doi.org/10.26434/chemrxiv.9864071.v2

Arene Dearomatization via a Catalytic N-Centered Radical CascadeReactionRory McAtee, Efrey Noten, Corey Stephenson

Submitted date: 22/04/2020 • Posted date: 23/04/2020Licence: CC BY-NC-ND 4.0Citation information: McAtee, Rory; Noten, Efrey; Stephenson, Corey (2019): Arene Dearomatization via aCatalytic N-Centered Radical Cascade Reaction. ChemRxiv. Preprint.https://doi.org/10.26434/chemrxiv.9864071.v2

This photocatalysis methodology leverages N-centered radicals, from easily prepared γ,δ-unsaturatedN-arylsulfonyl enamides, to initiate a carboamination/dearomatization cascade reaction that generatesstereodefined 1,4-cyclohexadiene-fused sultams. This unique reactivity serves as a general platform for arenedearomatization and the fused heterocyclic products are viewed as valuable building blocks for drugdiscovery programs.

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Arene Dearomatization via a Catalytic N-Centered Radical Cascade Reaction

Rory C. McAtee,[a] Efrey A. Noten,[a] and Corey R.J. Stephenson*[a]

[a]University of Michigan, Department of Chemistry, Willard Henry Dow Laboratory, 930 North University Ave., Ann Arbor MI

48109 United States.

E-mail: crjsteph@umich.edu

Abstract: Arene dearomatization reactions are an important class of synthetic technologies for the rapid assembly of unique

chemical architectures. Herein, we report a catalytic protocol to initiate a carboamination/dearomatization cascade that

proceeds through transient sulfonamidyl radical intermediates formed via a concerted proton-coupled electron transfer (PCET)

of strong N−H bonds leading to 1,4-cyclohexadiene-fused sultams. These reactions occur at room temperature under visible

light irradiation and are catalyzed by the combination of an iridium(III) photocatalyst and a dialkyl phosphate base. Reaction

optimization, substrate scope, and mechanistic features of this transformation are presented.

Main Text

Arenes obtained from inexpensive petrochemical feedstocks are incorporated on industrial scale into pharmaceuticals,

agrochemicals, and organic materials. Selective dearomatization reactions[1] of these flat, two-dimensional aromatic

compounds are modular strategies to access substituted, three-dimensional chemical space, including fused, complex

heterocyclic skeletons.[2] In addition, the potential to form stereogenic centers through substituent addition concomitant with

the dearomatization process is particularly appealing. Of the selective dearomatization methods reported (including, UV-

promoted photochemical cycloadditions,[3] oxidative,[4] enzymatic,[5] transition metal-mediated,[6] and nucleophilic

dearomatizations[7]), the Birch reduction of arenes to 1,4-cyclohexadienes (1,4-CHD) is most well-known relying on liquid

ammonia as solvent and pyrophoric alkali metals at cryogenic temperatures (Figure 1A).[8] Modifications of the canonical Birch

reduction conditions have expanded the scope and synthetic utility of the reaction.[9] While both electrochemical[10] and visible

light-mediated[11] arene dearomatization reactions have been reported with proven utility, they have not been integrated with

other reaction pathways via reactive intermediates. An alternative strategy addressing the inherent drawbacks of the classic

Birch reduction is to promote an arene dearomatization via a radical cascade sequence. Radical cascades, processes in which

multiple chemical bonds are formed in a single operation, are step and atom-economical means to rapidly build complex

organic molecules (Figure 1B).[12] Moreover, initiating cascade sequences from strong N−H bonds leading to dearomatized

molecular frameworks has the potential to impact a variety of synthetic endeavors.

Figure 1. Inspiration and Design for Our Carboamination/Dearomatization Cascade Reaction Platform.

(A) The classic Birch reduction for arene dearomatization. (B) The design principle of using a radical cascade approach for

arene dearomatization. (C) This work: catalytic radical carboamination/dearomatization cascade reactions.

Concerted proton-coupled electron transfer (PCET) has emerged as a powerful strategy for homolytic activation of strong

N−H bonds, often in the presence of weaker ones, avoiding the need for N-pre-functionalization.[13] The Knowles group recently

reported the activation of both amide[14] and sulfonamide[15] N−H bonds for intramolecular and intermolecular hydroamination

reactions, respectively, of electron neutral olefins. The authors propose an excited-state redox catalyst and a weak phosphate

base jointly mediate the concerted homolytic activation of the strong N−H bonds under visible l ight irradiation to afford transient

N-centered amidyl and sulfonamidyl radicals capable of adding to olefins with anti-Markovnikov regioselectivity. Separately,

Rovis and co-workers described the generation of amidyl radicals from trifluoroacetamide derivatives for sequential 1,5-HAT

and δ-C–H functionalization.[16] By using K3PO4 as base, trifluoroacetamides are deprotonated to the amide anions then

oxidized to the amidyl radical by the excited state of an iridium(III) photocatalyst.

With respect to sulfonamide-based N-radical alkene carboamination platforms, Chemler and co-workers have developed

racemic and enantioselective intramolecular Cu(II)-mediated oxidative N-radical cyclizations of alkenyl arylsulfonamides at

elevated temperatures (120 °C) to garner benzosultams in good yields. [17] Later, Kanai and co-workers reported an

intermolecular alkene carboamination reaction of aliphatic alkenes under Cu(I) catalysis and N-fluorobenzenesulfonimide

(NFSI) as both a bifunctional reagent, for C−C and C−N bond formation, and an oxidant for the concise synthesis of six-

membered sultams.[18] Very recently, Chen and Xiao described a process for a radical 5-exo cyclization/addition/aromatization

cascade of β,γ-unsaturated N-tosyl hydrazones under cooperative photocatalysis and cobalt catalysis enabling the synthesis

of dihydropyrazole-fused benzosultams.[19]

We reasoned that the work outlined above, along with our ongoing interests in alkene carboamination reactions with

bifunctional arylsulfonamide reagents,[20] would serve as a basis for developing a catalytic protocol to initiate a

carboamination/dearomatization cascade starting from γ,δ-unsaturated N-arylsulfonyl enamides 1 (Figure 1C). Ideally, this

process would proceed through transient sulfonamidyl radical intermediates formed via a visible light-mediated proton-coupled

electron transfer. This strategy obviates the need for N-pre-functionalization, elevated reaction temperatures, and

stoichiometric oxidants. The reaction would lead to the synthesis of 1,4-cyclohexadiene-fused sultams. Of note, fused sultams

have been shown to exhibit a broad range of biological activities[21] and have been used extensively as chiral auxiliaries for

chemical synthesis.[22] Herein, we describe the combination of the aforementioned reaction classes, whereby visible light-

mediated photoredox catalysis is used to promote and control a sulfonamidyl radical cyclization/dearomatization cascade

reaction.

At the outset, we recognized two major challenges in implementing this design strategy. The first was the potential for

competitive hydroamination,[13-15, 23] wherein the vicinal carbon-centered radical that is formed following N-radical cyclization

would undergo direct hydrogen atom transfer. The second challenge was rearomatization of the cyclohexadienyl radical

intermediate. With judicious choice of reaction additives and modifying reaction parameters we believed such challenges could

be surmounted.

Table 1. Reaction Optimization and Control Experiments.[a]

entry photocatalyst solvent yield (%)

1 A PhCF3 (0.2 M) 48

2 B PhCF3 (0.2 M) 32

3 C PhCF3 (0.2 M) 7

4 A PhCF3 (0.05 M) 67

5 A DMF (0.05 M) 50

6 A CH2Cl2 (0.05 M) 47

7 A 1,2-DCE (0.05 M) 65

8 A t-BuOH (0.05 M) 73

9 A PhCF3/t-BuOH (0.05 M) 83 (75)[b]

variation from best conditions (entry 9)

10 no blue LEDs 0

11 no photocatalyst 0

12 no NBu4OP(O)(OBu)2 0

See Supplementary Information for complete optimization details. [a]

Reactions were run on 0.1 mmol scale, and yields are determined by 19F-

NMR analysis relative to 1,3,5-trifluorobenzene (1 equiv) as an internal

standard. [b] Isolated yield of 2a on 0.2 mmol scale. Photocatalysts and

single-crystal X-ray of 2a:

Initially, we choose sulfonamide 1a as the model substrate to test the feasibility of the visible light-induced sulfonamidyl

carboamination/dearomatization cascade reaction and representative results are summarized in Table 1. The expected

reaction did occur with 1 mol% Ir photocatalyst A and 65 mol% of tetrabutylammonium dibutylphosphate base providing the

desired 1,4-cyclohexadiene-fused sultam 2a in 48% 19F-NMR yield and excellent diastereoselectivity (>20:1) following

irradiation with blue LEDs in trifluorotoluene (0.2 M) at room temperature (entry 1). Dearomatized product 2a was

unambiguously characterized by single-crystal X-ray analysis (CCDC: 1952459). Other iridium photocatalysts structurally

similar to A were also effective in these reactions (entries 2, 3), but the reaction yields diminished as the oxidation potential of

the excited-state species decreased. Importantly, decreasing the reaction concentration (0.05 M) delivered the desired product

in 67% yield (entry 4). Also, the reaction is moderately to equally successful in other solvents (entry 5-7) with tert-butanol

providing a noticeable increase in yield (entry 8). A 1:1 mixed solvent system of trifluorotoluene/ tert-butanol (0.05 M) was

finally identified as the optimal solvent combination (entry 9). When the reactions were run using conditions developed by

Rovis, relying on step-wise deprotonation/oxidation,[16] no product was isolated (See Supplementary Information for complete

optimization details). Control reactions of 1a lacking photocatalyst, base, or light were uniformly unsuccessful, and the starting

material was recovered unchanged (entries 10-12).

Next, we investigated the generality of this carboamination/dearomatization cascade reaction on a series of diversely

substituted sulfonamides (Figure 2). For example, arenes bearing various electron-withdrawing (2a-2j), electron-neutral (2n),

and electron-donating (2k-2o) groups delivered the desired dearomatized products in moderate to good yields (22-80%) and

excellent diastereoselectivity (>20:1). Of note, in the latter examples (2k-2o) featuring electron-donating groups, the

aromatized benzosultam product was isolated with the desired dearomatized product (See Supplementary Information for

complete details). Modifications to the alkene tether were well tolerated, allowing for the synthesis of an all-carbon spirocycle

(2p), tetracycle (2q), and cyclic carbamate (2r) in moderate to good yields (33-77%). Interestingly, 3-fluoro and 3,4-difluoro

substituted arylsulfonamide substrates generated single dearomatized regioisomers in good yields (2s, 2t) highlighting the

regio- and chemoselective nature of the C−C bond forming cyclization step. Furthermore, this methodology proved tolerant of

electron-rich heterocycles (2u), olefins (2v), amino acids (2w), aliphatic carbocycles (2x), and benzyl groups (2y) furnishing

the corresponding dearomatized products in good yields. Terminal olefin 3 failed to convert to the desired dearomatized

product (Figure 2C). Further, o-prenyl aniline derivative 4 and alkyl sulfonamide 5 were unreactive under the standard

conditions, returning starting material unchanged, highlighting the importance of the amide moiety for this process. Importantly,

many of the richly functionalized 1,4-cyclohexadiene products are envisaged to be valuable building blocks for post-

functionalization transformations. Studies to explore their synthetic utility are ongoing in our laboratory.

Figure 2. Reaction Scope.

(A) General reaction scheme; all reactions were run on 0.2 mmol scale and degassed by sparging with argon for 15 min prior

to exposure to optimized conditions. (B) Arylsulfonamide modifications. (C) Unsuccessful substrates. *Product isolated as an

inseparable mixture of diene and arene (between 3:1 to 1:4, diene:arene) (see Supplementary Information for full details).

To gain insight into the reaction mechanism, we initially performed Stern-Volmer luminescence quenching studies with

the model substrate 1a (See Supplementary Information). In accordance with previous studies by Knowles[15] and Molander,

[24] it was revealed that only in the presence of tetrabutylammonium dibutylphosphate base is the photoexcited state of catalyst

A quenched. Comparatively, there is no luminescence quenching when 1a is used alone. Performing cyclic voltammetry

studies of 1a in CH2Cl2 containing 0.1 M NBu4PF6 in the presence of varying concentrations of monobasic dibutyl phosphate

base, we found the onset oxidation potentials shifted to less positive potentials and current response increases with increasing

concentrations of phosphate base. Qualitatively, these results are consistent with a sulfonamidyl radical being generated under

a PCET process. Moreover, a deuterium labeling experiment was conducted to probe the role of tert-BuOH in this reaction.

By performing the reaction in the presence of tert-BuOD, the desired product (2a-D) was produced in 51% yield with complete

deuterium incorporation (Figure 3A). This result suggests that the tert-BuOH is serving as a reaction terminating proton

source, analogous to the classic Birch reduction.

Figure 3. Experiment to Probe Mechanism and Proposed Catalytic Cycle.

(A) Deuterium labelling experiment. (B) Proposed catalytic cycle.

A prospective catalytic cycle accounting for these observations, and those made during reaction optimization, is shown

in Figure 3B. In analogy to literature precedent,[15, 24] we anticipated that a phosphate base would first form a hydrogen-bonded

complex with the arylsulfonamide (i) N−H bond. The resultant non-covalent complex could participate in a concerted PCET

event with the excited state photocatalyst A leading to homolysis of the N−H bond and formation of a transient sulfonamidyl

radical intermediate (ii). Next, we expected the N-radical to undergo 5-exo cyclization onto the tethered alkene to furnish a

new C−N bond and a vicinal carbon-centered radical (iii). This alkyl radical is poised to undergo cyclization with the appended

arene to generate a stabilized cyclohexadienyl radical (iv) that can undergo single-electron reduction by the reduced Ir(II)

state of the photocatalyst (E[IrIII/IrII]= −1.07 V vs Fc+/Fc).[14] Favorable proton transfer between the cyclohexadienyl anion and

the phosphoric acid (pKa ≈ 12 in MeCN)[25] or tert-BuOH should follow delivering the dearomatized product, returning the

active forms of both catalysts.

In summary, we have reported the discovery and development of a proton-coupled electron transfer strategy to facilitate

a carboamination/dearomatization cascade reaction. Simple γ,δ-unsaturated N-arylsulfonyl enamides were converted into

complex and stereodefined 1,4-cyclohexadiene-fused sultams in satisfactory yields and excellent diastereoselectivity. This

mild catalytic system demonstrates a broad substrate scope and high functional group tolerance. Overall, we believe the

photochemical strategy outlined here will inspire future synthetic endeavors aimed at employing simple arene building blocks

for the rapid synthesis of complex, three-dimensional molecular frameworks in a single operation.

Experimental

To a dry 2-dram vial was added γ,δ-unsaturated N-arylsulfonyl enamides 1 (0.2 mmol), base, (65 mol%), and

photocatalyst (1 mol%). The vial contents were then dissolved in a 1:1 mixture of t-BuOH:PhCF3 (0.05 M). The solution was

degassed by sparging with argon for 15 min. The reaction was irradiated with two, H150 blue Kessil lamps positioned ~2 cm

away and cooled with an overhead fan for 14 hours. The reaction was concentrated in vacuo, loaded onto silica, and purified

by flash column chromatography to afford the desired 1,4-cyclohexadiene-fused sultams 2. No unexpected or unusually high

safety hazards were encountered. For detailed experimental procedures and characterization data for all compounds

presented above, see the Supplementary Information.

Acknowledgements

The authors acknowledge the financial support for this research from the NIH (GM127774) and the University of

Michigan. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship for

RCM (Grant No DGE 1256260). We thank Dr. Jeff W. Kampf for assistance with X-ray crystallographic analysis.

Keywords

photoredox catalysis • dearomatization • sultams • 1,4-cyclohexadiene • proton-coupled electron transfer • N-centered radicals

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