Chemoselective Strategy for the Direct Formation of Tetrahydro-2,5

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Chemoselective Strategy for the Direct Formation to Tetrahydro-2,5-methanobenzo[c]azepines or AzetoTetrahydroisoquinolines via Regio- and Stereoselective Reactions. Ervin Kovács, Balázs Huszka, Tamás Gáti, Miklós Nyerges, Ferenc Faigl, and Zoltán Mucsi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00798 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

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The Journal of Organic Chemistry

Chemoselective Strategy for the Direct Formation to Tetrahydro-2,5-methanobenzo[c]azepines or AzetoTetrahydroisoquinolines via Regio- and Stereoselective Reactions. Ervin Kovács,†,‡,* Balázs Huszka,† Tamás Gáti,§ Miklós Nyerges,§ Ferenc Faigl† and Zoltán Mucsi∥ †

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, H-1111 Hungary ‡ Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, H-1117 Hungary §

Servier Research Institute of Medicinal Chemistry, Budapest, H-1031 Hungary Ltd., Budapest, H-1094 Hungary

∥Femtonics

Supporting Information Placeholder

ABSTRACT: The present study reports regio- and highly diastereoselective preparative methods for the synthesis of versatile alkaloid type compounds from oxiranylmethyl tetrahydroisoquinolines. 2,5-Methanobenzo[c]azepines or azetidine fused heterocycles were synthetized in tandem reactions depending on the absence or presence of BF3 co-reagent. A high functional group tolerance has also been demonstrated. DFT calculations with explicit solvent model confirmed the proposed reaction mechanisms and the role of kinetic controls on the stereochemical outcome of the reported new methods.

INTRODUCTION The pyrrolidine- and azetidine-fused 1,2,3,4-tetrahydroisoquinolines are among the most frequently used heterocycles in medicinal chemistry due to the wide range of physiological activity displayed in their drug representatives. Some condensed 1,2,3,4-tetrahydroisoquinolines have antitumor properties,1–3 tetrahydroazeto[2,1-a]isoquinolines (1, Scheme 1) can manipulate hypotensive and anti-aggregant activity,4 others exhibit analgesic5–7 and anti-inflammatory4 action or play a role as the key intermediates of alkaloids.8,9 Pyrrolidine fused tetrahydroisoquinolines are abundant in nature, and occur in many Amaryllidaceae alkaloids10–15 (2a,b; in Scheme 1). Diversely substituted and fused azetidines have grown in popularity as building blocks throughout medicinal chemistry16–21 as has the use of methylene bridges within N-heterocycles are also useful tools to reduce the lipophilicity of drug-like compounds.22 Scheme 1. Skeleton of tetrahydroazeto[2,1-a]isoquinoline (1) and 2,5-methano-tetrahydro-2H-2benzazepine (2a and 2b).

Only a few approaches for the synthesis of these azetidine23and pyrrolidine-fused tetrahydroisoquinolines have been developed.4,6,8,24,25 Azeto[2,1-a]isoquinolines 1 have been prepared by multitude of routes; 1) via the related isoquinolines by intramolecular ring closure, 2) hydride reduction of the blactam into azetidine7; 3) using [2 + 2]-cycloaddition.26 The construction of the 2,5-methano-tetrahydro-2H-2benzazepine skeleton (2) has been achieved through only three main strategies27; Pictet–Spengler reaction11,28–31 or a ring closure of the pyrrolidine derivative,10,32 an intramolecular [3+2]-cycloaddition,13,14 and via intramolecular N-alkylation.12 Other special examples have also been reported like lactamization.33 The position of hydrogen/metal exchange during regioselective metalation of tetrahydroisoquinolines has been shown to depend on the N-substituent and the additives used in the reaction. Clean metalation of N-alkyl-tetrahydroisoquinolines could be accomplished in the C4 position with butyllithium.34– 41 Almena has reported a fast b-elimination from the C4 lithiACS Paragon Plus Environment

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ated N-methyl-tetrahydroisoquinoline during metalation and subsequent addition of an electrophilic reagent.42 This side reaction may be responsible for the lower yields of such metalation electrophile addition reaction sequences. For the selective C1 lithiation of N-methyl-1,2,3,4-tetrahydroisoquinoline, two strategies can be identified; the complexation of the isoquinoline nitrogen with BF336,43,44 or borane,45 or the introduction of an acyl group to isoquinoline nitrogen45–47 before metalation. Although, several N-oxiranyl-methyl substituted tetrahydroisoquinolines have been reported48,49 the organometallic synthesis of the skeleton of 1 and 2 from N-oxiranylmethyl1,2,3,4-tetrahydroisoquinolines is hitherto unknown. Herein we report new, stereoselective reactions to azetidine (1) and pyrrolidine (2) fused heterocycles from oxiranylmethyl group-substituted tetrahydroisoquinoline derivatives, along with the results of quantum chemical calculations, for the confirmation of the proposed reaction mechanism.

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In order to prepare the target compounds of type 1 and 2, the key intermediates 3 and 4 were synthesized from tetrahydroisoquinolines and 3-substituted-(oxiran-2-yl)methyl 4toluene-sulfonate (5 or 6) derivatives (Table 1).50

the 1,2,3,4-tetrahydroisoquinolines as the more reactive site in metalation reactions rather than the C1. The organometallic intermediates formed can be stabilized via an intramolecular nucleophilic reaction at the C1’ position of the oxiranyl moiety within the substrate. Parallel oxirane ring-opening and pyrrolidine ring closure procedures provide 7a-i and 8a,b. The dehalogenated starting material (3a) could only be isolated from the reaction mixtures of the chlorinated starting materials (3k-m), which could be accessed via chlorine/metal exchange followed by hydrolysis. Experimental data and quantum chemical calculations confirmed the high diastereoselectivity of the novel intramolecular reactions described above. To test the reaction feasibility, we examined the metalation of 3a by different types of organometallic base used in analogue cases.53 In the case of using 3 equivalent of LDA (lithium diisoproply amide) or LiTMP (lithium 2,2,6,6-tetramethyl pyperidide) or KHMDS (potassium hexamethyldisilazide), only unreacted 3a oxirane was isolated. The reaction was accomplished by BuLi or LiC-KOR (mixture of buthyl lithium and potassium tert-butoxyde), or the mixture of KHMDS and KOtBu, a complex mixture of products and decomposed compounds was obtained.

Table 1. Isolated yields of the synthesis of oxiranylmethyl1,2,3,4-tetrahydroisoquinoline derivatives (3a-m and 4a,b).

Table 2. Isolated yields of the synthesis of 7a-i; 8a,b and 9a-j, 10a,b tricycles

RESULTS AND DISCUSSION

Entry Reactant R 1 5 H 2 5 6-OMe 3 5 6-OMe 4 5 5-F 5 5 6- Bu 6 5 7- Bu 7 5 5-Me 8 5 6-Me 9 5 7-Me 10 5 7-CF 11 5 5-Cl 12 5 6-Cl 13 5 7-Cl 14 6 H 15 6 6-OMe 3

t t

3

R H 7-OMe H H H H H H H H H H H H 7-OMe 4

Yield 98% 88% 74% 81% 94% 95% 91% 89% 88% 66% 91% 98% 87% 89% 77%

Product 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 4a 4b

The obtained key intermediates 3a-m and 4a,b were treated with an excess of LiDA-KOR superbase (mixture of lithium diisopropylamide and potassium tert-butoxyde) in tetrahydrofuran at -78 °C. These conditions had been previously optimized using N-methyl oxiranes for similar reactions.51,52 On the basis of spectroscopic evidence, it was clear that the transfive membered ring, containing fused tricyclic compounds (7a-i and 8a,b), were formed regio- and diastereoselectively (Table 2, Route A) rather than azetidines as reported earlier.50 Noteworthy, the oxirane reacted only on at the C1’ position (Scheme 2), excluding the formation of some other possible tricyclic products. This observation is in accordance with the literature data,34,36,38–41 pointing to the C4 benzylic position of

Entry Reactant R R 1 3a H H 2 3b 6-OMe 7-OMe 3 3c 6-OMe H 4 3d 5-F H 5 3e 6- Bu H 6 3f 7- Bu H 7 3g 5-Me H 8 3h 6-Me H 9 3i 7-Me H 10 3j 7-CF H 11 4a H H 12 4b 6-OMe 7-OMe *product was not isolated 3

4

t

t

3

ROUTE A Yield Product 66% 7a 71% 7b 56% 7c 76% 7d 76% 7e 83% 7f 70% 7g 73% 7h 58% 7i -* -* 36% 8a 30% 8b

ROUTE B Yield Product 45% 9a 46% 9b 40% 9c 44% 9d 32% 9e 36% 9f 28% 9g 33% 9h 30% 9i 47% 9j 25% 10a 30% 10b

However, addition of boron trifluoride to the starting materials before metalation resulted in a new intramolecular reaction which has been absent from literature until now. Metalation of 3a-j and 4a,b boron trifluoride complexes followed by the intramolecular nucleophilic reaction with the oxirane moiety could produce azetidine or pyrrolidine-fused tricyclic products. These new reactions were accomplished with lithium 2,2,6,6-tetramethylpiperidide (LiTMP) providing the corre-

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sponding 1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinoline derivatives exclusively (Table 2, Route B). In most of the cases, typically the cis isomer was formed as the major product, but for 3d–i the trans isomers were also isolated as minor products (ca. 30% of the overall product). The compounds 9a-j were isolated with medium yields, while the trityloxymethyl group-containing products (10a,b) could be prepared after flash chromatography in lower yields. In addition, triphenylmethanol (20-40%) was also isolated in the case of products 8a,b and 10a,b.



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Scheme 2. Possible deprotonations of 3a and 3a.BF3 and the schematic representation of the formation of all the theoretically possible products from the two deprotonated forms of 3a (13A and 13B(BF3)).

Intramolecular ring opening of the BF3 complex 3a was attempted using the superbase LiDA-KOR, however, instead of the desired tricyclic product (9a), a new ring-opened compound (11a) was formed. We suppose the formation of the corresponding azetotetrahydroisoquinoline derivative as a first intermediate (9a.BF3 in Scheme 3), however the excess of the superbase may cause further metalation followed by epimerization and transmetalation resulting in the tetrahydroisoquinoline moiety being deprotonated at the C4 benzylic position (12a.BF3-H+), from which the styrene derivative (11a.BF3) can be formed by the subsequent spontaneous ring opening belimination.53 Scheme 3. Theoretised mechanism of formation of cisazetidine (9a.BF3-H+) and styrene derivative (11a.BF3-H+) from trans-azetidine (M: metalation; EP: epimerization; TM: transmetalation; bE: b-elimination).

Structure of the new tricyclic compounds were determined by NMR measurements. Positive DEPT in C4 signified pyrrolidine (one hydrogen in C4 position), however, negative DEPT was the evidence of the azetidine (two hydrogens in C4). Firstly, the chemical shift of H in C5 was determined. HMBC was used to confirm the link between the carbon at C4 and hydrogen at C5. The stereoisomerism was determined by NOE of H in C4 (in the case of pyrrolidines) or in C2 (for azetidines). Our results are in accordance with methods published earlier for tetrahydro-2H-azeto[2,1-a]isoquinolines.6,54–56 During the reaction mechanism studies, we focused solely on the ring closure steps from the metalation that lead to the products. Metalation of 3a could occur at two positions (C1 and C4), resulting in two anions (13A, 13B(BF3)). In addition, all the theoretically possible products which could be formed

from anion 13A or 13B(BF3) in routes A1, A2, B1 or B2 are depicted in Scheme 2. The starting metalation positions were selected according to the reaction conditions (without 34,36,38–41 or with BF336,43,44), disputed in the literature extensively. The computations were carried out at B3LYP/6-31G(d,p) level of theory57,58, considering implicit solvation, including explicit Li, K ions and two THF solvent molecules.59,60 Calculated enthalpy and Gibbs free energy changes of these products are given in the Supplementary Information. Without BF3, the deprotonation occurs at position of C434,36,38–41 (13A in Scheme 2), consequently, the two possible attacks either the closer (C1’) or the further electrophilic carbon atom (C2’) of the oxirane ring, leading to the two-two cis/trans isomer pairs of products 7a (route A1) and 14 (route A2 in Scheme 4). The comparison of the four transition states (TS) parameters showed the exclusive preference of the formation of the bridged trans products (trans-7a via A1), which is in a very good agreement with the experimental findings. However, the two possible alternative pathways for the BF3 complex 13B(BF3) (Scheme 4), also lead to two-two cis/trans isomer pairs of products 9 (route B1) and 15 (route B2). Standard quantum mechanical methods, excluding dynamic solvent environments, are not accurate enough to provide reliable pKA values for the deprotonation processes. However, the difference in pKA, the DpKA value is computable with correct precision and proved to be 1.59 for 13AÛ13B and 4.5 for 13A(BF3)Û13B(BF3). Comparison of the TS values and the energy levels of those products led us to conclude that the formation of the azetidine ring containing products (9a) are kinetically favoured. Although, between the two deprotonated products, the cis isomer (cis-9a.BF3–H+) is thermodynamically more stable than the trans (trans-9a.BF3–H+). The formation of the trans isomer is kinetically preferred due to its more favourable TS enthalpy (Scheme 4).


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Scheme 4. The mechanism of formation of possible products with or without BF3. Enthalpy (DH, kJ.mol–1) changes computed for TSs and deprotonated products from anion 13A or 13B(BF3) are given in tables. In the case of route A, one explicit Li+ and one K+ ion solvated by two THF molecules; for route B, two explicit Li+ ions, solvated by two THF molecules are implemented. All the data was calculated at B3LYP/6-31G(d,p). The structures are illustrated in the Sl.

Scheme 5. Supposed mechanism of formation of cisazetidine (cis-9a) derivative from trans-azetidine (trans-9a) together with the corresponding enthalpy (DH) changes computed, two explicit Li+ ion solvated by two THF molecules are implemented. All the data was calculated at B3LYP/6-31G(d,p).

without BF3 A1 TS cis-7–H+ A1 TS trans-7–H+ A2 TS cis-14–H+ A2 TS trans-14–H+

DH 37.5 -96.2 29.2 -118.6 48.3 -120.2 61.4 -105.5

With BF3 B1 TS cis-9a(BF3)–H+ B1 TS trans-9a(BF3)–H+ B2 TS cis-15(BF3)–H+ B2 TS trans-15(BF3)–H+

DH 60.3 -78.8 49.1 -45.0 72.3 -97.9 89.9 -106.3

Experimentally, typically cis-9a could be prepared as the product, consequently the question arises whether kinetically preferred trans-9a.BF3 could be transformed into the thermodynamically more stable cis-9a.BF3 under the reaction conditions applied. Lithiation of the borane complexes of 2phenylazetidines at the same position resulted similar epimerization.61 The excess base could deprotonate the product trans9a.BF3 and the formed double anion (trans-9a.BF3–H+) could be stabilized as cis-9a.BF3–H+ (depicted in Scheme 3). This mechanism was confirmed by DFT calculations (Scheme 5). The low activation gap between the deprotonated trans9a.BF3–H+ toward the thermodynamically more stable product cis-9a.BF3–H+, allows this process. Formation of the frequently observed styrene-type sideproduct (11a, Scheme 3) can be rationalized by an alternative deprotonation (transmetalation) of cis-9a.BF3–H+ at position C4 (cis-12a.BF3–H+), leading to cis-11a.BF3-H+. The activation enthalpy of this reaction, however, is considerably higher than the TS leading to the cis-9a product (See SI, Figure S216).

CONCLUSIONS In summary, a novel, highly stereo- and diastereoselective method has been developed for preparation of pyrrolidine and azetidine fused 1,2,3,4-tetrahydroisoquinolines (7a-i, 8a,b; 9aj and 10a,b), by using strong alkali amide-type bases. Results of quantum chemical investigations of the mechanism are in accordance with the experimental findings and shed light on the details of the novel intramolecular reactions. Deprotonation of the C4 position takes place in the presence of LiDAKOR superbase and the formed anions are more stable than



their C1 counterparts, providing a kinetically controlled, stereoselective intramolecular nucleophilic reaction at the closer carbon atom of the oxirane moiety to release transpyrrolidino-tetrahydroiso-quinolines (7a-i, 8a,b). When BF3 complexes of N-oxiranylmethyl-tetrahydroisoquinolines are treated with LiTMP, the C1 benzylic position is deprotonated easily and the intramolecular nucleophilic reaction takes place again at the C1’ position under kinetic control providing cisazetotetrahydro-isoquinoline derivatives (9a-j and 10a,b). The latter compounds can be formed via a second metalation– epimerisation process starting from the previously formed trans-isomers. The new synthetic methods developed can be widely used in the preparation of novel pharmaceutically interesting pyrrolidines and azetidine fused 1,2,3,4tetrahydroisoquinolines.

EXPERIMENTAL General remarks All commercial starting materials were purchased from Sigma-Aldrich Kft. Hungary and Merck Kft. Hungary and were used without further purification. All organometallic reactions were conducted under nitrogen atmosphere using Schlenk-technique under dry nitrogen atmosphere. Solvents were freshly distilled and dried over molecular sieves. Diisopropylamine and 2,2,6,6-tetramethylpiperidine were purified by distillation, stored on molecular sieve (4Å) under an inert atmosphere of nitrogen. Flash column chromatography was performed by a CombiFlash Rf 150 (Teledyne ISCO) apparatus using gradient elution in normal (silica column; hexane−ethyl acetate as eluent) phase mode. Gradient elution preparative HPLC was applied (HPLC Gilson 333 instrument, UV detector 220 nm) on a Phenomenex Gemini C18, 250×50.00 mm; 10 µm, 110A column using 0.4 g NH4HCO3 in 1 L water and acetonitrile (A/B) or 10 ml trifluoroacetic acid in 1 L water and acetonitrile (C/B) as the two solvents. TLC was performed on Merck Kieselgel 60 W F254 plates or Merck Aluminium oxide 60 F254 plates and spots were visualised by UV light or by exposing it with iodine or the aqueous solution of (NH4)6Mo7O24, Ce(SO4)2 and sulfuric acid. NMR spectra were obtained on a Bruker Avance III spectrometer operating at an equivalent 1H frequency of 500 MHz. Routine 1H, 13C, DEPT-135 NMR, COSY 45, HMBC, and NOESY spectra were acquired using CDCl3 or DMSO-d6 as solvent at room temperature. Notation for the 1H NMR spectral splitting patterns includes: singlet (s), doublet (d), triplet (t), broad (br) and multiplet/overlapping peaks (m). Signals are given as δ values in ppm, coupling constants (J) are expressed in Hertz. HRMS-EI+ data were obtained using either electronspray ionization (ESI) or electron impact (EI) techniques. High-resolution ESI analyses were performed on an Agilent 6230 TOF LC/MS spectrometer (ion trap; analyzed using Excalibur). High resolution EI was obtained on an Autospec (magnetic sector; analyzed using MassLynx). Synthesis of starting materials Among the starting materials of the syntheses of 3 and 4 the tetrahydroisoquinoline derviatives are commercially available, the tosylates 5 and 6 were prepared according to a literature procedure 50. General Experimental Methods A: General procedure for the preparation of trialkylamines (3 and 4) from tosylates.

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Tosylate (5 or 6, 2.0 mmol) was dissolved in pure and dry N,N-dimethylformamide (5 mL) and potassium iodide (1.0 mmol) was added into it and cooled to 0 °C. To this solution tetrahydroisoquinoline derivative (5a-n, 4.2 mmol) was added. The reaction mixture was heated at 40 °C and stirred for 24 hours then it was poured into a mixture of ice (20 g), saturated sodium hydrogencarbonate solution (40 mL) and diethyl ether (15 mL) than the phases were separated and the aqueous mixture was extracted with diethyl ether (4×15 mL). The ethereal solution was washed with brine (15 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluent: hexane and ethyl acetate from 0% to 50% using gradient elution). The pure product (3 or 4) was obtained as a yellowish oil. Yields are given in Table 1. B: General procedure for the preparation of pyrrolo tetrahydroisoquinolines via superbase induced reaction Tetrahydrofuran solution of potassium tert-butoxide (1M, 1.0 mmol, 1.0 mL) was cooled to -78 °C under nitrogen. To this solution diisopropylamine (1.0 mmol, 0.15 g) followed by a 1.59 M hexane solution of butyllithium (1.5 mmol, 0.94 mL) were added dropwise. The reaction mixture was stirred for 20 minutes at -78 °C. To this solution oxirane (3 or 4, 0.5 mmol) in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at the same temperature for 2 hours. Water (3.0 mL) and diethyl ether (5 mL) were added to the cold mixture then it was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was extracted with diethyl ether (3×5 mL). The collected organic solutions were washed with brine (1×5 mL), dired over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluent: dichloromethane and methanol from 0% to 50% using gradient elution). The pure product (7a-j or 8a,b) was obtained as a white solid. Yields are given in Table 2. C: General procedure for the preparation of azeto tetrahydroisoquinolines by LiTMP Tetrahydroisoquinoline derivative (3 or 4, 0.5 mmol) was dissolved in pure and dry tetrahydrofuran (2 mL) and cooled to 0°C. To this solution BF3•Et20 (0.076 mL, 0.6 mmol) was added dropwise under nitrogen and the solution was stirred for additional 20 minutes at 0 °C. 2,2,6,6-Tetramethylpyperidine (1.0 mmol, 0.17 mL) was dissolved in pure and dry tetrahydrofuran (2 mL) and cooled to -78 °C under nitrogen. To this solution butyllithium (1.59 M hexane solution, 1.0 mmol, 0.63 mL) was added dropwise. The reaction mixture was stirred for 20 minutes at -78 °C then the solution of tetrahydroisoquinoline derivative was added. The reaction mixture was stirred at the same temperature for 3 hours. Water (3.0 mL) and diethyl ether (5 mL) was added to the cold mixture then it was allowed to warm to room temperature. The phases were separated and the aqueous phase was extracted with diethyl ether (5×5 mL). The collected organic solution was washed with brine (1×10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to obtain pure products 9a-k, 10a,b and 11a,b. 2-(trans-(3-Propyloxiran-2-yl)methyl)-1,2,3,4tetrahydro-isoquinoline (3a): Prepared from 5 (1.00 g, 3.52 mmol), 1,2,3,4-tetrahydroisoquinoline (0.938 mL, 7.38 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 797 mg; 98% (yellowish oil).


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1 H NMR (CDCl3, 300 MHz) δH: 7.09-7.03 (3H, m aromatic H), 6.99-6.96 (1H, m aromatic H), 3.74 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 3.63 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 2.93-2.40 (7H, m, N-CH2CH2Ar, 2×oxirane H, oxiraneCHaHbN), 2.43 (1H, AB dd, J= 13.2 Hz, 6.6 Hz, oxiraneCHaHbN), 1.55-1.42 (4H, m, CH2CH2), 0.93 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 134.4, 133.9, 128.6, 126.5, 126.1, 125.5, 60.2, 56.7, 56.3, 56.3, 51.2, 33.8, 28.9, 19.3, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21NO 232.1696; Found 232.1686. 6,7-Dimethoxy-2-(trans-(3-propyloxiran-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline (3b): Prepared from 5 (1.00 g, 3.52 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (2.88 g, 7.38 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 1:1). Yield = 899 mg; 88% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.60 (1H, s aromatic H), 6.53 (1H, s aromatic H), 3.84 (3H, s, OCH3), 3.83 (3H, s, OCH3) 3.73 (1H, AB d, J= 14.4 Hz, ArCHaHbN), 3.59 (1H, AB d, J= 14.4 Hz, ArCHaHbN), 2.99-2.72 (7H, m, NCH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.46 (1H, AB dd, J= 12.6 Hz, 6.3 Hz, oxirane-CHaHbN), 1.65-1.42 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC:147.6, 147.3, 126.3, 125.9, 111.4, 109.5, 60.3, 57.0, 56.5, 56.0, 55.9, 51.4, 33.9, 28.5, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H25NO3 292.1907; Found 292.1915. 6-Methoxy-2-(trans-(3-propyloxiran-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline (3c): Prepared from 5 (645 mg, 2.4 mmol), 6-methoxy-1,2,3,4-tetrahydroisoquinoline (810 mg, 5.0 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 1:1). Yield = 432 mg; 74% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.95 (1H, d, J= 6.3 Hz aromatic H), 6.69 (1H, d, J= 6.3 Hz aromatic H), 6.64 (1H, s, aromatic H), 3.77 (3H, s, OCH3), 3.71 (1H, AB d, J= 14.4 Hz, ArHaHbN), 3.61 (1H, AB d, J= 14.4 Hz, ArCHaHbN), 2.952.72 (7H, m, N-CH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.48 (1H, AB dd, J= 12.9 Hz, 6.3 Hz, oxirane-CHaHbN), 1.611.44 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.2 Hz, CH2CH3). 13 C{1H} NMR (CDCl3, 75 MHz), δC: 158.0, 135.2, 127.5, 126.7, 113.3, 112,1, 60.3, 56.9, 56.6, 55.9, 55.3, 51.3, 33.9, 29.3, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23NO2 262.1802; Found 262.1792. 5-Fluoro-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3d): Prepared from 5 (500 mg, 1.85 mmol), 5-fluoro-1,2,3,4-tetrahydroisoquinoline (588 mg, 3.89 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 374 mg; 81% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.09 (1H, m, aromatic H), 6.88-6.81 (2H, m, aromatic H), 3.79 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 3.65 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 2.982.74 (7H, m, N-CH2CH2Ar, 2×oxirane -H, oxirane-CHaHbN), 2.47 (1H, AB dd, J= 15.0 Hz, 3.3 Hz, oxirane-CHaHbN), 1.611.43 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.2 Hz CH2CH3). 13 C{1H} NMR (CDCl3, 75 MHz), δC: 160.9 (d, J= 243 Hz), 137.1 (d, J= 5.3 Hz), 126.7 (d, J= 9.0 Hz), 122.0 (d, J= 3.0 Hz) 121. 8, (d, J= 18 Hz), 112.4, (d, J= 21.0 Hz), 60.2, 56.7 (d, J= 25.5 Hz), 55.9 (d, J= 2.3 Hz), 50.6, 33.8, 22.5, (d, J= 3.8 Hz), 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H20NOF 250.1602; Found 250.1605.

6-tert-Butyl-2-(trans-(3-propyloxiran-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline (3e): Prepared from 5 (680 mg, 2.52 mmol), 6-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline (1.00 g, 5.92 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 681 mg; 94% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.15 (1H, d, J= 8.1 Hz aromatic H), 7.11 (1H, s, aromatic H), 6.97 (1H, d, J= 8.1 Hz aromatic H), 3.75 (1H, AB d, J= 14.7 Hz, ArHaHbN), 3.41 (1H, AB d, J= 14.7 Hz, ArCHaHbN), 2.95-2.76 (7H, m, NCH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.49 (1H, AB dd, J= 12.9 Hz, 6.3 Hz, oxirane-CHaHbN), 1.55-1.47 (4H, m, CH2CH2CH3), 1.29 (9H, s, C(CH3)3), 0.97 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 149.1, 133.4, 131.6, 126.2, 125.4, 122. 8, 60.3, 57.0, 56.6, 56.1, 51.5, 34.3, 33.9, 31.4, 29.2, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H30NO 288.2322; Found 288.2328. 7-tert-Butyl-2-(trans-(3-propyloxiran-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline (3f): Prepared from 5 (680 mg, 2.52 mmol), 7-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline (1.00 g, 5.29 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 689 mg; 95% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.17 (1H, d, J= 8.1 Hz aromatic H), 7.05-7.02 (2H, m, aromatic H), 3.80 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 3.65 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 2.98-2.75 (7H, m, N-CH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.48 (1H, AB dd, J= 12.9 Hz, 6.3 Hz, oxirane-CHaHbN), 1.59-1.47 (4H, m, CH2CH2CH3), 1.29 (9H, s, C(CH3)3), 0.98 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 148.5, 134.0, 131.0, 128.3, 123.4, 123.3, 60.4, 57.0, 56.7, 56.5, 51.6, 34.3, 33.9, 31.4, 28.5, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H30NO 288.2322; Found 288.2325. 5-Methyl-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3g): Prepared from 5 (710 mg, 2.63 mmol), 5-methyl-1,2,3,4-tetrahydroisoquinoline (810 mg, 5.51 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 587 mg; 91% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.06-6.98 (2H, m, aromatic H), 6.88 (1H, d, J= 6.9 Hz, aromatic H), 3.77 (1H, AB d, J= 14.7 Hz, ArHaHbN), 3.66 (1H, AB d, J= 14.7 Hz, ArCHaHbN), 2.99-2.74 (7H, m, N-CH2CH2Ar, 2×oxirane H, oxirane-CHaHbN), 2.52-2.45 (1H, m, oxirane-CHaHbN), 2.21 (3H, s, Ar-CH3), 1.60-1.46 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.1 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 136.3, 134.4, 132.5, 127.6, 125.5, 124.3, 60.3, 56.9, 56.9, 56.6, 51.6, 33.9, 26.9, 19.3, 19.1, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23NO 246.1853; Found 246.1841. 6-Methyl-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3h): Prepared from 5 (658 mg, 2.44 mmol), 6-methyl-1,2,3,4-tetrahydroisoquinoline (754 mg, 5.12 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 532 mg; 89% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.92 (3H, bs, aromatic H), 3.74 (1H, AB d, J= 14.7 Hz, ArHaHbN), 3.64 (1H, AB d, J= 14.7 Hz, ArCHaHbN), 2.96-2.74 (7H, m, N-CH2CH2Ar, 2×oxirane H, oxirane-CHaHbN), 2.52-2.46 (1H, m, oxiraneCHaHbN), 2.28 (3H, s, Ar-CH3), 1.60-1.46 (4H, m,



CH2CH2CH3), 0.97 (3H, t, J= 7.1 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 135.6, 133.8, 131.5, 129.2, 126.5, 126.5, 60.3, 56.9, 56.6, 56.2, 51.4, 33.9, 28.9, 21.0, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23NO 246.1853; Found 246.1852. 7-Methyl-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3i): Prepared from 5 (775 mg, 2.88 mmol), 7-methyl-1,2,3,4-tetrahydroisoquinoline (888 mg, 6.05 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 620 mg; 88% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.00-6.92 (2H, m, aromatic H), 6.84 (1H, s, aromatic H), 3.73 (1H, AB d, J= 14.7 Hz, ArHaHbN), 3.64 (1H, AB d, J= 14.7 Hz, ArCHaHbN), 2.98-2.73 (7H, m, N-CH2CH2Ar, 2×oxirane H, oxiraneCHaHbN), 2.53-2.45 (1H, m, oxirane-CHaHbN), 2.28 (3H, s, Ar-CH3), 1.60-1.47 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.1 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 135.1, 134.3, 130.9, 128.5, 127.1, 127.1, 60.3, 56.9, 56.6, 56.4, 51.5, 33.9, 28.6, 21.0, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23NO 246.1853; Found 246.1846. 7-Trifluoromethyl-2-(trans-(3-propyloxiran-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline (3j): Prepared from 5 (640 mg, 2.37 mmol), 7-(trifluoromethyl)-1,2,3,4tetrahydro-isoquinoline (1.00 g, 4.98 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 567 mg; 66% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.37 (1H, d, J= 7.8 Hz aromatic H), 7.29 (1H, s, aromatic H), 7.20 (1H, d, J= 7.8 Hz aromatic H), 3.81 (1H, AB d, J= 15.0 Hz, ArHaHbN), 3.70 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 2.97-2.76 (7H, m, NCH2CH2Ar, 2×oxirane H, oxirane-CHaHbN), 2.52-2.44 (1H, m, oxirane-CHaHbN), 1.61-1.44 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 138.3, 135.3, 129.1, 128.1 (q, J= 32.1 Hz), 124.3 (d, J= 270 Hz), 123.5 (q, J= 3.8 Hz), 122.9 (q, J= 3.6 Hz), 60.1, 56.8, 56.5, 56.1, 50.9, 33.8, 29.0, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H21F3NO 300.1584; Found 300.1568. 5-Chloro-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3k): Prepared from 5 (500 mg, 1.85 mmol), 5-chloro-1,2,3,4-tetrahydroisoquinoline (651 mg, 3.89 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 445 mg; 91% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.20 (1H, d, J= 7.8 Hz aromatic H), 7.07 (1H, t, J= 7.8 Hz aromatic H), 6.94 (1H, d, J= 7.5 Hz aromatic H), 3.79 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 3.64 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 2.97-2.75 (7H, m, N-CH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.47 (1H, AB dd, J= 12.6 Hz, 6.6 Hz, oxirane-CHaHbN), 1.58-1.45 (4H, m, CH2CH2CH3), 0.95 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 136.8, 134.3, 132.3, 126.9, 126.6, 125.0, 60.1, 56.8, 56.5, 56.3, 51.1, 33.8, 27.3, 19.3, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H2lNO 266.1306; Found 266.1306. 6-Chloro-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3l): Prepared from 5 (500 mg, 1.85 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline (651 mg, 3.89 mmol) using General Procedure A. Purification: Flash chro-

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matography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 481 mg; 98% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.10-7.07 (2H, m aromatic H), 6.95 (1H, d J= 8.7 Hz aromatic H), 3.74 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 3.62 (1H, AB d, J= 15.0 Hz, ArCHaHbN), 2.96-2.43 (7H, m, N-CH2CH2Ar, 2×oxirane-H, oxirane-CHaHbN), 2.46 (1H, AB dd, J= 12.6 Hz, 6.3 Hz, oxirane-CHaHbN), 1.58-1.44 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 135.9, 133.0, 131.7, 128.4, 127.9, 125.9, 60.2, 56.8, 56.5, 55.8, 50.9, 33.8, 28.9, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21ClNO 266.1306; Found 266.1301. 7-Chloro-2-(trans-(3-propyloxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (3m): Prepared from 5 (500 mg, 1.85 mmol), 7-chloro-1,2,3,4-tetrahydroisoquinoline (651 mg, 3.89 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 2:1). Yield = 428 mg; 87% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.26-7.11 (1H, m aromatic H), 7.03-7.02 (2H, m, aromatic H), 3.73 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 3.62 (1H, AB d, J= 15.3 Hz, ArCHaHbN), 2.96-2.43 (7H, m, N-CH2CH2Ar, 2×oxirane-H, oxiraneCHaHbN), 2.46 (1H, AB dd, J= 13.2 Hz, 7.5 Hz, oxiraneCHaHbN), 1.58-1.49 (4H, m, CH2CH2CH3), 0.98 (3H, t, J= 7.2 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 136.3, 132.5, 131.2, 130.0, 126.40, 126.36, 60.1, 56.8, 56.5, 56.0, 51.0, 33.8, 28.4, 19.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21ClNO 266.1306; Found 266.1304. 2-(cis-(3-(Trityloxymethyl)oxiran-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline (4a): Prepared from 6 (1.00 g, 2.10 mmol), 1,2,3,4-tetrahydroisoquinoline (580 mg, 4.41 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 1:1). Yield = 850 mg; 89% (yellowish oil). 1 H NMR (CDCl3, 500 MHz) δH: 7.48-7.46 (6H, m, aromatic H), 7.32-7.23 (9H, m, aromatic H), 7.10-7.08 (3H, m, aromatic H), 6.97-6.95 (1H, m, aromatic H), 3.68 (1H, AB d, 15.0 Hz, NCHaHbAr), 3.58 (1H, AB d, 15.0 Hz, NCHaHbAr) 3.41 (1H, dd, J= 17.5 Hz, 9.5 Hz, CHaHbOTr), 3.25 (2H, m, oxirane H), 3.12 (1H, dd, J= 17.5 Hz, 7.5 Hz, CHaHbOTr), 2.76 (5H, m, CH2CH2, oxirane-CHaHb-N), 2.31 (1H, m, oxirane-CHaHb-N). 13C{1H} NMR (CDCl3, 75 MHz), δC: 143.7, 134.4, 134.0, 128.7, 127.9, 127.2, 126.6, 126.2, 125.7, 87.0, 62.1, 56.4, 56.3, 55.0, 54.1, 51.3, 29.0. HRMS (ESITOF) m/z: [M+H]+ Calcd for C32H32NO2 462.2433; Found 462.2442. 6,7-Dimethoxy-2-(cis-(3-(Trityloxymethyl)oxiran-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline (4b): Prepared from 5 (973 mg, 2.0 mmol), 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline (812 mg, 4.2 mmol) using General Procedure A. Purification: Flash chromatography on silica eluting with hexane/EtOAc (1:0 to 1:1). Yield = 750 mg; 77% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.48-7.46 (6H, m, aromatic H), 7.32-7.21 (9H, m, aromatic H), 6.57 (1H, s, aromatic H), 6.47 (1H, s, aromatic H), 3.83 (3H, s, CH3O), 3.79 (3H, s, CH3O), 3.61 (1H, AB d, 14.5 Hz, NCHaHbAr), 3.54 (1H, AB d, 14.5 Hz, NCHaHbAr) 3.56 (1H, m, CHaHbOTr) 3.25 (2H, m, oxirane H), 3.12 (1H, m, CHaHbOTr), 2.74 (5H, m, CH2CH2, oxirane-CHaHb-N), 2.31 (1H, m, oxirane-CHaHb-N). 13 C{1H} NMR (CDCl3, 75 MHz), δC: 147.6, 147.2, 143.7,


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128.6, 127.9, 127.1, 126.1, 125.7, 111.4, 109.4, 86.9, 62.0, 56.3, 55.9, 55.8, 54.9, 54.1, 51.3, 28.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H36NO4 522.2639; Found 522.2656. trans-4-(1-Hydroxybutyl)-1,3,4,5-tetrahydro-2,5methano-2H-2-benzazepine (7a): Prepared from 3a (275 mg, 1.19 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/methanol (1:0 to 4:1). Yield = 182 mg; 66% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.11-7.09 (2H, m aromatic H), 6.99-6.94 (2H, m aromatic H), 4,42 (1H, brs, OH), 4.32 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.73 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.57-3.53 (1H, m, CH-OH), 3.21 (1H, dd, J= 12.9 Hz, 4.8 Hz, N-CHaHb-CH-CH-OH), 3.06 (1H, dd, J= 10.8 Hz, 2.1 Hz, N-CHaHb-CH-Ar), 2.97-2.86 (3H, m, CH-CH2-Ar, N-CHaHb-CH-CH-OH, N-CHaHb-CH-Ar), 2.23-2.16 (1H, m, CH-CHOH), 1.57-1.36 (4H, m, CH2CH2), 0.94 (3H, t, J= 6.3 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 144.0, 132.6, 126.4, 126.3, 126.1, 125.6, 72.9, 59.4, 56.9, 56.9, 55.1, 43.0, 38.9, 19.0, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H22NO4 232.1696; Found 232.1691. trans-7,8-Dimethoxy-4-(1-hydroxybutyl)-1,3,4,5tetrahydro-2,5-methano-2H-2-benzazepine (7b): Prepared from 3b (500 mg, 1.72 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/methanol (1:0 to 1:1). Yield = 355 mg; 71% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.50 (2H, s aromatic H), 4.31 (1H, AB d, J= 17.1 Hz, ArCHaHbN), 3.87 (3H, s OCH3), 3.81 (3H, s OCH3), 3.69 (1H, AB d, J= 17.1 Hz, ArCHaHbN), 3.64-3.54 (1H, m, CHO), 3.20 (1H, dd, J= 12.9 Hz, 4.8 Hz, NCHaHb-CH-CH-OH), 2.75 (1H, dd, J= 11.1 Hz, 2.4 Hz, NCHaHb-CH-Ar), 3.01-2.88 (2H, m, N-CHaHb-CH-CH-OH, NCHaHb-CH-Ar), 2.77 (1H, d, J= 2.4 Hz CH-Ar), 2.55 (1H, br, OH), 2.24-2.17 (1H, m, CH-CHO), 1.60-1.38 (4H, m, CH2CH2), 0.97 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 147.7, 147.2, 136.3, 124.3, 109.6, 109.2, 73.4, 59.5, 57.1, 56.9, 56.1, 55.9, 55.5, 42.4, 38.9, 19.0, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H26NO3 292.1907; Found 292.1905. trans-4-(1-Hydroxybutyl)-7-methoxy-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7c) (TFA salt): Prepared from 3c (128 mg, 0.49 mmol) using General Procedure B. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 103 mg; 56% (yellowish oil). 1 H NMR (DMSO-d6, 500 MHz) δH: 11.24 (1H, bs, NH), 7.12 (1H, d, J= 9.0 Hz, aromatic H), 6.84 (1H, m, aromatic H), 6.83 (1H, m, aromatic H), 4.67 (AB d, J= 16.0 Hz, ArCHaHbN), 4.34 (1H, AB d, J= 16.0 Hz, ArCHaHbN), 3.74 (3H, s, OCH3), 3.64-3.61 (3H, m, OCH, N-CHaHb-CH-CH-O, N-CHaHb-CH-Ar), 3.46 (1H, dd, J= 12.0 Hz, 9.0 Hz, NCHaHb-CH-CH-OH), 3.41 (1H, d, J= 10.5 Hz, N-CHaHb-CHAr), 3.29 (1H, d, J= 3.0 Hz, Ar-CH), 2.21 (1H, m, Ar-CHCH), 1.43-1.24 (4H, m, CH2CH2), 0.88 (3H, t, J= 6.5 Hz, CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz), δC: 158.6, 141.5, 128.2, 117.8, 113.2, 111.3, 70.5, 55.3, 55.2, 53.8, 53.6, 53.3, 41.9, 37.7, 18.4, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO2 262.1802; Found 262.1802. trans-6-Fluoro-4-(1-hydroxybutyl)-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7d): Prepared from 3d (100 mg, 0.40 mmol) using General Procedure B. Purification:

Flash chromatography on silica eluting with dichloromethane/methanol (1:0 to 4:1). Yield = 76 mg; 76% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.06 (1H, dd, J= 13.5 Hz, 7.5 Hz, aromatic H), 6.83 (1H, t, J= 8.7 Hz, aromatic H), 6.76 (1H, d, J= 7.5 Hz, aromatic H), 4.34 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.76 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.58 (1H, m, CH-OH), 3.45 (1H, br, OH), 3.28-3.22 (2H, m, CHAr, N-CHaHb-CH-CH-OH), 3.09-2.87 (3H, m, N-CHaHb-CHCH-OH, N-CH2-CH-Ar), 2.21 (1H, dd, J= 12.6 Hz, 7.2 Hz, CH-CH-Ar) 1.93 (1H, m, CH-CH-OH), 1.66-1.32 (4H, m, CH2CH2), 0.96 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (CDCl3, 75 MHz), δC: 157.4 (d, J= 242 Hz), 135.0 (d, J= 5.5 Hz), 131.0 (d, J= 18.6 Hz), 126.8 (d, J= 8.2 Hz), 121.9 (d, J= 3.2 Hz), 112.5 (d, J= 21.7 Hz), 73.1, 59.2 (d, J= 2.0 Hz), 57.1, 56.1, 54.6, 38.8, 34.6 (d, J= 2.7 Hz), 18.8, 14.1. HRMS (ESITOF) m/z: [M+H]+ Calcd for C15H20FNO 250.1602; Found 250.1592. trans-7-tert-Butyl-4-(1-hydroxybutyl)-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7e): Prepared from 3e (90 mg, 0.31 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/ methanol (1:0 to 4:1). Yield = 68 mg; 76% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.17 (1H, dd, J= 13.5 Hz, 1.8 Hz, aromatic H), 6.98 (1H, d, J= 1.8 Hz, aromatic H), 7.00 (1H, d, J= 13.5 Hz, aromatic H), 4.38 (AB d, J= 17.1 Hz, ArCHaHbN), 3.75 (1H, AB d, J= 17.1 Hz, ArCHaHbN), 3.75 (1H, td, J= 7.2 Hz, 2.7 Hz, CHOH), 3.23 (1H, dd, J= 12.9 Hz, 5.1 Hz, N-CHaHb-CH-CH-OH), 3.11-3.05 (1H, m, N-CHaHbCH-Ar), 3.02-2.94 (2H, m, N-CHaHb-CH-CH-O, N-CHaHbCH-Ar), 2.87 (1H, d, J= 2.4 Hz, Ar-CH), 2.22 (1H, q, J= 6.6 Hz Ar-CH-CH) 1.84 (1H, bs, OH), 1.64-1.22 (13H, m, CH2CH2, C(CH3)3), 0.97 (3H, t, J= 6.75 Hz, CH2CH3). 13 C{1H} NMR (75 MHz, CDCl3), δC: 149.2, 143.7, 129.9, 126.1, 123.4, 122.5, 73.7, 59.3, 57.01, 56.8, 55.5, 43.4, 38.7, 34.4, 31.5, 18.8, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2311. trans-8-tert-Butyl-4-(1-hydroxybutyl)-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7f) TFA salt: Prepared from 3f (300 mg, 1.04 mmol) using General Procedure B. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 345 mg; 83% (yellowish oil). 1 H NMR (DMSO-d6, 500 MHz) δH: 10.94 (1H, bs, NH), 7.28 (1H, dd, J= 7.5 Hz, 1.0 Hz, aromatic H), 7.23 (1H, s, aromatic H), 7.16 (1H, d, J= 7.5 Hz, aromatic H), 4.75 (AB d, J= 16.0 Hz, ArCHaHbN), 4.40 (1H, AB d, J= 16.0 Hz, ArCHaHbN), 3.65-3.58 (3H, m, OCH, N-CHaHb-CH-CH-OH, N-CHaHb-CH-Ar), 3.51 (1H, dd, J= 12.5 Hz, 8.5 Hz, NCHaHb-CH-CH-OH ), 3.44 (1H, d, J= 10.5 Hz, N-CHaHb-CHAr), 3.28 (1H, d, J= 3.0 Hz, CH-Ar), 2.19 (1H, q, J= 6.3 Hz, CH-CHOH), 1.45-1.22 (13H, m, CH2CH2, C(CH3)3), 0.88 (3H, t, J= 6.5 Hz, CH2CH3) 13C{1H} NMR (DMSO-d6, 125 MHz), δC: 149.8, 137.2, 125.8, 125.7, 124.6, 123.4, 70.5, 55.9, 54.0, 53.8, 53.3, 41.2, 37.7, 34.3, 31.1, 18.2, 14.0. HRMS (ESITOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2329. trans-4-(1-Hydroxybutyl)-6-methyl-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7g): Prepared from 3g (160 mg, 0.65 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/ methanol (1:0 to 4:1). Yield = 112 mg; 70% (yellowish oil).



1 H NMR (CDCl3, 300 MHz) δH: 7.05-6.96 (2H, m, aromatic H), 6.82 (1H, d, J= 7.2 Hz, aromatic H), 4.37 (AB d, J= 17.4 Hz, ArCHaHbN), 3.73 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.60 (1H, m, OCH), 3.26 (1H, dd, J= 12.9 Hz, 4.8 Hz, N-CHaHb-CH-CH-OH), 3.11-3.05 (2H, m, N-CHaHbCH-Ar, N-CHaHb-CH-CH-OH), 3.00-2.91 (2H, m, N-CHaHbCH-Ar, Ar-CH), 2.32 (3H, s, Ar-CH3), 2.16 (1H, q, J= 6.8 Hz Ar-CH-CH), 1.66-1.36 (4H, m, CH2CH2), 0.96 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (75 MHz, CDCl3), δC: 142.2, 132.8, 132.5, 127.6, 125.8, 124.1, 73.3, 59.9, 57.1, 56.3, 55.2, 38.9, 38.4, 19.0, 18.9, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1853; Found 246.1864. trans-4-(1-Hydroxybutyl)-7-methyl-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7h): Prepared from 3h (165 mg, 0.67 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/ methanol (1:0 to 4:1). Yield = 120 mg; 73% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.93 (1H, d, J= 7.5 Hz, aromatic H), 6.86 (1H, d, J= 7.5 Hz, aromatic H), 6.79 (1H, s, aromatic H), 4.30 (AB d, J= 17.4 Hz, ArCHaHbN), 3.70 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.54 (1H, t, J= 6.3 Hz, HOCH), 3.19 (1H, dd, J= 12.9 Hz, 4.8 Hz, N-CHaHb-CH-CHOH), 3.04 (1H, dd, J= 11.1 Hz, 2.4 Hz, N-CHaHb-CH-Ar), 2.97-2.88 (2H, m, N-CHaHb-CH-CH-OH, N-CHaHb-CH-Ar), 2.81 (1H, d, J= 2.4 Hz, Ar-CH), 2.29 (3H, s, Ar-CH3), 2.19 (1H, q, J= 6.8 Hz Ar-CH-CH), 1.61-1.32 (4H, m, CH2CH2), 0.95 (3H, t, J= 6.5 Hz, CH2CH3). 13C{1H} NMR (75 MHz, CDCl3), δC: 143.9, 135.6, 129.5, 127.1, 126.4, 126.3, 73.0, 59.3, 57.0, 56.8, 55.2, 43.1, 39.0, 21.0, 19.1, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1853; Found 246.1867. trans-4-(1-Hydroxybutyl)-8-methyl-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (7i): Prepared from 3i (160 mg, 0.65 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/methanol (1:0 to 4:1). Yield = 93 mg; 58% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 6.92-6.86 (2H, m, aromatic H), 6.80 (1H, s, aromatic H), 4.30 (AB d, J= 17.4 Hz, ArCHaHbN), 3.71 (1H, AB d, J= 17.4 Hz, ArCHaHbN), 3.55 (1H, m, OCH), 3.21 (1H, dd, J= 12.9 Hz, 4.8 Hz, N-CHaHbCH-CH-OH), 3.05 (1H, dd, J= 11.1 Hz, 2.7 Hz, N-CHaHb-CHAr), 2.97-2.88 (2H, m, N-CHaHb-CH-CH-OH, N-CHaHb-CHAr), 2.85 (1H, d, J= 2.7 Hz, Ar-CH), 2.27 (3H, s, Ar-CH3), 2.18 (1H, q, J= 6.8 Hz Ar-CH-CH), 1.57-1.35 (4H, m, CH2CH2), 0.94 (3H, t, J= 6.5 Hz, CH2CH3). 13C{1H} NMR (75 MHz, CDCl3), δC: 141.1, 135.9, 132.4, 127.1, 126.8, 125.5, 73.0, 59.4, 56.9, 56.8, 55.2, 42.6, 39.0, 21.1, 19.0, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1853; Found 246.1876. trans-4-(1-Hydroxy-2-trityloxyethyl)-1,3,4,5-tetrahydro2,5-methano-2H-2-benzazepine (8a): Prepared from 4a (230 mg, 0.5 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/ methanol (1:0 to 4:1). Yield = 83 mg; 36% (yellowish oil). 1 H NMR (CDCl3, 500 MHz) δH: 7.42-7.38 (6H, m, aromatic H), 7.31-7.27 (9H, m, aromatic H), 7.26-7.21 (3H, m, aromatic H), 7.14-7.06 (2H, m, aromatic H), 6.98-6.93 (2H, m, aromatic H), 4.42 (1H, AB d, J= 17.0 Hz, ArCHaHbN), 3.80 (1H, AB d, J= 17.0 Hz ArCHaHbN), 3.57 (1H, m, HOCH), 3.30 (1H, d, J= 2.5 Hz, CH-Ar), 3.19 (1H, dd, J= 9.5 Hz, 3.5 Hz, N-CHaHb-CH-CH-OH), 3.15 (1H, dd, J= 11.0 Hz, 2.5 Hz,

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N-CHaHb-CH-Ar), 3.05 (1H, dd, J= 9.5 Hz, 7.0 Hz, N-CHaHbCH-CH-OH), 3.00 (1H, m, N-CHaHb-CH-Ar), 2.91 (2H, m, TrO-CH2), 2.29 (1H, q, J= 7.0 Hz, CH-CH-Ar). 13C{1H} NMR (CDCl3, 75 MHz), δC: 143.6, 142.6, 130.6, 128.6, 127.9, 127.2, 126.8, 126.8, 126.5, 126.4, 87.0, 71.7, 66.2, 58.7, 56.8, 54.5, 52.7, 40.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H32NO2 462.2433; Found 462.2439. trans-7,8-Dimethoxy-4-(1-hydroxy-2-trityloxyethyl)1,3,4,5-tetrahydro-2,5-methano-2H-2-benzazepine (8b): Prepared from 4b (500 mg, 0.96 mmol) using General Procedure B. Purification: Flash chromatography on silica eluting with dichloromethane/methanol (1:0 to 1:1). Yield = 151 mg; 30% (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.48-7.41 (6H, m, aromatic H), 7.36-7.22 (9H, m, aromatic H), 6.52 (1H, s, aromatic H), 6.46 (1H, s, aromatic H), 4.32 (1H, AB d, J= 17.1 Hz, ArCHaHbN), 3.81 (3H, s, OCH3) 3.80 (3H, s, OCH3), 3.65 (1H, AB d, J= 17.1 Hz, ArCHaHbN), 3.53 (1H, m, CH-OH), 3.46 (1H, bs, OH), 3.24-3.19 (2H, m, CH-CHaHb-N-CHaHbCH), 3.07 (1H, dd, J= 10.8 Hz, 3.0 Hz, N-CHaHb-CH-CH-Ar), 3.05-2.81 (3H, m, Ar-CH, TrO-CHaHb, N-CHaHb-CH-Ar), 2.70 (1H, dd, J= 12.9 Hz, 4.5 Hz, TrO-CHaHb), 2.22 (1H, m, CH-CH-Ar). 13C{1H} NMR (CDCl3, 75 MHz), δC: 147.8, 147.4, 143.7, 135.6, 128.6, 127.9, 127.2, 123.0, 109.5, 109.3, 87.0, 71.9, 66.6, 59.1, 57.2, 56.0, 55.9, 54.9, 53.5, 39.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H36NO4 522.2639; Found 522.2630. cis-1-(1-Hydroxybutyl)-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (cis-9a): Prepared from 3a (110 mg, 0.48 mmol) using General Procedure C. Purification: Flash chromatography on Florisil eluting with dichloromethane/methanol (1:0 to 0:1). Yield = 50 mg; 45% cis isomer (yellowish oil). 1 H NMR (CDCl3, 500 MHz) δH: 7.23-7.19 (3H, m, aromatic H), 7.05 (1H, d, J= 7.0 Hz, aromatic H), 4.91 (1H, d, J= 9.0 Hz, Ar-CH-N), 3.60 (1H, t, J= 8.0 Hz, N-CHaHb-CH), 3.46 (1H, t, J= 8.0 Hz, N-CHaHb-CH), 3.39 (1H, m, CH-OH), 3.203.10 (2H, m, N-CH2-CH, Ar-CHaHb), 2.93 (1H, ddd, J= 13.0 Hz, 5.0 Hz, 1.5 Hz, N-CHaHb-CH2), 2.66 (1H, td, J= 13.0 Hz, 3.0 Hz, N-CHaHb-CH2), 2.53 (1H, dd, J= 16.0 Hz, 1.5 Hz, ArCHaHb), 1.36-1.05 (4H, m, CH2CH2CH3), 0.80 (3H, t, J= 6.6 Hz, CH2CH3). 13C{1H} NMR (DEPT, CDCl3, 125 MHz), δC: 135.8, 134.6, 129.3, 127.3, 126.5, 126.5, 69.1, 62.2, 47.7, 44.2, 42.3, 37.4, 23.2, 18.7, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H22NO 232.1696; Found 232.1700. 7,8-Dimethoxy-1-(1-hydroxybutyl)-1,4,5,9b-tetrahydro2H-azeto[2,1-a]isoquinoline (9b): Prepared from 3b (150 mg, 0.52 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 97 mg; 46% (yellowish oil) cis and 21 mg; 10% trans (yellowish oil) isomers. cis-9b (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.94 (1H, bs, NH), 6.93 (1H, s, aromatic [5] H), 6.84 (1H, s, aromatic [8] H), 5.57 (1H, d, J= 9.0 Hz, Ar-CH), 4.17 (1H, dd, J= 10.0 Hz, 10.0 Hz, N-CHaHb-CH), 3.92 (1H, dd, J= 10.0 Hz, 7.5 Hz, N-CHaHb-CH), 3.79 (3H, s, [7]OCH3), 3.74 (3H, s, [8]OCH3), 3.42 (1H, td, J= 12.5 Hz, 4.0 Hz, N-CHaHb-CH2), 3.15-3.12 (1H, m, Ar-CHaHb), 3.12-3.08 (1H, m, N-CH2-CH), 3.07 (1H, dd, J= 7.5 Hz, 2.0 Hz, O-CH), 2.97 (1H, td, J= 12.5 Hz, 3.5 Hz, N-CHaHb-CH2), 2.88 (1H, td, J= 16.5 Hz, 3.5 Hz, Ar-CHaHb), 1.26-0.99 (4H, m, CH2CH2CH3), 0.67 (3H, t, J= 7.0 Hz, CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125


Page 11 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


MHz), δC: 148.5, 147.8, 125.6, 120.2, 112.2, 111.1, 66.3, 61.4, 55.7, 55.6, 49.9, 43.2, 40.5, 37.3, 22.4, 17.6, 13.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H25NO3 292.1907; Found 292.1910. trans-9b (TFA salt): 1H NMR (DMSO-d6 500 MHz) δH: 10.40 (1H, bs, NH), 6.96 (1H, s, aromatic [5] H), 6.77 (1H, s, aromatic [8] H), 5.34 (1H, d, J= 7.5 Hz, Ar-CH), 4.24 (1H, dd, J= 11.0 Hz, 8.5 Hz, N-CHaHb-CH), 3.85 (1H, m, N-CHaHbCH), 3.79 (3H, s, [7]OCH3), 3.76 (3H, s, [8]OCH3), 3.79 (1H, m, O-CH), 3.38 (1H, m, N-CHaHb-CH2), 3.12 (1H, m, ArCHaHb), 3.08 (1H, m, N-CHaHb-CH2), 2.90 (1H, m, ArCHaHb), 2.63 (1H, m, Ar-CH-CH), 1.35-1.25 (4H, m, CH2CH2CH3), 0.88 (3H, t, J=7.0 Hz, CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 148.6, 148.1, 125.5, 123.8, 112.5, 109.4, 67.4, 60.9, 55.7, 55.6, 49.5, 45.4, 45.1, 35.9, 22.9, 17.7, 13.5. 1-(1-Hydroxybutyl)-7-methoxy-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9c): Prepared from 3c (115 mg, 0.44 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 66 mg; 40% cis isomer (yellowish oil). cis-9c (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.50 (1H, bs, NH), 7.15 (1H, d, J= 8.0 Hz, aromatic H), 6.94 (1H, d, J= 3.0 Hz, aromatic H), 6.89 (1H, dd, J= 8.0 Hz, 3.0 Hz, aromatic H), 5.59 (1H, d, J= 9.0 Hz, ArCHN), 4.64 (1H, d, J= 5.5 Hz, OH), 4.18 (1H, t, J= 10.0 Hz, N-CHaHb-CH), 3.92 (1H, dd, J= 11.0 Hz, 7.5 Hz, N-CHaHb-CH), 3.76 (3H, s, OCH3), 3.43 (1H, m, NCHaHbCH2), 3.18 (1H, m, Ar-CHaHb), 3.08 (1H, m, ArCHCH), 3.02-2.93 (2H, m, OCH, NCHaHbCH2), 2.91 (1H, m, Ar-CHaHb), 1.22-0.94 (4H, m, CH2CH2CH3), 0.59 (3H, t, J= 7.5 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 158.8, 135.1, 128.7, 120.7, 113.3, 113.1, 66.2, 61.5, 55.2, 50.3, 43.4, 40.3, 37.2, 23.5, 17.8, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H23NO2 262.1806; Found 262.1802. 6-Fluoro-1-(1-hydroxybutyl)-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9d): Prepared from 3d (230 mg, 0.92 mmol) using General Procedure C Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 111 mg; 33% cis (yellowish oil) and 36 mg; 11% trans (yellowish oil) isomers. cis-9d (TFA salt): 1H NMR (DMSO-d6 500 MHz) δH: 10.77 (1H, bs, NH), 7.35 (1H, td, J= 8.0 Hz, J = 5.5 Hz, aromatic H), 7.17 (1H, t, J= 8.0 Hz, aromatic H), 7.07 (1H, d, J= 8.0 Hz, aromatic H), 5.70 (1H, d, J= 9.5 Hz, Ar-CH-N), 4.25 (1H, dd, J= 11.0 Hz, J = 9.0 Hz, N-CHaHb-CH), 4.01 (1H, dd, J= 11.0 Hz, J = 7.5 Hz, N-CHaHb-CH), 3.54 (1H, m, N-CHaHb-CH2), 3.21 (1H, m, Ar-CH-CH), 3.15 (1H, m, CH-OH), 3.11 (1H, m, N-CHaHb-CH2), 3.08 (1H, m, Ar- CHaHb), 3.02 (1H, m, ArCHaHb), 1.25-1.05 (4H, m, CH2CH2CH3), 0.70 (3H, t, J= 7.5 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 158.8 (d, J= 243.0 Hz), 131.1 (d, J= 4.8 Hz), 127.7 (d, J= 8.6 Hz), 122.6 (d, J= 3.4 Hz), 120.4 (d, J= 19.3 Hz), 113.8 (d, J=19.0 Hz), 65.5, 60.7 (d, J= 2.0 Hz), 50.2, 42.5, 40.0, 37.0, 17.4, 15.8 (d, J= 4.3 Hz), 13.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21FNO 250.1607; Found 250.1603. trans-9d (TFA salt): 1H NMR (DMSO-d6 500 MHz) δH: 10.28 (1H, bs, NH), 7.38 (1H, td, J= 8.0 Hz, J = 5.5 Hz, aromatic H), 7.20 (1H, t, J= 9.0 Hz, aromatic H), 7.05 (1H, d, J= 7.5 Hz, aromatic H), 5.44 (1H, d, J= 7.5 Hz, Ar-CH-N), 4.26 (1H, dd, J= 10.0 Hz, J = 8.0 Hz, N-CHaHb-CH), 3.90 (1H, t, J= 10.0 Hz, N-CHaHb-CH), 3.80 (1H, m, CH-OH), 3.42 (1H, m,

N-CHaHb-CH2), 3.25-3.12 (2H, m, N-CHaHb-CH2, Ar-CHaHb), 3.00 (1H, m, Ar-CHaHb), 2.73 (1H, m, Ar-CH-CH), 1.38-1.26 (4H, m, CH2CH2CH3), 0.87 (3H, t, J= 7.0 Hz CH2CH3). 13 C{1H} NMR (DMSO-d6, DEPT, 125 MHz), δC: 158.8 (d, J= 243 Hz), 134.3 (d, J= 5.1 Hz), 128.5 (d, J= 8.6 Hz), 118.2 (d, J= 20.5 Hz), 114.1 (d, J= 21.5 Hz), 67.1, 60.2 (d, J= 2.4 Hz), 49.8, 44.8, 44.2, 35.8, 17.7, 16.2, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21FNO 250.1607; Found 250.1610. 7-tert-Butyl-1-(1-hydroxybutyl)-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9e): Prepared from 3e (150 mg, 0.52 mmol) using General Procedure C.: Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 42 mg 20% cis (yellowish oil) and 29 mg 14% trans (yellowish oil) isomers. cis-9e (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.54 (1H, bs, NH), 7.35-7.33 (2H, m aromatic H), 7.15 (1H, d, J= 8.0 Hz, aromatic H), 5.61 (1H, d, J= 7.0 Hz, ArCHN), 4.20 (1H, m, N-CHaHb-CH), 3.90 (1H, m, N-CHaHb-CH), 3.44 (1H, m, N-CHaHb-CH2), 3.19 (1H, m, ArCHaHb) 3.07 (1H, m, ArCHCH), 3.00 (1H, m, N-CHaHb-CH2), 2.98 (1H, m, HOCH), 2.94 (1H, m, Ar-CHaHb), 1.27 (9H, s, C(CH3)3), 1.170.92 (4H, m, CH2CH2CH3), 0.50 (3H, t, J= 7.5 Hz CH2CH3). 13 C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 150.5, 133.1, 127.2, 125.9, 125.2, 123.9, 65.9, 61.4, 50.5, 43.6, 40.2, 36.9, 34.4, 31.1, 23.5, 17.6, 13.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2328. trans-9e (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.11 (1H, bs, NH), 7.39-7.35 (2H, m aromatic H), 7.12 (1H, d, J= 8.0 Hz, aromatic H), 5.35 (1H, t, J= 7.5 Hz, Ar-CH-N), 4.20 (1H, m, N-CHaHb-CH), 3.85 (1H, m, N-CHaHb-CH), 3.73 (1H, m, HOCH), 3.39 (1H, m, N-CHaHb-CH2), 3.23 (1H, m, Ar-CHaHb), 3.11 (1H, m, N-CHaHb-CH2), 2.94 (1H, m, ArCHaHb), 2.64 (1H, m, HOCHCH), 1.43-1.23 (4H, m, CH2CH2CH3), 1.28 (9H, s, C(CH3)3), 0.85 (3H, t, J= 7.0 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 150.7, 133.0, 129.5, 125.5, 125.3, 124.4, 67.5, 61.1, 49.7, 45.3, 45.1, 36.1, 34.4, 31.1, 23.9, 18.2, 13.9. HRMS (ESITOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2332. 8-tert-Butyl-1-(1-hydroxybutyl)-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9f): Prepared from 3f (120 mg, 0.42 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 30 mg; 18% cis (yellowish oil) and 19 mg 11% trans (yellowish oil) isomers. cis-9f (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.27 (1H, bs, NH), 7.37 (1H, dd, J= 8.0 Hz, 2.0 Hz aromatic H), 7.28 (1H, d, J= 8.0 Hz, aromatic H), 7.18 (1H, d, J= 2.0 Hz, aromatic H), 5.38 (1H, d, J= 7.0 Hz, Ar-CH-N), 4.21 (1H, m, N-CHaHb-CH), 3.85 (1H, m N-CHaHb-CH), 3.77 (1H, m, HOCH), 3.39 (1H, m, N-CHaHb-CH2), 3.20 (1H, m, ArCHaHb), 3.08 (1H, m, N-CHaHb-CH2), 2.91 (1H, m, ArCHaHb), 2.62 (1H, m, HOCHCH), 1.26 (9H, s, C(CH3)3), 1.341.22 (4H, m, CH2CH2CH3), 0.85 (3H, t, J= 7.0 Hz CH2CH3). 13 C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 149.9, 131.9, 130.6, 128.4, 125.1, 122.1, 67.9, 61.5, 50.0, 45.3, 45.1, 36.1, 34.4, 31.1, 23.2, 18.1, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2322. trans-9f (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 11.00 (1H, bs, NH), 7.35 (1H, d, J= 8.0 Hz aromatic H), 7.287.25 (2H, m, aromatic H), 5.64 (1H, bs, Ar-CH-N), 4.17 (1H,



m, N-CHaHb-CH), 3.90 (1H, m N-CHaHb-CH), 3.40 (1H, m, N-CHaHb-CH2), 3.17 (1H, m, Ar-CHaHb), 3.07 (1H, m, NCHaHb-CH2), 2.97-2.87 (2H, m, Ar-CHaHb, NCHCH), 2.83 (1H, m, HOCH), 1.26 (9H, s, C(CH3)3), 1.20-1.00 (3H, m, CH2CHaHbCH3), 0.83 (1H, m, CHaHbCH3), 0.56 (3H, t, J= 7.0 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 149.7, 131.1, 128.8, 128.5, 125.4, 124.9, 67.4, 62.2, 50.8, 43.8, 40.8, 37.6, 34.7, 31.4, 22.9, 18.5, 13.8. HRMS (ESITOF) m/z: [M+H]+ Calcd for C19H29NO 288.2322; Found 288.2313. 1-(1-Hydroxybutyl)-6-methyl-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9g): Prepared from 3g (170 mg, 0.69 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 52 mg; 21% (yellowish oil) cis and 17 mg, 7% trans (yellowish oil) isomers. cis-9g (TFA salt): 1H NMR (DMSO-d6, 300 MHz) δH: 10.96 (1H, bs, NH), 7.19 (2H, d, J= 4.5 Hz, aromatic H), 7.04 (1H, t, J= 4.5 Hz, aromatic H), 5.62 (1H, d, 9.3 Hz, Ar-CH), 4.21 (1H, t, J= 10.8 Hz, N-CHaHb-CH), 3.91 (1H, dd, J= 10.8 Hz, 8.1 Hz, N-CHaHb-CH), 3.49 (1H, m, N-CHaHb-CH2), 3.172.90 (5H, m, Ar-CH2, N-CHaHb-CH2, HOCHCH), 2.31 (3H, s, Ar-CH3), 1.24-0.92 (4H, m, CH2CH2CH3), 0.59 (3H, t, J= 7.1 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, 75 MHz), δC: 135.7, 132.1, 129.1, 128.6, 126.2, 124.9, 66.0, 61.2, 50.3, 43.2, 40.4, 37.2, 19.9, 19.0, 17.8, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1865. trans-9g (TFA salt): 1H NMR (DMSO-d6, 300 MHz) δH: 10.28 (1H, bs, NH), 7.21 (2H, d, J= 4.2 Hz, aromatic H), 7.02 (1H, t, J= 4.2 Hz, aromatic H), 5.36 (1H, bs, Ar-CH), 4.21 (1H, m, N-CHaHb-CH), 3.86 (1H, t, J= 10.1 Hz, N-CHaHbCH), 3.76 (1H, m, HOCH), 3.38 (1H, bs, N-CHaHb-CH2), 3.17-3.05 (2H, m, N-CHaHb-CH2, Ar-CHaHb), 2.95 (1H, m, Ar-CHaHb), 2.65 (1H, m, HOCHCH), 2.31 (3H, s, Ar-CH3), 1.38-1.20 (4H, m, CH2CH2CH3), 0.85 (3H, t, J= 6.9 Hz, CH2CH3). 13C{1H} NMR (DMSO-d6, 75 MHz), δC: 135.9, 132.2, 131.9, 129.3, 126.9, 123.1, 67.4, 60.8, 49.7, 45.3, 45.0, 36.1, 20.3, 18.9, 18.2, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1864. 1-(1-Hydroxybutyl)-7-methyl-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9h): Prepared from 3h (120 mg, 0.49 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 40 mg; 23% cis (yellowish oil) and 18 mg, 10% trans (yellowish oil) isomers. cis-9h (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.34 (1H, bs, NH), 7.13 (2H, bs aromatic H), 7.09 (1H, d, J= 8.0 Hz, aromatic H), 5.62 (1H, d, 9.0 Hz, Ar-CH), 4.43 (1H, bs, OH), 4.22 (1H, dd, J= 11.0 Hz, 9.0 Hz, N-CHaHb-CH), 3.97 (1H, dd, J= 11.0 Hz, 7.5 Hz, N-CHaHb-CH), 3.47 (1H, td, J= 12.5 Hz, 4.5 Hz, N-CHaHb-CH2), 3.17 (1H, m, Ar-CHaHb), 3.15 (1H, m, HOCH), 3.09 (1H, m, HOCHCH), 3.03 (1H, ddd, J= 12.5 Hz, 11.0 Hz, 4.0 Hz, N-CHaHb-CH2), 2.89 (1H, td, J= 17.0 Hz, 4.0 Hz, Ar-CHaHb), 2.31 (3H, s, Ar-CH3), 1.25-1.01 (4H, m, CH2CH2CH3), 0.65 (3H, t, J= 7.5 Hz CH2CH3). 13 C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 137.0, 132.8, 128.7, 127.1, 126.7, 125.4, 65.8, 61.6, 50.2, 43.5, 40.1, 37.0, 23.0, 20.3, 17.4, 13.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1851. trans-9h (TFA salt): 1H NMR (DMSO-d6, 500 MHz) δH: 10.30 (1H, bs, NH), 7.17 (1H, bs aromatic H), 7.15 (1H, d, J= 8.0 Hz, aromatic H), 7.08 (1H, d, J= 8.0 Hz, aromatic H), 5.38

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(1H, d, J= 8.0 Hz, Ar-CH), 4.26 (1H, dd, J= 10.5 Hz, 8.0 Hz, N-CHaHb-CH), 3.87 (1H, t, J= 10.5 Hz, N-CHaHb-CH), 3.78 (1H, m, HOCH), 3.39 (1H, m, N-CHaHb-CH2), 3.20 (1H, m, Ar-CHaHb), 3.15 (1H, m, N-CHaHb-CH2), 2.92 (1H, ddd, J= 16.0 Hz, 5.0 Hz, 2.0 Hz, Ar-CHaHb), 2.65 (1H, m, HOCHCH), 2.32 (3H, s, Ar-CH3), 1.40-1.24 (4H, m, CH2CH2CH3), 0.88 (3H, t, J= 7.0 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, DEPT, 125 MHz) δC: 137.3, 132.9, 129.0, 128.8, 127.7, 125.0, 67.4, 61.0, 49.7, 45.1, 45.1, 35.9, 23.5, 20.3, 17.7, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1849. 1-(1-Hydroxybutyl)-8-methyl-1,4,5,9b-tetrahydro-2Hazeto[2,1-a]isoquinoline (9i): Prepared from 3i (145 mg, 0.59 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 47 mg; 22% (yellowish oil) cis and 17 mg, 8% trans (yellowish oil) isomers. cis-7j (TFA salt): 1H NMR (DMSO-d6, 300 MHz) δH: 11.01 (1H, bs, NH), 7.21 (1H, d, J= 6.9 Hz, aromatic H), 7.12 (1H, d, J= 6.9 Hz, aromatic H), 7.03 (1H, s, aromatic H), 5.60 (1H, d, J= 8.1 Hz, Ar-CH), 4.19 (1H, t, J= 9.5 Hz, N-CHaHbCH), 3.93 (1H, t, J= 8.5 Hz, N-CHaHb-CH), 3.73 (1H, m, HOCH), 3.44 (1H, d, J= 10.8 Hz, N-CHaHb-CH2), 3.19-2.85 (5H, m, Ar-CH2, N-CHaHb-CH2, HOCHCH), 2.28 (3H, s, ArCH3), 1.25-0.88 (4H, m, CH2CH2CH3), 0.58 (3H, t, J= 6.0 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, 75 MHz), δC: 135.9, 130.4, 128.6, 128.5, 128.5, 127.6, 66.2, 61.5, 50.2, 43.5, 40.4, 37.2, 22.8, 20.6, 17.9, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1864. trans-7i (TFA salt): 1H NMR (DMSO-d6, 300 MHz) δH: 10.31 (1H, bs, NH), 7.24 (1H, d, J= 7.8 Hz, aromatic H), 7.14 (1H, d, J= 7.8 Hz, aromatic H), 7.00 (1H, s, aromatic H),, 5.35 (1H, t, J= 6.6 Hz, Ar-CH), 4.21 (1H, m, N-CHaHb-CH), 3.85 (1H, t, J= 10.1 Hz, N-CHaHb-CH), 3.76 (1H, m, HOCH), 3.38 (1H, m, N-CHaHb-CH2), 3.23-3.06 (2H, m, N-CHaHb-CH2, ArCHaHb), 2.90 (1H, m, Ar-CHaHb), 2.65 (1H, m, OCHCH), 2.29 (3H, s, Ar-CH3), 1.36-1.22 (4H, m, CH2CH2CH3), 0.86 (3H, t, J= 7.1 Hz CH2CH3). 13C{1H} NMR (DMSO-d6, 75 MHz), δC: 136.6, 132.1, 130.3, 128.7, 128.6, 125.7, 67.3, 61.0, 49.7, 45.4, 45.1, 36.1, 23.3, 20.6, 18.2, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H24NO 246.1854; Found 246.1861. cis-1-(1-Hydroxybutyl)-8-trifluoromethyl-1,4,5,9btetrahydro-2H-azeto[2,1-a]isoquinoline (9j): Prepared from 3j (125 mg, 0.42 mmol) using General Procedure C. Purification: preparative HPLC eluting with acetonitrile/NH4HCO3/water. Yield = 59 mg; 47% cis (yellowish oil) isomer. 1 H NMR (DMSO-d6, 500 MHz) δH: 7.49 (1H, m aromatic H), 7.42 (1H, m, aromatic H), 7.41 (1H, m, aromatic H), 4.86 (1H, d, J= 8.5 Hz, ArCHN), 3.34-3.25 (2H, m, NCH2CH), 3.10 (1H, m, Ar-CHaHb), 2.82-2.89 (2H, m, ArCHCH, NCHaHbCH2), 2.58-2.64 (2H, m, HOCH, Ar-CHaHb), 2.41 (1H, m, NCHaHbCH2), 1.22-0.857 (4H, m, CH2CH2CH3), 0.58 (3H, t, J= 7.5 Hz CH3). 13C{1H} NMR (CDCl3, 125 MHz), δC: 141.4, 136.5, 129.6, 126.3, 124.8, 122.3, 115.7, 68.6, 61.3, 49.9, 43.9, 42.2, 37.7, 23.0, 18.3, 13.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H21F3NO 300.1570; Found 300.1586. cis-1-(1-Hydroxy-2-trityloxyethyl)-1,4,5,9b-tetrahydro2H-azeto[2,1-a]isoquinoline (cis-10a): Prepared from 4a (160 mg, 0.35 mmol) using General Procedure C. Purification:


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preparative HPLC eluting with acetonitrile/NH4HCO3/water. Yield = 40 mg; 25% cis isomer (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.40-7.36 (6H, m, aromatic H), 7.31-7.18 (13H, m, aromatic H), 4.98 (1H, d, J= 6.3 Hz, Ar-CH-N), 3.29-3.21 (2H, m, CH-OH, NCHaHbCH), 3.082.94 (4H, m, TrOCH2, ArCHCH, NCHaHbCH), 2.90-2.81 (2H, m, NCHaHbCHaHb), 2.52-2.42 (2H, m, NCHaHbCHaHb). 13 C{1H} NMR (CDCl3, 75 MHz), δC: 143.8, 135.5, 134.4, 129.1, 128.8, 128.7, 128.0, 127.3, 126.4, 125.7, 87.0, 70.2, 65.1, 62.9, 48.3, 43.8, 40.6, 29.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H32NO2 462.2428; Found 462.2431. cis-7,8-Dimethoxy-1-(1-hydroxy-2-trityloxyethyl)1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinoline (cis-10b): Prepared from 4b (235 mg, 0.45 mmol) using General Procedure C Purification: preparative HPLC eluting with acetonitrile/NH4HCO3/water. Yield = 70 mg; 30% cis isomer (yellowish oil). 1 H NMR (CDCl3, 300 MHz) δH: 7.35-7.26 (15H, m, aromatic [Tr] H), 6.74 (1H, s, aromatic H), 6.68 (1H, s, aromatic H), 5.10 (1H, d, J= 6.6 Hz, Ar-CH-N), 3.91 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.41-3.24 (2H, m, CH-OH, TrOCHaHb), 3.10-2.90 (6H, m, TrOCHaHb, CH2-N-CH2, Ar-CHaHb-CH2), 2.78-2.65 (1H, m, Ar-CHaHb-CH2), 2.55-2.49 (1H, m, Ar-CHCH). 13C{1H} NMR (CDCl3, 75 MHz), δC: 148.8, 148.4, 143.3, 128.4, 128.0, 127.3, 124.6, 111.1, 111.0, 87.3, 69.2, 64.9, 63.0, 56.0, 56.0, 48.3, 42.8, 40.2, 22.7. HRMS (ESITOF) m/z: [M+H]+ Calcd for C15H22NO 522.2639; Found 522.2642. cis-3-(1-Hydroxybutyl)-2-(2-ethenylphenyl)azetidine (cis-11a) (TFA salt): Tetrahydroisoquinoline derivative (3a, 150 mg, 0.65 mmol) was dissolved in pure and dry tetrahydrofuran (2 mL) and cooled to 0°C. To this solution BF3•Et20 (0.10 mL, 0.78 mmol) was added dropwise under nitrogen and the solution was stirred for 20 minutes at 0 °C. Potassium tertbutoxide (1.3 mmol, 1.3 mL of 1M solution in THF) was cooled to -78 °C, to this solution diisopropylamine (1.3 mmol, 0.20 g) and butyllithium (1.95 mmol, 1.22 mL of 1.59 M hexane solution) were added dropwise. The reaction mixture was stirred for 20 minutes at -78 °C then a tetrahydrofuran (2 mL) solution of the oxirane (3a.BF3, 0.5 mmol) was added. The mixture was stirred at the same temperature for 2 hours. To this cold solution water (3.0 mL) and diethyl ether (5 mL) was added then it was allowed to warm to room temperature. The phases were separated and the aqueous phase was extracted with diethyl ether (5×5 mL). The collected organic solution was washed with brine (1×10 mL), dried over sodium sulfate and concentrated in vacuo. Purification: preparative HPLC eluting with acetonitrile/TFA/water. Yield = 44 mg; 20% (yellowish oil). 1 H NMR (DMSO-d6, 500 MHz) δH: 9.31 (1H, bs, NHaHb), 9.09 (1H, bs, NHaHb), 7.60 (1H, d, J= 7.0 Hz, aromatic H), 7.51 (1H, d, J= 7.0 Hz, aromatic H), 7.39 (1H, m, aromatic H), 7.37 (1H, m, aromatic H), 6.77 (1H, dd, J= 17.0 Hz, 11.0 Hz, =CH), 5.94 (1H, dd, J= 15.5 Hz, 8.0 Hz, ArCHCH), 5.77 (1H, d, J= 17.0 Hz, =CHaHb), 5.38 (1H, d, J= 11.0 Hz, =CHaHb), 4.17 (1H, m, NCHaHb), 3.79 (1H, m, NCHaHb), 3.31 (1H, m, HOCH), 2.97 (1H, m, HOCHCH), 1.15-1.01 (4H, m, CH2CH2) 0.67 (3H, t, J= 7.0 Hz, CH3). 13C{1H} NMR (DEPT, DMSOd6, 125 MHz), δC: 135.1 (Ar), 133.4 (=CH2), 131.5 (Ar), 128.6 (Ar), 128.2 (Ar), 126.0 (Ar), 126.0 (Ar), 118.1 (=CH), 66.4 (OC), 62.1 (ArCHN), 44.1 (NCH2), 42.8 (OCHCH), 37.1

(OCHCH2), 18.3 (CH2CH3), 14.1 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H22NO 232.1696; Found 232.1695. cis-3-(1-Hydroxybutyl)-2-(2-ethenyl-4,5-dimethoxyphenyl)azetidine (cis-11b) (TFA salt): It was isolated during the preparative HPLC purification of 9b. 1 H NMR (CDCl3, 300 MHz) δH: 9.01 (2H, bs, NH2), 7.17 (1H, s, aromatic H), 7.11 (1H, s, aromatic H), 6.71 (1H, dd, J= 17.2 Hz, 11.0 Hz, CH=CH2), 5.67 (1H, dd, J= 17.1 Hz, 1.1 Hz, CH=CHaHb), 5.29 (1H, dd, J= 11.1 Hz, 1.1 Hz, CH=CHaHb), 4.15 (1H, bs, N-CHaHb), 3.87 (1H, bs, Ar-CH), 3.85 (1H, bs, N-CHaHb), 3.83 (3H, s, OCH3), 3.81 (3H, s, OCH3), 3.41 (1H, m, HO-CH), 2.92 (1H, m, HOCH-CH), 1.22-0.98 (4H, m, CH2CH2), 0.68 (3H, t, J= 7.1 Hz, CH2CH3). 13C{1H} NMR (DEPT, DMSO-d6, 75 MHz), δC: 132.2, 127.7, 122.8, 116.0, 110.5, 109.3, 65.8, 61.2, 55.9, 55.6, 43.8, 42.5, 36.5, 17.4, 13.2. 66.6, 62.0, 56.7, 56.4, 44.6, 43.4, 37.3, 18.2, 14.0. Theoretical calculations All computations were carried out with the Gaussian09 program package (G09),57 using default convergence. Computations were carried out at B3LYP level of theory,58 using the 6-31G(d,p) basis set. The vibrational frequencies were computed at the same levels of theory, in order to confirm properly all structures as residing at minima on their potential energy hypersurfaces (PESs). Thermodynamic functions U, H, G and S were computed at 220.15 K. Beside the vacuum calculations, the IEFPCM method was also applied to model the solvent effect, by using the default settings of G09, modelling THF solvent.59 For more precise calculations, in the acid base reactions, the explicit-implicit solvent model was used.60 The reliability of the calculations are between 2–3 kJ mol–1.60 See the Supporting Information for row data.

ASSOCIATED CONTENT Supplementary data (spectra of compounds 3, 4, 7, 8, 9, 10 and 11; and quantumchemical calculations) related to this article are available.

AUTHOR INFORMATION Corresponding Author *Ervin Kovács, e-mail: [email protected] Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, H-1111 Hungary, Budafoki út 8, H-1111 Budapest, Hungary ORCID iD Ervin Kovács: 0000-0002-3939-6925 Ferenc Faigl: 0000-0001-7954-3558 Zoltán Mucsi: 0000-0003-3224-8847

Present Addresses ‡

Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary

Author Contributions Experiments and technical assistance was made by E.K. B.H. and Z.M. Theoretical calculations werre carried out by Z.M. Spectroscopic characterization was carried out by T.G., M.Ny., Z M. and E K. This manuscript was written by E.K., F.F., Z.M. with comments from all authors. E.K. supervised the project.



Notes The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENT This work was funded by grants provided by the Hungarian Scientific Research Fund (OTKA K 104528). Ervin Kovács is grateful to the National Research, Development and Innovation Office (NKFIH) for Postdoctoral Excellence Award (PD 128612). We thank Imre G. Csizmadia for critical evaluation of the manuscript and Stuart Johnson for linguistic revision.

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