Catalytic α-Selective Deuteration of Styrene Derivatives

Article abstract of DOI:10.1021/jacs.8b12874

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.

Full text of DOI:10.1021/jacs.8b12874

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Communication
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
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α
Catalytic -Selective Deuteration of Styrene Derivatives
Thomas R. Puleo, Alivia J. Strong and Jeffrey S. Bandar*
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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 pro-
ceeds via the base-catalyzed reversible addition of methanol
to styrenes in DMSO-d6 solvent. The concentration of meth-
anol 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.
α-selective styrene deuteration method remains undevel-
oped.
A large and continuously increasing number of enantiose-
lective styrene functionalization reactions provide rapid ac-
cess to benzylic stereocenters found in pharmaceuticals.10
Given that benzylic C–H bonds are prone to metabolic oxi-
dation11, improved access to α-deuterated styrenes could
harness the power of asymmetric functionalization method-
ologies to prepare chiral C–D isotopologues. Moreover, sty-
rene-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 fol-
lowed by addition of D2O.14 We herein report a practical
catalytic protocol for the α-selective deuteration of readily
available styrene derivatives (Figure 1).
Site-specific incorporation of deuterium into small mole-
cules 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, distribu-
tion, metabolism and excretion (ADME) properties of drug
candidates.1,3 Deuterium-labeled compounds also serve as
tracers and analytical standards to help elucidate the mecha-
nism and products of drug metabolism. In synthetic chemis-
try, deuterium-labeled compounds are widely used for kinet-
ic isotope effect measurements and to track reaction path-
ways.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
operationally trivial
high α-selectivity
catalytic
selective
labeling
H
D
diverse styrene scope
(this work)
access to d-labeled benzylic stereocenters
mechanistic value
H
D
X
X
KIE measurements
tracing experiments
MS standards
R
R
There have recently been significant advances made in se-
lective 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 compet-
ing arene C–H activation processes, vinyl positional selectivi-
ty increases the challenges associated with selective styrene
deuteration.8 Castarlenas and Oro have reported a Rh-
catalyzed method that addresses these issues to selectively
vs
potentially improved
ADME properties
common metabolic
oxidation site
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
prepare β,β-dideuterated styrenes.9 Currently, however, an
1
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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 dimethyl-
sulfoxide (DMSO) at 90 °C (Scheme 1a). This led us to hy-
pothesize that if the forward reaction was run in DMSO-d6
solvent, deuterium scrambling of MeOH to MeOD and re-
versible addition would result in α-selective styrene deuter-
ation.16 In an initial experiment, P4-t-Bu (10 mol%) catalyzed
Page 2 of 6
Although conceptually straightforward, the α-deuteration
pathway must outcompete multiple facile base-promoted
reactions to be generally selective and useful for a broad sty-
rene 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 base-
catalyzed styrene polymerization or possible SNAr side reac-
tions.21 A final requirement for high α-deuterated styrene
yield is that the equilibrium of the alcohol addition reaction
1
2
3
4
5
6
7
8
the α-selective deuteration of 1 in 88% yield with >99% deu-
terium incorporation (Scheme 1b). We found that KO-t-Bu
had similar activity and this base was selected as the pre-
ferred catalyst for further studies.17
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must disfavor the β-phenethyl ether.
Table 1. Styrene scope for catalytic -selective deuteration.
a
α
Scheme 1. Mechanistic experiments leading to the dis-
covery of styrene -deuteration.
α
KO-t-Bu (10 mol%)
H
D
>95% α-deuteration
MeOH (1 or 3 equiv)
<5% other deuteration
Ar
Ar
D
a) Equilibrium studies for nucleophilic addition of MeOH to styrene 1
(0.5 M)
DMSO-d6
P4-t-Bu
H
(10 mol%)
Cl
D
D
Br
+
MeOH
OMe
F3C
Ar
F3C
solvent
90 °C
1
2
F3C
in DMSO
1-α-d, 86% yieldb
>99% α-deuterated
4-α-d, 90% yield
97% α-deuterated
5-α-d, 70% yield
97% α-deuterated
[2]
[1] [MeOH]
in m-xylene
Keq = 0.20
Keq
=
Keq = 0.07
I
D
D
O
D
b) Exploiting unfavorable equilibrium for selective α-deuteration
Et2N
H
D
base
MeO2C
(10 mol%)
+
6-α-d, 77% yield
99% α-deuterated
7-α-d, 63% yield
99% α-deuterated
8-α-d, 74% yield
98% α-deuterated
MeOH
DMSO-d6
F3C
F3C
1 (1 equiv)
(3 equiv)
90 °C, 6 h
1-α-d
>99% α-deuterated
P4-t-Bu (88% yield) or KO-t-Bu (87% yield) >99% α-selective
D
D
D
base:
F3CS
Ph
9-α-d, 50% yield
95% α-deuterated
10-α-d, 93% yieldc
97% α-deuterated
11-α-d, 84% yield
97% α-deuterated
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
D
D
D
N
Cl
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
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
N
15-α-d, 78% yieldb
99% α-deuterated
16-α-d, 76% yield
97% α-deuterated
17-α-d, 83% yield
95% α-deuterated
Scheme 2. Possible deuteration pathway and challenges.
D
D
D
N
KO-t-Bu
MeO–H
KOMe
CD3
OMe
- t-BuOH
MeO–H
+
KO-t-Bu
DMSO-d6
N
D
F3C
18-d4, 67% yield
95% α-deuterated
19-α-d, 65% yield
97% α-deuterated
20-d2, 79% yield
95% α-deuterated
equilibrium-driven
H
D
α-deuteration
+
MeO–D
Ar
Ar
a
1
Isolated yields of alkene, % deuteration determined by H
and H NMR; reactions run between 50-130 °C at 0.5M of al-
kene in DMSO-d6, see Supporting Information. b 1H NMR yield,
isolated yields for product 1-α-d (52%) and 15-α-d (61%) were
decreased due to volatility. c NaH used instead of KO-t-Bu.
2
H
D
KOMe
KOMe
OMe
Ar
(3)
competing base-promoted pathways:
aromatic C–H deuteration
styrene polymerization
aromatic C–X SNAr (X = leaving group)
We found generally applicable reaction conditions using 1
or 3 equiv of MeOH and 10 mol% KO-t-Bu, although the
β-phenethyl ether formation
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optimal reaction temperature and time were adjusted empir-
1
We next performed reaction profile analysis studies to in-
ically for each substrate.22 Typically, H NMR monitoring of
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7
8
vestigate the critical role of MeOH in enabling selective α-
deuteration over competing side reactions. Using styrene 14,
we tracked α-deuterium incorporation (Figure 2a) and sty-
rene mass balance (14 + 14-α-d, Figure 2b) using varied
quantities of MeOH (0.25, 0.5 and 1.0 equiv). The deuter-
ation rate was notably faster when 0.25 equiv of MeOH was
used, but the mass balance rapidly approached 0%.25 In con-
two initial reaction attempts using 1 and 3 equiv of MeOH
allowed the identification of suitable conditions to obtain a
preparative-scale isolated yield; a description of this process
is provided in the Supporting Information.23 Table 1 shows a
diverse scope of styrene derivatives that undergo greater than
95% α-deuteration with less than 5% total deuteration in
other positions. Electron-poor to -neutral styrenes are suita-
ble substrates, whereas electron-rich variants are not electro-
philic enough to establish equilibrium under these condi-
tions.15 Halogenated styrenes, including ortho-substituted
bromide (4), chloride (5) and iodide (6) variants undergo
selective α-deuteration while avoiding SNAr reactions and
aromatic deuteration. Ester (7), amide (8), (trifluorome-
thyl)thio (9) and stilbene (10) functional groups in the me-
ta- and para-positions are also tolerated. Styrenes consisting
of extended aromatic systems and heteroarenes, both of
which contain relatively acidic arene C–H bonds, undergo
selective α-deuteration.24 This includes naphthalene (11 and
12), anthracene (13), pyridine (14 and 15), isoquinoline
(16) and quinoline (17) vinyl arenes. We found that β-
methylstyrene (18) undergoes α- and γ-deuteration, likely
through a simple deprotonation process.20 Meanwhile, a β-
methoxystyrene (19) and a stilbene derivative (20) undergo
selective deuteration. Additional substrates that were exam-
ined are provided in the Supporting Information.
9
trast, 1 equiv of MeOH led to complete α-deuteration while
preserving the mass balance above 90%. The major side
product of these reactions is the corresponding polystyrene,
which is the only observed product when KO-t-Bu is used
without any alcohol additive.21 These studies suggest that a
critical concentration of alcohol is required for rapid deuter-
ation of the developing benzylic anion by MeOD to outcom-
pete anionic styrene polymerization.
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Given the crucial role of the alcohol in this process, we rea-
soned that modifying its structure could overcome additional
competing side reactions. Although ortho-halogenated sty-
renes undergo efficient α-deuteration (Table 1), we found
that the more activated 2-chloro-3-vinylpyridine (21) pri-
marily underwent SNAr with only 21% α-deuteration of 21
when MeOH was used (see Supporting Information). We
reasoned that a larger, but still nucleophilic, alcohol could
promote α-deuteration over aromatic substitution. We dis-
covered that use of 1-cyclopropylethanol (22) and 18-
crown-6 led to 96% α-deuteration in 63% yield (equation
1).26 We expect this strategy could be utilized if other chal-
lenging substrates are encountered.
a) Styrene 14 deuteration rate dependence on MeOH stoichiometry
100
75
H
D
KO-t-Bu (10 mol%)
18-crown-6 (1 equiv)
OH
(eq 1)
+
DMSO-d6
(0.5 M)
Me
22 (3 equiv)
50
N
Cl
N
Cl 21-α-d
40 °C, 1 h
21 (1 equiv)
63% yield, 96% α-deuterated
1 eq MeOH
25
0.5 eq MeOH
0.25 eq MeOH
In addition to their value for mechanistic experiments, an-
0
other utility of α-deuterated styrenes is their elaboration to
deuterium-labeled chiral benzylic stereocenters of pharma-
ceutical relevance, positions frequently prone to metabolic
oxidation.11 To highlight this potential, Figure 3 shows three
deuterium-labeled chiral compounds, including the pharma-
ceutical cinacalcet (23), that were rapidly prepared from
substrates in Table 1.10a,27 We expect this simple catalytic
deuteration protocol will find use in these and related appli-
cations.
0
2
4
6
8
10
Time (h)
b) 14 + 14-α-d Mass balance dependence on MeOH stoichiometry
100
75
50
1 eq MeOH
25
stereodefined deuterated compounds prepared from 12-, 4-, and 11-α-d
0.5 eq MeOH
cinacalcet
cyclic carbonate
cyclopropane
0.25 eq MeOH
O
O
H
N
0
D
D
0
2
4
6
8
10
F3C
D
O
Time (h)
CO2Me
CO2Me
Me
Br
Figure 2. Reaction profile for the (a) deuteration rate and (b)
mass balance for substrate 14 from Table 1 at 70 °C; values
determined by 1H NMR spectroscopy.
23, 94% ee
24, 98% ee
25, 96% ee
84% yielda
74% yielda
65% yielda
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from α-deuterated styrenes in Table 1. Isolated yield of prod-
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uct starting from α-deuterated styrene substrate; see Support-
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ing Information for synthetic details.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is avail-
able free of charge on the ACS Publications website.
Experimental procedures and characterization data for all com-
pounds (PDF).
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AUTHOR INFORMATION
Corresponding Author
*jeff.bandar@colostate.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by startup funds from Colorado State
University. We thank Professor Andrew McNally (CSU) for
sharing additional resources and input on this manuscript. We
also thank Professor Yiming Wang (Pittsburgh) for advice on
this manuscript and for assistance with the ee determination of
compounds 24 and 25 in Figure 3.
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(13) For examples of these synthetic routes, see: (a) references 12c and
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(17) Use of CD3OD as a solvent provided no α-deuteration.
1
(18) Intermediate 3 is frequently observed by H NMR as a minor side
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(19) We also considered that a primary KIE in the elimination of
MeOH from ether 3 could contribute to the high α-deuterium incorpora-
tion. Subjection of α-deuterated styrenes to basic DMSO solutions resulted
in α-protium incorporation at a rate identical to styrene α-deuterium in-
corporation in basic DMSO-d6 solutions. This result suggests that a KIE in
the elimination step is not responsible for high α-deuterium incorporation.
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and
absolute
configuration
of
the
3-[4-(1-hydroxy-2-
methoxyethyl)phenoxy]-1-(isopropylamino)-2-propanols, the diastereo-
meric benzylic hydroxylation metabolites. J. Med. Chem. 1988, 31, 55. (g)
Sun, H.; Scott, D. O. Structure‐based Drug Metabolism Predictions for
Drug Design. Chem. Biol. Drug Des. 2010, 75, 3.
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Insights on Orthogonal Selectivity in Heterocycle Synthesis. ACS Catal.
2018, 8, 10111. (b) Fang, X.; Yu, P.; Cerai, G. P.; Morandi, B. Unlocking
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and-Modulated Palladium-Catalyzed Wacker Oxidation of Styrenes Using
TBHP. J. Am. Chem. Soc. 2005, 127, 2796. (e) Walker, K. L.; Dornan, L.
M.; Zare, R. N.; Waymouth, R. M.; Muldoon, M. J. Mechanism of Catalytic
Oxidation of Styrenes with Hydrogen Peroxide in the Presence of Cationic
Palladium(II) Complexes. J. Am. Chem. Soc. 2017, 139, 12495. (f) Pryor,
W. A.; Henderson, R. W.; Patsiga, R. A.; Carroll, N. Hydrogen Secondary
(21) (a) Anionic Polymerization: Principles, Practice, Strength, Conse-
quences and Applications; Hadjichristidis, N.; Hirao, A., Eds; ꢀSpringer:
Tokyo, Japan, 2015. (b) Baskaran, D.; Müller, A. H. E. Anionic Vinyl
Polymerization. In Controlled and Living Polymerization: From Mechanisms
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J. T. Anionic polymerization initiated by lithium diethylamide in organic
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solvents. III. Investigation of the polymerization of styrene. J. Polym. Sci. A,
1976, 14, 1565.
(25) We hypothesize that excess MeOH may participate in hydrogen-
bonding to the active potassium alkoxide ion pair, thus decreasing alkoxide
nucleophilicity; mechanistic studies concerning this issue are ongoing.
(26) When t-BuOH and other tertiary alcohols were examined for this
reaction, incomplete α-deuteration and low mass balance of the styrene was
observed.
(27) See the Supporting Information for details of the synthetic routes
to 23-25. (a) Niu, D.; Buchwald, S. L. Design of Modified Amine Transfer
Reagents Allows the Synthesis of α-Chiral Secondary Amines via CuH-
Catalyzed Hydroamination. J. Am. Chem. Soc. 2015, 137, 9716. (b) Sapeta,
K.; Kerr, M. A. The Cycloaddition of Nitrones with Homochiral Cyclopro-
panes. J. Org. Chem. 2007, 72, 8597.
1
2
3
4
5
6
7
8
(22) It is possible to use lower catalyst loadings of KO-t-Bu, although
the reaction takes significantly longer to reach completion. For example,
substrate 11-α-d requires 4 h to reach 97% α-deuteration using 10 mol%
KO-t-Bu at 130 °C according to the general procedure, while 5 mol% KO-t-
Bu required 24 h under identical conditions.
(23) The reaction must be conducted under inert atmosphere according
to the general procedure in the Supporting Information. Reactions run in
the presence of oxygen (1 atm balloon) resulted in no α-deuteration. The
deuteration reaction of substrate 14 in the presence of 1 and 5 equiv of
water resulted in 94% and 65% α-deuteration, respectively. These studies
indicate small quantities of water are tolerated, although excess water is not.
(24) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. What are the pKa val-
ues of C–H bonds in aromatic heterocyclic compounds in DMSO? Tetra-
hedron 2007, 63, 1568.
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catalytic
isotope
exchange
access to diverse
deuterium-labeled
benzylic stereocenters
H
D
R
R
Ar
Ar
O
H
D
N
D
O
F3C
D
O
CO2Me
CO2Me
Me
Br
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