Silver-Catalyzed Direct Csp2-H Phosphorylation of Indoles Leading to Phosphoindoles

Article abstract of DOI:10.1002/adsc.201600001

The silver carbonate-catalyzed direct C_sp²-H phosphorylation of indoles in the presence of magnesium nitrate is described. The reaction affords selectively phosphonoindoles in moderate to good yields through a radical process. This p

Full text of DOI:10.1002/adsc.201600001

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DOI: 10.1002/adsc.201600001
À
Silver-Catalyzed Direct Csp2 H Phosphorylation of Indoles
Leading to Phosphoindoles
Wang-Bin Sun,a Jian-Fei Xue,a Guo-Yu Zhang,a Run-Sheng Zeng,a,* Li-Tao An,b
Pei-Zhi Zhang,a and Jian-Ping Zoua,c,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow
University, 199 Renai Street, Suzhou, Jiangsu 215123, Peopleꢀs Republic of China
Fax: (+86)-512-6588-0335; phone: (+86)-512-6588-0336; e-mail: jpzou@suda.edu.cn or zengrunsheng@suda.edu.cn
College of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian, 111 West Changjiang Road,
b
Huai’an, Jiangsu 223300, Peopleꢀs Republic of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
c
Academy of Science, Shanghai 200032, Peopleꢀs Republic of China
Received: January 1, 2016; Revised: February 17, 2016; Published online: May 3, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600001.
À
Abstract: The silver carbonate-catalyzed direct
Csp2 H phosphorylation of indoles in the presence
of magnesium nitrate is described. The reaction af-
fords selectively phosphonoindoles in moderate to
good yields through a radical process. This protocol
provides an efficient and general method for the
preparation of 2- and 3-phosphorylated indoles.
direct indole Csp2 H functionalization towards form-
ing C C, C O, C B bonds,[9 ]and direct phosphoryla-
À
À
À
À
tion of (hetero)arenes,[10] the direct indole Csp2
À
H
phosphorylation still remains a challenge.[11] In our
past studies, we described some novel Mn(OAc)3-pro-
moted strategies for C P bond formation, herein,
we report an Ag-catalyzed direct Csp2 H phosphoryla-
tion of indoles leading to phosphoindoles.
[12]
À
À
Keywords: catalysis; indoles; phosphorylation; radi-
cal reactions; silver carbonate
The reaction of methyl 1H-indole-2-carboxylate
(1a) with diphenylphosphine oxide (2a) was selected
as model for screening. Different catalysts such as
Ag(I), Cu(II), Fe(III), and oxidants were screened ini-
tially, and it was found that a silver salt catalyst was
necessary and the best (Table 1 and the Supporting
The indole nucleus is widely found in natural products Information); Air, oxygen, potassium persulphate
and pharmaceutical drugs.[1,2,3,4] The introduction of (K2S2O8), or HNO3 were not suitable as oxidants
a phosphoryl group onto an indole skeleton can (Table 1, entries 1–6 and the Supporting Information).
strengthen or create new bioactivities. Recently, 3- Interestingly, the addition of Mg(NO3)2·6H2O and 4Š
phosphoindoles have been reported to be good inhibi- MS (molecular sieve) to the reaction mixture dramati-
tors against HIV-1, hence, the creation of new phos- cally increased the yields (Table 1, entries 7 and 8). In
phoindoles and development of novel approaches to this case, Ag2CO3 emerged as the best catalyst
phosphoindoles become important.[5] Up to now, (Table 1, entry 8). After the catalyst loading, amount
there have been only few known routes towards phos- of Mg(NO3)2·6H2O and 4Š MS, and reaction temper-
phoindoles. The Fischer cyclization is a prominent ature were screened, the optimal reaction conditions
early method for the synthesis of 2-phosphoindoles.[6] were determined to be methyl 1H-indole-2-carboxyl-
In 2004, Bisseret reported a palladium-assisted reac- ate (1a) (1 mmol), diphenylphosphine oxide (2a)
tion of o-(2,2-dibromovinyl)aniline with dialkyl phos- (2 mmol), Mg(NO3)2·6H2O (1.5 mmol) and 4Š MS
phite to afford 2-phosphoindoles.[7] Thereafter, (0.2 g) in CH3CN (3 mL) at 808C for 24 h to give
Oshima developed a palladium-catalyzed annulation methyl 3-(diphenylphosphoryl)-1H-indole-2-carboxyl-
of 1-alkynylphosphine sulfides with 2-iodoanilines to ate (3a) in 84% yield (Table 1, entry 10). The results
afford 2-phosphoindoles.[8]
showed that a suitable amount of water is favorable
for the reaction, hence the addition of 4Š MS (0.2 g)
À
Indoles are widely available, and so the direct Csp2
H phosphorylation would represent a powerful strat- to remove excess water (Table 1, entries 10–13).
egy for the synthesis of different types of phosphoin- Subsequently, the optimal reaction conditions ob-
doles. Although great progress has been made in the tained above were applied to the reaction of 2-substi-
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Table 1. Optimization of the reaction conditions.[a]
entry 8). Furthermore, the electronic effect of the sub-
stituents on the phenyl ring was investigated, and it
was observed that indoles bearing electron-withdraw-
ing groups such as F, Cl. Br or electron-donating
groups like Me, MeO all afforded the expected prod-
ucts in good yields (Table 2, entries 10–14). However,
the reaction of 5-nitroindole with 2a gave a low yield
of 3i (Table 2, entry 9); the strong electron-withdraw-
ing NO2 group could be responsible for this result. In
addition, dimethyl phosphite (2b) and diethyl phos-
phite (2c) were employed for the reaction with
methyl 1H-indole-2-carboxylate (1a), giving the ex-
pected methyl 3-phosphonyl-1H-indole-2-carboxylates
(3o and 3p) in 39% and 47% yields, respectively
(Table 2, entries 15 and 16) alongside phenyl ring
phosphonylated by-products. Interestingly, the reac-
tion of methyl N-methylindole-2-carboxylate (1b)
with 2b gave the corresponding product 3q in 69%
yield (Table 2, entry 17), indicating that indoles pro-
tected with electron-donating groups are suitable for
the reaction with dialkyl phosphites.
Entry
Catalyst (mol%)
Oxidant (equiv.)
Yield [%][b]
1
2
3
4
5
6
7
8
AgNO3 (20)
Ag2SO4 (20)
Ag2O (20)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
HNO3 (2)
Mg(NO3)2 (2)
Mg(NO3)2 (2)
Mg(NO3)2 (2)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
Mg(NO3)2 (1.5)
35[c,d]
48[c,d]
27[c,d]
trace[c,d]
21[c,d]
30[c,e]
75[c,f]
86[c,f]
85[c,f]
84[c,f]
11[c,g]
58[c,h]
23[c,i]
Ag2CO3 (20)
AgOAc (20)
AgNO3 (20)
AgNO3 (20)
Ag2CO3 (20)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
9
10
11
12
13
14
15
16
47[c,f,j]
72[c,f,k]
72[c,f,l]
With the results of the reaction of 2-substituted in-
doles (1) with diphenylphosphine oxide (2a) or dialkyl
phosphites (2b and 2c) in hand, the reaction was also
extended to 3-substituted indoles (4a–h), heteroarenes
(4l–n) and other phosphites (2d and 2e). Generally,
the reaction of 4 with 2 resulted in slightly lower
yields of the corresponding products 5 when com-
pared with their 2-substituted counterparts 3. This
might be accounted for based on the electron density
of the 2-position being lower than that of the 3-posi-
tion. Indoles 4 bearing electron-withdrawing groups
like COOMe, CN, CHO or phenyl ring at the 3-posi-
tion, all afforded the expected 2-(diphenylphosphor-
yl)-3-substituted indoles in yields ranging from 51–
68% (Table 3, entries 1–5) however, those bearing
electron-donating groups such as CH3, CH2OH did
[a]
Reaction conditions: 1a (1 mmol), 2a (2 mmol), CH3CN
(3 mL), 808C (oil bath) for 24 h.
Isolated yield, n.r. means no reaction.
The reaction was performed under an argon atmosphere.
Solvent: CH3CN (1.5 mL) and H2O (1.5 mL).
Using HOAc as solvent with no addition of HNO3, only
a trace of product was observed.
4Š MS (0.2 g), CH3CN (3 mL).
Without 4Š MS.
4Š MS (0.1 g).
CH3CN (0.75 mL)+H2O (0.25 mL).
508C (oil bath).
1008C (oil bath).
12 h.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
[j]
[k]
[l]
tuted indoles (1) and diphenylphosphine oxide (2a). not give the expected products, with the exception of
Indoles bearing electron-withdrawing groups like N-methyl-protected substrate 4g which afforded 1,3-
COOMe and phenyl at the 2-position, all afforded the dimethyl-2-(diphenylphosphoryl)indole (5g) in 15%
expected 3-(diphenylphosphoryl)-2-substituted indoles yield (Table 3, entries 6–8). Furthermore, the reac-
in good yields (Table 2, entries 1 and 3); this might be tions of dialkyl phosphites (2b and 2c) with 4a were
attributed to the intermediate carbon radical formed conducted, and as predicted, methyl 2-phosphonyl-
being stabilized by COOMe and phenyl group. How- 1H-indole-3-carboxylates (5i and 5j) were obtained in
ever, indoles bearing electron-donating groups such low yields of 31% and 30%, respectively (Table 3, en-
as CH3, CH2OH at the 2-position could only give the tries 9 and 10); however, 4a did not react with diphen-
expected products in 32% and 0% yields, respectively yl phosphite (2d) and diisopropyl phosphite (2e)
(Table 2, entries 5 and 7) since these groups will acti- (Table 3, entries 11 and 12). In addition, the reaction
vate the substrate thereby affecting the selectivity of of heteroarenes such as benzofuran (4l), benzothio-
the reaction. The N-protected indoles were also inves- phene (4m) and benzimidazole (4n) with diphenyl-
tigated, and it was found that N-methylindoles gave phosphine oxide (2a) were carried out, the results
the 3-phosphorylated indoles in yields similar to those showed that 4m and 4n gave the expected products in
of the NH unprotected analogues (Table 2, entries 2, 40% and 30% yields, respectively (Table 3, entries 13
4 and 6). Unfortunately, N-tosylindole did not react and 14), but no reaction was observed for 4n (Table 3,
with diphenylphophine oxide (2a) due to the strong entry 15).
electron-withdrawing tosyl group deactivating the
To know if the above conditions are suitable for the
indole towards electrophilic radical attack (Table 2, unsubstituted indole (6), the reaction of 6 with 2a was
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Table 2. Reactions of 2-substituted indoles (1) and diphenylphosphine oxide (2a) or dialkyl phosphites (2b and 2c).[a]
[a]
Reaction conditions: 1 (1 mmol), 2 (2 mmol), Ag2CO3 (0.1 mmol), Mg(NO3)2·6H2O (1.5 mmol), 4Š MS (0.2 g), CH3CN
(3 mL), 808C (oil bath) under an argon atmosphere for 24 h.
Isolated yield.
[b]
performed, but no reaction was observed. However, also the reactivity and selectivity depends on the
the reaction occurred with an excess of Ag2CO3 structure of the indole.
(2.2 equiv.), producing a mixture of 2-phosphorylated
In order to know whether reaction proceeds via
indole (7) and 2,3-diphosphorylatedindole (8) in 25% a radical pathway, the reaction of methyl 1H-indole-2-
and 51% yields, respectively (Scheme 1). This indi- carboxylate (1a) with diphenylphosphine oxide (2a) in
cates that both 2- and 3-positions of indole can be at- the presence of two equivalents of TEMPO was per-
tacked by the electrophilic phosphorus radical, and formed, giving no expected product 3a which supports
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Table 3. Reactions of 3-substituted indoles (4a–h) or heteroarenes (4l–n) with diphenylphosphine oxide (2a) or dialkyl phos-
phites (2b–e).[a]
[a]
Reaction conditions: 1 (1 mmol), 2 (2 mmol), Ag2CO3 (0.1 mmol), Mg(NO3)2·6H2O (1.5 mmol), 4Š MS (0.2 g), CH3CN
(3 mL), 808C (oil bath) under an argon atmosphere for 24 h.
Isolated yield.
[b]
that the reaction might proceed via a radical process. presence of 4Š MS. The reaction proceeded via
À
A plausible mechanism for the reaction of 2-substitut- a phosphorus-centered radical attack on the Csp2
H
ed indoles (1) with diphenylphosphine oxide (2a) is bond followed by deprotonation to form phospho-
proposed in Scheme 2. The phosphorus-centred radi- noindoles. The results indicated that a suitable
cal 6 derived from 2a selectively adds to position 3 of amount of water played a key role in the reaction.
indole (1) to form intermediate radical 7, followed by This protocol provides an efficient and general
oxidation and deprotonation to afford product 3.
method for the preparation of 2- and 3-phosphorylat-
In conclusion, we have successfully developed ed indoles in moderate to good yields.
À
a novel, Ag-catalyzed direct Csp2 H phosphorylation
of indoles with magnesium nitrate as additive in the
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À
H
Typical Procedure for Silver-Catalyzed Direct Csp2
Phosphorylation of Indoles
To a solution of the indole (1 mmol) in MeCN (3 mL), di-
phenylphosphine oxide (2a) (0.404 g, 2 mmol), Ag2CO3
(0.028 g, 0.1 mmol), Mg(NO3)2·6H2O (0.384 g, 1.5 mmol)
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