Synthesis and isomer distribution of 2-alkyltropinones and 2-alkylgranatanones Ryszard Lazny * , Karol Wolosewicz, Artur Ratkiewicz, Damian Pioro, Marcin Stocki Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland article info Article history: Received 13 September 2013 Received in revised form 12 November 2013 Accepted 2 December 2013 Available online 7 December 2013 Keywords: Tropane alkaloids a-Alkylation Tropinone Granatanone Hydrazone abstract Tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) metal (Li, Na, K, Mg) enolates were used to achieve a-alkylation. The reactions, regardless of the metal or conditions used, were low-yielding. N,N-Dime- thylhydrazones of tropinone and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan- 3-one) were prepared and a-alkylated using n-butyllithium as the lithiating reagent. Lithium amides, including a polymer-supported lithium amide, were less effective. The reactions were modelled using DFT calculations at the B3LYP 6-31G(d) level and the CPCM solvent model, revealing that the face- selective alkylations of tropinone and granatanone hydrazones favoured the exo-isomers. Granatanone and a-isopropyl tropinone derivatives resisted typical mild hydrolytic hydrazone cleavage (aqueous trifluoroacetic acid) and required more forceful conditions (p-TsOH, boiling dioxane). Using the hydra- zone alkylation strategy, 16 a-alkyl derivatives (benzyl, methyl, propyl, isopropyl, allyl, pentyl, heptyl, p- methoxybenzyl) were prepared in 52e90% yields overall. For the a-alkylated tropinones and gran- atanones (10 examples), the DFT calculations and experimental thermodynamic distributions in base catalysed equilibrations showed that except for the a-isopropyl derivatives, the endo-isomers were more stable than the exo-isomers and were the major products. For 2-isopropyltropinone, the bulky sub- stituent favoured the exo (axial) position in the bicyclic skeleton. The thermodynamic distribution for the a,a 0 -dibenzyl tropinone isomers was also evaluated. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Functionalised tropanes occur as both natural alkaloids and synthetic analogues and are a recognised group of compounds known for their biological activity. 1 Related compounds possessing granatane skeleton are less well-known (Fig. 1). Of the hundreds of known natural tropane and granatane derivatives, only a small number contain the 2-alkyl substituent 1 (typically benzyl 2 or methyl 3e5 ). The 2-alkyl motifs are often present in pharmacologi- cally studied synthetic tropanes 6,7 and are an important structural feature for binding to norepinephrine transporter (NET) sites. 8 Benzylated tropane has demonstrated affinity to nicotinic acetyl- choline receptor (nAChR) binding sites. 9 Tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and its analogue granatanone (9-methyl-9-azabicyclo[3.3.1]nonan-3-one) are inexpensive, commercially available, synthetically useful scaf- folds; these structures have been used for installing various sub- stituents on the a-carbons, as well as the other sides of the heterocyclic rings. 10,11 Notably, one of the most important synthetic transformations, the a-alkylation, has rarely been reported for tropinone and has never been reported for granatanone. 12,13 Al- though synthesising a- or a,a-alkyltropane-like skeletons via cy- cloaddition, 14 oxyallyl addition, 15,16 metathesis 17 and aldol condensation combined with hydrogenation 18,9 has been reported, direct alkylations remain neglected. Tropinone and granatanone enolates are attractive chiral intermediates that are accessed enantioselectively using asymmetric deprotonation. 11,18 Combining enantioselective deprotonation with consecutive alkylation might be the easiest potential asymmetric route toward a-alkyl de- rivatives. Previous experiments with tropinone enolates suggest N Me Tropane N Me Granatane R (endo) R (endo) R (exo) R (exo) 1 2 3 3 2 1 5 4 6 7 8 5 4 6 8 7 9 Fig. 1. Tropane and granatane scaffolds illustrating the endo and exo positions for the C-2 substituents (tropane/granatane atom numbering). * Corresponding author. Tel./fax: þ48 85 747 01 13; e-mail address: lazny@uwb. edu.pl (R. Lazny). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.12.008 Tetrahedron 70 (2014) 597e607
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Tetrahedron 70 (2014) 597e607
Contents lists avai
Tetrahedron
journal homepage: www.elsevier .com/locate/ tet
Synthesis and isomer distribution of 2-alkyltropinones and2-alkylgranatanones
Ryszard Lazny *, Karol Wolosewicz, Artur Ratkiewicz, Damian Pioro, Marcin StockiInstitute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland
a r t i c l e i n f o
Article history:Received 13 September 2013Received in revised form 12 November 2013Accepted 2 December 2013Available online 7 December 2013
0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.12.008
a b s t r a c t
Tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) metal (Li, Na, K, Mg) enolates were used to achievea-alkylation. The reactions, regardless of the metal or conditions used, were low-yielding. N,N-Dime-thylhydrazones of tropinone and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) were prepared and a-alkylated using n-butyllithium as the lithiating reagent. Lithium amides,including a polymer-supported lithium amide, were less effective. The reactions were modelled usingDFT calculations at the B3LYP 6-31G(d) level and the CPCM solvent model, revealing that the face-selective alkylations of tropinone and granatanone hydrazones favoured the exo-isomers. Granatanoneand a-isopropyl tropinone derivatives resisted typical mild hydrolytic hydrazone cleavage (aqueoustrifluoroacetic acid) and required more forceful conditions (p-TsOH, boiling dioxane). Using the hydra-zone alkylation strategy, 16 a-alkyl derivatives (benzyl, methyl, propyl, isopropyl, allyl, pentyl, heptyl, p-methoxybenzyl) were prepared in 52e90% yields overall. For the a-alkylated tropinones and gran-atanones (10 examples), the DFT calculations and experimental thermodynamic distributions in basecatalysed equilibrations showed that except for the a-isopropyl derivatives, the endo-isomers were morestable than the exo-isomers and were the major products. For 2-isopropyltropinone, the bulky sub-stituent favoured the exo (axial) position in the bicyclic skeleton. The thermodynamic distribution for thea,a0-dibenzyl tropinone isomers was also evaluated.
� 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Functionalised tropanes occur as both natural alkaloids andsynthetic analogues and are a recognised group of compoundsknown for their biological activity.1 Related compounds possessinggranatane skeleton are less well-known (Fig. 1). Of the hundreds ofknown natural tropane and granatane derivatives, only a small
atane
R (endo)
R (exo)2
1
89
endo and exo positions for the
e-mail address: lazny@uwb.
All rights reserved.
number contain the 2-alkyl substituent1 (typically benzyl2 ormethyl3e5). The 2-alkyl motifs are often present in pharmacologi-cally studied synthetic tropanes6,7 and are an important structuralfeature for binding to norepinephrine transporter (NET) sites.8
Benzylated tropane has demonstrated affinity to nicotinic acetyl-choline receptor (nAChR) binding sites.9
Tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and itsanalogue granatanone (9-methyl-9-azabicyclo[3.3.1]nonan-3-one)are inexpensive, commercially available, synthetically useful scaf-folds; these structures have been used for installing various sub-stituents on the a-carbons, as well as the other sides of theheterocyclic rings.10,11 Notably, one of the most important synthetictransformations, the a-alkylation, has rarely been reported fortropinone and has never been reported for granatanone.12,13 Al-though synthesising a- or a,a-alkyltropane-like skeletons via cy-cloaddition,14 oxyallyl addition,15,16 metathesis17 and aldolcondensation combined with hydrogenation18,9 has been reported,direct alkylations remain neglected. Tropinone and granatanoneenolates are attractive chiral intermediates that are accessedenantioselectively using asymmetric deprotonation.11,18 Combiningenantioselective deprotonation with consecutive alkylation mightbe the easiest potential asymmetric route toward a-alkyl de-rivatives. Previous experiments with tropinone enolates suggest
R. Lazny et al. / Tetrahedron 70 (2014) 597e607598
that their tridentate nucleophilic nature (Scheme 1) may severelycomplicate seemingly straightforward reactions because their se-lectivity depends on the electrophiles used.19,20
N
O
Me
B-MetN
OMet
Me
R-XR-X
R-X
consecutivealkylation
1 1-Met
Scheme 1. Possible alkylation sites and side reactions with tropinone metal enolates.
We reveal the development of a simple and general method fora-alkylating tropinone and granatanone, as well as a study of rel-ative isomer stability of the alkylated products.
2. Results and discussion
2.1. Direct alkylation
Tropinone metal enolates were alkylated under classical con-ditions with benzyl bromide. Various bases and conditions weretested, but the reactions invariably generated mixtures of severalproducts. Moreover, the desired products of C-monoalkylationwere expected to be the endo and exo isomers; bisalkylationproducts (a,a or a,a0-isomers) and other possible productsresulting from O- and N-alkylation were also expected (Schemes 1and 2). The isolated yields of the C-benzylation products are listedin Table 1.
Table 1Direct C-alkylation (benzylation) of tropinone with various bases
Entry Base ReM, (equiv)a Yield of a-benzyltropinone 1ab
a Reaction with the base for 1 h at 0 �C, followed by reaction with benzyl bromidefor 20 h from 0 �C to 20 �C; deprotonation and/or alkylation at �78 �C generatedeven more polyalkylated products.
b Mixture of isomers.c Magnesium diisopropylamide (MDA)made fromDIPA (0.55 equiv) and n-Bu2Mg
(0.55 equiv).d Magnesium diisopropylamide (MDA) made from DIPA (1.1 equiv) and n-Bu2Mg
(1.1 equiv).e Reaction without enolate separation gave worse purity of products.
N
O
Me
N
O
Me
Bn1) R-M2) BnBr
N
O
Me
BnBn
1a 1aa1
Scheme 2. Direct alkylation of tropinone with various metallating reagents (Table 1)provided monoalkylation and bisalkylation products after chromatography.
Apparently, tropinone enolates alkylations with the alkyl halide(benzyl bromide), regardless of conditions, were plagued by sidereactions and incomplete conversion.21
After testing alkali metal bases in the alkylation reaction, thebest yields of the desired product (1a) were 34e38% and obtainedusing strong lithium and potassium bases (Scheme 2, Table 1, en-tries 1, 3 and 6). However, kinetic conditions (strong base, entries1e6) did not favour monoalkylation more than thermodynamicconditions (weak base, entries 9 and 10). In all of these reactions,significant amounts of a dibenzylated derivative were formed;NMR spectroscopy revealed that this product was the a,a0-di-substituted ketone 1aa. Two isomers dominated the chromato-graphically purified dibenzyl product fraction. Based on the 1HNMR shifts of the a-CH and the 13C NMR signals, the two dominantdibenzyl products were identified as the symmetrical (the exo, exoor the endo, endo) and a non-symmetrical (the exo, endo) isomers of1aa in a ca. 1:3 ratio. The relative stability of the possible a,a0-dibenzyl derivative 1aa isomers was evaluated using a previouslyproven approach for tropinone22 and popular with organic chem-ists DFT calculations at the B3LYP 6-31G(d) level with the CPCMsolvent (CHCl3) model.23 The results are compared with the ex-perimental observations in Table 2. The calculations indicated thesymmetrical endo, endo-1aa isomer was the most stable product,with the exo, exo-1aa being 0.70 kcal/mol higher in energy and assuch the least stable isomer (Scheme 2, Table 2). The calculatedratio of isomers differed from the ratio measured in the unpurifiedproduct (21:79), as well as in the chromatographically purifiedproduct (ca. 1:3). To our satisfaction, the calculated relative con-centrations of the exo, endo-isomers (which was double the valuefrom the relative stability data due to presence of a racemate) andthe endo, endo-isomers agreed with the experimental ratio afterequilibrating the chromatographically obtained isomers in thepresence of a strong base (0.1 equiv KOH in MeOH for 48 h).Without the addition of strong base, the equilibration still occurredbecause of the amine group, but was slower; the observed changein isomer ratio over 3 weeks was less than 5%. After equilibration,the two dominant products were found in a 57:43 ratio of the majorendo, endo (symmetrical) product and the minor exo, endo (un-symmetrical) product. Other unidentified products were less than10% of the total composition. Thus the calculated and experimentalisomeric distributions supported our NMR-based stereochemicalassignments.
Table 2Relative stability and distribution of the major N-equatorial and N-axial in-vertomersa (compare Fig. 3) of three possible isomers of a,a0-dibenzyl tropinone(1aa)
Isomer exo, exo-1aa exo, endo-1aa endo, endo-1aa
N-Invertomer N-Me eq N-Me eq N-Me eq N-Me ax
Free energy (kcal/mol)b 0.70 0.30 0.00 0.12Invertomer distribution (%)c 9.2 36.1 30.1 24.5Calculated isomer
distribution (%)c9.2 36.1 54.6d
Observed isomerdistribution (%)e
ca. 10 39 51
a The axial N-invertomers of the exo, exo and the exo, endo forms were signifi-cantly higher in energy because they exhibited severe steric interactions betweenthe N-methyl group and the exo-alkyl group (compare Table 6, 1a); consequentlythey had a negligible contribution.
b Calculated using B3LYP 6-31G(d) and CPCM in chloroform (kcal/mol) at 25 �C.c Calculated based on relative free energies of invertomers.d The resulting sum of the equatorial and the axial N-methyl invertomers distri-
butions could be spectroscopically observed.e The isomeric ratio after equilibration with KOH for 48 h.
To mitigate the side reactions, we utilised both new andestablished methods. Generating a free lithium enolate usinga polymeric lithium amide and filtration24 did not decrease the
a R = Bnb R = Mec R = Pr,d R = i-Pr,e R = Allyl,f R = Pent,g R = Hept,h R = p-MeOC6H4CH2polymer supported amide 5
N
NLi
R. Lazny et al. / Tetrahedron 70 (2014) 597e607 599
polyalkylation.25 Alkylation using enolate deaggregative additives(TMEDA, HMPA or LiBr, typically 1 equiv) did not improve theoverall yield or selectivity, instead generating even more complexand hard-to-separate product mixtures. Due to the low overallyields of monoalkylation with significant polyalkylation that oc-curred regardless of metal enolate or additives, we resorted to anindirect method using N,N-dimethylhydrazone (DMH).26,27 Thisapproach was previously successful for cyclic amino ketonesimmobilised on polymeric support via hydrazone linkers.12,13,28
N
O
Men
N
N
Me n
N
N
N
Men
N
R
N
O
Men
R
1 n = 12 n = 2
Me2NNH2, p-TsOHDMHcleavage
2) RX, 0 oC to rt
1) n-BuLior LDAor Li amide 5
52-90%overall yield
3 n = 1 3a-h
4a-h
1a-h
2a-h
2.2. Alkylation via N,N-dimethylhydrazones
The N,N-dimethylhydrazones of tropinone and granatanonewere easily prepared (Scheme 3) in very good yields (90e95%). Weanticipated that reforming the ketone of tropinone or granatanone(Scheme 3) could be achieved using acidic hydrolysis because thetertiary amine group of tropinone is sensitive to the classicalcleavage conditions, such as N-methylation (methyl iodide, HClmethod29,30), oxidation (e.g., ozonolysis31) and complexation withcopper ions (e.g., CuCl2 method).32e34 However, the mild acidicconditions typically used to hydrolyse hydrazones (e.g., oxalicacid)35,36 were unsuitable due to problems with side products orlow conversion. Finally, the tropinone DMH was hydrolysedsmoothly using trifluoroacetic acid (TFA) in aqueous THF (v/v TFA/H2O/THF 20:10:70 at room temperature, 90% yield, Scheme 3).
Table 3Comparison of the tropinone N,N-dimethylhydrazone (3) alkylation (Scheme 4)yields using three different lithiating agents
Entry Hydrazone product, ReX n-BuLi LDA Li-amide 5a
a The azaenolate solution was separated from the polymeric reagent before al-kylation; reactions without separation gave worse purities of crude products.
Table 4Alkylations of tropinone (1) and granatanone (2) via their N,N-dimethylhydrazonesusing n-BuLi and alkyl halides RX
Scheme 3. Formation and hydrolysis of tropinone and granatanone N,N-dimethylhy-drazones (DMH’s).
hydrazone cleavage:n = 1: TFA, H2O, THF, rt; exept for R = i-Prn = 2, n = 1 R = i-Pr: p-TsOH, H2O, dioxane, reflux
4 n = 2
Scheme 4. Alkylation of tropinone and granatanone via N,N-dimethylhydrazones.
Interestingly, the granatanone hydrazone was quite resistant tohydrolysis; the cleavage required TFA in aqueous THF at elevatedtemperatures (50 �C, 20 h, TFA/H2O/THF v/v 10:10:80, 89% yield).Having found suitable hydrazone cleavage conditions, we lithiatedtropinone N,N-dimethylhydrazones with LDA, n-BuLi or polymericlithium amide 524 before adding the selected alkyl halides (Scheme4, Table 3).
n-Butyllithium was the most convenient reagent in hand andgave the best alkylation yields. Using LDA or the polymer-supported amine with the washing procedure24 provided no im-provement relative to n-BuLi. Therefore, n-BuLi was used for alky-lating the granatanone hydrazones.
The optimised indirect alkylation yields for tropinone andgranatanone are presented in Table 4. The alkylated N,N-dime-thylhydrazones are often obtained as mixtures of E/Z (anti/syn)hydrazone isomers.26 Analysing the NMR spectra of the alkylatedtropinone or granatanone hydrazones revealed two isomers.
The E/Z equilibration was likely responsible for the observedisomeric ratios. We expected the formation of the Z isomers typi-cally observed during the alkylation of lithiated hydrazones26 andthe subsequent interconversion over time (at room temperature),forming a mixture of Z/E forms. Indeed, the ratios changed overtime and during the chromatographic purifications. Because the a-alkyl substituted centres in hydrazones are stereochemically sta-ble,26 we concluded that the spontaneous but slow isomerisation ofthe alkylated hydrazones must have involved the interconversionof the E/Z forms. Therefore, the lithium azaenolate alkylations werehighly face-selective. However, the configuration (exo or endo) of
a Ratio of the E/Z isomers in the unpurified product by NMR.b Ratio of the endo/exo isomers by NMR after hydrazone cleavage.
N
O
Me
1, -alkyltropinones, n = 0,2, -alkylgranatanones, n = 1
n
N
O
Me
n
equator ial N-Me
Invertomers
axial N-Me
invertomers
R1
R2R1
R2
αα
Fig. 3. Isomeric (endo R1¼H, R2¼alkyl and exo R1¼alkyl, R2¼H) alkylated ketones 1 and2 with equatorial and axial N-methyl configurations (see Supplementary data forrepresentative 3D structures).
R. Lazny et al. / Tetrahedron 70 (2014) 597e607600
the stereogenic centre a to the hydrazone could not be positivelydetermined using the available spectroscopic data. Because theenolates of tropane-like systems usually react with electrophiles onthe exo-face, we expected the exo product to form pre-dominantly.37,38 To verify hypothesis and gain better insight intothe alkylation of lithium azaenolates 3 and 4, we resorted to DFTcalculation to ascertain the reaction parameters for the two pairs ofcompeting reactions. Each reaction represented the face-specificapproach of a reagent toward a tropinone or granatanone azae-nolate. The calculated free energies (DG and DGz) of methylationwith MeCl, which was chosen for simplicity, are presented in Table5. The calculations took into account the lowest energy reactantconformations (for a representative reaction diagram, see Fig. 2 andthe Supplementary data). Accepting that the DFT methodsemployed are typically accurate to only ca. 0.5 kcal/mol39,40 thedata obtained clearly indicated, for both the tropinone and thegranatanone hydrazones, faster reactions (DDGz¼2.3 and 13.2 kcal/mol) and higher thermodynamic gains (DDG¼7.5 and 8.2 kcal/mol)for the pathways leading to the exo isomers (Table 5).
Fig. 2. Energy versus reaction coordinate diagrams for model alkylation reactions of methyinvertomer for specific reagent approach): (a) equatorial N-methyl group, exo-approach, (bDMH and magnified pictures).
Table 5Calculated free energies (DG) and activation free energies (DGz) for the model re-actions (lithiated tropinone and granatanone DMH with MeCl in THF)a
1 Lithio-3 with N-Me eq, exo-approach 16.1 �67.22 Lithio-3 with N-Me ax endo-approach 18.4 �59.73 Lithio-4 with N-Me eq, exo-approach 8.4 �65.24 Lithio-4 with N-Me ax endo-approach 21.6 �57.0
a Calculated with B3LYP at 6-31G(d) level of theory using CPCM model at 25 �C.
Therefore, considering that the known E/Z isomerisation, con-figurational stability of the stereogenic centre a to the N,N-dia-lkylhydrazones and calculated data (Table 5) pointed towards exoforms as the kinetically and thermodynamically favoured products,we proposed that the isomeric hydrazone mixtures contained theE/Z forms of the exo isomers.
The overall effectiveness of the ketone alkylation remainedunaffected by the isomeric hydrazone formation (E/Z and exo/endo).Regenerating the ketone group in the tropinone or granatanoneskeletons formed an enolisable stereocentre; consequently, the a-alkyl substituted ketone exo/endo stereoisomers equilibrated.41 Theacid-promoted hydrolytic cleavage of the alkylated tropinone DMH(Table 4) was less effective than the cleavage of the unalkylatedanalogues. Cleaving the alkylated tropinone hydrazones 3aehfurnished good overall yields and purities of the a-alkylatedproducts.
Hydrazone hydrolysis occurred as expectedwith TFA inwet THF,excepting the isopropyl derivative 3d that was stable toward vari-ous cleavage conditions; this compound was eventually cleavedusing p-TsOH in dioxane at 100 �C (Scheme 4). Clearly, the bicyclicnature of the tropinone hydrazone combinedwith steric hindrance,especially with the bulkier a-alkyl substituents, obstructed theotherwise effective reaction. The overall yields and purities of theproducts were much improved over the direct alkylations (entry 1,Table 4 vs Table 1). Despite its similarity to tropinone, cleaving thealkylated granatanone N,N-dimethylhydrazones was even moreproblematic. Under typical conditions (TFA, wet THF) only the a-
l chloride with lithiated tropinone N,N-dimethylhydrazone (with the lowest energy N-) axial N-methyl, endo-approach (see Supplementary data for diagram for grantanone
R. Lazny et al. / Tetrahedron 70 (2014) 597e607 601
methyl derivative 2b could be cleaved appreciably (37% conversionover 20 h). More concentrated TFA (up to 50%), 6 M aqueous HCl,saturated oxalic acid, copper salts and peracids at 50e60 �C wereineffective for the rest of the alkylated granatanone hydrazones.However, using p-TsOH in refluxing dioxane was satisfactory (>90%conversion, 55e89% yield) for substituted granatanone hydrazones4aeh, similar to 3d (Scheme 4, Table 4). Clearly, the alkylatedgranatanone and the isopropyl derivatives of tropinone were moreresistant toward hydrolytic cleavage of the hydrazone group due tosteric congestion.
2.3. Distributions of the endo/exo isomers of the 2-alkylketones
The spectra of the alkylated tropinones and granatanonessuggested that the dominating isomers were the endo forms,except for the isopropyl derivatives of both tropinone and gran-atanone. Unexpectedly the bulky isopropyl substituent appearedto occupy the exo position. Closer inspection of the models andDFT calculations supported this observation. The relative freeenergies calculated for the endo and exo isomers of possible N-methyl invertomers42,22 for representative alkylated tropinonesand granatanones are presented in Table 6 with the correspond-ing thermodynamic distributions and experimentally observedratios of isomers. The calculated distributions are comparable tothe ratios observed after equilibrating the ketones under basicconditions (0.1 M KOH).43 Comparing the ratios obtained directlyfrom crude products or after chromatographic purification44 (i.e.,before the equilibration) indicates that the more stable isomersdominated the isomeric mixtures obtained after hydrazonecleavage.41
Table 6Calculated relative free energies for the equatorial and axial N-methyl invertomers of the endo and exo isomers of the a-alkyl ketones and the resulting isomeric distributionsversus the experimental dataa
a The free energies and distributions calculated using B3LYP 6-31G(d) CPCM in chloroform at 25 �C (kcal/mol).b Calculated as the sum of the distributed N-axial and the N-equatorial forms.c The isomeric ratios determined by 1H NMR before equilibration.d The isomeric ratios determined by 1H NMR after base-catalysed equilibration.
Both the experimental and calculated data supported the pre-ferred exo configuration for the bulky isopropyl substituent intropinone. For the granatanone analogue, the experimentally ob-served preference was less defined, but the calculations seemedinconclusive. This divergence in the relative stabilities of the tro-pinone and granatanone a-isopropyl isomers may be caused by thedifferences in the N-axial and N-equatorial invertomers’ stability.Due to the steric interactions between the equatorial N-methyl andthe C-6eC-7eC-8 bridge in granatanone, the axial N-methyl groupposition is definitely preferred; this interaction is less severe withtropinone’s C-6eC-7 bridge.22 In tropinone, the equatorial N-methyl group is preferred (ca. 2:1).42,22 An axial N-methyl groupmay interact with the exo-alkyl group in the a-alkylated de-rivatives. Consequently, granatanone accommodates the bulkyisopropyl group in the exo (pseudoaxial) position at a higher en-ergetic cost than tropinone. Consequently the exo and the endo
isomers of granatanone 2d are close in energy, while tropinone exo-1d is much more stable than its isomer endo-1d.
3. Conclusions
The direct alkylations of tropinone and granatanone enolatesremained plagued by side reactions, generating low yields of the a-alkylated product, regardless of the counter ion, solvent or condi-tions. The a,a- or a,a0-dialkylation products formed, complicatingthe isolation and purification processes. Utilising the N,N-dime-thylhydrazone intermediates circumvents the regioselectivity andpolyalkylation problems. The hydrazone alkylation was high-yielding and most likely favours the exo-isomers, as indicated bythe DFT calculations. Forceful acidic hydrazone cleavage conditions,especially for products with sterically demanding a-alkyl groups,such as isopropyl substituents, were needed to obtain satisfactoryoverall yields. The DFT calculations and base-catalysed equilibra-tions revealed that the endo isomers of the prepared alkylatedtropinones and granatanones are more stable than are the exo-isomers and dominate in the stereoisomeric a-alkylated ketoneproducts, excepting the a-isopropyl derivatives. The process in-volving hydrazone alkylation followed by acidic hydrazone cleav-age offers a simple and effective synthetic route toward a-alkyltropanes and granatanes.
4. Experimental section
4.1. General
All air sensitive reactions were carried out under argon. Thetetrahydrofuran used during dry reactionswas distilled from sodium
and benzophenone under an argon atmosphere; tropinone andgranatanone (pseudopelletierine) were supplied by Aldrich andwere dried in a desiccator over KOH before use. Hydrazones used inthe alkylation reactions were distilled and handled under argon. Theother commercially available reagents were used without furtherpurification. Reactions using N,N-dimethylhydrazine (volatile, toxic,carcinogenic) were carefully performed in a fume hood. TLC wascarried out using aluminium plates coated with silica gel (Merck,Kieselgel 60F254, 0.25 mm). The spots were detected using UV light(254 nm) and phosphomolybdic acid with charring. The 1H and 13CNMR spectra were recorded at ambient temperature in CDCl3 at400 MHz and 100 MHz, respectively. The chemical shifts are re-ported relative to TMS and referenced to the CDCl3 signals at d 7.260for 1H and 77.0 for 13C spectra. The infrared (IR) spectra wererecorded with a FTIR spectrometer in CHCl3; only the diagnosticpeaks are reported. High resolutionmass spectrawere recordedwith
R. Lazny et al. / Tetrahedron 70 (2014) 597e607602
a TOF spectrometer in ESI mode. The GC analyses were performedwith an Elite Series PE-5HT column (30 m�0.25 mm).
4.2. Typical procedure for direct tropinone alkylation
To a 0 �C solution of diisopropylamine (0.154 mL, 1.10 mmol) inTHF (4 mL) was added n-butyllithium (2.5 M solution in hexane,0.440mL,1.10mmol); the resultingmixture was stirred at 0 �C. After30 min, a solution of tropinone 1 (0.139 g, 1.00 mmol) in THF (2 mL)was added dropwise and the resulting mixture was stirred at 0 �C.After 2 h, benzyl bromide (0.131mL,1.10mmol) was added dropwisebefore the reaction mixture was allowed to warm slowly to roomtemperature overnight. The reaction was quenched with potassiumcarbonate (20% solution in water, 2 mL) and diluted with water(20 mL); the resulting mixture was extracted with dichloromethane(3�20 mL). The combined organic layers were dried with sodiumsulfate and concentrated under vacuum. The resulting mixture waspurified by flash chromatography (SiO2, methanol/dichloromethane(0:10 to 3:97)), yielding 1a (0.078 g, 34% one isomer) and 1aa(0.061 g, 19%, isomers mixture 90:10) as yellow oils.
4.3. Typical procedure A: alkylation of hydrazones with n-BuLi
To a 0 �C solution of hydrazone 3 (0.181 g, 1.00 mmol) in THF(1 mL) was added n-butyllithium (2.5 M solution in hexane,0.440 mL, 1.10 mmol), and the resulting mixture was stirred at 0 �Cfor 4 h. Subsequently, benzyl bromide (0.131 mL, 1.10 mmol) wasadded dropwise, and the reaction mixture was allowed to warmslowly to room temperature overnight. The reaction was quenchedwith potassium carbonate (20% solution in water, 2 mL) and water(20 mL); the resulting mixture was extracted with dichloromethane(3�20 mL). The combined organic layers were dried with sodiumsulfate and concentrated to provide 3a (0.254 g, 94%) as a yellow oil.
4.4. Typical procedure B: alkylation of hydrazones with LDA
To a 0 �C solution of diisopropylamine (0.154 mL, 1.10 mmol) inTHF (5 mL), was added n-butyllithium (2.5 M solution in hexane,0.440 mL, 1.10 mmol); the resulting mixture was stirred at 0 �C.After 0.5 h, 3 (0.181 g, 1.00 mmol) in THF (1 mL) was added drop-wise, and the reaction mixture was stirred at 0 �C. After 4 h, benzylbromide (0.131 mL, 1.10 mmol) was added dropwise, and the re-action mixture was allowed to warm slowly to room temperatureovernight. The reaction was quenched with potassium carbonate(20% solution in water, 2 mL) and water (20 mL); the resultingmixture was extracted with dichloromethane (3�20 mL). Thecombined organic layers were dried with sodium sulfate and con-centrated to give 3a (0.182 g, 67%) as a yellow oil.
4.5. Typical procedure C: alkylation of hydrazones with im-mobilised 5
The immobilised amine (0.600 g, 1.41 mmol/g, 0.865 mmol,placed in a solid-phase synthesis vessel fitted with a sintered glassfilter disc combined with a siphon tube and stopcock) was driedunder vacuum in a desiccator for 24 h, flushed with argon for10 min, washed with THF (3�5 mL), suspended in THF (4 mL) andcooled to 0 �C. After 15 min, n-BuLi (2.5 M in hexanes, 1.20 mL,3.00 mmol) was added. The suspensionwas intermittently agitatedwith flowing argon (the polymer turned brown). After 1.5 h, theTHF solution was separated by applying a positive pressure of ar-gon; the gel was washed with THF (4�5 mL), and the filtered so-lutions were discarded. The polymeric gel (lithium amide) wascovered with THF (<1 mL) and cooled to 0 �C. A solution of 3(0.123 g, 0.680 mmol) in THF (2 mL) was added dropwise withintermittent agitation. After 4 h, the azaenolate solution was sep-arated from the polymeric reagent using a sintered glass filter andcollected in a flask cooled to 0 �C. The polymeric gel was washedwith THF (3�5 mL) and the washings were combined with the si-phoned filtrate before being cooled to 0 �C. Benzyl bromide(0.095 mL, 0.800 mmol) was added dropwise. After the addition,the reaction mixture was slowly warmed to room temperatureovernight and quenched with potassium carbonate (20% solution inwater, 2 mL) and water (20 mL); the resulting mixture wasextracted with dichloromethane (3�20 mL). The combined organiclayers were dried with sodium sulfate and concentrated to give 3a(0.168 g, 91%) as a yellow oil. The polymeric reagent was washed(H2O, MeOH, THF), dried and reused in subsequent experiments.
R. Lazny et al. / Tetrahedron 70 (2014) 597e607 603
4.5.9. 3-(2,2-Dimethylhydrazono)-9-methyl-9-azabicyclo[3.3.1]non-ane (4). N,N-Dimethylhydrazine (7.99 mL, 6.31 g, 105 mmol) wasadded to a mixture of granatanone (pseudopelletierine, 2, 4.02 g,26.2 mmol) and acetic acid (99.5%, 1.30 mL, 22.8 mmol) under ar-gon. The reaction mixture was stirred and reflux for 20 h, then wascooled to room temperature and treated with potassium carbonate(20% solution in water, 10 mL). The resulting mixture was extractedwith Et2O (5�10 mL), the combined organic layers were dried withsodium sulfate and concentrated under vacuum to give 4 (4.61 g,90%) as a yellow oil. Rf: 0.1 (20% MeOH/DCM, v/v). 1H NMR (d,400 MHz, CDCl3): 3.10e3.02 (m, 3H), 2.76 (dd, J1¼15.6 Hz,J2¼6.0 Hz, 1H), 2.56 (s, 3H), 2.43 (s, 6H), 2.41e2.37 (m, 1H), 2.27 (d,J¼15.6 Hz, 1H), 2.00e1.85 (m, 2H), 1.75e1.64 (m, 1H), 1.60e1.50 (m,2H), 1.45e1.37 (m, 1H) ppm. 13C NMR (d, 100 MHz, CDCl3): 168.6,54.6, 53.9, 46.7, 40.9, 35.0, 29.3, 29.0, 28.9, 16.7 ppm ppm. IR:(CHCl3) 1626 cm�1. GCeMS: 20.13 min (40 �Ce5 �C/mine280 �C).MS: (EI, 70 eV, m/z) 195 (17, Mþ), 151 (14), 136 (5), 123 (4), 97 (11),96 (100), 95 (15), 94 (34). HRMS: (ESI, m/z) (MþþH) calculated forC11H22N3: 196.1808, found: 196.1806.
4.5.10. 2-Benzyl-3-(2,2-dimethylhydrazono)-9-methyl-9-azabicyclo[3.3.1]nonane (4a). Following typical procedure A, using 4 (0.195 g,1.00 mmol) and benzyl bromide (0.131 mL, 1.10 mmol) gavea crude product that was purified by distillation in a Kugelrohrapparatus (oven temp 180 �C, 3.6�10�2 Torr) to give 4e (0.283 g,99%) as a yellow oil. Rf: 0.50 (10% MeOH/DCM, v/v). 1H NMR (d,400 MHz, CDCl3) major isomer: 7.32e7.17 (m, 5H), 3.54 (dd,J1¼10.6 Hz, J2¼3.4 Hz, 1H), 3.20e3.05 (m, 2H), 2.73 (dd, J1¼13.0 Hz,J2¼3.9 Hz, 1H), 2.60e2.50 (m, 1H), 2.57 (s, 3H), 2.44 (s, 6H),2.40e2.35 (m, 1H), 2.25 (d, J¼13.0 Hz, 1H), 2.10e1.95 (m, 2H),1.85e1.70 (m, 1H), 1.47e1.40 (m, 1H), 1.29 (dd, J1¼16.9 Hz,J2¼3.4 Hz, 1H), 0.98 (dd, J1¼13.8 Hz, J2¼3.4 Hz, 1H) ppm. 13C NMR(d, 100 MHz, CDCl3) major isomer: 175.6, 140.7, 129.2, 128.1, 125.9,54.3, 54.2, 46.9, 45.4, 40.4, 38.6, 38.0, 22.8, 22.6, 17.5 ppm. IR:(CHCl3) 1623 cm�1. GCeMS: (three isomers) 32.09 min, 32.45 min(major), 33.18 min (40 �Ce5 �C/mine280 �C). MS: (EI, 70 eV, m/z)285 (5, Mþ), 241 (14), 184 (11), 97 (8), 96 (100), 94 (13). HRMS:(ESI, m/z) (MþþH) calculated for C18H28N3: 286.2278, found:286.2280.
4.5.11. 3-(2,2-Dimethylhydrazono)-2,9-dimethyl-9-azabicyclo[3.3.1]nonane (4b). Following typical procedure A, using 4 (0.195 g,1.00 mmol) and methyl iodide (0.068 mL, 1.10 mmol) gave a crudeproduct that was purified by distillation in a Kugelrohr apparatus(oven temp 140 �C, 0.36 Torr) to give 4b (0.196 g, 94%) as a yellowoil. Rf: 0.36 (20% MeOH/DCM, v/v). 1H NMR (d, 400 MHz, CDCl3)major isomer: 3.23 (q, J¼7.0 Hz, 1H), 2.93e2.87 (m, 1H), 2.77 (dd,J1¼15.0 Hz, J2¼6.0 Hz, 1H), 2.50e2.40 (m, 1H), 2.46 (s, 3H), 2.30 (s,6H), 2.15 (d, J¼15.0 Hz, 1H), 2.00e1.85 (m, 2H), 1.70e1.60 (m, 1H),1.35e1.30 (m, 1H), 1.20e1.14 (m, 1H), 1.14 (d, J¼7.0 Hz, 3H), 1.07 (dd,J1¼14.0 Hz, J2¼4.0 Hz, 1H) ppm. 13C NMR (d, 100 MHz, CDCl3) majorisomer: 176.2, 59.9, 54.2, 46.9, 40.8, 37.7, 37.6, 23.3, 22.2, 19.0,17.2 ppm. IR: (CHCl3) 1626 cm�1. GCeMS: (two isomers) 19.42 min(major), 19.72 min (40 �Ce5 �C/mine280 �C). MS: (EI, 70 eV, m/z)209 (11, Mþ),165 (8),108 (9), 98 (6), 97 (7), 96 (100), 95 (12), 94 (13).HRMS: (ESI,m/z) (MþþH) calculated for C12H24N3: 210.1965, found:210.1967.
4.5.12. 3-(2,2-Dimethylhydrazono)-9-methyl-2-propyl-9-azabicyclo[3.3.1]nonane (4c). Following typical procedure A, using 4 (0.195 g,1.00 mmol) and 1-iodopropane (0.107 mL, 1.10 mmol) gave a crudeproduct that was purified by distillation in a Kugelrohr apparatus(oven temp 130 �C, 1.7 Torr) to give 4c (0.232 g, 99%) as a yellow oil.
4.7.6. 2-Benzyl-9-methyl-9-azabicyclo[3.3.1]nonan-3-one(2a). Following typical procedure E, using 4a (0.023 g,0.080 mmol) gave the crude product that was purified by DFCchromatography [SiO2, methanol/dichloromethane (0:10 to 2:8)]to give 2a (0.017 g, 89%) as a brown oil. Rf: 0.53 (10% MeOH/DCM,v/v). 1H NMR (d, 400 MHz, CDCl3) major isomer: 7.35e7.25 (m, 2H),7.20e7.15 (m, 3H), 3.47 (dd, J1¼14.8 Hz, J2¼4.8 Hz, 1H), 3.30e3.25(m, 1H), 3.05e2.95 (m, 2H), 2.87e2.75 (m, 1H), 2.57 (s, 3H),2.44e2.38 (m, 1H), 2.28 (d, J¼15.5 Hz, 1H), 2.00e1.90 (m, 1H),1.85e1.70 (m, 2H), 1.60e1.45 (m, 2H), 1.42e1.35 (m, 1H) ppm. 13CNMR (d, 100 MHz, CDCl3) major isomer: 211.4, 139.9, 128.4, 128.2,126.0, 61.8, 59.1, 56.7, 50.5, 42.6, 40.9, 31.7, 29.0, 16.1 ppm. IR:(CHCl3) 1718 cm�1. GCeMS: (two isomers) 30.98 min, 31.76 min(major) (40 �Ce5 �C/mine280 �C). MS: (EI, 70 eV, m/z) 243 (19Mþ), 200 (5), 110 (21), 97 (17), 96 (100), 91 (17), 82 (9), 57 (11).HRMS: (ESI, m/z) (MþþH) calculated for C16H22NO: 244.1696,found: 244.1701.
4 . 7 . 7 . 2 , 9 -D ime t hy l - 9 - a z ab i c y c l o [ 3 . 3 .1 ] n onan -3 - on e(2b).5 Following typical procedure E, using 4b (0.106 g,0.500 mmol) gave the crude product that was purified by DFCchromatography [SiO2, methanol/dichloromethane (0:10 to 1:9)] togive 2b (0.047 g, 55%) as a brown oil. Rf: 0.31 (10%MeOH/DCM, v/v).1H NMR (d, 400 MHz, CDCl3) major isomer: 3.33e3.27 (m, 1H),
4.7.8. 9-Methyl-2-propyl-9-azabicyclo[3.3.1]nonan-3-one(2c). Following typical procedure E, using 4c (0.089 g, 0.370 mmol)gave the crude product that was purified by DFC chromatography[SiO2, methanol/dichloromethane (0:10 to 1:9)] to give 2c (0.059 g,81%) as a brown oil. Rf: 0.50 (10% MeOH/DCM, v/v). 1H NMR (d,400 MHz, CDCl3) major isomer: 3.35e3.25 (m, 1H), 3.23e3.15 (m,1H), 2.90e2.80 (m, 1H), 2.75e2.60 (m, 1H), 2.68 (s, 3H), 2.24 (d,J¼15.6 Hz, 1H), 2.00e1.90 (m, 2H), 1.80e1.73 (m, 1H), 1.66 (dd,J1¼13.4 Hz, J2¼2.1 Hz, 1H), 1.54 (dd, J1¼13.4 Hz, J2¼2.1 Hz, 1H),1.50e1.40 (m, 1H), 1.40e1.20 (m, 3H), 1.14e1.03 (m, 1H), 0.93 (t,J¼7.3 Hz, 3H) ppm. 13C NMR (d, 100 MHz, CDCl3) major isomer:211.8, 59.9, 56.6, 48.2, 42.5, 40.9, 28.9, 28.0, 23.7, 20.5, 16.0,14.1 ppm. IR: (CHCl3) 1695 cm�1. GCeMS: (two isomers) 20.90 min,21.42 min (major) (40 �Ce5 �C/mine280 �C). MS: (EI, 70 eV, m/z)195 (16, Mþ), 166 (23), 110 (15), 97 (10), 96 (100), 95 (11), 82 (6), 55(12). HRMS: (ESI,m/z) (MþþH) calculated for C12H22N3O: 196.1696,found: 196.1700.
4.7.9. 9-Methyl-2-isopropyl-9-azabicyclo[3.3.1]nonan-3-one(2d). Following typical procedure E, using 4d (0.047 g, 0.200mmol)gave the crude product that was purified by DFC chromatography[SiO2, methanol/dichloromethane (0:10 to 1:9)] to give 2d (0.029 g,74%) as a brown oil. Rf: 0.60 (10% MeOH/DCM, v/v). 1H NMR (d,400 MHz, CDCl3) major isomer: 3.28 (d, J¼4.8 Hz, 2H), 2.78 (dd,J1¼14.3 Hz, J2¼6.7 Hz, 1H), 2.67 (s, 3H), 2.40e2.30 (m, 1H), 2.23 (d,J¼14.3 Hz, 1H), 2.10e2.00 (m, 1H), 1.97e1.90 (m, 1H), 1.80e1.75 (m,1H), 1.75e1.65 (m,1H), 1.65e1.55 (m,1H), 1.50e1.40 (m, 2H), 1.10 (d,J¼6.5 Hz, 3H), 0.86 (d, J¼6.5 Hz, 3H) ppm. 13C NMR (d, 100 MHz,CDCl3) major isomer: 212.3, 59.7, 57.3, 54.9, 43.4, 41.1, 29.5, 24.7,24.6, 23.2, 19.5, 16.1 ppm. IR: (CHCl3) 1697 cm�1. GCeMS: (twoisomers) 17.63 min, 18.43 min (major) (40 �Ce8 �C/mine280 �C).MS: (EI, 70 eV, m/z) 195 (17, Mþ), 180 (13), 152 (7), 110 (18), 97 (11),96 (100), 94 (12), 82 (7). HRMS: (ESI, m/z) (MþþH) calculated forC12H22N3O: 196.1696, found: 196.1699.
4.7.10. 2-Al lyl-9-methyl-9-azabicyclo[3.3 .1]nonan-3-one(2e). Following typical procedure E, using 4e (0.071 g, 0.300 mmol)gave the crude product that was purified by DFC chromatography[SiO2, methanol/dichloromethane (0:10 to 1:9)] to give 2e (0.034 g,58%) as a brown oil. Rf: 0.52 (10% MeOH/DCM, v/v). 1H NMR (d,400 MHz, CDCl3) major isomer: 5.85e5.75 (m, 1H), 5.10e5.00 (m,2H), 3.35e3.25 (m, 1H), 3.20e3.10 (m, 1H), 2.90e2.70 (m, 2H), 2.65(s, 3H), 2.25 (d, J¼16.6 Hz, 1H), 2.00e1.90 (m, 2H), 1.80e1.65 (m,2H), 1.60e1.40 (m, 2H), 1.33e1.20 (m, 2H) ppm. 13C NMR (d,100 MHz, CDCl3) major isomer: 211.2, 136.2, 116.3, 59.4, 56.6, 48.3,42.4, 40.9, 30.3, 29.1, 23.6,16.0 ppm. IR: (CHCl3) 1698 cm�1. GCeMS:(two isomers) 12.98 min, 13.42 min (major) (40 �Ce8 �C/mine280 �C). MS: (EI, 70 eV,m/z) 193 (16, Mþ), 111 (17), 110 (25), 97(15), 96 (100), 94 (14), 82 (12), 57 (14). HRMS: (ESI, m/z) (MþþH)calculated for C12H20NO: 194.1539, found: 194.1542.
4.7.11. 9-Methyl-2-pentyl-9-azabicyclo[3.3.1]nonan-3-one(2f). Following typical procedure E, using 4f (0.060 g, 0.230 mmol)gave the crude product that was purified by DFC chromatography[SiO2, methanol/dichloromethane (0:10 to 1:9)] to give 2f (0.035 g,
R. Lazny et al. / Tetrahedron 70 (2014) 597e607 607
4.7.12. 2-Heptyl-9-methyl-9-azabicyclo[3.3.1]nonan-3-one(2g). Following typical procedure E, using 4g (0.149 g, 0.500 mmol)gave the crude product that was purified by DFC chromatography[SiO2, methanol/dichloromethane (0:10 to 1:19)] to give 2g(0.084 g, 73%) as a brown oil. Rf: 0.52 (10% MeOH/DCM, v/v). 1HNMR (d, 400 MHz, CDCl3) major isomer: 3.29e3.24 (m, 1H),3.18e3.12 (m, 1H), 2.79 (dd, J1¼15.5 Hz, J2¼6.7 Hz, 1H), 2.65 (s, 3H),2.58 (q, J¼6.4 Hz,1H), 2.21 (dd, J1¼15.5 Hz, J2¼1.0 Hz,1H), 2.00e1.90(m, 2H), 1.80e1.70 (m, 1H), 1.68e1.52 (m, 1H), 1.55e1.50 (m, 1H),1.47e1.40 (m, 1H), 1.36e1.20 (m, 11H), 1.14e1.08 (m, 1H), 0.88 (t,J¼6.6 Hz, 3H) ppm. 13C NMR (d, 100 MHz, CDCl3) major isomer:212.1, 59.8, 56.6, 48.4, 42.3, 41.0, 31.8, 29.6, 29.2, 27.2, 25.7 (2C),23.9, 22.5, 16.0, 14.0 ppm. IR: (CHCl3) 1697 cm�1. GCeMS: (twoisomers) 25.49 min, 26.08 min (40 �Ce5 �C/mine280 �C). MS: (EI,70 eV,m/z) 251 (3, Mþ), 207 (3), 193 (4), 110 (8), 98 (10), 97 (100), 96(32), 95 (14). HRMS: (ESI, m/z) (MþþH) calculated for C16H30NO:252.2322, found: 252.2327.
4.7.13. 2-(4-Methoxybenzyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (2h). Following typical procedure E, using 4h (0.136 g,0.430 mmol) gave the crude product that was purified by DFCchromatography [SiO2, methanol/dichloromethane (0:10 to 1:19)]to give 2h (0.093 g, 79%) as a brown oil. Rf: 0.46 (10%MeOH/DCM, v/v). 1H NMR (d, 400MHz, CDCl3) major isomer: 7.11 (d, J¼8.6 Hz, 2H),6.83 (d, J¼8.6 Hz, 2H), 3.79 (s, 3H), 3.40 (dd, J1¼14.5 Hz, J2¼4.5 Hz,1H), 3.30e3.23 (m, 1H), 3.00e2.95 (m, 2H), 2.82 (dd, J1¼15.5 Hz,J2¼6.7 Hz,1H), 2.58 (s, 3H), 2.37 (dd, J1¼14.5 Hz, J2¼8.6 Hz,1H), 2.28(dd, J1¼15.5 Hz, J2¼1.0 Hz, 1H), 2.00e1.90 (m, 1H), 1.80e1.70 (m,2H), 1.56e1.48 (m, 2H), 1.40e1.30 (m, 1H) ppm. 13C NMR (d,100 MHz, CDCl3) major isomer: 211.6, 157.9, 131.8, 129.5, 113.9, 59.1,56.7, 55.2, 50.6, 42.6, 40.9, 30.8, 29.0, 23.7, 16.1 ppm. IR: (CHCl3)3075, 1704, 1249 cm�1. GCeMS: (two isomers) 25.49 min,26.08 min (40 �Ce10 �C/mine325 �C). MS: (EI, 70 eV, m/z) 273 (54,Mþ), 230 (10), 121 (27), 110 (20), 97 (24), 96 (100), 95 (15), 82 (9).HRMS: (ESI, m/z) (MþþH) calculated for C17H24NO: 274.1802,found: 274.1807.
Acknowledgements
This work was supported by the University of Bialystok (BST-125) and the National Science Centre of Poland (Grant No. NN204 546939). The authors thank the computational centreof the University of Warsaw (ICM) for providing access to thesupercomputer resources and GAUSSIAN 09 program (GrantG33-03).
Supplementary data
The 1H NMR and 13C NMR spectra of intermediates and finalproducts, as well as results of DFT computations are available.Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2013.12.008.
References and notes
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44. The chromatographic purification did not affect measurably the exo/endoisomer ratios.
