The present invention is directed to a process for preparing a phenolic hydrocarbon starting from an aryl halogenide and making use of N2O as oxygen source.

The increasing emission of greenhouse gases represents a global environmental threat, and strategies to address this major issue have been the focus of intense research efforts in recent times. From the sustainability point of view, the development of chemical processes that extend beyond the traditional degradations and repurpose such gaseous byproducts as useful synthons to produce valuable chemical feedstocks is a highly coveted approach.

While the revalorization of CO2 or CH ₄ as C1 sources for organic synthesis through catalytic strategies has received a great deal of attention, much less interest has been placed in the chemical transformation of another major contributor to the global warming: nitrous oxide (N2O). Governmental reports together with recent scientific evidence coincide in alerting about the consequences that result from the increasing presence of this undervalued gas in the atmosphere. N2O exhibits a remarkable global warming potential of >300 times that of CO2, with a decomposition half-life in the atmosphere of >100 years.

Human activities have accelerated the emissions, with an estimated increase rate of N2O of 2% per decade. Yet, a detailed analysis through the lens of sustainable synthesis presents a unique opportunity for N2O revalorization, as it represents an excellent O-atom source: it is readily available, non-toxic (laughing gas), and releases benign N2 as byproduct upon O removal.

Conversely, N2O is a kinetically inert gas, whose activation require high temperatures (140- 350 °C) and pressures (50-200 bar), resulting in limited applications as oxidant for organic synthesis. Yet, the structure of N ₂ O has captivated chemists, who studied in detail coordination modes and reactivity thereof in a plethora of metal complexes. However, few reports focused on its activation toward the formation of C-0 bonds; arguably, among the most valuable bonds in organic synthesis, as it would permit access to highly coveted alcohols, ethers, epoxides, etc. Still, these occasional examples rely on traditional metal- oxo reactivity, which requires high temperatures (100-200 °C) and pressures (10 bar) or long reaction times (1 TON/week). In a groundbreaking report, Hillhouse (J. Am. Chem. Soc. 109, 5538-5539 (1987)) observed a fundamentally different outcome: upon exposure to N2O atmosphere, the O atom could be inserted into a Hf-Ph bond of 1 forging the desired Hf-O-Ph (2) with concomitant extrusion of N2 as illustrated in the Figures. However, regioselectivity issues arose, as the O atom was competitively transferred to the hydride ligand, thus also producing a Hf-O-H complex (3). Mechanistic studies on the O insertion step between various M-C(sp ² ) bonds using N2O, peroxides or oxygen suggest that an organometallic Baeyer-Villiger-type (OMBV) mechanism is operating, where the anionic carbon migrates to the encounter of the coordinated O atom, forging the M-O-C bond.

Based on these findings, the inventors aimed at unlocking the potential of N ₂ O as O-atom source in a catalytic system, toward a fundamentally different synthesis of phenols. In contrast to the traditional synthesis, after C-0 bond formation the oxidation state of the metal center remains intact, thus requiring an external reductant to close the cycle.

To orchestrate such reductive process, the inventors focused their attention on Ni and its demonstrated ability to maneuver between different oxidation states through SET. In the present invention, the inventors demonstrate that a mechanistically guided approach to activation of N2O with organometallic complexes results in the development of a mild and selective catalytic synthesis of high value phenols from aryl halides using N2O as electrophilic O-source. The remarkably mild conditions (25 °C and 1.5 - 2 atm) allow the accommodation of a variety of functional groups, including base-sensitive moieties, thus providing an orthogonal strategy to the current technologies as illustrated in the Figures. This catalytic protocol represents a radically distinct approach for the synthesis of C-0 bonds and provides a solution to the mild revalorization of N2O as a benign O source for synthesis.

Thus, the present invention is directed to a process for preparing a phenolic hydrocarbon wherein an aryl halogenide is reacted with N ₂ O, alkali iodide selected from sodium or potassium iodide, and Zn in the presence of a Ni-complex having a ligand selected from bipy-pyr and terpy, in a temperature range of 0 °C to 50 °C whereby the halogenide on the aryl moiety is replaced by hydroxyl.

The inventive process can be applied to a broad number of aryl halogenides including branched and polycyclic aryl or heteroaryl compounds, and the aryl or heteroaryl halogenide is usually selected from the aryl or heteroaryl bromide or aryl iodide. The aryl moiety, i.e. the aryl residue of the aryl halogenide, can be any aryl moiety, such as benzyl, naphthyl, anthracenyl, biphenyl, fluorenyl, indanolyl, thianthrenyl, quinolyl, and further aryl or heteroaryl moieties.

In more detail, the aryl halogenide is preferably selected from: monocyclic or polycyclic aromatic hydrocarbons having 6 to 22 carbon atoms, monocyclic or polycyclic heteroaromatic hydrocarbons having 5 to 21 carbon atoms, or monocyclic or polycyclic aralkyl hydrocarbons having 6 to 34 carbon atoms, each of which hydrocarbons may be substituted by one or more substituents selected from -OR, -F, -Cl, -Br, -I, -NR ₂ , -CF ₃ , -CN, -(C=O)-R, -(C=O)-O-R', -(C=O)-NR ₂ , - (P=O)(OR')) ₂ ,, -SO ₂ R', -SR, -SF ₅ , -B(OR') ₂ , wherein R represents hydrogen, an aliphatic hydrocarbon residue having 1 to 12 carbon atoms and wherein R' represents an aliphatic hydrocarbon residue having 1 to 12 carbon atoms.

The reaction solvent is usually a polar aprotic solvent such as /V,/V-dimethylacetamide, N,N- dimethylformamide, THF, etc.

The Ni-complex is prepared in situ in an aprotic polar solvent such as N,N- dimethylacetamide from a Ni halogenide such as NiBr ₂ or Nil ₂ (or the corresponding glyme and diglyme adducts) which are then complexed with a ligand (L) selected from bipy-pyr and terpy. A preformed adduct of the LNiBr ₂ or LNiCI ₂ is also a competent pre-catalyst.

The inventors have investigated the role of the ligand for the Ni-complex used in the inventive process in detail. Specifically, the inventors turned their attention to the synthesis of electronically asymmetric tridentate ligands. Using only one pyrazolyl allowed the identification of bipyridine-pyrazolyl as an excellent candidate for the catalytic synthesis of phenols using N ₂ O and aryl halides. Surprisingly, the homocoupling is dramatically suppressed. Other scaffolds, involving protic side arm-, nitrile containing, more flexible or more rigid ligands, resulted in diminished performance, albeit yield of phenol can be observed.

Fine-tuning the bipyridine-pyrazolyl scaffold did not improve the yields further, but still provided useful information on the important parameters to consider on the pyrazolyl moiety: 1) steric hindrance close to the Ni center is detrimental; 2) EWG in the heterocycles is detrimental; 3) EDG is tolerated and disubstitution is also tolerated as long as it is not close to the Ni center; 4) pyrazolyl scaffold is superior to triazene or thiophene. Thus, the ligands bipy-pyr and terpy are preferred. terpy bipy-pyr

Usually, the inventive process is carried out in a purified and dried reaction vessel under a N ₂ O-pressure higher than atmospheric pressure, sufficiently in the range of > 1 ,0 to 2,5 bar, preferably in the range of 1 ,5 to 2,0 bar, more preferably in the range of 1 ,9 to 2,0 bar.

The reaction time and reaction temperature are not critical and are in the range 12 to 36 hours, preferably 18 to 30 hours and in the range of 0 °C to 50 °C, preferably from 15 °C to 30 °C, respectively.

Definitions

For the terms used in the present text, the following definitions apply. The term “aliphatic” includes both saturated and unsaturated, straight chain (/.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term “alkyl” includes straight, branched and acyclic alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like. Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the like encompass both substituted and unsubstituted groups. In certain embodiments, “lower alkyl” is used to indicate those alkyl groups (acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted Ci- alkyl {e.g., — CH ₃ ). In certain embodiments, the alkyl group is a substituted Ci- alkyl.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6” is intended to encompass, Ci , C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs-6.

“Aryl” refers to a radical of a monocyclic or polycyclic e.g., bicyclic or tricyclic) 4n+2 aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is substituted Ce-14 aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system {e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom {e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom e.g., 2— indolyl) or the ring that does not contain a heteroatom {e.g., 5— indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1- 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6— bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includes at least one double or triple bond. A “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups {e.g., aryl or heteroaryl groups) as herein defined. Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds. Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise provided expressly. The term “optionally substituted” refers to substituted or unsubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted {e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

A heterosubstituent as defined according to the invention can be selected from OH, F, Cl, Br, I, CN, NO2, I-R ^S 2, NO, NCO, -NCS, -SON, SO3H, a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF3) ₂ , SF ₅ , aliphatic, aromatic, heteroaromatic, primary, secondary, tertiary amine or ammonium bound through N atom, - O-alkyl (alkoxy), -O-aryl, -O-heteroaryl -O-SiR ^s ₃ ,-S-S-R ^s , -S-R ^s , -S(O)-R ^S , -S(O) ₂ -R ^s , - COOH, -CO2-R ^S , -BR ^S 2, -PR ^S 2, -OPR ^S 2, amide, bound through C or N atom, formyl group, - C(O)-R ^S , -COOM, where M is a metal such as Li, Na, K, Cs, Ag. R ^s may be, independently from each other, the same or different and is each an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups; and/or optionally bridged by an -O- atom, represents a halogenide

The present inventions is further illustrated by the Figures and Examples. In the Figures, it is shown in:

Fig. 1. Relevance of nitrous oxide as green oxidant in the synthesis of phenol derivatives.

A. Overview of the properties of nitrous oxide.

B. Pioneering examples using N ₂ O as a reagent for organometallic chemistry.

C. Traditional C(sp ² )-0 reductive elimination and introduction of O-insertion as a new catalytic step.

D. Introducing the activation of N ₂ O into a Ni reductive catalytic cycle for crosselectrophile phenol synthesis. OAT: Oxygen Atom Transfer.

Fig. 2. Design principle and proof-of-concept.

A. Stoichiometric reactivity using bipyridine supported Ni(ll) oxidative addition complexes.

B. Ligand SAR unlocks the catalytic application of N ₂ O for the synthesis of phenols.

C. Stoichiometric reactivity of tridentate terpyridine supported Ni(ll) complexes and the involvement of Ni(l) species..

Fig. 3. Revalorization of N ₂ O as oxidant for the catalytic synthesis of phenols.

Scope of aryl iodides. [N ₂ ] = N ₂ detected by GC-TCD at the end of the reaction. All yields are of isolated pure material. Yield in brackets: ¹ H NMR yield calculated using dibromomethane as internal standard, £ Denotes use of terpy L18 as ligand instead of L50.

Fig. 4. Inventive reactions

A. Catalytic synthesis of phenols from aryl bromides using N ₂ O.

B. Exploring the insertion of O-atoms into densely functionalized aryl halides.

C. Using environmentally unfriendly greenhouse gases as building blocks for the synthesis of biologically relevant molecules. All yields are of isolated pure material. See Supplementary information for experimental details, £ Denotes use of terpy L18 as ligand instead of L50. Experimental Part

To this end, the inventors synthesized the product of oxidative addition 4, and studied its reactivity with N2O (Fig. 2A). It is well known that complexes such as 4 rapidly decompose towards homocoupling (5) and protodemetalation (6) at 25 °C when dissolved in DMA under argon or N2 (path a). This is exacerbated by the presence of reducing agents such as Zn or Mn (path b). Yet, when the inert (N2 or Ar) atmosphere is replaced by N2O, the bright red color of the solution of 4 remains, thus pointing towards a slower decomposition rate. After acidic workup, a 15% of phenol 7 is observed. However, when the same reaction is performed in the presence of a reducing agent, substantially higher yields of 7 were observed, with a remarkable 73% yield obtained when a combination of Zn and Nal was used (path d).

These results set up the stage for the development of a reductive catalytic protocol based on Ni catalysis using aryl halides. From ligand survey, it was evident that tridentate nitrogenated ligands with the general pattern of 2-substituted bipyridine were crucial to obtain catalytic activity, with terpyridine (L18) and 2-pyrazole bipyridine (L50) affording the highest yields of 9 (Fig. 2B). SAR analysis of the R group revealed three key features of the ligand for catalytic activity: 1) replacing the N atom for C-H or S prevents catalytic activity (L48 and L61); 2) steric encumbrance in the ortho position of the pyrazole unit prevents catalysis (L55 and L58); 3) whereas electron-deficient pyrazole (L57, L60) dramatically reduce catalytic activity, electron-rich pyrazole results in comparable yields as for L50 (L56, L59). To confirm Ni-ligand ligation in the reaction mixture, complex 10 was prepared and structurally characterized. A 75% yield of 9 as obtained using 10 as catalyst, thus confirming that the pre-ligated complex is catalytically competent. It is important to mention that L50 represents a new ligand platform within Ni catalysis, with virtually inexistent examples.

Since Fig. 2A and 2B suggest that formal Ni(l)-C(sp ² ) species might be involved, we prepared terpyridine-Ni derivatives such as 11 (Fig. 2C), since greater stability of the corresponding (terpy)Ni(l)-Ar has been noted. Similar to 4, reaction of 11 in the absence of reducing agent led to no phenol formation. Yet, reaction performed under N ₂ O in the presence of Zn and Nal afforded the desired mesitol (12) in 49% yield upon acidic work up. To further confirm the involvement of such formal Ni(l)-C(sp ² ) and the need for I in the tridentate system, the (tBu-terpy)Ni(l)— I (13) was reacted with Ph2Zn under N2O. Despite the reported instability of (terpy)Ni(l)— Ph, a significant 20% of phenol (14) was obtained. Altogether, it is suggestive that reduction of Ni(ll) species to formal Ni(l) and the aid of I salts in the system are of capital importance to forge the desired C(sp ² )-0 bond. Mechanistic investigations on M-Ar oxy insertions for late transition metals (Pd, Ni, Fe) reveal that subtle changes on ligand environment also lead to differences between a M- oxo or a BV pathway for Ar-0 bond formation. In our case, we suggest that within the continuum between the two extreme possibilities offered in the OMBV, the oxy-insertion of N2O in a d ⁹ complex lies towards the formation of the M-0 bond and N2, prior to Ar migration.

With the optimized catalytic system in hand, a preliminary scope of the aryl halide counterpart was interrogated. As shown in Fig. 3, aryl iodides bearing other halogens in both para- (9, 15, 16) and meta-positions (17-19) smoothly afforded the corresponding phenol in excellent yields. The presence of electron-withdrawing groups such as CF ₃ (7), ketone (20), ester (21 and 24) or nitrile (22-23) posed no difficulty for the C-0 bond formation. Electron-donating substituents such as alkyl (25), aryl (26), or even methoxy and thiomethyl (27-28) delivered phenol in good yields. Moreover, fluorene derivative (29) featuring benzylic C-H bonds was also amenable for phenol synthesis, albeit in 38% yield. A classical feature of reductive couplings is that steric hindrance at the orf/io-position can impede reactivity. Indeed, C-0 bond formation in indanone (31) and 1-chloro-2- iodobenzene (30) afforded slightly diminished yields. In contrast to 30, 32 was obtained in 79% yield, illustrating a possible beneficial chelating effect of the ortho OMe and the Ni center. A silylated benzylic alcohol (33) or a diethylphosphonate (34) were also tolerated in this protocol. Heterocycles such as indole (35), quinoline (36), carbazole (37) or dibenzothiophene (38) also afforded the corresponding phenol in good yields. Substrates prone to rapid oxidation after C-0 bond formation could be further functionalized in situ, as exemplified by the 68% yield obtained for the pivaloyl derivative 39. Iodide derivative of biologically active clofibrate could be converted to phenol 40 in 78% yield despite the presence of a tertiary a-oxy ester. It is important to mention that this protocol does not require the use of ROH nucleophiles, and hence base-sensitive functionalities such as esters or sensitive amides, which would hydrolyze upon heating, are tolerated. An example of this chemoselectivity is observed in the derivatization of a pinacolborane containing substrate. In this case, phenol 41 was still obtained in 56% yield, thus providing an orthogonal tool to classical oxidation. The observation of 7% yield of sulfoxide in the reaction of 28, and the low yield obtained for fluorenol 29, suggest that the oxy-insertion step lies towards the oxo-pathway in the continuum postulated for OMBV-type reactions. It is important to mention that N2 was detected by GC-TCD in the headspace once the reaction finished (Fig. 10 and 1 D). Additionally, when the only alternative source of O was labelled ( ¹⁸ O-DMF), no incorporation of ¹⁸ O in 14 was obtained. Altogether, this data supports that the OAT process proceeds via N2O activation.

The same optimized reaction conditions for aryl iodides permitted C-0 bond formation of more accessible and commercially available aryl bromides. Yet, electron-withdrawing substituents were required to allow C(sp ² )-Br cleavage to occur. In this sense, phenols bearing CF3 (7), Ac (20) and CN (22) in the para position, as well as paraben (21), could be obtained in high yields (Fig 4A). Medicinally relevant phthalide was also smoothly converted to the phenol (42), thus providing a 3-step shorter synthesis of this building block compared to the reported process method. Interestingly, phenols derived from TT-extended or conjugated systems such as naphthoate 43 or cinnamate 44 were also obtained in 65% and 78% respectively. In contrast to current light-mediated processes, no isomerization of the double bond in 44 was observed. Sulfur-containing scaffolds such as the base-sensitive methyl sulfone (45) were obtained in a remarkable 82% yield. Despite the high tendency for self-condensation reported for 46, a substantial 27% yield could also be isolated.

Complex aryl halides functionalized with sensitive moieties were then tested. For example, empagliflozin derivative, which contains a plethora of weak C-H bonds prone to HAT was smoothly converted to the corresponding phenol (47) in excellent yield (Fig 4B). An ester derivative of natural product eugenol afforded the desired phenol (48) in a remarkable 84% yield, highlighting the high chemoselectivity of this process over alternative oxidation through metal-oxo pathways. Despite of the tri-phasic nature of the protocol, synthesis of 48 could be scaled up to ca. 1 gram without the need for special setup. Substrates containing saturated N-heterocycles such as piperazinone 49, azetidine 50, pyrrolidinone (aniracetam intermediate) 51 , and nortropinone derivative 52 are well tolerated. The requirement of an electron-withdrawing group in order to activate the aryl bromide can be turned into a synthetic advantage, thus permitting regioselective control on the activated aryl bromide (53, 78%). Finally, a derivative of high-blood cholesterol drug ezetimibe could be smoothly converted into the corresponding phenol (54), without altering the chiral and unprotected secondary alcohol, the ester and strained p-lactam. Similar chemoselectivity can be observed in the conversion of paroxetine derivative 55. Finally, Fig. 4C illustrates a proof-of-concept of the potential for the revalorization of greenhouse gases for organic synthesis. It is now possible to combine N2O and CO2 revalorization strategies and obtain metaxolone (60), where 66% of the oxygen atoms originate from waste gaseous feedstock. A more strikingly example is illustrated in the synthesis bazedoxifene (67), an anti-breast and -pancreatic cancer drug candidate. Upon successful synthesis of the three phenolic building blocks from the parent halides (64, 87%; 12, 82%; 65, 53%), and further Fischer- indole reaction to access indole 66, the stage is set to obtain bazedoxifene (67) where all O atoms would be originated from N2O.

Through a distinct fundamental organometallic step, a catalytic protocol for the revalorization of N2O as green, mild and chemoselective O-atom insertion reagent for organic synthesis has been unlocked. A mechanistically guided voyage into the reactivity of N2O with Ni complexes revealed that the unique properties of formally low-valent Ni(l)— aryl permit the O-insertion in an efficient manner. The inert N2O molecule succumbs to activation under mild conditions toward a mild and selective synthesis of phenols from aryl halides. The catalytic system features an electronically asymmetric tridentate pyrazolyl- bipyridine ligand (L50) for the Ni center, which enables a selective C-0 bond formation. The reported conditions are simple and robust, allowing C-0 bond formation in densely functionalized molecules. Whereas other catalytic protocols capitalize on nucleophilic HO- counterparts, this method represents a unique example of catalytic C-0 bond formation with an electrophilic O-atom source, which in turn, can accommodate base-sensitive functionalities. Furthermore, this protocol demonstrates the feasibility of accessing relevant drugs, where N2O is the sole source of oxygen atoms. Unlocking the catalytic and selective O-insertion into M-C bonds under mild conditions opens the door to the usage of N2O for the formation of a plethora of O-rich molecules, thus influencing the design of future sustainable catalytic methods.

Experimental Part

Instruments

Unless otherwise stated, all manipulations were performed using Schlenk techniques under dry argon in heatgun-dried glassware. Anhydrous solvents were distilled from appropriate drying agents and were transferred under Argon: THF, Et20 (Mg/anthracene), CH2CI2 (CaH ₂ ), CH ₃ CN (CaH ₂ ), hexane, toluene (Na/K), benzene-d ₆ (MS), CD2CI2 (MS), CD ₃ CN (MS). GC-MS (FID): GC-MS-QP2010 equipped (Shimadzu Europe Analytical Instruments). ESI-MS: ESQ 3000 (Bruker). Accurate mass determinations: Bruker APEX III FT-MS (7 T magnet) or MAT 95 (Finnigan). GC-TCD measurements were performed on Agilent Technologies GO 7890B with a 30 m HP-Plot 5 A Molsieves column. Melting points were measured with an EZ-Melt Automated Melting Point Apparatus from Stanford Research Systems. NMR spectra were recorded using a Bruker AVIIIHD 300 MHz, Bruker AVIIIHD 400 MHZ, Bruker AVIII 500 MHz or Bruker AVneo 600 MHz NMR spectrometer. The chemical shifts (6) are given in ppm and were measured relative to solvent residual peak as an internal standard. For ¹ H NMR: CDCh, 8 7.26; CD ₃ CN, 8 1.94; CD2CI2, 8 5.32; CeD ₆ , 8 7.16. For ¹³ C NMR: CDCh, 8 77.16; CD3CN, 8 1.32; CD2CI2, 8 53.84; C ₆ D ₆ , 8 128.06. The data is being reported as (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet or unresolved bs = broad signal, coupling constant(s) in Hz, integration, interpretation). X-Band EPR spectra were recorded on a Bruker Elexsys E-500 CWX-band spectrometer. The sample tubes of 5 mm outer diameter were placed in a standard TE102 resonator. Low temperature measurements (10-30K) were obtained using an Oxford ESR 900 helium flow cryostat and a Mercury series temperature controller.

Chemicals

DMF-dz, THF-cfe and toluene-cfe were purchased from Eurisotop, degassed by repeated freeze-pump-thaw cycles, distilled from the proper drying agents, and stored over 4 A molecular sieves. 4 A molecular sieves were activated at 200 °C under high vacuum (1 x 10 ^-4 bar) for 3 days. Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. N2O was provided by Air Liquide (Distickstoffmonoxid UHP 5.0) containing less than 5 ppm N2, 1 ppm H2O and 1 ppm air and O2

Examples

Scope of the catalytic oxidation of aryl halides using N ₂ O

General procedure GP1 : (using bipy-pyr-L50)

For the scope, oven- and heatgun-dried pressure Schlenks with Teflon screw-cap and equipped with Teflon-coated stir bar were used. These Schlenks were brought to argon filled glovebox, along with a heatgun dried vial. Dried DMA was introduced to the vial. NiBr ₂ .diglyme (7.1 mg, 0.020 mmol, 10 mol%), bipy-pyr L50 (6.7 mg, 0.030 mmol, 15 mol%), Nal (45 mg, 0.30 mmol, 1.5 equiv), aryl halide (if solid, 0.20 mmol, 1.0 equiv), and zinc (20 mg, 0.30 mmol, 1.5 equiv) were introduced in the pressure Schlenk. Then, outside the glovebox, using a T-connection, the Schlenk was evacuated and refilled with N2O. This procedure was repeated three times. Then, under 1.5 atm of N2O, the Schlenk was opened and DMA (0.5 mL) was added using a syringe while stirring. (Stirring is important to avoid formation of agglomerates.) If the aryl halide is liquid, it is added at that time using the adapted size of Hamilton syringe. The Schlenk is then closed, and the pressure of N2O is increased to 1.9 - 2.0 atm. The reaction mixture was kept stirring at 1000 rpm, for 20 to 24 h, at RT. After the reaction, the Schlenk is carefully opened, and the reaction was first diluted using 1-2 mL of Et20 or EtOAc depending the solubility of the expected product. The mixture is quenched first with water (the quenching can be exothermic) followed by HCI (1 M), and extracted 3 times with Et20 (12 to 15 mL). The combined organic layers were washed with brine, dried over MgSCL, filtered and concentrated under reduced pressure. The crude is purified by column chromatography over silica gel using gradient of solvents.

General procedure 2: (terpy conditions)

The sole modification for these conditions are highlighted here: NiBr2.diglyme (7.1 mg, 0.020 mmol, 10 mol%), terpy L18 (7.0 mg, 0.030 mmol, 15 mol%), Nal (60 mg, 0.40 mmol, 2.0 equiv), aryl halide (if solid, 0.20 mmol, 1.0 equiv), and zinc (32.7 mg, 0.500 mmol, 2.5 equiv) were introduced in the pressure Schlenk.

10 l% NiB di l , ,

(2 atm) - N ₂

Scope of aryl iodides

Phenol (14)

14, 82%, (89%)

Following general procedure GP1 , using phenyl iodide (22 L, 0.20 mmol, 1.0 equiv) as starting material, 89% NMR yield of the expected product was observed using CH2Br2 as internal standard. Purification was performed using Pentane: Et20 (10:1 to 8:1) as eluent, affording 15.5 mg (0.165 mmol, 82% yield) of phenol (12) as a white solid. As a comparison, using GP2, 80% NMR yield was observed.

Rf (Pentane: Et20 = 8:2) 0.3 4-Fluorophenol (9)

9, 80%

Following general procedure GP1 , using 4-fluoro-phenyl iodide (23 pL, 0.20 mmol, 1.0 equiv) as starting material, 84% NMR yield was observed, using CH ₂ Br ₂ as internal standard. Purification was performed using Pentane:Et ₂ O (20:1 to 8:1) as eluent, affording 18.0 mg (0.161 mmol, 80% yield) of 4-fluorophenol (9) was obtained as a pale yellow solid. As a comparison, using GP2, 75% NMR yield was observed.

4-Chlorophenol (15)

15, 75%

Following general procedure GP1 , using 1-chloro-4-(iodo)benzene (47.7 mg, 0.200 mmol, 1.0 equiv) as starting material, 19.3 mg (0.150 mmol, 75% yield) of 4-chlorophenol (15) was obtained as a light yellow solid after purification using Pentane: Et ₂ O (19:1 to 10:1) as eluent.

4-Bromophenol (16)

16, 59%

Following general procedure GP1 , using 1-bromo-4-(iodo)-benzene (56.6 mg, 0.200 mmol, 1.0 equiv) as starting material, 20.4 mg (0.118 mmol, 59% yield) of 4-bromophenol (16) was obtained as a light yellow solid after purification using Pentane: Et ₂ O (19:1 to 10:1) as eluent.

3-Fluorophenol (17)

17, 82% Following general procedure GP1 , using 1-fluoro-3-iodobenzene (23.5 pL, 0.200 mmol, 1.0 equiv) as starting material, 18.4 mg (0.164 mmol, 82% yield) of 3-fluorophenol (17) was obtained as a light yellow oil after purification using Pentane: Et ₂ O (10:1 to 4:1) as eluent.

3-Chlorophenol (18)

18, 74%

Following general procedure GP1 , using 1-iodo-3-(chloro)benzene (24.7 pL, 0.200 mmol, 1.0 equiv) as starting material, 19.0 mg (0.148 mmol, 74% yield) of 3-chlorophenol (18) was obtained as a light yellowish oil after purification using Pentane:Et2O (10:1 to 4:1) as eluent.

3-Bromophenol (19)

19, 69%

Following general procedure GP1 , using 1-bromo-3-iodobenzene (25.5 pL, 0.200 mmol, 1.0 equiv) as starting material, 24 mg (0.14 mmol, 69% yield) of 3-bromophenol (19) was obtained as a light yellowish oil after purification using Pentane: Et ₂ O (15:1 to 10:1) as eluent.

4-(Trifluoromethyl)phenol (7)

75% from Ari 65% from ArBr

Following general procedure GP1 , using 1-iodo-4-(trifluoromethyl)benzene (29.4 pL, 0.200 mmol, 1.0 equiv) as starting material, 24.3 mg (0.150 mmol, 75% yield) of 4- (trifluoromethyl)phenol (7) was obtained as a light yellow solid after purification using Pentane: Et ₂ O (19:1 to 10:1) as eluent.

Following general procedure GP1 , using 1-bromo-4-(trifluoromethyl)benzene (26 pL, 0.20 mmol, 1.0 equiv) as starting material, 21.1 mg (0.130 mmol, 65% yield) of 4- (trifluoromethyl)phenol (7) was obtained as a light yellow solid after purification using Pentane: Et20 (19:1 to 10:1) as eluent.

1-(4-Hydroxyphenyl)ethan-1-one (20)

74% from Ari

84% from ArBr

Following general procedure GP1 , using 4-iodo-acetophenone (49.2 mg, 0.200 mmol, 1.0 equiv) as starting material, 20.1 mg (0.148 mmol, 74% yield) of 1-(4-Hydroxyphenyl)ethan- 1-one (20) was obtained as a white solid after purification (2 columns, first one short using Pentane: Et20 (10:1 to 5:1) then 2 ^nd column using DCM to DCM/EtOAc 95:5 as eluent).

Following general procedure GP1 , using 4-bromo-acetophenone (39.9 mg, 0.200 mmol, 1.0 equiv) as starting material, 22.8 mg (0.167 mmol, 84% yield) of 1-(4-Hydroxyphenyl)ethan- 1-one (20) was obtained as a white solid after purification using Pentane:Et2O (4:1 to 2:1).

Methyl 4-hydroxybenzoate (Paraben, 21) 68% from Ari 75% from ArBr

Following general procedure GP2, using methyl 4-iodobenzoate (52.4 mg, 0.200 mmol, 1.0 equiv) as starting material, 20.7 mg (0.136 mmol, 68% yield) of methyl 4-hydroxybenzoate (Paraben, 21) was obtained as a white solid after purification using Pentane: Et20 gradient (from 9:1 to 7:3) as eluent.

Following general procedure GP1 , using methyl 4-bromobenzoate (43 mg, 0.20 mmol, 1.0 equiv) as starting material, 22.8 mg (0.150 mmol, 75% yield) of methyl 4-hydroxybenzoate (Paraben, 21) was obtained as a white solid after purification using Pentane:Et2O gradient (from 9:1 to 7:3) as eluent.

Rf (Pentane: Et20 = 7:3) 0.2

4-Hydroxybenzonitrile (22)

22

67% from Ari

78% from ArBr

Following general procedure GP1 , using 4-iodo-benzonitrile (45.8 mg, 0.200 mmol, 1.0 equiv) as starting material, 15.9 mg (0.133 mmol, 67% yield) of 4-hydroxybenzonitrile (22) was obtained as a white solid after purification using DCM:EtOAc (99:1 to 97:3) as eluent, (no HCI was used during workup, and only water)

Following general procedure GP1 , using 4-bromo-benzonitrile (36.4 mg, 0.200 mmol, 1.0 equiv) as starting material, 18.6 mg (0.156 mmol, 78% yield) of 4-hydroxybenzonitrile (22) was obtained as a white solid after purification using DCM:EtOAc (99:1 to 97:3) as eluent, (no HCI was used during workup, and only water)

3-Hydroxybenzonitrile (23)

23, 58%

Following general procedure GP1, using 3-iodo-benzonitrile (45.8 mg, 0.200 mmol, 1.0 equiv) as starting material, 13.8 mg (0.116 mmol, 58% yield) of 3-hydroxybenzonitrile (23) was obtained as a light yellowish oil after purification using Pentane: Et20 (9:1 to 3:1) as eluent. No HCI was used during the workup.

Methyl 3-(4-hydroxyphenyl)propanoate (24)

24, 81%

Following general procedure GP1 , using methyl 3-(4-iodophenyl)propanoate (58 mg, 0.20 mmol, 1.0 equiv) as starting material, 29.1 mg (0.161 mmol, 81% yield) of methyl 3-(4- hydroxyphenyl)propanoate (24) was obtained as a light yellow solid after purification using Pentane: Et ₂ O (7:1 to 3:1) as eluent.

Rf (Pentane: Et ₂ O (6:4)) 0.40

4-Pentylphenol (25)

25, 79%

Following general procedure GP1 , using 1-iodo-4-(pentyl)benzene (39.7 pL, 0.200 mmol, 1.0 equiv) as starting material, 26.0 mg (0.158 mmol, 79% yield) of 4-pentylphenol (25) was obtained as a light yellow oil after purification using Pentane: Et20 (95:5 to 9:1) as eluent. Rf (Pentane: Et ₂ O (9:1)) 0.25

[1,1'-Biphenyl]-4-ol (26)

26, 73%

Following general procedure GP2, using 1-iodo-4-(phenyl)benzene (56 mg, 0.20 mmol, 1.0 equiv) as starting material, 24.8 mg (0.146 mmol, 73% yield) of [1 ,1'-Biphenyl]-4-ol (26) was

4-Methoxyphenol (Mequinol, 27)

27, 81%

Following general procedure GP1 , using 4-iodo-anisole (46.8 mg, 0.200 mmol, 1.0 equiv) as starting material, 20.2 mg (0.163 mmol, 81% yield) of 4-methoxyphenol (27) was obtained as a white solid after purification using Pentane:Et2O (10:1 to 4:1) as eluent.

4-(Methylthio)phenol (28)

28, 61 %

Following general procedure GP1 , using 4-iodo-thioanisole (50 mg, 0.20 mmol, 1.0 equiv) as starting material, 17.1 mg (0.122 mmol, 61% yield) of 4-(methylthio)phenol (28) was obtained as a white solid after purification using Pentane: Et20 (9:1 to 4:1) as eluent. Detection of 6-7% of the corresponding sulfoxide in the crude NMR. 9H-Fluoren-2-ol (29)

29, 38%

Following general procedure GP2, using 2-iodo-9H-fluorene (58.4 mg, 0.200 mmol, 1.0 equiv) as starting material, 14 mg (0.077 mmol, 38% yield) of 9H-Fluoren-2-ol (29) was obtained as a white solid after purification using Pentane:Et2O (10:1 to 8:1) as eluent, followed by a short column using only DCM as eluent to remove colorful impurities.

2-Chlorophenol (30)

30, 40%, (50%)

Following general procedure GP1 , using 1-chloro-2-iodobenzene (24.4 pL, 0.200 mmol, 1.0 equiv) as starting material, 10 mg (0.080 mmol, 40% yield) of 2-chlorophenol (30) was obtained as a white solid after purification using Pentane: Et20 (1 :0 to 8:1) as eluent. This compound is relatively volatile, and the isolated yield (40%) is quite lower than the NMR yield on the crude (50%).

4-Hydroxy-2,3-dihydro-1 H-inden-1 -one (31 )

31, 43%

Following general procedure GP1 , using 4-iodo-2,3-dihydro-1 H-inden-1-one (51.6 mg, 0.200 mmol, 1.0 equiv) as starting material, 12.8 mg (0.0864 mmol, 43% yield) of 4-hydroxy- 2,3-dihydro-1 H-inden-1-one (31) was obtained as a white solid after purification using DCM:EtOAc (99:1) as eluent.

Guaiacol (32)

32, 79%

Following general procedure GP1 , using 2-iodoanisole (26.1 pL, 0.200 mmol, 1.0 equiv) as starting material, 19.6 mg (0.158 mmol, 79% yield) of guaiacol (32) was obtained as a white solid after purification using Pentane: Et ₂ O (10:1 to 8:1) as eluent.

Rf (Pentane: Et ₂ O (7:3)) 0.45

4-(((Triisopropylsilyl)oxy)methyl)phenol (33)

33, 55%

Following general procedure GP1 , using ((4-iodobenzyl)oxy)triisopropylsilane (78.1 mg, 0.200 mmol, 1.0 equiv) as starting material, 31 mg (0.11 mmol, 55% yield) of 4- (((triisopropylsilyl)oxy)methyl)phenol (33) was obtained as a colorless sticky oil after purification using Pentane:Et ₂ O (10:1 to 8:1) as eluent.

Rf (Pentane: Et ₂ O (7:3)) 0.40

Diethyl (4-hydroxybenzyl)phosphonate (34)

34, 41%, (50%)

Following general procedure GP1 , using diethyl (4-iodobenzyl)phosphonate (70.8 mg, 0.200 mmol, 1.0 equiv) as starting material, NMR yield indicated 50% from the crude, and 20 mg (0.082 mmol, 41 % yield) of diethyl (4-hydroxybenzyl)phosphonate (34) was obtained as a solid after tedious purification using DCM:MeOH (1 :0 to 95:5) as eluent. tert-Butyl 5-hydroxy-1 H-indole-1 -carboxylate (35)

35, 74%

Following general procedure GP1 , using tert-butyl 5-iodo-1 H-indole-1-carboxylate (68.6 mg, 0.200 mmol, 1.0 equiv) as starting material, 34.7 mg (0.149 mmol, 74% yield) of tert- butyl 5-hydroxy-1H-indole-1-carboxylate (35) was obtained as a sticky light yellow foam after purification using Hexane:EtOAc (10:1 to 8:1) as eluent

Rf (Hexane: EtOAc (8:2)) 0.4

6-Hydroxy-quinoline (36)

XX, 38%

Following general procedure GP1 , using 6-iodo-quinoline (51 mg, 0.20 mmol, 1.0 equiv) as starting material, 11 mg (0.076 mmol, 38% yield) of 6-hydroxy-quinoline (36) was obtained as a white solid after purification using Hexane: EtOAc (2:1 to 1:1) as eluent.

Rf (Hexane: EtOAc (1 :1)) 0.20

9-Phenyl-9H-carbazol-3-ol (37)

37, 51 %

Following general procedure GP1 , using 3-bromo-9-phenyl-9H-carbazole (62.2 mg, 0.20 mmol, 1.0 equiv) as starting material, 26.4 mg (0.102 mmol, 51% yield) of 9-phenyl-9H- carbazol-3-ol (37) was obtained as a colorless oil after purification using hexanes: EtOAc (5:1) as eluent.

Rf (Hexanes: EtOAc (5:1)) 0.20.

Dibenzo[b,d]thiophen-2-ol (38)

Following general procedure GP1, using 2-bromodibenzo[b,d]thiophene (52.4 mg, 0.20 mmol, 1.0 equiv) as starting material, 14.8 mg (0.074 mmol, 37% yield) of dibenzo[b,d]thiophen-2-ol (38) was obtained as a white solid after purification using hexanes: EtOAc (5:1) as eluent.

Rf (Hexanes: EtOAc (5:1)) 0.20.

4-(Diphenylamino)phenyl pivalate (39)

S13 unstable 39, 68% towards oxidation

Following general procedure GP1 , using 4-iodo-triphenylamine (S13) (74.2 mg, 0.200 mmol, 1.0 equiv) as starting material, the pressure Schlenk was then carefully open under argon at the end of the first step, and pivalic anhydride (122 pL, 0.600 mmol, 3.0 equiv) was added to the crude reaction mixture and stirred for additional 2 h30 min at 50 °C. After that time, 10 mL of water and drops of NaHCOs were added and the crude was extracted 3 times using 12 mL of Et ₂ O. Then, the combined organic layers were washed using saturated NaHCOs, dried over MgSCL, filtered and concentrated under reduced pressure. Column chromatography over silica gel using full Pentane to Pentane:Et ₂ O (20:1) as eluent deliver 47.0 mg (0.136 mmol, 68% yield) of 4-(diphenylamino)phenyl pivalate (39) as obtained as a colorless oil.

Ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (40)

40, 78%

Following general procedure GP1 , using ethyl 2-(4-iodophenoxy)-2-methylpropanoate (66.8 mg, 0.200 mmol, 1.0 equiv) as starting material, 35.0 mg (0.156 mmol, 78% yield) of ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (40) was obtained as a off-white solid after purification using Pentane: Et ₂ O (8:1 to 2:1) as eluent.

Rf (Pentane: Et ₂ O (7:3)) 0.20

4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (41 )

Following general procedure GP1 , using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyliodide (66 mg, 0.20 mmol, 1.0 equiv) as starting material, 24.7 mg (0.112 mmol, 56% yield) of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (41) was obtained as a white solid after purification using Pentane: Et ₂ O (10:1 to 8:1) as eluent.

Rf (Hexane: EtOAc (3:1)) 0.3 Scope of aryl bromides

5-Hydroxyisobenzofuran-1 (3H)-one (42)

42, 58%

Following general procedure GP1 , using 5-bromphthalide (42.6 mg, 0.200 mmol, 1.0 equiv) as starting material, 17.5 mg (0.117 mmol, 58% yield) of 5-hydroxyisobenzofuran-1(3H)- one (42) was obtained as a white solid after purification using Hexane: EtOAc (9:1 to 5:1) as eluent.

Methyl 6-hydroxy-2-naphthoate (43)

43, 65%

Following general procedure GP1 , using methyl-6-bromo-2-naphthoate (53 mg, 0.20 mmol, 1.0 equiv) as starting material, 26.2 mg (0.130 mmol, 65% yield) of methyl-6-hydroxy-2- naphthoate (43) was obtained as a light brownish - off white solid after purification using DCM:EtOAc (99:1 to 97:3) as eluent followed by trituration in minimal amount of Pentane/DCM.

Ethyl (E)-3-(4-hydroxyphenyl)acrylate (44)

44, 78%

Following general procedure GP1 , using ethyl (E)-3-(4-bromophenyl)acrylate (37.5 pL mg) as starting material, 30.0 mg (0.156 mmol, 78% yield) of ethyl (E)-3-(4- hydroxyphenyl)acrylate (44) was obtained as a white solid after purification using Pentane:Et ₂ O (6:1 to 3:1) as eluent. No Z isomer was detected.

Rf (Pentane: Et ₂ O (7:3)) 0.2

4-(Methylsulfonyl)phenol (45)

45, 82%

Following general procedure GP1 , using 1-bromo-4-(methylsulfonyl)benzene (47 mg, 0.20 mmol, 1.0 equiv) as starting material, 28.2 mg (0.164 mmol, 82% yield) of 4- (methylsulfonyl)phenol (45) was obtained as a white solid after purification using Hexane: EtOAc (10:1 to 4:1) as eluent.

Rf (Hexane: EtOAc (6:4)) 0.5

Summary:

Catalytic activation and chemical repurposing of potent greenhouse nitrous oxide (N2O) has long remained a challenge due to its remarkable inertness. Herein, the inventors describe a protocol based on Ni catalysis that unlocks the intrinsic properties of N2O as a useful O source. The inventors report on the ability of N2O to undergo O-insertion into Ni-C bonds under mild conditions (room temperature, 1.5 - 2 bars N2O), in a manner akin to a Baeyer- Villiger reaction, thus delivering the C-0 bond and benign N ₂ . This fundamental organometallic C-0 bond-forming step differs from the canonical reductive elimination and enables a distinct catalytic approach for the conversion of aryl halides into phenols. The process was rendered catalytic by means of a unique bipyridine-pyrazole tridentate ligand for the Ni center, which permits selective C-0 insertion in high yields. The method is robust, mild, and highly selective, thus accommodating base-sensitive functionalities as well as permitting phenol synthesis on densely functionalized aryl halides.