Synthesis of Trifluoromethyl-allenes by Gold-Catalyzed Rearrangement of Propargyl Benzyl Ethers

Article abstract of DOI:10.1021/acs.orglett.6b02636

A new method for the synthesis of trifluoromethyl-allenes from easily accessible α-trifluoromethyl-propargyl benzyl ether derivatives following a gold-catalyzed intramolecular hydride transfer has been developed. Various di- and trisubstituted trifluoromethyl-allenes were obtained in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.6b02636

Letter
pubs.acs.org/OrgLett
Synthesis of Trifluoromethyl-allenes by Gold-Catalyzed
Rearrangement of Propargyl Benzyl Ethers
Arnaud Boreux,†,‡,∥ Geoffroy H. Lonca, Olivier Riant,* and Fabien Gagosz*
†,∥
,‡
,†,§
†
̀
Laboratoire de Synthese Organique, UMR 7652 CNRS/Ecole Polytechnique, Ecole Polytechnique, Route de Saclay, 91128
Palaiseau, France
‡
Institute of Condensed Matter and Nanosciences (IMCN), Division of Molecules, Solids and Reactivity (MOST), Universite
Catholique de Louvain, Place Louis Pasteur 1, bte L4.01.02, 1348 Louvain-la-Neuve, Belgium
́
*
S Supporting Information
ABSTRACT: A new method for the synthesis of trifluoromethyl-allenes from easily accessible α-trifluoromethyl-propargyl
benzyl ether derivatives following a gold-catalyzed intramolecular hydride transfer has been developed. Various di- and
trisubstituted trifluoromethyl-allenes were obtained in good to excellent yields.
CF -containing building blocks are privileged structural motifs
in medicinal chemistry and agrochemistry. As a consequence,
Scheme 1. Synthetic Approaches to Trifluoromethyl-allenes
3
1
substantial efforts have been made over the years by synthetic
organic chemists in order to design and develop methods
allowing efficient access to a variety of trifluoromethylated
2
3
species. Given the unique reactivity of allenes and their ability
to react in a wide range of transformations to build up valuable
4
complex structures, special attention has naturally been
brought to trifluoromethyl-allenes and how to access them.
The first syntheses of CF -allenes, which were reported several
3
5
decades ago, generally suffer from low efficiency and exhibit
limited scope. Current efforts in the domain are focused on
addressing these issues. From a general point of view, currently
available synthetic routes to CF -allenes 1 can be classified into
3
two main categories A and B (Scheme 1, top). CF -allenes can
3
be prepared starting from alkynyl or alkenyl substrates already
possessing a CF moiety (category A) by elimination
3
6
7
8
reactions, isomerizations, sigmatropic rearrangements, S 2′
reactions, and metal-catalyzed processes.
N
9
10,11
A more recently
developed alternative access to CF -allenes relies on the use of
3
a “Cu-CF ” reagent to introduce the CF moiety on an
3
3
1
2
activated alkynyl substrate (category B). Even if these
different methods are complementary with each other and
allow an overall access to a variety of functionalized CF3-
allenes, they are still suffering some limitations mainly in terms
of product formation selectivity and substrate accessibility.
Taking into account that alkyne derivatives are privileged
Our strategy, which is presented in the bottom part of
Scheme 1, relies on previous findings by us and others that gold
catalysts could be used to convert propargyl benzyl ethers into
substrates for the synthesis of CF -allenes 1 (Scheme 1, top)
3
and considering the remarkable ability of gold catalysts to
13
convert alkynes into a range of valuable structural motifs, we
envisaged gold catalysis as a potential useful synthetic tool for
the rapid, efficient, and selective synthesis of a range of
Received: September 1, 2016
14
diversely substituted CF -allenes.
3
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02636
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
5,16
allenes.
We indeed conceived that an activation of alkyne
Scheme 2. Substrate Scope: Gold-Catalyzed Formation of
Trifluoromethyl-allenes
,
substrate 2 by an electrophilic gold species might induce a 1,5-
hydride shift that would lead to the formation of an
oxocarbenium intermediate 3. A subsequent elimination of
benzaldehyde with concomitant regeneration of the gold
catalyst would deliver CF -allene 4. This approach, which
3
could lead to the formation of up to trisubstituted CF -allenes,
3
appeared to be particularly appealing since the required
trifluoromethylated substrates 2 could be rapidly and
conveniently obtained in a three-step sequence starting from
the readily available and relatively cheap ethyl trifluoroacetate.
We started our investigations with model substrate 2a and
looked for catalytic conditions that could allow its conversion
into CF -allene 4a. The main results are compiled into Table 1.
3
Table 1. Optimization of the Catalytic System
a
1
4
a is a volatile compound. The yield was assessed by H NMR
b
spectroscopy using 1,2-dichloroethane as an internal standard. CDCl3
was dried over 4 Å MS prior to usage.
The activity of 5, a gold catalyst which proved its efficiency in
1
5,17
hydride transfer reactions,
was first evaluated. Substrate 2a
18
was treated with 4 mol % of 5 in refluxing CDCl , and the
reaction was monitored by H NMR spectroscopy (Table 1,
3
1
entry 1). The formation of CF -allene 4a could be observed,
3
thus validating our approach, but the conversion of 2a was very
poor (<10%). In sharp contrast, a rapid conversion of 2a (1 h)
was observed when the more electrophilic phosphite and
19
20
phosphonite based gold complexes 6 and 7a were employed
as the catalysts (entries 2 and 3). Under these conditions, CF3-
allene 4a was obtained in 76% and 77% yield, respectively.
While lowering the reaction temperature to 23 °C noticeably
slowed down the conversion of 2a (entry 4), a slight
a
Reaction scale: 0.08−0.2 mmol. CDCl was dried over 4 Å MS prior
3
c
1
8
b
improvement in the yield was observed when CDCl dried
to usage.
Isolated yields unless otherwise noted. Volatile
3
21
compound: yield determined by 1H NMR spectroscopy using 1,2-
dichloroethane as an internal standard. 6 (4 mol %) was used as the
catalyst and the reaction was performed at 23 °C. Isolated in mixture
with indene 8w (2w:8w = 5:1); see Scheme 3.
over 4 Å MS was employed as the solvent (entry 5).
d
Interestingly, gold complex 7b, an analog of 7a with a more
e
−
coordinating NTf2 counteranion, was completely inefficient in
22
catalyzing the desired transformation (entry 6). Given the
generally observed higher thermal stability of phosphonite gold
23
complex 7a when compared to 6, experimental conditions
given in entry 5 (4 mol % of 7a in dry chloroform at 60 °C)
were retained to perform the scope of the reaction.
including silyl- and alkylethers (4b and 4d), esters (4c and 4j),
ketone (4j), imide (4e), and aromatics (4f and 4s−t). We were
pleased to observe that the transformation was applicable to
terminal alkyne substrates disubstituted at the propargylic
position. In this case, the reaction proved to be particularly
efficient as attested by the conversion of 2g−h and 2j into
As seen in Scheme 2, the reaction proved to be widely
applicable. A great variety of fluorinated substrates 2a−w were
converted into the corresponding di- or trisubstituted
fluorinated allenes 4a−w in yields ranging from 43% to 90%.
The reaction was shown to tolerate various functional groups
respectively 1,1-disubstituted CF -allenes 4g−h and 4j (87−
91% yield). Notably, none of the previously described
3
B
DOI: 10.1021/acs.orglett.6b02636
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6
a,c,12h
methods
allows the efficient and selective formation of
The reactivity of disubstituted CF -allenes utilizing other
3
alkyl-substituted CF -allenes such as 4g and 4j. The conversion
transition metal catalysts was also rapidly explored. While
previous studies have shown the ability of 1,1-disubtituted
trifluoromethylated allenes to react under Ru, Pd, or Cu
3
of epi-cholestanol derivative 2j into allene 4j shows the
functional group tolerance of the method and the possibility
to apply it to structurally complex molecules. The formation of
6c,12h
catalysis,
no example of metal-mediated transformations of
the simple CF -propadiene 4i is particularly representative of
the synthetic interest of the transformation. Indeed, the
1−3-disubstituted CF -allenes has been reported so far. A Pd-
3
3
catalyzed diborylation of CF -allene 4k was first attempted
3
26
preparation of 4i usually requires harsh experimental conditions
(Scheme 4, eq 1). We were pleased to observe that a
5c,d,f
or stoichiometric amounts of copper reagents.
Finally, it is
interesting to note that the method could be applied with the
same efficiency to substrates possessing other fluorinated
groups (2m, 2n, and 2v: CF CF ; 2o: CHF ), thus expanding
Scheme 4. Copper- and Palladium-Catalyzed Borylation of
Trifluoromethyl-allenes
2
3
2
the synthetic potential of the process.
We then explored the possibility for further functionalizing
the CF -allenes produced using this new method. By
3
capitalizing on the possibility of gold catalysts to activate
allenes toward their nucleophilic functionalization at position α
13
or γ (see Scheme 3, top), we envisaged to perform a one-pot
Scheme 3. Gold-Catalyzed Cascade Reactions Involving
Trifluoromethyl-allenes Intermediates
a
Reaction conditions: 4k (1 equiv), B pin (1.4 equiv), Pd(dba) (5
2
2
2
b
mol %), P(NMe ) (6 mol %), toluene (23 °C, 5 h). Reaction
2
3
conditions: 4k (1 equiv), B pin (1.4 equiv), IMesCuDBM (5 mol %),
2
2
MeOH (6 equiv), THF (23 °C, 15 h).
regioselective reaction took place giving rise to the formation of
the diborylated CF -alkene 10. This one was isolated in 60%
3
27
yield as a 1:2 mixture of E/Z isomers. The Cu-catalyzed
monoborylation of the same substrate proceeded with similar
efficiency to afford the regioisomeric boroalkene 11 as a 1:6
2
7,28
mixture of E/Z isomers (Scheme 4, eq 2).
Notably,
borylated compounds 10 and 11 represent a useful springboard
for further (metal-catalyzed) functionalization.
In conclusion, an original access to polysubstituted
trifluoromethyl-allenes starting from an inexpensive CF -source
3
was developed. The new synthetic method was found to be
easy to implement, efficient, selective, and applicable to a wide
variety of functionalized substrates. The reaction scope
highlighted the complementarity of the process with synthetic
methods previously reported in the literature for accessing CF3-
allenes. Preliminary studies on the subsequent functionalization
of these allenes by Au-, Pd-, or Cu-catalyzed reactions gave
promising results. Further studies in this domain are underway.
a
18
b
Reaction conditions: 7a (4 mol %), CDCl (0.2 M), 60 °C. Yield
3
1
ASSOCIATED CONTENT
determined by H NMR spectroscopy using 1,2-dichloroethane as an
internal standard.
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02636.
sequence of gold-catalyzed allene formation/intramolecular
nucleophilic addition. To validate this proposal, substrate 2w
possessing a potentially nucleophilic phenyl group at the
propargylic position was subjected to the optimized catalytic
Experimental procedures and characterization of all new
1
13
19
compounds including H, C, and F NMR analysis
(PDF)
24
conditions (Scheme 3). We were pleased to observe the
efficient formation of indene 8w (81% yield) as the result of an
intramolecular gold-catalyzed addition of the phenyl ring at the
γ position of the intermediately produced allene 4w. A similar
result was obtained with substrate 2x. With propargylic alcohol
derivatives 2y and 2z, the nucleophilic addition of the hydroxyl
functionality at the alternative α position of the allene moiety
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: olivier.riant@uclouvain.be.
E-mail: fgagosz@uottawa.ca.
9a,19,25
Present Address
proceeded (Scheme 3).
This led to the rapid and efficient
§
formation of the synthetically valuable CF -dihydrofurans 9y
Department of Chemistry and Biomolecular Sciences,
3
and 9z.
University of Ottawa, K1N 6N5, Ottawa, Canada.
C
DOI: 10.1021/acs.orglett.6b02636
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
Gagare, P. D.; Ramachandran, P. V. Tetrahedron Lett. 2014, 55, 5736.
(g) Ambler, B. R.; Peddi, S.; Altman, R. A. Synthesis 2014, 46, 1938.
∥A.B. and G.H.L. contributed equally.
(h) Ambler, B. R.; Peddi, S.; Altman, R. A. Org. Lett. 2015, 17, 2506.
Notes
(i) Ji, Y.-L.; Luo, J.-J.; Lin, J.-H.; Xiao, J.-C.; Gu, Y.-C. Org. Lett. 2016,
1
(
(
(
4
8, 1000. See also refs 5b and 5d.
13) For selected recent selected reviews on gold catalysis:
a) Obradors, C.; Echavarren, A. M. Acc. Chem. Res. 2014, 47, 902.
b) Wang, Y.-M.; Lackner, A. D.; Toste, F. D. Acc. Chem. Res. 2014,
7, 889. (c) Friend, C. M.; Hashmi, A. S. K. Acc. Chem. Res. 2014, 47,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are deeply appreciative of financial support from the Ecole
■
Polytechnique, Universite
FNRS (FRIA grant for A. Boreux) and thank Rhodia Chimie
Fine (Dr. F. Metz) for a generous gift of HNTf2.
́
Catholique de Louvain (UCL),
729. (d) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028.
(e) Jia, M.; Bandini, M. ACS Catal. 2015, 5, 1638. (f) Asiri, A. M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 4471.
(
14) For selected contributions from our group in the field of gold
catalysis, see: (a) Gronnier, C.; Boissonnat, G.; Gagosz, F. Org. Lett.
013, 15, 4234. (b) Henrion, G.; Chavas, T. E. J.; Le Goff, X.; Gagosz,
REFERENCES
■
2
(
1) (a) Thayer, A. M. Chem. Eng. News 2006, 84, 15. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
F. Angew. Chem., Int. Ed. 2013, 52, 6277. (c) Prechter, A.; Henrion, G.;
Faudot dit Bel, P.; Gagosz, F. Angew. Chem., Int. Ed. 2014, 53, 4959.
3
20. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J. N.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
014, 114, 2432.
2) For selected recent reviews, see: (a) Barata-Vallejo, S.; Lantano,
(
15) Bolte, B.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010,
32, 7294.
16) For selected gold-catalyzed reaction involving hydride transfers,
see: (a) Vasu, D.; Das, A.; Liu, R.-S. Chem. Commun. 2010, 46, 4115.
b) Bhunia, S.; Ghorpade, S.; Huple, D. B.; Liu, R.-S. Angew. Chem.,
Int. Ed. 2012, 51, 2939. (c) Barluenga, J.; Sigueiro, R.; Vicente, R.;
Ballesteros, A.; Tomas, M.; Rodríguez, M. Angew. Chem., Int. Ed. 2012,
1
(
2
(
B.; Postigo, A. Chem. - Eur. J. 2014, 20, 16806. (b) Chu, L.; Qing, F.-L.
Acc. Chem. Res. 2014, 47, 1513. (c) Alonso, C.; Martinez de Marigorta,
E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
(
̈
(
3) (a) Ye, J.; Ma, S. Acc. Chem. Res. 2014, 47, 989. (b) For a series
of reviews on the reactivity of allenes, see: Chem. Soc. Rev. 2014, 43,
879.
4) For a review on the use of allenes in synthesis, see: Yu, S.; Ma, S.
Angew. Chem., Int. Ed. 2012, 51, 3074.
5) (a) Coe, P. L.; Milner, N. E. J. Organomet. Chem. 1974, 70, 147.
b) Hung, M.-H. Tetrahedron Lett. 1990, 31, 3703. (c) Burton, D. J.;
Hartgraves, G. A.; Hsu, J. Tetrahedron Lett. 1990, 31, 3699.
d) Bouillon, J.-P.; Maliverney, C.; Merenyi, R.; Viehe, H. G. J.
5
2
1, 10377. (d) Wu, X.; Chen, S.-S.; Hu, Y.; Gong, L.-Z. Org. Lett.
014, 16, 3820. For the formation of allenes, see: (e) Lo, V. K.-Y.;
2
(
Wong, M.-K.; Che, C.-M. Org. Lett. 2008, 10, 517. See also:
f) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786. (g) Lo, V. K.-
Y.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem. Commun. 2010, 46,
13. (h) Tang, X.; Zhu, C.; Cao, T.; Kuang, J.; Lin, W.; Ni, S.; Zhang,
(
(
2
(
J.; Ma, S. Nat. Commun. 2013, 4, 2450. (i) Jiang, G.-J.; Zheng, Q.-H.;
Dou, M.; Zhuo, L.-G.; Meng, W.; Yu, Z.-X. J. Org. Chem. 2013, 78,
(
́
1
(
2
(
1783.
17) Jurberg, I. D.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc.
010, 132, 3543.
18) Deuterated chloroform was used for convenience in order to
Chem. Soc., Perkin Trans. 1 1991, 2147. (e) Hu, C.-M.; Qing, F.-L.;
Huang, W.-Y. J. Org. Chem. 1991, 56, 2801. (f) Duan, J.-X.; Chen, Q.-
Y. J. Chem. Soc., Perkin Trans. 1 1994, 725. (g) Werner, H.; Laubender,
M.; Wiedemann, R.; Windmuller, B. Angew. Chem., Int. Ed. Engl. 1996,
monitor the course of the reactions and assess the crude yields of
products. CDCl can naturally be replaced by regular CHCl .
(
(
(
byproducts derived from an initial Au-catalyzed addition of H O on
the alkyne moiety.
(
3
5, 1237. (h) Werner, H.; Wiedemann, R.; Laubender, M.;
Windmuller, B.; Steinert, P.; Gevert, O.; Wolf, J. J. Am. Chem. Soc.
002, 124, 6966.
6) (a) Han, H. Y.; Kim, M. S.; Son, J. B.; Jeong, I. H. Tetrahedron
3
3
19) Bolte, B.; Gagosz, F. J. Am. Chem. Soc. 2011, 133, 7696.
20) For the synthesis and use of gold complex 7a, see ref 14b.
21) The presence of water in the solvent led to the formation of
2
(
Lett. 2006, 47, 209. (b) Yamazaki, T.; Yamamoto, T.; Ichihara, R. J.
Org. Chem. 2006, 71, 6251. (c) Sam, B.; Montgomery, T. P.; Krische,
M. J. Org. Lett. 2013, 15, 3790.
2
22) It is assumed that the presence of the more coordinating NTf −
2
(
7) (a) Watanabe, Y.; Yamazaki, T. J. Fluorine Chem. 2010, 131, 646.
counteranion lowers the electrophilicity of the gold complex thus
diminishing its ability to make possible the hydride transfer.
(
(
b) Yamazaki, T.; Watanabe, Y.; Yoshida, N.; Kawasaki-Takasuka, T.
Tetrahedron 2012, 68, 6665. (c) Guissart, C.; Dolbois, A.; Tresse, C.;
Saint-Auret, S.; Blanchard, N.; Evano, G. Synlett 2016, DOI: 10.1055/
s-0035-1562518.
23) Gold complex 6 degrades at 60 °C within a few hours. Complex
a exhibits higher stability (see ref 14b) and was therefore retained for
7
studying the scope of the reaction assuming that longer reaction times
might be necessary depending on the substrates.
(
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647.
(
(
Morken, J. P. J. Am. Chem. Soc. 2004, 126, 16328.
(
(
(
8) (a) Hanzawa, Y.; Kawagoe, K.- i.; Yamada, A.; Kobayashi, Y.
Tetrahedron Lett. 1985, 26, 219. (b) Johnson, D.; Rodriguez, A.;
Kennedy, G. D.; Krishnan, G. J. Heterocycl. Chem. 1994, 31, 871. (c) Li,
P.; Liu, Z.-J.; Liu, J.-T. Tetrahedron 2010, 66, 9729.
́
24) Marion, N.; Diez-Gonzales, S.; de Fremont, P.; Noble, A. R.;
25) Hoffmann-Ro
26) Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.;
̈
der, A.; Krause, N. Org. Lett. 2001, 3, 2537.
(
9) (a) Watanabe, Y.; Yamazaki, T. Synlett 2009, 2009, 3352.
b) Aikawa, K.; Hioki, Y.; Mikami, K. Org. Lett. 2010, 12, 5716.
10) Pd-catalyzed reactions: (a) Sakamoto, T.; Takahashi, K.;
(
(
27) The reaction conditions were not optimized.
28) Yuan, W.; Ma, S. Adv. Synth. Catal. 2012, 354, 1867.
Yamazaki, T.; Kitazume, T. J. Org. Chem. 1999, 64, 9467. (b) Shimizu,
M.; Higashi, M.; Takeda, Y.; Jiang, G.; Murai, M.; Hiyama, T. Synlett
2
007, 2007, 1163. (c) Shimizu, M.; Higashi, M.; Takeda, Y.; Murai,
M.; Jiang, G.; Asai, Y.; Nakao, Y.; Shirakawa, E.; Hiyama, T. Future
Med. Chem. 2009, 1, 921. (d) Konno, T.; Tanikawa, M.; Ishihara, T.;
Yamanaka, H. Chem. Lett. 2000, 29, 1360.
(
11) Ag-catalyzed reaction: Liu, J.; Liu, Z.; Wu, N.; Liao, P.; Bi, X.
Chem. - Eur. J. 2014, 20, 2154.
12) (a) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem. 2009, 130,
54. (b) Zhao, T. S. N.; Szabo, K. J. Org. Lett. 2012, 14, 3966.
(
2
́
(
(
c) Jiang, X.; Qing, F.-L. Beilstein J. Org. Chem. 2013, 9, 2862.
d) Miyake, Y.; Ota, S.-I.; Shibata, M.; Nakajima, K.; Nishibayashi, Y.
Chem. Commun. 2013, 49, 7809. (e) Ji, Y.-L.; Kong, J.-J.; Lin, J.-H.;
Xiao, J.-C.; Gu, Y.-C. Org. Biomol. Chem. 2014, 12, 2903. (f) Li, G.;
D
DOI: 10.1021/acs.orglett.6b02636
Org. Lett. XXXX, XXX, XXX−XXX