New functionalized, differently fluorinated building-blocks via Michael addition to γ-fluoro-α-nitroalkenes

Article abstract of DOI:10.1016/j.jfluchem.2006.03.017

The Michael addition of ketone-derived enamines, metalated methylene active compounds and N-methyl pyrroles to γ-fluoro-α-nitroalkenes provided in moderate to good isolated yields the corresponding β-fluoroalkyl nitro compounds, which represent new intere

Full text of DOI:10.1016/j.jfluchem.2006.03.017

Journal of Fluorine Chemistry 127 (2006) 901–908
www.elsevier.com/locate/fluor
New functionalized, differently fluorinated building-blocks
via Michael addition to g-fluoro-a-nitroalkenes
Marco Molteni a, Roberto Consonni b, Tommaso Giovenzana a,
Luciana Malpezzi a, Matteo Zanda c,
*
a Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘‘G. Natta’’ del Politecnico di Milano, Via Mancinelli 7, I-20131 Milano, Italy
b C.N.R. Istituto per lo Studio delle Macromolecole, Via Bassini 15, 20133 Milano, Italy
c Istituto di Chimica del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
Received 8 February 2006; received in revised form 16 March 2006; accepted 26 March 2006
Available online 1 April 2006
Abstract
The Michael addition of ketone-derived enamines, metalated methylene active compounds and N-methyl pyrroles to g-fluoro-a-nitroalkenes
provided in moderate to good isolated yields the corresponding b-fluoroalkyl nitro compounds, which represent new interesting, highly
functionalized building blocks in organofluorine chemistry.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Michael additions, Nitroalkenes, Enamines
1. Introduction
Here we describe in full details the synthesis of compounds
1b–d, and the results of a study on the Michael addition of
ketones 2a–c (and their reactive derivatives such as enamines
and silyl enolethers) to 1a–d, that allows for an efficient entry to
b-fluoroalkyl g-nitroketones 3 (see Scheme 3) and the
corresponding carbinols 4 (see Scheme 4) [3,4]. In addition,
we describe the Michael reaction of 1a–c with metalated
methylene active compounds 9a–c and N-methyl azoles.
One of the key issues in organofluorine chemistry is the
availability of suitably functionalized fluorinated building
blocks to be used in the synthesis of more complex fluorinated
molecular structures.
g-Fluoro-a-nitroalkenes 1 (Fig. 1) have been so far scarcely
studied and exploited in the synthesis of functionalized
fluoroorganic molecules, despite the fact that they constitute
a very promising, highly reactive, yet easy-to-handle class of
fluorinated building blocks. Surprisingly, among the differently
fluorinated compounds 1a–d, only 3,3,3-trifluoro-1-nitropro-
pene 1a has been hitherto described in the literature [1].
Within the frame of a project aimed at the synthesis of
fluorinated peptidomimetics via aza-Michael reactions, we
became interested in the chemistry of g-fluoro-a-nitroalkenes 1
[2], thus we decided to undertake a research programme on the
synthetic opportunities offered by these interesting fluorinated
building-blocks in the preparation of fluoroorganic molecules
having potential interest in biomedicinal chemistry and
materials science.
2. Results and discussion
The reactivity of compounds 1 is nearly unexplored, as only
a handful of papers describing some examples of Diels–Alder
[5] and 1,3-dipolar reactions [6], Friedel–Crafts [7], aza-
Michael [2,8] and Michael reactions with methylene active
compounds [5] is present in the literature. More recently, in a
study on the enantioselective Michael addition of carbonyl
compounds catalyzed by chiral enamines, 1a was marginally
mentioned as a ‘‘difficult’’ substrate featuring low yields, and
low enantioselectivity as well [9].
The key g-fluoro-a-nitroalkenes 1 were prepared in moderate
to good yields by Henry (nitroaldol) reaction of nitromethane
with the corresponding fluoroaldehydes (Scheme 1) [10],
followed by P2O5 promoted dehydration of the intermediate
b-nitroalcohols 5.
* Corresponding author. Tel.: +39 02 23993084; fax: +39 02 23993080.
E-mail address: matteo.zanda@polimi.it (M. Zanda).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.03.017

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M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
Fig. 1. Fluorinated nitroalkenes 1a–d.
Scheme 3. Michael reactions of nitroalkenes 1a–d with enamines 7a–c.
Scheme 1. Preparation of 3-fluoro-1-nitroalkenes.
Table 1
Michael addition of enamines 7 to g-fluoro-a-nitroalkenes 1a
The Michael reaction between cyclopentanone and 1a was
chosen as a model, in order to identify the best conditions for the
synthesis of the b-trifluoromethyl g-nitroketone 3a (Scheme 2).
The reaction of lithiated 2a with 1a (conditions [a])
delivered the target product 3a in fair yields (56%), as a nearly
equimolar mixture of the two possible diastereomers. Attempts
to react the titanium enolate of 2a (conditions [b]) afforded
negligible amounts of 3a, whereas extended decomposition was
observed instead. The silyl enolether 6a [11] failed to afford
satisfactory yields of the desired product 3a both using
tetrabutylammonium fluoride (TBAF) as a promoter (condi-
tions [c]) and Mukaiyama-like conditions [d] [12]. In fact using
conditions [c] slow reaction and formation of complex mixtures
upon prolonged reaction times were observed, whereas using
conditions [d] extended decomposition was observed by TLC
monitoring. Rewardingly, the enamine derivative 7a [13]
reacted with 1a affording good yields of the target product 3a
(70%). Also in this case no diastereocontrol was observed. We
therefore decided to use enamines 7a–c as reagents of choice in
the Michael addition to a-fluoro-g-nitroalkenes 1a–d.
Entry
a-Fluoro-g-nitroalkene
Enamine
Product
Yield (%)b
1
2
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
7a
7a
7a
7a
7b
7b
7b
7b
7c
7c
7c
7c
3a
3b
3c
3d
3e
3f
3g
3h
3i
70c
40d
57
75
60
63
58
58
78
65
55
68
3
4
5
6
7
8
9
10
11
12
3j
3k
3l
a
Products 3a–h were obtained as nearly equimolar mixtures of diastereo-
mers.
b
c
d
Isolated yields.
About 15% of by-product 8a (Fig. 2) was formed.
About 30% of by-product 8b (Fig. 2) was formed.
As portrayed in Scheme 3 and Table 1, the reaction provided
moderate to good yields of a wide range of differently fluorinated
b-fluoroalkyl g-nitroketones 3a–l, demonstrating the viability of
the method, which should be of rather general scope.
In the case of entries 1 and 2, relevant amounts of by-products
8a and 8b (Fig. 2) arising by double Michael addition of the
enamine 7a to nitroalkenes 1a and 1b, respectively, were formed.
The structure of 8a was confirmed by X-ray diffraction.1 This
racemic by-product is rather interesting, as it is formed as a
largely predominant diastereomer having three stereogenic
centers with the relative configuration portrayed in Fig. 2.
The molecular geometry and the atomic numbering of 8a are
shown in Fig. 3a. The two trifluoropropyl-nitro fragments show
a different attachment to the central pentene ring, owing to the
presence of the endocyclic double bond. The C5–C1–C11–C13
and C5–C1–C11–C13 torsion angles have values of 169.1(2)8
and 130.4(2)8, respectively. The reciprocal position of the NO2
and CF3 groups on each side of the molecule is well defined by
1
CCDC 294989 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033; e-mail: deposi@ccdc.cam.ac.uk).
Scheme 2. Reaction of 1a with cyclopentanone and derivatives.

M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
903
Scheme 4. Reduction of g-nitroketones 3 to carbinols 4.
Fig. 2. Byproducts of the Michael reactions of 1a and b with enamine 7a.
the torsion angles C16–C14–C15–N2 [ꢀ71.5(2)8] and C13-C4-
C12-N1 [ꢀ161.4(2)8]. The pentene ring assumes an envelop
˚
conformation, with the C4 atom 0.214(3) A out of the mean C1/
C2/C3/C5 plane. The piperidine ring shows a regular chair
conformation. In the crystal, the supramolecular structure is
governed only by short non-bonded C–Hꢁ ꢁ ꢁO contacts. The C4
atom of each molecule acts as h0ydrogen bond donor towards
0
˚
the nitro O1 atom [C4ꢁ ꢁ ꢁO1 = 3.225(3) A, H(C4)ꢁ ꢁ ꢁO1
0
˚
= 2.342(3) A, C4–Hꢁ ꢁ ꢁO1 = 154(1)8] of a symmetry related
[x ꢀ 1/2, 3/2 ꢀ y, z] molecule, building up an infinite zig-zag
chain running along the a axis (Fig. 3b). This hydrogen bond
pattern may be described in terms of graph set C(8) [14].
Attempts to generate the enamines in situ by adding a
catalytic (and even stoichiometric) amount of L-proline to a
mixture of nitroalkene 1 and ketone 2 gave no trace of the target
molecules 3, instead we observed products arising from
irreversible aza-Michael addition of proline to 1.
Scheme 5. Reaction of nitroalkenes 1 with methylene active compounds 10.
(Table 2) that the main problem in these reactions is the
apparently poor stability of the acceptors 1 in strongly basic
environment. Therefore, if the Michael additions do not take
place very rapidly, the nitroalkenes decompose, lowering the
reaction yields.
Finally, we explored the Friedel–Crafts type reactivity of
nitroalkenes 1 with activated electronrich heteroaromatics,
such as N-methyl-pyrrole and N-methyl indole (Scheme 6). The
reactions took place without catalysis, providing fair yields of
the desired products 11 and 12.
Attempts to improve the reactions performance by using
N,N0-di[3,5-di(trifluoromethyl)phenyl]urea as catalyst [15] did
not show any detectable difference with respect to the
uncatalyzed reactions. This is probably due to the poor
hydrogen-bond acceptor properties of the nitro group of 1, that
prevents an effective hydrogen bond formation with the urea.
We next explored the possibility to reduce the ketones 3 to
the corresponding carbinols 4 (Scheme 4). Thus, 3i, 3j and 3l
were treated with NaBH4 delivering the target b-fluoroalkyl g-
nitroalcohols 4 in satisfactory yields and fair diastereocontrol.
Next, we explored the Michael addition of nitroalkenes 1
with sodium derivatives of methylene active compounds 9
(Scheme 5).
The reactions took place in DMF at 0 8C affording the target
products 10a–f in moderate to low yields. It should be noticed
Fig. 3. (a) ORTEP drawing of 8a, showing 20% probability thermal ellipsoids. (b) Part of the crystal structure of 8a showing the infinite zig-zag-chain of molecules
connected by C–Hꢁ ꢁ ꢁO interactions.

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M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
Table 2
4.2. General procedure for the preparation of g-fluoro-a-
nitroalkenes 1. Synthesis of 1b
Michael reactions of nitroalkenes 1a–c with methylene active compounds 9a–c
Entry
a-Fluoro-g-nitroalkene
Methylene
Product
Yield
(%)a
active compound
Chlorodifluoroacetaldehyde hydrate tech. (5.04 g, 38.0
mmol), nitromethane (2.11 g, 34.6 mmol) and sodium carbonate
(241 mg, 2.28 mmol) were mixed at room temperature under
vigorousstirring. Themixturewasheated at60 8C (ina few mina
dark red coloration appeared) for 3 h and then stirred at room
temperature overnight. The mixture was extracted with diethyl
ether, the organic layer was dried on anhydrous Na2SO4 and then
filtered. The organic solvent was carefully removed in vacuo at
low temperature. The resulting dark red oilwas treated with P2O5
(5.2 g, 36.8 mmol) added in one portion and the mixture
submitted to fractional distillation at atmospheric pressure.
Nitroalkene 1b was obtained as a green-yellow liquid distilled at
103–105 8C (2.11 g, 39%).
1
2
3
4
5
6
1a
1b
1a
1c
1a
1c
9a
9a
9b
9b
9c
9c
10a
10b
10c
10d
10e
10f
43
63
22
53
25
20
a
Isolated yields.
Nitroalkenes 1c and 1d were obtained by bulb to bulb
distillation using a Kugelrohr apparatus (temperature 80–
90 8C).
1a: analytical and spectroscopic data matched those
described in Ref. [5].
1b: 1H NMR (CDCl3): d = 7.37 (m, 1H), 7.25 (m, 1H); 19F
NMR (CDCl3): d = ꢀ54.69 (d, J = 7.8 Hz); 13C NMR (CDCl3):
d = 142.9, 131.4, 122.1 (t, J = 291.0 Hz). Anal. Calcd for
C3H2ClF2NO2: C, 22.88; H, 1.28. Found: C, 23.02; H, 1.34.
1c: 1H NMR (CDCl3): d = 7.28 (m, 1H), 7.10 (m, 1H), 6.40
(td, J = 53.7, 3.5 Hz); 19F NMR (CDCl3): d = ꢀ118.6 (dd,
J = 54.7, 8.2 Hz, 2F); 13C NMR (CDCl3): d = 143.8, 130.3 (t,
J = 23.8 Hz), 110.3 (t, J = 239.4 Hz).
Scheme 6. Friedel–Crafts type reactions.
Very slow reactions were observed in the reactions of 1b
with electronrich aromatics, such as 1-(N,N-diethylamino)-
naphthalene and 4-(2-propenyl)anisole.
3. Conclusion
1
1d: H NMR (CDCl3): d = 7.50 (m, 1H), 7.15; 19F NMR
In summary, the reactivity of fluorinated nitroalkenes 1a–d,
three of them prepared for the first time (1b–d), has been
investigated, in particular the Michael addition of ketone-
derived enamines 7a–c and methylene active compounds 9, as
well as the Friedel–Crafts reaction with N-methyl pyrrole and -
indole. The reduction of b-fluoroalkyl g-nitroketones 3i, 3j,
and 3l to b-fluoroalkyl g-nitroalcohols 4i, 4j, and 4l was also
explored. The reactions above afforded a wide range of
differently fluorinated building blocks, that might represent
useful starting materials for biologically interesting molecules.
(CDCl3): d = ꢀ85.7 (s, 3F), ꢀ117.8 (m, 2F); 13C NMR
(CDCl3): d = 146.4, 124.9 (t, J = 31.4 Hz), the CF2CF3 signal
was obscured due to its low intensity.
4.3. General procedure for the Michael addition of
enamines 7 to g-fluoro-a-nitroalkenes 1. Synthesis of 3i
To a stirred solution of 7c (110 mg, 0.63 mmol), in dry
dichloromethane, under nitrogen, at RT, was added a solution of
1a (89 mg, 0.63 mmol), in dichloromethane. A dark red-orange
color slowly appeared. After 2 h the organic solvent was
removed in vacuo, and the crude was purified by flash
chromatography (n-Hex/EtOAc 8:2), affording 124 mg of 3i
(78%).
4. Experimental section
4.1. General details
3a: Rf = 0.32, n-Hex/EtOAc 8:2; mixture 1:1 of two
diastereomers. 1H NMR (CDCl3): d = 4.95 (dd, J = 14.2,
5.8 Hz, 1H), 4.68 (dd, J = 14.2, 6.8 Hz, 1H), 4.60 (dd, J = 13.7,
7.2 Hz, 1H), 4.29 (dd, J = 13.7, 5.6 Hz, 1H), 3.87 (m, 1H), 3.55
(m, 1H), 2.60 (m, 1H), 2.48–2.02 (overlap, 9H), 1.93–1.74 (m,
3H), 1.68 (m, 1H); 19F NMR (CDCl3): d = ꢀ68.3 (d,
J = 7.4 Hz), ꢀ70.1 (d, J = 7.4 Hz); 13C NMR (CDCl3) (selected
signals): d = 194.6, 125.9 (q, J = 280.3 Hz), 72.2, 37.7 (q,
J = 28.9 Hz), 34.1. Anal. Calcd for C8H10F3NO3: C, 42.67; H,
4.48. Found: C, 42.77; H, 4.40.
Commercially available reagent-grade solvents were
employed without purification. All reactions where an organic
solvent was employed were performed under nitrogen atmo-
sphere, after flame-drying of the glass apparatus. Melting points
(m.p.) are uncorrected and were obtained on a capillary
apparatus. TLC were run on silica gel 60 F254 Merck. Flash
chromatographies (FC) were performed with silica gel 60 (60–
1
200 mm, Merck). H, 13C, and 19F NMR spectra were run at
250, 400 or 500 MHz. Chemical shifts are expressed in ppm (d),
using tetramethylsilane (TMS) as internal standard for 1H and
13C nuclei (dH and dC = 0.00), while C6F6 was used as external
standard (dF ꢀ 162.90) for 19F.
8a: Rf = 0.45, n-Hex/EtOAc 8:2. 1H NMR (CDCl3): d = 4.61
(m, 1H), 4.19 (d, J = 13.2 Hz, 1H), 3.54 (m, 1H), 3.38 (m, 1H),
3.11 (m, 2H), 2.82 (m, 2H), 2.44 (m, 1H), 2.27 (m, 1H), 2.02

M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
905
(m, 1H), 1.62 (m, 7H); 19F NMR (CDCl3): d = ꢀ67.5 (d,
J = 6.4 Hz, 3F), ꢀ70.4 (d, J = 8.7 Hz, 3F); 13C NMR (CDCl3):
d = 151.7, 127.0, 124.7, 109.3, 72.7, 69.7, 50.7, 42.9 (q,
J = 26.8 Hz), 42.0 (q, J = 27.8 Hz), 41.4, 28.7, 26.1, 23.9, 21.6.
Anal. Calcd for C16H21F6N3O4: C, 44.35; H, 4.88. Found: C,
44.21; H, 4.59.
3c: Rf = 0.31, n-Hex/EtOAc 8:2; mixture 5:1 of two
1
diastereomers. H NMR (CDCl3): d = 6.23 (m, 1H), 6.00 (m,
1H), 4.76 (m, 2H), 4.63 (dd, J = 14.6, 7.6 Hz, 1H), 3.40–3.03
(overlap, 2H), 2.49 (m, 2H), 1.82–1.65 (overlap, 4H); 19F NMR
(CDCl3): d = ꢀ122.0 (ddd, J = 287.5, 55.9, 10.6 Hz, 1F),
ꢀ124.4 (ddd, J = 287.5, 55.9, 15.9 Hz, 1F), ꢀ122.6 (ddd,
J = 287.5, 55.9, 11.9 Hz, 1F), ꢀ126.3 (ddd, J = 287.5, 55.9,
17.3 Hz, 1F); 13C NMR (CDCl3) mixture: d = 217.0, 216.9,
115.5 (t, J = 250.1 Hz), 115.3 (t, J = 243.9 Hz), 71.4, 72.2,
46.9, 46.2, 41.2, 41.0 (t, J = 20.7 Hz), 40.3 (t, J = 20.7 Hz),
37.6, 37.3, 27.1, 26.4, 20.6.
4.3.1. X-ray structural determination of 8a
The compound crystallises in the orthorhombic system,
˚
Pna2(1) space group, with cell parameters: a = 9.395(1) A,
3
˚
˚
˚
b = 12.339(1) A, c = 17.010 (1) A, V = 1972(1) A , Z = 4,
Dc = 1.460 g cmꢀ3, F(0 0 0) = 896. The crystal suitable for
X-ray analysis, with approximate dimensions of 0.3 mm
ꢂ 0.4 mm ꢂ 0.5 mm, was obtained upon slow crystallisation
from iPr2O. Intensities data were collected, at room tempera-
ture, on a Siemens P4 diffractometer with graphite mono-
1
3d: H NMR (CDCl3): d = 4.64 (dd, J = 14.1, 6.8 Hz, 1H),
4.21 (dd, J = 14.1, 4.5 Hz, 1H), 4.01 (m, 1H), 2.61 (m, 1H),
2.38 (m, 2H), 1.86 (m, 2H), 1.65 (m, 1H); 19F NMR (CDCl3):
d = ꢀ83.5 (s, 3F) ꢀ116.2 (dd, J = 292.0, 15.1 Hz, 1F), ꢀ119.1
(dd, J = 292.0, 12.9 Hz, 1F); 13C NMR (CDCl3): d = 70.1, 47.3,
37.9 (t, J = 21.9 Hz), 36.6 25.4, 20.3. Anal. Calcd for
C9H10F5NO3: C, 39.28; H, 3.66. Found: C, 39.48; H, 3.76.
3e: Rf = 0.34, n-Hex/EtOAc 8:2; mixture 5:1 of two
diastereomers. 1H NMR (CDCl3): major d = 4.83 (dd,
J = 14.6, 6.9 Hz, 1H), 4.45 (m, 1H), 4.0 (m, 1H), 3.0 (m,
1H), 2.55–1.94 (m, 5H), 1.78, 1.61 (m, 3H); minor d = 4.52 (dd,
J = 14.6, 8.4 Hz, 1H), 4.45 (m, 1H), 3.60 (m, 1H), 2.80 (m, 1H),
2.55–1.94 (m, 5H), 1.78–1.67 (m, 3H); 19F NMR (CDCl3):
d = ꢀ67.4 (d, J = 7.6 Hz, 3F), ꢀ69.5 (d, J = 7.6 Hz); 13C NMR
(CDCl3): major d = 207.9, 126.5 (q, J = 276.5 Hz), 70.7, 47.7,
41.7, 39.7 (q, J = 27.6 Hz), 28.9, 27.0, 24.9; minor d = 208.4,
125.9 (q, J = 276.5 Hz), 71.9, 48.4, 42.2, 31.5, 27.6, 25.2; MS
(70 eV): e/z (%): 240 [M+ + 1] (40), 193 (100), 165 (55), 55
(90), 41 (60).
˚
chromated Cu Ka radiation (l = 1.54179 A), using u/2u scan
technique, voltage 40 kV, current 40 mA. Unit cell parameters
were determined using 81 reflections in the range 10.488
ꢃ 2u ꢃ 63.38. A total of 2161 reflections (1714 unique,
R
int = 0.036) were collected up to 1308 in 2u and index range:
ꢀ11 ꢃ h ꢄ 1, ꢀ14 ꢃ k ꢄ 1, ꢀ1 ꢃ l ꢄ 19. Three standard
reflections, monitored every 100 reflections, showed no
intensity decay. No empirical adsorption correction was
deemed necessary. The structure was solved by direct method
using SIR97 program [16] which revealed the position of all
non H-atoms. The refinement was carried out on F2 by full-
matrix least-squares procedure with SHELXL97 [17] for 263
parameters, with anisotropic temperature factors for non-H
atoms. H atoms, were placed in geometrically calculated
positions and refined in a riding model. The final stage
converged to R = 0.0506 (Rw = 0.112) for 1260 observed
reflections (with I ꢄ 2s(I)), and R = 0.0885 (Rw = 0.135) for all
unique reflections. The goodness of fit, S, was 1.095. The final
difference map showed a maximum and minimum residual
3f: Rf = 0.39, n-Hex/EtOAc 8:2; mixture 1:1 of two
diastereomers. 1H NMR (CDCl3): major d = 4.88 (dd,
J = 14.2, 5.4 Hz, 1H), 4.45 (m, 1H), 3.69 (m, 1H), 2.87 (m,
1H), 2.58–1.67 (m, 8H); minor d = 4.58 (dd, J = 14.8, 7.4 Hz,
1H), 4.45 (m, 1H), 4.25 (m, 1H), 3.02 (m, 1H), 2.58–1.67 (m,
8H); 19F NMR (CDCl3): major d = ꢀ51.8 (dd, J = 165.4,
9.7 Hz, 1F), ꢀ52.3 (dd, J = 165.4, 9.7 Hz, 1F); minor d = ꢀ53.8
(dd, J = 166.4, 11.7 Hz, 1F), ꢀ55.1 (dd, J = 166.4, 11.7 Hz,
1F); 13C NMR (CDCl3): d = 129.4 (t, J = 296.2 Hz), 72.9, 71.3,
49.9, 49.0, 48.3 (t, J = 23.2 Hz), 45.5 (t, J = 23.8 Hz), 41.8,
32.2, 29.7, 28.8, 27.6, 27.0, 25.0; MS (70 eV): e/z (%): 256
[M+ + 1] (10), 181 (30), 77 (40), 55 (100), 41 (60).
peaks of 0.120 and ꢀ0.130 e Aꢀ3, respectively.
˚
3b: Rf = 0.41, n-Hex/EtOAc 8:2; mixture 1.5:1 of two
diastereomers. 1H NMR (CDCl3): d = 5.10 (dd, J = 13.6,
6.3 Hz, 1H), 4.75–4.62 (overlap, 3H), 4.29 (dd, J = 13.6,
5.4 Hz, 1H), 4.02 (m, 2H), 3.64 (m, 1H), 2.72 (m, 2H), 2.53–
2.30 (overlap, 6H), 2.25–2.04 (overlap, 6H), 1.98–1.55
(overlap, 7H); 19F NMR (CDCl3): d = –52.45 (dd, J = 10.2,
168 Hz, 1F) and ꢀ53.50 (dd, J = 10.2, 168 Hz, 1F) (minor
diastereomer), ꢀ54.95 (dd, J = 10.3, 168 Hz, 1F) and ꢀ56.80
(dd, J = 10.3, 168 Hz, 1F) (major diastereomer); 13C NMR
(CDCl3): d = 215.8, 214.8, 129.42 (t), 72.2, 71.3, 48.5, 46.6 (t,
J = 28.6 Hz), 37.6, 36.6, 28.2, 25.1, 20.47, 20.41; MS (70 eV):
e/z (%): 242 [M+ + 1] (20), 195 (40), 109 (70), 77 (100), 55
(90).
3g: Rf = 0.32, n-Hex/EtOAc; mixture 1:1 of two diaster-
eomers. 1H NMR (CDCl3): major d = 6.10 (td, J = 56.3,
3.81 Hz, 1H), 4.78 (dd, J = 14.4, 5.5 Hz, 1H), 4.45 (dd,
J = 14.4, 3.8 Hz, 1H), 3.13 (m, 1H), 2.76 (m, 1H), 2.47 (m, 1H),
2.36 (m, 1H), 2.22 (m, 1H), 2.15 (m, 1H), 2.00 (m, 1H), 1.67
(overlap 2H); minor d = 4.60 (dd, J = 14.4, 7.2 Hz, 1H), 4.50
(dd, J = 14.4, 5.1 Hz, 1H), 3.33 (m, 1H), 2.80 (m, 1H), 2.52 (m,
1H), 2.36 (m, 1H), 2.22 (m, 1H), 2.15 (m, 1H), 1.97 (m, 1H),
1.67 (m, 2H); 19F NMR (CDCl3): major d = ꢀ120.3 (ddd,
J = 288.2, 56.8, 18.8 Hz, 1F), ꢀ122.6 (ddd, J = 288.2, 56.8,
8.5 Hz, 1F); minor d = ꢀ120.8 13C NMR (CDCl3): major
d = 115.7 (t, J = 247.3 Hz), 71.5, 48.4, 42.1, 40.4 (t,
J = 20.3 Hz), 30.7, 29.6, 27.4; minor d = 115.7 (t,
J = 247.3 Hz), 71.51, 48.39, 41.8, 30.77, 27.4; MS (70 eV):
e/z (%): 222 [M+ + 1] (20), 175 (70), 55 (100), 41 (50).
8b: Rf = 0.45, n-Hex/EtOAc 8:2. 1H NMR (CDCl3):
d = 4.61 (m, 1H), 4.19 (d, J = 13.2 Hz, 1H), 3.54 (m, 1H),
3.38 (m, 1H), 3.11 (m, 2H), 2.82 (m, 2H), 2.44 (m, 1H), 2.27
(m, 1H), 2.02 (m, 1H), 1.62 (m, 7H); 19F NMR (CDCl3):
d = ꢀ52.7 (dd, J = 166.7, 10.2 Hz, 1F), ꢀ54.0 (dd, J = 166.7,
10.2 Hz, 1F), ꢀ54.1 (m, 1F), ꢀ57.3 (m, 1F); MS (70 eV): e/z
(%): 465 [M+ + 1] (40), 323 (100), 276 (65), 176 (70), 84 (80),
77 (55).

906
M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
3h: Rf = 0.37, n-Hex/EtOAc 8:2; mixture 2:1 of two
was extracted twice with EtOAc; the organic layers were dried
over Na2SO4, and the solvent was removed in vacuo.
The crude was purified by flash chromatography (n-Hex
100% to n-Hex/EtOAc 9:1), affording 428 mg of 4i (mixture of
two diastereomers) (73%).
diastereomers. 1H NMR (CDCl3): major d = 5.04 (dd,
J = 14.6, 5.0 Hz, 1H), 4.67 (m, 1H), 3.60 (m, 1H), 2.86 (m,
1H), 2.60–1.40 (m, 8H); minor d = 4.59 (dd, J = 14.0, 6.7 Hz,
1H), 4.44 (dd, J = 14.0, 7.9 Hz, 1H), 4.14 (m, 1H), 2.94 (m,
1H), 2.60–1.40 (m, 8H); 19F NMR (CDCl3): major d = ꢀ84.7
(s, 3F), ꢀ115.9 (dd, J = 277.0, 15.7 Hz, 1F), ꢀ117.3 (dd,
J = 277.0, 15.7 Hz, 1F); minor d = ꢀ84.2 (s, 3F), ꢀ115.4 (dd,
J = 277.0, 15.7 Hz, 1F), ꢀ119.9 (dd, J = 277.0, 15.7 Hz, 1F);
13C NMR (CDCl3): d = 208.1, 117.6, 74.5, 71.1, 70.3, 58.4,
48.9, 47.8, 41.9, 41.7, 37.1, 36.9 (t, J = 20.1 Hz), 31.5, 29.1,
26.9, 25.2, 24.8.
4i: Rf = 0.37, n-Hex/EtOAc 8:2; mixture of two diaster-
1
eomers 3.9:1.0 in ratio. H NMR (CDCl3): major distereomer
d = 7.35 (m, 5H), 4.85 (m, 1H), 4.65 (m, 2H), 3.39 (m, 1H), 2.41
(br, s, 1H), 2.17 (m, 1H), 1.91 (m, 1H), minor diastereomer; 19
F
NMR (CDCl3): minor diastereomer d = ꢀ54.6 (d, J = 8.5 Hz,
3F), major diastereomer ꢀ55.0 (d, J = 8.9 Hz, 3F); 13C NMR
(CDCl3): major diastereomer d = 142.7, 128.8, 128.60, 128.3,
126.5 (q, J = 281.0 Hz), 125.5, 72.8, 70.7, 39.1 (q, J = 26.9 Hz),
34.6; minor distereomer 143.4, 128.8, 128.3, 125.47, 73.5, 72.8,
40.4 (q, J = 27.6 Hz), 35.15; MS ESI: 285.8 [M + Na] (100%).
Anal. Calcd for C11H12F3NO3: C, 50.19; H, 4.60. Found: C,
50.03; H, 4.65.
3i: Rf = 0.35, n-Hex/EtOAc 8:2. FT-IR (film): nmax = 3063,
2971, 1690, 1566, 1425, 1380, 1176, 1125, 756 cmꢀ1; 1H NMR
(CDCl3): d = 7.95 (d, J = 7.6 Hz, 2H), 7.63 (m, 1H), 7.50 (m,
2H), 4.70 (dd, J = 13.8, 6.8 Hz, 1H), 4.62 (dd, J = 13.8, 4.1 Hz,
1H), 3.93 (m, 1H), 3.46 (dd, J = 17.7, 3.4 Hz, 1H), 3.33 (dd,
J = 17.7, 9.1 Hz, 1H); 19F NMR (CDCl3): d = ꢀ71.9 (d,
J = 7.4 Hz, 3F); 13C NMR (CDCl3): d = 194.7, 135.6, 134.1,
128.9, 128.1, 126.1 (q, J = 276.8 Hz), 72.4, 37.9 (q,
J = 28.6 Hz), 34.2; MS (ESI): 283.8 [M+ + Na]. Anal. Calcd
for C11H10F3NO3: C, 50.58; H, 3.86. Found: C, 50.44; H, 3.59.
3j: Rf = 0.37, n-Hex/EtOAc 8:2. 1H NMR (CDCl3): d = 7.96
(d, J = 7.2 Hz, 2H), 7.62 (m, 1H), 7.50 (m, 2H), 4.75 (dd,
J = 13.9, 6.4 Hz, 1H), 4.62 (dd, J = 13.9, 4.6 Hz, 1H), 4.08 (m,
1H), 3.54 (dd, J = 18.2, 3.4 Hz, 1H), 3.34 (dd, J = 18.2, 8.9 Hz,
1H); 19F NMR (CDCl3): d = ꢀ56.1 (dd, J = 166.7, 8.9 Hz, 1F),
ꢀ56.9 (dd, J = 166.7, 8.9 Hz, 1F); 13C NMR (CDCl3):
d = 194.7, 135.7, 134.1, 129.6 (t, J = 296.7 Hz), 128.9,
128.1, 73.4, 44.0 (t, J = 24.7 Hz), 35.8.
1
4j: Rf = 0.37, n-Hex/EtOAc 8:2. H NMR (CDCl3): major
d = 7.38 (m, 5H), 4.91 (m, 1H), 4.71 (m, 2H), 3.57 (m, 1H), 2.27
(m, 1H), 1.95 (m, 1H), 1.54 (br s, 1H); minor 7.38 (m, 5H), 4.76
(m, 2H), 3.66 (m, 1H), 2.16 (m, 1H), 2.00 (br, s, 1H), 1.89 (m,
1H); 19F NMR (CDCl3): d = ꢀ56.2 (m, 2F); 13C NMR (CDCl3):
major diastereomer d = 142.7, 130.0 (t, J = 293.0 Hz), 128.9,
128.4, 125.5, 73.9, 71.0, 45.0 (t, J = 23.3 Hz), 36.3; minor
diastereomer d = 143.4, 130.1 (t, J = 292.7 Hz), 128.9, 128.4,
125.5, 74.6, 73.2, 46.6 (t, J = 23.3 Hz), 36.8; MS ESI: 301.8
[M + Na] (100%). Anal. Calcd for C11H12ClF2NO3: C, 47.24;
H, 4.32. Found: C, 46.99; H, 4.22.
4l: Rf = 0.37, n-Hex/EtOAc 8:2. 1H NMR (CDCl3): d = 7.36
(m, 5H), 4.90 (m, 1H), 4.76 (m, 2H), 3.60 (m, 1H), 2.22 (m,
1H), 2.02 (br, s, 1H), 1.94 (m, 1H); 19F NMR (CDCl3): major
diastereomer d = ꢀ83.0 (s, 3F), ꢀ116.6 (dd, J = 275.7, 9.1 Hz,
1F), ꢀ121.5 (dd, J = 275.7, 18.3 Hz); minor diastereomer
d = ꢀ82.8, ꢀ117.9 (dd, 1F), ꢀ121.2 (dd, J = 275.7, 9.1 Hz, 1F),
ꢀ121.5 (dd, J = 275.7, 18.3 Hz, 1F); 13C NMR (CDCl3):
d = 142.7, 128.97, 128.94, 128.92, 128.5, 128.45, 125.4, 70.9,
37.8 (t, J = 21.4 Hz), the CF2CF3 signal was obscured due to its
low intensity; MS ESI: 335.8 [M + Na] (100%).
3k: Rf = 0.37, n-Hex/EtOAc 8:2. FT-IR (film): nmax = 3022,
2924, 1687, 1560, 1379, 1217, 1138, 1060, 735 cmꢀ1; 1H NMR
(CDCl3): d = 7.94 (d, J = 7.6 Hz, 2H), 7.61 (m, 1H), 7.48 (m,
2H), 6.16 (td, J = 55.6, 2.85 Hz, 1H), 4.71 (dd, J = 13.3, 5.2 Hz,
1H), 4.61 (dd, J = 13.3, 5.2 Hz, 1H), 3.44 (m,1H); 19F NMR
(CDCl3): d = ꢀ124.4 (ddd, J = 284.2, 55.0, 13.5 Hz, 1F),
ꢀ126.5 (ddd, J = 284.2, 55.0, 13.5 Hz, 1F); 13C NMR (CDCl3):
d = 196.0, 135.9, 133.9, 128.8, 128.0, 115.5 (t, J = 243.7 Hz),
72.6, 37.4 (t, J = 21.3 Hz), 33.9; ESI: 265.8 [M + Na].
3l: Rf = 0.37, n-Hex/EtOAc 8:2. 1H NMR (CDCl3): d = 7.94
(d, J = 7.4 Hz, 2H), 7.61 (m, 1H), 7.24 (m, 2H), 4.77 (dd,
J = 13.8, 6.0 Hz, 1H), 4.58 (dd, J = 13.8, 5.1 Hz, 1H), 4.08 (m,
1H), 3.50 (dd, J = 18.5, 4.5 Hz, 1H), 3.35 (dd, J = 18.5, 8.1 Hz,
1H); 19F NMR (CDCl3): d = ꢀ83.4 (s, 3F), ꢀ118.3 (dd,
J = 275.3, 10.1 Hz, 1F), ꢀ120.2 (dd, J = 275.3, 14.8, 1F); 13C
NMR (CDCl3): d = 194.6, 135.6, 128.9, 128.0, 118.8 (qt,
J = 287.21, 35.20 Hz, 2F), 115.0 (tq, J = 255.7, 37.1 Hz, 3F),
72.1, 35.3 (t, J = 20.1 Hz), 34.2; ESI: 333.8 [M + Na] (100%).
Anal. Calcd for C12H10F5NO3: C, 46.31; H, 3.24. Found: C,
46.33; H, 3.42.
4.5. General procedure for the reaction of 1 with
malonates 9 to afford 10
To a solution of 2-benzyl-malonic acid diethyl ester 9b in
DMF, at 0 8C, under nitrogen, NaH was added. The solution
was stirred at that temperature for 40 min, then, 3,3-difluoro-1-
nitro-propene 1c was added. The mixture was warmed to room
temperature and stirred for 2 h. Water was added (a white slurry
formed), and the suspension was extracted with EtOAc. The
collected organic layers were dried with sodium sulphate and
filtered. Finally the solvent was removed in vacuo and the crude
purified by FC (n-Hex/EtOAc 0–10%), affording 80 mg (53%)
of 10d.
4.4. General procedure for the reduction of oxo-
compounds 3 to alcohols 4
10a: analytical and spectroscopic data matched those
described in Ref. [7].
To a solution of 3i in THF/H2O (4:1), under N2, at 0 8C,
NaBH4 was added. The resulting mixture was stirred at that
temperature for 30 min, then HCl 1N was added. The mixture
10b: 1H NMR (CDCl3): d = 5.03 (dd, J = 13.5, 4.3 Hz, 1H,),
4,81 (dd, J = 13.5, 7.5 Hz, 1H), 4.23 (m, 5H), 3.91 (d, J =
4.00 Hz, 1H), 1.32 (m, 6H).

M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
907
10c: Rf = 0.37, n-Hex/EtOAc 8:2. FT-IR (film): nmax = 3021,
J = 248.2 Hz), 108.3, 107.7, 76.6, 39.5 (t, J = 22.1 Hz), 33.8.
Anal. Calcd for C8H10F2N2O2: C, 47.06; H, 4.94. Found: C,
46.97; H, 5,04.
1
1736, 1568, 1379, 1216, 1136, 758 cmꢀ1; H NMR (CDCl3):
d = 7.41–7.33 (m, 5H), 5.18 (d, J = 12.2 Hz, 1H), 5.15 (d,
J = 12.2 Hz, 1H), 4.64 (dd, J = 13.5, 4.3 Hz, 1H), 4.52 (dd,
J = 13.5, 7.5 Hz, 1H), 3.91 (m, 1H), 3.32 (d, J = 5.3 Hz, 1H),
2.04 (m, 1H), 1.94 (br, s, 1H), 0.97 (d, J = 6.5 Hz, 3H), 0.87(d,
J = 6.5 Hz, 3H); 19F NMR (CDCl3): d = ꢀ75.8 (d, J = 7.7 Hz);
MS (ESI): 414.2 [M + Na] (100%).
11b: Rf = 0.46 (n-Hex/EtOAc 8:2). 1H NMR (CDCl3):
d = 6.66 (m, 1H), 6.27 (m, 1H), 6.15, (m, 1H), 5.00 (dd,
J = 13.2, 4.5 Hz, 1H), 4.67 (dd, J = 13.2, 7.9 Hz, 1H), 4.58 (m,
1H), 3.67 (s, 3H); 19F NMR (CDCl3): d = ꢀ55.8 (dd, J = 163.7,
8.9 Hz, 1F), ꢀ56.8 (dd, J = 163.7, 11.2 Hz, 1F); 13C NMR
(CDCl3): d = 128.1 (t, J = 296.7 Hz), 124.4, 121.9, 109.1,
107.8, 74.5, 45.7 (t, J = 25.6 Hz,), 33.8 (t, J = 22.1 Hz), 33.8.
12: Rf = 0.40 (n-Hex/EtOAc 9:1). 1H NMR (CDCl3):
d = 6.67 (d, J = 7.58 Hz, 1H), 7.34 (m, 2H), 7.24 (m, 1H),
7.14 (s, 1H), 5.00 (m, 1H), 4.88 (m, 2H), 3.78 (s, 3H); 19F NMR
(CDCl3): d = ꢀ60.4 (dd, J = 167.3, 7.6 Hz, 1F), ꢀ61.6 (dd,
J = 167.3, 7.6 Hz, 1F); 13C NMR (CDCl3): d = 136.9, 132.1,
128.3, 122.6, 120.3, 118.7, 109.8, 74.9, 46.7 (t, J = 25.1 Hz),
32.9. Anal. Calcd for C12H11ClF2N2O2: C, 49.93; H, 3.84.
Found: C, 49.90; H, 3.88.
10d: Rf = 0.37, n-Hex/EtOAc 8:2. FT-IR (film):
max = 2986, 1732, 1565, 1370, 1263, 1215, 1069, 910,
n
736 cmꢀ1 1H NMR (CDCl3): d = 7.30 (m, 3H), 7.14 (m,
;
2H), 6.24 (t, J = 54.8 Hz, 1H), 4.69 (d, J = 16.1 Hz, 1H), 4.60
(dd, J = 16.1, 7.15 Hz, 1H), 4.25 (m, 2H), 4.12 (m, 2H), 3.75
(m, 1H), 3.49 (d, J = 14.9 Hz, 1H), 3.34 (d, J = 14.9 Hz, 1H),
1.27 (t, J = 7.15 Hz, 3H), 1.16 (t, J = 7.15 Hz, 3H); 19F NMR
(CDCl3): d = ꢀ120.0 (ddd, J = 291.9, 54.2, 9.3 Hz, 1F), ꢀ124.2
(ddd, J = 291.2, 54.2, 22.5 Hz, 1F); 13C NMR (CDCl3):
d = 168.7, 134.3, 129.8, 128.7, 127.8, 114.9 (t, J = 247.7 Hz),
70.8, 62.4, 43.8 (t, J = 25.6 Hz), 38.9, 13.8, 13.6; MS (ESI):
396.2 [M + Na] (100%). Anal. Calcd for C17H21F2NO6: C,
54.69; H, 5.67. Found: C, 54.89; H, 5.54.
Acknowledgments
10e: Rf = 0.37, n-Hex/EtOAc 8:2. FT-IR (film): nmax = 3022,
1701, 1566, 1379, 1255, 1217, 1130, 909, 758 cmꢀ1; 1H NMR
(CDCl3): d = 7.92 (m, 4H), 7.60 (m, 2H), 7.46 (m, 4H), 6.10 (d,
J = 4.4 Hz), 5.20 (m, 1H), 4.91(dd, J = 16.3, 7.4 Hz, 1H),
4.21(m, 1H); 19F NMR (CDCl3): d = ꢀ69.5 (J = 7.8 Hz, 3F);
13C NMR (CDCl3): d = 192.5, 192.1, 135.5, 134.6, 134.5,
134.4, 129.3, 129.1, 128.7, 124.5 (q, J = 281.7 Hz), 70.7, 51.0,
42.6 (q, J = 29.2 Hz); MS ESI: 366.4 [M + 1] (20%), 388.2
[M + Na] (100%).
Politecnico di Milano and CNR are gratefully acknowledged
for economic support.
References
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10f: Rf = 0.37, n-Hex/EtOAc 8:2. FT-IR (film): nmax = 3023,
(b) M. Molteni, A. Volonterio, M. Zanda, Org. Lett. 5 (2003) 3887–3890.
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1
1695, 1561, 1380, 1266, 1071, 738 cmꢀ1; H NMR (CDCl3):
d = 7.98 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 2H), 7.65 (m,
1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.43 (m, 2H), 6.16 (td,
J = 56.0, 4.24 Hz), 5.87 (d, J = 4.24 Hz, 1H), 4.88 (m, 2H), 3.74
(m, 1H); 19F NMR (CDCl3): d = ꢀ120.5 (ddd, J = 288.5,
56.5,14.5 Hz, 1F), ꢀ122.4 (ddd, J = 288.5, 56.5, 10.1 Hz, 1F);
13C NMR (CDCl3): d = 193.72, 193.7, 135.4, 134.9, 134.6,
134.2, 129.3, 129.1, 128.7, 128.6, 115.5 (t, J = 249.1 Hz), 71.3,
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4.6. General procedure for the Friedel–Crafts reaction of 1
with N-methyl heterocycles to afford 11–12
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solution was warmed to room temperature and stirred for 5 h,
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flash chromatography (n-Hex 100% to n-Hex/EtOAc 8:2),
affording 139 mg (62%) of 11b.
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11a: Rf = 0.43 (n-Hex/EtOAc 8:2). 1H NMR (CDCl3):
d = 6.64 (m, 1H), 6.13 (m, 2H), 5.92 (td, J = 56.2, 3.38 Hz, 1H),
4.85 (dd, J = 13.5, 5.8 Hz, 1H), 4.67 (dd, J = 13.5, 8.3 Hz, 1H),
4.16 (m, 1H), 3.65 (s, 3H); 19F NMR (CDCl3): d = ꢀ119.8 (ddd,
J = 282.7, 55.1, 9.4 Hz, 1F), ꢀ123.2 (ddd, J = 282.7, 55.1,
14.5 Hz, 1F); 13C NMR (CDCl3): d = 123.9, 115.2 (t,
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K. Mikami, T. Yajima, T. Takasaki, S. Matsukawa, M. Terada, T. Uchi-
maru, M. Maruta, Tetrahedron 52 (1996) 85–98;
(b) In the Henry reaction to give 5, we preferentially used nitromethane as

908
M. Molteni et al. / Journal of Fluorine Chemistry 127 (2006) 901–908
a limiting agent, in order to avoid its presence after distillation over P2O5
to give 1 (b.p. of nitromethane 101.2 8C; b.p. of 1b 103–105 8C).
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