Palladium-catalyzed ortho-selective C-H deuteration of arenes: Evidence for superior reactivity of weakly coordinated palladacycles

Article abstract of DOI:10.1002/anie.201305388

We disclose a protocol for the palladium-catalyzed ortho-selective C-H deuteration of arenes. Phenylacetic acids and benzoic acids are suitable substrates for this reaction. This reaction offers a catalytic route to ortho-deuterated phenylacetic acids and

Full text of DOI:10.1002/anie.201305388

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Angewandte
Communications
DOI: 10.1002/anie.201305388
À
C H Activation
À
Palladium-Catalyzed ortho-Selective C H Deuteration of Arenes:
Evidence for Superior Reactivity of Weakly Coordinated
Palladacycles**
Sandy Ma, Giorgio Villa, Peter S. Thuy-Boun, Anna Homs, and Jin-Quan Yu*
Abstract: We disclose a protocol for the palladium-catalyzed
À
ortho-selective C H deuteration of arenes. Phenylacetic acids
and benzoic acids are suitable substrates for this reaction. This
reaction offers a catalytic route to ortho-deuterated phenyl-
acetic acids and benzoic acids and demonstrates the sharp
difference in reactivity of palladacycle intermediates held
together by weak and strong coordination.
D
euterium-labeled compounds are widely used in mass
spectrometry as well as in mechanistic and metabolic
studies.[1,2] Furthermore, there is growing interest in selective
deuteration because deuterium incorporation can improve
the overall therapeutic and metabolic profile of a drug.[3]
Owing to the prevalence of the phenylacetic acid moiety in
drug molecules,[4] the directed ortho-deuteration of phenyl-
acetic acids would be an attractive step-economical route, as
current methods for accessing the same scaffold either require
multistep synthetic routes or are nonselective for the ortho
position [Eqs. (1)–(3)]. The first possible method is to use the
selective ortho-deuteration of benzamide derivatives through
directed stoichiometric ortho-metalation (DoM)[5,6] followed
by one-carbon homologation [Eq. (1)]. An alternative
approach is to use catalytic, cationic iridium complexes,
such as the Crabtree catalyst,[7] to ortho-metalate/deuterate
benzoic acid derivatives [Eq. (2); cod = 1,5-cyclooctadiene].
This protocol has been widely used to ortho-deuterate
benzamides, benzoic acid derivatives, and acetanilides in
high yields;[1b,8] however, this route still requires a one-
carbon-homologation step to access ortho-deuterated phenyl-
acetic acids. The third possible method is to use hetereoge-
neous mixed-transition-metal catalysts and D2 to afford the
deuterated phenylacetic acids, albeit in a nonselective manner
[Eq. (3)].[9] This reductive protocol may not be compatible
with functional groups that are prone to hydrogenation.
Inspired by our previous successes in the use of palladium
catalysts for the selective ortho-functionalization of arenes,[10]
we were eager to develop a palladium-catalyzed ortho-
selective deuteration protocol for phenylacetic acids and
other arene derivatives [Eq. (4)]. Despite extensive studies on
À
palladium-catalyzed ortho-directed C H activation reactions,
catalytic deuteration through cyclopalladation has not yet
been developed, largely because the stable palladacycles held
together by strong coordination do not readily undergo
protonolysis.[11] We envisioned that the recently established
À
reactivity of phenylacetic acids towards ortho-C H activation
through weak coordination[12] with palladium(II) catalysts
could enhance the protonolysis, thus leading to deuteration.
Herein, we report the palladium-catalyzed ortho-deuteration
of phenylacetic acids through protonolysis of palladacycles
held together by weak coordination. This catalytic protonol-
ysis pathway is mechanistically distinct from the D-exchange
processes based on the use of a metal and D2. Comparative
studies with 2-phenylpyridine and 2-benzylpyridine substrates
further illustrate that weakly coordinated palladacycles are
À
significantly more reactive in C H functionalization reac-
tions.
[*] Dr. S. Ma, Dr. G. Villa, P. S. Thuy-Boun, A. Homs, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Our initial efforts towards a palladium-catalyzed ortho-
Homepage: http://www.scripps.edu/chem/yu
À
selective C H deuteration commenced with the treatment of
[**] We gratefully acknowledge The Scripps Research Institute and the
US NSF (CHE-1011898) for financial support. We thank the US EPA
(STAR predoctoral fellowship for P.S.T.-B., Assistance Agreement
no. FP917296-01-0), the Swiss National Science Foundation (post-
doctoral fellowship for G.V.), and MINCINN (FPI fellowship for
A.H.).
(2-trifluoromethylphenyl)acetic acid (1a) with Pd(OAc)2
(5 mol%) in deuterated acetic acid. However, heating of
the reaction mixture at 1208C for 12 h led to 0% deuterium
incorporation (Scheme 1). In contrast, when Li2CO3 was
added under the same reaction conditions, ortho-deuterated
phenylacetic acid 2a was obtained with 99% deuterium
incorporation. More thorough screening revealed that inor-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305388.
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Scheme 1. Initial results.
ganic bases were crucial for the observed reactivity (Table 1).
This result was consistent with our previous findings that the
presence of sodium or potassium cations promotes the ortho-
palladation of benzoic and phenylacetic acids.[10b,13] However,
no reaction was observed with sodium chloride.[14]
Table 1: Optimization of the reaction conditions.[a]
Entry
Base
Solvent
Deuterium
incorporation [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
Li2CO3
Na2CO3
K2CO3
LiOAc
NaOAc
KOAc
NaCl
LiF
KHF2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
[D4]acetic acid
D2O
99
99
99
99
99
99
0
80
80
0
Scheme 2. Palladium-catalyzed ortho-deuteration of phenylacetic acids.
Conditions for ortho-deuteration (in a 50 mL sealed tube):
1 (0.5 mmol), Na2CO3 (0.75 mmol), Pd(OAc)2 (10 mol%), [D4]acetic
acid (5 mL), 1208C, 12 h. Conditions for a-reprotonation (in a 50 mL
sealed tube): crude 1 (0.5 mmol), NaOH (10 mmol), H2O (2 mL),
CH2Cl2 (2 mL), 1208C, 12 h. Deuterium incorporation determined by
1H NMR spectroscopic analysis after the first step is shown in square
brackets.[21] The yield of the isolated product after two steps is shown
in parentheses. Deuteration at the a-position was observed after the
first step, which necessitated the use of NaOH for reprotonation.
[D4]methanol
[D1]TFA
CDCl3
0
0
0
1
[a] Reaction conditions: 1a (0.5 mmol), base (0.75 mmol), Pd(OAc)2
(10 mol%), solvent (5 mL), 1208C, 12 h. The reactions were carried out
in a 50 mL sealed tube. [b] Deuterium incorporation at the aromatic
position was determined by 1H NMR spectroscopy. TFA=trifluoroacetic
acid.
[a] Deuterium incorporation was determined by H NMR spectroscopic
analysis of the corresponding methyl ester derivative (see the Support-
ing Information for details). [b] The yield of the isolated product after
the first step is given owing to product decomposition upon treatment
with NaOH. Deuterium incorporation at the a-position has been
omitted for clarity.
Different
deuterium-containing
solvents
(D2O,
determined after subsequent reprotonation at the a-position
under basic conditions. Trifluoromethyl-, methyl-, and
methoxy-substituted phenylacetic acids with ortho, meta,
and para substitution were examined. Nonselective over-
deuteration was observed for (2-methoxyphenyl)acetic acid
(1g), but ortho-selective deuteration was observed for (3-
methoxyphenyl)acetic acid (1h). Nitro-substituted phenyl-
acetic acids 1m and 1n as well as the nonsubstituted
phenylacetic acid 1o were also suitable substrates for
selective ortho-deuteration. Notably, the ortho-deuterated
product derived from ibuprofen (2p) was isolated in 88%
yield with 93% deuterium incorporation.
[D4]methanol, and [D1]TFA) were also tested, but no product
was observed in these reactions. Reaction times and temper-
atures were also briefly examined, which led to the identifi-
cation of our optimized reaction conditions: treatment of the
substrate with Pd(OAc)2 (10 mol%) and Na2CO3 (1.5 equiv)
in [D4]acetic acid at 1208C for 12 h.
A variety of substituted phenylacetic acids were exam-
ined, including both electron-deficient and electron-rich
substrates (Scheme 2). 1H NMR spectroscopic analysis
showed that the benzylic positions were also deuterated.
The yields of the ortho-deuterated phenylacetic acids were
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Scheme 4. ortho-Deuteration with palladacycles.
evaluated the reactivity of palladacyles 5 and 6 under our
deuteration conditions (Scheme 4). We used palladacycle 5,
which contains the cesium imidate derived from benzamide
3c weakly coordinated to the palladium metal center, as
a probe for investigating the reactivity of a palladacycle held
together by weak coordination under deuteration condi-
tions.[16,17] The treatment of complex 5 with deuterated acetic
acid at 1208C for 1 h afforded the ortho-deuterated benz-
amide, which was isolated in 88% yield as an 88:12 mixture of
di-ortho-deuterated and mono-ortho-deuterated products.[18]
Thus, the deuteration of palladacycle 5 gave mainly the di-
ortho-deuterated product, which suggests that the PdII species
formed after protonolysis remained bound to the imidate and
Scheme 3. Palladium-catalyzed ortho-deuteration of arenes. Conditions
for ortho-deuteration (in a 50 mL sealed tube): 3 (0.5 mmol), Na2CO3
(0.75 mmol), Pd(OAc)2 (10 mol%), [D4]acetic acid (5 mL), 1208C,
12 h. Deuterium incorporation as determined by 1H NMR spectroscop-
ic analysis is shown in square brackets.[16] The yield of the isolated
product is shown in parentheses. [a] Ar=4-CF3C6F4. [b] The reaction
was performed on a 0.2 mmol scale. [c] The product of ortho-deutera-
tion was subjected to a-reprotonation conditions (yield of the isolated
product after two steps). [d] Ar’=C6F5. [e] The reaction was performed
at 808C for 18 h. [f] Deuterium incorporation at the a-position has
been omitted for clarity. DG=directing group.
À
Substrates other than phenylacetic acids were also studied
(Scheme 3). The deuteration of benzoic acid (3a) and 2-
trifluoromethylbenzoic acid (3b) yielded the ortho-deuter-
ated acids with 61 and 65% deuterium incorporation,
respectively. We were pleased to find that deuteration of the
benzoic acid derived benzamide 3c afforded the ortho-
deuterated product 4c in 91% yield with 89% deuterium
incorporation. The pharmaceutically important sulfonamide
3d was also transformed into the ortho-deuterated product 4d
with 89% deuterium incorporation and in 73% yield.
Notably, the deuteration of N-methoxybenzamide 3e and 2-
phenylpyridine (3 f) proceeded in low yield, although these
two substrates are known to undergo facile cyclopallada-
tion.[15] The poor reactivity of the N-methoxybenzamide
remains to be elucidated; however, the low deuterium
incorporation observed with 2-phenylpyridine suggests that
weakly coordinated palladacycle intermediates are more
reactive towards protonolysis through an electrophilic-cleav-
age pathway. This understanding is reinforced by the results
obtained with 2-benzylpyridine (3g), which was ortho-deu-
terated to give 4g with 86% D incorporation in total, thus
suggesting that the less stable six-membered palladacycle is
more reactive towards functionalization with electrophilic
protons.
further cleaved the second ortho-C H bond. In contrast, the
treatment of palladacycle 6 with deuterated acetic acid at
1208C for 12 h promoted no reaction in either the presence or
absence of a base. These results suggest that palladacycles
that are derived from weak coordination are more reactive
towards electrophiles and imply that a weak coordination
mode between the substrate and the palladium metal center is
responsible for the observed reactivity under our deuteration
conditions.
We tentatively speculate that our deuteration proceeds
first by C H activation to generate an aryl–palladium(II)
À
complex 7 (Scheme 5).[13a] This intermediate can then react
with D+ to give the deuteration product and the PdII catalyst.
Reports on the interception of aryl–palladium(II) intermedi-
ates of type 7 by electrophiles, such as ketones, aldehydes, and
nitriles, are still rare.[19] We have reported previously that
À
aryl–palladium(II) complexes generated by C H activation
can react with alkyl halides through an electrophilic-cleavage
pathway.[20] Our deuteration protocol suggests that under PdII
In light of our observation that substrates that are
typically thought to coordinate strongly to the palladium
metal center, such as 2-phenylpyridine (3 f), undergo deuter-
ation in low yields, we wanted to elucidate whether weak
À
coordination was operative during the C H insertion step and
was responsible for the observed reactivity under our
deuteration conditions. To compare the reactivity of pallada-
cycles held together by either weak or strong coordination, we
Scheme 5. Proposed catalytic cycle.
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other electrophilic species. However, a mechanism that
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be disproved at this time.
In conclusion, we have developed an ortho-selective
deuteration of phenylacetic acids with palladium(II) catalysts.
Related benzoic acid derivatives were also suitable substrates
for this reaction. These results offer an attractive one-step
method to access ortho-deuterated phenylacetic acid com-
pounds. The observed catalytic deuteration provides further
evidence that palladacycles derived from weak coordination
are more reactive. The facile protonation also reveals their
potential reactivity towards other electrophiles.
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Received: June 23, 2013
Revised: October 30, 2013
Published online: November 29, 2013
À
Keywords: C H activation · deuteration · palladium ·
phenylacetic acids · weak coordination
.
À
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[15] In the absence of a base, the ortho-deuteration of 2-phenyl-
pyridine only proceeded to give trace amounts of the desired
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À
[16] Our attempts to isolate the C H insertion intermediate upon the
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1
[21] Because deuterium incorporation was determined by H NMR
spectroscopic analysis, there exists the possibility of an unknown
mixture of the mono-/di-ortho-deuteration product for para-
substituted and unsubstituted arenes.
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