Triol-promoted activation of C-F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl) propane

Article abstract of DOI:10.3762/bjoc.9.283

Activation of the C-F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bonddonating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bondaccepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields.

Full text of DOI:10.3762/bjoc.9.283

Triol-promoted activation of C–F bonds:
Amination of benzylic fluorides under highly
concentrated conditions mediated by
1,1,1-tris(hydroxymethyl)propane
Pier Alexandre Champagne, Alexandre Saint-Martin, Mélina Drouin
and Jean-François Paquin*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2451–2456.
Canada Research Chair in Organic and Medicinal Chemistry, CCVC,
PROTEO, Département de chimie, Université Laval, 1045 avenue de
la Médecine, Québec, QC, Canada G1V 0A6
doi:10.3762/bjoc.9.283
Received: 27 August 2013
Accepted: 17 October 2013
Published: 13 November 2013
Email:
Jean-François Paquin* - jean-francois.paquin@chm.ulaval.ca
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
* Corresponding author
Keywords:
C–F bond activation; highly concentrated conditions; nucleophilic
substitution; hydrogen bond; organofluorine; triol
© 2013 Champagne et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Activation of the C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-
donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-
accepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot inter-
fere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary
amines or anilines to form benzylic amines in good yields.
Introduction
The discovery of mild methods for the activation of C–F bonds was used as the hydrogen bond donor and co-solvent. DFT
is of high importance both from a fundamental point of view as calculations show that activation proceeds through stabilization
well as for potential practical applications [1]. Specifically for of the transition-state structure by, amongst other things,
aliphatic monofluorides, a number of transition metal-catalyzed hydrogen bonds between the fluorine atom and the water mole-
methods [1-9] and transition-metal-free methodologies [1,10- cules, and not simple transition-state electrostatic stabilization
12] have been developed. In continuation with our interest in by the solvent even though a mixture of polar solvent (iPrOH/
the activation of C–F bonds [13-16], we have recently reported H2O in a 1:1 ratio) is used (Figure 1).
that it was possible to enable the use of fluoride as a leaving
group in nucleophilic substitution reactions of activated alkyl For its activating role in our system, water appeared to work
fluorides through hydrogen bonding [17]. Particularly, water mostly as a triad of spatially and geometrically well-defined
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Beilstein J. Org. Chem. 2013, 9, 2451–2456.
Figure 1: SN2 reaction of activated alkyl fluorides and calculated transition state for the reaction of morpholine with benzyl fluoride with three mole-
cules of water.
hydrogen bond-donating moieties. We therefore wondered the best result (35%) being obtained in water (Table 1, entries
about what would happen if these three moieties (water mole- 1–3). While the effect of the triol seems minimal, it is possible
cules) were covalently linked together in the form of a triol, in these cases that 2, being both a hydrogen bond donor and
which could help the three O–H functionalities to position acceptor, is engaged in a hydrogen bond network with the
themselves strategically around the three lone pairs of fluorine, solvent, thus limiting its availability for the benzylic fluoride.
which acts as a hydrogen bond acceptor [18-21] (Figure 2). Interestingly, switching to solvents with better acceptor than
Revoking the need to have five molecules (substrate, nucleo- donor properties impeded the reaction [26]. Hence, the use of
phile and three water molecules) in a precise geometry could toluene (Table 1, entry 4), EtOAc (Table 1, entry 5), THF
also enable a faster reaction with less activating agent, which (Table 1, entry 6) and DMF (Table 1, entry 7) provided at best
means we could potentially use the triol as an additive rather traces of the desired benzylic amine 3. We speculate that the
than a solvent. Altogether, this strategy would represent a ability of the solvent to interact more strongly with the triol than
unique metal-free and unprecedented small-molecule-mediated would the substrate results in no reaction. Finally, "inert"
activation of C–F bonds.
solvents [26,27] such as hexane (Table 1, entry 8) and CH2Cl2
(Table 1, entry 9) were investigated. In both cases, little reac-
tion was observed without 2, and moderate conversions were
obtained with 2. In this instance, the solvent is unable to interact
with either the triol or the substrate and the enhanced reactivity
in the presence of the triol clearly demonstrates its activating
role in this transformation. At this point, since solvents seemed
more prone to hinder than help the reaction, we conducted an
experiment without any solvent (Table 1, entry 10). Gratify-
ingly, a 54% conversion was obtained in the presence of 2,
while no conversion at all could be observed without the acti-
vating agent. It is important to mention for this entry that even
if morpholine is the only liquid component at room temperature,
a homogeneous solution is generated around 60 °C by the
fusion of 1,1,1-tris(hydroxymethyl)propane (melting point
56–58 °C).
Figure 2: Proposed activation of C–F bonds mediated by a triol.
Herein, we report the feasibility of this concept for the amina-
tion of benzylic fluorides, activated alkyl fluorides [22], using
1,1,1-tris(hydroxymethyl)propane as the triol. Furthermore, op-
timization of the reaction conditions have revealed that the reac-
tion was best run under highly concentrated conditions [23].
Results and Discussion
Our initial investigations were performed using 4-phenylbenzyl Starting from our solvent-free conditions, which were providing
fluoride (1) [24] as the substrate and morpholine (3 equiv) as the better results, we envisioned that further optimization was
the nucleophile at 60 °C for 24 h. Commercially available 1,1,1- possible to improve the yield (Table 2). First, temperature had
tris(hydroxymethyl)propane (2) was selected as the triol and an important impact on conversion. Indeed, going from 60 °C
was used in a slight excess (1.1 equiv) [25] relative to the sub- (Table 2, entry 1) to 100 °C (Table 2, entry 3) smoothly effected
strate. Solvent screening was completed with and without added a full conversion. It was also possible to reduce the amount of
triol 2 in order to establish its effect on the reactivity and results morpholine used from 3 equiv (Table 2, entry 3) to 2 equiv
are reported in Table 1. In water or alcoholic solvent without (Table 2, entry 5) without any impact on the conversion.
added triol, low to moderate conversions were observed However, lower amounts (Table 2, entries 6 and 7) resulted in
(12–26%). This was expected since these are all hydrogen decreased conversions. While a reasonable explanation for the
bond-donor solvents [17,26]. A low but quantifiable increase in requirement of excess amine would be its role in capturing the
conversion is observed when 2 is added to these reactions, with HF released during the reaction, control experiments did not
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Beilstein J. Org. Chem. 2013, 9, 2451–2456.
Table 1: Initial screening.
entry
solvent
conversion (%)a
with 2
without 2
1
2
3
4
5
6
7
8
9
10
H2O
35
26
EtOH
iPrOH
toluene
AcOEt
THF
29
26
16
12
< 3
< 3
< 3
< 3
21
< 3
< 3
< 3
< 3
< 3
< 3
< 3
DMF
hexane
CH2Cl2
–
26
54
aDetermined by 1H NMR analysis of the crude reaction mixture.
Table 2: Fine-tuning.
entry
temperature
morpholine (equiv)
conversion (%)a
1
60
3
54
2
80
3
90
3
100
100
100
100
100
100
100
100
3
> 97
> 97
> 97 (86)b
91
4
2.5
2
5
6
1.5
1
7
70
8c
9d
10e
1
71
1
57
1
41
aDetermined by 1H NMR analysis of the crude reaction mixture. bIsolated yield. cEt3N (1 equiv) was also added. dK3PO4 (1 equiv) was also added.
eK2CO3 (1 equiv) was also added.
support this proposal. For instance, running the reaction lower conversions (Table 2, entries 9 and 10). The reasons for
with 1 equiv of morpholine in the presence of 1 equiv of such observations are unclear at present. Nonetheless, condi-
Et3N provided the same conversion (Table 2, entry 8) while tions presented in entry 5 were chosen for evaluation of the
using inorganic bases (1 equiv of either K3PO4 or K2CO3) gave scope.
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Beilstein J. Org. Chem. 2013, 9, 2451–2456.
As shown in Table 3, reactivity is not limited to benzylic fluo- as the 4-phenyl group can be exchanged for a 4-bromo (Table 3,
ride 1 and morpholine. A range of secondary amines can be entries 5–7), 4-tert-butyl (Table 3, entries 8–10) or 3-methoxy
used, as cyclic (Table 3, entries 1, 2, 5, 6, 8 and 11), acylic group (Table 3, entry 11) with only minor impact on the conver-
(Table 3, entries 3, 4, 9 and 10) and aromatic (Table 3, entry 7) sion. Overall, conversion into the desired product was superior
N-nucleophiles all provide good isolated yields. In the case of to 90% for all entries, and only the purification step proved
N-methylaminoethanol, complete selectivity was observed for detrimental to the isolated yields. This is further demonstrated
N-benzylation (Table 3, entries 4 and 10). The reaction also by the reaction run at a greater scale which facilitated the purifi-
tolerates simple electronic variations on the benzylic fluoride, cation and resulted in a higher isolated yield (Table 3, entry 1).
Table 3: Substrate scope.
entry
1
benzyl fluoride
R1R2NH
product
yield (%)a
86 (97)b
1
1
3
7
8
2
3
79
83
1
1
4
77c
9
5
6
72
64
4
4
10
11
7
8
4
5
56
86
12
13
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Beilstein J. Org. Chem. 2013, 9, 2451–2456.
Table 3: Substrate scope. (continued)
9
5
5
76
14
10
11
86c
15
63
6
16
aIsolated yield for reaction on 0.16 mmol scale. bIsolated yield for reaction on 0.81 mmol scale. cNo product of O-benzylation could be detected by
1H NMR on the crude reaction mixture.
Reactions of secondary benzylic fluorides were unfortunately FQRNT Network for Research on Protein Function, Structure,
untractable, and primary aliphatic amines (i.e. n-butylamine) and Engineering (PROTEO) and the Université Laval.
generated a mixture of inseparable mono- and dibenzylation
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