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Synthesis 2022; 54(07): 1684-1694
DOI: 10.1055/a-1696-6429
short review

Recent Progress in Chromium-Mediated Carbonyl Addition Reactions

Yuri Katayama
,
Harunobu Mitsunuma  ∗
,
Motomu Kanai  ∗

This work was supported by JSPS KAKENHI Grant Numbers JP17H06441 and JP17H06442 (Hybrid Catalysis) (M.K.), JP20H05843 (Dynamic Exciton) and JP21K15220 (H.M.).
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Abstract

Organochromium(III) species are versatile nucleophiles in complex molecule synthesis due to their high functional group tolerance and chemoselectivity for aldehydes. Traditionally, carbonyl addition reactions of organochromium(III) species were performed through reduction of organohalides either using stoichiometric chromium(II) salts or catalytic chromium salts in the presence of stoichiometric reductants [such as Mn(0)]. Recently, alternative methods emerged involving organoradical formation from readily available starting materials (e.g., N-hydroxyphthalimide esters, alkenes, and alkanes), followed by trapping the radical with stoichiometric or catalytic chromium(II) salts. Such methods, especially using catalytic chromium(II) salts, will lead to the development of sustainable chemical processes minimizing salt wastes and number of synthetic steps. In this review, methods for generation of organochromium(III) species for addition reactions to carbonyl compounds, classified by nucleophiles are described.

1 Introduction

2 Alkylation

2.1 Branch-Selective Reductive Alkylation of Aldehydes Using Unactivated Alkenes

2.2 Linear-Selective Alkylation of Aldehydes

2.2.1 Catalytic Decarboxylative Alkylation of Aldehydes Using NHPI ­Esters

2.2.2 Catalytic Reductive Alkylation of Aldehydes Using Unactivated Alkenes

2.2.3 Alkylation of Aldehydes via C(sp3)–H Bond Functionalization of Unactivated Alkanes

2.3 Catalytic α-Aminoalkylation of Carbonyl Compounds

3 Allylation

3.1 Catalytic Allylation of Aldehydes via Three-Component Coupling

3.2 Catalytic Allylation of Aldehydes via C(sp3)–H Bond Functionalization of Alkenes

4 Propargylation: Catalytic Propargylation of Aldehydes via Three-Component Coupling

5 Conclusion


#

Key words

chromium - nucleophilic addition - aldehyde - photoredox catalyst - radical-polar crossover
1

Introduction

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Yuri Katayama received her bachelor’s degree in pharmaceutical science from The University of Tokyo in 2021 under the supervision of Professor Motomu Kanai. She is currently pursuing her master’s degree in the Graduate School of Pharmaceutical Sciences, The University of Tokyo, under the supervision of Professor Motomu Kanai. Harunobu Mitsunuma was born in 1987 in Tokyo, Japan, and received his Ph.D. from The University of Tokyo in 2015 under the supervision of Professor Motomu Kanai. He joined Dainippon Sumitomo Pharmaceutical Company in 2015. In 2017, he moved to Professor Motomu Kanai’s laboratory at the University of Tokyo as a post-doctoral fellow and became an assistant professor in 2018. His research interest is the development of new synthetic methodology to accelerate drug development. Motomu Kanai graduated from The University of Tokyo in 1989. In the middle of his graduate course, he obtained an assistant professor position in Osaka University in 1992. He received his Ph.D. from Osaka University in 1995. After doing a postdoctoral work in the University of Wisconsin, USA, he was appointed as an associate professor in the University of Tokyo in 1997. He was promoted to full professor in 2010. His research interest is catalysis development linking molecular synthesis and life science.

Nucleophilic addition reactions of organometallic ­reagents to carbonyl compounds are fundamental in organic chemistry.[1] For example, Grignard reagents reported in 1900 are still commonly used today.[2] Due to their high basicity and nucleophilicity, however, Grignard reagents are of low functional group tolerance in general and often not suitable for late-stage uses in complex molecule synthesis.[3] In 1977, Nozaki and Hiyama reported nucleophilic addition of allylchromium(III) to aldehydes.[4] The reaction afforded branched homoallylic alcohols with excellent anti selectivity (Scheme [1a]). Following this report, the same authors’ group including Takai expanded the nucleophile scope.[5] In these works, organochromium(III) species were generated in situ through reduction of organohalides with stoichiometric chromium(II) salts, similarly to the generation of Grignard reagents from organohalides and magnesium(0). In 1986, Nozaki and Kishi independently identified a catalytic amount of nickel(II) salts as an essential component for the generation of alkenylchromium species from alkenyl halides.[6] Due to this series of important contributions, the chromium-mediated nucleophilic addition reactions of organohalides to carbonyl compounds are called Nozaki–­Hiyama–Takai–Kishi reactions (NHTK reactions). A wide range of substrates, such as allyl, alkenyl, aryl, alkyl, alkynyl, and propargyl halides or tosylates can be used in NHTK reactions.[7] Furthermore, Fürstner developed a catalytic version of NHTK reactions by using stoichiometric manganese(0) reductant and TMSCl as additives to regenerate chromium(II) salts from chromium(III) alkoxide intermediates (Scheme [1b]).[8] Fürstner’s work inspired the development of catalytic enantioselective variants of NHTK reaction (Scheme [1c]).[9] [10] Organochromium(III) reagents are less polarized than Grignard reagents, and thus more chemoselective and applicable to the synthesis of multifunctional molecules. These features make NHTK reactions suitable for total synthesis applications.[11] [12] Moreover, chromium salts are inexpensive and of low toxicity in the +2 and +3 oxidation states.[13]

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Scheme 1 Milestones in NHTK reactions

In NHTK reactions, organochromium(III) species are generated through one-electron reduction of organohalides by a chromium(II) salt, followed by interception of the generated organoradicals by another chromium(II) salt.[14] Pioneered by Kochi,[15] rate constants of the organoradical interception by chromium(II) (k1 ) and the homolytic cleavage of carbon–chromium(III) bonds (k2 ) have been reported (Scheme [2]). The interception of organoradicals by chromium(II) is generally very fast (k1 = 107–108 M–1·s–1), and is not much affected by the nature of organic radicals.[16] Rates of homolysis, however, vary depending on organochromium(III). Homolysis does not occur from primary alkylchromium(III), while secondary and tertiary alkylchromium(III) have certain homolysis rates (secondary: k2 = ca. 10–4 s–1, tertiary: k2 = 10–1–10–4 s–1).[17] Destabilization of organochromium(III) species due to steric hindrance, as well as stabilization of the organoradical due to the electronic effects of an α-hetero atom, can dictate the observed tendency. In addition, secondary and tertiary alkylchromium(III) can decompose through β-hydride elimination.[7b] These characteristics of organochromium(III) are consistent with the fact that secondary and tertiary alkylations are less common in NHTK reactions, whereas primary alkylations are more frequently reported.

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Scheme 2 Kinetic parameters for the formation and homolysis of Cr(III)–R bonds

In recent years, various methods for generating organoradicals under mild conditions have been studied, including those utilizing photoredox catalysis.[18] Combining such radical generation with chromium catalysis, novel NHTK-type reactions have been developed. The reductive radical-polar crossover process[19] involving interception of the radical with a chromium(II) salt generates the active organochromium(III) species. This strategy has enabled the use of readily available precursors, instead of organohalides. In this review, we introduce recent progress in chromium-mediated carbonyl addition reactions via organochromium species.


# 2

Alkylation

2.1

Branch-Selective Reductive Alkylation of Aldehydes Using Unactivated Alkenes

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Scheme 3 Branch-selective alkylation of aldehydes using unactivated alkenes

Shenvi developed a method for generating alkylchromium(III) species starting from feedstock alkenes (Scheme [3]).[20] This method enabled alkylation of aldehydes 1 using abundant chemical feedstocks and a silane without prefunctionalization. The reaction began with branch-selective hydrocobaltation of alkene 2 with phenylsilane through metal-hydride hydrogen atom transfer (MHAT) catalysis promoted by 10 mol% Co(salen) and 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate ([F+]).[21] In situ oxidative activation of cobalt(II) to (III) by [F+] gave higher product yield than using the preoxidized Co(salen)Cl catalyst. This is a rare example of branch-selective hydrometalation from electronically unbiased alkenes to produce carbanion equivalents. Alkylchromium(III) species was then formed from the alkylcobalt(III) species via transmetalation with a chromium(II) salt, which was formed from CrCl3 via reduction by the silane. This transmetalation was initiated by electron transfer from chromium(II) salt to the alkyl­cobalt(III) intermediate forming an unstable alkylcobalt(II) species. The alkylcobalt(II) species underwent homolysis to form a secondary alkyl radical, which was quickly intercepted by the chromium(II) salt (k = –107 M–1·s–1).[15] A related alkyl transfer from alkylcobalamines and -cobaloximes to chromium(II) salts was previously reported.[22] The generated stoichiometric alkylchromium(III) species reacted with aldehyde 1 to form the corresponding alcohols 3 (→ 3a–c) after aqueous workup. Since secondary alkylchromium(III) species are known to be unstable and prone to homolysis,[17] this is a rare example of addition reaction of secondary alkylchromium(III) species to carbonyl compounds.[23]


# 2.2

Linear-Selective Alkylation of Aldehydes

2.2.1 Catalytic Decarboxylative Alkylation of Aldehydes Using NHPI Esters

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Scheme 4 Decarboxylative alkylation of aldehydes using NHPI esters

In 2019, Baran developed a chromium-mediated decarboxylative alkylation of aldehydes 1 (Scheme [4]).[24] They used N-hydroxyphthalimide (NHPI) esters 4 prepared in one step from readily available carboxylic acids as radical precursors.[25] One-electron transfer from a chromium(II) salt to an NHPI ester generated alkyl radical 5 after decarboxylation. Radical 5 was captured by the chromium(II) salt to produce alkylchromium(III) species 6, which reacted with aldehydes. The presence of TMSCl increased the yield and afforded TMS-protected alcohols 7 (→ 7a–c) as products. In contrast to Shenvi’s reaction,[20] Baran’s reaction afforded sufficient yield for primary alkylation and only low yield for secondary alkylation.

Electrochemistry promises high atom-economy and scalability in general.[26] Especially for NHTK reactions, electrochemical reduction of chromium(III) regenerated chromium(II) and allowed for the use of catalytic chromium salts. Grigg, Tanaka, and Durandetti reported initial successes.[27] [28] [29] Drawbacks of those initial studies were, however, narrow substrate scope, difficult experimental setups, and use of expensive electrodes such as platinum. Recently, Reisman, Blackmond, and Baran developed electrochemical, catalytic NHTK-type reactions using alkenyl halides and NHPI esters,[25] achieving wide substrate scope with a simple setup (Scheme [5]).[30] The catalytic NHTK protocol using a chemical reducing reagent (Zn, Mn, Mg powder) was not applicable to NHPI esters. They supposed that rapid and selective cathodic reduction of chromium(III) is key to the efficient reaction progress. The reactivity was almost comparable to the previous stoichiometric reaction using the same radical precursor 4 (Scheme [4]), affording corresponding silyl ethers 8 with high functional group tolerance. The combination of an inexpensive aluminum-based sacrificial anode and a nickel-foam cathode were found to be the optimum electrode pair.

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Scheme 5 Catalytic electrochemical alkylation of aldehydes

# 2.2.2

Catalytic Reductive Alkylation of Aldehydes Using Unactivated Alkenes

Kanai and Mitsunuma reported a chromium-catalyzed, linear-selective reductive coupling between aldehydes 1 and unactivated alkenes 9 (Scheme [6]).[31] Hydrozirconation of alkene 9 with Schwartz’s reagent selectively produced linear alkylzirconium 10. Based on Qi’s report, visible light irradiation of 10 generated a primary alkyl radical 11 through homolysis of the C–Zr bond.[32] Alkyl radical 11 was then trapped by the chromium(II) catalyst to form alkylchromium(III) species 12. Nucleophilic addition of 12 to ­aldehyde 1 produced chromium alkoxide 13. Subsequently, 13 underwent ligand exchange with zirconium(IV), which had higher oxophilicity than chromium(III), to afford zirconium(IV) alkoxide 14 and a chromium(III) salt. The chromium(III) salt was reduced to chromium(II) [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE] by zirconium(III) [E 1/2(Cp2ZrCl2/Cp2ZrCl) = −1.63 V vs SCE], thus closing the catalytic cycle. The nucleophilic addition was chemoselective to aldehydes in the presence of other functional groups such as esters and amides, producing corresponding linear alkyl-substituted alcohols 15a–d with high functional group tolerance. Hydrozirconation was also chemoselective at a C=C double bond in the presence of a C≡C triple bond (→ 15b). The reaction was applicable to aliphatic aldehyde (→ 15e) and ketone (→ 15f). When internal alkenes were used as starting materials, the aldehyde addition proceeded at the terminal position affording linear alkylated products by a chain walking process (→ 15g).[33]

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Scheme 6 Catalytic linear-selective alkylation of aldehydes

# 2.2.3

Alkylation of Aldehydes via C(sp3)–H Bond Functionalization of Unactivated Alkanes

If organoradicals are generated through cleavage of C–H bonds in readily available compounds, such radical formation combined with interception by chromium(II) can minimize waste side products. Yahata et al. established a method for generating alkylchromium(III) species via direct C(sp3)–H activation by combining a hydrogen atom transfer (HAT) catalyst and a stoichiometric chromium salt (Scheme [7]).[34] They utilized tetrabutylammonium decatungstate (nBu4N)4[W10O32] (TBADT) as a photoredox catalyst for C(sp3)–H activation of alkanes 16 through a HAT mechanism.[35] The reaction began with abstraction of a hydrogen atom from alkanes to produce alkyl radical 17 by the photoexcited TBADT under 390 nm LED irradiation. Then, a chromium(III) salt was reduced to a chromium(II) salt [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE] by the reduced form of TBADT [E 1/2([W10O32]4–/[W10O32]5–) = –0.97 V vs SCE]. The chromium(II) salt intercepted alkyl radical 17 and generated alkylchromium(III) species 18, which reacted with an aldehyde to give the corresponding alcohol 19 after workup. The method was applicable to a wide range of substrates, such as cycloalkanes, amides and ethers with high chemoselectivity (→ 19a–d).

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Scheme 7 Chromium-mediated alkylation of aldehydes using unactivated alkanes

#
# 2.3

Catalytic α-Aminoalkylation of Carbonyl Compounds

Glorius reported a synthesis of 1,2-amino alcohols 22 from carbonyl compounds 20 and α-silyl amines 21 promoted by a combination of photoredox and chromium catalysts (Scheme [8]).[36] α-Amino carbanions are generally unstable due to destabilization by the lone pair of the nitrogen atom. Therefore, α-aminoalkylation of carbonyl compounds is not common. Glorius’ reaction, however, exhibited high reactivity and functional group tolerance, affording the products from aldehydes, ketones, and an acyl silane. Applications to late-stage functionalization were also demonstrated (→ 22b,c). Taking advantage of the radical mechanism, α-aminoalkylchromium(III) species 23 was generated from 21 by the dual catalysis,[37] at least for the first catalytic cycle [E 1/2(21 •+/21) = 0.4–0.8 V vs SCE in MeCN, E 1/2(*Ir(III)/Ir(II)) = 1.21 V vs SCE in MeCN]. The quantum yield of this dual catalysis was 12.5, suggesting a chain reaction mechanism. To rationalize the observed quantum yield, the authors suggested σ-bond metathesis mechanism for regeneration of 23 from the chromium alkoxide intermediate and 21, after the second catalytic cycle.

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Scheme 8 α-Aminoalkylation of carbonyls by chromium/photoredox dual catalysis

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# 3

Allylation

3.1

Catalytic Allylation of Aldehydes via Three-Component Coupling

Inspired by Takai’s and Zhang’s works on chromium-mediated three-component allylations of aldehydes 1, 1,3-dienes 24, and alkyl iodides,[38] Glorius reported a three-component allylation of 1, 24 and Hantzsch esters 25 by utilizing photoredox/chromium dual catalysis (Scheme [9]).[39] Upon irradiation, the oxidizing photoredox catalyst (PC) in an excited state [4CzIPN: E 1/2(*PC/PC•–) = 1.35 V vs SCE in MeCN] was quenched by 25 (E 1/2 = 1.10 V vs SCE in MeCN). The resulting radical cation extruded alkyl radical 26 with liberating pyridinium (pyH+) through homolytic cleavage of the R2–C bond.[40] The chromium(II) catalyst could trap 26 to produce alkylchromium(III) species 27, but this process was in equilibrium. The addition of 27 to an aldehyde was slow, especially when R2 was a secondary or a tertiary alkyl group. Therefore, alkyl radical 26 reacted with 1,3-diene 24 to produce allyl radical 28 (k = ca. 105 M–1·s–1),[41] which was then trapped by a chromium(II) salt to form allylchromium(III) species 29. The thus-generated 29 existed under equilibrium with its regioisomer. Nucleophilic attack to aldehyde 1, however, proceeded from 29 with ligand-coordinated and sterically-demanding chromium(III) positioned at the terminal carbon via a six-membered Zimmerman–Traxler chair transition state,[42] producing anti-chromium alkoxide 30 with high diastereoselectivity. Alkoxide 30 was protonated by the pyridinium salt (pyH+), which was generated from 25 in the initial step.[43] The chromium(III) salt was reduced to a chromium(II) salt [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE] by the reduced form of the photoredox catalyst [E 1/2(PC/PC•–) = –1.21 V vs SCE in MeCN]. Various 4-alkyl Hantzsch esters 25 were used as alkyl precursors (→ 31a, 31b). The regiocontrol in the addition of alkyl radical 26 to diene 24 was moderate, however, when using an unsymmetric diene (→ 31c). The enantioselective allylation was possible by using chiral bisoxazoline ligand L1, affording product 31d in excellent diastereo- and enantioselectivity.

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Scheme 9 Three-component allylation of aldehydes using chromium/photoredox dual catalysis

Recently, Hao and Shi reported a similar catalytic three-component coupling of aldehydes 1, 1,3-diene 24, and NHPI ester 32 (Scheme [10]).[44] They utilized Hantzsch ester (HE) as a photoactive reductant for the chromium catalyst.[45] Considering the reduction potential of the excited state of HE [E 1/2(HE•+/HE*) = –2.28 V vs SCE],[45] chromium(III) species was reduced by HE* [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE]. The resulting radical cation (HE•+) can further participate in the electron transfer events to produce pyH+. At the same time, alkyl radical 33 was generated by single electron transfer from HE* to 32 via an electron donor-acceptor complex.[46] The subsequent reaction mechanism was the same as Glorius’ three-component coupling (Scheme [9]), yielding product 34. Reactions with various NHPI esters generating primary, secondary, and tertiary alkyl radicals, proceeded smoothly to give homoallylic alcohols in good yield (→ 34a–c). Notably, a useful motif in medicinal chemistry, bicyclo[1.1.1]pentane, was successfully introduced into a bioactive compound derivative 34d.

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Scheme 10 Catalytic three-component allylation of aldehydes promoted by photoexcited Hantzsch ester

# 3.2

Catalytic Allylation of Aldehydes via C(sp3)–H Bond Functionalization of Alkenes

The addition of alkenes to carbonyl compounds is an ideal synthetic method for homoallylic alcohols. Carbonyl-ene reactions are a typical method for this purpose, however, electrophiles are limited to highly activated carbonyl groups, not simple aldehydes or ketones.[47] In 2018, Glorius reported allylation of aldehydes using alkenes and dual photoredox/chromium catalysis (Scheme [11]).[48] The reaction proceeded through direct catalytic generation of allylchromium(III) species from alkenes. Allyl(hetero)arenes and β-alkylstyrenes 35 could be used as allylchromium(III) precursors. The reaction was initiated by oxidation of an alkene 35 with the oxidizing photoexcited iridium(III) catalyst to produce allyl radical cation 36. This one-electron transfer pathway was experimentally supported by Stern–Volmer luminescence quenching analysis. Radical cation 36 was easily deprotonated to produce allyl radical 37. Then, radical 37 was trapped by a chromium(II) salt to form allylchromium(III) species 38. Species 38 added to aldehyde 1 via a six-membered chair transition state to yield chromium alkoxide 39 in an anti-selective fashion. Chromium alkoxide 39 was then protonated to produce the corresponding homoallylic alcohol 40 and a chromium(III) salt, which was reduced to a chromium(II) salt [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE] by an iridium(II) catalyst [E 1/2(Ir(II)/Ir(III)) = –1.37 V vs SCE in MeCN], closing the catalytic cycle. Both aromatic and aliphatic aldehydes were transformed to the corresponding homoallyl alcohols 40 chemoselectively in the presence of ketones and esters. In addition, alkenes bearing various α-position functional groups could be used as precursors of allylchromium(III) species. The reaction proceeded under mild and redox-neutral conditions, demonstrating high functional group tolerance (→ 40a–d).

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Scheme 11 Allylation of aldehydes using alkenes via chromium/photoredox dual catalysis

This dual catalysis was applied to the synthesis of monoprotected homoallylic 1,2-diols by using aldehydes 1 and enol ethers 41 as starting materials (Scheme [12]).[49] Allyl radical 42 was generated via photocatalyzed one-electron oxidation of 41 (E 1/2 {triisopropyl[(2-methylprop-1-en-1-yl)oxy]silane} = 1.64 V vs SCE in MeCN) by the oxidizing excited-state iridium(III) photoredox catalyst [E 1/2(*Ir(III)/Ir(II)) = 1.68 V vs SCE in MeCN]. After trapping the allyl radical by chromium(II), (Z)-γ-silyloxyallylchromium(III) species 43, which was stabilized by coordination of the internal oxygen atom, reacted with an aldehyde 1, affording anti-diol derivative 44. This reaction proceeded with enol ethers bearing various α- and β-substituents.

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Scheme 12 Monoprotected homoallylic 1,2-diol synthesis via dual chromium/photoredox catalysis

Kanai and Mitsunuma reported an asymmetric allylation of aldehydes 1 with unactivated hydrocarbon alkenes 45 using organophotoredox/chiral chromium dual catalysis (Scheme [13]).[50] They utilized acridinium salt PC1 bearing high oxidation potential as a photoredox catalyst [E 1/2(*D-Acr+/D-Acr•) = 2.24 V vs SCE]. Like Glorius’ reactions shown in Schemes 11 and 12, allyl radical 46 was generated from 45 [E 1/2(cyclohexene) = 2.37 V vs SCE] via one-electron oxidation by photoactivated PC1 and subsequent deprotonation. The chiral chromium(II) catalyst captured allyl radical 46 to form chiral allylchromium(III) complex 47, which reacted with aldehyde 1 to give enantiomerically- and diastereomerically-enriched chromium alkoxide 48 via a six-membered chair transition state. Chromium alkoxide 48 was protonated to produce the corresponding homoallylic alcohols 49 (→ 49a–d) and a chromium(III) salt, which was reduced to a chromium(II) salt [E 1/2(Cr(III)/Cr(II)) = –0.41 V vs SCE] by the reduced PC1 [E 1/2(D-Acr+/D-Acr•) = –0.46 V vs SCE]. The addition of magnesium salt [e.g., Mg(ClO4)2] was found to improve the reactivity and enantioselectivity. The rate acceleration by the magnesium salt additive was likely due to stabilization of the radical cation intermediate generated from alkenes by the oxidizing photoredox catalyst. This was supported by the transient absorption spectroscopy.

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Scheme 13 Catalytic asymmetric allylation of aldehydes via dual ­chromium/photoredox catalysis

Although Glorius and Kanai’s achievements have enabled catalytic and direct formation of allylchromium(III) species from alkenes via C–H bond activation, substrate scope of alkenes was limited to relatively electron-rich alkenes such as allyl (hetero)arenes, β-alkylstyrenes, and enol ethers for Glorius’ reaction[48] [49] and cyclic or tri- and tetrasubstituted hydrocarbon alkenes for Kanai’s reaction.[50] Because those reactions began with one-electron abstraction from alkenes by excited photoredox catalysts, the scope of alkenes depended on their oxidation potentials. Feedstock hydrocarbon alkenes containing higher oxidation potentials than excited photoredox catalysts were out of the scope of those reactions, despite their wide availability and synthetic usefulness.

In 2020, Kanai and Mitsunuma’s group expanded the alkene scope by introducing HAT catalysis to the acridinium/chromium complex dual catalysis developed in 2019,[50] constituting a ternary hybrid catalysis (Scheme [14]).[51] As a HAT catalyst, the authors used a sulfur-centered radical (RS•) generated from thiophosphoryl imide (TPI)[52] through one-electron oxidation by the photoexcited acridinium catalyst [E 1/2(*Mes-Acr+/Mes-Acr•) = 2.09 V vs SCE, E 1/2(Mes-Acr•/Mes-Acr+) = –0.58 V vs SCE)].[53] The HAT catalyst abstracted a hydrogen atom from an allylic C–H bond of alkene 50 to give allyl radical 51. This HAT process was feasible based on the bond dissociation energy (BDE) values: BDEs of an allylic C–H bond and an S–H bond are 85 and 87 kcal/mol, respectively. The subsequent mechanism of the allyl radical 51 formation was similar to the previous reports, giving homoallylic alcohols 52 with high anti selectivity.[50]

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Scheme 14 Catalytic asymmetric allylation of aldehydes via chromium/photoredox/HAT ternary hybrid catalysis

Under these conditions, feedstock alkenes 50 including 1-butene and 2-butene, annually produced on a 105 metric ton scale, could be used (→ 52a). The reaction proceeded with various aldehydes 1 containing potentially reactive functional groups, such as amines, sulfides, allyl C–H and benzyloxy C–H bonds (→ 52e–h). Due to high chemoselectivity, the reaction was applicable to functionalized substrates (→ 52i and 52j). Application to the asymmetric variant was possible using chiral BOX ligand L1 (→ 52k; for the structure of L1, see Scheme [9]).


#
# 4

Propargylation: Catalytic Propargylation of Aldehydes via Three-Component Coupling

Glorius developed a three-component carbonyl propargylation using a similar strategy to the allylation developed by the same group (Scheme [9] in Section 3.1), replacing 1,3-dienes with 1,3-enynes as radical acceptors (Scheme [15]).[54] Alkyl radical 26 generated from Hantzsch ester 25 through one-electron oxidation by the excited photoredox catalyst reacted with 1,3-enyne 53, generating a propargyl radical 54, which was trapped by a chromium(II) salt to generate an allenylchromium(III) 55. The C–C bond formation between 55 and aldehyde 1 proceeded through a six-membered cyclic transition state, affording various homopropargylic alcohols 56 (→ 56a–d). The degree of diastereoselectivity was substrate-dependent.

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Scheme 15 Three component propargylation of aldehydes using ­chromium/photoredox dual catalysis

# 5

Conclusion

Since the discovery of NHTK reactions in 1977, a number of nucleophilic addition reactions of organochromium(III) species to carbonyl compounds have been developed. Organochromium(III) species are especially versatile for natural product synthesis due to their high functional group tolerance and chemoselectivity for aldehydes. Originally, organochromium(III) species were prepared from the corresponding organohalides and chromium(II) salts, and the overall carbonyl addition is a reductive process. Recently, alternative methods using radical-polar crossover strategy have emerged, in which radicals generated from readily available starting materials act as precursors of organochromium(III). Further, electrochemistry and photoredox catalysis have enabled catalytic turnover of chromium, making the overall carbonyl addition process redox-neutral. The field is still at the initiation stage, however. For example, although allylchromium(III) species can now be generated from feedstock alkenes through C–H activation by a ternary hybrid catalysis (Scheme [14]), an excess of alkenes is generally required in solvent amounts for synthetically useful conversions. This hampers application of complex alkenes as substrates, which are synthesized through multiple steps. Further studies are necessary to overcome these new hurdles. Such research will open up new catalytic carbonyl addition chemistry beyond NHTK reactions, and more broadly Barbier–Grignard reactions.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Publication History

Received: 26 October 2021

Accepted after revision: 15 November 2021

Accepted Manuscript online:
15 November 2021

Article published online:
27 January 2022

© 2021. Thieme. All rights reserved

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Yuri Katayama received her bachelor’s degree in pharmaceutical science from The University of Tokyo in 2021 under the supervision of Professor Motomu Kanai. She is currently pursuing her master’s degree in the Graduate School of Pharmaceutical Sciences, The University of Tokyo, under the supervision of Professor Motomu Kanai. Harunobu Mitsunuma was born in 1987 in Tokyo, Japan, and received his Ph.D. from The University of Tokyo in 2015 under the supervision of Professor Motomu Kanai. He joined Dainippon Sumitomo Pharmaceutical Company in 2015. In 2017, he moved to Professor Motomu Kanai’s laboratory at the University of Tokyo as a post-doctoral fellow and became an assistant professor in 2018. His research interest is the development of new synthetic methodology to accelerate drug development. Motomu Kanai graduated from The University of Tokyo in 1989. In the middle of his graduate course, he obtained an assistant professor position in Osaka University in 1992. He received his Ph.D. from Osaka University in 1995. After doing a postdoctoral work in the University of Wisconsin, USA, he was appointed as an associate professor in the University of Tokyo in 1997. He was promoted to full professor in 2010. His research interest is catalysis development linking molecular synthesis and life science.
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Scheme 1 Milestones in NHTK reactions
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Scheme 2 Kinetic parameters for the formation and homolysis of Cr(III)–R bonds
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Scheme 3 Branch-selective alkylation of aldehydes using unactivated alkenes
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Scheme 4 Decarboxylative alkylation of aldehydes using NHPI esters
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Scheme 5 Catalytic electrochemical alkylation of aldehydes
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Scheme 6 Catalytic linear-selective alkylation of aldehydes
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Scheme 7 Chromium-mediated alkylation of aldehydes using unactivated alkanes
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Scheme 8 α-Aminoalkylation of carbonyls by chromium/photoredox dual catalysis
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Scheme 9 Three-component allylation of aldehydes using chromium/photoredox dual catalysis
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Scheme 10 Catalytic three-component allylation of aldehydes promoted by photoexcited Hantzsch ester
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Scheme 11 Allylation of aldehydes using alkenes via chromium/photoredox dual catalysis
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Scheme 12 Monoprotected homoallylic 1,2-diol synthesis via dual chromium/photoredox catalysis
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Scheme 13 Catalytic asymmetric allylation of aldehydes via dual ­chromium/photoredox catalysis
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Scheme 14 Catalytic asymmetric allylation of aldehydes via chromium/photoredox/HAT ternary hybrid catalysis
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Scheme 15 Three component propargylation of aldehydes using ­chromium/photoredox dual catalysis