Addition of N-heterocyclic carbenes to imines: phenoxide assisted deprotonation of an imidazolium moiety and generation of Breslow intermediates derived from imines

Article abstract of DOI:10.1021/ol802572n

Reactions between imidazolium-imine salts and base result in C-C bond formation via intermediate N-heterocyclic carbenes. In the presence of a proximal OH moiety, carbene formation occurs via intramolecular deprotonation by phenoxide. For simple imines, a reactive Breslow-type intermediate gives access to new heterocycles with the formation of six-and seven-member rings.

Full text of DOI:10.1021/ol802572n

ORGANIC
LETTERS
2009
Vol. 11, No. 1
245-247
Addition of N-Heterocyclic Carbenes to
Imines: Phenoxide Assisted
Deprotonation of an Imidazolium Moiety
and Generation of Breslow
Intermediates Derived from Imines
Stevan Simonovic, Jean-Ce´dric Frison, Hasan Koyuncu, Adrian C. Whitwood, and
Richard E. Douthwaite*
Department of Chemistry, UniVersity of York, Heslington, York, YO10 5DD, United Kingdom
red4@york.ac.uk
Received November 7, 2008
ABSTRACT
Reactions between imidazolium-imine salts and base result in C-C bond formation via intermediate N-heterocyclic carbenes. In the presence
of a proximal OH moiety, carbene formation occurs via intramolecular deprotonation by phenoxide. For simple imines, a reactive Breslow-type
intermediate gives access to new heterocycles with the formation of six- and seven-member rings.
Nucleophilic N-heterocyclic carbenes (NHC’s) have been
extensively investigated over the past decade principally for
application as ancillary ligands to metal-mediated catalysis and
as nucleophilic organocatalysts.1 Stoichiometric reactivity has
also been explored, particularly addition to multiple CdX
(where X ) O, S, C) and to a lesser extent formal insertion
into saturated C-H and N-H bonds.2 Furthermore, there are
many useful N-heterocyclic compounds derived from NHC
precursors such as imidazoles and imidazolium salts that exhibit
interesting and useful chemistry in their own right including
pharmaceuticals, components in biological systems, and as ionic
liquids.3 Therefore, the discovery of NHC reactivity has
potential implications encompassing catalyst design and deg-
radation and functional N-heterocycles.
One conspicuous reaction that has not been developed is
the addition of NHC’s to imines. For traditional carbenes,
reaction occurs via initial electrophilic addition of carbene
to the imine nitrogen atom giving azomethine ylide inter-
mediates and a range of products that are dependent on the
carbene.4 With respect to NHC’s there are now several
examples where reactions between imines and aldehydes are
catalyzed by an NHC;5 however, turnover appears to require
that the Breslow type intermediate 1 (Figure 1) acts as the
nucleophile to the imine.6
(3) (a) Eicher, T.; Hauptnamm, S. The Chemistry of Heterocycles:
Structure, Reactions, Synthesis, and Applications, 2nd ed.; Wiley-VCH:
Weinheim, 2003. For recent examples where metal NHC intermediates are
directly implicated in bicyclic heterocycle synthesis see: (b) Tan, K. L.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 3202. (c)
Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G. J. Am.
Chem. Soc. 2006, 128, 2452. (d) Rech, J. C.; Yato, M.; Duckett, D.; Ember,
B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2007, 129, 490. (e) Clement, N. D.; Cavell, K. J. Angew. Chem., Int. Ed.
2004, 43, 3845.
(1) (a) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-
VCH: Weinheim, 2006. (b) N-Heterocyclic Carbenes (NHC) in Transition
Metal Catalysis; Glorius, F., Ed.; Topic in Organometallic Chemistry, Vol.
28; Springer-Verlag: Berlin, 2006.
(2) (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J. P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34,
1021. (b) Kuhn, N.; Steimann, M.; Weyers, G. Z. Naturforsch. 1999, 54,
427. (c) Lloyd-Jones, G. C.; Alder, R. W.; Owen-Smith, G. J. J. Chem.
Eur. J. 2006, 12, 5361. (d) Frey, G. D.; Lavallo, V.; Donnadieu, B.;
Schoeller, W. W.; Bertrand, G. Science 2007, 316, 439.
(4) (a) Sasaki, T.; Eguchi, S.; Toi, N. J. Org. Chem. 1978, 43, 3810.
(b) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263.
10.1021/ol802572n CCC: $40.75
Published on Web 12/05/2008
2009 American Chemical Society

Preparative scale reactions allowed the isolation and charac-
terization of compounds 4a-c (Scheme 1) where NMR
spectroscopy ultimately confirmed the presence of signals
corresponding to two diastereoisomers RRR and RRS that are
differentiated by configuration at the new stereogenic center.
The molecular structures of (RRR)-4b (Supporting Informa-
tion) and (RRS)-4c (Figure 2) have been determined by single
Figure 1. Breslow-type intermediate.
Herein, we describe the intramolecular reaction between
NHC’s and imines to give Breslow-type intermediates that
provides access to new classes of heterocycles containing
six- and seven-member rings. In cases where a proximal
phenoxide group is present on the imine moiety, kinetic
evidence suggests that reaction proceeds via internal depro-
tonation of an imidazolium moiety by phenoxide, followed
by subsequent addition of NHC to imine. The use of chiral
imidazolium-imine salts has also allowed stereochemical
phenomena to be investigated.
Initial work focused on compounds 2a-c and 3a (Scheme
1) that represent precursors to chiral NHC-imine ligand
Figure 2. Molecular structure of RRS-4c. Thermal ellipsoids are
at 50% probability and hydrogen atoms have been removed for
clarity.
Scheme 1. Proposed Mechanism for the Formation of Betaine
crystal X-ray diffraction confirming the proposed formulations.
Interestingly, there is no indication of intra or intermolecular
hydrogen bonding between phenoxide (O-) and amine N(H)
groups, which contrasts with the hydrogen bonding observed
between imine-N and phenol-OH in the precursors.10
(4a-c) and Breslow Type (5a) Compounds
Determination of reaction rates by 1H NMR spectroscopy
in d4-methanol using KOMe as base was prompted by the
significantly slower synthesis of 4c. It should be noted that
most imidazolium deprotonation reactions for NHC synthesis
are conducted as heterogeneous mixtures whereas 2a-c
exhibit excellent solubility allowing kinetic data to be
acquired. At the concentrations studied, the formation of 4a
(k2 ) 40.3 ( 6 × 10-2 M-1s-1) and 4b (16.2 ( 7 × 10-2
M-1s-1) proceed according to a second order rate law that
is first order in both KOMe and 2a/b. However, for 4c (k1
) 0.565 ( 4 × 10-2 s-1) the reaction is pseudo first order
overall with respect to 2c. It is also clear that during reaction
slow epimerisation of the new stereogenic center of 4a and
4b is occurring and that the kinetic product is the RRS
diastereoisomer. Furthermore, on heating to 80 °C in the
absence of base, 4a-c exhibit H/D exchange in d4-methanol
at the new stereogenic center.
(5) (a) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. (b) Li, G. Q.; Dai,
L. X.; You, S. L. Chem. Commun. 2007, 852. (c) He, L.; Jian, T. Y.; Ye,
S. J. Org. Chem. 2007, 72, 7466. (d) Chan, A.; Scheidt, K. A. J. Am. Chem.
Soc. 2007, 129, 5334. (e) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008,
130, 418. (f) Zhang, Y. R.; He, L.; Wu, X.; Shao, P. L.; Ye, S. Org. Lett.
2008, 10, 277.
complexes which can be prepared without the need to isolate
free NHC-imine compounds.7 Indeed initial deprotonation
attempts did not lead to the formation of free NHC-imine
derivatives as judged by NMR spectroscopy. However,
reports describing hydrogen-bonding interactions between
imidazolium and phenoxide moieties8 and the possibility of
using 2a-c as hydrogen-bonding organocatalysts9 prompted
us to investigate the deprotonation of 2a-c.
(6) Reversible reactions between an NHC and activated N-tosy-
larylimines have been described in refs 5a and 5c.
(7) (a) Bonnet, L. G.; Douthwaite, R. E.; Kariuki, B. M. Organometallics
2003, 22, 4187. (b) Dyson, G.; Frison, J. C.; Simonovic, S.; Whitwood,
A. C.; Douthwaite, R. E. Organometallics 2008, 27, 281.
(8) Cowan, J. A.; Clyburne, J. A. C.; Davidson, M. G.; Harris, R. L. W.;
Howard, J. A. K.; Kupper, P.; Leech, M. A.; Richards, S. P. Angew. Chem.,
Int. Ed. 2002, 41, 1432.
Reaction between 2a-c and 1 equiv of KOMe in an NMR
tube showed, in the 1H NMR spectra the generation of product
signals with commensurate loss of the imine CH signal.
(9) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(b) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
(10) Dudek, G. O. J. Am. Chem. Soc. 1963, 85, 694.
246
Org. Lett., Vol. 11, No. 1, 2009

These data are consistent with the mechanism shown in
scheme 1. The pKa values of imidazolium NC(H)N (ca.
19-25)11 and iminophenol OH (ca. 8-10) suggest initial
deprotonation of 2a-c occurs at the phenol to give (I) which is
in equilibrium with an NHC-imine (II).12 Subsequent cycliza-
tion of II to an imidazolium amide (III)13 followed by formal
proton migration gives (4a-c). Pre-equilibrium between 2a-b
and Ia-b accounts for KOMe appearing in the rate equation
for these substrates, whereas for 2c the equilibrium is signifi-
cantly weighted toward Ic. The rate-limiting step for 4a-b is
initial deprotonation, where presumably the bulky tBu substit-
uents of Ib cause a reduction in rate relative to Ia. However,
for 4c intramolecular deprotonation (I to II) is rate-limiting
because the markedly lower basicity14 of the phenoxide moiety
in Ic.
Of more general significance, synthesis of 5b-c (Scheme
2) shows that cyclization is not limited to a constrained
cyclohexyl ring or C2 linker and is compatible with a simple
imidazolium moiety. Although single crystals of 5a-c have
yet to be grown, dioxygen and water stable derivatives can be
prepared by protonation to give compounds 6a-c (Scheme 2),
where protonation of 5a gives the diastereoisomers (RRR:RRS)
which exhibit the opposite excess to 4a-c. Additionally, in
contrast to 4a-c, H/D exchange in d4-methanol is not observed
at the new stereogenic center of 6a indicating that for 4a-c,
exchange, and potentially epimerisation, are assisted by the
proximal phenoxy-imine moiety. A single crystal diffraction
study of 6b (Figure 3) has been determined confirming the
Given the observation of formal nucleophilic addition of
putative NHC to the phenol-imines of 2a-c, deprotonation
of 3a and additional simple achiral analogues 3b-c (Scheme
2) was investigated. Reaction in alcohols gave intractable
Scheme 2
Figure 3. Molecular structure of 6b. Thermal ellipsoids are at 50%
probability and hydrogen atoms and anion have been removed for
clarity.
proposed formulation. New signals for the protonated carbon
atom in 6a-c are observed at ca 5.8 and 56 ppm in the 1H and
13C NMR, respectively.
In summary, unactivated imines undergo base-induced in-
tramolecular cyclization with NHCs to give Breslow-type
intermediates such as 5a-c. These compounds are likely to
exhibit nucleophilic reactivity beyond the simple protonation
described here, providing simple access to new heterocyclic
compounds. Nucleophilic reactivity of NHC toward an imine
has also been demonstrated via intramolecular deprotonation
of imidazolium by proximal phenoxide. Reaction occurs despite
the pKa differences between solvent (MeOH), acid (imidazo-
lium), and base (phenoxide) and is reminiscent of some
enzymatic processes, perhaps suggesting a motif for functional
NHC organocatalysts. Future work will explore the scope of
NHC-imine cyclization with respect to other azolium moieties
and the reactivity of compounds of class 5.
products; however, reaction between a mixture of 3a and 1
equiv of NaH in THF at 25 °C gives a red solution of the
enamine 5a (Scheme 1). Compound 5a has been character-
ized spectroscopically and isolated as an air and moisture
sensitive oil that is soluble in saturated hydrocarbons.
Distinctive NMR data include the 13C signals attributable to
the alkenic carbons at 95.1 (NCC) and 142.0 ppm (NCN)
respectively. Poor solubility of 3a in solvents compatible with
deprotonation prevented a kinetic study. However, a modified
mechanism (Scheme 1) similar to that for 4a-c is consistent
with the formation of 5a where an NHC-imine (II) is
accessed directly via deprotonation of the imidazolium
moiety followed by nucleophilic addition of NHC to imine
giving (III) and subsequent formal 1,2-H migration.
Acknowledgment. We thank EPSRC EP/C522842 and
University of York for financial support and Robert Thatcher
(Department of Chemistry, University of York) for X-ray
crystallography assistance.
(11) (a) Magill, A. M.; Cavell, K. J.; Yates, B. F. J. Am. Chem. Soc.
2004, 126, 8717. (b) Chu, Y.; Deng, H.; Cheng, J. P. J. Org. Chem. 2007,
72, 7790.
Supporting Information Available: Preparation and
characterizing data of all compounds, kinetic data for 4a-c
and crystallographic data of 4a, 4c and 6b. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) For a structurally characterized phenoxide-imidazolium adduct and
discussion of proton location, see ref 8.
(13) A related imidazolium-amide has been characterized for an N-
tosylarylimine in ref 5c.
(14) pKa’s of related phenols: phenol (9.99), 4-tert-butylphenol (10.23),
and 4-nitrophenol (7.15); from Lange’s Handbook of Chemistry, 14th ed;
McGraw-Hill: New York, 1992; Table 8.8.
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