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RSC Advances
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DOI: 10.1039/C5RA18459B
Journal Name
COMMUNICATION
Conclusions
3
1
Scheme 1
.
P NMR detection results and a proposed
/I ꢀmediated amidation of 1a
In conclusion, an efficient, mild and scalable amide formation
reaction promoted by P(OEt) and was developed.
mechanism for the P(OEt)
3
2
3
I
2
3
1
Mechanistic studies through P NMR detection demonstrated
that carboxylic-phosphoric mixed anhydrides were the key
intermediates for this reaction, which led to the desired
amides with very high regioselectivity. The advantageous of
this procedure include mild reaction condition, broad
substrate generality, easy removal of the by-product, and high
resistance to racemization.
Acknowledgements
This work was supported by Guangdong Natural Science
Foundation (Research Grant No. S2013010012465).
(
Table 2, Entries 17–18, see Supporting Information). Taking
into account that N-methylmorpholine (NMM) is widely used
in the synthesis of peptides as a weaker and better base than
5
,17
Et
as base in these cases.
In order to elucidate the role of P(OEt)
3
N to avoid racemization,
3
we used NMM instead of Et N
Notes and references
and I
P NMR spectroscopy to detect the reaction process and
possible mechanism was herein proposed (Scheme 1). The
solution of P(OEt) in CDCl showed a strong singlet at 138.8
2
,
we next used
1
For recent representative eamples and reviews, see: (a)
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3
3
1
a
3
3
ppm. Addition of iodine led to rapid decoloration of iodine and
appearance of a new signal at –41.1 ppm, indicating the
1
8
formation of diethyl iodophosphate
After adding benzoic acid 1a and Et
for about 30 minutes, the mixed anhydride
.1 ppm emerged and the peak of disappeared gradually. In
the end, the addition of n-BuNH resulted in the appearance of
diethyl phosphate at –1.1 ppm and generation of the desired
amide 3a. The reaction exhibited high regioselectivity since no
undesired by-product from attacking the amine on the
phosphorus center of the anhyride was observed.
A
[lit. ,
N to this reaction mixture
resonating at –
p
δ = –41.0 ppm].
3
(
4
f) V. R. Pattabiraman and J. W. Bode, Nature, 2011,
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8
A
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2
3
4
5
2
C
D
B
According to the above results, mixed carboxylic phosphoric
anhydrides are the reactive intermediates for the present
6
7
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reaction. That means the role of P(OEt)
different from that of PPh and I in the literature, which
3 2
and I is quite
8
3
2
believed to undergo acyl phosphonium species or acyl iodide.
It is reported that mixed carboxylic phosphoric anhydrides are
efficient activated intermediates for amide synthesis, which
generally show higher regioselectivity toward amine attack
than dicarboxynic mixed anhydrides and are often more
8
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9
1
0
1
2
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1
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1
d
resistent to racemization.
Many reagents, such as
1
9
diethylcyano-phosphate (DECP), diethyl phosphorochloridate
12 L. E. Barstow and V. J. Hruby, J. Org. Chem., 1971, 36
1305–1306.
1
1
,
2
DEPC), diphenylphosphoryl azide (DPPA), are used to
0
21
(
3
4
S. Yamada and Y. Takeuchi, Tetrahedron Lett., 1971, 12
595–3598.
,
prepare the mixed phosphoric anhydrides. Unfortunately,
these reagents are usually unstable, need to be prepared in
advance, or only show medium reactivity. The present
procedure provided a convenient and efficient way for the first
time to synthesize the mixed phosphoric anhydrides via in situ
formation of diethyl iodophosphate from readily available,
3
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1
6
A recent review about Weinreb amides: M. Nowak,
Synlett, 2015, 26, 561–562.
1
8b
3 2
cheap and stable compounds (i.e. P(OEt) and I ).
1
7
G. W. Anderson, J. E. Zimmerman and F. M. Callahan, J.
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