Synthesis of 2-Aminoazoles from Thioesters via α-Heterosubstituted Ketones by Copper-Mediated Cross-Coupling

Abstract

Facile synthesis of a variety of α-heterosubstituted ketones under mild conditions was achieved by copper-mediated cross-coupling of thioesters with functionalized organostannanes. Application of this coupling methodology provided a concise pathway for the conversion of carboxylic acids to 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles via thioesters in practical yields.

Graphical abstract

INTRODUCTION

α-Heterosubstituted methyl ketones are valuable intermediates in organic synthesis. Occasionally, they constitute notable structural features of various bioactive compounds and natural products.¹ General methods for their preparation involve the intermediacy of α-bromomethyl ketones, where the bromide is substituted by a nucleophilic heteroatom. α-Aminomethyl ketones are typically prepared from α-bromomethyl ketones with hexamethylene tetraamine,² sodium diformylamide,³ or potassium phthalimide.⁴ α-Hydroxymethyl ketones and α-fluoromethyl ketones are obtained by the treatment with alkali formates⁵ and tetrabutylammonium fluoride,⁶ respectively. Importantly, α-bromomethyl ketones are used as precursors of heterocycles such as 2-aminoheteroazoles in medicinal chemistry.^7,8 However, the preparation of α-bromomethyl ketones requires brominating reagents, diazomethane, and strict pH control over their multistep syntheses and thus has limitations for the late-stage functionalization of complex molecules.

A mild synthesis of ketones from readily available thioesters and organostannanes has been reported by Liebeskind et al.⁹ This reaction relies on the palladium-catalyzed, copper-mediated coupling under neutral conditions. Furthermore, a palladium-free, copper-mediated cross-coupling of thioesters with α-alkoxystannanes to give α-alkoxyketones has been developed.¹⁰ In the synthesis of the agelastatin alkaloids, Movassaghi has capitalized on the cross-coupling of thioesters with aminostannanes and its application to azaheterocycle synthesis.¹¹

RESULTS AND DISCUSSION

Herein, we describe our investigations utilizing mild, palladium-free cross-coupling for the synthesis of α-substituted methyl ketones and heterocycles from thioesters and functionalized organostannanes. Using Cu(I) additives with appropriate stannane coupling reagents, we achieved the synthesis of α-amino, α-oxy, α-thio, and α-fluoromethyl ketones. In addition, we developed the direct synthesis of 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles from thioesters via the copper-mediated cross-coupling reaction.

In our initial assessment of copper sources to mediate the coupling of thioesters and α-heterosubstituted organostannanes, the reaction of thioester 1a with (N-Boc-aminomethyl)-tri-n-butylstannane 2a was examined as a model system (Table 1). In the first attempt with 2 equiv of CuTC (copper(I) thiophene-2-carboxylate) and 2 equiv of the stannane in THF at 50 °C (entry 1), the desired ketone 3 was obtained in nearly quantitative yield. Deprotection occurred readily with HCl to get α-aminomethyl ketone. Using 1 equiv of CuTC (entry 2), the coupling reaction did not proceed to completion. All amounts of Cu(I) salts less than 2 equiv lead to longer reaction times and decreased ketone yields with recovery of thioester. We observed that Cu(I) halides and CuCN (entries 3–6) produced only traces of the α-aminoketone derivative with the recovery of the starting thioester. Decomposition of the thioester occurred with CuOTf (entry 7). CuOAc and CuDPP (copper(I) diphenylphosphate) were effective in the coupling reaction of thioester 1a and stannane 2a (entries 8 and 10). Although the use of Cu(OAc)₂ gave some ketone product (entry 9), it clearly gave a substantially lower yield compared to CuTC, CuOAc, and CuDPP.

Table 1.

Optimization of Copper Reagent in the Coupling of Thioester 1a with Aminomethylstannane 2a^a

entry	[Cu]	equiv	time, h	3, %	1a, %
1	CuTC	2	2	99	0
2	CuTC	1	18	65	26
3	CuCl	2	2	trace	>90
4	CuBr·Me2S	2	2	0	100
5	CuI	2	2	0	100
6	CuCN	2	2	0	100
7	CuOTf	2	1	0	0
8	CuOAc	2	2	97	0
9	Cu(OAc)2	2	18	57	nd
10	CuDPP	2	2	92	0

^aStandard conditions: 1a (0.1 mmol), 2a (2.0 equiv), Cu source, THF (0.1 M) mixed under argon at 50 °C.

The coupling reaction of thioester 1a with aminomethyl stannane 2a using CuOAc effectively proceeded in THF under inert conditions. To determine the effective reaction parameters, we optimized the solvent and investigated the influence of the atmosphere (Table 2). Of the different solvents screened, THF, dioxane, toluene, DCE, and DMF were found to be suitable. Among the solvents investigated, THF and DMF produced high yields of ketone 3 and were chosen for further studies. To our surprise, no ketone product was formed and no starting thioester was recovered in MeCN as the solvent (entry 2). Addition of water to THF decreased the yield to 19% (entry 3). On exposure to air or oxygen, the reaction resulted in low or no yield, respectively (entries 4, 5).

Table 2.

Influence of Solvent and Atmosphere^a,^b

entry	solvent	atmosphere	3, %	1a, %
1	THF	argon	97	0
2	MeCN	argon	0	0
3	1% H2O in THF	argon	19	78
4	THF	air	26	73
5	THF	oxygen	0	100

^aStandard conditions: 1a (0.1 mmol), 2a (2.0 equiv), CuOAc (2.0 equiv), THF (0.1 M) mixed under argon at 50 °C.

^bOrganic solvents were freshly distilled.

Investigations were continued under the identified standard conditions to examine a variety of α-heterosubstituted methyl and ethyl stannanes in cross-coupling reactions with thioesters (Table 3). We selected CuOAc and CuDPP as the copper sources because the resulting tin byproducts, n-Bu₃SnOAc or n-Bu₃SnOP(O)(Ph)₂, were more easily separable from the reaction mixture by column chromatography compared to CuTC byproducts. The coupling reaction was effective for both aromatic and aliphatic thioesters. We chose p-toluenethioester derivatives over benzenethioester or p-nitrobenzenethioester due to its ease of handling, general increase in yields of ketones, and reported lower toxicity of the thiol precursors.

Table 3.

Scope of Stannanes with Thioesters 1a and 1b

entry	thioester	stannane	productb	yield
1	1a	2a		97%
2	1b	2a		95%
3	1a			88%
4	1b	2b		81%
5	1a			96%
6	1b	2c		89%
7	1a			66%
8	1b	2d		67%
9	1a			81%
10	1b	2e		78%
11	1a			81%
12	1b	2f		71%
13	1a			78%
14	1b	2g		72%

^aStandard conditions: 1 (0.1 mmol), 2 (2.0 equiv), CuOAc (2.0 equiv), THF (0.1 M) mixed under argon at 50 °C.

^bR = 4-MeOC₆H₄

Both 4-methoxyphenylacetothioate 1a and 4-methoxybenzothioate 1b underwent efficient cross-coupling with Boc-protected (2a), Cbz-protected (2b), and acetyl-protected (2c) aminomethyl stannanes in excellent yields (Table 3, entries 1–6). In the case of N-Boc-α-aminoethyl stannane 2d, the resulting ketones 9 and 10 were obtained in moderate yields after heating at 80 °C for 24 h (entries 7 and 8). In the case of oxymethyl ketones, we initially examined acetoxymethyl stannane 2e,¹² which underwent the coupling reaction to provide the desired α-acetoxymethyl ketones 11 and 12 in DMF at 80 °C for 24 h (entries 9 and 10). On the other hand, no reaction occurred with the tert-butyldimethylsiloxymethyl-stannane even at elevated temperatures in DMF. Performing the cross-coupling with acetylthiomethylstannane 2f,¹³ CuDPP was found to be a more effective copper additive compared to CuOAc (entries 11 and 12). Although the coupling reaction with chloromethylstannane¹⁴ or iodomethylstannane¹⁵ did not take place, fluoromethylstannane 2g¹⁶ provided fluoromethyl ketones 15 and 16 (entries 13 and 14). Surprisingly, when CuOAc was used in this fluoromethylation reaction, the formation of the expected ketones (15 and 16) was accompanied by the formation of α-acetoxymethyl ketone byproducts (11 and 12). CuDPP suppressed the generation of byproducts, and good yields of fluoromethyl ketones were achieved.

After accomplishing the synthesis of several of α-heterosubstituted ketones, we evaluated this approach as a method for the synthesis of a variety of 2-aminoazoles from thioesters. Movassaghi et al. recently reported the synthesis of 2-aminoimdazoles using the coupling reaction of guanidinylmethylstannanes with thioesters, followed by cyclization under acidic conditions.^11b In our own studies, we also first evaluated and used this approach for the synthesis of 2-aminoimidazoles as a part of a program directed at the first enantioselective synthesis of dragmacidin D (Figure 1).¹⁷

Figure 1.

Structure of dragmacidin D.

Initial investigations with variably protected guanidylmethylstannanes revealed that fully protected tris-N-Boc gunanidyl reagent 2h is optimal in terms of coupling efficiency and overall yield of the heterocyclic product. The synthesis is best achieved by performing the cross-coupling first and then removing all Boc groups by treatment with trifluoroacetic acid in dichloromethane, which also accomplishes cyclocondensation of the intermediate ketone to 2-aminoimidazole in high yield. Cross-coupling of thioester 1a and stannane 2h was achieved in 95% yield, and subsequent cyclocondensation to 2-aminoimidazole 17 was performed in 88% isolated yield (Table 4, entry 1). This reaction was shown to be scalable, achieving 71% yield over the 2-step process starting with 1 g (3.7 mmol) of thioester 1a.

Table 4.

Two-Step Synthesis of 2-Aminoimidazoles

^aStandard conditions: Cross-coupling: 1 (0.1 mmol), 2h (2.0 equiv), CuOAc (2.0 equiv), THF (0.1 M) mixed under argon at 50 °C. Cyclization: ketone (50 µmol), TFA (1 mL), DCM (1 mL) mixed under argon at rt. Monitor by TLC.

Table 4 provides additional thioesters tested in this approach to aminoimidazoles. Benzothioate 1b and α-methyl phenylacetothioate 1d provided the corresponding heterocyclic products 18 and 20 in very high yields (entries 2 and 4). Moreover, α-methyl-4-substituted indole containing 2-aminoimidazole 21,¹⁸ which is found in the marine natural product dragmacidin D¹⁹ (Figure 1), could be synthesized from the thioester precursor 1e in good yield (entry 5). The thioester 1c containing a free phenol underwent the cross-coupling reaction and cyclization in 63% yield (entry 3).

In a similar fashion, we assessed the formation of 2-aminothiazoles from aromatic and aliphatic thioesters (Scheme 1). For this class of products, we found that mono-Boc isothiourea reagent 2j, easily prepared from iodomethyltributylstannane and Boc-protected thiourea,^15a,20 is the optimal choice compared to the bis-Boc reagent. Using DMF as the solvent at elevated temperatures, the heterocyclic product could be accessed directly in one step from the thioester precursor. Thus, upon treatment of 1a and stannane 2j with CuOAc in DMF at 80 °C, 2-aminothiazole derivative 23 was isolated in 81% yield. Similarly, 25 was prepared from aromatic thioester 1b under identical reaction conditions in 85% isolated yield.

Scheme 1.

Synthesis of 2-Aminothiazole from Stannanes 2j and 2k

Finally, we investigated the synthesis of 2-aminooxazoles following the same blueprint (Scheme 2). After exploring several variants of the isourea-functionalized stannane reagent, bis-N-Boc-protected stannane 2k emerged as the reagent of choice. Although the use of CuOAc led to the formation of a significant amount of byproducts, coupling of thioester 1a with reagent 2k in the presence of CuDPP under reflux in THF occurred in 72% isolated yield. Exposure of the product to trifluoroacetic acid in dichloromethane readily afforded 2-aminooxazole 27 in 80% isolated yield. Similarly, cross-coupling of aromatic thioester 1b was efficient under identical conditions (86% yield). In the final step, aromatization of 28 under acidic conditions afforded 2-aminooxazole 29 in high yield. Longer reaction times were necessary in the cyclization toward 29 compared to the formation of similar heterocycles 2-aminooxazole 27 and 2-AI 18. The slower reactivity of 28 is attributed to the lower nucleophilicity of the isourea group.

Scheme 2.

Synthesis of 2-Aminooxazole with Stannane 2k

CONCLUSIONS

In conclusion, we described a palladium-free, copper mediated cross-coupling of thioesters with heterosubstituted methylstannanes. By this approach, CuOAc or CuDPP were used as the reagents of choice for the operationally simple synthesis of 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles in a straightforward, 2-step protocol from readily available carboxylic acids via thioesters.

EXPERIMENTAL SECTION

General Information

All reactions were carried out under an inert atmosphere of dry argon in oven- or flame-dried glassware, unless the reaction procedure states otherwise. Tetrahydrofuran (THF) and ether (diethyl ether) were distilled from sodium-benzophenone in a continuous still under an atmosphere of argon. Dichloromethane, diiso-propylamine, and triethylamine were distilled from calcium hydride in a continuous still under an atmosphere of argon. Elevated reaction temperatures were controlled by thermocouples. Room-temperature reactions were carried out between 22 and 24 °C. Analytical thin-layer chromatography (TLC) was performed using precoated TLC plates with Silica Gel 60 F₂₅₄ and visualized using combinations of UV, anisaldehyde, ceric ammonium molybdate (CAM), potassium permanganate, and iodine staining. Flash column chromatography was performed using 40–63 µm silica gel as the stationary phase. Proton magnetic resonance spectra were recorded at 400, 500, and 600 MHz. Carbon magnetic resonance spectra were recorded at 126 MHz. All chemical shifts were reported in δ units relative to tetramethylsilane. High-resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI) with Q-TOF detection and electron ionization (EI) techniques.

General Procedure 1

S-4-Tolyl 4-Methoxyphenylacetothioate 1a

1-Ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (10.0 g, 52.2 mmol) was added portionwise to a mixture of 2-(4-methoxyphenyl)acetic acid (8.0 g, 48.1 mmol) and 1-hydroxybenzotriazole monohydrate (8.0 g, 52.2 mmol) in dichloromethane (100 mL) at 0 °C. After stirring for 30 min, 4-methylbenzenethiol (6.0 g, 48.3 mmol) was added to the solution, and the mixture was allowed to warm to 23 °C and stirred for 12 h. The reaction was quenched with saturated aqueous NaHCO₃ solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexanes) to afford S-4-tolyl 4-methoxyphenylacetothioate 1a as a colorless solid (10.8 g, 39.8 mmol, 83%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.25 (d, J = 7.5 Hz, 4H), 7.19 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 3.84 (s, 2H), 3.81 (s, 3H), 2.36 (s, 2H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 196.2, 159.0, 139.5, 134.3, 130.7, 129.9, 125.3, 124.3, 114.0, 55.2, 49.1, 21.2. HRMS (EI) [M]⁺ calcd for C₁₆H₁₆O₂S: 272.0871; found 272.0870.

S-4-Tolyl 4-Methoxybenzothioate 1b

1-Ethyl-3-(3-(dimethylamino) propyl)carbodiimide hydrochloride (1.9 g, 9.91 mmol) was added portionwise to a mixture of 4-methoxybenzoic acid (1.0 g, 6.57 mmol) and 1-hydroxybenzotriazole monohydrate (1.5 g, 9.80 mmol) in dichloromethane (20 mL) at 0 °C. After stirring for 30 min, 4-methylbenzenethiol (1.2 g, 9.66 mmol) was added to the solution, and the mixture was allowed to warm to 23 °C and stirred for 12 h. The reaction was quenched with saturated aqueous NaHCO₃ solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexanes) to afford S-4-tolyl 4-methoxybenzothioate 1b as a colorless solid (1.5 g, 5.88 mmol, 90%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.00 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H), 2.39 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 188.9, 163.9, 139.5, 135.0, 130.0, 129.6, 129.4, 124.0, 113.8, 55.5, 21.3. HRMS (EI) [M]⁺ calcd for C₁₅H₁₄O₂S: 258.0715; found 258.0714.

S-4-Tolyl 2-(4-Hydroxyphenyl)ethanethioate 1c

Boron tribromide (2.0 mL, 1.0 M in dichloromethane, 2.00 mmol) was added dropwise to a solution of S-4-tolyl 4-methoxyphenylacetothioate 1a (220 mg, 0.808 mmol) in dichloromethane (2.0 mL) at −78 °C. The reaction mixture was allowed to warm at 23 °C and stirred for 1 h. The reaction was quenched carefully with water at −78 °C and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (25% ethyl acetate in hexanes) to afford S-4-tolyl 2-(4-hydroxyphenyl)ethanethioate 1c as a colorless solid (204 mg, 0.079 mmol, 98%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.25 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.3 Hz, 4H), 6.80 (d, J = 8.5 Hz, 2H), 4.78 (s, 1H), 3.83 (s, 2H), 2.36 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 197.4, 155.1, 139.7, 134.3, 130.8, 130.0, 125.2, 124.1, 115.6, 49.1, 21.3. HRMS (EI) [M]⁺ calcd for C₁₅H₁₄O₂S: 258.0715; found 258.0712.

S-4-Tolyl 2-(4-Methoxyphenyl)propanethioate 1d

The title compound was prepared according to general procedure 1 using 2-(4-methoxyphenyl)propanoic acid (1.0 g, 5.72 mmol), 4-methylbenzenethiol (780 mg, 6.28 mmol), 1-ethyl-3-(3-(dimethylamino)-propyl)carbodiimide hydrochloride (1.3 g, 6.78 mmol), and 1-hydroxybenzotriazole monohydrate (1.1 g, 7.18 mmol) in dichloromethane (20 mL) and purification by column chromatography on silica gel (5% ethyl acetate in hexanes) to obtain 1d as a colorless solid (1.1 g, 3.95 mmol, 69%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.31–7.14 (m, 6H), 6.89 (d, J = 8.7 Hz, 2H), 3.93 (q, J = 7.1 Hz, 1H), 3.81 (s, 3H), 2.35 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 199.6, 159.0, 139.3, 134.3, 131.6, 129.8, 129.0, 124.5, 114.0, 55.1, 53.1, 21.2, 18.6. HRMS (EI) [M]⁺ calcd for C₁₇H₁₈O₂S: 286.1028; found 286.1026.

Ethyl 2-(2-Bromo-4-methoxyphenyl)acetate S-1

Thionyl chloride (2.4 mL, 33.1 mmol) was added dropwise to a solution of 2-(2-bromo-4-methoxyphenyl)acetic acid (2.7 g, 10.9 mmol) in ethanol (40 mL) at 0 °C. The reaction mixture was heated at reflux for 1 h. After cooling, the solvent was removed by evaporation, and the residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford ethyl 2-(2-bromo-4-methoxyphenyl)acetate S-1 as a colorless oil (2.7 g, 9.89 mmol, 90%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.19 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.83 (dd, J = 8.5, 2.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 170.8, 159.2, 131.7, 126.3, 125.1, 118.0, 113.6, 60.9, 55.5, 40.7, 14.2. HRMS (EI) [M]⁺ calcd for C₁₁H₁₃BrO₃: 272.0048; found 272.0050.

Ethyl 2-(2-Bromo-4-methoxyphenyl)propanoate S-2

Lithium hexamethyldisilazide (9.6 mL, 1.0 M in hexanes, 9.60 mmol) was added dropwise to a solution of ethyl 2-(2-bromo-4-methoxyphenyl)-acetate S-1 in THF (40 mL) at −78 °C, and the resulting solution was stirred at 0 °C for 30 min. Methyl iodide (0.85 mL, 13.7 mmol) was added to the above solution at −78 °C, and the reaction mixture was allowed to warm at 23 °C and stirred for 1 h. The reaction was quenched with a saturated aqueous NH₄Cl solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (5% ethyl acetate in hexanes) to afford ethyl 2-(2-bromo-4-methoxyphenyl)propanoate S-2 as a colorless oil (2.5 g, 8.71 mmol, 95%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.22 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.7 Hz, 1H), 6.85 (dd, J = 8.7, 2.7 Hz, 1H), 4.20–4.07 (m, 3H), 3.78 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 174.2, 158.8, 132.2, 128.6, 124.4, 118.0, 113.8, 60.8, 55.4, 43.8, 17.9, 14.1. HRMS (EI) [M]⁺ calcd for C₁₂H₁₅BrO₃: 286.0205; found 286.0210.

tert-Butyl 2-(Boc-amino)-3-(2-(1-ethoxycarbonylethane-1-yl)-5-methoxyphenyl)acrylate S-3

A mixture of ethyl 2-(2-bromo-4-methoxyphenyl)propanoate S-2 (3.9 g, 13.4 mmol), tert-butyl 2-(Bocamino) acrylate (4.0 g, 16.4 mmol), palladium(II) acetate (150 mg, 0.668 mmol), tri-(o-tolyl)phosphine (410 mg, 1.35 mmol), and triethylamine (10 mL) in acetonitrile (40 mL) was heated at 90 °C for 20 h. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford tert-butyl 2-(Boc-amino)-3-(2-(1-ethoxycarbonylethane-1-yl)-5-methoxyphenyl)acrylate S-3a as a yellow oil (4.0 g, 8.79 mmol, 66%) and its geometric isomer S-3b as a yellow solid (0.5 g, 1.11 mmol, 8.3%). S-3a: ¹H NMR (400 MHz,CDCl₃) δ (ppm): 7.24 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 6.88 (d, J = 2.8 Hz, 1H), 6.84 (dd, J = 8.6, 2.8 Hz, 1H), 6.12–6.07 (s, 1H), 4.18–4.03 (m, 2H), 3.87–3.78 (m, 1H), 3.76 (s, 3H), 1.56 (s, 9H), 1.44 (d, J = 7.1 Hz, 3H), 1.39 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 174.5, 164.0, 158.2, 152.7, 134.3, 131.8, 129.5, 128.0, 125.3, 115.1, 113.0, 81.9, 80.5, 60.8, 55.2, 41.2, 28.1, 28.0, 18.0, 14.1. HRMS (ESI) [M + Na]⁺ calcd for C₂₄H₃₅NO₇Na: 472.2311; found 472.2300. S-3b: ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.78 (ddd, J = 8.6, 2.8, 0.8 Hz, 1H), 6.60 (dd, J = 2.8, 0.9 Hz, 1H), 4.18–4.02 (m, 2H), 3.84 (q, J = 7.1 Hz, 1H), 3.75 (s, 3H), 1.50 (s, 9H), 1.38 (d, J = 7.0 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.11 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 174.9, 163.6, 157.7, 152.7, 138.0, 130.7, 127.0, 120.5, 114.6, 113.1, 82.3, 80.5, 60.5, 55.2, 41.6, 28.3, 27.3, 18.4, 14.1. HRMS (ESI) [M + Na]⁺ calcd for C₂₄H₃₅NO₇Na: 472.2311; found 472.2291.

Di-tert-butyl 4-(1-Ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-1,2-dicarboxylate S-4

A mixture of tert-butyl 2-(Boc-amino)-3-(2-(1-ethoxycarbonylethane-1-yl)-5-methoxyphenyl)acrylate S-3 (101 mg, 0.225 mmol), palladium(II) acetate (20 mg, 0.0891 mmol), and copper(II) acetate (122 mg, 0.672 mmol) in dimethyl sulfoxide (1.0 mL) was heated at 85 °C for 4 h. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford di-tert-butyl 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-1,2-dicarboxylate S-4 as a colorless oil (85 mg, 0.184 mmol, 82%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.15 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 4.16–4.08 (m, 2H), 4.08–3.97 (m, 1H), 3.89 (s, 3H), 1.64 (s, 9H), 1.60 (s, 9H), 1.56 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 174.5, 160.0, 150.6, 146.0, 129.1, 127.2, 126.8, 126.6, 119.7, 108.1, 105.9, 84.4, 81.8, 60.7, 55.5, 42.4, 28.2, 27.4, 17.9, 14.1. HRMS (ESI) [M + Na]⁺ calcd for C₂₄H₃₃NO₇Na: 470.2155; found 470.2152.

4-(1-Ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-2-carboxylic Acid S-5

Trifluoroacetic acid (30 mL) was added dropwise to 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-1,2-dicarboxylate S-4 (2.5 g, 5.32 mmol) in dichloromethane (30 mL) at 23 °C. After stirring for 30 min, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (100% ethyl acetate) to afford 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-2-carboxylic acid S-5 as a yellow solid (1.5 g, 5.15 mmol, 97%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.14 (s, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 4.22–4.01 (m, 3H), 3.97 (s, 3H), 1.61 (dd, J = 7.2, 1.5 Hz, 3H), 1.20 (td, J = 7.1, 2.6 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 174.8, 166.5, 145.7, 128.8, 127.4, 127.0, 125.8, 119.3, 109.6, 104.7, 60.8, 55.5, 42.7, 17.8, 14.1. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₁₇NO₅Na: 314.1003; found 314.1003.

4-(1-Ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole S-6

A solution of 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-2-carboxylic acid S-5 (1.5 g, 5.15 mmol) in quinoline (16 mL) was heated at 220 °C using microwave irradiation for 40 min. After cooling, the reaction mixture was quenched with 1 N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole S-6 as a brown oil (1.1 g, 4.29 mmol, 83%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.41 (s, 1H), 7.19 (t, J = 2.8 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.66–6.57 (m, 2H), 4.20–4.00 (m, 3H), 3.94 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 175.1, 145.3, 127.7, 126.3, 125.3, 123.5, 117.9, 101.6, 101.3, 60.5, 55.2, 42.9, 17.8, 14.1. HRMS (EI) [M]⁺ calcd for C₁₄H₁₇NO₃: 247.1208; found 247.1208.

4-(1-Carboxyethane-1-yl)-7-methoxy-1H-indole S-7

A solution of potassium hydroxide (210 mg, 3.74 mmol) in water (2.0 mL) was added dropwise to a solution of 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole S-6 (230 mg, 0.930 mmol) in THF–methanol (1:1, 4.0 mL) at 23 °C. After stirring for 3 h, the reaction mixture was quenched with 1 N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexanes) to afford 4-(1-carboxyethane-1-yl)-7-methoxy-1H-indole S-7 as a yellow solid (192 mg, 0.877 mmol, 94%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.48 (s, 1H), 7.18 (t, J = 2.8 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.61 (m, 2H), 4.09 (q, J = 7.2 Hz, 1H), 3.94 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 181.0, 145.5, 127.8, 126.3, 124.4, 123.7, 118.2, 101.8, 101.3, 55.3, 42.6, 17.3. HRMS (EI) [M]⁺ calcd for C₁₂H₁₃NO₃: 219.0895; found 219.0889.

7-Methoxy-4-(4-tolylsulfanyl-3-oxopropan-2-yl)-1H-indole 1e

The title compound was prepared according to general procedure 1 using 4-(1-carboxyethane-1-yl)-7-methoxy-1H-indole S-7 (700 mg, 3.19 mmol) and 4-methylbenzenethiol (800 mg, 6.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.0 g, 5.22 mmol), and 1-hydroxybenzotriazole monohydrate (800 mg, 5.22 mmol) in dichloromethane (15 mL). The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to obtain 7-methoxy-4-(4-tolylsulfanyl-3-oxopropan-2-yl)-1H-indole 1e as a yellow oil (816 mg, 2.51 mmol, 79%) ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 7.25–7.12 (m, 5H), 7.04 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 8.0 Hz), 6.63 (t, J = 2.5 Hz), 4.32 (q, J = 7.1 Hz, 1H), 3.97 (s, 3H), 2.34 (s, 3H), 1.67 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 200.1, 145.8, 139.1, 134.4, 129.7, 128.0, 126.4, 124.8, 123.8, 119.3, 101.8, 101.3, 55.2, 51.6, 21.2, 17.7. HRMS (EI) [M]⁺ calcd for C₁₉H₁₉NO₂S: 325.1136; found 325.1130.

N-(Tri-n-butylstannylmethyl)phthalimide S-9

Phthalimide potassium salt (1.8 g, 9.72 mmol) was added to a solution of tri-n-butylstannylmethyl iodide (3.0 g, 6.96 mmol) in DMF (30 mL) at 23 °C, and the mixture was stirred for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford N-(tri-n-butylstannylmethyl)-phthalimide S-9 as a colorless oil (2.9 g, 6.49 mmol, 93%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.79 (dd, J = 5.4, 3.1 Hz, 2H), 7.66 (dd, J = 5.4, 3.0 Hz, 2H), 3.23 (s, 2H), 1.62–1.36 (m, 6H), 1.32–1.23 (m, 6H), 1.02–0.89 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H).¹³C NMR (126 MHz, CDCl₃) δ (ppm): 168.8, 133.5, 132.3, 122.7, 28.9, 27.3, 21.2, 13.6, 10.4. HRMS (ESI) [M + Na]⁺ calcd for C₂₁H₃₃NO₂NaSn: 470.1426; found 470.1438.

tert-Butyl Tri-n-butylstannylmethylcarbamate 2a

Hydrazine monohydrate (4.0 mL, 81.8 mmol) was added dropwise to a solution of N-(tri-n-butylstannylmethyl)phthalimide S-9 (1.0 g, 2.22 mmol) in ethanol (30 mL) at 80 °C, and the reaction was stirred at 80 °C for 1 h. After cooling, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was submitted to the next step without purification.

Di-tert-butyl dicarbonate (450 mg, 2.06 mmol) and triethylamine (620 µL, 4.45 mmol) were added sequentially to a solution of the crude substrate (2.22 mmol) in dichloromethane (10 mL) at 23 °C. After stirring for 1 h, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel as a colorless oil (2% ethyl acetate in hexanes) to afford tert-butyl tri-n-butylstannylmethylcarbamate 2a (823 mg, 1.96 mmol, 88%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.50 (s, 1H), 2.78 (d, J = 5.0 Hz, 2H), 1.55–1.45 (m, 6H), 1.42 (s, 9H), 1.29 (h, J = 7.3 Hz, 6H), 1.00–0.78 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 156.8, 78.7, 29.1, 28.4, 27.4, 24.4, 13.7, 9.7. HRMS (ESI) [M + Na]⁺ calcd for C₁₈H₃₉NO₂NaSn: 440.1896; found 440.1893.

Benzyl Tri-n-butylstannylmethylcarbamate 2b

Hydrazine monohydrate (4.0 mL, 81.8 mmol) was added dropwise to a solution of N-(tri-n-butylstannylmethyl)phthalimide S-9 (1.0 g, 2.22 mmol) in ethanol (30 mL) at 80 °C, and the reaction was stirred at 80 °C for 1 h. After cooling, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was submitted to the next step without purification.

Benzyl chloroformate (300 µL, 2.10 mmol) and triethylamine (620 µL, 4.45 mmol) were added sequentially to a solution of the crude substrate (2.22 mmol) in dichloromethane (10 mL) at 23 °C. After stirring for 1 h, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (5% ethyl acetate in hexanes) to afford benzyl tri-n-butylstannylmethylcarbamate 2b as a colorless oil (804 mg, 1.77 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.40–7.23 (m, 5H), 5.09 (s, 2H), 4.73 (s, 1H), 2.90–2.78 (m, 2H), 1.52–1.41 (m, 6H), 1.36–1.22 (m, 6H), 0.89 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 157.3, 136.8, 128.4, 128.0, 128.0, 66.6, 29.0, 27.3, 24.9, 13.7, 9.7. HRMS (ESI) [M + Na]⁺ calcd for C₂₁H₃₇NO₂NaSn: 474.1739; found 474.1753.

N-(Tri-n-butylstannylmethyl)acetamide 2c

Hydrazine monohydrate (8.0 mL, 164 mmol) was added dropwise to a solution of N-(tri-n-butylstannylmethyl)phthalimide S-9 (1.9 g, 4.27 mmol) in ethanol (50 mL) at 80 °C, and the reaction was stirred at 80 °C for 1 h. After cooling, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was submitted to the next step without purification.

Triethylamine (1.8 mL, 12.9 mmol) and acetyl chloride (600 µL, 8.45 mmol) were added sequentially to a solution of the crude substrate (4.27 mmol) in dichloromethane (30 mL) at 0 °C. After stirring for 1 h, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexanes) to afford N-(tri-n-butylstannylmethyl)acetamide 2c as a yellow oil (1.4 g, 3.84 mmol, 90%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 5.66 (s, 1H), 2.82–2.69 (m, 2H), 1.94 (s, 3H), 1.57–1.39 (m, 6H), 1.33–1.28 (m, 6H), 0.95–0.81 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 169.9, 29.0, 27.3, 24.3, 22.7, 13.6, 10.2. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₃₃NONaSn: 382.1477; found 382.1491.

N-(1-(Tri-n-butylstannyl)ethyl)phthalimide S-11

n-Butyllithium (1.6 mL, 2.4 M in hexanes, 3.84 mmol) was added dropwise to a solution of diisopropylamine (520 mL, 3.71 mmol) in THF (15 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 30 min. Tri-n-butyltin hydride (1.0 mL, 3.72 mmol) was added to the above solution at 0 °C. After stirring for 30 min at the same temperature, acetaldehyde (210 µL, 3.76 mmol) was added, and the reaction mixture was allowed to warm at 23 °C and stirred for 1 h. The reaction mixture was quenched with a saturated aqueous NH₄Cl solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexanes) to afford 1-(tri-n-butylstannyl)ethanol S-10 as a colorless oil (796 mg, 2.37 mmol, 64%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.16 (m, 1H), 1.69–1.43 (m, 9H), 1.43–1.19 (m, 3H), 1.01–0.79 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 63.7, 29.2, 27.5, 24.6, 13.6, 8.3. [MS was not attained due to decomposition upon analysis.]

Diisopropyl azodicarboxylate (480 µL, 2.44 mmol) was added to a mixture of 1-(tri-n-butylstannyl)ethanol S-10 (820 mg, 2.45 mmol), phthalimide (440 mg, 2.99 mmol), and triphenylphosphine (640 mg, 2.44 mmol) in THF (10 mL) at 23 °C. After stirring for 4 h, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (5% ethyl acetate in hexanes) to afford N-(1-(tri-n-butylstannyl)ethyl)phthalimide S-11 as a yellow oil (847 mg, 1.83 mmol, 75%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.81 (dd, J = 5.4, 3.0 Hz, 2H), 7.68 (dd, J = 5.4, 3.0 Hz, 2H), 3.94 (m, 1H), 1.53–1.41 (m, 9H), 1.33–1.21 (m, 6H), 1.05–0.90 (m, 6H), 0.85 (m, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 169.0, 133.7, 132.2, 122.9, 31.4, 29.0, 27.4, 18.8, 13.6, 10.2. HRMS (ESI) [M + Na]⁺ calcd for C₂₂H₃₅NO₂NaSn: 484.1583; found 484.1571.

tert-Butyl 1-(Tri-n-butylstannyl)ethylcarbamate 2d

Hydrazine monohydrate (5.0 mL, 102.9 mmol) was added dropwise to a solution of N-(1-(tri-n-butylstannyl)ethyl)phthalimide S-3 (1.2 g, 2.59 mmol) in ethanol (30 mL) at 80 °C, and the reaction was stirred at 80 °C for 1 h. After cooling, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude residue was submitted to the next step without purification.

Di-tert-butyl dicarbonate (500 mg, 2.29 mmol) and triethylamine (720 µL, 5.17 mmol) were added sequentially to a solution of the crude substrate (2.59 mmol) in dichloromethane (12 mL) at 23 °C. After stirring for 1 h, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (2% ethyl acetate in hexanes) to afford tert-butyl 1-(tri-n-butylstannyl)ethylcarbamate 2d as a colorless oil (969 mg, 2.23 mmol, 86%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 4.60 (s, 1H), 3.26 (p, J = 7.9 Hz, 1H), 1.54–1.44 (m, 6H), 1.42 (s, 9H), 1.38–1.26 (m, 9H), 0.94–0.81 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 155.8, 78.7, 35.1, 29.2, 28.4, 27.5, 20.7, 13.7, 9.4. HRMS (ESI) [M + Na]⁺ calcd for C₁₉H₄₁NO₂NaSn: 454.2052; found 454.2063

Tri-n-butylstannylmethyl Acetate 2e

Triethylamine (650 µL, 4.66 mmol) and acetyl chloride (220 µL, 3.10 mmol) were added sequentially to a solution of tri-n-butylstannylmethanol (500 mg, 1.56 mmol) in dichloromethane (10 mL) at 23 °C. After stirring for 2 h, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (20% dichloromethane in hexanes) to afford tri-n-butylstannylmethyl acetate 2e as a colorless oil (414 mg, 1.14 mmol, 73%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 4.15 (s, 2H), 2.02 (s, 3H), 1.60–1.40 (m, 6H), 1.30 (tq, J = 14.5, 7.3 Hz, 6H), 1.00–0.82 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 171.9, 55.8, 28.9, 27.3, 20.7, 13.7, 9.6. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₃₂O₂NaSn: 383.1317; found 383.1335.

S-(Tri-n-butylstannylmethyl)ethanethioate 2f

Potassium thioacetate (800 mg, 7.01 mmol) was added portionwise to a solution of tri-n-butylstannylmethyl iodide (1.0 g, 2.32 mmol) in DMF (8.0 mL) at 23 °C. After stirring for 15 min, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (1% ethyl acetate in hexanes) to afford S-(tri-n-butylstannylmethyl)ethanethioate 2f as a colorless oil (864 mg, 2.28 mmol, 98%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 2.31 (s, 3H), 2.06 (s, 2H), 1.59–1.39 (m, 6H), 1.30 (sex, J = 7.3 Hz, 6H), 0.99–0.84 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 198.9, 29.8, 28.9, 27.2, 13.6, 10.1, 4.9. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₃₂ONaSSn: 399.1109; found 399.1099.

Tri-n-butylstannylmethylfluoride 2g

Deoxo-Fluor (50% in touluene, 1.2 mL, 3.25 mmol) was added dropwise to a solution of tri-n-butylstannylmethanol (466 mg, 1.45 mmol) in THF (8.0 mL) at 23 °C. After stirring for 10 min, the reaction was quenched carefully with water at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (100% hexanes) to afford tri-n-butylstannylmethylfluoride 2g as a colorless oil (323 mg, 1.00 mmol, 69%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.10 (dd, J = 47.3, 0.8 Hz, 2H), 1.65–1.39 (m, 6H), 1.39–1.24 (m, 6H), 1.00–0.85 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 81.6, 80.2, 29.0, 27.3, 13.7, 8.9. HRMS (EI) [M – C₄H₉]⁺ calcd for C₉H₂₀FSn: 263.0556; found 263.0578.

N,N′,N″-Tri-Boc-(tributylstannylmethyl)guanidine 2h

Di-tert-butyl azodicarboxylate (282 mg, 1.22 mmol) was added portionwise to a mixture of tri-n-butylstannylmethanol (393 mg, 1.22 mmol), tri-Boc-guanidine (440 mg, 1.22 mmol), and triphenylphosphine (321 mg, 1.22 mmol) in THF (5.0 mL) at 23 °C. After stirring for 2 h, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (2% ethyl acetate in hexanes) to afford N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)guanidine 2h as a colorless oil (623 mg, 0.941 mmol, 77%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.66 (s, 1H) 3.42 (s, 2H), 1.56–1.39 (m, 33H), 1.32–1.23 (m, 6H), 0.96–0.79 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 154.2, 151.2, 83.3, 34.2, 29.0, 28.1, 27.4, 13.7, 10.2. HRMS (ESI) [M + Na]⁺ calcd for C₂₉H₅₇N₃O₆NaSn: 682.3163; found 682.3161.

N,N′-Di-Boc-(tri-n-butylstannylmethyl)carbamimidothioate 2i

A solution of tri-n-butylstannyl iodide (980 mg, 2.27 mmol), N,N′-di-Boc thiourea (880 mg, 3.18 mmol), and triethylamine (800 µL, 5.74 mmol) in ethanol (10 mL) was heated at 80 °C for 2 h. After cooling, the solvent was removed by evaporation, and the residue was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (1% ethyl acetate in hexanes) to afford N,N′-di-Boc-(tri-n-butylstannylmethyl) carbamimidothioate 2i as a colorless oil (1.1 g, 1.86 mmol, 82%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.55 (s, 1H), 2.08 (s, 2H), 1.55–1.42 (m, 6H), 1.52 (s, 9H), 1.50 (s, 9H), 1.34–1.25 (m, 6H), 1.05–0.83 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 173.8, 160.8, 150.7, 82.9, 80.6, 29.0, 28.0, 27.3, 13.7, 10.3, 8.1. HRMS (ESI) [M + Na]⁺ calcd for C₂₄H₄₈N₂O₄NaSSn: 599.2254; found 599.2252.

N-Boc-(tri-n-butylstannylmethyl)carbamimidothioate 2j

A solution of tri-n-butylstannyl iodide (1.8 g, 4.18 mmol), N-Boc thiourea (1.0 g, 5.67 mmol), and triethylamine (1.2 mL, 8.61 mmol) in ethanol (20 mL) was heated at 80 °C for 2 h. After cooling, the solvent was removed by evaporation, and the residue was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (2% ethyl acetate in hexanes) to afford N-Boc-(tri-n-butylstannylmethyl)carbamimidothioate 2j as a colorless oil (1.6 g, 3.33 mmol, 80%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.11 (s, 2H), 1.54–1.46 (m, 6H), 1.49 (s, 9H), 1.35–1.25 (m, 6H), 1.10–0.95 (m, 6H), 0.91–0.87 (m, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 176.3, 161.5, 79.2, 28.8, 28.0, 27.1, 13.5, 10.1, 5.6. HRMS (ESI) [M + Na]⁺ calcd for C₁₉H₄₀N₂O₂NaSSn: 499.1726; found 499.1730.

N,N′-Di-Boc-(tri-n-butylstannylmethyl)carbamimidate 2k

Mercury(II) chloride (1.25 g, 4.60 mmol) was added portionwise to a mixture of tri-n-butylstannylmethanol (1.0 g, 3.11 mmol), di-Boc-thiourea (1.3 g, 4.70 mmol), and triethylamine (2.0 mL, 14.4 mmol) in dichloromethane (20 mL) at 0 °C. After stirring at 23 °C for 2 h, the suspension was filtered through Celite and washed with ethyl acetate. The filtrate was washed with water, and the combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (20% dichloromethane in hexanes) to afford N,N′-di-Boc-(tri-n-butylstannylmethyl) carbamimidate 2k as a colorless oil (818 mg, 1.45 mmol, 47%). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.55 (s, 1H), 4.39 (s, 2H), 1.54–1.42 (m, 6H), 1.49 (s, 9H), 1.48 (s, 9H), 1.32–1.23 (m, 6H), 0.96–0.81 (m, 15H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 162.0, 159.8, 148.5, 82.2, 80.1, 61.7, 28.9, 28.0, 27.9, 27.3, 13.6, 10.3. HRMS (ESI) [M + Na]⁺ calcd for C₂₄H₄₈N₂O₅NaSn: 583.2478; found 583.2476.

General Procedure 2

N-Boc-amino-3-(4-methoxyphenyl)-propan-2-one 3

Copper(I) acetate (27 mg, 0.220 mmol) was added to a solution of S-4-tolyl-4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol) and tert-butyl tri-n-butylstannylmethylcarbamate 2a (93 mg, 0.220 mmol) in THF (1.0 mL). The reaction was heated at 50 °C for 2 h. After cooling, the suspension was filtrated through Celite and washed with ethyl acetate. The filtrate was washed with water, and the combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexanes) to afford N-Boc-amino-3-(4-methoxyphenyl)propan-2-one 3 as a colorless solid (30 mg, 0.108 mmol, 98%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.15–7.09 (m, 2H), 6.89–6.83 (m, 2H), 5.19 (s, 1H), 4.03 (d, J = 4.8 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 2H), 1.42 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 203.7, 158.9, 155.5, 130.3, 125.0, 114.3, 79.8, 55.2, 49.6, 46.6, 28.2. HRMS (EI) [M]⁺ calcd for C₁₅H₂₁NO₄: 279.1471; found 279.1473.

2-Boc-amino-1-(4-methoxyphenyl)ethanone 4

The title compound was prepared according to general procedure 2 using copper(I) acetate (28 mg, 0.228 mmol), S-4-tolyl-4-methoxybenzothioate 1b (30 mg, 0.116 mmol), and tert-butyl tri-n-butylstannylmethylcarbamate 2a (97 mg, 0.231 mmol) in THF (1.0 mL) at 50 °C for 2 h, and 4 was obtained as a colorless solid (30 mg, 0.114 mmol, 98%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.92 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.56 (s, 1H), 4.59 (d, J = 4.5 Hz, 2H), 3.86 (s, 3H), 1.46 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 192.8, 164.1, 155.8, 130.1, 127.6, 114.0, 79.7, 55.5, 47.1, 28.3. HRMS (ESI) [M + Na]⁺ calcd for C₁₄H₁₉NO₄Na: 288.1212; found 288.1214.

1-Cbz-amino-3-(4-methoxyphenyl)propan-2-one 5

The title compound was prepared according to general procedure 2 using copper(I) acetate (27 mg, 0.220 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and benzyl tri-n-butylstannylmethylcarbamate 2b (100 mg, 0.220 mmol) in THF (1.0 mL) at 50 °C for 2 h, and 5 was obtained as a colorless solid (31 mg, 0.097 mmol, 88%) after purification by column chromatography on silica gel (20% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.39–7.28 (m, 5H), 7.13–7.11 (m, 2H), 6.89–6.84 (m, 2H), 5.44 (s, 1H), 5.10 (s, 2H), 4.11 (d, J = 4.7 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 2H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 203.2, 158.9, 156.0, 136.2, 130.3, 128.5, 128.0, 124.8, 114.3, 66.9, 55.2, 49.9, 46.5. HRMS (EI) [M]⁺ calcd for C₁₈H₁₉NO₄: 313.1314; found 313.1312.

2-Cbz-amino-1-(4-methoxyphenyl)ethanone 6

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and benzyl tri-n-butylstannylmethylcarbamate 2b (176 mg, 0.388 mmol) in THF (1.5 mL) at 50 °C for 2 h, and 6 was obtained as a colorless solid (47 mg, 0.156 mmol, 81%) after purification by column chromatography on silica gel (20% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.94 (d, J = 8.9 Hz, 2H), 7.42–7.30 (m, 5H), 6.96 (d, J = 8.9 Hz, 2H), 5.84 (s, 1H), 5.16 (s, 2H), 4.67 (d, J = 4.4 Hz, 2H), 3.88 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 164.2, 156.2, 136.4, 130.1, 128.5, 128.1, 128.0, 127.4, 114.0, 66.9, 55.5, 47.4. HRMS (ESI) [M + Na]⁺ calcd for C₁₇H₁₇NO₄Na: 322.1055; found 322.1063.

1-Acetylamino-3-(4-methoxyphenyl)propan-2-one 7

The title compound was prepared according to general procedure 2 using copper(I) acetate (42 mg, 0.343 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (46 mg, 0.169 mmol), and N-(tri-n-butylstannylmethyl) acetamide 2c (122 mg, 0.337 mmol) im THF (1.0 mL) at 50 °C for 2 h, and 7 was obtained as a colorless solid (36 mg, 0.162 mmol, 96%) after purification by column chromatography on silica gel (80% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.14–7.08 (m, 2H), 6.89–6.82 (m, 2H), 6.22 (s, 1H), 4.15 (s, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 1.99 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 203.4, 170.1, 158.9, 130.3, 124.8, 114.4, 55.2, 48.6, 46.8, 22.8. HRMS (EI) [M]⁺ calcd for C₁₂H₁₅NO₃: 221.1052; found 221.1049.

2-Acetylamino-1-(4-methoxyphenyl)ethanone 8

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and N-(tri-n-butylstannylmethyl) acetamide 2c (140 mg, 0.387 mmol) in THF (1.5 mL) at 50 °C for 2 h, and 8 was obtained as a colorless solid (36 mg, 0.173 mmol, 89%) after purification by column chromatography on silica gel (100% ethyl acetate). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.94 (dd, J = 9.0, 1.1 Hz, 2H), 6.95 (dd, J = 9.0, 1.1 Hz, 2H), 6.63 (s, 1H), 4.69 (d, J = 4.2 Hz, 2H), 3.87 (s, 3H), 2.09 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 192.5, 170.2, 164.2, 130.2, 127.3, 114.1, 55.5, 46.1, 23.0. HRMS (ESI) [M + Na]⁺ calcd for C₁₁H₁₃NO₃Na: 230.0793; found 230.0790.

3-Boc-amino-1-(4-methoxyphenyl)butan-2-one 9

The title compound was prepared according to general procedure 2 using copper(I) acetate (27 mg, 0.220 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and tert-butyl 1-(tri-n-butylstannyl)ethylcarbamate 2d (96 mg, 0.221 mmol) in THF (1.0 mL) at 65 °C for 24 h, and 9 was obtained as a colorless solid (21 mg, 0.726 mmol, 66%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.26 (s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.21 (s, 1H), 4.44–4.37 (m, 1H), 3.79 (s, 3H), 3.74 (d, J = 6.2 Hz, 2H), 1.31 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 207.3, 158.7, 155.1, 130.5, 125.3, 114.1, 79.7, 55.2, 54.5, 45.3, 28.3, 17.8. HRMS (EI) [M]⁺ calcd for C₁₆H₂₃NO₄: 293.1627; found 293.1632.

2-Boc-amino-1-(4-methoxyphenyl)propanone 10

The title compound was prepared according to general procedure 2 using copper(I) acetate (47 mg, 0.383 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and tert-butyl 1-(tri-n-butylstannyl)ethylcarbamate 2d (168 mg, 0.387 mmol) in THF (1.5 mL) at 65 °C for 2 h, and 10 was obtained as a colorless solid (36 mg, 0.129 mmol, 67%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.96 (dd, J = 9.3, 2.3 Hz, 2H), 6.95 (dd, J = 9.0, 2.2 Hz, 2H), 5.59 (d, J = 7.7 Hz, 1H), 5.27–5.20 (m, 1H), 3.87 (s, 3H), 1.45 (s, 9H), 1.39 (dd, J = 7.2, 2.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 197.8, 164.0, 155.2, 131.0, 127.0, 114.0, 79.5, 55.5, 50.7, 28.4, 20.2. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₂₁NO₄Na: 302.1368; found 302.1368.

1-Acetoxy-3-(4-methoxyphenyl)propan-2-one 11

The title compound was prepared according to general procedure 2 using copper(I) acetate (27 mg, 0.220 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and tri-n-butylstannylmethyl acetate 2e (80 mg, 0.220 mmol) in DMF (1.0 mL) at 80 °C for 24 h, and 11 was obtained as a colorless solid (20 mg, 0.886 mmol, 81%) after purification by column chromatography on silica gel (25% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.13 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.68 (s, 2H), 3.79 (s, 3H), 3.67 (s, 2H), 2.15 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 201.6, 170.1, 158.9, 130.4, 124.7, 114.3, 67.4, 55.2, 45.5, 20.4. HRMS (EI) [M]⁺ calcd for C₁₂H₁₄O₄: 222.0892; found 222.0896.

2-Acetoxy-1-(4-methoxyphenyl)ethanone 12

The title compound was prepared according to general procedure 2 using copper(I) acetate (28 mg, 0.228 mmol), S-4-tolyl 4-methoxybenzothioate 1b (30 mg, 0.116 mmol), and tri-n-butylstannylmethyl acetate 2e (84 mg, 0.231 mmol) in DMF (1.0 mL) at 80 °C for 24 h, and 12 was obtained as a colorless solid (19 mg, 0.129 mmol, 78%) after purification by column chromatography on silica gel (20% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.89 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.29 (s, 2H), 3.87 (s, 3H), 2.22 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 190.6, 170.4, 164.0, 130.0, 127.2, 114.0, 65.7, 55.5, 20.6. HRMS (ESI) [M + Na]⁺ calcd for C₁₁H₁₂O₄Na: 231.0633; found 231.0641.

1-Acetylsulfanyl-3-(4-methoxyphenyl)propan-2-one 13

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (62 mg, 0.221 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and S-(tri-n-butylstannylmethyl)ethanethioate 2f (84 mg, 0.222 mmol) in DMF (1.0 mL) at 80 °C for 24 h, and 13 was obtained as a colorless solid (21 mg, 0.890 mmol, 81%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.14 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.76 (s, 2H), 2.38 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 201.7, 194.3, 158.8, 130.5, 125.4, 114.3, 55.2, 48.0, 38.4, 30.1. HRMS (EI) [M]⁺ calcd for C₁₂H₁₄O₃S: 238.0664; found 238.0663.

2-Acetylsulfanyl-1-(4-methoxyphenyl)ethanone 14

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and S-(tri-n-butylstannylmethyl) ethanethioate 2f (147 mg, 0.388 mmol) in DMF (1.5 mL) at 80 °C for 24 h, and 14 was obtained as a colorless solid (31 mg, 0.137 mmol, 71%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.97 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 4.35 (s, 2H), 3.87 (s, 3H), 2.40 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 194.3, 191.7, 164.0, 130.8, 128.5, 113.9, 55.5, 36.3, 30.2. HRMS (EI) [M]⁺ calcd for C₁₁H₁₂O₃S: 224.0507; found 224.0511.

1-Fluoro-3-(4-methoxyphenyl)propan-2-one 15

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (103 mg, 0.367 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (50 mg, 0.184 mmol), and tri-n-butylstannylmethylfluoride 2g (119 mg, 0.368 mmol) in DMF (1.0 mL) at 80 °C for 24 h, and 15 was obtained as a yellow solid (26 mg, 0.142 mmol, 78%) after purification by column chromatography on silica gel (10% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.14 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.85 (d, J = 48 Hz, 2H), 3.80 (m, 5H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 204.4, 158.9, 130.5, 124.2, 114.3, 85.2, 83.7, 55.2, 44.6. HRMS (EI) [M]⁺ calcd for C₁₀H₁₁FO₂: 182.0743; found 182.0746.

2-Fluoro-1-(4-methoxyphenyl)ethanone 16

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and tri-n-butylstannylmethylfluoride 2g (125 mg, 0.387 mmol) in DMF (1.5 mL) at 80 °C for 24 h, and 16 was obtained as a colorless solid (23 mg, 0.139 mmol, 72%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.88 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 5.47 (dd, J = 50, 0.9 Hz, 2H), 3.88 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 192.0, 164.2, 130.3, 126.8, 114.1, 84.2, 82.7, 55.5. HRMS (EI) [M]⁺ calcd for C₉H₉FO₂: 168.0587; found 168.0593.

1-(N,N′,N″-Tri-Boc-guanidinyl)-3-(4-methoxyphenyl)propan-2-one S-12

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (62 mg, 0.221 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)guanidine 2h (146 mg, 0.220 mmol) in THF (1.0 mL) at 50 °C for 2 h, and S-12 was obtained as a colorless oil (52 mg, 0.0991 mmol, 90%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 10.63 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.59 (s, 2H), 3.78 (s, 3H), 3.71 (s, 2H), 1.48 (s, 18H), 1.40 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 202.0, 158.7, 153.0, 130.6, 125.5, 114.1, 84.1, 55.2, 55.1, 45.9, 28.0, 27.7. HRMS (ESI) [M + Na]⁺ calcd for C₂₆H₃₉N₃O₈Na: 544.2635; found 544.2630.

2-(N,N′,N″-Tri-Boc-guanidinyl)-1-(4-methoxyphenyl)ethanone S-13

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)guanidine 2h (256 mg, 0.386 mmol) in THF (1.5 mL) at 50 °C for 2 h, and S-13 was obtained as a colorless solid (95 mg, 0.187 mmol, 96%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.69 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.24 (s, 2H), 3.87 (s, 3H), 1.47, (s, 18H), 1.41 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 191.4, 163.7, 153.3, 130.2, 128.1, 113.8, 84.0, 55.5, 52.7, 28.1, 27.7. HRMS (ESI) [M + Na]⁺ calcd for C₂₅H₃₇N₃O₈Na: 530.2478; found 530.2467.

1-(N,N′,N″-Tri-Boc-guanidinyl)-3-(4-hydroxyphenyl)propan-2-one S-14

The title compound was prepared according to general procedure 2 using copper(I) acetate (47 mg, 0.383 mmol), S-4-tolyl 2-(4-hydroxyphenyl)ethanethioate 1c (50 mg, 0.194 mmol), and N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)guanidine 2h (256 mg, 0.386 mmol) in THF (1.5 mL) at 50 °C for 2 h, and S-14 was obtained as a colorless solid (67 mg, 0.133 mmol, 68%) after purification by column chromatography on silica gel (25% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 10.63 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 4.59 (s, 2H), 3.66 (s, 2H), 1.48 (s, 18H), 1.39 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 202.4, 155.4, 153.0, 148.8, 130.6, 130.3, 124.7, 115.7, 84.4, 55.0, 46.0, 28.0, 27.7. HRMS (ESI) [M + Na]⁺ calcd for C₂₅H₃₇N₃O₈Na: 530.2478; found 530.2467.

1-(N,N′,N″-Tri-Boc-guanidinyl)-3-(4-methoxyphenyl)butan-2-one S-15

The title compound was prepared according to general procedure 2 using copper(I) acetate (51 mg, 0.416 mmol), S-4-tolyl 2-(4-methoxyphenyl)propanethioate 1d (60 mg, 0.210 mmol), and N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)guanidine 2h (278 mg, 0.420 mmol) in THF (1.5 mL) at 50 °C for 2 h, and S-15 was obtained as a colorless oil (101 mg, 0.189 mmol, 90%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 10.59 (s, 1H), 7.16 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.56 (d, J = 17.8 Hz, 1H), 4.44 (d, J = 17.8 Hz, 1H), 3.81 (m, 1H), 3.77 (s, 3H), 1.47 (s, 18H), 1.39 (d, J = 13.7 Hz, 3H), 1.39 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 204.3, 158.8, 153.0, 131.9, 129.0, 114.3, 83.9, 82.3, 80.2, 55.2, 54.5, 49.1, 28.0, 27.6, 17.5. HRMS (ESI) [M + Na]⁺ calcd for C₂₇H₄₁N₃O₈Na: 558.2791; found 558.2780.

4-(1-(N,N′,N″-tri-Boc-guanidinyl)-2-oxo-butane-3-yl)-7-methoxy-1H-indole S-16

The title compound was prepared according to general procedure 2 using copper(I) acetate (48 mg, 0.392 mmol), 7-methoxy-4-(4-tolylsulfanyl-3-oxopropan-2-yl)-1H-indole 1e (64 mg, 0.197 mmol), and N,N′,N″-tri-Boc-(tri-n-butylstannylmethyl)-guanidine 2h (260 mg, 0.393 mmol) in THF (1.5 mL) at 50 °C for 2 h, and S-16 was obtained as a colorless oil (111 mg, 0.193 mmol, 98%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 10.54 (s, 1H), 8.45 (s, 1H), 7.18 (dd, J = 3.1, 2.5 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.57 (dd, J = 3.1, 2.3 Hz, 1H), 4.51 (d, J = 17.8 Hz, 1H), 4.42 (d, J = 17.8 Hz, 1H), 4.16 (q, J = 7.0 Hz, 1H), 3.94 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.48 (s, 18H), 1.32 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 204.8, 153.2, 145.5, 128.0, 126.4, 124.0, 123.8, 119.1, 102.0, 101.2, 83.7, 55.2, 54.4, 47.9, 28.0, 27.5, 16.3. HRMS (ESI) [M + Na]⁺ calcd for C₂₉H₄₂N₄O₈Na: 597.2890; found 597.2890.

N,N′-Di-Boc-3-(4-methoxyphenyl)-2-oxopropylcarbamimidothioate 22

The title compound was prepared according to general procedure 2 using copper(I) acetate (27 mg, 0.220 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (30 mg, 0.110 mmol), and N,N′-di-Boc-(tri-n-butylstannylmethyl)carbamimidothioate 2i (127 mg, 0.219 mmol) in THF (1.0 mL) at 50 °C for 24 h, and 22 was obtained as a colorless solid (23 mg, 0.0513 mmol, 47%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.49 (s, 1H), 7.17 (s, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.96 (s, 2H), 3.80 (s, 3H), 3.62 (s, 2H), 1.50 (s, 18H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 202.8, 169.5, 160.0, 158.7, 150.6, 130.8, 126.2, 114.0, 83.7, 80.9, 55.2, 49.0, 39.6, 28.0. HRMS (ESI) [M + Na]⁺ calcd for C₂₁H₃₀N₂O₆NaS: 461.1722; found 461.1711.

N,N′-Di-Boc-3-(4-methoxyphenyl)-2-oxopropylcarbamimidate 26

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (103 mg, 0.367 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (50 mg, 0.184 mmol), and N,N′-di-Boc-(tri-n-butylstannylmethyl)carbamimidate 2k (207 mg, 0.367 mmol) in THF (1.5 mL) at 65 °C for 24 h, and 26 was obtained as a colorless oil (56 mg, 0.132 mmol, 72%) after purification by column chromatography on silica gel (3% acetone in toluene). The NMR spectra of this compound showed keto and enol forms. ¹H NMR (500 MHz, CDCl₃) δ (ppm): [keto form] 10.92 (s, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.85 (dd, J = 15.2, 8.6 Hz, 2H), 4.56 (s, 2H), 3.78 (s, 3H), 3.65 (s, 2H), 1.49 (s, 9H), 1.38 (s, 9H). [enol form] 7.07 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 3.80–3.78 (m, 0.5 H), 3.51 (d, J = 11 Hz, 0.5 H), 3.39 (d, J = 14 Hz, 0.5 H), 3.15 (d, J = 14 Hz, 0.5 H), 1.60 (s, 9H), 1.45 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 201.3, 158.9, 158.8, 154.0, 151.8, 150.0, 149.6, 149.3, 147.5, 130.8, 130.4, 126.1, 125.1, 114.3, 114.1, 85.9, 85.1, 84.6, 83.3, 82.1, 55.2, 55.1, 51.6, 50.7, 46.2, 43.6, 28.1, 28.0, 27.9, 27.6. HRMS (ESI) [M + Na]⁺ calcd for C₂₁H₃₀N₂O₇Na: 445.1951; found 445.1958.

N,N′-Di-Boc-2-(4-methoxyphenyl)-2-oxoethylcarbamimidate 28

The title compound was prepared according to general procedure 2 using copper(I) diphenylphosphinate (65 mg, 0.232 mmol), S-4-tolyl 4-methoxybenzothioate 1b (30 mg, 0.116 mmol), and N,N′-di-Boc-(tri-n-butylstannylmethyl)carbamimidate 2k (131 mg, 0.233 mmol) in THF (1.0 mL) at 65 °C for 24 h, and 28 was obtained as a colorless solid (41 mg, 0.100 mmol, 86%) after purification by column chromatography on silica gel (25% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 11.04 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.13 (s, 2H), 3.87 (s, 3H), 1.50 (s, 9H), 1.40 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 191.3, 163.9, 154.4, 150.2, 149.4, 130.0, 127.9, 114.0, 85.0, 82.0, 55.5, 49.3, 28.0, 27.7. HRMS (ESI) [M + Na]⁺ calcd for C₂₀H₂₈N₂O₇Na: 431.1794; found 431.1783.

2-Boc-amino-4-(4-methoxybenzyl)thiazole 23

The title compound was prepared according to general procedure 2 using copper(I) acetate (54 mg, 0.441 mmol), S-4-tolyl 4-methoxyphenylacetothioate 1a (60 mg, 0.220 mmol), and N-Boc-(tri-n-butylstannylmethyl)-carbamimidothioate 2j (212 mg, 0.442 mmol) in DMF (1.5 mL) at 50 °C for 24 h, and 23 was obtained as a colorless solid (57 mg, 0.179 mmol, 81%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.15 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.31 (s, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 1.53 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 160.7, 158.2, 152.5, 151.6, 130.9, 130.0, 113.9, 107.5, 82.5, 55.2, 36.8, 28.3. HRMS (ESI) [M + Na]⁺ calcd for C₁₆H₂₀N₂O₃NaS: 343.1092; found 343.1079.

2-(Boc-amino)-4-(4-methoxyphenyl)thiazole 25

The title compound was prepared according to general procedure 2 using copper(I) acetate (47 mg, 0.383 mmol), S-4-tolyl 4-methoxybenzothioate 1b (50 mg, 0.194 mmol), and N-Boc-(tri-n-butylstannylmethyl)-carbamimidothioate 2j (186 mg, 0.388 mmol) in DMF (1.5 mL) at 80 °C for 24 h, and 25 was obtained as a colorless solid (51 mg, 0.165 mmol, 85%) after purification by column chromatography on silica gel (10% ethyl acetate in hexanes). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 10.17 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 1.33 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 160.8, 159.4, 152.6, 149.6, 127.4, 127.3, 114.0, 104.7, 82.1, 55.3, 27.8. HRMS (ESI) [M + Na]⁺ calcd for C₁₅H₁₈N₂O₃NaS: 329.0936; found 329.0929.

2-Amino-4-(4-methoxybenzyl)-1H-imidazole TFA Salt 17

Trifluoroacetic acid (2.0 mL) was added dropwise to a solution of 1-(N,N′,N″-tri-Boc-guanidinyl)-3-(4-methoxyphenyl)propan-2-one S-12 (83 mg, 0.159 mmol) in dichloromethane (2.0 mL). After stirring for 5 h, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to afford 2-amino-4-(4-methoxybenzyl)-1H-imidazole TFA salt 17 as a yellow solid (44 mg, 0.148 mmol, 93%). ¹H NMR (500 MHz, Acetone-d₆) δ (ppm): 7.70 (s, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.52 (s, 1H), 3.78 (s, 2H), 3.76 (s, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ (ppm): 159.8, 149.9, 130.7, 130.5, 128.3, 115.0, 110.0, 55.7, 30.8. HRMS (ESI) [M + H]⁺ calcd for C₁₁H₁₃N₃O: 204.1137; found 204.1133.

2-Amino-4-(4-methoxyphenyl)-1H-imidazole TFA Salt 18

Trifluoroacetic acid (2.0 mL) was added dropwise to a solution of 2-(N,N′,N″-tri-Boc-guanidinyl)-1-(4-methoxyphenyl)ethanone S-13 (83 mg, 0.159 mmol) in dichloromethane (2.0 mL). After stirring for 5 h, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to afford 2-amino-4-(4-methoxyphenyl)-1H-imidazole TFA salt 18 as a yellow solid (32 mg, 0.113 mmol, 91%). ¹H NMR (500 MHz, Acetone-d₆) δ (ppm): 11.87 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ (ppm): 160.9, 149.9, 128.7, 126.8, 121.6, 115.5, 108.1, 55.8. HRMS (ESI) [M + H]⁺ calcd for C₁₀H₁₂N₃O: 190.0980; found 190.0969.

2-Amino-4-(4-hydroxybenzyl)-1H-imidazole TFA Salt 19

Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of 1-(N,N′,N″-tri-Boc-guanidinyl)-3-(4-methoxyphenyl)propan-2-one S-14 (39 mg, 0.077 mmol) in dichloromethane (1.0 mL). After stirring for 2 h, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane with 0.5% TFA) to afford 2-amino-4-(4-hydroxybenzyl)-1H-imidazole TFA salt 19 as a yellow solid (20 mg, 0.070 mmol, 92%). ¹H NMR (500 MHz, methanol-d₄) δ (ppm): 7.06 (m, 2H), 7.74 (m, 2H), 6.41 (m, 1H), 3.72 (s, 2H), 3.35 (s, 1H). ¹³C NMR (126 MHz, methanol-d₄) δ (ppm): 157.4, 148.9, 130.6, 128.9, 128.8, 116.5, 110.2, 30.8. HRMS (EI) [M]⁺ calcd for C₁₀H₁₁N₃O: 189.0902; found 189.0898.

2-Amino-4-(1-(4-methoxyphenyl)ethyl)-1H-imidazole TFA Salt 20

Trifluoroacetic acid (2.0 mL) was added dropwise to a solution of 1-(N,N′,N″-tri-Boc-guanidinyl)-3-(4-methoxyphenyl)butan-2-one S-15 (101 mg, 0.189 mmol) and dichloromethane (2.0 mL), and 20 was obtained as a brown oil (58 mg, 0.184 mmol, 98%) after purification by column chromatography on silica gel (10% methanol in dichloromethane). ¹H NMR (500 MHz, Acetone-d₆) δ (ppm): 7.71 (s, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 1.2 Hz, 1H), 4.03–3.96 (m, 1H), 3.77 (s, 3H), 1.55 (d, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ (ppm): 159.8, 149.7, 136.1, 133.2, 129.3, 115.0, 109.2, 55.7, 36.4, 20.9. HRMS (ESI) [M + H]⁺ calcd for C₁₂H₁₆N₃O: 218.1293; found 218.1290.

2-Amino-4-(1-(7-methoxy-1H-indol-4-yl)ethyl)-1H-imidazole TFA Salt 21

Trifluoroacetic acid (270 µL, 3.63 mmol) was added dropwise to a solution of 4-(1-(N,N′,N″-tri-Boc-guanidinyl)-2-oxo-butane-3-yl)-7-methoxy-1H-indole S-16 (103 mg, 0.179 mmol) in dichloromethane (2.0 mL), and 21 was obtained as a purple solid (45 mg, 0.128 mmol, 72%) after purification by column chromatography on silica gel (10% methanol in dichloromethane). ¹H NMR (500 MHz, Acetone-d₆) δ (ppm): 10.31 (s, 1H), 7.65 (s, 2H), 7.26 (t, J = 2.8 Hz, 1H), 6.86 (dd, J = 7.9, 0.6 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 1.3 Hz, 1H), 6.53 (dd, J = 3.1, 2.1 Hz, 1H), 4.40–4.32 (m, 1H), 3.91 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, Acetone-d₆) δ (ppm): 149.7, 146.8, 132.9, 128.9, 127.9, 127.7, 125.2, 118.5, 109.4, 102.4, 101.3, 55.8, 34.7, 20.2. HRMS (ESI) [M + H]⁺ calcd for C₁₄H₁₆N₄O: 257.1402; found 257.1411.

2-Amino-4-(4-methoxybenzyl)thiazole 24

Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of N,N′-di-Boc-3-(4-methoxyphenyl)-2-oxopropylcarbamimidothioate 22 (22 mg, 0.0490 mmol) in dichloromethane (1.0 mL). After stirring for 1 h, the solvent was removed by evaporation, and the residue was quenched with saturated aqueous NaHCO₃ solution and extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexanes) to afford 2-amino-4-(4-methoxybenzyl)thiazole 24 as a yellow solid (11 mg, 0.0481 mmol, 98%). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.16 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.99 (s, 1H), 5.11 (s, 2H), 3.79 (s, 2H), 3.78 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ (ppm): 167.7, 158.1, 152.5, 131.1, 129.9, 113.8, 103.5, 55.2, 37.1. HRMS (ESI) [M + H]⁺ calcd for C₁₁H₁₃N₂OS: 221.0749; found 221.0745.

2-Amino-4-(4-methoxybenzyl)oxazole TFA Salt 27

Trifluoroacetic acid (2.0 mL) was added dropwise to a solution of N,N′-di-Boc-3-(4-methoxyphenyl)-2-oxopropylcarbamimidate 26 (55 mg, 0.129 mmol) in dichloromethane (2.0 mL). After stirring for 1 h, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (10% methanol in dichloromethane) to afford 2-amino-4-(4-methoxybenzyl)oxazole TFA salt 27 as a orange solid (31 mg, 0.103 mmol, 80%). ¹H NMR (500 MHz, CDCl₃ (0.5% TFA)) δ (ppm): 7.14 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.21 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H). ¹³C NMR (126 MHz, CDCl₃ (0.5% TFA)) δ (ppm): 158.5, 154.1, 129.9, 128.5, 125.4, 114.8, 107.3, 55.8, 30.8. HRMS (ESI) [M + Na]⁺ calcd for C₁₁H₁₂N₂O₂Na: 227.0796; found 227.0797.

2-Amino-4-(4-methoxyphenyl)-1H-imidazole TFA Salt 29

Trifluoroacetic acid (1.0 mL) was added dropwise to a solution of N,N′-di-Boc-2-(4-methoxyphenyl)-2-oxoethylcarbamimidate 28 (43 mg, 0.105 mmol) in dichloromethane (1.0 mL). After stirring for 10 h, the reaction mixture was concentrated. Because of the substrate’s low solubility, the yellow solid was washed with cold DCM (×3) to afford 2-amino-4-(4-methoxyphenyl)-1H-imidazole TFA salt 29 as a white solid (22 mg, 0.076 mmol, 81%). ¹H NMR (500 MHz, CDCl₃ (0.5% TFA)) δ (ppm): 7.34 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.63 (s, 1H), 3.87 (s, 3H). ¹³C NMR (126 MHz, CDCl₃ (0.5% TFA)) δ (ppm): 159.9, 154.3, 125.74, 125.70, 120.4, 115.1, 104.7, 55.7. HRMS (EI) [M]⁺ calcd for C₁₀H₁₂N₃O: 190.0980; found 190.0969.