Copper-catalyzed aerobic oxidative cross-coupling of arylamines and dialkylphosphites leading to N-arylphosphoramidates

Article abstract of DOI:10.1016/j.tetlet.2013.09.006

An efficient method to generate N-P bonds directly from N-H and P-H bonds is described. Various arylamines and dialkylphosphites were directly oxidized to the corresponding N-arylphosphoramidates at room temperature in moderate to good yields by using an inexpensive catalyst-oxidant (CuBr/air) system.

Full text of DOI:10.1016/j.tetlet.2013.09.006

Tetrahedron Letters 54 (2013) 6230–6232
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed aerobic oxidative cross-coupling of arylamines and
dialkylphosphites leading to N-arylphosphoramidates
⇑
⇑
Gao Wang, Qing-Ying Yu, Shan-Yong Chen , Xiao-Qi Yu
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2013
Revised 30 August 2013
Accepted 5 September 2013
Available online 12 September 2013
An efficient method to generate N–P bonds directly from N–H and P–H bonds is described. Various aryl-
amines and dialkylphosphites were directly oxidized to the corresponding N-arylphosphoramidates at
room temperature in moderate to good yields by using an inexpensive catalyst–oxidant (CuBr/air)
system.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Copper salts
N-arylphosphoramidates
R2
R3
Phosphoramidates have found wide applications as structure
motifs in bioactive compounds such as phosphoramidate-
substituted nucleosides, N-phosphoryl amino acids, and
N-phosphoryl peptides.1 Phosphoramidates also play a significant
role in organic synthesis. For example, N-arylphosphoramidates
have been used for the preparation of imines2 and various hetero-
cycles such as quinazolinediones3, aziridines4, and azetidines.5
Despite the increasing importance of phosphoramidates, only
two standard procedures have been widely used in the laboratory.
One route that forms phosphoramidates via the nucleophilic sub-
stitution of phosphorochloridates or phosphorodichloridates with
amines in the presence of a base (Scheme 1).6,1g Another involves
reactions of dialkyl or dibenzyl phosphites with amines using a
halogen source like CCl4 or other improved alternatives as activate
agents (Scheme 1).7 Other methods for the synthesis of phospho-
ramidates include the oxidation of phosphate trimesters with I2
in the presence of alkylamines and the reduction of nitroarenes
with triethyl phophite followed by phosphorylation with triethyl
phosphate.8 These procedures have in common that they are based
on the prefunctionalization–defunctionalization strategy. As results,
these procedures use additional active agents or produce unde-
sired by-products.
N
H
R1O
R2
R3
R1O
POCl3
P
R1O
N
R1OH
P
R1O
Cl
Base
R2
O
O
R3
N
H
R1O
R1O
R1O
R1O
R1O
R2
R3
CCl4
Base
P
Cl CCl3
P
H
R1O
P
N
O
- CHCl3
O
O
Scheme 1. The standard methods for the synthesis of phosphoramidates.
ment of C–C,10 N–N11, and P–P12 bond forming reactions via
dehydrogenative coupling. We envision that N–P bond may be
formed via cross-dehydrogenative coupling.13
We commenced our studies by examining the cross-coupling of
diisopropyl phosphite with excess p-methylaniline at room tem-
perature under air. In the absence of a catalyst, no desired product
was observed. Using 10 mol % of CuBr2 as the catalyst, 48% of de-
sired product was obtained. After screening different copper salts,
we found that CuBr performed the best (Table 1, entries 2–8). CuCl
also facilitated the reaction, but was less efficient than CuBr (entry
4
vs entry 3). Other catalysts including Cu(OAc)2ÁH2O, CuI,
Cu(OTf)2, and Cu2O were inefficient or inactive. Attempts to use
other transition-metal catalysts such as FeBr3 and CoBr2 were
unsuccessful. Impressively, no desired product was observed under
nitrogen (entry 9), indicating that oxygen is essential to this reac-
tion. We then surveyed the effect of different solvents (entries 10–
14). When toluene was replaced with ethyl acetate as the solvent,
we were pleased to find that the product could be obtained in 80%
yield. The reaction gave low yields in EtOH, THF, and H2O. In the
absence of a solvent, the reaction also performed, albeit with a
Recently, there has been increasing emphasis on reducing the
amount of toxic waste and byproducts arising from a chemical
process. As an effort to develop green chemistry for chemical syn-
thesis, a new concept of cross-dehydrogenative coupling was
established.9 To date, there is remarkable progress in the develop-
⇑
Corresponding authors. Tel./fax: +86 28 85415886.
E-mail address: xqyu@scu.edu.cn (X.-Q. Yu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.006

G. Wang et al. / Tetrahedron Letters 54 (2013) 6230–6232
6231
Table 1
Table 2
Copper-catalyzed cross-dehydrogenative coupling of p-methylaniline and diisopropyl
Copper catalyzed cross-dehydrogenative coupling of arylamines and dialkylphosph-
phosphatea
itesa
O
OR
OR
O
OR
OR
H
N
Ar NH2
+
H
P
Ar
P
O
OiPr
OiPr
O
OiPr
OiPr
H
N
NH2
+
H
P
P
1
2
3
Product
Yieldb Product
(%)
Yieldb
(%)
O
O
H
N
H
Yieldb (%)
P
OiPr
N
P
OiPr
Entry
Catalyst (mol %)
Solvent
64
80
65
OiPr
OiPr
1
2
3
4
5
6
7
8
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Ethyl acetate
EtOH
THF
H2O
—
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
N.D.
N.D.
54
45
17
3a
3b
H
CuBr2 (10)
CuBr (10)
CuCl (10)
Cu(OAc)2ÁH2O (10)
CuI (10)
Cu(OTf)2 (10)
Cu2O (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (2.5)
CuBr (5)
O
O
OiPr
H
N
F
N P OiPr
P
64
OiPr
OiPr
3d
6
3c
N.D.
N.D.
N.D.
80
52
60
39
49
54
80
O
Cl
H
N
9b
10
11
12
13
14c
15
16
17
18d
Cl
P OiPr
O
Oi Pr
H
N
OiPr
P
63
58
3e
Oi Pr
3f
O
O
H
N
H
N
Br
P
OiPr
MeO
P OiPr
63
49
OiPr
Oi Pr
3g
3h
CuBr (20)
CuBr (5)
32
78
Cl
O
OiPr
H
N
O
H
N
P
a
P
P
OiPr
Oi Pr
28
Trace
p-Methylaniline, 1.5 mmol; diisopropyl phosphite, 1 mmol; solvent, 1 mL;
under air; at room temperature; 22 h; isolated yields.
OiPr
3i
b
Under nitrogen.
No solvent.
50 °C; 8 h.
3j
H
N
C
O
OiPr
O
H
N
d
O2N
P
OiPr
OiPr
Oi Pr
N.R.
49
3k
moderate yield (entry 14). Further, the catalyst loading was
screened, and it was found that 5 mol % of CuBr was efficient to ob-
tain a reasonable yield (entries 15–17 and entry 10). When the
reaction was carried out at 50 °C, the yield decreased slightly (en-
try 18). In summary, 5 mol % of CuBr in ethyl acetate, at room tem-
perature, under air atmosphere were the optimized reaction
conditions.
With optimized conditions in hand, we investigated the scope
of this transformation (Table 2). Various phosphoramidates were
produced from arylamines and diisopropyl phosphite in moderate
to good yields (3a–j). This reaction was tolerant of several func-
tional groups. Both electron-rich and electron-deficient substrates
(para or meta substituted) were well-tolerated. Arylamines bearing
fluoro (3d), chloro (3e and 3f), or bromo (3g) groups were good
substrates, providing convenient handles for subsequent function-
alization processes. Arylamines bearing an ortho substituent or a
strong electron-withdraw substituent could not smoothly afford
3l
O
OiPr
OiPr
OiPr
N
HN
P
P
20
OiPr
30
(50c)
O
3m
3n
O
O
H
N
H
N
P
OEt
P OnBu
64
75
94
77
OEt
OnBu
3o
3p
O
O
H
N
H
N
Cl
P
OnBu
OnBu
Br
P
OnBu
OnBu
3q
3r
a
1, 1.5 mmol; 2, 1 mmol; ethyl acetate, 1 mL; CuBr, 5 mol %; under air; at room
temperature; 22 h.
b
Isolated yields.
c
N-methylaniline 5 mmol.
the desired product (3i–k). The cross-coupling of a-naphthylamine
with diisopropyl phosphite produced 3l in 49% yield. Although
alkylamines were not compatible with this method, benzylamine
is an acceptable substrate (3m). Secondary arylamines were not
good substrates for this transformation. But increasing the loading
of N-methylaniline to 5:1 (amine/phosphate ratio), the corre-
sponding product was obtained in an acceptable yield (3n). In
addition to diisopropyl phosphite, other dialkyl phosphites includ-
ing diethyl phosphite and di-n-butyl phosphite were also good
substrates for this cross-coupling reaction (3o–r). Interestingly,
di-n-butyl phosphite performed more effectively and afforded the
desired product in higher yield than other dialkyl phosphites. For
example, the reaction of p-methylanilide with di-n-butyl phos-
phite, diisopropyl phosphite, and diethyl phosphite afforded the
corresponding phosphoramidates in 94%, 80%, and 64% yields,
respectively (3p, 3b and 3o).
In conclusion, we have developed an efficient and green
method to prepare N-aryl-phosphoramidates via Cu-catalyzed
cross-dehydrogenative coupling.
Acknowledgments
We are grateful for financial support from the National Program
on Key Basic Research Project of China (973 Program,
2013CB328900) and the National Science Foundation of China
(Grant No. 21202107 and 20121001).
Supplementary data
Supplementary data (the detailed experimental procedures and
compounds characterization) associated with this article can be

6232
G. Wang et al. / Tetrahedron Letters 54 (2013) 6230–6232
5. (a) Yadav, L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 5652; (b)
Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron Lett. 2007, 48, 8037.
6. Li, S. O. J. Am. Chem. Soc. 1952, 74, 5959.
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.09.006.
7. (a) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945, 660; (b)
Gupta, A. K.; Acharya, J.; Dubey, D. K.; Kaushik, M. P. Synth. Commun. 2007, 37,
3403.
References and notes
8. (a) Nemer, M. J.; Ogilvie, K. K. Tetrahedron Lett. 1980, 21, 4149; (b) Haggam, R.;
Conrad, J.; Beifuss, U. Tetrahedron Lett. 2009, 50, 6627.
9. (a) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935–945; (b) Wendlandt, A. E.;
Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062; (c) Liu, C.; Zhang,
H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
10. (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. and references cited therein; (b) Li, Y.-
Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009, 48, 3817; (c)
Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
11. Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174.
12. Zhou, Y.; Yin, S.; Gao, Y.; Zhao, Y.; Goto, M.; Han, L.-B. Angew. Chem., Int. Ed.
2010, 49, 6852.
1. (a) Venkatachalam, T. K.; Goodman, P. A.; Qazi, S.; D’Cruz, O.; Uckun, F. M. Curr.
Pharm. Design 2004, 10, 1713; (b) Venkatachalam, T. K.; Samuel, P.; Qazi, S.;
Uckun, F. M. Bioorg. Med. Chem. 2005, 13, 5408; (c) Uckun, F. M.; Samuel, P.;
Qazi, S.; Chen, C.; Pendergrass, S.; Venkatachalam, T. K. Antiviral Chem.
Chemother. 2002, 13, 197; (d) Freel Meyers, C. L.; Borch, R. F. J. Med. Chem.
2000, 43, 4319; (e) Roman, C. A.; Balzarini, J.; Meier, C. J. Med. Chem. 2010, 53,
7675; (f) Ji, G. J.; Xue, C. B.; Zhao, Y. F. Synthesis 1988, 444; (g) Cai, Y. M.; Gao, X.;
Huang, X. T.; Wang, T. J.; Zhao, Y. F. Chin. J. Org. Chem. 2006, 26, 1677; (h)
Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263; (i) Mc Mahon, E. G.;
Palomo, M. A.; Moore, W. M. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 703.
2. Ciufolini, M. A.; Spencer, G. O. J. Org. Chem. 1989, 54, 4739.
13. During the preparation of this manuscript, Mizuno et al reported
a Cu-
catalyzed coupling reaction between dialkylphosphites and cyclic amides. See
Jin, X.; Yamaguchi, K.; Mizuno, N. Org. Lett. 2013, 15, 418.
3. Minami, T.; Ogata, M.; Hirao, I.; Tanaka, M.; Agawa, T. Synthesis 1982, 231.
4. Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron Lett. 2008, 49, 68.