Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines

Article abstract of DOI:10.1021/jacs.0c05131

Ammonium salts are used as phase-Transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. This process, which highlights the ability of hydrogen bonding phase-Transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-Transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

Full text of DOI:10.1021/jacs.0c05131

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Communication
Hydrogen Bonding Phase-Transfer Catalysis with Ionic
Reactants: Enantioselective Synthesis of #-Fluoroamines
Giulia Roagna, David M. H. Ascough, Francesco Ibba, Anna Chiara Vicini, Alberto
Fontana, Kirsten E. Christensen, Aldo Peschiulli, Daniel Oehlrich, Antonio Misale,
Andrés A. Trabanco, Robert S. Paton, Gabriele Pupo, and Veronique Gouverneur
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05131 • Publication Date (Web): 01 Jul 2020
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Page 1 of 6
Journal of the American Chemical Society
Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants:
Enantioselective Synthesis of -Fluoroamines
Giulia Roagna,§,† David M. H. Ascough,§,† Francesco Ibba,† Anna Chiara Vicini,† Alberto Fontana,‡
Kirsten E. Christensen,† Aldo Peschiulli,║ Daniel Oehlrich,║ Antonio Misale,‡ Andrés A. Trabanco, ‡
Robert S. Paton,†,ƒ Gabriele Pupo,†* and Véronique Gouverneur†*
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† University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK
‡ Discovery Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Calle Jarama 75A, 45007 Toledo, Spain
║Discovery Sciences Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg
30, Beerse B-2340, Belgium
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ƒ Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Supporting Information Placeholder
catalysts for non-enantioselective fluorination reactions with KF or
ABSTRACT: Ammonium salts are used as phase-transfer
catalysts for fluorination with alkali metal fluoride. We now
demonstrate that these organic salts, specifically azetidinium
triflates, are suitable substrates for enantioselective ring opening
with CsF and a chiral bis-urea catalyst. This process that highlights
the ability of hydrogen bonding phase-transfer catalysts to couple
two ionic reactants, affords enantioenriched γ-fluoroamines in high
yields. Mechanistic studies underline the role of the catalyst for
phase-transfer, and computed transition state structures account for
the enantioconvergence observed for mixtures of achiral
azetidinium diastereomers. The N-substituents in the electrophile
influence reactivity, but the configuration at nitrogen is
unimportant for enantioselectivity.
CsF (Scheme 1B, LHS).11f-g Such cationic phase-transfer scenario
(CPTC) would transform in situ formed azetidinium fluoride into
racemic γ-fluoroamine. We envisioned that HB-PTC using a chiral
bis-urea catalyst could offer
a viable approach for the
desymmetrization of achiral azetidinium salts with alkali metal
fluoride (Scheme 1A and 1B, RHS). This scenario is not without
challenges because the use of two pre-formed ionic reactants
implies high concentration of ions in solution, a drastic change
when compared to transformations featuring transiently formed ion
pairs.4a-b Significant variation in fluorination kinetics and
competitive binding events (e.g. azetidinium counter-anion X‒ vs.
F‒) can be expected.12 Computational studies indicated that a
neutral N-methyl chiral bis-urea4a binds a CsF unit more strongly
Asymmetric phase-transfer catalysis (PTC) is one of the most
practical methods for enantioselective synthesis.1 For many years,
PTC approaches to asymmetric fluorinations have used F2-derived
electrophilic reagents and cationic or anionic chiral species for
effective phase-transfer.2 Inspired by nature’s fluorinase,3 we
than 1,1-dimethyl azetidinium ion in 1,2-dichloroethane (ΔGurea
=
−69 kJ/mol, ΔGazet = −14 kJ/mol) (Scheme 1C).13a
Sun et al. (ref. 10)
This work
A.
R1 R2
N
R1 R2
N
N
*
O
O
O
H
N
reported
a complementary hydrogen bonding phase-transfer
vs.
P
H
*
O
N
H
F–
catalysis (HB-PTC) manifold, which employed alkali metal
fluoride for asymmetric nucleophilic fluorinations.4 Specifically, a
chiral N-alkylated bis-urea served as hydrogen bond donor (HBD)
catalyst to bring KF or CsF in solution. The process involves a
chiral urea-fluoride complex capable of ion-pairing with in situ
formed meso episulfonium or aziridinium ions. The ensuing
enantioselective desymmetrization afforded enantioenriched β-
fluorosulfides and β-fluoroamines. To date, all enantioselective
fluorinations carried out under PTC use non-ionic substrates,
including -keto esters, alkenes, -bromosulfides or -
chloroamines. An unexplored scenario in asymmetric C‒F bond
construction under PTC is the use of two ionic reactants. We
became interested in this challenge as we envisioned that
enantioselective desymmetrization of achiral azetidinium salts with
fluoride would afford γ-fluoroamines of high value for medicinal
chemistry.5 Azetidinium salts6 with non-nucleophilic counteranions
are bench stable solids,7a and can be prepared from commercially
or readily available azetidines.7b–c Few methods are available to
access enantioenriched γ-fluoroamines,8 and strategies for the
enantioselective installation of CH2F are scarce.9
In 2018, Sun and co-workers reported the desymmetrization of
azetidinium salts with mercaptobenzothiazoles and a chiral
phosphate catalyst (Scheme 1A, LHS).10 This pioneering study
encouraged experimentation applying this anionic PTC approach
(CAPT) with TBAF or CsF; none of our attempts yielded γ-
fluoroamines (Scheme S6). This result prompted the use of
HB-PTC as an alternative manifold. Mechanistically, achiral
azetidinium salts could themselves act as phase-transfer agents
enabling solubilization of solid alkali metal fluoride as azetidinium
fluoride. Indeed, ammonium salts,11a–c pyridinium salts11d and
imidazolium-based ionic liquids11e have been used as phase-transfer
RS
R4 R3
R4 R3
Chiral Anion Phase-Transfer Catalysis
CAPT
Hydrogen Bonding Phase-Transfer Catalysis
HB-PTC
(
)
(
)
RSH as external soluble nucleophile
Chiral Phosphate for stereocontrol
CsF as insoluble nucleophile
Chiral bis-urea for CsF solubilization/stereocontrol
B.
Enantioenriched
HB
PTC
CPTC
R1 R2
-fluoroamines

–
N
X
R2
N
R4N+ X–
cat.
urea* cat.
R4N+ X–
substrate
R3 R4
F
H2C
R4N+ X–
substrate
=
+ F–
insoluble
E
F
M
R1
E-LG
substrate
R4 R3
Bench
stable
*
via R4N+ F– (achiral)
via R4N+ F–
urea* (chiral)
HB-PTC with ionic reactants
Conventional PTC
This work:
F
CH2 motif on
stereogenic carbon
Azetidinium salts can be used
Tertiary, secondary and
primary -fluoro amines
as mixture of diastereomers
C.
O
R
Me
N
N
H
N
Me
Me
+
CsF
CsF
vs.
+
H
H
X–
N
N
Ph
R
O
R = 3,5-(CF3)2C6H3
G(1,2-DCE) = -14 kJ/mol
Phase-transfer by azetidinium
G(1,2-DCE) = -69 kJ/mol
Phase-transfer by neutral bis-urea
Scheme 1. A. Desymmetrization of azetidinium salts. B. R4N+X‒ as
catalyst (CPTC) vs. R4N+X‒ as substrate (HB-PTC).
C. Computational binding studies (R4N+X‒ treated as dissociated).
Encouraged by these findings,13b we surmised that azetidinium salts
(R4N+X) could undergo enantioselective fluorination with an alkali
metal fluoride (M+F–), in the presence of a chiral HBD catalyst
(urea*) if orchestrated hydrogen-bonding and ion metathesis
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Page 2 of 6
generate the soluble chiral ion pair [R4N]+[F•urea*]–. This species
cleavable releasing
transformations.
a primary amine amenable to myriad
1
2
3
4
5
6
7
8
could undergo C‒F bond formation with release of the
enantioenriched γ-fluoroamine and catalyst. Herein, we describe
the development of this unusual PTC process featuring two ionic
reactants and demonstrate that achiral azetidinium salts are
amenable to desymmetrization with CsF and a chiral BINAM-
derived bis-urea catalyst.
The benefit of the N-benzhydryl group on reactivity prompted
further investigation.14 Fluorination reactions performed on
differently N,N-disubstituted azetidinium salts under homogeneous
conditions (TBAF∙3H2O, 1,2-DCE, no catalyst) showed benzhydryl
being superior to all other N-substituents (Scheme S4). The
increased reactivity of N-benzhydryl azetidinium salts is therefore
unconnected with phase-transfer. Computed transition state
structures (TSs) for the fluorination of seven azetidinium ions by
free fluoride (homogeneous conditions) show that increased
experimental yields are consistent with smaller computed activation
barriers. N-Benzhydryl azetidinium ions have barriers to
fluorination ~ 6 kJ/mol lower than the corresponding N-benzyl
substrate. This can be traced to increased reactant strain: N-
benzhydryl azetidinium ions have more elongated C–N bonds and
earlier fluoride delivery TS positions compared to the methyl or
benzyl substrates (Figure 1).
Preliminary investigations unveiled details on the impact of the
structural features of azetidinium salts on reactivity (Table 1).
Table 1. Optimization of Reaction Conditions
F3C
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R2
R1
N
Ph R2
cat.
Cs (2 equiv.),
(5–10 mol%),
F
CF3
CF3
N
H
N
R
-OTf
F
N
*
R1
solvent (0.25 M), r.t.
24–48 h
H
N
H
N
Ph
1
2
O
mixture of
diastereomers
CF3
R1 = R2 = Bn;
R1 = Bn, R2 = Bzh
;
1aa
1ab
A
B
C
: R = H
: R = Et
i
R1 = Me, R2 = Bn; R1 = Et, R2 = Bzh
;
D
: R = Me
: R = Pr
R1 = Me, R2 = Bzh
;
Bzh = Benzhydryl
1a
Entry
R1
R2
cat.
A
A
A
B
solvent
Yielda
traces
traces
14%
20%
20%
45%
56%
47%
51%
40%
93%
>95%
98%
e.r.b
1
2
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Et
Bn
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
//
//
Bn
3
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
Bzh
55:45
55:45
75:25
74:26
67:33
79:21
81:19
96:4
4
5
C
6
D
D
D
D
D
D
D
D
7
8
1,2-DFB
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
9
10
11c, d
12
13c, e
Figure 1. Effect of N-benzhydryl on reactivity (Me, Bn and Bzh
series). IRC position calculated as C–N minus C–F distance.15
Et
96:4
Bn
Bn
96:4
The scope of -fluoroamine synthesis was examined next. High
yields and enantioselectivities were obtained with 3-aryl
azetidinium triflates. Substrates bearing aromatic groups with
electron-withdrawing and electron-donating substituents at meta or
para positions were converted with excellent yields and
enantioselectivities (2aa–2ha, up to 99% yield, 97.5:2.5 e.r.).
Heteroaromatic groups such as thiophene (2pa), pyrazole (2qa) and
indole (2ra) were compatible, representing pharmaceutically
relevant motifs (up to 99% yield, 94:6 e.r.). Additional highlights
are the suitability of N-allyl azetidinium salts (2ac, 2ic), the
tolerance of the reaction to 3-aryloxy- (2ia–2ja, up to 99% yield,
93.5:6.5 e.r.), 3-alkoxy- (2ka–2mb), and 3-phtalimido- groups
(2sa), as well as the synthesis of enantioenriched γ-fluoroamines
2oa, 2va–2ua featuring a tetrasubstituted stereogenic carbon.
Furthermore, 2ta bearing an ester group stands out as an immediate
precursor to enantioenriched fluorinated β-lactams and β-amino
acids.16 Tertiary fluoride 2wa was accessed in good yield and
moderate enantioselectivity. Substrates mono- or bis-alkylated at
position 3 were less successful (Scheme S7).13a Single-crystal X-
ray diffraction analysis of 2ma•HCl and 3ab (Scheme 3A) enabled
the assignment of the absolute configuration (S-catalyst affords S-
product).17
96:4
Reaction conditions: 0.05 mmol of 1, 0.25M, 10 mol% cat., 900 rpm
stirring, 24 h; Determined by 19F NMR (4-fluoroanisole as internal
a
standard); e.r. = enantiomeric ratio, determined by HPLC; c Yield of
b
isolated product. d 72 h, 10 mol% cat.; e 48 h, 5 mol% cat.
3-Phenyl N,N-dibenzyl and N-methyl-N-benzyl azetidinium
triflates afforded traces of product with CsF and catalyst (S)-A
(Table 1, entries 1‒2). When N-methyl-N-benzhydryl substrate 1a
was employed, the desired γ-fluoroamine was obtained in poor
yield and enantioselectivity (Table 1, entry 3). Notably, 1a reacted
with CsF in 1,2-DCE in the absence of catalyst to afford
γ-fluoroamine (±)-2a in 8% yield (Table S1). When this reaction
was carried out using the N-alkylated bis-urea catalysts (S)-B, (S)-
C or (S)-D, 2a was obtained in moderate yield and enantiomeric
ratio (e.r.) (Table 1, entries 4‒6). Solvent screening showed the
superiority of 1,2-DCE (Table 1, entries 7‒9, up to 81:19 e.r.). In
addition to the benzhydryl group, the second N-substituent also
influenced reactivity and enantioselectivity, with benzyl and ethyl
being superior to methyl (Table 1, entries 10‒13, up to 96:4 e.r.).
After optimization, the reaction of 1aa (d.r. 1:1.1) in 1,2-DCE with
CsF (2 equiv.) and N-isopropyl bis-urea catalyst (S)-D (5 mol%) at
r.t. afforded γ-fluoroamine 2aa in 98% yield and 96:4 e.r. (Table 1,
entry 13). N-Ethyl azetidinium triflate 1ab required longer reaction
time (72 h) and higher catalyst loading (10 mol %) to afford 2ab
(93% yield, 96:4 e.r., Table 1, entry 11). These findings were
encouraging because azetidinium salts can be used as mixture of
diastereomers, and both benzhydryl and benzyl groups are
This new catalytic protocol enabled the preparative scale synthesis
of γ-fluoroamines 3aa and 3ab (Scheme 3A). The reaction of one
gram of 1aa was conducted with a lower catalyst loading (3 mol%)
and no compromise in e.r. relative to the smaller scale reaction.
Deprotection and a single recrystallization gave the primary
γ-fluoroamine 3aa in 99:1 e.r. A similar protocol afforded
enantioenriched secondary γ-fluoroamine 3ab in 98.5:1.5 e.r. The
2
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Journal of the American Chemical Society
synthesis of the fluorinated analogue of Lorcaserin,18 a selective
serotonin 2C receptor agonist, FDA-approved for chronic-weight
management, illustrates the value of the method for accessing
valuable pharmaceutical motifs (Scheme 3B).
This is further supported by NMR studies which showed the
stronger binding preference of the catalyst for fluoride compared to
1
2
3
4
5
6
7
8
other anions (F‒>> TfO‒ ~ BF4 > PF6 );13a (iii) the linear
relationship between the enantiopurity of catalyst and product
supports the involvement of a single urea catalyst in the
enantiodetermining step (Table S7); (iv) when diastereomerically
pure N-methyl substituted cis-1a or trans-1a was subjected to
asymmetric fluorination under standard reaction conditions,
fluoroamine (S)-2a was formed with a comparable e.r. (80.5:19.5
and 80:20, respectively, Table S4).
‒
‒
Scheme 2. Reaction Scopea
F3C
O
CF3
CF3
N
H
N
D
(S)- (5–10 mol%)
Bzh
R
N
R'
R
N
iPr
F
Cs (2 equiv.)
OTf
F
H
H
N
Bzh
N
1,2-DCE dry (0.25 M),
r.t., 24–72 h
2aa–sa
(S)-
R'
1aa–sa
O
9
Scheme 3. A. Gram-Scale Reactions and Deprotection. B.
Enantioselective Synthesis of Fluorinated Lorcaserin.
D
(S)-
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
A.
Bn
–OTf
Bzh
Bn
Bn
N
(S)-D (3 mol%),
Ph Bn
N
Ph
R
i)
N
F
Cs (2 equiv.),
F
F
N
F
F
NH3
Cl–
F
N
Bzh
Bzh
Bzh
Bzh
1,2-DCE, r.t., 72 h
99% recovered catalyst
2aa
2ab
2ac
2ba
2ca
R = Bn, 98% yield, 96:4 e.r.
R = Et, 93% yield, 96:4 e.r.
R = All, 96% yield, 94:6 e.r.
88% yield, 97.5:2.5 e.r.
F
96% yield, 97:3 e.r.
Ph
1aa
2aa
3aa HCl
79% yield, 96:4 e.r.
recryst.
hexane/EtOH
(70% yield)
1:1.1 (cis:trans)
92% yield, 96:4 e.r.
CF3
1.00 g
Cl
99:1 e.r.
Bn
R
R
Bzh
D
(R)- (10 mol%),
Ph
Ph
H2
N
–OTf
ii)
F
F
F
N
N
N
F
Cs (2 equiv.),
Bzh
Bzh
Bzh
F
N
F
N
Bzh
1,2-DCE, r.t., 72 h
99% recovered catalyst
Cl–
2ea
2eb
2da
2fa
2fb
90% yield, 96:4 e.r.
Ph
R = Bn, 98% yield, 94.5:5.5 e.r.
R = Et, 97% yield, 95:5 e.r.
R = Bn, 99% yield, 95:5 e.r.
R = Et, 95% yield, 95:5 e.r.
Ph
1ab
2ab
3ab HCl
recryst.
DCM/Et2O
(87% yield)
10:1 (cis:trans)
82% yield, 96:4 e.r. 74% yield, 96:4 e.r.
1.01 g
98.5:1.5 e.r.
Bn
O
R
N
Reaction conditions
: i) Pd(OH)2 (10 mol%), MeOH:DCM (4:1), H2 (1 atm), 12 h then 1 M HCl in MeOH;
ii) Pd/C (10 mol%), MeOH:DCM (2:1), H2 (1 atm), 12 h then 1 M HCl in MeOH.
R
F
F
N
F
N
Bzh
81% yield, 96.5:3.5 e.r.
Bzh
Bzh
B.
2ia
2ib
2ic
2ga
2gb
2ha
R = Bn, 99% yield, 88:12 e.r.
R = Et, 84% yield, 93.5:6.5 e.r.
R = All, 91% yield, 85:15 e.r.
R = Bn, 82% yield, 97:3 e.r.
R = Et, 86% yield, 97:3 e.r.
MeO
Bzh Bn
Cl
OMe
NH
F
i) Cs (2 equiv.),
–OTf
N
i) (MeO)2CHCHO,
MeOH, r.t.,12 h
D
(R)- (5 mol%),
F
1,2-DCE, r.t., 48 h
F
NH2
Cl
ii) NaBrO3, Na2S2O4,
EtOAc/H2O, r.t., 2 h
O
R
N
O
R
N
ii) NaBH3CN, MeOH,
r.t., 12 h
O
Bn
N
F
F
F
F
Bzh
Bzh
Bzh
Cl
4a
2ka
2kb
2la
2lb
2ja
62% yield, 88:12 e.r.
1da
R = Bn, 87% yield, 93:7 e.r.
R = Et, 95% yield, 95:5 e.r.
R = Bn, 85% yield, 88:12 e.r.
R = Et, 99% yield, 91:9 e.r.
4b
81% yield, 96:4 e.r.
70% yield, 96:4 e.r.
1.8:1 (cis:trans)
1.00 g
Ph
O
OBn
R
N
NH
i) TfOH, DCM, r.t., 30 min
O
Et
N
F
Cl
Bzh
F
Bzh
ii) NaBH3CN, NaH2PO4,
THF, r.t., 4 h
F
2ma
2mb
2na
R = Bn, 96% yield, 95:5 e.r.
R = Et, 99% yield, 97:3 e.r.
87% yield, 86.5:13.5 e.r.
(S)-2ma HCl
Fluorinated Lorcaserin
86% yield, 96:4 e.r.
Br
Br
S
N
N
Bn
N
Et
N
Et
Finally, we turned our attention towards the origin of
enantioconvergence for this transformation. The TSs for
fluorination of 1a, mediated by catalyst (S)-D were computed using
density functional theory (DFT).19 An ensemble of TSs was
optimized for both cis and trans substrates (Figure 2). With cis
substrate (major diastereomer), both TSMajor-cis and TSMinor-cis
feature a face-to-face π-interaction between the phenyl in the 3-
position of the substrate and the catalyst (Figure 2Ai), orienting the
substrate in the catalytic pocket. In contrast, the benzhydryl groups
point in different directions. In TSMajor-cis the azetidinium ion
adopts its favored conformation, with an intramolecular CH---π
interaction worth approximately 2-5 kJ/mol (Figure 2Aii). In
TSMinor-cis, this is compensated by an aromatic edge-to-face
interaction of the benzhydryl group with the catalyst BINAM
backbone (Figure 2Aiii). When computed with N-ethyl substituent
(1ab), (S)-catalyst affords (S)-product with 91:9 e.r., consistent
with the experimental enantioselectivity of 96:4 e.r. Comparison of
TSMajor-cis with the lowest energy TS to major product with trans
substrate, TSMajor-trans, shows remarkable similarity, with
excellent superposition of catalyst, fluoride and substrate, with the
only exception being reversal of configuration at nitrogen, resulting
in the sterically demanding benzhydryl group pointing in a different
direction (Figure 2B). The enantioconvergence of the
diastereomers originates from the azetidinium N-substituents
projecting away from the catalyst, and the resulting indifference to
the configuration at nitrogen.20
O
F
F
N
F
Bzh
Bzh
Bzh
2oa
2pa
2qa
98% yield, 87:13 e.r.
51% yield, 83:17 e.r.
62% yield, 93.5:6.5 e.r.
O
OtBu
N
O
O
N
Bn
N
N
Bn
N
Bn
F
F
F
Bzh
Bzh
Bzh
2ra
2sa
2ta
99% yield, 94:6 e.r.
92% yield, 82.5:17.5 e.r.
(>99.5:0.5 e.r.)
98% yield, 92:8 e.r.
(99.5:0.5 e.r.)
CN
Et
Ph
F
OBn
Bn
N
Bn
F
N
F
N
F
Bzh
Bzh
Bzh
[b]
2ua
2va
2wa
88% yield, 87:13 e.r.
90% yield, 86:14 e.r.
87% yield, 84:16 e.r.
(95:5)
[a]
0.1 mmol scale, except for 1sa, 1ta, 1wa (0.5–1 mmol scale). Absolute
configuration assigned by analogy to (S)-2ma for all products except 2oa,
2ua–2wa featuring a tetrasubstituted stereogenic carbon; [b] 20 mol% cat. In
parenthesis, e.r after single recrystallization.
Further experimentation was undertaken to gain more insight on
this process: (i) the reaction of 1aa with 1 equiv. of [(S)-D∙F]–
[nBu4N]+ formed in situ or pre-formed from nBu4N+F-·3H2O in
1,2-DCE (0.25 M) afforded 2aa in 30% yield and 96:4 e.r.; this
result confirms the involvement of [(S)-D∙F]– for enantiocontrol
(Scheme S5), and highlights the detrimental impact of water on
yield (Table S5); (ii) exchanging OTf‒ of 1aa with PF6– gave 2aa
in identical e.r. (96:4), but in only 31% yield (Table S6). This
observation indicates that the counter-anion influences the efficacy
of phase transfer, and advocates against anion binding catalysis.
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Page 4 of 6
Notes
1
2
The authors declare no competing financial interests.
3
ACKNOWLEDGMENT
4
5
6
7
8
9
We thank Dr J. M. Brown for insightful discussions, the University
of
Oxford
Advanced
Research
Computing
facility
(http://dx.doi.org/10.5281/zenodo.22558) and the Extreme Science
and Engineering Discovery Environment (allocation TG-
CHE180056). This work was supported by EU H2020 Research
and Innovation Programme (Marie Skłodowska-Curie agreements
721902, 675071 and 789553), the Engineering and Physical
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Sciences
Research
Council
(EP/R010064,
SBM-CDT
EP/L015838/1), and the European Research Council (agreement
832994).
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Figure 2. Computed TSs for fluorination of 1a. A. TSs with cis-1a
and key structural features. B. Origin of enantioconvergence of
cis-1a and trans-1a demonstrated through the structural similarity
of the most favorable TSs with each diastereomer of substrate.
In conclusion, this study provides new insights on HB-PTC and
its application to high value fluorine-containing molecules. Neutral
N-alkylated bis-urea catalysts are more effective at fluoride binding
than azetidinium ions, a feature enabling efficient enantioselective
ring opening with CsF for the synthesis of γ-fluoroamines.
Considering that the use of ammonium salts as substrates is
uncommon in asymmetric catalysis,21 the principles outlined here
may encourage further studies to transform ionic starting materials
into enantioenriched products applying HB-PTC.
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ASSOCIATED CONTENT
4) (a) Pupo, G.; Ibba, F.; Ascough, D. M. H.; Vicini, A. C.; Ricci,
P.; Christensen, K. E.; Pfeifer, L.; Morphy, J. R.; Brown, J. M.;
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Synthesis of β-Fluoroamines. J. Am. Chem. Soc. 2019, 141, 2878.
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Thompson, A. L.; Paton, R. S.; Brown, J. M.; Gouverneur, V.
Coordination Diversity in Hydrogen- bonded Homoleptic
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Sparkes, H. A.; Thompson, A. L.; Brown, J. M.; Gouverneur, V.
Optimization/mechanistic data are provided in the Supporting
Information which is available free of charge on the ACS
publications website. Crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre (1973306-07)
and can be obtained free of charge.
AUTHOR INFORMATION
Corresponding Authors
gabriele.pupo@chem.ox.ac.uk
and veronique.gouverneur@chem.ox.ac.uk
Author Contributions
§ These authors contributed equally to this work.
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Hydrogen-bonded Homoleptic Fluoride–Diarylurea Complexes:
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Equivalent and Palladium‐Catalyzed Enantioselective Allylic
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Wu, T.; Phipps, R. J.; Toste, F. D. Advances in Catalytic
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Fluorination,
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Di-,
and
Trifluoromethylation, and Trifluoromethylthiolation Reactions.
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a desymmetrization reaction using sulphur
nucleophiles, see reference 10a.
7) (a) All triflate azetidiniums salts employed in this study are
bench stable solids; (b) All major chemical suppliers have 30–50
azetidines in their catalogues; (c) For a recent example of synthesis
of tetrasubstituted azetidines, see: Fawcett, A.; Murtaza, A.;
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Angew. Chem. Int. Ed. 2004, 43, 483. For selected examples of
19) (a) Calculations were performed using Gaussian 16 Rev. A.03
for optimization and frequency calculations, with single point
energy corrections performed with ORCA 4.2.0. The CPCM(1,2-
DCE)/ωB97X-D3/(ma)-def2-TZVPP//CPCM(1,2-DCE)/M06-2X/
def2-SVP(D) level of theory was used for all calculations. Full
computational details, including precise definition of the basis sets,
are provided in the supporting information. (b) Thermochemistry is
evaluated at 298.15 K, at 1 M standard concentration.
1
2
3
4
5
6
crown ether and glycols as solid-liquid phase-transfer catalysts for
KF, see: (f) Liotta, C. L.; Harris, H. P. Chemistry of Naked Anions.
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with Organic Substrates in Aprotic Organic Solvents. J. Am. Chem.
Soc. 1974, 96, 2250; (g) Deutsch, J.; Niclas, H. -J. A Convenient
and New Modified Preparation of Nitrosubstituted Aryl Fluorides.
Synth. Commun. 1991, 21, 505.
7
8
9
20) The full ensemble of computed TSs for reaction cis-1a and
trans-1a are provided in the SI.
12) (a) Turnover of the productive fluorination pathway will be
influenced by a change in substrate cation concentration (i.e. pre-
formed azetidinium versus in situ formed episulfonium). In
previous work (reference 4a), the episulfonium ion pair lies at +48
kJ/mol compared to the unionized precursor, corresponding to an
equilibrium constant of 4 x 10-9 at r.t. For a detailed analysis of
concentration effects in catalysis, refer to 12c-e; (b) High
concentrations of substrate counter-anion will also increase
competitive binding of the hydrogen bonding catalyst, potentially
hindering HB-PTC and/or facilitating alternative anion-binding
pathways; (c) Kozuch, S.; Shaik, S. How to Conceptualize
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112, 6032; (e) Uhe, A.; Kozuch, S.; Shaik, S. Automatic Analysis
of Computed Catalytic Cycles. J. Comput. Chem. 2011, 32, 978.
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32
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36
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38
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41
42
43
44
45
46
47
48
49
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51
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21) For rare examples, see: West, T. H.; Daniels, D. S. B.; Slawin,
A. M. Z.; Smith, A. D. An Isothiourea-Catalyzed Asymmetric
[2,3]-Rearrangement of Allylic Ammonium Ylides. J. Am. Chem.
Soc. 2014, 136, 12 and reference 10a.
Graphic for Table of Contents
R1 R2
HB
R2
R3 R4
PTC
TfO–
NH
F
N
N
F
R1
H2C
*
F
urea*cat., Cs
Cl
R4 R3
CH2
Fluorinated
Lorcaserin
Bench stable
Mixture of diastereomers
-fluoroamines
>30 examples

99% yield
97:3 e.r.
, up to
up to
13) (a) See Supporting Information for details; (b) Favourable
binding thermodynamics are necessary but not sufficient to ensure
catalytic activity. Under a Curtin-Hammett scenario, levels of
enantioselectivity and the differential reactivities of azetidinium
ions are determined by the relative stabilities of competing TSs.
F
HB-PTC with ionic reactants
CH2 motif on stereogenic carbon
14) N-Benzhydryl azetidinium salts also feature in the study of Sun
and co-workers (reference 10a).
15) A larger variation in key metrics occurs on changing from Bn
to Bzh. ΔG‡ was measured relative to TBAF + Azet+. ΔGRxn
measures the release of ring strain of the ion upon fluorination with
TBAF.
16) (a) Kunieda, T.; Nagamatsu, T.; Higuchi, T.; Hirobe, M. Highly
Efficient Oxazolone-derived Reagents for Beta-Lactam Formation
from Beta-amino Acids. Tetrahedron Lett. 1988, 29, 2203; (b)
Weiner, B.; Szymański, W.; Janssen, D. B.; Minaard, A. J.;
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656.
17) Low temperature single crystal X-ray diffraction data were
collected using
a Rigaku Oxford Diffraction SuperNova
diffractometer. Raw frame data were reduced using CrysAlisPro
and the structures were solved using 'Superflip’: (a) Palatinus, L.;
Chapuis, G. SUPERFLIP - A Computer Program for the Solution
of Crystal Structures by Charge Flipping in Arbitrary Dimensions.
J. Appl. Cryst. 2007, 40, 786. Successive refinement was performed
with CRYSTALS (b) Parois, P.; Cooper, R. I.; Thompson, A. L.
Crystal Structures of Increasingly Large Molecules: Meeting the
Challenges with CRYSTALS Software. Chem. Cent. J. 2015, 9:30;
(c) Cooper, R. I.; Thompson, A. L.; Watkin, D. J. CRYSTALS
Enhancements: Dealing with Hydrogen Atoms in Refinement. J.
Appl. Cryst. 2010, 43, 1100. Full refinement details are given in the
Supporting Information (cif file).
18) (a) Smilovic, I. G.; Cluzeau, J.; Richter, F.; Nerdinger, S.;
Schreiner, E.; Laus, G.; Schottenberger, H. Synthesis of
Enantiopure Antiobesity Drug Lorcaserin. Bioorg. Med. Chem.
2018, 26, 2686; (b) Zhu, Q.; Wang, J.; Bian, X.; Zhang, L.; Wei,
P.; Xu, Y. Novel Synthesis of Antiobesity Drug Lorcaserin
Hydrochloride. Org. Process Res. Dev. 2015, 19, 1263.
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