Download PDF
Synlett 2019; 30(16): 1924-1928
DOI: 10.1055/s-0039-1690675
letter
© Georg Thieme Verlag Stuttgart · New York

Iron-Catalyzed C–H Sulfonylmethylation of Indoles in Water–PEG400

Shuai Lu
,
Yu-Shen Zhu
,
Ke-Xin Yan
,
Tian-Wei Cui
,
Xinju Zhu  ∗
,
Xin-Qi Hao∗
,
Mao-Ping Song

Financial support from the National Natural Science Foundation of China (Grant No. 21672192 and 21803059), the China Postdoctoral Science Foundation (Grant No. 2016M602254 and 2016M600582), the Program for Science & Technology Innovation Talents in Universities of Henan Province (Grant No. 17HASTIT004), the Aid Project for the Leading Young Teachers in Henan Provincial Institutions (Grant No. 2015GGJS-157), and the Natural Science Foundation of Henan Province (Grant No. 182300410255) is gratefully appreciated.
Further Information

Publication History

Received: 18 June 2019

Accepted after revision: 23 August 2019

Publication Date:
10 September 2019 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

An iron-catalyzed C–H sulfonylmethylation of indoles in water–PEG400 has been developed using p-toluenesulfonylmethyl isocyanide. This protocol enables direct regioselective construction of Csp2–Csp3 bond at the C3 position of indoles with a broad range of substrate compatibility in moderate to good yields, which is cost-effective and environmentally friendly.


#

Key words

indoles - sulfonylmethylation - p-toluenesulfonylmethyl isocyanide

As a representative nitrogen-containing heterocycle, indole has served as a privileged scaffold in various natural products, drugs, and functional molecules.[1] Over the past decades, considerable attention has been received in the synthesis of indole skeleton[2] and regioselective functionalization[3] at the C2 and C3 position due to inherent reactivity of the pyrrole core. Up to now, significant progress has been made for arylation,[4] alkenylation,[5] alkynylation,[6] amination,[7] acylation,[8] sulfuration,[9] and alkylation[10] of indoles. On the other hand, sulfonyl methylated indoles[11] are common pharmacophores with wide applications in pharmaceuticals.[12] Meanwhile, the arylsulfonyl functionality is a versatile synthetic intermediate, which can be utilized to fulfill multiple transformations.[13] However, the direct sulfonylmethylation of indoles are still less explored.[14]

p-Toluenesulfonylmethyl isocyanide (TosMIC) is a unique synthon in organic synthesis to access various heterocycles via 1,3-dipolar cycloadditions.[15] Meanwhile, TosMIC has also found to be a sulfonylating agent to access benzoheteroles, α-sulfonated carbonyl compounds, and vinyl, allyl, and β-iodo vinylsulfones (Scheme [1, a]).[16] Also, sulfination of alcohols with TosMIC has been reported (Scheme [1, b]).[17] In addition, TosMIC can act as a C1 building block to construct benzothiazolethiones (Scheme [1, c]).[18] Moreover, TosMIC was utilized to realize C–H amidation with propargylic alcohols[19a] and anilines[19b] (Scheme [1, d]). Considering the versatility of TosMIC in organic chemistry, it is advisable to utilize TosMIC to realize other transformations.

Zoom Image
Scheme 1 Different transformations of TosMIC

Our group has been interested in developing an efficient methodology to achieve C–H functionalization of (hetero)aromatics.[20] Very recently, we have also reported C–H arylation, alkylation of indoles, and C–H allylation of indolines with arylboronic acids,[21a] maleimides,[21b] and vinylcyclopropanes.[21c] As a continuation of our previous work, we herein describe the regioselective C3-sulfonylmethylation of indoles using TosMIC as the reaction partner (Scheme [1, e]). This work presents a supplement and improvement of a previous report,[20c] wherein unprotected 1H-indole gave a poor yield. Specially, the current protocol utilizes iron salt as the catalyst, and a mixture of water and PEG400 was utilized as the nontoxic media, which is more cost-effective and environmentally benign.

Table 1 Optimization of Reaction Conditions for C3-Sulfonylmethylindolesa

Entry

Catalyst (mol%)

Solvent (ratio)

Atmosphere

Temp (°C)

Time (h)

Yield (%)b

1

FeCl3 (30)

H2O/PEG400 (7:3)

Ar

130

24

58

2

FeSO4·7H2O (30)

H2O/PEG400 (7:3)

Ar

130

24

73

3

FeC2O4 (30)

H2O/PEG400 (7:3)

Ar

130

24

55

4

FeCl2·4H2O (30)

H2O/PEG400 (7:3)

Ar

130

24

66

5

Fe(acac)3 (30)

H2O/PEG400 (7:3)

Ar

130

24

16

6

Fe(NO3)3·9H2O (30)

H2O/PEG400 (7:3)

Ar

130

24

46

7

FeSO4·7H2O (20)

H2O/PEG400 (7:3)

Ar

130

24

67

8

FeSO4·7H2O (15)

H2O/PEG400 (7:3)

Ar

130

24

68

9

FeSO4·7H2O (10)

H2O/PEG400 (7:3)

Ar

130

24

60

10

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

Ar

130

24

81

11

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

Ar

110

24

86

12

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

Ar

100

24

80

13

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

Ar

110

12

67

14

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

Ar

110

36

75

15

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

air

110

24

68

16

FeSO4·7H2O (15)

H2O/PEG400 (3:2)

O2

110

24

35

17

FeSO4·7H2O (15)

toluene

Ar

110

24

–

18

FeSO4·7H2O (15)

DMF

Ar

110

24

–

19

FeSO4·7H2O (15)

MeOH

Ar

110

24

55

a Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), iron salt, solvent (2 mL). Isolated yields.

To begin with, 1-H indole (1a) and TosMIC (2a) were utilized as the model substrates to optimize the reaction conditions (Table [1]). To our delight, the desired C3-tosylmethylated indole 3a was obtained in 58% yield in the presence of FeCl3 (30 mol%) in mixture solvent of H2O and PEG400 (v/v = 7:3) at 130 °C for 24 h. Subsequently, various iron salts were screened, which indicated that FeSO4·7H2O was the best choice to afford product 3a in 73% yield (Table [1], entries 1–6). Next, the amount of FeSO4·7H2O was adjusted, and the yield (68%) was not significantly decreased using 15 mol% FeSO4·7H2O (Table [1], entry 8). A survey of mixed solvent ratios revealed that H2O/PEG400 (v/v = 3:2) was beneficial to give 3a in 81% yield (Table [1], entry 10). To further improve the reaction efficiency, the reaction temperature was modulated. Product 3a could be isolated in 86% yield at 110 °C, while conducting the reaction at 100 °C led to a decreased yield (Table [1], entries 11 and 12). Moreover, it was found that either shortening or extending the reaction time would provide 3a in a decreased yield (Table [1], entries 13 and 14). When the reaction was carried out under air or oxygen atmosphere, 3a was generated in 68% and 35% yields, respectively (Table [1], entries 15 and 16). Moreover, other nonaqueous solvents, namely toluene, DMF, and MeOH, with different polarity and protic nature, were evaluated (Table [1], entries 17–19). No product was detected when toluene and DMF were utilized, while product 3a was obtained in 55% yield in MeOH, suggesting an SN1-type mechanism might be involved. Finally, other metal-based Lewis acids were also investigated, which all gave inferior results (see Table S1 in the Supporting Information).

Zoom Image
Scheme 2 Substrate scope of indoles. Reagents and conditions: 1 (0.1 mmol), 2a (0.3 mmol), FeSO4·7H2O (15 mol%), H2O/PEG400 = 3:2 (2 mL), under Ar, 110 °C, 24 h. a Scale-up: 1a (10 mmol, 1.17 g), 2a (30 mmol, 5.86 g).

With the optimized conditions in hand, the substrate scope of indoles was investigated (Scheme [2]).[22] In general, a wide range of functional groups, including fluoro (3b, 3k, 3o), chloro (3c), ester (3d, 3l), methoxy (3e, 3j, 3q), and benzyloxy (3f, 3n) at various positions of the benzene core were well tolerated under the current protocol. For C5-substituted indoles, products 3g–i were isolated in low yields. Next, C2-methyl- and phenyl-substituted indoles were also tested to give the corresponding products 3r and 3s in 73% and 96% yields, respectively. Apart from 1H-indoles, N-methylindole was also proved to be the ideal substrate to provide product 3t and 3u in 89% and 21% yields. Interestingly, when the C3 position of indole was occupied, the C2-tosylmethylated product 3v was obtained in 31% yield. Finally, we also attempted to achieve chelation-assisted functionalization, which unfortunately gave C3-tosylmethylated product 3w in 14% yield. Luckily, the absolute configuration of 3w was confirmed by X-ray diffraction (Figure S1 in the Supporting Information). To evaluate the synthetic utility of this protocol, a gram-scale reaction was conducted using 1H-indole (1a) and TosMIC (2a) as the substrate, which delivered product 3a in 57% yield.

Finally, we also attempted to achieve chelation-assisted functionalization, which unfortunately gave C3-tosylmethylated product 3w in 14% yield. Luckily, the absolute configuration of 3w was confirmed by X-ray diffraction (Figure S1 in the Supporting Information). To evaluate the synthetic utility of this protocol, a gram-scale reaction was conducted using 1H-indole (1a) and TosMIC (2a) as the substrate, which delivered product 3a in 57% yield.

Encouraged by the above results, the scope of the sulfonylmethylation reaction was further extended to different TosMIC derivatives (Scheme [3]). It was found that para-substituted TosMICs bearing both electron-withdrawing (F, Cl, and CF3) and electron-donating (OMe) groups could react with indoles smoothly to deliver products 4a–m in 37–84% yields.

To explore the reaction mechanism, a set of control experiments were carried out (Scheme [4]). Without FeSO4·7H2O, the C3-sulfonylmethylated product could not be detected, indicating the necessity of iron salt. Next, the radical scavenger reactions were performed under the optimized conditions. It was found that C3-sulfonylmethylated product 3a could still be isolated in 34% and 77% yield, respectively, when excess TEMPO (3 equiv) and BHT (3 equiv) was introduced into the catalytic system. Considering the preliminary results obtained in Table [1] (entries 17–19), it was postulated that an SN1-type C–C bond formation would be the key step.

Iron metals could coordinate with isocyanides to form mixed ligand complexes, which underwent facile C–N cleavage to form carbon cation species due to the strong binding ability between iron and cyanide.[23] On the basis of the control experiments and previous reports,[20c] [23] a plausible mechanism was proposed (Scheme [5]). The catalytic cycle initiates with the activation of TosMIC (2a) with Fe2+ to produce the electrophilic species A, which was converted into intermediate B. Next, nucleophilic substitution of intermediate B by 1H-indole (1a) results in the formation of intermediate C. Finally, the desired product 3a was achieved via H+ elimination.

In summary, we herein disclosed iron-catalyzed sulfonylmethylation of indoles with TosMIC in a nontoxic medium. A wide range of indoles and substituted TosMIC proceeded smoothly to afford products in moderate to good yield. This methodology is environmentally benign, cost-effective, and additive-free.

Zoom Image
Scheme 3 Substrate scope of the substituted TosMIC. Reagents and conditions: 1 (0.1 mmol), 2 (0.3 mmol), FeSO4·7H2O (15 mol%), H2O/PEG400 = 3:2 (2 mL), under Ar, 110 °C, 24 h.
Zoom Image
Scheme 4 Control experiments
Zoom Image
Scheme 5 Proposed reaction mechanism

#

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690675.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Different transformations of TosMIC
Zoom Image
Scheme 2 Substrate scope of indoles. Reagents and conditions: 1 (0.1 mmol), 2a (0.3 mmol), FeSO4·7H2O (15 mol%), H2O/PEG400 = 3:2 (2 mL), under Ar, 110 °C, 24 h. a Scale-up: 1a (10 mmol, 1.17 g), 2a (30 mmol, 5.86 g).
Zoom Image
Scheme 3 Substrate scope of the substituted TosMIC. Reagents and conditions: 1 (0.1 mmol), 2 (0.3 mmol), FeSO4·7H2O (15 mol%), H2O/PEG400 = 3:2 (2 mL), under Ar, 110 °C, 24 h.
Zoom Image
Scheme 4 Control experiments
Zoom Image
Scheme 5 Proposed reaction mechanism