Visible-Light-Driven Synthesis of 4-Alkyl/Aryl-2-Aminothiazoles Promoted by in Situ Generated Copper Photocatalyst

Article abstract of DOI:10.1021/acscatal.7b02818

Room-temperature synthesis of 4-alkyl/aryl-2-aminothiazoles from vinyl azides and ammonium thiocyanate was accomplished with the aid of copper salts and blue LED irradiation. Mechanism investigation indicates that in situ-formed Cu(NCS)₂^- plays dual important roles in the reaction: (1) as the photocatalyst to activate vinyl azides, (2) as the Lewis acid catalyst to promote ring opening of 2H-azirines with thiocyanide. This process is distinguished by high yields, mild conditions, low catalyst loadings, and tolerating numerous alkyl- and aryl vinyl azides with an array of functional groups.

Full text of DOI:10.1021/acscatal.7b02818

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Letter
Visible-Light-Driven Synthesis of 4-Alkyl/Aryl-2-Aminothiazoles
Promoted by In Situ Generated Copper Photocatalyst
wenlong lei, Tao Wang, Kai-Wen Feng, Li-Zhu Wu, and Qiang Liu
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Visible‐Light‐Driven Synthesis of 4‐Alkyl/Aryl‐2-Aminothiazoles
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Promoted by In Situ Generated Copper Photocatalyst
†
†
†
‡
†
Wen‐Long Lei, Tao Wang, Kai‐Wen Feng, Li‐Zhu Wu, Qiang Liu*
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China.
‡Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and
Chemistry & University of Chinese Academy of Sciences, the Chinese Academy of Sciences, Beijing 100190, P. R.
China.
ABSTRACT: Room‐temperature synthesis of 4‐alkyl/aryl‐2‐aminothiazoles from vinyl azides and ammonium thiocyanate
was accomplished with the aid of copper salts and blue LED irradiation. Mechanism investigation indicates that in situ
‐
formed Cu(NCS)2 plays dual important roles in the reaction: 1) as the photocatalyst to activate vinyl azides, 2) as the Lew‐
is acid catalyst to promote ring opening of 2H‐azirines with thiocyanide. This process is distinguished by high yields, mild
conditions, low catalyst loadings and tolerating numerous alkyl‐ and aryl vinyl azides with an array of functional groups.
KEYWORDS: visible light, in situ generated photocatalyst, intermolecular cyclization, copper salt, 2‐aminothiazole.
Copper is an inexpensive metal that is earth‐abundant
and readily available. The use of copper catalysts to effect
traditional thermal reaction has seen unprecedented
growth in recent decades.1 On the other hand, the copper
salts catalyzed photoreactions are far from reaching en‐
joyed the same level of success as thermal reactions.2,7,8
The root cause is a suitable photocatalyst should be ro‐
bust, absorb light efficiently, and have a long‐lived ex‐
cited state.3 Exactly, the relatively unstable and short‐
lived excited states of copper complexes retarded the ex‐
ploration of copper based photoreaction.4, 2d To improve
the efficiency of copper complexes as the photocatalysts
in the visible‐light driven transformations, complicated
ligand designs are always necessary for such reactions.5
More attractively, in situ generated photocatalysts (a
combination of simple transition metal salts with sub‐
strates) is an ingenious design, which is not only to
achieve an important transformation but also to avoid the
multi‐step synthesis of the catalyst.6 Recently, Jonas C.
Peters and Gregory C. Fu have reported a combination of
simple CuCl with substrates to achieve asymmetric C‐N
cross‐couplings induced by visible light.7 Moreover,
Hwang and coworkers have reported a series of C−C/C−N
cross‐coupling and C−H annulation reactions by in situ
generated photocatalysts with simple copper salts with
substrates.8 More recently, We disclosed that simple Cu(II)
salts can associate with 2‐arylaminoacetates to form
Cu(I)‐based intermediates which could be excited by visi‐
ble light.9 Subsequent energy transfer from the excited
Cu(I)‐based intermediate to molecular oxygen triggered
construction of a range of C‐C bonds in air. Despite these
contributions, the area of visible‐light driven reactions
catalyzed by in situ generated Cu(I) complexes remained
relatively underappreciated.
Scheme 1. Synthesis of 4‐Alkyl/Aryl‐2‐Aminothiazoles.
Thiocyanide is a highly affinitive ligand for Cu (I) salts.10
‐
The linear Cu(NCS)2 could be in situ prepared easily by
copper salts and excess amount of thiocyanide in room
temperature.11 As a continuing effort to develop sustaina‐
ble and environmentally benign photoreactions, as well as
the shortage of fossil fuels, we report a new methodology
in this paper that the in situ formed Cu(NCS)2 , which
plays the dual roles of both photocatalyst and Lewis acid
‐
catalyst,
promotes
synthesis
of
4‐alkyl/aryl‐2‐
aminothiazoles by directly constructing C‐S/C‐N bond
under visible light irradiation.
Compounds containing 2‐aminothiazole ring are a
commonly occurring structural motif found in natural
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products and pharmaceutical compounds.12 A diverse
various catalysts and solvents were screened under 5W
range of biological activities exhibited by this structure
include anticancer,13 anti‐inflammatory,14 antiviral,15 and
psychotropic activities.16 2‐aminothiazoles traditionally
are prepared by the intermolecular cyclization of α‐
halocarbonyl compounds with thioureas or ammonium
thiocyanate (Scheme 1).17
blue LED irradiation (λmax=455 nm) (see supporting in‐
formation). To our delight, we found that the reaction
with 10 mol % Cu(OAc)2 in CH3CN gave 4‐phenyl‐2‐
aminothiazole 2a in 95% isolated yield (entry 1). Interes‐
tingly, similar yields of 2a were isolated when cuprous
salts were used instead of Cu(OAc)2 (entries 4‐6), indicat‐
ing Cu(I) plays an important role in the photoreaction.
Further investigation established that both copper salts
and blue LED irradiation were required for an efficient
reaction (entries 2‐3). When Pd(OAc)2 was employed as
the catalysts, only few products were detected, indicating
the reaction mechanism is different from the reported
thermal reaction (entry 7).20 The replacement of NH4SCN
by KSCN decreased the yield of 3a sharply (entry 8), and
the yield increased significantly when 2.o equiv of
Brønsted acid KH2PO4 was added to the KSCN based
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Vinyl azides, a class of unique functionalized alkenes
with high intrinsic reactivity, could be easily prepared
from corresponding alkenes or alkynes.18 They have
served as prominent versatile synthons for the synthesis of
various nitrogen‐containing molecules.19 Recently, the
Pd(OAc)2 catalyzed intermolecular cyclization of vinyl
0
azides with potassium thiocyanate at 80 C has also been
reported.20 Yoon and co‐workers have reported that ener‐
gy transfer from Ir(Ⅲ) based photocatalysts to vinyl
azides produced 2H‐azirines.21 We hypothesize that ener‐
+
‐
system (entry 9). The results demonstrate that NH4 is
gy transfer from in situ produced Cu(NCS)2 to vinyl
necessary for the reaction as a proton donor. The copper‐
based catalytic system was so robust that the yield of 3a
kept no change even though the amount of Cu(OAc)2 was
decreased to 2 mol % (entries 10‐11).
azides could also take place and generate 2H‐azirines,
which is highly strained and easy to be attacked by thi‐
ocyanide at room temperature. The subsequent intramo‐
lecular nucleophilic attack of the cyanide with imino
anion should obtain the desired 2‐aminothiazoles. As this
process proceeds at room temperature and no noble met‐
al catalyst is employed, it may be open a new window for
pharmaceutical exploitation and the total synthesis of
natural products containing 2‐minothiazole structural
motif.
Having identified the optimal conditions, we next ex‐
amined the scope of aryl vinyl azides. As shown in Table 2,
various substituted aryl vinyl azides worked well with
ammonium thiocyanate to provide the desired 4‐aryl‐2‐
aminothiazoles in good to excellent yields. Among all the
examples presented, it was found that the electronic
property slightly affected the product yields. Aryl vinyl
Table 1. Optimization of the Reaction Conditions. a
Table 2. Scope of Aryl Vinyl Azides. a, b
entry
catalyst
x mol %(cat)
yield(%)d
1
2b
3
Cu(OAc)2
Cu(OAc)2
no catalyst
CuBr
10
10
0
95
n.r.
28
86
94
95
12
4
10
10
10
10
10
10
5
NH2
N
S
5
CuCl
6
CuSCN
2i 86%
7
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
8c
9c,e
10
11
23
NH2
N
S
69
95
95
N
2l 82%
2
a
Reaction conditions: vinyl azide (0.1 mmol, 1.0 equiv),
NH4SCN (0.2 mmol, 2.0 equiv) 1.0 mL CH3CN under an
argon atmosphere and irradiation of 5 W blue LEDs for 20
b
h at room temperature. Reaction performed in the ab‐
c
sence of light. 2.0 equiv KSCN instead of NH4SCN. d Iso‐
lated yields. e2.0 equiv KH2PO4 was added. n. r. = no
reaction.
a Reaction conditions: 1 (0.1 mmol, 1.0 equiv), NH4SCN
( 0.2 mmol, 2.0 equiv ), 5 mol % Cu(OAc)2 in 1.0 mL
CH3CN under an argon atmosphere and irradiation of 5W
blue LEDs for 20 h at room temperature. b Isolated yields.
We launched our study by subjecting vinyl azide 1a and
NH4SCN to various reaction conditions (Table 1). First,
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azides bearing electron‐donating substituent afforded
substrates. Phenyl, naphthyl, quinolyl, pyridyl and pyri‐
midyl vinyl azides also proceeded smoothly and furnished
the 2‐aminothiazoles in excellent yields upon isolation
(2k‐2n, 82%‐90%). Compound 2k, obtaining in 42% by Pd
catalyst20, can be prepared in 90% yield by our method.
Moreover, the polycyclic and 4, 5‐disubstituted amino‐
thiazoles can be also obtained in excellent yield (2o‐2p,
81%‐85%).
lower yields than those with electron‐withdrawing groups
in most cases. Many versatile functional groups, such as
halides, trifluoromethyl, ethenyl, or others, were all tole‐
rated under the reaction conditions, highlighting the po‐
tential of the method in organic synthesis (2f‐ 2j, 76% ‐
91%). Subsequently, we explored the challenging
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Table 3. Scope of Alkyl Vinyl Azides. a, b
We next turned our attention to alkyl vinyl azides
which frameworks have been realized as valuable motifs
in biological and medical chemistry. To our delight, alkyl
vinyl azides containing nitrogen, oxygen, sulfur, ester,
acid amide, double bond and triple bond as well as other
functional groups were applicable to synthesis of 2‐
aminothiazoles in good to excellent yields under the
standard reaction conditions (Table 3, 4a‐4o). Notably,
biologically active moieties such as pyridine (4j), couma‐
rin(4k), amino acid analogue(4m) and α, β‐unsaturated
carbonyl compounds (4o) were also tolerated in the pho‐
toreaction. Additionally, the substrates with 2‐azidooct‐1‐
ene and 2, 7‐diazidoocta‐1, 7‐diene proceeded smoothly
(4r‐4s, 72%‐89%). Finally, vinyl azides containing com‐
plex motifs such as cis‐9‐octadecenoic acid and bioactive
Cholesterol can also afford 2‐aminothiazoles derivative 4t
and 4u (61%‐86%).
To demonstrate the potential utility of the mild, opera‐
tionally simple strategy, further transformations were
carried out as shown in Scheme 2. We choose phenol as
the raw material to synthesize compound 4a by three
steps in excellent yield. Compound 5a, a potential potas‐
sium channel blocker, can be constructed from 4a
(Scheme 2, a) 22. Compound 4v, requiring four steps using
traditional synthetic approaches in low yield, can be con‐
structed in two steps with the methodology. A potential
TRPV3 modulators of 5b can be synthesized from 4v
(Scheme 2, b) 23. Further, Compound 4l, a possible anti‐
microbial and antitubercular agent, can be easily obtained
from 3l by two steps in our method. Using traditional
synthetic protocol would require five steps in harsh con‐
N
O
NH2
S
4p, 83%
ditions and low yield (Scheme 2, c) 12a
.
a Reaction conditions: 3 (0.1 mmol, 1.0 equiv), NH4SCN
( 0.2 mmol, 2.0 equiv ), 5 mol % Cu(OAc)2 in 1.0 mL
CH3CN under an argon atmosphere and irradiation of 5W
blue LEDs for 20 h at room temperature. b Isolated yields.
c36 h. d NH4SCN ( 0. 8 mmol, 4.0 equiv ). e 2.0 mL CH3CN.
Scheme 2. Synthetic Applications.22,23,12a
Once the scope of our methodology was explored, we
turned our attention to the reaction mechanism. As
shown in Figure 1, the UV‐vis absorption spectra of
Cu(OAc)2 or vinyl azide 1a is not obvious around 455 nm.
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While the mixture of Cu(OAc)2 and NH4SCN exhibits
intense absorption in the range of 350‐560 nm. We also
found that the solution of Cu(OAc)2 in MeCN turned from
light blue to claybank when NH4SCN was added. This
straightforward demonstated Cu(OAc)2 and NH4SCN
formed a photocatalyst in situ. To identify the in situ
formed copper species, the mixture of Cu(OAc)2 and
NH4SCN in MeCN was studied by HRMS. The peaks at
by blue LED irradiation. Then energy transfer from the
excited Cu(NCS)2 to vinyl azides takes place and produc‐
‐
es 2H‐azirines. Intermediate 2H‐azirines further trans‐
forms into Cu(Ⅰ)‐chelated α‐thiocyano enamine anion
through nucleophilic ring opening aziridines with thi‐
‐
ocyanide in the presence of Cu(NCS)2 . Finally, intramole‐
cular nucleophilic attack of the cyanide with imino anion
forms the desired 2‐aminothiazoles.
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179.8870 corresponding to [Cu(NCS)2 +H+], which has
‐
A) Mechanistic Studies.
been in situ prepared by Cu(OAc)2 and NH4SCN in room
temperature11. Furthermore, (SCN)2, formed as the by‐
‐
product of Cu(NCS)2 in situ preparation, was also de‐
tected by GC‐MS(see SI).
B) Proposed Mechanism.
(4)
(3)
(2)
(1)
claybank
light blue
Figure 1. The UV‐vis Absorption of Substrates.
The role of Cu(NCS)2‐ was investigated by the following
experiments. Firstly, excitation of the mixture of
Cu(OAc)2 and NH4SCN resulted in a maximal photolumi‐
nescence at 551 nm in acetonitrile solution, which was
quenched by vinyl azide 1a with a rate constant of 1.22 x
102 L∙mol‐1(see SI). Secondly, the photoreaction cannot be
fully suppressed even though 3.0 equiv of TEMPO was
added(see SI), indicating that radical pathway triggered
Scheme 3. Selected Mechanistic Studies and Pro‐
posed Reaction Mechanism for Synthesis of 2‐
Aminothiazoles.
In summary, we have disclosed a new methodology
about synthesizing
a broad range of 4‐alkyl/aryl‐2‐
aminothiazoles via copper‐promoted intermolecular cyc‐
lization under visible light irradiation. Moreover, the me‐
thod is distinguished by a broad scope, high yield, low
catalyst loadings and the mild, operationally simple strat‐
egy. We anticipate that this new intermolecular cycliza‐
tion protocol will be particularly used in pharmaceutical
exploitation and the total synthesis of natural products
containing 2‐minothiazole structural motif.
‐
by the electron transfer between Cu(NCS)2 and the sub‐
strate is not dominant. In addition, the reaction of 2H‐
azirine with NH4SCN produced the desired 2-
aminothiazole in excellent yield within 6 min with the aid
of copper salts such as Cu(OAc)2 and CuCl, while the
yield decreased to 28% in the absence of copper salts even
though the reaction time was prolonged to 20 h (Scheme
3, A). React‐IR monitoring of the consumption of 3‐
phenyl‐2H‐azirine provided a rate constant of 4.3 x 10‐3
mol∙L‐1∙S‐1 for the copper catalyzed ring‐opening process
(see SI). Finally, we found that Ir(ppy)3, a photocatalyst
which has been employed to produce 2H‐aziridines from
vinyl azides via energy transfer process 24, could also cata‐
lyze the 2‐aminothiazoles synthesis in the absence of
Cu(OAc)2 (Scheme 3, A). Therefore, it is plausible that
energy transfer from the excited Cu(NCS)2‐ to vinyl azides
generates the intermediate 2H‐azirines, which quickly
transformed to the products.
ASSOCIATED CONTENT
Experimental details, characterization data, and copies of
NMR spectra of new compounds. The Supporting Informa‐
tion is available free of charge on the ACS Publications web‐
site at DOI:
AUTHOR INFORMATION
Corresponding Author
*E‐mail: liuqiang@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
On the basis of these results, our mechanistic hypothe‐
sis was described as shown in Scheme 3B. Following in
ACKNOWLEDGMENT
‐
situ formation of Cu(NCS)2 by the reaction of Cu(OAc)2
with NH4SCN, 11 the photocatalyst Cu(NCS)2 is excited
‐
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NH2
N3
cat
Cu(OAc)2
N
S
NH4SCN
R
+
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R
37 examples
up to 95% yield
R= alkyl, phenyl, naphthyl,
quinolyl, pyridyl , pyrimidyl ...
broad scope
cheap and low catalyst loading
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