Base-promoted isomerization of CF3-containing allylic alcohols to the corresponding saturated ketones under metal-free conditions

Article abstract of DOI:10.3762/bjoc.13.149

Following to the computational expectation, our previously reported intriguing 1,3-proton shift of 4,4,4-trifluorobut-2-yn-1-ols was successfully extended to the 4,4,4-trifluorobut-2-en-1-ol system under metal-free conditions to afford the corresponding saturated ketones in high to excellent chemical yields using such a convenient and easy-to-handle base as DBU at the toluene refluxing temperature, and utilization of the corresponding optically active substrates unambiguously demonstrated that this transformation proceeded in a highly stereoselective fashion.

Full text of DOI:10.3762/bjoc.13.149

Base-promoted isomerization of CF3-containing allylic
alcohols to the corresponding saturated ketones
under metal-free conditions
Yoko Hamada, Tomoko Kawasaki-Takasuka and Takashi Yamazaki*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1507–1512.
Division of Applied Chemistry, Institute of Engineering, Tokyo
University of Agriculture and Technology, 2-24-16 Nakamachi,
Koganei 184-8588, Japan
doi:10.3762/bjoc.13.149
Received: 29 March 2017
Accepted: 09 July 2017
Published: 01 August 2017
Email:
Takashi Yamazaki* - tyamazak@cc.tuat.ac.jp
Associate Editor: P. R. Schreiner
* Corresponding author
© 2017 Hamada et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
allylic alcohols; chirality; computation; 1,3-proton shift; trifluoromethyl
Abstract
Following to the computational expectation, our previously reported intriguing 1,3-proton shift of 4,4,4-trifluorobut-2-yn-1-ols was
successfully extended to the 4,4,4-trifluorobut-2-en-1-ol system under metal-free conditions to afford the corresponding saturated
ketones in high to excellent chemical yields using such a convenient and easy-to-handle base as DBU at the toluene refluxing tem-
perature, and utilization of the corresponding optically active substrates unambiguously demonstrated that this transformation
proceeded in a highly stereoselective fashion.
Introduction
We have previously reported [1-3] an extremely efficient isom- latter intermediate would be occurred at the CF3-attached car-
erization process of γ-trifluoromethylated propargylic alcohols bon atom to produce the corresponding allenyl type intermedi-
1F to the corresponding α,β-unsaturated ketones (E)-5 by the ate. Furthermore, its keto–enol interconversion would result in
action of a weak base like Et3N under THF reflux conditions construction of the isomerized α,β-unsaturated ketones (E)-5
(Scheme 1). From the mechanistic point of view, deprotonation [4-6]. For a better comprehension of this interesting and effi-
of the propargylic proton Ha was considered to be the initial cient protocol, computation was performed [7] for obtaining the
step of this reaction and this step would be in competition with rough indication of the acidity of both protons Ha and Hb in 1F.
the proton abstraction from the OHb group in 1F. Thus, it was Moreover, the corresponding allylic alcohols 2F as well as their
our first understanding that during the equilibration between non-fluorinated counterparts 1H and 2H were also employed
3F-O and 3F-C, the irreversible reprotonation by way of the for comparison whose results were summarized in Table 1.
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Beilstein J. Org. Chem. 2017, 13, 1507–1512.
Scheme 1: Et3N-promoted isomerization of propargylic alcohols 1F.
Table 1: Destabilization energy ΔE of propargylic (1) and allylic (2) alcohols.
C–C bond
X
F
R
ΔE (kcal/mol)
ΔΔEc
ΔECa
ΔEOb
(kcal/mol)
triple
triple
CH3 (a)
Ph (b)
310.657
301.759
–d
311.705
309.628
316.344
313.653
–1.048
–7.869
–d
double
double
CH3 (a)
Ph (b)
313.332
–0.321
triple
triple
H
CH3 (a)
Ph (b)
338.596
324.957
351.919
332.565
319.647
317.154
324.077
320.943
18.949
7.803
double
double
CH3 (a)
Ph (b)
27.842
11.622
aΔEC: E3X-C − E1X or E4X-C − E2X. bΔEO: E3X-O − E1X or E4X-O − E2X. cΔΔE: ΔEC − ΔEO. dThe stable 4F-Ca was failed to be located using the
IEFPCM method.
For this purpose, evaluation was performed on the basis of the role in stabilization of both 3F-C and 4F-C, and the phenyl
energetic difference between neutral compounds and the corre- group as well as the carbon–carbon multiple bonds would also
sponding carbanion or alkoxide species: thus, in the former provide the additional preferable effect by their efficient reso-
instance, ΔEC as E3X-C − E1X (or E4X-C − E2X) or the latter nance. In the case of the propargylic alcohol 1Fa with a methyl
ΔEO as E3X-O − E1X (or E4X-O − E2X) in the case of propar- moiety as R, its electron-donating ability unambiguously desta-
gylic (or allylic) alcohols, respectively, as the simple measure bilized the carbanionic species 3F-Ca while the electron-with-
of destabilization. In the case of the non-fluorinated 1H and 2H drawal of a CF3 group nicely compensated this disadvantage,
series, as expected, a clear alkoxide preference was noticed irre- resulting in a better stability of 3F-Ca by 1 kcal/mol with
spective of the carbon–carbon unsaturation pattern. For the cor- respect to the alkoxide 3F-Oa. In the case of 1Fb, the phenyl
responding fluorinated counterparts, in spite of the failure to group worked nicely for increase of the energetic preference of
locate the energy minimum for 4F-Ca, it was found out in other 3F-Cb to 3F-Ob of about 7.9 kcal/mol. For the allylic alcohol
cases that ΔEC values were unanimously smaller than ΔEO 2Fb (R = Ph), although the ΔΔE value was small, the carban-
which led to the definitive conclusion that protons at the propar- ionic species 4F-Cb was calculated to be more (or at least
gylic and allylic positions should be more acidic than the ones almost equally) preferable to 4F-Ob. This result allowed us to
at the corresponding OH groups. The strongly electron-with- similarly anticipate the successful isomerization of CF3-contain-
drawing property of a CF3 group is considered to play a key ing allylic alcohols 2F to the corresponding saturated ketones 7
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Beilstein J. Org. Chem. 2017, 13, 1507–1512.
when the substrates possessed appropriate aromatic substitu- ene (TBD), as a catalyst. In spite of these two preceding studies,
ents as R.
we have also succeeded in attaining a similar level of chemical
yields as well as stereoselectivity to the latter process by using
With reference to these computational results, we decided to far-less expensive DBU (1,8-diazabicyclo[5.4.0]undec-7-ene),
employ the CF3-containing allylic alcohols (E)-6 at the γ-posi- whose results are reported in this article in detail.
tion as substrates for the amine-promoted isomerization, instead
of the corresponding propargylic alcohols 1F. Although a simi- Results and Discussion
lar Ru- [8-12] or Fe-catalyzed processes [13] have been previ- Preparation of substrates (E)-6 was carried out by way of our
ously demonstrated, our present work is considered to draw a recently reported one-pot procedure [16]: thus, after reaction of
clear line with these instances because of the apparently conve- an appropriate Grignard reagent and ethyl trifluoroacetate at
nient metal-free process. Moreover, the same type of proton −80 °C, a Horner–Wadsworth–Emmons reagent [17] activated
shift has also reported by two groups. For example, during the by LiBr and Et3N [18-20] was introduced to this solution at
reaction of (E)-2-(trifluoromethyl)vinylsilane and benzalde- room temperature, leading to the formation of (E)-6 after the
hyde in the presence of an excess amount of CsF, the resultant NaBH4 reduction of the resultant products (see Supporting
product (E)-2Fb was further converted in situ to the corre- Information File 1 for the detailed procedure).
sponding saturated ketone (E)-5b (R = Ph). Confirmation of this
process was performed by the action of DBU, resulting in 95% As shown in Table 2, we at first checked a type of bases suit-
conversion of the starting allylic alcohol (E)-2Fb [14]. Quite able for this isomerization in THF under reflux for 3 h. Al-
recently [15], the same proton shift was published by using the though Et3N was appropriate in the case of isomerization of
bicyclic guanidine-type base, 1,5,7-triazabicyclo[4.4.0]dec-5- propargylic alcohols 1F [1], this was not the case for the allylic
Table 2: Optimization of reaction conditions.
Yielda (%)
Entry
Solvent
Base
Temp. (°C)
Time (h)
7a
(E)-6a
1
2
THF
THF
Et3N
DBU
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
70
3
3
3
[93]
[20]
[99]
[99]
[4]
(67)
–
3
THF
K2CO3
NaOHb
NaOHc
NaOHb
DBU
3
4
THF
3
–
5
THF
3
(45)
(49)
4
6
MeOH
MeOH
MTBE
MeCN
DMF
3
[–]
7
3
[84]
[95]
[1]
8
DBU
3
9
9
DBU
3
(61)
64
10
11
12
13
14
15
16
17
18d
19e
20d
DBU
70
3
[29]
[11]
[15]
[94]
[44]
[0]
DMA
DBU
70
3
54
DMSO
DCM
DBU
70
3
67
DBU
reflux
70
3
–
toluene
THF
DBU
3
(46)
(87)
(93)
(91)
(91)
(95)
30
DBU
reflux
70
24
24
3
toluene
toluene
toluene
toluene
toluene
DBU
[0]
DBU
reflux
reflux
reflux
reflux
[0]
DBU
3
[0]
DBU
24
10
[0]
DABCO
[78]
a All yields were determined by 19F NMR and in brackets were described the recovery of (E)-6a. In the parentheses were shown the isolated yields.
bA 6 M aqueous solution was used. cSolid NaOH was used. d0.5 equiv of base was used. e0.1 equiv of base was used.
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Beilstein J. Org. Chem. 2017, 13, 1507–1512.
alcohol (E)-6a, forming the desired 7a only in a trace amount were summarized in Table 3. Entry 1 depicts the result already
with recovery of (E)-6a in a large amount (Table 2, entry 1). shown in entry 18 of Table 2 where the substrate (E)-6a was
Because Et3N was proved to be inadequate, utilization of DBU transformed into the saturated ketone 7a in 91% yield. A slower
with the higher basicity was tried at the next stage although this reaction was suspected for (E)-6b in Table 3, entry 2 because of
base gave detrimental results for the isomerization of 1F. Actu- the possible destabilizing effect of the partial anionic charge at
ally, DBU was found to work nicely in the present instance to the 3 position by the electron-donating 4-MeOC6H4 group as
afford the desired compound 7a in 67% isolated yield (Table 2, R2. However, the effect was only quite limited and isomeriza-
entry 2). The result that the stronger tertiary amine DBU tion of (E)-6b was occurred in the same 3 h period as entry 1
worked more effectively than Et3N was a clear support of our with recording 89% isolated yield. Moreover, as expected, the
computation at least from a qualitative point of view which esti- electron-withdrawing 4-fluorophenyl moiety worked nicely to
mated the lower acidity of the allylic proton rather than the one quantitatively furnish the ketone 7c in shorter time (Table 3,
in the propargylic position (ΔΔE of −0.321 and −7.869 kcal/mol entry 3). However, as shown in Table 3, entries 4 and 5, clear
for the allylic and propargylic series, respectively). Due to the retardation of this process was noticed for substrates with alkyl
unacceptable efficiency of K2CO3 and NaOH (Table 2, entries groups as R2. Different from the case of R2, an electronic effect
3–5), the solvent effect was surveyed at the next stage with of the substituent on the benzene ring of R1 affected this trans-
fixing the base to DBU. Polarity seemed to affect the reaction formation quite significantly, and the substrate (E)-6f with
significantly, and aprotic MeCN, DMF, and DMSO (Table 2, 4-MeOC6H4 and Ph(CH2)2- groups as R1 and R2, respectively,
entries 9, 10, and 12, respectively) showed a similar potency to experienced “double retardation” to require 48 h for attainment
THF with respect to chemical yields of 7a. Further investiga- of an adequate level of conversion. Because of such substituent
tion clarified that toluene was the best solvent from the stand- sensitivity of R1, alkyl groups at this position completely inhib-
point of the material balance, and with taking efficiency into ited the reaction (Table 3, entries 8 and 9). Entry 10 described
consideration, we eventually decided that, as described in the result for the non-fluorinated substrate (E)-6j possessing a
Table 2, entry 18, 3 h reflux in toluene with 0.5 equiv of DBU CH3 group instead of a CF3 moiety, and its simple recovery was
were the conditions of choice.
observed. Exchange of the strongly electron-withdrawing CF3
group to CH3 led to complete loss of the good stabilizing factor
Because we have successfully determined the appropriate reac- of the developing carbanionic species. As a result, the alkoxide
tion conditions for the present intriguing isomerization, clarifi- was more energetically preferred and thus this proton shift be-
cation of its scope and limitation was carried out whose results came difficult.
Table 3: Transformation of allylic alcohols (E)-6 to the corresponding ketones 7.
Yielda (%)
Entry
R1
R2
Time (h)
7
(E)-6
1
2
Ph
Ph
4-MeOC6H4-
4-FC6H4-
Et
3
3
91 (a)
89 (b)
>99 (c)
78 (d)
93 (e)
76 (f)
91 (g)
– (h)
[–]
[–]
Ph
3
Ph
Ph
2
[–]
4
24
24
48
3
[3b]
[–]
5
Ph
Ph(CH2)2-
Ph(CH2)2-
Ph(CH2)2-
Ph
6
4-MeOC6H4-
4-BrC6H4-
Ph(CH2)2-
Et
[–]
7
[–]
8
24
24
3
[75]
[89]
[77]
9
Ph
– (i)
10c
Ph
Ph
– (j)
aIsolated yields were shown and in brackets were described the recovery of the starting materials (E)-6. bYield determined by 19F NMR. cThis sub-
strate (E)-6j contains a CH3 group instead of a CF3 moiety with CH3 and Ph located at the opposite positions.
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Beilstein J. Org. Chem. 2017, 13, 1507–1512.
For the purpose of obtaining mechanistic information on the ene by the conductor-like polarizable continuum model
present reaction, three representative optically active substrates (CPCM). This energy barrier is considered to qualitatively cor-
(R,E)-6 were selected and submitted to the identical conditions respond to the requirement of toluene reflux temperature
as above (Table 4). Furthermore, in the case of (R,E)-6a, condi- (110–111 °C) for promotion of the desired proton shift. The
tions in entries 6 (6 M NaOH aq in MeOH) and 19 (DABCO in cleaving C1···H and forming C3···H bond lengths in TS-8h were
toluene) in Table 2 were also tried for comparison (see entries 2 calculated to be 220.0 and 238.1 pm which were significantly
and 3, respectively). Like the case of the corresponding racemic elongated from the ones of the corresponding substrate (R,E)-6h
compounds, the DBU-mediated proton shift was realized in a and product (R)-7h of 109.5 and 109.3 pm, respectively
similar fashion to afford the ketones 7 in excellent isolated (Figure 1). The partial charge at C3 became more negative
yields and, moreover, accomplished a quite high degree of (–0.338, –0.110, and –0.299 for TS-8h, (R,E)-6h, and (R)-7h,
chirality transmission (CT) on the basis of the chiral HPLC respectively) and H more positive (0.528, 0.172 and 0.244). The
analysis (Table 4, entries 1, 4, and 5). Unanimous formation of DABCO molecule with activating the proton was found to be
(R)-stereoisomers at the 3 position of 7 from (R,E)-6 led to situated right behind the C2 atom with the C2···H distance of
confirmation that the proton attached to C1 was migrated to C3 201.6 pm. The N···H distance of 104.4 pm was found to be only
from its si face, thus from the same back side if (R,E)-6 2.4 pm longer than the same bond in protonated DABCO which
possessed its conformation as shown in Table 4. Although would be one of the major reasons why the weaker base Et3N
DABCO attained the same level of CT (Table 4, entry 3) albeit did not work for this reaction.
a slower reaction rate, this is not the case for the conditions of
6 M NaOH aq in MeOH and only 21% CT was observed. The Conclusion
latter result would be because of the competing occurrence of As shown above, our original isomerization of CF3-containing
intermolecular reprotonation by the solvent.
propargylic alcohols 1F to the corresponding α,β-unsaturated
ketones (E)-5 was successfully extended to the transformation
The present interesting proton shift reaction was also computa- of allylic alcohols (E)-6 to saturated ketones 7. Different from
tionally simulated [7] by employing (R,E)-6h with the substitu- the previously reported transition metal-catalyzed protocols by
tion pattern of R1 = Ph and R2 = Me as the model substrate. For Cahard [8,9,13] and Liu [10-12], our transformation nicely
simplicity, 1,4-diazabicyclo[2.2.2]octane (DABCO) was em- proceeded with such a convenient and tractable tertiary amine
ployed as the representative base rather than DBU. Successful as DBU, thus under metal-free conditions like the cases of the
location of the transition state TS-8h at the B3LYP/6- Ando [14] and Martín-Matute groups [15]. Moreover, this
311++G** level of theory led to clear analysis that TS-8h was intriguing proton shift was clarified to be applied for optically
27.10 kcal/mol higher in energy than the combination of the active allylic alcohols whose chirality was transmitted almost in
substrate (R,E)-6h and the reactant DABCO under vacuum. a perfect fashion. These results should stem from the acidic
This barrier became lowered to 24.71 kcal/mol after the single nature of the allylic proton which was successfully estimated
point calculation by consideration of the solvent effect of tolu- from our independent computation. Further utilization of this
Table 4: DBU-promoted proton shift of the chiral allylic alcohols (R,E)-6.
Entry
R3
eeSa,b (% ee)
Yield (%)
eePa,b (% ee)
CTc (%)
1
2d
3e
4
H
H
83
86
87
80
80
88 (a)
63 (a)
60 (a)
85 (b)
88 (c)
85
18
86
77
78
>99
21
H
99
MeO
F
96
5
98
aeeS and eeP are the enantiomeric excess values for (R,E)-6 and (R)-7, respectively. bDetermined by HPLC analysis using CHIRALPAK OD and AD
columns for substrates and products, respectively. cCT: Chirality transmission. d6 M NaOH aq (6 equiv) in MeOH was used instead of DBU and tolu-
ene, and the reaction was continued for 24 h (30% of (R,E)-6a was isolated). eDABCO was used instead of DBU and the reaction was continued for
24 h (42% of (R,E)-6a was detected by 19F NMR).
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Beilstein J. Org. Chem. 2017, 13, 1507–1512.
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Supporting Information
Supporting Information File 1
Experimental procedures, characterization data, copies of
1H and 13C NMR spectra, HPLC charts for optically active
compounds, and computational details.
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Full optimization of each species was carried out using the
B3LYP/6-311++G** level of theory, followed by the single point
calculation using the IEFPCM method for consideration of the solvent
effect by THF.
1512