Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction

Article abstract of DOI:10.1039/C6OB02333A

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yiel

Full text of DOI:10.1039/C6OB02333A

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes
by intramolecular oxa-Michael reaction
Liliana Becerra-Figueroa,a Elodie Brun,b Michael Mathieson,b Louis J. Farrugia,b Claire Wilsonb,
Joëlle Prunetb* and Diego Gamba-Sáncheza*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly diastereoselective synthesis of trifluoromethylated 1,3-
dioxanes is described. The reaction proceeds by an addition/oxa-
Michael sequence and works efficiently under mild reaction
conditions, with a good substrate scope and acceptable to good
yields.
Trifluoromethyl-containing heterocycles and particularly
oxygenated heterocyclic systems have attracted growing
attention in the last few years.1 They are currently investigated
because of their interesting applications in medicine,
agriculture and material science, among others.2 In spite of the
continuous growth in this field, the synthesis of 1,3-dioxanes
remains unexplored. Consequently, the development of new
and efficient synthetic methods for that kind of heterocyclic
systems is at the same time a challenge and very desirable.
Since the seminal work published by Evans and Prunet in
1993,3 the addition/oxa-Michael cascade has demonstrated to
be useful in the construction of protected syn 1,3-diols4
(Scheme 1). The reaction substrates are homoallylic alcohols
functionalised by a Michael acceptor. The most usual reagent
is benzaldehyde but there are several examples in literature
where p-methoxy benzaldehyde has been used successfully.5
Concerning the Michael acceptor and the substitution pattern
the reaction has been explored with esters and amides,3
sulfones6 and sulfoxides,7 and in very few cases with
substituents α to the Michael acceptor.8
Scheme 1 Difference between the closest similar report and our work.
During our studies, a similar transformation on cyclic dienones
in the presence of triethylamine was described by Wang et al.9
Even if the yields were good, the selectivity was moderate in
most cases.
With our substrates, if the reaction is under thermodynamic
control as it is the case with benzaldehyde,3 the major
diastereomer should have all the large substituents in
equatorial positions (the two alkyl chains and presumably the
trifluoromethyl group).
Inspired by those previous results and by the need of a simple
method to synthesise CF3-containing dioxanes, we decided to
explore the intramolecular oxa-Michael reaction using
We started our investigation with the simple known ester 1a10
and explored the reaction under the conditions described by
Wang et al. (Table 1, entry 1). After 24 hours no reaction was
observed, and the starting material was recovered
quantitatively. The use of a larger quantity of base and ketone
or the use of another weak base such as potassium acetate did
not afford better results (entries 2 and 3); therefore, we
decided to turn our attention to bases and reaction conditions
more familiar to us.11
trifluoroacetophenone
and
a
homoallylic
alcohol
functionalised with an ester as substrates (Scheme 1).
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Table 1 Optimisation of the reaction conditions.
Entry Base (equiv.)
PhCOCF3
1.2 equiv.
2 equiv.
Time
24 h
12 h
12 h
12 h
6 h
Yield (%)
Selectivityb
1
2
Et3N (0.2)
Et3N (0.4)
-
-
-
-
Figure 1 X-ray structure of product 2a
.
3
AcOK (0.4)
tBuOLi (0.4)
tBuOK (0.4)
tBuOK (0.3)
tBuOK (0.3)
2 equiv.
-
-
4
2 equiv.
49
84
70c
79
80:20
88:12
>98:2
>98:2
The use of simple aliphatic substrates afforded the best results
(entries 1 to 4); there is no noticeable effect induced by the
chain extension, or by the presence of aromatic rings in the
aliphatic chain (compare entries 1 and 2). The use of branched
R groups is also acceptable and there is no influence on the
reaction diastereroselectivity; in fact, as these groups are in
equatorial position we indeed expected better selectivities
with these bulkier R groups. The reaction is also useful with
aromatic R substituents (entries 6 to 8); however, yields are
somehow lower when electron-withdrawing groups are
inserted (entry 8 vs. entry 7).
5
2 equiv.
6a
7a
3.3 equiv.
3.3 equiv.
2 h
6 h
aThe reaction was performed making successive additions of the base and the
ketone each 15 min. bDetermined by 1H NMR of crude product. c80 % brsm.
With tBuOLi and 2 equivalents of ketone (entry 4), the reaction
proceeded and the desired dioxane 2a was isolated in 49%
yield with a moderate selectivity, the major product has the
same stereochemistry in all cases (see below). The change of
counterion to potassium provided much better results and in 6
hours the product was isolated in 84 % yield with good
selectivity (entry 5). Typically an intramolecular conjugate
addition reaction of this kind is performed using successive
addition of base and carbonyl compound; it was demonstrated
that this serves to improve the selectivity and to increase the
reaction yield.3 Hence, we used three additions of 1.1
equivalents of ketone and 0.1 equivalents of base, but after 2
hours the reaction was not complete and the product was only
isolated in 70 % yield (80 % brsm, entry 6); however after 6
hours the starting material was completely consumed and the
product isolated in 79% yield (entry 7). In both cases only one
diastereomer was detected in the 1H NMR spectrum of the
crude reaction mixture and after purification of the product.
The stereochemistry of the major diastereomer remained
uncertain. We were confident about the cis stereochemistry of
the substituents in positions 4 and 6, but for position 2 the
configuration will be dependent on the relative steric
hindrance of Ph and CF3. Fortunately, compound 2a was
crystalline and X-ray crystallographic analysis provided its
structure (Figure 1), showing the CF3 is indeed in the equatorial
position.
The reaction mechanism is shown in Scheme 2. We postulated
that this reaction is under thermodynamic control as it is the
case with benzaldehyde,3 with
a reversible oxa-Michael
reaction. So, it is to be expected that the use of a more
electrophilic carbonyl compound (trifluoroacetophenone) will
cause a better reaction with the alkoxide
3, favouring the
formation of hemiketal alkoxide 4. We hypothesise that this
intermediate is stabilised by the inductive effect of the CF3
group, facilitating the reverse oxa-Michael addition and in
consequence improving the selectivity of the whole process.
Table 2 Reaction scope.a
Entry
R
Product
2a
Yield (%)b
1
2
3
4
5
6
7
8
PhCH2CH2
C6H13
79
80
81
82
70
67d
70
63
2b
Isopropyl
Chx
CH3CHOBnc
2c
2d
With these promising results in hand, we started the study of
2e
the reaction scope. All the starting materials
1 were obtained
Ph
2f
by cross metathesis reaction between the corresponding
homoallylic alcohol and methyl acrylate using Grubbs II
catalyst (2.5 % mol). These homoallylic alcohols were easily
prepared in one step from commercially available aldehydes
and allyl bromide using an aqueous Barbier reaction.12 Then
p-MeOPh
p-ClPh
2g
2h
aThe reaction was performed making successive additions of the base (0.1 equiv.)
and the ketone (1.1 equiv.) every 15 min. bYields are reported for pure
compounds; the 1H NMR spectra of the crude reaction mixtures showed in all
cases only one diastereomer. cThis product was obtained from enantiopure lactic
acid and the anti diastereomer from the cross methatesis reaction was isolated
(see supporting information). d80 % brsm.
we applied the optimised conditions to all substrates
1 and we
found in all cases excellent diastereoselectivity (see Table 2).
2 | J. Name., 2012, 00, 1-3
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Figure 2 X-ray structure of product 7c
.
We were also curious about the reactivity of a substrate with a
nitrogen substituent in the α position. Depending on the
substitution pattern of the nitrogen atom, the compound can
have an enamine character or the N-H group can be acidic
enough to be deprotonated before the alcohol.
Scheme 2 Reaction mechanism.
The next step was the investigation of the effect of a
substituent in the α position to the electron-withdrawing
group8 (results in Table 3); for this purpose, we synthesised
We were able to synthesize compound 6d by a Horner-
Wadswoth-Emmons reaction.13 As expected an extra
equivalent of base was needed in order to completely
deprotonate the NH group (entry 4). It is remarkable that this
reaction proceeded in very good yield and with good
selectivity, even if the deprotonation of the nitrogen can
induce a nucleophilic character to the carbon in the β position
to the ester. It is worth noting that in all the cases described in
table 3, the reported selectivity corresponds to the position of
R2; the reaction proceeds with complete selectivity for the
oxygen addition.
several α-substituted substrates
6 (see supporting information
for the reaction sequence). When the substituent in the α
position was a methyl group (entry 1), the outcome of the
reaction was disappointing. The product was observed in the
1H NMR spectrum along with the intermediate hemiketal and
the elimination product. We were able to isolate the desired
ketal with acceptable selectivity but in low yield. On the other
hand, the reaction with product 6b works smoothly and the
product was isolated with excellent selectivity and in
acceptable yield (entry 2); curiously the reaction was not
complete after 12 hours and some starting material was
recovered. The introduction of a methyl group γ to the ester
did not have significant effect on the selectivity (entry 3); in
this case the reaction was pushed to completion with 4
additions of base and ketone to furnish 7c in 90 % yield. It has
to be noted that the reaction on a substrate similar to 6c (with
R = iPr) with benzaldehyde as the electrophilic reagent
furnished the corresponding product in 35% yield (53% brsm)
with a 67:33 selectivity.8d
Fortunately, the stereochemistry of the substituent in the α
position could be determined by X-ray crystallographic analysis
of compound 7d as shown in Figure 2. Comparison of NMR
signals and coupling constants for the H-5 proton in 7d and 7b
allowed us to define the configuration at C5 for compound 7b
as shown in scheme 3. The stereochemistry at C5 of 7c M was
assumed to be the same as that of 7b
.
Some additional experiments were carried out in order to
illustrate the generality of our method. First, other Michael
acceptors such as Weinreb amides or sulfones were explored.
The cited literature3-8 shows that the reactivity of the Michael
acceptors does not have a great influence on the yield of the
oxa-Michael reaction. The main difference is the
diastereoselectivity.
Table 3 Reaction with α-substituted substrates.
Entry
1
R
R1
H
R2
R3
Et
Et
Et
Product, Yield Selectivity
PhCH2CH2
PhCH2CH2
Me
OCbb
7a, <27%a
7b, 54c %
7c, 90 %
7d, 85 %
82:18
>98:2
>98:2
82:18
2
H
3d
PhCH2CH2 Me
PhCH2CH2
OCb
4e
H
NHCHO Me
a
This value was calculated by analysis of the 1H NMR spectrum; the crude
mixture also contained the intermediate hemiketal and the elimination product;
a sample was purified for analytical purpose. b Cb = CON(iPr)2 c 83 % brsm. d The
e
reaction was performed using 4 additions of base and ketone. The starting
material was treated with 1.1 equivalents of base and ketone, then consecutive
additions of 0.1 equivalents of base and 1.1 equivalent of ketones were made.
Scheme 3 Stereochemistry for major (M) and minor (m) diastereomers.
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In conclusion, we have described a useful methodology for the
synthesis of CF3-containing 1,3-dioxanes with excellent
diastereoselectivity in most cases. We also reported our
preliminary conclusions about the reaction mechanism based
on literature reports and experimental observations. The
stereochemistry of the products was established by X-ray
crystallographic analysis and extrapolation.
Financial support for this work was provided by the University
of Glasgow, the EPSRC (doctoral fellowship for M.M.) and
Universidad de los Andes. L.B.-F acknowledges the Universidad
de los Andes and especially the Chemistry Department for a
fellowship and the Faculty of Science for financial support for
her internship. We also thank Mr. David Sotelo for recording
some of the NMR spectra.
Scheme 4 Weinreb amide and sulfone as Michael acceptors.
In consequence, we were curious to see if in our case Weinreb
amides or sulfones are desirable substrates and if the
selectivity is comparable to that obtained with esters.
As shown in scheme 4 the results are very good, the reaction
yields are comparable to those obtained with simple esters
and in both cases, scheme 4a and 4b, there was only one
diastereosisomer visible by 1H NMR of the crude reaction
Notes and references
1
2
(a) F. M. D. Ismail, J. Fluorine Chem., 2002, 118, 27; (b) J.-A.
Ma; D. Cahard, Chem. Rev., 2004, 104, 6119; (c) J. Nie; H.-C.
Guo; D. Cahard; J.-A. Ma, Chem. Rev., 2011, 111, 455; (d) Y.-J.
Lin; L.-N. Du; T.-R. Kang; Q.-Z. Liu; Z.-Q. Chen; L. He, Chem.
Eur. J., 2015, 21, 11773.
(a) F. Li; J. Nie; L. Sun; Y. Zheng; J.-A. Ma, Angew. Chem., Int.
Ed., 2013, 52, 6255; (b) J. Wang; W.-G. Kong; F. Li; J. Liu; Q.
Shen; L. Liu; W.-X. Zhao, Org. Biomol. Chem., 2015, 13, 5399;
(c) Y. Zhu; Z. Dong; X. Cheng; X. Zhong; X. Liu; L. Lin; Z. Shen;
P. Yang; Y. Li; H. Wang; W. Yan; K. Wang; R. Wang, Org. Lett.,
2016, 18, 3546.
mixture and isolated products
9 and 11. The stereochemistry
of these compounds was assigned by comparison with that of
the esters.
Finally, we decided to use another trifluoromethyl ketone; we
speculated that, if the ketone was more electrophilic than
trifluoroacetophenone, the hemiketal alkoxide
4 would be less
nucleophilic and so the reaction more difficult. Thus, if the
reaction worked with a ketone substituted in the aromatic ring
by a strong electron withdrawing group, then it would be
predictable than the reaction could be extended to the use of
almost any trifluoromethyl ketone. Scheme 5 shows the result
of the reaction using the m-nitro-trifluorocetophenone as the
electrophilic reagent. In this case the reaction proved to be
more difficult, four additions of base and 16 hours were
needed to complete the reaction; however, product 13 was
isolated in good yield and the reaction proceeded with
complete diastereoselectivity.
3
4
D. A. Evans; J. A. Gauchet-Prunet, J. Org. Chem., 1993, 58,
2446.
For a few selected examples, see: (a) D. T. Hung; J. B.
Nerenberg; S. L. Schreiber, J. Am. Chem. Soc., 1996, 118
11054; (b) T. J. Hunter; G. A. O'Doherty, Org. Lett., 2001, 3
2777; (c) T. A. Dineen; W. R. Roush, Org. Lett., 2004, 6, 2043;
(d) A. Vincent; J. Prunet, Synlett, 2006 2269; (e) E. de Lemos;
F.-H. Porée; A. Bourin; J. Barbion; E. Agouridas; M.-I. Lannou;
A. Commerçon; J.-F. Betzer; A. Pancrazi; J. Ardisson, Chem.
Eur. J., 2008, 14, 11092; (f) S. S. Palimkar; J. Uenishi, Org.
Lett., 2010, 12, 4160; (g) A. M. M. Albury; M. P. Jennings, J.
Org. Chem., 2012, 77, 6929; (h) R. W. Bates; T. G. Lek,
,
,
,
Synthesis, 2014, 1731; (i) T. J. Hunter; Y. Wang; J. Zheng; G.
A. O'Doherty, Synthesis, 2016, 48, 1700.
D. A. Evans; P. Nagorny; D. J. Reynolds; K. J. McRae, Angew.
Chem., Int. Ed., 2007, 46, 541.
(a) R. Oriez; J. Prunet, Tetrahedron Lett., 2010, 51, 256; (b) L.
Grimaud; D. Rotulo; R. Ros-Perez; L. Guitry-Azam; J. Prunet,
Tetrahedron Lett., 2002, 43, 7477.
In summary, the additional experiments let us to conclude that
different Michael acceptors and other trifluoromethyl ketones
can be used, thus making the method very general.
5
6
Finally, computational studies oriented to propose an
explanation for the difference in reactivity and selectivity
between the substrates, as well as additional experiments to
increase even more the reaction scope are currently under
investigation in our laboratory. The results will be reported in
due course.
7
8
D. Gamba-Sanchez; J. Prunet, J. Org. Chem., 2010, 75, 3129.
(a) L. Grimaud; R. de Mesmay; J. Prunet, Org. Lett., 2002, 4
,
419; (b) D. Rotulo-Sims; J. Prunet, Org. Lett., 2007, 9, 4147;
(c) R. Aouzal; J. Prunet, Org. Biomol. Chem., 2009, 7, 3594.
(d) R. Oriez, Master Thesis, Ecole Polytechnique (Palaiseau),
2006.
9
F. Li; J. Wang; M. Xu; X. Zhao; X. Zhou; W.-X. Zhao; L. Liu, Org.
Biomol. Chem., 2016, 14, 3981.
10 J. A. Gazaille; T. Sammakia, Org. Lett., 2012, 14, 2678.
11 In our previous studies the typical base employed was tBuOK
and we performed successive additions of base and carbonyl
compound.
12 A. Chattopadhyay, J. Org. Chem., 1996, 61, 6104.
13 P. A. Alexander; S. P. Marsden; D. M. Muñoz Subtil; J. C.
Reader, Org. Lett., 2005, 7, 5433.
Scheme 5 Reaction using m-nitrotrifluoroacetophenone.
4 | J. Name., 2012, 00, 1-3
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Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes
by intramolecular oxa-Michael reaction
Liliana Becerra-Figueroa, Elodie Brun, Michael Mathieson, Louis J. Farrugia, Claire Wilson,
Joëlle Prunetb* and Diego Gamba-Sáncheza*
Ar
CF3
O
OH
O
O
R3
F3C
Ar
R3
R
R
tBuOK, THF
R1 R2
R1 R2
R1 = H or Me
Ar = Ph, m-NO2Ph
Yields: 63% to 85%
dr: 82:18 to >98:2
R2 = H or NHCHO or OCb
R3 = CO2Me, CO2Et, SO2Tol, CONMeOMe
R = Alkyl, aryl
A rapid and simple method to access trifluoromethylated 1,3-dioxanes by a sequence
addition/oxa-Michael reaction has been developed; the reaction proceeds smoothly with
excellent stereo selectivity.