2024 年 72 巻 2 号 p. 234-239
The first lactam-type 2-iodobenzamide catalysts, 8-iodoisoquinolinones 8 (IB-lactam) and 9 (MeO-IB-lactam), were developed. These catalysts have a conformationally rigid 6/6 bicyclic lactam structure and are more reactive than the previously reported catalysts 2-iodobenzamides 4 (IBamide) and 5 (MeO-IBamide) for the oxidation of alcohols. The lactam structure could form an efficient intramolecular I---O interaction, depending on the size of the lactam ring.
Oxidation is one of the most important elementary reactions in organic chemistry and is widely employed for the production of bulk and fine chemicals. Historically, heavy metal oxidants such as chromium(VI), lead(IV), and mercury(II) have been extensively used; however, the high toxicity of these oxidants is a significant drawback to their use, especially in industry. Hypervalent iodine oxidants have recently attracted attention to as an environmentally benign and safe oxidant because they are nonmetallic, less toxic than heavy metals, easy to handle, and usable under mild conditions.1–11) For alcohol oxidation, pentavalent iodine reagents such as 2-iodoxybenzoic acid (IBX)12) and Dess–Martin periodinane (DMP)13) are well known and widely used (Fig. 1), and derivatives of these reagents have been also developed.14–40) However, oxidations using these stoichiometric oxidants require the separation and disposal of organic iodine waste. To achieve more eco-friendly methods, several catalytic hypervalent iodine reactions41–48) using 2-iodobenzoic acid (1),49–51) 2-iodobenzenesulfonic acid,52–54) and their derivatives22,55–63) with terminal oxidants have been reported. In these reactions, iodine(V) species are generated in situ to oxidize alcohols. During our investigation of catalytic hypervalent iodine chemistry,64–75) we recently reported that 2-iodobenzamide 4 (IBamide) could act as a catalyst at room temperature for the oxidation of alcohols 2 and 3 with Oxone (2KHSO5·KHSO4·K2SO4) as the terminal oxidant to form carbonyl compounds 6 and 776) (Chart 1a). Moreover, 2-iodo-5-methoxybenzamide 5 (MeO-IBamide) was shown to be a more reactive catalyst than IBamide.77) However, slightly longer reaction times are still required to complete the reaction, and thus, the development of a more reactive catalyst is desirable. Herein, we report the first lactam-type iodine catalysts, 8-iodoisoquinolinones 8 (IB-lactam) and 9 (MeO-IB-lactam), which can catalyze the oxidation of alcohols at room temperature much faster than IBamides (Chart 1b).
While investigating highly reactive iodobenzamide catalysts 4 and 5,76,77) we encountered the interesting results that the oxidation reaction using IBamide 4 proceeded faster than that using 1 at room temperature, whereas at 70 °C, oxidation using IBamide 4 was slower than that using 1.76) The higher reactivity of 4 at room temperature could be caused by the rapid formation of pentavalent iodine in situ because we observed that the oxidation of 5 to the corresponding pentavalent iodine species was much faster than that of 1 at room temperature.77) We also found that the ortho-relationship between the iodine atom and the amide group was crucial for the reactivity of the catalyst.77) In 2003, Zhdankin et al. synthesized several 2-iodoxybenzamides and showed that these amides have a pseudo-benziodoxole structure in which an intramolecular I---O secondary bond is observed in the solid-state by X-ray crystallographic analysis25) (Fig. 2). They proposed that this structural characteristic would increase the stability of I(V) amides. Recently, attempts have been made to introduce substituents bearing Lewis basicity at the ortho position of the iodine group to stabilize hypervalent iodine compounds.78–90) From these observations and discussions, we developed a working hypothesis to develop more reactive 2-iodobenzamide catalysts. A more efficient intramolecular I---O secondary bond between the iodine atom and amide carbonyl oxygen atom could stabilize the I(V) compound. More stable I(V) could cause the faster oxidation of I(I) to I(V). Faster oxidation of I(I) could lead to faster alcohol oxidation. Based on this hypothesis, we synthesized conformationally rigid five-, six-, and seven-membered lactam derivatives 11, 8, and 18, which were expected to form stronger I---O bonds and examined their reactivities for catalytic alcohol oxidation (Chart 2).
Reagents and conditions: (a) NBS, AIBN, MeCN, reflux, 4 h; (b) i-PrNH2, toluene, room temperature (r.t.), 13 h, 18% (2 steps); (c) NBS, AIBN, CCl4, 80 °C, 16.5 h; (d) NaCN, MeOH-H2O, 50 °C, 5.5 h, 27% (2 steps); (e) NaBH4, NiCl2-6H2O, MeOH, r.t., 8.5 h, 36%; (f) conc. H2SO4, NaNO2, H2O, 0 °C, 0.5 h then KI, 100 °C, 10 min, 54%; (g) NaH, i-PrI, N,N-dimethylformamide (DMF), r.t., 14 h, 71%; (h) NaH, i-PrI, DMF, 80 °C, 15 h, 84%; (i) n-BuLi, tetrahydrofuran (THF), −80 °C, 1 h then I2, −80 °C, 2 h, 92%.
Synthesis of five-membered lactam 11 was started from known methyl 2-methyl-6-iodobenzoate (10).91) Bromination at the benzylic position of 10 under radical conditions using N-bromosuccinimide (NBS) and 2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (azobis(isobutyronitrile), AIBN) and subsequent treatment with 2-aminopropane (isopropylamine) directly afforded the desired five-membered N-isopropylated76) lactam 11 in 18% yield in two steps. Six-membered lactam 8 was prepared from commercially available methyl 6-nitro-2-methylbenzoate (12) in a five-step-conversion. Bromination with a combination of NBS and AIBN, followed by homologation with sodium cyanide, afforded 13 in 27% yield (two steps). Treatment of 13 with sodium borohydride in the presence of nickel(II) chloride reduced both the nitro and cyano groups, and subsequent amidation produced lactam 14 in 36% yield. The Sandmeyer reaction of iodine compound 15 (54%) and the final N-alkylation of 15 by sodium hydride and 2-iodopropane furnished six-membered lactam 8 in 71% yield. Seven-membered lactam 18 was obtained by N-alkylation (84%) of known seven-membered lactam 1692) and subsequent iodination (92%) of the bromo group of the resultant 17 by lithiation with butyl lithium and trapping with iodine.
After preparing lactam derivatives 8, 11, and 18, the oxidation reactions of benzhydrol (2a) to benzophenone (6a) using the synthesized lactams were investigated and compared to the results of the reported oxidation using IBamide 4 under the reported conditions: 0.3 equivalent (equiv.) of the catalyst, 2.5 equiv. of Oxone, and 1 equiv. of Bu4NHSO4 in an 8 : 3 mixture of MeNO2 and water at room temperature (Table 1). When using IBamide 4, the oxidation of 2a was completed within 12 h to give ketone 6a in 98% yield (Entry 1).76,77) A similar reaction using five-membered lactam 11 was slower than that using IBamide 4, and the reaction was not completed within 48 h, with 39% of starting alcohol 2a remaining (Entry 2). In contrast, the reaction with six-membered lactam 8 proceeded much faster than that with 4, requiring only 5.5 h for completion (Entry 3). Seven-membered derivative 18 caused acceleration of the reaction and required 9.5 h for completion (Entry 4). As expected, fixing the direction of the carbonyl group of the benzamide unit as a lactam structure accelerated the oxidation of alcohol; however, the ring size strongly influenced the reaction rate. The best result was obtained using six-membered lactam 8-iodoisoquinolinone 8 (IB-lactam).
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|---|---|---|---|---|
| Entry | Catalyst | Time (h) | Yield (%) | Recovery of 2a (%) |
| 1c) | 4 (IBamide) | 12 | 93 | — |
| 2 | 11 | 48 | < 61 | 39 |
| 3 | 8 (IB-lactam) | 5.5 | 99 | — |
| 4 | 18 | 9.5 | 100 | — |
a) All reactions were performed on a 0.5 mmol scale. b) Isolated yield. c) Ref. 76.
To create a more reactive catalyst, we attempted to functionalize IB-lactam 8. As mentioned above, the introduction of an electron-donating group, such as a methoxy group, at the para-position of the iodine group accelerated the reactivity.64,77) We attempted to synthesize 8-iodo-5-methoxyisoquinolinone 9 and achieved a high yield conversion (Chart 3). The preparation of 9 was initiated by the reduction of 2-methoxyphenylacetonitrile (19) with a combination of sodium borohydride and nickel(II) chloride to give primary amine 20 in 73% yield. Cyclization of the lactam ring was successful using Ohwada’s method.93,94) Carbamate formation of 20 with dimethyl 2,2′-[carbonylbis(oxy)]dibenzoate gave 21 in 84% yield, which was brominated with NBS at the para position of the methoxy group to afford 22 in 98% yield before cyclization. Treatment of 22 with trifluoromethanesulfonic acid (TfOH) led to a Friedel-Crafts type cyclization to give lactam 23 in 86% yield. Finally, the desired 8-iodoisoquinolinone 8 was obtained through iodination of 23 (68%), followed by the N-alkylation of 24 (83%).
Reagents and conditions: (a) NaBH4, NiCl2-6H2O, MeOH, r.t., 2.5 h, 73%; (b) (o-MeO2CPhO)2CO, CH2Cl2, r.t., 12 h, 84%; (c) NBS, MeCN, r.t., 14 h, 98%; (d) TfOH, CH2Cl2, 0 °C, 3.5 h, 86%; (e) n-BuLi, THF, −80 °C, 1 h then I2, 0 °C, 4 h, 68%; (f) NaH, i-PrI, DMF, r.t., 13 h, 83%.
We then examined the oxidation of benzhydrol (2a) using methoxylated lactam 9 as the catalyst and compared the results with those using MeO-IBamide 5 and IB-lactam 8 (Table 1, Entry 3) under the same conditions (Table 2). Although reactions with both 5 and 8 required approximately 6 h to complete the oxidation (Entries 1, 2), methoxy-lactam 9 required a shorter reaction time (3.5 h) (Entry 3). Although a smaller amount (0.1 equiv.) of 9 was used in the reaction (Entry 5), the reaction required 6 h, which was almost the same as that using 0.3 equiv. of 5 or 8.
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|---|---|---|---|---|
| Entry a) | Catalyst | X | Time (h) | Yield (%) |
| 1c) | 5 (MeO-IBamide) | 0.3 | 6 | 93 |
| 2d) | 8 (IB-lactam) | 0.3 | 5.5 | 99 |
| 3 | 9 (MeO-IB-lactam) | 0.3 | 3.5 | 98 |
| 4 | 9 | 0.2 | 5 | 100 |
| 5 | 9 | 0.1 | 6 | 100 |
We found that MeO-IB-lactam 9 was the most reactive among the examined 2-iodobenzamide catalysts, and investigated the oxidation of various secondary alcohols 2b–e and primary alcohols 3a–d with 0.3 equiv. of 9 in the presence of 2.5 equiv. of Oxone and 1 equiv. of Bu4NHSO4 in an 8 : 3 mixture of MeNO2 and water at room temperature (Table 3). The table includes the results of similar oxidation reactions using MeO-IBamide 577) for comparison. Almost all the results showed that the reactions with MeO-IB-lactam 9 were much faster than those with MeO-IBamide 5. The catalyst 9 was stable under the oxidation conditions and it was recovered in 58–98% after reductive treatment, which was similar to 5.77)
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a) All reactions were performed on a 0.5 mmol scale. b) The results obtained for the oxidation using MeO-IBamide 5 are shown in parentheses [Ref. 77]. c) Isolated yield.
For considering the reaction mechanism, we examined an electrospray ionization (ESI)-MS study on the reaction of catalyst 9, Oxone, and Bu4NHSO4 without alcohol. The spectrum of the reaction mixture 1 h after mixing them showed the presence of iodine(III) and iodine(V) species (Supplementary Chart S1). A plausible catalytic cycle for the oxidation of alcohols by hypervalent iodine using IB-lactams 8 and 9 is shown in Chart 4. Monovalent iodines 8 and 9 were oxidized by Oxone to pentavalent iodine species via trivalent iodine. The pentavalent compound can oxidize alcohols to their corresponding carbonyl compounds, and the iodine itself is reduced to a trivalent species. Trivalent iodine can be re-oxidized to pentavalent iodine, which then acts as an oxidant again. The six-membered isoquinolinone structure of IB-lactams forms an efficient intramolecular I---O interaction in hypervalent iodine compounds, and the interaction could stabilize them to achive rapid oxidation to pentavalent iodine species. The overall oxidation of alcohols with IB-lactams should proceed faster than that with IBamdes.
We successfully developed the first lactam-type 2-iodobenzamide catalysts, 8-iodoisoquinolinones 8 (IB-lactam) and 9 (MeO-IB-lactam), which showed higher reactivity than our previously reported 2-iodobenzamide catalysts. These catalysts have a conformationally rigid 6/6 bicyclic lactam structure, which could achieve more efficient intramolecular I---O interactions. The precise role of the lactam structure in catalyst activation remains ambiguous and further studies to clarify the underlying mechanism are actively in progress.
Colorless amorphous solid. 1H-NMR (500 MHz, CDCl3) δ: 7.97 (1H, d, J = 8.0 Hz), 7.16 (1H, dd, J = 7.4, 1.1 Hz), 6.98 (1H, t, J = 7.7 Hz), 5.09 (1H, sept, J = 6.9 Hz), 3.38 (2H, t, J = 6.3 Hz), 2.87 (2H, t, J = 6.3 Hz), 1.19 (6H, d, J = 6.9 Hz); 13C-NMR (126 MHz, CDCl3) δ: 161.5, 141.4, 140.4, 131.5, 130.8, 127.1, 94.9, 44.1, 38.2, 29.7, 19.8; IR (neat, cm−1) ν 2975, 1644, 1586; HR-MS (ESI) Calcd for C12H15INO [M + H]+ 316.0193. Found 316.0192.
8-Iodo-2-isopropyl-5-methoxy-3,4-dihydroisoquinolin-1(2H)-one 9 (MeO-IB-lactam)Yellow amorphous solid. 1H-NMR (500 MHz, CDCl3) δ: 7.89 (1H, d, J = 8.6 Hz), 6.63 (1H, d, J = 8.6 Hz), 5.07 (1H, sept, J = 6.9 Hz), 3.83 (3H, s), 3.34 (2H, t, J = 6.3 Hz), 2.85 (2H, t, J = 6.3 Hz), 1.19 (6H, d, J = 6.9 Hz); 13C-NMR (126 MHz, CDCl3) δ: 161.4, 155.6, 140.8, 131.3, 129.7, 113.8, 82.8, 55.7, 44.0, 37.8, 22.4, 19.8; IR (neat, cm−1) ν 2974, 1643, 1569; HR-MS (ESI) Calcd for C13H17INO2 [M + H]+ 346.0299. Found 346.0299.
Typical Experimental Procedure for the Oxidation of Secondary Alcohols 2a–e:Secondary alcohol 2 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu4NHSO4 (170 mg, 0.50 mmol) in a mixture of MeNO2 (1.6 mL) and water (0.6 mL), followed by Oxone (768 mg, 1.25 mmol) at room temperature (25 °C). After 2 was completely consumed, as indicated by TLC, the resulting mixture was diluted using EtOAc and was washed with water. The organic layer was then washed with saturated aqueous Na2S2O3 and saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure ketone 6 and the catalyst.
Typical Experimental Procedure for the Oxidation of Primary Alcohols 3g–d:Primary alcohol 3 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu4NHSO4 (170 mg, 0.50 mmol) in a mixture of MeNO2 (1.6 mL) and water (0.6 mL), followed by Oxone (768 mg, 1.25 mmol) at room temperature (25 °C). After 3 was completely consumed, as indicated by TLC, the resulting mixture was diluted with EtOAc. The mixture was extracted with a saturated aqueous solution of NaHCO3. The organic layer was then washed with a saturated aqueous solution of Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give catalyst. The aqueous layer was acidified with 10% HCl solution and extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure carboxylic acid 7.
The authors declare no conflict of interest.
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