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
European Journal of Organic Chemistry 10.1002/ejoc.202000550

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: [email protected]
https://www1.gifu-u.ac.jp/~matsuila/

Accepted Manuscript
[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
a) Halogen/Mg-exchange reaction
developed for a facile synthesis of -aryl--trifluoromethyl alcohols,
X i-PrMgClꞏLiCl MgClꞏLiCl electrophile El
motifs of value in pharmaceutical molecules. The method displayed
FG FG FG
broad functional group tolerance, including reducible groups. Dual
roles of i-PrMgClꞏLiCl were exploited in the tandem reaction with X = I, Br or or
FG = CO2R, CN, OR, halogen MgClꞏLiCl El
commercially available iodoarenes or iodoheteroarenes and 2,2,2- Het
or Het
trifluoroethyl trifluoroacetate. The process encompasses three X Y n Y n

successive reactions in a one-pot process: the i-PrMgClꞏLiCl- Het Y = N, S, O, etc

n
Y n = 0,1
mediated iodine/magnesium-exchange reaction of iodoarenes or
iodoheteroarenes; nucleophilic addition of various generated aryl or
b) Isopropylation
heteroaryl magnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate;
O HO
and the reduction of in-situ generated aryl trifluoromethyl ketones with i-PrMgClꞏLiCl H+
R1 R2 R1 R2
i-PrMgClꞏLiCl, to produce the corresponding -aryl or -heteroaryl-- H2O

trifluoromethyl alcohols bearing various substituents, including

c) Reduction
reducible functional groups in good to excellent yields. O
i-PrMgClꞏLiCl H+ HO H
R1 R2 H2O R1 R2
The Turbo Grignard reagent (i-PrMgClꞏLiCl) introduced by
Knochel in 2004, is among the most general and promising d) Proton abstraction
reagents for the preparation of polyfunctionalized aryl, heteroaryl, i-PrMgClꞏLiCl electrophile
and alkenyl magnesium reagents by selective R1 R1 MgClꞏLiCl R1 El
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 On the other hand, in recent years, -aryl--trifluoromethyl
esters in the halogen/Mg-exchange reaction, due to increased alcohols have become more prominent in pharmaceutical
reactivity compared to the Mg metal or other Grignard reagents molecules, for example in LP-533401 and LX1606/LX1033, which
by the formation of a lithium chloride complex (Scheme 1a). 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 O
base (Scheme 1d) in addition to the halogen/Mg-exchange O
Cl
OR
reaction, there are no reports of synthetic methodologies that F OH
O NH2
O NH2
utilize two or more of these reactions successively in a one-pot N CF3 N N
manner. [1i] CF3 N N N
NH2
NH2
LP533401 R = H : LX1032
R = Et : LX1606 (Teiotristat eptiprate)

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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European Journal of Organic Chemistry 10.1002/ejoc.202000550

COMMUNICATION
syntheses that tolerate reducible functional groups. Examples of aryl Grignard reagents from iodo-arenes or -heteroarenes by
include reactions with the Ruppert-Prakash reagent (Scheme 2a) the iodine/Mg-exchange reaction with i-PrMgClꞏLiCl; 2) in-situ
[3]
or the tandem iodine/Mg-exchange reaction, arylation of generation of aryl trifluoromethyl ketones by the reaction of the
isopropyl or diphenylmethyl trifluoroacetate, and the Meerwein- formed aryl Grignard reagents with the trifluoroacetic acid ester;
Ponndorf-Verley type reduction of in-situ generated aryl and 3) the reduction of generated aryl trifluoromethyl ketones by
trifluoromethyl ketones by isopropoxide or diphenylmethoxide i-PrMgClꞏLiCl. (Figure 4). Advantages of the protocol include
(Scheme 2b). [4] However, the development of the methodologies tolerance of various reducible functional groups, and
for simple and efficient route to such compounds has still been straightforward operation and removal of by-products.
desired.
1) i-PrMgClꞏLiCl
(a) Trifluoromethylation using the Ruppert-Prakash reagent (more than 2 equiv.)
O
CF3SiR3 HO H 2) HO H
CHO cat. F - source I RF
H+ CF3 OR H+

Accepted Manuscript
FG FG FG RF
FG
H2O
H 2O
FG = 4-CN, 4-CO2Et, 3-CO2Et, 4-NO2 or OH
or H RF = CF3, CF2H, CF2Cl, CF2Me, CF2CF3 or
CHO R = Me, CH2CF3 HO H
N CF3
N FG = OMe, Me, Ph, Br, CN, CO2Et etc. RF
or Het
(b) Trifluoroacetylation of aromatic Grignard reagent and successive I Y n
MPV reduction with alkoxide (Yamazaki and our previous work) Het Y = N, S,
n = 0,1 + ROH +
O R
H Y n
Cl
ready removed
I i-PrMgClꞏLiCl F3C O R O O
Mg
(1.05 equiv.) (3 equiv.) R H 23 examples Up to 85% isolated yields
FG
Ar
Broad substrate scope Readily scalable
FG = 4-CN, THF, 25 °C 0 °C, then 40 °C Reducible functional group-tolerant
R CF3
4-CO2Et, 3-CO2Et
R = Me, Ph
or I Scheme 4. This work.
HO H HO H
N etc. H+
CF3 or CF3
H2O FG
N etc. When 1-iodo-4-methoxybenzene (1a) was added to 1 equiv. of i-
PrMgClꞏLiCl in THF at -40 °C, the iodine/Mg-exchange proceeded
Scheme 2. Previous work on the reducible functional group-tolerant
syntheses of -aryl--trifluoromethyl alcohols. smoothly to give the corresponding arylmagnesium reagent,
which readily reacted with 1.2 equiv. of methyl trifluoroacetate
(2a). The reaction afforded the corresponding trifluoromethyl
In 1953, McBee et al. reported that two types of Grignard reagents, ketone, 2,2,2-trifluoro-1-(4-methoxyphenyl)ethan-1-one (3a) and
including methyl- or ethyl-magnesium iodides and its equivalents, the hemiacetal and hydrate in a combined yield of
isopropylmagnesium bromide, were successfully employed for 46%, together with a 13% yield of 2,2,2-trifluoro-1-(4-
the successive alkylation and reduction of trifluoroacetic acid methoxyphenyl)ethan-1-ol (4a) and a trace amount of an
esters to afford the corresponding -trifluoromethyl secondary isopropylated adduct, 1,1,1-trifluoro-2-(4-methoxyphenyl)-3-
alcohols in moderate yields (Scheme 3). [5] methylbutan-2-ol (5a) (Table 1, entry 1).

1) rt, Et2O, 1 h Table 1. Optimization of reaction conditions using 1-iodo-4-

2) O methoxybenzene (1a)
2
H F3C OR ,
H H 0 °C, overnight H+ HO H HO
1) O
R1 X + + Mg + 1) solvent (1 ml)
2 H2 O R1 CF 3 R1 CF3 F3 C OMe
Br (R = Me, Et) I
2) i-PrMgClꞏLiCl THF sol.,
R1 = Me, Et (49-60%) (10-14%) 40 °C, then 0 °C, 10 min 2a (1.2 equiv.) H+

3) toluene (4 ml), 40 °C, 15 min 2) 40 °C, overnight H2 O

MeO
Scheme 3. Previous work on the successive alkylation and reduction of 1a (1 mmol)
trifluoroacetic acid esters with Grignard reagents. O HO H HO
CF3 + CF3 + CF3

MeO MeO MeO

However, this method suffers a significant disadvantage, which is 3a 4a 5a
the narrow scope of Grignard reagents, due to the difficulty of 19
Entry Solvent i-PrMgClꞏLiCl F NMR yield (%) of
preparing aryl or heteroaryl Grignard reagents with various (equiv.) Ketone 3a, its hemiacetal, and hydrate Alcohol 4a i-Pr-adduct 5a
reducible functional groups from the corresponding haloarenes 1 THF 1.0 46 13 trace
and haloheteroarenes and Mg metal. 2 THF 2.5 8 72 trace
3 toluene 2.5 0 81 (81) a trace
We present herein the development of a novel and straightforward
a
Yield of isolated product.
one-pot synthetic methodology entailing two distinct successive
reactions with the turbo Grignard reagent (i-PrMgClꞏLiCl), for the Increasing i-PrMgClꞏLiCl equivalents from 1 to 2.5 resulted in a
facile and reducible functional group-tolerant synthesis of -aryl- significant increase in the yield of the secondary trifluoromethyl
-trifluoromethyl alcohols from iodoarenes or iodeheteroarenes alcohol 4a (72%), while the combined yield of ketone 3a and its
and 2,2,2-trifluoroethyl trifluoroacetate (Scheme 4). This equivalents decreased to 8% (Entry 2). It should be noted that
approach entails three successive steps: 1) the in-situ formation the use of toluene as a solvent led to the complete reduction of
2

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European Journal of Organic Chemistry 10.1002/ejoc.202000550

COMMUNICATION
ketone 3a to increase the yield (81%) of the secondary yields, respectively. The reaction of 1-bromo-4-iodobenzene (1g)
trifluoromethyl alcohol 4a (entry 3). with 2.5 equiv. of i-PrMgClꞏLiCl and 1.2 equiv. of methyl
Next, other commmercially available fluorine-containing esters 2 trifluoroacetate (2a) provided the corresponding trifluoromethyl
were evaluated in the tandem dual reaction under this optimized alcohol 4g in a poor yield of 9% and trifluoromethyl ketone 3f as
reaction conditions (Method A). (Scheme 5). the major product in 52% yield. To improve the yield of alcohol
4g bearing the 4-bromophenyl group, the reaction conditions
1) O
were investigated in more detail, as shown in Table 2.
1) toluene (1 ml) OH
I 2) i-PrMgClꞏLiCl THF sol. (2.5 equiv.), RF OMe
40 °C, then 0 °C, 10 min 2 (1.2 equiv.) H+ RF
MeO 3) toluene (4 ml), 40 °C, 15 min 2)40 °C, overnight H2O MeO Table 2. Optimization of reaction conditions using 1-bromo-4-
1a (1 mmol) 4a,6a,7a,8a,9a
iodobenzene (1g)
1) O
1) toluene (1 ml)
OH OH OH 2) i-PrMgClꞏLiCl THF sol. F 3C OR O HO H HO
I
F H Cl (2.5 equiv.), Conditions 1 2 (1.2 equiv.) H+
CF3 + CF3 + CF3
Br 3) toluene, Conditions 2 2) Conditions 3 H 2O
Br Br Br
F F F F F F

Accepted Manuscript
1g (1 mmol) 3g 4g 5g
MeO MeO MeO

4a 81%a (81%)b 6a 76%a (76%)b 7a 86%a (85%)b

19F NMR yield (%) of
Additive Ketone 3g, its Alcohol i-Pr adduct
OH OH Entry Ester 2: R Conditions 1 toluene (ml) Conditions 2 Conditions 3 hemiacetal and hydrate 4g 5g

Me CF3
1 2a: Me 40 °C, then 0 °C, 10 min 4 40 °C, 15 min 40 °C, overnight 52 9 trace
2 2f: CH2CF3 40 °C, then 0 °C, 10 min 4 40 °C, 15 min 40 °C, overnight trace 51 6
F F F F
3 2f: CH2CF3 15 °C, 20 min 4 40 °C, 15 min 40 °C, overnight 8 59 8
MeO MeO
4 2f: CH2CF3 15 °C, 20 min 19 15 °C, 5 min 0 °C, 60 min trace 65 9
2f: CH2CF3 15 °C, 20 min 19 15 °C, 5 min 20 °C, 30 min trace 78 (78) a 10
8ac 76%a (75%)b 9a 86 %a (84%)b 5

a
Yield of isolated product.
a 19
F NMR yields. Yields of isolated product. c Ethyl ester for the synthesis of 8a was used.
b

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%
Hence, methyl 2,2-difluoroacetate, methyl 2-chloro-2,2-
(Table 2, entry 2). GC analysis revealed that the iodine/Mg-
difluoroacetate, ethyl 2,2-difluoropropanoate, and methyl
exchange with 1-bromo-4-iodobenzene (1g) proceeded efficiently
2,2,3,3,3-pentafluoropropanoate (2b-e) were reacted with 1-iodo-
at -15 °C for 20 min (Temp. 1 and conditions 1, entries 3-5). Then,
4-methoxybenzene (1a) and 2.5 equiv. of i-PrMgClꞏLiCl under the
the reaction conditions for the tandem nucleophilic addition of the
above-described conditions to deliver the corresponding the
in-situ generated 4-bromophenylmagnesium chloride and
corresponding difluoromethylated, chlorodifluoromethylated,
reduction of the in-situ generated trifluoromethyl ketone 3g by i-
difluoroethylated, and pentafluoroethylated alcohols 6a,7a,8a,
PrMgClꞏLiCl were examined. It was established that elevated
and 9a in good to excellent yields.
reaction temperatures were beneficial for both the nucleophilic
Other iodoarenes, such as 1-ethoxy-4-iodobenzene (1b) and 1-
addition (-40 °C to -15 °C, entries 3 and 4), as well as the
iodo-4-methylbenzene (1c), as well as 2-iodo-9,9-dimethyl-9H-
subsequent reduction of ketone 3g (0 °C to 20 °C, entries 4 and
fluorene (1f), also participated in the tandem dual reaction of i-
5). Furthermore, increasing the amount of added toluene from 4
PrMgClꞏLiCl with methyl trifluoroacetate (2a) to give the
ml to 19 ml (entries 3 and 4) was crucial for increasing the yields
corresponding trifluoromethyl alcohols 4b,4c, and 4f in high yields
of 4g, and it was obtained in 78% yield, along with 10% yield of
(Scheme 6).
isopropyl adduct 5g (entry 5).
Scheme 7 illustrates the scope of iodoarenes 1 and
1) toluene (1 ml)
1) O iodoheteroarenes 1 under this optimized reaction conditions
OH
I
2) i-PrMgClꞏLiCl THF sol. (2.5 equiv.),
40 °C, then 0 °C, 10 min
F3C OMe
(Method B).
2a (1.2 equiv.) H+ CF3
FG FG
3) toluene (4 ml), 40 °C, 15 min 2) 40 °C, overnight H2O
1 (1 mmol) 4

OH OH OH OH
Me
CF3 CF3 CF3 CF3
MeO EtO Me
4a 81%a (81%)b 4b 82%a (78%)b 4c 74%a (60%)b 4d 38%a (38%)b
ketone 3d 33%a
OH OH OH
Me Me
CF3 CF3 CF3

Br

4e 32%a (32%)b 4f 78%a (71%)b 4g 9%a

ketone 3e 37%a ketone 3g trace a ketone 3f 52%a
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%

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European Journal of Organic Chemistry 10.1002/ejoc.202000550

COMMUNICATION
1) O 1) O
1) toluene (1 ml)
1) toluene (1 ml)
OH 2) i-PrMgClꞏLiCl THF sol.,
2) i-PrMgClꞏLiCl THF sol. F3C OCH2 CF3 I F3 C OCH2 CF3
I 25 °C, 20 min 2f H+
(2.5 equiv.), 15 °C, 20 min 2f (1.2 equiv.) H+ CF3
FG FG EtO2 C 3) toluene, Temp. 1, 15 min 2) Temp. 1, overnight H 2O
3) toluene (19 ml), 15 °C, 5 min 2) 20 °C, 30 min H2 O
1 (1 mmol) 4 1m (1 mmol)
O HO H HO
CF3 CF3 CF3
OH OH OH OH + +
Me EtO2 C EtO 2 C EtO 2C
CF3 CF3 CF3 CF3 3m 4m 5m
MeO EtO Me
19 F NMR yield (%) of
4a 86%a (84%)b 4b 85%a (85%)b 4c 84%a (76%)b 4d 81%a (80%)b Entry i-PrMgClꞏLiCl Additive Ester 2f Temp. 1 Ketone 3m, its Alcohol i-Pr adduct
i-Pr adduct 5a tracea i-Pr adduct 5b tracea i-Pr adduct 5c 5%a i-Pr adduct 5d tracea (equiv.) toluene (ml) (equiv.) (°C) hemiacetal and hydrate 4m 5m

OH OH OH OH 1 2.5 4 1.2 20 trace 31 13

Me Me 2 2.5 4 1.2 40 trace 35 12
CF3 CF3 CF3 CF3 3 2.5 4 3.0 40 29 30 8
Br H 4 2.5 19 3.0 40 11 43 15
5 4.0 19 3.0 40 trace 54 (54) a 17

Accepted Manuscript
a Yield of isolated product.
4e 81%a (81%)b 4f 80%a (80%)b 4g 78%a (78%)b 4h 84%a (67%)b
i-Pr adduct 5e 11% a i-Pr adduct 5f 14%a i-Pr adduct 5g 10%a i-Pr adduct 5h 6%a

OH Me OH OH OH The reaction of ethyl 4-iodobenzoate (1m) with i-PrMgClꞏLiCl was

Br
CF3 CF3 CF3 CF3 monitored by GC analysis, which indicated that conditions of -
F 25 °C and 20 min were sufficient for the iodine/Mg-exchange
4i 81%a (67%)b 4j 70%a (67%)b 4k 45%a (44%)b 4l 36%a
reaction of 1m. It was established that lowering the reaction
i-Pr adduct 5i 6%a ketone 3l 6%a
i-Pr adduct 5l tracea temperature from -20 to -40 °C (entries 1 and 2), increasing the
OH OH OH OH
amount of i-PrMgClꞏLiCl to 4 equiv. (entries 4 and 5), as well as
CF3 CF3 CF3
S
CF3
that of the ester 2f to 3 equiv. (entries 2 and 3), and the addition
N
EtO2C N N of a large amount (19 mL) of toluene (entries 3 and 4), resulted in
Bn Ph
efficient conversion from the ketone hemiacetal alkoxide to
4m 40%a 4n 77%a (77%)b 4o 71%a (69%)b 4p 55%a (51%)b
ketone 3m trace a i-Pr adduct 5n tracea i-Pr adduct 5o trace a ketone 3p trace a
ketone 3m and increased the yield of 4m to 54%.
i-Pr adduct 5m 17%a i-Pr adduct 5p 18%a Under the optimized reaction conditions, not only the iodoarenes,
a 19
F NMR yields. b Yields of isolated products. such as 1-bromo-3-iodobenzene (1l), ethyl 4-iodobenzoate (1m),
ethyl 3-iodobenzoate (1q), and 3-iodobenzonitrile (1r) but also 3-
Scheme 7. Substrate scope of various iodo-arenes and -heteroarenes 1 iodopyridine (1s), participated well in the tandem reactions with i-
using 2,2,2-trifluoroethyl trifluoroacetate (2f) (Method B). PrMgClꞏLiCl and ester 2f to give the corresponding alcohols
4l,m,q,r,s in moderate to good yields, as shown in Scheme 8.
Finally, gram-scale synthesis of 2,2,2-trifluoro-1-(4-
Various iodoarenes 1a-e,g-i, such as 1-iodo-4-methoxybenzene methoxyphenyl)ethan-1-ol (4a) was performed by Method B using
(1a), 1-ethoxy-4-iodobenzene (1b), 1-iodo-4-methylbenzene (1c), 1-iodo-4-methoxybenzene (1a), as shown in Scheme 9.
1-iodo-3-methylbenzene (1d), 4-iodo-1,1'-biphenyl (1e), 1-bromo- Consequently, the reaction of 1-iodo-4-methoxybenzene (1a) with
4-iodobenzene (1g), iodobenzene (1h), and 1-fluoro-4- i-PrMgClꞏLiCl proceeded smoothly to give 2,2,2-trifluoro-1-(4-
iodobenzene (1i), smoothly reacted with i-PrMgClꞏLiCl to furnish methoxyphenyl)ethan-1-ol (4a) in 84% yield, analogous to results
the corresponding -aryl--trifluoromethyl alcohols 4a-i in good to from the 1 mmol scale. This result demonstrates that the
excellent yields. Fused iodoarenes, such as 2-iodo-9,9-dimethyl- operation is amenable to scale-up.
9H-fluorene (1f) and 1-iodonaphthalene (1k), likewise reacted
with i-PrMgClꞏLiCl to give the corresponding -aryl--
1) O
trifluoromethyl alcohols 4f, 4k in good to excellent yields. Although 1) toluene (1 ml) OH
2) i-PrMgClꞏLiCl THF sol. F3C OCH2CF3
the presence of a methyl group at the 2-position led to a decrease I (4 equiv.), 25 °C, 20 min 2f (3 equiv.) H+ CF3
FG
in the yield of 4j compared with substrates bearing the methyl at FG
3) toluene (19 ml), 40 °C, 15 min 2) 40 °C, overnight H2O
3- or 4-positions (81-84%), 1-iodo-2-methylbenzene (1j) 1 (1 mmol)
4

participated well in the reaction to give the -aryl--trifluoromethyl

OH OH OH
alcohol 4j in good yield. The reaction of iodoheteroarenes, such Br EtO2C
CF3 CF3 CF3
as 1-benzyl-4-iodo-1H-pyrazole (1n), 3-iodo-9-phenyl-9H-
EtO2 C
carbazole (1o), and 2-iodothiophene (1p) with i-PrMgClꞏLiCl and
4l 69%a (66%)b 4m 54%a (54%)b 4q 67%a (67%)b
2,2,2-trifluoroethyl trifluoroacetate (2f) proceeded smoothly to ketone 3l tracea ketone 3m tracea ketone 3q tracea
give the corresponding -trifluoromethyl alcohols 4n,4o, and 4p i-Pr adduct 5l 8%a i-Pr adduct 5m 17%a i-Pr adduct 5q 9%a
in good yields. OH OH
On the contrary, the reactions of 1-bromo-3-iodobenzene (1l) and NC
CF3 CF3
ethyl 4-iodobenzoate (1m) afforded lower yields (36% and 40%)
N
of the alcohols 4l and 4m, respectively. Therefore, further
4r 48%a (44%)b 4s 44%a (41%)b
optimization of the reaction conditions with regard to ethyl 4- ketone 3r 8%a ketone 3s 11% a
iodobenzoate (1m) was performed, as shown in Table 3. i-Pr adduct 5r 8%a i-Pr adduct 5s 8%a
a 19F NMR yields. b Yields of isolated product.

Scheme 8. Substrate scope of various iodo-arenes and -heteroarenes 1

Table 3. Optimization of reaction conditions using ethyl 4-iodobenzoate using 2,2,2-trifluoroethyl trifluoroacetate (2f) (Method C)
(1m)

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European Journal of Organic Chemistry 10.1002/ejoc.202000550

COMMUNICATION
1) O O
1) toluene (10 ml) OH
2) i-PrMgClꞏLiCl THF sol. F3C OCH2CF3
I
(2.5 equiv.), -15 °C, 20 min H+ I F3 C OR
2f (1.2 equiv.) CF3 i- PrMgClꞏLiCl MgClꞏLiCl 2
H2O MeO
FG
MeO 3) toluene (190 ml), -15 °C, 20 min 2) 20 °C, 30 min FG
1a (10 mmol) 4a (84%)
Iodine-magnesium Nucleophilic
2.35 g 1.74 g 1 exchange reaction addition
(R = Me, CH2 CF3)
Scheme 9. Gram-scale synthesis (Method B)

RO OMgClꞏLiCl O

To investigate the reaction mechanism, the reaction of CF3 CF3 + RO MgCl

FG FG
+ LiCl
trifluoromethyl ketone, 2,2,2-trifluoro-1-(4-methoxyphenyl)ethan- strong EW
group
1-one (3a), with i-PrMgClꞏLiCl in THF at -78 °C was performed Aryl trifluoromethyl
Mg alkoxide of aryl ketone 3
(Table 4, entry 1). Consequently, 2,2,2-trifluoro-1-(4-
trifluoromethyl ketone
methoxyphenyl)ethan-1-ol (4a) was obtained in 86% yield as the hemiacetal

Accepted Manuscript
major product, together with 9% of isopropylated adduct, 1,1,1-
H
trifluoro-2-(4-methoxyphenyl)-3-methylbutan-2-ol (5a).
Cl HO H
i-PrMgClꞏLiCl O H+
Mg
Me H
Table 4. Reduction of aryl trifluoromethyl ketone 3a with turbo Grignard H CF3
Reduction Ar H2 O FG
reagent
H CF3 4
Reduction
Cl Scheme 10. Proposed reaction mechanism of the one-pot successive dual
O
Me
Mg
H +
Major HO H turbo Grignard reactions
H H
Ar CF3
1) solvent (10 ml) H2O
2) i-PrMgClꞏLiCl H CF3 MeO
O THF sol. (1 equiv.) 4a The reaction of iodoarene 1 with i-PrMgClꞏLiCl in THF occurred
CF3
3) temp, 30 min smoothly via an iodine/Mg-exchange reaction to give the
MeO Minor
Nucleohilic HO corresponding arylmagnesium chloride under mild conditions.
3a (1 mmol) addition H+ CF3
The in-situ generated aryl magnesium chloride added to
H2O MeO
5a
trifluoroacetic acid ester 2 to give the corresponding aryl
trifluoromethyl ketone hemiacetal alkoxide, which is stabilized by
19
F NMR yield (%) of the existence of a strongly electron-withdrawing trifluoromethyl
Entry Solvent Temp (°C) Alcohol 4a i-Pr-adduct 5a
group. This was followed by the slow elimination of the alkoxide,
1 THF 78 86 9 leading to in-situ generated aryl trifluoromethyl ketone 3, in
2 THF-toluene (v/v=1/9) 40 91 trace
equilibrium with the aryl trifluoromethyl ketone hemiacetal
alkoxide. Notably, the iodine/Mg-exchange reaction and the
nucleophilic addition of the generated arylmagnesium chloride are
The use of mixed solvents, namely THF and toluene (v/v = 1/9), both faster than the nucleophilic addition of i-PrMgClꞏLiCl to ester
proved effective for the suppression of the nucleophilic addition 2. Next, the reduction of ketone 3 with i-PrMgClꞏLiCl proceeded
by the isopropyl to ketone 3a and acceleration of the reduction to preferentially over the nucleophilic addition of the isopropyl group,
give alcohol 4a in 92% yield, even at an elevated reaction to selectively afford -aryl--trifluoromethyl alcohol 4. The
temperature (-40 °C) (entry 2). addition of toluene in place of THF may be beneficial for lowering
The above-discussed results along with previous reports on the the polarity of the solvents, which thereby suppresses the
turbo Grignard reagent and McBee’s studies, allow us to propose nucleophilic addition of the isopropyl group.[4a] In the case of
the following plausible reaction mechanism for the reaction of iodoarenes bearing electron-withdrawing groups, the use of
iodoarene 1, i-PrMgClꞏLiCl, and trifluoroacetic acid ester 2, as trifluoroethyl ester 2f can promote the elimination of the alkoxide
shown in Scheme 10. from the trifluoromethyl ketone hemiacetal alkoxide, leading to
efficient in-situ generation of aryl trifluoromethyl ketone in the
reaction.
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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European Journal of Organic Chemistry 10.1002/ejoc.202000550

COMMUNICATION
and has several advantages, such as tolerance of a variety of Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley, Tetrahedron 2009, 65,
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We would like to thank Editage (www.editage.com) for English
6324-6325.
language editing.

Conflict of interest

Accepted Manuscript
The authors declare no competing financial interest.

Keywords: turbo Grignard reagent • tandem reaction •

halogen/magnesium-exchange reactions • reduction •
trifluoromethyl

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European Journal of Organic Chemistry 10.1002/ejoc.202000550

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.
1) i-PrMgClꞏLiCl
(more than 2 equiv.)
O
2) HO H
I RF OR H+ RF
FG FG
H2O
RF = CF3, CF2H, CF2Cl, CF2Me, CF2CF3 or
HO H

Accepted Manuscript
R = Me, CH2CF3
FG = OMe, Me, Ph, Br, CN, CO2Et etc. RF
or Het
I Y n
Het Y = N, S,
n n = 0,1 + ROH +
Y
ready removed

23 examples Up to 85% isolated yields

Broad substrate scope Readily scalable
Reducible functional group-tolerant

7
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