Sterically demanding imidazolinium salts through the activation and cyclization of formamides

Article abstract of DOI:10.1039/c2cc36329a

A new protocol was developed for the synthesis of sterically demanding imidazolinium salts. This procedure was adopted for the synthesis of seven NHC salts, including ones that were demonstrated to be inaccessible using the conventional orthoformate ester type cyclization method.

Full text of DOI:10.1039/c2cc36329a

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COMMUNICATION
Sterically demanding imidazolinium salts through the activation and
cyclization of formamidesw
Michael Tsimerman,a Debasis Mallik,a Tsukasa Matsuo,b Takashi Otani,b Kohei Tamaob
and Michael G. Organ*a
Received 13th June 2012, Accepted 1st September 2012
DOI: 10.1039/c2cc36329a
A new protocol was developed for the synthesis of sterically
demanding imidazolinium salts. This procedure was adopted for the
synthesis of seven NHC salts, including ones that were demonstrated
to be inaccessible using the conventional orthoformate ester type
cyclization method.
A limited number of saturated NHC salts are commercially
available and their reported syntheses are sparse. This may be
due to the challenge associated with their synthesis, especially
when the groups on the forming saturated imidazolinium core
are large.6 Conversely, syntheses of unsaturated NHC salts
often enjoy the advantages from the proximal rigid disposition
(cis) of cyclizing ends and the energy-gain upon formation of an
aromatic compound during the cyclization process.7 During the
synthesis of the saturated version, the high degrees of freedom
about the C–C single bond becomes a major hurdle, which is
exacerbated by larger substituents which destabilize the pseudo
cis arrangement required for cyclization.
N-heterocyclic carbenes (NHCs) have become ubiquitous as
ligands for transition metal catalyzed transformations and
as organocatalysts.1 The impressive performance of the first
(Pd-PEPPSI-IPr, 1) and second (Pd-PEPPSI-IPent, 3) generation
of PEPPSI-precatalysts in cross-coupling reactions prompted
us to further examine the effect of sterics of NHC-ligands on
catalysis. Our own research into palladium–NHC precatalysts
supports theories in the literature that steric bulk of the NHC
ligand is of great importance to catalyst activity.2 ‘‘Flexible
bulk’’3 from the 3-pentyl groups in Pd-PEPPSI-IPent was
instrumental in promoting certain reactions that were previously
reported as ‘‘challenging’’ in the literature.4 For some reactions,
Pd-PEPPSI-SIPr showed comparable activity to Pd-PEPPSI-IPr
but at lower temperature.5 Analogously, in an attempt to
perform cross-coupling at even lower temperatures than have
been achieved using Pd-PEPPSI-IPent, we turned our attention
to the synthesis of its saturated analogue 4 (Fig. 1).
Our approach began with formation and subsequent
reduction of bis-imine 7 using aniline 5.8 Surprisingly, treatment
of 7 with HCl and an orthoformate ester led only to the formation
of a mixture of mono-formamide (8) and bis-formamide (9).
Similarly, precipitation of the bis-ammonium dichloride salt and
subsequent addition of an orthoformate ester gave the same result.
Treatment of other, less bulky bis-amines with either set of
conditions is known to produce exclusively the imidazolinium
chloride salt. Nonetheless, the formation of mono-formamide 8
was not unproductive as it could serve as a precursor to the desired
imidazolinium salt (Scheme 1). After optimization, formamide 8
was isolated in 54% yield when 7 was treated with acetic formic
anhydride (AFA).9
Fig. 1 First and second generations of Pd-PEPPSI complexes.
a Department of Chemistry, York University, 4700 Keele Street,
Toronto, Ontario, Canada M3J 1P3. E-mail: organ@yorku.ca;
Fax: +416 736 5936; Tel: +416 736 5313
b Functional Elemento-Organic Chemistry Unit, RIKEN Advanced
Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
w Electronic supplementary information (ESI) available: Experimental
procedures and NMR data are available for compounds 6–9, 11,
17–32. See DOI: 10.1039/c2cc36329a
Scheme 1 Reagents and conditions: (a) (HCO)2 40% in H2O,
HCO2H, EtOH, 70 1C, 24 h, 75%; (b) NaCNBH3, AcOH, Et2O,
EtOH, rt, 4 h quantitative; (c) HC(OEt)3, HCl in dioxane, 1,4-dioxane,
microwave heating at 140 1C for 45 min, 3 : 1 8/9, 41% yield of 8.
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Formamides are known decomposition products of NHCs, and
precedence exists for the inter-conversion between the two
species.10 Less bulky mono-formamides could be cyclized to the
corresponding imidazolinium salts simply by treatment with neat
Brønstead acid.11 However, conversion of 8 to the corresponding
imidazolinium salt using various acidic protocols was unsuccessful
even at an elevated temperature. Evidently, the protonation of the
formamide carbonyl does not overcome the energy barrier for the
intramolecular attack by a sterically bulky amine nucleophile.
Alternatively, covalent activation of amide groups has been shown
to be a versatile and effective strategy for the formation of
carbon–carbon and carbon–heteroatom bonds.12
found to be trivial since the removal of toluene and the addition of
hexanes resulted in the exclusive precipitation of the imidazolinium
salts (NHC salts) and DIPEA ammonium triflate salts. Any
formamide that was unreacted or was regenerated following
hydrolysis of the triflylimminium triflate intermediate 14, was
recovered in the mother liquor. Prolonged reaction times did
not lead to full conversion, resulted rather in a more complex
reaction mixture that complicated purification.
Generally, separation of trialkyl ammonium and imidazol(in)ium
salts is difficult to achieve by crystallization. Aqueous washes are
often required that may decompose the imidazolinium salt and
necessitate additional steps for drying the product.17 As a conse-
quence, we developed a unique procedure to purify of the imid-
azolinium salt away from the Hunig’s salt contaminant. Treatment
of the mixture of salts with an equal weight of K2CO3 and crushed
4 A molecular sieves at 45 1C in toluene for 16 h produced, in
quantitative recovery, clean imidazolinium salt. The origin of the
purification may stem from selective deprotonation of the ammo-
nium salt and subsequent hydrogen bonding or ion–dipole inter-
actions between the free amine and the Zeolite framework.18 The
protocol was found to be general for the purification of the DIPEA
ammonium triflate salt from various imidazolinium salts and
facilitated the formation of 11 in 64% yield from 8 (Scheme 3).
While symmetric bis amine 17 was also successfully formylated
(18) and cyclized (19), following the work of Furstner et al. we were
able to modify the route towards the synthesis of unsymmetric
imidazolinium salts through precursors 20 and 22.15 Production
of chiral NHC salts with this protocol is of special interest to us
since high enantiocontrol can be achieved in a number of
transformations where bulk is moved close to the reaction site,
which in this case would be at the metal center.19 We were able
to synthesize several NHC salts 28–32 via their appropriate
precursors 23–27, ranging in steric bulk, and were even able to
incorporate the highly hindered EMind aniline (21) bearing two
ortho tertiary carbons (Scheme 4).20
The same strategy has been used for the synthesis of various
cyclic and acyclic formamidinium salts,13 and similar protocols have
been used in the preparation of triazolium14 and oxazolinium15
salts. The most general and relevant application of the formamide
activation strategy to generate imidazolium salts utilized POCl3.
However, all reported examples involved an sp2 hybridized nitrogen
nucleophile, which subsequently generated an aromatic imid-
azolium ring.16 We opted to activate the formamide via the
formation of covalent bonds to cyclize formamide 8 to the
corresponding imidazolinium salt.
Treatment of mono-formamide 8 with Tf2O did produce the
desired imidazolinium triflate salt (11), although once again the
steric bulk slowed the intramolecular attack on the triflylimminium
triflate moiety and 12 was produced alongside the desired
imidazolinium salt (Scheme 2). Presence of the strong electrophile
Tf2O in the presence of the amine resulted in an alternative,
irreversible reaction pathway to give the N-triflated sulfonamide
(12). A closer look at the reactivity pattern revealed that formation
of the desired salt (11) was deterred when the reaction was
performed under strictly anhydrous conditions with freshly distilled
Tf2O and toluene. Perhaps N-triflation becomes favoured over
desired O-triflation under anhydrous conditions while a trace
of water can produce triflic acid (from Tf2O) that mutes the
nucleophilicity of the nitrogen lone pair. However, we recognized
the detrimental effect of an unregulated amount of water on the
stability of intermediates such as triflylimminium triflate 14.
Consequently, we added a stoichiometric amount of ‘‘dry’’
TfOH prior to the addition of Tf2O to sequester the lone pair
of the free amine and yet maintain an anhydrous environment,
thus setting the stage for the Vilsmeyer–Haack reaction. This
strategy necessitated a suitable base that could free-base the
amine but would not attack the triflylimminium triflate
electrophile. After some investigation DIPEA (Hunig’s base)
was found to be optimal for the cyclization, irrespective of
steric encumbrance around the core of the final salt. This
reaction sequence produced the desired imidazolinium triflate
salt and avoided the formation of any N-triflated byproduct.
Purification of the imidazolinium salt from other species was
The formamide activation strategy was shown to be general
for the preparation of alkyl- and aryl-substituted imidazolinium
Scheme 2 Triflic anhydride-promoted cyclization of formamide 8.
Scheme 3 Process for formation/purification of imidazolinium salt 11.
Chem. Commun., 2012, 48, 10352–10354 10353
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Scheme 4 Reagents and conditions: (a) AFA, CH2Cl2, rt, 2 h, 57%
yield. (b) i. RNH2, tBuOH, toluene, p-TSA, microwave heating at 100 1C
for 1 h; ii. Na(CN)BH3, AcOH, tBuOH, CH2Cl2, rt, 16 h, 33–58% yield.
(c) i. TfOH, toluene, rt, 15 min; ii. Tf2O, 65 1C, 90 min; iii. iPr2NEt, 80 1C,
90 min; iv. K2CO3, 4 A MS, toluene, 45 1C, 18 h.
salts and is readily scalable due to the novel purification strategy
(vide supra). Careful choice of reagents ensures that only one
counteranion is present in the reaction mixture so that precipitation
of the product is facile and determination of the yield is
unambiguous. Importantly, the imidazolinium salt obtained is
suitable for metal complexation reactions where the presence of
different counter anions can affect the yield, kinetics of formation,
and purity of the final product (e.g., for Ru-complexes).21 Alter-
natively, the use of POCl3, while sometimes effective for the
cyclization step, generates a number of possible counteranions
that complicate analysis and require tedious purification.22
The formamide activation strategy facilitates cyclizations
that are too challenging for the orthoformate ester cyclization
protocol and thus allows the formation of more sterically
demanding NHC salts. Methods were developed to synthesize
symmetric and unsymmetric formamide precursors for the cycliza-
tion step, that led to alkyl- and aryl-substituted imidazolinium salts
in pure form that are ready for metal ligation.
15 A. Furstner, A. Alcarazo, V. Cesar and C. W. Lehmann, Chem.
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J. M. Lassaletta and R. Fernandez, Organometallics, 2006,
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17 Our attempts to purify NHC salts by aqueous washes resulted in
more complex reaction mixture in later steps. For similar observa-
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K. Tamao, Bull. Chem. Soc. Jpn., 2011, 84, 1178. For the synthesis
of EMind aniline, see the ESIw.
21 For counteranion effects on NHC–Ru complex formation see:
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M. Scholl, T.-L. Choi, S. Ding, M. W. Day and R. H. Grubbs,
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Notes and references
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22 The imidazolium salts formed by POCl3 required purification by
chromatography prior to precipitation, see ref. 16; see also Alder
et al. 2001 in ref. 13 and references therein.
4 S. Calimsiz and M. G. Organ, Chem. Commun., 2011, 47, 5181;
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This journal is The Royal Society of Chemistry 2012