- Email: [email protected]
Synthesis of compounds containing the isoprene unit
SYNTHESIS OF COMPOUNDS CONTA .INING THE ISOPRENE UNIT A STEREOSPECIFIC SYNTHESIS OF DEHYDRONEROL ISOVALERATE, A COMPONENT OF A~T~E~~S MONTANA L G. CARDILL&* M. ORENAand S. SANDRI lstituto Chimico “G. Ciamician”, Universiti di Bologna. Via Selmi 2.40126 Bologna, Italy (Received
in UK 28 My
197% Accep~ed~orpubljcofio~
14August 1975)
Abstract-A stereospecific synthesis of dehydronerol isovalerate, isolated from the roots of Anthemis montuna L., utilising the dianion of 3-methyl-2-butenoic acid is described.
Dehydronerol has been isolated for the first time from the roots of A~f~e~i~ ~o~f~~~ L. in the form of its isovalerate ester (I).’
WC,
2-
,!a
1
We wish to report a short highly stereospecific synthesis of this compound u&sing a new method,’ which permits a a@(Z), y&(E) conjugated head to tail isoprenic acid by means of an addition-elimination sequence. The key reagent of our synthetic approach is the dianion (2), easily obtained by metalation of 3-methyl-2 butenoic acid (3) by means of lithium diisopropyIamide.z,3 COOH .@&.A
In tetrahy~ofuran in the presence of small amounts of HMPT at low temperature the elec~ophi~ic attack is kinetically controlled and the regioselectivity depends upon the nature of counterions of 2, the C4 attack increasing with the increase in the ionic character of the organometa~lic bonds involved in 2. At reflux, on the contrary, the electrophilic attack on C2,but not that on C,, becomes reversible with consequent exclusive formation of the desired head to tail isoprenic structure also with lithium as counterion. One of the most interesting features of this reaction is its complete stereospecificity, leading exclusively to the “z” config~ation of the introduced double bond.t The hydroxyacid obtained converts quantitatively into the corresponding lactone (4) which in turn, by treatment with potassium t-butoxide, easily and stereospecifically gives the c@(Z), $(E) double unsaturated acid. Scheme 1 illustrates the whole synthesis.
2 +
J.&HO
-7q-J 0
We have shown that the regioselectivity of the electrophilic attack of a carbonyl compound to the polidentate dianion (2) depends on the conditions, the nature of the counterions and the structure of the carbonyl compound, leading to Ct and /or C, adducts: 2
+
RCHO OH -
YOOH
RyOH+“TJJ
i’flte exciusive formation of the “2” double bond confi~ration has some analogy in the behaviour of allylic carbanions against nucleophilic attack. See Ref. 2 for a brief discussion of this topic.
__A-+
-1 ~HJ~H
6
The dehydronerol(6) was prepared by reduction of the methyl ester (5) with LAH. The ester (1) was at last obtained in a yield of 90% by treatment of dehydronerol (6) with isovaleroyl chloride. All chemical and spectral properties of these compounds correspond to those described for the compounds isolated from the roots of Anthemis montana L.
IR spectra were determined with a Hilger and Watts H 907 Infracord spectrophotometer. NMR spectra were recorded with a
108
G.
CARDILLO
R 12 B Perkin-Elmer instrument with TMS as internal standard. UV spectra were determined with a 402 Perkin-Elmer spectrophotmeter in EtOH. Mass spectra were measured on a HitachiPerkin-Elmer RMU6D (single focus) spectrometer at 60 eV. TLC was performed on silica gel HF,,, (Merck) and column chromatography on silica gel 0.05-0.20 (Merck), with hexaneether as a solvent. THF was obtained dry and oxygen free by distillation over sodium and LAH under argon. Diisopropylamine was distilled from calcium hydride and stored over molecular sieves. Hexamethylphosphoramide was distilled from molecular sieves under argon. n-Butyllithium was purchased from Schuchardt (Munchen) as a 1.8 M soln in n-heptane. 3-Methyl-2-bufen-I-ol.To a suspension of MnO, (2Og)in 80 ml methylene chloride, 3-methyl-2-buten-l-al (2.9 g; 34 mmol) in 20 ml methylene chloride was added dropwise at 0”. After stirring for 30 min at O”,the mixture was filtered and the ppt was washed with ether. The organic layer was evaporated. After distillation of the residue (45”.20 mmHg), 2.5 g (85%)of 3-methyl-2-buten-l-al4 was obtained as colorless liquid; IR (neat): v,., I690 (C=O)and 1650(C=CH)cm-‘; NMR (Ccl,): (0) 2 s (CH,); 2.2 s (CH,); 5.85 d (C=CH-) (J = IOHz); IOd (CHO) (J = IOHz). 3-Methyl-5~2-methyl-I-propenyl)pent-2-en-5-elide (4). To a soln of diisopropylamine(4.1 g; 40 mmol) in I50 ml dry THF at 0” under argon, I.8 M n-BuLi (22 ml; 40 mmol) in n-heptane soln was slowly added. The mixture was stirred at 0” for I hr and at room temp for 3 hr. Then 3-methyl-2-butenoicacid (2 g; 20 mmol) in IOml THF was added at 0”. The mixture was stirred 0.5 hr. heated and stirred successively for 1.5hr at 45”. After cooling to -78”, HMPT (IOml) was added and then 3-methyl-2-buten-l-al(I.7 g; 20 mmol)in IOml THF was added in 20 min. After 2 hr the ice bath was removed and the mixture was stirred at room temp overnight and heated under reflux for 2 hr. The mixture was then diluted with ether and water and acidified with 3 N HCI. After extraction with ether, the organic layer was washed with 10% NaHCO, aq, water, and dried (Na$O,), and the solvent was removed in racuo. The purhcation of residue by chromatography gave 2.7 g of 4 (80%) as a yellow oil, eluted with hexane:ether I : I. IR (neat): Y,.. 1720(C=G)and 1650(C=CH)cm-‘; NMR (CDCI,):(S) I.75 s and I.77 s ((CH,),); 2 s (C&C=); 2.3 m (CIj-); 4.9-5.4 m (-C&O); 5.3 bs (=CH-CH-); 5.85 bs (=CH-C=G). Mass spectrum: M* 166mle. Mefhyl 3,7-dimethyl-2(2),4(E),bocfafrirnoofe (5). A soln of 4 IOmmol) in IOml dry THF Was added to a suspension of t-BuOK (I.2 g) in 25 ml THF, and stirred for 0.5 hr at 0”. The mixture was then diluted with ether and water and acidifiedwith 3 N HCI. The organic layer, after extraction with ether, was washed with water, dried (Na2S0,) and the solvent was removed in uacuo to give I .6 g (95%) of acid which was ester&d with diazomethane to give 5
62 d
quantitatively. IR (neat); v,.. 1720 (C=O), 1650 (C=CH), 970 (CH=CH (E)) cm ‘. NMR (CCL): (6) 1.85 s (CH&; 245 d (C&C=) (J = I Hz): 3.8 s (-OCH,); 5.65 bs (C&C=@; 609 br d ((CH,),C=CH) (J = IOHz); 6.85 double d (=CH-CH=) (J = IO, J’= 16Hz); +‘.?5d (CH-C=) (J = I6 Hz). UV. (EtOH): A,., 315; c = 35600. Mass spectrum: M’ 180m le. 3,7-l)imethyl-2(2).4(E),Coctafriene-I-ol(6). A soln of 5 (0.54g; 3 mmol) in IOml dry ether was slowly added to a stirred suspension of LAH (0.1I g; 3 mmol) in I5 ml dry ether, kept at -IO’. After stirring for 0.5 hr at -IO”, the complex was decomposed by adding sat NH.CI aq. and then extracted with ether. The organic layer, after washing with water, was dried (Na2S0,) and evaporated. The residue was chromatographed on silica gel. With hexane:ether 7:3, 6 (0.41g) was obtained. IR (neat): Y,.. 3400(OH), 970 (CH=CH(E)) cm-‘. NMR (CDCI,):(6) I.83 s ((C&)X=); I.9 d (C&C=) (J = I Hz); 2.9 bs (OH); 4.3 d (CI$OH) (J = 6 Hz); 5.55 br t (CH-CH,OH) (1 = 6 Hz); complex pattern from 6 to 6.5 (3 vinylic H). UV (EtOH): A,. 279; e = 22600. Mass spectrum: M- I52 m/e. 3,7-Dimethyl-2(2),4(E),boctatn’enylisoualerafe (1). To a soln of isovaleroyl chloride (0.3I g) in pyridine at 0”, 6 (0.31g; 2 mmol) was added. After stirring for I hr at room temp, the mixture was diluted with water and extracted with ether. The organic layer was washed with 3 N HCI, IO%NaHCO,, water, dried (Na,SO,) and evaporated. After removingof solvent, the residue was purifiedby TLC (hexane:ether 9: I) and 1 (0.41g) was obtained~lR (neat): Y,.. .__1730fC=O).970 (CH=CH (E)) cm-‘. NMR (CCL): (8) 0.95 d ((CH,),CH) (J= 7Hz); I.8 bs ‘((C&)X=); i.9 d (C&-C=) (J = I Hz); 2.13 m (-CH-CIj,-); 4.65 d (CH,GC=O)(J = 7 Hz); 5.4 br t (=CH-CHIO) (J = 7 Hz); complex pattern from 5.9 to 6.5 (3 vinylic H). UV (EtOH): A,.. 280; c = 27.700.Mass spectrum: M’ 236 m le. Acknowledgements-We thank Prof. G. Cainelli for discussions and his interest in this work, and the C.N.R., Rome, for a grant. REFERE?wEs
‘F. Bohlmannand H. Kapteyn, Tetrahedron Letters 2065(1973). ‘G. Cainelli. G. Cardilllo. M. Contento, G. Trapani and A. Umani-Ronchi,1. Chem. Sot. Perkin I. 400 (1973);G. Cainelli,G. Cardillo, M. Contento, P. Grasselli and A. Umani-Ronchi,Gaze. Chim. Ital. 103, I I7 (1973); G. Cainelli, G. Cardillo, M. Content0 and A. Umani-Ronchi, Ibid. 104, 625 (1974). ‘P. Creger, J. Am. Chem. Sot. 89, 2500 (1967). ‘J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen and T. Walker, 1. Chem. Sot. 1094 (1952).
in UK 28 My
197% Accep~ed~orpubljcofio~
14August 1975)
Abstract-A stereospecific synthesis of dehydronerol isovalerate, isolated from the roots of Anthemis montuna L., utilising the dianion of 3-methyl-2-butenoic acid is described.
Dehydronerol has been isolated for the first time from the roots of A~f~e~i~ ~o~f~~~ L. in the form of its isovalerate ester (I).’
WC,
2-
,!a
1
We wish to report a short highly stereospecific synthesis of this compound u&sing a new method,’ which permits a a@(Z), y&(E) conjugated head to tail isoprenic acid by means of an addition-elimination sequence. The key reagent of our synthetic approach is the dianion (2), easily obtained by metalation of 3-methyl-2 butenoic acid (3) by means of lithium diisopropyIamide.z,3 COOH .@&.A
In tetrahy~ofuran in the presence of small amounts of HMPT at low temperature the elec~ophi~ic attack is kinetically controlled and the regioselectivity depends upon the nature of counterions of 2, the C4 attack increasing with the increase in the ionic character of the organometa~lic bonds involved in 2. At reflux, on the contrary, the electrophilic attack on C2,but not that on C,, becomes reversible with consequent exclusive formation of the desired head to tail isoprenic structure also with lithium as counterion. One of the most interesting features of this reaction is its complete stereospecificity, leading exclusively to the “z” config~ation of the introduced double bond.t The hydroxyacid obtained converts quantitatively into the corresponding lactone (4) which in turn, by treatment with potassium t-butoxide, easily and stereospecifically gives the c@(Z), $(E) double unsaturated acid. Scheme 1 illustrates the whole synthesis.
2 +
J.&HO
-7q-J 0
We have shown that the regioselectivity of the electrophilic attack of a carbonyl compound to the polidentate dianion (2) depends on the conditions, the nature of the counterions and the structure of the carbonyl compound, leading to Ct and /or C, adducts: 2
+
RCHO OH -
YOOH
RyOH+“TJJ
i’flte exciusive formation of the “2” double bond confi~ration has some analogy in the behaviour of allylic carbanions against nucleophilic attack. See Ref. 2 for a brief discussion of this topic.
__A-+
-1 ~HJ~H
6
The dehydronerol(6) was prepared by reduction of the methyl ester (5) with LAH. The ester (1) was at last obtained in a yield of 90% by treatment of dehydronerol (6) with isovaleroyl chloride. All chemical and spectral properties of these compounds correspond to those described for the compounds isolated from the roots of Anthemis montana L.
IR spectra were determined with a Hilger and Watts H 907 Infracord spectrophotometer. NMR spectra were recorded with a
108
G.
CARDILLO
R 12 B Perkin-Elmer instrument with TMS as internal standard. UV spectra were determined with a 402 Perkin-Elmer spectrophotmeter in EtOH. Mass spectra were measured on a HitachiPerkin-Elmer RMU6D (single focus) spectrometer at 60 eV. TLC was performed on silica gel HF,,, (Merck) and column chromatography on silica gel 0.05-0.20 (Merck), with hexaneether as a solvent. THF was obtained dry and oxygen free by distillation over sodium and LAH under argon. Diisopropylamine was distilled from calcium hydride and stored over molecular sieves. Hexamethylphosphoramide was distilled from molecular sieves under argon. n-Butyllithium was purchased from Schuchardt (Munchen) as a 1.8 M soln in n-heptane. 3-Methyl-2-bufen-I-ol.To a suspension of MnO, (2Og)in 80 ml methylene chloride, 3-methyl-2-buten-l-al (2.9 g; 34 mmol) in 20 ml methylene chloride was added dropwise at 0”. After stirring for 30 min at O”,the mixture was filtered and the ppt was washed with ether. The organic layer was evaporated. After distillation of the residue (45”.20 mmHg), 2.5 g (85%)of 3-methyl-2-buten-l-al4 was obtained as colorless liquid; IR (neat): v,., I690 (C=O)and 1650(C=CH)cm-‘; NMR (Ccl,): (0) 2 s (CH,); 2.2 s (CH,); 5.85 d (C=CH-) (J = IOHz); IOd (CHO) (J = IOHz). 3-Methyl-5~2-methyl-I-propenyl)pent-2-en-5-elide (4). To a soln of diisopropylamine(4.1 g; 40 mmol) in I50 ml dry THF at 0” under argon, I.8 M n-BuLi (22 ml; 40 mmol) in n-heptane soln was slowly added. The mixture was stirred at 0” for I hr and at room temp for 3 hr. Then 3-methyl-2-butenoicacid (2 g; 20 mmol) in IOml THF was added at 0”. The mixture was stirred 0.5 hr. heated and stirred successively for 1.5hr at 45”. After cooling to -78”, HMPT (IOml) was added and then 3-methyl-2-buten-l-al(I.7 g; 20 mmol)in IOml THF was added in 20 min. After 2 hr the ice bath was removed and the mixture was stirred at room temp overnight and heated under reflux for 2 hr. The mixture was then diluted with ether and water and acidified with 3 N HCI. After extraction with ether, the organic layer was washed with 10% NaHCO, aq, water, and dried (Na$O,), and the solvent was removed in racuo. The purhcation of residue by chromatography gave 2.7 g of 4 (80%) as a yellow oil, eluted with hexane:ether I : I. IR (neat): Y,.. 1720(C=G)and 1650(C=CH)cm-‘; NMR (CDCI,):(S) I.75 s and I.77 s ((CH,),); 2 s (C&C=); 2.3 m (CIj-); 4.9-5.4 m (-C&O); 5.3 bs (=CH-CH-); 5.85 bs (=CH-C=G). Mass spectrum: M* 166mle. Mefhyl 3,7-dimethyl-2(2),4(E),bocfafrirnoofe (5). A soln of 4 IOmmol) in IOml dry THF Was added to a suspension of t-BuOK (I.2 g) in 25 ml THF, and stirred for 0.5 hr at 0”. The mixture was then diluted with ether and water and acidifiedwith 3 N HCI. The organic layer, after extraction with ether, was washed with water, dried (Na2S0,) and the solvent was removed in uacuo to give I .6 g (95%) of acid which was ester&d with diazomethane to give 5
62 d
quantitatively. IR (neat); v,.. 1720 (C=O), 1650 (C=CH), 970 (CH=CH (E)) cm ‘. NMR (CCL): (6) 1.85 s (CH&; 245 d (C&C=) (J = I Hz): 3.8 s (-OCH,); 5.65 bs (C&C=@; 609 br d ((CH,),C=CH) (J = IOHz); 6.85 double d (=CH-CH=) (J = IO, J’= 16Hz); +‘.?5d (CH-C=) (J = I6 Hz). UV. (EtOH): A,., 315; c = 35600. Mass spectrum: M’ 180m le. 3,7-l)imethyl-2(2).4(E),Coctafriene-I-ol(6). A soln of 5 (0.54g; 3 mmol) in IOml dry ether was slowly added to a stirred suspension of LAH (0.1I g; 3 mmol) in I5 ml dry ether, kept at -IO’. After stirring for 0.5 hr at -IO”, the complex was decomposed by adding sat NH.CI aq. and then extracted with ether. The organic layer, after washing with water, was dried (Na2S0,) and evaporated. The residue was chromatographed on silica gel. With hexane:ether 7:3, 6 (0.41g) was obtained. IR (neat): Y,.. 3400(OH), 970 (CH=CH(E)) cm-‘. NMR (CDCI,):(6) I.83 s ((C&)X=); I.9 d (C&C=) (J = I Hz); 2.9 bs (OH); 4.3 d (CI$OH) (J = 6 Hz); 5.55 br t (CH-CH,OH) (1 = 6 Hz); complex pattern from 6 to 6.5 (3 vinylic H). UV (EtOH): A,. 279; e = 22600. Mass spectrum: M- I52 m/e. 3,7-Dimethyl-2(2),4(E),boctatn’enylisoualerafe (1). To a soln of isovaleroyl chloride (0.3I g) in pyridine at 0”, 6 (0.31g; 2 mmol) was added. After stirring for I hr at room temp, the mixture was diluted with water and extracted with ether. The organic layer was washed with 3 N HCI, IO%NaHCO,, water, dried (Na,SO,) and evaporated. After removingof solvent, the residue was purifiedby TLC (hexane:ether 9: I) and 1 (0.41g) was obtained~lR (neat): Y,.. .__1730fC=O).970 (CH=CH (E)) cm-‘. NMR (CCL): (8) 0.95 d ((CH,),CH) (J= 7Hz); I.8 bs ‘((C&)X=); i.9 d (C&-C=) (J = I Hz); 2.13 m (-CH-CIj,-); 4.65 d (CH,GC=O)(J = 7 Hz); 5.4 br t (=CH-CHIO) (J = 7 Hz); complex pattern from 5.9 to 6.5 (3 vinylic H). UV (EtOH): A,.. 280; c = 27.700.Mass spectrum: M’ 236 m le. Acknowledgements-We thank Prof. G. Cainelli for discussions and his interest in this work, and the C.N.R., Rome, for a grant. REFERE?wEs
‘F. Bohlmannand H. Kapteyn, Tetrahedron Letters 2065(1973). ‘G. Cainelli. G. Cardilllo. M. Contento, G. Trapani and A. Umani-Ronchi,1. Chem. Sot. Perkin I. 400 (1973);G. Cainelli,G. Cardillo, M. Contento, P. Grasselli and A. Umani-Ronchi,Gaze. Chim. Ital. 103, I I7 (1973); G. Cainelli, G. Cardillo, M. Content0 and A. Umani-Ronchi, Ibid. 104, 625 (1974). ‘P. Creger, J. Am. Chem. Sot. 89, 2500 (1967). ‘J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen and T. Walker, 1. Chem. Sot. 1094 (1952).