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Home , Aluminium hydride, Deprotonation, Lithium iodide, Sodium amide, Sodium hydride

Synthetic Organic Reactions Mediated by

Derek Yiren Ong, Jia Hao Pang, and Shunsuke Chiba ＊

＊ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University Singapore 637371

(Received June 1, 2019; E ─ mail: [email protected])

Abstract: In synthetic organic chemistry, (NaH) has been utilized almost exclusively as a rou- tine Brønsted , while NaH has not been considered to work as a hydride donor. Recently, our group has serendipitously found that NaH can function as a unique hydride donor by its solvothermal treatment with sodium (NaI) or iodide (LiI) in (THF) as a solvent. This discovery led to the development of unprecedented reductive molecular transformations such as hydrodecyanation of α ─ quater- nary benzyl cyanides, controlled reduction of into , dearylation of arylphopsphine oxides, and hydrodehalogenation of haloarenes. Moreover, this concise protocol allows for the use of NaH as enhanced Lewis and Brønsted base, enabling directed aromatic C ─ H sodiation, nucleophilic amination of methoxy arenes, and C2 ─ amination of (the Chichibabin amination).

Ph 2PN(H)Dip with 2 equiv of BuLi followed by phenylsilane 1． Introduction 4a (Scheme 2A). Slootweg and Uhl revealed that P ─ Al based In the synthetic chemistry community, various types of frustrated Lewis pair (FLP) 3 can break polymeric lattice of covalent based on boron, aluminum, and silicon are hydrides to form soluble molecular hydrides 4 available (Scheme 1A). Their chemical reactivities are well (based on LiH) and 5 (based on NaH) (Scheme 2B). 4b It is investigated and they have been utilized as the reliable reagents worthy to note that the coordination mode of the NaH and of choice for desired hydride transfer processes such as hydride KH complexes is distinct from that of LiH. Namely, a softer 1 reduction of polar π ─ electrophiles. On the other hand, ionic Lewis acidic Na cation coordinates with the mesityl carbon, alkali/alkaline earth metal hydrides such as sodium hydride whereas a harder Li cation possess an ionic interaction with (NaH) are also readily available chemicals, which are utilized the phosphorous moiety. Chemical reactivity of these well ─ almost exclusively as a strong Brønsted base for routine depro- de ned molecular alkali metal complexes has thus far been tonation reactions in chemical synthesis (Scheme 1B). 2,3 The alkali metal hydrides possess a cubic halite Scheme 2. Molecular alkali metal hydrides. comprising of alkali metal cations and hydride bound each other strongly via electrostatic interaction, that results in their high lattice energies and thus renders them almost insolu- ble in common aprotic organic solvents.

Scheme 1. Hydride reagents for chemical synthesis.

Several seminal studies realized synthesis and characteriza- tion of molecular alkali metal hydrides through sophisticated design of ligands to stabilize the molecular states of the ionic hydrides over their Schlenk equilibrium towards the polymeric lattice. 4 For example, Stasch synthesized a beautiful LiH clus- ter complex [(DipNPPh 2) 4Li 8H 4] 1 (Dip=2,6 ─ iPr 2C 6H 3) by subsequent treatment of sterically bulky phosphinoamine

1060 （ 8 ） J. Synth. Org. Chem., Jpn. examined only for simple hydride transfer processes. Scheme 4. Reduction of by Al ─ based hydrides. During the course of our studies, we happened to encoun- ter a totally unexpected experimental outcome that implied unprecedented hydridic reactivity on NaH in the presence of dissolving iodide salts such as NaI or LiI. This serendipitous nding led us to develop a series of reductive molecular trans- formations such as hydrodecyanation of α ─ quaternary benzyl cyanides, controlled reduction of amides into aldehydes, dearylation of arylphopsphine oxides and hydrodehalogena- tion of haloarenes. Moreover, this concise protocol allows for use of NaH as enhanced Lewis acid and Brønsted base, center from readily available α ─ quaternary benzyl cyanides. enabling directed aromatic C ─ H sodiation, nucleophilic amina- We found that the reaction rate for the hydrodecyanation was tion of methoxy arenes, and C2 ─ amination of pyridines (the seriously affected by the electronic nature of the aromatic ring Chichibabin amination). This account describes discovery, (12a vs. 12b; 12c vs. 12d): electron ─ donating aromatic rings optimization, scope and limitation as well as detailed mecha- such as a 4 ─ methoxyphenyl group made the process much nistic discussion of these reactions. slower. It should be noted that the current protocol tolerates use of 6 ─ membered heteroaromatic ring such as a 2． Hydride Reduction ring (for 12h), which is often susceptible to the common 2.1 Hydrodecyanation of α Quaternary Benzylcyanides 5 hydride reduction conditions. In early 2015, we became─ interested in use of biaryl carbo- nitriles such as 7 (Scheme 3A) as a starting material for our Scheme 5. Substrate scope (selected examples). reaction development with copper . 6 For preparation of 7, we adopted a seemingly routine method, α ─ dimethylation of 6 with MeI using NaH as a Brønsted base. However, we were very surprised with the outcome by treatment of 6 with 5 equiv of NaH and 3.5 equiv of MeI in THF under reux con- ditions, which afforded not only desired 7 but also hydrodecya- nated 8. We assumed that alkane 8 is formed via hydro- decyanation of 7 by synergistic cooperation of NaH with NaI that should be formed in α ─ methylation of 6. As expected, the reaction optimization using simpler substrate 9 revealed that desired hydrodecyanation of 9 to 2 ─ isopropylnaphthalene (10) is observed only when NaH is mixed with either NaI or LiI (Scheme 3B).

Scheme 3. Discovery of hydrodecyanation.

When the reaction of 4 ─ methoxyphenyl substrate 11b, which needed 24 h for completion of the process, was pur- posely quenched after 3 h of stirring, we could isolate not only hydrodecyanated product 12b in 37% yield but also 13, that should be formed via and hydrolysis of iminyl anion intermediate 14 (Scheme 6). The formation of iminyl anion 14 indicated that hydride transfer occurs from NaH to the nitrile moiety and subsequent C ─ C bond cleavage toward formation of hydrodecyanated product 12b becomes slower when an electron ─ rich aromatic group is present. To obtain more insights for the C ─ C bond cleavage event,

Scheme 6. Identi cation of a reaction intermediate. This hydrodecyanation by the NaH ─ Li(Na)I system is complementary to the typical hydride reduction by aluminum hydrides: diisobutylaluminum hydride (DIBAL) affords the corresponding aldehyde, whereas lithium aluminum hydride 7 (LiAlH 4) gave the primary (Scheme 4). It was found that to perform this hydrodecyanation, the nitrile substrates should have to possess at least one aromatic 1 3 motif as the substituent R ─ R (Scheme 5). Thus, the method allows for concise construction of a tertiary benzylic carbon

Vol.77 No.11 2019 （ 9 ） 1061 we conducted the reactions of the optically active carbonitriles single hydride transfer as well as and via dou- 15 under the present reaction conditions. As shown in ble hydride transfer with C ─ N and C ─ O bond cleavage, respec- Scheme 7, the reactions of (+) ─ 15 and (-) ─ 15 both provided tively, from the transient anionic carbinol amine intermediates hydrodecyanated product 16 with good ratio of chirality reten- (Scheme 9A). 9 Controlled synthesis of aldehydes via single tion. hydride transfer requires keeping tetrahedral anionic carbinol amine intermediates intact before aqueous quench. For this Scheme 7. Decyanation of optically active substrates. purpose, the Winereb amides have been utilized practically with aluminum ─ based hydride reagents as the resulting tetra- hedral intermediates could form more stable 5 ─ membered ring 10 aluminum chelate complexes (Scheme 9B). However, N,O ─ dimethylhydroxylamine, the starting material for preparation of the Winereb amides, is much more expensive than simple amines such as dimethylamine. Therefore, there should be a need for development of practical and cost ─ economical reduc- tion processes for conversion of simpler carboxamides into the Based on these experimental outcomes and the computa- corresponding aldehydes in a controllable manner. 11 ─ 14 tional simulation, we proposed the following reaction mecha- nism for this hydrodecyanation (Scheme 8). The process is Scheme 9. Hydride reduction of amides. most likely initiated by hydride attack to the nitrile moiety from NaH in the presence of LiI, to afford iminyl sodium (or lithium) intermediate A, in which sodium (lithium) cation forms cation ─ π interaction with the aryl moiety. Subsequently, concerted C ─ C bond cleavage ─ 1,2 ─ shift occurs to give the hydrodecyanated product 2 and sodium (or lithium) cya- nide via transition state B, where the imine atom has partial positive charge (δ+) and the benzylic carbon possesses partial negative charge (δ-), and thus the hydrogen is rear- ranged to the adjacent carbon (δ-) via 1,2 ─ proton transfer. Thus, unique umpolung nature is observed during this decyana- tion: the anionic hydrogen (hydride) originated from NaH is altered to the cationic hydrogen (proton) in the later stage. Alternative stepwise pathway including fragmentation of imi- nyl anion A to benzylic carbanion C and hydrogen cyanide (most likely in the THF solvent cage) followed by immediate deprotonation is not ruled out as the mechanistic possibility (Scheme 8B).

Scheme 8. Proposed mechanisms.

In this context, we found that the NaH ─ NaI system enables reduction of N,N ─ dimethylcarboxamide 17 to 4 ─ anisaldehyde (18) in a controlled fashion (Scheme 10). More surprisingly, the reaction at even higher (reux in THF) temperature was still able to afford aldehyde 18 as a single product, indicating extremely stable nature of the resulting anionic carbinol amine intermediate.

Scheme 10. Controlled reduction of amides into aldehydes.

2.2 Controlled Reduction of Amides into Aldehydes 5,8 The discovery of the hydrodecyanation stimulated us to explore use of NaH for other types of hydride reduction. Car- boxamides are bench ─ stable and readily available chemicals, having rich chemical reactivity to undergo a variety of mole- cular transformations. Hydride reduction of carboxamides potentially provides three possible products: aldehydes through

1062 （ 10 ） J. Synth. Org. Chem., Jpn. This protocol was applicable to a wide variety of carbox- tion to form cyclohexanol 29. Similarly, the reduction of keto amides 19 ranging from aromatic and heteroaromatic alde- 30 allowed for isolation of keto aldehyde 31 in good hydes to aliphatic ones regardless of their electronic nature for yield. their controlled reduction into the corresponding aldehydes 20 (Scheme 11). It would be emphasized that the process can be Scheme 14. Chemoselective reduction of amide over . implemented at ambient temperature without special care for the procedure.

Scheme 11. Substrate scope (selected examples).

2.3 Dearylation of Arylphosphine Oxides 17 Among organophosphorus compounds, pentavalent phos- phorous derivatives, oxides, are commonly found very stable (thus less reactive) chemicals and often produced as a co ─ product of various oxidation processes such as the Mitsunobu and Wittig reactions (Scheme 15A, triphenylphos- phine oxide as an example). The process enabling deoxygen- ative reduction of phosphine oxides into is attrac- The reactions with sodium deuteride (NaD) 15 afforded tive. In this context, various covalent hydrides based on deuterated aldehydes in high deuterium incorporation rate boron, 18 aluminum, 19 , 20 and zirconium 21 have been uti- (Scheme 12). This should be one of the most step ─ and atom ─ lized (Scheme 15B), whereas ionic alkali metal hydrides has economical ways to synthesize deuterated aldehydes, which are been underused for this purpose. 22 of use for a variety of applications. 16 Scheme 15. Phosphine oxides. Scheme 12. Deuterium incorporation.

Another practical aspect of this reduction protocol with We became interested in use of our NaH ─ iodide system for the NaH ─ NaI system was the ability in retaining α ─ chirality in chemical reduction of phosphine oxides, with the assumption the reduction of optically active α ─ tertiary amides such as 25 of production of phosphines. However, unexpectedly, the reac- (Scheme 13). tion of triphenylphosphine oxide (32) under the NaH ─ NaI/LiI system afforded dephenylation product, diphenylphosphine Scheme 13. Retention of α ─ chirality. oxide (34), that should be formed via protonation of sodium (lithium) phosphinite 33 during the aqueous workup (Scheme 16A). Seyferth earlier reported dephenylative methyl- ation of triphenylphosphine oxide (32) by the treatment with MeLi (Scheme 16B). 23 In this reaction, methyldiphenylphos- phine oxide (35) and phenyllithium (36) are rstly formed and subsequent deprotonation affords carbanion 37, which can be Moreover, the NaH ─ NaI system showed very unique che- further functionalized with another electrophile such as benzo- moselectivity in reduction of keto amide 27 (Scheme 14). The phenone to form 38. reaction of 27 under the NaH ─ NaI system enabled chemose- Nevertheless, our protocol enabled further functionali- lective reduction of amide over ketone to afford keto aldehyde zation of sodium (lithium) phosphinite 33 with a variety of 28, that subsequently underwent intramolecular aldol cycliza- carbon electrophiles, thus allowing for concise conversion of

Vol.77 No.11 2019 （ 11 ） 1063 Scheme 16. Reductive dearylation of triphenylphosphine oxide. possibility to develop practical hydrodehalogenation of halo- arenes by using NaH as a hydride donor. 25 Although almost no reaction was observed when 2 ─ bromo ─ 6 ─ methoxynaphthalene (46) is treated solely with NaH, the NaH ─ LiI system enabled smooth hydrodebromination at 50 ℃ to form 2 ─ methoxynaph- thalene (47) in good yield (Scheme 19B).

Scheme 19. Discovery of hydrodebromination.

triphenylphosphine oxide (32) into functionalized phosphine oxides 39 (Scheme 17). The method allowed for use of not only 3 primary and secondary alkyl halides (P ─ C (sp ) bond forma- 2 tion via S N2) but also aryl halides (P ─ C (sp ) bond formation The process tolerated a series of electron ─ donating groups via nucleophilic aromatic substitution). (for 49a ─ 49c) as well as an moiety (for 49d) (Scheme 20A). Although the same reduction system could be Scheme 17. Substrate scope (selected examples). used for reduction of tertiary amides into aldehydes (section 2.2), secondary amides was found inert through formation of the corresponding inert amide anion. Thus, the hydrodebromi- nation of 2 ─ bromo ─ N ─ cyclohexylbenzamide (48e) could be performed selectively with keeping the secondary amido moi- ety intact. The reactions of heteroaromatic bromides 48f ─ 48h worked well. The outcomes from several substrates gave the important mechanistic insight. For example, the reaction of 2 ─ bromomesitylene (48i) proceeded smoothly to give debromi- nated mesitylene (49i) in excellent yield, indicating that the benzyne is unlikely involved as a reaction intermediate. More- over, radical probe experiments with ortho ─ butenyl and ortho ─ O ─ allyl substrates 48j and 48k indicated that radical mecha- nism is unlikely operating for the hydrodebromination. Based on these experimental outcomes as well as our kinetic and the-

Scheme 20. Substrate scope (selected examples) and a proposed mechanism.

Interestingly, the method could break dibenzophosphole oxide 40 in a regioselective manner to form phosphinite 41 bearing a biphenyl moiety, which could be further alkylated to form unsymmetrical tertiary biarylphosphine oxide 42 (Scheme 18).

Scheme 18. A reaction of dibenzophosphole oxide.

2.4 Hydrodehalogenation of Haloarenes 24 During the course of our studies on substrate scope for the hydrodecyanation (section 2.1), a reaction of 2 ─ bromo sub- strate 43 was tested (Scheme 19A). The reaction of 43 with NaH and NaI afforded not only hydrodecyanated product 44 but also hydrodebrominated one 45 in 14% and 44% yields, respectively. This unexpected nding stimulated us to explore a

1064 （ 12 ） J. Synth. Org. Chem., Jpn. oretical studies, we proposed concerted nucleophilic aromatic hydridic reaction conditions (for 58d). Interestingly, the reac- 26 substitution (cS NAr) through unprecedented 4 ─ membered tion of α,α,α ─ triphenylacetamide 57g gave benzamide 58g transition state, in which hydride attack to the π ＊─ orbital of without its reduction to the corresponding aldehyde probably 2 the C (sp ) ─ Br bond and elimination of bromide are occurring due to steric hindrance of a bulky ortho ─ diphenylmethyl group almost simultaneously (Scheme 20B). (Scheme 22B). 3． Directed Sodiation 27 Scheme 22. Substrate scope (selected examples). As described in section 2, we discovered that NaH can work as a hydride donor through its solvothermal treatment with NaI or LiI in THF, performing unprecedented hydride reduction of nitriles, amides, arylphosphine oxides, and halo- arenes. In our substrate scope study on the controlled amide reduction, we observed totally unexpected phenomena in the reaction of α ─ arylacetamide 50 (Scheme 21A). The reaction of α ─ arylacetamide 50 with the NaH ─ NaI system resulted in formation of 3 ─ isopropyl ─ 2 ─ naphthaldehyde (51), while expected aliphatic aldehyde 52 was not obtained at all. This nding showed another unique reactivity installed on the NaH with the NaI additive, that is, an enhanced Lewis acidity on the Na cation. Thus, the process was initiated by the formation of amide ─ NaH complex 53 through Lewis acid/base interaction and ensuing ortho ─ deprotonation (sodiation) to form arylso- dium intermediate 54 (Scheme 21B). Subsequent intramole- cular cyclization with the amide carbonyl group formed 4 ─ membered ring anionic carbinolamine 55, which underwent ring ─ opening through C ─ C bond cleavage to generate rela- tively stable benzylic carbanion 56 with formation of the aryl- amide moiety. This is a rare example of 1,3 ─ carbamoyl migra- In turn, treatment of α ─ (2 ─ tolyl) acetamide 59 with the tion through anionic C ─ Fries rearrangement. It should be NaH ─ NaI or LiI system resulted in formation of 2 ─ indanone noted that the reactions of 50 with sec ─ BuLi or LDA, which 60 as a sole product (Scheme 23A). In this case, the reaction are commonly used to induce the anionic Fries rearrangement, was initiated by directed deprotonation at the benzylic position did not provide the corresponding amide (a protonated form (lateral sodiation) from the NaH ─ amide complex 61 to form of intermediate 56). 28 Finally, hydride reduction of the benz- benzyl sodium 62, that underwent nucleophilic cyclization with amide moiety of 56 and protonation led to the formation of amide moiety to give tetrahedral anionic carbinol amine inter- aldehyde 51. mediate 63. Subsequent elimination of formed 2 ─ indanone 60, whereas further hydride reduction of its keto Scheme 21. A proposed reaction mechanism. carbonyl group could be prevented through formation of ind- enyl enolate 64 via deprotonation.

Scheme 23. Synthesis of 2 ─ indanone.

This protocol provided a new concise access to ortho ─ 2° ─ alkyl arylaldehydes 58 from readily available α ─ quaternary α ─ arylacetamides 57 through a multi ─ step sequence of ortho ─ sodiation, 1,3 ─ carbamoyl rearrangement, and controlled Snieckus reported construction of 9 ─ phenanthreol (66) by hydride reduction of the resulting benzamide (Scheme 22A). treatment of biarylamide 65 with LDA (Scheme 24A). 29 The This ortho ─ sodiation selectively occurred at the sterically less reaction proceeds through lateral lithiation to form benzyllith- hindred aromatic C ─ H bond (for 58c). Again, the NaH ─ NaI ium 67 followed by cyclization and aromatization from inter- system tolerated a pyridiyl ring that is sensitive to common mediate 68 with elimination of (C ─ N bond

Vol.77 No.11 2019 （ 13 ） 1065 cleavage). However, our protocol with the NaH ─ iodide system [cyclohexane ─ 1,3’ ─ ] (77). Formation of the latter two was not applicable for this phenanthrenol synthesis: the reac- heterocyclic products was rather surprising: they should be tion of biarylamide 69 with NaH and LiI gave aldehyde 70 constructed presumably via nucleophilic aromatic substitution through hydride reduction of the tertiary amide moiety as the of the methoxy moiety, that is commonly regarded as a poor major product (Scheme 24B). leaving group, by transient iminyl anion 78, where spirocyclic imine 77 is most likely formed rst and then it is reduced to 76. Scheme 24. Synthesis of 9 ─ phenanthreol by lateral lithiation. Scheme 26. Discovery of nucleophilic amination of methoxyarenes.

We were intrigued by the possibility to develop unprece- dented nucleophilic amination of methoxyarenes. 31 For this purpose, we examined use of aliphatic amines as the nucleo- phile, which are readily accessible, as the potential nucleophile. It was found that the NaH ─ LiI system is so effective to pro- mote the desired intramolecular nucleophilic amination of We assumed that secondary amides, which are not reduced methoxyarene 79 tethered with an N ─ benzylamine moiety to by the NaH ─ iodide system (see 49e in Scheme 20), could play a afford indoline 80 in good yield (Scheme 27). role for directed lateral sodiation. As expected, the reaction of secondary amide 71 underwent exclusive lateral sodiation and Scheme 27. Synthesis of indoline. cyclization to form anionic carbinol amine intermediate 72 (Scheme 25). Interestingly, it was found that the iodide additive (either NaI or LiI) differentiates the reaction course from 72: with NaI, C ─ N bold cleavage was observed to form 9 ─ phenan- threnol (66) in 70% yield, whereas the reaction with LiI induced C ─ O bond cleavage to afford 9 ─ phenanthrenamine 73 in 84% yield as the major product.

Scheme 25. Controlled synthesis of 9 ─ phenanthrenol and This amination protocol is capable of constructing a series 9 ─ phenanthrenamine. of ─ heterocycles 82, ranging from indolines (5 ─ mem- bered ring: 82a ─ 82d) and tetrahydroquinolines (6 ─ membered ring: 82e ─ 82h) to medium ─ size ring ones (82i ─ 82l), although yield of 10 membered ─ ring heterocycle 82l was low (Scheme 28). Similarly with hydrodehalogenation of haloarenes (section 2.4), concerted nucleophilic aromatic substitution mechanism was proposed for this nucleophilic amination of methoxy arenes, in which the transient Na amide nucleophile attacks to π ＊─ orbital of methoxyarene to kick out methoxide simultane-

ously (Scheme 29). This cS NAr mechanism could be supported by the DFT calculation and studies on the reaction kinetics. This nucleophilic amination of methoxyarenes could be extended to an intermolecular version. Especially, it is worthy of note that the method enables installation of amine functionality onto the C3 ─ position of pyridines (Scheme 30). 4． Enhanced Brønsted Base Selective C3 ─ amination of pyridines is still challenging: the 4.1 Nucleophilic Amination of Methoxyarenes 30 common nucleophilic aromatic substitution of (pseudo)

Our attempt on hydrodecyanation (section 2.1) of 2 ─ halopyridines with amine nucleophiles via the stepwise S NAr 32,33 methoxyphenyl substrate 74 provided a new insight on totally (addition ─ elimination) mechanism or via the correspond- 34,35 distinct chemical reactivity (Scheme 26). The reaction of 74 ing pyridyne intermediates (elimination ─ addition), which gave not only hydrodecyanated 2 ─ cyclohexylanisole (75) but have thus far been proven successful only for the C2 ─ and C4 ─ also spiro[cyclohexane ─ 1,3’ ─ indoline] (76) and spiro- amination due to the inherent nature of the pyridines or pyri-

1066 （ 14 ） J. Synth. Org. Chem., Jpn. Scheme 28. Substrate scope (selected examples). methoxypyridine (88) with n ─ butylamine (89) under the NaH ─ LiI system, we observed formation of a small amount of C2 ─ aminated pyridine 91 in addition to expected 3 ─ butylamino- pyridine (90) (Scheme 32A). This C2 ─ amination of pyridine 88 should occur via the mechanism of the Chichibabin amination, that has been implemented under harsh reaction conditions 37 and limited to install only a primary amino group ( ─ NH 2). Thus, the formation of C2 ─ aminated pyridine 91 driven us to further investigate the possibility to develop a new protocol of the Chichibabin amination, that could allow for use of various primary alkylamines under milder reaction conditions. We found that the Chichibabin amination of pyridine (92) with n ─ butylamine (89) could be mediated by the NaH ─ LiI system under rather milder reaction temperature of 85 ℃ to form 2 ─ butylaminopyridine (93) in 93% yield (Scheme 32B).

Scheme 32. Discovery of Chichibabin amination.

Scheme 29. A proposed reaction mechanism.

Scheme 30. Substrate scope (selected examples).

The method was versatile in preparation of a series of 2 ─ aminopyridine derivatives of potential use as a ligand of tran- sition metal catalysis. For example, the reaction of pyridine (92) with 1,3 ─ propanediamine (94) provided bis ─ pyridine adduct 95 in 79% yield (Scheme 33A). Double amination of 2,2’ ─ bipyridines 96 offers facile access to 6,6’ ─ diamino ─ 2,2’ ─ bipyridines 97 (Scheme 33B). 38

Scheme 33. Double C ─ H amination. dyne intermediates. This protocol allowed for iterative amination of dime- thoxypyridine such as 85 to install two different amine functionality at C3 and C5 position of 87 (Scheme 31).

Scheme 31. Iterative amination.

5． Conclusion In this account, we discussed our recent works on new use of NaH through its solvothermal treatment with NaI or LiI in 4.2 Chichibabin Amination 36 THF. Our protocol does not need any special requirement or When we examined nucleophile amination of 3 ─ caution to make use of NaH as such a unique hydride donor

Vol.77 No.11 2019 （ 15 ） 1067 (section 2), an enhanced Lewis acid (section 3) and a Brønsted 11） With Dialkylboranes and Aminoborohydride, see: Bailey, C. L.; Joh, base (section 4). We have conducted extensive materials chara- A. Y.; Hurley, Z. Q.; Anderson, C. L.; Singaram, B. J. Org. Chem. 2016, 81, 3619. cterization to elucidate the origin of these reactivies installed 12） With Lithium Diisobutylpiperidinohydroaluminate (LDBPA), see: 39 on NaH with NaI or LiI. Although we have not worked out Woo, S. M.; Kim, M. E.; An, D. K. Bull. Korean Chem. Soc. 2006, 27, the ultimate answer on this question, at this moment, we con- 1913. sider that we are observing the inherent reactivity of NaH 13） With the Schwartz Reagent [Cp 2Zr(H)Cl], see: (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, itself, an activated form of which is freshly generated through 129, 3408. (b) Zhao, Y.; Snieckus, V. Org. Lett. 2014, 16, 390. (c) counter metathesis of the inert state of NaH with NaI/LiI. White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, Our current interest is use of NaH as a potent hydride source 122, 11995. 14） With hydrosilanes, see: (a) Bower, S.; Kreutzer, K. A.; Buchwald, S. L. for generation of other main group metal hydrides through Angew. Chem., Int. Ed. Engl. 1996, 35, 1515. (b) Tinnis, F.; Volkov, A.; 40,41 readily available main group metal halides. It is our strong Slagbrand, T.; Adolfsson, H. Angew. Chem. Int. Ed. 2016, 55, 4562. (c) belief that the leveraging of main group metal hydrides to Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, exploit new molecular transformations continues to ourish 132, 12817. 15） Jenkner, H. US Patent US3116112A, 1953. and thus enhance our synthetic capability. 16） (a) Li, X.; Wu, S.; Chen, S.; Lai, Z.; Luo, H. ─ B.; Sheng, C. Org. Lett. 2018, 20, 1712. (b) Isbrandt, E. S.; Vandavasi, J. K.; Zhang, W.; Acknowledgements Jamshidi, M. P.; Newman, S. G. Synlett 2017, 28, 2851. (c) Kerr, W. J.; Reid, M.; Tuttle, T. Angew. Chem. Int. Ed. 2017, 56, 7808. (d) Niu, This work was supported by funding from Nanyang Tech- G. ─ H.; Hung, P. ─ R.; Chuang, G. J. Asian J. Org. Chem. 2016, 5, 57. (e) nological University (NTU) Singapore and the Singapore Korsager, S.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Ministry of Education (Academic Research Fund Tier 1: Chem. 2013, 78, 6112. (f) Spletstoser, J. T.; White, J. M.; Georg, G. I. Tetrahedron Lett. 2004, 45, 2787. 2015 ─ T1 ─ 001 ─ 040). We thank Prof. Ryo Takita (University of 17） Tejo, C.; Pang, J. H.; Ong, D. Y.; Oi, M.; Uchiyama, M.; Takita, R.; Tokyo) and Prof. Hajime Hirao (City University of Hong Chiba, S. Chem. Commun. 2018, 54, 1782. Kong) for their computational studies on our reactions. 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1068 （ 16 ） J. Synth. Org. Chem., Jpn. J. H.; Kaga, A.; Chiba, S. Chem. Commun. 2018, 54, 10324. PROFILE 31） For synthesis of indolenines, see: Huber, F.; Roesslein, J.; Gademann, K. Org. Lett. 2019, 21, 2560. Derek Yiren Ong completed his undergradu- 32） For use of halopyridines under basic reaction conditions, see: (a) Lin, ate studies in chemistry at Nanyang Techno- Y.; Li, M.; Ji, X.; Wu, J.; Cao, S. Tetrahedron 2017, 73, 1466. (b) logical University (NTU) Singapore in 2013. Bolliger, J. L.; Frech, C. M. Tetrahedron 2009, 65, 1180. (c) After working as an NMR technician at Pasumansky, L.; Hernández, A. R.; Gamsey, S.; Goralski, C. T.; NTU for 2.5 years, he started his PhD work Singaram, B. Tetrahedron Lett. 2004, 45, 6417. (d) Narayan, S.; in the laboratory of Shunsuke Chiba in 2016. Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45, 757. (e) He is currently focusing on chemistry of Kotsuki, H.; Sakai, H.; Shinohara, T. Synlett 2000, 116. (f) Pedersen, main group metal hydrides for methodology E. B.; Carlsen, D. Synthesis 1978, 844. development. 33） For C2 ─ H uorination and subsequent amination of pyridines, see: (a) Fier. P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 10139. (b) Fier, P. S.; Hartwig, J. F. Science 2013, 342, 956. 34） Den Hertog, H. J.; Van Der Plas, H. C., Hetarynes. In Advances in Jia Hao Pang completed his undergraduate Heterocyclic Chemistry Volume 4, 1965; pp 121 ─ 144. studies in chemistry at NTU Singapore in 35） For use of silyltriates for generation of pyridynes, see: (a) Medina, J. 2017 before beginning his PhD work in the M.; Jackl, M. K.; Susick, R. B.; Garg, N. K.; Tetrahedron 2016, 72, laboratory of Shunsuke Chiba at NTU. He is 3629. (b) Goetz, A. E.; Shah, T. K.; Garg, N. K. Chem. Commun. currently focusing on chemistry of main 2015, 51, 34. (c) Goetz, A. E.; Garg, N. K. Nat. Chem. 2013, 5, 54. group metal hydrides for methodology deve- 36） Pang, J. H.; Kaga, A.; Roediger, S.; Lin, M. H.; Chiba, S. Asian J. Org. lopment. Chem. 2019, in press (DOI: 10.1002/ajoc. 201900094R1). 37） For reviews on the Chichibabin reaction, see: (a) van der Plas, H. C.; Adv. Heterocycl. Chem. 2004, 86, 1. (b) McGill, C. K.; Rappa, A. Adv. Shunsuke Chiba earned his PhD in chemistry Heterocycl. Chem. 1988, 44, 1. (c) van der Plas, H. C.; Wozniak, M. in 2006 under supervision of Prof. Koichi Croat. Chem. Acta 1986, 59, 33. (d) Pozharskii, A. F.; Simonov, A. M.; Narasaka at the University of Tokyo. In Doron’kin, V. N. Russ. Chem. Rev. 1978, 47, 1042. 2007, he embarked on his independent career 38） For use of 6,6’ ─ diamino ─ 2,2’bipyridine as a ligand for transition metal as the faculty of NTU Singapore, where he is catalysis, see: (a) Yang, L.; Huang, Z.; Li, G.; Zhang, W.; Cao, R.; currently Professor of Chemistry. His re- Wang, C.; Xiao, J.; Xue, D. Angew. Chem. Int. Ed. 2018, 57, 1968. (b) search group focuses on methodology deve- DiMondo, D.; Thibault, M. F.; Britten, J.; Schlaf, M. Organometallics lopment in the area of synthetic chemistry 2013, 32, 6541. (c) Gotoh, R.; Yamanaka, M. Molecules 2012, 17, and catalysis. 9010. 39） Hong, Z.; Ong, D. Y.; Muduli, S. K.; Too, P. C.; Chan, G. H.; Tnay, Y. L.; Chiba, S.; Nishiyama, Y.; Hirao, H.; Soo, H. S. Chem. Eur. J. 2016, 22, 7108. 40） Ong, D. Y.; Yen, Z.; Yoshii, A.; Imbernon, J. R.; Takita, R.; Chiba, S. Angew. Chem. Int. Ed. 2019, 58, 4992. 41） All of our reactions listed in this account were conducted using 60% dispersion of NaH in mineral oil. NaI and LiI should be dried over

P 2O 5 before use because of their hygroscopic nature.

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