Asymmetric Synthesis of γ-Secondary Amino Alcohols via a Borrowing-Hydrogen Cascade

Article abstract of DOI:10.1021/acs.orglett.0c02614

The borrowing-hydrogen (or hydrogen autotransfer) process, where the catalyst dehydrogenates a substrate and formally transfers the H atom to an unsaturated intermediate, is an atom-efficient and environmentally benign transformation. Described here is an example of an asymmetric borrowing-hydrogen cascade for the formal anti-Markovnikov hydroamination of allyl alcohols to synthesize optically enriched γ-secondary amino alcohols. By exploiting the Ru-(S)-iPrPyme catalyst with minimal stereogenicity, a cascade process including dehydrogenation, conjugate addition, and asymmetric reduction was developed. The mild conditions, functional group tolerance, and broad substrate scope (54 examples) demonstrate the synthetic practicality of the catalytic system.

Full text of DOI:10.1021/acs.orglett.0c02614

pubs.acs.org/OrgLett
Letter
Asymmetric Synthesis of γ‑Secondary Amino Alcohols via a
Borrowing-Hydrogen Cascade
Yupeng Pan,† Yipeng You,† Dongxu He, Fumin Chen, Xiaoyong Chang, Ming Yu Jin,*
and Xiangyou Xing*
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ABSTRACT: The borrowing-hydrogen (or hydrogen autotransfer) process, where the catalyst dehydrogenates a substrate and
formally transfers the H atom to an unsaturated intermediate, is an atom-efficient and environmentally benign transformation.
Described here is an example of an asymmetric borrowing-hydrogen cascade for the formal anti-Markovnikov hydroamination of
allyl alcohols to synthesize optically enriched γ-secondary amino alcohols. By exploiting the Ru-(S)-iPrPyme catalyst with minimal
stereogenicity, a cascade process including dehydrogenation, conjugate addition, and asymmetric reduction was developed. The mild
conditions, functional group tolerance, and broad substrate scope (54 examples) demonstrate the synthetic practicality of the
catalytic system.
he borrowing-hydrogen1 (or hydrogen autotransfer)
hydrogenation over a broad scope of ketone substrates (Figure
Tprocess, which falls under the broader field of transfer 1B).4 We envisioned that given their strong dehydrogenation
hydrogenation,2 typically starts with the catalyst-mediated
ability and excellent reactivity in the asymmetric transfer
hydrogenation, these catalysts could effect the asymmetric
version of the aforementioned borrowing-hydrogen cascade to
generate optically enriched γ-secondary amino alcohols that
are featured extensively in the preparations of various
antidepressants.5
Here we report that under chirality-economy catalysis, an
array of racemic allyl alcohols and amines undergo a formal
anti-Markovnikov hydroamination that includes a cascade
process of dehydrogenation/conjugate addition/asymmetric
reduction to afford γ-secondary amino alcohols with high
enantioselectivity (Figure 1D). This catalytic protocol not only
serves as a powerful new extension of the asymmetric
borrowing-hydrogen methodology6,3c but also provides an
appealing alternative approach to access γ-secondary amino
alcohols that is distinct from widely used methods, such as the
asymmetric hydrogenation of β-amino ketones or the one-pot,
abstraction of hydrogen from the starting reagent and ends
with the incorporation of the abstracted hydrogen into the final
product. Featuring operational simplicity and no net hydrogen
loss or gain, this process is sustainable, environmentally benign,
and markedly atom-efficient, with a high proportion of material
incorporated into the product.1 Of particular interest to our
group, this strategy has been applied to the indirect, formal
anti-Markovnikov addition of carbon- or nitrogen-based
nucleophiles to allyl alcohols (Figure 1A).3 Such “one-pot”
relay cascades dehydrogenate allyl alcohols to give the
corresponding α,β-unsaturated carbonyl intermediates, fol-
lowed by the subsequent conjugate addition of nucleophiles
onto the intermediates to afford the β-functionalized carbonyl
compounds, which are finally hydrogenated with the metal
hydride to provide γ-functionalized alcohols. To date, such
processes have been independently reported by Williams,3a,b
Rodriguez,3c Oe,3d Wang,3e and Dydio.3f However, to the best
of our knowledge, enantioselectivity at the alcohol carbons was
not generated in these γ-functionalized alcohol products.
Contemplating enantioselectivity in such reactions, we
considered our recently developed Ru catalysts that have
significant chirality economy with only one stereogenic
element and yet are capable of effecting asymmetric transfer
Received: August 5, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02614
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Table 1. Optimization of Conditions
a
General conditions: ( )-1-phenylallyl alcohol 1 (0.2 mmol),
thiomorpholine 2 (0.4 mmol), catalysts A−E (0.25 mol %), KOtBu
b
(15 mol %), toluene/iPrOH 1:3 (2.0 mL), 23 °C, 4−12 h. Yields
were determined by 1H NMR using 1,4-dinitrobenzene as the internal
c
d
1
standard. Ratio was determined by crude H NMR. ee values were
determined by HPLC. Side product 4 was obtained in 4% yield with
81% ee. Reaction was performed at 0 °C for 12 h. Reaction was
performed at 50 °C for 12 h.
e
f
g
Figure 1. Asymmetric borrowing-hydrogen cascade for the formal
anti-Markovnikov hydroamination of allyl alcohols.
hydrogenation, longer reaction times resulted in higher
conversions and yields but erosion of the enantioselectivity.8
Therefore, in exchange for good enantioselectivity, the yield of
product 3 is moderately limited. When CH2Cl2 is used as the
cosolvent in combination with iPrOH, the ee increases to 94%,
whereas the yield and ratio of 3/4 decrease. The yield and
enantioselectivity of 3 were further improved when toluene
highly efficient transformation of enones and amines via a
Michael addition−asymmetric transfer hydrogenation cascade
process (Figure 1C).7
Our studies began by conducting the reaction with ( )-1-
phenylallyl alcohol (1) and thiomorpholine (2) as model
substrates in the presence of 0.25 mol % loading of Ru-catalyst
A and KOtBu (15 mol %) in CH2Cl2 at 23 °C (Table1, entry
1). To our delight, we obtained a 9:1 ratio of γ-amino alcohol
3 and the fully reduced side product 4, and the desired product
3 was produced in 79% yield with 60% ee. Subsequent
screening of various parameters revealed that the solvent plays
an important role in the overall reaction outcomes (Table 1,
entries 2−4). When iPrOH, which serves as a hydrogen donor
in the general transfer hydrogenation, was used as the
solvent,2,4 an apparent increase in the enantioselectivity was
observed, probably because iPrOH prohibits reversible
dehydrogenation of the product 3, and thus its high ee was
i
was used as the cosolvent in combination with PrOH (Table
1, entry 5). A variety of Ru catalysts of minimal stereogenicity
developed by us were surveyed, and all of them show
surprisingly good performances in generating enantioselectivity
in the desired product 3 (Table 1, entries 6−9). Although both
the enantioselectivity of 3 and the ratio of 3/4 were
maintained at 0 °C, a lower yield of 3 was obtained (Table
1, entry 10). In contrast, increasing the reaction temperature to
50 °C led to a higher yield of 3, albeit with a lower
enantioselectivity and a poor ratio of 3/4 (Table 1, entry 11).
With the optimal conditions in hand (Table 1, entry 5), we
then investigated whether they could be extended to a broader
family of substrates. As summarized in Table 2A, the catalyst A
was shown to be capable of effecting the cascade process of
i
maintained. PrOH also inhibits the formation of the side
product 4, providing a 13:1 ratio of 3/4 (Table 1, entry 4). It is
worth noting that due to the reversibility of the transfer
B
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Letter
a
Table 2. Asymmetric Synthesis of γ-Secondary Amino Alcohols: Scope of Racemic Allyl Alcohols and Amines
a
General conditions: allyl alcohol (0.2 mmol), thiomorpholine 2 (0.4 mmol), catalyst A (0.25 mol %), KOtBu (15 mol %), toluene/iPrOH 1:3,
b
total volume of solvents = 2.0 mL, 23 °C. Yields of isolated products are given. The ee values were determined by HPLC. Reaction was performed
at 50 °C for 12 h.
various racemic aryl-substituted allyl alcohols with thiomor-
pholine (2) with generally good enantiomeric excess (88−94%
ee). para-Substitution on the aryl ring by halogen (F, Cl, Br),
trifluoromethyl (CF3), ester (COOiPr), alkoxy (OCF3, OPh,
C
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OBn), methylthio (SMe), dimethylamino (NMe2), morpho-
linyl, alkyl (Me, Bu), phenyl or thienyl groups, which are
Scheme 1. Deuterium Labeling Experiments
t
either electron-donating or -withdrawing in nature, is all well
tolerated, leading to 88−93% ee in γ-amino alcohol products
5−19. Racemic aryl allyl alcohols bearing a meta-substitution,
including halogen (Cl, Br) and electron-donating methoxyl
(OMe) groups, were also transformed to the corresponding
alcohols with 91 to 93% ee (20−22). Allyl alcohols with 3,4-or
3,5-disubsitution on the aryl rings were investigated, and good
enantioselectivities (90−94% ees) were obtained in these cases
(23−26). Substrates with extended conjugation, such as
naphthalenyl-substituted allyl alcohols, were smoothly con-
verted to give γ-amino alcohol products 27 and 28 with 93%
ee, respectively. The structure of 28 was verified by X-ray
crystallography, which unambiguously confirmed the absolute
stereochemistry assignment. Finally, racemic allyl alcohols with
heteroaromatic substituents, such as quinoline, benzofuran,
benzothiophene, thiophene, and methylpyridine, were all
remarkably reactive to form the corresponding γ-amino
alcohols (29−33) with 88−91% ee.
To demonstrate the generality of this method, numerous
secondary amines were then successfully accommodated,
affording a range of γ-amino alcohols 34−57 in 45−72%
yields with 83−94% ee. As shown in Table 2B, cyclic
secondary amines, such as pyrrolidine, tetrahydroisoquinoline,
and morpholines, were readily reacted with ( )-1-phenylallyl
alcohol to give the corresponding alcohols 34−37 in 59−62%
yields with 83−94% ee. Acyclic secondary amines coupled to
both ( )-1-phenylallyl alcohol and ( )-2-(2-naphthyl)allyl
alcohol, affording the desired alcohols 38 and 39 with 90% ee,
respectively. A series of piperazine derivatives that are
significant pharmaceutical structures9 were than investigated,
and the alcohol products 40−48 were obtained with 85−94%
ee. The absolute configuration of 46 was also assigned as (R)-
configuration by X-ray analysis.
Gratifyingly, the 2-methoxyphenyl-substituted piperazine
furnished the antidepressant agents 52−55 in 53−60% yields
with 90−93% ee.5a We note that drug molecules, such as
amoxapine and vortioxetine, were smoothly coupled to racemic
allyl alcohols to deliver the alcohol products 49−51 and 56−
57 with 85−89% ee.10
of racemic allyl alcohols to valuable γ-amino alcohols that
occurs with high levels of enantioselectivity. This borrowing-
hydrogen process represents the first protocol for the formal
anti-Markovnikov reaction of racemic allyl alcohols to generate
high enantioselectivity at alcohol carbons in the γ-function-
alized alcohol products. Deuterium labeling studies indicate
i
that both the allyl alcohols and PrOH serve as hydrogen
donors in the cascade process. We believe that this work
represents a useful application of our chiral Ru catalysts,
demonstrating a high level of efficiency in asymmetric
induction.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02614.
Finally, deuterium labeling experiments were investigated
(Scheme 1). As illustrated in Scheme 1A, the reaction of the
fully deuterium-incorporated substrate ( )-deuterio-1 and 2 in
the presence of catalyst A, KOtBu, and toluene without iPrOH
was explored, and 94% deuterium incorporation was observed
at the benzylic position of the γ-amino alcohol deuterio-3,
indicating a typical borrowing-hydrogen cascade where the D
atom in ( )-deuterio-1 was transferred into the product
deuterio-3. When the reaction of ( )-deuterio-1 with 2 in the
Experimental procedures and characterization data (1H
and 13C NMR, HRMS) for all new compounds (PDF)
Accession Codes
CCDC 1977820−1977821 and 2009257 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
i
presence of PrOH was conducted, the D atom was partially
transferred to deuterio-3, and deuterium incorporation also
varied according to the reaction times, suggesting that the γ-
amino alcohols undergo a dedeuteration/hydrogenation
sequence. (Scheme 1B). Additionally, the reaction of ( )-1
and -2 in the presence of a combination of toluene/2-D-iPrOH
enables 35% deuterium incorporation into the γ-amino alcohol
deuterio-3 at its benzylic position (Scheme 1C). All together,
these results strongly support the notion that both the racemic
AUTHOR INFORMATION
Corresponding Authors
■
Xiangyou Xing − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055,
China; orcid.org/0000-0002-2456-0825; Email: xingxy@
sustech.edu.cn
Ming Yu Jin − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055,
China; Email: jinmy@sustech.edu.cn
i
allyl alcohols and PrOH were involved as hydride donors in
this asymmetric borrowing-hydrogen cascade.
In conclusion, we report a method catalyzed by the chirality-
economic Ru-(S)-iPrPyme for the direct conversion of a variety
D
https://dx.doi.org/10.1021/acs.orglett.0c02614
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Authors
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Yupeng Pan − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055,
China; orcid.org/0000-0002-4471-3219
Yipeng You − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055,
China; orcid.org/0000-0002-9977-4828
Dongxu He − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055, China
Fumin Chen − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055,
China; orcid.org/0000-0002-8290-2475
Xiaoyong Chang − Shenzhen Grubbs Institute and Department
of Chemistry, Guangdong Key Laboratory of Catalysis,
Southern University of Science and Technology, Shenzhen
518055, China; orcid.org/0000-0003-1394-6164
Complete contact information is available at:
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Author Contributions
†Y.P. and Y.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Shenzhen Nobel Prize Scientists Laboratory
Project (no. C17783101) and the Guangdong Provincial Key
Laboratory of Catalysis (no. 2020B121201002) for financial
support.
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