摘要:

2010(D'NHR~IJ.C.S. Perkin Ii TFA... ii Ion exchange I IRA LOO: A c d 1I I I o -phcnylene chlorophosphiteAmino-acids and Peptides. Part XV1.l Synthesis of Cyclo-[~-( a-amino)-~-alanylglycyl-~-(a-amino)-~-alanylglycyl] and Related Fourteen-membered CyclotetrapeptidesBy Cedric H. Hassall.*t Robert G. Tyson, and (in part) Kuldip K. Chexal, Department of Chemistry,The title cyclotetrapeptide was synthesised through cyclisation of the corresponding linear N-tosyl-N'-benzyloxy-carbonyltetrapeptide with imidazole and o-phenylene chlorophosphite, followed by deprotection. Cyclodi- [L-(ct-benzyloxycarbonylamino) -P-alanylglycyl] has been prepared by cyclodimerisation.EARLIER papers in this series2v3 have described pro- of the cyclopeptide (VIII) to reduce the likelihood, atcedures for the preparation of fourteen-membered the cyclisation stage, of racemisation or of interferingcyclotetradepsipeptides and cyclotetrapeptides through reactions due to the tosylamino-group.The procedureboth cyclodimerisation and the cyclisation of linear for the synthesis is outlined in the Scheme. When thesystems. This investigation has been concerned with preparation of the dipeptide (IV) was attempted byUniversity College of Swansea, Swansea SA2 8PP, GlamorganB ocIZ-Azpr-OH(I 1 + H -GLy - OMe(L IB y IDCciZ-Azpr -Gly-OCH3 (11)+ZTos-Azbr -OH (111) + H - Gly - OBu'? lDCC1 (DlTos-AzLr -GLy - OBu' IN)H2- Pd(O' IB oc 1 1 Z- A,pr - GLy( 2 ) 1 Tos-A2pr- Gly-OBu' ( V )A2pr = c+i - diaminopropionic acid( V I ) R'= Z, R2 = TOS ( V I I I ) R' = R2 = H(VIII R'=H, R~ = TOS (1x1 R ' = R ~ = ZSCHEMEthe synthesis of two related diaminocyclotetrapeptides,(VIII) and (XIV), which were designed as ' buildingblocks ' for the synthesis of a cylindrical peptidee4 Ofthe several alternatives, the linear tetrapeptide deriv-ative (V) was chosen as an intermediate for the synthesisthe acid chloride m e t h ~ d , ~ ? ~ a low yield was obtained,presumably owing to the formation of toluenesulphon-amide by the action of base, as illustrated for compound(X).Subsequent attempts at coupling by a mixed-anhydride synthesis involving pivalic acid or dicyclo-t Present address: Roche Products Ltd., Welwyn Garden City,Herts AL7 3AY.Part XV, J. Al-Hassan, J.S. Davies, and C. H. Hassall,J.C.S. Perkin I , 1974, 2342.C. H. Hassall, D. G. Sanger, and B. K. Handa, J . Chem. SOG.( C ) , 1971, 2814.a C. H. Hassall and 3. 0. Thomas, J . Chem. SOG. ( C ) , 1968,1496; C. H. Hassall, T. G. Martin, J. A. Schofield, and J. 0.Thomas, ibid., 1967, 997.C . H. Hassall, in ' Chemistry and Biology of Peptides,' ed. J .Meienhofer, Ann Arbor Science, Ann Arbor, 1972, p. 153.A. F. Beecham, J . Amer. Chem. SOC., 1947, 79, 3257; M. T.Leplawy, D. S. Jones, G. W. Kenner, and R. C. Sheppard, Tetra-hedron, 1960, 11, 39.E. A. Popenoe and U. duvigneaud. J . Amer. Chem. SOC..1954, 76, 6202.B. C. Barrass and D. T. Elmore, J . Chem. SOC., 1957, 3134.M. Zaoral, Coll. Czech. Chem. Comm., 1962, 2'9, 12731976hexylcarbodi-imide (DCCI) in dimethylformamide didnot give good yields.In the latter case, a substantialamount (30%) of the trisubstituted hydantoin (XII) wasproduced; it was identified by its lH n.m.r. spectrum.Presumably, it was formed by cyclisation of the N-acylurea (XI), a reaction reminiscent of the rearrange-ment of the peptide derivative N-tosylglycylglycylpyro-glutamyLS When the coupling was repeated with DCCIin methylene dichloride,l0J1 high yields (85%) of thedipeptide (IV) were obtained and none of the by-product(XII) was formed.The remaining stages of the synthesis of the protectedtetrapeptide (V) employed well established procedures.The identity and optical purity of the products were201 1of an L,L-isomer occurs less readily than of a D,L-fOlTn,presumably owing to the less favourable orientation forring closure of the linear intermediate.13J4 We haveobtained the product (XIV) but in only 5% yield bycyclodimerisation of the azide (XIII) in aqueous alkali.EXPERIMENTALM.p.s were determined with a Kofler hot-stage apparatusInfra-red spectra were determined for potassium bromidediscs, with a Perkin-Elmer 257 spectrophotometer. N.m.r.spectra were measured with a Varian HA100 (100 MHz)spectrometer (tetramethylsilane as internal standard).For optical rotation measurements we employed a Perkin-Elmer 141 polarimeter.Mass spectra were determinedwith an A.E.I. MS9 double-focusing spectrometer.ZNH- CH2-CH-CO - ZNH.CH2 * CH-CO I I I I + C6HllNH2( X I )(XI11NHZfconfirmed a t each stage.The cyclisation with o-phenylene chlorophosphite and imidazole in diethylphosphite gave a yield of over 60% of the cyclic com-pound (VI) ; the deprotected diaminocyclopeptide(VIII) was obtained through hydrogenolysis followed byreduction with sodium in liquid ammonia. The lHn.m.r. and the mass spectra of the cyclic compounds(V1)-(VIII) were in accord with the structures proposed.We undertook the preparation of cyclodi-[L-(a-benzyloxycarbonylamino) - p-alanylglycyl] (XIV) in orderto investigate the conformations of related D,L- and L,L-systems, as for the case of the related cyclotetradep-~ipeptides.~ There was some basis for expecting toachieve the synthesis of this peptide by cyclodimeris-ation. Similar cyclodepsipeptides have been preparedin this way and cyclodi-(p-alanylglycyl) is formed fromthe azide of the monomer.12 However, the formation* A.R. Battersbyand J. J. Reynolds, J . Chem. Soc., 1961,524.lo J. C. Sheehan, M. Goodman, and G. P. Hess, J . Amer. Chem.l1 N. A. Smart, G. T. Young, and M. W. Williams, J. Chem.Soc., 1956, 78, 1367.Soc., 1960, 3902.Measurements at high resolution were performed by usinga direct inlet system at a source temperature in the range250-300 "C. For t.1.c. we employed plates coated withKieselgel G (Merck) ; the following solvent systems:(A) ethanol-ammonia (s.g. 0.880) (5 : 1 vlv), (B) benzene-methanol-glacial acetic acid (10 : 2 : 1 v/v), (C) ethylacetate, (D) ethyl acetate-benzene ( 4 : 1 v/v), (E) ethylacetate-benzene (1 : 1 v/v), (F) benzene-ethyl acetate( 2 : 1 vlv), (G) acetone-chloroform (1 : 1 v/v); and thefollowing spray reagents: (I?) a saturated solution of iodinein chloroform; (Q) a 1% (w/v) solution of ninhydrin inacetone (the plate was then heated at 110 "C for 2 min).Light petroleum had b.p.60-80 "C unless otherwise speci-fied.L-a-BenzyloxycaYbonylamino- p-t-butoxycarbonylamino-$ropionyZglycine &?ethyl Estev (11) .-DCCI (6.19 g , 30l a H. Sekiguchi, Compt. rend., 1963, 256, 4012; M. Rothe. I.Rothe, T. Toth, and K.-D. Steffen, in ' Peptides: Proceedings ofthe Eighth Symposium,' ed. H. C . Beyermann et al., NorthHolland, Amsterdam, 1967, p. 8.Is V. T. Ivanov, Yu. A. Ovchinnikov, A. A. Kiryushkin, andM. M. Shemyakin in ' Peptides: Proceedings of the Sixth Euro-pean Symposium,' ed.L. Zervas, Pergamon, Oxford, 1966, p. 337.l4 Yu. A. Ovchinnikov, V. T. Ivanov, A. A. Kiryushkin, and&I. M. Shemyakin, Doklady Akad. Nauk S.S.S.R., 1963,158, 1222012 J.C.S. Perkin Immol) was added to a well stirred mixture of glycine methylester hydrochloride (3.77 g, 30 mmol), triethylamine (3.03 g,30 mmol) , and L-a-benzyloxycarbonylamino-p-t-butoxy-carbonylaminopropionic acid (10.14 g, 30 mmol) l5 indichloromethane (150 ml) at 0 "C. After 26 h NN'-dicyclohexylurea and triethylamine hydrochloride wereremoved by filtration, and the last traces of DCCI wereremoved by treating the solution with glacial acetic acid(0.2 ml) at 0 "C for 3 h and filtering. The filtrate was madeup to 400 ml, washed with 0.5~-hydrochloric acid (150 ml) ,0.5~-sodium hydrogen carbonate (150 ml), and water(2 x 150 ml), dried, and evaporated t o yield a solid (12.6 g)which crystallised from ethyl acetate-light petroleum asneedles.This product (10.3 g , 84%) had m.p. 129-130',[aIDlQ -26.8' (c 2 in CHC1,) (Found: C, 55.9; H, 6.7;N, 10.3. C1,H,,N,O, requires C, 55.7; H, 6.7; N, 10.3%),RF(E) 0.40, (F) 0.19, 7 (CDC1,) 2.70 (5 H, C,H,), 2.7-2.8br(1 H, NHCH,*CO), 3.73br (1 H, CH-NHZ), 4.65br (1 H,CH,*NHBoc), 4.92 (2 H, S, PhCH,*O), 5.68 (1 H, q, ZNH-CH-CO), 6.05 (2 H, d, NH*CH,*CO,), 6.32 (3 H, S, CO,*CH,),6.54 (2 H, t , BocNHCH,), and 8.58 (9 H, s, Me,C*O).D-~-BenzyloxycarbonyZanzino-a-tosylaminopropionic Acid(111) .-D-P-Amino-a-tosylaminopropionic acid ( 12.6 g , 0.05mol) was dissolved in N-sodium hydroxide (50 ml) andcooled to 0 "C in an ice-bath.Over 1 h, benzyl chloroform-ate (10 g, 0.059 mol) was added t o the stirred solution andthe pH was maintained at 9-10 by addition of N-sodiumhydroxide (50 ml). The sodium salt of the product pre-cipitated out during the reaction, and ice-cold water wasadded to aid dissolution. After the addition of the benzylchloroformate, the suspension was stirred at 0 "C for afurther 3 h. The resulting slurry was diluted t o 500 mland washed with ether (2 x 150 ml), and the aqueousphase was acidified at 20 "C t o pH 3 with S~-hydrochloricacid. The mixture was extracted with ethyl acetate(2 x 250 ml) and worked up in the usual way to yield theproduct (16.7 g, 85.2%) as a white, amorphous solid, m.p.57-60", [aID2O -26.5" (c 2 in CH,Cl,), [a],lQ $77.7' (c 4in Iv-NaOH) (Found: C, 54.6; H, 5.2; N, 7.2.C18H,,N,0,Srequires C, 55.1; H, 5.1; N, 7.1%), Rp(A) 0.72, (B) 0.61,7 (CDC1,) 0.20br (1 H, s, CO,H), 2.3-3.0 (4 H, AA'BB'pattern, MeC6H4*S0,), 2.78 (5 H, s, Ph), 3.90br (1 H, d,TosNHCH) , 4.40br (1 H, ZNHCH,) , 5.08 (2 H, s, PhCH,O) ,6.05 (1 H, q, TosNHCH), 6.57 (2 H, t, ZNHCH,), and 7.74(3 H, s, CH3C,H4*S0,).Crystallisation from benzene-light petroleum yielded$dates, m.p. 62-64' (Found: C, 61.1; H, 5.6; N, 6.1.C1,H2,N,0,S,C,H6 requires C, 61.3; H, 5.6; N, 6.0%),7 (CDCI,) 2.70 (c,H,).The dicycZohexylammonkm salt crystallised from ethylacetate as needles, m.p. 175-178', [a],as -50.9" (G 1 inEtOH).(Found: C, 62.7; H, 7.6; N, 7.2. C,,H,,N,O,Srequires C, 62.8; H, 7.6; N. 7.3%).~-@-BenzyZoxycarbonyEm~no-a-tosylamino~ro~~onylgZy-cine t-Butyl Ester (IV).-(a) DCCI (0.72 g, 3.5 mmol) wasadded to a mixture of the acid (111) (1.37 g, 3.5 mmol) andglycine t-butyl ester (0.46 g, 3.5 mmol) in dichloromethane(20 ml). After 23 h 0 "C the mixture was worked up inthe usual way t o give the product (1.5 g, 85x1, m.p. 142",[aID2O +25.7' (c 2 in CHC1,) (Found: C, 57.1; H, 6.5; N,8.4. C,,H,,N,O,S requires C, 57.0; H, 6.2; N, 8.3%).15 W. Broadbent, J. S. Morley, and B. E. Stone, J . Chem. SOC.(C), 1967, 2632.16 J. Rudinger, K. Poduska, and M. Zaoral, Coll. Czech. Chem.Comm., 1960, 25, 2022.RF(F) 0.41, T 2.22-2.82 (4 H, AA'BB' pattern, MeC,-H4*S02), 2.70 (5 H, s, Ph), 2.7-2.8br (1 H, CO*NH*CH,),3.48br (1 H, d, CH-NHvTos), 4.47br (1 H, CH,*NHZ),4.96 (2 H, s, OCH,Ph), 6.1-6.4 (3 H, m, NH*CH,CO, andTosNH*CHCO), 6.64 (2 H, t , ZNHCH,), 7.64 (3 H, s,CH3*C6H4*S02), and 8.55 (9 H, s, Me,CO,C).(b) When the reaction was carried out on a similar scalewith dimethylformamide (12 ml) rather than dichloro-methane as solvent, a mixture was obtained.The com-ponent which was less soluble in ethyl acetate was the pro-duct (IV), m.p. 142" (0.88 g, 50y0), but the mother liquorgave, by recrystallisation, 5-(benzyZoxycarbonyZamino-methyZ)-3-cyclohexyl-l-tosylhydantoin (0.51 g, 29.2%) asneedles, m.p. 146-147" (Found: C, 60.5; H, 5.7; N, 8.5.C2,H3QN306S requires C, 60.1; H, 5.8; N, 8.4%), RRR(F)4.98 (2 H, s, ArCH,), 5.0br (1 H, NH), 5.8-6.5 (4 H, m,N-CH*CH,*N and N*CH*[CH,],), 7.59 (3 H, s, ArCH,),and 7.8-9.0 (10 H, m, C,Hlo).propionylglycine Hydrazide.-The methyl ester (11) (4.09 g,10 mmol) in methanol (60 ml) was treated with an excessof hydrazine hydrate (1.7 ml, 44 mmol) during 6 h at 20 "C.Evaporation of solvent and the excess of hydrazine gavethe product, which crystallised from water (3.17 g, 74y0),m.p.115-117", [.ID2, -110.1" (c 2 in EtOH) (Found:C, 50.5; H, 6.5; N, 16.6. C18H,,N,0,,H,0 requires C,50.6; H, 6.8; N, 16.4y0), RF(A) 0.80 [red with reagent (Q)].~ro~ionylgZycyl-D-@-amino-a-tosy~am~no~ro~ionyZglycine t-ButyZ Ester (V) .-The azide was prepared from the precedinghydrazide (1.03 g, 2.5 mmol) by treatment with nitrosylchloride (0.28 g, 4.3 mmol) in dioxan (2.5 ml) and tetra-hydrofuran (8 ml) at - 20 "C during 20 min.The conditionswere similar t o those of Honzl and Rudinger l7 for othercases. The resulting solution was diluted with cold(- 10 "C) ethyl acetate (50 ml) and worked with a precooled(- 10 "C), saturated solution of sodium hydrogen carbonatein sodium chloride (20 ml). The ethyl acetate solutionwas dried and treated at 0 "C with a solution of @-amino-D-a-tosylaminopropionylglycine t-butyl ester (0.93 g, 2.5mmol) in ethyl acetate (10 ml). The product (1.6 g) hadseparated after 48 h 0 "C, giving crystals (1.45 g, 76%)from acetone-water, m.p. 142--143', [0(]D2l -5.3" (G 2 inMe,N*CHO) (Found: C, 53.5; H, 6.3; N, 10.9.C,4H48-N,OllS,H,O requires C, 53.5; H, 6.6; N, 11.0%), RF(C)MeC,H,*SO,), 2.70 (5 H, s, Ph), 4.90 (2 H, O*CH,Ph),7.62 (3 H, s, CH,-C,H,*SO,), 8.58 (9 H, s, Me,CO,C), and8.61 (9 H, s, Me,C*O-CO-NH).A lower yield of the tetrapeptide (71%) was obtainedwhen the reaction was camed out in aqueous conditionsby using procedures based on those developed by Bois-sonnasL- ~-Amino-u-benzyloxycarbonylaminop~o~ionylglycyZ-~-a-amino-a-tosylaminopropionylg1ycine.-The protectedtetrapeptide (V) (0.16 g. , 0.2 mmol) was dissolved in anhy-drous trifluoroacetic acid (2 ml) and kept at 20 "C for 30min. The residue obtained by evaporation was dissolved0.71, 7 2-2.8 (4 H, AA'BB', C,H4), 2.73 (5 H, S, Ph),L-a-Benzy Zoxycarbonylamino- a-t-butoxycarbonylamino-L-a-Benzyloxycarbonylamino-~-t-butoxycarbonyZamino-0.49, (D) 0.24, (G) 0.44, T (CDCl,) 2.2-2.8 (4 H, AA'BB',and Schwyzer l@ for azide coupling.l7 J.Honzl and J. Rudinger, Coll. Czech. Chem. Comm., 1961,P.-A. Jaquenoud and R. A. Boissonnas, Helv. Chim. Ada.19 B. Iselin and R. Schwyzer, Helv. Chim. Acta, 1961, 44, 169;26.2333.1959, 42, 788.R. Schwyzer and H. Kappeler, ibid., p. 19911976 2013in ethanol (1 ml) and water (2 ml). The solvent wasremoved under reduced pressure. The gum which remainedconsisted of essentially one product [Rp(A) 0.673. Thesolution, in ethanol (2 ml) and water (1 ml) was passedthrough a column (8.5 x 1 cm) of Amberlite 1RA-400(OAc-) which was then washed with N-acetic acid. Theeluate containing ninhydrin-positive material (first 25ml) was evaporated t o give the product (0.12 g, 92y0),m.p.143-146", [aID2O -1.8" ( G 2 in Me,N-CHO) (Found:C, 48.3; H, 5.6; N, 12.8. C25H,2N,0,S,C,H,0,,H,0requires C, 48.3; H, 5.7; N, 12.5%), Rp(A) 0.62 [violetwith reagent (Q)].Cyclo- [L- (a-benzyloxycarbonylamhao) -p-aZanylglycyl-D- (a-tosyZamilzo)-p-aZanyZglycyZ'j (VI) .-A solution of the preced-ing tetrapeptide (134 mg, 0.2 mmol), imidazole (15 mg,0.22 mmol), and o-phenylene chlorophosphite (54.6 mg,0.32 mmol) in diethyl phosphite (40 ml) was heated at140 "C in nitrogen for 10 h with occasional stimng. Aftercooling, the mixture was kept at 20 "C for 12 h. The paleyellow solution was filtered and evaporated under reducedpressure t o yield an amorphous white residue.This wastreated with ethyl acetate (10 ml) at 0 "C for 12 h, filtered,washed thoroughly with warm ethyl acetate, and thendried to yield the product (72 mg, 60%) as a white amor-phous solid. It chars without melting from 315 t o 350 "Cand shows [uID2O 0" ( G 1 in Me2SO) (Found: C, 51.0; H,5.3; N, 14.2. C,5H30N,0,S,H,0 requires C, 50.7; H, 5.4;N, 14.2%), RF(A-G) 0. An anhydrous sample was obtainedby heating the monohydrate at 140 "C, under reducedpressure, for 24 h (Found: C, 51.9; H, 5.1; N, 14.5.C,,H,,N,O,S requires C, 52.3; H, 5.3; N, 14.6%), T 1.98br(3 H, CO-NH), 2.3-2.8 (12 H, m, ArH and CONH), 5.02(2 H, s, ArCH,), 5.9-7.1 (10 H, m, aliphatic CH), and7.66 (3 H, s, ArCH,). The mass spectrum did not includea peak for the molecular ion but there was one (m/e 466)for the isocyanate arising from replacement of the -NHZfunction by -N%=O.Two typical fragmentations of thision m/e 466 are given below; other fragmentations observedcould be explained similarly in terms of both side-chain andring cleavages.cut sodium were added until a blue colour was maintainedfor 5 min. The excess of sodium was destroyed by addinga mixture of resins [Amberlite I R 120 (NH,+) and AmberliteIRA 400 (OH-) (1 : 1 ratio; 0.150 g)]. The mixture wasvigorously stirred a t 20 "C until the ammonia had evapor-ated (the last traces were removed under high vacuum).The residue was dissolved in water (5 ml) and the filtratewas neutralised with N-acetic acid (2.0 ml). On additionof ethanol (100 ml), the solution became milky.After6 h at 20 "C, the white precipitate was filtered off. Thevolume of filtrate was reduced t o 2 ml, more ethanol (100ml) was added, and the mixture was left at 20 "C for 7days to give small rods (0.011 g, 21%), charring slowlyabove 250 "C, [a]D20 50' (c 1 in iMe,N*CHO), Rp(A) 0.31,M+ 286.The bisbenzyloxycarbonyl derivative of (VIII) , preparedby using benzyloxycarbonyl chloride and work-up in theusual way, had Rp(A-G) 0, and charred slowly above310 "C. The mass spectrum was indistinguishable fromthat of the L,L-isomer (XIV).(XIV) .-L-a-Benzyloxycarbonylamino-p-t-butoxycarbonyl-aminopropionylglycine hydrazide (0.81 8 g, 2 mmol) wasdissolved in methanolic 2~-hydrogen chloride (35 ml) andkept for 2 h at 20 "C.The solvent was evaporated offunder reduced pressure and the white residue was trituratedwith dry ether for 24 h at 0 "C, filtered off, and dried to givea white hygroscopic solid (0.76 g), Rp(A) 0.28 [red withreagent (Q)]. This was dissolved in 0.2~-hydrochloricacid (10 ml, 2 mmol), cooled t o 0 "C in an ice-bath andmixed with a cold aqueous solution (2 ml) of sodium nitrite(0.133 g, 2 mmol). After stirring for 15 min at 0 OC. thesolution was poured into ice-cold water (1 1) containingsodium hydrogen carbonate (3 g) and set aside for 72 h at0 "C. The amorphous, pale brown solid (0.058 g) whichslowly precipitated out was filtered off and washed withacetone and warm ethyl acetate to yield the product (0.027 g,5.1%) as a white amorphous solid; i t chars slowly above290 "C with complete decomposition at 340 "C; (aID2*-12.5" (G 1 in Me,SO) (Found: C, 54.2; H, 5.6; N, 14.8.Cyclodi- [L- (a-benzy loxycarbonylamino) -p-aZanyZgZycyLJ[C,H,(CH,)*SO,.NH,]+(m/e 171) __)_ [C,H,]+(m/e 91) f( m / e 437)Cyclo- [L- (u-amino) -P-aZany Zglycyl-D- (a-tosylautzino) - p-alurzylglycyZl (VII).-A solution of compound (VI) (0.237 g,0.4 mmol) in purified dimethylformamide (80 ml) washydrogenated at room temperature and atmosphericpressure for 44 h over 10% palladium-charcoal (0.5 g).After work-up in the usual way, the residue was extractedinto warm water (100 m); the extract was filtered andevaporated to yield the Froduct (165 mg), crystals (110 mg,60%) from water, m.p.257-261" (decomp.), [.ID 2o +23.3"(G 1 in Me,N*CHO) (Found: C, 44.6; H, 5.6; N, 18.4.Cl,H,,N,O,S,H,O requires: C, 44.5; H, 5.7; N, 18.3%).RE(A) 0.51 [mauve with reagent (Q)], Mf 440.Cyclo- [L- (a-amino) - P-alanylglycyl-D- (a-amino) -P-alanyZ-gZycylJ (V111).--4 solution of compound (VII) (0.075 g,0.17 mmol) in liquid ammonia (25 ml) was vigorouslystirred at the b.p. of ammonia, and small pieces of freshlyC,,H30N,08,H,0 requires C, 54.5; H, 5 . 6 ; N, 14.7%),RF(A-G) 0 [no colour with reagent (Q)]. The massspectrum did not include a peak for the molecular ion butthere were peaks for monoisocyanate ( w / e 446) and di-isocyanate ( m / e 338). The sequential fragmentationpattern involving stepwise losses of 29 and 28 mass unitswas explained in terms of decomposition to neutral imineand carbon monoxide. The molecular formulae wereestablished by accurate mass measurements in each case :[6/617 Received, 31st March, 1976

ISSN:1472-7781    

DOI:10.1039/P19760002010

出版商:RSC    

年代:1976

数据来源: RSC