Mn(OAc)3-promoted regioselective free radical thiocyanation of indoles and anilines

Article abstract of DOI:10.1016/j.tetlet.2008.11.007

Mn(OAc)₃-promoted free radical thiocyanations of indoles and arylamines are introduced. Reactions performed under mild conditions give regioselective products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.11.007

Tetrahedron Letters 50 (2009) 347–349
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Tetrahedron Letters
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Mn(OAc)3-promoted regioselective free radical thiocyanation of indoles
and anilines
b,
Xiang-Qiang Pan a, Mao-Yi Lei a, Jian-Ping Zou a, , Wei Zhang
*
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 199 Renai Street, Suzhou, Jiangsu 215123, China
b Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Mn(OAc)3-promoted free radical thiocyanations of indoles and arylamines are introduced. Reactions
performed under mild conditions give regioselective products in good to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 12 October 2008
Revised 1 November 2008
Accepted 4 November 2008
Available online 7 November 2008
Thiocyanate is a versatile synthon1 which can be readily trans-
ferred to other functional groups such as sulfide,2 aryl nitrile,3 thio-
carbamate,4 and thionitrile.5 The development of new synthetic
methods for introducing thiocyanate functionality is always de-
manded. We recently reported Mn(OAc)3-promoted free radical
cyclization of thioformanilides to form benzothiozoles (Eq. 1).6
We found that Mn(OAc)3 could also mediate cyclization of hetero-
atom radicals to electron-rich aromatic rings to form O–C and P–C
bonds.7 Encouraged by the results obtained from the intramolecu-
lar reaction of sulfur radicals, we envisioned that this reaction may
also be possible to achieve in an intermolecular fashion and used
for synthesis of aryl thiocyanates.
SCN
Mn(OAc)3
HOAc
+
NH4SCN
ð2Þ
25 o
C
N
H
N
H
1a
2a
Table 1
Thiocyanation of indoles
SCN
Mn(OAc)3/HOAc
R
R
NH4SCN
+
N
H
N
25 °C
H
1a-1i
R1
2a-2i
R1
S
N
Mn(OAc)3
HOAc
S
Entry
1
Substrate
Producta
Yieldb (%)
83
R
ð1Þ
SCN
N
H
R
R2
R2
N
H
1a
N
H
Ammonium thiocyanate was chosen for thiocyanation of indole
1a under Mn(OAc)3-promoted radical reaction conditions. Acetic
acid was used as a solvent because it has a good solubility for
Mn(OAc)3. The reaction of 1a at room temperature yielded the de-
sired product 3-thiocyanato-1H-indole 2a in 83% yield (Eq. 2 and
Table 1, entry 1). The same reaction using N-methyl indole 1b as
the starting material gave 2b in 85% yield (Table 1, entry 2). The
reaction was further extended to include other substituted indoles.
It was found that 2-methylindole 1c gave 60% yield of 2c (Table 1,
entry 3). The lower yield is probably attributed to the steric
hindrance of 2-substituted indole.
2a
2b
SCN
2
3
4
85
60
85
N
N
1b
1c
SCN
N
H
N
2c
H
SCN
* Corresponding authors. Tel./fax: +86 512 65880336 (J.-P.Z.); tel.: +1 617 287
6147; fax: +1 617 287 6030 (W.Z.).
E-mail addresses: jpzou@suda.edu.cn (J.-P. Zou), wei2.zhang@umb.edu
(W. Zhang).
N
N
H
H
1d
2d
(continued on next page)
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.007

348
X.-Q. Pan et al. / Tetrahedron Letters 50 (2009) 347–349
Table 1 (continued)
to yield radical III. Mn(OAc)3 oxidizes III to cation IV followed by
Producta
Yieldb (%)
the loss of a proton to afford product 2a.
Entry
Substrate
After successfully developed the free radical-promoted thiocya-
nation reactions of indoles, we then explored the reactions of ani-
line and its derivatives. Aniline is an electron-rich system bearing a
free-amino group. The reaction of ammonium thiocyanate with
aniline 3a performed under the same condition described above
afforded desired product 4a in 83% yield (Eq. 3 and Table 2, entry
1). A comparison reaction on N-methylaniline 3d afforded product
4d in 84% yield (Table 2, entries 1 and 4). This result suggests that
both free and methyl-substituted amino groups tolerated to
OBz
OBz
SCN
5
91
N
N
H
H
1e
2e
SCN
BzO
BzO
6
87
N
H
N
2f
H
1f
Table 2
Thiocyanation of anilines
SCN
Br
Br
R2
H
Mn(OAc)3
HOAc
R2
H
7
8
9
92
50
N
N
NH4SCN
NCS
N
+
H
N
25 °C
1g
R1
3a-f
H
2g
R1
4a-f
SCN
Entry
1
Substrate
Producta
Yieldb (%)
NH2
2h
NH2
N
1h
N
H
H
83
SCN
3a
93
—
SCN
NH2
N
4a
2i
1i
N
H
H
NH2
CN
c
10
n.r.
2
3
4
5
6
81
87
84
85
86
N
1j
CH3
H
4b
CH3
3b
a
SCN
NH2
All products were characterized by NMR and MS spectra.
Isolated yield.
n.r. = no reaction observed.
b
c
NH2
Cl
Cl
Since 3-cyanoindole 1j did not react with ammonium thiocya-
nate (Table 1, entry 10), it is a strong evidence that the addition
is regioselective and only happens at the 3 position of indole.8
Other indole derivatives 1d–i also afforded good to excellent yields
(50–93%) of the desired products 2d–i (Table 1, entries 4–9).9
A plausible mechanism for this reaction is proposed in Scheme
1. Intermediate I formed by ligand-exchange is oxidized to NCS
radical II. The radical then attacks the electron-rich site of indole
4c
3c
SCN
NHCH3
NHCH3
3d
4d
SCN
NH2
NH2
CH3
Mn(OAc)3
SCN
Mn(III)
I
CH3
NH4SCN
ligand change
3e
4e
4f
SCN
NH2
[O]
Mn(II)
R
NH2
SCN
SCN
II
R
Br
3f
Br
N
H
N
SCN
O
H
III
1
NH2
NO2
HN
C
CH3
Mn(III)
SCN
Mn(II)
R
7
95c
SCN
- H+
3g
N
N
NO2
4g
H
H
a
IV
All products were characterized by NMR and MS spectra.
Isolated yield.
No thiocyanation, but only 4-nitro-N-acetylaniline 4g was obtained.
2a
b
c
Scheme 1.

X.-Q. Pan et al. / Tetrahedron Letters 50 (2009) 347–349
349
2. (a) Billard, T.; Langlois, B. R.; Medebielle, M. Tetrahedron Lett. 2001, 42, 3463;
(b) Nguyen, T.; Rubinstein, M.; Wakselman, C. J. Org. Chem. 1981, 46, 1938; (c)
Billard, T.; Large, S.; Langlois, B. R. Tetrahedron Lett. 1997, 38, 65; (d) Grieco, P.
A.; Yokoyama, Y.; Williams, E. J. Org. Chem. 1978, 43, 1283.
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4. (a) Riemschneider, R.; Wojahn, F.; Orlick, G. J. Am. Chem. Soc. 1951, 73, 5905; (b)
Riemschneider, R. J. Am. Chem. Soc. 1956, 78, 844.
Mn(OAc)3 oxidation. Different mono-substituted anilines 3b, 3c,
3e, and 3f were also reacted with ammonium thiocyanate, and
they all gave high yields (81–87%) of the corresponding products
4b, 4c, 4e, and 4f (Table 2, entries 2, 3, 5, and 6),10 and the thiocy-
anato group is selectively added to the para position of the amino
group. In the case of 4-nitroaniline 3g which has the 4-position
occupied, the thiocyanation could not take place, and gave only
4-nitro-N-acetylaniline 4g as an N-acylated by-product (Table 2,
entry 7).
5. Lee, Y. T.; Choi, S. Y.; Chung, Y. K. Tetrahedron Lett. 2007, 48, 5673 and
references cited therein.
6. Mu, X. J.; Zou, J. P.; Zeng, R. S.; Wu, J. C. Tetrahedron Lett. 2005, 46, 4345.
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(b) Mu, X. J.; Zou, J. P.; Qian, Q. F.; Zhang, W. Org. Lett. 2006, 8, 5291.
8. (a) Nair, V.; George, T. G.; Nair, L. G.; Panicker, S. B. Tetrahedron Lett. 1999, 40,
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2951; (d) Wu, G. L.; Liu, Q.; Shen, Y. L.; Wu, W. T.; Wu, L. M. Tetrahedron Lett.
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9. Typical experimental procedure for preparation of 3-thiocyanato-1H-indole 2a:
The indole 1a (1 mmol) and ammonium thiocyanate (1.2 mmol) were dissolved
in 10 mL acetic acid and treated with manganese(III) acetate (3.0 mmol) at
room temperature. The reaction mixture was stirred for 2 h. It was then diluted
with water (20 mL) and then extracted with dichloromethane (15 mL ꢀ 3), the
combined organic layer was dried over anhydrous Na2SO4. After removal of the
solvent under reduced pressure, the crude product was purified by column
chromatography on silica gel (eluted with acetone–petroleum ether = 1:4) to
give 2a in 83% yield, mp 73–76 °C. 1H NMR (400 MHz, CDCl3): d 8.79 (1H, br s,
NH), 7.78–7.22 (5H, m, C8H5N); 13C NMR (100 MHz, CDCl3): d 136.4, 131.6,
128.0, 124.2, 122.2, 119.0, 112.8, 112.6, 92.0; HRMS: m/z (%), calcd for C9H6N2S
(M+) 174.0252, found 174.0256 (M+, 100.00).
Mn(OAc)3
HOAc
NH2
NH4SCN
NCS
NH2
+
ð3Þ
25 o
C
3a
4a
In summary, Mn(OAc)3 can effectively promote the reaction of
ammonium thiocyanate with indoles or anilines to afford thiocya-
nated products. The reactions are conducted under mild conditions
and afford regioselective thiocyanated products in good to excel-
lent yields.
Acknowledgment
10. Typical experimental procedure for preparation of 4-thiocyanatoaniline (4a): The
aniline 3a (1 mmol) and ammonium thiocyanate (1.2 mmol) were dissolved in
10 mL acetic acid and treated with manganese(III) acetate (3.0 mmol) at room
temperature. The reaction mixture was stirred for 2 h. It was then diluted with
water (20 mL) and then extracted with dichloromethane (15 mL ꢀ 3), the
combined organic layer was dried over anhydrous Na2SO4. After removal of the
solvent under reduced pressure, the crude product was purified by column
chromatography on silica gel (eluted with acetone–petroleum ether = 1:4) to
give 4a in 83% yield, mp 52–53 °C. 1H NMR (400 MHz, CDCl3): d 7.33–6.63 (4H,
m, C6H4), 4.04 (2H, br s, NH2); 13C NMR (100 MHz, CDCl3): d 149.3, 134.8, 116.4,
112.9, 109.5; HRMS: m/z (%), calcd for C7H6N2S (M+) 150.0252, found 150.0251
(M+, 100.00).
J.P.Z. thanks the National Natural Science Foundation of China
for financial support (No. 20772088).
Supplementary data
Supplementary data (containing spectral data of 2a–i and 4a–g)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.11.007.
References and notes
1. Guy, R. G. In The Chemistry of Cyanates and their Thio Derivatives; Patai, S., Ed.;
John Wiley and Sons: New York, 1977.