanes)

The progress of cycloaddition reaction modality leading to seven-membered N–O heterocycles has been relatively slow. The [4+3]-type cycloaddition reactions are generally adopted to fabricate such heterocycles where nitrones are considered as part of a C-N-O donor synthon and another four-carbon coupling unit is typically obtained from the substrate design.

In 2011, Pagenkopf and co-workers used donor-acceptor cyclobutanes for [4+3] cycloaddition with nitrones for the synthesis of densely functionalized 1,2-oxazepanes (Scheme [23]).[46] This protocol also found, as first reported by Kerr and co-workers in 2003,[26] that a catalytic amount of Lewis acid Yb(OTf)3, temperature, and electronic effects of the nitrone have a substantial effect in governing the formation of cis and trans isomers.

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Scheme 23 Yb(III)-catalyzed [4+3] cycloaddition of donor-acceptor cyclobutanes with nitrones

In a noteworthy report, Tang and co-workers successfully accomplished the enantioselective [4+3] cycloaddition. The reaction was catalyzed by sterically encumbered chiralSaBox/Cu(II) complex and afforded optically active 1,2-oxazepanes from cyclobutane-1,1-dicarboxylate diesters and nitrones in high yields (Scheme [24]).[47]

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Scheme 24 Cu(II)/SaBox-catalyzed formal [4+3] cycloaddition of donor-acceptor cyclobutanes with nitrones

Shintani, Murakami, and Hayashi reported the Pd-catalyzed reaction of γ-methylidene-δ-valerolactones as a four-carbon 1,4-zwitterionic species in the [4+3]-cycloaddition reaction with nitrones (Scheme [25]).[44] A wide range of structurally decorated 1,2-oxazepanes were prepared in very high yields. Importantly, the use of a chiral phosphoramidite ligand was important to access these N–O heterocycles in excellent enantiomeric excess (Scheme [25]).[48]

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Scheme 25 Pd(0)-catalyzed [4+3] cycloaddition of γ-methylidene-δ-valerolactones with nitrones

In 2009, the Wang group elegantly merged the tandem cycloisomerization of 1-(alk-1-ynyl)cyclopropyl ketones with the [4+3] cycloaddition of nitrones (Scheme [26]).[49] Both Cu(OTf)2 and AuCl3 catalyzed this reaction to give oxazepane-based 5/7-bicyclic heterocycles in good yields and diastereoselectivity; PPh3AuOTf is also an effective catalyst for this [4+3] cycloaddition cascade.[32] The synthesis of enantioenriched 5,7-fused bicyclic furo[3,4-d][1,2]oxazepines was achieved using chiral MeO-dtbm-biphep-derived gold(I) complexes where a dynamic kinetic resolution process is responsible for the enhanced chiral induction (Scheme [26]).[50]

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Scheme 26 Cu(II)/Au-Catalyzed tandem cycloisomerization and [4+3] cycloaddition with nitrones

In 2020, Miao, Ren, and co-workers reported a [4+3]-cycloaddition strategy for the reaction of a non-classical all-carbon-based unconjugated 1,4-dipole with nitrones via Au(I) catalysis.[51] The 1,4-dipoles are in situ generated from cyclopropylidene-containing allenyl ketones. Intriguingly, the regioselectivity of this process can be reversed by changing the ligands on the Au(I) catalyst (Scheme [27]).

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Scheme 27 Divergent generation of carbon based 1,4-dipoles and subsequent furan-fused seven-membered heterocycles

# 4

Four-Membered N–O Heterocycles (1,2-Oxazetidines)

The four-membered N–O heterocycles are generally synthesized using a [2+2]-cycloaddition strategy where the nitroso species serve as a N–O bond donor synthon. Of note, a typical [2+2] cycloaddition will result a mixture of regioisomers I and II, however, the former is stable while the latter spontaneously decarboxylates to produce an imine (Scheme [28a]). Thus, a judicious catalytic system is necessary to favor the desired isomer I. In 2009, Fu and Dochnahl first disclosed the nucleophilic chiral pyrrolidino-substituted ferrocene (–)-Cat-A catalyzed asymmetric [2+2] cycloaddition of preformed ketenes with arylnitroso compounds to afford 1,2-oxazetidin-3-ones with high enantiomeric excess (Scheme [28b]).[52] This protocol also conveyed the importance of the steric and electronic nature of the aryl group of the nitrosoarene which controls the regioselectivity of the cycloadduct. Specifically, electron-withdrawing groups like CF3 in the ortho-position in the arene ring enforce the desired regioselectivity and also enhanced the enantioselectivity (Scheme [28b]). In 2010, Ye and co-workers showcased a similar [2+2]-cycloaddition strategy using a chiral NHC carbene catalyst that gave 1,2-oxazetidin-3-ones in moderate yields and enantioselectivity (Scheme [28c]).[53]

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Scheme 28 DMAP (4-(dimethylamino)pyridine) derivatives and NHC-catalyzed [2+2] cycloaddition of ketenes with nitrosoarenes

The Studer group utilized 2-nitrosopyridines for [2+2] cycloaddition with ketenes using Cu-diphosphine complexes.[54] The CF3-congener of a Walphos ligand based Cu(I) system governed the required regioselectivity of the cycloadduct and delivered 1,2-oxazetidin-3-ones with high stereoinduction (Scheme [29]). In this case, a concerted asynchronous [2+2]-cycloaddition pathway is most likely operating as supported through DFT calculations.

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Scheme 29 Cu(I)-catalyzed [2+2] cycloaddition of 2-nitrosopyridine with ketenes

In 2021, the Chatterjee group reported a blue LED light induced [2+2]-cycloaddition protocol of diazo compounds mediated in situ generated ketene intermediates (Wolff rearrangement) and nitrosoarenes to give 1,2-oxazetidin-3-one moieties in good yields (Scheme [30]).[55] This transition-metal-free and catalyst-free mild strategy has a wide substrate generality with α-diazo-β-keto esters having both electron-donating and -withdrawing substituents and arylnitroso species, albeit other diazo compounds like α-aryldiazoacetates underwent oxygenation with nitrosoarenes to give α-keto esters instead of oxazetidine moieties. This mechanistic change could be ascribed to the reactivity of the diazo species. In α-diazo-β-keto esters, both substituents are electron-withdrawing and thus the generated carbene immediately undergoes Wolff rearrangement to produce ketenes for the subsequent [2+2]-cycloaddition process.

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Scheme 30 Photoinduced [2+2] cycloaddition of nitrosoarenes with ketenes

In a related study, the Liu group exploited the catalytic activity of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF) catalyst in the [2+2] cycloaddition of substituted cyclopenta-1,3-dien-2-yl esters (alkene donors) with nitrosoarenes (Scheme [31]).[56] The 1,4-disubstituted alkene donors furnished two isolable cycloadducts of 6-oxa-7-azabicyclo[3.2.0]heptanes, which upon thermal hydrolysis afforded only 5-aminocyclopent-2-enones chemoselectively. The synthetic protocol also underwent a rapid ring-expansion towards the succinct synthesis of six-membered piperidone derivatives in the case of 4-substituted cyclopenta-1,3-dien-2-yl esters.

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Scheme 31 NaBArF-catalyzed [2+2] nitroso/alkene cycloaddition

# 5

Summary and Outlook

In this short review, we have witnessed a compelling growth of different cycloaddition strategies towards the synthesis of four-, six-, and seven-membered N–O heterocycles. To keep the discussion vibrant and informative, we have focused on the different pathways based on product categories and also addressed stereo- and regioselectivity issues along with potential application in natural product synthesis. The [4+2] cycloaddition with nitroso species is strategically advantageous to dispense 1,2-oxazine scaffolds. Various [3+3] cycloaddition and related cascade processes with nitrones are also established to fabricate such ring frameworks. Cycloaddition reactions to access seven-membered 1,2-oxazepanes majorly follow [4+3] annulation with nitrones, while synthesis of four-membered 1,2-oxazetidines involves [2+2] annulation of nitroso species. Despite a number of decisive breakthroughs, overall progress of this rich chemistry is relatively slow. Examples of catalytic enantioselective processes are currently limited and need systematic investigations. Also, cycloaddition strategies towards N–O heterocycles are somehow entangled to nitrones and nitroso derivatives and identification of different variant of N–O synthons is an open problem to explore. Furthermore, target-oriented reaction design, particularly for bioactive N–O heterocycles and natural products, still has not been adopted pervasively and demands a collective effort from the synthetic community. We anticipate that this short review will serve as a booster and may encourage the future generations to embrace pivotal challenges to make this arena more radiant, steering a new horizon for the synthesis of structurally adorned N–O heterocycles.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Mahiuddin Baidya
Department of Chemistry, Indian Institute of Technology
Madras, Chennai-600036
India   

Publication History

Received: 21 October 2021

Accepted after revision: 23 November 2021

Accepted Manuscript online:
23 November 2021

Article published online:
12 January 2022

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Prof. Mahiuddin Baidyawas born in 1983 (West Bengal, India) and received his Ph.D. from Ludwig-Maximilians-Universität München, Germany in 2009 under the supervision of Prof. Herbert Mayr. After post-doctoral studies with Prof. Hisashi Yamamoto at the University of Chicago, USA and the Molecular Catalyst Research Center, Chubu University, Japan, he joined at the department of Chemistry, Indian Institute of Technology, Madras in 2014. In 2018, he was promoted to Associate Professor. His current research interests focus on the development of novel concepts for transition-metal catalysis, organocatalysis, photo-redox catalysis, and synthesis of bioactive compounds. He serves as an Early Career Advisory Board (ECAB) member of ACS Catalysis journal and International Advisory Board Member of Chemistry – An Asian Journal. Dr. Prasanjit Ghosh (left), Ph.D. in organic chemistry from University of North Bengal, is a SERB-NPDF fellow and Swati Lekha Mondal (middle), M.Sc. from IIT-ISM Dhanbad, is a graduate student in his research group.
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Scheme 1 Alternative synthesis of N–O heterocycles
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Figure 1 Biologically active compound containing N–O heterocycles
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Scheme 2 Nitroso dienophiles and mode of [4+2] cycloaddition with dienes
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Scheme 3 HDA reaction between thebaine and an acylnitroso compound
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Scheme 4 [4+2] Cycloaddition of acylnitroso species with dienes
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Scheme 5 Cycloaddition reaction of nitrosoalkenes with enol ethers
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Scheme 6 Cycloaddition reaction of in situ formed zwitterionic nitrosoalkenes
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Scheme 7 Enantioselective [4+2] cycloaddition with nitrosoarenes
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Scheme 8 Enantioselective nitroso Diels–Alder reaction of 2-nitrosopyridines with a Cu complex
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Scheme 9 Chiral phosphoric acid catalyzed asymmetric [4+2] cycloaddition reaction of diene carbamates with nitroso species
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Scheme 10 Enantioselective [4+2] cycloaddition of nitrosoarenes with cross-dienamine
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Scheme 11 Au(I)-catalyzed nitroso-Povarov reaction and intramolecular annulation
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Scheme 12 Lewis acid catalyzed [3+3] cycloaddition of nitrones and cyclopropane-1,1-dicarboxylate diesters
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Scheme 13 Ni(II)-oxazoline ligand catalyzed asymmetric synthesis of 1,2-oxazinanes
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Scheme 14 Sc(OTf)3-catalyzed formal [3+3] cycloaddition of yne-ones with nitrones
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Scheme 15 Hydrogen-bonding-aided [3+3] cycloaddition
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Scheme 16 Synthesis of 1,2-oxazinanes via [3+3] cycloaddition of oxyallyl cation with nitrones
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Scheme 17 Cloke–Wilson-type rearrangement of 1,2-oxazine frameworks
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Scheme 18 Pd-catalyzed [3+3] cycloaddition of nitrones with a TMM synthon
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Scheme 19 Rh-catalyzed [3+3] cycloaddition of nitrones with vinylcarbene intermediates
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Scheme 20 Cu and Rh/Ag-catalyzed [3+3] cycloaddition reaction of enol diazoacetates with nitrones
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Scheme 21 Au(I)-catalyzed asymmetric tandem cyclization/[3+3] cycloaddition of 2-(alk-1-ynyl)alk-2-en-1-ones with nitrone
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Scheme 22 Pt(II)-catalyzed tandem intramolecular cyclization of 2-(alk-1-ynyl)anilines and [3+3] cycloaddition with nitrones
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Scheme 23 Yb(III)-catalyzed [4+3] cycloaddition of donor-acceptor cyclobutanes with nitrones
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Scheme 24 Cu(II)/SaBox-catalyzed formal [4+3] cycloaddition of donor-acceptor cyclobutanes with nitrones
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Scheme 25 Pd(0)-catalyzed [4+3] cycloaddition of γ-methylidene-δ-valerolactones with nitrones
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Scheme 26 Cu(II)/Au-Catalyzed tandem cycloisomerization and [4+3] cycloaddition with nitrones
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Scheme 27 Divergent generation of carbon based 1,4-dipoles and subsequent furan-fused seven-membered heterocycles
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Scheme 28 DMAP (4-(dimethylamino)pyridine) derivatives and NHC-catalyzed [2+2] cycloaddition of ketenes with nitrosoarenes
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Scheme 29 Cu(I)-catalyzed [2+2] cycloaddition of 2-nitrosopyridine with ketenes
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Scheme 30 Photoinduced [2+2] cycloaddition of nitrosoarenes with ketenes
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Scheme 31 NaBArF-catalyzed [2+2] nitroso/alkene cycloaddition