Reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and its use for the synthesis of new polyfluoroalkyl pyrroles and pyrrolidines

Article abstract of DOI:10.1039/c2ob26176f

The hitherto unreported reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and equimolar amounts of potassium-tert- butoxide proceeded mainly in the β-position of the α,β- unsaturated ketones in cases of α-nonsubstituted 1a-e an

Full text of DOI:10.1039/c2ob26176f

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PAPER
Reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate
and its use for the synthesis of new polyfluoroalkyl pyrroles and
pyrrolidines†‡
a
a
a
a
b
Ivan S. Kondratov, Violetta G. Dolovanyuk, Nataliya A. Tolmachova, Igor I. Gerus, Klaus Bergander,
b
b
Roland Fröhlich and Günter Haufe*
Received 19th June 2012, Accepted 17th August 2012
DOI: 10.1039/c2ob26176f
The hitherto unreported reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and
equimolar amounts of potassium-tert-butoxide proceeded mainly in the β-position of the α,β-unsaturated
ketones in cases of α-nonsubstituted 1a–e and α-methyl substituted ketones 1g–j. Other α- or
β-substituted ketones 1f,k–o gave mainly products 4 of initial attack at the carbonyl carbon. Depending
on the solvent, the major products of β-attack do exist in different tautomeric forms. Generally the open-
chain enol tautomers 5 predominate in the polar DMSO-d , while the cyclic γ-hemiaminals 8 are the
6
major tautomers in the less polar CDCl . Acid treatment of the latter compounds 8 led to the hitherto
3
unknown ethyl 5-polyfluoroalkyl-pyrrole-2-carboxylates 11 by elimination of formic acid. Catalytic
hydrogenation of pyrrole 11a was used for the synthesis of earlier unknown 5-trifluoromethyl proline 16.
Introduction
Polyfluoroalkyl alkoxyenones 1 are readily available, versatile
building blocks for the construction of different fluoroorganic
1
compounds. For instance, compounds 1 were applied to protect
2
amino acids in peptide synthesis, as starting materials for the
synthesis of mevalonic acid analogs and GABA-surrogates, as
3
4
Fig. 1 Reactivity of β-alkoxyalkenyl polyfluoroalkyl ketones 1.
well as for the preparation of different classes of fluoro-contain-
1
ing heterocycles and versatile fluorinated building blocks.
Most of the mentioned reactions of enone 1 are highly regio-
selective, but in some cases the regioselectivity of reactions with
particular C-nucleophiles dramatically depends on the con-
Most applications of enones 1 as starting materials include
reactions with nucleophiles, which can proceed both at the car-
bonyl group and in its β-position. During the last two decades
numerous reactions of enones 1 with various C-, N-, O- and
P-nucleophiles were investigated in order to disclose the particu-
larities of reactivity of compounds 1 and regioselectivity of the
transformations (Fig. 1).
5
6
ditions, as well as the substrate and reagent structures.
Reactions with glycine derivatives as C-nucleophiles are of
particular interest because the introduction of the α-aminoester
moiety becomes possible. This can be useful for the construction
of new amino acids and/or the formation of heterocyclic systems.
Earlier we described the reaction of alkoxyenones 1 with
N-benzoyl glycine that led to the formation of pyrones 2 via the
corresponding 2-phenyloxazolinone intermediates (Scheme 1,
the reactions of trifluoromethyl enone 1a are given as
a
Institute of Bioorganic Chemistry and Petrochemistry, National
Ukrainian Academy of Sciences, Murmanska 1, Kiev-94, 02660,
Ukraine
7
b
Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40,
examples). Recently, the reaction of enone 1a with (benzylide-
D-48149 Münster, Germany. E-mail: haufe@uni-muenster.de;
Fax: +49-251-83-39772; Tel: +49-251-83-33-33281
neamino) acetates to form trifluoroacetyl pyrroles 3 was
reported. It should be noted that the initial attack of nucleo-
8
†
Dedicated to Academician Professor Dr Valery P. Kukhar on the
occasion of his 70th birthday.
Electronic supplementary information (ESI) available: Spectroscopic
philes occurred in the β-position of enone 1a in both cases.
However, the heterocyclizations took place in different ways.
While the keto group of 1 and the carbonyl function of glycine
are involved in the cyclization leading to pyrones 2, a reaction of
the imino group at the α-position of the glycine moiety is
required for the formation of pyrroles 3.
‡
1
13
and mass spectrometric data, elemental analyses, and copies of H, C,
1
9
and F NMR spectra of all new compounds 1, 4, 5, 7, 8, 10, 11, 12, 13,
1
4, 15 and 16 together with X-ray data of compound 8d. CCDC
8
87922. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob26176f
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which were previously used for the preparation of N-formyl-
13
α-amino-α,β-unsaturated esters including the stereoselective
synthesis of some α-formylamino-β-trifluoromethyl-α,β-unsatu-
10b
rated esters starting from trifluoromethyl ketones (Scheme 2).
We found that treatment of trifluoromethyl enone 1a with
ethyl isocyanoacetate led to the expected compound 4a only as a
minor product (15%) formed by reaction of the carbonyl group
(
Scheme 3). The main reaction starts with an attack at the β-posi-
tion of the alkoxyenone 1a leading to the formation of product
a (main tautomer by NMR spectra in DMSO-d ). The regio-
5
6
selectivity of this reaction was not temperature dependent. Thus
at −40 and −90 °C the ratios of 4a were 14 and 12%, respect-
Scheme 1 Reaction of β-ethoxyvinyl trifluoromethyl ketone 1a with
ively. Since the reaction products of CF -ketones with isocyano-
3
glycine derivatives as C-nucleophiles.
acetate possessed the Z-configuration of the formed CvC
10b
double bond,
this configuration is also anticipated for the
Reactions of enones 1 with other glycine derivatives such as
alkyl isocyanoacetates have not been described in the literature
although isocyanoacetates are versatile polyfunctional reagents
with useful chemical properties. They were found to be
especially important in multicomponent reactions and in the syn-
CvC double bond of compound 4a.
As shown in Scheme 3, the initial attack at the β-position and
subsequent EtOH elimination gave intermediate 6a. Hydrolysis
of the isocyano group under acidic conditions led to the for-
mation of 7a, which in DMSO-d solution tautomerizes to the
6
9
thesis of amino acid derivatives. Also reactions of isocyano-
more stable enol tautomer 5a.
acetates with several fluorinated carbonyl compounds have been
After isolation of 5a the equilibrium of several tautomeric
10
investigated and applied to the stereoselective synthesis of
forms in DMSO-d
-solution was investigated (Scheme 4). The
6
1
0a,11
1
fluorinated amino acid derivatives.
Continuing our investigations on the synthesis of new fluori-
most distinctive signals of the H NMR spectrum of 5a in
12
nated amino acids, in this paper we present our results of the
reactions of enones 1 with ethyl isocyanoacetate and its appli-
cation to the synthesis of new fluorinated pyrroles.
Results and discussion
Reaction of α,β-unsubstituted enones 1a–e
The reaction of enones 1 with ethyl isocyanoacetate was investi-
gated under Schöllkopf’s conditions (t-BuOK, THF, −78 °C),
Scheme 2 Reactions of trifluoromethyl ketones with ethyl isocyano-
acetate to give ethyl N-formyl-α-amino-β-trifluoromethyl-α,β-unsatu-
rated esters.
Scheme 4 Equilibrium between compounds 5a, 7a–9a which were
identified in DMSO-d (5a, 8a) and CDCl (5a, 7a–9a) solutions.
1
0b
6
3
Scheme 3 Reaction of trifluoromethyl enone 1a with ethyl isocyanoacetate (isolated yields are presented in parentheses, see Table 1).
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DMSO-d are two doublets at δ = 5.85 and 7.28 ppm (J =
β-position were formed exclusively. In DMSO-d the tautomer
6
6
1
2.6 Hz), which correspond to protons of the Z,Z-1,3-diene
8b predominates (for the CHF -product, Table 1, entry 2), while
2
system. Two other doublets (δ ∼ 5.95 and 7.33 ppm, J = 12.5
Hz, 10% by integral intensity) were also observed in the spec-
trum, which presumably correspond to another stereoisomer
the tautomers 5c–e were mainly observed for CF Cl-, C F -,
2
2 5
C F -compounds (Table 1, entries 3–5). In addition, the DMSO-
3
7
d solutions of CHF - and CF Cl-products contained both cyclic
6
2
2
(
E,Z-, Z,E- or E,E-) of compound 5a. The cyclic tautomer 8a,
tautomers 8b,c and enols 5b,c, while for the C F - and C F -
2 5 3 7
formed as a result of intramolecular cyclization by nucleophilic
attack of the formamide nitrogen on the carbonyl group of tautomer
products only the corresponding enols 5d,e were found in
DMSO-d solution (see Table 1).
6
7
a, was also observed by NMR in a small amount (∼14% in
X-ray analysis of the C F product shows that only tautomer
2
5
DMSO-d ). The tautomer 7a itself was not observed in the mixture.
5d is present in the lattice (Fig. 2), which possesses the Z,Z-
6
17
In contrast the product of β-attack, the cyclic tautomer 8a, was
the major component of the equilibrium mixture in CDCl3.
Ketone 7a and its hydrate, the gem-diol 9a (see Scheme 4), as
configuration of the CvC double bonds. This configuration is
presumed to be the most stable for all compounds 5a–e in
DMSO-d solution.
6
well as the enol tautomer 5a, were also identified in CDCl solu-
The CHF -product exists as the single cyclic tautomer 8b in
CDCl3 solution, while equilibria of the keto-forms 7c–e and
3
2
1
19
14
tion by H and F NMR spectra. The minor open-chain forms
1
5
5
a, 7a and 9a constituted about 15% together. The part of
acyclic forms 5a, 7a and 9a increased when a more polar
solvent such as THF-d was added to the CDCl solution. Thus,
8
3
1
9
F NMR spectra in mixtures of CDCl /THF-d (10 : 1, 2 : 1,
3
8
1
5
: 1) indicated ratios of 8a/(5a + 7a + 9a) of 77 : 23, 58 : 42,
16
1 : 49, respectively. In solutions with >50% THF-d or pure
8
1
9
THF-d or CD CN the F NMR spectra became more complex
8
3
and several new peaks appeared between −72 and −83 ppm.
This reflects the presence of other stable tautomeric forms in
average share up to 27%.
Surprisingly, the reaction of ethyl isocyanoacetate with alkoxy-
enones 1b–e bearing other polyfluoroalkyl groups proceeded
with high regioselectivity under the same conditions (t-BuOK,
THF, −78 °C, Scheme 5). The products of initial attack on the
Fig. 2 Molecular structure of compound 5d obtained by X-ray diffrac-
tion. Thermal ellipsoids are shown with 50% probability.
6 3
Scheme 5 Reactions of enones 1b–e with ethyl isocyanoacetate (structure of products in DMSO-d and CDCl solutions, see Table 1 for ratio of
tautomers).
Table 1 Reaction of enones 1a–e with ethyl isocyanoacetate: products and their tautomers in DMSO-d
6
and CDCl
3
solutions
a
Starting
Entry compounds
Product(s), ratio
Major tautomer in
Minor tautomer in
Major tautomer(s)
Minor tautomer(s)
in CDCl (%)
a
a
R
f
(isolated yield, %)
DMSO-d
6
(%)
DMSO-d
6
(%)
in CDCl
3
(%)
3
b
c
1
2
3
4
5
1a
1b
1c
1d
1e
CF
CHF
CF Cl 5c 100 (64)
3
4a/5a, 15/85 (11/76) 5a (85)
8a (15)
5b (18)
8c (23)
—
8a (85)
5a, 7a, 9a (15)
—
b
2
8b 100 (72)
8b (82)
8b (100)
8c (85)
8d (58)
b
c
d
2
5c (77)
7c, 9c (15)
7d, 9d (48)
c
d
C
C
2
F
F
5
5d 100 (68)
5e 100 (51)
5d (100)
5e (100)
c
d
3
7
—
7e, 9e (54)
8e (46)
a
1
19
b
c
Product ratios of components were determined by H and F NMR spectroscopy. Major tautomer in DMSO-d
6
.
Along with signals of protons
corresponding to the Z,Z-1,3-diene, there were also peaks, which presumably correspond to another stereoisomer (E,Z-, Z,E- or E,E-) of compounds
d
5
a, 5c–e. The ratio 7 : 9 is in the range between 30 : 1 and 6 : 1 depending on concentration of the sample and moisture.
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cyclic forms 8c–e were observed in the other cases. Low
amounts (3–7%) of hydrate forms 9c–e were also observed.
The data shown in Table 1 indicate that within this series the
tautomeric ratio 8/(7 + 9) strongly depends on the size of the
polyfluoroalkyl group. Increasing the volume of the polyfluoro-
alkyl group (from CHF to C F ) resulted in a decreasing share
by NOE experiments, which indicated a trans-orientation of the
4-methyl and 5-CHF -groups. Due to the similarity of the spec-
2
tral data, the same relative configuration is anticipated for the
products 8f,h–j.
In the case of the α-halogen-substituted CF -enones 1k,l as
3
well as in the case of the cyclic alkoxyenones 1m,n (Scheme 8)
2
3 7
of cyclic tautomer 8 (from 100% to 46%). That fact can be
explained by an increase of intramolecular repulsion between the
Table 2 Reaction of enones 1f–j with ethyl isocyanoacetate: products,
ratios, yields
polyfluoroalkyl group and the neighboring CHO and CO Et
2
groups.
a
Starting
Products, ratio
Entry
compound
R
f
(isolated yield), %
Reaction of α- and β-substituted enones 1f–o
1
2
3
4
5
1f
1g
1h
1i
CF
CHF2
3
4f/8f, 77/23 (56/19)
4g/8g, 24/76 (17/54)
8h, 100 (46)
8i, 100 (66)
8j, 100 (70)
Next we investigated the reaction of a series of α-substituted
enones 1f–l with ethyl isocyanoacetate in order to explore the
influence of an α-substituent on the reactivity. Hitherto unknown
enones 1g–j were obtained by acylation of 1-ethoxypropene
CF
2
Cl
C
C
2
F
F
5
7
1j
3
1
8
a
1
19
according to the standard procedure (Scheme 6).
In the case of the reaction of CF - and CHF -enones 1f,g with
Determined by H and F NMR spectroscopy.
3
2
ethyl isocyanoacetate under typical conditions (t-BuOK, THF,
78 °C) a mixture of the alternative products 4f,g incorporating
−
the carbonyl group and products 8f,g formed by attack at the
β-position were obtained (Scheme 7, Table 2, entries 1,2).
In contrast the reaction of enones 1h–j was regioselective
giving the corresponding compounds 8h–j as single tautomers.
Other tautomers such as 5 or 7 were not observed by NMR spec-
troscopy in CDCl solutions. According to the NMR spectrum
3
of compound 8f in DMSO-d solution, less than 5% of the tauto-
6
mer 5f was present.
Compounds 8f–j were obtained as single diastereomers. The
relative configuration of the CHF -compound 8g was confirmed
2
Scheme 8 Reaction of enones 1k–m with ethyl isocyanoacetate and
the presumably unstable intermediate of initial attack at the β-position.
Scheme 6 Synthesis of enones 1g–j.
Scheme 7 Reactions of α-methyl enones 1f–j with ethyl isocyanoacetate and relative configuration of compound 8g established by NOE (isolated
yields are given in parentheses, see Table 2).
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the reaction led unexpectedly to products 4k–n incorporating the
carbonyl group exclusively. No trace of other products was
observed in the reaction mixtures.
Obviously, the formation of products of attack at the β-posi-
tion is disfavored because of increased steric interaction (in
comparison to unsubstituted 1a or α-Me-substituted enones 1f)
of the bulky α-substituent and the ethyl cyanoacetate anion in
the anticipated transition state (Scheme 8).
In the case of the β-methyl substituted enone 1o the reaction
also proceeded regioselectively on the carbonyl group. However,
along with product 4o the corresponding ketone 10 was formed
(Scheme 9, ratio 4o/10, 59 : 41) as a result of partial hydrolysis
20
Scheme 11 Synthesis of pyrroles 12a,b and 13.
of the methoxyvinyl group under the acidic work-up conditions.
Also by using a weaker acid (15% citric acid) we failed to
prevent formation of compound 10 (ratio 4o/10, 50 : 50). Com-
pound 4o was found to be unstable under the conditions of
column chromatography (silica gel). Only the product 10 was
isolated in 49% yield.
8
b,d,e and 4-methyl dihydropyrroles 8f,i,j to the corresponding
pyrroles 11, which were isolated in 52–76% yield (Scheme 10).
-Polyfluoroalkyl-2-ethoxycarbonyl pyrroles 11 have not been
5
described in the literature yet. Thus, the presented two-step
pathway starting from enones 1 through compounds 8 is a con-
venient method to synthesize 1-unsubstituted 5-polyfluoroalkyl
pyrrole carboxylates 11. The method demonstrates application of
ethyl isocyanoacetate for the preparation of α-polyfluoroalkyl
substituted pyrroles, while earlier only β-polyfluoroalkyl substi-
tuted pyrroles were synthesized using this reagent. By contrast
under acidic conditions compounds 8c,h containing a CF Cl
group and 8g containing a CHF group were transformed to the
Synthesis of pyrroles 11–14
The tautomers 8a–i have to be considered as hydroxy dihydro-
pyrroles and we expected that formal elimination of formic acid
would lead to the corresponding polyfluoroalkyl pyrroles 11.
This assumption was supported by the fact that traces of the cor-
responding pyrroles 11 were observed in the reaction mixtures
after work-up by 1 N HCl in the synthesis of compounds 8 (or
their tautomers 5 and 7).
21
2
2
acids 12a,b and aldehyde 13, respectively, as a result of acidic
hydrolysis of the polyfluoroalkyl groups (Scheme 11).
Similar lability of CHF2 and CF Cl groups was recently
2
22
described for the corresponding 3-polyfluoroalkyl pyrroles. We
failed to find a milder set of conditions in order to prevent
hydrolysis of the polyfluoroalkyl groups and for the synthesis of
pyrroles 11c,g,h.
Fluoroalkylated pyrroles are increasingly interesting for med-
1
9
icinal chemistry and agrochemistry. Therefore we investigated
2
0
formic acid elimination from 8a under acidic conditions
Scheme 10). Vigorous stirring of 8a in 15% HCl at r.t. for 24 h
(
Under the acidic conditions used for the synthesis of com-
pounds 11, the ketone 10 gave pyrrole 14 (Scheme 12).
The transformation took place as a result of intramolecular
heterocyclization between the carbonyl group and the formyla-
mino group with elimination of formic acid. However, pyrrole
was found to be most convenient. White crystals of pyrrole 11a
were isolated in 63% yield by filtration and purification by
column chromatography. Isolation by extraction and evaporation
of the solvent was found to be less effective due to the high vola-
tility of 11a. The same reaction conditions were successfully
applied for the transformation of 4-unsubstituted dihydropyrroles
1
4 was isolated in low yield (29%), because the heterocycliza-
tion is accompanied by side processes.
One application of pyrroles 11 is the synthesis of 5-polyfluoro-
alkyl derivatives of proline by reduction of the pyrrole ring.
Earlier we have shown that catalytic hydrogenation of
polyfluoroalkyl heterocyclic compounds was effectively used in
12
the synthesis of fluorinated amino acids. On the other hand,
catalytic hydrogenation of pyrroles is a well established method
23
for the synthesis of substituted pyrrolidines.
Scheme 9 Reaction of enone 1o with ethyl isocyanoacetate.
Scheme 12 Synthesis of pyrrole 14.
Most efficiently, 10% Pd/C in ethanol, 100 atm, 80 °C, 48 h
was used. In that case conversion was 100% and the product 15
was isolated as its hydrochloride in 51% yield (Scheme 13).
2
0
Scheme 10 Synthesis of pyrroles 11.
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and 400 MHz (Advance II) and from Agilent at 500 MHz
1
13
(
VNMRS) and 600 MHz (DD2) at 25 °C. TMS (for H and
C
19
NMR) and CCl F (for F NMR) were used as internal stan-
3
dards. IR spectra were recorded on a Bruker Vertex 70. Mass
spectra (ESI-MS) were measured on a MicroTof Bruker Dal-
tonics. The progress of reactions was monitored by TLC-plates
(silica gel 60 F254, Merck). Column chromatography was carried
out on silica gel 60 (Merck, particle size 0.040–0.063). Elemen-
tal analyses are correct within the limits of ±0.3% for C, H, N.
All starting materials were of the highest commercial quality
and were used without further purification. Starting enones
23a
1d
30b
30c
30d
30e
30f
1
a,
1b,d,e, 1c,
1f,
1k,l,
1m,n,
1o were syn-
3
Scheme 13 Synthesis of 5-CF -proline 16, a mimetic of pyroglutamic
acid.
thesized by known procedures.
2
4
Synthesis of α-methyl enones 1g–j (typical procedure)
E)-4-Ethoxy-1,1-difluoro-3-methyl-but-3-en-2-one (1g). A solu-
tion of difluoroacetyl chloride (22.9 g, 0.2 mol) in anhydrous
CH Cl (40 mL) was added to a mixture of 1-ethoxy-propene
(
Hydrolysis of the ester function with 6 N HCl led to diastereo-
24
pure 5-trifluoromethyl proline hydrochloride 16 in 69% yield.
While some CF -containing analogues of proline and their
2
2
3
2
5
(mixture of cis- and trans-isomers) (15.5 g, 0.18 mol) and pyri-
derivatives were described in the literature 5-CF -proline 16 or
3
dine (14.2 g, 0.18 mol) in CH Cl (200 mL) under stirring and
its derivatives have not been described in the literature
2
2
26,27
cooling to −10 °C. The reaction mixture was stirred at r.t. for
0 h, water (200 mL) was added and the aq. phase was extracted
with CH Cl (3 × 100 mL). The combined organic layers were
earlier.
As another 5-substituted proline derivative, this com-
2
pound is of considerable interest for instance in peptidomimetics
26,28
29
design.
On the other hand, according to Zanda’s principle,
2
2
dried over anhydrous Na SO and the solvent was evaporated.
which considers the CF –CHNH fragment as a bioisostere of the
2
4
3
The residue was distilled under reduced pressure giving enone
CO–NH-function, amino acid 16 can be presented as an analog
of the important bioregulator, pyroglutamic acid.
Attempts to apply these conditions for the catalytic hydrogen-
1
2
7
g as a light yellow liquid (b.p. 95–97 °C, 20 mm Hg). Yield:
1
0.6 g (63%). H NMR (500 MHz, CDCl ): δ = 1.37 (3H, t, J =
3
.2 Hz, CH ), 1.73 (3H, s, CH ), 4.17 (2H, q, J = 7.2 Hz,
ation of the CHF -pyrrole 11b failed, probably due to lability of
3
3
2
CH O), 5.97 (1H, t, J = 54.5 Hz, CHF ), 7.59 (1H, s, CH) ppm.
the CHF group under these conditions. The search for appropri-
2
2
2
13
C NMR (126 MHz, CDCl ): δ = 7.8, 15.3, 71.2, 111.9 (t, J =
ate hydrogenation conditions for pyrrole 11b as well as similar
polyfluoroalkyl pyrroles 11 is in progress.
3
2
54.3 Hz), 113.1, 163.4 (t, J = 6.2 Hz), 187.5 (t, J = 24.4 Hz)
19
ppm. F NMR (470.8 Hz, CDCl ): δ = –118.98 (d, J = 54.5 Hz,
3
CHF ) ppm. ESI-MS (m/z): calcd for C H F NaO (187.0541).
Found 187.0538.
2
7
10
2
2
Conclusions
The outcome of the reaction of β-alkoxyvinyl polyfluoroalkyl
ketones 1 with ethyl isocyanoacetate and potassium tert-butoxide
is strongly dependent on the structure of the starting enones. The
tautomers 5 or 8 resulting from initial attack at the β-position of
α-nonsubstituted 1a–e and α-methylsubstituted ketones 1g–j
were generally isolated as major products, while the reactions of
α- or β-substituted enones 1f,k–o led mainly to the products of
nucleophilic attack at the carbonyl carbon. Depending on the
solvent, different tautomeric forms were observed for these com-
pounds: enols 5, ketones 7 and cyclic hemiaminals 8. The latter
compounds are key intermediates for the synthesis of new
Reaction of enones 1a–o with ethyl isocyanoacetate. General
procedure. Ethyl isocyanoacetate (1.13 g, 10 mmol) in anhy-
drous THF (10 mL) was added dropwise via a syringe to a solu-
tion of t-BuOK (1.12 g, 10 mmol) in anhydrous THF (10 mL)
at −78 °C. After the addition was complete, the solution was
stirred at −78 °C for a further 30 min. Then a solution of the cor-
responding enone 1a–o (8 mmol) in THF was added dropwise
via a syringe. The mixture was stirred at −78 °C for 1 h and
warmed up to r.t. during 1–2 h. Aqueous HCl (1 N, 10 mL) was
added and the mixture was stirred for 30 min. The organic layer
2
was separated and the aqueous layer was extracted with CH Cl2
5
-polyfluoroalkyl-2-pyrrole carboxylates 11, which are interest-
(3 × 50 mL). The organic layers were combined, dried over
ing building blocks for agrochemical and medicinal chemistry
research. Catalytic hydrogenation of pyrroles 11 is a convenient
method for the preparation of 5-polyfluoroalkyl analogs, which
was demonstrated by the example of synthesis of earlier
Na SO , filtered and concentrated under reduced pressure. The
2
4
products were separated and purified by column chromatography
of the reaction mixture using an appropriate eluent.
unknown 5-CF -proline 16. Further investigations in the field of
pyrroles 11 hydrogenation are in progress.
Ethyl (2Z,4E)-5-ethoxy-2-formamido-3-(trifluoromethyl)-penta-
2,4-dienoate (4a). was obtained from enone 1a (1.34 g, 8 mmol)
and purified by column chromatography (EtOAc/c-hex, 1 : 2,
3
R = 0.36) giving compound 4a as a light yellow oil. Yield:
f
Experimental
1
0
7
7
.25 g (11%). H NMR (500 MHz, CDCl ): δ 1.29 (3H, t, J =
3
.1 Hz, CH ), 1.31 (3H, t, J = 7.1 Hz, CH ), 3.84 (2H, q, J =
3
3
General
.1 Hz, OCH ), 4.30 (2H, q, J = 7.1 Hz, OCH ), 5.46 (1H, d,
2
2
Melting points are uncorrected. NMR spectra were recorded on
spectrometers from Bruker at 300 MHz (Avance II and DRX)
J = 12.7 Hz, CH), 6.65 (1H, d, J = 12.7 Hz, CH), 7.71 (1H, s,
13
NH), 8.17 (1H, s, CHO). C NMR (126 MHz, CDCl ): δ 13.7,
3
Org. Biomol. Chem.
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1
2
4.5, 62.2, 66.1, 95.7, 117.4 (q, J = 29.9 Hz), 123.4 (q, J =
ρcalc = 1.616 g cm−3, μ = 0.170 mm−1, empirical absorption cor-
rection (0.943 ≤ T ≤ 0.975), Z = 2, triclinic, space group P1ˉ
(No. 2), λ = 0.71073 Å, T = 223(2) K, ω and φ scans, 5389
1
9
76.6 Hz), 127.3, 153.0, 158.8, 164.1. F NMR (470.8 Hz,
−60.58 (s, CF3). ESI-MS (m/z): calcd for
CDCl3):
δ
−1
C H F NNaO (304.0767). Found 304.0768.
reflections collected (±h, ±k, ±l), [(sin θ)/λ] = 0.62 Å , 2442
11
14
3
4
independent (Rint = 0.052) and 2073 observed reflections [I >
Ethyl
(2Z,4Z)-6,6,6-trifluoro-2-formamido-5-hydroxyhexa-2,4-
2
2
(
σ(I)], 187 refined parameters, R = 0.065, wR = 0.157, max.
dienoate (5a). was obtained from enone 1a (1.34 g, 8 mmol) and
was purified by column chromatography (EtOAc/c-hex, 1 : 2, Rf
0.36) giving compound 5a as a light yellow oil. Yield: 1.54 g
min.) residual electron density 0.37 (−0.22) e Å− , hydrogen
3
atom for N21 was refined freely, others were calculated and
refined as riding atoms.
=
(
1
76%). H NMR (500 MHz, DMSO-d ): δ 1.23 (3H, t, J =
6
6
.9 Hz, CH ), 4.17 (2H, q, J = 6.9 Hz, OCH ), 5.85 (1H, d, J =
3 2
1
2.6 Hz, CH), 7.28 (1H, d, J = 12.6 Hz, CH), 8.14 (1H, s,
1
3
Acknowledgements
CHO), 9.71 (1H, s, NH), 11.55 (1H, br. s, OH). C NMR
(
1
126 MHz, CDCl ): δ 14.5, 61.3, 100.6, 120.9 (q, J = 270.5 Hz),
23.4, 126.0, 144.7 (q, J = 31.7 Hz), 160.5, 164.3. F NMR
3
This work was supported by the Deutsche Forschungs-
gemeinschaft (Ha 2145/9-1; AOBJ: 560896). We thank Enamine
Ltd (Kiev) for technical and financial support and
Dr S. I. Vdovenko (Institute of Bioorganic Chemistry and Petro-
chemistry, National Ukrainian Academy of Sciences, Kiev,
Ukraine) for IR-experiments.
1
9
(
470.8 Hz, CDCl ), δ −70.74 (s, CF ). Anal. calcd for:
3
3
C H F NO (253.17): C, 42.70; H, 3.98; N, 5.53. Found C,
9
10
3
4
4
2.93; H, 3.82; N, 5.55. ESI-MS (m/z): calcd for
C H F NNaO (276.0454). Found 276.0455.
9
10
3
4
Ethyl
1-formyl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-
pyrrole-2-carboxylate (8a). was found to be a tautomer of 5a
which is the major compound in CDCl solution (see Table 1).
References
3
−
1
IR (CHCl ), cm : ν 1726, 1183, 1242, 1286, 1314, 1334, 1636,
3
1
1 For reviews see: (a) V. G. Nenajdenko and E. S. Balenkova, ARKIVOC,
1
666, 1727. H NMR (500 MHz, CDCl ): δ 1.35 (3H, t, J = 7.2
3
2011, 246; (b) S. V. Druzhinin, E. S. Balenkova and V. G. Nenajdenko,
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3
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1
Tetrahedron, 2007, 63, 7753; (c) V. G. Nenajdenko, E. S. Sanin and
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2
0.0 Hz, J = 3.4 Hz, H of CH ), 4.31 (2H, q, J = 7.2 Hz,
2 b 2
CH O), 6.25 (1H, s, CH), 6.46 (1H, br. s, OH), 9.30 (1H, s,
2
2
13
CHO). C NMR (126 MHz, CDCl ): δ 14.0, 38.6, 62.1, 93.3
3
(
1
(
q, J = 33.6 Hz), 121.4, 127.2 (q, J = 283.4 Hz), 133.1, 159.2,
3 I. S. Kondratov, I. I. Gerus, V. P. Kukhar and O. V. Manoilenko, Tetrahe-
dron: Asymmetry, 2007, 18, 1918.
19
64.1. F NMR (470.8 Hz, CDCl ): δ −84.48 (s, CF ). ESI-MS
3
3
4
(a) E. N. Shaitanova, I. I. Gerus, M. Yu. Belik and V. P. Kukhar, Tetra-
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6533.
m/z): calcd for C H F NNaO (276.0454). Found 276.0455.
9 10 3 4
Preparation of pyrroles 11–14 (typical procedure). Ethyl 5-
trifluoromethyl)-1H-pyrrole-2-carboxylate (11a). A mixture
5
(
2
0
6 I. S. Kondratov, I. I. Gerus, M. V. Furmanova, S. I. Vdovenko and
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of compound 8a (1.27 g, 5.0 mmol) and 15% aqueous HCl
50 mL) were vigorously stirred at r.t. for 24 h. The obtained pre-
(
7
I. I. Gerus, N. A. Tolmacheva, S. I. Vdovenko, R. Fröhlich and G. Haufe,
cipitate was filtered, washed with water, dried and purified by
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f
9
A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko,
compound 10a as a white solid. Yield: 0.65 g (63%). M.p. >
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−
1
8
1
0 °C (sublimation). IR (CHCl ), cm : ν 1132, 1175, 1279,
3
1
333, 1578, 1709, 3021, 3434. H NMR (500 MHz, CDCl ):
3
(b) D. Enders, Z.-X. Chen and G. Raabe, Synthesis, 2005, 306.
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3
2
1
3
11 C. Benhaim, L. Bouchard, G. Pelletier, J. Sellstedt, L. Kristofova and
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6
.59 (1H, s, CH), 6.88 (1H, s, CH), 10.20 (1H, br. s, NH).
C
NMR (126 MHz, CDCl ): δ 14.3, 61.3, 110.8, 114.8, 120.4 (q,
3
1
9
J = 267.2 Hz), 124.6 (q, J = 39.2 Hz), 125.4, 160.9. F NMR
470.8 Hz, CDCl ): δ −60.86 (s, CF ). ESI-MS (m/z): calcd for
C H F NNaO (230.0399). Found 230.0403.
(
3
3
8
8
3
2
13 U. Schöllkopf, F. Gerhart and R. Schröder, Angew. Chem., Int. Ed. Engl.,
1
969, 8, 672.
X-ray diffraction. The data set was collected with a Nonius
14 Earlier we obtained and investigated similar trifluoromethyl containing
1
5
gem-diols. The gem-diol 9a can be distinguished from the ketone 7a by
the following NMR signals: δα-CH2 = 3.72 (7a), δα-CH2 = 2.73 (7b); δ
7a) = −81.51, δ (9a) = −87.16.
KappaCCD diffractometer. Programs used: data collection,
3
1
F
COLLECT (Nonius B.V., 1998); data reduction, Denzo-SMN;
(
F
3
2
absorption
correction,
Denzo;
structure
solution,
1
1
5 I. S. Kondratov, I. I. Gerus, A. D. Kacharov, M. G. Gorbunova,
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6 The ratio of 5a/7a/9a is usually observed as ∼4 : 1 : 3 by NMR spectra. It
can change depending on moisture and compound concentration in the
sample.
33
34
SHELXS-97;
structure refinement, SHELXL-97;
and
graphics, XP (Bruker AXS, 2000). Thermal ellipsoids are shown
with 50% probability, R-values are given for observed reflec-
2
tions, and wR values are given for all reflections.
17 CCDC-887922 contains the supplementary crystallographic data for com-
17
X-ray crystal structure analysis of compound 5d:
C H F NO , M = 303.19, colourless crystals, 0.35 × 0.15 ×
pound 5d.
1
1
8 M. G. Gorbunova, I. I. Gerus and V. P. Kukhar, Synthesis, 2000, 738.
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1
0
10
5
4
0
7
.15 mm, a = 6.4262(3), b = 9.9510(3), c = 10.4639(4) Å, α =
3
3.787(2), β = 86.704(2), γ = 75.894(4)°, V = 623.11(4) Å ,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

View Online
2
2
0 For clearness just tautomers 8 are mentioned in order to avoid compli-
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4 The relative cis-configuration of products 16 and 17 is deduced by
2
23
analogy with hydrogenation results for similar compounds, however
was not established entirely since NOE-data for these compounds were
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configuration will be published in due course.
2
5 (a) J. Leroy and C. Wakselman, Can. J. Chem., 1976, 54, 218;
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1
(
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6 There were described some 1,3-oxazolidines which are considered as
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7 An approach to enantioselective synthesis of 5-trifluoromethyl proline
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Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2012