Synlett 2014; 25(1): 120-122
DOI: 10.1055/s-0033-1340053
letter
© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Protodecarboxylation and Aromatization of Tetrahydro-β-Carboline-3-Carboxylic Acids

Ramu Meesala
Centre For Drug Research, Universiti Sains Malaysia, Minden, 11800 USM, Penang, Malaysia   Fax: +60(4)6568669   Email: mnizam@usm.my
,
Mohd Nizam Mordi*
Centre For Drug Research, Universiti Sains Malaysia, Minden, 11800 USM, Penang, Malaysia   Fax: +60(4)6568669   Email: mnizam@usm.my
,
Sharif Mahsufi Mansor
Centre For Drug Research, Universiti Sains Malaysia, Minden, 11800 USM, Penang, Malaysia   Fax: +60(4)6568669   Email: mnizam@usm.my
› Author Affiliations
Further Information

Publication History

Received: 03 September 2013

Accepted after revision: 30 September 2013

Publication Date:
12 November 2013 (online)


Abstract

An efficient synthetic methodology has been developed to construct aromatic β-carbolines from tetrahydro-β-carboline-3-carboxylic acids by copper-promoted sequential decarboxylation and oxidative aromatization.


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The aromatic β-carboline moiety is found in a wide variety of natural products and synthetic congeners.[1] Compounds containing this fragment display a wide range of biological properties including antimalarial,[2] antitumor,[3] and anti-HIV activities.[4] β-Carbolines also exhibit potent binding affinities toward benzodiazepine receptors in the central nervous system, thereby acting as diazepam antagonists.[5] As a result of their significant potential as therapeutics, interest has grown in the development of methods for the efficient and rapid synthesis of β-carboline derivatives. A general synthetic method for its preparation is the dehydrogenation of a suitable tetrahydro-β-carboline precursor. Typical reported methods[6] involve heating the substrate with palladium on carbon,[6a] [b] [c] sulfur,[7] and SeO2 [8] for extended reaction times.

Decarboxylation of aromatic carboxylic acids by copper has been widely investigated since the 1960s by Sheppard,[9] Cohen,[10] Nilsson,[11] and others.[12] Sheppard et al. reported that cuprous arylcarboxylates readily decarboxylate on heating. Myers developed a palladium-catalyzed decarboxylative Heck-type reaction in 2002.[13] Gooßen reported a practical and an efficient large-scale synthesis of biaryls by using decarboxylative coupling.[14] Carboxylic acids have many advantages as surrogates of organometallic nucleophiles. They are stable, easy to make and store, and readily available. In addition, they generate carbon dioxide as a byproduct in the decarboxylation process instead of producing metal waste. A variety of decarboxylative coupling reactions of carboxylic acids have been developed over the past few decades.[15]

In this Letter, we describe a simple method for the synthesis of aromatic β-carbolines by sequential decarboxy­lation and aromatization of tetrahydro-β-carboline-3-carboxylic acids by employing 10 mol% of CuCl2 without any ligand. We initiated our studies by examining the reaction of tetrahydro-β-carboline-3-carboxylic acid in the presence of a catalytic amount (10 mol%) of copper salts, without any ligand, in DMF at 130 °C as shown in Table [1]. After examining various copper salts, the best outcome was obtained by using 10 mol% of CuCl2 (Table [1], entry 4). Cu(OAc)2 also catalyzed the reaction similarly (Table [1], entry 5). Copper(I) salts can also perform the reaction but with less efficiency (Table [1], entry 1–3).

Table 1 Screening of Reaction Conditions

Entry

Cu salt (mol%)

Time (h)

Yield (%)a

1

CuI (10)

6

76

2

CuBr (10)

6

72

3

CuCl (10)

6

74

4

CuCl2 (10)

1

81

5

Cu(OAc)2 (10)

3

75

a Isolated yields.

After having optimized reaction conditions, we attempted the decarboxylation–aromatization of various tetrahydro-β-carboline-3-carboxylic acid derivatives, obtained by Pictet–Spengler condensation of l-tryptophan with the appropriate aldehyde,[16] to explore the scope and generality of the reaction. The outcomes of the reactions[17] are presented in Table [2]. Yields were generally good and were observed to be dependent on the electronic characteristics of the substituent at C(1); substrates containing electron-donating groups (Table [2], entries 2 and 4) affording higher yields than those with electron-withdrawing groups (Table [2], entry 5). Finally, the conditions proved to be tolerant of aromatic functional groups.

Table 2 Cu-Mediated Decarboxylation and Aromatization of Tetrahydro-β-Carboline-3-Carboxylic Acids

Entry

Substrate

Product

Yield (%)a

1

1a

2a

81

2

1b

2b

84

3

1c

2c

77

4

1d

2d

87

5

1e

2e

63

a Isolated yields.

Based on previous reports,[18] a possible mechanism is outlined in Scheme [1]. Initially, the copper catalyst inserts into the carboxylate bond to give intermediate 4 which undergoes oxidative addition to provide intermediate 5. ­Finally, a rapid reductive elimination provides the decarboxylation to produce intermediate 6. On protonolysis, the intermediate 6 is converted into tetrahydro-β-carboline 7 which then transforms into the aromatic β-carboline by oxidative aromatization.

Zoom ImageZoom Image
Scheme 1 Proposed mechanism for copper-mediated decarboxy­lation and aromatization of tetrahydro-β-carboline-3-carboxylic acids

In summary, we have developed a convenient protocol for the synthesis of aromatic β-carbolines via copper(II)-­mediated decarboxylation and subsequent aromatization of tetrahydro-β-carboline-3-carboxylic acid precursors in the absence of a ligand.


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Acknowledgement

Financial support of this research provided by the Research University Grant Scheme of Universiti Sains Malaysia (RUT-USM) is gratefully acknowledged by the authors.

Supporting Information


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