Asymmetric Synthesis of Hydroquinolines with α,α-Disubstitution through Organocatalyzed Kinetic Resolution

Article abstract of DOI:10.1002/anie.202015008

The first kinetic resolution of hydroquinoline derivatives with α,α-disubstitution has been achieved through asymmetric remote aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. Mechanistic studies suggest a monomeric catalyst pathway proceeding through rate- and enantio-determining electrophilic attack promoted by a network of attractive non-covalent interactions between the substrate and catalyst. Facile subsequent removal and transformations of the newly introduced hydrazine moiety enable these protocols to serve as powerful tools for asymmetric synthesis of N-heterocycles with α,α-disubstitution.

Full text of DOI:10.1002/anie.202015008

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Accepted Article
Title: Asymmetric Synthesis of Hydroquinolines with α,α-Di-
substitutions via Organocatalyzed Kinetic Resolution
Authors: Yunrong Chen, Chaofan Zhu, Zheng Guo, Wei Liu, and
Xiaoyu Yang
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10.1002/anie.202015008
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Asymmetric Synthesis of Hydroquinolines with α,α-Disubstitution
via Organocatalyzed Kinetic Resolution
Yunrong Chen, Chaofan Zhu, Zheng Guo, Wei Liu, and Xiaoyu Yang*
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
[a]
Dr. Y. Chen, C. Zhu, Z. Guo, W. Liu and Prof. Dr. X. Yang
School of Physical Science and Technology
ShanghaiTech University
Shanghai 201210, China
E-mail: yangxy1@shanghaitech.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: The first kinetic resolution of hydroquinoline derivatives
with α,α-disubstitution has been achieved through asymmetric
remote aminations with azodicarboxylates enabled by chiral
phosphoric acid catalysis. Mechanistic studies suggest a monomeric
catalyst pathway proceeding via rate- and enantio-determining
electrophilic attack promoted by a network of attractive non-covalent
interactions between the substrate and catalyst. Facile subsequent
removal and transformations of the newly introduced hydrazine
moiety enable these protocols to serve as powerful tools for
asymmetric synthesis of N-heterocycles with α,α-disubstitution.
Recently, our group has disclosed the asymmetric
construction of axially chiral aniline derivatives through CPA
catalyzed
asymmetric
aminations
of
anilines
with
azodicarboxylates[15]. Herein, we report the first highly efficient
KR of hydroquinolines (including THQs, DHQs and 5,6-
dihydrophenanthridines) bearing α,α-disubstitution through
asymmetric remote amination reactions, in which the introduced
hydrazine moiety could be facilely removed to return the chiral
hydroquinolines (Figure 1, c).
N-containing heterocycles are the most important class of
structural motifs in the pharmaceutical and agrochemical
industries. In particular, the tetrahydroquinolines (THQs) and
their derivatives are found in numerous biologically active
natural products and small molecules.[1] Consequently, the
asymmetric catalytic synthesis of THQs has drawn considerable
research interest, and gained tremendous progress in recent
years, particularly through the strategy of asymmetric
hydrogenations[2], asymmetric additions[3] and asymmetric
Povarov reactions[4]. However, asymmetric synthesis of THQs
with α,α-disubstitution through these methods was either
inaccessible or extremely challenging and presented with limited
scope[5].
Kinetic resolution (KR) of amines is another powerful and
practical method to produce N-containing heterocycles[6]. Since
the pioneer work of kinetic resolution of amines by Fu and co-
workers[7], a series of elegant asymmetric N-acylations protocols
have been developed for the KR of (cyclic) amines, which were
developed by Birman[8], Seidel[9], Miller[10], Bode[11] and Spivey[12]
groups, respectively (Figure 1, a). Additionally, the asymmetric
dehydrogenation reactions were also well applied in the KR of
N-containing heterocycles, though the products of these
reactions were generated without chiral information. The
Akiyama group developed a delicate method for KR of cyclic
secondary amines through asymmetric dehydrogenation with
imines enabled by chiral phosphoric acid (CPA) catalysis[13]
(Figure 1, b). Recently, the Liu group disclosed KR of α-
Figure 1. Kinetic resolution of N-containing heterocycles with α-stereocenters.
Our study commenced with racemic 2-methyl-2-phenyl-
1,2,3,4-tetrahydroquinoline (1a) as a model substrate and
dibenzyl azodicarboxylate (2) as the amination reagent enabled
by CPA catalysis (Table 1). In the presence of TRIP catalyst (A1,
10 mol%) in CHCl3 at room temperature, the reaction between
racemic 1a (1.0 equiv.) and azodicarboxylate 2 (0.6 equiv.)
proceeded smoothly to generate the 6-aminated product 3a with
63% ee and recovered 1a with 71% ee, (corresponding to a
selectivity factor[16] of 9.1, entry 1). Next, a range of BINOL-
derived CPA catalysts were examined (entries 2-7), which
indicated the 3,3’-di-(9-anthracenyl)-substituted CPA A4 could
give a better s-factor of 13 (entry 4). Encouragingly, switching
the chiral scaffold of CPA A4 to H8-BINOL-type (A8) provided a
significantly improved s-factor of 22 (entry 8). The SPINOL-
derived CPA catalyst B1 and B2 were also evaluated, which
couldn’t improve the stereoselectivities (entries 9 and 10). Due
to the fast reaction rate enabled by catalyst A8 at ambient
temperature (reaction completed within 1 h), decreasing the
reaction temperature was also studied (entries 11-12), which
substituted
1,2-dihydroquinolines
(DHQs)
and
5,6-
dihydrophenanthridines through chiral iron complex catalyzed
asymmetric dehydrogenation, in which air was used as the
oxidant[14]. However, to the best of our knowledge, the scope of
all the aforementioned methods have been limited to KR of
cyclic amines with α-mono-substitution, and KR of cyclic amines
with α,α-disubstitution through these methods is formidable.
1
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10.1002/anie.202015008
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proved exceptionally beneficial for the KR performance of this
reaction. Finally, −40 °C was determined to be the optimal
temperature, at which the amination product 3a was obtained
with 91% ee and 1a was recovered with 95% ee, giving an s-
factor of 79 (entry 12, for more reaction condition optimizations
see Table S1 in SI).
Table 1. Optimizations of reaction conditions.[a]
[a] Reactions were run with 1 (0.2 mmol), 2 (0.12 mmol) with CPA (S)-A8
(0.02 mmol, 10 mol%) in CHCl3 (4 mL) at –40 °C in the presence of 5 Å
molecular sieves (100 mg) for 16 ~ 36 h. Yields were isolated yields. Ee
values were determined by HPLC analysis on a chiral stationary phase. s =
ln[(1-C)(1-ees)]/ln[(1-C)(1+ees)]. Conversion (C) = ees/(ees+eep). [b] At −50 °C.
b
Time
(h)
12
12
12
12
12
12
12
1
T
(oC)
20
eesb
(%)
71
34
12
81
63
74
59
77
63
9
eep
(%)
63
56
23
68
61
55
53
81
76
25
90
91
Entry
Cat
Cc (%)
sd
1
2
A1
A2
A3
A4
A5
A6
A7
A8
B1
B2
A8
A8
53
38
33
54
51
57
53
49
45
27
49
51
9.1
5.0
1.8
13
20
With the excellent KR performances of this method on
THQs with α,α-disubstitution, we turned our attention to DHQs,
which possessed a C=C bond for further derivatizations and
would be a valuable building block for the synthesis of THQ
derivatives (Table 3). However, applying the previous optimal
conditions on DHQ 1n only provided moderate selectivities.
Satisfyingly, after brief screening of the CPA catalysts (see
Table S2 in SI), we found the KR of DHQ 1n in the presence of
SPINOL-derived CPA catalyst (R)-B1 provided the 6-aminated
product 3n in 50% yield with 96% ee and recovered (S)-1n in 49%
yield with 98% ee, with an s-factor of 226. A variety of aryl
groups instead of the phenyl group were screened under these
optimal conditions, which showed that substituted phenyl groups
(1o-1q), 2-naphthyl group (1r) as well as the thienyl group (1s)
could be well tolerated. Notably, an α,α-dialkyl substituted DHQ
could be kinetically resolved as well, giving an s-factor of 91 (1t).
Substitutions at the 3- and 4-position of DHQ substrates were
also examined, which were well compatible with the standard
conditions (1u and 1v). Finally, the KR of 6,6-disubstituted 5,6-
dihydrophenanthridines was also studied. Satisfyingly, applying
the optimal reaction conditions for DHQs on these substrates
provided both the amination products and recovered SMs with
high enantioselectivities (1w-1y).
3
20
4
20
5
20
7.7
7.4
5.8
22
6
20
7
20
8
20
9
12
12
3
20
14
10
11e
12e
20
1.8
53
−20
−40
86
95
12
79
[a] Reactions were run with 1a (0.1 mmol), 2 (0.06 mmol) with CPA catalyst
(0.01 mmol, 10 mol%) in CHCl3 (2 mL) at designated temperatures. [b]
Determined by HPLC analysis on a chiral stationary phase. [c] Conversion (C)
= ees/(ees+eep). [d] s = ln[(1-C)(1-ees)]/ln[(1-C)(1+ees)]. [e] With 5 Å molecular
sieves (50 mg).
With the optimal kinetic resolution conditions in hand, we set
out to explore the scope of this reaction under the catalysis of
(S)-A8 catalyst (Table 2). A range of substituted phenyl groups
at the 2-position of THQs were initially examined, which
indicated that various para- and meta-substituted phenyl groups
could be well tolerated, regardless of the electronic nature of the
substituents (1b-1i). Next, a series of alkyl groups other than the
Me group at the 2-position of THQs were investigated under the
standard conditions, which were amenable variants, including
the Et (1j), allyl (1k) and benzyl (1l) groups. In addition, the
optimal KR reaction conditions were also attempted on α-mono-
substituted THQ (1m), which also provided excellent KR
performances, generating both recovered SM and product with
high enantioselectivities.
Table 3. Scope for kinetic resolution of DHQs and 5,6-dihydrophenanthridines
with α,α-disubstitution.[a]
Table 2. Scope for kinetic resolution of THQs with α,α-disubstitution.[a]
2
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10.1002/anie.202015008
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being critical to the mechanism of enantioinduction for catalyst
A8.[18]
In order to gain a clearer picture of the enantiodetermining
transition state, the relationship between differential kinetic
enantiomeric enhancement (DKEE)[19] and the ee of catalyst A8
in the KR reaction of THQ 1h was studied, and an approximately
linear relationship was observed, which suggested the absence
of multiple chiral components in the asymmetric transition state
(Figure 3, c)[19-20]. The order of catalyst in the KR reaction of
THQ 1h was also studied, and a linear relationship was found
between the initial reaction rate and the concentration of the
catalyst, suggesting a first-order dependence on CPA catalyst,
further consistent with the absence of non-linear effect (Figure 3,
d). The intermolecular competitive kinetic isotope effect (KIE)
experiment between (R)-1aD and (R)-1a was performed under
the catalysis of (R)-A8 (the matched substrate–catalyst pair),
giving a KIE value of 1.0 (see Figure S2 in SI), which suggested
the C-H cleavage step is probably not involved in the rate-
determining step.
On the basis of these experimental results, we proposed
that electrophilic addition to generate the dearomatized
intermediate (INT A) is the rate- and enantio-determining step
(Figure 2, c). Taken together, the mechanistic studies suggest a
model in which activation of both the THQ 1a and
azodicarboxylate 2 by a single CPA catalyst through dual
hydrogen-bonding facilitates the addition of C-6 of THQ 1a with
azodicarboxylate 2 to give the dearomatized addition product
INT A, in which the (S)-configurated 1a reacted preferentially.
Though steric effects cannot be ruled out as contributors to the
mechanism of enantioinduction, our results suggest that
attractive NCIs between substrates and the CPA catalyst are
critical to realize the kinetic resolution.[21] Facile aromatization of
INT A ultimately affords the 6-aminated THQ (S)-3a.
[a] The same conditions as in Table 2 expect CPA (R)-B1 (10 mol%) was used
instead. [b] CPA (R)-B2 (10 mol%) was used as catalyst. [c] At −20 °C.
To shed light on the mechanism of these highly selective
KR reactions, some control experiments were performed (Figure
2). Kinetic resolution of the α,α-disubstituted N-Me-THQ 4a
under the standard conditions afforded the amination product
with 61% ee and recovered (R)-4a with 60% ee, with an s-factor
of 7.6, which suggested the potential hydrogen-bonding between
the N-H moiety of THQ and the P=O functional group of the
catalyst is important for the stereoselectivity (Figure 2, a).
However, on the other hand, moderate stereoselectivity was still
achieved without the N-H group in the THQ substrate, which
implied the likely presence of other non-covalent interactions
(NCIs) between the substrate and catalyst[17]. To investigate this
hypothesis, catalytic hydrogenation of CPA (S)-A8 facilely
provided the (S)-A8’ catalyst, which should have similar steric
environments with the (S)-A8 catalyst, while possessing
substantially reduced capacity to engage in attractive aromatic
NCIs (Figure 2, b). Indeed, KR of racemic 1a using this catalyst
under the standard conditions only provided the product 3a with
59% ee and the recovered (R)-1a with 70% ee, corresponding to
an s-factor of 10, in sharp contrast to the excellent s-factor
obtained under CPA A8 catalysis. Moreover, (S)-A8’ promoted
the reaction with a slower rate compared to A8 (see Figure S1 in
SI), suggesting that the polyaromatic nature of the ortho-
substitutions of the CPA A8 is critically important not only for the
excellent stereoselectivity but also the high reactivity observed in
this reaction. To obtain additional insight into the basis of kinetic
resolution, Eyring analysis in the 20 °C to −40 °C temperature
range of catalyst (S)-A8 was studied. An excellent linear
relationship between ln(s) and 1/T was observed, from which the
∆∆H‡ and ∆∆S‡ of this reaction could be calculated (Figure 3, a).
These results implied that the high s-factor of this reaction was
controlled by enthalpy, with relatively small entropic
compensations. On the other hand, a linear relationship between
ln(s) and 1/T was only found in the temperature range of 20 °C
to −20 °C for the (S)-A8’ catalyzed reaction, with a significantly
smaller ∆∆H‡ value and comparable ∆∆S‡ value (Figure 3, b).
This change is consistent with attractive NCIs (e.g. π-π or CH-π)
Figure 2. Control experiments and proposed reaction mechanism.
3
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Figure 3. Mechanistic studies. a) Eyring analysis of KR of racemic 1a
catalyzed by (S)-A8 catalyst. b) Eyring analysis of KR of racemic 1a catalyzed
by (S)-A8’ catalyst. The differential activation parameters were calculated
using the following relationship: ln(s) = –∆∆H‡/RT + ∆∆S‡/R [where R = 1.986
cal/(mol•K)]. c) Plot of the DKEE versus the ee of CPA (S)-A8 in KR of
racemic 1h. DKEE = (s-1)/(s+1). d) Catalyst order determination for the KR
reaction of substrate 1h catalyzed by CPA (S)-A8.
Scheme 1. Derivatizations of chiral products.
In conclusion, we have disclosed the first highly efficient
kinetic resolution of hydroquinoline derivatives with α,α-
disubstitution through chiral phosphoric acid catalyzed remote
aminations with azodicarboxylates. A range of THQs, DHQs and
To demonstrate the practicality of these reactions, large-
scale KR experiment was performed. Encouragingly, the kinetic
resolution of DHQ 1n with reduced catalyst loading (0.5 mol% of
CPA (R)-B1) still provided comparable KR performances, giving
s-factor of 136 (see Figure S3 in SI).
A series of derivatizations of the chiral products were
conducted to prove the utilities of these methods. Cleavage of
the N-N bond of the 6-hydrazine group in 3n with the treatment
of bromoacetate and Cs2CO3 afforded the 6-N-Cbz substituted
DHQ 6n[22] (Scheme 1, a). Critically, treatment of 3n with KOH
solution at 75 °C led to the facile deamination reaction, providing
(S)-1n in 82% yield with retained enantiomeric excess. This
finding enables the hydrazine moiety to serve a temporary role
facilitating separation of the reactant enantiomers, thus allowing
the protocol above to serve as a catalytic resolution of both
enantiomers formally without modification.
5,6-dihydrophenanthridines
possessing
various
α,α-
disubstitution could be kinetically resolved with excellent yields
and selectivities. Mechanistic studies elucidated the reaction
mechanisms and highlighted the role of attractive non-covalent
interactions between the substrate and catalyst in the
stereodetermining step. Fruitful transformations of the products,
notably including removal of the hydrazine moiety to return
enantioenriched starting material, demonstrated the values of
these methods in preparing of N-containing heterocycles with
α,α-disubstitution.
Acknowledgements
To highlight the versatile reactivities of the C=C bond in
DHQ (R)-1n, a range of transformations were studied (Scheme
1, b). After protecting of the (R)-1n with the Cbz group,
We gratefully acknowledge NSFC (Grant No. 21702138,
21901162) and ShanghaiTech University start-up funding for
financial support. The authors thank the support from Analytical
Instrumentation Center (# SPST-AIC10112914), SPST,
ShanghaiTech University. We gratefully acknowledge Prof. M.
Levin (University of Chicago) and Prof. F. D. Toste (University of
California, Berkeley) for helpful discussion and proofreading of
the manuscript.
epoxidation[23]
,
dihalogenation,
hydroxylbromination
and
diazidation[24] of the olefin motif of 7n provided a wide array of
3,4-difuntionalized THQ derivatives with high efficiencies and
without erosion of optical purities.
Keywords: asymmetric organocatalysis • α,α-disubstitution •
hydroquinolines • kinetic resolution • remote amination
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10.1002/anie.202015008
Angewandte Chemie International Edition
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The first kinetic resolution of hydroquinoline derivatives with α,α-disubstitution was realized via organocatalyzed catalyzed
asymmetric remote aminations with azodicarboxylates, which represents a powerful protocol for asymmetric synthesis of N-
heterocycles with α-quaternary stereocenters. Mechanistic studies elucidate the reaction mechanisms and highlighted the role of
attractive non-covalent interactions between the substrate and catalyst.
6
This article is protected by copyright. All rights reserved.