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. Author manuscript; available in PMC: 2020 Mar 31.
Published in final edited form as: Adv Synth Catal. 2019 Nov 26;362(2):360–364. doi: 10.1002/adsc.201901419

B(C6F5)3-Catalyzed α-Deuteration of Bioactive Carbonyl Compounds with D2O

Yejin Chang a, Tanner Myers a, Masayuki Wasa a
PMCID: PMC7108789  NIHMSID: NIHMS1570053  PMID: 32256276

Abstract

An efficient deuteration process of α-C–H bonds in various carbonyl-based pharmaceutical compounds has been developed. Catalytic reactions are initiated by the action of Lewis acidic B(C6F5)3 and D2O, converting a drug molecule into the corresponding boron–enolate. Ensuing deuteration of the enolate by in situ-generated D2O+–H then results in the formation of α-deuterated bioactive carbonyl compounds with up to >98% deuterium incorporation.

Keywords: Deuterated drug, Frustrated Lewis pair, Late-stage functionalization, Cooperative catalysis

Exchanging the hydrogen atoms contained in a bioactive compound by deuterium may improve its properties.[1–4] A deuterated drug could have significantly lower rates of metabolism relative to the original molecule because of the kinetic isotope effect, and hence a longer half-life.[1–3] In particular, hydrogen isotope exchange (HIE) reaction targeting α-C–H bonds of bioactive carbonyl compounds is in high demand because of their tendency to undergo deprotonation in vivo and also due to their prevalence in pharmaceuticals.[3a,5–6] α-Deuteration of bioactive ketones have previously been achieved through Lewis base-catalyzed conversion of these molecules into enamine or enol intermediates.[6] Representative methods include α-C–H deuteration of ondansetron (A1) by pyrrolidine and D2O (Scheme 1A).[6b] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed α-deuteration process represents a notable strategy for isotopic labelling of 2-acetylphenothiazine (B1) and two other structurally related drugs (Scheme 1B).[6a] Still, development of a catalyst system for α-deuteration of carbonyl-based drugs that cannot be readily deprotonated by Lewis base catalysts and/or those containing base-sensitive functional groups stands as a significant challenge.[6–8]

Scheme 1.

Scheme 1.

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α-Deuteration of bioactive carbonyl compounds

We began by contemplating a method for α-deuteration of bioactive carbonyl compounds (1) by utilizing a Lewis acidic organoborane that can activate 1 towards deprotonation by D2O (Scheme 1C; I to II).[9–10] A potential complication of this approach is that the Lewis acid may form stable acid–base adducts with D2O as well as Lewis basic functional groups that may be contained in 1.[11–14] The application of frustrated Lewis pairs (FLPs), consisting of strongly Lewis acidic and hindered B(C6F5)3 and various Lewis bases, has emerged as an attractive strategy for overcoming undesired acid–base complexation.[9,12–14] We envisioned that B(C6F5)3 could activate 1,[9] thereby facilitating deprotonation by D2O to generate a boron–enolate and D2O+–H (I to II).[11–12] Ensuing deuteration of the enolate by D2O+–H would afford desired product 2. An alternative mechanistic scenario may entail the in situ formation of Brønsted acidic D2O–B(C6F5)3 which deuterates the carbonyl unit of 1. Ensuing D2O-catalyzed deprotonation of deuterated 1 affords an enol and D2O+–H which could then undergo α-deuteration to give 2 (See the SI for details). Here, we report B(C6F5)3-catalyzed and protecting group free method for α-deuteration of various bioactive carbonyl compounds.

We first set out to identify the reaction conditions for α-deuteration of nabumetone 1a. We probed the ability of B(C6F5)3 and D2O to catalyze the reaction between nabumetone 1a and D2O, generating 2a (Table 1). Treatment of 1a and D2O with 10 mol% B(C6F5)3 and 50 equivalent of D2O at 60, 80 or 100 °C afforded 2a in >95% yield (THF, 12 h); while only 6% of α-C–H bonds were converted to C–D bonds at 60 °C, d-incorporation could be improved to 89–95% at 80 and 100 °C (entries 1–3). When the reaction mixture was heated at 100 °C for 6 hours, 2a was generated with 82% and 83% deuterium incorporation (entry 4). Deuterium incorporation diminished to 75% and 77% with 5.0 mol% of B(C6F5)3 (entry 5). With 10 mol% of B(C6F5)3 and 10 equivalent of D2O there was only 76% and 79% of d-incorporation (entry 6). Less than 7% of labelling occurred without B(C6F5)3 or when less Lewis acidic BPh was used (entries 7–8). Less hindered BF3•OEt2 was found to be a potent catalyst, however 2a was obtained with lower level of d-incorporation (62% and 77%). These findings support the notion that strongly Lewis acidic and hindered B(C6F5)3 together with D2O constitute the most effective combination.[10]

Table 1.

Evaluation of Reaction Parameters [a,b,c]

graphic file with name nihms-1570053-t0005.jpg
entry Lewis acid
(mol%)		 Temperature
(°C)		 d-incorporation (%)
[C1] [C3]
  1 B(C6F5)3(10) 60   6 6
  2 B(C6F5)3(10) 80   89 89
  3 B(C6F5)3(10) 100 93 95
  4d B(C6F5)3(10) 100 82 83
  5 B(C6F5)3(10) 100 75 77
  6e B(C6F5)3(10) 100 76 79
  7 none 100 0 0
  8 BPh3(10) 100 7 <5
  9 BF3•OEt2(10) 100 62 77
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[a]

Conditions: nabumetone (1a, 0.1 mmol), D2O (50 equiv.), Lewis acid (5.0 or 10 mol%), THF (0.2 mL), 100 °C, 12 h.

[b]

Yield and deuterium incorporation level was determined by 1H NMR analysis of unpurified reaction mixtures with mesitylene as the internal standard.

[c]

Green label indicates sites that undergo deuteration.

[d]

The reaction mixture was allowed to stir for 6 h.

[e]

D2O (10 equiv.) was used.

An array of acyclic and cyclic bioactive ketones (1a–1h) underwent efficient deuteration (Table 2). This protocol was found to be compatible with compounds that contain an array of Lewis acid-sensitive functional groups. In addition to the ketone units of 1a–1h, methoxy (1a), theobromine (1b), carboxylic acid (1c), N-alkylamine (1e, 1f, 1g, 1h), and hydroxyl (1e, 1f) moieties were tolerated to give the deuteration products 2a–2h in 46 to >95% yield after purification by silica gel chromatography. Labeling took place with high regioselectivity for α-ketone C–H bonds. No deuterium incorporation at less acidic α-carboxylic acid C–H bond of loxoprofen (1c) was observed. In addition, progesterone which possesses acidic allylic C(6)–H bonds also underwent efficient deprotonation/deuteration at C(6); ensuing deuteration of the resulting enolate at C(4) affords 2d.

Table 2.

Deuteration of Bioactive Ketones [a,b,c]

graphic file with name nihms-1570053-t0006.jpg
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Next, we investigated possible labeling of pharmaceuticals that contain α-ester or α-imino C–H bonds (Scheme 2; 1h–1i). a-Deuteration of clopidogrel 1h gave 2h in 68% yield and 60% d-incorporation. With risperidone 1i, acidic C(9)–H bonds of 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one underwent efficient deuteration to give 2i. These results further demonstrate the tolerance of this deuteration protocol to Lewis acid-sensitive heterocycles such as 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1h) and benzo[d]isoxazole (1i).

Scheme 2.

Scheme 2.

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α-Deuteration of bioactive carbonyl compounds

The method is readily scalable. Reaction of 1.0 g of pentoxifylline 1b (3.6 mmol) or donepezil 1g (2.7 mmol) with D2O afforded 2b and 2g in 74% yield (0.74 g, >95% d-incorporation) and 91% yield (0.91 g, >98% d-incorporation), respectively (Scheme 3; 5.0 mol% B(C6F5)3, 50 equiv. D2O, 18 h, 100 °C).

Scheme 3.

Scheme 3.

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Gram-scale α-deuteration of bioactive ketones

The kinetic profile of α-deuteration of donepezil 1g was monitored through the 1H NMR spectroscopic analysis (Figure 1, see the SI for experimental details). While only 30% of α-carbonyl C–H bonds were converted to C–D bonds when the reaction mixture was allowed to react in the NMR machine for 1 hour, d-incorporation level gradually increased to 90% in 12 hours.

Figure 1.

Figure 1.

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Kinetic profile of α-deuteration of donepezil 1g

In summary, we have designed an efficient and regioselective deuterium labeling protocol of carbonyl C–H bonds in a series of pharmaceuticals. By implementing the cooperative catalytic function of B(C6F5)3 and D2O, we show that it is possible to convert a carbonyl-based drug to the corresponding boron–enolate, and that the same catalyst system can generate a labeling agent from D2O. The principles outlined herein, entailing conversion of carbonyl containing drugs into enolates and its reaction with an in situ generated electrophilic partner, provide a new rational framework for late-stage modification of a drug candidate. Studies along these lines are in progress.

Experimental Section

General Procedure for the Synthesis of 2a

To a 15 mL oven-dried pressure vessel was added nabumetone 1a (0.2 mmol), B(C6F5)3 (10 mol%), THF (0.4 mL), and D2O (10 mmol). The reaction mixture was allowed to stir for 12 hours at 100 °C. Upon completion, the reaction mixture was concentrated in vacuo. After purification by column chromatography (Et2O:hexanes = 1:9), 2a was obtained as a white solid (45 mg, >95% yield).

1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 – 7.07 (m, 2H), 3.89 (d, J = 2.0 Hz, 3H), 3.00 (s, 2H), 2.83 – 2.74 (m, 0.10H, 95%D), 2.13 – 2.08 (m, 0.14H, 95%D); 13C NMR (126 MHz, CDCl3) δ 208.22, 157.26, 157.21, 136.06, 133.06, 132.99, 129.03, 128.87, 128.86, 127.47, 126.92, 126.86, 126.19, 118.76, 105.62, 55.24, 44.58, 44.43, 44.29, 29.60, 29.55; IR (neat) 2931, 1703, 1633, 1604, 1484, 1461, 1391, 1246, 1232, 1161, 1030, 853, 817 cm−1; HRMS (DART) Calcd for C15H12D5O2 (MH+): 234.1537; found: 234.1547.

Supplementary Material

Supporting Information

Acknowledgements

Financial support was provided by the NIH (GM-128695), the Sloan Foundation, and Boston College.

Footnotes

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######

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Supplementary Materials

Supporting Information
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