One-Pot Copper-Catalyzed Cascade Bicyclization Strategy for Synthesis of 2-(1H-Indol-1-yl)-4,5-dihydrothiazoles and 2-(1H-Indol-1-yl)thiazol-5-yl Aryl Ketones with Molecular Oxygen as an Oxygen Source

Article abstract of DOI:10.1002/adsc.201801193

An atom-economical method for synthesizing N-heterocyclic indoles from readily available o-alkynylphenyl isothiocyanates and propargylamine derivatives is reported. This method involves a copper-catalyzed cascade bicyclization process consisting of an int

Full text of DOI:10.1002/adsc.201801193

Title: One-Pot Copper-Catalyzed Cascade Bicyclization Strategy for
Synthesis of 2-(1H-Indol-1-yl)-4,5-dihydrothiazoles and 2-(1H-
Indol-1-yl)thiazol-5-yl Aryl Ketones with Molecular Oxygen as an
Oxygen Source
Authors: Jialin Xie, Zhonglin Guo, Yuanqiong Huang, yi qu, Hongjian
Song, Haibin Song, Yuxiu Liu, and Qing-Min Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801193
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10.1002/adsc.201801193
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One-Pot Copper-Catalyzed Cascade Bicyclization Strategy for
Synthesis of 2-(1H-Indol-1-yl)-4,5-dihydrothiazoles and 2-(1H-
Indol-1-yl)thiazol-5-yl Aryl Ketones with Molecular Oxygen as
an Oxygen Source
Jialin Xie,[a] Zhonglin Guo,[a] Yuanqiong Huang,[a] Yi Qu,[a] Hongjian Song,[a], * Haibin
Song,[a] Yuxiu Liu[a] and Qingmin Wang[a],[b],
*
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of
China
b
E-mail: songhongjian@nankai.edu.cn; wangqm@nankai.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An atom-economical method for synthesizing N-
heterocyclic indoles from readily available o-alkynylphenyl
isothiocyanates and propargylamine derivatives is reported.
This method involves
a
copper-catalyzed cascade
bicyclization process consisting of an intramolecular 5-exo-
dig hydrothiolation reaction and an intramolecular
hydroamination reaction and, depending on whether or not
molecular oxygen is present, selectively affords Z-isomers
of 2-(1H-indol-1-yl)-4,5-dihydrothiazoles or 2-(1H-indol-1-
yl)thiazol-5-yl aryl ketones in satisfactory yields.
Mechanistic studies indicate that molecular oxygen acts as
the oxygen source for the ketone moiety in the products.
Figure 1. Biologically active compounds with indole and
thiazoline caffolds.
Keywords: Biologically Active; Copper; Cyclization;
Heterocyclic Indoles; Oxygen
Various
heterocycles
nitrogen-
have
and
been
sulfur-containing
synthesized from
The majority (59%) of small-molecule drugs have
nitrogen-containing heterocyclic scaffolds.[1] Indoles
in particular are commonly found in biologically
active molecules (Figure 1) and advanced materials
and have thus attracted considerable research
attention.[2] Since the classical Fischer indole
synthesis was reported,[3] the number of methods for
synthesizing functionalized indoles has burgeoned,[4]
and the most common methods include metal-
catalyzed cyclization reactions[5] and transition-metal-
catalyzed C–H bond activation reactions.[6] However,
despite these advances, there are only a few methods
for the construction of N-heterocyclic indoles; the
most commonly used methods involve coupling
reactions, such as the Buchwald–Hartwig amination
and Ullman-type coupling reactions, between indoles
and prefunctionalized heterocycles.[7] Except for the
coupling reaction, there are few practical methods for
building compounds with 2-(1H-indol-1-yl)-4,5-
dihydrothiazole and 2-(1H-indol-1-yl)thiazol-5-yl
aryl ketone skeletons from readily available
precursors.[8]
isothiocyanate substrates.[9] In particular, o-
alkynylphenyl isothiocyanates have been used to
construct fused-ring compounds via cascade
reactions,[10] which show higher overall efficiency
than traditional stepwise syntheses because multiple
C–C and C–X bonds can be formed in one pot.[11] For
example, in 2014, Cai et al. reported the formation of
5H-benzo[d]imidazo[5,1-b][1,3]thiazines by means
of copper-catalyzed [3+2] cascade cycloaddition
reactions between o-alkynylphenyl isothiocyanates
and isocyanides (Scheme 1a).[10c] Copper, which is
abundant in nature, has a wide range of valence states
and shows good affinity for molecular oxygen,[12] an
environmentally friendly oxygen source for organic
synthesis, although its activation remains a challenge.
Therefore, copper-promoted syntheses of organic
compounds under aerobic conditions have been the
subject of extensive research.[13] In particular, much
effort has been devoted to aerobic copper-promoted
bifunctionalization of alkynes to form carbonyl
compounds.[14] To our knowledge, all the reported
examples of such reactions have involved
aminooxygenation[14a–14e] and bioxygenation[14f–14h]
1
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10.1002/adsc.201801193
Advanced Synthesis & Catalysis
processes (Scheme 1b), and there are no examples of
alkyne bifunctionalization by means of aerobic
copper-catalyzed thiooxygenation.[15] One of the
limiting factors may be catalyst poisoning by sulfur
species.[16]
conditions: 1 (0.2 mmol), 2 (0.3 mmol), CuI (15 mol %),
DCE:CH3CN (9:1, 2 mL), under Ar, 80 °C, 10 h.
We began by investigating the reactions of o-
alkynylphenyl isothiocyanates
1 and propargyl
amines 2 (Scheme 2). Treatment of o-1a (0.3 mmol)
with 2a (0.45 mmol) in the presence of CuI (15
mol %) in CH3CN (3 mL) at 80 °C for 6 h under Ar
afforded the desired product, 2-(1H-indol-1-yl)-4,5-
dihydrothiazole 3aa, in 85% yield (for detailed
optimization studies, see Supporting Information [SI],
Table S1). Subsequently, we investigated the
substrate scope of the reaction to afford various 2-
(1H-indol-1-yl)-4,5-dihydrothiazoles 3. First, we
explored the effect of substituents R1 and R2 on 1 and
found that substrates 1a–1n, and 1p reacted with 2a
to afford the target products in good to excellent
yields. Neither the electronic properties of R1 nor its
position (para or meta) markedly affected the yields
of products 3aa–3ga.[18] The structure of 3ca was
confirmed by single-crystal X-ray analysis (see SI,
Table S3).[19] In addition, when R1 was H and R2 was
an aryl group, the target products (3ha–3na) were
obtained in satisfactory yields regardless of the
electronic properties of the substituent on the aryl
group. In addition, R2 could be H or cyclopropyl, but
the yield of 3oa obtained from the former substrate
was relatively low (17%). The reason for the low yield
of the product may be that Glaser coupling happened to
the terminal alkyne substrate in the presence of
amine.[20] We also investigated other aliphatic R2
groups, such as t-Bu and trimethylsilyl, but the
desired products were obtained in only trace amounts.
Scheme 1. One-pot, de novo synthesis of 2-(1H-indol-1-
yl)-4,5-dihydrothiazoles and 2-(1H-indol-1-yl)thiazol-5-yl
aryl ketones.
Inspired by the research described above, we
herein report that we have achieved the first copper-
catalyzed cascade bicyclization reactions between o-
alkynylphenyl isothiocyanates and propargylamine
derivatives (Scheme 1c), despite the fact that amines
are unstable to oxidants.[17] Unlike previously
reported reactions of similar substrates, these
reactions
afforded
2-(1H-indol-1-yl)-4,5-
dihydrothiazoles rather than fused-ring compounds.[10]
Furthermore, the reactions could also generate 2-(1H-
indol-1-yl)thiazol-5-yl aryl ketones when molecular
oxygen was present.
Scheme 3. Synthesis of 2-(1H-indol-1-yl)thiazol-5-yl aryl
a]
ketones. [ Isolated yields are reported.
We also evaluated the reactions of various
Scheme
2.
Synthesis
of
2-(1H-indol-1-yl)-4,5-
dihydrothiazoles. [a]Isolated yields are reported. [b]Reaction
propargylamine derivatives 2 with 1a. To our delight,
internal
propargylamine
derivatives
(2b–2i)
2
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10.1002/adsc.201801193
Advanced Synthesis & Catalysis
containing various aryl groups were compatible with
the reaction conditions, and the yields generally were
≥70%. Even the sterically hindered substrate 3-(o-
methylphenyl) propargylamine (2h) could be
converted to desired product 3ah in high yield (90%).
It is noteworthy that only Z-isomers were formed, as
determined by single-crystal X-ray analysis of 3ae
(see SI, Table S4);[19] this result may be due to kinetic
effects, as outlined in Baldwin’s rules.[21] When the
propargylamine had an α-substituent (2j–2l), the
reaction proceeded smoothly to furnish the desired
products (3aj–3al). Surprisingly, when a nitro group
was present on the phenyl ring, only aromatization
product 3am was obtained.
Intriguingly, in the presence of molecular oxygen,
carbonylation product 2-(1H-indol-1-yl)thiazol-5-yl
aryl ketone 4a was obtained in 64% yield from a one-
pot reaction of 1a and internal propargylamine 2b
(1.5 equiv) in toluene at 110 °C for 15 h in the
presence of CuI (20 mol %) and H2O (5 equiv)
(Scheme 3; for details on the optimization of the
reaction conditions, see Table S2 in the SI). Our next
step was to explore the substrate scope of this aerobic
reaction. First, we investigated the effect of the
substituent on the aryl moiety (R3) of the internal
propargylamine substrate. When the benzene ring
bore a methyl group or a halogen atom or was
replaced by a naphthalene ring, the desired products
(4b or 4f, 4c–4e, and 4h, respectively) were obtained
in yields of 47–60%. Unfortunately, this reaction was
sensitive to steric hindrance: 4g was not obtained
from a substrate with an o-methyl group on the
benzene ring. The structure of 4c was ascertained by
means of single-crystal X-ray analysis (see SI, Table
Scheme 4. Control experiments.
To investigate the reaction mechanism, we carried
out some control experiments (Scheme 4). In the
absence of a copper catalyst, reaction of 1a with 2a (a
terminal alkyne) or 2b (an internal alkyne) at 80 °C
for 4 h under argon yielded only 5; whereas when the
reaction was carried out in the presence of the copper
catalyst for 15 min, 5 and 2-(1H-indol-1-yl)-4,5-
dihydrothiazole 3aa or 3ab were obtained (eq 1).
Compound 6 was not detected under either of these
reaction conditions. These results prove that 5 was a
reaction intermediate and that it could be formed in
the absence of the copper catalyst; and these tests also
rule out the possibility that indole ring formation was
the first step. Furthermore, we found that subjecting 5
to the optimal reaction conditions led to the formation
of the final product (eq 2), confirming that 5 was
indeed an intermediate.
S5).[19] We were pleased to find that
a
propargylamine with an α-aryl group furnished 4i in
40% yield.
We next examined a series of o-alkynylphenyl
isothiocyanates 1, which provided products 4j–4u in
moderate yields. Specifically, when R1 was an aryl
group with an electron-donating group or an electron-
withdrawing group, the desired products (4j–4o) were
obtained in yields of 32–65%. Moreover, substrates
with various aryl substituents R2 on the C≡C bond
were also compatible with the reaction conditions,
giving products 4p–4t regardless of the electronic
properties of the substituent on the aryl group. It is
noteworthy that a cyclopropane-containing substrate
could also be converted to the corresponding product
(4u) in 66% yield, whereas a terminal alkyne formed
only a trace of carbonylation product 4v.
Next, we studied the mechanism of the aerobic
copper-catalyzed reaction (eqs 3–6). The reaction of
1a and 2b in the presence of H2 O under an 16O2
18
atmosphere did not afford [18O]-4a (eq 3), as
determined by high-resolution mass spectrometry
(see SI, Figure S1). This result indicates that the
oxygen atom originated from molecular oxygen
rather than from water. When TEMPO was added to
the reaction mixture under either O2 or Ar, the radical
scavenger did not markedly inhibit the reaction, and it
could serve as an oxidant. Moreover, addition of the
radical inhibitor BHT also did not substantially
inhibit the reaction (eq 4), a result that rules out the
involvement of a radical process. If the reaction was
quenched after 0.5 h, we could isolate 5b and 3ab (eq
4), indicating that 5b was an intermediate and that
3ab may also have been an intermediate. To assess
this possibility, we studied the reactions of 3ab under
various conditions (eq 5). Surprisingly, 4a was
obtained in 70% yield under the standard conditions
(eq 5a), and only a 5% yield of 4a was obtained in the
absence of the copper salt (eq 5b). These results
confirm that 3ab was in fact an intermediate and that
3
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10.1002/adsc.201801193
Advanced Synthesis & Catalysis
CuI was indispensable for the oxidation process. That
3ab reacted in the presence of BHT confirms that a
radical oxidation process was not involved (eq 5c).
Moreover, neither 7 nor 3ak underwent further
oxidation under the standard conditions (eq 6), which
indicates that 7 was not involved in this reaction and
that the α-H of the thiazoline ring was important
during oxidation.
yl)thiazol-5-yl aryl ketones in moderate yields by
successive formation of C–C, C–N, and C=O bonds.
It provides an alternative method for introducing
molecular oxygen, which serves both as the oxygen
source and as the oxidant, into the thiazole skeleton.
Studies of the use of this method for the construction
of other nitrogen heterocycles are in progress in our
laboratory.
On the basis of the results of the above-described
experiments and literature reports,[11, 15, 22] a plausible
mechanism for the formation of 3ab and 4a is
outlined in Scheme 5. First, thiourea A is rapidly
formed by a reaction of 1a and 2b. Then, a copper-
catalyzed intramolecular 5-exo-dig hydrothiolation
Experimental Section
2-(1H-Indol-1-yl)-4,5-dihydrothiazoles: An oven-dried
Schlenk tube was charged with o-alkynylphenyl
isothiocyanate 1a (0.3 mmol, 1 equiv), propargylamine
derivative 2a (0.45 mmol, 1.5 equiv), CuI (0.045 mmol, 15
mol %), and dry CH3CN (3.0 mL). The tube was evacuated
and backfilled with Ar three times. The reaction mixture
was stirred under Ar at room temperature for 15 min and
then at 80 °C for 6 h. After concentration of the solution in
vacuo, the residue was purified via flash silica gel column
chromatography with petroleum ether/ethyl acetate as the
eluent to afford desired compound 3.
reaction
and
a
subsequent
intramolecular
hydroamination reaction give
intermediate C.
Protonation of C yields 3ab and releases the catalyst,
thus completing catalytic cycle 1. In the next step,
3ab undergoes a copper-mediated oxidation by
molecular oxygen accompanied by thiazoline–
thiazole tautomerization (cycle 2)[22c] to form highly
active Cu-peroxo species D, which rapidly isomerizes
to organoperoxide E. Finally, E is transformed to
oxidation product 4a and [Cun-OH] by removal of the
benzyl proton and subsequent O–O bond cleavage.
[Cun-OH] is converted back to [Cun] by anion
exchange to complete catalytic cycle 2 and generate 1
equiv of H2O. An alternative mechanism (cycle 3)
has a low probability but has not been ruled out. This
alternative mechanism involves a direct oxidative
addition reaction between a small amount of vinyl-Cu
intermediate C and molecular oxygen to afford Cu-
peroxo species F. Rapid isomerization of F, O–O
bond cleavage, and isomerization of G generate 4a
and [Cun-OH].
2-(1H-Indol-1-yl)thiazol-5-yl Aryl Ketones: A oven-
dried Schlenk tube was charged with an o-alkynylphenyl
isothiocyanate 1 (0.2 mmol, 1 equiv), a propargylamine
derivative 2 (0.3 mmol, 1.5 equiv), CuI (0.040 mmol, 20
mol %), H2O (1.0 mmol, 5 equiv), and dry toluene (3.0
mL). The tube was evacuated and backfilled with oxygen
three times. The reaction mixture was stirred under oxygen
at 30 °C for 20 min and then at 110 °C for 15 h. After
concentration of the solution in vacuo, the residue was
purified via flash silica gel column chromatography with
petroleum ether/ethyl acetate as the eluent to afford desired
compound 4.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (nos. 21602117, 21672117, 21732002) and the Tianjin
Natural Science Foundation (no. 16JCZDJC32400) for generous
financial support for our programs.
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5
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