NIS/PhI(OAc)2-mediated diamination/oxidation of N-alkenyl formamidines: Facile synthesis of fused tricyclic ureas

Article abstract of DOI:10.1002/asia.201403281

Facile synthesis of bicyclic ureas by NIS/PhI(OAc)₂-mediated diamination/oxidation of N-alkenyl formamidines is reported. Bulky aromatic groups such as 2,6-diisopropylphenyl and mesityl and alkyl groups were tolerated towards the process. Sever

Full text of DOI:10.1002/asia.201403281

DOI: 10.1002/asia.201403281
Communication
Oxidation
NIS/PhI(OAc) -Mediated Diamination/Oxidation of N-Alkenyl
2
Formamidines: Facile Synthesis of Fused Tricyclic Ureas
[a]
[a]
[a]
[a]
[a]
[a, b]
Jun Zhang,* Weijie Wu, Xuejun Zhang, Gengtao Zhang, Sheng Xu, and Min Shi
[8]
reaction of alkenes in the presence of NIS. Recently, MuÇiz
et al. presented the intramolecular diamination of alkenes with
N-Boc sulfamides and N-sulfonyl ureas employing bromide cat-
Abstract: Facile synthesis of bicyclic ureas by NIS/
PhI(OAc) -mediated diamination/oxidation of N-alkenyl
2
formamidines is reported. Bulky aromatic groups such as
[9]
alysis with sodium chlorite as an oxidant. Michael et al. re-
ported an intramolecular aminooxygenation of alkenes with
2,6-diisopropylphenyl and mesityl and alkyl groups were
tolerated towards the process. Several control experi-
ments have been performed, and the reaction outcomes
indicate that the oxidation process is probably concerted
with the diamination cyclization, and succinimide generat-
ed from NIS-mediated aminoamidiniumation step promot-
[10]
ureas using PhI=O and an acid promoter. Wirth et al. also
developed the stereoselective aminooxygenation of alkenes
[11]
with ureas using an ArI(OAc) /acid system. Chang et al. em-
2
ployed PhI(OAc) and a halide additive to improve the intramo-
2
[12]
lecular diamination of alkenes with N-sulfonyl ureas.
ed the PhI(OAc) -mediated oxidation step. The new meth-
2
Most employed alkene substrates in these processes are
those having a second N-sulfonyl or N-carbamate substituent,
and very few cases involved those with a second N-alkyl or N-
aryl substituent. N-alkyl or N-aryl bicyclic ureas could be ob-
odology provides an efficient method for the synthesis of
fused tricyclic ureas.
II
tained by Cu -mediated intramolecular diamination of an
[4]
Vicinal diamines occur in a variety of bioactive molecules and
natural products, and serve as building blocks in organic trans-
formations as well as chiral ligands for stereoselective synthe-
alkene, but excess metal oxidant, a high temperature, and an
extended reaction time are required to achieve considerable
yields (a, Scheme 1). Metal-free methods for intramolecular dia-
[
1]
sis. Direct difunctionalization of alkenes is clearly an attractive
[
2]
route to generate vicinal diamines, and, since 2005, increas-
ing attention has been paid to the development of efficient
II [3]
II [4]
II [5]
I
[6]
catalytic procedures for Pd -, Cu -, Ni -, and Au-mediated
intramolecular diamination of alkenes. Very recently, metal-free
difunctionalization of alkenes has also been established to cir-
cumvent the toxicity and cost associated with metal catalysts.
MuÇiz et al. reported the intramolecular diamination and ami-
nooxygenation of alkenes with N-sulfonyl ureas in the pres-
[
3d]
ence of the iodonium reagent IPy BF (Py=pyridine). Widen-
2
4
hoefer et al. further employed N-iodosuccinimide (NIS) as an
efficient promoter for the intramolecular diamination and al-
[
7]
koxyamination of alkenes with N-sulfonyl ureas. Hennecke
et al. also reported an intramolecular anti-selective diamination
[
a] Dr. J. Zhang, W. Wu, X. Zhang, G. Zhang, Dr. S. Xu, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials
and
Institute of Fine Chemicals
School of Chemistry&Molecular Engineering
East China University of Science and Technology
1
30 Mei Long Road, Shanghai 200237 (China)
E-mail: zhangj@ecust.edu.cn
[b] Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
3
54 Fenglin Road, Shanghai 200032 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403281.
Scheme 1. Intramolecular diamination of alkenes with N-alkyl or N-aryl sub-
strates.
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Communication
mination of alkenes with N-alkyl or N-aryl ureas are still rare
Table 1. NIS/PhI(OAc)
formamidines: facile syntheses of fused tricyclic ureas.
2
-mediated diamination/oxidation of N-alkenyl
and often suffer from the formation of aminooxygenation
[a]
[
7,11]
products and poor yield (b, Scheme 1).
Recently, we have developed several synthetic strategies for
the facile preparation of various N-heterocyclic carbene precur-
[
13]
sor azolium salts starting from formamidines. Formamidines
could be prepared readily from one-pot condensation reac-
tions of two primary amines and orthoformate, and have only
two nitrogen reactive sites (Scheme 2). Therefore, we envisiond
[b]
Entry Starting Material
1
Product [%]
1a
1b
1c
1d
1e
1 f
2a (81)
2b (58)
2c (52)
2d (77)
2e (34)
2 f (35)
2
3
4
5
6
Scheme 2. Synthesis of N,N’-disubstituted formamidines.
that formamidines could be used as nitrogen sources for the
intramolecular diamination of alkenes. Herein, we report an un-
precedented NIS/PhI(OAc) -mediated diamination/oxidation of
2
N-alkenyl formamidines for the synthesis of bicyclic ureas, in
which succinimide generated from the NIS-mediated aminoa-
midiniumation step promoted the PhI(OAc) -mediated oxida-
2
tion step (c, Scheme 1).
Very recently, we found an efficient NIS-mediated aminoami-
diniumation of amidines for the synthesis of bicyclic imidazoli-
[
14]
dinium salts (Scheme 3).
Besides NIS, PhI(OAc)2 has also
7
1g
2g (30)
8
9
1h
1i
2h (81)
2i (77)
Scheme 3. NIS-mediated aminoamidiniumation of amidines.
been widely employed in both transition metal-catalyzed and
Lewis acid-promoted intramolecular difunctionalization of al-
kenes, due to its high oxidation potential. Therefore, we fur-
ther examined the reactivity of NIS towards the process in the
10
1j
2j (0)
presence of PhI(OAc) . Interestingly, combining NIS with
2
[
a] Reaction conditions: 1 equiv of NIS, CH
2 2
Cl (0.1m), 258C, 2–3 h. [b] Iso-
PhI(OAc) as oxidant led to unexpected formation of bicyclic
2
lated yields.
ureas 2 (Table 1). It was shown that bulky aromatic substitu-
ents such as 2,6-diisopropylphenyl and mesityl groups (for 2a
and 2b, Table 1) and alkyl groups (for 2c–2e, Table 1) were tol-
erated towards the process. Introducing a methoxy group in
the N-aryl substituent resulted in a substrate with lower reac-
tivity (for 2 f and 2g, Table 1), while, with formamidines 1h
and 1i bearing a methyl group in the N-aryl substituent, the
method proved to be more efficient, and the desired products
A plausible reaction mechanism for the NIS-mediated amino-
[14]
amidiniumation is as follows (Scheme 4).
Formamidine
1 reacts with NIS to afford an N-iodinated formamidine A, the
N-I group of which further oxidizes the double bond of the
alkene to form a cyclic iodinium ion B. Intermediate B subse-
quently undergoes a nucleophilic backside attack of the nitro-
gen atom to give cyclic formamidine C. Intermediate C under-
goes amidiniumation and closes the second ring to generate
aminoamidiniumation product 3.
Several control experiments were designed to investigate
the mechanism of the unexpected diamination/oxidation pro-
cess. Firstly, aminoamidiniumation product 3a, prepared from
1
h and 1i were formed in good yields (for 2h and 2i, Table 1).
This result indicates that the presence of a methoxy group in
the N-aryl substituent probably led to a lower stability of the
intermediate and/or product. Unfortunately, the methodology
did not work with N-4-pentenyl formamidine 1j (Entry 10,
Table 1). The structure of 2d was identified by NMR spectro-
[
4b]
scopic comparison with an authentic sample.
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These reaction outcomes indicate that the oxidation process
is probably concerted with the diamination cyclization, and
succinimide generated from aminoamidiniumation step pro-
moted the oxidation step. The diamination/oxidation process
presents a sustainable synthetic strategy to improve the syn-
thetic efficiency and allows the byproduct of one reaction to
be used to promote another reaction in a one-pot reaction.
The synthetic utility of fused tricyclic ureas 2 was preliminari-
ly investigated. Imidazolidine-2-thiones have been reported to
Scheme 4. Proposed reaction mechanism.
NIS-mediated aminoamidiniumation of 1a, was treated with
PhI(OAc)2 (2 equiv), and a low yield (30%) was obtained
[Eq. (1)]. Considering the transformation of NIS into succini-
mide during the aminoamidiniumation process and the poten-
exhibit a diverse range of biological and pharmaceutical activi-
[
2r,15]
[15]
tial reactivity of succinimide towards PhI(OAc)2,
we further
ties,
and represent excellent ligands in bioactive coinage
[16]
reacted 2a with PhI(OAc) (2 equiv) in the presence of succini-
metal complexes. Treatment of 2d with Lawesson’s reagent
smoothly afforded the desired thiourea 7 (Scheme 5).
2
mide (1.2 equiv), and an improved yield of 51% was achieved
[Eq. (2)]. Although the yield is still lower than that obtained
under the reaction conditions of the one-pot diamination/oxi-
dation of 1a, it should be noted that succinimide, a byproduct
generated from the NIS-mediated aminoamidiniumation step,
promoted the PhI(OAc) -mediated oxidation step. The method
2
also worked for the transformation of monocyclic imidazolidini-
um salt 4 into the corresponding monocyclic urea 5 [Eq. (3)].
Next, urea 6 was subjected to the standard reaction conditions
of the diamination/oxidation process, and the desired product
Scheme 5. Transformation of urea 2d into thiourea 7.
2
d was not observed. This excludes the possibility of oxidation
In conclusion, we present an unprecedented NIS/PhI(OAc)2-
mediated diamination/oxidation of N-alkenyl formamidines for
the synthesis of fused tricyclic ureas, in which succinimide gen-
erated from the NIS-mediated aminoamidiniumation step pro-
of the C1 atom occurring as the initial step [Eq. (4)]. Finally,
PhI(OAc) (2 equiv) itself could not transform formamidine 1a
into urea 2a [Eq. (5)].
2
motes the PhI(OAc) -mediated oxidation step. The resulting tri-
2
cyclic urea could be readily converted into a tricyclic thiourea.
The methodology provides efficient ways for the facile synthe-
sis of fused tricyclic ureas and fused tricyclic thioureas.
Acknowledgements
Financial support from Shanghai Pujiang Talent Program
(
11J1402500), the Shanghai Municipal Committee of Science
and Technology (11JC1402600), National Basic Research Pro-
gram of China (973)-2010CB833302, and the National Natural
Science Foundation of China for financial support (21171056,
u1162111 and u1362111) is greatly acknowledged.
Keywords: alkenes · aminoamidiniumation · deamination · N-
iodosuccinimide · oxidation
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Received: November 11, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
Oxidation
Jun Zhang,* Weijie Wu, Xuejun Zhang,
Gengtao Zhang, Sheng Xu, Min Shi
&& – &&
As simple as riding a tricycle: Facile
synthesis of fused tricyclic ureas by NIS/
ed. In this approach, succinimide, the
byproduct of the diamination step,
functions to promote the oxidation
step.
NIS/PhI(OAc) -Mediated Diamination/
2
Oxidation of N-Alkenyl Formamidines:
Facile Synthesis of Fused Tricyclic
Ureas
PhI(OAc) -mediated diamination/oxida-
2
tion of N-alkenyl formamidines is report-
Chem. Asian J. 2015, 00, 0 – 0
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These are not the final page numbers! ÞÞ