Efficient Preparation of Polyfunctional Indoles via a Zinc Organometallic Variation of the Fischer Indole Synthesis

Abstract

Functionalized organozinc reagents readily react with various aryldiazonium salts furnishing regioselectively polyfunctional indoles after heating with microwave irradiation. This new organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and can be readily scaled up.

Introduction

Polyfunctional indoles are privileged structures in drug discovery and are present in numerous natural products. [¹] The direct synthesis of polysubstituted indole derivatives has proven to be highly challenging due to the need of harsh and acidic reaction conditions (Fischer indole synthesis) [²] [³] or expensive transition metal catalysis. [4] Moreover, by means of classical approaches, regioisomeric mixtures are often obtained. [²] Recently, we have reported a new strategy for the regioselective preparation of polysubstituted indoles of type 1 from functionalized primary or secondary alkylzinc reagents of type 2. This organometallic variation of the Fischer indole synthesis tolerates a broad spectrum of functional groups (Scheme  [¹] , Procedures 1-3). [5] [6] Due to the good availability of functionalized organozincs, [7] [8] the efficiency, and practicability of the reaction, large-scale procedures should be possible. We report herein our efforts to prepare various polyfunctional indole derivatives in 10-20 mmol scale using this new method. Furthermore, we have applied the large-scale procedure to the preparation of the antidepressant iprindole (6) (4 g scale).

Scope and Limitations

A variety of functionalized primary or secondary alkyl­zinc bromides of type 2 are readily available via direct zinc insertion [9] or direct magnesium insertion [¹0] in the presence of ZnBr₂ from the corresponding alkyl bromides such as 3a or 3c or via transmetalation of s-BuLi with ZnBr₂ such as 3b. Addition to aryldiazonium tetrafluoroborates [¹¹] of type 4 led to the polyfunctional indoles of type 1 (Scheme  [¹] ).

Similarly, the secondary alkylzinc bromide 2d obtained after direct zinc insertion [9] with the reagent 3d [Zn (2 equiv), LiCl (1.1 equiv), ZnBr₂ (2 equiv), 50 ˚C, 12 h] added smoothly to a substituted aryldiazonium salt [¹¹] such as 4d (-60 ˚C to 25 ˚C) providing the azo compound 5a. After isomerization to the unsaturated hydrazine 5b, induced by addition of Me₃SiCl (1 equiv), heating by microwave irradiation (125 ˚C, 30 min) furnished regioselectively the polyfunctional indole 1d in 67% yield (Scheme  [²] ). No regioisomer like the indole 1e was detected. The presence of additional ZnBr₂ (2.0 equiv) proved to be essential to ensure a selective reaction with the diazonium salt in the next reaction step. In the absence of ZnBr₂, double addition products to diazonium salts were detected. The primary alkylzinc bromide 2a reacted with the aryldiazonium salt 4a (-60 to 25 ˚C) providing after microwave irradiation [Me₃SiCl (1 equiv), 125 ˚C, 90 min], the indole 1a in 90% yield (Table  [¹] , entry 1). Furthermore, the ester-substituted secondary alkylzinc bromide 2d added to the aryldiazonium tetrafluoroborate 4c furnishing under our standard conditions the 3-substituted indole 1f in 63% yield (Table  [¹] , entry 2). Similarly, s-BuZnBr˙LiCl added to various polyfunctional aryldiazonium salts (4a,b and 4e,f) affording regioselectively the functionalized 2,3-dimethylindole derivatives 1b and 1g-i in 68-80% yield (Table  [¹] , entries 3-6). Under the same reaction conditions, cyclopentylzinc bromide (2c) and substituted aryldiazonium salts such as 4a and 4c led to the corresponding indoles 1j and 1c in 68 and 72% yield, respectively (Table  [¹] , entries 7, 8). The secondary alkyl­zinc reagent c-HexZnBr˙LiCl (2e) added to readily available functionalized aryldiazonium tetrafluoroborates (4a,b, 4d, 4f,g) and provided polyfunctional tetrahydro-1H-carbazoles 1k-o in 73-91% yields (Table  [¹] , entries 9-13). Besides microwave irradiation, conventional heating was also successfully used in the case of electron-rich substrates; however, this required longer reaction time for the cyclization step to form the corresponding indole derivatives.

Table 1 Preparation of Polyfunctional Indole Derivatives of Type 1 on a 10 mmol Scale

Entry	Alkylzinc reagent	Aryldiazonium salt	Product	Yield (%)a
1	2a	4a	1a	90
2	2d	4c	1f	63
3	2b	4b R¹ = COMe, R² = H	1b	80
4	2b	4a R¹ = OMe, R² = NO2	1g	80
5	2b	4e R¹ = F, R² = H	1h	68
6	2b	4f R¹ = Br, R² = H	1i	80
7	2c	4a R¹ = OMe, R² = NO2	1j	68
8	2c	4c R¹ = OPiv, R² = H	1c	72
9	2e	4a R¹ = OMe, R² = NO2	1k	91
10	2e	4b R¹ = COMe, R² = H	1l	73
11	2e	4d R¹ = OMe, R² = H	1m	80
12	2e	4f R¹ = Br, R² = H	1n	80
13	2e	4g R¹ = CN, R² = H	1o	80
a Isolated yield of analytically pure product as determined by ¹H NMR spectroscopy.

As an application of this method, the pharmaceutical iprindole­, [¹²] a tricyclic antidepressant, was prepared in a one-pot procedure on a 20 mmol scale. Thus, cyclooctyl­zinc bromide (2f) added smoothly to phenyldiazonium tetrafluoroborate (4h) (-60 to 25 ˚C) leading after microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1 equiv) to the indole derivative 1p. Subsequent N-alkylation of the intermediate 1p [t-BuOK (1.2 equiv), 0 ˚C, 20 min; then Cl(CH₂)₃NMe₂ (1.2 equiv), 125 ˚C, 3 h] provided iprindole (6) in 72% yield (Scheme  [³] ).

In summary, we have demonstrated an efficient and regio­selective preparation of polyfunctional indoles using readily available functionalized primary and secondary alkylzinc reagents and substituted aryldiazonium salts. During the new indole synthesis, a range of sensitive functional groups such as nitro, ester, cyano, and keto groups are well tolerated. As an application of this method, the antidepressant iprindole was prepared on a four-gram scale. We have extended the reaction scope and improved the reaction conditions for the preparation of synthetically interesting indoles. The reactions could be performed with standard laboratory glassware and did not require the use of expensive chemicals or catalysts.

All reactions were carried out under argon atmosphere in dried glassware. All starting materials were purchased from commercial suppliers and used without further purification, unless otherwise stated. The functionalized aryldiazonium tetrafluoroborates 4a-h were prepared according to literature procedures. [¹¹] THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under N₂. The cyclization reaction induced by microwave irradiation was performed in a Biotage Initiator Unit (Biotage, Uppsala­, Sweden) in a closed-vessel system. Flash column chromatography was performed using Al₂O₃ from Merck (Al₂O₃ 90 active, activity grade II-III, 70-230 mesh ASTM). Yields refer to isolated compounds estimated to be >95% pure as determined by ^¹H NMR spectroscopy and capillary GC analysis.

Zinc Bromide Solution (1 M) in Tetrahydrofuran

A dry, argon-flushed 1 L Schlenk flask, equipped with a magnetic stirring bar and a septum was charged with ZnBr₂ (113 g, 0.5 mol) and heated to 150 ˚C for 5 h. After cooling to 25 ˚C under argon, anhyd THF (500 mL) was added slowly and stirred continuously until the salts had dissolved. The reagent ZnBr₂ (1 M in THF) was obtained as a colorless solution.

(4-Ethoxy-4-oxobutyl)zinc Bromide (2a); Typical Procedure 1 for Direct Zinc Insertion

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with Zn dust (2.54 g, 40 mmol) and dry LiCl (dried in vacuo with a heat gun at 450 ˚C for 5 min; 933 mg, 22 mmol). After the addition of THF (10 mL), Zn dust was activated with 1,2-dibromoethane (2 mol%) and Me₃SiCl (5 mol%). After stirring for 5 min, ethyl 4-bromobutanoate (3a; 3.9 g, 20 mmol) in THF (20 mL) was added at 25 ˚C to the suspension and the reaction mixture was stirred for 1 h at 50 ˚C. The supernatant solution was then cannulated into a new dry, argon-flushed Schlenk flask and titrated against I₂. The active alkylzinc reagent 2a was obtained with a concentration of 0.74 M in THF. [9]

Cyclopentylzinc Bromide (2c); Typical Procedure 2 for Direct Magnesium Insertion in the Presence of Zinc Bromide

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with Mg turnings (768 mg, 32 mmol) and LiCl (dried in vacuo with a heat gun at 450 ˚C for 5 min; 933 mg, 22 mmol). After the addition of THF (20 mL), the Mg was activated with 1,2-dibromoethane (2 mol%) and Me₃SiCl (5 mol%). After stirring for 5 min, ZnBr₂ (20 mmol, 20 mL, 1 Μ in THF) was added to the mixture. Thereafter, the suspension was cooled to 0 ˚C, cyclopentyl bromide (3c; 2.98 g, 20 mmol) in THF (20 mL) was added, and the reaction mixture was stirred for 4 h at 25 ˚C. The supernatant solution was then cannulated into a new dry, argon-flushed Schlenk flask and titrated against I₂. The active alkylzinc reagent 2c was obtained with a concentration of 0.36 M in THF. [¹0]

Ethyl (5-Methoxy-7-nitro-1 H -indol-3yl)acetate (1a); Typical Procedure 3

In a flame-dried and argon-flushed Schlenk flask, a solution of 2a (10 mmol, 13.5 mL, 0.74 M in THF) prepared via typical procedure 1 from ethyl 4-bromobutanoate (3a) was added dropwise to a solution of ZnBr₂ (20 mmol, 20 mL, 1 M in THF) at 25 ˚C. After stirring at 25 ˚C for 10 min, the organozinc reagent was transferred slowly to a solution of 4-methoxy-2-nitrobenzenediazonium tetrafluoroborate (4a; 3.34 g, 12.5 mmol) in THF (50 mL) at -60 ˚C. The reaction mixture was allowed to slowly warm to 25 ˚C. Subsequently, the solvent volume was reduced by half, Me₃SiCl (1.08 g, 10 mmol) was added, and the mixture was heated by microwave irradiation for 90 min at 125 ˚C. After the reaction mixture had cooled to 25 ˚C, the resulting solution was diluted with Et₂O (20 mL), and quenched with brine (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. Purification by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 95:5:0.3) afforded 1a as a red solid (2.50 g, 90%); mp 121.6-122.6 ˚C.

IR (ATR): 3390, 2940, 2854, 1708, 1584, 1562, 1512, 1476, 1440, 1410, 1362, 1308, 1266, 1208, 1192, 1130, 1090, 1040, 1022, 948, 932, 842 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 9.65 (br s, 1 H), 7.77 (d, J = 2.3 Hz, 1 H), 7.51 (d, J = 2.1 Hz, 1 H), 7.35 (d, J = 1.7 Hz, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 3.76 (s, 2 H), 1.28 (t, J = 7.0 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 171.3, 153.0, 132.4, 131.5, 126.4, 125.3, 112.2, 109.5, 106.5, 61.0, 56.4, 31.1, 14.2.

MS (70 eV, EI): m/z (%) = 278 (M⁺, 29), 206 (11), 205 (100), 159 (17).

HRMS (EI): m/z [M]⁺ calcd for C₁₃H₁₄N₂O₅: 278.0903; found: 278.0895.

1-(2,3-Dimethyl-1 H -indol-5-yl)ethanone (1b)

s-BuZnBr (2b; 10 mmol, 38.5 mL, 0.26 M in THF) was prepared via addition of s-BuLi (3b, 10 mmol, 8.33 mL, 1.2 M in hexane) to a solution of ZnBr₂ (30 mmol, 30 mL, 1 M in THF) at 0 ˚C with continuous stirring for 10 min. Following typical procedure 3, the resulting alkylzinc reagent was reacted with 4-acetylbenzenediazonium tetrafluoroborate (4b; 12.5 mmol, 2.92 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 95:5:0.3) to give 1b as a pale yellow solid (1.49 g, 80%); mp 179.0-181.0 ˚C.

IR (ATR): 3286, 1654, 1612, 1578, 1458, 1356, 1264, 1232, 1142, 970, 898, 794, 692, 648 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.27 (br s, 1 H), 8.14 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 2.67 (s, 3 H), 2.33 (s, 3 H), 2.25 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 198.7, 138.1, 132.4, 129.0, 129.0, 121.5, 119.9, 109.8, 108.7, 26.6, 11.5, 8.3.

MS (70 eV, EI): m/z (%) = 188 (16), 187 (M⁺, 87), 186 (20), 173 (14), 172 (100), 144 (51), 143 (20), 85 (13), 83 (12), 77 (14), 71 (27), 57 (36), 55 (23), 43 (32).

HRMS (EI): m/z [M]⁺ for C₁₂H₁₃NO: 187.0997; found: 187.0990.

1,2,3,4-Tetrahydrocyclopenta[ b ]indol-7-yl Pivalate (1c)

Following typical procedure 3, cyclopentylzinc bromide (2c; 10 mmol, 27.7 mL, 0.36 M in THF), prepared from cyclopentyl bromide (3c) via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4-[(2,2-dimethylpropanoyl)oxy]benzenediazonium tetrafluoroborate (4c; 12.5 mmol, 3.64 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 60 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 96:4:0.2) to give 1c as a white powder (1.86 g, 72%); mp 141.5-142.9 ˚C.

IR (ATR): 3392, 2950, 2851, 1730, 1623, 1580, 1475, 1461, 1162, 1137, 1112, 786, 625 cm^-¹.

^¹H NMR (300 MHz): δ = 7.89 (br s, 1 H), 7.15 (d, J = 8.7 Hz, 1 H), 7.08 (d, J = 2.4 Hz, 1 H), 6.73 (dd, J = 5.7 Hz, 2.4 Hz, 1 H), 2.84-2.75 (m, 4 H), 2.55-2.46 (m, 2 H), 1.40 (s, 9 H).

^¹³C NMR (75 MHz): δ = 178.15, 145.27, 144.51, 138.75, 124.94, 119.87, 113.98, 111.46, 110.51, 39.03, 28.59, 27.29, 25.86, 24.35.

MS (70 eV, EI): m/z (%) = 257 (M⁺, 32), 174 (14), 173 (100), 172 (42).

HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₉NO₂: 257.1416; found: 257.1412.

Ethyl (5-Methoxy-2-methyl-1 H -indol-3-yl)acetate (1d)

Following typical procedure 3, the alkylzinc reagent 2d (20 mmol, 22.2 mL, 0.90 M in THF), prepared from ethyl 4-bromopentanoate (3d) via typical procedure 1 (25 ˚C, 12 h) using ZnBr₂ (40 mmol, 40 mL, 1 M in THF), was reacted with 4-methoxybenzenediazonium tetrafluoroborate (4d; 25 mmol, 5.55 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 90 min) in the presence of Me₃SiCl (2.17 g, 20 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; isohexane-EtOAc-MeOH, 96:4:0.3) to give 1d as a pale yellow solid (3.35 g, 67%); mp 69.0-70.9 ˚C.

IR (ATR): 3314, 2976, 2924, 2832, 1708, 1588, 1486, 1454, 1370, 1320, 1264, 1216, 1172, 1124, 1102, 1030, 790, 686, 632 cm^-¹.

^¹H NMR (300 MHz): δ = 7.81 (br s, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 2.2 Hz, 1 H), 6.76 (dd, J = 8.8, 2.4 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 3.63 (s, 2 H), 2.35 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz): δ = 172.0, 154.1, 133.5, 130.1, 128.9, 110.9, 110.8, 104.5, 100.5, 60.6, 55.9, 30.6, 14.2, 11.7.

MS (70 eV, EI): m/z (%) = 247 (27), 175 (10), 174 (100), 131 (7).

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₁₇NO₃: 247.1208; found: 247.1204.

3-(2-Ethoxy-2-oxoethyl)-2-methyl-1 H -indol-5-yl Pivalate (1f)

Following typical procedure 3, the zinc reagent 2d (10 mmol, 11.1 mL, 0.90 M in THF), prepared from ethyl 4-bromopentanoate (3d) via typical procedure 1 (50 ˚C, 12 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4c (12.5 mmol, 3.65 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 1 h) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 90:10:0.5) to give 1f as a pale yellow solid (2.00 g, 63%); >250 ˚C (dec.).

IR (ATR): 3372, 2976, 2936, 1728, 1590, 1480, 1458, 1368, 1278, 1170, 1122, 1030, 900, 786 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.17 (br s, 1 H), 7.14 (s, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.59 (s, 2 H), 2.22 (s, 3 H), 1.39 (s, 9 H), 1.22 (t, J = 7.1 Hz, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 178.2, 172.0, 144.4, 134.3, 132.8, 128.6, 114.6, 110.6, 109.8, 104.3, 60.6, 38.9, 30.4, 27.2, 14.1, 11.4.

MS (70 eV, EI): m/z (%) = 317 (M⁺, 24), 244 (15), 233 (32), 161 (9), 160 (100), 159 (10), 131 (6), 57 (18).

HRMS (EI): m/z [M]⁺ calcd for C₁₈H₂₃NO₄: 317.1627; found: 317.1622.

5-Methoxy-2,3-dimethyl-7-nitro-1 H -indole (1g)

s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via the addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a solution of ZnBr₂ (30 mmol, 30 mL, 1 M in THF) at 0 ˚C with continuous stirring for 10 min. The resulting alkylzinc reagent was reacted, according to typical procedure 3, with 4a (12.5 mmol, 3.33 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 2 h). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 96:4:0.5) to give 1g as a red solid (1.77 g, 80%); mp 153.0-154.0 ˚C.

IR (ATR): 3420, 3370, 3110, 3024, 2914, 2836, 1604, 1576, 1502, 1474, 1458, 1388, 1364, 1330, 1288, 1192, 1178, 1140, 1082, 1044, 966, 878, 834, 756, 700, 606 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 9.25 (br s, 1 H), 7.61 (d, J = 2.2 Hz, 1 H), 7.30 (d, J = 2.2 Hz, 1 H), 3.89 (s, 3 H), 2.39 (s, 3 H), 2.19 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.6, 134.8, 133.8, 131.3, 124.8, 111.8, 107.9, 103.9, 56.4, 11.6, 8.3.

MS (70 eV, EI): m/z (%) = 221 (13), 220 (M⁺, 100), 219 (20), 205 (24), 174 (17), 159 (39), 131 (14), 130 (10).

HRMS (EI): m/z [M]⁺ calcd for C₁₁H₁₂N₂O₃: 220.0848; found: 220.0834.

5-Fluoro-2,3-dimethyl-1 H -indole (1h)

s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a solution of ZnBr₂ (30 mmol, 30 mL, 1 M in THF) at 0 ˚C with continuous stirring for 10 min. The resulting alkylzinc reagent was reacted according to typical procedure 3 with 4-fluorobenzenediazonium tetrafluoroborate (4e; 12.5 mmol, 2.62 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 90 min). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 96:4:0.2) to give 1h as a pale yellow solid (1.11 g, 68%); mp 98.2-99.0 ˚C.

IR (ATR): 3408, 2916, 2862, 1628, 1586, 1482, 1442, 1386, 1288, 1228, 1184, 1130, 944, 792, 702 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.64 (br s, 1 H), 7.06-7.17 (m, 2 H), 6.83 (dd, J = 8.8, 2.6 Hz, 1 H), 2.35 (s, 3 H), 2.17 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 157.7 (d, J = 233.4 Hz), 132.7, 131.5, 129.9 (d, J = 9.5 Hz), 110.4 (d, J = 9.8 Hz), 108.8 (d, J = 26.1 Hz), 107.5, 103.0 (d, J = 23.3 Hz), 11.6, 8.4.

MS (70 eV, EI): m/z (%) = 163 (M⁺, 18), 162 (24), 148 (15), 71 (54), 70 (18), 57 (75), 65 (38), 55 (26), 44 (32), 43 (100).

HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₀FN: 163.0797; found: 163.0796.

5-Bromo-2,3-dimethyl-1 H -indole (1i)

s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a solution of ZnBr₂ (30 mmol, 30 mL, 1 M in THF) at 0 ˚C with continuous stirring for 10 min. The resulting alkylzinc reagent reacted according to typical procedure 3 with 4-bromobenzenediazonium tetrafluoroborate (4f; 12.5 mmol, 3.38 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 90 min). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; isohexane-EtOAc-MeOH, 95:5:0.5) to give 1i as a pale yellow solid (1.79 g, 80%); mp 152.6-154.1 ˚C.

IR (ATR): 3396, 2914, 1572, 1466, 1426, 1386, 1302, 1274, 1238, 1044, 1002, 966, 898, 864, 798, 744, 668 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.62 (br s, 1 H), 7.59 (d, J = 1.7 Hz, 1 H), 7.19 (dd, J = 8.6, 1.7 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 2.33 (s, 3 H), 2.18 (s, 3 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 133.7, 132.2, 131.2, 123.4, 120.5, 112.2, 111.4, 106.9, 11.5, 8.3.

MS (70 eV, EI): m/z (%) = 226 (24), 225 (M⁺, 65), 224 (95), 223 (M⁺, 81), 222 (69), 210 (42), 208 (45), 143 (62), 115 (26), 89 (17), 75 (22), 71 (56), 57 (42), 44 (32), 43 (100).

HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₀ ⁷⁹BrN: 222.9997; found: 222.9974.

7-Methoxy-5-nitro-1,2,3,4-tetrahydrocyclopenta[ b ]indole (1j)

Following typical procedure 3, cyclopentylzinc bromide (2c; 10 mmol, 27.7 mL, 0.36 M in THF), prepared from cyclopentyl bromide (3c) via typical procedure 1 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4a (12.5 mmol, 3.33 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 90 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 96:4:0.2) to give 1j as a red solid (1.56 g, 68%); mp 138.0-139.0 ˚C.

IR (ATR): 3472, 2960, 2932, 2856, 1570, 1510, 1464, 1372, 1326, 1274, 1194, 1178, 1154, 1088, 1032, 836, 758 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 9.45 (br s, 1 H), 7.61 (d, J = 2.2 Hz, 1 H), 7.27 (d, J = 2.1 Hz, 1 H), 3.88 (s, 3 H), 2.85-2.99 (m, 2 H), 2.72-2.85 (m, 2 H), 2.46-2.69 (m, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.8, 147.8, 132.0, 130.0, 128.6, 120.4, 112.1, 103.7, 56.4, 28.7, 25.9, 24.1.

MS (70 eV, EI): m/z (%) = 233 (14), 232 (M⁺, 100), 231 (38), 186 (14), 185 (11), 171 (18), 143 (9).

HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₂N₂O₃: 232.0848; found: 232.0864.

6-Methoxy-8-nitro-2,3,4,9-tetrahydro-1 H -carbazole (1k)

Following typical procedure 3, cyclohexylzinc bromide (2e; 10 mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4a (12.5 mmol, 3.33 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 95:4:0.5) to give 1k as a red solid (2.25 g, 91%); mp 137.1-138.6 ˚C.

IR (ATR): 3424, 2934, 2844, 1734, 1604, 1574, 1508, 1466, 1440, 1382, 1278, 1194, 1134, 1036, 834, 758, 648, 606 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 9.27 (br s, 1 H), 7.62 (d, J = 2.1 Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 3.89 (s, 3 H), 2.77 (t, J = 5.9 Hz, 2 H), 2.65 (t, J = 5.9 Hz, 2 H), 1.89-2.00 (m, 2 H), 1.80-1.89 (m, 2 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 152.7, 138.1, 132.3, 131.5, 125.3, 111.7, 110.9, 103.9, 56.4, 23.2, 22.9, 22.8, 20.6.

MS (70 eV, EI): m/z (%) = 246 (10), 247 (M⁺, 78), 245 (11), 219 (11), 218 (100), 203 (8).

HRMS (EI): m/z [M]⁺ calcd for C₁₃H₁₄N₂O₃: 246.1004; found: 246.0997.

1-(2,3,4,9-Tetrahydro-1 H -carbazol-6-yl)ethanone (1l)

Following typical procedure 3, cyclohexylzinc bromide (2e; 10 mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4b (12.5 mmol, 3.33 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 90:10:0.5) to give 1l as a pale yellow solid (1.56 g, 73%); mp 122.5-124.0 ˚C.

IR (ATR): 3286, 2926, 2854, 1652, 1614, 1578, 1460, 1354, 1232, 1122, 812, 798, 686, 648 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.12 (s, 1 H), 8.09 (br s, 1 H), 7.78 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1 H), 2.73 (t, J = 5.9 Hz, 4 H), 2.65 (s, 3 H), 1.78-2.01 (m, 4 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 198.5, 138.5, 135.8, 129.2, 127.5, 121.7, 119.7, 111.8, 110.0, 62.7, 26.6, 23.2, 23.0, 20.8.

MS (70 eV, EI): m/z (%) = 214 (19), 213 (M⁺, 100), 212 (11), 198 (51), 185 (42), 170 (18), 142 (8).

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₁₅NO: 213.1154; found: 213.1151.

6-Methoxy-2,3,4,9-tetrahydro-1 H -carbazole (1m)

Following typical procedure 3, cyclohexylzinc bromide (2e; 10 mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4d (12.5 mmol, 2.77 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 95:4:0.5) to give 1m [¹³] as a pale yellow solid (2.25 g, 80%); mp 107.9-109.8 ˚C.

^¹H NMR (200 MHz, CDCl₃): δ = 7.56 (br s, 1 H), 7.15 (d, J = 8.6 Hz, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.6 Hz, 2.4 Hz, 1 H), 3.87 (s, 3 H), 2.73-2.69 (m, 4 H), 2.67-1.89 (m, 4 H).

6-Bromo-2,3,4,9-tetrahydro-1 H -carbazole (1n)

Following typical procedure 3, cyclohexylzinc bromide (2e; 10 mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4f (12.5 mmol, 3.38 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; isohexane-EtOAc-MeOH, 95:5:0.5) to give 1n as a pale yellow solid (2.00 g, 80%); mp 152.6-154.1 ˚C.

IR (ATR): 3400, 2938, 2906, 2848, 1578, 1434, 1310, 1232, 1046, 974, 862, 796 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.63 (br s, 1 H), 7.58 (d, J = 1.8 Hz, 1 H), 7.19 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 2.73-2.64 (m, 4 H), 1.95-1.84 (m, 4 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 135.60, 134.26, 129.68, 123.59, 120.42, 112.32, 111.71, 110.01, 23.22, 23.14, 23.06, 20.76.

MS (70 eV, EI): m/z (%) = 252 (10), 251 (M⁺, 76), 250 (26), 249 (M⁺, 81), 248 (16), 224 (12), 223 (98), 221 (100), 168 (19), 167 (15), 142 (11), 115 (12).

HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₂ ⁷⁹BrN: 249.0153; found: 249.0137.

2,3,4,9-Tetrahydro-1 H -carbazole-6-carbonitrile (1o)

Following typical procedure 3, cyclohexylzinc bromide (2e; 10 mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (20 mmol, 20 mL, 1 M in THF), was reacted with 4-cyanobenzenediazonium tetrafluo­roborate (4g; 12.5 mmol, 2.71 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (1.08 g, 10 mmol). The crude product was purified after the usual workup by flash column chromatography (Al₂O₃; isohexane-EtOAc-MeOH, 95:6:1) to give 1o as a pale yellow solid (1.56 g, 80%); mp 124.0-125.0 ˚C.

IR (ATR): 3314, 2926, 2846, 2216, 1686, 1622, 1478, 1318, 1236, 1180, 872, 806, 798, 626 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 8.13 (br s, 1 H), 7.76 (s, 1 H), 7.19-7.49 (m, 2 H), 2.74 (t, J = 5.7 Hz, 2 H), 2.67 (t, J = 5.8 Hz, 2 H), 1.75-2.03 (m, 4 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 137.4, 136.6, 127.7, 124.1, 123.1, 121.2, 111.0, 111.0, 101.7, 23.1, 22.9, 22.8, 20.6.

MS (70 eV, EI): m/z (%) = 197 (11), 196 (M⁺, 79), 195 (17), 169 (12), 168 (100).

HRMS (EI): m/z [M]⁺ calcd for C₁₃H₁₂N₂: 196.1000; found: 196.0997.

[3-(6,7,8,9,10,11-Hexahydro-5 H -cycloocta[ b ]indol-5-yl)propyl]dimethylamine (6, Iprindole)

Following typical procedure 3, cyclooctylzinc bromide (2f; 20 mmol, 57 mL, 0.35 M in THF), prepared from cyclooctyl bromide via typical procedure 2 (25 ˚C, 4 h) using ZnBr₂ (40 mmol, 40 mL, 1 M in THF), was reacted with phenyldiazonium tetrafluoroborate (4h; 25 mmol, 4.80 g). The hydrazone intermediate was heated by microwave irradiation (125 ˚C, 30 min) in the presence of Me₃SiCl (2.17 g, 20 mmol). After cooling to 0 ˚C, t-BuOK (24 mmol, 2.29 g) was slowly added. The reaction mixture was stirred for 20 min at 0 ˚C followed by the addition of (3-chloropropyl)dimethylamine (24 mmol, 2.92 g). The resulting solution was heated by microwave irradiation (125 ˚C, 3 h) and quenched with brine (50 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (Na₂SO₄) and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Al₂O₃; pentane-EtOAc-MeOH, 97:3:0.3) to give iprindole (6) as a yellow oil (4.09 g, 72%).

IR (ATR): 3050, 2920, 2848, 2814, 2764, 1464, 1370, 1338, 1316, 1180, 1040, 734, 696 cm^-¹.

^¹H NMR (300 MHz, CDCl₃): δ = 7.50 (d, J = 7.3 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.10 (t, J = 7.9 Hz, 1 H), 7.01-7.08 (m, 1 H), 4.12 (t, J = 7.6 Hz, 2 H), 2.79-2.95 (m, 4 H), 2.30 (t, J = 6.9 Hz, 2 H), 2.23 (s, 6 H), 1.83-1.97 (m, 2 H), 1.64-1.78 (m, 4 H), 1.35-1.47 (m, 4 H).

^¹³C NMR (75 MHz, CDCl₃): δ = 136.6, 136.0, 127.5, 120.1, 118.4, 117.6, 111.8, 108.9, 56.8, 45.4, 40.9, 30.4, 29.3, 28.7, 26.1, 25.9, 23.0, 22.9.

MS (70 eV, EI): m/z (%) = 284 (M⁺, 57), 213 (33), 212 (20), 198 (20), 185 (21), 184 (20), 171 (21), 170 (73), 157 (21), 156 (26), 145 (22), 144 (24), 71 (15), 58 (100), 43 (58), 41 (48).

HRMS (EI): m/z [M]⁺ calcd for C₁₉H₂₈N₂: 284.2252; found: 284.2246.

Acknowledgment

We thank the European Research Council (ERC) under the European Community’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement No. 227763 for financial support. Z.-G. Zhang thanks especially the Chinese Scholarship for financial support. We also thank BASF AG (Ludwigshafen), W. C. Heraeus GmbH (Hanau) and Chemetall GmbH (Frankfurt) for the generous gift of chemicals.

References

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• 1c Sundberg RJ. In Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky AR. Ress CW. Scriven EFV. Bird CW. Pergamon Press; Oxford: 1996. 
  Search in Google Scholar
• 1d Joule A. In Science of Synthesis   Vol. 10:  Thomas EJ. Thieme; Stuttgart: 2000.  Chap. 10.13.
  Search in Google Scholar
• 2a Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
  Search in Google Scholar
• 2b Zeni G. Larock RC. Chem. Rev.  2004,  104:  2285 
  Search in Google Scholar
• 3 Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
  CrossrefPubMedSearch in Google Scholar
• 4a Fischer E. Jourdan F. Ber. Dtsch. Chem. Ges.  1883,  16:  2241 
  Search in Google Scholar
• 4b Robinson B. The Fischer Indole Synthesis   Wiley-Interscience; New York: 1982. 
• 5 Handbook of Functionalized Organometallics   Knochel P. Wiley-VCH; Weinheim: 2005. 
• 6 Haag BA. Zhang Z.-G. Li J.-S. Knochel P. Angew. Chem. Int. Ed.  2010,  49: in press; DOI: anie.201005319
  Search in Google Scholar
• 7 Erdik E. Organozinc Reagents in Organic Synthesis   CRC-Press; Boca Raton: 1996. 
• 8a Dong Z. Manolikakes G. Li J. Knochel P. Synthesis  2009,  681 
• 8b Despotopoulou C. Gignoux C. McConnell D. Knochel P. Synthesis  2009,  3661 
• 8c Monzon G. Knochel P. Synlett  2010,  304 
• 8d Metzger A. Argyo C. Knochel P. Synthesis  2010,  882 
• 9 Krasovskiy A. Malakhov V. Gavryushin A. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  6040 
  CrossrefPubMedSearch in Google Scholar
• 10a Piller FM. Appukkuttan P. Gavryushin A. Helm M. Knochel P. Angew. Chem. Int. Ed.  2008,  47:  6802 
  Search in Google Scholar
• 10b Piller FM. Metzger A. Schade MA. Haag BA. Gavryushin A. Knochel P. Chem. Eur. J.  2009,  15:  7192 
  Search in Google Scholar
• 11a Haag BA. Peng Z. Knochel P. Org. Lett.  2009,  11:  4270 
  Search in Google Scholar
• 11b Sapountzis I. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  897 
  Search in Google Scholar
• 12a Rice LM. Hertz E. Freed ME. J. Med. Chem.  1964,  7:  313 
  Search in Google Scholar
• 12b Baxter BL. Gluckman MI. Nature  1969,  223:  750 
  Search in Google Scholar
• 13 Chen J. Hu Y. Synth. Commun.  2006,  36:  1485 
  CrossrefSearch in Google Scholar