Aryl radical cyclisation onto pyrroles

TETRAHEDRON

Pergamon

Tetrahedron 58 (2002) 1453±1464

Aryl radical cyclisation onto pyrroles

Carmen Escolano and Keith Jones^p

School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey KT1 2EE, UK

Received 30 October 2001; revised 28 November 2001; accepted 20 December 2001

AbstractÐThe intramolecular cyclisation of aryl radicals onto a pyrrole is studied. The cyclisation allows the synthesis of either the

spiropyrrolidinyloxindole or the pyrrolo[3,2-c]quinoline skeleton depending on the nature of the protecting group at the N-pyrrole atom. The

regiochemistry of the cyclisation is not affected by the substituents on the benzene ring. Some limitations on the utility of tosylmethyl-

1. Introduction

Intramolecular aryl radical cyclisation reactions have been

used by organic chemists in the synthesis of polycyclic

natural products.¹In particular, the intramolecular addition

of aryl radicals to multiple bonds is well documented in the

literature²and the addition of aryl radicals to benzene rings

followed by rearomatisation has also been reported.³In

contrast, there are only a few reports dealing with the intra-

molecular addition of aryl radicals to heterocyclic rings. For

example, Motherwell in the context of the synthesis of

heterobiaryls via intramolecular free radical ipso substitu-

tion reactions has reported some [1,7] addition of aryl

radicals onto quinoline, thiophene and pyridine derivatives.⁴

Tsuge⁵has reported the intramolecular addition of aryl

radical to the C-2 of the indole nucleus leading to dihydro-

indoles. The only previous examples of intramolecular

addition of aryl radical to pyrroles under reductive condi-

tions are due to Muchowski and deal exclusively with the

addition of aryl radicals to the C-2 of the pyrrole nucleus.⁶

Scheme 1.

In this paper we wish to report in full our studies concerning

the intramolecular addition of aryl radicals onto a pyrrole in

(2)-hors®line,¹⁰potent gastric (H/K) ATPase inhibitors,¹¹

which the linking chain is attached to the C-3 position.⁷

Using the radical precursors with the general structure A

shown in Scheme 1, aryl radical cyclisations were studied.

The cyclisation of compounds with the general structure A

is interesting in the context of natural product synthesis

because depending on the position at which the aryl radicals

adds onto the pyrrole nucleus, alkaloids with the spiro-

martinelline and martinellic acid (Fig. 1).¹²

2. Results and discussion

2.1. Preparation of radical precursors

pyrrolidinyloxindole

C or pyrrolo[3,2-c]quinoline D

Our interest in targets such as the natural products shown in

Fig. 1, led us to develop the general synthetic sequence

shown in Scheme 2 in order to prepare the radical precursors

with the general structure A. Reaction of 2-bromo-4-

methoxyaniline,¹³1a, with acryloyl chloride in dichloro-

methane and HuÈnig's base¹⁴gave the N-arylacrylamide 2a

in 93% yield. Reaction of methyl 4-amino-3-iodobenzo-

ate,¹⁵1b, with an excess of acryloyl chloride gave 2b in

nucleus could be accessed. These ring systems are

found in a wide range of biologically-active alkaloids

such as spirotryprostatin A and B,⁸(1)-elacomine,⁹

Keywords: radicals; cyclisation; pyrroles; regioselection; natural products.

Corresponding author. Tel.: 144-20-8547-8450; fax: 144-20-8547-

7562; e-mail: keith.jones@kingston.ac.uk

p

PII: S0040-4020(02)00007-8

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C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

pyrrole-3-carboxamides 4a¹⁸and 4c in 60 and 57% yield,

respectively. These results are in good agreement with our

previous results in which the reaction of 3d with TosMIC

gave 4d in 57% yield.^8bHowever, reaction of 3b with

TosMIC using the same experimental conditions as above

gave polymeric mixtures. When the reaction was conducted

in THF as a solvent and using potassium tert-butoxide as a

base the desired pyrrolo-3-carboxamide 4b, was formed but

in a very low yield together with the resulting transesteri®-

cation product 4e and starting material. Finally, 4b was

obtained in 26% yield when the N-methylamidobenzoate

3b was reacted with TosMIC in THF using NaHMDS¹⁹as

base. These results indicate that N-arylacrylamide substrates

carrying electron-withdrawing substituents on the aryl ring

are poor substrates for pyrrole formation via the TosMIC

reaction. As this process is basically a two-stage process

with initial (reversible) Michael addition followed by cycli-

sation to the pyrrole (irreversible), it appears that increasing

the Michael acceptor ability of the acrylamide compromises

the ability of the intermediate to cyclise presumably by

enhanced stabilisation of the intermediate enolate. Elec-

tron-donating substituents decrease the stability of the inter-

mediate accelerating the cyclisation reaction and leading to

higher yields of pyrrole.

Figure 1.

In order to further check this hypothesis, preparation of 3g,

an o-aminoacetanilide, was attempted. If, as postulated, the

success in the pyrrole formation reaction using TosMIC was

related to the Michael acceptor ability of the a,b-unsatu-

rated alkene involved, 3g would give the corresponding

pyrrole derivative in good yield. Thus, nitro-derivative 3f

was prepared in 79% overall yield by reaction of 4-meth-

oxy-2-nitroaniline, 1c, with acryloyl chloride in dichloro-

methane to give 2c, followed by methylation (NaH, CH₃I).

As expected, reaction of 3f with TosMIC using NaH as a

base in DMSO/ether led to polymeric mixtures in which the

pyrrole derivative could not be detected. Reaction of 3f with

86% yield. Previous studies by our group had shown that a

tertiary amide is required in order to attain the correct

conformation around the amide bond for cyclisation to

occur.¹⁶Thus, 2a,b were methylated (NaH, CH₃I) to give

tertiary amides 3a,b in very good yields. Alternatively, 2a

was alkylated with 2-(trimethylsilyl)ethoxymethyl chloride

(SEM-Cl) to give 3c in 92% yield. The change in the shift of

the H-6⁰proton (from d_H,8 in 2 to d_H,7 in 3) clearly

demonstrates the switch in conformation upon N-alkylation.

Reaction of 3a and 3c with tosylmethylisocyanide

(TosMIC) using NaH as a base in ether/DMSO¹⁷gave the

Scheme 2.

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

1455

studying the pyrrole ring formation. It is well known that

reductive cyclisation of o-nitroacetanilides using Fe,²³Sn²⁴

or hydrogen²⁵leads to benzimidazoles, but to our knowl-

edge the examples reported in this paper are the ®rst invol-

ving acrylamide derivatives.

With the pyrrole derivatives 4a±c in hand, substitution on

the pyrrole nitrogen was explored in order to give substrates

with differing electronic/steric properties. Reaction of 4a,

4b with di-t-butyl dicarbonate, triethylamine and catalytic

dimethylaminopyridine at low temperature led to N-Boc

protected pyrroles 5a, 5b in very good yields. Two different

N-protecting groups were tested on pyrrole 4c. On the one

hand, reaction of 4c with KH followed by treatment with

methyl chloroformate gave the methoxycarbonyl derivative

5c in 80% yield, and on the other, methylation (NaH, CH₃I)

of 4c furnished the N-methyl substituted pyrrole 5d in 72%

yield.

2.2. Radical cyclisations

Scheme 3.

The radical cyclisation precursors 4a, 4c, 5a and 5b were

subjected to standard reductive radical cyclisation condi-

tions [tributyltin hydride (0.02 M) in re¯uxing toluene

with a sub-stoichiometric amount of AIBN] (Scheme 4,

Table 1).

TosMIC using potassium tert-butoxide and THF as a

solvent, gave the pyrrolecarboxamide 4f in a low 20%

yield. The use of NaHMDS did not improve the yield.

Next, we decided to carry out the reduction of the nitro

group of 3f previous to the pyrrole formation. However,

all our attempts to carry out the conversion of 3f in 3g

were fruitless (Scheme 3). Treatment of 3f with palladium

on carbon and formic acid in triethylamine²⁰gave the benzi-

midazole derivative 6 in 80% yield, as a result of the reduc-

tion of the nitro group, attack of the newly formed amine

onto the amide carbonyl and reduction of the double bond in

the side chain. In a similar manner, reaction of 3f with

SnCl₂´H₂O²¹furnished the benzimidazole 7 in 70% yield.

Lastly, 3f was reduced with copper(II)acetylacetonate and

sodium borohydride at room temperature.²²Compound 8

was isolated in 60% yield. Although the nitro group was

reduced and no benzimidazole ring was obtained, the double

bond in the side chain was reduced thus precluding us from

Cyclisation of the N-unsubstituted pyrroles 4a and 4c gave a

mixture (ca. 2:1) of regioisomeric pyrroloquinolines

9a±10a and 9b±10b, respectively. Considering the reduc-

tive conditions involved in the cyclisation, the obtention of

the oxidized aromatic derivatives 9 and 10 rather than the

dehydroaromatic derivatives is surprising. However, oxida-

tion during Bu₃SnH mediated radical reactions has been

well documented.²⁶The 6-endo products 9a and 9b were

obtained as the major products in 37 and 34% yield, together

with the 6-exo products 10a and 10b (15 and 18% yield).

The structures of these isomeric pyrroloquinolines were

determined by proton NMR chemical shifts and comparison

with those for a previously synthesised pyrrolo[3,4-c]quino-

1

line, prepared by an unambiguous route. The H NMR

Scheme 4.

Table 1. Radical cyclisation reactions of compounds 4 and 5 (Scheme 4)

Radical

precursor

Substituents

9, yield (%)

10, yield (%)

11, yield (%)

4a

4c

5a

5b

5c

5d

R¹MeO, XBr, R²Me, R³H

R¹MeO, XBr, R²SEM, R³H

R¹MeO, XBr, R²Me, R³Boc

R¹CO₂Me, XI, R²Me, R³Boc

R¹MeO, XBr, R²SEM, R³CO₂Me

R¹MeO, XBr, R²SEM, R³Me

9a, 37

9b, 34

9c, 18

9d, 13

9e, 15

9f, 43

10a, 15

10b, 18

10c, 1

11c, 31

11d, 26

11e, 32

10d, 5

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C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

Scheme 5.

spectrum of 9a, 9b, 10a and 10b showed resonances for

only ®ve aromatic protons. In particular, the electronic

effect of the pyrrolic nitrogen in the shift of protons H-9

and H-3 in the cyclised derivatives was taken into account to

resolve the regioisomeric question. In compounds 9a and 9b

H-9 appears as a doublet at d_H7.57 and 7.70 and in 10a and

10b at d_H7.37 and 7.41 indicating a deshielding effect due to

the proximity of the pyrrolic nitrogen. In the same manner,

H-3 in 9a (d_H6.78) and 9b (d_H6.96) is shielded compared

to H-3 in compounds 10a (d_H7.23) and 10b (d_H7.35). No

products arising from 5-exo cyclisation were detected and in

both examples it is interesting to note that the major product,

the pyrrolo[3,2-c]quinoline skeleton, arises from the more

stable radical intermediate E (Scheme 5).

the major product, 11d (26% yield) showed the presence of

two rotamers in a ratio 1:1. The presence of two enaminic

protons H-4 (2d, d_H4.64 and 4.70) and H-3 (2d, d_H6.82 and

6.97) in the ¹H NMR and the methylene carbon (d_C54.7 and

55.3) and quaternary spiro-carbon (d_C57.0 and 58.2) in the

¹³C was observed. Together with the spiropyrrolidinyl

derivative, 11d, products arising from the 6-endo, 9d

(13%) and 6-exo 10d (5%) cyclisation were isolated. As

was observed before, an effect of the pyrrolic nitrogen in

the shift of H-9 (9d, d, d_H9.28 and 10d, d, d_H8.55) and H-3

(9d, d, d_H6.91 and 10d, d, d_H7.25) was observed in both

compounds.

It is noteworthy that when the radical cyclisation of 5b was

conducted using tris(trimethylsilylsilane) as a radical

mediator the reaction time increased from 1 to 4 h and

only the two products resulting from the 6-endo, 9d

and 6-exo, 10d cyclisation were isolated in low yield, 17

and 14%, respectively. The spiropyrrolidinyloxindole 11d

was not observed possibly due to the slower rate of hydro-

gen atom transfer from TTMSS providing tentative

evidence for the possibility of compounds 9 and 10 arising

by rearrangement of 11.

In contrast to this result, cyclisation of the N-t-Boc

derivative 5a gave a major product that proved to be the

spiropyrrolidinyl oxindole 11c in 31% yield, resulting from

5-exo cyclisation (via radical G).

The ¹H and ¹³C of 11c showed the presence of two rotamers

in a ratio 1:1. In the ¹H NMR of 11c two doublets at d_H4.73

and 4.80 (J3.8 Hz) and a doublet at d_H6.97 (J3.8 Hz)

were assigned as the enaminic protons H-4 and H-3, respec-

tively. In the ¹³C NMR methylene peaks appeared at d_C54.8

and 55.8 and the quaternary spiro-carbon at d_C57.6 and

58.7. The two other products showed resonances for ®ve

protons in the aromatic zone. Both products result from

the 6-endo and 6-exo cyclisation of the aryl radical gener-

ated upon the pyrrole ring. The major product 9c (18%

yield), contained the pyrrolo[3,2-c]quinoline skeleton.

Traces of 10c could be isolated. As before the difference

in the ¹H NMR signals due to H-9 (9c, d, d_H8.26 and 10c, d,

d_H7.20) and H-3 (9c, d, d_H6.85, and 10c, d, d_H7.98)

indicates the electronic effect of the pyrrolic nitrogen.

In order to investigate whether the regiochemistry of this

radical cyclisation arises from a steric effect of the bulky

N-t-Boc group, we decided to prepare and cyclise a

radical precursor in which the nitrogen was substituted

with a methoxycarbonyl group. Cyclisation of 5c under

the standard radical conditions furnished two products, the

spiropyrrolidinyloxindole 11e, 32% yield and the

pyrrolo[3,2-c]quinoline derivative 9e, 15% yield. As before,

1

the presence of enaminic protons in the H spectrum and

methylenic (d_C55.2 and 55.4) and quaternary spiro-carbon

signals in the ¹³C NMR (d_C57.0 and 58.2) indicates the

formation of the spiropyrrolidinyloxindole derivative.

Thus it appears as though an electronic affect is operating

and leading to the regioselectivity.

In a similar manner, cyclisation of 5b under the standard

conditions furnished a mixture of three products. As before,

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

1457

Finally, we examined the effect that an electron-donating

group, on the pyrrole nitrogen, can have on the radical

cyclisation reaction. Reaction of 5d with Bu₃SnH in the

standard conditions furnished 9f in 43% yield as the only

identi®ed compound, no products arising from the 5-exo or

6-exo cyclisation were detected. The structure of 9f was

con®rmed by an independent synthesis. Thus, methylation

of the already cyclised product 9b was carried out.

Deprotonation of 9b with potassium hydride followed by

reaction with MeI gave a product with identical analytical

characteristics to the one obtained from the radical

cyclisation of 5d.

abbreviations: ssinglet, ddoublet, ttriplet, qquartet,

brbroad and mmultiplet. Coupling constants were

reported in Hz. GC±MS was carried out on a HP5890 instru-

ment. High-resolution mass spectrometry was performed at

the Mass Spectrometry Centre, Chemistry Department,

King's College London. Microanalysis was performed at

University College London, Chemistry Department, Micro-

analytical Laboratory.

3.1.1. N-(2-Bromo-4-methoxyphenyl)acrylamide, 2a. To

a solution of 1a (14.3 g, 70.8 mmol) and N,N⁰-diisopropyl-

ethylamine (7.1 mL, 77.8 mmol) in ether (100 mL) at 08C,

acryloyl chloride (6.2 mL, 77.8 mmol) was slowly added.

The mixture was allowed to warm to room temperature and

stirring was continued for 4 h after which hydrochloric acid

(3 M, 50 mL) was added. The organic layer was washed

with water (3£50 mL) and dried. Chromatography (SiO₂,

hexane/EtOAc 1:1) gave 2a as a light purple solid (10.5 g,

93%), mp 116±1178C (EtOAc) [lit.²⁸120±1218C] (Found:

C, 47.03; H, 3.95; N, 5.45. C₁₀H₁₀BrNO₂requires C, 46.90;

H, 3.94; N, 5.47%); n_max(cm²¹) 3264 (w, N±H), 1659 (s,

amide CvO); d_H(300 MHz; CDCl₃) 3.67 (3H, s, OCH₃),

5.66 (1H, d, J10 Hz, C(O)CHvCHHtrans), 6.21 (1H, dd,

J16.9, 10 Hz, C(O)CHgemvCH₂), 6.36 (1H, dd, J16.9,

1.4 Hz, C(O)CHvCHHcis), 6.75 (1H, dd, J9.0, 2.6 Hz,

H-5⁰), 6.97 (1H, d, J2.6 Hz, H-3⁰), 7.60 (br s, 1H, NH),

8.07 (1H, d, J9 Hz, H-6⁰); d_C(CDCl₃) 55.6 (OCH₃), 113.7

(CH), 114.9 (C), 117.6 (CH), 123.7 (CH), 127.7 (CH₂),

128.8 (C), 131.1 (CH), 156.6 (C), 163.4 (amide CvO);

m/z 257/255 (11%, M¹), 201/199 (22), 176 (73, M¹2Br),

106 (17), 55 (100, C₃H₃O¹).

Interestingly, the NCH₂O protons in 4c, 5c and 5d appear as

two doublets (J10 Hz) owing to the chiral axis created by

the N±C_arylbond.

In conclusion, a series of radical precursors with the general

structure 4 and 5, have been prepared from p-substituted

acetanilides by formation of the pyrrolic nucleus using the

TosMIC reaction. Limitations in this reaction were found

when the benzene ring is substituted by an electron-

withdrawing group. On the other hand, benzimidazole

derivatives were obtained when the reductive cyclisation

of o-nitroacetanilide 3f was attempted. Finally, we have

shown that the regiochemistry of cyclisation of aryl radicals

onto pyrroles attached through an amide at the 3-position

(general structure A in Scheme 1) is governed by the nature

of the N-substituent on the pyrrole. Pyrroles substituted with

an electron-donating group (methyl) on nitrogen give

exclusively the pyrrolo[3,2-c]quinoline product arising

from 6-endo cyclisation. Pyrroles substituted on nitrogen

with an electron-withdrawing group (carbamate), give rise

to the spiropyrrolodinyloxindole as the major product via a

5-exo cyclisation. The regiochemistry is not affected by the

substituents on the benzene ring. According to these

observations, changing the substituent on the pyrrole will

allow controlled formation of either the spiropyrrolidinyl-

oxindole or pyrrolo[3,2-c]quinoline nucleus from a common

intermediate.

3.1.2. Methyl 3-iodo-4-acrylamidobenzoate, 2b. A solu-

tion of 1b (5 g, 18.0 mmol) and acryloyl chloride (2.1 mL,

27.0 mmol) in dichloromethane (50 mL) was heated for 3 h

under re¯ux. After cooling to room temperature, the mixture

was washed successively with saturated aqueous sodium

hydrogen carbonate (2£25 mL) and water (2£25 mL). The

organic layer was dried and evaporated under reduced pres-

sure. Recrystallisation (EtOAc/hexane 5:1) gave the title

compound, 2b as white crystals (3.6 g, 86%); n_max(cm²¹

)

3267 (m, N±H), 2948 (m, C±H), 1712 (s, ester CvO), 1664

(s, amide CvO); d_H(300 MHz; CDCl₃) 3.83 (3H, s, OCH₃),

5.80 (1H, dd, J10, 1 Hz, C(O)CHvCHHtrans), 6.24 (1H,

dd, J16.9, 10 Hz, C(O)CHgemvCH₂), 6.41 (1H, dd,

J16.9, 1 Hz, C(O)CHvCHHcis), 7.72 (1H, br s, NH),

7.94 (1H, dd, J8.6, 1.9 Hz, H-5⁰), 8.38 (1H, d,

J1.9 Hz, H-3⁰), 8.43 (1H, d, J8.6 Hz, H-6⁰); d_C

(CDCl₃) 52.3 (CH₃), 88.5 (C-2⁰), 120.2 (CH), 127.1 (C),

128.9 (CH₂), 130.8 (CH), 131.0 (CH), 140.2 (CH), 141.8

(C), 163.4 (amide CvO), 165.1 (ester CvO); m/z (EI) 331

(5%, M¹), 300 (2.5, M¹2CH₃O), 276 (7), 246 (20), 204

(90, M¹2I), 149 (5), 118 (8), 90 (13), 56 (100) (Found: M¹,

330.9707. C₁₁H₁₀INO₃requires M, 330.9698).

3. Experimental

3.1. General details

All reactions were carried out under argon and solutions

dried with magnesium sulphate. Where necessary, solvents

and reagents were dried and puri®ed according to recom-

mended procedures.²⁷Column chromatography was carried

out using the ¯ash chromatography technique. Thin layer

chromatography analysis was performed using silica gel 60

F-254 plates. Components were visualised by UV, iodine or

potassium permanganate. IR spectra were recorded on a

1

Perkin±Elmer Paragon 1000 Infrared spectrometer. H and

¹³C NMR spectra were recorded on a Bruker AM 300 spec-

trometer operating at 300 MHz for proton and 75 MHz for

carbon using CDCl₃as solvent and residual protic solvent

was used as internal reference, unless otherwise stated.

COSY and HETCOR experiments spectra were recorded

on a Bruker AM500. Chemical shifts (d_Hand d_C) values

are reported as parts per million (ppm). The multiplicity of

3.1.3. N-(2-Bromo-4-methoxyphenyl)-N-methylacryla-

mide, 3a. A solution of 2a (6.6 g, 25.8 mmol) in dry THF

(43 mL) was added to a stirred suspension of sodium

hydride (1.2 g of 60% dispersion in mineral oil,

30.7 mmol) in THF (70 mL). The mixture was stirred for

1 h after which methyl iodide (4.5 mL, 72.3 mmol)

was added and the solution stirred overnight. Water

(50 mL) was added to quench the reaction. The solvent

1

an H NMR signal is designated by one of the following

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C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

was evaporated in vacuo and the residue was dissolved in

ether (150 mL). The organic layer was washed with water

(3£50 mL), dried and evaporated under reduced pressure.

Chromatography (SiO₂, hexane/EtOAc 1:1) gave the title

compound, 3a as a light purple solid (5.1 g, 82%) mp

125±1268C (EtOAc); (Found: C, 48.86; H, 4.23; N, 5.08.

C₁₁H₁₂BrNO₂requires C, 48.91; H, 4.48; N, 5.19); n_max

(cm²¹) 2930 (s, C±H), 1661 (s, CvO); d_H(300 MHz;

CDCl₃) 3.08 (3H, s, NCH₃), 3.68 (3H, s, OCH₃), 5.34

(1H, dd, J10.3, 1.4 Hz, C(O)CHvCHHtrans), 5.75 (1H,

dd, J16.7, 10.3 Hz, C(O)CHgemvCH₂), 6.20 (1H, dd,

J16.7, 1.4 Hz, C(O)CHvCHHcis), 6.74 (1H, dd, J8.8,

2.8 Hz, H-5⁰), 7.02 (1H, d, J8.8 Hz, H-6⁰), 7.03 (1H, d,

J2.8 Hz, H-3⁰); d_C(CDCl₃) 36.1 (NCH₃), 55.7 (OCH₃),

114.5 (CH), 118.6 (CH), 123.8 (C), 127.7 (CH₂), 127.8

(CH), 130.3 (CH), 134.8 (C), 159.7 (C), 165.9 (CvO);

m/z 190 (100, M¹2Br), 175 (6.5), 120 (6).

C±H), 1678 (s, amide CvO), 1249 (s, Si±Me); d_H

(300 MHz; CDCl₃) 20.07 (9H, s, Si(CH₃)₃), 0.79±0.95

(2H, m, CH₂Si(CH₃)₃), 3.54±3.69 (m, 2H, OCH₂), 3.73

(3H, s, OCH₃), 4.48 (1H, s, J10.2 Hz, NCHHO), 5.48

(1H, dd, J10.3, 1.8 Hz, CHvCHtrans), 5.53 (1H, d,

J10.2 Hz, NCHHO), 5.83 (1H, dd, J16.6, 10.3 Hz,

CHgemvCH₂), 6.34 (1H, dd, J16.6, 1.8 Hz, CHvCHcis),

6.82 (1H, dd, J9, 2.9 Hz, H-5⁰), 7.10 (1H, d, J9 Hz,

H-6⁰), 7.11 (1H, d, J2.9 Hz, H-3⁰); d_C(CDCl₃) 21.5

(Si(CH₃)₃), 18.0 (CH₂Si), 55.5 (OCH₃), 66.2 (OCH₂), 76.3

(NCH₂), 114 (CH), 118.3 (CH), 124.0 (C), 127.7 (CH),

128.9 (CH₂), 131.7 (CH), 132.0 (C), 159.7 (C), 166.3

(amide CvO); m/z (EI) 387/385 (0.5%, M¹), 248 (100),

216 (25), 214 (29), 73 (45, SiMe₃¹), 55 (20) (Found:

M¹1Na, 408.0607. C₁₆H₂₅⁷⁹BrNO₃requires M1Na,

408.0587).

3.1.6. N-(2-Bromo-4-methoxyphenyl)-N-methyl-1H-3-

pyrrolecarboxamide, 4a.

3.1.4. Methyl 3-iodo-4-N-methylacrylamidobenzoate, 3b.

A solution of 2b (3.2 g, 9.6 mmol) in dry THF (16 mL) was

added to a stirred suspension of sodium hydride (460 mg of

60% dispersion in mineral oil, 11.6 mmol) in THF (26 mL).

The mixture was stirred for 1 h after which methyl iodide

(1.6 mL, 26.8 mmol) was added and the solution stirred

overnight. Water (10 mL) was added to quench the reaction.

The solvent was evaporated in vacuo and the residue was

dissolved in diethyl ether (100 mL). The organic layer was

washed with water (3£30 mL), dried and evaporated under

reduced pressure. Chromatography (SiO₂, hexane/EtOAc

4:1) gave the title compound, 3b as a white solid (2.6 g,

80%), mp 106±1078C (EtOAc) (Found: C, 42.19; H, 3.47;

N; 3.91. C₁₂H₁₂IO₃N requires C, 41.76; H, 3.50; N, 4.06%);

A

solution of 3a (3 g,

11.1 mmol) and TosMIC (2.2 g, 11.1 mmol) in THF

(42 mL) was added slowly to a stirred solution of potassium

tert-butoxide (2.5 g, 22.2 mmol) in THF (120 mL) at 08C.

Stirring was continued for 3 h after which water (10 mL)

was carefully added. The solvent was evaporated in vacuo

and the product was extracted with diethyl ether. The

organic layer was dried and evaporated under reduced

pressure. Chromatography (SiO₂, EtOAc) gave the title

compound, 4a as a white solid (2.06 g, 60%), mp 186±

1878C (hexane/EtOAc 1:2) (Found: C, 50.29; H, 4.22; N,

8.84. C₁₃H₁₃BrN₂O₂requires C, 50.50; H, 4.24; N, 9.06%);

n

_max(cm²¹) 3234 (w, N±H), 2996 (w, C±H), 1605 (s, amide

CvO); d_H(300 MHz; CDCl₃) 3.22 (3H, s, NCH₃), 3.75

(3H, s, OCH₃), 5.73 (1H, br s, H-4), 6.42 (1H, br s, H-5),

6.54 (1H, br s, H-2), 6.79 (1H, dd, J8.7, 2.8 Hz, H-5⁰),

7.10 (1H, d, J2.8 Hz, H-3⁰), 7.12 (1H, d, J8.7 Hz, H-6⁰),

8.80 (1H, br s, NH); d_C(CDCl₃) 37.2 (NCH₃), 55.7 (OCH₃),

110.0 (CH), 114.4 (CH), 117.6 (CH), 118.5 (CH), 119.1 (C),

122.6 (CH), 124.2 (C), 130.8 (CH), 136.8 (C), 159.4 (C),

165.4 (amide CvO); m/z 135 (1%), 120 (4), 107 (2.6), 94

(100), 77 (5), 66 (38).

n

_max(cm²¹) 2951 (w, C±H), 1724 (s, ester CvO), 1666 (s,

amide CvO), 1621 (s, CvC); d_H(300 MHz; CDCl₃) 3.19

(3H, s, NCH₃), 3.88 (3H, s, OCH₃), 5.46 (1H, dd, J10.3,

1.8 Hz, C(O)CHvCHHtrans), 5.72 (1H, dd, J16.6,

10.3 Hz, C(O)CHgemvCH₂), 6.34 (1H, dd, J16.6,

1.8 Hz, C(O)CHvCHHcis), 7.25 (1H, d, J8.1 Hz, H-6⁰),

8.02 (1H, dd, J8.1, 1.8 Hz, H-5⁰), 8.52 (1H, d, J1.8 Hz,

H-3⁰); d_C(CDCl₃) 35.5 (NCH₃), 52.2 (OCH₃), 99.1 (C-

2⁰), 127.3 (CH), 128.3 (CH₂), 128.9 (CH), 130.6 (CH),

131.0 (C), 140.8 (CH), 148.8 (C), 164.1 and 164.4 (amide

and ester CvO); m/z (EI) 346 (12%, M¹), 314 (13,

M¹2CH₃O), 291 (19, M¹2C₃H₃O), 260 (28), 218

(100, M¹2I), 133 (41), 105 (31), 90 (10), 69 (27), 56

(100) (Found: M¹, 344.9863. C₁₂H₁₂IO₃N requires M,

344.9856).

Note: if the addition of the TosMIC and amide is not done

slowly enough 12 is isolated: mp 93±948C (EtOAc) (Found:

C, 49.63; H, 4.35; N, 7.08. C₂₄H₂₅Br₂N₃O₄requires C,

49.76; H, 4.35; N, 7.25%); n_max(cm²¹) 3254 (w, N±H),

2930 (w, C±H), 1605 (w, amide CvO); d_H(400 MHz;

CDCl₃) 2.18 (2H, m, CH₂CO), 2.71 (2H, 2m, CH₂pyr),

3.20 (3H, s, N⁰CH₃), 3.34 (3H, s, N⁰⁰CH₃), 3.88 (3H, s,

OCH₃), 3.89 (3H, s, OCH₃), 5.73 (1H, 2 br s, H-4 rotamers),

6.23 (1H, 2 br s, H-2 rotamers), 6.91 (1H, m, ArH), 6.92

(1H, dd, J8.8, 2.8 Hz, H-5⁰), 7.10 (1H, dd, J8.8, 2.8 Hz,

H-5⁰⁰), 7.23 (3H, m, ArH), 9.31 (1H, br s, NH); d_C(CDCl₃)

HETCOR 22.2 (CH₂pyr), 34.0 (CH₂CO), 35.8 (N⁰CH₃),

36.9 (N⁰⁰CH₃), 55.5 (OCH₃), 107.0 (C-4), 114.1 and 114.1

(CH), 114.5 (CH), 118.0 (C), 118.2 and 118.2 (CH), 118.5

(CH), 121.2 (C-2), 123.2 (C), 123.9 (C), 129.7 (CH), 130.6

(CH), 131.2 (C), 134.5 (C), 136.6 (C), 159.2 (C), 159.5 (C),

165.6 (amide N⁰CvO), 173.2 (amide N⁰⁰CvO); m/z 217

(46%), 215 (47), 202 (98), 200 (100), 174 (12), 172

(12.5), 121 (1.7), 120 (2).

3.1.5.

N-(2-Bromo-4-methoxyphenyl)-N-(2-trimethyl-

silyl-ethoxymethyl)acrylamide, 3c. A solution of 2a

(3.7 g, 14.5 mmol) in THF (10 mL) was added carefully to

a suspension of potassium hydride (1.9 g, 14.5 mmol). The

mixture was stirred for 1 h after which 2-(trimethylsilyl)-

ethoxymethyl chloride (5 g, 28.9 mmol) was added and the

suspension was stirred overnight. Water (20 mL) was added

slowly to quench the reaction. The solvent was evaporated

in vacuo and the residue was dissolved in ethyl ether

(150 mL). The organic layer was washed with water

(2£50 mL), dried and evaporated under reduced pressure.

Chromatography (SiO₂, EtOAc/hexane 2:1) gave the title

compound, 3c as a brown oil (5.1 g, 92%) (Found: C,

49.63; H, 6.14; N, 3.61. C₁₆H₂₄BrNO₃Si requires C, 49.74;

H, 6.26; N, 3.63%); n_max(cm²¹) 2923 (s, N±H), 2854 (s,

3.1.7. N-(2-Bromo-4-methoxyphenyl)-N-(2-trimethylsilyl-

ethoxymethyl)-1H-3-pyrrolecarboxamide, 4c. A solution

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

1459

of 3c (4 g, 10.3 mmol) and TosMIC (2.0 g, 10.3 mmol) in

THF (40 mL) was added slowly to a stirred solution of

potassium tert-butoxide (2.3 g, 20.6 mmol) in THF

(115 mL) at 08C. Stirring was continued for 1 h after

which water (50 mL) was carefully added. The solvent

was evaporated in vacuo and the product was extracted

with ethyl acetate (3£150 mL). The organic layer was

dried and evaporated under reduced pressure. Chromato-

graphy (SiO₂, hexane/EtOAc 4:3) gave the title compound,

4c as a pale solid (2.5 g, 57%), mp 111.5±111.88C (EtOAc)

(Found: C, 50.99; H, 5.83; N, 6.48. C₁₈H₂₅BrN₂O₃Si

requires C, 50.82; H, 5.92; N, 6.59%); n_max(cm²¹) 3264

(w, N±H), 2952 (w, C±H), 1614 (s, amide CvO), 1249 (m,

Si±Me); d_H(300 MHz; CDCl₃) 20.07 (9H, s, Si(CH₃)₃),

0.93 and 0.97 (2H, 2dd, J6.8, 4.3 Hz, CH₂Si(CH₃)₃),

3.75 (m, 2H, OCH₂), 3.83 (3H, s, OCH₃), 4.59 (1H, d,

J10 Hz, NCHHO), 5.76 (1H, d, J10 Hz, NCHHO),

5.82 (1H, s, H-4), 6.48 (1H, s, H-5), 6.57 (1H, s, H-2),

6.89 (1H, dd, J8.7, 2.8 Hz, H-5⁰), 7.18 (1H, d, J

2.8 Hz, H-3⁰), 7.24 (1H, d, J8.7 Hz, H-6⁰), 9.08 (1H, br

s, NH); d_C(CDCl₃) 21.4 (Si(CH₃)₃), 18.2 (CH₂Si), 55.7

(OCH₃), 66.3 (OCH₂), 77.3 (NCH₂), 109.9 (CH), 114.1

(CH), 118.1 (CH), 118.5 (CH), 123.6 (CH), 124.5 (C),

The second eluate gave a mixture of the tert-butyl ester 4e

(12 mg, 19%) and the methyl ester 4b (5 mg, 9%).

Compound 4e: d_H(300 MHz; CDCl₃) 1.56 (9H, s, C(CH₃)₃),

3.27 (3H, s, NCH₃), 5.73 (1H, br s, H-4), 6.45 (1H, br s,

H-5), 6.61 (1H, br s, H-2), 7.28 (1H, d, J8.1 Hz, H-6⁰),

7.93 (1H, dd, J8.1, 1.9 Hz, H-5⁰), 8.45 (1H, d, J1.9 Hz,

H-3⁰), 8.99 (1H, br s, NH); d_C(CDCl₃) 28.8 (C(CH₃)₃), 37.1

(NCH₃), 82.1 (C(CH₃)₃), 99.4 (C-2⁰), 109.8 (CH), 117.8

(CH), 122.9 (CH), 129.4 (C), 130.6 (2£CH), 132.6 (C),

141.0 (CH), 150.9 (C), 163.5 (amide CvO), 164.9 (ester

CvO).

3.1.10. N-(4-Methoxy-2-nitrophenyl)acrylamide, 2c. A

solution of 1c (3 g, 17.8 mmol) and acryloyl chloride

(2.2 mL, 26.7 mmol) in dichloromethane (75 mL) was

heated for 3 h under re¯ux. After cooling to room tempera-

ture, the mixture was washed successively with saturated

aqueous sodium hydrogen carbonate (3£25 mL) and water

(2£25 mL). The organic layer was dried and evaporated

under reduced pressure. Chromatography (ethyl acetate/

hexane 1:1) gave the title compound 2c, as orange crystals

(3.6 g, 92%), mp 125±1278C (EtOAc) (Found: C, 54.25; H,

4.76; N, 12.32. C₁₀H₁₀N₂O₄requires C, 54.05; H, 4.54; N,

12.61%); n_max(cm²¹) 3344 (w, N±H), 2947 (m, C±H),

1691 (s, amide CvO), 1516 (s, C±NO₂); d_H(300 MHz;

CDCl₃) 3.98 (3H, s, OCH₃), 5.75 (1H, dd, J10, 1.3 Hz,

C(O)CHvCHHtrans), 6.23 (1H, dd, J16.9, 10 Hz,

C(O)CHgemvCH₂), 6.35 (1H, dd, J16.9, 1.3 Hz,

C(O)CHvCHHcis), 7.15 (1H, dd, J9.2, 3 Hz, H-5⁰),

7.58 (1H, d, J3 Hz, H-3⁰), 8.66 (1H, d, J9.2 Hz, H-6⁰),

10.25 (br s, 1H, NH); d_C(CDCl₃) 55.9 (OCH₃), 108.6 (CH),

123.4 (CH), 123.7 (CH), 128.5 (CH₂), 131.6 (CH),

137.0 (C), 155.0 (C), 163.8 (CvO); m/z (EI) 222

(68.3%, M¹), 168 (100), 153 (24.3), 122 (27.6), 106

(10.6), 56 (100) (Found: M¹, 222.0640. C₁₀H₁₀N₂O₄

requires M, 222.0640).

132.4 (CH), 134.1 (C), 159.7 (C-4⁰), 166.3 (amide CvO);

1

m/z (EI) 215 (7), 200 (6), 124 (9), 94 (100), 73 (51, SiMe₃

)

(Found: M¹1Na, 447.0716. C₁₈H₂₅⁷⁹BrN₂O₃Si requires

M1Na, 447.0703).

3.1.8. Methyl 3-iodo-4-(N-methyl-1H-3-pyrrolecarba-

moyl) benzoate, 4b. A solution of 3b (1.9 g, 5.7 mmol)

and TosMIC (1.2 g, 6.0 mmol) in THF (6 mL) was added

slowly to a stirred solution of sodium hydride (289 mg of

60% dispersion in mineral oil, 7.2 mmol) and 1,1,1,3,3,3-

hexamethyldisilazane (1.2 mL, 5.8 mmol) in THF (3 mL).

After 3 h the reaction mixture was evaporated in vacuo and

the residue was dissolved in ethyl acetate (150 mL) and

washed with saturated aqueous ammonium chloride

(2£50 mL). The organic layer was dried and evaporated

under reduced pressure. Chromatography (SiO₂, EtOAc)

gave the title compound, 4b as a white solid (562 mg,

26%) mp 98±998C (hexane/EtOAc 1:4) (Found: C, 44.33;

H, 3.53; N, 7.03. C₁₄H₁₃IN₂O₃requires C, 43.77; H, 3.41; N,

7.29%); n_max(cm²¹) 3253 (m, N±H), 2951 (m, C±H), 1728

(s, ester and amide CvO); d_H(300 MHz; CDCl₃) 3.34 (3H,

s, NCH₃), 3.97 (3H, s, OCH₃), 5.70 (1H, br s, H-4), 6.48

(1H, br s, H-5), 6.69 (1H, br s, H-2), 7.37 (1H, d, J8.1 Hz,

H-6⁰), 8.05 (1H, dd, J8.1, 1.8 Hz, H-5⁰), 8.59 (1H, s, H-3⁰),

9.75 (1H, br s, NH); d_C(CDCl₃) 37.1 (NCH₃), 52.5 (OCH₃),

99.4 (C-2⁰), 109.3 (CH), 118.1 (CH), 123.1 (CH), 129.5 (C),

130.7 (2£CH), 141.1 (CH), 151.2 (C), 164.8 (amide CvO),

165.6 (ester CvO); m/z 291 (64%), 257 (100, M¹2I), 94

(93) (Found: M¹1H, 385.0049. C₁₄H₁₃IN₂O₃requires

M1H, 385.0058).

3.1.11.

N-(4-Methoxy-2-nitrophenyl)-N-methylacryl-

amide, 3f. A solution of 2c (1 g, 4.5 mmol) in dry THF

(12 mL) was added to a stirred suspension of sodium

hydride (216 mg of 60% dispersion in mineral oil,

5.4 mmol) in THF (8 mL). The mixture was stirred for 1 h

after which methyl iodide (0.8 mL, 12.6 mmol) was added

and the solution stirred overnight. Water (10 mL) was added

to quench the reaction. The solvent was evaporated in vacuo

and the residue was dissolved in ether (60 mL). The organic

layer was washed with water (3£20 mL), dried and evapo-

rated under reduced pressure. Chromatography (SiO₂,

hexane/ethyl acetate 3:1) gave the title compound 3f, as a

orange solid (914 mg, 86%), mp 125±1268C (Et₂O) (Found:

C, 55.67; H, 5.22; N, 11.78. C₁₁H₁₂N₂O₄requires C, 55.93;

H, 5.12; N, 11.86%); n_max(cm²¹) 2995 (w, C±H), 1665 (s,

amide CvO), 1535 (s, C±NO₂); d_H(300 MHz; CDCl₃) 3.25

(3H, s, NCH₃), 3.89 (3H, s, OCH₃), 5.48 (1H, dd, J10.3,

1.6 Hz, C(O)CHvCHHtrans), 5.85 (1H, dd, J16.7,

10.3 Hz, C(O)CHgemvCH₂), 6.31 (1H, dd, J16.7,

1.6 Hz, C(O)CHvCHHcis), 7.17 (1H, dd, J8.7, 2.8 Hz,

H-5⁰), 7.27 (1H, d, J8.7 Hz, H-6⁰), 7.48 (1H, d, J2.8 Hz,

H-3⁰); d_C(CDCl₃) 38.7 (NCH₃), 55.8 (OCH₃), 109.8 (CH),

119.8 (CH), 126.8 (CH), 128.1 (CH₂), 128.7 (C), 131.7

(CH), 146.8 (C), 159.3 (C), 165.3 (CvO); m/z (EI)

237 (10%, M¹1H), 236 (14.2, M¹), 190 (100,

3.1.9. tert-Butyl 3-iodo-4-(N-methyl-1H-3-pyrrolecarba-

moyl) benzoate, 4e. A solution of 3b (50 mg, 0.14 mmol)

and TosMIC (27 mg, 0.14 mmol) in THF (3 mL) was added

slowly to a stirred solution of potassium tert-butoxide

(31 mg, 0.28 mmol) in THF (1 mL). After 30 min water

(5 mL) was added and the suspension was extracted with

ether (3£10 mL). The organic layer was dried and evapo-

rated under reduced pressure. Chromatography (SiO₂,

EtOAc) gave as ®rst eluate starting material (5 mg, 10%).

1460

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

M¹2NO₂), 182 (81), 175 (31), 149 (28), 121 (70), 92 (39),

77 (53) (Found: M¹, 236.0797. C₁₁H₁₂N₂O₄requires M,

236.0794).

J17.1, 1.5 Hz, CHvCHcis), 6.69 (1H, dd, J17.1,

11.0 Hz, CHgemvCH₂), 6.83 (1H, dd, J8.8, 2.3 Hz,

H-6), 7.09 (1H, d, J8.8 Hz, H-7), 7.15 (1H, d, J2.3 Hz,

H-4); d_C(CDCl₃) 29.8 (NCH₃), 55.7 (OCH₃), 101.4 (CH),

109.6 (CH), 112.9 (CH), 122.5 (CH₂), 122.8 (CH), 130.5

(C), 143.5 (C), 150.7 (C), 156.4 (C); m/z 188 (100, M¹), 173

(72), 145 (15) (Found: M¹, 188.0949. C₁₁H₁₂N₂O requires

M, 188.0950).

3.1.12.

pyrrole-carboxamide, 4f.

(4-Methoxy-2-nitrophenyl)-N-methyl-1H-3-

solution of 3f (1.3 g,

A

5.5 mmol) and TosMIC (1.07 g, 5.5 mmol) in THF

(20 mL) was added slowly to a stirred solution of potassium

tert-butoxide (1.23 g, 11 mmol) in THF (27 mL) at 08C.

Stirring was continued for 1 h after which water (15 mL)

was carefully added. The solvent was evaporated in vacuo

and the product was extracted with ethyl acetate (2£50 mL).

The organic layer was dried and evaporated under reduced

pressure. Chromatography (SiO₂, hexane/ethyl acetate 1:4)

gave the title compound 4f, as a pale oil (305 mg, 20%);

n_max(cm²¹) 1666 (s, amide CvO), 1537 (s, C±NO₂); d_H

(300 MHz; CDCl₃) 3.32 (3H, br s, NCH₃), 3.83 (3H, s,

OCH₃), 5.60 (1H, br s, H-4), 6.43 (1H, br s, H-5), 6.71

(1H, br s, H-2), 7.09 (1H, dd, J8.8, 2.9 Hz, H-5⁰), 7.26

(1H, dd, J8.8 Hz, H-6⁰), 7.35 (1H, d, J2.8 Hz, H-3⁰),

8.22 (1H, br s, NH); d_C(CD₃OD) 38.6 (NCH₃), 56.8

(OCH₃), 110.2 (CH), 111.4 (CH), 118.3 (C), 119.1

(CH), 121.2 (CH), 124.0 (CH), 132.1 (C), 133.3 (CH),

148.7 (C), 161.0 (C), 168.5 (CvO); m/z (EI) 229 (27%,

M¹2NO₂), 182 (90), 167 (5), 136 (4), 121 (10), 94

(100) (Found: M¹, 275.0906. C₁₃H₁₃N₃O₄requires M,

275.0907).

3.1.15. N-(2-Amino-4-methoxyphenyl)-N-methylpropio-

namide, 8. Sodium borohydride (118 mg, 3.12 mmol) was

added to a stirred solution of copper(II)acetylacetonate

(54.2 mg, 0.20 mmol) in ethanol (18 mL) to give a brown

suspension. Stirring was continued until a dark solid pre-

cipitated and the opaque solution turned clear. Compound 3f

(236 mg, 1 mmol) was then added very slowly as a solution

in ethanol (1 mL). After being stirring for 5 h the reaction

mixture was poured into water (5 mL), ®ltered and concen-

trated to low volume under reduced pressure. The aqueous

phase was extracted with dichloromethane (3£10 mL) and

the combined extracts were dried. Chromatography (SiO₂,

hexane/ethyl acetate 1:1) gave the title compound 8, as a

light brown solid (125 mg, 60%) mp 145±1468C (EtOAc)

(Found: C, 63.60; H, 7.64; N, 13.11. C₁₁H₁₆N₂O₂requires C,

63.44; H, 7.74; N, 13.45%); n_max(cm²¹) 3400 (d, N±H),

2937 (C±H), 1631 (s, amide CvO); d_H(300 MHz; CDCl₃)

0.98 (3H, t, J7 Hz, CH₂CH₃), 2.02 (2H, m, CH₂CH₃), 3.07

(3H, s, NCH₃), 3.68 (3H, s, OCH₃), 3.86 (2H, s, NH₂), 6.21

(2H, dd, J8.4, 2.7 Hz, H-5⁰), 6.25 (1H, d, J2.7 Hz, H-3⁰),

6.80 (1H, d, J8.4 Hz, H-6⁰); d_C(CDCl₃) 9.5 (CH₃), 26.7

(CH₂), 35.4 (NCH₃), 55.2 (OCH₃), 101.0 (CH), 104.3 (CH),

122.5 (C), 129.0 (CH), 143.7 (C), 160.1 (C), 175.6 (CvO);

m/z (EI) 190 (100%, M¹2H₂O), 175 (75), 147 (15)

(Found: M¹1H, 209.1296. C₁₁H₁₆N₂O₂requires M1H,

209.1290).

3.1.13. 2-Ethyl-5-methoxy-1-methyl-1H-benzimidazole,

6. A mixture of 3f (200 mg, 0.84 mmol), 10% palladium

on carbon (ca. 10 mg), triethylamine (1 mL, 7.28 mmol)

was heated under re¯ux. While stirring, formic acid

(0.26 mL, 7.05 mmol) was added dropwise. The mixture

was heated under re¯ux for 6 h. The reaction mixture was

®ltered through Celite and the solid was washed with ether

(2£20 mL). The organic phase was washed with saturated

aqueous sodium bicarbonate (2£10 mL), dried and evapo-

rated in vacuo. Chromatography (SiO₂, ethyl acetate/metha-

nol 19:1) gave the title compound 6, as yellow solid

(129 mg, 80%); n_max(cm²¹) 2939 (w, C±H), 1491, 1155;

d_H(300 MHz; CDCl₃) 1.35 (3H, t, J7.5 Hz, CH₂CH₃),

2.79 (2H, q, J7.5 Hz, CH₂CH₃), 3.59 (3H, s, NCH₃),

3.76 (3H, s, OCH₃), 6.79 (1H, dd, J8.7, 2.4 Hz, H-6),

7.06 (1H, d, J8.7 Hz, H-7), 7.14 (1H, d, J2.4 Hz, H-4);

d_C(CDCl₃) 11.7 (CH₃), 20.8 (CH₂), 29.6 (NCH₃), 55.8

(OCH₃), 101.6 (CH), 109.1 (CH), 111.6 (CH), 130.4 (C),

143.0 (C), 155.9 (C), 156.4 (C); m/z (EI) 190 (100%, M¹),

189 (66), 145 (75), 161 (13) (Found: M¹, 190.1106.

C₁₁H₁₄N₂O requires M, 190.1104).

3.1.16. tert-Butyl 3-[N-(2-bromo-4-methoxyphenyl)-N-

methyl-carbamoyl]-1H-1-pyrrolecarboxylate, 5a. Amide

4a (2.1 g, 6.79 mmol) was dissolved in THF (280 mL) and

cooled to 2788C. Triethylamine (2.2 g, 1.4 mL, 10.2 mmol)

was added followed by addition of di-tert-butyl dicarbonate

(2.2 g, 10.2 mmol) and a catalytic amount of DMAP. The

reaction mixture was stirred overnight, while it was allowed

to warm to room temperature. The solvent was removed in

vacuo, the residue was dissolved in ethyl acetate (150 mL)

and washed with water (3£50 mL). The organic layer was

dried and evaporated under reduced pressure. Chromato-

graphy (SiO₂, EtOAc) gave the title compound, 5a as a

colourless oil (2.5 g, 90%) (Found: C, 52.76; H, 5.32; N,

6.49. C₁₈H₂₁BrN₂O₄requires C, 52.82; H, 5.17; N, 6.84%);

n_max(cm²¹) 2925 (w, C±H), 1748 (s, carbamate CvO),

1636 (s, amide CvO); d_H(300 MHz; CDCl₃) 1.40 (9H, s,

C(CH₃)₃), 3.19 (3H, s, NCH₃), 3.70 (3H, s, OCH₃), 5.82 (1H,

br s, H-4), 6.76 (1H, br s, H-5), 6.79 (1H, dd, J8.7, 2.7 Hz,

H-5⁰), 6.85 (1H, br s, H-2), 7.08 (1H, d, J2.7 Hz, H-3⁰),

7.09 (1H, d, J8.7 Hz, H-6⁰); d_C(CDCl₃) 27.0 (C(CH₃)),

36.7 (NCH₃), 55.3 (OCH₃), 83.9 (C(CH₃)₃), 112.3 (CH),

114.1 (CH), 118.2 (CH), 118.8 (CH), 121.8 (C), 122.9

(CH), 123.7 (C), 130.3 (CH), 135.6 (C), 147.6 (carbamate

CvO), 159.4 (C), 164.1 (amide CvO); m/z (EI) 310/308

(1%), 229 (86), 215 (59), 200 (38), 120 (14), 94 (100)

(Found: M¹1H, 409.0763. C₁₈H₂₁N₂O₄⁷⁹Br requires

M1H, 409.0758).

3.1.14. 5-Methoxy-1-methyl-2-vinyl-1H-benzimidazole,²⁹

7. To a solution of 3f (200 mg, 0.84 mmol) in ethanol

(4 mL), concentrated hydrochloric acid (0.9 mL) and

SnCl₂´H₂O (758 mg, 3.36 mmol) was added. The suspen-

sion was heated under re¯ux for 4 h. The reaction mixture

was basi®ed with NaOH (2 M) and extracted with ethyl

acetate (2£20 mL). The organic phase was washed with

water (2£15 mL), dried and evaporated under reduced pres-

sure. Chromatography (SiO₂, hexane/ethyl acetate 2:1) gave

the title compound 7, as a colourless oil (115 mg, 70%);

n_max(cm²¹) 2925 (w, C±H), 1490, 1158; d_H(300 MHz;

CDCl₃) 3.67 (3H, s, NCH₃), 3.77 (3H, s, OCH₃), 5.57

(1H, dd, J11.0, 1.5 Hz, CHvCHtrans), 6.42 (1H, dd,

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

1461

3.1.17. tert-Butyl 3-[N-(2-iodo-4-methoxycarbonyl-

phenyl)-N-methylcarbamoyl]-1H-1-pyrrolecarboxylate,

5b. Amide 4b (345 mg, 0.9 mmol) was dissolved in THF

(48 mL) and cooled to 2788C. Triethylamine (0.2 mL,

1.3 mmol) was added followed by di-tert-butyl dicarbonate

(290 mg, 1.3 mmol) and a catalytic amount of DMAP. The

reaction mixture was stirred overnight, while it was allowed

to warm to room temperature. The solvent was removed in

vacuo and the residue was dissolved in ethyl acetate

(50 mL), washed with water (3£25 mL). The organic layer

was dried and evaporated under reduced pressure. Chroma-

tography (SiO₂, EtOAc) gave the title compound, 5b as a

pale brown oil (361 mg, 83%); n_max(cm²¹) 2955 (w, C±H),

1750 (s, carbamate CvO), 1728 (s, amide CvO); d_H

(300 MHz; CDCl₃) 1.41 (9H, s, C(CH₃)₃), 3.23 (3H, s,

NCH₃), 3.83 (3H, s, OCH₃), 5.73 (1H, br s, H-4), 6.85

(2H, br s, H-5 and H-2), 7.28 (1H, d, J8.1 Hz, H-6⁰),

7.95 (1H, dd, J8.1, 1.7 Hz, H-5⁰), 8.48 (1H, d, J

1.7 Hz, H-3⁰); d_C(CDCl₃) 27.4 (C(CH₃)₃), 36.8 (NCH₃),

52.3 (OCH₃), 84.2 (C(CH₃)₃), 99.2 (C-2⁰), 112.1 (CH),

119.1 (CH), 121.6 (C), 123.3 (CH), 129.3 (CH), 130.6

(CH), 130.8 (C), 140.9 (CH), 147.5 (C), 150.4 (carbamate

CvO), 164.6 (CvO), 164.2 (CvO); m/z (EI) 291 (66%),

257 (98), 94 (100) (Found: M¹1H, 485.0573. C₁₉H₂₁IN₂O₅

requires M1H, 485.0584).

hydride (85 mg of 60% dispersion in mineral oil,

2.1 mmol) in THF (28 mL). The mixture was stirred for

1 h after which methyl iodide (0.24 mL, 3.9 mmol) was

added and the solution stirred overnight. Water (10 mL)

was added to quench the reaction. The solvent was evapo-

rated in vacuo and the residue was dissolved in ethyl acetate

(50 mL). The organic layer was washed with water

(3£20 mL), dried and evaporated under reduced pressure.

Chromatography (SiO₂, hexane/EtOAc 5:6) gave the title

compound, 5d as a yellow oil (446 mg, 72%) (Found: C,

51.68; H, 6.21; N, 5.76. C₁₉H₂₇BrN₂O₃Si requires C, 51.93;

H, 6.19; N, 6.38%); n_max(cm²¹) 2940 (s, C±H), 1636 (s,

amide CO), 1261 (s, SiMe); d_H(300 MHz; CDCl₃) 0.0 (9H,

s, Si(CH₃)₃), 0.94 (2H, m, CH₂Si(CH₃)₃), 3.50 (3H, s,

NCH₃), 3.71 (3H, s, OCH₂), 3.82 (3H, s, OCH₃), 4.56

(1H, d, J10 Hz, NCHHO), 5.63 (1H, br s, H-4), 5.76

(1H, d, J10 Hz, NCHHO), 6.30 (1H, br s, H-5), 6.55

(1H, br s, H-2), 6.89 (1H, dd, J8.7, 2.8 Hz, H-5⁰), 7.18

(1H, d, J2.8 Hz, H-3⁰), 7.23 (1H, d, J8.7 Hz, H-6⁰); d_C

(CDCl₃) 21.1 (Si(CH₃)₃), 18.2 (CH₂Si), 36.3 (NCH₃), 55.7

(OCH₃), 66.0 (OCH₂), 77.3 (NCH₂), 110.4 (CH), 114.0

(CH), 118.3 (CH), 118.5 (C), 121.5 (CH), 124.6 (CH),

127.0 (CH), 132.4 (C), 134.1 (C), 159.7 (C), 166.3 (amide

CvO); m/z (EI) 359 (12%, M¹2Br), 301 (4), 213 (15), 138

(4), 119 (1), 108 (100), 73 (23, SiMe₃¹) (Found: M¹1Na,

461.0872. C₁₉H₂₇⁷⁹BrN₂O₃Si requires M1Na, 461.0851).

3.1.18. Methyl 3-[N-(2-bromo-4-methoxyphenyl)-N-(2-

trimethylsilylethoxymethyl)carbamoyl-1H-1-pyrrole-

carboxylate, 5c. A solution of 4c (230 mg, 0.54 mmol) in

THF (8 mL) was added dropwise to a suspension of

potassium hydride (93 mg of 35% dispersion in mineral

oil, 0.81 mmol) at 08C. The mixture was stirred for 1 h

after which methyl chloroformate (0.08 mL, 0.65 mmol)

was added and the suspension stirred overnight. Water

(2 mL) was added to quench the reaction. The solvent was

evaporated in vacuo and the residue was dissolved in ethyl

acetate (10 mL). The organic layer was washed with water

(3£10 mL), dried and evaporated under reduced pressure.

Chromatography (SiO₂, hexane/ethyl acetate 1:1) gave the

title compound, 5c as a yellow solid (209 mg, 80%), mp

78±818C (EtOAc) (Found: C, 49.31; H, 5.39; N, 5.68.

C₂₀H₂₇BrN₂O₅Si requires C, 49.69; H, 5.63; N, 5.79%);

n_max(cm²¹) 2954 (w, C±H), 1760 (s, carbamate CvO),

1651 (s, amide CvO), 1279 (s, Si±Me); d_H(300 MHz;

CDCl₃) 0.00 (9H, s, Si(CH₃)₃), 0.95 (2H, m, CH₂Si(CH₃)₃),

3.71 (2H, m, CH₂O), 3.81 (3H, s, OCH₃), 3.89 (3H, s,

COOCH₃), 4.59 (1H, d, J10 Hz, NCHHO), 5.72 (1H, d,

J10 Hz, NCHHO), 5.92 (1H, br s, H-4), 6.89 (1H, dd,

J8.7, 2.8 Hz, H-5⁰), 6.98 (1H, br s, H-5), 7.02 (1H, br s,

H-2), 7.16 (1H, d, J2.8 Hz, H-3), 7.23 (1H, d, J8.7 Hz

H-6⁰); d_C(CDCl₃) 21.27 (Si(CH₃)₃), 18.1 (CH₂Si), 54.3

(COOCH₃), 55.7 (OCH₃), 66.3 (OCH₂), 77.1 (NCH₂),

113.1 (CH), 114.0 (CH), 118.4 (CH), 119.4 (CH), 122.4

(C), 123.8 (CH), 124.3 (C), 132.0 (CH), 133.3 (C), 150.1

3.1.20. 8-Methoxy-5-methyl-4,5-dihydro-2H-pyrrolo[3,4-

c]-quinolin-4-one, 10a and 8-methoxy-5-methyl-4,5-

dihydro-1H-pyrrolo[3,2-c]quinolin-4-one, 9a. A suspen-

sion of 4a (150 mg, 0.5 mmol) and a sub-stoichiometric

amount of AIBN in toluene (32 mL) was heated under

re¯ux. Then, tri-n-butyltin hydride (0.1 mL, 0.5 mmol)

was added dropwise and the reaction mixture was stirred

at this temperature for 1 h. After evaporation of the solvent

the residue was chromatographed (SiO₂, EtOAc). The ®rst

eluate gave 10a as a yellow oil (30 mg, 15%); n_max(cm²¹

)

3156 (w, N±H), 2926 (m, C±H), 1620 (s, tertiary amide

CvO); d_H(300 MHz; CDCl₃) 3.82 (3H, s, NCH₃), 3.90

(3H, s, OCH₃), 6.76 (1H, t, J2.7 Hz, H-1), 7.03 (1H, dd,

J9.2, 2.8 Hz, H-7), 7.30 (1H, t, J2.7 Hz, H-3), 7.36 (1H,

d, J9.2 Hz, H-6), 7.38 (1H, d, J2.8 Hz, H-9); d_H

(300 MHz; CD₃OD) 3.68 (3H, s, NCH₃), 3.79 (3H, s,

OCH₃), 6.76 (1H, d, J2.8 Hz, H-1), 6.99 (1H, dd, J9.2,

2.9 Hz, H-7), 7.23 (1H, d, J2.8 Hz, H-3), 7.37 (1H, d,

J2.9 Hz, H-9), 7.38 (1H, d, J9.2 Hz, H-6); d_C(CDCl₃)

29.3 (NCH₃), 55.7 (OCH₃), 102.2 (CH), 106.5 (CH), 114.5

(CH), 116.4 (CH), 119.7 (C), 122.9 (C), 126.0 (CH), 126.6

(C), 130.9 (C), 155.0 (C); m/z (EI) 228 (23.7%, M¹), 213

(9.1, M¹2CH₃), 185 (12.2) (Found: M¹, 228.0898.

C₁₃H₁₂N₂O₂requires M, 228.0905). The second eluate

gave 9a as a colourless oil (75 mg, 37%); n_max(cm²¹

)

3117 (w, N±H), 2910 (w, C±H), 1614 (s, amide CvO);

d_H(300 MHz; CD₃OD) 3.77 (3H, s, NCH₃), 3.90 (3H, s,

OCH₃), 6.78 (1H, d, J3.0 Hz, H-3), 7.12 (1H, dd, J9.2,

2.8 Hz, H-7), 7.16 (1H, d, J3.0 Hz, H-2), 7.53 (1H, dd,

J9.2 Hz, H-6), 7.57 (1H, d, J2.8 Hz, H-9). d_C(CD₃OD)

29.9 (NCH₃), 56.1 (OCH₃), 104.6 (CH), 106.6 (CH), 115.6

(C), 116.5 (C), 117.0 (CH), 118.3 (CH), 123.8 (CH), 132.6

(C), 135.7 (C), 156.8 (C), 161.9 (amide CvO); m/z (EI) 228

(1%, M¹), 213 (100, M¹2CH₃), 197 (4.5, M¹2OCH₃), 167

(60) (Found: M¹1H, 229.0977. C₁₃H₁₂N₂O₂requires

M1H, 229.0986).

(carbamate CvO), 159.9 (C), 164.7 (amide CvO); m/z (EI)

425/423 (3%), 345 (6), 257 (6), 152 (84), 73 (100, SiMe₃

1

)

(Found: M¹, 482.0873. C₂₀H₂₇⁷⁹BrN₂O₅Si requires M,

482.0875).

3.1.19. 1-Methyl N-(2-bromo-4-methoxyphenyl)-N-(2-

trimethylsilylethoxymethyl)-1H-3-pyrrolecarboxamide,

5d. A solution of 4c (600 mg, 1.41 mmol) in dry THF

(18 mL) was added to a stirred suspension of sodium

1462

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

3.1.21. 8-Methoxy-5-(2-trimethylsilylethoxymethyl)-4,5-

dihydro-2H-pyrrolo[4,3-c]quinolin-4-one, 10b and 8-

methoxy-5-(2-trimethylsilylethoxymethyl)-4,5-dihydro-

1H-pyrrolo[3,2-c]quinolin-4-one, 9b. A suspension of 4c

(410 mg, 0.96 mmol) and a sub-stoichiometric amount of

AIBN in toluene (50 mL) was heated under re¯ux. Then,

tri-n-butyltin hydride (0.2 mL, 1.0 mmol) was added drop-

wise and the reaction mixture was stirred at this temperature

for 1 h. After evaporation of the solvent the residue was

chromatographed (SiO₂, hexane/EtOAc 2:3) The ®rst eluate

gave 10b as a yellow solid (60 mg, 18%); n_max(cm²¹) 3117

(w, N±H), 2910 (w, C±H), 1614 (s, amide CvO), 1228 (w,

SiMe); d_H(300 MHz; CDCl₃) 20.07 (9H, s, Si(CH₃)₃), 1.00

(2H, t, J8 Hz, CH₂Si(CH₃)₃), 3.77 (2H, t, J8 Hz, OCH₂),

3.96 (3H, s, OCH₃), 5.93 (2H, br s, NCH₂O), 6.84 (1H, t,

J2.5 Hz, H-1), 7.09 (1H, dd, J9.2, 2.7 Hz, H-7), 7.35

(1H, t, J2.5 Hz, H-3), 7.41 (1H, d, J2.7 Hz, H-9), 7.67

(1H, d, J9.2 Hz, H-6), 10.4 (1H, br s, NH); d_C(CDCl₃)

21.3 (Si(CH₃)₃), 18.1 (CH₂Si(CH₃)₃), 55.6 (OCH₃), 66.0

(NCH₂), 71.3 (NCH₂O), 102.6 (CH), 106.3 (CH), 114.7

(CH), 117.8 (CH), 119.7 (C), 122.2 (C), 126.4 (CH),

127.5 (C), 130.1 (C), 155.3 (C), 155.8 (CvO); m/z (EI)

344 (15%, M¹), 271 (100, M¹2SiMe₃), 228 (62), 197

(25), 73 (35, SiMe₃¹) (Found: M¹1Na, 367.1454.

C₁₈H₂₄N₂O₃Si requires M1Na, 367.1458). The second

eluate gave 9b as a colourless solid (112 mg, 34%); mp

169±1708C (isopropanol) (Found: C, 62.76; H, 7.02; N,

8.13. C₁₈H₂₄N₂O₃Si requires C, 62.51; H, 6.89; N, 7.94%);

(1H, d, J3.8 Hz, H-3), 7.10 (1H, d, J8.7 Hz, H-7); d_C

(CDCl₃) 27.3 (NCH₃), 28.3 (C(CH₃)₃), 54.8 and 55.8 (CH₂),

55.8 (OCH₃), 57.6 and 58.7 (C), 80.9 and 81.1 (C(CH₃)₃),

108.5 (CH), 108.5 (CH), 110.9 (CH), 113.2 and 113.4 (CH),

114.6 (CH), 122.4 (C), 128.8 (CH), 137.4 (C), 150.9 (car-

bamate CvO), 156.6 (C), 177.8 (amide CvO); m/z (EI)

330 (35%, M¹), 274 (33.8, M¹2C₄H₉), 257 (16.2,

M¹2C₄H₉O), 230 (64.8), 202 (37.5), 187 (24.1), 149

(50.1) (Found: M¹, 330.1575. C₁₈H₂₂N₂O₄requires M,

330.1579). The second eluate gave 9c as a colourless oil

(360 mg, 18%); n_max(cm²¹) 2933 (w, C±H), 1702 (s, car-

bamate CvO), 1656 (s, amide CvO); d_H(300 MHz;

CDCl₃) COSY 1.61 (9H, s, C(CH₃)₃), 3.69 (3H, s, NCH₃),

3.89 (3H, s, OCH₃), 6.85 (1H, d, J3.5 Hz, H-3), 7.04 (1H,

dd, J9.2, 2.8 Hz, H-7), 7.30 (1H, d, J9.2 Hz, H-6), 7.41

(1H, d, J3.5 Hz, H-2), 8.26 (1H, d, J2.8 Hz, H-9); d_C

(CDCl₃) HETCOR 28.2 (C(CH₃)₃), 29.7 (NCH₃), 55.5

(OCH₃), 85.4 (C(CH₃)₃), 108.4 (C-3), 109.0 (C-9), 115.1

(C), 116.0 (C-6), 116.1 (C-7), 121.0 (C), 126.8 (C-2),

132.8 (C), 134.3 (C), 149.5 (carbamate CvO), 153.9 (C),

158.9 (amide CvO); m/z (ES) 329 (26%, M¹11), 273 (100,

M¹2C₄H₇), 229 (100), 213 (25), 199 (14), 183 (14) (Found:

M¹1H, 329.1510. C₁₈H₂₀N₂O₄requires M1H, 329.1501).

The third eluate gave 10c as a yellow oil (20 mg, 1%); n_max

(cm²¹) 2960 (m, C±H), 1698 (s, amide CvO), 1659 (s,

carbamate CvO); d_H(300 MHz; CDCl₃) 1.59 (9H, s,

C(CH₃)₃), 3.58 (3H, s, NCH₃), 3.81 (3H, s, OCH₃), 6.90

(1H, dd, J9.1, 2.9 Hz, H-7), 7.14 (1H, d, J9.1 Hz,

H-6), 7.20 (1H, d, J2.9 Hz, H-9), 7.69 (1H, d, J2.1 Hz,

H-1), 7.98 (1H, d, J2.1 Hz, H-3) (Found M¹, 328.1423.

C₁₈H₂₀N₂O₄requires M, 328.1422).

n

_max(cm²¹) 3195 (w, N±H), 2954 (w, C±H), 1617 (s, amide

CvO), 1246 (w, SiMe); d_H(300 MHz; CDCl₃) 20.07 (9H,

s, Si(CH₃)₃), 1.02 (2H, t, J8.2 Hz, CH₂Si(CH₃)₃), 3.82

(2H, t, J8.2 Hz, OCH₂), 3.89 (3H, s, OCH₃), 6.01 (2H,

br s, NCH₂O), 6.96 (1H, t, J2.5 Hz, H-3), 7.14 (1H, t,

J2.5 Hz, H-2), 7.15 (1H, dd, J9.2, 2.8 Hz, H-7), 7.70

(1H, d, J2.8 Hz, H-9), 7.73 (1H, d, J9.2 Hz, H-6),

11.05 (1H, br s, NH); d_C(CDCl₃) 21.4 (Si(CH₃)₃), 18.1

(CH₂Si(CH₃)₃), 55.6 (OCH₃), 66.0 (OCH₂), 71.5 (NCH₂),

103.8 (CH), 106.8 (CH), 114.4 (C), 115.3 (C), 115.6

(CH), 118.1 (CH), 122.5 (CH), 131.0 (C), 134.8 (C),

155.2 (C), 160.7 (amide CvO); m/z (EI) 344 (19%, M¹),

3.1.23. tert-Butyl 5-methoxycarbonyl-1-methyl-2-oxo-

1,2-dihydrospiro[indole-3,3⁰-pyrrole]-1⁰-carboxylate,

11d, tert-butyl 8-methoxycarbonyl-5-methyl-4-oxo-4,5-

dihydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate, 9d

and tert-butyl-8-methoxycarbonyl-5-methyl-4-oxo-4,5-

dihydro-2H-pyrrolo[4,3-c]quinoline-2-carboxylate, 10d.

A suspension of 5b (600 mg, 1.23 mmol) and a sub-

stoichiometric amount of AIBN in toluene (63 mL) was

heated under re¯ux. Then, tri-n-butyltin hydride (0.36 mL,

1.36 mmol) was added dropwise and the reaction mixture

was stirred at this temperature for 1 h. After evaporation of

the solvent the residue was chromatographed (SiO₂, ethyl

acetate/hexane 1:1). The ®rst eluate gave 11d as a colourless

oil (115 mg, 26%); n_max(cm²¹) 2976 (w, C±H), 1704 (s,

CvO); d_H(300 MHz; CDCl₃) 1.41 and 1.46 (9H, 2s, C

(CH₃)₃), 3.19 (3H, s, NCH₃), 3.84 (3H, s, OCH₃), 3.88

(1H, d, J11.5 Hz, H-1), 4.07 and 4.11 (1H, 2d,

J11.5 Hz, H-1), 4.64 and 4.70 (1H, 2d, J3.8 Hz, H-4),

6.81 (1H, d, J8.1 Hz, H-7), 6.82 (0.5H, d masked, H-3),

6.97 (0.5H, d, J3.8 Hz, H-3), 7.83 (1H, s, H-10), 7.98 (1H,

dd, J8.1, 1.6 Hz, H-8); d_C(CDCl₃) 26.8 (NCH₃), 28.3

(C(CH₃)₃), 52.1 (OCH₃), 54.7 and 55.3 (CH₂), 57.07 and

58.24 (C), 81.1 and 81.3 (C(CH₃)₃), 107.6 (CH), 107.8

(CH), 125.1 (CH), 125.2 (C), 131.5 (CH), 132.6 (C),

133.9 and 134.1 (CH), 146.8 (C), 150.8 (carbamate

CvO), 166.6 (amide CvO), 178.0 (ester CvO); m/z (EI)

258 (100%), 241 (12), 230 (23), 199 (32) (Found: M¹1H,

359.1607. C₁₉H₂₂N₂O₅requires M1H, 359.1610). The

second eluate gave 9d as a colourless oil (57 mg, 13%)

n_max(cm²¹) 2951 (w, C±H), 1717 (s, ester and carbamate

CvO), 1663 (s, amide CvO); d_H(300 MHz; CDCl₃)

271 (63.3, M¹2SiMe₃), 228 (39.4), 199.1 (16.7), 167.1

1

(18), 73 (80, SiMe₃

C₁₈H₂₄N₂O₃Si requires M, 344.1556).

)

(Found: M¹, 344.1542.

3.1.22. tert-Butyl 5-methoxy-1-methyl-2-oxo-1,2-dihydro-

spiro[indole-3,3⁰-pyrrole]-1⁰-carboxylate, 11c, tert-butyl

8-methoxy-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-

c]quinoline-1-carboxylate, 9c and tert-butyl 8-methoxy-

5-methyl-4-oxo-4,5-dihydro-2H-pyrrolo[4,3-c]quino-

line-1-carboxylate, 10c. A suspension of 5a (2.5 g,

6.1 mmol) and a sub-stoichiometric amount of AIBN in

toluene (315 mL) was heated under re¯ux. Then, tri-n-

butyltin hydride (1.8 mL, 6.7 mmol) was added dropwise

and the reaction mixture was stirred at this temperature

for 1 h. After evaporation of the solvent the residue was

chromatographed (SiO₂, hexane/EtOAc 1:2). The ®rst

eluate gave 11c as a colourless oil (625 mg, 31%); n_max

(cm²¹) 2974 (w, C±H), 1702 (s, carbamate and amide

CvO); d_H(300 MHz; CDCl₃) 1.46 and 1.50 (9H, s,

C(CH₃)₃), 3.18 (3H, s, NCH₃), 3.77 (3H, s, OCH₃), 3.84

and 3.91 (1H, 2d, J12 Hz, H-1), 4.13 and 4.16 (1H, 2d,

J12 Hz, H-1), 4.73 and 4.80 (1H, 2d, J3.8 Hz, H-4), 6.72

(1H, d, J8.2 Hz, H-8), 6.79 (1H, d, J2.7 Hz, H-10), 6.97

C. Escolano, K. Jones / Tetrahedron 58 (2002) 1453±1464

1463

COSY 1.70 (9H, s, C(CH₃)₃), 3.83 (3H, s, NCH₃), 3.97 (3H,

s, OCH₃), 6.91 (1H, d, J3.5 Hz, H-3), 7.48 (1H, d,

J8.9 Hz, H-6), 7.53 (1H, d, J3.5 Hz, H-2), 8.13 (1H,

dd, J8.9, 1.9 Hz, H-7), 9.28 (1H, d, J1.9 Hz, H-9); d_C

(CDCl₃) HETCOR 27.7 (C(CH₃)₃), 29.9 (NCH₃), 52.2

(OCH₃), 86.3 (C(CH₃)), 108.3 (C-3), 114.3 (C), 115.0

(C-6), 120.9 (C), 122.6 (C), 127.5 (C-9), 127.8 (C-2),

129.1 (C-7), 134.3 (C), 141.3 (C), 149.8 (carbamate

CvO), 159.8 (amide CvO), 166.7 (ester CvO); m/z (EI)

256 (100%), 225 (51), 197 (13), 168 (25), 167 (3) (Found:

M¹1H, 357.1450. C₁₉H₂₀N₂O₅requires M1H, 357.1461).

The third eluate gave 10d as a colourless oil (22 mg, 5%)

n_max(cm²¹) 2920 (w, C±H), 1714 (s, carbamate and ester

CvO), 1643 (m, amide CvO); d_H(300 MHz; CDCl₃) 1.70

(9H, s, C(CH₃)₃), 3.78 (3H, s, NCH₃), 3.91 (3H, s, OCH₃),

6.83 (1H, s, H-1), 7.25 (1H, s, H-3), 7.40 (1H, d, J8.9 Hz,

H-6), 8.02 (1H, dd, J8.9, 2 Hz, H-7), 8.55 (1H, d, J2 Hz,

H-9); m/z (EI) 256 (100%), 225 (88), 197 (13), 169 (4), 168

(4), 167 (12) (Found: M¹, 356.1372. C₁₉H₂₀N₂O₅requires

M, 356.1369).

NCH₂O), 7.00 (1H, d, J3.6 Hz, H-3), 7.16 (1H, dd, J9.3,

2.9 Hz, H-7), 7.60 (1H, d, J3.6 Hz, H-2), 7.70 (1H, d,

J9.3 Hz, H-7), 8.41 (1H, d, J2.9 Hz, H-9); d_C(CDCl₃)

21.36 (Si(CH₃)₃), 18.1 (CH₂Si), 55.0 (COOCH₃), 55.6

(OCH₃), 66.3 (OCH₂), 71.7 (NCH₂), 108.5 (CH), 109.4

(CH), 110.4 (CH), 113.8 (CH), 116.7 (CH), 117.6 (CH),

120.8 (C), 126.7 (CH), 132.2 (C), 151.2 (carbamate

CvO), 154.4 (C), 159.7 (amide CvO); m/z (EI) 402 (28,

M¹), 344 (38), 329 (72, M¹2SiMe₃), 271 (36), 169 (68), 73

(100, SiMe₃¹). (Found: M¹, 402.1599. C₂₀H₂₆N₂O₅Si

requires M, 402.1610).

3.1.25. 8-Methoxy-1-methyl-5-(2-trimethylsilylethoxy-

methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-4-one,

9f. A suspension of 5d (266 mg, 0.60 mmol) and a sub-

stoichiometric amount of AIBN in toluene (32 mL) was

heated under re¯ux. Then, tri-n-butyltin hydride (0.13 mL,

0.66 mmol) was added dropwise and the reaction mixture

was stirred at this temperature for 1 h. After evaporation of

the solvent the residue was chromatographed (SiO₂, hexane/

EtOAc 3:4) to give the title compound, 9f as a yellow solid

(93 mg, 43%). n_max(cm²¹) 2955 (w, C±H), 1651 (s, amide

CvO), 1250 (w, SiMe); d_H(300 MHz; CDCl₃) 20.01 (9H,

s, Si(CH₃)₃), 0.98 (2H, t, J8 Hz, CH₂Si(CH₃)₃), 3.76 (2H,

t, J8 Hz, CH₂O), 3.95 (3H, s, NCH₃), 4.19 (3H, s, OCH₃),

5.88 (2H, br s, NCH₂O), 6.91 (2H, s, H-2 and H-3), 7.10

(1H, dd, J9.3, 2.7 Hz, H-7), 7.61 (1H, d, J2.7 Hz, H-9),

7.73 (1H, d, J9.3 Hz, H-6); d_C(CDCl₃) 21.3 (Si(CH₃)₃),

18.1 (CH₂Si), 38.0 (NCH₃), 55.7 (OCH₃), 65.9 (OCH₂), 71.5

(NCH₂), 105.8 (CH), 105.9 (CH), 113.1 (CH), 116.3 (C),

116.6 (C), 118.0 (CH), 128.6 (CH), 131.5 (C), 132.7 (C),

154.5 (C), 159.9 (amide CvO); m/z (EI) 358 (10%, M¹),

285 (100, M¹2SiMe₃), 257 (10), 242 (76), 211 (25), 119

(10), 169 (10), 73 (50, SiMe₃¹) (Found: M¹, 358.1700.

C₁₉H₂₆N₂O₃Si requires M, 358.1712).

A suspension of 5b (180 mg, 0.41 mmol) and a sub-

stoichiometric amount of AIBN in toluene (20 mL) was

heated under re¯ux. Tris(trimethylsilyl)silane (0.12 mL,

0.45 mmol) was added dropwise and the reaction mixture

was stirred at this temperature for 4 h. After evaporation of

the solvent the residue was chromatographed (SiO₂, hexane/

EtOAc 1:2). The ®rst eluate gave 9d as a colourless oil

(22 mg, 17%) and the second eluate gave 10d as a colourless

oil (18 mg, 14%).

3.1.24. Methyl 5-methoxy-1-(2-trimethylsilylethoxy-

methyl)-2-oxo-1,2-dihydrospiro[indole-3,3⁰-pyrrole]-1⁰-

carboxylate, 11e and methyl 8-methoxy-5-(2-trimethyl-

silylethoxymethyl)-4-oxo-4,5-dihydropyrrolo[3,2-c]-

quinoline-1-carboxylate, 9e. A suspension of 5c (130 mg,

0.27 mmol) and a sub-stoichiometric amount of AIBN in

toluene (14 mL) was heated under re¯ux. Then, tri-n-butyl-

tin hydride (0.06 mL, 0.27 mmol) was added dropwise and

the reaction mixture was stirred at this temperature for 1 h.

After evaporation of the solvent the residue was chromato-

graphed (SiO₂, hexane/EtOAc 1:1). The ®rst eluate gave 11e

as a colourless oil (35 mg, 32%); n_max(cm²¹) 2976 (w,

C±H), 1713 (s, carbamate CvO), 1651 (m, amide CvO);

d_H(300 MHz; CDCl₃) 0.00 (9H, s, Si(CH₃)₃), 0.94 (2H, t,

J8 Hz, CH₂Si(CH₃)₃), 3.58 (2H, t, J8 Hz, CH₂O), 3.80

and 3.84 (3H, 2s, COOCH₃), 3.82 (3H, s, OCH₃), 3.96 and

4.04 (1H, 2d, J11 Hz, H-1), 4.24 (1H, t, J12 Hz, H-1),

4.85 and 4.90 (1H, 2d, J4 Hz, H-4), 5.14, 5.18 (2H, ABq,

J10.5, 2.6 Hz, NCH₂O), 6.84±7.06 (4H, ArH and H-3); d_C

(CDCl₃) 21.43 (Si(CH₃)₃), 17.7 (CH₂Si), 53.0 (COOCH₃),

55.2 and 55.4 (CH₂), 55.8 (OCH₃), 57.0 and 58.2 (C), 66.1

(OCH₂), 69.8 (NCH₂), 109.5 and 109.7 (CH), 110.4 (CH),

110.5 (CH), 113.8 (CH), 132.6 and 133.4 (CH), 132.8 (C),

134.3 (C), 134.4 (C), 156.8 (C), 178.2 (amide CvO); m/z

(EI) 404 (27, M¹), 346 (22), 345 (19), 287 (16), 273 (19),

214 (8), 73 (100, SiMe₃¹) (Found: M¹, 404.1778.

C₂₀H₂₈N₂O₅Si requires M, 404.1778). The second eluate

gave 9e as a yellow oil (16 mg, 15%); n_max(cm²¹) 2940

(w, C±H), 1714 (m, carbamate CvO), 1659 (s, amide

CvO); d_H(300 MHz; CDCl₃) 20.07 (9H, s, Si(CH₃)₃),

0.98 (2H, t, J8 Hz, CH₂Si(CH₃)₃), 3.75 (2H, m, CH₂O),

3.94 (3H, s, COOCH₃), 4.15 (3H, s, OCH₃), 5.88 (2H, br s,

3.1.26. 8-Methoxy-1-methyl-5-(2-trimethylsilylethoxy-

methyl)-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-4-one,

9f. A solution of 9b (40 mg, 0.11 mmol) in dry THF (2 mL)

was added to a stirred suspension of sodium hydride (7 mg

of 60% dispersion in mineral oil, 0.17 mmol) in THF

(3 mL). The mixture was stirred for 1 h after which methyl

iodide (0.02 mL, 0.30 mmol) was added and the solution

stirred overnight. Water (5 mL) was added to quench the

reaction. The solvent was evaporated in vacuo and the

residue was dissolved in ethyl acetate (15 mL). The organic

layer was washed with water (3£10 mL), dried and evapo-

rated under reduced pressure. Chromatography (SiO₂,

hexane/EtOAc 3:4) gave 9f (30 mg, 72%).

Acknowledgements

C. E. thanks the European Union for funding (contract n8

ERBFMICT983265).

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Article Doi

Aryl radical cyclisation onto pyrroles

DOI: 10.1016/S0040-4020(02)00007-8

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