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DOI: 10.1039/C4RA02834A (Paper) RSC Adv., 2014, 4, 29668-29681

Environmentally benign diastereoselective synthesis of granatane and tropane aldol derivatives†

Aneta Nodzewska, Agnieszka Bokina, Katarzyna Romanowska and Ryszard Lazny*
Institute of Chemistry, University of Bialystok, Hurtowa 1, 15-399 Bialystok, Poland. E-mail: lazny@uwb.edu.pl

Received 31st March 2014 , Accepted 11th June 2014

First published on 12th June 2014

Abstract

Direct aldol reactions of tropinone and granatanone (pseudopelletierine) with aromatic aldehydes were promoted by the presence of water. The anti–syn-diastereoselectivity depended on the amount of water used or on the possibility of product precipitation from the reaction mixture. Some of the reactions showed excellent atom economy, a low E factor, and high diastereoselectivity (up to 98%). In several cases ‘seeding’ with the anti isomer, used to induce the deposition of solid products, improved the conversion (up to 1.8 times) and the anti–syn ratio (up to 98[thin space (1/6-em)]:[thin space (1/6-em)]2). The applicability of spontaneous direct aldol reactions in the presence of water was also extended to N-alkyl nortropanones or norgranatanones using an aqueous–organic medium. However, under these conditions only the exo,syn isomers of the N-substituted aldols were obtained. The syn-selectivity for the tropane- and granatane-related aldols is specific for water-promoted reactions and results from thermodynamic control.

Introduction

Stereoselective aldol reactions,1 including the recent organocatalytic2 versions, are prominent among C–C bond-forming transformations. Although the applications of tertiary amine catalysis (involving, e.g., a DBU–water complex,3 DBU,4 DIPEA,4 cinchona alkaloid derivatives,4,5 or pyridine6) and inorganic base7 in aldol addition are known, these applications have never involved the amine nitrogen of the substrate/product itself. Tropinone (1, 8-methyl-8-azabicyclo[3.2.1]octan-3-one, Scheme 1) and granatanone (2, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) are inexpensive scaffolds that can be used for the synthesis of valuable tropane and granatane derivatives.8 The general method for preparing the exo,anti aldols of tropinone,9 granatanone10 or related nor-analogues11 is the lithium amide base-directed8c,d,9,12 formation of the enolate, which is followed by an aldol addition reaction under anhydrous conditions. However, in some cases, using our spontaneous aldol addition of tropinone and related ketones to aldehydes in the presence of water,13 could prove to be a “green” and much more economical alternative on a bigger scale. Moreover, the reaction in the presence of small (ca. equimolar) amounts of water13 is the first practical method for the preparation of exo,syn isomers.10,14 Regardless of the method used, lithium enolate or aqueous, the only isomers formed are the exo forms, as shown in Scheme 1.14
image file: c4ra02834a-s1.tif
Scheme 1 Preparation of exo,anti and exo,syn-aldols of tropinone 3 and granatanone 4, and the selected subsequent products 5–9.

Based on the preliminary report,13,15 it can be proposed that obtaining reasonable conversion and diastereoselectivity in the water-promoted aldol reactions of the heterocyclic amino ketones 1 and 2 is conditioned by numerous factors, including the following: (i) a tertiary nitrogen atom built into the ketones-an achiral organocatalyst; (ii) water as the source of a strong base facilitating the enolization step; (iii) an aqueous solution as a perfect environment for spontaneous crystallization; (iv) formation of internal hydrogen bonds in the products; and (v) thermodynamic stability of the products formed. Although these factors could be identified, the actual yield and the exo,syn to exo,anti isomer ratio was dependent on the specific amino ketone and aldehyde used, and was difficult to control.

Herein, we disclose the complete experimental details of our investigations into the scope and limitations of water-promoted aldol reactions of tropinone and granatanone. The results of our attempts to improve the selectivity and overall efficiency, as well as product characterization, are presented. In addition, experimental optimization and efforts to extend this methodology to new N-substituted (i-Pr, Bn, Ph, Cbz) nortropinone and norgranatanone aldol derivatives are also included.

Results and discussion

We started by testing the reaction of simpler cyclic ketones. Cyclohexanone, an aldol donor without an intramolecular amine group, was chosen to compare the effect of the internal amine with the external tertiary amine. A monocyclic amino ketone related to tropinone, i.e., N-methyl-4-piperidone, was included to observe the difference introduced by the bicyclic skeleton of tropinone. The comparison of simple model experiments using benzaldehyde16 with and without the addition of water or tertiary amine are shown in Table 1. All the results (Table 1), except the reactions of tropinone with pure water,13 which are included for the sake of comparison, constitute a new study aimed at demonstrating unique structural features responsible for the observed reactions.
Table 1 Comparison of the aldol reactions of cyclohexanone, N-methyl-4-piperidone and tropinone with benzaldehyde in the presence of triethylamine and watera
Ketone Water [mL] Et3N [equiv.] Aldol
Conv.b [%] % aldolc Drb anti–syn
a Reaction conditions: 1 mmol of aldehyde, 2 mmol of ketone, 0.018 mL (1 equiv.) or 2.5 mL (140 equiv.) of water; reaction time: 1 day in aqueous emulsion (2.5 mL), 4 days in other cases.b The conversion and the exo,syn–exo,anti selectivity determined by 1H NMR spectroscopy (CHOH signals: 2-(hydroxy(phenyl)methyl)cyclohexanone:17 syn 5.40 ppm, 2.3 Hz, anti 4.79 ppm, 8.4 Hz; 3-(hydroxy(phenyl)methyl)-1-methyl-4-piperidone: syn 5.25 ppm, 1.8 Hz, anti 4.97 ppm, 7.3 Hz).c % aldol-ratio of aldols to other products (benzylidene derivatives, unidentified by-products, possibly hemiacetals, as reported for these types of reactants18). Similar results are obtained for both triethylamine or N-methylmorpholine.
Cyclohexanone — — — No product
Cyclohexanone — 0.3 — No product
Cyclohexanone 0.018 0.3 5 Undetermined
Cyclohexanone 2.5 0.3 90 75 44[thin space (1/6-em)]:[thin space (1/6-em)]56
N-Methyl-4-piperidone — — — No product
N-Methyl-4-piperidone — 0.3 — No product
N-Methyl-4-piperidone 0.018 — 20 70 46[thin space (1/6-em)]:[thin space (1/6-em)]54
N-Methyl-4-piperidone 0.018 0.3 3 Undetermined
N-Methyl-4-piperidone 2.5 — 80 10 Undetermined
N-Methyl-4-piperidone 2.5 0.3 20 5 Undetermined
Tropinone — — — No product
Tropinone — 0.3 — No product
Tropinone 0.018 — 95 ≥98 10[thin space (1/6-em)]:[thin space (1/6-em)]90
Tropinone 0.018 0.3 — No product
Tropinone 2.5 — 98 ≥98 95[thin space (1/6-em)]:[thin space (1/6-em)]5
Tropinone 2.5 0.3 90 ≥98 39[thin space (1/6-em)]:[thin space (1/6-em)]61

Most of the reactions with benzaldehyde showed low conversion and were plagued by the by-products. Cyclohexanone gave a reasonable, although not selective, aldol reaction only in an aqueous suspension with added amine. Interestingly, a mixture of cyclohexanone and aldehyde in dry triethylamine showed no reaction. A similar lack of reactivity was observed for N-methyl-4-piperidone and tropinone in the absence of water. A dry mixture of tropinone and benzaldehyde under neat reaction conditions gave no signs of the formation of an aldol after 4 days at room temperature. The same dry mixture with added triethylamine (0.3 equiv., 0.04 mL mmol−1 of tropinone) also did not yield aldols (Table 1). However, in the presence of 1 or more equivalents of water, the formation of a mixture of isomeric exo-aldols ensued in less than 1 day at ambient temperature. As expected, higher dilutions with water resulted in reversed stereoselectivity when compared with the neat reaction (Table 1).13 The current study clearly indicates that tropinone differs in reactivity and stereoselectivity from its monocyclic congener, N-methyl-4-piperidone and cyclohexanone. Note that only tropinone gave high conversion (95%) in the reaction with an equimolar amount of water. In addition, the current results, shown in Table 1, confirm our previous finding13 that water is evidently necessary for a tropinone (and other ketones) aldol reaction to proceed, possibly providing a source of stronger specific base, the hydroxide ion, which is advantageous for a faster enolization rate. However, we expected that the role of water in the reaction of bicyclic amino ketones, such as 1, could not be limited only to the source of strong base that facilitates the enolization step because of the intriguing dependence of stereoselectivity on the amount of water used in the reaction mixture. As the aldol addition is known to be reversible, we suspected that the dissolution of reacting species in water may affect the stability of the products formed if equilibrium was involved. The poor performance of the piperidone derivative showed that a successful and stereoselective aldol addition called for the bicyclic structure of the amino ketone reactant. Presence of an amine base was also critical as is evident by the lack of cyclohexanone reactions without Et3N. The addition of 0.3 equivalent of triethylamine to the reaction mixture lowered the selectivity or/and the yield of tropinone and piperidone aldols in the reactions in the presence of water (Table 1). Thus, this study supported the supposition of privileged bicyclic ketone structure with internal amine group.

Aldol reaction of bicyclic N-methyl amino ketones

As communicated previously, the stereoselectivity of the reaction of tropinone with benzaldehyde depended on the amount of water used. In a solventless (neat) reaction with an equimolar amount of water, the exo,syn-aldol was predominant, whereas in aqueous emulsion (ca. 140 equivalents of water), the exo,anti aldol was formed as the major isomer (Scheme 1 and Table 2).13 The racemic diastereomeric products formed have a stereogenic amine nitrogen atom that undergoes fast configurational inversion in solution at room temperature, typical for tropinone and granatanone derivatives.19 However, steric interactions with the exo-hydroxybenzyl group and the formation of internal hydrogen bond fix the N-methyl in the equatorial position of the piperidone ring (as found in crystal structures).10,20 Based on the DFT calculations, we proposed that the origins of stereoselectivity might be observed in the thermodynamic equilibration of the internal hydrogen bond stabilized conformers15 of the competing isomeric products, or in some cases, in the preferential crystallization of the solid products formed. The selectivity and conversion of the reaction were only decreased by the use of various additives (co-solvents, amines, metal salts, chiral additives). The current study showed that the yields and stereoselectivities for products 3a–g and 4a–b, as presented in Table 2, could not be improved in comparison with the previously optimized data.13 The data are included in Table 2 for the completeness of the results and the convenience of the reader. In the following section, we thoroughly discuss the new reactions yielding granatanone aldols 4c–g and all the by-products of the tropinone and granatanone reaction that have not been revealed in our preliminary study.13
Table 2 Diastereomeric ratios and yields of obtained aldols of tropinone (3) and granatanone (4) with aromatic aldehydes in the presence of watera
R1 Aldol Waterb [amt.] Dra anti–syn (yieldc [%]) Characteristic signals CH(OH) [CβH]h
a Experimental data for aldols 3a–g and 4a–b obtained from preliminary communications are included for the completeness of the results.13,15b Amount of water/reaction conditions: 1 equiv. (1 mmol of aldehyde, 2 mmol of tropinone or granatanone, 18 μL H2O), dilution (1 mmol of aldehyde, 2 mmol of tropinone or granatanone, 2.5 mL H2O).c The progress of reactions was monitored by 1H NMR spectroscopy (reaction time: 1–14 days). Yield of all the aldols (amount of anti and syn aldols).d Lower diastereomeric ratio (41[thin space (1/6-em)]:[thin space (1/6-em)]59) was observed for the oily mixture of anti–syn aldols. When the formation of a solid was observed, the selectivity anti–syn increased to >95[thin space (1/6-em)]:[thin space (1/6-em)]5 and yield to 75%.e Extension of reaction time to 7 days.f No solid product precipitated after 2 h. Extension of the reaction time to 18 h resulted in the formation of solid and change in selectivity anti–syn 5[thin space (1/6-em)]:[thin space (1/6-em)]95 and yield (93%).g Conversion determined by 1H NMR spectroscopy. Pure product was not isolated because of low conversion.h Characteristic signals found in 1H NMR spectra of the exo,syn and exo,anti products.
Ph 3a 1 equiv. 10[thin space (1/6-em)]:[thin space (1/6-em)]90 (84) syn 5.01 ppm (d, J = 2.6 Hz), anti 5.23 (d, J = 3.1)
Dilution 41[thin space (1/6-em)]:[thin space (1/6-em)]59 (55)
95[thin space (1/6-em)]:[thin space (1/6-em)]5 (75)d
p-NO2-C6H4 3b 1 equiv. 22[thin space (1/6-em)]:[thin space (1/6-em)]78 (76) syn 5.07 (d, J = 2.2), anti 5.31 (d, J = 2.6)
Dilution 64[thin space (1/6-em)]:[thin space (1/6-em)]36 (95)
51[thin space (1/6-em)]:[thin space (1/6-em)]49e
p-F-C6H4 3c 1 equiv. 20[thin space (1/6-em)]:[thin space (1/6-em)]80 (75) syn 4.97 (d, J = 1.9), anti 5.20 (d, J = 2.9)
Dilution 46[thin space (1/6-em)]:[thin space (1/6-em)]54 (43)
p-Cl-C6H4 3d 1 equiv. 14[thin space (1/6-em)]:[thin space (1/6-em)]86 (90) syn 4.98 (d, J = 2.6), anti 5.19 (d, J = 2.8)
Dilution 45[thin space (1/6-em)]:[thin space (1/6-em)]55 (69)
p-CF3-C6H4 3e 1 equiv. 17[thin space (1/6-em)]:[thin space (1/6-em)]83 (92) syn 5.10 (d, J = 2.4), anti 5.25 (d, J = 2.6)
Dilution 55[thin space (1/6-em)]:[thin space (1/6-em)]46 (77)
m-MeO-C6H4 3f 1 equiv. 10[thin space (1/6-em)]:[thin space (1/6-em)]90 (73) syn 4.90 (d, J = 2.1), anti 5.20 (d, J = 3.2)
Dilution 39[thin space (1/6-em)]:[thin space (1/6-em)]61 (46)
α-Naphthyl 3g 1 equiv. 5[thin space (1/6-em)]:[thin space (1/6-em)]95 (51) syn 5.79 (d, J = 1.8), anti 6.02 (d, J = 2.3)
Dilution 33[thin space (1/6-em)]:[thin space (1/6-em)]67 (34)
Ph 4a 1 equiv. 11[thin space (1/6-em)]:[thin space (1/6-em)]89 (45) syn 5.08 (d, J = 2.0), anti 5.27 (d, J = 3.6)
Dilution 39[thin space (1/6-em)]:[thin space (1/6-em)]61 (21)a
p-NO2-C6H4 4b 1 equiv. 20[thin space (1/6-em)]:[thin space (1/6-em)]80 (90) syn 5.13 (d, J = 1.7), anti 5.33 (d, J = 3.1)
Dilution 49[thin space (1/6-em)]:[thin space (1/6-em)]51 (2h)
5[thin space (1/6-em)]:[thin space (1/6-em)]95 (93%)f
p-F-C6H4 4c 1 equiv. 18[thin space (1/6-em)]:[thin space (1/6-em)]82 (48)g syn 5.03 (d, J = 1.0), anti 5.23 (d, J = 3.4)
Dilution 45[thin space (1/6-em)]:[thin space (1/6-em)]55 (27)g
p-Cl-C6H4 4d 1 equiv. 17[thin space (1/6-em)]:[thin space (1/6-em)]83 (29)g syn 5.03 (d, J = 2.2), anti 5.23 (d, J = 3.4)
Dilution 45[thin space (1/6-em)]:[thin space (1/6-em)]55 (46)g
p-CF3-C6H4 4e 1 equiv. 20[thin space (1/6-em)]:[thin space (1/6-em)]80 (61) syn 5.10 (br s), anti 5.31 (d, J = 3.0)
Dilution 17[thin space (1/6-em)]:[thin space (1/6-em)]83 (58)
m-MeO-C6H4 4f 1 equiv. 10[thin space (1/6-em)]:[thin space (1/6-em)]90 (17)g syn 5.04 (d, J = 1.6), anti 5.22 (d, J = 3.8)
Dilution 39[thin space (1/6-em)]:[thin space (1/6-em)]61 (22)g
α-Naphthyl 4g 1 equiv. 2[thin space (1/6-em)]:[thin space (1/6-em)]98 (8)g syn 5.82 (br s), anti 6.03 (d, J = 2.8)
Dilution 35[thin space (1/6-em)]:[thin space (1/6-em)]65 (12)g

Solventless reactions. Despite various attempts,14,21 the neat reaction with an approximately equimolar amount of water remained the most effective route of preparing exo,syn isomers of the aldols of tropinone, granatanone and their N-substituted nor-analogues (vide infra). As is evident from the examples of the neat reactions of tropinone (1) or granatanone (2) with selected aromatic aldehydes with 1 equivalent (18 μL per mmol of aldehyde) of added water, moderate to excellent exo,syn selectivity of aldols was obtained (exo,anti–exo,syn up to 2[thin space (1/6-em)]:[thin space (1/6-em)]98, Table 2). The exo,syn-3a–g and 4a–b, e products were synthesized using this method with fair to good yields (39–88%, Table 2). The products from aldehyde–ketone combinations, which did not give good conversion and selectivity (4c, d, f, g), were not isolated in pure form (no crystallization was possible) and remained inaccessible by any method. The decomposition of these exo,syn-aldols to starting materials during the attempts of crystallization and isolation was observed, and made isolation of these products difficult. Thus, the low stability of these syn products remains a major limitation in their synthesis. The neat aldol reactions of tropinone and granatanone left for longer times were complicated by the formation of condensation products (6–9, Scheme 1) in amounts dependent on specific reactants. This study showed that the extent of aldol dehydration, bis-aldol formation and bis-aldol dehydration products depended on the type of ketone.

As a rule, we observed that tropinone derivatives were less prone to water elimination (noticeable after 14 days at rt) than granatanone (elimination products appeared after 4 days, complicating the workup and the isolation of products). For instance, the neat reaction of tropinone with p-fluorobenzaldehyde after ca. 1 month produced a mixture of aldols and condensation products (Scheme 1) exo,syn-3c–exo,anti-3c–E-6c22–E,E-8c 26[thin space (1/6-em)]:[thin space (1/6-em)]26[thin space (1/6-em)]:[thin space (1/6-em)]22[thin space (1/6-em)]:[thin space (1/6-em)]26. Granatanone under analogous conditions produced mainly condensation products exo,syn-4c–exo,anti-4c–E-7c–E,E-9c 3[thin space (1/6-em)]:[thin space (1/6-em)]7[thin space (1/6-em)]:[thin space (1/6-em)]45[thin space (1/6-em)]:[thin space (1/6-em)]45. These aldol condensation by-products or their analogues were identified in the reaction mixtures using their characteristic NMR signals. In this work, representative new enones were characterized. Tropinone aldol condensation products (6a–c, R1 = Ph, p-NO2-C6H4, p-F-C6H4)22 as well as bis-condensation products (8a, b, d, R1 = Ph, p-NO2-C6H4, p-Cl-C6H4)23 and an granatanone analogue (9a R1 = Ph)24 have already been described.

Reactions in aqueous emulsion. For most reactions of aromatic aldehydes (p-F, p-Cl, p-CF3, m-MeO substituted benzaldehydes and α-naphthaldehyde) with tropinone (preliminary report)13 or granatanone (present study) in water (2.5 mL water per 1 mmol of aldehyde), the formation of a crude oily mixture of exo,anti and exo,syn aldols was observed. In these cases the products were isolated in moderate to good yields (34–77%, Table 2). Nonetheless, in some cases the spontaneous precipitation of products from the reaction mixture occurred, as in the case of the reaction of tropinone with benzaldehyde, where the exo,anti aldol 3a was obtained as a solid (98% conversion, 75% yield, Fig. 1, Table 2).13
image file: c4ra02834a-f1.tif
Fig. 1 Preparation of exo,anti-aldol of tropinone (2 mmol) and benzaldehyde (1 mmol) in water (2.5 mL), (a) emulsion at the beginning of the reaction (b) precipitate formed after stirring for 16 h.

Interestingly, in the reaction of p-nitrobenzaldehyde with granatanone in aqueous dilution, a solid precipitate was also formed. However, in this case, the exo,syn-aldol 4b was obtained.13 The equilibration under the reaction conditions could be followed by NMR monitoring, which showed the formation of a mixture of two isomers that were converted over time into one isomer (Fig. 2 shows the change observed by NMR monitoring in the aldol carbinol hydrogen regions). In this reasonably rapid reaction, after 2 h of stirring, the formation of the two isomers exo,anti and exo,syn in a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio (Fig. 2) was observed. However, on prolonged stirring (16 h), the exo,syn isomer formed with high diastereoselectivity (exo,anti–exo,syn 5[thin space (1/6-em)]:[thin space (1/6-em)]95). In this particular case, equilibration provided a more stable form,25 which also deposited as a solid from the reaction mixture. Although the more stable syn isomer of the tropinone p-nitro derivative 3b dominated in the presence of 1 equivalent of water (exo,anti–exo,syn 22[thin space (1/6-em)]:[thin space (1/6-em)]78, Table 2),13 in the current work, equilibration of isomeric products could be observed in dilution. After 16 h, the faster-forming anti isomer 3b still dominated (exo,anti–exo,syn 64[thin space (1/6-em)]:[thin space (1/6-em)]36, Table 2) in the aqueous mixture. However, with prolonged reaction time (a week of stirring of the reaction mixture) the equimolar mixture of exo,anti and exo,syn isomers was found.26 The same isomerization of the pure anti 3b (made via LDA procedure) to the syn form occurred during recrystallization attempts (DCM–hexane, ambient temperature). Thus, it appeared that the propensity for the crystallization of the stable isomeric forms could be used to advantage and allow, under proper conditions, for the conversion of one isomer to the other. On the other hand, in some cases, e.g., the trifluoro derivative of granatanone 4e, the attempted recrystallization was complicated by the retroaldolization as well as by the formation of a bis-aldol 5e (Scheme 1) of a closer unidentified stereochemistry. Considering this, obtaining the pure exo,syn-isomer from the exo,anti isomer (or vice versa) may be difficult unless the specific aldols are fairly stable and form crystals, as is the case for the p-nitrophenyl derivatives. Control experiments in aqueous conditions (Scheme 2) using either of the crystallized isomers of aldol 3a proved a significant propensity of aldols for retroaldolization and isomerization. Stirring of pure aldol exo,anti-3a in water (2.5 mL per mmol of aldol) for 16 h at ambient temperature produced a mixture containing 18% aldols (ratio of exo,syn-aldol to the starting exo,anti aldol: 37[thin space (1/6-em)]:[thin space (1/6-em)]63), as well as tropinone (1) and benzaldehyde (41% of each). Thus, the present work provided complete experimental support for product equilibration and the notion of thermodynamic control.


image file: c4ra02834a-f2.tif
Fig. 2 Fragments of 1H NMR spectra from the reactions of granatanone (2 mmol) and p-nitrobenzaldehyde (1 mmol) at rt in 2.5 mL water (left – 2 h, right – 16 h).

image file: c4ra02834a-s2.tif
Scheme 2 Retroaldolization and isomerization observed in the presence of water.

In our present study, we have found that, generally, in runs at higher dilution where no solids were formed, conversion and selectivity were typically lower (Table 2) for both tropinone and grantanone. It was rather clear that the improvement of the anti-selectivity for specific aldehydes could be expected only if the precipitation of the forming exo,anti product was induced.

To test the possibility of improving the results by product crystallization, several solid crystalline exo,anti isomers 3a–4g were prepared via adapted literature procedures using LDA deprotonation.12c,14 The exo,anti aldols were obtained in good yields (Table 3) and high stereomeric purities (crude ≥85%).

Table 3 Yields of the obtained exo,anti-aldols of tropinone (3) and granatanone (4) with aldehydes under anhydrous conditions (with LDA)a

image file: c4ra02834a-u1.tif
R1 Aldol Yield [%] Aldol Yield [%]
a Reaction conditions: (1) 1 mmol of ketone, 1.1 mmol of LDA, −78 °C, THF, 45 min, (2) 1.1 mmol of aldehyde, −78 °C, THF, 10 min, (3) 5 mL NH4Cl.
Ph 3a 95 4a 95
p-F-C6H4 3c 96 4c 76
p-Cl-C6H4 3d 82 4d 96
m-MeO-C6H4 3f 78 4f 87
α-Naphthyl 3g 75 4g 52

The reactions in water, which gave poor yields and no solid products, were subjected to ‘seeding’ by doping with small amounts of the exo,anti isomers (0.04 mmol, negligible mass in comparison with the yields of the products formed) with the purpose of inducing precipitation and driving equilibria. Such ‘seeding’ in most cases resulted in improved conversion and selectivity. The conversions improved by a factor of 1.3 to 1.8 in several cases, depending on the aldehyde used (Table 4). In other cases, the observed improvements were negligibly small (within experimental error seen from run to run). Rewardingly, the expected anti selectivity for tropinone aldols was also notably improved in several cases (up to 88[thin space (1/6-em)]:[thin space (1/6-em)]12, Table 4). The reactions of granatanone were often less selective and showed lower conversions compared with tropinone reactions. As a result, in general, the reactions of granatanone also responded worse to ‘seeding’ than the experiments with tropinone, except for the notable example of p-chlorobenzaldehyde, which showed excellent anti diastereoselectivity (>98%). This study and the unexpected excellent result in the granatanone series proves that the optimization of such reaction conditions on a case by case basis can be rewarding and is sensible, e.g., at the process development stage for both tropinone and granatanone. Extending reaction times for the cases exhibiting low conversions resulted in the formation of elimination products (aldol condensation). In particular, the low-yielding granatanone reactions gave mixtures of aldols (and bis-aldols e.g., 5e) admixed with the products of elimination, 7 and 9 (Scheme 1). Increasing reaction times slightly improved the conversions at the cost of overall product purity. In such cases, the isolation of pure isomers by crystallization or even chromatography (decomposition of aldols on column or PTLC on silica gel, alumina and reversed phases) was impossible. The aldol reaction of solid p-nitrobenzaldehyde and p-trifluorobenzaldehyde were not subjected to ‘seeding’ because of the high reactivity of these aldehydes, and are therefore not included in Table 4. The yields for these aldehydes were reasonably high without ‘seeding’ (58–95% in water).

Table 4 Preparation of the exo,anti-aldols of tropinone and granatanone and the effect of ‘seeding’ in low yielding aldol reactions showing no deposition of solid products
R1 (aldol) Reaction without “seeding”a Reaction with “seeding”b
Conversionc [%] (time [days]) anti–sync [%] Conversionc [%] (timed [days]) anti–sync [%] Yield antie [%]
a Only substrates (ketone and aldehyde) were stirred (see general procedure 2).b Substrates were stirred for one/two days and then a small amount of exo,anti aldol was added, and the mixture was stirred for another one/two days (see general procedure 3). Addition of exo,anti aldol at the beginning of the reaction did not induce the ‘seeding’ effect.c Conversion and the ratio of exo,anti to exo,syn were determined by 1H NMR spectroscopy.d Sum of the time before and after ‘seeding’ (total time).e Isolated yield of the exo,anti aldol.f With spontaneous deposition of solid products the yield was 75%.g Pure product was not isolated because of low conversion.
Ph (3a) 57 (2; no ppt) 41[thin space (1/6-em)]:[thin space (1/6-em)]59 75 (1 + 2, ppt) 76[thin space (1/6-em)]:[thin space (1/6-em)]24 52f
p-F-C6H4 (3c) 48 (4) 46[thin space (1/6-em)]:[thin space (1/6-em)]54 45 (2 + 2) 47[thin space (1/6-em)]:[thin space (1/6-em)]53 20
p-Cl-C6H4 (3d) 75 (4) 45[thin space (1/6-em)]:[thin space (1/6-em)]55 95 (1 + 2) 80[thin space (1/6-em)]:[thin space (1/6-em)]20 71
m-MeO-C6H4 (3f) 51 (4) 39[thin space (1/6-em)]:[thin space (1/6-em)]61 85 (1 + 2) 88[thin space (1/6-em)]:[thin space (1/6-em)]12 69
α-Naphthyl (3g) 40 (2) 33[thin space (1/6-em)]:[thin space (1/6-em)]67 58 (1 + 1) 56[thin space (1/6-em)]:[thin space (1/6-em)]44 29
Ph (4a) 25 (3) 39[thin space (1/6-em)]:[thin space (1/6-em)]61 31 (1 + 1) 39[thin space (1/6-em)]:[thin space (1/6-em)]61 —g
p-F-C6H4 (4c) 27 (3) 45[thin space (1/6-em)]:[thin space (1/6-em)]55 32 (1 + 1) 46[thin space (1/6-em)]:[thin space (1/6-em)]54 —g
p-Cl-C6H4 (4d) 46 (3) 45[thin space (1/6-em)]:[thin space (1/6-em)]55 83 (1 + 1) ≥98 anti 79
m-MeO-C6H4 (4f) 22 (3) 39[thin space (1/6-em)]:[thin space (1/6-em)]61 21 (1 + 1) 38[thin space (1/6-em)]:[thin space (1/6-em)]62 —g
α-Naphthyl (4g) 13 (3) 35[thin space (1/6-em)]:[thin space (1/6-em)]65 20 (2 + 2) 32[thin space (1/6-em)]:[thin space (1/6-em)]68 —g

The question might arise whether doping the reaction mixture with a small amount of the crystalline product induced crystallization or/and accelerated the reaction (autocatalytic or autoinductive effect). We investigated that the addition of a small amount of exo,anti aldol to the reactant mixture at the onset of the reaction has no effect on conversion and selectivity. However, doping the reaction mixture after stirring for 16 h, when the mixture was already saturated with forming products (significant conversion showed by NMR analysis), was distinctly beneficial for conversion and selectivity. This suggests that the induction of crystallization from product saturated reaction mixture is responsible for the ‘seeding’ effect but not the autocatalysis.

In addition to ‘seeding’, we also tested the effects of additives, such as co-solvents, on the reaction of tropinone with benzaldehyde at higher dilution. We tested DMF, THF, MeOH, EtOH, Et3N, DCM, Et2O, MTBE and N-methylformamide (0.5 mL of co-solvent and 2.5 mL of water per 1 mmol of aldehyde). Unfortunately, in each case, we observed the formation of products 3a with lower diastereoselectivity than in the reaction without these additives. During control experiments in dry protic organic solvent (MeOH, EtOH and N-methylformamide), aldols 3a together with aldol condensation products 6a were formed with very low conversions (up to 30%) and low selectivities. These experiments proved that the presence of water was not the necessary condition for aldolization if another polar protic solvent was used. Nevertheless, the anti product 3a could be synthesized with the best diastereoselectivity (exo,anti–exo,syn up to 95[thin space (1/6-em)]:[thin space (1/6-em)]5, Table 2) and best yield in an aqueous medium only.

Aldol reaction of N-benzyl and N-isopropyl amino ketones

In an effort to broaden the methodology of aqueous aldol reaction to analogous of tropinone, we investigated whether N-alkyl derivatives of nortropinone and norgranatanone (Fig. 3) can be used in direct aldol addition.
image file: c4ra02834a-f3.tif
Fig. 3 N-Substituted derivatives of nortropinone and norgranatanone successfully applied in aldol reaction in the presence of water.

Because the N-benzyl amines are synthetically important derivatives, we used them as representative probes. It appeared that the N-benzyl ketones 10–11 do not react appreciably under previously determined aqueous conditions (regardless whether ‘on water’ or neat). Because in this case the reactivity may be primarily hindered by limited solubility of the reactants (both aldehydes and ketones) in water, we looked for a suitable co-solvent. Testing the aqueous–organic mixtures (DMF, MeOH, EtOH) resulted in determining water–DMF mixture as the optimal medium (Table 5).

Table 5 Effects of reaction conditions on the synthesis of nortropinone aldols derivative with high dilution
Aldol Reaction conditionsa Timec [days] Conversiond [%] anti–synd [%]
a Reaction conditions: 1 mmol of p-bromobenzaldehyde, 2 mmol of N-benzylnortropinone.b Substrates were stirred for four days and then a small amount of exo,anti-aldol was added, and the mixture was stirred for another three days.c Progress of the reactions were monitored by 1H NMR spectroscopy.d Conversion and diastereomeric ratio determined by 1H NMR spectroscopy.
14i 2.5 mL H2O 4 20 25[thin space (1/6-em)]:[thin space (1/6-em)]75
2.5 mL H2O, seedingb 4 + 3 35 37[thin space (1/6-em)]:[thin space (1/6-em)]63
2.5 mL H2O, 0.5 mL DMF 4 96 25[thin space (1/6-em)]:[thin space (1/6-em)]75
2.5 mL H2O, 0.5 mL DMF, seedingb 4 + 3 88 25[thin space (1/6-em)]:[thin space (1/6-em)]75
2.5 mL H2O, 0.5 mL MeOH 4 33 26[thin space (1/6-em)]:[thin space (1/6-em)]74
2.5 mL H2O, 0.5 mL MeOH, seedingb 4 + 3 52 27[thin space (1/6-em)]:[thin space (1/6-em)]73
2.5 mL H2O, 0.5 mL EtOH 4 54 16[thin space (1/6-em)]:[thin space (1/6-em)]84
2.5 mL H2O, 0.5 mL EtOH, seedingb 4 + 3 58 23[thin space (1/6-em)]:[thin space (1/6-em)]77

The best conversion (96%) and diastereomeric ratio for 14i (exo,anti–exo,syn 25[thin space (1/6-em)]:[thin space (1/6-em)]75) were obtained without ‘seeding’. Thus, we demonstrated that using water-insoluble reactants, such as N-benzylnortropinone (10) and p-bromobenzaldehyde (Table 5), in the aqueous conditions, may lead to the effective and stereoselective formation of the exo,syn aldol. p-Bromobenzaldehyde was chosen to provide an aldol derivative suitable for stereochemical assignment and X-ray diffraction.27 The procedure was applicable to other N-benzyl analogues of tropinone and granatanone, as demonstrated by the representative examples of the preparation of phenyl, m-methoxy and p-nitro derivatives 14, 15 (Table 6). Interestingly, in the case of the N-benzyl derivatives, regardless of the amount of water used in the reaction mixture, the dominating products were the exo,syn isomers of aldols (exo,anti–exo,syn up to 8[thin space (1/6-em)]:[thin space (1/6-em)]92). Because there was no effect of varying the amount of added water on diastereoselectivity in the reaction of 10 and 11, we waived the use of the slow, time-demanding solventless reaction. Because in the tested aldol reactions of N-benzylnortropinone the exo,syn isomer predominated and the ‘seeding’ did not change the results (Table 5), no exo,anti products could be obtained by this methodology.

Table 6 Diastereomeric ratios and yields of obtained aldols of N-benzylnortropinone (14) and N-benzylnorgranatanone (15) with selected aldehydes in the presence of water
R1 Aldol Watera [amt.] Dr anti–synb (yield [%]) characteristic signals CH(OH) [CβH]d
a Amount of water/reaction conditions: 1 equiv. (1 mmol of aldehyde, 2 mmol of N-benzylnortropinone (10) or N-benzylnorgranatanone (11), 18 μL H2O, 20 days), dilution (1 mmol of aldehyde, 2 mmol of N-benzylnortropinone (10) or N-benzylnorgranatanone (11), 2.5 mL H2O, 0.5 mL DMF, 4 days).b Diastereomeric ratio determined by 1H NMR spectroscopy. Yield of all aldols (amount of exo,anti and exo,syn aldols).c Conversion determined by 1H NMR spectroscopy. Pure product was not isolated because of low conversion.d Characteristic signals found in 1H NMR spectra of the exo,syn and exo,anti products.
Ph 14a 1 equiv. 32[thin space (1/6-em)]:[thin space (1/6-em)]68 (41) syn 4.96 (d, J = 2.4), anti 5.11 (d, J = 3.2)
Dilution 22[thin space (1/6-em)]:[thin space (1/6-em)]78 (40)
p-NO2-C6H4 14b 1 equiv. 24[thin space (1/6-em)]:[thin space (1/6-em)]76 (89) syn 4.96 (d, J = 1.8), anti 5.15 (d, J = 2.6)
Dilution 28[thin space (1/6-em)]:[thin space (1/6-em)]72 (87)
m-MeO-C6H4 14f 1 equiv. 27[thin space (1/6-em)]:[thin space (1/6-em)]73 (31) syn 4.96 (d, J = 1.8), anti 5.08 (d, J = 3.1)
Dilution 21[thin space (1/6-em)]:[thin space (1/6-em)]79 (61)
p-Br-C6H4 14i 1 equiv. 32[thin space (1/6-em)]:[thin space (1/6-em)]68 (89) syn 4.88 (d, J = 2.2), anti 5.04 (d, J = 2.8)
Dilution 25[thin space (1/6-em)]:[thin space (1/6-em)]75 (88)
Ph 15a 1 equiv. 17[thin space (1/6-em)]:[thin space (1/6-em)]83 (50) syn 5.02 (d, J = 2.0), anti 5.16 (d, J = 4.0)
Dilution 32[thin space (1/6-em)]:[thin space (1/6-em)]68 (37)
p-NO2-C6H4 15b 1 equiv. No product syn 5.01 (d, J = 1.5), anti 5.22 (d, J = 3.1)
Dilution 37[thin space (1/6-em)]:[thin space (1/6-em)]63 (38)
m-MeO-C6H4 15f 1 equiv. No product syn 5.01 (br s), anti 5.13 (d, J = 4.0)
Dilution 8[thin space (1/6-em)]:[thin space (1/6-em)]92 (69)
p-Br-C6H4 15i 1 equiv. 29[thin space (1/6-em)]:[thin space (1/6-em)]71 (15)c syn 4.93 (d, J = 1.7), anti 5.09 (d, J = 3.6)
Dilution 28[thin space (1/6-em)]:[thin space (1/6-em)]72 (24)

The N-isopropyl analogues of tropinone and granatanone, solubilized by a water miscible co-solvent (DMF, opaque reaction mixture) reacted under the same conditions giving the syn-isomers as well. The aldols of N-isopropyl amino ketones 16 and 17 were obtained in good yields (Table 7), and in some cases with very good syn-diastereoselectivity (anti–syn 2[thin space (1/6-em)]:[thin space (1/6-em)]98). Despite high conversion, the crude isomeric mixtures crystallized very poorly. The pure isomers were usually hard to isolate. However, two N-isopropyl derivatives (exo,syn-17b and exo,syn-17i) were obtained as crystalline syn-isomers. The exo,anti and exo,syn configurations of the N-isopropyl products 16 and 17 were analogously assigned to the other aldols (3, 4, 14, 15) using relevant shifts and coupling constants of the characteristic doublets of the carbinol hydrogens –CH(OH)–R. The exo,anti isomer J is higher than for the exo,syn aldol, whereas the doublet for the exo,anti aldol is downfield relative to the signal of the exo,syn product.

Table 7 Diastereomeric ratios and yields of the obtained aldols of N-isopropylnortropinone (16) and N-isopropylnorgranatanone (17) with selected aldehydes in the presence of water
R1 Aldol Watera [amt.] Dr anti–synb (yield [%]) characteristic signals CH(OH) [CβH]d
a Amount of water/reaction conditions: 1 equiv. (1 mmol of aldehyde, 2 mmol of N-isopropylnortropinone (12) or N-isopropylnorgranatanone (13), 18 μL H2O, 20 days), dilution (1 mmol of aldehyde, 2 mmol of N-isopropylnortropinone (12) or N-isopropylnorgranatanone (13), 2.5 mL H2O, 0.5 mL DMF, 4 days).b Diastereomeric ratio determined by 1H NMR spectroscopy. Yield of all aldols (amount of exo,anti and exo,syn aldols).c Conversion determined by 1H NMR spectroscopy. Pure product was not isolated because of low conversion.d Characteristic signals found in 1H NMR spectra of the exo,syn and exo,anti products.
Ph 16a 1 equiv. 32[thin space (1/6-em)]:[thin space (1/6-em)]68 (41) syn 5.01 (d, J = 2.2), anti 5.22 (d, J = 2.4)
Dilution 35[thin space (1/6-em)]:[thin space (1/6-em)]65 (29)
p-NO2-C6H4 16b 1 equiv. 76[thin space (1/6-em)]:[thin space (1/6-em)]24 (88) syn 4.95 (d, J = 2.2), anti 5.17 (d, J = 2.3)
Dilution 45[thin space (1/6-em)]:[thin space (1/6-em)]55 (49)
m-MeO-C6H4 16f 1 equiv. 27[thin space (1/6-em)]:[thin space (1/6-em)]73 (37) syn 4.98 (d, J = 2.1), anti 5.19 (d, J = 2.4)
Dilution 37[thin space (1/6-em)]:[thin space (1/6-em)]63 (30)c
p-Br-C6H4 16i 1 equiv. 34[thin space (1/6-em)]:[thin space (1/6-em)]66 (80) syn 4.95 (d, J = 2.2), anti 5.17 (d, J = 2.3)
Dilution 60[thin space (1/6-em)]:[thin space (1/6-em)]40 (43)
Ph 17a 1 equiv. 29[thin space (1/6-em)]:[thin space (1/6-em)]71 (44) syn 5.06 (br s), anti 5.27 (d, J = 3.1)
Dilution 26[thin space (1/6-em)]:[thin space (1/6-em)]74 (30)c
p-NO2-C6H4 17b 1 equiv. 17[thin space (1/6-em)]:[thin space (1/6-em)]83 (88) syn 5.08 (br s), anti 5.33 (d, J = 2.8)
Dilution 43[thin space (1/6-em)]:[thin space (1/6-em)]57 (65)
m-MeO-C6H4 17f 1 equiv. 34[thin space (1/6-em)]:[thin space (1/6-em)]66 (40) syn 5.04 (br s), anti 5.24 (d, J = 3.2)
Dilution 33[thin space (1/6-em)]:[thin space (1/6-em)]67 (39)
p-Br-C6H4 17i 1 equiv. 2[thin space (1/6-em)]:[thin space (1/6-em)]98 (88) syn 4.99 (br s), anti 5.22 (d, J = 2.4)
Dilution 2[thin space (1/6-em)]:[thin space (1/6-em)]98 (69)

The N-phenyl, N-Cbz substituted nortropinone and quaternary ammonium salt (obtained in the reaction of tropinone with MeI) analogues were also tested in aldol reaction in aqueous dilution and in the presence of one equivalent of water. However, in test reactions with p-nitro- and p-bromobenzaldehyde, we did not observe the formation of any products. In the case of the N-phenyl analogue, the only observed reaction with p-nitrobenzaldehyde in water–Et3N produced an unresolved mixture dominated by by-products. Unfortunately, N-Cbz and quaternary ammonium salt derivatives of tropinone did not react with aldehydes neither in water and water–organic solvent nor in water–Et3N mixtures. This showed that these N-substituted nortropinones are too weakly basic, and also possibly too weak as hydrogen bond acceptors or too sterically hindered to give the exo-substituted hydrogen bond stabilised aldols15 (as can be inferred from no reaction with added external amine base).

Recycling of aqueous phase

When the reaction was performed in an aqueous emulsion, some aldol products (e.g. 3a, Fig. 1, 4b)13 could be easily separated by filtration, and the aqueous filtrate could be reused in the next run of the same reaction, thus avoiding the formation of problematic organics-contaminated aqueous waste.28 We proved that after the supplementation of the consumed reactants (amounts calculated based on yield of recovered product), the water phase could be used for the subsequent runs of the same reaction (up to 6 times was tested successfully in the present work). Such operations resulted in better mass utilization and higher E factor. As an advantage, the recycling procedure did not require extra reagents or solvents because the solid product was separated by filtration. The illustration of the performance of the reaction between p-nitrobenzaldehyde and granatanone in the recycled water phase is shown graphically in Fig. 4. As shown in the figure, the yields were close to 90% in all the runs and syn–anti-selectivity varied within experimental error. Thus, assuming that the average yield of the isolated product is 93%, the E factor29 for one run of this process is 0.61, and for three runs with recycling of the water phase containing unreacted reactants reaches an impressive 0.20 (see ESI†). This is especially noteworthy in the light of typical E factors in fine chemical production, which range from 5 to 50.29
image file: c4ra02834a-f4.tif
Fig. 4 Yield of filtered product and diastereomer ratio for six consecutive runs of the aldol reaction using recycled water phase.

Conclusions

This work supported the finding that the diastereoselectivities of the aldol reactions of tropinone and granatanone with aromatic aldehydes in the presence of water are dependent on the amount of water used and the precipitation of solid products. In the solventless reaction (1 equivalent of water) the exo,syn-isomers were typically the most stable forms, and dominated under the reaction conditions (thermodynamic equilibration). The addition of amines to the reaction had a detrimental effect on stereoselectivity. The current study shows that, in general, tropinone gives better results than granatanone. The neat reaction remained the only practical method for accessing exo,syn aldols. Using aqueous dilutions of the reaction mixture, depending on the reactants, two situations occurred: (i) mixtures of exo,anti- and exo,syn-products were formed with a small excess of a more stable isomer; or (ii) solid products precipitated and one isomer of aldol was obtained with high diastereoselectivity. In some cases, the precipitation of the exo,anti isomer from the aqueous reaction mixture was expediently induced by ‘seeding’, which caused a shift in the equilibrium giving very good diastereoselectivities (up to 98%) and good yields (up to 79%). In the unprecedented reactions of N-benzyl and N-isopropyl amino ketones, regardless of the amount of water used, the aldols with exo,syn configuration dominated the reaction mixture. The syn-selectivity in the aldol reactions of tropane related ketones is obtained exclusively in the water-promoted reactions and stems from uncommon thermodynamic control in stereoselective synthesis.

Although case-by-case optimization may be necessary (aqueous–organic medium, co-solvent, ‘seeding’) to allow the syntheses of specific N-methyl as well as N-alkyl derivatives, this methodology is an experimentally simple, economical and scalable way of accessing valuable aldols for further elaboration to alkaloids or their analogues.8a,9 In amenable cases, the water induced aldol reactions are characterized by excellent atom economy, and may also allow larger scale preparation of intermediates for the syntheses of bioactive tropane and granatane derivatives, fully conforming to benign chemistry (green chemistry) concepts.

Experimental

Only the aldol products that were crystallized as one isomer (at least 95% diastereomeric purity by NMR) are characterized in the experimental section.

General procedure 1 (for exo,syn-aldols 3 and 4)

Aldehyde (1 mmol) was added to a mixture of tropinone or granatanone (2 mmol) and water (18 μL, 1 mmol). The reaction mixture was then stirred at room temperature for 72 h or until NMR monitoring showed satisfactory conversion. The mixture was diluted with toluene (1 mL) and evaporated under vacuum at temperature below 30 °C (repeated three times). The crude product was crystallized from suitable solvents (diethyl ether, dichloromethane (DCM), hexane, heptane, AcOEt).

General procedure 2 (for precipitating exo,anti aldols 3 and 4)

Aldehyde (1 mmol) was added to a suspension of tropinone or granatanone (2 mmol) in water (2.5 mL, 140 mmol). The mixture was stirred at room temperature for 24 h or until NMR monitoring showed satisfactory conversion. The deposited solid mass was filtered, dried under high vacuum and the crude product recrystallized from DCM–hexane mixture.

General procedure 3 (exo,anti aldols 3 and 4)

‘Seeding’ is recommended for reactions with no spontaneous deposition of solid product or low conversion. Aldehyde (1 mmol) was added to a solution of tropinone or granatanone (2 mmol) in water (2.5 mL, 140 mmol) and the mixture was stirred at room temperature for 24 h or until NMR monitoring showed satisfactory conversion (Table 4). Then, a small portion of exo,anti aldol (ca. 0.010 g, 0.04 mmol) for inducing product crystallization was added and the mixture was stirred for an additional period of time (Table 4). The formed solid mass was filtered or extracted, dried under high vacuum, and the resulting crude product was recrystallized from mixed solvent (DCM–hexane) to give a white solid.

General procedure 4 (exo,anti aldols 3 and 4)

A solution of n-butyllithium in hexane (0.5 mL, 2.40 M, 1.2 mmol) was added dropwise to a cooled (0 °C) solution of diisopropylamine (0.17 mL, 1.2 mmol) in THF (5 mL). The mixture was stirred for 20 min at 0 °C, cooled to −78 °C, and then a solution of tropinone or granatanone (1 mmol) in THF (3 mL) was added. After stirring for 1 h, a solution of aldehyde (1.15 mmol) in dry THF (1 mL) was added and the mixture was stirred for another 10 min. Then, the reaction was quenched with saturated aqueous NH4Cl solution (7 mL) and extracted with DCM (3 × 10 mL). The combined extracts were dried over Na2SO4 and concentrated under vacuum. The crude product was crystallized from DCM–hexane to give a white solid.

General procedure 5 (for reactions of N-alkyl derivatives giving exo,syn aldols)

Aldehyde (0.50 mmol) was added to a mixture of N-alkyl amino ketone (10 or 11 or 12 or 13, 1 mmol), water (1.25 mL) and DMF (0.25 mL). The reaction mixture was stirred at room temperature for 4 days or until NMR monitoring showed satisfactory conversion. The mixture was extracted with DCM (3 × 10 mL). The combined extracts were dried (Na2SO4) and concentrated under vacuum. The crude product was crystallized from a suitable solvent.

Typical procedure 1 (for recycling of aqueous reaction medium)

p-Nitrobenzaldehyde (0.151 g, 1 mmol) was added to a suspension of granatanone (0.306 g, 2 mmol) in water (2.5 mL, 140 mmol). The mixture was stirred at room temperature for 24 h. The solid was filtered off, washed with water (0.1–0.5 mL; combined washings and the filtrate should not exceed 2.5 mL), and finally dried at room temperature under high vacuum (to maximise the transfer of solid product from a glass filter, washing with solvent is useful). p-Nitrobenzaldehyde (0.151 g, 1 mmol), and granatanone (0.153 g, 1 mmol) were added to the combined aqueous filtrate and washings, and the reaction followed by the product collection was repeated.
exo,syn-2-(Hydroxy(phenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,syn-3a)13,14. Compound exo,syn-3a was prepared according to the general procedure 1 (stirred for 7 days) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.184 g, 75%). Analytical sample was very slowly crystallized from diethyl ether mp 81–83 °C (decomp.); Rf: 0.60 (20% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.47–7.22 (m, 5H), 7.35 (br s, 1H), 5.01 (d, J = 2.6 Hz, 1H), 3.51–3.43 (m, 1H), 3.25–3.18 (m, 1H), 2.98 (ddd, J = 17.0 Hz, 5.2 Hz, 1.7 Hz, 1H), 2.43 (app dt, J = 17.0 Hz, 1.7 Hz, 1H), 2.39–2.37 (m, 1H), 2.37 (s, 3H), 2.20–2.03 (m, 2H), 1.70–1.61 (m, 1H), 1.42–1.35 (m, 1H); 13C-NMR: 210.7, 143.7, 128.3, 126.9, 125.5, 75.7, 63.1, 61.2 (2C), 50.3, 40.4, 26.8, 26.4.
exo,anti-2-(Hydroxy(phenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,anti-3a)8d,12c. Compound exo,anti-3a was prepared according to the general procedure 2 (stirred for 2 days in water, 0.184 g, 75%) or general procedure 4 (in THF with LDA, 0.233 g, 95%) and recrystallized from mixed solvent (DCM–hexane) to give a white solid; mp 118–121 °C (decomp.); Rf: 0.45 (20% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.32–7.25 (m, 5H), 5.23 (d, J = 3.1 Hz, 1H), 3.61–3.59 (m, 1H), 3.50–3.47 (m, 1H), 2.86 (ddd, J = 15.6 Hz, 4.6 Hz, 1.5 Hz, 1H), 2.47 (s, 3H), 2.45–2.43 (m, 1H), 2.35 (ddd, J = 15.7 Hz, 2.0 Hz, 2.0 Hz, 1H), 2.21–2.12 (m, 1H), 1.69–1.53 (m, 1H); 13C-NMR: 207.8, 141.7, 127.9, 127.1, 125.4, 76.5, 67.3, 64.2, 61.6, 51.4, 40.5, 26.3, 26.1.
exo,syn-2-(Hydroxy(4-nitrophenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,syn-3b). Compound exo,syn-3b was prepared according to the general procedure 1 (stirred for 7 days) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.160 g, 55%); mp: 156–158 °C; Rf: 0.65 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.28–8.23 (m, 2H), 7.67–7.61 (m, 2H), 5.08 (d, J = 2.4 Hz, 1H), 3.55–3.48 (m, 1H), 3.13–3.08 (m, 1H), 2.98 (ddd, J = 17.1 Hz, 5.3 Hz, 1.7 Hz, 1H), 2.48 (app dt, J = 17.2 Hz, 2.0 Hz, 1H), 2.40–38 (m, 1H), 2.38 (s, 3H), 2.23–2.08 (m, 2H), 1.73–1.55 (m, 1H), 1.46–1.38 (m, 1H); 13C-NMR: 209.5, 151.4, 147.1, 126.4, 123.6, 75.3, 62.3, 61.3, 61.1, 50.1, 40.4, 26.7, 26.4; IR: 2956, 2884, 1713, 1606, 1522, 1477, 1347, 1075, 854 cm−1; HRMS (ESI): calcd for C15H19N2O4 (M+ + H) 291.1345, found 291.1350.
exo,anti-2-(Hydroxy(4-nitrophenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,anti-3b). Compound exo,anti-3b was prepared according to the general procedure 4 and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.278 g, 96%); mp: 147–150 °C, Rf: 0.53 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.29 (s, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 5.29 (d, J = 2.5 Hz, 1H), 3.66 (d, J = 7.1 Hz, 1H), 3.49–3.46 (m, 1H), 2.75 (ddd, J = 16.1 Hz, 4.7 Hz, 1.9 Hz, 1H), 2.47 (s, 3H), 2.43 (d, J = 1.8 Hz, 1H), 2.35–2.25 (m, 2H), 2.24–2.10 (m, 1H), 1.68–1.52 (m, 2H); 13C-NMR: 207.1, 149.2, 147.1, 126.4, 123.4, 76.1, 67.6, 63.3, 61.5, 51.5, 40.6, 26.5, 26.3. IR: 2958, 1713, 1522, 1348 cm−1; HRMS (ESI): calcd for C15H19N2O4 (M+ + H) 291.1345, found 291.1352.
exo,syn-2-((4-Fluorophenyl)(hydroxy)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,syn-3c). Compound exo,syn-3c was prepared according to the general procedure 1 (stirred for 14 days) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.145 g, 55%); mp: 95–97 °C, Rf: 0.67 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.36–7.32 (m, 2H), 7.08 (t, J = 17.4 Hz, 8.7 Hz, 2H), 4.97 (d, J = 1.9 Hz, 1H), 3.57 (d, J = 7.2 Hz, 1H), 3.21–3.3.16 (m, 1H), 2.94 (dd, J = 16.9 Hz, 5.2 Hz, 1H), 2.45–2.38 (m, 1H), 2.35 (s, 3H), 2.32 (s, 1H), 2.18–2.11 (m, 2H), 1.68–1.60 (m, 1H), 1.41–1.30 (m, 1H). 13C-NMR: 210.4, 161.8 (d, 1JCF = 245 Hz), 139.3 (d, 4JCF = 3 Hz), 127.0 (d, 3JCF = 8 Hz), 115.1 (d, 2JCF = 21 Hz), 75.2, 63.1, 61.1, 50.2, 40.4, 26.7, 26.3. IR: 2956, 2884, 1709, 1605, 1508, 1238, 1072 cm−1; HRMS (ESI): calcd for C15H19FNO2 (M+ + H) 264.1400, found 264.1392.
exo,anti-2-((4-Fluorophenyl)(hydroxy)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,anti-3c). Compound exo,anti-3c was prepared according to the general procedure 4 and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.253 g, 96%); mp: 103–105 °C, Rf: 0.57 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.80 (br s, 1H), 7.23–7.21 (m, 2H), 7.04–6.92 (m, 2H), 5.20 (d, J = 2.9 Hz, 1H), 3.60 (d, J = 6.7 Hz, 1H), 3.52–3.46 (m, 1H), 2.82 (ddd, J = 15.8 Hz, 4.7 Hz, 2.0 Hz, 1H), 2.47 (s, 3H), 2.42–2.37 (m, 1H), 2.37–2.23 (m, 2H), 2.22–2.12 (m, 1H), 1.70–1.52 (m, 2H). 13C-NMR: 207.8, 161.9 (d, 1JCF = 489 Hz), 137.5 (d, 4JCF = 6 Hz), 127.1 (d, 3JCF = 16 Hz), 114.8 (d, 2JCF = 42 Hz), 76.1, 67.5, 64.2, 61.6, 51.5, 40.6, 26.4, 26.2. IR: 2958, 2884, 1712, 1511, 1232 cm−1; HRMS (ESI): calcd for C15H19FNO2 (M+ + H) 264.1400, found 264.1392.
exo,syn-2-((4-Chlorophenyl)(hydroxy)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,syn-3d). Compound exo,syn-3d was prepared according to the general procedure 1 (stirred for 14 days) and crystallized from mixed solvent (AcOEt–hexane) to give a white solid (0.207 g, 74%); mp: 98–99 °C, Rf: 0.73 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.05 (br s, 1H), 7.42–7.33 (m, 4H), 4.98 (d, J = 2.6 Hz, 1H), 3.51–3.42 (m, 1H), 3.20–3.16 (m, 1H), 2.95 (ddd, J = 17.0 Hz, 5.2 Hz, 1.7 Hz, 1H), 2.43 (dt, J = 17.0 Hz, 1.6 Hz, 1H), 2.36 (s, 3H), 2.32 (d, J = 1.7 Hz, 1H), 2.22–2.07 (m, 2H), 1.72–1.62 (m, 1H), 1.45–1.36 (m, 1H); 13C-NMR: 210.3, 142.3, 132.7, 128.5, 127.0, 75.2, 62.9, 61.3, 61.2, 50.2, 40.5, 26.8, 26.4. IR: 2956, 2884, 1708, 1491, 1073 cm−1. HRMS (ESI): calcd for C15H19ClNO2 (M+ + H) 280.1104, found 280.1112.
exo,anti-2-((4-Chlorophenyl)(hydroxy)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,anti-3d). Compound exo,anti-3d was prepared according to the general procedure 3 with seeding (reaction time in Table 4) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.199 g, 71%); mp: 134–138 °C, Rf: 0.60 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.90 (br s, 1H), 7.32–7.25 (m, 2H), 7.24–7.15 (m, 2H), 5.19 (d, J = 2.8 Hz, 1H), 3.60 (d, J = 6.9 Hz, 1H), 3.53–3.46 (m, 1H), 2.80 (ddd, J = 15.8 Hz, 4.7 Hz, 1.8 Hz, 1H) 2.46 (s, 3H), 2.42–2.37 (m, 1H), 2.36–2.24 (m, 1H), 2.22–2.17 (m, 1H), 1.69–1.60 (m, 1H), 1.59–1.51 (m, 1H); 13C-NMR: 207.6, 140.3, 132.7, 128.1, 126.8, 75.9, 67.3, 63.8, 61.5, 51.4, 40.4, 26.3, 26.1. IR: 2958, 1712, 1077, 841 cm−1; HRMS (ESI): calcd for C15H19ClNO2 (M+ + H) 280.1104, found 280.1109.
exo,syn-2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one (exo,syn-3e). Compound exo,syn-3e was prepared according to the general procedure 1 (stirred for 14 days) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.226 g, 72%); mp: 99–104 °C, Rf: 0.71 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.67–7.65 (m, 2H), 7.58–7.56 (m, 2H), 5.10 (d, J = 2.44Hz, 1H), 3.66–3.65 (m, 1H), 3.16 (d, J = 1.36 Hz, 1H), 3.00 (dd, J = 5.2 Hz, 1.7 Hz, 1H), 2.46 (dt, J = 17.00 Hz, 1.7 Hz, 1H), 2.38 (s, 3H), 2.21–2.10 (m, 2H), 1.72–1.62 (m, 1H), 1.45–1.35 (m, 1H). 13C-NMR: 209.9, 129.2 (q, 2JCF = 32 Hz), 125.8, 125.3 (q, 3JCF = 4 Hz), 124.1 (q, 1JCF = 271 Hz), 75.3, 62.6, 61.2, 61.1, 50.1, 40.3, 26.7, 26.4. IR: 2956, 1712, 1168, 1131, 1068, 1017 cm−1; HRMS (ESI): calcd for C16H19F3NO2 (M+ + H) 314.1368, found 314.1362.
exo,anti-2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one (exo,anti-3e). Compound exo,anti-3e was prepared according to the general procedure 4 and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.285 g, 91%); mp: 129–132 °C, Rf: 0.66 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.04 (br s, 1H), 7.58–7.52 (m, 2H), 7.39–7.32 (m, 2H), 5.25 (d, J = 2.6 Hz, 1H), 3.62 (d, J = 7.1 Hz, 1H), 3.51–3.45 (m, 1H), 2.79 (ddd, J = 15.9 Hz, 4.8 Hz, 2.9 Hz, 1H), 2.45 (s, 3H), 2.44–2.41 (m, 1H), 2.34–2.23 (m, 2H), 2.21–2.10 (m, 1H), 1.67–1.50 (m, 2H); 13C-NMR: 207.4, 145.8, 129.2 (q, 2JCF = 32 Hz), 125.8, 124.9 (q, 3JCF = 4 Hz), 124.4 (q, 1JCF = 271 Hz), 76.1, 67.5, 63.6, 61.5, 51.4, 40.4, 26.3, 26.2. IR: 2958, 1713, 1326, 1128, 1068 cm−1; HRMS (ESI): calcd for C16H19F3NO2 (M+ + H) 314.1368, found 314.1372.
exo,syn-2-(Hydroxy(3-methoxyphenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one (exo,syn-3f). Compound exo,syn-3f was prepared according to the general procedure 1 (stirred for 14 days) and crystallized from mixed solvent (DCM–Et2O) to give a white solid (0.171 g, 62%); mp: 82–84 °C, Rf: 0.65 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.9 (br s, 1H), 7.40–7.30 (m, 1H), 6.96–6.90 (m, 2H), 6.75–6.70 (m, 1H), 4.90 (d, J = 2.12 Hz, 1H), 3.76 (s, 3H), 3.45–3.35 (m, 1H), 3.20–3.12 (m, 1H), 2.87 (dd, J = 17.0 Hz, 5.0 Hz, 1H), 2.41–2.27 (m, 2H), 2.29 (s, 3H), 2.13–1.98 (m, 2H), 1.64–1.53 (m, 1H), 1.37–1.28 (m, 1H); 13C-NMR: 210.3, 159.9, 145.3, 129.1, 117.5, 112.2, 110.9, 77.0, 75.4, 62.8, 61.1, 60.9, 54.9, 50.0, 40.2, 26.5, 26.1. IR: 2957, 2883, 1711, 1601, 1490, 1257 cm−1. HRMS (ESI): calcd for C16H22NO3 (M+ + H) 276.1600, found 276.1605.
exo,anti-2-(Hydroxy(3-methoxyphenyl)methyl)-8-methyl-8-azabicyclo[3.2.1]-octan-3-one (exo,anti-3f). Compound exo,anti-3f was prepared according to the general procedure 3 with seeding (reaction time in Table 4) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.190 g, 69%); mp: 111–113 °C, Rf: 0.55 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.60 (br s, 1H), 7.22 (t, J = 2.1 Hz, 2H), 6.88–6.82 (m, 2H), 6.80–6.74 (m, 1H), 5.20 (d, J = 3.2 Hz, 1H), 3.78 (s, 3H), 3.58 (d, J = 6.8 Hz, 1H), 3.50–3.44 (m, 1H), 2.85 (ddd, J = 15.7 Hz, 4.7 Hz, 1.9 Hz, 1H), 2.46 (s, 3H), 2.36–2.21 (m, 3H), 2.19–2.11 (m, 1H), 1.71–1.52 (m, 2H); 13C-NMR: 207.9, 159.5, 143.5, 129.0, 118.0, 112.8, 111.3, 76.5, 67.5, 64.3, 61.8, 55.1, 51.5, 40.6, 26.4, 26.3. IR: 2958, 2884, 1713, 1603, 1467 cm−1; HRMS (ESI): calcd for C16H22NO3 (M+ + H) 276.1600, found 276.1607.
exo,syn-2-(Hydroxy(naphthalen-1-yl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,syn-3g). Compound exo,syn-3g was prepared according to the general procedure 1 (stirred for 14 days) and chromatographed on silica gel (DFC, 0–35% AcOEt–hexane + Et3N) to give a white solid (0.124 g, 42%); mp: 117–121 °C, Rf: 0.70 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.41 (br s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.96–7.86 (m, 2H), 7.83–7.78 (m, 1H), 7.60–7.53 (m, 2H), 7.52–7.47 (m, 1H), 5.79 (d, J = 1.8 Hz, 1H), 3.56–3.48 (m, 1H), 3.22 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 3.10–3.04 (ddd, J = 17.1 Hz, 5.2 Hz, 2.2 Hz, 1H), 2.63 (d, J = 1.50 Hz, 1H), 2.50 (dt, J = 17.0 Hz, 1.70 Hz, 1H), 2.44 (s, 3H), 2.21–2.12 (m, 1H), 2.10–1.97 (m, 1H), 1.72–1.60 (m, 1H), 1.36–1.22 (m, 1H); 13C-NMR: 211.2, 138.7, 133.8, 129.6, 128.9, 127.8, 126.5, 125.6, 125.2, 123.6, 122.6, 73.3, 61.5, 61.2, 60.8, 50.3, 40.6, 26.8, 26.4. IR: 3011, 2955, 1709, 1078 cm−1; HRMS (ESI): calcd for C19H22NO2 (M+ + H) 296.1651, found 296.1645.
exo,anti-2-(Hydroxy(naphthalen-1-yl)methyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (exo,anti-3g). Compound exo,anti-3g was prepared according to the general procedure 4 and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.222 g, 75%); mp: 169–172 °C, Rf: 0.60 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.94–7.82 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.1 Hz, 1H), 7.55–7.44 (m, 3H), 6.02 (d, J = 2.4 Hz, 1H), 3.73 (d, J = 7.1 Hz, 1H), 3.53–3.45 (m, 1H), 2.92 (ddd, J = 15.8 Hz, 4.6 Hz, 1.6 Hz, 1H), 2.67 (s, 1H), 2.49 (s, 1H), 2.37–2.23 (m, 2H), 2.22–2.10 (m, 1H), 1.68–1.50 (m, 2H); 13C-NMR: 207.5, 137.0, 133.6, 129.7, 129.2, 127.7, 125.8, 125.3, 125.0, 123.2, 121.9, 72.9, 67.5, 62.7, 61.6, 51.4, 40.7, 26.4, 26.3. IR: 2957, 1712, 1476, 1076; 318.1477 cm−1; HRMS (ESI): calcd for C19H22NO2 (M+ + H) 296.1651, found 296.1648.
exo,syn-2-(Hydroxy(phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-4a)14. Compound exo,syn-4a was prepared according to the general procedure 1 (stirred for 28 days) and crystallized from Et2O to give a white solid (0.101 g, 39%); mp: 117–118 °C (decomp.); Rf: 0.60 (30% AcOEt–hexane + 10% Et3N); 1H-NMR δ 7.62 (br s, 1H), 7.44–7.22 (m, 5H), 5.08 (d, J = 2.0 Hz, 1H), 3.34–3.28 (m, 1H), 3.17 (dd, J = 17.1 Hz, 7.2 Hz, 1H), 3.05 (d, J = 4.2 Hz, 1H), 2.64 (s, 3H), 2.54 (d, J = 17.1 Hz, 1H), 2.48 (s, 1H), 2.12–2.01 (m, 1H), 1.97–1.88 (m, 1H), 1.55–1.42 (m, 2H), 1.36–1.29 (m, 1H), 1.01–0.91 (m, 1H); 13C-NMR δ 211.6, 143.7, 128.2, 126.8, 125.4, 76.1, 60.0, 53.6, 53.5, 46.9, 39.6, 22.6, 22.3, 16.4.
exo,anti-2-(Hydroxy(phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-4a)10. Compound exo,anti-4a was prepared according to the general procedure 4 and crystallized (Et2O) to give a white solid (0.246 g, 95%); mp: 102–104 °C, Rf: 0.48 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.47–7.25 (m, 5H), 5.25 (d, J = 3.7 Hz, 1H), 3.37 (d, J = 2.0 Hz, 1H), 3.30–3.28 (m, 1H), 2.94 (dd, J = 16.1 Hz, 7.0 Hz, 1H), 2.72 (s, 3H), 2.59–2.56 (m, 1H), 2.42 (d, J = 16.1 Hz, 1H), 2.15–2.04 (m, 2H), 1.60–1.51 (m, 2H), 1.37–1.26 (m, 2H); 13C-NMR: 208.8, 141.5, 127.9, 127.2, 125.4, 77.7, 61.0, 60.5, 54.2, 48.4, 39.8, 22.5, 22.4, 16.5.
exo,syn-2-(Hydroxy(4-nitrophenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-4b)10. Compound exo,syn-4b was prepared according to the general procedure 2 without seeding (stirred for 1 day) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.268 g, 88%); mp: 172–174 °C (decomp.); Rf: 0.65 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.26–8.23 (m, 2H), 7.94 (br s, 1H), 7.64–7.62 (m, 2H), 5.13 (d, J = 1.7 Hz, 1H), 3.37–3.29 (m, 1H), 3.16 (dd, J = 17.2 Hz, 7.2 Hz, 1H), 2.92 (d, J = 4.4 Hz, 1H), 2.65 (s, 3H), 2.58 (d, J = 17.2 Hz, 1H), 2.48 (s, 1H), 2.12–2.02 (app tt, J = 13.7 Hz, 4.3 Hz, 1H), 2.00–1.89 (app tt, J = 14.0 Hz, 4.9 Hz, 1H), 1.65–1.42 (m, 1H) 1.39–1.31 (m, 1H), 1.01–0.96 (m, 1H); 13C-NMR: 210.6, 151.4, 147.2, 126.5, 123.7, 75.9, 59.4, 54.1, 53.7, 46.9, 39.8, 22.7, 22.5, 16.3.
exo,anti-2-(Hydroxy(4-nitrophenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-4b)10. Compound exo,anti-4b was prepared according to the general procedure 4 and crystallized (DCM–hexane) to give a white solid (0.280 g, 92%); mp: 177–182 °C, Rf: 0.53 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 8.18–8.12. (m, 2H), 7.99 (br s, 1H), 7.49–7.42 (m, 2H), 5.33 (d, J = 3.1 Hz, 1H), 3.45 (d, J = 4.2 Hz, 1H), 3.34–3.29 (m, 1H), 2.87 (dd, J = 16.4 Hz, 7.0 Hz, 1H), 2.74 (s, 3H), 2.60–2.57 (m, 1H), 2.42 (d, J = 16.4 Hz, 1H), 2.21–2.05 (m, 2H), 1.63–1.42 (m, 2H), 1.41–1.30 (m, 2H); 13C-NMR: 207.8, 149.1, 147.1, 126.3, 123.3, 77.0, 60.8, 60.1, 54.0, 48.5, 39.8, 22.6, 22.5, 16.4.
exo,anti-2-(4-Fluorophenyl)(hydroxy)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-4c). Compound exo,anti-4c was prepared according to the general procedure 4 and crystallized (DCM–hexane) to give a white solid (0.211 g, 76%); mp: 107–111 °C, Rf: 0.63 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.52 (br s, 1H), 7.26–7.21 (m, 2H), 7.01–6.98 (m, 2H), 5.23 (d, J = 3.4 Hz, 1H), 3.36 (d, J = 6.1 Hz, 1H), 3.30–3.21 (m, 1H), 2.92 (dd, J = 16.2 Hz, 7.0 Hz, 1H), 2.72 (s, 3H), 2.53–2.50 (m, 1H), 2.42 (d, J = 16.2 Hz, 1H), 2.15–2.05 (m, 2H), 1.58–1.53 (m, 2H), 1.34–1.30 (m, 2H); 13C-NMR: 208.7, 161.9 (d, 1JCF = 489 Hz), 137.3 (d, 4JCF = 6 Hz), 127.0 (d, 3JCF = 16 Hz), 114.8 (d, 2JCF = 43 Hz), 77.2, 61.0, 60.6, 54.2, 48.5, 39.8, 22.51, 22.47, 16.5; IR: 2945, 1704, 1510, 1127, 834 cm−1; HRMS (ESI): calcd for C16H21FNO2 (M+ + H) 278.1556, found 278.1563.
exo,anti-2-(4-Chlorophenyl)(hydroxy)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-4d). Compound exo,anti-4d was prepared according to the general procedure 3 with seeding (reaction time in Table 4) and crystallized from mixed solvent (DCM–hexane) to give a white solid (0.232 g, 79%); mp: 117–123 °C, Rf: 0.70 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.60 (br s, 1H), 7.32–7.26 (m, 2H), 7.24–7.16 (m, 2H), 5.22 (d, J = 3.4 Hz, 1H), 3.36 (d, J = 4.1 Hz, 1H), 3.33–3.27 (m, 1H), 2.90 (dd, J = 16.3 Hz, 7.0 Hz, 1H), 2.72 (s, 3H), 2.54–2.49 (m, 1H), 2.42 (d, J = 16.3 Hz, 1H), 2.18–2.04 (m, 2H), 1.60–1.45 (m, 2H), 1.36–1.37 (m, 2H); 13C-NMR: 208.6, 140.2, 132.9, 128.2, 126.9, 77.1, 60.8, 60.7, 54.2, 48.6, 39.9, 22.6, 22.5, 16.6; IR: 2945, 2901, 1701, 1128, 830 cm−1; HRMS (ESI): calcd for C16H21ClNO2 (M+ + H) 294.1261, found 294.1259.
exo,syn-2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]-nonan-3-one (exo,syn-4e). Compound exo,syn-4e was prepared according to the general procedure 1 (stirred for 28 days) and crystallized from mixed solvent (DCM–Et2O) to give a white solid (0.164 g, 50%); mp: 134–136 °C, Rf: 0.70 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.82 (br, 1H), 7.68–7.61 (m, 2H), 7.59–7.54 (m, 2H), 5.11 (s, 1H), 3.32 (br s, 1H), 3.16 (dd, J = 17.1 Hz, 7.2 Hz, 1H), 2.97 (s, 1H), 2.65 (s, 3H), 2.55 (d, J = 17.1 Hz, 1H), 2.48 (s, 1H), 2.13–2.03 (m, 1H), 2.02–1.88 (m, 1H), 1.65–1.44 (m, 2H), 1.40–1.30 (m, 1H), 1.04–0.95 (m, 1H); 13C-NMR: 211.1, 148.0, 129.3 (q, 2JCF = 33 Hz), 125.9, 125.3 (q, 3JCF = 4 Hz), 124.2 (q, 1JCF = 270 Hz), 75.9, 60.0, 53.9, 53.7, 46.9, 39.7, 22.7, 22.5, 16.4; IR: 2943, 1704, 1619, 1471, 1326, 1128, 1067 cm−1; HRMS (ESI): calcd for C17H21F3NO2 (M+ + H) 328.1524, found 328.1531.
exo,anti-2-(Hydroxy(4-(trifluoromethyl)phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]-nonan-3-one (exo,anti-4e). Compound exo,anti-4e was prepared according to the general procedure 4 and crystallized (DCM–heptane) to give a white solid (0.301 g, 92%); mp: 112–113 °C, Rf: 0.67 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.73 (br, 1H), 7.62–7.75 (m, 2H), 7.53–7.47 (m, 2H), 5.31 (d, J = 3.0 Hz, 1H), 3.44–4.40 (m, 1H), 3.48–3.29 (m, 1H), 2.92 (dd, J = 16.3 Hz, 7.0 Hz, 1H), 2.75 (s, 3H), 2.60–2.57 (m, 1H), 2.44 (d, J = 16.3 Hz, 1H), 2.22–2.08 (m, 2H), 1.62–1.49 (m, 2H), 1.41–1.30 (m, 2H); 13C-NMR: 208.3, 145.6, 129.4 (q, 2JCF = 32 Hz), 125.8, 125.0 (q, 3JCF = 4 Hz), 124.3 (q, 1JCF = 270 Hz), 77.4, 60.8, 60.5, 54.2, 48.6, 39.8, 22.6, 22.5, 16.5; IR: 2945, 1705, 1621, 1472, 1326, 1128, 1068 cm−1; HRMS (ESI): calcd for C17H21F3NO2 (M+ + H) 328.1524, found 328.1529.
exo,anti-2-(Hydroxy(3-methoxyphenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (exo,anti-4f). Compound exo,anti-4f was prepared according to the general procedure 4 and crystallized (DCM–hexane) to give a white solid (0.161 g, 87%); mp: 109–112 °C, Rf: 0.61 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.35 (br s, 1H), 7.33–7.27 (m, 1H), 6.89–6.85 (m, 2H), 6.80–6.75 (m, 1H), 5.22 (d, J = 3.8 Hz, 1H), 3.79 (s, 3H), 3.34 (d, J = 4.0 Hz, 1H), 3.30–3.28 (m, 1H), 2.95 (dd, J = 16.1 Hz, 7.0 Hz, 1H), 2.72 (s, 3H), 2.57–2.55 (m, 1H), 2.42 (d, J = 16.2 Hz, 1H), 2.12–2.08 (m, 2H), 1.55–1.51 (m, 2H), 1.34–1.30 (m, 2H); 13C-NMR: 208.8, 159.4, 143.3, 128.9, 117.9, 112.7, 111.1, 77.5, 61.0, 60.4, 55.0, 54.2, 48.4, 39.8, 22.52, 22.47, 16.6; IR: 2944, 2837, 1704, 1468, 1266 cm−1; HRMS (ESI): calcd for C17H24NO3 (M+ + H) 290.1756, found 290.1750.
exo,anti-2-(Hydroxy(naphthalen-1-yl)methyl)-9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (exo,anti-4g)10. Compound exo,anti-4g was prepared according to the general procedure 4 and crystallized (DCM–hexane) to give a white solid (0.161 g, 52%); mp: 125–128 °C; Rf: 0.56 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.90–7.86 (m, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.50–7.47 (m, 3H), 6.05 (d, J = 2.8 Hz, 1H), 3.53–3.50 (m, 1H), 3.40–3.30 (m, 1H), 3.05 (dd, J = 16.2 Hz, 7.0 Hz, 1H), 2.84–2.80 (m, 1H), 2.78 (s, 1H), 2.42 (dt, J = 16.2 Hz, 1.3 Hz, 1H), 2.22–2.05 (m, 2H), 1.60–1.46 (m, 2H), 1.40–1.25 (m, 2H); 13C-NMR: 208.5, 136.9, 133.6, 129.9, 129.2, 127.9, 125.9, 125.3, 125.1, 123.1, 121.9, 74.2, 60.7, 59.6, 54.2, 48.5, 40.0, 22.7, 22.6, 16.6.
exo,syn-8-Benzyl-2-(hydroxy(phenyl)methyl)-8-azabicyclo[3.2.1]octan-3-one (exo,syn-14a). Compound exo,syn-14a was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give the aldol isomer exo,syn-14a (0.096 g, 30%) as a white solid; mp: 85–87 °C, Rf: 0.26 (30% AcOEt–hexane + 10% Et3N); 1H NMR: 7.60 (br s, 1H), 7.44–7.36 (m, 5H), 7.22–7.13 (m, 3H), 7.02–6.98 (m, 2H), 4.96 (d, J = 2.4 Hz, 1H), 3.62–3.60 (m, 1H), 3.57 (s, 2H), 3.45–3.39 (m, 1H), 2.95 (dd, J = 16.9 Hz, 5.0 Hz, 1H), 2.46 (dt, J = 16.9 Hz, 1.8 Hz, 1H), 2.38 (s, 1H), 2.27–2.15 (m, 2H), 1.71 (t, J = 9.5 Hz, 1H), 1.48 (t, J = 9.7 Hz, 1H); 13C-NMR: 211.1, 143.3, 137.4, 129.6, 129.0, 128.2, 127.9, 126.7, 125.4, 76.0, 63.4, 59.3, 58.6, 57.3, 50.6, 26.9; IR: 3019, 2967, 1709, 1452, 1343, 1064 cm−1; HRMS (ESI): calcd for C21H24NO2 (M+ + H) 322.1807, found 322.1812.
exo,syn-8-Benzyl-2-(hydroxy(4-nitrophenyl)methyl)-8-azabicyclo[3.2.1]octan-3-one (exo,syn-14b). Compound exo,syn-14b was prepared according to the general procedure 5 and crystallized (Et2O) to give the aldol isomer exo,syn-14b (0.220 g, 60%) as a brown solid; mp: 130–132 °C, Rf: 0.45 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.97 (d, J = 8.8 Hz, 2H), 7.74 (br s, 1H), 7.50–7.35 (m, 6H), 6.98 (d, J = 8.6 Hz, 2H), 4.96 (d, J = 1.8 Hz, 1H), 3.73–3.62 (m, 2H), 3.43 (d, J = 12.3 Hz, 1H), 3.28 (d, J = 5.4 Hz, 1H), 3.99 (dd, J = 17.0 Hz, 4.9 Hz, 1H), 2.54 (d, J = 17.0 Hz, 1H), 2.32 (d, J = 1.2 Hz, 1H), 2.29–2.18 (m, 2H), 1.75 (t, J = 9.4 Hz, 1H), 1.48 (t, J = 9.4 Hz, 1H); 13C-NMR: 209.9, 150.8, 146.8, 137.1, 130.0, 129.1, 128.2, 126.3, 123.4, 75.6, 65.8, 62.5, 60.4, 57.5, 57.4, 50.5, 27.2, 26.7, 15.2; IR: 3030, 2960, 1714, 1607, 1522, 1347, 1077, 855 cm−1; HRMS (ESI): calcd for C21H23N2O4 (M+ + H) 367.1658, found 367.1653.
exo,syn-8-Benzyl-2-(hydroxy(3-methoxyphenyl)methyl)-8-azabicyclo[3.2.1]octan-3-one (exo,syn-14f). Compound exo,syn-14f was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give aldol as a white solid (0.157 g, 57%); mp: 146–150 °C, Rf: 0.35 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.68 (br s, 1H), 7.49–7.32 (m, 5H), 7.15 (t, J = 7.9 Hz, 1H), 6.83 (s, 1H), 6.78–6.72 (m, 1H), 6.67–3.61 (m, 1H), 4.96 (d, J = 1.8 Hz), 3.79 (s, 3H), 3.65 (d, J = 12.6 Hz, 1H), 3.60–3.50 (m, 1H), 3.50 (d, J = 13.0 Hz, 1H), 3.47–3.42 (m, 1H), 2.90 (dd, J = 16.7 Hz, 5 Hz, 1H), 2.49–2.38 (m, 2H), 2.25–2.13 (m, 2H), 1.75–1.65 (m, 1H), 1.55–1.45 (m, 1H); 13C-NMR: 211.0, 159.6, 145.2, 137.4, 129.3, 128.9, 127.9, 117.7, 112.4, 111.0, 75.9, 63.3, 59.5, 58.5, 57.2, 55.2, 50.5, 27.1, 26.7; IR: 2973, 2887, 1710, 1601, 1521, 1476, 1342 cm−1; HRMS (ESI): calcd for C16H22NO3 (M+ + H) 276.1600, found 276.1609.
exo,syn-8-Benzyl-2-((4-bromophenyl)(hydroxy)methyl)-8-azabicyclo[3.2.1]octan-3-one (exo,syn-14i)27. Compound exo,syn-14i was prepared according to the general procedure 5 and crystallized (Et2O) to give a white solid (0.116 g, 58%); mp: 155–156 °C; Rf: 0.40 (30% AcOEt–Hex); 1H NMR: 7.61 (br s, 1H), 7.49–7.44 (m, 3H), 7.40–7.32 (m, 2H), 7.30–7.26 (m, 2H), 6.80–6.74 (m, 2H), 4.88 (d, J = 2.2 Hz, 1H), 3.70–3.65 (m, 1H), 3.62 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 12.4 Hz, 1H), 3.40–3.35 (m, 1H), 2.96 (dd, J = 17.0 Hz, 5.1 Hz, 1H), 2.48 (dt, J = 17.0 Hz, 1.7 Hz, 1H), 2.21–2.27 (m, 1H), 2.25–2.15 (m, 2H), 1.78–1.67 (m, 1H), 1.53–1.42 (m, 1H); 13C NMR: 210.6, 142.4, 137.3, 131.2, 129.8, 129.1, 128.1, 127.2, 120.5, 75.6, 63.1, 59.9, 58.0, 57.4, 50.5, 27.1, 26.8.
exo,syn-9-Benzyl-2-(hydroxy(4-nitrophenyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-15b). Compound exo,syn-15b was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give aldol isomer exo,syn-15b (0.114 g, 30%) as a white solid; mp: 147–149 °C; Rf: 0.26 (20% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.96 (d, J = 8.7 Hz, 2H), 7.54–7.43 (m, 3H), 7.38–7.32 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.01 (d, J = 1.5 Hz, 1H), 4.01 (d, J = 12.5 Hz, 1H), 3.89 (d, J = 12.5 Hz, 1H), 3.54 (s, 1H), 3.17 (dd, J = 17.2 Hz, 7.1 Hz, 1H), 3.00 (d, J = 3.9 Hz, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.41 (s, 1H), 2.18–2.02 (m, 2H), 1.70–1.48 (m, 2H), 1.45–1.35 (m, 1H), 1.04–0.96(m, 1H); 13C-NMR: 211.0, 150.9, 146.9, 137.0, 130.0, 129.1, 128.2, 136.4, 123.4, 76.2, 59.5, 56.3, 53.7, 49.7, 47.3, 23.5, 22.6, 16.3; IR: 2976, 1702, 1601, 1521, 1346, 1109, 929 cm−1; HRMS (ESI): calcd for C22H25N2O4 (M+ + H) 381.1814, found 381.1820.
exo,syn-9-Benzyl-2-(hydroxy(3-methoxyphenyl)methyl)-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-15f). Compound exo,syn-15f was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give aldol isomer exo,syn-15f (0.252 g, 69%) as a white solid; mp 143–145 °C; Rf: 0.32 (20% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.47–7.35 (m, 5H), 7.17 (br s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.80 (s, 1H), 6.76–6.68 (m, 1H), 6.59 (d, J = 7.9 Hz, 1H), 5.01 (br s, 1H), 3.96 (d, J = 2.8 Hz, 2H), 3.78 (s, 3H), 3.42–3.35 (m, 1H), 3.28–3.22 (m, 1H), 3.08 (dd, J = 17.0 Hz, 7.1 Hz, 1H), 2.56–2.51 (m, 2H), 2.18–2.00 (m, 2H), 1.69–1.50 (m, 2H), 1.40–1.31 (m, 1H), 1.11–1.01(m, 1H); 13C-NMR: 159.6; 145.2; 137.1; 129.4; 129.2; 128.9; 127.9; 117.7; 112.3; 111.0; 76.4; 60.2; 56.2; 55.1; 52.1; 51.1; 47.2; 23.1; 23.0; 16.4; IR: 2976, 1701, 1601, 1521, 1491, 1047, 929 cm−1; HRMS (ESI): calcd for C23H28NO3 (M+ + H) 366.2069, found 366.2061.
exo,syn-2-(Hydroxy(4-nitrophenyl)methyl)-9-isopropyl-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-17b). Compound exo,syn-17b was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give a brown solid (0.123 g, 37%); mp: 137–141 °C, Rf: 0.84 (30% AcOEt–hexane + 10% Et3N); 1H NMR: 8.28–8.19 (m, 2H), 7.78 (br s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 5.08 (br s, 1H), 3.69 (br s, 1H), 3.30 (br s, 1H), 3.25–3.11 (m, 1H), 3.08 (dd, J = 17.2 Hz, 7.0 Hz, 1H), 2.58 (d, J = 17.2 Hz, 1H), 2.52 (s, 1H), 1.97–1.83 (m, 1H), 1.82–1.69 (m, 1H), 1.60–1.41 (m, 2H), 1.39–1.25 (m, 1H), 1.18 (dd, J = 22.9 Hz, 6.2 Hz, 6H), 1.04–0.90 (m, 1H); 13C-NMR: 211.7, 151.5, 147.1, 126.5, 123.5, 75.9, 59.2, 49.5, 48.8, 47.5, 47.2, 23.8, 23.6, 22.1, 21.6, 16.0; IR: 3020, 2940, 1706, 1601, 1522, 1346, 1109, 929 cm−1; HRMS (ESI): calcd for C18H25N2O4 (M+ + H) 333.1814, found 333.1820.
exo,syn-2-((4-Bromophenyl)(hydroxy)methyl)-9-isopropyl-9-azabicyclo[3.3.1]nonan-3-one (exo,syn-17i). Compound exo,syn-17i was prepared according to the general procedure 5 and crystallized (DCM–hexane) to give a brown solid (0.238 g, 65%); mp: 146–148 °C, Rf: 0.59 (30% AcOEt–hexane + 10% Et3N); 1H NMR: 7.55 (br s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.99 (s, 1H), 3.66 (br s, 1H), 3.22–3.12 (m, 1H), 3.06 (dd, J = 17.2 Hz, 7.1 Hz, 1H), 2.55 (d, J = 17.2 Hz, 1H), 2.47 (s, 1H), 1.96–1.85 (m, 1H), 1.81–1.70 (m, 1H), 1.61–1.41 (m, 2H), 1.35–1.27 (m, 1H), 1.16 (dd, J = 17.9 Hz, 6.2 Hz, 6H), 0.99–0.91 (m, 1H); 13C-NMR: 212.4, 142.8, 131.3, 127.4, 120.7, 75.8, 59.6, 49.3, 48.8, 47.4, 47.3, 23.9, 23.7, 22.2, 21.7, 16.1; IR: 3014, 2939, 1704, 1486, 1343, 1072 cm−1; HRMS (ESI): calcd for C18H25BrNO2 (M+ + H) 366.1069, found 366.1065.
2,4-Bis(hydroxy(4-(trifluoromethyl)phenyl)methyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (5e). Compound 5e was obtained as a yellow solid (0.025 g, 10%) by slow crystallization of exo,syn-4e (DCM–hexane, ambient temperature, 0.5 mmol scale); mp: 164–166 °C, Rf: 0.66 (30% AcOEt–hexane + 10% Et3N); 1H-NMR: 7.70 (br s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 5.35 (d, J = 5.4 Hz, 1H), 5.31 (d, J = 3.4 Hz, 1H), 3.43 (d, J = 3.7 Hz, 1H), 3.39 (t, J = 5.6 Hz, 1H), 3.15–3.05 (m, 1H), 2.80 (br s, 1H), 2.70–2.63 (m, 1H), 2.67 (s, 3H), 2.20–2.10 (m, 1H), 1.90–1.78 (m, 2H), 1.62–1.47 (m, 2H), 1.43–1.32 (m, 1H); 13C-NMR: 209.9, 145.4, 145.1, 129.6 (dq, 2JCF = 32 Hz, 4 Hz), 126.4, 125.1 (dq, 3JCF = 18 Hz, 4 Hz), 124.1 (dq, 1JCF = 270 Hz, 4 Hz), 76.6, 69.7, 61.5, 61.3, 61.0, 56.3, 39.6, 22.5, 18.9, 17.0; IR: 2977, 1695, 1621, 1521, 1415, 1326, 1131 cm−1; HRMS (ESI): calcd for C25H26F6NO3 (M+ + H) 502.1817, found 502.1824.
(E)-2-(4-Fluorobenzylidene)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (7c). Compound 7c was obtained as a by-product in a reaction with 1 equiv. of water (in ca. 1 month), according to the general procedure 1 (0.5 mmol scale), and purified by column chromatography on neutral aluminum oxide (0–10% AcOEt–hexane) to give a yellow oil (0.007 g, 5%); Rf: 0.16 (15% AcOEt–hexane, neutral alumina plate); 1H-NMR: 7.55 (s, 1H), 7.38–7.25 (m, 2H), 7.15–7.06 (m, 2H), 4.07 (br s, 1H), 3.33 (br s, 1H), 2.93 (dd, J = 18.3 Hz, 7.5 Hz, 1H), 2.43 (s, 3H), 2.48–2.35 (m, 1H), 2.18–1.96 (m, 2H), 1.89–1.77 (m, 1H), 1.75–1.65 (m, 2H), 1.54–1.40 (m, 1H); 13C-NMR: 200.2, 162.9 (d, 1JCF = 250 Hz), 137.6, 135.4, 131.9 (d, 3JCF = 9 Hz), 131.0 (d, 4JCF = 3 Hz), 115.8 (d, 2JCF = 22 Hz), 57.0, 54.5, 41.8, 39.5, 30.9, 16.5; IR: 2940, 1676, 1601, 1508, 1237, 835 cm−1; HRMS (ESI): calcd for C16H19FNO (M+ + H) 260.1451, found 260.1461.
(2E,4E)-2,4-Bis(4-fluorobenzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-one (8c). Compound 8c was obtained as a by-product in a reaction with 1 equiv. of water (in ca. 1 month), according to the general procedure 1, and crystallized (DCM–hexane) to give a yellow solid (0.035 g, 10%); mp: 141–142 °C, Rf: 0.67 (2% MeOH–DCM); 1H-NMR: 7.79 (br s, 2H), 7.42–7.34 (m, 4H), 7.16–7.08 (m, 4H), 4.39–4.28 (m, 2H), 2.67–2.55 (m, 2H), 2.32 (s, 3H), 2.07–1.95 (m, 2H); 13C-NMR: 187.6, 162.9 (d, 1JCF = 250 Hz), 138.2, 135.3, 132.1 (d, 3JCF = 9 Hz), 131.2 (d, 4JCF = 3 Hz), 115.7 (d, 2JCF = 22 Hz), 60.9, 35.9, 30.2; IR: 2975, 1674, 1602, 1508, 1157 cm−1; HRMS (ESI): calcd for C22H20F2NO (M+ + H) 352.1513, found 352.1509.
(2E,4E)-2,4-Bis(4-fluorobenzylidene)-9-methyl-9-azabicyclo[3.3.1]nonan-3-one (9c). Compound 9c was obtained as a by-product in a reaction with 1 equiv. of water (in ca. 1 month), according to the typical procedure 1, and purified by column chromatography on neutral aluminum oxide (0–10% AcOEt–hexane) to give a yellow solid (0.035 g, 10%); mp: 98–99 °C, Rf: 0.36 (15% AcOEt–hexane, neutral alumina plate); 1H-NMR: 7.84 (br s, 2H), 7.45–7.34 (m, 4H), 7.17–7.07 (m, 4H), 4.13 (br s, 2H), 2.27 (s, 3H), 2.23–2.10 (m, 2H), 2.00–1.91 (m, 2H), 1.83–1.74 (m, 1H), 1.63–1.50 (m, 1H); 13C-NMR: 189.4, 162.9 (d, 1JCF = 250 Hz), 137.3, 136.6, 132.1 (d, 3JCF = 9 Hz), 131.3 (d, 4JCF = 3 Hz), 115.8 (d, 2JCF = 21 Hz), 57.2, 42.4, 31.2, 17.2; IR: 2941, 1666, 1601, 1508, 1238, 837 cm−1; HRMS (ESI): calcd for C23H22F2NO (M+ + H) 366.1669, found 366.1660.

Acknowledgements

The work was supported by the University of Bialystok (BST-125 and BMN-172).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra of compounds prepared as described above. See DOI: 10.1039/c4ra02834a
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