Ruthenium(iv) porphyrin catalyzed phosphoramidation of aldehydes with phosphoryl azides as a nitrene source

Article abstract of DOI:10.1039/c2cc31686b

[Ru^IV(por)Cl₂] (por = porphyrin dianion) can efficiently catalyze nitrene insertion into aldehyde C-H bonds with phosphoryl azides as a nitrene source to give N-acylphosphoramidates in good to high yields.

Full text of DOI:10.1039/c2cc31686b

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COMMUNICATION
Ruthenium(IV) porphyrin catalyzed phosphoramidation of aldehydes with
phosphoryl azides as a nitrene sourcewz
Wenbo Xiao, Cong-Ying Zhou and Chi-Ming Che*
Received 7th March 2012, Accepted 20th April 2012
DOI: 10.1039/c2cc31686b
[RuIV(por)Cl2] (por = porphyrin dianion) can efficiently catalyze
nitrene insertion into aldehyde C–H bonds with phosphoryl azides
as a nitrene source to give N-acylphosphoramidates in good to
high yields.
have been proven to be effective catalysts for this transforma-
tion with PhIQNTs or TsNH2/PhI(OC(O)tBu)2 as a nitrene
source. Organic azides as an alternative nitrene source have
attracted considerable interest due to their versatility, easy
accessibility and the formation of environmentally benign
nitrogen gas as the only by-product in the catalysis. We and
other groups have demonstrated that the porphyrin complexes
of ruthenium(II),12 iron(III)13 and cobalt(II),14 dirhodium(II)
carboxylates,15 and ruthenium(II) Schiff base complexes16
can efficiently mediate nitrene insertion into sp3 and sp2
C–H bonds with organic azides. In previous work, we found
that dichlororuthenium(IV) porphyrin [RuIV(por)Cl2] displays
substantially higher catalytic activity than its carbonyl analogue
[RuII(por)(CO)] towards C–H bond oxidation, epoxidation of
alkenes and E–I reaction of alkenes.17 This result prompted us
to examine the activity of [RuIV(por)Cl2] towards nitrene
transfer and insertion reactions with organic azides as a nitrene
source, which is unprecedented in the literature. Herein, we
describe a highly efficient Ru(IV) porphyrin-catalyzed phos-
phoramidation of aldehydes with phosphoryl azides to form
N-acylphosphoramidates in good to high yields.
N-acylphosphoramidate is present in a number of bioactive
natural and unnatural compounds such as Agrocin 84,1
Microcin C72 and Phosmidosine3 (Fig. 1) known to exhibit
antifungal and antitumor activities. The synthetic procedures of
phosphoramidate compounds mainly rely on phosphorylation of
amides with chlorophosphonate,4 acylation of phosphoramides
with acyl chloride or mixed anhydrides,5 and coupling of phos-
phoramidites with amides followed by oxidation.6 However, the
need to use a strong base such as butyllithium, limited substrate
scope, and the requirement of multiple-step manipulation are the
limitations of these literature methods. Therefore, it is desirable
to develop a simple and efficient means for the construction of
N-acylphosphoramidate.
A straightforward route to N-acylsulfonamides via transition
metal-catalyzed nitrene insertion into aldehyde C–H bonds has
recently been reported. Dirhodium(II) carboxylates,7 ruthenium(II)
porphyrins,8 CuI/pyridine9 and FeCl2/pyridine10 or terpyridine11
In our preliminary study, we examined the phosphoramidation
of p-tolualdehyde by using diphenylphosphoryl azide (DPPA) as
a nitrene source and [RuII(TTP)(CO)] [TTP = meso-tetrakis-
(4-tolyl)porphyrin] as catalyst. Treatment of p-tolualdehyde with
DPPA (1.5 equiv.) in the presence of catalytic amount of
[RuII(TTP)CO] (5 mol%) in 1,2-dichloroethane under reflux
for 12 h afforded N-acylphosphoramidate 2a in 78% yield with
100% substrate conversion (Table 1, entry 1). In contrast,
[RuII(F20-TPP)(CO)], [RuII(p-cymene)Cl2]2, [CpRuII(COD)Cl],
[RuIIICl3ꢀ3H2O],
[CoII(F20-TPP)],
[FeIII(F20-TPP)Cl],
[RhII2(O2CCF3)4], and [CuII(OTf)2] all failed to catalyse/
mediate the phosphoramidation (entries 2–9) under similar
reaction conditions. We then examined the phosphoramidation
with [RuIV(TTP)Cl2] as catalyst. Under similar reaction
conditions, [RuIV(TTP)Cl2] catalyzed the amidation to give
2a in 92% yield and with 100% substrate conversion. With
[RuIV(TDCPP)Cl2] bearing a more bulky porphyrin ligand, a
lower product yield was obtained (70%). The effects of
temperature and solvent were examined. The reaction in
dichloromethane at 40 1C gave the best result (entry 13,
99% yield and 100% substrate conversion). No reaction was
observed in the absence of the ruthenium catalyst and with
[RuII(TTP)(CO)] as catalyst at 40 1C.
Fig. 1 Phosmidosine and dichlororuthenium(IV) porphyrins.
Department of Chemistry, State Key Laboratory of Synthetic
Chemistry, and Open Laboratory of Chemical Biology of the Institute
of Molecular Technology for Drug Discovery and Synthesis,
The University of Hong Kong, Pokfulam Road, Hong Kong, China.
E-mail: cmche@hku.hk; Fax: +852 2857-1586;
Tel: +852 2859-2154
w This article is part of the ChemComm ‘Porphyrins and phthalocyanines’
web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization. See DOI: 10.1039/c2cc31686b
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5871–5873 5871

Table 1 Screening catalysts and conditions for phosphoramidation
of aldehydes with phosphoryl azidesa
Table 2 [RuIV(TTP)Cl2]-catalyzed phosphoramidation of aldehydes
with DPPAa
Entry Aldehyde
Product
Conv.b (%) Yieldc (%)
Temp./ Conv.b
Yieldc
(%)
Entry Catalyst
Solvent 1C
(%)
1
2
3
4
5
6
7
8
[RuII(TTP)(CO)]
DCE
[RuII(F20-TPP)(CO)] DCE
[RuII(p-cymene)Cl2]2 DCE
84
84
84
84
84
84
84
84
84
84
84
40
40
100
NRe
NR
NR
NR
NR
NR
NR
NR
100
100
100
100
90
78
1
100
100
100
85
95
98
[CpRuII(COD)Cl]
[RuIIICl3ꢀ3H2O]
[CoII(F20-TPP)]
[FeIII(F20-TPP)Cl]
[Rh2II(O2CCF3)4]
[CuII(OTf)2]
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
2
3
9
10f
11f
12
13
14
15d
16
[RuIV(TTP)Cl2]
[RuIV(TDCPP)Cl2]
[RuIV(TTP)Cl2]
[RuIV(TTP)Cl2]
[RuIV(TTP)Cl2]
[RuIV(TTP)Cl2]
No catalyst
92
70
85
99
90
99
Toluene 40
DCM
DCE
40
84
100
NR
4
95
99
a
p-Tolualdehyde (0.2 mmol), DPPA (0.3 mmol), 3 A MS (25 mg),
b
catalyst (5 mol%), solvent (1 mL), 12 h. Conversion was determined
based on aldehyde by using 1H NMR. Based on conversion. DPPA
e
(0.24 mmol, 1.2 equiv.). NR = no reaction. Reaction time = 3 h.
c
d
5
6
100
70
74
96
f
With the optimized conditions, we examined the substrate scope
of [RuIV(TTP)Cl2]-catalyzed amidation of aldehydes with DPPA.
As depicted in Table 2, a variety of aryl and aliphatic aldehydes
reacted with DPPA in the presence of [RuIV(TTP)Cl2] to give
corresponding N-acylphosphoramidates in good to excellent
yields (56–99%) with high substrate conversions (78–100%). This
reaction shows excellent functional group tolerability as various
functionalities including hydroxyl, nitro, halide, CQC groups and
heterocycles are compatible with the protocol (entries 1–14). In
line with the amidation of aldehydes with PhIQNTs catalyzed
by CuI/pyridine9 and FeCl2/terpyridine,10 electron-rich aryl
aldehydes were more reactive than the electron-deficient ones using
the ‘‘[RuIV(TTP)Cl2] + DPPA’’ protocol giving higher product
yields and substrate conversions (entries 1–6). The electron-
deficient 4-nitrobenzaldehyde, which was reported to be unreactive
in the Cu(I) and Fe(II)-catalyzed amidation with PhIQNTs, could
undergo aldehydic C–H bond insertion with DPPA to afford the
corresponding product in 96% yield based on 70% substrate
conversion (entry 6). When compared with aryl aldehydes,
aliphatic aldehydes gave lower product yields of 60–62%
(entries 12–13). In the case of amidation of 3-phenylpropanal
where benzylic C–H bond amination is a potential competitive
reaction, only the aldehyde phosphoramidation product was
obtained in 62% yield (entry 13). Antipyrine is analgesic and
antipyretic and is often used in testing the effects of other
drugs or diseases of drug-metabolizing enzymes in the liver.
When 4-antipyrine carboxaldehyde 1o was used as a substrate,
the phosphoramidation product was obtained in 56% yield
and with 86% substrate conversion, the antipyrine moiety
remained intact (entry 14).
7
8
100
78
85
78
9
100
100
100
100
79
71
89
62
10
11
12
13
100
86
60
56
14
a
Aldehyde (0.2 mmol), DPPA (0.24 mmol), 3 A MS (25 mg),
b
[RuIV(TTP)Cl2] (5 mol%), CH2Cl2 (1 mL), 12 h. Conversion was
determined based on aldehyde by using 1H NMR. Based on
conversion.
c
We next investigated the scope of phosphoryl azides for the
[RuIV(TTP)Cl2]-catalyzed p-tolualdehyde amidation. As depicted
c
5872 Chem. Commun., 2012, 48, 5871–5873
This journal is The Royal Society of Chemistry 2012

Table 3 [RuIV(TTP)Cl2]-catalyzed phosphoramidation of p-tolualde-
chemoselectivity and functional group tolerability via nitrene
insertion into aldehyde C–H bonds with phosphoryl azides as
a nitrene source.
hyde with phosphoryl azidesa
We thank the financial support of Hong Kong Research Grant
Council (HKU 7052/07P, HKU 700708P, HKU1/CRF/08) and
the Areas of Excellence Scheme established under the University
Grants Committee of the HKSAR, China (AoE/P-10/01).
Conv.b Yieldc
EntryAzide
1
Product
(%)
(%)
Notes and references
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Scheme 1
in Table 3, various substituents of phosphoryl azide including
methyl, ethyl, 2,2,2-trichloroethyl, and p-nitrophenyl groups are
compatible with the protocol, and all of them led to excellent
product yields (85–99%) and 100% substrate conversion.
The Ru(IV)-catalyzed synthesis of N-acylphosphoramidate can
be scaled up. Slow addition of a solution of DPPA (0.33 g) in
DCM (2 mL) to a mixture of [RuIV(TTP)Cl2] (5 mol%) and
4-methoxybenzaldehyde (0.14 g) in DCM (3 mL) for 5 h at 40 1C
afforded the amidation product in 92% yield (0.42 g, Scheme 1).
The deuterium kinetic isotope effect for the reaction of
benzaldehyde, benzaldehyde-d6 and N3P(O)(OCH2CCl3)2 gave a
kH/kD value of 4.1, revealing rate determining carbon–hydrogen
bond cleavage. The catalysis probably involves the formation of a
reactive (imidophosphoryl)ruthenium species. A possibility is
that bis(imidophosphoryl)ruthenium(VI) porphyrin18 is formed
initially by the reaction of dichlororuthenium(IV) porphyrin
with phosphoryl azide, which is analogous to the oxidation of
dichlororuthenium(IV) porphyrin to dioxoruthenium(VI) porphyrin
by O2.17d This putative intermediate undergoes nitrene insertion
into the aldehyde C–H bond to give N-acylphosphoramidate. The
high activity of dichlororuthenium(IV) porphyrin probably stems
from Ru(IV) which facilitates the decomposition of phosphoryl
azide to generate the ruthenium–imido/nitrene species and
subsequent nitrene insertion into the aldehydic C–H bond.
In conclusion, we have developed an efficient method
for the synthesis of N-acylphosphoramidates with excellent
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5871–5873 5873