Copper-catalyzed aminothiolation of terminal alkynes with tunable regioselectivity

Article abstract of DOI:10.1039/c8cc09122f

A simple, mild, and efficient catalytic aminothiolation of terminal alkynes for the synthesis of both 2- and 3-substituted thiazolo[3,2-a]benzimidazoles is established upon catalysis with copper(i), in which complementary regioselectivities could be achieved by using sterically different phenanthroline-based ligands.

Full text of DOI:10.1039/c8cc09122f

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C8CC09122F
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COMMUNICATION
Copper-Catalyzed Aminothiolation of Terminal Alkynes with
Tunable Regioselectivity
Jinqiang Kuang,a,b Yuanzhi Xia,b* An Yang,b Heng Zhang,b Chenliang Su,a* and Daesung Leec
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple, mild, and efficient catalytic aminothiolation of roles for the tunable regioselectivity (Scheme 1, Eq. b).
terminal alkynes for the synthesis of both 2- and 3-substituted Scheme 1. Tunable Synthesis of 2- or 3-substituted
thiazolo[3,2-a]benzimidazoles is established under the catalysis thiazolo[3,2-a]benzimidazoles
of copper (I), in which complementary regioselectivities could be
Previous reports
achieved by using sterically different phenanthroline-based
ligands.
R
3
H
N
3
Br
Br
Cu(I)
N
2
N
R
(a)
or
SH
+
2
R
S
Transition metal-catalyzed functionalization of alkynes into the
corresponding alkenes with diverse functional groups has
emerged as a powerful synthetic tool.1 Due to the significant
potential from atom- and step-economic standpoints,
developing novel protocols for this direct functionalization
strategy has gained much attention in recent years.2,3
Imidazol[2,1-b]thiazole derivatives are heterocyclic compounds
displaying diverse pharmacological, such as antitumor,4
antifungal,5 antidiabetic,6 anthelmintic,7 cardiodepressant,8 and
antitubercular9 activities. Although compounds possessing the
imidazol[2,1-b]thiazole structure show such appealing
properties, efficient and selective method for the preparation of
these compounds is still much in demand.10-12 In 2010, Chen
and coworkers reported an elegant Cu-catalyzed approach to 2-
alkyl and 3-aryl imidazol[2,1-b]thiazole derivatives through
regioselective 1,2-aminothiolation of 1,1-dibromoalkenes,
wherein the regioselectivity was dependent on the substrate
structure (Scheme 1, Eq. a).11 To the best of our knowledge, a
catalytic aminothiolation of easily available terminal alkynes to
yield both 2- and 3-substituted thiazolo[3,2-a]benzimidazoles
with controllable selectivity has not been reported in literature.
N
N
N
S
( R = alkyl)
( R = aryl)
R1
This work
L-1
, I2
CuI/
3
N
R2
2
N
N
L-1
H
R1
+
S
N
N
(b)
SH
N
3
R2
N
2
R2
R1
N
N
L-2
, I2
CuI/
S
N
i-Pr
i-Pr
L-2
Initially, we examined the reaction of 4-chlorophenylacetylene (1a)
and 2-mercaptobenzimidazole (2a). The reaction proceeded
smoothly in the presence of CuI (10 mol%), 1,10-phenanthroline (20
o
mol%), I2 (1 equiv), and K2CO3 (2 equiv) at 80 C, affording 3aa
selectively in 63% yield (Table 1, entry 1). Other copper salts, such
as CuBr, CuCl, CuCN, CuBr2, and Cu(OTf)2, catalyzed the
aminothiolation reaction as well, albeit with inferior yields (see
Table S1 in Supporting Information). 1,10-Phenanthroline was found
to be the most effective ligand for obtaining 3aa compared to other
ligands examined (Table 1, entry 1 vs entries 2−5). To our delight,
when a slight excess (1.3 equiv) of 2a was employed, yield of
product 3aa was improved to 83% (Table 1, entry 6). Screening of
other solvents showed that ethanol and methanol were also suitable
for the transformation, producing 3aa in 79 and 75% yield,
respectively (see Table S1 in Supporting Information). Reaction in
ethereal solvents such as THF, 1,4-dioxane, and 1,2-
dimethoxyethane resulted in dramatically decreased yields (Table
S1). To be noted, when neocuproine was applied as ligand,
regioselectivity was turned towards the production of 2-aryl
substituted product 4aa, which was seldom reported in literature
(Entries 5 and 7). Pleasingly, reaction involving ligand L-2, a 1,10-
phenanthroline derivative containing isopropyl group at C2 and C9,
provided 4aa as the major product in 71% yield along with 3aa in 14%
yield at 40 oC (Entry 8).
Herein we report
a
copper-catalyzed protocol for
regioselective synthesis of both 2- and 3-substituted
thiazolo[3,2-a]benzimidazoles from terminal alkynes, wherein a
phenanthroline-based ligand and iodine play together crucial
a.SZU-NUS Collaborative Innovation Center for Optoelectronic Science
&
Technology, International Collaborative Laboratory of 2D Materials for
Optoelectronics Science and Technology of Ministry of Education, College of
Optoelectronic Engineering, Shenzhen University, Shenzhen 518060 (P. R. China).
E-mail: chmsuc@szu.edu.cn
b.College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou
325035 (P. R. China). E-mail: xyz@wzu.edu.cn
c. Department of Chemistry, University of Illinois at Chicago, 845 West Taylor
Street, Chicago, Illinois 60607
Electronic Supplementary Information (ESI) available: Optimization of solvent,
experimental details, characterization data, and copies of 1H and 13C NMR spectra
(PDF). CCDC 1847875. See DOI: 10.1039/x0xx00000x
With the optimized conditions for both regioisomers in hand, we
firstly explored the scope for the synthesis of isomer 3 with regard to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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various terminal alkynes (Table 2). Aryl alkynes bearing either and selectivity (Table 4, entry 11). Gratifyingly, alVkiyewneAsrticbleeOarnilninge
DOI: 10.1039/C8CC09122F
electron-withdrawing or electron-donating substituents on the ether and thioether moieties were also tolerated in the reaction,
aromatic ring, including fluoro, chloro, bromo, cyano, nitro, formyl, affording the desired products in modest yields yet good
trifluoromethyl, and methoxy groups were all compatible, affording regioselectivities (Table 4, entries 12 and 13).
the corresponding products 3aa–3ka in good to excellent yields.
Table 2. Synthesis of 3-substituted thiazolo[3,2-a]benzimidazoles
Notably, aryl alkynes with a heteroaromatic ring proved to be good
substrates, leading to products 3la–3oa containing multiple
heterocycle rings, which are of great pharmaceutical importance. To
our delight, even alkynes with a silyl group could be tolerated in this
transformation, furnishing 3qa and 3ra in modest yields. Alkyl
alkynes were also found to be suitable for the reaction (3sa–3ua).
Furthermore, alkynes bearing amino, indolyl, ether, thioether, and
even a free hydroxyl group could be converted to the corresponding
aminothiolation products in modest to excellent yields (3va–3Da).
from structurally diverse alkynes.a
H
R
N
L-1
CuI (10 mol%),
(20 mol%)
SH
+
N
R
I2 (1 equiv), K2CO3 (2 equiv)
N
1
air, CH3CN, 80 o
C
N
S
2a (
1.3 equiv)
3
R'
F3C
N
S
CF3
S
N
N
N
S
N
S
N
S
N
N
S
3ka
, 80%
3la
3ma
, 80%
Table 1. Optimization of reaction conditions for the synthesis of
thiazolo[3,2-a]benzimidazoles.a
, 59%
3aa
3ba
3ca
3da
3ea
, R' = Cl, 83%
, R' = Br, 65%
, R' = F, 85%
N
R
N
, R' = CN, 76%
, R' = NO2, 54%
, R' = CHO, 62%
N
N
N
N
3fa
CuI / Ligand
I2, K2CO3, CH3CN
N
S
N
H
N
N
3ga
3ha
N
S
N
3oa
S
, R' = OMe, 82%
, R' = nPr, 80%
, R' = Me, 90%
, R' = H, 88%
N
S
, 47%
R'
3aa
R'
+
SH
+
air, 80 oC, 17 h
3na
, 76%
, 66%
3pa
N
Cl
R' = H, L-1 (1,10-phen)
R' = Me,
R' = i-Pr,
N
3ia
3ja
R
Neocuproine
L-2
1a
2a (
1.0 equiv)
(R = 4-ClC6H4)
X
N
S
4aa
R'
SiR'3
N
N
N
N
S
N
S
Entry
1
2
3
4
Ligand
3aa (%)b
63
4aa (%)b
n.d.
n.d.
n.d.
n.d.
16
b
3va
, R' = cPr, 68%b,c
, X = NMe2, 59%
N
S
3sa
1,10-Phen (L-1)
2,2’-Bipyridine
TMEDA
PPh3 (40%)
Neocuproine
L-1
b
3wa, X =
37%
indol-1-yl,
, X = OPh, 88%
, X = SPh, 63%
3qa
, R' = Et, 72%
3ra
, R' = Me, 61%
t
b,c
3ta
, R' = Bu, 61%
3xa
3ya
b
, R' = nBu, 74%b,c
15
43
14
22
83
26
14
3ua
R''
OH
R'
3Aa
3Ba
3Ca
OH
, R',R'' = Ph,H, 48%
N
, R',R'' = Me,Me, 54%
N
N
S
5
, R',R'' = nC5H11,H, 55%
)5, 62%b
b
6c
n.d.
38
71
3Da, ', '' = (
R R CH2
3za
, 49%
N
S
7c,d
8c,d,e
Neocuproine
L-2
aConditions: 1 (0.2 mmol), 2a (0.2 mmol), CuI (0.02 mmol), L-1
(0.04 mmol), I2 (0.2 mmol), K2CO3 (0.4 mmol), CH3CN (1 mL) at
80 oC for 17 h. b1 (0.8 mmol) and 2a (0.2 mmol) were used.
cReaction at 100 oC for 64 h using CuI (25 mol%) and L-1 (50
mol%).
aConditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (0.02 mmol),
ligand (0.04 mmol), I2 (0.2 mmol), K2CO3 (0.4 mmol), CH3CN (1
mL) at 80 C for 17 h. Isolated yield. 2a (0.26 mmol). DMSO (1
o
b
c
d
e
mL) was used as solvent. CuI (25 mol%) and L-2 (30 mol%) at 40
It was found that the protocol could be readily scaled up. When
gram-scale (5 mmol) reactions were carried out, the desired products
were obtained with good yields and excellent selectivities (Scheme
2). The structure of regioisomer 4 has been further confirmed by X-
ray single-crystal diffraction analysis of 4na (see supporting
information).
oC. 1,10-Phen
=
1,10-phenanthroline, TMEDA
= N,N,N',N'-
tetramethylethylenediamine.
The effect of substituent on 2-mercaptobenzimidazole was also
investigated (Table 3). 2-Mercaptobenzimidazole with either an
electron-withdrawing (nitro) or electron-donating (methoxyl and
methyl) substituent afforded the corresponding products as a mixture
of two isomers in modest yields.
To gain insight into the mechanism of CuI-catalyzed
aminothiolation, several control experiments were carried out. When
the reaction was carried out without I2 under O2 atmosphere 3aa was
produced in 23% yield, whereas 3aa was not obtained under N2
(Scheme 3, Eq. a and b vs Entry 6, Table 1). These results suggest I2
is essential for the efficiency of the transformation and might behave
as more than an oxidant in the reaction. To evaluate whether a 1,2-
diiodoalkene might be the intermediate of the transformation,12c we
examined the reaction of independently prepared 1,2-diiodoalkene
1n' with 2-mercaptobenzimidazole, which furnished a mixture of
3na (17%) and 4na (13%) (Scheme 3, Eq. c). In contrast, the
reaction of pyridylacetylene 1n provided a significantly different
yield and ratio of 3na (13%) and 4na (71%) (Scheme 3, Eq. d),
which indicates the latter reaction with 1n does not proceed through
1,2-diiodoalkene intermediate 1n',13 even though the possibility of
its involvement in a minor pathway cannot be excluded.
Next, the scope of reaction affording 2-substituted thiazolo[3,2-
a]benzimidazoles 4 as major product was investigated (Table 4).
When aryl alkynes bearing an electron-withdrawing substituent such
as chloro, bromo, cyano, and trifluoromethyl group were employed,
regioselectivities of the reaction were generally good, affording
isomers 4aa–4ka as major products (Table 4, entries 1–4). However,
aryl alkynes bearing an electron-donating substituent provided
products with low regioselectivities (Table 4, entries 5 and 6).
Similarly, alkyne bearing an electron-deficient aromatic system
provided much higher regioselectivity than that with a relatively
electron-rich heteroaromatic system (Table 4, entries 8 and 9 vs
entry 7). The reaction of triethylsilylacetylene generated 4qa as a
sole isomer in good yield (Table 4, entry 10). Alkyl alkyne such as
1-hexyne 1u was a suitable substrate, furnishing 4ua in modest yield
2 | J. Name., 2012, 00, 1-3
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Table 3. Substituent effect on 2-mercaptobenzimidazole.a
COMMUNICATION
Scheme 3. Control experiments
View Article Online
DOI: 10.1039/C8CC09122F
R'
H
N
R
R'
without I2
L-1
CuI (10 mol%),
(20 mol%)
O2
+
N
SH
R
(a)
CuI (10 mol%)
3aa
3aa
(23%)
I2 (1 equiv), K2CO3 (2 equiv)
N
1
L-1
(20 mol%)
air, CH3CN, 80 o
C
N
S
1a
2a
I
+
2 (
3
1.3 equiv)
K2CO3 (2 equiv)
CH3CN, 80 o
C
(not detected)
(b)
(c)
6
6
O2N
Me
7
Ph-4-Cl
Ph-4-Cl
N2
7
N
N
N
H
Conditions A
Conditions A
N
S
N
S
3na
4na
(13%)
(17%)
+
I
3ac
3ac'
(7-NO2)
58% (1.1:1)c
(6-NO2) +
3ab
3ab'
(7-Me)
(6-Me) +
56% (1.1:1)b
1n'
1n
I2 (1 equiv)
6
6
6
(d)
(e)
3na
3na
4na
(13%)
(30%)
+
(71%)
(3%)
Me
MeO
7
MeO
7
Ph
N
Ph-4-Cl
Ph
7
N
N
N
4na
+
N
S
N
S
N
S
without I2
3ad
3ad'
3jb
3jb'
3jd
3jd'
(6-OMe) + (7-OMe)
(6-OMe) +
(7-OMe)
(6-Me) +
(7-Me)
64% (1.3:1)d
53% (1.5:1)
54% (1.2:1)b
2a
L-2
(12 mol%)
Conditions A:
(1.3 equiv),CuI (10 mol%),
K2CO3 (2 equiv), air, DMSO, 50 o
C
aConditions: 1 (0.2 mmol), 2 (0.26 mmol), CuI (0.02 mmol), Ligand
L-1 (0.04 mmol), I2 (0.2 mmol), K2CO3 (0.4 mmol), CH3CN (1 mL)
under air at 80 oC for 17 h. Isolated yield. bTwo isomers were
It is worthwhile to note that when the reaction was carried out with
ligand L-2 in the absence of I2, regioselectivity of the transformation
was reversed again (3na/4na = 10/1) and significantly lower yields
were obtained (Scheme 3, Eq. e), which indicates I2 is crucial in
controlling the regioselectivity as well as improving efficiency of the
reaction.
1
obtained as an inseparable mixture (ratio determined by H NMR).
cReaction was run at 100 oC for 46 h. dReaction with CuI (20 mol%)
and 1,10-phen (40 mol%) at 80 oC for 26 h.
Table 4. Substrate scope for the reversal of regioselectivity
affording 2-substituted thiazolo[3,2-a]benzimidazoles.a
L-2
I2 , K2CO3
CuI,
Based on these experiments, we propose plausible mechanisms for
the I2-assisted Cu-catalyzed aminothiolation of terminal alkynes to
afford product 3 and 4 (Scheme 4).[11-14] In Mechanism A, the
reaction proceeds with the formation of 1-alkynyl copper species A,
which then react with 2 to yield intermediate B. Upon activation of
the C–C triple bond with I2, a thermodynamically favored 6-endo-
dig cyclization would convert B to the next intermediate C.
Subsequently, C undergoes intramolecular substitution reaction to
afford the penultimate intermediate D,14 which upon proton transfer
yields product 3 and regeneration of 1-alkynyl copper species A. In
Mechanism B leading to regioisomer 4, the common intermediate B,
due to a strong repulsive interaction between iodine that activates the
C–C triple bond and the sterically bulky ligand L-2, proceeds
through a kinetically favored 5-exo-dig cyclization over a 6-endo-dig
cyclization to generate an intermediate F via the cyclized precursor
E. The intermediate F undergoes a thiocupration to afford G, which
leads to regioisomer 4 upon proton transfer.
H
N
R
N
N
SH
+
R
R
+
air, DMSO
40 oC, 17 h
N
N
S
1
N
S
3
4
2a (
1.3 equiv)
Entry
R (1)
3 (%)b
4 (%)b
4 : 3
1
2
3
4
5
6
7
8
9
4-ClC6H4 (1a)
4-BrC6H4 (1b)
4-CNC6H4 (1d)
14 (3aa) 71 (4aa)
20 (3ba) 59 (4ba)
5.1: 1
3.0: 1
6 (3da)
71 (4da) 11.8: 1
3,5-di-CF3C6H4 (1k) 11 (3ka) 74 (4ka)
6.7: 1
1: 2.2
1.2: 1
2.2: 1
4-MeOC6H4 (1g)
4-n-PrC6H4 (1h)
2-thienyl (1l)
52 (3ga) 24 (4ga)
38 (3ha) 44 (4ha)
22 (3la)
5 (3na)
48 (4la)
2-pyridyl (1n)
4-pyridyl (1o)
80 (4na) 16.0: 1
<8 (3oa) 84 (4oa) >10.5:
1
c
10
11
12
13
SiEt3 (1q)
n-Bu (1u)
–
71 (4qa)
–
11 (3ua) 42 (4ua)
3.8: 1
PhOCH2 (1x)
PhSCH2 (1y)
5 (3xa)
7 (3ya)
57 (4xa) 11.4: 1
68 (4ya) 9.7: 1
The regioselectivity in the reaction affording 4 with alkynes
containing an electron-withdrawing substituent is relatively higher
than that with an electron-donating one. This tendency of
regioselectivity corroborates the proposed mechanisms, where the
electron-withdrawing substituent on R on B renders the distal carbon
of the I2-activated triple bond more prone to nucleophile attack via
5-exo mode, resulting in the formation of intermediate E over C,
which will lead to final product 4.
aConditions: 1 (0.2 mmol), 2a (0.26 mmol), CuI (0.05 mmol), ligand
L-2 (0.06 mmol), I2 (0.2 mmol), K2CO3 (0.4 mmol), DMSO (1 mL)
under air at 40 oC for 17 h. bIsolated yield. c 3qa was not observed.
Scheme 2. Gram-scale regioselective aminothiolations.
Cl
2a
(1.3 equiv)
L-1
CuI (10 mol%),
(20 mol%)
In summary, we have developed
a novel Cu(I)-catalyzed
N
I2 (1 equiv), K2CO3 (2 quiv)
CH3CN, 80 oC, 22 h
methodology for tunable aminothiolation of terminal alkynes to
afford 2- and 3-substituted thiazolo[3,2-a]benzimidazoles selectively
under mild conditions. With the assistance of sterically different
ligands, 5-exo-dig and 6-endo-dig cyclization occurred to afford 2-
and 3-substituted thiazolo[3,2-a]benzimidazoles selectively. This
protocol features broad substrate scope, mild conditions, good and
tunable regioselectivity, excellent functional group tolerance, and
scalability. Further insight into the detailed mechanism and
application of the transformations to the preparation of heterocyclic
Cl
1a
N
S
(5 mmol)
3aa
, 70% (1.0 g)
2a
(1.3 equiv)
L-2
CuI (25 mol%),
(30 mol%)
N
N
N
I2 (1 equiv), K2CO3 (2 quiv)
DMSO, 50 oC, 18 h
N
S
1n
(5 mmol)
4na
, 78% (0.98 g)
3na
(contaminated with trace of
)
This journal is © The Royal Society of Chemistry 20xx
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Huang, L. Cheng, Q. Liu, D. Wang and L. Liu,VOiewrgA.rtiBclieoOmnloinle.
Chem., 2018, 16, 899.
compounds of pharmaceutical interests are currently being pursued.
DOI: 10.1039/C8CC09122F
2
For selected recent examples, see: (a) L. Liu, K. Sun, L. Su, J.
Dong, L. Cheng, X. Zhu, C.-T. Au, Y. Zhou and S.-F. Yin,
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Scheme 4. Proposed mechanism for I2-assisted Cu-catalyzed
regioselective aminothiolation
R
N
Mechanism A
HS
H
+
K2CO3
N
N
H
S
2
N
3
R
CuL
A
KHCO3
R
R
H
6-endo
1
R
I
I
R
K+
LCu
LCu
HS
K+
N
N
N
LCu
N
N
S
S
N
D
H
K2CO3
H
B
I2
+
K2CO3
I
KI
R
3
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(b) J. Kuang, S. Parveen and B. Breit, Angew. Chem. Int. Ed.,
2017, 56, 8422.
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Eur. J. Med. Chem., 2014, 75, 492.
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249.
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Milne, D. P. Carney, A. V. Lynch, J. J. Smith, S. Lavu, P. D.
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Med. Chem., 1966, 9, 545.
LCu
N
K+
S
KHCO3
N
+ KI
N
C
4
5
H
Mechanism B
HS
+
K2CO3
R
R
N
N
H
S
2
N
R
CuL
4
A
6
KHCO3
R
H
5-exo
1
I
R
CuL
N
7
8
K+
R
LCu
K+
LCu
S
N
N
N
N
S
S
N
G
R. Budriesi, P. Ioan, A. Locatelli, S. Cosconati, A. Leoni, M.
P. Ugenti, A. Andreani, R. Di Toro, A. Bedini, S. Spampinato,
L. Marinelli, E. Novellino and A. Chiarini, J. Med. Chem.,
2008, 51, 1592.
E
H
B
R
KI
Sterically hindered L
makes this pathway
more favorable
I2
+
K2CO3
9
G. C. Moraski, L. D. Markley, M. Chang, S. Cho, S. G.
Franzblau, C. H. Hwang, H. Boshoff and M. J. Miller, Bio.
Med. Chem., 2012, 20, 2214.
LCu
N
S
KHCO3
+ KI
N
F
10 (a) N. Pietrancosta, A. Moumen, R. Dono, P. Lingor, V.
Planchamp, F. Lamballe, M. Bähr, J.-L. Kraus and F. Maina,
J. Med. Chem., 2006, 49, 3645; (b) I. Laníos, P. E. Bender, K.
A. Razgaitis, B. M. Sutton, M. J. DiMartino, D. E. Griswold
and D. T. Walz, J. Med. Chem., 1984, 27, 72; (c) H. F.
Andrew and C. K. Bradsher, J. Heterocycl. Chem., 1967, 4,
577.
We thank the NSFC (21572163, 21873074 and 51502174), the
Shenzhen Peacock Plan (Grant No. 827000113, KQTD20160531120
42971), the Educational Commission of Guangdong Province (2016
KSTCX126), and the NSF (CHE-1764141, DL) for financial support.
Prof. Hongping Xiao is acknowledged for X-ray crystal structure
analysis.
11 H. Xu, Y. Zhang, J. Huang and W. Chen, Org. Lett., 2010, 12,
3704.
Conflicts of interest
There are no conflicts to declare.
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13 For more information, see control experiment in Supporting
Information.
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