Transient Protection of Organic Azides from Click Reactions with Alkynes by Phosphazide Formation

Article abstract of DOI:10.1021/acs.orglett.8b01692

A method for protecting organic azides from click reactions with alkynes is reported. Treatment of azides with Amphos affords phosphazides, which are stable under click reaction conditions and are easily converted back to azides by treatment with elemental sulfur. Thus, the method allows for facile modification of azide compounds via site-selective click reactions.

Full text of DOI:10.1021/acs.orglett.8b01692

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transient Protection of Organic Azides from Click Reactions with
Alkynes by Phosphazide Formation
Tomohiro Meguro,† Suguru Yoshida,*,† Kazunobu Igawa,‡ Katsuhiko Tomooka,‡
and Takamitsu Hosoya*,†
†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
‡Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
S
* Supporting Information
ABSTRACT: A method for protecting organic azides from click reactions with
alkynes is reported. Treatment of azides with Amphos affords phosphazides,
which are stable under click reaction conditions and are easily converted back to
azides by treatment with elemental sulfur. Thus, the method allows for facile
modification of azide compounds via site-selective click reactions.
rganic azides are widely used as pharmaceutical drugs
Oand versatile synthetic intermediates for nitrogen-
containing compounds.1 Moreover, the utility of azides has
expanded enormously with the rise of click chemistry
methodologies such as copper-catalyzed azide−alkyne cyclo-
addition (CuAAC)2 and strain-promoted azide−alkyne cyclo-
addition (SPAAC).3 These reactions present reliable and
convenient methods for molecular conjugation and have been
applied in a broad range of disciplines, including materials
sciences and chemical biology.4
With the growing availability of these click reactions, the
demand for functionalized azides and strained alkynes have
also increased. However, these functionalized molecules are
difficult to prepare straightforwardly by click reactions, because
click conjugation in the presence of other clickable groups with
higher reactivity is difficult to achieve selectively.5−7 In this
context, we recently developed a facile method for protecting
strained alkynes from the SPAAC reaction with azides by
complexation with a cationic copper salt (Figure 1A).8 This
method enabled selective CuAAC conjugation at the terminal
alkyne moiety of diyne 1 to afford triazole 2, leaving the
strained alkyne moiety with higher azidophilicity untouched.
To expand this concept, we have developed a protection
method for azides.
Figure 1. Backgrounds and basic concept of this work: (A) our
previous work, (B) typical reaction of a diazide compound with a
strained alkyne, (C) concept of this work, and (D) equilibrium
generation of phosphazide 5 from azide 3 and phosphine 4 and the
formation of aza-ylide 6.
Normally, an SPAAC reaction between a diazide compound
and a cyclooctyne derivative affords a mixture of cycloadducts,
particularly when the two azido groups in the diazide have
similar ynophilicities (Figure 1B). Furthermore, although there
are several reports on azido-type selective triazole formation
using multiazides, the azido groups are consumed in the order
of their reactivity, and leaving the most ynophilic azido group
unchanged is difficult.9 We reasoned that site-selective
protection of an azido group would enable site-selective click
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Phosphines for Preventing the SPAAC Reaction between Azide 3a and Cyclooctyne 7
a
a
a
entry
phosphine
4
8a (%)
5
(%)
6 (%)
b
1
2
3
4
5
6
7
8
9
none
PPh3
98
0
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a, 0
5b, 0
5c, 86
5d, 91
5e, 16
5f, 85
6a, 93
6b, 0
6c, 0
6d, 0
6e, 51
6f, 0
P(n-Bu)3
P(c-Hex)3
P(t-Bu)3
Ph2P(t-Bu)
PhP(t-Bu)2
4-F3C−C6H4P(t-Bu)2
4-Me2N−C6H4P(t-Bu)2 (Amphos)
P(NMe2)3
c
14
8
33
15
56
0
d
5g, 44
5h, quant
5i, quant
6g, 0
6h, 0
6i, 0
10
0
a
b
c
d
1
Yields based on H NMR analysis, unless otherwise noted. Isolated yield. Toluene solution (20 wt %) was used. Hexanes solution (10 wt %)
was used.
conjugation of diazide compounds (Figure 1C). To realize this
simple, but challenging, idea, we focused on equilibrium
generation of phosphazide 5 from azide 3 and phosphine 4
(Figure 1D).10 In the course of our previous study on azido-
type selective reduction by the Staudinger reaction, we found
that aromatic azides react smoothly with various phosphines to
afford aza-ylides or phosphazides, depending on the phosphine
used.10m,o A literature survey also indicated the equilibrium
generation of bulky phosphazides,10h prompting us to search
for a suitable phosphine that forms stable, yet reversible,
phosphazides upon the reaction with various azides.
achieved using the more electron-rich phosphine, Amphos
(4h), bearing a 4-(dimethylamino)phenyl group (Table 1,
entry 9). In addition, the reaction between 3a and
hexamethylphosphorous triamide (4i) also afforded phospha-
zide 5i quantitatively without formation of 8a (Table 1, entry
10).
A control experiment clearly demonstrated that the electron-
donating dimethylamino group of Amphos (4h) significantly
facilitates the formation of phosphazide 5h (see Figure 2).
An extensive screening revealed that bulky and electron-rich
phosphines efficiently prevented the SPAAC reaction between
aromatic azide 3a and cyclooctyne 7 (see Table 1). Without
phosphine, 3a reacted quantitatively with 7 in methanol-d4 to
afford triazole 8a (Table 1, entry 1). By pretreating 3a with a
phosphine for 1 h, the yield of 8a decreased, depending on the
type of phosphine employed (Table 1, entries 2−10).
Although cycloadduct 8a was not formed by the pretreatment
of 3a with triphenylphosphine or tri(n-butyl)phosphine, aza-
ylide 6a and a complex mixture of products, respectively, were
obtained instead, indicating that these phosphines are
unsuitable for our purposes (Table 1, entries 2 and 3). In
contrast, the use of bulky phosphine 4c or 4d afforded
phosphazide 5c or 5d, respectively, in high yields, while a small
amount of 8a was also obtained in these cases (Table 1, entries
4 and 5). To achieve efficient phosphazide formation without
the formation of 8a, several other bulky phosphines were
examined (Table 1, entries 6−9). While a significant amount of
aza-ylide 6e was obtained when tert-butyl(diphenyl)phosphine
(4e) was used (Table 1, entry 6), treatment of 3a with di(tert-
butyl)phenylphosphine (4f) afforded phosphazide 5f in high
yield (Table 1, entry 7). Although the corresponding aza-ylide
6f was not formed in this case, a small amount of 8a was
obtained. Therefore, the effect of the substituent on the phenyl
group of 4f was examined. While the efficiency for phosphazide
formation decreased upon using the more electron-deficient
phosphine 4g, bearing a 4-(trifluoromethyl)phenyl group
(Table 1, entry 8), quantitative phosphazide formation was
Figure 2. Control experiment: (A) preparation of an equilibrated
mixture of azide 3a and phosphazide 5g; (B) time-dependent
formation of phosphazide 5h from a mixture of 5g and 3a by
treatment with phosphine 4h.
Treatment of an equilibrated mixture of azide 3a and
phosphazide 5g in methanol-d4 (Figure 2A) with 4h resulted
in the time-dependent conversion of phosphazide 5g to 5h,
allowing complete conversion within 24 h (Figure 2B).
The inertness of phosphazide 5h was demonstrated under
various conditions. It was not only unreactive with a strained
alkyne, but also stable toward air, moisture, basic conditions,
and several amino acids. Furthermore, phosphazide 5h could
be purified by recrystallization, demonstrating that it is
kinetically stable at room temperature. Thus, treatment of
azide 3a with Amphos (4h) (1.1 equiv) in methanol for 1 h,
followed by the removal of methanol and recrystallization from
n-hexane and ethyl acetate afforded phosphazide 5h in an
excellent yield. In addition, the s-trans structure of 5h was
confirmed by X-ray crystallographic analysis of a fine crystal
obtained by recrystallization from methanol (see Figure 3).
B
DOI: 10.1021/acs.orglett.8b01692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Protection and Regeneration of Various Azides
Figure 3. X-ray crystal structure of phosphazide 5h.
The regeneration of azide 3a from phosphazide 5h was
efficiently and easily achieved using an oxidant, demonstrating
the ability of this system to serve as a protection method. After
extensive screening for an effective oxidant that reacts with
phosphazide 5h or regenerates phosphine 4h at room
temperature, we found that treatment of 5h in THF with
elemental sulfur (S8) regenerates azide 3a in an excellent yield
(see Table 2, entry 6). Conversely, an attempt to regenerate 3a
from phosphazide 5i under the same conditions was
unsuccessful, indicating that hexamethylphosphorous triamide
(4i) is unsuitable for protecting azides (Table 2, entry 7).
A wide range of azides could be protected completely from
the SPAAC reaction with cyclooctyne 7 by the phosphazide
formation with Amphos (4h) (Table 3, column A) and
regenerated efficiently by the treatment with S8 (Table 3,
column B). These include electron-deficient and electron-rich
aromatic azides 3b−f bearing nitro, methoxy, iodo, or chloro
groups at the para-, meta-, or ortho-positions (Table 3, entries
1−5). Aliphatic azide 3g was also protectable, expanding the
scope of this method (Table 3, entry 6). Notably, the azido
groups in N-succinimidyl ester 3h and propargyl amide 3i were
also rendered unclickable by treating with 4h and could be
regenerated leaving the reactive functional groups untouched
(Table 3, entries 7 and 8).
Using the protection method developed in this study, formal
aliphatic azido-selective click reactions of diazide 911 were
achieved (Scheme 1). Thus, treatment of 9 with an equimolar
amount of 4h resulted in a selective phosphazide formation at
the aromatic azido group to afford monoazide 10. The
phosphazide formation at the aromatic azido group of diazide
9 was favored more than that at the aliphatic azido group,
because the former phosphazide is more stabilized through the
direct resonance with the benzene ring. A similar aromatic
azido selectivity was observed in the Staudinger reduction.10m
Subsequent SPAAC reaction of 10 with cyclooctyne 7 and
removal of Amphos using S8 efficiently afforded aromatic azide
a
b
c
Yields based on 1H NMR analysis. Isolated yield. CH2Cl2 was used
instead of MeOH as a solvent.
11 in a one-pot manner.12 Similarly, the aromatic azido group
of diazide 9 was also protected from the CuAAC reaction with
a terminal alkyne. Thus, phosphazide formation with 4h,
CuAAC reaction with 12, removal of the copper salt by
aqueous ammonia solution, and treatment with S8 afforded
aromatic azide 13 in a high overall yield.12
The preferential phosphazide formation at the aromatic
azido group allowed for facile synthesis of a branched
Table 2. Oxidative Regeneration of Azide 3a from Phosphazides 5
a
entry
PR3
5
oxidant, solvent
yield of 3a (%)
1
2
3
4
5
6
7
Amphos
Amphos
Amphos
Amphos
Amphos
Amphos
P(NMe2)3
5h
5h
5h
5h
5h
5h
5i
NaIO4 (2.0 equiv), THF/H2O
mCPBA (2.0 equiv), CH2Cl2
(PhCO2)2 (2.0 equiv), CH2Cl2
DDQ (2.0 equiv), CH2Cl2/H2O
NBS (2.0 equiv), CH2Cl2
S8 (2.0 equiv), THF
42
10
58
0
90
b
99 (91)
S8 (10 equiv), THF
0
a
b
1
Yields based on H NMR analysis, unless otherwise noted. Isolated yield in parentheses.
C
DOI: 10.1021/acs.orglett.8b01692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
efficiently to afford hexakis(triazole) 16 without formation of
undesired products.
Scheme 1. Aliphatic Azido-selective Click Reactions of
Diazide 9 via Transient Protection of the Aromatic Azido
Group
In summary, we have developed a convenient method to
protect organic azides from click reactions with alkynes by
phosphazide formation. A wide range of azides can be
transiently protected by this method. The phophazides formed
tolerated CuAAC and SPAAC reactions and are easily
converted back to azides, enabling facile modification of
azide compounds by click reactions leaving the azido group
untouched. Further studies on the scope of protectable azides
and application of the method to the preparation of functional
azides are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01692.
Experimental procedures and characterization for new
compounds, including copies of NMR spectra (PDF)
multitriazole oligomer13 via an iterative site-selective CuAAC
reaction using aromatic azide 14 bearing two propargyl groups
(see Scheme 2). Thus, pretreatment of 14 with 4h and
subsequent CuAAC reaction with benzyl azide 3g, followed by
removal of the transient protective group afforded bistriazole
15 with the regenerated azido group in high yield. The second-
generation CuAAC reaction of azide 15 with the same
phosphazide prepared from 14 and 4h also proceeded
Accession Codes
CCDC 1844604 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Scheme 2. Sequential Site-selective CuAAC Reactions via
Transient Protection of Azides
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: s-yoshida.cb@tmd.ac.jp (S. Yoshida).
*E-mail: thosoya.cb@tmd.ac.jp (T. Hosoya).
ORCID
Suguru Yoshida: 0000-0001-5888-9330
Takamitsu Hosoya: 0000-0002-7270-351X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Japan Agency for Medical
Research and Development (AMED) under Grant Nos.
JP18am0101098 (Platform Project for Supporting Drug
Discovery and Life Science Research (BINDS)) and
JP18am0301024 (Basic Science and Platform Technology
Program for Innovative Biological Medicine); the Cooperative
Research Project of the Research Center for Biomedical
Engineering; the Research Program of “Five-Star Alliance” in
“NJRC Mater. & Dev.”; JSPS KAKENHI Grant Nos.
15H03118 and 18H02104 (B; T.H.), 16H01133 and
18H04386 (Middle Molecular Strategy; T.H.), 17H06414
(Organelle Zone; T.H.), 26350971 (C; S.Y.), 18J11113 (JSPS
Research Fellow; T.M.); and the Naito Foundation (S.Y.).
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DOI: 10.1021/acs.orglett.8b01692
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