Synthesis of aryl carbamates via copper-catalyzed coupling of aryl halides with potassium cyanate

Article abstract of DOI:10.1002/adsc.201200296

Coupling of aryl halides with potassium cyanate takes place at 100-110 °C in alcohols under the catalysis of CuI (cuprous iodide) and 2-(2,6-dimethylphenylamino)-2-oxoacetic acid, affording the corresponding aryl carbamates with great diversity. Copyright

Full text of DOI:10.1002/adsc.201200296

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DOI: 10.1002/adsc.201200296
Synthesis of Aryl Carbamates via Copper-Catalyzed Coupling of
Aryl Halides with Potassium Cyanate
Xinye Yang,a Yihua Zhang,a,* and Dawei Mab,*
a
Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
E-mail: zyhtgd@sohu.com
b
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: madw@mail.sioc.ac.cn
Received: April 9, 2012; Revised: May 17, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200296.
Abstract: Coupling of aryl halides with potassium
cyanate takes place at 100–1108C in alcohols under
the catalysis of CuI (cuprous iodide) and 2-(2,6-di-
methylphenylamino)-2-oxoacetic acid, affording the
corresponding aryl carbamates with great diversity.
Table 1. Screening of reaction conditions for the copper-cat-
alyzed coupling of potassium cyanate with 4-iodoanisole and
4-bromoanisole.[a]
Keywords: aryl halides; carbamates; copper salts;
coupling; ligands
The aryl carbamate moiety has been frequently found
in pharmaceutically important molecules. Recent ex-
amples include anticancer agents,[1] antituberculosis
agents,[2] mitogen-activated protein kinase 2 (MK2)
inhibitors,[3] matrix metalloprotease 12 inhibitors[4]
and HIV-1 protease inhibitors.[5] For a long time,
these compounds have been predominantly prepared
by condensation of anilines with phosgene deriva-
tives.[6] Recently, two alternative approaches using
metal catalysts have been reported.[7,8] One is the pal-
ladium-catalyzed reductive carbonylation of nitroar-
enes developed by Alper’s group,[7]and the other is
the copper-catalyzed coupling of arylboronic acids
with potassium cyanate discovered by Baghersad and
co-workers.[8]
Entry
X
[Cu] Ligand Base Temp. [oC] Yield [%][b]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
KOH 100
50
30
0
–
–
–
100
100
100
<5
80
82
70
60
<5
45
72
85
20
10
50
KOH 100
–
–
–
–
–
–
–
–
–
–
100
100
100
100
100
110
110
100
100
100
CuCl L6
CuBr L6
Cu2O L6
9
10
Br CuI
Br CuI
L6
L6
L6
L6
L6
L6
11[c]
12[c,d] Br CuI
Stimulated by Baghersadꢀs result, we envisioned
that aryl halides might go through a similar coupling
reaction, and thereby giving a more economic ap-
proach for preparing aryl carbamates. With this idea
in mind, we conducted a coupling of 4-iodoanisole
with potassium cyanate. It was found that under the
catalysis of 20 mol% CuI and 20 mol% N,N-dimethyl-
glycine, the reaction took place in n-BuOH at 1008C
to afford the desired carbamate 2a in 50% yield
(Table 1, entry 1). Changing the ligand to 1,10-phe-
nanthroline gave a decreased yield (entry 2), while
little product was obtained in the cases of 2,2,6,6-tet-
13[e]
14[f]
15[g]
I
I
I
CuI
CuI
CuI
[a]
Reaction conditions: aryl halide (0.5 mmol), potassium
cyanate (0.75 mmol), CuI (0.1 mmol), ligand (0.1 mmol),
base (0.1 mmol), n-BuOH (1 mL), 24 h.
Isolated yield.
1.0 mmol potassium cyanate was used.
[b]
[c]
[d]
[e]
[e]
[f]
0.2 mmol of L6 was used.
Using MeCN as solvent and adding 1 mmol of n-BuOH.
Using dioxane as solvent and adding 1 mmol of n-BuOH.
0.05 mol of CuI and 0.1 mol of L6 were used.
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Table 2. Coupling of aryl halides with potassium cyanate in
n-butanol.[a]
Entry
X
Y
Yield [%][b]
1
2
3
4
5
6
7
8
I
Br
I
Br
I
Br
I
Br
I
Br
I
Br
Br
I
Br
I
Br
I
Br
I
Br
I
I
H
H
4-Cl
4-Cl
4-OMe
4-OMe
4-Ac
4-Ac
4-Ph
85
90
78
80
82
85
80
80
80
82
70
80
62[c]
71
76
85
87
75
80
70
76
Figure 1. Structures of heteroaryl carbamates prepared via
copper-catalyzed coupling.
tron-rich or electron-poor, were found to be applica-
ble for this transformation. These results indicated
that electronic nature of the substrates has little influ-
ence on the reaction course. However, steric hin-
drance was found to have a great impact on this cou-
pling reaction, as evidenced by the fact that no cou-
pling occurred even at 110–1408C when two ortho-
substituted aryl iodides were used (entries 22 and 23).
Another notable feature of the present coupling re-
action is that a wide range of functional groups, such
as chloro, methoxy, ketone, amide, amino, and nitro
groups, were tolerated under these reaction condi-
tions. We also attempted to use some heteroaryl bro-
mides as the coupling partners, and were pleased to
observe that 2-pyridinyl-, 3-pyridinyl-, 2-thiophenyl-,
5-indolyl- and 4-indolyl-substituted products 3–7
(Figure 1) could be synthesized in 40–92% yields. This
advantage gives the flexibility for assembling func-
tionalized aryl carbamates from substituted aryl and
heteroaryl halides.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-Ph
4-NHAc
4-NHAc
4-NH2
3-F
3-F
3-Me
3-Me
3-Cl
3-Cl
3-NO2
3-NO2
2-Me
2-Cl
[d]
–
[d]
–
[a]
Reaction conditions: aryl iodide (0.5 mmol), potassium
cyanate (0.75 mmol), CuI (0.1 mmol), L6 (0.1 mmol), n-
BuOH (1 mL), 1008C, 24 h; or aryl bromide (0.5 mmol),
potassium cyanate (1.0 mmol), CuI (0.1 mmol), L6
(0.2 mmol), n-BuOH (1 mL), 1108C, 24 h.
Isolated yield.
Aryl bromide was recovered with about 15% yield.
Reaction was carried out at 110–1408C.
We next moved our attention to carrying out the
coupling reaction of aryl bromides with potassium cy-
anate in different alcohols (Table 3). In a sealed tube,
both methanol and ethanol worked well, affording
methyl and ethyl carbamates in good yields (en-
tries 1–9). The sterically bulky i-PrOH and functional-
[b]
[c]
[d]
ramethylheptane-3,5-dione and quinolin-8-ol as the ized allyl alcohol could also be employed, providing
ligand (entries 3 and 4). The best result was obtained the corresponding aryl carbamates in 75–90% yield
when 2-(2,6-dimethylphenylamino)-2-oxoacetic acid (entries 10–14). However, no desired product was iso-
(DMPAO) was utilized (entry 5). Using its salt as the lated when t-BuOH was utilized (entry 15), indicating
ligand, a similar result was observed in the absence of that tertiary alcohols are not favored in this transfor-
the base (entry 6). Switching the copper salt from CuI mation.
to CuCl, CuBr or Cu2O decreased the yields slightly
Although the detailed mechanism for the present
(entries 7–9). Under the same conditions, 4-bromoani- transformation is not clear, we proposed that the cou-
sole gave a moderate yield (entry 10). Improved re- pling reaction might go through a typical oxidative
sults could be obtained by adding more potassium cy- addition/reductive elimination process as outlined in
anate (entry 11) and ligand (entry 12). We also tried Scheme 1.[9] After formation of Cu(I) complex A
to carry out the reaction in MeCN and dioxane, and from CuI and L6, oxidative addition with aryl halides
reduce the catalytic loading, but failed to obtain satis- might afford Cu
ACHTUNGTRENNUNG
factory yields (entries 13–15). of B with potassium cyanate could deliver CuACHTUNGTRENNUNG
Using n-BuOH as the solvent we next explored the complex C, which would undergo reductive elimina-
reaction scope by varying the aryl halides. As sum- tion to produce aryl isocyanide D and regenerate the
marized in Table 2, a number of para- and meta-sub- complex A. Condensation of D with a suitable alco-
stituted aryl halides, no matter whether they are elec- hol could provide the corresponding aryl carbamate.
2
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Synthesis of Aryl Carbamates via Copper-Catalyzed Coupling of Aryl Halides
Table 3. Coupling of aryl bromides with potassium cyanate
In summary, we have demonstrated that coupling
of aryl halides with potassium cyanate could occur
under the catalysis of CuI and a bidentate ligand.
This result provides another example to demonstrate
the potential for extending copper-catalyzed arylation
processes by using unusual nucleophiles.[11] This
method is very reliable for preparing aryl carbamates
as a number of functionalized aryl halides could be
employed as the coupling partners. Thus, it may find
good applications in organic synthesis.
in different alcohols.[a]
Entry
Y
R
Yield [%][b]
1
2
3
4
5
6
7
8
4-OMe
4-Cl
3-Me
3-Cl
3-Ac
4-Ph
4-CO2H
4-OMe
4-Cl
4-OMe
4-Cl
3-Cl
H
4-Cl
Me
Me
Me
Me
Me
Me
Me
Et
75
70
80
81
75
72c
70c
79
83
75
90
85
80
75
–
Experimental Section
Typical Experimental Procedure
9
Et
A Schlenk tube was charged with 4-iodoanisole (0.5 mmol),
potassium cyanate (0.75 mmol), CuI (0.1 mmol), ligand
(0.1 mmol), and 1 mL of n-BuOH, evacuated and backfilled
with argon. The reaction mixture was stirred at 1008C for
24 h. The cooled reaction mixture was partitioned between
ethyl acetate and water. The organic layer was washed with
water, brine, and dried over Na2SO4, and concentrated. The
residue was purified by column chromatography on silica
gel using 1:5 ethyl acetate and hexanes as eluent to provide
butyl 4-methoxyphenylcarbamate.
10
11
12
13
14
15
i-Pr
i-Pr
i-Pr
allyl
allyl
t-Bu
3-Cl
[a]
Reaction conditions: aryl bromide (0.5 mmol), potassium
cyanate (0.75 mmol), CuI (0.1 mmol), L6 (0.2 mmol), sol-
vent (1 mL), 1108C, 24 h.
Isolated yield.
Aryl bromide was recovered in about 15% yield.
[b]
[c]
Acknowledgements
The authors are grateful to the Ministry of Science and Tech-
nology (grant 2009ZX09501-00), Chinese Academy of Scien-
ces and National Natural Science Foundation of China
(grants 20632050 & 20921091) for their financial support.
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Synthesis of Aryl Carbamates via Copper-Catalyzed
5
Coupling of Aryl Halides with Potassium Cyanate
Adv. Synth. Catal. 2012, 354, 1 – 5
Xinye Yang, Yihua Zhang,* Dawei Ma*
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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