Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study

Article abstract of DOI:10.1002/chem.202002543

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Br?nsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C?F stereocentre in high enantioselectivity, and is also amenable to stereogenic C?CF₃ bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.

Full text of DOI:10.1002/chem.202002543

Accepted Article
Accepted Article
Title: Catalytic enantioselective synthesis of heterocyclic vicinal
fluoroamines using asymmetric protonation: A method
development and mechanistic study
Authors: Allan J. B. Watson, Matthew W. Ashford, Chao Xu, John J.
Molloy, Cameron Carpenter-Warren, Alexandra M. Z Slawin,
and Andrew G. Leach
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002543
Link to VoR: https://doi.org/10.1002/chem.202002543
01/2020

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
Catalytic enantioselective synthesis of heterocyclic vicinal
fluoroamines using asymmetric protonation: A method
development and mechanistic study
Matthew W. Ashford,[a] Chao Xu,[a] John J. Molloy,[a] Cameron Carpenter-Warren,[a] Alexandra M. Z
Slawin,[a] Andrew G. Leach,[b]* and Allan J. B. Watson[a]*
[a]
M. W. Ashford, Dr C. Xu, Dr J. J. Molloy, C. Carpenter-Warren, Prof Dr A. M. Z. Slawin, 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
[b]
Dr A. G. Leach
School of Health Sciences
University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
Supporting information for this article is given via a link at the end of the document.
Abstract: A catalytic enantioselective synthesis of heterocyclic vicinal
fluoroamines is reported. A chiral Brønsted acid promotes aza-
Michael addition to fluoroalkenyl heterocycles to give a prochiral
enamine intermediate, which undergoes asymmetric protonation
upon rearomatization. The reaction accommodates a range of
azaheterocycles and nucleophiles, generating the C–F stereocenter
in high enantioselectivity, and is also amenable to stereogenic C–CF3
processes, substitution of a specific C–H for C–F in a methylene
represents a very efficient means of benefiting from this effect,
thus the introduction of fluorine in a stereoselective fashion holds
significant appeal.
(a) Deoxyfluorination
N
F
N
OH
F– reagent
F
Ar
Ar
Et2N SF3
bonds. Extensive DFT calculations provide evidence for
a
F
N
SO2F
R1
R2
R1
R2
stereocontrolled proton transfer from the catalyst to substrate as the
rate determining step, and show the importance of steric interactions
from the catalyst alkyl groups in enforcing high enantioselectivity.
Crystal structure data shows the dominance of non-covalent
interactions in the core structure conformation, enabling modulation
of the conformational landscape. Ramachandran-type analysis of
conformer distribution and protein data bank mining has indicated
benzylic fluorination using this approach has potential for improved
potency in several marketed drugs.
Ar = 2,6-(i-Pr2)C6H3
DAST
PhenoFluorTM
PyFluor
(b) Challenges with benzylic fluorination
F
OH
Me
F
DAST
Me
DAST
Me
+ TMS-morpholine
53.5:46.5 (S)
enantiopure (R)
97.5:2.5 e.r. (S)
(c) This work. Heterocyclic vicinal fluoroamines via asymmetric protonation
● Catalytic, enantioselective
● No F–, avoids SN1 issue
● Privileged scaffold
CPA cat.
Ar
Ar
ArNH2
N
N
NHAr
F
F
● Conformational control
vinyl fluoride
aniline
vicinal fluoroamine
Introduction
Scheme 1. (a) Deoxyfluorination and exemplar reagents. (b) Enantioerosion
during deoxyfluorination of benzylic alcohols. (c) This work. Chiral heterocyclic
vicinal fluoroamines by asymmetric protonation.
Incorporation of fluorine into organic compounds is prominent in
the pharmaceutical, agrochemical, and materials industries.[1] The
unique characteristics of the C–F bond enables modulation of
physicochemical properties while mitigating steric contributions.[2]
A key attribute is the intrinsic polarity of the C–F bond, which can
induce conformational changes through electrostatic and dipole
interactions with neighboring functional groups. Installation of a
chiral C–F bond with a vicinal relationship to a heteroatom or
electron-withdrawing group is particularly valuable as exploitation
of the gauche effect allows predictable conformational control.[3]
For example, fluorinated phenethylamines are especially valuable
based on the demonstrable utility of this compound class within
bioactive molecules[4] and the topological control afforded by the
gauche effect can enable bespoke biological target
engagement.[5] Similarly, fluorine is often considered as a minimal
change to block metabolism, for example of labile benzyl
positions.[2,6] Given the stereoselective nature of most metabolic
Deoxyfluorination of alcohols is the most common method
to install C(sp3)–F bonds, and numerous reagents have been
developed to facilitate this transformation (e.g., Scheme 1a).[7,8]
A
noted problem with introduction of
a benzyl fluoride via
deoxyfluorination is the propensity for stereochemical erosion due
to variable contribution of SN1 pathways (e.g., Scheme 1b).[8a,9]
This can be ameliorated in some cases by alteration of the
deoxyfluorination reagent in situ using specific additives; however,
this general problem arises specifically due to the nucleophilic
fluorinating reagents commonly used. An alternative strategy for
C(sp3)–F bond formation that avoids SN2 is via asymmetric
protonation of prochiral C(sp2)–F centres; however, there are
limited examples of this and none for benzylic C(sp3)–F.[10]
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
Here, we present a method for the enantioselective
synthesis of benzylic C(sp3)–F vicinal fluoroamines via
asymmetric protonation of in situ generated prochiral
fluoroenamines (Scheme 1c).[10-12] This method allows formation
of a new C–N bond and benzylic stereogenic C–F bond in a single
catalytic reaction, providing direct modular access to chiral
heterocyclic vicinal fluoroamines from readily accessible vinyl
fluoride precursors.[13] As the process does not rely upon the use
of a fluorinating reagent, this avoids the issue of stereochemical
erosion. The mechanism is fully investigated, with refinement of
previous proposals and we also show how the relationship of the
azaheterocycle, amine, and C–F bond provides unique
conformational control, which may offer benefits in drug design by
better alignment with bound ligand conformation.
to −20 °C had little effect on enantioselectivity but impacted
reaction efficiency (entry 5). A similar effect was observed by
lowering catalyst loading, where 10 mol% was less efficient but
maintained selectivity (entry 6). Control experiments supported a
catalyst-promoted reaction that lacked background reactivity
(entry 7).
The scope of the reaction was investigated (Scheme 3). A
range of aryl amine nucleophiles was accommodated with
variation in functional group (e.g., halides, alkyl groups, BPin,
heterocycles) and regiochemical substitution (ortho, meta, para)
was typically accommodated while maintaining selectivity
(Scheme 3a). Additionally, substitution on the aniline nitrogen was
tolerated (7m). It should be noted that the choice of solvent was
Table 1. Reaction development.
Results and Discussion
Ar
9a (20 mol%)
THF, –10 ºC
O
O
Method Development. We have previously shown that Brønsted
acid catalysis enables conjugate addition and highly selective
asymmetric protonation of prochiral enamines (Scheme 2a).[14]
However, this was only amenable with the steric control of
enamine geometry afforded by aryl substituents at the a-carbon:
alkyl substituents led to poor geometry control of the intermediate
enamine 3, resulting in lower enantioinduction in product 4. While
fluorine has a small steric footprint, we postulated that dipole
minimization might provide an alternative selectivity determinant
(Scheme 2b). Indeed, preliminary DFT studies highlighted the
preferred s-trans geometry for benchmark starting material 5a,
which was anticipated to assist geometrical control of the
developing fluoroenamine 6 and enhancing enantioinduction in 7.
O
P
N
OH
N
NHPh
F
5a
F
Ph NH2
7a
‘standard conditions’
Ar
9a
8
Ar = 2,4,6-(i-Pr)3C6H2
Entry
Deviation from ‘standard conditions’
Yield [%] (e.r. (R:S)) [a]
82 (96:4)[b]
89 (95:5)[b]
95 (89:11)
70 (75:25)
40 (96:4)
1
2
3
4
5
6
7
None
CPME
PhMe
CH2Cl2
(a) Previous work: Steric control of geometry (simplified mechanism)
–20 ºC
NHPh
Ar
N
Ar
N
Ar
–H
+H
Ar
R
A*
PhNH2
R
CPA
10 mol% 9a, –20 ºC
0 mol% 9a, –20 ºC
37 (95:5)
R
N
N
H
H
R
NH2Ph
0 (---)
3
1
2
4
A*
R = aryl: High diastereocontrol, ∼95:5 e.r.
R = alkyl: Low diastereocontrol, ∼80:20 e.r.
[a] Determined by HPLC using an internal standard. [b] Isolated yield.
(b) Formation of stereogenic C–F bonds: Dipole enforced control of geometry
important for conversion, due to solubility: product precipitation as
the reaction progressed became problematic for certain
substrates; however, changing ethereal solvent based on
substrate (THF or CPME) resolved this issue.
NHR
CPA, PhNH2
F
F
N
A*
N
N
H
F
5a
6
7
NH2Ph
∆∆G = 2.79 kcal mol–1
(s-trans)
Electronic stereocontrol
Predicted high e.r.
Control of enamine geometry
A range of vinylheterocycles was also generally well
accommodated (Scheme 3b). Variation in substitution of the
benchmark 2-vinylquinoline was straightforward (7a, 7n-q) and
the reaction tolerated quinoxaline (7r), benzothiazole (7s), and
pyridine (7t), with the latter a significantly more challenging
substrate due to its higher dearomatization barrier, hence
requiring a high temperature for the reaction to proceed, which
negatively affects enantioinduction.Significantly, the reaction also
allows enantioselective formation of stereogenic C–CF3 bonds
(11); however, catalyst loading had to be increased and reaction
temperature decreased to overcome a significant non-selective
background reaction observed for this substrate (see ESI).
Scheme 2. (a) Our previous work and simplified mechanism indicating
asymmetric induction is a function of enamine geometry control. (b) Preliminary
DFT conformational analysis suggesting high enamine diastereoselectivity.
Based on this hypothesis, a benchmark process was
established where 5a was subjected to aniline (8), and Brønsted
acid catalyst 9a (Table 1; a range of catalysts were evaluated,
vide infra and see ESI). Optimization of reaction parameters
delivered a system that afforded the desired product 7a in high
conversion and enantioselectivity (82% and 96:4 e.r.; entry 1).
Several observations relating to optimization were noted (see
Supporting Information (SI) for full details and additional
experiments). Ethereal solvents (THF, CPME) were particularly
effective (entries 1 and 2), with other solvents affording good to
excellent conversion but with notably poorer enantioselectivity
(entries 3 and 4). Lowering the reaction temperature from −10 °C
Mechanistic Analysis. Two main mechanistic pathways are
possible for the key asymmetric protonation event (Scheme 4).
The initial events common to both pathways involve reversible
protonation of the substrate (5a) by the catalyst to provide LUMO-
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
lowered intermediate complex 12 and enabling reversible aza-
Michael using PhNH2 (8) to deliver key intermediate 13. Two
mechanistic pathways are then possible from this intermediate:
pathway 1 proceeds via direct stereocontrolled proton transfer
from the anilinium via TS1 and delivers the product-catalyst
complex 15, which subsequently liberates the product (7a).
Alternatively, in pathway 2 proton transfer from the anilinium of 13
to the phosphate (via TS2) delivers 14, which undergoes
stereocontrolled proton transfer via TS3 to deliver 15. In our
previous report,[14] computational analysis supported pathway 1,
0.8 and H/D KIE of ca. 1.8, which may be affected by the pre-RDS
equilibrium associated with this reaction.
Goodman and others have shown that catalysis by BINOL-
derived catalysts, such as 9a, can be studied effectively and
efficiently by QM/MM ONIOM calculations where the quantum
mechanical aspects are described by B3LYP/6-31G** and the
molecular mechanics by UFF.[15] Accordingly, a more exhaustive
theoretical exploration was undertaken using this approach
(Figure 1 and ESI).
8
F
9a (20 mol%)
FG
FG
N
Ar
R
Ar
+
N
N
N
N
R
H
H
H
THF, –10 ºC, 3 d
12
F
7a-t
F
O
O
F
N
P
fluorovinyl heterocycle
heterocyclic
vicinal fluoroamine
5a
aniline
O
O
H
H
N
Ph
(a) Aryl amine scope (Het = 2-quinolyl)
NH2
O
H
O
P
13
O
O
O
O
NH2
NH2
Pathway 1
P
F
OH
O
N
9
H
MeS
H
N
Ph
7a
7b: 93%, 97:3a
O
7a: 82%, 96:4
7c: 74%, 91:9a
H
O
P
O
O
TS2
F
N
NH2
H
NH2
NH2
NH2
NH2
F
*
H
N
NHPh
N
Pathway 2
Ph
F
H
O
P
O
H
O
F3C
PinB
Br
O
RDS
15
P
Br
O
TS1
O
O
7d: 88%, 94:6a
7e: 93%, 97:3a
NH2
7f: 79%, 93:7b
7g: 71%, 90:10b 7h: 46%, 89:11a
O
NH2
RDS
NH2
NH2
F
N
Me
MeO
N
S
O
F
H
N
Ph
F
F
H
N
7i: 94%, 98:2a
7k: 58%, 94:6b
7l: 37%, 89:11b
7m: 88%, 92:8a
Ph
H
7j: 72%, 93:7
H
N
H
O
14
H
O
OH
O
P
O
O
(b) Heterocycle variation (aniline = PhNH2)
Me
P
TS3
O
O
F
Br
N
N
N
N
7p: 95%, 93:7c
MeO2C
F
F
F
F
Scheme 4. Proposed mechanistic pathways. Pathway 1 via direct proton
transfer from anilinium to prochiral center. Pathway 2 via proton transfer to/from
phosphate. RDS = rate determining step; TS = transition state.
7a: 82%, 96:4
7n: 50%, 91:9c
7o: 67%, 94:6c
Br
N
S
N
N
N
Experimentally, no background reaction was observed, which
was consistent with DFT calculations that indicated a prohibitively
high barrier for direct reaction of 5a with 8 (see ESI).
F
N
F
F
F
7r: 87%, 92:8c
7s: 75%, 96:4c
7t: 25%, 87:13d
7q: 85%, 98:2
Ph
Complexation of 5a with 9a to give 12 is moderately favorable,
with the preferred dipole-induced s-trans conformation of 5a also
retained in 12. This initial complex is held together by a H-bond
(OH…N = 1.63 Å) and a weak peri CH…O=P interaction (2.40 Å).
Complex 12 then undergoes dearomatizing aza-Michael addition
to deliver 13, where the loss of aromaticity is compensated for by
the formation of a tightly bound ionic interaction between the
anilinium NH and phosphate (P=O…HNHPH = 1.38 Å and
P=O…HNquin = 1.71 Å). Rearrangement within this complex by
proton transfer from the anilinium to the phosphate involves a low
barrier and yields a complex of the enamine (14) that is higher in
energy than reactants. All of these steps are therefore strongly
reversible and no significant concentration of any of the
intermediates subsequent to quinoline complexation would be
expected – this was confirmed by parallel NMR experiments (see
ESI).
N
N
N
H
CF3
CF3
11: 73% 90:10e
10
Scheme 3. Substrate Scope. Isolated yields. Enantiomeric ratios determined by
HPLC analysis on a chiral stationary phase. See ESI for details. [a] CPME,
−20 °C, 5 d. [b] −20 °C, 5 d. [c] CPME, −10 °C. [d] CPME, rt. [e] 1 equiv. of 9a,
CPME, −50 °C.
with selectivity arising from good shape and electrostatic
complementarity between the catalyst and TS1 leading to the
observed enantiomer. These purely quantum mechanical studies
did not yield transition states that would have supported pathway
2 (or other alternative mechanisms). A series of kinetic isotope
effect experiments were conducted via the use of 15N-aniline and
PhND2. However, these proved inconclusive, with independent
rate experiments (see ESI) resulting in observed 14/15N KIE of ca.
Transition states leading to each low energy conformation
of complex 15-(R) and 15-(S) were optimized leading to an array
of conformations for each of TS1 and TS3. Consistent with our
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
previous report,[14] pathway 1, via direct proton transfer to the
prochiral center was identified (TS1). This process has a
significant barrier (+35 kcal mol−1) but is predicted to be highly
stereoselective (∆∆G‡ = 4.4 kcal mol−1, >99:1 e.r.) in favor of the
experimentally observed enantiomer. Although this rationalizes
the stereoselectivity of the process, it is not consistent with the
experimental rate of reaction.
TS1-(R)
TS3-(R)
Pathway 1
+37.0
F
F
N
N
H
H
N
[+36.8]
Ph
H
TS1-(S)
TS1-(R)
N
H
H
O
+32.7
[+33.7]
Ph
O
O
H
O
P
P
O
O
O
O
+18.6
[+16.6]
TS3-(S)
TS3-(R)
+15.4
[+15.7]
Pathway 2
+10.9
[+7.6]
+9.2
[+9.9]
+6.9
[+5.6]
TS2
14
13
–0.8
[+0.3]
–0.9
[–6.5]
–7.2
[–10.7]
0.0
5a + 9a
7a + 9a
12
15-(R)
–8.4
[–13.1]
15-(S)
12
13
TS2
14
15
F
F
F
F
N
N
N
H
N
*
N
H
NHPh
H
N
H
Ph
H
H
H
H
N
N
H
F
O
P
Ph
Ph
O
O
O
H
O
O
O
O
O
OH
O
H
O
P
P
P
P
O
O
O
O
O
O
O
O
Figure 1. Free energy profile comparison (ONIOM (B3LYP/6-31G**:UFF), [single-point energy M06-2X/6-31G**(+PCM for Et2O)]). Two pathways are compared:
Pathway 1 – via direct proton transfer and pathway 2 – via proton transfer to and from the phosphate. Free energies in kcal mol−1 are reported relative to separated
substrate and catalyst bound to THF. All calculations were performed in Gaussian09 and free energies at −20 ºC and 1 M concentration were obtained using
goodvibes.[16]
However, pathway
2
was more consistent with the
Control substrates 7u-7w provided additional support of the
experimentally observed rate. The key step, in which the
stereochemistry is generated, involves protonation of the
enamine by the POH in complex 14 via TS3 and exhibits a clear
preference for the experimentally-observed enantiomer (∆∆G‡ =
+3.5 kcal mol−1), which arises from geometrical restrictions
between the catalyst and enamine in the developing transition
states TS3-(R) and TS3-(S) (vide infra). The i-Pr substituents of
catalyst 9a are also particularly important for imposing this
geometrical restriction (vide infra: Table 2 and Figure 3). This
mechanistic overview reveals that the catalyst provides its effect
by acting as both acid and base at each stage as required and
does so in a way that imposes specific shape requirements on the
substrate that interplay with the polar interactions that hold the
complex together.
DFT conclusions (Figure 2).
F
N
N
Cl
F
F
N
7u: 61%, 59:41[a]
7v: 68%, 50:50[b]
7w: 63%, 51:49[c]
Figure 2. Control substrates. Reaction conditions as per Scheme 3 unless
noted. [a] CPME. [b] CPME, rt. [c] CPME, 40 °C.
Despite moderate yields of product for each,
enantioinduction was poor, which arises from features that are not
well-tolerated in the lowest energy transition state. Substrate 7u
places the fused phenyl ring in a position that clashes with the i-
Pr groups of 9a in TS3. By contrast, 7v prevents the required
simultaneous interactions of 5a and 8 with 9a and also lacks the
dipole-induced geometry control. Lastly, the essential enamine
NH−OP H-bond in TS3 is impaired by the adjacent chlorine in
Based on these results, a complete reinvestigation of the
computational analysis of our previous process using aryl
substituents (Scheme 2a)[14] using the approach delineated above
suggests that Pathway 2 is a more likely reaction mechanism in
this process. The full profile for this reaction is provided in the ESI.
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
substrate 7w, weakening the association between the substrate
and catalyst.
investigated computationally, confirming the accelerating role of
the LUMO-lowering CF3 unit as previously observed for other
Michael acceptors.[17]
Table 2. Catalyst structure vs. enantioselectivity.
Implications for Conformational Control. The value of the
substructures accessible using the developed protocol was
explored by investigating their conformational properties. The
crystal structure of 7a shows an anti relationship between C–F
and the aniline nitrogen (dihedral angle = 179º), which is likely
preferred in comparison to the gauche due to a favorable
Npz···σ*C–F interaction (Figure 4). The C–F bond is almost
perpendicular to the carbon framework of the quinoline (dihedral
angle = 107º), which we believe arises due to a favorable σ*C–
F···pAr interaction competing with C–F/Nquin dipole minimization.[18]
Hydrogen bonding of the quinoline nitrogen with a hydrogen bond
donor would reduce this dipole and is a key feature of this system:
the crystal structure has an intermolecular hydrogen bond
between the quinoline nitrogen and the HNPh in an adjacent
molecule.
R
O
Cat. (20 mol%)
O
N
P
N
NHPh
F
OH
5a
THF, –20 ºC
O
R
F
Ph NH2
7a
9a-c
8
Entry
Catalyst
9a
R
Yield [%] (e.r. (R:S))[a]
40 (96:4)
1
2
3
2,4,6-(i-Pr)3C6H2
2,4,6-(Me)3C6H2
Ph
9b
9c
25 (88:12)
11 (58:42)
[a] Determined by HPLC using an internal standard.
With regards to the optimal catalyst, a catalyst survey
demonstrated the superior level of asymmetric induction using 9a
(Table 2; see ESI for full details). To determine the origin of this
enhanced selectivity, we analyzed 9a in comparison to the related
3,3’-mesityl (9b) and -phenyl (9c) analogues (Figure 3). As the
stereodirecting group on the catalyst is reduced in size from 9a to
9b and 9c, there is a general tendency for the barrier for the
catalyzed reaction to increase (from 16.2 to 16.6 and 18.5 kcal
mol−1, respectively), resulting in the observed diminished
conversion. This is accompanied by a sharp erosion in ∆∆G‡
between TS3-(R) and TS3-(S) – the energy associated with TS3-
(R) remains similar for all three and this erosion is principally
driven by a change in energy of TS3-(S). This is highlighted in the
preferred conformation of each of the three structures equivalent
to TS3-(S) (Figure 3). The red arrows (Figure 3a) indicate where
the bulk of the i-Pr groups of 9a press against both ends of the
bound substrate. This causes the break-up of an intramolecular
H-bond between the aniline nitrogen and the NH of the nitrogen
arising from the quinoline (2.48 Å for 9a, but 2.02 Å and 2.03 Å
for 9b and 9c, respectively); this interchanges with an interaction
between the aniline NH and a phosphate oxygen (2.01 Å for 9a,
but 2.69 Å and 2.67 Å for 9b and 9c, respectively). The
combination of the steric clashing and this change in hydrogen
bonding pattern clearly disfavors TS3-(S) compared to TS3-(R)
for 9a; this difference is significantly reduced for 9b and 9c.
(a) Conformational analysis amd crystal structure of 7a and 16
!
!
1
1
AcCl, Et3N
CH2Cl2, rt
N
NHPh
N
NAcPh
2
!
!
2
7a
16
F
F
!
!
1 = 180º
2 = 60º
!
1 = 110º
!
2 = 180º
(b) Ramachandran plot for 7a
(c) Potential pharmacokinetic enhancement from conformational control
OEt
O
(a) Catalyst 9a TS3-(S)
(b) Catalyst 9b TS3-(S)
(c) Catalyst 9c TS3-(S)
F
R
S
N
N
H
O
O
N
N
F
N
N
N
N
H
H
H
CN
NH
Ph
R = Cl, Me, CN
CONMe2
cathepsin L inhibitors
HIV reverse
transcriptase inhibitors
purine nucleoside
phosphorylase inhibitor
Figure 4. (a) Conformational analysis and crystal structures of 7a and 16. (b)
Ramachandran plot for 7a. (c) Drug-like molecules in PDB that may benefit from
conformational control induced by benzylic fluorination.
∆∆G‡ = +3.2 kcal mol–1
∆∆G‡ = +0.2 kcal mol–1
∆∆G‡ = –0.1 kcal mol–1
Figure 3. Structures equivalent to TS3-(S) for catalysts 9a, 9b, and 9c.
To reduce the impact of hydrogen bonding and any Npz
interactions, 7a was acetylated to give 16 (Figure 4a). The
preference towards the anti configuration is diminished, with the
gauche conformation noted in the crystal structure (FCCNAniline
dihedral angle = 58º). The dihedral angle between the C–F bond
and quinoline nitrogen is 174°, explicitly affected by the C–F/NAr
In line with experimental observations, the computational
model also confirms a lower rate of catalyzed reaction for 5t,
associated with the larger dearomatization barrier (see ESI). The
observed significant background reaction for 10 was also
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
dipole minimization and no longer modulated by the other effects
described.
Keywords: asymmetric • Brønsted acid • catalysis • fluorine •
heterocycles
Ramachandran plots for dihedral angles 1 and 2 of 7a, 16, and
the parent 2-pyridylethylamine (not shown) were computed and
reveal that the introduction of the benzylic fluoride has a profound
effect on the overall conformational landscape (Figure 4 and ESI).
7a and 16 display specific low energy conformations biased by
the presence of the fluorine and that are likely to be populated in
solution. This presents opportunities for application in drug
discovery by improving binding affinity and selectivity by
decreasing the population of alternative, less favorable
conformations. The protein databank was searched for ligands
that contain the 2-pyridylethylamine substructure and the
conformations that are populated in these crystal structures are
mapped onto the Ramachandran plot for 7a (Figure 4b, black
dots). Five compounds in particular adopt a conformation that
would be enhanced by the introduction of fluorine at the benzylic
position (Figure 4b, circled), including inhibitors of HIV reverse
transcriptase,[19] cathepsin L,[20] and purine nucleoside
phosphorylases (Figure 4c).[21] This highlights the value of this
structural change for enhancing potency and selectivity of
potential drug molecules.
[1]
a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886; b) P.
Jeschke, ChemBioChem 2004, 5, 571–589; c) M. H. Hung, W. B.
Farnham, A. E. Feiring, S. Rozen in Fluoropolymers: Synthesis, Vol. 1
(Eds.: G. Hougham, P. E. Cassidy, K. Johns, T. Davidson), Springer,
New York City, 1999, pp 51–66.
[2]
[3]
S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320–330.
a) C. R. S. Briggs, D. O’Hagan, J. A. K. Howard, D. S. Yufit, J. Fluorine
Chem. 2003, 119, 9–13; b) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308–
319; c) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. Ed. 2011,
50, 11860–11871; Angew. Chem. 2011, 123, 12062–12074; d) C.
Thiehoff, Y. P. Rey, R. Gilmour, Isr. J. Chem. 2017, 57, 92–100; e) M.
Aufiero, R. Gilmour, Acc. Chem. Res. 2018, 51, 1701–1710.
For general information, see: a) National Center for Biotechnology
[4]
Information. PubChem Compound Database; CID
=
1001,
https://pubchem.ncbi.nlm.nih.gov/compound/1001 (accessed February
20, 2018); b) The Merck Index — An Encyclopedia of Chemicals, Drugs,
and Biologicals, 13th ed. (Ed.: M. J. O’Neil), Merck and Co., New Jersey,
2001.
[5]
[6]
D. Traschel, Drug Test Anal. 2012, 4, 577–590.
E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J.
Med. Chem. 2015, 58, 8315−8359.
[7]
[8]
For selected reviews, see: a) F. D. Toste, X. Yang, T. Wu, R. J. Phipps,
Chem. Rev. 2015, 115, 826–870; b) D. Cahard, X. Xu, S. Couve-
Bonnaire, X. Pannecoucke, Chem. Soc. Rev. 2010, 39, 558–568.
For examples, see: a) S. Bresciani, D. O’Hagan, Tetrahedron Lett. 2010,
51, 5795–5797; b) F. Sladojevich, S. I. Arlow, P. Tang, T. Ritter, J. Am.
Chem. Soc. 2013, 135, 2470–2473; c) M. K. Nielsen, C. R. Ugaz, W. Li,
A. G. Doyle, J. Am. Chem. Soc. 2015, 137, 9571–9574; d) N. W.
Goldberg, X. Shen, J. Li, T. Ritter, Org. Lett. 2016, 18, 6102–6104; e)
W.-L. Hua, X.-G. Hu, L. Hunter, Synthesis 2017, 49, 4917–4930.
M. M. Bio, M. Waters, G. Javadi, Z. J. Song, F. Zhang, D. Thomas,
Synthesis 2008, 891–896.
Conclusion
In summary, a Brønsted acid-catalyzed aza-Michael/asymmetric
protonation method for the synthesis of heterocyclic vicinal
fluoroamines has been developed. The method allows access to
stereogenic C–F bonds in high selectivity and on a selection of
different heterocyclic templates. The method also translates to
establishing stereogenic CF3 analogues. The origin of reactivity
and stereoinduction has been investigated by extended DFT
calculations that have established a phosphate proton transfer as
being more consistent with experimental observations over a
direct proton transfer process. This has led to a revision of our
interpretation of the mechanism associated with our previous
report. Conformational control of the vicinal phenethylamine
system has been interrogated by DFT and crystallography,
identifying the likely preferred topologies in the solid and solution
state. This may have strategic applications in drug discovery by
introducing conformational bias to access conformations more
like the bound state, illustrated with examples extracted from the
PDB.[22]
[9]
[10] Examples on construction of chiral C(sp3)–F bonds via asymmetric
protonation, see: a) M. A. Baur, A. Riahi, F. Henin, J. Muzart,
Tetrahedron Asymm. 2003, 14, 2755−2761. b) T. Poisson, S. Oudeyer,
V. Dalla, F. Marsais, V. Levacher, Synlett 2008, 2447−2450. c) D.
Uraguchi, T. Kizu, Y. Ohira, T. Ooi, Chem. Commun. 2014, 50,
13489−13491. d) K. Liao, X.-S. Hu, R.-Y. Zhu, R.-H. Rao, J.-S. Yu, F.
Zhou, J. Zhou, Chin. J. Chem. 2019, 37, 799−806.
[11] For reviews on chiral counterions catalysis, see: a) T. Akiyama, K. Mori,
Chem. Rev. 2015, 115, 9277–9306; b) M. Mahlau, B. List, Angew. Chem.
Int. Ed. 2013, 52, 518–533; Angew. Chem. 2013, 125, 540–556; c) K.
Brak, E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534–561; Angew.
Chem. 2013, 125, 558–588; d) D. Kampen, C. M. Reisinger, B. List, Top.
Curr. Chem. 2010, 291, 395-456; e) T. Akiyama, Chem. Rev. 2007, 107,
5744–5758.
[12] For reviews on asymmetric protonation, see: a) J. T. Mohr, A. Y. Hong,
B. M. Stoltz, Nat. Chem. 2009, 1, 359–369; b) S. Oudeyer, J.-F. Brière,
V. Levacher, Eur. J. Org. Chem. 2014, 6103 –6119; c) J. P. Phelan, J. A.
Ellman, Beilstein J. Org. Chem. 2016, 12, 1203–1228.
Acknowledgements
We thank the University of St Andrews for a studentship (MWA),
[13] T. Hanamoto, T. Kobayashi, J. Org. Chem. 2003, 68, 6354–6359.
[14] C. Xu, C. W. Muir, A. G. Leach, A. R. Kennedy, A. J. B. Watson, Angew.
Chem. Int. Ed. 2018, 57, 11374–11377; Angew. Chem. 2018, 130,
11544–11547.
the Leverhulme Trust (Grant No. RPG-2015-308) for
a
postdoctoral fellowship (CX), and the University of St Andrews,
and the EPSRC National Mass Spectrometry Centre at Swansea
University for mass spectroscopy analyses. The authors would
like to acknowledge the assistance given by Research IT and the
use of the Computational Shared Facility at The University of
Manchester.
[15] a) J. P. Reid, J. M. Goodman, Chem. Eur. J. 2017, 23, 14248–14260; b)
J. P. Reid, J. M. Goodman, Org. Biomol. Chem. 2017, 15, 6943–6947;
c) J. P. Reid, L. Simon, J. M. Goodman, Acc. Chem. Res. 2016, 49,
1029–1041; d) L. Simón, J. M. Goodman, J. Am. Chem. Soc. 2008, 130,
8741–8747; e) L. Simon, J. M. Goodman, J. Am. Chem. Soc. 2009, 131,
4070–4077; f) L. Simon, J. M. Goodman, Org. Biomol. Chem. 2012, 10,
1905–1913; g) Y. Shibata, M. Yamanaka, J. Org. Chem. 2013, 78, 3731–
3736.
[16] a) Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
6
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino,
B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz,
A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F.
Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D.
Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A.
Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W.
Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J.
Fox, Gaussian, Inc., Wallingford CT, 2016; b) I. Funes-Ardoiz, R. S.
164; c) C. S. Teschers, C. G. Daniliuc, G. Kehr, R. Gilmour, J. Fluorine
Chem. 2018, 210, 1–5.
[19] a) J. Ren, J. Diprose, J. Warren, R. M. Esnouf, L. E. Bird, S. Ikemizu, M.
Slater, J. Milton, J. Balzarini, D. I. Stuart, D. K. Stammers, J. Biol. Chem.
2000, 275, 5633–5639; b) J. Ren, C. Nichols, L. Bird, P. Chamberlain, K.
Weaver, S. Short, D. I. Stuart, D. K. Stammers, J. Mol. Bio. 2001, 312,
795–805; c) J. Ren, C. E. Nichols, A. Stamp, P. P. Chamberlain, R. Ferris,
K. L. Weaver, S. A. Short, D. K. Stammers, FEBS J. 2006, 273, 3850–
3860.
[20] H. Tsuge, T. Nishimura, Y. Tada, T. Asao, D. Turk, V. Turk, N. Katunuma,
Biochem. Bioph. Res. Co. 1999, 266, 411–416.
[21] M. Faheem, J. B. Neto, P. Collins, N. M. Pearce, N. F. Valadares, L. Bird,
H. M. Pereira, F. V. Delft, J. A. R. G. Barbosa. Crystal Structure of purine
nucleoside phosphorylase Isoform 2 from Schistosoma mansoni in
complex with 2-fluoro-6-(2-pyridin-2-ylethylamino)benzonitrile. Protein
Data Bank, DOI: 10.2210/pdb6AWE/pdb.
Paton.
GoodVibes:
Version
2.0.3;
Zenodo,
2018.
https://doi.org/10.5281/zenodo.1435820.
[17] T. Yamazaki, S. Hiraoka, T. Kitazume, J. Org. Chem. 1994, 59, 5100–
5103.
[22] The research data supporting this publication can be accessed at
https://doi.org/10.17630/4dc10fba-3dae-4a9c-815f-6f0935372a67.
[18] a) T. Schaefer, R. W. Schurko, R. Sebastian, F. E. Hruska, Can. J. Chern.
1995, 73, 816–825; b) D. J. Tozer, Chem. Phys. Lett. 1999, 308, 160–
7
This article is protected by copyright. All rights reserved.

10.1002/chem.202002543
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
CPA cat.
● Catalytic, enantioselective
● No F–, avoids SN1 issue
Ar
Ar
ArNH2
N
N
NHAr
● Full mechanistic analysis
F
F
● Rationalization of catalyst selectivity
vinyl fluoride
vicinal fluoroamine
>20 examples
aniline
Chiral Brønsted acid catalysis enables the synthesis of heterocyclic vicinal fluoroamines via asymmetric protonation. The reaction
accommodates a range of azaheterocycle and nucleophile, generating the C–F stereocenter in high enantioselectivity, and allows
formation of chiral C–CF3 bonds. DFT calculations have provided insight into the reaction mechanism and conformational control of
the products is elucidated.
Institute and/or researcher Twitter usernames: @allanjbwatson
8
This article is protected by copyright. All rights reserved.