Synthesis of 1,3-diaryl-3-trifluoromethylcyclopropenes by transition-metal-free reaction of 2,2,2-trifluoroacetophenone tosylhydrazones with alkynes: The effect of the trifluoromethyl group

Article abstract of DOI:10.1039/c5cc10472f

1,3-Diaryl-3-trifluoromethylcyclopropenes and 2-aryl- or 2-alkyl-1,3-diaryl-3-trifluoromethylcyclopropenes are prepared in a very simple way by reaction between 1,1,1-trifluoroacetophenone tosylhydrazones and terminal or internal alkynes, respectively, in

Full text of DOI:10.1039/c5cc10472f

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DOI: 10.1039/C5CC10472F
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Synthesis of 1,3-Diaryl-3-trifluoromethylcyclopropenes by
Transition-Metal-Free Reaction of 2,2,2-Trifluoroacetophenone
Tosylhydrazones with Alkynes: The Effect of the Trifluoromethyl
Group
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Raquel Barroso,a Azucena Jiménez,a M. Carmen Pérez-Aguilar,a María-Paz Cabal,a,* Carlos
Valdésa,*
www.rsc.org/
1,3-Diaryl-3-trifluoromethylcyclopropenes and 2-aryl- or 2-alkyl- acetophenones, the 3,4,5-trisubstituted pyrazoles
3 are
1,3-diaryl-3-trifluoromethylcyclopropenes are prepared in a very obtained as pure regioisomers (scheme 1, a). The mechanism
simple way by reaction between 1,1,1-trifluoroacetophenone proposed for this transformation involves the 1,3-dipolar
tosylhydrazones and terminal or internal alkynes respectively in a cycloaddition of the diazo compound generated from the
base promoted process that does not require the presence of any tosylhydrazone with the terminal alkyne followed by a [1,5]-
metal catalyst. The essential role of the trifluoromethyl group, sigmatropic rearrangement (scheme 1, a). With the aim to
which enables the formation of the cyclopropenes instead of the expand this methodology to the synthesis of the biologically
expected pyrazoles has been computationaly investigated, relevant trifluoromethyl-substituted pyrazoles, the same
suggesting the participacion of a free carbene.
reaction was studied starting from tosylhydrazones 4 derived
from 2,2,2-trifluoroacetophenones.7,8 Surprisingly, the
expected pyrazoles were never detected, but instead, under the
proper reaction conditions, the trisubstituted or
The synthesis of organic molecules containing trifluoromethyl
substituents is a field of permanent interest in organic
synthesis, due to the strong influence of the fluorinated rests on
the physical, chemical and biological properties of the
compounds.1 In fact, trifluoromethylated molecules are of high
interest in medicinal, agrochemical and materials chemistry. On
the other hand, cyclopropenes, very strained carbocyclic
compounds, are versatile intermediates in organic synthesis as
a result of their high reactivity.2,3 Therefore, trifluoromethyl
substituted cyclopropenes might result in very interesting
intermediates for the preparation of more complex
trifluoromethyl-containing organic molecules. Various
methodologies have been described for the synthesis of 3-
trifluoromethylcyclopropenes with different substitution
patterns, consisting in all cases in metal catalyzed
cyclopropenation reactions between the corresponding
trifluoromethyl diazo compounds and alkynes. 4,5
tetrasubstituted 3-aryl-3-trifluoromethylcyclopropenes
5 or 7
were obtained as main product of the reaction (scheme 1, b).
We have recently reported the synthesis of 3,4,5- and 1,3,5-
trisubstituted pyrazoles by reactions of tosylhydrazones of
ketones with terminal alkynes, in the presence of a base.6 In
Scheme 1: (a) Synthesis of trisubstituted pyrazoles by reaction of tosylhydrazones
with terminal alkynes. (b) Differential behavior observed for the
trifluoromethylated tosylhydrazones presented in this work.
particular,
with
tosylhydrazones
1
derived
from
1
4
a.Departamento de Química Orgánica e Inorgánica and Instituto Universitario de
Química Organometálica “Enrique Moles”. Universidad de Oviedo. c/ Julián
Clavería 8. Oviedo, 33006. Spain. Email: pcabal@uniovi.es; acvg@uniovi.es
Electronic Supplementary Information (ESI) available: [Experimental procedures,
Considering the atractiveness of cyclopropenes as synthetic
intermediates, the great interest of trifluoromethylated organic
molecules, as well as the potential simplicity of this reaction, we
carried out a study to establish the scope and synthetic
usefulness of this particular transformation. Furthermore, the
characterization data and copies of the 1H and 13C NMR spectra for compounds
5
and
7. Computational details, energy tables and cartesian coordinates for the
stationary points represented in figure 1]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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trifluoromethylated involve the presence of a transition metal,4 and in some cases,
differential
behavior
of
the
View Article Online
4b
DOI: 10.1039/C5CC10472F
tosylhydrazones when compared with our previous results with the employment of a large excess of the alkyne. Moreover,
the
acetophenone
derivatives,
provided
additional those reactions are conducted from the isolated 1-(diazo-2,2,2-
trifluoroethyl)arenes, which are usually prepared from the
encouragement at the outset of this work.
Our initial experiments were conducted employing the corresponding tosylhydrazones, but in really low yields.8
tosylhydrazone of 2,2,2-trifluoroacetophenone 4a and Therefore, this simple methodology provides an advantageous
phenylacetylene, under the reaction conditions previously procedure
for
the
synthesis
of
1,3-diaryl-3-
developed for the synthesis of 3,4,5-trisubstituted pyrazoles trifluoromethylcyclopropenes
mentioned above (K2CO3 as base, 1,4-dioxane as solvent, at
5.
Table 1: Synthesis of 1,3-diaryl-3-trifluoromethylcyclopropenes
tosylhydrazones 4 with terminal alkynes.
5
by reaction of
various temperatures). Formation of the pyrazole was never
detected, and instead, a complex reaction mixture, suggesting
the incorporation of molecules of solvent, probably through a
C-H insertion process, was obtained.9 To avoid the competitive
reaction of the solvent, the same transformation was then
attempted without solvent and under a large excess of the
alkyne (10 equiv). Formation of the pyrazole was not detected
either, but instead the cyclopropene 5a was isolated in a
promising 38 % yield. This preliminary result was noteworthy
Compound
Ar1
Ph
Ph
Ph
Ph
Ph
Ph
Ar2
Ph
4-Tol
Yielda %
52
5a
5b
5c
5d
5e
5f
because it represented
a differential behavior of the
30
31
51
40
30
96
56
63
trifluoroacetophenone hydrazone 4a when compared with the
analogous non fluorinated tosylhydrazones. Additionally,
although limited examples of the synthesis of 3-aryl-3-
trifluoromethylcyclopropenes have been previously reported,
those methods require the employ of transition metal
catalysts.4,10 For these reasons, we decided to invest some
effort in order to find most convenient ways to achieve this
transformation.
4-F-C6H4
4-F3C-C6H4
4-Cl-C6H4
3-Thiophenyl
Ph
4-F3C-C6H4
4-F-C6H4
4-Cl-C6H4
Ph
5g
5h
5i
5j
5k
5l
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-MeO-C6H4
4-Tol
47
61
47
Ph
5m
4-MeO-C6H4
4-Cl-C6H4
47
a
Isolated yields after column chromatography.
We next turned out our attention to the reactions with
disubstituted alkynes , which would lead to the obtention of
totally substituted 3-trifluromethylcyclopropenes . Indeed,
6
7
under similar reaction conditions than those reported for the
terminal alkynes, the cyclopropenes were again the main
reaction product. Noteworthy, the yields were generally higher
than those reported for the terminal alkynes (Scheme 3). The
reaction was compatible with diarylacetylenes and also with
aryl alkyl disubstituted alkynes giving rise to 1,2,3-triaryl and
1,3-diaryl-2-alkylcyclopropenes respectively. Finally, the
reaction could be achieved with conjugated en-ynes, to provide
Scheme 2: Reaction of trifluoromethylated tosylhydrazone 4a with
phenylacetylene 2a: Preliminary studies.
Indeed, after extensive experimentation, it was found that
better results could be obtained by running the reaction
employing hexafluorobenzene as solvent, at 85 ⁰C and with a 1:
2 ratio of both reagents. In this way the cyclopropene 5a was
isolated in a 52 % yield. Thus, the employment of an unreactive
solvent under the reaction conditions turned out to be very
important for the success of the cyclopropenation reaction. 9
These reaction conditions were then applied to a set of
the 1-vinylcyclopropenes 7q-x 11
, which are appealing structures
with particularly interesting ring opening chemistry.12
Noteworthy, in these reactions, the process takes place
exclusively through the triple bond of the en-yne, leaving the
double bond untouched.
tosylhydrazones
4 and terminal alkynes 2. The results are
The different chemical behavior observed for the
summarized in table 1. As can be deduced from these data, the
reaction is useful for the synthesis of an array of 1,3-diaryl-3-
trifluoromethylcyclopropenes 5. Unfortunately, the reaction is
limited to aryl-substituted acetylenes, as alkyl-substituted
alkynes failed to provide the expected cyclopropene.
tosylhydrazones derived from acetophenones
1
and
trifluoroacetophenones in the reactions with terminal alkynes
4
(scheme 1) is really intriguing. Assuming that the first step in
every reaction will be the base promoted thermal
decomposition of the tosylhydrazone to give the diazo
In most cases the cyclopropenes
5 were obtained in moderate
compound
I (scheme 4), there are various possible reaction
yields. However, it is worth noting that the scarce previous
examples described of the synthesis of these cyclopropenes
pathways that might lead to the formation of either the
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pyrazole VI or the cyclopropane III (scheme 4). Thus, the cycloaddition that leads to the formation of the 3H-pyrazole IV
View Article Online
diazocompound I
could undergo a 1,3-dipolar cycloaddition, to is preferred by 3.1 kca·mol-1. InterestinDglOyI,: 1t0h.1e0s3e9/rCe5sCuClt1s04a7r2eF
provide the 3H-pyrazole IV, that may evolve, after the [1,5]- consistent with the experimental observations. According to
sigmatropic rearrangement to the 1H-pyrazole VI. This is indeed our calculations, the effect of the trifluoromethyl substitution
the case of the previously studied system Ib (X = H).6a affects both in 1,3-dipolar cycloaddition and in the carbene
Alternatively, from IV, the formation of the cyclopropene might formation by nitrogen release. There is a remarkable difference
then occur upon nitrogen extrusion, probably through a ring on the activation free energies for the dipolar cycloaddition
opening / ring closing pathway. A second possible reaction
pathway might consist on the decomposition of the diazo
(
a
Gact = 3.3 kcal·mol-1) between both systems, which features
higher barrier for the trifluoromethylated system.
compound
alkyne to provide directly the cyclopropene III. Obviously, for features a lower free energy of activation for the carbene
this reaction pathway to operate, the decomposition of the generation than Ib
Gact = 2.1 kcal·mol-1). Thus, considering
diazo compound by loss of nitrogen, must be favored towards that the generation of the carbene IIa is the favoured pathway
I, to give the carbene II, which would react with the Additionally, the trifluoro substituted diazo compound Ia
(
I
the 1,3-dipolar cycloaddition with the alkyne.
when X = F, the formation of the trifluoromethylcyclopropene
III must take place by reaction of the free carbene with the
alkyne. This process takes place through a concerted and very
early transition state with a relative low energy barrier Gact
= 7.4 kcal·mol-1). Thus, the diazo compound decomposition is
the rate limiting step for this process.
Scheme 3: Synthesis of 2-substituted-1,3-diaryl-3-trifluoromethylcyclopropenes
7
by reaction of tosylhydrazones 4 with internal alkynes.
In order to understand the different outcomes of the reactions,
and therefore the dramatic influence of the trifluoromethyl
group, we carried out some DFT computational studies starting
from Ia (X = F) and Ib (X = H).‡
Figure 1. Calculated reaction pathways for the formation of cyclopropenes III and
3H-pyrazoles IV by reaction of phenylacetylene with (1-diazo-2,2,2-
trifluoroethyl)benzene Ia (X = F) and 1-diazoethylbenzene Ib (X = H).
The main reactivity difference between the CH3 and the CF3
containing diazo compounds relays on the higher activation
energy of the 1,3-dipolar cycloaddition with the CF3-derived
diazo compound Ia. The geometries of the transition states are
quite similar for models
should be expected due to the presence of the slightly bulkier
fluorine atoms (figure 2, a). Nevertheless, possible
a and b, and no relevant steric influence
a
explanation for the different behavior observed could be found
by analysis of the energies of the frontier orbitals involved in the
1,3-dipolar cycloaddition. The presence of the CF3 substituent
lowers substantially the energy of the HOMO of the diazo
Scheme 4: Possible reaction pathways for the formation of 1H-pyrazoles VI and
cyclopropenes III
.
First of all, the two possibilites for the first step were computed
for both models Ia and Ib. For the trifluoromethyl series Ia we
found that the decomposition of the diazo compound to give
carbene IIa is favoured towards the 1,3-dipolar cycloaddition
with phenylacetylene by 2.3 kcal·mol-1. An activation free
energy value of 28.7 kcal·mol-1 was obtained for the diazo
compound decomposition. In contrast, for IIb, the 1,3-dipolar
compound. Considering in both cases
HOMO(dipole)-LUMO(dipolarophile) interaction,
a
dominant
the
stabilization of the HOMO of the diazo compound in Ia justifies
its lower reactivity in the 1,3-dipolar cycloaddition. Finally, the
ability of the free carbene II to participate in the
cyclopropenation reaction is enabled by its kinetic stability,
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1
(A) Organofluorine Compounds: Chemistry and Applications
derived from the lack of hydrogen atoms at the - position, and
also by the election of an unreactive solvent as
hexafluorobenzene.
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(Ed.: Hiyama, T.), Springer, New York, 2000. (b) P. Kirsch,
DOI: 10.1039/C5CC10472F
Modern Fluoroorganic Chemistry: Synthesis Reactivity,
Applications, Wiley-VCH, Weinheim, 2004. (c) I. Ojima,
Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-
Blackwell, Chichester, 2009. (d) M. Shimizu and T. Hiyama,
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Soloshonok, A. E. Sorochinsky and J. Wang,
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Chem. Rev., 2014, 114, 2432-2506.
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For some reviews on the synthetic interest of cyclopropenes:
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F. Miege, C. Meyer and J. Cossy, J. Acc. Chem. Res. 2015, 48
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Katsuki, J. Am. Chem. Soc. 2011, 133, 170-171.
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Müller, S. Grass,S. P. Shahi, and G. Bernardinelli, Tetrahedron
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Valdés, Angew. Chem., Int. Ed. 2015, 54, 13729-13733.
For the synthesis of trifluoromethylpyrazoles through 1,3-
dipolar cycloadditions from CF3-substituted
diazocompounds: (a) E. Y. Slobodyanyuk, O. S. Artamonov,
O. V. Shishkin and P. K. Mykhailiuk, Eur. J. Org. Chem. 2014,
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H.-U. Reissig, Helv. Chim. Acta, 2014, 97, 808-821.
4
5
Figure 2: Figure 2. (a) Transition structures TS(IV) obtained for the 1,3-dipolar
cycloadditions of phenylacetylene with the 1-(diazo-2,2,2-trifluoroethyl)benzene
Ia and 1-diazoethylbenzene Ib respectively obtained at the M06-2X/6-311++G**
level. (b) Representation of the energies of the Frontier Orbitals responsible for
the main interactions in the 1,3-dipolar cycloaddition. Frontier Orbital Energies
(eV) have been obtained from a single point HF/6-311G** calculation on the
geometries optimized at the M06-2X/6-311++G** level.
In summary, we have described a straightforward synthesis of
1,3-diaryl-3-trifluoromethylcyclopropenes by reaction of
tosylhydrazones with alkynes, without the need of any catalyst.
The presence of the trifluoromethyl group is essential for the
6
7
differential
behavior
of
the
1-diazo-2,2,2-
trifluoroethyl)benzene derivatives, which is due to
a
combination of their lower reactivity in 1,3-dipolar
cycloadditions with alkynes and their higher tendency to
generate a carbene upon nitrogen loss. These results might
stimulate the development of other transition metal-free
transformations based on these free carbenes.
8
9
For some other examples of reactions of 1-(diazo-2,2,2-
trifluoroethyl)arenes generated from tosylhydrazones: E.
Emer, J. Twilton, M. Tredwell, S. Calderwood, T. L. Collier, B.
Liégault, M. Taillefer and V. Gouverneur, Org. Lett. 2014, 16
6004-6007.
,
While preparing this manuscript, and in agreement with our
own observations, a paper dealing with the Büchner reaction
of 2,2,2-trifluoroacetophenone tosylhydrazone with
aromatic hydrocarbons was published: Z. Zhang, J. Feng, Y.
Xu, S. Zhang, Y. Ye, T. Li, X. Wang, J. Chen, Y. Zhang, and J.
Wang, Synlett, 2015, 59-62.
Financial support of this work by Ministerio de Economía y
Competitividad (MINECO) of Spain (Grant CTQ2013-41336-P) is
gratefully acknowledged. R.B. thanks FICYT (Principado de
Asturias, Spain) for
a predoctoral fellowship. A Clarín
postdoctoral fellowship (Principado de Asturias, Spain) to A. J. is
gratefully acknowledged. M. C. P.-A. thanks MINECO for a FPI
predoctoral fellowship. We wish to thank Dr. Isabel Merino for
assistance with NMR experiments.
10 It has been recently reported that the reaction of ethyl 2-
diazo-3,3,3-trifluoropropanoate with diphenylacetylene at
180 ⁰C leads to the corresponding cyclopropene with low
yield (ref 7b) instead of the expected pyrazole.
11 E. A. F Fordyce. T. Luebbers, and H. W. Lam, Org. Lett. 2008,
10, 3993-3996.
12 (a) Z.-B. Zhu and M. Shi, J. Org. Chem. 2009, 74, 2481-2485.
(b) Z.-B. Zhu, K. Chen, Y. Wei and M. Shi, Organometallics
2011, 30, 627-632.
Notes and references
‡ The calculations were conducted employing the Density
Functional Theory, with the M06-2X hybrid functional13 and the 6-
311++G** basis set employing the Gaussian 09 package. Solvation
effects considering benzene as the solvent were applied on the
gas phase optimized structures through the IEF-PCM at the same
level of theory. See ESI for details.
13 The M06-2X hybrid functional has been reported to give very
reliable kinetic values for a large number of organic
reactions: (a) Y. Zhao and D. G. Truhlar, Theor Chem Account
2008, 120, 215-241. (b) X. Xu,I. M. Alecu and D. G. Truhlar, J.
Chem. Theory Comput. 2011, 7, 1667–1676.
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