Palladium-Catalyzed Direct
C-3 Arylations of Indoles with an Air-Stable HASPO

Lutz Ackermann; Sebastian Barfüßer

doi:10.1055/s-0028-1087951

LETTER

Palladium-Catalyzed Direct C-3 Arylations of Indoles with an Air-Stable HASPO

Lutz Ackermann*, Sebastian Barfüßer
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax: +49(551)396777; e-Mail: Lutz.Ackermann@chemie.uni-goettingen.de;

Abstract

All articles of this category

Abstract

Efficient direct arylations of indoles occurred highly regioselectively at position C-3 with an in situ generated palladium complex derived from an air-stable HASPO, which enabled syntheses of diversely functionalized indoles, also with sterically hindered substrates.

Key words

C-H bond functionalization - heteroarenes - indoles - regioselectivity - palladium

Full Text

References

References and Notes

<A NAME="RG36908ST-1">1</A> Horton DA. Bourne GT. Smythe ML. Chem. Rev. 2003, 103: 893

<A NAME="RG36908ST-2">2</A> Humphrey GR. Kuethe JT. Chem. Rev. 2006, 106: 2875

<A NAME="RG36908ST-3">3</A> Eicher T. Hauptmann S. The Chemistry of Heterocycles 2nd ed.: Wiley-VCH; Weinheim: 2003.

<A NAME="RG36908ST-4">4</A> Gilchrist TL. Heterocyclic Chemistry 3rd ed.: Addison Wesley Longman; Harlow: 1997.

<A NAME="RG36908ST-5">5</A> Joule JA. Milles K. Heterocyclic Chemistry 4th ed.: Blackwell Science Ltd; Oxford: 2000.

<A NAME="RG36908ST-6">6</A> Ackermann L. Synlett 2007, 507

<A NAME="RG36908ST-7">7</A> Cacchi S. Fabrizi G. Chem. Rev. 2005, 105: 2873

<A NAME="RG36908ST-8">8</A> Krüger K. Tillack A. Beller M. Adv. Synth. Catal. 2008, 350: 2153

<A NAME="RG36908ST-9">9</A> Ackermann L. Modern Arylation Reactions Wiley-VCH; Weinheim: 2009.

Palladium-catalyzed cross-dehydrogenative arylations can proceed regioselectively at indoles. However, they display limited selectivities with respect to the coupling partner and rely on the use of (over)stoichiometric amounts of Cu(OAc)₂ or AgOAc as terminal oxidants:

<A NAME="RG36908ST-10A">10a</A> Potavathri S. Dumas AS. Dwight TA. Naumiec GR. Hammann JM. DeBoef B. Tetrahedron Lett. 2008, 49: 4050

<A NAME="RG36908ST-10B">10b</A> Stuart DR. Villemure E. Fagnou K. J. Am. Chem. Soc. 2007, 129: 12072

<A NAME="RG36908ST-10C">10c</A> Dwight TA. Rue NR. Charyk D. Josselyn R. DeBoef B. Org. Lett. 2007, 9: 3137

<A NAME="RG36908ST-10D">10d</A> Stuart DR. Fagnou K. Science 2007, 316: 1172 ; and references cited therein

For rhodium-catalyzed direct arylations of indoles, occurring largely with C-2 regioselectivity, see:

<A NAME="RG36908ST-11A">11a</A> Yanagisawa S. Sudo T. Noyori R. Itami K. Tetrahedron 2008, 64: 6073

<A NAME="RG36908ST-11B">11b</A> Yanagisawa S. Sudo T. Noyori R. Itami K. J. Am. Chem. Soc. 2006, 128: 11748

<A NAME="RG36908ST-11C">11c</A> Wang X. Lane BS. Sames D. J. Am. Chem. Soc. 2005, 127: 4996

<A NAME="RG36908ST-12">12</A> Stoichiometrically magnesiated indoles were shown to give rise to C-3 arylated indoles: Lane BS. Brown MA. Sames D. J. Am. Chem. Soc. 2005, 127: 8050

<A NAME="RG36908ST-13">13</A> de Mendoza P. Echavarren AM. In Modern Arylation Methods Ackermann L. Wiley-VCH; Weinheim: 2009. p.363

<A NAME="RG36908ST-14A">14a</A> Seregin IV. Gevorgyan V. Chem. Soc. Rev. 2007, 36: 1173

<A NAME="RG36908ST-14B">14b</A> Alberico D. Scott ME. Lautens M. Chem. Rev. 2007, 107: 174

Selected recent representative examples of palladium-catalyzed direct arylations of indoles:

<A NAME="RG36908ST-15A">15a</A> Lebrasseur N. Larrosa I. J. Am. Chem. Soc. 2008, 130: 2926

<A NAME="RG36908ST-15B">15b</A> Zhao J. Zhang Y. Cheng K. J. Org. Chem. 2008, 73: 7428

<A NAME="RG36908ST-15C">15c</A> Yang S.-D. Sun C.-L. Fang Z. Li B.-J. Li Y.-Z. Shi Z.-J. Angew. Chem. Int. Ed. 2008, 47: 1473

<A NAME="RG36908ST-15D">15d</A> Bellina F. Calandri C. Cauteruccio S. Rossi R. Eur. J. Org. Chem. 2007, 2147

<A NAME="RG36908ST-15E">15e</A> Deprez NR. Kalyani D. Krause A. Sanford MS. J. Am. Chem. Soc. 2006, 128: 4972 ; and references cited therein

<A NAME="RG36908ST-16">16</A> For elegant site-selective copper-catalyzed direct C-3 arylations of indoles employing [Ar₂I]X as arylating reagents, see: Phipps RJ. Grimster NP. Gaunt MJ. J. Am. Chem. Soc. 2008, 130: 8172

<A NAME="RG36908ST-17">17</A> For an early example of regioselective direct arylations of indoles, see: Akita Y. Itagaki Y. Takizawa S. Ohta A. Chem. Pharm. Bull. 1989, 37: 1477

<A NAME="RG36908ST-18">18</A> Ackermann L. Synthesis 2006, 1557

<A NAME="RG36908ST-19">19</A> Zhang Z. Hu Z. Yu Z. Lei P. Chi H. Wang Y. He R. Tetrahedron Lett. 2007, 48: 2415

For the recent use of a heterogenous palladium catalyst for direct C-3 arylations of 2-substituted indoles, see:

<A NAME="RG36908ST-20A">20a</A> Cusati G. Djakovitch L. Tetrahedron Lett. 2008, 49: 2499

<A NAME="RG36908ST-20B">20b</A> For a direct C-3 arylation of a 2-substituted indole, see: Djakovitch L. Dufaud V. Zaidi R. Adv. Synth. Catal. 2006, 348: 715

<A NAME="RG36908ST-21">21</A> For a recent report on the application of PCy₃ or Bn(n-Bu)₃NCl to palladium-catalyzed direct C-3 arylations of indoles, including 2-substituted ones, see: Bellina F. Benelli F. Rossi R. J. Org. Chem. 2008, 73: 5529

<A NAME="RG36908ST-22A">22a</A> Ackermann L. Org. Lett. 2005, 7: 439

<A NAME="RG36908ST-22B">22b</A> Kaspar LT. Ackermann L. Tetrahedron 2005, 61: 11311

<A NAME="RG36908ST-23">23</A> Ackermann L. Kaspar LT. Gschrei CJ. Chem. Commun. 2004, 2824

<A NAME="RG36908ST-24">24</A> Ackermann L. Sandmann R. Villar A. Kaspar LT. Tetrahedron 2008, 64: 769

<A NAME="RG36908ST-25A">25a</A> Ackermann L. Born R. Angew. Chem. Int. Ed. 2005, 44: 2444

<A NAME="RG36908ST-25B">25b</A> Ackermann L. Gschrei CJ. Althammer A. Riederer M. Chem. Commun. 2006, 1419

<A NAME="RG36908ST-25C">25c</A> Ackermann L. Spatz JH. Gschrei CJ. Born R. Althammer A. Angew. Chem. Int. Ed. 2006, 45: 7627

<A NAME="RG36908ST-26">26</A> Ackermann L. Org. Lett. 2005, 7: 3123

<A NAME="RG36908ST-27">27</A> Ackermann L. Althammer A. Born R. Angew. Chem. Int. Ed. 2006, 45: 2619

For recent examples of palladium-catalyzed direct arylations from our laboratories, see:

<A NAME="RG36908ST-28A">28a</A> Ackermann L. Althammer A. Fenner S. Angew. Chem. Int. Ed. 2009, 48: 201

<A NAME="RG36908ST-28B">28b</A> Ackermann L. Vicente R. Born R. Adv. Synth. Catal. 2008, 350: 741

<A NAME="RG36908ST-28C">28c</A> Ackermann L. Althammer A. Angew. Chem. Int. Ed. 2007, 46: 1627

<A NAME="RG36908ST-29">29</A> Unfortunately, under otherwise identical reaction conditions catalytic amounts of Bn(n-Bu)₃NCl^²¹ provided product 3a with lower isolated yields, as did the P-para-tolylated phosphonate derived from HASPO 4h (63%)

Carboxylic acids were used as additives in palladium- and ruthenium-catalyzed direct arylation reactions, which are believed to proceed through a concerted metalation-deprotonation mechanism: [Pd]:

<A NAME="RG36908ST-30A">30a</A> Lafrance M. Fagnou K. J. Am. Chem. Soc. 2006, 128: 16496

<A NAME="RG36908ST-30B">30b</A> [Ru]: Lafrance M. Gorelsky SI. Fagnou K. J. Am. Chem. Soc. 2007, 129: 14570

<A NAME="RG36908ST-30C">30c</A> Ackermann L. Vicente R. Althammer A. Org. Lett. 2008, 10: 2299

<A NAME="RG36908ST-30D">30d</A> Ackermann L. Mulzer M. Org. Lett. 2008, 10: 5043 ; and references cited therein

Representative Procedure - Synthesis of 3a (Table 1, Entry 10)
A suspension of Pd(OAc)₂ (5.6 mg, 0.025 mmol, 5.0 mol%) and 4h (28.4 mg, 0.05 mmol, 10 mol%) in dry dioxane (1 mL) was stirred for 30 min under N₂ at ambient temperature. K₂CO₃ (207.0 mg, 1.50 mmol), indole (1a, 59.0 mg, 0.50 mmol), and 4-bromotoluene (2a, 106.0 mg, 0.62 mmol) were added, and the suspension was stirred at 95 ˚C for 20 h. After the reaction mixture was cooled to ambient temperature, Et₂O (50 mL) and brine (50 mL) were added. The aqueous phase was extracted with Et₂O (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The remaining residue was purified by column chromatography on SiO₂ (n-hexane-EtOAc, 10:1) to yield 3a (97.0 mg, 94%) as a pale yellow solid; mp 107.4-108.3 ˚C). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 11.27 (br s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.64-7.56 (m, 3 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.19-7.07 (m, 2 H), 2.34 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 136.8 (C_q), 134.1 (C_q), 132.9 (C_q), 129.2 (CH), 126.3 (CH), 125.0 (C_q), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH), 115.6 (C_q), 111.8 (CH), 20.6 (CH₃). IR (KBr): 3387, 2361, 2337, 1653, 1617, 1116, 802, 747 cm^-¹. MS (EI): m/z (%) = 207 (100) [M⁺], 206 (37), 117 (12), 90 (8). ESI-HRMS: m/z calcd for C₁₅H₁₄N 208.1121: found: 208.1121. The spectral data are in accordance with those reported in the literature. [¹9]

Analytical Data Indole 3i: mp 80.3-82.2 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.19 (br s, 1 H), 7.62 (t, J = 1.8 Hz, 1 H), 7.53 (dt, J = 7.7, 1.6 Hz, 1 H), 7.39-7.23 (m, 5 H), 6.93 (dd, J = 8.8, 2.4 Hz, 1 H), 3.88 (s, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 154.9 (C_q), 137.5 (C_q), 134.6 (C_q), 131.7 (C_q), 130.0 (CH), 127.1 (CH), 125.9 (C_q), 125.8 (CH), 125.3 (CH), 123.0 (CH), 116.8 (C_q), 112.7 (CH), 112.2 (CH), 101.5 (CH), 56.0 (CH₃). IR (KBr): 3391, 1620, 1594, 1485, 1440, 1271, 1214, 791 cm^-¹. MS (EI): m/z (%) = 257 (100) [M⁺], 242 (26), 215 (33), 178 (13), 152 (15) 128 (11). ESI-HRMS: m/z calcd for C₁₅H₁₃ClNO: 258.0680; found: 258.0682.
Indole 3k: mp 134.1-135.8 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 8.07 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.53-7.50 (m, 2 H), 7.40-7.32 (m, 2 H), 7.18-7.07 (m, 3 H), 2.52 (s, 3 H), 2.46 (s, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 138.2 (C_q), 136.1 (C_q), 135.5 (C_q), 128.6 (CH), 128.1 (CH), 126.7 (CH), 125.2 (C_q), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (C_q), 120.4 (CH), 118.8 (C_q), 117.6 (CH), 21.7 (CH₃), 16.6 (CH₃). IR (KBr): 3411, 1653, 1635, 1540, 1457, 1113, 789, 751 cm^-¹. MS (EI): m/z (%) = 221 (100) [M⁺], 204 (10), 178 (10), 110 (6), 102 (7). ESI-HRMS: m/z calcd for C₁₆H₁₆N: 222.1277; found: 222.1277.
Indole 3l: mp 113.0-115.2 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.92 (br s, 1 H), 7.65 (d, J = 7.4 Hz, 1 H), 7.38-7.28 (m, 4 H), 7.18-7.07 (m, 3 H), 2.50 (s, 3 H), 2.42 (s, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 137.9 (C_q), 135.2 (C_q), 135.1 (C_q) 131.2 (C_q), 130.0 (CH), 128.3 (CH), 127.8 (C_q), 126.5 (CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH), 114.5 (C_q), 110.2 (CH), 21.7 (CH₃), 12.7 (CH₃). IR (KBr): 3392, 1682, 1653, 1559, 1457, 1306, 792, 746 cm^-¹. MS (EI): m/z (%) = 221 (100) [M⁺], 204 (20), 178 (9), 130 (15), 102 (15). ESI-HRMS: m/z calcd for C₁₆H₁₆N: 222.1277; found: 222.1272.