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

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.

Key words

catalysis - alkylations - regioselectivity - heterocycles - palladium - indoles - pyrroles

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.

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.

Scheme 2 The mechanism of the newly developed catalytic alkylation procedure

Table 1 Regioselective Direct Alkylation of 1H-Indole (1a) with Primary Alkyl Bromides 2a–j (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 2a–j 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 1b–k 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 1b–k 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]).

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 4a–c. 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 4a–c 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 4d–i (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.

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 4d–i 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]

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.

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%); R_f  = 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%); R_f = 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%); R_f = 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%); R_f = 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%); R_f = 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%); R_f = 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); R_f = 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%); R_f = 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

• 1a Sundberg RJ. Indoles . Academic Press; San Diego: 1996
• 1b Sundberg RJ In Comprehensive Heterocyclic Chemistry II . Vol. 2. Katritzky AR, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996: 119
• 1c Joule JA In Science of Synthesis, Thomas E. J. Vol. 10. Thieme; Stuttgart: 2000: 361
• 1d Gribble GW. J. Chem. Soc., Perkin Trans. 1 2000; 1045
• 1e Tois J, Franzén R, Koskinen A. Tetrahedron 2003; 59: 5395
• 1f d’Ischia M, Napolitano A, Pezzella A In Comprehensive Heterocyclic Chemistry III . Vol. 3. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Amsterdam: 2008. Chap. 1–4
• 2a Atta-ur-Rahman, Basha A. Indole Alkaloids . Harwood Academic; Amsterdam: 1997
• 2b Gribble GW In Rodd’s Chemistry of Carbon Compounds . 2nd ed., Suppl. 2, Vol. IV; Sainsbury M. Elsevier; Amsterdam: 1997. Chap. 9, 69
• 2c Mal D, Shome B, Dinda BK In Heterocycles in Natural Product Synthesis . Majumdar KC, Chattopadhyay SK. Wiley-VCH; Weinheim: 2011: 187

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