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

Article abstract of DOI:10.1021/acs.joc.5b01558

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.

Full text of DOI:10.1021/acs.joc.5b01558

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Article
Synthesis of 2-Aminoazoles from Thioesters via alpha-
Heterosubstituted Ketones by Copper-mediated Cross-Coupling
HIROYUKI KOBAYASHI, John A. Eickhoff, and Armen Zakarian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01558 • Publication Date (Web): 17 Sep 2015
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The Journal of Organic Chemistry
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Synthesis of 2-Aminoazoles from Thioesters via
Ketones by Copper-mediated Cross-Coupling
α-Heterosubstituted
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Hiroyuki Kobayashi,*,†,§,‡ John A. Eickhoff,§,‡ and Armen Zakarian*,§
† Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
§ Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
[TOC Graphic
]
‡ These authors contributed equally
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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. Appli-
cation 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.
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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 require brominating reagents, diazomethane, and strict pH
control over their multistep syntheses, and thus have 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.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 alka-
loids, Movassaghi has capitalized on the cross-coupling of thioesters with aminostannanes and its appli-
cation to azaheterocycle synthesis.11
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RESULTS AND DISCUSSION
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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-
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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 equivalents of
CuTC (copper(I) thiophene-2-carboxylate) and 2 equivalents of the stannane in THF at 50 ºC (entry 1),
the desired ketone 3 was obtained in nearly quantitative yield. Deprotection occurred readily with HCl
to get α-aminomethyl ketone. Using 1 equivalent of CuTC (entry 2), the coupling reaction did not pro-
ceed to completion. All amounts of Cu(I) salts less than 2 equivalents 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. De-
composition of the thioester occurred with CuOTf (entry 7). CuOAc and CuDPP (copper(I) diphe-
nylphosphate) 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.
The coupling reaction of thioester 1a with aminomethyl stannane 2a using CuOAc effectively pro-
ceeded 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
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ketone product was formed and no starting thioester recovered in MeCN as the solvent (entry 2). Addi-
tion 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).
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8
a
Table 1. Optimization of copper reagent in the coupling of thioester 1a with aminomethylstannane 2a
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entry
[Cu]
CuTC
equiv
time, h
3, %
99
65
trace
0
1a, %
0
1
2
2
1
2
2
2
2
2
2
2
2
2
18
2
CuTC
26
3
CuCl
>90
100
100
100
0
4
CuBr•Me2S
CuI
2
5
2
0
6
CuCN
2
0
7
CuOTf
CuOAc
Cu(OAc)2
CuDPP
1
0
8
2
97
57
92
0
9
18
2
nd
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0
a
Standard Conditions: 1a (0.1 mmol), 2a (2.0 equiv), Cu source, THF (0.1 M) mixed under argon at 50 °C.
a,b
Table 2. Influence of solvent and atmosphere
entry
solvent
THF
atmosphere
argon
3, %
97
0
1a, %
0
1
2
3
4
5
MeCN
argon
0
1% H2O in THF
THF
argon
19
26
0
78
air
73
THF
oxygen
100
a
b
Standard Conditions: 1a (0.1 mmol), 2a (2.0 equiv), CuOAc (2.0 equiv), THF (0.1 M) mixed under argon at 50 °C.
Organic 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 thi-
oesters. We chose p-toluenethioester derivatives over benzenethioester or p-nitrobenzenethioester due
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to its easy of handling, generally increase in yields of ketones and reported lower toxicity of the thiol
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3
precursors.
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Table 3. Scope of stannanes with thioesters 1a and 1b
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7
entry thioester
stannane
productb
yield
97%
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9
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2
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1b
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3
95%
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88%
81%
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2b
2b
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6
96%
89%
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1b
2c
2c
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8
66%
67%
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1b
2d
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9
81%
78%
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1b
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2e
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81%
71%
1a
1b
2f
2f
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78%
72%
1a
1b
2g
2g
16
a
b
Standard Conditions: 1 (0.1 mmol), 2 (2.0 equiv), CuOAc (2.0 equiv), THF (0.1 M) mixed under argon at 50 °C.
R=4-MeOC6H4
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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 (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 ºC 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 ºC 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). Alt-
hough 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 sup-
pressed the generation of byproducts and good yields of fluoromethyl ketones were achieved.
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After accomplishing the synthesis of several of α-heterosubstituted ketones, we evaluated this ap-
proach as a method for the synthesis of a variety of 2-aminoazoles from thioesters. Movassaghi 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 eval-
uated 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.
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Initial investigations with variably protected guanidylmethylstannanes revealed that fully protected
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tris-N-Boc gunanidyl reagent 2h is optimal in terms of coupling efficiency and overall yield of the het-
erocyclic product. The synthesis is best achieved by performing the cross-coupling first and then remov-
ing 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 thi-
oester 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 gram (3.7 mmol) of thioester
1a.
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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 under-
went the cross-coupling reaction and cyclization in 63% yield (entry 3).
Table 4. Two-step synthesis of 2-aminoimidazoles
entry
1
thioester
product
yield
88%
1a
17
2
3
91%
63%
1b
1c
18
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19
20
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88%
1d
1e
71%
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a
Standard 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. Cy-
clization: ketone (50 ꢀmol), TFA (1 mL), DCM (1 mL) mix under argon at rt. Monitor by TLC.
In a similar fashion, we assessed the formation of 2-aminothiazoles from aromatic and aliphatic thioe-
sters (Scheme 1). For this class of products, we found that mono-Boc isothiourea reagent 2j, easily pre-
15a,20
pared from iodomethyltributylstannane and Boc-protected thiourea,
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 stan-
nane 2j with CuOAc in DMF at 80 °C, 2-aminothiazole derivative 23 was isolated in 81% yield. Simi-
larly, 25 was prepared from aromatic thioester 1b under identical reaction conditions in 85% isolated
yield.
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 sig-
nificant 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 di-
chloromethane 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, aromatiza-
tion 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.
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Scheme 1. Synthesis of 2-aminothiazole from stannanes 2j and 2k
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Scheme 2. Synthesis of 2-aminooxazole with stannane 2k
CONCLUSIONS
In conclusion, we provided our method in using neutral, palladium-free, copper-mediated cross-
coupling conditions with thioates and organostannanes. We described how CuOAc and CuDPP were
used to achieve the synthesis of a variety of α-heteroatomic methyl ketones, we also provided our find-
ings on the operationally simple formation of 2-aminoimidazoles, 2-aminothiazoles, and 2-
aminooxazoles in great yield.
EXPERIMENTAL SECTION
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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, di-iso-propylamine and triethylamine were distilled from calcium hydride in a
continuous still under and atmosphere of argon. Elevated reaction temperatures were controlled by
thermo couples. Room temperature reactions were carried out between 22-24 °C. Analytical thin-layer
chromatography (TLC) was performed using pre-coated TLC plates with Silica Gel 60 F254 and visual-
ized using combinations of UV, anisaldehyde, ceric ammonium molybdate (CAM), potassium perman-
ganate, and iodine staining. Flash column chromatography was performed using 40-63 ꢀm silica gel as
the stationary phase. Proton magnetic resonance spectra were recorded at 400, 500, and 600 MHz. Car-
bon 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 elec-
trospray ionization (ESI) with Q-TOF detection and electron ionization (EI) techniques.
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General procedure 1.
S-4-Tolyl 4-methoxyphenylacetothioate 1a. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (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 chro-
matography on silica gel (15% ethyl acetate in hexanes) to afford S-4-tolyl 4-
1
methoxyphenylacetothioate 1a as a colorless solid (10.8 g, 39.8 mmol, 83%). H 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,
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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.
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S-4-Tolyl 4-methoxybenzothioate 1b. 1-Ethyl-3-(3-dimethylaminopropyl)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,
1
5.88 mmol, 90%). H 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 dichloro-
methane, 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 extract-
ed 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
1
mmol, 98%). H NMR (400 MHz, CDCl3) δ(ppm): 7.25 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.3 Hz, 4H),
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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.
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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-dimethylaminopropyl)carbodiimide hydrochlo-
ride (1.3 g, 6.78 mmol) and 1-hydroxybenzotriazole monohydrate (1.1 g, 7.18 mmol) in dichloro-
methane (20 mL) and purification by column chromatography on silica gel (5% ethyl acetate in hex-
1
anes) to obtain 1d as a colorless solid (1.1 g, 3.95 mmol, 69%). H 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
1
mmol, 90%). H 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,
13
3H). C 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.
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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, 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
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mmol, 95%). H 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-(Boc-
amino)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 com-
bined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was puri-
fied 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)
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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,
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55.2, 41.2, 28.1, 28.0, 18.0, 14.1. HRMS (ESI) [M+Na]+ calcd for C24H35NO7Na: 472.2311; found
4
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6
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472.2300. S-3b : H NMR (400 MHz, CDCl3) δ (ppm): 7.78 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.98 (s,
7
8
9
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.
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Di-tert-butyl 4-(1-ethoxycarbonylethane-1-yl)-7-methoxy-1H-indole-1,2-dicarboxylate S-4. A mix-
ture 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 mix-
ture 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-
1
methoxy-1H-indole-1,2-dicarboxylate S-4 as a colorless oil (85 mg, 0.184 mmol, 82%). H 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-
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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
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S-5 as a yellow solid (1.5 g, 5.15 mmol, 97%). H NMR (400 MHz, CDCl3) δ(ppm): 9.14 (s, 1H), 7.49
9
(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),
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1.61 (dd, J = 7.2, 1.5 Hz, 3H), 1.20 (td, J = 7.1, 2.6 Hz, 3H). C 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 quino-
line (16 mL) was heated at 220°C using microwave irradiation for 40 min. After cooling, the reaction
mixture was quenched with 1N 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 chroma-
tography on silica gel (10% ethyl acetate in hexanes) to afford 4-(1-ethoxycarbonylethane-1-yl)-7-
1
methoxy-1H-indole S-6 as a brown oil (1.1 g, 4.29 mmol, 83%). H 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),
13
3.94 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). C 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 1N HCl and extracted with ethyl acetate. The combined
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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)-
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5
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7-methoxy-1H-indole S-7 as a yellow solid (192 mg, 0.877 mmol, 94%). H NMR (400 MHz, CDCl3)
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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.
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7-Methoxy-4-(4-tolylsulfanyl-3-oxopropan-2-yl)-1H-indole 1e. The title compound was prepared ac-
cording 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
1
yellow oil (816 mg, 2.51 mmol, 79%) H 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-butylstannylmethyliodide (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-
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1
butylstannylmethyl)phthalimide S-9 as a colorless oil (2.9 g, 6.49 mmol, 93%). H 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.
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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 eth-
anol (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 ꢀL, 4.45 mmol) were added se-
quentially 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 com-
bined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was puri-
fied by column chromatography on silica gel as a colorless oil (2% ethyl acetate in hexanes) to afford
1
tert-butyl tri-n-butylstannylmethylcarbamate 2a. (823 mg, 1.96 mmol, 88%). H 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 eth-
anol (30 mL) at 80 °C, and the reaction was stirred at 80 °C for 1 h. After cooling, the reaction was
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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.
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Benzyl chloroformate (300 ꢀL, 2.10 mmol) and triethylamine (620 ꢀL, 4.45 mmol) were added sequen-
tially to a solution of the crude substrate (2.22 mmol) in dichloromethane (10 mL) at 23°C. After stir-
ring 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-
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butylstannylmethylcarbamate 2b as a colorless oil (804 mg, 1.77 mmol, 80%). H 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),
13
1.36 – 1.22 (m, 6H), 0.89 (m, 15H). C 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 ꢀL, 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 chro-
matography 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)
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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 –
1
2
3
13
0.81 (m, 15H). C NMR (126 MHz, CDCl3) δ (ppm): 169.9, 29.0, 27.3, 24.3, 22.7, 13.6, 10.2. HRMS
4
5
(ESI) [M+Na]+ calcd for C15H33NONaSn: 382.1477; found 382.1491.
6
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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, 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
ꢀL, 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-
1
(tri-n-butylstannyl)ethanol S-10 as a colorless oil (796 mg, 2.37 mmol, 64%). H 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 decom-
position upon analysis.]
Diisopropyl azodicarboxylate (480 ꢀL, 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 tri-
phenylphosphine (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 sil-
ica gel (5% ethyl acetate in hexanes) to afford N-(1-(tri-n-butylstannyl)ethyl)phthalimide S-11 as a yel-
low 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,
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13
6H), 0.85 (m, 9H). C NMR (126 MHz, CDCl3) δ(ppm): 169.0, 133.7, 132.2, 122.9, 31.4, 29.0, 27.4,
1
2
3
18.8, 13.6, 10.2. HRMS (ESI) [M+Na]+ calcd for C22H35NO2NaSn: 484.1583; found 484.1571.
4
5
6
7
8
9
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.
10
11
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Di-tert-butyl dicarbonate (500 mg, 2.29 mmol) and triethylamine (720 ꢀL, 5.17 mmol) were added se-
quentially 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 com-
bined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was puri-
fied by column chromatography on silica gel (2% ethyl acetate in hexanes) to afford tert-butyl 1-(tri-n-
1
butylstannyl)ethylcarbamate 2d as a colorless oil (969 mg, 2.23 mmol, 86%). H 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 ꢀL, 4.66 mmol) and acetyl chloride (220 ꢀL,
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 ex-
tracted 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% dichloro-
methane in hexanes) to afford tri-n-butylstannylmethyl acetate 2e as a colorless oil (414 mg, 1.14 mmol,
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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 =
1
2
3
13
14.5, 7.3 Hz, 6H), 1.00 – 0.82 (m, 15H). C NMR (126 MHz, CDCl3) δ(ppm): 171.9, 55.8, 28.9, 27.3,
4
5
20.7, 13.7, 9.6. HRMS (ESI) [M+Na]+ calcd for C15H32O2NaSn: 383.1317; found 383.1335.
6
7
8
9
10
11
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S-(Tri-n-butylstannylmethyl)ethanethioate 2f. Potassium thioacetate (800 mg, 7.01 mmol) was added
portionwise to a solution of tri-n-butylstannylmethyliodide (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-
1
butylstannylmethyl)ethanethioate 2f as a colorless oil (864 mg, 2.28 mmol, 98%). H 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
13
(m, 15H). C 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-
1
butylstannylmethylfluoride 2g as a colorless oil (323 mg, 1.00 mmol, 69%). H 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.
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N,N',N’’-Tri-Boc-(tri-butylstannylmethyl)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-
1
2
3
4
5
6
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9
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Boc-(tri-n-butylstannylmethyl)guanidine 2h as a colorless oil (623 mg, 0.941 mmol, 77%). H 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-
butylstannyliodide (980 mg, 2.27 mmol), N,N’-di-Boc thiourea (880 mg, 3.18 mmol) and triethylamine
(800 ꢀL, 5.74 mmol) in ethanol (10 mL) was heated at 80°C for 2 h. After cooling, the solvent was re-
moved 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-
1
(tri-n-butylstannylmethyl)carbamimidothioate 2i as a colorless oil (1.1 g, 1.86 mmol, 82%). H 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),
13
1.34 – 1.25 (m, 6H), 1.05 – 0.83 (m, 15H). C 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-butylstannyliodide (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
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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 sil-
ica gel (2% ethyl acetate in hexanes) to afford N-Boc-(tri-n-butylstannylmethyl)carbamimidothioate 2j
1
2
3
4
5
6
7
8
9
1
as a colorless oil (1.6 g, 3.33 mmol, 80%). H NMR (400 MHz, CDCl3) δ(ppm): 2.11 (s, 2H), 1.54 –
10
11
12
13
14
15
16
17
18
19
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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). C 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 2hr, 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% di-
chloromethane in hexanes) to afford N,N'-di-Boc-(tri-n-butylstannylmethyl)carbamimidate 2k as a col-
1
orless oil (818 mg, 1.45 mmol, 47%). H NMR (400 MHz, CDCl3) δ(ppm): 10.55 (s, 1H), 4.39 (s, 2H),
13
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). C 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 add-
ed 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
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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),
1
2
3
4
5
6
7
8
9
10
11
12
13
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5.19 (s, 1H), 4.03 (d, J = 4.8 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 2H), 1.42 (s, 9H). C 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 obtained 4 as a colorless solid (30 mg, 0.114 mmol, 98%) after purification by
1
column chromatography on silica gel (15% ethyl acetate in hexanes). H 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 obtained 5 as a colorless solid (31 mg,
0.097 mmol, 88%) after purification by column chromatography on silica gel (20% ethyl acetate in hex-
1
anes). H 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,
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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.
1
2
3
HRMS (EI) [M]+ calcd for C18H19NO4: 313.1314; found 313.1312.
4
5
6
7
8
9
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 obtained 6 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,
10
11
12
13
14
15
16
17
18
19
20
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23
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28
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31
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59
60
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2H), 5.84 (s, 1H), 5.16 (s, 2H), 4.67 (d, J = 4.4 Hz, 2H), 3.88 (s, 3H). C 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 obtained 7 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,
13
2H), 3.78 (s, 3H), 3.66 (s, 2H), 1.99 (s, 3H). C 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 gen-
eral procedure 2 using copper(I) diphenylphosphinate (109 mg, 0.388 mmol), S-4-tolyl 4-
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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 obtained 8 as a colorless solid (36 mg, 0.173 mmol,
1
2
3
4
5
1
89%) after purification by column chromatography on silica gel (100% ethyl acetate). H NMR (500
6
7
8
9
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.
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3-Boc-amino-1-(4-methoxyphenyl)butan-2-one 9. The title compound was prepared according to gen-
eral 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 obtained 9 as a colorless solid (21 mg, 0.726 mmol, 66%) after puri-
1
fication by column chromatography on silica gel (15% ethyl acetate in hexanes). H 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 –
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4.37 (m, 1H), 3.79 (s, 3H), 3.74 (d, J = 6.2 Hz, 2H), 1.31 (d, J = 7.1 Hz, 3H). C 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 gen-
eral 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 obtained 10 as a colorless solid (36 mg, 0.129 mmol, 67%) after purifica-
1
tion by column chromatography on silica gel (15% ethyl acetate in hexanes). H 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),
13
5.27 – 5.20 (m, 1H), 3.87 (s, 3H), 1.45 (s, 9H), 1.39 (dd, J = 7.2, 2.0 Hz, 3H). C NMR (126 MHz,
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The Journal of Organic Chemistry
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)
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[M+Na]+ calcd for C15H21NO4Na: 302.1368; found 302.1368.
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1-Acetoxy-3-(4-methoxyphenyl)propan-2-one 11. The title compound was prepared according to gen-
eral 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 obtained 11 as a colorless solid (20 mg, 0.886 mmol, 81%) after purification by
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column chromatography on silica gel (25% ethyl acetate in hexanes). H 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 obtained 12 as a colorless solid (19 mg, 0.129 mmol, 78%) after purification by column chro-
matography on silica gel (20% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ(ppm): 7.89 (d, J
13
= 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.29 (s, 2H), 3.87 (s, 3H), 2.22 (s, 3H). C 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 obtained 13 as a colorless solid (21 mg,
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Page 28 of 37
0.890 mmol, 81%) after purification by column chromatography on silica gel (15% ethyl acetate in hex-
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anes). H 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,
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3H), 3.78 (s, 2H), 3.76 (s, 2H), 2.38 (s, 3H). C 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.
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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 obtained 14 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 gen-
eral 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 obtained 15 as a yellow solid (26 mg, 0.142 mmol,
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78%) after purification by column chromatography on silica gel (10% ethyl acetate in hexanes). H
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.
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The Journal of Organic Chemistry
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 obtained 16 as a colorless solid (23 mg, 0.139 mmol,
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72%) after purification by column chromatography on silica gel (15% ethyl acetate in hexanes). H
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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 obtained
S-12 as a colorless oil (52 mg, 0.0991 mmol, 90%) after purification by column chromatography on sili-
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ca gel (15% ethyl acetate in hexanes). H 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,
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9H). C 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 pre-
pared 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 obtained
S-13 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
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