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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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Ph
0 ^
О TiCI3,Zn,THF ||V—
reflux
(3.7,
H N"J H
CF3CO 3'7A CF3CO 3.7B
Procedure
S-3-Phenyl-2-[N - (trifluoroacetyl)pyrrolidin-2-yl]indole[3]
A mixture of compound 3.7A (250mg, 0.64mmol), TiCl3 (209mg, 1.36mmol) and zinc dust (178 mg, 2.72 mmol) in THF (20 ml) was heated at reflux for 1 h in an argon atmosphere. The solution was cooled to room temperature and
3.3 INDOLES FROM o,N-D1ACYLANILINES
33
filtered through a short silica plug using EtOAc for elution. The product 3.7B (206 mg) was obtained in 90% yield.
References
1. A. Fiirstner and D. Jumbam, Tetrahedron 48, 5991 (1992).
2. A, Fiirstner, D. N. Jumbam and Ci. Seidel, Chem. Ber. 127, 1125 (1994).
3. A, Fiirstner, A. Hupperts, A. Ptock and E. Janssen, J. Org. Chem. 59, 5215 (1994).
-4-
Category Ic Cyclizations
Category Ic cyclizations involve formation of the C3-C3a bond and require aniline derivatives with a nitrogen substituent appropriate for such reaction. Some, but not all, such cyclizations also require an o-substituent, frequently halogen. The rctrosynthetic transformations corresponding to the most important of this group of syntheses are shown in Scheme 4.1
X \ i
ooc ax:
z Z
SCHEME 4.1
Retrosynthetic path a corresponds to Pd-catalysed exo-trig cyclization of o-halo-iV-allylanilines. Path b involves the endo-trig cyclization of o-halo-iV-vinyl anilines. Path с is a structurally similar cyclization which can be effected photochemically in the absence of an o-substituent. Retrosynthetic path d involves intramolecular Friedel-Crafts oxyalkylation followed by aromatiz-ation.
4.1 TRANSITION METAL-CATALYSED CYCLIZATION OF A/-ALLYL-AND W-PROPARGYL ANILINES
The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an
36
4 CATHGORY к CYCLIZAT10NS
o-halo-N-allylaniline is cyclized to an indole as represented by path a in Scheme 4.1. The first application of this reaction to indole synthesis was by Hegedus and co-workers[l]. The procedure involved extended heating of an N-allyl-o-iodoaniline with Pd(OAc)2 and Et3N in CH3CN. The reaction presumably involves a Pd(0) species which undergoes oxidative addition with the aryl iodide. Cyclization then provides an unstable alkylpalladium intermediate which undergoes elimination regenerating Pd(0). The initial heterocyclic product is an exo-alkylideneindoline but under these conditions they isomcrizc to 3-alkylindoles.
R R
An important reaction parameter is the choice of the base and Na2C03 or NaOAc have been shown to be preferable to Et3N in some systems[2]. The inclusion of NH4C1 has also been found to speed reaction[2]. An optimization of the cyclization of A'-allyl-2-benzyloxy-6-bromo-4-nitroaniline which achieved a 96% yield found Et3N to be the preferred base[3]. The use of acetyl or methanesulfonyl as N-protecting groups is sometimes advantageous (see Entries 4 and 5, Table 4.1).
The indole skeleton can also be constructed by Pd-mediated cyclization of N-propargyl-o-haloanilines. The vinylpalladium intermediates formed in the cyclization are sufficiently stable to permit further reaction[4,5]. For example,
Table 4.1
Indoles by cyclization of iV-allylaniline derivatives
Entry Substituents Cyclization conditions Yield (%) Ref.
1 3-(2-Propyl) Pd(OAc)2, Et3N 73 ГП
2 3-(l-Benzyloxycarbonylpyrrol- Pd(OAc),, Et3N 81 Г61
idin-2-ylmethyl)-5-(methane-
sulfonamidomcthyl)
3 7-Benzyloxy-3-methyl-5-nitro Pd(OAc)2, Et3N 96 Г31
4 EMethanesulfonyl-6-methoxy- Pd(OAc)2, AgCG3, PPh, 80 П1
3-methylene-2,3-dihydro
5 l-Acetyl-5-(,V-allylacetamido)- Pd(OAc)2, PPh3, Et3N 76 Г81
4,7-diacetoxy-3-methyl
4.1 TRANSITION METAL-CATALYSED CYCLIZATION
37
Table 4.2
Oxindoles by cyclization of Ar-alkcnoylanilincs
Entry Oxindole substituents Conditions Yield (%) Ref.
1 3-Benzylidene Pd(OAc)2, NaOAc 97 [2]
2 l-Methyl-spiro-3-cyclopent- Pd(OAc)2, PPh3 91 [9]
2-ene
3 l-Methyl-sp;>o-3-cyclohex- Pd2(dba)3, Ag3P04 74 [10]
2-ene R-BTNAP (80% ее)
4 1,3-Dimethyl-5-methoxy-3- Pd2(dba)3, S-BTNAP 84 [11]
(2-oxocthyl) (95%ee)
5 1,3-Dimethyl-5-methoxy n-Bu4Sn, AIBN 63 [12b]
6 3-Ethyl-5-methoxy-l- n-Bu4Sn, AIBN 64 [12d]
(oi-methylbenzyl) (2% ее)
7 2-(Ethoxycarbonylmethyl)- TMSC1, n-BuLi 85 [13]
1-methyl
reaction with arylzinc chlorides gives 3-arylideneindolines. Similar reactions have been observed for alkyl and alkynylzinc chlorides and with the zinc enolate of ethyl acctatc (Rcformatsky reagent).
The Ir cyclization pattern has also proved useful for the preparation of oxindoles from o-haloalkenoylanilines. Table 4.2 gives some examples.
R
X J Pd(0)
- N
S ° A
° (4.3)
Besides Pd-catalysed cyclizations, both radical[12] and organolithium[13] intermediates can give oxindoles by exo-trig additions.
I [|h O,, ,CH2Ph
J Bu3SnH
^ ■' " ' О (4.4)
38
4 CATEGORY I с CYCLIZATIONS
CO2C2H5
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