Ruthenium-catalyzed one-pot tandem isomerization-transfer hydrogenation reactions of γ-trifluoromethylated allylic alcohols and β-trifluoromethylated enones

Article abstract of DOI:10.1002/adsc.201300119

The ruthenium-2-propanol combination was found to transform γ-trifluoromethylated allylic alcohols and β-trifluoromethylated enones into the corresponding saturated alcohols in excellent yields via a one-pot tandem process involving isomerization and transfer hydrogenation(s). High stereospecificity was demonstrated and evidence for two mechanistic pathways is provided. The method was applied to a rapid synthesis of trifluoromethylated citronellol. Copyright

Full text of DOI:10.1002/adsc.201300119

FULL PAPERS
DOI: 10.1002/adsc.201300119
Ruthenium-Catalyzed One-Pot Tandem Isomerization–Transfer
Hydrogenation Reactions of g-Trifluoromethylated Allylic
Alcohols and b-Trifluoromethylated Enones
Vincent Bizet,a Xavier Pannecoucke,a Jean-Luc Renaud,b,*
and Dominique Caharda,*
a
UMR 6014 CNRS COBRA, Universitꢀ et INSA de Rouen, 76821 Mont-Saint-Aignan, France
Fax : (+33)-2-3145-2959; phone (+33)-2-3552-2466; e-mail: dominique.cahard@univ-rouen.fr
Normandie Universitꢀ, Universitꢀ de Caen Basse Normandie, UMR 6507 CNRS, Laboratoire de Chimie Molꢀculaire et
b
Thioorganique, 14050 Caen, France
E-mail: jean-luc.renaud@ensicaen.fr
Received: February 6, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300119.
Abstract: The ruthenium–2-propanol combination was demonstrated and evidence for two mechanistic
was found to transform g-trifluoromethylated allylic pathways is provided. The method was applied to
alcohols and b-trifluoromethylated enones into the a rapid synthesis of trifluoromethylated citronellol.
corresponding saturated alcohols in excellent yields
via a one-pot tandem process involving isomerization Keywords: allylic compounds; enones; fluorine; iso-
and transfer hydrogenation(s). High stereospecificity merization; ruthenium
Introduction
and Mannich-type reactions,[5] transfer hydrogena-
[7]
tion,[6] C H activation, fluorination,[8] or sequential
ꢀ
The importance of fluorinated compounds in all fields reactions through organocatalyzed enamine formation
of society is firmly established.[1] A better understand- have been reported.[9] Tandem reactions minimize the
ing of the fluorine effects combined with a boom of overall cost of a synthetic sequence, a point that
interest for organofluorine chemistry has produced an makes this approach increasingly popular and led us
enormous amount of data on new fluorinated mole- to investigate the tandem ruthenium-catalyzed iso-
cules as well as novel, highly sophisticated synthetic merization-transfer hydrogenation of not only g-CF3
methods.[2] In addition, simple transformations of allylic alcohols but also b-CF3 enones (Scheme 1).
fluorinated substrates into attractive new motifs This method offers a synthetic opportunity to build
through catalytic process with minimal atom waste the motif g-CF3 alcohol. For this purpose, 2-propanol
are eagerly sought after. In this context, we recently was used as both the solvent and the hydrogen source
explored the ruthenium-catalyzed isomerization of thus avoiding the use of hydrogen gas that would be
fluorinated allylic alcohols.[3] Interestingly, a specific necessary in a classical hydrogenation.
fluorine effect was observed that permutes the rate-
determining step from insertion for non-fluorinated
allylic alcohols to b-elimination for fluorinated allylic
alcohols. As a consequence, enantiospecific isomeriza-
tions were successful whereas the enantioselective
version is not yet established.[3] This isomerization is
an efficient, selective, redox-economical,[4f] atom-eco-
nomical, one-step internal process for the isomeriza-
tion of C=C bond of allylic alcohols into saturated
carbonyl compounds.[4] An additional value of the iso-
merization is the potential to further bring chemical
diversity by trapping intermediates; indeed, one-pot
catalytic tandem reactions that include aldolization from g-CF3 allylic alcohols or b-CF3 enones.
Scheme 1. Tandem isomerization–transfer hydrogenation
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Ruthenium-Catalyzed One-Pot Tandem Isomerization–Transfer Hydrogenation Reactions
From g-CF3 allylic alcohols 1, an isomerization re- Results and Discussion
action (i) would lead to the intermediate ketones 3
that further react in a transfer hydrogenation of C=O Optimization studies were performed with enone 2a
bond (ii) to give saturated alcohols 4. The net trans- in order to screen the reaction parameters and to de-
formation being the conversion of allylic alcohols into termine the best conditions. Various ruthenium com-
saturated alcohols, which is equivalent to a selective plexes (see Table 1) were evaluated in the reaction of
hydrogenation of the C=C allylic bond (Scheme 1, enone 2a in 2-propanol at reflux in the presence of
1!3!4).
cesium carbonate as base. With the notable exception
2A(PPh3)3 that affords 4a in 98% isolated yield
Because allylic alcohols 1 are synthesized from of RuCl CTHUNGTRENNUNG
enones 2 by reduction, we surmised that a one-pot after 4 h of reaction, none of other catalysts provided
process starting from 2 would lead to saturated alco- more that 16% yield of the desired saturated alcohol
hols 4. Indeed, a transfer hydrogenation of C=O bond 4a within the same reaction time.
of enones 2 would give 1 that further react as they
The catalyst loading could be reduced to 1 mol%
would have when used as starting material (Scheme 1, but the reaction time increased up to 36 h. The nature
2!1!3!4). However, a second mechanistic path- of the base was next investigated as well as the ratio
way could also operate via hydride addition on the catalyst/base (Table 2). Clearly, a base is essential for
C=C bond of enones 2 (iii) to generate intermediate the reaction with a strong preference for Cs2CO3 that
enolate anions, which upon quenching with a protic allows a complete conversion within 4 h. The optimal
source (i-PrOH) produce saturated ketones 3. A con- amount was established at 10 mol% of Cs2CO3, i.e.,
secutive transfer hydrogenation of C=O bond of 3 a 1:2 ratio of RuCl2ACHTNUTRGNEN(UG PPh3)3/Cs2CO3. The use of lower
would provide 4 (Scheme 1, 2!3!4). The net trans- or higher quantities is detrimental to the conver-
formation being the conversion of b-CF3 enones into sion.[12] For similar reasons, the starting concentration
saturated g-CF3 alcohols, which is equivalent to of enone 2a (or allylic alcohol 1a) in i-PrOH was
a double reduction of C=O and C=C bonds of an a,b- fixed at 0.2M.
unsaturated system. Tandem processes starting from
Methanol and ethanol were also examined as hy-
non-fluorinated enones are efficiently catalyzed by iri- drogen sources. Although the reaction proceeded in
dium complexes,[10] but lead to incomplete conver- these alcoholic media, the conversion was only partial
sions or non-specific reactions when catalyzed by within a reasonable time while the reaction was com-
ruthenium complexes.[11] However, the tandem iso- plete in less than 4 h in 2-propanol. The optimized
merization-hydrogen transfer has never been studied conditions for transformations of 1a and 2a into 4a
with fluorinated substrates. New insights into the are: 5 mol% RuCl
2ACHTNUGTREN(NNUG PPh3)3 in i-PrOH (0.2M) at 828C
effect of the CF3 group in terms of reaction mecha- with 10 mol% Cs2CO3 (see the Supporting Informa-
nism and stereocontrol are presented.
tion for full details). The optimized results applied to
various allylic alcohols are compiled in Table 3 and
those for enones in Table 4.
For the transformation of allylic alcohol 1a into 4a,
we monitored the reaction by 19F NMR (Scheme 2).
Table 1. Screening of catalysts.
Catalyst
Yields determined by 19F NMR [%]
2a
1a
3a
4a
RuCl
N
0
0
36
0
1
0
85
86
82
19
39
0
7
0
6
0
2
3
2
100
0
0
0
0
6
6
2
2
[Ru
[Ru
U
E
57
100
93
100
0
1
5
54
6
E
G
A
G
T
N
G
T
C
RuCl
RuCl
R
17
35
N
N
16
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Table 2. Screening of bases [transformation of 2a into 4a
with the aid of 5 mol% RuCl2ACTHNUTRGNEN(UG PPh3)3].
from the isomerization step in the tandem process.
Secondary allylic alcohols 1a–l (Table 3, entries 1–12)
lead to saturated alcohols 4a–l in excellent yields
albeit with poor diastereoisomeric ratios (71:29 at the
best) indicating an almost complete lack of open
chain 1,3-stereocontrol. Fortunately, the diastereoiso-
mers are separable by silica gel column chromatogra-
phy, in most cases.
We observed for allylic alcohol 1j (Table 3,
entry 10) a debromination which may be the result of
an oxidative addition of a ruthenium(0) complex fol-
lowed by a reductive elimination in the protic media
to give alcohols 4j and 4a as an inseparable mixture.
Intriguingly, the allylic alcohol 1k that features a t-Bu
carbinol moiety (Table 3, entry 11) is slowly converted
into ketone 3k and not further processed into alcohol
4k (see later in the text for a similar observation from
enone 2k and interpretation). The substrate scope was
extended to primary allylic alcohols 1m and 1n
(Table 3, entries 13 and 14) that are efficiently trans-
formed into alcohols 4m and 4n in excellent yields.
The intermediate aldehydes 3m and 3n have never
been observed; they react very quickly with the hy-
dride source and thus are not subjected to undesired
aldol reactions. This result nicely complements our
Base
ACHTUNGTRENNUNG(mol%)
Time Yields determined by 19F NMR [%]
[h]
2a
1a
3a
4a
none
2
4
2
4
2
4
4
4
4
4
2
4
2
4
2
4
2
4
99
98
81
46
0
0
0
0
8
4
0
0
0
0
0
0
0
0
0
6
27
0
0
0
0
1
2
8
15
9
2
0
6
54
38
74
71
57
48
73
64
50
44
0
0
5
12
91
98
100
92
9
K2CO3 (10)
Cs2CO3 (5)
Cs2CO3 (10)
Cs2CO3 (20)
Cs2CO3 (50)
Cs2CO3 (100)
t-BuOK (10)
24
13
8
8
18
22
31
42
27
36
50
55
7
i-PrONa (10)
KOH (10)
12
10
0
0
0
NaOH (10)
0
0
The starting allylic alcohol 1a was completely convert- previous results on the isomerization of allylic alco-
ed within the first 20 minutes of the process into hols in toluene for which only secondary allylic alco-
ketone 3a, which reached a maximum concentration hols were successfully isomerized.[3] We now have
before being consumed to end up with the two diaste- a complete toolbox for both primary and secondary
reomeric saturated alcohols 4a. This study clearly in- CF3-allylic alcohols. Interestingly, alcohol 4n is a CF3
dicates that ketone 3a is the intermediate resulting analogue of citronellol, a fragrance with organoleptic
Table 3. Scope of tandem isomerization–transfer hydrogenation of g-CF3 allylic alcohols 1.
Entry
R1
R2
Time [h]
Products [%][a]
4
Yield [%][{b]
1
3
4 (dr)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
t-Bu
Bn
H
Ph
Me
Bn
p-MeOC6H4
p-CF3C6H4
Ph
4
0
0
0
0
0
0
0
0
0
0
70
0
5
0
0
0
0
0
0
0
0
0
100 (56:44)
94 (29:71)
100 (42:58)
100 (59:41)
100 (45:55)
100 (51:49)
95 (33:67)
100 (55:45)
100 (46:54)
43 (47:53)
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
98
90
91
99
92
90
95
91
95
42[c]
0
12
24
24
2
24
12
24
24
24
24
24
20
24
Bn
o-MeOC6H4
p-MeOC6H4
p-BrC6H4
Ph
H
Ph
9
0
10
11
12
13
14
10
30
0
0
0
100
95
100
82
90
99
H
(CH3)2C=CH
(CH2)2
[a]
Ratios were determined by 19F NMR using trifluorotoluene as internal standard.
Yield of isolated alcohols 4.
Product 4j was isolated as a mixture with debrominated compound 4a in a ratio 4j/4a=1:1.
[b]
[c]
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Ruthenium-Catalyzed One-Pot Tandem Isomerization–Transfer Hydrogenation Reactions
Table 4. Scope of tandem isomerization–transfer hydrogenation of b-CF3 enones 2.
Entry
R1
R2
Time [h]
Products [%][a]
4
Yield [%][b]
2
3
1
4 (dr)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Me
Bn
p-MeOC6H4
p-CF3C6H4
Ph
4
0
0
0
0
0
0
0
0
0
0
0
0
0
23
0
0
7
0
0
0
0
0
63
0
0
0
0
0
3
0
0
100 (56:44)
96 (25:75)
2 (50:50)
100 (59:41)
100 (46:54)
93 (55:45)
100 (32:68)
100 (53:47)
97 (51:49)
64 (58:42)
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
93
92
n.d.
93
93
92
90
94
12
24
24
2
24
12
24
24
24
24
Ph
Me
Me
Me
Me
Ph
Bn
o-MeOC6H4
p-MeOC6H4
p-BrC6H4
Ph
9
10
11
94
14
100
4j
4k
64[c]
n.d.
t-Bu
[a]
Ratios were determined by 19F NMR using trifluorotoluene as internal standard.
Yield of isolated alcohols 4.
Product 4j was isolated as a mixture with debrominated compound 4a in a ratio 4j/4a=4:1.
[b]
[c]
properties dissimilar to those of the natural prod- C=O bond of the corresponding b-CF3 enones 2a–k.
uct.[13]
In order to gain an additional reaction step, we decid-
The preparation of g-CF3 secondary allylic alcohols ed to investigate the tandem reaction conditions di-
1a–k required the chemoselective reduction of the rectly on these b-CF3 enones. Interestingly, the satu-
rated alcohols 4a–k (Table 4) were obtained in high
yields, while non-fluorinated enones under rutheni-
um-catalyzed conditions usually afford moderate
yields of saturated alcohols.[11] It is notable that the
reactivity of our trisubstituted substrates that never-
theless feature a highly electron-withdrawing and
bulky CF3 group is excellent. This fluorine-accelerated
tandem reaction originates from a facilitated insertion
step in the isomerization thanks to the presence of
the CF3 group. Enone 2c (Table 4, entry 3) was fully
converted but the reaction stopped at allylic alcohol
1c although 1c was independently fully converted
within 4 h (Table 3, entry 3). In the transformation of
2c, a side-product resulting from the isomerization of
the C=C bond to the benzylic position was observed.
Debromination of bromo-substituted aryl derivatives
took place here again, but to a lesser extent, (Table 4,
entry 10).
Surprisingly, enone 2k led only to ketone 3k after
4 h whereas neither alcohol 1k nor 4k was observed.
A similar reactivity was already mentioned for a t-Bu
substituted non-fluorinated enone but not with such
a good chemoselectivity.[11b] The t-Bu group decreases
the electrophilic character of the carbonyl function by
an inductive effect rendering it less easily reducible
and favouring the transfer hydrogenation to the C=C
bond. This is a rare case of a chemoselective reduc-
tion of a b-CF3 unsaturated system.[14] To gain mecha-
Scheme 2. Monitoring of the tandem reaction of allylic alco-
hol 1a.
nistic insights, we conducted deuterium-labelling ex-
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then gradually reduced into diastereomeric alcohols
4a. The fact that allylic alcohol 1a and ketone 3a are
formed simultaneously in the early stage of the reac-
tion is indicative of a concomitant transfer hydrogena-
tion on the C=O and C=C bond with similar kinetics.
The chemoselective C=C bond reduction of enone 2k
into ketone 3k also supports two mechanistic path-
ways for which the relative contribution depends on
the R1 and R2 substituents. These observations led us
to propose a dual mechanism involving a 1,2-transfer
hydrogenation of the C=O bond and a 1,4-transfer hy-
Scheme 3. Monitoring of the tandem reaction of enone E-
2a.
periments with i-PrOH-2-d1 in which we observed
a significant loss of deuterium due to H–D scrambling
on the ruthenium to form RuHDACHTNUGRTNEUNG
(PPh3)3 complex[15–16]
and a reduced reactivity caused by a kinetic isotopic
effect. 19F NMR monitoring of the reaction showed
37% of deuterium incorporation at C-1 for allylic al-
cohol 1a, a result in agreement with results observed
in the transfer hydrogenation of simple ketones,[16b]
4.4% of deuterium incorporation at C-3 for ketone 3a
and no incorporation of deuterium at C-2 or on the
oxygen atom because these two positions are readily
exchangeable in the basic media. Deuteration at C-3
originates either from isomerization of deuterated 1a
or from an addition–elimination mechanism on 2a
through coordination of the C=C bond to the metal
hydride, a mechanism compatible with pathway 2!
3!4 (Scheme 1).[4e] Next, we monitored by 19F NMR
the reaction with b-CF3 enone 2a (Scheme 3). In the
basic media, a slight E/Z isomerization of enone E-2a
was observed; however, allylic alcohol Z-1a was not
detected. Enone E-2a reacted quickly to form allylic
alcohol E-1a and ketone 3a that both reached a maxi-
mum concentration within the first 15 minutes of the
process. After that time, enone E-2a and allylic alco-
hol 1a have almost disappeared and ketone 3a
Figure 1. Proposed mechanism for each step of the tandem
became the main product (ca. 75%). Ketone 3a was process.
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Ruthenium-Catalyzed One-Pot Tandem Isomerization–Transfer Hydrogenation Reactions
drogenation of the C=C bond (Figure 1, top). In the C-3 is controlled because poor diastereoselection was
literature, mechanistic evidence is given for the for- observed in the transfer hydrogenation step
mation of a ruthenium dihydride species as the active (Scheme 4).[17] The reaction was voluntarily stopped
catalyst in the transfer hydrogenation of ketones cata- when 1a was fully reacted but before complete con-
lyzed by RuCl2ACHTUNGTRENNUNG(PPh3)3 (the pre-catalyst), via two con- version into 4a.
secutive substitution reactions of chlorine atoms by
isopropoxide, followed by a b-elimination.[15] Transfer
hydrogenation would take place through the Conclusions
Ru(H)2ACHTUNGTRENNUNG(PPh3)3 species followed by the formation of
a ruthenium(0) complex Ru
ACHTUNGTREN(NNUG PPh3)3 after reductive In summary, we have described tandem isomeriza-
elimination. This latter complex could be responsible tion-transfer hydrogenation(s) of g-CF3 allylic alco-
for the debromination of substrates 1j and 2j.
hols and b-CF3 enones that allows the synthesis of sa-
As described on the top of Figure 1, Ru(H)2AHCTUNGTERNGUN(N PPh3)3 turated alcohols in high yields. Apart from the fact
first reacts with enones through hydroruthenation of that these fluorinated substrates were not previously
either the C=C or the C=O bond and reductive elimi- investigated in such a tandem process, the main dis-
nation to liberate the saturated ketone 3 in the coveries are: (i) the high yield ruthenium-catalyzed
former case or the allylic alcohol 1 in the latter case transformation of enones thanks to a fluorine-acceler-
both accompanied by the ruthenium(0) species. A fur- ated isomerization and (ii) the dual mechanism.
ther hydride transfer reaction may then furnish the Indeed, mechanistic evidence is given to validate
saturated alcohol 4. Ruthenium(II) catalyst is regener- a dual mechanism starting from enones according
ated by oxidation of 2-propanol. In contrast to the either to a 1,2-transfer hydrogenation - isomerization
isomerization mechanism invoking oxygen coordina- – 1,2-transfer hydrogenation (2!1!3!4) or via
tion proposed for isomerization run in toluene,[3] the a 1,4- followed by a 1,2-transfer hydrogenation (2!
isomerization conducted in i-PrOH with the aid of 3!4). In addition, the reaction conditions allow for
Ru(H)2ACHTUNGTRENNUNG(PPh3)3 species occurs through an addition– an enantiospecific process with stereocontrol at C-3
elimination mechanism (Figure 1, bottom).[4d,e] Coor- albeit without diastereoselection at C-1.
dination of the ruthenium dihydride to the C=C bond
of the allylic alcohol followed by hydroruthenation
led to a first intermediate that further evolves by b-
elimination and prototropy to liberate the ketone
Experimental Section
with regeneration of the active ruthenium catalyst
Ru(H)2ACHTUNGTRENNUNG(PPh3)3. In light of our observations and litera-
General Information
1H (300 MHz), 13C (75.5 MHz) and 19F (282 MHz) NMR
spectra were recorded on Bruker AVANCE 300. Chemical
shifts in NMR spectra are reported in parts per million from
TMS or CFCl3 resonance as the internal standard. IR spec-
tra were recorded on a Perkin–Elmer IRFT 1650 spectrome-
ter. The conversion and ratio of the corresponding products
were determined by 19F NMR analysis adopting a,a,a-tri-
fluorotoluene as internal standard with a D1 value=5 s.
Unless otherwise noted, all reagents were purchased from
commercial sources and were used without further purifica-
tion. Some catalysts were generously provided by Johnson-
Matthey. Characterization data and general procedure for
the synthesis of allylic alcohols 1, enones 2, and ketone 3
were previously reported.[3]
ture precedents, we propose the mechanism depicted
in Figure 1.
Recently, we reported the ruthenium-mediated syn-
specific 1,3-hydrogen shift of enantioenriched allylic
alcohols in toluene as solvent.[3] We now demonstrate
that the tandem isomerization-transfer hydrogenation
in 2-propanol as solvent and source of hydride is also
a highly enantiospecific process with 97% es (es=
enantiospecificity=100ꢂee product/ee substrate). Two
stereogenic centres are formed but only the one at
General Procedure for the Tandem Redox
Isomerization–Transfer Hydrogenation of g-CF3
Allylic Alcohols (1) or b-CF3 Enones (2)
In a Schlenk tube under nitrogen, were added g-CF3 allylic
alcohol 1 or b-CF3 enone 2 (0.25 mmol) and cesium carbon-
ate (8.1 mg, 0.025 mmol) in 2-propanol (1.25 mL). Complex
RuCl2ACHTNUGTRENUNG(PPh3)3 (12 mg, 0.0125 mmol) was then added and the
Scheme 4. Tandem isomerization-transfer hydrogenation of
enantioenriched allylic alcohol 1a.
mixture was heated at 828C until 19F NMR shows full con-
version. After evaporation of solvent, the crude product was
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Vincent Bizet et al.
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purified by column chromatography on silica gel (petroleum
ether/ethyl acetate=50/1) to give each diastereoisomers of
the corresponding saturated alcohol 4.
(m, 1H), 3.84 (s, 3H), 4.32–4.35 (m, 1H), 6.93–6.97 (m, 2H),
7.26–7.37 (m, 7H); 13C NMR (CDCl3): d=38.1 (q, J=
1.8 Hz), 46.0 (q, J=26.9 Hz), 55.3, 70.5, 114.2, 125.6, 126.1
(q, J=2.0 Hz), 127.2 (q, J=279.6 Hz), 127.9, 128.7, 130.4,
144.2, 159.5; 19F NMR (CDCl3): d=ꢀ70.5 (d, J=9.6 Hz);
HR-MS: m/z=310.1185, calcd. for C17H17F3O2 (M+):
310.1181; IR (neat): n=3417, 2943, 1515, 1244, 1179, 1151,
1105, 1053, 1034 cmꢀ1.
4,4,4-Trifluoro-1,3-diphenylbutan-1-ol (4a): Diastereoiso-
1
mer 1: colourless oil; H NMR (CDCl3): d=1.73 (bs, 1H),
2.09 (ddd, 1H, J=14.2 Hz, J=11.7 Hz, J=2.5 Hz), 2.28
(ddd, 1H, J=14.2 Hz, J=10.9 Hz, J=3.4 Hz), 3.63–3.75 (m,
1H), 4.22 (bd, 1H, J=10.8 Hz), 7.15–7.34 (m, 10H);
13C NMR (CDCl3): d=38.3 (q, J=2.0 Hz), 47.0 (q, J=
26.9 Hz), 70.6, 125.7, 127.2 (q, J=279.6 Hz), 128.1, 128.5,
128.8, 129.0, 129.5, 134.4 (q, J=2.0 Hz), 144.3; 19F NMR
(CDCl3): d=ꢀ70.1 (d, J=9.6 Hz); HR-MS: m/z=280.1078,
calcd. for C16H15F3O (M+): 280.1075; IR (neat): n=3393,
3037, 1256, 1152, 1108, 1052, 753, 699 cmꢀ1.
1
Diastereoisomer 2: light yellow oil; H NMR (CDCl3): d=
1.86 (bs, 1H), 2.34–2.49 (m, 2H), 2.98–3.13 (m, 1H), 3.82 (s,
3H), 4.51 (t, 1H, J=7.3 Hz), 6.88–6.93 (m, 2H), 7.16–7.19
(m, 2H), 7.23–7.26 (m, 2H), 7.30–7.40 (m, 3H); 13C NMR
(CDCl3): d=37.9 (q, J=1.8 Hz), 46.0 (q, J=27.0 Hz), 55.4,
72.4, 114.3, 126.4, 127.0 (q, J=279.8 Hz), 128.5, 129.0, 130.3,
142.9, 159.6; 19F NMR (CDCl3): d=ꢀ70.7 (d, J=9.3 Hz);
HR-MS: m/z=310.1188, calcd. for C17H17F3O2 (M+):
310.1181; IR (neat): n=3387, 2921, 1515, 1246, 1177, 1148,
1106, 1033, 1021 cmꢀ1.
Diastereoisomer 2: colourless oil. 1H NMR (CDCl3) d=
1.85 (bs, 1H), 2.37–2.46 (m, 2H), 3.06–3.20 (m, 1H), 4.51
(bt, J=7 Hz, 1H), 7.22–7.38 (m, 10H); 13C NMR (CDCl3):
d=38.0, 46.8 (q, J=27.1 Hz), 72.3, 126.4, 126.9 (q, J=
280.1 Hz), 128.5, 128.6, 128.9, 129.0, 129.3, 134.7, 142.9;
19F NMR (CDCl3): d=ꢀ70.2 (d, J=9.3 Hz); HR-MS: m/z=
280.1083, calcd. for C16H15F3O (M+): 280.1075; IR (neat):
4,4,4-Trifluoro-1-phenyl-3-(4-(trifluoromethyl)phenyl)bu-
1
tan-1-ol (4e): Diastereoisomer 1: light yellow oil; H NMR
(CDCl3): d=1.81 (bs, 1H), 2.14–2.24 (m, 1H), 2.43 (ddd,
1H, J=14.2 Hz, J=10.9 Hz, J=3.4 Hz), 3.83–3.98 (m, 1H),
4.28 (d, 1H, J=10.9 Hz),7.26–7.39 (m, 5H), 7.53 (d, 2H, J=
8.1 Hz), 7.69 (d, 2H, J=8.2 Hz); 13C NMR (CDCl3): d=38.1
(q, J=1.8 Hz), 46.8 (q, J=27.4 Hz), 70.5, 124.1 (q, J=
272.9 Hz), 125.7, 125.9 (q, J=3.8 Hz), 126.8 (q, J=
279.2 Hz), 128.3, 128.7, 129.9, 130.8 (q, J=32.7 Hz), 138.4,
143.8; 19F NMR (CDCl3): d=ꢀ63.2 (s), ꢀ69.9 (d, J=
9.4 Hz); HR-MS: m/z=348.0957, calcd. for C17H14F6O (M+):
348.0949; IR (neat): n=3387, 2940, 1324, 1258, 1159, 1116,
1070, 1057, 1020, 835, 700 cmꢀ1.
n=3374, 2931, 1454, 1257, 1149, 1108, 1019, 748, 699 cmꢀ1
.
4,4,4-Trifluoro-3-methyl-1-phenylbutan-1-ol (4b): Diaste-
1
reoisomer 1: white solid; H NMR (CDCl3): d=1.20 (d, J=
6.9 Hz, 3H), 1.58–1.63 (m, 1H), 1.85 (bs, 1H), 2.14 (ddd,
1H, J=13.9 Hz, J=10.2 Hz, J=3.6 Hz), 2.49–2.60 (m, 1H),
4.77 (dt, J=3.6 Hz, J=10.2 Hz, 1H), 7.30–7.38 (m, 5H);
13C NMR (CDCl3): d=12.4 (q, J=3.0 Hz), 34.9 (q, J=
26.6 Hz), 38.7 (q, J=2.2 Hz), 71.1, 125.8, 128.2, 128.9 (q, J=
278.9 Hz), 128.9, 144.3; 19F NMR (CDCl3): d=ꢀ74.0 (d, J=
9.2 Hz); HR-MS; m/z=218.0924, calcd. for C11H13F3O (M+):
218.0918; IR (neat): n=3396, 2910, 1262, 1169, 1131, 1092,
1050, 1016, 907, 731, 700 cmꢀ1.
1
Diastereoisomer 2: light yellow oil; H NMR (CDCl3): d=
1.89 (bs, 1H), 2.37–2.52 (m, 2H), 3.23–3.37 (m, 1H), 4.55 (t,
1H, J=7.2 Hz), 7.22–7.26 (m, 2H), 7.33–7.40 (m, 5H), 7.63
(d, 2H, J=8.1 Hz); 13C NMR (CDCl3): d=37.9 (q, J=
1.5 Hz), 46.6 (q, J=27.2 Hz), 72.1, 124.0 (q, J=272.2 Hz),
125.9 (q, J=3.8 Hz), 126.3, 126.6 (q, J=279.8 Hz, CF3),
128.7 (CAr), 129.1 (CAr), 129.7 (CAr), 130.8 (q, J=32.6 Hz,
CAr), 138.9, 142.7; 19F NMR (CDCl3): d=ꢀ63.2 (s), ꢀ69.9
(d, J=9.2 Hz); HR-MS: m/z=348.0952, calcd. for
C17H14F6O (M+): 348.0949; IR (neat): n=3347, 2940, 1324,
1258, 1155, 1113, 1070, 1019, 835, 755, 737, 701 cmꢀ1.
5,5,5-Trifluoro-4-phenylpentan-2-ol (4f): Diastereoisomer
1: colourless oil; 1H NMR (CDCl3): d=1.19 (d, 2H, J=
6.2 Hz), 1.27 (bs, 1H), 1.90–2.05 (m, 2H), 3.40–3.50 (m,
1H), 3.61–3.75 (m, 1H), 7.31–7.39 (m, 5H); 13C NMR
(CDCl3): d=24.6, 38.0 (q, J=2.0 Hz), 46.8 (q, J=26.9 Hz),
64.3, 127.3 (q, J=279.4 Hz), 128.3, 128.9, 129.4, 134.6 (q, J=
1.9 Hz); 19F NMR (CDCl3): d=ꢀ70.2 (d, J=9.7 Hz); HR-
MS: m/z=218.0920, calcd. for C11H13F3O (M+): 218.0918; IR
(neat): n=3364, 2970, 1259, 1156, 1109, 1088, 1024,
702 cmꢀ1.
1
Diastereoisomer 2: colourless oil; H NMR (CDCl3): d=
1.16 (d, J=7.0 Hz, 3H), 1.74–1.89 (m, 1H), 1.88 (bs, 1H),
2.06 (dt, J=5.8 Hz, J=14.0 Hz, 1H), 2.26–2.36 (m, 1H),
4.79–4.84 (m, 1H), 7.28–7.40 (m, 5H); 13C NMR (CDCl3):
d=14.0 (q, J=3.3 Hz), 35.3 (q, J=26.5 Hz), 39.3 (q, J=
2.0 Hz), 72.7, 126.0, 128.3, 128.6 (q, J=279.3 Hz), 128.9,
143.8; 19F NMR (CDCl3): d=ꢀ73.5 (d, J=9.0 Hz); HR-MS:
m/z=218.0927, calcd. for C11H13F3O (M+): 218.0918; IR
(neat): n=3368, 2959, 1266, 1167, 1128, 1092, 1018, 756,
700 cmꢀ1.
3-Benzyl-4,4,4-trifluoro-1-phenylbutan-1-ol (4c): Two dia-
stereoisomers (A:B=1:1.4): light yellow oil; 1H NMR
(CDCl3): d=1.68–1.84 (m, 2H, H2A+B +OHA+B), 1.91–2.12
(m, 1H, H2’A+B), 2.48–2.76 (m, 2H, H4A+B +H3A+B), 3.01–
3.10 (m, 1H, H4’A+B), 4.37–4.42 (m, 1H, H1B), 4.61–4.65 (m,
1H, H1A), 7.03–7.32 (m, 10H, HArA+B); 13C NMR (CDCl3):
d=34.7 (q, J=2.9 Hz, C4B), 35.2 (q, J=3.1 Hz, C4A), 36.9 (q,
J=1.8 Hz, C2B), 37.4 (q, J=1.5 Hz, C2A), 41.3 (q, J=24.9 Hz,
C
3A), 41.5 (q, J=25.3 Hz, C3B), 71.9 (C1B), 72.0 (C1A), 125.9
(CAr), 126.0 (CAr), 126.8 (CAr), 126.9 (CAr), 128.1 (CAr), 128.3
(q, J=280.1 Hz, CF3B), 128.4 (q, J=280.4 Hz, CF3A), 128.7
(CAr), 129.3 (CAr), 129.4 (CAr), 138.0 (CAr), 143.5 (CAr), 144.0
(CAr); 19F NMR (CDCl3): d=ꢀ70.8 (d, J=8.1 Hz, A), ꢀ71.3
(d, J=8.9 Hz, B); HR-MS: m/z=294.1236, calcd. for
C17H17F3O (M+): 294.1231; IR (neat): n=3389, 3028, 1456,
1255, 1175, 1148, 1109, 1082, 734, 697 cmꢀ1.
1
Diastereoisomer 2: colourless crystals; mp 598C; H NMR
(CDCl3): d=1.19 (d, 2H, J=6.2 Hz), 1.34 (bs, 1H), 2.02–
2.18 (m, 2H), 3.37–3.52 (m, 1H), 3.75–3.85 (m, 1H), 7.30–
7.37 (m, 5H); 13C NMR (CDCl3): d=23.4, 38.8 (q, J=
1.7 Hz), 47.2 (q, J=26.8 Hz), 66.0, 127.1 (q, J=280.3 Hz),
128.4, 129.0, 129.1, 135.2 (q, J=2.0 Hz); 19F NMR (CDCl3):
d=ꢀ70.0 (d, J=9.3 Hz); HR-MS: m/z=218.0921, calcd. for
C11H13F3O (M+): 218.0918; IR (neat): n=3291, 2978, 1260,
1146, 1124, 1077, 1067, 756, 703 cmꢀ1.
5,5,5-Trifluoro-4-(4-methoxyphenyl)pentan-2-ol (4d): Dia-
1
stereoisomer 1: light yellow oil; H NMR (CDCl3): d=1.79
(bs, 1H), 2.09–2.18 (m, 1H), 2.28–2.40 (m, 1H), 3.67–3.81
1400
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1394 – 1402

Ruthenium-Catalyzed One-Pot Tandem Isomerization–Transfer Hydrogenation Reactions
4-Benzyl-5,5,5-trifluoropentan-2-ol (4g): Two diastereoiso-
mers (A:B=1:1.6): light yellow oil; H NMR (CDCl3): d=
1st diastereoisomer: 19F NMR (CDCl3): d=ꢀ70.2 (d, J=
1
9.2 Hz).
2nd diastereoisomer: 19F NMR (CDCl3): d=ꢀ70.3 (d, J=
1.00–1.04 (m, 4H,
H
1A+B +OHA+B), 1.33–1.49 (m, 1H,
3A+B), 1.59–1.74 (m, 1H, H3’A+B), 2.45–2.71 (m, 2H,
5A+B +H4A+B), 2.93–3.06 (m, 1H, H5’A+B), 3.52–3.62 (m,
10.3 Hz)
H
H
5,5,5-Trifluoro-1-phenylpentan-2-ol (4l): Colourless oil;
1H NMR (CDCl3): d=1.55 (d, 1H, J=3.9 Hz), 1.56–1.82 (m,
2H), 2.00–2.21 (m, 1H), 2.21–2.42 (m, 1H), 2.60 (dd, 1H,
J=13.5 Hz, J=8.5 Hz), 2.78 (dd, 1H, J=13.5 Hz, J=
4.2 Hz), 3.78 (m, 1H), 7.13–7.30 (m, 5H); 13C NMR
(CDCl3): d=29.1 (q, J=2.8 Hz), 30.4 (q, J=28.9 Hz), 44.3,
71.3, 127.0, 127.5 (q, J=275.9 Hz), 128.9, 129.5, 137.7;
19F NMR (CDCl3): d=ꢀ66.8 (t, J=11.0 Hz); HR-MS: m/z=
218.0918, calcd. for C11H13F3O (M+): 218.0918; IR (neat):
n=3342, 2914, 1308, 1260, 1129, 1110, 1086 cmꢀ1.
4,4,4-Trifluoro-3-phenylbutan-1-ol (4m): Colourless oil;
1H NMR (CDCl3): d=1.51 (bs, 1H), 1.94–2.03 (m, 1H),
2.13–2.23 (m, 1H), 3.25–3.33 (m, 1H), 3.50–3.59 (m, 1H),
3.40–3.55 (m, 1H), 7.23–7.30 (m, 5H); 13C NMR (CDCl3):
d=31.9 (d, J=2.0 Hz), 46.6 (q, J=26.8 Hz), 59.5, 127.4 (q,
J=279.6 Hz), 128.6, 129.1, 129.4, 134.6 (q, J=1.9 Hz);
19F NMR (CDCl3): d=ꢀ70.1 (d, J=9.5 Hz); HR-MS: m/z=
204.0766, calcd. for C10H11F3O (M+): 204.0762; IR (neat):
n=3339, 2963, 1257, 1151, 1108, 1041, 1029, 700 cmꢀ1.
1H, H2B), 3.72–3.82 (m, 1H, H2A), 7.12–7.27 (m, 5H,
ArA+B); 13C NMR (CDCl3): d=24.0 (C1B), 24.4 (C1A), 34.7
(q, J=2.8 Hz, C5B), 35.2 (q, J=3.2 Hz, C5A), 37.5–37.6 (m,
3A+B), 41.2 (q, J=24.9 Hz, C4A), 42.0 (q, J=25.2 Hz, C4B),
65.1 (C2B), 65.7 (C2A), 126.8 (CArA+B), 128.4 (q, J=279.9 Hz,
CF3B), 128.5 (q, J=280.5 Hz, CF3A), 128.7 (CAr), 129.2 (CAr),
129.3 (CAr), 138.1 (CArA), 138.5 (CArB); 19F NMR (CDCl3):
d=ꢀ70.9 (d, J=9.1 Hz, A), ꢀ71.5 (d, J=9.1 Hz, B); HR-
MS: m/z=232.1082, calcd. for C12H15F3O (M+): 232.1075; IR
(neat): n=3375, 2973, 1254, 1160, 1112, 1085, 1072, 742,
699 cmꢀ1.
H
C
5,5,5-Trifluoro-4-(2-methoxyphenyl)pentan-2-ol (4h): Dia-
1
stereoisomer 1: colourless oil; H NMR (CDCl3): d=1.07 (d,
3H, J=6.2 Hz), 1.76–1.99 (m, 2H), 2.04 (bs, 1H), 3.31–3.33
(m, 1H), 3.79 (s, 3H), 4.13–4.28 (m, 1H), 6.85–6.95 (m, 2H),
7.18–7.28 (m, 2H); 13C NMR (CDCl3): d=23.4, 37.6 (q, J=
27.6 Hz), 38.8 (q, J=1.5 Hz), 56.2, 64.5, 111.3, 121.6, 123.2
(q, J=1.8 Hz), 127.5 (q, J=279.6 Hz), 128.4, 129.3, 157.7;
19F NMR (CDCl3): d=ꢀ69.2 (d, J=9.9 Hz); HR-MS: m/z=
248.1026, calcd. for C12H15F3O2 (M+): 248.1024; IR (neat):
n=3384, 2966, 2933, 1603, 1496, 1465, 1441, 1245, 1155,
1124, 1099, 1085, 1026, 753 cmꢀ1.
7-Methyl-3-(trifluoromethyl)-6-octenol (4n): Colourless
1
oil; H NMR (CDCl3): d=1.13–1.31 (m, 1H), 1.38–1.50 (m,
1H), 1.61–1.73 (m, 8H), 1.82–1.93 (m, 1H), 2.04–2.09 (m,
1H), 2.17–2.29 (m, 1H), 3.72 (t, 2H, J=7 Hz), 5.04–5.09 (m,
1H); 13C NMR (CDCl3): d=17.8, 25.4, 25.8, 28.3 (q, J=
2 Hz), 31.1 (q, J=2 Hz), 38.8 (q, J=25 Hz), 60.2, 123.3,
128.8 (q, J=279 Hz), 134.3; 19F NMR (CDCl3): d=ꢀ70.8 (d,
J=10 Hz); HR-MS: m/z=210.1237, calcd. for C10H17F3O
(M+): 210.1231; IR (neat): n=3334, 3934, 1453, 1379, 1259,
1151, 1114, 1053, 1029 cmꢀ1.
1
Diastereoisomer 2: colourless oil; H NMR (CDCl3): d=
1.17 (d, 2H, J=6.5 Hz), 1.40 (bs, 1H), 3.68–3.79 (m, 1H),
3.85 (s, 3H), 4.08–4.25 (m, 1H), 6.87–7.00 (m, 2H), 7.26–
7.37 (m, 2H); 13C NMR (CDCl3): d=23.2, 37.7 (q, J=
26.7 Hz), 38.8 (q, J=1.7 Hz), 55.9, 66.2, 111.1, 121.1, 123.7
(q, J=2.0 Hz), 127.3 (q, J=279.9 Hz), 128.6, 129.3, 157.4;
19F NMR (CDCl3): d=ꢀ69.9 (d, J=9.6 Hz); HR-MS: m/z=
248.1030, calcd. for C12H15F3O2 (M+): 248.1024; IR (neat):
n=3347, 2969, 1603, 1496, 1465, 1441, 1246, 1156, 1121,
1071, 1027, 753 cmꢀ1.
Acknowledgements
This work is promoted by the interregional CRUNCh net-
work. V.B. thanks the Rꢀgion Haute-Normandie for a fellow-
ship. Johnson–Matthey is acknowledged for a generous loan
of catalysts and helpful discussions.
5,5,5-Trifluoro-4-(4-methoxyphenyl)pentan-2-ol (4i): Dia-
stereoisomer 1: light yellow oil; H NMR (CDCl3): d=1.19
1
(d, 2H, J=6.2 Hz), 1.23 (bs, 1H), 1.88–2.04 (m, 2H), 3.42–
3.52 (m, 1H), 3.54–3.69 (m, 1H), 3.81 (s, 3H), 6.88–6.92 (m,
2H), 7.22–7.25 (m, 2H); 13C NMR (CDCl3): d=24.6, 38.0
(q, J=2.0 Hz), 45.9 (q, J=26.9 Hz), 55.4, 64.3, 114.3, 126.4
(q, J=2.0 Hz), 127.4 (q, J=279.3 Hz), 130.4, 159.5;
19F NMR (CDCl3): d=ꢀ70.6 (d, J=9.7 Hz); HR-MS: m/z=
248.1031, calcd. for C12H15F3O2 (M+): 248.1024; IR (neat):
n=3372, 2973, 1515, 1245, 1180, 1155, 1105, 1084, 1026 cmꢀ1.
Diastereoisomer 2: white solid; mp 678C; 1H NMR
(CDCl3): d=1.18 (d, 2H, J=6.2 Hz), 1.34 (bs, 1H), 1.99–
2.15 (m, 2H), 3.20–3.45 (m, 1H), 3.74–3.84 (m, 1H), 3.80 (s,
1H), 6.87–6.91 (m, 2H), 7.22–7.25 (m, 2H); 13C NMR
(CDCl3): d=23.3, 38.7 (q, J=1.7 Hz), 46.4 (q, J=26.9 Hz),
55.4, 66.1, 114.3, 127.0 (q, J=2.2 Hz), 127.1 (q, J=279.7 Hz),
130.1, 159.6; 19F NMR (CDCl3): d=ꢀ70.5 (d, J=9.3 Hz);
HR-MS: m/z=248.1028, calcd. for C12H15F3O2 (M+):
248.1024; IR (neat): n=3282, 2966, 1516, 1245, 1181, 1151,
1113, 1067, 1024 cmꢀ1.
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Adv. Synth. Catal. 2013, 355, 1394 – 1402