Synthesis of Multideuterated (Hetero)aryl Bromides by Ag(I)-Catalyzed H/D Exchange

Guang-Qi Hu, Jing-Wen Bai, En-Ci Li, Kai-Hui Liu, Fei-Fei Sheng, and Hong-Hai Zhang*

Letter

Synthesis of Multideuterated (Hetero)aryl Bromides by Ag(I)-

Catalyzed H/D Exchange

Cite This: Org. Lett. 2021, 23, 1554 −1560

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: Deterium-labeled (hetero)aryl bromide is one of the

most widespread applicable motifs to achieve important deuterated

architectures for various scientiﬁc applications. Traditionally, these

deterium-labeled (hetero)aryl bromides are commonly prepared via

multistep syntheses. Herein, we disclose a direct H/D exchange

protocol for deuteration of (hetero)aryl bromides using Ag CO as

catalyst and D O as deuterium source. This protocol is highly

eﬃcient, simply manipulated, and appliable for deuterium-labeling of over 55 (hetero)aryl bromides including bioactive druglike

molecules and key intermediates of functional materials. In addition, this method showed distinguishing site-selectivity toward the

existing transition-metal-catalyzed HIE process, leading to multideuterated (hetero)aryl bromides in one step.

he increasing applications of deuterium-labeled com-

Scheme 1. Methods for Synthesis of Deuterium-Labeled

Aryl Bromide

pounds in various scientiﬁc ﬁelds have recently attracted

increased attention. In the pharmaceutical industry, deute-

rium-labeling has been established as a powerful tool to explore

the ADME properties of active pharmaceutical ingredients. In

material science, deuterated and nondeuterated optoelectronic

materials could show diﬀerent behavior in crystallization,

resulting in a great impact on lighting quantum yield and

device eﬃciency. In organic chemistry, the kinetic isotope

eﬀect experiment is commonly applied in the elucidation of

reaction mechanism. In chemical analysis, selective deuterated

compounds are ideal standards for mass spectrum analysis of

environmental pollutants and residual pesticides.

As one of the most important substrates in organic

chemistry, aryl bromides were widely used as synthetic

building blocks enabling quick access to a wide array of

bioactive molecules, organic materials, and polymers via the

versatile cutting-edge transformations of C−Br bond. Tradi-

tionally, deuterated aryl bromides were commonly prepared

from bromination of the corresponding deuterated aryl

precursors (Scheme 1A). Although a range of deuterated

aryl bromides can be prepared by this method, the high cost,

due to multistep synthetic route beginning from the expensive

deuterated precursors, restricted its broad use. The alternative

way to prepare deuterated aryl bromides relied on a

rings (Scheme 1C). Despite many eﬀorts on the extension of

substrate scope, the reported transition-metal-catalyzed H/D

exchange protocols still relied on the use of directing groups

defunctionalisation-deuteration stratergy. However, the pre-

installation of leaving groups disadvantaged further application

of these protocols in deuterium-labeling of complicated

molecules (Scheme 1B). Direct hydrogen isotope exchange

Received: December 19, 2020

Published: February 15, 2021

(

HIE) is considered to be the most straightforward method for

quick access to deuterated arenes. Recently, direct HIE

reactions with transition metals including Ir, Pd, Ru, Pt,

Fe, Ni, and Co as catalyst have been well explored as a

prevalent method for selective deuterium-labeling of aromatic

2021 American Chemical Society

554

Org. Lett. 2021, 23, 1554−1560

Organic Letters

Letter

containing an N or O atom to assist H/D exchange processes

and to control site-selectivity. Direct H/D exchange of aryl

bromides is still a great challenge, mainly due to their relatively

lower reactivity of C−H bond and fragile nature of C−Br

better results than silver carbonate, which is consistent with

21a

our previous observations (entries 9−11, Table 1). We then

screened the solvents and found toluene is the best choice of

solvent (see table s1 ). Further investigation of solvent

indicated that concentration played an important role in the

H/D exchange process, and a better result of 1.06 deuterium

incorporation was obtained by using 0.1 mL of toluene as

solvent (entries 12−14, Table 1). Increasing the amount of

heavy water to 20 equiv can obviously improve deuterium

incorporation (entry 15, Table 1). However, continuously

increasing the amount of heavy water never gave better results,

probably due to the poor solubility of substrates in water (see

bond. For example, complete debromination was observed in

H/D exchange process with Pd/C as catalyst. Although H/D

exchange of bromobenzene with CD COOD as deuterium

source can be achieved by a cationic ligand coordinated

platinum complex as catalyst, direct deuteration of substrates

other than simple bromobenzene was still unexplored.

Therefore, a general method for direct H/D exchange of aryl

bromide with broad substrate scope is still in high demand.

Our group is devoted to developing new methods for

Table S2 ). Interestingly, by analyzing the H NMR spectrum

of the isolated product, we found that this H/D exchange

reaction showed distinguishing site selectivity with 1.6

deuterium incorporation at the ortho-position and 0.4

deuterium incorporation at the meta-position of the bromide

group. In addition, we found that conducting the reaction at

higher temperature can further increase the level of deuterium

incorporation, aﬀording 3.10 deuterium incorporation at 120

synthesis of deuterated organic compounds. Recently, we

have developed a silver salt catalyzed H/D exchange reaction

for deuteration of ﬁve-membered heterocycles and ﬂuoroar-

enes. However, due to their relatively lower reactivity, the

direct C−H activation of aryl bromides with silver salt as

catalyst is still unknown. In this paper, we disclose an

eﬃcient, convenient, and catalytic method for H/D exchange

of aryl bromide with silver salt as catalyst and heavy water as

deuterium source. The reaction showed broad substrate scope,

enabling quick access to many valuable deuterated aryl

bromides, which are commonly complicated to prepare with

other methods.

C (entries 16 and 17, Table 1). Other deuterium sources such

as CDCl , CD CN, and CD OD are demonstrated to be much

less eﬃcient (see Table S2). Therefore, the optimal conditions

were established with Ag CO /CyPh P as catalyst and D O/

toluene as cosolvent at 120 °C.

With the optimal reaction conditions in hand, we set out to

explore the generality of this method with respect to

functionalized aryl bromide. As shown in Scheme 2, the

para-substituted bromobenzenes showed excellent H/D

exchange eﬃciency, aﬀording products with deuterium

incorporation from 83% to 92% at the ortho-position (2aa−

Our initial eﬀorts toward H/D exchange of aryl bromide

commenced with the reaction of 4-bromotoluene and heavy

water employing the combination of silver carbonate and

phosphine ligands as catalyst. After thorough screening of

ligands, cyclohexyldiphenylphosphine (CyPh P) was found to

be the best to promote the HIE process, providing the product

with 0.77 deuterium incorporation (entries 1−8, Table 1).

Other silver salts were also tested, and none of them gave

aj). When the para-position of bromobenzene was sub-

stituted by alkyl, phenyl, alkyne, amine or carbonyl groups, the

H/D exchange reaction showed preferential orientation toward

ortho-position over meta-position, aﬀording products with

deuterium incorporation of 14% to 79% at meta-position

Table 1. Reaction Optimization

(

2aa−2af). On the other hand, the bromobenzenes substituted

by an alkoxyl group at para-position showed high level of

deuterium incorporation at both ortho- and meta-positions

(

2ag−2aj). These results suggested that deuterium incorpo-

ration at the meta-position could be controlled by steric eﬀects

and/or electronic eﬀects. On the basis of our results and the

reported reference, the selectivity of this H/D exchange

reaction may controlled by the acidity of the C−H bond, in

which H/D exchange occurred more easily adjacent to

electronegative elements. The bromobenzenes with ortho-

substitution were then tested, and we found the H/D exchange

will occur only at the ortho- and meta-position of the bromide

group, aﬀording products with no deuterium incorporation at

the para-position of bromide (2ak−2am). To the best of our

knowledge, the H/D exchange process showing this special

entry

Ag salt

ligand

Ph₃P

Sphos

DavePhos

JohnPhos

MePhos

CyPh₂P

Cy₃P

toluene

D incorporation

Ag CO₃

1 mL

0.5 mL

0.2 mL

0.1 mL

0.06

0.34

0.64

0.42

0.60

0.77

0.09

0.04

0.12

0.66

0.86

1.06

1.86

2.86

3.10

Ag CO₃

Cy PhP

Ag O

CyPh₂P

AgOAc

kind of site selectivity has been rarely observed, which could

CF COOAg

be a complementary strategy for producing valuable multi-

deuterated aryl bromides. We next examined aryl bromides

with meta-substitutions as starting materials, which also

showed a high level of deuterium incorporation at the ortho-

position and a moderate or good level of deuterium

incorporation at the meta-position (2an−2aq). In addition,

brominated polyarenes including 1-bromonaphthalene, 2-

bromonaphthalene, 2-bromonathraquinone, and 2-bromo-9,9-

dimethylﬂuorene all showed good H/D exchange eﬃciency

(2ar−2au). The H/D exchange of 9-bromophenanthrene

(2av) was observed selectively at the ortho-position of bromide

Ag CO₃

The reaction was conducted on 1 mmol of 1a, 10 mmol of D O, 0.2

mmol of Ag salt, and 0.5 mmol of ligand in toluene at 80 °C, 12 h.

Determined by GC−MS. 20 mmol of D O was used. At 100 °C.

At 120 °C.

555

Org. Lett. 2021, 23, 1554−1560

Organic Letters

Letter

Scheme 2. Deuteration of Brominated Arenes

functional materials as well as natural product derivatives have

been examined. First, introducing deuterium into menthol

derivatives and clotrimazole were successfully achieved (2ca

and 2 cd). Deuterated key intermediates of adapalene and

empagliﬂozin (2cb and 2cc) were readily synthesized from the

corresponding bromide precursors in excellent level of

deuterium incorporation. Furthermore, the important inter-

mediate for organic/polymeric phosphorescence material, 2,7-

dibromo-9,9-dimethylﬂuorene, was a good substrate for H/D

exchange, leading to fully deuterated product with excellent

level of deuterium incorporation (2ce).

The successful deuteration of aryl bromides promoted us to

investigate deuterium incorporation of heteroaryl bromides.

We ﬁrst examined the H/D exchange of brominated nitrogen-

containing heteroarenes because nitrogen-containing hetero-

arenes are common structure motifs in functional materials and

bioactive compounds. As shown in Scheme 3, monobromi-

Scheme 3. Deuteration of Brominated Heteroarenes

The reaction was conducted with compound 1 (1 mmol), D O (20

mmol), Ag CO (0.2 mmol), CyPh P (0.5 mmol) in 0.1 mL of

mmol), Ag CO (0.2 mmol), and CyPh P (0.5 mmol) in 0.1 mL of

toluene at 120 °C for 24 h; deuterium incorporation was estimated by

H NMR spectrum; isolated yield.

with deuterium incorporation of 96%. The high ortho-position

selectivity could be explained by its high reactivity toward C−

nated pyridine derivatives are good substrates for H/D

exchange, leading to products with multiple deuterium

incorporation (3a−3g). In addition, when the methyl group

was substituted at the ortho-position of pyridine, H/D

exchange of the methyl group was also observed (3d and

H activation, which has been well reported previously.

Moreover, we found 4-chlorotoluene and 4-iodotoluene are

also good substrates for this H/D exchange reaction, providing

the products with the same site-selectivity but less eﬃciency

3g). It could be explained by their relatively higher acidity,

than 4-bromotoluene (2aw−2ax). With multihalogenated

arenes as starting materials, fully deuterated arenes could be

easily prepared under the optimal condition (2ba−2bh). The

products with deuterium incorporation of 82%−93% at every

position were obtained. To further elaborate the utility of this

transformation, deuteration of key intermediates of drugs and

which was believed to play important role in Ag(I)-catalyzed

H/D exchange reaction. The multihalogenated pyridine

derivatives provided higher reactivity for H/D exchange,

leading to fully deuterated pyridines in most cases (3h−3l).

Brominated isoquinolines are also examined, providing good to

excellent level of deuterium incorporation at multiple positions

556

Org. Lett. 2021, 23, 1554−1560

Organic Letters

The Supporting Information is available free of charge at

Letter

(

3m and 3n). Deuteration of 6-bromoquinoxaline led to

Scheme 5. Control Experiments and Proposed Mechanism

of Ag CO -Catalyzed HIE

installation of three deuterium atoms in the phenyl ring (3o).

Besides the electro-deﬁcient heteroarenes, H/D exchange of

electron-rich brominated ﬁve-membered heterocycles was

further examined. Fully deuterated products with a high level

of deuterium incorporation were easily obtained (3p−3t). In

most cases, this H/D exchange protocol can introduce multiple

deuterium atoms in one step, which may ﬁnd wide applications

in development of novel functional materials and synthesis of

standards for MS analysis.

To further demonstrate the usefulness of this Ag CO -

catalyzed H/D exchange protocol, we conducted the trans-

formation of the C−Br bond to build up other useful

deuterated building blocks (Scheme 4). Deuteration of 1ag

Scheme 4. Transformation of C−Br Bond

The reaction was conducted with 2ag (0.5 mmol), potassium oxalate

-phenylcarbazole and 2,7-dibromo-9-phenylcarbazole showed

(

0.75 mmol), PdCl (0.02 mmol), and dppp (0.03 mmol) in NMP (1

a signiﬁcant reactive diﬀerence, which indicated that bromide

group is essential for this H/D exchange process (Scheme 5b).

On the basis of these experiments, we proposed a mechanistic

pathway as follows. The phosphine ligand coordinated silver

salt promoted C−H bond cleavage of 1al, which was followed

by H/D exchange between intermediate T2 and heavy water to

produce deuterated intermediate T3. Finally, deuterated aryl

bromide (2al) will generate from transformation of deuterium

to aryl ring and release of silver salt.

mL) at 150 °C under N . The reaction was conducted with 2ag (1

mmol), 4- ethynyltoluene (1.5 mmol), Pd(OAc) (0.02 mmol), PPh

(

0.2 mmol), and K CO (1.5 mmol) in DMSO (5 mL) at 80 °C

2 3

under N₂. The reaction was conducted with 2ag (1 mmol), N-

methylaniline (1.2 mmol), Pd(OAc) (0.01 mmol), Ruphos (0.2

mmol), and NaO Bu(1.5 mmol) at 110 °C under N . The reaction

was conducted with 2ag (1 mmol), bis(pinacolato)diboron (1.2

mmol), Pd(dppf)Cl (0.02 mmol), and KOAc (3 mmol) in DMSO (5

mL) at 80 °C under N . The reaction was conducted with 2ag (1.5

mmol), benzothiophene (1 mmol), Pd (dba) (0.005 mmol), Sphos

In summary, a convenient approach for direct incorporation

of deuterium into brominated (hetero)arenes with Ag CO as

(

0.01 mmol), and NaOtBu (3 mmol) in o-xylene (2 mL) at 140 °C

under N . The reaction was conducted with 2ag (1.0 mmol), 4-

catalyst has been disclosed. A good range of (hetero)arenes,

including brominated benzene, pyridine, quinoline, isoquino-

line, indole, benzothiophine, benzofuran, and benzoimizole,

have been demonstrated to be good substrates. The

distinguishing site-selectivity of this H/D exchange reaction

allowed this method to prepare multideuterated organic

compounds, which is extremely important in preparation of

standards for MS analysis. In addition, although aryl bromide

has been widely applied in synthesis of functional material and

drug molecules, the direct C−H activation of aryl bromide is

rarely reported. Our result demonstrated that C−H bond

cleavage of brominated (hetero)arenes by the assistant of silver

salt is feasible, which paves the way to functionalize

brominated arenes via the direct C−H bond activation route.

cyanobenzoic acid (1.5 mmol), Pd(PPh) (0.05 mmol), and KOAc (5

mmol) in toluene/H O (4/2 mL) at 140 °C under N .

(

1.86 g, 10 mmol) aﬀorded 2ag in 90% yield and 92%

deuterium incorporation at both the ortho- and meta-positions,

suggesting this H/D exchange protocol is readily scalable. As

shown in Scheme 4, the C−Br bond can be converted to

functional groups such as ester, amine, and boronic ester. The

cross-coupling of C−Br with diﬀerent partners can introduce

aryl, heteroaryl and alkyne groups into the original deuterated

phenyl ring. In addition, nearly no loss of deuterium

incorporation was observed in these transformations.

With the attempt to gain more insight into the reaction

mechanism, a series of control experiments have been

performed (Scheme 5). First, a mechanism involving free

radicals should be ruled out, due to no negative eﬀect with

radical inhibitor TEMPO as additive. Second, the one-pot

competitive reaction showed 4-bromobenzophenone is more

reactive than 4-bromotoluene toward H/D exchange, which

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.0c04139.

suggested the reaction may not follow an S Ar pathway

Experimental procedures, spectral data (PDF)

(Scheme 5a). Third, the one-pot competitive reaction between

557

Org. Lett. 2021, 23, 1554−1560

Organic Letters

Letter

e) Katsnelson, A. Heavy drugs draw heavy interest from pharma

AUTHOR INFORMATION

Corresponding Author

■

backers. Nat. Med. 2013 , 19 , 656. (f) Meanwell, N. A. Synopsis of

Some Recent Tactical Application of Bioisosteres in Drug Design. J.

Med. Chem. 2011, 54, 2529−2591.

Hong-Hai Zhang − Key Laboratory of Flexible Electronics

(

KLOFE) & Institute of Advanced Materials (IAM), Jiangsu

(3) (a) Shao, M.; Keum, J.; Chen, J.; He, Y.; Chen, W.; Browning, J.

F.; Jakowski, J.; Sumpter, B. G.; Ivanov, L. N.; Ma, Y. Z.; Rouleau, C.

M.; Smith, S. C.; Geohegan, D. B.; Hong, K.; Xiao, K. The Isotopic

Effects of Deuteration on Optoelectronic Properties of Conducting

Polymers. Nat. Commun. 2014 , 5 , 1 −11. (b) Kabe, R.; Notsuka, N.;

Yoshida, K.; Adachi, C. Afterglow Organic Light-Emitting Diode. Adv.

Mater. 2016, 28, 655−660. (c) Nguyen, T. D.; Hukic-Markosian, G.;

Wang, F.; Wojcik, L.; Li, X. G.; Ehrenfreund, E.; Vardeny, Z. V.

Isotope Effect in Spin Response of π −Conjugated Polymer Films and

Devices. Nat. Mater. 2010 , 9 , 345 −352. (d) Shi, C.; Zhang, X.; Yu, C.

H.; Yao, Y. F.; Zhang, W. Geometric Isotope Effect of Deuteration in

a Hydrogen-Bonded Host-Guest Crystal. Nat. Commun. 2018 , 9 , 481.

(4) (a) Simmons, E. M.; Hartwig, J. F. On the Interpretation of

Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by

Transition-Metal Complexes. Angew. Chem., Int. Ed. 2012, 51 , 3066 −

National Synergistic Innovation Center for Advanced

Materials (SICAM), Nanjing Tech. University (Nanjing

Tech.), Nanjing 211816, P.R. China; orcid.org/0000-

003-1413-8847; Email: iamhhzhang@njtech.edu.cn

Authors

Guang-Qi Hu − Key Laboratory of Flexible Electronics

(

KLOFE) & Institute of Advanced Materials (IAM), Jiangsu

National Synergistic Innovation Center for Advanced

Materials (SICAM), Nanjing Tech. University (Nanjing

Tech.), Nanjing 211816, P.R. China

Jing-Wen Bai − Key Laboratory of Flexible Electronics

(

KLOFE) & Institute of Advanced Materials (IAM), Jiangsu

072. (b) McKinney Brooner, R. E.; Widenhoefer, R. A. Stereo-

National Synergistic Innovation Center for Advanced

Materials (SICAM), Nanjing Tech. University (Nanjing

Tech.), Nanjing 211816, P.R. China

chemistry and Mechanism of the Bronsted Acid Catalyzed Intra-

molecular Hydrofunctionalization of an Unactivated Cyclic Alkene.

Chem. - Eur. J. 2011 , 17 , 6170 −6178. (c) Giagou, T.; Meyer, M. P.

Kinetic Isotope Effects in Asymmetric Reactions. Chem.Eur. J.

En-Ci Li − Key Laboratory of Flexible Electronics (KLOFE) &

Institute of Advanced Materials (IAM), Jiangsu National

Synergistic Innovation Center for Advanced Materials

010, 16, 10616−10628. (d) Evans, L. A.; Fey, N.; Lloyd-Jones, G.

C.; Munoz, M. P.; Slatford, P. A. Cryptocatalytic 1,2-Alkene

Migration in a σ −Alkyl Palladium Diene Complex. Angew. Chem.,

Int. Ed. 2009, 48, 6262−6265.

(5) (a) Waterstraat, M.; Hildebrand, A.; Rosler, M.; Bunzel, M.

Development of a QuEChERS-Based Stable-Isotope Dilution LC-

MS/MS Method To Quantitate Ferulic Acid and Its Main Microbial

and Hepatic Metabolites in Milk. J. Agric. Food Chem. 2016 , 64 ,

(

SICAM), Nanjing Tech. University (Nanjing Tech.),

Nanjing 211816, P.R. China

Kai-Hui Liu − Key Laboratory of Flexible Electronics

(

KLOFE) & Institute of Advanced Materials (IAM), Jiangsu

National Synergistic Innovation Center for Advanced

Materials (SICAM), Nanjing Tech. University (Nanjing

Tech.), Nanjing 211816, P.R. China

667 −8677. (b) Atzrodt, J.; Derdau, V. Pd- and Pt-catalyzed H/D

exchange methods and their application for internal MS standard

preparation from a Sanofi-Aventis perspective. J. Labelled Compd.

Radiopharm. 2010, 53, 674−685.

Fei-Fei Sheng − Key Laboratory of Flexible Electronics

(

KLOFE) & Institute of Advanced Materials (IAM), Jiangsu

National Synergistic Innovation Center for Advanced

Materials (SICAM), Nanjing Tech. University (Nanjing

Tech.), Nanjing 211816, P.R. China

(6) (a) Yin, L.; Liebscher, J. Carbon-Carbon Coupling Reactions

Catalyzed by Heterogeneous Palladium Catalysts. Chem. Rev. 2007 ,

07 , 133 −173. (b) Biffis, A.; Centomo, P.; Zotto, A. D.; Zecca, M. Pd

Metal Catalysts for Cross-Couplings and Related Reactions in the

1st Century: A Critical Review. Chem. Rev. 2018, 118, 2249 −2295.

c) Sakamoto, J.; Rehahn, M.; Wegner, G.; Schluter, A. D. Suzuki

Polycondensation: Polyarylenes a la Carte. Macromol. Rapid Commun.

009 , 30 , 653 −687. (d) Leone, A. K.; Mueller, E. A.; McNeil, A. J.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c04139

The History of Palladium-Catalyzed Cross-Couplings Should Inspire

Notes

The authors declare no competing ﬁnancial interest.

the Future of Catalyst-Transfer Polymerization. J. Am. Chem. Soc.

2018 , 140 , 15126 −15139. (e) Yokozawa, T.; Ohta, Y. Transformation

of Step-Growth Polymerization into Living Chain-Growth Polymer-

ization. Chem. Rev. 2016, 116 (4), 1950−1968.

ACKNOWLEDGMENTS

We thank the National Natural Science Foundation of China

Grant Numbers 21704041, 22075135), Six Talent Peaks

Project in Jiangsu Province (Grant No. XCL-027), and

Nanjing Scientiﬁc Research Foundation for Returned Scholars

for support.

■

(

(7) (a) Kaishap, P. P.; Duarah, G.; Sarma, B.; Chetia, D.; Gogoi, S.

Ruthenium(II)-Catalyzed Synthesis of Spirobenzofuranones by a

Decarbonylative Annulation Reaction. Angew. Chem., Int. Ed. 2018 ,

7 , 456 −460. (b) Xu, C.; Shen, Q. Palladium-Catalyzed Trifluor-

omethylthiolation of Aryl C-H Bonds. Org. Lett. 2014, 16, 2046−

049. (c) Gonzalez, J. A.; Ogba, O. M.; Morehouse, G. F.; Rosson, N.;

REFERENCES

■

1) (a) 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 , 1758 −1784.

2) (a) Sanderson, K. Big Interest in Heavy Drugs. Nature 2009,

Houk, K. N.; Leach, A. G.; Cheong, P. H. Y.; Burke, M. D.; LIoyd-

Jones, G. C. MIDA Boronates are Hydrolysed Fast and Slow by Two

Different Mechanisms. Nat. Chem. 2016, 8, 1067−1075.

(

(8) (a) Liu, C.; Chen, Z.; Su, C.; Zhao, X.; Gao, Q.; Ning, G. H.;

Zhu, H.; Tang, W.; Leng, K.; Fu, W.; Tian, B.; Peng, X.; Li, P.; Xu, Q.

H.; Zhou, W.; Loh, K. P. Controllable Deuteration of Halogenated

Compounds by Photocatalytic D2O Splitting. Nat. Commun. 2018, 9,

80−88. (b) Chong, E.; Kampf, J. W.; Ariafard, A.; Canty, A. J.;

Sanford, M. S. Oxidatively Induced C-H Activation at High Valent

Nickel. J. Am. Chem. Soc. 2017, 139, 6058−6061. (c) Patra, T.;

Mukherjee, M.; Ma, J.; Kalthoff, F. S.; Glorius, F. Visible-Light-

Photosensitized Aryl and Alkyl Decarboxylative Functionalization

Reactions. Angew. Chem., Int. Ed. 2019, 58, 10514−10520. (d) Barker,

G.; Webster, S.; Johnson, D. G.; Curley, R.; Andrews, M.; Young, P.

58 , 269. (b) Navratil, A. R.; Shchepinov, M. S.; Dennis, E. A.

Lipidomics Reveals Dramatic Physiological Kinetic Isotope Effects

during the Enzymatic Oxygenation of Polyunsaturated Fatty Acids Ex

Vivo. J. Am. Chem. Soc. 2018, 140, 235−243. (c) Zhang, Y.;

Tortorella, M. D.; Wang, Y.; Liu, J.; Tu, Z.; Liu, X.; Bai, Y.; Wen, D.;

Lu, X.; Lu, Y.; Talley, J. J. Synthesis of Deuterated Benzopyran

Derivatives as Selective COX-2 Inhibitors with Improved Pharmaco-

kinetic Properties. ACS Med. Chem. Lett. 2014 , 5 , 1162 −1166.

d) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the

Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611.

558

Org. Lett. 2021, 23, 1554−1560

Organic Letters

Catalysed Tritiation of Pharmaceuticals. Science 2016 , 529 , 195 −199.

Letter

C.; Macgregor, S. A.; Lee, A. L. Gold-Catalyzed Proto- and

Platinum on Carbon in Deuterium Oxide. Adv. Synth. Catal. 2018,

360, 2303−2307.

(14) (a) Yu, R. P.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-

(b) Arevalo, R.; Chirik, P. J. Enaling Two-Electron Pathways with

Iron and Cobalt: From Ligand Design to Catalytic Applications. J.

Am. Chem. Soc. 2019, 141, 9106−9123.

Deuterodeboronation. J. Org. Chem. 2015, 80, 9807−9816.

(e) Amin, H. I. M.; Raviola, C.; Amin, A. A.; Mannucci, B.; Protti,

S.; Fagnoni, M. Molecules 2019, 24, 2164−2173. (f) Uchiyama, N.;

Shirakawa, E.; Nishikawa, R.; Hayashi, T. Iron-Catalyzed Oxidative

Coupling of Arylboronic Acids with Benzene Derivativest through

Homolytic Aromatic Substitution. Chem. Commun. 2011, 47, 11671−

(

1673.

(15) (a) Yang, H.; Zarate, C.; Palmer, W. N.; Rivera, N.; Hesk, D.;

Chirik, P. J. Site-Selective Nickel-Catalyzed Hydrogen Isotope

Exchange in N -Heterocycles and Its Application to the Tritiation of

Pharmaceuticals. ACS Catal. 2018, 8, 10210−10218. (b) Zarate, C.;

Yang, H.; Bezdek, M. J.; Hesk, D.; Chirik, P. J. Ni(I)-X Complexes

Bearing a Bulky -Diimine Ligand: Synthesis, Structure and Superior

Catalytic Performance in the Hydrogen Isotope Exchange in

Pharmaceuticals. J. Am. Chem. Soc. 2019 , 141 , 5034 −5044. (c) Corpas,

J.; Viereck, P.; Chirik, P. J. C(sp2)-H Activation with Pyridine

Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange of

Arenes Using Benzene-d6 as a Deuterium Source. ACS Catal. 2020,

10, 8640−8647.

9) For selected reviews of H/D exchange, see: (a) Atzrodt, J.;

Derdau, V.; Kerr, W. J.; Reid, M. C-H Functionalization for Hydrogen

Isotope Exchange. Angew. Chem., Int. Ed. 2018, 57 , 3022 −3047.

(b) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The Renaissance

of H/D Exchange. Angew. Chem., Int. Ed. 2007 , 46 , 7744 −7765.

c) Lockley, W. J. S.; Heys, J. R. Metal-Catalysed Hydrogen Isotope

Exchange Labelling: a Brief Overview. J. Labelled Compd. Radiopharm.

010 , 53 , 635 −644. (d) Sattler, A. Hydrogen/Deuterium (H/D)

Exchange Catalysis in Alkanes. ACS Catal. 2018, 8, 2296−2312.

10) (a) Kerr, W. J.; Mudd, R. J.; Reid, M.; Atzrodt, J.; Derdau, V.

Iridium-Catalyzed Csp -H Activation for Mild and Selective Hydro-

gen Isotope Exchange. ACS Catal. 2018, 8, 10895−10900.

(16) (a) Palmer, W. N.; Chirik, P. J. Cobalt-Catalyzed Stereo-

(b) Burhop, A.; Prohaska, R.; Weck, R.; Atzrodt, J.; Derdau, V.

retentive Hydrogen Isotope Exchange of C(sp )-H Bonds. ACS Catal.

Burgess Iridium(I)-Catalyst for Selective Hydrogen Isotope Exchange.

J. Labelled Compd. Radiopharm. 2017 , 60 , 343 −348. (c) Kerr, W. J.;

Reid, M.; Tuttle, T. Iridium-Catalyzed Formyl-Selective Deuteration

of Aldehydes. Angew. Chem., Int. Ed. 2017, 56, 7808−7812. (d) Kerr,

W. J.; 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. (e) Ellames, G. J.; Gibson, J. S.;

Herbert, J. M.; McNeill, A. H. The Scope and Limitations of

Deuteration Mediated by Crabtree ’s Catalyst. Tetrahedron 2001, 57,

2017 , 7 , 5674 −5678. (b) Zhang, J.; Zhang, S.; Gogula, T.; Zou, H.

Versatile Regioselective Deuteration of Indoles via Transition-Metal-

Catalyzed H/D Exchange. ACS Catal. 2020 , 10 , 7486 −7494.

(17) (a) Zhou, J.; Hartwig, J. F. Iridium-Catalyzed H/D Exchange at

Vinyl Groups without Olefin Isomerization. Angew. Chem., Int. Ed.

2008 , 47 , 5783 −5787. (b) Lulinski, S.; Serwatowski, J. Regiospecific

Metalation of Oligobromobenzenes. J. Org. Chem. 2003, 68, 5384−

5387. (c) Rawalpally, T.; Ji, Y.; Shankar, A.; Edwards, W.; Allen, J.;

Jiang, Y.; Cleary, T. P.; Pierce, M. E. A Practical Method for

Stabilizing Lithiated Halogenated Aromatic Compounds. Org. Process

Res. Dev. 2008, 12, 1293−1298.

487−9497. (f) Hey, R. Investigation of [IrH (Me CO) (PPh ) ]BF

as a Catalyst of Hydrogen Isotope Exchange of Substrates in Solution.

J. Chem. Soc., Chem. Commun. 1992, 680−681. (g) Valero, M.; Weck,

R.; Gussregen, S.; Atzrodt, J.; Derdau, V. Highly Selective Directed

Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic

Amides. Angew. Chem., Int. Ed. 2018, 57, 8159−8163. (h) 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

(18) Ito, N.; Esaki, H.; Maesawa, T.; Imamiya, E.; Maegawa, T.;

Sajiki, H. Efficient and Selective Pt/C-Catalyzed H-D Exchange

Reaction of Aromatic Rings. Bull. Chem. Soc. Jpn. 2008, 81, 278−286.

(19) Emmert, M. H.; Gary, J. B.; Villalobos, J. M.; Sanford, M. S.

Platinum and Palladium Complexes Containing Cationic Ligands as

Catalysts for Arene H/D Exchange and Oxidation. Angew. Chem., Int.

Ed. 2010, 49, 5884−5886.

(20) (a) Guo, L.; Xu, C.; Wu, D. C.; Hu, G. Q.; Zhang, H. H.; Hong,

K.; Chen, S.; Liu, X. Cascade alkylation and deuteration with aryl

iodides via Pd/norbornene catalysis: an efficient method for the

synthesis of congested deuterium-labeled arenes. Chem. Commun.

2019 , 55 , 8567 −8570. (b) Zhang, H. H.; Bonnesen, P. V.; Hong, K.

Palladium-catalyzed Br/D exchange of arenes: selective deuterium

incorporation with versatile functional group tolerance and high

efficiency. Org. Chem. Front. 2015, 2, 1071−1075.

017, 358, 1182−1187. (i) Liu, W.; Cao, L.; Zhang, Z.; Zhang, G.;

Huang, S.; Huang, L.; Zhao, P.; Yan, X. Mesoionic Carbene-Iridium

Complex Catalyzed Ortho-Selective Hydrogen Isotope Exchange of

Anilines with High Functional Group Tolerance. Org. Lett. 2020, 22,

210−2214. (j) Valero, M.; Kruissink, T.; Blass, J.; Weck, R.;

Gussregen, S.; Plowright, A. T.; Derdau, V. CH-Functionalization-

Prediction of Selectivity in Iridium(I) Catalyzed Hydrogen Isotope

Exchange Competition Reactions. Angew. Chem., Int. Ed. 2020, 59,

(21) (a) Li, E. C.; Hu, G. Q.; Zhu, Y. X.; Zhang, H. H.; Shen, K.;

Hang, X. C.; Zhang, C.; Huang, W. Ag CO -Catalyzed H/D

11) (a) Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J. Q.

626−5631.

Exchange of Five-Membered Heteroarenes at Ambient Temperature.

Org. Lett. 2019, 21 , 6745 −6749. (b) Hu, G. Q.; Li, E. C.; Zhang, H.

H.; Huang, W. Ag(I)-Mediated Hydrogen Isotope Exchange of

Mono-Fluorinated (Hetero)arenes. Org. Biomol. Chem. 2020, 18,

6627−6633.

Palladium-Catalyzed ortho -Selective C-H Deuteration of Arenes:

Evidence for Superior Reactivity of Weakly Coordinated. Angew.

Chem., Int. Ed. 2014, 53, 734 −737. (b) Xu, H.; Liu, M.; Li, L. L.; Cao,

Y. F.; Yu, J. Q.; Dai, H. X. Palladium-Catalyzed Remote meta-C-H

Bond Deuteration of Arenes Using a Pyridine Template. Org. Lett.

(22) For selected publications of Ag(I)-mediated cross-coupling

reactions by C −H activation, see: (a) Yang, Y.; Lan, J.; You, J.

Oxidative C-H/C-H Coupling Reactions between Two (Hetero)-

arenes. Chem. Rev. 2017, 117, 8787−8863. (b) Kuhl, N.; Hopkinson,

M. N.; Wencel-Delord, J.; Glorius, F. Beyond Directing Groups:

Transition-Metal-Catalyzed C-H Activation of Simple Arenes. Angew.

Chem., Int. Ed. 2012 , 51 , 10236 −10254. (c) Lee, S. Y.; Hartwig, J. F.

Palladium-Catalyzed, Site-Selective Direct Allylation of Aryl C-H

Bonds by Silver-Mediated C-H Activation: A Synthetic and

Mechanistic Investigation. J. Am. Chem. Soc. 2016, 138, 15278 −

15284. (d) Ricci, P.; Kramer, K.; Cambeiro, X. C.; Larrosa, I. Arene-

Metal π -Complexation as a Traceless Reactivity Enhancer for C-H

Arylation. J. Am. Chem. Soc. 2013, 135, 13258−13261.

019, 21, 4887−4891. (c) 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−

(

53.

12) (a) Neubert, L.; Michalik, D.; Bahn, S.; Imm, S.; Neumann, H.;

Atzrodt, J.; Derdau, V.; Holla, W.; Beller, M. Ruthenium-Catalyzed

Selective α ,β -Deuteration of Bioactive Amines. J. Am. Chem. Soc.

012, 134, 12239−12244. (b) Palazzolo, A.; Feuillastre, S.; Pferfer,

V.; Garcia-Argote, S.; Bouzouita, D.; Tricard, S.; Chollet, C.; Marcon,

E.; Buisson, D. A.; Cholet, S.; Fenaille, F.; Lippenss, G.; Chaudret, B.;

Pieters, G. Angew. Chem., Int. Ed. 2019, 58, 4891−4895.

(

13) (a) Park, K.; Matsuda, T.; Yamada, T.; Monguchi, Y.; Sawama,

Y.; Doi, N.; Sasai, Y.; Kondo, S.; Sawama, Y.; Sajiki, H. Direct

Deuteration of Acrylic and Methacrylic Acid Derivatives Catalyzed by

(23) For HIE at both ortho- and meta- positions by Ru catalyst, see:

(a) Zhao, L. L.; Liu, W.; Zhang, Z.; Zhao, H.; Wang, Q.; Yan, X.

559

Org. Lett. 2021, 23, 1554−1560

Organic Letters

Werz, D. B.; Maiti, D. Palladium-Catalyzed Selective meta-C-H

Letter

Ruthenium-Catalyzed ortho - and meta -H/D Exchange of Arenes. Org.

Lett. 2019, 21, 10023−10027. For selective HIE at the meta-position

by Pd catalyst, see: (b) Bag, S.; Petzold, M.; Sur, A.; Bhowmick, S.;

Deuteration of Arenes: Reaction Design and Application. Chem. - Eur.

J. 2019, 25, 9433−9437. (c) Xu, H.; Liu, M.; Li, L. J.; Cao, Y. F.; Yu,

J. Q.; Dai, H. X. Palladium-Catalyzed Remote meta-C-H Bond

Deuteration of Arenes Using a Pyridine Template. Org. Lett. 2019, 21,

24) (a) Mochida, K.; Kawasumi, K.; Segawa, Y.; Itami, K. Direct

887−4891.

Arylation of Polycylic Aromatic Hydrocarbons through Palladium

Catalysis. J. Am. Chem. Soc. 2011, 133, 10716−10719. (b) Collins, K.

D.; Honeker, R.; Vasquez-Cespedes, S.; Tang, D. T. D.; Glorius, F. C-

H Arylation of Triphenylene, Naphthalene and Related Arenes using

Pd/C. Chem. Sci. 2015, 6, 1816−1824.

25) For C −H activation of chlorobenzene, see: Li, Z.; Duan, W. L.

Palladium-Catalysed C-H Alkenylation of Arenes with Alkynes:

Stereoselective Synthesis of Vinyl Chlorides via a 1,4-Chlorine

Migration. Angew. Chem., Int. Ed. 2018, 57, 16041−16045.

(

26) (a) Zhao, W.; He, Z.; Lam, J. W. Y.; Peng, Q.; Ma, H.; Shui, Z.;

Bai, G.; Hao, J.; Tang, B. Z. Rational Molecular Design for Achieving

Persistent and Efficient Pure Organic Room-Temperature Phosphor-

escence. Chem. 2016 , 1 , 592 −602. (b) Gan, N.; Shi, H.; An, Z.;

Huang, W. Recent Advances in Polymer-Based Metal-Free Room-

Temperature Phosphorescent Materials. Adv. Funct. Mater. 2018, 28,

27) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical

802657.

Journey of Innovative Organic Architectures That Have Improved

Our Lives. J. Chem. Educ. 2010, 87, 1348−1349.

(28) Shen, K.; Fu, Y.; Li, J. N.; Liu, L.; Guo, Q. X. What are the pK

values of C-H bonds in aromatic heterocyclic compounds in DMSO.

Tetrahedron 2007, 63, 1568−1576.

560