Metal-free aminoamidiniumation employing N-iodosuccinimide: Facile syntheses of bicyclic imidazolidiniums and cyclic vicinal diamines

Article abstract of DOI:10.1039/c4cc07082h

NIS-mediated aminoamidiniumation has been developed for the syntheses of bicyclic imidazolidinium salts, which could be readily converted into cyclic vicinal diamines.

Full text of DOI:10.1039/c4cc07082h

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COMMUNICATION
Metal-free aminoamidiniumation employing N-iodosuccinimide: facile
syntheses of bicyclic imidazolidiniums and cyclic vicinal diamines
Jun Zhang,*,a Gengtao Zhang,a Weijie Wu,a Xuejun Zhang,a and Min Shia,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
NIS-mediated aminoamidiniumation have been developed for
the syntheses of bicyclic imidazolidinium salts, which could be
readily converted into cyclic vicinal diamines.
Vicinal diamines have attracted much attention for their
Figure 1. Selected cyclic vicinal diamines and NHC carbenes
10 occurrence in a variety of bioactive molecules and natural
products, and for their use as building blocks in organic
transformation, and chiral ligands for stereoselective
synthesis.1 For example, chiral cyclic vicinal diamines A are
wellꢀknown efficient chiral catalytic source for the
15 enantioselective borane reduction of prochiral ketones (Figure
1).2 Imidazolidinꢀ2ꢀylidene carbene are among the most
important vicinal diamine deriviates due to their widespread
and spectacular applications as organocatalysts and as ligands
for organometallic catalysis.3 Elaborately tuning the structural
20 parameters of Nꢀheterocyclic carbene (NHC) scaffold could
directly and precisely influence their catalytic performance.
Recently, several typies of NHCs having a fused ring in their
scaffolds, such as B, C, and D, have been developed for
organocatalysts and as ligands for organometallic catalysis.3,4
25 The fused ring could twist the framework, and hamper
rotation of the Nꢀsubstituent, thereby rendering decomposition
pathway unfavorable, increasing the stability of catalysts,
and/or create a tunable chiral environment.
Metalꢀfree systems, such as IPy2BF4 (Py = pyridine),6d Nꢀ
35 iodosuccinimide (NIS),10 KBr/NaClO2,11 ArI(OAc)2 (or
PhI=O)/acid12, and PhI(OAc)2/ halide reagent13 systems have
been also established for this process to circumvent the
toxicity and cost issue associated with metal catalysts.
Recently, we have developed several synthetic strategies for
40 the facile preparation of various NHC carbene precursor
azolium salts starting from formamidines.14 Unsymmetric
formamidines could be prepared readily from one pot
condensation reaction of two primary amines and
orthoformate [eqn (1)].14,15 Therefore, we envisiond that the
45 N,N’ꢀdisubstituted amidines could be used as efficient
nitrogen sources. Herein, we report an NISꢀmediated
aminoamidiniumation of amidines for the synthesis of bicyclic
imidazolidinium salts [eqn (2)], which could be readily
converted into corresponding cyclic vicinal diamines A,
50 including a chiral vicinal diamine (Figure 1).
Direct difunctionalization of alkenes is clearly an
30 attractive route to generate vicinal diamines,5 and, since 2005,
much resurgent attention have been paid to the development
of efficient catalytic procedures for Pd(II)ꢀ,6 Cu(II)ꢀ,7 Au(I)ꢀ,8
and Ni(II)ꢀmediated9 intramolecular diamination of alkenes.
a Key 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.
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
formamidine 1a, which was synthesized throught one pot
55 condensation reaction of 2,4,6ꢀtrimethylaniline, allylaniline,
and triethylorthoformate in 49 % yeild. NIS (1 equiv) was
proven to be efficient to promote this process to bicyclic
imidazolidinium salts 2a, while NCS and NBS led to
disappointing results (entries 1~3, Table 1). Iodine showed
60 less reactive towards the process than NIS (entries 4, Table 1).
Eꢀmail: zhangj@ecust.edu.cn
Tel: +086 021 64252995
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032 China
Tel: +086 021 64252995
† Electronic Supplementary Information (ESI) available: Experimental
and spectroscopic data for all compounds. CCDC 1017139 (2a), CCDC
1017140 (2c), CCDC 1016877 (2i), CCDC 1017141 (2l), and CCDC
1017397 ((S,S)ꢀ5). For ESI and crystallographic data in CIF or other
electronic format See DOI: 10.1039/b000000x/
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DOI: 10.1039/C4CC07082H
Lower yields were obtained when using CH2Cl2 and THF as
solvents (entries 5 and 6, Table 1). Increasing either reaction
temperature or the amount of NIS led to lower yields (entries
7~9, Table 1), and addition of NaHCO3 as base disfavoured
the formation of 2a (entry 10, Table 1).
Chart 1. NISꢀpromoted intramolecular aminoamidiniumation of
amidine[a][b]
5
n
n
I
NIS (1~2 equiv)
H
R2,3
N
R1
Toluene, 25 o
C
N
N
R1
N
R2,3
Table 1. Intramolecular aminoamidiniumation of formamidine 1a[a]
R4
2a~2k (n = 1 or 2)
R4
1a~1k (n = 1 or 2)
I
I
I
N
N
N
N
N
N
Cy
Dipp
Mes
2a, 73%
2b, 36%
2c, 64%
Reagent
(equiv)
Yield
(%)[b]
Entry
Solvent
Additive
Ph
Ph
I
I
N
N
N
N
Dipp
Ph
I
1
2
3
4
5
6
7
8
NCS (1.0)
NBS (1.0)
NIS (1.0)
I2 (1.0)
NIS (1.0)
NIS (1.0)
NIS (1.0) [c] toluene
NIS (1.5)
NIS (2.0)
NIS (1.0)
toluene
toluene
toluene
toluene
DCM
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
trace
trace
73
2d, 42%
2e, 58%
Ph
Ph
I
I
N
N
N
N
Mes
N
N
35
49
53
64
66
59
Ph
Ph
Ph
2g, 36%
Ph
2f, 69%
Ph
2h, 77%
THF
Ph
Ph
Ph
Ph
I
I
I
Ph
Ph
toluene
toluene
toluene
N
N
Mes
N
N
Mes
N
N
p-tolyl
9
10
Ph
2k, 56%
Ph
2i, 76%
Ph
2j, 63%
NaHCO3 55
[a] Reaction conditions: Solvent (0.1 M), 25 oC, 1h. [b] Isolated
10 yields. [c] 120 oC. Mes = mesityl.
[a] Reaction conditions: NIS (1 equiv for 2a~2e, 2 equiv for
2f~2k), toluene (0.1 M), 25 oC, 1~3 h. [b] Isolated yields.
DIPP = 2,6ꢀdiisopropylphenyl.
Under optimized condition, the generality and scope of
this new synthetic protocol was investigated (Chart 1).
Besides aryl groups (for 2a and 2b, Chart 1), alkyl groups at
nitrogen atom were also tolerated (for 2c~2e, Chart 1). Yields
15 were generally moderate to good. Formamidines with
sterically demanding aryl Nꢀsubstituents, such as 2,6ꢀ
diisopropylphenyl group, were also reactive under reaction
condition (for 2b). Further study exhibited, besides
formamidines, benzamidines were tolerated towards the
20 process as well (for 2f~2k, Chart 1). This method allowed for
cyclization of benzamidines with a variety of Nꢀsubstituents,
even those with sterically demanding mesityl group (for 2f, 2i,
and 2k, Chart 1). Notably, Nꢀ5ꢀhexenyl benzamidines could
also be cyclized to form the 6ꢀmembered ring imidazolinium
25 salt 2k. Single crystals of 2a, 2c, and 2i suitable for Xꢀray
diffraction analysis were obtained (Figure S1 for 2a, Figure
S2 for 2c, and Figure S3 for 2i, see Supporting Information),
and their structures confirm the formation of the desired
imidazolinium salts.
Ph
Ph
Ph
Ph
NIS (1 equiv)
Toluene, 25 o
I
Ph
Ph
C
C
H
N
N
N
Dipp
N
Dipp
1l
2l (44%)
D
D
Ph
Ph
NIS (1 equiv)
Toluene, 25 o
I
Ph
Ph
H
N
N
N
Dipp
N
Dipp
1m (75:25, Z:E)
2m (53%, 75:25, cis:trans)
Scheme 1. Stereochemical control experiment
results of control experiments, we propose a plausible reaction
mechanism (Scheme 2). Formamidine 1 reacts with NIS to
afford an Nꢀiodinated formamidine A, the NꢀI group of which
45 further oxidizes the double bond of the alkene to form cyclic
iodinium ion B. Intermediate B is subsequently underwent a
nucleophilic backside attack of nitrogen atom to give cyclic
formamidine C. It suggests that the first CꢀN bond formation
proceeds through a transꢀaminoꢀiodination. Intermediate C
50 undergoes an SN2 amidiniumation under an inversion of
configuration to form second CꢀN bond and closes the second
ring to generate aminoamidiniumation product 2.
30
Two experiments were carried out to investigate the
mechanism of the two CꢀN bondꢀforming steps. Treatment of
(E)ꢀ1l with NIS offered antiꢀconfigured 2l as single
diastereoisomer, indicating that the process is stereospecific
regarding the double bond geometry and also proving our new
Using the resulting amidine salts 2, we finally explored
transformation of them into corresponding vicinal diamines
55 (Scheme 3). Treatment formamidine salt 2a with KOtBu in
THF resulted in a ringꢀopening process, and subsequently
hydrolysis led to form 2ꢀsubstituted indoline 3. In the case of
benzamidine salt 2h, ringꢀopening reaction proceeded in the
presence of KOH, and subsequently hydrolysis gave free
35 methodology to be compatible with internal alkenes (Scheme
1). The Xꢀray crystal structure of 2l confirmed its constitution
and relative anti configuration (Figure S4 for 2l, see
Supporting Information). Selectively deuterated formamidines
1m was also submitted to the NISꢀmediated process, and the
40 expected cisꢀconfigured 2m were obtained (Scheme 1). Based
on the aminoamidiniumation products and the observed
2
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DOI: 10.1039/C4CC07082H
diamine 4. Inspired by the successful results mentioned above,
Financial support from Shanghai Pujiang Talent Program
we attempted to obtain enantiopure cyclic vicinal diamine
(11PJ1402500), the Shanghai Municipal Committee of
Science and Technology (11JC1402600), National Basic
30 Research Program of China (973)ꢀ2010CB833302, and the
National Natural Science Foundation of China for financial
support (21171056, 21072206, 20872162, 20821002 and
20732008) is greatly acknowledged.
Notes and references
35
40
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50
55
60
65
70
75
80
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Scheme 2. Proposed reaction mechanism
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1) KOtBu, THF, 25 oC, 8h
I
2) HCl, MeOH, 25 oC, 8h
N
N
Mes
3
N
N
N
Mes
H
H
2a
3 (47% for two steps)
Ph
Ph
Ph
I
1) KOH, MeOH, 25 oC, 8h
2) HCl, H2O, 8h
Ph
N
N
N
Ph
H
H
Ph
Ph
4
5
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2h
4 (62% for two steps)
I
Ph
NIS (1 equiv)
toluene, 25 oC, 4h
Ph
H
N
N
N
N
(
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(S,S)-5 (36%)
1n
I
Ph
+
N
N
(R,S)-5 (31%)
Ph
1) KOtBu, THF, 25 oC, 8h
2) HCl, H2O, 25 oC, 8h
(S,S)-5
N
N
6
H
H
(S,S)-6 (70% for two steps)
Scheme 3. Liberation of the corresponding free diamines from
the cyclic amidine salts
using our new developed methodology. We chose (S)ꢀ1ꢀ
phenylethanamine as a chiral auxiliary, and prepared the
corresponding formamidine 1n. Treatment of 1n with NIS
afforded the diastereomeric products (S,S)-5 and (R,S)-5 as a
mixture (51:49 dr). The diastereomers (S,S)-5 and (R,S)-5
could be easily separated by recrystallization. The absolute
configuration of (S,S)-5 was confirmed by the Xꢀray
10 diffraction analysis of its single crystals (Figure S5 for (S,S)-5,
see Supporting Information). (S,S)-5 could be further
transformed into chiral free diamine (S,S)-6 in diastereoꢀ and
enantiopure form by the aforementioned method. The chiral
auxiliary methodology affords an efficient method for
15 synthesis of chiral 2ꢀsubstituted indolines, and other chiral
vicinal diamines.
5
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In
conclusion,
we
present
an
NISꢀmediated
aminoamidiniumation for the synthesis of bicyclic
imidazolidinium salts, starting from readily available
20 amidines. The methods proceed under very practical and clean
reaction conditions without the need for any additive. The
resultant bicyclic imidazolidinium salts could be readily
converted into 2ꢀsubstituted pyrrolidine and indoline diamines.
Our methodologies provide efficient methods for the concise
25 syntheses of bicyclic imidazolidinium salts and cyclic vicinal
diamines.
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