Aromatic azido-selective reduction via the staudinger reaction using tri-n-butylphosphonium tetrafluoroborate with triethylamine

Article abstract of DOI:10.1246/cl.161159

An efficient method for the reduction of aromatic azides to anilines via the Staudinger reaction using tri-n-butylphosphonium tetrafluoroborate with triethylamine in aqueous tetrahydrofuran solution is reported. The method enables the aromatic azido-selective reduction of 3-azido-5-(azidomethyl)benzene derivatives to efficiently afford anilines bearing an azidomethyl group.

Full text of DOI:10.1246/cl.161159

Advance Publication Cover Page
AromaticAzido-selective Reduction via the Staudinger Reaction
Using Tri-n-butylphosphonium Tetrafluoroborate with Triethylamine
Tomohiro Meguro, Suguru Yoshida,* and Takamitsu Hosoya*
Advance Publication on the web January 24, 2017
doi:10.1246/cl.161159
© 2017 The Chemical Society of Japan
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Publication manuscripts.

Aromatic Azido-selective Reduction via the Staudinger Reaction
Using Tri-n-butylphosphonium Tetrafluoroborate with Triethylamine
Tomohiro Meguro, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: s-yoshida.cb@tmd.ac.jp, thosoya.cb@tmd.ac.jp)
according to a reported method,2a heating under acidic
conditions, afforded 2a, albeit in low yield (Entry 2). Several
other attempts to prepare 2a by the reduction of 1a based on
reported conditions5 were totally unsuccessful (Entries 3–6).
An efficient method for the reduction of aromatic azides
to anilines via the Staudinger reaction using tri-n-
butylphosphonium tetrafluoroborate with triethylamine in
aqueous tetrahydrofuran solution is reported. The method
enables aromatic azido-selective reduction of 3-azido-5-
(azidomethyl)benzene derivatives to efficiently afford anilines
bearing an azidomethyl group.
Table 1. Attempts for selective reduction of diazide 1a.
MeO2C
N3
MeO2C
NH2
Keywords: Azide | Staudinger reaction | Reduction |
Conditions
Aniline
1a
2a
N3
N3
The Staudinger reaction,1 the reaction between organic
azides and trivalent phosphorus compounds, affords
Entry
1
Conditions
Conversion/%a Yield/%a
PPh3 (1.0 equiv)
iminophosphoranes
(aza-ylides),
which
are
useful
100
0
THF/H2O (10:1, v/v), rt, 24 h
PPh3 (1.0 equiv), THF, rt, 2 h;
then 5 M aq. HCl, MeOH, 100 °C, 48 h
BH3·THF (1.0 equiv), THF, rt, 24 h
NaI (50 mol %), BF3·OEt2 (2.0 equiv)
MeCN, rt, 24 h
intermediates for preparing various nitrogen-containing
compounds. In particular, the reaction of azides with
triphenylphosphine in an aqueous solution, which allows for
the subsequent hydrolysis of aza-ylide intermediates, has been
widely used to prepare a variety of amines. However, the
reduction of aromatic azides via the Staudinger reaction using
triphenylphosphine often requires harsh conditions for the
hydrolysis step owing to the high stability of aza-ylides.2
2
3
4
100
26
37
0
19
0
Al(OTf)3 (20 mol %), NaI (3.0 equiv)
MeCN, rt, 24 h
5
6
20
6
0
0
Gd(OTf)3 (20 mol %), NaI (3.0 equiv)
MeCN, rt, 24 h
MeO2C
N
N
N
path a
aYields determined by 1H NMR analysis.
PR3
MeO2C
N
I
N
N
N
N
A
H
N
N
O
NH2
excess
P(CH2CH2CO2H)3
path a
Boc
1a
N
N
N
H
MeO2C
N
N
O
MeOH, rt
PR3
N
N
O
N3
4
Aza-yilide
was not detected.
N
Boc
O
path b
H
N
path b
O
II
O
N
N
N
Boc
PPh3
PR3
PPh3
O
3
MeOH, rt
O
Scheme 1. Possible reactions between diazide 1a and a phosphine.
5
stable in MeOH
B
Ph2P
O
O
In the course of our recent studies on azide chemistry,3
we also faced a problem in achieving the selective reduction
of the aromatic azido group of methyl 3-azido-5-
(azidomethyl)benzoate (1a) via the Staudinger reaction using
Ph Ph
rapid
hydrolysis
R
P
6
NH2
N
O
R
NH2
R
N3
THF, H2O
(9/1)
rt
7
NH2
triphenylphosphine (Scheme 1). We assumed that
a
Figure 1. (A) Staudinger reaction of azide
triphenylphosphine. (B) Reduction of
(diphenylphosphino)benzamide (6).
3
with TCEP or
using o-
nucleophilic attack by the phosphine on the aromatic azido
group of diazide 1a (path a) would be more favored than that
on the aliphatic azido group (path b) because the phosphazide
intermediate I would be more stabilized than II by the direct
resonance between the triazenide and the benzene ring.1b,4 As
we expected, the reaction of 1a with triphenylphosphine in
aqueous tetrahydrofuran (THF) at room temperature
selectively occurred at the aromatic azido group to form the
corresponding aza-ylide. However, desired aniline 2a was not
obtained probably due to the stability of the formed aza-ylide
(Table 1, Entry 1). An attempt to hydrolyze the aza-ylide
azides
As there are a few reports of the successful reduction of
aromatic azides under mild conditions via the Staudinger
reaction,6 we refocused our attention on this approach. For
example, Abe, Ito, and co-workers reported that azide 3 was
efficiently reduced by treatment with an excess of tris(2-
carboxyethyl)phosphine (TCEP),7 which is a frequently used
reductant in biological studies, to afford a rhodamine
derivative
4
exclusively,
while
treatment
with

2
triphenylphosphine provided the robust aza-ylide 5 (Figure
1A).6b The same group also developed a new azide-reducing
reagent, o-(diphenylphosphino)benzamide (6), which was
designed and synthesized to accelerate the hydrolysis of the
aza-ylide 7 through neighboring group participation (Figure
1B).6e In these reports, however, limited reduction of aromatic
azides was demonstrated and selectivity between aromatic and
aliphatic azides was not examined. In particular, the reactivity
of aromatic azides with a wide range of organophosphorus
compounds and subsequent hydrolysis of resulting aza-ylides
have not been studied systematically. To establish a practical
method for aromatic azido-selective reduction of diazides like
1a, preferably using a commercially available reagent that is
easy to handle, we herein revisited the Staudinger reaction of
aromatic azides.
whereas
the
hydrolysis
was
sluggish
when
tricyclohexylphosphine or tri-t-butylphosphine were used
(Entries 7 and 8).8 Furthermore, the reduction of azide 8a to
aniline 9a was also promoted efficiently using air-stable tri-n-
butylphosphonium tetrafluoroborate or TCEP·HCl in
combination with triethylamine, which was added to
regenerate the salt-free phosphine in situ (Entries 9 and 10).
Considering the availability of the reagent and ease of
handling, we used tri-n-butylphosphonium tetrafluoroborate
as the phosphine source in further studies.
Table 2. Screen of organophosphorus compounds for reduction of azide
8a.
PR3
N3 (1.2 equiv)
NH2
We initially monitored the reaction between 4-
(ethoxycarbonyl)phenyl azide (8a) and triphenylphosphine in
THF-d8 and D2O (10/1, v/v) at room temperature by H NMR
(Figure 2). Azide 8a was completely consumed within 1 h and
formation of aza-ylide 10 was observed. Even after 24 h, only
a trace amount of aniline 9a was formed, indicating the high
stability of aza-ylide 10 in the aqueous solution.
THF, H2O
(10/1)
rt, 12 h
EtO2C
EtO2C
8a
9a
1
Entry
PR3
PPh3
Conversion/%a Yield/%b
1
2
100
100
0
0
quant.
0
P(2-furyl)3
P(C6F5)3
P(NMe2)3
P(OMe)3
P(n-Bu)3
P(c-Hex)3
P(t-Bu)3
3
4
100
100
100
100
100
100
100
0c
5
0d
PPh3
(1.3 equiv)
N3
NH2
N
PPh3
+
6
quant.
26e
0c
THF-d8, D2O
(10/1)
rt
EtO2C
EtO2C
EtO2C
7
9a
10
8a
8
f
C-1: 8a
9
P(n-Bu)3·HBF4, NEt3
P(CH2CH2COOH)3·HCl, NEt3
94
f
10
quant.
aConversion of 8a determined by 1H NMR analysis. bYields of 9a
determined by 1H NMR analysis. cPhosphazide was obtained. dA
mixture of aza-ylide and phosphonamide (48:52) was obtained.
eAza-ylide was obtained. f1.2 equiv. of NEt3 was added.
C-2: 8a + PPh3 (1 h)
C-3: 8a + PPh3 (24 h)
C-4: 9a
The
conditions
using
tri-n-butylphosphonium
tetrafluoroborate with triethylamine (Table 2, Entry 9) were
applicable to the reduction of various aromatic azides (Figure
3). A variety of substrates, bearing electron-deficient or
electron-rich groups such as halogeno, nitro, ethoxycarbonyl,
or methoxy groups at either the ortho-, meta-, or para-
positions, were reduced to afford the corresponding anilines
9b–g in high yields. Even the reduction of 2,6-
diisopropylphenyl azide (8h), which has bulky substituents at
both ortho-positions, proceeded smoothly to afford the
desired product 9h efficiently. Unexpectedly, treatment of
Figure 2. Monitoring the reaction between azide 8a and
triphenylphosphine in THF-d8 and D2O (10/1, v/v) at room temperature
by 1H NMR.
To achieve efficient transformation of aromatic azides
into anilines under mild conditions, we screened for an
organophosphorus compound that afforded aniline 9a from
azide 8a in aqueous THF at room temperature (Table 2).
Similar to the result described above, the desired aniline 9a
was not obtained by using triphenylphosphine, although azide
8a was completely consumed (Entry 1). Successful
transformation of azide 8a into aniline 9a took place using
tri(2-furyl)phosphine, which is a more electron-deficient
phosphine than triphenylphosphine (Entry 2). However,
highly electron-deficient tris(pentafluorophenyl)phosphine did
not react with azide 8a (Entry 3). Smooth consumption of
azide 8a was observed when tris(dimethylamino)phosphine or
trimethyl phosphite was used, but aniline 9a was not obtained
(Entries 4 and 5).8 Various trialkylphosphines reacted with
azide 8a efficiently, while the reaction rate of the hydrolysis
step varied depending on the bulkiness of the phosphines
(Entries 6–8). In particular, tri-n-butylphosphine smoothly
reduced azide 8a to quantitatively afford aniline 9a (Entry 6),
benzyl
azide
(8i)
with
tri-n-butylphosphonium
tetrafluoroborate and triethylamine resulted in a complex
mixture,9 while treatment with triphenylphosphine afforded
benzylamine (9i) in 98% yield.10

3
P(n-Bu)3·HBF4
(1.2 equiv)
NEt3 (1.2 equiv)
P(n-Bu)3·HBF4
(1.0 equiv)
NEt3
NH2
N3
R
N3
R
NH2
(1.2 equiv)
THF, H2O
(10/1)
rt, 15 h
R
R
THF, H2O
(10/1)
rt, 24 h
9
8
N3
N3
2
1
NH2
NH2
NH2
NH2
MeO2C
NH2
I
NH2
NC
NH2
I
Cl
O2N
MeO
9e
quant.
9b
97%
9c
77%
9d
90%
N3
N3
N3
MeO
NH2
NH2
CO2Et
NH2
NH2
2a
98%
2b
89%
2c
99%
N3
OH
OMe
NH2
NH2
9i
not detected
9f
96%
9g
94%
9h
89%
Figure 3. Reduction of various azides 8.
N3
2e
89%
N3
2d
90%
A competition experiment clearly showed that the
reaction conditions allowed for the selective reduction of
phenyl azide (8j) in the presence of benzyl azide (8i);
treatment of a mixture of 8j (1.2 equiv) and 8i (1.2 equiv)
with tri-n-butylphosphonium tetrafluoroborate (1.0 equiv) in
the presence of triethylamine (1.2 equiv) afforded aniline (9j)
exclusively (eq 1).8,11 When an equimolar mixture of 8j and
2,6-diisopropylphenyl azide (8h) was treated with the
reagents in a similar manner, preferential reduction of
sterically unhindered 8j was observed (eq 2).8 This selectivity
was opposite to that which we previously observed in the
concerted click reaction with a cyclooctyne derivative, in
which the clickability of doubly sterically-hindered phenyl
azide 8h was significantly enhanced by the steric inhibition of
resonance.3h These results demonstrating the reaction-
dependent selective reactivity of different types of azides such
as 8h–8j would be useful information to achieve sequential
molecular conjugations based on orthogonal click chemistry.
Figure 4. Aromatic azido-selective reduction of di- and triazides 1.
In summary, we have revisited the Staudinger reaction of
aromatic azides and found that the use of commercially
available
and
air-stable
tri-n-butylphosphonium
tetrafluoroborate with triethylamine in aqueous THF solution
efficiently promoted their transformation into anilines. The
method was applicable to the reduction of a wide range of
aromatic azides, including those substituted with an
azidomethyl group, in which the aromatic azido-selective
reduction proceeded efficiently.
This work was supported by Platform for Drug
Discovery, Informatics, and Structural Life Science from
MEXT and AMED, Japan; JSPS KAKENHI grant numbers
15H03118 (B; T.H.), 16H01133 (Middle Molecular Strategy;
T.H.), and 26350971 (C; S.Y.); Suntory Foundation for Life
Sciences (S.Y.); and Naito Foundation (S.Y.).
P(n-Bu)3·HBF4
(1.0 equiv)
NEt3
Supporting Information for characterization of new
compounds is available electronically on J-STAGE.
N3
NH2
(1.2 equiv)
N3
NH2
+
(1)
+
THF, H2O
(10/1)
rt, 15 h
8j
(1.2 equiv)
9i
9j
90%
8i
(1.2 equiv)
0%
References and Notes
P(n-Bu)3·HBF4
(1.0 equiv)
NEt3
1
a) March’s Advanced Organic Chemistry, Reactions, Mechanisms,
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Tetrahedron 2007, 63, 523.
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N3
N3
NH2
NH2
(1.2 equiv)
+
(2)
+
THF, H2O
(10/1)
rt, 15 h
8j
(1.2 equiv)
9h
9j
58%
8h
(1.2 equiv)
24%
Based on the optimized conditions, the aromatic azido-
selective Staudinger reactions of 3-azido-5-
(azidomethyl)benzene derivatives 1a–1d,3i bearing an
methoxycarbonyl, iodo, cyano group, or hydroxy group
respectively, were successfully achieved to afford 3-
(azidomethyl)anilines 2a–2d in excellent yields (Figure 4).
Furthermore, aromatic azido-selective reduction of triazide
1e3a also took place uneventfully to afford aniline 2e leaving
two aliphatic azido groups untouched.
2
3

4
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5
7
8
9
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See Supporting Information for details.
Treatment of phenethyl azide with P(n-Bu)3·HBF4 and
triethylamine also afforded a complex mixture. Currently, the
reason why the reduction of alkyl azides failed is unclear.
Treatment of benzyl azide (8i) with triphenylphosphine in THF-d8
and D2O (10/1, v/v) for 15 h afforded benzylamine (9i) in 98%
10
11
1
yield, which was determined based on H NMR analysis by using
1,1,2,2-tetrachloroethane as an internal standard.
Benzyl azide (8i) was recovered quantitatively.