A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines, and Pharmaceuticals

Article abstract of DOI:10.1021/jacs.7b11710

Methods to incorporate deuterium and tritium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism, and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, and pharmaceuticals are converted into heterocyclic phosphonium salts and then isotopically labeled. The isotopes are incorporated in high yields and, in general, with exclusive regioselectivity.

Full text of DOI:10.1021/jacs.7b11710

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Communication
A General Strategy for Site-Selective Incorporation of Deuterium
and Tritium into Pyridines, Diazines and Pharmaceuticals
John Koniarczyk, David Hesk, Alix Overgard, Ian W Davies, and Andrew McNally
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2018
Downloaded from http://pubs.acs.org on January 29, 2018
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A General Strategy for Site-Selective Incorporation of Deuterium
and Tritium into Pyridines, Diazines and Pharmaceuticals
J. Luke Koniarczyk,† David Hesk,§ Alix Overgard,† Ian W. Davies§ and Andrew McNally*†
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†Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
§Merck Research Laboratories, Rahway, New Jersey 07065, United States.
Supporting Information Placeholder
Deuteration can Increase Drug Bioavailability and Reduce Toxicity (1)
ABSTRACT: Methods to incorporate deuterium and trit-
Deutetrabenazine
(Huntington's Disease)
– FDA Approved
O
O
ium atoms into organic molecules are valuable for me-
dicinal chemistry. The prevalence of pyridines and dia-
zines in pharmaceuticals means that new ways to label
these heterocycles will present opportunities in drug
design and facilitate absorption, distribution, metabolism
and excretion (ADME) studies. A broadly applicable
protocol is presented wherein pyridines, diazines and
pharmaceuticals are converted into heterocyclic phos-
phonium salts and then isotopically labeled. The iso-
topes are incorporated in high yields and, in general,
with exclusive regioselectivity.
N
N
i-Bu
Fe
N
N
H3CO
H3CO
H3CO
HO
H
SCys
D3CO
N
CYP-450
metabolism
D3CO
Me
N
H
N
N
O
S
Mo
S
N
N
H
HO
S
OH
D
D
NHMe
N
N
N
N
aldehyde oxidase
metabolism
N
O
Me
Me
VX-984 (Oncology)
– Phase I Clinical Trials
Selective Tritiation of the 4-Position ( ) of Pyridines in Drugs is Unknown (2)
Me
NMe2
MeO2S
Cl
T
N
Cl
N
Hydrogen isotopes play vital roles in medicinal chem-
istry and are used to study the pharmacokinetic and
pharmacodynamic (PK/PD) properties of drug com-
pounds.1 Deuterated compounds are used to elucidate
metabolic pathways, study reaction mechanisms and as
mass spectrometry and nuclear magnetic resonance
standards.2,3 Tritium, on the other hand, is often em-
ployed as a radiotracer for ADME studies.1 We herein
describe a broadly applicable, site-selective method to
install hydrogen isotopes into pharmaceuticals with dis-
tinct regioselectivity compared to existing protocols.
T
T
N
via Chirik's
Fe-catalyzed
HIE reaction
Chlorph-
enamine
N
Me
N
Loratadine
Etoricoxib
Cl
CO2Et
Selective Hydrogen Isotope Installation via Heterocyclic Phosphonium Salts (3)
O
H
Ph
P
+
D/ T
1) C–PPh3
Formation
Ph
Ph
O
O
Azaarene
X
X
D/ T
R
R
2) M2CO3,
R'OD or R'OT
R'O
X
Anion-Equivalent
N
R
N
N
For tritium labeling, a metabolically stable site is pre-
ferred to prevent the label degrading during ADME stud-
ies. For both deuteration and tritiation, it is therefore
important to have methods that install hydrogen isotopes
at various positions of pyridines and diazines.
An emerging strategy to improve the PK/PD profile of
a therapeutic is to install deuterium at sites subject to
oxidative metabolism by cytochrome P450 enzymes (eq
1).4-6 Deutetrabenazine, a treatment for symptoms of
Huntington’s disease and the first FDA approved deuter-
ated drug, mitigates metabolism by inclusion of stronger
C–D bonds, resulting in a higher dosing efficacy and
fewer adverse effects.7 However, metabolism is increas-
ingly found to occur on pyridines and diazines by mo-
lybdenum-containing enzymes such as aldehyde oxidas-
es (AOs).8 Deuterated compound VX-948 was devel-
oped because of excessive AO metabolism and is cur-
rently in phase I clinical trials.4a While AO metabolism
of C–H bonds adjacent to the heterocyclic nitrogen is
most common, this process can be unpredictable and
occur at other positions on the scaffold.
Methods to label azaarenes include transforming halo-
gentated precursors, metalation-trapping processes and
hydrogen isotope exchange (HIE) reactions.9-12 For ex-
ample, Chirik’s recent Fe-catalyzed process performs
multiple C–H to C–D/T exchanges and steric factors
control regioselectivity (eq 2).12a Our laboratory de-
scribed that a range of pyridines and diazines can be
regioselectively transformed into phosphonium salts; we
envisioned a labeling process using an isotopic form of
water or methanol and a metal carbonate (eq 3). A phos-
phorane is a key postulated intermediate that functions
as
an
azaarene
anion
equivalent,
and
a
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Table 1. Deuteration Scope: Azaarenes and Drug-Like Lead Compoundsa,b,c
1
2
3
H
PPh3
X
D
OTf
R
Tf2O; PPh3; NEt3 or DBU
K2CO3 (1.5 equiv)
X
X
R
R
4
5
6
7
8
9
CH2Cl2 or EtOAc, –78 ºC to rt
sequential addition
CD3OD:D2O 9:1 (0.3 M), rt
N
N
N
Heterocyclic
Phosphonium Salt
Deuterated
Azaarene
Azaarene
D
Azaarene Scope
D
D
Me
S
Ph
D
D
D
D
D
F
Ph
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
N
Me
N
Ph
N
Ph
N
N
N
Me
1a, (84%), 83%
1b, (87%), 89%
1c, (72%), 74%
1d, (69%), 71%
1e, (47%), 83%
1f, (59%), 84%
1g, (60%), 87%
1h, (57%), 80%
F
D
D
O
MeO
Me
Me
D
D
D
D
D
N
F3C
Ph
CN
Cl
Br
Ph
N
N
N
N
O
O
Me
N
F
N
Me
N
n-Bu
N
N
1i, (73%), 92%
1j, (64%), 91%
1k, (42%), 80%
1l, (62%), 56%b
1m, (83%), 62%
1n, (81%), 83%
1o, (85%), 77%
D
MeO
D
D
CN
Cl
p-Tol
D
Me
N
D
N
D
Et
Cl
Me
Br
N
N
MeO
n-Bu
1r, (75%), 89%
N
N
Me
Me
N
N
N
Cl
N
N
D
N
D
N
1q, (49%), 70%b
1s, (45%), 72%
1t, (83%), 80%c
1u, (64%), 65%
1v, (45%), 60%b 1w, (50%, >20:1 r.r.), 81%
1p, (76%), 92%
Small Molecule Fragments
D
S
D
D
Me
O
D
N
D
N
N
O
N
N
N
N
N
N
N
N
N
N
Et
N
S
N
N
N
N
Et
O
O
2a, (30%, >20:1 r.r.), 88%b
2b, (79%, 5.3:1 r.r.), 82%
2c, (65%), 90%
2d, (61%), 92%
2e, (89%), 78%
aIsolated yields of single regioisomers (unless stated) shown with yields of phosphonium salts in parentheses. bRun with
K2CO3 (1.5 equiv), DMF/D2O (9:1, 0.3 M). Yield calculated by 1H NMR using 1,3,5-trimethoxybenzene as a standard.
c
fragmentation-trapping event is driven by forming CO2
and Ph3PO.13,14 The process uses commercial reagents,
simple experimental protocols and has broad substrate
scope, including late-stage labeling. Notably, hydrogen
isotopes are selectively installed at the 4-position of pyr-
idines, a different regioselectivity profile from current
labeling methods and not reliant on halogenated precur-
sors.
mediates (1n-1p). When the 4-position is blocked, the 2-
position is deuterated (1q & 1r). Other heterocycles
such as azaindoles, pyrazines and pyrimidines also per-
form well in this protocol (1s-1w). Small molecule
fragments, with multiple heterocycles and functional
groups, are common as lead compounds in drug discov-
ery programs. These structures are more challenging for
selective functionalization because of the additional re-
active sites and potential for interference with the phos-
phonium salt-forming reaction. A set of representative
compounds containing benzoxazoles and piperazines are
accommodated, and pyridines can be selectively deuter-
ated over 2-amino pyrimidines (2a-2e). Our attention
then turned to deuterating pharmaceuticals and other
biologically active molecules. Late-stage functionaliza-
tion is advantageous as deuterated versions of pharma-
ceutical candidates can be rapidly accessed.16 These
compounds are more complex than simple pyridines or
lead compounds and can have unfavorable physical
properties, particularly poor solubility. Table 2 illustrates
that the phosphonium salt formation-deuteration strategy
is uniformly effective for azaarene-containing drugs.
Nicotine, pyriproxifen, triprolidine, vismodegib and
chlorphenamine all installed the isotope at the 4-position
of the pyridine with complete regioselectivity (3a-3e).
For bisacodyl, the DMF/D2O protocol was used to avoid
Table 1 shows that pyridine and diazine building
blocks can be transformed into phosphonium salts and
subsequently deuterated by a 9:1 mixture of CD3OD and
D2O using potassium carbonate as a nucleophile. The
D2O component of the reaction medium solubilizes the
carbonate base and increases the rate of deuteration (see
the Supporting Information). For pyridines 1a-1p, the
deuterium label is incorporated exclusively in the 4-
position with only traces of C–H products observed by
1H NMR. A range of monosubstituted as well as 2,3- and
2,5-disubstituted pyridines containing a diverse array of
functional groups are effective (1a-1m). For 1l, a 9:1
mixture of DMF/D2O functions effectively as an alterna-
tive solvent system, albeit with slower rates (see also 1q,
1v & 2a).15 Pyridines with 3,5-substituents are also deu-
terated with complete regioselectivity, including halo-
gens in these positions without forming pyridyne inter-
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Table 2. Deuteration Scope: Pharmaceuticals and Other Bioactive Moleculesa,b,c
1
2
3
H
PPh3
X
D
OTf
Drug
K2CO3 (1.5 equiv)
Tf2O; PPh3; NEt3 or DBU
X
X
Drug
Drug
4
5
6
7
8
9
CD3OD:D2O 9:1 (0.3 M), rt
CH2Cl2 or EtOAc, –78 ºC to rt
sequential addition
N
N
N
Heterocyclic
Phosphonium Salt
Deuterated
Drug
Azaarene
Bioactive Molecules
D
D
O
O
D
D
S
Me
Me
H
N
N
(48% D)
O
N
N
O
N
Me
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Cl
p-Tol
O
Cl
D-Pyriproxyfen (Nylar)
3b, (61%), 66%
D-Triprolidine
3c, (51%), 84%
D-Vismodegib (Erivedge)
3d, (31%, 7:1 r.r.)b, 73%
D-Nicotine
3a, (76%), 79%
D
D
D
OAc
F
Me
N
N
N
N
N
Me
N
Cl
O
N
OBn
N
Cl
D
N
Bn
Cl
OAc
D
D-Chlorphenamine (Piriton)
D-Bisacodyl (Dulcolax)
3f, (80%), 84%c
N-Bn D-Varenicline (Chantix)
D-Quinoxyfen
3i, (84%), 79%
OBn-D-Cinchonidine
3h, (58%), 71%c
3e, (40%), 86%
3g, (52%), 89%
D
N
O
O
MeN
S
N
Cl
Me
N
D
Me
D
(80% D)
Cl
N
HN
N
Me
H
Me
N
N
N
H
H
N
Me
D
AcO
O
N
H
CO2Et
D-Abiraterone Acetate (Zytiga)
D-Loratadine (Claritin)
D-Etoricoxib (Arcoxia)
3l, (73%), 96%
D-Imatinib (Gleevec)
3m, (75%, 20:1 r.r.), 92%
3j, (67%), 62%c
3k, (88%), 79%, 73%c
aIsolated yields of single regioisomers (unless stated) shown with yields of phosphonium salts in parentheses. bSalt isolated
with 8% of an unknown impurity. cRun with K2CO3 (1.5 equiv), DMF/D2O (9:1, 0.3 M).
methanolysis of the phenolic acetates (3f). Quinoxyfen,
as well as protected versions of cinchonidine and vare-
nicline are applicable to the protocol with the isotope
installed at the 2-position of the nitrogen heteroaromatic
(3g-3i). Abiraterone acetate, a prostate cancer drug, is
also effective in this two-step protocol (3j). Chirik’s Fe-
catalyzed HIE reaction deuterated loratadine at the 2-
and 3-positions of the pyridine and highlights the dis-
tinct, and contra-steric, 4-position selectivity observed
using this protocol (3k).12a Etoricoxib and imatinib are
challenging substrates due to the bis-heterobiaryl motifs
in their structures. For etoricoxib, we observe exclusive
reactivity at the 2,5-disubstituted pyridine17 and imatinib
is deuterated in a 20:1 ratio at the pyridine 4-position
over the 2-amino pyrimidine (3l & 3m).
sioned a means to generate high-concentration MeOT by
a metal-catalyzed HIE between MeOH and T2 gas.18-20
T2 gas is the preferred source due to high isotopic purity
and safer handling. In practice, a solution of MeOH in
THF is exposed to 1 Ci T2 gas at 0.13 atmospheres with
Pd/C as the exchange catalyst (eq 4). After the exchange,
the mixture is filtered, rinsed with the respective solvent
and added to the phosphonium salt and carbonate. The
exchange protocol could be used in other applications
that require high activity solutions of MeOT (or THO).
We chose a selection of phosphonium derivatives of
pharmaceuticals to test these protocols and the radio-
chemical yields are well within the range required for
ADME studies (Table 3). Triprolidine and abiraterone
acetate salts are tritiated by MeOT following the HIE
protocol and stirring in THF with Cs2CO3 (4c & 4j).
Tritiated loratadine (4k) is obtained via this method; a
fresh bottle of Cs2CO3 resulted in higher mCi values
compared with base stored on the benchtop representing
a more effective and reliable protocol, presumably due
to lower residual water content. Stock solutions of THO
can also be used in both THF and DMF to account for
molecules with different solubilites. A tritium analogue
of etoricoxib was obtained in good radiochemical yield
using both methods (4l). Finally, a 20:1 mixture of
imatinib phosphonium salt regioisomers functioned well
To tritiate pharmaceuticals, we adapted the reaction
protocol to accommodate the typical isotope sources
used in radiolabeling laboratories. Firstly, stock solu-
tions of tritiated water are available and would represent
a convenient means for labeling, provided sufficient
radiochemical yields are observed. Secondly, we envi
Generation of high-concentration MeOT via hydrogen isotope exchange
Pd/C cat.
MeO
H
MeO
T
(4)
T2 (1 Ci), THF, r.t.
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No competing financial interests have been declared.
in the MeOT tritiation protocol with the calculated radi-
1
2
3
4
5
6
7
8
ochemical yield closely matching an isolated sample of
radiopure material (4m). This study shows that pyridine-
containing drugs can be tritiated and the methods are
straightforward to apply in radiolabeling laboratories.
ACKNOWLEDGMENT
This work was supported by start-up funds from Colorado
State University.
Table 3. Tritiation of Pharmaceuticalsa
REFERENCES
PPh3
T
(1) (a) Lappin, G.; Temple, S. Radiotracers in Drug Development.
CRC Press, Taylor and Francis Group: Boca Raton, FL, 2006. (b)
Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf,
L. Chem. Res. Toxicol. 2012, 25, 532. (c) Marathe, P. H.; Shyu, W.
C.; Humphreys, W. G. Curr. Pharm. Des. 2004, 10, 2991. (d) Elmore,
C. S. Annu. Rep. Med. Chem. 2009, 44, 515. (e) Lockley, W. J. S.;
McEwan, A.; Cooke, R. J. Labelled Comp. Radiopharm. 2012, 55,
235. (f) Voges, R.; Heys, J. R.; Moenius, T. Preparation of Com-
pounds Labelled with Tritium and Carbon-14. John Wiley & Sons,
Chichester, 2009.
(2) (a) Scheppele, S. E. Chem. Rev. 1972, 72, 511. (b) Cleland, W.
W. Arch. Biochem. Biophys. 2005, 433, 2.
(3) Busenlehner, L. S.; Armstrong, R. S. Arch. Biochem. Biophys.
2005, 433, 34.
(4) (a) Mullard, A. Nat. Rev. Drug Discov. 2016, 15, 219. (b) Gant,
T. G. J. Med. Chem. 2013, 57, 3595. (c) Elmore, C. S.; Bragg, R. A.
Bioorg. Med. Chem. Lett. 2015, 25, 167. (d) Harbeson, S. L.; Tung, R,
D. Annu. Rep. Med. Chem. 2011, 46, 403.
(5) Jarman, M.; Poon, G. K.; Rowlands, M. G.; Grimshaw, R. M.;
Horton, M. N.; Potter, G. A.; McCague. R. Carcinogenesis 1995, 4,
683.
(6) Harbeson, S. L.; Tung, R. D. MedChem. News 2014, 8, 8.
(7) Mullard, A. Nat. Rev. Drug Discov. 2017, 16, 305.
(8) Xu, Y.; Li, L.; Wang, Y.; Xing, J.; Zhou, L.; Zhong, D.; Luo,
X.; Jiang, H.; Chen, K.; Zheng, M.; Deng, P.; Chen, X. J. Med. Chem.
2017, 60, 2973.
(9) (a) Alonso, F.; Beletskaya, I. P; Yus, M. Chem. Rev. 2002, 102,
4009. (b) Janni, M.; Peruncheralathan, S. Org. Biomol. Chem. 2016,
14, 3091.
(10) (a) Plé, N.; Turck, A.; Couture, K.; Quéguiner, G. J. Org.
Chem. 1995, 60, 3781. (b) Pierrat, P.; Gros, P.; Fort, Y. Synlett 2004,
2319. (c) Hawad, H.; Bayh, O.; Hoarau, C.; Trécourt, F.; Quéguiner,
G.; Marsais, F. Tetrahedron 2008, 64, 3236. (d) Grainger, R.; Nikmal,
A.; Cornella, J.; Larrosa, I. Org. Biomol. Chem. 2012, 10, 3172.
(11) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmerman. Angew. Chem.
Int. Ed. 2007, 46, 7744.
(12) (a) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, P.; Chirik, P. Na-
ture 2016, 529, 195. (b) Crabtree, R.; Felkin, H.; Morris, G. J. Or-
ganomet. Chem. 1977, 141, 205. (c) Nilsson, G. N.; Kerr, W. J. J.
Labelled Comp. Radiopharm. 2010, 53, 662.
(13) (a) Hilton, M. C.; Dolewski, R. D.; McNally, A. J. Am. Chem.
Soc. 2016, 138, 13806. (b) Anders, E.; Markus, F. Tet. Lett. 1987, 28,
2675. (c) Haase, M.; Goerls, H.; Anders, E. Synthesis 1998, 195.
(14) (a) Shimada, M.; Sugimoto, O.; Sato, A.; Tanji, K. Heterocy-
cles 2011, 83, 837. (b) Nguyen, B. V.; Burton, D. J. J. Fluorine
Chem. 2012, 135, 144. (c) Deng, Z.; Lin, J.-H.; Xiao, J.-C. Nat.
Commun. 2016, 7:10337.
(15) Typical reaction time in 9:1 CD3OD/D2O is 3 hours vs. 15
hours in 9:1 DMF/D2O. Compounds 1l, 1q, 1v, 2a, 3f, 3h, 3j and 3k
use the latter protocol.
(16) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska,
S. W. Chem. Soc. Rev. 2016, 45, 546.
(17) The C–D bonds at the methyl sulfone can be converted back
to C–H bonds by stirring with K2CO3 in 9:1 MeOH/H2O.
(18) Sajiki, H.; Kurita, T.; Esaki, H.; Aoki, F.; Maegawa, T.; Hiro-
ta, K. Org. Lett. 2004, 6, 3521.
OTf
Drug
A
Cs2CO3, MeOT, THF, rt
Drug
9
B
C
Cs2CO3, THO, THF, rt
K2CO3, THO, DMF, rt
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Heterocyclic
Phosphonium Salt
Tritiated
Drug
T
T
N
Cl
T
Me
N
N
N
Me
H
H
N
T-Loratadine, 4k
AcO
CO2Et
Me
11.5b Ci mmol-1
21.1c Ci mmol-1
1.8b,d Ci mmol-1
4.6e Ci mmol-1
T-Abiraterone
Acetate, 4j
A
A
B
C
T-Triprolidine, 4c
10.6b Ci mmol-1
18.4c Ci mmol-1
A
A
MeN
O
O
N
S
N
T
Me
Cl
HN
N
Me
N
N
N
O
N
H
Me
T
19.1c Ci mmol-1
A
27.5c Ci mmol-1
17.6b,d Ci mmol-1
A
B
T-Etoricoxib,
T-Imatinib,
(isolated 17.3 Ci mmol-1
at 99.6% radiochemical purity)
4l
4m
aMeOH HIE protocol: MeOH (10 µL), 6.5 mg Pd/C, 1.0
Ci T2 (0.13 atm). 8.3-29.1 mg of phosphonium salts used in
this study. Reported Ci mmol-1 values calculated from the
crude Ci mmol-1 corrected for radiochemical purity. See
Supporting Information for experimental details. bBenchtop
Cs2CO3 used. cFresh bottle of Cs2CO3 used. dUsing 500
mCi THO at 50 Ci/cc. eUsing 150 mCi THO at 50 Ci/cc.
In summary, heterocyclic phosphonium salts are
broadly applicable as reagents to install hydrogen iso-
topes onto azaarenes and pharmaceuticals. The im-
portant features of this approach are: orthogonal regiose-
lectivity compared to existing methods, wide substrate
scope and simple experimental protocols. We believe
that these methods will find applications in drug discov-
ery and radiolabeling groups due to the interest in deu-
terated therapeutics and the necessity for ADME studies.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Morimoto, H.; Williams, P. G. Fusion Sci. Technol. 1992, 21,
246.
(20) After submitting this manuscript, MacMillan independently
reported a related HIE approach: Loh, Y. Y.; Nagao, K.; Hoover, A.
J.; Hesk, D.; Rivera, N. R.; Colletti, S. L.; Davies, I. W.; MacMillan,
D. W. C. Science 2017, 358, 1182.
AUTHOR INFORMATION
*andy.mcnally@colostate.edu.
Funding Sources
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Site-Selective Deuteration and Tritiation via Heterocyclic Phosphonium Salts
O
O
O
O
S
S
Me
Me
Cl
Cl
1) C–P Bond-Formation
2) M2CO3, D or T Installation
N
N
N
N
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Me
D/ T
H
Me
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Broad scope
Distinct regioselectivity
Simple protocols
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