Direct oxidative C-P bond formation of indoles with dialkyl phosphites

Article abstract of DOI:10.1055/s-0031-1289700

The direct phosphonation of indoles was developed. In this reaction, dialkyl phosphites and indoles were used as substrates, and the C-P bond was formed through oxidative coupling mediated by silver(I) acetate. Various indoles and different dialkyl phosphites were effective substrates for the reaction, and dialkylphosphoryl-substituted indoles were obtained in up to 71% yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289700

PAPER
941
Direct Oxidative C–P Bond Formation of Indoles with Dialkyl Phosphites
Formation of
D
ialk
a
oxyphosph
o
oryl-Substitu
l
ted Ind
o
oles ng Wang, Xincheng Li, Fan Wu, Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, P. R. of China
Fax +86(411)84379223; E-mail: bswan@dicp.ac.cn
Received 13 December 2011; revised 15 January 2012
a
palladium-assisted cyclization–coupling reaction10
Abstract: The direct phosphonation of indoles was developed. In
this reaction, dialkyl phosphites and indoles were used as substrates,
and the C–P bond was formed through oxidative coupling mediated
by silver(I) acetate. Various indoles and different dialkyl phosphites
(Scheme 1, route B). However, multiple steps were neces-
sary for the synthesis of substrates and harsh conditions
were involved. We surmised that these problems can be
were effective substrates for the reaction, and dialkylphosphoryl- circumvented by instead using the direct phosphonation
substituted indoles were obtained in up to 71% yield.
of indoles. Herein, we describe a new method for the syn-
thesis of indolylphosphonates in one step via direct oxida-
tive coupling oxidized by silver(I) acetate (Scheme 1,
route C).
Key words: indole, dialkyl phosphite, phosphonation, silver ace-
tate, oxidative coupling
To identify suitable conditions for the direct phosphona-
tion of indoles, the coupling of 1H-indole (1a) and diethyl
phosphite (2a) was chosen as a model reaction. Initially
using silver(I) acetate as the oxidant and 1,2-dichloro-
ethane as the solvent gave the desired product 3aa in 44%
yield (Table 1, entry 1). When other silver oxidants were
used under the same conditions, 3aa was obtained in low-
er yields (entries 2 and 3). To our surprise, using manga-
nese(III) acetate as the oxidant, which has proved to be
efficient for the phosphonation of pyrroles,8 gave 3aa in a
lower, 28%, yield (entry 4). It was also disappointing that
other oxidants were completely ineffective in the oxida-
tive coupling of 1a and 2a (entries 5–7). Although several
transition metals such as copper, iron, palladium, and
rhodium were added, no improvement in the efficiency of
the reaction resulted.11 In the next stage, the influence of
the solvent was examined on the silver(I) acetate cata-
lyzed reaction. In comparison to the reaction in 1,2-
dichloroethane, the use of solvents such as 1,4-dioxane,
toluene, ethanol and acetonitrile gave 3aa in lower yields
(entries 8–11). The use of N,N-dimethylformamide or
dimethyl sulfoxide as the solvent gave only trace amounts
Aryl and heteraryl phosphites are important chemicals in
organic synthesis, medicinal chemistry, and nucleic acid
chemistry.1 Several methods based on established reac-
tions have been developed for the synthesis of dialkyl
arylphosphonates over the last decade; the Michaelis–
Arbuzov reaction has been frequently used.2 Since the re-
ported palladium-catalyzed coupling of aryl and vinyl
bromides in 1980s by Hirao and co-workers,3 various
methods for the transition-metal-catalyzed (such as Pd,
Cu, and Ni) cross-coupling reactions of aryl halides and
phosphonates have been developed.4 Worthy of note is a
new method of C–P bond by palladium-catalyzed oxida-
tive coupling of arylboronic acids or aryltrifluoroborates
with phosphonates developed by Larhed;5a a similar reac-
tion catalyzed by copper was recently reported by Fang
and co-workers.5b On the other hand, the direct phospho-
nation of arenes or hetarenes is a powerful and efficient
tool that gives easy access to arylphosphonates. Fields,6a
Effenberger,6b,c and Zhang6d have reported the synthesis
of arylphosphonates by direct phosphonation using tert-
butyl peroxide, ammonium cerium(IV) nitrate, sodium
persulfate/silver nitrate, or manganese(III). Significant
progress was achieved by Ishii and co-workers,7 who uti-
lized the manganese(II) acetate/cobalt(II) acetate-cata-
lyzed direct C–P bond formation of arenes through a C–H
bond-activation reaction. However, to the best of our
knowledge, the first example of direct phosphonation of
hetarenes was reported by Zhang and co-workers in
2006.8
previous work
route A
NHNH2
Fischer
cyclization
O
P
R3
OR2
OR2
+
R3
O
R1
O
R1
OR2
P
route B
OR2
N
NH2
As potential biologically active chemicals, indolylphos-
phonates are accessible by only a few routes. Fischer cy-
clization (Scheme 1, route A) is the predominate method,
which has been used by several groups for the synthesis of
indolylphosphonates.9 In 2004, Eustache developed a new
method for the synthesis of indolylphosphonates utilizing
Pd-assisted
cyclization–
coupling
H
O
P
Br
+
OEt
H
Br
OEt
this work
route C
oxidative
coupling
O
P
O
H
OR2
OR2
OR2
R1
P
R1
+
H
SYNTHESIS 2012, 44, 941–945
x
x
.x
x
.2
0
1
1
OR2
N
N
H
H
Advanced online publication: 14.02.2012
DOI: 10.1055/s-0031-1289700; Art ID: H114911SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Methods for the synthesis of indolylphosphonates

942
H. Wang et al.
PAPER
of difficult to separate products (entries 12 and 13). To and electron-donating groups, a radical process was pro-
improve the efficiency of the reaction, the addition of var- posed as the phosphonation reaction pathway. This hy-
ious acids, which were used to activate the substrate in pothesis was supported by the regioselectivity of this
previous work,12 to the reaction was examined, but disap- reaction and the outcome of the reaction of phosphite 2a
pointingly this had no influence on the yield of the prod- with 2-phenyl-1H-indole (1f) (entry 16). To further con-
uct.11
firm the radical intermediate in the reaction, the radical in-
hibitor butylated hydroxytoluene (BHT) was added to the
reaction of 1a and 2a, and none of the desired product 3aa
was obtained. As shown in Scheme 2, dialkyl phosphite is
initially oxidized to radical 5 by silver(I) acetate, sequen-
tial addition of 5 to indole 1a affords the intermediate 6,
which is then converted into the desired product 3aa by
oxidation with silver(I) acetate.
Using the optimized reaction conditions, various substi-
tuted indoles 1a–f were reacted with dialkyl phosphites
2a–c (Table 2). In general, indoles 1a–f were readily con-
verted into the corresponding indolylphosphonates 3ac–
ec in moderate to good yields. Indoles bearing either an
electron-donating group 1b or an electron-withdrawing
group 1c readily reacted with dialkyl phosphites 2a–c, al-
beit with lower yields compared indole 1a (entries 4–9 vs. In conclusion, indoles were, for the first time, successfully
entries 1–3). Sterically hindered 3-methyl-1H-indole (1d) phosphonated by C–P bond formation through direct oxi-
was also converted into the desired indolylphosphonates dative coupling using silver(I) acetate. A wide variety of
3da–dc in moderate yields (entries 10–12). Interestingly, indoles and dialkyl phosphites participated in the reaction
a small amount of 3-phosphonation indole products, 4ea, to afford the desired indolylphosphonates in up to 71%
4eb, and 4ec, were obtained when 1-methyl-1H-indole yield. Efforts to improve the efficiency of the reaction and
(1e) was used as the substrate (entries 13–15). Important- confirm the mechanism are in progress.
ly, when 2-methyl- and 2-phenyl-1H-indole (1f) were
used as substrates, 2-methyl-1H-indole gave no product
whereas 2-phenyl-1H-indole (1f) was phosphonated to af-
ford 4fa in good yield (entry 16).
All substrates were purchased from Sigma-Aldrich and used with-
out further purification. Flash column chromatography was per-
formed using 300–400 mesh silica gel with the indicated solvent
system according to standard techniques. Nuclear magnetic reso-
nance spectra were recorded on Bruker DRX-500 MHz spectrome-
ters. High-resolution mass spectra were performed on a Micromass
HPLC Q-TOF mass spectrometer.
The mechanism of the reaction, however, remains un-
clear. Based on the influence of the electron-withdrawing
Table 1 Optimization of the Reaction Conditionsa
O
P
O
P
oxidant
Dialkoxyphosphoryl-Substituted Indoles 3 and 4; General Pro-
cedure
+
OEt
OEt
2a
OEt
OEt
H
solvent, 90 °C
N
N
H
H
Indole 1 (0.5 mmol) and AgOAc (0.75 mmol) were weighed under
air and placed in a 1-dram vial with a Teflon cap and sealed. Subse-
quently, the tube was evacuated and back filled with argon (3 cy-
cles). Diethyl phosphite 2 (0.25 mmol) and CH2Cl2 (2 mL) were
added under an argon atmosphere, and the cap was sealed. After
heated in an oil bath at 90 °C for 24 h, CH2Cl2 (5 mL) was added to
dilute the mixture. The mixture was filtered through Celite, and the
solvent was distilled under vacuum. The crude product was purified
by flash column chromatography (silica gel, CH2Cl2–acetone, 30:1
to 10:1) to give the desired product.
1a
3aa
Entry
Oxidant
AgOAc
Ag2CO3
Ag2O
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Yieldb (%)
1
44
24
23
28
–
2
3
4
Mn(OAc)3
BQc
2-(Diethoxyphosphoryl)-1H-indole (3aa)
White solid; yield: 27.9 mg (44%).
5
1H NMR (400 MHz, CDCl3): d = 10.44 (s, 1 H), 7.68 (d, J = 8.0 Hz,
1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.17–7.10
(m, 1 H), 7.06–7.01 (m, 1 H), 4.26–4.07 (m, 4 H), 1.34 (t, J = 7.1
Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 138.62 (d, J = 13.0 Hz), 127.63
(d, J = 16.0 Hz), 124.97 (s), 124.61 (s), 122.79 (s), 121.92 (d,
J = 1.0 Hz), 112.49 (d, J = 2.0 Hz), 111.73 (d, J = 17.0 Hz), 63.03
(d, J = 5.0 Hz), 16.46 (d, J = 7.0Hz).
6
DDQ
–
7
PhI(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
–
8
1,4-dioxane
27
39
35
19
–
9
toluene
EtOH
10
11
12
13
31P NMR (160 MHz, CDCl3): d = 11.17.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NNaO3P: 276.0766;
MeCN
DMSO
DMF
found: 276.0762.
–
2-(Dimethoxyphosphoryl)-1H-indole (3ab)
Pale yellow solid; yield: 25.0 mg (44%).
1H NMR (500 MHz, CDCl3): d = 10.35 (s, 1 H), 7.70–7.66 (m, 1 H),
7.52 (dd, J = 8.3, 0.8 Hz, 1 H), 7.34–7.27 (m, 1 H), 7.15 (ddd,
a Reaction conditions: indole 1a (0.5 mmol), phosphite 2a (0.25
mmol), oxidant (0.75 mmol), 90 °C, 24 h.
b Isolated yields.
c BQ = 1,4-benzoquinone.
Synthesis 2012, 44, 941–945
© Thieme Stuttgart · New York

PAPER
Formation of Dialkoxyphosphoryl-Substituted Indoles
943
Table 2 Phosphonation of Indolesa
O
OR2
P
R1
R1
R1
O
O
OR2
AgOAc (3 equiv)
DCE, 90 °C
OR2
OR2
+
P
OR2
OR2
+
P
H
N
N
N
H
H
H
1
2
3
4
2a: R2 = Et
2b: R2 = Me
2c: R2 = i-Pr
Entry
1
Indole
1a
1a
1a
1b
1b
1b
1c
R1
Phosphite
2a
R2
Et
Products
3aa
Ratio 3/4
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
15:1
Yieldsb (%)
H
44
44
37
34
37
19
22
18
24
71
53
37
39
44
29
71
2
H
2b
Me
i-Pr
Et
3ab
3
H
2c
3ac
4
5-OMe
5-OMe
5-OMe
5-CO2Me
5-CO2Me
5-CO2Me
3-Me
3-Me
3-Me
1-Me
1-Me
1-Me
2-Ph
2a
3ba
5
2b
Me
i-Pr
Et
3bb
6
2c
3bc
7
2a
3ca
8
1c
2b
Me
i-Pr
Et
3cb
9
1c
2c
3cc
10
11
12
13
14
15
16
1d
1d
1d
1e
2a
3da
2b
Me
i-Pr
Et
3db
2c
3dc
2a
3ea/4ea
3eb/4eb
3ec/4ec
4fa
1e
2b
Me
i-Pr
Et
20:1
1e
2c
20:1
1f
2a
<1:99
a Reaction conditions: indole (0.5 mmol), phosphite (0.25 mmol), AgOAc (0.75 mmol), DCE (2 mL), 90 °C, 24 h.
b Isolated yields.
c The ratio of major and minor products.
H
N
O
P
H
O
P
H
O
O
•
AgOAc
AgOAc
1a
OEt
OEt
2a
•
P
OEt
OEt
P
OEt
OEt
OEt
H
N
H
N
OEt
H
5
6
3aa
Scheme 2 Possible mechanism for the phosphonation of indole
J = 7.9, 7.1, 0.8 Hz, 1 H), 7.06 (ddd, J = 4.2, 2.0, 0.8 Hz, 1 H), 3.81
(d, J = 11.5 Hz, 6 H).
2-(Diisopropoxyphosphoryl)-1H-indole (3ac)
Pale yellow solid; yield: 26.2 mg (37%).
13C NMR (126 MHz, CDCl3): d = 138.75 (d, J = 13.0 Hz), 127.60
(d, J = 15.6 Hz), 124.87 (s), 123.10 (s), 122.00 (s), 121.35 (s),
120.80 (s), 112.66 (s), 112.36 (d, J = 17.5 Hz), 53.42 (d, J = 5.2
Hz).
1H NMR (500 MHz, CDCl3): d = 10.31 (s, 1 H), 7.70–7.65 (m, 1 H),
7.51 (dd, J = 8.3, 0.7 Hz, 1 H), 7.28 (dd, J = 7.9, 7.3 Hz, 1 H), 7.16–
7.11 (m, 1 H), 7.02 (ddd, J = 4.3, 2.0, 0.8 Hz, 1 H), 4.77–4.67 (m, 2
H), 1.39 (d, J = 6.2 Hz, 6 H), 1.26 (d, J = 6.2 Hz, 6 H).
31P NMR (202 MHz, CDCl3): d = 13.86 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C10H12NNaO3P: 248.0453;
13C NMR (126 MHz, CDCl3): d = 138.45 (d, J = 12.8 Hz), 127.78
(d, J = 15.5 Hz), 126.58 (s), 124.83 (s), 124.41 (s), 121.95 (s),
120.55 (s), 112.41 (s), 111.38 (d, J = 16.9 Hz), 71.81 (d, J = 5.1
Hz), 24.30 (d, J = 3.7 Hz), 23.97 (d, J = 5.1 Hz).
found: 248.0449.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 941–945

944
H. Wang et al.
PAPER
31P NMR (202 MHz, CDCl3): d = 8.48 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C14H20NO3NaP: 304.1079;
1H NMR (500 MHz, CDCl3): d = 10.51 (s, 1 H), 8.47 (d, J = 0.7 Hz,
1 H), 8.00 (dd, J = 8.7, 1.3 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.14
(d, J = 3.8 Hz, 1 H), 3.94 (s, 3 H), 3.84 (d, J = 11.5 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 167.94 (s), 140.99 (d, J = 12.6
Hz), 127.20 (d, J = 15.6 Hz), 125.89 (s), 125.34 (s), 123.14 (s),
113.58 (d, J = 16.7 Hz), 112.22 (s), 53.60 (d, J = 5.3 Hz), 52.18 (s).
found: 304.1072.
2-(Diethoxyphosphoryl)-5-methoxy-1H-indole (3ba)
Pale yellow solid; yield: 24.0 mg (34%).
1H NMR (500 MHz, CDCl3): d = 9.98 (s, 1 H), 7.39 (d, J = 8.9 Hz,
1 H), 7.08 (d, J = 2.4 Hz, 1 H), 7.00–6.93 (m, 2 H), 4.24–4.04 (m, 4
H), 3.85 (s, 3 H), 1.33 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 154.86 (s), 133.91 (d, J = 13.0
Hz), 128.05 (d, J = 15.4 Hz), 125.18 (s), 123.43 (s), 116.22 (s),
113.22 (s), 111.35 (d, J = 17.2 Hz), 102.26 (s), 62.97 (d, J = 5.0
Hz), 55.94 (s), 16.47 (d, J = 6.7 Hz).
31P NMR (202 MHz, CDCl3): d = 12.61 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C12H14NNaO5P: 306.0508;
found: 306.0507.
Methyl 2-(Diisopropoxyphosphoryl)-1H-indole-5-carboxylate
(3cc)
Pale yellow solid; yield: 20.7 mg (24%).
31P NMR (202 MHz, CDCl3): d = 10.69 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C13H18NNaO4P: 306.0871;
1H NMR (500 MHz, CDCl3): d = 11.03 (s, 1 H), 8.46 (s, 1 H), 7.98
(dd, J = 8.7, 1.0 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.09 (dd,
J = 4.3, 1.2 Hz, 1 H), 4.81–4.70 (m, 2 H), 3.94 (s, 3 H), 1.40 (d,
J = 6.2 Hz, 6 H), 1.29 (d, J = 6.2 Hz, 6 H).
found: 306.0867.
2-(Dimethoxyphosphoryl)-5-methoxy-1H-indole (3bb)
Pale yellow solid; yield: 23.5 mg (37%).
13C NMR (126 MHz, CDCl3): d = 168.08 (s), 140.93 (d, J = 12.7
Hz), 128.47 (s), 127.29 (d, J = 15.5 Hz), 126.72 (s), 125.30 (d,
J = 18.7 Hz), 122.74 (s), 112.48 (d, J = 16.6 Hz), 112.22 (s), 72.19
(d, J = 5.3 Hz), 52.10 (s), 24.27 (d, J = 3.8 Hz), 23.96 (d, J = 5.0
Hz).
31P NMR (202 MHz, CDCl3): d = 7.48 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C16H22NNaO5P: 362.1133;
1H NMR (500 MHz, CDCl3): d = 10.18 (s, 1 H), 7.41 (d, J = 8.9 Hz,
1 H), 7.08 (d, J = 2.3 Hz, 1 H), 7.01–6.94 (m, 2 H), 3.84 (s, 3 H),
3.80 (d, J = 11.5 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 154.90 (s), 134.12 (d, J = 13.2
Hz), 127.97 (d, J = 15.8 Hz), 123.40 (s), 121.64 (s), 116.46 (s),
113.31 (s), 111.81 (d, J = 17.3 Hz), 102.20 (s), 55.93 (s), 53.37 (d,
J = 5.1 Hz), 29.89 (s).
found: 362.1128.
2-(Diethoxyphosphoryl)-3-methyl-1H-indole (3da)
Pale yellow solid; yield: 47.1 mg (71%).
31P NMR (202 MHz, CDCl3): d = 13.79 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C11H14NNaO4P: 278.0558;
1H NMR (500 MHz, CDCl3): d = 9.51 (s, 1 H), 7.66–7.62 (m, 1 H),
7.44 (d, J = 8.3 Hz, 1 H), 7.30 (dd, J = 8.0, 7.3 Hz, 1 H), 7.17–7.12
(m, 1 H), 4.17 (ddq, J = 14.3, 10.1, 7.1 Hz, 2 H), 4.06 (ddq, J = 10.1,
8.3, 7.1 Hz, 2 H), 2.50 (d, J = 2.0 Hz, 3 H), 1.32 (q, J = 6.9 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 138.06 (d, J = 12.8 Hz), 128.51
(d, J = 16.4 Hz), 124.95 (s), 121.97 (d, J = 17.6 Hz), 120.24 (s),
120.01 (s), 119.44 (s), 117.70 (s), 112.25 (s), 52.85 (d, J = 4.7 Hz),
9.56 (s).
found: 278.0562.
2-(Diisopropoxyphosphoryl)-5-methoxy-1H-indole (3bc)
Pale yellow solid; yield: 14.4 mg (19%).
1H NMR (500 MHz, CDCl3): d = 9.96 (s, 1 H), 7.38 (d, J = 8.9 Hz,
1 H), 7.08 (d, J = 2.4 Hz, 1 H), 6.99–6.92 (m, 2 H), 4.76–4.65 (m, 2
H), 3.85 (s, 3 H), 1.38 (d, J = 6.2 Hz, 6 H), 1.26 (d, J = 6.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 154.78 (s), 133.75 (d, J = 12.9
Hz), 128.15 (d, J = 15.4 Hz), 126.96 (s), 125.21 (s), 115.93 (s),
113.15 (s), 110.95 (d, J = 17.1 Hz), 102.32 (s), 71.74 (d, J = 5.1
Hz), 55.94 (s), 24.30 (d, J = 3.8 Hz), 23.98 (d, J = 5.1 Hz).
31P NMR (202 MHz, CDCl3): d = 12.09 (d, J = 5.8 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C13H18NNaO3P: 290.0922;
found: 290.0918.
31P NMR (202 MHz, CDCl3): d = 8.35 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NNaO4P: 334.1184;
2-(Dimethoxyphosphoryl)-3-methyl-1H-indole (3db)
Pale yellow solid; yield: 31.8 mg (53%).
found: 334.1177.
1H NMR (500 MHz, CDCl3): d = 9.81 (s, 1 H), 7.64 (d, J = 8.0 Hz,
1 H), 7.47 (d, J = 8.3 Hz, 1 H), 7.30 (t, J = 7.6 Hz, 1 H), 7.14 (t,
J = 7.5 Hz, 1 H), 3.77 (d, J = 11.6 Hz, 6 H), 2.50 (d, J = 2.0 Hz, 3
H).
13C NMR (126 MHz, CDCl3): d = 137.89 (d, J = 12.8 Hz), 128.34
(d, J = 16.4 Hz), 124.78 (s), 121.80 (d, J = 17.6 Hz), 120.07 (s),
119.84 (s), 119.27 (s), 117.53 (s), 112.08 (s), 52.67 (d, J = 4.7 Hz),
9.39 (s).
Methyl 2-(Diethoxyphosphoryl)-1H-indole-5-carboxylate (3ca)
Pale yellow solid; yield: 17.1 mg (22%).
1H NMR (500 MHz, CDCl3): d = 10.86 (s, 1 H), 8.46 (d, J = 0.7 Hz,
1 H), 7.98 (dd, J = 8.7, 1.0 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.12
(dd, J = 4.3, 1.1 Hz, 1 H), 4.26–4.12 (m, 4 H), 3.94 (s, 3 H), 1.36 (t,
J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 168.02 (s), 141.00 (d, J = 12.6
Hz), 127.22 (d, J = 15.5 Hz), 126.74 (s), 125.61 (s), 125.26 (s),
122.92 (s), 112.95 (d, J = 16.6 Hz), 112.26 (s), 63.32 (d, J = 5.3
Hz), 52.14 (s), 16.47 (d, J = 6.6 Hz).
31P NMR (202 MHz, CDCl3): d = 15.51 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C11H14NNaO3P: 262.0609;
found: 262.0609.
31P NMR (202 MHz, CDCl3): d = 9.78 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C14H18NNaO5P: 334.0820;
2-(Diisopropoxyphosphoryl)-3-methyl-1H-indole (3dc)
Pale yellow solid; yield: 27.5 mg (37%).
1H NMR (500 MHz, CDCl3): d = 9.61 (s, 1 H), 7.63 (dd, J = 8.0, 0.6
Hz, 1 H), 7.45 (d, J = 8.3 Hz, 1 H), 7.28 (dd, J = 7.9, 7.2 Hz, 1 H),
7.16–7.11 (m, 1 H), 4.70–4.63 (m, 2 H), 2.50 (d, J = 2.0 Hz, 3 H),
1.40 (d, J = 6.2 Hz, 6 H), 1.20 (d, J = 6.2 Hz, 6 H).
found: 334.0818.
Methyl 2-(Dimethoxyphosphoryl)-1H-indole-5-carboxylate
(3cb)
Pale yellow solid; yield: 12.6 mg (18%).
Synthesis 2012, 44, 941–945
© Thieme Stuttgart · New York

PAPER
Formation of Dialkoxyphosphoryl-Substituted Indoles
945
13C NMR (126 MHz, CDCl3): d = 137.59 (d, J = 12.7 Hz), 128.75
(d, J = 16.2 Hz), 124.52 (s), 122.62 (s), 121.00–120.45 (m), 120.17
(s), 119.81 (s), 112.17 (s), 71.37 (d, J = 4.7 Hz), 24.32 (d, J = 3.8
Hz), 23.87 (d, J = 5.1 Hz), 9.85 (s).
13C NMR (101 MHz, DMSO): d = 145.89 (s), 145.66 (s), 136.81
(d, J = 15.0 Hz), 132.24 (s), 130.51 (d, J = 13.2 Hz), 130.08 (s),
129.42 (s), 128.53 (s), 122.96 (s), 121.38 (d, J = 14.5 Hz), 112.25
(s), 98.09 (s), 95.96 (s), 61.30 (d, J = 5.1 Hz), 16.49 (d, J = 6.8 Hz).
31P NMR (202 MHz, CDCl3): d = 9.49 (s).
31P NMR (160 MHz, DMSO): d = 17.21 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NNaO3P: 318.1235;
HRMS (ESI): m/z [M] calcd for C18H20NO3P: 329.1181; found:
found: 318.1235.
329.1183.
2-(Diethoxyphosphoryl)-1-methyl-1H-indole (3ea) and
3-(Diethoxyphosphoryl)-1-methyl-1H-indole (4ea)
Pale yellow liquid; yield: 26.3 mg (39%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (500 MHz, CDCl3): d = 7.67 (d, J = 8.0 Hz, 1 H), 7.40–
7.31 (m, 2 H), 7.19–7.13 (m, 2 H), 4.24–4.10 (m, 4 H), 3.95 (s, 3 H),
1.35 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 140.29 (d, J = 12.3 Hz), 127.33
(s), 126.73 (d, J = 15.6 Hz), 125.60 (s), 124.71 (s), 122.34 (s),
120.46 (s), 114.26 (d, J = 17.4 Hz), 110.15 (d, J = 1.9 Hz), 62.83 (d,
J = 5.3 Hz), 31.99 (s), 16.49 (d, J = 6.5 Hz).
Acknowledgment
We are grateful for the financial support from the National Basic
Research Program of China (2010CB833300).
References
31P NMR (202 MHz, CDCl3): d = 10.01 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C13H18NNaO3P: 290.0922;
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Maier, L., Eds.; Wiley-Interscience: New York, 1976.
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found: 290.0914.
2-(Dimethoxyphosphoryl)-1-methyl-1H-indole (3eb) and
3-(Dimethoxyphosphoryl)-1-methyl-1H-indole (4eb)
Pale yellow liquid, 26.4 mg (44%).
1H NMR (500 MHz, CDCl3): d = 7.68 (d, J = 8.0 Hz, 1 H), 7.40–
7.32 (m, 2 H), 7.20–7.13 (m, 2 H), 3.94 (s, 3 H), 3.81 (d, J = 11.4
Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 140.37 (d, J = 12.4 Hz), 126.70
(d, J = 15.7 Hz), 125.84 (s), 124.89 (s), 124.10 (s), 122.37 (s),
120.56 (s), 114.68 (d, J = 17.3 Hz), 110.21 (s), 53.24 (d, J = 5.4
Hz), 31.98 (s).
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31P NMR (202 MHz, CDCl3): d = 13.03 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C11H14NNaO3P: 262.0609;
found: 262.0603.
2-(Diisopropoxyphosphoryl)-1-methyl-1H-indole (3ec) and
3-(Diisopropoxyphosphoryl)-1-methyl-1H-indole (4ec)
Pale yellow liquid, 21.0 mg (29%).
1H NMR (500 MHz, CDCl3): d = 7.67 (d, J = 8.0 Hz, 1 H), 7.34 (dt,
J = 8.4, 7.6 Hz, 2 H), 7.18 (dd, J = 4.5, 0.6 Hz, 1 H), 7.14 (ddd,
J = 7.9, 6.7, 1.2 Hz, 1 H), 4.80–4.70 (m, 2 H), 3.94 (s, 3 H), 1.39 (d,
J = 6.2 Hz, 6 H), 1.27 (d, J = 6.2 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 140.20 (d, J = 12.1 Hz), 128.97
(s), 127.24 (s), 126.79 (d, J = 15.7 Hz), 124.50 (s), 122.33 (s),
120.35 (s), 113.96 (d, J = 17.5 Hz), 110.09 (s), 71.59 (d, J = 5.4
Hz), 32.01 (s), 24.32 (d, J = 3.9 Hz), 23.98 (d, J = 4.9 Hz).
31P NMR (202 MHz, CDCl3): d = 7.57 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C15H22NNaO3P: 318.1235;
found: 318.1229.
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3-(Diethoxyphosphoryl)-2-phenyl-1H-indole (3fa)
(11) The influence of metals and acids were tested and listed in
the Supporting Information.
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Chem. Int. Ed. 2009, 48, 9127. (b) Wang, D.-S.; Chen,
Q.-A.; Zhou, Y.-G.; Zhang, X.-M. J. Am. Chem. Soc. 2010,
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Pale yellow solid; yield: 58.1 mg (71%).
1H NMR (400 MHz, DMSO): d = 12.17 (s, 1 H), 7.93 (d, J = 7.9 Hz,
1 H), 7.77 (d, J = 7.4 Hz, 2 H), 7.50 (dd, J = 14.9, 7.2 Hz, 4 H), 7.19
(dt, J = 24.0, 7.3 Hz, 2 H), 4.01–3.77 (m, 4 H), 1.07 (t, J = 7.0 Hz,
6 H).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 941–945