Organic Syntheses Procedure

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Org. Synth. 2002, 78, 36

DOI: 10.15227/orgsyn.078.0036

INDOLE SYNTHESIS BY Pd-CATALYZED ANNULATION OF KETONES WITH o-IODOANILINE: 1,2,3,4-TETRAHYDROCARBAZOLE

[ 1H-Carbazole, 2,3,4,9-tetrahydro- ]

Submitted by Cheng-yi Chen and Robert D. Larsen¹ .

Checked by Adam Charnley and Steven Wolff.

1. Procedure

To a 100-mL, two-necked flask, is added a mixture of cyclohexanone (5.9 g, 60 mmol) , o-iodoaniline (4.4 g, 20 mmol) , and 1,4-diazabicyclo[2.2.2]octane (DABCO) (6.7 g, 60 mmol) in N,N-dimethylformamide (DMF) (60 mL). The mixture is degassed three times via nitrogen/vacuum, followed by the addition of palladium acetate (Pd(OAc)₂) (2.24 mg, 0.1 mmol) (Note 1). The mixture is degassed twice and heated at 105°C for 3 hr or until completion of the reaction (Note 2). The reaction mixture is cooled to room temperature and partitioned between isopropyl acetate (150 mL) and water (50 mL). The organic layer is separated, washed with brine (50 mL), and concentrated under vacuum to dryness. The residue is chromatographed on 50 g of silica gel using 700 mL of ethyl acetate-heptane (1:6) as the eluent to give 2.22 g of 1,2,3,4-tetrahydrocarbazole (65%) as a pale brown solid (Note 3).

2. Notes

1. Both cyclohexanone and o-iodoaniline were purchased from Lancaster Synthesis and used directly in the reaction without further purification.

2. The reaction generally takes 3-5 hr to complete and is monitored by TLC (R_f = 0.50, SiO₂, eluted with EtOAc - heptane, 1:4).

3. The product is fully characterized: mp 116-118°C; IR (neat) cm⁻¹: 3401, 2928, 2848, 1470, 1305, 1235, 739 ; ¹H NMR (300 MHz, CDCl₃) δ: 1.86-1.99 (br m, 4 H), 2.74 (br t, 4 H, J = 6), 7.08-7.71 (br m, 2 H), 7.29 (m, 1 H), 7.49 (m, 1 H), 7.64 (br s, 1 H) ; ¹³C NMR (75 MHz, CDCl₃) δ: 20.05, 22.20, 22.32, 22.42, 108.98, 109.61, 116.81, 118.12, 119.96, 126.82, 133.30, 134.66 . Anal. Calcd for C₁₂H₁₃N: C, 84.17; H, 7.65; N, 8.18. Found: C, 82.87; H, 7.53; N, 7.84.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

The indole nucleus is a common and important feature of a variety of natural products and medicinal agents.² The traditional approach for preparing the indole nucleus is the Fischer indole reaction.³ As this reaction has shortcomings, the palladium-catalyzed coupling of ortho-haloanilines is becoming an excellent alternative.⁴ Recently, the submitters disclosed a new and efficient method for indole synthesis using a palladium-catalyzed annulation between o-iodoanilines and ketones (Scheme 1).⁵

As illustrated in Chart 1, this reaction is applicable to a variety of o-iodoanilines and cyclic ketones to prepare the desired indoles in good yields. The coupling reaction is highly regioselective.⁶ For example, condensation of o-iodoaniline 1, R=1-(1,2,4-triazolyl)methyl, with 2-methylcyclohexanone gave tetrahydrocarbazole 11 in 68% yield. Reaction of 3-methylcyclohexanone with o-iodoaniline formed tetrahydrocarbazole 12 predominantly. The reaction is also compatible with cyclopentanone and cycloheptanone (compounds 8 and 9). The reaction tolerates a variety of functional groups, especially the acid-sensitive ketal (10), carbamate (14), or the benzyl triazole⁷ (8, 9 and 11). These compounds, which would be unstable under the conditions of the traditional Fischer indole reaction,⁸ were conveniently synthesized using this method. The structurally interesting indole 15 was prepared from 3-quinuclidinone hydrochloride (1.0 equiv) in 55% yield. The interesting coupling of the indole nucleus onto a steroid was also achieved with 5α-cholestanone (1.0 equiv) affording 13 exclusively in 79% yield. Pyruvic acid and acetyl silane were also acceptable substrates, used to prepare indoles 16 and 17 in 82% and 64% yield respectively. Overall, the simple procedure, mild reaction conditions, and availability of the starting materials render this method a valuable addition to indole chemistry.

The high regioselectivity of these reactions follows the same pattern as those of 2- and 3-substituted cyclohexanones when converted to enamines.⁹ Apparently, A¹^,² and A¹^,³ strain in the transition state controls the regiochemistry. The additive magnesium sulfate (MgSO₄), presumably acting as a dehydrating agent, was found to promote the annulation (for compounds 7, 8, 11, 13, 15 and 17), indicating that the formation of the imine or enamine intermediate is critical to the reaction. The annulation of dehydrocholic acid and o-iodoaniline clearly demonstrated the high efficiency of this reaction as both excellent chemoselectivity and regioselectivity were observed (18). The coupling reaction led to the unique combination of indole and steroid moieties into one interesting molecule.

References and Notes

Process Research Department, Merck Research Laboratories, Division of Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065.
Saxton, J. E. "The Chemistry of Heterocyclic Compounds"; John Wiley and Sons: New York, 1994; Vol. 25, Part IV.
For reviews on the Fischer indole reaction, see: Robinson, B. "The Fischer Indole Synthesis"; John Wiley and Sons: New York, 1982; Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607; Gribble, G. W. Contemp. Org. Synth. 1994, 1, 145 and references cited therein.
(a) For a 'one-pot' synthesis of indoles under non-acidic conditions (S_RN1 reaction), see: Beugelmans, R.; Roussi, G. J. Chem. Soc., Chem. Commun. 1979, 950; (b) Bard, R. R.; Bunnett, J. J. J. Org. Chem. 1980, 45, 1546; (c) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127; (d) Suzuki, H.; Thiruvikraman, S. V.; Osuka, A. Synthesis 1984, 616 and references cited therein; (e) dAngelo, J.; Desmaele, D.; Tetrahedron Lett. 1990, 31, 879.
Chen, C.-y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676 and references cited therein.
For a recent example of a regioselective Fischer indole reaction mediated by organoaluminum amides, see: Maruoka, K.; Oishi, M.; Yamamoto, H. J. Org. Chem. 1993, 58, 7638.
Chen, C.-y; Lieberman, D. R.; Larsen, R. D.; Reamer, R. A.; Verhoeven, T. R.; Reider, P. J.; Cottrell, I. F.; Houghton, P. G. Tetrahedron Lett. 1994, 35, 6981.
A Fischer indole reaction in pyridine has been reported: Welch, W. M. Synthesis 1977, 645.
Cook, A. G. "Enamines: Synthesis, Structure, and Reactions", 2nd ed.; Marcel Dekker, Inc.: New York, 1988.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

o-Iodoaniline:
Aniline, o-iodo- (8);
Benzenamine, 2-iodo- (9); (615-43-0)

1,2,3,4-Tetrahydrocarbazole:
Carbazole, 1,2,3,4-tetrahydro- (8);
1H-Carbazole, 2,3,4,9-tetrahydro- (9); (942-01-8)

Cyclohexanone (8,9); (108-94-1)

1,4-Diazabicyclo[2.2.2]octane: DABCO (8,9); (280-57-9)

N,N-Dimethylformamide: CANCER SUSPECT AGENT:
Formamide, N,N-dimethyl- (8,9); (68-12-2)

Palladium acetate:
Acetic acid, palladium(2+) salt (8,9); (3375-31-3)

Notes

References/EndNotes

Article Compounds

Authors