Key words
tetrahydro-β-carboline-3-carboxylic acids - decarboxylation - aromatization - copper - aromatic β-carboline
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.
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.
