Preparation of Diorganomagnesium Reagents by Halogen-Lithium Exchange of Functionalized Heteroaryl Halides and Subsequent in situ Trapping with MgCl 2·liCl in Continuous Flow

Article abstract of DOI:10.1055/s-0040-1707167

A halogen-lithium exchange in the presence of MgCl ₂·LiCl on a broad range of heterocyclic scaffolds using a commercial flow set-up with n BuLi as exchange reagent is reported. The resulting diheteroarylmagnesium species were subsequently trapped with various electrophiles, such as ketones, aldehydes, allylic bromides, or disulfides affording functionalized heterocycles. A scale-up was performed by simply increasing the run-time without further optimizations.

Full text of DOI:10.1055/s-0040-1707167

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–K
paper
A
en
R. H. Nishimura et al.
Paper
Synthesis
Preparation of Diorganomagnesium Reagents by Halogen–
Lithium Exchange of Functionalized Heteroaryl Halides and
Subsequent in situ Trapping with MgCl2·LiCl in Continuous Flow
Rodolfo Hideki Vicente Nishimura‡a
Niels Weidmann‡b
Flow
Batch
0.1 s
–78 °C
nBuLi
1.5 equiv
Paul Knochel*b
0
0
0
0-0
0
0
1-7
9
1
3-
4
3
3
2
F
Mg
2
a Colegiado de Ciê ncias Farmacê uticas, Universidade Federal do
Vale do São Francisco, Avenue Jośe de Śa Maniç oba, Petrolina,
56304-205 Petrolina, Brazil
12 mL•min–1
F
HO
F
N
F
Br
F
b Ludwig-Maximilians-Universität München, Department
Chemie, Butenandtstraße 5–13, 81377 München, Germany
Paul.knochel@cup.uni-muenchen.de
E
N
95%
F
N
adamantanone
1.5 equiv
25 °C, 10 min
1.0 equiv
+
MgCl2·LiCl
0.5 equiv
‡ These authors contributed equally.
In memory of Prof. Dr. Rolf Huisgen
Received: 28.05.2020
Accepted after revision: 30.05.2020
Published online: 29.06.2020
Yoshida and others utilized (self-made) flow reactors to
achieve ultra-fast mixing within a millisecond scale and
precise control over reaction parameters such as reaction
time and temperature and successfully applied it to
halogen–lithium exchange reactions.10
DOI: 10.1055/s-0040-1707167; Art ID: ss-2020-t0286-op
Abstract A halogen–lithium exchange in the presence of MgCl2·LiCl
on a broad range of heterocyclic scaffolds using a commercial flow set-
up with nBuLi as exchange reagent is reported. The resulting dihet-
eroarylmagnesium species were subsequently trapped with various
electrophiles, such as ketones, aldehydes, allylic bromides, or disulfides
affording functionalized heterocycles. A scale-up was performed by
simply increasing the run-time without further optimizations.
Table 1 Optimization of in situ Trapping Br/Li-Exchange Conditions of
3-Bromoquinoline (1a) and Subsequent Batch Reaction with Cyclohexa-
none (3a)
Flow
nBuLi
Batch
Key words heterocycles, flow chemistry, organomagnesium re-
agents, transmetalation, halogen–lithium exchange
0.1 s–2.5 s
–78 °C–0 °C
X equiv
Mg
2
12 mL•min–1
Br
N
Heterocyclic rings are found in numerous target mole-
cules of interest for their bioactive properties and for agri-
cultural and pharmaceutical uses.1 Therefore, efficient
preparations of functionalized heterocycles have attracted
considerable attention in the past decades.2 Organolithiums
are standard organometallic reagents in organic syntheses.3
Due to their high reactivity, organolithium compounds
have often been used to functionalize heterocycles. Never-
theless, preparation and handling of heteroaromatic lithi-
um compounds is still challenging, mainly because of their
limited stability, low selectivity,4 and limited functional
group tolerance.5 Among different methods to prepare het-
eroaromatic lithium species,6 the halogen–lithium ex-
change was found to be one of the most efficient prepara-
tions of a broad variety of lithium compounds.7 Recently,
we have reported an in situ trapping transmetalation meth-
od using MgCl2·LiCl for the direct preparation of the more
stable organomagnesiums after halogen–lithium exchange
reactions.8 In recent years, continuous flow technology
emerged as a promising technique to address current syn-
thetic problems especially in organometallic chemistry.9
2a
OH
E
N
N
cyclohexanone
(3a)
1.5 equiv
4a: 62%
1a
1.0 equiv
+
MgCl2·LiCl
X equiv
25 °C, 10 min
Entry Base
Temp Additives
Time GC-Yield (%)
(s)
(equiv)
(°C)
(equiv)
1
2
3
4
5
6
7
8
9
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
nBuLi (1.0)
PhLi (1.0)
–78
MgCl2∙LiCl (0.5)
MgCl2∙LiCl (0.5)
MgCl2∙LiCl (0.5)
MgCl2∙LiCl (0.5)
None
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.1
0.1
62
–40
–20
0
65
67
22
–20
–20
–20
–20
–20
18
MgCl2∙LiCl (1.0)
MgCl2∙LiCl (0.5)
MgCl2∙LiCl (0.5)
MgCl2·LiCl (0.5)
61
59
nBuLi (1.0)
nBuLi (1.5)
68
76 (62,a 61b)
a Yield of analytically pure isolated product.
b Yield of analytically pure isolated product on a 5 mmol scale.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
R. H. Nishimura et al.
Paper
Synthesis
Table 2 In Situ Exchange-Transmetalation for (Iso)quinoline Halides of Type 1, Leading via Intermediate Diorganomagnesium Species of Type 2 to
Functionalized Heteroarenes of Type 4
Entry
Diorganomagnesium species of
type 2
Electrophile
Product of type 4a
Temp (°C); flow rate (mL/min); Time (s)
Mg
2
O
1
2
3
4
OH
N
3ad
2a: –20; 12; 0.1b,c
N
4a: 62%
HO
O
Mg
2
N
N
2a: –20; 12; 0.1b,c
3bd
4b: 72%
Mg
2
S
N
N
S
S
N
N
N
2a: –20; 12; 0.1b,c
4c: 88%
3cd
F
F
HO
O
Mg
2
N
F
N
F
3bd
2b: –78; 12; 0.1b,c
4d: 95%
F
O
F
HO
Mg
2
5
6
N
F
Cl
N
F
Cl
2b: –78; 12; 0.1b,c
3dd
O
4e: 95%
N
OH
N
2
Mg
3bd
2c: 0, 6, 2.5c,e
4f: 73%
OMe
OMe
N
O
N
7
OH
2
Mg
3bd
2d: –20; 6; 2.5b,c
4g: 73%
F
F
S
F
Mg
2
S
p-tolyl
p-tolyl
S
8
9
3ed
N
Me
N
F
2b: –78; 12; 0.1b,c
4h: 73%
N
Cy
S
3fd
S
N
Cy
2
Mg
S
Cy
2c: 0, 6, 2.5c,e
4i: 90%
OMe
OMe
N
Br
N
10
2
Mg
3gf
2d: –20; 6; 2.5b,c
4j: 71%
a Yield of analytically pure isolated product.
b The diorganomagnesium species was prepared from the corresponding heteroaryl bromide.
c The diorganomagnesium species was prepared from nBuLi solution (0.30 M).
d Reaction conditions: 1.5 equiv, 10 min, 25 °C.
e The diorganomagnesium species was prepared from the corresponding heteroaryl iodide.
f Reaction conditions: 1.5 equiv, 0.1 equiv CuCN∙2LiCl, 10 min, 25 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

C
R. H. Nishimura et al.
Paper
Synthesis
Herein, we report a halogen–lithium exchange in the
presence of MgCl2·LiCl to prepare heteroaromatic magne-
sium species, which were subsequently trapped with vari-
ous electrophiles, such as ketones, aldehydes, allylic bro-
mides, or disulfides leading to functionalized heterocycles.
In preliminary experiments, we have optimized the
Br/Li-exchange of 3-bromoquinoline (1a) in the presence of
MgCl2·LiCl with nBuLi as exchange reagent leading to the
corresponding diorganomagnesium reagent 2a using a
combined flow rate of 12 mL/min in a continuous flow set-
up. Subsequent batch-trapping with cyclohexanone (3a) af-
forded the desired tertiary alcohol 4a. At –78 °C, this reac-
tion led to the functionalized quinoline 4a in 62% GC-yield
(Table 1, entry 1). Increasing the temperature resulted in a
slightly increased GC-yield (65–67%, entries 2, 3), whereas
the GC-yield dropped dramatically at 0 °C (22%, entry 4).
Addition of MgCl2·LiCl was mandatory for successful reac-
tions since a reaction without MgCl2·LiCl led to 18% GC-
yield (entry 5), possibly due to a fast degradation of the het-
eroaryllithium species. Increasing the amount of MgCl2·LiCl
did not lead to an improved yield (61%, entry 6). Replacing
nBuLi by PhLi led to a slight decrease to 59% GC-yield (entry
7). Further optimization of the nBuLi concentration and re-
action time increased the GC-yield of 4a to 76% (isolated
yield: 62%, entries 8, 9). A scale-up of the reaction was per-
formed by increasing the run-time from 10 to 250 seconds.
The desired tertiary alcohol 4a was isolated in 61% yield on
a 5 mmol scale, which was comparable with the yield ob-
tained on a 0.2 mmol scale (62%, entry 9).
converted to its magnesium species at –20 °C within 1.3
seconds. Subsequent batch-quench with cyclohexanone
(3a) led to the tertiary alcohol 7a in 60% yield (Table 3, en-
try 1). Furthermore, a scale-up to 2.0 mmol was possible
without any optimization by increasing the run-time re-
sulting in a similar yield (61%). Applying the standard flow
conditions to 3-bromothiophene (5b) afforded functional-
ized thiophene 7b in 92% yield after batch-quench with
adamantanone (3b) (entry 2).
Table 3 In Situ Exchange-Transmetalation for Heteroaryl Halides of
Type 5, Leading via Intermediate Diorganomagnesium Species of Type
6 to Functionalized Heteroarenes of Type 7
Flow
nBuLi
Batch
0.1 s–1.3 s
–40 °C to –20 °C
1.5 equiv
Mg
2
12 mL•min–1
Br
E
X
6a–d
E
X
X
1.5 equiv
products
5a–d
1.0 equiv
25 °C, 10 min
of type 7
X = NBoc, S, O
+
MgCl2·LiCl
0.5 equiv
Entry Diorganomagnesium species of Electrophile
Product of type
type 6
7a
Temp (°C); flow rate (mL/min);
Time (s)
With these optimized conditions in hand, we investigat-
ed the in situ trapping halogen-exchange reaction on sub-
stituted (iso)quinolines. The intermediate diheteroarylmag-
nesium 2a reacted with cyclohexanone (3a) and adamanta-
none (3b) affording the tertiary alcohols 4a and 4b in 62–
72% isolated yields (Table 2, entries 1, 2).
Mg
2
O
HO
N
Boc
N
Boc
1
6a: –20; 12; 1.3b,c
3ad
7a: 60% (61%)e
Using 2,2′-dipyridyl disulfide (3c) as electrophile afford-
ed the thioether 4c in 88% yield (Table 2, entry 3). Further,
the range of substrates was extended to various substituted
quinolines and isoquinolines of type 1, which were convert-
ed to the corresponding diheteroarylmagnesiums of type 2
and subsequently trapped with ketones or disulfides of
type 3 resulting in functionalized (iso)quinolines of type 4.
Sterically hindered ketones such as adamantanone (3b) and
4-chlorophenyl cyclopropyl ketone (3d) gave the tertiary
alcohols 4d–g (73–95%, entries 4–7). Also, addition of the
intermediate magnesium species 2b and 2c to disulfides 3e
and 3f led to the thioethers 4h,i in 73–90% yield (entries 8,
9). Further, we have investigated allylation reactions. By
adding 10 mol% CuCN·2LiCl, allylation of 2d using cyclo-
hexene bromide (3g) led to the allylated isoquinoline 4j in
71% yield (entry 10).
Mg
2
O
OH
S
S
2
3
6b: –20; 12; 1.3b,c
3bd
7b: 92%
Mg
2
SBu
nBu
S
S
nBu
S
S
6c: –20; 12; 1.3b,c
3hd
7c: 94%
Mg
2
O
OH
O
O
4
6d: –40; 12; 0.1b,c
3ad
7d: 60%
a Yield of analytically pure isolated product.
b The diorganomagnesium species was prepared from the corresponding
heteroaryl bromide.
To demonstrate the broad applicability of in situ trap-
ping exchange reactions in continuous flow, we investigat-
ed various nitrogen-, sulfur- and oxygen-containing hetero-
cycles of type 5. Therefore, NBoc-protected indole 5a was
c The diorganomagnesium species was prepared from nBuLi solution (0.30
M).
d Reaction conditions: 1.5 equiv, 10 min, 25 °C.
e Scale-up was performed on a 2 mmol scale.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

D
R. H. Nishimura et al.
Paper
Synthesis
Table 4 (continued)
It was also possible to perform a Br/Li-exchange on 3-
bromobenzothiophene (5c) applying the same conditions,
providing diheteroarylmagnesium 6c. A subsequent batch
quench with Bu2S2 afforded 3-(butylthio)benzothiophene
(7c) in 94% yield (Table 3, entry 3). Also, 3-bromofuran (5d)
was converted to the corresponding bis-magnesium species
6d within 0.1 second at –40 °C. Consecutive batch-trapping
with cyclohexanone (3a) led to the functionalized furan 7d
in 60% isolated yield (entry 4).
Notably, challenging substrates of type 8 bearing two
bromides were successfully exchanged with excellent regio-
selectivity.11 2,4-Dibromoquinoline (8a) was selectively
exchanged at 4-position using nBuLi (0.9 equiv). The result-
ing diorganomagnesium species 9a was subsequently
trapped with norcamphor (3i) affording 10a in 58% isolated
yield (Table 4, entry 1). Remarkably, the exchange reaction
of 2,5-dibromopyridine (8b) proceeded at 0 °C in contrast
to batch reactions, which were usually performed at –78 °C.
The diheteroarylmagnesium was selectively formed at 5-
position. After batch addition to ketones 3b,3i, 3j, and 3k or
cyclohexene bromide (3g) using 10 mol% CuCN·2LiCl, the
functionalized pyridines 10b–f were obtained in 56–89%
yield (entries 2–6). 2,5-Dibromopyrazine (8c) was ex-
changed using this method at –20 °C within 1.3 seconds re-
action time. The resulting magnesium intermediate 9c was
directly quenched with cyclohexanone (3a) resulting in the
corresponding tertiary alcohol 10g in 67% yield (entry 7).
Noteworthy, using a 0.38 M nBuLi solution, we demonstrat-
ed that a double exchange was feasible without further op-
timization of the reaction conditions resulting in the bis-
allylated product 10h in 62% yield (entry 8).
Entry Diorganomagnesium species of Electrophile Product of type 10a
type 9
Temp (°C); flow rate (mL/min);
Time (s)
Br
Mg
2
O
N
Br
N
OH
2
3
4
9b: 0; 12; 1.3b,c
3id
10b: 68% d.r.>99:1
HO
O
Mg
2
Br
N
Br
N
9b: 0; 12; 1.3b,c
3bd
10c: 67%
HO Me
Ph
O
Mg
2
Me
Br
N
Br
N
9b: 0; 12; 1.3b,c
3jd
10d: 56%
OH
O
Mg
2
Br
N
Br
N
5
6
7
9b: 0; 12; 1.3b,c
3kd
3ge
3ad
10e: 89%
Mg
2
Br
Br
N
Br
N
9b: 0; 12; 1.3b,c
10f: 61%
OH
N
N
Mg
2
O
N
Br
Br
N
9c: –20; 12; 1.3b,c
10g: 67%
Table 4 In Situ Exchange-Transmetalation for Sensitive Heteroaryl Di-
bromides of Type 8, Leading via Intermediate Diorganomagnesium Spe-
cies of Type 9 to Polyfunctional Heteroarenes of Type 10
N
N
MgX
N
Br
XMg
N
Flow
nBuLi
Batch
8
9d: –20; 12; 1.3b,f
3gg
10h: 62%
1.3 s
–20 °C–0 °C
0.9 equiv
a Yield of analytically pure isolated product.
b The diorganomagnesium species was prepared from the corresponding
heteroaryl bromide.
X
12 mL•min–1
Mg
X
2
c The diorganomagnesium species was prepared from nBuLi solution (0.18
M).
X
X
9a–d
E
d Reaction conditions: 1.5 equiv, 10 min, 25 °C.
e Reaction conditions: 1.5 equiv, 0.1 equiv CuCN·2LiCl, 10 min, 25 °C.
f The organomagnesium species was prepared from nBuLi solution (0.38
M).
E
X
Br
X
1.5 equiv
25 °C, 10 min
products
of type 10
8a–d
1.0 equiv
X = CH,N
+
g Reaction conditions: 3.0 equiv, 0.2 equiv CuCN·2LiCl, 10 min, 25 °C.
MgCl2·LiCl
0.5 equiv
In summary, we have reported a halogen–lithium ex-
change in the presence of MgCl2·LiCl on a broad range of
heterocyclic scaffolds using a commercial flow set-up and
nBuLi as exchange reagent. The resulting diheteroarylmag-
nesium species were subsequently trapped with various
electrophiles, such as ketones, aldehydes, allylic bromides,
or disulfides affording functionalized heterocycles. A scale-
Entry Diorganomagnesium species of Electrophile Product of type 10a
type 9
Temp (°C); flow rate (mL/min);
Time (s)
Mg
2
O
N
N
Br
Br
OH
1
9a: –20; 12; 1.3b,c
3id
10a: 58% d.r.>99:1
Thieme. All rights reserved. Synthesis 2020, 52, A–K

E
R. H. Nishimura et al.
Paper
Synthesis
up was performed by simply increasing the run-time with-
out further optimizations.
IR (Diamond-ATR, neat): 3153, 3059, 2926, 2900, 2851, 1574, 1495,
1448, 1427, 1369, 1267, 1235, 1183, 1151, 1131, 1041, 982, 972, 967,
961, 918, 896, 817, 785, 749 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.02 (d, J = 2.3 Hz, 1 H), 8.23 (d, J = 2.0
Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 7.79 (dd, J = 8.1, 1.2 Hz, 1 H), 7.67
(ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.52 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 2.35
(s, 1 H), 1.96–1.75 (m, 7 H), 1.72–1.65 (m, 2 H), 1.40–1.25 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 149.1, 147.1, 142.0, 131.3, 129.2,
129.0, 128.1, 127.8, 126.8, 72.4, 38.8 (2 C), 25.4, 22.1 (2 C).
Tetradecane (nC14H30) was used as internal standard for GC-analyses.
All flasks were heat gun dried (650 °C) under vacuum and backfilled
with argon after cooling. Syringes, which were used to transfer re-
agents and solvents, were purged with argon three times prior to use.
Batch-quenching reactions were carried out with magnetic stirring.
Flow reactions were performed on a commercially available flow sys-
tem. An Uniqsis FlowSyn system was used. Carrier solvents as well as
reactant solutions were stored under argon and injected to carrier
solvent streams. All reactions were performed in coiled tube reactors.
Coiled reactors were made from PFA or PTFE Teflon (I.D. = 0.80 mm or
0.25 mm, O.D. = 1.60 mm) tubing and T-pieces (I.D. = 0.50 mm) were
used as mixers. Prior to performing reactions, the systems were dried
by flushing with anhyd THF (flow rate of all pumps: 1.00 mL/min;
run-time: 30 min).
MS (EI, 70 eV): m/z (%) = 227 (13), 225 (21), 209 (38), 208 (21), 207
(14), 205 (29), 204 (24), 194 (19), 185 (13), 184 (100), 181 (12), 180
(77), 171 (43), 168 (10), 167 (27), 166 (18), 156 (53), 154 (10), 152
(10), 142 (10), 130 (11), 128 (51), 115 (13).
HRMS (EI): m/z calcd for [C15H17NO]: 227.1310; found: 227.1315.
2-(Quinolin-3-yl)adamantan-2-ol (4b)
According to the TP, a solution of 3-bromoquinoline (1a; 42 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 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, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
2-adamantanone (3b; 45 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chro-
matographical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1
→ 8:2) afforded the title compound 4b as a white solid; yield: 40 mg
(0.143 mmol, 72%); mp 239.1–240.0 °C.
A detailed description of general information is provided in the Sup-
porting Information.
Typical Procedure (TP) Using an Uniqsis Flow Setup for Tertiary Al-
cohols (See also Scheme SI 1 in the Supporting Information)
An nBuLi solution in hexane (0.30 M, 1.5 equiv) and a solution of 3-
bromoquinoline (1a; 0.20 M, 1.0 equiv) and MgCl2·LiCl (0.10 M, 0.5
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 the solution of 1a and MgCl2·LiCl. The solu-
tions were simultaneously injected into separate streams of THF, re-
spectively (pump A: THF; pump B: THF, combined flow rates: 12.0
mL/min), each of which passed a pre-cooling loop (volpre = 1.00 mL, T1
= –20 °C, residence time: 6 s), before they were mixed in a T mixer
(PTFE, I.D. = 0.50 mm). The combined stream passed a PTFE reactor
tube (VolR = 0.02 mL; residence time: t1 = 0.1 s, T1 = –20 °C) and was
subsequently injected into a flask containing a stirred solution of cy-
clohexanone (3a; 1.5 equiv) in THF. The reaction mixture was stirred
further for 10 min at 25 °C and quenched with a sat. aq NH4Cl solu-
tion. The aqueous phase was extracted with EtOAc and the combined
organic phases were dried and filtered. After removal of the solvent in
vacuo, flash column chromatographical purification with suited iso-
hexane:EtOAc mixtures afforded the desired tertiary alcohol 4a in
62% isolated yield.
IR (Diamond-ATR, neat): 2907, 2896, 2889, 1493, 1104, 1089, 1052,
1026, 921, 907, 783, 747 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.13 (d, J = 2.4 Hz, 1 H), 8.23 (d, J = 2.2
Hz, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.82 (dd, J = 8.1, 1.2 Hz, 1 H), 7.71
(ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.55 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H), 2.73
(s, 2 H), 2.47 (d, J = 11.9 Hz, 2 H), 1.99–1.94 (m, 1 H), 1.86–1.71 (m, 9
H).
13C NMR (100 MHz, CDCl3):  = 149.6, 147.4, 137.9, 132.8, 129.6,
129.1, 128.2 (2 C), 126.9, 75.3, 37.7, 35.8 (2 C), 35.0 (2 C), 32.9 (2 C),
27.6, 26.9.
MS (EI, 70 eV): m/z (%) = 278 (18), 260 (15), 253 (24), 251 (14), 227
(19), 226 (12), 225 (100), 209 (36), 207 (51), 191 (11), 150 (27), 129
(59), 128 (19), 102 (15), 91 (13), 80 (12), 79 (30), 78 (16), 42 (15).
Preparation of the Products
1-(Quinolin-3-yl)cyclohexanol (4a)
HRMS (EI): m/z calcd for [C19H20NO]: 278.1550; found: 278.1540 (M –
According to the TP, a solution of 3-bromoquinoline (1a; 42 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 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, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
cyclohexanone (3a; 30 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2)
afforded the title compound 4a as a white solid; yield: 28 mg
(0.12 mmol, 62%); mp 153.5–155.0 °C.
H).
3-(Pyridin-2-ylthio)quinoline (4c)
According to the TP, a solution of 3-bromoquinoline (1a; 42 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 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, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
1,2-di(pyridin-2-yl)disulfane (3c; 66 mg, 0.30 mmol, 1.5 equiv) in
THF. 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
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

F
R. H. Nishimura et al.
Paper
Synthesis
were dried (anhyd Na2SO4) and filtered. After removal of the solvent,
flash chromatographical purification (silica gel, isohexane:EtOAc =
9:1 → 8:2 → 7:3) afforded the title compound 4c as a yellow solid;
yield: 42 mg (0.18 mmol, 88%); mp 90.9–92.8 °C.
T-mixer. The combined stream passed a 0.02 mL reactor tube (0.1 s,
–78 °C) and was subsequently injected into a flask containing a
stirred solution of (4-chlorophenyl)(cyclopropyl)methanone (3d;
54 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromatographical purifica-
tion (silica gel, isohexane:EtOAc = 100:0 → 95:5 → 8:2) afforded the
title compound 4e as a white solid; yield: 66 mg (0.19 mmol, 95%);
mp 170.6–172.0 °C.
IR (Diamond-ATR, neat): 3043, 2985, 1568, 1556, 1488, 1443, 1419,
1370, 1352, 1324, 1277, 1256, 1227, 1150, 1144, 1123, 1086, 1043,
1017, 984, 960, 946, 916, 866, 788, 761, 750, 724 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.97 (d, J = 2.2 Hz, 1 H), 8.42 (d, J = 1.9
Hz, 1 H), 8.42–8.40 (m, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.83–7.81 (m, 1
H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.59 (ddd, J = 8.1, 7.0, 1.1 Hz, 1
H), 7.50 (ddd, J = 8.0, 7.5, 1.9 Hz, 1 H), 7.07–7.03 (m, 2 H).
13C NMR (150 MHz, CDCl3):  = 159.5, 154.9, 150.0, 147.6, 141.9,
137.0, 130.6, 129.6, 128.4, 127.9, 127.4, 125.3, 122.0, 120.8.
IR (Diamond-ATR, neat): 1642, 1580, 1488, 1380, 1366, 1328, 1171,
1143, 1106, 1102, 1092, 1055, 1021, 1011, 974, 849, 837, 829, 818,
812, 804, 762 cm–1
.
MS (EI, 70 eV): m/z (%) = 238 (13), 237 (100).
1H NMR (600 MHz, CDCl3):  = 8.94 (dd, J = 4.3, 1.7 Hz, 1 H), 8.42–8.40
(m, 1 H), 7.54 (d, J = 13,3 Hz, 1 H), 7.46 (dd, J = 8.5, 4.3 Hz, 1 H), 7.37–
7.33 (m, 2 H), 7.31–7.27 (m, 2 H), 3.17 (dd, J = 7.7, 3.4 Hz, 1 H), 1.92–
1.84 (m, 1 H), 0.79–0.73 (m, 1 H), 0.69–0.58 (m, 3 H).
HRMS (EI): m/z calcd for [C14H9N2S]: 237.0492; found: 237.0483 (M –
H).
13C NMR (150 MHz, CDCl3):  = 161.2 (dd, J = 250.2, 10.3 Hz), 155.4
(dd, J = 258.9, 10.3 Hz), 152.7, 147.6 (dd, J = 16.1, 5.4 Hz), 145.0, 133.4,
130.2 (dd, J = 7.2, 1.8 Hz), 128.4 (2 C), 127.1 (2 C), 121.2 (t, J = 2.7 Hz),
120.7 (dd, J = 17.3, 12.6 Hz), 117.1 (d, J = 19.3 Hz), 110.6 (dd, J = 24.6,
4.5 Hz), 77.3 (d, J = 2.5 Hz), 22.1 (dd, J = 7.4, 2.7 Hz), 2.5 (t, J = 2.9 Hz, 2
C).
2-(5,7-Difluoroquinolin-6-yl)adamantan-2-ol (4d)
According to the TP, a solution of 6-bromo-5,7-difluoroquinoline (1b;
49 mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 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 a flask containing a
stirred solution of 2-adamantanone (3b; 45 mg, 0.30 mmol,
1.5 equiv) in THF. 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 organ-
ic phases were dried (anhyd Na2SO4) and filtered. After removal of the
solvent, flash chromatographical purification (silica gel, isohex-
ane:EtOAc = 100:0 → 95:5 → 8:2) afforded the title compound 4d as a
white solid; yield: 60 mg (0.19 mmol, 95%); mp 201.5–202.9 °C.
MS (EI, 70 eV): m/z (%) = 319 (34), 318 (20), 317 (100), 192 (54), 165
(12), 164 (12), 139 (20), 111 (11), 43 (17).
HRMS (EI): m/z calcd for [C19H14ClF2NO]: 345.0732; found: 345.0741.
2-(Isoquinolin-1-yl)adamantan-2-ol (4f)
According to the TP, a solution of 1-iodoisoquinoline (1c; 51 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 equiv) were prepared. The precooled solutions
were mixed with an overall 6 mL/min flowrate in a T-mixer. The com-
bined stream passed a 0.25 mL reactor tube (2.5 s, 0 °C) and was sub-
sequently injected into a flask containing a stirred solution of 2-ada-
mantanone (3b; 45 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 100:0 → 9:1) af-
IR (Diamond-ATR, neat): 3311, 3280, 2968, 2937, 2915, 2897, 2891,
2848, 1633, 1626, 1576, 1483, 1457, 1406, 1382, 1369, 1358, 1353,
1328, 1285, 1272, 1193, 1177, 1164, 1103, 1084, 1057, 1049, 1033,
1026, 1014, 1000, 971, 939, 853, 820, 805, 760 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.90 (dd, J = 4.3, 1.7 Hz, 1 H), 8.36 (dd,
J = 8.4, 0.9 Hz, 1 H), 7.54 (d, J = 14.8 Hz, 1 H), 7.40 (dd, J = 8.5, 4.3 Hz, 1
H), 2.94 (s, 2 H), 2.63 (s, 1 H), 2.44 (d, J = 10.9 Hz, 2 H), 1.93–1.84 (m, 4
H), 1.77 (s, 3 H), 1.70 (d, J = 12.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 162.8 (dd, J = 252.9, 12.5 Hz), 155.9
(dd, J = 259.7, 11.8 Hz), 152.5, 147.2 (dd, J = 16.7, 6.0 Hz), 130.3 (dd, J =
8.5, 1.8 Hz), 120.9 (t, J = 2.8 Hz), 119.9 (dd, J = 16.9, 13.1 Hz), 117.4
(dd, J = 21.0, 1.2 Hz), 110.9 (dd, J = 26.7, 4.2 Hz), 79.9 (dd, J = 3.2, 2.3
Hz), 37.6 (3 C), 33.2 (2 C), 26.6 (3 C), 26.5.
forded the title compound 4f as
a white solid; yield: 41 mg
(0.15 mmol, 73%); mp 174.1–176.0 °C.
IR (Diamond-ATR, neat): 3424, 3052, 2951, 2939, 2932, 2920, 2903,
2894, 2848, 1619, 1590, 1556, 1467, 1451, 1442, 1350, 1342, 1315,
1310, 1304, 1286, 1174, 1137, 1103, 1073, 1044, 1035, 1013, 992,
962, 938, 914, 867, 820, 805, 799, 744, 694, 681, 665 cm–1
.
MS (EI, 70 eV): m/z (%) = 315 (87), 298 (14), 297 (57), 220 (22), 219
(24), 207 (16), 195 (31), 194 (100), 193 (14), 192 (99), 179 (14), 178
(27), 166 (12), 165 (30), 164 (16), 121 (23), 93 (16), 91 (11), 81 (28),
80 (17), 79 (35), 77 (11), 67 (21), 43 (20), 41 (18).
1H NMR (400 MHz, CDCl3):  = 8.92 (d, J = 8.8 Hz, 1 H), 8.41 (d, J = 5.6
Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.60 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H),
7.52–7.48 (m, 2 H), 2.82 (s, 2 H), 2.57 (d, J = 10.9 Hz, 2 H), 2.20 (s, 1 H),
2.06–2.00 (m, 3 H), 1.78–1.71 (m, 7 H).
HRMS (EI): m/z calcd for [C19H19F2NO]: 315.1435; found: 315.1430.
13C NMR (100 MHz, CDCl3):  = 163.4, 139.8, 137.8, 129.2, 128.5,
127.7, 126.6, 125.8, 120.6, 80.5, 47.1, 39.4, 38.2, 38.0 (2 C), 35.2, 33.6,
27.7, 27.4.
(4-Chlorophenyl)(cyclopropyl)(5,7-difluoroquinolin-6-yl)metha-
nol (4e)
According to the TP, a solution of 6-bromo-5,7-difluoroquinoline (1b;
49 mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 equiv) were prepared. The pre-
cooled solutions were mixed with an overall 12 mL/min flowrate in a
MS (EI, 70 eV): m/z (%) = 279 (21), 278 (100), 260 (80), 253 (18), 225
(70), 218 (26), 209 (26), 207 (67), 204 (18), 184 (27), 180 (26), 168
(24), 167 (29), 166 (23), 156 (28), 150 (31), 146 (17), 143 (21), 130
(29), 129 (87), 128 (63), 102 (22), 91 (19), 79 (38), 77 (17).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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R. H. Nishimura et al.
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Synthesis
HRMS (EI): m/z calcd for [C19H20NO]: 278.1550; found: 278.1544 (M –
H).
13C NMR (100 MHz, CDCl3):  = 161.9 (dd, J = 250.9, 5.5 Hz), 158.9 (dd,
J = 257.4, 6.7 Hz), 152.9, 148.5 (dd, J = 14.2, 4.9 Hz), 137.6, 130.8 (2 C),
130.4 (3 C), 130.1, 129.8 (dd, J = 4.2, 2.1 Hz), 121.1 (t, J = 2.7 Hz), 116.6
(dd, J = 18.0, 1.7 Hz), 110.0 (dd, J = 23.2, 4.8 Hz), 21.2.
2-(3-Methoxyisoquinolin-8-yl)adamantan-2-ol (4g)
MS (EI, 70 eV): m/z (%) = 287 (71), 286 (10), 269 (16), 268 (72), 267
(40), 266 (27), 254 (10), 253 (30), 143 (26), 91 (31), 85 (11), 83 (11),
69 (16), 65 (18), 57 (22), 55 (22), 43 (22), 41 (18).
According to the TP, a solution of 8-bromo-3-methoxyisoquinoline
(1d; 48 mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 equiv) were prepared. The pre-
cooled solutions 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,
–20 °C) and was subsequently injected into a flask containing a
stirred solution of 2-adamantanone (3b; 45 mg, 0.30 mmol,
1.5 equiv) in THF. 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 organ-
ic phases were dried (anhyd Na2SO4) and filtered. After removal of the
solvent, flash chromatographical purification (silica gel, isohex-
ane:EtOAc = 100:0 → 95:5 → 8:2) afforded the title compound 4g as
white crystals; yield: 45 mg (0.5 mmol, 73%); mp 190.0–193.2 °C.
HRMS (EI): m/z calcd for [C16H11F2NS]: 287.0580; found: 287.0583.
1-(Cyclohexylthio)isoquinoline (4i)
According to the TP, a solution of 1-iodoisoquinoline (1c; 51 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 equiv) were prepared. The precooled solutions
were mixed with an overall 6 mL/min flowrate in a T-mixer. The com-
bined stream passed a 0.25 mL reactor tube (2.5 s, 0 °C) and was sub-
sequently injected into a flask containing a stirred solution of dicyclo-
hexyl disulfide (3f; 69 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 98:2 → 19:1) af-
forded the title compound 4i as a pale yellow oil; yield: 44 mg
(0.18 mmol, 90%).
IR (Diamond-ATR, neat): 3411, 2956, 2935, 2913, 2902, 2887, 2855,
2845, 1618, 1592, 1484, 1462, 1447, 1427, 1381, 1339, 1321, 1308,
1289, 1257, 1250, 1225, 1188, 1162, 1147, 1103, 1095, 1077, 1037,
1017, 1007, 996, 965, 948, 869, 805, 762, 736, 704, 664 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.97 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H),
7.49 (dd, J = 7.3, 1.3 Hz, 1 H), 7.44 (t, J = 7.3 Hz, 1 H), 6.96 (s, 1 H), 4.02
(s, 3 H), 2.80 (s, 2 H), 2.63 (d, J = 12.6 Hz, 2 H), 2.06 (s, 1 H), 1.96–1.93
(m, 1 H), 1.82–1.67 (m, 9 H).
13C NMR (100 MHz, CDCl3):  = 160.2, 151.2, 142.4, 141.6, 128.8,
126.3, 123.6, 123.3, 102.0, 77.9, 54.2, 38.4 (2 C), 37.9 (2 C), 33.5, 27.8
(2 C), 27.1 (2 C).
IR (Diamond-ATR, neat): 3048, 2924, 2849, 1619, 1582, 1549, 1493,
1460, 1447, 1333, 1307, 1297, 1260, 1227, 1204, 1182, 1147, 1142,
1025, 1013, 997, 987, 886, 864, 841, 811, 793, 782, 741, 704, 675 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.30 (d, J = 5.7 Hz, 1 H), 8.22 (dd, J = 8.4,
0.7 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.64 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H),
7.54 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H), 7.32 (d, J = 5.7 Hz, 1 H), 4.17–4.13
(m, 1 H), 2.18–2.15 (m, 2 H), 1.83–1.79 (m, 2 H), 1.68–1.65 (m, 1 H),
1.61–1.49 (m, 4 H), 1.38–1.33 (m, 1 H).
MS (EI, 70 eV): m/z (%) = 309 (19), 291 (21), 290 (12), 188 (17), 187
(12), 186 (100), 172 (14), 165 (12), 160 (31), 159 (26), 158 (27), 157
(26), 150 (20), 129 (10), 115 (12), 91 (20), 81 (11), 80 (13), 79 (42), 77
(16).
13C NMR (150 MHz, CDCl3):  = 159.8, 142.0, 135.6, 130.3, 127.4,
HRMS (EI): m/z calcd for [C20H23NO2]: 309.1729; found: 309.1725.
127.2, 127.0, 124.9, 117.1, 42.6, 33.4 (2 C), 26.3, 26.0 (2 C).
MS (EI, 70 eV): m/z (%) = 210 (17), 162 (11), 161 (100), 134 (12), 128
(18), 67 (17).
5,7-Difluoro-6-(p-tolylthio)quinoline (4h)
According to the TP, a solution of 6-bromo-5,7-difluoroquinoline (1b;
49 mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 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 a flask containing a
stirred solution of 1,2-di-tolyldisulfane (3e; 74 mg, 0.30 mmol,
1.5 equiv) in THF. 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 organ-
ic phases were dried (anhyd Na2SO4) and filtered. After removal of the
solvent, flash chromatographical purification (silica gel, isohexane:
EtOAc = 100:0 → 95:5 → 8:2) afforded the title compound 4h as a yel-
low solid; yield; 42 mg (0.146 mmol, 73%); mp 99.5–101.5 °C.
HRMS (EI): m/z calcd for [C15H17NS]: 243.1082; found: 243.1081.
8-(Cyclohex-2-en-1-yl)-3-methoxyisoquinoline (4j)
According to the TP, a solution of 8-bromo-3-methoxyisoquinoline
(1d; 48 mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 equiv) were prepared. The pre-
cooled solutions 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,
–20 °C) and was subsequently injected into a flask containing a
stirred solution of 3-bromocyclohex-1-ene (3g; 48 mg, 0.30 mmol,
1.5 equiv) and CuCN·2LiCl solution (0.02 mL, 1 M in THF, 0.1 equiv) in
THF. Stirring was continued for 10 min at 25 °C before sat. aq. NH4Cl
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 chro-
matographical purification (silica gel, isohexane:EtOAc = 100:0 →
95:5 → 8:2) afforded the title compound 4j as a pale yellow oil; yield:
34 mg (0.14 mmol, 71%).
IR (Diamond-ATR, neat): 2918, 2853, 1628, 1589, 1573, 1555, 1490,
1483, 1455, 1431, 1397, 1376, 1362, 1342, 1333, 1302, 1280, 1203,
1162, 1146, 1116, 1088, 1082, 1041, 1018, 1013, 850, 837, 804, 758,
703, 695 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.95 (dd, J = 4.3, 1.7 Hz, 1 H), 8.37 (dd,
J = 8.5, 1.0 Hz, 1 H), 7.63 (dd, J = 9.6, 1.1 Hz, 1 H), 7.44 (dd, J = 8.5, 4.3
Hz, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 2.30 (s, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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R. H. Nishimura et al.
Paper
Synthesis
IR (Diamond-ATR, neat): 3017, 2928, 2857, 2833, 1621, 1590, 1567,
1487, 1465, 1445, 1422, 1391, 1349, 1318, 1289, 1258, 1247, 1228,
1222, 1176, 1169, 1146, 1133, 1074, 1038, 1018, 975, 882, 876, 852,
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 chro-
matographical purification (silica gel, isohexane:EtOAc = 100:0 →
95:5) afforded the title compound 7b as a pale yellow oil; yield: 43 mg
(0.18 mmol, 92%).
796, 765, 743, 723, 694, 681, 664 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.29 (s, 1 H), 7.54 (d, J = 8.3 Hz, 1 H),
7.48 (dd, J = 8.3, 6.9 Hz, 1 H), 7.23 (dd, J = 6.9, 0.9 Hz, 1 H), 7.01 (s, 1 H),
6.05–6.00 (m, 1 H), 5.81 (dq, J = 10.1, 2.6 Hz, 1 H), 4.24 (m, 1 H), 4.04
(s, 3 H), 2.22–2.15 (m, 3 H), 1.80–1.67 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.1, 147.4, 143.5, 140.3, 130.3,
129.5, 129.4, 124.4, 123.7, 123.2, 102.0, 54.3, 37.1, 31.6, 25.3, 21.0.
IR (Diamond-ATR, neat): 3552, 3442, 3106, 2901, 2854, 1468, 1449,
1409, 1352, 1324, 1287, 1264, 1233, 1184, 1172, 1102, 1078, 1042,
1007, 999, 980, 941, 927, 888, 868, 844, 795, 781, 766, 736, 670 cm–1
.
1H NMR (400 MHz, CD2Cl2):  = 7.31 (dd, J = 5.0, 2.9 Hz, 1 H), 7.27 (dd,
J = 2.9, 1.4 Hz, 1 H), 7.19 (dd, J = 5.0, 1.4 Hz, 1 H), 2.37 (d, J = 9.9 Hz, 4
H), 1.86 (s, 1 H), 1.75–1.67 (m, 9 H), 1.57 (s, 1 H).
13C NMR (100 MHz, CD2Cl2):  = 149.0, 126.3, 126.1, 121.6, 74.6, 38.3,
37.9 (2 C), 35,6 (2 C), 33.4 (2 C), 28.1, 27.9.
MS (EI, 70 eV): m/z (%) = 239 (69), 238 (100), 234 (23), 210 (90), 196
(32), 184 (30), 182 (45), 180 (49), 168 (37), 167 (63), 166 (46), 165
(35), 158 (38), 154 (52), 153 (26), 152 (40), 140 (25), 139 (44), 128
(23), 126 (21), 115 (47), 89 (20), 79 (41), 78 (20).
HRMS (EI): m/z calcd for [C16H17NO]: 239.1310; found: 239.1309.
MS (EI, 70 eV): m/z (%) = 234 (21), 219 (13), 217 (37), 216 (12), 187
(10), 150 (26), 111 (20), 79 (13), 42 (25).
tert-Butyl 3-(1-Hydroxycyclohexyl)-1H-indole-1-carboxylate (7a)
HRMS (EI): m/z calcd for [C14H18OS]: 234.1078; found: 234.1075.
According to the TP, a solution of N-Boc-3-bromoindole (5a; 59 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.3 s, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
cyclohexanone (3a; 30 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 100:0 → 95:5 →
8:2) afforded the title compound 7a as a white solid; yield: 38 mg
(0.12 mmol, 60%); mp 128.6–130.3 °C.
3-(Butylthio)benzo[b]thiophene (7c)
According to the TP, a solution of 3-bromobenzo[b]thiophene (5c; 43
mg, 0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol,
0.5 equiv) in THF (total volume: 1.00 mL) and a solution of nBuLi
(0.30 M in hexane, 0.30 mmol, 1.5 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 0.25 mL reactor tube (1.3 s,
–20 °C) and was subsequently injected in a flask containing a stirred
solution of dibutyl disulfide (3h; 54 mg, 0.30 mmol, 1.5 equiv) in THF.
Stirring was continued for 10 min at 25 °C before sat. aq NH4Cl solu-
tion was added to quench the reaction. The aqueous phase was ex-
tracted with EtOAc (3 × 30 mL) and the combined organic phases
were dried (anhyd Na2SO4) and filtered. After removal of the solvent
flash chromatographical purification (silica gel, isohexane:EtOAc =
100:0 → 99:1) afforded the title compound 7c as a pale yellow oil;
yield: 42 mg (0.19 mmol, 94%).
IR (Diamond-ATR, neat): 3530, 2939, 2923, 2853, 1704, 1473, 1454,
1442, 1380, 1365, 1349, 1306, 1298, 1275, 1261, 1253, 1228, 1190,
1182, 1148, 1141, 1119, 1091, 1055, 1047, 1031, 1019, 983, 966, 907,
IR (Diamond-ATR, neat): 3096, 3060, 2954, 2925, 2869, 1737, 1480,
1463, 1453, 1435, 1419, 1377, 1308, 1272, 1253, 1223, 1146, 1099,
852, 842, 809, 771, 765, 747, 713, 655 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.15 (d, J = 7.9 Hz, 1 H), 7.89 (d, J = 7.8
Hz, 1 H), 7.49 (s, 1 H), 7.30 (ddd, J = 8.4, 7.3, 1.2 Hz, 1 H), 7.22 (ddd, J =
8.2, 7.3, 1.1 Hz, 1 H), 2.04–1.98 (m, 4 H), 1.87–1.71 (m, 5 H), 1.67 (s,
11 H).
13C NMR (100 MHz, CDCl3):  = 150.0, 136.3, 129.0, 128.5, 124.3,
122.4, 121.7, 121.5, 115.5, 83.8, 71.1, 38.0 (2 C), 28.4 (3 C), 25.9, 22.1
(2 C).
1062, 1018, 962, 937, 914, 825, 780, 753, 730, 723, 703 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.95–7.93 (m, 1 H), 7.88–7.85 (m, 1 H),
7.44 (ddd, J = 8.3, 7.0, 1.2 Hz, 1 H), 7.40 (dd, J = 7.9, 1.1 Hz, 1 H), 7.38
(s, 1 H), 2.90 (t, J = 7.2 Hz, 2 H), 1.66–1.58 (m, 2 H), 1.50–1.41 (m, 2 H),
0.91 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 140.0, 139.3, 127.5, 126.2, 124.9,
124.5, 123.0, 122.7, 34.6, 31.7, 21.9, 13.8.
MS (EI, 70 eV): m/z (%) = 259 (31), 242 (11), 241 (68), 216 (17), 198
(13), 197 (67), 196 (26), 182 (10), 172 (29), 170 (11), 168 (43), 167
(16), 154 (11), 144 (10), 130 (21), 117 (20), 61 (10), 57 (100), 56 (13),
55 (14), 45 (12), 44 (23), 43 (81), 41 (47).
MS (EI, 70 eV): m/z (%) = 222 (32), 166 (100), 165 (14), 134 (12), 121
(20).
HRMS (EI): m/z calcd for [C12H14S2]: 222.0537; found: 222.0532.
HRMS (EI): m/z calcd for [C19H25NO3]: 315.1834; found: 315.1824.
1-(Furan-3-yl)cyclohexan-1-ol (7d)
According to the TP, a solution of 3-bromofuran (5d; 29 mg, 0.20 M,
0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in THF (to-
tal volume: 1.00 mL) and a solution of nBuLi (0.30 M in hexane,
0.30 mmol, 1.5 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, –40 °C) and was
subsequently injected into a flask containing a stirred solution of cy-
clohexanone (3a; 30 mg, 0.30 mmol, 1.5 equiv) in THF. 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
Adamantan-2-yl(thiophen-3-yl)methanol (7b)
According to the TP, a solution of 3-bromothiophene (5b; 33 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.3 s, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
2-adamantanone (3b; 45 mg, 0.30 mmol, 1.5 equiv) in THF. Stirring
was continued for 10 min at 25 °C before sat. aq NH4Cl solution was
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

I
R. H. Nishimura et al.
Paper
Synthesis
Na2SO4) and filtered. After removal of the solvent, flash chromato-
graphical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1) af-
forded the title compound 7d as a pale yellow oil; yield: 20 mg
(0.12 mmol, 60%).
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 chromatographical
purification (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2) afforded
the title compound 10b as a white solid; yield: 33 mg (0.12 mmol,
68%); mp 150.8–152.3 °C.
IR (Diamond-ATR, neat): 3445, 2930, 2857, 2360, 1753, 1633, 1448,
1341, 1318, 1280, 1260, 1178, 1161, 1147, 1134, 1114, 1088, 1052,
1033, 1021, 972, 956, 929, 888, 872, 837, 787, 725 cm–1
.
IR (Diamond-ATR, neat): 3352, 2952, 2870, 2360, 1576, 1558, 1457,
1H NMR (400 MHz, CDCl3):  = 7.38–7.36 (m, 2 H), 6.42 (dd, J = 1.6, 1.1
Hz, 1 H), 1.86–1.78 (m, 3 H), 1.75–1.67 (m, 3 H), 1.63–1.49 (m, 4 H),
1.37–1.29 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 143.2, 138.3, 108.5 (2 C), 69.4, 38.7 (2
C), 25.7, 22.3 (2 C).
1358, 1310, 1294, 1147, 1089, 1022, 974, 958, 909, 829, 731 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.47 (dd, J = 2.7, 0.6 Hz, 1 H), 7.70 (dd,
J = 8.4, 2.7 Hz, 1 H), 7.43 (dd, J = 8.4, 0.7 Hz, 1 H), 2.51 (d, J = 3.5 Hz, 1
H), 2.36 (t, J = 4.2 Hz, 1 H), 2.21 (ddd, J = 13.3, 4.8, 2.8 Hz, 1 H), 2.18–
2.11 (m, 1 H), 1.92 (s, 1 H), 1.69–1.63 (m, 1 H), 1.53–1.48 (m, 3 H),
1.47–1.42 (m, 1 H), 1.38 (dq, J = 10.3, 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 148.2, 143.7, 140.5, 137.0, 127.7, 79.5,
47.6, 47.0, 38.8, 37.8, 28.9, 22.3.
MS (EI, 70 eV): m/z (%) = 166 (77), 151 (12), 148 (26), 137 (14), 133
(14), 123 (100), 110 (19), 108 (11), 95 (58), 91 (27), 81 (28), 77 (13),
67 (28).
HRMS (EI): m/z calcd for [C10H14O2]: 166.0994; found: 166.0988.
MS (EI, 70 eV): m/z (%) = 214 (38), 212 (39), 202 (31), 201 (58), 200
(33), 199 (60), 188 (32), 186 (98), 184 (100), 158 (18), 156 (18), 133
(20).
2-(2-Bromoquinolin-4-yl)bicyclo[2.2.1]heptan-2-ol (10a)
According to the TP, a solution of 2,4-dibromoquinoline (8a; 57 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
norcamphor (3i; 33 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 100:0 → 95:5 →
9:1) afforded the title compound 10a as a white solid; yield: 33 mg
(0.11 mmol, 58%); mp 216.8–218.2 °C.
HRMS (EI): m/z calcd for [C12H14BrNO]: 267.0259; found: 267.0252.
2-(6-Bromopyridin-3-yl)adamantan-2-ol (10c)
According to the TP, a solution of 2,5-dibromopyridine (8b; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, 0 °C) and was
subsequently injected into a flask containing a stirred solution of 2-
adamantanone (3b; 45 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2)
afforded the title compound 10c as a white solid; yield: 37 mg
(0.12 mmol, 67%); mp 163.0–164.8 °C.
IR (Diamond-ATR, neat): 3378, 2961, 2940, 2928, 2867, 1572, 1554,
1500, 1409, 1357, 1339, 1312, 1280, 1267, 1254, 1225, 1165, 1147,
1096, 1084, 1045, 1023, 1002, 994, 959, 888, 872, 836, 796, 770, 753,
692 cm–1
.
IR (Diamond-ATR, neat): 3356, 2906, 2855, 2361, 1575, 1559, 1458,
1H NMR (400 MHz, CDCl3):  = 8.46 (dd, J = 8.6, 1.0 Hz, 1 H), 8.00 (dd,
J = 8.4, 0.8 Hz, 1 H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.53 (ddd, J =
8.4, 6.9, 1.4 Hz, 1 H), 7.49 (s, 1 H), 2.92 (d, J = 3.5 Hz, 1 H), 2.33 (t, J =
3.9 Hz, 1 H), 2.29–2.20 (m, 2 H), 2.04 (s, 1 H), 1.95 (dd, J = 13.3, 3.3 Hz,
1 H), 1.76–1.51 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 155.5, 150.3, 141.8, 130.0, 129.7,
127.9, 126.5, 125.4, 121.3, 80.5, 48.3, 46.2, 39.2, 37.6, 29.0, 22.0.
1364, 1090, 1049, 1008, 969, 912, 831 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.47 (d, J = 2.6 Hz, 1 H), 7.69 (dd, J = 8.4,
2.7 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 2.49 (s, 2 H), 2.38 (d, J = 12.0 Hz, 2
H), 1.91 (t, J = 2.8 Hz, 1 H), 1.87 (s, 1 H), 1.82–1.70 (m, 7 H), 1.60 (d, J =
13.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 148.5, 140.9, 140.2, 136.6, 128.2, 74.8,
37.6, 35.6 (2 C), 34.8 (2 C), 32.8 (2 C), 27.4, 26.7.
MS (EI, 70 eV): m/z (%) = 251 (58), 249 (62), 238 (43), 236 (36), 234
(37), 232 (26), 210 (25), 209 (37), 208 (38), 207 (37), 206 (39), 192
(24), 182 (28), 170 (100), 154 (42), 153 (25), 152 (26), 142 (49), 140
(53), 128 (77), 127 (88), 115 (84), 77 (26), 75 (30), 67 (54).
MS (EI, 70 eV): m/z (%) = 309 (20), 307 (23), 291 (98), 289 (100), 228
(32), 210 (16), 207 (16), 200 (16), 189 (19), 188 (32), 187 (21), 186
(61), 184 (63), 159 (26), 158 (24), 157 (28), 156 (26), 151 (58), 133
(27), 93 (25), 91 (23), 81 (43), 79 (39), 77 (15).
HRMS (EI): m/z calcd for [C16H16BrNO]: 317.0415; found: 317.0410.
HRMS (EI): m/z calcd for [C15H18BrNO]: 307.0572; found: 307.0566.
2-(6-Bromopyridin-3-yl)bicyclo[2.2.1]heptan-2-ol (10b)
1-(6-Bromopyridin-3-yl)-1-phenylethan-1-ol (10d)
According to the TP, a solution of 2,5-dibromopyridine (8b; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, 0 °C) and was
subsequently injected into a flask containing a stirred solution of nor-
camphor (3i; 33 mg, 0.30 mmol, 1.5 equiv) in THF. Stirring was con-
According to the TP, a solution of 2,5-dibromopyridine (8b; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, 0 °C) and was
subsequently injected into a flask containing a stirred solution of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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R. H. Nishimura et al.
Paper
Synthesis
acetophenone (3j; 28 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2)
afforded the title compound 10d as a colorless oil; yield: 28 mg
(0.10 mmol, 56%).
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 chro-
matographical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1
→ 8:2) afforded the title compound 10f as a colorless oil; yield: 26 mg
(0.11 mmol, 61%).
IR (Diamond-ATR, neat): 3021, 2931, 2860, 2836, 2360, 2342, 1670,
1653, 1576, 1559, 1451, 1395, 1377, 1346, 1300, 1131, 1088, 1022,
IR (Diamond-ATR, neat): 2920, 2361, 2342, 2332, 1576, 1559, 1457,
1449, 1374, 1093, 1022, 766, 700 cm–1
.
882, 848, 829, 793, 737, 724 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.40 (d, J = 2.6 Hz, 1 H), 7.57 (dd, J = 8.3,
2.6 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 3 H), 7.34 (td, J = 6.8, 1.8 Hz, 2 H), 7.28
(dt, J = 7.1, 1,4 Hz, 1 H), 2,43 (s, 1 H), 1.96 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 148.1, 146.4, 143.0, 140.7, 136.7, 128.7
(2 C), 127.8, 127.6, 125.8 (2 C), 74.9, 30.8.
1H NMR (400 MHz, CDCl3):  = 8.22 (t, J = 1.6 Hz, 1 H), 7.39 (d, J = 1.6
Hz, 2 H), 5.97–5.92 (m, 1 H), 5.64–5.60 (m, 1 H), 3.43–3.37 (m, 1 H),
2.12–2.06 (m, 2 H), 2.01–1.98 (m, 1 H), 1.74–1.57 (m, 2 H), 1.53–1.45
(m, 1 H).
13C NMR (100 MHz, CDCl3):  = 150.0, 141.3, 139.7, 138.1, 130.1,
128.2, 127.8, 38.8, 32.4, 24.9, 20.8.
MS (EI, 70 eV): m/z (%) = 265 (12), 264 (96), 263 (13), 262 (100), 186
(63), 184 (64), 158 (15), 156 (15).
MS (EI, 70 eV): m/z (%) = 239 (38), 238 (10), 237 (40), 236 (11), 224
(45), 222 (46), 211 (16), 210 (33), 209 (17), 208 (34), 173 (12), 171
(12), 158 (70), 156 (10), 143 (31), 142 (14), 131 (10), 130 (100), 128
(19), 117 (16), 104 (10), 103 (16), 77 (12).
HRMS (EI): m/z calcd for [C13H12BrNO]: 277.0102; found: 277.0098.
(6-Bromopyridin-3-yl)dicyclopropylmethanol (10e)
HRMS (EI): m/z calcd for [C11H12BrN]: 237.0153; found: 237.0145.
According to the TP, a solution of 2,5-dibromopyridine (8b; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, 0 °C) and was
subsequently injected into a flask containing a stirred solution of di-
cyclopropyl ketone (3k; 33 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chro-
matographical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1
→ 8:2) afforded the title compound 10e as a colorless oil; yield:
43 mg (0.16 mmol, 89%).
1-(5-Bromopyrazin-2-yl)cyclohexan-1-ol (10g)
According to the TP, a solution of 2,5-dibromopyrazine (8c; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.30 M in hex-
ane, 0.30 mmol, 1.5 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.3 s, –20 °C) and
was subsequently injected into a flask containing a stirred solution of
cyclohexanone (3a; 30 mg, 0.30 mmol, 1.5 equiv) in THF. 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 chromato-
graphical purification (silica gel, isohexane:EtOAc = 95:5 → 9:1 → 8:2)
afforded the title compound 10g as a white solid; yield: 31 mg
(0.12 mmol, 67%); mp 70.4–72.8 °C.
IR (Diamond-ATR, neat): 3354, 3086, 3008, 1575, 1560, 1451, 1427,
1355, 1288, 1165, 1138, 1122, 1084, 1022, 999, 969, 926, 913, 872,
858, 827, 735 cm–1
.
IR (Diamond-ATR, neat): 3460, 2917, 2851, 1737, 1727, 1443, 1377,
1365, 1353, 1303, 1271, 1259, 1227, 1158, 1144, 1132, 1118, 1108,
1H NMR (400 MHz, CDCl3):  = 8.57 (dd, J = 2.6, 0.7 Hz, 1 H), 7.73 (dd,
J = 8.3, 2.6 Hz, 1 H), 7.43 (dd, J = 8.4, 0.7 Hz, 1 H), 1.47 (s, 1 H), 1.18–
1.09 (m, 2 H), 0.64–0.54 (m, 4 H), 0.46–0.33 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 148.1, 142.2, 140.4, 136.3, 127.1, 72.6,
20.4 (2 C), 2.3 (2 C), 0.1 (2 C).
1099, 1037, 1028, 1014, 981, 927, 905, 891, 851, 835, 764 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.59 (s, 2 H), 3.09 (s, 1 H), 1.92–1.64
(m, 9 H), 1.39–1.28 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 160.5, 145.5, 142.0, 138.9, 73.1, 37.9
(2 C), 25.3, 21.8 (2 C).
MS (EI, 70 eV): m/z (%) = 241 (56), 239 (57), 238 (10), 228 (58), 226
(62), 224 (26), 199 (25), 197 (23), 186 (95), 184 (100), 160 (26), 158
(26), 156 (26), 145 (15).
MS (EI, 70 eV): m/z (%) = 230 (84), 228 (88), 227 (14), 215 (54), 213
(54), 203 (15), 201 (28), 199 (28), 187 (95), 186 (15), 185 (100), 183
(15), 175 (33), 174 (75), 173 (35), 172 (79), 160 (22), 159 (31), 158
(23), 157 (29).
HRMS (EI): m/z calcd for [C12H14BrNO]: 267.0259; found: 268.0333
[M + H].
HRMS (EI): m/z calcd for [C10H13BrN2O]: 256.0211; found: 256.0205.
2-Bromo-5-(cyclohex-2-en-1-yl)pyridine (10f)
According to the TP, a solution of 2,5-dibromopyridine (8b; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.10 M, 0.10 mmol, 0.5 equiv) 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 0.25 mL reactor tube (1.3 s, 0 °C) and was
subsequently injected into a flask containing a stirred solution of 3-
bromocyclohex-1-ene (3g; 48 mg, 0.30 mmol, 1.5 equiv) and
CuCN·2LiCl solution (0.02 mL, 1 M in THF, 0.1 equiv) in THF. Stirring
2,5-Di(cyclohex-2-en-1-yl)pyrazine (10h)
According to the TP, a solution of 2,5-dibromopyrazine (8d; 47 mg,
0.20 M, 0.20 mmol) and MgCl2·LiCl (0.20 M, 0.10 mmol, 0.5 equiv) in
THF (total volume: 1.00 mL) and a solution of nBuLi (0.48 M in hex-
ane, 0.48 mmol, 2.4 equiv) were prepared. The precooled solutions
were mixed with an overall 12 mL/min flowrate in a T-mixer. The
combined stream passed a 0.25 mL reactor tube (1.3 s, 0 °C) and
was subsequently injected in a flask containing a stirred solution of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

K
R. H. Nishimura et al.
Paper
Synthesis
3-bromocyclohex-1-ene (3g; 97 mg, 0.60 mmol, 3.0 equiv) and
CuCN·2LiCl solution (0.04 mL, 1 M in THF, 0.2 equiv) in THF. 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 chro-
matographical purification (silica gel, isohexane:EtOAc = 4:1) afford-
ed the title compound 10h as a colorless oil; yield: 30 mg (0.13 mmol,
62%).
B. J. Med. Chem. 1981, 24, 1165. (d) Vicentini, C. B.; Mares, D.;
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Chem. Soc. Rev. 2008, 37, 2620. (f) Lutter, F. H.; Hofmayer, M. S.;
Hammann, J. M.; Malakhov, V.; Knochel, P. Generation and Trap-
ping of Functionalized Aryl- and Heteroarylmagnesium and -Zinc
Compounds, In Organic Reactions, Vol. 100; Denmark, S. E., Ed.;
Wiley: Hoboken, 2019.
(3) (a) Clayden, J. In Organolithiums: Selectivity for Synthesis;
Baldwin, J. E.; Williams, R. M., Ed.; Pergamon: Oxford, 2002.
(b) Whisler, M. C.; Mac-Neil, S.; Snieckus, V.; Beak, P. Angew.
Chem. Int. Ed. 2004, 43, 2206. (c) Morija, K.; Schwärzer, K.;
Karaghiosoff, K.; Knochel, P. Synthesis 2016, 48, 3141. (d) Bellan,
A. B.; Knochel, P. Synthesis 2019, 51, 3536. (e) Skotnitzki, J.;
Kremsmair, A.; Knochel, P. Synthesis 2020, 52, 189.
(f) Skotnitzki, J.; Kremsmair, A.; Kicin, B.; Saeb, R.; Ruf, V.;
Knochel, P. Synthesis 2020, 52, 873.
IR (Diamond-ATR, neat): 3021, 2928, 2859, 2836, 1476, 1447, 1432,
1340, 1145, 1129, 1032, 988, 896, 879, 724 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.42 (s, 2 H), 5.99–5.96 (m, 2 H), 5.77
(d, J = 10.1 Hz, 2 H), 3.62–3.58 (m, 2 H), 2.17–2.05 (m, 6 H), 1.80–1.65
(m, 6 H).
13C NMR (100 MHz, CDCl3):  = 157.9, 143.1, 129.8, 127.7, 41.5, 41.0,
30.5, 25.0 (2C), 24.0, 21.1 (2C), 21.0, 17.6, 17.4, 14.8.
MS (EI, 70 eV): m/z (%) = 241 (11), 240 (67), 239 (32), 225 (18), 212
(34), 211 (100), 199 (20), 197 (16), 186 (14), 185 (11), 183 (24), 174
(72), 173 (29), 171 (14), 169 (17), 159 (25), 157 (28), 146 (14), 145
(25), 120 (21), 77 (11).
(4) (a) Asai, T.; Takata, A.; Ushiogi, Y.; Iinuma, Y.; Nagaki, A.;
Yoshida, J.-I. Chem. Lett. 2011, 40, 393. (b) Iddon, B. Heterocycles
1983, 20, 1127. (c) Nagaki, A.; Yamada, S.; Doi, M.; Tomida, Y.;
Takabayashi, N.; Yoshida, J.-I. Green Chem. 2011, 13, 1110.
(5) (a) Oda, S.; Yamamoto, H. Angew. Chem. Int. Ed. 2013, 52, 8165.
(b) Kim, H.; Min, K.-I.; Inoue, K.; Im, D.-J.; Kim, D.-P.; Yoshida, J.-
i. Science 2016, 352, 691. (c) Armstrong, D. R.; Crosbie, E.; Hevia,
E.; Mulvey, R. E.; Ramsay, D. L.; Robertson, S. D. Chem. Sci. 2014,
5, 3031.
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metallics: Applications in Synthesis, Vol. 1; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005, 7–45. (b) Becker, M. R.; Ganiek, M.
A.; Knochel, P. Chem. Sci. 2015, 6, 6649. (c) Skotnitzki, J.;
Kremsmair, A.; Keefer, D.; Gong, Y.; de Vivie-Riedle, R.; Knochel,
P. Angew. Chem. Int. Ed. 2019, 59, 320. (d) Ramón, D. J.; Yus, M.
Tetrahedron 1996, 52, 13739. (e) Olofson, R. A.; Dougherty, C. M.
J. Am. Soc. Chem. 1973, 95, 582.
HRMS (EI): m/z calcd for [C16H20N2]: 240.1626; found: 240.1622.
Funding Information
Funding Information: Studienstiftung des Deutschen Volkes, (Grant /
Award Number: ) Fundação de Amparo à Pesquisa do Estado de São
Paulo, (Grant / Award Number: '2018/08856-5')R. H. V. Nishimura
thanks Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP, Grant number: 2018/08856-5) for financial support. N.
Weidmann thanks the German Academic Scholarship Foundation for
a fellowship. We thank the DFG and LMU for financial support. We
further thank BASF (Ludwigshafen) and Albemarle (Frankfurt) for the
generous gift of chemicals, and Vapourtec and Uniqsis for technical
support.
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(7) (a) Rogers, H. R.; Houk, J. J. Am. Chem. Soc. 1982, 104, 522.
(b) Reich, H. J.; Phillips, N. H.; Reich, I. L. J. Am. Chem. Soc. 1985,
107, 4101. (c) Jedlicka, B.; Crabtree, R. H.; Siebahn, P. E. M.
Organometallics 1997, 16, 6021. (d) Reich, H. J. J. Org. Chem.
2012, 77, 5471.
(8) (a) Ketels, M.; Ganiek, M. A.; Weidmann, N.; Knochel, P. Angew.
Chem. Int. Ed. 2017, 56, 12770. (b) Heinz, B.; Balkenhohl, M.;
Knochel, P. Synthesis 2019, 51, 4452.
Acknowledgment
We thank BASF (Ludwigshafen) and Albemarle (Frankfurt) for the
generous gift of chemicals and Vapourtec and Uniqsis for technical
support. N. Weidmann thanks the German Academic Scholarship
Foundation for a fellowship.
(9) General advances in flow chemistry: (a) Brodmann, T.; Koos, P.;
Metzger, A.; Knochel, P.; Ley, S. V. Org. Process Res. Dev. 2012, 16,
1102. (b) Ghislieri, D.; Gilmore, K.; Seeberger, P. H. Angew.
Chem. Int. Ed. 2015, 54, 678. (c) Battilocchio, C.; Feist, F.; Hafner,
A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley,
S. V. Nat. Chem. 2016, 8, 360. (d) Seo, H.; Katcher, M. H.; Jamison,
T. F. Nat. Chem. 2017, 9, 453.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707167.
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References
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K