New Three-Component Glyoxylation-Decarbonylative Stille Coupling Sequence to Acyl Heterocycles under Mild Conditions

Abstract

A consecutive sequence of glyoxylation of 1-methyl-1H-indole, 1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine or N-substituted pyrroles with oxalyl chloride and subsequent decarbonylative Stille coupling under very mild, Lewis acid free conditions using all reactants in equimolar quantities is reported. As an illustration, this glyoxylation-decarbonylative coupling sequence was elaborated into a consecutive, four-component synthesis of 1-methyl-3-(1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-1H-indole.

The selective formation of unsymmetrical ketones by cross-coupling reactions is of significant interest in organic chemistry. [¹] Therefore, many different ways to introduce the carbonyl group have been developed. Besides the well-established Friedel-Crafts-type acylations, [²] cross-coupling reactions have been introduced as catalytic alternatives. Most of the methods directly start from acid chlorides due to their easy availability. In cases where the acid chlorides are either not readily available or difficult to handle, cross coupling cannot prevail. An obvious solution to this problem are carbonylative cross-coupling reactions starting from aryl halides and carbon monoxide [³] or other carbon monoxide sources such as molybdenum hexacarbonyl. [4] Although mild carbonylations utilizing carbon monoxide at ambient pressure have been reported, the effective concentration of carbon monoxide in the reaction mixture is of crucial importance for full conversion and still represents a limitation of the method. Alternatively, decarbonylative cross coupling of α-dicarbonyl compounds can be considered. In particular, catalytic decarbonylations are highly desirable and have recently received considerable attention. For instance, palladium-catalyzed decarbonylative carbostannylations under mild conditions [5] and decarbonylative Heck reactions [6] at high temperatures and long reaction times have been reported. Recently, we established a new decarbonylative Sonogashira­ coupling of glyoxylyl chlorides, [7] which are in situ generated at room temperature from oxalyl chloride as an easy-to-handle carbon monoxide surrogate. In a one-pot sequence of Friedel-Crafts acylation of electron-rich heterocycles with oxalyl chloride (glyoxylation), followed by decarbonylative Sonogashira coupling, alkynones are obtained in good to excellent yields under mild conditions.

The Stille reaction is known to proceed under mild reaction conditions with high tolerance for many functional groups. Moreover, Stille couplings of acid chlorides are well precedented. [8] In addition, α-oxo acid chlorides have been successfully applied in the synthesis of 1,2-diketones. [9] Here, we report an extension of the glyoxylation-decarbonylative coupling methodology in which we have devised a consecutive three-component synthesis of ketones by a glyoxylation-decarbonylative Stille coupling sequence using electron-rich heterocycles, oxalyl chloride and organostannanes.

First, we tested the glyoxylation-decarbonylative Stille coupling of 1-methyl-1H-indole (1) with tributyl(phenylethynyl)stannane (2a) and tributyl(thiophen-2-yl)stannane (2b) via the in situ generated indole-3-glyoxylyl chloride, which gives rise to the formation of the N-methylindolyl ketones 3 (Scheme  [¹] , Table  [¹] ).

By applying 1 mol% of the air-stable precatalyst PdCl₂(PPh₃)₂, a 36% yield of the desired product 3a could be isolated (Table  [¹] , entry 1). One equivalent of triethyl­amine is stoichiometrically necessary to scavenge the hydrochloric acid generated in the glyoxylation step. Interestingly, addition of a second equivalent of triethyl­amine suppresses the formation of the non-decarbonylated byproduct (as detected by TLC) and also leads to an increase in the overall yield (Table  [¹] , entries 2 and 3). In the absence of triethylamine, the formation of the desired product 3b cannot be detected by TLC (Table  [¹] , entry 8). It is known that the addition of copper iodide often increases the yield in Stille coupling reactions (‘copper effect’). [¹0] Indeed, with stannane 2a as a substrate, the ‘copper effect’ could be confirmed (Table  [¹] , entry 4); however, with tributyl(thiophen-2-yl)stannane (2b), the addition of copper iodide did not exert any effect (Table  [¹] , entries 5 and 6). Presumably, in the case of the coupling with tributyl(phenylethynyl)stannane (2a) in the presence of copper iodide, transmetalation produces a copper acetylide for a terminating Sonogashira coupling. As a consequence, tributyl(thiophen-2-yl)stannane (2b) was chosen as the model stannane for further optimization of the decarbonylative Stille coupling (Table  [¹] , entries 7-15). After 20 hours at room temperature, the decarbonylative Stille coupling was essentially complete (Table  [¹] , entry 7). A rapid precatalyst screening revealed that none of the other precursors gave a higher yield of 3b than PdCl₂(PPh₃)₂ (Table  [¹] , entries 9-12). Upon stirring the mixture at 60 ˚C, complete conversion was achieved within one hour (Table  [¹] , entry 13). The coupling without decarbonylation [9] was attempted under palladium-free conditions (Table  [¹] , entry 14) and with copper iodide (Table  [¹] , entry 15), but the TLC control showed no conversion, even after 20 hours.

Despite the general smoothness of the Stille reaction, the separation of organotin residues during workup has occasionally been known to hamper the isolation of pure reaction products. Besides trituration of the flash-chromatographed product in n-pentane under sonication in an ultrasound bath, neither removal of tin residues by fluoridation with aqueous potassium fluoride solution or tetrabutylammonium fluoride, [¹¹] nor flash chromatography on silica gel containing potassium fluoride (10:1), [¹²] furnished completely organotin-free products. The best workup protocol is to stir the reaction mixture after the decarbonylative Stille coupling step with an excess of potassium hydroxide in methanol [¹³] overnight at room temperature, followed by aqueous workup, to obtain an essentially tin-free product.

With this convenient method in hand and starting from 1-methyl-1H-indole (1), 1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (4) or the N-substituted pyrroles 6 and 8, the glyoxylation-decarbonylative Stille coupling sequence furnished various acyl heterocycles 3, 5, 7 and 9 in moderate to good yields (Scheme  [²] , Table  [²] ).

The structures of compounds 3, 5, 7 and 9 were unambiguously supported by NMR spectroscopy, mass spectrometry and combustion analysis, and later corroborated by an X-ray crystal structure analysis of compound 3b (Figure  [¹] ). [¹4]

For the indole derivatives, 1-methyl-1H-indole (1) and 7-azaindole 4, the glyoxylation occurs at the most electron-rich 3-position (Table  [²] , entries 1-7). The N-substituted pyrroles 6 are regioselectively glyoxylated at the 2-position (Table  [²] , entries 8-11). If the 2- and 5-positions are blocked, as in the case of 1,2,5-trimethyl-1H-pyrrole (8), expectedly, the glyoxylation occurs at the 3-position (Table  [²] , entry 12). The application of the N-substituted indole 1, the 7-azaindole 4 and the pyrrole derivatives 6 and 8 supports the tolerance of the glyoxylation-decarbonylative Stille coupling sequence for a variety of N-heterocycles as substrates. In contrast to findings by Milstein and Stille, [8b] the decarbonylative Stille coupling is not inhibited by the formation of unreactive palladium carbonyl complexes but rather proceeds smoothly under mild conditions. Upon application of a wide range of unsaturated, aromatic and even heterocyclic stannanes 2, the glyoxylation-decarbonylative Stille coupling sequence furnishes various acyl heterocycles 3, 5, 7 and 9. Tributyl(phenylethynyl)stannane (2a) gives rise to the alkynones 3a and 7a (Table  [²] , entries 1 and 8). Interestingly, with tributyl(vinyl)stannane (2e), enones such as 3e and 9 can be prepared in a one-pot fashion as highly reactive Michael systems (Table  [²] , entries 5 and 12). Upon extending the reaction time to 20 hours, the yield for the sequence with 1-methyl-1H-indole (1) and tributyl(phenyl)stannane (2f) could be increased from 16% to 68% of 3f (Table  [²] , entry 6); however, in the case of stannane 2e, an extension of the reaction time to 20 hours brought no significant increase in the yield (Table  [²] , entry 5).

Encouraged by the ease and broad versatility of the sequence, we probed the extension to a consecutive four-component pyrazoline synthesis (Scheme  [³] ). Starting from 1-methyl-1H-indole (1), the glyoxylation-decarbonylative Stille coupling sequence with vinylstannane 2e furnishes enone 3e, which was reacted in situ with methylhydrazine (10) to give the pyrazoline 11 in 66% yield. Indeed, the isolated yield of 11 was higher than the isolated yield of 3e, emphasizing the advantage of the one-pot sequence over a stepwise protocol with isolation of reactive, intermediate products.

The structure of the pyrazoline 11 was unambiguously supported by NMR spectroscopy, mass spectrometry and combustion analysis.

In conclusion, we have developed a straightforward, novel, one-pot three-component synthesis of unsymmetrical heterocyclic ketones by glyoxylation of 1-methyl-1H-indole (1), the 7-azaindole 4 or the N-substituted pyrrole derivatives 6 and 8 with oxalyl chloride and subsequent decarbonylative Stille coupling of the in situ generated heteroareneglyoxylyl chlorides with various stannanes including vinyl and alkynyl, as well as N- and S-heterocyclic derivatives. As already demonstrated for glyoxylation-decarbonylative alkynylation, [7] this sequence can be performed on a 5 mmol scale under mild conditions and with only equimolar quantities of reagents and a high tolerance for various substituents. In addition, our consecutive, four-component synthesis of 1-methyl-3-(1-methyl-4,5-dihydro-1H-pyrazol-3-yl)-1H-indole (11) illustrates­ the conceptual versatility of the glyoxylation-decarbonylative cross-coupling methodology as an entry to multicomponent syntheses of densely functionalized heterocycles.

Table 2 Three-Component Glyoxylation-Decarbonylative Stille Coupling Synthesis of Ketones 3, 5, 7 and 9 ^a (continued)

Entry	Starting electron-rich heterocycle	Stannane 2	Reaction time (decarbonylative Stille coupling step)	Ketone product	Isolated yield (%)
1	1	2a: R¹ = C≡CPh	1 h	3a	81
2	1	2b: R¹ = thiophen-2-yl	1 h	3b	81
3	1	2c: R¹ = thiophen-3-yl	1 h	3c	66
4	1	2d: R¹ = pyridin-2-yl	1 h	3d	75
5	1	2e: R¹ = CH=CH2	20 hb	3e	58
6	1	2f: R¹ = Ph	20 h	3f	68
7	4	2b: R¹ = thiophen-2-yl	1 h	5	62c
8	6a: R² = Me	2a: R¹ = C≡CPh	1 h	7a	82
9	6a: R² = Me	2b: R¹ = thiophen-2-yl	1 h	7b	88
10	6b: R² = CH2CH2CN	2b: R¹ = thiophen-2-yl	1 h	7c	85
11	6c: R² = Bn	2b: R¹ = thiophen-2-yl	1 h	7d	81
12	8	2e: R¹ = CH=CH2	1 h	9	57
a See Scheme  [²] . The reactions were performed in THF [c(1, 6 or 8) = 0.2 M] using 5.00 mmol of 1-methyl-1H-indole (1) or N-substituted pyrroles 6 or 8 under the optimized reaction conditions. b After 1 h (for the decarbonylative Stille coupling step), ketone 3e could be isolated in 52% yield. c The glyoxylation step was performed in DME [c(4) = 0.2 M] using 5.00 mmol of 7-azaindole 4 at 100 ˚C for 2 h.

All reactions were carried out in oven-dried Schlenk glassware using septa and syringes under argon atmosphere. THF was dried using an MBraun MB SPS-800 system. Et₃N was refluxed under argon over ketyl sodium, distilled and stored in a Schlenk flask over KOH pellets under argon atmosphere. 1-Methyl-1H-indole (1), 1-methyl-1H-pyrrole (6a), 3-(1H-pyrrol-1-yl)propanenitrile (6b), 1-benzyl-1H-pyrrole (6c), 1,2,5-trimethyl-1H-pyrrole (8), tri­butyl(phenylethynyl)stannane (2a), tributyl(thiophen-2-yl)stannane (2b), tributyl(pyridin-2-yl)stannane (2d), tributyl(vinyl)stannane (2e) and tributyl(phenyl)stannane (2f) are commercially available and were purchased from Acros Organics N. V., Aldrich Chemie GmbH, Fluka AG, ABCR GmbH & Co. KG, and Merck Serono KGaA. Oxalyl chloride was purchased from Merck Serono KGaA. All commercial grade reagents were used as supplied without further purification. Tributyl(thiophen-3-yl)stannane (2c) was prepared according to literature procedures. [¹5] MeOH (p.a.) and KOH (p.a.) used for the removal of tin residues were purchased from Aldrich­ Chemie GmbH and Roth GmbH & Co. KG. The purification of products was performed on silica gel 60 (0.015-0.040 mm) from Merck Serono KGaA using a Biotage SP1 Flash Purification System (SP-SNAP 340-g cartridges) and petroleum ether (boiling range 40-60 ˚C)-EtOAc as eluent (isocratic or gradient). The crude mixtures were adsorbed onto Celite^® 545 (0.02-0.10 mm) from Merck Serono KGaA before chromatographic purification. The reaction progress was monitored qualitatively using TLC silica gel 60 F₂₅₄ aluminum sheets (5 × 7.5 cm) obtained from Merck Serono KGaA. The spots were detected with UV light at 254 nm and using aq KMnO₄ soln. ^¹H, ^¹³C and 135-DEPT NMR spectra were recorded on a Bruker DRX 500 spectrometer; CDCl₃ was used as solvent and TMS was used as reference (δ = 0.0). The type of carbon atoms was determined on the basis of the 135-DEPT NMR spectra. EI mass spectra were measured on Varian MAT 311A and Finnigan MAT 8200 spectrometers. IR spectra were obtained on a Bruker Vector 22 FT-IR instrument; solids were measured as KBr pellets and oils as films on KBr plates. Melting points (uncorrected) were measured on a Reichert-Jung Thermovar apparatus. Elemental analyses were carried out in the microanalytical laboratory of the Institut für Pharmazeutische Chemie in Düsseldorf. The X-ray crystal structure was measured on a Stoe IPDS diffractometer.

Glyoxylation-Decarbonylative Stille Coupling Sequence; General Procedure

1-Methyl-1H-indole (1), 7-azaindole 4 (see analytical data for 5) or N-substituted pyrroles 6 or 8 (5.00 mmol) in anhyd THF (25 mL) was placed under argon atmosphere in a screw-cap vessel with a septum, and the mixture was degassed with argon for 5 min and cooled to 0 ˚C (ice water). After 15 min, oxalyl chloride (0.44 mL, 5.00 mmol) was added dropwise to the mixture at 0 ˚C. The mixture was allowed to warm to r.t. (water bath) and was stirred for 4 h. Then, PdCl₂(PPh₃)₂ (177 mg, 0.25 mmol), anhyd Et₃N (1.39 mL, 10.0 mmol) and a stannane 2 (5.00 mmol) were successively added to the mixture which was stirred at 60 ˚C for 1 h. The evolution of carbon monoxide was observed. After complete conversion (the product formation was monitored by TLC), the mixture was allowed to cool to r.t. and MeOH (25 mL) and KOH (0.66 g, 10.0 mmol) were added. The mixture was stirred at r.t. for 20 h. Then, H₂O (25 mL) was added and the mixture was extracted with CH₂Cl₂ (4 × 50 mL, monitored by TLC). The combined organic layers were dried (anhyd Na₂SO₄). The solvents were removed under reduced pressure, and the residue was absorbed onto Celite^® and purified by chromatography on silica gel [petroleum ether (40-60 ˚C)-EtOAc] to give the ketones 3, 5, 7 or 9 after drying under reduced pressure. In some cases, it was necessary to additionally purify the product by suspending it in n-pentane, sonication in an ultrasound bath, filtration and drying under reduced pressure.

1-(1-Methyl-1 H -indol-3-yl)-3-phenylprop-2-yn-1-one (3a)

According to the standard procedure, the reaction with stannane 2a (1.84 mL, 5.00 mmol) gave 3a as a yellow solid; yield: 1.05 g (81%); mp 111-113 ˚C.

IR (KBr): 3053, 2204, 1593, 1525, 1490, 1469, 1398, 1377, 1339, 1272, 1250, 1198, 1149, 1123, 1088, 1049, 1011, 950, 794, 769, 751, 689, 567, 529, 430 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.85 (s, 3 H), 7.31-7.46 (m, 6 H), 7.63-7.66 (m, 2 H), 7.93 (s, 1 H), 8.40-8.44 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 33.7 (CH₃), 87.6 (C_q), 87.9 (C_q), 109.9 (CH), 118.4 (C_q), 120.8 (C_q), 122.5 (CH), 123.1 (CH), 123.9 (CH), 125.8 (C_q), 128.6 (CH), 130.1 (CH), 132.7 (CH), 137.7 (C_q), 138.9 (CH), 171.1 (C_q).

MS (EI, 70 eV): m/z (%) = 260 (21), 259 (100) [M]⁺, 232 (14), 231 (69), 230 (14), 216 (11), 158 (16) [M - C₈H₅]⁺, 129 (7) [C₉H₅O]⁺, 116 (18) [C₈H₆N]⁺.

Anal. Calcd for C₁₈H₁₃NO (259.3): C, 83.37; H, 5.05; N, 5.40. Found: C, 83.57; H, 4.97; N, 5.41.

(1-Methyl-1 H -indol-3-yl)(thiophen-2-yl)methanone (3b)

According to the standard procedure, the reaction with stannane 2b (1.64 mL, 5.00 mmol) gave 3b as a yellow solid; yield: 981 mg (81%); mp 243-246 ˚C. Crystallization (CH₂Cl₂-n-pentane) gave yellow crystals.

IR (KBr): 3110, 2930, 1686, 1586, 1572, 1522, 1465, 1421, 1388, 1370, 1266, 1238, 1186, 1156, 1125, 1086, 1063, 1011, 934, 868, 846, 811, 771, 750, 735, 670, 568 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.84 (s, 3 H), 7.14 (dd, J = 5.0, 3.7 Hz, 1 H), 7.30-7.38 (m, 3 H), 7.59 (dd, J = 5.0, 1.1 Hz, 1 H), 7.72 (dd, J = 3.7, 1.1 Hz, 1 H), 7.77 (s, 1 H), 8.39-8.43 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 34.0 (CH₃), 110.1 (CH), 115.9 (C_q), 123.0 (CH), 123.0 (CH), 124.1 (CH), 127.7 (C_q), 127.9 (CH), 131.4 (CH), 131.7 (CH), 136.5 (CH), 137.8 (C_q), 145.8 (C_q), 181.8 (C_q).

MS (EI, 70 eV): m/z (%) = 242 (18), 241 (100) [M]⁺, 240 (20), 159 (10), 158 (90) [M - C₄H₃S]⁺, 149 (11), 130 (8) [C₉H₈N]⁺, 111 (4) [C₅H₃OS]⁺, 71 (11), 57 (15), 43 (15).

Anal. Calcd for C₁₄H₁₁NOS (241.3): C, 69.68; H, 4.59; N, 5.80. Found: C, 69.66; H, 4.72; N, 5.55.

(1-Methyl-1 H -indol-3-yl)(thiophen-3-yl)methanone (3c)

According to the standard procedure, the reaction with stannane 2c (1.86 g, 5.00 mmol) gave 3c as a yellow solid; yield: 802 mg (66%); mp 115 ˚C.

IR (KBr): 3129, 3096, 3050, 2910, 1799, 1686, 1606, 1573, 1526, 1463, 1413, 1376, 1359, 1339, 1262, 1238, 1200, 1178, 1151, 1128, 1080, 1040, 1009, 936, 866, 839, 820, 800, 756, 646, 619, 591, 579, 562 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.82 (s, 3 H), 7.30-7.37 (m, 4 H), 7.56 (m, 1 H), 7.63 (s, 1 H), 7.86 (m, 1 H), 8.40-8.43 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 33.5 (CH₃), 109.6 (CH), 116.3 (C_q), 122.6 (CH), 122.6 (CH), 123.6 (CH), 125.9 (CH), 127.1 (C_q), 128.1 (CH), 129.6 (CH), 136.8 (CH), 137.5 (C_q), 143.7 (C_q), 184.2 (C_q).

MS (EI, 70 eV): m/z (%) = 242 (10), 241 (58) [M]⁺, 159 (11), 158 (100) [M - C₄H₃S]⁺, 130 (9) [C₉H₈N]⁺, 111 (6) [C₅H₃OS]⁺, 103 (9), 77 (11).

Anal. Calcd for C₁₄H₁₁NOS (241.3): C, 69.68; H, 4.59; N, 5.80. Found: C, 69.51; H, 4.42; N, 5.80.

(1-Methyl-1 H -indol-3-yl)(pyridin-2-yl)methanone (3d)

According to the standard procedure, the reaction with stannane 2d (1.70 mL, 5.00 mmol) gave 3d as a yellow solid; yield: 882 mg (75%); mp 103-105 ˚C.

IR (KBr): 3139, 3050, 1736, 1686, 1617, 1578, 1563, 1511, 1460, 1365, 1270, 1230, 1156, 1123, 1074, 1033, 1012, 872, 748, 692, 624, 574, 428 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.84 (s, 3 H), 7.28-7.38 (m, 3 H), 7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 7.86 (td, J = 7.8, 1.8 Hz, 1 H), 8.14-8.17 (m, 1 H), 8.61 (dt, J = 7.2, 1.5 Hz, 1 H), 8.68-8.70 (m, 1 H), 8.71 (s, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 34.0 (CH₃), 110.0 (CH), 114.2 (C_q), 123.3 (CH), 123.4 (CH), 123.8 (CH), 124.0 (CH), 126.1 (CH), 128.6 (C_q), 137.4 (C_q), 137.5 (CH), 141.0 (CH), 148.5 (CH), 157.2 (C_q), 186.7 (C_q).

MS (EI, 70 eV): m/z (%) = 237 (13), 236 (67) [M]⁺, 235 (16), 159 (12), 158 (100) [M - C₅H₄N]⁺, 130 (5) [C₉H₈N]⁺, 118 (10), 103 (10), 77 (8) [C₅H₃N]⁺, 43 (11).

Anal. Calcd for C₁₅H₁₂N₂O (236.3): C, 76.25; H, 5.12; N, 11.86. Found: C, 76.00; H, 5.29; N, 11.72.

1-(1-Methyl-1 H -indol-3-yl)prop-2-en-1-one (3e)

According to the standard procedure (20 h for the Stille coupling step), the reaction with stannane 2e (1.54 mL, 5.00 mmol) gave 3e as a yellow solid; yield: 534 mg (58%); mp 101-104 ˚C.

IR (KBr): 3107, 1645, 1588, 1574, 1530, 1468, 1414, 1371, 1335, 1299, 1233, 1146, 1125, 1089, 1011, 983, 956, 924, 801, 753, 695, 571, 428 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.75-3.79 (m, 3 H), 5.70-5.74 (m, 1 H), 6.39-6.44 (m, 1 H), 6.93-7.01 (m, 1 H), 7.27-7.35 (m, 3 H), 7.66-7.68 (m, 1 H), 8.45-8.49 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 33.5 (CH₃), 109.7 (CH), 116.7 (C_q), 122.7 (CH), 122.9 (CH), 123.7 (CH), 126.3 (CH₂), 126.7 (C_q), 133.7 (CH), 135.9 (CH), 137.6 (C_q), 184.7 (C_q).

MS (EI, 70 eV): m/z (%) = 186 (10), 185 (80) [M]⁺, 159 (12), 158 (100) [M - C₂H₃]⁺, 130 (9) [C₉H₈N]⁺, 77 (12).

Anal. Calcd for C₁₂H₁₁NO (185.2): C, 77.81; H, 5.99; N, 7.59. Found: C, 77.59; H, 6.27; N, 7.48.

(1-Methyl-1 H -indol-3-yl)(phenyl)methanone (3f)

According to the standard procedure (20 h for the Stille coupling step), the reaction with stannane 2f (1.68 mL, 5.00 mmol) gave 3f as a yellow solid; yield: 800 mg (68%); mp 111-113 ˚C.

IR (KBr): 3051, 1619, 1574, 1524, 1471, 1372, 1267, 1233, 1126, 1077, 1025, 875, 751, 719, 697, 669, 573, 435 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.82 (s, 3 H), 7.31-7.37 (m, 3 H), 7.44-7.56 (m, 4 H), 7.72-7.78 (m, 2 H), 8.41-8.45 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 33.5 (CH₃), 109.6 (CH), 115.6 (C_q), 122.7 (CH), 122.7 (CH), 123.6 (CH), 127.2 (C_q), 128.3 (CH), 128.6 (CH), 131.0 (CH), 137.5 (C_q), 137.9 (CH), 140.9 (C_q), 190.8 (C_q).

MS (EI, 70 eV): m/z (%) = 236 (16), 235 (86) [M]⁺, 159 (11), 158 (100) [M - C₆H₅]⁺, 130 (5) [C₉H₈N]⁺, 77 (11), 71 (10), 57 (23), 43 (10), 43 (18).

Anal. Calcd for C₁₆H₁₃NO (235.3): C, 81.68; H, 5.57; N, 5.95. Found: C, 81.39; H, 5.73; N, 5.74.

[1-(4-Methoxybenzyl)-1 H -pyrrolo[2,3- b ]pyridin-3-yl](thiophen-2-yl)methanone (5)

The sequence was performed according to the standard procedure, but in DME (25 mL) at 100 ˚C for 2 h for the glyoxylation step. The reaction with stannane 2b (1.64 mL, 5.00 mmol) gave 5 as a colorless solid; yield: 1.09 g (62%); mp 106 ˚C.

IR (KBr): 2926, 2833, 1609, 1572, 1524, 1509, 1448, 1428, 1416, 1396, 1349, 1306, 1252, 1245, 1190, 1175, 1107, 1036, 871, 828, 809, 769, 735, 710, 648, 584, 537, 510 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.78 (s, 3 H), 5.50 (s, 2 H), 6.84-6.89 (m, 2 H), 7.12-7.15 (m, 1 H), 7.22-7.31 (m, 3 H), 7.57-7.70 (m, 2 H), 7.92 (s, 1 H), 8.45-8.47 (m, 1 H), 8.64-8.67 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 48.4 (CH₂), 55.7 (CH₃), 114.7 (C_q), 114.8 (CH), 119.2 (CH), 120.2 (C_q), 128.1 (CH), 128.7 (C_q), 129.7 (CH), 131.5 (CH), 131.7 (CH), 132.3 (CH), 134.7 (CH), 145.1 (C_q), 145.4 (CH), 148.6 (C_q), 159.9 (C_q), 181.6 (C_q).

MS (EI, 70 eV): m/z (%) = 349 (2), 348 (11) [M]⁺, 237 (9) [M - C₅H₃OS]⁺, 122 (9), 121 (100) [C₈H₉O]⁺.

Anal. Calcd for C₂₀H₁₆N₂O₂S (348.4): C, 68.94; H, 4.63; N, 8.04. Found: C, 68.71; H, 4.57; N, 8.07.

1-(1-Methyl-1 H -pyrrol-2-yl)-3-phenylprop-2-yn-1-one (7a)

According to the standard procedure, the reaction with stannane 2a (1.84 mL, 5.00 mmol) gave 7a as a dark yellow oil; yield: 855 mg (82%).

IR (film): 3108, 3060, 2997, 2951, 2459, 2202, 1608, 1524, 1489, 1465, 1443, 1401, 1330, 1270, 1234, 1206, 1177, 1159, 1090, 1058, 984, 920, 884, 791, 757, 734, 690, 632, 603, 548 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.97 (s, 3 H), 6.19 (dd, J = 4.1, 2.4 Hz, 1 H), 6.87-6.88 (m, 1 H), 7.29 (dd, J = 4.1, 1.7 Hz, 1 H), 7.35-7.45 (m, 3 H), 7.59-7.63 (m, 2 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 37.8 (CH₃), 88.0 (C_q), 88.1 (C_q), 109.5 (CH), 121.1 (C_q), 124.2 (CH), 129.0 (CH), 130.6 (CH), 132.7 (C_q), 133.0 (CH), 133.2 (CH), 167.3 (C_q).

MS (EI, 70 eV): m/z (%) = 210 (18), 209 (100) [M]⁺, 208 (71), 181 (29), 180 (45), 129 (11) [C₉H₅O]⁺, 115 (17).

Anal. Calcd for C₁₄H₁₁NO (209.2): C, 80.36; H, 5.30; N, 6.69. Found: C, 80.10; H, 5.13; N, 6.71.

(1-Methyl-1 H -pyrrol-2-yl)(thiophen-2-yl)methanone (7b)

According to the standard procedure, the reaction with stannane 2b (1.64 mL, 5.00 mmol) gave 7b as a yellow oil; yield: 843 mg (88%).

IR (film): 3106, 2950, 2464, 1614, 1525, 1463, 1417, 1379, 1329, 1254, 1141, 1094, 1049, 904, 869, 853, 816, 785, 739, 666, 606, 566 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.97 (s, 3 H), 6.18 (dd, J = 4.1, 2.5 Hz, 1 H), 6.89-6.92 (m, 1 H), 7.03 (dd, J = 4.1, 1.7 Hz, 1 H), 7.12 (dd, J = 5.0, 3.7 Hz, 1 H), 7.60 (dd, J = 5.0, 1.2 Hz, 1 H), 7.75 (dd, J = 3.7, 1.2 Hz, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 37.6 (CH₃), 108.7 (CH), 121.3 (CH), 128.0 (CH), 130.6 (C_q), 131.8 (CH), 132.4 (CH), 132.7 (CH), 145.2 (C_q), 177.6 (C_q).

MS (EI, 70 eV): m/z (%) = 192 (17), 191 (100) [M]⁺, 190 (51), 158 (20), 111 (20), 108 (25) [M - C₄H₃S]⁺, 94 (15), 53 (14), 39 (16).

Anal. Calcd for C₁₀H₉NOS (191.3): C, 62.80; H, 4.74; N, 7.32. Found: C, 62.51; H, 4.79; N, 7.06.

3-[2-(Thiophen-2-ylcarbonyl)-1 H -pyrrol-1-yl]propanenitrile (7c)

According to the standard procedure, the reaction with stannane 2b (1.64 mL, 5.00 mmol) gave 7c as a yellow oil; yield: 977 mg (85%).

IR (film): 3108, 2961, 2251, 1732, 1601, 1527, 1466, 1416, 1354, 1337, 1257, 1180, 1133, 1089, 1048, 889, 868, 853, 813, 740, 663, 611 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 3.00 (t, J = 6.3 Hz, 2 H), 4.55 (t, J = 6.3 Hz, 2 H), 6.28 (dd, J = 3.8, 2.7 Hz, 1 H), 7.08-7.18 (m, 3 H), 7.64 (d, J = 5.0 Hz, 1 H), 7.76 (d, J = 3.8 Hz, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 20.9 (CH₂), 45.8 (CH₂), 109.9 (CH), 118.1 (C_q), 122.6 (CH), 128.0 (CH), 129.7 (C_q), 131.7 (CH), 132.94 (CH), 133.0 (CH), 144.6 (C_q), 177.6 (C_q).

MS (EI, 70 eV): m/z (%) = 231 (13), 230 (100) [M]⁺, 197 (32), 190 (42) [C₁₀H₈NOS]⁺, 189 (21), 157 (10), 147 (8) [C₈H₇N₂O]⁺, 111 (35) [C₅H₃OS]⁺, 97 (20).

Anal. Calcd for C₁₂H₁₀N₂OS (230.3): C, 62.59; H, 4.38; N, 12.16. Found: C, 62.49; H, 4.17; N, 11.87.

(1-Benzyl-1 H -pyrrol-2-yl)(thiophen-2-yl)methanone (7d)

According to the standard procedure, the reaction with stannane 2b (1.64 mL, 5.00 mmol) gave 7d as a milky, colorless oil; yield: 1.08 g (81%).

IR (film): 3105, 3031, 2927, 1605, 1524, 1496, 1462, 1415, 1354, 1332, 1246, 1130, 1085, 1048, 869, 853, 816, 716, 675, 611 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 5.60 (s, 2 H), 6.24 (dd, J = 4.0, 2.6 Hz, 1 H), 6.98-7.01 (m, 1 H), 7.08 (dd, J = 4.0, 1.6 Hz, 1 H), 7.11 (dd, J = 4.9, 3.8 Hz, 1 H), 7.14-7.17 (m, 2 H), 7.20-7.25 (m, 1 H), 7.26-7.31 (m, 2 H), 7.58 (dd, J = 5.0, 1.1 Hz, 1 H), 7.73 (dd, J = 3.7, 1.1 Hz, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 52.6 (CH₂), 109.3 (CH), 122.0 (CH), 127.6 (CH), 127.9 (CH), 128.0 (CH), 129.1 (CH), 130.3 (C_q), 131.1 (CH), 132.5 (CH), 132.9 (CH), 138.6 (C_q), 145.2 (C_q), 177.6 (C_q).

MS (EI, 70 eV): m/z (%) = 267 (23) [M]⁺, 156 (36) [M - C₅H₃OS]⁺, 111 (41) [C₅H₃OS]⁺, 91 (50) [C₇H₇]⁺, 83 (48) [C₄H₃S]⁺, 57 (100) [C₂HS]⁺.

Anal. Calcd for C₁₆H₁₃NOS (267.3): C, 71.88; H, 4.90; N, 5.24. Found: C, 71.96; H, 5.11; N, 5.02.

1-(1,2,5-Trimethyl-1 H -pyrrol-3-yl)prop-2-en-1-one (9)

According to the standard procedure, the reaction with stannane 2e (1.54 mL, 5.00 mmol) gave 9 as a yellow solid; yield: 468 mg (57%); mp 73-75 ˚C.

IR (KBr): 3096, 2912, 1639, 1594, 1570, 1521, 1429, 1415, 1372, 1344, 1295, 1220, 1187, 1154, 1044, 1006, 989, 951, 790, 728, 691, 561 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 2.21 (s, 3 H), 2.58 (s, 3 H), 3.41 (s, 3 H), 5.64-5.68 (m, 1 H), 6.26-6.35 (m, 2 H), 6.97 (dd, J = 17.1, 10.4 Hz, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 12.5 (CH₃), 12.8 (CH₃), 30.5 (CH₃), 107.7 (CH), 120.0 (C_q), 126.4 (CH₂), 128.4 (C_q), 135.3 (CH), 137.2 (C_q), 186.4 (C_q).

MS (EI, 70 eV): m/z (%) = 164 (11), 163 (100) [M]⁺, 162 (74), 147 (24) [M - CH₄]⁺, 136 (81) [M - C₂H₃]⁺, 134 (15), 108 (12), 67 (10), 56 (14) [C₃H₄O]⁺.

Anal. Calcd for C₁₀H₁₃NO (163.2): C, 73.59; H, 8.03; N, 8.58. Found: C, 73.45; H, 8.03; N, 8.36.

1-Methyl-3-(1-methyl-4,5-dihydro-1 H -pyrazol-3-yl)-1 H -indole (11)

1-Methyl-1H-indole (1; 669 mg, 5.00 mmol) in anhyd THF (25 mL) was placed under an argon atmosphere in a screw-cap vessel with a septum, and the mixture was degassed with argon for 5 min and cooled to 0 ˚C (ice water). After 15 min, oxalyl chloride (0.44 mL, 5.00 mmol) was added to the mixture at 0 ˚C. The mixture was allowed to warm to r.t. (water bath) and was stirred for 4 h. Then, PdCl₂(PPh₃)₂ (177 mg, 0.25 mmol), anhyd Et₃N (1.39 mL, 10.0 mmol) and tributyl(vinyl)stannane (2e; 1.54 mL, 5.00 mmol) were successively added to the mixture which was stirred at 60 ˚C for 1 h. The evolution of carbon monoxide was observed. Then, methylhydrazine (10; 0.54 mL, 10.0 mmol) was added and the mixture was stirred at 60 ˚C for 1 h. After complete conversion (the product formation was monitored by TLC), the mixture was allowed to cool to r.t. and MeOH (25 mL) and KOH (0.66 g, 10.0 mmol) were added. The mixture was stirred at r.t. for 20 h. Then, H₂O (25 mL) was added and the mixture was extracted with CH₂Cl₂ (4 × 50 mL). The combined organic layers were dried (anhyd Na₂SO₄). The solvents were removed under reduced pressure, and the residue was absorbed onto Celite^® and purified by chromatography on silica gel [petroleum ether (40-60 ˚C)-EtOAc] to give the pyrazoline 11. It was necessary to additionally purify the product by suspending it in n-pentane, sonication in an ultrasound bath, filtration and drying under reduced pressure.

Yield: 704 mg (66%); yellow solid; mp 110-112 ˚C.

IR (KBr): 3060, 2945, 2834, 2803, 2776, 1719, 1655, 1591, 1543, 1524, 1473, 1442, 1422, 1403, 1367, 1336, 1293, 1237, 1167, 1139, 1113, 1013, 956, 884, 851, 805, 768, 742, 630, 568, 528 cm^-¹.

^¹H NMR (500 MHz, CDCl₃): δ = 2.94 (s, 3 H), 3.00-3.12 (m, 4 H), 3.77 (s, 3 H), 7.18-7.34 (m, 4 H), 8.27 (m, 1 H).

^¹³C NMR (125 MHz, CDCl₃): δ = 33.0 (CH₃), 35.2 (CH₂), 44.3 (CH₃), 55.7 (CH₂), 109.1 (CH), 109.9 (C_q), 120.6 (CH), 122.6 (CH), 122.7 (CH), 125.6 (C_q), 128.9 (CH), 137.5 (C_q), 149.2 (C_q).

MS (EI, 70 eV): m/z (%) = 213 (100) [M]⁺, 212 (37), 211 (57), 210 (12), 170 (15) [M - C₂H₅N]⁺, 156 (13) [M - C₂H₅N₂]⁺, 155 (17), 144 (15), 128 (12), 106 (18), 105 (15).

Anal. Calcd for C₁₃H₁₅N₃ (213.3): C, 73.21; H, 7.09; N, 19.70. Found: C, 73.41; H, 6.87; N, 19.53.

Acknowledgment

This work was supported by Merck Serono, Darmstadt, and the Fonds der Chemischen Industrie (scholarship to B.O.A.T.).

References

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• 10e Lu L. Burton DJ. Tetrahedron Lett.  1997,  38:  7673 
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• 10f Ye J. Bhatt RK. Falck JR.
  J. Am. Chem. Soc.  1994,  116:  1 
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• 10g Wang Y. Burton DJ. Org. Lett.  2006,  8:  1109 
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  Crossref
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  Search in Google Scholar
• 15b Arnswald M. Neumann WP.
  J. Org. Chem.  1993,  58:  7022 
  Search in Google Scholar

CCDC 775726 (compound 3b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].

References

• 1 For a review on palladium-catalyzed carbonylative couplings, see: Brennführer A. Neumann H. Beller M. Angew. Chem. Int. Ed.  2009,  48:  4114 
  CrossrefPubMedSearch in Google Scholar
• 2 Wynne JH. Lloyd CT. Jensen SD. Boson S. Stalick WM. Synthesis  2004,  2277 
  Thieme Connect
• 3a Karpov AS. Merkul E. Rominger F. Müller TJJ. Angew. Chem. Int. Ed.  2005,  44:  6951 
  Search in Google Scholar
• 3b Ahmed MSM. Mori A. Org. Lett.  2003,  5:  3057 
  Search in Google Scholar
• 4 Stonehouse JP. Chekmarev DS. Ivanova NV. Lang S. Pairaudeau G. Smith N. Stocks MJ. Sviridov SI. Utkina LM. Synlett  2008,  100 
  Thieme Connect
• 5 Nakao Y. Satoh J. Shirakawa E. Hiyama T. Angew. Chem. Int. Ed.  2006,  45:  2271 
  CrossrefSearch in Google Scholar
• 6a Gooßen LJ. Paetzold J. Angew. Chem. Int. Ed.  2004,  43:  1095 
  Search in Google Scholar
• 6b Gooßen LJ. Paetzold J. Angew. Chem. Int. Ed.  2002,  41:  1237 
  Search in Google Scholar
• 7 Merkul E. Oeser T. Müller TJJ. Chem. Eur. J.  2009,  15:  5006 
  CrossrefPubMedSearch in Google Scholar
• 8a Milstein D. Stille JK. J. Am. Chem. Soc.  1978,  100:  3636 
  Search in Google Scholar
• 8b Milstein D. Stille JK. J. Org. Chem.  1979,  44:  1613 
  Search in Google Scholar
• 8c Labadie JW. Stille JK. J. Am. Chem. Soc.  1983,  105:  6129 
  Search in Google Scholar
• 9 Kashiwabara T. Tanaka M. J. Org. Chem.  2009,  74:  3958 
  CrossrefSearch in Google Scholar
• 10a Liebeskind LS. Fengl RW. J. Org. Chem.  1990,  55:  5359 
  Search in Google Scholar
• 10b Farina V. Kapadia S. Krishnan B. Wang C. Liebeskind LS. J. Org. Chem.  1994,  59:  5905 
  Search in Google Scholar
• 10c Casado AL. Espinet P. Organometallics  2003,  22:  1305 
  Search in Google Scholar
• 10d Han X. Stolz BM. Corey EJ. J. Am. Chem. Soc.  1999,  121:  7600 
  Search in Google Scholar
• 10e Lu L. Burton DJ. Tetrahedron Lett.  1997,  38:  7673 
  Search in Google Scholar
• 10f Ye J. Bhatt RK. Falck JR.
  J. Am. Chem. Soc.  1994,  116:  1 
  Search in Google Scholar
• 10g Wang Y. Burton DJ. Org. Lett.  2006,  8:  1109 
  Search in Google Scholar
• 11 Leibner JE. Jacobus J. J. Org. Chem.  1979,  44:  449 
  CrossrefSearch in Google Scholar
• 12 Harrowven DC. Guy IL. Chem. Commun.  2004,  1968 
  Crossref
• 13 Renaud P. Lacote E. Quaranta L. Tetrahedron Lett.  1998,  39:  2123 
  CrossrefSearch in Google Scholar
• 15a Adam MJ. Ruth TJ. Jivan S. Pate BD. J. Fluorine Chem.  1984,  25:  329 
  Search in Google Scholar
• 15b Arnswald M. Neumann WP.
  J. Org. Chem.  1993,  58:  7022 
  Search in Google Scholar

CCDC 775726 (compound 3b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].