Copper(I)-catalyzed one-pot synthesis of 2-iminobenzo-1,3-oxathioles from ortho-iodophenols and isothiocyanates

Article abstract of DOI:10.1002/adsc.200800461

A novel and efficient formation of 2-iminobenzo-1,3-oxathioles from readily available precursors via a copper(I)-catalyzed one-pot cascade process has been developed. Various 2-iminobenzo-1,3-oxathioles, which might be useful in pharmaceutical and biochemical areas, were conveniently synthesized in good to excellent yields.

Full text of DOI:10.1002/adsc.200800461

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DOI: 10.1002/adsc.200800461
Copper(I)-Catalyzed One-Pot Synthesis of 2-Iminobenzo-
1,3-oxathioles from ortho-Iodophenols and Isothiocyanates
Xin Lv,a Yunyun Liu,a Weixing Qian,a and Weiliang Baoa,*
a
Department of Chemistry, Xixi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: July 25, 2008; Published online: November 4, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800461.
Abstract: A novel and efficient formation of 2-imi-
nobenzo-1,3-oxathioles from readily available pre-
cursors via a copper(I)-catalyzed one-pot cascade
process has been developed. Various 2-iminobenzo-
1,3-oxathioles, which might be useful in pharma-
ceutical and biochemical areas, were conveniently
synthesized in good to excellent yields.
been demonstrated to be important in the context of
potential pharmaceutical or biochemical activities.[2b,3]
Only a few methods have been reported for the
synthesis of 2-imino-1,3-oxathioles, particularly for
the assembly of 2-iminobenzo-1,3-oxathioles.[1b,3a,4]
Kulka reported the preparation of N-acyl-2-imino-1,3-
oxathioles from O-alkyl acylcarbamothioates and 2-
chloro ketones.[4d] One approach to 2-iminobenzo-1,3-
oxathioles utilized the Rh(II)-catalyzed reaction of a-
diazocarbonyl compounds with isothiocyanates.[4b]
They also could be derived from benzo-1,3-oxathiole-
2-thiones,[1b] or synthesized by [4+1] cycloaddition.[3a]
However, these approaches might be limited due to
their narrow scopes, special or expensive metal cata-
lysts and reagents, unsatisfactory efficiencies, or the
Keywords: copper(I) catalysis; 2-iminobenzo-1,3-
À
oxathioles; intramolecular C S bond formation;
ortho-iodophenol; one-pot reactions
The 1,3-oxathiole motifs are found in a variety of tedious mutistep manipulation. Therefore, concise
useful heterocyclic derivatives applied as biologically and efficient methods to give these heterocyclic
active compounds[1] and pharmaceutical products[2] motifs are still in demand.
(Figure 1, A–D). For example, oxathiolone-fused
Batey et al. have reported Cu- or Pd-catalyzed in-
À
chalcones A have been studied for their antibacterial, tramolecular C S cross-coupling for the preparation
antifungal and tuberculostatic activities,[1a] oxathio- of benzothiazoles.[5] Recently, one-pot strategies for
lones B are used as neuroprotective agents,[2a] com- the synthesis of various useful heterocyclic com-
À
pound C with an imino group is found to be an agro- pounds based on the copper-catalyzed CACTHNUTRGNE(NUG aryl) X
chemical pesticide,[1b] and 2-imino-1,3-oxathioles D (X=N, C, O, etc.) bond formation have been stud-
might possess fungicidal activity.[1c] Among the 1,3- ied.[6–8] They have received much attention because of
oxaACHTUNGTRENNUNGthiole derivatives, 2-imino-1,3-oxathioles have their more convenient “one-pot” manipulations and
good efficiencies. For example, indazoles could be ef-
ficiently formed via CuO-catalyzed N-arylation of hy-
drazines followed by intramolecular dehydration.[6e]
Several benzimidazoles were synthesized via aryl ami-
nation/condensative cyclization processes.[6a–d] Also,
À
C C coupling/cyclization methods for the synthesis of
indoles[7a–d,f,g] and C C coupling/intramolecular C O
coupling protocols for the formation of benzofurans[8c]
have also been disclosed during the recent years.
To the best of our knowledge, there is no report
about the formation of 2-imino-1,3-oxathioles via a
one-pot copper-catalyzed coupling process. Herein we
have designed a novel and efficient one-pot cascade
reaction to synthesize 2-iminobenzo-1,3-oxathioles:
À
À
Figure 1. Several 1,3-oxathiole derivatives reported as bio-
logically active compounds and pharmaceutical products.
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Table 1. Optimization of the reaction conditions.[a]
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ortho-iodophenol would undergo the intermolecular
À
addition/intramolecular C S coupling process with
isothiocyanate in the Cu(I)-ligand-base system. Our
proposed approach is summarized in Scheme 1. In the
Entry Copper(I) Ligand
Base
Sovent Yield
[%][b]
69,
1
CuI
Cs2CO3 DME
Cs2CO3 DMF
63[c]
2
3
4
5
CuI
CuI
CuI
CuI
L1
L1
L1
L1
16
Cs2CO3 CH3CN 84
Cs2CO3 Dioxane 92
Cs2CO3 Toluene 97,
72[d]
97[e]
Cs2CO3 Toluene 23
,
Scheme 1. Proposed one-pot synthesis of 2-iminobenzo-1,3-
oxathioles via intermolecular addition/intramolecular C S
coupling.
À
6
7
CuI
CuI
l-Proline L2
Cs2CO3 Toluene 93
Cs2CO3 Toluene 22
8
CuI
presence of a proper base, the nucleophilic oxygen of
ortho-iodophenol 1 would attack the carbon atom of
NCS on isothiocyanatobenzene 2, and intermediate 4
could be formed (step a).[9] In the presence of a
proper copper(I) catalyst and ligand, 4 might convert
9
CuI
Cs2CO3 Toluene trace
10
11
12
13
14
15
16
17
CuI
CuI
CuI
CuI
–
CuBr
CuCl
Cu2O
–
Cs2CO3 Toluene trace
K3PO4 Toluene 89
K2CO3 Toluene 88
L1
L1
L1
L1
L1
L1
L1
À
into the product 3 via an intramolecular C S coupling
Na2CO3 Toluene
7
(step b). In the latter step, the sulfur atom would take
priority over nitrogen atom in the assaulting action.
In our preliminary experiments, 2-iodophenol 1a
and isothiocyanatobenzene 2a were chosen as the
model substrates. Our reaction was originally carried
out in DME with CuI (10 mol%) as the catalyst, 1,10-
phenanthroline (20 mol%) as the ligand and Cs2CO3
(2.0 equiv.) as the base at 808C[10] under an N2 atmos-
phere. To our delight, the starting materials disap-
peared and the anticipated product 3a was obtained
in moderate yield after 24 h (Table 1, entry 1). The IR
Cs2CO3 Toluene n.d.[f]
Cs2CO3 Toluene 70
Cs2CO3 Toluene 73
Cs2CO3 Toluene 16
[a]
Reaction conditions: 2-iodophenol 1a (1.0 mmol), isothiocya-
natobenzene 2a (1.0 mmol), copper source (0.1 mmol), ligand
(0.2 mmol) and base (2.0 mmol, 2.0 equiv.) in solvent
(2.0 mL) under N2, at 808C for 24 h.
Isolated yield.
A subsequential procedure was conducted.
The reaction temperature was 658C.
[b]
[c]
[d]
[e]
[f]
specrum of 3a showed
a strong absorption at
The reaction temperature was 908C.
The desired product was not detected (n.d.).
1655 cmÀ1, this indicated the presence of an imino
group. In the 13C NMR spectrum, the carbon atom of
imino group appeared at d=160.3 ppm. Other struc-
tural characterizations were also carried out and its selected and the corresponding optimization was con-
structure could be established (1H NMR, MS and ele- ducted as follows.
mental analysis). We also tried a two-step procedure
Firstly, we investigated the influence of solvents
during our original research. A mixture of 1a while other conditions were settled (Table 1, en-
(1.0 mmol), 2a (1.0 mmol) and Cs2CO3 (2.0 mmol) in tries 1–5). When DMF was used, the result deteriorat-
DME (2.0 mL) was stirred at 808C without any cata- ed (entry 2). The yields were greatly enhanced both
lyst and ligand. The mixture was analyzed by TLC in CH3CN and dioxane (entries 3 and 4). Toluene
every 20 min. Both of the starting materials were con- seemed to be the best solvent (entry 5). Decreasing
sumed completely within 1.0 h. Then CuI (10 mol%) the reaction temperature gave an obviously lower
and L1 (20 mol%) were added immediately. The mix- yield, while hardly any change was observed at a
ture was stirred for 24 h at 808C and the same desired slightly higher temperature (entry 5). Several ligands
product 3a was isolated in 63% yield (Table 1, were tested (entries 6–10). l-Proline and glycine were
entry 1). Comparing the two methods, the former one not suitable for this process. N,N-Dimethylglycine was
is superior for its concise single-step manipulation good, but 1,10-phenanthroline proved to be better.
and better yield. Therefore, the former procedure was Ethyl 2-oxocyclohexanecarboxylate, which performed
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Copper(I)-Catalyzed One-Pot Synthesis of 2-Iminobenzo-1,3-oxathioles
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Table 2. CuI-catalyzed one-pot synthesis of 2-iminobenzo-1,3-oxathioles from 2-iodophenol 1a and aryl isothiocyanates 2a–
2h.[a]
Entry
1
ortho-Iodophenol
Isothiocyanate
Product
Temperature/Time
Yield [%][b]
97
1a
2a
2b
3a
3b
808C/24 h
2
808C/24 h
91
3
4
2c
3c
808C/24 h
808C/30 h
89
88
2d
3d
5
2e
3e
808C/24 h or 908C/30 h 69 or 86
6
7
2f
2g
3f
3g
758C 20 h
708C 18 h
91
92
8
2h
3h
808C 20 h
93
[a]
Reaction conditions: ortho-iodophenol (1.0 mmol), isothiocyanate (1.0 mmol), CuI (0.1 mmol), L1 (0.2 mmol) and Cs2CO3
(2.0 mmol, 2.0 equiv) in toluene (2.0 mL) under N2.
Isolated yield.
[b]
as an efficient and versatile ligand in our previous entries 1–8). The isothiocyanates bearing both elec-
work,[11] was also tested. However, the ligand seemed tron-donating groups (p-Me, m-Me and o-Me) and
unsuitable in this process (entry 9). Hardly any antici- electron-withdrawing groups (m-Cl, m-CF3 and p-Br)
pated product was observed without
a ligand seemed to be reactive and the products were obtained
(entry 10). Different bases were examined (entry 5, in good to excellent yields (entries 2–4 and entries 6–
entries 11–13), and Cs2CO3 showed as the optimal 8). Strong electron-donating substituents on the iso-
base. In a blank experiment, the reaction did not pro- thiocyanate might do harm to the reaction and de-
ceed in the absence of copper catalyst (entry 14). crease its reactivity (entry 5). However, once the tem-
When the copper source was switched to CuBr, CuCl perature was raised, the yield improved obviously.
or Cu2O (entries 15–17), the yield decreased
Encouraged by the above results, we further inves-
(entry 17). Therefore, the optimized conditions were tigated the scope and the generality of the method by
to use a combination of CuI (10 mol%) and 1,10-phe- varying the ortho-iodophenols, which could be facilely
nanthroline (20 mol%) in the presence of Cs2CO3 derived from the para-substituted phenols (Table 3,
(2.0 equiv.) as base in toluene.
entries 1–13). To our delight, generally the reactions
With the optimal conditions established, we then proceeded successfully in moderate to excellent
tried to investigate the scope of this methodology. yields, although higher temperatures and longer times
Firstly, the reactions of 2-iodophenol 1a with various were required. The isothiocyanates bearing electron-
substituted isothiocyanates 2 were examined (Table 2, withdrawing groups as well as weak electron-donating
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Table 3. CuI-catalyzed one-pot synthesis of 2-iminobenzo-1,3-oxathioles from substituted ortho-iodophenols and isothiocya-
nates.[a]
Entry
1
ortho-Iodophenol
Isothiocyanate
Product
Temperature/Time Yield [%][b]
1b
2a
3j
858C/26 h
858C/30 h
808C/26 h
858C/30 h
908C/30 h
96
90
86
84
63
2
3
4
5
1b
1b
1b
1b
2b
2c
2d
2e
3j
3k
3l
3m
6
7
8
1b
1c
1c
2h
2a
2b
3n
3o
3p
808C/22 h
858C/26 h
858C/28 h
81
94
86
9
1c
2e
3q
908C/30 h
67
10
11
12
13
14
1c
1c
1b
1d
1e
2f
2i
3r
3s
3t
3u
858C/24 h
908C/30 h
908C/30 h
908C/40 h
908C/36 h
85
75[c,d]
64[c,e]
52
2l
2a
2a
[f]
–
–
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Copper(I)-Catalyzed One-Pot Synthesis of 2-Iminobenzo-1,3-oxathioles
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Table 3. (Continued)
Entry
ortho-Iodophenol
Isothiocyanate
Product
Temperature/Time Yield [%][b]
[f]
15
1f
2a
–
808C/30 h
–
[a]
Reaction conditions: ortho-iodophenol (1.0 mmol), isothiocyanate (1.0 mmol), CuI (0.1 mmol), L1 (0.2 mmol) and Cs2CO3
(2.0 mmol, 2.0 equiv.) in toluene (2.0 mL) under N2.
Isolated yield.
The amount of the isothiocyanate 2i was 1.1 equiv.
[b]
[c]
[d]
A mixture of anti and syn isomers was obtained (the isomeric ratio was about 89:11, approximately as determined by
1H NMR).
[e]
[f]
A mixture of anti and syn isomers was obtained (the isomeric ratio was about 86:14, approximately as determined by
1H NMR).
A complicated mixture was obtained.
Phen·H2O (40 mg, 0.20 mmol, 20 mol%) and ortho-iodophe-
nol 1 (1.0 mmol). The tube was evacuated and backfilled
with N2 (this procedure was repeated 3 times). Under a
counter flow of N2, toluene (1.0 mL) was added by syringe
and the mixture was pre-stirred for about 0.5 h at room tem-
groups gave satisfactory results (entries 2–4, 6, 8 and
10), while that bearing the strong electron-donating
group p-MeO reacted slowly and a lower yield was
obtained (entries 5 and 9). In comparison with aryl
isothiocyanates, alkyl isothiocyanates seemed less re-
active (entries 11 and 12). The ortho-iodophenol with
a p-Cl substituent seemed less reactive and only gave
a moderate yield, for its ability to attack the electro-
philic carbon of NCS was weaker and step a might be
influenced (entry 13). 1-Iodonaphthalen-2-ol 1e was
tried under the similar conditions. Unfortunately no
desired product was detected (entry 14). Probably the
steric hindrance of the naphthyl ring influenced the
intramolecular coupling process (step b). Finally, a
diiodide 1f was also tested. However, only a complex
mixture was obtained and so further isolation was un-
executed (entry 15). We thought this might due to the
complicated intermolecular reactions, as well as the
steric hindrance.
perature. Then
a solution of isothiocyanate 2 (1.0~
1.1 mmol) in toluene (1.0 mL) was added via syringe under
a counter flow of N2. The tube was sealed and the mixture
was allowed to stir at the temperature indicated in Table 2.
The reaction was monitored by TLC. After the starting ma-
terial was consumed completely and the bottom dot was un-
changed, the reaction was stopped and cooled to room tem-
perature. The reaction mixture was directly passed through
celite. After being rinsed with further 30 mL of Et2O, the
combined filtrate was concentrated by rotatory evaporation.
The residue was purified by column chromatography on
silica gel to give the pure product. For more details, see Sup-
porting Information.
In summary, we have designed and developed a
novel, efficient and concise method for copper(I)-cat-
alyzed one-pot synthesis of 2-iminobenzo-1,3-oxa-
thioles. A simple “one-pot” operation was conducted,
readily available starting materials were employed
and relatively mild conditions were applied. Various
2-iminobenzo-1,3-oxathioles, which might be poten-
tially applicable in the pharmaceutical and biochemi-
cal areas, were conveniently synthesized in moderate
to excellent yields. The reaction also performed as a
À
Acknowledgements
This work was financially supported by the Specialized Re-
search Fund for the Doctoral Program Foundation of Higher
Education of China (No. 2060335036).
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