Asymmetric Transfer Hydrogenation of Unhindered and Non-Electron-Rich 1-Aryl Dihydroisoquinolines with High Enantioselectivity

Article abstract of DOI:10.1021/acs.orglett.0c02034

The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for imine ATH.

Full text of DOI:10.1021/acs.orglett.0c02034

pubs.acs.org/OrgLett
Letter
Asymmetric Transfer Hydrogenation of Unhindered and Non-
Electron-Rich 1‑Aryl Dihydroisoquinolines with High
Enantioselectivity
Jonathan Barrios-Rivera, Yingjian Xu,* and Martin Wills*
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ABSTRACT: The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer
hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position
results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an
electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for
imine ATH.
ince the first report by Noyori et al. in 19961 of the
S
asymmetric transfer hydrogenation (ATH)2 of one-
substituted 3,4-dihydroisoquinolines (DHIQs) 1 to form
asymmetric tetrahydroisoquinolines (THIQs) 2 (Figure 1)
Figure 1. Dihydroisoquinoline (DHIQ) reduction by ATH with
arene/Ru/TsDPEN complexes 1−4 (Figures 2 and 3).
Figure 2. Catalysts employed in the ATH of DHIQs: 1−4, known
catalysts for this application; 5−7, complexes reported in this paper.
using Noyori−Ikariya catalysts (arene/Ru/TsDPEN type)
such as 1 and 2, there has been a great deal of interest in
this class of reaction.3 Other catalysts, including the related
tethered catalysts such as 34 and the N′-alkylated TsDPEN-
based catalysts such as 4,5 (Figure 2) have been applied to the
ATH of DHIQs. 1-Alkyl (including 1-benzyl and 2-phenethyl)
DHIQs are generally excellent substrates that give products
with high enantioselectivities (ee’s) (Figure 3) when catalysts 1
and 2 are used in the reactions.1,3,6 In contrast, 1-aryl-
substituted DHIQs exhibit a more complex pattern of
reactivity with this class of catalyst, and previous work has
indicated that they can be consistently reduced to products
with high ee only if there is an ortho substituent on the
aromatic ring at the one-position of the substrate (Figure 3).1,7
This is presumably due to the requirement for the presence of
a hindered substituent at this position.
Received: June 19, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02034
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
and ester-containing catalysts 5−7 (Figure 2)13 in the ATH of
unhindered/electron-poor 1-aryl DHIQs and found that these
worked very well with these challenging substrates, with 5
being the best in our studies. In common with other reports on
DHIQ ATH,6 we used a 5:2 azeotropic combination of formic
acid and triethylamine (FA/TEA) as the hydrogen source.
Products were formed with a higher enantioselectivity than
that with any other arene/Ru/TsDPEN ATH catalysts that we
are aware of.
In our initial tests, we used catalyst (R,R)-5 in the reduction
of the parent 1-phenyl-DHIQ 8 in a formic acid 5:2 azeotrope
(FA/TEA) alongside a range of catalysts (Figure 5, Table 1).
Figure 5. Asymmetric reduction of DHIQ 8 (Table 1).
a
Table 1. ATH of 2-Phenyl DHIQ 8
entry
catalyst
t (h)
conv (%)
ee (%)
1
2
3
4
5
7
8
9
(R,R)-1
(R,R)-2
(R,R)-3
(R,R)-5
(R,R)-5
(R,R)-6
(R,R)-7
(R,R)-4
48
48
16
24
24
48
96
72
45
11
97
93
90
86
77
12
24
42
10
Figure 3. Summary of the state-of-the-art of DHIQ ATH using arene/
Ru/TsDPEN catalysts (R,R)-1 and (R,R)-2 and closely related
derivatives. Dihydroisoquinoline (DHIQ) reduction products are
illustrated.
b
90
c
90
91
49
0
In addition, an electron-rich aromatic ring in the fused arene
component of the DHIQ (typically one or two methoxy
groups)6,7 is also beneficial for the formation of products with
high ee to be generated in the reductions of 1-aryl DHIQs. In
contrast, very few reports have appeared on the ATH of non-
electron-rich 2-aryl/non-ortho-substituted DHIQs.7b DHIQ
ATH has also been reported using the Rh(III) and Ir(III)/Cp*
derivatives of the Noyori−Ikariya Ru(II) catalysts, with a
similar pattern of results observed but also with some complex
observations reported from a study of the kinetics of the
reductions.8 Therefore, this class remains an unsolved
challenge for ATH with arene/Ru/TsDPEN catalysts such as
1−4 even some 24 years since Noyori et al.’s first report,
despite their potential for the synthesis of valuable
pharmaceutical target molecules such as solifenacin9a and
TRPM8 antagonists9b (Figure 4). Other approaches to the
a
Conditions as given in Figure 5. The solvent is DCM unless
b
otherwise indicated. Product isolated in 70% yield at 96 h (98%
conversion). In all cases, the configuration of 9 was the same (and as
illustrated) and was determined by the correlation with the reported
result using (R,R)-1.7b Solvent is MeCN.
c
Because its ATH using catalyst (R,R)-1 had been reported to
give product 9 with only 29% ee (90% yield),7b this was felt to
have obvious scope for improvement. To eliminate the
significant effect of the solvent (we have preciously found
that catalysts (R,R)-5−7 perform most effectively in DCM),
our repeat of the reduction of substrate 9 with catalyst (R,R)-1
in DCM gave a product with only 24% ee and 45% conversion.
Using the cymene derivative (R,R)-2, product 9 was formed
with only 11% conversion and 42% ee, and with tethered
catalyst (R,R)-3, the result was worse, with a product formed
with only 10% ee (although with a conversion of 97%). With
furan-containing catalyst (R,R)-5, however, reduction to THIQ
9 was achieved with an impressive 90% ee (93% conversion
and 70% isolated yield), and the enantioselectivity was
unchanged in DCM and MeCN solvents. Catalyst (R,R)-6,
bearing a thiophene ring, gave a reduction product with 91% ee
but just 86% conversion after the same 48 h of reaction time,
whereas ester-containing catalyst (R,R)-7 gave a product with
just 77% conversion (in 96 h) and 49% ee. Significantly, the
reduction using the N′-benzyl-functionalized catalyst (R,R)-4
gave a racemic product with just 12% conversion, highlighting
the remarkable effect of the heterocyclic ring on the reduction
selectivity.
Figure 4. Structure of solifenacin, a muscarine acetylcholine receptor
antagonist, and a recently reported TRPM8 antagonist that formed
the basis for further optimizations.
enantiomeric synthesis of 1-aryl THIQs include the use of Ir/
chiral diphosphines in asymmetric hydrogenation,10 the
incorporation of ATH catalysts into a protein structure,11
and enzymatic methods.12 In this Letter, we describe a
practical solution to the challenge presented by unhindered/
electron-poor 1-aryl DHIQs based on the accessible (arene)/
Ru/TsDPEN class of ATH catalysts.
Having made this unexpected observation, we tested the
reductions of a further series of non-electron-rich DHIQs using
catalyst (R,R)-5 and obtained the products illustrated in Figure
6. It was found that para- and meta-substituted products were
consistently formed with high ee, typically 90% or greater, and,
During the course of an ongoing project on N-alkylated
TsDPEN ligands in the complexes, we evaluated heterocycle-
B
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Figure 7. Products of the ATH of electron-rich 1-aryl and 1-methyl
DHIQs in this project using catalyst (R,R)-5 and the conditions
a
shown in Figure 5 (overnight reaction time). First report, to our
knowledge, of the formation by ATH using arene/Ru/TsDPEN
b
catalysts. Formate formed.
As expected on the basis of previous literature reports,1,6,7
dimethoxy-substituted 1-aryl imines were reduced with high ee
with (R,R)-5, slightly higher than similar reported examples
using catalyst (R,R)-1 (24: 84% ee, 27: 75% ee);7b however,
the difference was not as significant as that for the electron-
poor products in Figure 6. It should be noted that the imine
precursor of 26 was fully reduced; however, the product was
formed as a mixture of formylated (major) and nonformylated
(minor) amines. In addition, we compared catalyst (R,R)-5
with the reported results for the formation of the methyl-
substituted products 28 and 29, and the products were formed
with 81 and 80% ee, respectively; slightly lower ee values than
have already been reported using (R,R)-1 and (R,R)-2 as ATH
catalysts (Figure 1).1−3,6
It is not exactly clear how the modified catalyst (R,R)-5
controls the asymmetric reduction in these cases. However, the
control of the enantioselectivity of the reduction is believed to
involve a transition state in which the protonated iminium ion
forms a H bond to the SO2 of the tosyl group while a known
η6/CH interaction also operates to stabilize the transition state
(Figure 8A),3 which is analogous to the control of ketone
reductions with this class of catalyst.14 However, the selectivity
is likely to be low because the transitions state (ts) for the
reduction to either enantiomer can be stabilized by similar
interactions. The additional furan group (in (R,R)-5) may
engage in an interaction that serves to stabilize the ts, leading
to the observed major enantiomer (Figure 8B). The lack of
selectivity observed with catalyst (R,R)-4 suggests that this is
an electronic effect involving the heteroatom rather than a
simpler steric or π-stacking effect. Conversely, the additional
steric hindrance in (R,R)-5 results in slower reduction (and
hence incomplete conversions) for more hindered substrates,
that is, those containing ortho-substituted aryl groups.
Figure 6. Products from non-electron-rich DHIQ reduction obtained
in this project using catalyst (R,R)-5 and the conditions shown in
Figure 5 (overnight reaction time). Configurations were assigned by
analogy to 9 (Table 1). aFirst report, to our knowledge, of the
b
formation by ATH using arene/Ru/TsDPEN catalysts. 85% yield,
92% ee reported using (R,R)-1.7b
where comparable, with higher ee than that reported for
catalyst (R,R)-1 (15: 36% ee, 16: 36% ee, 18: 39% ee, 19: 79%
ee).7b Several of the products were reported, to the best of our
knowledge, for the first time with high ee using an arene/Ru/
TsDPEN catalyst in ATH (indicated in Figure 6). Tolerated
substituents included meta- and para-chloro and -methyl and
para-bromo, -iodo, -methoxy, -nitro, and -trifluoromethyl
groups (not all meta-substituted substrates were tested) as
well as meta/para combinations of electron-rich groups. The
synthesis of amine 15 was also carried out on a 1.1 g (5 mmol)
scale and gave a product with 91% ee in 71% isolated yield. In
contrast, the furan catalyst (R,R)-5 is less effective at the ATH
of ortho-substituted aryl-substituted substrates; the reduction
of the ortho-chlorophenyl substrate gave no product 12, and
the ortho-methyl/methyloxyphenyl imines gave products 17
and 19, respectively, in low yield, although with excellent ee.
Hence there is a clear complementary (and mutually exclusive)
pattern of selectivity between Noyori−Ikariya catalysts such as
(R,R)-1 and (R,R)-2 and the heterocycle-functionalized (R,R)-
5. This may reflect the extra steric hindrance around catalyst
(R,R)-5, which is less accommodating to a bulky 2-aryl
substituent; however. the formation of a racemic product using
catalyst (R,R)-4 in the prototype substrate test indicates the
importance of the additional involvement of the furan in the
reaction transition state.
In conclusion, we have demonstrated that the addition of a
heterocyclic group to the basic nitrogen atom of the TsDPEN
ligand in an arene/Ru/TsDPEN ATH complex renders it an
excellent catalyst for the reduction of a previously very
challenging class of DHIQ substrate for this application. The
value of the methodology is highlighted by the formation of
products 9 and 21, which are precursors of pharmaceutical
target molecules (Figure 5). The mode of action remains to be
fully understood, but the presence of a heterocycle is
The study was also extended to a series of electron-rich
substrates and the simpler 1-methyl substrates, with the
resulting THIQs (yields and ee’s) shown in Figure 7.
C
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NMR spectra and HPLC spectra relating to ee and dr
determination (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Martin Wills − Department of Chemistry, The University of
Warwick, Coventry CV4 7AL, United Kingdom; orcid.org/
0000-0002-1646-2379; Email: m.wills@warwick.ac.uk
Yingjian Xu − GoldenKeys High-tech Materials Co., Ltd., Guian
New Area, Guian 550025, Guizhou Province, China;
Email: goldenkeys9996@thegoldenkeys.com.cn
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Jonathan Barrios-Rivera − Department of Chemistry, The
University of Warwick, Coventry CV4 7AL, United Kingdom
Complete contact information is available at:
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Notes
The authors declare the following competing financial
interest(s): Y.X. is the founder and CEO of GoldenKeys
High-tech Materials Co., Ltd.
The research data (and/or materials) supporting this
publication can be accessed at http://wrap.warwick.ac.uk/.
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ACKNOWLEDGMENTS
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We thank Warwick University and GoldenKeys High-Tech
Materials Co., Ltd. for funding (of J.B.-R. grant number
QKHJC[2018]1406) via the Warwick Collaborative Post-
graduate Scholarship Scheme.
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