and other CÀheterobonds.13 In continuation of our
exploration in CDC reactions,14 we envisioned that the
AthertonÀTodd-type coupling reaction could be per-
formed using iodine as a catalyst. As a result, herein we
report our recent finding on iodine-mediated phophor-
ylations of amines and alcohols without using excess
coupling partner or external base. Special techniques
such as the slow addition of the phosphite (via syringe
pump) are not required, and the strategy does not
require metal salts.
Scheme 1
thesynthesesof phosphoramidate/phosphateesterslargely
involve treating alcohol/amine with appropriate phos-
phorus halides (Scheme 1).8 Phosphorylation of alcohols
has been achieved by using phosphoryl oxazolidinones in
the presence of Lewis acids.9 However, most of the methods
use toxic reagents, harsh reaction conditions, and stoichio-
metric amount of reagents and require multistep reactions.8
Moreover, phosphorus reagents used are more sensitive
and are oxidatively and thermally unstable. For example,
the classical Atherton and Todd reaction for the synthesis
of phosphoramidates employs phosphites, triethylamine,
and toxic CCl4 as a solvent.10a The StaudingerÀphosphite
reaction and other such reactions require either organic
azides or phosphoryl azides.10bÀd To circumvent these pro-
blems, recently, Mizuno and co-workers reported a cross
coupling of phosphites and amides (large excess) to form
phosphoramidates by using Cu(II) acetate and a stoichio-
metric amount of base.11 During the preparation of this
manuscript, Hayes et al. reported a Cu-catalyzed cross-
coupling reaction of phosphites with amines using Cu(I)
iodide as the catalyst, along with stoichiometric amounts
of base and 2 equiv of the amine.12
Table 1. Screening Studiesa
entry
iodine ource
oxidant
air
solvent conversionb (%)
1
I2 (10 mol %)
I2 (10 mol %)
I2 (10 mol %)
I2 (5 mol %)
I2 (10 mol %)
CH2Cl2
15
90
98
78
7
2
aq TBHPc CH2Cl2
d
3
aq H2O2
aq H2O2
O2
CH2Cl2
CH2Cl2
CH2Cl2
d
4
5
6
TBAI (10 mol %) aq TBHPc CH2Cl2
60
60
83
12
25
17
17
5
d
7
TBAI (10 mol %) aq H2O2
CH2Cl2
8
NaI (10 mol %)
NaI (10 mol %)
NIS (10 mol %)
KI (10 mol %)
KI (10 mol %)
NBS (10 mol %)
none
aq TBHPc CH2Cl2
d
9
aq H2O2
aq H2O2
aq H2O2
CH2Cl2
CH2Cl2
CH2Cl2
d
d
10
11
12
13
14
15
16
17
aq TBHPc CH2Cl2
aq TBHPc CH2Cl2
d
aq H2O2
aq H2O2
aq H2O2
aq H2O2
CH2Cl2
H2O
17
20
94
90
d
d
d
I2 (10 mol %)
I2 (10 mol %)
I2 (10 mol %)
Cross-hetero-dehydrogenative coupling (CHDC) reac-
tions, which do not require prefunctionalized starting
materials, are emerging as highly efficient, atom economic-
al and shorter routes for constructing CÀC, CÀN, CÀP,
EtOAc
MeCN
a Reaction conditions: 1 (0.72 mmol), 2 (0.72 mmol), solvent (2 mL),
I2 (10 mol %), H2O2 (1 equiv). b Conversions based on 1H NMR data.
c 70% solution in H2O. d 50% solution in H2O.
(9) (a) Jones, S.; Selitsianos, D. Org. Lett. 2002, 4, 3671. (b) Jones, S.;
Selitsianos, D.; Thompson, K. J.; Toms, S. M. J. Org. Chem. 2003, 68,
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Jones, S.; Smanmoo, C. Org. Lett. 2005, 7, 3271. (e) Liu, C.-Y.; Pawar,
V. D.; Kao, J.-Q.; Chen, C.-T. Adv. Synth. Catal. 2010, 352, 188.
(10) (a) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc.
1945, 660. (b) Wilkening, I.; Signore, d. G.; Hackenberger, C. P. R.
Chem. Commun. 2008, 2932. (c) Serwa, R.; Wilkening, I.; Del Signore,
The screening studies were started by reacting diethyl phos-
phite (1) with indoline (2) in the presence of I2 (10 mol %)
and using air as a terminal oxidant, which afforded diethyl
indolin-1-ylphosphonate (3aa) in 15% yield (entry 1,
Table 1). Performing the reaction in the presence of aq
TBHP or H2O2, resulted in the formation of product 3aa
in excellent yield (entries 2 and 3, Table 1). Reducing the
amount of iodine to 5 mol % resulted in a decrease in the
yield of coupled product 3aa to 78% (entry 4, Table 1).
Employing other iodine sources such as TBAI, NaI,
KI, and NIS with aq TBHP or H2O2 for the reaction
furnished low to moderate yields of 3aa (entry 6À12,
Table 1). Using N-bromosuccinimide (NBS) as a halo-
gen source furnished the expected product in trace
amount (entry 13, Table 1). Reaction of 1 with 2 in the
absence of iodine formed the coupled product 3aa in low
yield (17%, entry 14, Table 1). Solvent screening studies
revealed that CH2Cl2 or EtOAc or MeCN were suitable
solvents for the transformation (entries 15À17). As
H2O2 is an inexpensive and an environmentally benign
€
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Org. Lett., Vol. 15, No. 23, 2013
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