Regioselective reactivity of some 5,7-dimethoxyindoles

Tetrahedron 61 (2005) 4989–5004

*

Glenn C. Condie, Michelle F. Channon, Andrew J. Ivory, Naresh Kumar and David StC. Black

School of Chemistry, University of New South Wales, UNSW Sydney NSW 2052, Australia

Received 16 December 2004; revised 23 February 2005; accepted 10 March 2005

Available online 7 April 2005

Abstract—The reactivity of some 5,7-dimethoxyindoles with respect to electrophiles has been investigated. The favoured sites for reaction

are C3 and C4 and regioselectivity can be controlled by the judicious arrangement of electron-withdrawing substituents. Results of

formylation, acylation, the Mannich reaction, bromination and nitration are described.

1. Introduction

found to be the most effective for the synthesis of the

carboxylate 6. 3,5-Dimethoxybenzaldehyde was condensed

with the ethyl azidoacetate to give methyl 2-azido-3-(3,5-

dimethoxyphenyl)propenoate in high yield and purity. This

intermediate could then be pyrolized to the corresponding

indole in reﬂuxing xylene. However, it was found that the

use of 1,2-dichlorobenzene gave a cleaner reaction. The

indole 6 was isolated in 87% yield. Either ethyl azidoacetate

or methyl azidoacetate could be used in this reaction

because the presence of sodium methoxide and methanol

ensured that the condensed product was always the methyl

ester 6. In general, ethyl azidoacetate^10,11was utilised and

was prepared according to the method reported by Allen and

co-workers for the preparation of methyl azidoacetate.¹²

The indole 6 was N-methylated to give compound 7 and a

bis-alkylation with a,a⁰-dibromo-m-xylene gave compound

8 in good yield.

The reactivity of indoles towards electrophiles is of

fundamental importance in heterocyclic chemistry. While

it is well established that the most nucleophilic site of an

indole nucleus is the C3 position, the targeted reactivity at

other sites can expand its synthetic applications immensely.

4,6-Dimethoxyindoles have been shown to exhibit enhanced

reactivity, especially at C7.^1–4Here, we examine the

behaviour of some simple 5,7-dimethoxyindoles, including

methyl 5,7-dimethoxyindole-2-carboxylate, towards a range

of electrophiles.

2. Results and discussion

2.1. Synthesis of 5,7-dimethoxyindoles

4,6-Dimethoxyindoles have been synthesized very effec-

tively by the cyclisation of an acylaminoketone.¹Conse-

quently, this approach was also investigated for the

preparation of some 3-aryl-5,7-dimethoxyindoles. 2,4-

Dimethoxyaniline was reacted with 4-bromophenacyl

bromide and the resulting relatively unstable aminoketone

was treated directly with triﬂuoroacetic anhydride to give

the triﬂuoroacetamide 9. However, all attempts to cyclise

this compound, using either triﬂuoroacetic acid or poly-

phosphoric acid, failed. The 5,7-dimethoxyindoles 1–8

could potentially undergo reaction at C3 and C4. Therefore,

achievement of regioselectivity became a major point of

interest and a key synthetic goal (Scheme 1).

The preparation of 5,7-dimethoxyindole 1 was ﬁrst reported

in 1953 by Su¨s and co-workers⁵via the decarboxylation of

the corresponding 2-carboxylic acid. However, in 1970

Crohare and co-workers⁶reported an alternative synthesis,

which was followed shortly after in the same year by yet

another synthesis by Mulligan and LaBerge, involving

reductive cyclisation of 3⁰,5⁰-dimethoxy-2⁰-nitro-2-nitro-

styrene.⁷The last method has been used in this study. The

parent 5,7-dimethoxyindole 1 was methylated, benzylated,

acetylated and phenylsulfonated on nitrogen to yield the

corresponding N-substituted compounds 2–5. Methyl 5,7-

dimethoxyindole-2-carboxylate 6 has been synthesized

from the related carboxylic acid following a Reissert indole

synthesis.⁶However, the Hemetsberger methodology^8,9was

2.2. Formylation

Keywords: Indoles; Formylation; Acylation; Regioselectivity.

*

Vilsmeier–Haack formylation of 5,7-dimethoxyindole 1

with one equivalent of phosphoryl chloride in DMF at 0 8C

Corresponding author. Tel.: C61 2 9385 4657; fax: C61 2 9385 6141;

e-mail: d.black@unsw.edu.au

doi:10.1016/j.tet.2005.03.048

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G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

hydrolysed off during the reaction work-up, and the

corresponding 4-carbaldehyde 11 was obtained in 87%

yield. Presumably, the 3-position is relatively deactivated

by the electron-withdrawing N-acetyl group. Attempted

formylation of the N-phenylsulfonylindole 5 led to exten-

sive decomposition.

Scheme 1.

gave the 3- and 4-carbaldehydes, 10 and 11, respectively, in

66 and 33% yield. Use of excess phosphoryl chloride and a

little warming gave the 3,4-dicarbaldehyde 12 in 93% yield.

Interestingly, the dialdehyde 12 underwent reaction with

ammonia to give the pyrroloisoquinoline 13 in quantitative

yield, and also with nitromethane and potassium hydroxide

to give the benzindole 14 in 63% yield. In general, the

indole-3-carbaldehydes 15 and 18 were formed in

preference to the 4-carbaldehydes 16 and 19 in formylation

reactions of the N-methyl and N-benzylindoles 2 and 3,

respectively. Selectivity for the 3-carbaldehyde was

increased with a lowering of temperature, and was more

effective with the N-methylindole 2 than the N-benzylindole

3. Replacement of phosphoryl chloride with triﬂic

anhydride gave reduced amounts of the 3-carbaldehyde

and led to the only reaction in which the 4-carbaldehyde

predominated: this was the reaction of 5,7-dimethoxyindole

1 at 0 8C. The 3,4-dialdehydes 17 and 20 could also be

obtained in almost quantitative yields from the indoles 2 and

3, respectively.

A more satisfactory regioselective reaction arises in the case

of the indole ester 6. When it was treated with a slight excess

of the Vilsmeier–Haack reagent at 0 8C for 2 h the indole-4-

carbaldehyde 22 was obtained in quantitative yield.

Attempts to achieve diformylation of indole 6 either directly

with excess reagent or via the formylation of aldehyde 22

failed. Even when phosphoryl chloride was used as the

solvent and the reaction temperature was increased to near

the boiling point, diformylation was not observed.

Hydrolysis of formylindole ester 22 was easily achieved

by heating it in aqueous ethanolic potassium hydroxide

solution, and the acid 23 was obtained as a pale yellow

powder in 95% yield.

In comparison, it was noted that the corresponding

Vilsmeier–Haack reactions on the known 5,7-dimethyl-

indole^14,15gave only the 5,7-dimethylindole-3-carbalde-

hyde¹⁵in high yield, and no 4-substituted product was

detected. A similar Vilsmeie–Haack reaction of 5,7-

dimethylindole using N,N-dimethylacetamide and phos-

phoryl chloride gave an 82% yield of the previously

unreported 3-acetylindole 21.

It is worth noting that the corresponding formylation of

the known¹⁶methyl 5,6,7-trimethoxyindole-2-carboxylate

24 produced a 70:30 ratio of 3-formylindole 25 to

4-formylindole 26, in an overall yield of 84%. The related

N-methylindole¹⁷27 gave formylation only at C3: the

3-formyl ester 28 was produced only in 15% yield and could

not be fully characterized, but the major product in 69%

yield was the related acid 29, as a result of facile ester

hydrolysis on work-up. The N-t-Boc indole derivative 30

could not be formylated successfully without loss of the Boc

substituent.

Surprisingly, regioselective formylation was observed in the

reaction of the N-acetylindole 4, with the acetyl group being

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

4991

2.3. Acylation

4-formylindole 22 at C3 was unsuccessful. This result

suggests that the triﬂuoroacetyl group of compound 39

might be twisted out of the plane of the indole nucleus,

thereby decreasing conjugation with the ring and conse-

quently decreasing the electron withdrawing effect of the

triﬂuoroacetyl group at C4 with respect to C3. A comparison

of the ¹H NMR spectra of the 4-triﬂuoroacetylindole 39 and

4-formylindole 22 reveals a signiﬁcant difference in the

heights of the two methoxy signals of indole 39 compared

with the two methoxy signals of indole 22 which are almost

equal in height. This suggests that there is some steric

hindrance between the triﬂuoroacetyl group and the

adjacent 5-methoxy group of 4-triﬂuoroacetylindole 39,

causing the triﬂuoroacetyl group to be twisted out of the

plane of the indole nucleus.

The results of acetylation of indoles 1–3 were similar to

those of formylation, and both 3- and 4-acetyl-indoles were

obtained. Reaction of phosphoryl chloride and N,N-

dimethylacetamide at room temperature with indoles 1

and 2 gave mainly the 3-acetyl derivatives 31 (41%) and 33

(79%), respectively, with smaller amounts of the 4-acetyl

compounds 32 (29%) and 34 (7%), respectively. Greater

selectivity was observed for the N-methylindole 2. Effective

reaction of the N-benzylindole 3 required warming to

40–60 8C for production of the major 3-acetyl derivative 35

(60%) and the minor 4-acetyl derivative 36 (20%). No 3,4-

diacetyl compound could be formed under these conditions,

but reaction of indole 3 with acetyl chloride and tin (IV)

chloride gave a the 3,4-diacetyl derivative 37 in 34% yield.

Indole 6 was heated in dichloromethane with trichloroacetyl

chloride for 2 days without reaction, except for very minor

decomposition. This result suggests that C4 of indole 6 is

too hindered for the bulky trichloroacetyl chloride to

approach. The related reaction occurs smoothly at C7 in

4,6-dimethoxyindoles.²

The indole ester 6 failed to react under modiﬁed Vilsmeier–

Haack acetylation conditions, even at 60 8C for several

days. However, when it was treated with acetyl chloride and

antimony (V) chloride, the 4-acetylindole 38 was isolated in

moderate yield, and the 3-acetyl isomer could not be

detected. Treatment of indole 6 with an excess of

triﬂuoroacetic anhydride in THF for 3 days at room

temperature gave the 4-triﬂuoroacetyl derivative 39 in

88% yield. Substitution occurred exclusively at C4 and no

substitution at C3 was observed. The triﬂuoroacetyl

derivative 39 was treated with base in an attempt to

transform the compound into either the 4-carboxylic acid or,

if hydrolysis could not be controlled, the 2,4-dicarboxylic

acid. After heating with aqueous ethanolic potassium

hydroxide for 20 min the reaction was complete and

work-up produced the 4-triﬂuoroacetyl-2-carboxylic acid

derivative 40 in 82% yield. This was surprising, since it was

expected that the triﬂuoroacetyl group would be hydrolyzed

more easily than the ester group.

Oxalyl chloride is known to react readily with simple and

activated indoles.^1,2,18,19In the case of 3-substituted-4,6-

dimethoxyindoles, mixtures of 2- and 7-substituted

glyoxyloyl chlorides are obtained, with regioselectivity

being strongly inﬂuenced by the solvent. Reactions of

indoles 1–3 with oxalyl chloride gave only 3-substituted

products in high yields. Ether was the most effective

solvent, allowing precipitation of the glyoxyloyl chloride,

which could then be converted into the corresponding

methyl amides 42–44 by reaction with methylamine.

Additionally, the primary amide 45 and tertiary amide 46

were prepared and characterized. The amide 43 could also

be formylated to give the 4-formyl analog 47 in low yield. In

contrast, reaction of the indole ester 6 with oxalyl chloride

gave a chloro-oxalyl derivative, which was not isolated,

but quenched with ammonia and 3,5-dimethoxyaniline,

respectively, to give the 4-substituted primary amide 48 and

the secondary amide 49 in high yields and purity. The

reaction of indole 6 with oxalyl chloride again exempliﬁes the

directing ability of the methoxy groups and the deactivation

of the 3-position by the ester group. While Crohare and

co-workers were able to react 5,7-dimethoxyindole 1 with

The triﬂuoroacetyl derivative 39 could be formylated by

reaction with the Vilsmeier–Haack reagent in neat phos-

phoryl chloride at 60 8C for 2 days, to give the 3-formyl-4-

triﬂuoroacetylindole 41 in 85% yield. It is signiﬁcant

that the triﬂuoroacetyl group survived intact and that

formylation occurred, since attempted formylation of

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G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

oxalyl chloride selectively at C3,⁷the inclusion of an ester

group at C2 allows for selective reaction at C4.

4. Experimental

4.1. General information

2.4. Mannich reaction

Melting points (uncorrected) were measured using a Mel-

Temp melting point apparatus. Microanalyses were per-

formed by the Microanalysis Unit of the Australian National

University, Canberra or the University of Otago, New

Zealand. Infrared spectra were recorded as Nujol mulls on a

Perkin–Elmer 298 or a Perkin–Elmer 580B spectrometer.

Ultraviolet-visible spectra were recorded in methanol

(unless otherwise stated) on a Hitachi UV-3200 spec-

Indole 6 underwent the Mannich reaction to give 4-(N,N-

dimethylaminomethyl)indole 50 in 78% yield. Once again,

substitution occurred exclusively at C4. In contrast, Crohare

and co-workers prepared 5,7-dimethoxygramine in 36%

yield from 5,7-dimethoxyindole 1, with no mention of any

other products.⁷

1

trometer. H and ¹³C NMR spectra were obtained in the

designated solvents on a Bruker AC300F (300 MHz)

spectrometer or at 500 MHz with a Bruker AM-500

spectrometer. ¹H NMR data are reported as follow:

chemical shift measured in parts per million (ppm) down-

ﬁeld from TMS (d), multiplicity, observed coupling

constant (J) in Hertz (Hz), proton count. Multiplicities are

reported as singlet (s), broad singlet (bs), doublet (d), triplet

(t), quartet (q), quintet (quin) and multiplet (m). ¹³C NMR

chemical shifts are reported in ppm downﬁeld from TMS

and identiﬁable carbons are given. The EI and ES mass

spectra were recorded on an AEI MS 12 mass spectrometer

at 70 eV ionizing potential and 8000 V accelerating voltage

with an ion source temperature of 210 8C. MALDI (matrix

assisted laser desorption) mass spectra were recorded on a

Finnigan MAT Lasermat 2000 for high molecular weight

compounds. The principal ion peaks m/z are reported

together with their percentage intensities relative to the

base peak (where possible). Kieselgel 60H (Merck, Art

7736) was employed for ﬂash chromatography and thin-

layer chromatography (t.l.c.) was performed on DC

Aluminium Foil Kieselgel F₂₅₄(Merck, Art 5554). Pre-

parative thin layer chromatography was performed on 3 mm

plates using Merck silica gel 7730 60GF₂₅₄. Solvents and

reagents were puriﬁed by literature methods. Petroleum

ether refers to the hydrocarbon fraction of boiling range

60–80 8C. Compounds were detected by short and long

ultraviolet light and with iodine vapor.

2.5. Bromination

Kruse and Meyer have previously investigated the bromina-

tion of ethyl 5-methoxyindole-2-carboxylate²⁰and their

results indicated that the 3-bromoindole is the kinetic

product, formed quickly but reversibly, and was the major

product when the reaction was quenched after only 30 s or

less. Extended reaction time (24 h) allowed for the isolation

of the 4-bromoindole in high yield. These results have been

complemented by the more recent work of Murakami and

co-workers.²¹Exposures of indole 6 to bromine for between

30 s and 3 days gave almost quantitative yields of the

4-bromoindole 51, the 3-bromoindole not being observed.

In an attempt to observe the 3-bromoindole, the reaction was

quenched after 1–2 s, and just a trace of the 3-bromoindole

1

could be observed by H NMR spectroscopy.

2.6. Nitration

When indole 6 was treated with nitric acid absorbed on

silica gel²²a mixture of multiple products formed, however,

the 4-nitroindole 52 was easily retrieved via chromato-

graphy in 40% yield. Reduction of 4-nitroindole 52 gave the

4-aminoindole 53 in 59% yield, and this compound could

serve as a promising precursor to pyrroloquinones.

4.2. Preparation of indoles

4.2.1. 5,7-Dimethoxyindole (1).¹³3,5-Dimethoxybenzalde-

hyde (5.00 g, 30 mmol), nitromethane (5.0 mL, 92 mmol),

and ammonium acetate (2.50 g, 32 mmol) were dissolved in

glacial acetic acid (20 mL) and gently reﬂuxed for 1.5 h.

The reaction mixture was cooled to room temperature and

for a short period in ice. The product was ﬁltered and

washed with cold 95% ethanol to yield pure 3,5-dimethoxy-

b-nitrostyrene (4.09 g, 65%) as yellow needles, mp 133 8C

(lit.¹³133.5–134.5 8C). n_max: 3114, 1604, 1514, 1347, 1212,

1

1063, 970, 835 cm^K1. H NMR spectrum (CDCl₃): d 3.79

3. Conclusions

and 3.83 (2s, 6H, OMe), 6.58 (t, JZ2.4 Hz, 1H, aryl H),

6.66 (d, JZ2.4 Hz, 2H, aryl H), 7.54 (d, JZ14 Hz, 1H, CH),

7.92 (d, JZ14 Hz, 1H, CHNO₂). Mass spectrum: m/z 210

(MC1, 12%), 209 (M, 100), 162 (25).

Activated 5,7-dimethoxyindoles undergo preferential

electrophilic substitution at C3 rather than C4, unless an

electron withdrawing group is present at N1 or C2, when

substitution at C4 is favoured. This behaviour is illustrated

by examples of formylation, acylation, aminomethylation,

bromination and nitration. Good selectivity can be achieved

and some sequential substitution processes provide

possibilities for further structural elaboration.

To a solution of 3,5-dimethoxy-b-nitrostyrene (4.0 g,

19 mmol) in acetic anhydride (80 mL) at 60 8C was added

with stirring powdered anhydrous copper (II) nitrate (8.00 g,

43 mmol) portionwise over 70 min. The reaction was

complete when brown fumes ﬁrst appeared. The reaction

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

4993

mixture was poured over ice and allowed to stand overnight.

The precipitated yellow solid was ﬁltered and washed with

water to yield 3,5-dimethoxy-2-nitro,b-nitrostyrene (3.94 g,

81%) as a yellow powder, mp 189–190 8C (lit.⁶179–

bromide (6.7 mL, 56 mmol) was added, and the reaction

mixture was cooled brieﬂy in ice then stirred at room

temperature for 2 h. The reaction mixture was diluted with

water and extracted with diethyl ether. The organic layer

was washed with water, dried (MgSO₄), and concentrated to

yield 1-benzyl-5,7-dimethoxyindole 3 as dark yellow

crystals (6.51 g, 86%), mp 86.5–87 8C (from petroleum

ether). (Found: C, 76.1; H, 6.7; N, 5.2. C₁₇H₁₇NO₂

requires C, 76.4; H, 6.4; N, 5.2%). l_max: 208 nm (3

46,000 cm^K1M^K1), 261 (9400), 292 (5600), 300 (4900).

n_max: 1583, 1494, 1316, 1267, 1205, 1148, 1051, 825,

726 cm^K1. ¹H NMR spectrum (CDCl₃): d 3.79 and 3.83 (2s,

6H, OMe), 5.56 (s, 2H, CH₂), 6.30 (d, JZ2.2 Hz, 1H, H6),

6.40 (d, JZ3.0 Hz, 1H, H3), 6.66 (d, JZ2.2 Hz, 1H, H4),

6.99 (d, JZ3.0 Hz, 1H, H2), 7.07 (m, 2H, aryl H), 7.25 (m,

3H, aryl H). ¹³C NMR spectrum (CDCl₃): d 52.3 (CH₂),

55.3 and 55.6 (OMe), 93.9, 94.8 and 101.8 (aryl CH), 121.5

(aryl C), 126.6 (2C, aryl CH), 127.0 (aryl CH), 128.4 (2C,

aryl CH), 129.3 (aryl CH), 130.4, 139.7, 147.9 and 154.6

(aryl C). Mass spectrum: m/z 268 (MC1, 18%), 267 (M,

96), 146 (24), 131 (34), 91 (100).

181 8C). n_max: 1595, 1522, 1347, 1214, 1178 cm^{K1 1}H

.

NMR spectrum (CDCl₃): d 3.90 and 3.92 (2s, 6H, OMe),

6.58 (d, JZ2.5 Hz, 1H, aryl H), 6.65 (d, JZ2.5 Hz, 1H, aryl

H), 7.46 (d, JZ14 Hz, 1H, CH), 7.93 (d, JZ14 Hz, 1H,

CHNO₂). Mass spectrum: m/z 255 (MC1, 13%), 254 (M,

100), 208 (72), 141 (91), 136 (74), 120 (75).

Iron powder (32.0 g) was added to a solution of 3,5-

dimethoxy-2-nitro,b-nitrostyrene (4.00 g, 15.7 mmol) in

80% aqueous acetic acid (130 mL). When the initial

exothermic reaction was complete (approximately

30 min), the reaction mixture was heated to 80 8C for

15 min and then stirred at room temperature for 1 h. The

reaction mixture was diluted with water and extracted with

dichloromethane. The organic layer was washed succes-

sively with water and saturated sodium bicarbonate

solution, dried (MgSO₄), and concentrated to yield a black

solid. Flash column chromatography (50:50 dichloro-

methane–petroleum ether) afforded 5,7-dimethoxyindole 1

(1.48 g, 53%) as an off-white crystalline solid, mp 82–83 8C

(lit.⁶81–83 8C). n_max: 3353, 1597, 1311, 1148, 1045, 932,

4.2.4. 1-Acetyl-5,7-dimethoxyindole (4). Dry dimethyl

sulfoxide (20 mL) was added to powdered potassium

hydroxide (0.95 g, 16.9 mmol) and the reaction mixture

was stirred at room temperature for 10 min. 5,7-Dimethoxy-

indole 1 (0.80 g, 4.52 mmol) was added, and the stirring was

continued for 1 h. The solution was decanted from the

excess potassium hydroxide (which was washed with 5 mL

dry dimethyl sulfoxide) and transferred to another reaction

ﬂask containing acetic anhydride (3.95 mL, excess). The

reaction mixture was cooled brieﬂy in ice, then placed under

a nitrogen atmosphere and stirred at room temperature

overnight. The reaction mixture was diluted with water and

extracted with diethyl ether. The organic phase was washed

with water, dried (Na₂SO₄), and concentrated to give a

brown oil (1.25 g). The oil was separated using ﬂash column

chromatography (dichloromethane) followed by preparative

thin layer chromatography (50:50 dichloromethane–

petroleum ether) affording 1-acetyl-5,7-dimethoxyindole 4

(0.75 g, 76%) as a pale tan solid, mp 52–55 8C. (Found: C,

65.9; H, 6.0; N, 6.2. C₁₂H₁₃NO₃requires C, 65.7; H, 6.0; N,

6.4%). l_max: 209 nm (3 23,000 cm^K1M^K1), 244 (17,000),

1

815, 537 cm^K1. H NMR spectrum (CDCl₃): d 3.85 and

3.93 (2s, 6H, OMe), 6.35 (d, JZ2.2 Hz, 1H, H6), 6.45 (t,

JZ2.7 Hz, 1H, H3), 6.69 (d, JZ2.2 Hz, 1H, H4), 7.14 (t,

JZ2.8 Hz, 1H, H2), 8.25 (bs, 1H, NH). Mass spectrum: m/z

178 (MC1, 12%), 177 (M, 100), 162 (58), 34 (42), 119 (26).

4.2.2. 5,7-Dimethoxy-1-methylindole (2). Dimethyl

sulfoxide (50 mL) was added to powdered potassium

hydroxide (2.54 g, 45.2 mmol) and the mixture was stirred

at room temperature for at least 5 min. 5,7-Dimethoxyindole

1 (2.0 g, 11.3 mmol) was then added and the mixture was

stirred at room temperature for 1 h. The reaction mixture

was cooled brieﬂy in ice, iodomethane (1.64 mL,

26.3 mmol) was added, and the reaction mixture stirred at

room temperature for a further 1 h. The reaction mixture

was diluted with water and extracted with diethyl ether. The

organic layer was washed with water, dried (MgSO₄), and

concentrated to yield 5,7-dimethoxy-1-methylindole 2

(2.12 g, 98%) as a white powder, mp 49–52.5 8C. (Found:

C, 69.1; H, 6.9; N, 7.3. C₁₁H₁₃NO₂requires C, 69.3; H, 7.1;

N, 7.1%). l_max: 230 nm (3 32,000 cm^K1M^K1), 262

1

313 (7900). n_max: 1684, 1589, 1271, 1222, 1152 cm^K1. H

NMR spectrum (CDCl₃): d 2.64 (s, 3H, COMe), 3.85 and

3.92 (2s, 6H, OMe), 6.47 (d, JZ2.3 Hz, 1H, H6), 6.50 (d,

JZ3.6 Hz, 1H, H3), 6.64 (d, JZ2.3 Hz, 1H, H4), 7.59 (d,

JZ3.6 Hz, 1H, H2). ¹³C NMR spectrum (CDCl₃): d 25.8

(COMe), 55.7 (2C, OMe), 95.2, 97.2 and 108.0 (aryl CH),

119.5 (aryl C), 128.2 (aryl CH), 134.5, 148.5 and 157.4 (aryl

C), 169.5 (COMe). Mass spectrum: m/z 220 (MC1, 6%),

219 (M, 48), 177 (100), 162 (73), 134 (61), 131 (25), 119

(36), 103 (29).

(14,000), 268 (15,000), 295 (10,000), 301 (9000). n_m₁_ax

:

1593, 1497, 1315, 1217, 1153, 1042, 820, 805 cm^K1. H

NMR spectrum (CDCl₃): d 3.87 and 3.92 (s, 6H, OMe), 4.02

(s, 3H, NMe), 6.35 (d, JZ2.3 Hz, 1H, H6), 6.37 (d, JZ

3.1 Hz, 1H, H3), 6.67 (d, JZ2.0 Hz, 1H, H4), 6.90 (d, JZ

3.1 Hz, 1H, H2). ¹³C NMR spectrum (CDCl₃): d 36.2

(NMe), 55.3 and 55.6 (OMe), 93.8, 94.4 and 100.7 (aryl

CH), 121.9 (aryl C), 129.9 (aryl CH), 130.2, 148.1 and 154.5

(aryl C). Mass spectrum: m/z 192 (MC1, 10%), 191 (M,

100), 176 (83), 148 (46).

4.2.5. 5,7-Dimethoxy-1-phenylsulfonylindole (5). Dry

dimethyl sulfoxide (4 mL) was added to powdered potas-

sium hydroxide (0.23 g, 4.16 mmol) and the reaction

mixture was stirred at room temperature for 10 min. 5,7-

Dimethoxyindole 1 (0.20 g, 1.13 mmol) was added, and the

stirring was continued for 1 h. The solution was decanted

from the excess potassium hydroxide and transferred to

another reaction ﬂask containing freshly distilled phenyl-

sulfonyl chloride (1.44 mL, 11.3 mmol). The reaction

4.2.3. 1-Benzyl-5,7-dimethoxyindole (3). Dimethyl

sulfoxide (60 mL) was added to powdered potassium

hydroxide (6.32 g, 0.113 mol) and the mixture was stirred

at room temperature for at least 5 min. 5,7-Dimethoxyindole

1 (5.00 g, 28.2 mmol) was then added and the mixture

stirred at room temperature for a further 45 min. Benzyl

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G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

mixture was cooled brieﬂy in ice, then placed under a

nitrogen atmosphere and stirred at room temperature for 5 h.

The reaction mixture was then diluted with water and

extracted with diethyl ether. The organic phase was washed

successively with water and saturated sodium hydrogen

carbonate solution, dried (Na₂SO₄), and concentrated to

give a brown oil (0.11 g). Separation using radial chroma-

tography (dichloromethane) afforded the phenylsulfonyl-

indole 5 as a cream solid (74 mg, 21%). The product was too

unstable to be characterised fully. ¹H NMR spectrum

(CDCl₃): d 3.62 and 3.79 (2s, 6H, OMe), 6.31 (d, JZ2.0 Hz,

1H, H6), 6.57 (d, JZ3.6 Hz, 1H, H3), 6.60 (d, JZ2.3 Hz,

1H, H4), 7.50 (m, 3H, ArH), 7.79 (d, JZ3.8 Hz, 1H, H2),

7.83 (m, 2H, ArH). Mass spectrum: m/z 318 (MC1, 3%),

317 (M, 12), 177 (62), 162 (41), 141 (100), 134 (54). HRMS

(ES) Found: MCNa^C, 340.0618. C₁₆H₁₅NO₄S requires

MCNa^C, 340.0614.

(aryl C), 162.10 (CO₂Me). Mass spectrum: m/z 235 (M, 60),

203 (100), 174 (46), 160 (22), 117 (22).

4.2.7. Methyl 5,7-dimethoxy-1-methylindole-2-carboxyl-

ate (7). A solution of methyl 5,7-dimethoxyindole-2-

carboxylate 6 (1.00 g, 4.25 mmol) in dimethyl sulfoxide

(10.0 mL) was stirred with powdered potassium hydroxide

(0.63 g, 11 mmol) for 1 h at room temperature. Methyl

iodide (0.45 mL, 7.2 mmol) was added and stirring

continued for 2.5 h before addition of iced water. The

resulting precipitate was ﬁltered, washed with water, dried,

and puriﬁed via ﬂash column chromatography (dichloro-

methane) to give indole 7 (0.995 g, 94%) as a white solid,

mp 76–79 8C. (Found: C, 62.73; H, 6.14; N, 5.72.

C₁₃H₁₅NO₄requires C, 62.64; H, 6.07; N, 5.62%). l_max

:

242 nm (3 23,900 cm^K1M^K1), 274 (7710, sh), 283 (9290,

sh), 297 (19,100), 334 (4280). n_max: 1711, 1627, 1588, 1531,

1475, 1426, 1393, 1318, 1240, 1204, 1165, 1144, 1086,

1

1047, 815, 800, 732 cm^K1. H NMR spectrum (CDCl₃): d

4.2.6. Methyl 5,7-dimethoxyindole-2-carboxylate (6). A

solution of sodium methoxide was prepared via the

portionwise addition of sodium (1.18 g, 51.3 mmol) to

anhydrous methanol (20 mL), with stirring under a nitrogen

atmosphere. The methoxide solution was cooled in a salt-ice

slurry and stirred during the dropwise addition of a solution

of 3,5-dimethoxybenzaldehyde (1.03 g, 6.2 mmol) and

methyl azidoacetate (7.1 g, 62 mmol) in anhydrous metha-

nol (20 mL), under a nitrogen atmosphere. The resulting

mixture was stirred in ice for a further 3 h with cooling and

then poured onto crushed ice. The resulting precipitate was

ﬁltered, washed with water, and dried to give methyl

2-azido-3-(3,5-dimethoxyphenyl)propenoate (1.42 g, 87%)

as a pale yellow powder, mp 94–97 8C. (Found: C, 55.6; H,

5.4; N, 14.1. C₁₂H₁₃N₃O₄. 0.2 C₁₂H₁₃NO₄requires C, 55.7;

H, 5.1; N, 14.4%). l_max: 239 nm (3 8310 cm^K1M^K1), 311

(19,400); n_max: 2108, 1717, 1698, 1597, 1437, 1384, 1293,

3.82, 3.88 and 3.92 (3s, 9H, OMe), 4.32 (s, 3H, NMe), 6.58

and 6.39 (d, 2H, JZ2.3 Hz, H4 and H6), 7.12 (s, 1H, H3).

¹³C NMR spectrum (CDCl₃): d 34.99 (NMe), 51.82, 55.83,

and 55.92 (OMe), 94.18 (C6), 98.39 (C4), 110.66 (C3),

126.29, 127.87, 128.47, 149.12 and 155.36 (aryl C), 162.83

(CO₂Me). Mass spectrum: m/z 250 (20%), 249 (M, 100),

234 (76), 206 (38), 191 (32), 174 (27), 160 (21), 129 (22).

4.2.8. Dimethyl 1,3-phenylenebis(5,7-dimethoxyindol-1-

ylmethyl-2-carboxylate) (8). A solution of indole 6 (0.25 g,

1.06 mmol) in dimethyl sulfoxide (5.0 mL) was stirred with

powdered potassium hydroxide (74 mg, 1.3 mmol) for

70 min at room temperature. a,a⁰-Dibromo-m-xylene

(0.14 g, 0.53 mmol) was added and stirring continued for

24 h. The solution was then acidiﬁed with dilute hydro-

chloric acid and the resulting precipitate was ﬁltered,

washed with water, and dried. Puriﬁcation via gravity

column chromatography (dichloromethane) gave indole 8

(0.27 g, 89%) as a pale yellow glassy solid, mp 69–73 8C.

(Found: C, 67.1; H, 5.8; N, 5.0. C₃₂H₃₂N₂O₈requires C,

67.1; H, 5.6; N, 4.9%). l_max: 242 nm (3 41,000 cm^K1M^K1),

277 (19,000, sh), 297 (33,000), 335 (8500). n_max: 1717,

1

1245, 1208, 1155, 1089, 1053 cm^K1; H NMR spectrum

(CDCl₃): d 3.81 (s, 6H, OMe), 3.91 (s, 3H, CO₂Me), 6.47 (t,

1H, JZ2.3 Hz, H4⁰), 6.83 (s, 1H, CH]C), 6.98 (d, 2H, JZ

2.3 Hz, H2⁰and H6⁰). ¹³C NMR spectrum (CDCl₃): 52.89

(CO₂Me), 55.35 (OMe), 101.83 (C4⁰), 108.44 (C2⁰and C6⁰),

125.62 and 134.63 (aryl C and CH]C), 160.45 (C3⁰and

C5⁰), 163.88 (CO₂Me). Mass spectrum: m/z 263 (M, 9%),

235 (31), 203 (100), 176 (95), 174 (60), 160 (24), 146 (31),

133 (21), 121 (22), 116 (31); HRMS (ES) Found: M^C,

263.0906. C₁₂H₁₃N₃O₄requires M^C, 263.0906.

1582, 1536, 1478, 1457, 1322, 1239, 1208, 1156, 1093 cm^K1

.

¹H NMR spectrum (CDCl₃): d 3.54, 3.76, and 3.84 (3s, 9H,

OMe), 5.98 (s, 4H, CH₂), 6.28 (d, 2H, JZ2.3 Hz, H4), 6.51

(s, 1H, xylenyl H2), 6.59 (d, 2H, JZ2.3 Hz, H6), 6.81 (dd,

2H, JZ7.9, 7.5 Hz, xylenyl H4 and H6), 7.07 (t, 1H, JZ7.9,

7.5 Hz, xylenyl H5), 7.13 (s, 2H, H3). ¹³C NMR spectrum

(CDCl₃): d 50.14 (CH₂), 51.79, 55.60, and 55.95 (OMe),

94.33 (C4), 98.79 (C6), 111.79 (C3), 124.25, 125.01, and

128.44 (xylenyl CH), 125.90, 128.09, 128.13, 140.73,

148.82 and 155.56 (aryl C), 162.42 (CO₂Me). Mass

spectrum: m/z 573 (MC1, 1%), 440 (100), 426 (71), 371

(23), 332 (34), 321 (21), 266 (24), 252 (44), 228 (43).

A solution of methyl 2-azido-3-(3⁰,5⁰-dimethoxyphenyl)-

propenoate (6.73 g, 25.6 mmol) in 1,2-dichlorobenzene

(100 mL) was added dropwise over a period of 2 h to 1,2-

dichlorobenzene (25 mL), heated at reﬂux. The solvent was

then distilled under reduced pressure, the remaining residue

was boiled in n-hexane, and then ﬁltered hot to give the

indole ester 6 (5.09 g, 85%) as a colourless granular solid,

mp 125–128 8C. (Found: C, 61.3; H, 5.6; N, 6.0. C₁₂H₁₃NO₄

requires C, 61.3; H, 5.6; N, 6.0%). l_max: 240 nm (3

21,200 cm^K1M^K1), 275 (9040, sh), 294 (19,400), 326

(4400). n_max: 3321, 1704, 1591, 1539, 1436, 1310, 1244,

4.2.9. N-Triﬂuoroacetyl-1-(4-bromophenyl)-2-(2,4-

dimethoxyphenylamino)-ethanone (9). A mixture of 2,4-

dimethoxyaniline (5.00 g, 32.6 mmol), 4-bromophenacyl

bromide (10.89 g, 39.2 mmol), sodium hydrogen carbonate

(5.49 g, 65.3 mmol) in absolute ethanol (100 mL) was

reﬂuxed for 4 h. The reaction mixture was allowed to cool to

room temperature and the solvent removed under reduced

pressure. The resulting oil was redissolved in dry acetone

and ﬁltered twice to remove sodium hydrogen carbonate.

1

1206, 1148, 1096 cm^K1. H NMR spectrum (CDCl₃): d

3.83, 3.92, and 3.93 (3s, 9H, OMe), 6.42 (d, 1H, JZ1.9 Hz,

H6), 6.64 (d, 1H, JZ1.9 Hz, H4), 7.10 (d, 1H, JZ2.3 Hz,

H3), 8.95 (bs, 1H, NH). ¹³C NMR spectrum (CDCl₃): d

51.82, 55.40 and 55.60 (OMe), 93.66 (C6), 97.32 (C4),

108.48 (C3), 123.74, 126.77, 127.82, 146.80 and 155.44

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

4995

The solvent was removed under reduced pressure, affording

a red-brown oil. This was redissolved in dry distilled

tetrahydrofuran (130 mL) followed by the addition of

triﬂuoroacetic anhydride (10.1 mL, 71.5 mmol) and

pyridine (5.82 mL, 72.0 mmol). The reaction mixture was

stirred at room temperature for 7 h. The solvent was

removed under reduced pressure, to afford a dark brown

oil, which was chromatographed on silica (70:30 dichloro-

methane–petroleum ether) to yield the amidoketone 9

(6.22 g, 43%) as colourless prisms, mp 141–142 8C (from

ethyl acetate and petroleum ether). (Found: C, 48.6; H, 3.1;

N, 3.0. C₁₈H₁₅BrF₃NO₄requires C, 48.5; H, 3.4; N, 3.1%).

l_max: 206 nm (3 42,000 cm^K1M^K1), 231 (14,000), 257

75 min. Methyl iodide (0.13 mL, 2.1 mmol) was added and

stirring continued for 1 h before the red solution was poured

into water. The resulting precipitate was ﬁltered, washed

with water, and dried to give the title compound (0.48 g,

92%) as an off-white powder, mp 92–94 8C (lit.¹⁷syrup).

l_max: 239 nm (3 14,700 cm^K1M^K1), 304 (20,800). n_max

:

1709, 1483, 1473, 1451, 1241, 1227, 1146, 1113, 1083,

994 cm^K^{1 1}H NMR spectrum (CDCl₃): d 3.88 (s, 6H,

.

OMe), 3.92 and 3.99 (2s, 6H, OMe), 4.29 (s, 3H, NMe), 6.79

(s, 1H, H4), 7.14 (s, 1H, H3). ¹³C NMR spectrum (CDCl₃): d

33.47 (NMe), 51.35, 56.02, 61.20 and 61.67 (OMe), 98.01

(C4), 110.45 (C3), 122.54, 127.98, 128.17, 140.72, 141.80

and 149.52 (aryl C), 162.21 (CO₂Me). Mass spectrum: m/z

279 (M, 100), 264 (89), 221 (31), 206 (22).

1

(21,000). n_max: 1704, 1687, 1588, 1213, 1195 cm^K1. H

NMR spectrum (CDCl₃): d 3.81 and 3.84 (2s, 6H, OMe),

4.31 and 5.65 (d, JZ17.4 Hz, 2H, CH₂); 6.44 (dd, JZ2.6,

8.7 Hz, 1H, H5), 6.48 (d, JZ2.6 Hz, 1H, H3); 7.46 (bd, JZ

8.7 Hz, 1H, H6), 7.61 and 7.79 (m, 4H, aryl H). ¹³C NMR

spectrum (CDCl₃): d 55.5 and 55.7 (OMe), 56.5 (CH₂), 99.1

and 103.8 (aryl CH), 116.2 (q, JZ288 Hz, CF₃); 120.8 and

129.0 (aryl C), 129.4 (2C, aryl CH), 131.5 (aryl CH), 132.1

(2C, aryl CH), 133.6 and 156.0 (aryl C), 158.0 (q, JZ36 Hz,

COCF₃), 161.5 (ArC), 191.1 (CO). Mass spectrum: m/z 447

(M, ⁸¹Br, 27%), 445 (M, ⁷⁹Br, 28), 262 (56), 183 (40), 165

(100), 150 (34).

4.2.13. Methyl 1-(tert-butyloxycarbonyl)-5,6,7-tri-

methoxyindole-2-carboxylate (30). A mixture of methyl

5,6,7-trimethoxyindole-2-carboxylate

24

(1.00 g,

3.77 mmol), di-tert-butyl dicarbonate (1.65 g, 7.56 mmol),

and 4-dimethylaminopyridine (91 mg, 0.76 mmol) in aceto-

nitrile (20.0 mL) was stirred at 40 8C for 1.5 h under a

nitrogen atmosphere. The solvent was removed and the

residue puriﬁed via ﬂash column chromatography (20%

light petroleum/dichloromethane) to give indole 30 (1.31 g,

95%) as a white powder, mp 109–112 8C. (Found: C, 59.5;

H, 6.2; N, 4.1. C₁₈H₂₃NO₇requires C, 59.2; H, 6.3; N,

3.8%). l_max: 239 nm (3 12,000 cm^K1M^K1), 276 (8860, sh),

299 (19,900). n_max: 1760, 1715, 1489, 1431, 1371, 1256,

1234, 1157, 1124, 1060 cm^K1. ¹H NMR spectrum (CDCl₃):

d 1.66 (s, 9H, cme₃), 3.88, 3.89, 3.92 and 3.96 (4s, 12H,

OMe), 6.79 and 7.09 (s, 2H, H3 and H4). ¹³C NMR

spectrum (CDCl₃): d 27.79 (CMe₃), 52.39, 56.61, 61.66 and

61.72 (OMe), 85.45 (CMe₃), 98.44 (C4), 111.62 (C3),

122.82, 126.96, 127.69, 140.27, 142.39, 151.00 and 151.27

(CO and aryl C), 161.47 (CO₂Me). Mass spectrum: m/z 365

(M, 5%), 265 (47), 250 (31), 233 (36), 218 (25), 57 (100).

4.2.10. Methyl 2-azido-3-(3⁰,4⁰,5⁰-trimethoxyphenyl)pro-

penoate.¹⁶A solution of sodium methoxide was prepared

via the portionwise addition of sodium (10.3 g, 0.448 mmol)

to anhydrous methanol (160 mL) with stirring under a

nitrogen atmosphere. The methoxide solution was cooled in

a salt-ice slurry and stirred during the dropwise addition of a

solution of 3,4,5-trimethoxybenzaldehyde (14.50 g,

73.9 mmol) and ethyl azidoacetate (63.6 g, 493 mmol) in

anhydrous methanol (175 mL) over 2 h. The resulting

mixture was further stirred for 6.5 h with cooling and then

poured onto crushed ice. The resulting precipitate was

ﬁltered, washed with water, and dried to give the title

compound (18.11 g, 84%) as a pale yellow powder, mp

86–89 8C. ¹H NMR spectrum (CDCl₃): d 3.89 (3s, 9H,

OMe), 3.91 (s, 3H, OMe), 6.84 (s, 1H, CH), 7.09 (s, 2H, H2⁰

and H6⁰).

4.3. Formylation of indoles

4.3.1. Formylation of 5,7-dimethoxyindole (1). An ice-

cold solution of phosphoryl chloride (0.32 mL, 4.05 mmol)

in dimethylformamide (1 mL) was added dropwise to a

stirred ice-cooled solution of indole 1 (1.32 g, 4.00 mmol)

in dimethylformamide (1 mL). The reaction mixture was

allowed to come to room temperature and then made

strongly basic with sodium hydroxide solution (20%). The

resulting yellow precipitate was ﬁltered, washed with water,

dried and puriﬁed by column chromatography (dichloro-

methane) to give two products.

4.2.11. Methyl 5,6,7-trimethoxyindole-2-carboxylate

(24).¹⁶A solution of methyl 2-azido-3-(3⁰,4⁰,5⁰-trimethoxy-

phenyl)-propenoate (17.84 g, 60.8 mmol) in 1,2-dichloro-

benzene (250 mL) was added dropwise over 3 h to stirred

1,2-dichlorobenzene (25 mL) held at reﬂux. The resulting

solution was heated at reﬂux for a further 40 min and then

distilled under reduced pressure. The residue was triturated

with light petroleum and the resulting precipitate was

ﬁltered, washed with light petroleum, and dried to give the

title compound (14.73 g, 91%) as a pale yellow powder, mp

106–110 8C (lit.¹⁶101–103 8C). ¹H NMR spectrum

(CDCl₃): d 3.89 (s, 3H, OMe), 3.92 (s, 6H, OMe), 4.06 (s,

3H, OMe), 6.81 (s, 1H, H4), 7.10 (d, 1H, JZ2.3 Hz, H3),

8.98 (bs, 1H, NH).

(i) 5,7-Dimethoxyindole-3-carbaldehyde 10 (0.55 g, 66%),

mp 130 8C. (Found: C, 64.3; H, 5.7; N, 6.6. C₁₁H₁₁NO₃

requires C, 64.4, H, 5.4; N, 6.8%). l_max: 242 nm (3

8300 cm^K1M^K1), 247 (18,000), 264 (12,000), 308

(7100). n_max: 1623, 1283, 1234, 1157, 785 cm^{K1 1}H

.

NMR spectrum (CDCl₃): d 3.85 and 3.88 (2s, 6H, OMe),

6.41 (d, JZ2.1 Hz, 1H, H6), 7.34 (d, JZ2.1 Hz, 1H, H4),

7.73 (d, JZ3.2 Hz, 1H, H2), 9.55 (bs, 1H, NH), 9.98 (s, 1H,

CHO). ¹³C NMR spectrum (CDCl₃): d 55.49 and 55.85

(OMe), 94.68, 96.39 and 135.01 (C4, C6 and C2), 119.82,

122.41 and 125.64 (C3, C3a and C7a), 146.45 and 157.63

(COMe), 185.54 (CHO). Mass spectrum: m/z 206 (MC1,

13%), 205 (M, 100), 190 (37), 162 (34).

4.2.12. Methyl 5,6,7-trimethoxy-N-methylindole-2-car-

boxylate (27).¹⁷A solution of methyl 5,6,7-trimethoxy-

indole-2-carboxylate 24 (0.50 g, 1.88 mmol) in dimethyl

sulfoxide (15.0 mL) was stirred with powdered potassium

hydroxide (0.224 g, 4.0 mmol) at room temperature for

4996

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

(ii) 5,7-Dimethoxyindole-4-carbaldehyde 11 (0.27 g, 33%),

mp 176–177 8C. (Found: C, 64.3; H, 5.7; N, 6.6. C₁₁H₁₁NO₃

requires C, 64.4; H, 5.4; N, 6.8%). l_max: 222 nm (3

8300 cm^K1M^K1), 238 (7700), 254 (8900), 247 (14,000).

diluted with water. The product was extracted with

dichloromethane, dried (Na₂SO₄), and concentrated to

give a non-homogeneous yellow-black solid. Preparative

thin layer chromatography (95:5 chloroform–methanol)

afforded compound 14 (0.35 g, 63%) as a bright yellow

powder, mp 188.5–190.5 8C. (Found: C, 60.7; H, 3.7; N,

1

n_max: 1632, 1575, 1324, 1171 cm^K1. H NMR spectrum

(CDCl₃): d 3.83 and 3.92 (2s, 6H, OMe), 6.20 (s, 1H, H6),

7.11 (t, JZ2.6 Hz, 1H, H3), 7.16 (t, JZ2.8 Hz, 1H, H2);

9.79 (bs, 1H, NH), 10.40 (s, 1H, CHO). ¹³C NMR spectrum

(DMSO-d₆): d 56.2 and 57.3 (OMe), 89.8, 103.0 and 152.7

(C6, C2 and C3), 109.7, 121.4 and 126.9 (C3a, C4 and C7a),

152.7 and 161.9 (COMe), 187.5 (CHO). Mass spectrum: m/z

206 (MC1, 15%), 205 (M, 100), 204 (37), 189 (24), 188 (24).

10.7. C₁₃H₁₀N₂O₄requires C, 60.5; H, 3.9; N, 10.8%). l_max

:

206 nm (3 13,000 cm^K1M^K1), 245 (16,000), 281 (16,000),

341 (5200), 364 (5100), 390 (4200). n_max: 2948, 1639, 1497,

1344, 1291, 1225, 1178, 749 cm^K^{1 1}H NMR spectrum

.

(CDCl₃): d 4.06 and 4.62 (2s, 6H, OMe), 6.42 (s, 1H, H7),

8.59 (s, 1H, H2), 8.84 (d, JZ1.6 Hz, 1H, H5), 9.09 (d, JZ

1.6 Hz, 1H, H3). ¹³C NMR spectrum (CDCl₃): d 56.6 and

61.5 (OMe), 101.5 (aryl CH), 117.4 (aryl C), 120.5 and

120.7 (aryl CH), 127.6, 132.9, 133.2 and 145.8 (aryl C),

152.1 (aryl CH), 159.8 and 161.3 (aryl C). Mass spectrum:

m/z 259 (MC1, 30%), 258 (M, 100), 257 (MK1, 65), 229

(88), 228 (43), 183 (55), 182 (48), 139 (31).

4.3.2. Formylation of 5,7-dimethoxyindole (1) with

excess reagent: 5,7-dimethoxyindole-3,4-dicarbaldehyde

(12). An ice-cold solution of phosphoryl chloride (0.64 mL,

8.1 mmol) in dimethylformamide (1 mL) was added drop-

wise to a stirred ice-cooled solution of indole 1 (1.32 g,

4.00 mmol) in dimethylformamide (1 mL). The reaction

mixture was allowed to come to room temperature and then

warmed to 40 8C for 30 min. On cooling it was made

strongly basic with sodium hydroxide solution (20%). The

resulting yellow precipitate was ﬁltered off, washed with

water, and dried to give dialdehyde 12 (0.88 g, 94%), mp

249.5–251.5 8C (from methanol). (Found: C, 61.8; H, 4.8;

4.3.5. Formylation of 5,7-dimethoxy-1-methylindole (2).

To a stirred solution of 5,7-dimethoxy-1-methylindole 2

(0.40 g, 2.10 mmol) in dry dimethylformamide (5.0 mL) at

0 8C was added dropwise an ice-cold solution of phosphoryl

chloride (0.29 mL, 3.11 mmol) in dry dimethylformamide

(2.0 mL). The reaction mixture was stirred in ice for 10 min,

then poured over ice and basiﬁed with 10% aqueous sodium

hydroxide solution. After standing overnight at room

temperature the solid was ﬁltered, washed with water and

dried. Preparative thin layer chromatography (dichloro-

methane) afforded two products.

N, 5.9. C₁₂H₁₁NO₄requires C, 61.8; H, 4.8; N, 6.0%). l_max

:

212 nm (3 4900 cm^K1M^K1), 245 (7500), 290 (8300), 330

(8600). n_max: 1647, 1625, 1573, 1221, 1149 cm^K1. ¹H NMR

spectrum (DMSO-d₆): d 3.98 and 4.09 (s, 6H, OMe), 6.73 (s,

1H, H6), 8.03 (d, JZ3.4 Hz, 1H, H2), 10.52 and 10.66 (2s,

2H, CHO), 12.66 (br s, 1H, NH). ¹³C NMR spectrum

(DMSO-d₆): d 56.3 and 57.2 (OMe), 91.1 (aryl CH), 111.0,

120.1, 122.4 and 123.2 (aryl C), 133.9 (aryl CH), 152.9 and

163.3 (aryl C), 188.3 and 189.4 (CHO). Mass spectrum: m/z

233 (M, 100%), 232 (MK1, 31), 218 (22), 205 (73), 190

(46), 174 (27), 162 (43), 148 (34), 134 (22), 119 (23).

(i) 5,7-Dimethoxy-1-methylindole-4-carbaldehyde 16

(34 mg, 7%) as a white powder, mp 140.5–142 8C.

(Found: C, 66.0; H, 6.1; N, 6.3. C₁₂H₁₃NO₃requires C,

65.7; H, 6.0; N, 6.4%). l_max: 213 nm (3 34,000 cm^K1M^K1),

228 (27,000), 252 (24,000), 258 (25,000), 356 (27,000).

1

n_max: 1630, 1577, 1337, 1256, 1213, 786 cm^K1. H NMR

spectrum (CDCl₃): d 3.95, 3.98 and 4.00 (3s, 9H, OMe and

NMe), 6.26 (s, 1H, H6), 7.03 (d, JZ3.1 Hz, 1H, H3), 7.24

(d, JZ3.1 Hz, 1H, H2), 10.52 (s, 1H, CHO). ¹³C NMR

spectrum (CDCl₃): d 36.5 (NMe), 55.6 and 57.1 (OMe),

89.1 and 102.5 (aryl CH), 110.4, 121.6 and 128.8 (aryl C),

133.4 (aryl CH), 153.6 and 161.7 (aryl C), 188.7 (CHO).

Mass spectrum: m/z 220 (MC1, 23%), 219 (M, 100), 218

(MK1, 47), 202 (29), 176 (32), 173 (29), 162 (39).

4.3.3. 6,8-Dimethoxypyrrolo[4,3,2-de]isoquinoline (13).

A mixture of 5,7-dimethoxyindole-3,4-dicarbaldehyde 12

(3.00 g, 12.9 mmol), concentrated aqueous ammonia

solution (3.0 mL, excess) and 95% methanol (360 mL)

was heated under reﬂux for 3 h. After cooling to room

temperature, the solvent was removed under reduced

pressure and the product dried under vacuum to yield

compound 13 (2.74 g, 99%) as a bright yellow powder, mp

175–177 8C. (Found: C, 67.4; H, 4.9; N, 12.9. C₁₂H₁₀N₂O₂

requires C, 67.3; H, 4.7; N, 13.1%). l_max: 211 nm (3

17,000 cm^K1M^K1), 223 (21,000), 268 (14,000), 302

(4400), 332 (4300), 344 (5500), 393 (4400). n_max: 1646,

1615, 1581, 1225, 1186, 938, 836 cm^K1. ¹H NMR spectrum

(CDCl₃): d 4.04 and 4.62 (2s, 6H, OMe), 6.37 (s, 1H, H7),

8.59 (s, 1H, H2), 9.14 and 9.33 (2s, 2H, H3 and H5). ¹³C

NMR spectrum (CDCl₃): d 56.3 and 61.2 (OMe), 101.0 (aryl

CH), 115.1, 127.2, 128.5 and 134.9 (aryl C), 143.4, 144.7

and 151.5 (aryl CH), 159.1 and 160.8 (aryl C). Mass

spectrum: m/z 214 (M, 100%), 213 (65), 169 (49), 141 (42).

(ii) 5,7-Dimethoxy-1-methylindole-3-carbaldehyde 15

(0.29 g, 63%) as off-white needles, mp 127–128 8C (from

ethyl acetate and petroleum ether). (Found: C, 65.5; H, 6.3;

N, 6.1. C₁₂H₁₃NO₃requires C, 65.7; H, 6.0; N, 6.4%). l_max

:

219 nm (3 52,000), 246 (34,000), 251 (41,000), 265

(26,000), 315 (18,000). n_max: 1650, 1275, 1202, 1150,

1

1117 cm^K1. H NMR (CDCl₃): d 3.88 and 3.89 (2s, 6H,

OMe), 4.04 (s, 3H, NMe), 6.39 (d, JZ2.1 Hz, 1H, H6), 7.35

(d, JZ2.5 Hz, 1H, H4), 7.45 (s, 1H, H2), 9.90 (s, 1H, CHO).

¹³C NMR (DMSO-d₆): d 37.1 (NMe), 55.3 and 55.8 (OMe,

94.3and 96.2(aryl CH), 116.9, 122.0 and 127.0 (aryl C), 141.5

(aryl CH), 147.9 and 156.9 (aryl C), 184.2 (CHO). Mass

spectrum: m/z 219 (M, 100%), 204 (53), 176 (34), 161 (25).

4.3.4. 6,8-Dimethoxy-4-nitrobenz[cd]indole (14). A

mixture of 5,7-dimethoxyindole-3,4-dicarbaldehyde 12

(0.50 g, 2.14 mmol), nitromethane (0.12 mL, 2.22 mmol),

potassium hydroxide (0.13 g, 2.23 mmol) in 95% methanol

(75 mL) was heated under reﬂux for 3 h. The reaction

mixture was allowed to cool to room temperature, and

4.3.6. Formylation of 5,7-dimethoxy-1-methylindole (2)

with excess reagent: 5,7-dimethoxy-1-methylindole-3,4-

dicarbaldehyde (17). Phosphoryl chloride (3.65 mL,

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

4997

39.2 mmol) was added to an ice-cold solution of 5,7-

dimethoxy-1-methylindole 2 (1.50 g, 7.8 mmol) in dry

dimethylformamide (15 mL) with stirring and cooling in

ice, and the reaction mixture was heated with stirring at

70 8C for 10 min. After cooling to room temperature, the

reaction mixture was poured over ice and basiﬁed using

10% aqueous sodium hydroxide. After standing overnight,

the precipitate was ﬁltered, washed with water and dried to

give dicarbaldehyde 17 (1.85 g, 95%) as yellow crystals, mp

218–219 8C (from methanol). (Found: C, 63.0; H, 5.5; N,

84.2 mmol) was added to an ice-cold solution of 1-benzyl-

5,7-dimethoxyindole 3 (4.50 g, 16.8 mmol) in dry dimethyl-

formamide (15 mL) with stirring and cooling in ice, and the

reaction mixture was heated with stirring at 70 8C for

15 min. After cooling to room temperature, the reaction

mixture was poured over ice and basiﬁed using concentrated

aqueous sodium hydroxide solution. After standing over-

night, the precipitate was ﬁltered, washed with water and

dried to give dicarbaldehyde 20 (5.40 g, 99%) as a white

powder, mp 260.5–261 8C (from dichloromethane). (Found:

C, 70.7; H, 5.5; N, 4.2. C₁₉H₁₇NO₄requires C, 70.6; H, 5.3;

N, 4.3%). l_max: 295 nm (3 10,000 cm^K1M^K1), 337

(12,000). n_max: 1663, 1640, 1596, 1570, 1248, 1208, 1058,

857 cm^K1. ¹H NMR spectrum (DMSO-d₆): d 3.96 and 3.97

(2s, 6H, OMe), 5.64 (s, 2H, CH₂), 6.67 (s, 1H, H6), 7.13 (m,

2H, aryl H), 7.29 (m, 3H, aryl H), 8.35 (s, 1H, H2), 10.48

and 10.62 (2s, 2H, CHO). ¹³C NMR spectrum (CDCl₃): d

54.0 (CH₂), 55.7 and 57.1 (OMe), 90.8 (aryl CH), 112.2,

120.1, 122.3 and 125.8 (aryl C), 126.7, 2C (aryl CH), 127.9

(aryl CH), 128.8, 2C (aryl CH), 137.1 (aryl C), 137.8 (aryl

CH), 153.8 and 163.6 (aryl C), 188.9 and 191.2 (CHO).

Mass spectrum: m/z 323 (M, 23%), 91 (100).

5.6. C₁₃H₁₃NO₄requires C, 63.2; H, 5.3; N, 5.7%). l_max

295 nm (3 14,000 cm^K1M^K1), 336 (14,000). n_max: 1650,

1569, 1253, 1217, 1120, 1055, 857 cm^K^{1 1}H NMR

:

.

spectrum (CDCl₃): d 3.96, 3.99 and 4.02 (3s, 9H, OMe

and NMe), 6.31 (s, 1H, H6), 7.76 (s, 1H, H2), 10.54 and

10.81 (2s, 2H, CHO). ¹³C NMR (DMSO-d₆: d 37.7 (NMe),

56.6 and 57.2 (OMe), 91.6 (aryl CH), 110.8, 118.3, 122.2

and 124.7 (aryl C), 139.2 (aryl CH), 154.5 and 163.4 (aryl

C), 188.1 and 189.0 (CHO). Mass spectrum: m/z 248 (MC1,

28%), 247 (M, 100), 219 (74), 204 (61), 176 (51), 162 (39).

4.3.7. Formylation of 1-benzyl-5,7-dimethoxyindole (3).

Formylation of the benzylindole was carried out by the

Vilsmeier–Haack method used for 5,7-dimethoxy-1-

methylindole 2 starting from 1-benzyl-5,7-dimethoxyindole

3 (0.20 g, 0.75 mmol) in dry dimethylformamide (3.0 mL)

and phosphoryl chloride (0.10 mL, 1.07 mmol) in dry

dimethylformamide (1.5 mL). Preparative thin layer

chromatography (dichloromethane) afforded 1-benzyl-5,7-

dimethoxyindole-4-carbaldehyde 19 (77 mg, 34%) as a

cream powder, mp 136.5–140 8C. (Found: C, 73.0; H, 6.0;

4.3.9. Formylation of 1-acetyl-5,7-dimethoxyindole (4).

Phosphoryl chloride (0.41 mL, 4.45 mmol) was added to a

frozen solution of 1-acetyl-5,7-dimethoxyindole 4 (0.65 g,

2.97 mmol) in dry dimethylformamide (13 mL) under a dry

nitrogen atmosphere at K94 8C. The reaction mixture was

allowed to come to room temperature gradually over 2 h

then stirred at room temperature for a further 3 h. The

reaction mixture was poured over ice and basiﬁed with 10%

aqueous sodium hydroxide solution. After standing over-

night the solid was ﬁltered, washed with water and dried,

affording 4-carbaldehyde 11 (0.53 g, 87%) as a white

powder. Conﬁrmation of this product was obtained by

comparison with an authentic sample using ¹H NMR

spectroscopy and thin layer chromatography.

N, 4.5. C₁₈H₁₇NO₃requires C, 73.2; H, 5.8; N, 4.7%). l_max

:

209 nm (3 24,000 cm^K1M^K1), 251 (12,000), 352 (11,000).

1

n_max: 1640, 1572, 1329, 1247, 1213, 1163 cm^K1. H NMR

spectrum (DMSO-d₆): d 3.93 and 3.95 (2s, 6H, OMe), 5.54

(s, 2H, CH₂), 6.52 (s, 1H, H6), 7.08 (m, 3H, aryl H and H3),

7.25 (m, 3H, aryl H), 7.55 (d, JZ2.6 Hz, 1H, H2), 10.39 (s,

1H, CHO). ¹³C NMR spectrum (CDCl₃): d 52.6 (CH₂), 55.5

and 57.0 (OMe), 89.6 and 103.4 (aryl CH), 110.5 and 121.2

(aryl C), 126.3, 2C (aryl CH), 127.2 (aryl CH), 128.5, 2C

(aryl CH), 129.2 (aryl C), 133.1 (aryl CH), 139.1, 153.3 and

161.7 (aryl C), 188.8 (CHO). Mass spectrum: m/z 295 (M,

73%), 91 (100).

4.3.10. Formylation of 5,7-dimethylindole. Combination

of ice-cold solutions of phosphoryl chloride (0.19 mL,

2.07 mmol) in dimethylformamide (1 mL) and 5,7-

dimethylindole^14,15(0.20 g, 1.38 mmol) in dimethylforma-

mide (1 mL), followed by stirring at 0 8C for 15 min and

treatment with sodium hydroxide solution (20%) gave 5,7-

dimethylindole-3-carbaldehyde (0.22 g, 92%) as a pale

yellow powder, mp 139 8C (lit.¹⁵121–122 8C).

1-Benzyl-5,7-dimethoxyindole-3-carbaldehyde 18 (0.14 g,

61%) was obtained as a cream powder, mp 144–145.5 8C.

(Found: C, 73.1; H, 6.0; N, 4.6. C₁₈H₁₇NO₃requires C, 73.2;

H, 5.8; N, 4.7%). l_max: 217 nm (3 29,000 cm^K1M^K1), 245

4.3.11. Formylation of methyl 5,7-dimethoxyindole-2-

carboxylate (6). Dimethylformamide (5.0 mL) was cooled

in an iced water bath, treated with phosphoryl chloride

(3.0 mL, 32 mmol), and stirred for 20 min. This solution

was then added dropwise, over 8 min, to a similarly cooled

solution of methyl 5,7-dimethoxyindole-2-carboxylate 6

(3.00 g, 12.8 mmol) in dimethylformamide (15.0 mL) with

stirring. The resulting solution was stirred further with

cooling for 2 h before a small amount of chilled water was

added and the mixture basiﬁed to high pH with 5 M sodium

hydroxide. The mixture was then stirred at ambient

temperature for 30 min before the resulting precipitate

was ﬁltered, washed with water, and dried to give the

4-formylindole ester 22 (3.34 g, 100%) as a cream coloured

powder, mp 270–276 8C. (Found: C, 59.2; H, 5.0; N, 5.3.

C₁₃H₁₃NO₅requires C, 59.3; H, 5.0; N, 5.3%). l_max: 243 nm

(16,000), 251 (19,000), 265 (13,000), 313 (8100). n_max

:

1650, 1277, 1193, 1170, 1143 cm^K1. H NMR spectrum

(DMSO-d₆): d 3.77 and 3.79 (2s, 6H, OMe), 5.60 (s, 2H,

CH₂), 6.45 (d, JZ2.1 Hz, 1H, H6), 7.26 (m, 6H, aryl H and

H4), 8.28 (s, 1H, H2), 10.39 (s, 1H, CHO). ¹³C NMR

spectrum (CDCl₃): d 53.4 (CH₂), 55.4 and 55.8 (OMe), 94.8

and 97.1 (aryl CH), 118.5 and 122.2 (aryl C), 127.0, 2C (aryl

CH), 127.7 (aryl C), 127.8 (aryl CH), 128.8, 2C (aryl CH),

137.4 (aryl C), 139.0 (aryl CH), 147.8 and 157.5 (aryl C),

184.6 (CHO). Mass spectrum: m/z 296 (MC1, 43%), 295 (M,

96), 204 (22), 190 (25), 174 (39), 159 (43), 131 (34), 91 (100).

1

4.3.8. Formylation of 1-benzyl-5,7-dimethoxyindole (3)

with excess reagent: 1-benzyl-5,7-dimethoxyindole-3,4-

dicarbaldehyde (20). Phosphoryl chloride (7.85 mL,

4998

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

(3 24,200 cm^K1M^K1), 325 (20,400), 354 (13,100), 370

(8850, sh). n_max: 3431, 3127, 1721, 1624, 1573, 1527, 1473,

1378, 1345, 1260, 1222 cm^K1. ¹H NMR spectrum (CDCl₃):

d 3.94, 3.99, 4.07 (3s, 9H, OMe), 6.44 (s, 1H, H6), 7.95 (d,

JZ2.3 Hz, 1H, H3), 9.10 (bs, 1H, NH), 10.53 (s, 1H, CHO).

¹³C NMR spectrum (DMSO-d₆): d 57.51, 56.64, and 52.21

(OMe), 93.02 (C6), 109.02 (C3), 109.70, 123.89, 125.41,

130.34, 153.84, 161.52 (aryl C), 162.82 (CO₂Me), 187.48

(CHO). Mass spectrum: m/z 263 (M, 100%), 231 (68), 230

(64), 202 (100), 174 (42), 160 (41).

spectrum: m/z 293 (M, 32%), 279 (100), 264 (85), 246 (27),

221 (35), 206 (31), 204 (29), 149 (21).

(ii) Methyl 4-formyl-5,6,7-trimethoxyindole-2-carboxylate

26 (0.169 g, 25%) was obtained as a pale yellow powder,

mp 140–143 8C. (Found: C, 57.5; H, 5.1; N, 4.7. C₁₄H₁₅NO₆

requires C, 57.3; H, 5.2; N, 4.8%). l_max: 232 nm (3

14,000 cm^K1M^K1), 258 (16,000), 277 (5100, sh), 344

(18,000). n_max: 3337, 3227, 1716, 1697, 1649, 1568, 1281,

1

1261, 1215, 1201, 1138, 1100, 1038, 924, 766 cm^K1. H

NMR spectrum (CDCl₃): d 3.93 (s, 6H, OMe), 4.02 and 4.20

(2s, 6H, OMe), 7.91 (d, JZ2.3 Hz, 1H, H3), 9.25 (bs, 1H,

NH), 10.47 (s, 1H, CHO). ¹³C NMR spectrum (CDCl₃): d

52.07, 61.00, 61.60 and 63.33 (OMe), 109.96 (C3), 117.20,

120.98, 127.52, 129.35, 141.38, 144.97 and 157.37 (aryl C),

162.00 (CO₂Me), 189.31 (CHO). Mass spectrum: m/z 293

(M, 100%), 278 (41), 261 (25), 260 (22), 246 (68), 232 (29),

218 (23), 190 (21), 188 (32), 174 (29), 160 (45), 144 (27),

132 (21), 117 (20), 104 (25).

4.3.12. 4-Formyl-5,7-dimethoxyindole-2-carboxylic acid

(23). Methyl 4-formyl-5,7-dimethoxyindole-2-carboxylate

22 (1.00 g, 3.80 mmol) was reﬂuxed in aqueous/ethanolic

(1:1) potassium hydroxide (0.5 M, 40 mL) for 35 min. After

cooling, the yellow solution was acidiﬁed with 5 M

hydrochloric acid and the resulting precipitate ﬁltered

through a frit. The precipitate was washed with water and

dried to give the title compound (0.90 g, 95%) as a pale

yellow powder, mp O275 8C (decomp.). (Found: C, 55.2;

H, 4.9; N, 5.4. C₁₂H₁₁NO₅. 0.66 H₂O requires C, 55.2; H,

4.8; N, 5.4%). l_max: 242 nm (3 21,000 cm^K1M^K1), 262

(9000, sh), 324 (17,000), 352 (13,000, sh), 369 (8200, sh).

4.3.14. Formylation of methyl 5,6,7-trimethoxy-1-

methylindole-2-carboxylate.

Dimethylformamide

(1.0 mL) was cooled in a salt-ice slurry and treated with

phosphoryl chloride (0.2 mL, 2 mmol) and stirred for

15 min. The resulting solution was then added dropwise,

over 3 min, to a similarly cooled and stirred solution of

methyl 5,6,7-trimethoxy-N-methylindole-2-carboxylate 27

(0.250 g, 0.895 mmol) in dimethylformamide (3.0 mL). The

resulting solution was stirred at ambient temperature for 6 h

and then heated for 30 min in an oil bath at 75 8C. After re-

cooling in a salt-ice slurry, the mixture was treated with

chilled water, basiﬁed to high pH with 5 M sodium

hydroxide, and then extracted with ethyl acetate. The

aqueous layer was kept aside (see below), while the organic

extract was washed with brine, dried (MgSO₄), and

concentrated to give methyl 3-formyl-5,6,7-trimethoxy-N-

methylindole-2-carboxylate 28 (42 mg, 15%) as an off-

white powder. ¹H NMR spectrum (CDCl₃): d 3.92 and 3.94

(2s, 6H, OMe), 4.01 (s, 6H, OMe), 4.28 (s, 3H, NMe), 7.75

(s, 1H, H4), 10.48 (s, 1H, CHO). ¹³C NMR spectrum

(CDCl₃): d 34.46 (NMe), 52.37, 56.10, 61.17 and 61.79

(OMe), 98.94 (C4), 119.48, 121.48, 126.37, 133.52, 140.67,

142.21 and 152.29 (aryl C), 161.13 (CO₂Me), 188.21

(CHO).

n_max: 3597, 3458, 1690, 1639, 1573, 1264, 1229, 1215 cm^K1

.

¹H NMR spectrum (DMSO-d₆): d 3.96 and 4.04 (2s, 6H,

OMe), 6.68 (s, 1H, H6), 7.60 (d, JZ1.9 Hz, 1H, H3), 10.37

(s, 1H, CHO), 11.97 (bs, 1H, NH). ¹³C NMR spectrum

(DMSO-d₆) 56.57 and 57.52 (OMe), 92.74 (C6), 108.75

(C3), 109.87, 123.69, 125.64, 131.87, 153.75, 162.60,

162.69 (CO₂H and aryl C), 187.49 (CHO). Mass spectrum:

m/z 249 (M, 100%), 231 (36), 230 (45), 202 (45), 188 (20),

160 (28).

4.3.13. Formylation of methyl 5,6,7-trimethoxyindole-2-

carboxylate (24). Dimethylformamide (2.0 mL) was cooled

in a salt-ice slurry and treated with phosphoryl chloride

(0.3 mL, 3.2 mmol) and stirred for 15 min. The resulting

solution was then added dropwise, over 5 min, to a similarly

cooled and stirred solution of methyl 5,6,7-trimethoxy-

indole-2-carboxylate 24 (0.600 g, 2.26 mmol) in dimethyl-

formamide (5.0 mL). The resulting solution was stirred at

ambient temperature for 22 h and then heated for 2 h in an

oil bath at 75 8C. After cooling, the mixture was poured onto

crushed ice and basiﬁed to high pH with 5 M sodium

hydroxide and then extracted with ethyl acetate. The organic

extract was washed twice with brine, dried (MgSO₄), and

concentrated to give a pale yellow powder. Puriﬁcation via

ﬂash column chromatography (2% methanol/dichloro-

methane) gave two isomers.

4.3.15. 3-Formyl-5,6,7-trimethoxy-N-methylindole-2-

carboxylic acid (29). The basiﬁed aqueous layer from the

above reaction was acidiﬁed to low pH with 5 M

hydrochloric acid and extracted with ethyl acetate. The

organic extract was washed with brine, dried (MgSO₄), and

concentrated to give the title compound (0.190 g, 69%) as a

yellow powder, mp O173 8C (dec.). (Found: C, 57.3; H,

5.2; N, 4.6. C₁₄H₁₅NO₆requires C, 57.3; H, 5.2; N, 4.8%).

(i) Methyl 3-formyl-5,6,7-trimethoxyindole-2-carboxylate

25 (0.392 g, 59%) was obtained as a white powder, mp

184–188 8C. (Found: C, 57.2; H, 5.0; N, 4.9. C₁₄H₁₅NO₆

requires C, 57.3; H, 5.2; N, 4.8%). l_max: 233 nm (3

16,000 cm^K1M^K1), 251 (20,000), 277 (7700, sh), 335

(13,000). n_max: 3132, 3112, 1721, 1649, 1463, 1450, 1271,

l_max: 256 nm (3 18,000 cm^K1M^K1), 333 (13,000). n_max

:

1698, 1591, 1513, 1470, 1413, 1372, 1245, 1115, 1041,

1

1020 cm^K1. H NMR spectrum (CDCl₃): d 3.94, 3.97 and

1

1247, 1216, 1118 cm^K1. H NMR spectrum (CDCl₃): d

4.04 (s, 9H, OMe), 4.52 (s, 3H, NMe), 7.21 (s, 1H, H4),

10.14 (s, 1H, CHO). ¹³C NMR spectrum (CDCl₃): d 56.17,

61.27 and 61.84 (OMe), 35.34 (NMe), 94.21 (C4), 160.17

(CO₂Me), 115.64, 124.19, 126.60, 131.93, 141.80, 142.60

and 152.90 (aryl C), 186.42 (CHO). Mass spectrum: m/z 293

(M, 100%), 278 (27), 249 (22), 234 (62), 206 (21), 191 (65),

3.92, 3.95, 4.03 and 4.09 (4s, 12H, OMe), 7.61 (s, 1H, H4),

9.47 (bs, 1H, NH), 10.68 (s, 1H, CHO). ¹³C NMR spectrum

(CDCl₃): d 52.70, 56.23, 61.25 and 61.37 (OMe), 98.48

(C4), 119.74, 121.37, 124.50, 130.37, 138.56, 140.89,

152.83 (aryl C), 160.70 (CO₂Me), 188.44 (CHO). Mass

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

4999

176 (43), 173 (39), 163 (31), 155 (35), 149 (25), 148 (24),

147 (21), 146 (20).

stirring and cooling in ice. 5,7-Dimethoxy-1-methylindole

2 (0.20 g, 1.05 mmol) was added with stirring, and the

reaction mixture was stirred at room temperature for 2 h,

then poured over ice and basiﬁed with 10% aqueous sodium

hydroxide solution. After standing overnight, the precipitate

was ﬁltered, washed with water and dried. Preparative thin

layer chromatography (dichloromethane) yielded two

products.

4.4. Acylation of indoles

4.4.1. Acetylation of 5,7-dimethylindole. Combination of

ice-cold solutions of phosphoryl chloride (1.28 mL,

13.7 mmol), dimethylacetamide (3.8 mL, 40.9 mmol) and

5,7-dimethylindole (0.20 g, 1.38 mmol), followed by heat-

ing at 40–60 8C for 43 h and treatment with sodium

hydroxide solution (20%) gave 3-acetyl-5,7-dimethylindole

21 (0.21 g, 82%) as a pale brown powder, mp 223–224 8C.

(Found: C, 77.0; H, 7.3; N, 7.2. C₁₂H₁₃NO requires C, 77.0;

H, 7.0; N, 7.5%). l_max: 210 nm (3 6100 cm^K1M^K1), 244

(16,000), 300 (12,000). n_max: 3264, 1637, 1530, 1306, 1148,

(i) 4-Acetyl-5,7-dimethoxy-1-methylindole 34 (16 mg, 7%)

as a white powder, mp 83–84 8C. l_max: 213 nm (3

6000 cm^K1M^K1), 219 (5100), 256 (3500), 343 (3300).

1

n_max: 1620, 1567, 1330, 1239, 1211, 1108, 972 cm^K1. H

NMR spectrum (CDCl₃): d 2.64 (s, 3H, COMe), 3.94 and

3.98 (2s, 3H and 6H, OMe and NMe), 6.32 (s, 1H, H6), 6.98

(d, JZ3.1 Hz, 1H, H3), 7.07 (d, JZ3.1 Hz, 1H, H2). ¹³C

NMR spectrum (CDCl₃): d 33.0 (COMe), 36.6 (NMe), 55.5

and 57.1 (OMe), 90.2 and 102.8 (aryl CH), 112.6, 122.0 and

130.1 (aryl C), 132.5 (aryl CH), 151.4 and 157.3 (aryl C),

199.2 (COMe). Mass spectrum: m/z 233 (M, 80%), 218

(100), 203 (33), 160 (30), 132 (44). HRMS (ES) Found:

MCNa^C, 256.0941. C₁₃H₁₅NO₃requires MCNa^C,

256.0944.

1

927 cm^K1. H NMR spectrum (DMSO-d₆): d 2.35 (s, 3H,

COMe), 2.43 and 2.44 (2s, 6H, Me), 6.83 (s, 1H, H6), 7.81

(s, 1H, H4), 8.21 (d, JZ2.5 Hz, 1H, H2), 11.77 (br s, 1H,

NH). Mass spectrum: m/z 187 (M, 45%), 172 (100), 144

(18).

4.4.2. Acetylation of 5,7-dimethoxyindole (1). Phosphoryl

chloride (1.05 mL, 11.3 mmol) was added to ice-cold

dimethylacetamide (3.2 mL, 33.9 mmol) with stirring and

cooling in ice. 5,7-Dimethoxyindole 1 (0.20 g, 1.13 mmol)

was added with stirring, and the reaction mixture was stirred

at room temperature for 2 h, then poured over ice and

basiﬁed with 10% aqueous sodium hydroxide solution.

After standing overnight, the precipitate was ﬁltered,

washed with water and dried. Preparative thin layer

chromatography (dichloromethane) yielded two products.

(ii) 3-Acetyl-5,7-dimethoxy-1-methylindole 33 (0.19 g,

79%) was obtained as a white powder, mp 164–165 8C.

(Found: C, 67.1; H, 6.7: N, 5.8. C₁₃H₁₅NO₃requires C, 66.9;

H, 6.5; N, 6.0%). l_max: 218 nm (3 30,000 cm^K1M^K1), 250

(19,000), 264 (11,000), 315 (9700). n_max: 1635, 1615, 1586,

1280, 1214, 1144, 1111 cm^K1. ¹H NMR spectrum (CDCl₃):

d 2.44 (s, 3H, COMe), 3.85, 3.87 and 3.98 (3s, 9H, OMe and

NMe), 6.34 (d, JZ2.0 Hz, 1H, H6), 7.44 (s, 1H, H2), 7.46

(d, JZ2.0 Hz, 1H, H4). ¹³C NMR spectrum (CDCl₃): d 27.3

(COMe), 37.2 (NMe), 55.3 and 55.6 (OMe), 95.0 and 95.9

(aryl CH), 116.4, 122.2 and 128.5 (aryl C), 136.3 (aryl CH),

147.9 and 157.0 (aryl C), 192.8 (COMe). Mass spectrum:

m/z 234 (MC1, 33%), 233 (M, 92), 218 (100), 203 (37), 190

(42), 175 (64), 160 (63), 109 (39).

(i) 4-Acetyl-5,7-dimethoxyindole 32 (72 mg, 29%) as a

white powder, mp 198.5–201 8C. (Found: C, 65.5; H, 6.2; N,

6.1. C₁₂H₁₃NO₃requires C, 65.7; H, 6.0; N, 6.4%). l_max

:

208 nm (3 25,000), 224 (16,000), 252 (11,000), 336

(13,000). n_max: 3258, 1612, 1562, 1311, 1212, 1173,

1099 cm^K^{1 1}H NMR spectrum (DMSO-d₆): d 2.52 (s,

.

3H, COMe), 3.94 and 4.02 (2s, 6H, OMe), 6.57 (s, 1H, H6),

6.91 (t, JZ2.6, 2.6 Hz, 1H, H3), 7.27 (t, JZ2.6, 2.6 Hz, 1H,

H2), 11.28 (s, 1H, NH). ¹³C NMR spectrum (CDCl₃): d 32.9

(COMe), 55.5 and 57.2 (OMe), 90.1 and 104.9 (aryl CH),

112.9 and 121.9 (aryl C), 126.2 (aryl CH), 128.5, 149.7 and

157.8 (aryl C), 199.3 (COMe). Mass spectrum: m/z 219 (M,

85%), 204 (100), 189 (57), 146 (47), 118 (49), 103 (41).

4.4.4. Acetylation of 1-benzyl-5,7-dimethoxyindole (3).

Phosphoryl chloride (0.28 mL, 3.00 mmol) was added to

ice-cold dimethylacetamide (0.85 mL, 9.14 mmol) with

stirring and cooling in ice. 1-Benzyl-5,7-dimethoxyindole

3 (80 mg, 0.30 mmol) was added with stirring, and the

reaction mixture was stirred at 50–60 8C for 3.5 h, then

poured over ice and basiﬁed with 10% aqueous sodium

hydroxide solution. The turbid yellow solution was heated

at 100 8C brieﬂy, then cooled, diluted with water and

extracted with dichloromethane. The extract was washed

with water, dried (Na₂SO₄), and concentrated to give a

brown oil. Preparative thin layer chromatography (dichloro-

methane) yielded two products.

(ii) 3-Acetyl-5,7-dimethoxyindole 31 (0.10 g, 41%) as a

white powder, mp 174.5–176 8C. (Found: C, 65.5; H, 6.2; N,

6.2. C₁₂H₁₃NO₃requires C, 65.7; H, 6.0; N, 6.4%). l_max

:

213 nm (3 28,000 cm^K1M^K1), 243 (15,000), 248 (17,000),

262 (10,000), 308 (7500). n_max: 3204, 1613, 1297, 1221,

1

1209, 1140 cm^K1. H NMR spectrum (CDCl₃): d 2.51 (s,

3H, COMe), 3.87 and 3.88 (2s, 6H, OMe), 6.40 (d, JZ

2.0 Hz, 1H, H6), 7.45 (d, JZ2.0 Hz, 1H, H4), 7.75 (d, JZ

3.1 Hz, 1H, H2), 9.16 (s, 1H, NH). ¹³C NMR spectrum

(CDCl₃): d 27.4 (COMe), 55.4 and 55.8 (OMe), 95.1 and

95.7 (aryl CH), 118.6, 122.0 and 126.5 (aryl C), 130.9 (aryl

CH), 146.3 and 157.3 (aryl C), 193.9 (COMe). Mass

spectrum: m/z 219 (M, 69%), 204 (100), 189 (25), 146 (20).

(i) 4-Acetyl-1-benzyl-5,7-dimethoxyindole 36 (19 mg, 20%)

as a white powder, mp 111–112 8C. l_max: 216 nm (3

29,000 cm^K1M^K1), 250 (17,000), 260 (11,000), 314

(8300). n_max: 1633, 1575, 1335, 1247, 727 cm^{K1 1}H

.

NMR spectrum (CDCl₃): d 2.65 (s, 3H, COMe), 3.86 and

3.93 (2s, 6H, OMe), 5.55 (s, 2H, CH₂), 6.31 (s, 1H, H6),

7.02 (m, 2H, aryl H), 7.12 and 7.16 (d, JZ3.0 Hz, 2H, H2

and H3), 7.25 (m, 3H, aryl H). ¹³C NMR spectrum (CDCl₃):

d 33.0 (COMe), 52.5 (CH₂), 55.4 and 57.0 (OMe), 90.6 and

103.7 (aryl CH), 112.7 and 121.5 (aryl C), 126.3, 2C (aryl

4.4.3. Acetylation of 5,7-dimethoxy-1-methylindole (2).

Phosphoryl chloride (0.98 mL, 10.5 mmol) was added to

ice-cold dimethylacetamide (2.92 mL, 31.4 mmol) with

5000

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

CH), 127.1 (aryl CH), 128.5, 2C (aryl CH), 130.4 (aryl C),

132.2 (aryl CH), 139.4, 151.1 and 157.3 (aryl C), 199.4

(COMe). Mass spectrum: m/z 309 (M, 84%), 295 (21), 294

(100), 91 (54). HRMS (ES) Found: MCNa^C, 332.1283.

C₁₉H₁₉NO₃requires MCNa^C, 332.1257.

chromatography (dichloromethane) to give compound 38

(0.212 g, 60%) as a pale yellow powder, mp 217–220 8C.

(Found: C, 60.5; H, 5.5; N, 5.2. C₁₄H₁₅NO₅requires C, 60.6;

H, 5.5; N, 5.1%). l_max: 242 nm (3 22,400 cm^K1M^K1), 264

(11,700, sh), 317 (16,800), 346 (11,300, sh), 362 (5960, sh).

n_max: 3309, 1703, 1634, 1580, 1532, 1439, 1251, 1210,

1172, 984 cm^K1. ¹H NMR spectrum (CDCl₃): d 2.65 (s, 3H,

Me), 3.92, 3.96 and 4.02 (3s, 9H, OMe), 6.46 (s, 1H, H6),

7.82 (d, JZ2.6 Hz, 1H, H3), 9.02 (s, 1H, NH). ¹³C NMR

spectrum (CDCl₃): d 32.75 (COMe), 51.88, 55.62 and 57.08

(OMe), 92.74 (C6), 110.63 (C3), 113.23, 123.55, 127.57,

128.71, 150.23 and 158.11 (aryl C), 162.13 (CO₂Me),

198.51 (COMe). Mass spectrum: m/z 277 (M, 40%), 262

(33), 230 (100).

(ii) 3-Acetyl-1-benzyl-5,7-dimethoxyindole 35 (56 mg, 60%)

was obtained as a white powder, mp 151–152 8C. (Found: C,

73.6; H, 6.3; N, 4.3. C₁₉H₁₉NO₃requires C, 73.8; H, 6.2; N,

4.5%). l_max: 216 nm (3 36,000 cm^K1M^K1), 250 (21,000),

265 (13,000), 316 (11,000). n_max: 1636, 1534, 1495, 1294,

1211, 1146, 975, 832 cm^K1. ¹H NMR spectrum (CDCl₃): d

2.46 (s, 3H, COMe), 3.79 and 3.89 (2s, 6H, OMe), 5.59 (s,

2H, CH₂), 6.38 (d, JZ2.2 Hz, 1H, H6), 7.11 (m, 2H, aryl

H); 7.30 (m, 3H, aryl H), 7.51 (d, JZ2.2 Hz, 1H, H4), 7.58

(s, 1H, H2). ¹³C NMR (CDCl₃): d 27.4 (COMe), 53.2 (CH₂),

55.4 and 55.8 (OMe), 95.3 and 96.5 (aryl CH), 117.4 and

122.0 (aryl C), 126.7, 2C (aryl CH), 127.6 (aryl CH), 128.7,

2C (aryl CH), 135.6 (aryl CH), 138.0, 147.7 and 157.3 (aryl

C), 193.1 (COMe). Mass spectrum: m/z 309 (M, 45%), 173

(24), 145 (33), 91 (100).

4.4.7. Methyl 4-triﬂuoroacetyl-5,7-dimethoxyindole-2-

carboxylate (39). Triﬂuoroacetic anhydride (0.32 mL,

2.3 mmol) was added dropwise with stirring to an ice-

cooled solution of methyl 5,7-dimethoxyindole-2-carboxyl-

ate 6 (0.50 g, 2.13 mmol) in anhydrous tetrahydrofuran

(10.0 mL), under a nitrogen atmosphere. The mixture was

stirred at ambient temperature for 3 days. Water was then

added and the resulting precipitate ﬁltered, washed with

water, and dried to give compound 39 (0.62 g, 88%) as a

cream powder, mp 201–205 8C. (Found: C, 51.0; H, 3.8; N,

4.4.5. Friedel–Crafts acetylation of 1-benzyl-5,7-

dimethoxyindole

(3):

3,4-diacetyl-1-benzyl-5,7-

dimethoxyindole (37). A solution of anhydrous tin (IV)

chloride (2.2 mL, 18.8 mmol) in dry benzene (10 mL) was

added dropwise with stirring to an ice-cold suspension of

1-benzyl-5,7-dimethoxyindole 3 (0.50 g, 1.87 mmol) in dry

benzene (40 mL) containing acetyl chloride (1.33 mL,

18.7 mmol). The reaction mixture was heated at 40–50 8C

for 20 min. Water (100 mL) was added to the reaction

mixture, which was then stirred at room temperature for 2 h.

The benzene layer was separated and the aqueous layer was

extracted with dichloromethane. The dichloromethane and

benzene solutions were combined, dried (Na₂SO₄), and

concentrated to yield a black oil. Flash column chromato-

graphy (98:2 chloroform–methanol) yielded 3,4-diacetyl-1-

benzyl-5,7-dimethoxyindole 37 (0.22 g, 34%) as an off-

white powder, mp 190–191.5 8C. (Found: C, 71.6; H, 6.3; N,

4.2. C₁₄H₁₂F₃NO₃requires C, 50.8; H, 3.7; N, 4.2%). l_max

:

250 nm (3 18,200 cm^K1M^K1), 274 (6720, sh), 340

(14,700), 359 (14,200, sh). n_max: 3305, 1720, 1655, 1573,

1

1301, 1256, 1216, 1193, 1156, 1132, 981 cm^K1. H NMR

spectrum (CDCl₃): d 3.94, 3.97 and 4.06 (3s, 9H, OMe),

6.43 (s, 1H, H6), 7.64 (d, JZ2.3 Hz, 1H, H3), 9.15 (s, 1H,

NH). ¹³C NMR spectrum (CDCl₃): d 52.06, 55.89 and 57.00

(OMe), 92.03 (C6), 106.76 (aryl C), 109.29 (C3), 114.79

and 118.62 (COCF₃), 123.42, 128.03, 129.36, 152.68 and

160.19 (aryl C), 161.77 (CO₂Me), 180.85 and 180.37

(COCF₃). Mass spectrum: m/z 331 (M, 28%), 262 (53), 230

(100).

4.4.8. 4-Triﬂuoroacetyl-5,7-dimethoxyindole-2-car-

boxylic acid (40). Methyl 4-triﬂuoroacetyl-5,7-dimethoxy-

indole-2-carboxylate 39 (0.250 g, 0.755 mmol) was heated

under reﬂux in aqueous ethanolic (1:1) potassium hydroxide

(0.5 M, 10 mL) for 20 min. After cooling, the orange

solution was acidiﬁed with 10% aqueous hydrochloric

acid and the resulting precipitate ﬁltered through a frit,

washed with water, and dried to give the acid 40 (0.164 g,

69%) as an off-white powder, mp O250 8C (decomp.).

(Found: C, 49.4; H, 3.3; N, 4.7. C₁₃H₁₀F₃NO₅requires C,

49.2; H, 3.2; N, 4.4%). l_max: 248 nm (3 17,800 cm^K1M^K1),

277 (6930, sh), 340 (13,900), 361 (13,300, sh). n_max: 3465,

3.8. C₂₁H₂₁NO₄requires C, 71.8; H, 6.0; N, 4.0%). l_max

203 nm (3 45,000), 248 (22,000), 317 (11,000). n_max: 1696,

1647, 1579, 1285, 1204, 737 cm^K^{1 1}H NMR spectrum

:

.

(CDCl₃): d 2.41 and 2.69 (2s, 6H, COMe), 3.82 and 3.84 (2s,

6H, OMe), 5.60 (s, 2H, CH₂), 6.44 (s, 1H, H6), 7.09 (m, 2H,

aryl H), 7.31 (m, 3H, aryl H), 7.62 (s, 1H, H2). ¹³C NMR

spectrum (CDCl₃): d 27.1 and 33.0 (COMe), 53.4 (CH₂),

55.6 and 57.6 (OMe), 93.2 (aryl CH), 117.5, 118.4, 122.6

and 123.5 (aryl C), 126.5, 2C (aryl CH), 127.7 (aryl CH),

128.8, 2C (aryl CH), 137.0 (aryl CH), 137.7, 147.9 and

153.0 (aryl C), 191.1 and 203.6 (COMe). Mass spectrum:

m/z 351 (M, 16%), 336 (50), 91 (100).

1692, 1661, 1584, 1298, 1167, 1142 cm^K^{1 1}H NMR

.

spectrum (DMSO-d₆): d 3.96 and 4.07 (2s, 6H, OMe),

6.74 (s, 1H, H6), 7.35 (s, 1H, H3), 12.21 (bs, 1H, NH). ¹³C

NMR spectrum (DMSO-d₆): d 56.62 and 57.37 (OMe),

92.89 (C6), 104.70 (aryl C), 108.13 (C3), 115.01 and 118.85

(COCF₃), 123.69, 127.34, 131.80, 154.48 and 160.92 (aryl

C), 162.16 (CO₂H), 178.90 and 179.37 (COCF₃). Mass

spectrum: m/z 317 (M, 37%), 248 (62), 230 (100), 144 (20).

4.4.6. Methyl 4-acetyl-5,7-dimethoxyindole-2-carboxyl-

ate (38). A solution of methyl 5,7-dimethoxyindole-2-

carboxylate 6 (0.30 g, 1.28 mmol) and acetyl chloride

(0.4 mL, 6 mmol) in dichloromethane (10.0 mL) was stirred

under a nitrogen atmosphere with cooling via a salt-ice

slurry. Antimony pentachloride (0.4 mL, 3 mmol) was

added dropwise over 2 min and stirring continued for

80 min with cooling. The dark mixture was then poured

onto crushed ice and extracted with dichloromethane. The

organic extract was washed with water, dried (MgSO₄),

concentrated and the residue was puriﬁed by gravity column

4.4.9. Methyl 4-triﬂuoroacetyl-3-formyl-5,7-dimethoxy-

indole-2-carboxylate (41). A solution was prepared via the

dropwise addition of dimethylformamide (0.36 mL,

4.7 mmol) to phosphoryl chloride (1.0 mL) in a salt-ice

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

5001

slurry and then stirred for 15 min. This solution was then

added dropwise over 5 min, to a similarly cooled and stirred

solution of ester 39 (0.150 g, 0.453 mmol) in phosphoryl

chloride (3.0 mL). The mixture was stirred at room

temperature for 3 h and then with heating at 60 8C for 2

days before it was poured onto crushed ice, and treated with

solid sodium hydrogen carbonate over 2 h. The resulting

mixture was diluted with water and extracted with

dichloromethane. The organic extract was washed with

water, dried (MgSO₄), and concentrated to give a yellow

residue. Puriﬁcation via ﬂash column chromatography (1%

methanol/dichloromethane) gave compound 41 (0.159 g,

98%) as a yellow powder, mp 170–175 8C. (Found: C, 50.3;

H, 3.3; N, 3.9. C₁₅H₁₂F₃NO₆requires C, 50.2; H, 3.4; N,

3.9%). l_max: 256 nm (3 14,000 cm^K1M^K1), 284 (8500, sh),

317 (11,000), 349 (6600). n_max: 3310, 1741, 1715, 1661,

1271, 1204, 1137 cm^K1. ¹H NMR spectrum (CDCl₃): d 3.89

(s, 3H, OMe), 4.04 (s, 6H, OMe), 6.59 (s, 1H, H6), 9.61 (bs,

1H, NH), 10.47 (s, 1H CHO). ¹³C NMR spectrum (CDCl₃):

d 52.99, 55.87 and 57.67 (OMe), 94.29 (C6), 108.71 (aryl

C), 114.43 and 118.28 (COCF₃), 119.09, 121.54, 122.30,

131.70, 148.84 and 156.74 (aryl C), 160.04 (CO₂Me),

182.29 and 182.79 (COCF₃), 186.34 (CHO). Mass spec-

trum: m/z 359 (M, 15%), 290 (37), 258 (100).

petroleum ether). (Found: C, 61.0; H, 6.1; N, 9.9.

C₁₄H₁₆N₂O₄requires C, 60.9; H, 5.8; N, 10.1%). l_max

:

216 nm (3 36,000 cm^K1M^K1), 258 (17,000), 277 (11,000),

1

348 (9000). n_max: 3367, 1618, 1294, 775 cm^K1. H NMR

spectrum (CDCl₃): d 2.95 (d, JZ5.1 Hz, 3H, NHMe; 3.89

(s, 6H, OMe), 4.04 (s, 3H, NMe), 6.39 (d, JZ2.1 Hz, 1H,

H6), 7.49 (d, JZ2.0 Hz, 1H, H4), 7.52 (bs, 1H, NHMe),

8.75 (s, 1H, H2). ¹³C NMR spectrum (CDCl₃): d 25.8

(NHMe), 37.7 (NMe), 55.4 and 55.7 (OMe), 95.5 and 96.4

(aryl CH), 111.6, 121.5 and 130.2 (aryl C), 142.2 (aryl CH),

148.1 and 157.9 (aryl C), 163.5 (CONH), 179.7 (CO). Mass

spectrum: m/z 276 (M, 16%), 218 (100).

4.5.3. N-Methyl-2-(1-benzyl-5,7-dimethoxyindol-3-

yl)glyoxylamide (44). 1-Benzyl-5,7-dimethoxyindole 3

(0.30 g, 1.12 mmol) was dissolved in anhydrous diethyl

ether (10 mL), oxalyl chloride (0.24 mL, 2.75 mmol) was

added, and the reaction mixture was stirred for 15 min at

room temperature under a nitrogen atmosphere. The

resulting red precipitate was ﬁltered off, added to methyl-

amine (10 mL, 24% aqueous solution) and stirred for 1 h.

The yellow precipitate was ﬁltered off, washed with water

and dried to yield the 3⁰-glyoxylamide 44 (0.35 g, 89%) as

pale yellow needles, mp 212.5–214 8C (from ethyl acetate

and petroleum ether). (Found: C, 68.2; H, 5.9; N, 7.8.

C₂₀H₂₀N₂O₄requires C, 68.2; H, 5.7; N, 8.0%). l_max: 278 (3

9900 cm^K1M^K1), 348 (8400). n_max: 3364, 1613, 1296,

1204, 1163, 776 cm^K1. ¹H NMR spectrum (CDCl₃): d 2.94

(d, JZ5.1 Hz, 3H, NMe), 3.79 and 3.89 (2s, 6H, OMe), 5.58

(s, 2H, CH₂), 6.39 (d, JZ2.1 Hz, 1H, H6), 7.15 (m, 2H, aryl

H), 7.26 (m, 3H, aryl H), 7.51 (bs, 1H, NH), 7.53 (d, JZ

2.6 Hz, 1H, H4), 8.91 (s, 1H, H2). ¹³C NMR spectrum

(CDCl₃): d 25.8 (NHMe), 53.5 (CH₂), 55.4 and 55.7 (OMe),

95.6 and 96.8 (aryl CH), 112.2 and 121.0 (aryl C), 126.8, 2C

(aryl CH), 127.6 (aryl CH), 128.6, 2C, (aryl CH), 130.3 and

137.4 (aryl C), 141.8 (aryl CH), 147.8 and 157.9 (aryl C),

163.4 (CONH), 179.9 (CO). Mass spectrum: m/z 352 (M,

10%), 294 (40), 91 (100).

4.5. Reactions of indoles with oxalyl chloride and

amines: formation of glyoxylic amides

4.5.1. N-Methyl-2-(5,7-dimethoxyindol-3-yl)glyoxyl-

amide (42). 5,7-Dimethoxyindole 1 (0.20 g, 1.13 mmol)

was dissolved in anhydrous diethyl ether (10 mL), oxalyl

chloride (0.25 mL, 2.87 mmol) was added and the mixture

stirred for 1.75 h at room temperature under a nitrogen

atmosphere. The resulting red precipitate was ﬁltered off,

added to methylamine (10 mL, 24% aqueous solution) and

stirred for 1 h. The yellow precipitate was ﬁltered off,

washed with water and dried to yield the 3⁰-glyoxylamide

42 (0.17 g, 57%) as a bright yellow powder, mp 232 8C (lit.⁷

228–229 8C) (from ethyl acetate). l_max: 275 nm (3

13,000 cm^K1M^K1), 340 (9200). n_max: 3350, 1612, 1223,

4.5.4. 2-(5,7-Dimethoxy-1-methylindol-3-yl)glyoxyl-

amide (45). 5,7-Dimethoxy-1-methylindole 2 (1.30 g,

6.82 mmol) was dissolved in anhydrous diethyl ether

(40 mL), oxalyl chloride (1.49 mL, 17.1 mmol) was

added, and the reaction mixture was stirred for 15 min at

room temperature under a nitrogen atmosphere. The red

precipitate was ﬁltered off, added to concentrated aqueous

ammonia solution (10 mL) and stirred for 1 h. The yellow

precipitate was ﬁltered off, washed with water and dried to

yield glyoxylamide 45 (1.48 g, 90%) as a yellow powder, mp

255 8C. (Found: C, 59.8; H, 5.1; N, 10.5. C₁₃H₁₄N₂O₄requires

C, 59.5; H, 5.4; N, 10.7%). l_max: 258 nm (3 11,000 cm^K1

M^K1), 279 (8200), 346 (7400). n_max: 3448, 3152, 1691, 1612,

1

1144 cm^K1. H NMR spectrum (CDCl₃): d 2.97 (d, JZ

5.6 Hz, 3H, N-Me), 3.91 and 3.93 (2s, 6H, OMe), 6.43 (d,

JZ2.0 Hz, 1H, H6), 7.47 (d, JZ2.0 Hz, 1H, H4), 7.49 (bs,

1H, NHMe), 8.94 (bs, 1H, NH), 8.98 (d, JZ3.1 Hz, 1H,

H2). ¹³C NMR (DMSO-d₆): d 25.6 (NMe), 55.3 and 55.5

(OMe), 95.1 and 95.5 (aryl CH), 112.6, 121.2 and 127.8

(aryl C), 137.1 (aryl CH), 146.8 and 157.1 (aryl C), 164.1

(CONH), 181.9 (CO). Mass spectrum: m/z 262 (M, 24%),

204 (100), 189 (27). Treatment of the ﬁltrate with excess

methylamine (24% aqueous solution) gave a further crop of

the 3⁰-glyoxylamide 42 (59 mg, 20%).

1594, 1274, 1224, 1104, 850 cm^K^{1 1}H NMR spectrum

.

4.5.2. N-Methyl-2-(5,7-dimethoxy-1-methylindol-3-

yl)glyoxylamide (43). 5,7-Dimethoxy-1-methylindole 2

(0.30 g, 1.57 mmol) was dissolved in anhydrous diethyl

ether (10 mL), oxalyl chloride (0.34 mL, 3.90 mmol) was

added, and the reaction mixture was stirred for 15 min at

room temperature under a nitrogen atmosphere. The

resulting red precipitate was ﬁltered off, added to methyl-

amine (10 mL, 24% aqueous solution) and stirred for 1 h.

The yellow precipitate was ﬁltered off, washed with water

and dried to yield the 3⁰-glyoxylamide 43 (0.34 g, 78%) as

pale yellow needles, mp 170 8C (from ethyl acetate and

(DMSO-d₆): d 3.79 and 3.88 (2s, 6H, OMe), 4.02 (s, 3H,

NMe), 6.47 (d, JZ2.1 Hz, 1H, H6), 7.36 (d, JZ2.0 Hz, 1H,

H4), 7.69 and 8.01 (2bs, 2H, NH₂), 8.50 (s, 1H, H2). ¹³C NMR

spectrum (DMSO-d₆): d 37.1 (NMe), 55.3 and 55.8 (OMe),

95.1and 96.1(aryl CH), 110.9, 121.2 and 129.3 (aryl C), 141.6

(aryl CH), 148.0 and 157.2 (aryl C), 166.0 (CONH₂), 182.2

(CO). Mass spectrum: m/z 262 (M, 29%), 218 (100).

4.5.5. N,N-Dimethyl-2-(1-benzyl-5,7-dimethoxyindol-3-

yl)glyoxylamide (46). Glyoxylamide 46 was prepared by

5002

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

the method used for glyoxylamide 45 using 1-benzyl-5,7-

dimethoxyindole 3 (0.30 g, 1.12 mmol), oxalyl chloride

(0.15 mL, 1.72 mmol), anhydrous diethyl ether (40 mL) and

40% aqueous dimethylamine solution (2!10 mL, excess).

Glyoxylamide 46 (0.37 g, 89%) was obtained as pale tan

plates, mp 174–175 8C (from dichloromethane and

petroleum ether). (Found: C, 68.7; H, 6.0; N, 7.5.

1618, 1573, 1259, 1216 cm^K1. ¹H NMR spectrum (DMSO-

d₆): d 3.84 (s, 6H, OMe), 4.04 (s, 3H, OMe), 6.73 (s, 1H,

H6), 7.56 (s, 1H, H3), 7.26 and 7.68 (2s, 2H, CONH₂), 12.22

(s, 1H, indole NH) (the signals at 7.26, 7.68 and 12.22 ppm

exchanged with D₂O). ¹³C NMR spectrum (DMSO-d₆): d

52.18, 56.63 and 58.18 (OMe), 94.48 (C6), 109.21 (C3),

107.97, 124.51, 126.79, 129.96, 153.25 and 160.86 (aryl C),

161.56 (CO₂Me), 170.44 (CONH₂), 190.88 (CO). Mass

spectrum: m/z 306 (M, 10%), 262 (76), 230 (100), 144 (25).

C₂₁H₂₂N₂O₄requires C, 68.8; H, 6.1; N, 7.6%). l_max

:

273 nm (e 12,000 cm^K1M^K1), 330 (9900). n_max: 1622,

1286, 1242, 1051, 981, 936, 827 cm^K1. ¹H NMR spectrum

(CDCl₃): d 3.06 and 3.07 (2s, 6H, NMe₂), 3.78 and 3.89 (2s,

6H, OMe), 5.56 (s, 2H, CH₂), 6.39 (d, JZ2.0 Hz, 1H, H6),

7.12 (m, 2H, aryl H), 7.29 (m, 3H, aryl H), 7.46 (d, JZ

2.1 Hz, 1H, H4), 7.75 (s, 1H, H2). ¹³C NMR spectrum

(CDCl₃): d 34.4 and 37.5 (NMe), 53.4 (CH₂), 55.4 and 55.7

(OMe), 95.2 and 96.9 (aryl CH), 113.6 and 121.8 (aryl C),

126.7, 2C (aryl CH), 127.6 (aryl CH), 128.6, 2C (aryl CH),

128.8 and 137.5 (aryl C), 138.9 (aryl CH), 147.7 and 157.7

(aryl C), 167.5 (CONMe₂), 185.6 (CO). Mass spectrum: m/z

366 (M, 5%), 294 (100).

4.5.8. Methyl 5,7-dimethoxy-4-(3⁰,5⁰-dimethoxyphenyl-

oxamoyl)indole-2-carboxylate (49). A stirred solution of

methyl 5,7-dimethoxyindole-2-carboxylate 6 (0.10 g,

0.43 mmol) and oxalyl chloride (0.07 mL, 0.8 mmol) in

anhydrous diethyl ether (10 mL) was heated at reﬂux under

nitrogen for 27 h. The mixture was then cooled in a salt-ice

slurry and treated with 3,5-dimethoxyaniline (50 mg,

0.50 mmol). The open ﬂask was then heated for 15 min,

the ether allowed to evaporate, and the resulting precipitate

was ﬁltered through a frit, washed with water, and dried to

give glyoxylamide 49 (0.40 g, 84%) as a cream powder, mp

212–215 8C (from methanol). (Found: C, 57.5; H, 5.2; N,

5.5. C₂₂H₂₂N₂O₈.H₂O requires C, 57.4; H, 5.3; N, 6.1%).

l_max: 242 nm (3 32,900 cm^K1M^K1), 280 (10,800, sh), 311

(20,000), 326 (18,000, sh). n_max: 3310, 3229, 1696, 1614,

1579, 1259, 1213, 1171 cm^K1. ¹H NMR spectrum (CDCl₃):

d 3.81 (s, 6H, OMe), 3.89, 3.94 and 4.04 (3s, 9H, OMe),

6.29 (d, JZ1.9₀Hz, 1H,₀H4⁰), 6.43 (s, 1H, H6), 6.91 (d, JZ

1.9 Hz, 2H, H2 and H6 ), 7.57 (d, JZ2.3 Hz, 1H, H3), 8.02

(s, 1H, indole NH), 9.12 (s, 1H, CONH) (the signals at 8.02

and 9.12 ppm exchanged with D₂O). ¹³C NMR spectrum

(CDCl₃): d 52.59, 55.86, 56.38 and 58.49 (OMe), 93.46

(C6), 97.38 (C4⁰), 98.63 (C2⁰and C6⁰), 109.46 (C3), 109.06,

124.21, 127.90, 129.58, 139.64, 152.63, 160.76 and 161.54

(aryl C), 162.39 and 163.87 (CONH and CO₂Me), 190.48

(CO). Mass spectrum: m/z 442 (M, 2%), 279 (100), 262

(40), 248 (20), 247 (95), 246 (34), 230 (34), 218 (83), 204

(26), 160 (22). HRMS Found: M^C, 442.1375. C₂₂H₂₂N₂O₈

requires M^C, 442,1376.

4.5.6. N-Methyl-2-(4-formyl-5,7-dimethoxy-1-methyl-

indol-3-yl)glyoxylamide (47). To a stirred solution of

glyoxylamide 43 (0.20 g, 0.73 mmol) in dry dimethyl-

formamide (5.0 mL) at 0 8C was added dropwise an ice-cold

solution of phosphoryl chloride (0.14 mL, 1.50 mmol) in

dry dimethylformamide (1.5 mL). The reaction mixture was

stirred at room temperature for 24 h, then poured over ice,

basiﬁed with 10% aqueous sodium hydroxide solution and

allowed to stand overnight, and the solution was extracted

with dichloromethane. The extract was washed with water,

dried (Na₂SO₄), and concentrated to give an orange powder.

Preparative thin layer chromatography (95:5 chloroform–

methanol) afforded glyoxylamide 47 (40 mg, 18%) as

yellow crystals, mp 219–221 8C (from dichloromethane

and petroleum ether). l_max: 212 nm (3 26,000 cm^K1M^K1),

220 (24,000), 248 (18,000), 319 (14,000). n_max: 3389, 1693,

1

1652, 1636, 1579, 1290, 1224 cm^K1. H NMR spectrum

(DMSO-d₆): d 2.66 (d, JZ4.6 Hz, 3H, NHMe), 3.93, 4.01

and 4.04 (3s, 9H, OMe and NMe), 6.68 (s, 1H, H6), 8.13 (s,

1H, H2), 8.49 (d, JZ5.1 Hz, 1H, NHMe), 10.27 (s, 1H,

CHO). ¹³C NMR spectrum (CDCl₃): d 25.9 (NHMe), 37.7

(NMe), 55.8 and 57.1 (OMe), 91.3 (aryl CH), 111.9, 113.6,

122.2 and 126.7 (aryl C), 140.7 (aryl CH), 152.9 (aryl C),

160.8 and 163.3 (aryl C and CONH), 182.3 (CO), 188.9

(CHO). Mass spectrum: m/z 304 (M, 11%), 246 (100).

HRMS (ES) Found: MCNa^C, 327.0953. C₁₅H₁₆N₂O₅

requires MCNa^C, 327.0951.

4.6. Mannich reaction

4.6.1. Methyl 5,7-dimethoxy-4-N,N-dimethylamino-

methylindole-2-carboxylate (50). A solution of 40%

aqueous dimethylamine (1.0 mL) and 38% aqueous formal-

dehyde (0.10 mL) in glacial acetic acid (1.0 mL) was added

dropwise over 7 min to a stirred solution of methyl 5,7-

dimethoxyindole-2-carboxylate 6 (0.25 g, 1.06 mmol) in

glacial acetic acid (4.0 mL). The resulting solution was

stirred for 2 days at ambient temperature before it was

diluted with water, cooled in an iced water bath, and basiﬁed

to high pH with 5 M sodium hydroxide. The resulting

precipitate was ﬁltered, washed with water, and dried to

give compound 50 (0.24 g, 78%) as a ﬁne white powder, mp

148–151 8C. (Found: C, 59.8; H, 6.8; N, 9.0.

C₁₅H₂₀N₂O₄$0.5H₂O requires C, 60.0; H, 7.0; N, 9.3%).

l_max: 241 nm (3 29,700 cm^K1M^K1), 296 (19,600), 331

(4750). n_max: 3325, 1698, 1324, 1282, 1252, 1216 cm^K1. ¹H

NMR spectrum (CDCl₃): d 2.26 (s, 6H, NMe₂), 3.64 (s, 2H,

CH₂), 3.86, 3.92 and 3.96 (3s, 9H, OMe), 6.52 (s, 1H, H6),

7.29 (s, 1H, H3), 8.94 (s, 1H, NH). ¹³C NMR spectrum

(CDCl₃): d 45.37 (NMe₂), 54.31 (CH₂), 51.73, 55.44 and

58.05 (OMe), 94.67 (C6), 107.91 (C3), 110.98, 123.73,

4.5.7. Methyl 4-oxamoyl-5,7-dimethoxyindole-2-car-

boxylate (48). A stirred solution of methyl 5,7-dimethoxy-

indole-2-carboxylate 6 (0.100 g, 0.425 mmol) and oxalyl

chloride (0.07 mL, 0.8 mmol) in anhydrous diethyl ether

(10.0 mL) was heated at reﬂux under nitrogen for 27 h. The

mixture was then cooled in a salt-ice slurry and treated with

aqueous ammonia (2.5 M, 6.0 mL). The open ﬂask was

heated for 15 min, the ether allowed to evaporate, and the

resulting precipitate was ﬁltered through a frit, washed with

water, and dried to give glyoxylamide 48 (0.10 g, 79%) as a

cream powder, mp 254–258 8C. (Found: C, 52.4; H, 5.1; N,

8.5. C₁₄H₁₄N₂O₆.0.8H₂O requires C, 52.3; H, 4.9; N, 8.7%).

l_max: 242 nm (3 20,000 cm^K1M^K1), 277 (7600, sh), 325

(15,000), 353 (11,000, sh). n_max: 3404, 3306, 3171, 1698,

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

5003

127.22, 129.52, 145.95 and 152.88 (aryl C), 162.09

(CO₂Me). Mass spectrum: m/z 292 (M, 22%), 248 (82),

216 (100).

concentrated to give a dark solid that was puriﬁed via

ﬂash column chromatography (dichloromethane) to give the

amine 53 (35 mg, 59%) as a yellow powder, mp 141–

144 8C. (Found: C, 57.4; H, 5.8; N, 11.4. C₁₂H₁₄N₂O₄

requires C, 57.6; H, 5.6; N, 11.2%). l_max: 254 nm (3

28,500 cm^K1M^K1), 299 (13,300), 367 (3880). n_max: 3403,

3323, 1687, 1539, 1519, 1444, 1360, 1330, 1270 cm^K1. ¹H

NMR spectrum (CDCl₃): d 3.86, 3.91 and 3.92 (3s, 9H,

OMe), 6.56 (s, 1H, H6), 7.14 (d, JZ1.9 Hz, 1H, H3), 8.91

(s, 1H, NH). ¹³C NMR spectrum (CDCl₃): d 52.33, 56.50

and 59.08 (OMe), 97.84 (C6), 106.17 (C3), 120.09, 123.18,

125.09, 126.86, 128.11 and 139.30 (aryl C), 162.46

(CO₂Me). Mass spectrum: m/z 250 (M, 45%), 235 (26),

218 (27), 203 (100), 202 (10), 109 (27).

4.7. Bromination

4.7.1. Methyl 4-bromo-5,7-dimethoxyindole-2-carboxyl-

ate (51). Bromine (0.02 mL, 0.4 mmol) was added all at

once to a vigorously stirred solution of methyl 5,7-

dimethoxyindole-2-carboxylate 6 (91 mg, 0.39 mmol) in

glacial acetic acid (5.0 mL) at room temperature. Stirring

was continued for 30 s before water was added and the

resulting emulsion extracted with ethyl acetate. The organic

extract was washed twice with a saturated sodium hydrogen

carbonate solution, then once with brine, dried (MgSO₄),

and concentrated to give the bromo compound 51 (122 mg,

100%) as a white powder, mp 183–185 8C. (Found: C, 46.0;

H, 4.0; N, 4.3. C₁₂H₁₂BrNO₄requires C, 45.9; H, 3.9; N,

4.5%). l_max: 241 nm (3 33,800 cm^K1M^K1), 296 (20,600),

Acknowledgements

We thank the Australian Research Council for ﬁnancial

support.

1

329 (5160). n_max: 3312, 1704, 1316, 1249, 1211 cm^K1. H

NMR spectrum (CDCl₃): d 3.93, 3.94 and 3.97 (3s, 9H,

OMe), 6.55 (s, 1H, H6), 7.18 (d, JZ2.6 Hz, 1H, H3), 9.04

(s, 1H, NH). ¹³C NMR spectrum (CDCl₃): d 51.98, 55.69

and 58.53 (OMe), 95.76 (C6), 108.70 (C3), 94.64, 123.79,

127.60, 129.11, 146.13 and 151.03 (aryl C), 161.76

(CO₂Me). Mass spectrum: m/z 315 (M, ⁸¹Br, 61%), 313

(M, ⁷⁹Br, 60), 283 (85), 282 (25), 281 (100), 268 (26), 266

(24), 254 (34), 252 (36), 240 (37), 238 (34), 144 (35).

References and notes

1. Black, D. St.C.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.;

Kim, M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust.

J. Chem. 1994, 47, 1741–1750.

4.8. Nitration

2. Black, D. St.C.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.;

Keller, P. A.; Kumar, N.; Nugent, S. J. Tetrahedron 1994, 50,

10497–10508.

4.8.1. Methyl 5,7-dimethoxy-4-nitroindole-2-carboxylate

(52). A solution of methyl 5,7-dimethoxyindole-2-car-

boxylate 6 (0.20 g, 0.85 mmol) in dichloromethane

(10.0 mL) was stirred at room temperature in the presence

of concentrated nitric acid adsorbed on silica gel, for

35 min. The resulting dark mixture was diluted with

dichloromethane and then immediately puriﬁed via ﬂash

column chromatography (dichloromethane) to give the nitro

compound 52 (96 mg, 40%) as a yellow powder, mp 236–

237 8C. (Found: C, 51.2; H, 4.3; N, 10.3. C₁₂H₁₂N₂O₆

requires C, 51.4; H, 4.3; N, 10.0%). l_max: 237 nm (3

19,000 cm^K1M^K1), 250 (15,000, sh), 273 (7400, sh), 333

(11,000), 370 (10,000). n_max: 3304, 1704, 1286, 1249,

3. Black, D. St.C.; Craig, D. C.; Kumar, N. Aust. J. Chem. 1996,

49, 311–318.

4. Black, D. St.C.; Kumar, N.; McConnell, D. B. Tetrahedron

1996, 52, 8925–8936.

5. Su¨s, V. O.; Glos, M.; Mu¨ller, K.; Eberhardt, H. D.

Justus Liebigs Ann. Chem. 1953, 583, 150–160.

6. Mulligan, P. J.; LaBerge, S. J. Med. Chem. 1970, 13,

1248–1249.

7. Crohare, R.; Merkuza, V. M.; Gonzalez, H. A.; Ruveda, E. A.

J. Heterocycl. Chem. 1970, 7, 729–732.

8. Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem.

1970, 101, 161–165.

1

1214 cm^K1. H NMR spectrum (DMSO-d₆): d 3.85, 4.00

9. Moody, C. J. In Trost, B. M., Fleming, I., Eds.; Comprehensive

Organic Synthesis; Pergamon: Oxford, 1991; Vol. 7, pp 21–38.

10. Forster, M. O.; Fierz, H. E. J. Chem. Soc. 1908, 93, 72–85.

and 4.07 (3s, 9H, OMe), 6.77 (s, 1H, H6), 7.35 (d, JZ

2.3 Hz, 1H, H3), 12.59 (s, 1H, NH). ¹³C NMR spectrum

(DMSO-d₆): d 52.36, 57.00 and 58.07 (OMe), 94.01 (C6),

108.06 (C3), 122.87, 123.41, 123.80, 130.41, 152.68 and

154.15 (aryl C), 161.16 (CO₂Me). Mass spectrum: m/z 280

(M, 58%), 249 (20), 248 (100), 219 (22), 218 (35), 216 (84),

172 (20), 145 (20), 144 (60).

´

11. Knouzi, N.; Vaultier, M.; Carrie, R. Bull. Soc. Chim. Fr. 1985,

5, 815–819.

12. Allen, M. S.; Hamaker, L. K.; La Loggia, A. J.; Cook, J. M.

Synth. Commun. 1992, 22, 2077–2102.

13. Lloyd, H. A.; Kielar, E. A.; Highet, R. J.; Uyeo, S.; Fales,

H. M.; Wildman, W. C. J. Org. Chem. 1962, 27, 373–377.

´

14. Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez, M.;

4.8.2. Methyl 4-amino-5,7-dimethoxyindole-2-carboxyl-

ate (53). A suspension of methyl 5,7-dimethoxy-4-nitro-

indole-2-carboxylate 52 (66 mg, 0.24 mmol) and 10%

palladium/charcoal (9 mg) in absolute ethanol (15.0 mL)

was heated at reﬂux during the dropwise addition of a

solution of hydrazine hydrate (0.2 mL) in absolute ethanol

(1.5 mL) over 2 min. Heating was continued for 2 h before

the hot mixture was ﬁltered and concentrated. The

remaining syrup was dissolved in dichloromethane and

washed three times with brine, dried (MgSO₄), and

´

Garcıa-Martın, M. A.; Gonzalez, J. M. J. Org. Chem. 1996, 61,

´

5804–5812.

15. Hiremath, S. P.; Purohit, M. G. Indian J. Chem. 1974, 12,

493–495.

16. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.;

Kitos, P. A.; Suntornwat, O. J. Am. Chem. Soc. 1990, 112,

8961–8971.

17. Muratake, H.; Okabe, K.; Takahashi, M.; Tonegawa, M.;

Natsume, M. Chem. Pharm. Bull. 1997, 45, 799–806.

5004

G. C. Condie et al. / Tetrahedron 61 (2005) 4989–5004

18. Giua, M. Gazz. Chim. Ital. 1924, 54, 593–597.

19. Black, D. St.C.; Kumar, N.; McConnell, D. B. Tetrahedron

1996, 52, 8925–8936.

Yokoyama, Y.; Murakami, Y. Heterocycles 1992, 34,

2349–2362.

22. Jones, A. W.; Purwono, B.; Bowyer, P. K.; Mitchell, P. S. R.;

Kumar, N.; Nugent, S. J.; Jolliffe, K. A.; Black, D. St.C.

Tetrahedron 2004, 60, 10779–10786.

20. Kruse, L. I.; Meyer, M. D. J. Org. Chem. 1984, 49, 4761–4768.

21. Tani, M.; Ikegami, H.; Tashiro, M.; Hiura, T.; Tsukioka, H.;

Kaneko, C.; Notoya, T.; Shimizu, M.; Uchida, M.; Aida, Y.;

Article Doi

Regioselective reactivity of some 5,7-dimethoxyindoles

DOI: 10.1016/j.tet.2005.03.048

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Article abstract of DOI:10.1016/j.tet.2005.03.048

Full text of DOI:10.1016/j.tet.2005.03.048

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