Intramolecular aminochalcogenation and diamination of alkenes employing N-iodosuccinimide

Article abstract of DOI:10.1016/j.tetlet.2015.01.154

A NIS-mediated intramolecular diamination and aminosulfuration of alkenes with N-alkyl or N-aryl thioureas is reported. A chiral cyclic thiourea was also synthesized by the methodology. The protocol is also proven to be efficient in the intramolecular dia

Full text of DOI:10.1016/j.tetlet.2015.01.154

Accepted Manuscript
Intramolecular aminochalcogenation and diamination of alkenes empolying N-
iodosuccinimide
Jun Zhang, Xuejun Zhang, Weijie Wu, Gengtao Zhang, Sheng Xu, Min Shi
PII:
S0040-4039(15)00204-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.154
TETL 45824
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
25 November 2014
14 January 2015
23 January 2015
Please cite this article as: Zhang, J., Zhang, X., Wu, W., Zhang, G., Xu, S., Shi, M., Intramolecular
aminochalcogenation and diamination of alkenes empolying N-iodosuccinimide, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.01.154
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Intramolecular aminochalcogenation and
diamination of alkenes empolying N-
iodosuccinimide
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Jun Zhang∗, Xuejun Zhang, Weijie Wu, Gengtao Zhang, Sheng Xuand Min Shi

1
Tetrahedron Letters
journal homepage: www.els evier.com
Intramolecular aminochalcogenation and diamination of alkenes empolying N-
iodosuccinimide
Jun Zhanga, ∗, Xuejun Zhanga, Weijie Wua, Gengtao Zhanga, Sheng Xua nd Min Shia,b
aKey Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and
Technology, 130 Mei Long Road, Shanghai 200237, China.
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032 China
ARTICLE INFO
ABSTRACT
Article history:
Received
A NIS-mediated intramolecular diamination and aminosulfuration of alkenes with N-alkyl or N-
aryl thioureas is reported. A chiral cyclic thiourea was also synthesized by the methodology. The
protocol is also proven to be efficient in the intramolecular diamination and/or
aminooxygenation of alkenes with N-alkyl or N-aryl ureas and ones with N-carbamate
sulfamides. The resulting bicyclic thiourea could be further transformed into bicyclic guanidine.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Aminosulfuration
Diamination
Alkenes
N-iodosuccinimide
Aminooxygenation
Vicinal diamines occur in a variety of bioactive molecules and
natural products, and serve as building blocks in organic
transformation, and chiral ligands for stereoselective synthesis.1
Direct difunctionalization of alkenes is clearly an attractive route
to generate vicinal diamines,2 and, since 2005, much resurgent
attention have been paid to the development of efficient catalytic
procedures for Pd(II)-,3 Cu(II)-,4 Ni(II)-,5 and Au(I)-mediated6
intramolecular diamination of alkenes. Very recently, metal-free
difunctionalization of alkenes have been also established to
circumvent the toxicity and cost issue associated with metal
catalysts. Muñiz et al. reported the intramolecular diamination
and aminooxygenation of alkenes with N-sulfonyl ureas in the
presence of iodonium reagent IPy2BF4 (Py = pyridine).3
Widenhoefer et al. further employed N-iodosuccinimide (NIS) as
an efficient promoter for the intramolecular diamination and
alkoxyamination of alkenes with N-sulfonyl ureas.7 Hennecke et
al. also reported an intramolecular anti-selective diamination
reaction of alkenes in the presence of NIS.8 Recently, Muñiz et
al. presented an intramolecular diamination of alkenes with N-
Boc sulfamides and N-sulfonyl ureas employing bromide
catalysis with sodium chlorite as oxidant.9 Michael et al. reported
an intramolecular aminooxygenation of alkenes with ureas using
PhI=O and an acid promoter.10 Wirth et al. also developed
stereoselective aminooxygenation and diamination of alkenes
using chiral ArI(OAc)2 /acid systems.11 Chang et al. employed
PhI(OAc)2 and a halide additive to improve the intramolecular
diamination of alkenes with N-sulfonyl ureas.12
However, most employed alkene substrates in these processes
are those having a N-sulfonyl, or N-carbamate group, and, in the
case of ones with N-alkyl or N-aryl ureas and sulfamides, excess
metal oxidant, high temperature and extended reaction time are
required to achieve considerable yields for the diamination of
alkenes (a, Scheme 1).4 Metal-free methods for intramolecular
diamination of alkenes with N-alkyl or N-aryl ureas are still rare,
and often suffered from the formation of aminooxygenation
products and poor yield. (b, Scheme 1).7,11
As an important vicinal diamine derivatives, imidazolidine-2-
thiones have been reported to exhibit a diverse range of
biological and pharmaceutical activities,13 represent excellent
ligands in bioactive coinage metal complexes,14 and serve as
important precursors for the synthesis of guanidines.15 Although a
variety of functional groups were used as nitrogen sources for
oxidative difunctionalization of alkenes, thioureas haven’t been
employed for this process yet. As part of our ongoing interest in
the development of new methodology for the synthesis of cyclic
vicinal diamines and their application in catalysis,16 herein we
first report a NIS-mediated intramolecular diamination and
aminosulfuration of alkenes with N-alkyl or N-aryl thioureas (c,
Scheme 1). The protocol is also applied successfully to the
oxidative difunctionalization of those with N-alkyl or N-aryl
ureas and N-carbamate sulfamides.
———
∗ Corresponding author. Tel.: +86-021-64252995; e-mail: zhangj@ecust.edu.cn

2
Tetrahedron
base led to an improved total yield towards diamination and
aminosulfuration (Table 1, entry 4). Using NBS, almost no
formation of alkene difunctionalization product could be
observed (Table 1, entry 5). Lowering the reaction temperature to
o
-30 C led to a decreased yield (Table 1, entry 6), and reducing
the amount of NIS to 1.5 equiv resulted in significant decrease in
reaction yield (Table 1, entry 7). Using either CH2Cl2 or THF as a
solvent led to poor yields (Table 1, entries 8 and 9).
Under optimized condition, the generality and scope of this
synthetic protocol were investigated (Table 2). Different from N-
2-allylphenyl thiourea 1a, N-pentenyl thioureas 1b~1d with a
second N-alkyl substituent were cyclized to afford cyclic
thioureas 2b~2d as an only product with moderate yields
(40~72%), respectively (Table 2, entries 2~4). Notably, upon
treatment with NIS, thiourea 1c having a chiral auxiliary could be
cyclized to form the diastereomeric products (S, S)-2c and (R, S)-
2c as a mixture with moderate diastereoselectivity (75:25 dr)
(Table 2, entry 3). The diastereomers (S, S)-2c and (R, S)-2c can
be easily separated by recrystallization. The absolute
configuration of (S, S)-2c was confirmed by the X-ray diffraction
analysis of its single crystals (Figure 1).17 The chiral auxiliary
methodology affords an efficient method for synthesis of chiral
cyclic thiourea. Contrary to 1b~1d, N-pentenyl thioureas 1e~1g
with a second N-aryl substituent were cyclized to afford 2-
aminothiazoline thioureas 3e~3g as an only product with low
yields (15~31%), respectively (Table 2, entries 5~7). Either
electron-deficient substituent (4-CF3) or electron-donating group
(4-OMe) was tolerated towards the process. We further examined
the reactivity of NIS towards the alkene difunctionalization with
N-alkyl or N-aryl ureas 4a~4d. Due to the low solubility of
4a~4d in toluene, we carried out the reactions in MeCN. Upon
treatment with NIS, 4a~4d were cyclized with good to excellent
total yields (63~98 %), respectively (Table 2, entries 8~11).
Aminooxygenation product 6a was obtained as an only product
in the cyclization of N-2-allylphenyl urea 4a (Table 2, entry 8).
Reaction of N-2-allylphenyl urea 4b with NIS also predominately
gave the aminooxygenation product 6b, with diamination product
5a isolated as a minor compound (Table 2, entry 9). Under the
reaction condition, both N-pentenyl ureas 4c and 4d gave the
corresponding aminooxygenation products and diamination
products in high total yields (86~96 %) but low selectivity (Table
2, entries 10 and 11).
Scheme 1. Intramolecular diamination of alkenes with N-
alkyl or N-aryl substrates
Bromine and iodine reagents are often used to activate and
oxidize alkene through the formation of halonium ions. We
started our investigation with reacting halogen reagents with the
difunctionalization of N-alkenyl thiourea 1a (Table 1). Among
common used iodine reagent, NIS exhibited the most activity to
promote this process to afford a mixture of diamination product
2a and aminosulfuration product 3a with low selectivity (Table 1,
entry 1). Other iodine reagents such as Py2IBF4 and
PhI(OAc)2/TMSOTf led to disappointing results (Table 1, entries
2 and 3), though they were efficient promoters under same
reaction
conditions
towards
other
intramolecular
difunctionalizations of alkenes.3d,11 Adding NaHCO3 (1 equiv) as
Table 1. Intramolecular diamination and aminosulfuration of
thiourea 1a[a]
Yield (%)[b]
Reagent
(equiv)
Base
(1 equiv)
Solvent
Toluene
Entry
2a
3a
NIS (2.0)
–
–
Toluene
Toluene
1
2
29
19
Py2IBF4 (1.5)
0
2
10
3
PhI(OAc)2
(2.0) TMSOTf
(1.0)
3[c]
–
CH2Cl2
4
NIS (2.0)
NBS (2.0)
NIS (2.0)
NIS (1.5)
NIS (2.0)
NIS (2.0)
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
34
0
22
4
Figure 1. Molecular structure of (S,S)-2c.
5
6[d]
7
15
5
24
11
23
12
8
0
9
25
[a] Reaction conditions: Solvent, 0~25 oC, 4 h. [b] Isolated
yields. [c] -78~25 oC. [d] -30 oC.

3
Table 2. Intramolecular Aminochalcogenation and Diamination of
Thioureas and Ureas[a]
Chart 1. Intramolecular Diamination of Sulfamides[a][b]
7
8
entry
Starting Material
Product[b]
8a (84 %)
8b (77 %)
1
Muñ
iz et
al.
1a
1b
2a (34 %)
3a (22 %)
recentl
y
presen
2
3
4
8c (89 %)
8d (90 %)
2b (40 %)
[a] Reaction conditions: NIS (2 equiv), NaOMe (2 equiv),
DMF, 40 oC, 8 h. [b] Isolated yields.
ted
a
KBr-
catalyz
(S,S)-2c/(R,S)-2c
(72 %, dr = 3:1)
ed intramolecular diamination of alkenes with N-carbamate
sulfamides using sodium chlorite as oxidant in the presence of
NaOAc as base.9 We also tested our methodology in the process,
and NIS was proven to be an efficient promoter towards the
process (Chart 1). In the presence of 2 equiv NIS and NaOMe as
a base, methyl, benzyl, and tert-butyl substituted N-carbamate
sulfamides were successfully transformed into the corresponding
dicyclic sulfamides 8a~8c in good yields (77~89 %),
respectively. Notably, the 6-membered ring sulfamide 8d could
also be prepared in high yield of 90 % through the methodology.
(S)-1c
1d
2d (52 %)
5
6
7
Ar=Ph, 1e
3e (15 %)
3f (31 %)
3g (15 %)
Ar = 4-CF3C6H4, 1f
Ar = 4-OMeC6H4, 1g
8
9
4a
6a (63 %)
Scheme 2. Diamination of internal alkene
An experiment was carried out to investigate the mechanism
of the two C-N bond-forming steps in the NIS-promoted
intramolecular diamination of alkenes with N-carbamate
sulfamides (Scheme 2). Treatment of (E)-7e with NIS offered
anti-configured 8e as a single diastereoisomer, indicating that the
process is stereospecific regarding the double bond geometry.
The result also proved the new methodology to be compatible
with internal alkenes.
4b
4c
5b (24 %)
5c (38 %)
5d (55 %)
6b (74 %)
6c (48 %)
6d (41 %)
10
11
Ph
Ph
Ph
Ph
4d
(COCl)2
toluene, 60 oC,
16 h
N
N Bn
N
N
Bn
Cl
S
[a] Reaction conditions: NIS (2 equiv), Solvent (toluene as solvent for
1a~1g; acetonitrile as solvent for 4a~4d), NaHCO3 (1 equiv), 0~25 oC,
2~3 h. [b] Isolated yields.
Cl
2b
Ph
Ph
BnNH2, Et3N
MeCN, 60 oC,
16 h
N
N
Bn
N
Bn
34 % for two steps
9,
Scheme 3. Synthesis of cyclic guanidine from bicyclic thiourea
Cyclic guanidines are widely present in a variety of the marine
natural products,18 and used as organocatalysts,19 ligands in metal
complexes,20 and powerful organic bases.21 Using a literature
method,15 chlorination of cyclic thiourea 2b with oxalyl chloride

4
Tetrahedron
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3).
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Belmonte, M. Escudero-Adán, E. C. Martin, E. Muñiz, K. Chem.
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In conclusion, we present a NIS-mediated intramolecular
diamination and aminosulfuration of alkenes with N-alkyl or N-
aryl thioureas. A chiral cyclic thiourea was also synthesized by
the methodology. The protocol was further submitted to the
oxidative difunctionalization of alkenes with N-alkyl or N-aryl
ureas and those with N-carbamate sulfamides. The resulting
bicyclic thiourea could be readily converted into bicyclic
guanidine. The methodology provides efficient way for the facile
syntheses of bicyclic thioureas, ureas, and guanidines.
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Tang, C. Ho, B. Ankersen, M. Stidsen, C. E. Crider, A. M. J.
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Jurca, B. C. Ilies, M. A. Eur. J. Med. Chem. 1998, 33, 83.
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Chem. Commun. 2012, 48, 9192; (c) Zhang, J. Fu, J. Su, X. Qin,
X. Zhao, M. Shi, M. Chem. Commun. 2012, 48, 9625; (d) Zhang,
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17. CCDC 1017398 ((S,S)-2c) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Financial support from Shanghai Pujiang Talent Program
(11PJ1402500), and the National Natural Science Foundation of
China for financial support (21171056, u1162111 and u1362111)
is greatly acknowledged.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/
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5
Intramolecular
Aminochalcogenation And
Diamination of Alkenes Empolying
N-iodosuccinimide
Jun Zhang∗, Xuejun Zhang, Weijie Wu, Gengtao Zhang,
Sheng Xuand Min Shi
A NIS-mediated intramolecular diamination and
aminosulfuration of alkenes with N-alkyl or N-aryl
thioureas has been developed, which is also proven
to be efficient in the intramolecular diamination
and/or aminooxygenation of alkenes with N-alkyl
or N-aryl ureas and ones with N-carbamate
sulfamides.