Visible-Light Photoredox-Catalyzed Coupling Reaction of Azoles with α-Carbamoyl Sulfides

Article abstract of DOI:10.1021/acs.joc.6b01108

A simple, straightforward strategy for the synthesis of N-substituted azoles is reported that involves a visible-light photoredox-catalyzed coupling reaction of azoles with α-carbamoyl sulfides. A variety of heterocyclic units, including pyrazoles, benzop

Full text of DOI:10.1021/acs.joc.6b01108

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Article
Visible Light Photoredox-Catalyzed Coupling
Reaction of Azoles with alpha- Carbamoylsulfides
Lucie Jarrige, Guillaume Levitre, and Géraldine Masson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01108 • Publication Date (Web): 17 Jun 2016
Downloaded from http://pubs.acs.org on June 18, 2016
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The Journal of Organic Chemistry
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Visible Light PhotoredoxꢀCatalyzed Coupling Reaction
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of Azoles with αꢀCarbamoylsulfides
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Lucie Jarrige, Guillaume Levitre, and Géraldine Masson*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université ParisꢀSud, Université Parisꢀ
Saclay, 1, av. de la Terrasse, 91198 GifꢀsurꢀYvette Cedex, France.
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AUTHOR EMAIL ADDRESS: geraldine.masson@cnrs.fr
ABSTRACT
A simple straightforward strategy for the synthesis of Nꢀsubstituted azoles is reported, which involves
visible light photoredoxꢀcatalyzed coupling reaction of azoles with αꢀcarbamoylsulfides. A variety of
heterocyclic units, including pyrazoles, benzopyrazoles, benzoimidazoles and purines can be efficiently
incorporated under mild reaction conditions in respectable yields.
INTRODUCTION
The fiveꢀmembered heterocycles containing nitrogen has attracted significant interest in organic and
medicinal chemistry over the past several decades. Scaffolds containing a pyrazole1 or imidazole2 are
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found in a number of pharmaceutically and biologically active important molecules. Therefore, the
development of efficient synthetic methods of these heterocycles is highly demanded. Among various
methods available,3ꢀ6 the incorporation of these valuables azoles into a α position of amines is certainly
one of the most simple and direct approach. However, despite a wide variety of easily available fiveꢀ
membered heterocycles, such strategies have been mentioned in literature only briefly.7 Recently, we
have reported an efficient visibleꢀlight photoredox8 catalyzed addition of various aryl and heteroaryl to
αꢀamidosulfides9aꢀe as Nꢀcarbamoylimine precursors9 leading to the rapid generation of a range of
functionalized Nꢀprotected aryl or heteroarylamines.10,11 In line of this work,10,12 we envisioned that this
method could be utilized to incorporate a wide range of aromatic 5ꢀmembered azacyclic units. This
would lead to the formation of 2ꢀaminomethylꢀazoles which are present in various bioactive moleꢀ
cules.13 We report herein an efficient visibleꢀlight photoredox catalyzed Nꢀalkylation of azoles and
fused azoles 2 into αꢀamidosulfides 1 leading to the rapid and efficient generation of a range of
functionalized 2-aminomethyl-azoles 4 (Scheme 1).
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Scheme 1. PhotoredoxꢀCatalyzed Synthesis of NꢀAlkylꢀSubstituted azoles
RESULTS AND DISCUSSION
We have already reported that the reaction of pyrazole (2a) and tertꢀbutylꢀ(1ꢀ(ethylthio)ꢀ3ꢀ
phenylpropyl)carbamate (1a) in the presence of 2.5 mol % Ru(bpy)3(PF6)2 photocatalyst 4a under
visible light irradiation (5W blue LEDs) in dichloromethane/tꢀBuOH (8:2, v/v) at room temperature
yielded the desired product 4a in 70% yield after 24 h.10 Although in the previous article, mainly
electron rich aromatic were examined, due to our interest in oxidative activation of CꢀS bond adjacent to
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a nitrogen,9c,10 we reꢀexamined the photoredox Nꢀalkylation reaction to expand their synthetic utility
and gain additional insight into this visibleꢀlight photredox process. Performance of the other
photoredoxꢀcatalyst, such as Ru(bpy)3Cl2, Ru(bpz)3Cl and eosin (Table 1 entries 2ꢀ4),14 was inferior to
that of Ru(bpy)3(PF6)2. Yields were lower in the absence of tꢀBuOH (entry 7) or with
hexafluoroisopropanol or EtOH as the coꢀsolvent (entries 8 and 9).15 As already observed by us the
concentration of 1a in the reaction is very important, the use of 0.5 M in MeCN being the best
concentration for a good yield. Any change in this concentration led to a drop of the yield (entries 5 and
6 vs. 1). The reaction did not proceed at all in strict oxygenꢀfree conditions (entry 10). In contrast, the
yield of the product was increased to 88% (entry 11) when the reaction was carried out in presence of
air (open to air, without bubbling air). Moreover, no reaction proceeds in anaerobic condition, only
starting material was revovered (entry 16). These results indicated that the ruthenium complex
undergoes oxidative quenching of its excited state with oxygen to give the strongly oxidizing
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11
Ru(bpy)33+.8 Other oxidative quenchers such as BrCCl3 and methyl viologen were evaluated (entries
12 and 13) the conclusion was that the oxygen is superior to others.
Table 1. Optimization of Reaction Conditions for the Synthesis of αꢀCarbamoylpyrazoles.a
entry
1
additive
yield (%)b
70
3
Ru(bpy)3(PF6)2 (3a)
tꢀBuOH
Ru(bpy)3Cl2 (3b)
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tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
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Ru(bpz)3Cl2 (3c)
41c
45d
50e
28e
Eosin Y (3d)
3a
3a
3a
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3a
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HFIP
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tracef
traceg
88h
19i
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EtOH
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tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
tꢀBuOH
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19j
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0k
0k,l
3a
3a
0m
aGeneral conditions: 1 (0.10 mmol), pyrazole 2a (0.15 mmol), 3 (0.025 equiv), additive (10 equiv) in MeCN (0.5 mL)
irradiated at rt for 24 h. bYields referred to chromatographically pure product. cIrradiated with green LEDs. d MeCN (1 mL). e
MeCN (2 mL). f αꢀcarbamoylether was isolated as major product. g Oxygenꢀfree conditions. h With air. iBrCCl3 (0.025 mmol)
was used as oxidative quencher. Methyl viologen (0.025 mmol) was used as oxidative quencher. Starting material was
recovered. lWithout any irradiation. mUnder free oxygen.
j
k
Then, with the optimized reaction conditions in hand, we examined the scope and limitations of the
photoredoxꢀcatalyzed Nꢀalkylation reaction. As shown in Table 2, various αꢀcarbamoylsulfides 1 were
explored by using pyrazole (2a) as the reactant. The yields of Nꢀalkylated products 4 resulting from
aliphatic αꢀcarbamoylsulfides 1 were generally moderate to excellent. The photocatalytic system also
proved to be efficient for various linear aliphatic αꢀcarbamoylsulfides 1b-1d leading to the coupling
products (4bꢀ4d, entries 1ꢀ3) in good to excellent yields. We were pleased to find that the presence of
functional groups such as benzyl ether (4d, entry 3) and alkyne (4e, entry 4)16 was tolerated. The
reaction between αꢀcarbamoylsulfides derived from βꢀbranched aldehydes 1f and 1g with pyrazole 2a
under the same conditions afforded moderate to good yields of corresponding Nꢀalkylated products 4f
and 4g (entries 5ꢀ6). The replacement of the Boc group 1a with a Cbz group 1i has no influence on the
efficiency of the amidoalkylation (entry 9). In addition, the catalytic process can be applied to an
aromatic αꢀamidosulfide such as 1h, although the yield was slightly lower (entry 7). However, when the
reaction was carried out with 5 mol% of Ru(bpy)3(PF6)2 3a under otherwise identical conditions, the
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expected Nꢀalkylated products 4h and 4i were isolated in better yields (entries 7 and 8).
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Table 2. Reactions of Various αꢀCarbamoylsulfides 1 with Pyrazole 2a.a
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entry
1
R1
Product
yield (%)b
87
4
C6H13
4b
C2H5
2
3
61
58
4c
C8H9O
4d
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47c
C8H5
4e
C3H7
C3H5
5
6
75
41
4f
4g
7
45(60) c
C6H5
4h
4i
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9
66c
C6H5
C8H9
85
4j
a Reaction conditions: 1 (0.10 mmol), pyrazole 2a (0.15 mmol), 3a (0.025 equiv), tꢀBuOH (10.0 equiv) in MeCN (0.5 mL)
irradiated at rt for 24 h. bYields referred to chromatographically pure product. cWith 5 mol% of 3a.
We next examined the coupling reaction of several azoles as well as fused azoles 2. As shown in
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Table 3, the presence of an electronꢀdonating group and an electronꢀwithdrawing group on the pyrazole
ring 2b-2d were found to be suitable substrates giving the corresponding Nꢀalkyalted products 4kꢀ4o
(entries 1ꢀ5) in good yields. Interestingly, when the 3ꢀmethylpyrazole 2d was employed, the
photocatalyzed Nꢀalkylation reaction led only to the formation of the less congested regioisomer 4o
(entry 5). Similarly, the reaction of arylꢀfused pyrazoles such as benzopyrazole 2e went very smoothly
affording 4p in excellent yield (91% yield, entry 6). Unsubstituted imidazole 2f provided the
corresponding coupling adducts 4q in a low yield, even with 5 mol% of 3a (entries 7). On the other
hand, when the benzoimidazole 2h was the nucleophile in the reaction, Nꢀalkylated products (4r-4t)
were isolated in much better yields (entries 8ꢀ10). Most remarkably, the coupling reaction worked well
with purine to afford an efficient access to azacyclic purine azaꢀnucleosides 4u (entry 11).7a
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Table 3. Reactions of αꢀCarbamoylsulfides 1 with Various Azoles 2.a
entry
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R1
Product
yield (%)b
66
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C8H9
4k
C8H9
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4l
C7H15
4m
C8H9
C3H7
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C8H9
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C8H9
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4r
4s
4t
NHCbz
N
N
C3H7
C8H9O
C8H9
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4u
a Reaction conditions: 1 (0.10 mmol), pyrazole 2a (0.15 mmol), 3a (0.025 equiv), tꢀBuOH (10.0 equiv) in MeCN (0.5 mL)
irradiated at rt for 24 h. bYields referred to chromatographically pure product. cWith 5 mol% of 3a.
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The following control experiments were conducted to gain some mechanistic insight. No reaction
took place in the absence of light and/or photocatalyst. Moreover, the formation of 4 was inhibited in
the presence of radical scavengers such as TEMPO and galvinoxyl suggesting that a radical/cationic
process is involved in this reaction. On the basis of the above results as well as other reports, a plausible
reaction mechanism is shown in Scheme 5. Based on the literature8,17,18 and our previous study, 10 we
propose a plausible catalytic cycle for the present Nꢀalkylation reaction as depicted in Scheme 2. First,
Ru2+ is excited to *Ru2+ under blue Leds irradiation. Then, this excited state undergoes an oxidative
quenching with oxygen molecule to give Ru3+ and superoxide radical anion (O2●−). This strong oxidant
Ru3+ is prone to activate αꢀcarbamoylsulfides 1 through an additional singleꢀelectron oxidation step
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causing the generation of radical cation 5, and regenerating the groundꢀstate Ru2+ 3. The resulting
radical cation 5 may undergo a fragmentation to cleave the labile NꢀS bond and give the Nꢀcarbamoyl
iminium 6 as well as thiyl radical 7 Unfortunately, all attempts to prove the formation of this radical
was unsuccessful.19 In parallel, the thiyl radical 7 is then proposed to dimerize to form disulfide 8. A
small amount of disulfide was isolated from this reaction, confirming our assumption.10 However, an
alternative pathway involving the conversion of αꢀcarbamoylsulfides 1 into radical cation 5 by radical
chain propagation cannot be excluded at the current stage.8,20 Indeed, when we irradiated 1a in presence
of 2a with blue LEDs for 1 h, the corresponding 6a was isolated in 26 % yield. While an increase in
yield (41 %) was obtained when 1a was stirred under dark conditions for 23 h after 1 h irradiation (see
the supporting information). According to these experiments, the both mechanisms may proceed
simultaneously.
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Scheme 2. Plausible reaction mechanism
CONCLUSION
In summary, we have developed an efficient photoredoxꢀcatalyzed coupling strategy for the
construction of Nꢀsubstituted azoles from readily available αꢀamidosulfides. This protocol features mild
conditions, a relatively broad scope, and high atomꢀeconomy in generating an array of 2ꢀaminomethylꢀ
azoles with high efficiency. Further investigations are underway to probe the mechanism and to extend
the scope of the Nꢀalkylation.
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EXPERIMENTAL SECTION
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Materials and General methods. All reagents were obtained from commercial suppliers and used
without further purification unless otherwise noted. Analytical thinꢀlayer chromatography (TLC) was
performed on plates precoated with silica gel layers. NMR spectra (1H, 13C) were recorded with 500 and
300 MHz spectrometers. Flash column chromatography was carried out using 40ꢀ63 ꢁm particle sized
silica gel. Preparative thin layer chromatography (prep TLC) was performed using silica gel 60 F254
plates. Visualization was accomplished by irradiation with a UV light at 254 nm. Highꢀresolution mass
spectra (HRMS) were recorded using electrospray ionization (ESI) and a timeꢀofꢀflight (TOF) analyzer,
in positiveꢀion or negativeꢀion detection mode. Infrared spectra were taken using solids or neat oils on a
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diamond surface, and the results are given in cmꢀ1 All reactions were carried out under argon
.
atmosphere in oven dried glassware with magnetic stirring. Reagents were obtained from commercial
supplier and used without further purification unless otherwise noted. All solvents used in the reactions
were distilled from appropriate drying agents prior to use. Visible light irradiations were performed with
a Flexled INSPIRE LED lamp (3.6 W; λ = 465 nm). Ru(bpy)3(PF6)2 was purchased from Sigma
Aldrich. All other commercially available reagents and solvents were used without further purification.
The αꢀamidosulfides 1 were prepared according to literature procedure.7b,c
General Procedure: A flameꢀdried test tube, flushed with Air, was charged with the corresponding
αꢀamidosulfide 1 (0.1 mmol, 1.0 equiv) and dissolved in MeCN (0.5 mL) and tꢀBuOH (0.1 mL, 10
equiv). Ru(bpy)3(PF6)2 3a (2.2 mg, 2.50 mol%) then the corresponding azole 2 (0.15 mmol, 1.50 equiv)
was then added. The resultant reaction mixture was irradiated with blue LEDs during 24 h. Then, the
reaction mixture was directly purified by flash chromatography on silica gel (nꢀHeptane/EtOAc) to
afford the corresponding pure compound 4a-4u.
Tert-Butyl (3-phenyl-1-(1H-pyrazol-1-yl)propyl)carbamate (4a).10 Reaction on 29.5 mg (0.100
mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative TLC:
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heptane/ethyl acetate 7/3, to afford 26.6 mg of a colourless solid, 88% yield. MP: 86–97°C. IR (cm–1):
3249, 2973, 1698, 1529, 1446, 1407, 1366, 1294, 1239, 1148, 1095, 1047, 1010, 990, 958, 863, 804,
761, 698. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.63 (s, 1H), 7.57 (s, 1H), 7.31 (t, J = 7.2 Hz, 2H), 7.22
(t, J = 7.1 Hz, 1H), 7.15 (d, J = 7.6 Hz, 2H), 6.26 (s, 1H), 5.84 (d, J = 9.2 Hz, 1H), 5.77 (m, 1H),
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2.54ꢀ2.51 (m, 3H), 2.43ꢀ2.36 (m, 1H), 1.42 (s, 9H). C NMR (CDCl3, 75 MHz) δ (ppm): 154.7, 140.3,
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140.2, 130.0, 128.6 (× 2), 128.5 (× 2), 126.3, 104.9, 80.3, 66.4, 36.0, 31.5, 28.3 (× 3). HRMS (ESI
TOF): m/z = 324.1702 [M+Na]+, C17H23N3O2Na requires 324.1688.
Tert-Butyl (1-(1H-pyrazol-1-yl)heptyl)carbamate (4b). Reaction on 32 mg (0.092 mmol) of tertꢀbutyl
(1ꢀ(phenylthio)heptyl)carbamate (1b). Eluent for the flash column chomatorgraphy: heptane/ethyl
acetate 7/3, to afford 24.3 mg of a colourless solid, 87% yield. MP: 60–61°C. IR (cm–1): 3213, 2930,
1
1702, 1537, 1448, 1404, 1390, 1363, 1299, 1280, 1248, 1158, 1088, 1046, 1000, 869, 760, 747, 686. H
NMR (CDCl3, 300 MHz) δ (ppm): 7.48 (s, 2H), 6.13 (s, 1H), 5.72 (br s, 1H), 5.52 (br s, 1H), 2.12 (br s,
13
1H), 1.98 (br s, 1H), 1.33 (s, 9H), 1.28ꢀ1.08 (m, 8H), 0.78 (t, J = 6.7 Hz, 3H). C NMR (CDCl3, 75
MHz) δ (ppm): 154.8, 140.0, 129.6, 104.7, 80.2, 67.2, 34.7, 31.6, 28.6, 28.3 (× 3), 25.3, 22.5, 14.0.
HRMS (ESI TOF): m/z = 304.2004 [M+Na]+, C15H27N3O2Na requires 304.2001.
Tert-Butyl (1-(1H-pyrazol-1-yl)propyl)carbamate (4c). Reaction on 21.9 mg (0.099 mmol) of tertꢀ
butyl (2ꢀmethylꢀ1ꢀ(phenylthio)propyl)carbamate (1c). Eluent for the flash column chomatorgraphy:
heptane/ethyl acetate 9/1, to afford 13.8 mg of a colourless solid, 61% yield. MP: 75–76°C. IR (cm–1):
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3208, 2973, 1714, 1699, 1543, 1366, 1302, 1288, 1247, 1163, 1097, 1042, 1004, 827, 764, 742. H
NMR (CDCl3, 300 MHz) δ (ppm): 7.58 (s, 2H), 6.23 (s, 1H), 5.74–5.66 (m, 2H), 2.23–1.99 (m, 2H),
1.42 (s, 9H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.8, 140.0, 129.7, 104.7,
80.2, 68.5, 28.2 (× 3), 28.0, 9.8. HRMS (ESI TOF): m/z = 226.1552 [M+H]+, C11H20N3O2 requires
226.1556.
Tert-Butyl (2-(benzyloxy)-1-(1H-pyrazol-1-yl)ethyl)carbamate (4d). Reaction on 31.1 mg (0.099
mmol) of tertꢀbutyl (2ꢀ(benzyloxy)ꢀ1ꢀ(ethylthio)ethyl)carbamate (1d). Eluent for the preparative TLC:
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heptane/ethyl acetate 7/3, to afford 18.5 mg of a colourless solid, 58% yield. MP: 83–84°C. IR (cm–1):
3219, 2969, 2931, 2891, 1698, 1525, 1369, 1308, 1241, 1155, 1134, 1087, 1042, 1027, 957, 757, 737,
699. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.64 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.39–7.28
(m, 3H), 7.26–7.24 (m, 2H), 6.29 (t, J = 2.0 Hz, 1H), 6.02 (m, 1H), 5.86 (d br, J = 8.5 Hz, 1H), 4.48 (s,
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2H), 4.00–3.89 (m, 2H), 1.45 (s, 9H) . C NMR (CDCl3, 75 MHz) δ (ppm): 154.6, 140.0, 137.4, 129.2,
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128.5 (× 2), 127.9, 127.7 (× 2), 105.2, 80.6, 73.4, 70.5, 66.3, 28.2 (× 3). HRMS (ESI TOF): m/z =
318.1804 [M+H]+, C17H24N3O3 requires 318.1818
Tert-Butyl (2-(benzyloxy)-1-(1H-pyrazol-1-yl)ethyl)carbamate (4e). Reaction on 29.1 mg (0.100
mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)carbamate (1e). Eluent for the preparative
TLC: heptane/ethyl acetate 7/3, to afford 14 mg of white foam, 47% yield. IR (cm–1): 3241, 2978, 2240,
1705, 1512, 1492, 1444, 1394, 1368, 1324, 1247, 1155, 1085, 1046, 1027, 1009, 994, 966, 918, 862,
804, 756, 691. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.70 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H),
7.47–7.42 (m, 2H), 7.34ꢀ7.27 (m, 3H), 6.85 (d, J = 9.2 Hz, 1H), 6.27 (t, J = 1.8 Hz, 1H), 5.94 (d , J =
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9.2 Hz, 1H), 1.42 (s, 9H). C NMR (CDCl3, 75 MHz) δ (ppm): 140.9, 132.2 (x 2), 129.4, 128.7, 128.5
(x 2), 121.3, 106.1 (x 2), 86.0, 82.6, 59.2, 29.9, 28.2 (x 3). HRMS (ESI TOF): m/z = 320.1381
[M+Na]+, C17H19N3O2Na requires 320.1375. m/z = 126.1552 [M+H]+, C12H20N3O2 requires 126.1556
Tert-Butyl (2-methyl-1-(1H-pyrazol-1-yl)propyl)carbamate (4f). Reaction on 22.1 mg (0.099 mmol)
of tertꢀbutyl (2ꢀmethylꢀ1ꢀ(phenylthio)propyl)carbamate (1f). Eluent for the flash column
chomatorgraphy: heptane/ethyl acetate 7/3, to afford 13.7 mg of a colourless solid, 57% yield. MP:
116ꢀ117°C. IR (cm–1): 3223, 2974, 1703, 1537, 1392, 1366, 1300, 1248, 1157, 1088, 1041, 1017, 939,
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876, 853, 810, 754, 701. H NMR (CDCl3, 300 MHz) δ (ppm): 7.55 (s, 1H), 7.51 (s, 1H), 6.21 (s, 1H),
5.52 (d, J = 7.7 Hz, 1H), 5.37 (t, J = 9.0 Hz, 1H), 2.38 (h, J = 6.5 Hz, 1H), 1.40 (s, 9H), 1.06 (d, J = 6.6
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Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H). C NMR (CDCl3, 75 MHz) δ (ppm): 155.2, 140.0, 130.0, 104.4,
80.1, 72.8, 33.1, 28.2 (× 3), 18.8, 18.6. HRMS (ESI TOF): m/z = 240.1715 [M+H]+, C12H22N3O2
requires 240.1712 and m/z = 262.1534 [M+Na]+, C12H21N3O2Na requires 262.1531
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Tert-butyl (cyclopropyl(1H-pyrazol-1-yl)methyl)carbamate (4g). Reaction on 21.3 mg (0.099 mmol)
of tertꢀbutyl (cyclopropyl(ethylthio)methyl)carbamate (1g). Eluent for the flash column
chomatorgraphy: heptane/ethyl acetate 9/1, to afford 9.8 mg of a colourless solid, 41% yield. MP:
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85ꢀ86°C. IR (cm–1): 3343, 3006, 2932, 1690, 1528, 1309, 1251, 1235, 1152, 1021, 758. H NMR
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(CDCl3, 300 MHz) δ (ppm): 7.59 (s, 1H), 7.56 (s, 1H), 6.25 (t, J = 2.0 Hz, 3H), 5.75 (m, 1H), 5.20 (t, J
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= 8.5 Hz, 1H), 1.64 (m, 1H), 1.43 (s, 9H), 0.75–0.35 (m, 2H) . C NMR (CDCl3, 75 MHz) δ (ppm):
154.9, 139.8, 128.8, 104.9, 80.4, 71.0, 28.3 (× 3), 15.9, 3.5 (× 2). HRMS (ESI TOF): m/z = 260.1373
[M+Na]+, C12H19N3O2Na requires 260.1375.
Tert-Butyl (phenyl(1H-pyrazol-1-yl)methyl)carbamate (4h). Reaction on 26.7 mg (0.099 mmol) of
tertꢀbutyl ((ethylthio)(phenyl)methyl)carbamate (1h). Eluent for the preparative TLC: heptane/ethyl
acetate 7/3, to afford 16.3 mg of a colourless solid, 60% yield. MP: 125ꢀ126°C. IR (cm–1): 3251, 2968,
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1702, 1530, 1390, 1365, 1329, 1269, 1242, 1176, 1154, 1046, 1009, 918, 868, 817, 765. H NMR
(CDCl3, 300 MHz) δ (ppm): 7.67 (s br, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.40ꢀ7.33 (m, 3H), 7.20ꢀ7.18 (m,
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2H), 7.15 (d br, J = 8.7 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 6.03 (d br, J = 8.6 Hz, 1H), 1.48 (s, 9H). C
NMR (CDCl3, 75 MHz) δ (ppm): 154.6, 140.4, 138.2, 129.4, 128.8 (× 2), 128.7, 126.2 (× 2), 105.4,
80.8, 69.2, 28.3 (× 3). HRMS (ESI TOF): m/z = 296.1362 [M+Na]+, C15H19N3O2Na requires 296.1375.
tert-butyl ((2-bromophenyl)(1H-pyrazol-1-yl)methyl)carbamate (4i). Reaction on 34.6 mg (0.100
mmol) of tertꢀbutyl ((2ꢀbromophenyl)(ethylthio)methyl)carbamate (1i). Eluent for the preparative TLC:
heptane/ethyl acetate 2/8, to afford 23.2 mg of a white foam, 66% yield. IR (cm–1): 2926, 1702, 1509,
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1367, 1248, 1153, 1027, 754. H NMR (CDCl3, 300 MHz) δ (ppm): 7.73ꢀ7.66 (m, 1H), 7.64ꢀ7.55 (m,
1H), 7.36ꢀ7.26 (m, 2H), 7.24ꢀ7.15 (m, 2H), 6.34ꢀ6.26 (m, 1H), 5.91ꢀ5.64 (m, 1H), 3.85 (s, 1H), 1.45 (s,
9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 140.6, 137.4, 133.5, 130.4, 128.1, 128.0, 125.0, 112.4, 111.8,
105.7, 102.4, 56.0, 28.3 (x 3). HRMS (ESI TOF): m/z = 374.0470 [M+Na]+, C15H18BrN3O2Na requires
374.0480.
Benzyl (3-phenyl-1-(1H-pyrazol-1-yl)propyl)carbamate (4j). Reaction on 33 mg (0.100 mmol) of
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benzyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1j). Eluent for the preparative TLC: heptane/ethyl
acetate 7/3, to afford 28.6 mg of a colourless oil, 85% yield. IR (cm–1): 3302, 3029, 1703, 1529, 1497,
1231, 1043, 1029, 748, 696. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.65 (s, 1H), 7.60 (s, 1H), 7.40–7.20
(m, 8H), 7.14–7.11 (m, 2H), 6.41 (d br, J = 9.2 Hz, 1H), 6.28 (s, 1H), 5.81 (t, J = 8.1 Hz, 1H), 5.16 (d,
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J = 12.1 Hz, 1H), 5.00 (d, J = 12.3 Hz, 1H), 2.63–2.32 (m, 4H). C NMR (CDCl3, 75 MHz) δ (ppm):
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155.5, 140.4, 140.1, 136.0, 130.1, 128.6 (× 2), 128.5 (× 2), 128.4 (× 2), 128.2, 128.1, 126.3, 126.1,
105.0, 67.1, 66.8, 35.8, 31.4. HRMS (ESI TOF): m/z = 336.1703 [M+H]+, C20H22N3O2 requires
336.1712.
Tert-Butyl (1-(4-nitro-1H-pyrazol-1-yl)-3-phenylpropyl)carbamate (4k). Reaction on 29.5 mg
(0.100 mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative
TLC: heptane/ethyl acetate 6/4, to afford 22.9 mg of a colourless solid, 66% yield. MP: 140–141°C. IR
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(cm–1): 3333, 3142, 2980, 1689, 1524, 1512, 1315, 1289, 1274, 1154, 861, 817, 752, 705. H NMR
(CDCl3, 300 MHz) δ (ppm): 8.29 (s br, 1H), 8.15 (s, 1H), 7.36ꢀ7.23 (m, 3H), 7.16ꢀ7.13 (m, 2H),
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5.73ꢀ5.57 (m, 2H), 2.67ꢀ2.32 (m, 4H), 1.44 (s, 9H). C NMR (CDCl3, 75 MHz) δ (ppm): 154.3, 139.3,
136.4, 135.3, 128.8 (× 2), 128.3 (× 2), 126.7 (x 2), 81.4, 68.2, 35.1, 31.3, 28.2 (× 3). HRMS (ESI TOF):
m/z = 381.1337 [M+Cl]–, C17H22N4O4Cl requires 381.1330.
Tert-Butyl (1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-phenylpropyl)carbamate (4l). Reaction on 29.5 mg
(0.100 mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative
TLC: heptane/ethyl acetate 6/4, to afford 26.1 mg of a colourless solid, 79% yield. MP: 121–122°C. IR
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(cm–1): 3187, 2981, 1703, 1538, 1454, 1273, 1243, 1156, 1054, 1031, 779, 767, 717, 694. H NMR
(CDCl3, 300 MHz) δ (ppm): 7.32–7.13 (m, 5H), 6.10 (d br, J = 9.2 Hz, 1H), 5.77 (s, 1H), 5.70 (m, 1H),
2.52–2.33 (m, 4H), 2.27 (s, 3H), 2.24 (s, 3H), 1.42 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.8,
148.4, 140.7, 139.6, 128.5 (× 2), 128.4 (× 2), 126.1, 104.7, 79.0, 62.2, 36.4, 31.5, 28.3 (× 3), 13.7, 10.7.
HRMS (ESI TOF): m/z = 330.2169 [M+H]+, C19H28N3O2 requires 330.2182.
Tert-Butyl (1-(3,5-dimethyl-1H-pyrazol-1-yl)octyl)carbamate (4m). Reaction on 28.9 mg (0.099
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mmol) of tertꢀbutyl (1ꢀ(phenylthio)octyl)carbamate (1k). Eluent for the flash column chomatorgraphy:
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heptane/ethyl acetate 7/3, to afford 29 mg of oil, 59% yield. IR (cm–1): 3190, 2927, 2857, 1705, 1556,
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1459, 1365, 1350, 1290, 1273, 1246, 1178, 1048, 1001, 873, 780, 753. H NMR (CDCl3, 300 MHz) δ
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(ppm): 5.74 (s, 1H), 5.71ꢀ5.59 (m, 2H), 2.35 (s, 3H), 2.23 (s, 3H), 2.16ꢀ1.88 (m, 2H), 1.41 (s, 9H), 1.34ꢀ
0.99 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.8, 148.2, 134.4,
104.4, 79.8, 62.8, 35.3, 31.6, 29.0, 28.7, 28.2 (x3), 25.2, 22.5, 13.9, 13.6, 10.7. HRMS (ESI TOF): m/z
= 324.2646 [M+H]+, C18H34N3O2 requires 324.2651.
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Tert-butyl (1-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropyl)carbamate (4n). Reaction on 22.1 mg
(0.099 mmol) of tertꢀbutyl (2ꢀmethylꢀ1ꢀ(phenylthio)propyl)carbamate (1f). Eluent for the flash column
chomatorgraphy: heptane/ethyl acetate 7/3, to afford 20.1 mg of a white foam, 75% yield. IR (cmꢀ1):
3196, 2977, 1699, 1539, 1475, 1459, 1390, 1362, 1294, 1247, 1166, 1041, 1010, 950, 881, 858, 845,
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779, 738. H NMR (CDCl3, 300 MHz) δ (ppm): 5.73 (s, 1H), 5.70 (s, 1H), 5.27 (t, J = 9.9 Hz, 1H),
2.42ꢀ2.26 (m, 4H), 2.22 (s, 3H), 1.40 (s, 9H), 1.08 (d, J = 6.6 Hz, 3H), 0.64 (d, J = 6.6 Hz, 3H). 13C
NMR (CDCl3, 75 MHz) δ (ppm): 155.3, 148.3, 139.8, 104.4, 79.9, 68.6, 33.9, 28.4 (x3), 19.2, 18.7,
13.8, 11.0. HRMS (ESI TOF): m/z = 268.2031 [M+H]+, C14H26N3O2 requires 268.2025.
Tert-Butyl (1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-phenylpropyl)carbamate (4o). Reaction on 29.5
mg (0.100 mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative
TLC: heptane/ethyl acetate 6/4, to afford 27.2 mg of a white foam, 86% yield. IR (cm–1): 3214, 3028,
2977, 2931, 1709, 1521, 1497, 1454, 1391, 1366, 1327, 1292, 1272, 1245, 1162, 1048, 1028, 998, 911,
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868, 752, 699. H NMR (CDCl3, 300 MHz) δ (ppm): 7.47ꢀ7.40 (m, 1H), 7.28ꢀ7.24 (m, 2H), 7.20ꢀ7.15
(m, 1H), 7.12ꢀ7.09 (m, 2H), 5.98ꢀ5.96 (m, 1H), 5.82ꢀ5.75 (m, 1H), 5.63ꢀ5.56 (m, 1H), 2.56ꢀ2.40 (m,
3H), 2.29 (s, 3H), 2.25 (m, 1H), 1.38 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 149.5, 139.5, 130.9,
128.6 (x 2), 128.5, 126.3, 104.9, 104.5, 66.3, 62.5, 36.1, 31.6, 28.4 (x3), 13.9, 10.8. HRMS (ESI TOF):
m/z = 316.2018 [M+H]+, C18H26N3O2 requires 316.2025.
Tert-Butyl (1-(1H-indazol-1-yl)-3-phenylpropyl)carbamate (4p). Reaction on 50 mg (0.10 mmol) of
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tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative TLC: heptane/ethyl
acetate 7/3, to afford 32 mg of a colourless solid, 91% yield. MP: 129–130°C. IR (cm–1): 3194, 3027,
2972, 1710, 1544, 1366, 1287, 1263, 1250, 1156, 1121, 1045, 1028, 1010, 911, 853, 790, 761, 734, 702,
657. 1H NMR (CDCl3, 300 MHz) δ (ppm): 8.14 (s br, 1H), 7.79 (dd, J = 8.8 and 0.9 Hz, 1H), 7.72 (dt, J
= 8.4 and 1.0 Hz, 1H), 7.38–7.20 (m, 4H), 7.16–7.11 (m, 3H), 6.49 (d br, J = 9.0 Hz, 1H), 6.07 (m, 1H),
2.72–2.48 (m, 4H), 1.39 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.7, 143.6, 141.3, 139.5,
132.5, 128.7 (× 2), 128.4 (× 2), 126.6, 123.2, 122.6, 120.3, 110.8, 80.8, 62.4, 36.0, 31.7, 28.2 (× 3).
HRMS (ESI TOF): m/z = 352.2014 [M+H]+, C21H26N3O2 requires 352.2025.
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Tert-Butyl (1-(1H-imidazol-1-yl)-3-phenylpropyl)carbamate (4q). Reaction on 29.5 mg (0.100
mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative TLC: pure
ethyl acetate, to afford 6.3 mg of a colourless solid, 21% yield. MP: 158–159°C. IR (cm–1): 3181, 2972,
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2936, 1702, 1284, 1254, 1218, 1159, 1073, 1047, 1025, 768, 755, 739, 701, 660. H NMR (CDCl3, 300
MHz) δ (ppm): 7.63 (s br, 1H), 7.26 7.12 (m, 3H), 7.06 6.96 (m, 4H), 5.68 (br s, 1H), 5.35 (br s, 1H),
2.56 (t, J = 7.6 Hz, 2H), 2.24 (m, 2H), 1.34 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.4, 139.5,
135.9, 129.2, 128.7 (× 2), 128.4 (× 2), 126.6, 116.3, 81.0, 63.2, 36.5, 31.6, 28.3 (× 3). HRMS (ESI
TOF): m/z = 302.1860 [M+H]+, C17H24N3O2 requires 302.1869.
tert-Butyl (1-(1H-benzo[d]imidazol-1-yl)-3-phenylpropyl)carbamate (4r).10 Reaction on 29.5 mg
(0.100 mmol) of tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative
TLC: heptane/ethyl acetate 2/8, to afford 27.6 mg of a colourless oil, 79% yield. IR (cm–1): 2978, 1706,
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1492, 1455, 1366, 1250, 1156, 1047, 1026, 741, 698. H NMR (CDCl3, 300 MHz) δ (ppm): 8.01 (s br,
1H), 7.80 (s, 1H), 7.51 (br s, 1H), 7.28ꢀ7.19 (m, 5H), 7.11ꢀ7.09 (m, 2H), 5.99 (br s, 1H), 5.81 (br s, 1H),
2.65 (m, 2H), 2.49 (m, 2H), 1.37 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.7, 143.6, 141.3,
139.5, 132.5, 128.7 (× 2), 128.4 (× 2), 126.6, 123.2, 122.6, 120.3, 110.8, 80.8, 62.4, 36.0, 31.7, 28.2 (×
3). HRMS (ESI TOF): m/z = 352.2010 [M+H]+, C21H26N3O2 requires 352.2025.
Tert-butyl (1-(1H-benzo[d]imidazol-1-yl)-2-methylpropyl)carbamate (4s). Reaction on 22.1 mg
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(0.100 mmol) of tertꢀbutyl (2ꢀmethylꢀ1ꢀ(phenylthio)propyl)carbamate (1f). Eluent for the flash column
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chomatorgraphy: heptane/ethyl acetate 2/8, to afford 19.5 mg of a white foam, 67% yield. IR (cmꢀ1):
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2976, 1707, 1491, 1457, 1392, 1367, 1310, 1282, 1219, 1158, 1043, 1011, 848, 772, 742. H NMR
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(CDCl3, 300 MHz) δ (ppm): 8.09ꢀ8.00 (m, 1H), 7.86ꢀ7.78 (m, 1H), 7.59ꢀ7.47 (m, 1H), 7.35ꢀ7.24 (m,
2H), 5.86ꢀ5.31 (m, 2H), 2.60ꢀ2.34 (m, 1H), 1.38 (s, 9H), 1.16 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz,
3H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.8, 143.9, 141.6, 132.8, 123.1, 122.4, 120.4, 110.7 (x 2),
68.8, 32.6, 28.2 (x3), 19.0, 18.9. HRMS (ESI TOF): m/z = 290.1865 [M+H]+, C16H24N3O2 requires
290.1869.
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Tert-butyl (1-(1H-benzo[d]imidazol-1-yl)-2-(benzyloxy)ethyl)carbamate (4t). Reaction on 31.1 mg
(0.100 mmol) of tertꢀbutyl (2ꢀ(benzyloxy)ꢀ1ꢀ(ethylthio)ethyl)carbamate (1d). Eluent for the preparative
TLC: heptane/ethyl acetate 2/8, to afford 27.3 mg of a colourless solid, 74% yield. MP: 83–84°C. IR
(cm–1): 3219, 2969, 2931, 2891, 1698, 1525, 1369, 1308, 1241, 1155, 1134, 1087, 1042, 1027, 957, 757,
1
1
737, 699. H NMR (CDCl3, 300 MHz) δ (ppm): H NMR (CDCl3, 300 MHz) δ (ppm): 8.24 (br s, 1H),
7.81ꢀ7.77 (m, 1H), 7.59 (br s, 1H), 7.30ꢀ7.17 (m, 7H), 6.20ꢀ6.05 (m, 1H), 5.87(d, J = 8.7 Hz, 1H), 4.47
(s, 2H), 3.92ꢀ3.75 (m, 2H), 1.31 (s, 9H). 13C NMR (CDCl3, 75 MHz) δ (ppm): 154.5, 143.4, 141.7,
136.7, 133.0, 128.8 (x 2), 128.4 (x 2), 128.1 (x 2), 123.3, 122.6, 120.3, 110.6, 74.0, 70.6, 61.2, 28.3 (x
3). HRMS (ESI TOF): m/z = 368.1964 [M+H]+, C21H26N3O3 requires 368.1974.
Tert-butyl (3-phenyl-1-(9H-purin-9-yl)propyl)carbamate (4s). Reaction on 29.5 mg (0.100 mmol) of
tertꢀbutyl (1ꢀ(ethylthio)ꢀ3ꢀphenylpropyl)carbamate (1a). Eluent for the preparative TLC: heptane/ethyl
acetate 6/4, to afford 28.6 mg of a white foam, 81% yield. IR (cm–1): 2977, 1711, 1595, 1494, 1455,
1
1392, 1368, 1343, 1299, 1250, 1158, 1049, 909, 850, 794, 736, 700. H NMR (CDCl3, 300 MHz) δ
(ppm): 9.15 (s, 1H), 8.97 (s, 1H), 8.11 (s, 1H), 7.33ꢀ7.27 (m, 1H), 7.26ꢀ7.16 (m, 2H), 7.14ꢀ7.05 (m, 2H),
13
6.05ꢀ5.88 (m, 2H), 2.86ꢀ2.53 (m, 4H), 1.38 (s, 9H). C NMR (CDCl3, 75 MHz) δ (ppm): 152.3, 150.9,
148.8, 145.3, 139.3, 128.7 (x2), 128.3 (x2), 126.6, 63.8, 60.5, 34.6, 31.7, 28.2 (x3), 26.2, 21.2. HRMS
(ESI TOF): m/z = 354.1928 [M+H]+, C19H24N5O2 requires 354.1930.
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AUTHOR INFORMATION
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Corresponding Authors
*geraldine.masson@cnrs.fr
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Author Contributions
All authors have given approval to the final version of the manuscript.
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
L.J. thanks the Université ParisꢀSud for doctoral fellowships and G.L thanks Labex Charm3at for a
financial support of Master.
SUPPORTING INFORMATION
Experimental details, characterization of new compounds, selected NMR and HPLC spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
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(19) Hydroperoxyl radical can spontaneously disproportionate to hydrogen peroxide (H2O2) and
singlet dioxygen. In order to prove the formation of H2O2 during the process, we tried to capture it by
olefins such as styrene or cyclohexene. Unfortunately, in both cases no epoxide resulting from the
trapping of the H2O2 could be observed.
(20) Megan A. Cismesiaa and Tehshik P. Yoon Chem. Sci. 2015, 6, 5426.
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