Catalytic Enantioselective Synthesis of α-Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation

Article abstract of DOI:10.1002/anie.201806956

The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl-substituted N-heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N-heterocycles, nucleophiles, and substituents on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst-induced LUMO lowering, with site-selective, rate-limiting, intramolecular asymmetric proton transfer from the ion-paired prochiral intermediate.

Full text of DOI:10.1002/anie.201806956

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Accepted Article
Title: Catalytic enantioselective synthesis of chiral azaheteroaryl
ethylamines via dearomatizing aza-Michael/rearomatizing
asymmetric protonation
Authors: Allan J. B. Watson, Chao Xu, Andrew Leach, Calum Muir, and
Alan Kennedy
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806956
Angew. Chem. 10.1002/ange.201806956
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http://dx.doi.org/10.1002/ange.201806956

10.1002/anie.201806956
Angewandte Chemie International Edition
COMMUNICATION
α
Catalytic enantioselective synthesis of -chiral azaheteroaryl
ethylamines by asymmetric protonation
Chao Xu,[a] Calum W. Muir,[b] Andrew G. Leach,[c] Alan R. Kennedy,[b] and Allan J. B. Watson[a]*
Abstract: The direct enantioselective synthesis of chiral
(a) Benzylic sterocentres and arylethylamines in bioactive substances
HO
Cl
azaheteroarylethylamines from vinyl aza-heterocycles and anilines is
NMe2
i-Pr2N
reported.
A chiral phosphoric acid (CPA) catalyst promotes
OH
HO
HO
HO
dearomatizing aza-Michael addition giving a prochiral exocyclic aryl
enamine, which undergoes asymmetric protonation upon
rearomatization. The reaction accommodates a broad range of
azaheterocycle, nucleophile, and substituent on the prochiral centre,
generating the products in high enantioselectivity. DFT studies
support a facile nucleophilic addition based on catalyst-induced
LUMO lowering, with site-selective, rate-limiting, intramolecular
asymmetric proton transfer from the ion-paired prochiral intermediate.
H2NOC
NH
NHMe
N
N
Cl
HO
epinepherine
disopyramide
(antiarrhythmic)
chlorpheniramine
(antihistamine)
fenoldopam
(hormone)
(antihypertensive)
(b) Design plan. An asymmetric protonation approach
FG
A*
R
N
HA* cat.
ArNH2
FG
FG
A*
R
H
N
N
H
H
N
Ar
R
H
vinyl heterocycle
LUMO lowered
(Hetero)arylethylamines are prolific in natural and synthetic
bioactive molecules and pharmaceuticals for numerous disease
indications.[1] Natural substances such as adrenaline,
amphetamine, histamine, and thyroxine are critically important to
human health and have been used as templates for the
development of treatments for a broad range of disease states.
Access to de novo chiral scaffolds has proven valuable for the
development of new ligands for discrete targets (e.g., Scheme
1a).
dearomatizing
aza-Michael
H
–H+/+H+
• Simple materials
• Priviliged scaffold
FG
FG
β
α
R
H
aromatizing
asymmetric
protonation
N
H
N
NHAr
Ar
N
• Catalytic, enantioselective
R
H
H
A*
Scheme 1. (a) Examples of (hetero)arylethylamines. (b) This work:
(Hetero)arylethylamines via conjugate addition/asymmetric protonation.
On heterocyclic scaffolds, numerous approaches have been
made to allow formation of the α- and β-stereocentre.[2,3]
However, methods to directly access the α-stereocentre on the
β-amino template are rare. Asymmetric hydrogenation is
perhaps the most effective but requires prior synthesis of an
enamine precursor,[4] while hydroamination is generally more
effective intramolecularly.[5]
Vinyl heterocycles are competent conjugate acceptors[2] and
aza-Michael addition to vinyl heterocycles has been shown to
proceed in refluxing AcOH.[7] We reasoned that a CPA catalyst
might allow LUMO-lowering protonation of a 1,1-disubstituted 2-
vinyl azaheterocycle to allow a more facile reaction (Scheme
1b).[8,9]
Subsequent
asymmetric
protonation
upon
rearomatization would set the α-stereocentre.[10-12] While
seemingly straightforward, the system must be pKa balanced.
Since both reactants and the product would contain Lewis basic
sites, mismatched pKa may inhibit catalyst turnover.
Enantiofacial control during the key asymmetric protonation
event would be catalyst-driven and contingent on high
diastereocontrol in the formation of the prochiral enamine
intermediate, enforced by H-bonding between the catalyst and
both reactants during the dearomatizing nucleophilic addition.
Here, we present a method for the asymmetric synthesis of
this important compound class based on a chiral phosphoric
acid (CPA)-catalyzed dearomatizing aza-Michael/rearomatizing
asymmetric protonation of 1,1-vinyl azaheterocycles (Scheme
1b). This provides direct modular access to chiral
azaheteroarylethyl amines from simple precursors via the
formation of a new C-N bond, and with concomitant formation of
the α-stereocentre in high enantioselectivity.[6] DFT studies are
presented to rationalize the observed reactivity as well as the
origin of the asymmetric induction.
Using an amine nucleophile, the dearomatizing conjugate
addition would likely be reversible. As such, we hypothesized
that the dearomatization would be facilitated by the retention of a
benzenoid ring. Accordingly, initial reaction development was
based on the 1,1-disubstituted 2-vinyl quinoline 1 and aniline 2
as our benchmark system. An initial round of screening of CPAs
identified the widely successful TRIP catalyst 3 as the most
promising (Table 1, see ESI for full details of catalyst
investigation).[10,11,13] Stronger CPAs were ineffective, which we
attribute to ineffective catalyst turnover due to the weaker
conjugate base. No conversion was recorded in the absence of
catalyst (entry 1); however, 73% conversion to 4a with 91:9 e.r.
was recorded using 20 mol% 3 at 0 °C (entry 2) with THF found
to be the most suitable solvent (entries 2-6). Optimization of
catalyst and nucleophile loading and temperature (entries 7-11)
delivered an effective system that provided 75% conversion to
4a with 97:3 e.r. using 20 mol% 3 at –20 °C (entry 9). Lower
[a]
Dr C. Xu, Dr A. J. B. Watson
EaStCHEM, School of Chemistry
University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: aw260@st-andrews.ac.uk
C. W. Muir, Dr A. R. Kennedy
Department of Pure and Applied Chemistry
University of Strathclyde
[b]
[c]
295 Cathedral Street, Glasgow, G1 1XL (UK)
Dr A. G. Leach
School of Pharmacy and Biomolecular Sciences
Liverpool John Moores University
Byrom Street, Liverpool L3 3AF (UK)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806956
Angewandte Chemie International Edition
COMMUNICATION
catalyst loadings were not favorable over same reaction time
period (entries 10 and 11).†
3 (20 mol%)
FG
FG
Ar
R
Ar
N
+
N
N
N
R
H
THF, –20 °C
R
R
4a-4am
vinyl heterocycle
aniline
β-aminoazaheterocycle
Table 1. Reaction development.[a]
(a) Aryl amine scope
NH2
NH2
NH2
Ar
Ar
Cl
Br
N
N
H
Ph
4a: 75%, 97:3
NH2
4b: 90%, 96:4
NH2
4c: 69%, 97:3
O
O
P
N
3 (x mol%)
NH2
OH
NH2
N
NHPh
O
Ph
1
solvent, X °C
Ph
Ph NH2
4a
Ar
F3C
Bpin
3
I
F
2
Ar = 2,4,6-(i-Pr)3C6H2
4d: 72%, 92:8
4e: 91%, 89:11
4f: 60%, 96:4
4g: 70%, 96:4
NH2
NH2
NH2
NH2
NH2
Entry
3 (mol%)
-----
20
Solvent
THF
Temp. (°C)
% conv. (e.r.)[b]
0 (---)
Me
MeO
F
CN
F
F
1
0
4h: 74%, 93:7
4i: 74%, 93:7
4j: 56%, 90:10
4k: 85%, 97:3
4l: 65%, 97:3
NH2
NH2
NH2
2
THF
0
73 (91:9)
75 (78:22)
4 (---)
Me
N
H
N
H
S
O
S
3
20
Et2O
0
4m: 68%, 93:7
4n: 27%, 87:13
4o: 47%, 91:9
4p: 87%,>99:1
4q: 74%, 91:9
4
20
CH2Cl2
PhMe
0
(b) Stereocentre variation
5
20
0
84 (60:40)
62 (78:22)
76 (94:6)
57 (96:4)
75 (97:3)
26 (95:5)
14 (92:8)
N
NHPh
F3C
MeO
6
20
Hexane
THF
0
R
4a: 71%, 96:4
4r: 71%, 96:4
4s: 58%, 93:7
7
20
–10
–20
–20
–20
–20
Me
OMe
MeO
O
O
8
20
THF
9[c]
10[c]
11[c]
20
THF
4t: 78%, 94:6
4u: 97%, 97:3
4v: 99%, 95:5
4w: 50%, 94:6
4x: 98%, 95:5
F3C
F
10
THF
F
N
O
Me
5
THF
Me
CF3
4y: 77%, 95:5
4z: 86%, 97:3
4aa: 99%, 96:4
4ab: 53%, 95:5
4ac: 69%, 95:5
[a] 1 (1 equiv), 2 (2 equiv), solvent (0.5 M). [b] Determined by HPLC analysis.
See ESI. [c] Using 3 equiv 2.
(c) Azaheterocycle variation
Me
FG
N
NHPh
N
NHPh
Ph
N
NHPh
Ph
Ph
4a: 71%, 96:4
4ad: 64%, 84:16
The generality of the method is shown in Scheme 2. A broad
range of aniline was tolerated, with small variations of efficiency
and selectivity as a function of the electronic parameters of the
anilines, in line with DFT observations of key π-stacking
interactions (vide infra). Alkyl amines were not successful due to
catalyst inhibition through salt formation (not shown, see ESI).
The substituent on the prochiral center could be varied to a
range of aryl units without major impact on the enantioselectivity
(Scheme 2b). Alkyl groups were not tolerated well, giving
moderate enantioselectivity (not shown; see ESI), which we
believe stems from the removal of key π-stacking interactions
between the components (vide infra).
Br
Me
F
N
NHPh
N
NHPh
N
NHPh
Ph
Ph
Ph
4ag: 31%, 51:49a
4ae: 96%, 96:4
4af: 66%, 90:10
R
NHPh
O
N
NHPh
S
N
NHPh
Ph
N
Ph
Ph
R = H, 4aj: 37%, 57:43a
R = CO2Me, 4ak: 67%, 77:23a
4ai: 56%, 69:31
4ah: 94%, 92:8
N
Pd/C, H2
EtOH, RT
N
NHPh
N
N
NHPh
4al
41%, 97:3
Ph
4am
Ph
56%, 95:5b
N
N
N
Ar
O
N
N
NHPh
H
N
N
H
H
Ar
N
Ph
OH
arginine
mimetic
αv-integrin chemotype
pulmonary fibrosis
5
>99%
Scheme 2. Substrate scope. Isolated yields. Enantiomeric ratio determined by
HPLC analysis. See ESI. aReaction temp. = 40 °C. bUsing 100 mol% 3 at –40
°C.
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10.1002/anie.201806956
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COMMUNICATION
Lastly, the azaheterocycle could be varied to a number of
derivatives, adhering to the regiochemical requirements of the
vinyl unit (Scheme 2c). Less reactive heterocyclic templates
required increased temperature for reactivity (4aj, 4ak), which
compromised enantioinduction. Introducing a substituent to the
3-positon of the quinoline (4ag) template led to major negative
effects on conversion and selectivity, due to allylic strain
consistent with the mechanistic rationale (vide infra), while some
stark selectivity variance was observed between similar
pre-RLS equilibrium. The C-N bond in this intermediate is weak
(C-N = 1.57 Å) and the species relies on stabilization via a
strong hydrogen bond between the anilinium ion and the
phosphate oxygen (N-H…O=P, N-H = 1.12 Å and H-O = 1.42 Å).
The anilinium also benefits from a π-cation interaction with the
catalyst. The retention of the quinolinium-phosphate H-bond, the
anilinium-phosphate H-bond, and the CH-O H-bond imposes
tight geometric limits on the bound substrate. Alternative modes
of aniline addition are significantly disfavored (not shown, see
heterocyclic templates based on electronic differences (e.g., 4ah, ESI for details).
4ai).
Ion pair
8
undergoes the rate-limiting rearomatizing
An example of potential utility in medicinal chemistry is
shown from 4am. Hydrogenation of naphthyridine 4am delivers
piperidinopyridine scaffold 5, an arginine mimetic[14] and,
specifically, a key pharmacophore within RGD αv-integrin drug
discovery.[15]
asymmetric protonation. Using the R-catalyst (shown), this gives
preferential protonation of the Re-face of the enamine to deliver
the S-product, proceeding via 4- membered transition state TS2,
transferring the proton from the anilinic ammonium rather than
heterocyclic NH to deliver the quinolinium product ion pair 9.
This event is favored by ca. 0.7 kcal mol-1 over the alternative
protonation of the Si-face. Interestingly, H-bonding of the chiral
anion to the heterocyclic NH and an anilinium NH controls this
protonation event, but the anion is not involved as a proton
shuttle. The three anchoring polar interactions are retained in
the transition state. A key observation from these calculations
was the product ion pair complex 9 is higher in free energy than
substrate activation complex 7, which suggests no product
inhibition of the catalysis. An intramolecular H-bonding
interaction between the newly installed aniline NH and the
heterocyclic nitrogen, as observed in solid state (e.g., 4g,
Scheme 2a), may explain tempered Lewis basicity in the product,
facilitating catalyst turnover.
The mechanism of the process was rationalized by DFT
calculations (Scheme 3).[16] Protonation of the substrate 1 by
catalyst 6 leads to LUMO-lowered pyridinium ion pair 7, which
also benefits from a CH-O hydrogen bond between the C8-H
and another of the phosphate oxygens (H-O = 2.33 Å). H-
bonding interactions between the catalyst, heterocycle, and
incoming nucleophile (2) orients 2 to pick up additional π-
stacking interactions with the aryl substituent on the prochiral
centre (phenyl, in the model shown), enforcing high levels of
diastereocontrol in the formation of the prochiral enamine in the
subsequent conjugate addition. Based on this preorganization,
the addition is a surprisingly low energy process proceeding via
TS1 to deliver the key prochiral E-enamine intermediate ion pair
8. This intermediate cannot be observed (NMR) based on the
TS1: Conjugate addition
TS2: Asymmetric protonation
Me
Me
Me
Me
Me
Me
Me
H
Me
H
.....
H
O
O
N
.....
O
O
H
N
P
O
Me
Me
P
O
..O......
+30.9
O
Me
Me
H
N
H
H
H
Me
N
Me
........
Me
Me
Ar
O
+9.1
+8.6
O
O
P
Ar
N
H
NHPh
O
Ph
O
O
9
O
Ar
N
P
–2.6
OH
1
Ph
Ph NH2
Ar
2
Energy values in kcal mol–1
6
–16.4
N
NHPh
–6.0
Ar = 2,6-(i-Pr)2C6H3
4a Ph
Substrate activation
Key prochiral intermediate
Ar
Ar
O
O
O
O
Ph
P
P
N
H
N
H
O
O
O
O
Ph
Ph
N
H
H
8
Ar
Ar
7
Scheme 3. DFT calculated energy profile for preferred pathway. Free energies in kcal/mol (computed at 298 K with corrections to 1
M) were computed at the M06-2X/6-31+G*(+IEFPCM)//M06-2X/3-21G level of theory.[17-21]
This article is protected by copyright. All rights reserved.

10.1002/anie.201806956
Angewandte Chemie International Edition
COMMUNICATION
Preliminary kinetic studies support a 1st order dependency
with respect to all three components (vinyl heterocycle, aniline
nucleophile, and catalyst), consistent with the DFT analysis (see
[4]
[5]
[6]
For a review of asymmetric hydrogenation of enamines, see: J.-H. Xie,
S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713–1760.
T. E. Müller, K. C. Hultzsch, M. Yus, H. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795–3892.
ESI). Finally, 31P NMR and HRMS analysis supported
a
During the preparation of this manuscript, two reports of catalytic
preferential substrate/catalyst pairing (i.e., 1•3) rather than
product/catalyst (i.e., 4a•3), consistent with the turnover
hypothesis (see ESI).
enantioselective preparation of α-stereocentres using
CPA/photoredox catalysis approach were reported. See: (a) R. S. J.
Proctor, H. J. Davis, R. J. Phipps, Science
a combined
DOI:10.1126/science.aar6376; (b) Y. Yin, Y. Dai, H. Jia, J. Li, L. Bu, B.
Qiao, X. Zhao, Z. Jiang, J. Am. Chem. Soc. 2018, 140, 6083–6087.
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77, 5434–5436; (b) H. E. Reich, R. Levine, R. J. Am. Chem. Soc. 1955,
77, 4913–4915.
In summary, we have developed
a
CPA-catalyzed
enantioselective synthesis of α-chiral azaheteroaryl ethylamines
via dearomatizing aza-Michael/rearomatizing asymmetric
protonation. DFT and kinetic studies have given insight into the
mechanism of the reaction, which will guide future applications
of this approach towards the design and synthesis of
functionalized heterocyclic scaffolds.
[7]
[8]
[9]
For a recent CPA-catalyzed conjugate addition of a nucleophilic carbon
radical to vinyl azaheterocycles, see ref 6b.
For previous organocatalyzed conjugate addition to vinyl heterocycles,
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Acknowledgements
We thank the Leverhulme Trust for funding (C.X.; RPG-2015-
308) and GSK for a PhD studentship (C.W.M.). We thank the
EPSRC UK National Mass Spectrometry Facility at Swansea
University for analyses.
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Keywords: asymmetric catalysis • Brønsted acid • DFT •
[12] For
a
recent demonstration of CPA-catalyzed enantioselective
heterocycles • stereochemistry
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†
For preliminary assessment of non-linearity and H2O effects, see ESI.
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10.1002/anie.201806956
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Chao Xu, Calum W. Muir, Andrew G.
Leach, Alan R. Kennedy, and Allan J. B.
Watson*
Page No. – Page No.
Catalytic enantioselective synthesis
of α-chiral azaheteroaryl ethylamines
by asymmetric protonation
(S)-TRIP tease. The direct enantioselective synthesis of chiral
azaheteroarylethylamines from vinyl aza-heterocycles and anilines is reported. A
chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza-Michael addition
to generate a prochiral exocyclic aryl enamine, which undergoes asymmetric
protonation upon rearomatization giving the products in high selectivity. DFT
studies have provided insight into the mechanism.
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