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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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8. L. G. Beholz and J. R. Stille, J. Org. Chem. 58, 5095 (1993).
9. Reference 3, pp. 637-54.
10. L. 1. Zamshlyaeva, O. A. Fomin, L. D. Kvacheva. Y. N. Novikov and N. N. Suvorov. Bull.
Acad. Sci. USSR, Chem. SciEngl. Transl. 33, 1455 (1984).
56
7 CATEGORY Идс CYCLIZATIONS
11. Reference 3, pp. 655-7.
12. J. T. Fitzpatrick and R. D. Hiser, J. Org. Chem. 22, 1703 (1957).
13. F. M. Miller and W. N. Schinske, J. Org. Chem. 43, 3384 (1978); M. A. Khan and J. F. da Rocha, J. Heterocycl. Chem. 15, 913 (1978).
14. D. N. Plutitskii, Y. I. Smushkevich and N. N. Suvorov, J. Org. Chem., USSR, Engl. Transt. 23, 1395 (1987).
15. W. M. Welch, Synthesis 645 (1977).
16. H. Hayashi, K, Kurokawa, W. Hosokawa, T. Tanaka and T. Okazaki, J. Catalysis 66, 49
(1980).
17. N. N. Suvorov, V. N. SlikiPkova and N. Ya, Podkhalyuzma, Chem. Heterocycl. CmpdsEngl. Trans!. 24, 1191 (1988).
18. S. Esteban, J. M. Marinas. M. P. Martinez-Alcazar, M. Martinez and A R. Agarabeitia, Bull. Soc. Chim. Belg. 92, 715 (1983).
7.1.2 Regioselectivity
The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e.g. ethanolic HCl, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methylindoles and cyclization occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path.
R
There are a number of cases in which it has been shown that more strongly acidic conditions can shift the direction of indolization from the more substituted group to the less subsituted one[l-6]. Mechanistic interpretation of this cffcct has suggested that either enehydrazine formation or its rearrangement can be rate-determining. Rate-determining enehydrazine formation could favour reaction through the less-substituted regioisomer while rate-determining rearrangement would proceed preferentially through the more substituted and thermodynamically preferred enehydrazine. These ideas are outlined in Scheme 7.2.
7.1 FISCHER INDOLE SYNTHESIS
57
determining step
CH2R
ArNHty+=C
H CH3
\
R R
ArNHF)J- С rdLB~ r Г If [f -► | |[ y-CH3
н CHq i NH2 +
Hfltprminmn I
NH2 h
ОС
ch2r ch2r
ArNHN-+ С _^ ^Х-^~~и^сн2р
H CH2
rate-determining NH2 ’
step nh2 h
SCHEME 7.2
Recently the proposal has been advanced that rearrangement might occur through both mono- and di- protonated intermediates, with the latter favouring ratc-dctcrmining enehydrazine formation and fast rearrangement^]. A study of solvent and kinetic isotope effects has indicated that reaction in strongly acidic solution may proceed through an intermediate in which the aromatic ring is protonated. This non-aromatic cyclohexadienylium ion would be expected to have a much lower activation energy for sigmatropic rearrangement, permitting the enehydrazine formation to become rate-determining[7].
Very recent work has uncovered a different and promising approach to control of regioselectivity of Fischcr indolization. It was found that use of dialkylaluminium amides, specifically diethylaluminium 2,2,6.6-tetramethyl-piperidide (DA I MP), promoted indolization of ,V-methylarylhydrazones[8]. The regioselectivity was dependent on the stereochemistry of the hydrazone. Thus for the /V-methylphenylhydrazone of benzyl и-propyl ketone, the Z-isomer gave mainly 2-benzyl-3-ethyl-l-methylindole while the £-isomer gave mainly l-methyl-3-phenyl-2-propylindole. The dependence on hydrazone stereochemistry could result from preferential syn deprotonation via a
58
7 CATEGORY Ik CYCLIZATIONS
DATMP complex. So far this methodology has been demonstrated only for iV-alkylarylhydrazones.
CH2CH2CH3
N=(
N CH2Ph
CH3
CH2CH3
Ch^Ph
N
CH3
Cb^Ph
N СИ2СИ2СИ3 CH3
Ph
N
CH3
СН2СИ2СН3
(7.4)
N
E12A|/ hx I
CHR
n' CH2R OH,
Et2AI
I CHR
N CH2R CH3
Another issue of regioselectivity arises with mefa-substituted arylhydrazones from which either 4- or 6-substitutcd indoles can be formed. Robinson has tabulated extensive data on this point[9], A study comparing regioselectivity of cyclization as catalysed by HCl/EtOH and ZnCl2 was carried out for several m-substituted arylhydrazones of diethyl ketone[10]. The results given in Table
7.1 show some dependence on catalyst but mixtures are obtained under all conditions studied.
Table 7.1
Regioselectivity in m-substituted arylhydrazones
Entry Substituent Reaction medium 6:4 Ratio
1 NO, ZnCI, 3:7
2 NO, HC1, EtOH 1:1
3 Cl ZnCl2 0.8:1
4 Cl HC1, EtOH 1.3:1
5 c2h5 ZnCl2 1.2:1
6 c2h5 HC1, EtOH 1.8:1
7 CH3O ZnCl2 1:1
8 ch,o HC1, EtOH 5.4:1
Data from Reference 10 of Section 7.1.2.
7.1 FISCHER INDOLE SYNTHESIS
59
References
1. H, Illy and L. Funderburk, J, Org. Chem. 33. 4283 (1968).
2. M, H, Palmer and P. S. McIntyre, J Chem. Soc., В 446 (1969).
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