Assembly of Thiosubstituted Benzoxazoles via Copper-Catalyzed Coupling of Thiols with 5-Iodotriazoles Serving as Diazo Surrogates

Article abstract of DOI:10.1021/acs.joc.0c00931

An efficient cascade approach to thiosubstituted benzoxazoles has been developed. The transformation starts with in situ generation of a diazo compound via annulation-triggered electrocyclic opening of the 1,2,3-triazole ring. The subsequent Cu-catalyzed trapping of diazo intermediates by various thiols affords the desired heterocycles in generally good yields of up to 91%. The protocol features very good functional group tolerance and is applicable to substrates with different electronic properties.

Full text of DOI:10.1021/acs.joc.0c00931

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Article
Assembly of thiosubstituted benzoxazoles via copper-catalyzed
coupling of thiols with 5-iodotriazoles serving as diazo surrogates
Yury Nikolaevich Kotovshchikov, Gennadij Vladimirovich Latyshev, Elena A.
Kirillova, Uliana D. Moskalenko, Nikolay V. Lukashev, and Irina P. Beletskaya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00931 • Publication Date (Web): 07 Jun 2020
Downloaded from pubs.acs.org on June 8, 2020
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Assembly of thiosubstituted benzoxazoles via copper-catalyzed coupling of thiols with 5-
iodotriazoles serving as diazo surrogates
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Yury N. Kotovshchikov,*,a Gennadij V. Latyshev,a Elena A. Kirillova,a Uliana D. Moskalenko,a,b Nikolay V. Lukasheva
and Irina P. Beletskayaa
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E-mail: kotovshchikov@org.chem.msu.ru
a Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskiye Gory 1, Moscow, 119991, Russia
b Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
ABSTRACT
An efficient cascade approach to thiosubstituted benzoxazoles has been developed. The
transformation starts with in situ generation of diazo compound via annulation-triggered
electrocyclic opening of 1,2,3-triazole ring. The subsequent Cu-catalyzed trapping of diazo
intermediates by various thiols affords desired heterocycles in generally good yields up to 91%. The
protocol features very good functional group tolerance and is applicable to substrates with different
electronic properties.
Masked diazo
R'S
N
R
O
Free diazo
N-
N+
H
S
N
Annulation
induced
diazo
N
N
N
N
Cu
O
R
release
R
OH
I
31 examples (up to 91%)
R''
INTRODUCTION
Diazo compounds represent a well-known class of highly reactive valuable synthetic intermediates
being utilized in the preparation of a great variety of functionalized molecules.1 The insertion of
carbenoids, generated from diazo compounds, into heteroatom-H (X-H) bond became a reliable
approach to formation of C-X bonds. While N-H and O-H insertions are known for a long time and
are well developed, the insertion into S-H bond is much less investigated. Nevertheless, several
methods involving Cu,2 Rh,3 and Fe4 catalysts were reported.
A number of diazoalkanes are available by several synthetic routes including acylation of
diazomethane, diazotization of primary amines, diazo transfer, etc.5 Despite an apparent synthetic
utility of diazo compounds, there are several drawbacks of their application regarding potential
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safety risks. Thus, diazo compounds are known to be hazardous chemicals, mainly due to their
toxicity, low thermal stability, and explosive nature. Therefore, it is more preferable to use some
stable substances capable of transforming to diazo compounds in situ upon a special treatment. The
most widely employed procedures for the generation of diazo compounds include the oxidation of
hydrazones6 and base-induced decomposition of tosylhydrazones.7 While the oxidative conditions
are not compatible with thiols, the use of sulfonylhydrazones for insertion into S-H bonds was
limited,3b,8 due to the concurrent formation of sulfone via capture of the obtained sulfinate
byproduct.9
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Some types of 1,2,3-triazoles can also serve as diazo precursors via electrocyclic ring-opening. In
particular, the corresponding ring-chain tautomerism is well-established for N-sulfonyltriazoles10
and triazolopyridines11. In the presence of transition metals or Lewis acids12 as well as under
thermal or photochemical activation13 these compounds can be used for a generation of carbenes or
metallocarbenoids. This methodology is being extensively studied in the last few years and is
successfully employed in design of efficient approaches to various structures, including
pharmaceutically relevant and natural compounds.14
However, sulfur-containing substrates are rarely involved in these transformations (Scheme 1). The
formal insertion into C-S bond was limited to allyl sulfides (via Doyle-Kirmse reaction)15 and
intramolecular RS group migration.16 Some processes involving C=S double bond participation,17
S-S bond insertion,18 and 1,3-addition of thioesters19 were also reported. The insertion into S-H
bond was not investigated for these diazo surrogates.
R'SH
N2
SR'
cat
R
R
R
-N2
Stable diazo surrogates
Free diazo
N
N2
NNHTs
N
I
N
N
N
N
R
R
R
N N
rare
sulfinate
abundant
OH
N
R'O2S
R
capture mostly
never used
Scheme 1. The diazo reactivity in S-H bond insertion.
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Halogenated 1,2,3-triazoles are known to be rather unreactive heterocycles readily available by Cu-
catalyzed 1,3-dipolar cycloaddition.20 They have been widely explored only as valuable substrates
for cross-coupling reactions and related processes.21 As a part of our ongoing interest in the 1,2,3-
triazole chemistry,22 we revealed that 5-iodotriazoles bearing a pendant phenol group can be used as
a new convenient type of diazo surrogates.23 While these compounds are bench-stable, the heating
of them in basic media evokes cyclization and unmasks hidden diazo functionality.
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Herein, we report an efficient protocol for the Cu-catalyzed cascade affording 2-(1-
thioalkyl)benzoxazoles. To the best of our knowledge, this is the first example of S-H insertion for
carbenoids generated from triazole-based diazo surrogates. This scaffold was shown to exhibit a
broad range of biological activity, including antibacterial,24 antifungal,25 antiviral,26 and
antidiabetic27 (Scheme 2). While the modern 2-step approaches exist,28 it is commonly assembled
via 3-step procedure, including halogenation of carboxylic acid derivative, benzoxazole formation,
and nucleophilic substitution.26c,29
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Previous approaches:
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benzoxazole
formation
C-S bond
formation
Classic (3 separate steps): derivatization
F
Br
Hal
O
R
N
F
R'SCN
SR'
R
N
O
TDAE
R'SH
SN2
or
N
O
R'SH
SRN
1
Present work:
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Modern
(2 steps)
R
R
N
masked
diazo
N
Cu
Cu
R'SH
DMSO
N
I
R'SH
O
N
OH
benzoxazole
precursor
one-pot procedure
S
F
F
N
N
S
N
O
N
NHPh
N
N
N
O
antidiabetic
(FATP1 inhibitor)
F3C
O
anti-HIV
S
N
S
O
HN
O
SPh
N
O
antidiabetic
NH
O
Cl
Cl
N
O
Cl
SPh
antimicrobial
anti-HIV
Scheme 2. Proposed approach to thiolated benzoxazoles.
RESULTS AND DISCUSSION
We began our studies by exploring the conditions for a model reaction between iodotriazole 1a and
1,3-benzothiazole-2-thiol in basic media. A series of experiments was carried out by varying several
parameters, including a catalyst, a base, and a reaction temperature (Table 1). Non-catalytic reaction
in the presence of Et3N as a base in dioxane at 100 °C gave thiosubstituted benzoxazole 2a only in
poor yield 17% (entry 1). Alkene 4 was observed as a byproduct of diazo intermediate 3
decomposition via Bamford-Stevens-like transformation.30 An addition of 20 mol% BF3·Et2O to the
reaction mixture led to a negligible improvement of the result (cf. entries 1 vs. 2), probably, due to a
deactivation of the Lewis acid by Et3N.
Table 1. Optimization of reaction conditionsa
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N
S
Pr
HS
Bu
Bu
I
N
N
S
S
N
catalyst, base
N
N
O
N
+
O
dioxane
100 °C, 16 h
OH
8
9
1a
2a
4
N2
N
10
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12
O
Bu
3
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Entry
Catalyst (mol%)
Base/T (°C)
Yield (%)b
2a
17
20
53
72
17
69
80
65
59
4
4
1
–
Et3N/100
Et3N/100
Et3N/100
Et3N/100
Et3N/100
Et3N/100
Et3N/100
DIPEA/100
DABCO/100
pyridine/100
TMG/100
DBU/100
Et3N/100
Et3N/80
32
36
5
2
BF3·Et2O (20)
Rh2(esp)2 (2.5)
CuI (10)
3
4
4
5
CuTC (10)
33
5
6
Cu(SIMes)Cl (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
Cu(Ph3P)3Br (10)
7
3
8
4
9
6
10
11
12
13c
14
1
33
35
75
68
61
7
7
3
2
15
Et3N/120
2
a
All reactions were performed with 1a (0.1 mmol) and 1,3-benzothiazole-2-thiol (0.2 mmol) in the presence of a catalyst, a base (0.2 mmol) in
dioxane (1 mL) for 16 h under an Ar atmosphere. b Determined by 1H NMR. c Reaction time 4 h.
We screened representative transition metal catalysts (entries 3–7 in Table 1) in order to increase
the selectivity and the efficiency of our reaction. Almost all additives suppressed the formation of
alkene 4 and improved the yield of 2a. Although Rh catalysts are the most popular for generation of
carbenoids from N-sulfonyltriazoles, in our case the use of 2.5 mol% Rh2(esp)2 was found to be less
efficient than 10 mol% CuI (cf. entries 3 vs. 4). This fact can be considered a significant
achievement, owing to an obvious higher abundance and a much lower cost of Cu. During the study
of other Cu catalysts, CuTC proved inefficient (entry 5), while Cu(I)-NHC complex gave a result
comparable to that of CuI (cf. entries 4 vs. 6). Readily available complex Cu(Ph3P)3Br was the most
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efficient catalyst providing the highest yield of 2a (80%) with only trace amounts of byproduct 4
(entry 7).
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9
The screening of bases (entries 7–12 in Table 1) revealed that Et3N was the most appropriate one.
Other tertiary amines as well as stronger bases DBU and TMG gave 2a in lower yields. Pyridine
was found to be too weak base to promote the cyclization of 1a, therefore, the reaction proceeded
very poorly (entry 10), and a lot of unchanged starting material was recovered. The shortening of
the reaction time from 16 to 4 h slightly diminished the yield of 2a (cf. entries 7 vs. 13). Either
decrease or increase of the reaction temperature (entries 14 and 15) also lowered the yield, thus, the
temperature of 100 °C was accepted as optimal.
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Under the optimized reaction conditions, we studied the scope of sulfur nucleophiles which can
engage in thiolative trapping of diazo compound 3 generated in situ from iodotriazole 1a (Scheme
3). A wide range of heterocyclic thiols was successfully involved in this domino reaction furnishing
thiosubstituted benzoxazoles 2a–n in yields up to 91%. It is noteworthy that a selective SH insertion
was observed in the presence of free NH groups (2c, 2f, 2n). Good to high yields were achieved for
various azole-derived thiols, containing imidazole (2h), 1,2,4-triazole (2j, 2k), tetrazole (2i), oxa-
and thiadiazoles (2d–f) as well as some benzannulated azoles (2a–c). Azine-derived thiols also
afforded the corresponding products 2l–n, albeit in diminished yields (not higher than 50%),
especially in the case of pyrimidine-2-thiol (2m, 19%). A reasonable yield was observed in the
reaction of 1a with a partially saturated heterocyclic thiol (2g, 56%).
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N
Bu
S
Bu
I
N
N
(2 equiv)
HS
N
N
N
Cu(Ph3P)3Br (10 mol%)
O
5
6
Et3N, dioxane
100 °C, 16 h
OH
7
1a
2
8
9
Bu
Bu
S
Bu
S
X
S
S
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11
12
13
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N
N
N
N
N
N
O
O
X
O
N
N
H2N
2a
2b
2f
, X=S, 68%
, X=O, 74%
2d
2e
, 62%
, X=O, 82%
, X=S, 70%
(66% [1.2 mmol scale])
2c
, X=NH, 84%
Bu
Bu
Bu
S
S
S
S
N
N
N
N
N
N
N
O
O
N
, 57%
O
N
N
O
2h
2i
, 72%
2g
, 56%
S
OMe
Bu
Bu
S
N
N
N
N
N
N
N
O
N
O
N
N
NO2
NO2
2j
2k
, 83%
, 91%
Bu
Bu
Bu
S
S
N
S
N
N
N
N
N
O
O
O
NH
N
2l
2m
2n
, 42%
, 50%
, (19%)
1
Scheme 3. Scope of sulfur nucleophiles (yields determined by H NMR are presented in
parentheses).
With the aim of further extending the scope of sulfur nucleophiles, we tried to perform a reaction of
iodotriazole 1a with thiophenol (Scheme 4). However, this attempt led to reductive dehalogenation
of 1a affording compound 5 instead of desired product 2o. The same result was obtained in the
reaction of 1a with methyl thioglycolate. It should be noted that deiodinated triazole 5 was also
detected as a byproduct in reactions with those thiols which gave 2 in moderate yields. In fact, the
highest yields were obtained with heterocyclic thiols which are known to predominantly exist in a
tautomeric thione form. Thus, the absence of the thiol form in a high concentration prevents
iodotriazole 1 from the reduction.
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To overcome the limitation of easily oxidizable thiols, we conducted the reaction employing a
sequential addition of the reagents. Initially, the heating of 1a in the absence of sulfur nucleophiles
produced alkyl iodide 6 via a Cu-catalyzed diazo trapping (Scheme 4).31 The subsequent addition of
the thiophenol led to a nucleophilic substitution of the iodide affording arylthiosubstituted
benzoxazole 2o, albeit in a rather low yield.
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Bu
Bu
N
N
N
N
ArSH (2 equiv)
N
N
Cu(Ph3P)3Br (10 mol%)
I
H
Et3N, dioxane
100 °C, 16 h
OH
1a
OH
5
Ar = 4-BrC6H4
Bu
Bu
I
SAr
Cu(Ph3P)3Br
(10 mol%)
ArSH
(2 equiv)
90 °C, 16 h
N
N
O
O
Et3N, dioxane
90 °C, 2 h
6
2o
, 31% (44%)
Scheme 4. Reaction of 1a with 4-bromothiophenol.
An alternative way for the introduction of the arylthio-group was implemented through a reaction of
1a with a preformed copper(I) thiophenolate (Scheme 5). The absence of the thiol in the reaction
mixture allowed us to avoid the undesirable reduction of iodotriazole 1a. Thus, diazobenzoxazole 3,
generated in situ from 1a, smoothly reacted with PhSCu furnishing 2p in 72% yield. Despite an
obvious drawback of using stoichiometric amounts of Cu, this approach appeared more efficient in
comparison with delayed addition of the thiol and significantly improved the yield. Moreover,
copper(I) thiophenolate is readily available and inexpensive reagent which is also devoid of
unpleasant odor, in contrast to thiophenol.
Bu
Bu
N
N
CuS
(2 equiv)
S
N
N
I
O
Et3N, dioxane
100 °C, 16 h
OH
1a
2p
, 72%
Bu
N2
N
O
Et3N
PhSCu
100 °C
3
Scheme 5. Reaction of 1a with copper(I) thiophenolate.
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To demonstrate the general character of the process, we investigated the scope of iodotriazoles 1
acting as diazo surrogates (Scheme 6). A collection of functionalized benzoxazoles 2q–ad was
prepared in moderate to high yields (41–86%) under the optimized reaction conditions. Either
electron-donating (Me, OMe) or electron-withdrawing (I, Br, Cl, CO2Me, NO2) groups in the
phenol ring were tolerated by the developed protocol. The lowest yield was observed for
iodotriazole 1f bearing 4-(hydroxymethyl)phenol fragment (product 2u, 41%) which can be
involved in the para-quinone methide chemistry with an excess of the thiol.32 No detrimental effect
was detected for nitro group (2x, 84%), which could slow down the cyclization step due to a
significant decrease of the phenolate nucleophilicity. Despite possible substitution of halogens in
the aromatic ring by thiols under Cu catalysis,33 this anticipated side process wasn’t observed, and
the products 2s, 2t, and 2v containing Cl, I, and Br, respectively, were obtained in good yields (68–
86%). The inertness of aryl halides under the reaction conditions leaves an opportunity of further
functionalization of the products by well-established Pd-catalyzed chemistry.
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7
O
N
R
S
R
(2 equiv)
N
N
HS
N
N
N
N
Cu(Ph3P)3Br (10 mol%)
I
O
O
N
Et3N, dioxane
100 °C, 16 h
OH
X
1
2
X
8
9
Bu
Bu
2q
, X=Me, 69%
S
S
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2r
, X=CO2Me, 65%
N
N
N
N
2s
2t
, X=Cl, 75%
, X=I, 68%
O
O
O
O
N
N
HO
X
OMe
2u
, 41%
Bu
Bu
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
N
N
N
Br
2v
2w
NO2 2x
, 84%
, 86%
, 76%
S
Ph
N
n
S
S
N
N
N
N
N
N
O
O
O
O
O
O
N
N
2y
2z
2aa
2ab
, 79%
, 73%
n=1,
n=0,
, 57%
, 0%
HO
O
MeO2C
MeO2C
HN
N
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
N
N
2ac
2ad
2ae
, 46%
, 66%
, 63%
Scheme 6. Scope of iodotriazoles.
The reaction proceeded smoothly with the substrates bearing branched aliphatic substituents in the
triazole ring (2w, 2z) including some bulky ones, such as cyclohexyl group (2y). A somewhat
diminished yield was achieved in the case of a benzyl substituent (2aa, 57%), due to a favorability
of competing elimination and formation of an alkene with extended conjugation. Curiously enough,
a complex mixture containing only traces of 2ab was obtained in the reaction with Ph-substituted
iodotriazole 1q, although this substrate was expected to give the target compound in a high yield
due to the absence of β-hydrogen. The protocol tolerated the presence of hydroxyl (2ac), amide
(2ad), and ester (2ae) groups in the alkyl side chain, although a substantial steric effect exerted by
the malonyl fragment led to a reasonable yield of 2ae (46%).
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Iodotriazole 1p demonstrated an unexpected reactivity (Scheme 7). The anticipated product 2af,
initially forming via thiolative diazo trapping, was found to be very prone to intramolecular
nucleophilic attack. We were unable to detect 2af in the 1H NMR spectrum of the reaction mixture
even using only a small excess of thiol. Due to anchimeric assistance of neighboring
azaheterocycle, an OH group of 2af underwent facile substitution, followed by nucleophilic ring-
opening of the cationic intermediate 7 and formation of compounds 8. Interestingly, the
nucleophilic attack in 7 occurred exclusively at the more crowded carbon leading to a cleavage of a
C–S rather than a C–N bond. Probably, a significantly higher yield of 8b (69%) can be accounted
for a superior nucleophilicity of imidazole in comparison with oxadiazole ring.
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SH
X
(3 equiv)
Y
N
N
X
S
Y
Z
N
N
CuI (10 mol%)
O
N
N
N
Z
X
OH
S
Et3N, dioxane
90 °C, 16 h
I
Z
OH
1p
8
Y
N
N
H
N
S
Z
O
O
O HNEt3
Z
X
Y
Et3NH
S
S
N
-Et3N
-H2O
N
X
X
Y
2af
7
Z
Y
S
S
S
N
N
O
N
O
N
N
N
O
N
S
N
N
N
O
8a
8b
, 69%
, 33%
Scheme 7. Double thiolation of 1p.
Computational methods are widely used for the dissection of the mechanism in reactions involving
1,2,3-triazoles.34 Various mechanistic pathways to thioalkylbenzoxazoles were modeled by DFT at
B3LYP35/ma-SVP36/SMD37(dioxane) level of theory.38 The substrate I-1 was chosen as
representative triazolylphenol. The overall transformation of 1 to 2 can be divided into two major
steps: the formation of benzoxazole ring (non-catalytic reaction, Scheme 8) and Cu-catalyzed
thiolation of diazobenzoxazole (Scheme 9).
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The nucleophilic substitution in iodotriazole can proceed either via triazole ring opening (Scheme 8,
paths 1 and 3) proposed previously by Fokin39 or via SNAr-like mechanism (path 2). The ring-
opening in I-1 requires moderate activation energy (23 kcal/mol) and affords relatively unstable
diazoimine I-2. The deprotonation of I-2 should produce phenolate I-3, which cannot be localized
and spontaneously transforms to diazobenzoxazole I-4 with extrusion of iodide. Direct nucleophilic
substitution in I-5 (path 2) is slightly less favorable (ΔG≠=25.1 kcal/mol) and affords triazole-fused
benzoxazole I-6. The analogous triazoles are known to exist in equilibrium with more stable
diazoimine form40 and are predicted to easily rearrange to I-4. The calculations are also consistent
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with our previous observation on the formation of diazobenzoxazole under the similar conditions.
TS4
27.9
TS2
25.1
TS1
23.0
OH
N
O
N
1
G
23.0
path
OH
base
base

N
path
2
N
I-2
11.5
N
I-1
1
I-2
N2
N2
path
I
I
I
3

base
I-3
I-1
0.0
I-5
0.0
path
base
3
path
spont.
G
2
path

- I
27.9
TS3
O
N
-11.3
O
O
G
G
15.8
N
25.1
N
N
N2
N
- I
N
I-6
-27.1
N
I-5
I-6
I-4
I
I-4
-32.6
Scheme 8. Plausible mechanisms for the formation of diazobenzoxazole.
Though the calculations show a little preference for path 1 over path 2 in our system, the prevalence
of the chosen reaction path is highly dependent on the basicity of the medium. The strong base
capable to efficiently deprotonate phenol will shift the I-1 – I-5 equilibrium to the right yielding the
preferential formation of I-4 via path 2. On the contrary, weak bases will favor path 1. Since
dioxane is incapable to act as an efficient H-bond donor, the basicity of anionic species (e.g. I-3 and
I-5) will be significantly increased.41 The basicity of Et3N in dioxane is governed by moderate H-
bond acceptor ability of the solvent and will be affected to a lesser degree. Thus, path 1 is expected
to operate under our conditions.
Two catalytic cycles for transformation of I-4 to the final product are consistent with the
experimental observations (Scheme 9). Both mechanisms involve the formation of copper carbenoid
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with subsequent migration of Cu(I) counterion to carbon atom and protodecupration. The migration
of iodide, affording iodomethylbenzoxazole I-10I, requires the additional nucleophilic substitution
step.
8
9
The actual nature of copper catalyst in the system, containing excess of iodide, heterocyclic thiol,
and tertiary amine is not clear. The heating of 1 in the presence of Et3N and copper catalyst affords
a homogeneous solution. In contrast, formation of a yellow precipitate, attributed to copper thiolate,
was observed under our typical conditions. We attempted to model the reaction of
diazobenzoxazole I-4 and exemplary complexes of Cu(I) with Me3N (I-7).
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TS5S
32.9

I-4
X
X
= I
=
O
30.5
32.9
30.5
TS5I
G=
N
N2
N
X
S
N
NMe3
Cu
Me3N
X
Cu
O
N
X
I-7
TS6S
I-8
O
I-8S
2.5
I-10I I-10S
1.0
I-9I
-2.0
I-4
0.0
1.8
1.5
G=
0.5
TS6I
H+

SN2, X=I
-1.3
I-8I
Me3N
X
Cu
N
RS
N
O
N
Cu
S
I-9S
spont.
N
Me3N
O
O
I-9I
I-9S
-16.1
Scheme 9. Plausible mechanisms for the copper-catalyzed diazo trapping.
The copper-mediated extrusion of nitrogen proceeds with relatively high barrier (ΔG≠ c.a. 32
kcal/mol). The rearrangement of carbenoids I-8 to α-substituted organocopper I-9 is extremely
facile. The reaction is almost thermoneutral for X=I and exergonic for thiolate, due to an additional
stabilization of the product by chelation. The subsequent protonation should regenerate the catalyst
and yield α-substituted benzoxazole derivatives I-10.
The calculations show a subtle preference for the reaction to proceed via iodomethylbenzoxazole I-
10I. Both the formation of iodide 6 (Scheme 4) and the reaction of diazobenzoxazole with PhSCu
(Scheme 5) were observed. Nevertheless, we didn’t detect even traces of iodide 6 by HPLC in the
reaction of 1a with thiols under standard conditions. Observed formation of very stable copper
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thiolate suggests a low concentration of CuI in the reaction media. Thus, we believe that the
majority of the product is formed by direct migration of thiolate from copper to carbon.
CONCLUSION
8
9
In conclusion, we have elaborated an efficient protocol to assemble thiosubstituted benzoxazoles.
Our approach is based on employing readily available (5-iodotriazolyl)phenols 1 as convenient
precursors of diazobenzoxazoles 3. Cu-catalyzed trapping of diazo intermediates by a formal
insertion into SH bond furnished functionalized benzoxazoles in reasonable to high yields up to
91%. The procedure demonstrated very good functional group tolerance, and diverse heterocyclic
thiols were successfully involved in the developed cascade reaction. Our group is currently
exploring other useful annulation-triggered transformations of iodotriazoles.
EXPERIMENTAL SECTION
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General information
NMR spectra were recorded with Bruker Avance 400, Agilent 400MR (1H 400 MHz, 13C 100.6
MHz), and Bruker Avance 600 (1H 600 MHz, 13C 151 MHz) spectrometers at ambient temperature.
Chemical shifts are presented in ppm (δ scale) and referenced to hexamethyldisiloxane (δ = 0.05
1
13
ppm) or tetramethylsilane (δ = 0 ppm) in the H NMR spectra and to the solvent signal in the C
NMR spectra. MALDI-TOF spectra were recorded with a Bruker Daltonics UltraFlex instrument in
a dithranol or a cinnamic acid matrix using PEG 300, PEG 400 or PEG 600 as the internal standard.
ESI-TOF spectra were recorded with a Thermo Scientific Orbitrap Elite instrument. Elemental
analyses were performed with an Elementar Vario MICRO cube apparatus. Column
chromatography was carried out on Macherey–Nagel silica gel 60 (0.040–0.063 mm). Iodotriazoles
1a-g, 1i, 1m, and 1p were previously reported.23
DFT calculations were performed using ORCA 4.2.0 program package38 at B3LYP35/ma-SVP36
level of theory employing def2-ECP pseudopotential for iodine.42 Single point energies were
evaluated at the same level of theory within the framework of SMD model37 using dioxane as
solvent. RIJCOSX43 approximation was used to speed up the calculations. Thermodynamic
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properties were calculated for ideal gas at 298.15 K using QRRHO approach44 for vibrational
entropy correction. The nature of optimized intermediates and transition states was verified by
frequency analysis. IRC calculations were performed to verify the connectivity of the PES.
CYLView45 was used to visualize structure of the intermediates.
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General procedure A for preparation of 1-iodoalkynes (S1)46
A solution of MeONa was prepared from Na (101 mg, 4.40 mmol, 1.1 equiv) and MeOH (10 mL).
Terminal alkyne (4.00 mmol, 1 equiv) was added to the reaction mixture followed by addition of I2
(1.020 g, 4.02 mmol, 1.005 equiv) by portions (1–2 mol % of CuI was also added in specified
cases). After stirring at ambient temperature for 1–2 h, the reaction mixture was diluted with water
(50 mL) and a solution of Na2SO3 was added to remove an excess of iodine (discoloration
occurred). Then the product was extracted with CH2Cl2 (3 × 20 mL). Combined organic extracts
were dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was
used in the next step without further purification.
1-Iodo-5-methylhex-1-yne47 (S1a):
Prepared from 5-methylhex-1-yne (0.793 mL, 6.00 mmol) according to the general procedure A in
the presence of CuI (11.5 mg, 0.06 mmol, 1 mol %) using an excess of MeONa (18.0 mmol, 3
equiv). Yield 1.033 g (78 %). Yellowish liquid; 1H NMR (400 MHz, CDCl3) δ 2.37 (t, J = 7.5 Hz,
2H), 1.67 (nonet, J = 6.7 Hz, 1H), 1.41 (td, J = 7.5, 6.7 Hz, 2H), 0.89 (d, J = 6.7 Hz, 6H); 13C{1H}
NMR (100.6 MHz, CDCl3) δ 94.8 (Cquat), 37.3, 27.1, 22.1 (2C), 18.8, –7.8 (Cquat).
(Iodoethynyl)cyclohexane48 (S1b):
Prepared from ethynylcyclohexane (0.522 mL, 4.00 mmol) according to the general procedure A in
1
the presence of CuI (15.3 mg, 0.08 mmol, 2 mol %). Yield 491.5 mg (53 %). Yellowish oil; H
NMR (400 MHz, CDCl3) δ 2.47 (tt, J = 9.2, 3.7 Hz, 1H, CH), 1.77–1.58 (m, 4H), 1.49–1.32 (m,
3H), 1.30–1.16 (m, 3H).
(3-Iodoprop-2-yn-1-yl)cyclohexane (S1c):
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Prepared from prop-2-yn-1-ylcyclohexane (0.578 mL, 4.00 mmol) according to the general
procedure A in the presence of CuI (11.5 mg, 0.06 mmol, 1 mol %) using an excess of MeONa
(12.0 mmol, 3 equiv). Yield 969.8 mg (98 %). Yellowish liquid; 1H NMR (600 MHz, CDCl3) δ 2.25
(d, J = 6.7 Hz, 2H), 1.83–1.60 (m, 5H), 1.47 (ttt, J = 11.3, 6.7, 3.4 Hz, 1H), 1.30–1.18 (m, 2H), 1.13
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(qt, J = 12.4, 3.3 Hz, 1H), 1.04–0.91 (m, 2H); C{1H} NMR (151 MHz, CDCl3) δ 93.7 (Cquat),
37.2, 32.5 (2C), 28.5, 26.1, 26.0 (2C), –6.9 (Cquat); HRMS (MALDI-TOF, cinnamic acid) calcd for
C9H13INa [M+Na]+ 270.9954; found 270.9964.
(3-Iodoprop-2-yn-1-yl)benzene49 (S1d):
Prepared from (3-iodoprop-2-yn-1-yl)benzene (0.870 mL, 7.00 mmol) according to the general
procedure A in the presence of CuI (15.3 mg, 0.08 mmol, 2 mol %). Yield 1.315 g (78 %).
1
Yellowish oil; H NMR (600 MHz, CDCl3) δ 7.34–7.29 (m, 4H), 7.26–7.22 (m, 1H), 3.77 (s, 2H);
13C{1H} NMR (151 MHz, CDCl3) δ 135.9 (Cquat), 128.6 (2C), 127.8 (2C), 126.8, 91.9 (Cquat), 27.1,
–4.1 (Cquat).
Dimethyl (3-iodoprop-2-yn-1-yl)(methyl)malonate (S1e):
Prepared from dimethyl methyl(prop-2-yn-1-yl)malonate (276.3 mg, 1.50 mmol) according to the
1
general procedure A. The crude product contained 13 % of unreacted starting material (by H
NMR) and was used in the next step without further purification. Yield 330.1 mg (71 %). Yellowish
oil; H NMR (400 MHz, CDCl3) δ 3.73 (s, 6H), 2.95 (s, 2H), 1.53 (s, 3H); C{1H} NMR (100.6
MHz, CDCl3) δ 171.1 (2Cquat), 89.1 (Cquat), 71.3 (Cquat), 52.9 (2C), 28.1, 19.9, –3.0 (Cquat).
General procedure B for preparation of 2-(5-iodo-1H-1,2,3-triazol-1-yl)phenyl acetates (S2)
2-Azidophenyl acetate (2.00 mmol), 1-iodoalkyne S1 (2.20 mmol), CuI (19.1 mg, 0.100 mmol, 5
mol %), and tris[(1-tert-butyl-1H-1,2,3-triazol-4-yl)methyl]amine (TTTA) (42.8 mg, 0.100 mmol, 5
mol %) were mixed under an Ar atmosphere in THF (10 mL). The reaction mixture was stirred at
50 °C in an oil bath overnight or for several days (TLC control), then diluted with CH2Cl2 (50 mL),
washed with EDTA solution (50 mL) and water (50 mL). The organic layer was dried with
1
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anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was purified by column
4
5
chromatography.
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2-[5-Iodo-4-(3-methylbutyl)-1H-1,2,3-triazol-1-yl]phenyl acetate (S2h):
Prepared from 2-azidophenyl acetate (443 mg, 2.50 mmol) and S1a (666 mg, 3.00 mmol) according
to the general procedure B; eluent: hexanes–EtOAc = 4:1. Yield 793 mg (79 %). Off-white solid;
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1
mp 103–105 °C; H NMR (400 MHz, CDCl3) δ 7.62–7.55 (m, 1H), 7.47–7.37 (m, 3H), 2.80–2.71
(m, 2H), 2.06 (s, 3H), 1.71–1.58 (m, 3H), 0.98 (d, J = 6.2 Hz, 6H); C{1H} NMR (100.6 MHz,
13
CDCl3) δ 167.8 (Cquat), 152.2 (Cquat), 145.7 (Cquat), 131.4, 129.3 (Cquat), 128.6, 126.3, 123.9, 80.6
(Cquat), 37.9, 27.6, 24.1, 22.4 (2C), 20.5; HRMS (MALDI-TOF, dithranol) calcd for C15H19IN3O2
[M+H]+ 400.0516; found 400.0515.
2-(4-Cyclohexyl-5-iodo-1H-1,2,3-triazol-1-yl)phenyl acetate (S2j):
Prepared from 2-azidophenyl acetate (354.3 mg, 2.00 mmol) and S1b (491.5 mg, 2.10 mmol)
according to the general procedure B; eluent: hexanes–EtOAc = 6:1. Yield 442.0 mg (54 %). Light
1
yellow solid; mp 131–133 °C; H NMR (400 MHz, CDCl3) δ 7.61–7.56 (m, 1H), 7.48–7.37 (m,
3H), 2.71 (tt, J = 11.9, 3.5 Hz, 1H), 2.05 (s, 3H), 1.96–1.72 (m, 7H), 1.49–1.28 (m, 3H); C{1H}
13
NMR (100.6 MHz, CDCl3) δ 167.8 (Cquat), 155.7 (Cquat), 145.8 (Cquat), 131.4, 129.3 (Cquat), 128.7,
126.3, 123.9, 79.6 (Cquat), 36.1, 32.0 (2C), 26.4 (2C), 25.8, 20.6; HRMS (MALDI-TOF, dithranol)
calcd for C16H19IN3O2 [M+H]+ 412.0516; found 412.0513.
2-[4-(Cyclohexylmethyl)-5-iodo-1H-1,2,3-triazol-1-yl]phenyl acetate (S2k):
Prepared from 2-azidophenyl acetate (354.3 mg, 2.00 mmol) and S1c (570.4 mg, 2.30 mmol)
according to the general procedure B; eluent: hexanes–EtOAc = 4:1. Yield 522 mg (61 %). White
solid; mp 96–99 °C; 1H NMR (600 MHz, CDCl3) δ 7.58 (ddd, J = 8.2, 7.8, 1.9 Hz, 1H), 7.46 (ddd, J
= 7.8, 1.7, 0.4 Hz, 1H), 7.42 (td, J = 7.8, 1.4 Hz, 1H) , 7.40 (ddd, J = 8.2, 1.4, 0.4 Hz, 1H), 2.64 (d,
J = 7.1 Hz, 2H), 2.05 (s, 3H, 1.86–1.77 (m, 1H), 1.75–1.69 (m, 4H), 1.69–1.64 (m, 1H), 1.29–1.20
(m, 2H), 1.18 (qt, J = 12.3, 3.1 Hz, 1H), 1.10–1.02 (m, 2H); C{1H} NMR (151 MHz, CDCl3) δ
13
167.7 (Cquat), 151.0 (Cquat), 145.8 (Cquat), 131.4, 129.4 (Cquat), 128.7, 126.3, 123.8, 82.0 (Cquat), 38.2,
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33.5, 33.0, 26.3, 26.1 (2C), 20.5; HRMS (MALDI-TOF, dithranol) calcd for C17H21IN3O2 [M+H]+
426.0673; found 426.0675.
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2-(4-Benzyl-5-iodo-1H-1,2,3-triazol-1-yl)phenyl acetate (S2l):
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9
Prepared from 2-azidophenyl acetate (442.9 mg, 2.50 mmol) and S1d (665 mg, 2.75 mmol)
according to the general procedure B; eluent: hexanes–EtOAc = 3:1 and 2:1. Yield 662 mg (63 %).
White solid; mp 117–120 °C; 1H NMR (400 MHz, CDCl3) δ 7.60–7.55 (m, 1H), 7.47–7.37 (m, 3H),
7.35–7.27 (m, 4H), 7.25–7.19 (m, 1H), 4.14 (s, 2H), 1.97 (s, 3H); 13C{1H} NMR (100.6 MHz,
CDCl3) δ 167.7 (Cquat), 150.7 (Cquat), 145.7 (Cquat), 138.2 (Cquat), 131.5, 129.2 (Cquat), 128.6 (2C),
128.53, 128.47 (2C), 126.5, 126.3, 123.9, 81.7 (Cquat), 32.4, 20.5; HRMS (MALDI-TOF, dithranol)
calcd for C17H15IN3O2 [M+H]+ 420.0203; found 420.0204.
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2-[4-(Chloromethyl)-5-iodo-1H-1,2,3-triazol-1-yl]phenyl acetate (S2n'):
2-[4-(Hydroxymethyl)-5-iodo-1H-1,2,3-triazol-1-yl]phenyl acetate23 (1.616 g, 4.50 mmol) was
dissolved in a mixture of CH2Cl2 (25 mL) and Et3N (0.94 mL, 6.75 mmol, 1.5 equiv) under an Ar
atmosphere. Methanesulfonyl chloride (0.366 mL, 4.73 mmol, 1.05 equiv) was added to the
obtained solution dropwise under stirring at 0 °C. Then the reaction was left at ambient temperature
overnight. The obtained mixture was diluted with CH2Cl2 (75 mL) and washed with water (100
mL). Then the organic layer was dried with anhydrous Na2SO4, and the solvent was evaporated in
vacuo. The residue was purified by column chromatography (eluent: CH2Cl2–MeOH = 100:1).
Yield 1.027 g (60 %). Yellowish solid; mp 109–110 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (ddd, J
= 8.2, 6.8, 2.4 Hz, 1H), 7.47–7.39 (m, 3H), 4.74 (s, 2H), 2.06 (s, 3H); 13C{1H} NMR (100.6 MHz,
CDCl3) δ 167.7 (Cquat), 148.2 (Cquat), 145.7 (Cquat), 131.8, 128.9 (Cquat), 128.4 (Cquat), 126.4, 124.0,
83.3 (Cquat), 36.3, 20.5; HRMS (MALDI-TOF, dithranol) calcd for C11H10ClIN3O2 [M+H]+
377.9501; found 377.9508.
2-[4-(Azidomethyl)-5-iodo-1H-1,2,3-triazol-1-yl]phenyl acetate (S2n):
S2n' (489 mg, 1.30 mmol), NaN3 (338 mg, 5.20 mmol, 4 equiv), and 18-crown-6 (34.3 mg, 0.13
mmol, 10 mol %) were mixed in acetone (2.5 mL). The reaction mixture was stirred at ambient
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temperature overnight, then diluted with CH2Cl2 (30 mL), and washed with water (30 mL). The
organic layer was dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The
residue was purified by column chromatography (eluent: hexanes–EtOAc = 4:1). Yield 383 mg
(77 %). Yellowish solid; mp 99–101 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (ddd, J = 8.3, 6.1, 3.1
Hz, 1H), 7.46–7.40 (m, 3H), 4.50 (s, 2H), 2.07 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 167.8
(Cquat), 146.8 (Cquat), 145.7 (Cquat), 131.9, 128.9 (Cquat), 128.5, 126.4, 124.1, 83.1 (Cquat), 45.5, 20.5;
HRMS (MALDI-TOF, dithranol) calcd for C11H10IN6O2 [M+H]+ 384.9904; found 384.9918.
Dimethyl {[1-(2-acetoxyphenyl)-5-iodo-1H-1,2,3-triazol-4-yl]methyl}(methyl)malonate (S2o):
Prepared from 2-azidophenyl acetate (177.6 mg, 1.00 mmol) and S1e (324.1 mg, 1.12 mmol)
according to the general procedure B; eluent: hexanes–EtOAc = 2:1. Yield 388.9 mg (80 %). White
solid; mp 137–139 °C; 1H NMR (400 MHz, CDCl3) δ 7.61–7.54 (m, 1H), 7.44–7.35 (m, 3H), 3.77
(s, 6H), 3.37 (s, 2H), 2.07 (s, 3H), 1.51 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 171.7
(2Cquat), 167.9 (Cquat), 147.2 (Cquat), 145.9 (Cquat), 131.6, 129.4 (Cquat), 128.6, 126.3, 123.9, 83.9
(Cquat), 53.9 (Cquat), 52.8 (2C), 31.7, 20.4, 20.0; HRMS (MALDI-TOF, dithranol) calcd for
C17H19IN3O6 [M+H]+ 488.0313; found 488.0308.
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2-(4-Phenyl-5-iodo-1H-1,2,3-triazol-1-yl)phenyl acetate (S2q):
Prepared from 2-azidophenyl acetate (1.972 g, 11.1 mmol) and (iodoethynyl)benzene (2.748 g, 12.1
mmol) according to the general procedure B; eluent: CH2Cl2. Yield 3.467 g (77 %). Off-white solid;
1H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H), 7.60 (m, 1H), 7.51–7.38 (m, 6H), 2.07 (s, 3H);
13C{1H} NMR (100.6 MHz, CDCl3) δ 167.8 (Cquat), 149.6 (Cquat), 145.9 (Cquat), 131.7, 129.9 (Cquat),
129.2 (Cquat), 128.9, 128.7, 128.6 (2C), 127.5 (2C), 126.3, 124.0, 79.1 (Cquat), 20.7.
General procedure C for preparation of 2-(5-iodo-1H-1,2,3-triazol-1-yl)phenols (1)
K2CO3 (2.00 mmol, 2 equiv) was added to a solution of 2-(5-iodo-1H-1,2,3-triazol-1-yl)phenyl
acetate S2 (1.00 mmol) in MeOH (10 mL). The obtained suspension was stirred at ambient
temperature for 30 min (TLC control), then diluted with 10 % HCl (40 mL) and extracted with
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CH2Cl2 (3 × 25 mL). Combined organic extracts were dried with anhydrous Na2SO4, and the
solvents were evaporated in vacuo. The residue was purified by column chromatography.
2-[5-Iodo-4-(3-methylbutyl)-1H-1,2,3-triazol-1-yl]phenol (1h):
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Prepared from S2h (675 mg, 1.69 mmol) according to the general procedure C; eluent: CH2Cl2–
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MeOH = 30:1. Yield 543 mg (90 %). Light yellow solid; mp 170–172 °C (dec.); H NMR (600
MHz, CDCl3–CD3OD) δ 7.39 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H) 7.23 (dd, J = 7.9, 1.7 Hz, 1H), 7.06
(dd, J = 8.3, 1.2 Hz, 1H), 6.99 (ddd, J = 7.9, 7.5, 1.2 Hz, 1H), 4.07 (br s, 1H), 2.76–2.71 (m, 2H),
1.70–1.62 (m, 3H), 0.98 (d, J = 6.4 Hz, 6H); C{1H} NMR (151 MHz, CDCl3–CD3OD) δ 152.3
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(Cquat), 151.6 (Cquat), 131.6, 128.1, 124.1 (Cquat), 119.3, 116.7, 82.2 (Cquat), 37.7, 27.4, 23.9, 22.0
(2C); HRMS (MALDI-TOF, dithranol) calcd for C13H17IN3O [M+H]+ 358.0411; found 358.0412.
2-(4-Cyclohexyl-5-iodo-1H-1,2,3-triazol-1-yl)phenol (1j):
Prepared from S2j (428 mg, 1.04 mmol) according to the general procedure C; eluent: CH2Cl2–
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MeOH = 30:1. Yield 359.2 mg (94 %). White solid; mp 160–162 °C (dec.); H NMR (600 MHz,
CDCl3–CD3OD) δ 7.39 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.22 (dd, J = 7.9, 1.7 Hz, 1H), 7.05 (dd, J =
8.3, 1.2 Hz, 1H), 6.98 (ddd, J = 7.9, 7.5, 1.2 Hz, 1H), 4.35 (br s, 1H), 2.71 (tt, J = 12.1, 3.6 Hz, 1H),
1.98–1.86 (m, 4H), 1.80–1.69 (m, 3H), 1.43 (qt, J = 12.8, 3.2 Hz, 2H), 1.34 (qt, J = 12.7, 3.2 Hz,
1H); C{1H} NMR (151 MHz, CDCl3–CD3OD) δ 154.9 (Cquat), 152.3 (Cquat), 131.5, 128.1, 124.0
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(Cquat), 119.2, 116.6, 81.3 (Cquat), 35.9, 31.6 (2C), 26.1 (2C), 25.4; HRMS (MALDI-TOF, dithranol)
calcd for C14H17IN3O [M+H]+ 370.0411; found 370.0418.
2-[4-(Cyclohexylmethyl)-5-iodo-1H-1,2,3-triazol-1-yl]phenol (1k):
Prepared from S2k (511 mg, 1.20 mmol) according to the general procedure C; eluent: CH2Cl2–
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MeOH = 30:1. Yield 460 mg (100 %). White solid; mp 162–163 °C (dec.); H NMR (400 MHz,
CDCl3–CD3OD) δ 7.38 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.27 (dd, J = 7.9, 1.7 Hz, 1H), 7.08 (dd, J =
8.3, 1.1 Hz, 1H), 6.99 (ddd, J = 7.9, 7.5, 1.1 Hz, 1H), 2.71 (br s, 1H), 2.62 (d, J = 7.0 Hz, 2H),
1.84–1.61 (m, 6H), 1.31–0.98 (m, 5H); 13C{1H} NMR (100.6 MHz, CDCl3–CD3OD) δ 152.1
(Cquat), 150.9 (Cquat), 131.7, 128.1, 124.3 (Cquat), 119.7, 117.3, 83.0 (Cquat), 38.0, 33.6, 33.0 (2C),
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384.0565.
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2-(4-Benzyl-5-iodo-1H-1,2,3-triazol-1-yl)phenol (1l):
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Prepared from S2l (655.0 mg, 1.56 mmol) according to the general procedure C using a mixture of
MeOH (15 mL) and THF (4 mL) as a solvent; eluent: CH2Cl2–MeOH = 30:1. Yield 557 mg (95 %).
White solid; mp 166–169 °C; 1H NMR (600 MHz, CDCl3–CD3OD) δ 7.40–7.36 (m, 1H), 7.36–7.33
(m, 2H), 7.32–7.28 (m, 2H), 7.24–7.20 (m, 2H), 7.04 (dd, J = 8.2, 1.2 Hz, 1H), 6.97 (td, J = 7.6, 1.2
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Hz, 1H, 4.11 (s, 2H), 4.06 (br s, 1H); C{1H} NMR (151 MHz, CDCl3–CD3OD) δ 152.3 (Cquat),
150.1 (Cquat), 137.8 (Cquat), 131.7, 128.4 (2C), 128.2 (2C), 128.1, 126.3, 124.1 (Cquat), 119.3, 116.8,
83.2 (Cquat), 32.1; HRMS (MALDI-TOF, dithranol) calcd for C15H12IKN3O [M+K]+ 415.9657;
found 415.9655.
N-{[1-(2-Hydroxyphenyl)-5-iodo-1H-1,2,3-triazol-4-yl]methyl}acetamide (1n):
Azide S2n (421.3 mg, 1.10 mmol) and Ph3P (287.4 mg, 1.10 mmol, 1.0 equiv) were dissolved in
CH2Cl2 (10 mL) under an Ar atmosphere, and the obtained solution was stirred at ambient
temperature for 5 h. Then acetic anhydride (0.114 mL, 1.21 mmol, 1.1 equiv) was added dropwise.
After 2 h of stirring the reaction mixture was diluted with CH2Cl2 (20 mL) and washed with water
(30 mL). Then the organic layer was dried with anhydrous Na2SO4, and the solvent was evaporated
in vacuo. The residue was mixed with K2CO3 (151.4 mg, 1.10 mmol, 1.0 equiv) in MeOH (10 mL).
The obtained suspension was stirred at ambient temperature for 30 min (TLC control), then diluted
with 10 % HCl (40 mL) and extracted with CH2Cl2 (3 × 25 mL). Combined organic extracts were
dried with anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was purified
by column chromatography (eluent: CH2Cl2–MeOH = 10:1). Yield 336 mg (86 %). White solid; mp
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146–150 °C (dec.); H NMR (400 MHz, CDCl3–CD3OD) δ 7.41 (ddd, J = 8.3, 7.5, 1.6 Hz, 1H),
7.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.08 (dd, J = 8.3, 1.1 Hz, 1H), 6.99 (ddd, J = 7.9, 7.5, 1.1 Hz, 1H),
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(Cquat), 152.3 (Cquat), 147.7 (Cquat), 132.0, 128.1, 123.8 (Cquat), 119.6, 117.1, 83.2 (Cquat), 35.3, 22.3;
HRMS (MALDI-TOF, dithranol) calcd for C11H12IN4O2 [M+H]+ 358.9999; found 358.9995.
Dimethyl {[1-(2-hydroxyphenyl)-5-iodo-1H-1,2,3-triazol-4-yl]methyl}(methyl)malonate (1o):
Prepared from S2o (382.6 mg, 0.785 mmol) according to the general C procedure using a mixture
of MeOH (12 mL) and THF (4 mL) as a solvent; eluent: CH2Cl2–MeOH = 30:1. Yield 341 mg (98
%). White solid; mp 165–167 °C (dec.); 1H NMR (400 MHz, CDCl3–CD3OD) δ 7.40–7.34 (m, 1H),
7.22–7.17 (m, 1H), 7.04 (br d, J = 8.2 Hz, 1H), 6.97 (br t, J = 7.6 Hz, 1H), 3.78 (s, 6H), 3.35 (s,
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2H), 2.93 (br s, 1H), 1.52 (s, 3H); C{1H} NMR (100.6 MHz, CDCl3–CD3OD) δ 172.1 (2Cquat),
152.2, 146.8, 131.8, 128.2, 124.2 (Cquat), 119.7, 117.4, 85.1 (Cquat), 53.9 (Cquat), 52.8 (2C), 31.6,
19.9; HRMS (MALDI-TOF, dithranol) calcd for C15H17IN3O5 [M+H]+ 446.0207; found 446.0214.
2-(4-Phenyl-5-iodo-1H-1,2,3-triazol-1-yl)phenol (1q):
Prepared from S2q (3.271 g, 8.07 mmol) according to the general procedure C; eluent: CH2Cl2–
MeOH = 30:1. Yield 2.700 g (92 %). White solid; 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H),
7.98 (m, 2H), 7.53 (m, 2H), 7.48–7.41 (m, 2H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H), 7.12 (d, J = 8.3 Hz,
1H), 7.01 (m, 1H); 13C{1H} NMR (100.6 MHz, DMSO-d6) δ 152.9 (Cquat), 148.0 (Cquat), 131.9,
130.5 (Cquat), 128.9, 128.7 (2C), 128.3, 126.8 (2C), 124.4 (Cquat), 119.2, 116.8, 85.0 (Cquat); HRMS
(MALDI-TOF, dithranol) calcd for C14H11IN3O [M+H]+ 363.9941; found 363.9924; Anal. calcd for
C14H10N3O: C, 46.30; H, 2.78; N, 11.57; found C, 46.34; H, 3.01; N, 11.35.
General procedure D for preparation of 2-(1-thioalkyl)-1,3-benzoxazoles (2)
In a vial with a screw cap iodotriazole 1 (0.20 mmol), thiol (0.40 mmol, 2 equiv), Cu(Ph3P)3Br
(18.6 mg, 0.020 mmol, 10 mol %), and Et3N (55.8 µL, 0.40 mmol, 2 equiv) were mixed under an
Ar atmosphere in dioxane (2 mL). The reaction mixture was stirred at 100 °C in a dry block for
16 h, then diluted with CH2Cl2 (20 mL), washed with saturated solution of Na2CO3 (20 mL) and
water (20 mL). The organic layer was dried with anhydrous Na2SO4, and the solvents were
evaporated in vacuo. The residue was purified by column chromatography.
2-[1-(1,3-Benzothiazol-2-ylthio)pentyl]-1,3-benzoxazole (2a):
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Brownish oil; H NMR (400 MHz, CDCl3) δ 7.87 (br d, J = 8.2 Hz, 1H), 7.73 (br d, J = 8.2 Hz,
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Hz, 1H), 2.42–2.21 (m, 2H), 1.64–1.34 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H); C{1H} NMR (100.6
MHz, CDCl3) δ 165.1 (Cquat), 163.9 (Cquat), 153.0, 150.8 (Cquat), 141.0 (Cquat), 135.7 (Cquat), 126.1,
125.2, 124.6, 124.4, 122.0, 121.0, 120.2, 110.7, 45.1, 33.4, 29.2, 22.2, 13.8; HRMS (MALDI-TOF,
dithranol) calcd for C19H19N2OS2 [M+H]+ 355.0933; found 355.0936.
2-{[1-(1,3-Benzoxazol-2-yl)pentyl]thio}-1,3-benzoxazole (2b):
Prepared from 1a (85.8 mg, 0.25 mmol) and 1,3-benzoxazole-2-thiol (75.6 mg, 0.5 mmol)
according to the general procedure D; eluent: CH2Cl2. Yield 62.7 mg (74 %). The reaction
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performed on a 1.2 mmol of 1a afforded 268 mg (66%) of 2b.Yellow oil; H NMR (400 MHz,
CDCl3) δ 7.73–7.67 (m, 1H), 7.63–7.58 (m, 1H), 7.52–7.46 (m, 1H), 7.43–7.38 (m, 1H), 7.34–7.19
(m, 4H), 5.33 (t, J = 7.5 Hz, 1H), 2.43–2.22 (m, 2H), 1.61–1.34 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100.6 MHz, CDCl3) δ 164.8 (Cquat), 162.6 (Cquat), 151.9 (Cquat), 150.7 (Cquat), 141.7
(Cquat), 140.9 (Cquat), 125.3, 124.5, 124.3, 124.1, 120.2, 118.8, 110.7, 110.0, 44.3, 33.3, 29.1, 22.1,
13.8; HRMS (MALDI-TOF, dithranol) calcd for C19H19N2O2S [M+H]+ 339.1162; found 339.1167.
2-[1-(1H-Benzimidazol-2-ylthio)pentyl]-1,3-benzoxazole (2c):
Prepared from 1a (85.8 mg, 0.25 mmol) and 1H-benzimidazole-2-thiol (75.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 70.5 mg (84 %). Yellow
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solid; mp 86–88 °C; H NMR (400 MHz, CDCl3) δ 12.04 (br s, 1H, NH), 7.70–7.64 (m, 1H), 7.51
(br s, 2H), 7.46–7.41 (m, 1H), 7.33–7.25 (m, 2H), 7.19–7.13 (m, 2H), 4.93 (t, J = 7.6 Hz, 1H),
2.33–2.08 (m, 2H), 1.54–1.17 (m, 4H), 0.80 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100.6 MHz,
CDCl3) δ 166.7 (Cquat), 150.4 (Cquat), 147.3 (Cquat), 140.4 (Cquat), 125.4, 124.7, 122.4 (2C), 119.8,
110.8, 44.1, 32.8, 29.3, 22.0, 13.7, 2 signals of benzimidazole ring were not observed due to
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broadness; HRMS (MALDI-TOF, dithranol) calcd for C19H20N3OS [M+H]+ 338,1322; found
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Prepared from 1a (85.8 mg, 0.25 mmol) and 5-methyl-1,3,4-oxadiazole-2-thiol (58.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 62.0 mg (82 %).
Yellowish oil; 1H NMR (400 MHz, CDCl3) δ 7.73–7.66 (m, 1H), 7.54–7.47 (m, 1H), 7.38–7.28 (m,
2H), 5.03 (t, J = 7.5 Hz, 1H), 2.46 (s, 3H), 2.40–2.17 (m, 2H), 1.59–1.31 (m, 4H), 0.88 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 165.3 (Cquat), 164.2 (Cquat), 161.9 (Cquat), 150.7
(Cquat), 140.8 (Cquat), 125.4, 124.5, 120.2, 110.7, 44.7, 33.1, 29.1, 22.0, 13.7, 11.0; HRMS (MALDI-
TOF, dithranol) calcd for C15H18N3O2S [M+H]+ 304.1114; found 304.1122.
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2-{1-[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]pentyl}-1,3-benzoxazole (2e):
Prepared from 1a (85.8 mg, 0.25 mmol) and 5-methyl-1,3,4-thiadiazole-2-thiol (66.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 56.2 mg (70 %). Yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.72–7.66 (m, 1H), 7.53–7.46 (m, 1H), 7.36–7.28 (m, 2H), 5.15
(dd, J = 8.0, 7.0 Hz, 1H), 2.69 (s, 3H), 2.37–2.16 (m, 2H), 1.59–1.31 (m, 4H), 0.88 (t, J = 7.1 Hz,
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3H); C{1H} NMR (100.6 MHz, CDCl3) δ 166.4 (Cquat), 164.7 (Cquat), 162.3 (Cquat), 150.7 (Cquat),
140.8 (Cquat), 125.3, 124.5, 120.1, 110.7, 45.7, 33.1, 29.1, 22.1, 15.6, 13.7; HRMS (MALDI-TOF,
dithranol) calcd for C15H18N3OS2 [M+H]+ 320.0886; found 320.0895; Anal. calcd for C15H17N3OS2:
C, 56.40; H, 5.36; N, 13.15; S, 20.07; found C, 56.63; H, 5.56; N, 12.90; S, 19.78.
5-{[1-(1,3-Benzoxazol-2-yl)pentyl]thio}-1,3,4-thiadiazol-2-amine (2f):
Prepared from 1a (85.8 mg, 0.25 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (66.6 mg, 0.5 mmol)
according to the general procedure D; eluent: CH2Cl2–MeOH = 20:1. Yield 49.4 mg (62 %). Off-
white solid; mp 126–128 °C; 1H NMR (400 MHz, CDCl3) δ 7.67–7.60 (m, 1H), 7.52–7.45 (m, 1H),
7.34–7.26 (m, 2H), 6.36 (br s, 2H), 4.64 (dd, J = 8.3, 7.0 Hz, 1H), 2.30–2.07 (m, 2H), 1.54–1.27 (m,
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4H), 0.86 (t, J = 7.1 Hz, 3H); C{1H} NMR (100.6 MHz, CDCl3) δ 171.3 (Cquat), 164.8 (Cquat),
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150.6 (Cquat), 149.2 (Cquat), 140.6 (Cquat), 125.3, 124.5, 120.0, 110.7, 46.9, 32.5, 29.2, 22.1, 13.7;
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HRMS (ESI) calcd for C14H17N4OS2 [M+H]+ 321.0828; found 321.0833.
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2-[1-(4,5-Dihydro-1,3-thiazol-2-ylthio)pentyl]-1,3-benzoxazole (2g):
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Prepared from 1a (85.8 mg, 0.25 mmol) and 4,5-dihydro-1,3-thiazole-2-thiol (59.6 mg, 0.5 mmol)
according to the general procedure D; eluents: hexanes–EtOAc = 20:1 and 10:1. Yield 43.0 mg
(56 %). Yellowish oil; 1H NMR (600 MHz, CDCl3) δ 7.72–7.68 (m, 1H), 7.52–7.48 (m, 1H), 7.34–
7.28 (m, 2H), 5.21 (t, J = 7.7 Hz, 1H), 4.21 (dt, J = 14.7, 7.9 Hz, 1H), 4.18 (dt, J = 14.7, 7.9 Hz, 1H,
CH2S), 3.38 (dt, J = 10.6, 7.9 Hz, 1H), 3.36 (dt, J = 10.6, 7.9 Hz, 1H), 2.27–2.19 (m, 1H), 2.16–
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2.09 (m, 1H), 1.51–1.31 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); C{1H} NMR (151 MHz, CDCl3) δ
165.5 (Cquat), 163.4 (Cquat), 150.7 (Cquat), 141.1 (Cquat), 125.0, 124.3, 120.1, 110.7, 64.1, 43.8, 35.8
(CH2N), 33.4, 29.2, 22.1, 13.8; HRMS (MALDI-TOF, dithranol) calcd for C15H19N2OS2 [M+H]+
307.0933; found 307.0939; Anal. calcd for C15H18N2OS2: C, 58.79; H, 5.92; N, 9.14; S, 20.92;
found C, 58.78; H, 5.94; N, 8.82; S, 20.63.
2-{1-[(1-Methyl-1H-imidazol-2-yl)thio]pentyl}-1,3-benzoxazole (2h):
Prepared from 1a (85.8 mg, 0.25 mmol) and 1-methyl-1H-imidazole-2-thiol (57.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 1:1. Yield 54.1 mg (72 %). White
solid; mp 126–128 °C; 1H NMR (400 MHz, CDCl3) δ 7.68–7.62 (m, 1H), 7.49–7.43 (m, 1H), 7.34–
7.27 (m, 2H), 7.09 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 4.54 (dd, J = 8.6, 6.7 Hz, 1H), 3.31
(s, 3H), 2.31–2.10 (m, 2H), 1.56–1.30 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100.6
MHz, CDCl3) δ 165.7 (Cquat), 150.5 (Cquat), 140.9 (Cquat), 138.0 (Cquat), 130.2, 125.1, 124.4, 123.1,
119.9, 110.5, 46.7, 33.2, 32.4, 29.3, 22.1, 13.7; HRMS (ESI) calcd for C16H20N3OS [M+H]+
302.1322; found 302.1309; Anal. calcd for C16H19N3OS: C, 63.76; H, 6.35; N, 13.94; S, 10.64;
found C, 63.50; H, 6.49; N, 13.73; S, 10.33.
2-{1-[(1-Methyl-1H-tetrazol-5-yl)thio]pentyl}-1,3-benzoxazole (2i):
Prepared from 1a (85.8 mg, 0.25 mmol) and 1-methyl-1H-tetrazole-5-thiol (58.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 43.5 mg (57 %). Yellow
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oil; 1H NMR (400 MHz, CDCl3) δ 7.72–7.65 (m, 1H), 7.53–7.46 (m, 1H), 7.38–7.29 (m, 2H), 5.16
(t, J = 7.4 Hz, 1H), 3.85 (s, 3H), 2.41–2.21 (m, 2H), 1.60–1.32 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100.6 MHz, CDCl3) δ 164.1 (Cquat), 152.0 (Cquat), 150.6 (Cquat), 140.7 (Cquat), 125.6,
124.7, 120.2, 110.7, 45.8, 33.6, 33.2, 29.0, 22.1, 13.7; HRMS (MALDI-TOF, dithranol) calcd for
C14H18N5OS [M+H]+ 304.1227; found 304.1225.
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2-(1-{[4-(4-Methoxyphenyl)-5-(4-nitrophenyl)-4H-1,2,4-triazol-3-yl]thio}pentyl)-1,3-benzo-
xazole (2j):
Prepared from 1a (68.6 mg, 0.2 mmol) and 4-(4-methoxyphenyl)-5-(4-nitrophenyl)-4H-1,2,4-
triazole-3-thiol (131.3 mg, 0.4 mmol) according to the general procedure D; eluent: CH2Cl2–
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MeOH–Et3N = 200:2:1. Yield 94 mg (91 %). Brown solid; mp 157–159 °C; H NMR (600 MHz,
CDCl3) δ 8.14–8.09 (m, 2H, 3,5-CH(C6H4NO2)], 7.69–7.64 (m, 1H), 7.64–7.60 (m, 2H), 7.49–7.45
(m, 1H), 7.35–7.29 (m, 2H), 7.03 (br d, J = 8.3 Hz, 2H), 6.87 (br d, J = 8.3 Hz, 2H), 5.14 (dd, J =
8.1, 6.7 Hz, 1H), 3.83 (s, 3H), 2.35–2.21 (m, 2H), 1.55–1.33 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ 164.8 (Cquat), 160.7 (Cquat), 153.2 (Cquat), 152.4 (Cquat), 150.6
(Cquat), 148.1 (Cquat), 140.9 (Cquat), 132.5 (Cquat), 128.5 (2C), 128.3 (2C), 125.6 (Cquat), 125.2, 124.4,
123.6 (2C), 120.0, 115.2 (2C), 110.6, 55.5, 45.0, 33.3, 29.1, 22.0, 13.7; HRMS (MALDI-TOF,
dithranol) calcd for C27H26N5O4S [M+H]+ 516.1700; found 516.1704.
2-(1-{[5-(4-Nitrophenyl)-4-(tetrahydrofuran-2-ylmethyl)-4H-1,2,4-triazol-3-yl]thio}pentyl)-
1,3-benzoxazole (2k):
Prepared from 1a (68.6 mg, 0.2 mmol) and 5-(4-nitrophenyl)-4-(tetrahydrofuran-2-ylmethyl)-4H-
1,2,4-triazole-3-thiol (122.5 mg, 0.4 mmol) according to the general procedure D; eluents: hexanes–
EtOAc = 2:1 and 1:1. Equimolar mixture of diastereomers. Yield 81.7 mg (83 %). Off-white solid;
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mp 151–154 °C; H NMR (400 MHz, CDCl3) δ 8.30 (br d, J = 8.3 Hz, 2H), 7.86–7.78 (m, 2H),
7.73–7.67 (m, 1H), 7.53–7.47 (m, 1H), 7.39–7.32 (m, 2H), 5.16–5.05 (m, 1H), 4.04–3.79 (m, 3H),
3.65–3.50 (m, 2H), 2.45–2.26 (m, 2H), 2.00–1.68 (m, 3H), 1.63–1.30 (m, 5H), 0.95–0.87 (m, 3H);
13C{1H} NMR (100.6 MHz, CDCl3) δ 164.9 (2Cquat), 154.4 (Cquat), 154.3 (Cquat), 150.4 (2Cquat),
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150.3 (Cquat), 150.2 (Cquat), 148.3 (2Cquat), 140.7 (2Cquat), 133.71 (Cquat), 133.68 (Cquat), 129.9 (2C),
129.8 (2C), 125.3 (2C), 124.5 (2C), 123.69 (2C), 123.67 (2C), 120.0 (2C), 110.6 (2C), 76.9, 76.8,
67.90, 67.86, 48.62, 48.61, 46.2 (2C), 33.14, 33.10, 29.13, 29.11, 28.94, 28.91, 25.3 (2C), 22.0
(2C), 13.7 (2C); HRMS (MALDI-TOF, dithranol) calcd for C25H28N5O4S [M+H]+ 494.1857; found
494.1860.
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2-[1-(Pyridin-2-ylthio)pentyl]-1,3-benzoxazole (2l):
Prepared from 1a (85.8 mg, 0.25 mmol) and pyridine-2-thiol (55.6 mg, 0.5 mmol) according to the
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general procedure D; eluent: hexanes–EtOAc = 10:1. Yield 37.0 mg (50 %). Brown oil; H NMR
(400 MHz, CDCl3) δ 8.41 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.69–7.64 (m, 1H), 7.49–7.41 (m, 2H),
7.31–7.24 (m, 2H), 7.18 (dt, J = 8.1, 1.0 Hz, 1H), 6.96 (ddd, J = 7.4, 5.0, 1.0 Hz, 1H), 5.43 (dd, J =
8.1, 7.1 Hz, 1H), 2.33–2.22 (m, 1H), 2.20–2.10 (m, 1H), 1.57–1.31 (m, 4H), 0.86 (t, J = 7.1 Hz,
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3H); C{1H} NMR (100.6 MHz, CDCl3) δ 166.8 (Cquat), 156.9 (Cquat), 150.7 (Cquat), 149.5, 141.2
(Cquat), 136.2, 124.8, 124.2, 122.4, 120.0 (2C), 110.6, 41.1, 33.4, 29.3, 22.2, 13.8; HRMS (MALDI-
TOF, dithranol) calcd for C17H19N2OS [M+H]+ 299.1213; found 299.1222.
3-{[1-(1,3-Benzoxazol-2-yl)pentyl]thio}-5H-[1,2,4]triazino[5,6-b]indole (2n):
Prepared from 1a (34.3 mg, 0.1 mmol) and 5H-[1,2,4]triazino[5,6-b]indole-3-thiol (40.4 mg, 0.2
mmol) according to the general procedure D. Yield 16.5 mg (42 %). Yellowish solid; mp 224–
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226 °C; H NMR (400 MHz, CDCl3–CD3OD) δ 8.34 (br d, J = 7.8 Hz, 1H), 7.69–7.64 (m, 1H),
7.62–7.57 (m, 1H), 7.55–7.50 (m, 1H), 7.47 (br d, J = 8.1 Hz, 1H), 7.40–7.35 (m, 1H, 7- or 8-
CH(Ar)], 7.35–7.29 (m, 2H), 5.46 (dd, J = 8.4, 7.3 Hz, 1H), 2.40–2.20 (m, 2H), 1.64–1.36 (m, 4H),
0.91 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3–CD3OD) δ 166.4 (Cquat), 166.2 (Cquat),
150.6 (Cquat), 146.9 (Cquat), 141.4 (Cquat), 140.3 (Cquat), 139.9 (Cquat), 130.8, 125.2, 124.5, 122.7,
122.2, 119.5, 118.1 (Cquat), 112.2, 110.8, 42.0, 32.6, 29.4, 22.1, 13.7; HRMS (MALDI-TOF,
dithranol) calcd for C21H20N5OS [M+H]+ 390.1383; found 390.1388.
2-{1-[(4-Bromophenyl)thio]pentyl}-1,3-benzoxazole (2o):
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In a vial with a screw cap 1a (34.3 mg, 0.1 mmol), Cu(Ph3P)3Br (9.3 mg, 0.010 mmol, 10 mol %),
and Et3N (27.8 µL, 0.20 mmol, 2 equiv) were mixed under an Ar atmosphere in dioxane (2 mL).
The reaction mixture was stirred at 90 °C for 2 h. After cooling to ambient temperature, 4-
bromothiophenol (37.8 mg, 0.2 mmol, 2 equiv) was added to the reaction mixture and the heating
was continued at 90 °C for 16 h. The product was extracted with CH2Cl2 (20 mL), washed with
saturated solution of Na2CO3 (20 mL) and water (20 mL). The organic layer was dried with
anhydrous Na2SO4, and the solvents were evaporated in vacuo. The residue was purified by column
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chromatography (eluent: hexanes–EtOAc = 15:1). Yield 11.5 mg (31 %). Yellowish oil; H NMR
(400 MHz, CDCl3) δ 7.67–7.62 (m, 1H), 7.51–7.46 (m, 1H), 7.36–7.27 (m, 4H), 7.21–7.17 (m, 2H),
4.34 (dd, J = 8.4, 7.0 Hz, 1H), 2.23–2.12 (m, 1H), 2.09–1.99 (m, 1H), 1.55–1.29 (m, 4H), 0.87 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 165.8 (Cquat), 150.6 (Cquat), 140.8 (Cquat),
134.5 (2C), 132.05 (2C), 132.00 (Cquat), 125.1, 124.4, 122.4 (Cquat), 120.0, 110.6, 46.4, 32.5, 29.4,
22.2, 13.8; HRMS (MALDI-TOF, dithranol) calcd for C18H19BrNOS [M+H]+ 376.0365; found
376.0362.
2-[1-(Phenylthio)pentyl]-1,3-benzoxazole (2p):
Prepared from 1a (68.6 mg, 0.2 mmol) and copper(I) thiophenolate (51.8 mg, 0.3 mmol) according
to the general procedure D without addition of the copper catalyst; eluent: hexanes–EtOAc = 15:1.
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Yield 43 mg (72 %). Yellowish oil; H NMR (600 MHz, CDCl3) δ 7.67–7.64 (m, 1H), 7.51–7.47
(m, 1H), 7.38–7.34 (m, 2H), 7.33–7.27 (m, 2H), 7.24–7.20 (m, 3H), 4.38 (dd, J = 8.5, 6.8 Hz, 1H),
2.24–2.17 (m, 1H), 2.11–2.04 (m, 1H), 1.55–1.47 (m, 1H), 1.43–1.32 (m, 3H), 0.88 (t, J = 7.2 Hz,
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3H); C{1H} NMR (151 MHz, CDCl3) δ 166.1 (Cquat), 150.7 (Cquat), 140.9 (Cquat), 132.98 (Cquat),
132.96 (2C), 128.9 (2C), 128.0, 124.9, 124.2, 120.0, 110.5, 46.5, 32.7, 29.5, 22.2, 13.8; HRMS
(MALDI-TOF, dithranol) calcd for C18H20NOS [M+H]+ 298.1260; found 298.1261.
5-Methyl-2-{1-[(5-methyl-1,3,4-oxadiazol-2-yl)thio]pentyl}-1,3-benzoxazole (2q):
Prepared from 1b (89.3 mg, 0.25 mmol) and 5-methyl-1,3,4-oxadiazole-2-thiol (58.1 mg, 0.5 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 54.8 mg (69 %). Brown
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oil; 1H NMR (400 MHz, CDCl3) δ 7.50–7.47 (m, 1H), 7.38 [d, J = 8.4 Hz, 1H), 7.18–7.13 (m, 1H),
5.02 (dd, J = 8.1, 6.9 Hz, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.40–2.18 (m, 2H), 1.58–1.33 (m, 4H),
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13.7, 11.0; HRMS (MALDI-TOF, dithranol) calcd for C16H20N3O2S [M+H]+ 318.1271; found
318.1277.
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Methyl 2-{1-[(5-methyl-1,3,4-oxadiazol-2-yl)thio]pentyl}-1,3-benzoxazole-5-carboxylate (2r):
Prepared from 1c (80.2 mg, 0.2 mmol) and 5-methyl-1,3,4-oxadiazole-2-thiol (46.5 mg, 0.4 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 3:1. Yield 47 mg (65 %). Red oil;
1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 1.7 Hz, 1H), 8.09 (dd, J = 8.6, 1.7 Hz, 1H), 7.55 (d, J =
8.6 Hz, 1H), 5.03 (dd, J = 8.0, 7.0 Hz, 1H), 3.94 (s, 3H), 2.47 (s, 3H), 2.39–2.17 (m, 2H), 1.59–1.33
(m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 166.4 (Cquat), 165.7 (Cquat),
165.4 (Cquat), 161.7 (Cquat), 153.5 (Cquat), 140.9 (Cquat), 127.3, 127.1 (Cquat), 122.2, 110.6, 52.3, 44.6,
32.9, 29.1, 22.0, 13.7, 11.0; HRMS (MALDI-TOF, dithranol) calcd for C17H19KN3O4S [M+K]+
400.0728; found 400.0724.
5-Chloro-2-{1-[(5-methyl-1,3,4-oxadiazol-2-yl)thio]pentyl}-1,3-benzoxazole (2s):
Prepared from 1d (75.5 mg, 0.2 mmol) and 5-methyl-1,3,4-oxadiazole-2-thiol (46.5 mg, 0.4 mmol)
according to the general procedure D; eluent: hexanes–EtOAc = 4:1. Yield 51 mg (75 %).
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Yellowish oil; H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H),
7.31 (dd, J = 8.6, 1.9 Hz, 1H), 5.01 (t, J = 7.5 Hz, 1H), 2.47 (s, 3H), 2.37–2.15 (m, 2H), 1.57–1.32
(m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 165.8 (Cquat), 165.4 (Cquat),
161.8 (Cquat), 149.2 (Cquat), 141.9 (Cquat), 130.1, 125.8, 120.2, 111.5, 44.5, 32.9, 29.0, 22.0, 13.7,
11.0; HRMS (MALDI-TOF, dithranol) calcd for C15H16ClN3O2SNa [M+Na]+ 360.0544; found
360.0537.
5-Iodo-2-{1-[(5-methyl-1,3,4-oxadiazol-2-yl)thio]pentyl}-1,3-benzoxazole (2t):
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