Fluoroalkylated α,β-unsaturated imines as synthons for the preparation of fluorinated triazinane-2,4-diones and dihydropyrimidin-2(1 H)-ones

Article abstract of DOI:10.1021/jo500745u

A regioselective addition of isocyanates to fluoroalkylated α,β-unsaturated imines 1 is described. Fluoroalkyl-substituted triazinane-2,4-diones 4 are obtained by the reaction of phenyl isocyanate with fluorinated imines 1, while fluorinated dihydropyridin-2(1H)-ones 7 are prepared when tosyl isocyanate is used. Tetrahydro-pyridin-2(1H)-one 10 is obtained by catalytic reduction of dihydropyridin-2(1H)-one 7. Computational studies are performed to explain the different behaviors of both isocyanates and the mechanisms of the processes.

Full text of DOI:10.1021/jo500745u

Article
pubs.acs.org/joc
Fluoroalkylated α,β-Unsaturated Imines as Synthons for the
Preparation of Fluorinated Triazinane-2,4-diones and
Dihydropyrimidin-2(1H)‑ones
Guillermo Fernandez de Troconiz, Ana M. Ochoa de Retana, Gloria Rubiales, and Francisco Palacios*
́
́
Departamento de Química Organ
Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria, Spain
́
ica I and Centro de Investigacion Lascaray (Lascaray Research Center) Facultad de Farmacia,
S
* Supporting Information
ABSTRACT: A regioselective addition of isocyanates to fluoroalkylated α,β-unsaturated imines 1 is described. Fluoroalkyl-
substituted triazinane-2,4-diones 4 are obtained by the reaction of phenyl isocyanate with fluorinated imines 1, while fluorinated
dihydropyridin-2(1H)-ones 7 are prepared when tosyl isocyanate is used. Tetrahydro-pyridin-2(1H)-one 10 is obtained by
catalytic reduction of dihydropyridin-2(1H)-one 7. Computational studies are performed to explain the different behaviors of
both isocyanates and the mechanisms of the processes.
the preparation of bicyclic DHMPs was reported. We have been
involved in the chemistry of heterodienes derived from amino
acids and have developed synthetic methodologies for the
preparation of 1-azadienes such as α,β-unsaturated imines,
hydrazones, or oximes. We also reported an efficient procedure
for the synthesis of electron-poor 1-azadienes derived from α-
amino acids or α-aminophosphonates using an aza-Wittig
approach, as well as successful normal ADA reactions of α,β-
unsaturated N-arylimines, hydrazones, and ADA reaction of
α,β-unsaturated sulfinylmines with electron-rich dienophiles
and Michael additions (1,4 addition) of α,β-unsaturated N-
arylimines. In the development of new fluorinated substrates,
we prepared the first stable N-unsubstituted α,β-unsaturated
imine27 Ia (Scheme 2) from primary fluorine-substituted
enaminophosphonates,28,29 and we used these derivatives for
the preparation of vinylogous α-aminonitriles IIIa,30 β-
aminonitriles IIIb (X = CN),30 and β-aminoesters IIIb (X =
CO2Et),31 obtained by 1,2-addition of trimethylsilyl cyanide,
acetonitrile, or ethyl acetate, while the regioselective Michael
addition of α-carbanions derived from carboxylic esters and
nitriles to fluorinated imines I may afford functionalized
pyridine derivatives IV.31,32
INTRODUCTION
■
α,β-Unsaturated imines (I, Scheme 1), also called 1-azadienes,
are a versatile family of compounds with a wide range of
applications in preparative organic chemistry.1 These substrates
are used not only for the preparation of six-membered
heterocycles through the well-known aza-Diels−Alder reaction
(ADAR, compounds II, Scheme 1)2 but also for the
construction of five-membered heterocycles by means of the
[4 + 1] cycloadditions for the synthesis of pyrroles3 or the [3 +
2] cycloadditions for the preparation of both β-lactams4a and
highly fuctionalizad cyclopentenes.4b Moreover, owing to their
ambident electrophilic character, α,β-unsaturated imines can
either undergo 1,25 or conjugate 1,46 nucleophilic addition
processes (compounds III and IV, Scheme 1). However,
controlling the regioselectivity is generally difficult, and very
often the double-nucleophilic addition products are obtained.7
Dihydropyrimidin-2(1H)-ones (DHPMs) are important het-
erocycles8,9 that form the core of a wide number of biologically
active derivatives,10 such as antihypertensive,11 anticancer,12
antioxidant,13 antimicrobial,14 anti-HIV activities,15 NaI sym-
porter16 or enzyme inhibitors,17 calcium channel blockers,18
and selective A2B adenosine receptor antagonists.19
In this context, the development of new methods for the
preparation of fluorine-substituted heterocycles is an interesting
goal in synthetic organic chemistry not only because of their
use in medicinal chemistry22 but also for the development of
active ingredients for crop protection23 and materials.24
Continuing with our interest in the chemistry of fluorinated
derivatives as well as 1-azadienes, here we report the
In this context, fluoroorganic compounds have received a
great deal of attention since the incorporation of a fluorine
containing group into an organic molecule dramatically alters
its physical, chemical and biological properties.20 Due to the
unique properties of the fluorine atom, fluorinated molecules
occupy a significant place21 in pharmaceutical/medicinal,22
agrochemical,23 and material sciences.24
In recent years, an elegant and efficient preparation of
DHMPs has been developed from isocyanates and α,β-
unsaturated imines,25 and when alkenyloxazolines26 were used
Received: April 1, 2014
© XXXX American Chemical Society
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equivalent of phenyl isocyanate 2a, followed by cyclization,
afforded triazinane derivatives 4a−e. A second pathway is
possible whereby the first zwitterionic intermediate by an 1,3-
H-shift could give nonisolated monoadduct 6, which by
addition of a second equivalent of phenyl isocyanate 2a
followed by ring closure can similarly afford the six-membered
heterocycles 4a−e. Formally, the process may be considered as
a [2 + 2 + 2] cycloaddition involving the very reactive CN
double bond from the imines 1 and both CN bonds from the
two molecules of isocyanate 2a. Similar [2 + 2 + 2]
cycloaddition processes involving two molecules of phenyl
isocyanate and the CN of aldimines,33a ketimines,5a
hydrazones,33b isoquinolines,33c or acetimidates33d have been
described. Although triazinane-2,4-dione heterocycles have
been used in herbicidal formulations34 and in pharmaceutical
compositions,35 few examples of preparation of the triazinane-
2,4-dione heterocycles have been reported.33 This process
represents, as far as we know, the first example of preparation of
fluorinated triazinane-2,4-diones 4.
To have a better understanding of factors controlling the
process, we computationally examined the reactions between
azadienes 1a (R1 = p-CH3C6H4, RF = CF3), 1c (R1 = p-
NO2C6H4, RF = CF3), 1d (R1 = 2-furyl, RF = CF3), 1e (R1 = 2-
furyl, RF = CHF2), and 1f (R1 = p-F-C6H4, RF = CF3) and
phenyl isocyanate 2a (see the Supporting Information for
details).36−42 Thus, the approach of 1-azadienes 1a,c−f to
phenyl isocyanate could take place preferentially in the
configuration s-trans-1Z,3E (see Figure 1 in the Supporting
Information) through transition states TS1a,c−f or TS2a,c−f
which could lead to two different zwitterion intermediates
M1a,c−f or M2a,c−f. respectively (Scheme 4). Computational
results indicate that in the presence of THF, the activation
barriers corresponding to the approach 1-azadienes 1a,c−f
through transition structures TS2a,c−f are very similar to
activation barriers corresponding to transition structures
TS1a,c−f and calculated free energy differences indicate that
zwitterionic intermediates M2a,c−f are more stable than
M1a,c−f (see Table 1 and Figures 2 and 3 in the Supporting
Information for a comparative of results), although all the
processes are slightly endothermic, with reaction energies for
the formation of M2a,c−f ranging from 1.8 kcal/mol (for M2e,
R1 = 2-furyl, RF = CHF2) to 6.5 kcal/mol (for M2c, R1 = p-
NO2C6H4, RF = CF3).43 As an example in Figure 1, the energy
profile for the reaction of 1a with 2a to give M1a and M2a is
shown.
Scheme 1. Reactivity Pattern of α,β-Unsaturated Imines I
preparation of novel fluoroalkyl-substituted triazinane diones V
and DHPMs VI (Scheme 2).
RESULTS AND DISCUSSION
■
Synthesis of Fluoroalkylated Triazinane-2,4-diones 4.
Unsaturated imines 1 were prepared in good yields by
olefination reaction of phosphorated enamines and aldehyde-
s,27a,28 and DHPMs are a class of important heterocycles used
not only in preparative organic chemistry8 but also in medicinal
chemistry.11−19 Our initial approach to fluorinated DHPMs was
based on the ADA reaction of 1-azadiene 1 and phenyl
isocyanate.25 However, the treatment of α,β-unsaturated imine
1a (R1 = p-CH3C6H4, RF = CF3) with phenyl isocyanate 2a at
room temperature did not give the fluorinated DHPMs 3a, and
the corresponding vinylogous triazinane-2,4-dione 4a (R1 = p-
CH3C6H4, RF = CF3, Scheme 3) was obtained instead in a
regioselective fashion in low yield. This compound 4a was
characterized on the basis of spectroscopic data. The high-
resolution mass spectrum (HRMS, M+ 451.1508) is consistent
with the incorporation of two molecules of phenyl isocyanate
2a into fluorinated azadiene 1 (1:2 cycloadduct).
This behavior prompted us to reexamine the process in order
to improve the low yield obtained initially. When 2 equiv of
phenyl isocyanate 2a was used, the isolation of the triazinane-
2,4-dione 4a in good yield (85%, Scheme 3, Table 1, entry 1)
was achieved. The process was also extended to trifluor-
omethyl- and difluoromethyl-substituted imines 1b−e (RF =
CF3, CHF2) containing aromatic (R = p-NO2C6H4) or
heteroaromatic (R1 = 2-furyl) substituents, and the correspond-
ing heterocycles 4b−e were obtained in good yields (Scheme 3,
Table 1, entries 2−5).
The formation of these heterocycles 4a−e could be explained
as outlined in Scheme 3. Addition of phenyl isocyanate 2a to
unsaturated imines 1a−e may give initially the corresponding
zwitterionic intermediate 5, which by addition of a second
Next, we studied the second step of the reaction for the
generation of vinylogous triazinane derivatives 4 (1:2 cyclo-
adducts) vs the alternative DHPMs 3 (1:1 cycloadducts). The
Scheme 2. Nucleophilic Reactions (1,2 vs 1,4) of Fluorinated α,β-Unsaturated Imines I and Reactions with Isocyanates
B
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Scheme 3. Synthesis of Fluoroalkylated Triazinane-1,3-diones 4
Table 1. Fluoroalkylated Triazinane-2,4-diones 4
a
entry
compd
R1
RF
yield (%)
1
2
3
4
5
4a
4b
4c
4d
4e
p-CH3C6H4
p-NO2C6H4
p-NO2C6H4
2-furyl
CF3
85
75
83
92
90
CHF2
CF3
CF3
2-furyl
CHF2
a
Yield of isolated purified compounds obtained from 1a−e.
hypothetical formation of DHPMs 3 could be explained by
direct intramolecular cyclization of the more stable zwitterionic
intermediates M2a,c−f. However, the formation of triazinane
compounds 4a,c−f may involve the addition of a second
molecule of isocyanate 2a to intermediates M2a,c−f to give,
through transition structures TS5a,c−f, new zwitterionic
intermediates M3a,c−f, that finally cyclize to triazinane
products 4, through transition structures TS6a,c−f (see
Scheme 4). Alternatively, nonisolated monoadducts 6a,c−f
may be generated from the first zwitterionic intermediates
M2a,c−f through a TS4a,c−f. The addition of a second
Figure 1. Energy profile for transformation from reactants 1a and 2a
to zwitterionic intermediates M1a and M2a at the M06-2X(PCM)/6-
311+G**//B3LYP/6-31G* + ΔZPVE level (unit: kcal/mol) using
tetrahydrofuran as solvent.
Scheme 4. Different Pathways for the Reaction of 1a,c−f with 2a
C
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Figure 2. Energy profile for transformation from zwitterionic intermediate M2a to the products 3a, 4a, and 6a at the M06-2X(PCM)/6-311+G**//
B3LYP/6-31G* + ΔZPVE level (unit: kcal/mol) using tetrahydrofuran as solvent.
equivalent of phenyl isocyanate 2a followed by ring closure
would lead to heterocycles 4a,c−f. Thus, we studied and
compared, (i) the formation of M3a,c−f through TS5a,c−f, (ii)
the formation of 3a,c−f through TS3a,c−f, and (iii) the
formation of 6a,c−f through TS4a,c−f (Scheme 4).
account the observed versatility of α,β-unsaturated imines 1
as starting materials for the preparation of acyclic compounds
and nitrogen heterocycles, we extended the study of the
reactivity to isocynates containing an electron-withdrawing
group, such a tosyl group, in order to test if the presence of this
group might drive the process to fluorinated DHPM-
monoadducts. The addition of tosyl isocyanate 2b to
In all cases, in the presence of THF as the solvent,
computational results indicate that the pathways involving
transition structures TS5a,c−f for the formation of zwitterionic
intermediates M3a,c−f exhibit the lowest activation barriers
(see Table 2 and Figure 4 in the Supporting Information for
details).43 The processes for the formation of 3 and 6 are
exothermic, but it is very important to note that the activation
barriers associate with the cyclization of M3a,c−f to give 4a,c−f
through TS6a,c−f are very low (in THF lower than 5 kcal/mol
in all cases), reflecting that the reaction is very facile and the
cyclization is very fast. Moreover, in all cases, the formation of
4a,c−f from M3a,c−f is much more exothermic (around 20
kcal/mol in all cases) than the formation of 3a,c−f and also
(around 30 kcal/mol in all cases) for the formation of 6a,c−f.
As an example in Figure 2, the energy profile for the formation
of compounds 3a, 4a, and 6a from M2a is shown (for full
comparisons of energetics, see the Supporting Information).
These computational results indicate that the formation of
4a,c−f in solution of THF is favored kinetically and
thermodynamically and is in agreement with the experimental
results. As an example see Figure 4 in the Supporting
Information, which summarizes the stationary points found in
the reaction of 2a and 1f. These results are consistent with
those previously described44 for the [2 + 2] reaction of
isocyanates with electron withdrawing groups and olefins with
electron donanting groups, because the reaction is very
effective, but takes place through zwitterionic intermediates in
a two-step process favored by the presence of a solvent.
Similarly, a stepwise process with the participation of
zwitterionic intermediates is used in a computational study to
understand the mechanisms of three-component reaction
between imidazoles, isocyanates and cyanophenylacetylene to
generate imidazole carboxamides.45 Therefore, the mechanism
proposed in Scheme 3 is consistent with both experimental and
computational results.
fluorinated unsaturated imine 1a (R1 = p-CH3C6H4, RF
=
CF3) in THF at rt gave the corresponding cycloadduct 7a (R1 =
CH3C6H4, RF = CF3, Scheme 5, Table 2, entry 1) in good yield.
Fluoroalkylated 3,4-dihydropyrimidin-2(1H)-one 7a was
characterized based on its spectroscopic data. HRMS (M+
410,0912) is consistent with the incorporation of one molecule
of tosylisocyanate 2b into azadiene 1a and formation of
monoadduct 7a. 1H NMR spectra of conpound 7a also show a
well-resolved doublet at δH = 5.76 ppm with a coupling
3
constant of JHH = 6.0 Hz, corresponding to the 4-H of the
dihydropyridone ring, as well as a double quadruplet at δH =
6.09 ppm with coupling constants 4JFH = 1.6 Hz and 3JHH = 6.0
Hz for 5-H, while only one signal appears in 19FNMR as a
single peak at δF = −70.6 ppm. The scope of the process is very
wide, given that heterocycles 7 containing not only aromatic
substituent (R1 = p-FC6H4, Table 2, entry 2) and
heteroaromatic substituent (R1 = 2-furyl, Table 2, entries 3−
5) but also trifluoromethyl (RF = CF3, Table 2, entries 2 and 3)
Scheme 5. Synthesis of Fluoroalkylated 3,4-Dihydropyridin-
2(1H)-ones 7 and 3,4,5,6-Tetrahydropyridin-2(1H)-one 10.
Synthesis of Fluoroalkylated 3,4-Dihydro- 7 and
3,4,5,6-Tetrahydropyridin-2(1H)-ones 10. Taking into
D
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was also observed for the reaction of alkenyloxazolines with
isocyanates.26a
Table 2. Fluoroalkylated 3,4-Dihydropyrimidin-2(1H)-ones
7 and 4-(Trifluoromethyl)tetrahydropyrimidin-2-one 10
As was the case for 2a, the approximation of azadienes 1a,c−f
to isocyanate 2b in a nonconcerted process will take place
preferentially in configuration s-trans-1Z,3E through transition
states TS7a,c−f or TS8a,c−f, and therefore, the different
approach could lead to two different zwitterion intermediates
M4a,c−f or M5a,c−f (Scheme 6). In all cases, in the presence
of THF as the solvent, the activation barriers corresponding to
the approach of dienes 1a,c−f through transition structures
TS7a,c−f are very similar to activation barriers corresponding
to transition structures TS8a,c−f, and as expected its values
decrease relative to the gas phase. As an example, in Figure 3,
the energy profile for the reaction of 1a with 2b to give M4b
and M5a is shown. Moreover, all the processes are exothermic,
and calculated free energy differences indicate that zwitterionic
intermediates M5a,c−f are more stable than M4a,c−f (see
Table 3 and Figures 5 and 6 in the Supporting Information for
a comparison of results).
Therefore, the formation of M5a,c−f in a solution of THF is
favored kinetically and thermodynamically. In addition, these
results indicate that TS7a,c−f and TS8a,c−f are very early, the
activation energy of this first step is very low (ranging from 1 to
5 kcal/mol, computing a B3LYP(PCM)/6-311 +G** +ΔZPVE
level of theory using tetrahydrofuran as solvent) and supports
the idea that not only is this step of the reaction very
straightforward but also that the formation of M5a,c−f is very
rapid. Thus, isocyanate 2b is probably completely consumed
before the second step of the reaction (see the Supporting
Information for a comparison of results).
Concerning the second step of the process, in the presence of
THF the cyclization of more stable zwitterionic intermediate
M5a,c−f to give 7a,c−f exhibit, in all cases, lower activation
barriers (around half in all cases),47 through transition
structures TS9a,c−f, than those involving transition structures
TS10a,c−f for the formation of acyclic monoadduct 9a,c−f. As
an example, in Figure 4, the energy profile for the formation of
compounds 7a and 9a from M5a is shown. Both processes are
exothermic, but the formation of DHPMs 7a,c−f is much more
exothermic (more than 15 kcal/mol in all cases),47 than the
formation of monoadduct 9a,c−f. These results indicate that
kinetically and thermodynamically the formation of fluoroalky-
lated 3,4 dihydropyrimidin-2(1H)-ones 7 is favored and is in
a
entry
compd
R1
RF
yield (%)
1
2
3
4
5
6
7a
7f
p-CH3C6H4
p-FC6H4
2-furyl
CF3
78
68
75
71
72
CF3
7d
7e
7g
10
CF3
2-furyl
CHF2
C2F5
2-furyl
b
86
a
b
Yield of isolated purified compounds obtained from 1. Yield
obtained from 7f.
and difluoromethyl (RF = CHF2, Table 2, entry 4) and
pentafluoroethyl (RF = C2F5, Table 2, entry 5) derivatives may
also be prepared (Scheme 5).
Formation of fluoroalkylated DHPMs 7 may be explained via
the pathway depicted in Scheme 5. The process may be
initiated by a nucleophilic attack from the NH of the imino
group from unsaturated imine 1 to the CN double bond of
tosyl isocyanate 2b to give a zwitterionic intermediate 8
followed by an intramolecular cyclization to give DHPMs 7.
Likewise, a 1,3-H-rearrangement from intermediate 8 may give
monoadduct 9, and subsequent intramolecular nucleophilic
addition may lead to DHPMs 7. However, another pathway
involving a concerted [4 + 2] cycloaddition (DA reaction)
involving unsaturated imines 1 (1-azadiene) and isocyanate 2a
(dienophile) could also explain the formation of fluorinated
DHPMs 7.
For this reason, a computational study46 was performed to
explain the different behavior observed when tosyl isocyante 2b
vs phenyl isocyanate 2a reacted with fluorinated imines 1 and
to determine the most favored mechanism of the processes. It is
also interesting to note that all our attempts to locate a
transition state corresponding to the DA reaction that would
lead to the formation of the products 7 through a concerted
process met with no success. All of the starting geometries
converged to either a transition structure where the bond N-
imimic−C-isocyanate (with a distance N-isocyanate−C-4aza-
diene higher than 3 Å) began to form or a transition structure
with the bond N-imimic−C-isocyanate formed, where the bond
N-isocyanate C-4-azadiene began to be created upon the
optimization at the B3LYP/6-31G* + ZPVE level. This feature
Scheme 6. Different Pathways for the Reaction of 1a,c−f with 2b
E
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may give the corresponding fluoroalkyl-substituted tetrahy-
dropyrimidin-2(1H)-one 10. Computational and experimental
studies indicate that fluoroalkylated α,β-unsaturated imines 1
reacted through the iminic nitrogen with the electron-deficient
carbon of isocyanates 2 leading to zwitterionic intermediates
which participate in a stepwise mechanism to give fluorinated
heterocycles 4 and 7. When phenyl isocyanate 2a is used the
nitrogen atom in zwitterionic intermediate 5 is more
nucleophilic and therefore may favor the addition of a second
equivalent of isocyanate 2a to give triazinane-2,4-diones 4.
Conversely, the reaction of tosyl isocyanate 2b and
fluoroalkylated α,β-unsaturated imines 1 may take place via a
nonconcerted process though a zwitterionic intermediate 8,
which is generated very rapidly and is favored kinetically and
thermodynamically. Subsequent cyclization to give DHPMs 7
in a second step is also favored kinetically and thermodynami-
cally. The scope of the reaction is not limited to the
trifluoromethyl group, given that not only difluoromethyl but
also perfluoroethyl groups may be used. Substituted triazinane
derivatives 4,33−35 dihydro- 7, and tetrahydropyrimidinones
10,8−19 are important building blocks in organic synthesis and
in the preparation of biologically active compounds of interest
in medicinal chemistry,22 agricultural,23 and material sciences.24
Figure 3. Energy profile for transformation from reactants 1a and 2b
to zwitterionic intermediates M4a and M5a at the M06-2X(PCM)/6-
311+G**//B3LYP/6-31G* + ΔZPVE level (unit: kcal/mol) using
tetrahydrofuran as solvent.
EXPERIMENTAL SECTION
■
Solvents for extraction and chromatography were of technical grade.
All solvents used in reactions were freshly distilled. All other reagents
were recrystallized or distilled as necessary. All reactions were
performed under an atmosphere of dry nitrogen. Melting points are
uncorrected. IR−FT spectra were recorded with an infrared
spectrometer, and absorbance frequencies are given at maximum of
intensity in cm−1. High-resolution mass spectra (HRMS) were
obtained using an electron spray ionization (ESI) method with a
Figure 4. Energy profile for transformation from zwitterionic
intermediate M5a to the products 7a and 9a at the M06-2X(PCM)/
6-311+G**//B3LYP/6-31G* + ΔZPVE level (unit: kcal/mol) using
tetrahydrofuran as solvent.
1
time-of-flight Q-TOF system. H (300, 400 MHz) and 13C (75, 100
MHz) spectra were recorded on a 300 or 400 MHz spectrometers,
respectively, in CDCl3 or CD3OD, as specified below. Chemical shifts
(δH) are reported in parts per million (ppm), relative to TMS as
internal standard. Chemical shifts (δC) are reported in parts per
million (ppm), relative to CDCl3 or CD3OD, as internal standards in a
broad band decoupled mode. Chemical shifts for 19F NMR are
reported in ppm downfield from fluorotrichloromethane (CFCl3). The
abbreviations used are as follows: s, singlet; d, doublet; dd, double-
doublet; dq, double-quadruplet; t, triplet; q, quartet; m, multiplet.
Flash-column chromatography was carried out using commercial
grades of silica gel finer than 230 mesh. Analytical thin-layer
chromatography (TLC) was performed on precoated silica gel 60
F254 plates, and spot visualization was accomplished by UV light (254
nm) or KMnO4 solution. Unsaturated imines 1 were prepared
following a literature procedure.34a,35
agreement with the experimental results and with the tentative
proposed mechanism in Scheme 5. As examples, see Figures 7
and 8 in the Supporting Information where the stationary
points found in the reaction of 2b with 1c and 2b with 1e,
respectively, are summarized.
Finally, the hydrogenation of fluoroalkylated DHPMs 7f (R1
= p-FC6H4, RF = CF3), was explored in order to increase the
diversity with new fluorinated heterocycles such as tetrahy-
dropyrimidin-2-ones (THPMs). The reduction of the cyclic
enaminic C−C double bond was performed by means of
hydrogenation with Pd/C in methanol and afforded the
corresponding 4-trifluoromethyl tetrahydropyrimidin-2-one 10
in good yield (86%, Scheme 5, Table 2, entry 6) as a mixture of
diastereoisomer (ratio 1/1). This strategy represents, as far as
we know, the first example of preparation of fluorinated di- 7
and tetrahydropyrimidin-2-ones 10.
General Procedure for the Synthesis of Fluoroalklated
Triazinane-2,4-diones 4. Phenyl isocyanate (2 mmol, 238 mg)
was added to a solution of α,β-unsaturated imine (1 mmol) in
anhydrous THF (15 mL). The reaction was stirred at room
temperature until TLC showed the disappearance of the α,β-
unsaturated imine (16−20 h). Then the reaction was filtered through
a glass vacumm filtration funnel with Celite, and the solvent was
evaporated under reduced pressure. The crude product was purified by
column chromatography using silica gel (hexane/ethyl acetate).
6-(4-Methylstyryl)-1,3-diphenyl-6-(trifluoromethyl)-1,3,5-triazi-
nane-2,4-dione (4a). Compound 4a was obtained as a white solid
(383 mg, 85%) from imine 1a as described in the general procedure:
CONCLUSION
■
In conclusion, this paper describes a simple, mild, and
convenient strategy for the preparation of fluoroalkyl-
substituted triazene-2,4-diones 4 obtained by regioselective
1,4-addition of two molecules of phenyl isocyanate 2a to
fluoroalkylated α,β-unsaturated imines 1. However, dihydro-
pyrimidin-2(1H)-ones 7 may be prepared by the reaction of
α,β-unsaturated imines 1 with tosyl isocyanate 2b. Catalyst-
mediated hydrogenation of dihydropyrimidin-2(1H)-ones 7
1
mp 225−227 °C; H NMR (CDCl3) δ 7.63 (br, 1H), 7.24−7.45 (m,
3
3
10H), 7.16 (d, JHH = 16.1 Hz, 1H), 7.07 (d, JHH 7.9 Hz, 2H), 6.93,
3
3
(d, JHH = 7.9 Hz, 2H), 5.66 (d, JHH = 16.2 Hz, 1H), 2.34 (s, 3H)
ppm; 13C NMR (CDCl3) δ 152.7, 151.4, 139.9, 136.6, 136.2, 134.6,
1
131.8, 131.7, 129.7, 129.3, 129.2, 128.8, 127.4, 122.0 (q, JFC = 292.1
Hz), 117.9, 72.7 (q, JFC = 30.8 Hz), 21.6 ppm; 19F NMR (CDCl3) δ
2
F
dx.doi.org/10.1021/jo500745u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−80.5 ppm; IR νmax 3210, 3089, 1732, 1660 cm−1; HRMS (ESI) m/z
calcd for C25H20F3N3O2 [M+] 451.1508, found [M+] 451.1519.
6-(Difluoromethyl)-6-(4-nitrostyryl)-1,3-diphenyl-1,3,5-triazi-
nane-2,4-dione (4b). Compound 4b was obtained as a yellow solid
(348 mg, 75%) from imine 1b as described in the general procedure:
νmax 3361, 3116, 2991, 1361, 1175 cm−1; HRMS (ESI) m/z calcd for
C19H17F3N2O3S [M+] 410.0912, found [M+] 410.0925.
4-(Furan-2-yl)-3-tosyl-6-(trifluoromethyl)-3,4-dihydropyrimidin-
2(1H)-one (7d). Compound 7d was obtained as a white solid (290 mg,
75%) from imine 1d as described in the general procedure: mp 205−
1
3
1
3
207 °C; H NMR (CDCl3) δ 7.49 (d, JHH = 8.3 Hz, 2H), 7.43 (br,
1H), 7.23 (d, 3JHH = 1.6 Hz, 1H), 7.10 (d, 3JHH = 8.4 Hz, 2H), 6.37 (d,
3JHH = 3.1 Hz, 1H), 6.31 (dd, 3JHH = 1.7 Hz, 3JHH = 3.2 Hz, 1H), 6.15
(d, 3JHH = 6.1 Hz, 1H), 5.66 (d, 3JHH = 6.2 Hz, 1H, CH), 2.32 (s, 3H)
ppm; 13C NMR (CD3OD) δ 150.8, 149.0, 145.2, 144.7, 136.4, 129.8,
mp 232−234 °C; H NMR (CDCl3) δ 8.05 (d, JHH = 8.6 Hz, 2H),
7.00−7.45 (m, 13H), 7.21 (d, 3JHH = 16.2 Hz, 1H), 5.99 (t, 3JFH = 54.8
3
Hz, 1H,), 5.83 (d, JHH = 17.3 Hz, 1H) ppm; 13C NMR (CDCl3) δ
152.9, 151.5, 148.2, 140.9, 136.0, 134.6, 133.8, 131.3, 129.7, 129.6,
1
129.3, 129.2, 128.8, 128.0, 124.4, 113.9 (t, JFC = 254.3 Hz), 72.1 (t,
2
1
2
2JFC = 22.7 Hz) ppm; 19F NMR (CDCl3) δ −130.6 (dd, JFH = 54.9
129.0, 127.2 (q, JFC = 35.2 Hz), 116.2 (q, JFC = 273.0 Hz), 111.5,
109.8, 104.9 (q, 3JFC = 4.5 Hz), 51.7, 21.7 ppm; 19F NMR (CDCl3) δ
−70.7 ppm; IR νmax 3350, 3116, 2989, 1359, 1169 cm−1; HRMS (ESI)
m/z calcd for C16H13F3N2O4S [M+] 386.0548, found [M+] 386.0557.
6-(Difluoromethyl)-4-(furan-2-yl)-3-tosyl-3,4-dihydropyrimidin-
2(1H)-one (7e). Compound 7e was obtained as a yellow solid (291
mg, 71%) from imine 1e as described in the general procedure: mp
2
2
2
Hz, JFF = 278.5 Hz), −132.4 (dd, JFH = 54.9 Hz, JFF = 278.4 Hz)
ppm; IRνmax 3212, 3112, 1715, 1667 cm−1; HRMS (ESI) m/z calcd for
C24H18F2N4O4 [M+] 464.1296, found [M+] 464.1308.
6-(4-Nitrostyryl)-1,3-diphenyl-6-(trifluoromethyl)-1,3,5-triazi-
nane-2,4-dione (4c). Compound 4c was obtained as a yellow solid
(400 mg, 83%) from imine 1c as described in the general procedure:
1
3
1
3
191−193 °C; H NMR (CDCl3) δ 7.52 (d, JHH = 7.8 Hz, 1H), 7.24
mp 221−223 °C; H NMR (CDCl3) δ 8.50 (br, 1H), 7.99 (d, JHH
=
3
3
8.7 Hz, 2H), 7.40−7.15 (m, 10H), 7.22 (d, 3JHH = 16.5 Hz, 1H), 6.87
(d, 3JHH = 8.5 Hz, 2H), 5.72 (d, 3JHH = 16.2 Hz, 1H) ppm; 13C NMR
(CDCl3) δ 140.7, 135.9, 134.5, 134.4, 131.6, 129.7, 129.6, 129.3, 129.2,
128.6, 128.1, 124.3 (q, JFC = 292.9 Hz), 122.3, 72.4 (q, JFC = 31.0
Hz) ppm; 19F NMR (CDCl3) δ −80.4 ppm; IR νmax 3225, 3112, 1712,
1682 cm−1; HRMS (ESI) m/z Calcd for C24H17F3N4O4 [M+]
482.1201, found [M+] 482.1213.
(d, JHH = 7.7 Hz, 2H,), 7.20 (br, 1H,), 7.11 (d, JHH = 7.2 Hz, 2H),
3
3
6.35 (m, 1H), 6.29 (d, JHH = 1.7 Hz, 1H), 6.14 (d, JHH = 7.3 Hz,
1H), 6.03 (t, 3JFH = 52.7 Hz, 1H), 5.42 (d, 3JHH = 7.3 Hz, 1H), 2.31 (s,
3H) ppm; 13C NMR (CDCl3) δ 150.0, 149.8, 144.7, 143.4, 135.6,
1
2
129.4, 129.1, 111.3 (t, JFC = 250.0 Hz), 110.6, 109.0, 102.1 (3JFC
=
=
1
10.2 Hz), 52.0, 21.5 ppm; 19F NMR (CDCl3) δ −120.1 (dd, JFH
2
2
2
2
54.9 Hz, JHH = 305.2 Hz), −122.3 (dd, JFH = 54.9 Hz, JHH = 305.2
Hz) ppm; IR νmax 3349, 3109, 2981, 1352, 1165 cm−1; HRMS (ESI)
m/z calcd for C16H14F2N2O4S [M+] 368.0642, found [M+] 368.0639.
4-(4-Fluorophenyl)-3-tosyl-6-(trifluoromethyl)-3,4-dihydropyrimi-
din-2(1H)-one (7f). Compound 7f was obtained as a white solid (281
mg, 68%) from imine 1f as described in the general procedure: mp
6-(2-(Furan-2-yl)vinyl)-1,3-diphenyl-6-(trifluoromethyl)-1,3,5-tria-
zinane-2,4-dione (4d). Compound 4d was obtained as a beige solid
(392 mg, 92%) from imine 1d as described in the general procedure:
1
mp 236−237 °C; H NMR (CDCl3) δ 7.35−7.14 (m, 12H), 6.86 (d,
3JHH = 15.9 Hz, 1H), 6.30 (m, 1H), 6.17 (m, 1H), 5.67 (3JHH = 15.9
Hz, 1H) ppm; 13C NMR (CDCl3) δ 152.2, 151.1, 150.0, 143.9, 135.8,
1
3
196−198 °C; H NMR (CDCl3) δ 8.29 (br, 1H), 7.29 (d, JHH = 8.2
Hz, 2H), 7.23 (dd, 3JHH = 8.5 Hz, 3JFH = 5.3 Hz, 2H), 7.01 (d, 3JHH
=
1
134.3, 131.3, 129.2, 128.9, 128.5, 124.5 (q, JFC = 293.0 Hz), 124.1,
8.5 Hz, 2H), 6.95 (d, 3JHH = 8.5 Hz, 2H), 6.03 (d, 3JHH = 5.8 Hz, 1H),
5.67 (d, 3JHH = 5.9 Hz, 1H), 2.28 (s, 3H) ppm; 13C NMR (CDCl3) δ
2
116.5, 112.6, 111.7, 72.5 (q, JFC = 30.9) ppm; 19F NMR (CDCl3) δ
−80.2 ppm; IR νmax 3189, 3094, 1736, 1650 cm−1; HRMS (ESI) m/z
calcd for C22H16F3N3O3 [M+] 427.1143, found [M+] 427.1148.
6-(Difluoromethyl)-6-(2-(furan-2-yl)vinyl)-1,3-diphenyl-1,3,5-tria-
zinane-2,4-dione (4e). Compound 4e was obtained as a beige solid
(368 mg, 90%) from imine 1e as as described in the general
1
161.3 (d, JCF= 252.3 Hz), 150.1, 144.9, 135.2, 134.8, 129.2, 128.7,
2
1
125.5 (q, JFC = 36.7 Hz), 119.2 (q, JFC = 272.6 Hz), 116.3, 116.0,
106.1 (q, 3JFC = 4.3 Hz), 58.2, 21.5 ppm; 19F NMR (CDCl3) δ −70.6,
−111.9 ppm; IR νmax 3354, 3113, 2986, 1359, 1172 cm−1; HRMS
(ESI) m/z calcd for C18H14F4N2O3S [M+] 414.0661, found [M+]
414.0670.
1
procedure: mp 226−228 °C; H NMR (CDCl3) δ 7.35−7.10 (m,
11H), 6.91 (br, 1H), 6.72 (d, 3JHH3 = 15.9 Hz, 1H), 6.27 (m, 1H), 6.17
4-(Furan-2-yl)-6-(perfluoroethyl)-3-tosyl-3,4-dihydropyrimidin-
2(1H)-one (7g). Compound 7g was obtained as a brown solid (314
mg, 72%) from imine 1g as described in the general procedure: mp
3
3
(d, JHH = 3.0 Hz, 1H), 5.82 (t, JFH = 55.0 Hz, 1H), 5.68 (d, JFH
=
15.9 Hz, 1H) ppm; 13C NMR (CDCl3) δ 152.4, 151.5, 150.3, 143.7,
135.9, 134.5, 131.0, 129.2, 129.0, 128.9, 128.8, 128.3, 123.3, 118.7,
113.7 (t, 1JFC = 253.4 Hz), 112.1, 111.6, 72.1 (t, 2JFC = 21.8 Hz) ppm;
1
3
173−175 °C; H NMR (CDCl3) δ 8.19 (br, 1H), 7.45 (d, JHH = 7.9
3
3
Hz, 2H), 7.24 (m, 1H), 7.10 (d, JHH = 8.3 Hz, 2H), 6.35 (d, JHH
=
=
19F NMR (CDCl3) δ −130.7 (dd, JFH = 54.9 Hz, JFF = 272.2 Hz),
2
2
3.2 Hz, 1H), 6.29 (m, 1H), 6.18 (d, 3JHH = 6.2 Hz, 1H), 5.61 (3JHH
−133.0 (dd, 2JFH = 54.8 Hz, 2JFF = 272.3 Hz) ppm; IR νmax 3230, 3100,
1717, 1675, 1663 cm−1; HRMS (ESI) m/z calcd for C22H17F2N3O3
[M+] 409.1238, found [M+] 409.1247.
6.3 Hz, 1H), 2.30 (s, 3H) ppm; 13C NMR (CDCl3) δ 149.8, 149.5,
144.7, 143.6, 135.3, 129.0, 128.9, 112.0−130.1 (m), 110.5, 109.3, 105.3
(t, JFC = 6.5 Hz,), 51.7, 21.5 ppm; 19F NMR (CDCl3) δ −84.5,
3
−120.8 (q, 2JFF = 67.8 Hz) ppm; IR νmax 3346, 3102, 2993, 1352, 1160
cm−1; HRMS (ESI) m/z calcd for C17H13F5N2O4S [M+] 436.0516,
found [M+] 436.0519.
General Procedure for the Synthesis of 3,4-Dihydropyr-
imidin-2-(1H)-ones 7. Tosyl isocyanate (1 mmol, 117 mg) was
added to a solution of fluoroalkylated β-unsubstituted imine (1 mmol)
in anhydrous THF (15 mL). The reaction mixture was stirred at room
temperature until TLC showed the disappearance of the fluorinated
α,β-unsaturated imine (20−22 h). Then, a saturated solution of
NH4Cl (10 mL) was added, the reaction mixture was extracted with
DCM (3 × 25 mL), dried over anhydrous MgSO4, and filtered, and
the solvent was evaporated under reduced pressure. The crude product
was purified by column chromatography using silica gel (hexane/ethyl
acetate).
Procedure for the Synthesis of the Fluoroalkylated
Tetrahydropyrimidin-2-(1H)-one 10. To a solution of fluoroalky-
lated 3,4-dihydropyrimidin-2-(1H)-one 7f (1 mmol, 414 mg) and Pd/
C (0.1 mmol, 106 mg) in anhydrous methanol (10 mL) was applied
80 psi of hydrogen, and the reaction was stirred until TLC showed the
disappearance of the starting material (24 h). Then, a saturated
solution of NH4Cl (10 mL) was added, the reaction mixture was
extracted with DCM (3 × 25 mL), dried with anhydrous MgSO4, and
filtered, and the solvent was evaporated under reduced pressure. The
crude product was purified by column chromatography using silica gel
(hexane/ethyl acetate) to afford 10 as a white solid (357 mg, 86%):
4-(p-Tolyl)-3-tosyl-6-(trifluoromethyl)-3,4-dihydropyrimidin-
2(1H)-one (7a). Compound 7a was obtained as a white solid (320 mg,
78%) from imine 1a as described in the general procedure: mp 188−
1
3
1
3
190 °C; H NMR (CDCl3) δ 8.53 (br, 1H), 7.81 (d, JHH = 8.3 Hz,
mp 189−191 °C; H NMR (CDCl3) δ 7.55 (d, JHH = 8.4 Hz, 4H),
7.32 (d, 3JHH = 8.2 Hz, 4H), 7.15 (d, 3JHH = 8.5 Hz, 4H), 6.92 (d, 3JHH
= 8.5 Hz, 4H), 5.70 (m, 2H), 4.78 (br, 2H), 4.08 (m, 2H), 2.44 (s,
3H), 2.40 (s, 3H), 2.55−2.70 (m, 2H) ppm; 13C NMR(DMSO) δ
151.5, 144.9, 142.5, 142.0, 137.3, 130.1, 129.8, 129.6, 129.0, 128.1,
125.2, 115.2, 115.1, 56.7, 50.6 (q, 2JFC = 32.2 Hz), 50.5 (q, 2JFC = 32.2
Hz), 29.6, 21.7, 21.6 ppm; 19F NMR (CDCl3) δ −77.1, −77.2, −114.2
3
3
2H), 7.35 (d, JHH = 8.4 Hz, 2H), 7.19 (d, JHH = 8.0 Hz, 2H,), 7.06
3
4
3
(d, JHH = 8.1 Hz, 2H), 6.09 (dq, JFH = 1.6 Hz, JHH = 6.0 Hz, 1H),
5.76 (d, 3JHH = 6.0 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H) ppm; 13C NMR
(CDCl3) δ 150.3, 139.5, 139.4, 136.2, 135.7, 129.5, 128.9, 127.4, 126.6,
125.9 (q, 2JFC = 36.0 Hz), 119.6 (q, 1JFC = 272.5 Hz), 106.8 (q, 3JFC
=
4.3 Hz,), 59.1, 21.7, 21.4 ppm; 19F NMR (CDCl3) δ −70.6 ppm; IR
G
dx.doi.org/10.1021/jo500745u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ppm; IR (NaCl) νmax 3350, 3098, 2990, 1364 cm−1; HRMS (ESI) m/z
7903−7906. (c) Van Meenen, E.; Moonen, K.; Acke, D.; Stevens, C.
V. ARKIVOC 2006, 1, 31−45. (d) Moonen, K.; Van Meenen, E.;
calcd for C18H16F4N2O3S [M+] 416.0818, found [M+] 416.0815.
́
Verwee, A.; Stevens, C. V. Angew. Chem., Int. Ed. 2005, 44, 7407−
ASSOCIATED CONTENT
* Supporting Information
7411.
■
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S
Copies of 1H NMR and 13C NMR spectra of compounds 4a−e,
7a,d−g, and 10. Computational Studies: details about
structures of stationary points associated with the reactions of
2a and 2b with azadienes 1a,c−f, Cartesian coordinates,
harmonic analysis data, and energies for all the stationary
points discussed. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: francisco.palacios@ehu.es.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Direccio
́
n General de Investigacio
́
n del
́
Ministerio de Ciencia y Tecnologia (MICINN, Madrid DGI,
CTQ2012-34.323) as well as the Gobierno Vasco and The
University of the Basque Country (GV/EJ, IT 422-10; UPV/
EHU, UFI-QOSYC 11/12) UPV) for supporting this work.
UPV/EHU-SGIKER technical support (MICINN, GV/EJ,
European Social Fund) is also gratefully acknowledged.
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