Copper-catalyzed oxidative cross-coupling of H-phosphonates and amides to N-acylphosphoramidates

Article abstract of DOI:10.1021/ol303420g

A simple combination of copper(II) acetate (Cu(OAc)₂) and an appropriate base could promote oxidative cross-coupling of H-phosphonates and amides using air as a terminal oxidant. The substrate scope was broad with respect to both dialkyl H-phosphonates and nitrogen nucleophiles (including oxazolidinone, lactam, pyrrolidinone, urea, indole, and sulfonamide derivatives), giving the corresponding P-N coupling products in moderate to high yields.

Full text of DOI:10.1021/ol303420g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Oxidative
Cross-Coupling of H‑Phosphonates
and Amides to N‑Acylphosphoramidates
Xiongjie Jin, Kazuya Yamaguchi, and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
tmizuno@mail.ecc.u-tokyo.ac.jp
Received December 14, 2012
ABSTRACT
A simple combination of copper(II) acetate (Cu(OAc)2) and an appropriate base could promote oxidative cross-coupling of H-phosphonates and
amides using air as a terminal oxidant. The substrate scope was broad with respect to both dialkyl H-phosphonates and nitrogen nucleophiles
(including oxazolidinone, lactam, pyrrolidinone, urea, indole, and sulfonamide derivatives), giving the corresponding PꢀN coupling products in
moderate to high yields.
N-Acylphosphoramidates are very important structural
key motifs in various bioactive natural products and pharma-
ceuticals such as Agrocin 84,1 Microcin C7,2 Phosmidosin,3
and Fosaprepitant,4 which are reported to show antifungal,
antitumor, and antiemetic activities (Figure S1). In general,
N-acylphosphoramidates have been synthesized by multistep
nongreen procedures. For example, the most widely utilized
procedure is nucleophilic substitution of chlorophosphonates
with amides in the presence of strong bases, e.g., n-BuLi
(Figure 1, A).5 Another approach to N-acylphosphorami-
dates is a reaction of phosphoramides with acyl chlorides
or mixed anhydrides (Figure 1, B).6 Recently, Che and
co-workers have reported a ruthenium(IV) porphyrine
complex-catalyzed phosphoramidation of aldehydes with
phosphoryl azides (Figure 1, C).7 However, these reported
procedures have utilized chlorophosphonates as starting
materials, which are generally prepared by chlorination of
H-phosphonates or phosphates using hazardous reagents,
e.g., Cl2, COCl2, or SO2Cl2.8 Thus, they have severe draw-
backs, which include tedious multistep procedures, hand-
ling of toxic reagents, and production of large amounts of
waste during not only phosphorylation but also chlorina-
tion steps. The development of novel green synthetic
procedures for N-acylphosphoramidates directly using
H-phosphonates as starting materials is very desirable,
because they are more readily available and easy-to-handle
in comparison with chlorophosphonates and, most impor-
tantly, no prefunctionalization step of H-phosphonates is
required, which can greatly improve the overall synthetic
efficiency of N-acylphosphoramidates. To date there is
remarkable progress in the development of PꢀC9 and
Pꢀheteroatom10 bond forming reactions via direct activa-
tion of the PꢀH bond. Recently, copper-catalyzed (or
mediated) oxidative cross-coupling was proven to be a
highly efficient approach for the construction of CꢀC and
(1) Tate, M. E.; Murphy, P. J.; Roberts, W. P.; Kerr, A. Nature 1979,
280, 697.
ꢀ
ꢀ
(2) Guijarro, J. I.; Gonzalez-Pastor, J. E.; Baleux, F.; Millan, J. L. S.;
Castilla, M. A.; Rico, M.; Moreno, F.; Delepierre, M. J. Biol. Chem.
1995, 270, 23520.
(3) Uramoto, M.; Kim, C.-J.; Shinya, K.; Kusakabe, H.; Isono, K.
J. Antibiot. 1991, 44, 375.
(4) Lasseter, K. C.; Gambale, J.; Jin, B.; Bergman, A.; Constanzer,
M.; Dru, J.; Han, T. H.; Majumdar, A.; Evans, J. K.; Murphy, M. G.
J. Clin. Pharmacol. 2007, 47, 834.
(5) Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.; Parchett,
A. A.; Combs, P.; Roth, A.; Busch, R. D.; Mellin, T. N. J. Med. Chem.
1989, 32, 1886.
(6) Adams, L. A.; Cox, R. J.; Gibson, J. S.; Mayo-Martin, M. B.;
Walter, M.; Whittingham, W. Chem. Commun. 2002, 2004.
(7) Xiao, W.; Zhou, C.-Y.; Che, C.-M. Chem. Commun. 2012, 48, 5871.
(8) (a) Kosolapoff, G. M.; Maier, L. Organic Phosphorus Compounds;
Wiley-Interscience: New York, 1972. (b) Hartley, F. R. The Chemistry of
Organophosphorus Compounds; Wiley: New York, 1996. (b) Quin, L. D.
A Guide to Organophosphorus Chemistry; Wiley: New York, 2000. (c) Gupta,
H. K.; Mazumder, A.; Garg, P.; Gutch, P. K.; Dubey, D. K. Tetrahedron Lett.
2008, 49, 6704.
r
10.1021/ol303420g
XXXX American Chemical Society

Table 1. Oxidative Cross-Coupling of 1a and 2a under Various
Conditionsa
yield (%)
conv of
entry
catalyst
Cu(OAc)2
1a/2a
1a (%)
3aa
4aa
1b
2c
3
1/2
1/2
1/2
1/3
1/3
1/5
1/1
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
1/3
82
93
99
99
93
>99
93
97
>99
>99
2
17
51
81
90
84
89
68
89
62
63
1
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
[Cu(μ-OH)(tmen)]2Cl2
CuCl2
1
1
4
1
5d
6
1
1
7
6
8
1
9
38
37
nd
6
10
11
12
13
14
15
16
17
18
19
20
21
Figure 1. Synthetic procedures for N-acylphosphoramidates.
Cu(acac)2
CuI
12
44
3
1
heteroatomꢀC bonds (including PꢀC and NꢀC bonds).11
Quite recently, we have also developed the copper-catalyzed
aerobic oxidative cross-coupling of terminal alkynes and
amides to ynamides.12
Our continuing interest in copper-catalyzed aerobic
oxidative cross-coupling reactions prompted us to explore
novel methodology to synthesize N-acylphosphoramidates.
3
CuSO4 5H2O
25
nd
nd
nd
nd
nd
nd
nd
nd
2
Cu(OH)2
Cu2O
nd
nd
nd
nd
nd
nd
nd
nd
<1
<1
<1
<1
<1
7
Ni(OAc)2 4H2O
3
Co(OAc)2 4H2O
3
Fe(OAc)2
Mn(OAc)2 4H2O
3
Pd(OAc)2
none
<1
a Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), Et3N
(0.2 mmol), MS 4 A (100 mg), toluene (2 mL), 80 °C, under air (1 atm). A
toluene solution of 1a (1 mL, 0.2 M) was added to the reaction mixture
over 30 min by a syringe pump, and the reaction mixture was stirred for
an additional 10 min. Conversion and yield were determined by GC
analysis. nd = not detected (<1%). b Mixed in a single step, without MS
4 A, 40 min. c Mixed in a single step, MS 4 A (100 mg), 40 min.
d Cu(OAc)2 (5 mol %).
(9) For selected reviews and examples, see: (a) Han, L.-B.; Tanaka,
M. Chem. Commun. 1999, 395. (b) Prim, D.; Campagne, J.; Joseph, D.;
Andrioletti, B. Tetrahedron 2002, 58, 2041. (c) Schwan, A. Chem. Soc.
Rev. 2004, 33, 218. (d) Delacroix, O.; Gaumont, A. C. Curr. Org. Chem
2005, 9, 1851. (e) Glueck, D. S. Synlett 2007, 2627. (f) Coudray, L.;
Montchamp, J. Eur. J. Org. Chem. 2008, 3601. (g) Kagayama, T.;
Nakano, A.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2006, 8, 407. (h) Hou,
C. D.; Ren, Y. L.; Lang, R.; Hu, X. X.; Xia, C. G.; Li, F. W. Chem.
Commun. 2012, 48, 5181. (i) Han, L.-B.; Ono, Y.; Shimada, S. J. Am.
Chem. Soc. 2008, 130, 2752. (j) Gao, Y.; Wang, G.; Chen, L.; Xu, P.;
Zhao, Y.; Zhou, Y.; Han, L.-B. J. Am. Chem. Soc. 2009, 131, 7956. (k)
Ohmiya, H.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44,
2368. (l) Xiang, C.-B.; Bian, Y.-J.; Mao, X.-R.; Huang, Z.-Z. J. Org.
Chem. 2012, 77, 7706.
In this paper, we demonstrate for the first time the successful
application of copper-catalyzed aerobic oxidative cross-
coupling to form PꢀN bonds, i.e., cross-coupling of H-
phosphonates and amides to N-acylphosphoramidates.
The present catalyst system can employ air as a terminal
oxidant and produces water as a sole byproduct, providing
a quite simple, efficient, and green synthetic route to highly
important N-acylphosphoramidate functionalities (Figure 1,
lower). To the best of our knowledge, there is no pre-
existing example of a metal-catalyzed aerobic oxidative
cross-coupling of phosphorus and nitrogen nucleophiles to
form PꢀN bonds.
(10) (a) Stephan, D. W. Angew. Chem., Int. Ed. 2000, 39, 314. (b)
Clark, T. J.; Lee, K.; Manners, I. Chem.;Eur. J. 2006, 12, 8634. (c)
Greenberg, S.; Stephan, D. W. Chem. Soc. Rev. 2008, 37, 1482. (d) Less,
R. J.; Melen, R. L.; Naseri, V.; Wright, D. S. Chem. Commun. 2009,
4929. (e) Waterman, R. Dalton Trans. 2009, 18. (f) Waterman, R. Curr.
Org. Chem 2008, 12, 1322. (g) Dorn, H.; Singh, R. A.; Massey, J. A.;
Lough, A. J.; Manners, I. Angew. Chem., Int. Ed. 1999, 38, 3321. (h)
Dorn, H.; Singh, R. A.; Massey, J. A.; Nelson, J. M.; Jaska, C. A.;
Lough, A. J.; Manners, I. J. Am. Chem. Soc. 2000, 122, 6669. (i) Han,
€
L.-B.; Tilley, T. D. J. Am. Chem. Soc. 2006, 128, 13698. (j) Bohm,
V. P. W.; Brookhart, M. Angew. Chem., Int. Ed. 2001, 40, 4694. (k) Shu,
R.; Hao, L.; Harrod, J. F.; Woo, H.-G.; Samuel, E. J. Am. Chem. Soc.
1998, 120, 12988. (l) Zhou, Y.; Yin, S.; Gao, Y.; Zhao, Y.; Goto, M.;
Han, L.-B. Angew. Chem., Int. Ed. 2010, 49, 6852.
(11) For recent reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400. (b) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (c) Wendlandt, A. E.; Suess, A. M.; Stahl,
S. S. Angew. Chem., Int. Ed. 2011, 50, 11062. (d) Shao, Z.; Peng, F.
Angew. Chem., Int. Ed. 2010, 49, 9566. (e) Parrodi, C. A.; Walsh, P. J.
Angew. Chem., Int. Ed. 2009, 48, 4679. (f) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780. (g) Hirano, K.; Miura, M. Chem.
Commun. 2012, 48, 10704.
First, we optimized the reaction conditions by using
Cu(OAc)2 (OAc = acetate) (10 mol %) as a catalyst for the
cross-coupling of diisopropylphosphonate (1a) and 2-oxa-
zolidinone (2a) to diisopropyl(2-oxooxazolidin-3-yl)-
phosphonate (3aa). In the presence of Cu(OAc)2 and
triethylamine (Et3N) under 1 atm of air, the reaction of
1a and 2a (1:2, mixed in a single step) gave the desired
cross-coupling product 3aa in 17% yield (Table 1, entry 1).
(12) Jin, X.; Yamaguchi, K.; Mizuno, N. Chem. Commun. 2012, 48,
4974.
B
Org. Lett., Vol. XX, No. XX, XXXX

In this case, most of 1a decomposed to unidentified by-
products possibly due to hydrolytic decomposition, result-
ing in a low yield of 3aa. When molecular sieves 4 A (MS 4 A)
was added to the reaction mixture, the yield of 3aa
increased up to 51% along with a trace amount of a
pyrophosphate (4aa) derived from the homocoupling of 1a
(Table 1, entry 2). Further improvement of the yield of 3aa
up to 81% was achieved by slow addition of 1a to the
reaction mixture containing Cu(OAc)2, Et3N, and MS 4 A
under open air conditions (Table 1, entry 3). These results
could be attributed to the successful suppression of the
hydrolytic decomposition of 1a by the use of MS 4 A and
the slow addition of 1a. Upon changing the molar ratio of
1a to 2a from 1:2 to 1:3, a 90% yield of 3aa was obtained
(Table 1, entry 4). The use of the reduced amount of
Cu(OAc)2 (5 mol %) resulted in only a slight decrease in
theyield of 3aa (Table1, entry 5). Nofurtherincreaseinthe
yield of 3aa was observed when using 5 equiv of 2a
(Table 1, entry 6). The cross-coupling proceeded even with
1 equiv of 2a with respect to 1a albeit in a moderate yield of
3aa (Table 1, entry 7).
Among the various copper catalysts examined, Cu(OAc)2
showed the highest activity and selectivity for the cross-
coupling of 1a and 2a (Table 1, entry 4). Cu(OTf)2 (OTf =
triflate) showed almost the same activity and selectivity
as those of Cu(OAc)2 (Table 1, entry 8). Other copper
catalystssuchas[Cu(μ-OH)(tmen)]2Cl2 (tmen=N,N,N0,N0-
tetramethylethylendiamine), CuCl2, Cu(acac)2 (acac =
acetylacetonate), CuI, and CuSO4 5H2O showed lower
3
activities and/or selectivities than those of Cu(OAc)2
(Table 1, entries 9ꢀ13). Cu(OH)2 and Cu2O, which were
reported to be highly efficient catalysts for the cross-
coupling of terminal alkynes and amides,12 showed no
activity for the present cross-coupling (Table 1, entries 14
and 15). Other commonly utilized metal acetates such as
Ni(OAc)2 4H2O, Co(OAc)2 4H2O, Fe(OAc)2, Mn(OAc)2
3
3
3
4H2O, and Pd(OAc)2 were not effective for the present cross-
coupling (Table 1, entries 16ꢀ20).
In the present Cu(OAc)2-catalyzed cross-coupling, var-
ious inorganic and organic bases could effectively promote
the reaction, affording 3aa in high yields (Table S1). For
the cross-coupling of 1a and 2a, K2CO3 was the best base,
giving 3aa in an almost quantitative yield (Table S1, entry 4).
Although the cross-coupling proceeded to some extent
in the absence of bases, the yield of 3aa was significantly
decreased (Table S1, entry 12). The best solvent was
toluene, and other solvents such as 1,2-dichloroethane,
1,4-dioxane, 2- propanol, acetonitrile, DMF, and DMSO
were not effective (Table S2). When the reaction of 1a and
2a was carried out under an Ar atmosphere, only a
“stoichiometric” amount of 3aa with respect to Cu(OAc)2
was obtained (Table S2, entry 2). This result suggests that
reductive elimination of the PꢀN bonds takes place, and
then the reduced copper species can be reoxidized by O2
(air) during the present cross-coupling (Scheme S1).
Finally, we investigated the scope of the present Cu-
(OAc)2-catalyzed oxidative cross-coupling of H-phospho-
nates and amides using air as a terminal oxidant. The
suitable reaction conditions, especially the best bases
Figure 2. Aerobic oxidative cross-coupling of various H-phos-
phonates and nitrogen nucleophiles. Reaction conditions: 1
(0.2 mmol), 2(0.6 mmol), Cu(OAc)2 (10mol%),K2CO3 (0.2 mmol),
MS 4 A (100 mg), toluene (2 mL), 80 °C, under air (1 atm). A
toluene solution of 1 (1 mL, 0.2 M) was added to the reaction
mixture over 30 min by a syringe pump, and the reaction mixture
was stirred for an additional 10 min (unless otherwise noted).
The isolated yields (based on 1) are reported. a 4-Methylpyridine
(0.8 mmol) instead of K2CO3. b 1.5 h. c 2,20-Bipyridyl (20 mol %).
d 6,60-Dimethylbipyridyl (20 mol %). e 1 h.
(Table S3), were dependent on the types of substrates.
Under the optimized reaction conditions, various kinds of
structurally diverse N-acylphosphoramidates could be
synthesized from H-phosphonates and amides (Figure
S2). The isolation of the N-acylphosphoramidate products
obtained from the present oxidative cross-coupling of
H-phosphonates and amides was very easy.13 The isolated
yields of products are summarized in Figure 2. For the
cross-coupling of benzooxazolidinone (2b) and 1a, a good
Org. Lett., Vol. XX, No. XX, XXXX
C

yield was achieved by using 4-methylpyridine as a base
instead of K2CO3 (Table S3). A 5-substituted oxazolidi-
none (2c) smoothly reacted with 1a to give the cross-
coupling product in an almost quantitative yield. The
coupling of 4-, 5-, 6-, and 7-membered aliphatic cyclic
amides (2dꢀ2g) with 1a afforded the corresponding
N-acylphosphoramidates in high to excellent yields. Pyrroli-
dinone derivatives (2h and 2i) were also good substrates. A
bicyclic lactam, 2-azabicyclo[2.2.1]hept-5-en-3-one (2j),
was also a suitable nitrogen nucleophile to provide the
corresponding N-phosphoroamidate in an excellent yield.
Cyclic urea derivatives (2k and 2l) also worked well as
coupling partners for 1a. Notably, indole (2mꢀ2o) and
sulfonamide (2p) derivatives could be utilized as nitrogen
nucleophiles. With regard to H-phosphonates, various
dialkylphosphonates (1aꢀ1d) couldbe utilizedascoupling
partners, affording the corresponding N-acylphosphora-
midates in high yields.
In summary, we have successfully developed the copper-
catalyzed aerobic oxidative cross-coupling of H-phospho-
nates and amides to N-acylphosphoramidates. Various
kinds of dialkyl H-phosphonates and nitrogen nucleo-
philes (including oxazolidinone, lactam, pyrrolidinone,
urea, indole, and sulfonamide derivatives) could be utilized
as coupling partners, affording the corresponding PꢀN
coupling products. The oxidative cross-coupling demon-
strated herein will provide a new green, practical synthetic
route to N-acylphosphoramidates, which completely avoids
utilization of (hazardous) stoichiometric reagents (e.g.,
chlorophosphonates, Cl2, COCl2, SO2Cl2, n-BuLi, and/or
NaN3 in conventional procedures, Figure 1) and the forma-
tion of vast amounts of byproducts, and will be one of the
reliable choices for synthesis of these types of PꢀN function-
alities. By referring to the literature on copper-mediated
aerobic oxidative cross-coupling reactions,12,14 the present
reaction possibly proceeds according to Scheme S1.15
Detailed mechanistic studies are now in progress.
(13) The cross-coupling was carried out via the following procedure.
Into a Pyrex glass test tube (volume: ca. 20 mL) were successively placed
Cu(OAc)2 (10 mol % with respect to a H-phosphonate (1)), a base (1ꢀ4
equiv with respect to 1), an amide (2, 3 equiv with respect to 1), MS 4 A
(100 mg), toluene (1 mL), and a Teflon-coated magnetic stir bar. After
the reaction mixture was stirred for 5 min, a toluene solution of 1 (0.2 M,
1 mL) was added to the reaction mixture over 30 min by a syringe pump at
80 °C, and the reaction mixture was stirred for an additional 10ꢀ60 min
at 80 °C under open air conditions. After the reaction was completed, an
internal standard (naphthalene) was added to the reaction mixture, and
the conversion of 1 and the product yield were determined by GC
analysis. As for the isolation of products (N-acylphosphoramidates),
an internal standard was not added. After the reaction, the base and MS
4 A were filtered off, and then the filtrate was concentrated by evapora-
tion of toluene. The crude product was subjected to column chromato-
graphy on silica gel (Silica Gel 60N (63-210 μm), Kanto Chemical, 2.5 cm
ID ꢁ 15 cm length, typically chloroform/acetone = 5:1 (v/v); diethy-
lether/n-hexane = 2:1 (v/v) for 3ab, 3am, and 3ao; chloroform/acetone =
10:1 (v/v) for 3an and 3ap), giving the pure N-acylphosphoramidate. The
productswere identifiedbyGC-MS andNMR (1H, 13C, and 31P) analyses
(see the Supporting Information).
Acknowledgment. This work was supported in part by
Grants-in-Aid for Scientific Researches from the Ministry
of Education, Culture, Sports, Science and Technology.
Supporting Information Available. Full experimental
details, Tables S1ꢀS3, Figures S1 and S2, Scheme S1, and
spectral data of N-acylphosphoramidates. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(15) The present reaction possibly proceeds through the following
three steps: (i) coordination of amidate and phosphite species to the
copper center to form a Cu(phosphite)(amidate) intermediate (5), (ii)
reductive elimination to form the corresponding N-acylphosphorami-
dates, and (iii) reoxidation of the reduced copper species by O2 (air) to
regenerate active copper species (Scheme S1). Bases likely play two
important roles: (i) abstract NꢀH protons from amides and (ii) increase
concentration of phosphite forms (10).
(14) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833. (b) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc.
2010, 132, 2522. (c) Chu, L.; Qing, F. J. Am. Chem. Soc. 2010, 132, 7262.
(d) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2012, 51, 6993.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX