Synthesis of N-aryl indole-2-carboxylates via an intramolecular palladium-catalysed annulation of didehydrophenylalanine derivatives

Article abstract of DOI:10.1016/S0040-4039(99)02344-8

Nitrogen substituted indole-2-carboxylates can be prepared via an intramolecular palladium-catalysed amination reaction of didehydrophenylalanine derivatives using PdCl₂(dppf) and KOAc in DMF at 90°C to form the indole nucleus. The specific for

Full text of DOI:10.1016/S0040-4039(99)02344-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1623–1626
Synthesis of N-aryl indole-2-carboxylates via an intramolecular
palladium-catalysed annulation of didehydrophenylalanine
derivatives
Julien A. Brown ∗
Celltech Chiroscience Plc, 216 Bath Road, Slough, Berkshire, SL1 4EN, UK
Received 15 November 1999; accepted 16 December 1999
Abstract
Nitrogen substituted indole-2-carboxylates can be prepared via an intramolecular palladium-catalysed amination
reaction of didehydrophenylalanine derivatives using PdCl2(dppf) and KOAc in DMF at 90°C to form the indole
nucleus. The specific formation of (Z)-isomers from Horner–Wadsworth–Emmons reaction of phosphonylglyci-
nates and 2-iodobenzaldehydes was crucial to the success of the process. The product N-substituted indole-2-
carboxylates were isolated in high yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amination; Horner–Wadsworth–Emmons; indole-2-carboxylate; palladium catalysis.
Indole-2-carboxylates substituted on nitrogen with an aryl or acyl group are a relatively poorly descri-
bed class of compounds. Previous syntheses of N-arylindole-2-carboxylates have relied on Ullmann co-
upling, transition metal mediated coupling or aromatic nucleophilic attack to arylate the indole nitrogen.
These methods are not entirely satisfactory, for example, the copper mediated Ullmann coupling which
has remained the standard method of construction of the N-aryl bond. Although useful for compounds
with activated aryl halides, this method usually requires high temperatures and gives variable yields.1,2
Alternatively, Barton et al. have described a copper-catalysed phenylation of indole derivatives using
triphenylbismuth bis-trifluoroacetate. Using this methodology they found that ethyl indole-2-carboxylate
undergoes N-phenylation in a yield of 30%.3 Russell et al. have demonstrated nucleophilic aromatic
substitution in the synthesis of these compounds.4 Their method uses the sodium salt of indole-2-
carboxylates to displace aryl fluorides bearing strongly electron withdrawing groups in the ortho or para
position to give products in yields of between 9 and 84%. Alternative preparations reliant upon formation
of the heterocyclic portion built from an aromatic amino group are known, for example the Nenitzescu
reaction, but this and other methods involving cyclisation require lengthy syntheses.5 Ischii and co-
workers have shown that the Fischer indolisation of ethyl pyruvate 2-(4-methoxyphenyl)phenylhydrazone
can yield an N-aryl indole-2-carboxylate derivative in moderate yield,6,7 however, this reaction is limited
∗
Fax: +44 (0) 1753 536 632; e-mail: jbrown@celltech.co.uk (J. A. Brown)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02344-8
tetl 16272

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to the formation of compounds in which the phenyl portion of indole nucleus bears an electron donating
substituent. Thus, the need for a flexible procedure compatible with a wide range of functionality is clear.
Recently the arylation of amines and anilines using aryl halides with palladium or nickel catalysis
has been well documented by Hartwig and Buchwald.8 In addition Buchwald has recently shown the
palladium-catalysed cyclisation of secondary amides and carbamates to give indanes and indanones.9 In
this communication, we present an approach to N-substituted indole-2-carboxylates using an intramole-
cular palladium-catalysed amination reaction to form the heterocyclic core of the indole nucleus with the
nitrogen substituent installed prior to cyclisation (Scheme 1).
Scheme 1.
N-Aryl-α-phosphonylglycines (3) were prepared according to the rhodium carbenoid insertion method
developed by Haigh and Moody.10 Thus, ethyl 2-diazo-2-diethoxyphosphonylacetate (1) (1 equiv.) and
the appropriate aniline (2) (1 equiv.) were heated in toluene at 110°C with catalytic Rh2(OAc)4 for
between 4 and 18 h by which time the reaction was complete. Horner–Wadsworth–Emmons (HWE)
reaction of the N-aryl-α-phosphonylglycine (3) derivatives with 2-iodobenzaldehydes (4: X=H, 5-NO2,
4-NO2, 5-OMe) using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base in dichloromethane at room
temperature gave the corresponding didehydro compounds (5) in excellent yield. Although the HWE
reaction of N-acyl-α-phosphonylglycine derivatives with aldehydes is well known,11 we believe this is
the first report of N-aryl-α-phosphonylglycine derivatives being used in this reaction. In each case a single
geometrical isomer was formed which on the basis of ROESY experiments the double bond was assigned
as Z. Treatment of these compounds with PdCl2 (dppf) (0.05 equiv.) and KOAc (3 equiv.) in DMF at 90°C
cleanly gave the substituted indoles (6) in good yield, typically, reactions were complete within 4 h.12
The electronic nature of the substituents on the phenyl ring bearing the iodine atom had little effect on the
yield of cyclisation, compounds with electron withdrawing, neutral or electron donating groups reacting
equally well (Table 1). It is noteworthy that the final N-substituted products are formed with little, if any,
concomitant formation of de-iodinated products.
The cyclisation of N-acyl didehydroamino acid derivatives was an obvious extension to this metho-
dology. The necessary N-acyl-α-phosphonylglycines (7) were prepared from commercially available N-
Cbz-α-phosphonylglycine methyl ester via removal of the protecting group followed by an EDC coupling
with the appropriate acid. HWE reaction with 2-iodo-4-methoxybenzaldehyde gave (Z)-didehydro com-

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Table 1
N-Aryl indole-2-carboxylates
pounds (8) in high yield which were cyclised to give N-acyl indole-2-carboxylates (9) in the same manner
as above (Scheme 2) again in good overall yield (Table 2).
Scheme 2.
Table 2
N-Acyl indole-2-carboxylates
In conclusion, we have demonstrated an efficient, general method for the synthesis of N-substituted
indole-2-carboxylates, which uses a simple procedure and work up, giving the products in high overall
yield and is complementary to existing strategies.
Acknowledgements
The author thanks Dr. R. J. Taylor for provision and interpretation of 2D NMR and 13C NMR spectra.

1626
References
1. Lopez-Alvaredo, P.; Avendano, C.; Menendez, J. C. J. Org. Chem. 1995, 60, 5678–5682.
2. Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657–2660.
3. a) Barton, D.H. R.; Finet, J.-P.; Khamsi, J. Tetrahedron Lett. 1988, 29, 1115–1118. (b) Barton, D. H. R.; Finet, J.-P.; Khamsi,
J. Tetrahedron Lett. 1986, 27, 3615–3618.
4. Beach, M. J.; Hope, R.; Klaubert, Russell, R. K. Synth. Commun. 1995, 25, 2165–2183.
5. Smith III, W. J.; Sawyer, J. S. Tetrahedron Lett. 1996, 37, 299–302.
6. Ishii, H.; Sugiura, T.; Akiyama, Y.; Ichikawa, Y.; Watanabe, T.; Murakami, Y. Chem. Pharm. Bull. 1990, 38, 2118–2126.
7. Ishii, H.; Takeda, H.; Hagiwara, T.; Sakamoto, M.; Kogusuri, K. J. Chem. Soc., Perkin Trans. 1 1989, 2407–2414.
8. For reviews, see: (a) Hartwig, J. F. Synlett 1997, 329. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067.
9. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37.
10. Moody, C. J.; Ferris, L.; Haigh, D. J. Chem. Soc., Perkin Trans. 1 1996, 2885–2888.
11. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Riedl, B. Synthesis 1992, 487–490.
12. Typical reaction conditions. For entry 7: (a) To a solution of the phosphonylacetate (3) (230 mg, 0.6 mmol) and 2-iodo-5-
methoxybenzaldehyde (157 mg, 0.6 mmol) in dichloromethane (5 ml) at room temperature was added DBU (0.10 ml, 1.1
equiv.) The reaction was stirred for 30 min and then partitioned between EtOAc (50 ml) and water (50 ml). The organics
were separated and washed with water (3×20ml), and brine (20 ml), and then dried (MgSO4), filtered and concentrated in
vacuo. The crude product was purified by triturating with diethyl ether to give the product (5) as a yellow solid (249 mg,
84%.) FTIR νmax (solid) 3346, 1707, 1689, 1601cm−1. 1H NMR (300 MHz, CDCl3) δ 1.34 (3H, t, J=7.1 Hz), 1.40 (3H, t,
J=7.1 Hz), 3.38 (3H, s), 4.28 (2H, q, J=7.1 Hz), 4.36 (2H, q, J=7.1 Hz), 6.43 (1H, dd, J=3.0, 8.8 Hz), 6.54 (2H, d, J=8.7 Hz),
6.56 (1H, s), 6.78 (1H, d, J=3.0 Hz), 7.14 (1H, s), 7.68 (1H, d, J=8.8 Hz), 7.74 (2H, d, J=8.7 Hz) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.2, 14.4, 55.0, 60.5, 62.3, 89.8, 114.1, 116.1, 117.4, 122.3, 123.7, 127.6, 130.5, 138.5, 139.5, 145.1, 159.4,
165.9, 166.4 ppm. m/z (ESI+, 70 V) found MH+496. (b) To a solution of the iodoalkene (5) (148 mg, 0.3 mmol) in DMF
(5 ml) under N2 at room temperature was added KOAc ( 95 mg, 1 mmol) and PdCl2(dppf) (14 mg, 6 mol%). The mixture
was heated to 90°C for a period of 30 min, and then partitioned between EtOAc (50 ml) and water (50 ml). The aqueous
was separated and the organics washed with water (4×25 ml), brine (30 ml), dried (MgSO4), filtered and solvent removed
in vacuo to give a brown oil. Column chromatography (eluant 4:1, hexane:EtOAc) gave the product (6) as a clear oil (111
mg, 94%). FTIR νmax. (film) 2982, 1710, 1610cm−1. 1H NMR (300 MHz, CDCl3) δ 1.24(3H, t, J=7.2 Hz), 1.43 (3H,t, J=7.2
Hz), 3.86 (3H, s), 4.23 (2H, q, J=7.1 Hz), 4.43 (2H, q, J=7.1 Hz), 6.95 (1H, dd, J=2.2, 9.1 Hz), 7.02 (1H, d, J=9.1 Hz), 7.11
(1H, d, J=2.1 Hz), 7.39 (2H, d, J=8.2 Hz), 7.42 (1H, s), 8.20 (2H, d, J=8.2 Hz) ppm. 13C NMR (100 MHz, CDCl3) δ 14.5,
14.8, 56.1, 61.0, 61.6, 103.0, 112.2, 112.5, 117.5, 127.1, 128.3, 129.6, 130.3, 130.5, 130.8, 136.1, 143.1, 155.7, 161.5, 166.3
ppm. m/z (ESI+, 70 V) found MH+368.