Iron(II)-promoted synthesis of 2-aminothiazoles via C-N bond formation from vinyl azides and potassium thiocyanate

Article abstract of DOI:10.1002/adsc.201400856

A simple protocol to prepare the privileged 2-aminothiazoles promoted by ferrous sulfate heptahydrate via C-N bond formation from vinyl azides and commercially available potassium thiocyanate has been developed. A wide range of vinyl azides are tolerated to afford the expected polysubstituted 2-aminothiazoles in reasonably good yields. The use of the non-toxic substrates and catalyst renders the reaction more environmentally friendly than traditional approaches.

Full text of DOI:10.1002/adsc.201400856

UPDATES
DOI: 10.1002/adsc.201400856
À
Iron(II)-Promoted Synthesis of 2-Aminothiazoles via C N Bond
Formation from Vinyl Azides and Potassium Thiocyanate
Guolin Zhang,a,* Binhui Chen,a Xiao Guo,a Shanshan Guo,a and Yongping Yua,*
a
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang
University, Hangzhou 310058, Peopleꢀs Republic of China
E-mail: guolinzhang@zju.edu.cn or yyu@zju.edu.cn
Received: August 29, 2014; Revised: December 25, 2014; Published online: March 4, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400856.
Abstract: A simple protocol to prepare the privi-
tioned methods also suffered from unsatisfactory
yields, harsh reaction conditions, expensive and detri-
mental metal precursors as well as the pollution con-
cern of a-halocarbonyl compounds.
Nowadays, vinyl azides have emerged as important
synthons although they were once regarded as “sleep-
ers” of the reactive azido species for a long time. In
recent years, our group[13] and others[14] have devel-
oped numerous heterocycle syntheses from vinyl
azides.
leged 2-aminothiazoles promoted by ferrous sulfate
À
heptahydrate via C N bond formation from vinyl
azides and commercially available potassium thio-
cyanate has been developed. A wide range of vinyl
azides are tolerated to afford the expected polysub-
stituted 2-aminothiazoles in reasonably good yields.
The use of the non-toxic substrates and catalyst ren-
ders the reaction more environmentally friendly
than traditional approaches.
Iron salts have proved useful for several catalyzed
reactions including cross-couplings, oxidations, and re-
ductions. Since iron is cheap, non-toxic, and environ-
mentally friendly, its application has attracted much
attention.[15] Recently, it is demonstrated that vinyl
azides could be activated by iron(II) salts providing
access to heterocyclic systems.[16] These previous
Keywords: 2-aminothiazoles; azides; green chemis-
try; homogeneous catalysis; iron
À
À
2-Aminothiazoles are powerful motifs in pharmaceut- works include intramolecular N O or N N bond for-
ical research and exhibit a broad spectrum of biologi- mation catalyzed by iron(II) bromide,[16b] intramolecu-
[16a]
cal activities including antiviral,[1] antiprion,[2] anti-in- lar C H amination catalyzed by iron(II) bromide,
À
flammatory,[3] antimicrobial,[4] antitubercular,[5] and iron(II)
chloride,[16c]
iron(II)
triflate,[16d]
or
anticancer activities.[6] Besides, films of conjugated [Fe(F20TPP)Cl].[16e] To the best of our knowledge,
polyaminothiazole also demonstrate electrochemical there are no prior examples of iron(II)-catalyzed in-
properties with high thermal stability.[7]
termolecular reactions of vinyl azides and other reac-
In view of the important utility of 2-aminothiazoles, tants. Herein, we report a general method for the syn-
numerous methods to access this ring system have thesis of polysubstituted 2-aminothiazoles promoted
been reported in the literature, mostly based on the by non-toxic FeSO4·7H2O from vinyl azides and po-
À
Hantzsch-type condensation of a-halocarbonyl com- tassium thiocyanate via C N bond formation and
pounds with thiourea.[8] 2-Aminothiazoles are also probe toward the mechanism.
prepared through the reactions of a-thiocyanato car-
Initially, vinyl azide 1a, potassium thiocyanate 2a,
bonyl compounds with aromatic or aliphatic amine were selected as model reactants to optimize the reac-
hydrochlorides,[9] one-pot reaction of enolizable ke- tion conditions (Table 1). No corresponding product
tones with a mixture of N-bromosuccinimide, thiourea was observed without any additives (Table 1, entry 5)
and benzoyl peroxide,[10] one-pot reaction of isothio- or with acids served as the additives (Table 1, en-
cyanates, amidines/guanidines and various halomethy- tries 19 and 20). Metal complexes known to decom-
lenes,[11] and multicomponent reaction of a-bromocar- pose azides, namely Fe(III) (Table 1, entries 2 and
bonyl compounds and amines using trimethylsilyl iso- 22), Cu(I) (Table 1, entry 3), and Cu(II) salts (Table 1,
thiocyanate.[12] However, it is still challenging to pre- entry 4), performed less efficiently than Fe(II) salts
pare polysubstituted 2-aminothiazoles, especially 4- (Table 1, entries 1 and 21). The strong complexation
carbonyl-2-aminothiazoles. Besides, the above-men- between thiocyanate and iron(III) and the strong
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Guolin Zhang et al.
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Additive (equiv.)
2a (equiv.)
Temp. [oC]
Conversion [%][b]
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
toluene
dioxane
n-propanol
H2O
CH3NO2
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
FeSO4·7H2O (1)
Fe(NO3)3·9H2O (1)
CuCN (1)
CuCl2 (1)
–
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
2
2
2
2
2
2
2
80
80
80
80
80
80
80
80
80
80
rt
60
100
80
80
80
80
80
80
80
80
80
88
28
trace
42
n.r.
88
95
98
n. r
93
n.r.
94
FeSO4·7H2O (1)
FeSO4·7H2O (1)
FeSO4·7 H2O(1)
FeSO4·7H2O (1)
FeSO4·7H2O (1)
FeSO4·7H2O (1)
FeSO4·7H2O (1)
FeSO4·7H2O (1)
FeSO4·7H2O(1)
FeSO4·7H2O (1)
FeSO4·7H2O (0.1)
FeSO4·7H2O (0.3)
FeSO4·7H2O (0.5)
HCl (0.5)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
96
83
98
36
84
98 (94)[c]
n.r.
n.r.
68
H2SO4 (0.5)
FeCl2·4H2O (0.5)
FeCl3 (0.5)
24
[a]
Reaction conditions: vinyl azide (0.5 mmol, 1.0 equiv.), potassium thiocyanate, 2 mL of solvent. n.r.=no reaction.
Determined by LC-MS, based on the disappearance of the starting vinyl azide. The most successful entry is highlighted in
[b]
bold.
Isolated yield.
[c]
complexation between cyanide and copper may ac- sium thiocyanate to provide the corresponding poly-
count for the low yields. Besides, low yields were ob- substituted 2-aminothiazoles with excellent yields.
tained when FeSO4·7H2O was replaced by The reaction could tolerate vinyl azides with aromatic
FeCl2·4H2O (Table 1, entry 21). Then a range of sol- or alkyl substitution at the R2 position and aromatic
vents (Table 1, entries 6-10) were screened, employ- or alkoxy substitution at the R1 position. Notably, a-
ment of n-propanol (Table 1, entry 8) showed a slight azidovinyl ethyl esters bearing an ethoxy group at the
improvement in the yield. The reaction was also as- R1 position afforded products with an n-propoxy
sessed at different temperatures (Table 1, entries 11– group at the corresponding position due to a transes-
13) with a decrease in the yield. Besides, the yields terification with the solvent n-propanol (3p–3w).
were maintained when a smaller amount of potassium However, the reaction afforded products with an
thiocyanate 2a (Table 1, entries 15) and FeSO4·7H2O ethoxy group at the corresponding position when the
(Table 1, entries 18) was applied. On the basis of solvent was replaced by C2H5OH (3x compared to
above studies, the most favorable reaction conditions 3w). Generally, vinyl azides with electron-withdrawing
for the formation of 3a were established. The vinyl groups at the R1 position gave somewhat poorer re-
azides were readily prepared according to the litera- sults (3e, 3f, 3h compared to 3a–3d). However, sub-
ture.[17]
stituents with different electronic properties at the R2
With the optimized reaction conditions in hand, the position had little effect on the yields of the products
scope of the reaction was studied using a set of vinyl (3g compared to 3a; 3f, 3h compared to 3e; 3k com-
azides. As shown in Table 2, both a-azidovinyl ke- pared to 3b). Interestingly, when the R2 position was
tones and a-azidovinyl esters worked well with potas- substituted with bromobenzene, there was a distinct
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Iron(II)-Promoted Synthesis of 2-Aminothiazoles via C N Bond Formation
Table 2. Scope of the reaction.[a,b]
[a]
Reactions were carried out in n-propanol (2.0 mL) with 1 (0.5 mmol, 1.0 equiv.), 2 (1 mmol, 2.0 equiv.),
FeSO4·7H2O (0.25 mmol, 0.5 equiv.), 808C.
Isolated yield.
Refluxed in C2H5OH for 12 h.
[b]
[c]
decrease in yields when the bromine was substituted was almost no reaction when hydrogen was substitut-
at the ortho or meta position (3i, 3j compared to 3k), ed at the R1 position (3o).
which indicated that steric hindrance at the R2 posi-
On the basis of the above experimental results, the
tion may block the binding of vinyl azides and potas- following possible mechanism for this cycloaddition
sium thiocyanate. Meanwhile, heteroaryl motifs such reaction is proposed, as outlined in Scheme 1. Initial
as pyridine (3l), furan (3m, 3u) were successfully in- coordination of iron(II) to the azide and carbonyl
corporated. In addition, the method also tolerated hy- provides iron(II)-azide complex I, increasing the elec-
drogen (3w, 3x) or alkyl substitution (3n, 3v) at the R2 trophilicity of the pendant olefin.[18] Attack of potassi-
position in reasonably good yields. However, there um thiocyanate expels N2 to produce the intermediate
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Guolin Zhang et al.
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Scheme 1. Proposed reaction mechanism.
II. Intramolecular attack of the electron-rich N-atom
to the cyano group, followed by aromatization, would
generate the polysubstituted 2-aminothiazoles.
Experimental Section
General Procedure for the Synthesis of 3
A mixture of vinyl azide 1 (0.5 mmol), potassium thiocya-
nate 2 (1 mmol), FeSO4·7H2O (0.25 mmol) was stirred in n-
propanol (2 mL) at 808C for 12 h (reflux in C2H5OH to
afford 3x). After the completion of the reaction, the solvent
was removed under reduced pressure. The crude residue
was then diluted with water and extracted three times with
ethyl acetate. The combined organic extracts were washed
with brine, dried over Na2SO4, concentrated and purified by
flash chromatography (PE/EA) on slica gel to afford 3a–3x.
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Acknowledgements
This work is supported financially by the Project of Science
Technology Department of Zhejiang Province (2012C33065),
the Project of Education Department of Zhejiang Province
(Y201223193), the National Science Foundation of China
(No. 81072516), and the Program for Zhejiang Leading
Team of S&T Innovation (2011R50014).
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