Reductive Heck cyclization versus δ-carbon elimination/decarboxylation: synthesis of dihydroindole and indoles from Baylis-Hillman adducts

DOI: 10.1016/j.tetlet.2008.11.127

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Tetrahedron Letters p. 3154 - 3157 (2009)

Update date:2022-07-30

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Authors:

Kim, Hoo Sook

Lee, Hyun Seung

Kim, Se Hee

Kim, Jae Nyoung

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Article abstract of DOI:10.1016/j.tetlet.2008.11.127

Modified Baylis-Hillman adducts having 2-bromoaniline moiety at the primary position underwent Pd-mediated reductive Heck type cyclization to produce dihydroindole derivatives. The same starting materials can also be used for the synthesis of indole deriv

Full text of DOI:10.1016/j.tetlet.2008.11.127

Tetrahedron Letters 50 (2009) 3154–3157

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Reductive Heck cyclization versus d-carbon elimination/decarboxylation:

synthesis of dihydroindole and indoles from Baylis–Hillman adducts

Hoo Sook Kim, Hyun Seung Lee, Se Hee Kim, Jae Nyoung Kim

Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea

a r t i c l e i n f o

a b s t r a c t

Article history:

Modiﬁed Baylis–Hillman adducts having 2-bromoaniline moiety at the primary position underwent Pd-

mediated reductive Heck type cyclization to produce dihydroindole derivatives. The same starting mate-

rials can also be used for the synthesis of indole derivatives under slightly different conditions via the

concomitant d-carbon elimination and decarboxylation process.

Received 8 October 2008

Revised 6 November 2008

Accepted 8 November 2008

Available online 25 December 2008

Keywords:

Palladium

Reductive Heck cyclization

d-Carbon elimination

Baylis–Hillman adduct

Indole

Dihydroindole

Chemical transformations of Baylis–Hillman adducts have

received much attention during the last two decades.^1,2Various

cyclic and acyclic compounds have been prepared from Baylis–

Hillman adducts by various chemical transformations.^1,2Although

Pd-mediated chemical transformations of modiﬁed Baylis–Hillman

adducts started very recently, it provided many interesting hetero-

cyclic compounds.^2,3Recently, we reported unusual formation of

cyclopropane-fused dihydrobenzofuran derivatives from the mod-

iﬁed Baylis–Hillman adducts having 2-bromophenol moiety.³In

the reaction, the palladium intermediate activated C(sp³)–H bond

and produced cyclopropane-fused compound in moderate yield.³

During the study, we also examined the reaction of 1a having 2-

bromoaniline moiety and found the formation of dihydroindole

2a (19%) and indole 4a (21%) instead of cyclopropane derivative

5a (Scheme 1).³

The mechanism for the formation of 2a can be regarded as the

reductive Heck type reaction involving the intermediate (II), which

might be converted to 2a by dimethylamine generated from DMF.⁴

Compound 4a could be formed via the base-mediated isomeriza-

tion of 3a, which might be generated from (II) via the d-carbon

elimination and concomitant decarboxylation process,^5,6as de-

picted in Scheme 1.

efﬁcient conditions for both products. Some representative trials

are summarized in Table 1. As in entry 3, Pd(OAc)₂/PPh₃/Et₃N/

HCOOH conditions afforded compound 2a in reasonable yield

(64%) in DMF at 80 °C in short time (30 min).^7,8In the reaction,

we did not observe the formation of 3-benzylidene derivative 3a

(vide infra). When the reaction of 1a was carried out under the

inﬂuence of Pd(OAc)₂/PPh₃/Et₃N in aqueous CH₃CN (reﬂuxing,

18 h), we isolated 3a in 72% yield, very fortunately.^8,9

Encouraged by the results, starting materials 1b–g were synthe-

sized from the bromide of Baylis–Hillman adduct and 2-bromoani-

lines as shown in Scheme 2.^2,3With these compounds 1b–g, we

examined the synthesis of 2b–g and 3b–g as summarized in

Scheme 3. Reductive Heck type cyclizations of 1b–g under the opti-

mized conditions (Table 1, entry 3) produced desired dihydroin-

doles 2b–g in moderate to good yields (47–80%). The mechanism

can be imagined as shown in Scheme 4, involving the intermediates

(I)–(III). Rapid conversion of (II) into (III) by formate anion and the

following elimination of CO₂and Pd(0) explained the short-reaction

time (30 min). Variable amounts of (I) produced the reduction

compound 7 via the intermediate (IV). Actually small amounts of

reduction compounds were observed on TLC in all cases, and iso-

lated in appreciable amounts (28–36%) in some case (7c,d,g).

The synthesis of 3-benzylidene dihydroindole 3b–g was also

examined under the optimized conditions (Table 1, entry 6). When

the N-substituent of 1 is tosyl (1b), acetyl (1c and 1d), and ester

group (1g), desired compounds 3b–d and 3g were obtained in

moderate to good yields (56–75%). However, the reaction with

N-benzyl derivatives (1e and 1f) failed completely. We did not

We reasoned that both compounds 2a and 4a can be prepared

selectively by choosing the suitable reaction conditions. Thus, we

examined the reactions of 1a under various conditions and found

* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.

E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).

doi:10.1016/j.tetlet.2008.11.127

H. S. Kim et al. / Tetrahedron Letters 50 (2009) 3154–3157

3155

COOMe

Pd(0)

Ref. 3

2a (19%)

4a (21%)

BrPd

δ-carbon elimination

decarboxylation

COOMe

C(sp³)-H activation

BrPd

MeOOC

BrPd

COOMe

(I)

5a (not formed)

(II)

Scheme 1.

Table 1

Optimization of reaction conditions with compound 1a

Entry

Conditions

1a (%)

2a (%)

3a (%)

4a (%)

1^Ref.

Pd(OAc)₂(10 mol %)/K₂CO₃(20 equiv)

TBAB (10 equiv)/DMF, 110 °C, 90 min