Enantioselective Hydrogenation of Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/chem.201705370

The enantioselective synthesis of tetrahydroimidazo[1,2-a]pyridines by direct hydrogenation was achieved using a ruthenium/N-heterocyclic carbene (NHC) catalyst. The reaction forgoes the need for protecting or activating groups, proceeds with complete regioselectivity, good to excellent yields, enantiomeric ratios of up to 98:2, and tolerates a broad range of functional groups. 5,6,7,8-Tetrahydroimidazo[1,2-a]pyridines, which are found in numerous bioactive molecules, were directly obtained by this method, and its applicability was demonstrated by the (formal) synthesis of several functional molecules.

Full text of DOI:10.1002/chem.201705370

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Title: Enantioselective Hydrogenation of Imidazo[1,2-a]pyridines
Authors: Christoph Schlepphorst, Mario Wiesenfeldt, and Frank Glorius
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Enantioselective Hydrogenation of Imidazo[1,2-a]pyridines
Christoph Schlepphorst, Mario P. Wiesenfeldt and Frank Glorius*
Abstract: The enantioselective synthesis of tetrahydroimidazo[1,2-
a]pyridines via direct hydrogenation was achieved using
a
ruthenium/N-heterocyclic carbene (NHC) catalyst. The reaction
forgoes the need for protecting or activating groups, proceeds with
complete regioselectivity, good to excellent yields, enantiomeric ratios
of up to 98:2, and tolerates a broad range of functional groups.
5,6,7,8-Tetrahydroimidazo[1,2-a]pyridines, which are found in
numerous bioactive molecules, are directly obtained by this method
and its applicability was demonstrated by the (formal) synthesis of
several functional molecules.
Chiral saturated heterocycles are prevalent in secondary
metabolites and, as a result, have been exploited as biologically
active building blocks as well as synthetic intermediates
especially in pharmaceutical and agrochemical research.[1]
Traditionally, these motifs are prepared via enantioselective
cycloadditions or cyclizations which often require tedious
multistep substrate syntheses and provide a limited scope.[2]
Alternatively, the enantioselective hydrogenation of readily
available heteroarenes has recently emerged as a straightforward
route to access these valuable motifs.[3] However, some common
obstacles have to be addressed. These include the aromatic
stabilization and the ability of some substrates as well as their
corresponding products, especially those containing nitrogen, to
bind to the catalyst. This can lead to catalyst deactivation as well
as diminished enantioselectivity due to the undesired binding
competition with the productive coordination of the unsaturated
ring system. Consequently, methods to lower the inherent
aromaticity of heterocycles and/or prevent binding to the metal
catalyst have been employed for the reduction of N-
heterocycles.[4] Likewise, examples for the direct hydrogenation
of N-,[3,5] O-,[6] S-,[4b,7] and all-carbocyclic aromatic compounds[8]
are known.
Figure 1. Bioactive molecules and chiral ligands containing the substituted
tetrahydroimidazo[1,2-a]pyridine scaffold.
5,6,7,8-Tetrahydroimidazo[1,2-a]pyridines are found in numerous
bioactive molecules including those outlined in Figure 1.[9]
Furthermore, Andersson and co-workers developed a series of
chiral P,N-ligands based on this framework, which show distinct
reactivity
and
high
enantioinduction
in
Ir-catalyzed
hydrogenations and Pd-catalyzed intermolecular Heck
reactions.[10] However, to the best of our knowledge, no catalytic
enantioselective method to construct the chiral substituted
5,6,7,8-tetrahydroimidazo[1,2-a]pyridine core has been reported
to date, and either enantio-enriched starting materials or chiral
resolution techniques have to be employed to access the desired
enantiopure products. Based on our previous studies in the field
of enantioselective arene hydrogenation,[5g,6a,b,7,8a,11] especially a
study concerning the enantioselective reduction of indolizines,[11]
we envisaged that our ruthenium–N-heterocyclic carbene
(NHC[12]) catalyst could be effective in the catalytic reduction of
imidazo[1,2-a]pyridines. Herein, we disclose a direct ruthenium–
NHC-catalyzed enantioselective hydrogenation of imidazo[1,2-
a]pyridines to afford chiral 5,6,7,8-tetrahydroimidazo[1,2-
a]pyridines.
In an initial experiment, readily accessible 5-methylimidazo[1,2-
a]pyridine 1a was reacted with the in situ prepared Ru(NHC)2
catalyst[13] in n-hexane under 70 bar hydrogen pressure at 25 °C
(Table 1). The reaction cleanly generated the desired
tetrahydroimidazo[1,2-a]pyridine 2a with 50% conversion and an
enantiomeric ratio of 90:10. No side products were detected. The
observed chemoselectivity was in line with the results obtained for
the indolizine hydrogenation and can be explained by the
preservation of one aromatic imidazole ring in the product. Due to
the bridge head nitrogen, a neutral aromatic resonance structure
after partial reduction can only be drawn in the five-membered
ring, which is in sharp contrast to other bicyclic heteroarenes,
such as azaindoles.[5h] Note that Zhou’s enantioselective
hydrogenation of activated pyrrolo[1,2-a]pyrazinium salts[4c]
likewise results in the reduction of the six-membered ring.
Exploration of the reaction conditions revealed that tert-amyl
alcohol was the best solvent in terms of both yield and e.r. (entries
C. Schlepphorst, M. P. Wiesenfeldt, Prof. Dr. F. Glorius
Westfälische Wilhelms-Universität Münster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/index.html
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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1–6). Full conversion was achieved by a simple increase of the
hydrogen pressure from 70 to 100 bar and thus enabled the
isolation of 2a in quantitative yield after a facile acid/base
extraction (entry 7). A decrease of the reaction temperature from
25 °C to 0 °C led to an increase of the e.r., however, the
conversion was slightly reduced (entry 8). X-ray crystallographic
analysis of the corresponding hydrochloride salt confirmed the
structure and revealed its absolute configuration.
debenzylation was observed in the hydrogenation of 1h
illustrating the mild reaction conditions and orthogonality to Pd-
catalyzed hydrogenolysis. The products 2i and 2j were purified by
chromatography due to their rapid desilylation upon exposure to
acid. Substrates 1k and 1l bearing sterically and electronically
distinct aryl groups were also converted to the corresponding
products in excellent yields, albeit with diminished e.r.
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Solvent
n-hexane
Et2O
Conversion[b]
50%
E.r.[c]
90:10
94.5:5.5
71:29
94:6
2
68%
3
toluene
THF
64%
4
59%
Scheme 1. Substrate scope of 5-substituted imidazo[1,2-a]pyridines 1a–l.
General conditions: [Ru(cod)(2-methylallyl)2] (0.02 mmol), KOt-Bu (0.04 mmol)
and (S,S)-SINpEt·HBF4 (0.04 mmol), 1a–l (0.2 mmol), t-AmylOH (1 mL). Yields
of isolated products are given. Absolute configurations are assigned in analogy
to 2a. [a] The reaction was performed at 0.3 M concentration and 150 bar H2
pressure. [b] Isolated product contains 4% of inseparable starting material. [c]
The reaction was performed in n-hexane. TBS = tert-butyldimethylsilyl.
5
PhCF3
87%
85:15
95.5:4.5
95.5:4.5
98:2
6
t-AmylOH
t-AmylOH
t-AmylOH
93%
7[d]
8[d,f]
99% (99%)[e]
74%
Next, the effect of an additional substituent on the imidazole ring
on the reaction outcome was investigated (Scheme 2).
Hydrogenation of the substrate bearing a phenyl substituent in the
2-position (1m) provided the corresponding product with
preserved high yield and enantiocontrol. A variety of functional
groups were tolerated on the aryl group (2n–s) without loss of
enantioselectivity. Only a methoxy substituent in para-position
(2s) led to both diminished yield and e.r. A substrate bearing a
cyano group (1r) could be hydrogenated with high
enantioselectivity and complete reduction of the nitrile to a
benzylic primary amine. The generally somewhat lower yields of
disubstituted products, in the absence of any side products,
compared to 2a–l, were identified to be caused by the lower
solubility of the hydrochloride salts in the aqueous phase during
the workup procedure. Therefore, 2q was purified by
chromatography instead, giving a substantially increased yield of
92% compared to 31% after extractive workup. Moreover, the
hydrogenation of imidazo[1,2-a]pyridines with functional groups
directly attached to the imidazole ring was possible, as
exemplified by products 2t and 2u, which could be isolated in
good to excellent yields and e.r. values. 2,5-Disubstituted silyl
protected alcohol 2v could also be isolated in quantitative yield
and good enantioselectivity showcasing that the methyl group is
[a] General conditions: [Ru(cod)(2-methylallyl)2] (0.02 mmol), KOt-Bu
(0.04 mmol) and (S,S)-SINpEt·HBF4 (0.04 mmol), 1a (0.2 mmol), solvent
(1 mL). See the Supporting Information for detailed experimental conditions.
[b] The conversion was determined by 1H-NMR. [c] The e.r. was determined
by chiral HPLC. [d] The reaction was performed under 100 bar H2 pressure.
[e] Isolated yield in parentheses. [f] The reaction was performed at 0 °C. tert-
AmylOH = 2-methyl-2-butanol. Cod = 1,5-Cyclooctadiene.
Under the optimized reaction conditions, a series of 5-substituted
imidazo[1,2-a]pyridines were hydrogenated to the corresponding
5,6,7,8-tetrahydroimidazo[1,2-a]pyridines 2 in high yields and
enantioselectivities (Schemes 1 and 2).[14] Many functional groups
such as pyridines, amides, amines, (silyl)-ethers, esters and
different halides were well-tolerated offering opportunities for
further functionalization of the obtained products. An increase in
chain length of the 5-substituent (substrates 2b–d, Scheme 1)
hardly affected the enantioselectivity, while excellent yields were
maintained. The comparison of the results for the structurally
similar phenethyl- and pyridinylethyl products (2d and 2e)
indicated that an additional Lewis-basic coordination ability could
lead to a slight decrease in enantiocontrol. A similar observation
was made for the amide and amine substrates 1f and 1g.
Substrates 1e–g were converted into their corresponding
products in excellent yields after a slight increase of concentration
and hydrogen pressure. Benzyl- and silyl protected alcohols 1h–j
were also successfully hydrogenated.[15] Note that no
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not a necessity for this substitution pattern. Scale-up of the
reaction to 1.5 mmol was shown for this substrate. No decrease
in yield or enantioselectivity was observed. 5-Methyl-3-
phenylimidazo[1,2-a]pyridine 1w bearing the substituents in
closer proximity delivered the corresponding product 2w in
conserved high yield, albeit with diminished e.r.
used racemic 2a in their study, obtained by heterogeneous
hydrogenation of 1a. The targeted synthesis of diastereomers is
now feasible using our method.
In order to show the applicability of this method towards other
structurally related nitrogen-rich heterocycles, an imidazo[1,5-
a]pyridine derivative as well as a pyrazolo[1,5-a]pyridine were
efficiently reduced in good yield and e.r.. 3, whose configuration
was proven by x-ray crystallographic analysis, and 4 were
obtained from the corresponding starting materials, indicating the
generality of the catalyst towards azaindolizine substrates in
terms of reactivity as well as chemo- and enantioselectivity
(Scheme 3).
Scheme 3. Enantioselective hydrogenation of 5-methylimidazo[1,5-a]pyridine
and 7-methylpyrazolo[1,5-a]pyridine. Yields of isolated products are given.
Scheme 4. Synthesis of functional molecules containing the tetrahydro-
imidazopyridine scaffold.
In summary, we have developed the first enantioselective
catalytic synthesis of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines,
which are found in numerous bioactive molecules, via direct
hydrogenation of readily available imidazo[1,2-a]pyridines, using
a ruthenium–NHC-catalyst. The reported method is completely
regioselective, and the corresponding products are obtained in
good to excellent yields and enantioselectivities. To showcase the
applicability of this newly developed method, two direct
precursors for bioactive molecules as well as a novel chiral NHC
ligand derived from an imidazo[1,5-a]pyridine were synthesized.
The application of this protocol as a platform for the preparation
of useful three-dimensional functional heterocycles is anticipated.
Scheme 2. Substrate scope of disubstituted imidazo[1,2-a]pyridines 1m–w.
General conditions: [Ru(cod)(2-methylallyl)2] (0.02 mmol), KOt-Bu (0.04 mmol)
and (S,S)-SINpEt·HBF4 (0.04 mmol), 1m–w (0.2 mmol), t-AmylOH (1 mL).
Yields of isolated products after acid/base extraction are given. [a] Isolated yield
after column chromatography instead is given in parentheses. [b] The
corresponding nitrile compound 1r was used as substrate. [c] The reaction was
performed at 0.3 M concentration and 150 bar H2 pressure.
To demonstrate the synthetic utility of this method, further
derivatizations and applications were carried out (Scheme 4).
Firstly, we sought to apply our method to the synthesis of new
chiral NHC ligands.[16] Methylation of 3 with methyl iodide
proceeded smoothly to generate imidazolium salt 5, which could
be further reacted with [Rh(cod)Cl]2 proving its ability to act as a
ligand (Scheme 4a). Furthermore, silyl ether 2j was deprotected
and oxidized in the same reaction under Jones-oxidation
conditions to provide carboxylic acid 6 in 66% yield. This
compound can undergo an Ugi reaction to yield the IDH1 mutant
inhibitor 7 as demonstrated by Zhou (Scheme 4b).[9b] Finally, the
muscarinic receptor antagonist 8 can be prepared in one step
from 2a as shown by Kaiser (Scheme 4c).[9d] Note that the authors
Experimental Section
General procedure: [Ru(2-methylallyl)2(cod)] (6.3 mg, 20 μmol, 0.1 equiv.),
KOtBu (4.5 mg, 40 μmol, 0.2 equiv.) and SINpEt•HBF4 (18.7 mg, 40 μmol,
0.2 equiv.) were stirred at 70 °C in n-hexane (1 mL) for 16 h to yield a
yellow suspension of the ruthenium bis-NHC complex. The mixture was
added to the imidazo[1,2-a]pyridine substrate 1 (0.2 mmol, 1 equiv.) in a
7 mL dram vial under an argon atmosphere and the solvent was removed
in vacuo. tert-Amyl alcohol (0.7 mL, 0.3 M or 2 mL, 0.1 M) was added and
the vial was transferred to an argon filled 150 mL stainless-steel reactor.
The autoclave was purged with hydrogen gas four times before the
reaction pressure was set to 100 bar (or 150 bar). The hydrogenation
reaction was performed at 25 °C for 24 hours. After the autoclave was
carefully depressurized, the mixture was concentrated in vacuo and
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purified by acid/base extraction or flash chromatography on silica gel to
afford the desired product 2.
[6]
For selected examples of enantioselective hydrogenation of O-
heteroarenes, see Ref. 3 a–e) and references therein. For more recent
examples: a) N. Ortega, S. Urban, B. Beiring, F. Glorius Angew. Chem.
Int. Ed. 2012, 51, 1710; b) J. Wysocki, N. Ortega, F. Glorius Angew.
Chem. Int. Ed. 2014, 53, 8751. c) L. Pauli, R. Tannert, R. Scheil, A. Pfaltz
Chem. Eur. J. 2015, 21, 1482; d) T. Miao, Z.-Y. Tian, Y.-M. He, F. Chen,
Y. Chen, Z.-X. Yu, Q.-H. Fan Angew. Chem. Int. Ed. 2017, 56, 4135.
S. Urban, B. Beiring, N. Ortega, D. Paul, F. Glorius J. Am. Chem. Soc.
2012, 134, 15241.
Acknowledgements
We are grateful to the Studienstiftung des Deutschen Volkes (M.
P. W.), the Deutsche Forschungsgemeinschaft (F. G., Leibniz
Award) for generous financial support and Dr. K. Ditrich (BASF)
for the donation of chiral amines. We thank Dr. W. Li and Dr. Z.
Nairoukh for many helpful discussions. We also thank Dr. C. G.
Daniliuc for x-ray crystallographic analysis.
[7]
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a) S. Urban, N. Ortega, F. Glorius Angew. Chem. Int. Ed. 2011, 50, 3803;
b) R. Kuwano, R. Morioka, M. Kashiwabara, N. Kameyama Angew.
Chem. Int. Ed. 2012, 51, 4136; c) R. Kuwano, R. Ikeda, K. Hirasada,
Chem. Commun. 2015, 51, 7558.
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Hamada, T. Takeuchi J. Antibiotics 1992, 45, 1404; b) J. Popovici-Muller,
J. O. Saunders, F. Salituro, Z. Cai, S. Yan, D. Zhou Therapeutically
Active Compounds and Their Methods of Use. International Patent
WO2013107405, Jan 21, 2013; c) C. S. Burgey, A. Ginnetti, A. Nomland,
Fused Heterocyclic Azaindane Carboxamide CGRP Receptor
Antagonists. International Patent WO2013066360, Dec 16, 2011; d) C.
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Hatoum, V. C. Lowe, J. C. Prosser, B. L. Sturm, L. Noronha-Blob J. Med.
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Keywords: enantioselective hydrogenation • N-heterocyclic
carbenes • imidazopyridines • ruthenium • heterocycles
[1]
[2]
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[10] a) P. Kaukoranta, M. Engman, C. Hedberg, J. Bergquist, P. G.
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[3]
For recent reviews on enantioselective hydrogenation of aromatic
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Zhou, Acc. Chem. Res. 2007, 40, 1357. c) D.-S. Wang, Q.-A. Chen, S.-
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[11] N. Ortega, D.-T. D. Tang, S. Urban, D. Zhao, F. Glorius Angew. Chem.
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[12] a) M. N. Hopkinson, M. Schedler, C. Richter, F. Glorius Nature 2013, 510,
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Organometallic Synthesis; Wiley-VCH Verlag: Weinheim.
[4]
[5]
For a review on substrate activation in the hydrogenation of N-
heterocycles: a) B. Balakrishna, J. L. Núñez-Rico, A. Vidal-Ferran, Eur.
J. Org. Chem. 2015, 5293. For S-heterocycles: b) P. Tosatti, A. Pfaltz,
Angew.Chem. Int. Ed. 2017, 56, 4579; c) for a more related example: W.-
X. Huang, C.-B. Yu, L. Shi, Y.-G. Zhou Org. Lett. 2014, 16, 3324.
For selected examples of enantioselective hydrogenation of N-
heteroarenes, see Ref. 3 a–e) and references therein. For more recent
examples: a) Y. Duan, L. Li, M.-W. Chen, C.-B. Yu, H.-J. Fan, Y.-G. Zhou
J. Am. Chem. Soc. 2014, 136, 7688. b) M. Chang, Y. Huang, S. Liu, Y.
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[14] Our attempts to hydrogenate 6-, 7-, or 8-methylimidazo[1,2-a]pyridine
afforded the corresponding products with low e.r. values.
[15] The hydrogenation of substrates containing unprotected (primary)
alcohols resulted in low conversions.
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Soc. Rev. 2004, 33, 619; for structurally related NHCs: f) D. Hirsch-Weil,
K. A. Abboud, S. Hong Chem. Commun. 2010, 46, 7525.
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Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
The enantioselective hydrogenation of imidazopyridines was achieved using a
ruthenium(II)-NHC catalyst. Excellent yields and enantioselectivities are obtained
and a variety of functional groups is tolerated. This method provides straightforward
access to valuable enantio-enriched tetrahydroimidazopyridines from readily
available aromatic precursors, and its applicability was demonstrated by the
synthesis of direct precursors to bioactive molecules and a novel chiral NHC ligand.
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