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Synlett 2024; 35(03): 303-306
DOI: 10.1055/a-2122-8631
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Organic Chemistry Under Visible Light: Photolytic and Photocatalytic Organic Transformations

Photocatalytic 1,4-Addition of Aromatic Aldehydes or Ketones via Umpoled Carbinol Anions

Shintaro Okumura  ∗
a   Institute for Molecular Science (IMS), Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
,
Teruki Takahashi
a   Institute for Molecular Science (IMS), Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
,
Kaoru Torii
a   Institute for Molecular Science (IMS), Okazaki, Aichi 444-8787, Japan
,
Yasuhiro Uozumi  ∗
a   Institute for Molecular Science (IMS), Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
› Author Affiliations

This work was supported by JSPS KAKENHI (Grants JP21K14635 and JP21K18968).
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Abstract

A 1,4-addition reaction of aromatic aldehydes or ketones to electron-deficient olefins was achieved under photocatalytic conditions. In the reaction, an umpoled carbinol anion generated in situ through two successive one-electron reductions of the carbonyl compound reacted nucleophilically with the electron-deficient olefin. Various electron-deficient aromatic aldehydes and ketones successfully underwent the reaction to afford the corresponding γ-functionalized alcohols.


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Key words

1,4-addition reaction - carbinol anions - umpolung - photocatalysis - iridium catalysis - alcohols

Carbonyl chemistry is dominated by nucleophilic addition reactions in which a carbonyl compound (an aldehyde or ketone) serves as an electrophilic carbinol cation synthon to form a secondary or tertiary alcohol product [Scheme [1](a)]. In contrast to the well-investigated conventional chemistry of carbonyl compounds, their umpoled nucleophilic reactivity has been less well explored [Scheme [1](b)].[1] Symmetrization of the carbonyl reactivity, which would permit carbonyl compounds to react as nucleophilic carbinol anions (i.e., carbinol cation/anion umpolung), could open a new avenue in synthetic organic chemistry.

We recently reported the anionic reductive coupling of an aromatic aldehyde or ketone with a second carbonyl compound under photocatalytic conditions [Schemes 1(c) and 1(d)].[2] [3] In these reactions, two successive one-electron reductions of the carbonyl compound generated the corresponding carbinol anion, which reacted nucleophilically with CO2 to give a mandelic acid derivative [Scheme [1](c)] or with an aldehyde or ketone to give an unsymmetric 1,2-diol [Scheme [1](d)]. Our success in this umpoled carbonyl 1,2-addition prompted us to examine the corresponding 1,4-addition reaction [Scheme [1](e)].

Zoom Image
Scheme 1 1,2- and 1,4-additions of aromatic carbonyl compounds via umpoled carbinol anions

1,4-Addition of radical species to electron-deficient olefins, the so-called Giese reaction,[4] [5] is known to take place under photocatalytic conditions.[4c] However, carbinol radicals[6] are not fully compatible with the photocatalytic Giese-type 1,4-addition reaction and often dimerize to form vicinal 1,2-diols (i.e., they undergo pinacol coupling) (Scheme [2]).[7] [8] [9] Indeed, to the best of our knowledge, well-developed research on the photocatalytic intermolecular Giese reaction of carbinol radicals has been limited to the recent pioneering reports of the groups of He and Guan,[10] and Lin.[11] We had good reason to believe that our findings on the photocatalytic generation of carbinol anions through a two-electron reduction of carbonyl substrates should realize an ionic 1,4-addition of carbinols, offering a good alternative to the ketyl Giese reaction.[12]

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Scheme 2 Reactions of carbinol radicals; pinacol dimerization vs ketyl Giese reaction.

First, we examined the reductive 1,4-addition of methyl 4-acetylbenzoate (1a) to acrylonitrile (2A) (Table [1]). The reaction was smoothly promoted by the iridium complex Ir(ppy)2(dtbbpy)PF6 (Ir-PC; ppy = 2-phenylpyridinato; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine) and 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzimidazole (DMBI) in N,N-dimethylacetamide (DMA) in the presence of CO2 gas under blue-light irradiation (λ = 448 nm). CO2 (5 mL) was bubbled for 30 seconds through a solution of Ir-PC (1 mol%), DMBI (2.0 equiv), and acrylonitrile (2A; 5 equiv) in DMA (4 mL).[13] The resulting solution was irradiated with blue light (LEDs; λ = 448 nm) under nitrogen at 20 °C while a solution of methyl 4-acetylbenzoate (1a) in DMA (1 mL) was added dropwise over 80 minutes. Irradiation was continued for a further 70 minutes to give the γ-hydroxybutyronitrile derivative 3aA in 70% NMR yield, along with a trace of the homocoupled dimer 4a (Table [1], entry 1). The best result was achieved with 3.0 equivalents of DMBI, which gave a 92% NMR yield (76% isolated yield) of 3aA (entry 2).[14] Control experiments showed that the Ir catalyst, DMBI reductant, and blue-light irradiation were all essential for the formation of 3aA (entries 3–5). In the absence of CO2, the yield of 3aA decreased to 18% and that of the dimer 4a increased to 37% (entry 6), showing that the undesired homocoupling of ketyl radicals through a one-electron reduction of 1a was the dominant reaction pathway. This is consistent with our earlier findings that CO2 promotes successive one-electron reductions of ketyl radicals to produce carbinol anions.[3] [15]

Table 1 1,4-Addition of Methyl 4-Acetylbenzoate (1a) to Acrylonitrile (2A)a

Entry

Variation

Yieldb (%)

3aA

4a

1

none

70

 1

2

DMBI (3 equiv)

92 (76)

 3

3

without Ir-PC

 0

 0

4

without DMBI

 0

 0

5

without light

 0

 2

6

without CO2

18

37

7c

–

11

45

a A 0.2 M solution of 1a (0.2 mmol) in DMA (1 mL) was added dropwise to a solution of 2A (1.0 mmol), Ir-PC (0.002 mmol), and DMBI (0.4 mmol, 2.0 equiv) in DMA (4 mL), previously bubbled with CO2 (5 mL), under blue LED irradiation (λ = 448 nm) at 20 °C for 2.5 h.

b NMR yield. The isolated yield is shown in parentheses.

c The reaction was carried out according to the conditions reported by He, Guan, and co-workers[10] in the presence of 10 mol% B(C6F5)3, Hantzsch ester (2.0 equiv), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%).

When the reaction was carried out under the photocatalytic ketyl Giese conditions reported by He, Guan and co-workers,[10] with 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6 [dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridinato] and 2.0 equivalents of diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (Hantzsch ester) in the presence of tris(pentafluorophenyl)borane [B(C6F5)3; 10 mol%] as a co-catalyst, the homocoupled dimer 4a was formed as the major product in 45% yield (Table [1], entry 7). Carbonyl substrates for the intermolecular ketyl Giese reaction are limited to electron-rich aromatic compounds and, indeed, electron-deficient 1a underwent a radical pinacol coupling rather than the ketyl Giese reaction, resulting in the formation of the homodimer 4a (entry 7). Consequently, the present ionic 1,4-addition of two-electron-reduced carbinol anions is complementary to the ketyl Giese reaction.

The 1,4-addition reactions of a variety of ketones were then examined (Scheme [3]). 4-Acetylbenzoic acid (1b), with an acidic proton, gave the γ-hydroxybutyronitrile 3bA in a 43% yield (75% NMR yield). Acetophenones 1c and 1d bearing cyano and methylsulfanyl groups, respectively, coupled with 2A to give the corresponding products 3cA and 3dA in yields of 84 and 61%. Substrate 1e, bearing a trifluoromethyl substituent that has a high inductive effect, also underwent the coupling reaction to afford product 3eA in 67% yield. Benzophenones 1f and 1g both coupled with 2A to form products 3fA and 3gA, which contained sterically hindered quaternary carbinol carbons, in yields of 92 and 80%, respectively, showing that an electron-donating methoxy group is also tolerated in the reaction. The 1,4-addition of electron-deficient aromatic aldehydes 1h and 1i, which can readily undergo the radical pinacol coupling, also proceeded under the photocatalytic conditions. Thus, aromatic aldehydes bearing a methyl ester (1h) or cyano group (1i) gave products 3hA and 3iA in isolated yields of 60 and 38% (66% NMR), respectively. α,β-Unsaturated esters and sulfones were also eligible olefins: the 1,4-addition of 1a, 1g, or 2-(trifluoromethyl)benzaldehyde (1j) to tert-butyl acrylate (2B) gave the corresponding γ-hydroxy esters 3aB, 3gB, and 3jB in yields of 51, 56, and 51%, respectively. Phenyl vinyl sulfone (2C) also reacted with 1a to afford the γ-hydroxy sulfone 3aC in 48% (72% NMR) yield.

Zoom Image
Scheme 3 Substrate scope. Reaction conditions: aldehyde or ketone 1 (0.2 mmol), olefin 2 (1.0 mmol, 5.0 equiv), Ir-PC (0.002 mmol, 1 mol %), DMBI (0.6 mmol, 3.0 equiv), DMA (5 mL), CO2 (5 mL, bubbled), blue LED irradiation (λ = 448 nm), 20 °C, 2.5 h. Isolated yields (NMR yields in parentheses) are reported. a DMBI (2.0 equiv) was used.

We then performed a deuteration experiment using D2O, which barely reacts with radical species but reacts readily with anionic species. When the photocatalytic coupling of ketone 1j and enoate 2B was carried out under the standard conditions in the presence of D2O, ketone 1j preferentially reacted with D2O to give the C-deuterated alcohol 5j- d in 69% NMR yield with 96% incorporation of deuterium, along with 4% of the γ-hydroxy ester 3jB (Scheme [4]). This result indicated the intermediacy of a carbinol anion.

Zoom Image
Scheme 4 Deuteration experiment

A plausible reaction mechanism is shown in Scheme [5]. We have previously shown that the first one-electron reduction (to form A), an O-carboxylation (to form B), and a second one-electron reduction (to form C) take place almost simultaneously; these give the carbinol anion C, with suppression of the dimerization of ketyl radical intermediates (pinacol coupling).[3] In the deuteration experiment (Scheme [4]), ketone 1j, rather than olefin 2A, reacted with D2O under the photocatalytic conditions where the second reduction of ketyl radical A should proceed much faster than the ketyl Giese reaction. This strongly suggests that the resulting carbinol anion C reacts ionically with olefin 2 to afford the desired 1,4-addition product.

Zoom Image
Scheme 5 Plausible reaction pathway

In conclusion, we have developed a 1,4-addition reaction of aromatic aldehydes or ketones with electron-deficient olefins under photocatalytic conditions with CO2 as an additive to give the corresponding γ-substituted secondary or tertiary alcohols, respectively, in up to 92% yield. The reaction proceeds via umpoled carbinol anions, generated through two successive one-electron reductions to achieve an ionic 1,4-addition of the carbonyl compound.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2122-8631.
  • Supporting Information

  • References and Notes

  • 2 Okumura S, Uozumi Y. Org. Lett. 2021; 23: 7194
    CrossrefPubMedSearch in Google Scholar
  • 3 Okumura S, Takahashi T, Torii K, Uozumi Y. Chem. Eur. J. 2023; e202300840
    CrossrefPubMed
  • 9 For a photocatalytic intermolecular Giese-type allylation of carbonyl compounds with vinyl sulfones via carbinol radicals, see: Qi L, Chen Y. Angew. Chem. Int. Ed. 2016; 55: 13312
    CrossrefPubMedSearch in Google Scholar
  • 10 Gu J.-Y, Zhang W, Jackson SR, He Y.-H, Guan Z. Chem. Commun. 2020; 56: 13441
    CrossrefPubMedSearch in Google Scholar
  • 11 For an example of a metal–organic layer (MOL)-mediated ketyl Giese addition in which the MOL suppressed the undesired pinacol dimerization, see: Fan Y, You E, Xu Z, Lin W. J. Am. Chem. Soc. 2021; 143: 18871
    CrossrefPubMedSearch in Google Scholar
  • 12 For a report on an ionic 1,4-addition of diaryl ketones using an excess of TiCl4–Mg, see: Pons J.-M, Santelli M. Tetrahedron 1990; 46: 513
    CrossrefSearch in Google Scholar
  • 13 The amount of CO2 that dissolved in the DMA (5 mL) was up to 0.04 M (see the Supplementary Information, Section 2–1).
  • 14 Methyl 4-(3-Cyano-1-hydroxy-1-methylpropyl)benzoate (3aA); Typical Procedure Ir(ppy)2(dtbbpy)PF6 (1.88 mg, 0.0021 mmol, 1 mol%) and DMBI (134.2 mg, 0.60 mmol, 3 equiv) were placed in a 20 mL Schlenk tube equipped with a stirrer bar. The Schlenk tube was filled with N2 by vacuum–refill cycles (×3). DMA (4 mL) was added, and CO2 (5 mL) was bubbled into the solution over 30 s using a syringe pump. A N2 balloon was attached to the Schlenk tube, and acrylonitrile (2A; 52.7 mg, 1.0 mmol, 5 equiv) was added. By using a syringe pump, a solution methyl 4-acetylbenzoate (1a; 35.9 mg, 0.20 mmol) in DMA (1 mL) was added dropwise over 80 min to the reaction mixture under blue-light irradiation (λ = 448 nm) at 20 °C, and the mixture was stirred for a further 70 min. 2 M aq HCl was added and the resulting mixture was extracted with EtOAc (×3). The combined organic phase was washed with water (×2) and brine, then dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography [silica gel, 20–35% EtOAc–hexane (gradient)] to give a white solid; yield: 35.6 mg (0.15 mmol, 76%). IR (ATR): 3454 (m), 2257 (m), 1719 (s), 1279 (s) cm–1. 1H NMR (396 MHz, CDCl3): δ = 8.03 (d, J = 8.6 Hz, 2 H), 7.49 (d, J = 8.6 Hz, 2 H), 3.92 (s, 3 H), 2.46–2.38 (m, 1 H), 2.18 (t, J = 7.7 Hz, 2 H), 2.10–2.02 (m, 1 H), 1.99 (s, 1 H), 1.64 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 166.9, 150.7, 130.0, 129.3, 124.9, 120.0, 73.7, 52.3, 39.5, 30.7, 12.2. HRMS (ESI+): m/z [M + Na]+ calcd for C13H15NNaO3: 256.0944; found: 256.0951.

Corresponding Authors

Shintaro Okumura
Institute for Molecular Science (IMS)
Okazaki, Aichi 444-8787
Japan   

Yasuhiro Uozumi
Institute for Molecular Science (IMS)
Okazaki, Aichi 444-8787
Japan   

Publication History

Received: 02 June 2023

Accepted after revision: 04 July 2023

Accepted Manuscript online:
04 July 2023

Article published online:
14 August 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

  • 2 Okumura S, Uozumi Y. Org. Lett. 2021; 23: 7194
    CrossrefPubMedSearch in Google Scholar
  • 3 Okumura S, Takahashi T, Torii K, Uozumi Y. Chem. Eur. J. 2023; e202300840
    CrossrefPubMed
  • 9 For a photocatalytic intermolecular Giese-type allylation of carbonyl compounds with vinyl sulfones via carbinol radicals, see: Qi L, Chen Y. Angew. Chem. Int. Ed. 2016; 55: 13312
    CrossrefPubMedSearch in Google Scholar
  • 10 Gu J.-Y, Zhang W, Jackson SR, He Y.-H, Guan Z. Chem. Commun. 2020; 56: 13441
    CrossrefPubMedSearch in Google Scholar
  • 11 For an example of a metal–organic layer (MOL)-mediated ketyl Giese addition in which the MOL suppressed the undesired pinacol dimerization, see: Fan Y, You E, Xu Z, Lin W. J. Am. Chem. Soc. 2021; 143: 18871
    CrossrefPubMedSearch in Google Scholar
  • 12 For a report on an ionic 1,4-addition of diaryl ketones using an excess of TiCl4–Mg, see: Pons J.-M, Santelli M. Tetrahedron 1990; 46: 513
    CrossrefSearch in Google Scholar
  • 13 The amount of CO2 that dissolved in the DMA (5 mL) was up to 0.04 M (see the Supplementary Information, Section 2–1).
  • 14 Methyl 4-(3-Cyano-1-hydroxy-1-methylpropyl)benzoate (3aA); Typical Procedure Ir(ppy)2(dtbbpy)PF6 (1.88 mg, 0.0021 mmol, 1 mol%) and DMBI (134.2 mg, 0.60 mmol, 3 equiv) were placed in a 20 mL Schlenk tube equipped with a stirrer bar. The Schlenk tube was filled with N2 by vacuum–refill cycles (×3). DMA (4 mL) was added, and CO2 (5 mL) was bubbled into the solution over 30 s using a syringe pump. A N2 balloon was attached to the Schlenk tube, and acrylonitrile (2A; 52.7 mg, 1.0 mmol, 5 equiv) was added. By using a syringe pump, a solution methyl 4-acetylbenzoate (1a; 35.9 mg, 0.20 mmol) in DMA (1 mL) was added dropwise over 80 min to the reaction mixture under blue-light irradiation (λ = 448 nm) at 20 °C, and the mixture was stirred for a further 70 min. 2 M aq HCl was added and the resulting mixture was extracted with EtOAc (×3). The combined organic phase was washed with water (×2) and brine, then dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography [silica gel, 20–35% EtOAc–hexane (gradient)] to give a white solid; yield: 35.6 mg (0.15 mmol, 76%). IR (ATR): 3454 (m), 2257 (m), 1719 (s), 1279 (s) cm–1. 1H NMR (396 MHz, CDCl3): δ = 8.03 (d, J = 8.6 Hz, 2 H), 7.49 (d, J = 8.6 Hz, 2 H), 3.92 (s, 3 H), 2.46–2.38 (m, 1 H), 2.18 (t, J = 7.7 Hz, 2 H), 2.10–2.02 (m, 1 H), 1.99 (s, 1 H), 1.64 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 166.9, 150.7, 130.0, 129.3, 124.9, 120.0, 73.7, 52.3, 39.5, 30.7, 12.2. HRMS (ESI+): m/z [M + Na]+ calcd for C13H15NNaO3: 256.0944; found: 256.0951.

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Zoom Image
Scheme 1 1,2- and 1,4-additions of aromatic carbonyl compounds via umpoled carbinol anions
Zoom Image
Scheme 2 Reactions of carbinol radicals; pinacol dimerization vs ketyl Giese reaction.
Zoom Image
Scheme 3 Substrate scope. Reaction conditions: aldehyde or ketone 1 (0.2 mmol), olefin 2 (1.0 mmol, 5.0 equiv), Ir-PC (0.002 mmol, 1 mol %), DMBI (0.6 mmol, 3.0 equiv), DMA (5 mL), CO2 (5 mL, bubbled), blue LED irradiation (λ = 448 nm), 20 °C, 2.5 h. Isolated yields (NMR yields in parentheses) are reported. a DMBI (2.0 equiv) was used.
Zoom Image
Scheme 4 Deuteration experiment
Zoom Image
Scheme 5 Plausible reaction pathway