Redox catalysis in free-radical reactions: New, simple, convenient intramolecular homolytic aromatic substitutions

Redox catalysis in free-radical reactions: New, simple, convenient intramolecular homolytic aromatic substitutions

Tetrahedron Letters, Pergamon Vol. 36, No. 24, pp. 4307-4310, 1995 ElsevierScienceLid Printedin GreatBritain 0040-4039/95 $9.50+0.00 0040-4039(95)0...

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Tetrahedron Letters,


Vol. 36, No. 24, pp. 4307-4310, 1995 ElsevierScienceLid Printedin GreatBritain 0040-4039/95 $9.50+0.00


R e d o x C a t a l y s i s in F r e e - R a d i c a l R e a c t i o n s : N e w , S i m p l e , C o n v e n i e n t Intramolecular Homolytic Aromatic Substitutions

Siivia Araneo. Francesca Fontana. Francesco Minisci*. Francesco Recupero. Anna Serri

Dipartimentodi Chimicadel Politecnico.via Mancinelli.7. 1-20131 M,ano. Italy

Ab/raet: Three new icmerat,m ~ e tnd convenient~ of immmlece~ homobytica ~ m i c substitution~ i n g to homocydicand heterocycliccompoundshavebeen developedby addition of affl or nucleophilicalkyl radicals to alkenes conjugated with electron-withdrawinggrmq~ in the presence of metal salt redox systems. Aryl and nucleophilic flkyl radicals add rapidly to electron-deficient glk~'l'le$1 (eq.1), with relevant applications2.

R'+ CH2=CH-X




X : electro~withdrawh~ggroup k = 10S-10SM'ls'l at 3OOK


For synthetic purposes, the fate of the radical adduct is important: if its evolution is selective, the reaction acquires a synthetic value. Reduction, oxidation and alterrafin$ addition to conjugated glkenes of the radical adducts have been widely utilized for selective s y n t h e ~ . A further po~'bility of selective evolution of the

radical adduct is the intramolecular addition to an aromatic ~

followed by a fast rearomafiz~on of the

cyclohexadienyl radical. In this l.~ter, we report simple, cheap and convenient reacting Injsterm, ~

in most

respects to the alternating addition to conjugated g l k c l l ~ S I , which have allowed the developnm~ of • vsriety of new intramolectdar homolytic m'omatic substitutions, based on this concept. Thus, when N,N-dimethylaniline (2) is oxidized in benzene solution by t-BuOOH in the presence of acrylonitrile and a catalytic amount of Cu(OAc)2 the tctrahydroquinoline derivative (3) was obtsined.


I + CH2=CH-CH + t-BuOOH

+ t-BeotI ÷ ~ o



3 ~

Similarly, H,N..dicthylanilin¢ (4) gives the corresponding derivative (5)




S 4



We explain the formation of 3 and 5 by the fi'ee-radical redox chain3 ofeqs. 3-7

t-BuOOH + Cu(1)

t-BuO" + HOOBu-t

t-BuO"+ Cu(II) + OH"


t-BuOH+ t-BuOO"


@j.N.. I

t-BuO0" (t-BuO') + 2

t-BuOOH(t-BuOH) +



I 6






4----~ ~ CN


+ Cu(II)

3 + Cu(1) + H +


CN The dealkylation of the amine is a side reaction (eq.8) 6 + C'u(ID + H 2°


Ph-NH-CH3 + H C H O

+ Cu(1) + H +


A different methodology is based on the stoiohiometry of eq.9

+ CH2ffiCH-Y + $208= 7

x = CH2,O, N R


+ CO2 + 2 HSO4" $



Y - CN.COP,,COOR The reaction was carried out in a three-solvent, two-phase system (H20 , CI-CH2-CH2-CI, CH3CN 1:1:1). Reagents of structure analogous to 7 are easily prepared from chloroacetic acid and phenols or anilines (X -- O or NR) or by hydrogenation of cinnamic acids (X ffi CH2). The mechanism is similar to that of eqs. 6 and 7 as for what concerns the addition and cyclization steps, while the primary radical is generated4 according to the redox chain ofeqs. 10 and 11.



+ S2Os=



2A80I) + 2So("


-~ Ar-X-CH2 + CO 2 + H + + Ag(1)



Reactions like eq.6 appear to be reversible in the cyc2ization step, since the yields in derivatives of structure 8 are very poor in the absence of Cu(II) or Fe(m)salts, which shift the equilibrium to the right by a fast oxidation of the cyclohexadienyl radical (eq.7). Also in this case, the oxidation of the intermediate radical 9 is a byprocess. Aryl radicals add very rapidly to electron-deficient alkenes; Meerwein reaction (the haloarylation of alkenes by diazonium salts) is a classical synthetic application. Thus, the decomposition of benzoylperoxide in the presence of a-alkenes conjugated with electron-withdrawing groups (Y) leads to the polymerization of the alkene; however, if the reaction is carried out in the presence of Cu(OAc)2, the polymer formation is greatly reduced, and significant yields of the two isomer compounds 10 are obtained (eq.12).

(PhCOO)2 + 2 CH2=CH-Y Cu(II))

~ ~. ~ Y

+ CO2 + PhCOOH


10 Y Again the reversibility of the intramolecular radical addition plays the fundamental role: the phenyl radical, generated by benzoylperoxide, adds to the double bond, initiating the radical polymerization (eq.13); the presence of the Cu0]) salt favours the intramolecular addition of the intermediate radical I I (eq.14), thus preventing the propagation of its polymerization. The Cu(1) salt formed (eq.14) is oxidized by benzoyl peroxide, initiating a redox chain (eq.15)

Ph" + CH2=CH-Y


etc. II

11 ~

+ Cu(II)




10 + Cu(I) + H+


Y (PhCOO)2 + Cu(I)


Ph" + CO2 + PhCOO"+ Cu(II)


The results and the experimental conditions are reported in the Table. This new reaction is particularly useful for the synthesis of carbocycfic and heterocyclic compounds, due to its applicability to a wide variety of alkylanilines, of 7-type carboxylic acids, of alkenes and of cheap and easily available sources of aryl radicals; furthermore, the experimental conditions are simple and other facile synthetic procedures for the same purposes are unavailable. We believe that these preliminary results can be


further improved by a careful choice of radical sources, metal salt catalysis, solvent and temperature, in order to improve the effectiveness of the intramolecular free-radical aromatic addition (eqs. 6, 14), mostly to prevent its reversibility, and to avoid oxidation of the intermediate radicals 6 and 9. Table. Intramolecular aromatic substitutions according to eqs. 2~ 9 and 12. Substrate Y Procedure a Solvent Reaction Products

2 4 7 (X = CH2) 7 (X = CH2) 7 (X = CH2) 7 (X = O) 7 (X = N-COCH3) (PhCOO)2 (PhCOO)2 (PhCOO)2

Yieida (%)b



benzene benzene

3 5

50 31


B B B B Bc C C C

H20, CI-CH2-CH2-CICH3CN I-I20, CI.CH2-CH2-Cl CH3CN 1-120, CI-CH2-CH2-CICH3CN H20, CH2C12,CH3CN H20, CH2C12,CH3CN t-BuOH t-BuOH t-BuOH

g g 8 S $ 10 10 10

87 64 30 41 16 23 18 12

a Procedure A: 5 mmol of dialkylanlline, 5 mmol of acrylonltrile, 0.05 mmol of Cu(OAc)2 in benzene (10 mL) were heated for 18 hrs at 50°C. Procedure B: 5 mmol of 7, 10 mmol of CH2=CH-Y, 5 mmol ofNa2S208 , 1 mmol of AgNO 3 and 0.5 mmol ofFe(NO3) 3 in a mixture of H20 (25 mL), CI-CH2-CH2-CI (25 mL) and CH3CN (25 mL) were refluxed for 4 hrs. Procedure C: 1 mmol ofbenzoylperoxide, 4 mmol of CH2=CH-Y, 0.1 mmol of Cu(OAc)2 in 30 mL of t-BuOH were refluxed for 6 hrs. All the reaction products were characterized by MS and NMR spectra. b yields of cyclized product based on the oxidant. e Procedure B is modified in that only 0.05 mmol ofFe(NO3) 3 were used. References. I. Minisci, F.; Carorma, T.; Cecere, M.; Galli, R.; Malatesta, V. Tetrahedron Lett. 196S, 5609; Minlsei, F.; Zammori, P.; Bernardi, R.; Ceeere, M.; Galli, R. Tetrahedron 1970, 26, 4153; Minisei, F. Acc.Chem.Res. 1975, 8, 165; Citterio, A.; Minlsei, F.; Amoldi, A. J..Org.Chem. 1979, 44, 2674; Citterio, A.; Minlsei, F.; Serravalle, M. J.Chem.Res. (M) 1981, 2174; Minisei, F. Fundamental Research in Homogeneous CataO,sis', Graziani, M. Ed.; Plenum Publ.Co., 1984; p. 173; Minisei, F.; Vismara, E. Organic Synthesis: Modern Trends; Chizhov, O., Ed.; Blaekwell Scientific Publ., 1987; p. 229. 2. Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bondr, Baldwin, J.E., Ed.; Pergamon Press: Oxford, 1986. 3. Minisei, F.; Fontana, F.; Aranen, S.; Reeupero, F.; Banff, S.; Quiei, S.J.Am.Chem.Soc. 1995, 117, 226. 4. Fontana, F.; Minisei, F.; Nogueira Barbosa, M.C.; Vismara, E. Tetrahedron 1990, 46, 2525.

(Received in UK 7 March 1995; revised 19 April 1995; accepted 21 April 1995)