Imidazolium ylides from a conjugate addition-proton transfer route and their cycloaddition reactions

Article abstract of DOI:10.1039/c1cc12255j

4,5-Dihydroimidazolium ylides formed by conjugate addition-proton transfer from dihydroimidazoles and doubly-activated electron-deficient alkenes afford 2:1 cycloadducts in a one-pot process wherein the alkene also acts as a dipolarophile.

Full text of DOI:10.1039/c1cc12255j

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Imidazolium ylides from a conjugate addition–proton transfer route and
their cycloaddition reactionsw
Raymond C. F. Jones,*a James N. Iley,b Maria Sanchis-Amat,a Xiaohui Zhang,b
Vickie McKee,a Simon J. Colesc and Thomas Gelbrichc
Received 18th April 2011, Accepted 27th May 2011
DOI: 10.1039/c1cc12255j
4,5-Dihydroimidazolium ylides formed by conjugate addition–
proton transfer from dihydroimidazoles and doubly-activated
electron-deficient alkenes afford 2 : 1 cycloadducts in a one-pot
process wherein the alkene also acts as a dipolarophile.
Uncovering new methods for stereocontrolled construction of
pyrrolidine rings continues, fuelled by the biologically active
molecules containing this substructure.1 Dipolar cycloaddition
of azomethine ylides is a key method,2 and we have developed
4,5-dihydroimidazolium ylides for stereoselective pyrrolidine
synthesis via pyrrolo[1,2-a]imidazoles.3 Three of five bonds in
the new pyrrolidine ring are formed via an ylide formation-
cycloaddition cascade. We have reported the ylide formation
from 4,5-dihydroimidazoles by (i) N-alkylation-deprotonation
(e.g. Scheme 1),3 or (ii) a catalytic cycle of metal carbenoid
insertion onto the imine N-atom.4 The diastereoselection is
rationalised by an anti dipole conformation and endo approach
of dipole to dipolarophile (Scheme 1) to establish the stereo-
chemistry at C-5 and C-7 of the cycloadducts.
Scheme 1 Reagents: i, BrCH2X, CH2QCHY, THF reflux, then
DBU; ii, NaBH3CN, H+; then Pd(OH)2, H2.
unexpected 2 : 1 adduct 2a (30%) (Scheme 2); the relative
stereochemistry was secured by X-ray crystallographic analysis
(Fig. 1).w Formation of such 2 : 1 adducts is rationalised by
conjugate addition of the dihydroimidazole to the electron-
deficient alkene moiety of the maleimide, followed by proton
transfer in the zwitterionic intermediate to give the more stable 1,3-
dipole (Scheme 2).7 The imidazolium ylide then undergoes dipolar
cycloaddition to a second molecule of maleimide, which thus acts
as both Michael acceptor and dipolarophile. The relative stereo-
chemistry of 2a is consistent with our model for the transition
Protocol (i) involves stoichiometric base and approach
(ii) metal complexes as catalysts. Whilst developing protocol (ii),
we made the serendipitous discovery of a novel route to the
dihydroimidazolium ylides involving no added reagent beyond
the dihydroimidazole and a doubly activated dipolarophile,
that provides unexpected 2 : 1 adducts between dihydroimidazole
and dipolarophile. This approach avoids (often lachrymatory)
active halide alkylating agents of method (i) and reactive diazo
compounds of method (ii). We report here on this third approach
to dihydroimidazolium ylides, which provides derivatives related
to spiro-oxindole alkaloids5 and complex a,a-disubstituted proline
natural products.6
Heating achiral substrate 1-benzyl-4,5-dihydroimidazole 1
with N-methylmaleimide (CH2Cl2 reflux, 24 h) afforded
a Department of Chemistry, Loughborough University, Loughborough,
Leics, LE11 3TU, UK. E-mail: r.cf.jones@lboro.ac.uk;
Fax: +44 1509 223925; Tel: +44 1509 222557
b Department of Chemistry & Analytical Sciences,
The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
c EPSRC National Crystallography Service, School of Chemistry,
University of Southampton, Highfield, Southampton, SO17 1BJ, UK
w Electronic supplementary information (ESI) available: Typical experi-
mental procedure, data for key compounds, X-ray crystallographic data
tables. CCDC 823959–823961. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c1cc12255j
Scheme 2 Reagent: i, N–R maleimide, CH2Cl2 reflux, 24 h.
Chem. Commun., 2011, 47, 7965–7967 7965
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Fig. 1 X-Ray crystal structure of 2 : 1 cycloadduct 2a.
state (Scheme 1):3 the anti dipole refers to the non-activating dipole
substituent, and the endo approach to C-7 of the cycloadduct
pyrrolo[1,2-a]imidazole core. Using N-phenylmaleimide in this
reaction led to corresponding 2 : 1 adduct 2b (36%).
Fig. 2 X-Ray crystal structure of minor 2 : 1 cycloadduct 5a.
In both examples, a minor product was found: a trace of 3a
isolated alongside adduct 2a, and 3b (8%) isolated with 2b. These
minor products, relative stereochemistry determined by NOE
studies, correspond to exo approach of dipole to dipolarophile.
Adduct 2b showed significant enhancement of C-7(H) and
C-6(H) signals on irradiation of C-7a(H) and C-7(H), respectively
(pyrrolo[1,2-a]imidazole numbering of the cycloadduct core),
indicating all three protons to be cis. In contrast, isomer 3b
showed only small enhancement of C-7a(H) on irradiation of
C-7(H) but a large enhancement of the cis-proton at C-6(H),
suggesting an anti arrangement of C-7(H) and C-7a(H); irradia-
tion of C-5(CH2) showed enhancement of C-6(H), confirming
them to be on the same face of the molecule. Coupling constants
3J(7,7a) were also characteristic: in 2a,b J = 7.6 Hz, where models
show a dihedral angle close to 01, whereas in 3a,b with a dihedral
angle nearer to 901, J = ca. 2 Hz.
Replacing the maleimide by a fumarate ester, the corres-
ponding 2 : 1 adducts were obtained in a slower reaction
(CH2Cl2 reflux, 48 h). Thus dimethyl fumarate led to major 4a
(45%) and minor 5a (10%) 2 : 1 adducts (Scheme 3). Minor
adduct 5a, stereostructure secured by X-ray crystal structure
(Fig. 2),w proved to be the diastereisomer predicted by our
transition state model, whereas major product 4a was determined
(comparison NOE studies) to be the C-7a epimer.
Scheme 4 Epimerisation at C-7a.
The dipolarophile-derived portion of the isolated adducts clearly
shows the C-6 and C-7 ester groups to be trans, i.e. the alkene has
fumarate geometry when it acts as dipolarophile, suggesting the
conjugate addition is rate-determining. Using diethyl fumarate led
to the corresponding 2 : 1 adducts 4b (42%) and 5b (21%).
Allowing this latter reaction to proceed for an extended period
(CH2Cl2 reflux, 10 days), the major 2 : 1 adduct 4b (20%) was
isolated along with secondary products that provided further
support for the proposed mechanism. Thus the formation of
enamino ester 6 (3%) and pyrrolo[1,2-a]pyrazine 7 (6%) is
rationalised by proton loss from the aminoiminium ion involved
in 4b/5b equilibration (Scheme 4) and lactam formation from 6.
Kinetic product 5b was not observed after these extended reaction
times.
We speculate that kinetic product 5a epimerizes to the thermo-
dynamic isomer 4a either under the reaction conditions or during
silica gel chromatography, presumably via aminal-aminoiminium
ion equilibrium (Scheme 4), as we have reported in other
dihydroimidazolium ylide cycloadditions.3 The latter possibility
is consistent with the observation that an isolated sample of minor
product 5a is converted into the same mixture of products 4a/5a
by the trace of acid present in untreated CDCl3 during NMR
examination. In support of our mechanistic proposal, when
dimethyl maleate was used instead of fumarate under the same
conditions, a mixture of the same two products was observed, 4a
(38%) and 5a (2%). Interconversion of maleate to the more stable
fumarate can be mediated by initial reversible conjugate addition
of the dihydroimidazole to the electron-deficient maleate alkene.8
The rate difference between maleimide and fumarate reactions,
attributed to the latter being less effective conjugate addition
acceptors, was exploited in formation of 1 : 1 : 1 adducts where
the Michael acceptor and dipolarophile were not the same
compound. When N-methylmaleimide was added slowly over
72 h to a mixture of dihydroimidazole 1 and dimethyl fumarate
(CH2Cl2 20 1C), 1 : 1 : 1 adduct 8a was isolated (24%)
(Scheme 5), stereochemistry as predicted by the transition state
model and secured by an X-ray crystal structure (Fig. 3)w and
NOE studies, along with C-7a epimer 9 (7%) and traces of the
2 : 1 adducts 2a/3a derived from the maleimide. N-Phenyl-
maleimide likewise afforded 1 : 1 : 1 adduct 8b (37%) and the
2 : 1 adducts 2b/3b (6%, 0.5%, respectively). These results suggest
the maleimides react preferentially as acceptors and that the
1,3-dipole formed is trapped by the fumarate present in excess.
The dihydroimidazolium ylide formation and reaction
was extended to chiral dihydroimidazoles: (R)-1-benzyl-
4-phenyl-4,5-dihydroimidazole 103 and N-methylmaleimide
Scheme 3 Reagent: i, (E)- or (Z)-RO2CHQCHCO2R, CH2Cl2 reflux,
48 h.
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enolate onto the dihydroimidazolium function. Using dimethyl
ethynedicarboxylate (CH2Cl2 20 1C, 72 h), where no proton
shift in the conjugate adduct is possible, six-membered adduct
15 was observed in low yield (5%). The unexpected structure
of 15 was supported by, for example, methine proton signals at
dH 7.8 and dC 147 showing an sp2 methine carbon atom, and
implying that the initial 1,4-cycloadduct has ring-opened and
the pendant amino function reclosed onto the alternative
pyridinium ion C-2 position.9
Scheme 5 Reagent: i, (E)-MeO2CHQCHCO2Me, N–R maleimide
added slowly, CH2Cl2 20 1C, 72 h.
We have demonstrated a novel conjugate addition-proton
transfer protocol for formation of dihydroimidazolium ylides,
and their 2 : 1 or 1 : 1 : 1 adducts with suitable dipolarophiles.
The cycloadducts are of value as building blocks towards
heterocyclic molecules of biological potential. Although some
yields are moderate, the cascade rapidly generates complexity,
with three new bonds and two new rings, so has good utility.
We acknowledge studentship support from Loughborough
University (M. S-A.) and The Open University (X. Z.), and the
EPSRC Mass Spectrometry Service Centre (Swansea) for high
resolution MS data, and thank STFC for access to station
16.2SMX of the SRS at Daresbury.
Fig. 3 X-Ray crystal structure of 1 : 1 : 1 cycloadduct 8a, stereochemistry
inverted from refined coordinates to correlate with Scheme 5. There are
two enantiomorphous molecules in the asymmetric unit and the space
group is centrosymmetric.
(CH2Cl2 reflux, 72 h) afforded 2 : 1 adduct 11a as the only
identifiable product (52%) (Scheme 6). This stereochemistry,
supported by spectroscopic data, is as predicted by the transition
state model. The chiral centre in 10 confers optical activity on
the adduct; cycloaddition occurs on the face of the formed
dipole opposite to the phenyl group as expected from our
earlier reports.3 N-Phenylmaleimide provided 2 : 1 adduct 11b
(73%), structure assigned by NMR methods in comparison to 11a.
Methyl or ethyl fumarate esters as acceptors and dipolarophiles led
to the 2 : 1 adducts 12a,b (33, 48%, respectively) in a much slower
reaction.
Notes and references
z We have to date been unable to isolate 1 : 1 : 1 adducts from reactions
of dihydroimidazole 1 with a doubly activated alkene as Michael
acceptor and a mono-activated alkene as dipolarophile.
We have established that the acceptor/dipolarophile alkene
must carry two electron-withdrawing groups by attempting
reactions of 1 with mono-activated alkenes such as propenoate
esters and 2-phenylnitroethene, when no pyrrolidine forma-
tion was observed.z These experiments did nevertheless
provide support for our proposed mechanistic sequence. In
the case of 2-phenylnitroethene (CH2Cl2 20 1C, 24h) the initial
conjugate adduct did not undergo proton transfer (which
would now be unfavourable) and behaved as a 1,4-dipole to
afford six-membered adducts 13 in low yield (3%) along with
the ring-opened derivative 14 (36%) of a diastereomeric
cycloadduct. This cycloaddition is rationalised as a two-step
process: a second conjugate addition and closure of the generated
1 For example: F. Bellina and R. Rossi, Tetrahedron, 2006, 62, 7213;
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Wiley-Interscience, Hoboken, 2003, p. 169.
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Scheme 6 Reagents: i, N–R maleimide, CH2Cl2 reflux, 72 h; ii,
(E)-RO2CHQCHCO2R, CH2Cl2 reflux, 17 days.
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Chem. Commun., 2011, 47, 7965–7967 7967