A practical and efficient method for late-stage deuteration of terminal alkynes with silver salt as catalyst

Article abstract of DOI:10.1016/j.tetlet.2020.152807

A practical and efficient H/D exchange method for selective deuteration of terminal alkynes was disclosed. The reaction was simply performed with CF₃COOAg as catalyst at room temperature, affording products with high level of deuterium incorporation. The excellent site-selectivity and promising functional group tolerance of this protocol enabled deuteration of pharmaceuticals and nature product derivatives.

Full text of DOI:10.1016/j.tetlet.2020.152807

Tetrahedron Letters 66 (2021) 152807
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical and efficient method for late-stage deuteration of terminal
alkynes with silver salt as catalyst
⇑
Ding-Chuan Wu, Jing-Wen Bai, Lei Guo, Guang-Qi Hu, Kai-Hui Liu, Fei-Fei Sheng, Hong-Hai Zhang ,
Zheng-Yi Sun, Kang Shen , Xiang 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.), 30 Puzhu Road, Nanjing 211816, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and efficient H/D exchange method for selective deuteration of terminal alkynes was dis-
Received 21 November 2020
Revised 19 December 2020
Accepted 25 December 2020
Available online 12 January 2021
3
closed. The reaction was simply performed with CF COOAg as catalyst at room temperature, affording
products with high level of deuterium incorporation. The excellent site-selectivity and promising func-
tional group tolerance of this protocol enabled deuteration of pharmaceuticals and nature product
derivatives.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Late-stage deuteration
Terminal alkyne
Silver salt
Introduction
Our group is devoted to develop novel method for preparation
of deuterated compounds [13]. Recently, we have successfully
The increasing applications of deuterium-labeled compounds in
various scientific fields [1–4] have recently demanded for conve-
nient, selective, and especially catalytic methods for their prepara-
tion [5–7]. As one of the most utilized synthons in organic
reactions, terminal alkynes have been widely applied in organic
synthesis [8]. Thus, deuterated terminal alkynes become a com-
mon reagent being applied in mechanistic study in chemical and
biological processes [9], and served as a versatile building block
enabling quick access to a good range of important deuterium-
labeled molecular architectures [10]. Although much effort has
been made for preparation of deuterated compounds, the synthesis
of deuterated terminal alkynes is mainly relied on traditional
method of a subsequent hydrogen abstraction and quenching pro-
cess by strong bases [11]. However, use of stoichiometric amounts
of alkali metals or organic/inorganic bases leading to poor func-
tional group tolerance disadvantaged further application of these
protocols in late-stage deuterium-labeling. Recently, a catalytic
H/D exchange protocol of terminal alkynes has been disclosed,
despite using expensive ruthenium complex as catalyst (Scheme 1)
achieved selective deuteration of five-membered heterocycles via
a silver salt catalyzed H/D exchange protocol under mild condition
[14]. Due to the cheap cost and wide application in organic reac-
tions, silver salt is considered to be a potential catalyst for prepa-
ration of many useful
deuterated organic compounds [15]. It has been well studied
that activation of the C(sp)-H bond of terminal alkynes can be pro-
moted by prior
p coordination of silver salt to triple bond, which
enabled cross-coupling of terminal alkynes with a series of mole-
cules [16]. However, these transformations are always completed
in the presence of excess amount of bases, which are believed to
play an important role in the formation of key intermediate silver
acetylide. In addition, a mechanism study of C(sp)-H bond activa-
tion showed that deuterated terminal alkynes can be produced
with stoichiometric AgOTf and excess amount of CD COOD as deu-
3
terium source [17]. However, the silver salt mediated H/D
exchange process with catalysis mode has rarely been explored.
3
Herein, we disclose an efficient H/D exchange protocol with CF -
COOAg as catalyst and heavy water as deuterium source at room
temperature, which enabled preparation of a series of deuterated
terminal alkynes, especially deuterated bioactive molecules with
sensitive functional groups.
[
12]. Thus, an efficient catalytic approach for selective deuterium-
labeling of terminal alkynes under mild condition is highly
demanded.
As shown in Table 1, our initial efforts focused on H/D exchange
process of terminal alkyne 1a with different silver salt as catalyst.
Although silver chloride and silver bromide are totally ineffective
(Table 1, entries 1–2), to our delight, deuterium-labeled terminal
⇑
Corresponding authors.
E-mail addresses: iamhhzhang@njtech.edu.cn (H.-H. Zhang), iamkangshen@
njtech.edu.cn (K. Shen), iamxliu@njtech.edu.cn (X. Liu).
https://doi.org/10.1016/j.tetlet.2020.152807
0
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Ding-Chuan Wu, Jing-Wen Bai, L. Guo et al.
Tetrahedron Letters 66 (2021) 152807
atom% deuterium incorporation was observed with CH
vent (Table 1, entries 13–19). Therefore, the optimal condition
was established with CF COOAg as catalyst in CH Cl at 25 °C.
2 2
Cl as sol-
3
2
2
Importantly, although homo-coupling byproduct was commonly
observed in metal-catalyzed transformations involving terminal
alkynes, we found deuterium-labeled terminal alkynes is the only
product under the optimal reaction condition.
With the optimal reaction condition in hand, we set out to
explore the generality of this method with respect to different ter-
minal alkynes as shown in Table 2. The benzyl propargyl ethers
with different substitutions were first examined (2a-2f). We found
several functional groups, including fluoride, nitro, phenyl and
methyl groups, were compatible with the standard condition,
affording products 2a-2f with 91% to 97% deuterium incorporation.
In addition, benzyl propargyl amine (2 g) with free NAH bond was
also found to be good substrate, affording 93% deuterium incorpo-
ration. The attempt for H/D exchange of two terminal alkynes in
one molecule (2 h) was also realized, providing high level of deu-
terium incorporation at both terminal alkynes. Moreover, we found
tert-butyl propiolate (2i) is a good substrate for this H/D exchange
protocol, affording product with 94% deuterium incorporation. Aryl
alkynes with different substitutions (2j-2 t) were then tested. Both
electron-donating and electron-withdrawing groups on the para-,
meta- and ortho-positions of aryl alkynes were compatible with
standard condition. In all cases, the reaction showed excellent site
selectivity with H/D exchange occurring at alkyne terminal CAH
even in the presence of aldehyde or methoxyl groups [14]. The
combination of simple operation process in the open air without
exclusion of oxygen or water and facile isolation process through
filtration, extraction and concentration without further purifica-
tion by column chromatograph made this method very attractive
for large-scale preparation. Finally, we were delighted to find this
H/D exchange reaction was amenable to scale up using 1.1 g of
Scheme 1. Various Routes for deuterium incorporation of terminal alkyne.
Table 1
Condition optimal.
Entry
Catalyst
Solvent
D incorporation
2
m without loss of efficiency.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
AgCl
AgBr
DME (0.5 M)
DME (0.5 M)
DME (0.5 M)
DME (0.5 M)
DME (0.5 M)
DME (0.5 M)
DME (0.5 M)
DME (1 M)
DME (0.7 M)
DME (0.3 M)
DME (0.5 M)
DME (0.5 M)
Toluene (0.5 M)
DMSO (0.5 M)
Dioxane (0.5 M)
THF (0.5 M)
DCM (0.5 M)
DMF (0.5 M)
2%
3%
The excellent site-selectivity and promising functional group
tolerance of this protocol promoted us to investigate its potential
application in deuteration of pharmaceuticals and natural product
derivatives. As shown in Table 3, the H/D exchange of nucleotide
derivatives was successfully achieved in 95% and 86% deuterium
Ag
CF
Ag
AgOAc
2
O
32%
92%
53%
78%
54%
83%
76%
83%
86%
85%
87%
86%
84%
76%
96%
87%
82%
3
COOAg
2
CO
3
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
3
3
3
3
3
3
3
3
3
3
3
3
3
3
SO Ag
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
COOAg
Table 2
Substrates scope.
0
1
2
3
4
5
6
7
8
9
a
3
CH CN (0.5 M)
a.The reaction was conducted on 0.4 mmol of 1a, 8 mmol of D
2
O, 5 mol % of
CF COOAg, in different solvents at 25 °C; level of deuterium incorporation was
3
o
determined by GC-MS.b.at 40 C. c.at 60 °C.
2 2 3 3
alkynes were indeed obtained by using Ag O, Ag CO , CF COOAg,
AgOAc and CF
3 3
SO Ag as catalyst (Table 1, entries 3–7). Among
them, CF COOAg was identified as the most effective catalyst,
3
affording product with 92% deuterium incorporation. We found
concentration played an important role in the H/D exchange pro-
cess, as a higher level of deuterium incorporation was observed
by performing reaction in 0.5 M solution (Table 1, entries 4, 8–
1
0). The test of reaction in different temperature showed that ele-
vated temperature has no positive effect on H/D exchange process
Table 1, entries 11–12). The choice of solvent is crucial, and high
(
2

Ding-Chuan Wu, Jing-Wen Bai, L. Guo et al.
Tetrahedron Letters 66 (2021) 152807
Table 3
Deuteration of pharmaceuticals and natural product derivatives.
incorporation (4a and 4b). Deuterated glucofuranose (4c), sesamol
(4d), estrone (4e) and a-amino acid (4f) derivatives were synthe-
sized from the corresponding terminal alkyne precursors in high
level of deuterium incorporation. It is noteworthy that excellent
site-selectivity of deuteration was observed in these cases, though
these molecules contained sensitive chemical bonds such as NAH
bond, as well as CAH bond neighboring to carbonyl or carboxylate
groups. Moreover, the reaction using mecarbinate derivatives as
substrate lead to 96% deuterium incorporation (4g).
With the attempt to get more insight into the reaction mecha-
nism, a series of experiments have been performed. We first con-
ducted the reaction without silver salt, and no deuterium
incorporation was observed. Replacement of silver trifluoroacetate
with potassium trifluoroacetate resulted in much lower level of
deuterium incorporation (Scheme 2a). These results suggested that
silver salt was essential for this H/D exchange process. It is well
reported that silver acetylide served as intermediate in the silver
catalyzed coupling reactions of terminal alkynes [16]. However,
we noticed that silver acetylide derivatives were commonly pre-
pared with water as solvent at room temperature [18], which made
us doubt that H/D exchange reaction proceeded via silver acetylide.
Indeed, no formation of compounds 6a and 2b were observed with
silver acetylide 5a and 5b as substrates under the standard condi-
tion at room temperature (Scheme 2b), which suggested that silver
acetylide may not be responsible for the H/D exchange process.
According to these experiment results, we proposed a mechanistic
pathway as follows (Scheme 2c): Terminal CAH bond was first
activated by the coordination of silver salt with triple bond. Then,
the step of H/D exchange between heavy water and terminal alky-
nes may occur, followed by the release of deuterated terminal alky-
nes and silver salt.
Scheme 2. Control Experiments and Proposed Mechanistic Pathway.
extension of this silver catalyzed H/D exchange reaction to other
type of substrates is still ongoing in our laboratory.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We thank the National Natural Science Foundation of China
(Grant Numbers 21704041), Six Talent Peaks Project in Jiangsu
Province (Grant Numbers XCL-027) and Nanjing Scientific Research
Foundation for Returned Scholars for support. We thank Kunlun
Hong (Oak Ridge National Laboratory) for assistance with the
preparation of the manuscript.
In summary, a practical approach for H/D exchange of terminal
alkynes with CF COOAg as catalyst is disclosed. There are several
3
advantages of this reaction. First of all, this reaction showed excel-
lent functional group tolerance under mild condition, which
enabled directly deuterium-labelling of bioactive molecules. Sec-
ond, it is an operational-friendly process, avoiding the fussy oper-
2
ation including protection with N and purification by column
chromatograph. Third, the deuterated terminal alkynes were easily
prepared with high level of deuterium incorporation. Thus, these
advantages made this reaction an extremely practical and efficient
method for preparation of deuterated terminal alkynes. Further
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152807.
3

Ding-Chuan Wu, Jing-Wen Bai, L. Guo et al.
Tetrahedron Letters 66 (2021) 152807
Synthesis 44 (2012) 184–193;
i) R. Grainger, A. Nikmal, J. Cornella, I. Larrosa, Org. Biomol. Chem. 10 (2012)
172–3174;
References
(
3
[
1] (a) J. Atzrodt, V. Derdau, W.J. Kerr, M. Reid, Angew. Chem. Int. Ed. 57 (2018)
758–1784;
b) A.R. Navratil, M.S. Shchepinov, E.A. Dennis, J. Am. Chem. Soc. 140 (2018)
35–243;
c) Y. Zhang, M.D. Tortorella, Y. Wang, J. Liu, Z. Tu, X. Liu, Y. Bai, D. Wen, X. Lu,
Y. Lu, J.J. Talley, ACS Med. Chem. Lett. 5 (2014) 1162–1166;
(
(
j) Z.Z. Zhou, J.H. Zhao, X.Y. Gou, X.M. Chen, Y.M. Liang, Org. Chem. Front. 6
2019) 1649–1654.
1
(
2
(
[
8] (a) I.T. Trotus, T. Zimmermann, F. Schueth, Chem. Rev. 114 (2014) 1761–1782;
(
(
b) U. Wille, Chem. Rev. 113 (2013) 813–852;
c) B. Godoi, R.F. Schumacher, G. Zeni, Chem. Rev. 111 (2011) 2937–2980.
[
9] (a) G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc. 132 (2010) 1474–
475;
b) T. Tsuchimoto, H. Matsubayashi, M. Kaneko, Y. Nagase, T. Miyamura, E.
Shirakawa, J. Am. Chem. Soc. 130 (2008) 15823–15835;
c) A.S.K. Hashmi, M. Rudolph, H.U. Siehl, M. Tanaka, J.W. Bats, W. Frey, Chem.
Eur. J. 14 (2008) 3703–3708.
(
(
(
(
d) T.G. Gant, J. Med. Chem. 57 (2014) 3595–3611;
e) A. Katsnelson, Nature Med. 6 (2013) 656;
f) N.A. Meanwell, J. Med. Chem. 54 (2011) 2529–2591;
g) K. Sanderson, Nature 458 (2009) 269.
1
(
(
[
2] (a) M. Shao, J. Keum, J. Chen, Y. He, W. Chen, J.F. Browning, J. Jakowski, B.G.
Sumpter, L.N. Ivanov, Y.Z. Ma, C.M. Rouleau, S.C. Smith, D.B. Geohegan, K. Hong,
K. Xiao, Nature Comm. 5 (2014) 1–11;
[
[
10] Y. Yabe, Y. Sawama, Y. Monguchi, H. Sajiki, Chem. Eur. J. 19 (2013) 484–488.
11] (a) T. Yamada, K. Park, Y. Monguchi, Y. Sawama, H. Sajiki, RSC Adv. 5 (2015)
(
(
b) R. Kabe, N. Notsuka, K. Yoshida, C. Adachi, Adv. Mater. 28 (2016) 655–660;
c) T.D. Nguyen, G. Hukic-Markosian, F. Wang, L. Wojcik, X.G. Li, E.
92954–92957;
(
(
(
b) F. Perez, Y. Ren, T. Boddaert, J. Rodriguez, Y. Coquerel, J. Org. Chem. 80
2015) 1092–1097;
c) S.P. Bew, G.D. Hiatt-Gipson, J.A. Lovell, C. Poullain, Org. Lett. 14 (2012)
Ehrenfreund, Z.V. Vardeny, Nature Mater. 9 (2010) 345–352.
[
[
3] (a) M. Waterstraat, A. Hildebrand, M. Rosler, M. Bunzel, J. Agric. Food Chem. 64
(
(
2016) 8667–8677;
b) J. Atzrodt, V.J. Derdau, Label Compd. Radiopharm 53 (2010) 674–685.
4
(
5
56–459;
d) C. Sabot, K.A. Kumar, C. Antheaume, C. Mioskowski, J. Org. Chem. 72 (2007)
001–5004;
4] (a) C. Shi, X. Zhang, C.H. Yu, Y.F. Yao, W. Zhang, Nature Commun. 9 (2018) 1–9;
b) S. Cantekin, D.W.R. Balkenende, M.M.J. Smulders, A.R.A. Palmans, E.W.
Meijier, Nature Chem. 3 (2011) 42–46;
c) R.P. White, J.E.G. Lipson, J.S. Higgins, Macromolecules 43 (2010) 4287–
293.
(
(
(
(
e) J.C. Cintrat, F. Pillon, B. Rousseau, Tetrahedron Lett. 42 (2001) 5001–5003;
f) G. Sirokman, A. Molnar, M. Bartok, J. Labelled Compd. Radiopharm. 27
1989) 439–448.
(
4
[
12] (a) B. Chatterjee, C. Gunanathan, Chem. Commun. 52 (2016) 4509–4512;
b) J.I. Ito, R. Asai, H. Nishiyama, Org. Lett. 12 (2010) 3860–3862.
[
[
5] For selected reviews of H/D exchange, see: (a) J. Atzrodt, V. Derdau, W.J. Kerr,
M. Reid, Angew. Chem. Int. Ed. 2018, 57, 3022-3047; (b) J. Atzrodt, V. Derdau,
T. Fey, J. Zimmermann, Angew. Chem. Int. Ed. 2007, 46, 7744-7765. (c) W.J.S.
Lockley, J.R. Heys, J. Label Compd. Radiopharm. 2010, 53, 635-644. (d) A.
Sattler, ACS Catal. 2018, 8, 2296-2312.
6] For recent publications of H/D exchange, see: (a) S. Ma, G. Villa,, P.S. Thuy-
Boun, A. Homs, J.Q. Yu, Angew. Chem. Int. Ed. 2014, 53, 734-737. (b) W.J. Kerr,
M. Reid, T. Tuttle, Angew. Chem. Int. Ed. 2017, 56, 7808-7812. (c) H. Yang, C.
Zarate, W.N. Palmer, N. Rivera, D. Hesk, P.J. Chirik, ACS Catal. 2018, 8, 10210-
(
[
13] (a) L. Guo, C. Xu, D.C. Wu, G.Q. Hu, H.H. Zhang, K. Hong, S. Chen, X. Liu, Chem.
Commun. 55 (2019) 8567–8570;
(
b) H.H. Zhang, P.V. Bonnesen, K. Hong, Org. Chem. Front. 2 (2015) 1071–1075.
[
[
14] E.C. Li, G.Q. Hu, Y.X. Zhu, H.H. Zhang, K. Shen, X.C. Hang, C. Zhang, W. Huang,
Org. Lett. 21 (2019) 6745–6749.
15] (a) G. Fang, X. Cong, G. Zanoni, Q. Liu, X. Bi, Adv. Synth. Catal. 359 (2017)
1422–1502;
(
(
b) Q.Z. Zheng, N. Jiao, Chem. Soc. Rev. 45 (2016) 4590–4627;
c) G. Fang, X. Bi, Chem. Soc. Rev. 44 (2015) 8124–8173.
1
0218. (d) B.M. Ahmed, G.J. Mezei, Org. Chem. 2018, 83, 1649-1653. (e) M.
Zhang, X.A. Yuan, C. Zhu, J. Xie, Angew. Chem. Int. Ed. 2019, 58, 312-316. (f) B.
Chatterjee, C. Gunanathan, Chem. Commun. 2016, 52, 4509-4512. (g) M. Liu, X.
Chen, T. Chen, S.F. Yin, Org. Biomol. Chem. 2017, 15, 2507-2511. (h) L. Gao, S.
Perato, S. Garcia-Argote, C. Taglang, L.M. Martinez-Prieto, C. Chollet, D.A.
Buisson, V. Dauvois, P. Lesot, B. Chaudret, B. Rousseau, S. Feuillastre, G. Pieters,
Chem. Commun. 2018, 54, 2986-2989. (i) M. Valero, R. Weck, S. Gussregen, J.
Atzrodt, V. Derdau, Angew. Chem. Int. Ed. 2018, 57, 8159-8163. (j) W.J. Kerr, R.
J. Mudd, M. Reid, J. Atzrodt, V. Derdau, ACS Catal. 2018, 8, 10895-10900. (k) R.P.
Yu, D. Hesk, N. Rivera, I. Pelczer, P.J. Chirik, Science 2016, 529, 195-199. (l) Y.Y.
Loh, K. Nagao, A.J. Hoover, D. Hesk, N.R. Rivera, S.L. Colletti, I.W. Davies, D.W.C.
MacMillan, Science 2017, 530, 1182-1187.
[
16] (a) G. Fang, X. Bi, Chem. Soc. Rev. 44 (2015) 8124–8173;
b) T. Wang, S. Chen, A. Shao, M. Gao, Y. Huang, A. Lei, Org. Lett. 17 (2015)
18–121;
c) D. Shi, Z. Liu, Z. Zhang, W. Shi, H. Chen, ChemCatChem 7 (2015) 1424–
426;
(
1
(
1
(
(
(
(
d) J.R. Hu, L.H. Liu, X. Hu, H.D. Ye, Tetrahedron 70 (2014) 5815–5819;
e) C. He, S. Guo, J. Ke, J. Hao, H. Xu, H. Chen, A. Lei, J. Am. Chem. Soc. 134
2012) 5766–5769;
f) C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei, Chem. Commun. 48 (2012)
1
(
2
1073–11075;
g) X. Zhang, W.Z. Zhang, X. Ben, L.L. Zhang, X.B. Lv, Org. Lett. 13 (2011) 2402–
405;
[
7] (a) V. Soulard, G. Villa, D.P. Vollmar, P. Renaud, J. Am. Chem. Soc. 140 (2018)
1
55–158;
(
(
(
h) P. Li, L. Wang, Synlett 14 (2006) 2261–2265;
i) S. Cao, Q. Ji, H. Li, M. Pang, H. Yuan, J. Zhang, X. Bi, J. Am. Chem. Soc. 142
2020) 7083–7091.
(
(
(
(
b) M. Janni, S. Peruncheralatthan, Org. Biomol. Chem. 14 (2016) 3091–3097;
c) H. Sajiki, T. Kurita, H. Esaki, F. Aoki, T. Maegawa, K. Hirotta, Org. Lett. 6
2004) 3521–3523;
[
17] G.S. Lewandos, J.W. Maki, J.P. Ginnebaugh, Organometallics 1 (1982) 1700–
705.
18] (a) R.H. Pouwer, C.M. Williams, A.L. Raine, J.B. Harper, Org. Lett. 7 (2005)
323–1325;
b) I.I. Roslan, J. Sun, G.K. Chuah, S. Jaenicke, Adv. Synth. Catal. 357 (2015)
19–726;
c) Z. Liu, J. Liu, L. Zhang, P. Liao, J. Song, X. Bi, Angew. Chem. Int. Ed. 53 (2014)
305–5309.
d) M. Kuriyama, N. Hamaguchi, G. Yano, K. Tsukuda, K. Sato, O. Onomura, J.
1
Org. Chem. 81 (2016) 8934–8946;
[
(
(
(
e) M. Kuriyama, S. Kujirada, K. Tsukuda, O. Onomura, Adv. Synth. Catal. 359
2016) 1043–1048;
f) J.L. Koniarczyk, D. Hesk, A. Overgard, I.W. Davies, A. McNally, J. Am. Chem.
1
(
7
(
Soc. 140 (2018) 1990–1993;
(
(
g) K. Burglova, S. Orochenkov, J. Hlavac, Org. Lett. 18 (2016) 3342–3345;
h) M. Rudzki, A. Alcalde-Aragones, W.I. Dzik, N. Rodriguez, L.J. GooBen,
5
4