I) Anion; Synthesis of Parallels That of the Corresponding H-C-0-C--=0 Group N-Heterocycles and Alkaloids of Estersliil (Torsional Angle About the Bold Bonds ~0"

(C3)-X [3] a) Preparation of the esters (4a) and pa). R. Schmierer. Dissertation. Uni- versitat Stuttgart 1980; b) preparation of the esters (461 and (66): C. Helm- chen. G Grolemerer, A. Selrm, unpublished. Hd (41 M. W. Rathke. A. Lmdert. J. Am. Chem. SOC. 93. 231R(1971). for optimum LKHIPA LiCHIPA yields the base must be present in excess (in the case of urethanes 2 equival- THF THFiHMF'T 4 : 1 (4) ents, in the case of sulfonamides 1 5 equivalents). j. J [5] a) Apparatus, see G. Helmchen. G. Nili, D. Flockerrr. W. Schuhle, M S. K Youse/. Angew. Chem. 91. 64 (1979): Angew. Chem. Int. Ed Engl. 18. 62 (C3)-x (C3)-X p' (1979): petroleum ether (low-boiling)/ethyl acetate mixtures of suitable eluotropy were used as eluents; b) G. Helmchen. G. Nit/, D Nockerri. M. S. K. Youssg, Angew. Chem. 91, 65 (1979). Angew. Chem. 91. 65 ( 1979); An- gew. Chem. Int. Ed. Engl. 18. 63 (1979). 16) a) Ethanol (95%). 0'C. onlv applicable in the cane of /Na). h) the urethane5 1R'-X R'-X' 171,) and /Xaj yield 2.3-bornanediul, in the case ofthe sullbnamideh 17bj and (9h). flb) and (3bj are reobtained. 171 All the new compounds gave correct analyses and characteristic spectra. [XI An example: E. Ade. G. Helmchen. C Heiligenmann. Tetrahedron Lett. 1980, 1137. [9] a) A. I. Meyers. E. S. Snyder, J. J. H. Ackerman. J. Am Chem. Soc. 100. Scheme 1. Configurations of educt. intermediates and products in the asym- 8186 (1978): b) K. G. Davenport. H. Eichenauer, D. Enders. M. Newcomb, D. metric alkylation of the esters (4). E. Bergbreirer, J. Am. Chem. SOC.101. 5654 (1979) [lo] R. E. Ireland. A. K. Willard. Tetrahedron Lett. 1975, 3975: R. E Ireland, R. H. Mueller. A. K. Willard. J. Am. Chem. Soc. 98. 2868 (1976). The configurational relationships can all be explained on [ 111 Cf G. Helmchen. Tetrahedron Lett. 1974. 1527: L. Golka, Dissertation. Uni- the basis of the following hypotheses (cf. Scheme 1): versitat Stuttgart 1980 1) According to Ireland and Willard the esters Alkyl- 112) E. Ruch, Acc. Chem. Res. 5. 49 (1972). CH,-COOR are deprotonated with lithium amides in THF 1131 G. Helmchen ef 01.. unpublished results. preferably to Z-, in THF-HMPT (4: 1) preferably to E-enolates (selectivity in each casea4: I)["l; thus, 2- or E-(11) can Selective Reduction of the Nitro to the Amino be generated selectively from (4). Functional Group by means of the 2) The conformation of the H-C-0-C-OLi group Phthalocyaninecobalt (I) Anion; Synthesis of parallels that of the corresponding H-C-0-C--=0 group N-Heterocycles and Alkaloids of estersliil (torsional angle about the bold bonds ~0"). 3) Attack of the electrophile R2-X at the enolate is By Heiner Eckert''] blocked by the group X; that is in the case of (11) it takes The directed transformation of functional groups, while place from the front side. Under otherwise equal conditions, other functionalties with similar reaction specifity are re- therefore, Z- and E-enolates are alkylated to inversely confi- tained intact, is one of the most frequently encountered gurated products. problems in synthetic organic chemistry. The reduction of 4) The esters (4) and (5) as well as (4) and (6) are hetero- nitro to amino groups is the best route to the important aro- chiral'"' with respect to the X-C-eH-0 group (e=C-2 matic amine class of compounds; it is however well known""l or C-3), and therefore under the same conditions give prod- that this is often accompanied by reactions of other function- ucts with inverse configuration of the acyl group. al groups (C-=--C,'; C----O, -C=N, aryl halides)[']. Under 5) Inversely configurated products are also formed in the basic reaction conditions rearrangement products and prod- reactions of (4)-(6)with R2-X' when R' = R", R2= R" and ucts arising from N-coupling are often produced in consider- R' = R", R2= R" (cf. references cited infsa)). able The reduction of unsaturated compounds Other than in the case of the systems described in'"], com- in the presence of metallic macrocycles of the vitamin Bi2 plexation of the lithium by X in (4)-(6) does not seem to structure type, although not with stable phthalocyaninemetal play an important role. This is supported by results obtained anions, has already been describedI3! with esters of 2-aminoalcohols [(I), X = N(alky1)aryl; N-al- Aromatic and aliphatic nitro compounds (1) can be re- kylephedrine] and 1,2-diols and their derivatives [(l),(Z), duced to primary amines (2) at room temperature using X = 0-alkyl and O(CH2)20CH3,2,2'-binaphthol, trans-1,2- weakly basic conditions in protic solvents e. g. alcohols, in the cycl~hexandiol]l'~~. presence of the phthalocyaninecobalt (I) anion[CoiPcla. Received: September 24. 1980 [Z 659b IE] The reaction proceeds cleanly and selectively: the following German version: Angew. Chem. 93, 209 (1981) functional groups do not react; arenes and aryl halides, C--:-C CAS Registry numbers: double bonds even when activated, cyanides and isocyan- (4aj (R'=CH'Ph). 76529-52-7: (4a) (R'=CHI), 75817-71-9: (40) ides, aldehydes and ketones, carboxylic acid esters and am- (R'= CH2CHCH2). 76529-53-8: (4a) (R'=nC,Hu). 76529-54-9 (4a) (R'= nC,,H,.q). 76529-55-0: /Sa) (R'=CH,Ph). 76529-56-1: (50) (R'=CH,). 6 [Co'Pcp 76529-57-2: (50) (R=nC,,H,,). 76529-58-3: (461 (R'=CH,). 76529-59-4: (6b) 02N-R-X (R'=CH3). 76529-60-7: (R)-(7a) (R'=CHIPh. R'=CH,). 76529-61-8; (S)-(7a) MeOH (R'=CH\, R'=PhCH>), 76582-32-6; (R)-(70) (R'=CHZPh. R'=CH'CHCHr). 76529-62-9: (S)-(7a) (R'= CH2CHCH2. R3= PhCH?). 76582-33-7; (R)-(7a) (R'=CH,Ph. R'=nC4Hs). 76529-63-0; (S)-(7aj (R'=nC4H,. R'=PhCH2). 76582-34-8: (R)-/7a) (R'=CH,CHCH2. R'=CH,). 76529-64-1: (S)-(7a) (R'=CH,, R'=CH>CHCH2), 76582-35-9 (S)-(7a) (R'=CH,. R'=iC4HY). 76529-65-2: (R)-/7a)(R'=nC,*H23. R'=CH,), 75879-21-9. (S)-(7a)(R'=CH,, R'= nClhHp),75817-73- I. (R)-(7a)(R'= CH,. R' = iC,Hq). 76582-36-0; (S)-(Xa) (R'=CH,Ph. R'=CH,). 76529-66-3: (R)-(Xa)(R'=CH,, R'=PhCH'), 76582- NC-(CHJ-CN Ph-CH=CH-CO,Et 84-8; (S)-/84(R'=nC,,?H,,. R"=CH>). 76529-67-4: (R)-(8o) (R'=CH,. R'=nC,,Hd. 76582-37-1; (S)-(7bj (R'=CH,. R2=C,4H2V).76529-68-5: (R)- i 3) (4) (7bj (R'= CH,. R'=IIC,~H~~),76582-38-2; (R)-(Pb)(R'=CH,. R'=nC,,H2,). 76582-85-9; (S)-(9bj(R'= CH,. R'= nC,4H24).76582-39-3

[I] G. He/mchen. R. Schmrerer. Angew. Chem. 93, 208 (1981); Angew. Chem. Int Ed. Engl. 20. 205 (1981). ['I Dr. H. Eckert [2] T Kaneko. D. L. Turner. M. Newcomb. D. E Bergbrerter. Tetrahedron Lett. Orgdnisch-chemisches Institut der Technischen Universitat Miinchen 1979. 103 Lichtenbergstrasse 4. D-8046 Garching (Germany)

208 0 Verlag Chemie, GmbH, 6940 Weinherm. 1981 0570-0833/81/0202-0208 $ 02 50/0 Angew. Chem. Int. Ed. Engl. 20 (1981) No. 2 ides (see Table 1). The high yields, in particular with (lg) CHn and (li) which have a strong tendency to form side products, 6[Co'Pcp R3dN 0& indicate the extremely high selecti~ity'~"~of the stable (ii). (Ik) + MeOH N' CH3 phthalocyaninecobalt (I) anion. Apart from its role in reduc- 260 h ' ' tion reactions [CO'PC]~only participates in substitution reaction~[~"'with alkylf4blor acyl Control experiments 171 (8a). R3 = H(62%) indicated that even at long reaction times, hexanedinitrile (3) (Sb) ,R3 = Cl(5 1%) and ethyl cinnamate (4) were not attacked by [Co'Pc]'; only 0 the transesterification of (4) was observed. Both the charac-

Table 1. Selective reduction of nitro compounds (1). which contain other reactive eo functional groups, to amines (2) by means of [Co'Pcle at 2C-25"C in meth- \'. OH anol. 19)

R X i [h] Yield 1x1

a nGH, 95 66 b a-Naphthyl 48 70 Procedure c C& p-CI 80 91 d CbH, P-F 26 63 (2): Under a nitrogen atmosphere, Li[CoPc] .4.5 tetrahy- e CeH, p-CH2-CN 62 95 drofuran (THF)191 (17-18 g, 19-20 mmol) is dissolved in 100 f CbH, p-NC 72 76 cm3 Nz-saturated methanol. The deep green solution is 65 [a] 82 g ca, p-CH=CH-COzEt treated with 3.0 mmol (1) and stirred at 20-25 "C (Table 1). h CJL p-CO-CH, 90 78 i C,H, o-CHO 90 96 10 cm3 HzO is then poured into the reaction mixture, C02 and air passed in for 5 min and the mixture centrifuged to [a] EtOH as Solvent separate the deep blue precipitate (5 min; 3000 rpm) which is then washed twice with methanol. The combined centrifu- teristic selectivity and reactivity parameter "supernucleophil- gates are then concentrated and the residue distributed be- icity relative to alkyl halides" (R~~,~= 10.8)1'"1 and low re- tween ether and water. The organic phase is dried over duction potential (- 0.37 V)[5b1of the phthalocyanineco- NaZSO4and the solvent evaporated; compound (2) remains. balt(I)anion, have been determined in preliminary investiga- For compound (2a) the mixture is not treated with HZO,but tions of its mechanism of action@land for reduction proc- with 50 cm' of INhydrochloric acid and centrifuged. The esses. centrifugate is then made alkaline with NaOH and extracted As a result of its high selectivity and mild conditions of with ether. The ether phase is extracted with 10 cm3 of 1 N reaction, this reduction method is highly suitable for use in hydrochloric acid and water and the combined aqueous ex- the synthesis of N-heterocycles by the Friedlander reac- tracts concentrated, by means of which (2a).HCl remains. (6): Under a N2 atmosphere, Li[CoPc].4.5 THFI9I (12-13 g, 13-14 mmol) is dissolved in 70 cm3 N2-saturated methanol. The deep green solution is treated with an excess of (6) (cu. 50 mmol), 2.0 mmol (li) or (lk) and stirred at 20-25 "C (see Table 2). Following this, 5 cm' of H20 is added to the green reaction mixture, CO, and air passed into the mixture tion"'. The nitroaldehydes (li) or (lk) were reduced in this for 5 min, before being centrifuged (5 min; 3000 rpm) from way in a one-pot reaction and, without being isolated, the the deep blue precipitate, which is then washed once with sensitive aldehydes produced were condensed with the ke- ethanol and twice with ether. The combined centrifugates are concentrated, the still damp residue distributed between 0.5 N hydrochloric acid and hexane, and the hexane phase Table 2. Synthesis of N-heterocycles (6) from nitro compounds using the onepot procedure in methanol at 20-25 "C. extracted twice with water. The combined aqueous phases are washed with hexane, neutralized with 5 N NaOH and ex- Educts R' RZ R.' i Pro- Yield tracted with ether. The ether extract is dried over KOH and [h] ducts ['.I concentrated; (6) remains behind. (8a): Under a nitrogen atmosphere, Li[CoPc]. 4.5 THFI'l (li) + (5a) CH, H H 63 (60) 77 flk)+ f5aJ CH, H CI 160 (66) 87 (11.9 g, 13.2 mmol) is dissolved in 70 (3111' methanol which (Ii) + (Sb) CHI CH, H 49 (6r) 71 Ial had been saturated with N,. The deep green solution is (I1) + {SC) C,H, H H 96 (6d) 88 treated with (li) (302 mg, 2.0 mmol) and (7) (376 mg, 2.0 [a] No isomeric 2-Ethylquinol1ne. mmol)18"1and stirred at 20-22 "C for 260 h. Following this, 5 cm3 H20 is added to the reaction mixture, C02 and air passed in for 5 mins and the mixture then centrifuged (5 min, tones (5); it was therefore unnecessary to protect the reactive functional groups in the intermediates (Table 2). The synthe- 3000 rpm) from the deep blue precipitate; the latter is sis of the alkaloid comptothecine (9) and its derivatives['], washed with warm (50°C) nitrobenzene (5 x 40 cm'). Fur- which are powerful antitumor agents, was successfully car- ther washing with methanol (3 x 40 cm') and ether (2 x 40 cm') and drying at 60 "C yields Co"Pc (7.35 g, 98%). Solvent ried out by condensing (li) or (lk) with (7) to give the tetra- cyclic systems (8a) or (8b) respectively (A-B-C-D) with yields is removed from the combined nitrobenzene centrifugates of 62 and 51% respectively; it is particularly noteworthy that and the residue triturated in methanol and filtered. Yield 340 (7) contains groups which can be further reduced. The clas- mg (62%) (8a). M. p. = 340 "C (decomp.). sic, base catalyzed Friedlander reaction using freshly pre- pared and (7) proceeds in only 20% yield and leads to the (2i) Received: May 19, 1980, supplemented formation of side products which are difficult to sepa- October 6. 1980 [Z 696 IE] German version: Angew. Chem. 93. 216 (1981)

Angew Chem Ini. Ed Engl 20 (1981) No. 2 0 Verlag Chemie, GmbH, 6940 Wemherm. 1981 0570-0833/81/0202-0209 $ 02 5010 209 CAS Registry numbers: the values of e,(R) for the alkali metal thulium halides can (la), 108-03-2; (Ib), 86-57-7; (Ic), 100-00-5: (Id), 350-46-9; (le), 555-21-5; (la, be determined unequivocally from measurements of the 619-72-7: (Ig), 953-26-4 (Ih). 100-19-6; (1;). 552-89-6; (lk),6628-86-0 (Za), 107- 10-8. (2b). 134-32-7: (2c). 106-47-8; (Zd), 371-40-4; (Ze), 354425-0 (Za,873-74-5; magnetic susceptibility. From these considerations, a ligand (2g), 5048-82-8; (Zh), 99-92-3; (21). 556-18-3; (50). 67-641; (Sb), 78-93.); (Sc). 98- “magnetochemical series” can be drawn up. Table 1 shows 86-2; (6a). 91-634. (66). 9246-6: (6c), 1721-89-7; (6d). 612-96-4; (7). 58610-63-2; values of e,(R) compared with those of the overlap integrals @a), 6691 1-21-3; (Xb), 76529-26-5. Li[CoPc]. 14516-90-6 S?(R).The values of $(R) for the quaternary sodium compounds[2e,qwere calculated fromi5]using the 4f-Er3+ and 4f-

Y b3+ respectively, and the corresponding np-li- [I] a) Houben-Weyl: Methoden der Organischen Chemie. Bd. 11/1. Thieme, Stuttgart 1957: b) R. A. Eg/i, Helv. Chim. Acta 51, 2090 (1968); c) i? R. Le- gand function of X-16b1(for NT-CsTm02 of 02-,2p solu- wis, S. Archer, J. Am. Chem. SOC.71,3753 (1949); d) T. Satoh, S. Suzuki. Te- tion function for the + 2 potential welli6‘’) for the respective trahedron Lett. 1969, 4555. Tm3+-ligand ion distance R. Then the average value was 121 a) Maki. A. Sugilnma, K. Kikuchi, S. Seto. Chem. Lett. 1975, 1093: b) H. Y. J. formed. Since the Hartree-Fock Sp-function for I - could not Barber, E. Lunf. J. Chem. SOC.1960, 1187. (31 a) A. Fischli. Helv. Chim. Acta 62, 882 (1979); b) N. M. Ricroch, A. Gaudem- be found in the literature, the calculation of the respective er, J. Organomet. Chem. 67, 119 (1974); c) Y. Ohgo, S. Takeuchi, J. Yoshimu- overlap integrals was not performed in this case. ra, Bull. Chem. SOC.Jpn. 44, 282 (1971). [4] a) H. Eckert. A. Schier. Angew. Chem. 91.841 (1979); Angew. Chem. Int. Ed. Table I. A0 parameters e.,(R),overlap integrals S:(R) and Tm” ligand ion dis- Engl. 18, 794 (1979): b) R. Taube, H. Drew T. Duc-Hiep, Z. Chem. 9, 115 tances R. for NT-CsTrnOl and Cs2NaTmX6 (X = F. Cl. Br, I). (1969); c) H. Eckerf, I. Lagerfund, I. Ugi, Tetrahedron 33, 2243 (1977). [51 a) H. Eckert, I. Ugi, Angew. Chem. 87, 847 (1975); Angew. Chem. Int. Ed. Compound e..(R) s,;(R)- 104 R Ref. Engl. 14,825 (1975); b) D. W Clack, N. S. Hush, J. S. Woolsey, Inorg. Chim. Icm ‘I Ipml Acta 19, 129 (1976). 161 H. Eckerf, unpublished results NT-CsTm02 450 [a] 2.47 219.8 PI I71 a) J. Eltasberg, P. Friedunder. Ber. Dtsch. Chem. Ges. 25, 1752 (1892); b) w CszNaTmF, 450f 10 2.36 217 PI I2fI Borsche, F. Sell, Chem. Ber. 83, 78 (1950). CslNaTmCI, 2155 10 [c] 0.81 269 [dl [2e.fl IS] a) Shanghai No. 5 Pharmaceutical Plant. Shanhai No. 12 Pharmaceutical CslNaTmBr, 1452 8 [c] 0.60 284 [dl I2e.fl Plant. Shanghai Institute of Pharmaceutical Industrial Research, and Cs2NaTmIh 125f 5 - 308 [dl [Ze] Shanghai Institute of Materia Medica. Scientia Sinica 21, 87 (1978): b) P. C. Pan, S. Y. Pan. Y. H. Tu. S. Y. Wang. T. Y. Owen, Acta Chim Sinica 33, 71 [a] Without determination of the errors involved [bI cf. [7]. [c] Average value, in- (1975): c) H. Eckert, C. Sang!, Y. Kiesel, M. List/. unpublished results. cluding the values for lithium and potassium compounds. [d] Sum of the ionic ra- [91 H Eckert, I. Ugi, Justus Liebigs Ann. Chem. 1979, 278. dii of Tm‘ + and ligand ion for the coordination number 6: R. D. Shannon, Acta Crystallogr. A 32, 751 (1976).

With the exception of NT-CSY~O~~~~]the unequivocal determination of e,(R) from magnetic studies of this type did not prove possible for the remaining compounds. As an ap- “Magnetochemical Series” proximation a value of e,(R)/e,(R)=3 can be used for the for Lanthanoid Compounds‘**’ halidesl4”I.The values of e,(R) for the ratio e<,(R)/e,(R)=3 By Werner Urland”] also allow the ligands to be arranged in a “magnetochemical Dedicated to Professor Wilhelm Klemm on the occasion series” (Table 2). of his 85th birthday Klemm was the first to make use of magnetic measure- Table 2. A0 parameters e,,(R)for e,,(R)/e,(R)= 3. overlap integrals S:(R). and ments to determine the “valence” of rare earth elements in Yb”-ligand ion distances R for NT-CsYb02 and CszNaYbX, (X=F, CI. Br) compounds where this was not immediately apparent from their composition (e.g. Ce’“02, Ce’iiS2)[i1.In this article it will be shown that magnetochemistry also enables statements to be made about the chemical bonding in lanthanoid com- NT-CsYb02 360+30 2.18 219 12bI Cs2NaYbF, 3601-30 2.11 216 I2gl pounds. Cs>NaYbCI, 252 [a] 0.72 267 [bl [2g.81 Powdered samples of NT-CST~O,~~”~(NT e low tempera- CslNaYbBr, 160flO 0.59 278 [2gl ture form), NT-CSY~O,‘~~],CsAPrF6 (A = K, Rb)’”’, [a] For e,,(R)/e,(R)=1.62. [b] C Meyer. personal communication Cs2AHoF6 (A = Na,K, Rb)IZd1,Cs2LiTmX6 (X = C1, Br, c~~NaTm1,[”~,CSzKTmX6 (x= c1, Br)Izq, CsATrnF, (A=Na, K, Rb)12q, Cs2AYbF6 (A=Na, K, Rb)IZg1and When the ligands are ordered according to increasing C~,NaYbBr,[~g1were studied over the temperature range of e,(R) values, (cf. Tables 1 and 2), the following “magneto- 3-250 K using the Faraday method. Their magnetic behav- chemical series” arises: iour could be explained applying a model of paramagne- ti~ml~~lin which the influence of the crystal field was treated by the Angular Overlap (AO) The conventional crystal field parameters can be expressed in terms of the A0 Table 3. A0parameters e,,(R)for e,,(R)/e,(R)=3.overlap integrals S,‘,(R)and parameters, e,(R) and e,(R), which are directly related to the M’+-F ~ distances R for CsZAMF, (A=K, Rb; M=Pr. Ho. Tm. Yb). U- and .rr-covalent contribution to the chemical bonding and Compound e..(R) s,:(R). 10“ R Ref should be proportional to the square of the respective over- [cm ‘I Ipml lap integral[3b].If it is assumed, on the basis of earlier investi- ~~~~ ~~ ~ CslKPrFh 7201-30 6.90 gation~[~],that the value of the ratio, e,(R)/e,(R), lies be- 227 [a] [Zc] tween 2 and 6 for all the compounds considered here, then CslRbPrF, 690 i 30 CslKHoF, Cs2RbHoF, 4201-30 2.88 [b] 219 [2dI CslKTmF, 420c 10 Cs2RbTmF6 390+10 2.36 217 Ial Pfl [‘I Priv. Doz. Dr. W. Urland Cs2KYbF, institut fur Anorganische und Analytische Chemie der Universitat Cs2RbYbF, 360*30 2.11 216 [a1 [%I Heinrich-Buff-Ring 58, D-6300 Giessen I (Germany) I”] This work was supported by the Deutsche Forschungsgemeinschaft [a] Cf. 171. [b] Average value including functions for 4f-Dy” and 4f-ErZ+[6a].

210 0 Verlag Chemie. GmbH, 6940 Weinheim. 1981 057O-O833/X1/0202~0210 $ 02.50/0 Angew. Chem. Int. Ed. Engl 20 (1981) NO. 2