Triazole formation of phosphinyl alkynes with azides through transient protection of phosphine by copper

Article abstract of DOI:10.1039/d0cc06551j

An efficient preparation method of functionalized phosphines by copper-catalyzed azide-alkyne cycloaddition (CuAAC) through the transient protection of phosphine from the Staudinger reaction is disclosed. Diverse phosphines were prepared from phosphinyl a

Full text of DOI:10.1039/d0cc06551j

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DOI: 10.1039/D0CC06551J
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Triazole formation of phosphinyl alkynes with azides through
†
transient protection of phosphine by copper
Norikazu Terashima, Yuki Sakata, Tomohiro Meguro, Takamitsu Hosoya, and Suguru Yoshida*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient preparation method of functionalized phosphines by phosphines affording stable azaylides (Figure 1B). Since these
copper-catalyzed azide–alkyne cycloaddition (CuAAC) through the biocompatible reactions enable facile chemical modification of
transient protection of phosphine from the Staudinger reaction is biomolecules, an efficient method to synthesize a wide variety of
disclosed. Diverse phosphines were prepared from phosphinyl functionalized phosphines will serve in the modification of
alkynes and azides by the click reaction at the ethynyl group functionalized 2,6-dichlorophenyl or perfluorophenyl azide
without damaging the phosphinyl group. Double- and triple-click derivatives.
assemblies of azides were accomplished by triazole formations and
robust azaylide formation.
A
Our previous work
Cl
N3
Click chemistry has played significant roles to prepare functional
H
N
O
rapid
aza-ylide
formation
FG2
molecules in a broad range of research fields such as materials
chemistry, pharmaceutical chemistry, and chemical biology.1–6
Various click reactions including copper-catalyzed azide–alkyne
cycloaddition (CuAAC)2 and strain-promoted azide–alkyne
cycloaddition (SPAAC)3 have been developed so far for efficient
conjugations of molecules.4,5 On the basis of emerging click
reactions, a number of methods to assemble modules using
trivalent platforms have been gained attention.6 We herein
disclose a method assembling azides onto a newly designed
trivalent platform molecule through the CuAAC reaction of
phosphinyl alkynes with azides via transient protection of
phosphine from Staudinger reaction by the treatment with copper.
Recently, our group7 and Ramström and Yan’s group8
independently reported rapid Staudinger reactions forming
azaylides with good stability (Figures 1A and 1B).9 For example,
we found that 2,6-dichlorophenyl azides spontaneously react
with triphenylphosphine derivatives to furnish robust azaylides
(Figure 1A). Of note, this rapid Staudinger reaction realized
efficient chemical modification inside cells, while SPAAC
reactions inside cells are not always easy due to the instability of
cyclooctynes inside cells.10 Ramström, Yan, and coworkers also
reported a Staudinger reaction between perfluoroaryl azides and
Cl
FG1
Cl
N
H
O
N
+
P
O
H
N
Ph
Ph
FG2
Cl
FG1
N
H
O
Ph2P
B
Ramström and Yan’s work
F
F
N3
H
N
rapid
aza-ylide
formation
F
F
O
F
FG1
F
N
F
O
F
P
FG2
H
+
Ph
N
Ph
O
FG1
O
Ph2P
Initial attempt
FG2
C
BnN3 2a (1.0 equiv)
(MeCN)4CuBF4 (5 mol %)
TBTA (5 mol %)
O
O
N
N
N
N
H
N
H
CH2Cl2, rt
Ph2P
Ph2P
Bn
1a
(1.1 equiv)
3a
not detected
D
This work
1. Cu
2.
Cu
Ph2P
N3
2
FG
cat. TBTA
3. chelator
Ph2P
FG
Ph2P
N
protection of phosphine
by complexation with copper
N
N
1
3
Fig. 1 Background of this study. (A) Our previous study. (B) Ramström and Yan’s work.
(C) Initial attempt. (D) This work. TBTA = tris(benzyltriazolylmethyl)amine.
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai,
Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: s-yoshida.cb@tmd.ac.jp
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization for new compounds including NMR spectra. For ESI see DOI:
10.1039/x0xx00000x
We at first assumed that a CuAAC reaction of phosphinyl
alkynes with azides realizes the efficient preparation of
functionalized phosphines, which can react rapidly with
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Chem. Commun., 20XX, 00, 1-4 | 1
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electron-deficient azides.11,12 However, an attempt using participated in the alkyne-selective click reaction to provide
View Article Online
phosphinyl alkyne 1a with azide 2a in the presence of copper triazoles 3d and 3e 7,14
Triazole 3f was successfully synthesized
.
DOI: 10.1039/D0CC06551J
catalysis resulted in failure due to the Staudinger reaction at the using picolyl azide through efficient CuAAC reaction and
phosphinyl group (Figure 1C). Considering our recent success on removal of the copper with aqueous DTPA·5Na. The preparation
the protection of cyclooctynes,13 we then conceived an idea to of functional phosphines 3g
achieve the facile synthesis of triazole 3a from phosphinyl reaction of phosphinyl alkyne 1a with a variety of azides having
alkyne under mild conditions (Figure 1D). The idea was that functions such as biotin, HaloTag ligand, and poly(ethyleneoxy)
pretreatment of phosphinyl alkyne with copper for the moieties.
protection from the Staudinger reaction followed by CuAAC
reaction with azides and removal of copper salt will enable the
–3i was achieved by the click
1
1
1. (MeCN)4CuBF4
(1.2 equiv)
2
CH2Cl2, rt, 30 min
2. RN3 2 (1.0 equiv)
TBTA (5 mol %)
rt, 1 h
selective triazole formation.
O
O
Table 1 Optimization of the reaction conditions
N
N
N
N
H
H
3. aq. DTPA·5Na
(20 equiv)
rt, 15 h
1. copper salt (1.2 equiv)
N
Ph2P
Ph2P
Ph2P
Ph2P
CH2Cl2, rt, 30 min
2. BnN3 2a (1.0 equiv)
additive, rt, 1 h
1a
3
R
O
O
(1.2 equiv)
N
N
H
N
H
N
O
O
3. chelator (20 equiv)
rt, 15 h
N
Ph2P
Ph2P
N
N
N
N
Bn
N
H
N
H
1a
3a
N
(1.2 equiv)
N
Ph2P
3b
3c
79%
87%
entry
copper salt
additive
chelator
yield/%
O
O
1
2
3
4
(CH3CN)4CuBF4 TBTA (5 mol %)
(CH3CN)4CuBF4 TBTA (5 mol %)
(CH3CN)4CuBF4 TBTA (5 mol %)
(CH3CN)4CuBF4 TBTA (5 mol %)
aq. EDTA·2Na
aq. NTA·2Na
aq. DTPA·5Na
PS-TPP
12
23
84
3
OMe
NO2
N
N
N
H
N
H
N
N
N
N
Cl
N
i-Pr
Ph2P
3d
3e
87%
87%
Cl
i-Pr
O
5
6
(CH3CN)4CuBF4 TBTA (5 mol %) SiliaMetS Thiourea
(CH3CN)4CuBF4 TBTA (5 mol %) SiliaMetS Triamine
34
91
N
N
H
O
N
N
Ph2P
N
H
N
7
CuSO4·5H2O
CuI
Na asocorbate
aq. DTPA·5Na
aq. DTPA·5Na
n.d.
17
O
O
O
N
Ph2P
3f
8b
i-Pr2NEt (3.0 equiv)
O
quant.
HN
H
NH
H
NH
O
N
3g
56%
EDTA·2Na = ethylenediamine-N,N,N’,N’-tetraacetic acid disodium salt. EDTA·2Na =
ethylenediamine-N,N,N’,N’-tetraacetic acid disodium salt. NTA·2Na = nitrilotriacetate
disodium salt. DTPA·5Na = diethylene triamine pentaacetic acid pentasodium salt
O
S
O
N
N
H
N
N
N
H
N
O
N
Ph2P
N
Ph2P
Efficient synthesis of triazole 3a from phosphinyl alkyne 1a
and azide 2a was accomplished by the protection of the
phosphinyl group and CuAAC reaction both using a cationic
copper salt, and following deprotection with a suitable chelator
(Table 1). Firstly, the treatment of phosphinyl alkyne 1a with
(CH3CN)4CuBF4 followed by the addition of azide and a
catalytic amount of TBTA2c realized the desired CuAAC
reaction with avoiding the Staudinger reaction as expected,
although triazole 3a was obtained in low yields by the
subsequent removal of the copper with aqueous EDTA·2Na or
NTA·2Na (entries 1 and 2). The use of aqueous DTPA·5Na as a
chelator remarkably improved the yield of triazole 3a (entry 3).
Triazole 3a was also obtained in high yield using SiliaMetS
Triamine (entry 6), while the deprotection with other metal
scavengers such as polystyrene-supported triphenylphosphine
and SiliaMetS Thiourea resulted in low efficiencies (entries 4
and 5). In sharp contrast, the efficient triazole formation was not
easy under other conditions for the CuAAC reaction using
CuSO4·5H2O2b or copper iodide2a (entries 7 and 8).
O
Cl
MeO
O
O
3h
83%
O
O
O
HN
O
3i
O
O
83%
Fig. 2 Triazole formation using various azides.
1. (MeCN)4CuBF4
(1.2 equiv)
CH2Cl2, rt, 30 min
2. BnN3 2a (1.0 equiv)
TBTA (5 mol %)
rt, 1 h
Ph2P
Bn
N
Ph2P
3. aq. DTPA·5Na
(20 equiv)
rt, 15 h
N
N
1
(1.2 equiv)
3’
N
Bn
N
O
N
N
MeO2C
Ph2P
H
N
O
N
3j
3k
32%
Bn
N
78%
PPh2
O
O
Bn
N
H
N
O
O
N
Bn
Ph2P
3m
N
N
N
N
O
36%
O
O
Bn
PPh2
3l
84%
N
N
A wide range of click-conjugated phosphines
3 were
Ph2P
3n
67%
N
synthesized from phosphinyl alkyne 1a and various azides
(Figure 2). Electron-donating and -deficient aromatic azides
smoothly reacted with 1a to afford triazoles 3b and 3c in high
yields without the azaylide formation. Bulky but highly reactive
2,6-dichlorophenyl and 2,6-diisopropylphenyl azides also
Fig. 3 Triazole formation using various alkynes.
2 | Chem. Commun., 20XX, 00, 1-4
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1. (MeCN)4CuBF4
(1.2 equiv)
CH2Cl2, rt, 30 min
2. RN3 (1.0 equiv)
TBTA (5 mol %)
rt, 1 h
through the CuAAC reaction and azaylide formation will serve
in the fluorescent modification oDfOI:a10z.i1d0e3-9i/nDc0oCrCp0o6ra55te1dJ
biomolecules with fluorescent azides and phosphinyl alkynes.
View Article Online
O
O
N
Cl
N
H
N
H
N
Cl
N
3.
N
A
P
Ph2P
N3
Ph
R
HPPh2
cat. Pd(OAc)2
NEt3
6
SiMe3
8
1a
O
OMe
4
Ph
O
OMe
Br
O
OMe
(1.2 equiv)
Cl
cat. (Ph3P)2PdCl2
cat. CuI
Cl 2d
SiliaMetS Triamine
(20 equiv)
rt, 15 h
i-Pr2NH, DMF
MeCN
reflux
Ph2P
80 °C
I
Ph2P
Br
SiMe3
5
7
9
95%
68%
O
aq. NaOH
N
N
O
Cl
N
THF, rt
OH
N
H
11
N
N
P
Ph
NEt2
O
H2N
O
Ph
EDC·HCl
DMAP
N
O
Cl
N
Cl
N
O
N
H
O
NH
O
N
N
CH2Cl2
rt
P
–
Et2N
SO3
O
12
62%
Ph
Ph
Cl
Bn
Ph2P
4a
94%
10
(2 steps)
O
4b
Ph2P
94%a
S
NH
O
O
B
O
12
O
MeO2C
N
CH2Cl2, rt;
90%
N
Cl
N
N
Cl
N
H
N
N3
H
N
N
N
P
N
2m
P
Ph
Ph
Ph
Ph
Cl
Me
3.
1. (MeCN)4CuBF4
CH2Cl2, rt
2.
Cl
Cl
EtO2C
Me
N3
Cl 2d
SiliaMetS Triamine
rt, 15 h;
O
N3
OMe
Me
4c
88%a
O
N
4d
67%a
B
F
2b
N
MeO
TBTA (5 mol %)
rt, 1 h
F
N
CO2Et
Me
89%
Fig. 4 Double-click conjugation using phosphinyl alkyne 1a. aAzaylide formation with 2d
was performed after the removal of copper with aq. DTPA·5Na instead of SiliaMetS
Triamine.
CO2Me
N
N
N
N
+ isomer
O
NH
O
N
We succeeded in the facile preparation of click-conjugated
13
phosphines
3 from a variety of alkynyl phosphines 1 (Figure 3).
Cl
N
For example, the click conjugation enabled us to synthesize
ortho-ester-substituted triarylphosphine 3j in good yield, which
will contribute to the Staudinger–Bertozzi ligation with alkyl
azides.15 Triazoles 3k and 3l were also prepared in moderate to
high yields from the corresponding alkyne-substituted esters. It
is worthy to note that the alkoxy group can be released by the
Staudinger–Bertozzi ligation.16 Alkyl(diaryl)phosphine 3m was
successfully synthesized by the click reaction at the ethynyl
group without the formation of azaylide by virtue of the
P
N
N
Ph
Ph
Cl
OMe
Fig. 5 Triple-click conjugation using 12. (A) Synthesis of platform molecule 12. (B)
Assembly of azides 2b, 2d, and 2m onto platform 12.
We then turned attention to develop a trivalent platform 12
having a phosphine, terminal alkyne, and cycloalkyne moieties
for triple-click conjugation by SPAAC, CuAAC, and robust
azaylide formation (Figure 5). The trivalent platform 12 was
designed with consideration that the SPAAC reaction
predominantly took place when an equimolar mixture of a
dibenzo-fused cyclooctyne and triphenylphosphine was treated
with aliphatic azide.7 A 4-step synthesis of platform 12 was
realized from methyl 3-bromo-5-iodobenzoate
diphenylphosphine ( ), alkyne , and cycloalkyne 11 (Figure
5A). Indeed, iodo-selective phosphinylation15 of
and
subsequent Sonogashira coupling17 at the remaining bromo
group with alkyne provided in good yields. Hydrolysis of the
ester moiety and desilylprotonation was accomplished by
treating with aqueous sodium hydroxide. Condensation of the
protection
with
copper.
Ethynyl(diphenyl)phosphine
participated in the CuAAC reaction to afford triazole 3n leaving
the phosphine moiety untouched through the complexation with
copper.
Efficient double-click conjugation was realized by the
CuAAC reaction of 1a with diverse azides followed by the
Staudinger reaction with 2,6-dichlorophenyl azide (2d) forming
robust azaylides (Figure 4). For instance, after transient
protection of phosphinyl alkyne 1a with copper and following
triazole formation with benzyl azide (2a), the addition of
SiliaMetS triamine and azide 2d resulted in the double-click
conjugation to afford azaylide 4a in high yield. Fluorescent
azides bearing sulforhodamine, julolidine-fused coumarin, and
BODIPY moieties smoothly reacted with phosphinyl alkyne 1a
(5) with
6
8
5
8
9
9
resulting carboxylic acid 10 with DIBAC 11 proceeded smoothly
to afford trivalent platform 12 efficiently.18
to furnish fluorescent azaylides 4b–d through the protection of
diphenylphosphinyl group. Thus, the double-click conjugation
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Journal Name
and V. V. Popik, Chem. Commun., 2016, 52, 553. (f) T. Meguro, S.
Assembly of azides 2b, 2d, and 2m onto trivalent platform
Yoshida, K. Igawa, K. Tomooka and T. Hosoya, Org.VLieewttA.,rt2ic0le1O8,nl2in0e,
DOI: 10.1039/D0CC06551J
12 was achieved in good efficiency (Figure 5B). Firstly, SPAAC
reaction of platform 12 with azide 2m at the DIBAC moiety
selectively proceeded without damaging the phosphine and
terminal alkyne moieties. Then, CuAAC reaction of azide 2b at
the remaining terminal alkyne moiety was realized through the
protection of the phosphinyl group with copper. Finally, we
succeeded in the deprotection and azaylide formation with azide
2d in the presence of SiliaMetS triamine. Thus, this efficient
triple-click assembly onto trivalent platform 12 will allow us to
synthesize multi-functionalized molecules from simple azide
modules.
In summary, we have developed an efficient synthetic
method of click-conjugated phosphines from phosphinyl alkynes
via the protection of phosphines with copper. Double- and triple-
click reactions assembling azides were achieved using platform
molecules having phosphinyl and alkyne moieties. Further
studies including other metals for the protection and applications
to the preparation of molecular probes are ongoing.
The authors thank Dr. Takashi Niwa (RIKEN, Center for
Biosystems Dynamics Research (BDR)) for HRMS analyses.
This work was supported by JSPS KAKENHI Grant Numbers
JP19K05451 (C; S.Y.), JP18H02104 (B; T.H.), JP18H04386
(Middle Molecular Strategy; T.H.), and JP18J11113 (JSPS
Research Fellow; T.M.); the Naito Foundation (S.Y.); the Japan
Agency for Medical Research and Development (AMED) under
Grant Numbers JP20am0101098 (Platform Project for
Supporting Drug Discovery and Life Science Research, BINDS);
and the Cooperative Research Project of Research Center for
Biomedical Engineering.
4126.
5
6
(a) A.-C. Knall and C. Slugovc, Chem. Soc. Rev., 2013, 42, 5131. (b)
Z.-J. Zheng, D. Wang, Z. Xu and L.-W. Xu, Beilstein J. Org. Chem.,
2015, 11, 2557. (c) S. Yoshida, Bull. Chem. Soc. Jpn., 2018, 91, 1293.
(d) S. Yoshida, Org. Biomol. Chem., 2020, 18, 1550.
(a) P. R. Werkhoven, H. van de Langemheen, S. van der Wal, J. A. W.
Kruijtzer and R. M. J. Liskamp, J. Pept. Sci., 2014, 20, 235. (b) V.
Vaněk, J. Pícha, B. Fabre, M. Buděšínský, M. Lepšík and J. Jiráček,
Eur. J. Org. Chem., 2015, 3689. (c) B. Fabre, J. Pícha, V. Vaněk, I.
Selicharová, M. Chrudinová, M. Collinsová, L. Žáková, M.
Buděšínský and J. Jiráček, ACS Comb. Sci., 2016, 18, 710. (d) B. Fabre,
J. Pícha, V. Vaněk, M. Buděšínský and J. Jiráček, Molecules, 2015, 20,
19310. (e) A.-C. Knall, M. Hollauf, R. Saf and C. Slugovc, Org.
Biomol. Chem., 2016, 14, 10576. (f) S. Yoshida, K. Kanno, I. Kii, Y.
Misawa, M. Hagiwara and T. Hosoya, Chem. Commun., 2018, 54,
3705. (g) T. Yokoi, H. Tanimoto, T. Ueda, T. Morimoto and K.
Kakiuchi, J. Org. Chem., 2018, 83, 12103. (h) T. Yokoi, T. Ueda, H.
Tanimoto, T. Morimoto and K. Kakiuchi, Chem. Commun., 2019, 55,
1891. (i) T. Meguro, Y. Sakata, T. Morita, T. Hosoya and S. Yoshida,
Chem. Commun., 2020, 56, 4720.
T. Meguro, N. Terashima, H. Ito, Y. Koike, I. Kii, S. Yoshida and T.
Hosoya, Chem. Commun., 2018, 54, 7904.
M. Sundhoro, S. Jeon, J. Park, O. Ramström and M. Yan, Angew.
Chem., Int. Ed., 2017, 56, 12117.
(a) W. Luo, J. Luo, V. V. Popik and M. S. Workentin, Bioconjugate
Chem., 2019, 30, 1140. (b) L. Cheng, X. Kang, D. Wang, Y. Gao, L.
Yi and Z. Xi, Org. Biomol. Chem., 2019, 17, 5675.
7
8
9
10 R. van Geel, G. J. M. Pruijn, F. L. van Delft and W. C. Boelens,
Bioconjugate Chem., 2012, 23, 392.
11 (a) F. Dolhem, M. J. Johansson, T. Antonsson and N. Kann, J. Comb.
Chem., 2007, 9, 477. (b) R. Veillard, E. Bernoud, I. Abdellah, J.-F.
Lohier, C. Alayrac and A.-C. Gaumont, Org. Biomol. Chem., 2014, 12,
3635. (c) M. Robert, J. Vallée, P. Majkut, D. Krause, M. Gerrits and
C. P. R. Hackenberger, Chem. Eur. J., 2015, 21, 970
12 (a) M.-A. Kasper, M. Glanz, A. Stengl, M. Penkert, S. Klenk, T. Sauer,
D. Schumacher, J. Helma, E. Krause, C. Cardoso, H. Leonhardt and C.
P. R. Hackenberger, Angew. Chem., Int. Ed., 2019, 58, 11625. (b) M.-
A. Kasper, M. Gerlach, A.F.L. Schneider, C. Groneberg, P. Ochtrop,
S. Boldt, D. Schumacher, J. Helma, H. Leonhardt, M. Christmann and
C. P. R. Hackenberger, ChemBioChem, 2020, 21, 113. (c) A. L.
Baumann, S. Schwagerus, K. Broi, K. Kemnitz-Hassanin, C. E. Stieger,
N. Trieloff, P. Schmieder and C. P. R. Hackenberger, J. Am. Chem.
Soc., 2020, 142, 9544.
13 (a) S. Yoshida, Y. Hatakeyama, K. Johmoto, H. Uekusa and T. Hosoya,
J. Am. Chem. Soc., 2014, 136, 13590. (b) S. Yoshida, T. Kuribara, H.
Ito, T. Meguro, Y. Nishiyama, F. Karaki, Y. Hatakeyama, Y. Koike, I.
Kii and T. Hosoya, Chem. Commun., 2019, 55, 3556. (c) K. Adachi, T.
Meguro, Y. Sakata, K. Igawa, K. Tomooka, T. Hosoya and S. Yoshida,
Chem. Commun., 2020, 56, 9823. (d) N. Makio, Y. Sakata, T. Kuribara,
K. Adachi, Y. Hatakeyama, T. Meguro, K. Igawa, K, Tomooka, T.
Hosoya and S. Yoshida, Chem. Commun., 2020, 56, 11449.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
(a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
Ed., 2001, 40, 2004. (b) C. S. McKay and M. G. Finn, Chem. Biol.,
2014, 21, 1075. (c) J. Lahann, Click Chemistry for Biotechnology and
Materials Science, John Wiley & Sons, West Sussex, 2009.
2
(a) C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002,
67, 3057. (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B.
Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596. (c) T. R. Chan, R.
Hilgraf, K. B. Sharpless and V. V. Fokin, Org. Lett., 2004, 6, 2853. (d)
X.-M. Liu, A. Thakur and D. Wang, Biomacromolecules, 2007, 8,
2653. (e) M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952.
(f) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302.
(a) M. F. Debets, C. W. J. van der Doelen, F. P. J. T. Rutjes and F. L.
van Delft, ChemBioChem, 2010, 11, 1168. (b) J. C. Jewett and C. R.
Bertozzi, Chem. Soc. Rev., 2010, 39, 1272. (c) E. M. Sletten and C. R.
Bertozzi, Acc Chem Res., 2011, 44, 666. (d) S. Arumugam, S. V. Orski,
N. E. Mbua, C. McNitt, G.-J. Boons, J. Locklin and V. V. Popik, Pure
Appl. Chem., 2013, 85, 1499. (e) J. Dommerholt, F. P. J. T. Rutjes and
F. L. van Delft, Top. Curr. Chem., 2016, 374, 16.
(a) I. E. Valverde, A. F. Delmas and V. Aucagne, Tetrahedron, 2009,
65, 7597. (b) B. C. Sanders, F. Friscourt, P. A. Ledin, N. E. Mbua, S.
Arumugam, J. Guo, T. J. Boltje, V. V. Popik and G.-J. Boons, J. Am.
Chem. Soc., 2011, 133, 949. (c) J. Dommerholt, O. van Rooijen, A.
Borrmann, C. F. Guerra, F. M. Bickelhaupt and F. L. van Delft, Nat.
Commun., 2014, 5, 5378. (d) R. R. Ramsubhag and G. B. Dudley, Org.
Biomol. Chem., 2016, 14, 5028. (e) D. A. Sutton, S.-H. Yu, R. Steet
14 (a) S. Yoshida, A. Shiraishi, K. Kanno, T. Matsushita, K. Johmoto, H.
Uekusa and T. Hosoya, Sci. Rep., 2011, 1, 82. (b) S. Yoshida, J. Tanaka,
Y. Nishiyama, Y. Hazama, T. Matsushita and T. Hosoya, Chem.
Commun., 2018, 54, 13499.
3
4
15 E. Saxon and C. R. Bertozzi, Science, 2000, 287, 2007.
16 (a) A. R. Van Dyke, L. S. Etemad, M. J. Vessicchio, G. A. Naclerio
and V. Jedson, ChemBioChem, 2016, 17, 1602. (b) W. Luo, P. Gobbo,
P. N. Gunawardene and M. S. Workentin, Langmuir, 2017, 33, 1908.
17 R. Chinchilla and C. Nájera, Chem. Rev., 2007, 107, 874
18 M. F. Debets, S. S. van Berkel, S. Schoffelen, F. P. J. T. Rutjes, J. C.
M. van Hest, and F. L. van Delft, Chem. Commun., 2010, 46, 97.
4 | Chem. Commun., 20XX, 00, 1-4
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ChemComm
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Journal Name
COMMUNICATION
Graphical abstract for the contents page
View Article Online
DOI: 10.1039/D0CC06551J
xxx
Triazole formation of phosphinyl alkynes with
azides through transient protection of phosphine by
copper
Norikazu Terashima, Yuki Sakata, Tomohiro Meguro,
Takamitsu Hosoya, and Suguru Yoshida*
An efficient preparation of functionalized phosphines by triazole
formation through the transient protection of phosphine from the
Staudinger reaction is disclosed. Double- and triple-click
assemblies of azides were accomplished.
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