Atom-economic, regiodivergent, and stereoselective coupling of imidazole derivatives with terminal allenes

Article abstract of DOI:10.1002/anie.201309126

New Rh- and Pd-catalyzed regiodivergent and stereoselective intermolecular coupling reactions of imidazole derivatives with mono-substituted allenes are herein reported. Using a Rh^I/Josiphos system, perfect regioselectivities and high enantiomeric excess were obtained, while a Pd ^II/dppf system gave linear products with high regioselectivities and high E/Z selectivities. This method permits the atom economic synthesis of valuable branched and linear allylic imidazole derivatives. Copyright

Full text of DOI:10.1002/anie.201309126

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DOI: 10.1002/anie.201309126
Asymmetric Catalysis
Atom-Economic, Regiodivergent, and Stereoselective Coupling of
Imidazole Derivatives with Terminal Allenes**
Kun Xu, Niels Thieme, and Bernhard Breit*
Abstract: New Rh- and Pd-catalyzed regiodivergent and
stereoselective intermolecular coupling reactions of imidazole
derivatives with mono-substituted allenes are herein reported.
Using a RhI/Josiphos system, perfect regioselectivities and high
enantiomeric excess were obtained, while a PdII/dppf system
gave linear products with high regioselectivities and high E/Z
selectivities. This method permits the atom economic synthesis
of valuable branched and linear allylic imidazole derivatives.
F
unctionalization of nitrogen-containing heterocycles is an
Scheme 1. Transition metal catalyzed allylation of imidazole deriva-
tives. THF=tetrahydrofuran.
important topic since these structural motifs are prevalent in
natural products, agrochemicals, and pharmaceuticals (Fig-
ure 1).[1a–e] Additionally, their application in ligand and
catalyst design, supramolecular chemistry, and nanotechnol-
ogy has attracted much attention.[1b,c] To this end, N-allylation
of heterocyclic compounds is of particular interest because of
synthesis of allylic derivatives. Limitations of these
approaches include the requirement of a stoichiometric
amount of a leaving group or an oxidant, thus making them
less attractive in terms of atom economy.[11] Therefore, new
methods for atom-economic and selective allylation are
highly desirable. Our previous exploration on the rhodium-
catalyzed enantioselective coupling of allenes and alkynes
with carboxylic acids and anilines has exhibited a powerful
atom economical-complement to transition metal catalyzed
asymmetric allylic substitutions and allylic oxidations.[12–15]
We report herein a regiodivergent and stereoselective cou-
pling of imidazole derivatives with terminal allenes and it
allows access to both a-chiral branched and achiral linear
allylic derivatives using rhodium and palladium catalyst
systems, respectively (Scheme 1). To our best knowledge,
this is the first example of a transition metal catalyzed atom-
economic, regiodivergent, and stereoselective coupling of
heterocycles with allenes.
The initial experiments were performed with benzimida-
zole and cyclohexylallene in the presence of [{Rh(cod)Cl}2]
(2.5 mmol%) and DPEphos (10 mmol%) in 1,2-dichloro-
ethane (DCE) at 808C. To our delight, the desired branched
product was isolated with a promising 49% yield as a single
regioisomer. The feasibility of benzimidazole as a pronucleo-
phile encouraged us to screen different types of chiral
bidentate phosphine ligands.[16] Biaryl-type bisphosphine
ligands[16] and the Josiphos ligand J1 (Table 1, entry 1) led
to poor results. We were pleased to observe that changing to
the more-electron-rich and bulkier cyclohexyl Josiphos ligand
J2 led to a significant increase in the yield and ee value
(Table 1, entry 2). A fine tuning of the steric effects by
replacing the cyclohexyl group with the tert-butyl group
resulted in 97% ee with a slightly lower yield (72%; Table 1,
entry 3). Ligands with a smaller bite angle gave no reaction or
only traces of product, and (R,R)-diop gave moderate yield
Figure 1. Examples of bioactive imidazole derivatives.
the versatility of the allylic moiety, which allows further
elaboration and even straightforward syntheses towards
biologically active target molecules.[2] Despite the importance
of the N-allylation of heterocycles, efficient methods are still
rare.[3] Only one example has been reported using imidazole
derivatives (Scheme 1).[3a] Furthermore, the synthesis of the
corresponding achiral linear products usually use prefunc-
tionalized allylic derivatives with a leaving group under base-
promoted or metal-catalyzed conditions.[4]
Over the past few decades, allylic substitution[5–9] and
allylic oxidation[10] have been the preferred methods for the
[*] K. Xu, N. Thieme, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the DFG, the International Research
Training Group “Catalysts and Catalytic Reactions for Organic
Synthesis” (IRTG 1038), the Fonds der Chemischen Industrie, and
the Krupp Foundation. We thank Umicore, BASF, and Wacker for
generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309126.
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Table 1: Optimization of rhodium/palladium-catalyzed regiodivergent
Table 2: Scope of the rhodium-catalyzed enantioselective coupling of
and stereoselective coupling.
imidazole derivatives with allenes.
Entry[a,b]
Ligand
Yield [%][c]
B/L[d]
ee [%][e]
E/Z[f]
1
2
3
4
5
6
7
8
J1
J2
J3
55
83
72
100:0
100:0
100:0
9:91
9:91
5:95
14:86
7:93
<1:99
<1:99
24
89
97
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DPEphos
dppp
dppb
(Æ)-Binap
Xantphos
dppf
(74)[g]
(48)[g]
(71)[g]
78
(77)[g]
71
–
9
>99:1
>98:2
10[h]
dppf
89
[a] Entries 1–3, Conditions A: [{Rh(cod)Cl}2] (2.5 mol%), ligand
(10 mol%), DCE (0.25m), 808C, 18 h. [b] Entries 4–10, Conditions B:
[{Pd(h3-allyl)Cl}2] (2.5 mol%), ligand (5.0 mol%), THF (0.4m), 808C,
18 h. [c] Yield of isolated product. [d] Branched and linear ratio was
1
determined by H NMR analysis of the crude reaction mixture.
[e] Determined by HPLC using a chiral stationary phase. [f] Determined
by 1H NMR spectroscopy of the isolated products. [g] Yield of linear
1
products in the crude reaction mixture as determined by H NMR
spectroscopy using 1,3,5-trimethoxybenzene as internal standard.
[h] 1.2 equiv benzimidazole. binap=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl, cod=1,5-cyclooctadiene, DCE=1,2-dichloroethane, DPE-
phos=bis[(2-diphenylphosphino)phenyl]ether, dppb=1,4-bis(diphenyl-
phosphino)butane, dppf=1,1’-bis(diphenylphosphino)ferrocene,
dppp=l,3-bis(diphenylphosphino)propane, Xantphos=4,5-Bis(diphe-
nylphosphino)-9,9-dimethylxanthene.
Yield is that of the isolated product. The branched and linear ratio was
determined by H NMR analysis of the crude reaction mixture. The
ee values were determined by HPLC using a chiral stationary phase.
[a] Reaction was carried out at 1008C. Chp=cycloheptyl, TBS=tert-
butyldimethylsilyl, Trt=trityl, Phth=phthaloyl.
1
(1d and 1h). A halogenated imidazole substrate gave good
yield (1g) and permits further elaboration on the imidazole
ring. To our delight, a free hydroxy group was tolerated, albeit
at a slightly elevated temperature was required (1e). To
expand the scope of allenes, the monosubstituted allenes were
readily prepared in one or two steps from commercially
available starting materials.[16] Both a-branched allenes (1a
and 1o) and linear alkyl-substituted allenes (1j and 1m) were
suitable substrates. Allenes bearing protected alcohols (1k
and 1n) and phthalimide (1l) were also compatible, and could
afford useful hydroxy and amino groups upon deprotection.
In the case of the palladium-catalyzed coupling reactions,
various imidazole derivatives reacted smoothly with the
allenes to give the complementary linear allylation products
with good to excellent yields, and excellent linear and
E selectivities in most cases (2a–2h; Table 3).[17c] Imidazole
bearing an unprotected aldehyde group has no detrimental
effect on the reaction (2i). Different monosubstituted allenes
were also compatible under the palladium-catalyzed condi-
tions (2j–2p), albeit slightly lower E selectivities were
obtained when less bulky a-linear substituted allenes were
used.
(69%) but disappointing enantioselectivity (22%).[16] In all
cases, the branched product was observed exclusively.
We speculated that a suitable palladium catalyst in
combination with an achiral bidentate diphosphine ligand
might give access to the regiocomplementary linear allylation
product.[13] Our preliminary study focused on identification of
a
suitable ligand. Indeed, by using [{Pd(h3-allyl)Cl}2]
(2.5 mol%) and DPEphos (5.0 mol%), the desired linear
product (74%) was obtained with good linear/branched (L/B)
selectivity (91:9). We then tested a range of achiral bidentate
diphosphine ligands with different bite angles. The ligand
dppf proved to be superb in terms of the regioselectivity
(Table 1, entry 4–9), and a slight excess of benzimidazole
(1.2 equiv) led to an increased yield of 89% with excellent
L/B and E/Z selectivity (Table 1, entry 10). Surprisingly, the
reaction proceeded smoothly without any additive.[13]
With the optimized reaction conditions in hand, we then
investigated the scope of different imidazole derivatives with
allenes. For the synthesis of chiral branched products,[17a]
a wide range of imidazole derivatives were suitable substrates
with good to excellent yield and enantioselectivity
(Table 2).[17b] Both electron-withdrawing (1 f and 1h) and
electron-donating substituents (1b and 1d) were tolerated
with up to 99% yield (1b) and up to 98% enantioselectivity
To study the possible mechanism, isotope-labeling experi-
ments were conducted with [D2]benzimidazole and cyclo-
hexylallene under standard rhodium-catalyzed conditions
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Table 3: Scope of the palladium-catalyzed linear-selective coupling of
imidazole derivatives with allenes.
Scheme 3. Proposed mechanism of the rhodium-catalyzed coupling of
imidazole derivatives with allenes.
The palladium-catalyzed reactions may follow a similar
mechanism, but the reductive elimination (or external
attack) step favors the less hindered position and thus affords
the linear product.[19,20]
To conclude, we have developed the first atom-economic,
regiodivergent, and stereoselective coupling of imidiazole
derivatives with allenes by using rhodium and palladium
catalyst systems. A broad range of imidazole derivatives
smoothly coupled with various allenes to obtain both chiral
branched and achiral linear products. Excellent regioselectiv-
ities and stereoselectivities were achieved in most cases.
Future studies will focus on mechanistic investigations and
the extension of this methodology to other nitrogen-contain-
ing heterocycles as well as their applications in target-
oriented synthesis.
Received: October 18, 2013
Published online: January 20, 2014
Yield is that of the isolated product. The branched and linear ratio was
determined by 1H NMR analysis of the crude reaction mixture. The E/Z
ratio was determined by 1H NMR spectroscopy of the isolated products.
Keywords: allenes · allylic compounds · asymmetric catalysis ·
.
heterocycles · rhodium
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À
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