Direct Esterification of Carboxylic Acids with Perfluorinated Alcohols Mediated by XtalFluor-E

Article abstract of DOI:10.1021/acs.orglett.6b03365

The direct esterification of carboxylic acids with perfluorinated alcohols mediated by XtalFluor-E is reported. The corresponding polyfluorinated esters are obtained in moderate to excellent yields with a broad range of carboxylic acids, including aromati

Full text of DOI:10.1021/acs.orglett.6b03365

Letter
pubs.acs.org/OrgLett
Direct Esterification of Carboxylic Acids with Perfluorinated Alcohols
Mediated by XtalFluor‑E
Mathilde Vandamme, Lea Bouchard, Audrey Gilbert, Massaba Keita, and Jean-Franco
̧
is Paquin*
́
CCVC, PROTEO, Dep
́
artement de chimie, Universite
́
Laval, 1045 avenue de la Med
́
ecine, Queb
́
ec, Queb
́
ec, Canada G1V 0A6
S
* Supporting Information
ABSTRACT: The direct esterification of carboxylic acids with perfluori-
nated alcohols mediated by XtalFluor-E is reported. The corresponding
polyfluorinated esters are obtained in moderate to excellent yields with a
broad range of carboxylic acids, including aromatic, heteroaromatic,
aliphatic, and nonracemic chiral substrates, using only a slight excess (2
equiv) of the perfluorinated alcohol. Control experiments indicate that the reaction does not proceed through the formation of
an acyl fluoride but most likely through a (diethylamino)difluoro-λ4-sulfanyl carboxylate intermediate.
erfluorination of an organic compound can profoundly
From a practical aspect, a method that would obviate this
preactivation step would be highly desirable. In that regard, the
use of a Dean−Stark apparatus (Scheme 1, eq 2)7 and synthesis
through a Fischer esterification reaction (Scheme 1, eq 3)8 have
been described occasionally. However, in the former case, the
perfluorinated alcohol is used in large excess, while in the latter,
it is used as the solvent, which limits the utility of this approach
to low-molecular-weight perfluoroalcohols. Finally, a Steglich
esterification using carbodiimide reagents has been explored
(Scheme 1, eq 4).9 Although this approach is more
straightforward, the use of carbodiimide reagents leads to the
formation of urea byproducts that are sometimes difficult to
separate from the desired product.
P
modify its physicochemical properties.1 Within the large
family of perfluorinated molecules, polyfluorinated esters with
the fluorine located on the alkoxy chain (e.g., 1 in Scheme 1)
Scheme 1. Previous Work and the Current Method
A few years ago, the research team of Cossy and our group
independently reported the synthesis of amides from carboxylic
acids mediated by (Et2NSF2)BF4 (XtalFluor-E).10−13 In this
reaction, XtalFluor-E served to activate the carboxylic acid in
situ prior to the attack by the amine. Although XtalFluor-E was
primarily developed for the deoxofluorination of alcohols, we
hypothesized that because of the low nucleophilicity of
perfluorinated alcohols,14,15 selective activation of the carbox-
ylic acid over the perfluorinated alcohol with XtalFluor-E could
be possible, thus leading to a direct synthesis of 1 (Scheme 1,
eq 5).13e Herein we report the direct esterification, mediated by
XtalFluor-E, of a broad range of carboxylic acids using only a
slight excess of various perfluorinated alcohols. Notably, and as
opposed to the use of diimide reagents, this system generates
water-soluble side products, which facilitates purification.
Selected optimization data using 5-phenylvaleric acid (2)
with 2,2,2-trifluoroethanol (TFE) are reported in Table 1. The
use of a slight excess of XtalFluor-E with Et3N (2.5 equiv) and
TFE as the solvent provided the desired ester 3 in 68% yield
(Table 1, entry 1). Product 3 was obtained in 75% yield with a
1:1 TFE/CH2Cl2 mixture (Table 1, entry 2). Further dilution
to 1:9 provided an improved yield of 88% (Table 1, entry 3).
have found applications in medicinal chemistry,2 as monomers
for the synthesis of perfluorinated polymers,3 and in organic
chemistry as substrates and/or reagents4 as well as for other
usages.5
They are generally prepared through preactivation of the
carboxylic acid (mostly as the acyl chloride, i.e., X = Cl) prior to
the reaction with the polyfluorinated alcohol (Scheme 1, eq 1).6
Received: November 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03365
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Table 1. Optimization Results for the Esterification of 5-
Phenylvaleric acid (2) with TFE Using XtalFluor-E
Scheme 2. Results for the Esterification of Various
a b
a
,
Carboxylic Acids with TFE Using XtalFluor-E
b
entry
y
solvent
yield (%)
1
2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0
TFE
68
75
88
80
60
74
58
TFE/CH2Cl2 (1:1)
TFE/CH2Cl2 (1:9)
TFE/THF (1:9)
3
4
5
TFE/toluene (1:9)
TFE/EtOAc (1:9)
6
7
TFE/CH3CN (1:9)
TFE/CH2Cl2 (1:9)
TFE/CH2Cl2 (1:9)
TFE/CH2Cl2 (1:9)
TFE (2 equiv) in CH2Cl2
TFE (1.2 equiv) in CH2Cl2
c
8
60
9
1
89
90
84
55
10
11
12
1.5
1.5
1.5
a
See the Supporting Information for the detailed experimental
b
procedures. The optimized conditions are shown in bold. Isolated
yields. Estimated by NMR analysis of the crude reaction mixture.
c
Using other cosolvents (THF, toluene, EtOAc, and CH3CN)
instead of CH2Cl2 provided lower yields (58−80%) (Table 1,
entries 4−7). Running the reaction in the absence of Et3N
provided a considerably lower yield as estimated by NMR
analysis of the crude reaction mixture (Table 1, entry 8), but
1.5 equiv seemed to be the optimal amount (Table 1, entries 9
and 10). Finally, the amount of TFE could be reduced to 2
equiv without a major effect on the outcome (Table 1, entry
11), although further reducing it to 1.2 equiv resulted in a lower
yield (Table 1, entry 12). The conditions shown in Table 1,
entry 11 were chosen as the optimized ones.
With those conditions in hand, the esterification of other
carboxylic acids was investigated, and the results are shown in
Scheme 2. Various aromatic carboxylic acids provided the
desired esters 4−8 in moderate to excellent yields. The reaction
could also be performed on a gram scale, as illustrated by the
esterification of 1.00 g of 4-nitrobenzoic acid in 97% yield.
Interestingly, the TFE esters of all regioisomers of picolinic acid
(9−11) could be obtained in good yields (71−75%). A β-keto
carboxylic acid such as phenylglyoxylic acid reacted well,
providing ester 12 in 74% yield. Aliphatic carboxylic acids could
also be used as substrates for this transformation, as illustrated
by the use of derivatives of phenylacetic acid and isonipecotic
acid. In the latter case, a Cbz protecting group is preferred over
a benzyl group, probably because of the reduced basicity of the
nitrogen. Phthalic acid and a benzylmalonic acid could both be
bisesterified to provide 17 and 18, respectively, in good yields
when the stoichiometry of the reagents was adjusted
accordingly. The reaction could be extended to nonracemic
chiral carboxylic acids. For instance, Cbz-protected L-phenyl-
alanine could be esterified with TFE to provide ester 19 in 85%
yield. Likewise, the reactions of O-benzyl-(S)-lactic acid and O-
methyl-(R)-mandelic acid provided esters 20 and 21,
respectively, in good yields. In all cases, chiral HPLC analyses
showed no loss of enantiopurity.
a
See the Supporting Information for the detailed experimental
b
c
procedures. Isolated yields are shown. The reaction was performed
on a 5.98 mmol scale (i.e., 1.00 g of the acid). TFE (4.0 equiv),
XtalFluor-E (2.2 equiv), and Et3N (3 equiv) were used instead.
d
2-propanol (HFIP, 22), 2,2,3,3,3-pentafluoro-1-propanol
(PFPOH, 23), 2,2,3,3,4,4,4-heptafluoro-1-butanol (24),
2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-1-octanol (25), and
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-1-nonanol (26)
were used. A wide range of carboxylic acids could be esterified
(or bisesterified in the case of phthalic acid) to provide the
corresponding esters 27−46 in moderate to excellent yields
(45−96%).
To gain insight into the reaction mechanism, a series of
control experiments were run. First, we reacted 25 with
XtalFluor-E, omitting the carboxylic acid and Et3N (Scheme 4,
eq 1). A moderate conversion of 66% was obtained, and NMR
analysis of the crude reaction mixture revealed the formation of
To further extend the utility of this transformation,
esterification with other perfluorinated alcohols was explored,
as shown in Scheme 3. For that purpose, 1,1,1,3,3,3-hexafluoro-
B
DOI: 10.1021/acs.orglett.6b03365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Selected Results for the Esterification of Various Carboxylic Acids with Perfluorinated Alcohols Using XtalFluor-E
a
b
c
See the Supporting Information for the detailed experimental procedures. Isolated yields are shown. 23 or 25 (4.0 equiv), XtalFluor-E (2.2 equiv),
and Et3N (3 equiv) were used instead.
reaction of perfluorinated alcohols with XtalFluor-E likely
originates from their impaired nucleophilicity due to the
powerful inductive effect of the adjacent fluorine atoms.14 Next,
in two separate experiments, we investigated whether the
reaction proceeds through an acyl fluoride, as it has been shown
that XtalFluor-E is able to convert a carboxylic acid to an acyl
fluoride, albeit slowly in the absence of an external source of
fluoride.10b To this end, 4-nitrobenzoic acid (48)17 was
subjected to the reaction conditions without any perfluorinated
alcohol. After 16 h, a low conversion of ca. 40% to the
corresponding acyl fluoride 49 was determined by NMR
analysis (Scheme 4, eq 2). In addition to this slow formation of
the acyl fluoride, which is not compatible with the time
required for the completion of the esterification reaction, no
transformation was observed when independently synthesized
acyl fluoride 49 was allowed to react with perfluorinated alcohol
25 (Scheme 4, eq 3). On the basis of those two observations,
we discarded the acyl fluoride pathway. Hence, our current
working hypothesis is the following: First, deprotonation of the
carboxylic acid by Et3N would lead to the more nucleophilic
carboxylate.11 Reaction of the latter with XtalFluor-E would
generate (diethylamino)difluoro-λ4-sulfanyl carboxylate 50.5,6
Under the reaction conditions, the formation of the acyl
fluoride would be slower than the reaction of 50 with the
perfluorinated alcohol, which would generate the desired
perfluorinated ester in addition to diethylaminosulfinyl
fluoride.18
Scheme 4. Control Experiments and Mechanistic
Hypothesis
a
In summary, we have reported the use of XtalFluor-E as an
effective promoter for the direct esterification of carboxylic
acids using perfluorinated alcohols. The corresponding
polyfluorinated esters are obtained in moderate to excellent
yields with a broad range of carboxylic acids, including
aromatic, heteroaromatic, aliphatic, and nonracemic chiral
substrates, using only a slight excess (2 equiv) of the
perfluorinated alcohol. Control experiments indicated that the
reaction does not proceed through the formation of an acyl
a
See the Supporting Information for the detailed experimental
b
procedures. The counterions have been omitted for clarity.
sulfinate 47 (20%) along with some unidentified XtalFluor-E-
related products.10b The fluoride16 corresponding to 25 was not
observed. For comparison, complete conversion in less than 5
min was reported with hydrocinnamyl alcohol.10b The slower
C
DOI: 10.1021/acs.orglett.6b03365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
fluoride but most likely through a (diethylamino)difluoro-λ4-
sulfanyl carboxylate intermediate.
(8) For example, see refs 2a,e, 4f, and 5b.
(9) For example, see ref 4d,e.
(10) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier,
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(b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.;
Laflamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03365.
́
J. Org. Chem. 2010, 75, 3401−3411. (c) Mahe, O.; L’Heureux, A.;
Couturier, M.; Bennett, C.; Clayton, S.; Tovell, D.; Beaulieu, F.;
Paquin, J.-F. J. Fluorine Chem. 2013, 153, 57−60.
(11) Orliac, A.; Gomez Pardo, D.; Bombrun, A.; Cossy, J. Org. Lett.
2013, 15, 902−905.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
́
(12) Mahe, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013,
2013, 4325−4331.
(13) For other contributions from our group using XtalFluor-E, see:
(a) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.; Paquin, J.-F. Org. Biomol.
Chem. 2012, 10, 988−993. (b) Pouliot, M.-F.; Angers, L.; Hamel, J.-D.;
Paquin, J.-F. Tetrahedron Lett. 2012, 53, 4121−4123. (c) Pouliot, M.-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-francois.paquin@chm.ulaval.ca.
ORCID
F.; Mahe,
́
O.; Hamel, J.-D.; Desroches, J.; Paquin, J.-F. Org. Lett. 2012,
O.; Paquin, J.-F.
14, 5428−5431. (d) Keita, M.; Vandamme, M.; Mahe,
́
Jean-Franco̧ is Paquin: 0000-0003-2412-3083
Notes
Tetrahedron Lett. 2015, 56, 461−464. (e) Desroches, J.; Champagne,
P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243−
2246. (f) Keita, M.; Vandamme, M.; Paquin, J.-F. Synthesis 2015, 47,
3758−3766.
The authors declare no competing financial interest.
(14) Beg
29.
́ ́
ue, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18−
ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, the Fonds de
■
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DOI: 10.1021/acs.orglett.6b03365
Org. Lett. XXXX, XXX, XXX−XXX