Reduction of the Diazo Functionality of Α-Diazocarbonyl Compounds Into a Methylene Group by NH3BH3 Or Nabh4 Catalyzed by Au Nanoparticles

nanomaterials

Article Reduction of the Diazo Functionality of α-Diazocarbonyl Compounds into a Methylene Group by NH3BH3 or NaBH4 Catalyzed by Au Nanoparticles

Marios Kidonakis and Manolis Stratakis *

Department of Chemistry, University of Crete, 71003 Voutes, Heraklion, Greece; [email protected] * Correspondence: [email protected]; Tel.: +30-2810545087

Abstract: Supported Au nanoparticles on TiO2 (1 mol%) are capable of catalyzing the reduction of the carbene-like diazo functionality of α-diazocarbonyl compounds into a methylene group

[C=(N2) → CH2] by NH3BH3 or NaBH4 in methanol as solvent. The Au-catalyzed reduction that occurs within a few minutes at room temperature formally requires one hydride equivalent (B-H)

and one proton that originates from the protic solvent. This pathway is in contrast to the Pt/CeO2- catalyzed reaction of α-diazocarbonyl compounds with NH3BH3 in methanol, which leads to the corresponding hydrazones instead. Under our stoichiometric Au-catalyzed reaction conditions, the ketone-type carbonyls remain intact, which is in contrast to the uncatalyzed conditions where they are selectively reduced by the boron hydride reagent. It is proposed that the transformation occurs via the formation of chemisorbed carbenes on Au nanoparticles, having proximally activated the boron hydride reagent. This protocol is the ﬁrst general example of catalytic transfer hydrogenation of the carbene-like α -ketodiazo functionality. Keywords: α-diazocarbonyl compounds; transfer hydrogenation; boron hydrides; heterogeneous Citation: Kidonakis, M.; Stratakis, M. catalysis; supported Au nanoparticles Reduction of the Diazo Functionality of α-Diazocarbonyl Compounds into a Methylene Group by NH3BH3 or

NaBH4 Catalyzed by Au 1. Introduction Nanoparticles. Nanomaterials 2021, 11, The reduction of the carbene-like diazo functionality into a methylene group 248. https://doi.org/10.3390/nano [C=(N2) → CH2] in α-diazocarbonyl compounds is not a well-studied transformation 11010248 in the past, and there are scattered examples in the literature. Decades ago, the Wolfrom method [1] was reported, which employs hydriodic acid as the reducing agent and then a Received: 18 December 2020 protocol involving catalytic amounts of diethyl peroxydicarbonate in isopropanol [2]. The Accepted: 13 January 2021 α β β Published: 18 January 2021 interesting transformation of -diazo- -hydroxy esters into -keto esters [3,4] catalyzed by Rh2(OAc)4 could be seen as a relevant example and apparently involves an intramolecular

Publisher’s Note: MDPI stays neutral transfer hydrogenation. Bu3SnH has been also used as reducing agent with Cu(acac)2 as with regard to jurisdictional claims in catalyst under irradiation [5], as well as a series of early transition metallocenes in the published maps and institutional affil- presence of H2O[6]. Finally, the relevant to this concept Pd/C-catalyzed hydrogenation of iations. a specific type of diazo compounds (α-diazo-β-hydroxy esters) [7] appears as a practical reductive method providing β-hydroxy esters in moderate to good yields. Recently, we presented the first example of Au-catalyzed hydrosilylation of α-diazocarbonyl compounds using recyclable and reusable Au nanoparticles on TiO2 as the active catalytic sites (Scheme1)[ 8]. This reaction proceeds in short reaction times in Copyright: © 2021 by the authors. α Licensee MDPI, Basel, Switzerland. anhydrous 1,2-dichloroethane (DCE) affording -silyl carbonyl compounds in high yields. This article is an open access article It is most likely that this transformation involves not only the activation of the diazo com- distributed under the terms and pounds on Au NPs forming chemisorbed Au-carbenes [9] but proximally chemisorbed hy- conditions of the Creative Commons drosilanes as well. The only side product of the hydrosilylation reaction is the replacement Attribution (CC BY) license (https:// of the diazo group by two hydrogen atoms [C=(N2) → CH2]. This side pathway depends creativecommons.org/licenses/by/ on the amount of moisture in the solvent and apparently arises from the chemisorbed H 4.0/). species on the Au nanoparticle. This observation initiated our efforts to develop a new

Nanomaterials 2021, 11, 248. https://doi.org/10.3390/nano11010248 https://www.mdpi.com/journal/nanomaterials Nanomaterials 2021, 11, 248 2 of 10

on the amount of moisture in the solvent and apparently arises from the chemisorbed H species on the Au nanoparticle. This observation initiated our efforts to develop a new methodology for the reduction of the diazo functionality of α-diazocarbonyl compounds Nanomaterials 2021, 11, 248 2 of 10 into a methylene group. When we contacted the Au/TiO2-catalyzed hydrosilylation of diazo compound 1a in DCE in the additional presence of H2O (0.5 equivalent), the product selectivity alteredmethodology, affording for the reduction the reduced of the diazo ester functionality 3a in 72% of α-diazocarbonyl relative yield compounds versus 28% of the anticipated hydrosilylationinto a methylene group. product When we 2a contacted. Although the Au/TiO the 2relative-catalyzed hydrosilylationyield of 3a ofcan be further diazo compound 1a in DCE in the additional presence of H2O (0.5 equivalent), the product increased byselectivity increasing altered, the affording equivalents the reduced of ester water3a in added 72% relative into yield the versus reaction 28% of themixture, at the same time, a anticipatedhigh excess hydrosilylation of hydrosilane product 2a should. Although be the used, relative as yieldhydrosilanes of 3a can be further react with H2O (a increased by increasing the equivalents of water added into the reaction mixture, at the reaction that is also catalyzed by Au/TiO2). Thus, we sought for an alternative and cheaper same time, a high excess of hydrosilane should be used, as hydrosilanes react with H2O reducing agent(a reaction to replace that is also hydrosilane catalyzed by Au/TiO and 2 establish). Thus, we sought a more for an practical alternative methodology and to achieve this reductivecheaper reducing transformation. agent to replace hydrosilane and establish a more practical methodology to achieve this reductive transformation.

Scheme 1. Hydrosilylation of α-diazo carbonyl compounds catalyzed by Au/TiO ; reversal of chemoselectivity of the Scheme 1. Hydrosilylation of α-diazo carbonyl compounds2 catalyzed by Au/TiO2; reversal of attempted hydrosilylation of diazo compound 1a in the presence of 0.5 equivalents of H O. chemoselectivity of the attempted hydrosilylation of diazo2 compound 1a in the presence of 0.5 equivalents of H2O.Over the past two decades, supported Au nanoparticles (Au NPs) and other nano Au(0) materials have attracted signiﬁcant attention due to their surprising ability to catalyze a plethora of organic transformations, despite the metallic character of Au atoms on Over thenanoparticles past two [10 decades–13], including, supported transfer hydrogenation Au nanoparticles reductive processes (Au [14 NPs),15]. Given and other nano Au(0) materialsthe heterogeneous have attracted nature ofsignificant Au NP-catalyzed attention processes due and that to they their can surprising be easily recycled ability to cata- and reused on the vast majority of the reported protocols, they can be considered as benign lyze a plethoragreen of catalysts. organic transformations, despite the metallic character of Au atoms on nanoparticles [10–13], including transfer hydrogenation reductive processes [14,15]. 2. Results Given the heterogeneous nature of Au NP-catalyzed processes and that they can be easily At the outset, we investigated the possible Au/TiO2-catalyzed reduction of the model recycled andcompound reused on1a intothe thevast desired majority product of3a the, using reported the readily protocols, available boron they hydride can be considered as benign greenreagents catalysts. NH3BH3 and NaBH4. Ammonia borane complex [16,17] as well as sodium borohydride [18] have been used efﬁciently in the past for the reduction of alkynes or nitro compounds using Au/TiO2 as catalyst. While no reaction occurs in a series of dry 2. Results aprotic solvents (dichloromethane, diethyl ether, hexane, or benzene), to our pleasure, we found that the treatment of 1a with NH3BH3 (0.4 molar equivalent) or NaBH4 (0.3 molar At the outset,equivalent) we in investigated MeOH for 15 min the at room possible temperature Au/TiO resulted2- incatalyzed the quantitative reduction formation of the model compound 1aof into the reduced the desired product 3a product(Scheme2). 3a In the, using absence the of Au/TiO readily2 or available in the presence boron of the hydride rea- support itself (TiO2, routile, or anatase), no transformation took place even after prolonged gents NH3BHreaction3 and timesNaBH (12 h)4. atAmmonia 50 ◦C, which borane is indicative complex that Au NPs [16 are,17] the catalyticas well sites. as sodium borohydride [18] have been used efficiently in the past for the reduction of alkynes or nitro compounds using Au/TiO2 as catalyst. While no reaction occurs in a series of dry aprotic solvents (dichloromethane, diethyl ether, hexane, or benzene), to our pleasure, we found that the treatment of 1a with NH3BH3 (0.4 molar equivalent) or NaBH4 (0.3 molar equivalent) in MeOH for 15 min at room temperature resulted in the quantitative formation of the reduced product 3a (Scheme 2). In the absence of Au/TiO2 or in the presence of the support itself (TiO2, routile, or anatase), no transformation took place even after prolonged reaction times (12 h) at 50 °C, which is indicative that Au NPs are the catalytic sites. The amounts of boron hydride reagents that are necessary to achieve a quantitative reduction indicate that one hydride equivalent from either NH3BH3 or NaBH4 is required; thus, the second hydrogen atom on the product arises from the protic solvent (methanol). To test this hypothesis, we performed the reduction of diazo compound 1b with NaBH4 in methanol-d4 (Scheme 2). Analysis of the reaction mixture revealed the presence of D

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atoms in the products. The monodeuterated 3b-d1 was formed in 60% relative yield, along with dideuterated 3b-d2 (15%) and non-deuterated 3b-d0 (25%). The incorporation of H atoms from protic solvents in the Au/TiO2-catalyzed semireduction of alkynes using NH3BH3 has been already shown by our group in the past [16]. An analogous H/D scrabbling pattern in products has been reported in the Pd-catalyzed hydrogenation of N-tosylhydrazones in MeOD [19]. However, a different product distribution was seen in the reduction of 1b with NaBD4 (98% D) in methanol-d0 (Scheme 2). Under these conditions, the fully protonated product 3b-d0 was the major one (65% relative yield), along with 3b- d1 (25%) and 3b-d2 (10%). Finally, the reduction of 1b with NaBD4 in methanol-d4 afforded Nanomaterials 2021, 11, 248 3 of 10 product 3a-d2 with 92% deuterium incorporation. The incomplete deuteration in the latter experiment is attributed to traces of moisture present in the reaction medium.

SchemeScheme 2.2. Reduction ofof α-diazocarbonyl-diazocarbonyl compoundcompound1a 1aby by boronboron hydridehydride reagentsreagents in in methanol methanol catalyzed catalyzed by by Au/TiO Au/TiO22,, andand D-labelingD-labeling experimentsexperiments inin thethe reductionreduction ofof compoundcompound 1b1b..

TheThese amounts observations of boron support hydride our reagents consideration that are regarding necessary the to achieveorigins of a quantitativethe two hy- reductiondrogen atoms indicate: one that hydride one hydride from NaBH equivalent4 or NH from3BH either3 and one NH 3protonBH3 or from NaBH MeOH.4 is required; In the thus,accompanying the second mechanistic hydrogen atom analysis on the, we product will comment arises from on the the differences protic solvent in the (methanol). product Todistribution test this hypothesis, between 3b we-d2 performed, 3b-d1, and the 3b- reductiond0, upon replacing of diazocompound NaBH4 with1b NaBDwith NaBH4 or meth-4 in methanol-anol-d0 withd4 (Schememethanol2).-d Analysis4. of the reaction mixture revealed the presence of D atoms in theThe products. observed The result monodeuterated is outstanding,3b- dgiven1 was that formed the inreduction 60% relative is very yield, fast, along occurs with at dideuteratedroom temperature3b-d2 with(15%) low and loading non-deuterated of the catalyst,3b-d0 and(25%). the Theamount incorporation of the reducing of H atoms agent fromis stoichiometric protic solvents in terms in the of Au/TiO hydride2-catalyzed equivalents. semireduction Thus, for instance, of alkynes one using molar NH equivalent3BH3 has beenof NH already3BH3 can shown formally by our achieve group the in reduction the past [16 of]. three An analogous molar equivalents H/D scrabbling of the α pattern-diazo- incarbonyl products compound. has been reportedThe catalyst in the can Pd-catalyzed be recycled hydrogenation at the end of ofeachN-tosylhydrazones reaction by simple in MeODfiltration [19 and]. However, then reused a different after being product washed distribution with dichloromethane was seen in the and reduction dried in of the1b ovenwith NaBDat 90 °4C(98% for 2 D) h. inWe methanol- were abled0 to(Scheme perform2). five Under consecutive these conditions, catalytic the runs fully with protonated the same productbatch of 3bcatalyst-d0 was without the major observing one (65% any relative obvious yield), deterioration along with in terms3b-d1 o(25%)f yields. and We3b em--d2 (10%).phasize Finally, herein the the unique reduction nature of 1b of ourwith catalytic NaBD4 system,in methanol- as it knownd4 afforded [20] that product in the 3aanal--d2 with 92% deuterium incorporation. The incomplete deuteration in the latter experiment is ogous treatment of α-diazocarbonyl compounds with three molar equivalents of NH3BH3 attributed to traces of moisture present in the reaction medium. under single-atom platinum on ceria catalysis conditions (Pt1/CeO2), the corresponding hydrazonesThese observations are formed instead, support as our seen consideration in Scheme 3.regarding the origins of the two hydrogen atoms: one hydride from NaBH4 or NH3BH3 and one proton from MeOH. In the accompanying mechanistic analysis, we will comment on the differences in the product distribution between 3b-d2, 3b-d1, and 3b-d0, upon replacing NaBH4 with NaBD4 or methanol-d0 with methanol-d4. The observed result is outstanding, given that the reduction is very fast, occurs at room temperature with low loading of the catalyst, and the amount of the reducing

agent is stoichiometric in terms of hydride equivalents. Thus, for instance, one molar equivalent of NH3BH3 can formally achieve the reduction of three molar equivalents of the α-diazocarbonyl compound. The catalyst can be recycled at the end of each reaction by simple ﬁltration and then reused after being washed with dichloromethane and dried in the oven at 90 ◦C for 2 h. We were able to perform ﬁve consecutive catalytic runs with the same batch of catalyst without observing any obvious deterioration in terms of yields. We emphasize herein the unique nature of our catalytic system, as it known [20] that in the analogous treatment of α-diazocarbonyl compounds with three molar equivalents Nanomaterials 2021, 11, 248 4 of 10

Nanomaterials 2021, 11, 248 4 of 10 of NH3BH3 under single-atom platinum on ceria catalysis conditions (Pt1/CeO2), the corresponding hydrazones are formed instead, as seen in Scheme3.

Scheme 3. α TheScheme reaction 3. of The-diazocarbonyl reaction of compounds α-diazocarbonyl with NH 3compoundsBH3 in methanol with under NH different3BH3 in catalytic methanol conditions. under different catalytic conditions.Subsequently, we examined the reduction of a series of α-diazocarbonyl compounds. The results are summarized in Figure1. In all cases, the reaction proceeds smoothly Subsequently,within 15 min, we theexamined transformation the reduction is quantitative, of a series and the of isolated α-diazocarbonyl yields are very compounds. high, as The resultsthe are products summarized do not essentiallyin Figure require1. In all any cases chromatographic, the reaction puriﬁcation proceeds insmoothly the majority within 15 min, theof transformation the cases. Noteworthily, is quantitative the transformation, and the is isolated highly chemoselective yields are very given high that, the as the reduction of the generated Au-carbenes is faster than that of the ketone moiety. Thus, products do not essentially require any chromatographic purification in the majority of the reaction of α-diazo ketones 1j–l with 0.35–0.4 molar equivalents of NH3BH3 or with the cases. Noteworth0.25–0.30 molarily, equivalentsthe transformation of NaBH4 solely is highly provided chemoselective ketones 3j–l, respectively, given that leaving the reduction of the thegenerated ketone moiety Au-carbenes intact. In is the faster case ofthan using that excess of the of ketone reducing moi agentety. (≈ Thus2.5 hydride, the reaction of α-diazoequivalents), ketones both 1j– thel with diazo 0.35 and– the0.4 ketonemolar functionalities equivalents areof reducedNH3BH quantitatively3 or with 0.2 to5–0.30 the corresponding alcohols. In the literature, it is well established that in the reduction of molar equivalents of NaBH4 solely provided ketones 3j–l, respectively, leaving the ketone α-diazocarbonyl compounds with NaBH4, having an extra ketone carbonyl functionality, moiety intactthe. diazo In the group case remains of using intact excess [21]. The of same reducing holds in agent their reduction(≈2.5 hydride using biocatalytic equivalents), both the diazoconditions and the (ketoreductases, ketone functionalities NADPH [22 are]). reduced Notably, wequantitatively found that in to the the absence correspond- of ing alcohols.Au/TiO In the2, theliterature reaction, ofit 1lis withwell NH established3BH3 or NaBH that4 yieldsin the a reduction complex mixture of α-diazocarbonyl of products, and this is quite reasonable given the expected instability of the anticipated α-diazo alcohol. compounds with NaBH4, having an extra ketone carbonyl functionality, the diazo group Additionally, while the results shown in Figure1 were done at 0.2–0.3 mmol scale of the remains intactα-diazocarbonyl [21]. The same compounds, holds we in performedtheir reduction the reduction using of biocatalytic compound 1a conditionsin a 3 mmol (ke- Nanomaterials 2021,toreductases, 11, 248 scale NADPH at 0 ◦C, producing [22]). Notably, the methylene we found product that3a inin the almost absence quantitative of Au/TiO yield5 2of within, the10 reac-

tion of 1l with15 min, NH which3BH shows3 or NaBH that our4 y protocolields a complex is operational mixture for larger-scale of products, experiments. and this is quite reasonable given the expected instability of the anticipated α-diazo alcohol. Additionally, while the results shown in Figure 1 were done at 0.2–0.3 mmol scale of the α-diazocarbonyl compounds, we performed the reduction of compound 1a in a 3 mmol scale at 0 °C, producing the methylene product 3a in almost quantitative yield within 15 min, which shows that our protocol is operational for larger-scale experiments. As noted earlier in Scheme 3, hydrazones are formed exclusively in the Pt1/CeO2- catalyzed reaction of α-diazocarbonyl compounds using three molar equivalents of ammonia borane in MeOH [20]. We emphasize that in case of using an excess of reducing agent in our Au/TiO2-catalyzed transformation, the corresponding hydrazones were seen as minor products. For instance, in the reduction of substrate 1a, we observed the following. Using 0.5–0.6 molar equivalents of NaBH4 (≈100% excess in terms of hydride equivalents), hydrazone 4a [20] was observed in 8% yield relative to product 3a. With 1.2 molar equivalents, 4a is formed in 25% relative yield and with three molar equivalents in 38% (Scheme 4). On the other hand, using excess of NH3BH3, the reaction is more selective, with byproduct 4a being formed in merely 3% relative yield if using 1.0 molar equivalent of ammonia borane and 5% relative yield with 3.0 molar equivalents. The only substrate Figure 1. Reduction of α-diazocarbonyl compounds by NH3BH3 or NaBH4 catalyzed by Au/TiO2. a Witha one additional B- Figure 1. Reductionthat exhibited of α-diazocarbonyl an obviously compounds higher by NH3 selectivityBH3 or NaBH 4incatalyzed terms byof Au/TiOhydrazone2. With formation one additional was the α- H equivalent, the corresponding alcohols of the ketones 3j–l were isolated in > 90% yield. b In this case, the corresponding B-H equivalent,di theazocarbonyl corresponding alcoholscompound of the ketones1i. The3j–l were treatment isolated in of >90% 1i yield.withb Inone this case,hydride the corresponding equivalent from hydrazone (Ε/Ζ = 85/15) was formed in 15% relative yield using NH3BH3 and in 25% with NaBH4. The isolated yield refers hydrazone (E/Z = 85/15) was formed in 15% relative yield using NH3BH3 and in 25% with NaBH4. The isolated yield to the reactionNH with3BH NH3 3orBH 3NaBH. 4 resulted in the partial formation of the corresponding hydrazone 4i refers to the reaction with NH BH . [23] (E/Z = 85/15,3 3 see Supporting Information) in 15% and 25% relative yield, respectively. Hydrazone 4a was isolated, and we found that it does not lead to product 3a either upon treatment with 1 mol% Au/TiO2 under conditions identical to our protocol reaction or in the presence of the reductants (NH3BH3 or NaBH4) again in the presence of Au/TiO2 (MeOH, 15 min, 25 °C), and it is recovered intact (Scheme 4). Therefore, it is not a reaction intermediate. The same was observed with hydrazone 4i. We comment on the origins of formation of the hydrazone side products in the accompanying mechanistic discussion and in Scheme 5.

Scheme 4. Au/TiO2-catalyzed reaction of 1a with excess of NaBH4 or NH3BH3, and a proof that hydrazones are not reaction intermediates.

The possible mechanistic scenario of the reductive process is presented in Scheme 5. Based on previous studies regarding the Au/TiO2-catalyzed reaction of α-diazocarbonyl compounds with hydrosilanes where Au-carbenes were invoked as intermediates [8], and the Au/TiO2-catalyzed semihydrogenation of alkynes with NH3BH3 [16] where Au-hydrides are the reactive species, we envision the formation of intermediate I, which can be described as a Schrock-type carbene [24] having chemisorbed on the electrophilic Au nanoparticle, which is a molecule of NH3BH3 on the same catalytic site. The elimination of NH2BH2 from I generates Au-dihydride intermediate II, which delivers the two H atoms on the former carbene carbon atom presumably in a stepwise manner (via intermediate III), thus leading to the final reduction product, with its concomitant liberation from the surface of nanoparticle Aun. The NH2BH2 reacts with methanol, providing the methoxy- bearing amine borane adduct IV shown in Scheme 5, which possesses even more reactive

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As noted earlier in Scheme3, hydrazones are formed exclusively in the Pt 1/CeO2- catalyzed reaction of α-diazocarbonyl compounds using three molar equivalents of ammonia borane in MeOH [20]. We emphasize that in case of using an excess of reducing agent in our Au/TiO2-catalyzed transformation, the corresponding hydrazones were seen as minor products. For instance, in the reduction of substrate 1a, we observed the following. Using 0.5–0.6 molar equivalents of NaBH4 (≈100% excess in terms of hydride equivalents), hydrazone 4a [20] was observed in 8% yield relative to product 3a. With 1.2 molar equivalents, 4a is formed in 25% relative yield and with three molar equivalents in 38% (Scheme4). On the other hand, using excess of NH3BH3, the reaction is more selective, with byproduct 4a being formed in merely 3% relative yield if using 1.0 molar equivalent of ammonia borane and 5% relative yield with 3.0 molar equivalents. The only substrate that exhibited an obviously higher selectivity in terms of hydrazone formation was the α-diazocarbonyl compound 1i. The treatment of 1i with one hydride equivalent from NH3BH3 or NaBH4 resulted in the partial formation of the corresponding hydrazone 4i [23](E/Z = 85/15, see Supplementary Materials) in 15% and 25% relative yield, respectively. Hydrazone 4a was isolated, and we found that it does not lead to product 3a either upon treatment with a Figure 1. Reduction of α-diazocarbonyl compounds1 mol% Au/TiO by 2NHunder3BH conditions3 or NaBH identical4 catalyzed to our protocol by Au/TiO reaction2. orWith in the one presence additional B- H equivalent, the corresponding alcohols ofof thethe reductants ketones (NH3j–l3 BHwere3 or isolated NaBH4) again in > in 90% the presenceyield. b ofIn Au/TiO this case,2 (MeOH, the corresponding 15 min, 25 ◦C), and it is recovered intact (Scheme4). Therefore, it is not a reaction intermediate. hydrazone (Ε/Ζ = 85/15) was formed in 15%The relative same was yield observed using with NH hydrazone3BH3 and4i. Wein comment25% with on NaBH the origins4. The of formation isolated of yield the refers to the reaction with NH3BH3. hydrazone side products in the accompanying mechanistic discussion and in Scheme5.

Scheme 4. Au/TiO2-catalyzed reaction of 1a with excess of NaBH4 or NH3BH3, and a proof that hydrazones are not Scheme 4. Au/TiO2-catalyzed reaction of 1a with excess of NaBH4 or NH3BH3, and a proof that reaction intermediates. hydrazones are not reaction intermediates. The possible mechanistic scenario of the reductive process is presented in Scheme5. Based on previous studies regarding the Au/TiO2-catalyzed reaction of α-diazocarbonyl The possiblecompounds mechanistic with hydrosilanes scenario where of Au-carbenesthe reductive were invokedprocess as is intermediates presented [8], in Scheme 5. Based on previousand the Au/TiOstudies2-catalyzed regarding semihydrogenation the Au/TiO of2 alkynes-catal withyzed NH reaction3BH3 [16] whereof α- Au-diazocarbonyl hydrides are the reactive species, we envision the formation of intermediate I, which can compounds withbe described hydrosilanes as a Schrock-type where carbene Au-carbenes [24] having chemisorbedwere invoked on the as electrophilic intermediates Au [8], and the Au/TiO2-nanoparticle,catalyzed which semihydrogenation is a molecule of NH3BH of3 onalkynes the same catalyticwith NH site.3 TheBH elimination3 [16] where Au-hydrides are theof reactive NH2BH2 from species,I generates we envision Au-dihydride the intermediate formationII, whichof intermediate delivers the two I, H which can be atoms on the former carbene carbon atom presumably in a stepwise manner (via inter- described as a Schrock-type carbene [24] having chemisorbed on the electrophilic Au nanoparticle, which is a molecule of NH3BH3 on the same catalytic site. The elimination of NH2BH2 from I generates Au-dihydride intermediate II, which delivers the two H atoms on the former carbene carbon atom presumably in a stepwise manner (via intermediate III), thus leading to the final reduction product, with its concomitant liberation from the surface of nanoparticle Aun. The NH2BH2 reacts with methanol, providing the methoxy- bearing amine borane adduct IV shown in Scheme 5, which possesses even more reactive

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hydrides relative to NH3BH3. Amine borane IV reduces a second molecule of α-diazocarbonyl compound through a similar catalytic cycle on Aun, and it is transformed into NH2BH(OMe)2, which finally undergoes a third Aun-catalyzed reduction round. The final fate of ammonia borane is its transformation into NH4B(OMe)4 [25], which is proved by 11B NMR (see Supporting Information). Similarly, the final fate of NaBH4 is the formation of the analogous salt NaB(OMe)4, which resonates at about 3 ppm [26] in 11B NMR (see Supporting Information). If an excess of reducing agent is added, then the population of Au nanoparticle dihydro sites (intermediate V) increases, and subsequently, these sites can reduce the α-diazocarbonyl compounds through a side pathway that does not require their chemisorption on an Au nanoparticle. This pathway is similar to what was suggested 1 2 3 3 Nanomaterials 2021in, the11, 248 Pt /CeO -catalyzed reduction of the α-diazocarbonyl compounds with NH BH [20]. 6 of 10 The D-labeling experiments presented in Scheme 2 can be rationalized, taking into account the proposed mechanism. Thus, in the reduction of 1b with NaBH4 in methanol- d4, the major product is 3b-d1 having one H from a B-H bond and one D from the O-D mediate III), thus leading to the final reduction product, with its concomitant liberation functionality of the solvent. The observation in parallel of the disproportionation products from the surface of nanoparticle Aun. The NH2BH2 reacts with methanol, providing the 3b-d2 and 3b-d0 methoxy-bearingimplies that boron amine hydrides borane adductare partiallyIV shown exchanged in Scheme by5, whichD atoms possesses from the even more O-D functionality of the protic solvent under the reaction conditions; likewise, silicon- reactive hydrides relative to NH3BH3. Amine borane IV reduces a second molecule of hydrides do in theα-diazocarbonyl Au/TiO2-catalyzed compound reduction through of a similar quinolines catalytic [27]. cycle Notably, on Aun in, and analogous it is transformed metal-catalyzedinto labeling NH2BH(OMe) experiments2, which such finally as undergoesin the semihydrogenation a third Aun-catalyzed of alkynes reduction em- round. The ploying R3SiH(D)final [28] fate or of NaBH ammonia4(D4) borane [25], and is its MeOH(D) transformation or H into2(D2 NH)O as4B(OMe) the proton4 [25], sources, which is proved 11 no analogous isotopicby B NMRscrabbling (see Supplementary is observed. Materials).The H/D exchange Similarly, of the boron final fate hydrides of NaBH is4 veryis the formation of the analogous salt NaB(OMe) , which resonates at about 3 ppm [26] in 11B NMR (see obvious in the reduction of 1b with NaBD4 in CH4 3OH, where the fully protonated 3b-d0 is Supplementary Materials). If an excess of reducing agent is added, then the population of the major product, while 3b-d0 and 3b-d2 are the minor ones. The differences in product Au nanoparticle dihydro sites (intermediate V) increases, and subsequently, these sites can distribution amongreduce these the α two-diazocarbonyl labeling experiments compounds throughare rather a side related pathway to the that different does not requirede- their gree of Au/TiO2chemisorption-catalyzed H/D on exchange an Au nanoparticle. processes This of boron pathway-H(D) is similar reagents to what from was the suggested sol- in vent [MeOH orthe MeOH Pt1/CeO-d4], 2arising-catalyzed from reduction intrinsic of isotope the α-diazocarbonyl effects. compounds with NH3BH3 [20].

Scheme 5.SchemeMechanistic 5. Mechanistic considerations considerations in the reduction in oftheα-diazocarbonyl reduction of α compounds-diazocarbonyl with NH compounds3BH3 catalyzed with by Au/TiO2 (the catalyticNH3 sitesBH3 ofcatalyzed nanoparticles by Au/TiO are indicated2 (the catalytic as Aun). sites of nanoparticles are indicated as Aun).

The D-labeling experiments presented in Scheme2 can be rationalized, taking into account the proposed mechanism. Thus, in the reduction of 1b with NaBH4 in methanol- d4, the major product is 3b-d1 having one H from a B-H bond and one D from the O- D functionality of the solvent. The observation in parallel of the disproportionation products 3b-d2 and 3b-d0 implies that boron hydrides are partially exchanged by D atoms from the O-D functionality of the protic solvent under the reaction conditions; likewise, silicon-hydrides do in the Au/TiO2-catalyzed reduction of quinolines [27]. Notably, in analogous metal-catalyzed labeling experiments such as in the semihydrogenation of alkynes employing R3SiH(D) [28] or NaBH4(D4)[25], and MeOH(D) or H2(D2)O as the proton sources, no analogous isotopic scrabbling is observed. The H/D exchange of boron hydrides is very obvious in the reduction of 1b with NaBD4 in CH3OH, where the fully protonated 3b-d0 is the major product, while 3b-d0 and 3b-d2 are the minor ones. The differences in product distribution among these two labeling experiments are rather related Nanomaterials 2021, 11, 248 7 of 10

to the different degree of Au/TiO2-catalyzed H/D exchange processes of boron-H(D) reagents from the solvent [MeOH or MeOH-d4], arising from intrinsic isotope effects.

3. Experimental Section 3.1. Catalyst

The supported Au nanoparticles on TiO2 having a gold content ≈1 wt%, which were used in our studies, are commercially available from Strem Chemicals Inc. (Newburyport, MA, USA) The average crystallite size of Au nanoparticles is ≈2–3 nm. Prior to use, they were grinded in a mortar, and the resulting purple dust was kept in a dark-colored bottle.

3.2. Reactants The majority of α-diazocarbonyl compounds used in this study were available from previous studies in our lab [8]. The rest of them were prepared by α-diazotization of the corresponding carbonyl compounds with 4-acetamidobenzenesulfonyl azide in the presence of DBU as base [29]. Copies of the 1H and 13C NMR spectra of the α-diazocarbonyl compounds can be found in the Supplementary Materials.

3.3. Catalytic Reactions Typical procedure of the title reaction: In a vial are placed 0.3 mmol of the α- diazocarbonyl compound, 0.09 mmol (3.5 mg) of NaBH4 (0.3 equiv) or 0.12 mmol (3.7 mg) of NH3BH3 (0.4 equiv), and 70 mg of Au/TiO2 (1.0 mol% in Au, as the catalytic system contains 1% Au w/w) in 0.5 mL of methanol. The heterogeneous mixture is stirred for 15 min at room temperature and within that period occurs complete consumption of the diazo compound (the supernatant reaction mixture turns to colorless). Then, the slurry is filtered with the aid of 2 mL of dichloromethane or any other volatile solvent such as diethyl ether under a low pressure through a short pad of silica gel, and the filtrate is evaporated. No chromatographic purification of the products is required in most of the cases, as the reactions are quantitative and yield only one product.

3.4. Characterization of Products 1 Methyl 2-phenylacetate (3a). H NMR (500 MHz, CDCl3): 7.35–7.27 (m, 5H), 3.70 (s, 3H), 3.64 13 (s, 2H); C NMR (125 MHz, CDCl3): 172.0, 133.9, 129.2, 128.6, 127.1, 52.0, 41.2. 1 Methyl 2-(p-tolyl)acetate (3b). H NMR (500 MHz, CDCl3): 7.18 (d, J = 8.0 Hz, 2H), 7.13 (d, 13 J = 8.0 Hz, 2H), 3.68 (s, 3H), 3.59 (s, 2H), 3.33 (s, 3H); C NMR (125 MHz, CDCl3): 172.2, 136.7, 130.9, 129.2, 129.0, 51.9, 40.7, 21.0. 1 Methyl 2-(4-methoxyphenyl)acetate (3c). H NMR (500 MHz, CDCl3): 7.20 (d, J = 8.5 Hz, 2H), 13 6.86 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 3.57 (s, 2H); C NMR (125 MHz, CDCl3): 172.3, 158.6, 130.2, 126.0, 113.9, 55.1, 51.9, 40.2. 1 Methyl 2-(3-methoxyphenyl)acetate (3d). H NMR (500 MHz, CDCl3): 7.24 (t, J = 8.0 Hz, 1H), 13 6.88–6.81 (m, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 3.61 (s, 2H); C NMR (125 MHz, CDCl3): 171.8, 159.6, 135.3, 129.5, 121.5, 114.8, 112.5, 55.1, 52.0, 41.1. 1 Methyl 2-(4-chlorophenyl)acetate (3e). H NMR (500 MHz, CDCl3): 7.29 (d, J = 8.5 Hz, 2H), 13 7.21 (d, J = 8.5 Hz, 2H), 3.69 (s, 3H), 3.60 (s, 2H); C NMR (125 MHz, CDCl3): 171.6, 133.1, 132.3, 130.6, 128.7, 52.1, 40.4. 1 Methyl 2-(4-ﬂuorophenyl)acetate (3f). H NMR (500 MHz, CDCl3): 7.26–7.23 (m, 2H), 7.01 (t, 13 J = 8.5 Hz, 2H), 3.70 (s, 3H), 3.60 (s, 2H); C NMR (125 MHz, CDCl3): 171.9, 161.9 (d, JC-F = 243.5 Hz), 130.8 (d, JC-F = 8.0 Hz), 129.6 (d, JC-F = 3.5 Hz), 115.4 (d, JC-F = 21.5 Hz), 52.1, 40.2. 1 Allyl 2-phenylacetate (3g). H NMR (500 MHz, CDCl3): 7.35–7.28 (m, 5H), 5.95–5.87 (m, 1H), 5.28 (qd, J1 = 17.5 Hz, J2 = 1.5 Hz, 1H), 5.22 (qd, J1 = 10.5 Hz, J2 = 1.5 Hz, 1H), 4.61 (td, Nanomaterials 2021, 11, 248 8 of 10

13 J1 = 6.0 Hz, J2 = 1.5 Hz, 2H), 3.66 (s, 2H); C NMR (125 MHz, CDCl3): 171.2, 133.9, 132.0, 129.2, 128.5, 127.1, 118.2, 65.4, 41.3. 1 (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-phenylacetate (3h). H NMR (500 MHz, CDCl3): 7.34–7.24 (m, 5H), 4.71–4.66 (m, 1H), 3.61 (d, J = 16.0 Hz, 1H), 3.60 (d, J = 16.0 Hz, 1H), 1.99–1.96 (m, 1H), (1.77–1.71, m, 1H), 1.70–1.63 (m, 2H), 1.51–1.43 (m, 1H), 1.39–1.33 (m, 1H), 1.08–0.97 (m, 2H), 0.90 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H), 0.79 (d, J = 7.0 Hz, 13 3H); C NMR (125 MHz, CDCl3): 171.1, 134.3, 129.1, 128.4, 126.9, 74.6, 47.0, 41.8, 40.7, 34.2, 31.3, 26.1, 23.4, 22.0, 20.7, 16.2. 1 Ethyl 3-phenylpropanoate (3i). H NMR (500 MHz, CDCl3): 7.30–7.19 (m, 5H), 4.13 (q, J = 7.0 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): 172.9, 140.6, 128.5, 128.3, 126.2 60.4, 35.9, 31.0, 14.2. 1 1-Phenylpropan-2-one (3j). H NMR (500 MHz, CDCl3): 7.34 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 2H), 3.70 (s, 2H), 2.16 (s, 3H); 13C NMR (125 MHz, CDCl3): 206.4, 134.2, 129.4, 128.8, 127.1, 51.0, 29.3. 1 1-(4-Chlorophenyl)propan-2-one (3k). H NMR (500 MHz, CDCl3): 7.30 (t, J = 8.5 Hz, 2H), 13 7.12 (t, J = 8.5 Hz, 2H), 3.67 (s, 2H), 2.16 (s, 3H); C NMR (125 MHz, CDCl3): 205.6, 133.0, 132.5, 130.7, 128.8, 50.0, 29.4. 1 Propiophenone (3l). H NMR (500 MHz, CDCl3): 7.97 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): 200.8, 136.9, 132.9, 128.5, 128.0, 31.8, 8.2. 1 Methyl (E)-2-hydrazono-2-phenylacetate (4a). H NMR (500 MHz, CDCl3): 7.51–7.29 (m, 5H), 13 7.55 (t, J = 7.5 Hz, 1H), 6.28 (br s, 2H), 3.84 (s, 3H); C NMR (125 MHz, CDCl3): 164.8, 137.3, 129.4, 129.4, 129.2, 128.8, 52.4. 1 Ethyl 2-hydrazono-3-phenylpropanoate (4i). H NMR (500 MHz, CDCl3), E-isomer (major): 7.32–7.20 (m, 5H), 6.04 (br s, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3,90 (s, 2H), 1.37 (t, J = 7.0 Hz, 3H). Z-isomer (minor): 8.16 (br s, 2H), 7.32–7.20 (m, 5H), 4.14 (q, J = 7.0 Hz, 2H), 3,69 (s, 2H), 13 1.22 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3), E-isomer (major): 165.2, 138.1, 134.8, 129.0, 128.0, 126.9, 61.5, 30.5, 14.3. Z-isomer (minor): 162.7, 139.2, 130.4, 128.8, 128.1, 126.1, 60.2, 39.5, 14.0. Copies of the 1H and 13C NMR spectra of all products can be found in the Supplementary Materials.

4. Conclusions In summary, we presented a novel and useful transfer hydrogenation methodology for the reduction of the carbene moiety of α-diazocarbonyl compounds into a methylene group catalyzed by recyclable and reusable supported Au nanoparticles on TiO2. The reductant can be readily available NH3BH3 or NaBH4. The characteristic of the reduction protocol is that one stoichiometric hydride equivalent from the boron hydride reagent and one proton that arises from the protic solvent (methanol) are required. In case of using an excess of reducing agent, a side catalytic pathway operates that reduces the α-diazocarbonyl compounds into the corresponding hydrazones. This work exempliﬁes the unique catalytic behavior of Au nanoparticles relative to other supported metallic noble metals such as Pt [20], where the reductive pathway of the formation of hydrazones occurs exclusively.

Supplementary Materials: Copies of 1H and 13C NMR of reactants and products are available online at https://www.mdpi.com/2079-4991/11/1/248/s1. Author Contributions: M.K. performed all the experiments and prepared the manuscript. M.S. supervised this work and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript. Nanomaterials 2021, 11, 248 9 of 10

Funding: The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under the HFRI PhD Fellowship grant (GA No. 31449). Data Availability Statement: Data is contained within the article or Supplementary Materials. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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