Chromium-Catalyzed Cross-Coupling Reactions of Alkylmagnesium Reagents with Halo-Quinolines and Activated Aryl Chlorides

Article abstract of DOI:10.1055/s-0035-1561615

An efficient protocol for chromium(III)-catalyzed C(sp²)-C(sp³) cross-coupling is reported. The alkylations of halo-quinoline and phenacyl derivatives proceed at room temperature within minutes using the tetrahydrofuran-soluble chrom

Full text of DOI:10.1055/s-0035-1561615

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
A. B. Bellan et al.
Paper
Synthesis
Chromium-Catalyzed Cross-Coupling Reactions of Alkylmagne-
sium Reagents with Halo-Quinolines and Activated Aryl Chlorides
Andreas B. Bellan
Olesya M. Kuzmina
Violeta A. Vetsova
Paul Knochel*
CrCl3·3THF
AlkylMgX
25 °C, 15 min
N
X
N
Alkyl
R
R
13 examples
up to 91% yield
R: H, 4-Me, 4-CO2Et, 6-Cl
Department of Chemistry, Ludwig-Maximilians-Universität München,
Butenandtstrasse 5-13, Haus F, 81377 München, Germany
paul.knochel@cup.uni-muenchen.de
R'
R'
Cl
CrCl3·3THF
AlkylMgX
O
FG
25 °C, 15 min
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
and in recognition of his outstanding contribution to asymmetric catalysis.
Alkyl
4 examples
up to 88% yield
R': H, Ph
Received: 01.03.2016
Accepted after revision: 14.03.2016
Published online: 27.04.2016
plex was prepared by Soxhlet extraction of CrCl3 with THF
and a catalytic amount of zinc powder (Scheme 1).
In a preliminary experiment, we treated 2-chloroquino-
line (1a) with phenylethylmagnesium bromide (2a) (1.5
equiv), prepared from the corresponding bromide and
Mg/LiCl, in the presence of CrCl3·3THF (3 mol%) at 25 °C.16
We observed full conversion after 15 minutes of reaction
time and obtained 91% yield of the desired cross-coupling
product 3a. In contrast to other transition metals such as
iron or cobalt, no homo-coupling byproducts were ob-
served. We were also able to reduce the amount of
CrCl3·3THF from 3 mol% to 0.5 mol% with no decrease in the
yield using this Grignard reagent (Scheme 2).
DOI: 10.1055/s-0035-1561615; Art ID: ss-2016-t0152-op
Abstract An efficient protocol for chromium(III)-catalyzed C(sp2)–
C(sp3) cross-coupling is reported. The alkylations of halo-quinoline and
phenacyl derivatives proceed at room temperature within minutes us-
ing the tetrahydrofuran-soluble chromium(III) complex CrCl3·3THF. The
reactions occur without the formation of homo-coupling side products,
which are common for the related iron-, cobalt- or manganese-cata-
lyzed cross-coupling reactions.
Key words magnesium, chromium, quinolines, cross-coupling,
Grignard reagents
MgBr·LiCl
Although, palladium- and nickel-catalyzed cross-cou-
plings using Grignard reagents are well known, alternative
cross-couplings using transition-metal catalysts such as
iron, cobalt or copper salts are cost efficient options and
have therefore been studied with great attention.1–9
2a
N
Cl
N
Ph
CrCl3·3THF (0.5 mol%)
THF, 25 °C, 15 min
1a
3a, 91%
Recently, we reported that chromium(II) chloride cata-
lyzes the cross-coupling of various aryl- and heteroaryl-
magnesium reagents with electron-deficient aryl and het-
eroaryl halides.10–12 We showed also that CrCl2 catalyzes the
direct oxidative arylation of pyridines, aryl oxazolines, and
imines with aryl Grignard reagents.13 In addition, CrCl2 cat-
alyzes the amination of N-heterocyclic chlorides.14
Herein, we report a simple procedure allowing the
cross-coupling of alkylmagnesium reagents with electron-
deficient unsaturated substrates using CrCl3·3THF, a chro-
mium(III) catalyst that is well soluble in THF.15 This com-
Scheme 2 First example of the chromium(III)-catalyzed coupling of al-
kylmagnesium reagents and (hetero)aryl chlorides
We extended this coupling reaction to primary alkyl-
magnesium derivatives such as 2b,c and obtained the al-
kylated quinolines 3b,c in 65–79% yield under the same re-
action conditions (Table 1, entries 1 and 2). In these cross-
couplings, we used Grignard reagents complexed with
LiCl.16 Control experiments using alkylmagnesium reagents
in the absence of LiCl led to no differences in the yield or
reaction time. The related 2-chloro-4-methylquinoline (1b)
reacted similarly with the Grignard reagents 2a–e leading,
within 15 minutes at 25 °C, to the 2-alkylated quinolines
3d–h in 56–82% yield (Table 1, entries 3–7). Electron-defi-
cient 2,6-dichloroquinoline (1c) underwent a regioselective
Zn (3 mol%)
CrCl3
CrCl3·3THF
97%
THF, 70 °C, 16 h
Scheme 1 Preparation of THF-soluble CrCl3·3THF
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
A. B. Bellan et al.
Paper
Synthesis
cross-coupling with various primary alkylmagnesium re-
agents 2a–e furnishing the expected 2-alkylated-6-chloro-
quinolines 3i–m in 58–84% yield (Table 1, entries 8–12).17
The reaction scope could be somewhat extended and
functionalized 2-bromoquinoline 1d as well as 1-iodoiso-
quinoline (1e) reacted well with the alkylmagnesium re-
agent 2a producing the expected products 3n,o, both in 50%
yield (Scheme 3).
Table 1 Chromium-Catalyzed Cross-Coupling Reactions of Alkylmagnesium Reagents 2a–e with Bicyclic Heteroarenes 1a–c
CrCl3·3THF (3 mol%)
AlkylMgX (1.5 equiv)
THF, 25 °C, 15 min
N
Alkyl
N
Cl
R
R
1a–c
3b–m
R: H, Me, Cl
Entry
1
Electrophile
Magnesium reagent
Product/Yielda
MgBr·LiCl
N
N
Cl
1a
2b
3b: 79%
Et MgBr·LiCl
2c
2
3
1a
N
Et
3c: 65%
Me
N
Me
2a
N
Cl
1b
3d: 82%
Me
4
1b
2b
2c
N
3e: 79%
Me
5
6
7
8
1b
1b
1b
N
Et
3f: 79%
Me
Me MgCl
2d
N
Me
3g: 56%
Me
MgBr·LiCl
2e
2a
N
3h: 69%
Cl
Cl
N
N
Cl
1c
3i: 58%
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
A. B. Bellan et al.
Paper
Synthesis
Table 1 (continued)
Entry
Electrophile
Magnesium reagent
Product/Yielda
Cl
9
1c
2b
N
3j: 77%
Cl
10
11
12
1c
1c
1c
2c
2d
2e
N
N
N
Et
3k: 63%
Cl
Me
3l: 83%
Cl
3m: 84%
a Yield of isolated pure product.
Interestingly, alkylmagnesium halides also reacted
smoothly with aryl chlorides bearing an electron-with-
drawing function, such as a phenacyl group or an imine, at
the ortho position. Thus, the Grignard reagent 2a coupled
with 2-chlorobenzophenone (4a) in the presence of 3 mol%
CrCl3·3THF within 15 minutes at 25 °C furnishing the al-
kylated benzophenone 5a in 70% yield. Using the less reac-
tive Grignard reagent, Me3SiCH2MgCl·LiCl18 (2f) provided
the benzophenone 5b in 88% yield. Also, imine 4b was read-
ily alkylated with 2a producing, after acidic hydrolysis, the
ortho-alkylated benzaldehyde 5c in 71% yield. Although,
secondary alkylmagnesium halides normally undergo these
cross-couplings in moderate yield, cyclopropylmagnesium
bromide complexed with lithium chloride (2g) underwent a
rapid cross-coupling with 4b leading to the aldehyde 5d in
74% yield (Scheme 4).
kylated products. These cross-couplings do not show any
traces of homo-coupling, which are typical in iron- or co-
balt-mediated cross-couplings. Further investigations on
extending the reaction scope are underway in our laborato-
ry.
R'
Ph
CrCl3·3THF (3 mol%)
AlkylMgX (2a, 2f, 2g)
Ph
O
O
N
or
Alkyl
5a–d
THF, 25 °C, 15 min
R': H, Ph
Cl
Cl
4a
4b
Ph
Ph
H
O
H
O
O
O
TMS
Ph
Ph
In summary, we have shown that primary alkylmagne-
sium reagents rapidly undergo cross-couplings with chloro-
quinolines, iodoisoquinolines, and activated aryl chlorides
at 25 °C within 15 minutes leading to the corresponding al-
5a: 70%
5b: 88%
5c: 71%
5d: 74%
Scheme 4 Chromium-catalyzed cross-couplings of activated aryl chlo-
rides
CO2Et
N
CO2Et
N
Br
I
1d
1e
N
2a
N
Ph
CrCl3·3THF (3 mol%)
THF, 25 °C, 15 min
CrCl3·3THF (3 mol%)
THF, 25 °C, 15 min
Ph
3n: 50%
3o: 50%
Scheme 3 Cross-coupling of bromide 1d and iodide 1e with the Grignard reagent 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
A. B. Bellan et al.
Paper
Synthesis
Unless otherwise stated, all reactions were carried out with magnetic
stirring and in flame-dried glassware under argon. Syringes which
were used to transfer anhydrous solvents or reagents were purged
with argon prior to use. Reactions were monitored by gas chromatog-
raphy or by thin-layer chromatography. TLC was performed using alu-
minum plates coated with SiO2 (Merck 60, F-254) and visualized by
UV radiation. Purification by column chromatography was performed
using silica gel 60 (40–63 mm, 230–400 mesh, ASTM from Merck).
Commercially available starting materials were used without further
purification unless otherwise stated. THF was continuously refluxed
and freshly distilled from sodium benzophenone. Commercially avail-
able Grignard reagents were titrated against iodine in THF prior to
use. Other Grignard reagents were prepared from the corresponding
bromides by insertion of magnesium in the presence of lithium chlo-
ride, and were titrated against iodine in THF prior to use. Yields refer
to isolated yields of compounds estimated to be >95% pure as deter-
mined by 1H NMR (25 °C) and capillary GC analysis. Melting points
were measured with a Büchi B-540 apparatus and are uncorrected.
Infrared spectra (IR) were recorded on a Perkin Elmer spectrum BX-
59343 instrument. For detection, a Smiths Detection DuraSamplIR II
Diamond ATR sensor was used. IR data are reported in frequency of
absorption (cm–1). NMR spectra were recorded on a Bruker Avance III
HD 400 spectrometer in CDCl3 and chemical shifts are reported in
parts per million (ppm). H–H coupling constants are reported in Hz.
Mass spectra and high-resolution mass spectra (HRMS) were record-
ed on Finnigan MAT 90 or Finnigan MAT 95 instruments using elec-
tron ionization (EI).
IR (ATR): 3026, 2923, 2856, 1618, 1599, 1502, 1452, 1425, 1310, 819,
748, 694 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.5 Hz, 1 H), 8.07 (d, J = 8.4
Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.5
Hz, 1 H), 7.39–7.21 (m, 6 H), 3.34 (dd, J = 9.8, 6.3 Hz, 2 H), 3.21 (dd, J =
9.7, 6.3 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 161.9, 148.0, 141.6, 136.3, 129.5,
128.9, 128.6, 128.5, 127.6, 126.9, 126.1, 125.9, 121.6, 41.1, 36.0.
MS (EI, 70 eV): m/z (%) = 233 (95) [M]+, 232 (100), 217 (17), 156 (55),
129 (23), 128 (14), 115 (11), 91 (15).
HRMS (EI): m/z [M]+ calcd for C17H15N: 233.1204; found: 233.1204.
2-(2-Cyclohexylethyl)quinoline (3b)
A cross-coupling was performed according to the typical procedure
between 2-chloroquinoline (1a) (81 mg) and Grignard reagent 2b
(0.87 mL, 0.86 M). After purification by flash column chromatography
(i-hexane–EtOAc, 9:1), the title compound 3b (95 mg, 79%) was ob-
tained as a yellow oil.
IR (ATR): 2919, 2848, 1600, 1561, 1502, 1447, 1425, 824, 749 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 10.9, 8.7 Hz, 2 H), 7.74 (dd,
J = 8.1, 1.4 Hz, 1 H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.45 (ddd, J =
8.0, 6.8, 1.2 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 3.01–2.92 (m, 2 H), 1.85–
1.76 (m, 2 H), 1.75–1.60 (m, 5 H), 1.39–1.29 (m, 1 H), 1.29–1.08 (m, 3
H), 1.04–0.90 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 163.5, 147.9, 136.2, 129.3, 128.9,
127.5, 126.7, 125.6, 121.4, 37.8, 37.8, 36.9, 33.3, 26.7, 26.4.
MS (EI, 70 eV): m/z (%) = 156 (38) [M–cyclohex]+, 144 (10), 143 (100).
CrCl3·3THF (0.1 M)
A dry, argon-flushed Soxhlet extraction apparatus was charged with
anhydrous CrCl3 (5.0 g, 31.6 mmol, 1.0 equiv) and Zn dust (62 mg,
0.95 mmol, 0.03 equiv).15 The reaction mixture was extracted for 24 h
with refluxing THF (250 mL). The mixture was allowed to cool to r.t.
and the THF was removed in vacuo. The violet solid (11.5 g, 97%) was
stored in a Schlenk flask under argon. THF (10 mL) was added and the
Cr(III) complex partially dissolved. This solution was transferred into
a tared Schlenk flask under argon and the THF was removed in vacuo.
The weight of the resulting solid was determined and enough THF
was added to obtain a 0.1 M solution.
HRMS (EI): m/z [M – H]+ calcd for C17H20N: 238.1590; found:
238.1592.
2-Ethylquinoline (3c)
A cross-coupling was performed according to the typical procedure
between 2-chloroquinoline (1a) (81 mg) and Grignard reagent 2c
(0.65 mL, 1.15 M). After purification by flash column chromatography
(i-hexane–EtOAc, 9:1), the title compound 3c (51 mg, 65%) was ob-
tained as a yellow oil.
IR (ATR): 2969, 2933, 1618, 1602, 1504, 1426, 839, 753 cm–1
.
Chromium-Mediated Cross-Coupling; Typical Procedure
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.3 Hz, 1 H), 8.03 (d, J = 8.6
Hz, 1 H), 7.76 (dd, J = 8.1, 1.4 Hz, 1 H), 7.67 (ddd, J = 8.5, 6.9, 1.5 Hz, 1
H), 7.47 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 3.00 (q,
J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 164.1, 147.9, 136.4, 129.4, 128.9,
127.6, 126.8, 125.7, 120.9, 32.5, 14.2.
A dry, argon-flushed Schlenk tube (10 mL), equipped with a stirring
bar and a septum, was charged with a solution of CrCl3·3THF
(0.15 mL, 0.1 M in THF, 0.015 mmol, 0.03 equiv), the corresponding
(hetero)aryl halide (0.5 mmol, 1.0 equiv) and THF (2.5 mL). The alkyl-
magnesium bromide solution (0.75 mmol, 1.5 equiv) was added drop-
wise over 2 min via syringe at r.t. After 15 min, the reaction mixture
was quenched with sat. NH4Cl solution (1 mL) and diluted with H2O
(4 mL). The phases were separated and the aq phase was extracted
with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4 and filtered. The solvent was
removed in vacuo and the crude residue was purified by flash column
chromatography to give the respective cross-coupled product.
MS (EI, 70 eV): m/z (%) = 157 (55) [M]+, 156 (100), 129 (22), 128 (15).
HRMS (EI): m/z [M – H]+ calcd for C11H10N: 156.0808; found:
156.0806.
2-(4-Methylphenethyl)quinoline (3d)
A cross-coupling was performed according to the typical procedure
between 2-chloro-4-methylquinoline (1b) (89 mg) and Grignard re-
agent 2a (0.82 mL, 0.91 M). After purification by flash column chro-
matography (i-hexane–EtOAc, 9:1), the title compound 3d (101 mg,
82%) was obtained as a colorless oil.
2-Phenethylquinoline (3a)
A cross-coupling was performed according to the typical procedure
between 2-chloroquinoline (1a) (81 mg) and Grignard reagent 2a
(0.85 mL, 0.88 M) with CrCl3·3THF (2.5 μmol, 25 μL, 0.5 mol%). After
purification by flash column chromatography (i-hexane–EtOAc, 9:1),
the title compound 3a (106 mg, 91%) was obtained as a yellow oil.
IR (ATR): 3061, 3027, 2923, 1602, 1562, 1496, 1450, 754, 699 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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A. B. Bellan et al.
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1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.3
Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.34–7.15 (m,
5 H), 7.11 (s, 1 H), 3.24 (dd, J = 10.3, 5.8 Hz, 2 H), 3.14 (dd, J = 10.0, 5.5
Hz, 2 H), 2.67 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 161.7, 147.9, 144.4, 141.8, 129.5,
129.2, 128.6, 128.5, 127.0, 126.1, 125.7, 123.8, 122.4, 41.1, 36.1, 18.9.
MS (EI, 70 eV): m/z (%) = 247 (100) [M]+, 87 (246), 232 (28), 231 (13),
170 (67), 143 (32), 116 (12), 115 (19), 91 (12).
HRMS (EI): m/z [M]+ calcd for C18H17N: 247.1361; found: 247.1356.
MS (EI, 70 eV): m/z (%) = 157 (100) [M]+, 156 (19), 115 (13), 44 (12).
HRMS (EI): m/z [M]+ calcd for C11H11N: 157.0891; found: 157.0883.
2-(But-3-en-1-yl)-4-methylquinoline (3h)
A cross-coupling was performed according to the typical procedure
between 2-chloro-4-methylquinoline (1b) (89 mg) and Grignard re-
agent 2e (0.88 mL, 0.85 M). After purification by flash column chro-
matography (i-hexane–EtOAc, 9:1), the title compound 3h (63 mg,
69%) was obtained as a yellow oil.
IR (ATR): 3063, 2975, 2921, 1602, 1561, 1508, 1446, 1411, 910, 860,
754 cm–1
.
2-(2-Cyclohexylethyl)-4-methylquinoline (3e)
A cross-coupling was performed according to the typical procedure
between 2-chloro-4-methylquinoline (1b) (89 mg) and Grignard re-
agent 2b (0.87 mL, 0.86 M). After purification by flash column chro-
matography (i-hexane–EtOAc, 9:1), the title compound 3e (100 mg,
79%) was obtained as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.00 (m, 1 H), 7.94 (dd, J = 8.4, 1.4
Hz, 1 H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.49 (ddd, J = 8.2, 6.9, 1.3
Hz, 1 H), 7.13 (d, J = 1.1 Hz, 1 H), 5.93 (ddt, J = 16.9, 10.2, 6.6 Hz, 1 H),
5.09 (dq, J = 17.1, 1.7 Hz, 1 H), 5.04–4.95 (m, 1 H), 3.06–2.97 (m, 2 H),
2.66 (d, J = 1.0 Hz, 3 H), 2.63–2.53 (m, 2 H).
IR (ATR): 2919, 2848, 2360, 1602, 1561, 1446, 754 cm–1
.
13C NMR (101 MHz, CDCl3): δ = 161.8, 147.8, 144.4, 137.9, 129.4,
129.2, 126.9, 125.6, 123.7, 122.2, 115.2, 38.6, 34.0, 18.8.
MS (EI, 70 eV): m/z (%) = 197 (58) [M]+, 184 (100), 170 (62), 157 (72),
144 (92), 130 (15), 115 (32).
HRMS (EI): m/z [M]+ calcd for C14H15N: 197.1204; found: 197.1207.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.00 (m, 1 H), 7.90 (dd, J = 8.4, 1.4
Hz, 1 H), 7.64 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.46 (ddd, J = 8.2, 6.8, 1.3
Hz, 1 H), 7.11 (d, J = 1.1 Hz, 1 H), 2.98–2.85 (m, 2 H), 2.63 (d, J = 1.0 Hz,
3 H), 1.85–1.77 (m, 2 H), 1.76–1.58 (m, 5 H), 1.41–1.08 (m, 4 H), 1.03–
0.83 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 163.2, 147.7, 144.2, 129.3, 129.0,
126.8, 125.4, 123.6, 122.1, 37.9, 37.8, 36.8, 33.3, 26.7, 26.4, 18.7.
MS (EI, 70 eV): m/z (%) = 253 (2) [M]+, 170 (37), 158 (11), 157 (100).
HRMS (EI): m/z [M]+ calcd for C18H23N: 253.1830; found: 253.1825.
6-Chloro-2-phenethylquinoline (3i)
A cross-coupling was performed according to the typical procedure
between 2,6-dichloroquinoline (1c) (99 mg) and Grignard reagent 2a
(0.87 mL, 0.86 M). After purification by flash column chromatography
(i-hexane–EtOAc, 19:1), the title compound 3i (78 mg, 58%) was ob-
tained as a colorless solid.
2-Ethyl-4-methylquinoline (3f)
Mp 94.6–95.8 °C.
A cross-coupling was performed according to the typical procedure
between 2-chloro-4-methylquinoline (1b) (89 mg) and Grignard re-
agent 2c (0.65 mL, 1.15 M). After purification by flash column chro-
matography (i-hexane–EtOAc, 9:1), the title compound 3f (68 mg,
79%) was obtained as a colorless oil.
IR (ATR): 2949, 2924, 2856, 1594, 1558, 1488, 1452, 1308, 1073, 830,
820, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 9.0 Hz, 1 H), 7.90 (d, J = 8.5
Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 7.61 (dd, J = 9.0, 2.4 Hz, 1 H), 7.33–
7.16 (m, 6 H), 3.30–3.24 (m, 2 H), 3.20–3.11 (m, 2 H).
IR (ATR): 2969, 2933, 2873, 1604, 1562, 1507, 1448, 862, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 8.5, 0.7 Hz, 1 H), 7.91 (dd,
J = 8.4, 0.8 Hz, 1 H), 7.65 (ddd, J = 8.4, 6.8, 1.5 Hz, 1 H), 7.47 (ddd, J =
8.2, 6.8, 1.3 Hz, 1 H), 7.12 (d, J = 1.0 Hz, 1 H), 2.94 (q, J = 7.6 Hz, 2 H),
2.64 (s, 3 H), 1.37 (t, J = 7.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 163.7, 147.7, 144.4, 129.3, 129.1,
126.8, 125.4, 123.6, 121.6, 32.3, 18.8, 14.2.
13C NMR (101 MHz, CDCl3): δ = 162.2, 146.4, 141.4, 135.3, 131.5,
130.6, 130.3, 128.6, 128.5, 127.4, 126.3, 126.1, 122.5, 41.0, 35.8.
MS (EI, 70 eV): m/z (%) = 266 (100) [M – H]+, 192 (17), 190 (48), 163
(18), 91 (26).
HRMS (EI): m/z [M – H]+ calcd for C17H1335ClN: 266.0731; found:
266.0726.
MS (EI, 70 eV): m/z (%) = 171 (48) [M]+, 170 (76), 70 (12), 61 (18), 45
(15), 43 (100).
6-Chloro-2-(2-cyclohexylethyl)quinoline (3j)
HRMS (EI): m/z [M – H]+ calcd for C12H12N: 170.0964; found:
170.0964.
A cross-coupling was performed according to the typical procedure
between 2,6-dichloroquinoline (1c) (99 mg) and Grignard reagent 2b
(0.87 mL, 0.86 M). After purification by flash column chromatography
(i-hexane–EtOAc, 19:1), the title compound 3j (105 mg, 77%) was ob-
tained as a colorless solid.
2,4-Dimethylquinoline (3g)
A cross-coupling was performed according to the typical procedure
between 2-chloro-4-methylquinoline (1b) (89 mg) and commercial
MeMgCl (2d) (0.32 mL, 2.34 M). After purification by flash column
chromatography (i-hexane–EtOAc, 9:1), the title compound 3g (44
mg, 56%) was obtained as a colorless oil.
Mp 69.2–70.3 °C.
IR (ATR): 2919, 2849, 1599, 1557, 1489, 1447, 1072, 875, 829, 810 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.6 Hz, 2 H), 7.74 (d, J = 2.4
Hz, 1 H), 7.60 (dd, J = 9.0, 2.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 3.02–
2.91 (m, 2 H), 1.86–1.76 (m, 2 H), 1.75–1.61 (m, 4 H), 1.41–1.12 (m, 4
H), 1.03–0.90 (m, 2 H), 0.90–0.80 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 164.0, 146.4, 135.4, 131.3, 130.6,
130.3, 127.4, 126.3, 122.4, 37.9, 37.7, 36.9, 33.4, 26.8, 26.5.
IR (ATR): 2952, 2922, 1604, 1564, 1447, 859, 758 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 8.5, 1.2 Hz, 1 H), 7.95 (dd,
J = 8.4, 1.3 Hz, 1 H), 7.67 (ddd, J = 8.4, 6.8, 1.4 Hz, 1 H), 7.50 (ddd, J =
8.2, 6.8, 1.2 Hz, 1 H), 7.14 (d, J = 1.2 Hz, 1 H), 2.70 (s, 3 H), 2.67 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.8, 147.8, 144.3, 129.3, 129.3,
126.7, 125.6, 123.7, 122.9, 25.4, 18.8.
MS (EI, 70 eV): m/z (%) = 273 (3) [M]+, 192 (12), 190 (38), 176 (100).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
A. B. Bellan et al.
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Synthesis
HRMS (EI): m/z [M]+ calcd for C17H2035ClN: 273.1284; found:
Ethyl 2-Phenethylquinoline-4-carboxylate (3n)
273.1292.
A cross-coupling was performed according to the typical procedure
between ethyl 2-bromoquinoline-4-carboxylate (1d) (140 mg) and
Grignard reagent 2a (0.87 mL, 0.86 M). After purification by flash col-
umn chromatography (i-hexane–EtOAc, 19:1), the title compound 3n
(76 mg, 50%) was obtained as a yellow oil.
6-Chloro-2-ethylquinoline (3k)
A cross-coupling was performed according to the typical procedure
between 2,6-dichloroquinoline (1c) (99 mg) and Grignard reagent 2c
(0.65 mL, 1.15 M). After purification by flash column chromatography
(i-hexane–EtOAc, 29:1), the title compound 3k (60 mg, 63%) was ob-
tained as a yellow oil.
IR (ATR): 3063, 3027, 2981, 1721, 1594, 1507, 1371, 1268, 1242, 1200,
1147, 1026, 797, 776, 750, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.69 (dd, J = 8.5, 1.4 Hz, 1 H), 8.12 (dt,
J = 8.4, 1.0 Hz, 1 H), 7.76–7.69 (m, 2 H), 7.58 (ddd, J = 8.3, 6.9, 1.3 Hz, 1
H), 7.32–7.22 (m, 4 H), 7.22–7.14 (m, 1 H), 4.47 (q, J = 7.1 Hz, 2 H),
3.38–3.27 (m, 2 H), 3.23–3.09 (m, 2 H), 1.45 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 166.5, 161.3, 149.0, 141.3, 135.5,
129.7, 129.5, 128.6, 128.5, 127.4, 126.2, 125.5, 123.7, 122.8, 61.9, 40.9,
35.7, 14.4.
IR (ATR): 2970, 2934, 2874, 1598, 1490, 1302, 1188, 1074, 897, 876,
829 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.02–7.94 (m, 2 H), 7.76 (d, J = 2.4 Hz, 1
H), 7.61 (dd, J = 9.0, 2.4 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 2.99 (q, J = 7.7
Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 164.5, 146.4, 135.5, 131.4, 130.6,
130.3, 127.4, 126.3, 121.9, 32.4, 14.0.
MS (EI, 70 eV): m/z (%) = 305 (100) [M]+, 274 (46), 231 (28), 199 (16),
MS (EI, 70 eV): m/z (%) = 190 (100) [M – H]+, 164 (16), 143 (22), 128
91 (21), 71 (43), 57 (63), 43 (93).
HRMS (EI): m/z [M]+ calcd for C20H19O2N: 305.1416; found: 305.1408.
(13).
HRMS (EI): m/z [M – H]+ calcd for C11H935ClN: 190.0418; found:
190.0412.
1-Phenethylisoquinoline (3o)
A cross-coupling was performed according to the typical procedure
between 1-iodoisoquinoline (1e) (128 mg) and Grignard reagent 2a
(0.87 mL, 0.86 M). After purification by flash column chromatography
(i-hexane–EtOAc, 19:1), the title compound 3o (58 mg, 50%) was ob-
tained as a yellow oil.
6-Chloro-2-methylquinoline (3l)
A cross-coupling was performed according to the typical procedure
between 2,6-dichloroquinoline (1c) (99 mg) and Grignard reagent 2d
(0.32 mL, 2.34 M). After purification by flash column chromatography
(i-hexane–EtOAc, 19:1), the title compound 3l (74 mg, 83%) was ob-
tained as a colorless solid.
IR (ATR): 3052, 3026, 2929, 1622, 1586, 1562, 1496, 1453, 1388, 1358,
823, 744, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 5.7 Hz, 1 H), 8.11–8.05 (m, 1
H), 7.75 (d, J = 8.2 Hz, 1 H), 7.60 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H), 7.51
(ddd, J = 8.3, 6.9, 1.4 Hz, 1 H), 7.47 (dd, J = 5.8, 0.9 Hz, 1 H), 7.28–7.23
(m, 4 H), 7.20–7.12 (m, 1 H), 3.58–3.51 (m, 2 H), 3.18–3.10 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 161.1, 142.0, 142.0, 136.3, 129.9,
128.6, 128.6, 127.5, 127.2, 127.0, 126.2, 125.2, 119.5, 37.4, 35.6.
MS (EI, 70 eV): m/z (%) = 232 (100) [M – H]+, 217 (17), 156 (41), 129
(35), 115 (19), 91 (17), 43 (12).
HRMS (EI): m/z [M – H]+ calcd for C17H14N: 232.1121; found:
232.1117.
Mp 95.2–96.0 °C.
IR (ATR): 2951, 2916, 1597, 1557, 1489, 1369, 1066, 885, 833, 805 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 2.3 Hz, 1 H), 7.93 (d, J = 3.2
Hz, 1 H), 7.74 (d, J = 2.4 Hz, 1 H), 7.60 (dd, J = 9.0, 2.4 Hz, 1 H), 7.29 (d,
J = 8.4 Hz, 1 H), 2.73 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.5, 146.4, 135.3, 131.4, 130.4,
127.2, 126.3, 123.0, 25.5.
MS (EI, 70 eV): m/z (%) = 177 (100) [M]+, 162 (11), 142 (26), 140 (11),
115 (21), 43 (29).
HRMS (EI): m/z [M]+ calcd for C10H835ClN: 177.0345; found: 177.0343.
(2-Phenethylphenyl)(phenyl)methanone (5a)
2-(But-3-en-1-yl)-6-chloroquinoline (3m)
A cross-coupling was performed according to the typical procedure
between 2-chlorobenzophenone (4a) (434 mg, 2.0 mmol) and
Grignard reagent 2a (3.49 mL, 0.86 M) with CrCl3·3THF (0.6 mL, 0.06
mmol). After purification by flash column chromatography (i-hex-
ane–EtOAc, 29:1), the title compound 5a (400 mg, 70%) was obtained
as a colorless oil.
A cross-coupling was performed according to the typical procedure
between 2,6-dichloroquinoline (1c) (99 mg) and Grignard reagent 2e
(0.88 mL, 0.85 M). After purification by flash column chromatography
(i-hexane–EtOAc, 39:1), the title compound 3m (90 mg, 84%) was ob-
tained as a colorless oil.
IR (ATR): 3076, 2920, 1640, 1598, 1556, 1488, 1072, 909, 875, 829,
IR (ATR): 3061, 3025, 2925, 2860, 1662, 1597, 1494, 1448, 1314, 1267,
811 cm–1
.
927, 757, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.97–7.90 (m, 2 H), 7.71 (d, J = 2.3 Hz, 1
H), 7.58 (dd, J = 9.0, 2.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 5.90 (ddt, J =
16.9, 10.2, 6.5 Hz, 1 H), 5.06 (dd, J = 17.1, 1.7 Hz, 1 H), 4.98 (dd, J =
10.3, 1.6 Hz, 1 H), 3.12–2.97 (m, 2 H), 2.70–2.47 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 162.4, 146.3, 137.6, 135.3, 131.4,
130.5, 130.3, 127.4, 126.2, 122.4, 115.5, 38.5, 33.7.
MS (EI, 70 eV): m/z (%) = 216 (100) [M – H]+, 204 (15), 190 (38), 177
(31), 163 (18), 140 (27).
HRMS (EI): m/z [M – H]+ calcd for C13H1135ClN: 216.0575; found:
216.0568.
1H NMR (400 MHz, CDCl3): δ = 7.78–7.68 (m, 2 H), 7.56–7.47 (m, 1 H),
7.42–7.31 (m, 3 H), 7.24 (dd, J = 7.6, 1.5 Hz, 2 H), 7.20 (dd, J = 7.3, 1.3
Hz, 1 H), 7.18–7.10 (m, 2 H), 7.10–6.99 (m, 3 H), 2.99–2.88 (m, 2 H),
2.85–2.75 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 198.6, 141.6, 140.8, 138.5, 137.9,
133.2, 130.4, 130.3, 130.2, 128.8, 128.5, 128.5, 128.3, 126.0, 125.5,
38.2, 35.6.
MS (EI, 70 eV): m/z (%) = 286 (2) [M]+, 195 (100), 177 (13), 165 (20),
91 (22).
HRMS (EI): m/z [M]+ calcd for C21H18O: 286.1358; found: 286.1353.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
A. B. Bellan et al.
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Synthesis
Phenyl{2-[(trimethylsilyl)methyl]phenyl}methanone (5b)
13C NMR (101 MHz, CDCl3): δ = 192.9, 146.2, 135.0, 134.1, 130.2,
126.7, 126.2, 11.9, 8.6.
MS (EI, 70 eV): m/z (%) = 145 (22) [M – H]+, 131 (69), 128 (21), 115
(100), 103 (44), 90 (49), 77 (32), 63 (29), 51 (23).
HRMS (EI): m/z [M – H]+ calcd for C10H9O: 145.0648; found: 145.0651.
A cross-coupling was performed according to the typical procedure
between 2-chlorobenzophenone (4a) (108 mg) and Grignard reagent
2f (1.03 mL, 0.73 M). After purification by flash column chromatogra-
phy (i-hexane–EtOAc, 39:1), the title compound 5b (118 mg, 88%)
was obtained as a colorless oil.
IR (ATR): 3061, 2953, 2897, 1659, 1597, 1447, 1262, 1246, 1152, 927,
837, 760, 699 cm–1
.
Acknowledgment
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 7.6 Hz, 2 H), 7.56 (t, J = 7.2
Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.31 (d, J = 7.6
Hz, 1 H), 7.18–7.09 (m, 2 H), 2.35 (s, 2 H), –0.05 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 198.6, 141.2, 138.4, 136.4, 132.9,
130.4, 130.3, 130.3, 130.1, 128.4, 123.4, 24.3, –1.3.
MS (EI, 70 eV): m/z (%) = 267 (100) [M – H]+, 253 (24), 178 (14), 165
(23), 149 (18), 111 (12), 73 (47), 69 (18), 57 (12), 43 (24).
HRMS (EI): m/z [M – H]+ calcd for C17H19O28Si: 267.1200; found:
This work was supported by the CNRS and Chimie ParisTech (Paris,
France), as well as by the Ludwig-Maximilians-University (Munich,
Germany) in the framework of the International Associated Laborato-
ry IrMaCaR between the research groups of P. Knochel and G. Cahiez.
We thank the Deutsche Forschungsgemeinschaft (DFG) for financial
support. We also thank BASF SE (Ludwigshafen, Germany) and Rock-
wood Lithium GmbH for the generous gift of chemicals.
267.1184.
Supporting Information
2-Phenethylbenzaldehyde (5c)
Supporting information for this article is available online at
A cross-coupling was performed according to the typical procedure
between 1-(2-chlorophenyl)-N-phenylmethanimine (4b) (108 mg)
and Grignard reagent 2a (0.87 mL, 0.86 M). The reaction mixture was
stirred with 2 M HCl (2 mL) for 1 h before work-up. After purification
by flash column chromatography (i-hexane–EtOAc, 39:1), the title
compound 5c (75 mg, 71%) was obtained as a yellow oil.
http://dx.doi.org/10.1055/s-0035-1561615.
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References
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IR (ATR): 3062, 3026, 2924, 2859, 1691, 1599, 1573, 1495, 1452, 1191,
755, 724, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.18 (s, 1 H), 7.82 (dd, J = 7.6, 1.5 Hz, 1
H), 7.48 (td, J = 7.5, 1.5 Hz, 1 H), 7.38 (td, J = 7.5, 1.3 Hz, 1 H), 7.32–
7.25 (m, 2 H), 7.24–7.16 (m, 4 H), 3.37–3.29 (m, 2 H), 2.94–2.87 (m, 2
H).
13C NMR (101 MHz, CDCl3): δ = 192.4, 144.4, 141.3, 133.9, 133.8,
132.5, 131.3, 128.7, 128.5, 126.8, 126.2, 38.4, 35.0.
(7) Hammann, J. M.; Haas, D.; Steib, A. K.; Knochel, P. Synthesis
2015, 47, 1461.
MS (EI, 70 eV): m/z (%) = 210 (16) [M]+, 192 (10), 132 (12), 91 (100),
(8) Thapa, S.; Kafle, A.; Gurung, S.; Montoya, A.; Riedel, P.; Giri, R.
Angew. Chem. Int. Ed. 2015, 54, 8236.
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C.; Knochel, P. Synlett 2015, 26, 1049.
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(17) Small amounts of the reduced dechlorinated coupling products
were obtained as side products (up to 17%, depending on the
Grignard reagent).
65 (29), 61 (11), 43 (48).
HRMS (EI): m/z [M]+ calcd for C15H14O: 210.1045; found: 210.1028.
2-Cyclopropylbenzaldehyde (5d)
A cross-coupling was performed according to the typical procedure
between 1-(2-chlorophenyl)-N-phenylmethanimine (4b) (108 mg)
and Grignard reagent 2g (0.86 mL, 0.87 M). The reaction mixture was
stirred with 2 M HCl (2 mL) for 1 h before work-up. After purification
by flash column chromatography (i-hexane–EtOAc, 39:1), the title
compound 5d (54 mg, 74%) was obtained as a colorless oil.
IR (ATR): 3005, 2854, 2758, 1689, 1599, 1489, 1288, 1224, 1191, 1030,
823, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.60 (s, 1 H), 7.82 (dd, J = 7.7, 1.5 Hz, 1
H), 7.48 (td, J = 7.6, 1.6 Hz, 1 H), 7.36–7.27 (m, 1 H), 7.13 (d, J = 7.8 Hz,
1 H), 2.63 (tt, J = 8.5, 5.3 Hz, 1 H), 1.14–1.04 (m, 2 H), 0.82–0.76 (m, 2
H).
(18) Clark, J. S.; Romiti, F. Angew. Chem. Int. Ed. 2013, 52, 10072.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G