Key words indoles - Heck reaction - β-nitroacrylates - cyclization - Michael addition
Over the years, several synthetic methods have been proposed that can be used to access functionalized indole systems.[1 ] This continuous interest reflects the importance of this heterocyclic system due to its presence in numerous synthetic and naturally occurring molecules.[2 ] The main synthetic tactics used for preparing functionalized indoles can be classified as: (i) construction of a pyrrole system onto a benzene precursor,[3 ] (ii) benzannulation of pyrroles,[4 ] and (iii) derivatization of a preformed indole core, usually by C-3 Friedel–Crafts reaction in combination with electron-poor alkenes (a),[5 ] or by the functionalization of the benzylic position via alkylideneindolenine intermediates (b)[6 ] (Scheme [1 ]).
In this context, pathway (i) has been the most investigated and, recently, efforts have been directed towards metal-catalyzed ring construction, which ensures mild reaction conditions and the possibility of introducing a variety of functionalities into the indole ring.[7 ] Although some important goals have been reached, further drawbacks need to be overcome, and the identification of new substrates that can be easily converted into functionalized indoles remains a research topic of great interest.
In this regard, following our ongoing studies on β-nitroacrylate chemistry,[8 ] we have disclosed a novel and simple one-pot synthesis of α-enamino esters 4 that can be directly transformed into alkyl indole-2-carboxylates 5 by palladium-catalyzed Heck reaction (Scheme [2 ]).[9 ]
Scheme 1 Common synthetic approaches for the synthesis of functionalized indoles
Scheme 2 Our synthetic approach
The thus-obtained indole derivatives 5 , or their acid form (R2 = H), belong to an important sub-class of indoles that are widely used as strategic intermediates for the synthesis of important biologically active molecules,[10 ] however, despite their importance, only a few synthetic methods have been reported. Among them, the Japp–Klingemann reaction followed by Fischer rearrangement (A),[11 ] and the Hemetsberger–Knittel indole synthesis (B) (Scheme [3 ])[12 ] are two of the most well-known methods; however, both these approaches have important limitations. The former approach is rather complex, requiring the preparation of the appropriate β-keto esters and the arendiazonium salts, and harsh acidic reaction conditions are needed to promote the Fischer cyclization. On the other hand, the Hemetsberger–Knittel synthesis entails the use of hazardous azidoacetates, restricting functionalization to the benzene ring and usually furnishing the indoles in very low yields.
Scheme 3 Japp–Klingemann/Fischer (A) and Hemetsberger–Knittel (B) approaches
In this regard, our synthetic strategy, which exploits the high reactivity of β-nitroacrylates 1 in combination with o -bromoanilines 2 , represents a novel, convenient and alternative strategic approach.
To optimize our protocol, we first studied the aza-Michael reaction and were pleased to observe complete conversion of 1a and 2a into 3a at 70 °C (24 h), under solvent-free conditions (Table [1 ]). We then treated crude 3a with a range of bases and solvents, obtaining the best yield of 4a (87%) by using two equivalents of TBD on polymer[13 ] in MeCN (Table [1 ], entry 3).
Table 1 Optimization Studies
Entry
Base (equiv)
Solvent
Time (h)
Yield of 4a (%)a
1
TBD on polymer (1)
MeCN
9
41
2
TBD on polymer (1.5)
MeCN
9
67
3
TBD on polymer (2)
MeCN
5
87
4
KF/Al2 O3 (2)
MeCN
5
31
5
carbonate on polymer (2)
MeCN
5
43
6
TMG (2)
MeCN
3
77
7
TBD on polymer (2)
CPME
5
–
8
TBD on polymer (2)
CH2 Cl2
5
81
9
TBD on polymer (2)
EtOAc
5
9
a Yield of pure isolated product.
Having optimized the synthesis of 4a , we extended our protocol to prepare title compounds 5a –j by submitting crude 4a –j , which were readily obtained by TBD-filtration and solvent evaporation, to the Kondo reaction conditions,[9a ] obtaining, in all cases, good overall yields of indoles (Table [2 ]).
Table 2 Preparation of Indole-2-carboxylic Acid Esters 5
Indole 5
Yield (%)a
5a
60 (52)b
5b
56
5c
50
5d
44
5e
59
5f
51
5g
55
5h
51
5i
49
5j
47
a Yield of pure isolated product.
b Heck reaction conditions: Microwave, 190 °C, MeCN, 1.5 h.
In conclusion, our approach provides simple access to functionalized alkyl indole-2-carboxylates, which are useful synthetic intermediates.[14 ] By the appropriate selection of β-nitroacrylate and o -bromoaniline precursors, it is possible to introduce different substituents onto the benzene ring, modify the ester moiety, and introduce several functionalities onto the C-3 alkyl chain. Furthermore, thanks to the simple conditions used to prepare intermediates 4 , the whole process involves just one aqueous work-up and a single chromatographic purification.
