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1986 ,51 , 536-53736 J . Org. Chem

51), 424 ( M - 3 AcOH, 46), 364 ( M - 4 AcOH, 56), 313 (4P), 2537 Hz, 26- and 27-H3), 1.00 (3 H ,S, 19-H3 ), 2.04-2.05 (12H, CHSCO),3.83 (1 H dd , J = 11.0, 7.0 Hz , 21- H), 3.97(1 H d d , J = 11.0, 4.5

(100); IH NM R (CDCl,) 6 0.85 ( 3 H, s, 18-H3),0.88 (6 H, d , J =

Hz, 21-H ), 4.64 (1 H dd , J = 11.0, 5.0 H z, 1 2-H ), 4.90(1 H , brs, W1 = 11.0 Hz, 6 a-H ), 5.07 (1 H, b r s, Wli2 = 7 Hz, 30 -H) .

Acknowledgment. Th is study was supported by M .P.I.(Roma). We thank the supply Departm ent of ZoologicalSta tion (N apoli) for collection of the animals. Mass spec trawere provided by th e "Servizio di Spe ttrometria di massa"

of the CNR and the U niversit i di Napoli. Th e assistanceof the staff is gratefully acknowledged.Registry No. 1, 99494-32-3;l a , 99458-05-6;l b , 99458-07-8;

IC , 99458-08-9;2, 99458-04-5;2a, 99458-06-7;3, 99475-53-3.

A General, Selective , and Convenient Procedureof Homolytic Formylation of Heteroaromatic

Bases

C l a u d i o G i o r d a n o

Z A M B O N C H I M I C AS . p . A . ,26 Cormano , I ta ly

F r a n c e s c o M i n i s c i , * Elena Vi s m a r a , * and S i l v i o L e v i

Dipartimento di Chimica del Politecnico, 32 Milan o , I t a l y

Received Ju ly 2, 1985

The substitution of protonated heteroaromatic bases bynucleophilic carbon-centered radicals reproduces th e nu -merous aspects of th e aromatic Friedel-Crafts alkylationand acylation, formylation included, but with oppositereactivity and se1ectivity.l

The formylation by trioxane has till now given poorresults; ' the main reason is that th e reaction has beencarried o ut a t room te mpe rature, which requires almoststoichiometric amo unts of Fe(I1) salt. T he relatively highconcentration of Fe(II1) salt formed according to eq1 and2 determ ines the fa st oxidation2 of the trioxanyl radicalgenerated by hydrogen abstraction from trioxane (eq3 and4). Th e competition of the reactions2 an d 4 leads to poor

~ - B ~ O O H F t ' - - ~ u O * Fe t OH- ( 1 )3+t - 8 ~ 0 . t Fez ' + Ht - - BuOH t Fe3+ ( 2 )yields of attack of the trioxanyl radical to the proton atedheteroaromatic base (eq5) . We have developed a new

0-0

MeI

(1) Minisci,F. Top . Curr. Chem. 1976,62, 1. Vismara, E. Chim. Ind.

(2 ) Citterio,A, ; Gentile, A,; Minisci,F.; Serravalle, M.; Ventura,S. J .( M i l a n )1983, 65, 34 . Gardini , G. P. Tetrahedron Lett . 1972, 4113.

Chem. SOC.,Chem. Commun. 1983, 916.

0022-326318611951-0536$01.50/0 0

Table I. Formylation of Heteroaromatic Bases

posit iont - of

hete roaromat ic base BuOO H, formyla- conver-(mmol) mmo l t ion s ion ,% yield," %

quinoline (16)

4-methylquinol ine

4-methylquinol ine

2-methylquinol ine

isoquinoline (14)quinoxali i ie (14)benzoth iazo le (14)

(14)

(14)

(14)

32 2 (58%) 81 92

17 2 65 95

33 2 89 94

32 4 65 94

30 1 83 9228 2 38 9430 2 37 90

4 (42%)

a GLC, based on conver ted he te roaromat ic compound.

procedure3 by combining the therm al effect and the redoxcatalysis which allows use of small a mo unt s of Fe(I1) sal t(1YO)to minimize therefore the competitive reactions2 an d4 and to obtain much higher yields.

Moreover th e new procedure is much simpler becausethe sm all amount of catalyst does not interfere during theisolation of the reaction products, whereas with stoichio-metric iron salt considerable amountof Fe(II1) hydroxide

precipitates during the separation of the reaction products(sometimes complexing the heterocyclic com pounds) an dheavily affects the overall process.

Th e reaction is very selective and only the positionsaand y of the heterocyclic ring are substituted. Th e resultsare reported in Table I; the conversions can be furtherincreased by increasing the amount of t-BuOOH. No re-action takes place in the absence of iron salt a t the t em-perature used in the table, and only traces of substitutionproducts are formed at room tempe rature in the presenceof the catalytic amounts of employed Fe(I1) salt, thusclearly indicating that the combination of the thermaleffect and t he redox catalysis is necessary for the successof the reaction. Th e Fe(I1) salt consumed in eq1 is re-generated in the oxidationof the heteroaromatic radicaladduct (eq 6).

+ + \ b0 4

Fez+ t H' ( 6 )

Hydrogen peroxide can be used instead of t-BuO OH; thestoichiometry is shown by the eq7. Th e difference be-tween t-BuOOH a nd aqueous HzOz s that t-BuOOH leadsto 97-98% of trioxanyl derivatives and only to2-370 ofthe aldehyde generated by hydrolysis. Th e trioxanyl

t HzOz - r CH O t 2CH20 + 2 H p ( 7 )derivative can be useful,as a masked aldehyde, for furthertransformations, an d the hydrolysis can be accomplishedat the r ight step. HzOzalways leads t o mixturesof com-parable amounts of trioxanyl derivatives and aldehyde dueto the presence of more water;it is convenient in this caset o transform all the reaction products to the aldehyde bycomplete hydrolysis.

1,3-Dioxolanecan also be utilized by a similar procedurefor the synthesis of heteroaromatic aldehydes, but the

(3 ) Minisci, F.; Giordano, C.; Vismara ,E.: Levi, S.: Tortelli, V. I tal .

z tFaAoA r H

+Lo)

Pat. 23798A184, 1984.

1986 A m e r i c a n C h e m i c a l S o c i e t y

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J. Org. Chem. 1986, 51 , 537-540 537

+0-0

Ar H t n t t -BuOOHh-(] tO V

( 6 0 %) (30%

tho1 . to1

ArCHO ArCHCH20H

IOH

t - BuOH t H20 ( 8 )

process is not selective (eq8).

Experimental SectionFormylation Using t -BuOOH-General Procedure. A

solution of the heteroaromatic base, CF,COOH (equimolecularwith the base), and t-BuOO H in the am ounts reported in the tableand 0.7% of ferrous sulfate (based on the hydropero xide) wererefluxed for5 h with 120 g of trioxa ne an d 200 mL of acetonitrile.T he solution was conc entrate d by distilling th e solvent, basifiedwith 5% NaOH solut ion (50 mL, and extracted with ether (3X50). GLC and TLC analyses reveal only the presence of thestarting base and of th e trioxanyl derivative and small amounts(2-3%) of aldehyde. Th e solvent was distil led and the residuerefluxed with 50 mL of 10% HzS04,mad e basic with5% NaOH,extracted with ether, and analyzed by GLC (with internalstandard, 2- or 4-methylquinoline). T he results are reported inthe table. All the aldehydes were isolatedas pure sam ples by silicagel chromatograph y (1:l hexane-ethyl acetate under pressure)and identified by com parison with authe ntic compounds (m p, IR,NMR, MS). '

Formylation of 4-Methylquinoline Using H z 0 2 Th e pro-cedure is identical with tha t used with t-BuOO H with the onlydifference being that 1 mol of 30% H2Ozper mol of lepidine isused. GLC and TL C show tha t the reaction product is a mixtureof unreacted lepidine and 2-trioxanyl- and 2-formyllepidine. Thehydrolysis by 10% H2 S0 4 eads to a m ixture of lepidine and2-formyllepidine. GLC analysis (2-m ethylquinoline as internalstand ard) indicates a conversion of 38% a nd a yield of 93% basedon converted lepidine. Th e 2-formyllepidine (m p 76-77 "C) hasbeen isolated by silica gel chromatography and identified bycomparison (IR, NMR, MS) wi th an authent ic sample .

Reaction of Lepidine with 1,3-Dioxolane. Lepidine (14mmo l), 16 mmol of CF,COOH, 24 mmol of t-BuOO H, and0.1mmol of ferrous sulf ate in100 mL of 1,3-dioxolane were warmedunder stirring for5 h a t 78 "C. Th e solution was then concentratedby distilling the dioxolane, made basic by5% NaOH solut ion,extracted with ether, and analyzed by GLC (2-m ethylquinolineas internal standard ). Th e conversion of lepidine was 93%; theyields of 2-dioxolan-2-yl-4-methylquinoline nd 2-dioxolan-4-yl-4-methylquinoline were 61% an d 3070, respectively. Th eproducts were isolated by silica gel chromatography.

2-Dioxolan-4-yl-4-methylquinoline: iquid; NM R (CDCl,)d 2.7 (s, 3 H, M e-4), 4-4.5 (m, 2H, OCHC H,O), 5.1-5.3 (m, 3 H ,CHO, OCHzO),7.4-8.1 (m,5 H, Ar) ; MS,m / e 215 (M'.), 201, 185,184, 170, 157, 143, 115.

2-Dioxolan-2-yl-4-methylquinoline, iquid, was identified bycomparison (IR , NMR, M S) with an auth entic sample prepared

by ethylene glycol ketalizationof 2-formyl-4-methylquinoline.Byhydrolysis with 10% HzS04it is transformed in 2-formyl-4-methylquinoline.

Acknowledgment. Th is work was suppo rted by Pro-getto Finalizzato Chimica Fine e Secondaria, CNR.

Registry No. t-BuOzH , 75-91-2; HzOz,7722-84-1; quinoline,91-22-5;4-methylquinoline, 491-35-0;2-methylquinoline, 91-63-4;isoquinoline, 119-65-3;quinoxaline, 91-19-0; benzothiazole, 95-16-9;2-formylquinoline, 5470-96-2; 4-formylquinoline, 4363-93-3;2-formyl-4-methylquinoline, 40105-30-4;2-methyl-4-formylquinoline,6760-22-1; I-formylisoquinoline, 4494-18-2; 2-formylquinoxaline,1593-08-4; 2-formylbenzothiazole, 6639-57-2; trioxane, 110-88-3;2-(dioxolan-4-yl)-4-methylquinoline, 9687-43-1; 2-(dioxolan-2-yl)-4- meth ylqu inoline , 99687-44-2; 1,3-dioxolane, 646-06-0; 2-trioxanyllepidine, 40105-26-8.

Methylcopper(1)-Catalyzed Selective ConjugateReduction of a,@-Unsaturated Carbonyl

Compounds by Diisobutylaluminum Hydride inthe Presence of Hexamethylphosphoric Triamide

Tetsuo Tsuda,* Toshio Hayashi, Hiroshi Satomi,Tadashi Kawam oto, and Takeo Saegusa*

D ep ar tmen t of Synthetic Chemistry, Faculty ofEngineer ing , Kyoto Univers i ty, Yoshida, Kyoto , Jap an606

Received May 29, 1985

Selective conjugate reduction (1,4-reduction) of a, @- un-saturated carbonyl compounds is an im portant transfor-ma tion in organic synthesis. Especially, the selectiveconjugate reduction on highly functionalized molecules isa recent subject of considerable interes t. Several transi-tion-metal hydride reagents including those produced insitu from transition-metal compounds and conventionalreducing reagents have been developed.] Previously wereported t ha t cuprous iodide catalyzes conjugate reductionof a,@-unsaturated arbonyl compounds by lithium alu-minu m hydride (LA H) in the presence of hexamethyl-phosphoric triamide (H MP A).2 However, the efficiencyan d selectivity of th e reduction were not very high. Di-

isobutylaluminum hydride (DIBAH ) is a widely employedreducing reagent in organic synthesis, andit is interestingto exploit novel reducing reactivity of DIBAH modifiedby a transition -meta l compound. Herein is reported me-thylcopper(1)-catalyzed highly efficient and selective con-jugate reduction of a,@ -unsatu rated arbonyl compoundsby DIBAH in the presence of HMPA (eq1) .

MeCu c a l a l y s l+ HAl-i-Bu, T HF - HM PA, .c-

-CH-C =C-OAl-i-Bu,-

O+ -CH-CH-C=O (1)

I I I I l l

Reduction of a,@-unsaturatedcarbonyl compounds by

DIBAH generally takes place a t the carbonyl group(1,2-reducti on) to produce allylic alcohols. It has been nowfound that a remarkable change of reducing reactivity ofDIBAH is brough t abo ut by addition of HMP A. As isshown in Table I, conjugate reduction of truns-2-hexena1,2-cyclohexen-l-one, and mesityl oxide by DIBAH waseffectuated in a mixed solvent of HM PA- THF (v/v,15)a t 0 OC-room tem pe rat ure in a good yield of ca.90%without any 1,2-reduction. T he DIBAH -HMPA systemas a reagent of conjugate reduction, however, lacks gen-erali ty, owing to I imitation of applicable substrates.Conjugate reduction of3-methyl-2-cyclopenten-1-one nda,@ -unsaturate d esters such as m ethyl crotonate a ndmethyl cinnamate by DIBAH-HMPA did not proceedeffectively.

Addition of a catalytic amount of MeCu which wasprepared in situ from an equimolar reaction of methyl-lithium and CU I o the DIBAH-HMPA system produceda dramatic effect to cause at-50 "C selective an d quan -titative conjugate reduction of a variety of a,@-unsaturatedcarbonyl compounds including a,@ -unsatu rateds t e r s and@,@ -dialkyl-substituted ,p-enones witho ut an y 1,2-reduc-tion. The results are summarized in TableI. A role ofMeCu is crucial. Addition of an equimolar amoun t of

(1) (a) Keinan,E.; Gleize, P. A. Tetrahedron L e t t . 1982,23, 47 7 an dreferences therein . (b)Four, P.; Guibe, F. etrahedron L e t t . 1982, 23,1825.

(2 ) Tsuda, T.; Fujii, T.; Kawasaki, K.; Saegusa,T. J . Chem. SOC.,Chem. Commun. 1980, 1013.

0022-326318611951-0537$01.50/0 0 1986 American Chemical Socie ty