Palladium-Catalyzed Carbon Isotope Exchange on Aliphatic and Benzoic Acid Chlorides

Article abstract of DOI:10.1021/jacs.8b09808

An operationally simple protocol for a palladium-catalyzed ¹³CO and ¹⁴CO exchange with activated aliphatic and benzoic carbonyls is presented. Several ¹³C and ¹⁴C building blocks, natural product derivatives, an

Full text of DOI:10.1021/jacs.8b09808

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Communication
Palladium-Catalyzed Carbon Isotope Exchange
on Aliphatic and Benzoic Acid Chlorides
Donald R. Gauthier, Jr., Nelo R Rivera, Haifeng Yang, Danielle M Schultz, and C. Scott Shultz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09808 • Publication Date (Web): 01 Nov 2018
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Palladium-Catalyzed Carbon Isotope Exchange on Aliphatic
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Donald R. Gauthier, Jr.,* Nelo R. Rivera, Haifeng Yang, Danielle M. Schultz and C. Scott
Shultz
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United
States
Supporting Information Placeholder
and their derivatives comprise one of the most important
structural motifs in pharmaceuticals, agrochemicals and
organic materials and are often selected as targets for
radiocarbon labeling.10,11,12 Herein we report a general
carbon isotope exchange method for substrates containing
carboxylic acids utilizing 13CO and 14CO, readily available
sources of isotopically labeled carbon.13
ABSTRACT: An operationally simple protocol for
a
Palladium-catalyzed 13CO and 14CO exchange with
activated aliphatic and benzoic carbonyls is presented.
Several 13C and 14C building blocks, natural product
derivatives, and pharmaceuticals have been prepared to
showcase the method for late-stage carbon isotope
incorporation and its functional group compatibility.
Radiolabeled pharmaceutical compounds, typically
featuring tritium and carbon-14, provide vital knowledge of
drug metabolism and disposition.1 During early phases of
pharmaceutical discovery, the radioisotope selection
process must weigh the benefits and liabilities incurred by
labeling with either tritium or 14C. Hydrogen isotope
exchange performed directly on the target molecule offers
inexpensive, rapid access to tritiated compounds;2 however,
the sites of tritiation often coincide with sites of metabolism,
thus rendering these strategies unproductive. On the other
hand, the metabolic stability engendered by imbedding 14C
firmly into the carbon framework of the molecule is
attractive. Despite this important advantage, the synthesis
of 14C tracers can be prohibitively difficult and expensive,
often requiring de novo synthetic routes structured around
the limited collection of commercially available 14C raw
materials.3 Furthermore, these methods involve handling
and purification of radioactive intermediates that result in
significant amounts of long-lived radiocarbon waste (T1/2
5730 years). Nonetheless, 14C radiotracers are essential to
the clinical development of a drug candidate.4 Therefore,
the concept of late-stage isotope exchange, routine for
swapping isotopes of hydrogen, would be highly valuable as
a carbon labeling strategy to address these challenges.5
Scheme 1. Hydrogen and Carbon Isotope Exchange.
Initial studies were focused on looking at an array of Pd-
ligand complexes in 1.5 atm of 13CO (as a surrogate for
precious 14CO) with dihydrocinnamoyl chloride as the
activated acid (Table 1). Significant 13CO incorporation was
observed by LCMS analysis with several ligands including
XantPhos, tBuXPhos, and P(o-tol)3; however, competitive -
hydride elimination from the presumed [Pd-alkyl]
intermediate to liberate styrene was observed as
a
significant byproduct under many conditions. Fortunately,
this side reaction was minimized in toluene using the P(o-
tol)3 ligand.
Table 1. 13CO Exchange in Dihydrocinnamoyl Chloride
Using Pd-Catalysis.
cat. Pd2dba3, ligand
O
O
13C
13CO
1.5 atm
solvent, 75 oC, 15h
+
Ph
Ph
Cl
Ph
Cl
Hydrogen isotope exchange relies on C-H activation,
often metal catalyzed,6 followed by tritiation of a metal
complex, typically utilizing T2 gas or tritiated water as the
source of tritium (Scheme 1). Extending this strategy to 14C
is expected to be more challenging as the breaking of a C-C
bond is generally much higher in energy than that of a C-H
bond. Premised on well-established metal catalyzed
carbonylation7 and recent reports demonstrating palladium
catalyzed carbonyl exchange by Arndtsen8 and Morandi,9
we envisaged facile 12CO/14CO exchange could occur with
a suitably activated carboxylic acid derivative under a partial
atmosphere of 14CO. Moreover, the use of carboxylic acids
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aMicroscale screen conditions: 10 mol% Pd2dba3, 10 mol%
Chamber A:
CO Gas Generation
2-Chamber Reactor
(COware)
Chamber B:
CO-exchange Reaction
bidentate ligand or 20 mol% monodentate ligand, pressurized with
13CO gas using a regulator, 0.25M, 75 °C, 15 h, then aqueous
LiOH. b13C incorporation and acid/styrene ratios as determined by
UPLC-MS at 210 nm.
1
2
3
4
5
6
7
8
O
C
Me
*
Cl
O
O
Pd / L
Pd / L
*
C
O
C
*
R
Cl
R
Cl
Having demonstrated proof of concept in our initial
screening we sought to explore the scope of this chemistry.
As a result, we turned to the use of 13COgen or 14COgen,
developed by Skrydstrup,14 as a convenient and precise
method for introducing 13CO or 14CO gas into the reaction.15
The sealed two chamber system (COware) allowed for
accurate dispensing of 1.5 equivalents COgen into one
chamber, making the liberated CO gas available for Pd-
catalyzed exchange in the connecting chamber. In contrast
to our catalyst screening study that used a large excess of
13CO gas, we aimed to minimize the labeled COgen due to
the high cost of carbon-14 reagents. Therefore, the percent
enrichment is limited by the equivalents of COgen. In the
present study, we chose 1.5 equivalents COgen as it can
provide up to 60% isotope enrichment if the system reaches
equilibrium16 by distributing the label equally amongst the
free CO gas and the acid chloride substrate. Since carbon-
14 is detectable at very low concentrations, often high
specific activity (SA)17 compounds are diluted with the
unlabeled compound to meet dosimetry requirements;18
therefore, even modest levels of enrichment can be suitable
for in vivo studies. In our initial assessment using Pd[(o-
tol)3P]2 as catalyst, substituted aromatic and primary
aliphatic acid chlorides were observed to perform with the
highest levels of isotopic exchange (Table 2). Secondary
aliphatic acid chlorides exchanged to a lesser degree than
primary. These conditions failed with tertiary acid and N-
protected -amino acid chlorides with the primary
observation being recovery of unlabeled starting material. In
general, exchange was not significantly affected by the
benzoyl chloride substitution patterns; however, exchange
was attenuated by strong chelating o-substituents (Table 2,
entries 2i and 2j).
*1 (COgen)
denotes
13C or 14
*
C
Chamber A:
1
(1.5 equiv.), Cy2NMe
*
O
5 mol% Pd[(t-Bu)3P]2, NMP, 75 
C
O
O
H2O
Cl
O
C
*
+
Cl
R
OH
R
OH
Chamber B:
10 mol% Pd[(o-tol)3P]2
toluene, 75 C, 18h
9
%*Cb (% yieldc)
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O
13C
O
O
13C
13C
OH
OH
OH
O2N
O
2a 41% (88% yield)
2b 25.0% (84% yield)
53.7% (80% yield)d
2c 29.6% (90% yield)
O
O
13C
Me
O
13C
13C
OH
OH
OH
Boc
N
Me2N
Me
Me
H
2e 28.8% (82% yield)
2f 13.8% (84% yield)
55.8% (88% yield)d
2d 39% (86% yield)
Me
O
13C
MeO
O
Me2N
O
13C
MeS
O
13C
13C
OH
OH
OH
OH
2i <5% (ND)
2g 28.3% (85% yield)
2h 42.4% (82% yield)
2j <5% (ND)
O
13C
O
O
13C
OH
C
*
OH
OH
13C: 48% (90% yield)
14C: 27% (16% yield)
SA = 16.8 mCi/mmol
2m
2n
2k 46% (85% yield)
2l 52% (78% yield)
aConditions: Chamber A: 1.5 equiv. COgen, 5 mol% Pd[(t-
Bu)3P]2, 3 equiv. Cy2NMe, 0.5M NMP, 75 °C; Chamber B: 0.1 – 0.3
g of substrate, 10 mol% Pd[(o-tol)3P]2, 0.25M toluene, 75 °C, 18h.
bPercent carbon isotope enrichment. Isolated yield of *C enriched
c
acid. eUsed Pd[(t-Bu)3P]2 as catalyst in Chamber B.
Table 2. Exchange Scope: Benzoic and Aliphatic Acidsa
To further demonstrate the utility of the labeling method,
we performed both 13C and 14C labeling on a set of
biologically active substrates (Table 3). The method proved
effective on the penultimate precursor to Lipitor (3a),
yielding 39% 13C incorporation with 1.5 equiv. 13CO. This
concise labeling strategy highlights the simplicity and power
of the transformation compared to previous approaches.19
A
diverse series of pharmaceuticals containing primary
aliphatic acids and substituted benzoic acids likewise
underwent smooth exchange, including gamma secretase
inhibitor MK-0752,20 GPR40 agonist TAK-875,21 steric acid,
prostaglandin
D2
receptor
antagonist
MK-0524,22
Lonazolac, Ataluren, Tafamidis, HCV polymerase inhibitor
3j,15a and Telmisartan.
Table 3. Exchange on Biologically Active Substratesa
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O
O
Chamber A:
Cl
O
[Pd0]Ln
1 (1.5 equiv.), Cy2NMe
5 mol% Pd[(t-Bu)3P]2, NMP, 75 
O
Ar
Ar
II
*
*
Me
*
O
1
2
O
[Pd ] Ln
Cl
H2O
Cl
C
C
*
+
Cl
+
R
OH
Ar
CO
R
OH
Cl
Me
Chamber B:
F
Me
%
Cb (% yieldc)
O
F
*
10 mol% Pd[(o-tol)3P]2
toluene, 75 C, 18h
3
4
5
6
CO
Cl
Cl
O
[PdII] Ln
O
O
Ar
C
*
II
*
A
OH
[Pd ] Ln
Me
Me Me
O
Ar
O
O
O
O
13C
S
E
Me
7
8
9
H
N
OH
F
N
Cl
MK-0752
O
Me
Lipitor acetonide (3a)
39% (20% yield)
F
(3b)13C: 52.5% (67% yield)
(3c)14C: 37.4% (20% yield)
SA = 23.3 mCi/mmol
Cl
Me
Cl
Cl
OC [PdII] Ln
*
+ CO
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OC [PdII] Ln
OC [PdII] Ln
*
O
13C
Ar
H
Me
Ar
OH
Me
Ar
- CO
Me
O
13C
MeO2S
O
Me
Me
D
C
B
OH
14
O
O
TAK-875 (3d)
57.3% (45% yield)
Steric Acid (3e)
45% (69% yield)
Me
Figure 1. Proposed Pd-cat. CO-Exchange Mechanism
We then performed a second round of screening focusing
on bulky and electron-rich ligands that would facilitate both
CO exchange and C-Cl reductive elimination (step A to F),
utilizing (S)-ibuprofen chloride (4) as a model chiral benzylic
acid that gave negligible exchange under the Pd/P(o-tol)3
conditions. To our delight, several bulky and electron rich
catalysts were shown to promote CO exchange at 75 °C;
however, it was determined that the product had completely
isomerized to unbranched acid 5. Performing the exchange
at 50 °C gave predominantly the desired branched acid 6a
albeit with diminished enantiopurity (Scheme 2). We
suspect that the observed isomerization at elevated
temperatures can be attributed to β-hydride elimination/re-
insertion pathway either through A or C/D (Figure 1).20a
Remarkably, running the reaction at ambient temperature
resulted in high incorporation of 13CO with no isomerization
or loss in %ee observed.28 While we do not have a complete
understanding of this observation we hypothesize that
benzylic acid chlorides allow facile decarbonylation through
stabilization of the developing negative charge on the alkyl
group by the adjacent aromatic ring (Figure 1, B).
O
13C
O
13C
F
OH
Cl
HO
N
Lonazolac (3g)
30.1% (68% yield)
O
S
Me
N
N
Cl
O
MK-0524 (3f)
32% (80% yield)
O
Cl
O
N
13C
O
13C
O
N
OH
N
OH
F
Cl
Tafamidis (3i)f
17.2% (54% yield)
60.2% (61% yield)e
Ataluren (3h)d
32.7% (71% yield)
57.8% (73% yield)e
NMe2
N
O
13C
13C
OH
O
N
HO
N
N
Me
N
N
Telmisartan (3k)f
53.9% (67% yield)
(3j)f
22% (80% yield)
Me
Me
aConditions: Chamber A: 1.5 equiv. COgen, 5 mol% Pd[(t-
Bu)3P]2, 3 equiv. Cy2NMe, 0.5M NMP, 75 °C; Chamber B: 0.1 – 0.3
g of substrate, 10 mol% Pd[(o-tol)3P]2, 0.25M toluene, 75 °C, 18h.
bPercent carbon isotope enrichment. Isolated yield of *C enriched
c
Scheme 2. CO Exchange Optimization for (S)-Ibuprofen
acid. dSubstrate in 1,4-dioxane. ePd[(t-Bu)3P]2 as catalyst in
Chamber B. fSubstrate in NMP.
Me
Me
Me
Me
Me
Me
13CO (1 atm)
10 mol% Pd2(dba)3
20 mol% tBuXPhos
13C
O
O2H
O
13C
Having demonstrated the applicability of this methodology
on pharmaceutically relevant compounds containing
aromatic and primary aliphatic acids, we sought to
understand why secondary and tertiary acids had variable
performance under the Pd/P(o-tol)3 catalyzed conditions. A
mechanism to describe the exchange is displayed in Figure
1 (A to F) and is related to carbonylation/decarbonylation
studies for acyl group isomerization with palladium
complexes.23,24 Based on literature precedent, we
suspected that either decarbonylation (A to C) or C-Cl
reductive elimination (F to product) is turn-over limiting and
that the employment of bulky and electron rich ligands could
potential facilitate both processes. Specifically, work by
Sanford has shown that the use of BrettPhos can greatly
accelerate decarbonylative processes by allowing more
facile generation of an unsaturated PdII species.25 Moreover,
Arndtsen has reported that PtBu3 greatly accelerates C-Cl
reductive elimination from Pd-benzoyl(chloride) complexes
due to the ligand providing both an electron rich and
hindered environment but also an empty coordination site
for CO association.8,26,27
Cl
OH
0.25 M toluene
temp, time
Me
Me
(S)-Ibuprofen (6a)
(S)-Ibuprofen Chloride (4)
5
(98% ee)
temp, time
75 C, 18h
50 C, 18h
23 C, 18h
ratio 5:6a
100 : 0
1 : 3 (70% ee)
0 : 100 (98%ee)
Transition of these conditions to the dual chambered
system with 13COgen and Pd[(t-Bu)3P]2 as catalyst provided
13C-labeled (S)-Ibuprofen (6a), Suprofen (6b) and (S)-
Naproxen (6c) in high yield (Table 4) with >30% 13C
incorporation.14 Bulky electron rich catalysts also proved
highly effective for non-benzylic secondary acids, providing
GPR40 agoPAM candidate (6d,e)29 and phenylcyclopropyl
acid 6f both in good yield with high isotopic enrichment. -
Methylhydryocinnamic acid (6g) gave only -methylstyrene
products using bulky electron rich ligands; however, (o-
tol)3P minimized decarbonylation and furnished 6g with
18% 13C without loss of enantiopurity. In general, tertiary
acid chlorides were resistant to exchange; however,
benzylic cyclopropyl acid 6i was found to exchange with a
high degree of isotopic enrichment. These conditions were
also successfully applied to BMS-986020.30 In addition, we
also compared the performance of Pd[(t-Bu)3P]2 with
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benzoyl chlorides that gave modest exchange with Pd[(o-
straightforward approach that allows late stage carbon
isotope incorporation using a dual chamber system where
labeled CO is generated and exchanged under a Pd-
catalyzed process. The utility of this method is highlighted
by the ability to carry out incorporation of 13C and 14C into
substrates bearing primary, secondary, tertiary and
aromatic acid chlorides. A series of structurally diverse
pharmaceutical agents were also successfully labeled with
no isomerization or racemization detected. Work is ongoing
to expand the scope using other carbonyl exchange
conditions, and to explore further the application of carbon
isotope exchange in the development new radiolabeling
methods.
1
2
3
4
5
6
7
8
tol)3P]2 and found significant improvement, nearing or
attaining perfect 60% 13C enrichment (Table 2: 2b and 2f,
Table 3: 3h and 3i).
Table 4. Exchange on Secondary and Tertiary Acidsa
Chamber A:
1
(1.5 equiv.), Cy2NMe
*
O
O
5 mol% Pd[(t-Bu)3P]2, NMP, 75 
C
O
H2O
13C
Cl
+
Cl
R
OH
R
OH
Chamber B:
10 mol% catalyst
toluene, temperature, 18h
O
%
Cb (% yieldc)
*
9
Secondary Benzylic Acids: Pd[(t-Bu)3P]2, 23 o
C
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
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34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
MeO
Me
O
S
O
13C
O
13C
13C
Me
ASSOCIATED CONTENT
Supporting Information
OH
OH
OH
Me
Me
(S)-Ibuprofen (6a)
Me
(S)-Naproxen (6c)
(98% ee)
37.2% (92% yield)
Suprofen (6b)
(98%ee)
31.8 (86% yield)
58.9% (81% yield)
The Supporting Information is available free of charge on
the ACS Publications website.
Secondary Non-Benzylic Acids: Pd2(dba)3, JohnPhos, 75oC
O
F
13C
Experimental proceedure and compound characterization
(PDF)
OH
MeO
O
6f
46.8% (77% yield)
C
O
*
OH
13C: 43.1% (39% yield)
Me
6d
6e 14
AUTHOR INFORMATION
Corresponding Author
C: 40.3% (24% yield)
SA = 25.2 mCi/mmol
Secondary Non-Benzylic Acids: Pd2(dba)3, (o-tol)3P, 75oC
*donald_gauthier@merck.com
ORCID
O
O
14C
13C
Me
OH
OH
6h
Donald
R.
Gauthier,
Jr.:
0000-0003-2825-0530
6g
18% (54% yield)
Me
14C: 33% (23% yield)
Me
O
SA = 20.7 mCi/mmol
Notes
Tertiary Benzylic Acids: Pd[(t-Bu)3P]2, 75oC
The authors declare no competing financial interests.
N
O
MeO
O
13C
Me
O
ACKNOWLEDGMENT
BMS-986020 (6j)
44.5% ( 30% yield)
OH
NH
Me
Ph
O
13C
O
6i
50.3% (47% yield)
We thank Rebecca Ruck and Benjamin Sherry for editing,
David Hesk, Sumei Ren and Patrick Fier for helpful
suggestions, Jinchu Liu for analytical and preparative
chromatography support, Mikhail Reibarkh for NMR support
and Professor David MacMillan for helpful discussion.
OH
aConditions: Chamber A: 1.5 equiv. COgen, 5 mol%
Pd[(t-Bu)3P]2, equiv. Cy2NMe, 0.5M NMP, 75 °C;
Chamber B: 0.1 – 0.3g of substrate, 10 mol% catalyst,
0.25M toluene, indicated temp., 18h. bPercent carbon
isotope enrichment. cIsolated yield of *C enriched acid.
3
REFERENCES
(Word Style "TF_References_Section"). References are placed
at the end of the manuscript. Authors are responsible for the
accuracy and completeness of all references. Examples of the
recommended formats for the various reference types can be found
Subsequent to the carbon isotope exchange, the labeled
acid chloride product can serve as a versatile intermediate.
For example, after exchange with 14CO on acid chloride 7,
[14C]MK-5395 was prepared by simple addition of the
at
http://pubs.acs.org/page/4authors/index.html.
Detailed
information on reference style can be found in The ACS Style
Guide, available from Oxford Press.
requisite amine (Scheme 3). In
a
similar manner,
[13C]finasteride (10) was prepared in with 44.6% 13C
incorporation.
Scheme 3.
Extended Substrate Scope for CO
Exchange: Pharmaceuticals Containing Amides
Me
O
Cl
14C
O
O
13C
N
14C
CF3
13C Cl
N
O
NH
H
O
H
H
H
H
H
H
Me
Me
O
N
O
N
N
N
H
H
H
H
N
N
MK-5395 (8)
14C: 42.8% (41% yield)
SA = 26.7 mCi/mmol
Finasteride (10)
13C: 44.6% (32% yield)
9
7
In summary, late stage carbon isotope exchange
significantly enhances the ability to produce metabolically
stable tracers that aid in the development and
understanding of the interplay of pharmacophores with
biological systems. As such, we have developed
a
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All commercial 14C compounds originate from [14C]barium carbonate (Ba14CO3), generated from prolonged neutron
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irradiation of metal nitrides. See: (a) Jiang, B.; Zhai, S.; Wei, H.; Liu, Y.; Zeng, B. Preparation of high specific activity [14C]-
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Late-stage carbon isotope exchange has limited precedent: (a) For examples of late-stage exchange of methyl-sulfones to
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Sulfinic Acids from Methyl Sulfones. Org. Lett. 2016, 18, 5994. (b) For Pd-catalyzed decarboxylative cyanation, see:
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using [13C] and [14C]-KCN. J. Label. Compd. Radiopharm. 2015, 58, 425. (c) For applications of 14C labeling multiwalled
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Carriere, M.; Poncy, J.; Chau, Q.; Maximilien, R.; Dive, V.; Taran, F. Preparation of 14C-Labeled Multiwalled Carbon
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For recent advances in tritium labeling technology, see: (a) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-
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Lee, Y. H.; Morandi, B. Metathesis-active ligands enable a catalytic functional group metathesis between aroyl chlorides
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Nielsen, D. U.; Neumann, K. T.; Lindhardt, A. T.; Skrydstrup, T. Recent developments in carbonylation chemistry using
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A typical reconstitution strategy starts from the available unlabeled carboxylic acid, utilizes a Curtius rearrangement,
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The advantages of carbon isotope exchange at carboxylic acid centers have been recognized; however, these uncatalyzed
processes necessitate large excesses of precious radioactive reagents and extreme reaction temperatures thus are not practical
or tolerant of molecular complexity, see: (a) Charig, A.; Kinscherf, K.; Gargiullo, B.; Roman, S.; Connors, T. F.; Unkefer,
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16 Isotopic incorporation at equilibrium is expressed as *CO / COtotal x 100%. In the current study, 1.5 equiv. *COCOgen / (1.5
equiv. *COCOgen + 1.0 equiv. COsubstrate) x 100% = 60% *C.
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Specific activity (SA) is the measurement of radioactivity per mmol, reported as mCi/mmol and directly correlated to the
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