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Synlett 2009(5): 808-812  
DOI: 10.1055/s-0028-1087951
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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;

Further Information

Publication History

Received 11 December 2008
Publication Date:
24 February 2009 (online)

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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

Indoles are arguably the most abundant heterocyclic substructures in drug discovery. [¹] [²] Therefore, a continued strong demand exists for generally applicable syntheses of this structural motif. [³-5] Valuable strategies for the de novo formation of indole’s N-heterocyclic moiety were developed. [6-8] However, direct functionalization reactions of unreactive C-H bonds in indoles constitute an attractive alternative. In this context, particularly, transition-metal catalysis was found to be highly promising, and set the stage for the development of novel direct arylation methodologies. [9] In considering this approach for intermolecular transformations, achieving regioselectivity represents a major challenge. Interestingly, the majority of known protocols for catalytic direct arylations of 2,3-unsubstituted indoles provides predominantly the C-2 functionalized products, [¹0-¹²] likely occurring via an electrophilic metalation at C-3, along with a subsequent 1,2-migration. [¹²-¹7] In a recently communicated exception, however, isolated palladium complexes derived from secondary phosphine oxides (SPO) [¹8] were shown to enable highly regioselective direct C-3 arylations of 2,3-unsubstituted indoles. [¹9] Unfortunately, this remarkable protocol provided often comparable low yields, and proved not applicable to direct arylations of a 2-substituted [²0] [²¹] indole. [¹9] Given our interest in efficient syntheses of highly substituted indoles, [²²-²4] as well as in the use of air-stable heteroatom-substituted secondary phosphine oxides (HASPO) in transition-metal catalysis, [6] [²5-²7] we probed the application of our preligands to palladium-catalyzed [²8] direct arylations of indoles, on which we report herein.

Table 1 Air-Stable SPO and HASPO Preligands in Palladium-­Catalyzed Direct Arylation of Indole 1a a

Entry Preligand Yield (%)
 1 - 11
 2 Mes2P(O)H 4a -
 3 (o-Tol)2P(O)H 4b 13
 4 (t-Bu)2P(O)H 4c 15
 5 (1-Ad)2P(O)H 4d 6
 6

4e 10
 7

4f 21
 8
 9

4g 44
10b
10

4h 94
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), Pd(OAc)2 (5 mol%), preligand (10 mol%), K2CO3 (3.0 equiv), 1,4-dioxane (4 mL), 95 ˚C, 20 h; yields of isolated products.
b Additive: t-BuCO2H (30 mol%).

At the outset of our studies, we explored the catalytic activity of in situ generated palladium complexes derived from representative SPO and HASPO preligands 4a-h (Table  [¹] ). Preliminary experiments revealed that 1,4-dioxane as solvent and K2CO3 as base provided superior results, whereas the use of polar aprotic solvents, such as NMP or DMA, resulted in no cross-coupling between the starting materials. Unfortunately, various in situ formed (HA)SPO-based complexes gave rise to unsatisfactory results (entries 2-7). [²9] In contrast, more efficient catalysis was accomplished with the aid of HASPO preligands 4g and 4h (entries 8-10).

While the addition of pivalic acid [³0] in substoichiometric amounts inhibited catalytic activity (entry 9), sterically hindered TADDOL derivative 4h led to an efficient and selective formation of desired indole 3a (entry 10).

With an optimized catalytic system in hand, we explored its scope in direct arylations of indoles 1a-d using a range of substituted aryl bromides 2b-l (Table  [²] ). [³¹] [³²] We were pleased to observe that electrophiles 2 displaying valuable functional groups could be employed for regioselective direct arylations of indole 1a (entries 1-6). Further, the catalytic system displayed a notable chemoselectivity, allowing for the selective coupling of bromochloroarene 2h (entries 7, and 8). Sterically more hindered electrophile 2i was converted with comparable efficacy (entry 9), as were substituted pronucleophilic indoles 1b and 1c (entries 8-10). Contrary to the previously reported SPO-based methodology, [¹9] this enabled the preparation of more congested 2,3-disubstituted indole 3l (entry 11). However, reactions with di-ortho or nitro-substituted aryl bromides 2k and 2l occurred with lower efficacy (entries 12 and 13).

Table 2 Palladium-Catalyzed Direct C-3 Arylations of Indoles 1 a (continued)

Entry 1 R¹ 2 R² Product Yield (%)
1 1a H 2b H 3b

81
2 1a H 2c 4-MeO 3c

66
3 1a H 2d 3-EtO2C 3d

69
4 1a H 2e 4-Ph(O)C 3e

53
 5 1a H 2f 3-Me(O)C 3f

62
 6 1a H 2g 4-Me2N 3g

61
 7 1a H 2h 3-Cl 3h

65
 8 1b 5-MeO 2h 3-Cl 3i

56
 9 1b 5-MeO 2i 2-Me 3j

81
10 1c 7-Me 2j 3-Me 3k

50
11 1d 2-Me 2j 3-Me 3l

53
12 1b 5-MeO 2k 2,4,6-Me3 3m

23
13 1a H 2l 4-O2N 3n

4
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (5 mol%), 4h (10 mol%), K2CO3 (3.0 equiv), 1,4-dioxane (0.5 M), 95 ˚C, 20 h; yields of isolated products.

As to the mechanism of this transformation, we propose a catalytic cycle comprising oxidative addition of the organic electrophile to a palladium(0) species, followed by electrophilic functionalization of the indole by the generated palladium(II) species, and subsequent reductive elimination. The exact reason as to why these catalytic ­reactions proceed with excellent C-3 selectivity is, as yet, not fully understood, and warrants further mechanistic studies.

In summary, we have developed a highly efficient catalytic system for direct C-3 arylations of indoles. Thus, an in situ generated palladium complex derived from an air-­stable HASPO preligand allowed for regioselective arylations of various indoles employing diversely functionalized bromides as electrophiles.

Acknowledgment

Support by the DFG and the German-Israeli-Foundation (GIF) is gratefully acknowledged.

    References and Notes

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    CrossrefSearch in Google Scholar
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  • 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:
  • 10a Potavathri S. Dumas AS. Dwight TA. Naumiec GR. Hammann JM. DeBoef B. Tetrahedron Lett.  2008,  49:  4050 
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  • For rhodium-catalyzed direct arylations of indoles, occurring largely with C-2 regioselectivity, see:
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  • 12 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 
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  • Selected recent representative examples of palladium-catalyzed direct arylations of indoles:
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  • 16 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 
    Search in Google Scholar
  • 17 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 
    CrossrefSearch in Google Scholar
  • 18 Ackermann L. Synthesis  2006,  1557 
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  • For the recent use of a heterogenous palladium catalyst for direct C-3 arylations of 2-substituted indoles, see:
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    Search in Google Scholar
  • 20b For a direct C-3 arylation of a 2-substituted indole, see: Djakovitch L. Dufaud V. Zaidi R. Adv. Synth. Catal.  2006,  348:  715 
    Search in Google Scholar
  • 21 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 
    CrossrefSearch in Google Scholar
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  • 23 Ackermann L. Kaspar LT. Gschrei CJ. Chem. Commun.  2004,  2824 
    Crossref
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    Search in Google Scholar
  • 25b Ackermann L. Gschrei CJ. Althammer A. Riederer M. Chem. Commun.  2006,  1419 
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  • 27 Ackermann L. Althammer A. Born R. Angew. Chem. Int. Ed.  2006,  45:  2619 
    CrossrefPubMedSearch in Google Scholar
  • For recent examples of palladium-catalyzed direct arylations from our laboratories, see:
  • 28a Ackermann L. Althammer A. Fenner S. Angew. Chem. Int. Ed.  2009,  48:  201 
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  • 29 Unfortunately, under otherwise identical reaction conditions catalytic amounts of Bn(n-Bu)3NCl²¹ 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]:
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31

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 (Cq), 134.1 (Cq), 132.9 (Cq), 129.2 (CH), 126.3 (CH), 125.0 (Cq), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH), 115.6 (Cq), 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]

32

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 (Cq), 137.5 (Cq), 134.6 (Cq), 131.7 (Cq), 130.0 (CH), 127.1 (CH), 125.9 (Cq), 125.8 (CH), 125.3 (CH), 123.0 (CH), 116.8 (Cq), 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 (Cq), 136.1 (Cq), 135.5 (Cq), 128.6 (CH), 128.1 (CH), 126.7 (CH), 125.2 (Cq), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (Cq), 120.4 (CH), 118.8 (Cq), 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 (Cq), 135.2 (Cq), 135.1 (Cq) 131.2 (Cq), 130.0 (CH), 128.3 (CH), 127.8 (Cq), 126.5 (CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH), 114.5 (Cq), 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.

    References and Notes

  • 1 Horton DA. Bourne GT. Smythe ML. Chem. Rev.  2003,  103:  893 
    CrossrefPubMedSearch in Google Scholar
  • 2 Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 
    CrossrefPubMedSearch in Google Scholar
  • 3 Eicher T. Hauptmann S. The Chemistry of Heterocycles   2nd ed.:  Wiley-VCH; Weinheim: 2003. 
    Search in Google Scholar
  • 4 Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Addison Wesley Longman; Harlow: 1997. 
    Search in Google Scholar
  • 5 Joule JA. Milles K. Heterocyclic Chemistry   4th ed.:  Blackwell Science Ltd; Oxford: 2000. 
    Search in Google Scholar
  • 6 Ackermann L. Synlett  2007,  507 
    Thieme Connect
  • 7 Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 
    CrossrefPubMedSearch in Google Scholar
  • 8 Krüger K. Tillack A. Beller M. Adv. Synth. Catal.  2008,  350:  2153 
    CrossrefSearch in Google Scholar
  • 9 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:
  • 10a Potavathri S. Dumas AS. Dwight TA. Naumiec GR. Hammann JM. DeBoef B. Tetrahedron Lett.  2008,  49:  4050 
    Search in Google Scholar
  • 10b Stuart DR. Villemure E. Fagnou K. J. Am. Chem. Soc.  2007,  129:  12072 
    Search in Google Scholar
  • 10c Dwight TA. Rue NR. Charyk D. Josselyn R. DeBoef B. Org. Lett.  2007,  9:  3137 
    Search in Google Scholar
  • 10d Stuart DR. Fagnou K. Science  2007,  316:  1172 ; and references cited therein
    Search in Google Scholar
  • For rhodium-catalyzed direct arylations of indoles, occurring largely with C-2 regioselectivity, see:
  • 11a Yanagisawa S. Sudo T. Noyori R. Itami K. Tetrahedron  2008,  64:  6073 
    Search in Google Scholar
  • 11b Yanagisawa S. Sudo T. Noyori R. Itami K. J. Am. Chem. Soc.  2006,  128:  11748 
    Search in Google Scholar
  • 11c Wang X. Lane BS. Sames D. J. Am. Chem. Soc.  2005,  127:  4996 
    Search in Google Scholar
  • 12 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 
    CrossrefSearch in Google Scholar
  • 13 de Mendoza P. Echavarren AM. In Modern Arylation Methods   Ackermann L. Wiley-VCH; Weinheim: 2009.  p.363 
  • 14a Seregin IV. Gevorgyan V. Chem. Soc. Rev.  2007,  36:  1173 
    Search in Google Scholar
  • 14b Alberico D. Scott ME. Lautens M. Chem. Rev.  2007,  107:  174 
    Search in Google Scholar
  • Selected recent representative examples of palladium-catalyzed direct arylations of indoles:
  • 15a Lebrasseur N. Larrosa I. J. Am. Chem. Soc.  2008,  130:  2926 
    Search in Google Scholar
  • 15b Zhao J. Zhang Y. Cheng K. J. Org. Chem.  2008,  73:  7428 
    Search in Google Scholar
  • 15c Yang S.-D. Sun C.-L. Fang Z. Li B.-J. Li Y.-Z. Shi Z.-J. Angew. Chem. Int. Ed.  2008,  47:  1473 
    Search in Google Scholar
  • 15d Bellina F. Calandri C. Cauteruccio S. Rossi R. Eur. J. Org. Chem.  2007,  2147 
  • 15e Deprez NR. Kalyani D. Krause A. Sanford MS. J. Am. Chem. Soc.  2006,  128:  4972 ; and references cited therein
    Search in Google Scholar
  • 16 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 
    Search in Google Scholar
  • 17 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 
    CrossrefSearch in Google Scholar
  • 18 Ackermann L. Synthesis  2006,  1557 
    Thieme Connect
  • 19 Zhang Z. Hu Z. Yu Z. Lei P. Chi H. Wang Y. He R. Tetrahedron Lett.  2007,  48:  2415 
    CrossrefSearch in Google Scholar
  • For the recent use of a heterogenous palladium catalyst for direct C-3 arylations of 2-substituted indoles, see:
  • 20a Cusati G. Djakovitch L. Tetrahedron Lett.  2008,  49:  2499 
    Search in Google Scholar
  • 20b For a direct C-3 arylation of a 2-substituted indole, see: Djakovitch L. Dufaud V. Zaidi R. Adv. Synth. Catal.  2006,  348:  715 
    Search in Google Scholar
  • 21 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 
    CrossrefSearch in Google Scholar
  • 22a Ackermann L. Org. Lett.  2005,  7:  439 
    Search in Google Scholar
  • 22b Kaspar LT. Ackermann L. Tetrahedron  2005,  61:  11311 
    Search in Google Scholar
  • 23 Ackermann L. Kaspar LT. Gschrei CJ. Chem. Commun.  2004,  2824 
    Crossref
  • 24 Ackermann L. Sandmann R. Villar A. Kaspar LT. Tetrahedron  2008,  64:  769 
    CrossrefSearch in Google Scholar
  • 25a Ackermann L. Born R. Angew. Chem. Int. Ed.  2005,  44:  2444 
    Search in Google Scholar
  • 25b Ackermann L. Gschrei CJ. Althammer A. Riederer M. Chem. Commun.  2006,  1419 
  • 25c Ackermann L. Spatz JH. Gschrei CJ. Born R. Althammer A. Angew. Chem. Int. Ed.  2006,  45:  7627 
    Search in Google Scholar
  • 26 Ackermann L. Org. Lett.  2005,  7:  3123 
    Search in Google Scholar
  • 27 Ackermann L. Althammer A. Born R. Angew. Chem. Int. Ed.  2006,  45:  2619 
    CrossrefPubMedSearch in Google Scholar
  • For recent examples of palladium-catalyzed direct arylations from our laboratories, see:
  • 28a Ackermann L. Althammer A. Fenner S. Angew. Chem. Int. Ed.  2009,  48:  201 
    Search in Google Scholar
  • 28b Ackermann L. Vicente R. Born R. Adv. Synth. Catal.  2008,  350:  741 
    Search in Google Scholar
  • 28c Ackermann L. Althammer A. Angew. Chem. Int. Ed.  2007,  46:  1627 
    Search in Google Scholar
  • 29 Unfortunately, under otherwise identical reaction conditions catalytic amounts of Bn(n-Bu)3NCl²¹ 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]:
  • 30a Lafrance M. Fagnou K. J. Am. Chem. Soc.  2006,  128:  16496 
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  • 30b [Ru]: Lafrance M. Gorelsky SI. Fagnou K. J. Am. Chem. Soc.  2007,  129:  14570 
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  • 30c Ackermann L. Vicente R. Althammer A. Org. Lett.  2008,  10:  2299 
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  • 30d Ackermann L. Mulzer M. Org. Lett.  2008,  10:  5043 ; and references cited therein
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31

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 (Cq), 134.1 (Cq), 132.9 (Cq), 129.2 (CH), 126.3 (CH), 125.0 (Cq), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH), 115.6 (Cq), 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]

32

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 (Cq), 137.5 (Cq), 134.6 (Cq), 131.7 (Cq), 130.0 (CH), 127.1 (CH), 125.9 (Cq), 125.8 (CH), 125.3 (CH), 123.0 (CH), 116.8 (Cq), 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 (Cq), 136.1 (Cq), 135.5 (Cq), 128.6 (CH), 128.1 (CH), 126.7 (CH), 125.2 (Cq), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (Cq), 120.4 (CH), 118.8 (Cq), 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 (Cq), 135.2 (Cq), 135.1 (Cq) 131.2 (Cq), 130.0 (CH), 128.3 (CH), 127.8 (Cq), 126.5 (CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH), 114.5 (Cq), 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.

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