A facile preparation of backbone-substituted, functionalized and chiral imidazolinium salts

Article abstract of DOI:10.1039/c1cc15609h

A versatile and modular method for the preparation of various backbone-substituted, functionalized and chiral imidazolinium salts from the reaction of formamidines with alkene oxides has been described, providing a more straightforward access to substitut

Full text of DOI:10.1039/c1cc15609h

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COMMUNICATION
A facile preparation of backbone-substituted, functionalized and chiral
imidazolinium saltsw
Jun Zhang,*a Xiaolong Su,a Jun Fua and Min Shi*ab
Received 10th September 2011, Accepted 10th October 2011
DOI: 10.1039/c1cc15609h
A versatile and modular method for the preparation of various
backbone-substituted, functionalized and chiral imidazolinium salts
from the reaction of formamidines with alkene oxides has been
described, providing a more straightforward access to substituted
imidazolinium salts than the previously reported methods.
Recently, the saturated N-heterocyclic carbenes (NHCs),
imidazolidin-2-ylidenes, have received much attention partially
due to their increased Lewis basicity, which led to an improved
catalytic activity in ruthenium-based metathesis compared with
their unsaturated counterparts, imidazol-2-ylidenes.1 Since
imidazolidin-2-ylidenes are usually prepared in situ by the
deprotonation of their precursor imidazolinium salts, the
preparation of these imidazolinium salts is highly desirable.2
Thus far, imidazolinium salts are mainly synthesized from cycliza-
tion of triethyl orthoformate with the corresponding diamines.
However, these diamines are not readily available, and their
preparations generally include either a palladium catalyzed C–N
coupling or a condensation and reduction sequence. Moreover,
the cyclization processes usually require harsh conditions and have
poor reproducibility.2 An alternative approach, proposed recently
by Bertrand, is the deprotonation of formamidine with nBuLi and
further cyclization with ‘‘dielectrophiles’’, 1,2,3-dioxathiolane-2,2-
dioxide. This method has been modified by Grubbs and his
coworkers.4 Imidazolinium salts were obtained by alkylation
of formamidines with 1,2-dichloroethane in the presence of
diisopropylethylamine. Cavell and his co-workers have
obtained imidazolinium salts by alkylation of formamidines
with dibromides in the presence of K2CO3.5 Very recently,
McGarrigle and Aggarwal have reported a modified method to
prepare imidazolinium salts from the reaction of formamidines with
vinylsulfonium salt, produced in situ from bromoethylsulfonium
salt6 (Scheme 1).
Scheme 1 Most important routes to imidazolinium salts.
However, these methodologies suffer from significant
limitations; (1) the first approach needs inert moisture free condi-
tions,3 and (2) the latter three approaches require harsh conditions4
such as at high temperature (110 1C) or under refluxing in
acetonitrile.5,6 More importantly, these methodologies do not allow
the formation of backbone substituted imidazolinium salts,
presumably due to the steric hindrance within the dielectrophile
reagent.3 In the NHC-based Ru catalysts, placing substituents on
the backbone of the imidazolidin-2-ylidenes has been found to
render a decomposition pathway unfavorable by restricting the
rotation of the N-aryl groups, which significantly impacts catalyst
stability and activity.7 Following Bertrand’s method,3 we
envisioned that epoxide could be used as a ‘‘pro-dielectrophile’’
in the preparation of imidazolinium salts from the ring opening
reaction of epoxide with formamidine and subsequent cyclization
(Scheme 1). Various epoxides can be easily prepared from
cyclodehydrohalogenation of b-halo alcohols and epoxidation
of alkenes. As part of our studies on the design and synthesis
of novel chiral NHC ligands for asymmetric catalysis,8 we
herein wish to report a new synthetic strategy using epoxide
as a ‘‘pro-dielectrophile’’ for the facile preparation of various
backbone-substituted, functionalized and chiral imidazolinium
salts under mild reaction conditions (Scheme 1).
Our initial study focused on the reaction of N,N0-dimesityl-
formamidine 1a and commercially available styrene oxide
(Table 1, entry 1). Using NaH as a base, the ring opening
reaction proceeded smoothly to give 2a in good yield and weak
bases such as K2CO3, triethylamine and diisopropylethylamine
gave 2a in poor yields. Subsequent treatment of the intermediate,
alcohol 2, with triflic anhydride (Tf2O) in Et3N gives the
corresponding triflate derivative, which affords imidazolinium
salt 3a in 83% overall yield (Table 1, entry 1). Reducing the
number of substitutes at the N-aryl ortho positions dramatically
decreased the reaction rate of the first ring opening step, and
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.
E-mail: zhangj@ecust.edu.cn; Tel: +86 021 64252995
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China.
E-mail: mshi@mail.sioc.ac.cn; Tel: +86 021 64252995
w Electronic supplementary information (ESI) available: CCDC
841930, 841928, and 841931. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1cc15609h
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12541–12543 12541

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Table 1 Synthesis of various imidazolinium saltsa
epoxides, leading to various backbone substituted imidazolinium
salts in good overall yields (Table 1, entries 4–6). Either
functionalities in epoxides such as phenoxy, vinyl, and ester
groups or bromo functionality in the aryl group of formamidine
were tolerated both on the ring opening of alkene oxides and on the
following ring closing, due to the mild reaction conditions of our
new method (Table 1, entries 7–10). These resulting imidazolinium
salts 3g–3h with different functionalities indicated that they are
useful in terms of flexible synthetic utility for further derivatization.
Very recently, Blechert and his coworkers have developed a
successful strategy for the preparation of chiral imidazolidin-
2-ylidene A used in ruthenium-based asymmetrical metathesis,
in which the backbone substituent (isopropyl) was used to
induce a significant twist of the monosubstituted arene ring to
reach the optimal transfer of chirality, and a planar mesityl
substituent was employed on the another side to avoid steric
hindrance diminishing the reactivity.9 Hoveyda and his coworkers
also reported a chiral monosubstituted imidazolidin-2-ylidene
B with a similar backbone for Cu-catalyzed asymmetric allylic
alkylation10 (Fig. 1). The catalysts based on A or B exhibited
excellent enantioselectivities, and, in some cases, improved
enantioselectivities compared to those based on their parent
C2-symmetrical NHCs C. Thus, we also attempted to use our
new synthetic method to prepare chiral monosubstituted
imidazolinium salts with commercially available (R)-styrene oxide
and the results are summarized in Table 2. The desired chiral
imidazolinium salt (S)-4a-OTf was afforded in 83% yield (Table 2,
entry 1). To determine its absolute configuration, (S)-4a-OTf was
converted to the corresponding iodide (S)-4a-I by treatment of
(S)-4a-OTf with excess NaI (p. S41, see ESIw). The X-ray
crystal structure of (S)-4a-I showed that it has the S configuration
(Fig. S3, see ESIw), indicating that inversion of the configuration of
(R)-styrene oxide occurred in the two-step synthesis. The ee value
of pure (S)-4a-OTf was determined as 99% on the basis of chiral
HPLC analysis of its derivative imidazolidin-2-thione (S)-4a0,
which was obtained by a classic method (Scheme S5, see ESIw).
We further investigated the reaction of (R)-styrene oxide
with the unsymmetrical N,N0-diarylformamidines 1e and 1f.
Only one regioisomer (S)-4b-OTf or (S)-4c-OTf in which the
backbone-substituted phenyl group is on the carbon atom
close to the mono-substituted aryl ring was formed (Table 2,
entries 2 and 3). (S)-4b-OTf and (S)-4c-OTf are highly desirable
chiral monosubstituted imidazolinium salts, from which we could
further synthesize the corresponding chiral imidazolidin-2-ylidenes
with similar optimal transfer and control of chirality to those
described above for chiral carbenes A and B. The regiochemistry
of products (S)-4b-OTf and (S)-4c-OTf has been confirmed by
X-ray crystal structure of (S)-4b-OTf (Fig. S4, see ESIw) and NOE
spectroscopic investigation of (S)-4b-OTf and (S)-4c-OTf.
Yieldb
[%]
Time/h
Step 1, 2
Entry Formamidines Imidazolinium salts
1
2
1a
1b
12 h, 5 h 83
24 h, 5 h 14
10 hc, 5 h 51c
3
4
5
1c
1a
1a
12 h, 5 h 78
10 hc, 5 h 81c
12 h, 5 h 62
6
7
8
1a
1d
1a
12 hc, 5 h 68c
12 h, 5 h 85
12 h, 8 h 61
9
1a
1a
12 h, 8 h 75
12 h, 8 h 73
10
a
Reaction conditions. Step 1: 1 (2.4 mmol), epoxide (2 mmol), NaH
(3.0 mmol), DMF (15 mL), 25 1C. Step 2: Tf2O (2.2 mmol), Et3N
b
(2.2 mmol), DCM (10 mL), 25 1C. Isolated yield of the desired
imidazolinium salts. 70 1C.
To gain more mechanistic insight into this intriguing regio-
chemistry, we further investigated the regioselectivity in the key
first ring opening step. We prepared the authentic formamidinyl
c
higher reaction temperature is required (Table 1, entry 2).
Notably, the increase of steric hindrance on the N-aryl ortho
positions has no significant influence on the reaction outcome
(Table 1, entries 1 and 3). To show the generality and scope of this
new synthetic protocol, structurally diverse and functionalized
epoxides were treated with formamidines and it was found that
our new approach is compatible with several different aliphatic
Fig. 1 Chiral backbone-substituted imidazolidin-2-ylidene.
c
12542 Chem. Commun., 2011, 47, 12541–12543
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Table 2 Synthesis of chiral imidazolinium saltsa
Scheme 3 Regioselective methylation of the urea complex 6.
crowded environment. The presumption is supported by our
observation that N,N0-dimesitylformamidine 1a is far more
active than N,N0-bis(2-iPrphenyl)formamidine 1b at 25 1C
(Table 1, entries 1 and 2). In the case of 1g having two
disubstituted arene rings, the N atom near the less hindered
mesityl ring attacked the (R)-styrene oxide, offering the major
product (S)-4d-OTf, while the minor product (S)-4e-OTf
resulted from the nucleophilic attack of the N atom near the
more hindered diisopropylphenyl ring. The regiochemistry
was confirmed by the X-ray crystal structure of (S)-4d-I
(Fig. S4, see ESIw), obtained by treatment of (S)-4d-OTf with
excess NaI (p. S41, see ESIw).
In conclusion, we have established a facile and versatile method
for the preparation of various imidazolinium salts. Noticeably, this
novel synthetic strategy for the preparation of chiral backbone-
monosubstituted imidazolinium salts is more straightforward, and
does not involve any transition-metal catalyzed reaction compared
to the previously reported methods.
N,N0-
Entry Diarylformamidine
Yieldb
[%]
Imidazolinium salts
1
83
2
3
45c
43c
51
4
11
Financial support from the Shanghai Municipal Committee of
Science and Technology (08dj1400100-2), National Basic Research
Program of China (973)-2010CB833302, Shanghai Pujiang
Talent Program (11PJ1402500), and the National Natural Science
Foundation of China for financial support (21171056, 21072206,
20472096, 20872162, 20672127, 20821002 and 20732008) is greatly
acknowledged.
a
Reaction conditions. Step 1: 1 (2.4 mmol), epoxide (2 mmol), NaH
(3.0 mmol), DMF (15 mL), 25 1C, 10 h. Step 2: Tf2O (2.2 mmol), Et3N
b
(2.2 mmol), DCM (10 mL), 25 1C, 5 h. Isolated yield of the desired
imidazolinium salts. 70 1C (step 1).
c
alcohols 5a and 5b by an alternative method (Scheme 2). The ring
opening products 2a and 2b from 1a and 1b (Scheme S2,
see ESIw) have been identified as the same as 5a and 5b,
respectively, by NMR spectroscopy, indicating that the selective
nucleophilic attack occurred at the less hindered carbon of
styrene oxide. Thus we postulated that the regioselective products
(S)-4b-OTf and (S)-4c-OTf probably resulted from the selective
attack of the nitrogen atom near the disubstituted arene ring at
the less hindered carbon of (R)-styrene oxide in the first step
and the subsequent cyclization. The regiochemistry observed
here is quite similar to that in the methylation of the urea
complex 6 (Scheme 3). The treatment of 6 with methyl iodide
resulted in regioselective methylation with the nitrogen carrying
disubstituted arene ring to afford 7.11 The authors presumed that
the twist in the Ar–N bond imposed by the steric requirements of
two substituents in the ortho positions prevents delocalization of
the anion into the more hindered ring, increasing electron density
and reactivity at the nearer nitrogen atom, despite its more
Notes and references
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´
S. Bellemin-Laponnaz and V. Cesar, Chem. Rev., 2011, 111, 2705;
(b) F. E. Hahn and M. C. Jahnke, Angew. Chem., Int. Ed., 2008,
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3 R. Jazzar, H. Liang, B. Donnadieu and G. Bertrand, J. Organomet.
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4 K. M. Kuhn and R. H. Grubbs, Org. Lett., 2008, 10, 2075.
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7 K. M. Kuhn, J.-B. Bourg, C. K. Chung, S. C. Virgil and
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Scheme 2 Alternative synthesis of the alcohols 5a and 5b.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12541–12543 12543