Sustainable organophosphorus-catalysed Staudinger reduction

Article abstract of DOI:10.1039/c8gc02136h

A highly efficient and sustainable catalytic Staudinger reduction for the conversion of organic azides to amines in excellent yields has been developed. The reaction displays excellent functional group tolerance to functionalities that are otherwise prone to reduction, such as sulfones, esters, amides, ketones, nitriles, alkenes, and benzyl ethers. The green nature of the reaction is exemplified by the use of PMHS, CPME, and a lack of column chromatography.

Full text of DOI:10.1039/c8gc02136h

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Sustainable organophosphorus-catalysed Staudinger reduction
Danny C. Lenstra, Peter Lenting and Jasmin Mecinović*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient and sustainable catalytic Staudinger reduction
for the conversion of organic azides to amines in excellent yields
has been developed. The reaction displays excellent functional
group tolerance to functionalities that are otherwise prone to
reduction, such as sulfones, esters, amides, ketones, nitriles,
alkenes, and benzyl ethers. The green nature of the reaction is
exemplified by the use of PMHS, CPME, and a lack of column
chromatography.
Organic azides are important intermediates in the synthesis of
various classes of nitrogen containing molecules. For instance,
azides are used in the azide-alkyne Huisgen cycloaddition,
various related strain promoted click reactions, Aza-Wittig
reaction, Staudinger ligation, and Staudinger reduction.1 The
transformation of organic azides to amines can be achieved by
means of catalytic hydrogenation in the presence of H2 and
transition metal catalyst, such as Pd.2 Also, strong reducing
agents, such as lithium aluminium hydride (LiAlH4), efficiently
reduce azides to amines.3 Under these conditions, however,
functional group tolerance is severely hampered; catalytic
hydrogenation typically results in reduction of the nitro group,
and alkene and alkyne functionalities, whereas with LiAlH4
carboxylic acids and esters are reduced. Another commonly
used approach in converting azides to amines is the Staudinger
reduction (also known as Staudinger reaction) (Scheme 1a). In
the classic Staudinger reaction, stoichiometric amounts of
triphenylphosphine react with the azide to form a phosphazide
intermediate, which subsequently loses N2 to form an aza-
ylide; in the presence of water, this aza-ylide forms the desired
amine and triphenylphosphine oxide by-product.4
a
Scheme 1 Classic Staudinger reduction in the presence of stoichiometric amounts of
b
triphenylphoshphine. Catalytic Staudinger reduction in the presence of 5 mol% 1-
c
phenyl-dibenzophosphole
1
with phenylsilane as
a
reducing agent. This work:
Catalytic Staudinger reduction in the presence of 3 mol% triphenylphosphine and
poly(methylhydrosiloxane) (PMHS) as a green reducing agent in cyclopentylmethyl
d
ether (CPME) as a green solvent. Phosphine oxides 2–4 that are commonly used in
organophosphorus catalysis.
the desired products can be troublesome.5 To circumvent the
formation of significant amounts of phosphine oxide waste, a
catalytic Staudinger reduction was reported by van Kalkeren et
al. in 2012.6 In situ reduction of the formed aza-ylide
intermediate by phenylsilane, followed by an aqueous work-up
afforded the desired amine product and reformation of
The formation of large amounts of phosphine oxide by-
product under stoichiometric conditions is highly undesirable,
as it results in poor overall atom economy and separation from
dibenzophosphole 1 (Scheme 1b).
Besides the Staudinger reduction, various other phosphine-
catalysed transformations, including the Appel, Mitsunobu,
Wittig, Staudinger ligation and amide-bond formation
reactions have been developed recently.7 In contrast to the
catalytic Staudinger reduction, most of these reactions appear
to rely on in situ reduction of phosphine oxides, which are
formed during the reaction, to phosphines. Because the
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Table 1 Optimisation of the catalytic Staudinger reductiona
reduction of triphenylphosphine oxide is difficult and often
requires harsh conditions (i.e. elevated temperature, reactive
silane as reducing agent),8 triphenylphosphine has typically
been replaced by other phosphines (or phosphine oxide pre-
catalysts), which are more prone to reduction. For instance, 3-
Entry
Phosphine
(equiv.)
Solvent
Yield (%)b
methyl-1-phenyl-2-phospholene 1-oxide 2 was used in the
catalytic aza-Wittig reaction9 and very recently by our group in
the catalytic amidation between carboxylic acids and amines
1
2
3
1
2
3
4
(0.03)
(0.03)
(0.03)
(0.03)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
n-Heptane
2-MeTHF
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
79
82
70
72
94
29
11
24
0
97
91
58
69
94
54
28
<1
<1
0
(Scheme 1d).7f In addition, phosphine oxides
3 and 4, were
used as catalysts in the catalytic Wittig and Mitsunobu
reactions, respectively.7b, 7d
4
5
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.03)
Ph3P (0.02)
Ph3P (0.01)
Ph3P (0.03)
Ph3PO (0.03)
Ph3PO (0.10)
-
6c
To date, most, if not all, reported catalytic
organophosporus reactions are lacking sufficiently green
characteristics, mainly due to uses of environmentally
problematic solvents and reducing agents. Here we report the
7
8
9
10
11d
12e
13f
14
15
16c
17
18
19
20g
development of
a
sustainable and highly efficient
organophosphorus-catalysed Staudinger reduction using
poly(methylhydrosiloxane) (PMHS) as a green reducing agent
and cyclopentylmethyl ether (CPME) as a renewable solvent
(Scheme 1c).10
We started our investigations by testing whether the
previously reported dibenzophosphole
1 was compatible with
poly(methylhydrosiloxane) as a reducing agent in the catalytic
Staudinger reduction in toluene. We were pleased to find that
79% of 4-nitrophenethylamine was obtained from 4-
CPME
CPME
Ph3P (0.03)
2
a
4-nitrophenethyl azide (0.5 mmol), PMHS (Mw 2450 Da, 0.08 mmol, 6 Si-H
equiv.), phosphine (oxide), solvent (2.5 mL, 0.2 M), for 20 hours at reflux;
nitrophenethyl azide in the presence of 3 mol% of
equivalents of PMHS (Mw 2450 Da) (Table 1, entry 1). When
phosphine oxide was used, 82% of amine was obtained
under the same conditions (Table 1, entry 2). Cyclic phosphine
oxide pre-catalysts and were also evaluated; similar NMR
1 and 6 Si-H
b
c
NMR yield using 1,3,5-trimethoxybenzene as an internal standard; reaction
d
e
at T = 80 °C; 9 Si-H equiv. PMHS (0.12 mmol); 3 Si-H equiv. PMHS (0.04
mmol); f 8 hours reaction time; g no PMHS added.
2
3
4
to 3 Si-H equivalents resulted in a lower production (58%) of
amine (Table 1, entry 12). Thus we decided to use 6 Si-H
equivalents of PMHS in all subsequent experiments (0.08
mmol of total PMHS). Shortening the reaction time to 8 hours
led to the formation of 69% of amine, indicating that the
reaction is relatively fast in the first few hours (Table 1, entry
yields of 70 and 72% of amine were obtained (Table 1, entries
3-4). We were particularly pleased to find that use of cheap
and commercially available triphenylphosphine resulted in the
formation of 94% 4-nitrophenethylamine (Table 1, entry 5).
Triphenylphosphine appears to be a comparatively better
catalyst than 2-4, likely because these are actually precatalysts
13). A more detailed time course of the reaction was also
that exist in the forms of phosphine oxides, thus requiring
another catalytic cycle in the presence of PMHS. Decreasing
the reaction temperature to 80 °C in toluene drastically
decreased the yield, as only 29% of amine was formed (Table
1, entry 6). Thus, we tested various solvents with high boiling
points, and found that the reaction proceeded very poorly in
both 1,4-dioxane (11%) and n-heptane (24%) (Table 1, entries
7-8).
investigated (Figure S1). Interestingly, even in the presence of
2 mol% of Ph3P, 94% of amine was obtained, whereas
decreasing the catalyst loading to 1 mol% produced the amine
in a somewhat lower, but still comparatively good 54% yield
under standard conditions (Table 1, entries 14-15). Lowering
the reaction temperature resulted in a significantly lower yield;
i.e. at 80 °C only 28% of amine was formed (Table 1, entry 16).
Notably, when triphenylphosphine was replaced by
triphenylphosphine oxide, hardly any amine was formed at 3
mol% and 10 mol% loadings (<1%, Table 1, entries 17-18). This
observation suggests that PMHS does not possess the ability to
reduce Ph3PO to Ph3P, and as a result, yields no amine
product; this result is in agreement with Beller’s work.8b To
confirm this observation, we performed a control experiment
in which we attempted to reduce triphenylphosphine oxide
(0.1 mmol) by PMHS (0.16 mmol) under our reaction
conditions. In line with our expectations, no reduction of
phosphine oxide was observed by 31P NMR (Figure S2). With
the aim of providing better insight into the molecular
requirements for the catalytic reaction, we also carried out
two important control experiments. No amine product was
We were particularly curious to explore whether the model
catalytic reaction works well in 2-methyltetrahydrofuran (2-
MeTHF) and cyclopentylmethyl ether (CPME), both being
green and sustainable solvents produced from biomass.10b, 11
No amine product was observed when the reaction was
carried out in 2-MeTHF, likely due to lower reaction
temperature (Table 1, entry 9). However, we were indeed very
pleased to find that the catalytic Staudinger reduction
proceeds very well in CPME; nearly quantitative NMR yield
(97%) of amine was achieved under standard conditions (i.e. 3
mol% Ph3P, 6 Si-H equiv. PMHS, 106 °C, 20 h) (Table 1, entry
10). Increasing the amount of PMHS did not improve the yield
of the reaction (Table 1, entry 11), whereas decreasing PMHS
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formed when the reaction was carried out in the presence of
PMHS, but in the absence of triphenylphosphine (Table 1,
entry 19). Similarly, we only observed traces (2%) of
conversion of azide to amine in the presence of 3 mol% of Ph3P
and in the absence of PMHS (Table 1, entry 20).
1) Ph3P (3 mol%), PMHS (6 Si-H equiv.),
CPME, 106 °C, 20 h
R
N3
R NH2
2) H2O (10 equiv.)
NH2
NH2
NH2
Having identified the optimal reaction conditions for the
Ph3P-catalysed Staudinger reduction, we set out to explore the
scope of the reduction on various organic azides. In addition to
carrying out the reactions under green conditions, as
exemplified by the use of reducing agent PMHS and solvent
CPME, we also successfully attempted to produce amine
products directly from precipitation as hydrochloride salts,
thus eliminating a purification step (e.g. extraction and/or
column chromatography) that typically requires large amounts
O2N
NO2
a
1
2
3
91%
97%
95%
88%
NH2
NH2
NH2
Cl
OMe
4
5
6
9
99%
78%
94%
of
environmentally
problematic
solvents.
4-
O
O
NH2
NH2
NH2
Nitrophenethylamine and phenethylamine were obtained in
excellent 91% and near quantitative 97% isolated yields,
Br
F
respectively (Scheme 2, compounds
2-nitrophenethyl azide produced 2-nitrophenethylamine with
an 88% isolated yield (Scheme 2, compound ). It is
noteworthy that no reduction of the nitro group was observed
for compounds and under these conditions, demonstrating
1 and 2). The reduction of
7
8
96%
85%
NH2
3
S
NH2
NH2
BnO
CN
12
1
3
that our catalytic reaction has good chemoselectivity and
presents an advantage compared to the H2-mediated
conversion of azides to amines, a method that also reduces the
nitro group to an amino group.12 3-Chlorophenethyl azide and
4-methoxyphenethyl azide underwent virtually quantitative
(99% and 95%) conversions to corresponding amines (Scheme
10
13
11
88%
89%
66%
81%
85%
NH2
NH2
NH2
O
O
S
O
Me
OMe
14
15
18
93%
96%
98%
2, compounds
Benzyl azide underwent excellent conversion (94%) to
benzylamine (Scheme 2, compound ). The reaction also
proceeded well with 1-naphthylmethyl azide, which was
successfully reduced and produced 78% 1-
naphthylmethylamine (Scheme 2, compound ). The
4 and 5).
N
NH2
NH2
O
NH2
Ph
O
6
N
H
O
OMe
16
17
94%
7
NH2
organophosphorus-catalysed Staudinger reduction under
green conditions also works well for disubstituted benzyl
azides; 2-fluoro-4-bromobenzylamine and piperonylamine
were obtained with 96% and 85% yields, respectively (Scheme
S
NH2
NH2
HO
N
N
F
19
22
20
23
21
24
89%
84%
93%
2, compounds
8 and 9). A thioether containing azide was
H
N
efficiently reduced to produce 88% of the corresponding
amine (Scheme 2, compound 10).
F
NH2
NH2
7
NH2
Having shown that the nitro group remains unaffected by
our organocatalytic reaction conditions (vide supra), we
further explored the chemoselective nature of the reaction.
The reduction of benzyloxy-substituted benzyl azide only took
place on the azide site (89% yield), whereas the benzyloxy
protecting group was not removed under our conditions;
again, this result highlights the advantage of our developed
method over the alternative hydrogenation method (Scheme
2, compound 11). 3-Cyanobenzyl azide was efficiently reduced
to 3-cyanobenzylamine (66% yield), while the reduction-prone
cyano group remained intact (Scheme 2, compound 12). The
chemoselective nature of our method reported here was
furthermore demonstrated by a highly selective reduction of
the azide functional group in the presence of alkene
functionality (93% yield, Scheme 2, compound 13), and a
complete inability of reduction of the sulfone moiety in 4-
61%
43%
NH2
75%
NH2
NH2
O
O
b
b
b
25
26
27
14% (68% )
10% (79% )
2% (25% )
H2N
NH2
NH2
MeO
b
28
29
0%
18%
30
34% (76% )
Scheme 2 Substrate scope for the organophosphorus-catalysed Staudinger reduction.
Amines obtained as hydrochloride salts upon precipitation with 4.0 M HCl in dioxane;
a isolated yield; b isolated yield in the presence of 10 mol% triphenylphosphine.
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methylsulfone-substituted benzyl azide (Scheme 2, compound
14, 96% yield). No reduction of the carboxylic ester, ketone
and amide functional groups was observed: esters 15 and 16
were obtained with excellent yields of 81% and 94%
respectively, ketone 17 with 98%, and amide 18 with 85%
isolated yield. These results are important because they show
that the ester, ketone, and amide functionality remains intact
under our conditions; in contrast, a common reducing agent
LiAlH4 reduces both the azide and these functional groups.13
Reduction of an azide that contains a free alcohol, (4-
hydroxymethyl)benzyl azide, also proceeded very well; (4-
hydroxymethyl)benzylamine 19 was obtained with 89%
isolated yield. This observation could shorten synthetic
pathways as no alcohol protecting group manipulations need
to be performed. Heterocycle-containing azides were tolerated
well in the catalytic Staudinger reaction; the reduction of 5-
(azidomethyl)thiazole produced 84% of amine 20. Moreover,
pyridine- and indole-derived amines 21 and 22 were obtained
with 93% and 61% isolated yields. We also examined two
entirely aliphatic azides, 1-octylazide and 2-fluoroethyl azide,
which were reduced to give 43% and 75% of corresponding
amines in the form of hydrochloride salt, respectively (Scheme
2, compounds 23 and 24). Sterically hindered secondary azides
reacted poorly; at 3 mol% triphenylphosphine only 10% of 1-
phenyl-2-aminopropane 25 and 2% of 1-phenyl-1-
aminopropane 26 were obtained. The reduction of ethyl (S)-2-
azido-4-phenylbutanoate proceeded slightly better to afford
25% of amine 27, whereas only 18% of 1-aminoindane 28 was
isolated in the presence of 3 mol% triphenylphosphine. To
investigate whether the yield for secondary amines could be
improved, we performed the catalytic reduction of several
secondary azides in the presence of 10 mol%
triphenylphosphine and obtained significantly better yields of
79% (amine 25), 25% (amine 26), and 68% (amine 27). For
tertiary 1-azidoadamantane, the reaction did not yield any
amine product 29, possibly due to an increased sterics effect.
The catalytic reduction of 4-azidoanisole, an example of
aromatic amine, in the presence of 3 mol% yielded 34% of 4-
anisidine 30. Increasing the amount of triphenylphosphine to
10 mol%, however, significanly improved the yield of 30 to
76%.
Ph3P
R
HN Me
H2O
Si
R-NH2
O
N3-R
N2
n
n
H Me
Si
O
Ph3P
N
R
Scheme 3 Proposed mechanism for the PMHS-mediated organophosphorus-catalysed
Staudinger reduction.
reduction is proposed in Scheme 3. First, triphenylphosphine
reacts with the azide to form an aza-ylide intermediate and
nitrogen gas is released from the reaction mixture. The aza-
ylide is then reduced by PMHS to form a silylamine species and
triphenylphosphine, which can re-enter the catalytic cycle.
Upon the addition of water, the silylamine is hydrolysed and
the desired amine product is obtained.
In summary, we have developed a highly efficient and
sustainable
organophosphorus-catalysed
Staudinger
reduction, which has several advantages over the existing
method.6 It uses i) cheap and commercially available
triphenylphosphine in very small amounts (3 mol%); ii)
poly(methylhydrosiloxane), as a green reducing agent; iii)
cyclopentylmethyl ether, a sustainable solvent produced from
renewable sources; and iv) no column purification is required
to obtain pure products, as amines are produced as
hydrochloride salts upon precipitation. Our newly developed
green and catalytic Staudinger reduction enables the
preparation of a wide range of amines in excellent isolated
yields (up to 99%). Notably, we demonstrate the
chemoselective nature of the reaction, by showing an
excellent functional group tolerance; i.e. nitro-, cyano-, alkene,
ester, amide, ketone, benzyl ether, and sulfonyl groups were
not reduced by PMHS. Furthermore, the reaction is amenable
to multi-gram scale. We hope that this work will inspire the
development of other important organophosphorus-catalysed
reactions under green conditions.
Conflicts of interest
To show the applicability of our newly developed
methodology, we carried out organophosphorus-catalysed
Staudinger reduction of two representative azides on a
multigram scale. 4-Nitrophenethyl azide (25 mmol, 4.8 gram)
and phenethyl azide (25 mmol, 3.7 gram) were successfully
reduced under standard reaction conditions. From these
reactions, 4.9 grams (97% isolated yield) of 4-
There are no conflicts to declare.
Notes and references
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phenethylamine 2 were obtained as hydrochloride salts. Again,
no work-up and column chromatography were required, and
the products were obtained in excellent (>98%) purity as
assessed by analytical HPLC (Figure S3 and S4).
Based on the previous report6 and the observation that
PMHS is unable to reduce triphenylphosphine oxide to
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4 | J. Name., 2012, 00, 1-3
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Table of Contents
A highly efficient and sustainable organophosphorus-catalysed Staudinger reduction for the
conversion of azides to amines in excellent yields is reported.