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Catalytic #-Selective Deuteration of Styrene Derivatives Thomas R. Puleo, Alivia J. Strong, and Jeffrey S Bandar J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12874 • Publication Date (Web): 09 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019
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Journal of the American Chemical Society
Catalytic α-Selective Deuteration of Styrene Derivatives Thomas R. Puleo, Alivia J. Strong and Jeffrey S. Bandar* Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States Supporting Information Placeholder ABSTRACT: We report an operationally simple protocol for
the catalytic α-deuteration of styrenes. This process proceeds via the base-catalyzed reversible addition of methanol to styrenes in DMSO-d6 solvent. The concentration of methanol is shown to be critical for high yields and selectivities over multiple competing side reactions. The synthetic utility of α-deuterated styrenes for accessing deuterium-labeled chiral benzylic stereocenters is demonstrated.
Site-specific incorporation of deuterium into small molecules is frequently practiced to access isotopically labeled compounds with broad utility in chemical research.1 The increased strength of C–D bonds often imparts significant changes in reactivity compared to the C–H isotopologue.2 In the context of medicinal chemistry, deuterium incorporation is a commonly used strategy to alter the absorption, distribution, metabolism and excretion (ADME) properties of drug candidates.1,3 Deuterium-labeled compounds also serve as tracers and analytical standards to help elucidate the mechanism and products of drug metabolism. In synthetic chemistry, deuterium-labeled compounds are widely used for kinetic isotope effect measurements and to track reaction pathways.4 Due to this widespread value, catalytic methods for the direct conversion of C–H bonds into C–D bonds with controlled regioselectivity are in high demand.5 There have recently been significant advances made in selective hydrogen isotope exchange processes, especially at benzylic positions, adjacent to heteroatoms and on aromatic rings.5,6 Meanwhile, the deuteration of alkenes has also been recognized to have high value due to the synthetic and mechanistic utility of isotopically labeled olefins. Although a number of impressive metal-catalyzed deuteration methods have been reported for unactivated alkenes, extension to styrene derivatives is less developed.7 In addition to competing arene C–H activation processes, vinyl positional selectivity increases the challenges associated with selective styrene deuteration.8 Castarlenas and Oro have reported a Rhcatalyzed method that addresses these issues to selectively prepare β,β-dideuterated styrenes.9 Currently, however, an
α-selective styrene deuteration method remains undeveloped. A large and continuously increasing number of enantioselective styrene functionalization reactions provide rapid access to benzylic stereocenters found in pharmaceuticals.10 Given that benzylic C–H bonds are prone to metabolic oxidation11, improved access to α-deuterated styrenes could harness the power of asymmetric functionalization methodologies to prepare chiral C–D isotopologues. Moreover, styrene-α-d1 is amongst the most studied deuterium-labeled alkenes and increased access to its derivatives could facilitate additional mechanistic studies.12 Commonly practiced routes to α-deuterated styrenes involve multistep procedures and use expensive deuteride reagents (e.g. LiAlD4) that limit functional group tolerance.13 An alternative reported method involves the selective hydroalumination of arylalkynes followed by addition of D2O.14 We herein report a practical catalytic protocol for the α-selective deuteration of readily available styrene derivatives (Figure 1). catalytic selective labeling
H
operationally trivial
D
high α-selectivity diverse styrene scope
(this work)
access to d-labeled benzylic stereocenters H X D X R common metabolic oxidation site
vs
R
mechanistic value KIE measurements tracing experiments
potentially improved ADME properties
MS standards
Figure 1. Catalytic α-selective deuteration of styrenes.
We recently reported that the organic superbase P4-t-Bu is a highly active catalyst for the anti-Markovnikov addition of alcohols to styrene derivatives, a reaction controlled by thermodynamic equilibria.15 Our subsequent mechanistic studies revealed that methanol (MeOH) addition in polar solvents leads to an unfavorable equilibrium constant for formation of the ether product. Using the addition of MeOH to 4-(trifluoromethyl)styrene (1) as a model reaction, we
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measured equilibrium yields of β-phenethyl ether 2 of 21% (Keq = 0.20) in m-xylene and 9% (Keq = 0.07) in dimethylsulfoxide (DMSO) at 90 °C (Scheme 1a). This led us to hypothesize that if the forward reaction was run in DMSO-d6 solvent, deuterium scrambling of MeOH to MeOD and reversible addition would result in α-selective styrene deuteration.16 In an initial experiment, P4-t-Bu (10 mol%) catalyzed the α-selective deuteration of 1 in 88% yield with >99% deuterium incorporation (Scheme 1b). We found that KO-t-Bu had similar activity and this base was selected as the preferred catalyst for further studies.17 Scheme 1. Mechanistic experiments leading to the discovery of styrene α-deuteration.
Although conceptually straightforward, the α-deuteration pathway must outcompete multiple facile base-promoted reactions to be generally selective and useful for a broad styrene scope. For example, basic DMSO-d6 solutions are known to readily deuterate weakly acidic arene C–H bonds.20 A potentially larger challenge is avoiding basecatalyzed styrene polymerization or possible SNAr side reactions.21 A final requirement for high α-deuterated styrene yield is that the equilibrium of the alcohol addition reaction must disfavor the β-phenethyl ether. Table 1. Styrene scope for catalytic α-selective deuteration.a
+
Keq =
DMSO-d6 (0.5 M)
in m-xylene
in DMSO
[1] [MeOH]
Keq = 0.20
Keq = 0.07
Br
D
Cl
D
F3C 1-α-d, 86% yieldb >99% α-deuterated I
4-α-d, 90% yield 97% α-deuterated
D
+ F3C
1 (1 equiv)
MeOH (3 equiv)
DMSO-d6
base: P4-t-Bu (88% yield) or KO-t-Bu (87% yield)
1-α-d >99% α-deuterated >99% α-selective
We propose the α-deuteration process proceeds by the pathway outlined in Scheme 2. First, KO-t-Bu catalyzes MeO–H/D exchange with DMSO-d6 and forms KOMe. KOMe then undergoes nucleophilic addition to the styrene with concomitant deuteration of the developing benzylic anion by MeOD, generating partially deuterated β-phenethyl ether 3. Finally, KOMe-catalyzed MeOH elimination from 3 forms the α-deuterated styrene. Mechanistic studies (vide infra) support this sequence of events and the critical role of MeOH.18 We suspect that styrene deuteration is driven to completion by equilibration with excess DMSO-d6.19 Scheme 2. Possible deuteration pathway and challenges.
H Ar
F3CS
D
KOMe
D Ar
H
Ar (3)
KOMe
OMe
competing base-promoted pathways: aromatic C–H deuteration
aromatic C–X SNAr (X = leaving group)
styrene polymerization
β-phenethyl ether formation
D
D
10-α-d, 93% yieldc 97% α-deuterated
11-α-d, 84% yield 97% α-deuterated
D
D
D N
Cl 12-α-d, 79% yield >99% α-deuterated
13-α-d, 83% yield 99% α-deuterated
14-α-d, 83% yield 97% α-deuterated
D
D
D
N N 15-α-d, 78% yieldb 99% α-deuterated
N
16-α-d, 76% yield 97% α-deuterated
17-α-d, 83% yield 95% α-deuterated
D CD3
equilibrium-driven α-deuteration
8-α-d, 74% yield 98% α-deuterated
Ph
9-α-d, 50% yield 95% α-deuterated
MeO–H +
KO-t-Bu
+
D
KOMe
- t-BuOH
DMSO-d6 MeO–D
7-α-d, 63% yield 99% α-deuterated
D
KO-t-Bu
MeO–H
MeO2C 6-α-d, 77% yield 99% α-deuterated
F3C
90 °C, 6 h
D
O Et2N
D
base (10 mol%)
5-α-d, 70% yield 97% α-deuterated
D
b) Exploiting unfavorable equilibrium for selective α-deuteration H
D
F3C
2
[2]
>95% α-deuteration
