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Intramolecular [4+2] cycloaddition of an indolenine
Tetrahedron Letters, Vo1.22, No.19, pp 1823 - 1826, 1981 Printed in Great Britain
IRTRAMOLRCULARc4+2]
CYCLOADDITIOB
OOJO-4039/81/191823-04$02.00/O 01981 Pergamon Press Ltd.
OF AB
IKDOLRliIRR1~2
Josef HdjiEek and Jan Trojsnek Research Institutefor Pharmacy and Bioohemietry, 19404 Prague 9, Cseuhoslovakia
Smmnary:Attemptedtransformationof readily accessible18-methyleneoincadlfformlne (I) to lndolenineVI in acidic medium affordedunexpectedly the intramolecular [4+2] cyoloadduotVIII in almost quantitativeyield Aspldospermanealkaloids,especiallythose possessingthe 1,2 or 2,16 unsaturation,are suitablestartingmaterialsfor the synthesesof several types (I) seemed to be of indole alkaloids.Among them, 18-methylenevincadlfformine a versatilesyntheticintermediate,the ally1 groupinghaving been alreadyutlUsed In aspidospermanealkaloidsohemlstry3S4.In order to achieve this objective, the Kuehne's exoellentstereospecificapproach*was successfullyadopted. Thus, alkylationof cyclohexylimineof 4-pentena16(II) with ohlorobromopropane In the presence of LDA' followedby acid hydrolysisat pH 3 for 15 h (RT) gave 2-allyl-5-chloropentanal (III)[78 9%;bp 63 'C/80 Pa; 'H-RMR (CDC13)b 9.62 (la, d, J-l Hs), 5.70 (lH), 5.10 (lH), 3.55 (2H); IR (CHC13)2820, 2700, 1715, 1636 cm"]. This aldehydewas reactedwith methyl l-methyl-1,2,3,4-tetrahydropyrido[3,4-b]lndole-1-carboxylate (IV)5Ptogive, after heating in toluene under reflux for 115 h followedby 15 h refluxlngIn the presenoe of DDU, the desired 18-methylenevincadlfformlne (I) [50,5 %; mp 108-110,5'C (acetonitrile); 'H-KKR (CDC13)b 8.90 (lH, be), 7.20-6.60(4H, complex),5.50 (lH, com4.82 (la, bd, J-10 HI), 4.63 (lEI,bd, 5~16 Ho), 3.71 (3H, a); IR (CHC13)3340, 1670, 1600 cm-'; UV (ICeOH) me (log E) 331 (4,078),300 (3,954),227 (4,033)]. Aspidospennanealkaloidspossessinga 8-anllinoacrylate moiety oan be easlly convertedto the oorrespondingindoleninesby hydrolysisand decarboxylationg. However,when the base I was subjectedto alkalinehydrolysis,and the sold VII thus obtained (quant.yield) was refluxedIn 3 % aqueoushydrochlorlo aoid for 25 minutes, the only produot isolatedin almost quantitativeyield was Identifiedas the dienelmineVIII [94,5 %; mp 142-146 'C (ether); 'H-RHR (CDC13)6 6.67-6.13(4H, oomplex),3.08-0.76 (208, complex);IR (CHC13)2939, 2867, 2781, 1635, 1556 om-'; UV nm (loge): (IreOH-R20 1:l) 319 (3,571),259mln (2,130).(IsOH-0,l1pHCl 1:l) 351 (3,616),295min (2,838),260 (3,318)]. The primary process involvedin mass spectrometryof imine VIII is very pro1823
1824
CH2-CH-CH2-CH2-CH:N II
CHg-CH-CHyCH-CHO I CHyCH2-CHyCI
bably a retro-Diels-Alder openinglO (scheme 1). Therefore, the mass spectral f’regmentetlon attern should parallel that of 1,2-dehydroaepidospermidine and ite aongeners 9 , as evidenced by strong peak at 14% 70 (C4H8B, 45 5). However, eubstantlal differences in number of intense peaks are observed, which may be attributed to the presence of ally1 side ohain. The structure B may be frag mented in several rays. Apart from oharacterlstlc p - C4E81@ fragment (path g,), the loss of ally1 grouping (path &) or of elements of propene by oyolio meohanism (path 2; lone of m/s 250, baBe peak) beoomee important in this case. On the other hand, the oily 180uethylene-1,2-dehydroaspldospermidinel” (VI) Is exalusioely formed when the decarboxylatlon of acid VII is carried out In boiling beusene (96 %), even in the presence of p-toluenesulphonio acid. The dieneimlne VIII is produoed In traoe amounts only even by decarboxylatlon in aoetio aald at 100 ‘C. A remarkable effect of strong aoids on the rate of the cycloaddition reaction is illustrated by the fact that the indolenine VI is quantitatively transformed into the cyoloadduct VIII by 15 minutes refluxing In l-3 56 aqueous hydroohlorio acid. To our knewledge, this Is the first omo of lntramoleoular [4+2] oyoloaddition reaction of lndolenines. Inspection of laoleoular models clearly shows that the double bond of the ally1 group ia Ideally oriented with reepect to
1825
SCHEME
1
-
e-
\ /otd VIII
\ I
/+
N'
222,ClbH16B,37%(34%6)
70,C4H&45%(43%)
B x,M+
,$,I$t4~
,61%( 54%)
path
p
1826
the plane of the indoleninemoiety. Experimentsare now In progreesae to the scope and utility of thie reaction.
REFEREECESand BOTES 1)
On Alkaloids.Part KKKVI. Part KKKV: Collect.Czech. Chem. Commun., In prese
2)
PreeentedIn part at the Meeting on Enamine Chemistry,April 28-30, 1980, Liblioe,Csechoslovakia
3) Saxton J.E., Smith A.J., Lawton 0.: TetrahedronLett. m, G., Saxton J.E., Smith A.J.: Tetrahedron2, 1641 (1977)
4161; Lawton
4) HdjiEek J.: PhB. Theaia, Prague 1980; HdjiEek J., TrojanekJ.: Paper preeented at the Meeting on BloorganicChemietry,May 2-4, 1979, Llblice,Czreohoslooakia 5) Kuehne P.E., Huebner J.A., Rateko T.H.: J. Org. Chem. M, 2477 (1979) 6) Preparedby condensationof 4-pentenalwith cgclohexylaminein 74,5 % yield; bp 87-88,5 'C/1,1 kPa 7) Kuehne M.E., Mateko T.H., Bohnert J.C., Kirkemo C.L.: J. Org. Chem. fi, 1063 (1979) (laGMe-MeOH, 8) PreparedIn 82 46yield by baee catalysedtraneeeterification 1 h reflux) of the ethyl ester V, which in turn was obtainedby condeneation of tryptaminehydrochloridewith ethyl pyruoatein refluxingethanol; 82,5 %; mp 114-115Oc 9) Zsadon B., Otta K.: Acta Chlm. Aoad. Sol Hung. %, 87 (1971)and referentea cited therein 10) The naee epeotrum18 almoet identicalwith that of indolenlneVI; for relative intenaitieeof VI abe echeme 1, in parenthesee 11) Biemann K., SpittellerG.: J. Amer. Chem. Sot. 8& 4578 (1962) (Received
in UK 2 March
1981)
IRTRAMOLRCULARc4+2]
CYCLOADDITIOB
OOJO-4039/81/191823-04$02.00/O 01981 Pergamon Press Ltd.
OF AB
IKDOLRliIRR1~2
Josef HdjiEek and Jan Trojsnek Research Institutefor Pharmacy and Bioohemietry, 19404 Prague 9, Cseuhoslovakia
Smmnary:Attemptedtransformationof readily accessible18-methyleneoincadlfformlne (I) to lndolenineVI in acidic medium affordedunexpectedly the intramolecular [4+2] cyoloadduotVIII in almost quantitativeyield Aspldospermanealkaloids,especiallythose possessingthe 1,2 or 2,16 unsaturation,are suitablestartingmaterialsfor the synthesesof several types (I) seemed to be of indole alkaloids.Among them, 18-methylenevincadlfformine a versatilesyntheticintermediate,the ally1 groupinghaving been alreadyutlUsed In aspidospermanealkaloidsohemlstry3S4.In order to achieve this objective, the Kuehne's exoellentstereospecificapproach*was successfullyadopted. Thus, alkylationof cyclohexylimineof 4-pentena16(II) with ohlorobromopropane In the presence of LDA' followedby acid hydrolysisat pH 3 for 15 h (RT) gave 2-allyl-5-chloropentanal (III)[78 9%;bp 63 'C/80 Pa; 'H-RMR (CDC13)b 9.62 (la, d, J-l Hs), 5.70 (lH), 5.10 (lH), 3.55 (2H); IR (CHC13)2820, 2700, 1715, 1636 cm"]. This aldehydewas reactedwith methyl l-methyl-1,2,3,4-tetrahydropyrido[3,4-b]lndole-1-carboxylate (IV)5Ptogive, after heating in toluene under reflux for 115 h followedby 15 h refluxlngIn the presenoe of DDU, the desired 18-methylenevincadlfformlne (I) [50,5 %; mp 108-110,5'C (acetonitrile); 'H-KKR (CDC13)b 8.90 (lH, be), 7.20-6.60(4H, complex),5.50 (lH, com4.82 (la, bd, J-10 HI), 4.63 (lEI,bd, 5~16 Ho), 3.71 (3H, a); IR (CHC13)3340, 1670, 1600 cm-'; UV (ICeOH) me (log E) 331 (4,078),300 (3,954),227 (4,033)]. Aspidospennanealkaloidspossessinga 8-anllinoacrylate moiety oan be easlly convertedto the oorrespondingindoleninesby hydrolysisand decarboxylationg. However,when the base I was subjectedto alkalinehydrolysis,and the sold VII thus obtained (quant.yield) was refluxedIn 3 % aqueoushydrochlorlo aoid for 25 minutes, the only produot isolatedin almost quantitativeyield was Identifiedas the dienelmineVIII [94,5 %; mp 142-146 'C (ether); 'H-RHR (CDC13)6 6.67-6.13(4H, oomplex),3.08-0.76 (208, complex);IR (CHC13)2939, 2867, 2781, 1635, 1556 om-'; UV nm (loge): (IreOH-R20 1:l) 319 (3,571),259mln (2,130).(IsOH-0,l1pHCl 1:l) 351 (3,616),295min (2,838),260 (3,318)]. The primary process involvedin mass spectrometryof imine VIII is very pro1823
1824
CH2-CH-CH2-CH2-CH:N II
CHg-CH-CHyCH-CHO I CHyCH2-CHyCI
bably a retro-Diels-Alder openinglO (scheme 1). Therefore, the mass spectral f’regmentetlon attern should parallel that of 1,2-dehydroaepidospermidine and ite aongeners 9 , as evidenced by strong peak at 14% 70 (C4H8B, 45 5). However, eubstantlal differences in number of intense peaks are observed, which may be attributed to the presence of ally1 side ohain. The structure B may be frag mented in several rays. Apart from oharacterlstlc p - C4E81@ fragment (path g,), the loss of ally1 grouping (path &) or of elements of propene by oyolio meohanism (path 2; lone of m/s 250, baBe peak) beoomee important in this case. On the other hand, the oily 180uethylene-1,2-dehydroaspldospermidinel” (VI) Is exalusioely formed when the decarboxylatlon of acid VII is carried out In boiling beusene (96 %), even in the presence of p-toluenesulphonio acid. The dieneimlne VIII is produoed In traoe amounts only even by decarboxylatlon in aoetio aald at 100 ‘C. A remarkable effect of strong aoids on the rate of the cycloaddition reaction is illustrated by the fact that the indolenine VI is quantitatively transformed into the cyoloadduct VIII by 15 minutes refluxing In l-3 56 aqueous hydroohlorio acid. To our knewledge, this Is the first omo of lntramoleoular [4+2] oyoloaddition reaction of lndolenines. Inspection of laoleoular models clearly shows that the double bond of the ally1 group ia Ideally oriented with reepect to
1825
SCHEME
1
-
e-
\ /otd VIII
\ I
/+
N'
222,ClbH16B,37%(34%6)
70,C4H&45%(43%)
B x,M+
,$,I$t4~
,61%( 54%)
path
p
1826
the plane of the indoleninemoiety. Experimentsare now In progreesae to the scope and utility of thie reaction.
REFEREECESand BOTES 1)
On Alkaloids.Part KKKVI. Part KKKV: Collect.Czech. Chem. Commun., In prese
2)
PreeentedIn part at the Meeting on Enamine Chemistry,April 28-30, 1980, Liblioe,Csechoslovakia
3) Saxton J.E., Smith A.J., Lawton 0.: TetrahedronLett. m, G., Saxton J.E., Smith A.J.: Tetrahedron2, 1641 (1977)
4161; Lawton
4) HdjiEek J.: PhB. Theaia, Prague 1980; HdjiEek J., TrojanekJ.: Paper preeented at the Meeting on BloorganicChemietry,May 2-4, 1979, Llblice,Czreohoslooakia 5) Kuehne P.E., Huebner J.A., Rateko T.H.: J. Org. Chem. M, 2477 (1979) 6) Preparedby condensationof 4-pentenalwith cgclohexylaminein 74,5 % yield; bp 87-88,5 'C/1,1 kPa 7) Kuehne M.E., Mateko T.H., Bohnert J.C., Kirkemo C.L.: J. Org. Chem. fi, 1063 (1979) (laGMe-MeOH, 8) PreparedIn 82 46yield by baee catalysedtraneeeterification 1 h reflux) of the ethyl ester V, which in turn was obtainedby condeneation of tryptaminehydrochloridewith ethyl pyruoatein refluxingethanol; 82,5 %; mp 114-115Oc 9) Zsadon B., Otta K.: Acta Chlm. Aoad. Sol Hung. %, 87 (1971)and referentea cited therein 10) The naee epeotrum18 almoet identicalwith that of indolenlneVI; for relative intenaitieeof VI abe echeme 1, in parenthesee 11) Biemann K., SpittellerG.: J. Amer. Chem. Sot. 8& 4578 (1962) (Received
in UK 2 March
1981)