Stereospecific aerobic oxidative dehydrocoupling of P(O)H bonds with amines catalyzed by copper

Article abstract of DOI:10.1246/bcsj.20130310

Copper-catalyzed stereospecific oxidative dehydrocouplings of P(O)H bonds with amines under air took place effi-ciently at room temperature to afford the corresponding amidophosphorus compounds in high yields. Mechanistic studies showed that this dehydroc

Full text of DOI:10.1246/bcsj.20130310

400
Bull. Chem. Soc. Jpn. Vol. 87, No. 3, 400-402 (2014)
Short Articles
Table 1. Copper-Catalyzed Aerobic Oxidative Dehydro-
coupling of (i-PrO)2P(O)H with n-BuNH2
Selected Papers
a)
[Cu] (2mol%), air
n-BuNH
n-BuNHP(O)(Oi-Pr)
(i-PrO) P(O)H +
2
2
2
Stereospecific Aerobic Oxidative
Dehydrocoupling of P(O)-H Bonds
with Amines Catalyzed by Copper
solvent, 25 °C, 3 h
1a
2a
(i-PrO) P(O) P(O)(Oi-Pr) + (i-PrO) P(O)
O
P(O)(Oi-Pr)
2
2
2
2
3a
4a
Run
[Cu]
CuBr2
Solvent (mL)
Yield/% (2a/3a/4a)b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14c)
15c)
THF (1)
THF (5)
acetone (5)
DMF (5)
56/43/®
86/10/1
67/0.2/27
63/®/9
5.1/75/0.2
26/4/®
91/8/®
56/33/®
73/16/®
77/22/®
93/6/®
1/16/®
0.2/2/®
99/®/®
99/®/®
Yongbo Zhou,*1 Jia Yang,1 Tieqiao Chen,1
Shuang-Feng Yin,1 Daoqing Han,1 and Li-Biao Han*2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl
DMSO (5)
MeCN (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
EtOAc (5)
1State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering,
Hunan University, Changsha 410082, P. R. China
CuCl2
CuBr
2National Institute of Advanced Industrial Science and
Technology (AIST), Tsukuba, Ibaraki 305-8565
CuI
Cu(OAc)2
[Cu(acac)2]
CuI
Received November 6, 2013
E-mail: libiao-han@aist.go.jp
CuBr2
a) A mixture of 1a (1.0 mmol), n-BuNH2 (1.1 mmol), and the
Cu catalyst (0.02 mmol) in the solvent was stirred under air at
room temperature. b) Yields and selectivity were determined by
31P NMR spectroscopy. c) 1a (1.0 mmol) in 3 mL of EtOAc was
added dropwise to a mixture of Cu catalyst (0.02 mmol) and
n-BuNH2 (1.1 mmol) in 5 mL of EtOAc at room temperature.
Copper-catalyzed stereospecific oxidative dehydrocou-
plings of P(O)-H bonds with amines under air took place effi-
ciently at room temperature to afford the corresponding amido-
phosphorus compounds in high yields. Mechanistic studies
showed that this dehydrocoupling reaction proceeded stereo-
specifically with inversion of stereochemistry at phosphorus.
Transition-metal-catalyzed oxidative dehydrocoupling (abbre-
viated as ODHC hereafter) reaction is emerging as a green syn-
thetic tool in recent years.1-3 By using this method, substrates can
be coupled without the need of prefunctionalization. Therefore,
ODHCs are more economical and environmentally benign than
traditional coupling reactions that produce stoichiometric amounts
of waste salts. Aerobic ODHCs are of particular interest because
these reactions do not use hazardous oxidants and only produce
water as the by-product. Despite the vast number of dehydrocou-
pling reactions reported, it seems that a stereospecific dehydro-
coupling has not been realized.3 In addition, although a large
number of ODHCs are developed and frequently reviewed,1,2
heteroatom-heteroatom bond-forming reactions via ODHCs of
the corresponding heteroatom-hydrogen E-H bonds are still rela-
tively limited.3
We are engaging in the development of new methods for the
preparation of organophosphorus compounds via metal catalysis4
and have successfully disclosed copper-catalyzed oxidative de-
hydrocouplings of H-phosphonates with alkynes and selective
oxidative homo-dehydrocouplings of H-phosphonates.3a,3b As
an extension of this copper-mediated oxidative dehydrocoupling
methodology, herein we disclose that cheap copper can efficiently
catalyze the aerobic ODHCs of P(O)-H compounds 1 with amines
to produce the useful amidophosphonates and phosphinates 2 even
at room temperature (eq 1). This oxidative dehydrocoupling takes
place highly stereospecifically with inversion of configuration at
phosphorus to generate new enantiomerically pure P-chiral phos-
phorus compounds. To the best of our knowledge, this reaction
represents the first stereospecific dehydrocoupling reaction. It was
noted that during the preparation of this manuscript, very recently a
copper-catalyzed dehydrocoupling of amines with H-phosphonates
(RO)2P(O)H appeared (vide infra).3h,3i
cat. [Cu]
Z1Z2P(O)H
Z1Z2P(O)NHR
ð1Þ
+
RNH2
air, 25 °C
1
2
Compounds bearing P(O)-N bonds are useful in organic synthe-
sis, biology, and materials.5 They have been traditionally prepared
via substitution reactions of the corrosive, moisture-sensitive phos-
phoryl halides P(O)-X with amines or via Todd reactions by reac-
tions of P(O)H compounds with amines in the presence of CCl4.6
As shown in Table 1, a mixture of (i-PrO)2P(O)H (1 mmol) and
n-BuNH2 (1.1 mmol) was stirred in THF (1 mL) in the presence
of CuBr2 (0.02 mmol) under air at room temperature. After 3 h,
the oxidative cross-coupling product amidophosphonate 2a was
obtained in 56% yield (Run 1). By-products from the reaction
observed were 3a and 4a generated via the homo-dehydrocoupling
of (i-PrO)2P(O)H.3b The formation of these by-products could
be efficiently suppressed by tuning the reaction conditions. Thus,
a higher selectivity to 2a was obtained when the reaction was
conducted in diluted THF (Run 2). Both solvent and the catalyst
were crucial to this reaction. Among the solvents tested (THF,
acetone, DMF, DMSO, and MeCN), ethyl acetate gave 91% yield
of 2a (Run 7). As for the copper catalyst, in addition to CuBr2, CuI
(Run 11) also produced a high yield of 2a, whereas CuCl and
CuCl2 are inferior to CuI. Other catalysts such as Cu(OAc)2 and
[Cu(acac)2] only showed poor activity. Finally, by slowly adding
(i-PrO)2P(O)H to a mixture of the copper catalyst and butylamine
dissolved in ethyl acetate, the formation of the by-products could be
efficiently suppressed, affording 2a in a quantitative yield (Runs 14
Published on the web December 17, 2013; doi:10.1246/bcsj.20130310

Y. Zhou et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 3 (2014)
Table 2. Copper-Catalyzed Aerobic Oxidative Dehydrocoupling of P(O)-H Compounds with Aminesa)
401
CuBr2 (2 mol%)
Z1Z2P(O)H
Z1Z2P(O)NHR
+
RNH2
air, 25 °C, 3 h
Run
P(O)H compound 1
Amine
Product 2
Yield/%b)
(R1O)2P(O)H
R2NH2
(R1O)2P(O)NHR2
1
2
3
4
5
6
R1 = i-Pr, R2 = n-Bu
R1 = Me, R2 = n-Bu
R1 = Et, R2 = n-Bu
R1 = n-Bu, R2 = n-Bu
R1 = n-C12H25, R2 = n-Bu
R1 = PhCH2, R2 = n-Bu
O
2a
2b
2c
2d
2e
2f
93
91
92
95
96
94
O
7
8
9
2g
2h
2i
95
95
91
P(O)H
O
P(O)NHn-Bu
O
(i-PrO)2P(O)H
t-BuNH2
H2N
(i-PrO)2P(O)NHt-Bu
NHP(O)(Oi-Pr)2
Ph
Ph
H2N
NHP(O)(Oi-Pr)2
10c)
2j
89
CO2Me
H2N
CO2Me
11
12
2k
86
89
(i-PrO)2P(O)NH
(EtO)2P(O)H
2l
(EtO)2P(O)NH
13
14
n-C6H13NH2
n-BuNH2
H2N
n-C6H13NHP(O)(OEt)2
Ph(i-PrO)P(O)NHn-Bu
NHP(O)Ph(OEt)
2m
2n
92
91
Ph(i-PrO)P(O)H
15c)
Ph(EtO)P(O)H
2o
93
CO2Me
CO2Me
16c)
n-BuNH2
2p
90
O
P
H
O
P
O
O
n-BuHN
17c)
18c)
Ph2P(O)H
(i-PrO)2P(O)H
n-Bu2NH2
n-BuNH
Ph2P(O)NHn-Bu
(i-PrO)2P(O)Nn-Bu2
2q
2r
13
21
i-PrO
i-PrO
O
O
P
P
H
O
O
H2N
N
O
N
O
O
O
19c)
2s
86
NH
CO2Me
HN
HN
CO2Me
O
O
a) 1 (1.0 mmol) in 3 mL of EtOAc was added dropwise to a mixture of CuBr2 (0.02 mmol) and an amine
(1.1 mmol) in 5 mL of EtOAc. b) Isolated yields. c) CuBr2 (0.03 mmol), 8 h. d) CuI (0.04 mmol), 12 h.
and 15). A copper catalyst is essential for this coupling. In the
absence of a copper catalyst, no reaction took place at all.
method to allow the access to highly functionalized targets.
Optically pure P-stereogenic H-phosphinates8 can also be used
as the substrate in the reaction (eq 2). Thus, optically pure (RP)-
(¹)-menthyl phenylphosphinate and (RP)-(¹)-menthyl benzyl-
phosphinate reacted with butylamine to afford the corresponding
optically active amidophosphinate in high yields. As confirmed
by NMR, only one diastereomer was formed in the mixture. When
a diastereomeric mixture (R = Ph, RP/SP = 60/40) was used as the
substrate, a diastereomeric mixture of the product was obtained
with the same ratio of 60/40. The configuration at phosphorus
of the product was determined to be RP by comparison with
an authentic sample9 having a (RP)-configuration at phosphorus,
indicating that this Cu-catalyzed aerobic oxidative dehydrocou-
pling reaction takes place in a stereospecific way with inversion of
configuration at phosphorus.
This aerobic oxidative dehydrocoupling reactions could be
applied to a variety of compounds (Table 2). Thus, first, similar to
1a, a variety of H-phosphonates, including the less bulky (Runs 2-
4), long-chained (Run 5), and the cyclic (Run 7), reacted efficiently
with butylamine to give the corresponding amidophosphonates in
excellent yields (Runs 2-7). These H-phosphonates also reacted
with various primary amines including the bulky t-butyl amine
(Run 8). An ester of amino acid (Run 10) also reacted efficiently
to give the corresponding dehydrocoupling products in high
yields under similar conditions. In addition to H-phosphonates,
H-phosphinates also reacted with amines to produce the desired
products in high yields (Runs 14-16). However, diphenylphosphine
oxide gave a low yield of the coupling reaction due to a severe
oxidation of Ph2P(O)H to Ph2PO2H (Run 17). Dibutylamine also
reacted slowly to give low yields of the product (Run 18). Worth
noting is that when the highly functionalized H-phosphonate
(Run 19), an analogue of nucleotide which shows unique biologi-
cal activity,7 was used, an anti-HIV analogue could be readily
produced, clearly demonstrating the high potential of this new
O
O
CuBr2 (3 mol%)
P
R1NH2
R1HN
P
+
MenO
ð2Þ
OMen
H
air, 25 °C, 8 h
R
R
(RP)
(RP)
Men = (−)-menthyl
R = Ph, R1 = n-Bu, 2t, 91% yield; R = Ph ,R1 = t-Bu, 2u, 87% yield;
R = CH2Ph, R1 = n-Bu, 2v, 93% yield

402
Bull. Chem. Soc. Jpn. Vol. 87, No. 3 (2014)
© 2013 The Chemical Society of Japan
CuBr2
H2O
P(O)H
Supporting Information
Typical experimental procedures, 1H, 13C, and 31P NMR spectra
of compound 2. This material is available free of charge on the
web at: http://www.csj.jp/journals/bcsj/.
P(O)Br
CuBr
+
HBr
O2
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