H–D Exchange Deuteration of Arenes at Room Temperature - Organic

2 days ago - ... by platinum group metals on carbon in a mixed solvent of 2-propanol and D2O at room temperature to produce deuterium-labeled arenes...
5 downloads 0 Views 1MB Size
Download PDF
Communication pubs.acs.org/OPRD

Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

H−D Exchange Deuteration of Arenes at Room Temperature Yoshinari Sawama,* Akihiro Nakano, Takumi Matsuda, Takahiro Kawajiri, Tsuyoshi Yamada, and Hironao Sajiki* Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

Downloaded via IOWA STATE UNIV on February 4, 2019 at 21:12:40 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

Scheme 1. Comparison of Deuterations of Benzoic Acid (1a) under Novel and Previous Reaction Conditions

ABSTRACT: Arene nuclei efficiently underwent the hydrogen (H)−deuterium (D) exchange reaction catalyzed by platinum group metals on carbon in a mixed solvent of 2-propanol and D2O at room temperature to produce deuterium-labeled arenes. Platinum on carbon (Pt/C) and iridium on carbon (Ir/C) were applicable catalysts, and the various arenes bearing a carbonyl group, fluorine, phenolic hydroxy group, amino group, or phosphonic acid on the aromatic nucleus were effectively deuterated. Nonheating conditions are valuable for the scalable industrial preparation. KEYWORDS: deuteration, arene, room temperature, platinum group metal, heterogeneous catalyst

using sealed reaction apparatus under an Ar atmosphere (Scheme 1, eq 3).

1. INTRODUCTION Deuterium (D)-labeled compounds are utilized in a wide variety of scientific fields,1 such as mechanistic investigations of organic reactions, tracers in microanalyses, elucidation of drug metabolism, heavy drugs,2 quantitative mass spectrometry analyses,3 etc., because of the specific property of the D atom as a stable isotope of the H atom and the isotope effect, such as the higher bond dissociation energy of the C−D bond in comparison with the corresponding C−H bond. The H−D exchange reaction is a straightforward methodology within various synthetic methods.4,5 We have continuously developed the platinum group metal-catalyzed H−D exchange reactions of various organic compounds based on activation of the catalyst metal using hydrogen gas (H2).6,7 Among them, benzoic acid (1a) was less reactive, and comparatively harsh reaction conditions were required to achieve excellent D contents on its aromatic nucleus (Scheme 1, eqs 1 and 2). H2 is a key activator of Pt metal supported on carbon, and the Pt/ C-catalyzed deuteration of 1a could efficiently proceed in D2O under H2 at atmospheric pressure at 180 °C (Scheme 1, eq 1).6b Platinum group metals on carbon, such as Pt/C, can catalyze the dehydrogenation of secondary alcohols to ketones accompanied by the generation of H2 .8 Therefore, H 2 generated in situ via the Pt/C-catalyzed dehydrogenation8 of 2-propanol (isopropanol, i-PrOH)7 as a secondary alcohol was also utilized as an activator of Pt metal to produce deuteriumlabeled benzoic acid (1a-d5) in a mixed solvent [i-PrOH/chexane (c-Hex)/D2O] at 100 °C (Scheme 1, eq 2).7b c-Hex plays an important role as a cosolvent to increase the solubility of 1a. Here we demonstrate that the deuteration of arenes proceeds smoothly at room temperature under the simply improved reaction conditions without the additional cosolvent © XXXX American Chemical Society

2. RESULTS AND DISCUSSION Benzoic acid (1a) (0.25 mmol) underwent the 10% Pt/C (6 mol %)-catalyzed deuteration in D2O (2 mL) or a mixed solvent (i-PrOH/D2O = 1/2 mL) under a H2 atmosphere in a test tube connected to a H2 balloon at room temperature for 24 h to produce deuterium-labeled benzoic acid (1a-d5) with moderate D contents in low yield (Table 1, entries 1 and 2). H2 could facilitate the hydrogenation of the aromatic nucleus to produce cyclohexanecarboxylic acid as a byproduct, resulting in the low yield of 1a-d5. The deuteration in other mixed solvents (i-PrOH/c-Hex/D2O = 0.1/0.9/2 mL, entry 3; i-PrOH/D2O = 1/2 mL, entry 4) under an Ar atmosphere using an Ar balloon proceeded inefficiently, although the arene reduction as a side reaction was significantly suppressed. Surprisingly, the H−D exchange reaction proceeded smoothly in a test tube tightly sealed with a septum in i-PrOH/D2O (1/ 2 mL) under an Ar atmosphere, and the D contents were dramatically improved (entry 5). Meanwhile, the reactions in a sealed test tube enclosed with H2 or air resulted in low D contents (entries 6 and 7). H2 gas is known to react with O2 in the presence of the platinum group metals to produce H2O2, which is instantaneously degraded to H2O in the presence of the platinum group metal catalyst.9 Therefore, the slight amount of H2 generated by the Pt/C-catalyzed dehydrogenation of i-PrOH was rapidly consumed in the presence of O2 in Special Issue: Japanese Society for Process Chemistry Received: November 20, 2018

A

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Table 1. Optimization of the H−D Exchange Reaction of Benzoic Acid (1a)

Table 2. Catalyst Efficiency

D contents (%)

D contents (%) entry 1b 2 3c 4 5 6 7 8

conditions H2 balloona H2 balloona Ar balloona Ar balloona sealed under Are sealed under H2e sealed under aire under Ar bagf

a 81 96 23 77 95 66 16 94

b 80 95 17 58 94 63 11 94

c 53 78 10 20 86 48 6 87

yield (%) 27d 18d 98 96 >99 55 98 >99

a

The reaction was carried out in an 18 mL test tube connected to a rubber balloon filled with H2 or Ar. bThe reaction was performed in only D2O (2 mL) without i-PrOH. ci-PrOH/c-Hex/D2O (0.1/0.9/2 mL) was used as a mixed solvent. dThe formation of cyclohexanecarboxylic acid as a byproduct was observed. eThe reaction was carried out in an 18 mL test tube that was tightly sealed with a septum after the replacement of the inside air with the corresponding gas. fA gas collecting bag (1 L) was used instead of a rubber balloon.

entry

catalyst

a

b

c

yield (%)

1 2 3a 4 5 6 7 8 9b 10c

10% Pt/C 5% Pt/C 10% Pt/C 10% Pd/C 10% Au/C 10% Rh/C 10% Ru/C 10% Ir/C 10% Ir/C 10% Ir/C

95 94 95 2 0 4 7 95 95 94

94 94 93 0 0 0 4 95 94 94

86 58 70 0 0 0 0 94 93 94

>99 97 >99 (>99)d (>99)d (>99)d >99 >99 >99 89

a

Sodium benzoate (1b) was used as the substrate. bThe reaction was carried out in a 30 mL sealed glass tube under an Ar atmosphere, and the inside pressure was maintained at ca. 1.0 bar during the 24 h reaction. c5 mmol of 1a was used in a 200 mL tightly sealed roundbottom flask. dRecovery of the nonlabeled substrate (1a).

Table 3. Cosolvent Effect air to give the low D contents (entry 7). The sealed conditions could avoid contamination with O2 by the invasion of O2 into the reaction tube (entry 5), while O2 gas could pass through the rubber balloon material to deactivate the deuteration process under the Ar atmosphere using the Ar balloon (entries 3 and 4). The use of a gas collecting bag, in which the inside gas tightly remains, instead of a rubber balloon, also gave high D contents (entry 8). (Photographs of the reaction apparatuses using the rubber balloon, sealed test tube, and gas collecting bag are shown in the Supporting Information.) It was found that 5% Pt/C instead of 10% Pt/C was also applicable, although the D content at the ortho position of 1a was moderately lower (Table 2, entry 1 vs 2). Sodium benzoate (1b) was effectively deuterated in the presence of 10% Pt/C without any influence of the solubility (entry 3). A variety of platinum group metal on carbon catalysts were investigated next. While 10% Pd/C, Au/C, Rh/C, and Ru/C were ineffective (entries 4−7), 10% Ir/C also indicated an excellent catalytic activity to give 1a-d5 with excellent D contents and yield (entry 8). The difference in the catalytic activities of these catalysts was not clearly examined. The deuteration could effectively proceed without any increase of inside pressure (1.0 bar) (entry 9), and the generation of a slight amount of H2 gas could be detected from the inside gas by GC-TCD analysis during the deuteration. During the present deuteration (entry 1), a slight amount of H2 can be generated to activate the platinum metal and promote the deuteration under strictly maintained inactive inside gas (Ar) conditions at room temperature. In particular, inflammable H2 did not accumulate in the reaction apparatus. Additionally, the 5 mmol scale reaction of 1a could be accomplished (entry 10). The use of MeOH or t-BuOH instead of i-PrOH hardly facilitated the desired deuteration (Table 3, entry 1 vs 2 and 3), and the deuteration never proceeded in only D2O without i-PrOH (entry 4). The addition of acetone (1 mL), which is a product of the dehydrogenation of i-PrOH, as a cosolvent of D2O was also ineffective (entry 5). The use of i-PrOD-d8 as a

D contents (%)

a

entry

cosolvent

a

b

c

yield (%)

1 2 3 4 5 6 7

i-PrOH MeOH t-BuOH none acetone i-PrOD-d8 1,4-butanediol

95 12 0 0 0 86 0

95 9 0 0 0 60 0

94 8 0 0 0 64 17

>99 99 (>99)a (>99)a (98)a >99 96

Recovery yield of nonlabeled substrate.

cosolvent gave lower deuteration efficiency compared with the use of i-PrOH (entry 6), and 1,4-butanediol was also ineffective. The Ir/C-catalyzed dehydrogenation of i-PrOH smoothly proceeded to generate H2 for the activation of Ir/C without any byproducts except acetone,8 while the dehydrogenation of i-PrOD-d8 was slower because of the isotope effect. The efficient incorporation of deuterium into 1a was performed within 12 h (Table 4, entry 1 vs 2), and moderate D incorporation was obtained even after 6 h (entry 3). Although the reduction of the Ir/C loading to 3 mol % also maintained the efficient D contents of 1a-d5 (entry 1 vs 4), an Ir/C loading of 1 mol % resulted in significantly decreased deuteration efficiency (entry 5). The reduction of the usage of i-PrOH and D2O to half or quarter could also produce 1a-d5 without significant loss of the D contents (entries 6 and 7). Additionally, the 5 g scale deuteration could be accomplished in the presence of 3 mol % Ir/C to give the desired 1a-d5 with high D contents and quantitative isolated yield (eq 4). The scope of substrates, including fluorinated compounds,10 for the present deuteration was examined using 10% Pt/C B

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Table 4. Effects of Reaction Time, Catalyst Loading, and Solvent Concentration

Scheme 2. Scope of Substrates for Pt/C-Catalyzed Deuterationa

D contents (%) entry

X

Y

Z

time (h)

a

b

c

yield (%)

1 2 3 4 5 6 7

6 6 6 3 1 6 6

1 1 1 1 1 0.5 0.25

2 2 2 2 2 1 0.5

24 12 6 24 24 24 24

95 94 71 94 63 92 90

95 94 44 94 62 90 86

94 92 56 91 58 81 75

>99 98 97 99 >99 97 96

(Scheme 2).11,12 o- or p-Fluorobenzoic acid (1c, 1d) were also efficiently deuterated. Substrates bearing a hydroxy group within the molecule (1e−h) were applicable, and an indole derivative (1i) could be deuterated with moderate D contents. Acetophenone derivatives (1j−m) bearing various functional groups on the aromatic nucleus also underwent the desired deuteration, and benzamides (1n and 1o) and phenylphosphonic acid (1p) were also deuterium-labeled. Additionally, O-tert-butyldimethylsilylphenol (1q) effectively underwent the deuteration without deprotection. Chlorobenzene, bromobenzene, and iodobenzene derivatives could not be applied, as they mainly produced the reduced products. The use of 10% Ir/C instead of 10% Pt/C improved the deuterium efficiencies in some cases (Scheme 3).11 Benzamide (1r), acetanilides (1s−u), acetophenone derivatives (1v), and methyl salicylate (1w) were more efficiently deuterated. The aromatic nuclei of 1-naphthol (1x) and 4,4′-bis(fluorophenyl)methane (1y) were also deuterated. Although the variability of the deuteration-position-dependent deuterium efficiencies cannot be clearly explained, it could depend on the steric hindrance and/or electronic properties of the substrates. The deuteration of salicylic acid (2-hydroxybenzoic acid, 1z) also proceeded effectively in the presence of 10% Ir/C or 10% Pt/C (6 mol %) at room temperature to give multiple deuterium-labeled products (1z-d4) (eq 5). The deuteration efficiency at the 5-position of 1z in the 10% Ir-catalyzed reaction was slightly lower, while the D content at the 6position was somewhat unsatisfactory under the 10% Pt/Ccatalyzed conditions. On the other hand, the mixed use4c,6d of 10% Ir/C and 10% Pt/C (each 3 mol %) obviously improved the D contents at the 5- and 6-positions to give the desired 1zd4 with over 90% D at all of the aromatic carbons. The deuterium-labeling efficiencies of acetanilide derivatives (1t and 1u) and 1-naphthol (1x) could be also improved by the concurrent use of 10% Pt/C and 10% Ir/C (Scheme 3 vs eq 6). The details of the synergic effect using Pt/C and Ir/C are unclear. An advantage of the present deuteration method at room temperature is shown by the deuteration of 4,4′-difluorobenz-

a

The reactions were carried out using 10% Pt/C in an 18 mL test tube that was tightly sealed with a septum under Ar gas. bThe defluorinated product (9%) was obtained as a byproduct.

hydrol (1h). As shown in Scheme 1, the desired deuterated product (1h-d8) was obtained under 10% Pt/C-catalyzed reaction conditions in i-PrOH/D2O at room temperature with high deuteration efficiency and yield. On the other hand, the Pt/C-catalyzed deuteration under atmospheric H2 at 180 °C6b provided only moderate deuterium contents in low yields (10%) as a result of the significant hydrogenolysis of the fluorine and hydroxyl group (eq 7). Furthermore, the use of the mixed solvent (i-PrOH/c-Hex/D2O) at 100 °C7b resulted in lower deuterium incorporation (eq 8).

3. CONCLUSION We have developed the efficient Pt/C- or Ir/C-catalyzed deuteration of aromatic nuclei bearing various functional C

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Scheme 3. Scope of Substrates for Ir/C-Catalyzed Deuterationa

labeled without defluorination. D2O is an inexpensive deuterium source, and the heterogeneous 10% Pt/C or 10% Ir/C can be removed from the reaction mixture by simple filtration. Therefore, the present deuteration is expected to be an alternative for the preparation of useful deuterium-labeled functional materials and useful for the industrial preparation without heating conditions.

4. EXPERIMENTAL SECTION As a representative example, “10% Pt/C (6 mol %)” has the following meaning: 10% w/w platinum on carbon equivalent to 6 mol % as the platinum amount versus the amount of substrate used. Typical Procedure Using Pt/C or Ir/C. Arene (0.25 mmol), 10% Pt/C (29.3 mg, 0.015 mmol, 6 mol %) or 10% Ir/ C (28.9 mg, 0.015 mmol, 6 mol %), i-PrOH (1 mL), and D2O (2 mL) were added to an 18 mL test tube, which was sealed with a septum, and the inside gas was immediately replaced by Ar using a vacuum pump. The reaction mixture was stirred at room temperature for 24 h and then filtered through a membrane filter (Millipore Millex-LH, 0.45 μm) together with AcOEt (20 mL) and H2O (5 mL) to remove the catalyst. The combined filtrates were extracted with AcOEt (20 mL × 3), and the organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel column chromatography if necessary. Typical Procedure Using Pt/C and Ir/C. Arene (0.25 mmol), 10% Pt/C (14.6 mg, 0.0075 mmol, 3 mol %) and 10% Ir/C (14.4 mg, 0.0075 mmol, 3 mol %), i-PrOH (1 mL), and D2O (2 mL) were added to an 18 mL test tube, which was sealed with a septum, and the inside gas was immediately replaced by Ar using a vacuum pump. The reaction mixture was stirred at room temperature for 24 h and then filtered through a membrane filter (Millipore Millex-LH, 0.45 μm) together with AcOEt (20 mL) and H2O (5 mL) to remove the catalyst. The combined filtrates were extracted with AcOEt (20 mL × 3), and the organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel column chromatography if necessary. Scaled-Up Reaction. 1a (5g, 41.0 mmol), 10% Ir/C (2.36 g, 1.23 mmol), i-PrOH (82 mL), and D2O (164 mL) were added to a 500 mL flask, which was sealed with a septum, and the inside gas was immediately replaced by Ar using a vacuum pump. The reaction mixture was stirred at room temperature for 24 h and then filtered through a Celite pad together with AcOEt (300 mL) and H2O (50 mL) to remove the catalyst. The combined filtrates were extracted with AcOEt (300 mL × 3), and the organic layers were dried over Na2SO4 and then concentrated in vacuo. Consequently, 1a-d5 (5.15 g, 40.7 mmol) was obtained in 99% yield.

a

The reactions were carried out using 10% Ir/C in an 18 mL test tube that was tightly sealed with a septum under Ar gas, unless otherwise noted. bThe defluorinated product (4%) was obtained as a byproduct.

groups in a mixed solvent of i-PrOH and D2O at room temperature. The concurrent use of Pt/C and Ir/C was newly developed to improve deuteration efficiencies. Many biochemically useful fluorinated compounds could also be deuteriumD

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

■

Communication

2007, 119, 7890−7911; Angew. Chem., Int. Ed. 2007, 46, 7744−7765. (b) Herbert, J. M. Deuterium Exchange Promoted by Iridium Complexes Formed in situ. J. Labelled Compd. Radiopharm. 2010, 53, 658−661. (c) Sawama, Y.; Monguchi, Y.; Sajiki, H. Efficient H−D Exchange Reactions Using Heterogeneous Platinum-Group Metal on Carbon−H2−D2O System. Synlett 2012, 23, 959−972. (d) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C-H Functionalisation for Hydrogen Isotope Exchange: Angew. Chem., Int. Ed. 2018, 57, 3022−3047. (e) Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. New Gateways to the Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method Utilizing Hydrogen as a Catalyst Activator. Chem. Pharm. Bull. 2018, 66, 21−28. (5) For selected papers on arene deuteration, see: (a) Prechtl, M. H. G.; Hölscher, M.; Ben-David, Y.; Theyssen, N.; Loschen, R.; Milstein, D.; Leitner, W. H/D Exchange at Aromatic and Heteroaromatic Hydrocarbons Using D2O as the Deuterium Source and Ruthenium Dihydrogen Complexes as the Catalyst. Angew. Chem., Int. Ed. 2007, 46, 2269−2272. (b) Duttwyler, S.; Butterfield, A. M.; Siegel, J. S. Arenium Acid Catalyzed Deuteration of Aromatic Hydrocarbons. J. Org. Chem. 2013, 78, 2134−2138. (c) Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Palladium- Catalyzed ortho-Selective C-H Deuteration of Arenes: Evidence for Superior Reactivity of Weakly Coodinated Palladacycles. Angew. Chem., Int. Ed. 2014, 53, 734−737. (d) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Ironcatalysed tritiation of pharmaceuticals. Nature 2016, 529, 195−199. (e) Liang, X.; Duttwyler, S. Efficient Brønsted-Acid-Catalyzed Deuteration of Arenes and Their Transformation to Functionalized Deuterated Products. Asian J. Org. Chem. 2017, 6, 1063−1071. (6) For examples using additional H2 as an activator of metals, see: (a) Sajiki, H.; Ito, N.; Esaki, H.; Maesawa, T.; Maegawa, T.; Hirota, K. Aromatic ring favorable and efficient H−D exchange reaction catalyzed by Pt/C. Tetrahedron Lett. 2005, 46, 6995−6998. (b) Ito, N.; Esaki, H.; Maesawa, T.; Imamiya, E.; Maegawa, T.; Sajiki, H. Pt/ C-catalyzed efficient H−D exchange reaction of aromatic rings and its scope and limitations. Bull. Chem. Soc. Jpn. 2008, 81, 278−286. (c) Ito, N.; Watahiki, T.; Maesawa, T.; Maegawa, T.; Sajiki, H. H−D Exchange Reaction Taking Advantage of a Synergistic Effect of a Heterogeneous Pd and Pt Mixed Catalyst. Synthesis 2008, 2008, 1467−1478. (d) Maegawa, T.; Ito, N.; Oono, K.; Monguchi, Y.; Sajiki, H. Bimetallic Palladium−Platinum on Carbon Catalyzed H−D Exchange Reaction: Synergistic Effect on Multiple Deuterium Incorporation. Synthesis 2009, 2009, 2674−2678. (e) Sajiki, H. In New Horizons of Process Chemistry: Scalable Reactions and Technologies; Tomioka, K., Shioiri, T., Sajiki, H., Eds.; Springer Nature, 2017; pp 29−40. (7) For examples using in situ-generated H2 as an activator of metals, see: (a) Sawama, Y.; Yabe, Y.; Shigetsura, M.; Yamada, T.; Nagata, S.; Fujiwara, Y.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Platinum on Carbon-Catalyzed Hydrodefluorination of Fluoroarenes Using Isopropyl Alcohol-Water-Sodium Carbonate Combination. Adv. Synth. Catal. 2012, 354, 777−782. (b) Sawama, Y.; Yamada, T.; Yabe, Y.; Morita, K.; Shibata, K.; Shigetsura, M.; Monguchi, Y.; Sajiki, H. Platinum on Carbon-Catalyzed H−D Exchange Reaction of Aromatic Nuclei Due to Isopropyl Alcohol-Mediated Self-Activation of Platinum Metal in deuterium oxide. Adv. Synth. Catal. 2013, 355, 1529−1534. (c) Sawama, Y.; Mori, M.; Yamada, T.; Monguchi, Y.; Sajiki, H. Hydrogen Self-Sufficient Arene Reduction to Cyclohexane Derivatives Using a Combination of Platinum on Carbon and 2Propanol. Adv. Synth. Catal. 2015, 357, 3667−3670. (8) (a) Sawama, Y.; Morita, K.; Yamada, T.; Nagata, S.; Yabe, Y.; Monguchi, Y.; Sajiki, H. Direct Deuteration of Acrylic and Methacrylic Acid Derivatives Catalyzed by Platinum on Carbon in Deuterium Oxide. Green Chem. 2014, 16, 3439−3443. (b) Sawama, Y.; Morita, K.; Asai, S.; Kozawa, M.; Tadokoro, S.; Nakajima, J.; Monguchi, Y.; Sajiki, H. Palladium on Carbon-Catalyzed Aqueous Transformation of Primary Alcohols to Carboxylic Acids Based on Dehydrogenation under Mildly Reduced Pressure: Adv. Synth. Catal. 2015, 357, 1205−1210.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00383. Synthetic procedures and spectroscopic data for the products (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yoshinari Sawama: 0000-0002-9923-2412 Tsuyoshi Yamada: 0000-0002-6048-5578 Hironao Sajiki: 0000-0003-2792-6826 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the N.E. CHEMCAT Corp. for the kind gift of the catalysts. This study was partially supported by the Research Foundation for Pharmaceutical Sciences (to Y.S.), a Grant-inAid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) (16K08169 to Y.S.), and a Grant-in-Aid from JSPS (15J01556 to T.Y.).

■

REFERENCES

(1) For reviews, see: (a) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D. J. Metal−catalysed Isotopic Exchange Labelling: 30 Years of Experience in Pharmaceutical R&D. J. Labelled Compd. Radiopharm. 2010, 53, 731−738. (b) Lockley, W. J. S.; Heys, J. R. Metal−catalysed Hydrogen Isotope Exchange Labelling: a brief overview. J. Labelled Compd. Radiopharm. 2010, 53, 635−644. (c) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium− and Tritium−Labelled Compounds: Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57, 1758−1784. (2) (a) Nelson, S. D.; Trager, W. F. The Use of Deuterium Isotope Effects to Probe the Active Site Properties, Mechanism of Cytochrome P450-catalyzed Reactions, and Mechanisms of Metabolically Dependent Toxicity. Drug Metab. Dispos. 2003, 31, 1481−1498. (b) Schneider, F.; Hillgenberg, M.; Koytchev, R.; Alken, R.-G. Enhanced Plasma Concentration by Selective Deuteraion of Rofecoxib in Rats. Arzneim. Forsch. 2006, 56, 295−300. (c) Maltais, F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.; Laitinen, L.; Huang, H.; Liao, S.; Gao, H.; Tsao, H.; Block, E.; Ma, C.; Shawgo, R. S.; Town, C.; Brummel, C. L.; Howe, D.; Pazhanisamy, S.; Raybuck, S.; Namchuk, M.; Bennani, Y. L. In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats. J. Med. Chem. 2009, 52, 7993−8001. (d) Sanderson, K. Big interest in heavy drugs. Nature 2009, 458, 269. (e) Meanwell, N. A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529−2591. (f) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the Label in the Drug: J. Med. Chem. 2014, 57, 3595−3611. (3) (a) Stokvis, E.; Rosing, H.; Beijnen, J. H. Stable Isotopically Labeled Internal Standards in Quantitative Bioanalysis using Liquid Chromatography/Mass Spectrometry: Necessity or Not? Rapid Commun. Mass Spectrom. 2005, 19, 401−407. (b) Hewavitharana, A. K. Matrix Matching in Liquid Chromatography−Mass Spectrometry with Stable Isotope Labelled Internal Standards−Is It Necessary? J. Chromatogr. A 2011, 1218, 359−361. (4) For reviews, see: (a) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The Renaissance of H/D Exchange. Angew. Chem. E

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

(9) Monguchi, Y.; Ida, T.; Maejima, T.; Yanase, T.; Sawama, Y.; Sasai, Y.; Kondo, S.; Sajiki, H. Palladium on Carbon-catalyzed Gentle and Quantitative Combustion of Hydrogen at Room Temperatures. Adv. Synth. Catal. 2014, 356, 313−318. (10) Chloro-, bromo-, and iodoarene derivatives were inapplicable. Deuterium-labeled products with low D contents and/or hydrogenated byproducts were generated. (11) 10% Ir/C was applicable to some substrates that were less reactive under the 10% Pt/C-catalyzed conditions. The comparison of the catalytic activities of 10% Pt/C and 10% Ir/C is described in the Supporting Information. (12) Defluorinated byproducts were generated in some reactions (see the Supporting Information). Heating conditions facilitate defluorination of aromatic fluorides (see ref 7a).

F

DOI: 10.1021/acs.oprd.8b00383 Org. Process Res. Dev. XXXX, XXX, XXX−XXX