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

Abstract

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, K _i (σ₂)=200 nM; the highest σ₁ affinity was recorded for the corresponding 2‐benzofuran derivative with a CH₂C=O linker (cis‐29, K _i (σ₁)=129 nM).

No O for affinity: Numerous σ₂ receptor ligands inhibit tumor cell growth. In this project, two σ₂ pharmacophoric elements were connected via various linkers to achieve high‐affinity σ₂ ligands. Structure‐affinity relationship studies revealed that compounds with an ethylene linker exhibit higher σ₂ affinity than compounds containing a carbonyl moiety within the linker.

1. 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. ^[1] 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. ^[2]

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.[ ³ , ⁴ ] 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. ^[5] 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. ^[6] During the following years, the correlation between the σ₂ receptor and PGRMC1 protein complex was considered controversial. ^[7] 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. ^[8] 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. ^[9] 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.[ ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ ] 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.[ ¹⁶ , ¹⁷ ] 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). ^[18] Haloperidol and its homopiperazine analog SYA013 exhibit high σ₂ affinity and, furthermore, antiproliferative effects on different tumor cell lines, including Panc‐1. ^[19] 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. ^[20]

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). ^[21] 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). ^[22] 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.[ ²³ , ²⁴ ]

The 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline residue is a pharmacophoric element present in several σ₂ receptor ligands.[ ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ ] (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 ^[32] ) with an ethylene and tetramethylene linker, respectively, showed high σ₂ affinity and selectivity over the σ₁ receptor. ^[33] 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. ^[34] (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.

2. Results and Discussion

2.1. 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 ^[35] and 12. ^[36] and cyclohexanamines 11 ^[34] and 13 with 2‐benzopyran and 2‐benzofuran scaffold. a) 5 steps; ^[35] b) 7 steps; ^[34] c) 4 steps; ^[36] d) 4 steps;[ ³⁷ , ³⁸ ] 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.[ ³⁵ , ³⁶ ] 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[ ³⁷ , ³⁸ ] 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 ^[39] –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. S_N2 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.

2.2. 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. ^[40]

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).

3. 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.[ ³⁵ , ³⁶ ] 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−H_alkyl), 1435, 1366 (C=C_arom). 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−H_alkyl), 1458, 1439 (C=C_arom). 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. ^[39] 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−H_alkyl), 1651 (C=O), 1520, 1443 (C=C_arom). 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−H_alkyl), 1636 (C=O), 1547, 1447 (C=C_arom). 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−H_alkyl), 1643 (C=O), 1447 (C=C_arom). 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−H_alkyl), 1636 (C=O), 1543, 1443 (C=C_arom). 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−H_alkyl), 1643 (C=O), 1543, 1443 (C=C_arom). 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−H_alkyl), 1651 (C=O), 1555, 1462, 1431 (C=C_arom). 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‐4_isoquinoline), 29.7 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 44.4 (0.5 C, C‐3_isoquinoline), 44.9 (0.5 C, C‐1_isoquinoline), 48.2 (0.5 C, C‐1_isoquinoline), 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‐8_isoquinoline), 110.9 (0.5 C, C‐8_isoquinoline), 112.9 (0.5 C, C‐5_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 125.6 (1 C, C‐8), 126.1 (1 C, C‐8a_isoquinoline), 126.9 (1 C, C‐4a_isoquinoline), 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‐6_isoquinoline, C‐7_isoquinoline), 170.7 (0.5 C, C=O), 170.8 ppm (0.5 C, C=O). FTIR (neat): ν [cm⁻¹]=2978, 2835 (C−H_alkyl), 1624 (C=O), 1516, 1454 (C=C_arom). 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‐4_isoquinoline), 29.1 (1 C, C‐3′ or C‐5′), 29.3 (1 C, C‐3′ or C‐5′), 29.6 (0.5 C, C‐4_isoquinoline), 36.2 (1 C, C‐4), 36.4 (1 C, C‐2′), 38.9 (1 C, C‐6′), 41.6 (0.5 C, C‐3_isoquinoline), 43.6 (0.5 C, C‐3_isoquinoline), 45.2 (0.5 C, C‐1_isoquinoline), 46.9 (0.5 C, C‐1_isoquinoline), 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‐8_isoquinoline), 111.0 (0.5 C, C‐8_isoquinoline), 113.0 (0.5 C, C‐5_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 125.6 (0.5 C, C‐8), 125.7 (0.5 C, C‐8), 125.8 (0.5 C, C‐8a_isoquinoline), 126.3 (0.5 C, C‐8a_isoquinoline), 127.5 (1 C, C‐7), 127.67 (1 C, C‐6), 127.74 (0.5 C, C‐4a_isoquinoline), 128.2 (0.5 C, C‐4a_isoquinoline), 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‐6_isoquinoline, C‐7_isoquinoline), 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−H_alkyl), 1640 (C=O), 1516, 1435 (C=C_arom). 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‐4_isoquinoline), 30.0 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 44.6 (0.5 C, C‐3_isoquinoline), 45.2 (0.5 C, C‐1_isoquinoline), 48.3 (0.5 C, C‐1_isoquinoline), 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‐8_isoquinoline), 111.0 (0.5 C, C‐8_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 113.3 (0.5 C, C‐5_isoquinoline), 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‐8a_isoquinoline), 126.9 (0.5 C, C‐4a_isoquinoline), 127.8 (0.5 C, C‐8a_isoquinoline), 128.0 (0.5 C, C‐4a_isoquinoline), 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‐6_isoquinoline, C‐7_isoquinoline), 170.9 (0.5 C, C=O), 171.0 ppm (0.5 C, C=O). FTIR (neat): ν [cm⁻¹]=2913, 2735 (C−H_alkyl), 1636 (C=O), 1516, 1447 (C=C_arom). 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‐4_isoquinoline), 29.6 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 43.7 (0.5 C, C‐3_isoquinoline), 45.2 (0.5 C, C‐1_isoquinoline), 46.9 (0.5 C, C‐1_isoquinoline), 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‐8_isoquinoline), 111.0 (0.5 C, C‐8_isoquinoline), 113.0 (0.5 C, C‐5_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 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‐8a_isoquinoline), 126.3 (0.5 C, C‐8a_isoquinoline), 127.8 (0.5 C, C‐4a_isoquinoline), 128.2 (0.5 C, C‐4a_isoquinoline), 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‐6_isoquinoline or C‐7_isoquinoline), 149.38 (0.5 C, C‐6_isoquinoline or C‐7_isoquinoline), 149.41 (0.5 C, C‐6_isoquinoline or C‐7_isoquinoline), 149.5 (0.5 C, C‐6_isoquinoline or C‐7_isoquinoline), 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−H_alkyl), 1643 (C=O), 1516, 1435 (C=C_arom). 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‐4_isoquinoline), 29.6 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 43.6 (0.5 C, C‐3_isoquinoline), 45.2 (0.5 C, C‐1_isoquinoline), 46.8 (0.5 C, C‐1_isoquinoline), 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‐8_isoquinoline), 111.0 (0.5 C, C‐8_isoquinoline), 113.0 (0.5 C, C‐5_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 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‐8a_isoquinoline), 126.3 (0.5 C, C‐8a_isoquinoline), 127.7 (0.5 C, C‐4a_isoquinoline), 128.2 (0.5 C, C‐4a_isoquinoline), 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‐6_isoquinoline, C‐7_isoquinoline), 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−H_alkyl), 1643 (C=O), 1516, 1435 (C=C_arom). 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‐4_isoquinoline), 29.6 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 52.3 (0.5 C, C‐3_isoquinoline), 56.4–56.6 (m, 4 C, C‐1_isoquinoline, 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‐8_isoquinoline), 113.1 (0.5 C, C‐5_isoquinoline), 113.2 (0.5 C, C‐5_isoquinoline), 125.7 (1 C, C‐8), 127.40 (1 C, C‐4a_sioquinoline or C‐8a_isoquinoline), 127.44 (1 C, C‐4a_sioquinoline or C‐8a_isoquinoline), 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‐6_sioquinoline or C‐7_isoquinoline), 149.2 (1 C, C‐6_sioquinoline or C‐7_isoquinoline), 170.4 (0.5 C, C=O), 170.5 ppm (0.5 C, C=O). FTIR (neat): ν [cm⁻¹]=2924, 2835 (C−H_alkyl), 1639 (C=O), 1516, 1443 (C=C_arom). 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‐4_isoquinoline), 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‐3_isoquinoline), 56.35 (1 C, 3‐OCH₃), 56.44 (1 C, 7‐OCH₃), 56.5 (1 C, 6‐OCH₃), 56.8 (1 C, C‐1_isoquinoline), 62.3 (1 C, COCH₂N), 77.1 (1 C, C‐1), 97.9 (1 C, C‐3), 111.1 (1 C, C‐8_isoquinoline), 113.2 (1 C, C‐5_isoquinoline), 125.4 (1 C, C‐8), 127.1 (1 C, C‐4a_isoquinoline), 127.4 (1 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 149.4 (1 C, C‐6_isoquinoline), 172.1 ppm (1 C, C=O). FTIR (neat): ν [cm⁻¹]=3341 (N−H), 2928, 2832 (C−H_alkyl), 1674 (C=O), 1516, 1447 (C=C_arom). 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‐4_isoquinoline), 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‐3_isoquinoline), 56.4 (2 C, C‐1_isoquinoline, 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‐8_isoquinoline), 113.1 (1 C, C‐5_isoquinoline), 125.7 (1 C, C‐8), 127.2 (1 C, C‐4a_isoquinoline), 127.5 (1 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 149.2 (1 C, C‐6_isoquinoline), 171.9 ppm (1 C, C=O). FTIR (neat): ν [cm⁻¹]=3298 (N−H), 2978, 2924, 2835 (C−H_alkyl), 1639 (C=O), 1512, 1443 (C=C_arom). 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‐4_isoquinoline), 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‐3_isoquinoline), 56.4 (1 C, C‐1_isoquinoline), 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‐8_isoquinoline), 113.0 (1 C, C‐5_isoquinoline), 125.7 (1 C, C‐8), 126.9 (1 C, C‐8a_isoquinoline), 127.1 (1 C, C‐4a_isoquinoline), 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‐7_isoquinoline), 149.4 (1 C, C‐6_isoquinoline), 174.8 ppm (1 C, C=O). FTIR (neat): ν [cm⁻¹]=3275 (N−H), 2924, 2855 (C−H_alkyl), 1639 (C=O), 1516, 1447 (C=C_arom). 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‐4_isoquinoline), 29.51 (0.5 C, C‐4_isoquinoline), 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‐3_isoquinoline), 55.2 (1 C, 3‐OCH₃), 56.4–56.6 (m, 3 C, C‐1_isoquinoline, 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‐8_isoquinoline), 113.11 (0.5 C, C‐5_isoquinoline), 113.13 (0.5 C, C‐5_isoquinoline), 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‐4a_isoquinoline), 127.40 (0.5 C, C‐4a_isoquinoline), 127.6 (0.5 C, C‐8a_isoquinoline), 127.7 (0.5 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 148.83 (0.5 C, C‐7_isoquinoline), 149.16 (0.5 C, C‐6_isoquinoline), 149.17 (0.5 C, C‐6_isoquinoline), 170.39 (0.5 C, C=O), 170.40 ppm (0.5 C, C=O). FTIR (neat): ν [cm⁻¹]=2913, 2735 (C−H_alkyl), 1636 (C=O), 1516, 1447 (C=C_arom). 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‐4_isoquinoline), 33.8 (1 C, C‐2′), 35.1 (1 C, C‐6′), 45.1 (1 C, C‐4′), 52.6 (1 C, C‐3_isoquinoline), 55.0 (1 C, 3‐OCH₃), 56.4 (1 C, 7‐OCH₃), 56.5 (1 C, 6‐OCH₃), 56.7 (1 C, C‐1_isoquinoline), 62.1 (1 C, COCH₂N), 87.0 (1 C, C‐1), 107.1 (1 C, C‐3), 111.1 (1 C, C‐8_isoquinoline), 113.1 (1 C, C‐5_isoquinoline), 121.8 (1 C, C‐7), 124.2 (1 C, C‐4), 127.2 (1 C, C‐4a_isoquinoline), 127.5 (1 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 149.4 (1 C, C‐6_isoquinoline), 172.1 ppm (1 C, C=O). FTIR (neat): ν [cm⁻¹]=3341 (N−H), 2932, 2832 (C−H_alkyl), 1674 (C=O), 1516, 1463, 1451 (C=C_arom). 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‐4_isoquinoline), 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‐3_isoquinoline), 54.9 (1 C, 3‐OCH₃), 56.4 (1 C, C‐1_isoquinoline), 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‐8_isoquinoline), 113.2 (1 C, C‐5_isoquinoline), 121.8 (1 C, C‐7), 124.2 (1 C, C‐4), 127.2 (1 C, C‐4a_isoquinoline), 127.5 (1 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 149.2 (1 C, C‐6_isoquinoline), 172.0 ppm (1 C, C=O). FTIR (neat): ν [cm⁻¹]=3333 (N−H), 2932, 2909, 2832 (C−H_alkyl), 1667 (C=O), 1516, 1439 (C=C_arom). 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‐4_isoquinoline), 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‐3_isoquinoline), 56.1 (1 C, N_isoquinoline CH₂CH₂N), 56.46 (2 C, 3‐OCH₃, 6‐OCH₃ or 7‐OCH₃), 56.51 (1 C, N_isoquinolineCH₂ CH₂N), 56.7 (1 C, 6‐OCH₃ or 7‐OCH₃), 56.9 (1 C, C‐1_isoquinoline), 75.6 (1 C, C‐1), 97.9 (1 C, C‐3), 111.2 (1 C, C‐8_isoquinoline), 113.0 (1 C, C‐5_isoquinoline), 125.7 (1 C, C‐8), 127.3 (1 C, C‐8a_isoquinoline), 127.4 (1 C, C‐4a_isoquinoline), 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‐7_isoquinoline), 149.3 ppm (1 C, C‐6_isoquinoline). FTIR (neat): ν [cm⁻¹]=2947, 2820, 2778 (C−H_alkyl), 1516, 1466, 1454 (C=C_arom). 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, N_isoquinolineCH ₂CH₂N, 3‐H _isoquinoline), 2.86–2.95 (m, 5H, 4‐H, N_isoquinolineCH₂CH 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‐4_isoquinoline), 31.5 (1 C, C‐6′), 34.1 (1 C, C‐2′), 36.2 (1 C, C‐4), 44.7 (1 C, N_isoquinolineCH₂ CH₂N), 52.5 (1 C, C‐4′), 52.5 (1 C, C‐3_isoquinoline or N_isoquinoline CH₂CH₂N), 56.3 (1 C, 3‐OCH₃), 56.4–56.5 (m, 2 C, 6‐OCH₃, 7‐OCH₃), 56.8 (1 C, C‐1_isoquinoline), 58.0 (1 C, C‐3_isoquinoline or N_isoquinoline CH₂CH₂N), 77.8 (1 C, C‐1), 97.9 (1 C, C‐3), 111.3 (1 C, C‐8_isoquinoline), 113.1 (1 C, C‐5_isoquinoline), 125.9 (1 C, C‐8), 127.4 (1 C, C‐4a_isoquinoline), 127.5 (1 C, C‐7), 127.55 (1 C, C‐6), 127.62 (1 C, C‐8a_isoquinoline), 130.0 (1 C, C‐5), 132.4 (1 C, C‐4a), 143.2 (1 C, C‐8a), 148.9 (1 C, C‐7_isoquinoline), 149.3 ppm (1 C, C‐6_isoquinoline). FTIR (neat): ν [cm⁻¹]=3368 (N−H), 2924, 2832 (C−H_alkyl), 1516, 1447 (C=C_arom). 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, N_isoquinolineCH 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, N_isoquinolineCH₂CH 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‐4_isoquinoline), 36.2 (1 C, C‐4), 36.5 (1 C, C‐2′), 39.0 (1 C, C‐6′), 44.3 (1 C, N_isoquinolineCH₂ CH₂N), 52.4 (1 C, C‐3_isoquinoline), 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‐1_isoquinoline), 57.4 (1 C, C‐4′), 58.2 (1 C, N_isoquinoline CH₂CH₂N), 77.4 (1 C, C‐1), 97.8 (1 C, C‐3), 111.2 (1 C, C‐8_isoquinoline), 113.0 (1 C, C‐5_isoquinoline), 125.7 (1 C, C‐8), 127.4 (1 C, C‐4a_isoquinoline), 127.50 (1 C, C‐7), 127.53 (1 C, C‐8a_isoquinoline), 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‐7_isoquinoline), 149.3 ppm (1 C, C‐6_isoquinoline). FTIR (neat): ν [cm⁻¹]=3402 (N−H), 2928, 2832 (C−H_alkyl), 1516, 1447 (C=C_arom). 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.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supplementary

M. Bergkemper, D. Schepmann, B. Wünsch, ChemMedChem 2021, 16, 1184.