MnIII-catalyzed phosphorylation of vinyl azides: The synthesis of β-keto phosphine oxides

Article abstract of DOI:10.1016/j.tetlet.2017.04.069

Mn^III-catalyzed functionalization of vinyl azides via phosphorylation was developed to synthesize various β-keto phosphine oxides in high yields. The transformation is operated in mild conditions and tolerant of a range of functional groups. Control reaction indicates that the reaction mechanism might proceed via the generation of a phosphonated iminyl radical intermediate.

Full text of DOI:10.1016/j.tetlet.2017.04.069

Accepted Manuscript
MnIII-catalyzed Phosphorylation of Vinyl Azides: The synthesis of β-keto phos-
phine oxides
Pai Tang, Can Zhang, En Chen, Binhui Chen, Wenteng Chen, Yongping Yu
PII:
S0040-4039(17)30519-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.069
TETL 48861
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 April 2017
15 April 2017
21 April 2017
Please cite this article as: Tang, P., Zhang, C., Chen, E., Chen, B., Chen, W., Yu, Y., MnIII-catalyzed Phosphorylation
of Vinyl Azides: The synthesis of β-keto phosphine oxides, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.04.069
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Graphical Abstract
MnIII-catalyzed Phosphorylation of Vinyl
Azides: The synthesis of β-keto phosphine
oxides
Leave this area blank for abstract info.
Pai Tang, Can Zhang, En Chen, Binhui Chen,
Wenteng Chen,* Yongping Yu*
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, P. R. China

1
Tetrahedron Letters
journal homepage: www.els evier.com
MnIII-catalyzed Phosphorylation of Vinyl Azides: The synthesis of β-keto phosphine
oxides
Pai Tang, Can Zhang, En Chen, Binhui Chen, Wenteng Chen,* Yongping Yu*
a College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
MnIII-catalyzed functionalization of vinyl azides via phosphorylation was developed to
synthesize various β-keto phosphine oxides in high yields. The transformation is operated in
mild conditions and tolerant of a range of functional groups. Control reaction indicates that the
reaction mechanism might proceed via the generation of a phosphonated iminyl radical
intermediate.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl azides
Radical reaction
Functionalization
Phosphorylation
Mn catalysis
Previous work
1. Introduction
AgNO3 (5%)/CuSO4 5H2O (10%)
K2S2O8 (4.0 eq)
O
O
P
O
P
R3
R4
R3
R4
Organophosphorus compounds play vital role in organic
1
chemistry, pharmaceuticals and material science. Among them,
R2
O2
+
H
R1
+
+
a)
b)
R1
DCM-H2O, rt
R2
β-keto phosphine oxides are highly valuable and interesting
intermediates that facilitate the α, β-unsaturated carbonyl
compounds via the Horner-Wadsworth-Emmons (HWE)
O
O
O
OR2
CuOTf (5%)/FeCl3(10%)
R1
R2
O
P
+
O2
P
H
OR2
R1
R2
O
Et3N, DMSO, 70 o
C
2
3
reactions,
diversified construction of heterocycles or the
synthesis of chiral β-hydroxy phosphonic acids. 4 In recent years,
strategies between organophosphorus radicals
acceptor have been well developed for affording
O
O
P
O
P
R3
R2
Cu(acac)2(10%)/FeCl3(20%)
Et3N, DMSO, 80 o
R3
R2
H
H
+
+
O2
5
R1
O
c)
d)
R1
and radical
C
CuSO4 5H2O(10%)/NH3 H2O(25%)
TBHP (2.0 eq)
O
O
P
organophosphorus compounds, especially for the formation of β-
R3
R2
R3
R2
P
COOH
5a-5f
+
R1
MeCN, 60 o
C
R1
keto phosphine oxides.
(Scheme 1a-f) However, reported
works required O2 assistance, co-catalyst system or
stoichiometric amount of catalyst.
O
O
P
O
OR3
OR3
CuBr2(2.5%)FeBr3(5%)
Et3N, DMSO, 55o
R3
O
e)
P H
+
+
O2
R1
R2
R1
R3O
C
R2
Vinyl azides as attractive and challenging three-atom synthons
have drawn much attention for their application for diverse
6
heterocylces construction. The unique properties of the azide
O
O
P
R2
R2
O
Mn(OAc)3 (2.0 eq)
f)
R2
R2
R1
P
H
+
R1
CH3OH, air, rt
group adjacent to an alkene moiety facilitate to tune this
functional group into interesting building blocks. Moreover,
vinyl azides have been employed as a potential radical acceptor
in organic synthesis. 7 For example, formation of pyridines via
This work
g)
O
O
P
O
7b
Mn(acac)3 (20%)
R1
R3
R2
R3
R2
radical reactions of vinyl azides with cyclopropanols,
7d
P
H
+
R1
NMP, 60 o
C
7c
trifluoromethylation or perfluoroalkylation
N3
of vinyl azides
through iminyl radicals. Recently, our group has reported an
R1=aryl, alkyl
R2=aryl, aryloxy, alkoxy
R3=aryl, aryloxy, alkoxy
efficient synthesis of 5-thiocyano-2-aminothiazoles via Fe-
7e
catalyzed radical cyclization of vinyl azides.
Thus, in the
Scheme 1. The formation of β-keto phosphine oxides via a P-
centered radical.
continue interest in functionalization of vinyl azides, the
development of interesting radicals with vinyl azides is still
attracting.
Here, we disclose a MnIII-catalyzed phosphorylation of vinyl
azides with phosphine oxides to afford iminyl radicals.
Subsequent conversion of the transient radicals for the β-

2
Tetrahedron
ketophosphine oxides. (Scheme 1-g) Preliminary mechanistic
investigation revealed that the phosphine oxides radical is likely
involved in the phosphorylation process.
Following the established reaction conditions for the
construction of 3a, the generality of this β-ketophosphonate 3
synthesis was examined using a series of vinyl azides 1. α-Aryl-
substituted vinyl azides were facile to give the corresponding
products 3 in good yields (Table 2, 3a-3i). The addition of the
phosphonate radical to vinyl azides bearing electron-withdrawing
groups (Table 2, 3e-3i) or electron-rich aryl groups (Table 2, 3b-
3d) proceed smoothly to give the corresponding β-keto
phosphonate in good yields. α-Alkyl-substituted vinyl azide was
also capable of coupling with the phosphine oxide radical
efficiently (Table 2, 3j). While trisubstituted vinyl azides having
an aryl group at the β-position failed to be employed in this
synthesis, probably due to steric hindrance (Table 2, 3k).
2. Results and discussion
We envisioned utilizing H-phosphonate (2a) as a source of
radical. Interesting, a diethyl (2-oxo-2-phenylethyl) phosphonate
(3a) was isolated in 18% yield by the reaction with vinyl azide
(1a) using a 50 mol% amount of Mn(OAc)3ꢀ2H2O (Table 1, entry
1). Increasing the amount of Mn(OAc)3ꢀ2H2O to 80 mol% or 100
mol% lead to a slight increase in the yields (25%, Table 1, entries
2-3). While 68% of the product (3a) was observed when the
reaction was performed with 2.5 equivalents of Mn(OAc)3ꢀ2H2O
(Table 1, entry 4). The combined of catalytic amount of Mn (III)
and other oxidant such as DDQ resulted in a lower yield (12%,
Table 1, entry 5). Other manganese salts such as
Mn(OAc)2ꢀ4H2O and Mn(acac)3 were also investigated (Table 1,
entries 6-7). Utilization of Mn (III) acetylacetonate [Mn(acac)3]
was found to be essential in rendering this reaction with an
excellent yield of 70%. Reducing the catalyst loading to 20 mol
% could still initiate this reaction with a slightly decreased yield
of 60% (Table 1, entry 8). The reaction yields can be improved
by elevating the reaction temperature (Table 1, entries 9-10).
Next, we intended to explore the relationship of the solvent
systems in this reaction. Conducting the reaction in DMSO, DMF
and DCE gave the product 3a in moderate yields (Table 1, entries
11-13), while the reaction conducted in NMP gave 3a in 92%.
Therefore, the best yield of 3a (92%) was obtained by employing
Table 2. Substrate scope of vinyl azides a
o
20 mol% Mn(acac)3 in N-methyl-2-pyrrolidone (NMP) at 60 C
for 6 h.
Table 1. Optimization of the reaction conditions a
a.The reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol, 1.0 equiv.)
and Mn(acac)3 (0.2 mmol, 0.2 equiv.) in NMP (2 mL containing 90
µL of H2O) stirring at 60 oC for 6 h unless otherwise noted.
entry
additive (equiv.)
solvent yield(%)b
1
2
3
4
Mn(OAc)3ꢀ2H2O(0.5)
Mn(OAc)3ꢀ2H2O(0.8)
Mn(OAc)3ꢀ2H2O(1.0)
Mn(OAc)3ꢀ2H2O(2.5)
NMP
NMP
NMP
NMP
18
25
25
68
Next, the generality of phosphine oxides was also examined
using α-azidostyrene and 1-(1-azidovinyl)-3-nitrobenzene as
shown in Table 3. Not only dialkyl and diaryl H-phosphonates
(4a-4c) but also diarylphosphine oxide (4d) and
benzyloxyphosphine oxides (4e-4f) were successfully converted
into the corresponding β-keto phosphine oxides 4 with the yields
of 69%-88%, thus demonstrating the broad applicability of the
present process.
Mn(OAc)3ꢀ2H2O(0.5)+
DDQ(2.0)
5
NMP
12
6
Mn(OAc)2ꢀ4H2O(0.5)
Mn(acac)3(0.5)
Mn(acac)3(0.2)
Mn(acac)3(0.2)
Mn(acac)3(0.2)
Mn(acac)3(0.2)
Mn(acac)3(0.2)
Mn(acac)3(0.2)
NMP
NMP
NMP
NMP
NMP
DMSO
DMF
DCM
5
7
70
60
71
92
78
70
73
Table 3. Substrate scope of R2P(O)H compounds a
8
9c
10d
11d
12d
13d
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), additive in
o
solvent (1.0 mL containing 18 µL of H2O) stirring at 25 C for 6
b.
d.
h. Yield of the isolated product .c. performed at 40 oC
performed at 60 oC
a.The reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol, 1.0 equiv.)

3
Acknowledgements
and Mn(acac)3 (0.2 mmol, 0.2 equiv.) in NMP (2 mL containing
90 µL of H2O) stirring at 60 oC for 6 h unless otherwise noted.
This work was supported from the National Natural Science
Foundation of China (No. 81273356 and 81473074), National
Science & Technology Major Projects for "Major New Drugs
Innovation and Development" of China (2014ZX09304002-007)
and Arthritis & Chronic Pain Research Institute, USA to Y. Yu;
National Natural Science Foundation of China (No. 81402778) to
W. Chen.
To gain insight into the reaction mechanism for the formation
of 3a, control experiments were subsequently carried out
(Scheme 2). When TEMPO (2, 2, 6, 6-tetramethyl-1-
piperidinyloxy), a widely used radical scavenger, was added into
the reaction system, the formation of 3a was completely inhibited.
When the reaction was performed under N2, the desired product
3a was obtained. While product 3a failed to afford in anhydrous
NMP. This findings imply that the reaction involves a radical
process and the keto group comes from water in solvents.
Supporting Information
Supplementary data (Experimental procedures, characterization
1
data, and copies of H and 13C NMR spectra for all products)
associated with this article can be found in the online version, at
http://dx.doi.org/
Note
*Corresponding authors: E-mail: wentengchen@zju.edu.cn (for
W. Chen); E-mail: yyu@zju.edu.cn (for Y. Yu)
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Scheme 2. Control reaction
Based on these observations,
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Scheme 3. The reaction might be initiated by the addition of
phosphine oxide radical , generated by one-electron
oxidation of by Mn (III), to vinyl azide , affording iminyl
a
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3
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Scheme 3. A possible reaction mechanism
3. Conclusion
In summary, we have developed Mn (III)-catalyzed radical
phosphorylation of vinyl azides using phosphine oxides. Further
investigation of the reaction mechanism showed that this reaction
probably proceed through an oxidant radical pathway. Moreover,
the reaction process features an operation with functional-group
tolerance and high yields.

4
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5
Highlights:
1. MnIII-catalyzed functionalization of vinyl azides via phosphorylation.
2. The transformation is operated in mild conditions and tolerant of a range of functional groups.
3. The procedure afforded the β-keto phosphine oxides in high yields.