An efficient synthesis of imidazolinium salts using vinyl sulfonium salts

Article abstract of DOI:10.1021/ol2009472

The synthesis of imidazolinium salts from the reaction of formamidines and (2-bromoethyl)diphenylsulfonium triflate is described. A variety of symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction time

Full text of DOI:10.1021/ol2009472

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3060–3063
An Efficient Synthesis of Imidazolinium
Salts Using Vinyl Sulfonium Salts
Eoghan M. McGarrigle,* Sven P. Fritz, Ludovic Favereau, Muhammad Yar,† and
Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
eoghan.mcgarrigle@bristol.ac.uk; V.Aggarwal@bristol.ac.uk
Received April 11, 2011
ABSTRACT
The synthesis of imidazolinium salts from the reaction of formamidines and (2-bromoethyl)diphenylsulfonium triflate is described. A variety of
symmetrical and unsymmetrical imidazolinium triflate salts were synthesized in high yield in short reaction times under mild conditions. Aromatic
and aliphatic N-substituents work well. The reaction is proposed to proceed via generation of a vinyl sulfonium salt intermediate from the
bromoethylsulfonium triflate.
The use of N-Heterocyclic Carbenes (NHCs) as ligands
and as organocatalysts has become widespread since the
first report of the isolation of a stable NHC by Arduengo.1
Imidazolium and imidazolinium salts are commonly used
as precursors to NHCs; thus synthetic methods to access
these heterocycles are important.2ꢀ8
Scheme 1 shows the three bond disconnections most
commonly applied in the synthesis of these heterocycles.
† Current address: Chemistry Department, King Fahd University of
Petroleum & Minerals, P.O. Box 1347, Dhahran 31261, Saudi Arabia.
(1) (a) Arduengo, A. J., III; Harlow, R. L.; Kline, M. A. J. Am. Chem.
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Grubbs, R. H. Chem. Rev. 2010, 110, 1746–1787. (c) Samojzowicz, C.;
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Vougioukalakis, G. C.; Grubbs, R. H. Organometallics 2007, 26, 2469–
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Org. Lett. 2009, 11, 3710–3713. For the ring closure of 1,3-diamines with
orthoformates, see: (m) Alder, R. W.; Blake, M. E.; Bortolotti, C.;
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or trichloromethyl groups. For examples, see: (a) Wanzlick, H. W.
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r
10.1021/ol2009472
Published on Web 05/19/2011
2011 American Chemical Society

Disconnection ‘a’ can be an SN2 displacement of a
leaving group by nitrogen or a metal-catalyzed CꢀN
bond formation.5 Disconnection ‘c’ is typically the
reaction of a diamine with an orthoformate and a
source of HX.5,6 The required diamine is typically
formed either by a reductive amination with glyoxal
or by alkylation of the diamine. Disconnection ‘b’
corresponds to a reaction between what is formally an
ethyl dication and a formamidine.7,8 The formamidine can,
in turn, be generated from the reaction of an amine with
an orthoformate. R-Halocarbonyl compounds have often
been used to form the ethyl bridge. However, more recently
the use of ‘dielectrophiles’ such as dihaloethanes has been
described.7,8 In particular, Kuhn and Grubbs have described
Recently, it has been shown that vinylsulfonium salt 2
and the more stable bromoethylsulfonium salt 1 are both
highly effective in annulation reactions, e.g., in the synthesis
of morpholines and oxazepines.9,10 Herein, we describe the
application of these salts in a simple and rapid method for
the synthesis of imidazolinium salts.
Scheme 2 shows our proposed reaction pathway based
on analogous reactions with amino alcohols. Thus, treat-
ment of bromoethylsulfonium salt 1 with base leads to the
formation of vinylsulfonium salt 2 in situ.11 The vinylsul-
fonium salt 2 is an excellent electrophile and should react
rapidly with 3 to form sulfur ylide 4. Following proton
transfer to unmask a second electrophilic center, an intra-
molecular nucleophilic attack would be expected to dis-
place Ph2S to give the desired imidazolinium triflate salt 5.
Scheme 1. Approaches to the Synthesis of Imidazolinium Salts
Scheme 2. Proposed Mechanism for the Synthesis of Imidazo-
linium Salts 3
Table 1 shows the results of the initial screening of
reaction conditions using mesityl-substituted formami-
a two-step synthesis of imidazolinium salts.7 Anilines were
reacted with ethyl orthoformate to yield formamidines,
which were heated at 120 °C in dichloroethane in a sealed
tube to give symmetrical and unsymmetrical imidazoli-
nium salts in good yields. This method worked well
with electron-rich anilines, but anilines bearing very bulky
groups or electron-withdrawing groups did not work
well. Nonetheless the simplicity of this method makes it
attractive.
Although there are a range of methods for the synthesis
of imidazolinium salts, there are drawbacks and/or limita-
tions in substrate scope in all cases. Thus, in many cases,
extra reduction steps are required due to the oxidation
state of the starting materials and these limit the functional
groups that can be tolerated.5,6aꢀ6c,6eꢀ6i In addition, the
synthesis of nonsymmetrical salts (R1 ¼ R2) would be
challenging with some methods.6aꢀd,i
€
dine 3a as a model substrate. The use of Hunig’s base
(iPr2EtN) and acetonitrile gave rise to high yields of
imidazolinium salt 5a in just 2.5 h at room temperature.
The product could be isolated without recourse to
chromatography; washing with Et2O and water to re-
move Ph2S and diisopropylethylammonium bromide
gave analytically pure triflate salt 5a. We note that the
intermediacy of a vinylsulfonium salt in the reaction is
supported by the following observations: (i) direct use of
vinylsulfonium salt 2 gave similar yields; (ii) the use of
2-bromoethyl triflate instead of 1 gave much lower yields
under the optimized conditions.
(10) (a) Kim, K. H.; Jimenez, L. S. Tetrahedron: Asymmetry 2001, 12,
999–1005. (b) Bornholdt, J.; Felding, J.; Kristensen, J. L. J. Org. Chem.
2010, 75, 7454–7457. (c) Yamanaka, H.; Matsuo, J.; Kawana, A.;
Mukaiyama, T. ARKIVOC 2004, 42–65. (d) Yamanaka, H.; Matsuo,
J.; Kawana, A.; Mukaiyama, T. Chem. Lett. 2003, 32, 626–627. (e)
Matsuo, J.; Yamanaka, H.; Kawana, A.; Mukaiyama, T. Chem. Lett.
2003, 32, 392–393. (f) Yamanaka, H.; Yamane, Y.; Mukaiyama, T.
(9) (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2008, 47, 3784–3786. (b) Hansch, M.; Illa, O.; McGarrigle,
E. M.; Aggarwal, V. K. Chem.;Asian J. 2008, 3, 1657–1663. (c) Yar,
M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257–260.
(d) Fritz, S. P.; Mumtaz, A.; Yar, M.; McGarrigle, E. M.; Aggarwal,
V. K. Eur. J. Org. Chem. 2011, early view, DOI: 10.1002/ejoc.201100337;
for other related work using vinylsulfonium salts, see: (e) Unthank,
M. G.; Hussain, N.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2006, 45,
7066–7069. (f) Kokotos, C. G.; McGarrigle, E. M.; Aggarwal, V. K.
Synlett 2008, 2191–2195. (g) Unthank, M. G.; Tavassoli, B.; Aggarwal,
V. K. Org. Lett. 2008, 10, 1501–1504. (h) Yar, M.; Unthank, M. G.;
McGarrigle, E. M.; Aggarwal, V. K. Chem.;Asian. J. 2011, 6, 372–375.
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~
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Heterocycles 2004, 63, 2813–2826. (g) Catalan-Munoz, S.; Muller, C. A.;
Ley, S. V. Eur. J. Org. Chem. 2010, 183–190. (h) Maeda, R.; Ooyama, K.;
Anno, R.; Shiosaki, M.; Azema, T.; Hanamoto, T. Org. Lett. 2010, 12,
2548–2550. (i) Xie, C. S.; Han, D. Y.; Hu, Y.; Liu, J. H.; Xie, T. A.
Tetrahedron Lett. 2010, 51, 5238–5241. (j) Xie, C. S.; Han, D. Y.; Liu,
J. H.; Xie, T. Synlett 2009, 3155–3158. (k) An, J.; Chang, N.-J.; Song,
L.-D.; Jin, Y.-Q.; Ma, Y.; Chen, J.-R.; Xiao, W.-J. Chem. Commun.
2011, 47, 1869–1871.
(11) Salt 1 is a commercially available stable crystalline salt and is
preferred to vinylsulfonium salt 2 for ease of handling.
Org. Lett., Vol. 13, No. 12, 2011
3061

Table 1. Optimization of the Annulation Procedure
Table 2. Synthesis of Imidazolinium Salts Using Bromoethyl-
sulfonium Salt 1
time
yield
(%)a
entry
base
DBU
solvent
(h)
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
THF
16
30
56
58
78
88
90
91
NaH
16
16
7
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
CF3C6H5
EtOAc
MeCN
3
3
2.5
a Isolated yield.
Having found suitable reaction conditions, the reaction
scope was explored (Table 2). The N-aryl symmetrical
formamidines 5bꢀe all gave high yields in less than 4 h
in refluxing acetonitrile. Particularly of note is the fact
that bulky formamidines gave high yields in short reaction
times (entries 3, 4, 9). This scope compares favorably to
the method of Grubbs7 (after 7 days in refluxing dichlor-
oethane, the reaction to make 5d had reached 60%
conversion).
The method was readily extended to the use of symme-
trical formamidines bearing aliphatic N-substituents
(reported to be problem substrates for the Grubbs
method), and especially important are the unsymmetrical
formamidines12 bearing both an aromatic and an aliphatic
N-substituent (entries 7, 8) or two different aromatic
groups (entry 6).
In almost all cases, elemental analyses of the products
were consistent with analytically pure triflate salts being
obtained.13,14 Interestingly, in the case of 5e the bromide
(12) For example, Grubbs has recently reported an N-aryl, N-alkyl
N-heterocyclic carbene (NHC) ruthenium metathesis catalyst which was
highly selective for the kinetic ethenolysis of methyl oleate at low catalyst
loading (500 ppm): Thomas, R. M.; Keitz, B. K.; Champagne, T. M.;
Grubbs, R. H. J. Am. Chem. Soc. 2011, asap, DOI: 10.1021/ja200246e.
(13) For examples where the counterion is important in transition-
metal-catalyzed reactions, see: (a) Adam, W.; Roschmann, K. J.; Saha-
€
Moller, C. R. Eur. J. Org. Chem. 2000, 3519–3521. (b) Collman, J. P.;
Zeng, L.; Brauman, J. I. Inorg. Chem. 2004, 43, 2672–2679. (c) Houlden,
C. E.; Bailey, C. D.; Ford, J. G.; Gagn, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066–10067. (d)
Drent, E.; van Broekhoven, J. A. M.; Doyle, M. J. J. Organomet. Chem.
1991, 417, 235–251. (e) Evans, L. A.; Fey, N.; Harvey, J. N.; Hose, D.;
Lloyd-Jones, G. C.; Murray, P.; Orpen, A. G.; Osborne, R.;
Owen-Smith, G. J. J.; Purdie, M. J. Am. Chem. Soc. 2008, 130,
14471–14473. (f) Clark, T. P.; Landis, C. R. J. Am. Chem. Soc. 2003,
a Isolated yield. b rt. c With vinylsulfonium triflate 2 instead of 1, at
reflux. d With 10ꢀ13% triflate counterion as contaminant.
~
125, 11792–11793. (g) Antoniotti, S.; Dalla, V.; Dunach, E. Angew.
Chem., Int. Ed. 2010, 49, 7860–7888.
salt was isolated with ca. 10% of the triflate salt as a
‘contaminant’.
In the case of symmetrically substituted salts there is no
need to preform the formamidine; a one-pot synthesis from
the requisite amine is possible. Thus, triethylorthoformate
and the amine can be reacted to form a formamidine; after in
(14) There are limits to how well elemental analysis can distinguish
between the bromide and the triflate salt. While the results were entirely
consistent with the triflate salts for 5aꢀd,fꢀi, contamination with up to
ca. 10% bromide instead of triflate would still give satisfactory analyses.
The exact limit is dependent on the molecular weight of the imidazoli-
nium part.
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Org. Lett., Vol. 13, No. 12, 2011

applicable to the synthesis of symmetrical and unsymmetrical
imidazolinium salts bearing aromatic or aliphatic groups. A
one-pot procedure from commercially available materials
has been shown to be effective for symmetrical imidazolinium
triflate salts. Of particular note are the excellent results that
can be obtained with sterically hindered amines.
Scheme 3. One-Pot Synthesis of Imidazolinium Triflates from
Amines and Bromoethylsulfonium Triflate 1
Acknowledgment. S.P.F. thanks the EPSRC for a scho-
larship. M.Y. thanks the Higher Education Commission
(HEC) of Pakistan and University of Bristol for support of
a studentship. V.K.A. thanks the Royal Society for a
Wolfson Research Merit Award, EPSRC for a Senior
Research Fellowship, and Merck for research support.
vacuo drying and addition of solvent, base, and bro-
moethylsulfonium salt 1 to the reaction vessel, the imidazo-
linium salts 5a,i were isolated in excellent yields (Scheme 3).
In conclusion, we have demonstrated that the synthesis of
imidazolinium salts can be achieved in high yields and short
reaction times using a simple, mild procedure. The method is
Supporting Information Available. Synthesis and char-
acterization of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
3063