Access to indoles via Diels-Alder reactions of 5-methylthio-2-vinylpyrroles with maleimides

July 2013

Access to Indoles via Diels–Alder Reactions of 5-Methylthio-2-vinylpyrroles

795

with Maleimides

Wayland E. Noland,* Nicholas P. Lanzatella, Rozalin R. Dickson, Mary E. Messner, and Huy H. Nguyen

Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, USA

*

E-mail: nolan001@umn.edu

Additional Supporting Information may be found in the online version of this article.

Received May 13, 2011

DOI 10.1002/jhet.1571

Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com).

Diels–Alder reactions of 5-methylthio-2-vinyl-1H-pyrroles with maleimides followed by isomerization

gave tetrahydroindoles in moderate to good yield. Aromatization using activated MnO₂in reﬂuxing toluene

gave the corresponding 2-methylthioindoles in good yields, and demethylthioation using Raney nickel gave

the 2-H indoles in excellent yields. The protection of the adducts produced aromatization in improved yield,

demonstrating the effectiveness of the methylthio group as a protecting group for pyrroles; however, 5-

methylthio-2-vinylpyrrole was shown to perform with slightly less efﬁciency than 2-vinylpyrrole in Diels–Alder

reactions, indicating the protective group was more deactivating than desired. This route toward indoles offers

high convergency and conveniently available starting materials that are easily puriﬁed. Bis-methylthioated

vinylpyrroles were shown to have potential as highly activated Diels–Alder dienes.

J. Heterocyclic Chem., 50, 795 (2013).

INTRODUCTION

or increasing reactivity at the vinyl group. The a-position of

pyrrole is the most reactive; therefore, we were interested in

blocking that location. To enhance the efﬁciency of the

normal electron-demand [4 + 2] cycloaddition, we sought

a removable electron-donating functionality that would

increase the electron density of the diene through conju-

gation. We were also interested in placing removable

electron-donating groups on the vinyl group itself for

temporary enhancement of reactivity. We anticipated that

an increase in the reactivity of the diene would broaden

the library of indoles conceivably achievable via this

method by allowing the use of less electron-deﬁcient

dienophiles.

Because of the high reactivity of the pyrrole system,

several types of removable groups at the a-position have

been used with pyrrole to prevent unwanted reactions [8].

Often used in the setting of porphyrin synthesis [9], most

of the methods developed involve electron-withdrawing

protecting groups because of a desire to attenuate the reactiv-

ity of the pyrrole [10]. These include carboxylate [11] and

aldehyde groups [8], which are commonly removed, with

aldehydes being oxidized ﬁrst, by using high temperatures

The ubiquity of indole among biologically active

compounds, synthetic [1] and natural [2], has generated

continuing interest in useful ways to generate this struc-

ture [3]. We have reported that tetrahydroindoles are

available via 2-vinylpyrroles derived from acid-catalyzed

condensation of pyrrole with cyclic ketones, followed by in

situ trapping by various maleimides in Diels–Alder reactions

[4,5]. We have reported that indoles are available from

oxidation of tetrahydroindoles synthesized by Diels–Alder

reactions of both N-H and N-methyl-2-vinylpyrroles [6],

and of N-p-toluenesulfonyl-3-vinylpyrroles[7], with N-

substituted maleimides. In comparing the efﬁciency

of the Diels–Alder reactions of N-H-2-vinylpyrroles and

N-tosyl-3-vinylpyrrole, we were inspired by the apparent

increase in efﬁciency caused by the use of the N-tosyl

group, which was later able to be removed. Seeking to

expand the usefulness of the technique, we chose to study

the use of electron-donating protective groups on the 2-

vinylpyrrole diene. Addition of the protective group was

aimed to prevent unwanted side reactions while maintaining

796

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Vol 50

with strong base or acid, causing saponiﬁcation followed

by decarboxylation. Other electron-withdrawing protective

groups used are the more mildly cleavable sulﬁnyl and

sulfonyl groups [12], using Raney nickel or radical-induced

reductive desulfonylation with Bu₃SnH/AIBN [13], and the

2,4-dinitrobenzenesulﬁnyl group, which can be removed by

oxidation and then treatment with phenylthiol [12]. Because

these protecting groups would decrease the electron density

of 2-vinylpyrrole and would therefore likely cause an unde-

sirable decrease in Diels–Alder reactivity, they did not suit

our purposes.

corresponding 3-(1-benzylthio)vinylpyrrole gave the Diels–

Alder adduct with DMAD in 31% yield; surprisingly, the

yields we achieved in our work with Diels–Alder reactions

of the comparatively deactivated N-toluenesulfonyl-3-vinyl-

pyrrole with maleimides were much higher [7]. The poor

yields in the pyrrole case of Murase et al. could have been

caused by predominance of s-trans geometry in the diene

system because of steric repulsion from the benzylthio

functionality; indeed, the authors suggest this is the reason

only trace products were found when trying the analogous

experiment with DMAD and 2-(1-benzylthio)vinyl-N-

methylpyrrole. However, this does not explain adequately

the 70% yield achieved in the indole work of Murase

et al., as steric interactions between indole and its 3-

(1-benzylthio)vinyl group would be, if anything, greater

than those between pyrrole and its 3-(1-benzylthio)vinyl

group. We postulated that undesired reactions of the pyrrole

at the reactive a-unsubstituted site, which are not possible in

the indole case, are more likely to be blamed for the differ-

ences in yield. This is a hypothesis we hoped to verify by

examining the reactivity of a pyrrole with a-protecting groups

in combination with 1-alkylthio-substituted vinyl groups.

Comparatively few examples exist of electron-donating

functionalities being used to a-protect pyrrole. The only

example, to the best of our knowledge, is the alkylthio

group, recently reported by Lindsey and coworkers

[14,15]. The alkylthio group has the advantage of being

easily removed using Raney nickel, and a variety of 5-

alkylthiopyrroles are readily available from the

corresponding 5-thiocyanatopyrrole. After protection, further

functionalization of pyrrole to the aldehyde via electrophilic

aromatic substitution may be enhanced because of the

electron-releasing characteristics of the thio-functionality

[16]. It was hoped that adequate electron donation would

be provided to enhance or maintain Diels–Alder reactivity,

without deactivation of the aldehyde toward Wittig methyle-

nation, necessary for formation of the vinyl functionality.

Several examples exist demonstrating the use of

removable groups to enhance the efﬁciency of Diels–Alder

reactions. Removable hydrophilic 2-pyridyldimethylsilyl

groups on a diene were shown to enhance water solubility

as a means of increasing the efﬁciency of the Diels–Alder

reaction [17]. Furan has been shown to have increased

reactivity as a Diels–Alder diene when substituted at the

2-position with methylthio [18,19] and phenylthio [19]

groups, which were not removed later. To the best of

our knowledge, there are no other prior studies that

examine the use of removable electron-donating groups

in conjugation with the diene as a means to enhance

Diels–Alder reactivity.

By placing removable electron-donating functionalities

on the vinyl group in combination with a-protection, a

bis-alkylthio-substituted hyper electron-rich system was

envisioned, which later could be dideprotected in a

single step. Diels–Alder reactions of sulfonyl-substituted

[20,21], sulﬁnyl-substituted [22], and sulfanyl-substituted

[21,23] dienes are known, although none of the examples

found involved removal of the sulfur group after the

Diels–Alder reaction. Murase et al. [24] showed that 3-

(1-(methylthio)vinyl)indoles and 3-(1-(benzylthio)vinyl)

indoles underwent [4 + 2] cycloadditions with dimethyl

acetylenedicarboxylate (DMAD) in 67 and 70% yields,

respectively. In the only example found of Diels–Alder

reactions of vinylpyrroles having an alkylthio-substituted

vinyl group, Murase et al. [25] showed that the

RESULTS AND DISCUSSION

Synthesis of starting materials and Diels–Alder reactions

Mono-alkylthioation. Initially, it was hoped that the 5-

protective group employed would enhance crystallinity in

the 2-vinylpyrrole at room temperature, potentially

allowing the beneﬁt of facile puriﬁcation via

recrystallization, as vinylpyrroles are typically unstable

on silica gel. With this in mind, 5-phenylthio- and 5-(4-

phenoxyphenylthio)-2-vinylpyrroles 7 [26] and 8 were

chosen ﬁrst (Scheme 1). Although Lindsey et al. [14]

demonstrated that 5-phenylthiopyrrole 3 is deactivated

toward deuterium exchange relative to pyrrole itself, it

was hoped that any lessening of reactivity would be

slight and would be outweighed by ease of puriﬁcation.

Pyrrole was treated with ammonium thiocyanate to

give thiocyanatopyrrole 1 [27], which was immediately

subjected to a Grignard reaction giving, after time-

consuming workups, 3 and 4 [26]. The crude Grignard

products were then used in a Vilsmeier–Haack reaction,

giving, after ﬂash chromatography, aldehydes 5 and 6 in

44% yield over four steps [28,29]. A Wittig reaction using

sodium ethoxide in THF [30], or Corey’s modiﬁcation

[31], followed by ﬂash chromatography, gave 5-arylthio-

2-vinylpyrroles 7 and 8 in 38 and 66% yields,

respectively. Unfortunately, all attempts at crystallizing

these pyrroles in a freezer failed; thus, they are probably

liquids at room temperature. During chromatography on

silica gel, several closely eluting impurities were not fully

removed and some decomposition occurred; therefore,

the decision was made not to bring vinylpyrroles 7 and

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5-Methylthio-2-vinylpyrroles with Maleimides

Scheme 1. Synthesis of 5-phenylthio, 5-(4-phenoxyphenyl)thio, and 5-methylthio-2-vinylpyrroles 7, 8, 13, and 14.

8 to analytical purity until their reactivity as Diels–Alder

dienes could be determined.

puriﬁcation; any N-methyl-5-methylthio-2-pyrrolecarboxal-

dehyde 12 that codistilled was easily removed by tritura-

Vinylpyrroles 7 and 8 (1.1 equiv) were stirred with

4-ethylphenylmaleimide 16 in chloroform for several

days, but with TLC, no reaction was observed to occur.

The vinylpyrrole was used in excess because our past

experience with vinylpyrroles indicated any adduct formed

would be eluted during chromatography very near to the

maleimide [6,7]. The reaction mixtures were reﬂuxed for

tion with hexanes. Lastly, a Wittig reaction was

performed on 11 by using potassium tert-butoxide in

THF [6], which, following vacuum distillation, gave the

desired 5-methylthio-2-vinylpyrrole 13 in 69% yield.

Methylthio-protected vinylpyrrole 13 (1.1 equiv) was

stirred with 4-ethylphenylmaleimide 16 in chloroform for

24 h, at which point TLC indicated that one new product

had been formed and the limiting reagent 16 had been

1

ﬁve days, but still, no new TLC spots appeared; H NMR

1

completely consumed (Scheme 2). At ﬁrst, the H NMR

conﬁrmed that only starting materials were present in the

reaction mixture. The same results were observed when

DMAD was employed as the dienophile.

of rearranged Diels–Alder adduct 21 was bafﬂing, as there

was no N-H peak. An extra peak in the carbonyl region of

the ¹³C NMR indicated the distinctive thio–imine function-

ality of the rearranged adduct [33]; COSY and NOE experi-

ments also veriﬁed the structure, with no exo-addition

product being detectable by NMR.

The N-methylvinylpyrrole 14 was synthesized in com-

parable yield by using the same procedure outlined in

Scheme 1 for N-H diene 13, with vacuum distillation being

used to purify both aldehyde 12 and vinylpyrrole 14. In

Diels–Alder reactions with vinylpyrrole 13, the dieno-

philes N-phenyl, N-(4-ethylphenyl), N-(3-methoxyphenyl),

and N-(4-bromophenyl)maleimides 15–18 were used,

giving rearranged adducts 20–23 in 55, 71, 61, and 81%

yields, respectively. Small amounts of adducts 25–28,

which had rearranged to the aromatic pyrrole structure,

were detected in all four cases, but because of the small

amounts formed, only 25 (9% yield) was isolated and

fully characterized. Conversely, Diels–Alder reactions

Arylthio substituents were apparently too electron-

withdrawing to maintain reactivity of the diene. The

methylthio group was tried next, with some degree of

conﬁdence, because studies by Lindsey et al. [14] have

demonstrated that 5-alkylthio substituents activate pyrrole

toward deuterium exchange at the 2-position 1.4-fold to

fourfold, but the 3-position was deactivated ﬁvefold to

sevenfold, and the 4-position was strongly activated

eightfold to 25-fold, as compared with N-H-pyrrole. 5-

Thiocyanatopyrrole 1 was treated successively with 2 M

sodium hydroxide and methyl iodide for 2.5 h, giving

5-methylthiopyrrole 9 in 77% yield over two steps from

pyrrole; a small amount of N-methyl-5-methylthiopyrrole

10 was also generated (about 5% by mass, as determined

1

by H NMR) [32]. The crude 9 was then subjected to a

Vilsmeier–Haack reaction [28,29], giving aldehyde 11 in

91% yield, which was conveniently vacuum-distilled for

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Scheme 2. Diels–Alder reactions of 5-methylthio-2-vinylpyrroles 13 and 14.

with N-(dimethylamino) 19 formed 24 (<5% yield) and the

major adduct rearranged to the aromatic pyrrole struc-

ture 29. The more basic N,N-dimethylaminomaleimide 19

may be able to facilitate the rearrangement to the aromatic

adduct 29 [6] by more easily enabling a 1,3-proton shift

than maleimides 15–18. However, combining adduct 22

with triethylamine in chloroform for about a week

produced only minimal rearrangement to the aromatic

adduct 27; thus, we were unable to verify this theory. In

another explanation, the loss of steric bulk due to the lack

of N-phenylmaleimide groups in the adducts 29 and 24

may cause a difference in structure that makes the aromatic

adduct 29 more stable than unrearranged adduct 24. It

was decided not to pursue further Diels–Alder reactions

with N-(4-bromophenyl)maleimide 18 because of difﬁcul-

ties with puriﬁcation of adduct 23 and because of difﬁculty

experienced in the characterization of 4-bromophenyl

compounds in our past work with 2-vinylpyrroles [6]. For

N-methyl-2-vinylpyrrole 14, Diels–Alder reactions with

maleimides 15–17 and 19 gave adducts 30–33 in 30,

44, 41, and 66% yields, respectively. These yields are

lower than those observed in our previous work with

2-vinylpyrroles [6], which had 73 and 92% average yields,

respectively, with N-H- and N-methyl- 2-vinylpyrroles in

Diels–Alder reactions run in chloroform.

The results demonstrate that the methylthio group

deactivates the vinylpyrrole toward [4 + 2] cycloaddition

chemistry; thus, the inductive effect of the sulfur overcomes

the effect of its p-electron or d-electron donation to the

diene. It is notable that no “double-addition” Michael-type

products were detected, such as were seen in our work with

unsubstituted 2-vinylpyrroles [6]; just as the methylthio

group decreases the electron density of the diene, it also

likely makes the adduct a worse Michael component by

decreasing its nucleophilicity because of the inductive effect

of sulfur. Additionally, rearrangement to the thio–imine may

occur too quickly for a Michael addition to occur with the

rearranged adduct. The activation energy for formation of

Michael addition products from conjugated thio–imines

20–23, which were stable enough to be easily isolated, is

probably higher than that from the adducts with C5–C5a

unrearranged double-bonds formed in our work with unsub-

stituted 2-vinylpyrroles, which we were not able to isolate in

that work; rather, we isolated the rearranged aromatic-type

isomers of the adducts, with structures similar to those of

minor products 25–28[6]. Further evidence of the stability

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5-Methylthio-2-vinylpyrroles with Maleimides

of 20–23 was the observation that minor product 25 slowly

converted to 20 over several weeks at room temperature,

whereas the rearranged adducts isolated in our unsubstituted

2-vinylpyrrole work were not observed to isomerize [6].

The Diels–Alder reaction of vinylpyrrole 13 with

DMAD was also attempted (Scheme 2). The DMAD was

added slowly to the vinylpyrrole at 0^ꢀC, but black tars

formed rapidly, likely indicating a polymerization reaction.

After ﬂash chromatography with ethyl acetate/hexanes,

only ~10% mass recovery occurred, with most of the mate-

rial remaining at the top of the column, producing further

evidence that the main reaction was not the desired

Diels–Alder reaction. The mass peak corresponding to

the expected adduct 34 was detected using HRMS, but

the adduct was not generated in sufﬁcient quantity to

isolate and characterize. Rather, the major product isolated

was dimethyl 2-methylthiomaleate 35[34], corresponding

to the result of a Michael addition of the methylthio group

to DMAD, with demethylthioation of the vinylpyrrole. The

soft electrophilic characteristics of DMAD may make a

Michael addition from sulfur, a soft nucleophile, preferred

over a Diels–Alder reaction [35], although extensive varia-

tion of the reaction conditions was not attempted.

Bis-methylthioation. To synthesize bis-methylthioated

vinylpyrroles 42 and 43, 2-methylthiopyrroles 36 and 37

[27] were ﬁrst acetylated using a Vilsmeier–Haack

reaction, giving 2-acetyl-5-methylthiopyrroles 38 and 39

(Scheme 3) [13,36]; Muchowski et al. [29] have

demonstrated that the 5-methylthio group has a directing

effect to give acylation exclusively at the 2-position.

Although N-H-acetylpyrrole 38 was a crystalline solid

that could be recrystallized for facile puriﬁcation, N-

methylacetylpyrrole 39 was a liquid that on TLC showed

several closely spotting impurities; two fractional vacuum

distillations gave 39 in a purity of approximately 7:1

by mass. 2-Acetyl-5-methylthiopyrroles 38 and 39 were

then treated with Lawesson’s reagent [37], giving N-H- and

N-methyl- 2-acetyl-5-methylthiopyrroles 40 and 41 [24,25].

The thioacetylpyrroles 40 and 41 were then treated at

0^ꢀC with sodium hydride (1.5 equiv) for 10 min followed

by the addition of methyl iodide (1.5 equiv) and stirring

for 30 min at 0^ꢀC, giving the 5-methylthio-2-(1-

(methylthio)vinyl)pyrroles 42 and 43 [24,25]. From TLC

analysis, it was seen that N-H-thioacetylpyrrole 40 gave

a single product in the ﬁrst 15 min, which then began

to convert into another product with a higher R_f

1

value. Comparison of TLCs and H NMR analysis of the

products revealed that the N-H-vinylpyrrole 42 was being

transformed into the N-methylvinylpyrrole 43 in the

presence of sodium hydride and methyl iodide. The ratio

of N-methyl to N-H product depended on the time allowed

before the reaction was quenched with aqueous ammonium

chloride and was generally at least 1:1 by mass. For the

reaction to run long enough for complete conversion of

the starting N-H-thioacetylpyrrole 40 to the corresponding

vinylpyrroles, a larger amount of N-methylvinylpyrrole

was produced, with a ratio of 42 and 43 being approxi-

mately 1:2 by mass. Perhaps the use of lower temperatures

could help avoid this problem in the future. When ﬂash

chromatography of the mixture of 42 and 43 was attempted

on silica gel by using ethyl acetate/hexanes, signiﬁcant

degradation of the vinylpyrroles was observed. However,

when generated from N-methyl-thioacetylpyrrole 41,

vinylpyrrole 43 had impurities caused by the use of impure

41. These impurities did not allow formation of the pure

vinylpyrroles that were desired for ease of analysis of the

subsequent Diels–Alder reactions. Therefore, the mixture

of bis-methylthioated vinylpyrroles 42 and 43 formed from

N-H-thioacetylpyrrole 40 was used as the starting material.

The approximately 1:2 mixture of bis-methylthioated

N-H and N-methylvinylpyrroles 42 and 43 was allowed

to react with 1-(4-ethylphenyl)maleimide 16 (0.8 equiv)

in chloroform at room temperature (Scheme 4). The vinyl-

pyrrole was used in excess to simplify puriﬁcation because

previous experience has shown that the Diels–Alder adduct

is generally eluted during column chromatography very near

to the maleimide starting material. After 3 days, all the N-H-

vinylpyrrole 42 was consumed, but both N-methylvinylpyr-

role 43 and maleimide 16 remained. The reaction was

reﬂuxed, and after 5 h, little change was observed by TLC

Scheme 3. Synthesis of bis-methylthioated vinylpyrroles 42 and 43.

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Scheme 4. Diels–Alder reactions of bis-methylthioated vinylpyrroles 42 and 43.

analysis; therefore, in a desire to prevent destruction or rear-

rangement of the products that were anticipated to have

formed, the reaction was stopped at that time, with some

N-methylvinylpyrrole 43 and maleimide 16 still remaining

in the reaction mixture.

be puriﬁed enough to be fully characterized. However, in

consideration of ¹H and ¹³C NMR, TLC (prior to decompo-

sition, a single spot in 1:1 ethyl acetate/hexanes, R_fꢁ 0.42),

and HRMS data (M + Na⁺calculated 409.1016, found

409.1026), it is likely that product 46 was a rearranged

adduct formed from the N-H-vinylpyrrole 42. The isolated

vinylpyrrole 43 in combination with the uncharacterized

degradation products resulting from chromatography of 43

approximately completed the mass balance for this reaction.

The mixture of bis-methylthioated N-methyl and N-H-

vinylpyrroles 42 and 43 was allowed to react with vinyl-

boronic acid 2-methyl-2,4-pentanediol ester 47 (0.8 equiv)

in chloroform at room temperature in hope that the reaction

would give an adduct that could be easily used as a Suzuki

coupling partner (Scheme 5) [38]. After 3 days at room

temperature, no reaction was observed by TLC, so the

mixture was reﬂuxed. After 5 days, no reaction was detected

The crude reaction mixture was subjected to chromatog-

raphy and, as expected, the remaining N-methylvinylpyrrole

43 suffered degradation, and several other new TLC spots

formed. Along with the maleimide 16, three new products

were isolated, all of which were formed during the Diels–

Alder reaction. The major product isolated was the expected

rearranged adduct 44 from N-methylvinylpyrrole 43. Addi-

tionally, a double-addition type product 45 was isolated,

likely formed by a Michael addition between the adduct

from N-methylvinylpyrrole 43 and another molecule of

maleimide 16. Although in our prior work with unsubsti-

tuted 2-vinylpyrroles, double-addition products were

formed from a Michael addition at the 5-position of the

adducts, this is the ﬁrst example of a Michael addition from

an adduct at the b-pyrrole position. There appears to be no

precedent for this type of double-addition product in the

literature. These types of products may not have formed in

our earlier work, or elsewhere in the present work, because

the activation energy required to form 45 could be lowered

by resonance stabilization of the thio–imine functionality

with the 5-methylthio group in the Michael addition inter-

mediate (Fig. 1). A third new product, compound 46, was

isolated but did not seem to be stable and was not able to

1

by TLC and an H NMR of the crude reaction showed no

sign of the desired Diels–Alder products 48a and 48b.

Aromatization of Diels–Alder adducts. Tetrahydroindoles

20–22, 29, and 30–33 were aromatized using activated

MnO₂(5 equiv) in reﬂuxing toluene for 3 h, giving indoles

52–58 in 32–87% yields (Scheme 6). The activated MnO₂

was generated from manganese(II) sulfate and potassium

permanganate [39], which was also used in our prior work

with 2- and 3-vinypyrroles [6,7]. The average yield from

these dehydrogenations was 69%, slightly less than the

74% average yield of aromatizations in our 3-vinylpyrrole

work and higher than the 54% average achieved in

aromatizing the adducts in our prior work with 2-

vinylpyrroles. This indicates that the methylthio group may

provide some degree of stability to the tetrahydroindoles,

which possessed conjugated thio–imine functionality or a

methylated heterocyclic nitrogen, during the aromatization

process. Tetrahydroindole 29 lacked the stabilization that

the conjugated thio–imines 20–22 possessed, potentially

contributing to the high degree of degradation observed

when it was allowed to reﬂux with activated MnO₂in

toluene, resulting in a lower yield (32%) than in the

aromatization of 20–22 (63–84% yields).

Figure 1. A possible stabilized intermediate toward double-addition

product 45.

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5-Methylthio-2-vinylpyrroles with Maleimides

Scheme 5. Attempted Diels–Alder reaction between vinylboronate 47 and vinylpyrroles 42 and 43.

Scheme 6. Aromatization of Diels–Alder adducts.

Deprotection of indoles. To cleave carbon–sulfur bonds,

2-vinylpyrrole in Diels–Alder reactions, indicating the

protective group to be more deactivating than desired.

This route toward indoles offers high convergency and

conveniently available starting materials that are easily

puriﬁed. Bis-methylthioated vinylpyrroles were shown to

have potential as highly activated Diels–Alder dienes,

but either steric bulk or a thermodynamic preference for

the s-trans conﬁguration of the diene prevented the

increase in efﬁciency that was desired.

a variety of organometallic or metallic reagents may be used,

of which Raney nickel is employed most frequently [14,40].

Methylthioated indoles 51–58 were deprotected using excess

Raney nickel in acetone over 2 h at room temperature, giving

indoles 59–66 in 54–100% yields (Scheme 7).

CONCLUSION

Diels–Alder reactions of 5-methylthio-2-vinyl-1H-

pyrroles with maleimides followed by isomerization

gave tetrahydroindoles in moderate to good yield. Aro-

matization using activated MnO₂in reﬂuxing toluene

gave the corresponding 2-methylthioindoles in good yields,

and demethylthioation using Raney nickel gave the 2-H

indoles in excellent yields. The protection of the adducts

resulted in aromatization in improved yields, demonstrating

the effectiveness of the methylthio group as a protecting

group for pyrroles; however, 5-methylthio-2-vinylpyrrole

was shown to perform with slightly less efﬁciency than

EXPERIMENTAL

General. Solvents and reagents were purchased and used as

received. Flash chromatography was performed using 230–450

mesh silica gel. MPLC refers to medium pressure liquid

chromatography, performed using 325–635 mesh silica gel.

Ethyl acetate/hexanes were used as eluent unless otherwise

indicated. TLC analyses were performed on plastic-backed

plates precoated with 0.2 mm silica with F₂₅₄indicator.

Infrared spectra were recorded on a 4000 FT-IR spectrometer;

only the most intense and/or diagnostic peaks are reported.

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Scheme 7. Deprotection of indoles 51–58.

High-resolution mass spectra were recorded with a time-of-ﬂight

instrument using electrospray ionization with PEG as an internal

calibrant. For NMR spectra, chemical shifts (d) were referenced

to the solvent. ¹³C NMR spectra were proton-decoupled.

Melting points were uncalibrated. Elemental analyses were

performed by M-H-W Laboratories, Phoenix, AZ. Petroleum

ether refers to the 35–60^ꢀC boiling point fraction.

and 1-methylpyrrole (17.8mL, 16.223 g, 0.2 mol) in methanol

(150 mL). The thick mixture was stirred vigorously at RT for

12h, preferably using a mechanical stirrer. The round-bottom

ﬂask was immersed in an ice bath, with continued vigorous

stirring, and ice was added slowly until heat was no longer

evolved, and then water was added (100 mL). The mixture was

vacuum-ﬁltered on a fritted glass funnel, the ﬁlter cake was

washed with dichloromethane (5 Â 25 mL), the washings and

ﬁltrate were placed in a separatory funnel, and the organic

layer was removed. The water layer was extracted with

dichloromethane (3 Â 50 mL), the combined organics were

washed with brine and dried over anhydrous sodium sulfate,

the solvents were removed using a rotating evaporator, and the

crude products from each of the two reactions were combined,

giving crude 1-methyl-2-thiocyanato-1H-pyrrole 2 as a dark-

colored foul-smelling liquid, used immediately as is in the next

step [43]. Methyl iodide (74.86 mL, 170.33 g, 1.2 mol) was added

to the freshly prepared 2-thiocyanatopyrrole 2. By using an ice

bath to maintain temperature at RT, 2 N NaOH (0.60 L, 1.2 mol)

was added carefully, and the mixture was stirred at RT for

2.5 h. The mixture was acidiﬁed to neutrality using 1 N HCl

and extracted with dichloromethane (3 Â 150 mL). The

dichloromethane was washed with water (100 mL) and brine

(100 mL) and dried over sodium sulfate, and the solvent was

removed using a rotating evaporator, giving 10 (38.33 g, 75%

over two steps) as a dark-colored slightly viscous liquid. The

¹H NMR data matched those found in the literature [43,44].

The material was used without further puriﬁcation in the

next step.

2-Thiocyanato-1H-pyrrole (1) [27]. In a 1-L round-bottom

ﬂask, Oxone^W(184.434 g, 0.3 mol) was added to a mixture of

ammonium thiocyanate (22.836 g, 0.3 mol) and pyrrole

(13.89 mL, 13.418 g, 0.2 mol) in methanol (150 mL). The thick

mixture was stirred vigorously at RT for 30 min. The round-

bottom ﬂask was immersed in an ice bath, with vigorous stirring

and ice was added slowly until heat was no longer evolved, and

then water was added (100 mL). The mixture was vacuum-

ﬁltered on a fritted glass funnel, the ﬁlter cake was washed with

dichloromethane (3 Â 25 mL), the washings and ﬁltrate were

placed in a separatory funnel, and the organic layer was

removed. The water layer was extracted with dichloromethane

(5 Â 25 mL), the combined organics were washed with brine

and dried over anhydrous sodium sulfate, and the solvents were

removed using a rotating evaporator, giving 1 as a dark-colored

burnt-rubber-smelling liquid, used immediately as is in the next

step. Caution: If 2-thiocyanatopyrrole 1 is allowed to contact

the skin, even in small amounts, dark red splotches appear

beneath the skin over the next 24 h and, although painless, they

do not disappear for up to a month [41].

2-Methylthio-1H-pyrrole (9) [32].

Methyl iodide

(37.43 mL, 85.16 g, 0.6 mol) was added to the freshly prepared

2-thiocyanatopyrrole 1. Carefully, by using an ice bath to

maintain temperature at RT, 2 N NaOH (0.30 L, 0.60 mol) was

added, and the mixture was stirred at RT for 2.5 h. The mixture

was acidiﬁed to neutrality using 1 N HCl and extracted with

dichloromethane (3 Â 75 mL). The dichloromethane was washed

with water (50 mL) and brine (50 mL) and dried over sodium

sulfate, and the solvent was evaporated using a rotating

evaporator, giving 9 (34.52 g, 76% over two steps) as a dark-

colored slightly viscous liquid. ¹H NMR data matched those

found in the literature [42]. The material was used in the next

step without further puriﬁcation.

5-Methylthio-1H-pyrrole-2-carboxaldehyde (11) [45].

The

literature procedure [28] was used, with pyrrole 9 (34.5 g,

0.305 mol), followed by vacuum distillation at about 40–60^ꢀC/

0.15mm Hg. It was difﬁcult to record an accurate boiling point

during distillation because the compound crystallized on the

thermometer and needed to be melted with a heat gun. The

distillate was triturated with hexanes (5Â 30 mL) to remove any

codistilled 5-methylthio-N-methyl-1H-pyrrole-2-carboxaldehyde

12. The solid was recrystallized from dichloromethane/petroleum

ether, giving 11 (39.16 g, 91%) as white crystals: mp

101.5–102.5^ꢀC; ¹H NMR (300 MHz, CDCl₃, d) 9.50 (bs, 1H,

1-H), 9.41 (s, 1H, formyl-H), 6.96 (dd, J = 3.8, 2.6 Hz, 1H, 3-H),

6.31 (dd, J = 3.6, 2.4 Hz, 1H, 4-H), 2.52 (s, 3H, SCH₃); ¹³C NMR

(75 MHz, CDCl₃, d) 178.5, 137.1, 134.3, 123.9, 113.4, 18.4.

1-Methyl-2-methylthio-1H-pyrrole (10) [27,32]. In each of

two 1-L round-bottom ﬂasks, Oxone^W(184.43g, 0.300mol) was

added to a mixture of ammonium thiocyanate (22.83 g, 0.300 mol)

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

July 2013

Access to Indoles via Diels–Alder Reactions of

803

5-Methylthio-2-vinylpyrroles with Maleimides

1-Methyl-5-methylthio-1H-pyrrole-2-carboxaldehyde (12).

(3.16 g, 18.3 mmol) at RT for 24h, giving 25 and 20 (3.117 g,

1

The literature procedure [28] was used, with pyrrole 10 (50.88 g,

55%) as a brown powder: mp 139–141^ꢀC; H NMR (300 MHz,

0.40 mol), followed by vacuum distillation at 59^ꢀC/0.02 mm Hg,

CDCl₃, d) 7.33–7.46 (m, 3H, Ph), 7.14–7.19 (m, 2H, Ph), 5.80

(ddd, J=7.5, 3.5, 2.3 Hz, 1H, 5-H), 3.81 (dd, J=17.1, 3.9 Hz, 1H,

8-H), 3.46 (dd, J = 8.9, 7.1 Hz, 1H, 8ba-H), 3.29 (ddd, J = 8.8,

7.1, 1.6 Hz, 1H, 3aa-H), 3.06 (ddddd, J = 9.6, 7.1, 3.9, 2.3,

2.3 Hz, 1H, 8aa-H), 2.98 (ddd, J = 15.5, 7.7, 1.7 Hz, 1H, 4b-H),

2.98 (dd, J = 17.4, 9.6 Hz, 1H, 8-H), 2.50 (s, 3H, SCH₃), 2.35

(dddd, J = 15.3, 6.9, 3.6, 2.3 Hz, 1H, 4a-H); ¹³C NMR (75MHz,

CDCl₃, d) 182.6, 179.3, 177.4, 159.8, 132.4, 129.8, 129.4, 127.2,

107.3, 41.9, 41.1, 40.2, 37.6, 26.0, 14.6; IR (KBr, cm^À1) 3100

(w), 3050(w), 2960(m), 2943(m), 2926(m), 2890(m), 2842(m),

1774(m), 1703(s), 1594(w), 1533(m), 1498(m), 1450(w), 1422

(m), 1391(s), 1340(m), 1314(w), 1287(m), 1204(s), 1095(m),

1074(m), 1023(w), 996(w), 953(w), 863(w), 840(w), 815(w), 800

(w), 780(w), 754(m), 695(w); HRMS m/z (M+ Na⁺) calcd

335.0825, found 335.0826. Anal. Calcd for C₁₇H₁₆N₂O₂S: C,

65.36; H, 5.16; N, 8.97. Found: C, 65.51; H, 5.37; N, 8.77.

1

giving 12 (24.09g, 51%) as white crystals: mp 24–25^ꢀC; the H

NMR data matched those found in the literature [44].

2-Methylthio-5-vinyl-1H-pyrrole (13). Potassium t-butoxide

(14.000 g, 0.125 mol) was added slowly to methyltriphenyl-

phosphonium bromide (33.581g, 0.094mol) in THF (100 mL)

at 0^ꢀC. The bright yellow color characteristic of the ylide was

observed immediately. The mixture was stirred at RT under

nitrogen for 30min and then cooled to 0^ꢀC. A solution of

aldehyde 11 (8.75 g, 0.062mol) in THF (20 mL) was added

over 5 min, with stirring, and the mixture was reﬂuxed for

30min until TLC analysis indicated the reaction was complete.

The mixture was allowed to cool to RT and ﬁltered using a

fritted glass funnel, and the solids on the frit were washed

with diethyl ether (4 Â 25mL). The ﬁltrate was washed with

saturated NaHSO₃(50 mL), saturated Na₂CO₃(50 mL), and

brine (50mL) and dried over anhydrous Na₂SO₄. The solvents

were removed using a rotating evaporator, and the residue was

2-(4-Ethylphenyl)-7-methylthio-4,8,8aa,8ba-tetrahydro-

2H,3aaH-pyrrolo[3,4-e]indole-1,3-dione (21).

The general

vacuum-distilled at 39.0^ꢀC/0.02 mm Hg, giving 13 as

a

method was used with vinylpyrrole 13 (2.68g, 19.3mmol) and

maleimide 16 (3.53 g, 17.5 mmol) at RT for 24 h, giving 21

(4.230 g, 71%) as a cream-colored powder: mp 140–142^ꢀC; ¹H

NMR (300 MHz, CDCl₃, d) 7.27 (d, J=7.8 Hz, 2H, Ph), 7.09 (d,

J=8.4 Hz, 2H, Ph), 5.81 (ddd, J=7.5, 3.6, 2.7 Hz, 1H, 5-H), 3.83

(dd, J = 17.3, 4.4 Hz, 1H, 8-H), 3.47 (dd, J = 8.9, 7.4 Hz, 1H,

8ba-H), 3.29 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H, 3aa-H), 3.08

(ddddd, J = 9.7, 7.4, 4.6, 2.6, 2.0 Hz, 1H, 8aa-H), 3.00 (ddd,

J = 15.5, 7.5, 1.8 Hz, 1H, 4b-H), 2.99 (dd, J = 17.4, 9.9 Hz, 1H,

8-H), 2.67 (q, J = 7.7 Hz, 2H, CH₂CH₃), 2.52 (s, 3H, SCH₃),

2.36 (dddd, J = 15.5, 6.7, 3.5, 2.2 Hz, 1H, 4a-H), 1.24 (t,

J = 7.7 Hz, 3H, CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃, d)

181.9, 178.8, 176.8, 159.2, 145.0, 129.3, 128.7, 126.4, 106.7,

colorless liquid (5.99 g, 69%): ¹H NMR (300MHz, CDCl₃, d)

8.47 (bs, 1H, 1-H), 6.53 (dd, J = 18.0, 11.4 Hz, 1H, 1′-H), 6.36

(dd, J = 3.6, 2.4, 1H, pyrrole-b-H), 6.24 (dd, J = 3.0, 3.0 Hz,

1H, pyrrole-b-H), 5.34 (d, J = 18.0Hz, 1H, 2′-H cis to

pyrrole), 5.07 (d, J = 11.1Hz, 1H, 2′-H trans to pyrrole), 2.40

(s, 3H, SCH₃); ¹³C NMR (75 MHz, CDCl₃, d) 133.7, 127.5,

123.4, 116.7, 110.7, 109.8, 22.3; IR (CH₂Cl₂thin ﬁlm, cm^À1

)

3445(bs), 3053(s), 2987(w), 2925(w), 1633(m), 1538(w), 1453

(m), 1424(m), 1374(w), 1314(w), 1266(s), 1135(m), 1036(m),

982(m), 893(m), 781(s), 739(s), 705(s), 638(m). Anal. Calcd

for C₇H₉NS: C, 60.39; H, 6.52; N, 10.06. Found: C, 60.13; H,

6.32; N, 9.84.

1-Methyl-2-methylthio-5-vinyl-1H-pyrrole (14).

The

41.3, 40.5, 39.6, 37.1, 28.7, 25.4, 15.5, 14.0; IR (KBr, cm^À1

)

3053(m), 2967(s), 2927(s), 2848(m), 2595(w), 1771(w), 1702

(s), 1528(s), 1514(s), 1459(w), 1397(s), 1337(m), 1313(m),

1283(m), 1251(w), 1205(s), 1092(m), 1077(m), 1052(w), 1020

(w), 996(w), 958(w), 897(w), 862(w), 839(m), 799(m), 657(w);

HRMS m/z (M + Na⁺) calcd 363.1138, found 363.1136. Anal.

Calcd for C₁₉H₂₀N₂O₂S: C, 67.03; H, 5.92; N, 8.23. Found: C,

66.99; H, 6.00; N, 8.18.

procedure for 13 was used using aldehyde 12 (14.37 g,

92.6 mmol). The residue was distilled at 57.0^ꢀC/0.02 mm Hg,

giving 14 as a colorless liquid (11.46g, 81%): ¹H NMR

(300 MHz, CDCl₃, d) 6.63 (dd, J=17.4, 11.1, 1H, 1′-H), 6.39–6.41

(m, 2H, pyrrole-b-H), 5.57 (d, J=17.4 Hz, 1H, 2′-H cis to

pyrrole), 5.15 (d, J=11.4 Hz, 1H, 2′-H trans to pyrrole), 3.72 (s,

3H, NCH₃), 2.29 (s, 3H, SCH₃); ¹³C NMR (75MHz, CDCl₃, d)

135.6, 126.7, 125.2, 116.6, 112.9, 106.8, 31.4, 20.0; IR (CH₂Cl₂

thin ﬁlm, cm^À1) 3092(w), 3049(m), 2984(m), 2943(m), 2921(s),

2849(w), 2305(w), 1803(w), 1692(w), 1622(m), 1461(w), 1435

(s), 1408(m), 1388(w), 1306(m), 1265(s), 1200(w), 1151(w), 1092

(w), 1038(w), 1018(w), 978(m), 968(m), 897(m), 766(s), 742(s),

705(s), 630(m). Anal. Calcd for C₈H₁₁NS: C, 62.70; H, 7.24;

N, 9.14. Found: C, 62.81; H, 6.99; N, 8.86.

2-(3-Methoxyphenyl)-7-methylthio-4,8,8aa,8ba-tetrahydro-

2H,3aaH-pyrrolo[3,4-e]indole-1,3-dione (22).

The general

method was used with vinylpyrrole 13 (2.023 g, 14.5 mmol) and

maleimide 17 (2.684 g, 13.2 mmol) at RT for 24 h, giving 22

1

(2.744 g, 61%) as an orange powder: mp 151–152^ꢀC; H NMR

(300 MHz, CDCl₃, d) 7.34 (dd, J = 8.3, 8.3 Hz, 1H, 5′-H), 6.92

(ddd, J = 8.4, 2.7, 0.9 Hz, 1H, 4′-H), 6.77 (ddd, J = 7.8, 2.0,

1.1 Hz, 1H, 6′-H), 6.71 (dd, J = 2.1, 2.1 Hz, 1H, 2′-H), 5.81

(ddd, J = 7.5, 3.6, 2.7 Hz, 1H, 5-H), 3.82 (dd, J = 17.1, 4.2 Hz,

1H, 8-H), 3.80 (s, 3H, OCH₃), 3.47 (dd, J = 8.9, 7.4 Hz, 1H,

8ba-H), 3.29 (ddd, J = 8.8, 7.1, 1.6 Hz, 1H, 3aa-H), 3.08 (ddddd,

J = 10.4, 7.4, 4.2, 2.7, 2.1 Hz, 1H, 8aa-H), 3.00 (ddd, J = 15.6,

7.5, 1.5 Hz, 1H, 4b-H), 2.99 (dd, J = 17.0, 10.4 Hz, 1H,

8-H), 2.52 (s, 3H, SCH₃), 2.36 (dddd, J = 15.6, 7.0, 3.5,

2.1Hz, 1H, 4a-H); ¹³C NMR (75MHz, CDCl₃, d) 182.0,

178.6, 176.6, 160.1, 159.2, 132.8, 129.9, 118.9, 114.6, 112.5,

General method for Diels–Alder reactions. A mixture of

vinylpyrrole (1.1 equiv) and dienophile (1.0 equiv) in chloroform

(20 mL) was stirred at RT for 24 h and, if TLC analysis indicated

insigniﬁcant consumption of the dienophile, was reﬂuxed for

24 h, at which point the TLC analysis indicated completion of

the reaction. The solvent was removed using a rotating

evaporator. The crude adduct was puriﬁed by MPLC using

ethyl acetate/hexanes as eluent followed by recrystallization

from dichloromethane/petroleum ether, giving the desired

product in moderate to good yields.

106.7, 55.5, 41.3, 40.5, 39.6, 37.1, 25.4, 14.0; IR (KBr, cm^À1

)

3068(m), 3003(m), 2957(s), 2923(s), 2834(m), 2571(w), 1775

(w), 1703(s), 1607(m), 1590(m), 1522(m), 1490(m), 1457(m),

1427(m), 1383(s), 1337(m), 1313(m), 1286(s), 1255(s), 1227

(m), 1190(s), 1166(s), 1135(m), 1094(m), 1083(m), 1048(m),

7-Methylthio-2-phenyl-4,8,8aa,8ba-tetrahydro-2H,3aaH-

pyrrolo[3,4-e]indole-1,3-dione(20).

The general method was

used with vinylpyrrole 13 (2.78g, 20.0 mmol) and maleimide 15

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

804

W. E. Noland, N. P. Lanzatella, R. R. Dickson, M. E. Messner, and H. H. Nguyen

Vol 50

1023(w), 960(w), 865(w), 843(w), 810(m), 783(w), 690(m);

HRMS m/z (M + Na⁺) calcd 365.0931, found 365.0919. Anal.

Calcd for C₁₈H₁₈N₂O₃S: C, 63.14; H, 5.30; N, 8.18. Found: C,

62.82; H, 5.18; N, 7.98.

Ph), 6.54 (s, 1H, 8-H), 4.07 (ddd, J = 8.1, 1.3, 1.3 Hz, 1H,

8ba-H), 3.55 (s, 3H, NCH₃), 3.41 (ddd, J = 8.0, 4.9, 4.9 Hz,

1H, 3aa-H), 2.49–2.63 (m, 3H, 5-H, 4b-H), 2.60 (s, 3H,

SCH₃), 2.04 (dddd, J = 13.3, 9.9, 5.9, 5.1 Hz, 1H, 4a-H); ¹³C

NMR (75 MHz, CDCl₃, d) 178.6, 177.5, 132.7, 131.6, 129.7,

129.0, 126.9, 124.1, 114.8, 111.1, 41.1, 40.8, 30.8, 22.2, 21.9,

19.7; IR (KBr, cm^À1) 3061(w), 2980(w), 2952(m), 2918(m),

2845(m), 1774(m), 1711(s), 1595(m), 1496(m), 1448(m), 1389(s),

1346(m), 1289(m), 1210(s), 1187(s), 1155(s), 1138(m), 1098(m),

1071(w), 1051(w), 1028(w), 964(m), 911(w), 890(m), 873(m), 830

(m), 795(m), 780(m), 750(s), 698(m); HRMS m/z (M + Na⁺) calcd

349.0982, found 349.0989. Anal. Calcd for C₁₈H₁₈N₂O₂S: C,

66.23; H, 5.56; N, 8.58. Found: C, 66.25; H, 5.76; N, 8.40.

2-(4-Bromophenyl)-7-methylthio-4,8,8aa,8ba-tetrahydro-

2H,3aaH-pyrrolo[3,4-e]indole-1,3-dione(23).

The general

method was used with vinylpyrrole 13 (1.54 g, 11mmol) and

maleimide 18 (2.5 g, 10mmol) at RT for 24h, giving 23 (3.54 g,

81%) as cream-colored crystals: mp 188–190^ꢀC; ¹H NMR

(300MHz, DMSO-d₆, d) 7.66 (d, J = 8.4 Hz, 2H, Ph), 7.06 (d,

J = 8.7 Hz, 2H, Ph), 5.62 (ddd, J = 6.9, 3.4, 3.3 Hz, 1H, 5-H), 3.54

(dd, J = 8.7, 7.0 Hz, 1H, 8ba-H ), 3.52 (dd, J = 16.2, 4.2 Hz, 1H,

8-H), 3.31 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H, 3aa-H), 3.07 (ddddd,

J = 9.9, 7.0, 4.2, 3.4, 2.5 Hz, 1H, 8aa-H), 2.99 (dd, J = 16.9,

9.9 Hz, 1H, 8-H), 2.65 (ddd, J = 15.6, 7.2, 1.5 Hz, 1H, 4b-H) 2.42

(s, 3H, SCH₃), 2.29 (dddd, J = 15.6, 7.2, 3.3, 1.5 Hz, 1H, 4a-H);

¹³C NMR (75MHz, DMSO-d₆, d) 181.9, 179.8, 178.1, 160.6,

133.1, 132.4, 130.0, 122.4, 107.1, 42.3, 41.4, 40.2, 37.6, 26.0, 14.6.

7-Methylthio-2-phenyl-3aa,4,5,8ba-tetrahydro-2H,6H-pyrrolo

2-(4-Ethylphenyl)-6-methyl-7-methylthio-3aa,4,5,8ba-tetrahydro-

2H,6H-pyrrolo[3,4-e]indole-1,3-dione (31).

The general

method was used with vinylpyrrole 14 (2.069g, 13.05mmol) and

maleimide 16 (2.386 g, 11.86 mmol) with reﬂux for 24 h, giving

31 (1.827 g, 44%) as cream-colored crystals: mp 185–186^ꢀC;

¹H NMR (300MHz, CDCl₃, d) 7.25 (d, J = 9.3 Hz, 2H, Ph),

7.14 (d, J = 8.8 Hz, 2H, Ph), 6.53 (s, 1H, 8-H), 4.06 (ddd, J = 7.8,

1.2, 1.2 Hz, 1H, 8ba-H), 3.55 (s, 3H, NCH₃), 3.40 (ddd, J = 8.0,

4.9, 4.9 Hz, 1H, 3aa-H), 2.65 (q, J = 7.6 Hz, 2H, CH₂CH₃), 2.52–

2.66 (m, 2H, 5-H), 2.52 (dddd, J = 13.8, 4.7, 4.7, 4.7 Hz, 1H, 4b-

H), 2.25 (s, 3H, SCH₃), 2.04 (dddd, J = 13.3, 9.8, 6.0, 5.2 Hz, 1H,

4a-H), 1.22 (t, J = 7.5 Hz, 3H, CH₂CH₃); ¹³C NMR (75MHz,

CDCl₃, d) 178.8, 177.6, 145.2, 131.6, 130.2, 129.2, 126.8, 124.0,

114.8, 111.2, 41.1, 40.8, 30.8, 29.3, 22.2, 21.9, 19.7, 16.2; IR

(KBr, cm^À1) 3090(w), 3040(w), 2930(s), 2927(s), 2894(m), 2868

(m), 2845(m), 1776(w), 1706(s), 1607(w), 1513(m), 1444(m),

1392(s), 1345(m), 1289(m), 1256(w), 1232(w), 1207(m), 1175(s),

1137(m), 1105(w), 1055(w), 1023(w), 998(w), 963(m), 952(w),

909(w), 874(w), 839(w), 820(m), 797(m), 770(w), 730(w), 695

(m); HRMS m/z (M + Na⁺) calcd 377.1292, found 377.1293.

Anal. Calcd for C₂₀H₂₂N₂O₂S: C, 67.77; H, 6.26; N, 7.90.

Found: C, 67.55; H, 6.00; N, 7.60.

[3,4-e]indole-1,3-dione(25).

The procedure for compound 20

was used and then isolated by MPLC, and followed with

recrystallization from methylene chloride/petroleum ether, giving

1

25 (513mg, 9%) as a cream-colored powder: mp 166–168^ꢀC; H

NMR (300 MHz, CDCl₃, d) 7.99 (bs, 1H, 6-H), 7.31–7.46

(m, 3H, Ph), 7.22–7.27 (m, 2H, Ph), 6.50 (d, J = 2.7 Hz, 1H,

8-H), 4.07 (d, J = 8.1 Hz, 1H, 8ba-H), 3.41 (ddd, J = 8.0,

5.0, 5.0 Hz, 1H, 3aa-H), 2.56–2.63 (m, 2H, 5-H), 2.48

(dddd, J = 13.5, 4.6, 4.6, 4.6 Hz, 1H, 4b-H), 2.33 (s, 3H,

SCH₃), 2.02 (dddd, J = 13.0, 7.8, 7.8, 5.3 Hz, 1H, 4a-H); ¹³C

NMR (75 MHz, CDCl₃, d) 178.6, 177.5, 132.6, 130.1, 129.7,

129.1, 126.9, 121.8, 114.8, 112.4, 40.9, 40.7, 22.4, 22.4, 20.1;

IR (KBr, cm^À1) 3350(bs), 3050(w), 2921(m), 2851(m), 1776(w),

1709(s), 1595(w), 1498(m), 1453(w), 1436(w), 1382(s), 1309(w),

1290(w), 1258(w), 1236(w), 1185(m), 1152(m), 1086(m), 1040

(w), 1010(w), 995(w), 970(w), 910(w), 873(w), 823(w), 806(w),

789(w), 740(m), 693(m); HRMS m/z (M+ Na⁺) calcd 335.0825,

found 335.0824. Anal. Calcd for C₁₇H₁₆N₂O₂S: C, 65.36; H,

5.16; N, 8.97, for C₁₇H₁₆N₂O₂SÁ0.33H₂0: C, 64.15; H, 5.27; N,

8.80. Found: C, 64.15; H, 5.33; N, 8.50.

2-(3-Methoxyphenyl)-6-methyl-7-methylthio-3aa,4,5,8ba-

tetrahydro-2H,6H-pyrrolo[3,4-e]indole-1,3-dione (32).

The

general method was used with vinylpyrrole 14 (2.069 g,

13.05 mmol) and maleimide 17 (2.410 g, 11.86mmol) with reﬂux

for 24 h, giving 32 (1.729g, 41%) as cream-colored crystals: mp

2-Dimethylamino-7-methylthio-3aa,4,5,8ba-tetrahydro-2H,6H-

1

pyrrolo[3,4-e]indole-1,3-dione (29).

The general method was

161–162^ꢀC; H NMR (300 MHz, CDCl₃, d) 7.32 (dd, J = 8.3,

used with vinylpyrrole 13 (1.76g, 12mmol) and maleimide 19

(1.61 g, 11mmol) with reﬂux for 24 h, giving 29 (2.08 g, 62%) as

a peach-colored glass: mp 104–106^ꢀC; ¹H NMR (300 MHz,

CDCl₃, d) 8.20 (bs, 1H, 6-H), 6.40 (d, J = 2.7 Hz, 1H, 8-H), 3.80

(d, J = 8.1Hz, 1H, 8ba-H), 3.12 (ddd, J = 7.8, 5.4, 5.4 Hz, 1H,

3aa-H), 2.81 (s, 6-H, NCH₃), 2.20–2.55 (m, 2H, 5-H), 2.29 (s, 3-H,

SCH₃), 2.26 (dddd, J = 13.8, 8.7, 5.7, 5.4 Hz, 1H, 4b-H), 1.95

(dddd, J = 13.8, 5.4, 5.4, 5.4 Hz, 1H 4a-H); ¹³C NMR

(300 MHz, CDCl₃, d) 178.0, 176.9, 130.0, 121.6, 114.6, 111.9,

8.3 Hz, 1H, 5′-H), 6.78–6.91 (m, 3H, 2′-H, 4′-H, 6′-H), 6.54

(s, 1H, 8-H), 4.06 (d, J = 8.1 Hz, 1H, 8ba-H), 3.78 (s, 3H,

OCH₃), 3.55 (s, 3H, NCH₃), 3.40 (ddd, J = 8.1, 5.0, 5.0 Hz, 1H,

3aa-H), 2.46-2.68 (m, 3H, 5-H, 4b-H), 2.25 (s, 3H, SCH₃), 2.04

(dddd, J = 14.4, 9.5, 5.3, 4.8 Hz, 1H, 4a-H); ¹³C NMR (75MHz,

CDCl₃, d) 178.6, 177.4, 160.6, 133.7, 131.6, 130.4, 124.1,

119.2, 114.9, 114.8, 112.8, 111.1, 56.1, 41.1, 40.8, 30.8, 22.2,

21.9, 19.7; IR (KBr, cm^À1) 3103(m), 3060(w), 3034(w), 2996

(m), 2977(m), 2944(s), 2928(s), 2914(s), 2849(m), 2839(m),

1781(w), 1708(s), 1606(m), 1591(m), 1567(w), 1493(m), 1443(m),

1390(s), 1368(m), 1348(w), 1332(w), 1316(w), 1292(s),

1252(m), 1230(m), 1208(m), 1176(s), 1137(m), 1095(w), 1039(m),

1008(w), 968(w), 953(w), 903(w), 889(w), 859(w), 835(w),

808(w), 795(m), 754(w), 734(w), 695(m), 653(w); HRMS m/z

(M + Na⁺) calcd 379.1088, found 379.1087. Anal. Calcd

for C₁₉H₂₀N₂O₃S: C, 64.02; H, 5.66; N, 7.86. Found: C,

63.89; H, 5.62; N, 7.63.

44.6, 39.2, 39.0, 22.7, 22.3, 20.2; IR (CH₂Cl₂thin ﬁlm, cm^À1

)

3314(w), 2975(m), 2937(m), 1717(s), 1709(s), 1559(s), 1360

(m), 1196(m), 1140(m), 1083(m), 1017(m0, 800(m), 732(m);

HRMS m/z (M + Na⁺) calcd 302.0934, found 302.0941. Anal.

Calcd for C₁₄H₁₉N₃O₂S: C, 55.89; H, 6.13; N, 15.04. Found:

C, 55.82; H, 6.05; N, 14.82.

6-Methyl-7-methylthio-2-phenyl-3aa,4,5,8ba-tetrahydro-2H,6H-

pyrrolo[3,4-e]indole-1,3-dione (30).

The general method was

used with vinylpyrrole 14 (2.069 g, 13.05 mmol) and maleimide

15 (2.054g, 11.86 mmol) with reﬂux for 24h, giving 30 (1.153g,

30%) as cream-colored crystals: mp 130–131^ꢀC; ¹H NMR

(300MHz, CDCl₃, d) 7.31–7.45 (m, 3H, Ph), 7.22–7.27 (m, 2H,

2-Dimethylamino-6-methyl-7-methylthio-3aa,4,5,8ba-tetrahydro-

2H,6H-pyrrolo[3,4-e]indole-1,3-dione (33).

The general

method was used with vinylpyrrole 14 (5.84 g, 0.038mol) and

maleimide 19 (3.56g, 0.025mol) with reﬂux for 24h, giving 33

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

July 2013

Access to Indoles via Diels–Alder Reactions of

805

5-Methylthio-2-vinylpyrroles with Maleimides

(3.98 g, 66%) as colorless crystals: mp 133–134^ꢀC; ¹H NMR

(300MHz, CDCl₃, d) 6.50 (s, 1H, 8-H), 3.81 (d, J = 7.8 Hz, 1H,

8ba-H), 3.52 (s, 3H, NCH₃), 3.13 (ddd, J = 7.9, 5.3, 5.1 Hz, 1H,

3aa-H), 2.83 (s, 6H, N(CH₃)₂), 2.42–2.62 (m, 2H, 5-H), 2.30

(dddd, J = 13.5, 5.2, 5.2, 5.1 Hz, 1H, 4b-H), 2.23 (s, 3H, SCH₃),

1.99 (dddd, J = 14.0, 8.7, 5.5, 5.5 Hz, 1H, 4a-H) ¹³C NMR

(300 MHz, CDCl₃, d) 178.0, 176.9, 131.5, 124.0, 114.7, 110.7,

44.6, 39.3, 39.1, 30.8, 22.6, 21.8, 19.8; IR (KBr, cm^À1) 2940

(w), 1776(m), 1706(s), 1654(m), 1560(w), 1442(m), 1369(m),

1346(w), 1292(w), 1187(m), 1148(m), 1107(w), 1033(w), 968

(w), 906(w), 875(w), 823(w), 802(w), 768(w), 630(w); HRMS

m/z (M + Na⁺) calcd 316.1091, found 316.1093. Anal. Calcd

for C₁₄H₁₉N₃O₂S: C, 57.31; H, 6.53; N, 14.32. Found: C,

57.11; H, 6.38; N, 14.12.

2.4 Hz, 1H, 5a-H), 3.65 (s, 3H, 6-Me), 3.33 (ddd, J = 9.2, 7.1,

2.0 Hz, 1H, 3aa-H), 3.03 (ddd, J = 14.6, 2.0, 2.0 Hz, 1H, 4b-H),

2.65 (q, J = 7.6 Hz, 2H, CH₂CH₃), 2.27 (s, 3H, MeS), 2.18

(s, 3H, MeS), 2.16 (ddd, J = 14.7, 6.9, 3.9 Hz, 1H, 4a-H), 1.22

(t, J = 7.7 Hz, 3H, CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃, d)

179.5, 177.3, 145.2, 130.7, 129.9, 129.2, 127.0, 125.9, 114.6,

112.7, 39.6, 38.4, 38.2, 30.5, 29.3, 26.4, 21.4, 16.13, 16.11; IR

(KBr, cm^À1) 2965(m), 2916(m), 1775(w), 1705(s), 1514(m),

1444(m), 1432(m), 1395(m), 1347(w), 1309(w), 1296(w), 1258

(w), 1216(m), 1191(m), 1139(w), 1109(w), 960(w), 870(w),

837(w), 817(m), 789(w), 761(w); HRMS m/z (M + Na⁺) calcd

423.1172, found 423.1187. Anal. Calcd for C₂₁H₂₄N₂O₂S₂: C,

62.97; H, 6.04; N, 6.99. Found: C, 62.77; H, 5.95; N, 6.77.

2-(4-Ethylphenyl)-8-(1-(4-ethylphenyl)-2,5-dioxopyrrolidin-3-

yl)-5b,7-bis(methylthio)-3aa,4,5a,8ba-tetrahydro-2H,6H-

pyrrolo[3,4-e]indole-1,3-dione (45). By using the procedure for

44 and MPLC to isolate 45 from the crude product, recrystallization

from methylene chloride/petroleum ether followed, giving 45

(54 mg, 7%) as white crystals: mp 207–208^ꢀC; ¹H NMR

(300 MHz, CDCl₃, d) 7.32 (d, J=8.7 Hz, 2H, Ph), 7.24–7.27 (m,

4H, Ph), 7.16 (d, J = 8.4 Hz, 2H, Ph), 4.80 (dd, J = 9.8, 6.8 Hz,

1H, 3′-H), 4.26 (d, J = 9.3 Hz, 1H, 8ba-H), 4.10 (dd, J = 3.8,

2.3 Hz, 1H, 5a-H), 3.72 (s, 3H, 6-Me), 3.28 (ddd, J = 9.0, 7.4,

1.5 Hz, 1H, 3aa-H), 3.24 (dd, J = 9.6, 17.7, 9.6 Hz, 1H, 4′-H),

3.05 (dd, J = 18.0, 6.6 Hz, 1H, 4′-H), 3.01 (ddd, J = 14.6, 2.0,

2.0 Hz, 1H, 4b-H), 2.69 (q, J = 7.6 Hz, 2H, CH₂CH₃), 2.66 (q,

J = 7.6 Hz, 2H, CH₂CH₃), 2.20 (s, 3H, MeS), 2.19 (s, 3H, MeS),

2.13 (ddd, J=14.5, 7.1, 3.9 Hz, 1H, 4a-H), 1.26 (t, J=7.5 Hz, 3H,

ÀCH₂CH₃), 1.23 (t, J=7.5 Hz, 3H, ÀCH₂CH₃); ¹³C NMR

(75 MHz, CDCl₃, d) 179.4, 179.1, 177.5, 176.8, 145.4, 145.3,

130.80, 130.76, 130.5, 129.4, 129.2, 127.4, 126.9, 39.2, 38.6,

2-Methylthio-5-thioacetyl-1H-pyrrole (40) [24,25].

2-

Methylthio-5-acetylpyrrole 38 [13,36] (8.657 g, 55.773mmol) was

dissolved in THF (250 mL). Lawesson’s reagent (27.07 g,

66.928mmol) was added, and the mixture was stirred at RT for

3 h, at which time TLC indicated complete consumption of the

starting material. The solvent was removed using a rotating

evaporator, and the crude product was ﬂash chromatographed on

a short silica gel column by using 1:2 ethyl acetate: hexanes. The

solvent was removed using a rotating evaporator, giving 40

(7.735g, 81%) as brown plates: mp 75–76^ꢀC; ¹H NMR

(300MHz, CDCl₃, d) 9.50 (bs, 1H, 1-H), 6.94 (dd, J = 3.9,

2.4 Hz, 1H, 3-H), 6.27 (dd, J = 4.2, 2.7 Hz, 1H, 4-H), 2.84 (s, 3H,

thioacetyl), 2.52 (s, 3H, thioacetyl); ¹³C NMR (75 MHz, CDCl₃, d)

143.2, 140.8, 116.0, 114.0, 34.1, 17.7; IR (KBr, cm^À1) 3291

(bs), 2977(m), 1709(w), 1524(m), 1459(m), 1432(m), 1379(s),

1341(m), 1319(m), 1227(m), 1190(m), 1142(m), 1078(w), 1059

(m), 990(w), 970(w), 969(w), 931(w), 865(w), 832(s), 760(s).

Anal. Calcd for C₇H₉N₁S₂: C, 49.09; H, 5.30; N, 8.18. Found: C,

48.98; H, 5.46; N, 7.99.

1-Methyl-2-methylthio-5-thioacetyl-1H-pyrrole (41) [24,25].

Crude N-methyl-2-methylthio-5-acetylpyrrole 39 [13,36] (9.15 g,

54.064mmol, included approximately 13% 2- and 3-acetyl-N-

methylpyrrole by mass) was dissolved in THF (250 mL).

Lawesson’s reagent (26.24g, 64.877mmol) was added, and the

mixture was stirred at RT for 3 h, at which time TLC indicated

complete consumption of the starting materials. The solvent was

removed using a rotating evaporator, and the crude product was

ﬂash chromatographed on a short silica gel column by using 1:2

ethyl acetate: hexanes. The solvent was removed using a rotating

evaporator, giving 41 (5.207g, 52%) as a dark-colored foul-

smelling liquid that included approximately 15% impurities

by mass: ¹H NMR (300 MHz, CDCl₃, d, only peaks from

41 reported) 7.17 (d, J = 4.5 Hz, 1H, 3-H), 6.17 (d, J = 4.8 Hz, 1H,

4-H), 4.07 (s, 3H, 1-CH₃), 2.95 (s, 3H, thioacetyl), 2.48 (s, 3H,

SCH₃); HRMS m/z (M+ H⁺) calcd 186.0412, found 186.0402.

2-(4-Ethylphenyl)-5b,7-bis(methylthio)-3aa,4,5a,8ba-

38.5, 38.2, 30.8, 29.33, 29.31, 26.2, 16.2, 16.1; IR (KBr, cm^À1

)

2960(m), 2923(m), 1776(w), 1709(s), 1514(m), 1457(w), 1419

(w), 1388(m), 1353(w), 1177(s), 986(w), 970(w), 877(w), 829

(m), 753(m), 732(w); HRMS m/z (M + Na⁺) calcd 624.1962,

found 624.1984. Anal. Calcd for C₃₃H₃₅N₃O₄S₂: C, 65.86; H,

5.86; N, 6.98. Found: C, 65.98; H, 6.01; N, 6.84.

General method for dehydrogenation of the Diels–Alder

adducts.

A mixture of the adduct (1 equiv) and activated

MnO₂[39] (5 equiv) in toluene (20 mL) was stirred under reﬂux

for 24 h at which point TLC analysis indicated complete

conversion of the starting materials. The mixture was cooled to

RT and vacuum-ﬁltered through a ﬁne glass-fritted funnel. The

insoluble manganese salts were washed with several portions of

dichloromethane until the washings ran colorless (5 Â 20 mL),

and the combined organic ﬁltrate and washings were evaporated

to dryness using a rotating evaporator.Following evaporation,

the crude mixtures were puriﬁed by MPLC with ethyl acetate/

hexanes as eluent and succeeded by recrystallization from

dichloromethane/petroleum ether, giving the desired product in

fair to good yield.

tetrahydro-2H,6H-pyrrolo[3,4-e]indole-1,3-dione (44).

A

mixture of the vinylpyrroles 42 and 43 [2.919 mmol, generated

freshly from 2-methylthio-5-thioacetyl-1H-pyrrole 40 (500 mg),

approximately 1:2 42: 43 by mass [24,25]], and the maleimide 16

(1.1equiv) in chloroform was stirred at RT for 3 d and then

reﬂuxed for 5 h. The solvent was removed using a rotating

evaporator. The crude adduct was puriﬁed by MPLC using ethyl

acetate/hexanes as eluent, followed by recrystallization from

methylene chloride/petroleum ether, giving 44 (405 mg, 38%) as a

7-Methylthio-2-phenyl-2H,6H-pyrrolo[3,4-e]indole-1,3-dione

(51).

The general method was used with adduct 20 (3.138 g,

10.05 mmol), giving 51 (1.941 g, 63%) as yellow crystals: mp

282–283^ꢀC; ¹H NMR (300 MHz, DMSO-d₆, d) 12.29 (bs,

1H, 6-H), 7.64 (d, J = 8.1 Hz, 1H, 5-H), 7.54 (d, J = 8.1 Hz,

1H, 4-H), 7.48–7.55 (m, 2H, Ph), 7.37–7.45 (m, 3H, Ph), 6.68

(s, 1H, 7-H), 2.64 (s, 3H, SCH₃); ¹³C NMR (75 MHz, DMSO-

d₆, d) 169.4, 169.0, 143.6, 143.1, 133.5, 129.9, 128.7, 128.4,

124.8, 124.6, 121.1, 116.4, 116.2, 99.0, 34.6; IR (KBr, cm^À1) 3289

(bs), 3095(w), 3060(w), 2980(w), 2995(w), 2930(w), 1749(m),

1

white powder: mp 136–137^ꢀC; H NMR (300 MHz, CDCl₃, d)

7.25 (d, J = 8.7 Hz, 2H, Ph), 7.19 (d, J = 8.7 Hz, 2H, Ph), 6.50 (s,

1H, 7-H), 4.13 (d, J = 9.3 Hz, 1H, 8ba-H), 4.07 (dd, J = 3.9,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

806

W. E. Noland, N. P. Lanzatella, R. R. Dickson, M. E. Messner, and H. H. Nguyen

Vol 50

1703(s), 1598(w), 1494(m), 1468(m), 1420(w), 1386(s), 1367(s),

1324(w), 1283(m), 1219(m), 1151(m), 1093(m), 1018(w), 960(w),

943(w), 844(w), 826(w), 793(w), 766(w), 752(s), 725(w), 686(m),

667(w), 625(m); HRMS m/z (M + Na⁺) calcd 331.0512, found

331.0511. Anal. Calcd for C₁₇H₁₂N₂O₂S: C, 66.22; H, 3.92; N,

9.08, for C₁₇H₁₂N₂O₂SÁ0.37H₂O: C, 64.82; H, 4.08; N, 8.89.

Found: C, 64.83; H, 3.80; N, 8.76.

6-Methyl-7-methylthio-2-phenyl-2H,6H-pyrrolo[3,4-e]indole-

1,3-dione (55). The general method was used with adduct 30

(0.314 g, 0.962 mmol), giving 55 (224 mg, 72%) as light-orange

crystals: mp 239–240^ꢀC; ¹H NMR (300 MHz, DMSO-d₆, d)

7.87 (dd, J = 8.3, 0.75 Hz, 1H, 5-H), 7.61 (d, J = 8.4 Hz, 1H, 4-

H), 7.38–7.55 (m, 5H, Ph), 6.74 (d, J = 0.9 Hz, 1H, 8-H), 3.80

(s, 3H, NCH₃), 2.66 (s, 3H, SCH₃); ¹³C NMR (75 MHz,

DMSO-d₆, d) 169.3, 168.9, 146.1, 143.5, 133.4, 130.0, 128.8,

128.4, 124.9, 123.9, 121.2, 116.0, 115.6, 98.7, 31.8, 16.9; IR

(KBr, cm^À1) 3120(m), 3060(m), 3010(m), 2930(m), 1753(m),

1705(s), 1595(w), 1502(m), 1477(s), 1426(m), 1378(s), 1343(m),

1318(m), 1293(m), 1232(m), 1182(m), 1168(w), 1095(m),

1063(w), 998(w), 958(w), 907(w), 849(w), 820(w), 802(w), 740

(m), 730(m), 692(m), 662(w); HRMS m/z (M + Na⁺) calcd

345.0669, found 345.0679. Anal. Calcd for C₁₈H₁₄N₂O₂S: C,

67.06; H, 4.38; N, 8.69. Found: C, 66.89; H, 4.37; N, 8.52.

2-(4-Ethylphenyl)-6-methyl-7-methylthio-2H,6H-pyrrolo[3,4-

2-(4-Ethylphenyl)-7-methylthio-2H,6H-pyrrolo[3,4-e]indole-

1,3-dione (52). The general method was used with adduct 21

(5.263 g, 15.46 mmol), giving 52 (3.016 g, 58%) as yellow

crystals: mp 280–282^ꢀC; ¹H NMR (300 MHz, DMSO-d₆, d)

12.30 (bs, 1H, 6-H), 7.67 (dd, J = 8.3, 0.8 Hz, 1H, 5-H), 7.56

(d, J = 8.1 Hz, 1H, 4-H), 7.36 (d, J = 8.7 Hz, 2H, Ph), 7.33 (d,

J = 8.4 Hz, 2H, Ph), 6.71 (dd, J = 1.8, 0.6 Hz, 1H, 8-H), 2.67

(q, J = 7.6 Hz, 2H, CH₂CH₃), 2.67 (s, 3H, SCH₃), 1.23 (t,

1

J = 7.7 Hz, 3H, CH₂CH₃); H NMR (300 MHz, Acetone-d₆, d)

11.28 (bs, 1H, 6-H), 7.76 (dd, J = 8.1, 0.9 Hz, 1H, 5-H), 7.61

(d, J = 8.4 Hz, 1H, 4-H), 7.44 (d, J = 8.7 Hz, 2H, Ph), 7.38

(d, J = 8.7 Hz, 2H, Ph), 6.85 (d, J = 2.1, 0.9 Hz, 1H, 8-H), 2.74

(q, J = 7.6 Hz, 2H, CH₂CH₃), 2.74 (s, 3H, ÀSCH₃), 1.29 (t,

J = 7.5 Hz, 3H, CH₂CH₃); ¹³C NMR (75 MHz, DMSO-d₆, d)

168.9, 168.5, 143.8, 143.0, 142.5, 130.4, 128.7, 127.8, 124.2,

124.1, 120.6, 115.7, 115.5, 98.4, 28.4, 16.2, 16.0; IR (KBr,

cm^À1) 3352(bs), 3041(w), 2971(m), 2927(m), 2856(w), 1753(m),

1695(s), 1516(m), 1491(m), 1464(m), 1456(m), 1419(w), 1386(s),

1365(s), 1318(w), 1277(m), 1232(m), 1180(w), 1154(m), 1117(w),

1097(m), 1061(w), 1016(w), 949(w), 810(w), 801(w), 760(m),

750(m); HRMS m/z (M + Na⁺) calcd 359.0825, found 359.0836.

Anal. Calcd for C₁₉H₁₆N₂O₂S: C, 67.84; H, 4.79; N, 8.33. Found:

C, 67.60; H, 5.20; N, 8.44.

2-(3-Methoxyphenyl)-7-methylthio-2H,6H-pyrrolo[3,4-e]

indole-1,3-dione (53). The general method was used with adduct

22 (2.260 g, 6.60mmol), giving 53 (1.879g, 84%) as yellow

crystals: mp 232–233^ꢀC; ¹H NMR (300MHz, DMSO-d₆, d)

12.31 (bs, 1H, 6-H), 7.66 (d, J = 8.4 Hz, 1H, 5-H), 7.55 (d,

J = 8.1 Hz, 1H, 4-H), 7.43 (dd, J = 8.1, 8.1 Hz, 1H, 5′-H),

6.98–7.06 (m, 3H, 2′-H, 4′-H, 6′-H), 6.70 (d, J = 0.9 Hz, 1H,

8-H), 3.79 (s, 3H, OCH₃), 2.67 (s, 3H, SCH₃); ¹³C NMR

(75 MHz, DMSO-d₆, d) 168.7, 168.3, 160.0, 143.0, 142.5,

134.0, 130.0, 124.2, 124.0, 120.5, 120.0, 115.8, 115.5, 113.7,

98.5, 55.8, 16.0; IR (KBr, cm^À1) 3316(bs), 2957(w), 2922(w),

1753(m), 1703(s), 1607(m), 1495(m), 1459(m), 1387(m), 1371(m),

1316(w), 1288(w), 1264(m), 1217(m), 1181(w), 1152(w),

1098(m), 1034(w), 1022(w), 977(w), 946(w), 902(w),

852(w), 800(w), 768(m), 715(m), 680(w); HRMS m/z

(M + Na⁺) calcd 361.0638, found 361.0643. Anal. Calcd for

C₁₈H₁₄N₂O₃S: C, 63.89; H, 4.17; N, 8.28. Found: C, 63.71;

H, 4.12; N, 8.13.

e]indole-1,3-dione (56).

The general method was used with

adduct 31 (0.320 g, 0.903 mmol), giving 56 (261 mg, 80%) as

yellow crystals: mp 200–201^ꢀC; ¹H NMR (300 MHz, DMSO-

d₆, d) 7.87 (d, J = 8.4 Hz, 1H, 5-H), 7.60 (d, J = 8.4 Hz, 1H, 4-

H), 7.26–7.41 (m, 4H, Ph), 6.75 (s, 1H, 8-H), 3.80 (s, 3H,

NCH₃), 2.66 (s, 3H, SCH₃), 2.66 (q, J = 7.7 Hz, 2H, CH₂CH₃),

1.21 (t, J = 7.5 Hz, 3H, CH₂CH₃); ¹³C NMR (75 MHz, DMSO-

d₆, d) 169.5, 169.0, 146.0, 144.5, 143.5, 131.0, 129.3, 128.4,

124.9, 123.9, 121.3, 115.9, 115.5, 98.7, 31.7, 29.0, 16.9, 16.8;

IR (KBr, cm^À1) 3140(w), 3105(w), 3050(w), 2953(m), 2926

(m), 2880(m), 1761(m), 1703(s), 1625(w), 1515(m), 1480(m),

1423(w), 1376(s), 1342(m), 1294(w), 1236(w), 1180(w), 1118(w),

1084(m), 1000(w), 962(w), 855(w), 844(w), 823(w), 750(m),

721(w), 677(w), 665(w); HRMS m/z (M + Na⁺) calcd

373.0982, found 373.0982. Anal. Calcd for C₂₀H₁₈N₂O₂S: C,

68.55; H, 5.18; N, 7.99. Found: C, 68.31; H, 5.40; N, 7.83.

2-(3-Methoxyphenyl)-6-methyl-7-methylthio-2H,6H-pyrrolo

[3,4-e]indole-1,3-dione (57).

with adduct 32 (0.307 g, 0.861 mmol), giving 57 (251 mg,

83%) as

yellow powder: mp 237–238^ꢀC; ¹H NMR

The general method was used

a

(300 MHz, DMSO-d₆, d) 7.88 (dd, J = 8.1, 0.6 Hz, 1H, 5-H),

7.61 (d, J = 8.1 Hz, 1H, 4-H), 7.41 (dd, J = 8.0 Hz, 1H, 5′-H),

6.97-7.05 (m, 3H, 2′-H, 4′-H, 6′-H), 6.76 (d, J = 0.8 Hz, 1H,

8-H), 3.81 (s, 3H, NCH₃), 3.77 (s, 3H, OCH₃), 2.69 (s, 3H,

SCH₃); IR (KBr, cm^À1) 3100(w), 3030(w), 3005(w), 2960(w),

2940(w), 1752(m), 1710(s), 1607(w), 1591(w), 1491(m), 1478

(m), 1437(w), 1407(w), 1378(s), 1343(m), 1310(w), 1290(m),

1256(s), 1213(m), 1182(m), 1100(m), 1044(m), 995(w), 969

(w), 862(w), 831(w), 750(m), 722(w), 680(w), 620(w); HRMS

m/z (M + Na⁺) calcd 375.0775, found 375.0781. Anal. Calcd

for C₁₉H₁₆N₂O₃S: C, 64.76; H, 4.58; N, 7.95, for

C₁₉H₁₆N₂O₃SÁ0.31H₂O: C, 63.78; H, 4.68; N, 7.83. Found: C,

63.76; H, 4.85; N, 7.67.

2-Dimethylamino-7-methylthio-2H,6H-pyrrolo[3,4-e]indole-

1,3-dione (54). The general method was used with adduct 29

(0.400 g, 1.43 mmol), giving 54 (120 mg, 32%) as an orange

2-Dimethylamino-6-methyl-7-methylthio-2H,6H-pyrrolo[3,4-

1

solid: mp 259–261^ꢀC; H NMR (300 MHz, CDCl₃, d) 8.55 (bs,

e]indole-1,3-dione (58).

The general method was used with

1H, N-H), 7.56 (d, 1H, 6.0 Hz, 4-H), 7.50 (dd, 1H, 6.0,

0.75 Hz, 5-H), 6.87 (dd, 1H, 1.2, 0.7 Hz, 8-H), 3.06 (s, 6H,

NCH₃), 2.63 (s, 3H, SCH₃); ¹³C NMR (500 MHz, CDCl₃, d)

168.4, 168.3, 141.5, 141.1, 124.0, 122.6, 119.3, 115.5, 114.5,

100.1, 44.9, 16.6, 0.86; IR (KBr, cm^À1) 3191(s), 2957(m), 2919

(m), 1779(m), 1734(m), 1718(s), 1701(s), 1656(w), 1652(w),

1555(w), 1440(w), 1363(w), 1202(w), 1142(w), 1083(w), 789(w);

HRMS m/z (M+ Na⁺) calcd 298.0621, found 298.0617. Anal.

Calcd for C₁₃H₁₃N₃O₂S: C, 56.71; H, 4.76; N, 15.26. Found: C,

56.56; H, 4.97; N, 15.08.

adduct 33 (0.159 g, 0.54 mmol), giving 58 (136 mg, 87%) as a

1

yellow powder: mp 167–168^ꢀC; H NMR (300 MHz, CDCl₃, d)

7.51 (d, J = 8.1 Hz, 1H, 5-H), 7.40 (d, J = 8.4Hz, 1H, 4-H), 6.74

(s, 1H, 8-H), 3.72 (s, 3H, NCH₃), 3.03 (s, 6H, N(CH₃)₂), 2.58

(s, 3H, SCH₃); ¹³C NMR (300MHz, CDCl₃, d) 169.3, 169.1,

145.1, 143.3, 123.9, 123,2, 120.0, 115.8, 113.6, 99.4, 45.7, 31.1,

17.3; IR (KBr, cm^À1) 2994(m), 2964(m), 2923(m), 2884(m),

1767(s), 1706(m), 1479(s), 1448(s), 1423(m), 1368(s), 1354(s),

1342(s), 1323(w), 1293(m), 1247(w), 1173(m), 1100(s), 1024(s),

994(m), 970(w), 927(w); HRMS m/z (M+ Na⁺) calcd 312.0778,

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

July 2013

Access to Indoles via Diels–Alder Reactions of

807

5-Methylthio-2-vinylpyrroles with Maleimides

found 312.0782. Anal. Calcd for C₁₄H₁₅N₃O₂S: C, 58.11; H, 5.23;

N, 14.52. Found: C, 58.21; H, 5.40; N, 14.37.

2-Dimethylamino-2H,6H-pyrrolo[3,4-e]indole-1,3-dione

(62).

The general method was used with 2-(methylthio)

indole 54 (19 mg, 0.069 mmol), giving 62 (8.6 mg, 54%) as

bright-yellow crystals: ¹H and ¹³C NMR spectra matched

the literature values [6].

General method for demethylthioation of 2-methylthioin-

doles. The indole was dissolved in acetone (5 mL), and Raney

nickel (300 mg, 5.11mmol) was added in excess, in several

portions, at 30-min intervals over the time of the reaction. The

reaction mixture was stirred at RT and monitored by TLC; the

starting material was observed to be completely consumed after

2 h. The mixture was ﬁltered, and the ﬁltrate was washed with

brine, dried over sodium sulfate, and evaporated to dryness

using a rotating evaporator. MPLC with ethyl acetate/hexanes

as eluent followed by recrystallization from dichloromethane/

petroleum ether was used, giving the desired product in

excellent yield.

6-Methyl-2-phenyl-2H,6H-pyrrolo[3,4-e]indole-1,3-dione

(63) [6].

The general method was used with 2-(methylthio)

indole 55 (0.081 g, 0.251 mmol), giving 63 (66 mg, 95%) as

yellow crystals: mp 221–222^ꢀC; ¹H NMR (300 MHz, CDCl₃,

d) 7.77 (d, J = 8.4 Hz, 1H, 4-H), 7.64 (dd, J = 8.3, 0.8 Hz,

1H, 5-H), 7.48–7.54 (m, 4H, Ph), 7.35–7.41 (m, 2H, 7-H,

Ph), 7.05 (dd, J = 3.3, 0.9 Hz, 1H, 8-H), 3.92 (s, 3H, NCH₃);

¹³C NMR (75 MHz, CDCl₃, d) 169.6, 169.1, 141.9, 135.2,

133.0, 129.7, 128.2, 127.3, 125.0, 124.4 (likely two

overlapping peaks), 116.8, 115.1, 101.6, 34.2; IR (KBr,

cm^À1) 3100(m), 3080(m), 2920(m), 2905(m), 1757(s), 1705

(s), 1625(w), 1591(m), 1502(s), 1456(m), 1413(w), 1379(s),

1291(m), 1239(w), 1219(m), 1182(w), 1758(w), 1124(w), 1096

(m), 1066(w), 1024(w), 989(w), 953(w), 901(w), 843(w), 823

(w), 785(w), 780(m), 741(s), 690(m), 624(m); HRMS m/z

(M + Na⁺) calcd 299.0792, found 299.0785. Anal. Calcd for

C₁₇H₁₂N₂O₂: C, 73.90; H, 4.38; N, 10.14. Found: C, 73.67; H,

4.18; N, 10.38.

2-Phenyl-2H,6H-pyrrolo[3,4-e]indole-1,3-dione (59) [6]. The

general method was used with 2-(methylthio)indole 51

(0.066 g, 0.214 mmol)L, giving 59 (38 mg, 68%) as yellow

1

crystals: mp 269–270^ꢀC; H NMR (300 MHz, CDCl₃, d) 8.74

(bs, 1H, 6-H), 7.76 (d, J = 8.4 Hz, 1H, 4-H), 7.72 (dd, J = 8.4,

0.9 Hz, 1H, 5-H), 7.48–7.55 (m, 5H, 7-H, Ph), 7.36–7.48 (m,

1H, Ph), 7.13 (ddd, J = 3.2, 3.2, 1.1 Hz, 1H, 8-H); ¹³C NMR

matched the literature data [6]; IR (KBr, cm^À1) 3292(bs), 3105(w),

3080(w), 3010(w), 2970(w), 2910(m), 2870(w), 1768(m), 1702(s),

1627(m), 1595(w), 1496(m), 1468(m), 1443(w), 1385(s), 1370(s),

1344(m), 1270(w), 1230(m), 1156(m), 1113(w), 1094(m), 1069

(w), 1007(w), 956(w), 914(w), 892(w), 827(w), 755(m), 692(w);

HRMS m/z (M + Na⁺) calcd 285.0635, found 285.0635. Anal.

Calcd for C₁₆H₁₀N₂O₂: C, 73.27; H, 3.84; N, 10.68. Found: C,

73.28; H, 3.65; N, 10.35.

2-(4-Ethylphenyl)-6-methyl-2H,6H-pyrrolo[3,4-e]indole-1,3-

dione (64). The general method was used with 2-(methylthio)

indole 56 (0.101 g, 0.288 mmol), giving 64 (77 mg, 88%) as

1

yellow crystals: mp 192–193^ꢀC; H NMR (300 MHz, CDCl₃, d)

7.76 (d, J = 8.4 Hz, 1H, 4-H), 7.63 (d, J = 8.4H, 1H, 5-H), 7.39

(d, J = 8.1 Hz, 2H, Ph), 7.33 (d, J = 8.4 Hz, 2H, Ph), 7.36 (d,

J = 2.4 Hz, 1H, 7-H), 7.05 (d, J = 2.4 Hz, 1H, 8-H), 3.91 (s, 3H,

NCH₃), 2.71 (q, J = 7.5 Hz, 2H, CH₂CH₃), 1.28 (t, J = 7.5 Hz,

3H, CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃, d) 169.8, 169.2,

144.4, 141.9, 135.1, 130.4, 129.2, 127.2, 125.1, 124.5, 124.4,

116.7, 115.0, 101.6, 34.2, 29.3, 16.2; IR (KBr, cm^À1) 3140(w),

3106(m), 3040(w), 2969(m), 2934(m), 2880(w), 2860(w),

1757(s), 1703(s), 1626(w), 1590(w), 1511(s), 1458(m), 1418(w),

1379(s), 1366(s), 1297(m), 1263(w), 1241(w), 1233(m), 1178(m),

1120(m), 1086(s), 1046(w), 989(w), 969(w), 951(w), 880(w),

852(w), 828(w), 815(w), 803(m), 770(m), 750(m), 661(w),

638(w); HRMS m/z (M + Na⁺) calcd 327.1105, found

327.1110. Anal. Calcd for C₁₉H₁₆N₂O₂: C, 74.98; H, 5.30;

N, 9.20, for C₁₉H₁₆N₂O₂Á0.13H₂O: C, 74.41; H, 5.34; N,

9.13. Found: C, 74.40; H, 5.32; N, 8.93.

2-(4-Ethylphenyl)-2H,6H-pyrrolo[3,4-e]indole-1,3-dione (60)

[6].

The general method was used with 2-(methylthio)indole

52 (0.068g, 0.202mmol), giving 60 (46 mg, 78%) as light-yellow

1

crystals: mp 172–173^ꢀC; H NMR spectra matched those in the

literature [6]; ¹³C NMR (75 MHz, CDCl₃, d) 169.4, 168.9, 144.1,

140.8, 130.1, 129.7, 128.7, 126.8, 124.8, 123.6, 123.4, 116.5,

102.0, 28.7, 15.6; HRMS m/z (M + Na⁺) calcd 313.0948, found

313.0948. Anal. Calcd for C₁₈H₁₄N₂O₂: C, 74.47; H, 4.86; N,

9.65. Found: C, 74.62; H, 5.32; N, 9.31.

2-(3-Methoxyphenyl)-2H,6H-pyrrolo[3,4-e]indole-1,3-dione

(61). The general method with 2-(methylthio)indole 53 (0.066 g,

0.195mmol) was used, giving 61 (57 mg, 100%) as light-yellow

crystals: mp 202–203^ꢀC; ¹H NMR (300MHz, DMSO-d₆, d)

12.02 (bs, 1H, 6-H), 7.87 (dd, J = 8.3, 0.8 Hz, 1H, 5-H), 7.82

(dd, J = 2.9, 2.9 Hz, 1H, 5′-H), 7.63 (d, J = 8.1 Hz, 1H, 4-H),

7.43 (dd, J = 8.1, 8.1 Hz, 1H, 4′-H), 6.98–7.07 (m, 3H, 7-H, 2′-

2-(3-Methoxyphenyl)-6-methyl-2H,6H-pyrrolo[3,4-e]indole-

1,3-dione (65).

The general method was used with 2-

(methylthio)indole 57 (0.101 g, 0.287 mmol), giving 65 (76 mg,

87%) as yellow crystals: mp 180–181^ꢀC; ¹H NMR (300 MHz,

CDCl₃, d) 7.76 (d, J = 8.3, 1H, 4-H), 7.63 (dd, J = 8.1, 1.1 Hz,

1H, 5-H), 7.40 (dd, J = 8.3, 8.3 Hz, 1H, 5′-H), 7.37

(d, J = 3.0 Hz, 1H, 7-H), 7.04–7.11 (m, 3H, 8-H, 2′-H, 6′-H),

6.91–6.96 (m, 1H, 4′-H), 3.92 (s, 3H, NCH₃), 3.85 (s, 3H, OCH₃);

¹³C NMR (75MHz, CDCl₃, d) 169.6, 169.0, 160.6, 141.9,

135.2, 134.0, 130.3, 125.0, 124.42, 124.39, 119.6, 116.8, 115.1,

114.5, 112.9, 101.6, 56.1, 34.2; IR (KBr, cm^À1) 3150(w),

3105(m), 3010(m), 2962(m), 2934(m), 2820(w), 1811(m),

1760(m), 1704(s), 1603(m), 1588(m), 1513(w), 1492(m),

1457(m), 1440(w), 1379(s), 1366(s), 1286(m), 1255(s), 1229(m),

1212(m), 1116(w), 1093(m), 1044(m), 989(w), 967(w), 876(w),

827(w), 814(w), 779(w), 743(s), 705(w), 624(w); HRMS m/z

(M+ Na⁺) calcd 329.0897, found 329.0899. Anal. Calcd for

C₁₈H₁₄N₂O₃: C, 70.58; H, 4.61; N, 9.15. Found: C, 70.65; H,

4.79; N, 8.97.

1

H, 6′-H), 6.85–6.88 (m, 1H, 8-H), 3.79 (s, 3H, OCH₃); H NMR

(300MHz, acetone-d₆) 11.2 (bs, 1H, 6-H), 7.95 (dd, J = 8.1,

0.9 Hz, 1H, 5-H), 7.82 (dd, J = 2.9, 2.9 Hz, 1H, 7-H), 7.68

(d, J = 8.4 Hz, 1H, 4-H), 7.45 (dd, J = 8.3, 8.3 Hz, 1H, 5’-H),

7.14–7.16 (m, 1H, 4′-H or 6′-H), 7.12 (dd, J = 1.8, 0.9 Hz, 1H,

2′-H), 7.01 (ddd, J= 3.3, 2.3, 1.1 Hz, 1H, 8-H), 6.98–7.01 (m, 1H,

4′-H or 6′-H), 3.79 (s, 3H, OCH₃); ¹³C NMR (75MHz, DMSO-d₆,

d) 168.8, 168.5, 160.0, 141.4, 134.0, 132.6, 130.0, 124.2,

123.1, 123.0, 120.1, 117.6, 115.9, 113.8, 100.5, 55.9; IR

(KBr, cm^À1) 3362(m), 3304(m), 2922(w), 1762(m), 1703(s),

1606(m), 1496(m), 1461(m), 1387(m), 1370(m), 1343(w),

1319(w), 1262(m), 1217(w), 1154(w), 1097(w), 1072(w),

1039(w), 1009(w), 972(w), 906(w), 852(w), 740(w), 715(w);

HRMS m/z (M + Na⁺) calcd 315.0741, found 315.0733. Anal.

Calcd for C₁₇H₁₂N₂O₃: C, 69.86; H, 4.14; N, 9.58. Found:

C, 69.61; H, 4.32; N, 9.36.

Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

808

W. E. Noland, N. P. Lanzatella, R. R. Dickson, M. E. Messner, and H. H. Nguyen

Vol 50

2-Dimethylamino-6-methyl-2H,6H-pyrrolo[3,4-e]indole-1,3-

M.; Viso, A. Chem Eur J 2005, 11, 5136; (c) Chou, S.-S. P.; Liang,

P.-W. J Chin Chem Soc 2000, 47, 83.

[23] Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Synth Commun

2007, 37, 2131.

[24] Murase, M.; Hosaka, T.; Koike, T.; Tobinaga, S. Chem Pharm

Bull 1989, 37, 1999.

dione (66). The general method was used with 2-(methylthio)

indole 58 (0.057 g, 0.20 mmol), giving 66 (44 mg, 92%) as

1

orange crystals: H and ¹³C NMR spectra matched the literature

data [6].

[25] Murase, M.; Yoshida, S.; Hosaka, T.; Tobinaga, S. Chem

Pharm Bull 1991, 39, 489.

Acknowledgment. N.P.L., R.R.D., M.E.M., and H.N.N. thank the

Wayland E. Noland Research Fund for the generous ﬁnancial

support of this project.

[26] Campiano, G.; Nacci, V.; Bechelli, S.; Ciani, S. M.; Garofalo,

A.; Fiorini, I.; Wikstrom, H.; de Boer, P.; Liao, Y.; Tepper, P. G.;

Cagnotto, A.; Mennini, T. J Med Chem 1998, 41, 3763.

[27] Wu, G.; Liu, Q.; Shen, Y.; Wu, W.; Wu, L. Tetrahedron Lett

2005, 5831.

[28] Silverstein, R. M.; Ryskiewicz, E. E.; Willard, C. Org Synth

Coll Vol IV 1963, 831.

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Journal of Heterocyclic Chemistry

DOI 10.1002/jhet

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Access to indoles via Diels-Alder reactions of 5-methylthio-2-vinylpyrroles with maleimides

DOI: 10.1002/jhet.1571

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Full text of DOI:10.1002/jhet.1571

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