Regioselective synthesis of N-acetylureas by manganese(III) acetate reaction of 1,3-disubstituted thioureas

Article abstract of DOI:10.1016/j.tetlet.2006.02.013

Reactions of asymmetrical 1,3-disubstituted thioureas with manganese(III) acetate produce regioselective N-acetylureas. A mechanism for this novel transformation is proposed.

Full text of DOI:10.1016/j.tetlet.2006.02.013

Tetrahedron Letters 47 (2006) 2323–2325
Regioselective synthesis of N-acetylureas by manganese(III)
acetate reaction of 1,3-disubstituted thioureas
Xue-Jun Mu,a Jian-Ping Zou,a,* Qiu-Feng Qiana and Wei Zhangb,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
1 Shizi St. Suzhou, Jiangsu 215006, China
bFluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970 William Pitt Way, Pittsburgh, PA 15238, USA
Received 11 January 2006; revised 31 January 2006; accepted 2 February 2006
Available online 20 February 2006
Abstract—Reactions of asymmetrical 1,3-disubstituted thioureas with manganese(III) acetate produce regioselective N-acetylureas.
A mechanism for this novel transformation is proposed.
Ó 2006 Elsevier Ltd. All rights reserved.
Since Bush and Finkbeiner’s pioneering work reported
three decades ago,1 manganese(III)-based oxidative free
radical reaction has become a powerful synthetic
method.2 One of the important applications of manga-
nese(III) reagent is for acetylations. For example,
Mn(OAc)3 can be used for enantioselective acylation
of a,b-unsaturated ketones3 and acetoxylation of fuller-
ene derivatives.4 However, to the best of our knowledge,
no such reagent has ever been used for N-acetylation
reactions. We report here the first example of
Mn(OAc)3-promoted regioselective N-acetylation of 1,3-
disubstituted thioureas in the synthesis of N-acetyl-
ureas.
We first attempted the acetylation using equimolar
amount of Mn(OAc)3Æ2H2O and 1,3-di-p-tolylthiourea
1b in MeCN. The 1-acetyl-1,3-di-p-tolylurea 2b was gen-
erated in 10% yield. At a 2:1 molar ratio of Mn(OAc)3Æ
2H2O to 1b, the yield of 2b was improved to 66%
(Scheme 1). Reactions in different solvents (CH2Cl2,
EtOH, MeOH, and AcOH) and at different tempera-
tures were also attempted, but no further yield improve-
ment was observed. The structure of compound 2b
(R = p-tolyl) was confirmed by X-ray crystallography
analysis (Fig. 1).
Under the optimized conditions using 2 equiv of
Mn(OAc)3Æ2H2O and MeCN as a solvent, reactions of
symmetrical 1,3-diarylthioureas were performed and
results are listed in Table 1.13 It was found that 1,3-
diarylthioureas afforded N-acetylated products in good
to excellent yields (Table 1, entries 1–10). In contrast,
only trace amount of product was detected from reac-
tions of 1,3-dialkylthioureas (Table 1, entries 11–12).
Ureas and thioureas are useful synthons for the con-
struction of heterocyclic compounds.5 N-acylureas have
important agrochemical6 and pharmaceutical applica-
tions.7 Dopamine D2 agonist Cabergoline, for example,
has been used for the treatment of Parkinson’s disease.8
For the synthesis of N-acylureas,9 direct acylation of
symmetrical ureas10 or carbodiimides11 is an efficient
approach. However, because the reactions are not regio-
selective, only symmetrical ureas or carbodiimides pro-
duce single products.12 The Mn(OAc)3-mediated N-
acetylation reactions described in this letter can be used
to produce single N-acetylureas from symmetrical or
asymmetrical thioureas bearing aryl and alkyl groups.
Asymmetrical 1,3-disubstituted thioureas 314 were
used to study the regioselectivity of acetylation
reactions (Table 2). We found that reactions of
O
H
N
H
N
O
Mn(OAc)3.2H2O
CH3CN, reflux
R
R
R
N
R
N
H
S
1
2
*
Corresponding authors. Tel./fax: +86 512 65112371 (J.-P.Z.); tel.: +1
412 826 3062; fax: +1 412 826 3053 (W.Z.); e-mail addresses:
wuyanhong@pub.sz.jsinfo.net; w.zhang@fluorous.com
R = Aryl
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.013

2324
X.-J. Mu et al. / Tetrahedron Letters 47 (2006) 2323–2325
Table 2. Acetylation of asymmetrical disubstituted thioureas 3a–k
O
O
H
H
Mn(OAc)3.2H2O
N
N
R2
R2
R1
N
R1
4
N
CH3CN, reflux
3 h
H
S
3
R1 = aryl; R2 = alkyl
Entry
Product
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
Ph
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Propyl
68
60
62
73
64
65
59
60
71
64
59
o-MeC6H4
m-MeC6H4
p-ClC6H4
p-IC6H4
Ph
p-MeC6H4
m-MeC6H4
p-ClC6H4
p-IC6H4
Ph
Figure 1. X-ray crystal structure of compound 2b.
4g
4h
4i
Table 1. Acetylation of disubstituted thioureas 1a–l
10
11
4j
4k
O
O
H
H
Mn(OAc)3.2H2O
N
N
R
a After flash column chromatography.
R
R
N
R
N
CH3CN, reflux
3 h
H
S
1a-l
2a-l
Entry
Product
R
Yielda (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
p-MeC6H4
72
66
63
76
63
86
76
88
69
52
Trace
Trace
o-MeC6H4
m-MeC6H4
p-MeOC6H4
p-ClC6H4
o-ClC6H4
p-BrC6H4
m-BrC6H4
p-IC6H4
2g
2h
2i
10
11
12
2j
2k
2l
Benzyl
Cyclohexyl
a After flash column chromatography.
Figure 2. X-ray crystal structure of compound 4e.
1-aryl-3-alkylthioureas had similar or slightly lower
yields than those of symmetrical 1,3-diarylthioureas,
and only single regioisomer was isolated from reactions
of asymmetrical 1,3-disubstituted thioureas. The struc-
ture of product 4e was confirmed by X-ray crystallogra-
phy analysis (Fig. 2).
H
H
N
N
R2
N
N
Mn(OAc)3
R2
1
1
R
R
O
O
S
SH
SH
N
H
major
5
Mn
3
AcO
OAc
A possible mechanism for the regioselective N-acetyla-
tion is proposed in Scheme 2. 1-Aryl-3-alkylthiourea 3
can exist as isothioureas 5 or 6, in which 5 is more stable.
Compound 5 reacts with Mn(OAc)3 to produce 7. The
oxygen attack followed by the fragmentation of Mn(II)
and release of H2S15 produces 8. This compound under-
goes O!N acyl migration16 to give N-acetylurea 4. The
aryl group is needed to promote the acetylation of 7.
This mechanism explains why yields from reactions of
1,3-diarylthioureas were slightly higher than that of 1-
aryl-3-alkylthioureas, and why it was difficult to acetyl-
ate 1,3-dialkylthioureas.
H
N
7
N
1
R
R2
- Mn (II)
- H2S
minor
6
R1 = aryl
R2 = alkyl
1
R
O
O
N
O
R2
R2
N
N
H
O
1
H
R
4
8
Scheme 2. Proposed mechanism for N-acetylation.
In summary, Mn(III)-mediated N-acetylation of 1,3-
disubstituted thioureas has been developed for regio-
selective synthesis of N-acetylureas. The reaction can
be performed under mild conditions and give products
in good yields.
Acknowledgements
We thank the Key Laboratory of Organic Synthesis of
Jiangsu Province and Suzhou Scientific Committee, for
financial supports (JSK016 and SG 0219).

X.-J. Mu et al. / Tetrahedron Letters 47 (2006) 2323–2325
2325
8. Brambilla, E.; Di Salle, E.; Briatico, G.; Mantegani, S.;
Temperilli, A. Eur. J. Med. Chem. 1989, 24, 421.
Supplementary data
9. Ravn, J.; Ankersen, M.; Begtrup, M.; Lau, J. F. Tetra-
hedron. Lett. 2003, 44, 6931, and references cited therein.
10. (a) Weisz, I. Hung. Patent 49848; Chem. Abstr. 1990, 113,
171518; (b) Dmitrichenko, M. Y.; Rozinov, V. G.;
Donskikh, V. I.; Ratovskii, G. V.; Sergienko, L. M.;
Dolgushin, G. V.; Valeev, R. B. Zh. Obshch. Khim. 1988,
58, 2252–2261; (c) Yamada, K.; Kishikawa, K.; Kohmoto,
S. Chem. Lett. 1988, 351; (d) Panzeri, A.; Ceriani, L.;
Griggi, P.; Nesi, M. Eur. Patent 523668; Chem. Abstr.
1993, 118, 234337; (e) Panzeri, A.; Nesi, M.; DiSalle, E.
WO Patent 9220700; Chem. Abstr. 1993, 118, 124875; (f)
Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004, 1355.
11. (a) Corriu, R. J. P.; Gerard, F. L.; Perot-Petta, M.
Synthesis 1991, 954; (b) Anglada, J. M.; Campos, T.;
Camps, F.; Moreto, J. M.; Pages, L. J. Heterocycl. Chem.
1996, 33, 1259; (c) Zimmermann, D. M.; Olofson, R. A.
Tetrahedron Lett. 1970, 11, 3453.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.02.013.
References and notes
1. Bush, J. B., Jr.; Finkbeiner, H. J. Am. Chem. Soc. 1968,
90, 5903; See also Williams, G. J.; Hunter, N. R. Can. J.
Chem. 1976, 54, 3830.
2. Reviews on manganese(III)-based oxidative free radical
reaction: (a) Snider, B. B. Chem. Rev. 1996, 96, 339; (b)
Melikyan, G. G. Synthesis 1993, 833; For recent examples
of manganese(III)-based radical reactions, see: (c) Demir,
A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003, 68,
578; (d) Zhang, Z.; Wang, G.-W.; Miao, C.-B.; Dong,
Y.-W.; Shen, Y.-B. Chem. Commun. 2004, 1832; (e) Snider,
B. B.; Duvall, J. R. Org. Lett. 2004, 6, 1265–1268; (f)
Swain, N. A.; Brown, R. C. D.; Bruton, G. J. Org. Chem.
2004, 69, 122; (g) Huang, J. W.; Shi, M. J. Org. Chem.
2005, 70, 3859.
3. Mn(OAc)3-mediated acetoxylation of a,b-unsaturated
ketones: (a) Demir, A. S.; Camkerten, N.; Gercek, Z.;
Duygu, N.; Reis, O.; Arikan, E. Tetrahedron 1999, 55,
2441; (b) Demir, A. S.; Hamamci, H.; Doganel, F.;
Camkerten, N.; Aksoy-Cam, H. Turkish J. Chem. 2000,
24, 141; (c) Demir, A. S.; Hamamcl, H.; Sesenoglu, O.;
Aydogan, F.; Capanoglu, D.; Neslihanoglu, R. Tetra-
hedron: Asymmetry 2001, 12, 1953; (d) Demir, A. S.;
Sesenoglu, O. Org. Lett. 2002, 4, 2021; (e) Tanyel, C.;
Iyigun, C. Tetrahedron 2003, 59, 7135; (f) Demir, A. S.;
Reis, O.; Igdir, A. C. Tetrahedron 2004, 60, 3427.
4. Chen, Z. X.; Wang, G. W. J. Org. Chem. 2005, 70, 2380.
5. Zeng, R. S.; Zou, J. P.; Zhi, S. J.; Chen, J.; Shen, Q. Org.
Lett. 2003, 5, 1657.
12. Scott, W. A.; Kevin, E. H.; Andrew, M. A.; Peter, G. M.
W. J. Org. Chem. 2002, 67, 7147.
13. General procedures for preparation of 1-acetyl-1,3-di-p-
tolylurea 2b: To a solution of 1,3-di-p-tolylthiourea 1b
(0.26 g, 1 mmol) dissolved in 15 mL of acetonitrile was
added Mn(OAc)3Æ2H2O (0.54 g, 2 mmol) in two portions.
The solution was refluxed for 3 h until the color of
solution changed from brown to pale yellow. After the
removal of acetonitrile under vacuum, the residue was
dissolved in acetone, filtered, concentrated and purified by
flash column chromatography on silica gel and eluted with
4:1 petroleum ether/acetone to give 1-acetyl-1,3-di-p-
tolylurea 2b in 66% yield; mp 138–140 °C; IR (KBr,
1
cmꢀ1) t 3211, 1713, 1663; H NMR (CDCl3): d 11.35 (s,
1H, NH), 7.45–7.09 (m, 8H, 2C6H4), 2.40 (s, 3H, CH3),
2.29 (s, 3H, CH3), 1.99 (s, 3H, CH3); 13C NMR (CDCl3): d
175.5, 152.4, 139.5, 136.7, 135.6, 134.0, 130.8, 129.9, 129.1,
120.5, 27.0, 21.6, 21.3; HRMS (M+) m/z calcd for
C17H18N2O2 282.1368, found 282.1364.
6. (a) Wellinga, K.; Mulder, R.; van Daalen, J. J. J. Agric.
Food Chem. 1973, 21, 348; (b) Nakagawa, Y.; Kitahara,
K.; Nishioka, T.; Iwamura, H.; Fujita, T. Pestic. Biochem.
Physiol. 1984, 21, 309.
7. Goodman, L. S.; Gilman, A. The Pharmacological Basis of
Therapeutics, 6th ed.; MacMillan: New York, 1980.
14. Ramadas, K.; Srinivasan, N.; Janarthanan, N. Tetra-
hedron Lett. 1993, 34, 6447.
15. H2S was checked by Pb(OAc)2 test paper.
16. Volonterio, A.; Arellano, C. R.; Zanda, M. J. Org. Chem.
2005, 70, 2161.