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Synlett 2010(17): 2593-2596  
DOI: 10.1055/s-0030-1258585
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Hypervalent Iodine(III) Mediated Decarboxylative Halogenation of Indolecarboxylic Acids for the Synthesis of Haloindole Derivatives

Hiromi Hamamoto, Hideaki Umemoto, Misako Umemoto, Chiaki Ohta, Masashi Dohshita, Yasuyoshi Miki*
School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Fax: +81(6)67212505; e-Mail: y_miki@phar.kindai.ac.jp;

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Publication History

Received 2 July 2010
Publication Date:
23 September 2010 (online)

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Abstract

The treatment of 1-methylindole-2,3-dicarboxylic acid with hypervalent iodine(III) reagent, phenyliodine diacetate (PIDA), in the presence of lithium bromide gave 1-methyl-3,3-dibromooxindole. However, the reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxylic acid with PIDA in the presence of lithium bromide afforded 2,3-dibromo-1-(phenylsulfonyl)indole. In a similar manner, the 2,3-dichloro- and 2,3-diiodo-indole derivatives were obtained by the reaction of the indole-2,3-dicarboxylic acids with PIDA in the presence of lithium chloride and iodide.

Key words

indolecarboxylic acid - decarboxylation - bromination - chlorination - iodation

The Hunsdiecker reaction, the reaction of heavy-metal salt of carboxylic acids with halogens to give organic halides, is an example of classical decarboxylative halogenation reaction. [¹] Thus the decarboxylative halogenation that can provide halogenated organic compounds from carboxylic acids, an important class of intermediates, by simple chemical transformation is very attractive. Recently, several Hunsdiecker-type reactions have been investigated using the various reagent conditions, especially using hypervalent iodine compounds in the point of green chemistry. [²] Camps reported that 2- and 4-nitrobenzoic acids having electron-withdrawing substituent could be converted into the corresponding bromonitrobenzenes in moderate yield by decarboxylative bromination using phenyliodine diacetate (PIDA) and bromine under irradiation, but in the case of 2- and 4-methoxybenzoic acids, possessing a electron-donating substituent, were recovered and this result shows that the conversion of electron-rich aromatic carboxylic acid into the corresponding bromo­benzene is quite difficult. [³] Although the decarboxylative halogenation is an attractive method for the synthesis of simple halogenated organic compounds, the application of the Hunsdiecker-type reactions for the synthesis of natural products or bioactive compounds is still limited. [³] [4]

Bromoindole alkaloids have been isolated as the secondary metabolites of marine organisms, such as sponges, ­tunicates, etc., and are promising sources of new biologically active molecules. [5] 2,3,6-Tribromoindole, [6] 2,3,5,6-tetrabromoindole, [7] the polybromo(bisindoles), [8] and bromochloroindoles [9] were isolated. The synthesis of the bromoindoles is usually performed by the direct bromination of indoles using bromine, pyridinium tribromide, N-bromosuccinimide, etc., but the yields or the selectivity are not satisfactory in general. There is no such report of indolecarboxylic acids except for the synthesis of the 2,3-diiodoindoles by the decarboxylative iodination of indole-2-carboxylic acids, but in the case of indole-2-carboxylic acids without having an electron-donating substituent, the yield of the 2,3-diiodoindoles are low. [¹0] Recently, we reported the synthesis of the 2,3-dibromoindoles by the decarboxylative bromination of indole-2,3-dicarboxylic acids by using Oxone ® and lithium bromide, but 2,3-dichloro- or 2,3-diiodo-indoles were not obtained. [¹¹]

We now investigated the Hunsdiecker-type decarboxylative halogenation of 1-substituted indole-2,3-dicarboxylic acids 1 utilizing hypervalent iodine reagent, by the way the effective strategy for halogenation because hypervalent iodine reagents have low toxicity relative to heavy metals and are readily available and their reactivities are similar to those of heavy metals. [¹²]

The reaction of 1-(phenylsulfonyl)indole-2,3-dicarboxylic acid (1a) [¹³] with 3 equivalents of PIDA [¹4] in the presence of the same equivalents of lithium bromide in THF gave a mixture of 3-bromoindole-2-carboxylic acid (2a) and 2,3-dibromoindole (3a) [¹5] in 36% and 35% yields, respectively, but the treatment of 1a with PIDA (4 equiv) afforded 3a in 86% yield (Table  [¹] , entries 1, 2). However, when the reaction of 1a with PIDA was carried out using potassium bromide instead of lithium bromide, 5 equivalents of PIDA or CH2Cl2 as the solvent, the yields of 3a were relative low (33-72%, Table  [¹] , entries 3-5, Scheme  [¹] ).

Scheme 1 The reaction of 1a with PIDA in the presence of lithium bromide

Table 1 Synthesis of 2a and 3a
Entry PIDA (equiv) MBr Solvent Time
(h) 		Yield of 2a (%) Yield of 3a (%)
1 3 LiBr THF 51 36 35
2 4 LiBr THF  2 - 86
3 4 KBr THF 22  6 72
4 5 LiBr THF  3 - 71
5 5 LiBr CH2Cl2  0.5 - 33

Scheme 2 The reaction of 1b with PIDA in the presence of lithium bromide

Table 2 Synthesis of 2b and 4b
Entry PIDA (equiv) Solvent Time
(h) 		Yield of 2b (%) Yield of 4b (%)
1 1 THF 1 57 -
2 2 THF 2 74 -
3 3 THF 1 - 78
4 3 CH2Cl2 0.5 - 73

Scheme 3 Plausible reaction mechanism leading to 4b

Table 3 Synthesis of 3 and 4b from Indolecarboxylic Acids 6 and 7
Entry Compd CO2H R Yield of 3 (%) Yield of 4b (%)
1 6a 2- SO2Ph 83 -
2 7a 3- SO2Ph 81 -
3 6b 2- Me - 80
4 7b 3- Me - 80

Scheme 4 The reaction of 6 and 7 with PIDA in the presence of lithium bromide

The reaction of 1-methylindole-2,3-dicarboxylic acid (1b) [¹6] with 1 equiv or 2 equiv of PIDA in the presence of the same equivalents of lithium bromide in THF gave 3-bromoindole-2-carboxylic acid (2b) [¹7] in 57% or 74% yields, respectively (Table  [²] , entries 1, 2). When the reaction of 1b with 3 equivalents of PIDA was examined, the corresponding 2,3-dibromoindole (3b), the desired product was not isolated and 3,3-dibromo-1-methyloxindole (4b) [¹8] was obtained as the sole product in 78% yield (entry 3). In addition, the reaction of 1b with 3 equivalents of PIDA in CH2Cl2 instead of THF also afforded 4b in slightly lower yield (73%, entry 4). When 3-bromoindole-2-carboxylic acid (2b) was treated with with PIDA (2 equiv) and lithium bromide in THF at room temperature (30 min), 4b was obtained in 90% yield (Scheme  [²] ).

One possible explanation for the formation of 3,3-dibromo-1-methyloxindole (4b) is envisaged as shown in Scheme  [³] . The bromination of 1-methyl-2,3-dibromo­indole (3b), which would obtained after the second ­Hunsdiecker-type decarboxylative bromination of 1b, lead to intermediate 5. Treatment of 5 with water by workup provides 4b. The absence of 3,3-dibromo-1-(phenylsulfonyl)oxindole on the reaction with 1a, possessing electron-withdrawing N-substituent in Table  [¹] may support this explanation. Although the detailed reaction mechanism is still not clear, the dibromooxindole derivatives could be also potentially attractive synthons in indole alkaloid syntheses.

The reaction of 1-(phenylsulfonyl)indole-2-carboxylic acid (6a) or 1-(phenylsulfonyl)indole-3-carboxylic acid (7a) with 4 equivalents of PIDA in the presence of the same equivalents of lithium bromide in THF gave 3a in 81-83% yields (Table  [³] , entries 1, 2), but from 1-methylindole-2-carboxylic acid (6b) or 1-methylindole-3-carboxylic acid (7b), 4b was isolated in 80% yields (entries 3, 4). The same results were obtained with the reaction of 1 with PIDA and lithium bromide (Scheme  [4] ).

Next, we examined the reactivity of 1 toward lithium chloride or iodide to synthesize the dichloro- or diiodo-­indoles 8 (Table  [4] ). The reaction of 1-(phenylsulfonyl) ­indole-2,3-dicarboxylic acid (1a) with less than 4 equivalents of PIDA in the presence of lithium chloride in THF gave 2,3-dichloroindole (8a) in low yield, but the treatment of 1a with PIDA (6 equiv) afforded 8a in 80% yield (entry 1). 2,3-Diiodo-1-(phenylsulfonyl)indole (8b) was not isolated by the treatment of 1a with 6 equivalents of PIDA in the presence of lithium iodide in THF, but in a mixture of 2,2,2-trifluoroethanol and CH2Cl2 (1:1) as a solvent instead of THF, 8b [¹9] was obtained in 89% yield (entry 2). The reaction of 1b with PIDA (4 equiv) in the presence of lithium chloride gave 3,3-dichlorooxindole 9 [²0] in 77% yield, and 2,3-diiodo-1-methylindole (8c) [²¹] was isolated in 87% yield in the presence of lithium iodide (Table  [4] , entries 3, 4; Scheme  [5] ).

Scheme 5 The reaction of 1 with PIDA in the presence of lithium chloride or iodide

Table 4 Synthesis of 8 and 9 [²²]
Entry R PIDA (equiv) LiX Time (h) Yield of 8 (%) Yield of 9 (%)
1 SO2Ph 6 LiCl 6 80 -
2 SO2Ph 5 LiI 3 89a -
3 Me 4 LiCl 6 - 77
4 Me 4 LiI 1.5 87 -
a 2,2,2-Trifluoroethanol and CH2Cl2 (1:1) was used as a solvent instead of THF.

In conclusion, we demonstrated the decarboxylative halogenation of indolecarboxylic acid derivatives using the Hunsdiecker-type reaction. The exciting result obtained with the reaction of the indole-2,3-dicarboxylic acids 1 with PIDA in the presence of lithium halide prompted us to extend our procedure to the selective synthesis of indole alkaloids.

Acknowledgment

This work was partially supported by a Grant-in-Aid of the Ministry of Education, Culture, Sport, Science, and Technology and also in part ‘High-Tech Research Center Project’ for Private Universities and matching fund subsidy.

22

Typical Procedure for the Decarboxylative Halogenation of Indole-2,3-dicarboxylic Acid(1) with PIDA in the Presence of Lithium Halide
To a mixture of PIDA and lithium halide in THF (10 mL) was added indolecarboxylic acids 1, 6, 7 (1 mmol) at r.t., and then the reaction mixture was stirred. H2O was added to the reaction mixture, and the mixture was extracted with CH2Cl2. The combined extracts were washed with 2-3% Na2S2O3 solution, then H2O, and dried over Na2SO4. The extracts were concentrated under reduced pressure to give a solid, which was purified by column chromatography on silica gel to afford the 3-halogenoindole-2-carboxylic acids(2), 2,3-dihalogenoindoles 3, 8, and 3,3-dihalogeno-oxindoles 4, 9.
1-Phenylsulfonyl-3-bromoindole-2-carboxylic Acid (2a)
Mp 124-125 ˚C. IR (mull): ν = 2856, 2585, 1697 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.24-7.36 (3 H, m), 7.50-7.68 (3 H, m), 7.91 (1 H, dd, J = 8.0, 1.5 Hz), 8.25-8.32 (2 H, m). HRMS (EI): m/z calcd for C15H11NSO4Br2S: 379.9592; found: 379.9602.
1-Phenylsulfonyl-2,3-dibromoindole (3a)
Mp 143 ˚C (lit.¹5 mp 141-143 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 7.22-7.40 (5 H, m), 7.46-7.54 (1 H, m), 7.78-7.84 (2 H, m), 8.19-8.25 (1 H, m).
3-Bromo-1-methylindole-2-carboxylic Acid (2b)
Mp 184-186 ˚C [lit.¹7 mp 180 ˚C (dec)]. IR (KBr): ν = 1671 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.99 (3 H, s, CH3), 7.22 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.40 (1 H, t, J = 8.0 Hz, H-6 or H-5), 7.54 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.62 (1 H, d, J = 8.0 Hz, H-7 or H-4).
3,3-Dibromo-1-methyloxindole (4b)
Mp 202-204 ˚C (lit.¹8 mp 204-205 ˚C). IR (CHCl3): ν = 1737 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.26 (3 H, s, CH3), 6.86 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, dt, J = 8.0, 1.5 Hz, H-5 or H-6), 7.34 (1 H, dt, J = 8.0, 1.5 Hz, H-6 or H-5), 7.62 (1 H, dd, J = 8.0, 1.5 Hz, H-7 or H-4). ¹³C NMR (100 MHz, DMSO-d 6): δ = 169.16, 139.64, 131.87, 130.37, 125.38, 124.05, 110.08, 45.28, 27.03. HRMS (EI): m/z calcd for C9H7NOBr2: 302.8895; found: 302.8883.
1-Phenylsulfonyl-2,3-dichloroindole (8a)
Mp 122 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 7.30-7.63 (6 H, m), 7.84-7.92 (2 H, m), 8.28 (1 H, br d, J = 8.0 Hz, H-7 or H-4). ¹³C NMR (100 MHz, DMSO-d 6): δ = 137.59, 134.70, 134.40, 129.30, 126.94, 126.54, 126.14, 124.57, 121.24, 118.15, 114.98, 113.78. HRMS (EI): m/z calcd for C14H9NO2Cl2S: 324.9677; found: 324.9737.

1-Phenylsulfonyl-2,3-diiodoindole (8b)
Mp 165-167 ˚C (lit.¹9 mp 166-167 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 7.25-7.60 (6 H, m), 7.90 (2 H, br d, J = 8.0 Hz), 8.28 (1 H, br d, J = 8.0 Hz, H-7).
2,3-Diiodo-1-methylindole (8c)
Mp 76-77 ˚C (lit.²0 mp 76-78 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 3.89 (3 H, s, CH3), 7.10-7.42 (4 H, m). ¹³C NMR (100 MHz, DMSO-d 6): δ = 138.11, 131.15, 122.71, 120.80, 120.50, 111.06, 99.78, 71.72, 36.09. HRMS (EI): m/z calcd for C9H7NI2: 382.8668; found: 382.8671.
3,3-Dichloro-1-methyloxindole (9)
Mp 144-147 ˚C (lit.²¹ 143 ˚C). IR (KBr): ν = 1740 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 3.25 (3 H, s, CH3), 6.85 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.39 (1 H, t, J = 8.0, 1.5 Hz, H-6 or H-5), 7.61 (1 H, d, J = 8.0 Hz, H-7 or H-4). ¹³C NMR (100 MHz, CDCl3): δ = 168.80, 140.58, 131.85, 129.16, 125.13, 124.70, 124.14, 109.08, 26.98.

22

Typical Procedure for the Decarboxylative Halogenation of Indole-2,3-dicarboxylic Acid(1) with PIDA in the Presence of Lithium Halide
To a mixture of PIDA and lithium halide in THF (10 mL) was added indolecarboxylic acids 1, 6, 7 (1 mmol) at r.t., and then the reaction mixture was stirred. H2O was added to the reaction mixture, and the mixture was extracted with CH2Cl2. The combined extracts were washed with 2-3% Na2S2O3 solution, then H2O, and dried over Na2SO4. The extracts were concentrated under reduced pressure to give a solid, which was purified by column chromatography on silica gel to afford the 3-halogenoindole-2-carboxylic acids(2), 2,3-dihalogenoindoles 3, 8, and 3,3-dihalogeno-oxindoles 4, 9.
1-Phenylsulfonyl-3-bromoindole-2-carboxylic Acid (2a)
Mp 124-125 ˚C. IR (mull): ν = 2856, 2585, 1697 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.24-7.36 (3 H, m), 7.50-7.68 (3 H, m), 7.91 (1 H, dd, J = 8.0, 1.5 Hz), 8.25-8.32 (2 H, m). HRMS (EI): m/z calcd for C15H11NSO4Br2S: 379.9592; found: 379.9602.
1-Phenylsulfonyl-2,3-dibromoindole (3a)
Mp 143 ˚C (lit.¹5 mp 141-143 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 7.22-7.40 (5 H, m), 7.46-7.54 (1 H, m), 7.78-7.84 (2 H, m), 8.19-8.25 (1 H, m).
3-Bromo-1-methylindole-2-carboxylic Acid (2b)
Mp 184-186 ˚C [lit.¹7 mp 180 ˚C (dec)]. IR (KBr): ν = 1671 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.99 (3 H, s, CH3), 7.22 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.40 (1 H, t, J = 8.0 Hz, H-6 or H-5), 7.54 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.62 (1 H, d, J = 8.0 Hz, H-7 or H-4).
3,3-Dibromo-1-methyloxindole (4b)
Mp 202-204 ˚C (lit.¹8 mp 204-205 ˚C). IR (CHCl3): ν = 1737 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 3.26 (3 H, s, CH3), 6.86 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, dt, J = 8.0, 1.5 Hz, H-5 or H-6), 7.34 (1 H, dt, J = 8.0, 1.5 Hz, H-6 or H-5), 7.62 (1 H, dd, J = 8.0, 1.5 Hz, H-7 or H-4). ¹³C NMR (100 MHz, DMSO-d 6): δ = 169.16, 139.64, 131.87, 130.37, 125.38, 124.05, 110.08, 45.28, 27.03. HRMS (EI): m/z calcd for C9H7NOBr2: 302.8895; found: 302.8883.
1-Phenylsulfonyl-2,3-dichloroindole (8a)
Mp 122 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 7.30-7.63 (6 H, m), 7.84-7.92 (2 H, m), 8.28 (1 H, br d, J = 8.0 Hz, H-7 or H-4). ¹³C NMR (100 MHz, DMSO-d 6): δ = 137.59, 134.70, 134.40, 129.30, 126.94, 126.54, 126.14, 124.57, 121.24, 118.15, 114.98, 113.78. HRMS (EI): m/z calcd for C14H9NO2Cl2S: 324.9677; found: 324.9737.

1-Phenylsulfonyl-2,3-diiodoindole (8b)
Mp 165-167 ˚C (lit.¹9 mp 166-167 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 7.25-7.60 (6 H, m), 7.90 (2 H, br d, J = 8.0 Hz), 8.28 (1 H, br d, J = 8.0 Hz, H-7).
2,3-Diiodo-1-methylindole (8c)
Mp 76-77 ˚C (lit.²0 mp 76-78 ˚C). ¹H NMR (400 MHz, CDCl3): δ = 3.89 (3 H, s, CH3), 7.10-7.42 (4 H, m). ¹³C NMR (100 MHz, DMSO-d 6): δ = 138.11, 131.15, 122.71, 120.80, 120.50, 111.06, 99.78, 71.72, 36.09. HRMS (EI): m/z calcd for C9H7NI2: 382.8668; found: 382.8671.
3,3-Dichloro-1-methyloxindole (9)
Mp 144-147 ˚C (lit.²¹ 143 ˚C). IR (KBr): ν = 1740 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 3.25 (3 H, s, CH3), 6.85 (1 H, d, J = 8.0 Hz, H-4 or H-7), 7.17 (1 H, t, J = 8.0 Hz, H-5 or H-6), 7.39 (1 H, t, J = 8.0, 1.5 Hz, H-6 or H-5), 7.61 (1 H, d, J = 8.0 Hz, H-7 or H-4). ¹³C NMR (100 MHz, CDCl3): δ = 168.80, 140.58, 131.85, 129.16, 125.13, 124.70, 124.14, 109.08, 26.98.

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Scheme 1 The reaction of 1a with PIDA in the presence of lithium bromide

Scheme 2 The reaction of 1b with PIDA in the presence of lithium bromide

Scheme 3 Plausible reaction mechanism leading to 4b

Scheme 4 The reaction of 6 and 7 with PIDA in the presence of lithium bromide

Scheme 5 The reaction of 1 with PIDA in the presence of lithium chloride or iodide