Synthesis of fluorinated and non-fluorinated bicyclic amidines through ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201101091

An efficient method for the synthesis of fluorinated and non-fluorinated imidazoazepines by a ring-closing metathesis reaction as the key step is described. The influence of the fluorine atoms on the preparation of these bicyclic systems is also studied. The synthesis of fluorinated and non-fluorinated 3,5,8,9-tetrahidro-2H-imidazo[1,2-a]azepines and 2,3,5,8-tetrahydroimidazo[1,2-a]pyridines by using imidazolines as synthetic intermediates is reported. Thecondensation of esters and 1,2-diamines in the presence of trimethylaluminum provided the imidazolines that were transformed into suitable dienes for a ring-closing metathesis reaction. Copyright

Full text of DOI:10.1002/ejoc.201101091

FULL PAPER
DOI: 10.1002/ejoc.201101091
Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines through
Ring-Closing Metathesis
Ana C. Cuñat,*[a] Sonia Flores,[b] Judit Oliver,[a] and Santos Fustero*[b,c]
Keywords: Amidines / Nitrogen heterocycles / Metathesis / Fluorine
An efficient method for the synthesis of fluorinated and non-
fluorinated imidazoazepines by a ring-closing metathesis re-
action as the key step is described. The influence of the fluor-
ine atoms on the preparation of these bicyclic systems is also
studied.
Introduction
The amidine group constitutes a relevant moiety in or-
ganic and medicinal chemistry, as it can be found in the
structures of numerous natural products,[1] many of which
display biological activity against different pathogens.[2] It
can also be found in compounds with tumor suppressor
properties, which act as protein–protein interaction inhibi-
tors, as in the family of cis-imidazolines known as Nutley
inhibitors or Nutlins[3] (Figure 1). On the other hand, amid-
ines as well as guanidines are considered strong organic
bases thanks to the resonance stabilization of the amidin-
ium ion that results from protonation of the imino nitrogen
atom.[4] This feature turns the amidine structure into a de-
sirable moiety for potential drug design as arginine mim-
ics.[5] Apart from this basic character, neutral amidines may
be considered as N-based donor ligands in coordination
chemistry[6] and have also been used as synthetic intermedi-
ates in the preparation of heterocyclic compounds.[4]
Due to the importance of this substructure, several meth-
ods for the preparation of amidines have been devised.[7]
However, very few of them have dealt with the synthesis of
its bicyclic counterpart.[8] In this sense, lactams appeared as
suitable starting materials for an intramolecular attack of
an azido group on a lactam function.[9] Imidazolines are
also synthetic precursors of bicyclic amidines through tran-
sition-metal-catalyzed microwave-assisted intramolecular
Figure 1. Amidines with pharmacological activity.
C-2 alkylation through C–H bond activation.[10] Alterna-
tively, intramolecular bromoamination of amidine-contain-
ing olefin functionalities allows the creation of tricyclic amid-
ines.[11] Additionally, a thermally generated imidazoline-
derived carbene was also employed to obtain bicyclic amid-
ines by insertion into olefins.[12] More recently, proline has
been used as a starting material for the preparation of chiral
bicyclic imidazolines through carboxylic amide derived
imidoyl chlorides.[13]
We envisioned the possibility of using imidazolines bear-
ing two pendant olefins as starting materials, which upon
ring-closing metathesis (RCM) should establish the bicyclic
system. With the increasing accessibility of fluorinated
building blocks, the CF2-synthon approach has emerged as
a convenient strategy to synthesize a variety of fluorinated
derivatives.[14] This gem-difluoro moiety, frequently used in
medicinal chemistry due to its synthetic accessibility and
its inertness in biological systems, can provide the resulting
products with modified physicochemical and biological
properties, as well as new interactions with the drug target,
often leading to improved pharmacological features.[14,15]
Herein, we report a versatile strategy for the preparation
of bicyclic amidines, particularly imidazo[1,2-a]azepines, by
using RCM as the key step. The correct choice of starting
materials would allow for the control of the ring size, as
outlined in Scheme 1. Both, fluorinated and non-fluori-
nated amidines were prepared to study the influence of a
gem-difluoro moiety in this type of heterocycle.
[a] Departamento de Química Orgánica, Facultad de Química,
Universidad de Valencia, Dr. Moliner,
50, Burjassot, 46100 Valencia, Spain
E-mail: ana.cunat@uv.es
[b] Departamento de Química Orgánica, Facultad de Farmacia,
Universidad de Valencia,
Vicente Andrés Estellés s/n, 46100 Valencia, Spain
E-mail: santos.fustero@uv.es
[c] Laboratorio de Moléculas Orgánicas,
Centro de Investigación Príncipe Felipe,
46012 Valencia, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101091.
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A. C. Cuñat, S. Flores, J. Oliver, S. Fustero
Table 1. Synthesis of imidazolines 3.
FULL PAPER
Scheme 1.
Results and Discussion
Synthesis of Imidazolines 3
The first step of our study was the preparation of imid-
azolines 3 (Table 1). We first evaluated one of the usual con-
ditions employed to generate the imidazoline unit, which
involved treatment of the corresponding nitriles and di-
amines in basic media or, alternatively, with 4 n HCl in di-
oxane. However, the use of fluorinated nitriles under these
conditions gave complex reaction mixtures. We decided
then to apply a different methodology by treatment of un-
saturated esters 1[16] and diamines 2 with trialkylaluminum
derivatives.[17] By using ester 1a and diamine 2c as model
substrates, the reactions were initially performed in re-
fluxing toluene in the presence of trimethylaluminum
(2.0 equiv.), but only a low yield of the desired product was
isolated. However, we found that when the reaction was
performed in refluxing dichloromethane, the corresponding
imidazoline 3c was obtained in 86% yield (Table 1, En-
try 3). The extension of these optimized conditions to dif-
ferent esters 1 and diamines 2 led us to obtain a new family
of imidazolines 3 in moderate to good yields (Table 1).
cis-1,2-Cyclohexanediamine (cis-2c; Table 1, Entries 3, 6,
and 9), meso-1,2-diphenylethylendiamine (cis-2d; Table 1,
Entries 4, 7, and 10), and (1R,2R)-(+)-1,2-diphenylethylen-
diamine (trans-2d; Table 1, Entry 5) successfully led to the
corresponding imidazolines 3 in good yields.[18] With ethyl-
enediamine (2a; Table 1, Entries 1 and 8) and 1,2-propane-
diamine (2b; Table 1, Entry 2) the isolated yield of the final
imidazolines dropped off due to the hydrolysis of the imid-
azoline moiety to the corresponding amide during the puri-
fication conditions.[19] This process is especially important
with ester 1c and amine 2a, where the amide arising from
the hydrolysis of imidazoline 3g was the only product de-
tected (Table 1, Entry 8).[20]
It is known that imidazolines are susceptible to slow hy-
drolysis towards the corresponding amides upon exposure
to air, although they are quite stable when handled under
an atmosphere of nitrogen.[21] In this study, hydrolysis was
observed to be more favorable with imidazolines derived
from 1,2-propanediamine (2b) and, particularly, ethylenedi-
amine (2a) probably due to their decreased steric require-
ments compared to those of amines 2c and 2d.
[a] Isolated yield after flash column chromatography. [b] Crude
1
yield determined by H NMR spectroscopy. [c] See ref.[19]
aromatization event to yield the corresponding imidazole
Regarding the influence of the gem-difluoro moiety in during the purification process. Thus, during the isolation
the process, although the chemical yields of the fluorinated of compound cis-3f, small amounts of the corresponding
and non-fluorinated imidazolines were comparable, the imidazole (ca. 10%) were observed. However, in the case of
non-fluorinated counterparts required longer reaction times their fluorinated analogues, for example, cis-3d and cis-3i,
to go to completion (Table 1, Entries 6–8). On the other imidazole formation was not observed, as could be expected
hand, the non-fluorinated analogues tended to undergo an by the electron-withdrawing effect of the fluorine atoms.
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Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines
Taking into account that 4,5-diarylimidazolines are relevant Preparation of N-Allylated Imidazolines 4
structures in medicinal chemistry and are present in hor-
mone modulators[22] and antitumor therapy agents,[3] the
methodology described herein would allow for the prepara-
tion of fluorinated analogues of these biologically impor-
tant derivatives (see Table 1, Entries 4, 5, and 11).
The next step of our synthetic strategy was the genera-
tion of the dienic system by N-allylation of imidazolines 3.
Due to the problems encountered in the isolation of imid-
azolines 3, the allylation process was carried out by em-
ploying, in most cases, the crude reaction mixture obtained
in their formation. Thus, the reaction was performed under
standard conditions by treatment of a solution of imid-
azolines 3 (crude product without purification) and allyl
bromide in THF/DMF (3:1) with sodium hydride. After the
workup, desired N-allylated imidazolines 4 were obtained
in moderate to good yields (Table 2).[25]
The allylation reaction took place with moderate to good
yield for the fluorinated imidazolines derived from esters 1a
and 1c (Table 2, Entries 1–3, 6, and 7). However, the yields
of non-fluorinated products 4d and 4e dropped dramati-
cally (Table 2, Entries 4 and 5). Again, we observed better
behavior of the fluorinated derivatives, which were obtained
in a more efficient manner than their non-fluorinated ana-
logues.
At this point, the special spectral features of some imid-
azolines 3 should be mentioned. These compounds are in
equilibrium with their tautomeric form,[23] as shown by the
1H and 13C NMR spectra of some products (some signals
appear broad or obscured).[24] For asymmetric 1,2-di-
aminopropane, both imidazoline regioisomers are possible.
In this case, the tautomeric equilibrium was so rapidly es-
tablished at room temperature that average NMR signals
were observed for the unique imidazoline compound iso-
lated after purification (see the Experimental Section).
Table 2. Synthesis of N-allylated imidazolines 4.
Ring-Closing Metathesis (RCM) of Imidazolines 4
The last step of our synthetic strategy was the RCM reac-
tion of dienic imidazolines 4. In this context, the metathesis
reaction has become a very useful synthetic tool for the
preparation of olefins.[26] Moreover, the presence of hetero-
cyclic groups in potentially active substrates has increased
the interest in this reaction. The protection of nitrogen-con-
taining groups and, alternatively, the addition of acids as
additives are the current strategies to achieve ring closure in
heterocyclic systems and prevent catalyst deactivation.[27,28]
Using compound 4a as a model substrate, we initially
performed the optimization of the RCM reaction to find
suitable conditions for this process. The obtained results are
depicted in Table 3.
Table 3. Optimization conditions of the RCM reaction.
Entry Catalyst (mol-%) Additive Solvent[a] Product % Yield[b]
1
2
3
4
5
6
7
8
G1 (5)
G2 (5)
HG (5)
G2 (5)
G1 (5)
G2 (5)
G2 (10)
HG2 (5)
–
–
–
DCM
DCM
toluene
DCM
DCM
DCM
DCM
DCM
SM[c]
SM[c]
SM[c]
SM[c]
5a
5a
5a
5a
–
–
–
Ti(OiPr)4
pTSA[d]
pTSA[d]
pTSA[d]
pTSA[d]
–
30
99
45
80
[a] All reactions were conducted under reflux for 30 min. [b] Iso-
lated yield. [c] Starting material. [d] pTSA: p-toluenesulfonic acid.
[a] Isolated yield after flash column chromatography.
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A. C. Cuñat, S. Flores, J. Oliver, S. Fustero
FULL PAPER
As expected by previous work with related aromatic Table 4. RCM reaction of imidazolines 4.
imidazole derivatives, the reaction without additives did not
take place, recovering the starting material unaltered with
all the catalysts employed (Figure 2) either in refluxing
DCM or toluene (Table 3, Entries 1–3). Likewise, the use
of Ti(OiPr)4 as additive, to avoid the formation of chelates
between the basic nitrogen atoms of the imidazolines and
the catalyst, did not produce any change in the reaction
(Table 3, Entry 4). Finally, the use of p-toluenesulfonic acid
(pTSA) as additive to generate the imidazolium ion and
prevent the inactivation of the Grubbs catalyst by the lone
pair of the imidazole nitrogen atom[28b] led to the metathe-
sis products. By employing the first-generation Grubbs cat-
alyst (G1), 5a was obtained in 30% yield (Table 4, Entry 5).
The best result was obtained with 5 mol-% of the second-
generation Grubbs catalyst (G2; Table 3, Entry 6) in re-
fluxing DCM. The use of higher catalyst loadings (Table 3,
Entry 7) or the use of Hoveyda–Grubbs second-generation
catalyst (HG2; Table 3, Entry 8) provided lower yields of
final imidazoline 5a.[29]
Figure 2. Catalyst employed.
The optimized conditions involved the pretreatment of
imidazoline 4a with pTSA (1.1 equiv.) in DCM for 30 min.
After adding catalyst G2 (5 mol-%), the mixture was heated
at reflux for another 30 min. These conditions were then
applied to the rest of imidazolines 4 (Table 4).
Under the optimized conditions, imidazolines 4a–e cy-
clized to afford the desired bicyclic and tricyclic imid-
[a] The reaction was performed in refluxing toluene.
azolines 5a–e in moderate to good yields (Table 4, En-
tries 1–5).[30,31] The slightly lower yields observed for imid-
azolines 5b,e (Table 4, Entries 2 and 5) are due to the partial
aromatization of the imidazoline ring towards the corre-
sponding imidazole under the purification conditions. Sub-
strate 4f was inert under the optimized conditions, and
when the reaction was performed in refluxing toluene,
cross-metathesis product 6f (Table 4, Entry 6) was obtained
in 23% yield.[32]
RCM of compound 4g took place in an efficient manner,
giving rise to the corresponding six-membered ring. How-
ever, although in the crude reaction mixture bicyclic prod-
uct 5g could clearly be identified as the major product (by
1H and 19F NMR spectroscopy, see the Experimental Sec-
tion), during purification HF elimination occurred, and the
major isolated product was 7g, in 64% yield, together with
a small amount of benzimidazole 8g arising from the aro-
matization of the imidazoline unit (ca. 9% yield, Scheme 2). Scheme 2.
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Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines
1 H), 5.26 (d, J = 17.2 Hz, 1 H), 5.81 (ddt, J = 17.2, 10.2, 7.1 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.8, 20.8, 28.0, 28.0,
39.9 (t, J = 24.6 Hz), 57.3, 64.4, 117.0 (t, J = 241.9 Hz), 121.1,
127.9 (J = 5.1 Hz), 161.2 (t, J = 30.3 Hz) ppm. 19F NMR
Conclusions
We have developed a new synthetic procedure for the
preparation of fluorinated and non-fluorinated imid-
azolines 3 from readily available esters 1 and commercially
available diamines 2 in the presence of trimethylaluminum
as a catalyst. These imidazolines were N-allylated to afford
dienic intermediates 4, which were subjected to RCM to
afford bicyclic and tricyclic amidines 5 in moderate to good
yields. Both amidines 4 and 5 are structurally interesting
compounds, and the application of this synthetic sequence
to study the reactivity of these derivatives and the prepara-
tion of biologically active derivatives are currently un-
derway in our laboratories.
(282.4 MHz, CDCl3): δ = –102.4 (dt, JFF = 267.0 Hz, JHF
=
16.9 Hz, 1 F), –100.9 (dt, JFF = 267.0 Hz, JHF = 16.9 Hz, 1 H)
ppm. HRMS (EI): calcd. for C11H16F2N2 [M]+ 214.1281; found
214.1275.
General Procedure for the Synthesis of N-Allylimidazolines 4: So-
dium hydride (0.77 mmol) was added to a solution of imidazoline
(0.61 mmol) and allyl bromide (1.02 mmol) in a mixture of THF/
DMF (3:1, 4 mL) at 0 °C. When TLC showed total consumption
of the starting material, the mixture was diluted with diethyl ether
(5.0 mL) and washed with water (2ϫ5 mL). The combined organic
layers were washed with brine (5 mL) and dried with anhydrous
Na2SO4. The oily residue was subjected to flash column
chromatography as detailed below.
Experimental Section
cis-N-Allyl-2-(1,1-difluoro-3-butenyl)-4,5-dihydro-4,5-diphenylimid-
azole (4b): According to the general procedure described above,
imidazoline cis-3d (190.0 mg, 0.61 mmol) afforded N-allylimid-
azoline 4b (191.0 mg) as a yellowish oil in 90% yield after flash
column chromatography (n-hexane/ethyl acetate, 2:1) on silica gel
deactivated by treatment with 2 % triethylamine in hexane. 1H
NMR (300 MHz, CDCl3): δ = 3.07–3.36 (m, 2 H), 3.29 (dd, J =
15.8, 8.1 Hz, 1 H), 4.40 (dd, J = 15.8, 3.2 Hz, 1 H), 4.99 (d, J =
17.2 Hz, 1 H), 5.11 (d, J = 11.7 Hz, 1 H), 5.16 (d, J = 10.0 Hz, 1
H), 5.35 (d, J = 17.2 Hz, 1 H), 5.37 (d, J = 10.2 Hz, 1 H), 5.50 (d,
J = 11.7 Hz, 1 H), 5.80 (dddd, J = 17.2, 10.0, 8.1, 3.2 Hz, 1 H),
6.05 (ddt, J = 17.2, 10.2, 7.0 Hz, 1 H), 6.81 (dd, J = 7.3, 3.9 Hz, 2
H), 6.86 (dd, J = 7.7, 2.1 Hz, 2 H), 6.97 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 40.1 (t, J = 23.6 Hz), 47.1 (t, J = 4.1 Hz),
69.2, 72.6, 117.9 (t, J = 241.6 Hz), 118.3, 120.9, 126.5, 127.2, 127.4,
127.7, 127.8, 127.9, 128.6 (t, J = 5.0 Hz), 133.0, 135.5, 138.2, 159.8
(t, J = 30.3 Hz) ppm. 19F NMR (282.4 MHz, CDCl3): δ = –100.9
(ddd, JFF = 282.3 Hz, JHF = 24.6 Hz, JHF = 14.6 Hz, 1 F), –99.3
General Experimental Techniques: All melting points were deter-
mined by using a Kofler hot-stage apparatus. Optical rotations
were determined by using a 10-cm path length cell. High-resolution
mass spectra were recorded with a VG AutoSpec spectrometer by
employing electron impact (EI, 70 eV) or fast atom bombardment
(FAB) techniques and with a Q-TOF premier mass spectrometer
with an electrospray source by using electrospray ionization tech-
1
nique (ESI). H NMR spectra were recorded with Avance Bruker
spectrometers, in the solvent indicated, at 300 or 400 MHz and 13
C
NMR spectra at 75 or 100 MHz. 19F NMR spectra were acquired
at 282 MHz with high-power proton decoupling. 1H NMR spectra
were referenced to residual CHCl3 (δ = 7.26 ppm), 13C NMR spec-
tra to the central component of the CDCl3 triplet at δ = 77.0 ppm,
and 19F NMR spectra to CFCl3 as the internal reference, which
was set at δ = 0.00 ppm. Carbon substitution degrees were estab-
lished by DEPT pulse sequences. Reaction progress was monitored
by thin-layer chromatography (TLC) performed on F254 silica gel
plates. The plates were visualized by immersion with ethanolic ceric
ammonium molybdate and heating. Flash column chromatography
was performed, as indicated in each case, by using silica gel 60
(0.040–0.063 mm) or silica gel Sepra NH2 (50 μm, 64 Å). All opera-
tions involving air-sensitive reagents were performed under an inert
atmosphere of dry nitrogen by using syringe techniques, oven-dried
glassware, and freshly distilled and dried solvents. Solvents and rea-
gents were purified by standard methods.[33]
(dddd, JFF = 282.3 Hz, JHF = 18.9 Hz, JHF = 15.0 Hz, JHF
=
3.0 Hz, 1 F) ppm. HRMS (EI) calcd. for C22H22F2N2 [M]+
352.1751; found 352.1741.
General Procedure for the Preparation of Compounds 5 by Ring-
Closing Metathesis: pTSA (0.044 mmol) was added to a stirred
solution of dienic imidazolines 4 (0.04 mmol) in anhydrous dichlo-
romethane (2.0 mL), and the solution was heated at reflux for
30 min. After cooling down to room temperature, the second-gen-
eration Grubbs catalyst (5 mol-%) was added, and the mixture was
heated at reflux for another 30 min. The obscured solution was
quenched with 10% aqueous NaHCO3 (5.0 mL) and extracted with
dichloromethane (3ϫ5.0 mL). The combined organic layers were
washed with brine (5.0 mL), dried with anhydrous Na2SO4, and
concentrated in vacuo. The residue was subjected to flash column
chromatography.
General Procedure for the Preparation of Imidazolines 3: Trimeth-
ylaluminum (2 m in hexane, 2.44 mmol) was added dropwise at 0 °C
to a solution of diamine 2 (1.22 mmol) in dichloromethane
(0.6 mL). The mixture was stirred at room temperature for 1 h. The
reaction was cooled down again to 0 °C, and a solution of ethyl
ester 1 (1.22 mmol) in dichloromethane (0.9 mL) was added. The
resulting mixture was heated at 70 °C for 3 h (overnight for non-
fluorinated compounds). The reaction mixture was cooled down to
room temperature and quenched with methanol (1.0 mL). The
crude mixture was filtered through a Celite pad, washed with
DCM, and concentrated in vacuo. The oily residue was subjected
to flash column chromatography.
6,6-Difluoro-1,3,4,4a,6,7,10,11a-octahydro-2H-azepino[1,2-a]benz-
imidazole (5a): According to the general procedure described above,
N-allylimidazoline 4a (10.0 mg, 0.47 mmol) afforded tricyclic amid-
ine 5a (9.0 mg) as a yellowish solid in 99 % yield after flash
chromatography (n-hexane/ethyl acetate, 1:1) on silica gel Sepra
cis-2-(1,1-Difluoro-3-butenyl)-3a,4,5,6,7,7a-hexahydrobenzoimid- NH2 (50 μm, 64 Å). Mp 90–92 °C. 1H NMR (300 MHz, CDCl3): δ
azole (3c): According to the general procedure described above,
ethyl ester 1a (200.0 mg, 1.22 mmol) afforded imidazoline 3c
(223.0 mg) as a white solid in 86% yield after flash chromatography
(n-hexane/ethyl acetate, 2:1) on silica gel. M.p. 67–69 °C. 1H NMR
= 1.21–1.94 (m, 8 H), 2.79–2.94 (m, 2 H), 3.48 (dt, J = 8.1, 5.6 Hz,
1 H), 3.55–3.75 (m, 2 H), 3.78–3.86 (m, 1 H), 5.54–5.62 (m, 1 H),
5.77–5.84 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.4,
21.4, 24.5, 28.1, 36.4 (t, J = 26.8 Hz), 42.4, 62.1, 63.8, 116.2 (t, J
(300 MHz, CDCl3): δ = 1.23–1.89 (m, 8 H), 2.93 (td, J = 16.9, = 241.9 Hz), 122.5 (t, J = 6.3 Hz), 126.3, 160.8 (t, J = 27.6 Hz)
7.1 Hz, 2 H), 3.78 (br. s, 2 H), 4.78 (br. s, 1 H), 5.24 (d, J = 10.2 Hz, ppm. 19F NMR (282.4 MHz, CDCl3): δ = –100.5 (dt, JHF
=
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A. C. Cuñat, S. Flores, J. Oliver, S. Fustero
FULL PAPER
McKay, J. R. Somoza, N. Chauret, C. Seto, J. Scheigetz, G.
Wesolowski, F. Masse, S. Desmarais, M. Ouellet, J. Med.
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14.6 Hz, JHF = 4.7 Hz, 2 F) ppm. HRMS (EI): calcd. for
C12H16F2N2 [M]+ 226.1282; found 226.1284.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data for new prod-
ucts, and complete details about the synthesis of new products.
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Acknowledgments
We would like to thank the Ministerio de Ciencia e Innovación
(MICINN) (CTQ2010-19774) of Spain and the Generalitat Valen-
ciana (PROMETEO/2010/061) for financial support. S. F. expresses
her thanks for a predoctoral fellowship (FPU Programme).
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1
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Eur. J. Org. Chem. 2011, 7317–7323

Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines
in our laboratories: S. Fustero, M. Sánchez-Roselló, D. Jimé-
nez, J. F. Sanz-Cervera, C. del Pozo, J. L. Aceña, J. Org. Chem.
2006, 71, 2706–2714.
of a co-catalyst. Considering the lowering in nitrogen basicity
induced by the fluorine atoms, it is reasonable to think that the
RCM process would work better in those cases. However, in
our study the nitrogen atom was previously protonated by
treatment with TsOH, and therefore, the nitrogen lone pair
does not operate in this case, which may explain the small dif-
ference found between the fluorinated and the non-fluorinated
derivatives.
[30] In this study, the presence of fluorine atoms seems to have no
significant effect, for example, on the final chemical yield. In
this context, several examples where the presence of fluorine
atoms plays an important role have recently been described.
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[32] When the reaction was performed with the G2 catalyst in re-
fluxing toluene an equimolecular mixture of starting material
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[31] It is important to mention that in all the aforementioned cases
Received: July 26, 2011
Published Online: October 19, 2011
(see, ref.[30]), the RCM process was performed in the absence
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