One-Pot and Reducible-Functional-Group-Tolerant Synthesis of α-Aryl- and α-Heteroaryl-α-Trifluoromethyl Alcohols via Tandem Trifluoroacetylation and MPV Type Reduction

Article abstract of DOI:10.1002/ejoc.201901049

We have developed a new one-pot synthesis of α-aryl- and α-heteroaryl-α-trifluoromethyl alcohols carrying not only arenes with electron-withdrawing groups but also electron-deficient nitrogen-containing heteroarenes, which are of increasing interest becau

Full text of DOI:10.1002/ejoc.201901049

A Journal of
Accepted Article
Title: One-pot and Reducible Functional Group-Tolerated Synthesis of
α-Aryl- and α-Heteroaryl-α-Trifluoromethyl Alcohols via Tandem
Trifluoroacetylation and MPV Type Reduction
Authors: Kazumasa Funabiki, Ayaka Hayakawa, Ryunosuke Kani,
Toshiyasu Inuzuka, and Yashuhiro Kubota
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901049
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901049
Supported by

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
One-pot and Reducible Functional Group-Tolerated Synthesis of
-Aryl- and -Heteroaryl--Trifluoromethyl Alcohols via Tandem
Trifluoroacetylation and MPV Type Reduction
Kazumasa Funabiki,*[a] Ayaka Hayakawa,[a] Ryunosuke Kani,[a] Toshiyasu Inuzuka[b] and Yashuhiro
Kubota [a]
Abstract: We have developed a new one-pot synthesis of -aryl-
and -heteroaryl--trifluoromethyl alcohols carrying not only arenes
with electron-withdrawing groups but also electron-deficient nitrogen-
containing heteroarenes, which are of increasing interest because
these compounds are some of the most important units in current
fluorine-containing inhibitors or antagonists. This new method
includes three tandem reactions in a one-pot synthesis: (1) the in
situ generation of functionalized aromatic and electron-deficient
heteroaromatic Grignard reagents, (2) trifluoroacetylation of the
generated Grignard reagents with diphenylmethyl trifluoroacetate,
and (3) successive Meerwein-Ponndorf-Verley type reduction. It
offers several advantages, including no need for expensive transition
metals and gaseous trifluoromethylating reagents, toleration of not
only reducible functional groups on the aryl groups but also electron-
Figure 1. Recent inhibitors and antagonists carrying α-aryl-α-trifluoromethyl
alcohol units.
deficient nitrogen-containing heterocycles, easy scalability, and the
ability to suppress the formation of the bis-aldol product as a by-
product by changing the ester moiety of the trifluoroacetate from an
isopropyl to a diphenylmethyl group.
Electron-donating group-substituted aryl- and electron-rich
heteroaryl--trifluoromethyl alcohols can be synthesized by (1)
reduction of aryl or heteroaryl trifluoromethyl ketones, which can
be easily prepared by trifluoroacetylation of not only arenes
carrying electron-donating groups such as hydroxyl, alkoxy, and
dialkylamino groups but also electron-rich heteroarenes, such as
pyrrole and indole in the presence of a strong Lewis acid such
as AlCl3, CoCl3, or DMAP under a high reaction temperature
(Scheme 1(a)),[5] and (2) Friedel-Crafts reaction of electron-rich
arenes and heteroarenes with trifluoroacetaldehyde (Scheme
Introduction
Fluorine-containing organic molecules are important frameworks
in functional organic molecules, medicines and pesticides.[1]
Almost two decades ago, various synthetic methods for the
preparation of -alkyl--trifluoromethyl alcohols including an
asymmetric version were developed, and these compounds
have attracted attention as important skeletons for liquid crystal
molecules.[2] As shown in Figure 1, recently, there has been
increasing interest in α-aryl-α-trifluoromethyl alcohols, since
these compounds are some of the most important units in
fluorine-containing inhibitors[3] and antagonists,[4] such as LP-
533401, LX1606, and LX1032. Among them, LP-533401 is a
remarkable inhibitor of gut-derived serotonin (GDS) and has the
potential to become a new class of bone anabolic drugs for the
treatment of osteoporosis.
1(b)) [6]
.
(a) Previous Work 1: Reduction of trifluoromethyl ketones
EDG: Electron-donating group
OH
O
O
O
EDG
EDG
EDG
reducing
agents
CF3
CF3
F3C
O
CF3
or
or
or
O
OH
CF3
CF3
N
N
H
N
H
Therefore, it is important to develop more advanced, simple and
efficient syntheses of not only α-aryl-α-trifluoromethyl alcohols
carrying various substituents on the aryl group but also α-
heteroaryl-α-trifluoromethyl alcohols.
H
Electron-rich
heteroaromatic
(b) Previous Work 2: Friedel-Crafts reaction of CF3CHO
OH
CF3
OH
CF3
O
EDG
EDG
H
CF3
or
or
[a]
[b]
Prof. Dr. K. Funabiki,* A. Hayakawa, R. Kani, and Dr. Y. Kubota
Department of Chemistry and Biomolecular Science, Gifu University
1-1 Yanagido, Gifu, 501-1193 Japan
E-mail: funabiki@gifu-u.ac.jp
Dr. T. Inuzuka,
N
H
N
H
Division of Instrumental Analysis, Life Science Research Center,
Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Scheme 1. Reported examples of the synthesis of -electron-donating group-
substituted aryl- and electron-rich heteroaryl--trifluoromethyl alcohols
Supporting information for this article is available on the WWW under
xxxxxxxxxx.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
However, these methodologies are not suitable for the
preparation of -aryl--trifluoromethyl alcohols carrying electron-
withdrawing groups on the phenyl ring, such as ester, cyano,
and nitro groups or -electron-deficient heteroaryl groups, since
trifluoroacetylation of electron-withdrawing group-substituted
arenes or electron-deficient heteroarenes is quite difficult even
at a high reaction temperature and with the addition of Lewis
acids. Therefore, another route that involves trifluoromethylation
of the corresponding aldehydes using various nucleophilic
trifluoromethylating agents, such as Ruppert-Prakash reagent,[7a-
In this paper, we describe in detail a new one-pot synthesis of -
aryl- and -heteroaryl--trifluoromethyl alcohols carrying not
only arenes with electron-withdrawing groups but also electron-
deficient nitrogen-containing heteroarenes, which are of
increasing interest because these compounds are some of the
most important units in current fluorine-containing inhibitors or
antagonists. This new method includes three tandem reactions
in a one-pot synthesis: (1) the in situ generation of functionalized
aromatic and electron-deficient heteroaromatic Grignard
reagents from various commercially available functionalized
i]
iodotrifluoromethane,[7j,k] trifluoromethane,[7l] borazine,[7m] and
iodoarenes and iodoheteroarenes with a turbo Grignard reagent
other compounds,[7n,o] has been developed for this purpose, as
shown in Scheme 2.
(i-PrMgClꞏLiCl),
(2) trifluoroacetylation of the generated
[10-15]
Grignard reagents with diphenylmethyl trifluoroacetate, and (3)
successive Meerwein-Ponndorf-Verley type reduction, as shown
in Scheme 4.
Scheme 2. Reported examples of the synthesis of -electron-withdrawing
group-substituted aryl- and electron-deficient heteroaryl--trifluoromethyl
alcohols
Scheme 4. Present Work
This methodology offers several advantages, such as no need
for expensive transition metals and gaseous trifluoromethylating
reagents, toleration of not only reducible functional groups on
the aryl groups but also electron-deficient nitrogen-containing
heterocycles, easy scalability, and the ability to supress the
formation of the bis-aldol product as a by-product by changing
the ester moiety of the trifluoroacetic acid ester from an
isopropyl to a diphenylmethyl group.
As shown in Scheme 3, Yamazaki et al. reported an interesting
example for the preparation of -phenyl--trifluoromethyl alcohol,
based on the electron-withdrawing property of fluorine atoms, by
the tandem reaction of isopropyl trifluoroacetate with phenyl
magnesium bromide (PhMgBr) and Meerwein-Ponndorf-Verley
(MPV) type reduction of the in situ-generated trifluoromethyl
phenyl ketone with magnesium isopropoxide.[8],[9]
Results and Discussion
Scheme 3. Synthesis of -phenyl--trifluoromethyl alcohol by the reaction of
trifluoroacetic acid ester with PhMgBr and successive MPV type reduction
The reactions of an in situ-generated functionalized aromatic
Grignard
reagent,
(4-(ethoxycarbonyl)phenyl)magnesium
chloride, derived from ethyl 4-iodobenzoate (1a) and a turbo
Grignard reagent (i-PrMgClꞏLiCl), with isopropyl trifluoroacetate
(2a), and successive Meerwein-Ponndorf-Verley (MPV) type
reduction of the in situ-generated trifluoromethyl ketone 3a were
examined, as shown in Table 1.
Although this paper has been described in detail regarding the
effects of various fluoroalkyl groups compared with non-
fluorinated groups, only one example of the use of Grignard
reagents (PhMgBr) has been reported and there is no example
of the use of aromatic Grignard reagents carrying functional
groups or heteroaromatic Grignard reagents.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
Table 1. Reactions of isopropyl trifluoroacetate (2a) with aromatic Grignard
reagent derived from 1a and successive MPV type reduction of in situ-
generated trifluoromethyl ketone
Table 2. Screening of the reaction conditions for tandem trifluoroacetylation
and MPV type reduction using diphenylmethyl trifluoroacetate (2b)
As a result, ethyl 4-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (4a)
and bis-aldol product, diethyl 4,4'-(1,1,1,7,7,7-hexafluoro-2,6-
dihydroxy-4-oxoheptane-2,6-diyl)dibenzoate (5a), were obtained
in 34% and 19% 19F NMR yields, respectively. Bis-aldol product
5a could be produced by the reaction of in situ-generated
trifluoromethyl ketone 3a with acetone derived from isopropoxide.
The addition of toluene (5 ml) in the MPV type reduction step not
only increased -trifluoromethylated alcohol 4a to 42% yield but
also decreased bis-aldol adduct 5a (10%).
Under the optimized reaction conditions, other iodoarenes with
various substituents on the benzene ring including a naphthyl
group were used, as shown in Scheme 5.
To prevent the formation of the bis-aldol product 5a as a by-
product, the use of diphenyl trifluoroacetate (2b) in place of
isopropyl trifluoroacetate (2a) and screening of the reaction
conditions were examined, as shown in Table 2. When the
reaction of diphenylmethyl trifluoroacetate (2b) in place of
isopropyl trifluoroacetate (2a) was carried out under the same
reaction conditions, not only the alcohol 4a but also the
intermediate ketone 3a and its equivalents were produced in
38% and 26% 19F NMR yields, respectively (entry 1).
Prolongation of the reaction time from 1 h to overnight improved
the yield of alcohol 4a (56%) (entry 2). When the reaction
temperature was raised to 40 °C in the MPV type reduction step,
reduction proceeded more efficiently and the corresponding
alcohol 4a was obtained in a yield of 71% (entry 3). MPV type
reduction at reflux temperature reduced the yield (66%) of the
product 4a (entry 4). Even when the amount of diphenylmethyl
trifluoroacetate (2b) was reduced to 3 equiv., alcohol 4a was
obtained in a similar high 19F NMR and isolated yields (75%)
comparable to that with 4 equiv. (entry 5). The use of 1.5 equiv.
of diphenylmethyl trifluoroacetate (2b) at 40 °C gave a lower
yield (61%) of the alcohol 4a (entry 6).
Scheme 5. Reactions of diphenylmethyl trifluoroacetate (2b) with
functionalized aromatic Grignard reagents and successive MPV type reduction
of in situ-generated trifluoromethyl ketones
Thus, various iodoarenes 1 were treated with 1.05 equiv. of i-
PrMgClꞏLiCl in THF at -25 °C and 3 equiv. of diphenylmethyl
trifluoroacetate (2b), and the resultant mixtures were heated to
40 °C and stirred overnight. As a result, iodoarenes 1 with
electron-withdrawing groups, such as an ethoxycarbonyl group,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
O
Ph
Ph
a cyano group, a bromine atom, and a trifluoromethyl group at
the 3- or 4-position, also participated in the successive reaction
to give the corresponding alcohols 4a,b,c,e,f in 64-84% 19F
NMR yields and 47-76% isolated yields. A fuzed iodoarene
such as 1-iodonaphthalene (1d) also reacted smoothly with the
i-PrMgCl∙LiCl complex and diphenylmethyl trifluoroacetate (2b)
to give the corresponding ketone, followed by MPV type
reduction leading to the product 4d in moderate yield. The
isolated yields of some products were lower than the 19F NMR
yields because some of the products are volatile due to the
presence of a CF3 group.
OH
F3C
O
i-PrMgClꞏLiCl
(1.05 equiv.)
I
2b (3 equiv.)
H
CF3
Het
N
Het
N
H2O
0 °C, 5 min
then 40 °C, overnight
THF
THF, -25 °C, 0.5 h
4
1
OMe OH
CF3
O
OH
CF3
OH
OH
N
N
CF3
CF3
N
N
N
MeO
N
O
N
4h 58%a (49%)b
4i 63%a (61%)b
4j 70%a (19%)b
4kc 59%a (21%)b
a 19F NMR Yields. b Yields of isolated products. c After diphenylmethyl trifluoroacetate
(4 equiv.) was added, the reaction mixture was warmed to 0 °C, 5 min. Then, the
reaction mixture was stirred at 23 °C overnight.
Although the reaction of Grignard reagent carrying
a 4-
methoxyphenyl group as an electron-donating group with
diphenylmethyl trifluoroacetate (2b) also proceeded under the
same reaction conditions, the corresponding alcohol 4g and bis-
Grignard reagent adduct 6g were obtained in 22% and 31% 19F
NMR yields, respectively (Scheme 6). Optimization of the
reaction conditions, such as increasing the amount of the ester
2b and lowering the reaction temperature from 40 °C to 23 °C
resulted in the increase of the yield of the alcohol 4g (52% 19F
NMR yield and 42% isolated yield).
Scheme 7. Reactions of diphenylmethyl trifluoroacetate (2b) with nitrogen-
containing heteroaromatic Grignard reagents and successive MPV type
reduction of in situ-generated trifluoromethyl ketones
As shown in Scheme 8, other diphenylmethyl esters 2c,d
carrying a chlorodifluoromethyl and a pentafluoroethyl group
reacted with 4-bromophenylmagnesium chloride generated from
4-iodobromobenzene and i-PrMgClꞏLiCl, to give the
corresponding -chlorodifluoro and -pentafluoroethyl alcohols
7f,8f in 30-56% 19F NMR yields and 14-45% isolated yields.
Scheme 6. Reactions of diphenylmethyl trifluoroacetate (2b) with Grignard
reagent carrying a methoxy group and successive MPV type reduction of in
situ-generated trifluoromethyl ketone
Scheme 8. Reactions of diphenylmethyl chlorodifluoroacetate (2c) and
pentafluoropropionate (2d) with Grignard reagents and successive MPV type
reduction of the corresponding in situ-generated ketones
As shown in Scheme 7, the alcohols 4h,i,j carrying pyrimidine,
uracil and pyridine rings, which are electron-deficient nitrogen-
containing heterocycles, were also obtained in good yields (58-
70% 19F NMR yields and 19-61% isolated yields) through
tandem iodine-Mg exchange reaction of iodoheteroarenes,
addition of the generated Grignard reagents to ester 2b and
MPV type reduction of the generated trifluorometyl ketones in a
one-pot manner. In the case of Grignard reagent with an
electron-donating pyrazole ring, when the reaction was
performed at a lower temperature (23 °C), the corresponding
alcohol 4k was obtained in good yield (59% 19F NMR yield) but
low isolated yield (21%) due to its high volatility.
The yields of the products 7f,8f are lower than that (84%) of the
trifluoromethylated product 4f due to the greater steric hindrance
of the chlorodifluoromethyl and pentafluoroethyl groups than the
trifluoromethyl group.[16]
Finally, gram-scale synthesis was performed, as shown in
Scheme 9. The reaction proceeded even after scale-up to 10
mmol (2.9 g) to give the alcohol 4f in an isolated yield of 44%
(1.1 g).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
Diphenylmethanol (2.79 g, 15 mmol) and pyridine (3.48 g, 44.0 mmol)
were dissolved in dry toluene (20 ml). After trifluoroacetic anhydride
(3.83 g, 17.9 mmol) was added dropwise, the reaction mixture was
warmed to 50 °C and stirred for 2 h. The reaction mixture was then
cooled slowly to room temperature, water (20 ml) was added, and the
mixture was stirred for 1 h. After the mixture was treated with 10% HCl
aq, the aqueous phase was removed. The organic phase was then
washed with water (20 ml X 2) and brine (20 ml X 1), dried over
anhydrous Na2SO4, and concentrated under vacuum to give
diphenylmethyl trifluoroacetate (2b) (3.862 g, 92%).
Scheme 9. Gram-scale synthesis
Benzhydryl 2,2,2-trifluoroacetate (2b).[17] IR (KBr) 1782 (C=O) cm-1; 1H
NMR (CDCl3) 7.09 (s, 1H, CH), 7.37-7.49 (m, 10H, aryl H); 13C NMR
(CDCl3) 81.1 (s), 114.8 (q, J = 286.3 Hz), 127.2 (s), 128.90 (s), 128.94
(s), 138.0 (s), 156.7 (q, J = 42.4 Hz); 19F NMR (CDCl3) 74.8 (s, 3F).
Conclusions
We have developed a new one-pot synthesis of -aryl- and -
heteroaryl--trifluoromethyl alcohols carrying not only arenes
with the electron-withdrawing groups but also electron-deficient
nitrogen-containing heteroarenes, which are of increasing
interest because these compounds are some of the most
important units in current fluorine-containing inhibitors or
antagonists.
Benzhydryl 2-chloro-2,2-difluoroacetate (2c). Yield 82%; IR (KBr)
1778 (C=O) cm-1; HRMS (EI) found: m/z 296.0406 [M]+. Calcd for C15H11
35ClF2O2, 296.0416; 1H NMR (CDCl3) 6.97 (s, 1H, CH), 7.32-7.41 (m,
10H, aryl H); 13C NMR (CDCl3) 81.3 (s), 117.1 (t, J = 301.1 Hz), 127.2
(s), 128.86 (s), 128.92 (s), 138.1 (s), 158.4 (t, J = 34.8 Hz); 19F NMR
(CDCl3) 63.8 (s, 2F).
This new method includes three tandem reactions in a one-pot
synthesis: (1) in situ generation of functionalized aromatic and
electron-deficient heteroaromatic Grignard reagents from
various commercially available functionalized iodoarenes and
Benzhydryl 2,2,3,3,3-pentafluoropropanoate (2d). Yield 95%; IR (KBr)
1774 (C=O) cm-1; HRMS (EI) found: m/z 330.0661 [M]+. Calcd for C16H11
F5O2, 330.0679; 1H NMR (CDCl3) 7.02 (s, 1H, CH), 7.31-7.41 (m, 10H,
aryl H); 13C NMR (CDCl3)81.5 (s), 106.1 (tq, J = 263.3 Hz, 41.7 Hz),
117.9 (qt, J = 287.5 Hz, 68.1 Hz), 127.1 (s), 128.9 (s), 130.0 (s), 138.0 (s),
157.6 (t, J = 29.6 Hz); 19F NMR (CDCl3) 82.5 (s, 2F), 121.4 (s, 2F).
iodoheteroarenes with
a
turbo Grignard reagent, (2)
trifluoroacetylation of the generated Grignard reagents with
diphenylmethyl trifluoroacetate, and (3) successive Meerwein-
Ponndorf-Verley type reduction. This synthesis offers several
advantages, such as no need for expensive transition metals
and gaseous trifluoromethylating reagents, toleration of not only
reducible functional groups on the aryl groups but also electron-
deficient nitrogen-containing heterocycles, easy scalability, and
the ability to supress the formation of the bis-aldol product as a
by-product by changing the ester moiety of the trifluoroacetic
acid ester from an isopropyl to a diphenylmethyl group.
Typical Procedure for the Trifluoroacetylation of In situ-Generated
Functionalized Aromatic Grignard Reagents and Successive MPV
Reduction with Diphenylmethyl Trifluoroacetate (2b).
To a THF solution of i-PrMgCl∙LiCl (1.3 M) (1.05 mmol, 0.81 ml) was
added ethyl 4-iodobenzoate (1a) (0.283 g, 1 mmol) at 25 °C under an
argon atmosphere. After the reaction mixture was stirred at that
temperature for 30 min, diphenylmethyl trifluoroacetate (2b) (0.857 g, 3.1
mmol) was added. The resultant mixture was warmed to 0 °C and stirred
for 5 min. The reaction mixture was then stirred at 40 °C overnight. The
reaction mixture was quenched with NH4Cl aq solution (20 ml), extracted
with diethyl ether (30 ml X 3), dried over NaSO4, and concentrated under
vacuum to give a residue. After the yields were measured by 19F NMR
with benzotrifluoride, the residue was purified by chromatography
(dichloromethane) to give ethyl 4-(2,2,2-trifluoro-1-hydroxyethyl)benzoate
(4a) (0.187 g, 75%).
Experimental Section
Measurement.
1H NMR spectra were measured at 400 MHz in
deuterochloroform (CDCl3) or hexadeuteroacetone (CD3COCD3)
solutions with residual solvents as internal standards. 13C NMR spectra
were obtained at 100 MHz in CDCl3 or CD3COCD3 solution with residual
solvents as internal standards. 19F NMR spectra were recorded at 376
MHz or 372 MHz in CDCl3 or CD3COCD3 solutions with
trichlorofluoromethane (CFCl3) as an external standard.
Ethyl 4-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (4a). Yield 75%; Rf
0.23 (dichloromethane); mp = 74.3-74.9 ºC; IR (KBr) 1724 (C=O), 3414
(OH) cm-1; HRMS (ESI) found: m/z 249.0735 [M+H]+. Calcd for
C11H12F3O3, 249.0739; 1H NMR (CDCl3) 1.37 (t, J = 7.22 Hz, 3H,
OCH2CH3), 4.06 (d, J = 4.60 Hz, 1H, OH), 4.34 (q , J = 7.22 Hz, 2H,
OCH2CH3), 5.04-5.12 (m, 1H, CH), 7.53 (d , J = 8.30 Hz, 2H, aryl H),
8.00 (d , J = 8.30 Hz, 2H, aryl H); 13C NMR (CDCl3) 14.3 (s), 61.6 (s),
72.3 (q, J = 32.0 Hz), 124.2 (q, J = 283.1 Hz), 127.6 (s), 129.8 (s), 131.2
(s), 139.2 (s), 166.8 (s); 19F NMR (CDCl3) 78.0 (d, J = 6.8 Hz, 3F).
Materials.
purchased from Aldrich Co.
Turbo Grignard reagent (i-PrMgCl∙LiCl complex) was
Dehydrated THF and toluene were
purchased from Kanto Chemical Co. Pure products were isolated by
column chromatography using silica gel (Wakogel C-200, 100-200 mesh,
Wako Pure Chemical Ind., Ltd. or Silica gel 60, spherical, 40-50 m,
Kanto Chemical Co., Inc.). Analytical TLC was performed on Merck
precoated (0.25 mm) silica gel 60 F254 plates. All chemicals were of
reagent grade and, if necessary, were purified in the usual manner prior
to use. Benzhydryl 2,2,2-trifluoroacetate (2b)[17] was prepared according
Diethyl 4,4'-(1,1,1,7,7,7-hexafluoro-2,6-dihydroxy-4-oxoheptane-2,6-
diyl)dibenzoate (5a).[15] Rf 0.31 (hexane/ethyl acetate = 3/1); IR (KBr)
1717 (C=O), 3437 (OH) cm-1; HRMS (ESI+) found: m/z 573.1323. Calcd
for C25H24F6NaO7: [M+Na]+, 573.1324; Major isomer: 1H NMR (CDCl3)
1.38 (t, J = 7.18 Hz, 6H, OCH2CH3 X 2), 3.28 (d, J = 17.40 Hz, 2H,
CHAHB X 2), 3.47 (d, J = 17.40 Hz, 2H, CHAHB X 2), 4.37 (q, J = 7.18 Hz,
4H, OCH2CH3 X 2), 4.79 (s, 2H, OH X 2), 7.54 (d, J = 8.55 Hz, 4H, aryl
H) , 8.01 (d, J = 8.55 Hz, 4H, aryl H); 13C NMR (CDCl3) 14.3 (s), 47.2
(s), 61.5 (s), 76.0 (q, J = 29.5 Hz), 124.1 (q, J = 285.3 Hz), 126.34 (s),
129.77 (s), 131.19 (s), 141.2 (s), 166.15 (s), 208.3 (s); 19F NMR (CDCl3)
80.1 (s, 6F); Minor isomer: 1H NMR (CDCl3) 1.38 (t, J = 7.09 Hz, 6H,
to the literatures.
Alcohols 4b,c,d,e,f,g,j,k, 6g, 7f, and 8f are
commercially available from Aldrich Partner Products, Enamine Building
Blocks, SynQuest, 1Click Chemistry Stock Products, Aurora Building
Blocks, Fluorochem Product List, Boc Sciences, or UkrOrgSyntez Led.
Synthesis of Diphenylmethyl Trifluoroacetate (2b).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
OCH2CH3 X 2), 3.33 (d, J = 17.10 Hz, 2H, CHAHB X 2), 3.42 (d, J = 17.10
Hz, 2H, CHAHB X 2), 4.38 (q, J = 7.09 Hz, 4H, OCH2CH3 X 2), 4.83 (s, 2H,
OH X 2), 7.49 (d, J = 8.55 Hz, 4H, aryl H) , 7.98 (d, J = 8.55 Hz, 4H, aryl
H); 13C NMR (CDCl3) 14.3 (s), 47.1 (s), 61.5 (s), 76.0 (q, J = 29.5 Hz),
124.1 (q, J = 285.3 Hz), 126.27 (s), 129.80 (s), 131.17 (s), 141.3 (s),
166.22 (s), 208.7 (s); 19F NMR (CDCl3) 80.0 (s, 6F).
(s, 3H, OCH3), 4.00 (s, 3H, OCH3), 5.34-5.45 (m, 1H, OH), 6.04 (d, J =
5.90 Hz, 1H, CH), 8.47 (s, 1H, aryl H); 13C NMR ((CD3)2CO)54.6 (s),
55.2 (s), 65.2 (q, J = 32.9 Hz), 110.5 (s), 125.8 (q, J = 281.8 Hz), 159.1
(s), 166.5 (s), 169.3 (s); 19F NMR ((CD3)2CO) 79.2 (d, J = 5.9 Hz, 3F).
1,3-Dimethyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidine-2,4(1H,3H)-
dione (4i). Yield 61%; Rf 0.43 (hexane/ethyl acetate = 1/2); mp = 143.8-
144.8 ºC; IR (KBr) 1667 (C=C), 1724 (C=O), 3526 (OH) cm-1; HRMS
(ESI) found: m/z 261.0448 [M+Na]+. Calcd for C8H9F3N2O3Na, 261.0463;
1H NMR ((CD3)2CO) 3.25 (s, 3H, CH3), 3.48 (s, 3H, CH3), 5.16-5.24 (m,
1H, OH), 5.85 (d, J = 6.30 Hz, 1H, CH), 7.78 (s, 1H, aryl H); 13C NMR
((CD3)2CO) 27.9 (s), 37.3 (s), 65.9 (q, J = 32.6 Hz), 107.5 (s), 125.8 (q,
J = 281.9 Hz), 145.0 (s), 152.0 (s), 163.0 (s); 19F NMR ((CD3)2CO)
79.4 (d, J = 6.3 Hz, 3F).
Ethyl 3-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (4b). Yield 47%; Rf
0.33 (toluene/ethyl acetate = 20/1); IR (KBr) 1701 (C=O), 3449 (OH) cm-
1
;
1H NMR (CDCl3) 1.36 (t, J = 7.11 Hz, 3H, OCH2CH3), 4.10 (br s, 1H,
OH), 4.34 (q , J = 7.11 Hz, 2H, OCH2CH3), 5.08 (q, J = 6.73 Hz, 1H, CH) ,
7.44 (t , J = 7.68 Hz, 1H, aryl H), 7.68 (d , J = 7.68 Hz, 1H, aryl H), 8.01
(d , J = 7.68 Hz, 1H, aryl H), 8.11 (s, 1H, aryl H); 13C NMR (CDCl3) 14.2
(s), 61.6 (s), 72.3 (q, J = 31.9 Hz), 124.3 (q, J = 282.2 Hz), 128.8 (s),
130.55 (s), 130.61 (s), 132.1 (s), 135.0 (s), 166.8 (s); 19F NMR (CDCl3)
78.2 (d, J = 6.7 Hz, 3F).
2,2,2-Trifluoro-1-(pyridin-4-yl)ethan-1-ol (4j). Yield = 19%; Rf 0.23
(hexane/ethyl acetate = 2/1); IR (KBr) 3156 (OH) cm-1; 1H NMR (CDCl3)
5.09 (q, J = 6.60 Hz, 1H, CH), 6.47 (br s, 1H, OH), 7.54 (d, J = 4.55 Hz,
2H, aryl H), 8.55 (d, J = 4.55 Hz, 2H, aryl H); 13C NMR (CDCl3) 71.1 (q,
4-(2,2,2-Trifluoro-1-hydroxyethyl)benzonitrile (4c). Yield 67%; Rf 0.35
(hexane/ethyl acetate = 3/1); mp = 97.5-98.5 ºC; IR (KBr) 2234 (C≡N),
3379 (OH) cm-1; 1H NMR (CDCl3) 3.36 (br s, 1H, OH), 5.00-5.23 (m, 1H,
CH), 7.63 (d , J = 8.20 Hz, 2H, aryl H), 7.70 (d , J = 8.20 Hz, 2H, aryl H);
13C NMR (CDCl3) 71.9 (q, J = 32.3 Hz), 113.2 (s), 118.4 (s), 123.9 (q, J
= 282.4 Hz), 128.4 (s), 132.4 (s), 139.2 (s); 19F NMR (CDCl3) 78.1 (d,
J = 6.6 Hz, 3F).
J = 31.9 Hz), 122.7 (s), 124.1 (q, J = 284.8 Hz), 145.5 (s), 148.8 (s); 19
NMR (CDCl3) 77.7 (s, d, J = 6.6 Hz, 3F).
F
2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethan-1-ol (4k). Yield 21%;
Rf 0.34 (hexane/ethyl acetate = 1/1); IR (KBr) 1724 (C=N), 3603 (OH)
cm-1; 1H NMR (CDCl3)  3.86 (s, 3H, CH3), 5.00 (q, J = 6.73 Hz, 1H, CH),
7.466 (s, 1H, aryl H) , 7.471 (s, 1H, aryl H), Signal derived from OH were
not able to be assigned; 13C NMR (CDCl3) 39.1 (s), 66.0 (q, J = 33.6
Hz), 116.1 (s), 124.6 (q, J = 281.8 Hz), 129.7 (s), 138.3 (s); 19F NMR
(CDCl3) 79.1 (d, J = 6.7 Hz, 3F).
2,2,2-Trifluoro-1-(naphthalen-1-yl)ethan-1-ol (4d). Yield = 36%; Rf 0.25
(hexane/dichloromethane = 1/1); IR (KBr) 3368 (OH) cm-1, 1H NMR
(CDCl3) 3.04 (d, J = 4.50 Hz, 1H, OH), 5.76-5.92 (m, 1H, CH), 7.45-
7.63 (m, 3H, aryl H), 7.83 (d, J = 7.20 Hz, 1H, aryl H), 7.87-7.97 (m, 2H,
aryl H), 8.03 (d, J = 8.00 Hz, 1H, aryl H); 13C NMR (CDCl3) 69.0 (q, J =
32.3 Hz), 122.9 (s) , 124.8 (q, J = 281.9 Hz), 125.3 (s), 125.9 (s), 126.0
(s), 126.9 (s), 129.1 (s), 130.0 (s), 130.3 (s), 131.2 (s), 133.8 (s); 19F
NMR (CDCl3) 76.7 (d, J = 6.6 Hz,, 3F).
1-(4-Bromophenyl)-2-chloro-2,2-difluoroethan-1-ol (7f). Yield 45%; Rf
0.20 (hexane/dichloromethane = 1/1); IR (KBr) 3414 (OH) cm-1; 1H NMR
(CDCl3) 2.91 (d, J = 3.57 Hz, 1H, OH), 4.99-5.06 (m, 1H, CH), 7.36 (d,
J = 8.07 Hz, 2H, aryl H), 7.54 (d, J = 8.50 Hz, 2H, aryl H); 13C NMR
(CDCl3) 76.8 (t, J = 27.7 Hz), 123.9 (s), 128.7 (t, J = 296.9 Hz), 129.6
(s), 131.7 (s), 133.2 (s); 19F NMR (CDCl3)  63.0 (dd, J = 165.8 Hz, 7.1
Hz, F), 64.9 (dd, J = 165.8 Hz, 8.5 Hz, F).
2,2,2-Trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-ol (4e).
Yield
49%; Rf 0.30 (hexane/acetone = 6/1); IR (KBr) 3418 (OH) cm-1; 1H NMR
(CDCl3) 3.09 (d, J = 4.50 Hz,1H, OH), 5.02-5.16 (m, 1H, CH), 7.61 (d, J
= 8.30 Hz, 2H, aryl H), 7.68 (d, J = 8.30 Hz, 2H, aryl H); 13C NMR
(CDCl3) 72.3 (q, J = 32.2 Hz), 124.0 (q, J = 273.4 Hz), 124.1 (q, J =
280.9 Hz), 125.7 (q, J = 3.8 Hz), 131.9 (q, J = 32.6 Hz), 137.8 (s); 19F
NMR (CDCl3) 78.3 (d , J = 6.7 Hz, 3F), 62.8 (s, 3F).
1-(4-Bromophenyl)-2,2,3,3,3-pentafluoropropan-1-ol (8f). Yield 14%;
Rf 0.28 (hexane/dichloromethane = 1/1); IR (KBr) 3406 (OH) cm-1; 1H
NMR (CDCl3) 2.61 (d, J = 4.94 Hz, 1H, OH), 5.08-5.12 (m, 1H, CH),
7.34 (d, J = 8.07 Hz, 2H, aryl H), 7.56 (d, J = 8.50 Hz, 2H, aryl H); 13C
NMR (CDCl3) 71.6 (dd, J = 27.7 Hz, 23.0 Hz), 112.9 (ddq, J = 261.6 Hz,
255.5 Hz, 35.5 Hz), 119.1 (qt, J = 287.5 Hz, 70.9 Hz), 124.1 (s), 129.6 (s),
132.0 (s), 132.9 (s); 19F NMR (CDCl3) 81.0 (s, 3F), 121.7 (dd, J =
276.1 Hz, 7.6 Hz, F), 129.1 (dd, J = 276.1 Hz, 16.2 Hz, F).
1-(4-Bromophenyl)-2,2,2-trifluoroethan-1-ol (4f). Yield 76%; Rf 0.28
(hexane/diethyl ether = 9/1); IR (KBr) 3375 (OH) cm-1; 1H NMR (CDCl3)
3.10 (br s, 1H, OH), 4.97 (q, J = 6.30 Hz, 1H, CH), 7.34 (d, J = 8.55 Hz,
2H, aryl H), 7.54 (d, J = 8.55 Hz, 2H, aryl H); 13C NMR (CDCl3)72.3 (q,
J = 31.9 Hz), 123.9 (s), 124.1 (q, J = 282.2 Hz), 129.2 (s), 131.9 (s),
132.9 (s); 19F NMR (CDCl3) 78.4 (d , J = 6.3 Hz, 3F).
Acknowledgements
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethan-1-ol (4g). Yield 15%; Rf 0.40
(hexane/diethyl ether = 2 /1); IR (KBr) 3426 (OH) cm-1; 1H NMR (CDCl3)
2.74 (d, J = 4.00 Hz, 1H, OH), 3.82 (s, 3H, OMe), 4.89-5.03 (m, 1H,
CH), 6.93 (d, J = 8.55 Hz, 2H, aryl H), 7.39 (d, J = 8.55 Hz, 2H, aryl H);
13C NMR (CDCl3)  55.4 (s), 72.5 (q, J = 32.2 Hz), 114.1 (s), 124.4 (q, J =
281.9 Hz), 126.3 (s), 128.9 (s), 160.5 (s); 19F NMR (CDCl3) 78.4 (d, J
= 7.6 Hz, 3F).
We thank Mr. Sawada for measuring HRMS of the products. .
Conflict of interest
The authors declare no conflict of interest.
2,2,2-trifluoro-1,1-bis(4-methoxyphenyl)ethan-1-ol (6g). Yield 29%; Rf
0.18 (hexane/dichloromethane = 1/2); IR (KBr) 3445 (OH) cm-1; 1H NMR
(CDCl3) 3.10 (br s, 1H, OH), 3.80 (s, 6H, OMe), 6.87 (d, J = 9.00 Hz,
4H, aryl H), 7.41 (d, J = 9.00 Hz, 4H, aryl H); 13C NMR (CDCl3) 55.3 (s),
79.0 (q, J = 29.1 Hz), 113.6 (s), 125.6 (q, J = 286.6 Hz), 128.9 (s), 131.9
(s), 159.6 (s); 19F NMR (CDCl3) 74.5 (s, 3F).
Keywords: trifluoromethyl • alcohols• turbo Grignard reagent •
Meerwein-Ponndorf-Verley type reduction • nitrogen-containing
heterocycles
[1]
For recent reviews, see. (a) V. Gouverneur, K. Seppelt, Eds, Chem.
Rev. 2015, 115, 566-1306. (b) E. P. Gillis, K. J. Eastman, M. D. Hill, D.
J. Donnelly, N. A. Meanwell, J. Med. Chem. 2015 58, 218315-218359.
(c) V. Gouverneur and K. Müller, Eds., Fluorine in Pharmaceutical and
1-(2,4-Dimethoxypyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol (4h). Yield
49%; Rf 0.35 (hexane/ethyl acetate = 3 /1); mp = 142.0-142.6 ºC; IR
(KBr) 1721 (C=N), 3503 (OH) cm-1; HRMS (ESI) found: m/z 261.0464
[M+Na]+. Calcd for C8H9F3N2O3Na, 261.0463; 1H NMR ((CD3)2CO)  3.96
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
Medicinal Chemistry: From Biophysical Aspects to Clinial Applications,
2012, Word Scientific Publishing Co. Pte. Ltd. (d) R. Berger, G.
Resnati, P. Metrangolo, E. Weberd and J. Hulliger, Chem. Soc. Rev.
2011, 40, 3496-3508.
(m) J. B. Geri, M. M. W. Wade, N. K. Szymczak, Angew. Chem. Int. Ed.
2018, 57, 1381-1385. With benzimidazolium salts: (n) K. Kawazoe, K.
Yoshioka, PCT Int. Appl. 2015199109. With CF3S(O)NR1R2, see: (o) D.
Inschauspe, J. -B. Sortais, T. Billard, B. R. Langlois, Synlett 2003, 233-
235.
[2]
[3]
For examples, see. (a) Y. Takanishi, H. Takezoe,; Y. Suzuki, I.
Kobayashi, T. Yajima, M. Terada, K. Mikami, Angew. Chem. Int. Ed.
1999, 38, 2354-2356. (b) K. Mikami, T. Yajima, M. Terada, Y. Suzuki, I.
Kobayashi, Chem. Commun. 1997, 57-58
[8]
[9]
T. Yamazaki, T. Terajima, T. Kawasaki, Tetrahedron 2008, 64, 2419-
2424.
For Meerwein-Ponndorf-Verley (MPV) type reduction including
asymmetric version of trifluoromethyl ketones, see. (a) H. Huang, H.
Zong, G. Bian, L. Song, J. Org. Chem. 2015, 80, 12614–12619. (b) K.
Funabiki, H. Iwata, Y. Yano, Y. Kubota, M. Matsui, Org. Chem. Front.
2015, 2, 369-371. (c) M. Calvillo-Barahona, C. Cordovilla, M. N. Genov,
J. M. Martinez-Ilarduya, P. Espinet, Dalton Trans. 2013, 42, 14576-
14582. (d) K. Mikami, T. Murase, Y. Itoh, J. Am. Chem. Soc. 2007, 129,
11686-11687. (e) Y. S. Sokeirik, K. Sato, M. Omote, A. Ando, I.
Kumadaki, Tetrahedron Lett. 2006, 47, 2821-2824. (f) Y. S. Sokeirik, K.
Sato, A. Ando, I. Kumadaki, J. Fluorine Chem. 2006, 127, 150-152. (g)
S. Sasaki, T. Yamauchi, H. Kubo, M. Kanai, A. Ishii, K. Higashiyama,
Tetrahedron Lett. 2005, 46, 1497-1500. (h) K. H. Yong, J. M. Chong,
Org. Lett. 2002, 4, 4139-4142. (i) S. A. Lermontov, S. V. Shkavrov, N. V.
Kuryleva, J. Fluorine Chem. 2003, 121, 223-225. (j) D. Nasipuri, P. K.
Bhattacharya, J. Chem. Soc., Perkin Trans. 1 1977, 576-578. (k) J. D.
Morrison, R. W. Ridgway, J. Org. Chem. 1974, 39, 3107-3110.
(a) K. A. Lyseng-Williamson, Drugs 2018, 78, 941-950. (b) D. Pawlak, B.
Znorko, B. Kalaska, T. Domaniewski, R. Zawadzki, P. Lipowicz, M.
Doroszko, U, Łebkowska, P. Grabowski, K. Pawlak, Bone 2018, 113,
124-136. (c) G. M. G. Lima B. J. M. Corazza R. M. Moraes F. E. de
Oliveira L. D. de Oliveira G. C. N. Franco D. S. Perrien F. Elefteriou
A. L. Anbinder, J. Periodontal Res. 2016, 51, 661-668. (d) D. R.
Goldberg, S. De Lombaert, R. Aiello, P. Bourassa, N. Barucci, Q.
Zhang, V. Paralkar, J. Valentine, W. Zavadoski, Bioorg. Med. Chem.
Lett. 2016, 26, 1124-1129. (e) C. -M. Oh, J. Namkung, Y. Go, K. E.
Shong, K. Kim, H. Kim, B. -Y. Park, H. W. Lee, Y. H. Jeon, J. Song, M.
Shong, V. K. Yadav, G. Karsenty, S. Kajimura, I. -K. Lee, S. Park, H.
Kim, Nat. Commun. 2015, 6, 6794. (f) J. J. Kim, H. Wang, J. D. Terc, B.
Zambrowicz, Q. M. Yang, W. I. Khan, Am. J. Physiol. 2015, 309, G455–
G465. (g) V. Yadav, S. Balaji, P. S. Suresh, X. S. Liu, X. Lu, Z. Li, X. E.
Guo, J. J. Mann, Anil. K. Balapure, M. D. Gershon, R. Medhamurthy, M.
Vidal, G. Karsenty, P. Ducy, Nat. Med. 2010, 16, 308-312. (h) K. G.
Margolis, K. Stevanovic, Z. Li, Q. M. Yang, T. Oravecz, B. Zambrowicz,
K. G. Jhaver, A. Diacou, M. D. Gershon, Gut 2014, 63, 928-937.
J. Y. Gauthier, M. Belley, D. Deschenes, J. -F. Fournier, S. Gagne, Y.
Gareau, M. Hamel, M. Henault, H. Hyjazie, S. Kargman, G. Lavallee, J.
-F. Levesque, L. Li, Y. Mamane, J. Mancini, N. Morin, E. Mulrooney, J.
Robichaud, M. Therien, G. Tranmer, Z. Wang, J. Wu, W. C. Black,
Bioorg. Med. Chem. Lett. 2011, 21, 2836-2839.
[10] For recent reviews of turbo Grignard reagent, see. (a) P. Knochel, W.
Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sapountzis,
V. A. Vu, Angew. Chem. Int. Ed. 2003, 42, 4302-4320. (b) R. L. -Y. Bao,
R. Zhao, L. Shi, Chem. Commun. 2015, 51, 9744-9744.
[4]
[5]
[11] For fluorination, see. (a) S. Yamada, A. Gavryushin, P. Knochel, Angew.
Chem. Int. Ed. 2010, 49, 2215-2218. (b) P. Anbarasan, H. Neumann,
M. Beller, Angew. Chem. Int. Ed. 2010, 49, 2219-2222.
[12] For fluoroalkylation, see. M. Shiosaki, M. Inoue, Tetrahedron Lett.
2014, 55, 6839-6843.
(a) J. Margalef, T. Slagbrand, F. Tinnis, H. Adolfsson, M. Dieguez, O.
Pamies, Adv. Synth. Catal. 2016, 358, 4006-4018. (b) Y. Harauchi, C.
Takakura, T. Furumoto, R. C. Yanagita, Y. Kawanami, Tetrahedron:
Asymmetry 2015, 26, 333-337. (c) D. V. Yarmoliuk, V. V. Arkhipov, M.
V. Stambirskyi, Y. V. Dmytriv, O. V. Shishkin, A. A. Tolmachev and P. K.
Mykhailiuk, Synthesis 2014, 46, 1254-1260. (d) L. Mitchell, P.
Williamson, B. Ehrlichova, A. E. Anderson, V. R. Seymour, S. E.
Ashbrook, N. Acerbi, L. M. Daniels, R. I. Walton, M. L. Clarke, P. A.
Wright, Chem. Eur. J. 2014, 20, 17185-17197. (e) B. Raimer and T.
Lindel, Chem. Eur. J. 2013, 19, 6551-6555. (f) S. S. Ribeiro, C.
Raminelli and A. L. M. Porto, J. Fluorine Chem. 2013, 154, 53-59. (g) H.
Zhao, B. Qin, X. Liu and X. Feng, Tetrahedron 2007, 63, 12731-12734.
(h) A. D. Allen, R. Girdhar, M. P. Jansen, J. D. Mayo and T. T. Tidwell,
J. Org. Chem. 1986, 51, 1324-1331.
[13] For trifluoromethylthiolation, see. F. Baert, J. Colomb, T. Billard, Angew.
Chem. Int. Ed. 2012, 51, 10382-10385.
[14] For other example with trifluoromethyl phenyl ketone, see. J. T. Kuethe,
K. M. Maloney, Tetrahedron 2013, 69, 5248-5258.
[15] For trifluoroacetylation, see. K. Funabiki, A. Hayakawa, T. Inuzuka, Org.
Biomol. Chem. 2018, 18, 913-918.
[16] K. W. Tafts Jr, Steric Effects in Organic Chemistry, Newman, M. S.; Ed,
John Wiley & Suns, New York, 1956, p. 556.
[17] B. Denegri, O. Kronja, J. Org. Chem. 2009, 74, 5927-5933.
[6]
[7]
(a) L. Mitchell, P. Williamson, B. Ehrlichova, A. E. Anderson, V. R.
Seymour, S. E. Ashbrook, N. Acerbi, L. M. Daniels, R. I. Walton, M. L.
Clarke, P. A. Wright, Chem. Eur. J. 2014, 20, 17185-17197. (b) S. M.
Landge, D. A. Borkin, B. Török, Tetrahedron Lett. 2007, 48, 6372-6376.
(c) Y. Gong, K. Kato, H. Kimoto, Bull. Chem. Soc. Jpn. 2000, 73, 249-
250. (d) A. Ishii, A. V. Soloshonok, K. Mikami, J. Org. Chem. 2000, 65,
1597-1600.
With TMSCF3: (a) D. X. Ngo, W. W. Kramer, B. J. McNicholas, H. B.
Gray, B. J. Brennan, Inorg. Chem. 2019, 58, 737–746. (b) K. Mishra, K.
C. Bharadwaj, R. M. Singh, Tetrahedron Lett. 2018, 59, 3439-3442. (c)
V. A. Pistritto, J. M. Paolillo, K. A. Bisset, N. E. Leadbeater, Org. Biomol.
Chem. 2018, 16, 4715-4719; (d) S. Okusu, K. Hirano, Y. Yasuda, E.
Tokunaga, N. Shibata, RSC Adv. 2016, 86, 82716-82720. (e) J. Sun, X.
Peng, H. Guo, Tetrahedron Lett. 2015, 56, 797-800. (f) H. Cheng, Y.
Pei, F. Leng, J. Li, A. Liang, D. Zou, Y. Wu, Y. Wu, Tetrahedron Lett.
2013, 54, 4483-4486. (g) C. B. Kelly, M. A. Mercadante, T. A. Hamlin,
M. H. Fletcher, N. E. Leadbeater, J. Org. Chem. 2012, 77, 8131-8141.
(h) M. Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley, Tetrahedron
2009, 65, 6611-6625. (i) J. J. Song, Z. Tan, J. T. Reeves, F. Gallou, N.
K. Yee, C. H. Senanayake, Org. Lett. 2005, 7, 2193-2193. With CF3I: (j)
S. Aït-Mohand, N. Takechi, M. Médebielle, W. R. Dolbier, Jr., Org. Lett.
2001, 3, 4271-4273. (k) K. Aikawa, W. Toya, Y. Nakamura, K. Mikami,
Org. Lett. 2015, 17, 4996-4999. With HCF3: (l) B. Musio, E. Gala, S. V.
Ley, ACS Sustainable Chem. Eng. 2018, 6, 1489–1495. With borazine:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901049
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
K. Funabiki,* A. Hayakawa, R. Kani, T.
Inuzuka, and Y. Kubota
Page No. – Page No.
One-pot and Reducible Functional
Group-Tolerated Synthesis of -Aryl
and -Heteroaryl -Trifluoromethyl
Alcohols via Tandem
Text for Table of Contents
Trifluoroacetylation and MPV Type
Reduction
Tandem Reaction:
Tandem reaction, such as (1) the in situ generation of functionalized aromatic and electron-deficient heteroaromatic
Grignard reagents, (2) trifluoroacetylation with diphenylmethyl trifluoroacetate, and (3) successive Meerwein-
Ponndorf-Verley type reduction giving -aryl- and -heteroaryl--trifluoromethyl alcohols is reported.
This article is protected by copyright. All rights reserved.