14508 | Chem. Commun., 2014, 50, 14508--14511 This journal is©The Royal Society of Chemistry 2014

Cite this:Chem. Commun., 2014,

50, 14508

Mo(CO)6 catalysed chemoselective hydrosilylationof a,b-unsaturated amides for the formation ofallylamines†

Alexey Volkov, Fredrik Tinnis,* Tove Slagbrand, Ida Pershagen and Hans Adolfsson*

Molybdenum hexacarbonyl (Mo(CO)6) was used as an efficient catalyst

for the chemoselective reduction of the amide functionality in

a,b-unsaturated compounds, under hydrosilylation conditions using

1,1,3,3-tetramethyldisiloxane (TMDS) as the hydride source.

Selective reduction of carboxylic acid derivatives is a highly impor-tant transformation in both academia and industry. Stoichiometrichydride reagents such as alumino- or borohydrides are well-established for the reduction of carbonyl compounds; however,resulting in significant amounts of waste.1 Alternative catalyticmethods are therefore highly desirable, and among the carboxylicacid derivatives, the amide is the most challenging functionality toreduce. Only a few examples of catalytic hydrogenation of amideshave been reported to date.2 Most of these procedures involvethe cleavage of the C–N bond, resulting in the formation of thecorresponding deacylated amine and alcohol.3 Unfortunately,selective hydrogenation of amides is not applicable for sub-strates containing olefins. Hydrosilylation of amides is a morecommonly employed approach and different transition metalssuch as Ru,4 Rh,5 Ir,6 and Pt7 were reported to catalyse thereduction of amides under relatively mild conditions. RecentlyBeller and co-workers showed that [Fe3(CO)12], Cu(OTf)2 andZn(OAc)2 are efficient catalysts for the reduction of amides underhydrosilylation conditions.8 These systems were also demon-strated to be chemoselective tolerating for instance ether, esterand alkene groups. Similarily, the group of Nagashima reportedon an iron-catalysed hydrosilylation of amides under thermaland photo-assisted conditions using TMDS as a hydride source.9

Furthermore, our group recently demonstrated the efficiency ofan in situ generated iron/NHC (N-heterocyclic carbene) complexfor this transformation.10 Molybdenum is an abundant and anon-toxic metal which has been studied mainly for catalytic

oxidation reactions; however, molybdenum has also been used forcatalytic reduction of carbonyl compounds.11 The group of Royoreported on the evaluation of different dioxo molybdenum com-plexes for the hydrosilylation of aldehydes and ketones.12 The samegroup also showed that the reduction of imines, esters and amidescan be promoted by catalytic amounts of MoO2Cl2.13 Mo(CO)6 is aninexpensive and commercially available metal complex that hasbeen less explored for catalytic hydrosilylation reactions. Recentlythe group of Pannell performed mechanistic investigations onMo(CO)6 and (Me3N)Mo(CO)5-catalysed hydrosilylation of DMF;however, the scope of the amide reduction was not further investi-gated.14 Mo(CO)6 was also reported by Keinan and Perez as anefficient catalyst for the selective hydrosilylation of olefins.15 Theauthors showed that it was possible to obtain a high selectivity forthe reduction of alkenes over different carbonyl functionalities, suchas ketones, esters, carboxylic acids and amides. Herein, we presenta Mo(CO)6 catalysed hydrosilylation protocol that displays theopposite selectivity i.e the chemoselective reduction of the amidefunctionality in a,b-unsaturated compounds (Scheme 1).

The target allylamines obtained in our hydrosilylation protocol arecommon motifs in pharmaceutical compounds and are importantsynthetic intermediates for a wide range of organic compounds.16

The initial screening of silanes in the Mo(CO)6 catalysed hydro-silylation, showed that 1,1,3,3-tetramethyldisiloxane (TMDS) gave

Scheme 1 Chemoselective reduction under hydrosilylation conditionscatalysed by Mo(CO)6.

Department of Organic Chemistry, Arrhenius Laboratory Stockholm University,

SE-106 91, Stockholm, Sweden. E-mail: tinnis@organ.su.se, hansa@organ.su.se;

Fax: +46-8-154908

† Electronic supplementary information (ESI) available: See DOI: 10.1039/c4cc07150f

Received 10th September 2014,Accepted 27th September 2014

DOI: 10.1039/c4cc07150f

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full conversion of the starting a,b-unsaturated tertiary amide 1a(Table 1, entry 1).17 The reaction proved to be selective towardsthe reduction of the amide functionality and only the corre-sponding allylamine 2a was detected. Interestingly, the samereactivity and selectivity for amide reduction were observedusing PhSiH3 (Table 1, entry 2). This result stands in contrast tothe previously developed protocol by Keinan and Perez, wherethe reduction of alkenes over tertiary amides was reportedusing PhSiH3. However, the group of Keinan only evaluatedterminal alkenes, which supposedly are more susceptible for1,4-addition, and therefore more readily reduced. Since TMDSis cheaper and less water sensitive than PhSiH3, we continuedour studies with this silane. The reaction could be performed indifferent solvents; however, full conversion was only achievedin THF (Table 1, entries 5–7). Furthermore, the amount ofTMDS could be lowered to 1.5 equivalents without decreasingthe conversion (Table 1, entry 7).

With the optimized conditions in hand, we evaluated a varietyof different a,b-unsaturated tertiary amide substrates in order todetermine the scope of the Mo-catalysed hydrosilylation protocol(Table 2).

The evaluation of different tertiary amides resulted in moderateto good yields of the corresponding allylamines. The piperidine,pyrrolidine and morpholine amines were obtained in highyields (Table 2, entries 1–3), whilst the N,N-dimethyl amideand N,N-dibenzylamides gave lower yields of the correspondingamines, 73% and 51% respectively (Table 2, entries 4 and 5).

We then evaluated a selection of substrates with different arylgroups in the b-position (Scheme 2). The tertiary diamine 4a wasobtained in good yield (82%). The p-bromo substituted amide 3bunderwent reduction without any competing dehalogenation, andallylamine 4b was furnished in 91% yield. The p-hydroxy substitutedaryl allylamine (4c) and the heteroaryl allylamines (4d–4e) were allisolated in yields around 90%.

We also evaluated a substrate with substituents in both aand b-positions. In spite of the greater steric demand imposedby the a-methyl-b-phenyl substituted substrate 5, allyl amine 6was readily obtained in a yield of 88% (Scheme 3). Notably thereduction led to an isomerisation of the double bond and theallyl amine was isolated as a mixture of Z/E-isomers in a ratio

of 1 : 5. The amine with E-configuration was proven to be themajor isomer by a 1H NMR-NOE experiment.

When instead the b,g-unsaturated amide 7 was subjectedto the reaction, interestingly full conversion into the corresponding

Table 1 Optimization of reaction conditionsa

Entry Silane Equiv. Solvent Conv.b

1 TMDS 2.0 THF Full2 PhSiH3 2.0 THF Full3 (MeO)3SiH 2.0 THF 61%4 PMHS 2.0 THF 20%5 TMDS 2.0 Toluene 84%6 TMDS 2.0 MeCN 95%7 TMDS 1.5 THF Full

a Amide 1a (1.0 mmol), Mo(CO)6 (5.0 mol%), silane (1.5–2.0 equiv.),solvent (2 mL), reaction temperature 65 1C for 24 h. b Determinedby 1H NMR.

Table 2 Evaluation of tertiary amides in the Mo(CO)6 catalysed hydrosilylationa

Entry Amide Product Yieldb (%)

1 87

2 89

3 89

4 73

5 51

a Amide (1.0 mmol), Mo(CO)6 (5 mol%), TMDS (1.5 mmol), THF (2 mL),reaction temperature 65 1C for 24 h. b Isolated yields.

Scheme 2 Evaluation of aryl substituted olefins at the b-position.

Scheme 3 Evaluation of the a,b-substituted substrate.

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14510 | Chem. Commun., 2014, 50, 14508--14511 This journal is©The Royal Society of Chemistry 2014

enamine 7a was observed (Scheme 4). There are very few examplesof catalytic reduction of amides towards direct enamine formation.The group of Nagashima reported on an iridium catalyst for thispurpose, and we recently reported on a t-BuOK catalysed hydro-silylation of amides for the formation of enamines.18 Moreover,Buchwald and co-workers have previously demonstrated enamineformation from amides using stoichiometric amounts of Ti(OiPr)4

in combination with diphenylsilane (Ph2SiH2).19

The general order of reactivity for hydrosilylation of amideshas been reported as follows; tertiary 4 secondary c primary.20

This trend was also observed using the Mo(CO)6 protocol(Scheme 5). For the reduction of secondary amide 8, the catalystloading had to be increased to 10 mol% and the reaction timeprolonged to 48 h in order to obtain a satisfactory yield of thecorresponding amine 9. Keinan and Perez were able to selectivelyreduce the olefin of N-methylcinnamamide, employing similarconditions.15 We suggest that the selectivity switch observed inour protocol stems from the use of a different silane. Recently,Nagashima and co-workers showed that the synergetic effect ofdual Si–H groups in TMDS promotes high efficiency and selectivityfor the reduction of carboxamides.7a It is possible that the use ofTMDS results in the observed change in selectivity when employinga,b-unsaturated secondary amide substrates.

In addition, we evaluated the primary amide cinnamamide,which proved to be even more challenging, and the catalystloading had to be increased to 30 mol% in order to obtain a fullconversion of the starting material. Unfortunately, the highercatalyst loading also resulted in a non-selective reduction and amixture of the saturated primary amide and the primary allylicamine was obtained.

In order to demonstrate the synthetic utility of the chemo-selective Mo-catalysed reduction of a,b-unsaturated amides, wetargeted the antifungal pharmaceutical Naftifine.21 We recentlydeveloped an efficient catalytic method for the direct amidation ofnon-activated carboxylic acids,22 and we decided to combine theamidation protocol with the Mo(CO)6 catalysed amide reductiondescribed herein, for the synthesis of Naftifine (Scheme 6). Cinnamicacid (10) was allowed to react with 1-naphthylmethylamine (11)under direct amidation conditions using ZrCl4 (10 mol%), toobtain amide 12 in 91% yield. Subsequently, amide 12 wasmethylated using methyl iodide and the corresponding tertiary

amide 13 was then reduced under the standard hydrosilylationconditions. The final step provided the target Naftifine (14) in92% yield, and the three step synthesis gave an overall yield of78% from the corresponding carboxylic acid and amine.

In conclusion, we have developed a mild and chemoselectivereduction of a,b-unsaturated tertiary and secondary amides to obtainthe corresponding allylic amines. The selective amide reductioncatalysed by the inexpensive Mo(CO)6 complex employs TMDS as anefficient and easy-to-handle hydride source. In addition, we wereable to combine our previous protocol for amide formationwith the Mo(CO)6 catalysed procedure for the synthesis ofNaftifine. It is noteworthy to mention that in this three-steppreparation, two steps were efficiently catalysed by inexpensiveand benign metals. Further studies on amide reduction towardsenamine formation, and chemoselective hydrosilylation usingMo(CO)6 are currently being performed.

The Swedish Research Council, the Knut and Alice WallenbergFoundation, and Stockholm University are gratefully acknowledgedfor financial support.

Notes and references1 (a) J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in

Organic Synthesis, Wiley, New York, 2nd edn, 1997; (b) W. G. Gribble,Chem. Soc. Rev., 1998, 27, 395.

2 (a) M. A. A. Nunez, G. R. Eastham and D. J. Cole-Hamilton, Chem.Commun., 2007, 3154; (b) E. Balaraman, B. Gnanaprakasam, L. J. W.Shimon and D. Milstein, J. Am. Chem. Soc., 2010, 132, 16756;(c) G. Beamson, A. J. Papworth, C. Philipps, A. M. Smith andR. Whyman, Adv. Synth. Catal., 2010, 352, 869; (d) J. M. John andS. H. Bergens, Angew. Chem., Int. Ed., 2011, 50, 10377.

3 Examples of hydrogenation protocols in which the C–N bond ispreserved. (a) J. Coetzee, D. L. Dodds, J. Klankermayer, S. Brosinksi,W. Leitner, A. M. Z. Slawin and D. J. Cole-Hamilton, Chem. – Eur. J.,2013, 19, 11039; (b) M. Stein and B. Breit, Angew. Chem., Int. Ed.,2013, 52, 2231.

4 (a) Y. Motoyama, K. Mitsui, T. Ishida and H. Nagashima, J. Am.Chem. Soc., 2005, 127, 13150; (b) S. Hanada, T. Ishida, Y. Motoyama

Scheme 4 Hydrosilylation of the b,g-unsaturated amide.

Scheme 5 Hydrosilylation of a secondary amide.

Scheme 6 Combination of catalytic direct amidation and Mo(CO)6 cata-lysed amide reduction in the synthesis of Naftifine.

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and H. Nagashima, J. Org. Chem., 2007, 72, 7551; (c) B. Li,J.-B. Sortais and C. Darcel, Chem. Commun., 2013, 49, 3691.

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9 Y. Sunada, H. Kawakami, T. Imaoka, Y. Motoyama and H. Nagashima,Angew. Chem., Int. Ed., 2009, 48, 9511.

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106, 2455; (b) S. C. A. Sousa, I. Cabrita and A. C. Fernandes, Chem.Soc. Rev., 2014, 41, 5641.

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D. Tomlinson, R. Gappa, A. J. Metta-Magana, H. Ito and H. Pannell,Organometallics, 2013, 32, 3788.

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D. Berney, J. Med. Chem., 1986, 29, 112; (b) A. Stutz, Angew. Chem.,Int. Ed., 1987, 99, 323; (c) M. Johannsen and K. Jørgensen, Chem.Rev., 1998, 98, 1689; (d) J. E. Birnbaum, J. Am. Acad. Dermatol., 1990,23, 782.

17 The purity of the Mo(CO)6 used in the screening was 98%. Similarresults were obtained when Mo(CO)6 with a purity of 99.9% wasused instead.

18 (a) Y. Motoyama, M. Aoki, N. Takaoka, R. Aoto and H. Nagashima,Chem. Commun., 2009, 1574; (b) A. Volkov, F. Tinnis andH. Adolfsson, Org. Lett., 2014, 16, 680.

19 S. Bower, K. A. Kreutzer and S. L. Buchwald, Angew. Chem., Int. Ed.Engl., 1996, 35, 1515.

20 D. Addis, S. Das, K. Junge and M. Beller, Angew. Chem., Int. Ed., 2011,50, 6004.

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