Tailor-made synthesis of various backbone-substituted imidazolinium salts by triflic anhydride mediated intramolecular cyclisation

Article abstract of DOI:10.1039/c2cc34952c

We have found a Tf₂O-mediated intramolecular cyclization reaction and have revealed an intriguing stereoselectivity and a regioselectivity during the preparation of intermediate alcohols, which allow for the tailor-made synthesis of various backbone-substituted imidazolinium salts, and structurally specific syn-4,5-disubstituted imidazolinium salts.

Full text of DOI:10.1039/c2cc34952c

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COMMUNICATION
Tailor-made synthesis of various backbone-substituted imidazolinium
salts by triflic anhydride mediated intramolecular cyclisationw
Jun Zhang,*a Xiaolong Su,a Jun Fu,a Xinke Qin,a Meixin Zhaoa and Min Shi*ab
Received 11th July 2012, Accepted 26th July 2012
DOI: 10.1039/c2cc34952c
We have found a Tf2O-mediated intramolecular cyclization
reaction and have revealed an intriguing stereoselectivity and a
regioselectivity during the preparation of intermediate alcohols,
which allow for the tailor-made synthesis of various backbone-
substituted imidazolinium salts, and structurally specific syn-4,5-
disubstituted imidazolinium salts.
C and D have also been found to have widespread applications in
asymmetrical catalyses.4 However, modification of the backbone of
these chiral carbenes is still a great challenge, mainly due to a lack
of synthetic methods and/or the accessible disubstituted diamines.
The deprotonation of the N-heterocyclic ring precursors is
the most frequently used method to afford a free or ligated
NHC; thus a synthetic method to prepare these heterocycles is
highly desirable.5 Bertrand et al. proposed a retrosynthetic
disconnection of imidazolidinium salts and prepared them by
the addition of ‘‘di-electrophiles’’ to lithiated formamidines.6
From then on, much attention was paid to develop the synthetic
route to prepare backbone-unsubstituted imidazolinium
salts using formamidines and other ‘‘di-electrophiles’’, such as 1,2-
dichloroethane,7 dibromides,8 and vinylsulfonium salts.9 Recently,
we have reported a synthetic strategy for the facile preparation of
various backbone-monosubstituted imidazolinium salts, starting
from the ring opening reaction of epoxide with formamidine, which
affords the intermediate alcohol, and subsequent Tf2O-mediated
cyclization to the desired imidazolinium salt.10 Unfortunately,
during our further investigation, we have found that the previous
methods cannot allow preparation of imidazolinium salts from
less reactive N,N0-di(biphenyl-2-yl)formamidine (1a) or N,N0-
di(naphthalen-1-yl)formamidine (1b), and cannot provide a
modular synthesis of the imidazolinium salts having a 4,5-
disubstituted backbone ([eqn (S1)–(S6)], p. S2–S3, see ESIw).
Herein, we report a Tf2O-mediated intramolecular cyclization
reaction, as well as an intriguing regioselectivity and a stereo-
selectivity during the preparation of intermediate alcohols,
which allow for the tailor-made synthesis of various backbone-
substituted imidazolinium salts, such as backbone-multisubstituted
and syn-4,5-disubstituted ones.
Recently, the saturated N-heterocyclic carbenes (NHCs),
imidazolidin-2-ylidenes, have received much attention partially
due to their increased Lewis basicity, compared with their
unsaturated counterparts, imidazol-2-ylidenes.1 The number,
nature and position of the substituents on both the nitrogen
atoms and the backbone of NHCs have been found to play an
important role in NHC-promoted reactions, and it is conceivable
that the direct backbone substitution would have greater
influence on the donor ability of NHC than the substitution
on the N-aryl groups.2 The Ru complex containing trimethylated
NHC A (Ar = mesityl), under the optimized conditions, was
found to require only 25 ppm to reach 100% conversion in the
ring-closing metathesis of diethyl diallylmalonate (Fig. 1).2a
Interestingly, ruthenium-based catalysts bearing NHC B with
syn-dimethyl groups on the backbone were revealed to be
among the most efficient monophosphine ruthenium catalysts
known in the RCM reaction leading to tetrasubstituted olefins.3
Chiral backbone-disubstituted imidazolidin-2-ylidenes of types
Fig. 1 Backbone-substituted imidazolidin-2-ylidenes.
Recently, a-halo ketones and a-bromo methylester were
used in straightforward preparations of 4,5-dialkylimidazolium
salts and 5-substituted imidazolium-4-olates, respectively.11 The
a-halo carbonyl compounds were chosen as alkylation reagents
since they are commercially available or can be easily prepared,
and the carbonyl group increases the reactivity of the halides for
substitution reactions. Thus, using NaH or Et3N as a base,
not only N,N0-dimesitylformamidine 1c but also less reactive
1a and 1b reacted well with a-halo ketones and/or a-bromo
esters to give corresponding carbonyl compounds 2a–2j in
39–99% yields (p. S4, see ESIw).
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: Experimental
and spectroscopic data for all compounds. CCDC 887378–887383 for
compounds 3p, 3q, 4b, (R,S)-5b, 3l, and 3r. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2cc34952c
With the carbonyl compounds 2a–j in hand, we then inves-
tigated further transformation into the corresponding alcohols.
c
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close to the carbonyl group arising from the substitution on the
a-position. The high syn selectivity could be well understood by
the Cram open-chain model.12 In the intermediates I and II, the
groups attached to the asymmetric a carbon atom can be
arranged as NF (NF = formamidine moiety) > R (Me or
Ph) > H with regard to their effective bulkiness. ‘‘That
diastereomer will predominate which would be formed by the
approach of the entering group from the least hindered side of
the double bond when the rotational conformation of the C–C
bond is such that the double bond (CQO) is flanked by the
two least bulky groups attached to the adjacent asymmetric
center.’’12b Between the two possible Cram conformations
(Fig. 2), conformation II would be attacked by the H atom
preferentially from the side nearer to the small group (H) and
hence is thermodynamically more stable than I. Consequently,
the reduction takes place through the conformation II,
and the subsequent cyclization to afford syn-4,5-disubstituted
imidazolinium salts 3q and 3r.
ð1Þ
Scheme 1 Synthesis of backbone-substituted imidazolinium salts.
Delightfully, either the reduction by NaBH4 (method A) or
LiAlH4 (method C) or the addition by Grignard reagents
(method B and method D) proceeded smoothly to give the
desired intermediate alcohols, which were immediately used
for the next step after simple workup (Scheme 1). The resulting
alcohols were treated with Tf2O in the presence of Et3N to
afford the desired imidazolinium salts 3a–p in 30–80% overall
yields with varying degrees of backbone substitution, depending
on what kind of a-halo carbonyl compounds and/or Grignard
reagents were chosen. Single crystals of 3l and 3p suitable
for X-ray diffraction analysis were obtained (Fig. S2 and S3,
see ESIw), and their structures confirm the formation of the
desired backbone-multisubstituted imidazolinium salts.
Fig. 2 Possible pathway for the synthesis of syn-4,5-disubstituted
imidazolinium salts.
We next examined the methodology of unsymmetrical
formamidines, 1d and 1e (Fig. 3). In our original work, we
found that in the reaction of (R)-styrene oxide with the
unsymmetrical formamidine 1d, the nitrogen atom near the
aryl ring with two ortho substituents having more electron
density attacked (R)-styrene oxide and led to the formation of
(S)-4a having a backbone-substituent (phenyl group) on the carbon
atom close to the o-tolyl group (Fig. 3).10 We then investigated
the reaction using a-bromoacetophenone as alkylation reagent.
Interestingly, addition of alkyl Grignard reagents having a
b-H atom, such as EtMgBr, into phenyl-substituted ketones 2h
and 2i, both of which have an a-substituent (methyl group for
2h and phenyl group for 2i), furnished only the reduced
alcohols without any trace of the addition product. Surprisingly,
the resultant alcohols underwent cyclization to offer imidazolinium
salts 3q and 3r with a syn-4,5-disubstituted backbone in 45–51%
overall yields, respectively [eqn (1)]. The X-ray diffraction analyses
of single crystals of 3q and 3r have unambiguously confirmed the
interesting stereoselectivity (Fig. S4 and S5, see ESIw). The result
followed an unusual pathway for the reaction of the Grignard
reagent with ketone: the reduction of carbonyl compounds to
alcohols through a b-hydride transfer of the alkyl group in the
Grignard reagent, which is likely due to increased steric hindrance
Fig. 3 Unsymmetrical formamidines, 1d, 1e, and imidazolinium salts
(S)-4a.
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The reaction of 1d with a-bromoacetophenone proceeded
smoothly in the first step, and, after conversion into the
corresponding alcohol, subsequent cyclization afforded 4b in
46% overall yield [eqn (2)]. Interestingly, in contrast to (S)-4a,
4b bears a phenyl group on the backbone carbon atom close
to the 2,6-dipropylphenyl group. It indicates that the first
alkylation step occurred at the nitrogen atom near the o-tolyl
group having less steric hindrance in 1d. In the case of 1e,
alkylation occurred at the nitrogen atom near the mesityl
group, which afforded 4c bearing a backbone-substituent
(phenyl group) close to the phenylethyl group in 47% overall
yield [eqn (3)]. The interesting regiochemistries during these
transformations have been confirmed by NOE spectroscopic
investigation of (S)-4a10 and 4c (Fig. S1, see ESIw), and X-ray
crystal structure of (S)-4a10 and 4b (Fig. S6, see ESIw). We
also used racemic styrene oxide to react with 1e, which, as
expected, afforded 4d with a backbone-substituent close to the
mesityl group in 39% yield, due to the nitrogen atom near the
phenylethyl group having more electron density [eqn (4)]. 4d
was treated with KN(SiMe3)2 (KHMDS) in the presence of
CS2, leading to the formation of a mixture of NHC–CS2
adducts (S,S)-5a and (R,S)-5b in a ratio of 1 : 1. Gratifyingly,
the two diastereomeric isomers could be conveniently isolated
by column chromatography, and the X-ray crystal structure of
(R,S)-5b confirmed the regiochemistry in the formation of 4d
(Fig. S7, see ESIw).
the less steric repulsion in the transition state is required due to the
sterically congested reaction site. Thus the alkylation of
unsymmetrical formamidine with a-bromoacetophenone
predominantly takes place at the nitrogen atom near the less
sterically hindered N-substituent. Therefore, we presumed that
the steric hindrance of the 1-phenylethyl group is more than
that of the mesityl group in 1e.
In summary, the present Tf2O-mediated intramolecular
cyclization reaction allows for a convenient molecular editing
of substituents on the backbone of the imidazolinium salts. We
observed an intriguing stereoselectivity and a regioselectivity,
providing a convenient method for synthesizing structurally
specific imidazolinium salts.
Financial support from Shanghai Pujiang Talent Program
(11PJ1402500), the Fundamental Research Funds for the Central
Universities (WK1114014), the Shanghai Municipal Committee of
Science and Technology (11JC1402600), National Basic Research
Program of China (973)-2010CB833302, and the National
Natural Science Foundation of China (21171056, 21072206,
20472096, 20872162, 20672127, 21121062 and 20732008) is
greatly acknowledged.
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c
9194 Chem. Commun., 2012, 48, 9192–9194
This journal is The Royal Society of Chemistry 2012