Activation of hydrocinnamic acids with pentafluorophenol versus pentafluorothiophenol: Reactivity towards hexylamine

Article abstract of DOI:10.1016/j.jfluchem.2008.09.013

In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids, namely hexylamide of hydrocinnamic, 3,4-dimethoxyhydrocinnamic, 4-hydroxy-3-methoxyhydrocinnamic and 3,4-dihydroxyhydrocinnamic acids via pentafluorophenyl

Full text of DOI:10.1016/j.jfluchem.2008.09.013

Journal of Fluorine Chemistry 130 (2009) 169–174
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Activation of hydrocinnamic acids with pentafluorophenol versus
pentafluorothiophenol: Reactivity towards hexylamine
b
c
c
c
Fernanda M.F. Roleira a, , Fernanda Borges , Lourdes C.R. Andrade , Jose A. Paixao , Maria J.M. Almeida ,
˜
*
´
´
d
a
Rui A. Carvalho , Elisiario J. Tavares da Silva
a CEF, Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Coimbra University, 3000-295 Coimbra, Portugal
b UQFM, Laboratory of Organic Chemistry, Faculty of Pharmacy, Porto University, 4050-047 Porto, Portugal
c CEMDRX, Department of Physics, Faculty of Sciences and Technology, Coimbra University, 3004-516 Coimbra, Portugal
d CNC, Department of Biochemistry, Faculty of Sciences and Technology, Coimbra University, 3004-516 Coimbra, Portugal
A R T I C L E I N F O
A B S T R A C T
Article history:
In this work we describe and compare the synthesis of four new hexylamides of hydrocinnamic acids,
namely hexylamide of hydrocinnamic, 3,4-dimethoxyhydrocinnamic, 4-hydroxy-3-methoxyhydrocin-
namic and 3,4-dihydroxyhydrocinnamic acids via pentafluorophenyl esters (PFPEs) versus pentafluor-
ophenyl thioesters (PFPTs) intermediates. It was found that the PFPE are the best intermediates for this
kind of synthesis giving reactions with less by products, easier work-up, higher overall yields and with
the best reactivity towards hexylamine. The X-ray structures of two PFPE are also reported.
ß 2008 Elsevier B.V. All rights reserved.
Received 6 June 2008
Received in revised form 23 September 2008
Accepted 24 September 2008
Available online 7 October 2008
Keywords:
Hydrocinnamic acids
Pentafluorophenyl esters
Pentafluorophenyl thioesters
Hexylamides
Phenols
X-ray structures
1. Introduction
One way to perform amidation reactions is via carboxylic group
activated intermediates, particularly active esters [2]. A commonly
Oxidative stress has been implicated in the pathophysiology of
neurodegenerative diseases [1]. Since our endogenous antioxidant
defenses are not always completely effective it seems reasonable
to propose that exogenous antioxidants could be very effective in
diminishing the cumulative effects of oxidative damage. However,
the therapeutic use of most of the antioxidants investigated as
therapeutic agents is limited since they do not cross the blood–
brain barrier (BBB). Therefore, novel antioxidant molecules
designed for potential neuroprotective treatment should have a
high degree of lipophilicity in order to penetrate the BBB [1]. In this
context we have designed and synthesised new lipophylic
antioxidants, based on compounds with well-known antioxidant
properties, by introducing an alkyl chain in hydrocinnamic acids
via an amide bond. For this, several hexylamides have been
prepared by different ways.
used active ester is the pentafluorophenyl ester (PFPE) [3–8],
which is usually prepared from the reaction of a carboxylic acid
with pentafluorophenol using a diimide, such as dicyclohexylcar-
bodiimide (DCC), as a coupling agent [3,4,7]. A valuable application
of PFPE is in the peptide synthesis [3–5,9–12]. These active esters
are relatively non-polar, stable to chromatographic purification
and extended storage [4,9]. More recently, pentafluorophenyl
thioesters (PFPT) were also shown to be good intermediates for the
conversion of hindered acids in amides proving to be very good N-
acylating agents in particular situations [13]. Nevertheless, very
few papers describing the use of PFPT as intermediates for the
synthesis of amides have been found in the literature [14,15].
In this work the above-mentioned methods have been explored
throughout the study of carboxylic acid activation of several
hydrocinnamic acids with pentafluorophenol (PFP) versus penta-
fluorothiophenol (PFTP). Accordingly, the reactivity of the activa-
tors towards a series of hydrocinnamic acids has been pointed out
as well as the reactivity of the active esters towards hexylamine in
order to produce the respective hexylamides.
* Corresponding author. Tel.: +351 239 859 992; fax: +351 239 827 126.
E-mail address: froleira@ff.uc.pt (Fernanda M.F. Roleira).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.09.013

170
F.M.F. Roleira et al. / Journal of Fluorine Chemistry 130 (2009) 169–174
Scheme 1. Synthesis of PFPE 5–8 and PFPT 9–12.
Scheme 2. Synthesis of hexylamides 13–16.
2. Results and discussion
was the expected result considering the existence of an incomplete
reaction when using PFTP as pointed out in the previous
discussion. Besides, the usual purification by column chromato-
graphy was insufficient to obtain the pure PFPT (9–12). Therefore,
further purification by crystallisation was performed which lead to
a dramatic decrease of the yield due to product degradation during
this process. Compound 12 could not be further purified by
crystallisation because it is oil and attempts to make a second
chromatography result in complete degradation of the product.
That is why the amount of product obtained after column
chromatography is reported (Table 1).
It was also noted that the yields of PFPE and PFPT are higher as
the number of hydroxyl groups in the aromatic ring is lower
reaching the best yields for compounds 6 and 10, the dimethoxy
substituted PFPE and PFPT, respectively (Table 1). The absence of
substituents as in the case of compounds 5 and 9 diminished the
yield relatively to compounds 6 and 10, respectively, showing
some benefit with the presence of activating electron donor groups
in the aromatic ring, for this kind of reactions. The hydroxyl groups
being activating groups are very reactive substituents giving rise to
reactions with more side products, whish appears reflected in the
lower yields obtained for compounds 7, 11 and 8, 12.
The synthesis of hexylamides (13–16) begins with the known
hydrocinnamic acids (1–4) which are converted into the corre-
sponding PFPE (5–8) and PFPT (9–12) by reaction with PFP or PFTP,
respectively, and DCC, in dioxane, at room temperature (Scheme 1)
[16]. Subsequent reaction of the active esters (5–8) and thioesters
(9–12) with hexylamine, in chloroform, at room temperature
provided the required hexylamides (13–16) (Scheme 2) [17].
Looking at Table 1, one can see that activation of hydrocinnamic
acids with PFP occurs almost with the same reaction time as
activation with PFTP. However, with PFP, the described reaction
time corresponds to complete reactions whereas with PFTP
corresponds to incomplete reactions. In fact, when using PFTP, it
was possible to observe by TLC that after 1.5 h of activation for
compound 1 and after 4 h of activation for compounds 2, 3 and 4,
no more PFTP remained in reaction, in spite of had been used in
excess. On the contrary, a lot of hydrocinnamic acid remained in
reaction. This can be explained by the observation that after 1.5 or
4 h, respectively, the most part of the PFTP had been transformed in
another product, which is visible on a TLC plate, and therefore the
activation reaction cannot proceed anylonger. This product could
result from PFTP decomposition (Supporting information).
Compounds 5 [18], 8 [17], and 9 [19], had been previously
synthesised, being 5 and 9 obtained by a different way.
Compounds 5–12 were fully characterised by physical and
spectroscopic data. Particularly 19F NMR pointed out the presence
Concerning the yields of the activation reactions using PFP
versus PFTP (Table 1) it is clear that PFP produces better yields than
PFTP, when compared on the basis of pure reaction products. This
Table 1
Reaction (Rx)–time and yield of reactions of hydrocinnamic acids (1–4) with PFP versus PFTP.
Acids
Rx–time (h)
Yield (%)a
Product
Rx–time (h)b
Yield (%)c,d
Product
1
2
3
4
0.5
4
78
87
61
42
5
6
7
8
1.5
4
79/17
95/29
74/15
37/e
9
10
11
12
4
4
4
4
a
Yield after column chromatography (one TLC spot).
Incomplete reactions.
b
c
Amount of product after column chromatography (not pure/TLC).
Yield after column chromatography and crystallisation (one TLC spot).
Not possible to purify due to product instability.
d
e

F.M.F. Roleira et al. / Journal of Fluorine Chemistry 130 (2009) 169–174
171
Fig. 1. ORTEP structure for PFPE 6.
Fig. 2. ORTEP structure for PFPE 7.
of five aromatic fluorine atoms in these compounds. In fact, the
13C NMR signals of the carbon atoms in the pentafluorophenyl
ring bearing the fluorine atoms are not easy to acquire, even by
increasing the number of scans, using higher sample amounts or
using a powerful 500 MHz NMR spectrometer. However, we
include in Supporting information a representative 13C NMR
spectrum of compound 9 acquired along several hours in an
almost saturated solution of CDCl3 and using a 500 MHz NMR
spectrometer. The complex splitting patterns due to the strong
coupling between carbon and fluorine atoms significantly
lowers the intensity of the 13C NMR signals of the fluorinated
carbons. In order to avoid this drawback, we investigate a 13C
double resonance fluorine decoupling technique applied to the
appears to be also a suitable technique to easily and rapidly
acquire the 13C signals of these carbon atoms that can be seen
now as intense singlet peaks. Nevertheless, 19F NMR still seems
to be the right option to elucidate the structure of the penta-
fluorophenyl ring.
Compounds 6 and 7 were further studied by X-ray crystal-
lography [20] (Figs. 1 and 2). Selected metric parameters are listed
in Tables 2 and 3. Apart from the aromatic ring substituents, both
molecules are very similar. The 3-methoxy group, common to
compounds 6 and 7, is located in different stereo positions, being
towards the right of the molecule on 6 and towards the left on 7.
This is a consequence of the stereo position of the hydroxyl group
of 7 leading to an intramolecular O4–H44–O3 hydrogen bond with
˚
representative compound
9
(Supporting information). This
an O4–O3 distance of 2.601(3) A and an angle of 115.798. In both
Table 2
Table 3
Selected bond lengths and bond angles for 6.
Selected bond lengths and bond angles for 7.
˚
˚
Bond
Bond length (A)
Angle
Bond angle (8)
Bond
Bond length (A)
Angle
Bond angle (8)
C1–C2
1.482 (4)
1.515 (4)
1.508 (4)
1.399 (4)
1.380 (5)
1.378 (4)
1.375 (5)
1.383 (6)
1.365 (5)
1.347 (4)
1.385 (4)
1.186 (4)
1.370 (4)
1.375 (4)
1.418 (5)
C4–C3–C2
113.4 (3)
121.4 (3)
120.5 (4)
119.1 (3)
117.8 (3)
117.4 (3)
115.6 (3)
110.8 (3)
121.0 (3)
119.8 (3)
128.1 (3)
121.1 (3)
124.8 (3)
124.8 (3)
119.8 (3)
C1–C2
1.486 (3)
1.507 (3)
1.511 (3)
1.386 (3)
1.384 (3)
1.385 (4)
1.370 (3)
1.366 (3)
1.366 (4)
1.337 (3)
1.378 (3)
1.177 (3)
1.368 (3)
1.375 (3)
1.409 (3)
C4–C3–C2
112.3 (2)
119.9 (2)
120.8 (2)
118.7 (2)
120.9 (2)
118.5 (2)
117.1 (2)
109.8 (2)
120.1 (2)
121.1 (2)
129.0 (2)
121.3 (2)
126.3 (2)
113.4 (2)
119.0 (2)
C2–C3
C5–C4–C3
C2–C3
C5–C4–C3
C3–C4
C10–C11–C12
C11–C10–C15
C7–O3–C16
C8–O4–C17
C10–O1–C1
O1–C1–C2
C3–C4
C10–C11–C12
C11–C10–C15
C7–C8–O4
C4–C9
C4–C9
C6–C7
C6–C7
C8–C9
C8–C9
C6–O3–C16
C10–O1–C1
O1–C1–C2
C10–C11
C10–C15
C14–C15
C13–F3
C1–O1
C1–O2
C8–O4
C10–O1
C17–O4
C10–C11
C10–C15
C14–C15
C13–F3
C1–O1
C1–O2
C6–O3
C10–O1
C16–O3
O1–C10–C11
O1–C10–C15
O2–C1–C2
O1–C10–C11
O1–C10–C15
O2–C1–C2
O2–C1–O1
O3–C7–C6
O2–C1–O1
O3–C6–C5
O4–C8–C9
O3–C6–C7
F1–C11–C10
F1–C11–C10

172
F.M.F. Roleira et al. / Journal of Fluorine Chemistry 130 (2009) 169–174
Table 4
Reaction (Rx)–time and yield of reactions of PFPE and PFPT with hexylamine and overall yield of amides (13–16) from hydrocinnamic acids (1–4).
Amides
PFPE (5–8)
PFPT (9–12)
Rx–time (min)
Yield (%)
Overall yield (calcd %)
Rx–time (min)
Yield (%)
Overall yield (calcd %)
13
14
15
16
15
30
15
15
69
75
99
90
54
65
60
38
10
15
10
10
59
56
68
74a
10
16
10
b
–
a
Decreased yield due to the impure starting material 12.
b
Not calculated due to absence of the partial yield of the previous reaction.
structures, the bond distances C1–O1 and C10–O1 (Figs. 1 and 2;
Tables 2 and 3) are significantly different from the expected values
[21], the first one being higher and the last one smaller, a fact also
noticed in a similar pentafluorophenyl ester structure, previously
reported by our group [22].
a Bruker-AMX 300 spectrometer. Chemical shifts were recorded in
values (ppm) downfield from TMS as internal standard for 1H and
d
13C and upfield from CFCl3 as internal standard for 19F NMR. The
HRMS analyses were made on a QTof instrument from Applied
Biosystems using the electrospray technique. X-ray diffraction
analysis of 6 and 7 was measured using a MACH-3 Nonius
diffractometer.
Considering now the preparation of the hexylamides 13–16
from PFPE versus PFPT (Table 4) it was possible to observe very
short reaction times being even shorter from PFPT. Nevertheless,
the yields are again 10–30% more favourable to PFPE. In this case,
the yields increased from 13, the amide with no substituents in the
aromatic ring, to 16, the amide with two hydroxyls in the aromatic
ring, reaching 99% with the 4-hydroxy-3-methoxy substituted
compound 15. Once more, the presence of activating electron
donor groups in the aromatic ring of active esters and thioesters is
favourable to the amidation reaction. The short reaction time of
these amidation reactions could prevent now the existence of
undesirable side reactions involving the hydroxyl groups.
Concerning overall yields of amides from hydrocinnamic acids
(Table 4) one can see the existence of the same pattern of yields
observed in the preparation of PFPE and PFPT, that is an higher
yield for the dimethoxy substituted compound 14 and a smaller
yield for compounds with hydroxyl substituents, as 15 and 16. This
is due to the contribution of the partial yields of the activation
reactions to the overall yields.
Chemicals were purchased from Sigma, Aldrich and Fluka and
used as supplied by the manufacturers. Solvents were dried, when
referred, according described procedures.
Activation reaction of hydrocinnamic acids were also per-
formed in other experimental conditions particularly in which
concern temperature (beginning the reaction at 0 8C) and the use of
an inert atmosphere (N2), but with similar results.
4.1. General procedure to obtain the PFPE (5–8) and PFPT (9–12)
A mixture of the hydrocinnamic acid (3.5 mmol), DCC (849 mg,
4 mmol), and pentafluorophenol or pentafluorothiophenol
(743 mg, 4 mmol or 0.6 ml, 4.4 mmol, respectively), in anhydrous
dioxane (15 ml) was stirred at room temperature during 4 h
(unless specified). After this time, the mixture was cooled to 0 8C,
and dicyclohexylurea was separated and removed by filtration. The
filtrate was taken to dryness and the residue was subjected to flash
column chromatography (silica gel 60 – particle size: 0.040–
0.063 mm) to provide the PFPE as solids and the PFPT as solids or, in
case of 12, as oil.
Compounds 13–16 were also fully characterised by physical
and spectroscopic data. HRMS data have been obtained to support
the molecular structure assignment.
Detailed results concerning antioxidant profiles of the prepared
lipophilic amides will be reported elsewhere.
4.2. Pentafluorophenyl 3-phenylpropanoate (5)
Reaction time: 0.5 h; chromatography solvent: petroleum ether
3. Conclusion
(PE)/Et2O 9:1. Yield 855 mg, 78%: mp 31–32 8C; IR (ATR):
(C O), 1514, 1454, 984 cmÀ1 1H NMR (300 MHz, Me2SO-d6):
7.32–7.30 (m, 5H, Ar-H), 3.15 (t, J = 7.0 Hz, 2H, CH2), 3.01 (t,
J = 7.0 Hz, 2H, CH2); 13C NMR (75.4 MHz, Me2SO-d6):
168.9, 139.5,
128.4 (2C), 128.2 (2C), 126.3, 33.9, 29.8; 19F NMR (282.4 MHz,
Me2SO-d6):
n 1778
;
d
In summary, four new amides have been synthesised using
active esters (PFPE and PFPT) as well as eight intermediate esters
and thioesteres (5–12). It was possible unequivocally conclude
that PFPE are the best intermediates for the kind of synthesis and
the kind of compounds studied because they gave rise to reactions
with less by products, easier work-up, and higher overall yields. In
addition, they disclose the best reactivity towards the nucleophilic
hexylamine. They are also more stable than PFPT, particularly
when phenol groups are present. The existence of activating
electron donor groups in the aromatic ring of PFPE and PFPT seems
to be favourable to the amidation reaction. In addition, two new
PFPE have been studied by X-ray crystallography.
d
d
-176.8 (d, J = 25 Hz, 2F), À181.5 (t, J = 23 Hz, 1F),
À186.0 to À186.2 (m, 2F).
4.3. Pentafluorophenyl 3-(3,4-dimethoxyphenyl)propanoate (6)
Chromatography solvent: PE/CHCl3 7:3. Yield 1.14 g, 87%:
mp 72–73 8C; IR (ATR):
1H NMR (300 MHz, Me2SO-d6):
3.74 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.09 (t, J = 7.0 Hz, 2H, CH2),
2.92 (t, J = 7.0 Hz, 2H, CH2); 13C NMR (75.4 MHz, Me2SO-d6):
168.9, 148.6, 147.3, 131.9, 120.0, 112.1, 111.7, 55.4, 55.3, 34.2,
29.5; 19F NMR (282.4 MHz, Me2SO-d6):
n
1791 (C O), 1512, 1463, 986 cmÀ1
6.92–6.80 (m, 3H, Ar-H),
;
d
d
4. Experimental
Mps were determined on a Reichert Thermopan hot block
apparatus and were not corrected. IR spectra were recorded on a
Jasco 420FT-IR spectrometer. The 1H NMR, 13C NMR and 19F NMR
spectra were recorded at 300, 75.6 and 282.4 MHz, respectively, on
d
À176.9 (dd, J = 23 Hz,
J = 3 Hz, 2F), À181.5 (t, J = 24 Hz, 1F), À186.0 to À186.2 (m, 2F);
HRMS: m/z [M+Na]+ calcd for C17H13F5O4: 399.0626; found:
399.0632.

F.M.F. Roleira et al. / Journal of Fluorine Chemistry 130 (2009) 169–174
173
4.4. Pentafluorophenyl 3-(4-hydroxy-3-methoxyphenyl)propanoate
(7)
4.9. S-Pentafluorophenyl 3-(3,4-dihydroxyphenyl)propanethioate
(12)
Chromatography solvent: PE/Et2O 7:3. Yield 763 mg, 61%: mp
96–97 8C; IR (ATR): 3522 (O–H), 1793 (C O), 1517, 1455,
986 cmÀ1 1H NMR (300 MHz, Me2SO-d6):
8.78 (br s, 1H, OH),
6.88–6.68 (m, 3H, Ar-H), 3.75 (s, 3H, OCH3), 3.09 (t, J = 7.4 Hz,
2H, CH2), 2.89 (t, J = 7.4 Hz, 2H, CH2); 13C NMR (75.4 MHz,
Chromatography solvent: PE/Et2O 5:5. Amount of product
obtained: 466 mg, 37%, as oil. IR (NaCl plates): 3427 (O–H), 1719
(C O), 1639, 1514, 1455, 963 cmÀ1 1H NMR (300 MHz, Me2SO-
d6): 8.74 (s, 1H, OH), 8.71 (s, 1H, OH), 6.61–6.42 (m, 3H, Ar-H),
2.98 (t, J = 7.3 Hz, 2H, CH2), 2.65 (t, J = 7.3 Hz, 2H, CH2); 19F NMR
(282.4 MHz, Me2SO-d6):
n
n
;
d
;
d
Me2SO-d6):
d
169.0, 147.4, 144.9, 130.2, 120.3, 115.3, 112.4,
d
À156.1 to À156.2 (m, 2F), À171.5 (t,
55.4, 34.4, 29.6; 19F NMR (282.4 MHz, Me2SO-d6):
d
À176.9 (dd,
J = 23 Hz, 1F), À183.6 to À183.7 (m, 2F).
J = 23 Hz, J = 3 Hz, 2F), À181.6 (t, J = 24 Hz, 1F), À186.1 to À186.2
(m, 2F); HRMS: m/z [M+Na]+ calcd for C16H11F5O4: 385.0469;
found: 385.0471.
Note: Due to the instability of compound 12 it was not possible
to obtain satisfactory 13C NMR spectra.
4.10. General procedure to obtain the hexylamides (13–16)
4.5. Pentafluorophenyl 3-(3,4-dihydroxyphenyl)propanoate (8)
from PFPE or PFPT
Chromatography solvent: PE/Et2O 6:4. Yield 502 mg, 42%: mp
A solution of PFPE or PFPT (0.35 mmol), hexylamine (0.1 ml;
0.75 mmol) in CHCl3 (2 ml) was stirred at room temperature for
15 min (unless specified). After this time, the mixture was cooled
and the ammonium salt formed was separated by filtration. The
filtrate was taken to dryness and the residue was subjected to flash
column chromatography (silica gel 60 – particle size: 0.040–
0.063 mm) to provide the hexylamides as white solids or, in one
case, as oil.
74–75 8C; IR (ATR):
985 cmÀ1 1H NMR (300 MHz, Me2SO-d6):
(s, 1H, OH), 6.66–6.50 (m, 3H, Ar-H), 3.02 (t, J = 7.3 Hz, 2H, CH2),
2.82 (t, J = 7.3 Hz, 2H, CH2); 13C NMR (75.4 MHz, Me2SO-d6):
168.9, 145.1, 143.7, 130.3, 118.8, 115.7, 115.4, 34.5, 29.4; 19F NMR
(282.4 MHz, Me2SO-d6):
n
3466 (O–H), 1759 (C O), 1517, 1450,
;
d
8.77 (s, 1H, OH), 8.75
d
d
À176.7 (dd, J = 25 Hz, J = 3 Hz, 2F),
À181.6 (t, J = 23 Hz, 1F), À186.1 to À186.3 (m, 2F).
4.6. S-Pentafluorophenyl 3-phenylpropanethioate (9)
4.11. N-Hexyl-3-phenylpropanamide (13)
Reaction time: 1.5 h; chromatography solvent: PE. Amount of
product obtained: 913 mg, 79%; further purification by crystal-
lisation (n-hexane) gave 197 mg, 17% of yield: mp 67–68 8C; IR
From PFPE: chromatography solvent: CHCl3/EtOAc 9:1; yield:
56 mg, 69%.
From PFPT: chromatography solvent: CHCl3/EtOAc 9:1; yield:
48 mg, 59%.
(ATR):
(300 MHz, Me2SO-d6):
2H, CH2), 2.94 (t, J = 7.4 Hz, 2H, CH2); 13C NMR (75.4 MHz, Me2SO-
d6):
173.7, 140.8, 128.3 (2C), 128.2 (2C), 125.9, 35.2, 30.0; 19F
NMR (282.4 MHz, Me2SO-d6):
n
1728 (C O), 1642, 1510, 1484, 963 cmÀ1
;
1H NMR
d
7.30–7.18 (m, 5H, Ar-H), 3.23 (t, J = 7.4 Hz,
Mp 29–30 8C; IR (ATR):
n
3316 (N–H stretch), 1635 (C O), 1539
7.78 (t,
(N–H bend) cmÀ1 1H NMR (300 MHz, Me2SO-d6):
;
d
d
J = 5.1 Hz, 1H, NH) 7.29–7.14 (m, 5H, Ar-H) 3.04–2.97 (m, 2H,
NHCH2) 2.80 (t, J = 7.7 Hz, 2H, CH2) 2.34 (t, J = 7.7 Hz, 2H, CH2)
1.35–1.20 (m, 8H, 4CH2) 0.86 (t, J = 6.7 Hz, 3H, CH3); 13C NMR
d
À156.1 to À156.2 (m, 2F), À171.6
(t, J = 23 Hz, 1F), À183.5 to À183.7 (m, 2F).
(75.47 MHz, Me2SO-d6):
37.0, 31.1, 31.0, 29.1, 26.0, 22.0, 13.9; HRMS: m/z [M+H]+ calcd for
15H23NO: 234.1857; found: 234.1859.
d 171.0, 141.3, 128.2 (4C), 125.8, 38.4,
4.7. S-Pentafluorophenyl 3-(3,4-dimethoxyphenyl)propanethioate
(10)
C
Chromatography solvent: PE/CHCl3 6:4. Amount of product
obtained: 1.26 g, 92%; further purification by crystallisation (Et2O)
4.12. N-Hexyl-3-(3,4-dimethoxyphenyl)propanamide (14)
gave 397 mg, 29% of yield: mp 68–69 8C; IR (ATR):
n
1728 (C O),
From PFPE: chromatography solvent: CHCl3/EtOAc 7:3; yield:
77 mg, 75%.
1641, 1510, 1484, 963 cmÀ1 1H NMR (300 MHz, Me2SO-d6):
;
d
6.89–6.74 (m, 3H, Ar-H), 3.74 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.21
(t, J = 7.4 Hz, 2H, CH2), 2.88 (t, J = 7.4 Hz, 2H, CH2); 13C NMR
From PFPT: chromatography solvent: CHCl3/EtOAc 7:3; yield:
57 mg, 56%.
(75.4 MHz, Me2SO-d6):
d
173.9, 148.5, 147.0, 133.3, 119.9, 112.1,
Mp 58–59 8C; IR (ATR):
n
3298 (N–H stretch), 1636 (C O), 1547
7.76 (t,
111.7, 55.4, 55.3, 35.5, 30.0; 19F NMR (282.4 MHz, Me2SO-d6):
d
(N–H bend) cmÀ1 1H NMR (300 MHz, Me2SO-d6):
;
d
À156.1 to À156.2 (m, 2F), À171.6 (t, J = 23 Hz, 1F), À183.5 to
À183.8 (m, 2F); HRMS: m/z [M+Na]+ calcd for C17H13F5O3S:
415.0397; found: 415.0408.
J = 5.2 Hz, 1H, NH), 6.83–6.79 (m, 2H, Ar-H), 6.68 (dd, J = 8.1 Hz,
J = 1.6 Hz, 1H, Ar-H), 3.72 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.03–
2.97 (m, 2H, NHCH2), 2.73 (t, J = 7.6 Hz, 2H, CH2), 2.32 (t, J = 7.6 Hz,
2H, CH2), 1.35–1.21 (m, 8H, 4CH2), 0.85 (t, J = 6.6 Hz, 3H, CH3); 13
C
4.8. S-Pentafluorophenyl 3-(4-hydroxy-3-methoxyphenyl)
NMR (75.47 MHz, Me2SO-d6): d 171.1, 148.5, 146.9, 133.8, 119.9,
propanethioate (11)
112.1, 111.7, 55.4, 55.3, 38.4, 37.3, 31.0, 30.7, 29.1, 26.0, 22.0, 13.9;
HRMS: m/z [M+H]+ calcd for C17H27NO3: 294.2069; found:
294.2068.
Chromatography solvent: PE/Et2O 7:3. Amount of product
obtained: 974 mg, 74%; further purification by crystallisation
(Et2O) gave 197 mg, 15% of yield: mp 82–83 8C; IR (ATR):
(O–H), 1723 (C O), 1643, 1517, 1455, 959 cmÀ1 1H NMR
(300 MHz, Me2SO-d6): 8.78 (s, 1H, OH), 6.84–6.61 (m, 3H, Ar-
H), 3.75 (s, 3H, OCH3), 3.18 (t, J = 7.4 Hz, 2H, CH2), 2.85 (t, J = 7.4 Hz,
2H, CH2); 13C NMR (75.4 MHz, Me2SO-d6):
173.9, 147.3, 144.6,
131.6, 120.2, 115.2, 112.4, 55.5, 35.7, 30.0; 19F NMR (282.4 MHz,
Me2SO-d6):
À156.1 to À156.2 (m, 2F), À171.6 (t, J = 23 Hz, 1F),
À183.5 to À183.7 (m, 2F).
n
3485
4.13. N-Hexyl-3-(4-hydroxy-3-methoxyphenyl)propanamide (15)
;
d
From PFPE: chromatography solvent: CHCl3/EtOAc 6:4; yield:
97 mg, 99%.
From PFPT: chromatography solvent: CHCl3/EtOAc 6:4; yield:
66 mg, 68%.
d
d
Mp 81–82 8C; IR (ATR):
n
3514 (O–H), 3295 (N–H stretch), 1635
1H NMR (300 MHz, Me2SO-d6):
(C O), 1545 (N–H bend) cmÀ1
;
d

174
F.M.F. Roleira et al. / Journal of Fluorine Chemistry 130 (2009) 169–174
8.68 (s, 1H, OH), 7.75 (t, J = 5.4 Hz, 1H, NH), 6.74 (d, J = 1.7 Hz, 1H,
Ar-H), 6.64 (d, J = 7.9 Hz, 1H, Ar-H), 6.56 (dd, J = 8.0 Hz, J = 1.8 Hz,
1H, Ar-H), 3.73 (s, 3H, OCH3), 3.04–.97 (m, 2H, NHCH2), 2.69 (t,
J = 7.7 Hz, 2H, CH2), 2.30 (t, J = 7.7 Hz, 2H, CH2), 1.36–1.20 (m, 8H,
4CH2), 0.86 (t, J = 6.7 Hz, 3H, CH3); 13C NMR (75.47 MHz, Me2SO-
F(000) = 736; m (Cu Ka
) = 1.329 mmÀ1; T = 293 K; direct methods
(Shelxs) for structure solution.
Acknowledgment
d6):
d 171.2, 147.3, 144.5, 132.1, 120.2, 115.1, 112.3, 55.4, 38.4,
ˆ
The authors are grateful to FCT (Fundac¸a˜o para a Ciencia e
Tecnologia) for financial support of this research. Project POCI/QUI/
55631/2004 (cofinanced by the European Community fund
FEDER).
37.5, 31.0, 30.8, 29.1, 26.0, 22.0, 13.9; HRMS: m/z [M+H]+ calcd for
C16H25NO3: 280.1912; found: 280.1913.
4.14. N-Hexyl-3-(3,4-dihydroxyphenyl)propanamide (16)
Appendix A. Supplementary data
From PFPE: chromatography solvent: CHCl3/EtOAc 4:6; yield:
83 mg, 90%, as oil.
From PFPT: chromatography solvent: CHCl3/EtOAc 4:6; yield:
69 mg, 74%, as oil.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2008.09.013.
IR (NaCl plates):
;
n
3319 (O–H and N–H stretch), 1628 (C O)
8.6 (s, 2H, OH) 7.74 (t,
References
cmÀ1 1H NMR (300 MHz, Me2SO-d6)
d
J = 5.5 Hz, 1H, NH), 6.61–6.55 (m, 2H, Ar-H), 6.41 (dd, J = 8 Hz,
J = 2.0 Hz, 1H, Ar-H) 3.03–2.97 (m, 2H, NHCH2), 2.61 (t, J = 7.7 Hz,
2H, CH2), 2.25 (t, J = 7.7 Hz, 2H, CH2), 1.37–1.20 (m, 8H, 4CH2), 0.86
[1] B. Halliwell, Drugs Aging 18 (2001) 685–716.
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(t, J = 6.7 Hz, 3H, CH3); 13C NMR (75.47 MHz, Me2SO-d6):
d 171.2,
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144.9, 143.2, 132.1, 118.6, 115.6, 115.3, 38.4, 37.5, 31.0, 30.6, 29.1,
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266.1750; found: 266.1748.
4.15. X-ray crystallographic data for 6
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Suitable crystals were obtained as thin needles from the slow
evaporation of a Et2O solution. C17H13F5O4; colourless, cubic;
FW = 376.27; monoclinic, space group P21 (No. 4); a = 9.0835(11),
˚
b = 8.3577(8), c = 11.0398(5) A;
a = 90, b = 98.780(7), g = 908;
V = 828.29(13) A ; Z = 2; Dcalc = 1.509 g cmÀ3, F(000) = 384;
(Cu Ka
) = 1.266 mmÀ1; T = 293 K; direct methods (Shelxs) for
m
3
˚
structure solution.
4.16. X-ray crystallographic data for 7
Suitable crystals were obtained as thin needles from the slow
evaporation of a Et2O solution. C16H11F5O4; colourless, prism;
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Acta Cryst. E62 (2006) o193–o194.
FW = 362.25; monoclinic, space group P21/n (No. 14);
˚
a = 10.0240(9), b = 15.0869(13), c = 10.2681(5) A;
a
= 90,
3
= 908; V = 1550.7(2) A ; Z = 4; Dcalc = 1.552 g cmÀ3
,
˚
b
= 93.007(8),
g