One-Pot Successive Turbo Grignard Reactions for the Facile Synthesis of α-Aryl-α-Trifluoromethyl Alcohols

Article abstract of DOI:10.1002/ejoc.202000550

A novel straightforward one-pot methodology for two successive turbo Grignard reagent (iPrMgCl·LiCl) reactions, was developed for a facile synthesis of α-aryl-α-trifluoromethyl alcohols, motifs of value in pharmaceutical chemistry. The method displayed broad functional group tolerance, including reducible groups. Dual roles of iPrMgCl·LiCl were exploited in the tandem reaction with commercially available iodoarenes or iodoheteroarenes and 2,2,2-trifluoroethyl trifluoroacetate. The process encompasses three successive reactions in a one-pot process: the iPrMgCl·LiCl-mediated iodine/magnesium-exchange reaction of iodoarenes or iodoheteroarenes; nucleophilic addition of various generated aryl or heteroarylmagnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate; and the reduction of in-situ generated aryl trifluoromethyl ketones with iPrMgCl·LiCl, to produce the corresponding α-aryl or α-heteroaryl-α-trifluoromethyl alcohols bearing various substituents, including reducible functional groups in good to excellent yields.

Full text of DOI:10.1002/ejoc.202000550

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One-Pot Successive Turbo Grignard Reactions for the Facile
Synthesis of α-Aryl-α-Trifluoromethyl Alcohols
Authors: Ryunosuke Kani, Toshiyasu Inuzuka, Yasuhiro Kubota, and
Kazumasa Funabiki
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000550
Link to VoR: https://doi.org/10.1002/ejoc.202000550
01/2020

10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
One-Pot Successive Turbo Grignard Reactions for the Facile
Synthesis of -Aryl--Trifluoromethyl Alcohols
Ryunosuke Kani,[a] Toshiyasu Inuzuka,[b] Yasuhiro Kubota,[a] and Kazumasa Funabiki[a]*
[a]
R. Kani, Dr. Y. Kubota, and Prof. Dr. K. Funabiki*
Department of Chemistry and Biomolecular Science
Gifu University
1-1 Yanagido, Gifu 501-1193, Japan
E-mail: funabiki@gifu-u.ac.jp
https://www1.gifu-u.ac.jp/~matsuila/
[b]
Dr. T. Inuzuka
Division of Instrumental Analysis
Life Science Research Center, Gifu University
1-1 Yanagido, Gifu 501-1193, Japan
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A novel straightforward one-pot methodology for two
successive turbo Grignard reagent (i-PrMgClꞏLiCl) reactions, was
developed for a facile synthesis of -aryl--trifluoromethyl alcohols,
motifs of value in pharmaceutical molecules. The method displayed
broad functional group tolerance, including reducible groups. Dual
roles of i-PrMgClꞏLiCl were exploited in the tandem reaction with
commercially available iodoarenes or iodoheteroarenes and 2,2,2-
trifluoroethyl trifluoroacetate. The process encompasses three
successive reactions in a one-pot process: the i-PrMgClꞏLiCl-
mediated iodine/magnesium-exchange reaction of iodoarenes or
iodoheteroarenes; nucleophilic addition of various generated aryl or
heteroaryl magnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate;
and the reduction of in-situ generated aryl trifluoromethyl ketones with
i-PrMgClꞏLiCl, to produce the corresponding -aryl or -heteroaryl--
trifluoromethyl alcohols bearing various substituents, including
reducible functional groups in good to excellent yields.
a) Halogen/Mg-exchangereaction
MgClꞏLiCl
MgClꞏLiCl
X
El
El
i-PrMgClꞏLiCl
electrophile
FG
FG
FG
X = I, Br
FG = CO2R, CN, OR, halogen
or
or
Het
Y
Het
Y
or
n
n
X
Het
Y = N, S, O, etc
n = 0,1
n
Y
b) Isopropylation
O
H+
HO
R1 R2
-PrMgClꞏLiCl
i
i
R1 R2
H2O
c) Reduction
O
H
H+
HO
-PrMgClꞏLiCl
R1 R2
R1 R2
H2O
The Turbo Grignard reagent (i-PrMgClꞏLiCl) introduced by
Knochel in 2004, is among the most general and promising
reagents for the preparation of polyfunctionalized aryl, heteroaryl,
d) Proton abstraction
i-PrMgClꞏLiCl
electrophile
R1
R1
MgClꞏLiCl
R1
El
and
alkenyl
magnesium
reagents
by
selective
halogen/magnesium (Mg)-exchange reactions of various halo-
arenes and -heteroarenes. It enables the synthesis of a variety of
Scheme 1. Reactions of the turbo Grignard reagent.
complex molecules at laboratory and industrial scale.[1]
A
significant advantage of the reagent is the tolerance of various
functional groups, such as esters, nitriles, hydroxyl, and boronic
esters in the halogen/Mg-exchange reaction, due to increased
reactivity compared to the Mg metal or other Grignard reagents
by the formation of a lithium chloride complex (Scheme 1a).
On the other hand, in recent years, -aryl--trifluoromethyl
alcohols have become more prominent in pharmaceutical
molecules, for example in LP-533401 and LX1606/LX1033, which
are tryptophan inhibitors used for the treatment of osteoporosis
and of gastrointestinal symptoms related to the carcinoid
syndrome (Figure 1). [2]
Although i-PrMgClꞏLiCl has been employed as
a carbon
nucleophile (Scheme 1b), a reducing agent (Scheme 1c), and a
base (Scheme 1d) in addition to the halogen/Mg-exchange
reaction, there are no reports of synthetic methodologies that
utilize two or more of these reactions successively in a one-pot
manner. [1i]
O
O
Cl
OR
F
OH
O
NH2
O
NH2
CF3
N
N
N
CF3
N
N
N
NH2
NH2
R = H : LX1032
R = Et : LX1606 (Teiotristat eptiprate)
LP533401
Figure 1. Pharmaceutical molecules with an -trifluoromethyl ether motif.
Although various synthetic approaches to -aryl--trifluoromethyl
alcohols have been developed, there are limited examples of
1
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10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
syntheses that tolerate reducible functional groups. Examples
of aryl Grignard reagents from iodo-arenes or -heteroarenes by
the iodine/Mg-exchange reaction with i-PrMgClꞏLiCl; 2) in-situ
generation of aryl trifluoromethyl ketones by the reaction of the
formed aryl Grignard reagents with the trifluoroacetic acid ester;
and 3) the reduction of generated aryl trifluoromethyl ketones by
i-PrMgClꞏLiCl. (Figure 4). Advantages of the protocol include
tolerance of various reducible functional groups, and
straightforward operation and removal of by-products.
include reactions with the Ruppert-Prakash reagent (Scheme 2a)
[3]
or the tandem iodine/Mg-exchange reaction, arylation of
isopropyl or diphenylmethyl trifluoroacetate, and the Meerwein-
Ponndorf-Verley type reduction of in-situ generated aryl
trifluoromethyl ketones by isopropoxide or diphenylmethoxide
(Scheme 2b). [4] However, the development of the methodologies
for simple and efficient route to such compounds has still been
desired.
i-PrMgClꞏLiCl
1)
(more than 2 equiv.)
(a) Trifluoromethylation using the Ruppert-Prakash reagent
O
CF3SiR3
HO
H
H
HO
2)
cat. F- source
CHO
H+
OR
I
RF
H+
CF3
FG
RF
FG
or
FG
RF CF CF H CF Cl CF Me CF CF
3
FG
H2O
H2O
FG
or
= 4-CN, 4-CO2Et, 3-CO2Et, 4-NO2
OH
or
=
,
3
,
,
,
H
2
2
2
2
HO H
RF
CHO
N
R = Me, CH2CF3
FG = OMe, Me, Ph, Br, CN, CO2Et etc.
CF3
N
Het
Y
or
I
(b) Trifluoroacetylation of aromatic Grignard reagent and successive
MPV reduction with alkoxide (Yamazaki and our previous work)
n
Y = N, S,
n = 0,1
Het
R
+
OH +
n
R
O
Y
H
R
ready removed
Cl
Mg
O
O
O
F3C
i-PrMgClꞏLiCl
(1.05 equiv.)
I
23 examples
Broad substrate scope
Reducible functional group-tolerant
Up to 85% isolated yields
Readily scalable
H
R
(3 equiv.)
FG
FG
Ar
0 °C, then 40 °C
THF, 25 °C
= 4-CN,
R
CF3
4-CO2Et, 3-CO2Et
R = Me, Ph
or
Scheme 4. This work.
I
H
HO
H
HO
H+
H2O
etc.
N
CF3
etc.
CF3
or
FG
When 1-iodo-4-methoxybenzene (1a) was added to 1 equiv. of i-
PrMgClꞏLiCl in THF at -40 °C, the iodine/Mg-exchange proceeded
smoothly to give the corresponding arylmagnesium reagent,
which readily reacted with 1.2 equiv. of methyl trifluoroacetate
(2a). The reaction afforded the corresponding trifluoromethyl
ketone, 2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-1-one (3a) and
its equivalents, the hemiacetal and hydrate in a combined yield of
N
Scheme 2. Previous work on the reducible functional group-tolerant
syntheses of -aryl--trifluoromethyl alcohols.
In 1953, McBee et al. reported that two types of Grignard reagents,
including
methyl-
or
ethyl-magnesium
iodides
and
isopropylmagnesium bromide, were successfully employed for
the successive alkylation and reduction of trifluoroacetic acid
esters to afford the corresponding -trifluoromethyl secondary
alcohols in moderate yields (Scheme 3). [5]
46%, together with
a
13% yield of 2,2,2-trifluoro-1-(4-
methoxyphenyl)ethan-1-ol (4a) and a trace amount of an
isopropylated adduct, 1,1,1-trifluoro-2-(4-methoxyphenyl)-3-
methylbutan-2-ol (5a) (Table 1, entry 1).
1) rt, Et2O, 1 h
Table 1. Optimization of reaction conditions using 1-iodo-4-
methoxybenzene (1a)
2)
O
F3C
OR2
,
H
H
H
H+
H
HO
HO
0 °C, overnight
O
1)
R1X
R1 = Me, Et
+
+ Mg
+
1) solvent (1 ml)
i-PrMgClꞏLiCl
40 °C, then 0 °C, 10 min
R1 CF3
(49-60%)
R1 CF3
(10-14%)
F3C OMe
H2O
(R2 = Me, Et)
2)
THF sol.,
Br
I
H+
2a (1.2 equiv.)
3) toluene (4 ml), 40 °C, 15 min 2) 40 °C, overnight H2O
MeO
1a (1 mmol)
Scheme 3. Previous work on the successive alkylation and reduction of
O
trifluoroacetic acid esters with Grignard reagents.
H
HO
HO
CF3
CF3 +
+
CF3
MeO
MeO
MeO
However, this method suffers a significant disadvantage, which is
the narrow scope of Grignard reagents, due to the difficulty of
preparing aryl or heteroaryl Grignard reagents with various
reducible functional groups from the corresponding haloarenes
and haloheteroarenes and Mg metal.
3a
4a
5a
19F NMR yield (%) of
Entry Solvent
i-PrMgClꞏLiCl
(equiv.)
Ketone 3a, its hemiacetal, and hydrate
Alcohol 4a
5a
i-Pr-adduct
1
2
3
THF
THF
toluene
46
8
0
13
72
81 (81)a
1.0
2.5
2.5
trace
trace
trace
We present herein the development of a novel and straightforward
one-pot synthetic methodology entailing two distinct successive
reactions with the turbo Grignard reagent (i-PrMgClꞏLiCl), for the
facile and reducible functional group-tolerant synthesis of -aryl-
-trifluoromethyl alcohols from iodoarenes or iodeheteroarenes
a
Yield of isolated product.
Increasing i-PrMgClꞏLiCl equivalents from 1 to 2.5 resulted in a
significant increase in the yield of the secondary trifluoromethyl
alcohol 4a (72%), while the combined yield of ketone 3a and its
equivalents decreased to 8% (Entry 2). It should be noted that
the use of toluene as a solvent led to the complete reduction of
and 2,2,2-trifluoroethyl trifluoroacetate (Scheme 4).
This
approach entails three successive steps: 1) the in-situ formation
2
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10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
ketone 3a to increase the yield (81%) of the secondary
trifluoromethyl alcohol 4a (entry 3).
Next, other commmercially available fluorine-containing esters 2
were evaluated in the tandem dual reaction under this optimized
reaction conditions (Method A). (Scheme 5).
yields, respectively. The reaction of 1-bromo-4-iodobenzene (1g)
with 2.5 equiv. of i-PrMgClꞏLiCl and 1.2 equiv. of methyl
trifluoroacetate (2a) provided the corresponding trifluoromethyl
alcohol 4g in a poor yield of 9% and trifluoromethyl ketone 3f as
the major product in 52% yield. To improve the yield of alcohol
4g bearing the 4-bromophenyl group, the reaction conditions
were investigated in more detail, as shown in Table 2.
O
1)
1) toluene (1 ml)
-PrMgClꞏLiCl
OH
RF
RF
THF sol. (2.5 equiv.),
Me
O
2) i
I
H+
2
40 °C, then 0 °C, 10 min
(1.2 equiv.)
Table 2. Optimization of reaction conditions using 1-bromo-4-
iodobenzene (1g)
MeO
1a
3) toluene (4 ml), 40 °C, 15 min
2)40 °C, overnight
H2O
MeO
4a,6a,7a,8a,9a
(1 mmol)
O
1)
1) toluene (1 ml)
OH
OH
OH
O
H
HO
HO
R
O
F3
C
i-PrMgClꞏLiCl
(2.5 equiv.),
2)
THF sol.
Conditions 1
I
H+
H2
2 (1.2 equiv.)
Conditions 3
2)
F
H
Cl
CF3
CF3
CF3
+
+
O
toluene, Conditions 2
3)
Br
Br
Br
Br
F
F
F
F
F F
1g (1 mmol)
3g
4g
5g
MeO
MeO
MeO
19F NMR yield (%) of
81%a (81%)b
OH
76%a (76%)b
OH
86%a (85%)b
7a
4a
6a
Additive
toluene (ml) Conditions
3g
, its
Ketone
Alcohol
i-Pr adduct
2
R
Conditions
1
2
Conditions
3

40 °C, overnight 52
hemiacetal and hydrate 4g
5g
Entry Ester
:
Me
CF3
4
1
2
3
4
5
2a: Me
40 °C, then 0 °C, 10 min
40 °C, 15 min
9
trace
2f: CH2CF3 40 °C, then 0 °C, 10 min
2f: CH2CF3 15 °C, 20 min
2f: CH2CF3 15 °C, 20 min
2f: CH2CF3 15 °C, 20 min
4
40 °C, 15 min 40 °C, overnight trace
6
51
59
65
F
F
F F
4
40 °C, 15 min 40 °C, overnight
15 °C, 5 min °C, 60 min
15 °C, 5 min 20 °C, 30 min
8
8
MeO
MeO
9a
19
19
0
trace
trace
9
78 (78)a
10
76%a (75%)b
86 %a (84%)b
8ac
a Yield of isolated product.
a 19F NMR yields. b Yields of isolated product. c Ethyl ester for the synthesis of
was used.
8a
Scheme 5. Substrate scope of fluorine-containing esters 2 (Method A).
The use of commercially available 2,2,2-trifluoroethyl
trifluoroacetate (2f) in place of methyl trifluoroacetate (2a)
successfully improved the yields of alcohol 4g from 9% to 51%
(Table 2, entry 2). GC analysis revealed that the iodine/Mg-
exchange with 1-bromo-4-iodobenzene (1g) proceeded efficiently
at -15 °C for 20 min (Temp. 1 and conditions 1, entries 3-5). Then,
the reaction conditions for the tandem nucleophilic addition of the
in-situ generated 4-bromophenylmagnesium chloride and
reduction of the in-situ generated trifluoromethyl ketone 3g by i-
PrMgClꞏLiCl were examined. It was established that elevated
reaction temperatures were beneficial for both the nucleophilic
addition (-40 °C to -15 °C, entries 3 and 4), as well as the
subsequent reduction of ketone 3g (0 °C to 20 °C, entries 4 and
5). Furthermore, increasing the amount of added toluene from 4
ml to 19 ml (entries 3 and 4) was crucial for increasing the yields
of 4g, and it was obtained in 78% yield, along with 10% yield of
isopropyl adduct 5g (entry 5).
Hence, methyl 2,2-difluoroacetate, methyl 2-chloro-2,2-
difluoroacetate, ethyl 2,2-difluoropropanoate, and methyl
2,2,3,3,3-pentafluoropropanoate (2b-e) were reacted with 1-iodo-
4-methoxybenzene (1a) and 2.5 equiv. of i-PrMgClꞏLiCl under the
above-described conditions to deliver the corresponding the
corresponding difluoromethylated, chlorodifluoromethylated,
difluoroethylated, and pentafluoroethylated alcohols 6a,7a,8a,
and 9a in good to excellent yields.
Other iodoarenes, such as 1-ethoxy-4-iodobenzene (1b) and 1-
iodo-4-methylbenzene (1c), as well as 2-iodo-9,9-dimethyl-9H-
fluorene (1f), also participated in the tandem dual reaction of i-
PrMgClꞏLiCl with methyl trifluoroacetate (2a) to give the
corresponding trifluoromethyl alcohols 4b,4c, and 4f in high yields
(Scheme 6).
Scheme
7
illustrates the scope of iodoarenes
1
and
1)
O
iodoheteroarenes 1 under this optimized reaction conditions
(Method B).
1) toluene (1 ml)
i-PrMgClꞏLiCl
OH
CF3
Me
O
F3C
2)
THF sol. (2.5 equiv.),
I
H+

40 °C, then 0 °C, 10 min
2a
(1.2 equiv.)
FG
1
FG
2) 40 °C, overnight
3) toluene (4 ml), 40 °C, 15 min
H2O
(1 mmol)
4
OH
CF3
OH
CF3
OH
OH
CF3
Me
CF3
EtO
4b
MeO
Me
4c
38%a (38%)b
82%a (78%)b
81%a (81%)b
OH
74%a (60%)b
4d
4a
a
ketone 3d
33%
OH
OH
CF3
Me
Me
CF3
CF3
Br
a
78%a (71%)b
32%a (32%)b
a
4g
4f
9%
4e
a
a
ketone 3f
ketone 3g
52%
ketone 3e
trace
37%
a 19F NMR yields. b Yields of isolated product.
Scheme 6. Substrate scope of iodoarenes 1 using methyl trifluoroacetate
(2a) (Method A).
The use of 1-iodo-3-methylbenzene (1d) and 4-iodo-1,1'-biphenyl
(1e) afforded the corresponding trifluoromethyl alcohols 4d and
4e in 38% and 32% yields, respectively, together with the
corresponding trifluoromethyl ketones 3d and 3e in 33% and 37%
3
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10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
O
1)
3C
1)
O
1) toluene (1 ml)
2) i-PrMgClꞏLiCl THF sol.,
25 °C, 20 min
1) toluene (1 ml)
OH
CF3
CH2CF3
O
F
CH CF
O
F3C
I
-PrMgClꞏLiCl
2) i
THF sol.
2
3
H+
I
2f
H+
(2.5 equiv.), 15 °C, 20 min
2f
(1.2 equiv.)
FG
FG
1
H2
O
EtO2
C
2) Temp. 1, overnight
3) toluene, Temp. 1, 15 min
H2O
3) toluene (19 ml), 15 °C, 5 min 2) 20 °C, 30 min
1m (1 mmol)
(1 mmol)
4
O
HO
H
HO
CF3
CF3
CF3
OH
CF3
OH
CF3
OH
CF3
OH
+
+
EtO2
C
EtO2
C
Me
EtO2C
CF3
3m
4m
5m
MeO
Me
EtO
19F NMR yield (%) of
86%a (84%)b
-Pr adduct 5a
85%a (85%)b
-Pr adduct 5b
84%a (76%)b
-Pr adduct 5c
81%a (80%)b
2f
4a
4b
4c
4d
Additive
Ester
Temp.
1
Ketone 3m, its
i-Pr adduct
Entry i-PrMgClꞏLiCl
Alcohol
a
a
a
a
-Pr adduct 5d
(equiv.)
toluene (ml) (equiv.) (°C)
hemiacetal and hydrate
4m
5m
i
trace
OH
CF3
i
trace
OH
i
5%
i
trace
4
4
1.2
1.2
3.0
3.0
3.0
20
trace
trace
29
13
12
8
OH
CF3
OH
CF3
1
2
3
4
5
2.5
2.5
2.5
2.5
4.0
31
35
30
43
Me
Me

40
CF3
4
40
40
19
19
11
15
Br
H

40
trace
54 (54)a 17
a Yield of isolated product.
81%a (81%)b
80%a (80%)b
i-Pr adduct 5f
78%a (78%)b
84%a (67%)b
i-Pr adduct 5h
6%
4e
4f
4g
4h
a
a
a
a
i-Pr adduct 5e
i-Pr adduct 5g
11%
14%
10%
OH
OH
CF3
OH
Me
The reaction of ethyl 4-iodobenzoate (1m) with i-PrMgClꞏLiCl was
monitored by GC analysis, which indicated that conditions of -
25 °C and 20 min were sufficient for the iodine/Mg-exchange
reaction of 1m. It was established that lowering the reaction
temperature from -20 to -40 °C (entries 1 and 2), increasing the
amount of i-PrMgClꞏLiCl to 4 equiv. (entries 4 and 5), as well as
that of the ester 2f to 3 equiv. (entries 2 and 3), and the addition
of a large amount (19 mL) of toluene (entries 3 and 4), resulted in
efficient conversion from the ketone hemiacetal alkoxide to
ketone 3m and increased the yield of 4m to 54%.
Under the optimized reaction conditions, not only the iodoarenes,
such as 1-bromo-3-iodobenzene (1l), ethyl 4-iodobenzoate (1m),
ethyl 3-iodobenzoate (1q), and 3-iodobenzonitrile (1r) but also 3-
iodopyridine (1s), participated well in the tandem reactions with i-
PrMgClꞏLiCl and ester 2f to give the corresponding alcohols
4l,m,q,r,s in moderate to good yields, as shown in Scheme 8.
OH
CF3
Br
CF3
CF3
F
81%a (67%)b
70%a (67%)b
45%a (44%)b
36%
ketone 3l
6%
a
4i
4j
4k
4l
a
a
-Pr adduct 5i
i
6%
a
i-Pr adduct 5l
trace
OH
OH
OH
CF3
OH
S
CF3
CF3
CF3
N
N
Bn
N
EtO2C
4m
Ph
a
4n
4o
40%
77%a (77%)b
i-Pr adduct 5n
71%a (69%)b
i-Pr adduct 5o
55%a (51%)b
4p
a
a
a
a
ketone 3m
ketone 3p
trace
trace
trace
trace
-Pr adduct 5p
18%
a
a
-Pr adduct 5m
i
17%
i
a 19F NMR yields. b Yields of isolated products.
Scheme 7. Substrate scope of various iodo-arenes and -heteroarenes 1
using 2,2,2-trifluoroethyl trifluoroacetate (2f) (Method B).
Finally,
gram-scale
synthesis
of
2,2,2-trifluoro-1-(4-
Various iodoarenes 1a-e,g-i, such as 1-iodo-4-methoxybenzene
(1a), 1-ethoxy-4-iodobenzene (1b), 1-iodo-4-methylbenzene (1c),
1-iodo-3-methylbenzene (1d), 4-iodo-1,1'-biphenyl (1e), 1-bromo-
4-iodobenzene (1g), iodobenzene (1h), and 1-fluoro-4-
iodobenzene (1i), smoothly reacted with i-PrMgClꞏLiCl to furnish
the corresponding -aryl--trifluoromethyl alcohols 4a-i in good to
excellent yields. Fused iodoarenes, such as 2-iodo-9,9-dimethyl-
9H-fluorene (1f) and 1-iodonaphthalene (1k), likewise reacted
with i-PrMgClꞏLiCl to give the corresponding -aryl--
trifluoromethyl alcohols 4f, 4k in good to excellent yields. Although
the presence of a methyl group at the 2-position led to a decrease
in the yield of 4j compared with substrates bearing the methyl at
3- or 4-positions (81-84%), 1-iodo-2-methylbenzene (1j)
participated well in the reaction to give the -aryl--trifluoromethyl
alcohol 4j in good yield. The reaction of iodoheteroarenes, such
as 1-benzyl-4-iodo-1H-pyrazole (1n), 3-iodo-9-phenyl-9H-
carbazole (1o), and 2-iodothiophene (1p) with i-PrMgClꞏLiCl and
2,2,2-trifluoroethyl trifluoroacetate (2f) proceeded smoothly to
give the corresponding -trifluoromethyl alcohols 4n,4o, and 4p
in good yields.
methoxyphenyl)ethan-1-ol (4a) was performed by Method B using
1-iodo-4-methoxybenzene (1a), as shown in Scheme 9.
Consequently, the reaction of 1-iodo-4-methoxybenzene (1a) with
i-PrMgClꞏLiCl proceeded smoothly to give 2,2,2-trifluoro-1-(4-
methoxyphenyl)ethan-1-ol (4a) in 84% yield, analogous to results
from the 1 mmol scale. This result demonstrates that the
operation is amenable to scale-up.
O
1)
1) toluene (1 ml)
i-PrMgClꞏLiCl
OH
CF3
CH CF
O
F3C
2f
(3 equiv.)
2)
THF sol.
2
3
H+
I

(4 equiv.), 25 °C, 20 min
FG
FG
1
H2O
3) toluene (19 ml), 40 °C, 15 min 2) 40 °C, overnight
4
(1 mmol)
OH
CF3
OH
CF3
OH
Br
EtO2C
4q
CF3
EtO2C
69%a (66%)b
54%a (54%)b
67%a (67%)b
4l
4m
a
a
a
ketone 3l
ketone 3m
ketone 3q
trace
trace
trace
i-Pr adduct 5l 8%a
i-Pr adduct 5m 17%a
i-Pr adduct 5q 9%a
OH
OH
CF3
On the contrary, the reactions of 1-bromo-3-iodobenzene (1l) and
ethyl 4-iodobenzoate (1m) afforded lower yields (36% and 40%)
of the alcohols 4l and 4m, respectively. Therefore, further
optimization of the reaction conditions with regard to ethyl 4-
iodobenzoate (1m) was performed, as shown in Table 3.
NC
CF3
N
48%a (44%)b
a
4s
4r
44%a (41%)b
a
ketone 3r
ketone 3s
8%
11%
a
a
i-Pr adduct 5r
i-Pr adduct 5s
8%
8%
a 19F NMR yields. b Yields of isolated product.
Scheme 8. Substrate scope of various iodo-arenes and -heteroarenes 1
using 2,2,2-trifluoroethyl trifluoroacetate (2f) (Method C)
Table 3. Optimization of reaction conditions using ethyl 4-iodobenzoate
(1m)
4
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10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
O
1)
O
1) toluene (10 ml)
OH
CF3
CH CF
F3C
O
2
3
i-PrMgClꞏLiCl
2)
THF sol.
I
R
O
F3C
H+
I
(2.5 equiv.),
-15 °C, 20 min
2f
(1.2 equiv.)
2) 20 °C, 30 min
PrMgClꞏLiCl
i-
MgClꞏLiCl
2
FG
H2O
MeO
1a
3) toluene (190 ml),
-
15 °C, 20 min
FG
MeO
Iodine-magnesium
exchange reaction
Nucleophilic
addition
(10 mmol)
2.35 g
4a
(84%)
1.74 g
1
(R = Me, CH2CF3)
Scheme 9. Gram-scale synthesis (Method B)
O
R
O
MgClꞏLiCl
O
+
+
R MgCl
O
CF3
To investigate the reaction mechanism, the reaction of
trifluoromethyl ketone, 2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-
1-one (3a), with i-PrMgClꞏLiCl in THF at -78 °C was performed
(Table 4, entry 1). Consequently, 2,2,2-trifluoro-1-(4-
methoxyphenyl)ethan-1-ol (4a) was obtained in 86% yield as the
major product, together with 9% of isopropylated adduct, 1,1,1-
trifluoro-2-(4-methoxyphenyl)-3-methylbutan-2-ol (5a).
CF3
FG
FG
LiCl
strong EW
group
Aryl trifluoromethyl
Mg alkoxide of aryl
trifluoromethyl ketone
hemiacetal
ketone 3
H
Cl
Mg
HO
H
O
H+
i-PrMgClꞏLiCl
Me
H
Ar
Table 4. Reduction of aryl trifluoromethyl ketone 3a with turbo Grignard
reagent
CF3
H
FG
Reduction
H2O
H
CF3
4
Reduction
Scheme 10. Proposed reaction mechanism of the one-pot successive dual
turbo Grignard reactions
Cl
O
Major
H
HO
Mg
H+
Me
H
H
CF3
Ar
1) solvent (10 ml)
-PrMgClꞏLiCl
THF sol. (1 equiv.)
H2O
H
MeO
2) i
CF3
O
4a
The reaction of iodoarene 1 with i-PrMgClꞏLiCl in THF occurred
smoothly via an iodine/Mg-exchange reaction to give the
corresponding arylmagnesium chloride under mild conditions.
The in-situ generated aryl magnesium chloride added to
trifluoroacetic acid ester 2 to give the corresponding aryl
trifluoromethyl ketone hemiacetal alkoxide, which is stabilized by
the existence of a strongly electron-withdrawing trifluoromethyl
group. This was followed by the slow elimination of the alkoxide,
leading to in-situ generated aryl trifluoromethyl ketone 3, in
equilibrium with the aryl trifluoromethyl ketone hemiacetal
alkoxide. Notably, the iodine/Mg-exchange reaction and the
nucleophilic addition of the generated arylmagnesium chloride are
both faster than the nucleophilic addition of i-PrMgClꞏLiCl to ester
2. Next, the reduction of ketone 3 with i-PrMgClꞏLiCl proceeded
preferentially over the nucleophilic addition of the isopropyl group,
to selectively afford -aryl--trifluoromethyl alcohol 4. The
addition of toluene in place of THF may be beneficial for lowering
the polarity of the solvents, which thereby suppresses the
nucleophilic addition of the isopropyl group.[4a] In the case of
iodoarenes bearing electron-withdrawing groups, the use of
trifluoroethyl ester 2f can promote the elimination of the alkoxide
from the trifluoromethyl ketone hemiacetal alkoxide, leading to
efficient in-situ generation of aryl trifluoromethyl ketone in the
reaction.
CF3
3) temp, 30 min
MeO
3a
Minor
HO
Nucleohilic
addition
H+
H2O
(1 mmol)
CF3
MeO
5a
19F NMR yield (%) of
Entry Solvent
4a
Temp (°C)
Alcohol
5a
i-Pr-adduct
1
2
THF
78
40
86
91
9
trace
THF-toluene (v/v=1/9)
The use of mixed solvents, namely THF and toluene (v/v = 1/9),
proved effective for the suppression of the nucleophilic addition
by the isopropyl to ketone 3a and acceleration of the reduction to
give alcohol 4a in 92% yield, even at an elevated reaction
temperature (-40 °C) (entry 2).
The above-discussed results along with previous reports on the
turbo Grignard reagent and McBee’s studies, allow us to propose
the following plausible reaction mechanism for the reaction of
iodoarene 1, i-PrMgClꞏLiCl, and trifluoroacetic acid ester 2, as
shown in Scheme 10.
We have developed a novel synthetic one-pot methodology
involving two distinct successive turbo Grignard reagent (i-
PrMgClꞏLiCl)-mediated transformations for the facile synthesis of
-aryl or -heteroaryl--trifluoromethyl alcohols, which are
important pharmaceutical motifs. The strategy exhibited a wide
substrate scope and tunable reaction conditions. Tandem
reactions using i-PrMgClꞏLiCl with commercially available
iodoarenes and 2,2,2-trifluoroethyl trifluoroacetate consist of
three tandem reactions, namely, the iodine/Mg-exchange of iodo-
arenes or -heteroarenes with i-PrMgClꞏLiCl, nucleophilic addition
of various aryl- or heteroaryl-magunesium reagents to 2,2,2-
trifluoroethyl trifluoroacetate, and the reduction of in-situ
generated aryl trifluoromethyl ketones by i-PrMgClꞏLiCl in a one-
pot process. This methodology can be applied to a variety of iodo-
arenes or –heteroarenes, as well as fluorine-containing esters
5
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10.1002/ejoc.202000550
European Journal of Organic Chemistry
COMMUNICATION
Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley, Tetrahedron 2009, 65
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and has several advantages, such as tolerance of a variety of
reducible functional groups on the aromatic rings, ease of
operation, and readily removable side-products.
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Acknowledgements
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We would like to thank Editage (www.editage.com) for English
language editing.
Conflict of interest
The authors declare no competing financial interest.
Keywords: turbo Grignard reagent • tandem reaction •
halogen/magnesium-exchange reactions • reduction •
trifluoromethyl
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6
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European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Tandem Reaction: one-pot synthetic methodology involving two successive reactions of the turbo Grignard reagent for the synthesis
of -aryl or -heteroaryl--fluoroalkyl alcohols with good functional group tolerance.
i-PrMgClꞏLiCl
1)
(more than 2 equiv.)
O
H
HO
2)
I
RF
H+
OR
RF
FG
RF CF CF H CF Cl CF Me CF CF
3
FG
H2O
or
=
,
3
,
,
,
2
2
2
2
HO H
RF
R = Me, CH2CF3
FG = OMe, Me, Ph, Br, CN, CO2Et etc.
Het
Y
or
I
n
Y = N, S,
n = 0,1
Het
Y
R
+
OH +
n
ready removed
23 examples
Broad substrate scope
Up to 85% isolated yields
Readily scalable
Reducible functional group-tolerant
7
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