Asymmetric Hydrogenation of In Situ Generated Isochromenylium Intermediates by Copper/Ruthenium Tandem Catalysis

Article abstract of DOI:10.1002/anie.201611291

The first asymmetric hydrogenation of in situ generated isochromenylium derivatives is enabled by tandem catalysis with a binary system consisting of Cu(OTf)₂ and a chiral cationic ruthenium–diamine complex. A range of chiral 1H-isochromenes were obtained in high yields with good to excellent enantioselectivity. These chiral 1H-isochromenes could be easily transformed into isochromanes, which represent an important structural motif in natural products and biologically active compounds. The chiral induction was rationalized by density functional theory calculations.

Full text of DOI:10.1002/anie.201611291

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611291
German Edition: DOI: 10.1002/ange.201611291
Tandem Reactions
Asymmetric Hydrogenation of In Situ Generated Isochromenylium
Intermediates by Copper/Ruthenium Tandem Catalysis
Tingting Miao, Zi-You Tian, Yan-Mei He, Fei Chen, Ya Chen, Zhi-Xiang Yu,* and Qing-
Hua Fan*
Abstract: The first asymmetric hydrogenation of in situ
generated isochromenylium derivatives is enabled by tandem
catalysis with a binary system consisting of Cu(OTf)2 and
a chiral cationic ruthenium–diamine complex. A range of
chiral 1H-isochromenes were obtained in high yields with good
to excellent enantioselectivity. These chiral 1H-isochromenes
could be easily transformed into isochromanes, which repre-
sent an important structural motif in natural products and
biologically active compounds. The chiral induction was
rationalized by density functional theory calculations.
realized by transition-metal catalysis and/or organocatalysis.[8]
Despite this great progress, asymmetric variants of these
transformations were developed only recently, mainly
because of the lack of coordination sites within their planar
structure (Hꢀckel aromatic compounds), which is often
crucial for achieving high reactivity and/or stereoselectivity.[9]
Most recently, the groups of Akiyama[9g] and Terada[9h]
independently reported notable examples of asymmetric
transfer hydrogenation (ATH) reactions of in situ generated
isochromenyliums by chiral-counteranion-directed catalysis.
These methods, however, still suffer from some drawbacks,
such as high catalyst loadings and lack of substrate generality
(only one dialkyl-substituted substrate with 22% ee). To the
best of our knowledge, catalytic AHs of isochromenylium
derivatives, which would provide a facile and environmentally
friendly approach to important enantiopure O-containing
heterocycles, have not been reported thus far.[9g,h,10]
Most recently, we found that the cationic ruthenium
complexes of chiral monosulfonated diamines are very
efficient catalysts for the AH of various N-heteroaromatic
compounds with excellent reactivity and enantioselectivity.[5]
Encouraged by these results, we attempted to use these
catalyst systems for the AH of the highly reactive isochro-
menyliums. According to reported methods,[9a] isochromeny-
liums can be generated in situ by treatment of ortho-
(alkynyl)aryl ketones with various metal catalysts. It was
thus important to find two compatible catalysts for the overall
reaction that also control the chemoselectivity and enantio-
selectivity (Scheme 1). Herein, we report the first AH of
a range of in situ generated O-heteroaromatic isochromeny-
lium derivatives by bimetallic tandem catalysis that provides
the corresponding 1H-isochromenes in high yields and
enantioselectivities.
O
ptically active, saturated or partially saturated hetero-
cycles are important structural motifs of many biologically
active compounds, natural products, and chiral ligands.[1]
While a huge number of methods have been developed for
the synthesis of such chiral compounds, asymmetric hydro-
genation (AH) of often readily available heteroaromatic
compounds represents one of the most straightforward and
efficient approaches.[2] Since Murata and co-workers reported
the first homogeneous AH of 2-methylquinoxaline in 1987,[3]
a variety of bicyclic and monocyclic N-heteroaromatic com-
pounds have been hydrogenated with very good reactivity and
excellent enantioselectivity.[4,5] However, significantly fewer
effective AHs of oxygen- and sulfur-containing heteroaro-
matic compounds have been reported.[6]
Isochromenyliums are highly reactive intermediates that
are often generated in situ for various transformations, and
have found wide applications in synthetic chemistry.[7–9] Over
the last decade, a range of catalytic cascade reactions based on
isochromenyliums, such as [3+2] annulations, [4+2] cyclo-
additions, and nucleophilic addition reactions, have been
[*] T. Miao, Y.-M. He, F. Chen, Y. Chen, Prof. Dr. Q.-H. Fan
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (CAS)
University of Chinese Academy of Sciences
Beijing 100190 (P.R. China)
For our initial investigations, ortho-(alkynyl)aryl ketone
1a was chosen as the model substrate as a precursor of the
corresponding isochromenylium ion.[9g,h] Several chiral tran-
sition-metal complexes that had previously been proven to be
and
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin 300072 (P.R. China)
E-mail: fanqh@iccas.ac.cn
Z.-Y. Tian, Prof. Dr. Z.-X. Yu
BNLMS, Key Laboratory of Bioorganic Chemistry and Molecular
Engineering, College of Chemistry, Peking University
Beijing, 100871 (P.R. China)
E-mail: yuzx@pku.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611291.
Scheme 1. Enantioselective hydrogenation of the in situ generated
isochromenyliums.
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efficient AH catalysts were examined in combination with
Cu(OTf)2 as the second catalyst (Table 1; see also the
Supporting Information, Table S1). However, the desired
product was obtained in rather low yields and enantioselec-
reaction, affording the desired R-configured 1H-isochro-
menes 2a–2s in excellent yields and enantioselectivities
(Table 2). Introducing electron-donating or electron-with-
Table 2: Scope of the tandem reaction.[a]
Table 1: Catalyst screening.[a]
Entry
Catalyst
I
Catalyst
II
Conv.
[%][b]
Yield [%][b]
ee of
2a
2a’
2a [%][c]
[d]
[d]
1
2
3
4
Cu(OTf)2
AgOTf
–
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(S,S)-3a
(S,S)-3a
(S,S)-3a
(S,S)-3b
(S,S)-3b
(S,S)-3b
>95
>95[e]
24
>95
>95
>95
>95
70
–
92
>95
>95
–
–
88
88
5[f]
91
93
91
[d]
21
–
[d]
[d]
[d]
5[g]
6[g,h]
–
–
[a] Reaction conditions: 1a (0.1 mmol) in 0.5 mL THF, I (10 mol%), II
(10 mol%), H2 (50 atm), stirred at room temperature for 24 h.
[b] Determined by 1H NMR analysis of the crude product mixture with
1,3,5-trimethoxybenzene as the internal standard. [c] Determined by
HPLC analysis with a chiral OD-H column. [d] Compound 2a or 2a’ not
observed. [e] A complex mixture was obtained. [f] The ee value of 2a’.
[g] Ethylene glycol dimethyl ether (GDME) as the solvent, 4 h. [h] Cu-
(OTf)2 (3 mol%) and (S,S)-3b (1 mol%), 24 h. Tf=trifluoromethane-
sulfonyl.
tivities when frequently used complexes based on a chiral
diphosphine ligand, such as BINAP/RuII, BINAP/RhI, and
BINAP/IrI, were used. Gratifyingly, the tandem reaction with
ruthenium–diamine catalyst (S,S)-3a proceeded smoothly in
THF, affording exclusively chiral 1H-isochromene 2a in
> 95% yield and 88% ee (Table 1, entry 1). Several other
p-Lewis acidic metal complexes, such as AgOTf, Zn(OTf)2,
Pd(OAc)2, and W(CO)6, were also tested; however, only
AgOTf gave the desired product with similar enantioselec-
tivity but in lower yield (Table 1, entry 2). Subsequently,
several chiral ruthenium–diamine catalysts were screened
with Cu(OTf)2 as the optimal catalyst I. The catalytic
performance was clearly affected by the N-sulfonate sub-
stituents, and catalyst (S,S)-3b turned out to be optimal in
terms of both catalytic activity and enantioselectivity
(Table S1). Interestingly, the ratio of the Cu and Ru catalysts
significantly influenced the outcome of this tandem reaction.
Rather low yields and enantioselectivities were observed with
5 mol% Cu(OTf)2 and 10 mol% (S,S)-3a under otherwise
identical reaction conditions (Table S5). Most importantly,
excellent yields and similar enantioselectivities were also
achieved with a much lower catalyst loading (Table 1,
entry 6).[11]
[a] Reaction conditions: 1a–1s (0.1 mmol), Cu(OTf)2 (10 mol%), (S,S)-
3b (10 mol%), H2 (50 atm), stirred at room temperature for a certain
period of time (2a–2j, 2q, 2r: 4 h; 2k–2o, 2s: 16 h; 2p: 24 h). For 2a–
2p, the hydrogenation was done in GDME. For 2q–2s, the hydro-
genation was done in DCM. The absolute configurations of the products
were determined by comparison with literature data.[9g,h] [b] Cu(OTf)2
(3 mol%), (S,S)-3b (1 mol%), 24 h.
drawing substituents at the para position of the aryl group at
the alkyne terminus did not affect the reaction outcome, and
high yields and excellent enantioselectivities were still
observed (2a–2 f). The high yields and enantioselectivities
were also maintained when the catalyst loadings were
reduced. Substrates bearing linear or branched alkyl chains
at the R1 position also reacted smoothly without a decrease in
yield or enantioselectivity (2g and 2h). The introduction of
a fluorine substituent on the tethered aryl ring slightly
decreased the ee (2i and 2j). Gratifyingly, tandem reactions
of substrates with alkyl substituents at both the R1 and R2
position afforded the desired products with slightly lower but
still good reactivities and enantioselectivities (2k–2o), which
are much better than the 22% ee achieved when 2l was
obtained by transfer hydrogenation.[9h] Interestingly, substrate
1p, bearing a sterically demanding tert-butyl group at the R2
position, gave the corresponding product in good yield, albeit
Under the optimized reaction conditions, a variety of
ortho-(alkynyl)aryl ketones were subjected to the tandem
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with much lower enantioselectivity. For substrates with an
aryl substituent at the R1 position, the reactions proceeded
smoothly irrespective of whether R2 was an aryl or alkyl group
when dichloromethane (DCM) was used as the solvent (2q–
2s).
The usefulness of this catalytic asymmetric tandem
reaction was exemplified by the scale-up synthesis of a few
R-configured 1H-isochromenes (Scheme 2). With Cu(OTf)2
Scheme 3. Control experiments to confirm the involvement of isochro-
menylium intermediates.
Scheme 2. Scale-up reactions and product transformation.
(3 mol%) and (S,S)-3b (1 mol%), the 1H-isochromenes
(R)-2a and (R)-2b were isolated in greater than 90% yield
and with the same enantiopurity as for the small-scale
reactions. Heterogeneous hydrogenation of (R)-2b provided
the corresponding chiral isochromane with excellent diaste-
reoselectivity.
To understand the mechanistic details of this tandem
reaction, several control experiments were carried out. First,
we checked whether side product 2a’ undergoes intramolec-
ular cyclization under the reaction conditions. As expected,
no conversion was observed, and 2a’ was recovered. In
a deuterium labeling study (Scheme 3a), 80% and 60%
deuterium incorporation was observed at the C1 and C4
position, respectively.[12] In addition, the stable isochromeny-
lium salt 5q was successfully synthesized and reacted with an
À
excess amount of a Ru H complex. The yield and enantio-
purity of the product were similar to those achieved in the
standard tandem reaction starting from ortho-(alkynyl)aryl
ketone 1q (Scheme 3b). These results indicate that isochro-
menyliums are intermediates of these tandem reactions.
Based on the results obtained above, a plausible reaction
mechanism was proposed for the cooperative catalysis
process (Scheme 4). First, the ortho-(alkynyl)aryl ketone
reacts with Cu(OTf)2 to generate isobenzopyrylium salt
A.[8b] Meanwhile, the ruthenium–diamine catalyst reacts
Scheme 4. Proposed catalytic cycle and the transition states computed
for the hydride transfer.
Density functional theory (DFT) calculations at the
B3LYP/6-31G(d,p)(LANL2DZ for Ru) level of theory[13]
were carried out to gain further insight into the origin of the
enantioselectivity. Two hydride transfer transition states
TS(R) and TS(S), which lead to the R- and S-configured
products, respectively, were located (Scheme 4 and
Scheme S4). It was found that TS(R) is favored over TS(S)
by 2.4 kcalmolÀ1 in terms of the Gibbs free energy in DCM
solution (the energy difference in the gas phase is 2.0 kcal
molÀ1), suggesting that the R-configured product is the
kinetically favored product of the reaction. This is consistent
with our experimental observations (Table 2, 2 f). It was
À
with dihydrogen to produce a Ru H complex and TfOH.
À
Then, protonolysis of the C Cu bond of A by TfOH
regenerates Cu(OTf)2 and gives the isobenzopyrylium inter-
mediate B.[8b] Finally, hydride transfer from the Ru H
À
complex to isobenzopyrylium intermediate B affords the
desired product and regenerates the ruthenium–diamine
catalyst.
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found that the most favorable transition state TS(R) was
stabilized by three hydrogen bonding interactions between
the O atoms of the tosyl group of the catalyst and two
different H atoms (one from the methyl group and one on the
fused arene ring) of the substrate. The fused arene ring of the
À
substrate is almost perpendicular to the C H2 bond that is
adjacent to the N-tosyl group of the catalyst, affording
a CH(sp3)–p interaction that is similar to that found in
Noyoriꢁs ketone ATH system.[14] These stabilization interac-
tions by hydrogen bonding and CH(sp3)–p attractions in
TS(R) were supported by AIM calculations.[15] Such
CH(sp3)–p stabilizing interactions are absent in the compet-
ing transition state TS(S) even though TS(S) features three
À À
C H O interactions between hydrogen atoms on the fused
arene ring of the substrate and the tosylate oxygen atoms.
These interactions could be weaker than the hydrogen
bonding and CH(sp3)–p interactions in TS(R), and conse-
quently, TS(S) is not favored in the reduction process.
In conclusion, we have demonstrated that in situ gener-
ated isochromenyliums can be enantioselectively hydrogen-
ated by CuII/RuII tandem catalysis. A broad range of ortho-
(alkynyl)aryl ketones were transformed into chiral isochro-
menes in high yields with good to excellent enantioselectivity.
This method thus provides a practical and green approach for
the construction of optically pure isochromenes and other
O-containing heterocycles. We believe that this strategy will
stimulate further work on the asymmetric hydrogenation of
other challenging reactive heteroaromatic compounds.
Acknowledgements
We thank the National Natural Science Foundation of China
(21232008, 21232001, 21473216, and 21521002) and CAS
(QYZDJSSW-SLH023) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · heterocycles · hydrogenation ·
ruthenium · tandem reactions
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isochromanes, see: a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc.
1998, 120, 9074; b) L. M. Tewierik, C. Dimitriadis, C. D. Donner,
M. Gill, B. Willems, Org. Biomol. Chem. 2006, 4, 3311; c) P.
Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011, 133,
Manuscript received: November 17, 2016
Revised: January 11, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Tandem Reactions
T. Miao, Z.-Y. Tian, Y.-M. He, F. Chen,
Y. Chen, Z.-X. Yu,*
Q.-H. Fan*
&&&& — &&&&
Asymmetric Hydrogenation of In Situ
Generated Isochromenylium
Intermediates by Copper/Ruthenium
Tandem Catalysis
Two metal catalysts: The title reaction is
catalyzed by a binary system based on
Cu(OTf)2 and a chiral ruthenium–dia-
mine complex. A range of chiral 1H-
isochromenes were obtained in high
yields with good to excellent enantiose-
lectivities, and were easily transformed
into isochromanes.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!