Catalytic Deuterium Incorporation within Metabolically Stable β-Amino C-H Bonds of Drug Molecules

Article abstract of DOI:10.1021/jacs.9b08662

An efficient deuteration process of β-amino C-H bonds in various N-alkylamine-based pharmaceutical compounds has been developed. Catalytic reactions begin with the action of Lewis acidic B(C₆F₅)₃ and Br?nsted basic N-alkylamine, converting a drug molecule into the corresponding enamine. The acid/base catalysts also promote the dedeuteration of acetone-d₆ to afford a deuterated ammonium ion. Ensuing deuteration of the enamine then leads to the formation of β-deuterated bioactive amines with up to 99% deuterium incorporation.

Full text of DOI:10.1021/jacs.9b08662

Subscriber access provided by University of Glasgow Library
Communication
Catalytic Deuterium Incorporation within Metabolically
Stable #-Amino C–H Bonds of Drug Molecules
Yejin Chang, Ahmet Yesilcimen, Min Cao, Yuyang Zhang,
Bochao Zhang, Jessica Zee Chan, and Masayuki Wasa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Sep 2019
Downloaded from pubs.acs.org on September 3, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Catalytic Deuterium Incorporation within Metabolically Stable -Amino C–H Bonds of Drug
Molecules
‡
‡
Yejin Chang, Ahmet Yesilcimen, Min Cao, Yuyang Zhang, Bochao Zhang, Jessica Z. Chan, and Masayuki Wasa*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
RECEIVED DATE (automatically inserted by publisher); wasa@bc.edu
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Abs tract: An efficient deuteration process of -amino C–H
bonds in various N-alkylamine-based pharmaceutical
compounds has been developed. Catalytic reactions begin
with the action of Lewis acidic B(C
N-alkylamine, converting drug molecule into the
corresponding enamine. The acid/base catalysts also
promote the dedeuteration of acetone-d to afford a
6 5 3
F ) and Brønsted basic
a
6
deuterated ammonium ion. Ensuing deuteration of the
enamine then leads to the formation of -deuterated
bioactive amines with up to 99% deuterium incorporation.
Deuterium-labeled pharmaceuticals are pivotal diagnostic
tools in research aimed at determination of the corresponding
1
-6
biological outcomes and metabolites. Drugs containing C–D
bonds have been prepared through multistep synthesis involving
3
the reduction of unsaturated or halogenated intermediates.
However, innovations in organometal-catalyzed C–H activation
have enabled direct hydrogen isotope exchange (HIE) at C–H
4-6
bonds for deuterium.
In particular, HIE reaction targeting
3
C(sp )–H bonds of pharmaceuticals that contain an N-alkylamine
unit is in high demand because these entities constitute over 50%
7
of the top-selling commercial drugs. The state-of-the-art
processes include Beller’s - and -amino C–H deuteration of
metoclopramide (A1) and two other structurally related drug
5
molecules promoted by Ru-based Shvo catalyst (Figure 1A).
MacMillan’s photoredox-mediated -deuteration and -tritiation
represents a notable strategy for isotopic labelling of a range of N-
6
alkylamine-based drugs (Figure 1B). Still, development of
methods for regioselective deuteration of poorly reactive -amino
3
C(sp )–H bonds of drugs containing Lewis acid- and base-
sensitive functional groups with an inexpensive deuterium source
and promoted by non-precious metal-based catalysts is a
8
,9
significant
challenge.
Regioselective
deuteration
of
metabolically stable -amino C–H bonds (vs more labile -amino
C–H bonds) is particularly attractive as it minimizes the loss of
1-3
the label due to exchange.
We began by contemplating a possible way to design a
method for deuteration of biologically active compounds that
contain an N-alkylamine unit (1) with readily available acetone-d
as a source of deuterium (Figure 1C). We considered utilizing a
combination of Lewis acid and Brønsted base catalysts that would
6
2
1
0-12
function cooperatively.
6 5 3
We envisioned that B(C F ) could
receive a hydride from an amine (1), generating a borohydride and
13-19
an iminium ion (I).
Subsequently, a Brønsted basic amine
1
3-16
catalyst would deprotonate I, furnishing enamine II.
Figure 1. Amino C–H deuteration of biologically active molecules.
Concurrently, the N-alkylamine could dedeuterate B(C
6 5 3
F ) -
activated acetone-d 2, generating an enolate and a deuterated
6
We first set out to identify a desirable combination of
2
0
ammonium ion (III). Ensuing deuteration (IV) of the enamine II
by III gives an iminium ion; subsequent borohydride reduction
would afford -deuterated product 3. Here, we report the
development of a catalyst system for -amino C–H deuteration of
bioactive amines.
catalysts. We probed the ability of B(C
bases to catalyze the reaction between verapamil 1a and acetone-
2 (6.8 equivalent), generating 3a (Table 1). Treatment of 1a
and 2 with 5.0 mol% B(C and 10 mol% NEt , NBn , or 1,2,2,
,6-pentamethylpiperidine (PMP) afforded 3a in >90% yield
6 5 3
F ) and various Brønsted
d
6
6
F
5
)
3
3
3
6
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
(
toluene, 125 °C, 1 h); 16-34% of -amino C–H bonds were
chromatography. Labeling took place with high regioselectivity
for -amino C–H bonds. In addition, drug molecules that possess
acidic -carbonyl C–H bonds also underwent efficient deuteration
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
converted to C–D bonds (entries 1–3). With more Brønsted basic
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), no labeling was
observed (entry 4). When the transformation was performed
without a Brønsted base co-catalyst, 3a was generated with 35%
and 21% deuterium incorporation (entry 5), suggesting that N-
alkylamines 1a and/or 3a can promote deprotonation of the
iminium ion (I, Figure 1C; NR
incorporation diminished to <10% with 5.0 mol% of B(C
reaction temperature of 100 °C (entry 6), but when the reaction
mixture was heated at 150 °C, 3a was obtained with >80%
1
(3d, 3j) based on analysis of H NMR spectra of unpurified
mixtures. Nonetheless, in case of 3d, -carbonyl C–D bonds of
indolin-2-one underwent H–D exchange during purification.
Table 2. Deuteration of Acyclic -Amino C–H Bonds a,b,c
3
= 1a and/or 3a). Deuterium
and
6 5 3
F )
labeling (entry 7). With 10 mol% B(C
improvement (entry 8, 88% and 92%). However, by reacting 1a
with two batches of 5.0 mol% of B(C and 2 (6.8 equivalent),
we were able to obtain 3a with >95% deuterium incorporation
entry 9). There was no labeling without B(C or when the
less hindered BF or the less Lewis acidic BPh were used (entries
0–12). These findings support the notion that strongly acidic
B(C together with sterically demanding and electron-rich N-
6 5 3
F ) there was only minor
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6 5 3
F )
(
6 5 3
F )
3
3
1
6 5 3
F )
1
0
alkylamine constitute the most effective combination.
Table 1. Evaluation of Reaction Parameters a,b,c,d
a
6
Conditions: verapamil (1a, 0.1 mmol), acetone-d (2, 0.68 mmol), organoborane,
Brønsted base, toluene (0.4 mL), under N
2
, 1 h. b Yield and deuterium incorporation
level was determined by 1H NMR analysis of unpurified reaction mixtures with
a
6 5 3
Conditions: N-alkylamine (1, 0.2 mmol), acetone-d6 (2, 1.36 mmol), B(C F ) (10
b
mesitylene as the internal standard. c Green label indicates sites that are beta to N. d
mol%), toluene (0.8 mL), under N , 150 °C, 3 h.
product. Deuterium incorporation level was determined by H NMR analysis of the
isolated and purified product. Green label indicates sites that are beta to N. Red
Yield of isolated and purified
1
2
Conditions: verapamil (1a, 0.2 mmol), acetone-d
mol%), toluene (0.8 mL), under N , 150 C, 1 h. Isolated and purified 3a was reacted
with acetone-d (2, 1.36 mmol), B(C (5.0 mol%), toluene (0.8 mL), under N
50 C, 1 h.
6
(2, 1.36 mmol), B(C
6 5
F
)
3
(5.0
c
2
label is used for any other sites that undergo deuteration. Blue color indicates
6
F
6 5
)
3
2
,
protecting groups. d Conditions: N-alkylamine (1, 0.2 mmol), acetone-d
mmol), B(C F ) (5.0 mol%), toluene (0.8 mL), under N
6 5 3 2
6
(2, 1.36
, 150 °C, 3 h. After the
filtration of the crude reaction mixture through a pad of silica gel and removal of
volatiles, acetone-d (2, 1.36 mmol), B(C (5.0 mol%), and toluene (1.0 mL)
were added under N , and then heated at 150 °C, 3 h. The reaction was carried out
1
Acyclic -amino C–H bonds in a number of pharmaceuticals
1a–1j) underwent efficient deuteration (Table 2). This protocol
6
6 5 3
F )
(
e
2
was found to be compatible with compounds that contain an array
of Lewis acid-sensitive functional groups. In addition to the N-
alkylamine units of 1a–1j, cyano (1a), ester (1b), amide (1d, 1e,
1
3
in two batches, using 10 mol% of B(C
second. For details, see the SI.
6 5 3
F ) in the first batch, and 5.0 mol% in the
For substrates that possess electronically and sterically
disparate -amino C–H bonds (1a, 1b, 1c, 1d, 1g, 1h, 1j),
deuterium labeling occurred at varying levels. With verapamil 1a,
f) and ketone (1j) were tolerated to give the deuteration products
a–3j in 77 to >95% yield after purification by silica gel
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
benzylic C2–H and non-benzylic C4–H bonds were converted to
cinacalcet 3h was obtained with >98% of -amino C2–H bonds
selectively converted into C–D bonds. With less sterically
hindered secondary amines nortriptyline 1i and propafenone 1j,
1
2
3
4
5
6
7
8
9
C–D bonds in >95%, but deuteration of non-benzylic C4–H bonds
was more efficient (Table 1, entries 5-9). With dicyclomine 1b,
while 90% of C2’–H bonds of N-ethyl groups was deuterated,
only 23% of C1–H bonds adjacent to an ester group were
converted to C–D bonds. Similar reactivity was observed with
clomiphene 1c: 90% of C2’–H bonds were converted into C2’–D
bonds, but 15% of -aryloxy C1–H bonds were deuterated.
Ropinirole 1d was labeled at benzylic C1–H bonds (63%), and
C2’–H bonds of N-propyl group (86%).
Although the catalytic protocol tolerates an array of functional
groups, isotopic labeling was more efficient with substrates
bearing a protecting group. For instance, 80% of -C–H bonds of
lidocaine 1e, which possesses acidic amide N–H bonds, was
converted to C–D bonds to give 3e. However, deuteration of N-
benzyl-protected lidocaine 1f proceeded more efficiently to afford
3f with 96% d-incorporation; in addition, deuteration of -
carbonyl C–H bonds was also observed (9%). Cinacalcet 1g
containing a secondary amine moiety was a compatible substrate
to provide 3g (63% [C2] and 8% [C2’]), and N-benzyl-protected
6
their reaction with acetone-d may inhibit labeling. However, with
an N-benzhydryl group installed, 3i and 3j could be readily
generated. Silyl protection of the secondary alcohol proved to be
effective in the case of propafenone 1j, giving 3j (76% [C2] and
0% at more sterically hindered [C2’]).
Next, we investigated possible labeling of various
pharmaceuticals that contain cyclic -amino C–H bonds (Table 3;
1k–1s). A variety of Lewis acid-sensitive heterocycles such as
piperidine (1k–1q), 1,4-diazepane (1r), piperazine (1s), thiophene
(1k, 1l), indanone (1m), benzodioxole (1o, 1p), benzothiophene
(1q), as well as benzoimidazole (1r) were tolerated to give the
corresponding deuteration products in 85 to >95% yield. With
clopidogrel 1k, prasugrel 1l, and donepezil 1m, both -amino C–
H bonds and enolizable -carbonyl C–H bonds underwent
efficient deuteration to give 3k–3m, but acidic -keto C–D bond
of 3l was converted to C–H bond during purification. Less acidic
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

-amide C–H bond of bupivacaine 1n was not deuterated. With
bupivacaine 1n and raloxifene 1q that contain acyclic and cyclic
-amino C–H bonds, labeling of the cyclic C–H bond was more
Table 3. Deuteration of Cyclic Amino C–H Bonds a,b,c

efficient (>90% vs 29% for the acyclic C–H). N-Benzyl (1o) and
N-benzhydryl (1p)-protected paroxetine gave 3o and 3p,
respectively. The level of labeling for the more hindered 3p (92%)
was superior to 3o (76%). Furthermore, deuteration of the C5–H
bond occurred selectively, while the tertiary C3–H bond remained
intact. Deuteration of emedastine 1r was found to take place at
C2–H (33%) and C6–H (61%) bonds. All eight C–H bonds of
piperazine ring of O-TBS-protected dropropizine 1s underwent
deuteration to afford 3s (>86%). Using this protocol, -amino C–
H deuteration occurred only when these bonds were also alpha to
a carbonyl group (3f) or beta to a N atom (3r and 3s).
The method is scalable. Treatment of 1.4 g (3.0 mmol) of
6 5 3 6
verapamil 1a with 5.0 mol% B(C F ) , 20.4 mmol of acetone-d
(toluene, 12 h, 150 °C), followed by filtration through a pad of
silica gel and repeating the aforementioned procedure afforded 3a
in 95% yield (2.9 mmol, 1.3 g) and >93% deuterium incorporation
(Scheme 1).
Scheme 1. Scale-up experiment
To summarize, we have designed an efficient and
regioselective deuterium labeling of -amino C–H bonds in
various bioactive molecules, provided that sufficient steric
congestion is present around the reacting amine. By implementing
6 5 3
the cooperative action of B(C F ) and N-alkylamine catalyst
system, we show that it is possible to convert an N-alkylamine-
based pharmaceutical compound to the corresponding enamine,
and that the same catalyst system can generate a labeling agent
a
6 6 5 3
Conditions: N-alkylamine (1, 0.2 mmol), acetone-d (2, 1.36 mmol), B(C F ) (10
, 150 °C, 3 h. b Yield of isolated and purified
mol%), toluene (0.8 mL), under N
2
1
product. Deuterium incorporation level was determined by H NMR analysis of the
isolated and purified product. c Green label indicates sites that are beta to N. Red
label is used for any other sites that undergo deuteration. Blue color indicates
6
from acetone-d . The principles outlined herein, entailing
protecting groups. d Conditions: N-alkylamine (1, 0.2 mmol), acetone-d
conversion of amine containing drugs into enamines and its
reaction with in situ generated electrophilic partner, provide a new
rational framework for late-stage modification of a drug candidate.
Studies along these lines are in progress.
6
(2, 1.36
, 150 °C, 3 h. After the
filtration of the crude reaction mixture through a pad of silica gel and removal of
volatiles, acetone-d (2, 1.36 mmol), B(C (5.0 mol%), and toluene (1.0 mL)
were added under N , and then heated at 150 °C, 3 h. The reaction was carried out
6 5 3 2
mmol), B(C F ) (5.0 mol%), toluene (0.8 mL), under N
6
6 5 3
F )
e
2
in two batches, using 10 mol% of B(C
second. For details, see the SI.
6 5 3
F ) in the first batch, and 5.0 mol% in the
Author Information
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
Corresponding Author
*wasa@bc.edu
(6) Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.; Rivera, N. R.; Colletti, S.
L.; Davies, I. W.; MacMillan, D. W. C. Photoredox-catalyzed deuteration
and tritiation of pharmaceutical compounds. Science 2017, 358,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Author Contributions
1
182−1187.
‡
Y. C. and A. Y. contributed equally to this paper.
(7) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical Journey of
Innovative Organic Architectures That Have Improved Our Lives. J. Chem.
Educ. 2010, 53, 1348−1349.
Notes
The authors declare no competing financial interest.
3
(
8) For reviews involving transformations of C(sp )−H bonds, see: (a) Dick, A.
Acknowledgements. Financial support was provided by the NIH
R.; Sanford, M. S. Transition metal catalyzed oxidative functionalization
of carbon-hydrogen bonds. Tetrahedron 2006, 62, 2439−2463. (b)
Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, monoanionic auxiliary-
directed functionalization of carbon-hydrogen bonds. Acc. Chem. Res.
2015, 48, 1053−1064. (c) He, J.; Wasa, M.; Chan, K. S. L.; Shao., Q; Yu,
J.-Q. Palladium-catalyzed transformations of alkyl C−H bonds. Chem. Rev.
2017, 117, 8754−8786. (d) Chu, J. C. K.; Rovis, T. Complementary
(
GM-128695), the Sloan Foundation, and Boston College. We thank
Professor Amir H. Hoveyda for helpful discussions.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
strategies for directed C(sp )−H functionalization: A comparison of
References
transition-metal-catalyzed activation, hydrogen atom transfer, and
(
1) For selected reviews on hydrogen isotope exchange, see: (a) Atzrodt, J.;
Derdau, V.; Fey, T.; Zimmermann, J. The Renaissance of H/D Exchange.
Angew. Chem., Int. Ed. 2007, 46, 7744−7765. (b) Harbeson, S. L.; Tung, R.
D. Deuterium Medicinal Chemistry: A New Approach to Drug Discovery
and Development. MedChem News 2014, 2, 8−22. (c) Atzrodt, J.; Derdau,
V.; Kerr, W. J.; Reid, M. Deuterium- and Tritium-Labelled Compounds:
Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57,
carbine/nitrene transfer. Angew. Chem., Int. Ed. 2018, 57, 62−101. (e) He,
3
C.; Whitehurst, W. G.; Gaunt, M. J. Palladium-Catalyzed C(sp )–H Bond
Functionalization of Aliphatic Amines. Chem 2019, 5, 1031−1058.
9) (a) Yu, P.; Zheng, S.-C.; Yang, N.-Y.; Tan, B.; Liu, X.-Y. Phosphine-
catalyzed remote -C−H functionalization of amines triggered by
(
trifluoromethylation
bistrifluoromethylated enamides and oxazoles. Angew. Chem., Int. Ed.
015, 54, 4041−4045. (b) Ma, L.; Paul, A.; Breugst, M.; Seidel, D. Redox-
of
alkenes:
One-pot
synthesis
of
1
758−1784. (d) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C−H
Functionalisation for Hydrogen Isotope Exchange. Angew. Chem., Int. Ed.
018, 57, 3022−3047. (e) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani,
A. A. Applications of Deuterium in Medicinal Chemistry. J. Med. Chem.
019, 62, 5276−5297.
2
neutral aromatization of cyclic amines: Mechanistic insights and
harnessing of reactive intermediates for amine - and -C−H
functionalization. Chem. Eur. J. 2016, 22, 18179−18189.
2
2
(
10)For reviews of frustrated Lewis pair chemistry, see: (a) Frustrated Lewis
Pairs I: Uncovering and Understanding; Stephan, D. W.; Erker, G. Eds.;
Springer: Berlin, 2013; Vol. 332. (b) Frustrated Lewis Pairs II: Expanding
the Scope; Erker, G.; Stephan, D. W. Eds.; Springer: Berlin, 2013; Vol.
(2) (a) Penner, N.; Klunk, L. J.; Prakash, C. Human Radiolabeled Mass
Balance Studies: Objectives, Utilities and Limitations. Biopharm. Drug
Dispos. 2009, 30, 185−203. (b) Miyoshi, S.; Mitsuoka, K.; Nishimura, S.
A. in Radioisotopes—Applications in Bio-Medical Science, Singh, N., Ed.;
InTech–Open Access Publisher, 2011; Chapter 5.
3
34. (c) Ashley, A. E.; O'Hare, D. FLP-mediated activations and
reductions of CO
2
and CO. Top. Curr. Chem. 2013, 334, 191−218. (d)
(
3) For the multistep synthesis of hydrogen isotope-labeled drugs, see: (a)
Maltais, F.; Jung, Y. C.; Chen, M.; Tanoury, J.; Perni, R. B.; Mani, N.;
Laitinen, L.; Huang, H.; Liao, S.; Gao, H.; Tsao, H.; Block, E.; Ma, C.;
Shawgo, R. S.; Town, C.; Brummel, C. L.; Howe, D.; Pazhanisamy, S.;
Raybuck, S.; Namchuk, M.; Bennani, Y. L. In Vitro and In Vivo Isotope
Effect with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of
Deuterated Telaprevir versus Telaprevir in Rats. J. Med. Chem. 2009, 52,
Feng, X.; Du, H. Metal-free asymmetric hydrogenation and hydrosilylation
catalyzed by frustrated Lewis pairs. Tetrahedron Lett. 2014, 55,
6
959−6964. (e) Stephan, D. W.; Erker, G. Frustrated Lewis pair chemistry:
Development and perspectives. Angew. Chem., Int. Ed. 2015, 54,
400−6441. (f) Stephan, D. W. Frustrated Lewis pairs. J. Am. Chem. Soc.
6
2015, 137, 10018−10032. (g) Oestreich, M.; Hermeke, J.; Mohr, J. A
unified survey of Si–H and H–H bond activation catalysed by electron-
deficient boranes. Chem. Soc. Rev. 2015, 44, 2202−2220. (h) Stephan, D.
W. The broadening reach of frustrated Lewis pair chemistry. Science 2016,
7
993−8001. (b) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D.
J. Metal-catalysed isotopic exchange labelling: 30 years of experience in
pharmaceutical R&D. J. Labelled Comp. Radiopharm. 2010, 53, 731−738.
(c) Lockey, W. J. S.; McEwen, A.; Cooke, R. Tritium: a coming of age for
drug discovery and development ADME Studies. J. Labelled Comp.
Radiopharm. 2012, 55, 235−257. (d) Elmore, C. S.; Bragg, R. A. Isotope
chemistry; a useful tool in the drug discovery arsenal. Bioorg. Med. Chem.
Lett. 2015, 25, 167−171.
3
54, aaf7229.
(
11)For selected reviews on cooperative catalysis, see: (a) Tian, S-K.; Chen,
Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, Li. Asymmetric Organic
Catalysis with Modified Cinchona Alkaloids. Acc. Chem. Res. 2004, 37,
6
21−631. (b) Shibasaki, M.; Kumagai, N. in Cooperative Catalysis:
Designing Efficient Catalysts for Synthesis, Peters, R., Eds.; Wiley-VCH:
(
4) For organometal-catalyzed hydrogen isotope exchange reactions, see: (a)
Pieters, G.; Taglang, C.; Bonnefille, E.; Gutmann, T.; Puente, C.; Berthet,
J.-C.; Dugave, C.; Chaudret, B.; Rousseau, B. Regioselective and
Stereospecific Deuteration of Bioactive Aza Compounds by the Use of
Ruthenium Nanoparticles. Angew. Chem., Int. Ed. 2014, 53, 230−234. (b)
Taglang, C.; Martinez-Prieto, L. M.; del Rosal, I.; Maron, L.; Poteau, R.;
Philippot, K.; Chaudret, B.; Perato, S.; Lone, A. S.; Puente, C.; Dugave,
C.; Rousseau, B.; Pieters, G. Enantiospecific C−H Activation Using
Ruthenium Nanocatalyst. Angew. Chem., Int. Ed. 2015, 54, 10474−10477.
New York, 2015; Chapter 1.
(12)For selected reviews on enantioselective non-covalent catalysis, see: (a)
Phipps, R. J.; Hamilton, G. L.; Toste, F. D. The progression of chiral
anions from concepts to applications in asymmetric catalysis. Nat. Chem.
2012, 4, 603−614. (b) Brak, K.; Jacobsen, E. N. Asymmetric Ion-Pairing
Catalysis. Angew. Chem., Int. Ed. 2013, 52, 534−561. (c) Neel, A. J.;
Hilton, M. J.; Sigman, M. S.; Toste, F. D. Exploiting non-covalent π
interactions for catalyst design. Nature 2017, 543, 637−646.
(13) (a) Millot, N.; Santini, C. C.; Fenet, B.; Basset, J. M. Formation and
characterization of zwitterionic stereoisomers from the reaction of
(c) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-catalyzed
tritiation of pharmaceuticals. Nature 2016, 529, 195−199. (d) Hale, L. V.
A.; Szymczak, N. K. Stereoretentive Deuteration of -Chiral Amines with
+
−
B(C
Inorg. Chem. 2002, 2002, 3328−3335. (b) Dureen, M. A.; Brown, C. C.;
Stephan, D. W. Addition of enamines or pyrroles and B(C “Frustrated
6 5 3 2 2 6 5 3
F ) and NEt Ph: (E)- and (Z)-[EtPhN =CHCH −B (C F ) ]. Eur. J.
D
2
O. J. Am. Chem. Soc. 2016, 138, 13489−13492. (e) Chatterjee, B.;
Krishnakumar, V.; Gunanathan, C. Selective -Deuteration of Amines and
Amino Acids using D O. Org. Lett. 2016, 18, 5892−5895. (f) Kerr, W. J.;
6 5 3
F )
Lewis Pairs” to alkynes. Organometallics 2010, 29, 6422−6432. (c) Farrell,
J. M.; Heiden, Z. M.; Stephan, D. W. Metal-Free Transfer Hydrogenation
Catalysis by B(C F ) . Organometallics 2011, 30, 4497−4500.
6 5 3
2
Lindsay, D. M.; Reid, M.; Atzrodt, J.; Derdau, V.; Rojahn, P.; Weck, R.
Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions:
C−H activation of unprotected tetrazoles. Chem. Commun. 2016, 52,
6669−6672. (g) Valero, M.; Weck, R.; Gussregen, S.; Atzrodt, J.; Derdau,
Volker. Highly Selective Directed Iridium-Catalyzed Hydrogen Isotope
Exchange Reactions of Aliphatic Amides. Angew. Chem., Int. Ed. 2018, 57,
(14) Focante, F.; Mercandelli, P.; Sironi, A.; Resconi, L. Complexes of
tris(pentafluorophenyl)boron with nitrogen-containing compounds:
Synthesis, reactivity and metallocene activation. Coord. Chem. Rev. 2006,
2
50, 170−188.
(15) (a) Zhang, J.; Park, S.; Chang, S. Catalytic access to bridged sila-N-
8
159− 8163. (h) Kerr, W. J.; Mudd, R. J.; Reid, M.; Atzrodt, J.; Derdau, V.
3
2
heterocycles from piperidines via cascade sp and sp C–Si bond formation.
J. Am. Chem. Soc. 2018, 140, 13209−13213. (b) Li, R.; Chen, Y.; Jiang,
K.; Wang, F.; Lu, C.; Nie, J.; Chen, Z.; Yang, G.; Chen, Y.-C.; Zhao, Y.;
3
Iridium-Catalyzed Csp −H Activation for Mild and Selective Hydrogen
Isotope Exchange. ACS. Catal. 2018, 8, 10895−10900. (i) Sawama, Y.;
Nakano, A.; Matsuda, T.; Kawajiri, T.; Yamada, T.; Sajiki, H. H−D
Exchange Deuteration of Arenes at Room Temperature. Org. Process Res.
Dev. 2019, 23, 648−653.
Ma, C. B(C
using p-quinone methides via borrowing hydrogen. Chem. Commun. 2019,
5, 1217−1220.
6 5 3
F ) -catalyzed redox-neutral β-alkylation of tertiary amines
5
(
5) Neubert, L.; Michalik, D.; Bahn, S.; Imm, S.; Neumann, H.; Atzrodt, J.;
Derdau, V.; Holla, W.; Beller, M. Ruthenium-Catalyzed Selective ,-
Deuteration of Bioactive Amines. J. Am. Chem. Soc. 2012, 134,
12239−12244.
(16) (a) Maier, A. F. G.; Tussing, S.; Schneider, T.; Flörke, U.; Qu, Z.-W.;
Grimme, S.; Paradies, J. Frustrated Lewis pair catalyzed dehydrogenative
oxidation of indolines and other heterocycles. Angew. Chem., Int. Ed. 2016,
5
5,
12219−12223.
(b)
Kojima,
M.;
Kanai,
M.
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Tris(pentafluorophenyl)borane-catalyzed acceptorless dehydrogenation of
N-heterocycles. Angew. Chem., Int. Ed. 2016, 55, 12224−12227.
17) (a) Schwendemann, S.; Fröhlich, R.; Kehr, G.; Erker, G. Intramolecular
frustrated N/B Lewis pairs by enamine hydroboration. Chem. Sci. 2011, 2,
1842–1849. (b) Chen, G.-Q.; Kehr, G.; Daniliuc, C. G.; Bursch, M.;
Grimme, S.; Erker, G. Intermolecular Redox-Neutral Amine C–H
1
2
3
4
5
6
7
8
(
Functionalization Induced by the Strong Boron Lewis Acid B(C
6 5 3
F ) in the
Frustrated Lewis Pair Regime. Chem. Eur. J. 2017, 23, 4723–4729.
(
18) Shang, M.; Chan, J. Z.; Cao, M.; Chang, Y.; Wang, Q.; Cook, B.; Torker,
S.; Wasa, M. C–H Functionalization of amines via alkene-derived
nucleophiles through cooperative action of chiral and achiral Lewis acid
catalysts: Applications in enantioselective synthesis. J. Am. Chem. Soc.
2
018, 140, 10593−10601.
9
(
19) Tian, J.-J.; Zeng, N.-N.; Liu, N.; Tu, X.-S.; Wang, X.-C. Intramolecular
cyclizations of vinyl-substituted N,N-dialkyl arylamines enabled by
borane-assisted hydride transfer. ACS Catalysis 2019, 9, 295−300.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6 5 3
(20) For B(C F ) and N-alkylamine-catalyzed deprotonation of carbonyl
compounds, see: (a) Shang, M.; Wang, X.; Koo, S. M.; Youn, J.; Chan, J.
Z.; Yao, W.; Hastings, B. T.; Wasa, M. Frustrated Lewis acid/Brønsted
base catalysts for direct enantioselective -amination of carbonyl
compounds. J. Am. Chem. Soc. 2017, 139, 95−98. (b) Cao, M.; Yesilcimen,
A.; Wasa, M. Enantioselective Conia-Ene-Type Cyclizations of Alkynyl
Ketones through Cooperative Action of B(C
6 5 3
F ) , N-Alkylamine and a Zn-
Based Catalyst. J. Am. Chem. Soc. 2019, 141, 4199−4203.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment