Synthesis 2014; 46(01): 35-41
DOI: 10.1055/s-0033-1338523
practical synthetic procedures
© Georg Thieme Verlag Stuttgart · New York

Regioselective Direct C–H Alkylation of NH Indoles and Pyrroles by a Palladium/Norbornene-Cocatalyzed Process

Lei Jiao
Lehrstuhl für Organische Chemie I and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany   Fax: +49(89)28913315   Email: [email protected]
,
Thorsten Bach*
Lehrstuhl für Organische Chemie I and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany   Fax: +49(89)28913315   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 29 July 2013

Accepted: 03 August 2013

Publication Date:
17 September 2013 (online)

 


Abstract

Nitrogen-containing heterocycles, including 1H-indoles and electron-deficient 1H-pyrroles, undergo a palladium/norbornene-cocatalyzed regioselective alkylation at the C–H bond adjacent to the NH group. A primary alkyl halide is used as the electrophile and the reaction proceeds smoothly under mild conditions to give 2-alkyl-1H-indoles and 2-substituted or 2,3-disubstituted 5-alkyl-1H-pyrroles in good yields.


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Zoom Image
Scheme 1
1

Introduction

Indoles and pyrroles are two important classes of N-heterocycles that occur widely in natural products, drugs, and biologically active molecules.[1] Alkyl-substituted indoles and pyrroles are of particular interest, because they form key structural elements of many structurally unique and biologically active natural products (Figure [1]).[2] However, few methods are available for constructing such structures by direct C–H substitution. Although considerable advances have been made in the direct C–H functionalization of indoles and pyrroles,[3] the regioselective installation of an alkyl group onto these heterocyclic nuclei remains a challenge. Indoles undergo Friedel–Crafts alkylation selectively at the more electron-rich C3 position,[4] but it is difficult to achieve direct C2 alkylation.[5] [6] In the case of pyrroles, Friedel–Crafts-type direct alkylation with alkyl electrophiles usually results in a mixture of regioisomers;[7] other methods for regioselective alkylation of pyrroles are either circuitous or limited in substrate scope.[8] Therefore, there remains a considerable need for efficient and regioselective methods for alkylation of indoles and pyrroles.

Zoom Image
Figure 1 Natural products containing an alkylindole or alkylpyrrole structure

Inspired by the Catellani reaction,[9] we developed a palladium(II)/norbornene-cocatalyzed process that provides straightforward access to α-alkyl-substituted indole and pyrrole derivatives from NH indoles[10] and pyrroles[11] (Scheme [1]). In this reaction, the N-heterocycle interacts with palladium(II) and norbornene to give intermediate A, which then undergoes an intramolecular ortho-palladation to give palladaheterocycle B in the presence of a base (Scheme [2]).[10b] [11] Subsequently, intermediate B reacts with the alkyl halide by oxidative addition, reductive elimination, norbornene expulsion, and protodepalladation to give the alkyl-substituted heterocycle. The role of norbornene in this process is to act as a transpositional cocatalyst that assists palladium in activating the α-C–H bond of NH indoles and pyrroles, providing excellent regioselectivities for the alkylation reactions (C2-alkylation on indole and C5-alkylation on 2-substituted and 2,3-disubstituted pyrroles). This reaction adds to the toolbox of synthetic methods for direct C–H functionalization of N-heterocycles.

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Scheme 2 The mechanism of the newly developed catalytic alkylation procedure

Table 1 Regioselective Direct Alkylation of 1H-Indole (1a) with Primary Alkyl Bromides 2aj (Scheme [1, ]Procedure 1a)

Entrya

Temp (°C)

Time (h)

Product

Yieldb (%)

 1

70

14

3aa

67c

 2

90

61

3ab

59c

 3

70

14

3ac

58c

 4

70

14

3ad

82

 5

70

14

3ae

73

 6

90

20

3af

65

 7

70

14

3ag

72

 8

70

14

3ah

56c

 9

70

19.5

3ai

65

10

70

14

3aj

66c

a Reaction conditions: indole 1 (1 mmol), primary alkyl bromide 2 (2 mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), K2CO3 (2 mmol), DMA + 0.5 M H2O (5 mL), under argon.

b Yield of isolated product.

c A minor amount of the 2,3-dialkyl-1H-indole was isolated as a byproduct.


# 2

Scope and Limitations

The alkylation of 1H-indole (1a) with alkyl bromides 2aj proceeded smoothly with the palladium(II)/norbornene cocatalytic system to give 2-alkyl-1H-indoles regioselectively (Procedure 1, variant a).[10a] As shown in Table [1, a] broad range of functionalized primary alkyl bromides are suitable as reaction partners. The reactions were conducted with bis(acetonitrile)dichloropalladium(II) as catalyst, norbornene as cocatalyst, and potassium carbonate as base in N,N-dimethylacetamide as solvent containing 0.5 M water as an additive. In general, the 2-alkylation products were obtained in moderate to good yields and, in certain cases, minor amounts of the 2,3-dialkyl-1H-indole (4–19%) were obtained as overalkylation byproducts. The steric effect of the alkyl bromide plays an important role in the alkylation reaction; primary alkyl bromides bearing a tertiary carbon center in the β-position reacted slowly (entries 2 and 6), whereas a secondary alkyl halide (2-iodopropane) failed to react. The reaction of 1H-indole with ethyl 3-bromopropanoate failed to give the desired alkylation product as a result of elimination of hydrobromic acid under basic conditions to form ethyl acrylate. The use of an alkyl iodide instead of the corresponding alkyl bromide accelerated the reaction, but resulted in a considerable amount of the 2,3-dialkylation byproduct. Alkyl tosylates failed to react. Therefore, both reactivity and stability should be taken into account when choosing the alkyl coupling partners in this reaction.

1H-Indoles bearing electron-donating or electron-withdrawing substituents were superior substrates in this 2-alkylation reaction (Procedure 1, variant a).[10a] Table [2] lists some results obtained with 5-, 6-, and 7-substituted 1H-indoles 1bk and various primary alkyl bromides. Interestingly, electron-deficient 1H-indoles usually afforded better yields of the 2-alkylindole products than did electron-rich 1H-indoles (compare entries 1–4 with entries 5–11), but a weaker base, such as potassium bicarbonate or dipotassium hydrogen phosphate had to be used to prevent generation of undesired N-alkylindole byproducts. Halogen-substituted 1H-indoles were suitable substrates and successfully gave the corresponding halogen-substituted 2-alkyl-1H-indoles (for example, entries 4–8), allowing access to more-complex heterocyclic compounds through cross-coupling reactions.

Table 2 Regioselective Direct Alkylation of Substituted 1H-Indoles 1bk with Primary Alkyl Bromides 2 (Scheme [1, ]Procedure 1a)

Entrya

Base (equiv)

Time (h)

Product

Yieldb (%)

 1

K2CO3 (2)

18

3bd

68

 2

K2CO3 (2)

14

3cg

62c

 3

K2CO3 (2)

20

3dk

59d

 4

K2CO3 (2)

14

3ee

76

 5

KHCO3 (3)

15

3fk

74

 6

KHCO3 (3)

14

3gk

85

 7

KHCO3 (3)

38

3gl

56e

 8f

KHCO3 (4)

14

3hk

65

 9

KHCO3 (3)

14

3ij

87

10

KHCO3 (3)

14

3jg

86

11

K2HPO4 (3)

17

3kk

90

a Reaction conditions: indole 1 (1 mmol), primary alkyl bromide 2 (2 mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), base, DMA + 0.5 M H2O (5 mL), 70 °C, under argon.

b Yield of isolated product.

c 23% of the indole substrate was recovered.

d A minor amount of 2,3-dialkyl-1H-indole was isolated as a byproduct.

e 24% of the indole substrate was recovered.

f 4 equiv of BuBr were used.

The same procedure also permits the 2-alkylation of 3-substituted 1H-indole derivatives (Scheme [3]).[10b] The alkylation of 3-methyl-1H-indole (1m) with butyl bromide proceeded more slowly than the alkylation of 1H-indole and gave a moderate yield of the 2,3-dialkylated indole 3mk. Therefore, an optimization study was conducted to improve this type of reaction, especially for more complex substrates. A modified procedure (Procedure 1, variant b) using alkyl iodide 2n as the electrophile, palladium(II) chloride as the catalyst, and N,N-dimethylformamide–dimethyl sulfoxide as a solvent mixture in an atmosphere of air resulted in good conversion and a high yield in the 2-alkylation of tryptophol derivative 1n (Scheme [3]).

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Scheme 3 Regioselective direct alkylation of 3-substituted 1H-indoles (Scheme [1, ]Procedure 1b)

Because of the structural similarity between indole and pyrrole, our palladium(II)/norbornene-cocatalyzed alkylation process can also be applied to pyrrole derivatives.[11] Interestingly, we found that the reaction worked properly only with electron-deficient pyrrole derivatives, and that it failed in the case of 1H-pyrrole itself and other electron-rich pyrroles. Given that the pyrrole nucleus is more electron rich and less acidic (pK a = 23) than indole (pK a = 20.95),[12] it is possible that electron-deficient pyrroles meet the electronic requirement of this reaction more closely. Alkyl 1H-pyrrole-2-carboxylates were found to be ideal substrates, and they underwent smooth 5-alkylation reactions with various primary alkyl bromides. In a slight departure from Procedure 1, these reactions were conducted by using potassium bicarbonate as a mild base in dry N,N-dimethylacetamide at 90 ºC under air (Procedure 2). Table [3] shows some typical examples of 5-alkylation reactions of pyrrole-2-carboxylates 4ac. The yields were generally good to excellent, and in all cases a single regioisomer was obtained. Although higher temperatures and longer reaction times were required for satisfactory conversion, this reaction, like the indole alkylation reaction, showed good tolerance to a range of functional groups. A limitation of this reaction is that is appears to be restricted to 1H-pyrrole-2-carboxylates as substrates; 2-cyano-, 2-(dimethylaminocarbonyl)-, 2-formyl-, and 2-acetyl-substituted 1H-pyrroles failed to give the desired products. Methyl 1H-pyrrole-3-carboxylate gave a mixture of 5-alkylation and 2,5-dialkylation products in low yield. Therefore, this procedure is best suited for the alkylation of alkyl 1H-pyrrole-2-carboxylates.

Table 3 Regioselective Direct Alkylation of Electron-Deficient 1H-Pyrroles 4ac with Primary Alkyl Bromides 2 (Scheme [1, ]Procedure 2)

Entrya

Time (h)

Product

Yieldb (%)

 1

22

5aa

86

 2

22

5ba

84

 3

22

5ac

71

 4c

22

5an

77

 5

22

5cn

52

 6

22

5ao

89

 7d

21

5ah

87

 8

23

5ap

90

 9

22

5bp

79

10

22

5ai

84

11

22

5ag

68

12

22

5aq

82

13

22

5bq

83

a Reaction conditions: pyrrole 4 (1 mmol), primary alkyl bromide 2 (2 mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), KHCO3 (3 mmol), DMA (1 mL), 90 ºC, under air.

b Yield of isolated product.

c DMA (3 mL) was used as the solvent.

d The reaction was conducted under 1 atm O2 in a 9:1 v/v mixture of DMA and DMSO.

Procedure 2 can also be applied to a series of 2,3-disubstituted electron-deficient 1H-pyrroles 4di (Table [4]).[11] These substrates gave 5-alkylation products regioselectively, albeit in lower yields than pyrrole-2-carboxylates. Both alkoxycarbonyl and acyl groups can be used as electron-withdrawing substituents on either the C2- or the C3-position of pyrrole, although pyrrole carboxylates were found to be superior. A chlorinated pyrrole substrate 4i underwent smooth alkylation to give the chloro-substituted alkylpyrrole 5iq in high yield (entry 9). Because many methods have been reported for synthesizing 2,3-disubstituted electron-deficient pyrroles,[13] a combination of these methods and the present 5-alkylation procedure provides regioselective access to a range of advanced functionalized pyrrole derivatives.

Zoom Image
Scheme 4 Natural products aspidospermidine (6), goniomitine (7), and mycalazal 14 (8) synthesized through regioselective direct α-alkylation of N-heterocycles

The utility of the alkylation method for constructing α-alkylated N-heterocycles was showcased by its successful application in total syntheses of the Aspidosperma alkaloids aspidospermidine (6) and goniomitine (7)[10b] and the lipophilic pyrrole natural product mycalazal 14 (8).[11] In the syntheses of aspidospermidine and goniomitine, the indole alkylation protocol permitted an unprecedented synthetic strategy in which the creation of the indole C2–alkyl bonds served as key steps in building the core structures of the two natural products. The syntheses were completed via the key intermediates 3ai and 3nm, respectively. In the synthesis of mycalazal 14, reduction of the pyrrole 5-tetradecylation product 5aa was carried out to afford the target molecule (Scheme [4]).

Table 4 Regioselective Direct Alkylation of 2,3-Disubstituted Electron-Deficient 1H-Pyrroles 4di with Primary Alkyl Bromides 2 (Scheme [1, ]Procedure 2)

Entrya

Time (h)

Product

Yieldb (%)

1c

28

5dk

62

2

23

5dp

70

3

22

5ep

69

4d

23

5fk

52

5

23

5fq

71

6

23

5gk

45

7

23

5gp

47

8d,e

22

5hk

59

9e

22

5iq

91

a Reaction conditions: pyrrole 4 (1 equiv), primary alkyl bromide 2 (2 equiv), PdCl2(MeCN)2 (0.1 equiv), norbornene (2 equiv), KHCO3 (3 equiv), DMA (1 mL per mmol of pyrrole substrate 4, c = 1 M), 90 ºC, under air.

b Yield based on recovered starting material.

c BuBr (4 equiv) and KHCO3 (5 equiv) were used.

d c = 0.2 M.

e K2HPO4 (3 equiv) as base.


# 3

Summary

A straightforward and synthetically useful method for the regioselective α-alkylation of NH-indoles and pyrroles has been developed that uses a palladium(II)/norbornene cocatalytic system. The method provides a one-step transformation of easily available N-heterocycles and alkyl halides into structurally diverse alkylation products not readily available by conventional synthetic methods. The utility of this method was demonstrated by total syntheses of several indole- and pyrrole-based natural products.


#

Particulars of the reagents, substrates, and other chemicals that were used, together with analytical details, can be found in the appropriate references.[10a] [b] [11]


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Procedures

Typical procedures for the various substrate classes shown in the schemes and in the tables are described below. Procedure 1 is subdivided into two variants (1a and 1b) that require modification of the catalyst and the solvent.


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Procedure 1a (Tables 1 and 2)[10a]

A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00 mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00 mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze–pump–thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 °C or 90 °C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in a rotary evaporator (60 °C water bath, 8–10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3.

Analytical data for representative 2-alkyl-1H-indole products 3aa, 3bd, 3ee, and 3ij are provided below. Data for other products can be found in the appropriate reference.[10a]


#

2-Tetradecyl-1H-indole (3aa)

White solid; yield: 213 mg (0.679 mmol, 67%); Rf  = 0.64 (pentane–Et2O, 9:1, UV); mp 58–60 °C.

IR (ATR): 3413, 2916, 2847, 1616, 1584, 1551, 1457, 1408, 1290, 1231 cm–1.

1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.23–1.34 (m, 20 H), 1.35–1.42 (m, 2 H), 1.71 (app quin, J ≈ 7.5 Hz, 2 H), 2.74 (t, J = 7.6 Hz, 2 H), 6.21 (br s, 1 H), 7.06 (app dt, J = 0.9, J ≈ 7.5 Hz, 1 H), 7.10 (app dt, J = 0.9, J ≈ 7.5 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.52 (d, J = 7.2 Hz, 1 H), 7.83 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 14.3, 22.8, 28.5, 29.3, 29.49, 29.52, 29.6, 29.7, 29.81, 29.85, 32.1, 99.6, 110.4, 119.7, 119.9, 121.1, 129.0, 136.0, 140.2.

MS (EI, 70 eV): m/z (%) = 313 (45) [M+], 144 (45) [M – C12H25]+, 130 (100) [M – C13H27]+.

HRMS (EI, 70 eV): m/z [M+] calcd for C22H35N: 313.2764; found: 313.2759.


#

7-Methyl-2-{2-[tert-butyl(dimethyl)siloxy]ethyl}-1H-indole (3bd)

Pale-yellow oil; yield: 196 mg (0.677 mmol, 68%); Rf = 0.65 (pentane­–Et2O, 9:1, UV).

IR (ATR): 3437, 2954, 2927, 2856, 1614, 1559, 1496, 1461, 1329, 1254 cm–1.

1H NMR (500 MHz, CDCl3): δ = 0.10 (s, 6 H), 0.97 (s, 9 H), 2.45 (s, 3 H), 2.98 (t, J = 5.6 Hz, 2 H), 3.94 (t, J = 5.6 Hz, 2 H), 6.22 (s, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.98 (app t, J ≈ 7.5 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 8.70 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.3, 16.9, 18.3, 26.1, 31.2, 63.3, 100.3, 117.7, 119.68, 119.70, 121.7, 127.9, 135.7, 138.3.

MS (EI, 70 eV): m/z (%) = 289 (21) [M+], 232 (100) [M – C4H9]+, 158 (26) [M – TBSO]+, 109 (36).

HRMS (EI, 70 eV): m/z [M+] calcd for C17H27NOSi: 289.1856; found: 289.1856.


#

6-Chloro-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (3ee)

Pale-yellow oil; yield: 212 mg (0.758 mmol, 76%); Rf = 0.29 (pentane–Et2O, 2:1, UV).

IR (ATR): 3256, 2950, 2878, 1616, 1580, 1541, 1457, 1293, 1201 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.53–1.68 (m, 4 H), 1.75–1.81 (m, 1 H), 1.83–1.89 (m, 1 H), 3.02 (app t, J ≈ 5.9 Hz, 2 H), 3.48–3.53 (m, 1 H), 3.71 (app dt, J = 9.6, J ≈ 5.9 Hz, 1 H), 3.81–3.85 (m, 1 H), 4.05 (dt, J = 9.6, J ≈ 5.9 Hz, 1 H), 4.63 (dd, J = 4.8, 2.8 Hz, 1 H), 6.21–6.22 (m, 1 H), 7.02 (dd, J = 8.4, 1.9 Hz, 1 H), 7.26–7.29 (m, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 8.64 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 20.1, 25.4, 28.7, 31.0, 63.0, 67.3, 99.7, 100.1, 110.6, 120.2, 120.7, 126.9, 127.1, 136.5, 138.8.

MS (EI, 70 eV): m/z (%) = 281 (11) [M+, 37Cl], 279 (25) [M+, 35Cl], 232 (6), 195 (73), 177 (31), 164 (100), 85 (61).

HRMS (EI, 70 eV): m/z [M+] calcd for C15H18 35ClNO2: 279.1021; found: 279.1017.


#

Methyl 2-(5-Ethoxy-5-oxopentyl)-1H-indole-5-carboxylate (3ij)

White solid; yield: 266 mg (0.877 mmol, 87%); Rf = 0.30 (pentane–Et2O, 9:1, UV); mp 91–92 °C.

IR (ATR): 3336, 2932, 2861, 1712, 1695, 1614, 1556, 1439, 1325, 1292, 1238 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.69–1.80 (m, 4 H), 2.35 (t, J = 7.0 Hz, 2 H), 2.77 (t, J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 4.13 (q, J = 7.1 Hz, 2 H), 6.31 (m, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.83 (dd, J = 8.5, 1.7 Hz, 1 H), 8.28 (m, 1 H), 8.52 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 14.3, 24.5, 27.9, 28.5, 34.0, 51.9, 60.5, 100.9, 110.2, 121.7, 122.7, 122.8, 128.5, 138.8, 141.0, 168.6, 173.8.

MS (EI, 70 eV): m/z (%) = 303 (56) [M+], 257 (34), 201 (100), 188 (68), 170 (26), 129 (21).

HRMS (EI, 70 eV): m/z [M+] calcd for C17H21NO4: 303.1465; found: 303.1456.


#

Ethyl (±)-4-[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-2-yl]-2-ethylbutanoate (3nm); Procedure 1b (Scheme [3])[10b]

A 250-mL round-bottom flask equipped with a magnetic stirring bar and a rubber septum was charged with indole 1n (1.55 g, 5.63 mmol), norbornene (1.06 g, 11.3 mmol), K2CO3 (3.12 g, 22.6 mmol), alkyl iodide 2m (6.11 g, 22.6 mmol), and PdCl2 (100 mg, 0.564 mmol). Anhydrous DMF (25.3 mL), anhydrous DMSO (2.8 mL), and H2O (269 mg, 14.9 mmol) were then added sequentially. The flask was placed in a preheated oil bath at 60 °C and the mixture was stirred under a balloon pressure of air for 26 h. The mixture was then cooled to r.t. and diluted with Et2O (50 mL). H2O was added to dissolve inorganic salts, and the resulting mixture was extracted with Et2O (3 × 50 mL). The extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography [silica gel, pentane–Et2O (15:1 to 5:1)] to give a pale-brown oil [yield: 1.71 g (73%); Rf = 0.49 (pentane–Et2O, 2:1, UV)], together with recovered starting material 1n (243 mg, 16% recovery).

IR (ATR): 3391, 2930, 2856, 1732, 1715, 1462, 1385, 1254, 1192 cm–1.

1H NMR (500 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.89 (t, J = 7.4 Hz, 3 H), 0.892 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.46–1.54 (m, 1 H), 1.63–1.70 (m, 1 H), 1.75 (app ddt, J = 12.9, 4.6 Hz, J ≈ 8.2 Hz, 1 H), 1.94–2.01 (m, 1 H), 2.33–2.38 (m, 1 H), 2.66 (app dt, J = 14.9 Hz, J ≈ 8.1 Hz, 1 H), 2.79 (ddd, J = 14.9, 8.6, 5.4 Hz, 1 H), 2.88–2.97 (m, 2 H), 3.77 (t, J = 7.8 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 7.06 (app dt, J = 1.1 Hz, J ≈ 7.4 Hz, 1 H), 7.11 (app dt, J = 1.1 Hz, J ≈ 7.5 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.51 (d, J = 7.7 Hz, 1 H), 8.16 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = –5.1, 11.9, 14.5, 18.6, 24.1, 25.8, 26.2, 28.4, 32.8, 46.9, 60.6, 64.0, 108.4, 110.6, 118.3, 119.2, 121.2, 128.8, 135.4, 135.5, 176.3.

MS (EI, 70 eV): m/z (%) = 417 (29) [M+], 360 (27) [M – C4H9]+, 314 (12), 272 (100) [M – CH2OTBS]+, 240 (30), 198 (30).

HRMS (EI, 70 eV): m/z [M+] calcd for C24H39NO3Si: 417.2694; found: 417.2691.


#

Procedure 2 (Tables 3 and 4)[11]

A reaction tube (30 × 190 mm) equipped with a magnetic stirring bar and a rubber septum was charged with 1H-pyrrole substrate 4 (1.00 mmol), norbornene (188 mg, 2.00 mmol), KHCO3 (300 mg, 3.00 mmol), PdCl2(MeCN)2 (25.9 mg, 0.100 mmol), and alkyl bromide 2 (2.00 mmol). Anhydrous DMA (1 mL) was added, and the tube was heated in an aluminum block at 90 °C under a balloon pressure of air. When the reaction was complete (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was washed with H2O (20 mL), and the organic phase was separated. The aqueous layer was extracted with Et2O (2 × 20 mL). The organic layers were combined, washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel) to afford the alkylation product 5.

Analytical data for representative pyrrole alkylation products 5ap, 5fq, and 5iq are provided below. Data for other products can be found in the corresponding reference.[11]


#

Ethyl 5-(4-Ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (5ap)

Pale-yellow solid; yield: 228 mg (0.900 mmol, 90%); Rf = 0.15 (pentane­–Et2O, 3:1, UV); mp 54–56 °C.

IR (ATR): 3224, 2978, 1719, 1683, 1201 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.97 (app quin, J ≈ 7.4 Hz, 2 H), 2.33 (t, J = 7.3 Hz, 2 H), 2.69 (t, J = 7.5 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 5.98 (app t, J ≈ 3.2 Hz, 1 H), 6.83 (dd, J = 3.7, 2.5 Hz, 1 H), 9.44 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 14.3, 14.6, 24.8, 27.1, 33.5, 60.2, 60.5, 108.5, 116.0, 121.7, 137.5, 161.5, 173.3.

MS (EI, 70 eV): m/z (%) = 253 (60) [M+], 207 (35), 165 (70), 152 (100), 106 (75).

HRMS (EI, 70 eV): m/z [M+] calcd for C13H19NO4: 253.1309; found: 253.1305.


#

Ethyl 5-[2-(1,3-Dioxan-2-yl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate (5fq)

Pale-purple oil; yield: 165 mg (0.617 mmol, 61%; 71% based on recovered pyrrole substrate 4f); Rf = 0.20 (pentane–Et2O, 1:2, UV).

IR (ATR): 3278, 2926, 1655, 1458, 1232 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H), 1.34–1.38 (m, 1 H), 1.88 (dt, J = 5.0, 7.4 Hz, 2 H), 2.09 (app tq, J = 5.0 Hz, J ≈ 12.8 Hz, 1 H), 2.47 (s, 3 H), 2.64 (J = 7.4 Hz, 2 H), 3.74–3.80 (m, 2 H), 4.12 (dd, J = 11.7, 5.0 Hz, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 4.57 (t, J = 5.0 Hz, 1 H), 6.21 (d, J = 2.9 Hz, 1 H), 8.69 (br s, 1 H).

13C NMR (90.6 MHz, CDCl3): δ = 13.3, 14.6, 21.5, 25.8, 34.5, 59.3, 66.9, 101.5, 106.8, 111.4, 130.0, 134.4, 166.0.

MS (EI, 70 eV): m/z (%) = 267 (60) [M+], 222 (33), 205 (100), 166 (49), 131 (76).

HRMS (EI, 70 eV): m/z [M+] calcd for C14H21NO4: 267.1465; found: 267.1463.


#

Ethyl 3-Chloro-5-[2-(1,3-dioxan-2-yl)ethyl]-1H-pyrrole-2-carboxylate (5iq)

White solid; yield: 257 mg (0.893 mmol, 91%); Rf = 0.13 (pentane–EtOAc 4:1, UV); mp 93–94 °C.

IR (ATR): 3276, 2969, 1673, 1491 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H), 1.37–1.40 (m, 1 H), 1.92 (app q, J ≈ 6.3 Hz, 2 H), 2.06–2.16 (m, 1 H), 2.72 (t, J = 7.0 Hz, 2 H), 3.79 (app t, J ≈ 11.8 Hz, 2 H), 4.16 (dd, J = 11.6, 4.9 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 4.59 (t, J = 4.7 Hz, 1 H), 5.96 (d, J = 2.9 Hz, 1 H), 9.62 (br s, 1 H).

13C NMR (126 MHz, CDCl3): δ = 14.6, 21.9, 25.8, 33.8, 60.5, 67.1, 101.0, 109.8, 117.0, 119.2, 136.6, 160.4.

MS (EI, 70 eV): m/z (%) = 289 (30) [M+, 37Cl], 287 (90) [M+, 35Cl], 212 (85), 140 (100), 114 (70), 101 (89).

HRMS (EI, 70 eV): m/z [M+] calcd for C13H18 35ClNO4: 287.0919; found: 287.0918.


#
#

Acknowledgement

This project was supported by the Deutsche Forschungsgemeinschaft (Ba 1372/19-1). L.J. acknowledges the Alexander von Humboldt Foundation for a postdoctoral fellowship.

  • References


    • For reviews, see:
    • 3a Cacchi S, Fabrizi G. Chem. Rev. 2005; 105: 2873
    • 3b Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173
    • 3c Joucla L, Djakovitch L. Adv. Synth. Catal. 2009; 351: 673
    • 3d Bandini M, Eichholzer A. Angew. Chem. Int. Ed. 2009; 48: 9608
    • 3e Beck EM, Gaunt MJ. Top. Curr. Chem. 2010; 292: 85
    • 3f Broggini G, Beccalli EM, Fasana A, Gazzola S. Beilstein J. Org. Chem. 2012; 8: 1730
  • 4 Joule JA, Mills K. Heterocyclic Chemistry . 5th ed. Wiley; Chichester: 2010: 373

    • The direct C2 functionalization of indole can be achieved through C2-lithiation of N-protected indoles. For examples, see:
    • 5a Shirley DA, Roussel PA. J. Am. Chem. Soc. 1953; 75: 375
    • 5b Sundberg RJ, Russell HF. J. Org. Chem. 1973; 38: 3324
    • 5c Hasan I, Marinelli ER, Lin LC, Fowler FW, Levy AB. J. Org. Chem. 1981; 46: 157
    • 5d Katritzky AR, Akutagawa K. Tetrahedron Lett. 1985; 26: 5935
    • 5e Gharpure M, Stoller A, Bellamy F, Firnau G, Snieckus V. Synthesis 1991; 1079
    • 5f Fukuda T, Mine Y, Iwao M. Tetrahedron 2001; 57: 975
    • 5g De Simone F, Gertsch J, Waser J. Angew. Chem. Int. Ed. 2010; 49: 5767
    • 6a Nakao Y, Kashihara N, Kanyiva KS, Hiyama T. Angew. Chem. Int. Ed. 2010; 49: 4451
    • 6b Nagib DA, MacMillan DW. C. Nature (London) 2011; 480: 224
    • 6c Lee D.-H, Kwon K.-H, Yi CS. Science (Washington D. C.) 2011; 333: 1613
    • 6d Ding Z, Yoshikai N. Beilstein J. Org. Chem. 2012; 8: 1536
    • 6e Pan S, Ryu N, Shibata T. J. Am. Chem. Soc. 2012; 134: 17474
    • 7a Skell PS, Bean GP. J. Am. Chem. Soc. 1962; 84: 4655
    • 7b Griffin CE, Obrycki R. J. Org. Chem. 1964; 29: 3090
    • 7c Castro AJ, Deck JF, Ling NC, Marsh JP. Jr, Means GE. J. Org. Chem. 1965; 30: 344
    • 7d Bean GP. J. Org. Chem. 1967; 32: 228
    • 7e Papadopoulos EP, Tabello KI. Y. J. Org. Chem. 1968; 33: 1299
    • 7f Reinecke MG, Sebastian JF, Johnson HW. Jr, Pyun C. J. Org. Chem. 1972; 37: 3066
    • 7g Wang N.-C, Teo K.-E, Anderson HJ. Can. J. Chem. 1977; 55: 4112

      For selected recent examples of direct alkylation of pyrroles, see:
    • 8a Guerrero MA, Miranda LD. Tetrahedron Lett. 2006; 47: 2517
    • 8b Guadarrama-Morales O, Méndez F, Miranda LD. Tetrahedron Lett. 2007; 48: 4515
    • 8c Trost BM, Müller C. J. Am. Chem. Soc. 2008; 130: 2438
    • 8d Sheng Y.-F, Gu Q, Zhang A.-J, You S.-L. J. Org. Chem. 2009; 74: 6899
    • 8e Zaitsev AB, Gruber S, Plüss PA, Pregosin PS, Veiros LF, Wörle M. J. Am. Chem. Soc. 2008; 130: 11604
    • 8f Liu Y, Cao Z, Du H. J. Org. Chem. 2012; 77: 4479
    • 8g Jorapur YR, Lee C.-H, Chi DY. Org. Lett. 2005; 7: 1231
    • 8h Jorapur YR, Chi DY. Bull. Korean Chem. Soc. 2011; 32: 3130

      For reviews, see:
    • 9a Catellani M. Synlett 2003; 298
    • 9b Catellani M. Top. Organomet. Chem. 2005; 14: 21
    • 9c Catellani M, Motti E, Della Ca’ N. Acc. Chem. Res. 2008; 41: 1512
    • 9d Martins A, Mariampillai B, Lautens M. Top. Curr. Chem. 2010; 292: 1
    • 10a Jiao L, Bach T. J. Am. Chem. Soc. 2011; 133: 12990
    • 10b Jiao L, Herdtweck E, Bach T. J. Am. Chem. Soc. 2012; 134: 14563
  • 11 Jiao L, Bach T. Angew. Chem. Int. Ed. 2013; 52: 6080
  • 12 Bordwell FG. Acc. Chem. Res. 1988; 21: 456

    • For selected examples, see:
    • 13a Cambie RC, Moratti SC, Rutledge PS, Woodgate PD. Synth. Commun. 1990; 20: 1923
    • 13b Rolfs A, Liebscher J. Angew. Chem. Int. Ed. Engl. 1993; 32: 712
    • 13c Hwang SH, Kurth MJ. Tetrahedron Lett. 2002; 43: 53
    • 13d Bellur E, Langer P. Tetrahedron Lett. 2006; 47: 2151
    • 13e Lygin AV, Larionov OV, Korotkov VS, de Meijere A. Chem. Eur. J. 2009; 15: 227
    • 13f Bellur E, Yawer MA, Hussain I, Riahi A, Fatunsin O, Fischer C, Langer P. Synthesis 2009; 227
    • 13g Hekmatshoar R, Sadjadi S, Sadjadi S, Heravi MM, Beheshtiha YS, Bamoharram FF. Synth. Commun. 2010; 40: 1708

  • References


    • For reviews, see:
    • 3a Cacchi S, Fabrizi G. Chem. Rev. 2005; 105: 2873
    • 3b Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173
    • 3c Joucla L, Djakovitch L. Adv. Synth. Catal. 2009; 351: 673
    • 3d Bandini M, Eichholzer A. Angew. Chem. Int. Ed. 2009; 48: 9608
    • 3e Beck EM, Gaunt MJ. Top. Curr. Chem. 2010; 292: 85
    • 3f Broggini G, Beccalli EM, Fasana A, Gazzola S. Beilstein J. Org. Chem. 2012; 8: 1730
  • 4 Joule JA, Mills K. Heterocyclic Chemistry . 5th ed. Wiley; Chichester: 2010: 373

    • The direct C2 functionalization of indole can be achieved through C2-lithiation of N-protected indoles. For examples, see:
    • 5a Shirley DA, Roussel PA. J. Am. Chem. Soc. 1953; 75: 375
    • 5b Sundberg RJ, Russell HF. J. Org. Chem. 1973; 38: 3324
    • 5c Hasan I, Marinelli ER, Lin LC, Fowler FW, Levy AB. J. Org. Chem. 1981; 46: 157
    • 5d Katritzky AR, Akutagawa K. Tetrahedron Lett. 1985; 26: 5935
    • 5e Gharpure M, Stoller A, Bellamy F, Firnau G, Snieckus V. Synthesis 1991; 1079
    • 5f Fukuda T, Mine Y, Iwao M. Tetrahedron 2001; 57: 975
    • 5g De Simone F, Gertsch J, Waser J. Angew. Chem. Int. Ed. 2010; 49: 5767
    • 6a Nakao Y, Kashihara N, Kanyiva KS, Hiyama T. Angew. Chem. Int. Ed. 2010; 49: 4451
    • 6b Nagib DA, MacMillan DW. C. Nature (London) 2011; 480: 224
    • 6c Lee D.-H, Kwon K.-H, Yi CS. Science (Washington D. C.) 2011; 333: 1613
    • 6d Ding Z, Yoshikai N. Beilstein J. Org. Chem. 2012; 8: 1536
    • 6e Pan S, Ryu N, Shibata T. J. Am. Chem. Soc. 2012; 134: 17474
    • 7a Skell PS, Bean GP. J. Am. Chem. Soc. 1962; 84: 4655
    • 7b Griffin CE, Obrycki R. J. Org. Chem. 1964; 29: 3090
    • 7c Castro AJ, Deck JF, Ling NC, Marsh JP. Jr, Means GE. J. Org. Chem. 1965; 30: 344
    • 7d Bean GP. J. Org. Chem. 1967; 32: 228
    • 7e Papadopoulos EP, Tabello KI. Y. J. Org. Chem. 1968; 33: 1299
    • 7f Reinecke MG, Sebastian JF, Johnson HW. Jr, Pyun C. J. Org. Chem. 1972; 37: 3066
    • 7g Wang N.-C, Teo K.-E, Anderson HJ. Can. J. Chem. 1977; 55: 4112

      For selected recent examples of direct alkylation of pyrroles, see:
    • 8a Guerrero MA, Miranda LD. Tetrahedron Lett. 2006; 47: 2517
    • 8b Guadarrama-Morales O, Méndez F, Miranda LD. Tetrahedron Lett. 2007; 48: 4515
    • 8c Trost BM, Müller C. J. Am. Chem. Soc. 2008; 130: 2438
    • 8d Sheng Y.-F, Gu Q, Zhang A.-J, You S.-L. J. Org. Chem. 2009; 74: 6899
    • 8e Zaitsev AB, Gruber S, Plüss PA, Pregosin PS, Veiros LF, Wörle M. J. Am. Chem. Soc. 2008; 130: 11604
    • 8f Liu Y, Cao Z, Du H. J. Org. Chem. 2012; 77: 4479
    • 8g Jorapur YR, Lee C.-H, Chi DY. Org. Lett. 2005; 7: 1231
    • 8h Jorapur YR, Chi DY. Bull. Korean Chem. Soc. 2011; 32: 3130

      For reviews, see:
    • 9a Catellani M. Synlett 2003; 298
    • 9b Catellani M. Top. Organomet. Chem. 2005; 14: 21
    • 9c Catellani M, Motti E, Della Ca’ N. Acc. Chem. Res. 2008; 41: 1512
    • 9d Martins A, Mariampillai B, Lautens M. Top. Curr. Chem. 2010; 292: 1
    • 10a Jiao L, Bach T. J. Am. Chem. Soc. 2011; 133: 12990
    • 10b Jiao L, Herdtweck E, Bach T. J. Am. Chem. Soc. 2012; 134: 14563
  • 11 Jiao L, Bach T. Angew. Chem. Int. Ed. 2013; 52: 6080
  • 12 Bordwell FG. Acc. Chem. Res. 1988; 21: 456

    • For selected examples, see:
    • 13a Cambie RC, Moratti SC, Rutledge PS, Woodgate PD. Synth. Commun. 1990; 20: 1923
    • 13b Rolfs A, Liebscher J. Angew. Chem. Int. Ed. Engl. 1993; 32: 712
    • 13c Hwang SH, Kurth MJ. Tetrahedron Lett. 2002; 43: 53
    • 13d Bellur E, Langer P. Tetrahedron Lett. 2006; 47: 2151
    • 13e Lygin AV, Larionov OV, Korotkov VS, de Meijere A. Chem. Eur. J. 2009; 15: 227
    • 13f Bellur E, Yawer MA, Hussain I, Riahi A, Fatunsin O, Fischer C, Langer P. Synthesis 2009; 227
    • 13g Hekmatshoar R, Sadjadi S, Sadjadi S, Heravi MM, Beheshtiha YS, Bamoharram FF. Synth. Commun. 2010; 40: 1708

Zoom Image
Scheme 1
Zoom Image
Figure 1 Natural products containing an alkylindole or alkylpyrrole structure
Zoom Image
Scheme 2 The mechanism of the newly developed catalytic alkylation procedure
Zoom Image
Scheme 3 Regioselective direct alkylation of 3-substituted 1H-indoles (Scheme [1, ]Procedure 1b)
Zoom Image
Scheme 4 Natural products aspidospermidine (6), goniomitine (7), and mycalazal 14 (8) synthesized through regioselective direct α-alkylation of N-heterocycles