New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine N-oxides with hexafluoropropene

Article abstract of DOI:10.1002/chem.200701416

Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N-O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1 -aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.

Full text of DOI:10.1002/chem.200701416

FULL PAPER
DOI: 10.1002/chem.200701416
New Synthesis of 2-Heteroarylperfluoropropionic Acids Derivatives by
Reaction of Azine N-Oxides with Hexafluoropropene
Rafał Loska and Mieczysław Ma˛kosza*[a]
Dedicated to Professor Paul Tarrant on the occasion of his 93rd birthday in appreciation of his great contribution to fluorine
chemistry
Abstract: Hexafluoropropene reacts
with aromatic azine N-oxides under
mild conditions to produce fluorides of
2-heteroarylperfluoropropionic acids.
The reaction proceeds as 1,3-dipolar
cycloaddition followed by spontaneous
lines, the in situ formed acyl fluorides
give the corresponding esters and
amides. They can be also treated sepa-
rately with nucleophiles to produce the
respective acylation products, whereas
their hydrolysis leads to unstable car-
boxylic acids that undergo spontaneous
decarboxylation to 1-aryl-1,2,2,2-tetra-
fluoroethanes. This new reaction pro-
vides a simple and general method of
synthesizing 2-heteroarylperfluoropro-
pionic acid derivatives that were previ-
ously unknown and unavailable.
À
scission of the N O bond in the isoxa-
Keywords: acylation
·
cycloaddi-
zolidine ring and elimination of HF.
When the reaction is carried out in the
presence of alcohols or N-alkyl ani-
tion · fluorine · nitrogen heterocy-
cles · reaction mechanisms
Introduction
“profen” family of non-steroidal anti-inflammatory drugs.
The presence of a fluorine atom in the a position was ex-
pected to prevent racemisation of the compound under
physiological conditions and to modify its metabolism and
interactions with the receptor.[3] Such a fluorinated analogue
would remain active, owing to the similar “physiological”
size of fluorine and hydrogen,[4] whereas its configurational
stability would enable investigations into the stereochemis-
try of its binding to the receptor. To date, only few synthetic
methods for preparing such compounds have been reported.
Rozen and co-workers developed a method based on elec-
trophilic fluorination of ketene acetals with AcOF, leading
to 2-fluoroalkanoic acids and esters, including those with
aryl groups in the 2 position.[5] Schlosser obtained a 2-fluori-
nated analogue of ibuprofen by treating the corresponding
hydroxyl derivative with diethylaminosulfur trifluoride
(DAST).[3] A route via 2-aryl-2-fluoropropanols prepared
from 2-arylpropene oxides by BF3-catalysed ring-opening
was described by Haufe et al.[6]
Heteroaromatic compounds that incorporate fluorinated
substituents in the ring are presently widely applied as novel
pharmaceuticals, crop protection agents and liquid crystal-
line compounds.[1] Their significant and constantly growing
practical importance is inspiring the search for new synthetic
methods that allow the introduction of such substituents
into the aromatic ring, selectively and under mild reaction
conditions. In particular, it would be of great interest to de-
velop new reactions that selectively afford products with a
partially fluorinated side-chain that bears functional groups
suitable for further functionalisation. Such compounds could
be used, for example, as precursors in the synthesis of new
pharmaceuticals that incorporate a heterocyclic subunit with
a side-chain bearing functional groups responsible for the
biological activity and fluorine atoms that prevent metabolic
oxidative and/or hydrolytic decomposition of the drug.[2]
In particular, there is a growing interest in the new side-
chain-fluorinated derivatives of 2-arylpropionic acids—the
2-Aryl-substituted perfluoropropionic acids have been
rarely investigated. Their potentially interesting properties
were first pointed out by Ricci and Ruzziconi, who elaborat-
ed a general approach to the synthesis of 2-phenanthryl-2-
fluoropropionic and 2-phenanthrylperfluoropropionic esters
and acids.[7] Apart from their contribution, there are current-
ly no general methods to access 2-arylperfluoropropionic
[a] Dr. R. Loska, Prof. Dr. M. Ma˛kosza
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01–224 Warsaw 42 (Poland)
Fax : (+48)2263-26681
E-mail: icho-s@icho.edu.pl
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2577

acid derivatives. Only a few examples of such compounds
have been reported so far.[8]
are stable fluorinated isoxazolidine derivatives 2, as de-
scribed by Knunyants and co-workers.[13] With azine N-
oxides, the observed products are azines 3 substituted with a
1,2,2,2-tetrafluoroethyl group in the C2 position of the aro-
matic ring.[14-16] In this case, re-aromatisation of the ring pro-
In this article, we wish to present a new and general reac-
tion that allows access to a wide range of 2-heteroarylper-
fluoropropionic and 3,3,3-trifluoropropionic acyl fluorides
that are readily converted into esters, amides, etc. with a
heteroaryl group at 2-position. However, the respective free
carboxylic acids cannot be isolated because they undergo
immediate decarboxylation, owing to the presence of a ni-
trogen atom at the 2 position of the heteroaryl group.
In recent years, our group has been investigating new re-
actions in which a fluorinated substituent is introduced into
the aromatic ring by means of oxidative nucleophilic substi-
tution of hydrogen with fluorinated carbanions. We have al-
ready described the oxidative nucleophilic trifluoromethyla-
tion of nitroarenes[9] and reactions of azinium (pyridinium,
quinolinium etc.) salts with CF3À[10] or with perfluoroispropyl
carbanions, generated in the reaction mixture from hexa-
fluoropropene (CF2=CFCF3, HFP) and KF(s).[11] The two
crucial steps of these reactions were, nucleophilic addition
of the carbanions to the electrophilic homo- or heteroaro-
matic ring and subsequent aromatisation of the negatively
charged sH complexes or neutral dihydroazines upon addi-
tion of an oxidant.
À
vides the driving force for N O bond scission in the transi-
ent 4,5,5-trifluoro-4-trifluoromethylisoxazolidines 2, which
generally cannot be isolated. Nevertheless, we have isolated
and characterised an isoxazolidine derived from quinoline
N-oxide 1a,[16] giving support for the reaction mechanism
shown in Scheme 2. This mechanism was proposed by
Scheme 2. The mechanism of the reaction of HFP with azine N-oxides
proposed in ref. [15].
Another mechanistic pathway that starts with the addition
of perfluorocarbanion to strongly electrophilic aromatic
rings and which might lead to products of similar type could
be nucleophilic cine substitution in the aromatic azine N-
oxides. They are well-known as educts for the functionalisa-
tion of heteroaromatic rings in reactions with nucleo-
philes.[12] Unfortunately, our attempts to effect a nucleophil-
ic cine substitution in the O-acylated or O-alkylated N-
oxides with fluorinated carbanions have been unsuccessful
so far. The few positive results we were able to obtain will
be published elsewhere. However, in the course of these
studies we made interesting observations concerning 1,3-di-
polar cycloaddition of azine N-oxides with hexafluoropro-
pene, which are the subject of the present paper.
Banks, Haszeldine et al. and is based on the observation of
some side-products.[15] According to this mechanism, further
transformations of 2 leading to the products 3 involve loss
of difluorophosgene F2C=O, which was detected among the
volatile products of this reaction, together with carbon diox-
ide.
In the current paper, we present evidence that the trans-
formation of the isoxazolidines formed in the 1,3-dipolar cy-
cloaddition of fluoroalkenes with aromatic N-oxides pro-
ceeds according to a different mechanism. These findings al-
lowed us to elaborate a novel, three-component reaction of
azine N-oxides with HFP in the presence of oxygen, sulphur
or nitrogen nucleophiles. It also provides access to a wide
range of derivatives of 2-heteroarylperfluoropropionic acids
with the general structure 5–7 or 8, containing a partially
fluorinated side-chain with an ester or amide functional
group (Scheme 3). We have shown that the reaction leading
The outcome of the reaction of HFP (and other fluorinat-
ed alkenes) with compounds of the general structure 1,
+
À
À
À
which contain the X C=N (Y) O moiety, depends on
whether this fragment is or is not part of an aromatic ring
(Scheme 1). In the latter case (nitrones), the final products
Scheme 3. The novel reaction of azine N-oxides 1 with HFP in the pres-
Scheme 1. Reactions of HFP with nitrones and N-oxides of azines.
ence of protic nucleophiles presented in this paper.
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2-Heteroarylperfluoropropionic Acids
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to the products 3 is only a specific case of this general pro-
MeOH instead of D2O, furnished mainly the methyl ester
cess.
5a (Scheme 5).
Results and Discussion
Reactions of quinoline N-oxide with HFP and MeOH or
D2O: In the course of our investigations on the reaction of
HFP with azines N-oxides we were looking for the reaction
medium that ensures the highest rate at room temperature
and under moderate pressure (glass pressure tube). Under
such mild conditions the reaction provides the products 3
very cleanly, but it is rather slow unless a polar solvent is
used, such as DMF or MeCN.[16] In particular, it was inter-
esting to perform the reaction in a protic solvent. Unexpect-
edly, after 48 h of reaction of quinoline N-oxide (1a) with
HFP in MeOH at room temperature we observed exclusive
formation of methyl ester 5a in a moderate yield. No prod-
uct 3a containing a CHFCF3 group was formed (Scheme 4).
Scheme 5. Reaction of 1a with HFP in the presence of a) D2O and reac-
tions finished by addition of b) D2O or c) MeOH.
These results strongly indicate that both possible types of
products (3 and 5) originate from a common intermediate,
which is gradually formed in the reaction mixture containing
N-oxide, HFP and DMF and which does not undergo further
transformations until water or MeOH is added. This inter-
mediate is probably an acyl fluoride 9, which originates
from alcohol 4 (or its anion 4’) by elimination of hydrogen
Scheme 4. Reaction of quinoline N-oxide with HFP in MeOH to give a
2-arylperfluoropropionic acid methyl ester.
À
fluoride, instead of C C bond cleavage to produce COF2
(Scheme 6). If this bond was cleaved in a process concurrent
This is an interesting result from the synthetic point of
view because a simple change of the reaction medium re-
sults in selective formation of a different product. Moreover,
it prompted us to investigate the mechanism of the 1,3-dipo-
lar cycloaddition of N-oxides with HFP in more detail be-
cause none of the intermediates proposed in the previous
mechanism (Scheme 2) can account for the formation of an
ester of type 5a instead of product 3a if an alcohol is pres-
ent in the reaction mixture.
In our previous studies, the reactions of N-oxides with
HFP were carried out in an aprotic solvent and gave prod-
ucts 3, which were isolated by aqueous work-up of the reac-
tion mixture.[16] We decided to perform a few experiments in
which D2O or MeOH were added after the reaction of 1a
with HFP. According to Scheme 2, the carbanion formed
after the retro-aldol cleavage of the oxyanion 4’ is protonat-
ed by the proton originally present at the C2 position of the
Scheme 6. Formation of acyl fluoride 9 from the isoxazolidine derivative
2.
to the formation of fluoride 9, then products 3 would always
be present along with the products of type 5–8. This is not
the case, as was determined in the experiment from
Scheme 4 and many experiments described in the next sec-
tions. The formation of non-deuterated 3a in the reactions
in Scheme 5 is attributable to the presence of H2O in D2O
and MeOH used.
Although the formation of methyl esters 5 from acyl fluo-
ride and MeOH is straightforward, formation of the prod-
ucts containing a CHFCF3 group in the presence of water
requires further comment. Apparently, the expected carbox-
ylic acid 10 obtained by hydrolysis of 9 cannot be isolated.
aromatic ring. Reaction of N-oxide 1a with HFP in DMF/
[16]
D2O 5:1 afforded product 3a,
which was almost com-
pletely deuterated in the side-chain. Of course, this may
result from H-to-D exchange with the solvent in 3, 4 or 4’ if
they are sufficiently long-lived. However, in another experi-
ment we treated N-oxide 1a with HFP in dry DMF and then
added D2O to the reaction mixture after 14 h at room tem-
perature. In this case, we again obtained deuterated product
3a. In a separate experiment we confirmed that 3a does not
exchange a proton for a deuteron in the DMF/D2O mixture.
Finally, a similar reaction, but finished by addition of
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M. Ma˛kosza and R. Loska
Instead it must undergo a facile decarboxylation according
the pathway depicted in Scheme 7 to produce the observed
product of type 3. To verify this hypothesis we performed
formed into 3a in the chloroform solution, which is slightly
acidic.
Discussion of the mechanism: In light of the above experi-
ments a modified, generalised mechanism for the reaction
of HFP with aromatic N-oxides can be proposed
(Scheme 9). The reaction begins with 1,3-dipolar cycloaddi-
Scheme 7. Spontaneous decarboxylation of carboxylic acids 10 derived
from acyl fluorides 9.
hydrolysis of the ester 5a under basic conditions. If the reac-
tion mixture was acidified after 20 h, gas evolution was ob-
served and product 3a was isolated exclusively in a yield of
88% (Scheme 8).
Scheme 9. The revised mechanism for the reaction of azine N-oxides with
HFP, accounting for the formation of the perfluoropropionic acids esters
and amides.
Scheme 8. Hydrolysis of methyl ester 5a leads to the decarboxylated
product 3a containing a CHFCF3 substituent.
tion of N-oxide to HFP to give a 4,5,5-trifluoro-4-trifluoro-
methylisoxazolidine derivative 2, which could be isolated
and characterised in the case of 2a, as we have previously
reported.[16] Re-aromatisation of the heterocyclic ring by
Because a carboxylic acid of type 10 cannot be obtained
as a consequence of its facile decarboxylation, we attempted
to isolate its salt by using an ion-pair extraction technique.
In an experiment similar to the one shown in Scheme 8, in-
stead of acidifying the reaction mixture we diluted it with
water, added 2 equivalents of nBu4N+FÀ·3H2O and extract-
ed with CH2Cl2. We envisioned that lipophilic ion pairs con-
taining an ammonium cation and anion of 10a would be ex-
tracted into the organic phase, provided that the latter ion is
sufficiently stable. Drying the CH2Cl2 solution over anhy-
drous Na2SO4 and evaporation gave an oily residue. The
1H NMR spectrum of the residue in CDCl3 revealed that it
contained an equimolar amount of compound 3a and some
nBu4N+-containing inorganic salt. This result does not di-
rectly confirm the isolation of the (nBu4N)+10aÀ salt, but it
does suggest that it must have been extracted from water to
the CH2Cl2 organic phase and then it was probably trans-
À
means of proton abstraction and N O bond cleavage leads
to oxyanion 4’. This anion eliminates HF to give acyl fluo-
ride 9. In the presence of nucleophilic reagents, such as
water or alcohols, or in fact any protic nucleophiles of the
general type HXR’R’’, as described in the following sections,
this intermediate is transformed, respectively, into a carbox-
ylic acid 10 or an acylation product 5–8 (for example, ester
5a). In the former case, the acid undergoes spontaneous de-
carboxylation to give the products 3 with a CHFCF3 group,
which have already been observed by Mailey and Ocone or
Banks, Haszeldine et al. in reactions between N-oxides and
HFP finished by aqueous workup.[14,15]
The hypothesis regarding the transformation of 4 into 9
by elimination of HF instead of difluorophosgene differs
from the earlier proposal by Banks, Haszeldine et al.[15]
However, the main gaseous product in their experiments
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2-Heteroarylperfluoropropionic Acids
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was also CO2, which according to the mechanism from
Scheme 9 is formed at the decarboxylation step. COF2 was
also detected, but the experiments were run under harsh
conditions (autoclave, high temperature and pressure) that
might have caused some other unidentified side-reactions.
The mechanism shown in Scheme 9 has potentially useful
synthetic implications—one may expect that apart from
products 3 the reaction of aromatic N-oxides and perfluoro-
with isomeric 2- and 6-methoxynicotinic acid methyl esters.
These side-products were probably formed by means of a
cine nucleophilic substitution in the N-oxide with MeOH
acting as a nucleophile and probably HFP or other electro-
philic species transforming the N-oxide oxygen atom into a
good leaving group. Increasing the temperature to 808C
raised the yield to 61% (entry 2). Considering that during
the reaction 2 equiv of HF are produced, we attempted to
neutralise the mixture by adding various bases (entries 3–5).
Unfortunately, the yields were actually lower. In the case of
K2CO3, the only reaction was oligomerisation of HFP. Final-
ly, we attempted to use additional solvents with MeOH used
only as an additive to the reaction mixture. The reactions
with mixtures of MeOH and MeCN or DMF gave the ex-
pected esters 5b and 5b’ as the sole products in a high com-
bined yield of 87% (entry 9, DMF/MeOH 6.2:1, i.e.,
10 equiv of MeOH relative to 1b). These conditions were
then used to investigate reactions of other N-oxides, as de-
scribed in the next section.
A
À
À
Ar CFRf CO2R’ (Rf =CF3 in the case of HFP). Moreover,
the fact that the nucleophile can be added after the reaction
of the N-oxide with HFP to give 9 is completed implies that
it is possible to use nucleophiles which normally react di-
rectly with HFP, for example, amines. In fact, the range of
accessible products would be limited only by the range of
nucleophiles that can be acylated by an acyl fluoride. In the
following sections we describe preparative reactions with
protic nucleophiles of the type HXR’R’’, where X=O, N or
S.
It should be noted that no products of type 3 were detect-
ed in any of experiments shown in Table 1.
Optimisation of the reaction of methyl nicotinate N-oxide
with HFP and MeOH: As alcohols do not react with HFP
in the absence of strong bases, their reaction with 1 and
Synthesis of esters of 2-heteroarylperfluoropropionic acids
from N-oxides, HFP and alcohols: The optimized conditions
(Table 1, entry 9) were used to perform a series of reactions
of various N-oxides of six- and five-membered heterocycles.
The results are summarised in Table 2. Pyridine N-oxides
containing substituents of different electronic and steric
character (H, alkyl, Cl, CN, CO2Me), as well as N-oxides of
imidazole or thiazole, all afforded the respective 2-heteroar-
ylperfluoropropionic acid methyl esters in good or very
good yields. These compounds were the exclusive products
or were formed along with only traces of the products of
type 3, with the exception of the reaction with quinoxaline
dioxide 1j that produced large amounts of 3j. Its formation
results from the presence of water in the substrate, which is
a highly hygroscopic compound. In some cases, the reaction
performed at room temperature (entries 6, 11, 12) or over a
longer period of time (entry 7) gave comparable or better
results compared to the standard conditions.
À
À
HFP to give heteroarylperfluoropropionic esters Ar CFRf
CO2R’ can be performed by mixing all the reagents together
at the beginning of the reaction. Because the reaction of
comparatively reactive quinoline N-oxide (1a) in the pre-
liminary experiment in Scheme 4 gave 5a only in a moder-
ate yield, we attempted to find better conditions. The reac-
tions of moderately active methyl nicotinate N-oxide (1b)
with HFP and MeOH under various conditions are shown in
Table 1.
The reaction under conditions similar to those from
Scheme 4 (Table 1, entry 1) gave a mixture of isomeric prod-
ucts 5b and 5b’ in a moderate total yield of 36% together
Table 1. Optimisation of the conditions of the reaction between HFP, 1b
and MeOH.
To check the scalability of the process, the reaction of pyr-
idine N-oxide (1c; Table 2, entry 3) was performed with
19 mmol of substrate. The product, which is volatile in this
case, was isolated in a good yield after aqueous work-up and
distillation under reduced pressure.
Conditions
Yields of products (%)
5b
5b’
5b+5b’ 2-OMe
Instead of MeOH, other alcohols can be also used to pro-
duce the respective esters, as demonstrated by the examples
of the reactions of 4-tert-butylpyridine N-oxide (1d) and 3-
benzyl-4,5-dimethylimidazole N-oxide (1k) shown in
Scheme 10. We also attempted a reaction of 1d with HFP
and 2,2,2-trifluoroethanol. Formation of the expected prod-
uct was confirmed by the 1H NMR spectrum of the crude re-
action mixture, but we were unable to obtain an analytical
sample because it was too prone to decompose by hydrolysis
and decarboxylation to give 3d.
1
2
3
MeOH, RT, 24 h
24
24
0
12
37
0
36
61
0[a]
ꢀ20
17
0
MeOH, 808C, 24 h
MeOH, 1.2 equiv K2CO3,
RT, 24 h
MeOH, 2.4 equiv NaHCO3,
RT, 24 h
4
8
11
19
ꢀ5
5
6
MeOH, 2.4 equiv Py, RT, 24 h
PhMe/MeOH 6.2:1, 808C, 5 h
traces traces
–
traces
all products detected;
low conversion
7
8
9
MeCN/MeOH 6.2:1, 808C, 5 h 29[b]
DMF/MeOH 3:1, 808C, 5 h
DMF/MeOH 6.2:1, 808C, 5 h
42[b]
44
53
71
79
87
traces
0
0
35
34
[a] Oligomerisation of HFP occurred. [b] Based on the 1H NMR spec-
trum of the mixture of 5b and 5b’ purified by column chromatography.
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M. Ma˛kosza and R. Loska
Table 2. Synthesis of methyl 2-heteroarylperfluoropropionates from N-
oxides, HFP and methanol.
Substrate
Products and yields
1
2
1a
1b
5a (75%)
5b (34%)
5b’ (53%)
5c (76%)
3
4
1c
1d
Scheme 10. Examples of preparation of esters from N-oxides, HFP and
alcohols.
5d (70%)
5e (85%)
tion of HFP, 1d and p-toluidine afforded products 11 and 12
exclusively (Scheme 11).[18]
5
1e
6
7
8
1 f
1g
1h
5 f (34%)[a]
5g (30%)[b]
5h (43%)
Scheme 11. Reaction of HFP with primary amine is faster than the reac-
tion with an N-oxide.
From the discussion of the previous sections it follows
that this problem could be solved by separating the two
steps of the reaction with respect to time, namely, formation
of acyl fluorides followed by their subsequent reaction with
a nucleophile. An example of such a process is the esterifi-
cation reaction in Scheme 5. The following experiment was
thus performed (Scheme 12): 4-tert-butylpyridine N-oxide
and HFP were reacted in DMF at 808C for 5 h in a pressure
tube, then the reaction mixture was cooled to room temper-
ature, excess HFP was evaporated under reduced pressure,
9
1i
1j
5i (28%)
5j (38%)
(+37% of 3j)
10
11
12
1k[17]
5k (34%)[c]
5l (80%)[d]
1l
[a] 44% after 24 h at RT. [b] 29% after 24 h at 808C. [c] 30% after 16 h
at RT. [d] After 24 h at RT.
Synthesis of amides of 2-heteroarylperfluoropropionic acids:
As expected, preliminary attempts to obtain amides of 2-
heteroarylperfluoropropionic acids analogously to the syn-
thesis of esters, that is by mixing together HFP, azine N-
oxide and aliphatic or primary aromatic amines, did not pro-
vide any of the expected amides because a direct reaction
between the amine and HFP prevailed. For example, reac-
Scheme 12. The two step, one-pot procedure for the preparation of
amides 7.
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2-Heteroarylperfluoropropionic Acids
FULL PAPER
and p-toluidine (2 equivalents) in DMF was added dropwise.
After 14 h at room temperature and aqueous work-up, tolu-
A
thesis of esters, no product containing a CHFCF3 substituent
was detected. A similar reaction of quinoline N-oxide and
diethylamine produced tertiary amide 7aa.
In the course of further experiments we found that better
yields of amides can be obtained if triethylamine is added at
08C along with the amine which is acylated. Its role is prob-
ably to neutralise HF evolved during the formation of the
acyl fluoride intermediate. We used this protocol to obtain
more elaborate amides 7b, 7b’, 7c, 7ka, 7kb and 7m (from
2,2’-bipyridyl N-oxide (1m)) in fairly good yields
(Scheme 13).
Scheme 14. Direct preparation of tertiary amides of 2-heteroarylperfluor-
opropionic acids with secondary amines of low nucleophilicity. i) HFP,
DMF, 2 equiv of amine, RT, 24 h; [a] yield based on the starting indoline.
lowed by its reaction with 4-chlorothiophenol to give 6e in a
moderate yield (Scheme 15).
Scheme 15. The two-step, one-pot procedure for the preparation of thio-
ester 6e. i) HFP, DMF, 808C, 5 h; ii) 2 equiv of p-ClC6H4SH, DMF, RT,
14 h.
Reactions of other fluorinated alkenes: In the preliminary
experiments we found that 2H-pentafluoropropene (PFP)
reacts with aromatic N-oxides and protic nucleophiles in a
manner similar to HFP. Reaction of 1a with N-ethylaniline
in the presence of PFP in DMF at room temperature afford-
ed the expected tertiary amide 8a in a good yield. Com-
pound 8a was obtained in nearly the same yield as the anal-
ogous product 7ab from HFP, which suggests that both al-
kenes exhibit similar activity in the 1,3-dipolar cycloaddition
reaction with aromatic N-oxides (Scheme 16).
Scheme 13. The two-step, one-pot procedure for the preparation of
amides 7 in the presence of NEt3. [a] The first step for 24 h at RT.
[b] The first step for 24 h.
Activity of some alkylarylamines towards HFP is low
enough to allow a simplified synthesis of the respective 2-
heteroaryl-perfluoropropionic amides in a way analogous to
the synthesis of esters. For example, quinoline N-oxide
reacts with HFP and N-ethylaniline at room temperature to
provide amide 7ab as the sole product. The reaction of 1k
and indoline gave amide 7kc together with some side-prod-
uct 13 from the reaction of indoline with HFP (Scheme 14).
Scheme 16. Preparation of trifluoropropionic amide 8.
Chlorotrifluoroethylene, CF2=CFCl, exhibits
a much
lower activity than HFP towards aromatic N-oxides. Its reac-
tion with MeOH and 1a, which is one of the most active N-
oxides we studied in the reactions with HFP, provided the
ester 14a in a reasonable yield only under forcing conditions
(Scheme 17).
Synthesis of thioesters from thiols: The preparation of thio-
esters is exemplified by the reaction performed according to
the two-step, one-pot protocol in which the acyl fluoride 9e
is first formed from 4-chloropyridine N-oxide and HFP, fol-
Chem. Eur. J. 2008, 14, 2577 – 2589
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2583

M. Ma˛kosza and R. Loska
The azine N-oxides were prepared either by the traditional method
(heating with 30% H2O2-AcOH)[12a] or from the reaction with a urea-hy-
drogen peroxide complex (UHP) and trifluoroacetic anhydride.[21]
General procedure for reactions of azines N-oxides with fluoroalkenes
and alcohols. Synthesis of 2-heteroarylperfluoropropionic methyl esters:
The fluoroalkene (ꢀ0.5 mL, 4 mmol) was condensed in a glass pressure
tube at À788C under an argon atmosphere. DMF (2.4 mL; or other sol-
vent, see text), N-oxide (0.95 mmol) and MeOH (0.385 mL, 9.50 mmol)
were introduced, and the pressure tube was closed with a Teflon valve.
The contents of the tube were stirred vigorously at 808C for 5 h. The
tube was opened, the reaction mixture was poured into water (10 mL),
and the products were extracted with CH2Cl2 (3”5mL). Combined or-
ganic layers were washed with water (5”10 mL), dried over anhydrous
Na2SO4 and concentrated. The products were purified by column chro-
matography (silica gel; 10:1 or 5:1 mixtures of hexanes/AcOEt or hex-
anes/Et2O).
Scheme 17. Reaction of quinoline N-oxide (1a) with chlorotrifluoroethy-
lene and MeOH.
Further investigation of the scope of the reactions of PFP
and other fluoroalkenes is under way in our laboratory.
Conclusion
Methyl 2-(2’-quinolinyl)perfluoropropionate (5a): Pale yellow oil;
Hexafluoropropene reacts with azine N-oxides along a 1,3-
dipolar cycloaddition pathway to produce unstable isoxazoli-
1H NMR (400 MHz): d=3.99 (d, 5J
ACHTREUNG
(ddd, 3J
U
ACHTREUNG
À
ACHTREUNG
dines that undergo rapid aromatisation by N O bond scis-
3
3
ACHTREUNG
(dd, J
A
sion, followed by elimination of HF to give 2-heteroaryl-
2,3,3,3-tetrafluoropropionic acid fluorides as the final prod-
ucts. These intermediates, which are stable in anhydrous
aprotic media, can react with a variety of protic nucleo-
philes. Quenching the reaction mixture with water causes
hydrolysis of the fluoride followed by decarboxylation. The
overall result is thus an introduction of a 1,2,2,2-tetrafluoro-
8.7 Hz, 1H; Har); 13C NMR (100.6 MHz): d=53.6, 93.6 (dq, 1J
ACHTREUNG
3
4
ACHTREUNG
200.0 Hz, J
(C,F)=5.2 Hz, J
121.1 (qd, 1J
ACHTREUNG
130.1, 130.3, 137.7, 147.0 (d, 4J
G
ACHTREUNG
25.9 Hz), 163.5 ppm (d, 2J
3
ACHTREUNG
À168.53 (q, J
(F,F)=8.3 Hz,
3F, CFCF3); IR (film): n˜ =3066, 2960, 1770, 1596, 1505, 1439, 1301, 1276,
1209, 1181, 1114, 1041, 829, 801, 759 cmÀ1; MS(70 eV, EI): m/z (%): 287
(100) [M]+, 272 (22), 256 (7), 243 (12), 228 (62), 178 (54), 174 (29), 158
(32), 128 (41); EI-HRMS: m/z: calcd for C13H9NO2F4: 287.0569 [M]+;
found: 287.0574; elemental analysis calcd (%) for C13H9NO2F4 (287.2): C
54.37, H 3.16, N 4.88, F 26.46; found: C 53.92, H 2.97, N 5.01, F 26.43.
ethyl group into the heteroaromatic ring. When the reaction
of HFP with N-oxides is carried out in the presence of weak
nucleophiles, such as alcohols and alkyl aryl amines, the cor-
responding esters and amides of 2-arylperfluoropropionic
acids are obtained in good yields. Alternatively, acylation of
a variety of amines and thiols can be performed by means
of a two-step, one-pot procedure.[19]
The above-described reaction has a general character: by
changing the N-oxide, fluoroalkene and nucleophile it is
possible to independently modify the three parts of the de-
sired molecule, the heterocyclic moiety, the fluorinated frag-
ment and the functionality present in the acyl group. This
process could be thus applied to the construction of combi-
natorial libraries of partially fluorinated compounds in the
search for new pharmacologically interesting lead structures.
Methyl 2-(5’-methoxycarbonylpyridin-2’-yl)perfluoropropionate (5b):
Colourless crystalline solid, m.p. 94–958C (hexanes/Et2O); 1H NMR
(400 MHz): d=3.95 (d, 5J
OCH3), 7.81 (d, 3J
4J(H,H)=2.1 Hz, 1H; Har), 9.22 ppm (dm, 4J
13C NMR (100.6 MHz): d=52.8, 53.9, 92.8 (dq, 1J
(C,F)=31.0 Hz), 120.8 (qd, 1J(C,F)=285.4 Hz, 2J
(C,F)=29.3 Hz), 121.4
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
3
4
ACHTREUNG
2
(d, J
G
(C,F)=25.9 Hz), 162.9 (d, 2J
(376.4 MHz): d=À170.15 (q, 3J
(d, 3J
(F,F)=7.8 Hz, 3F, CFCF3); IR (film): n˜ =2961, 1772, 1735, 1599,
1439, 1295, 1212, 1192, 1123, 1042, 1026, 740 cmÀ1; MS(70 eV, EI): m/z
(%): 295 (52) [M]+, 280 (51), 264 (41), 251 (79), 236 (72), 186 (81), 59
(100); EI-HRMS: m/z: calcd for C11H9NO4F4: 295.0468 [M]+; found:
295.0466; elemental analysis calcd (%) for C11H9NO4F4 (295.2): C 44.76,
H 3.07, N 4.75, F 25.74; found: C 44.68, H 3.10, N 4.71, F 25.71.
Methyl 2-(3’-methoxycarbonylpyridin-2’-yl)perfluoropropionate (5b’):
Pale yellow oil; 1H NMR (400 MHz): d=3.90 (s, 3H; OCH3), 3.90 (s,
Experimental Section
3H; OCH3), 7.50 (ddd, 3J
8.15 (dd, 3J(H,H)=7.8 Hz, 4J
(H,H)=4.9 Hz, 4J(H,H)=1.3 Hz, 1H; Har); 13C NMR (100.6 MHz): d=
52.9, 53.9, 92.9 (dq, 1J(C,F)=202.6 Hz, 2J(C,F)=30.2 Hz), 121.0 (qd, 1J-
(C,F)=287.1 Hz, 2J(C,F)=27.6 Hz), 124.4, 127.0, 138.5, 149.6 (d, 2J-
ACHTREUNG
General information: The reactions of fluoroalkenes were performed
under an argon atmosphere (technical grade argon) in a flame-dried glass
pressure tube (ꢀ3.5 mL volume) equipped with a Teflon valve and a
magnetic stirring element. The solvents used in these reactions were com-
mercially available puriss p.a. grade solvents (DMF, MeCN, MeOH) or
were distilled before use (toluene). Solvents for extraction or chromatog-
raphy were freshly distilled before use. Other reagents were either used
as obtained from the manufacturer or purified according to literature
procedures.[20] Flash chromatography was performed by using silica gel 60
(0.040–0.063 mm). Thin-layer chromatography was performed by using
pre-coated silica gel plates and visualised under a UV lamp. NMR spec-
tra were recorded in CDCl3 at the spectrometer frequencies indicated in
the description of each compound. Chemical shifts are given in ppm rela-
tive to TMSfor 1H and 13C NMR spectra and CFCl3 for 19F NMR spec-
tra. IR spectra were recorded by using a FT-IR spectrometer. Mass spec-
tra were obtained by using electron impact (EI) or electrospray (ESI)
ionisation.
G
ACHTREUNG
U
ACHTREUNG
U
ACHTREUNG
U
ACHTREUNG
A
ACHTREUNG
(376.4 MHz): d=À162.88 (q, 3J
ACHTREUNG
(d, 3J
(F,F)=8.1 Hz, 3F, CFCF3); IR (KBr): n˜ =3017, 2963, 1758, 1726,
A
1588, 1442, 1300, 1268, 1215, 1169, 1144, 1115, 1091, 1062, 1035, 971, 778,
755, 681, 636 cmÀ1; MS(70 eV, EI): m/z (%): 295 (10) [M]+, 280 (18), 264
(26), 250 (39), 236 (100), 206 (45), 177 (16), 150 (38), 139 (31); EI-
HRMS: m/z: calcd for C11H9NO4F4: 295.0468 [M]+; found: 295.0455; ele-
mental analysis calcd (%) for C11H9NO4F4 (295.2): C 44.76, H 3.07, N
4.75, F 25.74, found: C 44.66, H 3.02, N 4.77, F 25.73.
Methyl 2-(4’-tert-butylpyridin-2’-yl)perfluoropropionate (5d): Colourless
oil; 1H NMR (400 MHz): d=1.35 (s, 9H; tBu), 3.95 (s, 3H; OCH3), 7.39
(dd, 3J
N
N
2584
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2577 – 2589

2-Heteroarylperfluoropropionic Acids
FULL PAPER
3
8.54 ppm (d, J
N
1600, 1440, 1312, 1276, 1212, 1162, 1132, 1046, 1008, 796 cmÀ1; MS(70 eV,
EI): m/z (%): 262 (13) [M]+, 247 (11), 231 (4), 218 (34), 203 (24), 153
(37), 59 (100); EI-HRMS: m/z: calcd for C10H6N2O2F4: 262.0365 [M]+;
found: 262.0370; elemental analysis calcd (%) for C10H6N2O2F4 (262.2): C
45.82, H 2.31, N 10.69, F 28.99; found: C 45.89, H 2.38, N 10.65, F 29.07.
35.1, 53.7, 93.2 (dq, 1J
N
ACHTREUNG
A
G
ACHTREUNG
G
ACHTREUNG
(C,F)=23.3 Hz); 19F NMR (376.4 MHz): d=À169.38 (q, 3J
ACHTREUNG
7.8 Hz, 1F, CFCF3), À76.47 ppm (d, 3J
ACHTREUNG
Methyl 2-(1’-isoquinolinyl)perfluoropropionate (5i): Yellow oil; 1H NMR
(400 MHz): d=3.91 (d, 5J(H,F)=0.4 Hz, 3H; OCH3), 7.66 (ddd, 3J-
G
(film): n˜ =2968, 2875, 1771, 1602, 1439, 1309, 1275, 1209, 1181, 1098,
1046, 1002, 852, 807 cmÀ1; MS(70 eV, EI): m/z (%): 293 (45) [M]+, 278
(100), 234 (70), 218 (40); EI-HRMS: m/z: calcd for C13H15NO2F4:
293.1039 [M]+; found: 293.1031; elemental analysis calcd (%) for
C13H15NO2F4 (293.3): C 53.24, H 5.16, N 4.78, F 25.91; found: C 53.00, H
5.20, N 4.81, F 25.76.
A
G
U
8.1 Hz, 4J
7.89 (d, J
8.54 ppm (d, J
96.1 (dq, 1J
286.2 Hz, 2J
4J
ACHTREUNG
3
ACHTREUNG
N
Methyl 2-(4’-chloropyridin-2’-yl)perfluoropropionate (5e): White solid,
m.p. 45–468C; 1H NMR (400 MHz): d=3.94 (s, 3H; OCH3), 7.44 (dd, 3J-
ACHTREUNG
ACHTREUNG
(H,H)=5.3 Hz, 4J
G
A
N
ACHTREUNG
3
2
ACHTREUNG
(d, J
1J
A
164.1 ppm (d, J
3J(F,F)=8.5 Hz, 5J
8.6 Hz, 3F, CFCF3); IR (film): n˜ =3061, 2960, 1771, 1587, 1439, 1341,
1297, 1270, 1259, 1215, 1204, 1170, 1123, 1081, 1034, 941, 833, 752 cmÀ1
;
G
E
G
A
(F,H)=3.1 Hz, 1F, CFCF3), À74.08 ppm (d, 3J
G
E
ACHTREUNG
(C,F)=1.7 Hz), 151.5 (d, 2J
(C,F)=25.9 Hz), 162.8 ppm (d, 2J
G
23.3 Hz); 19F NMR (376.4 MHz): d=À170.15 (q, 3J
N
MS(70 eV, EI): m/z (%): 287 (100) [M]+, 272 (41), 256 (5), 243 (7), 228
(68), 208 (18), 178 (28), 174 (26), 158 (16), 128 (38); EI-HRMS: m/z:
calcd for C13H9NO2F4: 287.0569 [M]+; found: 287.0574; elemental analy-
sis calcd (%) for C13H9NO2F4 (287.2): C 54.37, H 3.16, N 4.88, F 26.46;
found: C 53.79, H 3.26, N 4.80, F 26.40.
CFCF3), À76.37 ppm (d, 3J
(F,F)=7.6 Hz, 3F, CFCF3); IR (KBr): n˜ =
2970, 2925, 1760, 1578, 1306, 1281, 1210, 1195, 1127, 1042, 852, 705 cmÀ1
;
MS(70 eV, EI): m/z (%): 271 (26) [M]+, 256 (27), 240 (7), 227 (22), 212
(27), 193 (10), 177 (15), 162 (50), 112 (26), 59 (100); EI-HRMS: m/z:
calcd for C9H6NO235ClF4: 271.0023 [M]+; found: 271.0015; elemental
analysis calcd (%) for C9H6NO2ClF4 (271.6): C 39.80, H 2.23, N 5.16, Cl
13.05, F 27.98; found: C 39.65, H 1.98, N 5.24, Cl 12.91, F 28.00.
Methyl ester (5j): Pale yellow oil; 1H NMR (400 MHz): d=4.01 (s, 3H;
OCH3), 7.81–7.93 (m, 2H; Har), 8.17 (dm, 3J
ACHTREUNG
8.57 (dm, 3J
ACHTREUNG
Methyl 2-(4’,6’-dimethylpyridin-2’-yl)perfluoropropionate (5 f): Yellow
crystalline solid, m.p. 35–368C (hexanes/Et2O); 1H NMR (400 MHz): d=
U
ACHTREUNG
1
32.8 Hz), 118.8, 120.5 (qd, J
U
2.37 (s, 3H; CH3), 2.49 (s, 3H; CH3), 3.93 (d, 5J
A
3J
G
ACHTREUNG
OCH3), 7.06 (d, 4J
A
25.9 Hz), 162.0 ppm (d, 2J
ACHTREUNG
3
3
ACHTREUNG
N
À171.58 (q, J
A
(F,F)=7.8 Hz,
A
G
A
284.5 Hz, 2J
C
ACHTREUNG
3
3
ACHTREUNG
À167.88 (q, J
(F,F)=8.1 Hz,
G
3F, CFCF3); IR (KBr): n˜ =2964, 1763, 1613, 1445, 1302, 1211, 1183, 1159,
1108, 1067, 1032, 862, 792, 687 cmÀ1; MS(70 eV, EI): m/z (%): 265 (100)
[M]+, 250 (28), 246 (5), 234 (13), 221 (20), 206 (85), 187 (22), 171 (14),
156 (55); EI-HRMS: m/z: calcd for C11H11NO2F4: 265.0726 [M]+; found:
265.0731; elemental analysis calcd (%) for C11H11NO2F4 (265.2): C 49.82,
H 4.18, N 5.28, F 28.65; found: C 49.50, H 4.12, N 5.30, F 28.70.
found: C 47.37, H 2.94, N 9.09, F 25.04.
G
G
3
5.9 Hz, 1H; CHF), 7.83 (dd, J
ACHTREUNG
3J
A
G
ACHTREUNG
1.0 Hz, 1H; Har), 8.58 ppm (dd, 3J
G
ACHTREUNG
Methyl 2-(6’-methoxycarbonylpyridin-2’-yl)perfluoropropionate (5g):
Pale yellow oil; 1H NMR (400 MHz): d=3.98 (s, 3H; OCH3), 3.99 (s,
C
ACHTREUNG
1
A
3H; OCH3), 7.89 (dd, 3J
A
G
G
ACHTREUNG
3
3
2
ACHTREUNG
(t, J
(H,H)=8.0 Hz, 1H; Har), 8.22 ppm (dm, J
13C NMR (100.6 MHz): d=52.9, 53.8, 92.9 (dq, 1J
(C,F)=31.9 Hz), 120.9 (qd, 1J(C,F)=285.4 Hz, 2J
N
G
A
G
ACHTREUNG
(d, 3J
(C,F)=5.2 Hz), 126.4, 138.5, 147.9, 150.3 (d, 2J
163.2 (d, 2J
ACHTREUNG
3
À167.93 (q, J
(F,F)=7.9 Hz, 1F, CFCF3), À76.03 ppm (d, J
3F, CFCF3); IR (film): n˜ =2965, 1761, 1732, 1458, 1445, 1317, 1295, 1237,
1218, 1186, 1160, 1138, 1082, 1042, 996, 806, 768, 757, 747, 722, 697,
644 cmÀ1; MS(70 eV, EI): m/z (%): 295 (<1) [M]+, 265 (12), 237 (100),
206 (7), 186 (10), 177 (27); EI-HRMS: m/z: calcd for C11H9NO4F4:
295.0468 [M]+; found: 295.0458; elemental analysis calcd (%) for
C11H9NO4F4 (295.2): C 44.76, H 3.07, N 4.75, F 25.74; found: C 44.78, H
2.94, N 4.79, F 25.66.
AHCTREUNG
ACHTREUNG
AHCTREUNG
AHCTREUNG
Methyl 2-(4’-cyanopyridin-2’-yl)perfluoropropionate (5h): Pale yellow
C
G
ACHTREUNG
oil; 1H NMR (400 MHz): d=3.95 (d, 5J
A
G
ACHTREUNG
(ddd, 3J
(H,H)=5.0 Hz, 4J
N
2
ACHTREUNG
N
G
ACHTREUNG
A
N
10.6 Hz, 3F, CFCF3); IR (film): n˜ =3037, 2960, 2926, 2865, 1771, 1498,
1435, 1357, 1301, 1263, 1238, 1212, 1181, 1130, 1093, 1057, 1030, 939, 819,
741, 696, 667 cmÀ1; MS(70 eV, EI): m/z (%): 344 (13) [M]+, 285 (3), 91
(100); EI-HRMS: m/z: calcd for C16H16N2O2F4: 344.1148 [M]+; found:
344.1154; elemental analysis calcd (%) for C16H16N2O2F4 (344.3): C 55.82,
H 4.68, N 8.14, F 22.07; found: C 55.31, H 4.55, N 8.06, F 21.94.
A
ACHTREUNG
G
ACHTREUNG
(C,F)=25.9 Hz),
162.4 ppm
(d,
2J
ACHTREUNG
(376.4 MHz): d=À170.50 (q, 3J
ACHTREUNG
(d, 3J
(F,F)=8.3 Hz, 3F, CFCF3); IR (film): n˜ =3080, 2964, 2243, 1771,
A
Chem. Eur. J. 2008, 14, 2577 – 2589
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2585

M. Ma˛kosza and R. Loska
Methyl 2-(benzothiazol-2’-yl)perfluoropropionate (5l): Pale yellow oil;
1H NMR (400 MHz): d=4.01 (s, 3H; OCH3), 7.49 (dd, 3J
(H,H)=7.9 Hz,
7.2 Hz, 1H; Har), 7.55 (dd, 3J
(H,H)=8.3 Hz, 7.3 Hz, 1H; Har), 7.95 (dm,
3J(H,H)=8.1 Hz, 1H; Har), 8.16 ppm (dm, 3J
(H,H)=8.2 Hz, 1H; Har);
13C NMR (100.6 MHz): d=54.4, 91.4 (dq, 1J(C,F)=201.7 Hz, 2J
(C,F)=
33.6 Hz), 120.3 (qd, 1J(C,F)=286.2 Hz, 2J
(C,F)=29.3 Hz), 121.7, 124.5,
126.8, 126.9, 135.1, 152.4, 157.8 (d, 2J(C,F)=28.4 Hz), 161.7 ppm (d, 2J-
(F,F)=8.4 Hz,
(F,F)=8.9 Hz, 3F, CFCF3); IR (film): n˜ =
2970, 1772, 1512, 1435, 1308, 1260, 1203, 1184, 1138, 1010, 942, 910, 796,
759, 725, 670 cmÀ1; MS(70 eV, EI): m/z (%): 293 (100) [M]+, 249 (19),
234 (65), 215 (11), 184 (93), 148 (44); EI-HRMS: m/z: calcd for
C11H7NO2SF4: 293.0134 [M]+; found: 293.0139; elemental analysis calcd
(%) for C11H7NO2SF4 (293.2): C 45.06, H 2.41, N 4.78, S10.94, F 25.91;
found: C 45.03, H 2.42, N 4.67, S11.22, F 25.52.
(d, 2J
C
ACHTREUNG
G
ACHTREUNG
G
(film): n˜ =2968, 1765, 1602, 1517, 1305, 1250, 1208, 1178, 1098, 1035,
1002, 851, 826 cmÀ1; MS(EI 70 eV) m/z (%): 399 (2) [M]+, 235 (100),
220 (10), 200 (6), 121 (28); HRMS: m/z: calcd for C20H21NO3F4: 399.1458
[M]+; found: 399.1451; elemental analysis calcd (%) for C20H21NO3F4
(399.4): C 60.15, H 5.30, N 3.51, F 19.03; found: C 60.34, H 5.50, N 3.36,
F 19.10.
U
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
(C,F)=24.1 Hz); 19F NMR (376.4 MHz): d=À161.49 (q, 3J
ACHTREUNG
1F, CFCF3), À76.21 ppm (d, 3J
ACHTREUNG
Allyl 2-(4’-tert-butylpyridin-2’-yl)perfluoropropionate (5dc): Colourless
1
oil; H NMR (400 MHz): d=1.34 (s, 9H; tBu), 4.85 (m, 2H; OCH2), 5.28
(dd, 3J
(H,H)=10.4 Hz, 2J
G
(H,H)), 5.37 (dd, 3J-
A
N
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
Large-scale preparation of methyl 2-(2’-pyridyl)perfluoropropionate (5c):
HFP (ꢀ8.2 g, 55 mmol) was condensed into a thick-walled, round-bot-
tomed flask (100 mL volume) at À788C under an argon atmosphere.
DMF (48 mL), methanol (7.7 mL) and freshly vacuum-dried pyridine N-
oxide (1c; 1.80 g, 18.9 mmol) were added and the flask was sealed. The
reaction mixture was vigorously stirred at 80–858C for 5 h. After cooling
to RT, the reaction mixture was poured into water (ꢀ200 mL), and the
product was extracted with CH2Cl2 (3”100 mL). The organic phase was
washed with water (5”100 mL), dried over anhydrous Na2SO4 and
evaporated. The crude product was purified by distillation (558C at
G
G
ACHTREUNG
1
2
4
G
(C,F)=29.3 Hz), 122.3, 149.2 (d, J-
G
ACHTREUNG
(C,F)=22.4 Hz); 19F NMR (376.4 MHz): d=À169.11 (q, 3J
ACHTREUNG
1F, CFCF3), À76.35 ppm (d, 3J
ACHTREUNG
2970, 2875, 1770, 1603, 1481, 1407, 1367, 1308, 1273, 1208, 1183, 1141,
1099, 1039, 1002, 938, 852 cmÀ1; MS(70 eV, EI): m/z (%): 319 (6) [M]+,
304 (18), 275 (46), 260 (18), 236 (62), 234 (72), 220 (41), 206 (20), 41
(100); EI-HRMS: m/z: calcd for C15H17NO2F4: 319.1195 [M]+; found:
319.1184; elemental analysis calcd (%) for C15H17NO2F4 (319.3): C 56.43,
H 5.37, N 4.39, F 23.80; found: C 56.36, H 5.27, N 4.47, F 23.95.
ꢀ0.1 mmHg) to obtain 3.40 g (76%) of 5c as
a colourless liquid.
1H NMR (400 MHz): d=3.95 (s, 3H; OCH3), 7.42 (ddm, 3J
A
Ester 5kb: Colourless oil; 1H NMR (400 MHz): d=1.95 (s, 3H; CH3),
3
2.18 (s, 3H; CH3), 4.99 (d, 2J(H,H)=12.9 Hz, 1H; CH2), 5.09 (d, 2J-
A
7.7 Hz, 5.0 Hz, 1H; Har), 7.71 (d, J
ACHTREUNG
3J
G
G
ACHTREUNG
U
(H,H)=12.9 Hz, 1H; CH2), 5.26
AHCTREUNG
AHCTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
2H; C6H4); 13C NMR (100.6 MHz): d=8.6, 12.6, 47.8 (d, 4J
ACHTREUNG
(C,F)=25.0 Hz),
ACHTREUNG
6.0 Hz), 67.5, 90.4 (dq, 1J
A
ACHTREUNG
(376.4 MHz): d=À169.33 (q, 3J
G
2
1
ACHTREUNG
1J
N
A
(C,F)=272.5 Hz), 125.4,
(d, 3J
(F,F)=7.8 Hz, 3F, CFCF3); IR (film): n˜ =3065, 2962, 1770, 1589,
G
125.4, 127.5, 127.5, 127.9, 128.7, 130.6 (q, 2J
ACHTREUNG
1439, 1317, 1303, 1276, 1209, 1183, 1126, 1041, 784, 753, 726 cmÀ1; MS
(70 eV, EI): m/z (%): 237 (63) [M]+, 222 (63), 206 (12), 193 (34), 178
(62), 159 (21), 143 (35), 128 (100), 78 (57), 59 (96); EI-HRMS: m/z: calcd
for C9H7NO2F4: 237.0413 [M]+; found 237.0416; elemental analysis calcd
(%) for C9H7NO2F4 (237.2): C 45.58, H 2.97, N 5.91, F 32.04; found: C
44.89, H 2.91, N 5.96, F 31.51.
(C,F)=24.1 Hz), 134.9, 135.7, 138.1, 161.8 ppm (d, 2J
ACHTREUNG
19F NMR (376.4 MHz): d=À163.50 (q, 3J
ACHTREUNG
À74.49 (d, 3J
(F,F)=9.9 Hz, 3F, CFCF3), À63.22 ppm (s, 3F, CF3); IR
(CH2Cl2): n˜ =2926, 1772, 1436, 1327, 1299, 1261, 1169, 1129, 1067,
1018 cmÀ1; MS(70 eV, EI): m/z (%): 488 (17) [M]+, 469 (2), 285 (8), 91
(100); EI-HRMS: m/z: calcd for C23H19N2O2F7: 488.1335 [M]+; found:
488.1350; elemental analysis calcd (%) for C23H19N2O2F7 (488.4): C 56.56,
H 3.92, N 5.74, F 27.23; found: C 56.76, H 3.88, N 5.55, F 27.13.
Methyl 2-chloro-2-fluoro-2-(2’-quinolinyl)acetate (14a): Pale yellow oil;
1H NMR (400 MHz): d=3.96 (s, 3H; OCH3), 7.61 (ddd, 3J
ACHTREUNG
8.1 Hz, 6.9 Hz, 4J
7.0 Hz, 4J(H,H)=1.5 Hz, 1H; Har), 7.85 (dd, 3J
1.2 Hz, 1H; Har), 7.89 (d, J
8.5 Hz, 4J(H,H)=0.8 Hz, 1H; Har), 8.30 ppm (d, 3J
Har); 13C NMR (100.6 MHz): d=54.1, 104.4 (d, 1J
(C,F)=252.6 Hz), 117.4
(d, 4J(C,F)=2.6 Hz), 127.5, 128.1, 129.9, 130.3, 137.9, 146.5, 154.9 (d, 2J-
(C,F)=25.9 Hz), 165.1 ppm (d, (C,F)=29.3 Hz);
2J 19F NMR
(H,H)=1.1 Hz, 1H; Har), 7.75 (ddd, 3J
ACHTREUNG
Amide 7d: HFP (ꢀ0.5 mL, 4 mmol) was condensed at À788C into a
glass pressure tube. DMF (2.0 mL) and 4-tert-butylpyridine N-oxide (1d;
144 mg, 0.95 mmol) were added, and the tube was sealed with a Teflon
valve. The reaction mixture was vigorously stirred at 808C for 5 h. After
cooling to RT, the pressure tube was opened, and the unreacted hexa-
fluoropropene and products of its oligomerisation were removed under
reduced pressure (water pump). p-Toluidine (204 mg, 1.9 mmol) solution
in DMF (1.0 mL) was added, and the reaction mixture was stirred over-
night at RT (ꢀ14 h). It was then poured into water (10 mL), and the
product was extracted with CH2Cl2 (3”5mL). The organic phase was
washed with water (5”20 mL), dried (Na2SO4) and evaporated. The
crude product was purified by column chromatography (SiO2, hexanes/
AcOEt 5:1). After evaporation, the title compound was obtained as a
light-yellow crystalline solid. Yield: 207 mg (59%); m.p. 130–1318C (cy-
H
G
ACHTREUNG
3
3
ACHTREUNG
G
(H,H)=
U
ACHTREUNG
AHCTREUNG
ACHTREUNG
H
ACHTREUNG
(376.4 MHz): d=À109.18 ppm (s); IR (film): n˜ =3064, 2957, 1770, 1595,
1504, 1437, 1280, 1097, 1021, 824, 783, 706 cmÀ1; MS(70 eV, EI): m/z
(%): 253 (32) [M]+, 194 (100), 158 (39), 128 (34); EI-HRMS: m/z: calcd
for C12H9NO235ClF: 253.0306 [M]+; found: 253.0311; elemental analysis
calcd (%) for C12H9NO2ClF (253.7): C 56.82, H 3.58, N 5.52, Cl 13.98, F
7.49; found: C 56.67, H 3.53, N 5.51, Cl 13.69, F 7.59.
The preparation of esters from other alcohols was performed according
to the procedure described for methyl esters and by using 10 equiv of the
appropriate alcohol.
1
clohexane/Et2O); H NMR (400 MHz): d=1.35 (s, 9H; tBu), 2.32 (s, 3H;
CH3), 7.15 (d, 3J
G
G
4
A
N
p-Methoxybenzyl 2-(4’-tert-butylpyridin-2’-yl)perfluoropropionate (5db):
Pale yellow oil; 1H NMR (400 MHz): d=1.31 (s, 9H; tBu), 3.79 (s, 3H;
AHCTREUNG
OCH3), 5.32 (AB, 2J
8.8 Hz, 2H; C6H4), 7.29 (dm, 3J
(H,H)=5.1 Hz, 4J
(H,H)=1.8 Hz, 1H; Har), 7.62 (s, 1H; Har), 8.50 ppm
(d, 3J(H,H)=5.1 Hz, 1H; Har); 13C NMR (100.6 MHz): d=30.4, 35.0,
55.2, 68.3, 93.1 (dq, J
3J(C,F)=6.0 Hz), 121.1 (qd, 1J
126.5, 130.2, 149.2, 149.9 (d, 2J
A
(H,H)=
(H,H)=8.8 Hz, 2H; C6H4), 7.36 (dd, 3J-
E
AHCTREUNG
A
N
H
E
25.0 Hz), 158.8 (d, 2J
H
1
2
ACHTREUNG
G
(C,F)=31.0 Hz), 113.9, 118.6 (d,
19F NMR (376.4 MHz): d=À177.13 (q, 3J
H
E
A
À76.96 ppm (d, 3J
U
N
1690, 1611, 1548, 1512, 1209, 1176, 1091, 824 cmÀ1; MS(70 eV, EI): m/z
2586
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 2577 – 2589

2-Heteroarylperfluoropropionic Acids
FULL PAPER
(%): 368 (4) [M]+, 353 (1), 235 (100), 215 (13), 200 (22); EI-HRMS: m/z:
calcd for C19H20N2OF4: 368.1512 [M]+; found: 368.1519; elemental analy-
sis calcd (%) for C19H20N2OF4 (368.4): C 61.95, H 5.47, N 7.60, F 20.63;
found: C 61.97, H 5.39, N 7.59, F 20.60.
2-(2’-Pyridyl)perfluoropropionic N-n-butylamide (7c): Pale yellow oil;
1H NMR (400 MHz): d=0.92 (t, 3J
(H,H)=7.3 Hz, 3H; CH3), 1.35 (m,
G
3
2H; CH2), 1.55 (m, 2H; CH2), 3.37 (m, 2H; NCH2), 7.44 (ddd, J
7.5 Hz, 4.8 Hz, 4J(H,H)=1.3 Hz, 1H; Har), 7.81 (dd, 3J(H,H)=8.1 Hz, 4J-
(H,H)=0.9 Hz, 1H; Har), 7.87 (td, 3J(H,H)=7.5 Hz, 4J
(H,H)=1.8 Hz,
Har), 8.68 ppm (dm, 3J(H,H)=4.8 Hz, 1H; Har); 13C NMR (100.6 MHz):
d=13.5, 19.8, 31.1, 39.6, 91.6 (dq, 1J(C,F)=197.4 Hz, 2J
(C,F)=31.0 Hz),
121.1 (qd, 1J(C,F)=286.2 Hz, 2J(C,F)=29.3 Hz), 121.7 (d, 3J
(C,F)=
7.8 Hz), 124.9, 137.6 (d, 4J(C,F)=1.7 Hz), 148.8 (d, 4J
(C,F)=1.7 Hz),
150.1 (d, 2J(C,F)=24.1 Hz), 161.5 ppm (d, 2J(C,F)=21.6 Hz); 19F NMR
(376.4 MHz): d=À175.09 (q, J
(F,F)=8.8 Hz, 3F, CF3); IR (film): n˜ =3333, 2962, 1694, 1539, 1469, 1437,
A
A
ACHTREUNG
A
N
ACHTREUNG
2,3,3,3-Tetrafluoropropionic toluamide (11): Pale yellow crystals, m.p. 90–
918C (hexanes/Et2O); 1H NMR (400 MHz): d=2.33 (s, 3H; CH3), 5.18
AHCTREUNG
(dq, 2J
8.5 Hz, 2H; Har), 7.43 (d, 3J
NH); 13C NMR (100.6 MHz): d=21.1, 85.9 (dq, 1J
(C,F)=33.6 Hz), 120.7, 120.8 (qd, 1J(C,F)=282.8 Hz, 2J
(C,F)=18.1 Hz); 19F NMR
(F,H)=46.8 Hz, 1F, CHF), À76.31 ppm
G
U
(H,H)=
(H,H)=8.5 Hz, 2H; Har), 8.00 ppm (s, 1H;
(C,F)=205.2 Hz, 2J-
(C,F)=25.9 Hz),
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
G
3
3
130.0, 133.3, 136.0, 159.0 ppm (d, 2J
A
(376.4 MHz): d=À200.70 (dm, 2J
AHCTREUNG
1273, 1199, 754 cmÀ1; MS(70 eV, EI): m/z (%): 278 (<1) [M]+, 263 (3),
235 (7), 206 (13), 179 (100), 159 (55); EI-HRMS: m/z: calcd for
C12H14N2OF4: 278.1042 [M]+; found: 278.1048; elemental analysis calcd
(%) for C12H14N2OF4 (278.2): C 51.80, H 5.07, N 10.07, F 27.31; found: C
51.99, H 5.05, N 9.95, F 27.10.
3
(dd, J(F,F)=9.8 Hz, J(F,H)=7.4 Hz, 3F, CF3); IR (KBr): n˜ =3331, 3208,
U
3147, 2930, 1697, 1674, 1608, 1552, 1516, 1350, 1268, 1256, 1194, 1149,
1095, 870, 820 cmÀ1; MS(70 eV, EI): m/z (%): 235 (100) [M]+, 134 (62),
106 (99), 91 (37); EI-HRMS: m/z: calcd for C10H9NOF4: 235.0620 [M]+;
found: 235.0617; elemental analysis calcd (%) for C10H9NOF4 (235.2): C
51.07, H 3.86, N 5.96, F 32.31; found: C 50.79, H 4.01, N 5.86, F 32.49.
Amide 7ka: Colourless crystalline solid, m.p. 131–1328C (hexanes/Et2O);
1H NMR (400 MHz): d=1.96 (s, 1H; CH3), 2.12 (s, 1H; CH3), 4.58 (dd,
Compound 12: Pale yellow oil; 1H NMR (400 MHz): d=2.31 (s, 6H;
2J
C
N
ACHTREUNG
CH3), 5.62 (dq, 2J
A
ACHTREUNG
CH2Ph), 5.33 (d, 2J
ACHTREUNG
ACHTREUNG
6.8 Hz, 2H; Ph), 7.19–7.34 (m, 4H; Har), 7.44 (td, 3J
A
ACHTREUNG
(C,F)=231.9 Hz), 129.4, 129.8, 132.6, 133.4, 135.9, 143.1 (d, 2J
(C,F)=
G
A
3J
48.4 (d, 3J
119.6 (d, 2J
30.2 Hz), 121.9 (m), 122.5 (dm, 2J
273.3 Hz), 125.5, 127.3, 127.5, 128.7, 130.0 (d, J
2J(C,F)=31.0 Hz, 3J(C,F)=3.4 Hz), 133.4 (d, 2J
160.3 (d, 2J (C,F)=250.9 Hz); 19F NMR
(F,F)=11.7 Hz, 1F, CFCF3), À113.33 (m,
(F,F)=11.7 Hz, 3F, CFCF3), À59.41 (s,
ACHTREUNG
A
N
ACHTREUNG
A
G
(F,F)=
12.4 Hz, 3J
(F,H)=5.0 Hz, CF3); IR (film): n˜ =3453, 3027, 2924, 1658,
A
N
ACHTREUNG
1601, 1535, 1504, 1320, 1266, 1197, 1146, 1077, 831, 814 cmÀ1; MS(70 eV,
EI): m/z (%): 324 (90) [M]+, 218 (90), 107 (77), 91 (100); EI-HRMS:
m/z: calcd for C17H16N2F4: 324.1250 [M]+; found: 324.1244.
A
ACHTREUNG
3
AHCTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
2-(2’-Quinolinyl)perfluoropropionic N,N-diethylamide (7aa): The title
compound was prepared in analogous manner to 7d, but the reaction
with HFP was performed for 3 h at RT, and the second step (after evapo-
rating the excess of HFP) was executed by adding neat diethylamine
(347 mg, 493 mL, 4.75 mmol). Colourless crystalline solid, m.p. 88–898C
(376.4 MHz): d=À170.88 (q, 3J
ACHTREUNG
1F, C
(sp2)-F), À76.90 ppm (d, 3J
3F, CF3); IR (KBr): n˜ =3328, 3070, 2918, 1685, 1540, 1471, 1452, 1431,
1367, 1323, 1216, 1183, 1170, 1138, 1118, 1069, 957, 934, 799, 724 cmÀ1
;
MS(70 eV, EI): m/z (%): 505 (28) [M]+, 286 (58), 195 (81), 91 (100); EI-
HRMS: m/z: calcd for C23H19N3OF8: 505.1400 [M]+; found: 505.1413; el-
emental analysis calcd (%) for C23H19N3OF8 (505.4): C 54.66, H 3.79, N
8.31, F 30.07; found: C 54.53, H 3.91, N 8.32, F 31.01.
(hexanes/Et2O); 1H NMR (400 MHz): d=0.93 (t, 3J
CH3), 1.21 (t, 3J
(H,H)=7.2 Hz, 3H; CH3), 2.78 (m, 1H; CH2), 3.08 (m,
1H; CH2), 3.19 (m, 1H; CH2), 3.72 (m, 1H; CH2), 7.64 (ddd, 3J
(H,H)=
8.2 Hz, 6.8 Hz, 4J
(H,H)=1.1 Hz, 1H; Har), 7.74–7.80 (m, 2H; Har), 7.88
(d, 3J(H,H)=8.1 Hz, 1H; Har), 8.16 (d, 3J
(H,H)=8.4 Hz, 1H; Har),
8.32 ppm (d, J
(H,H)=8.6 Hz, 1H; Har); 13C NMR (100.6 MHz): d=11.8,
13.6 (d, 5J(C,F)=1.7 Hz), 40.8, 41.5 (d, 4J(C,F)=8.7 Hz), 94.8 (dq, 1J-
(C,F)=204.3 Hz, J
1J(C,F)=285.4 Hz, 2J
137.6, 147.2 (d, 4J(C,F)=1.7 Hz), 150.3 (d, 2J
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
1
Amide 7kb: Obtained as a 6.7:1 (from H NMR) mixture of diastereoiso-
A
ACHTREUNG
3
ACHTREUNG
mers, only the major one could be isolated in a pure form. White needles,
m.p. 136–1388C (hexanes/Et2O); 1H NMR (400 MHz): d=1.49 (d, 3J-
A
ACHTREUNG
2
3
ACHTREUNG
AHCTREUNG
N
G
(C,F)=3.4 Hz), 121.6 (qd,
A
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
(d, 2J
A
ACHTREUNG
CFCF3), À75.64 ppm (d, 3J
(F,F)=7.0 Hz, 3F, CFCF3); IR (KBr): n˜ =
2973, 1671, 1462, 1291, 1213, 1163, 1094, 827, 769 cmÀ1; MS(70 eV, EI):
m/z (%): 328 (2) [M]+, 308 (37), 237 (100), 229 (48), 209 (28), 178 (26),
128 (22), 100 (39), 72 (50); EI-HRMS: m/z: calcd for C16H16N2OF4:
328.1199 [M]+; found: 328.1186; elemental analysis calcd (%) for
C16H16N2OF4 (328.3): C 58.54, H 4.91, N 8.53, F 23.15; found: C 58.48, H
4.78, N 8.43, F 23.03.
A
N
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
3
ACHTREUNG
A
(KBr): n˜ =3312, 3031, 2981, 2975, 1677, 1537, 1431, 1212, 1171, 1132,
1068, 750, 699 ppm; MS(70 eV, EI): m/z (%): 433 (7) [M]+, 418 (2), 286
(62), 285 (53), 195 (68), 105 (30), 91 (100); EI-HRMS: m/z: calcd for
C23H23N3OF4: 433.1777 [M]+; found: 433.1771; elemental analysis calcd
(%) for C23H23N3OF4 (433.4): C 63.73, H 5.35, N 9.69, F 17.53; found: C
63.45, H 5.61, N 9.44, F 17.42.
General one-pot, two-step procedure for preparation of 2-heteroarylper-
fluoropropionic amides: Fluoroalkene (ꢀ0.5 mL, 4 mmol) was con-
densed in a glass pressure tube at À788C under an argon atmosphere.
DMF (2.4 mL) and N-oxide (0.95 mmol) were introduced, and the pres-
sure tube was closed with a Teflon valve. The contents of the tube were
stirred vigorously at 808C for 5 h. (or in some cases at RT, see
Scheme 13). After cooling to RT, the pressure tube was opened, and the
unreacted hexafluoropropene and products of its oligomerisation were
removed under reduced pressure by using a water pump. The reaction
mixture was subsequently cooled to 08C (argon atmosphere), and NEt3
(192 mg, 265 mL, 1.9 mmol) and the appropriate primary or secondary
amine (1.9 mmol) were added with stirring. The reaction mixture was al-
lowed to slowly reach room temperature. After about 14 h, the mixture
was poured into water (10 mL), and the products were isolated similarly
to the procedure for 2-heteroarylperfluoropropionic methyl esters.
Amide 7m: Pale yellow crystals, m.p. 113–1148C (Et2O); 1H NMR
(400 MHz): d=7.39 (ddd, 3J
U
ACHTREUNG
1H; Har), 7.71 (dd, 3J
A
3
4
(ddd, J
A
(H,H)=2.0 Hz, J
(td, 3J
A
N
ACHTREUNG
A
ACHTREUNG
A
ACHTREUNG
4
3
ACHTREUNG
4
G
N
A
N
ACHTREUNG
AHCTREUNG
Chem. Eur. J. 2008, 14, 2577 – 2589
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2587

M. Ma˛kosza and R. Loska
(100.6 MHz): d=91.3 (dq, 1J
121.0 (qd, 1J(C,F)=286.2 Hz, 2J
124.6, 127.8, 137.3, 138.1, 139.1 (d, 4J
(d, 2J(C,F)=25.9 Hz), 149.3, 154.1, 155.9 (d, 3J
(d, 2J
8.6 Hz, 1F, CF), À76.58 ppm (d, J
C
G
m/z: calcd for C23H21N3OF4: 431.1621 [M]+; found: 431.1632; elemental
analysis calcd (%) for C23H21N3OF4 (431.4): C 64.03, H 4.91, N 9.74, F
17.61; found: C 64.14, H 4.84, N 9.89, F 17.61.
G
ACHTREUNG
AHCTREUNG
U
ACHTREUNG
2,3,3,3-Tetrafluoropropionic amide (13): Colourless crystalline solid, m.p.
101–1028C (hexanes/Et2O); 1H NMR (400 MHz): d=3.24 (t, 3J
ACHTREUNG
A
3
AHCTREUNG
A
N
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
125.5, 127.7, 131.3, 142.0, 158.4 ppm (d, 2J
ACHTREUNG
(376.4 MHz): d=À200.32 (dq, 2J
A
ACHTREUNG
Amide 7b: Pale yellow oil; 1H NMR (400 MHz): d=1.20 (t, 3J
CF), À75.66 ppm (dd, 3J
A
ACHTREUNG
3
7.1 Hz, 3H; CH3), 1.20 (t, J
A
(KBr): n˜ =2923, 1677, 1598, 1486, 1433, 1350, 1260, 1196, 1151, 1121, 868,
757 cmÀ1; MS(70 eV, EI): m/z (%): 247 (100) [M]+, 146 (55), 128 (52),
118 (99), 91 (82); EI-HRMS: m/z: calcd for C11H9NOF4: 247.0620 [M]+;
found: 247.0629; elemental analysis calcd (%) for C11H9NOF4 (247.2): C
53.45, H 3.67, N 5.67, F 30.74; found: C 53.57, H 3.53, N 5.71, F 30.70.
2”CH2), 3.35–3.43 (m, 2H; NCH2), 3.43–3.53 (m, 2H; OCH2), 3.57–3.68
(m, 2H; OCH2), 3.99 (s, 3H; OCH3), 4.48 (m, 1H; CH(OEt)2), 7.62 (s,
3
1H; NH), 7.92 (d, J(H,H)=8.2 Hz, 1H; Har), 8.44 (dd, J(H,H)=8.2 Hz,
A
4J(H,H)=2.0 Hz, 1H; Har), 9.25 ppm (m, 1H; Har); 19F NMR
U
(376.4 MHz): d=À174.63 (q, 3J(F,F)=8.7 Hz, 1F, CFCF3), À76.39 (d, 3J-
G
A
3,3,3-Trifluoro-2-(2’-quinolinyl)propionic N-ethyl-N-phenylamide (8a):
Colourless crystalline solid, m.p. 97–998C (benzene/Et2O); 1H NMR
447.1511 [M+Na]+; found: 447.1514.
(400 MHz): d=1.11 (t, 3J
13.4 Hz, 3J
(H,H)=7.2 Hz, 1H; NCH2), 4.79 (q, 3J
(m, 2H; Har), 7.36 (m, 3H; Har), 7.56 (ddd, 3J
(H,H)=1.2 Hz, 1H; Har), 7.70 (ddd, 3J(H,H)=8.5 Hz, 6.9 Hz, 4J
U
ACHTREUNG
Amide 7b’: Pale yellow oil; 1H NMR (400 MHz): d=1.20 (t, 3J
(H,H)=
7.1 Hz, 6H; 2”CH3), 1.60–1.80 (m, 4H; 2”CH2), 3.46–3.55 (m, 2H;
NCH2), 3.60–3.67 (m, 2H; OCH2), 3.98–4.06 (m, 1H; OCH2), 4.08–4.17
U
U
(m, 1H; OCH2), 4.52 (t, 3J
G
(OEt)2), 7.71 (dd, 3J-
(H,H)=
(H,H)=1.8 Hz, Har); 13C NMR (100.6 MHz): d=15.3, 18.4, 20.2,
G
ACHTREUNG
A
4
ACHTREUNG
1.5 Hz, 1H; Har), 7.83 (d, J
U
4.8 Hz, J
23.1, 30.8, 40.8, 41.6, 61.3, 87.0 (dq, J
102.3, 126.5, 137.1, 146.5 (d, 2J
(C,F)=17.2 Hz), 154.8, 161.5, 162.7 ppm
(d, 2J
(C,F)=21.6 Hz), 200.5; 19F NMR (376.4 MHz): d=À178.47 (q, 3J-
(F,F)=12.3 Hz, 1F, CFCF3), À77.73 (d, J(F,F)=11.6 Hz, 3F, CFCF3).
7.9 Hz, 4J
G
1
G
Har); 13C NMR (100.6 MHz): d=12.7, 44.8, 56.1 (q, 2J
AHCTREUNG
1
120.9, 124.0 (q, J
ACHTREUNG
ACHTREUNG
129.8, 129.8, 136.8, 140.7, 147.6, 151.0 (q, 3J
3J
3
ACHTREUNG
N
(C,F)=1.7 Hz); 19F NMR (376.4 MHz): d=À65.94 ppm (d, 3J
ACHTREUNG
One-step preparation of 2-heteroarylperfluoropropionic amides: These
reactions were performed analogously to the syntheses of 2-heteroaryl-
perfluoropropionic methyl esters by using reagent quantities and condi-
tions specified in Scheme 14 and Scheme 16.
8.6 Hz, CF3); IR (KBr): n˜ =3067, 2986, 2935, 1676, 1595, 1494, 1411,
1341, 1301, 1263, 1177, 1160, 1105, 825, 777, 757, 709 cmÀ1; MS(70 eV,
EI): m/z (%): 358 (8) [M]+, 238 (18), 211 (100), 191 (20), 128 (18), 120
(52); EI-HRMS: m/z: calcd for C20H17N2OF4: 358.1293 [M]+; found:
358.1282; elemental analysis calcd (%) for C20H17N2OF3 (358.4): C 67.03,
H 4.78, N 7.82, F 15.90; found: C 67.04, H 4.85, N 7.86, F 15.90.
2-(2’-Quinolinyl)perfluoropropionic N-ethyl-N-phenylamide (7ab): Col-
ourless crystalline solid, m.p. 133–1358C (cyclohexane/Et2O); 1H NMR
(400 MHz): d=1.17 (t, 3J
(H,H)=7.2 Hz, 3H; CH3), 3.72–3.87 (m, 2H;
E
Thioester 6e: This compound was prepared analogously to amide 7d by
adding p-chlorothiophenol (275 mg, 1.9 mmol) to the DMF solution of
acyl fluoride 9e instead of the amine. Pale yellow oil; 1H NMR
CH2), 7.06 (m, 3H; Har), 7.20–7.45 (m, 3H; Har), 7.62 (tm, 3J
7.2 Hz, 1H; Har), 7.75–7.83 (m, 2H; Har), 7.98 (d, 3J
3
8.20 ppm (d, J
A
(400 MHz): d=7.35 (d, 3J
8.7 Hz, 2H; C6H4), 7.47 (dd, 3J
Har), 7.77 (s, 1H; Har), 8.63 ppm (d, J
(100.6 MHz): d=96.0 (m), 120.3 (qd, 1J
28.4 Hz), 122.3 (d, 3J(C,F)=7.8), 122.9 (d, 4J
136.0, 136.9, 145.8, 150.1 (d, 2J(C,F)=24.1), 150.6 (d, 3J
188.7 ppm (d, 2J
(C,F)=30.2); 19F NMR (376.4 MHz): d=À170.28 (q, 3J-
(F,F)=8.7 Hz, 1F, CFCF3), À75.67 ppm (d, 3J
(F,F)=8.7 Hz, 3F, CFCF3);
A
ACHTREUNG
46.3, 94.6 (dq, 1J
6.9 Hz), 121.5 (qd, 1J
127.8, 128.2, 129.2, 129.8, 129.9, 130.2, 136.9, 139.3 (d, 4J
146.8 (d, 4J(C,F)=2.5 Hz), 151.1 (d, 2J(C,F)=25.0 Hz), 161.6 ppm (d, 2J-
A
ACHTREUNG
3
AHCTREUNG
A
ACHTREUNG
A
A
ACHTREUNG
H
A
ACHTREUNG
À75.90 ppm (d, 3J
(F,F)=6.3 Hz, 3F, CFCF3); IR (KBr): n˜ =3055, 2979,
AHCTREUNG
1679, 1593, 1496, 1408, 1287, 1215, 1165, 1105, 829, 769, 704 cmÀ1; MS
(70 eV, EI): m/z (%): 376 (14) [M]+, 356 (3), 229 (76), 120 (100); EI-
HRMS: m/z: calcd for C20H16N2OF4: 376.1199 [M]+; found: 376.1210; el-
emental analysis calcd (%) for C20H16N2OF4 (376.4): C 63.83, H 4.29, N
7.44, F 20.19; found: C 63.92, H 4.24, N 7.45, F 20.30.
A
ACHTREUNG
IR (film): n˜ =3063, 1723, 1575, 1478, 1391, 1280, 1212, 1188, 1144, 1014,
821, 750 cmÀ1; MS(70 eV, EI): m/z (%): 383 (3) [M]+, 240 (100), 212
(89), 162 (25), 143 (21), 108 (15); EI-HRMS: m/z: calcd for
C14H7NOSCl2F4: 382.9562 [M]+; found: 382.9556; elemental analysis
calcd (%) for C14H7NOSCl2F4 (384.2): C 43.77, H 1.83, N 3.65, S8.35, Cl
18.46, F 19.78; found: C 43.67, H 1.66, N 3.78, S8.63, Cl 18.44, F 19.78.
Amide 7kc: Colourless crystalline solid, m.p. 152–1548C (cyclohexane/
CH2Cl2); 1H NMR (400 MHz): d=2.08 (s, 3H; CH3), 2.20 (s, 3H; CH3),
2.90 (t, 3J
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
3
5
(H,H)=8.1 Hz, 1H; Har); 13C NMR (100.6 MHz): d=9.0, 12.9, 28.3 (d, J-
Acknowledgement
4
4
ACHTREUNG
G
N
We wish to thank Prof. Henryk Koroniak (Adam Mickiewicz Uniwersity,
Poznan) for the generous gift of pentafluoropropene. This work was sup-
ported by the Polish Ministry of Science and Higher Education (grant no.
3 T09 A 043 27).
G
G
ACHTREUNG
2
ACHTREUNG
ACHTREUNG
(C,F)=19.8 Hz); 19F NMR (376.4 MHz): d=À166.12 (q, 3J
ACHTREUNG
1F, CF), À75.01 ppm (d, 3J
ACHTREUNG
2924, 1684, 1598, 1481, 1461, 1437, 1407, 1282, 1210, 1172, 1130, 1073,
997, 760, 743, 720, 687 cmÀ1; MS(70 eV, EI): m/z (%): 431 (4) [M]+, 411
(9), 340 (4), 314 (11), 294 (100), 285 (31), 195 (24), 91 (67); EI-HRMS:
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Received: September 7, 2007
Published online: January 11, 2008
Chem. Eur. J. 2008, 14, 2577 – 2589
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2589