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Highly Chemoselective Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using SmI2/Amine/H2O under Mild Conditions
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School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2268–2271
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https://doi.org/10.1021/ja412578t
Published January 24, 2014

Copyright © 2014 American Chemical Society. This publication is licensed under CC-BY.

Abstract

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Highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O is reported. The reaction proceeds with C–N bond cleavage in the carbinolamine intermediate, shows excellent functional group tolerance, and delivers the alcohol products in very high yields. The expected C–O cleavage products are not formed under the reaction conditions. The observed reactivity is opposite to the electrophilicity of polar carbonyl groups resulting from the nX → π*C═O (X = O, N) conjugation. Mechanistic studies suggest that coordination of Sm to the carbonyl and then to Lewis basic nitrogen in the tetrahedral intermediate facilitate electron transfer and control the selectivity of the C–N/C–O cleavage. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild electron transfer conditions.

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The reduction of carboxylic acid derivatives is among the most important and valuable processes in organic chemistry. (1) In particular, the reduction of amides has captured much attention as a practical method for the synthesis of amines from bench-stable amide precursors. (2) Over the past decades, many reagents and conditions for this transformation have been reported, (3) including recent breakthroughs in highly chemoselective (3a) and metal-free reductions. (3g) However, in contrast to the reduction of amides to amines, which typically proceeds via C–O bond cleavage in the tetrahedral intermediate, the development of practical methods for the reduction of amides to alcohols via selective C–N bond scission remains a formidable challenge (Figure 1).

Figure 1

Figure 1. (a) Divergent reaction pathways in the reduction of amides. (b) This work: the first general, highly chemoselective reduction of amides to alcohols.

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Very few examples of the chemoselective reduction of amides to alcohols have been reported. Early studies by Brown and co-workers based on typical metal hydride reagents (B–H, Al–H) revealed that the selective C–N cleavage is in principle feasible; however, only one reagent (LiEt3BH) and for only one class of substrates (aromatic N,N-dimethylamides) afforded appreciable C–N cleavage selectivity. (4) Subsequently, the groups of Hutchins, (5a) Singaram, (5b, 5c) and Myers (5d, 5e) studied metal amide–borane complexes for the reduction of sterically unhindered tertiary amides to alcohols. However, this chemistry highlighted a number of limitations, including the low reactivity and/or C–O bond cleavage selectivity for the reduction of primary and secondary amides, inadequate functional group tolerance, and the use of pyrophoric organometallic reagents that decrease the practicality of these methods. Recently, considerable advancements using catalytic hydrogenation have been reported. (6-8)

Milstein and co-workers developed a reduction of secondary and tertiary amides to alcohols that employs a Ru pincer catalyst at elevated temperatures and high H2 pressures (THF, 110 °C, 10 atm) and proceeds in excellent yields and C–N cleavage selectivity. (6) Ikariya (7) and Bergens (8) reported hydrogenation of activated secondary and tertiary amides/lactams using Ru catalysts at high temperatures and H2 pressures (100 °C, 50 atm). Additionally, Enthaler and co-workers reported a bimetallic Mo complex for the catalytic hydrosilylation of N-aryl tertiary amides with good C–N scission chemoselectivity. (9) However, these reactions suffer from limited substrate scope and typically require highly specialized pressure tube and glovebox equipment, which limits their laboratory application. Moreover, primary and secondary amides are difficult substrates because of the presence of free NH bonds. To date, a general method for the reduction of amides to alcohols with high C–N bond cleavage chemoselectivity under mild and practical reaction conditions has not been reported despite the significance of this transformation for the synthesis of fundamental building blocks, such as alcohols, from bench-stable amide precursors.

Herein we report the first general method for the reduction of all types of amides (primary, secondary, and tertiary) to alcohols using the SmI2/amine/H2O reducing system via a single electron transfer mechanism. (10) The reaction proceeds with excellent C–N bond cleavage selectivity at room temperature under mild, operationally simple reaction conditions. Notably, this process constitutes the first general method for the synthesis of ketyl-type radicals from unactivated amides. (11)

We recently reported the reduction of esters using SmI2/amine/H2O. (12) This reagent system efficiently mediates the reduction of esters, lactones, and carboxylic acids under mild conditions via open-shell reaction pathways, which are orthogonal to the traditional closed-shell mechanisms. (13) We sought to apply this chemistry to the reduction of unactivated amides. (14) We started our investigation by screening the reaction conditions using a cyclic amide substrate, 1-phenylpiperidin-2-one [see the Supporting Information (SI)]. (15) We were pleased to find that the SmI2/Et3N/H2O system mediates the reduction of 1-phenylpiperidin-2-one in excellent 96% yield with >95:5 C–N/C–O bond cleavage selectivity. Remarkably, these conditions could be readily applied to a range of acyclic amides to afford the corresponding alcohols with excellent C–N/C–O cleavage selectivity and yield (Table 1). Primary, secondary, and tertiary amides afforded the alcohol reduction products in high yields (entries 1–5).

Table 1. Reduction of Amides to Alcohols Using SmI2a
Table a

Conditions: R = Ph(CH2)2, SmI2 (8 equiv), THF, Et3N, H2O, 23 °C. See the SI for full experimental details.

Alicyclic amides (Table 1, entries 6–8), including strained azetidine (entry 6) and aziridine (see the SI) substrates resulted in high selectivity for C–N cleavage. Several amides bearing a directing functionality were subjected to the reaction conditions to determine whether Sm(II) chelation could influence the C–N cleavage selectivity (entries 9–12). In all cases, only alcohol products were formed, suggesting that chelation does not override the inherent reaction pathway. (16) We also found that amides featuring substituents known to afford mixtures of C–N/C–O cleavage products with other reagents (2a) were amenable to the Sm(II) reduction protocol and that useful levels of chemoselectivity were obtained with these substrates (entries 13 and 14). We note, however, that N,N-diisopropylamide was unreactive under our reaction conditions (entry 15). (17)

Next, the substrate scope of the reaction was investigated with regard to substitution at the α carbon of the amide with the knowledge that there is an unmet need for the reduction of primary and secondary amides (cf. tertiary amides) to alcohols using existing hydride-mediated (3, 4) and hydrogenation (6-9) methodologies (Table 2). Amides with increasing steric demand at the α carbon were suitable substrates for the reduction (entries 1–5), including a very hindered N,N-diethyl adamantyl amide (entry 5). Aromatic amides could be reduced to the corresponding alcohols with excellent C–N cleavage selectivity (entries 6–8). The method is compatible with a broad range of functional groups, including terminal and internal alkenes (see the SI; isomerization of an internal cis olefin was not observed); aryl fluorides, chlorides, bromides; trifluoromethylphenyl groups; aryl ethers; aromatic rings; and electron-rich heterocycles such as indoles (entries 9–16). In all cases, excellent selectivity for the C–N cleavage was observed. Furthermore, complex biologically active steroid scaffolds and drug molecules bearing unprotected alcohols and amines were subjected directly to the reaction conditions to afford the corresponding alcohols in high yields (entries 17 and 18). In contrast, acidic protons are not tolerated by the recently disclosed highly chemoselective reductions of amides, (3) emphasizing the mild reaction conditions and functional group tolerance of Sm(II) systems. Additional studies showed that high selectivity is also possible in the presence of other functional groups (e.g., esters; see the SI for details).

Table 2. Substrate Scope in the Reduction of Amides to Alcohols Using SmI2a
Table a

Conditions: SmI2 (4–8 equiv), THF, Et3N, H2O, 23 °C. See the SI for full experimental details.

It is particularly noteworthy that the reduction of enantioenriched amides derived from Myers and Evans auxiliaries could be achieved in good yield and selectivity to give the corresponding products in high ee (Scheme 1). The reduction of a diastereoisomer of 5 (see the SI) afforded the corresponding alcohol (S)-6 with high ee. These results demonstrate that amides bearing α-enolizable chiral centers can be readily reduced using this methodology. The recovery of the auxiliaries has not been optimized.

Scheme 1

Scheme 1. Reduction of Enantioenriched Amides to Alcohols Using SmI2
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Several studies were conducted to gain insight into the reaction mechanism (see Scheme 2 and the SI): (1) The reduction of trans-cyclopropane radical clocks 8 (18) using limiting SmI2 resulted in rapid cyclopropyl ring opening to give acyclic amides 9 and alcohols 10 in the following ratios: 78:22 (primary amide), 85:15 (secondary amide), and 92:8 (tertiary amide). Cyclopropyl carbinol 11 was not detected. In an additional experiment using SmI2/H2O (i.e., without amine), cyclopropane ring opening was observed without further reduction of acyclic amide 9 to alcohol 10. These results suggest that the first electron transfer to the amide carbonyl is reversible and that the rate of the second electron transfer is sensitive to the substitution of the amide nitrogen. (2) The reductions of amides 1a, 1b, and 1e with SmI2/D2O/amine (83% D2 and kH/kD = 1.37 ± 0.1, primary amide; 95% D2 and kH/kD = 1.34 ± 0.1, secondary amide; 97% D2 and kH/kD = 1.32 ± 0.1, tertiary amide) suggested that anions are generated and protonated by H2O in a series of electron transfer steps (19) and that proton transfer is not involved in the rate-determining step of the reaction. (3) Control experiments using H218O (2.59% 18O incorporation, primary amide; 4.19%, secondary amide; 14.20%, tertiary amide) showed that amide hydrolysis, or hydrolysis of an iminium intermediate, is not a predominant pathway. (4) Selectivity studies demonstrated the following order of amide reactivity: 1° > 2° > 3°. Moreover, >95:5 selectivity was obtained in the reduction of primary amides over esters and activated over aliphatic secondary amides. (5) A Hammett study performed using a series of 4-substituted 2-phenylacetamides (12) showed a large positive ρ value of 0.52 (R2 = 0.98), which can be compared with the ρ value of 0.49 for ionization of phenylacetic acids in H2O at 25 °C. (6) The Taft correlation study, obtained by plotting log(kobs) versus ES for a series of N-alkyl-3-phenylpropanamides showed a large positive slope of 0.92 (R2 = 0.99). The results from the Hammett and Taft studies are consistent with a mechanism involving Sm coordination to the substrate and buildup of partial negative charge on the carbon of the amide carbonyl. (13g)

Scheme 2

Scheme 2. Studies Designed To Probe the Mechanism of the Reduction of Amides to Alcohols using SmI2 (R′, R″ = H; for R′ = H, R″ = n-Bu and R′, R″ = Et, See the SI)
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Overall, these results are in agreement with a mechanism involving coordination of the azaphilic Lewis acid Sm (20) to nitrogen either before or after the initial electron transfer. (21) We postulate that the high chemoselectivity for C–N versus C–O cleavage results from the fact that a protonated hemiaminal is not formed in the reaction. Furthermore, collapse of the carbinolamine intermediate with selective C–N cleavage is likely promoted by the coordination of SmX3 (X = I, OH) to the Lewis basic nitrogen (20) (see Figure 1B).

In summary, the first general reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O has been developed. The reaction proceeds with high selectivity for C–N bond cleavage under mild and operationally simple reaction conditions. The mechanism involves reversible first electron transfer and electrophilic activation of the amide bond. This protocol demonstrates a broad substrate scope and provides the corresponding alcohols in excellent yields with chemoselectivity orthogonal to that of existing closed-shell processes. We fully expect that this method will be of great interest for the synthesis of functionalized alcohol-containing building blocks. Studies of the application of Sm(II) to chemoselective reductions and reductive cyclizations of functional groups are underway and will be reported shortly.

Supporting Information

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Experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.

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Author Information

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  • Corresponding Authors
    • Michal Szostak - School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
    • David J. Procter - School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
  • Authors
    • Malcolm Spain - School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
    • Andrew J. Eberhart - School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
  • Author Contributions

    M. Spain and A. J. Eberhart contributed equally.

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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We acknowledge the EPSRC and GSK for financial support.

References

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    Catalytic hydrogenation of org. carbonates, carbamates and formates is of significant interest both conceptually and practically, because these compds. can be produced from CO2 and CO, and their mild hydrogenation can provide alternative, mild approaches to the indirect hydrogenation of CO2 and CO to methanol, an important fuel and synthetic building block. Here, we report for the first time catalytic hydrogenation of org. carbonates to alcs., and carbamates to alcs. and amines. Unprecedented homogeneously catalyzed hydrogenation of org. formates to methanol has also been accomplished. The reactions are efficiently catalyzed by dearomatized PNN Ru(II) pincer complexes derived from pyridine- and bipyridine-based tridentate ligands. These atom-economical reactions proceed under neutral, homogeneous conditions, at mild temps. and under mild hydrogen pressures, and can operate in the absence of solvent with no generation of waste, representing the ultimate green' reactions. A possible mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroarom. pincer core.
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Cite this: J. Am. Chem. Soc. 2014, 136, 6, 2268–2271
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https://doi.org/10.1021/ja412578t
Published January 24, 2014

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  • Abstract

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    Figure 1

    Figure 1. (a) Divergent reaction pathways in the reduction of amides. (b) This work: the first general, highly chemoselective reduction of amides to alcohols.

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    Scheme 1

    Scheme 1. Reduction of Enantioenriched Amides to Alcohols Using SmI2
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    Scheme 2

    Scheme 2. Studies Designed To Probe the Mechanism of the Reduction of Amides to Alcohols using SmI2 (R′, R″ = H; for R′ = H, R″ = n-Bu and R′, R″ = Et, See the SI)
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  • References

    This article references 21 other publications.

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      A review with 24 refs. discusses the general types of reactions used in processes for the prepn. of drug candidates from the process chem. R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer in order to evaluate potential gaps in chem. technologies for the prepn. of pharmaceuticals. The presence and incorporation of asymmetry in drug candidates, the substitution patterns of arom. and heteroarom. starting materials, and the use of protecting groups and of acylation, alkylation, arylation, oxidn., redn., carbon-carbon bond-forming, and substitution reactions in processes for the prepn. of drug candidates are discussed.
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      A general and selective copper-catalyzed reduction of secondary amides
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      In situ-generated cationic copper/pybox catalyst systems allow for the selective redn. of secondary amides into the corresponding amines under mild conditions. This novel protocol has a wide substrate scope and shows good functional group tolerance.
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      Zinc-catalyzed chemoselective reduction of tertiary and secondary amides to amines
      Das, Shoubhik; Addis, Daniele; Junge, Kathrin; Beller, Matthias
      Chemistry - A European Journal (2011), 17 (43), 12186-12192CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the redn. of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for org. synthesis.
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      3e
      A convenient and general iron-catalyzed reduction of amides to amines
      Zhou, Shaolin; Junge, Kathrin; Addis, Daniele; Das, Shoubhik; Beller, Matthias
      Angewandte Chemie, International Edition (2009), 48 (50), 9507-9510, S9507/1-S9507/124CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A convenient redn. of amides with polymethylhydrosiloxane catalyzed byFe3(CO)12 is described. Amines were obtained in excellent to good yields under the reaction conditions.

      For an excellent review, see:

      (f) Das, S.; Zhou, S.; Addis, D.; Junge, K.; Enthaler, S.; Beller, M. Top. Catal. 2010, 53, 979
      3f
      Selective Catalytic Reductions of Amides and Nitriles to Amines
      Das, Shoubhik; Zhou, Shaolin; Addis, Daniele; Enthaler, Stephan; Junge, Kathrin; Beller, Matthias
      Topics in Catalysis (2010), 53 (15-18), 979-984CODEN: TOCAFI; ISSN:1022-5528. (Springer)
      A review. This personal account summarizes our recent developments of catalytic hydrosilylations and hydrogenations of carboxylic amides and nitriles to selectively give amines. Special focus is given to highly chemoselective iron- and zinc-catalyzed redns. of amides.
      (g) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18
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      (h) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817
      3h
      Controlled and Chemoselective Reduction of Secondary Amides
      Pelletier, Guillaume; Bechara, William S.; Charette, Andre B.
      Journal of the American Chemical Society (2010), 132 (37), 12817-12819CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      This communication describes a metal-free methodol. involving an efficient and controlled redn. of secondary amides to imines, aldehydes, and amines in good to excellent yields under ambient pressure and temp. The process includes a chemoselective activation of a secondary amide with triflic anhydride in the presence of 2-fluoropyridine. The electrophilic activated amide can then be reduced to the corresponding iminium using triethylsilane, a cheap, rather inert, and com. available reagent. Imines can be isolated after a basic workup or readily transformed to the aldehydes following an acidic workup. The amine moiety can be accessed via a sequential reductive amination by the addn. of silane and Hantzsch ester hydride in a one-pot reaction. Moreover, this redn. tolerates various functional groups that are usually reactive under reductive conditions and is very selective to secondary amides.

      For an elegant application of chemoselective amide bond activation, see:

      (i) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228
      3i
      Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides
      Bechara, William S.; Pelletier, Guillaume; Charette, Andre B.
      Nature Chemistry (2012), 4 (3), 228-234CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The development of efficient and selective transformations is crucial in synthetic chem. as it opens new possibilities in the total synthesis of complex mols. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous org. functionalities. In this context, we report a general and chemoselective method based on an activation/addn. sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the obsd. exceptional functional group tolerance, allowing the facile addn. of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly obsd. over-addn. or redn. side reactions. The methodol. has been applied to the formal synthesis of analogs of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsym. diketones in a one-pot procedure.
      (j) Reeves, J. T.; Tan, Z.; Marsini, M. A.; Han, Z. S.; Xu, Y.; Reeves, D. C.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Adv. Synth. Catal. 2013, 355, 47
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      3k
      Catalytic Hydrogenation of Amides to Amines under Mild Conditions
      Stein, Mario; Breit, Bernhard
      Angewandte Chemie, International Edition (2013), 52 (8), 2231-2234CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We have developed the first general catalytic hydrogenation of secondary and tertiary amides using a Pd/Re/graphite catalyst. This catalyst displays the highest activity reported to date.
      (l) Cheng, C.; Brookhart, M. J. Am. Chem. Soc. 2012, 134, 11304
      3l
      Iridium-Catalyzed Reduction of Secondary Amides to Secondary Amines and Imines by Diethylsilane
      Cheng, Chen; Brookhart, Maurice
      Journal of the American Chemical Society (2012), 134 (28), 11304-11307CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Catalytic redn. of secondary amides to imines and secondary amines has been achieved using readily available iridium catalysts such as [Ir(COE)2Cl]2 with diethylsilane as reductant. The stepwise redn. to secondary amine proceeds through an imine intermediate that can be isolated when only 2 equiv of silane is used. This system requires low catalyst loading and shows high efficiency (up to 1000 turnovers at room temp. with 99% conversion have been attained) and an appreciable level of functional group tolerance.
      (m) Park, S.; Brookhart, M. J. Am. Chem. Soc. 2012, 134, 640
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      (n) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 15032
      3n
      Practical access to amines by platinum-catalyzed reduction of carboxamides with hydrosilanes: Synergy of dual Si-H groups leads to high efficiency and selectivity
      Hanada, Shiori; Tsutsumi, Emi; Motoyama, Yukihiro; Nagashima, Hideo
      Journal of the American Chemical Society (2009), 131 (41), 15032-15040CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The synergetic effect of two Si-H groups leads to efficient redn. of carboxamides to amines by platinum catalysts under mild conditions. The rate of the reaction is dependent on the distance of two Si-H groups; 1,1,3,3-tetramethyldisiloxane (TMDS) and 1,2-bis(dimethylsilyl)benzene are found to be an effective reducing reagent. The redn. of amides having other reducible functional groups such as NO2, CO2R, CN, C=C, Cl, and Br moieties proceeds with these groups remaining intact, providing a reliable method for the access to functionalized amine derivs. The platinum-catalyzed redn. of amides with polymethylhydrosiloxane (PMHS) also proceeds under mild conditions. The reaction is accompanied by automatic removal of both platinum and silicon wastes as insol. silicone resin, and the product is obtained by simple extn. A mechanism involving double oxidative addn. of TMDS to a platinum center is discussed.
      (o) Motoyama, Y.; Mitsui, K.; Ishida, T.; Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150
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      (p) Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009, 48, 9511
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      (q) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, 122, 11995
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      (r) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408
      3r
      Mild and Selective Hydrozirconation of Amides to Aldehydes Using Cp2Zr(H)Cl: Scope and Mechanistic Insight
      Spletstoser, Jared T.; White, Jonathan M.; Tunoori, Ashok Rao; Georg, Gunda I.
      Journal of the American Chemical Society (2007), 129 (11), 3408-3419CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      An investigation of the use of Cp2Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amides, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for redn. as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides. Results from NMR expts. suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition expts. revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the obsd. excellent selectivity for tertiary amides vs. esters. Expts. regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addn. of p-anisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addn. of water that forms the aldehyde.
    4. 4
      Brown, H. C.; Kim, S. C. Synthesis 1977, 635
      4
      An unusual reduction of tertiary amides with carbon-nitrogen fission
      Brown, Herbert C.; Kim, S. C.
      Synthesis (1977), (9), 635-6CODEN: SYNTBF; ISSN:0039-7881.
      Tertiary amides RCONR12 (I; R = Ph, Pr, n-hexyl, Me2CH, Me3C, cyclohexyl; R1 = Me) were reduced by LiBHEt3 in THF at 0-25° with C-N bond cleavage to give alcs. RCH2OH in 71-100% yields. The reaction time was 1-7 h. For I [R = Pr; R12 = (CH2)4, Et2, and (Me2CH2)2] reaction times and yields were, resp.: 32 h, 62%; 24 h, 50%; and 24 h, 0%; this shows the lowering of reactivity of I by steric hindrance.
    5. 5
      (a) Hutchins, R. O.; Learn, K.; El-Telbany, F.; Stercho, Y. P. J. Org. Chem. 1984, 49, 2438
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      (b) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.; Goralski, C. T.; Singaram, B. J. Org. Chem. 1994, 59, 6378
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      For an excellent overview, see:

      (c) Pasumansky, L.; Goralski, C. T.; Singaram, B. Org. Process Res. Dev. 2006, 10, 959
      5c
      Lithium Aminoborohydrides: Powerful, Selective, Air-Stable Reducing Agents
      Pasumansky, Lubov; Goralski, Christian T.; Singaram, Bakthan
      Organic Process Research & Development (2006), 10 (5), 959-970CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      A review. Lithium aminoborohydrides (LABs) are a new class of powerful, selective, air-stable reducing agents, which can be prepd. as solids, as 1-2 M THF solns., or generated in situ for immediate use. LABs can be synthesized from any primary or secondary amines, hence permitting control of the steric and electronic environment of these reagents. Solid LAB reagents can be used in dry air as easily as sodium borohydride and maintain their chem. activity for at least 6 mo when stored under nitrogen or dry air at 25 °C. THF solns. of LABs retain their chem. activity for at least 9 mo when stored under N2 at 25 °C. LAB reagents are non-pyrophoric and only liberate hydrogen slowly in protic solvents above pH 4. LABs reduce arom. and aliph. esters at 0 °C in air. Tertiary amides are selectively reduced to the corresponding amine or alc., depending on the steric environment of the LAB whereas α,β-unsatd. aldehydes and ketones undergo selective 1,2-redn. to the corresponding allylic alcs. Aliph. and arom. azides are readily reduced to the corresponding primary amines using only 1.5 equiv of LAB. A novel tandem amination/redn. reaction has been developed in which 2-(N,N-dialkylamino)benzylamines are generated from 2-halobenzonitriles and lithium N,N-dialkylaminoborohydride (LAB) reagents. These reactions are believed to occur through a tandem SNAr amination/redn. mechanism wherein the LAB reagent promotes halide displacement by the N,N-dialkylamino group and the nitrile is subsequently reduced. The (N,N-dialkylamino)benzylamine products of this reaction are easily isolated after a simple aq. workup procedure in very good to excellent yields. Lithium aminoborohydride reagents initiate the amination or redn. of alkyl methanesulfonate esters, as dictated by reaction conditions. Alkyl methanesulfonate esters treated with unhindered LABs provide tertiary amines in excellent yield. Redn. to the corresponding alkane is achieved by using a hindered LAB reagent or by forming the highly reactive Super-Hydride reagent in situ using LAB and a catalytic amt. of triethylborane.
      (d) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37, 3623
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      (e) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496
      5e
      Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones
      Myers, Andrew G.; Yang, Bryant H.; Chen, Hou; McKinstry, Lydia; Kopecky, David J.; Gleason, James L.
      Journal of the American Chemical Society (1997), 119 (28), 6496-6511CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The use of pseudoephedrine as a practical chiral auxiliary for asym. synthesis is described in full. Both enantiomers of pseudoephedrine are inexpensive commodity chems. and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcs., aldehydes, and ketones.
    6. 6
      (a) Balaraman, E.; Gnanaprakasam, B.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 16756
      6a
      Direct Hydrogenation of Amides to Alcohols and Amines under Mild Conditions
      Balaraman, Ekambaram; Gnanaprakasam, Boopathy; Shimon, Linda J. W.; Milstein, David
      Journal of the American Chemical Society (2010), 132 (47), 16756-16758CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The selective, direct hydrogenation of amides to the corresponding alcs. and amines with cleavage of the C-N bond was discovered. The expected products of C-O cleavage are not formed (except as traces in the case of anilides). The reaction proceeds under mild pressure and neutral, homogeneous conditions using a dearomatized, bipyridyl-based PNN Ru(II) pincer complex as a catalyst, I. The postulated mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroarom. pincer core and does not involve hydrolytic cleavage of the amide. The simplicity, generality, and efficiency of this environmentally benign process make it attractive for the direct transformations of amides to alcs. and amines in good to excellent yields.

      For other elegant applications of Ru(II) complexes, see:

      (b) Balaraman, E.; Gunanathan, C.; Zhang, J.; Shimon, L. J. W.; Milstein, D. Nat. Chem. 2011, 3, 609
      6b
      Efficient hydrogenation of organic carbonates, carbamates and formates indicates alternative routes to methanol based on CO2 and CO
      Balaraman, Ekambaram; Gunanathan, Chidambaram; Zhang, Jing; Shimon, Linda J. W.; Milstein, David
      Nature Chemistry (2011), 3 (8), 609-614CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Catalytic hydrogenation of org. carbonates, carbamates and formates is of significant interest both conceptually and practically, because these compds. can be produced from CO2 and CO, and their mild hydrogenation can provide alternative, mild approaches to the indirect hydrogenation of CO2 and CO to methanol, an important fuel and synthetic building block. Here, we report for the first time catalytic hydrogenation of org. carbonates to alcs., and carbamates to alcs. and amines. Unprecedented homogeneously catalyzed hydrogenation of org. formates to methanol has also been accomplished. The reactions are efficiently catalyzed by dearomatized PNN Ru(II) pincer complexes derived from pyridine- and bipyridine-based tridentate ligands. These atom-economical reactions proceed under neutral, homogeneous conditions, at mild temps. and under mild hydrogen pressures, and can operate in the absence of solvent with no generation of waste, representing the ultimate green' reactions. A possible mechanism involves metal-ligand cooperation by aromatization-dearomatization of the heteroarom. pincer core.
      (c) Balaraman, E.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2011, 50, 11702
      There is no corresponding record for this reference.
    7. 7
      (a) Ito, M.; Koo, L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T. Angew. Chem., Int. Ed. 2009, 48, 1324
      7a
      Hydrogenation of N-acylcarbamates and N-acylsulfonamides catalyzed by a bifunctional [Cp*Ru(PN)] complex
      Ito, Masato; Koo, Lee Wei; Himizu, Akio; Kobayashi, Chika; Sakaguchi, Ayaka; Ikariya, Takao
      Angewandte Chemie, International Edition (2009), 48 (7), 1324-1327CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The bifunctional ruthenium complex facilitates the interaction with substrates bearing less electrophilic carbon atoms than ketones, epoxides, and imides. The title reaction was applicable to the redn. of Evans' asym. alkylation products to the chiral alcs. along with good recovery of the chiral oxazolidinone auxiliary.
      (b) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi, A.; Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 4240
      7b
      Catalytic Hydrogenation of Carboxamides and Esters by Well-Defined Cp*Ru Complexes Bearing a Protic Amine Ligand
      Ito, Masato; Ootsuka, Takashi; Watari, Ryo; Shiibashi, Akira; Himizu, Akio; Ikariya, Takao
      Journal of the American Chemical Society (2011), 133 (12), 4240-4242CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A novel catalytic method for the straightforward hydrogenation of carboxamides and esters to primary alcs. has been developed. E.g. hydrogenation of phthalide I to give 89% diol II was catalyzed by Cp*RuCl(2-C5H4NCH2NH2). Chiral modification in the ligand sphere of the well-defined Cp*Ru catalyst mol. opens up a new possibility for the development of an enantioselective hydrogenation of racemic substrates via dynamic kinetic resoln.

      For a review, see:

      (c) Dub, P. A.; Ikariya, T. ACS Catal. 2012, 2, 1718
      7c
      Catalytic Reductive Transformations of Carboxylic and Carbonic Acid Derivatives Using Molecular Hydrogen
      Dub, Pavel A.; Ikariya, Takao
      ACS Catalysis (2012), 2 (8), 1718-1741CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A review. A comprehensive overview on homogeneous catalytic hydrogenation of carboxylic acids and its derivs. as well as carbonic acid derivs. with transition metal-based mol. catalysts is described. Despite the tremendous potential in the hydrogenation of these less electrophilic carbonyl compds. using mol. hydrogen in synthetic org. chem., their redn. still relies mostly on the stoichiometric use of metal hydride reagents, such as LiAlH4, NaBH4, and their derivs. For the past decade, a significant and rapid progress in particularly ester hydrogenation has been achieved by utilization of conceptually new bifunctional mol. catalysts originating from the metal-ligand cooperation effects. The bifunctional-catalyst-promoted hydrogenation using mol. hydrogen is now realized to be a practical tool in synthetic org. chem. in both academia and industry. The industrial outlook for the present hydrogenation is bright because of its operational simplicity, scope, economic viability, and growing awareness of the need for green chem.
    8. 8
      John, J. M.; Bergens, S. H. Angew. Chem., Int. Ed. 2011, 50, 10377
      8
      A Highly Active Catalyst for the Hydrogenation of Amides to Alcohols and Amines
      John, Jeremy M.; Bergens, Steven H.
      Angewandte Chemie, International Edition (2011), 50 (44), 10377-10380, S10377/1-S10377/24CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Reaction between 2 equiv of Ph2P(CH2)2NH2 and the Ru precursor cis-[Ru(CH3CN)2(η3-C3H5)-(cod)]BF4 (cod = 1,5-cyclooctadiene) in THF at 60 °C forms isomers of the π-allyl complex in near-quant. yield (in soln.) by displacement of the cod and MeCN ligands. Hydrogenation of amides gives the corresponding alcs. and amines using this ruthenium complex in the presence of KN[Si(CH3)3].
    9. 9
      Krackl, S.; Someya, C. I.; Enthaler, S. Chem.—Eur. J. 2012, 18, 15267
      9
      Reductive Cleavage of Amides to Alcohols and Amines Catalyzed by Well-Defined Bimetallic Molybdenum Complexes
      Krackl, Sebastian; Someya, Chika I.; Enthaler, Stephan
      Chemistry - A European Journal (2012), 18 (48), 15267-15271, S15267/1-S15267/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We have demonstrated that bimetallic molybdenum complexes could serve as precatalysts for the C-N bond cleavage of amides by using a hydrosilane as the reductant.
    10. 10

      For reviews of metal-mediated radical reactions, see:

      (a) Gansäuer, A.; Bluhm, H. Chem. Rev. 2000, 100, 2771
      There is no corresponding record for this reference.
      (b) Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2012, 51, 9238
      There is no corresponding record for this reference.
      (c) Streuff, J. Synthesis 2013, 45, 281
      10c
      The electron-way: metal-catalyzed reductive umpolung reactions of saturated and α,β-unsaturated carbonyl derivatives
      Streuff, Jan
      Synthesis (2013), 45 (3), 281-307CODEN: SYNTBF; ISSN:0039-7881. (Georg Thieme Verlag)
      A review. Reductive umpolung reactions of satd. and unsatd. carbonyl compds. enable the direct synthesis of 1,2-, 1,4-, 1,6-, etc. substituted carbon frameworks that are difficult to access by other methodologies. Herein, the evolution from stoichiometric to catalytic processes with high chemo-, regio-, and stereoselectivity is discussed for each carbon-carbon bond connection type. At certain points, summaries of the known reaction conditions and discussions of the underlying mechanisms are included.
      (d) Radicals in Synthesis I and II; Gansäuer, A., Ed.; Topics in Current Chemistry, Vols. 263–264; Springer: Berlin, 2006.
      There is no corresponding record for this reference.

      For recent reviews of SmI2, see:

      (e) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307
      10e
      Sequencing reactions with samarium(II) iodide.
      Molander, Gary A.; Harris, Christina R.
      Chemical Reviews (Washington, D. C.) (1996), 96 (1), 307-38CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review with 97 refs. emphasizing the utility of SmI2 in prepn. of complex compds. through 1-pot, multistep (radical/anionic, anionic/radical, anionic/anionic) sequences.
      (f) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745
      There is no corresponding record for this reference.
      (g) Kagan, H. B. Tetrahedron 2003, 59, 10351
      10g
      Twenty-five years of organic chemistry with diiodosamarium: an overview
      Kagan, Henri B.
      Tetrahedron (2003), 59 (52), 10351-10372CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science B.V.)
      A review. Chem. and applications of samarium iodide (SmI2) were reviewed. A review.
      (h) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140
      10h
      Samarium diiodide mediated reactions in total synthesis
      Nicolaou, K. C.; Ellery, Shelby P.; Chen, Jason S.
      Angewandte Chemie, International Edition (2009), 48 (39), 7140-7165CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Introduced by Henri Kagan more than three decades ago, samarium diiodide (SmI2) has found increasing application in chem. synthesis. This single-electron reducing agent has been particularly useful in C-C bond formations, including those found in total synthesis endeavors. This Review highlights selected applications of SmI2 in total synthesis, with special emphasis on novel transformations and mechanistic considerations. The examples discussed are both illustrative of the power of this reagent in the construction of complex mols. and inspirational for the design of synthetic strategies toward such targets, both natural and designed.
      (i) Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155
      10i
      Recent advances in the chemoselective reduction of functional groups mediated by samarium(II) iodide: a single electron transfer approach
      Szostak, Michal; Spain, Malcolm; Procter, David J.
      Chemical Society Reviews (2013), 42 (23), 9155-9183CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Recently, samarium(II) iodide reductants were emerged as powerful single electron donors for the highly chemoselective redn. of common functional groups. Complete control of the product formation was achieved on the basis of a judicious choice of a Sm(II) complex/proton donor couple, even in the presence of extremely sensitive functionalities (iodides, aldehydes). In most cases, the redns. were governed by thermodn. control of the first electron transfer, which opens up new prospects for unprecedented transformations via radical intermediates under mild regio-, chemo- and diastereoselective conditions that were fully orthogonal to hydrogenation or metal-hydride mediated processes.
    11. 11

      For selected studies of cyclizations of acyl-type radicals, see:

      (a) Parmar, D.; Duffy, L. A.; Sadasivam, D. V.; Matsubara, H.; Bradley, P. A.; Flowers, R. A., II; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 15467
      There is no corresponding record for this reference.
      (b) Parmar, D.; Matsubara, H.; Price, K.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2012, 134, 12751
      There is no corresponding record for this reference.
      (c) Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Org. Lett. 2012, 14, 146
      There is no corresponding record for this reference.
      (d) Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D. J. Angew. Chem., Int. Ed. 2013, 52, 12559
      There is no corresponding record for this reference.
    12. 12

      A study of the mechanism of ester reduction using SmI2/amine/H2O will be reported separately.

      There is no corresponding record for this reference.
    13. 13
      (a) Szostak, M.; Spain, M.; Procter, D. J. Chem. Commun. 2011, 47, 10254
      There is no corresponding record for this reference.
      (b) Szostak, M.; Spain, M.; Procter, D. J. Org. Lett. 2012, 14, 840
      There is no corresponding record for this reference.

      For other studies of SmI2/amine/H2O, see:

      (c) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Lett. 1995, 36, 949
      There is no corresponding record for this reference.
      (d) Dahlén, A.; Hilmersson, G. Chem.—Eur. J. 2003, 9, 1123
      13d
      Instantaneous SmI2/H2O/amine-mediated reductions in THF
      Dahlen, Anders; Hilmersson, Goran
      Chemistry - A European Journal (2003), 9 (5), 1123-1128CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The SmI2-mediated redns. of ketones, imines, and α,β-unsatd. esters have been shown to be instantaneous in the presence of H2O and an amine in THF. The SmI2-mediated redns. are not only shown to be fast and quant. by the addn. of H2O and an amine, but the workup procedures are also simplified. Competing expts. with SmI2/H2O/amine confirmed that α,β-unsatd. esters could be selectively reduced in the presence of ketones or imines. Comparison of analog ligands showed that nitrogen and phosphorus ligands are superior to oxygen and sulfur ligands in these redns. The trialkylphosphine 1,2-bis(dimethylphosphino)ethane (DMPE) provided a primary kinetic isotope effect, yielding a kH/kD of 4.5.
      (e) Dahlén, A.; Hilmersson, G. J. Am. Chem. Soc. 2005, 127, 8340
      There is no corresponding record for this reference.
      (f) Ankner, T.; Hilmersson, G. Tetrahedron 2009, 65, 10856
      There is no corresponding record for this reference.
      (g) Ankner, T.; Stålsmeden, A. S.; Hilmersson, G. Chem. Commun. 2013, 49, 6867
      There is no corresponding record for this reference.
    14. 14

      Kamochi and Kudo described the reduction of aryl carboxylic acid derivatives using SmI2, but this process is low-yielding and/or limited in scope. See:

      (a) Kamochi, Y.; Kudo, T. Chem. Lett. 1993, 1495
      There is no corresponding record for this reference.
      (b) Kamochi, Y.; Kudo, T. Bull. Chem. Soc. Jpn. 1992, 65, 3049
      There is no corresponding record for this reference.

      Electrochemical methods for the reduction of amides have been reported. See:

      (c) Benkeser, R. A.; Watanabe, H.; Mels, S. J.; Sabol, M. A. J. Org. Chem. 1970, 35, 1210
      There is no corresponding record for this reference.
      (d) Shono, T.; Masuda, H.; Murase, H.; Shimomura, M.; Kashimura, S. J. Org. Chem. 1992, 57, 1061
      There is no corresponding record for this reference.
    15. 15

      Cyclic carboxylic acid derivatives are more reactive towards Sm(II) because of anomeric stabilization of the radical anion. (11a)

      There is no corresponding record for this reference.
    16. 16
      Szostak, M.; Spain, M.; Choquette, K. A.; Flowers, R. A., II; Procter, D. J. J. Am. Chem. Soc. 2013, 135, 15702
      There is no corresponding record for this reference.
    17. 17

      Complete recovery of the staring material was observed. In contrast, lithium amidotrihydroborate affords mixtures of C–N/C–O cleavage products with similar substrates. (5d) This divergent reactivity should prove useful in the selective reduction of this class of amides.

      There is no corresponding record for this reference.
    18. 18
      Newcomb, M. Tetrahedron 1993, 49, 1151
      There is no corresponding record for this reference.
    19. 19
      (a) Dahlén, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393
      There is no corresponding record for this reference.
      (b) Flowers, R. A., II. Synlett 2008, 1427
      There is no corresponding record for this reference.
      (c) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330
      There is no corresponding record for this reference.
    20. 20
      (a) Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun. 1999, 1703
      There is no corresponding record for this reference.
      (b) Evans, W. J. Inorg. Chem. 2007, 46, 3435
      There is no corresponding record for this reference.
    21. 21
      (a) Laurence, C.; Gal, J.-F. Lewis Basicity and Affinity Scales: Data and Measurement; Wiley-Blackwell: Chichester, U.K., 2009.
      There is no corresponding record for this reference.
      (b) Cox, C.; Lectka, T. Acc. Chem. Res. 2000, 33, 849
      There is no corresponding record for this reference.

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