Download PDF
Synlett 2023; 34(14): 1655-1661
DOI: 10.1055/s-0042-1751443
synpacts

Photoexcited Nitroarenes as Anaerobic Oxygen Atom Transfer ­Reagents

Dan E. Wise
,
Marvin Parasram  ∗

New York University Start Up Funds. American Chemical Society Petroleum Research Fund (65501-DNI1).
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Applications of photoexcited nitroarenes have been underdeveloped in organic synthesis. Since early reports on the direct excitation of nitroaromatics with harsh UV light, these synthetically useful reagents have not been tamed for use in modern synthetic chemistry. We have developed practical synthetic protocols for the anaerobic oxidation of hydrocarbon substrates using commercially available nitroarenes as photochemically activated oxidants under visible light. Using this approach, a wide variety of olefins are anaerobically cleaved to their corresponding carbonyls, and aliphatic C–H bonds are hydroxylated to give alcohols. The anaerobic reaction conditions enable oxidatively sensitive functional groups to be tolerated and the employment of visible light makes this method highly sustainable. Mechanistic studies support that the photoexcited nitroarene biradical intermediate is responsible for the oxygen atom transfer events.

1 Introduction

2 Alkene Cleavage Promoted by Photoexcited Nitroarenes

3 Photoinduced Nitroarene-Mediated C–H Hydroxylation

4 Conclusions


#

Key words

photochemistry - nitroarenes - biradical - cleavage of alkenes - olefins - carbonyl - C–H hydroxylation - anaerobic oxidation
Zoom Image
Dan Wise(right) completed his undergraduate and doctoral studies in chemistry at the University of Bristol (UK) under the supervision of Prof. Paul Pringle working in the fields of organophosphorus and organometallic chemistry. He then moved to New York University (USA) as a postdoctoral associate in the group of Prof. Marvin Parasram where he is carrying out research in synthetic methodology development and photochemistry. Marvin Parasram (left) earned his BSc in chemistry from Stony Brook University (USA) before completing his doctoral studies at the University of Illinois at Chicago (USA) supervised by Prof. Vladimir Gevorgyan where he focused on Pd-catalyzed synthetic methods development. He then joined the group of Prof. Abigail Doyle at Princeton University (USA) as a National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Scholar where he developed dual Ni/photoredox-catalyzed methods. In 2020, he began his independent career at New York University where his group is developing sustainable photochemical methods for organic synthesis.
1

Introduction

1.1

Hydrocarbon Oxidation Reactions

Traditional methods for the oxidative cleavage of alkenes rely on hazardous conditions and toxic, highly oxidizing reagents that severely limit the substrate scope and synthetic utility (Scheme [1a]).[1] [2] [3] Ozonolysis is a popular and longstanding method used to oxidatively cleave feedstock alkenes to their carbonyl compounds via highly reactive 1,2,3-ozonides. However, the required two-step sequence to first generate ozone via an ozonizer and then transfer it to a reaction vessel at cryogenic temperatures renders the procedure difficult to implement. In addition, the high reactivity of ozone leads to poor regiocontrol.[4,5] As an alternative approach, the Lemieux–Johnson reaction employs OsO4 and NaIO4 to generate carbonyls via the oxidative fragmentation of an osmate ester intermediate.[6] [7]

Zoom Image
Scheme 1 Strategies for the oxidative cleavage of alkenes and the hydroxylation of aliphatic C–H bonds

While this obviates the use of O3 and catalytic quantities of OsO4 can be used, the toxic reagent readily sublimes at room temperature and the highly oxidative conditions limit substrate scope. Recently, modern photochemical techniques to promote alkene cleavage using transition-metal catalysts, enzymes, or electron-donor-acceptor complexes have been reported.[8] [9] [10] [11] [12] However, these are not without risk because they often rely on O2 as the terminal oxidant.

Another indispensable method in the toolbox of oxidative hydrocarbon functionalization is the direct conversion of inert C–H bonds into alcohols (Scheme [1b]).[13] Usually, to activate strong C(sp3)–H bonds, highly oxidizing conditions are employed which limit site selectivity in C–H hydroxylation reactions.[14] Many innovative strategies to overcome these high activation barriers and selectivity concerns have been reported.[15] [16] [17] Selective C–H hydroxylation directed by transition-metal catalysts uses a pre-organization strategy enabled by a tethered directing group that overcome issues with regioselectivity. However, directing groups are often difficult to subsequently remove, and the use of expensive metal catalysts and ligands are often required. Alternatively, for specific substrates, P450 enzyme catalyzed routes can achieve C–H hydroxylation in high yield, however, high costs and the lengthy time requirements for enzyme evolution detract from the general applicability of these methods.[18,19] In light of the aforementioned drawbacks, methods that leverage the reactivity of excited-state species and radical intermediates generated under photochemical conditions are highly warranted.

To circumvent some of the inherent limitations of using these harsh oxidants, we were drawn to nitroarenes due to their isoelectronic relationship to ozone. Calculations from Houk and coworkers have shown that dipolar cycloaddition of the nitro group with olefins is thermodynamically challenging (ΔH ‡ = 29.6 kcal/mol) compared to that of ozone (ΔH ‡ = 2.1 kcal/mol).[20] Recently, reports have emerged using nitroarenes,[21] [22] as efficient oxygen atom transfer reagents. Therefore, we hypothesized if photoexcited nitroarenes could enable anaerobic oxygen atom transfer events that could address the disadvantages of the previously discussed oxidation reactions and offer a practical strategy to the synthetic community.


# 1.2

Nitroarene Photochemistry

The photophysical properties of nitroarenes were investigated in the 1950s using high-energy Hg arc lamps as UV light sources.[23] [24] Early work from Testa provided key evidence that the n→π* excitation of nitrobenzene in isopropyl alcohol could lead to a hydrogen atom abstraction event.[25] The seminal report of Büchi and Ayer showed that when nitrobenzene was irradiated with UV light in the presence of solvent quantities of cyclohexene, a mixture of products comprised of aldehyde, carboxylic acid, and azobenzene was detected in less than 10% yield (Scheme [2a]).[26] The transformation was proposed to proceed through a 5-membered 1,3,2-dioxazolidine cycloadduct, however, this was reported to be unstable and not isolable for characterization. Further studies by de Mayo and others on the photocycloaddition of nitroarenes with olefins uncovered that the transient 1,3,2-dioxazolidine intermediates were thermally unstable and may have decomposed through a radical pathway, generating aryl nitrene byproducts.[27] [28] [29] While studying nitroarene photoreduction, Döpp and coworkers showed that sterically hindered nitrobenzenes could abstract hydrogen atoms from ortho-alkyl substituents.[30] The field remained largely dormant until 1992, when Oda reported the first isolable 1,3,2-dioxazolidine generated from 1,3,5-trinitrobenzene and the sterically demanding olefin adamantylideneadamantane (Scheme [2b]).[31] Under thermal or acidic conditions, the stable dioxazolidine decomposed to adamantanone, the product resulting from oxygen transfer from the nitroarene to the hydrocarbon.

Zoom Image
Scheme 2 Conceptual overview of photoexcited nitroarenes as anaerobic oxygen transfer reagents

Based on these literature precedents, and with the availability of wavelength-tailored photochemical light sources, we considered whether nitroarenes could be employed as easily handled oxygen atom transfer agents.[32] [33] An overview of our proposed strategies for anaerobic hydrocarbon oxidation is presented in Scheme [2c]. We reasoned that irradiation with focused 390 nm light could populate the biradical T 1 (n→π*) excited state of the nitrobenzene.[34] [35] This energy input could overcome the high thermodynamic barrier for [3+2] cycloaddition with olefins and would allow for a stepwise, radical [3+2] cycloaddition with alkenes to give an oxygen and carbon-centered biradical intermediate.[20] [36] [37]

Zoom Image
Scheme 3 Initial studies on the anaerobic cleavage of 1

Next, rapid radical ring closure to give the 1,3,2-dioxazolidine intermediate followed by C–C σ-bond cleavage would yield the carbonyl products. Additionally, we hypothesized that the nitroarene T 1 biradical could undergo intermolecular hydrogen atom abstraction in the presence of a saturated hydrocarbon substrate rather than an alkene.[38] Radical recombination leading to the N-arylhydroxylamine ether intermediate followed by its fragmentation would yield alcohol products resulting from direct nitroarene mediated C(sp3)–H hydroxylation (Scheme [2c]).


#
# 2

Alkene Cleavage Promoted by Photoinduced Nitroarene

2.1

Initial Discovery

With the goal of applying photoexcited nitroarenes to anaerobically cleave a variety of alkenes, we considered methods to enable photoexcitation in the visible-light spectrum rather than using high-energy UV light. Hence, we postulated that an electron-deficient nitroarene could form an electron-donor-acceptor (EDA) complex with an electron-rich alkene, where the complex could undergo excitation with lower energy light.[8] , [39] [40] [41] We began our investigation by understanding the photophysical properties of 4-fluorostyrene (1) and 4-cyanonitrobenzene (2). We performed UV-visible spectroscopy studies to probe for the formation of an EDA complex between 1 and 2. While the absorption maxima for 2 (25 μM) is at λ = 260 nm, at the reaction concentration (100 mM), an absorption tail at λ > 400 nm was observed (Scheme [3a]). Unexpectedly, a combination of 1 and 2 did not exhibit any bathochromic shift, indicating that an EDA complex is not formed in the ground state. Only after irradiation of the mixture with 390 nm light, a red shift in the absorption was observed, leading us to conclude that electron-deficient nitroarene 2 was the sole photoabsorbing species, and a photoexcited state could be accessed with 390 nm light in the absence of alkene.

Despite no detectable EDA complex, the reaction between 1 and 2 in MeCN solvent under 390 nm irradiation led to an 88% 19F NMR yield of aldehyde 3 (Scheme [3b]). Studies varying the electronics of the nitroarene indicated that electron-deficient derivatives were most effective in the anaerobic cleavage of styrene 1 delivering aldehyde 3 in almost quantitative yield under nitroarene limiting conditions (Scheme [3b]). Conversely, electron-rich nitroarenes were virtually ineffective in the same transformation. After further optimization of the reaction parameters, we found that the alkene could be used as the limiting reagent and 1.5 equivalents of 2 were sufficient to achieve full alkene conversion.


# 2.2

Scope and Selectivity Studies

A range of aldehyde and ketone products could be obtained from their parent olefins of varying degrees of substitution in good to excellent yields. A wide variety of electron-rich, -neutral, and -poor styrenes performed well under the reaction conditions. Of particular importance are the scope studies highlighted in Scheme [4]. First, styrenes bearing oxidatively sensitive functional groups that are not tolerated in classical oxidative cleavage methods were smoothly oxidized under the present method demonstrating the inherent benefits of using mild, anaerobic conditions. Both primary and secondary aniline derivatives, as well as common cross-coupling partners including phenol, boronic acid pinacol ester, and bromide were tolerated. Another major advantage of this method was demonstrated through selectivity studies incorporating styrenes tethered with a terminal alkene or an internal alkyne.

Zoom Image
Scheme 4 Selected scope and selectivity studies of the photoexcited nitroarene promoted anaerobic cleavage of alkenes

Conventional methods, such as ozonolysis, often cannot discriminate between multiple π-systems in the same molecule, leading to low regioselectivity and poor yields. In these cases, both styrenes delivered the corresponding aldehyde and ketone in 52% and 66% yield, respectively, while no reactivity at the other π-system was observed. Moreover, we sought to demonstrate that anaerobic cleavage of more complex heterocyclic or aliphatic alkenes could be achieved. Notably, the cytotoxic quinoline and therapeutic betulin derivatives were oxidized in 53% and 25% yields, respectively. Both yields are comparable to those reported using ozonolysis, however, the ease of the reaction setup and additional safety benefits of this protocol illustrate that our method is highly practical compared to ozonolysis.


# 2.3

Investigating the Reaction Mechanism

Having established an operationally simple anaerobic oxidation protocol facilitated by photoexcited nitroarenes, we were able to observe several key reaction intermediates and account for the obtained reaction byproducts. Using conventional carbocation and both carbon and oxygen radical traps, we proposed that the reaction likely proceeds through an oxygen-centered biradical intermediate. Cyclopropane radical clock experiments confirmed the presence of a short-lived carbon/oxygen biradical intermediate and that the rate of radical ring closure to form the dioxazolidine is competitive with cyclopropane ring opening.

Zoom Image
Scheme 5 (a) PhotoNMR spectroscopy experiments to detect dioxazolidine intermediates Int I and Int II; (b) proposed mechanism of the photoexcited nitroarene promoted anaerobic cleavage of alkenes.

Using variable-temperature PhotoNMR spectroscopy the anaerobic cleavage of styrene 4 promoted by 2 was monitored at –40 ℃ (Scheme [5a]). By simultaneously recording 1H and 19F NMR spectra under constant irradiation at 395 nm, the formation of the elusive aryl 1,3,2-dioxazolidine (Int I) was detected with the formation of a small amount of cleavage product 5. At –40 ℃, a second set of 1H and 19F resonances appeared that was in agreement with the structure of 1,4,2-dioxazolidine (Int II), presumably formed via 1,3-dipolar cycloaddition of 5 and carbonyl imine 6. Upon warming the reaction mixture from –40 ℃ to –20 ℃, both Int I and Int II were rapidly consumed with concomitant formation of nitrone 7 that was in equilibrium with the unstable oxaziridine 8. Upon warming to room temperature, it was found that 8 undergoes rearrangement to amide 9, a common byproduct of the transformation.

In accordance with the mechanism presented in Scheme [5b], photoexcitation of nitroarenes with 390 nm light generates the T 1 (n→π*) biradical which, via a stepwise radical mechanism, can cyclize with olefins to form dioxazolidine intermediates (Int I).[42] The fragmentation of Int I was reported to generate an aryl nitrene intermediate,[26] however, numerous attempts to trap the aryl nitrene were unsuccessful. This suggests that the fragmentation of Int I likely does not proceed through the mechanism outlined by Büchi, Ayer, and de Mayo.[26] [28] Based on the formation of carbonyl imine 6 and PhotoNMR studies, our mechanistic findings support the thermally promoted polar fragmentation pathway whereby two 1,4,2-dioxazolidine intermediates (Int IIa/b) are formed, and these have been observed for the first time by in situ NMR spectroscopy. Their decomposition releases the aldehyde or ketone products and an aryl nitrone byproduct that is potentially hydrolyzed.


#
# 3

Photoinduced Nitroarene-Mediated C–H Hydroxylation

Zoom Image
Scheme 6 Leveraging the biradical reactivity of nitroarenes for anaerobic C–H hydroxylation

Based on our mechanistic understanding of the anaerobic cleavage of alkenes, efforts by our group have uncovered that nitroarenes can serve as photoactive reagents to promote anaerobic C–H hydroxylation of aliphatic substrates.[33] Our mechanistic approach differs from the vast majority of prior methods that use molecular oxygen as the terminal oxidant in combination with highly unselective oxidizing agents, transition-metal catalysts, or enzymes.[13] Key to the development of this reaction was the realization that the photoexcited nitroarene biradical can act as both the hydrogen atom transfer (HAT) and oxygen atom transfer (OAT) reagent (Scheme [6]). In the presence of C(sp3)–H bonds, the nitroarene biradical intermediate first undergoes HAT to generate an oxygen-centered dihydroxyaniline radical and an alkyl radical. These can recombine to give an N-arylhydroxylamine ether intermediate, which, following fragmentation and loss of nitrosoarene, generates the C–H hydroxylation product.

Following reaction optimization, we found mild conditions to selectively oxidize both benzylic and unactivated C(sp3)–H bonds (10) under 390 nm irradiation to generate a wide range of functionalized alcohols (Scheme [7]). Using 2-chloro-4-nitropyridine (12), an interesting reactivity profile emerged from competition substrates possessing a combination of primary, secondary, and tertiary benzylic C–H bonds. The monohydroxylated products were isolated in good yields with secondary sites proving most active towards oxidation, followed by primary, and then by tertiary. In addition, HFIP was found to be an essential cosolvent to prevent competing overoxidation to the ketone or aldehyde products, presumably resulting from a second HAT event of the formed α-hydroxy C–H bond.[43]

Zoom Image
Scheme 7 Selected scope and selectivity studies of the photoexcited nitroarene promoted C(sp3)–H hydroxylation

Unactivated C(sp3)–H bonds can also be hydroxylated using nitroarene 13. We found that the reduced reactivity compared with benzylic substrates could be overcome by using excess substrate, the employment of highly electron-deficient nitroarene 13, and extended reaction time (48 h). Secondary and tertiary sites could be hydroxylated in high yields and, remote electron-withdrawing functional groups, such as pivalate and phthalimide were tolerated under the reaction conditions. Unfunctionalized hydrocarbons could also be hydroxylated at their secondary or tertiary sites in high yields. The method was extended to more complex, bioactive substrates where we found that primary, secondary, and tertiary C–H hydroxylation occurred in moderate to good yield. Of particular note, the ibuprofen ester derivative was hydroxylated at the secondary benzylic site selectively over the tertiary sites, rendering this method complementary to previously reported procedures that are selective for the tertiary benzylic site.[44]

Our mechanistic studies, including radical clock and kinetic isotope effect experiments, support that radical intermediates are formed under the reaction conditions and that HAT is involved in the rate-limiting step of the reaction. Detection of the N-arylhydroxylamine ether intermediate by PhotoNMR spectroscopy and high-resolution mass spectrometry uncovered that the radical recombination event is a key step in the transformation that leads to the C–H hydroxylation product. Taken together, these mechanistic studies indicate that the photoexcited nitroarene acts as both the HAT and OAT reagent. Overall, this practical, photochemical method for C–H hydroxylation delivers a wide range of alcohols in good yields without the need for harsh reaction conditions or strong oxidants.


# 4

Conclusions

We have developed novel methods that use photoexcited nitroarenes as oxygen atom transfer reagents to cleave olefins and oxidize inert C–H bonds under anaerobic conditions. Our approach builds on fundamental photophysical studies carried out on nitroarenes in the 1950s and provides a platform to conduct these useful oxidation reactions under ozone- and oxygen-free conditions. Both the alkene cleavage and C–H hydroxylation protocols described use inexpensive, commercially available nitroarenes, and are readily scalable using benign violet LEDs. Notably, these processes broaden the synthetic scope of otherwise harsh oxidation reactions, enabling oxygen-sensitive functional groups to be tolerated. The photochemical reactions described herein are safe, easy to set up, and feature simple workup and purification procedures that enhance their practicality. Further studies on the photochemistry of nitroarenes could uncover salient features that may be advantageous in many synthetic scenarios. We anticipate that further application of photoexcited nitroarenes will significantly expand synthetically useful oxygen atom transfer reactions under mild conditions.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Marvin Parasram
New York University, Department of Chemistry
24 Waverly Place, 3rd Floor, New York, NY, 10003
USA   

Publication History

Received: 04 March 2023

Accepted: 16 March 2023

Article published online:
21 April 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Dan Wise(right) completed his undergraduate and doctoral studies in chemistry at the University of Bristol (UK) under the supervision of Prof. Paul Pringle working in the fields of organophosphorus and organometallic chemistry. He then moved to New York University (USA) as a postdoctoral associate in the group of Prof. Marvin Parasram where he is carrying out research in synthetic methodology development and photochemistry. Marvin Parasram (left) earned his BSc in chemistry from Stony Brook University (USA) before completing his doctoral studies at the University of Illinois at Chicago (USA) supervised by Prof. Vladimir Gevorgyan where he focused on Pd-catalyzed synthetic methods development. He then joined the group of Prof. Abigail Doyle at Princeton University (USA) as a National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Scholar where he developed dual Ni/photoredox-catalyzed methods. In 2020, he began his independent career at New York University where his group is developing sustainable photochemical methods for organic synthesis.
Zoom Image
Scheme 1 Strategies for the oxidative cleavage of alkenes and the hydroxylation of aliphatic C–H bonds
Zoom Image
Scheme 2 Conceptual overview of photoexcited nitroarenes as anaerobic oxygen transfer reagents
Zoom Image
Scheme 3 Initial studies on the anaerobic cleavage of 1
Zoom Image
Scheme 4 Selected scope and selectivity studies of the photoexcited nitroarene promoted anaerobic cleavage of alkenes
Zoom Image
Scheme 5 (a) PhotoNMR spectroscopy experiments to detect dioxazolidine intermediates Int I and Int II; (b) proposed mechanism of the photoexcited nitroarene promoted anaerobic cleavage of alkenes.
Zoom Image
Scheme 6 Leveraging the biradical reactivity of nitroarenes for anaerobic C–H hydroxylation
Zoom Image
Scheme 7 Selected scope and selectivity studies of the photoexcited nitroarene promoted C(sp3)–H hydroxylation