HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 5, 2010, pp. 1169-1182
Received, 9th January, 2010, Accepted, 25th February, 2010, Published online, 26th February, 2010.
DOI: 10.3987/COM-10-11904

■ Regioselective Synthesis of 3-Indolyl(alkoxy)acetates

Oscar R. Suárez-Castillo,* Myriam Meléndez-Rodríguez, Indira C. Cano-Escudero, Sandra Luz De Ita-Gutiérrez, Maricruz Sánchez-Zavala, Martha S. Morales-Ríos, and Pedro Joseph-Nathan

Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, Mineral de la Reforma, Hidalgo, 42184, Mexico

Abstract

The regioselective synthesis of N-carbomethoxy-2-alkoxyindolenines and α-alkoxyindoles is reported. Bromination of indole 5 with NBS/AIBN/CCl4 gave α-bromoindole 6 which after treatment with ROH/3Å molecular Sieves afforded (Z-) and (E)-2-alkoxyindolenines 8a-d as the main products, together with minor amounts of α-alkoxyindoles 9a-d. The reversed regioselectivity was achieved in the absence of molecular Sieves to give α-alkoxyindoles 9a-d as the main products, while no traces of Z- or E-8a-d were detected.

INTRODUCTION
Indole-3-acetic acid (1a) and its derivatives 1b-e are plant growth-regulators (auxins), among them α-methoxy derivatives 1c and 1e increase the physiological effectiveness and strikingly translocate in plants.1

Hydroxylation or alkoxylation at α position of 1a,b is achieved by oxidating reagents like DDQ,2 SeO23 or FeCl3,4 while δ-alkoxylation of tetrahydro-β-carbolines is attained by means of anodic oxidation with MeOH/HCl.5 It is worth noting that DDQ oxidation at α position of indoles affords the corresponding ketones2 through the incorporation of hydoxyl or alkoxyl groups at the α position due to selection of substrates and reaction conditions.2c-f Another strategy to prepare α-hydroxyl and alkoxyl derivatives is Friedel-Crafts reaction of indoles with carbonyl compounds or alkyl halides.6 The synthesis of α-hydroxyl indole derivatives has also been achieved by reduction of the corresponding α-carbonylindole derivatives with NaBH4 and LiAlH4,7 while two less frequently used strategies consist in the hydrolysis of α-bromoalkylindoles8 and in deamination or demethoxylation of the α-aminoindolyl acetates or 2-methoxyindolenines.9
In continuation with our studies on the bromination of indole derivatives,10 in this work we describe the easy synthesis of α-alkoxylindole-3-acetates as potential plant growth-regulators through bromination of indoles 1 and 10 with NBS/AIBN/CCl4 followed by alkoxylation using various alcohols.

RESULTS AND DISCUSSION
We previously reported10a the bromination of indolylmalonate 2 with Br2/CCl4 to give indolylbromomalonate 3, which on treatment with various alcohols in the presence of 3 Å molecular Sieves (MS) gave 2-alkoxyindolenines 4 in excellent yields through allylic substitution at the C2 position (Scheme 1).

Thus, we envisioned that the less hindered methyl indolylbromoacetate 6 (Scheme 2) would allow direct substitution of the bromine atom at α position with various alcohols to give α-alkoxylindolylacetates 9. Thus, treatment of 5 with Br2/CCl4 at room temperature afforded indolylbromoacetate 6, which without isolation was treated with MeOH and 3 Å MS under reflux, whereby expected 9a was not obtained. Instead a mixture of isomeric 2-methoxyindolenines Z-8a (26%, δH4 = 7.51) and E-8a (11%, δH4 = 8.80) was produced together with 2-bromoindolylacetate 7 (33%). This latter compound 7 was formed during the first step by bromination of 5. Since it is known that MS affects the reaction outcome, we decided to carry out the methoxylation of 6 in the absence of MS. Under this reaction conditions alkoxyindole 9a was obtained in 26% yield, together with 7 in 41% yield (Table 2, entry 1). Chromatographic attempts to separate 6 from 7 resulted in decomposition of 6.

It follows from this result that MS promotes nucleophilic attack of MeOH at the C2 position regardless of the steric hindrance at α position in compound 6. It is known that Faujasite zeolites behave as a nucpleophile and/or a base in the presence of alkyl halides and that the Na cation present in this solid assists the C-halogen bond cleavage.11 Such interaction should avoid the nucleophilic attack of MeOH at α of 6, and as a consequence the nucleophilic attack at C2 is effected.
As the main drawback of this methodology is the low yielding of compounds 8a or 9a due to formation of 7 in first step, we decided to apply the bromination methodology described by Cook et al.12 Thus, the use of NBS/AIBN/CCl4 afforded compound 6, as the main product, as evidenced by 1H NMR analysis of the reaction crude. When 6 was reacted with MeOH in the presence of MS, a mixture of 2-methoxyindolenines Z-8a (δH4 = 7.51) and E-8a (δH4 = 8.80) was obtained in 73% and 12% yield, respectively, together with α-methoxyindole 9a in 9% yield, while the 2-bromoindolylacetate 7 was detected only in traces (Table 1, entry 2). In a similar way, treatment of 6 with EtOH, i-PrOH and t-BuOH gave the results as shown in Table 1, entries 3-5. As can be seen, the combined yields for compounds Z-8b-d and E-8b-d were gradually decreasing while the yields for compounds 9b-d were gradually increasing. Thus nucleophilic attack at positon C2 or α in indole 6 depends greatly on the steric effect of the used alcohol. As the steric effect of the alcohol increases, the steric interaction with the carbamate group becomes important, thus favoring the nucleophilic attack at position α in 6. This assumption was demonstrated when 10, containing the bulkier Boc group, was treated with MeOH in the presence of MS (Scheme 3) giving Z-12 (δH4 = 7.49) in only 53% yield together with 13 in 20% yield compared to 6 (Table 1, entry 2).

We next carried out the reaction of intermediate 6 with the same alcohols in the absence of MS to afford the α-alkoxylated products 9 in good yields whereby no 2-alkoxyindolenines Z-8 nor E-8 were detected (Table 2).

These reactions followed the expected reactivity, that is, as bulkier the alcohol is, as longer is the alkoxylation time of 6 (See experimental). The reaction of 6 with MeOH afforded 9a in 85% yield (entry 2). It is worth noting that reaction of 6 with EtOH gave 9b in 16% yield together with the trasesterified product 9e in 62% yield (Scheme 2, Table 2, entry 3), while when i-PrOH was used, expected 9c was obtained in 50% yield together with the trasesterified product 9f in 39% yield (entry 4). When 6 was reacted with t-BuOH, 9d was obtained in 52% yield without transesterified product (entry 5).
As described above, for the reaction of α-bromoindolylacetates 6 and 11 with alcohols, in the presence of MS, the corresponding 2-alkoxyindolenines Z-8a-d are predominantly formed over their respective isomers E-8a-d.13 In order to explain this result the energy characteristics for these Z- and E- isomers were calculated. A conformational search was carried out by means of systematic and Monte Carlo protocols within the Spartan 04 program14 from which the mayor conformers were further submitted to geometry optimization using DFT calculations at the B3LYP/6-31G(d) level.15 The relative energies for the mayor Z-8a-d and E-8a-d isomeric pairs are shown in Table 3.
As can be deduced from Table 3 and Figure 1, isomers Z-8a-d and Z-12 are more stable by 1.58-3.21 kcal/mol, which matches very well with experimental results. On the other hand, the 1H NMR spectra of alkoxyindolenines Z-8, E-8 and 12 evidence slow rotation around the N-CO2Me bond,10a giving rise to the two mayor s-cis and s-trans conformers denoted by the C(7a)-N(1)-C=O torsion angle. For example, both s-cis and s-trans mayor conformers of Z-12 and E-12 and their DFT energies are shown in Figure 1. Compound 12 gave crystals suitable for X-ray diffraction analysis, the corresponding structure being shown in Figure 2, where it is evident that the s-cis-(Z)-12 isomer is preferred in the crystalline state.

In conclusion, we developed a simple protocol for the synthesis of 3-indolyl(alkoxy)acetates 9a-f as potential plant growth-regulators. The procedure employs operationally facile reaction conditions, giving good yields and therefore providing advantages over those previously reported.

EXPERIMENTAL
Melting points were determined on a Büchi B-540 apparatus. IR spectra were recorded on a Perkin Elmer 2000 FT-IR spectrophotometer. The 1H and 13C NMR spectra were obtained on a JEOL Eclipse 400 spectrometer using CDCl3 as solvent and TMS as the internal reference. For complete assignments 2D NMR spectra, HMQC and HMBC were used. Chemical shifts are reported in ppm from TMS. Data are reported as follows: chemical shift, integration, multiciplity (s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, br = broad, m = multiplet), coupling constant (Hz) and assignment. Low-resolution mass spectra were recorded at an ionizing voltage of 70 eV on a Hewlett Packard 5989-A spectrometer. High-resolution (HR) mass spectra were measured on a JEOL JMS-SX 102A mass spectrometer at Instituto de Química, UNAM-México. Microanalytical determinations were performed on a Perkin Elmer 2400 series PCII apparatus. Analytical thin-layer chromatography (TLC) was done on silica gel 60 F254 coated aluminum sheets (0.25 mm thickness) with a fluorescent indicator. Visualization was accomplished with UV light (254 nm). Flash chromatography was done using silica gel 60 (230-400 mesh) from Aldrich.

General bromination-alkoxylation procedure in the presence of MS
Bromination
Method A: To a solution of 5 (0.1 g, 0.4 mmol) in CCl4 (5 mL) was added Br2 (0.8 mmol, 41 µL) and the resulting mixture was stirred at rt for 5 h. The mixture was treated with a saturated aqueous solution of NaHSO3 (10 mL) and stirred during 30 min. The aqueous phase was separated and extracted with CH2Cl2 (10 mL) and the combined organic layer was washed with brine (2 x 10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure, yielding a mixture of 6 (55%) and 7 (45%).
Method B: To a solution of 5 (0.25 g, 1.01 mmol) or 10 (0.5 g, 1.73 mmol) in CCl4 (15-20 mL) were added 2.2 equiv de NBS (0.40 g, 2.22 mmol for 5 and 0.60 g, 3.8 mmol for 10) and 0.05 equiv de AIBN (8 mg, 0.05 mmol for 5 and 30 mg, 0.19 mmol for 10). The mixture was heated under reflux in a nitrogen atmosphere for 2 h. After cooling to rt the reaction mixture was washed with brine (2 x 20 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. Compound 5 gave 6 (87%) and 7 (13%).
Alkoxylation
To a solution of the appropiate crude products 6 or 11 (Method A or B) in 30 mL of the corresponding alcohol (MeOH, EtOH, i-PrOH, t-BuOH) was added molecular Sieves (3 Å) (3.75 g for 6 and 7.5 g for 11) and heated under reflux during 2 h (MeOH), 5 h (EtOH), 10 h (i-PrOH) and 16 h (t-BuOH) for 6, and 3 h (MeOH) for 11. After cooling to rt the mixture was filtrated and concentred in vacuum. The resultant crude products Z-8a-d, 12 and 13 were purified by flash column chromatography on silica gel eluting with EtOAc/hexane 1:4 and with EtOAc/hexane 1:7, respectively.

Methyl Z-(1-carbomethoxy-2-methoxy-3-indolylidene)acetate (8a). Preparated from 5 as white crystals (Method A: 0.03 g, 26%, Method B: 0.204 g, 73.0%); mp 92-94 °C (EtOAc/hexane); 1H NMR (CDCl3, 400 MHz) δ 7.91 (1H, brs, H-7), 7.51 (1H, dd, J = 7.7, 0.7 Hz, H-4), 7.41 (1H, t, J = 7.8 Hz, H-6), 7.07 (1H, t, J = 7.7 Hz, H-5), 6.70 (1H, d, J = 1.9 Hz, H-2), 6.38 (1H, d, J = 1.8 Hz, H-8), 3.92 (3H, s, NCO2CH3), 3.82 (3H, s, CO2CH3), 3.50 (3H, brs, OCH3); 13C NMR (CDCl3, 100 MHz) δ 165.8 (CO2CH3), 153.1 (NCO2CH3), 150.1 (C-3), 144.5 (C-7a), 132.9 (C-6), 125.7 (C-3a), 123.4 (C-5), 121.4 (C-4), 116.0 (C-7), 111.6 (C-8), 88.7 (C-2), 55.7 (OCH3), 53.0 (NCO2CH3), 51.7 (CO2CH3); IR (KBr) νmax 3121, 3000, 2918, 2835, 1954, 1704, 1645, 1598, 1478, 1447 cm-1; EIMS m/z 277 [M+] (49), 262 (38), 246 (100), 230 (71), 218 (46), 159 (47), 59 (65); Anal. Calcd for C14H15NO5: C 60.64; H 5.45; N 5.05. Found: C 60.63; H 5.48; N 4.77; FABHMRS m/z 277.0954 (calcd for C14H15NO5 , 277.0950).

Methyl Z-(1-carbomethoxy-2-ethoxy-3-indolylidene)acetate (8b). Preparated from 5 as white crystals (Method B: 0.174 g, 59.0%); mp 100-102 °C (EtOAc/hexane); 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, brs, H-7), 7.49 (1H, d, J = 7.7 Hz, H-4), 7.39 (1H, t, J = 7.9 Hz, H-6), 7.05 (1H, td, J = 7.7, 0.7 Hz, H-5), 6.70 (1H, d, J = 1.9 Hz, H-2), 6.34 (1H, d, J = 1.5 Hz, H-8), 3.91 (3H, s, NCO2CH3), 3.85 (2H, br, OCH2), 3.81 (3H, s, CO2CH3), 1.16 (3H, t, J = 6.9 Hz, OCH3); 13C NMR (CDCl3, 100 MHz) δ 165.9 (CO2CH3), 153.3 (NCO2CH3), 150.7 (C-3), 144.5 (C-7a), 132.9 (C-6), 125.8 (C-3a), 123.5 (C-5), 121.7 (C-4), 116.4 (C-7), 111.4 (C-8), 88.5 (C-2), 65.5 (OCH2CH3), 53.0 (NCO2CH3), 51.7 (CO2CH3), 15.7 (CH2CH3); IR (KBr) νmax 3089, 2977, 2956, 2899, 1719, 1659, 1471, 1439 cm-1; EIMS m/z 291 [M+] (42), 262 (25), 247 (63), 246 (100), 230 (63), 59 (77); Anal. Calcd for C15H17NO5: C 61.85; H 5.88; N 4.81. Found: C 61.83; H 5.95; N 4.67. FABHMRS m/z 291.1109 (calcd for C15H17NO5 , 291.1107).

Methyl Z-(1-carbomethoxy-2-isopropoxy-3-indolylidene)acetate (8c). Preparated from 5 as white solid (Method B: 0.073 g, 24.0%); mp 76-78 °C (EtOAc/hexane); 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, brs, H-7), 7.50 (1H, d, J = 7.7 Hz, H-4), 7.40 (1H, t, J = 7.7 Hz, H-6), 7.06 (1H, t, J = 7.5 Hz, H-5), 6.83 (1H, s, H-2), 6.33 (1H, d, J = 1.5 Hz, H-8), 4.04 (1H, br, OCH(CH3)2), 3.88 (3H, s, NCO2CH3), 3.78 (3H, s, CO2CH3), 1.22 (3H, brs, OCH(CH3)2), 1.12 (3H, d, J = 6.2 Hz, OCH(CH3)2); 13C NMR (CDCl3, 100 MHz) δ 165.8 (CO2CH3), 153.4 (NCO2CH3), 150.9 (C-3), 144.5 (C-7a), 132.7 (C-6), 126.4 (C-3a), 123.6 (C-5), 121.8 (C-4), 116.7 (C-7), 111.5 (C-8), 86.8 (C-2), 71.2 (OCH(CH3)2), 53.0 (NCO2CH3), 51.7 (CO2CH3), 23.9 (OCH(CH3)2), 22.6 (OCH(CH3)2); IR (film) νmax 2974, 2953, 1719, 1658, 1469, 1441 cm-1; EIMS m/z 305 [M+] (28), 262 (13), 246 (100), 188 (36), 144 (13), 59 (8), 43 (3); FABHRMS m/z 305.1266 (calcd for C16H19NO5, 305.1263).

Methyl Z-(1-carbomethoxy-2-tertbutoxy-3-indolylidene)acetate (8d). Preparated from 5 as a yellow oil (Method B: 86 mg, 27%, obtained as a mixture of Z-8d/E-8d, 1.0/0.2 ratio); 1H NMR (CDCl3, 400 MHz) δ 8.72 (1H, d, J = 8.1 Hz, H-4), 7.73 (1H, d, J = 8.4 Hz, H-7), 7.38 (1H, t, J = 7.9 Hz, H-6), 7.09 (1H, t, J = 7.7 Hz, H-5), 6.06 (1H, s, H-2), 6.01 (1H, s, H-8), 3.88 (3H, s, NCO2CH3), 3.79 (3H, s, CO2CH3), 1.35 (9H, s, 3CH3); 13C NMR (CDCl3, 100 MHz) δ 165.7 (CO2CH3), 153.5 (NCO2CH3), 152.4 (C-3), 146.0 (C-7a), 132.6 (C-6), 129.2 (C-4), 124.7 (C-3a), 123.6 (C-5), 116.6 (C-7), 114.8 (C-8), 87.4 (C-2), 76.7 (C(Me)3), 52.8 (NCO2CH3), 51.6 (CO2CH3), 28.5 (3 CH3); IR (film) νmax 2974, 2953, 2854, 1720, 1659, 1469, 1441 cm-1; EIMS m/z 319 [M+] (38), 246 (100), 231 (52), 203 (81), 172 (66), 59 (66); FABHRMS m/z 319.1420 (calcd for C17H21NO5, 319.1420).

Methyl E-(1-carbomethoxy-2-terbutoxy-3-indolylidene)acetate (8d). Preparated from 5 as a yellow oil (Method B: 86 mg, 27%, obtained as a mixture of Z-8d/E-8d, 1.0/0.2 ratio); 1H NMR (CDCl3, 400 MHz) δ 7.71 (1H, br, H-7), 7.49 (1H, d, J = 7.7 Hz, H-4), 7.38 (1H, t, J = 7.8 Hz, H-6), 7.06 (1H, t, J = 7.7 Hz, H-5), 6.95 (1H, s, H-2), 6.26 (1H, s, H-8), 3.88 (3H, s, NCO2CH3), 3.79 (3H, s, CO2CH3), 1.35 (9H, s, 3CH3); 13C NMR (CDCl3, 100 MHz) δ 165.7 (CO2CH3), 153.5 (NCO2CH3), 152.9 (C-3), 144.4 (C-7a), 132.3 (C-6), 127.5 (C-3a), 123.8 (C-5), 121.9 (C-4), 117.8 (C-7), 110.8 (C-8), 83.8 (C-2), 76.7 (C(CH3)3), 52.8 (NCO2CH3), 51.6 (CO2CH3), 28.5 (3CH3); IR (film) νmax 2974, 2953, 2854, 1720, 1659, 1469, 1441 cm-1; EIMS m/z 319 [M+] (38), 246 (100), 231 (52), 203 (81), 172 (66), 59 (66); FABHRMS m/z 319.1420 (calcd for C17H21NO5, 319.1420).

Methyl Z-(1-terbuthoxy-2-methoxy-3-indolylidene)acetate (12). Preparated from 10 as white crystals (0.29 g, 53%); mp 109-111 °C (EtOAc/hexane); 1H NMR (CDCl3, 400 MHz); δ 7.84 (1H, brs H-7), 7.49 (1H, d, J = 7.3 Hz, H-4), 7.38 (1H, td, J = 8.4, 1.1 Hz, H-6), 7.03 (1H, td, J = 7.7, 0.9 Hz, H-5), 6.60 (1H, d, J = 1.5 Hz, H-2), 6.35 (1H, d, J = 1.5 Hz, H-8), 3.82 (3H, br, CO2CH3), 3.60 (3H, s, OCH3), 1.61 (9H, s, 3CH3); 13C NMR (CDCl3, 100 MHz) δ 166.1 (CO2CH3), 151.9 (NCO2t-Bu), 151.0 (C-3), 145.0 (C-7a), 132.9 (C-6), 125.8 (C-3a), 123.2 (C-5), 121.6 (C-4), 116.4 (C-7), 111.2 (C-8), 89.2 (C-2), 82.4 (C(Me3)), 57.5 (OCH3), 51.6 (CO2CH3), 28.5 (3CH3); IR (KBr) νmax 3093, 2977, 2937, 1725, 1698, 1659, 1601, 1470 cm-1; EIMS m/z 319 [M+] (6), 187 (56), 172 (16), 160 (11), 128 (12), 57 (100); Anal. Calcd for C17H21NO5: C 63.94; H 6.63; N 4.39. Found: C 64.09; H 6.69; N 4.00.

Methyl-2-(1-carbomethoxy-3-indolyl)-2-tertbuthoxyacetate (13). Preparated from 10 as a yellow oil (0.119 g, 22.0%); 1H NMR (CDCl3, 400 MHz) δ 8.16 (1H, d, J = 8.4 Hz, H-7), 7.74 (1H, d, J = 7.7 Hz, H-4), 7.70 (1H, s, H-2), 7.34 (1H, td, J = 7.9, 1.3 Hz, H-6), 7.25 (1H, td, J =7.5, 1.1 Hz, H-5), 5.06 (1H, s, H-8), 3.74 (3H, s, CO2CH3), 3.45 (3H, s, OCH3), 1.67 (9H, s, 3CH3); 13C NMR (CDCl3, 100 MHz) δ 170.9 (CO2CH3), 149.5 (NCO2t-Bu), 135.8 (C-7a), 128.3 (C-3a), 125.4 (C-2), 125.0 (C-6), 123.1 (C-5), 120.2 (C-4), 115.9 (C-3), 115.4 (C-7), 84.2 (C(Me3)), 76.4 (C8), 57.4 (OCH3), 52.5 (CO2CH3), 28.3 (3CH3); IR (KBr) νmax 3454, 3104, 3009, 2980, 2956, 2860, 1732, 1458, 1442, 1247 cm-1; EIMS m/z 319 [M+] (5), 187 (100), 172 (35), 128 (68), 57 (56).

General procedure for the alkoxylation whitout MS
A solution of crude 6 in 25 mL of the appropriate alcohol (MeOH, EtOH, i-PrOH, t-BuOH) was heated under reflux during 4 h (MeOH), 6 h (EtOH), 12 h (i-PrOH) and 36 h (t-BuOH). After cooling to rt the mixture was concentred in vacuum and the resultant crude products were purified by flash column chromatography on silica gel eluting with EtOAc/hexane 1:4.

Methyl 2-(1-carbomethoxy-3-indolyl)-2-methoxyacetate (9a). Preparated from 5 as a pale yellow solid (Method A: 0.029 g, 26%, Method B: 0.238 g, 85.0%); mp 68-69 °C (EtOAc: Et2O:hexanes); 1H NMR (CDCl3, 400 MHz) δ 8.18 (1H, d, J = 8.0 Hz, H-7), 7.75 (1H, dd, J = 7.9, 0.9 Hz, H-4), 7.72 (1H, s, H-2), 7.36 (1H, td, J = 7.9, 1.2 Hz, H-6), 7.28 (1H, td, J = 7.5, 1.1 Hz, H-5), 5.05 (1H, s, H-8), 4.04 (3H, s, NCO2CH3), 3.74 (3H, s, CO2CH3), 3.45 (3H, s, OCH3); 13C NMR (CDCl3, 100 MHz) δ 170.6 (CO2CH3), 151.2 (NCO2CH3), 135.7 (C-7a), 128.1 (C-3a), 125.1 (C-6), 124.9 (C-2), 123.3 (C-5), 120.3 (C-4), 116.7 (C-3), 115.2 (C-7), 76.1 (C-8), 57.3 (OCH3), 53.9 (NCO2CH3), 52.4 (CO2CH3); IR (film) νmax 3461, 3105, 2956, 2860, 1733, 1607, 1459 cm-1; EIMS m/z 277 [M+] (11), 218 (100), 159 (28), 116 (13), 59 (13); Anal. Calcd for C14H15NO5: C 60.64; H 5.45; N 5.05. Found: C 60.71; H 5.47; N 4.79. FABHRMS m/z 277.0945 (calcd for C14H15NO5, 277.0950).

Methyl 2-(1-carbomethoxy-3-indolyl)-2-ethoxyacetate (9b). Preparated from 5 as a white solid (Method A: 0.0144 g, 12%, Method B: 0.046 g, 16.0%); mp 68-70 °C EtOAc/hexane; 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, brd, J = 8.1 Hz, H-7), 7.76 (1H, d, J = 7.7 Hz, H-4), 7.71 (1H, s, H-2), 7.36 (1H, td, J = 7.6, 1.1 Hz, H-6), 7.27 (1H, t, J = 7.7 Hz, H-5), 5.16 (1H, s, H-8), 4.04 (3H, s, NCO2CH3), 3.74 (3H, s, CO2CH3), 3.65 (1H, dq, J = 9.1, 7.0 Hz, OCH2CH3), 3.58 (1H, dq, J = 9.0, 7.0 Hz, OCH2CH3), 1.28 (3H, t, J = 6.9 Hz, OCH2CH3); 13C NMR (CDCl3, 100 MHz) δ 171.1 (CO2CH3), 151.5 (NCO2CH3), 135.8 (C-7a), 128.4 (C-3a), 125.3 (C-6), 124.7 (C-2), 123.5 (C-5), 120.5 (C-4), 117.4 (C-3), 115.3 (C-7), 74.7 (C-8), 65.5 (OCH2CH3), 54.0 (NCO2CH3), 52.6 (CO2CH3), 15.3 (OCH2CH3); IR (film) νmax 3119, 2928, 1743, 1455 cm-1; EIMS m/z 291 [M+] (12), 232 (100), 204 (39), 144 (14), 117 (31), 59 (17); FABHRMS m/z 291.1109 (calcd for C15H17NO5, 291.1107).

Methyl 2-(1-carbomethoxy-3-indolyl)-2-isopropoxyacetate (9c). Preparated from 5 as a yellow oil (Method A: 0.038 g, 31%, Method B: 0.153 g, 50%); 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, brd, J = 8.1 Hz, H-7), 7.78 (1H, dd, J = 6.6, 0.7 Hz, H-4), 7.70 (1H, s, H-2), 7.35 (1H, td, J = 7.8, 1.2 Hz, H-6), 7.27 (1H, td, J = 7.6, 0.9 Hz, H-5), 5.26 (1H, d, J = 0.7 Hz, H-8), 4.03 (3H, s, NCO2CH3), 3.75 (1H, sept, J = 6.2 Hz, OCH(CH3)2), 3.73 (3H, s, CO2CH3), 1.27, 1.22 (6H, 2d, J = 6.2 Hz, OCH(CH3)2); 13C NMR (CDCl3, 100 MHz) δ 171.4 (CO2CH3), 151.3 (NCO2CH3), 135.7 (C-7a), 128.3 (C-3a), 125.0 (C-6), 124.4 (C-2), 123.2 (C-5), 120.4 (C-4), 117.8 (C-3), 115.2 (C-7), 72.2 (C-8), 70.9 (OCH(CH3)2), 53.9 (NCO2CH3), 52.3 (CO2CH3), 22.1 (OCH(CH3)2), 22.0 (OCH(CH3)2); IR (film) νmax 3120, 2972, 1739, 1456 cm-1; EIMS m/z 305 [M+] (8), 246 (52), 204 (100), 132 (9), 117 (25); FABHRMS m/z 305.1272 (calcd for C16H19NO5, 305.1263).

Methyl 2-(1-carbomethoxy-3-indolyl)-2-tert-buthoxyacetate (9d). Preparated from 5 as a pale yellow solid (Method A: 0.02 g, 15%, Method B; 0.167 g 52%); mp 75-77 °C (EtOAc/hexane); 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, d, J = 7.7 Hz, H-7), 7.76 (1H, d, J = 8.1 Hz, H-4), 7.69 (1H, s, H-2), 7.35 (1H, td, J = 7.4, 1.1 Hz, H-6), 7.28 (1H, td, J = 7.2, 1.1 Hz, H-5), 5.32 (1H, s, H-8), 4.03 (3H, s, NCO2CH3), 3.72 (3H, s, CO2CH3), 1.30 (9H, s, 3CH3); 13C NMR (CDCl3, 100 MHz) δ 172.8 (CO2CH3), 151.3 (NCO2CH3), 135.7 (C-7a), 128.2 (C-3a), 124.9 (C-6), 123.8 (C-2), 123.1 (C-5), 120.2 (C-4), 119.4 (C-3), 115.2 (C-7), 76.0 (C(CH3)3), 68.0 (C-8), 53.8 (NCO2CH3), 52.3 (CO2CH3), 27.9 (C(CH3)3); IR (film) νmax 2976, 1743, 1456 cm-1; EIMS m/z 319 [M+] (4), 260 (13), 246 (10), 204 (100), 117 (14), 57 (14); Anal. Calcd for C17H21NO5: C 63.94; H 6.63; N 4.39. Found: C 63.98; H 6.73; N 4.18. FABHRMS m/z 319.1422 (calcd for C17H21NO5, 319.1420).

Ethyl 2-(1-carbomethoxy-3-indolyl)-2-ethoxyacetate (9e). Preparated from 5 as a pale yellow oil (Method B: 0.192 g, 62.0%); 1H NMR (CDCl3, 400 MHz) δ 8.17 (1H, d, J = 7.3 Hz, H-7), 7.78 (1H, d, J = 8.0 Hz, H-4), 7.72 (1H, s, H-2), 7.35 (1H, t, J = 7.9 Hz, H-6), 7.27 (1H, t, J = 8.1 Hz, H-5), 5.14 (1H, s, H-8), 4.24 (1H, dq, J = 10.8, 7.0 Hz, CO2CH2CH3), 4.17 (1H, dq, J = 10.7, 7.0 Hz, CO2CH2CH3), 4.02 (3H, s, NCO2CH3); 3.65 (1H, dq, J = 9.0, 7.2 Hz, OCH2CH3), 3.58 (1H, dq, J = 8.9, 7.1 Hz, OCH2CH3), 1.28 (3H, t, J = 6.9 Hz, OCH2CH3), 1.22 (3H, t, J = 7.1 Hz, CO2CH2CH3); 13C NMR (CDCl3, 100 MHz) δ 170.6 (CO2Et), 151.3 (NCO2Me), 135.8 (C-7a), 128.4 (C-3a), 125.1 (C-6), 124.6 (C-2), 123.3 (C-5), 120.5 (C-4), 117.5 (C-3), 115.2 (C-7), 74.7 (C-8), 65.3 (OCH2CH3), 61.4 (CO2CH2CH3), 54.0 (NCO2CH3), 15.3 (CO2CH2CH3), 14.2 (OCH2CH3); IR (film) νmax 3122, 3053, 2937, 2978, 2899, 1746, 1569 cm-1; EIMS m/z 305 [M+] (10), 260 (2), 232 (100), 204 (40), 117 (23), 59 (11); FABHRMS m/z 305.1266 (calcd for C16H19NO5, 305.1263).

Isopropyl 2-(1-carbomethoxy-3-indolyl)-2-isopropoxyacetate (9f). Preparated from 5 as a pale yellow oil (Method B: 0.131 g, 39.0%); 1H NMR (CDCl3, 400 MHz); δ 8.17 (1H, brd, J = 8.5 Hz, H-7), 7.79 (1H, d, J = 7.7 Hz, H-4), 7.70 (1H, s, H-2), 7.34 (1H, td, J = 7.7, 1.1 Hz, H-6), 7.26 (1H, td, J = 7.5, 1.1 Hz, H-5), 5.20 (1H, s, H-8), 5.07 (1H, sept, J = 6.2 Hz, CO2CH(CH3)2), 4.02 (3H, s, NCO2CH3), 3.77 (1H, sept, J = 6.1 Hz, OCH(CH3)2), 1.28, 1.23 (6H, 2d, J = 6.2 Hz, OCH(CH3)2), 1.25, 1.14 (6H, 2d, J = 6.2 Hz, CO2CH(CH3)2); 13C NMR (CDCl3, 100 MHz) δ 170.7 (CO2i-Pr), 151.4 (NCO2CH3), 135.8 (C-7a), 128.5 (C-3a), 125.0 (C-6), 124.3 (C-2), 123.2 (C-5), 120.6 (C-4), 118.2 (C-3), 115.2 (C-7), 72.7 (C-8), 71.1 (OCH(CH3)2), 69.1 (CO2CH(CH3)2), 54.0 (NCO2CH3), 22.4 (OCH(CH3)2), 22.0 (OCH(CH3)2), 21.9 (CO2CH(CH3)2); 21.7 (CO2CH(CH3)2). IR (film) νmax 3123, 2977, 2880, 1743, 1570, 1455 cm-1; EIMS m/z 333 [M+] (6), 246 (42), 204 (100), 117 (21); FABHRMS m/z 333.1569 (calcd for C18H23NO5, 333.1576).

Methyl 2-(2-bromo-1-carbomethoxy-3-indolyl)-acetate (7). Preparated from 5 (Method A) as a pale yellow solid and obtained together with alkoxyindole 9a-d (0.05 g, 41.0%; 0.03 g, 20%, 0.05 g, 37% and 0.02 g, 11%, respectively); 1H NMR (CDCl3, 400 MHz) δ 8.03 (1H, d, J = 8.1 Hz, H-7), 7.46 (1H, dt, J = 7.7, 0.7 Hz, H-4), 7.29 (1H, td, J = 7.8, 1.6 Hz, H-6), 7.24 (1H, td, J = 7.4, 1.3 Hz, H-5), 4.05 (3H, s, NCO2CH3), 3.76 (2H, s, H-8), 3.68 (3H, s, CO2CH3); 13C NMR (CDCl3, 100 MHz) δ 170.3 (CO2CH3), 151.1 (NCO2CH3), 136.2 (C-7a), 128.7 (C-3a), 124.9 (C-6), 123.4 (C-5), 118.3 (C-4), 117.1 (C-3), 115.5 (C-7), 110.8 (C-2), 53.8 (NCO2CH3), 52.2 (CO2CH3), 31.3 (C-8); IR (film) νmax 2955, 2849, 1747, 1449 cm-1; EIMS m/z 326/324 [M+] (69), 268/266 (100), 224 (93), 143 (88), 101 (48), 77 (14), 75 (23), 59 (63). FABHRMS m/z 325.0102 (calcd for C13H12BrNO4, 324.9950).

Single crystal structure determination of 12. Suitable crystals were obtained by slow evaporation of a EtOAc/hexane solution. A crystal measuring 0.30 x 0.24 x 0.20 mm was mounted on a Bruker Smart 6000 CCD diffractometer. The crystal was triclinic, space group P-1, with cell dimensions a = 9.207(2), b = 9.538(2), c = 10.115(3) Å, α = 73.817(6), β = 82.253(6) and γ = 84.675(6), V = 843.8(4) Å3, ρcalc = 1.257 g/cm3 for Z = 2, C17H21O5N, MW = 319.35, and F(000) = 340 e. The total reflections were 5553 (graphite-monochromated Mo Kα radiation, λ = 0.71073 Å), the unique reflections were 1074 and the observed reflections were 1073. The structure was solved by direct methods using SIR2004, the final discrepancy indices, refining 216 parameters, were RF = 5.8%, Rw = 15.4%, and the highest residual peak in the final difference Fourier map showed an electron density of 0.20 e/Å3. The CCDC deposition number is 764379.

ACKNOWLEDGEMENTS
We are pleased to acknowledge the financial support from CONACYT (Mexico), grant 83723.

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