Synthetic studies towards N -substituted 3-vinyl-4-piperidineacetic acid derivatives

The synthesis and full characterization of two new ( E )-2-butenyl)-5-amino-2-pentenoates, ( Z )-4-[ N -(3-buten-1-yl)benzamido]-2-buten-1-ol, and ( Z )-1-chloro-4-[ N -(3-buten-l-yl)benzamido]-2-butene are reported. These were designed as substrates for a projected thermal ene cyclization leading to the N -substituted 3-vinyl-4-piperidineacetic acid scaffold. Although conditions for this ene-cyclization have not yet been uncovered, the ease of preparation of these ene-cyclization substrates gives promise for their future use.


Introduction
2][3] Although the formation of six-membered ring compounds by the analogous cyclization of 1,7-dienes (1 to 2) is less stereoselective and proceeds in lower yield, [1][2][3] good yields of cyclic products have been obtained from 1,7-dienes containing carbonyl-activated enophile or ene components. 4 Given the aforementioned precedent, we imagined that the thermal intramolecular ene cyclization of the carbonyl-activated indole diene 3 would be a viable synthetic route to highly substituted 2-(2-piperidinyl)indoles 4.These latter intermediates are of interest in a Friedel-Crafts-type cyclization approach to the Corynanthe and sarpagine alkaloid ring systems.Thus, in the cyclization step we envisioned formation of the piperidine C-4, C-5 bond with concomitant generation of the C-5 vinyl substituent.Assuming kinetic stereoselection, we presumed that the bulky N-protected 2-indolyl substituent would occupy a pseudoequatorial position in the developing chair transition states thus providing the desired cis-diaxial disposition of C-2-H and C-4-H present in these alkaloids.Moreover, even though four diastereomeric piperidines are theoretically possible, only the two alternative chair-chair transition states giving rise to cis and trans esters 4a and 4b, might be expected to predominate.Also, a pseudoequatorial orientation of the E-enophile might favor formation of product 4b.Since the ene cyclization of activated 1,6-and 1,7-dienes that lack a methyl substituent at the terminus of the ene unit (e.g., 3) can be capricious, [8][9][10] we examined the cyclization of a model 1,7-dienyl system first.Model diene 5 was particularly intriguing since deprotection of the product(s) would give meroquinene (6a, cis-3ethenyl-4-piperidineacetic acid), a key intermediate in several total syntheses 11,12 of Cinchona alkaloids, and/or the unnatural trans-diastereomer 6b, which was used to forge the D and E rings of the heteroyohimbe alkaloid ajmalicine. 13gure 3. Proposed ene cyclization of diene 5 forming meroquinene (6a) and/or 3-epi-meroquinene (6b).
The synthesis of diene 5 was accomplished in five steps from 2-piperidone (7) (Scheme 1).Aqueous barium hydroxide hydrolysis 14 of 7 and liberation of the amino acid from its barium salt with carbon dioxide afforded 5-aminopentanoic acid (8) in 95% yield.Treatment of 8 in a 1,4-dioxane-water (1:1) mixture containing 2.5 equivalents of triethylamine with BOC-ON ([2-(tert-butoxycarbonyloxyimino)-2phenylacetonitrile] 15 provided the crystalline t-BOC amino acid 9 in 75% yield.Esterification of acid 9 with benzyl bromide and triethylamine in refluxing chloroform 16 provided the benzyl ester 10 in 62% yield.Alkylation of 10 with trans-crotyl chloride 17 and sodium hydride in HMPA (0 °C to r.t., 8 h) furnished the monoolefin 11 but in only 25% yield.Since benzyl alcohol was also isolated from the reaction mixture (23% yield), the low yield of 11 can be attributed to the initially generated anion undergoing an intramolecular condensation to give the UV transparent imide 12 (not isolated).Deprotonation of ester 11 in THF at -78 °C with one equivalent of LDA followed by reaction of the enolate with phenylselenenyl chloride provided the selenide intermediate which was converted into the α,β-unsaturated ester 5 (40% yield) via selenoxide formation/elimination with sodium periodate in methanol/water at room temperature. 18The trans (E)stereochemistry of the newly formed double bond was readily apparent from inspection of the 300 MHz 1 H NMR spectrum of 5 in CDCl 3 .The C-3 proton appears as a doublet of triplets centered at δ 6.96 which overlap to form a 1:2:2:2:1 pentet; the C-3 proton in 5 is trans-coupled to the C-2 proton (J 16 Hz) and is also split by the "geminal" C-4 methylene protons (J 7 Hz).The other vinyl proton of this ABX spin system, the C-2 proton, appeared as a sharp doublet (J 16 Hz) centered at δ 5.88.These coupling constants and chemical shifts are characteristic of an α,β-unsaturated ester with trans-geometry; 19 the calculated chemical shifts for the C-2 and C-3 protons are δ 5.86 (δ 5.88 observed) and δ 5.87 (δ 6.96 observed), respectively. 19,20e examined both the thermal ene reaction 3 as well as Lewis acid-induced cyclization [4][5][6][7]10 of the diene ester 5. Howver, no reaction was observed in refluxing toluene (110 °C), and heating a 2% solution of 5 in oxylene (145 °C) led to its slow decomposition as evidenced by the formation of benzyl alcohol by TLC.When neat 5 was heated under argon at 205 °C for several hours, complete decomposition was observed.Following Oppolzer's work 10 on the Lewis acid-promoted ene cyclization of 1,6-diene esters, we treated 5 with two ARKAT USA, Inc equivalents of diethylaluminum chloride in dry dichloromethane at -78 °C.Unfortunately, the anticipated enecyclization of 5 did not occur.When three quivalents of Et 2 AlCl were employed (-78 °C, 3 h), cleavage of the benzyl ester group resulted.We turned our attention to the synthesis of diene 13 by a route similar to that used in the preparation of 5, reasoning that the methyl ester and N-benzoyl protective groups would be more stable to the projected cyclization conditions and, in the event of the successful ene cyclization, would provide known diastereomeric piperidines 14a and 14b 21 (Scheme 2).To circumvent the apparent intramolecular condensation reaction observed in the alkylation of 10, we examined the alkylation of the dianion of acid amide 15.N-Benzoyl 5aminopentanoic acid (15) was commercially available and also could be conveniently prepared from 8 with benzoyl chloride in 1N aqueous sodium hydroxide at 0 °C (41%).Satisfyingly, treatment of a mixture of amino acid 15 and trans-crotyl chloride in dry DMF at -5 °C with excess sodium hydride furnished the desired amide 16 in 65% yield (~100% based on recovered starting material).Diazomethane methylation of 16 in ether at 0 °C gave the methyl ester 17 in 94% analytically pure yield.Unlike the colorless solution that was obtained by deprotonation of 11 with LDA, similar treatment of ester 17 with LDA at low temperature produced a dark purple solution which decolorized on quenching with phenyl-selenenyl chloride.Sodium periodate treatment of the crude reaction mixture led to a mixture of several very polar products, which were not identified.The known susceptibility of tertiary benzamides to nucleophilic attack 22 suggests that intramolecular condensation of the generated anion on the amide moiety had taken place.We anticipated that this difficulty could be circumvented by N-alkylation of the trans-α,β-unsaturated ester 18. Wewould not have expected intramolecular attack on the ester carbonyl as this requires placing a trans-double bond in a six-membered ring transition state.
Although 18 has been prepared in several steps by two different routes from phthalimide, 23 we envisioned that it would be possible to introduce the double bond in one step from the dianion of ester 19 via successive selenation of the enolate, oxidation and selenoxide elimination.As anticipated, treatment of ester 19, which was readily prepared from 15 with diazomethane in ether-methanol (99% yield), with two equivalents of LDA at -78 °C in THF followed by the oxidative selenation protocol provided the desired enoate 18 in 74% yield.Because ester 18 was not easily separable from starting material 19 by chromatographic means, we found it convenient to isolate the intermediate α-phenylselenenyl derivative prior to oxidation and selenoxide elimination.In the 300 MHz 1 H NMR spectrum of 18 in CDCl 3 , the C-1 vinyl protons appear as a doublet of narrow multiplets centered at δ 5.89, trans-coupled to the C-3 proton (J 16.5 Hz), and the C-2 vinyl proton appeared as a doublet of triplets centered at δ 6.93 split by C-3H and by the geminal methylene protons (J gem 6.7 Hz).Unfortunately, alkylation of 18 with sodium hydride and crotyl chloride HMPA at 0 °C, irrespective of the order of addition of reactants or concentration, consistently gave one major product (25% isolated yield in one case) which was assigned the structure 20 on the basis of elemental analysis and spectroscopic data.The 300 MHz 1 H NMR spectrum of 20 in CDCl 3 exhibited very complex aromatic and aliphatic regions.A triplet centered at δ 6.85 was assigned to the single vinyl proton coupled to the geminal methylene protons (J gem 6.9 Hz).The E-configuration depicted (vinyl proton cis to the ester group) follows from a comparison with the vinyl chemical shifts of E-and Z-methyl 2-methyl-2-butenoates 19 which resonate at δ 6.73 and δ 5.98, respectively (vide supra), and the C-3 vinyl proton of E-enoates 18 (δ 6.93) and 5 (δ 6.96).Broad exchangeable triplets centered at δ 7.55 and δ 7.13 were ascribed to the two amide protons in 20.Other salient features included two methyl esters signals at δ 3.61 and δ 3.57 and two "haystack" multiples, each integrating for one proton, centered at δ 2.10 and δ 1.85.These latter signals, the only ones present above δ 2.5, were attributed to the methylene protons attached to the chiral center at C-3 of the heptenoate backbone.The dimeric by-product 20 may arise via intramolecular Michael attack of the generated amide anion from 18 on the enoate, followed by conjugate addition of the formed enolate on a second molecule of starting material to give intermediate dihydro-1,3-oxazine 21.Base-catalyzed fragmentation of the oxazine ring or elimination on acidic work-up would give 20.Danheiser 24 reported the formation of dihydro-1,3-oxazine byproducts 22 from the titanium tetrachloride-catalyzed [2+3] cyclization of alicyclic N-acylimmonium ions and allenylsilanes, presumably via a related process involving amide capture of a vinyl cation intermediate.

Scheme 3. Suggested route to dimer 20 from 18.
We examined the "hydrogen bond-assisted" N-alkylation 25 of 18 with crotyl chloride using potassium fluoride on alumina.Ando 26 has reported that secondary amides and lactams can be smoothly N-alkylated with benzyl chloride in acetonitrile in the presence of KF-alumina.However, in the case of 18 no reaction was observed.Similarly, attempts to N-alkylate 18 under S N 1 conditions 27 with silver trifluoroacetate at 100 °C produced no reaction.Therefore, we pursued a different synthetic route to the dienoate 13 (Scheme 4).Our plan was to construct the dienoate double bond in the last step from aldehyde 23 via a Horner-Wadsworth-Emmons reaction. 28Accordingly, the commercially available bromide 24 was converted into the azide 25 with sodium azide under phase transfer conditions (PTC) and the crude azide was subjected to Staudinger conditions 29 to provide the amino acetal 26 in 65% overall yield from 24. Acylation of 26 with benzoyl chloride and triethylamine in methylene chloride at 0 °C delivered the benzamide 27 (87% yield), which was alkylated with crotyl chloride and sodium hydride in DMF to provide amide acetal 28 in high yield.Acidic hydrolysis 30 of 28 in AcOH-THF-H 2 O (2:2:1) at reflux provided the desired aldehyde 23 but in only 28% yield; also isolated were starting material 28 (14%) and elimination by-product 29 (25%).Treatment of 23 with the sodium salt of methyl diethylphosphonoacetate, generated with sodium hydride in dimethoxyethane (DME) at 0 °C, 31 provided the desired dienoate 13 in 78% yield.Inspection of the 300 MHz 1 H NMR of 13 (in CDCl 3 ) revealed, inter alia, the expected low field multiplet centered at δ 6.97 for the C-3 vinyl proton and a doublet centered at δ 5.91 for the trans-coupled C-1 vinyl protons (J 15.6 Hz), thus corresponding nicely to the 1  Thus far, our attempts to effect the ene cyclization of 13 to 14 under thermal and Lewis acid conditions analogous to those employed for 5 have been unsuccessful.Thermolysis of 13 under argon at 300 °C leads to extensive decomposition.Lower temperatures (220 °C, 250 °C) and longer reaction times produced very little reaction although the formation of several very minor products was observed by TLC.Similarly, attempts to cyclize 13 in methylene chloride, even at reflux, with excess diethylaluminum chloride, resulted in no reaction.Interestingly, treatment of 13 with excess Et 2 AlCl in the absence of solvent at room temperature gave an unidentified substance, which does not appear by 1 H NMR and IR spectroscopy to be the desired ene product or the product of an intramolecular hetero-Diels-Alder reaction. 32While our cyclization studies have been limited by the available supply of 13, it is clear that the monoactivated 1,7-diene 13 is less reactive than anticipated.
4][35][36][37] The formal ene addition of allylic Grignard reagents and allylic organolithium compounds to olefins and subsequent trapping of the cyclized organometallic intermediate with various electrophiles has led to the preparation of 1,3-disubstituted cyclopentane and cyclohexane derivatives in a regio-and stereoselective manner (vide infra). 38,39We envisioned that the metallo-ene synthesis of the N-benzoyl derivative of meroquinene (6a) and its trans isomer 6b could serve as a model study for the synthesis of the pivotal 2-(2piperidinyl)indole intermediates that we required in our Corynanthe/sarpagine studies.We thought that the relative cis configuration about the C-3, C-4 bond of meroquinene (6a) might be achieved in a regioselective thermal cyclization of the Z-allylic Grignard (ene unit) 30 as shown retrosynthetically in Figure 4. Model considerations show that a chair-boat transition state results in the steric congestion of allylic and olefinic protons thus favoring formation of the cis-substituted piperidine 31 via the relatively unstrained chair-chair transition state B. A suitable precursor to the Z-allylic Grignard 30 appeared to be the tetrahydropyranyl (THP) ether 32, which was derivable from 4-benzamido-1-butene (33) and allylic chloride 35 (Scheme 5).Despite Brown's report 40 on the smooth reduction of allyl cyanide to 3-butenylamine (36) with aluminum hydride, we obtained very low yields (8-12%) of 36 by this procedure.Amine 36 could, however, be conveniently prepared from 3butenyl alcohol in two steps.Thus, 3-butenyl alcohol (34) was converted into the N-alkylphthalimide 37 in 85% yield via a Mitsunobu reaction with triphenylphosphine and diethyl azodicarboxylate (DEAD).Imide 37 was subsequently treated with hydrazine hydrate in ethanol to give 36 in 54% distilled yield.3-Butenylamine (36)  was then converted to 4-benzamido-1-butene (33) 41 in 84% yield with benzoyl chloride in 10% aqueous sodium hydroxide.The synthesis of the requisite THP-protected chloride 35 was accomplished in two steps from 2-butene-1,4-diol.Following the report of Thuy and Maitte, 42 38 was prepared in 49% yield by refluxing a benzene solution of 2-butene-1,4-diol and dihydropyran (DHP) in the presence of active montmorillonite.The alcohol 38 was readily transformed into allylic chloride (35) using methanesulfonyl chloride and a mixture of lithium chloride and S-collidine in DMF at 0 °C. 43,44Reaction of amide 33 with 1.5 equivalents of sodium hydride in dry THF and alkylation of the resulting sodium salt with allylic chloride 35 at 55 °C for several hours furnished a mixture of amide product 32 and starting material 33 which appeared as one spot by TLC.Separation was achieved by THP-ether deprotection in AcOH-THF-H 2 O (4:2:1) at 45-50 °C for four hours. 45lash chromatography of the resulting mixture afforded the desired dienol 39 in 47% yield (from 33).ARKAT USA, Inc Compound 39 was transformed into the allylic chloride 40 using methanesulfonyl chloride and a mixture of lithium chloride and S-collidine in DMF at 0 °C (Scheme 6).The unstable allylic chloride 40 was purified by rapid filtration through silica gel to give analytically pure 40 in 73% yield.Conversion of 40 into the corresponding Grignard reagent 41 with magnesium turnings was accomplished by entrainment with 1,2dibromoethane in THF at 60 °C.However, quenching the reaction at 0 °C with carbon dioxide led to the isolation of decomposition product 33 and not to the desired piperidine 42.Presumably, the benzamide 33 arises from vinylogous β-elimination of Grignard 41 and concomitant formation of butadiene.In future work this latter complication may be circumvented by replacing the Grignard species 41 with a bis-metallo species such as 43.

Conclusions
We have described the syntheses of several new dienes (i.e., 5, 13, 39 and 40) preparatory for an ene cyclization leading to the N-substituted 3-vinyl-4-piperidineacetic acid scaffold, which is embedded in numerous alkaloids.Although conditions for the ene-cyclization have yet to be found, the relative ease of preparation of these cyclization diene substrates presages the opportunity for their future use.