Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers.

With the aim to develop new σ2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2-benzopyran and 2-benzofuran scaffolds were connected to the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety by variable linkers. In addition to flexible alkyl chains, linkers containing an amide as functional group were synthesized. The 2-benzopyran and 2-benzofuran scaffold of the spirocyclic compounds were synthesized from 2-bromobenzaldehyde. The amide linkers were constructed by acylation of amines with chloroacetyl chloride and subsequent nucleophilic substitution, the alkyl linkers were obtained by LiAlH4 reduction of the corresponding amides. For the development of σ2 receptor ligands, the spirocyclic 2-benzopyran scaffold is more favorable than the ring-contracted 2-benzofuran system. Compounds bearing an alkyl chain as linker generally show higher σ affinity than acyl linkers containing an amide as functional group. A higher σ1 affinity for the cis-configured cyclohexanamines than for the trans-configured derivatives was found. The highest σ2 affinity was observed for cis-configured spiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine connected to the tetrahydroisoquinoline system by an ethylene spacer (cis-31, Ki (σ2 )=200 nM; the highest σ1 affinity was recorded for the corresponding 2-benzofuran derivative with a CH2 C=O linker (cis-29, Ki (σ1 )=129 nM).

Introduction

σ Receptors, initially classified as class of opioid receptors, are well established as unique class of receptors without any homology to opioid receptors or NMDA receptors. Based on the results of comprehensive radioligand binding studies and biochemical analysis, the class of σ receptors was further divided into two distinct subtypes, which were termed σ1 and σ2 receptor.

The σ1 receptor has been cloned from different species, including human, rat, mouse, and guinea pig. The crystal structure of the human σ1 receptor was recently reported by Kruse et al.[ , ] In contrast to the σ1 receptor, details concerning the σ2 receptor have been rather vague for many years. As a result from photoaffinity labeling studies a molecular weight of 21.5 kDa was postulated for the σ2 receptor. Xu and co‐workers utilized a photoaffinity probe to label σ2 receptors in rat liver and proposed that the σ2 receptor binding site resides within the progesterone receptor membrane component 1 (PGRMC1) complex. During the following years, the correlation between the σ2 receptor and PGRMC1 protein complex was considered controversial. In 2017, the σ2 receptor was isolated from calf liver tissue and identified as the endoplasmic reticulum (ER)‐resident membrane protein TMEM97, which is also described as MAC30 (meningioma‐associated protein 30). Subsequent molecular cloning and binding experiments confirmed this result. Mutagenesis studies identified two aspartate residues as crucial for binding of [3H]DTG, a radioligand frequently used in σ2 receptor binding assays. Furthermore, it was demonstrated that the TMEM97 ligands elacridar (1; Figure 1) and Ro 48‐8071 showed the same K i values towards cell membranes from Sf9 cells overexpressing the TMEM97 protein and σ2 receptor overexpressing MCF‐7 cells. According to these findings, the σ2 receptor is now often termed σ2 receptor/TMEM97. In 2018, Riad et al. demonstrated that the σ2 receptor/TMEM97 protein, the PGRMC1 protein and the LDL receptor form a ternary complex, which is necessary for the rapid internalization of LDL. In contrast to the σ1 receptor, no crystal structure of the σ2 receptor protein has been published so far.

Figure 1

Elacridar and some prototypical σ2 receptor ligands.

For a variety of tumor cells an overexpression of σ2 receptors was demonstrated, including breast cancer, lung cancer, colon cancer, leukemia and prostate cancer.[ , , , , , ] It was also shown that σ2 receptor agonists are capable of killing tumor cells via apoptotic and non‐apoptotic mechanisms. For example, several derivatives of the high affinity σ2 receptor agonist PB28 (3; Figure 1) are able to inhibit the growth of pancreatic cancer cells and the neuroblastoma SK−N‐SH cell line.[ , ] Very recently, it has been found that the potent and selective σ2 receptor ligand PB221 inhibits the proliferation of brain tumor murine astrocytoma cells (ALTS1C1). Haloperidol and its homopiperazine analog SYA013 exhibit high σ2 affinity and, furthermore, antiproliferative effects on different tumor cell lines, including Panc‐1. Therefore, the development of σ2 receptor ligands is a very promising goal. However, very recently it was reported that σ2 receptor ligands could also induce cytotoxic effects in σ2/TMEM97 knock out and σ2/TMEM97 and PGRMC1 double knock out cell lines. It was concluded that the cytotoxic effects of these σ2 ligands could not be mediated by the σ2 receptor, but other mechanisms have to be responsible for these cytotoxic effects.

In Figure 1, some prototypical σ2 receptor ligands are shown. The spirocyclic benzofuran siramesine (2) displays a considerable selectivity for the σ2 receptor (K i=0.12 nM) over the σ1 receptor (K i=17 nM). PB28 (3) with the 4‐(cyclohexyl)piperazine substructure is also a potent σ2 ligand (K i=0.68 nM), but exhibits even higher affinity towards the σ1 subtype (K i=0.38 nM). In the group of bicyclic compounds some morphans (e. g., CB184, 4) and granatanes (e. g., SV119, 5) display high σ2 receptor affinity and high selectivity over the σ1 receptor.[ , ]

The 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline residue is a pharmacophoric element present in several σ2 receptor ligands.[ , , , , , , , , ] (Figure 2) Mach and co‐workers published a series of benzamides connected to the 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline residue by linkers of different chain lengths. Among this series, 7 and 8 (ISO‐1 ) with an ethylene and tetramethylene linker, respectively, showed high σ2 affinity and selectivity over the σ1 receptor. The same isoquinoline ring system is also a structural element of the σ2 ligand 1 (Figure 1).

Figure 2

Lead compounds with a tetrahydroisoquinoline ring system showing a preference for σ2 receptors over σ1 receptors.

In a previous study, we have reported that the spirocyclic 2‐benzopyran derivatives trans‐6 and cis‐6 bearing the 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline residue without linker show medium to high affinity to the σ2 receptor. (Figure 2) However, the selectivity over the σ1 subtype is moderate and has room for improvement. Therefore, it was envisaged to synthesize a new set of σ2 selective ligands by introducing a linker between the spirocyclic 2‐benzopyran scaffold and the isoquinoline ring system. To exploit further structure affinity relationships, not only alkyl chains were planned as linkers, but also amides with variable chain lengths and different positions of the carbonyl group were designed. Moreover, a ring contraction of the spirocyclic 2‐benzopyran to the spirocyclic 2‐benzofuran ring system was planned as this compound class is also known for its high σ affinity from previous studies. An overview of the structure modifications is presented in Figure 3.

Figure 3

Overview of planned σ2 receptor ligands with various linkers.

Results and Discussion

Synthesis

For the synthesis of the designed σ ligands, spirocyclic 2‐benzopyrans and 2‐benzofurans 10–13 with endocyclic and exocyclic amino moiety were synthesized starting from 2‐bromobenzaldehyde (Scheme 1).

Scheme 1

Outline of the synthesis of spirocyclic piperidines 10 and 12. and cyclohexanamines 11 and 13 with 2‐benzopyran and 2‐benzofuran scaffold. a) 5 steps; b) 7 steps; c) 4 steps; d) 4 steps;[ , ] e) NH4 HCO2, Pd/C, CH3OH, 17–21 h, 65 °C; trans‐13, 86 %, cis‐13, 66 %.

The spirocyclic piperidines 10 and 12 were prepared by addition of an aryllithium intermediate at N‐benzyl‐protected piperidin‐4‐one as previously described.[ , ] The exocyclic primary amines trans‐11 and cis‐11 were obtained as reported in ref. [34]. Transfer hydrogenolysis using NH4 HCO2 in the presence of Pd/C converted trans‐ and cis‐configured benzylamines trans‐9 and cis‐9[ , ] into the diastereomeric primary amines trans‐13 and cis‐13. The secondary amine 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline HCl (14 HCl) was commercially available (Scheme 1).

The amines 10–14 were acylated with α‐chloroacetyl chloride affording chloroacetamides 15 –17 and 19–20. The homologous 4‐chlorobutyryl derivative cis‐18 was prepared by reaction of cis‐11 with 4‐chlorobutyryl chloride. The amides 15–20 were obtained in yields of 56–89 % (Scheme 2). Acylation of tetrahydroisoquinoline 14 with 3‐chloropropionyl chloride did not lead to the desired 3‐chloropropinamide.

Scheme 2

Acylation of amines with chloroacyl chlorides. *The spirocyclic piperidines 16 and 19 were not isolated, but directly used for subsequent nucleophilic substitution with 14.

The final compounds were obtained by nucleophilic substitution of the terminal chloride in the side chain of the amides 15–20. The acylated spirocyclic 2‐benzopyrans 16–18 and 2‐benzofurans 19 and 20 were reacted with the tetrahydroisoquinoline 14, while the acylated isoquinoline 15 underwent a nucleophilic substitution with the spirocyclic amines 10–13. In Table 1, the products and yields of these transformations are summarized.

Table 1

Nucleophilic substitution at chloroamides 15–20.[a]

Chloroamide	Amine	Product	Yield [%]
15	10	21	22
15	trans‐ 11	trans‐22	–*
15	cis‐ 11	cis‐22	60
15	12	23	36
15	trans‐ 13	trans‐24	54
15	cis‐ 13	cis‐24	43
16	14	25	75
trans‐17	14	trans‐26	83
cis‐17	14	cis‐26	62
cis‐18	14	cis‐27	19
19	14	28	44
trans‐20	14	trans‐29	66
cis‐20	14	cis‐29	86

[a] For structures, see Scheme 2 and Table 2. *The product could not be isolated.

–*

The nucleophilic substitution of the 2‐chloroacetylated isoquinoline derivative 15 with spirocyclic amines 10–13 in DMF with TBAI as catalyst resulted in the formation of the desired compounds 21–24 in satisfactory yields. Due to purification problems, the benzopyran‐based spirocyclic compound trans‐22 could not be isolated in pure form for testing. SN2 reaction of spirocyclic chloroacetamides 16, 17 and 20 with the tetrahydroisoquinoline 14 provided the amides 25, 26 and 29 in 62–86 % yields. The pure spirocyclic benzofuran 28 was obtained in only 44 % yield, due to purification problems. While the nucleophilic substitution of the 2‐chloroacetylated compounds 16, 17, 19, and 20 with tetrahydroisoquinoline 14 led to clean conversions, he corresponding 4‐chlorobutyramide 18 reacted slower to produce cis‐27, which was isolated in only 19 % yield (Table 1).

During the reaction to obtain the secondary amines trans‐22, cis‐22, trans‐24 and cis‐24, formation of tertiary amines as side‐products was observed (double nucleophilic substitution). The R f values of the tertiary amines was almost identical to the R f value of the secondary amines, rendering the fc purification of the desired products very difficult. Although the isolation and purification of the secondary amines cis‐22, trans‐ 24 and cis‐24 was successful, trans‐22 could not be isolated in sufficient purity.

As not only linkers bearing a carbonyl group were planned, derivatives 30, trans‐31 and cis‐31 with an ethylene linker between the amino moiety of the spirocyclic benzopyran and the tetrahydroisoquinoline were synthesized. (Scheme 3) This type of compounds features two basic amino moieties instead of one and can therefore adopt different orientations within the binding pocket of both σ receptor subtypes. Additionally, the effect of the carbonyl moiety on the binding affinity and selectivity can be studied.

Scheme 3

Synthesis of isoquinolines 30, trans‐31 und cis‐31 with an ethylene linker. a) LiAlH4, THF, 2–22 h, 70 °C, 63 % (30), 86 % (trans‐31), 76 % (cis‐31).

At first, a direct alkylation of the tetrahydroisoquinoline 14 was envisaged. For this purpose, 2‐bromoethanol was oxidized with Dess‐Martin perioidinane to afford 2‐bromoacetaldehyde. The aldehyde should be attached to the isoquinoline 14 in a reductive alkylation with NaBH(OAc)3. Unfortunately, after 4 h reaction time the alkylated isoquinoline could not be isolated. Next, a nucleophilic substitution with 1,2‐dibromoethane and K2CO3 in CH3CN was performed. But even after a reaction time of 18 h the desired product could not be obtained. The reaction conditions which led to a successful acylation of the isoquinoline 14 (DMF, Et3N and TBAI) also didn′t lead to the formation of the alkylated product. Finally, the desired alkylated amines 30, trans‐31 and cis‐31 were synthesized by reduction of the corresponding amides 25, trans‐26 and cis‐26 with LiAlH4. (Scheme 3) The piperidine derivative 30 was obtained in 63 % yield after 2 h heating to reflux. trans‐31 and cis‐31 were isolated after 22 h in 86 and 76 % yield, respectively.

σ1 and σ2 receptor affinity

Competitive binding assays with tritiated radioligands were utilized to determine the σ1 and σ2 receptor affinity of the synthesized compounds. In the σ1 binding assay, [3H]‐(+)‐pentazocine was used as radioligand and homogenates of guinea pig brains served as receptor material. The σ2 assay was performed with the radioligand [3H]‐di(o‐tolyl)guanidine ([3H]DTG) and homogenates of rat liver were used as receptor material. The nonselective properties of DTG was compensated by masking σ1 receptors with an excess of non‐tritiated (+)‐pentazocine.

In Table 2, the receptor affinities of the synthesized compounds are summarized. In comparison to the lead compounds trans‐7 and cis‐7, the 2‐benzopyran derivatives with an acetyl linker generally show a lower σ2 affinity. The highest σ2 affinity was observed for cis‐26 with a K i value of 371 nM. In this compound, the acyl group is located at the spirocyclic ring system. When the acyl moiety is located at the isoquinoline ring system (cis‐22), the σ2 affinity is reduced (11 % inhibition of radioligand binding). A similar trend was observed for the corresponding piperidine derivatives 25 and 21 with K i values of 534 nM and 19 % inhibition of radioligand binding, respectively.

Table 2

σ1 and σ2 receptor affinities of synthesized compounds.

Compound	X	Y	n	K i [nM]±SEM[a]
				σ1	σ2
trans‐6	–	–	1	639	58±27
cis‐6	–	–	1	1200	105±8
21	C=O	CH2	1	319	19 %
cis‐22	C=O	CH2	1	740	11 %
23	C=O	CH2	0	0 %	0 %
trans‐24	C=O	CH2	0	15 %	0 %
cis‐24	C=O	CH2	0	1600	9 %
25	CH2	C=O	1	518	534
trans‐26	CH2	C=O	1	7 %	4 %
cis‐26	CH2	C=O	1	1000	371
cis‐27	(CH2)3	C=O	1	712	2100
28	CH2	C=O	0	19 %	3400
trans‐29	CH2	C=O	0	1300	1900
cis‐29	CH2	C=O	0	129	0 %
30	CH2	CH2	1	608	348
trans‐31	CH2	CH2	1	1400	499
cis‐31	CH2	CH2	1	251	200

[a] K i values are given as means of 3 different experiments; percentage values indicate inhibition of the radioligand at a concentration of 1 μM of the test compound.

–

–

–

–

The σ1 affinity of the piperidine derivative 21 is higher than that of the corresponding cyclohexanamine derivative cis‐ 22. A general observation is that the σ1 affinity is higher for the compounds bearing the acyl group at the isoquinoline ring. For the development of σ1 ligands with the 2‐benzoypran scaffold, it can therefore be concluded that the basic center at the spirocyclic ring system should be retained.

For the derivatives with the 2‐benzofuran scaffold similar observations were made in terms of σ2 affinity. The introduction of an acetyl spacer led to loss of σ2 affinity, independent of the position of the acyl moiety (e. g., trans‐24, cis‐24, 28). In contrast to the 2‐benzopyrans, the σ1 affinity of the piperidine derivatives of the spirocyclic 2‐benzofurans was not higher than the respective cyclohexanamines. A notable exception is cis‐29 with a K i value of 129 nM at the σ1 receptor. This compound even represents a σ1 receptor selective ligand despite the 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline structural element.

The elongation of the acyl linker also led to a decrease in σ2 affinity, while the σ1 affinity was slightly increased. For the butyramide cis‐27 a K i value of 2100 nM at the σ2 receptor and 712 nM at the σ1 receptor was observed.

For the derivatives 30, cis‐31 and trans‐31 with an ethylene linker an increased σ2 affinity in comparison to the corresponding amides (e. g., 21, cis‐22) was found. The σ1 receptor affinity of the cyclohexanamines cis‐31 and trans‐31 was also increased, resulting in a loss of σ2 preference of cis‐31. The piperidine 30 shows a slight preference for the σ2 receptor (K i values of 348 nM and 608 nM, respectively).

Conclusion

The introduction of a spacer between the spirocyclic 2‐benzopyran and 2‐benzofuran scaffold and the tetrahydroisoquinoline system was envisaged to study structure affinity relationships and evaluate possibilities to optimize selectivity of the lead compounds trans‐7 and cis‐7. A set of compounds with amide and alkyl spacers was synthesized and pharmacologically evaluated in competitive binding assays. Although the introduction of the linker generally resulted in a loss of σ affinity in comparison to the lead compounds 7 without linker, some interesting observations could be made. Compounds containing the 2‐benzopyran scaffold showed a higher affinity than the corresponding 2‐benzofurans. Compounds 30, trans‐31 and cis‐31 with an ethylene linker displayed higher affinity than compounds with an amide in the side chain. The introduction of the linker in compounds 21 and cis‐29 resulted in an unexpected selectivity for the σ1 receptor. In conclusion, the combination of wo promising σ2 pharmacophoric elements, that is, the connection of an O‐containing spirocyclic system with the tetrahydroisoquinoline moiety by different spacers, did not provide high‐affinity σ2 selective ligands. However, the synthesized σ ligands allow an interesting insight into the limitations of acyl chains as linker between the two pharmacophoric elements. cis‐31 and trans‐31 could serve as a starting point for further structural modifications resulting in higher σ2 affinity and selectivity.

Experimental Section

Chemistry, General

Unless otherwise noted, moisture sensitive reactions were conducted under dry nitrogen. CH2Cl2 was distilled over CaH2. THF was distilled over sodium/benzophenone. Thin layer chromatography (tlc): Silica gel 60 F254 plates (Merck). Flash chromatography (fc): Silica gel 60, 40–64 μm (Merck); parentheses include: diameter of the column (d), length of the stationary phase (l), fraction size (V), eluent. Melting point: Melting point apparatus Mettler Toledo MP50 melting point system, uncorrected. MS: microTOF−Q II (Bruker Daltonics); APCI, atmospheric pressure chemical ionization; microTof mass spectrometer (Bruker Daltonics); ESI, electrospray ionization. IR: FTIR spectrophotometer MIRacle 10 (Shimadzu) equipped with ATR technique. Nuclear magnetic resonance (NMR) spectra were recorded on Agilent 600‐MR (600 MHz for 1H, 151 MHz for 13C) or Agilent 400‐MR spectrometer (400 MHz for 1H, 101 MHz for 13C); δ in ppm related to tetramethylsilane and measured referring to CHCl3 (δ=7.26 ppm (1H NMR) and δ=77.2 ppm (13C NMR)) and CHD2OD (δ=3.31 ppm (1H NMR) and δ=49.0 ppm (13C NMR)); coupling constants are given with 0.5 Hz resolution; the assignments of 13C and 1H NMR signals were supported by 2‐D NMR techniques where necessary (data not shown); multiplicities of the signals are abbreviated as follows: s=singlet, d=doublet, t=triplet, q=quartet; dd=doublet of doublets, m=multiplet. HPLC: pump: LPG‐3400SD, degasser: DG‐1210, autosampler: ACC‐3000T, UV‐detector: VWD‐3400RS, interface: DIONEX UltiMate 3000, data acquisition: Chromeleon 7 (Thermo Fisher Scientific); column: LiChrospher® 60 RP‐select B (5 μm), LiChroCART® 250–4 mm cartridge; guard column: LiChrospher® 60 RP‐select B (5 μm), LiChroCART® 4–4 mm cartridge (no.: 1.50963.0001), manu‐CART® NT cartridge holder; flow rate: 1.0 mL/min; injection volume: 5.0 μL; detection at λ=210 nm; solvents: A: water with 0.05 % (v/v) trifluoroacetic acid; B: acetonitrile with 0.05 % (v/v) trifluoroacetic acid: gradient elution: (A %): 0–4 min: 90 %, 4–29 min: 90→0 %, 29–31 min: 0 %, 31–31.5 min: 0→90 %, 31.5–40 min: 90 %. The purity of all compounds was determined by this method. Unless otherwise mentioned, the purity of all test compounds is higher than 95 %.

Synthetic procedures

The synthesis of the spirocyclic piperidines 10 and 12 has been reported in the literature.[ , ] The synthesis of exocyclic primary amines trans‐11 and cis‐11 was described in ref. [34]. The synthesis of trans‐ and cis‐configured benzylamines trans‐9 and cis‐9 was reported in ref. [37] and [38].

trans‐3‐Methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐amine (trans‐13)

A solution of benzylamine trans‐9 (248 mg, 0.76 mmol), ammonium formate (255 mg, 4.05 mmol, 5.3 equiv) and 10 % Pd/C (35 mg, 0.03 mmol, 4 mol‐%) in CH3OH (15 mL) was heated to reflux for 17 h. The mixture was filtered through Celite, washed with CH2Cl2 (150 mL) and concentrated in vacuo. 1 M NaOH (15 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Yellow oil, yield 153 mg (86 %). C14H19NO2 (233.3 g/mol). TLC: R f=0.03 (cyclohexane/ethyl acetate 67 : 33+1 % N,N‐dimethylethanamine). HRMS (APCI, method 1): m/z 234.1477 (calcd. 234.1489 for C14H20NO2 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.58–1.64 (m, 1H, 2′‐H), 1.65–1.76 (m, 3H, 3′‐H, 5′‐H, 6′‐H), 2.01–2.09 (m, 4H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 3.11–3.15 (m, 1H, 4′‐H equ), 3.47 (s, 3H, OCH 3), 6.04 (s, 1H, 3‐H), 7.34–7.38 (m, 2H, 4‐H, 5‐H), 7.38–7.42 (m, 1H, 6‐H), 7.49 ppm (d, J=7.7 Hz, 1H, 7‐H). A signal for the NH2 protons is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=30.5 (1 C, C‐3′ or C‐5′), 30.7 (1 C, C‐3′ or C‐5′), 34.0 (1 C, C‐2′), 35.2 (1 C, C‐6′), 47.2 (1 C, C‐4′), 54.8 (1 C, OCH3), 88.0 (1 C, C‐1), 106.9 (1 C, C‐3), 122.6 (1 C, C‐7), 124.2 (1 C, C‐4), 128.9 (1 C, C‐5), 130.3 (1 C, C‐6), 138.8 (1 C, C‐3a), 148.8 ppm (1 C, C‐7a). FTIR (neat): ν [cm−1]=3364 (N−H), 2924, 2855 (C−Halkyl), 1435, 1366 (C=Carom). Purity (HPLC): 93.9 %, t R=8.7 min.

cis‐3‐Methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐amine (cis‐13)

A solution of benzylamine cis‐9 (414 mg, 1.28 mmol), ammonium formate (406 mg, 6.44 mmol, 5.0 equiv) and 10 % Pd/C (55 mg, 0.05 mmol, 4 mol‐%) in CH3OH (25 mL) was heated to reflux for 21 h. The mixture was filtered through Celite, washed with CH2Cl2 (200 mL) and concentrated in vacuo. 1 M NaOH (15 mL) was added and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Yellow oil, yield 198 mg (66 %). C14H19NO2 (233.3 g/mol). TLC: R f=0.02 (cyclohexane/ethyl acetate 67 : 33+1 % N,N‐dimethylethanamine). HRMS (APCI, method 1): m/z 234.1479 (calcd. 234.1489 for C14H20NO2 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.63–1.68 (m, 1H, 2′‐H), 1.68–1.76 (m, 2H, 3′‐H, 5′‐H), 1.82–1.89 (m, 4H, 3′‐H, 5′‐H, 6′‐H), 1.93 (td, J=13.5/4.1 Hz, 1H, 2′‐H), 2.82 (tt, J=11.5/3.8 Hz, 1H, 4′‐H ax), 3.49 (s, 3H, OCH 3), 6.05 (s, 1H, 3‐H), 7.23 (d, J=7.4 Hz, 1H, 7‐H), 7.32–7.41 ppm (m, 3H, 4‐H, 5‐H, 6‐H). A signal for the NH2 protons is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=32.5 (1 C, C‐3′ or C‐5′), 32.9 (1 C, C‐3′ or C‐5′), 37.6 (1 C, C‐2′), 38.9 (1 C, C‐6′), 50.5 (1 C, C‐4′), 54.9 (1 C, OCH3), 87.1 (1 C, C‐1), 107.1 (1 C, C‐3), 121.7 (1 C, C‐7), 124.2 (1 C, C‐4), 128.9 (1 C, C‐5), 130.4 (1 C, C‐6), 138.7 (1 C, C‐3a), 148.6 ppm (1 C, C‐7a). FTIR (neat): ν [cm−1]=3356 (N−H), 2928, 2859 (C−Halkyl), 1458, 1439 (C=Carom). Purity (HPLC): 99.3 %, t R=10.5 min.

2‐Chloro‐1‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethan‐1‐one (15)

The compound was synthesized according to the literature. 2‐Chloroacetyl chloride (0.12 mL, 1.51 mmol, 1.2 equiv) was slowly added to a solution of isoquinoline 14⋅HCl (281 mg, 1.22 mmol) and Et3N (0.42 mL, 3.03 mmol, 2.5 equiv) in CH2Cl2 (30 mL) under N2 at 0 °C. After stirring for 4.5 h at RT, H2O (50 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2.5 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 67 : 33). Pale yellow solid, m.p. 109 °C, yield 247 mg (75 %). C13H16ClNO3 (269.7 g/mol). R f=0.26 (cyclohexane/ethyl acetate 50 : 50). HRMS (APCI): m/z 270.0864 (calcd. 270.0891 for C13H17 35ClNO3 [MH+]). 1H NMR (400 MHz, CDCl3): δ=2.80 (t, J=6.0 Hz, 0.8H, 4‐H), 2.89 (t, J=5.9 Hz, 1.2H, 4‐H), 3.73 (t, J=5.9 Hz, 1.2H, 3‐H), 3.81–3.88 (m, 6.8H, 3‐H, 6‐OCH 3, 7‐OCH 3), 4.15 (s, 1.2H, COCH 2Cl), 4.16 (s, 0.8H, COCH 2Cl), 4.62 (s, 0.8H, 1‐H), 4.67 (s, 1.2H, 1‐H), 6.59–6.65 ppm (m, 2H, 5‐H, 8‐H). 13C NMR (101 MHz, CDCl3): δ=27.9 (0.4 C, C‐4), 29.1 (0.6 C, C‐4), 40.7 (0.4 C, C‐3), 41.3 (0.6 C, COCH2Cl), 41.6 (0.4 C, COCH2Cl), 44.1 (0.6 C, C‐3), 44.6 (0.6 C, C‐1), 47.7 (0.4 C, C‐1), 56.13 (1.2 C, 6‐OCH3, 7‐OCH3), 56.18 (0.8 C, 6‐OCH3, 7‐OCH3), 109.0 (0.4 C, C‐8), 109.5 (0.6 C, C‐8), 111.4 (0.6 C, C‐5), 111.7 (0.4 C, C‐5), 123.7 (0.4 C, C‐8a), 124.6 (0.6 C, C‐8a), 125.6 (0.6 C, C‐4a), 126.7 (0.4 C, C‐4a), 148.0 (1.2 C, C‐6, C‐7), 148.2 (0.8 C, C‐6, C‐7), 165.5 (0.4 C, C=O), 165.6 ppm (0.4 C, C=O). FTIR (neat): ν [cm−1]=2974, 2932 (C−Halkyl), 1651 (C=O), 1520, 1443 (C=Carom). Purity (HPLC): 99.7 %, t R=15.9 min.

trans‐2‐Chloro‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (trans‐17)

2‐Chloroacetyl chloride (19 μL, 0.24 mmol, 1.2 equiv) was slowly added to a solution of amine trans‐11 (50 mg, 0.20 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.5 equiv) in CH2Cl2 (5 mL) under N2 at 0 °C. After stirring for 6.5 h at RT, H2O (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=16 cm, V=5 mL, cyclohexane/ethyl acetate 50 : 50). Pale yellow solid, m.p. 144 °C, yield 36 mg (56 %). C17H22ClNO3 (323.8 g/mol). R f=0.22 (cyclohexane/ethyl acetate 67 : 33). HRMS (APCI): m/z 292.1080 (calcd. 292.1099 for C16H19 35ClNO2 [M‐CH3OH+H+]). 1H NMR (600 MHz, CD3OD): δ=1.68–1.72 (m, 1H, 2′‐H), 1.76–1.81 (m, 2H, 3′‐H, 5′‐H), 1.88 (td, J=14.1/3.8 Hz, 1H, 6′‐H), 1.92–1.97 (m, 1H, 6′‐H), 2.10–2.25 (m, 3H, 2′‐H, 3′‐H, 5′‐H), 2.81 (dd, J=15.6/7.4 Hz, 1H, 4‐H), 2.94 (dd, J=15.6/3.1 Hz, 1H, 4‐H), 3.55 (s, 3H, OCH 3), 4.12–4.16 (m, 1H, 4′‐H equ), 4.13 (s, 2H, COCH 2Cl), 4.92 (dd, J=7.4/3.1 Hz, 1H, 3‐H), 7.10 (dd, J=7.6/1.3 Hz, 1H, 5‐H), 7.17 (td, J=7.4/1.3 Hz, 1H, 6‐H), 7.20–7.23 (m, 1H, 7‐H), 7.29 ppm (dd, J=7.8/1.3 Hz, 1H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=26.2 (1 C, C‐3′), 26.3 (1 C, C‐5′), 32.0 (1 C, C‐6′), 34.4 (1 C, C‐2′), 36.1 (1 C, C‐4), 43.4 (1 C, COCH2Cl), 45.8 (1 C, C‐4′), 56.4 (1 C, OCH3), 77.4 (1 C, C‐1), 97.9 (1 C, C‐3), 125.7 (1 C, C‐8), 127.5 (1 C, C‐7), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.5 (1 C, C‐4a), 143.0 (1 C, C‐8a), 169.2 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3321 (N−H), 2928, 2851 (C−Halkyl), 1636 (C=O), 1547, 1447 (C=Carom). Purity (HPLC): 94.8 %, t R=18.9 min.

cis‐2‐Chloro‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (cis‐17)

2‐Chloroacetyl chloride (19 μL, 0.24 mmol, 1.2 equiv) was slowly added to a solution of amine cis‐11 (50 mg, 0.20 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.5 equiv) in CH2Cl2 (5 mL) under N2 at 0 °C. After stirring for 6 h at RT, H2O (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 67 : 33). Colorless solid, m.p. 148 °C, yield 40 mg (60 %). C17H22ClNO3 (323.8 g/mol). R f=0.44 (cyclohexane/ethyl acetate 50 : 50). HRMS (APCI): m/z 292.1072 (calcd. 292.1099 for C16H19 35ClNO2 [M‐CH3OH+H+]). 1H NMR (600 MHz, CD3OD): δ=1.77–1.91 (m, 5H, 2′‐H ax, 3′‐H, 5′‐H, 6′‐H equ), 1.92–1.97 (m, 1H, 5′‐H), 2.08 (td, J=13.2/3.9 Hz, 1H, 6′‐H ax), 2.13 (dq, J=14.0/2.9 Hz, 1H, 2′‐H equ), 2.81 (dd, J=15.6/7.5 Hz, 1H, 4‐H), 2.94 (dd, J=15.8/2.9 Hz, 1H, 4‐H), 3.58 (s, 3H, OCH 3), 3.88 (tt, J=11.3/4.7 Hz, 1H, 4′‐H ax), 4.03 (s, 2H, COCH 2Cl), 4.92 (dd, J=7.5/3.1 Hz, 1H, 3‐H), 7.09 (d, J=7.3 Hz, 1H, 5‐H), 7.16 (td, J=7.2/1.9 Hz, 1H, 6‐H), 7.18–7.24 ppm (m, 2H, 7‐H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=28.7 (1 C, C‐5′), 28.8 (1 C, C‐3′), 36.1 (1 C, C‐4), 36.5 (1 C, C‐2′), 39.1 (1 C, C‐6′), 43.3 (1 C, COCH2Cl), 49.7 (1 C, C‐4′), 56.4 (1 C, OCH3), 76.9 (1 C, C‐1), 97.9 (1 C, C‐3), 125.7 (1 C, C‐8), 127.6 (1 C, C‐7), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.5 (1 C, C‐8a), 168.6 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3302 (N−H), 2932, 2862 (C−Halkyl), 1643 (C=O), 1447 (C=Carom). Purity (HPLC): 97.1 %, t R=18.6 min.

cis‐4‐Chloro‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)butanamide (cis‐18)

4‐Chlorobutyryl chloride (27.4 μL, 0.24 mmol, 1.1 equiv) was slowly added to a solution of amine cis.11 (54 mg, 0.22 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.3 equiv.) in CH2Cl2 (15 mL) under N2 at 0 °C. After stirring for 4 h at RT, H2O (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Colorless solid, m.p. 126 °C, yield 69 mg (89 %). C19H26ClNO3 (351.9 g/mol). R f=0.37 (cyclohexane/ethyl acetate 50 : 50). HRMS (ESI): m/z 374.1504 (calcd. 374.1493 for C19H26 35ClNO3Na [MNa+]). 1H NMR (400 MHz, CD3OD): δ=1.78–1.94 (m, 6H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 2.02–2.17 (m, 4H, 2′‐H, 6′‐H, COCH2CH 2CH2Cl), 2.39 (t, J=7.3 Hz, 2H, COCH 2CH2CH2Cl), 2.82 (dd, J=15.7/7.5 Hz, 1H, 4‐H), 2.94 (dd, J=15.7/3.2 Hz, 1H, 4‐H), 3.60 (s, 3H, OCH 3), 3.63 (t, J=6.5 Hz, 2H, COCH2CH2CH 2Cl), 3.81–3.91 (m, 1H, 4′‐H ax), 4.93 (dd, J=7.4/3.2 Hz, 1H, 3‐H), 7.10 (d, J=7.0 Hz, 1H, 5‐H), 7.14–7.26 ppm (m, 3H, 6‐H, 7‐H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=28.9 (1 C, C‐3′ or C‐5′), 29.1 (1 C, C‐3′ or C‐5′), 30.0 (1 C, COCH2 CH2CH2Cl), 34.2 (1 C, COCH2CH2CH2Cl), 36.1 (1 C, C‐4), 36.5 (1 C, C‐2′), 39.1 (1 C, C‐6′), 45.1 (1 C, COCH2CH2 CH2Cl), 49.1 (1 C, C‐4′), 56.4 (1 C, OCH3), 77.0 (1 C, C‐1), 97.8 (1 C, C‐3), 125.7 (1 C, C‐8), 127.5 (1 C, C‐6 or C‐7), 127.7 (1 C, C‐6 or C‐7), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.5 (1 C, C‐8a), 174.1 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3306 (N−H), 2928, 2862 (C−Halkyl), 1636 (C=O), 1543, 1443 (C=Carom). Purity (HPLC): 72.3 %, t R=19.6 min.

trans‐2‐Chloro‐N‐(3‐methoxy‐3H‐spiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (trans‐20)

2‐Chloroacetyl chloride (20 μL, 0.25 mmol, 1.2 equiv) was slowly added to a solution of amine trans‐13 (49 mg, 0.21 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.4 equiv) in CH2Cl2 (10 mL) under N2 at 0 °C. After stirring for 6 h at RT, H2O (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=20 cm, V=5 mL, cyclohexane/ethyl acetate 67 : 33). Colorless solid, m.p. 123 °C, yield 45 mg (69 %). C16H20ClNO3 (309.8 g/mol). R f=0.50 (cyclohexane/ethyl acetate 50 : 50). HRMS (ESI): m/z 332.1037 (calcd. 332.1024 for C16H20 35ClNO3Na [MNa+]). 1H NMR (600 MHz, CD3OD): δ=1.61–1.66 (m, 1H, 2′‐H), 1.78 (dddd, J=13.6/5.7/4.1/1.9 Hz, 1H, 6′‐H equ), 1.83–1.92 (m, 2H, 3′‐H, 5′‐H), 1.97–2.15 (m, 4H, 2′‐H, 3′‐H, 5′‐H, 6′‐H ax), 3.48 (s, 3H, OCH 3), 4.07–4.14 (m, 1H, 4′‐H equ), 4.11 (s, 2H, COCH 2Cl), 6.05 (s, 1H, 3‐H), 7.35–7.38 (m, 2H, 4‐H, 5‐H), 7.38–7.43 ppm (m, 2H, 6‐H, 7‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=27.4 (1 C, C‐3′ or C‐5′), 27.6 (1 C, C‐3′ or C‐5′), 34.0 (1 C, C‐2′), 35.3 (1 C, C‐6′), 43.4 (1 C, COCH2Cl), 46.6 (1 C, C‐4′), 55.0 (1 C, OCH3), 87.3 (1 C, C‐1), 107.0 (1 C, C‐3), 122.1 (1 C, C‐7), 124.3 (1 C, C‐4), 129.0 (1 C, C‐5), 130.4 (1 C, C‐6), 138.9 (1 C, C‐3a), 148.5 (1 C, C‐7a), 169.0 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3302 (N−H), 2932 (C−Halkyl), 1643 (C=O), 1543, 1443 (C=Carom). Purity (HPLC): 97.6 %, t R=14.6 min.

cis‐2‐Chloro‐N‐(3‐methoxy‐3H‐spiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (cis‐20)

2‐Chloroacetyl chloride (20 μL, 0.25 mmol, 1.2 equiv) was slowly added to a solution of amine cis‐13 (50 mg, 0.21 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.4 equiv) in CH2Cl2 (8 mL) under N2 at 0 °C. After stirring for 6 h at RT, H2O (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=18 cm, V=10 mL, cyclohexane/ethyl acetate 33 : 67). Colorless solid, m.p. 165 °C, yield 51 mg (78 %). C16H20ClNO3 (309.8 g/mol). R f=0.48 (cyclohexane/ethyl acetate 50 : 50). HRMS (ESI): m/z 332.1014 (calcd. 332.1024 for C16H20 35ClNO3Na [MNa+]). 1H NMR (600 MHz, CD3OD): δ=1.69 (dq, J=13.6/3.0 Hz, 1H, 2′‐H equ), 1.82–1.94 (m, 6H, 3′‐H, 5′‐H, 6′‐H), 2.00 (td, J=13.5/4.1 Hz, 1H, 2′‐H ax), 3.49 (s, 3H, OCH 3), 3.87 (tt, J=11.1/3.9 Hz, 1H, 4′‐H ax), 4.03 (s, 2H, COCH 2Cl), 6.07 (s, 1H, 3‐H), 7.26 (d, J=7.5 Hz, 1H, 7‐H), 7.33–7.38 (m, 2H, 4‐H, 5‐H), 7.39–7.42 ppm (m, 1H, 6‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=29.3 (1 C, C‐3′), 29.7 (1 C, C‐5′), 37.5 (1 C, C‐2′), 38.7 (1 C, C‐6′), 43.3 (1 C, COCH2Cl), 49.5 (1 C, C‐4′), 54.9 (1 C, OCH3), 86.8 (1 C, C‐1), 107.2 (1 C, C‐3), 121.8 (1 C, C‐7), 124.2 (1 C, C‐4), 129.0 (1 C, C‐5), 130.5 (1 C, C‐6), 138.6 (1 C, C‐3a), 148.3 (1 C, C‐7a), 168.6 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3271 (N−H), 2978, 2940, 2866 (C−Halkyl), 1651 (C=O), 1555, 1462, 1431 (C=Carom). Purity (HPLC): 98.1 %, t R=15.1 min.

1‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐2‐{3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,4′‐piperidin]‐1′‐yl}ethan‐1‐one (21)

A solution of piperidine 10 (43 mg, 0.18 mmol), chloroacetamide 15 (58 mg, 0.22 mmol, 1.2 equiv), Et3N (0.09 mL, 0.65 mmol, 3.6 equiv) and TBAI (9 mg, 0.02 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 18 h. H2O (70 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=25 cm, V=10 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine; d=1 cm, l=20 cm, V=3 mL, cyclohexane/ethyl acetate 67 : 33+1 % N,N‐dimethylethanamine→1 : 1+1 % N,N‐dimethylethanamine). Pale yellow oil, yield 31 mg (22 %). C27H34N2O5 (466.6 g/mol). R f=0.46 (CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 467.2531 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (400 MHz, CD3OD): δ=1.70 (dq, J=13.5/2.8 Hz, 0.5H, 3′‐H equ), 1.75–1.85 (m, 1H, 3′‐H, 5′‐H), 1.95 (dq, J=13.9/2.6 Hz, 0.5H, 5′‐H equ), 2.00–2.09 (m, 1.5H, 3′‐H, 5′‐H), 2.29 (td, J=13.1/4.5 Hz, 0.5H, 3′‐H ax), 2.57–2.73 (m, 2H, 2′‐H, 6′‐H), 2.73–3.00 (m, 6H, 4‐H, 2′‐H, 6′‐H, 4‐H isoquinoline), 3.38–3.52 (m, 2H, COCH 2N), 3.54 (s, 1.5H, 3‐OCH 3), 3.57 (s, 1.5H, 3‐OCH 3), 3.81–3.90 (m, 8H, 3‐H isoquinoline, 6‐OCH 3, 7‐OCH 3), 4.66 (s, 1H, 1‐H isoquinoline), 4.80 (s, 1H, 1‐H isoquinoline), 4.90 (dd, J=7.2/3.2 Hz, 0.5H, 3‐H), 4.95 (dd, J=7.2/3.2 Hz, 0.5H, 3‐H), 6.76–6.83 (m, 1.5H, 5‐H isoquinoline, 8‐H isoquinoline), 6.86 (s, 0.5H, 8‐H isoquinoline), 7.01–7.05 (m, 0.5H, 8‐H), 7.06–7.14 (m, 1H, 5‐H) 7.14–7.26 ppm (m, 2.5H, 6‐H, 7‐H, 8‐H). 13C NMR (101 MHz, CD3OD): δ=28.6 (0.5 C, C‐4isoquinoline), 29.7 (0.5 C, C‐4isoquinoline), 35.86 (0.5 C, C‐4), 35.89 (0.5 C, C‐4), 37.18 (0.5 C, C‐5′), 37.20 (0.5 C, C‐5′), 39.6 (0.5 C, C‐3′), 39.7 (0.5 C, C‐3′), 41.7 (0.5 C, C‐3isoquinoline), 44.4 (0.5 C, C‐3isoquinoline), 44.9 (0.5 C, C‐1isoquinoline), 48.2 (0.5 C, C‐1isoquinoline), 50.2–50.7 (m, 2 C, C‐2′, C‐6′), 56.2–56.4 (m, 3 C, 3‐OCH3, 6‐OCH3, 7‐OCH3), 61.68 (0.5 C, COCH2N), 61.74 (0.5 C, COCH2N), 75.2 (0.5 C, C‐1), 75.4 (0.5 C, C‐1), 97.55 (0.5 C, C‐3), 97.59 (0.5 C, C‐3), 110.6 (0.5 C, C‐8isoquinoline), 110.9 (0.5 C, C‐8isoquinoline), 112.9 (0.5 C, C‐5isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 125.6 (1 C, C‐8), 126.1 (1 C, C‐8aisoquinoline), 126.9 (1 C, C‐4aisoquinoline), 127.37 (0.5 C, C‐7), 127.39 (0.5 C, C‐7), 127.56 (0.5 C, C‐6), 127.62 (0.5 C, C‐6), 129.9 (0.5 C, C‐5), 130.0 (0.5 C, C‐5), 132.4 (0.5 C, C‐4a), 132.5 (0.5 C, C‐4a), 141.89 (0.5 C, C‐8a), 141.92 (0.5 C, C‐8a), 149.0–149.3 (m, 2 C, C‐6isoquinoline, C‐7isoquinoline), 170.7 (0.5 C, C=O), 170.8 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=2978, 2835 (C−Halkyl), 1624 (C=O), 1516, 1454 (C=Carom). Purity (HPLC): 92.1 %, t R=17.4 min.

cis‐1‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐2‐[N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)amino]ethan‐1‐one (cis‐22)

A solution of chloroacetamide 15 (32 mg, 0.12 mmol), amine cis‐11 (36 mg, 0.15 mmol, 1.2 equiv), Et3N (0.06 mL, 0.43 mmol, 2.9 equiv) and TBAI (5 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 7 d. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=29 cm, V=10 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine). Pale yellow oil, yield 35 mg (60 %). C28H36N2O5 (480.6 g/mol). R f=0.29 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 481.2700 (calcd. 481.2697 for C28H37N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.64–1.78 (m, 2H, 2′‐H, 3′‐H), 1.78–1.92 (m, 4H, 3′‐H, 5′‐H, 6′‐H), 1.92–2.02 (m, 1H, 6′‐H), 2.07–2.13 (m, 1H, 2′‐H), 2.63–2.72 (m, 1H, 4′‐H ax), 2.77–2.82 (m, 2H, 4‐H, 4‐H isoquinoline), 2.87 (t, J=6.0 Hz, 1H, 4‐H isoquinoline), 2.89–2.95 (m, 1H, 4‐H), 3.56 (s, 1.5H, OCH 3), 3.57 (s, 1.5H, 3‐OCH 3), 3.65 (s, 2H, COCH 2NH), 3.70 (t, J=5.9 Hz, 1H, 3‐H isoquinoline), 3.80–3.83 (m, 1H, 3‐H isoquinoline), 3.82 (s, 6H, 6‐OCH 3, 7‐OCH 3), 4.61 (s, 1H, 1‐H isoquinoline), 4.66 (s, 1H, 1‐H isoquinoline), 4.89–4.92 (m, 1H, 3‐H), 6.76–6.79 (m, 1.5H, 5‐H isoquinoline, 8‐H isoquinoline), 6.80 (s, 0.5H, 8‐H isoquinoline), 7.06–7.09 (m, 1H, 5‐H), 7.12–7.20 ppm (m, 3H, 6‐H, 7‐H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=28.8 (0.5 C, C‐4isoquinoline), 29.1 (1 C, C‐3′ or C‐5′), 29.3 (1 C, C‐3′ or C‐5′), 29.6 (0.5 C, C‐4isoquinoline), 36.2 (1 C, C‐4), 36.4 (1 C, C‐2′), 38.9 (1 C, C‐6′), 41.6 (0.5 C, C‐3isoquinoline), 43.6 (0.5 C, C‐3isoquinoline), 45.2 (0.5 C, C‐1isoquinoline), 46.9 (0.5 C, C‐1isoquinoline), 48.1 (0.5 C, COCH2NH), 48.3 (0.5 C, COCH2NH), 56.4–56.6 (m, 3 C, 3‐OCH3, 6‐OCH3, 7‐OCH3), 57.47 (0.5 C, C‐4′), 57.49 (0.5 C, C‐4′), 77.37 (0.5 C, C‐1), 77.39 (0.5 C, C‐1), 97.8 (1 C, C‐3), 110.9 (0.5 C, C‐8isoquinoline), 111.0 (0.5 C, C‐8isoquinoline), 113.0 (0.5 C, C‐5isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 125.6 (0.5 C, C‐8), 125.7 (0.5 C, C‐8), 125.8 (0.5 C, C‐8aisoquinoline), 126.3 (0.5 C, C‐8aisoquinoline), 127.5 (1 C, C‐7), 127.67 (1 C, C‐6), 127.74 (0.5 C, C‐4aisoquinoline), 128.2 (0.5 C, C‐4aisoquinoline), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.61 (0.5 C, C‐8a), 142.62 (0.5 C, C‐8a), 149.2–149.6 (m, 2 C, C‐6isoquinoline, C‐7isoquinoline), 171.4 (0.5 C, C=O), 171.5 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=3375 (N−H), 2978, 2936, 2909 (C−Halkyl), 1640 (C=O), 1516, 1435 (C=Carom). Purity (HPLC): 98.0 %, t R=17.7 min.

1‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐2‐{3‐methoxy‐3H‐spiro[[2]benzofuran‐1,4′‐piperidin]‐1′‐yl}ethan‐1‐one (23)

A solution of piperidine 12 (40 mg, 0.18 mmol), chloroacetamide 15 (50 mg, 0.19 mmol, 1.0 equiv), Et3N (0.09 mL, 0.65 mmol, 3.6 equiv) and TBAI (7 mg, 0.02 mmol, 0.1 equiv) in DMF (5 mL) was stirred at RT for 19 h. H2O (70 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo, and the residue was purified twice by fc (d=2 cm, l=25 cm, V=10 mL, CH2Cl2/CH3OH 95 : 5; d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Pale yellow solid, m.p. 103 °C, yield 30 mg (36 %). C26H32N2O5 (452.6 g/mol). R f=0.30 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 453.2406 (calcd. 453.2384 for C26H33N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.52 (dq, J=13.5/2.7 Hz, 0.5H, 3′‐H equ), 1.61 (dq, J=13.6/2.8 Hz, 0.5H, 3′‐H equ), 1.70 (dq, J=13.5/2.7 Hz, 0.5H, 5′‐H equ), 1.78 (dq, J=13.6/2.8 Hz, 0.5H, 5′‐H equ), 1.88–2.00 (m, 1H, 3′‐H ax, 5′‐H ax), 2.09 (td, J=13.1/4.5 Hz, 0.5H, 5′‐H ax), 2.17 (td, J=13.2/4.5 Hz, 0.5H, 3′‐H ax), 2.55–2.66 (m, 2H, 2′‐H, 6′‐H), 2.81 (t, J=6.1 Hz, 1H, 4‐H isoquinoline), 2.84–2.89 (m, 1H, 2′‐H or 6′‐H), 2.90–2.96 (m, 2H, 2′‐H or 6′‐H, 4‐H isoquinoline), 3.40–3.43 (m, 2H, COCH 2N), 3.47 (s, 1.5H, 3‐OCH 3), 3.49 (s, 1.5H, 3‐OCH 3), 3.79–3.87 (m, 8H, 3‐H isoquinoline, 6‐OCH 3, 7‐OCH 3), 4.65 (s, 1H, 1‐H isoquinoline), 4.76 (d, J=15.9 Hz, 0.5H, 1‐H isoquinoline), 4.79 (d, J=15.9 Hz, 0.5H, 1‐H isoquinoline), 6.04 (s, 0.5H, 3‐H), 6.06 (s, 0.5H, 3‐H), 6.77 (s, 1H, 5‐H isoquinoline, 8‐H isoquinoline), 6.79 (s, 0.5H, 5‐H isoquinoline), 6.83 (s, 0.5H, 8‐H isoquinoline), 7.15 (d, J=7.6 Hz, 0.5H, 4‐H), 7.29 (d, J=7.6 Hz, 0.5H, 4‐H), 7.32–7.43 ppm (m, 3H, 5‐H, 6‐H, 7‐H). 13C NMR (151 MHz, CD3OD): δ=28.8 (0.5 C, C‐4isoquinoline), 30.0 (0.5 C, C‐4isoquinoline), 38.07 (0.5 C, C‐3′), 38.14 (0.5 C, C‐3′), 39.60 (0.5 C, C‐5′), 39.64 (0.5 C, C‐5′), 41.8 (0.5 C, C‐3isoquinoline), 44.6 (0.5 C, C‐3isoquinoline), 45.2 (0.5 C, C‐1isoquinoline), 48.3 (0.5 C, C‐1isoquinoline), 50.9–51.7 (m, 2 C, C‐2′, C‐6′), 54.98 (0.5 C, 3‐OCH3), 55.01 (0.5 C, 3‐OCH3), 56.5–56.6 (m, 2 C, 6‐OCH3, 7‐OCH3), 61.89 (0.5 C, COCH2N), 61.92 (0.5 C, COCH2N), 85.5 (1 C, C‐1), 107.1 (0.5 C, C‐3), 107.2 (0.5 C, C‐3), 110.9 (0.5 C, C‐8isoquinoline), 111.0 (0.5 C, C‐8isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 113.3 (0.5 C, C‐5isoquinoline), 121.7 (0.5 C, C‐4), 121.8 (0.5 C, C‐4), 124.21 (0.5 C, C‐7), 124.25 (0.5 C, C‐7), 126.3 (0.5 C, C‐8aisoquinoline), 126.9 (0.5 C, C‐4aisoquinoline), 127.8 (0.5 C, C‐8aisoquinoline), 128.0 (0.5 C, C‐4aisoquinoline), 129.08 (0.5 C, C‐6), 129.12 (0.5 C, C‐6), 130.49 (0.5 C, C‐5), 130.51 (0.5 C, C‐5), 138.86 (0.5 C, C‐7a), 138.92 (0.5 C, C‐7a), 148.01 (0.5 C, C‐3a), 148.02 (0.5 C, C‐3a), 149.2–149.5 (m, 2 C, C‐6isoquinoline, C‐7isoquinoline), 170.9 (0.5 C, C=O), 171.0 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=2913, 2735 (C−Halkyl), 1636 (C=O), 1516, 1447 (C=Carom). Purity (HPLC): 99.7 %, t R=14.9–17.0 min.

trans‐1‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐2‐[N‐(3‐methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐yl)amino]ethan‐1‐one (trans‐24)

A solution of chloroacetamide 15 (30 mg, 0.11 mmol), amine trans‐13 (26 mg, 0.11 mmol, 1.0 equiv), Et3N (0.05 mL, 0.36 mmol, 3.3 equiv.) and TBAI (5 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 3 d. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=18 cm, V=10 mL, cyclohexane/ethyl acetate 33 : 67+1 % N,N‐dimethylethanamine→20 : 80+1 % N,N‐dimethylethanamine; d=2 cm, l=31 cm, V=10 mL, CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). Colorless solid, m.p. 66 °C, yield 28 mg (54 %). C27H34N2O5 (466.6 g/mol). R f=0.33 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 467.2533 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.52–1.60 (m, 1H, 2′‐H), 1.66–1.74 (m, 1H, 6′‐H), 1.77–1.86 (m, 2H, 3′‐H, 5′‐H), 2.01–2.13 (m, 4H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 2.81 (t, J=6.0 Hz, 1H, 4‐H isoquinoline), 2.81 (t, J=6.0 Hz, 1H, 4‐H isoquinoline), 2.90–2.94 (m, 1H, 4′‐H equ), 3.46 (s, 1.5H, 3‐OCH 3), 3.47 (s, 1.5H, 3‐OCH 3), 3.65 (s, 2H, COCH 2NH), 3.73 (t, J=5.9 Hz, 1H, 3‐H isoquinoline), 3.80–3.86 (m, 7H, 3‐H isoquinoline, 6‐OCH 3, 7‐OCH 3), 4.67 (s, 1H, 1‐H isoquinoline), 4.68 (s, 1H, 1‐H isoquinoline), 6.04 (s, 0.5H, 3‐H), 6.05 (s, 0.5H, 3‐H), 6.77 (s, 0.5H, 5‐H isoquinoline), 6.78 (s, 0.5H, 5‐H isoquinoline), 6.79 (s, 0.5H, 8‐H isoquinoline), 6.81 (s, 0.5H, 8‐H isoquinoline), 7.30–7.41 (m, 3.5H, 4‐H, 5‐H, 6‐H, 7‐H), 7.44 ppm (d, J=7.5 Hz, 0.5H, 7‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=27.9 (0.5 C, C‐3′ or C‐5′), 28.0 (0.5 C, C‐3′ or C‐5′), 28.11 (0.5 C, C‐3′ or C‐5′), 28.14 (0.5 C, C‐3′ or C‐5′), 28.8 (0.5 C, C‐4isoquinoline), 29.6 (0.5 C, C‐4isoquinoline), 34.0 (0.5 C, C‐2′), 34.1 (0.5 C, C‐2′), 35.2 (0.5 C, C‐6′), 35.3 (0.5 C, C‐6′), 41.5 (0.5 C, C‐3isoquinoline), 43.7 (0.5 C, C‐3isoquinoline), 45.2 (0.5 C, C‐1isoquinoline), 46.9 (0.5 C, C‐1isoquinoline), 49.7 (1 C, COCH2NH), 54.2 (0.5 C, C‐4′), 54.3 (0.5 C, C‐4′), 54.8 (1 C, 3‐OCH3), 56.47 (0.5 C, 6‐OCH3 or 7‐OCH3), 56.50 (0.5 C, 6‐OCH3 or 7‐OCH3), 56.5 (0.5 C, 6‐OCH3 or 7‐OCH3), 56.6 (0.5 C, 6‐OCH3 or 7‐OCH3), 88.1 (1 C, C‐1), 106.9 (1 C, C‐3), 110.9 (0.5 C, C‐8isoquinoline), 111.0 (0.5 C, C‐8isoquinoline), 113.0 (0.5 C, C‐5isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 122.4 (0.5 C, C‐7), 122.5 (0,5 C, C‐7), 124.16 (0.5 C, C‐6), 124.19 (0.5 C, C‐6), 125.8 (0.5 C, C‐8aisoquinoline), 126.3 (0.5 C, C‐8aisoquinoline), 127.8 (0.5 C, C‐4aisoquinoline), 128.2 (0.5 C, C‐4aisoquinoline), 128.88 (0.5 C, C‐5), 128.90 (0.5 C, C‐5), 130.30 (0.5 C, C‐4), 130.31 (0.5 C, C‐4), 138.7 (0.5 C, C‐3a), 138.8 (0.5 C, C‐3a), 148.7 (1 C, C‐7a), 149.3 (0.5 C, C‐6isoquinoline or C‐7isoquinoline), 149.38 (0.5 C, C‐6isoquinoline or C‐7isoquinoline), 149.41 (0.5 C, C‐6isoquinoline or C‐7isoquinoline), 149.5 (0.5 C, C‐6isoquinoline or C‐7isoquinoline), 171.7 (0.5 C, C=O), 171.8 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=3321 (N−H), 2978, 2928 (C−Halkyl), 1643 (C=O), 1516, 1435 (C=Carom). Purity (HPLC): 95.3 %, t R=14.5 min.

cis‐1‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐2‐[N‐(3‐methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐yl)amino]ethan‐1‐one (cis‐24)

A solution of chloroacetamide 15 (47 mg, 0.17 mmol, 1.3 equiv), amine cis‐13 (32 mg, 0.14 mmol), Et3N (0.06 mL, 0.43 mmol, 3.1 equiv.) and TBAI (6 mg, 0.02 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 6 d. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=29 cm, V=10 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine). Yellow oil, yield 28 mg (43 %). C27H34N2O5 (466.6 g/mol). R f=0.23 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 467.2534 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.64–1.70 (m, 1H, 2′‐H), 1.72–1.83 (m, 3H, 3′‐H, 5′‐H, 6′‐H), 1.83–1.93 (m, 2H, 2′‐H, 6′‐H), 1.93–2.00 (m, 2H, 3′‐H, 5′‐H), 2.64–2.72 (m, 1H, 4′‐H ax), 2.81 (t, J=6.2 Hz, 1H, 4‐H isoquinoline), 2.87 (t, J=6.0 Hz, 1H, 4‐H isoquinoline), 3.49 (s, 1.5H, 3‐OCH 3), 3.49 (s, 1.5H, 3‐OCH 3), 3.67 (s, 2H, COCH 2N), 3.70 (t, J=6.0 Hz, 1H, 3‐H isoquinoline), 3.80–3.85 (m, 7H, 3‐H isoquinoline, 6‐OCH 3, 7‐OCH 3), 4.61 (s, 1H, 1‐H isoquinoline), 4.66 (s, 1H, 1‐H isoquinoline), 6.04 (s, 0.5H, 3‐H), 6.05 (s, 0.5H, 3‐H), 6.76–6.79 (m, 1.5H, 5‐H isoquinoline, 8‐H isoquinoline), 6.80 (s, 0.5H, 8‐H isoquinoline), 7.18–7.25 (m, 1H, 7‐H), 7.31–7.40 ppm (m, 3H, 4‐H, 5‐H, 6‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=28.8 (0.5 C, C‐4isoquinoline), 29.6 (0.5 C, C‐4isoquinoline), 29.7 (1 C, C‐3′ or C‐5′), 30.0 (1 C, C‐3′ or C‐5′), 37.3 (1 C, C‐2′), 38.7 (1 C, C‐6′), 41.6 (0.5 C, C‐3isoquinoline), 43.6 (0.5 C, C‐3isoquinoline), 45.2 (0.5 C, C‐1isoquinoline), 46.8 (0.5 C, C‐1isoquinoline), 48.0 (0.5 C, COCH2N), 48.2 (0.5 C, COCH2N), 55.0 (1 C, 3‐OCH3), 56.5–56.6 (m, 2 C, 6‐OCH3, 7‐OCH3), 57.2 (1 C, C‐4′), 87.30 (0.5 C, C‐1), 87.32 (0.5 C, C‐1), 107.1 (1 C, C‐3), 110.9 (0.5 C, C‐8isoquinoline), 111.0 (0.5 C, C‐8isoquinoline), 113.0 (0.5 C, C‐5isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 121.68 (0.5 C, C‐7), 121.70 (0.5 C, C‐7), 124.2 (1 C, C‐4), 125.7 (0.5 C, C‐8aisoquinoline), 126.3 (0.5 C, C‐8aisoquinoline), 127.7 (0.5 C, C‐4aisoquinoline), 128.2 (0.5 C, C‐4aisoquinoline), 129.0 (1 C, C‐5), 130.4 (1 C, C‐6), 138.8 (1 C, C‐3a), 148.5 (1 C, C‐7a), 149.2–149.6 (m, 2 C, C‐6isoquinoline, C‐7isoquinoline), 171.2 (0.5 C, C=O), 171.3 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=3402 (N−H), 2928, 2855 (C−Halkyl), 1643 (C=O), 1516, 1435 (C=Carom). Purity (HPLC): 98.1 %, t R=15.1 min.

2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐1‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,4′‐piperidin]‐1′‐yl)ethan‐1‐one (25)

2‐Chloroacetyl chloride (19 μL, 0.24 mmol, 1.2 equiv) was slowly added to a solution of piperidine 10 (46 mg, 0.20 mmol) and Et3N (0.07 mL, 0.50 mmol, 2.5 equiv) in CH2Cl2 (4 mL) under N2 at 0 °C. After 5 h of stirring at RT, H2O (10 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo, and the residue was purified by fc (d=2 cm, l=18 cm, V=10 mL, cyclohexane/ethyl acetate 67 : 33→50 : 50). Chloroacetamide 16: Pale yellow oil, yield 25 mg (40 %). C16H20ClNO3 (309.8 g/mol).

A solution of chloroacetamide 16 (25 mg, 0.08 mmol), isoquinoline 14⋅HCl (20 mg, 0.09 mmol, 1.1 equiv), Et3N (0.03 mL, 0.22 mmol, 2.8 equiv) and TBAI (5 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 63 h. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Pale yellow solid, m.p. 165 °C, yield 30 mg (75 %). C27H34N2O5 (466.6 g/mol). R f=0.26 (cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 467.2521 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.76–1.86 (m, 1.5H, 3′‐H, 5′‐H), 1.90–1.96 (m, 0.5H, 5′‐H), 1.99–2.10 (m, 1.5H, 3′‐H, 5′‐H), 2.17 (td, J=13.3/4.6 Hz, 0.5H, 5′‐H), 2.79–2.93 (m, 5H, 4‐H, 3‐H isoquinoline, 4‐H isoquinoline), 2.93–2.98 (m, 1H, 4‐H), 3.13–3.23 (m, 1H, 2′‐H), 3.37 (d, J=14.0 Hz, 1H, COCH 2N), 3.54 (s, 1.5H, 3‐OCH 3), 3.55 (s, 1.5H, 3‐OCH 3), 3.56–3.66 (m, 3H, 6′‐H, COCH 2N, 1‐H isoquinoline), 3.67–3.72 (m, 1H, 1‐H isoquinoline), 3.79–3.82 (m, 6H, 6‐OCH 3, 7‐OCH 3), 4.09–4.14 (m, 1H, 6′‐H), 4.50–4.57 (m, 1H, 2′‐H), 4.96 (dd, J=6.9/3.2 Hz, 0.5H, 3‐H), 4.98 (dd, J=7.0/3.2 Hz, 0.5H, 3‐H), 6.69 (s, 0.5H, 8‐H isoquinoline), 6.69 (s, 0.5H, 8‐H isoquinoline), 6.70 (s, 0.5H, 5‐H isoquinoline), 6.72 (s, 0.5H, 5‐H isoquinoline), 6.94–6.97 (m, 0.5H, 8‐H), 7.00 (dd, J=7.5/1.6 Hz, 0.5H, 8‐H), 7.08–7.17 ppm (m, 3H, 5‐H, 6‐H, 7‐H). 13C NMR (151 MHz, CD3OD): δ=29.5 (0.5 C, C‐4isoquinoline), 29.6 (0.5 C, C‐4isoquinoline), 36.0 (1 C, C‐4), 37.6 (0.5 C, C‐3′), 38.2 (0.5 C, C‐5′), 39.6 (0.5 C, C‐2′), 39.7 (0.5 C, C‐2′), 39.8 (0.5 C, C‐3′), 40.4 (0.5 C, C‐5′), 43.48 (0.5 C, C‐6′), 43.50 (0.5 C, C‐6′), 52.2 (0.5 C, C‐3isoquinoline), 52.3 (0.5 C, C‐3isoquinoline), 56.4–56.6 (m, 4 C, C‐1isoquinoline, 3‐OCH3, 6‐OCH3, 7‐OCH3), 61.28 (0.5 C, COCH2N), 61.30 (0.5 C, COCH2N), 76.08 (0.5 C, C‐1), 76.11 (0.5 C, C‐1), 98.15 (0.5 C, C‐3), 98.22 (0.5 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.1 (0.5 C, C‐5isoquinoline), 113.2 (0.5 C, C‐5isoquinoline), 125.7 (1 C, C‐8), 127.40 (1 C, C‐4asioquinoline or C‐8aisoquinoline), 127.44 (1 C, C‐4asioquinoline or C‐8aisoquinoline), 127.6 (0.5 C, C‐7), 127.7 (0.5 C, C‐7), 128.0 (1 C, C‐6), 130.2 (1 C, C‐5), 132.6 (1 C, C‐4a), 141.32 (0.5 C, C‐8a), 141.34 (0.5 C, C‐8a), 148.8 (1 C, C‐6sioquinoline or C‐7isoquinoline), 149.2 (1 C, C‐6sioquinoline or C‐7isoquinoline), 170.4 (0.5 C, C=O), 170.5 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=2924, 2835 (C−Halkyl), 1639 (C=O), 1516, 1443 (C=Carom). Purity (HPLC): 99.4 %, t R=17.4 min.

trans‐2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (trans‐26)

A solution of chloroacetamide trans‐17 (29 mg, 0.09 mmol), isoquinoline 14⋅HCl (23 mg, 0.10 mmol, 1.1 equiv), Et3N (0.04 mL, 0.29 mmol, 3.2 equiv) and TBAI (3 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 68 h. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=18 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine; d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Colorless oil, yield 36 mg (83 %). C28H36N2O5 (480.6 g/mol). R f=0.11 (cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 481.2695 (calcd. 481.2697 for C28H37N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.66–1.72 (m, 2H, 2′‐H, 6′‐H), 1.73–1.78 (m, 2H, 3′‐H, 5′‐H), 1.90–1.95 (m, 1H, 6′‐H), 1.96–2.00 (m, 1H, 2′‐H), 2.10–2.17 (m, 1H, 5′‐H), 2.17–2.24 (m, 1H, 3′‐H), 2.77 (dd, J=15.7/7.3 Hz, 1H, 4‐H), 2.90 (dd, J=15.7/3.1 Hz, 1H, 4‐H), 2.92–2.95 (m, 2H, 3‐H isoquinoline), 2.98 (t, J=5.6 Hz, 2H, 4‐H isoquinoline), 3.30 (s, 2H, COCH 2N), 3.53 (s, 3H, 3‐OCH 3), 3.72 (s, 5H, 1‐H isoquinoline, 7‐OCH 3), 3.85 (s, 3H, 6‐OCH 3,), 4.19 (quint, J=3.3 Hz, 1H, 4′‐H equ), 4.88 (dd, J=7.4/3.1 Hz, 1H, 3‐H), 6.68 (s, 1H, 8‐H isoquinoline), 6.71 (dd, J=7.9/1.2 Hz, 1H, 8‐H), 6.80 (s, 1H, 5‐H isoquinoline), 6.89–6.92 (m, 1H, 7‐H), 7.05 (dd, J=7.6/1.3 Hz, 1H, 5‐H), 7.10 ppm (td, J=7.4/1.2 Hz, 1H, 6‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=26.5 (1 C, C‐3′), 26.6 (1 C, C‐5′), 30.1 (1 C, C‐4isoquinoline), 32.2 (1 C, C‐6′), 34.6 (1 C, C‐2′), 36.1 (1 C, C‐4), 44.6 (1 C, C‐4′), 52.7 (1 C, C‐3isoquinoline), 56.35 (1 C, 3‐OCH3), 56.44 (1 C, 7‐OCH3), 56.5 (1 C, 6‐OCH3), 56.8 (1 C, C‐1isoquinoline), 62.3 (1 C, COCH2N), 77.1 (1 C, C‐1), 97.9 (1 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.2 (1 C, C‐5isoquinoline), 125.4 (1 C, C‐8), 127.1 (1 C, C‐4aisoquinoline), 127.4 (1 C, C‐8aisoquinoline), 127.5 (1 C, C‐7), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.4 (1 C, C‐4a), 142.6 (1 C, C‐8a), 148.9 (1 C, C‐7isoquinoline), 149.4 (1 C, C‐6isoquinoline), 172.1 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3341 (N−H), 2928, 2832 (C−Halkyl), 1674 (C=O), 1516, 1447 (C=Carom). Purity (HPLC): 90.6 %, t R=17.0 min.

cis‐2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (cis‐26)

A solution of chloroacetamide cis‐17 (34 mg, 0.10 mmol), isoquinoline 14⋅HCl (26 mg, 0.11 mmol, 1.1 equiv), Et3N (0.04 mL, 0.29 mmol, 2.9 equiv) and TBAI (4 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 66 h. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Colorless solid, m.p. 176 °C, yield 31 mg (62 %). C28H36N2O5 (480.6 g/mol). R f=0.08 (cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 481.2720 (calcd. 481.2697 for C28H37N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.77–1.95 (m, 6H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 2.05–2.14 (m, 2H, 2′‐H, 6′‐H), 2.77–2.84 (m, 3H, 4‐H, 3‐H isoquinoline), 2.86–2.90 (m, 2H, 4‐H isoquinoline), 2.93 (dd, J=15.7/3.1 Hz, 1H, 4‐H), 3.22 (s, 2H, COCH 2Cl), 3.54 (s, 3H, 3‐OCH 3), 3.67 (s, 2H, 1‐H isoquinoline), 3.80 (s, 3H, 7‐OCH 3), 3.81 (s, 3H, 6‐OCH 3), 3.88–3.95 (m, 1H, 4′‐H ax), 4.91 (dd, J=7.4/3.1 Hz, 1H, 3‐H), 6.65 (s, 1H, 8‐H isoquinoline), 6.72 (s, 1H, 5‐H isoquinoline), 7.09 (d, J=7.4 Hz, 1H, 5‐H), 7.16 (td, J=7.2/1.8 Hz, 1H, 6‐H), 7.18–7.24 ppm (m, 2H, 7‐H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=29.0 (1 C, C‐3′ or C‐5′), 29.2 (1 C, C‐3′ or C‐5′), 29.4 (1 C, C‐4isoquinoline), 36.1 (1 C, C‐4), 36.6 (1 C, C‐2′), 39.1 (1 C, C‐6′), 49.0 (1 C, C‐4′), 52.3 (1 C, C‐3isoquinoline), 56.4 (2 C, C‐1isoquinoline, 3‐OCH3), 56.47 (1 C, 6‐OCH3), 56.51 (1 C, 7‐OCH3), 62.0 (1 C, COCH2N), 76.9 (1 C, C‐1), 97.9 (1 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.1 (1 C, C‐5isoquinoline), 125.7 (1 C, C‐8), 127.2 (1 C, C‐4aisoquinoline), 127.5 (1 C, C‐8aisoquinoline), 127.6 (1 C, C‐7), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.5 (1 C, C‐8a), 148.9 (1 C, C‐7isoquinoline), 149.2 (1 C, C‐6isoquinoline), 171.9 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3298 (N−H), 2978, 2924, 2835 (C−Halkyl), 1639 (C=O), 1512, 1443 (C=Carom). Purity (HPLC): 98.1 %, t R=17.5 min.

cis‐4‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐N‐(3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐yl)butanamide (cis‐27)

A solution of isoquinoline 14⋅HCl (27 mg, 0.12 mmol), chlorobutyramide cis‐18 (45 mg, 0.13 mmol, 1.1 equiv), Et3N (0.05 mL, 0.36 mmol, 3.0 equiv) and TBAI (5 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 6 d. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=32 cm, V=10 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine; d=1 cm, l=25 cm, V=3 mL, CH2Cl2/CH3OH 95 : 5). Pale yellow oil, yield 11 mg (19 %). C30H40N2O5 (508.7 g/mol). R f=0.19 (CH2Cl2/CH3OH 95 : 5). HRMS (ESI): m/z 509.3024 (calcd. 509.3010 for C30H41N2O5 [MH+]). 1H NMR (400 MHz, CD3OD): δ=1.74–1.91 (m, 6H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 1.97 (quint, J=7.5 Hz, 2H, COCH2CH 2CH2N), 2.02–2.09 (m, 1H, 6′‐H), 2.09–2.15 (m, 1H, 2′‐H), 2.31 (t, J=7.3 Hz, 2H, COCH 2CH2CH2N), 2.65 (t, J=7.8 Hz, 2H, COCH2CH2CH 2N), 2.78–2.88 (m, 3H, 4‐H, 3‐H isoquinoline), 2.88–2.92 (m, 2H, 4‐H isoquinoline), 2.95 (dd, J=15.7/3.2 Hz, 1H, 4‐H), 3.58 (s, 3H, 3‐OCH 3), 3.68 (s, 2H, 1‐H isoquinoline), 3.79–3.90 (m, 1H, 4′‐H ax), 3.817 (s, 3H, 6‐OCH 3 or 7‐OCH 3), 3.818 (s, 3H, 6‐OCH 3 or 7‐OCH 3), 4.93 (dd, J=7.5/3.2 Hz, 1H, 3‐H), 6.69 (s, 1H, 8‐H isoquinoline), 6.73 (s, 1H, 5‐H isoquinoline), 7.08–7.13 (m, 1H, 5‐H), 7.15–7.20 (m, 1H, 6‐H), 7.20–7.24 ppm (m, 2H, 7‐H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (101 MHz, CD3OD): δ=23.8 (1 C, COCH2 CH2CH2N), 28.8 (1 C, C‐4isoquinoline), 29.0 (1 C, C‐3′ or C‐5′), 29.1 (1 C, C‐3′ or C‐5′), 35.0 (1 C, COCH2CH2CH2N), 36.2 (1 C, C‐4), 36.6 (1 C, C‐2′), 39.1 (1 C, C‐6′), 49.1 (1 C, C‐4′), 52.0 (1 C, C‐3isoquinoline), 56.4 (1 C, C‐1isoquinoline), 56.4 (1 C, 3‐OCH3), 56.47 (1 C, 6‐OCH3 or 7‐OCH3), 56.53 47 (1 C, 6‐OCH3 or 7‐OCH3), 58.4 (1 C, COCH2CH2 CH2N), 77.0 (1 C, C‐1), 97.9 (1 C, C‐3), 111.2 (1 C, C‐8isoquinoline), 113.0 (1 C, C‐5isoquinoline), 125.7 (1 C, C‐8), 126.9 (1 C, C‐8aisoquinoline), 127.1 (1 C, C‐4aisoquinoline), 127.6 (1 C, C‐7), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.5 (1 C, C‐8a), 149.0 (1 C, C‐7isoquinoline), 149.4 (1 C, C‐6isoquinoline), 174.8 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3275 (N−H), 2924, 2855 (C−Halkyl), 1639 (C=O), 1516, 1447 (C=Carom). Purity (HPLC): 93.5 %, t R=17.9 min.

2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐1‐{3‐methoxy‐3H‐spiro[[2]benzofuran‐1,4′‐piperidin]‐1′‐yl}ethan‐1‐one (28)

2‐Chloroacetyl chloride (36 μL, 0.45 mmol, 1.2 equiv) was slowly added to a solution of piperidine 12 (83 mg, 0.38 mmol) and Et3N (0.12 mL, 0.87 mmol, 2.3 equiv) in CH2Cl2 (10 mL) under N2 at 0 °C. After stirring for 6 h at RT, H2O (10 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=2 cm, l=19 cm, V=10 mL, cyclohexane/ethyl acetate 67 : 33). Chloroacetamide 19: Pale yellow oil, yield 50 mg (44 %). C15H18ClNO3 (295.8 g/mol).

A solution of chloroacetamide 19 (50 mg, 0.17 mmol, 1.2 equiv), isoquinoline 14⋅HCl (33 mg, 0.14 mmol), Et3N (0.07 mL, 0.50 mmol, 3.6 equiv) and TBAI (6 mg, 0.02 mmol, 0.1 equiv) in DMF (6 mL) was stirred at RT for 5 d. H2O (70 mL) was added and the aqueous layer was extracted with CH2Cl2 (4×30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=25 cm, V=10 mL, CH2Cl2/CH3OH 95 : 5; d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Pale yellow oil, yield 31 mg (49 %). C26H32N2O5 (452.6 g/mol). R f=0.16 (cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 453.2403 (calcd. 453.2384 for C26H33N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.59–1.67 (m, 1H, 3′‐H, 5′‐H), 1.77–1.84 (m, 1H, 3′‐H, 5′‐H), 1.88–1.94 (m, 0.5H, 3′‐H), 1.96–2.05 (m, 1H, 3′‐H, 5′‐H), 2.09 (td, J=13.3/4.8 Hz, 0.5H, 5′‐H), 2.82–2.85 (m, 2H, 3‐H isoquinoline), 2.86–2.90 (m, 2H, 4‐H isoquinoline), 3.13–3.19 (m, 1H, 2′‐H), 3.40 (d, J=8.3 Hz, 0.5H, COCH 2N), 3.42 (d, J=8.3 Hz, 0.5H, COCH 2N), 3.50 (s, 1.5H, 3‐OCH 3), 3.51 (s, 1.5H, 3‐OCH 3), 3.53–3.61 (m, 2H, 6′‐H, COCH 2N), 3.66 (s, 1H, 1‐H isoquinoline), 3.67 (s, 1H, 1‐H isoquinoline), 3.79–3.82 (m, 6H, 6‐OCH 3, 7‐OCH 3), 4.16–4.21 (m, 1H, 6′‐H), 4.56–4.62 (m, 1H, 2′‐H), 6.09 (s, 0.5H, 3‐H), 6.10 (s, 0.5H, 3‐H), 6.67 (s, 0.5H, 8‐H isoquinoline), 6.68 (s, 0.5H, 8‐H isoquinoline), 6.71 (s, 0.5H, 5‐H isoquinoline), 6.72 (s, 0.5H, 5‐H isoquinoline), 7.11–7.13 (m, 0.5H, 4‐H), 7.15–7.17 (m, 0.5H, 4‐H), 7.34–7.40 ppm (m, 3H, 5‐H, 6‐H, 7‐H). 13C NMR (151 MHz, CD3OD): δ=29.47 (0.5 C, C‐4isoquinoline), 29.51 (0.5 C, C‐4isoquinoline), 38.0 (0.5 C, C‐3′), 38.7 (0.5 C, C‐5′), 39.5 (0.5 C, C‐3′), 40.1 (1 C, C‐2′, C‐5′), 40.5 (0.5 C, C‐2′), 43.9 (0.5 C, C‐6′), 44.2 (0.5 C, C‐6′), 52.2 (1 C, C‐3isoquinoline), 55.2 (1 C, 3‐OCH3), 56.4–56.6 (m, 3 C, C‐1isoquinoline, 6‐OCH3, 7‐OCH3), 61.1 (0.5 C, COCH2N), 61.2 (0.5 C, COCH2N), 85.9 (1 C, C‐1), 107.4 (1 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.11 (0.5 C, C‐5isoquinoline), 113.13 (0.5 C, C‐5isoquinoline), 121.75 (0.5 C, C‐4), 121.77 (0.5 C, C‐4), 124.4 (1 C, C‐7), 127.38 (0.5 C, C‐4aisoquinoline), 127.40 (0.5 C, C‐4aisoquinoline), 127.6 (0.5 C, C‐8aisoquinoline), 127.7 (0.5 C, C‐8aisoquinoline), 129.3 (1 C, C‐6), 130.58 (0.5 C, C‐5), 130.60 (0.5 C, C‐5), 138.9 (1 C, C‐7a), 147.3 (1 C, C‐3a), 148.82 (0.5 C, C‐7isoquinoline), 148.83 (0.5 C, C‐7isoquinoline), 149.16 (0.5 C, C‐6isoquinoline), 149.17 (0.5 C, C‐6isoquinoline), 170.39 (0.5 C, C=O), 170.40 ppm (0.5 C, C=O). FTIR (neat): ν [cm−1]=2913, 2735 (C−Halkyl), 1636 (C=O), 1516, 1447 (C=Carom). Purity (HPLC): 98.7 %, t R=14.3–16.7 min.

trans‐2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐N‐(3‐methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (trans‐29)

A solution of chloroacetamide trans‐20 (40 mg, 0.13 mmol), isoquinoline 14⋅HCl (33 mg, 0.14 mmol, 1.1 equiv), Et3N (0.05 mL, 0.36 mmol, 2.8 equiv.) and TBAI (48 mg, 0.13 mmol, 1.0 equiv) in DMF (4 mL) was stirred at RT for 66 h. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=20 cm, V=10 mL, cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine; d=2 cm, l=18 cm, V=10 mL, cyclohexane/ ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). Colorless solid, m.p. 107 °C, yield 40 mg (66 %). C27H34N2O5 (466.6 g/mol). R f=0.11 (cyclohexane/ethyl acetate 50 : 50+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 467.2549 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.55–1.61 (m, 1H, 2′‐H), 1.71–1.77 (m, 1H, 6′‐H), 1.79–1.90 (m, 4H, 2′‐H, 3′‐H, 5′‐H, 6′‐H), 2.06–2.16 (m, 2H, 3′‐H, 5′‐H), 2.92 (t, J=5.9 Hz, 2H, 3‐H isoquinoline), 2.97 (t, J=5.9 Hz, 2H, 4‐H isoquinoline), 3.29 (s, 2H, COCH 2N), 3.47 (s, 3H, 3‐OCH 3), 3.70 (s, 2H, 1‐H isoquinoline), 3.74 (s, 3H, 7‐OCH 3), 3.85 (s, 3H, 6‐OCH 3), 4.17 (quint, J=3.7 Hz, 1H, 4′‐H equ), 6.03 (s, 1H, 3‐H), 6.68 (s, 1H, 8‐H isoquinoline), 6.75 (d, J=7.5 Hz, 1H, 7‐H), 6.80 (s, 1H, 5‐H isoquinoline), 7.24 (t, J=7.4 Hz, 1H, 6‐H), 7.29–7.36 ppm (m, 2H, 4‐H, 5‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=27.4 (1 C, C‐3′ or C‐5′), 27.7 (1 C, C‐3′ or C‐5′), 30.1 (1 C, C‐4isoquinoline), 33.8 (1 C, C‐2′), 35.1 (1 C, C‐6′), 45.1 (1 C, C‐4′), 52.6 (1 C, C‐3isoquinoline), 55.0 (1 C, 3‐OCH3), 56.4 (1 C, 7‐OCH3), 56.5 (1 C, 6‐OCH3), 56.7 (1 C, C‐1isoquinoline), 62.1 (1 C, COCH2N), 87.0 (1 C, C‐1), 107.1 (1 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.1 (1 C, C‐5isoquinoline), 121.8 (1 C, C‐7), 124.2 (1 C, C‐4), 127.2 (1 C, C‐4aisoquinoline), 127.5 (1 C, C‐8aisoquinoline), 129.0 (1 C, C‐5), 130.4 (1 C, C‐6), 138.7 (1 C, C‐3a), 148.2 (1 C, C‐7a), 149.0 (1 C, C‐7isoquinoline), 149.4 (1 C, C‐6isoquinoline), 172.1 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3341 (N−H), 2932, 2832 (C−Halkyl), 1674 (C=O), 1516, 1463, 1451 (C=Carom). Purity (HPLC): 92.4 %, t R=14.0 min.

cis‐2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)‐N‐(3‐methoxy‐3H‐spiro[[2]benzofuran‐1,1′‐cyclohexan]‐4′‐yl)acetamide (cis‐29)

A solution of chloroacetamide cis‐20 (35 mg, 0.11 mmol), isoquinoline 14⋅HCl (30 mg, 0.13 mmol, 1.2 equiv), Et3N (0.05 mL, 0.36 mmol, 3.3 equiv) and TBAI (4 mg, 0.01 mmol, 0.1 equiv) in DMF (4 mL) was stirred at RT for 6 d. H2O (80 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×60 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=2 cm, l=29 cm, V=10 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine; d=2 cm, l=31 cm, V=10 mL, CH2Cl2/CH3OH 199 : 1+1 % N,N‐dimethylethanamine). Yellow oil, yield 45 mg (86 %). C27H34N2O5 (466.6 g/mol). R f=0.31 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 467.2531 (calcd. 467.2540 for C27H35N2O5 [MH+]). 1H NMR (400 MHz, CD3OD): δ=1.70 (dq, J=13.3/2.9 Hz, 1H, 2′‐H equ), 1.78–1.97 (m, 6H, 3′‐H, 5′‐H, 6′‐H), 2.01 (td, J=13.4/4.1 Hz, 1H, 2′‐H ax), 2.81–2.86 (m, 2H, 3‐H isoquinoline), 2.87–2.92 (m, 2H, 4‐H isoquinoline), 3.24 (s, 2H, COCH 2N), 3.49 (s, 3H, 3‐OCH 3), 3.69 (s, 2H, 1‐H isoquinoline), 3.81 (s, 3H, 7‐OCH 3), 3.83 (s, 3H, 6‐OCH 3), 3.92 (tt, J=11.4/4.1 Hz, 1H, 4′‐H ax), 6.07 (s, 1H, 3‐H), 6.67 (s, 1H, 8‐H isoquinoline), 6.74 (s, 1H, 5‐H isoquinoline), 7.28 (d, J=7.5 Hz, 1H, 7‐H), 7.32–7.45 ppm (m, 3H, 4‐H, 5‐H, 6‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (101 MHz, CD3OD): δ=29.4 (1 C, C‐4isoquinoline), 29.6 (1 C, C‐3′), 30.0 (1 C, C‐5′), 37.5 (1 C, C‐2′), 38.8 (1 C, C‐6′), 48.8 (1 C, C‐4′), 52.3 (1 C, C‐3isoquinoline), 54.9 (1 C, 3‐OCH3), 56.4 (1 C, C‐1isoquinoline), 56.48 (1 C, 6‐OCH3 or 7‐OCH3), 56.52 (1 C, 6‐OCH3 or 7‐OCH3), 62.0 (1 C, COCH2N), 86.9 (1 C, C‐1), 107.2 (1 C, C‐3), 111.1 (1 C, C‐8isoquinoline), 113.2 (1 C, C‐5isoquinoline), 121.8 (1 C, C‐7), 124.2 (1 C, C‐4), 127.2 (1 C, C‐4aisoquinoline), 127.5 (1 C, C‐8aisoquinoline), 129.0 (1 C, C‐5), 130.5 (1 C, C‐6), 138.6 (1 C, C‐3a), 148.3 (1 C, C‐7a), 148.9 (1 C, C‐7isoquinoline), 149.2 (1 C, C‐6isoquinoline), 172.0 ppm (1 C, C=O). FTIR (neat): ν [cm−1]=3333 (N−H), 2932, 2909, 2832 (C−Halkyl), 1667 (C=O), 1516, 1439 (C=Carom). Purity (HPLC): 88.0 %, t R=14.4 min.

1′‐[2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,4′‐piperidine] (30)

LiAlH4 (7 mg, 0.19 mmol, 6.4 equiv) was added to a solution of amide 25 (16 mg, 0.03 mmol) in THF (3 mL) under N2. The mixture was heated to reflux for 2 h. After cooling to RT, H2O (10 mL) was added, the precipitate was filtered off, and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=1 cm, l=21 cm, V=3 mL, CH2Cl2/CH3OH 97 : 3+1 % N,N‐dimethylethanamine; d=1 cm, l=21 cm, V=3 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine). Yellow oil, yield 10 mg (63 %). C27H36N2O4 (452.6 g/mol). R f=0.24 (CH2Cl2/CH3OH 95 : 5+1 % N,N‐dimethylethanamine). HRMS (ESI): m/z 453.2754 (calcd. 453.2748 for C27H37N2O4 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.82 (dq, J=13.8/2.6 Hz, 1H, 3′‐H equ), 2.00 (ddd, J=14.2/12.5/4.3 Hz, 1H, 5′‐H ax), 2.06 (dq, J=14.3/2.8 Hz, 1H, 5′‐H equ), 2.26 (td, J=13.4/4.3 Hz, 1H, 3′‐H ax), 2.64–2.74 (m, 2H, 2′‐H, 6′‐H), 2.75–2.86 (m, 7H, 4‐H, 3‐H isoquinoline, NCH 2CH 2N), 2.88 (t, J=5.7 Hz, 2H, 4‐H isoquinoline), 2.91–2.97 (m, 3H, 4‐H, 2′‐H, 6′‐H), 3.55 (s, 3H, 3‐OCH 3), 3.67 (s, 2H, 1‐H isoquinoline), 3.80 (s, 3H, 7‐OCH 3), 3.81 (s, 3H, 6‐OCH 3), 4.94 (dd, J=7.2/3.2 Hz, 1H, 3‐H), 6.68 (s, 1H, 8‐H isoquinoline), 6.71 (s, 1H, 5‐H isoquinoline), 7.10 (d, J=7.5 Hz, 1H, 5‐H), 7.18 (ddd, J=7.6/6.2/2.4 Hz, 1H, 6‐H), 7.19–7.24 ppm (m, 2H, 7‐H, 8‐H). 13C NMR (151 MHz, CD3OD): δ=29.1 (1 C, C‐4isoquinoline), 36.1 (1 C, C‐4), 37.1 (1 C, C‐5′), 39.5 (1 C, C‐3′), 50.9 (1 C, C‐2′), 51.0 (1 C, C‐6′), 52.5 (1 C, C‐3isoquinoline), 56.1 (1 C, Nisoquinoline CH2CH2N), 56.46 (2 C, 3‐OCH3, 6‐OCH3 or 7‐OCH3), 56.51 (1 C, NisoquinolineCH2 CH2N), 56.7 (1 C, 6‐OCH3 or 7‐OCH3), 56.9 (1 C, C‐1isoquinoline), 75.6 (1 C, C‐1), 97.9 (1 C, C‐3), 111.2 (1 C, C‐8isoquinoline), 113.0 (1 C, C‐5isoquinoline), 125.7 (1 C, C‐8), 127.3 (1 C, C‐8aisoquinoline), 127.4 (1 C, C‐4aisoquinoline), 127.6 (1 C, C‐7), 127.9 (1 C, C‐6), 130.2 (1 C, C‐5), 132.7 (1 C, C‐4a), 141.9 (1 C, C‐8a), 148.9 (1 C, C‐7isoquinoline), 149.3 ppm (1 C, C‐6isoquinoline). FTIR (neat): ν [cm−1]=2947, 2820, 2778 (C−Halkyl), 1516, 1466, 1454 (C=Carom). Purity (HPLC): 91.2 %, t R=14.0 min.

trans‐N‐[2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (trans‐31)

LiAlH4 (4 mg, 0.12 mmol, 5.3 equiv) was added to a solution of amide trans‐26 (11 mg, 0.02 mmol) in THF (3 mL) under N2. The mixture was heated to reflux for 22 h. After cooling to RT, H2O (10 mL) was added, the precipitate was filtered off, and the aqueous phase was extracted with CH2Cl2 (5×10 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified twice by fc (d=1 cm, l=25 cm, V=3 mL, CH2Cl2/CH3OH 99 : 1+1 % N,N‐dimethylethanamine; d=1 cm, l=25 cm, V=3 mL, CH2Cl2/CH3OH 99 : 1→97 : 3+1 % N,N‐dimethylethanamine). Yellow solid, m.p. 73 °C, yield 9 mg (86 %). C28H38N2O4 (466.6 g/mol). R f=0.33 (CH2Cl2/CH3OH 90 : 10+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 467.2895 (calcd. 467.2904 for C28H39N2O4 [MH+]). 1H NMR (600 MHz, CD3OD): δ=1.60 (dt, J=9.5/2.0 Hz, 1H, 2′‐H), 1.78–1.83 (m, 2H, 3′‐H, 5′‐H), 1.84–1.89 (m, 2H, 6′‐H), 2.06–2.13 (m, 1H, 5′‐H), 2.13–2.17 (m, 2H, 2′‐H, 3′‐H), 2.73–2.85 (m, 5H, 4‐H, NisoquinolineCH 2CH2N, 3‐H isoquinoline), 2.86–2.95 (m, 5H, 4‐H, NisoquinolineCH2CH 2N, 4‐H isoquinoline), 3.02 (quint, J=3.0 Hz, 1H, 4′‐H equ), 3.55 (s, 3H, 3‐OCH3), 3.66 (s, 2H, 1‐H isoquinoline), 3.78 (s, 3H, 7‐OCH 3), 3.82 (s, 3H, 6‐OCH 3), 4.90 (dd, J=7.5/3.1 Hz, 1H, 3‐H), 6.68 (s, 1H, 8‐H isoquinoline), 6.73 (s, 1H, 5‐H isoquinoline), 7.01–7.08 (m, 2H, 5‐H, 7‐H), 7.09–7.13 (m, 1H, 6‐H), 7.17 ppm (d, J=7.8 Hz, 1H, 8‐H). A signal for the NH proton is not observed in the spectrum. 13C NMR (151 MHz, CD3OD): δ=25.9 (1 C, C‐3′), 26.2 (1 C, C‐5′), 29.5 (1 C, C‐4isoquinoline), 31.5 (1 C, C‐6′), 34.1 (1 C, C‐2′), 36.2 (1 C, C‐4), 44.7 (1 C, NisoquinolineCH2 CH2N), 52.5 (1 C, C‐4′), 52.5 (1 C, C‐3isoquinoline or Nisoquinoline CH2CH2N), 56.3 (1 C, 3‐OCH3), 56.4–56.5 (m, 2 C, 6‐OCH3, 7‐OCH3), 56.8 (1 C, C‐1isoquinoline), 58.0 (1 C, C‐3isoquinoline or Nisoquinoline CH2CH2N), 77.8 (1 C, C‐1), 97.9 (1 C, C‐3), 111.3 (1 C, C‐8isoquinoline), 113.1 (1 C, C‐5isoquinoline), 125.9 (1 C, C‐8), 127.4 (1 C, C‐4aisoquinoline), 127.5 (1 C, C‐7), 127.55 (1 C, C‐6), 127.62 (1 C, C‐8aisoquinoline), 130.0 (1 C, C‐5), 132.4 (1 C, C‐4a), 143.2 (1 C, C‐8a), 148.9 (1 C, C‐7isoquinoline), 149.3 ppm (1 C, C‐6isoquinoline). FTIR (neat): ν [cm−1]=3368 (N−H), 2924, 2832 (C−Halkyl), 1516, 1447 (C=Carom). Purity (HPLC): 61.5 %, t R=14.7 min.

cis‐N‐[2‐(6,7‐Dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]‐3‐methoxy‐3,4‐dihydrospiro[[2]benzopyran‐1,1′‐cyclohexan]‐4′‐amine (cis‐31)

LiAlH4 (8 mg, 0.22 mmol, 6.0 equiv.) was added to a solution of amide cis‐26 (17 mg, 0.04 mmol) in THF (3 mL) under N2. The mixture was heated to reflux for 19 h. After cooling to RT, H2O (10 mL) was added, the precipitate was filtered off, and the aqueous phase was extracted with CH2Cl2 (4×10 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo and the residue was purified by fc (d=1 cm, l=25 cm, V=3 mL, CH2Cl2/CH3OH 98 : 2→98 : 2+1 % N,N‐dimethylethanamine). Yellow solid, m.p. 70 °C, yield 13 mg (76 %). C28H38N2O4 (466.6 g/mol). R f=0.26 (CH2Cl2/CH3OH 90 : 10+1 % N,N‐dimethylethanamine). HRMS (APCI): m/z 467.2921 (calcd. 467.2904 for C28H39N2O4 [MH+]). 1H NMR (400 MHz, CD3OD): δ=1.65–1.82 (m, 3H, 2′‐H, 3′‐H, 5′‐H), 1.82–1.96 (m, 3H, 3′‐H, 5′‐H, 6′‐H), 2.03 (td, J=13.5/4.2 Hz, 1H, 6′‐H), 2.10–2.18 (m, 1H, 2′‐H), 2.71–2.78 (m, 3H, 4′‐H ax, NisoquinolineCH 2CH2N), 2.78–2.85 (m, 3H, 4‐H, 3‐H isoquinoline), 2.88 (t, J=5.9 Hz, 2H, 4‐H isoquinoline), 2.91–2.98 (m, 3H, 4‐H, NisoquinolineCH2CH 2N), 3.58 (s, 3H, 3‐OCH 3), 3.64 (s, 2H, 1‐H isoquinoline), 3.82 (s, 3H, 6‐OCH 3 or 7‐OCH 3), 3.82 (s, 3H, 6‐OCH 3 or 7‐OCH 3), 4.92 (dd, J=7.4/3.2 Hz, 1H, 3‐H), 6.69 (s, 1H, 8‐H isoquinoline), 6.73 (s, 1H, 5‐H isoquinoline), 7.10 (d, J=7.2 Hz, 1H, 5‐H), 7.14–7.22 ppm (m, 3H, 6‐H, 7‐H, 8‐H). A signal for the NH proton was not observed. 13C NMR (101 MHz, CD3OD): δ=29.0 (1 C, C‐3′ or C‐5′), 29.1 (1 C, C‐3′ or C‐5′), 29.2 (1 C, C‐4isoquinoline), 36.2 (1 C, C‐4), 36.5 (1 C, C‐2′), 39.0 (1 C, C‐6′), 44.3 (1 C, NisoquinolineCH2 CH2N), 52.4 (1 C, C‐3isoquinoline), 56.4 (1 C, 3‐OCH3), 56.47 (1 C, 6‐OCH3 or 7‐OCH3), 56.53 (1 C, 6‐OCH3 or 7‐OCH3), 56.8 (1 C, C‐1isoquinoline), 57.4 (1 C, C‐4′), 58.2 (1 C, Nisoquinoline CH2CH2N), 77.4 (1 C, C‐1), 97.8 (1 C, C‐3), 111.2 (1 C, C‐8isoquinoline), 113.0 (1 C, C‐5isoquinoline), 125.7 (1 C, C‐8), 127.4 (1 C, C‐4aisoquinoline), 127.50 (1 C, C‐7), 127.53 (1 C, C‐8aisoquinoline), 127.7 (1 C, C‐6), 130.1 (1 C, C‐5), 132.6 (1 C, C‐4a), 142.6 (1 C, C‐8a), 148.9 (1 C, C‐7isoquinoline), 149.3 ppm (1 C, C‐6isoquinoline). FTIR (neat): ν [cm−1]=3402 (N−H), 2928, 2832 (C−Halkyl), 1516, 1447 (C=Carom). Purity (HPLC): 69.2 %, t R=14.5 min.

Receptor binding studies

The σ1 and σ2 affinities were recorded as described in ref. [40]. Details of the assays are given in the Supporting Information.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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