Introduction

A base-catalyzed reaction that forms a carbon–carbon bond via proton transfer is an ideal reaction for constructing basic molecular skeletons from an atom economical point of view. Over the past decade, several base-catalyzed reactions have been intensively studied; however, available substrates for nucleophilic carbanion formation by deprotonation have been limited to those bearing relatively acidic hydrogens. Organobases, such as TEA (triethylamine) and others, offer relatively mild basicity. On the other hand, organosuperbases, such as phosphazenes and proazaphosphatranes, show stronger basicity and these superbases have recently been utilized in organic synthesis as reagents or catalysts. However, they have often been stoichiometrically employed in synthetic reactions and organosuperbase-catalyzed carbon–carbon bond forming reactions are limited. We focused on their characters, such as strong basicity, and decided to utilize organosuperbases as catalysts for reactions using less reactive substrates as nucleophiles.

During the course of my Ph.D., I have investigated the following organosuperbase-catalyzed carbon-carbon bond forming reactions: (1) Highly efficient organosuperbase-catalyzed Mannich-type reactions of sulfonylimidates, and (2) Development of organosuperbase-catalyzed addition reactions of isonitriles and nitriles as nucleophiles.

1. Highly Efficient Organosuperbase-Catalyzed Mannich-type Reactions of Sulfonylimidates

Over the past two decades, Mannich-type reactions have been widely used for the synthesis of nitrogen-containing compounds. While most of these reactions utilize preformed enolates and their derivatives as nucleophiles for stereoselective reactions, the development of direct-type reactions, i.e., the in situ generation and use of carbonyl nucleophiles, has only recently become a focused area of research. Given the synthetic versatility of esters, the use of these substrates as nucleophiles is especially important. However, there are only a few examples of the use of ester equivalents bearing no activating α-substituents, such as COR or CN. This is due to the high pKa value of the esters α-hydrogen. We have recently developed a reactive ester equivalent, a sulfonylimidate, and successfully applied it to Mannich-type reactions with imines in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) or an alkali earth metal alkoxide or amide, and obtained the desired adducts in good yields with high stereoselectivities. However, catalyst activity was not sufficient for achieving high catalyst turnover number (TON) or turnover frequency (TOF), and substrates were limited to aromatic imines. In order to address these matters, I decided to utilize organosuperbases as catalysts for this reaction. I initially investigated the catalytic activity of organosuperbases in Mannich-type reactions of sulfonylimidates (Table 1). The reactions of 2,5-xylyl sulfonylimidate (1a) and benzaldehyde-derived N-Boc imine (2a) in the presence of organosuperbases, tert-butyliminotri(pyrrolidino)ph osphorane (BTPP) and iBu-proazaphosphatrane (iBu-PAP), (5 mol%) in DMF at 0 oC afforded the desired product in high yields with high selectivities, whilst the reaction time was reduced. Further optimization of the reaction conditions revealed that the catalytic activities of BTPP and iBu-PAP were much higher than that of DBU, and that iBu-PAP showed the highest activity with high diastereoselectivity. The reaction conditions were further optimized, resulting in both highyield and selectivity (93% yield,anti/syn = 98/2; Table 1, entry 7).The optimized conditions werefound to be applicable to a widerange of substrates (Table 2).N-Boc imines derived fromvarious aromatic aldehydesbearing both electron-donatingand -withdrawing substituents,meta- and ortho-substitutedbenzaldehydes, andheteroaromatic aldehydes, allprovided the correspondingdesired adducts in high yieldswith high anti-selectivity. I alsoexamined reactions with aliphaticaldehyde-derived N-Boc imines(Table 2). It is remarkable thatsterically hindered pivalaldehyde-derived N-Bocimine (2h) reacted smoothly to afford the desired adduct in high yield with high selectivity (Table 2, entry 9). However no desired product was obtained when using DBU as the catalyst (Table 2, entry 10). Enolizable aliphatic aldehyde-derived N-Boc imines, including linear aliphatic aldehydes, afforded the desired adducts in high yields with high anti-selectivity. In contrast to the DBU-catalyzed Mannich-type reactions of sulfonylimidates, iBu-PAP showed high catalytic activity for both aromatic and aliphatic aldehyde-derived N-Boc imines. I then conducted a mechanistic investigation of iBu-PAP-catalyzed reactions of sulfonylimidates. To clarify the reaction profile of the iBu-PAP-catalyzed Mannich-type reaction, especially in the early stage, I monitored the reaction using a MIcro-Channeled Cell for Synthesis monitoring (MICCS) (Figure 1). The profiles of the initial stages of the iBu-PAP-catalyzed reaction are summarized in Figure 2. While DBU was used as a base promoter, a linear relationship between time and conversion was observed (Figure 2, dashed line (□)), Figure 2, continuous line (◆) provides confirmation that the iBu-PAP-catalyzed reaction had a clear induction period. A possible explanation for the induction period may be slow deprotonation of the α-hydrogen of the sulfonylimidate due to steric hindrance associated with iBu-PAP. Based on this consideration, we changed the addition order of the substrates in the MICCS-NMR analysis. When N-Boc imine was the last reagent added (Figure 2, dotted line (△)), the reaction proceeded notably faster than for the reaction in which iBu-PAP was added last. In the case of experiment (c) (△) no induction period was observed. This result also suggests that slow deprotonation of the α-hydrogen of the sulfonylimidate is the main reason for the induction period. This acceleration was also observed in the reactions with several N-Boc imines derived from aromatic and aliphatic aldehydes. The mechanistic study indicated that the iBu-PAP worked as an initiator of these reactions; this could suppress undesired side reactions, for example, in cases where N-Boc imines derived from aliphatic aldehydes were employed.

2. Development of Organosuperbase-Catalyzed Addition Reactions of Isonitriles and Nitriles as Nucleophiles.

Having investigation iBu-PAP-catalyzed Mannich-type reactions of sulfonylimidates as nucleophiles, I next applied organosuperbase chemistry to addition reactions of less reactive substrates. While isonitrile (isocyanide) and nitrile are stable and offer synthetic versatility, there are few examples of the use of isonitriles or nitriles bearing no electron-withdrawing groups such as COR and CN at α-position due to the high pKa value of isonitrile or nitrile α-hydrogen. I conducted the reactions using isonitriles or nitriles as nucleophiles via activation of the generally inactive α-hydrogens by employing organosuperbases as cataysts. The reaction of benzylisonitrile (pKa = 27.4) (4) with benzaldehyde (5) in the presence of iBu-PAP (5 mol%) afforded the heterocyclic product, 2-oxazoline, in high yield with good selectivity (Scheme 1, (a)). Benzylisonitile (4) also reacted with the benzaldehyde-derived N-Ph imine (7) to afford the heterocyclic product, 2-imidazoline, in high yield with high selectivity (Scheme 1, (b)). These are rare examples of organosuperbase-catalyzed cycloaddition reactions of benzylisonitrile as a nucleophile for the synthesis of 2-oxazoline and 2-imidazoline. Furthermore, nitriles bearing no electron-withdrawing groups at its α-position, which are less reactive substrates, were successfully employed in the organosuperbase-catalyzed Michael reactions. Compared to simple non-activated nitriles, the relatively reactive benzylnitrile (pKa = 21.9) (9a) reacted with N,N-dimethylcinnamamide (10a), an α,β-unsaturated amide, to afford the desired adduct in high yield with good selectivity (Scheme 2, (a)). On the other hand, in the case of using less reactive acetonitrile (pKa = 31.3) (9b) or propionitrile (pKa = 32.5) (9c), as nucleophiles, the reactions proceeded to afford the desired adducts in moderate yields respectively (Scheme 2, (b)).

Conclusion

In conclusion, by using oraganosuperbases as catalysts, less reactive substrates such as ester equivalents, isonitriles and nitriles were catalytically activated via deprotonation of an α-hydrogen and directly employed as nucleophiles for carbon-carbon bond forming Mannich-type reactions, cycloaddition and Michael reactions.

Table 1. Organosuperbase-catalyzed Mannich-type reactions of sulfonylimidates.

Table 2. Substrate scope: reaction with N-Boc imines derived from aromatic and aliphatic aldehyde.

Figure 1. MICCS

Figure 2. Reaction profile with varying bases monitored by 1H MICCS-NMR spectroscopy.

Scheme 1. Organosuperbase-catalyzed cycloaddition reactions of benzylisonitriles.

Scheme 2. Organosuperbase-catalyzed Michael reactions of nitriles.

本論文は、有機超強塩基触媒を用いる炭素––炭素結合生成反応の開発について、2章に渡って述べたものである。

水素原子の移動のみを伴って炭素––炭素結合を生成する塩基反応は、有機分子の基本骨格を構築する有用な反応であり、原子効率の観点からも理想的である。これまでに様々な塩基を用いる反応が開発されてきたが、近年、リン原子を含み、より強力な塩基性を有するフォスファゼンやプロアザフォスファトランといった有機超強塩基が注目を集めている。しかしながら、これまでこれらの有機超強塩基は主に化学量論量、反応に用いられており、その強塩基性ゆえに触媒再生は困難であると考えられ、有機超強塩基を触媒として用いる炭素—炭素結合生成反応はこれまでほとんど開発されてこなかった。

このような背景のもと、本論文は、強い塩基性や構造修飾が可能な構造を有するなど有機超強塩基の持つ可能性に着目し、有機超強塩基を触媒として用い、酸性度の低い水素原子を有する基質を炭素求核剤として用いる反応の開発を行ったものである。

まず、第1章では、有機超強塩基を触媒として用いるスルホニルイミデートの高効率的Mannich型反応について述べている。これまでに、有用なβ—アミノカルボニル化合物を与えるMannich型反応は広く研究されているが、α位に電子求引性置換基を持たない基質を直接的に用いる反応の例は限られていた。最近になり、当研究室では新規エステル等価体であるスルホニルイミデートを開発し、触媒量の三級塩基もしくはアルカリ土類金属の存在下、イミンとの直接的Mannich型反応が効率良く進行し、高い収率、高い立体選択性をもって目的物が得られることを報告している。しかしながら、その触媒活性は必ずしも十分でなく、また、用いることのできる求電子剤も芳香族アルデヒド由来のイミンに限られていた。本論文はこれらの問題の解決に取り組み、まず、イミンとスルホニルイミデートのMannich型反応において、有機超強塩基であるフォスファゼンBTPPおよびプロアザフォスファトランiBu-PAPが高い触媒活性を有することを見いだしている。BTPP、iBu-PAPのいずれの触媒活性も三級アミンのそれよりも高く、中でもiBu-PAPが最も高い触媒活性を示すことを明らかにしている。本反応は高い基質一般性を有し、電子供与基や電子求引基を有する様々な芳香族アルデヒドばかりでなく、一般に副反応が起こりやすく反応制御が難しいとされている脂肪族アルデヒド由来のN-Bocイミンについても、高い収率、高い立体選択性で対応する目的物が得られることを見いだしている。

さらに本論文では、iBu-PAPを触媒として用いるスルホニルイミデートのMannich型反応の反応機構解析を行っている。フローシステムを導入した核磁気共鳴装置(MICCS-NMR)を用いて反応を詳細に観測し、これまで類似の反応では観測されなかった誘導期の存在を明らかにしている。さらに詳細に反応機構解析を行い、iBu-PAPは反応開始剤として作用し、真の触媒塩基種は生成物塩基とする反応機構を提唱している。

続いて第2章では、イソニトリル、ニトリルを炭素求核剤として用いる触媒的付加反応の開発について述べている。イソニトリルやニトリルは有機合成化学において重要な合成中間体であり、生成物の汎用性の観点からも有益な化合物であるが、そのα位水素原子のpKaは高く、α位に電子求引性置換基を持たないイソニトリルやニトリルを炭素求核剤として直接的反応に用いた例は限られていた。本論文では、有機超強塩基を用いることで、一般に不活性なα位水素原子を活性化させ、イソニトリルやニトリルを炭素求核剤として用いる反応の検討を行っている。その結果、触媒量のiBu-PAPの存在下、ベンジルイソニトリルとベンズアルデヒドや対応するイミンとの付加環化反応が進行し、環化体であるオキサゾールが高い収率、良好な立体選択性をもって得られることを見いだしている。これらは、ベンジルイソニトリルを炭素求核剤として用いる環化付加反応の珍しい例である。さらに、有機超強塩基を触媒として用いるニトリルのMichael反応に適用し、目的の付加体が高い収率、良好な立体選択性をもって得られることを明らかにしている。

以上のように、本論文は、有機超強塩基を触媒として用いることで、エステル等価体であるスルホニルイミデートやイソニトリル、ニトリルといった不活性な基質をα位水素原子の脱プロトン化を経て触媒的に活性化し、炭素求核剤としてMannich型反応、付加環化反応、Michael反応などの炭素––炭素結合生成反応を効率的に行うことができることを明らかにしたものである。なお、本論文は、小林 修、山下恭弘、増田光一郎との共同研究であるが、論文提出者が主体となって分析及び検証を行ったもので、論文提出者の寄与が十分であると判断する。したがって、博士(理学)の学位を授与できると認める。