Halogen-Lithium Exchange of Sensitive (Hetero)aromatic Halides under Barbier Conditions in a Continuous Flow Set-Up

Article abstract of DOI:10.1055/s-0040-1707259

A halogen-lithium exchange reaction of (hetero)aromatic halides performed in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, and imines using BuLi as exchange reagent and a commercially available flow set-up is reported. The organolithiums generated in situ were instantaneously trapped with various electrophiles (Barbier conditions) resulting in the formation of polyfunctional (hetero)arenes. This method enables the functionalization of (hetero)arenes containing highly sensitive functional groups such as esters, which are not tolerated in batch conditions.

Full text of DOI:10.1055/s-0040-1707259

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–L
paper
A
en
N. Weidmann et al.
Paper
Synthesis
Halogen–Lithium Exchange of Sensitive (Hetero)aromatic Halides
under Barbier Conditions in a Continuous Flow Set-Up
Niels Weidmann◊a
Barbier reaction in flow
0.1 s
Rodolfo H. V. Nishimura◊b
Johannes H. Harenberga
–78 °C
nBuLi
(0.9 equiv)
N
O
N
Paul Knochel*a
0
0
0
0
-0
0
0
1
-
7
9
1
3
-
4
3
3
2
12 mL/min
Ph
Ph
+
N
Li Ph
Ph
N
O
N
+
OH
99%
a Ludwig-Maximilians-Universität München, Department Che-
mie, Butenandtstraße 5–13, 81377 München, Germany
Paul.knochel@cup.uni-muenchen.de
b Colegiado de Ciências Farmacêuticas, Universidade Federal do
Vale do São Francisco, Avenue José de Sá Maniçoba, Petrolina,
56304-205 Petrolina, Brazil
Ph
Ph
N
I
(1.0 equiv)
(1.0 equiv)
◊ These authors contributed equally
In memory of Prof. Dr. Kilian Muñiz
Corresponding Author
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstraße 5–13, 81377 München, Germany
Received: 21.07.2020
Accepted after revision: 29.07.2020
Published online: 02.09.2020
various (hetero)aryllithium derivatives in the presence of
electrophiles (Barbier conditions). In addition, the precise
control of reaction parameters such as temperature, reac-
tion time, and ultra-fast mixing using a commercial flow
set-up allows convenient reaction conditions at noncryo-
genic temperatures and scale-ups without further optimi-
zation of the reaction conditions.8
Herein, we report a Barbier halogen–lithium exchange
reaction of sensitive (hetero)aromatic halides of type 1 us-
ing nBuLi or tBuLi as exchange reagents in the presence of
various electrophiles of type 2 using a commercially avail-
able flow set-up.9 The resulting lithiated (hetero)aromatic
species of type 3 were quenched in situ with various elec-
trophiles resulting in a broad range of functionalized (hetero)-
aromatic products of type 4. We first screened the stoichi-
ometry of 1-chloro-4-iodobenzene (1a) and p-anisaldehyde
(2a, playing the role of an in situ electrophile) as well as the
reaction time and temperature (Scheme 1).
DOI: 10.1055/s-0040-1707259; Art ID: ss-2020-t0392-op
Abstract A halogen–lithium exchange reaction of (hetero)aromatic
halides performed in the presence of various electrophiles such as alde-
hydes, ketones, Weinreb amides, and imines using BuLi as exchange re-
agent and a commercially available flow set-up is reported. The organo-
lithiums generated in situ were instantaneously trapped with various
electrophiles (Barbier conditions) resulting in the formation of poly-
functional (hetero)arenes. This method enables the functionalization of
(hetero)arenes containing highly sensitive functional groups such as
esters, which are not tolerated in batch conditions.
Key words heterocycles, flow chemistry, organolithiums, Barbier re-
action, halogen–lithium exchange
Functionalized (hetero)arenes play an important role in
the elaboration of pharmaceuticals and agrochemicals.1
New strategies for the functionalization of aromatics and
heteroaromatics are still needed for extending the reaction
scope.2 In the past, lithium bases have been used to produce
various lithiated aromatics and heteroaromatics.3 However,
some major drawbacks, including a low functional group
tolerance and moderate stability of the resulting (hetero)-
aryllithiums, have been noticed.4 To overcome these limita-
tions, other organometallic reagents, such as organomagne-
sium and organozinc species with increased stability were
used.5 Nevertheless, their low reactivity towards electro-
philes often requires the presence of transition metal cata-
lysts.5 Recently, Yoshida and others reported an increased
compatibility of lithiated compounds bearing functional
groups under continuous flow conditions.6 Inspired by
Yoshida’s work and having in mind, that the halogen–lithi-
um exchange is a fast reaction for the generation of lithiated
(hetero)aromatics,7 we have examined the preparation of
flow
0.1 s
–78 °C
nBuLi
Li
CHO
OMe
OH
(1.0 equiv)
12 mL/min
CHO
+
I
Cl
OMe
+
MeO
Cl
Cl
4aa: 95%
3a
(1.0 equiv)
(1.0 equiv)
1a
2a
Scheme 1 Halogen–lithium exchange reaction of functionalized
(hetero)aryl halides of type 1 under Barbier conditions and in situ trap-
ping with various electrophiles of type 2 affording polyfunctionalized
(hetero)aryls of type 4 using a commercial continuous flow set-up
We found that by using a combined flow rate of
12 mL/min at –78 °C, arene 1a (1.0 equiv), electrophile 2a
(1.5 equiv), and nBuLi (1.5 equiv) as exchange reagent, a
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L
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B
N. Weidmann et al.
Paper
Synthesis
complete iodine–lithium exchange was obtained within 0.1
second and instantaneous trapping with p-anisaldehyde
(2a) led to the secondary alcohol 4aa in 72% GC-yield. In-
creasing the reaction time (up to 24 s) or conducting the re-
action at elevated temperatures (up to 0 °C) led to a de-
creased GC-yield of 62–65%. Finally, optimal results were
achieved using aromatic iodide 1a (1.0 equiv), aldehyde 2a
(1.0 equiv), and nBuLi (1.0 equiv) as exchange reagent. The
addition of nBuLi to p-anisaldehyde leading to a secondary
alcohol was a negligible side-reaction and 4aa was obtained
in 95% yield (Scheme 1). Similarly, 1,3-difluoro-2-iodoben-
zene (1b) gave the organolithium reagent 3b at –20 °C
within 1.9 seconds, which was subsequently trapped with
2a resulting in the secondary alcohol 4ba in 82% yield
(Scheme 2). The reaction of 1-methyl-4-iodobenzene (1c)
with p-anisaldehyde (2a) afforded the desired product 4ca
in 70% yield. The method was applied to dihalogenated
starting materials such as 1,4-diiodobenzene (1d) and 1-
bromo-2-iodobenzene (1e). The in situ generated organo-
lithiums 3d,e were immediately trapped with 2a resulting
in the corresponding alcohols 4da and 4ea in 85–87% yield.
As expected, using 1,4-diiodobenzene (1d) merely one io-
dine was exchanged. Additionally, 1-bromo-3-iodobenzene
(1e) underwent a clean I–Li exchange providing the benz-
hydryl alcohol 4ea in 85% yield. The exchange of 1-iodo-2-
(trifluoromethyl)benzene (1f) using nBuLi only led to the
undesired BuLi addition to the aldehyde, however, by using
tBuLi (2.0 equiv), the desired organolithium 3f was ob-
tained. After in situ trapping with o-anisaldehyde (2b) the
desired alcohol 4fb was isolated in 73% yield.
In contrast to the less reactive magnesium or zinc spe-
cies, we could trap the corresponding highly reactive lithi-
um species in situ using Barbier conditions with various ke-
tones resulting in tertiary alcohols. Remarkably, sterically
hindered ketones, which are prone to undergo a reduction
with lithium reagents,10 such as 2-adamantanone (2c) and
4-chlorophenyl cyclopropyl ketone (2d) were satisfactorily
used as trapping agents (Scheme 3). Thus, the aryllithium
3a was quenched with 2c and 2d resulting in the tertiary
alcohols 4ac,ad in 86–87% yield. Then, arenes bearing fluo-
ro, bromo, and iodo substituents were investigated using
our optimum flow conditions. The in situ generated aryl-
lithiums 3d, 3e, and 3g were subsequently trapped by cy-
clohexanone (2e), norcamphor (2f), 4-chlorophenyl cyclo-
propyl ketone (1d), and adamantanone (2c) affording the
functionalized arenes 4dd, 4df, 4ee, and 4gc in 66–91%
yield. Moreover, 1,2-difluoro-4-iodobenzene (1g) reacted
instantaneously with acetophenone (2g) without any de-
tection of aldol side products affording the alcohol 4gg in
64% yield. Similarly, 1-methyl-4-iodobenzene (1c) led after
in situ trapping of the lithiated species 3c with adamanta-
none (2c) and cyclohexanone (2e) to the corresponding ter-
tiary alcohols 4cc and 4ce in 76–92% yield. Notably, lithia-
tion of 1-iodo-2-(trifluoromethyl)benzene (1f) using the
optimum conditions in the presence of acetophenone (2g)
resulted in the organolithium 3f, which after in situ trap-
ping with acetophenone (2g) afforded the alcohol 4fg in
60% yield. Extending the flow procedure to isocyanates as in
situ trapping reagents was also possible. Thus, the addition
of 1f to phenyl isocyanate (2h) under our standard condi-
tions afforded the corresponding amide 4fh in 83% yield.
Next, we examined a Wurtz–Fittig-type coupling11 using
dodecyl iodide (1.5 equiv) in the absence of any transition
metal catalyst. To our delight, the alkylated arene 4fi was
obtained in 77% yield.2
We examined the behavior of ethyl 4-iodobenzoate
(1h), bearing an ester functionality, which is not tolerated
under batch conditions using lithium bases.12 However,
with a flow set-up we were able to perform an iodine–lithium
exchange in the presence of acetophenone (2g, 1.0 equiv).
The in situ trapping of the lithiated arene 3h resulted in the
desired tertiary alcohol 4hg in 91% yield, whereas a batch
reaction led to undesired side reactions and decomposition
of ester 1h (Scheme 4). Furthermore, the functionalization
of heterocycles is a key synthetic task for the elaboration of
pharmacological active compounds and agrochemicals.2 To
demonstrate the broad applicability of Barbier halogen–
lithium exchange reactions, we investigated its compatibili-
ty with heteroaromatic halides of type 5, affording func-
tionalized heterocycles of type 7 via the heteroaryllithium
species of type 6. Notably, 2-bromopyridine (5a) was used
to generate the highly reactive intermediate 2-pyridyllithi-
um (6a) at –78 °C within 0.1 second.
flow
batch
nBuLi
(0.9–1.0 equiv)
0.1 to 3.8 s
–78 to 0 °C
or
tBuLi
(2.0 equiv)
HO
H
Li
O
Ar
4–12 mL/min
FG
+
FG
Ar
H
Hal
O
FG
+
6 examples
of type 4
70–95% yield
3a–f
Ar
H
(1.0 equiv)
1a–f
(1.0 equiv)
2a,b
OH
F
OH
OH
Cl
OMe
F
OMe
Me
OMe
4aa: 95%a,b,c
4ba: 82%c,d,e
4ca: 70%c,d,e
OH
OH
CF3 OH OMe
Br
I
OMe
OMe
4da: 87%a,c,f
4ea: 85%b,c,g
4fb: 73%e,h,i
Scheme 2 Halogen–lithium exchange reaction of functionalized aryl
halides under Barbier conditions and in situ trapping with aldehydes using
a commercial continuous flow set-up. a –78 °C, 12 mL/min, 0.1 s.
b nBuLi = 1.0 equiv. c From the corresponding iodide. d –20 °C, 8 mL/min,
1.9 s. e tBuLi = 2.0 equiv. f nBuLi = 0.9 equiv. g 0 °C, 12 mL/min, 0.1 s.
h –20 °C, 4 mL/min, 3.8 s. i From the corresponding bromide.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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N. Weidmann et al.
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Synthesis
and secondary amine 7al in 59–62% yield (entries 4, 5). The
tertiary alcohol 7bc was obtained upon in situ quenching of
organolithium 6b at 0 °C within 7.5 seconds from 3-bro-
mopyridine (5b), whereas the bromine–lithium exchange
under batch conditions usually was performed at –78 °C
(entry 6). Further, 2,5-dibromopyridine (5c) was lithiated in
flow with nBuLi (0.9 equiv) with complete regioselectivity.
Upon an immediate quench of resulting lithium species 6c
with various sterically demanding ketones such as adaman-
tanone (2c) and 2,4-dimethylpentan-3-one (2m) solely the
2-substituted pyridines 7cc and 7cm were obtained in 53–
64% yield (entries 7, 8). Further, 3-iodo-2-methylpyridine
(5d) was subjected to these conditions affording after in
situ trapping with ketones 2d and 2n the desired tertiary
alcohols 7dd and 7dn in 81–92% yield (entries 9, 10). Fur-
ther, 2-iodopyrimidine (5e) was lithiated at –78 °C within
0.1 second affording upon Barbier trapping with ketones 2n
and 2o the sterically demanding tertiary alcohols 7eo and
7en in 79–99% yield (entries 11, 12).
flow
batch
nBuLi
(0.9–1.0 equiv)
0.1 to 3.8 s
–78 to 0 °C
or
tBuLi
(2.0 equiv)
Li
E
4–12 mL/min
FG
+
E-X
FG
Hal
FG
+
E-X
(1.0 equiv)
organolithiums
of type 3
products
of type 4
(1.0 equiv)
substrates
of type 1
electrophiles
of type 2
Cl
Cl
Br
OH
OH
OH
HO
Cl
I
4ac: 86%a,b,c
4ad: 87%a,b,c
4ee: 91%c,d,e
4df: 76%a,c,e
Me
HO
F
F
F
OH
OH
F
I
Cl
Me OH
4dd: 84%a,c,e
4gc: 66%c,f,g
4gg: 64%c,f,g
4cc: 76%c,f,g
CF3
O
Me
CF3
Ph
CF3
OH
Table 1 Halogen–Lithium Exchange Reaction of Functionalized Het-
eroaryl Halides of Type 5 under Barbier Conditions and in situ Trapping
of Intermediate Organolithiums of Type 6 with Electrophiles of Type 2
Affording Functionalized Heteroaryls of Type 7 in Continuous Flow
HN
Ph
C12H25
4fi: 77%g,h,i,j
HO Me
4ce: 92%c,f,g
4fg: 60%g,h,i
4fh: 83%g,h,i
Scheme 3 Halogen–lithium exchange reaction of functionalized aryl
halides under Barbier conditions and in situ trapping with sterically hin-
dered ketones, phenyl isocyanate and dodecyl iodide using a continuous
flow set-up. a –78 °C, 12 mL/min, 0.1 s. b nBuLi = 1.0 equiv. c From the
corresponding iodide. d 0 °C, 6 mL/min, 0.1 s. e nBuLi = 0.9 equiv. f –20 °C,
8 mL/min, 1.9 s. g tBuLi = 2.0 equiv. h –20 °C, 4 mL/min, 3.8 s. i From the
corresponding bromide. j Dodecyl iodide (1.5 equiv) was used.
Entry Metal species
Temp (°C); Time (s);
Flow rate (mL/min)
Electrophile
Product
O
OH
tBu tBu
N
tBu
tBu
N
Li
6a
–40; 0.1; 12
1
2
2j
7aj: 93%a
0.1 s
–78 °C
flow
batch
nBuLi
Me
Ph
HO
O
Li
OH
(1.00 equiv)
O
N
+
N
Li
I
12 mL/min
Ph
Me
O
CO2Et
+
CO2Et
4hg: 91%
6a
–40; 0.1; 12
2c
7ac: 98%b
Ph
Me
3h
CO2Et
(1.0 equiv)
1h
(1.0 equiv)
O
2g
N
N
Li
HO
batch
Cl
I
nBuLi (1.00 equiv)
O
6a
–40; 0.1; 12
3
4
2d
7ad: 99%b
+
decomposition
Ph
Me
–78 °C, THF
CO2Et
O
CF3
1.0 equiv
Me
0.2 mmol
1.0 equiv
N
N
N
Li
OMe
CF3
O
Scheme 4 In situ trapping iodine–lithium exchange reaction of highly
sensitive ethyl 4-iodobenzoate (1h) under Barbier conditions using a
commercial continuous flow set-up
6a
–40; 0.1; 12
2k
7ak: 62%b
Ph
N
Ph
NH
N
N
Li
Ph
Trapping of 6a with sterically demanding ketones 2c,
Ph
2d, and 2j afforded the tertiary alcohols 7ac, 7ad, and 7aj in
93–99% yield (Table 1, entries 1–3). Quenching with Wein-
reb amide 2k and imine 2l led to the desired ketone 7ak
6a
–40; 0.1; 12
5
2l
7al: 59%b
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D
N. Weidmann et al.
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Synthesis
lides led to a broad range of functionalized (hetero)arenes
in good to excellent yields. Further extensions of this work
are currently under way in our laboratories.
Entry Metal species
Electrophile
Product
Temp (°C); Time (s);
Flow rate (mL/min)
HO
O
Li
N
Tetradecane (nC14H30), dodecane (nC12H26), or undecane (nC11H24
)
N
were used as internal standards for GC analysis. All flasks were heat
gun dried (650 °C) under vacuum and backfilled with argon after
cooling. Syringes, which were used to transfer reagents and solvents,
were purged with argon three times prior to use. Batch quenching re-
actions were carried out with magnetic stirring. Flow reactions were
performed on commercially available flow systems. A Vapourtec E-se-
ries Integrated Flow Chemistry System with 3rd Pump Kit, Organome-
tallic Kit, Collection Valve Kit, and Cryogenic Reaction Kit or an Uniq-
sis FlowSyn system was used. If the Vapourtec System was used, hex-
ane solutions of nBuLi or tBuLi and THF solutions of the remaining
reactants were kept in flasks with rubber septa under an argon atmo-
sphere. If the Uniqsis system was used, carrier solvents as well as re-
actant solutions were stored under argon and injected to carrier sol-
vent streams. All reactions were performed in coiled tube reactors.
Coiled reactors were made from PFA or PTFE Teflon (I.D. = 0.8 mm or
0.25 mm, O.D. = 1.6 mm) tubing and T-pieces (I.D. = 0.5 mm) were
used as mixers. Prior to performing reactions, the systems were dried
by flushing with anhyd THF or hexane (flow rate of all pumps: 1.00
mL/min; run-time: 30 min).
6b
0; 7.5; 2
6
2c
7bc: 60%a
Br
O
Br
OH
N
N
Li
6c
7
8
2c
7cc: 64%b
–78; 0.15; 8
Br
Br
O
OH
iPr
N
iPr
iPr
N
Li
iPr
6c
2m
7cm: 53%b
–78; 0.15; 8
O
Li
HO
N
Me
Cl
Cl
N
Me
6d
9
2d
7dd: 81%b
–78; 0.1; 12
Flow and Subsequent Batch Quenching Reactions; General Proce-
dure
Ph
Ph
OH
Li
O
A nBuLi solution in hexane (0.20 M, 1.0 equiv) and a solution of (hete-
ro)aryl halide (0.20 M, 1.0 equiv) and electrophile (0.20 M, 1.0 equiv)
in THF were prepared. Injection loop A (volinj = 1.00 mL) was loaded
with nBuLi as exchange reagent and injection loop B (volinj = 1.00 mL)
was loaded with a solution containing (hetero)aryl halide and electro-
phile. The solutions were simultaneously injected into separate
streams of THF, respectively (pump A: THF; pump B: THF, flow rates:
Ph
Ph
N
Me
N
Me
6d
10
11
12
2n
7dn: 92%b
–78; 0.1; 12
O
N
N
Ph
N
1.00–6.00 mL/min), each of which passed a pre-cooling loop (volpre
=
N
Li
HO Ph
1.00 mL, T1 = –78 to 0 °C, residence time: 10–60 s), before they were
mixed in a T-mixer (PTFE, I.D. = 0.5 mm). The combined stream
passed a PTFE reactor tube (VolR = 0.02–0.25 mL; residence time: t1 =
0.1–3.4 s, T1 = –78 to 0 °C) and was subsequently collected in a flask.
The reaction mixture was quenched with sat. aq NH4Cl solution. The
aqueous phase was extracted with EtOAc and the organic phases were
dried and filtered. After removal of the solvent in vacuo, flash column
chromatography (silica gel, suitable isohexane:EtOAc mixture) afford-
ed the functionalized (hetero)arenes.
6e
2o
7eo: 79%b
–78; 0.1; 12
N
O
N
OH
Ph
N
Ph
Ph
N
Li
Ph
6e
–78; 0.1; 12
2n
7en: 99%b
a tBuLi: 2.0 equiv, prepared from the corresponding bromide.
b nBuLi: 0.9 equiv, prepared from the corresponding iodide.
Halogen–Lithium Exchange of (Hetero)aryl Halides with nBuLi as
Exchange Reagent; Typical Procedure 1 (TP1) Using an Uniqsis
Flow Setup
In summary, we have reported a general method to
functionalize (hetero)aryl halides using a halogen–lithium
exchange under Barbier conditions in continuous flow. The
merger of flow technology and highly reactive organolithi-
ums enables a functional group tolerance commonly not
accessible using lithium reagents under batch conditions. In
situ trapping with various electrophiles such as aldehydes,
ketones, imines, Weinreb amides, isocyanates, and alkyl ha-
An nBuLi solution in hexane (0.18 M, 0.9 equiv) and a solution of 2-
bromopyridine (5a; 41 mg, 0.20 M, 1.0 equiv), and 2-adamantanone
(2c; 30 mg, 0.20 M, 1.0 equiv) in THF were prepared. Injection loop A
(volinj = 1.00 mL) was loaded with nBuLi as exchange reagent and in-
jection loop B (volinj = 1.00 mL) was loaded with a solution containing
5a and 2c. The solutions were simultaneously injected into separate
streams of THF, respectively (pump A: THF; pump B: THF, flow rates:
6.00 mL/min), each of which passed a pre-cooling loop (volpre = 1.00
mL, T1 = –78 °C, residence time: 10 s) before they were mixed in a T-
mixer (PTFE, I.D. = 0.5 mm). The combined stream passed a PTFE reac-
tor tube (VolR = 0.02 mL; residence time: t1 = 0.1 s, T1 = –78 °C) and
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N. Weidmann et al.
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Synthesis
was subsequently collected in a flask. The reaction mixture was
quenched with sat. aq NH4Cl. The aqueous phase was extracted with
EtOAc and the organic phases were combined, dried, and filtered. Af-
ter removal of the solvent in vacuo, flash column chromatography
(silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title
compound 7ac as white crystals (45 mg, 0.18 mmol, 98%). See below
for full characterization of 7ac.
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 100:0 → 95:5 → 8:2) afforded the title compound
4ba as a colorless oil; yield: 41 mg (0.16 mmol, 82%).
IR (Diamond-ATR, neat): 3415, 2838, 1510, 1303, 1231, 1169, 1064,
1010, 868 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.35–7.29 (m, 2 H), 7.25 (tt, J = 8.4, 6.4
Hz, 1 H), 6.95–6.83 (m, 4 H), 6.19 (d, J = 8.4 Hz, 1 H), 3.79 (s, 3 H), 2.73
(dt, J = 9.4, 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 160.9 (dd, J = 248.2, 8.3 Hz, 2 C), 159.2,
134.4, 129.6 (t, J = 10.7 Hz), 127.1 (2 C), 119.6 (t, J = 16.4 Hz), 113.9 (2
C), 112.4–111.8 (m, 2 C), 67.6 (t, J = 3.5 Hz), 55.4.
Halogen–Lithium Exchange of (Hetero)aryl Halides with tBuLi as
Exchange Reagent; Typical Procedure 2 (TP2) Using a Vapourtec E-
Series Integrated Flow Chemistry System
A tBuLi solution in hexane (0.40 M, 2.0 equiv) and a solution of 2-bro-
mopyridine (5a; 32 mg, 0.20 M, 1.0 equiv) and hexamethylacetone
(2j; 28 mg, 0.20 M, 1.0 equiv) in THF were prepared. The solutions
were pumped from their flasks through a suction needle with a flow-
rate of 6.00 mL/min. After passing a PTFE tube (volpre = 1.00, T1 = –40
°C, residence time: 10 s) for precooling, the solutions were mixed in a
T-mixer (PTFE, I.D. = 0.5 mm). The combined stream passed a PTFE re-
actor tube (VolR = 0.02 mL; residence time: t1 = 0.1 s, T1 = –40 °C) and
was subsequently collected in an empty flask. The reaction mixture
was quenched with sat. aq NH4Cl solution. The aqueous phase was ex-
tracted with EtOAc and the organic phases were combined, dried, and
filtered. After removal of the solvent in vacuo, flash column chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 7aj as a yellow solid (41 mg, 0.19 mmol, 93%). See
below for full characterization.
MS (EI, 70 eV): m/z (%) = 250 (45), 233 (27), 141 (98), 137 (34), 109
(100), 108 (29), 94 (22).
HRMS (EI): m/z calcd for [C14H12F2O2]: 250.0805; found: 250.0799.
(4-Methoxyphenyl)(p-tolyl)methanol (4ca)
According to TP2, a solution of 1-iodo-4-methylbenzene (1c; 0.20 M,
44 mg, 0.20 mmol) and p-anisaldehyde (2a; 0.20 M, 27 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi (0.40 M
in hexane, 0.40 mmol, 2.0 equiv) were prepared. The precooled solu-
tions were mixed with an overall 8 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.9 s, –20 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 4ca as a
white solid; yield: 32 mg (0.14 mmol, 70%); mp 63.8–64.7 °C.
1H NMR (400 MHz, CD2Cl2):  = 7.31–7.19 (m, 4 H), 7.19–7.10 (m, 2
H), 6.89–6.81 (m, 2 H), 5.75 (d, J = 3.4 Hz, 1 H), 3.77 (s, 3 H), 2.32 (s, 3
H), 2.25 (dd, J = 3.5, 0.6 Hz, 1 H).
13C NMR (100 MHz, CD2Cl2):  = 159.6, 142.1, 137.7, 137.2, 129.6 (2 C),
128.2 (2 C), 126.7 (2 C), 114.3 (2 C), 76.0, 55.8, 21.3.
(4-Chlorophenyl)(4-methoxyphenyl)methanol (4aa)
According to TP1, a solution of 1-chloro-4-iodobenzene (1a; 0.20 M,
48 mg, 0.20 mmol) and p-anisaldehyde (2a; 0.20 M, 27 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.20 M
in hexane, 0.20 mmol, 1.00 equiv) were prepared. The precooled solu-
tions were mixed with an overall 12 mL/min flowrate in a T-mixer.
The combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C)
and was subsequently injected into an empty flask. Stirring was con-
tinued for 10 min at 25 °C before sat. aq NH4Cl solution was added to
quench the reaction. The aqueous phase was extracted with EtOAc (3
× 30 mL) and the combined organic phases were dried (anhyd Na2SO4)
and filtered. After removal of the solvent, flash chromatography (sili-
ca gel, isohexane:EtOAc = 100:0 → 95:5 → 7:3) afforded the title com-
pound 4aa as a white solid; yield: 47 mg (0.19 mmol, 95%); mp 54.2–
56.7 °C.
The spectroscopic data match the literature values.14
(4-Iodophenyl)(4-methoxyphenyl)methanol (4da)
According to TP1, a solution of 1,4-diiodobenzene (1d; 0.20 M, 66 mg,
0.20 mmol) and p-anisaldehyde (2a; 0.20 M, 27 mg, 0.20 mmol) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M in hex-
ane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 4da as a
white solid; yield: 53 mg (0.16 mmol, 87%); mp 94.6–96.0 °C.
1H NMR (400 MHz, CD2Cl2):  = 7.34–7.29 (m, 4 H), 7.28–7.22 (m, 2
H), 6.89–6.84 (m, 2 H), 5.76 (s, 1 H), 3.77 (s, 3 H), 2.42 (s, 1 H).
13C NMR (100 MHz, CD2Cl2):  = 159.8, 143.6, 136.6, 133.4, 128.9 (2 C),
128.3 (4 C), 114.4 (2 C), 75.5, 55.8.
The spectroscopic data match the literature values.13
(2,6-Difluorophenyl)(4-methoxyphenyl)methanol (4ba)
According to TP1, a solution of 1,3-difluoro-2-iodobenzene (1b; 0.20
M, 50 mg, 0.20 mmol) and p-anisaldehyde (2a; 0.20 M, 27 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.20 M
in hexane, 0.20 mmol, 1.0 equiv) were prepared. The precooled solu-
tions were mixed with an overall 12 mL/min flowrate in a T-mixer.
The combined stream passed a 0.25 mL reactor tube (1.3 s, 0 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
IR (Diamond-ATR, neat): 3253, 1741, 1510, 1392, 1249, 1217, 1110,
1019, 1000, 799 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.68–7.62 (m, 2 H), 7.25–7.21 (m, 2 H),
7.14–7.09 (m, 2 H), 6.88–6.82 (m, 2 H), 5.72 (d, J = 2.9 Hz, 1 H), 3.79 (s,
3 H), 2.30 (d, J = 3.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 159.4, 143.8, 137.5 (2 C), 135.8, 128.5
(2 C), 128.0 (2 C), 114.1 (2 C), 93.0, 75.4, 55.4.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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N. Weidmann et al.
Paper
Synthesis
MS (EI, 70 eV): m/z (%) = 340 (28), 231 (50), 152 (24), 137 (16), 135
(100), 109 (70), 108 (31), 94 (14).
quench the reaction. The aqueous phase was extracted with EtOAc (3
× 30 mL) and the combined organic phases were dried (anhyd Na2SO4)
and filtered. After removal of the solvent, flash chromatography (sili-
ca gel, isohexane:EtOAc = 100:0 → 95:5) afforded the title compound
4ac as a white solid; yield: 45 mg (0.17 mmol, 86%); mp 84.2–85.7 °C.
HRMS (EI): m/z calcd for [C14H13IO2]: 339.9960; found: 339.9955.
(3-Bromophenyl)(4-methoxyphenyl)methanol (4ea)
IR (Diamond-ATR, neat): 2931, 2896, 1493, 1093, 1014, 970, 932, 911,
According to TP1, a solution of 1-bromo-3-iodobenzene (1e; 0.20 M,
57 mg, 0.20 mmol) and p-anisaldehyde (2a; 0.20 M, 27 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M
in hexane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solu-
tions were mixed with an overall 6 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (2.5 s, 0 °C) and was
subsequently injected into an empty flask. Stirring was continued for
10 min at 25 °C before sat. aq NH4Cl solution was added to quench the
reaction. The aqueous phase was extracted with EtOAc (3 × 30 mL)
and the combined organic phases were dried (anhyd Na2SO4) and fil-
tered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 100:0 → 95:5 → 9:1) afforded the title compound
4ea as a yellow oil; yield: 45 mg (0.15 mmol, 85%).
822, 720 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.49–7.44 (m, 2 H), 7.36–7.31 (m, 2 H),
2.50 (s, 2 H), 2.38 (d, J = 12.5 Hz, 2 H), 1.90 (t, J = 2.9 Hz, 1 H), 1.73 (d, J
= 12.9 Hz, 7 H), 1.64 (d, J = 13.4 Hz, 2 H), 1.55 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 144.0, 133.1, 128.9 (2 C), 127.2 (2 C),
75.4, 37.7, 35.8 (2 C), 34.9 (2 C), 33.0 (2 C), 27.5, 26.9.
MS (EI, 70 eV): m/z (%) = 253 (21), 141 (33), 139 (100), 91 (25), 81
(20), 80 (19), 79 (45).
HRMS (EI): m/z calcd for [C16H19ClO]: 262.1124; found: 262.1121.
Bis(4-chlorophenyl)(cyclopropyl)methanol (4ad)
1H NMR (400 MHz, CDCl3):  = 7.57 (t, J = 1.8 Hz, 1 H), 7.40 (ddd, J =
7.9, 2.1, 1.1 Hz, 1 H), 7.32–7.25 (m, 3 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.92–
6.87 (m, 2 H), 5.76 (s, 1 H), 3.82 (s, 3 H), 2.37 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 159.4, 146.4, 135.7, 130.5, 130.1,
129.5, 128.1 (2 C), 125.1, 122.7, 114.2 (2 C), 75.3, 55.4.
According to TP1, a solution of 1-chloro-4-iodobenzene (1a; 0.20 M,
48 mg, 0.20 mmol) and (4-chlorophenyl)(cyclopropyl)methanone
(2d; 0.20 M, 36 mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a
solution of nBuLi (0.20 M in hexane, 0.20 mmol, 1.0 equiv) were pre-
pared. The precooled solutions were mixed with an overall 12
mL/min flowrate in a T-mixer. The combined stream passed a 0.02 mL
reactor tube (0.1 s, –78 °C) and was subsequently injected into an
empty flask. Stirring was continued for 10 min at 25 °C before sat. aq
NH4Cl solution was added to quench the reaction. The aqueous phase
was extracted with EtOAc (3 × 30 mL) and the combined organic
phases were dried (anhyd Na2SO4) and filtered. After removal of the
solvent, flash chromatography (silica gel, isohexane:EtOAc = 100:0 →
95:5) afforded the title compound 4ad as a colorless oil; yield: 51 mg
(0.17 mmol, 87%).
The spectroscopic data match the literature values.15
(2-Methoxyphenyl)[2-(trifluoromethyl)phenyl]methanol (4fb)
According to TP2, a solution of 1-bromo-2-(trifluoromethyl)benzene
(1f; 0.20 M, 45 mg, 0.20 mmol) and o-anisaldehyde (2b; 0.20 M, 27
mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 4 mL/min flowrate in a
T-mixer. The combined stream passed a 0.25 mL reactor tube (3.8 s,
–20 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 85:15) afforded
the title compound 4fb as a pale yellow oil; yield: 41 mg (0.15 mmol,
73%).
1H NMR (400 MHz, CDCl3):  = 7.38–7.33 (m, 4 H), 7.30–7.26 (m, 4 H),
1.87 (s, 1 H), 1.60–1.51 (m, 1 H), 0.63–0.58 (m, 2 H), 0.47–0.42 (m, 2
H).
13C NMR (100 MHz, CDCl3):  = 145.4 (2 C), 133.3 (2 C), 128.4 (4 C),
128.3 (4 C), 76.6, 21.7, 1.9 (2 C).
The spectroscopic data match the literature values.17
1-(3-Bromophenyl)cyclohexanol (4ee)
1H NMR (600 MHz, CDCl3):  = 7.69 (d, J = 7.9 Hz, 1 H), 7.66 (d, J = 7.9
Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.28 (d, J = 7.8
Hz, 1 H), 6.99 (d, J = 1.8 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.84 (dd, J =
8.2, 2.6 Hz, 1 H), 6.31 (d, J = 3.2 Hz, 1 H), 3.81 (s, 3 H), 2.41 (d, J = 3.7
Hz, 1 H).
13C NMR (150 MHz, CDCl3):  = 159.8, 144.6, 142.4, 132.5 (d, J = 1.0
Hz), 129.7, 129.6, 127.9, 127.8 (q, J = 30.1 Hz), 125.7 (q, J = 5.8 Hz),
124.5 (q, J = 274.1 Hz), 118.9, 113.0, 112.3, 70.8 (q, J = 2.4 Hz), 55.3.
According to TP1, a solution of 1-bromo-3-iodobenzene (1e; 0.20 M,
57 mg, 0.20 mmol) and cyclohexanone (2e; 0.20 M, 20 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M
in hexane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solu-
tions were mixed with an overall 6 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (2.5 s, 0 °C) and was
subsequently injected into an empty flask. Stirring was continued for
10 min at 25 °C before sat. aq NH4Cl solution was added to quench the
reaction. The aqueous phase was extracted with EtOAc (3 × 30 mL)
and the combined organic phases were dried (anhyd Na2SO4) and fil-
tered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 100:0 → 95:5 → 9:1) afforded the title compound
4ee as a colorless oil; yield: 42 mg (0.16 mmol, 91%).
1H NMR (400 MHz, CDCl3):  = 7.66 (t, J = 1.9 Hz, 1 H), 7.42 (ddd, J =
7.8, 1.8, 1.1 Hz, 1 H), 7.37 (ddd, J = 7.9, 2.0, 1.1 Hz, 1 H), 7.21 (t, J = 7.9
Hz, 1 H), 1.85–1.62 (m, 11 H).
13C NMR (100 MHz, CDCl3):  = 152.0, 129.9, 129.8, 128.2, 123.4,
122.6, 73.1, 38.9 (2 C), 25.5, 22.2 (2 C).
The spectroscopic data match the literature values.16
Adamant-2-yl(4-chlorophenyl)methanol (4ac)
According to TP1, a solution of 1-chloro-4-iodobenzene (1a; 0.20 M,
48 mg, 0.20 mmol) and 2-adamantanone (2c; 0.20 M, 30 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.20 M
in hexane, 0.20 mmol, 1.0 equiv) were prepared. The precooled solu-
tions were mixed with an overall 12 mL/min flowrate in a T-mixer.
The combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C)
and was subsequently injected into an empty flask. Stirring was con-
tinued for 10 min at 25 °C before sat. aq NH4Cl solution was added to
The spectroscopic data match the literature values.18
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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N. Weidmann et al.
Paper
Synthesis
2-(4-Iodophenyl)bicyclo[2.2.1]heptan-2-ol (4df)
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 4gc as a white solid; yield: 35 mg (0.13 mmol,
66%); mp 89.9–90.4 °C.
According to TP1, a solution of 1,4-diiodobenzene (1d; 0.20 M, 66 mg,
0.20 mmol) and norcamphor (2f; 0.20 M, 22 mg, 0.20 mmol) in THF
(total volume: 1.00 mL) and a solution of nBuLi (0.18 M in hexane,
0.18 mmol, 0.9 equiv) were prepared. The precooled solutions were
mixed with an overall 12 mL/min flowrate in a T-mixer. The com-
bined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and was
subsequently injected into an empty flask. Stirring was continued for
10 min at 25 °C before sat. aq NH4Cl solution was added to quench the
reaction. The aqueous phase was extracted with EtOAc (3 × 30 mL)
and the combined organic phases were dried (anhyd Na2SO4) and fil-
tered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 4df as
white crystals; yield: 43 mg (0.14 mmol, 76%); mp 92.8–94.9 °C.
IR (Diamond-ATR, neat): 3320, 1605, 1520, 1449, 1389, 1276, 1148,
1045, 945 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.34 (ddd, J = 12.5, 7.7, 2.3 Hz, 1 H),
7.29–7.22 (m, 1 H), 7.15 (dt, J = 10.1, 8.4 Hz, 1 H), 2.46 (t, J = 2.9 Hz, 2
H), 2.41–2.31 (m, 2 H), 1.90 (h, J = 3.1 Hz, 1 H), 1.80–1.68 (m, 7 H),
1.64 (dt, J = 13.6, 2.5 Hz, 2 H), 1.53 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 151.3 (dd, J = 120.5, 12.6 Hz), 148.8
(dd, J = 121.6, 12.6 Hz), 142.8 (t, J = 4.2 Hz), 121.8 (dd, J = 6.1, 3.5 Hz),
117.4 (d, J = 16.9 Hz), 115.1 (d, J = 17.8 Hz), 75.3, 37.6, 35.9 (2 C), 34.9
(2 C), 33.0 (2 C), 27.4, 26.8.
IR (Diamond-ATR, neat): 3336, 2941, 2865, 1579, 1449, 1309, 1142,
1019, 1000, 958 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.68–7.63 (m, 2 H), 7.29–7.24 (m, 2 H),
2.54–2.51 (m, 1 H), 2.31 (td, J = 5.9, 5.3, 2.5 Hz, 1 H), 2.23 (ddd, J =
13.2, 4.9, 2.8 Hz, 1 H), 2.19–2.10 (m, 1 H), 1.68 (s, 1 H), 1.66–1.60 (m,
1 H), 1.55–1.41 (m, 4 H), 1.34 (ddt, J = 10.1, 3.4, 1.7 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 264 (13), 247 (15), 246 (100), 221 (15), 204
(13), 141 (43), 91 (10).
HRMS (EI): m/z calcd for [C16H18F2O]: 264.1326; found: 264.1313.
13C NMR (100 MHz, CDCl3):  = 148.9, 137.4 (2 C), 128.2 (2 C), 92.5,
80.7, 47.4, 46.9, 38.9, 37.7, 29.1, 22.4.
1-(3,4-Difluorophenyl)-1-phenylethan-1-ol (4gg)
MS (EI, 70 eV): m/z (%) = 259 (11), 246 (55), 231 (100), 187 (57), 169
According to TP2, a solution of 4-bromo-1,2-difluorobenzene (1g;
0.20 M, 39 mg, 0.20 mmol) and acetophenone (2g; 0.20 M, 24 mg,
0.20 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 8 mL/min flowrate in a
T-mixer. The combined stream passed a 0.25 mL reactor tube (1.9 s,
–20 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 4gg as a pale yellow oil; yield: 30 mg (0.13 mmol,
64%).
(14), 141 (14), 132 (23).
HRMS (EI): m/z calcd for [C13H15IO]: 314.0168; found: 314.0163.
(4-Chlorophenyl)(cyclopropyl)(4-iodophenyl)methanol (4dd)
According to TP1, a solution of 1,4-diiodobenzene (1d; 0.20 M, 66 mg,
0.20 mmol) and (4-chlorophenyl)(cyclopropyl)methanone (2d; 0.20
M, 36 mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a solution
of nBuLi (0.18 M in hexane, 0.18 mmol, 0.9 equiv) were prepared. The
precooled solutions were mixed with an overall 12 mL/min flowrate
in a T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1
s, –78 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1) afforded the title
compound 4dd as a pale yellow oil; yield: 58 mg (0.15 mmol, 84%).
IR (Diamond-ATR, neat): 3417, 3060, 1510, 1446, 1373, 1298, 1275,
1157, 1101, 917, 875 cm–1
.
1H NMR (400 MHz, CD2Cl2):  = 7.42–7.39 (m, 2 H), 7.35–7.24 (m, 4
H), 7.13–7.09 (m, 2 H), 2.34 (s, 1 H), 1.92 (s, 3 H).
IR (Diamond-ATR, neat): 3575, 3476, 3079, 1902, 1593, 1483, 1390,
13C NMR (100 MHz, CD2Cl2):  = 150.4 (dd, J = 246.6, 12.7 Hz), 149.6
(dd, J = 246.6, 12.7 Hz), 147.9, 146.3 (dd, J = 4.7, 3.8 Hz), 128.9 (2 C),
127.8, 126.2 (2 C), 122.5 (dd, J = 6.3, 3.5 Hz), 117.2 (d, J = 16.9 Hz),
115.7 (d, J = 18.3 Hz), 76.0 (d, J = 1.3 Hz), 31.2.
1367, 1296, 1144, 1060, 982 cm–1
.
1H NMR (400 MHz, CD2Cl2):  = 7.67–7.63 (m, 2 H), 7.40–7.35 (m, 2
H), 7.32–7.27 (m, 2 H), 7.21–7.16 (m, 2 H), 2.00 (s, 1 H), 1.56 (tt, J =
8.3, 5.5 Hz, 1 H), 0.62–0.55 (m, 2 H), 0.43 (tdd, J = 5.2, 4.2, 1.7 Hz, 2 H).
13C NMR (100 MHz, CD2Cl2):  = 147.3, 146.0, 137.6 (2 C), 133.5, 129.4
(2 C), 128.9 (2 C), 128.6 (2 C), 93.3, 77.0, 21.8, 2.2, 2.1.
MS (EI, 70 eV): m/z (%) = 220 (13), 219 (100).
HRMS (EI): m/z calcd for [C14H12F2O]: 234.0856; found: 234.0844.
MS (EI, 70 eV): m/z (%) = 358 (32), 356 (100), 343 (19), 231 (36), 165
(16), 141 (15), 139 (46).
2-(p-Tolyl)adamantan-2-ol (4cc)
According to TP2, a solution of 1-iodo-4-methylbenzene (1c; 0.20 M,
44 mg, 0.20 mmol) and 2-adamantanone (2c; 0.20 M, 30 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi (0.40 M
in hexane, 0.40 mmol, 2.0 equiv) were prepared. The precooled solu-
tions were mixed with an overall 8 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.9 s, –20 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4), and
HRMS (EI): m/z calcd for [C16H14ClIO]: 383.9778; found: 383.9775.
2-(3,4-Difluorophenyl)adamantan-2-ol (4gc)
According to TP2, a solution of 4-bromo-1,2-difluorobenzene (1c;
0.20 M, 39 mg, 0.20 mmol) and 2-adamantanone (2g; 0.20 M, 30 mg,
0.20 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 8 mL/min flowrate in a
T-mixer. The combined stream passed a 0.25 mL reactor tube (1.9 s,
–20 °C) and was subsequently injected into an empty flask. Stirring
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N. Weidmann et al.
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filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 4cc as a
white solid; yield: 37 mg (0.15 mmol, 76%); mp 73.6–75.4 °C.
13C NMR (100 MHz, CD2Cl2):  = 148.8 (d, J = 1.3 Hz), 146.5 (d, J = 1.3
Hz), 132.0 (d, J = 1.1 Hz), 129.8, 128.8 (q, J = 6.8 Hz), 128.6 (2 C), 128.3
(q, J = 31.2 Hz), 128.1, 127.5, 125.8 (2 C), 125.2 (q, J = 273.9 Hz), 77.6,
33.2 (d, J = 1.4 Hz).
IR (Diamond-ATR, neat): 3450, 2930, 2887, 1514, 1349, 1192, 1082,
1020, 971, 934 cm–1
.
MS (EI, 70 eV): m/z (%) = 251 (46), 232 (14), 231 (97), 212 (15), 211
(100), 183 (26).
1H NMR (400 MHz, CDCl3):  = 7.44 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.2
Hz, 2 H), 2.55 (s, 2 H), 2.41 (d, J = 12.3 Hz, 2 H), 2.35 (s, 3 H), 1.91 (s, 1
H), 1.76–1.70 (m, 9 H), 1.48 (s, 1 H).
HRMS (EI): m/z calcd for [C15H13F3O]: 266.0918; found: 266.0906.
13C NMR (100 MHz, CDCl3):  = 142.6, 137.0, 129.5 (2 C), 125.5 (2 C),
N-Phenyl-2-(trifluoromethyl)benzamide (4fh)
75.6, 37.8, 35.8 (2 C), 35.1 (2 C), 33.1 (2 C), 27.6, 27.1, 21.1.
According to TP1, a solution of 1-iodo-2-(trifluoromethyl)benzene
(1f; 0.20 M, 54 mg, 0.20 mmol) and phenyl isocyanate (2h; 0.20 M, 24
mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.18 M in hexane, 0.18 mmol, 0.9 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 12 mL/min flowrate in a
T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1 s,
–78 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 9:1) afforded the title com-
pound 4fh as white crystals; yield: 42 mg (0.15 mmol, 83%); mp
145.1–147.7 °C.
1H NMR (400 MHz, CDCl3):  = 7.74 (d, J = 7.6 Hz, 1 H), 7.64 (dd, J = 4.2,
1.3 Hz, 2 H), 7.61–7.56 (m, 4 H), 7.37 (dd, J = 8.6, 7.3 Hz, 2 H), 7.18 (t,
J = 7.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 165.9, 137.5, 135.9 (q, J = 2.0 Hz),
132.3, 130.3, 129.3 (2 C), 128.7, 127.5 (q, J = 31.7 Hz), 126.6 (q, J = 4.9
Hz), 125.2, 123.7 (q, J = 273.8 Hz), 120.4 (2 C).
MS (EI, 70 eV): m/z (%) = 242 (34), 227 (29), 224 (43), 121 (19), 119
(100), 91 (28).
HRMS (EI): m/z calcd for [C17H22O]: 242.1671; found: 242.1659.
1-(p-Tolyl)cyclohexan-1-ol (4ce)
According to TP2, a solution of 1-iodo-4-methylbenzene (1c; 0.20 M,
44 mg, 0.20 mmol) and cyclohexanone (2e, 0.20 M, 20 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi (0.40 M
in hexane, 0.40 mmol, 2.0 equiv) were prepared. The precooled solu-
tions were mixed with an overall 8 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.9 s, –20 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 4ce as a
white solid; yield: 35 mg (0.18 mmol, 92%); mp 53.3–55.2 °C.
1H NMR (400 MHz, CDCl3):  = 7.41 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2
Hz, 2 H), 2.35 (s, 3 H), 1.86–1.71 (m, 7 H), 1.66–1.61 (m, 2 H), 1.57 (s, 1
H), 1.36–1.26 (m, 1 H).
The spectroscopic data match the literature values.20
1-Dodecyl-2-(trifluoromethyl)benzene (4fi)
13C NMR (100 MHz, CDCl3):  = 146.6, 136.4, 129.0 (2 C), 124.6 (2 C),
According to TP2, a solution of 1-iodo-2-(trifluoromethyl)benzene
(1f; 0.20 M, 45 mg, 0.20 mmol) and dodecyl iodide (2i; 0.30 M, 89 mg,
0.30 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 4 mL/min flowrate in a
T-mixer. The combined stream passed a 0.25 mL reactor tube (3.8 s,
–20 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
hexane (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane) afforded the title compound 4fi as a
colorless oil; yield: 48 mg (0.15 mmol, 77%).
73.1, 39.0 (2 C), 25.7, 22.4 (2 C), 21.1.
The spectroscopic data match the literature values.19
1-Phenyl-1-[2-(trifluoromethyl)phenyl]ethan-1-ol (4fg)
According to TP2, a solution of 1-bromo-2-(trifluoromethyl)benzene
(1f; 0.20 M, 45 mg, 0.20 mmol) and acetophenone (2g; 0.20 M, 24 mg,
0.20 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 4 mL/min flowrate in a
T-mixer. The combined stream passed a 0.25 mL reactor tube (3.8 s,
–20 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 85:15) afforded
the title compound 4fg as a pale yellow oil; yield: 32 mg (0.12 mmol,
60%).
IR (Diamond-ATR, neat): 2955, 2853, 1466, 1312, 1167, 1122, 1060,
1035, 766, 654 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.60 (dd, J = 7.9, 1.3 Hz, 1 H), 7.45 (td,
J = 7.6, 1.3 Hz, 1 H), 7.32 (d, J = 7.7 Hz, 1 H), 7.26 (d, J = 15.3 Hz, 1 H),
3.19 (t, J = 7.1 Hz, 3 H), 2.80–2.71 (m, 2 H), 1.82 (pent, J = 7.1 Hz, 3 H),
1.66–1.51 (m, 2 H), 1.39 (dt, J = 9.1, 4.1 Hz, 7 H), 0.88 (t, J = 6.8 Hz, 8
H).
13C NMR (100 MHz, CDCl3):  = 141.8 (q, J = 1.6 Hz), 131.6, 130.9,
128.3 (q, J = 29.7 Hz), 125.8 (q, J = 5.8 Hz), 125.6, 124.7 (d, J = 273.9
Hz), 33.6, 32.8, 32.0, 30.5, 29.7, 29.6, 29.5, 29.4, 28.6, 22.7, 14.2, 7.4.
IR (Diamond-ATR, neat): 3455, 2983, 1494, 1374, 1270, 1163, 1095,
1070, 1032, 959 cm–1
.
1H NMR (400 MHz, CD2Cl2):  = 7.75 (dd, J = 8.0, 1.2 Hz, 1 H), 7.71 (d,
J = 8.0 Hz, 1 H), 7.57 (td, J = 7.8, 0.9 Hz, 1 H), 7.47–7.41 (m, 1 H), 7.32–
7.21 (m, 5 H), 2.52 (s, 1 H), 1.98 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 161 (10), 160 (100), 159 (43), 109 (10), 91
(21).
HRMS (EI): m/z calcd for [C19H29F3]: 314.2221; found: 314.2213.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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Synthesis
Ethyl 4-(1-Hydroxy-1-phenylethyl)benzoate (4hg)
1H NMR (400 MHz, CDCl3):  = 8.58 (ddd, J = 4.8, 1.9, 1.0 Hz, 1 H), 7.68
(td, J = 7.8, 1.9 Hz, 1 H), 7.49 (dt, J = 8.0, 1.1 Hz, 1 H), 7.16 (ddd, J = 7.5,
4.8, 1.1 Hz, 1 H), 2.67 (q, J = 3.3 Hz, 2 H), 2.49–2.35 (m, 2 H), 2.16 (s, 1
H), 1.90 (pent, J = 3.1 Hz, 1 H), 1.83–1.60 (m, 9 H).
13C NMR (100 MHz, CDCl3):  = 164.3, 149.4, 136.7, 122.2, 120.3, 37.9,
35.1 (2 C), 35.0 (2 C), 33.0 (2 C), 27.5, 27.2.
According to TP1, a solution of ethyl 4-iodobenzoate (1h; 0.20 M, 55
mg, 0.20 mmol) and acetophenone (2g, 0.20 M, 24 mg, 0.20 mmol) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.20 M in hex-
ane, 0.20 mmol, 1.0 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title compound
4hg as a pale yellow oil; yield: 49 mg (0.18 mmol, 91%).
1H NMR (400 MHz, CD2Cl2):  = 7.98–7.93 (m, 2 H), 7.53–7.48 (m, 2
H), 7.43–7.39 (m, 2 H), 7.35–7.29 (m, 2 H), 7.27–7.22 (m, 1 H), 4.33 (q,
J = 7.1 Hz, 2 H), 2.40 (s, 1 H), 1.96 (s, 3 H), 1.36 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CD2Cl2):  = 166.8, 153.7, 148.1, 129.8 (2 C), 129.7,
128.8 (2 C), 127.7, 126.3 (2 C), 126.3 (2 C), 76.5, 61.4, 31.0, 14.7.
The spectroscopic data match the literature values.23
(4-Chlorophenyl)(cyclopropyl)(pyridin-2-yl)methanol (7ad)
According to TP1, a solution of 2-iodopyridine (5f; 0.20 M, 41 mg,
0.20 mmol) and (4-chlorophenyl)(cyclopropyl)methanone (2d; 0.20
M, 36 mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a solution
of nBuLi (0.18 M in hexane, 0.18 mmol, 0.9 equiv) were prepared. The
precooled solutions were mixed with an overall 12 mL/min flowrate
in a T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1
s, –78 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 7ad as a colorless oil; yield: 50 mg (0.18 mmol,
99%).
The spectroscopic data match the literature values.21
2,2,4,4-Tetramethyl-3-(pyridin-2-yl)pentan-3-ol (7aj)
According to TP2, a solution of 2-bromopyridine (5a; 0.20 M, 31 mg,
0.20 mmol) and 2,2,4,4-tetramethylpentan-3-one (2j; 0.20 M, 28 mg,
0.20 mmol) in THF (total volume: 1.00 mL) and a solution of tBuLi
(0.40 M in hexane, 0.40 mmol, 2.0 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 12 mL/min flowrate in a
T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1 s,
–40 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 7aj as a yellow solid, yield: 41 mg (0.19 mmol,
93%); mp 42.7–43.8 °C.
IR (Diamond-ATR, neat): 3339, 1592, 1489, 1433, 1356, 1294, 1211,
1152, 1048, 994 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.48 (ddd, J = 4.9, 1.7, 1.0 Hz, 1 H), 7.63
(td, J = 7.7, 1.7 Hz, 1 H), 7.49–7.43 (m, 2 H), 7.28–7.15 (m, 4 H), 5.74 (s,
1 H), 1.59 (tt, J = 8.2, 5.3 Hz, 1 H), 0.67–0.54 (m, 2 H), 0.45 (dtd, J = 9.5,
5.5, 4.3 Hz, 1 H), 0.35 (dddd, J = 9.0, 8.1, 6.1, 4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 163.8, 147.1, 145.3, 137.1, 133.1, 128.7
(2 C), 128.3 (2 C), 122.4, 121.2, 75.0, 20.5, 1.9, 0.8.
MS (EI, 70 eV): m/z (%) = 218 (23), 141 (25), 139 (78), 134 (58), 132
(20), 106 (28), 96 (54), 93 (21), 79 (37), 78 (100), 75 (28).
HRMS (EI): m/z calcd for [C15H14ClNO]: 259.0764; found 258.0680 (M
– H).
1H NMR (400 MHz, CDCl3):  = 8.50 (ddd, J = 5.0, 1.7, 1.2 Hz, 1 H), 7.64
(ddd, J = 8.9, 6.9, 1.8 Hz, 1 H), 7.60 (dt, J = 8.2, 1.3 Hz, 1 H), 7.20 (ddd,
J = 6.9, 5.0, 1.3 Hz, 1 H), 1.04 (s, 18 H).
13C NMR (100 MHz, CDCl3):  = 162.5, 145.9, 135.1, 123.4, 121.9, 82.0,
41.5 (2 C), 29.6 (6 C).
Pyridin-2-yl[4-(trifluoromethyl)phenyl]methanone (7ak)
According to TP1, a solution of 2-iodopyridine (5f; 0.20 M, 41 mg,
0.20 mmol) and N-methoxy-N-methyl-4-(trifluoromethyl)benzamide
(2k; 0.20 M, 33 mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a
solution of nBuLi (0.18 M in hexane, 0.18 mmol, 0.9 equiv) were pre-
pared. The precooled solutions were mixed with an overall 12
mL/min flowrate in a T-mixer. The combined stream passed a 0.02 mL
reactor tube (0.1 s, –78 °C) and was subsequently injected into an
empty flask. Stirring was continued for 10 min at 25 °C before sat. aq
NH4Cl solution was added to quench the reaction. The aqueous phase
was extracted with EtOAc (3 × 30 mL) and the combined organic
phases were dried (anhyd Na2SO4) and filtered. After removal of the
solvent, flash chromatography (silica gel, isohexane:EtOAc = 95:5 →
9:1) afforded the title compound 7ak as a yellow oil; yield: 30 mg
(0.11 mmol, 62%).
1H NMR (400 MHz, CDCl3):  = 8.73 (ddd, J = 4.7, 1.6, 0.9 Hz, 1 H),
8.23–8.09 (m, 3 H), 7.95 (td, J = 7.7, 1.7 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 2
H), 7.54 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 192.9, 154.2, 148.8, 139.4, 137.5, 133.9
(q, J = 32.6 Hz), 131.4 (2 C), 126.9, 125.2 (q, J = 3.7 Hz, 2 C), 124.9,
123.8 (q, J = 273 Hz).
The spectroscopic data match the literature values.22
2-(Pyridin-2-yl)adamantan-2-ol (7ac)
According to TP1, a solution of 2-iodopyridine (5f; 0.20 M, 41 mg,
0.20 mmol) and 2-adamantanone (2c; 0.20 M, 30 mg, 0.20 mmol) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M in hex-
ane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title compound
7ac as white crystals; yield: 45 mg (0.18 mmol, 98%); mp 109.6–
110.3 °C.
The spectroscopic data match the literature values.24
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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N. Weidmann et al.
Paper
Synthesis
N-[Phenyl(pyridin-2-yl)methyl]aniline (7al)
ca gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title com-
pound 7cc as white crystals; yield: 37 mg (0.12 mmol, 64%); mp
115.7–117.3 °C.
According to TP1, a solution of 2-iodopyridine (5f; 0.20 M, 41 mg,
0.20 mmol) and N,1-diphenylmethanimine (2l; 0.20 M, 36 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M
in hexane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solu-
tions were mixed with an overall 12 mL/min flowrate in a T-mixer.
The combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C)
and was subsequently injected into an empty flask. Stirring was con-
tinued for 10 min at 25 °C before sat. aq NH4Cl solution was added to
quench the reaction. The aqueous phase was extracted with EtOAc (3
× 30 mL) and the combined organic phases were dried (anhyd Na2SO4)
and filtered. After removal of the solvent flash chromatography (silica
gel, isohexane:EtOAc = 95:5 → 9:1) afforded the title compound 7al
as a brown oil; yield: 29 mg (0.12 mmol, 59%).
IR (Diamond-ATR, neat): 3367, 2916, 2854, 1451, 1372, 1336, 1092,
1056, 1004, 975 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.73 (d, J = 2.3 Hz, 1 H), 8.59 (d, J = 2.4
Hz, 1 H), 7.98 (dd, J = 8.4, 2.2 Hz, 1 H), 7.80 (dd, J = 8.5, 2.4 Hz, 1 H),
7.38 (d, J = 8.4 Hz, 1 H), 7.28 (dd, J = 8.5, 0.8 Hz, 1 H), 2.61 (t, J = 2.9 Hz,
2 H), 2.39 (dd, J = 12.7, 3.1 Hz, 2 H), 2.19 (s, 1 H), 1.93–1.86 (m, 1 H),
1.81–1.66 (m, 6 H), 1.60 (dt, J = 13.3, 2.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.3, 162.9, 155.2, 150.3, 145.0,
139.3, 122.4, 121.9, 119.1, 91.6, 37.7, 35.1, 35.0, 34.9, 32.9, 32.9, 27.4,
27.0.
MS (EI, 70 eV): m/z (%) = 307 (19), 206 (11), 205 (10), 158 (10), 88
(22), 61 (36), 45 (11), 43 (100).
1H NMR (400 MHz, CDCl3):  = 8.60 (d, J = 4.3 Hz, 1 H), 7.62 (td, J = 7.7,
1.7 Hz, 1 H), 7.46 (d, J = 7.3 Hz, 2 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.33 (t, J =
7.5 Hz, 2 H), 7.25 (d, J = 7.0 Hz, 1 H), 7.19–7.08 (m, 3 H), 6.68 (t, J = 7.3
Hz, 1 H), 6.63 (d, J = 7.7 Hz, 2 H), 5.59 (s, 1 H), 5.46 (s, 1 H).
HRMS (EI): m/z calcd for [C15H18BrNO]: 307.0572; found: 307.0576.
13C NMR (100 MHz, CDCl3):  = 160.9, 149.2, 147.0, 142.5, 136.9, 129.2
(2 C), 128.9 (2 C), 127.6, 127.4 (2 C), 122.3, 121.9, 117.5, 113.6 (2 C),
63.3.
3-(5-Bromopyridin-2-yl)-2,4-dimethylpentan-3-ol (7cm)
According to TP1, a solution of 5-bromo-2-iodopyridine (5c; 0.20 M,
47 mg, 0.20 mmol) and 2,4-dimethylpentan-3-one (2m; 0.20 M, 23
mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.18 M in hexane, 0.18 mmol, 0.9 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 8 mL/min flowrate in a
T-mixer. The combined stream passed a 0.02 mL reactor tube (0.15 s,
–78 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 7cm as a yellow oil; yield: 27 mg (0.11 mmol,
53%).
The spectroscopic data match the literature values.25
2-(Pyridin-3-yl)adamantan-2-ol (7bc)
According to TP2, a solution of 3-bromopyridine (5b; 0.20 M, 31 mg,
0.20 mmol) and 2-adamantanone (2c; 0.20 M, 30 mg, 0.20 mmol) in
THF (total volume: 1.00 mL) and a solution of tBuLi (0.40 M in hexane,
0.40 mmol, 2.0 equiv) were prepared. The precooled solutions were
mixed with an overall 12 mL/min flowrate in a T-mixer. The com-
bined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and was
subsequently injected into an empty flask. Stirring was continued for
10 min at 25 °C before sat. aq. NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title compound
7bc as white crystals; yield: 27 mg (0.12 mmol, 60%); mp 148.0–
148.7 °C.
IR (Diamond-ATR, neat): 3417, 2933, 1464, 1381, 1318, 1237, 1209,
1128, 1092, 1017 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.74 (dd, J = 2.1, 0.8 Hz, 1 H), 8.60 (dd, J
= 2.3, 0.8 Hz, 1 H), 8.45 (dd, J = 2.6, 0.7 Hz, 1 H), 7.96 (dd, J = 8.4, 2.1
Hz, 1 H), 7.79 (dd, J = 8.5, 2.3 Hz, 1 H), 7.60 (dd, J = 8.3, 0.7 Hz, 1 H),
7.45 (dd, J = 8.3, 2.6 Hz, 1 H), 7.19 (dd, J = 8.5, 0.8 Hz, 1 H), 7.09 (dd, J =
8.4, 0.9 Hz, 1 H), 4.98 (s, 1 H), 2.33–2.24 (m, 2 H), 0.80 (d, J = 6.7 Hz, 6
H), 0.76 (d, J = 6.9 Hz, 6 H).
1H NMR (400 MHz, CDCl3):  = 8.63 (d, J = 2.4 Hz, 1 H), 8.42 (dd, J = 4.8,
1.6 Hz, 1 H), 7.82 (dt, J = 8.1, 2.1 Hz, 1 H), 7.27 (dd, J = 8.0, 4.7 Hz, 1 H),
2.53 (q, J = 3.1 Hz, 2 H), 2.42 (dd, J = 12.8, 3.2 Hz, 2 H), 1.91 (t, J = 3.2
Hz, 1 H), 1.81–1.67 (m, 7 H), 1.61 (dt, J = 13.2, 2.7 Hz, 2 H), 1.24 (s, 1
H).
13C NMR (100 MHz, CDCl3):  = 160.6, 153.2, 152.0, 148.3, 144.2,
140.5, 138.7, 136.2, 122.7, 122.1, 118.9, 91.0, 80.1, 34.4, 17.6, 16.8.
13C NMR (100 MHz, CDCl3):  = 147.8, 147.5, 141.0, 133.9, 123.7, 74.6,
MS (EI, 70 eV): m/z (%) = 61 (15), 45 (12), 43 (100).
37.7, 35.4 (2 C), 34.7 (2 C), 32.8 (2 C), 27.5, 26.9.
The spectroscopic data match the literature values.26
HRMS (EI): m/z calcd for [C12H18BrNO]: 271.0572; found: 229.9995
(M – C3H8).
2-(5-Bromopyridin-2-yl)adamantan-2-ol (7cc)
(4-Chlorophenyl)(cyclopropyl)(2-methylpyridin-3-yl)methanol
(7dd)
According to TP1, a solution of 5-bromo-2-iodopyridine (5c; 0.20 M,
47 mg, 0.20 mmol) and 2-adamantanone (2c; 0.20 M, 30 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M
in hexane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solu-
tions were mixed with an overall 8 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.88 s, –20 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted times with EtOAc (3 ×
30 mL) and the combined organic phases were dried (anhyd Na2SO4)
and filtered. After removal of the solvent, flash chromatography (sili-
According to TP1, a solution of 3-iodo-2-methylpyridine (5d; 0.20 M,
44 mg, 0.20 mmol) and (4-chlorophenyl)(cyclopropyl)methanone
(2d; 0.20 M, 36 mg, 0.20 mmol) in THF (total volume: 1.00 mL) and a
solution of nBuLi (0.18 M in hexane, 0.18 mmol, 0.9 equiv) were pre-
pared. The precooled solutions were mixed with an overall 12
mL/min flowrate in a T-mixer. The combined stream passed a 0.02 mL
reactor tube (0.1 s, –78 °C) and was subsequently injected into an
empty flask. Stirring was continued for 10 min at 25 °C before sat. aq
NH4Cl solution was added to quench the reaction. The aqueous phase
was extracted times with EtOAc (3 × 30 mL) and the combined organ-
ic phases were dried (anhyd Na2SO4) and filtered. After removal of the
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

K
N. Weidmann et al.
Paper
Synthesis
solvent, flash chromatography (silica gel, isohexane:EtOAc = 6:4) af-
forded the title compound 7dd as a white solid; yield: 42 mg (0.15
mmol, 81%); mp 173.3–174.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.70 (d, J = 4.8 Hz, 2 H), 7.75–7.66 (m, 2
H), 7.29 (ddd, J = 7.7, 6.9, 1.2 Hz, 2 H), 7.22–7.17 (m, 1 H), 7.15 (t, J =
4.9 Hz, 1 H), 5.50 (d, J = 0.7 Hz, 1 H), 3.85–3.66 (m, 1 H), 2.21–2.08 (m,
1 H), 2.02–1.88 (m, 1 H), 1.88–1.71 (m, 3 H), 1.64–1.52 (m, 1 H).
IR (Diamond-ATR, neat): 1494, 1456, 1194, 1144, 1092, 1013, 988,
963 cm–1
.
13C NMR (100 MHz, CDCl3):  = 171.8, 156.8 (2 C), 144.3, 128.0 (2 C),
127.0, 126.4 (2 C), 119.2, 78.7, 44.1, 22.4, 21.7, 17.4.
1H NMR (400 MHz, CDCl3):  = 8.40 (dd, J = 4.8, 1.7 Hz, 1 H), 8.32 (dd,
J = 7.9, 1.7 Hz, 1 H), 7.35–7.29 (m, 2 H), 7.29–7.21 (m, 3 H), 2.57 (s, 1
H), 2.19 (s, 3 H), 1.59 (tt, J = 8.0, 5.6 Hz, 1 H), 0.73–0.58 (m, 3 H), 0.49–
0.40 (m, 1 H).
MS (EI, 70 eV): m/z (%) = 186 (13), 185 (100), 107 (14), 105 (12), 97
(10), 79 (10), 77 (10).
HRMS (EI): m/z calcd for [C15H16N2O]: 240.1263; found: 240.1256.
13C NMR (100 MHz, CDCl3):  = 158.3, 147.9, 144.0, 140.1, 134.8,
133.0, 128.3 (2 C), 127.7 (2 C), 120.6, 76.1, 24.5, 22.1, 2.2, 2.0.
Diphenyl(pyrimidin-2-yl)methanol (7en)
MS (EI, 70 eV): m/z (%) = 247 (29), 245 (88), 232 (23), 139 (31), 120
(32), 61 (23), 43 (100).
According to TP1, a solution of 2-iodopyrimidine (5e; 0.20 M, 41 mg,
0.20 mmol) and benzophenone (2n; 0.20 M, 36 mg, 0.20 mmol) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M in hex-
ane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C) and
was subsequently injected into an empty flask. Stirring was continued
for 10 min at 25 °C before sat. aq NH4Cl solution was added to quench
the reaction. The aqueous phase was extracted with EtOAc (3 × 30
mL) and the combined organic phases were dried (anhyd Na2SO4) and
filtered. After removal of the solvent, flash chromatography (silica gel,
isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded the title compound
7en as a white solid; yield: 51 mg (0.18 mmol, 99%).
1H NMR (400 MHz, CDCl3):  = 8.78 (d, J = 4.9 Hz, 2 H), 7.48–7.43 (m, 4
H), 7.34–7.26 (m, 6 H), 7.24 (d, J = 4.9 Hz, 1 H), 6.05 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 172.1, 156.8 (3 C), 145.3, 128.1 (4 C),
128.0 (4 C), 127.5 (2 C), 119.4, 81.2.
The spectroscopic data match the literature values.27
HRMS (EI): m/z calcd for [C16H16ClNO]: 273.0920; found: 273.0909.
(2-Methylpyridin-3-yl)diphenylmethanol (7dn)
According to TP1, a solution of 3-iodo-2-methylpyridine (5d; 0.20 M,
44 mg, 0.20 mmol) and benzophenone (2n; 0.20 M, 36 mg, 0.20
mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi (0.18 M
in hexane, 0.18 mmol, 0.9 equiv) were prepared. The precooled solu-
tions were mixed with an overall 12 mL/min flowrate in a T-mixer.
The combined stream passed a 0.02 mL reactor tube (0.1 s, –78 °C)
and was subsequently injected into an empty flask. Stirring was con-
tinued for 10 min at 25 °C before sat. aq NH4Cl solution was added to
quench the reaction. The aqueous phase was extracted with EtOAc (3
× 30 mL) and the combined organic phases were dried (anhyd Na2SO4)
and filtered. After removal of the solvent, flash chromatography (sili-
ca gel, isohexane:EtOAc = 6:4) afforded the title compound 7dn as
white crystals; yield: 49 mg (0.17 mmol, 92%); mp 146.1–148.1 °C.
IR (Diamond-ATR, neat): 3079, 1575, 1434, 1266, 1159, 1047, 1026,
738 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.40 (dt, J = 4.9, 1.6 Hz, 1 H), 7.39–7.28
(m, 6 H), 7.25–7.18 (m, 4 H), 7.10–6.94 (m, 2 H), 3.20 (dd, J = 10.0, 3.6
Hz, 1 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 159.0, 148.0, 145.8 (2 C), 140.3, 136.9
(2 C), 128.4 (4 C), 127.7 (5 C), 120.1, 82.2, 25.5.
Funding Information
R. H. V. Nishimura thanks FAPESP (2018/08856-5) for financial sup-
port. N. Weidmann thanks the German Academic Scholarship Foun-
dation
Forschungsgemeinschaft
for
a
fellowship.
and
We
thank
the
Deutsche
Ludwig-Maximilians-Universität
MS (EI, 70 eV): m/z (%) = 198 (35), 183 (100), 155 (15), 154 (24), 120
(37), 105 (75), 93 (64), 92 (23), 77 (25).
München for financial support.
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HRMS (EI): m/z calcd for [C19H17NO]: 275.1310; found: 275.1306.
Acknowledgment
Cyclobutyl(phenyl)(pyrimidin-2-yl)methanol (7eo)
We thank BASF (Ludwigshafen) and Albemarle (Frankfurt) for the
generous gift of chemicals and Uniqsis for technical support.
According to TP1, a solution of 2-iodopyrimidine (5e; 0.20 M, 41 mg,
0.20 mmol) and cyclobutyl(phenyl)methanone (2o; 0.20 M, 32 mg,
0.20 mmol) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.18 M in hexane, 0.18 mmol, 0.9 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 12 mL/min flowrate in a
T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1 s,
–78 °C) and was subsequently injected into an empty flask. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
added to quench the reaction. The aqueous phase was extracted with
EtOAc (3 × 30 mL) and the combined organic phases were dried (an-
hyd Na2SO4) and filtered. After removal of the solvent, flash chroma-
tography (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 7eo as a white solid; yield: 37 mg (0.14 mmol,
79%); mp 84.8–85.6 °C.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707259. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L