Water-Compatible Synthesis of 2-Trifluoromethyl-1,3-Dioxanes

Article abstract of DOI:10.1002/ejoc.201801367

A water-compatible method for the diastereoselective synthesis of 2-trifluormethyl-1,3-dioxanes is described. The reaction proceeds under mild reaction conditions using simple inorganic bases; it has a very good substrate scope and can be performed with different Michael acceptors. Additionally, the reaction products can be further functionalized, showing an excellent perspective for future applications.

Full text of DOI:10.1002/ejoc.201801367

A Journal of
Accepted Article
Title: Water-Compatible Synthesis of 2-Trifluoromethyl-1,3-Dioxanes
Authors: Liliana Becerra-Figueroa, Alexander Tiniakos, Joëlle Prunet,
and Diego Gamba-Sánchez
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801367
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801367
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10.1002/ejoc.201801367
European Journal of Organic Chemistry
COMMUNICATION
Water-Compatible Synthesis of 2-Trifluoromethyl-1,3-Dioxanes
Liliana Becerra-Figueroa,[a] Alexander F. Tiniakos,[b] Joëlle Prunet,*[b] and Diego Gamba-Sánchez*[a]
Abstract: A water-compatible method for the diastereoselective
synthesis of 2-trifluormethyl-1,3-dioxanes is described. The reaction
proceeds under mild reaction conditions using simple inorganic
bases; it has a very good substrate scope and can be performed with
different Michael acceptors. Additionally, the reaction products can be
further functionalized, showing an excellent perspective for future
applications.
generation of a hemiacetal anion that reacts in a Michael addition.
This reaction, known since 1993,[11] has been applied to the
synthesis of many natural products –as a method to obtain
protected syn 1,3-diols-,[12] used with different Michael
acceptors[13] and reviewed very recently in the literature.[14]
Unfortunately, this reaction uses strong bases and requires
anhydrous conditions. Inspired by our previous results and trying
to generate a suitable and general method to synthesize 2-
trifluoromethyl-1,3-dioxanes, we decided to explore the reaction
using aqueous fluoral hydrate and simple inorganic bases
(Scheme 1b). Herein we describe our results in this field, offering
a water-compatible method for the diastereoselective synthesis of
fluorinated dioxanes and showing some subsequent
functionalization of the obtained molecules.
Introduction
Fluorinated molecules are ever-present in different aspects of our
daily life,[1] especially in areas like agrochemistry,[2] medicinal
chemistry,[3] and materials chemistry,[4] among others. The
trifluoromethyl group stands out as one of the most important in
the chemistry of fluorinated molecules, and the number of drugs
and drug candidates bearing this group is impressive.[5] The
methods for introducing the trifluoromethyl group in organic
molecules can be divided in two main groups: direct
trifluoromethylation,[6] which is a field of a tremendous growth in
recent years, and the use of small molecules bearing this group
as reagents or starting materials. Consequently, new methods for
installing the trifluoromethyl group in organic molecules are highly
desirable.
a.
Ar
CF3
O
OH
O
O
R3
F3C Ar
R3
R
R
tBuOK, THF
Anhydrous conditions
R1 R2
R1 R2
R1 = H or Me
Ar = Ph, m-NO2Ph
R2 = H or NHCHO or OCb
R3 = CO2Me, CO2Et, SO2Tol, CONMeOMe
R = Alkyl, aryl
Previous approach
Trifluoromethylation emerged as a preferred alternative mainly
because the availability of trifluoromethylated small molecules is
pretty limited. Among them fluoral (trifluoroacetaldehyde) can be
considered as a suitable starting material because of its inherent
reactivity compared with other aldehydes. Unfortunately, pure
fluoral is an unstable gas, difficult to prepare and to use; however,
its hydrate aqueous solution is commercially available and easy
to handle. The difficulty to prepare fluorinated molecules in
aqueous media has been the focus of many researches and
reviewed recently;[7] additionally the generation of stereogenic
centers containing a fluorine atom or a trifluoromethyl group is
also a very important field of investigation.[8]
CF3
b.
HO OH
OH
O
O
F3C
H
EWG
EWG
R
KOH, THF/H2O
R
EWG = COOEt, SO2Tol, NMeOMe
This work
Scheme 1. State of the art and proposed strategy.
Results and Discussion
We recently described the preparation of trifluoromethylated 1,3-
dioxanes using trifluoroacetophenones with α,β-unsaturated-δ-
hydroxy Michael acceptors[9] and we expanded the reaction
scope to the use α,β-unsaturated α-amino-δ-hydroxycarboxylic
acid esters (Scheme 1a).[10] The method is based on the in situ
The starting materials are easily prepared in two or three steps
from commercially available aldehydes (the experimental details
and the synthetic routes are described in the supporting
information). We started our study using the same reaction
conditions that are employed with benzaldehyde as the
electrophilic reagent (Table 1, entry 1). Unfortunately, the desired
dioxane 2a was obtained in only 7% yield, and 44% of the
hemiacetal 3a was isolated. It has to be mentioned that the
stereochemistry of the two isomers of the dioxane was
determined by NOE experiments. The CF3 group is always 1,3-
cis and the group in position 5 is cis in the major isomer and trans
for the minor one; in consequence the diastereomeric ratio refers
to 1,3-cis-1,5-cis and 1,3-cis-1,5-trans isomers. We decided to
increase the amount of base in order to deprotonate the
hemiacetal intermediate; after 12 hours we isolated 66% of
dioxane and 26% of hemiacetal (entry 2). The reaction of tBuOK
[a]
[b]
Dr. L. Becerra-Figueroa, Dr. D. Gamba-Sánchez
Laboratory of Organic Synthesis, Bio and Organocatalysis,
Chemistry Department, Universidad de los Andes
Cra 1 No. 18A-12 Q:305. Bogota 111711 (Colombia)
E-mail: da.gamba1361@uniandes.edu.co
http://lsoboc.uniandes.edu.co/
A. Tiniakos, Dr. J. Prunet
WestCHEM, School of Chemistry, University of Glasgow, Joseph
Black Building, University Avenue, Glasgow G12 8QQ, UK
E -mail: joelle.prunet@glasgow.ac.uk
http://www.chem.gla.ac.uk/wp/prunetgroup/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801367
European Journal of Organic Chemistry
COMMUNICATION
with water should produce KOH in solution, so we tried using
directly KOH as base and increasing the reaction time. The yield
for the dioxane did not improve, but the hemiacetal was not
detected (entry 3); presumably the hemiacetal is not stable
enough and it is degraded after long reaction times. As the
reaction in under thermodynamic control, increasing the
temperature allowed us to isolate the desired dioxane in very
good yield and selectivity; we thus used the conditions of entry 4
to study the scope of our method.
the conversion (compare products 2k vs 2l); however, in both
cases the selectivity is good, and some starting material can be
recovered. Heteroaromatic rings proved also problematic but
better conversions, selectivities and yields were obtained
comparing with strongly activated aromatics (see products 2m
and 2n). Finally, a-substituted (with O and N) substrates were
unreactive under these reaction conditions.
CF3
KOH (1.2 eq) X 4 times
Fluoral hydrate 75% aq
(1.1 eq) x 4 times
OH
O
O
O
O
Table 1[a]. Optimization of the reaction conditions
R
OMe
THF
12 to 15h
R
OMe
1
2
CF3
O
O
O
O
3
CF3
CF3
HO OH
OH
O
R
R
OMe
OMe
1
5
O
O
O
O
O
O
F3C
H
2a
CF3
OH
R
OMe
OMe
68% dr N.D.a
dr: 90:10b
OEt
Base, THF
5
1a
73% dr: 84:16a
dr: 85:15b
2c
2b
O
R = CH2CH2
CF3
CF3
3a
O
O
O
O
O
O
OEt
OMe
86% dr N.D.a
dr: 97:3b
Entry
1
Conditions
3a[b]
2a[b]
d.r. ratio
58% dr: 82:12a
dr: 90:10b
2d
2e
(Fluoral 1.1 equiv; tBuOK 0.1
44%
7%
91:9[c]
CF3
equiv) 3 additions, 7h, 0ºC
O
O
O
2
3
4
(Fluoral 1.1 equiv; tBuOK 1.0
equiv) 5 additions, 12h, 0ºC
26%
66%
64%
83%
77:23[d]
75:25[c]
OMe
71% dr: N.D.a
dr: >98:2b
87:13[c]
2f
(Fluoral 1.1 equiv; KOH 1.0
equiv) 5 additions, 24h, 0ºC
traces
N.D.
CF3
CF3
(Fluoral 1.1 equiv; KOH 1.2
equiv) 4 additions, 12h, r.t.
89:11[d]
90:10[c]
O
O
O
O
O
O
OMe
dr: N.D.a
O
Ph
2h
OMe
O
73% dr N.D.a
[a] A complete table is presented in the supporting information. [b] Isolated
yield. [c] Determined by 1H NMR of purified product [d] Determined by 1H NMR
of crude reaction product.
38%
2g
dr: 92:8b
62% brsm dr: 88:12b
CF3
CF3
Using KOH under the conditions described above, we applied the
reaction to different substrates (Scheme 2). We started by
changing the R group using another unbranched alkyl chain
(product 2b), obtaining comparable results. The use of a
cyclohexyl as a branched chain (product 2c) did not increase the
selectivity, which is surprising since the increased steric
hindrance should favor the cis,cis product. Fortunately, with an
isopropyl group better yields and selectivities were observed,
according to expectation (product 2d). The fused bicyclic dioxane
2e was obtained in acceptable yield and good selectivity, showing
the usefulness of this method with additional alkyl groups g to the
Michael acceptor. Substrates with trisubstituted alkenyl groups
afforded good yields and complete selectivity (see product 2f).
Oxygenated groups have been described as problematic in this
kind of reactions. In our case the conversion was low, but the
selectivity was good (product 2g); increasing the reaction time did
not improve the conversion. We then turned our attention to
substrates with aromatic substituents, showing that substrates
with simple aromatic groups (2h), slightly deactivated (2i) or
activated (2j) groups lead to good yields and very good
selectivities. Unfortunately, the more activated the ring, the poorer
O
O
O
O
O
O
OEt
dr: 86:14a
OMe
70% dr: 93:7a
dr: 93:7b
56%
2i
2j
Cl
98% brsm dr: 88:12b
CF3
CF3
O
O
O
O
O
O
MeO
MeO
OMe
dr: N.D.a
OMe
dr: N.D.a
9%
28%
O
67% brsm dr: 89:11b
2k
37% brsm dr: 83:17b
2l
CF3
CF3
O
O
O
Cl
O
O
O
OMe
36% dr: 93:7a
dr: 93:7b
N
OMe
dr: N.D.a
46%
O
2m
2n
83% brsm dr: 92:8b
Scheme 2. Reaction Scope. adr of unpurified reaction mixture; bdr of purified
product.
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10.1002/ejoc.201801367
European Journal of Organic Chemistry
COMMUNICATION
Fortunately, other Michael acceptors proved suitable of this
reaction and products 5 and 7 were obtained in good yields and
selectivities from the corresponding sulfones 4 and Weinreb
amides 6, respectively, as shown in Scheme 3.
The results shown in Scheme 4 illustrate reactions of the ester 2a
that do not affect the dioxane ring: with concentrated aqueous HCl,
the acid 8 was isolated as the sole product; reduction under strong
conditions furnished the free alcohol 9 also in good yield. The use
DIBAL-H with a substrate without other oxidized functions
(product 10) led to the deprotection of the primary alcohol after
long reaction times; otherwise 10 was recovered unchanged. It
has to be mentioned that under the typical conditions used to
cleave benzylidene acetals like [H2/Pd(C), H2/Pd(OH)2 or even
harder conditions employed to cleave acetals with strong electron
withdrawing groups like (nBuLi, Na, or Zn/AcOH), the starting
material was quantitatively recovered, proving the great stability
of trifluoromethyl acetals and confirming their usefulness in late
stage functionalization.
a.
CF3
KOH (1.2 eq) X 4 times
Fluoral hydrate 75% aq
(1.1 eq) x 4 times
OH
O
S
O
O
O
O
S
O
R
Tol
R
Tol
THF, 12h
4
5
84 % dr: 80:20a
dr: 86:14b
R = PhCH2CH2
b.
CF3
KOH (1.2 eq) X 4 times
Fluoral hydrate 75% aq
(1.1 eq) x 4 times
OH
O
O
O
O
N
N
Conclusions
THF, 12h
6
7
OMe
OMe
69 % dr: N.D.a
dr: 98:2 b
In summary, we have described
diastereoselective synthesis of
a
water-compatible and
2-trifluoromethylated-1,3-
dioxanes; the use of aqueous fluoral hydrate is a good alternative
to the use of toxic and dangerous gaseous fluoral. The Michael
acceptor substrates are obtained by simple synthetic pathways
and the reaction has a very good substrate scope. Furthermore,
we demonstrated the excellent stability of trifluoromethylated
acetals and the possibility to further functionalize them.
Scheme 3. Reaction with sulfones and Weinreb amides.
Acetals have been used as protecting groups for alcohols and
diols for many years. The most commonly used for diols are
aromatic (phenyl and p-methoxyphenyl) and aliphatic (acetonide);
however, other groups coming from highly activated aldehydes
have also been reported as alternative protecting groups for 1,3-
diols, such as the 3,4-dinitrophenyl[15] and trichloromethyl
groups.[16]. In consequence, the stability of acetals is well
established particularly under basic conditions. However, acetals
with strong electron-withdrawing groups (e.g. trichloromethyl)
were easily cleaved under strongly basic and reductive conditions.
As we were interested in the synthesis of trifluoromethylated
dioxanes, it was important for us to demonstrate their stability and
that they can be further functionalized, but also that they can resist
typical and even stronger conditions used to deprotect other
acetals.
Experimental Section
To a solution of homoallylic alcohol (1 equiv.) in THF (0.2 M) at room
temperature was added aqueous fluoral (75% in H2O) (1.1 equiv.) followed
by KOH (1.2 equiv.). The resulting mixture was stirred for 1 h at room
temperature. A second portion of aqueous fluoral (75% in H2O) (1.1 equiv.)
and KOH (1.2 equiv.) was added. After 15 min, a third addition of fluoral
and base was made, and 15 min later a fourth addition was performed
under the same conditions. The resulting mixture was then stirred at room
temperature for 12 -14 h and quenched with a saturated aqueous NH4Cl
solution. The aqueous phase was extracted with AcOEt (4 x 10mL) and
the combined organic layers were dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The crude residue was purified by flash column
chromatography.
a.
CF3
CF3
O
O
O
HCl 37%
47 %
O
O
O
O
Ph
b.
OMe
OMe
Ph
OH
Acknowledgements
8
2a
Financial support for this work was provided by Universidad de
los Andes and the University of Glasgow. L.B.-F acknowledges
the Universidad de los Andes and especially the Chemistry
Department for a fellowship. A.F.T acknowledges the EPSRC for
a studentship (Doctoral training allocation EP/K503058/1). We
thank Claire Armstrong for preliminary experiments.
CF3
CF3
O
O
O
O
LiAlH4
86 %
Ph
c.
Ph
OH
2a
9
CF3
CF3
O
O
DIBAL-H
70 %
O
O
Keywords: Water-compatible • stable acetals • oxa-Michel •
Ph
OTBDPS
Ph
OH
trifluoromethyl • dioxanes
9
10
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COMMUNICATION
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European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Diastereoselective Synthesis
CF3
HO OH
F3C
OH
H
O
O
Liliana Becerra-Figueroa, Alexander
Felix Tiniakos, Joëlle Prunet* and Diego
Gamba-Sánchez*
EWG
R
EWG
Further
Functionalization
R
KOH, THF/H2O
EWG = COOEt, SO2Tol, NMeOMe
R= Alkyl, aryl, alquenyl
High Yield and Selectivity
Page No. – Page No.
A simple and practical method for the diastereoselective synthesis of fluorinated
dioxanes using aqueous fluoral and KOH was developed. The products were
obtained with high yields and selectivities, besides they proved to be stable enough
to resist further functionalization. The reaction is easily performed and well tolerated
with a broad range of substrates.
Water-Compatible Synthesis of 2-
Drifluoromethyl-2,3-Dioxanes
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