Iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide

Article abstract of DOI:10.1021/jo5018052

An iridium-catalyzed phosphoramidation of arene C-H bonds with phosphoryl azide as the amino source is described. The direct C-H phosphoramidation of arenes bearing pyridinyl, pyrazoyl, and quinolinyl as the directing group has good functional group toler

Full text of DOI:10.1021/jo5018052

Note
pubs.acs.org/joc
Iridium-Catalyzed Phosphoramidation of Arene C−H Bonds with
Phosphoryl Azide
Changduo Pan,†,‡ Ning Jin, Honglin Zhang, Jie Han, and Chengjian Zhu*
†
†
†
†State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
2
10093, P. R. China
‡
Wenzhou Institute of Industry & Science, Wenzhou 325000, P. R. China
S Supporting Information
*
ABSTRACT: An iridium-catalyzed phosphoramidation of
arene C−H bonds with phosphoryl azide as the amino source
is described. The direct C−H phosphoramidation of arenes
bearing pyridinyl, pyrazoyl, and quinolinyl as the directing
group has good functional group tolerance and occurs
smoothly under mild conditions, providing N-aryl phosphor-
amidates in good yields.
hosphoramidates are key structural units that exist in1
Scheme 1. Direct Amidation of C−H Bonds with Organic
Azides
P
various kinds of bioactive molecules and pharmaceuticals.
Thus, the composition of phosphoramidate is of great
significance and a variety of approaches have been explored.
The conventional methods were usually limited to the reaction
2
of suitable phosphorus halides with amines. The Cu- or I -
2
catalyzed oxidative coupling of phosphites with amines were
3
also described. The Staudinger-phosphite reaction furnishes an
alternative approach for phosphoramidate formation using
4
organic azides. However, among those methods, direct
approaches to access N-aryl phosphoramidates were less
5
studied.
Recently, notable advances have been achieved in the direct
6
amination of C−H bonds. Especially, organic azides were
proven to be “energetic reagents” for the direct C−H amination
since nitrogen as the sole byproduct is released during the “NR”
AgOAc (Table 1, entry 8). To our delight, increasing the
amount of AgOAc to 50 mol % led to a 75% yield of product
(Table 1, entry 18). Further studies disclosed the solvent was
crucial. Among the solvents screened such as DCM, DCE, EA,
7
transfer process. For example, elegant approaches for Rh- or
Ru-catalyzed direct amidation of arene C−H bonds with
8
sulfonyl, alkyl, or aryl azides were disclosed by Chang.
THF, dioxane, and CH CN, DCM was the best, whereas only a
3
9n
Subsequently, we and other groups also described the C−H
amidation of arenes with sulfonyl azides. Recently, iridium
trace of product was observed in THF, dioxane, or CH CN.
3
9
Control experiments showed that the product 3aa was not
obtained without [IrCp*Cl ] and a trace of product was
catalysts also attracted special attention for C−H amidation.
2
2
Chang developed the Ir-catalyzed direct C−H amidation with
observed in the absence of AgSbF (Table 1, entries 19 and
6
10
sulfonyl azides or acyl azides. However, the phosphoramida-
tion of an arene C−H bond with phosphoryl azide has not been
reported before. Herein, we disclose the Ir-catalyzed C−H
phosphoramidation of an arene with a phosphoryl azide to
provide N-aryl phosphoramidate (Scheme 1).
20). It is noted that the reaction could be performed to access
3aa in an acceptable 67% yield on a 1 mmol scale.
Next, we attempted to explore the substrate scope of this
protocol. As illustrated in Table 2, the C−H phosphoramida-
tion of arene with phosphoryl azide ran smoothly, affording the
products in good yields. Substituents such as methoxy, chloro,
fluoro, trifluoromethyl, and carboxylate groups in the ortho-,
meta-, and para-position on the 2-arylpyridine were well
tolerated. Notably, a halogen group which is available for
further transformation was compatible (Table 2, 3ha−3ja).
First, we chose 2-phenylpyridine (1a) and diphenyl
phosphorazidate (2a) as the model reaction. After several
catalysts were screened, a 20% yield of product 3aa was
obtained in the presence of [IrCp*Cl ] , while no product was
2
2
observed using [RhCp*Cl ] or [RuCl (p-cymene)] as the
2
2
2
2
catalyst (Table 1, entries 3−4). Next, we attempted to elevate
the yield by investigating the additive. We found the yield could
Received: August 5, 2014
be increased to 50% with the combination of AgSbF and
6
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
a
Table 1. Screening of Conditions for Phosphoramidation
Table 2. Scope of 2-Aryl Pyridine
yield
(%)
entry
catalyst
[IrCp*Cl2]2
[IrCp*Cl2]2
[RhCp*Cl2]2
additive (mol %)
solvent
1
2
3
4
5
6
AgSbF (16)
DCM
DCM
DCM
DCM
DCM
DCM
20
21
0
6
AgNTf (16)
2
AgSbF (16)
6
[RuCl (p-cymene)]
AgSbF (16)
0
2
2
6
[IrCp*Cl2]2
[IrCp*Cl2]2
AgSbF (50)
25
trace
6
AgSbF (16)/
6
Cu(OAc) (20)
2
7
8
9
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
AgSbF (16)/
DCM
DCM
DCM
DCM
DCM
THF
trace
50
6
HOAc (20)
AgSbF (16)/
6
AgOAc (20)
AgSbF (16)/
30
6
NaOAc (20)
10
11
12
13
14
15
16
17
18
AgSbF (16)/
33
6
CsOAc (20)
AgSbF (16)/
36
6
AgBF (20)
4
AgSbF (16)/
trace
45
6
AgOAc (20)
AgSbF (16)/
DCE
6
AgOAc (20)
AgSbF (16)/
acetone
EA
35
6
AgOAc (20)
AgSbF (16)/
40
6
AgOAc (20)
AgSbF (16)/
dioxane
trace
trace
75
6
AgOAc (20)
AgSbF (16)/
CH CN
6
3
AgOAc (20)
AgSbF (16)/
DCM
6
AgOAc (50)
1
9
0
[IrCp*Cl2]2
−
AgOAc (50)
DCM
DCM
trace
0
2
AgSbF (16)/
6
AgOAc (50)
a
Conditions: 1a (0.1 mmol), 2a (0.2 mmol), catalyst (4 mol %),
additive, and solvent (1.0 mL) under Ar, 24 h, 60 °C.
Particularly, the reaction exhibited good regioselectivity. For
example, when arylpyridines 1c and 1f were submitted to the
procedure, the sole products 3ca and 3fa were obtained due to
less steric hindrance. Substrates substituted on the pyridine
motif were also applicable to this phosphoramidation
procedure. The desired products were obtained in good yields
when substitutions occurred at the 3-, 4-, or 5-position of
pyridine (Table 2, 3na, 3oa, and 3pa). The diethyl
phosphorazidate was also a proper substrate for this process,
albeit a moderate yield was obtained (Table 2, 3ab).
Next, we tried to further investigate other directing groups
instead of pyridine (Table 3). To our delight, the desired
products were obtained in moderate yields when pyrazole
group was used as the directing group. As expected,
benzo[h]quinolone was also a good partner in the Ir-catalyzed
C−H phosphoramidation process, providing the diphenyl
benzo[h]quinolin-10-ylphosphoramidate 5fa in 55% yield.
To access some insights into the mechanism, a series of
preliminary isotopic experiments were conducted. A significant
H/D scrambling was observed in the ortho-position of 2-
a
Conditions: 1 (0.1 mmol), 2 (0.2 mmol), [IrCp*Cl ] (4 mol %),
2
2
AgSbF (16 mol %), AgOAc (50 mol %) and DCM (1.0 mL) under
Ar, 24 h, 60 °C.
6
phenylpyridine 1a when it was treated with a catalytic amount
of [IrCp*Cl ] and AgSbF in DCM and D O (Scheme 2, eq
1). When the reaction was performed in the presence of
diphenyl phosphorazidate in DCM/D O, deuterium incorpo-
ration was also observed in the unreacted 1a (Scheme 2, eq 2).
2
2
6
2
2
2
These results suggested that the sp C−H bond cleavage in this
phosphoramidation is a reversible process. In addition, the
result that the D-incorporation is higher in the phosphor-
amidated product (40% D) than in the recovered starting
material (10% D) also showed that C−H activation occurs
faster than the exchange of substrate coordinated to the
catalyst. Moreover, the kinetic isotope effect (k /k = 1.04)
H
D
was determined by an intermolecular competition experiment
with isotopically labeled 1a′ (Scheme 2, eq 3). It also indicated
2
that cleavage of the sp C−H bond in this phosphoramidation
B
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 3. Scope of 1-Aryl-1H-pyrazole
Scheme 3. Direct C−H Phosphoramidation Catalyzed by
Iridacyclic Intermediate 6
Scheme 4. Proposed Mechanism
a
Conditions: 4 (0.1 mmol), 2a (0.2 mmol), [IrCp*Cl ] (4 mol %),
2
2
AgSbF (16 mol %), AgOAc (50 mol %), and DCM (1.0 mL) under
6
Ar, 24 h, 60 °C.
11a
is reversible. Notablely, an iridacyclic intermediate 6 treated
with AgSbF could catalyze the direct C−H phosphoramidation
6
of 2-phenylpyridine with diphenyl phosphorazidate (Scheme
3
). This result showed that the cationic metallacycle 6 may be
the precatalyst in this phosphoramidation.
According to the above-mentioned mechanistic experiments
10
and previous studies, we proposed a possible mechanistic
pathway in Scheme 4. First, treatment of a dimeric iridium
species with AgSbF and AgOAc generates the active Ir(III)
6
catalyst, which induces a C−H bond cleavage of 1a to produce
11
a cyclometalated Ir(III) complex A. Subsequently, coordina-
tion of the phosphoryl azide to A to form the Ir-species B,
followed by migratory insertion, leads to the intermediate C,
phosphoramidation product 3aa and generates the active Ir
complex.
In summary, we have developed an iridium-catalyzed
phosphoramidation of arene C−H bonds with phosphoryl
releasing byproduct N . Finally, protonolysis of C provides the
2
Scheme 2. Deuteration Experiments
C
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz), 125.1, 122.4, 120.4, 120.3, 116.8 (d, J = 1.5 Hz), 20.9. 31P NMR
azide. This present reaction is compatible with several directing
groups such as pyridinyl, pyrazoyl, and quinolinyl, and the
direct C−H phosphoramidation of the substrates with various
−1
(
1
CDCl , 162 MHz): δ −7.48. IR (cm ) ν 3452, 3038, 2920, 1536,
3
463, 1412, 1258, 1154, 1011. HRMS (ESI) m/z calcd for
+
C H N NaO P (M + Na) 439.1182, found 439.1180.
24
21
2
3
functional groups (−OMe, −Me, −Cl, −F, −CF , −COOMe,
3
Diphenyl (5-Methoxy-2-(pyridin-2-yl)phenyl)phosphoramidate
−
t-Bu) proceeded smoothly under mild conditions, providing
N-aryl phosphoramidates in good yields.
3ea). Colorless liquid (31.5 mg, 73%). 1H NMR (CDCl , 400
(
3
MHz): δ 11.61 (d, J = 12.2 Hz, 1H), 8.42 (d, J = 4.1 Hz, 1H), 7.75−
7
.70 (m, 1H), 7.66−7.64 (m, 2H), 7.30−7.24 (m, 8H), 7.15−7.11 (m,
1
3
1
EXPERIMENTAL SECTION
3H), 6.63 (dd, J = 2.5, 8.8 Hz, 1H), 3.86 (s, 3H). C{ H} NMR
(CDCl , 100 MHz): δ 161.1, 157.6, 150.6 (d, J = 6.9 Hz), 146.8, 141.3,
■
1
3
General Information. NMR spectra (400 MHz for H, 100 MHz
13
31
137.3, 129.7, 125.1, 120.91, 120.90, 120.5, 120.4, 116.6 (d, J = 10.0
for C, 162 MHz for P) were recorded in CDCl3 at ambient
temperature on a NMR spectrometer. Chemical shifts are reported in
31
Hz), 108.2, 104.4 (d, J = 2.4 Hz), 55.4. P NMR (CDCl , 162 MHz):
3
−1
δ −7.64. IR (cm ) ν 3458, 3036, 2912, 1521, 1472, 1420, 1251, 1148,
δ units, parts per million (ppm). Coupling constants (J) are described
+
in Hz. All 13C NMR spectra were accessed with 1H decoupling. HRMS
1016. HRMS (ESI) m/z calcd for C H N NaO P (M + Na)
2
4
21
2
4
4
55.1131, found 455.1130.
Diphenyl (4-Methoxy-2-(pyridin-2-yl)phenyl)phosphoramidate
3fa). Colorless liquid (30.6 mg, 71%). 1H NMR (CDCl , 400
data were performed on a TOF LC/MS.
Diphenyl phosphorazidate 2a is commercially available. The diethyl
(
3
phosphorazidate 2b was synthesized according to the reported
1
2
1
MHz): δ 10.94 (d, J = 12.0 Hz, 1H), 8.49 (d, J = 4.8 Hz, 1H), 7.78−
literature.
1
1
H NMR (CDCl , 400 MHz): δ 4.14−4.06 (m, 4H),
3
13
1
7.75 (m, 1H), 7.68−7.63 (m, 2H), 7.27−7.19 (m, 10H), 7.13−7.09
.36−1.32 (m, 6H). C{ H} NMR (CDCl , 100 MHz): δ 63.7, 63.6,
6.0, 15.9.
3
13
1
(
m, 2H), 6.98 (dd, J = 8.9, 2.9 Hz, 1H), 3.84 (s, 3H). C{ H} NMR
(
CDCl , 100 MHz): δ 157.5, 154.6, 150.6 (d, J = 6.8 Hz), 147.4, 137.5,
Caution: the phosphoryl azides may be explosive, please operate
carefully.
Typical Procedure for Iridium-Catalyzed Phosphoramida-
3
1
32.5, 129.6, 125.8 (d, J = 9.7 Hz), 125.0 (d, J = 1.0 Hz), 122.1, 121.9,
3
1
1
20.9 (d, J = 1.9 Hz), 120.4 (d, J = 4.8 Hz), 115.5, 114.5, 55.7.
P
−1
tion of Arene C−H Bonds with Phosphoryl Azide. The mixture
of 2-phenylpyridine 1a (0.1 mmol, 15.5 mg), diphenyl phosphor-
azidate 2a (0.2 mmol, 55 mg), [IrCp*Cl ] (4 mol %, 3.2 mg), AgSbF
6
NMR (CDCl , 162 MHz): δ −7.03. IR (cm ) ν 3446, 3027, 2916,
1526, 1468, 1416, 1246, 1130, 1009. HRMS (ESI) m/z calcd for
C
3
+
H
21
N
NaO
P (M + Na) 455.1131, found 455.1133.
2
2
24
2
4
(
16 mol %, 6.2 mg), AgOAc (50 mol %, 8.3 mg), and DCM (1.0 mL)
Diphenyl (5-(tert-Butyl)-2-(pyridin-2-yl)phenyl)phosphoramid-
1
was added into a sealed tube. After stirring at 60 °C for 24 h under Ar,
the mixture was concentrated and then purified by preparative TLC on
GF254 (petroleum/ethyl acetate) to access the product 3aa.
ate(3ga). Colorless liquid (31.6 mg, 69%). H NMR (CDCl , 400
3
MHz): δ 11.70 (d, J = 12.3 Hz, 1H), 8.49 (d, J = 4.7 Hz, 1H), 7.77−
7.69 (m, 3H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.28−7.23 (m, 8H),
13
1
Diphenyl (2-(Pyridin-2-yl)phenyl)phosphoramidate (3aa). Color-
7.18−7.09 (m, 4H), 1.37 (s, 9H). C{ H} NMR (CDCl , 100 MHz):
3
1
less liquid (30.1 mg, 75%). H NMR (CDCl , 400 MHz): δ 11.61 (d, J
δ 157.7, 153.8, 150.7 (d, J = 6.8 Hz), 147.1, 139.2, 137.3, 129.7, 128.2,
125.0 (d, J = 1.1 Hz), 121.4 (d, J = 4.8 Hz), 121.1 (d, J = 10.0 Hz),
3
=
12.2 Hz, 1H), 8.48 (d, J = 4.9 Hz, 1H), 7.75−7.68 (m, 4H), 7.41−
3
1
7
.37 (m, 1H), 7.29−7.22 (m, 8H), 7.20−7.17 (m, 1H), 7.14−7.06 (m,
120.5, 120.4, 118.9, 116.8 (d, J = 2.4 Hz), 34.9, 31.2. P NMR
1
−1
3
H). 13C{ H} NMR (CDCl , 100 MHz): δ 157.7, 150.6 (d, J = 6.8
(CDCl , 162 MHz): δ −7.37. IR (cm ) ν 3442, 3021, 2910, 1512,
3
3
Hz), 147.1, 139.4, 137.5, 130.4, 129.7, 128.7, 125.1 (d, J = 1.0 Hz),
1456, 1396, 1240, 1128, 1022. HRMS (ESI) m/z calcd for
+
1
24.0 (d, J = 10.0 Hz), 121.9, 121.8 (d, J = 12.4 Hz), 120.5, 120.4,
C H N NaO P (M + Na) 481.1652, found 481.1650.
27
27
2
3
31
1
19.6 (d, J = 2.4 Hz). P NMR (CDCl , 162 MHz): δ −7.49. IR
Diphenyl (5-Fluoro-2-(pyridin-2-yl)phenyl)phosphoramidate
3
−1
(3ha). Colorless liquid (31.1 mg, 74%). 1H NMR (CDCl , 400
(
cm ) ν 3474, 3065, 1589, 1456, 1433, 1399, 1276, 1162, 1012.
3
+
HRMS (ESI) m/z calcd for C H N NaO P (M + Na) 425.1026,
MHz): δ 11.97 (d, J = 11.8 Hz, 1H), 8.47 (d, J = 4.9 Hz, 1H), 7.79−
7.75 (m, 1H), 7.70−7.65 (m, 2H), 7.50−7.47 (m, 1H), 7.31−7.23 (m,
8H), 7.21−7.18 (m, 1H), 7.16−7.12 (m, 2H), 6.80−6.76 (m, 1H).
23
19
2
3
found 425.1028.
Diphenyl (5-Methyl-2-(pyridin-2-yl)phenyl)phosphoramidate
1
(
3ba). Colorless liquid (30.2 mg, 77%). H NMR (CDCl , 400
13
1
3
C{ H} NMR (CDCl , 100 MHz): δ 163.6 (d, J
= 247.1 Hz),
C−F
3
MHz): δ 11.86 (d, J = 11.7 Hz, 1H), 8.48 (d, J = 4.3 Hz, 1H), 7.79−
1
57.0, 150.5 (d, J = 6.9 Hz), 147.0, 141.6 (d, J = 10.9 Hz), 137.6, 130.2
7
9
.75 (m, 2H), 7.69−7.67 (m, 1H), 7.63−7.61 (m, 1H), 7.31−7.20 (m,
(d, J = 10.2 Hz), 129.7, 125.1 (d, J = 1.1 Hz), 121.6 (d, J = 13.3 Hz),
13 1
H), 7.16−7.12 (m, 2H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H). C{ H}
1
2
20.4, 120.3, 119.9 (q, JC−F = 3.1 Hz, J = 10.1 Hz), 108.8 (d, J
=
C−F
NMR (CDCl , 100 MHz): δ 157.7, 150.7 (d, J = 6.9 Hz), 146.9, 140.7,
31
3
1.7 Hz), 119.9 (q, J = 2.5 Hz, J = 25.6 Hz). P NMR (CDCl , 162
C−F
3
1
1
2
2
39.4, 137.4, 129.7, 128.5, 125.1 (d, J = 0.8 Hz), 122.8, 121.4 (d, J =
−1
MHz): δ −8.24. IR (cm ) ν 3460, 3042, 1529, 1468, 1410, 1251,
0.9 Hz), 121.2 (d, J = 10.1 Hz), 120.5, 120.4, 120.1 (d, J = 2.3 Hz),
P (M + Na)+
H18FN NaO
2 3
1.6. 31P NMR (CDCl , 162 MHz): δ −7.43. IR (cm−1) ν 3463, 3052,
1144, 1016. HRMS (ESI) m/z calcd for C23
43.0931, found 443.0932.
Diphenyl (5-Chloro-2-(pyridin-2-yl)phenyl)phosphoramidate
3
4
924, 1568, 1460, 1424, 1390, 1256, 1142, 1008. HRMS (ESI) m/z
+
calcd for C H N NaO P (M + Na) 439.1182, found 439.1182.
3ia). Colorless liquid (31.8 mg, 73%). 1H NMR (CDCl , 400
24
21
2
3
(
3
Diphenyl (4-Methyl-2-(pyridin-2-yl)phenyl)phosphoramidate
3ca). Colorless liquid (29.9 mg, 72%). 1H NMR (CDCl , 400
MHz): δ 11.85 (d, J = 11.7 Hz, 1H), 8.48 (d, J = 4.3 Hz, 1H), 7.79−
(
3
7
9
.75 (m, 2H), 7.69−7.67 (m, 1H), 7.63−7.61 (m, 1H), 7.31−7.20 (m,
MHz): δ 11.33 (d, J = 12.2 Hz, 1H), 8.47 (d, J = 4.2 Hz, 1H), 7.77−
13 1
H), 7.16−7.12 (m, 2H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H). C{ H}
7
.73 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.48
NMR (CDCl , 100 MHz): δ 156.8, 150.4 (d, J = 6.9 Hz), 147.1, 140.8,
(
s, 1H), 7.28−7.16 (m, 10H), 7.13−7.09 (m, 2H), 2.36 (s, 3H).
3
1
3
1
137.7, 136.0, 129.8, 129.6, 125.2 (d, J = 1.0 Hz), 122.1 (d, J = 10.0
Hz), 122.0 (d, J = 6.3 Hz), 121.7, 120.4, 120.3, 119.4 (d, J = 2.4 Hz).
C{ H} NMR (CDCl , 100 MHz): δ 157.8, 150.6 (d, J = 6.9 Hz),
3
1
1
2
3
47.2, 137.4, 136.8, 131.1 (d, J = 10.3 Hz), 129.7, 129.2, 125.0 (d, J =
3
1
−1
P NMR (CDCl , 162 MHz): δ −7.64. IR (cm ) ν 3445, 3036, 1518,
.1 Hz), 124.1 (d, J = 9.9 Hz), 121.9, 121.6, 120.5, 120.4, 119.6 (d, J =
3
.2 Hz), 20.8. 3 P NMR (CDCl , 162 MHz): δ −7.27. IR (cm ) ν
1
−1
1460, 1401, 1248, 1132, 1010. HRMS (ESI) m/z calcd for
C H ClN NaO P (M + Na) 459.0636, found 459.0635.
3
+
460, 3046, 2915, 1548, 1451, 1420, 1250, 1150, 1006. HRMS (ESI)
23 18
2
3
+
Diphenyl (3-Chloro-2-(pyridin-2-yl)phenyl)phosphoramidate
m/z calcd for C H N NaO P (M + Na) 439.1182, found 439.1181.
24
21
2
3
(
3ja). Colorless liquid (30.9 mg, 71%). 1H NMR (CDCl , 400
Diphenyl (3-Methyl-2-(pyridin-2-yl)phenyl)phosphoramidate
3
1
(
3da). Colorless liquid (31.2 mg, 75%). H NMR (CDCl , 400
MHz): δ 8.63 (d, J = 4.8 Hz, 1H), 7.77−7.72 (m, 1H), 7.63 (d, J = 8.7
3
MHz): δ 8.65 (d, J = 4.2 Hz, 1H), 7.73−7.68 (m, 1H), 7.54 (d, J = 8.1
Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.33−7.25 (m, 6H), 7.20−7.12 (m,
7H). 13C{ H} NMR (CDCl
1
, 100 MHz): δ 154.3, 150.2 (d, J = 6.6
3
Hz, 1H), 7.31−7.22 (m, 6H), 7.16−7.08 (m, 7H), 7.00 (d, J = 7.6 Hz,
1
3
1
1
1
1
H), 6.81 (d, J = 11.3 Hz, 1H), 2.15 (s, 3H). C{ H} NMR (CDCl ,
Hz), 149.1, 138.8 (d, J = 1.7 Hz), 136.8, 133.3 (d, J = 1.4 Hz), 130.0,
129.8, 127.1, 125.3 (d, J = 1.2 Hz), 124.4, 122.9, 120.3, 120.2, 118.0
3
00 MHz): δ 156.3, 150.7 (d, J = 6.6 Hz), 149.7, 136.9, 136.8 (d, J =
0.9 Hz), 129.7, 129.5 (d, J = 10.6 Hz), 129.0, 126.0, 125.2 (d, J = 1.1
(d, J = 1.5 Hz). 31P NMR (CDCl , 162 MHz): δ −8.17. IR (cm ) ν
−1
3
D
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3
452, 3025, 1532, 1452, 1409, 1239, 1123, 1002. HRMS (ESI) m/z
Diethyl (2-(Pyridin-2-yl)phenyl)phosphoramidate (3ab). Colorless
+
1
calcd for C H ClN NaO P (M + Na) 459.0636, found 459.0633.
liquid (15.9 mg, 52%). H NMR (CDCl , 400 MHz): δ 10.82 (d, J =
23
18
2
3
3
Diphenyl (4-(Pyridin-2-yl)-[1,1′-biphenyl]-3-yl)phosphoramidate
11.1 Hz, 1H), 8.63 (d, J = 4.7 Hz, 1H), 7.83−7.74 (m, 2H), 7.67 (d, J
= 7.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.24
(t, J = 6.0 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.22−4.05 (m, 4H), 1.31
(
3ka). Colorless liquid (34.9 mg, 73%). 1H NMR (CDCl , 400
3
MHz): δ 11.83 (d, J = 12.1 Hz, 1H), 8.49 (d, J = 4.8 Hz, 1H), 8.00 (d,
J = 1.7 Hz, 1H), 7.78−7.75 (m, 3H), 7.68−7.66 (m, 2H), 7.47−7.44
(t, J = 7.0 Hz, 6H). 13C{ H} NMR (CDCl , 100 MHz): δ 158.1, 147.3,
1
3
(
7
m, 2H), 7.39−7.37 (m, 1H), 7.34−7.32 (m, 1H), 7.27−7.24 (m, 8H),
140.0, 137.4, 130.2, 128.8, 123.6 (d, J = 9.7 Hz), 122.0, 121.6, 121.0,
1
3
1
31
.21−7.17 (m, 1H), 7.14−7.10 (m, 1H). C{ H} NMR (CDCl , 100
118.7 (d, J = 2.4 Hz), 62.7 (d, J = 5.0 Hz), 16.1 (d, J = 7.0 Hz).
P
3
−1
MHz): δ 157.4, 150.6 (d, J = 6.8 Hz), 147.1, 142.9, 140.0 (d, J = 8.5
NMR (CDCl , 162 MHz): δ −1.98. IR (cm ) ν 3435, 3026, 1533,
1452, 1399, 1242, 1133, 1010. HRMS (ESI) m/z calcd for
3
Hz), 137.5, 129.7, 129.0, 128.9, 127.9, 127.1, 125.17, 125.16, 122.7 (d,
3
1
+
J = 10.0 Hz), 121.7, 120.52, 120.50, 120.4, 118.0 (d, J = 2.3 Hz).
P
C H N NaO P (M + Na) 329.1026, found 329.1027.
15
19
2
3
−1
NMR (CDCl , 162 MHz): δ −8.28. IR (cm ) ν 3459, 3020, 1541,
444, 1413, 1242, 1116, 1012. HRMS (ESI) m/z calcd for
Diphenyl (2-(1H-Pyrazol-1-yl)phenyl)phosphoramidate (5aa).
3
1
1
Colorless liquid (26.9 mg, 69%). H NMR (CDCl , 400 MHz): δ
3
+
C H N NaO P (M + Na) 501.1339, found 501.1341.
8.97 (d, J = 10.8 Hz, 1H), 7.76 (dd, J = 8.2, 1.0 Hz, 1H), 7.70−7.68
2
9
23
2
3
Methyl 3-((Diphenoxyphosphoryl)amino)-4-(pyridin-2-yl)-
(m, 2H), 7.34−7.25 (m, 6H), 7.20−7.13 (m, 6H), 7.10−7.06 (m, 1H).
1
13
1
benzoate (3la). Colorless liquid (28.0 mg, 61%). H NMR (CDCl ,
3
C{ H} NMR (CDCl , 100 MHz): δ 150.3 (d, J = 6.8 Hz), 140.9,
3
4
(
00 MHz): δ 11.60 (d, J = 12.1 Hz, 1H), 8.55 (d, J = 4.9 Hz, 1H), 8.44
1
32.7 (d, J = 2.3 Hz), 129.7, 129.5, 128.7 (d, J = 10.6 Hz), 128.1, 125.3
d, J = 1.0 Hz, 1H), 7.82−7.72 (m, 4H), 7.30−7.24 (m, 9H), 7.15−
31
(d, J = 1.1 Hz), 122.6, 122.4, 120.4, 120.3, 107.1. P NMR (CDCl3,
1
7
1
1
8
1
1
.11 (m, 2H), 3.96 (s, 3H). 13C{ H} NMR (CDCl , 100 MHz): δ
−1
3
162 MHz): δ −8.03. IR (cm ) ν 3444, 3036, 1541, 1440, 1390, 1236,
1
66.5, 156.7, 150.5 (d, J = 6.9 Hz), 147.4, 139.5, 137.7, 131.5, 129.7,
+
120, 1009. HRMS (ESI) m/z calcd for C H N NaO P (M + Na)
21 18 3 3
28.7, 127.6 (d, J = 9.9 Hz), 125.2 (d, J = 1.0 Hz), 122.7, 122.5 (d, J =
4
14.0978, found 414.0977.
Diphenyl (5-Methyl-2-(1H-pyrazol-1-yl)phenyl)phosphoramidate
31
.6 Hz), 120.6 (d, J = 2.3 Hz), 120.5, 120.4, 52.4. P NMR (CDCl3,
−1
1
62 MHz): δ −8.13. IR (cm ) ν 3472, 3036, 2918, 1560, 1458, 1418,
(5ba). Colorless liquid (26.3 mg, 65%). H NMR (CDCl , 400 MHz):
3
260, 1208, 1120, 1022. HRMS (ESI) m/z calcd for C H N NaO P
δ 8.84 (d, J = 10.8 Hz, 1H), 7.67−7.63 (m, 2H), 7.55 (s, 1H), 7.31−
2
5
21
2
5
+
(
M + Na) 483.1080, found 483.1080.
Diphenyl (2-(Pyridin-2-yl)-3-(trifluoromethyl)phenyl)phos-
phoramidate (3ma). Colorless liquid (31.0 mg, 66%). 1H NMR
CDCl , 400 MHz): δ 8.67 (d, J = 4.9 Hz, 1H), 7.89 (d, J = 7.7 Hz,
7.25 (m, 4H), 7.20−7.13 (m, 7H), 6.87 (dd, J = 8.1, 1.1 Hz, 1H), 2.39
(s, 3H). 13C{ H} NMR (CDCl , 100 MHz): δ 150.4 (d, J = 6.8 Hz),
1
3
1
40.7, 138.3, 132.4 (d, J = 2.3 Hz), 129.7, 129.5, 125.3 (d, J = 1.1 Hz),
(
31
3
123.3, 122.3, 120.7 (d, J = 1.8 Hz), 120.4, 120.3, 106.8. P NMR
1
6
1
1
H), 7.55−7.47 (m, 2H), 7.33−7.25 (m, 5H), 7.19−7.08 (m, 7H),
−1
(
CDCl , 162 MHz): δ −7.94. IR (cm ) ν 3438, 3030, 2920, 1538,
3
.31 (d, J = 10.4 Hz, 1H). 13C{ H} NMR (CDCl , 100 MHz): δ 153.9,
1
3
1444, 1401, 1242, 1126, 1012. HRMS (ESI) m/z calcd for
50.1 (d, J = 6.7 Hz), 149.6, 138.1 (d, J = 1.9 Hz), 137.1, 129.8, 129.5,
29.4, 125.8 (q, JC−F = 2.6 Hz), 125.5, 125.4, 123.3, 122.7, 120.8 (q,
+
C H N NaO P (M + Na) 428.1134, found 428.1134.
22
20
3
3
Diphenyl (4-Methoxy-2-(1H-pyrazol-1-yl)phenyl)phosphoramid-
3
1
1
JC−F = 5.2 Hz), 120.2, 120.1. P NMR (CDCl , 162 MHz): δ −8.30.
ate (5ca). Colorless liquid (26.5 mg, 63%). H NMR (CDCl , 400
3
3
−1
IR (cm ) ν 3466, 3028, 1538, 1462, 1408, 1262, 1125, 1028. HRMS
MHz): δ 8.51 (d, J = 10.8 Hz, 1H), 7.69−7.62 (m, 3H), 7.29−7.25 (m,
+
(
4
ESI) m/z calcd for C H F N NaO P (M + Na) 493.0899, found
4H), 7.18−7.12 (m, 6H), 6.89 (dd, J = 8.9, 2.8 Hz, 1H), 6.82 (s, 1H),
24 18 3 2 3
6.41 (t, J = 2.1 Hz, 1H), 3.81 (s, 3H). 13C{ H} NMR (CDCl , 100
1
93.0897.
Diphenyl (2-(3-Methylpyridin-2-yl)phenyl)phosphoramidate
3na). Colorless liquid (28.2 mg, 68%). 1H NMR (CDCl , 400
3
MHz): δ 155.2, 150.4 (d, J = 6.7 Hz), 141.0, 129.7, 129.5, 125.8 (d, J =
2.0 Hz), 125.2 (d, J = 0.9 Hz), 121.8 (d, J = 1.6 Hz), 120.3, 120.2,
(
3
3
1
MHz): δ 8.45 (d, J = 4.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (d, J =
1
(
13.0, 108.9, 107.1, 55.8. P NMR (CDCl , 162 MHz): δ −7.42. IR
3
−1
7
8
(
.6 Hz, 1H), 7.41−7.37 (m, 1H), 7.34−7.23 (m, 6H), 7.18−7.08 (m,
cm ) ν 3446, 3026, 2916, 1532, 1452, 1408, 1236, 1133, 1032.
HRMS (ESI) m/z calcd for C H N NaO P (M + Na) 444.1084,
13 1
+
H), 2.11 (s, 3H). C{ H} NMR (CDCl , 100 MHz): δ 156.1, 150.3
3
22 20 3 4
d, J = 6.5 Hz), 146.6, 139.7, 136.8, 132.4, 129.7, 129.4, 128.4 (d, J =
found 444.1081.
1
0.4 Hz), 125.2 (d, J = 1.1 Hz), 122.6, 122.1, 120.4, 120.3, 119.6, 19.7.
Diphenyl (5-Chloro-2-(1H-pyrazol-1-yl)phenyl)phosphoramidate
3
1
−1
1
P NMR (CDCl , 162 MHz): δ −7.52. IR (cm ) ν 3442, 3042, 2909,
(5da). Colorless liquid (26.3 mg, 62%). H NMR (CDCl , 400 MHz):
3
3
1
520, 1453, 1420, 1251, 1128, 1006. HRMS (ESI) m/z calcd for
C H N NaO P (M + Na) 439.1182, found 439.1181.
δ 9.15 (d, J = 10.5 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.71−7.66 (m,
+
2H), 7.32−7.28 (m, 4H), 7.21−7.14 (m, 7H), 6.87 (dd, J = 8.5, 2.2
2
4
21
2
3
Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H). 13C{ H} NMR (CDCl , 100 MHz):
1
Diphenyl (2-(4-Methylpyridin-2-yl)phenyl)phosphoramidate
3
(
3oa). Colorless liquid (27.0 mg, 65%). 1H NMR (CDCl , 400
δ 150.2 (d, J = 6.8 Hz), 141.3, 133.9 (d, J = 2.0 Hz), 133.5, 129.8,
129.5, 127.1 (d, J = 10.5 Hz), 125.4 (d, J = 1.1 Hz), 123.1, 122.5,
3
MHz): δ 11.69 (d, J = 12.2 Hz, 1H), 8.45 (d, J = 5.0 Hz, 1H), 7.72 (d,
120.3, 120.2, 107.3. 31P NMR (CDCl , 162 MHz): δ −8.81. IR (cm )
−1
J = 8.2 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.39−7.35 (m,
3
1
2
=
H), 7.28−7.22 (m, 8H), 7.13−7.05 (m, 3H), 7.01 (d, J = 5.0 Hz, 1H)
ν 3442, 3028, 1544, 1460, 1416, 1232, 1112. HRMS (ESI) m/z calcd
.39 (s, 3H). 13C{ H} NMR (CDCl , 100 MHz): δ 157.4, 150.6 (d, J
1
+
3
for C H ClN NaO P (M + Na) 448.0588, found 448.0589.
21 17
3
3
6.8 Hz), 148.6, 146.8, 139.5, 130.2, 129.7, 128.6, 125.0 (d, J = 0.9
Diphenyl (2-(3-Methyl-1H-pyrazol-1-yl)phenyl)phosphoramidate
1
Hz), 124.2 (d, J = 10.1 Hz), 122.7, 121.8, 120.5, 120.3, 119.5 (d, J =
(5ea). Colorless liquid (24.3 mg, 60%). H NMR (CDCl , 400 MHz):
3
−1
2
3
.2 Hz), 21.4. 31P NMR (CDCl , 162 MHz): δ −7.45. IR (cm ) ν
δ 9.08 (d, J = 11.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 2.4
Hz, 1H), 7.31−7.19 (m, 10H), 7.17−7.12 (m, 2H), 7.07−7.03 (m,
3
438, 3032, 2912, 1552, 1460, 1411, 1242, 1136, 1018. HRMS (ESI)
m/z calcd for C H N NaO P (M + Na) 439.1182, found 439.1180.
+
13
1
1H), 6.19 (d, J = 2.4 Hz, 1H), 2.31 (s, 3H). C{ H} NMR (CDCl ,
24
21
2
3
3
Diphenyl (2-(5-Fluoropyridin-2-yl)phenyl)phosphoramidate
100 MHz): δ 150.6, 150.4 (d, J = 6.8 Hz), 132.5 (d, J = 2.2 Hz), 130.1,
129.7, 127.7, 125.2 (d, J = 1.1 Hz), 122.5, 122.1, 120.4, 120.3, 120.2
1
(
3pa). Colorless liquid (30.2 mg, 72%). H NMR (CDCl , 400
3
31
MHz): δ 10.81 (d, J = 11.9 Hz, 1H), 8.34 (d, J = 2.9 Hz, 1H), 7.74 (d,
J = 7.5 Hz, 1H), 7.59 (dd, J = 8.9, 4.2 Hz, 1H), 7.61 (d, J = 7.9 Hz,
(d, J = 1.8 Hz), 106.9, 13.7. P NMR (CDCl , 162 MHz): δ −8.00. IR
3
−1
(cm ) ν 3432, 3020, 2924, 1523, 1451, 1410, 1250, 1120, 1001.
+
1
7
J
H), 7.51−7.46 (m, 1H), 7.42−7.37 (m, 1H), 7.29−7.21 (m, 8H),
HRMS (ESI) m/z calcd for C H N NaO P (M + Na) 428.1134,
22
20
3
3
1
3
1
.15−7.06 (m, 3H). C{ H} NMR (CDCl , 100 MHz): δ 158.0 (d,
C−F
found 428.1132.
3
= 255.2 Hz), 154.0, 150.3 (d, J = 6.9 Hz), 138.8, 135.3 (d, JC−F
=
Diphenyl Benzo[h]quinolin-10-ylphosphoramidate (5fa). Color-
1
2
4.4 Hz), 130.3, 129.7, 128.8, 125.2 (d, J = 1.0 Hz), 124.7 (d, J = 18.4
less liquid (23.4 mg, 55%). H NMR (CDCl , 400 MHz): δ 14.11 (d, J
3
Hz), 123.7 (d, J = 10.0 Hz), 123.4 (d, J = 4.4 Hz), 122.1, 120.4 (d, J =
= 12.0 Hz, 1H), 8.76 (dd, J = 4.5, 1.8 Hz, 1H), 8.18 (dd, J = 8.0, 1.8
Hz, 1H), 8.18 (dd, J = 8.0, 1.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.68
(t, J = 7.9 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H),
7.48 (dd, J = 8.0, 4.5 Hz, 1H), 7.34−7.28 (m, 8H), 7.13−7.09 (m,
31
4
.8 Hz), 119.7 (d, J = 2.2 Hz). P NMR (CDCl , 162 MHz): δ −7.60.
3
−1
IR (cm ) ν 3467, 3042, 1556, 1470, 1420, 1402, 1262, 1144, 1025.
HRMS (ESI) m/z calcd for C H FN NaO P (M + Na) 443.0931,
+
23
18
2
3
2H). 13C{ H} NMR (CDCl , 100 MHz): δ 150.7 (d, J = 6.8 Hz),
1
found 443.0930.
3
E
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
47.9, 145.6, 140.7, 136.3, 135.4, 129.7, 129.2, 128.8, 127.1, 125.3,
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31
10.6 Hz), 116.0 (d, J = 2.8 Hz). P NMR (CDCl , 162 MHz): δ
3
−1
−
7.41. IR (cm ) ν 3460, 3030, 1565, 1508, 1463, 1421, 1260, 1142,
1
+
1
4
028. HRMS (ESI) m/z calcd for C H N NaO P (M + Na)
25 19 2 3
49.1026, found 449.1028.
Procedure of H/D Exchange Experiment on 1a. The mixture
of 2-phenylpyridine 1a (0.1 mmol, 15.5 mg), [IrCp*Cl ] (4 mol %,
(
2
2
3.2 mg), AgSbF (16 mol %, 6.2 mg), AgOAc (50 mol %, 8.3 mg), and
6
(
DCM/D O (0.9 mL/0.1 mL) was added into a sealed tube. After
2
stirring at 60 °C for 12 h under Ar, the mixture was concentrated and
then purified by preparative TLC on GF254 (petroleum/ethyl acetate)
to access 1a-[Dn]. The D-incorporation of 26% in 1a-[Dn] was
(
1
1
estimated by H NMR spectroscopy. H NMR (CDCl , 400 MHz): δ
3
8
7
1
.70 (d, J = 4.6 Hz, 1H), 8.00−7.97 (m, 1.74H), 7.77−7.71 (m, 2H),
(
.48−7.39 (m, 3H), 7.24−7.21 (m, 1H). MS (ESI) m/z: 156.42,
57.42 (M + H) , 178.50, 179.58 (M + Na) .
+
+
Procedure of H/D Exchange Experiment on 1a with 2a. The
2
(
5
3
(
2
(
mixture of 2-phenylpyridine 1a (0.1 mmol, 15.5 mg), diphenyl
phosphorazidate 2a (0.2 mmol, 55 mg), [IrCp*Cl ] (4 mol %, 3.2
mg), AgSbF (16 mol %, 6.2 mg), AgOAc (50 mol %, 8.3 mg), and
DCM/D O (0.9 mL/0.1 mL) was added into a sealed tube. After
stirring at 60 °C for 12 h under Ar, the mixture was concentrated and
then purified by preparative TLC on GF254 (petroleum/ethyl acetate)
2
2
6
2
to access 1a-[Dn] and 3aa-[Dn]. The D-incorporation of 10% in 1a-
1
[
Dn] and 40% in 3aa-[Dn] was estimated by H NMR spectroscopy.
1
1
8
7
a-[Dn]: H NMR (CDCl , 400 MHz): δ 8.70 (d, J = 4.7 Hz, 1H),
3
.00−7.97 (m, 1.9H), 7.77−7.71 (m, 2H), 7.49−7.39 (m, 3H), 7.24−
+
1
.21 (m, 1H). MS (ESI) m/z: 156.58, 157.58 (M + H) . 3aa-[Dn]: H
5
(
NMR (CDCl , 400 MHz): δ 11.60 (d, J = 11.2 Hz, 1H), 8.49 (d, J =
3
4
.8 Hz, 1H), 7.80−7.69 (m, 3.6H), 7.41−7.37 (m, 1.0 H), 7.29−7.19
(
m, 9H), 7.14−7.07 (m, 3H). MS (ESI) m/z: 403.75, 404.67 (M +
+
+
H) , 425.58, 426.33 (M + Na) .
Procedure of Intermolecular Competition Experiment with
Isotopically Labeled 1a′. The mixture of 2-phenylpyridine 1a (0.05
mmol), 1a′ (0.05 mmol), diphenyl phosphorazidate 2a (0.2 mmol),
[
(
IrCp*Cl ] (4 mol %, 3.2 mg), AgSbF (16 mol %, 6.2 mg), AgOAc
2 2 6
50 mol %, 8.3 mg), and DCM (1.0 mL) was added into a sealed tube.
After stirring at 60 °C for 12 h under Ar, the mixture was concentrated
and then purified by preparative TLC on GF254 (petroleum/ethyl
1
acetate) to access 3aa and 3aa′. H NMR (CDCl , 400 MHz): δ 11.61
3
(
d, J = 12.2 Hz, 1H), 8.48 (d, J = 4.8 Hz, 1H), 7.78−7.68 (m, 3.51H),
7
7
4
.41−7.37 (m, 0.51H), 7.29−7.22 (m, 8H), 7.20−7.17 (m, 1H), 7.14−
+
.08 (m, 2.52H). MS (ESI) m/z: 403.83, 406.67, 407.67 (M + H) ,
25.75, 428.42, 429.33 (M + Na) .
+
ASSOCIATED CONTENT
■
*
S
Supporting Information
1
H, 13C, and 31P NMR spectra of all the products, ESI spectra
of compounds 1a-[Dn], 3aa-[Dn], and 3aa′. This material is
(
2
(
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
2
1
Corresponding Author
*
E-mail: cjzhu@nju.edu.cn.
Notes
(
1
The authors declare no competing financial interest.
30, 12414. (b) Davies, D.; Donald, S.; Al-Duaij, O.; Macgregor, S.;
Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210.
ACKNOWLEDGMENTS
(12) Kim, S.; Jung, D.; Chang, S. J. Org. Chem. 2007, 72, 9769.
■
This work is supported by the National Natural Science
Foundation of China (21172106 and 21372114), the National
Basic Research Program of China (2010CB923303), and the
Research Fund for the Doctoral Program of Higher Education
of China (20120091110010). C.P. thanks the support of
Natural Science Foundation of China (21272178).
F
dx.doi.org/10.1021/jo5018052 | J. Org. Chem. XXXX, XXX, XXX−XXX