Showcasing research from Professor Jitendra Bera’s laboratory, Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India

Hydrosilylative reduction of primary amides to primary amines catalyzed by a terminal [Ni–OH] complex

An efficient and selective hydrosilylative reduction of

primary amides to primary amines catalysed by a terminal

[Ni–OH] complex is demonstrated. The bench-stable

catalyst is portrayed over a nickel ore Garnierite gemstone.

The chemistry is presented on the background of the

Lav–Kush barrage built on the river Ganges, located

at the outskirts of Kanpur city.

The background photo was taken by Girish Pant.

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See Pragati Pandey and Jitendra K. Bera, Chem . Commun ., 2021, 57 , 9204.

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The helical supramolecular assembly of oligopyridylamide

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9204 | Chem. Commun., 2021, 57, 9204–9207 This journal is © The Royal Society of Chemistry 2021

Cite this: Chem. Commun., 2021,

57, 9204

Hydrosilylative reduction of primary amidesto primary amines catalyzed by a terminal[Ni–OH] complex†

Pragati Pandey and Jitendra K. Bera *

A terminal [Ni–OH] complex 1, supported by triflamide-functionalized

NHC ligands, catalyzes the hydrosilylative reduction of a range of

primary amides into primary amines in good to excellent yields under

base-free conditions with key functional group tolerance. Catalyst 1 is

also effective for the reduction of a variety of tertiary and secondary

amides. In contrast to literature reports, the reactivity of 1 towards

amide reduction follows an inverse trend, i.e., 18 amide 4 38 amide 4 28

amide. The reaction does not follow a usual dehydration pathway.

The straightforward synthetic accessibility and the high abun-dance of carboxamides in natural systems render them desirableprecursors for the synthesis of amines – an important class ofcompounds for both the bulk- and fine-chemicals industry.1

Traditional methods of accessing amines suffer from severallimitations, including the (over)stoichiometric use of difficult-to-handle hydride reagents, poor product selectivity, low functionalgroup tolerance, tedious purification procedures and copiouswaste generation.2 An attractive alternative to conventional meth-ods is the transition metal-catalyzed hydrosilylative reduction ofamides.3 Due to the low electrophilicity of the amide carbonyl,amide reductions are very challenging compared with othercarbonyl derivatives. Among different classes of amides, thereduction of primary amides is the most difficult. It potentiallyfollows different reaction pathways leading to a mixture ofproducts, such as nitriles, primary amines, secondary iminesand/or secondary amines.3a A multitude of 4d/5d metal-basedcatalysts are known for the efficient reduction of tertiary andsecondary amides.4 In recent years, main group and base metal-catalyzed amide reductions have also appeared.5 However, ageneral protocol for the direct hydrosilylative reduction of primaryamides to primary amines remains elusive.6

The hydrosilylative reduction of primary amides is compli-cated by the competing silane-assisted dehydration to nitriles.7

Using a [RuCl2(mesitylene)]2/PhSiH3 combination, Darcel et al.demonstrated the selective reduction of primary amides tosecondary amines that proceeds via the nitrile intermediate.8

In 2012, Beller employed two different iron catalysts for thedehydration of primary amides to nitriles and subsequentreduction to primary amines.9 Following the same two-stepapproach, Nagashima has employed an iron/cobalt dual-metalsystem for the synthesis of primary amines albeit with limitedscope10 (Scheme 1(a)). Recently Mandal et al. have reported theMn(III)-catalysed hydrosilylative reduction of primary amides toprimary amines that proceeds via the nitrile intermediate in thepresence of a base (Scheme 1(b)).11

A noteworthy report on the direct conversion of primaryamides to primary amines involves the Ru3(CO)12/TMDS sys-tem, but the scope is limited to only six substrates that givemoderate yields.6d This work offers a protocol for the direct

Scheme 1 Metal-catalyzed reduction of primary amides to primary amines.

Department of Chemistry and Center for Environmental Science and Engineering,

Indian Institute of Technology Kanpur, Kanpur 208016, India.

E-mail: jbera@iitk.ac.in

† Electronic supplementary information (ESI) available: Experimental proceduresand analytical data. CCDC 1952208–1952212. For ESI and crystallographic data inCIF or other electronic format see DOI: 10.1039/d1cc03537a

Received 1st July 2021,Accepted 16th August 2021

DOI: 10.1039/d1cc03537a

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hydrosilylative reduction of a range of primary amides toprimary amines catalyzed by a bench-stable terminal [Ni–OH]complex 1 (Scheme 1(c)). Control experiments revealed that thereaction does not follow a dehydration/reduction pathway, butinstead, a direct deoxygenation pathway is more likely.

The treatment of a zwitterionic triflamide-functionalized NHCprecursor LH-NTf with Ni(acac)2 (2 : 1 molar ratio) in the presenceof KOtBu in refluxing THF afforded a neutral NiII complex, whichhas been formulated as [Ni(L-NTf)(L-NHTf)(OH)] (1). The molecu-lar structure of 1 (Fig. 1) consists of Ni metal attached to two NHCligands in a cis arrangement. One of the ligands chelates the metalthrough a carbene carbon (Ni1–C1A = 1.851(4) Å) and a triflamidonitrogen (Ni1–N6 = 1.976(3) Å), while the second ligand is attachedto the metal through only the carbene carbon (Ni–C1 = 1.864(4) Å).A terminal hydroxo completes the distorted square-planar geo-metry around the Ni center. The source of the hydroxo ligand ispresumably the adventitious water molecules present in thereaction medium, which react with KOtBu to give OH. TheNi1–O5 distance 1.928(3) Å, which is consistent with other relatedNi–OH complexes.12 The hydroxo unit engages in intramolecularhydrogen-bonding interactions with the free pendant –NHTf andthe metal-coordinated –NTf oxygen from two ligands, whichappear to stabilize the terminal [Ni–OH] complex.13 Complex 1is further characterized via its NMR, ESI-MS and FT-IR spectra(see ESI† for details).

Complex 1 is stable in the open air and does not decompose incommon organic solvents for several weeks. It is unreactive withhydrogen (30 bar in THF) and also with HCl in diethyl ether.The Ni–OH failed to react with the bulky oxophilic reagentsbis(pinacolato)diboron and 1-phenyl-2-trimethylsilylacetylene.However, 1 undergoes facile ligand metathesis reactions withMe3SiN3 and Me3SiCl to give the corresponding azido andchloro products.14 When 1 was reacted with PhSiH3, a signal atd�11.33 ppm was observed in the 1H NMR spectra, indicating theformation of a [Ni–H] species (Fig. S35, ESI†).15 The reactivity of 1with hydrosilanes prompted us to evaluate its catalytic potentialfor the hydrosilylative reduction of amides.

The reaction of benzamide with 1 (5 mol%) and PhSiH3

(4 equiv.) at 110 1C in toluene for 12 h brought about quanti-tative conversion with an 81% yield of benzylamine. Encour-aged by this initial result, the reaction parameters were

optimized using benzamide as a model substrate (Table S2,ESI†). Among a variety of silanes, PhSiH3 provided the bestconversion to the primary amine. Relatively less sensitivesilanes, like TMDS or PMHS, were not effective. Finally, acombination of 1 (2 mol%) and PhSiH3 (3 equiv.) in 3 mL oftoluene at 110 1C for 12 h resulted in the quantitative conver-sion of benzamide to benzylamine with a negligible amount ofthe nitrile and the secondary imine. Lowering the catalystloading, the amount of silane and the temperature resultedin either poor conversion of the amide or reduced selectivity forthe amine. No reaction took place in the absence of 1. Thesolvent had a significant influence in terms of the reactivity andselectivity (Table S3, ESI†). Replacing toluene with CH2Cl2, TCE orTHF resulted in a significant drop in conversion. For CH3CN,however, the selectivity was reversed and the dehydrated productnitrile was obtained in high yield (85–100%) (Table S4, ESI†).

Under the optimized reaction conditions, the scope andlimitation of the primary amide reduction catalyzed by 1 wereinvestigated (Table 1). Aromatic substrates with electron-donating groups were reduced in high yield to the corres-ponding primary amines (entries 2–6). Sterically hinderedsubstrates featuring naphthyl and 4-phenylbenzamide weretolerated with the formation of small amounts of nitriles(entries 7 and 8). 4-Aminobenzamide gave an excellent yieldof 97% (entry 9). The chloro and trifluoromethyl amides gavemoderate to good yields (entries 10–12). Ester and cyano groupswere tolerated under the reductive conditions (entries 13and 14). However, for the cyano derivative, a mixture of4-cyanobenzylamine and 4-cyanobenzonitrile were obtained ina 60 : 40 ratio, respectively. The olefinic bond in cinnamylamidewas reduced under the catalytic conditions and afforded amixture of the corresponding amine and nitrile in an 80 : 20ratio, respectively (entry 15).

Heterocyclic amides complicated the reactions. The reduction ofnicotinamide resulted in a good yield (65%) of the corresponding

Fig. 1 Synthesis and X-ray structure of 1.

Table 1 Primary amide reduction catalyzed by 1a

a Conversions are determined via GC-MS using mesitylene as an inter-nal standard. b Isolated yields of amine salts obtained upon treatmentwith 1 M HCl/diethyl ether are given in parentheses. c PhSiD3 (3 equiv.).

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amine (entry 16), whereas isonicotinamide showed an excellentconversion but with a reversal of selectivity (entry 17). Furan andthiophene derivatives gave the corresponding amines in 78% and47% yield, respectively, with side products (entries 18 and 19). Thealiphatic substrates 2-phenylacetamide, adamantyl carboxamide,1-naphthylacetamide and cyclohexyl amide afforded good to excel-lent yields of the corresponding amine salts (entries 20–23).Alkylamides with medium and short chains gave good isolatedyields of 45–80% (entries 24–26). The low yield (45%) of ethylaminewas probably due to its volatile nature (entry 25). The reduction ofacrylamide gave a moderate yield (57%) of the propylamine salt asthe single product (entry 26). Employing PhSiD3, a-deuteroaminesalt with 495% deuterium incorporation was isolated in high yield(entry 27). Thus, a-deuterated amines, a useful precursor in deut-erated drug synthesis, could be accessed using this protocol.

In order to assess the role of the terminal hydroxide and torecognize the importance of the ligand construction around themetal center, a set of related catalysts 4–6 with various metal-to-ligand ratios bearing different ancillary ligands were synthe-sized (Table 2).14b The dinuclear [Ni(L-NTf)(OH)]2 (4), with a1 : 1 metal-to-ligand ratio and supported by two bridging –OHgroups, gave selectively the secondary amine. Complex 5, withone chelated L-NTf and a Cp, and the Ni–allyl complex 6, withtwo L-NHTf ligands, afforded a mixture of reduced products.Different Ni salts NiCl2(dme), Ni(OAc)2�4H2O, NiCl2, Ni(COD)2

and Ni(acac)2 invariably gave a mixture of products whereeither the secondary imine or the secondary amine is predo-minant. The presence of a terminal hydroxide and stericcrowding at the metal center appear to control the catalystactivity.

Catalyst 1 converts a wide range of tertiary amides to thecorresponding amines under the same optimized conditions asemployed for the primary amides (Table S5, ESI†). Interestingly,it took a longer reaction time than the primary amides (24 h vs.12 h) to achieve similar conversions. A competitive reactionbetween benzamide and N,N0-dimethylbenzamide showed 94%conversion of the primary amide and 18% of the tertiary amidein 3 h (Table S6, ESI†).

The reduction of tertiary amides featuring dialkyl, diaryl andalkyl/aryl benzamide derivatives gave excellent to good yields(96–77% Table S5, entries 1–5, ESI†). By contrast, bulky

substituents (i-Pr, or cyclohexyl) resulted in reduced yields of40–62% (entries 6 and 7). Further, pyrrolidine, piperidine andmorpholine derivatives of benzamide were also reduced inquantitative yields of 94–96% (entries 8–10). However, piper-azine derived di-amide gave a mixture of fully and partiallyreduced corresponding amines in a 1 : 1 ratio (entry 11). Bycontrast, 1-benzoylpyrrolidin-2-one afforded a moderate yieldof 48% with the reduction of both amide groups (entry 12). Theelectron-donating and electron-withdrawing substituents atN-benzoylpiperidine derivatives resulted in excellent to goodyields of 92–65% (entries 13–15). Ester, heterocycle and halogensubstituents were also tolerated with high to moderate yields of88–48% (entries 16–18).

Further, the reactivity of 1 was evaluated for secondaryamide reductions as well. A range of secondary amides wasreduced selectively to the corresponding secondary amines withgood to excellent yields. However, in comparison to primaryamides, secondary amides were also found to be less reactive,hence a higher catalyst loading (5 mol%) and additionalequivalents of PhSiH3 (4 equiv.) were required (Table S7, ESI†).Interestingly, the acetamide derivatives of secondary amides(entries 1–7) were more reactive than benzamide derivatives(entries 8 and 9). The secondary amides with ester and halogenfunctional groups were also tolerated to give significant yieldsbut with longer reaction times (entries 13–15) These results arein stark contrast to the activities displayed by numerouscatalysts that efficiently reduce tertiary and secondary amidesbut fail to give the primary amine from the primary amide.4,5

The formation of the primary amine could be via thecorresponding nitrile intermediate. When benzonitrile wassubjected to hydrosilylative conditions, reduction did not occurwithin 12 h (Scheme S8, ESI†). The progress of the benzamidereduction was then monitored via GC-MS analysis (Fig. S36(a),ESI†). The plot shows a gradual decrease in the concentrationof benzamide with a concomitant increase in benzylaminereaching B90% after 3 h, after which a saturation plateauwas observed. All through the reaction profile, only traceamounts of nitrile and secondary imine (o5%) were observed.An argument could be made that nitrile is the transient species,which is readily converted to the amine under catalytic condi-tions. To discard that possibility, another reaction was per-formed involving benzamide and benzonitrile in a 1 : 1 ratio(Fig. S36(b), ESI†). The formation of benzylamine is dominatedby the concomitant consumption of benzamide. The amount ofnitrile actually increases slightly up to around 4 h. As thereaction progresses, a trace of secondary imine was alsoobserved, which probably results from the reaction betweennitrile and the primary amine. Taken together, these resultsstrongly indicate that nitrile is not the intermediate product inthe formation of benzylamine from benzamide.

Although catalyst 1 provides ready and selective access toprimary amines from primary amides, proposing a mechanisticscheme has turned out to be a difficult task at this time. A[Ni–H] species, observed using 1H NMR, could be considered asthe active catalyst.15 Such [Ni–H] products are precedented inthe reactions of Ni-siloxide/alkoxide with silanes via a

Table 2 Catalysts evaluation for reduction of primary amideab

a Conversions are determined via GC-MS using mesitylene as aninternal standard. b Product distribution ratios {a : b : c : d}.

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concerted s-bond metathesis.16 Subsequent hydride insertioninto the monosilylated amide followed by silane-assisted deox-ygenation may lead to amine formation with the release ofsiloxane (Scheme S9, ESI†).17 Silylation of one of the N–H bondsis essential18a for primary amine formation, which in turnsuppress the formation of the nitrile.18b,c A side reaction(Scheme S10, ESI†) from [Ni–H] to the dehydration productnitrile, via a disilylimidate intermediate, may be argued as apossibility. However, nitrile does not undergo hydrogenationunder the reaction conditions and nor was a disilylimidateintermediate identified in the reaction mixture via GC or29Si NMR.7a,b,18

Finally, the clear preference of 1 for primary amidereduction could be attributed to the stabilization of theN-silylated amide via hydrogen-bond interactions of the amidehydrogen with the pendant triflamide unit in the ligand con-struct (Scheme S9, ESI†). The higher nucleophilicity of thetertiary amide is responsible for its better reactivity, whereasthe secondary amide is the least active substrate as its silylatedproduct lacks amide hydrogen to gain additional stability byinteraction with the ligand framework.

In conclusion, we report here the hydrosilylative reductionof a range of primary, secondary and tertiary amides to thecorresponding amines in good to excellent yields, catalyzed by abench-stable terminal [Ni–OH] complex. The reactivity of 1towards amide reduction follows the trend 11 amide 4 31amide 4 21 amide. The higher activity of the primary amideis credited to the ligand-assisted stabilization of the silylatedamide N–H in the secondary coordination sphere via hydrogen-bond interactions. Such a possibility does not arise for second-ary and tertiary amides. Studies divulge that primary amineformation does not favour the supposed two-step dehydration/reduction pathway. A detailed mechanistic investigation isunderway in our laboratory to fully comprehend the intricaciesof this peculiar Ni–OH system.

This work is financially supported by the SERB, India. J. K. B.thanks SERB, India for the J. C. Bose fellowship. P. P. thanksCSIR, India for the fellowship.

Conflicts of interest

There are no conflicts to declare.

Notes and references1 (a) A. Greenberg, C. M. Breneman and J. F. Liebman, Biochemistry,

and Materials Science, John Wiley & Sons, Inc., New York, 2003;(b) S. A. Lawrence, Amines: Synthesis, Properties and Applications,Cambridge University Press, Cambridge, 2004.

2 (a) J. Seyden-Penne, Reductions by the Alumino- and Boro-hydrides inOrganic Synthesis, John Wiley & Sons, Inc., New York, 1997;(b) N. G. Gaylord, Reduction With Complex Metal Hydrides, Inter-science, New York, 1956.

3 For reviews, see: (a) A. M. Smith and R. Whyman, Chem. Rev., 2014,114, 5477–5510; (b) A. Volkov, F. Tinnis, T. Slagbrand, P. Trillo andH. Adolfsson, Chem. Soc. Rev., 2016, 45, 6685–6697; (c) A. Chardon,

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6 (a) M. Igarashi and T. Fuchikami, Tetrahedron Lett., 2001, 42,1945–1947; (b) S. Laval, W. Dayoub, L. Pehlivan, E. Metay,A. Favre-Reguillon, D. Delbrayelle, G. Mignani and M. Lemaire,Tetrahedron Lett., 2011, 52, 4072–4075; (c) T. Zhang, Y. Zhang,W. Zhang and M. Luo, Adv. Synth. Catal., 2013, 355, 2775–2780;(d) J. T. Reeves, Z. Tan, M. A. Marsini, Z. S. Han, Y. Xu, D. C. Reeves,H. Lee, B. Z. Lu and C. H. Senanayake, Adv. Synth. Catal., 2013, 355,47–52.

7 (a) S. Hanada, Y. Motoyama and H. Nagashima, Eur. J. Org. Chem.,2008, 4097–4100; (b) S. Zhou, D. Addis, S. Das, K. Junge andM. Beller, Chem. Commun., 2009, 4883–4885; (c) S. Elangovan,S. Quintero-Duque, V. Dorcet, T. Roisnel, L. Norel, C. Darcel andJ. B. Sortais, Organometallics, 2015, 34, 4521–4528; (d) Y. Wang,L. Fu, H. Qi, S.-W. Chen and Y. Li, Asian J. Org. Chem., 2018, 7,367–370; (e) S. Ren, Y. Wang, F. Yang, H. Sun and X. Li, Catal.Commun., 2019, 120, 72–75.

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17 The side product siloxane was converted to polysiloxanes under thereaction conditions. See ESI for details.

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