Cp*RhIII-Catalyzed Sterically Controlled C(sp3)?H Selective Mono- and Diarylation of 8-Methylquinolines with Organoborons

Article abstract of DOI:10.1002/chem.201905591

Herein, the Rh^III-catalyzed selective monoarylation and diarylation (symmetrical and unsymmetrical) of 8-methylquinolines with organoboron reagents are disclosed. The selective monoarylation of primary C(sp³)?H bonds is achieved by using 7-substituted 8-methylquinolines or by changing the quantity of the aryl boronic acids. The method is also applicable for the arylation of 2-ethylpyridines, and the heteroarylation with thiophene-2-ylboronic acids. Symmetrical and unsymmetrical diarylation of 8-methylquinolines have been carried out in one-pot and sequential manner, respectively. Late-stage monoarylation of oxime derivatives and gram-scale synthesis of monoarylated products has also been carried out. A mechanistic study revealed that the current reaction is first order with respect to both reactants and a five-membered rhodacycle intermediate may be involved in the catalytic cycle.

Full text of DOI:10.1002/chem.201905591

A Journal of
Accepted Article
Title: Cp*Rh(III)-Catalyzed Sterically Controlled C(sp3)-H Selective
Mono- and Diarylation of 8-Methylquinolines with Organoborons
Authors: Rakesh Kumar, Diksha Parmar, Shiv Shankar Gupta, Devesh
Chandra, Ankit Kumar Dhiman, and Upendra Sharma
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To be cited as: Chem. Eur. J. 10.1002/chem.201905591
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Cp*Rh(III)-Catalyzed Sterically Controlled C(sp3)-H Selective Mono- and
Diarylation of 8-Methylquinolines with Organoborons
Rakesh Kumar,[a] Diksha Parmar,[a] Shiv Shankar Gupta,[a] Devesh Chandra,[a] Ankit Kumar Dhiman[a]
and Upendra Sharma*[a]
Abstract: Herein Rh(III)-catalyzed selective mono-arylation and
diarylation (symmetrical and unsymmetrical) of 8-methylquinolines
with organoboron reagents is disclosed. The selective
monoarylation of primary C(sp3)-H bond is achieved by using the 7-
substituted 8-methylquinolines or by changing the quantity of aryl
boronic acids. The method is also applicable for the arylation of 2-
ethylpyridine, and heteroarylation with thiophene-2-ylboronic acid.
Symmetrical and unsymmetrical diarylation of 8-methylquinolines has
been carried out in one-pot and sequential manner, respectively. Late-
stage mono-arylation of oxime derivative and gram-scale synthesis of
mono-arylated product has also been carried out. The mechanistic
study revealed that the current reaction is first order with respect to
both reactants and a five-membered rhodacycle intermediate may be
involved in the catalytic cycle.
2-ethylpyridines. During the compilation of current work, Ghosh et.
al reported the Rh-catalyzed C(sp3)-H activation of 8-methyl
quinolines followed by functionalization with diazo compounds but
this method is only applicable for the introduction of
naphthol/phenol moieties.[17]
Introduction
TM-catalyzed C-H bond activation leading to C-C bond
construction has been largely applied for the synthesis of various
natural products and other organic molecules, because of its
notable
potential
in
terms
of
step-economy
and
chemoselectivity.[1] In the past two decades, tremendous efforts
have been made for the C(sp2)-H bond functionalization using
Rh(III)-catalyst due to its high efficiency and selectivity.[2]
Although Rh(III)-catalyst has been explored widely for the
functionalization of C(sp2)-H bond,[3] it’s application in less
reactive C(sp3)-H bond activation is still at its initial stage of
development.[4] Recently, efforts have been made for Rh(III)-
catalyzed alkylation,[5] alkenylation,[6] amination,[7] acylation,[8]
aminocarbonylation,[9] borylation,[10] and arylation[11] of the C(sp3)-
H bonds, particularly of the 8-methylquinolines owing to the easy
formation of the five-membered rhodacycle intermediate.
The C(sp3)-arylation has great significance for the construction
of important bioactive molecules[12] and the early examples mostly
include the Pd-catalyzed arylation of primary C(sp3)-H bond with
diaryliodonium salts, aryl halides and benzene (Scheme 1a).[13]
Although, the organoboron reagents have been utilized for the
C(sp2)-H functionalization of heterocyclic compounds,[14] their use
in Rh(III)-catalyzed construction of the C(sp3)-C(sp2) bonds is
limited.[15] Homocoupling of organoboron reagents always
remains a challenge mainly in C(sp3)-H bond functionalization. In
a recent report, the Rh(II)/N-Heterocyclic Carbene-catalyzed
diarylation of the 8-methylquinoline with bromobenzene has been
disclosed by Chang group.[16] Similarly, Glorius group also
reported the Rh(III)-catalyzed arylation of 2-alkylpyridines and
diarylmethanes with triarylboroxine (Scheme 1b).[11a] However,
these methods are either not applied or not applicable for the
selective mono-arylation of 8-methylquinolines as the mixture of
mono and diarylated products were obtained in the case of
Scheme 1. TM-Catalyzed C(sp3)-H Arylation
In continuation of our interest in C(sp3)-H bond
activation/functionalization of 8-methylquinolines[18] herein, we
unveiled the first Rh(III)-catalyzed highly selective mono-arylation
of the 8-methylquinolines with bench stable arylboronic acids. The
chemoselectivity is sterically controlled in case of C7-substituted-
8-methylquinolines whereas, in the case of 8-methylquinolines
without C7-substituent, the mono- or symmetrical di-arylation is
achieved by controlling the amount of arylboronic acids.
Additionally, the current method is also applicable for the selective
unsymmetrical diarylation of 8-methyl quinolines (Scheme 1c).
Results and Discussion
Initially, 7-chloro-8-methyl quinoline (1a) was reacted with 4-
amylphenylboronic acid (2a, 2 equiv) using [RhCp*Cl2]2/AgSbF6,
Ag2CO3 and DCE at 100 °C for 24 h to get the product (3a) in
37% yield (Table 1, entry 2). Different additives were screened
and yield increases to 52% with Cu(OTf)2 (Table 1, entry 3).
Eliminating AgSbF6 and using only Cu(OTf)2 as an additive also
gave the product (3a) in 53% yield (Table 1, entry 4). Further,
optimization of reaction conditions afforded product (3a) in 62%
yield with AgOTf (10 mol%) as an additive and 2a (2.5 equiv)
(Table 1, entry 5). Moreover, using triflic anhydride (10 mol%) as
an additive and 2a (2.5 equiv) afforded 3a in 76% yield (Table 1,
entry 1). The solvent screening revealed that DCE gave the
highest yield of the desired product (Table 1, entries 1, 6-8). Using
Ag2CO3, MnO2 or CuO as an oxidant instead of Ag2O did not
[a] R. Kumar, D. Parmar, S. S. Gupta, D. Chandra, A. K. Dhiman, U. Sharma
Natural Product Chemistry and Process Development Division and AcSIR,
CSIR-IHBT, Palampur, India;
E-mail: upendra@ihbt.res.in; upendraihbt@gmail.com
1
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Various para-substituted phenylboronic acids with electron-
withdrawing and electron-donating groups gave the desired
monoarylated products in moderate to excellent yields (Table 2,
3a-j). Among them, the halogen-substituted phenylboronic acids
provided the desired products in highest yields (Table 2, 3g-h, 87-
90%). However, only 20% yield of the product was observed with
(4-acetoxyphenyl)boronic acid (Table 2, 3j). Similarly, the meta-
substituted phenylboronic acids also afforded the desired
monoarylated product in 35-65% yields (Table 2, 3l-n). The
reaction of 1a with 3,5-trifluoromethyl phenylboronic acid provided
a mixture of mono and diarylated product under the developed
reaction conditions. When the reaction was carried at 80℃ with a
decreased quantity of 3,5-trifluoromethyl phenylboronic acid (1.2
equiv), the only monoarylated product was obtained in 65% yield
(3n). No product was obtained in the case of (3-
hydroxyphenyl)boronic acid (3k). The ortho-substituted
phenylboronic acid provided the desired product in low yield this
may be due to the steric hindrance (3o). Benzo[d][1,3]dioxol-5-
ylboronic acid also reacted successfully with 1a to afford the
desired monoarylated product in 74% yield (3p). Further, other
arylation source such as triphenylboroxine and potassium
phenyltrifluoroborate were also found compatible under the
developed reaction conditions (Table 2, entry 3d).
prove fruitful (Table 1, entry 9, 14-15). Control reactions without
triflic anhydride or Ag2O provided traces of product (Table 1,
entries 10-11). The lower yield of the product was obtained at
room temperature (Table 1, entries 12). Replacing [RhCp*Cl2]2
with Co-catalyst not proved fruitful for current arylation reaction
(Table 1, entries 13). After detailed optimization (Table S1),[19] the
reaction conditions were finalized, and the reaction of 7-chloro-8-
methyl quinoline (1, 0.1 mmol) with 4-amylphenylboronic acid (2a,
0.25 mmol) using [RhCp*Cl2]2 (5 mol%), Tf2O (10 mol%), Ag2O (2
equiv) in DCE (0.2 M) at 100 °C for 24 h under inert atmosphere
afforded 68% of the isolated product (Table 1, entry 1).
Table 1. Optimization study[a]
Sr. No.
variation from Standard Condition
-
yield (%)[b]
1[d]
76 (68)[c]
After studying the substrate scope concerning arylboronic
acids, different 8-methyl quinoline derivatives were reacted with
2a (Table 3). In contrast to 7-substituted 8-methyl quinoline, the
reaction of 8-methylquinolines with 4-amylphenylboronic acid (2a)
(2.5 equiv) at 100 ℃ provided the mixture of mono and diarylated
product (6:1) in 45% yield (Table 3, entry 3q). Complete selectivity
for mono-arylation in the case of 7-substituted 8-methyl quinoline
might be due to steric hindrance of the substituent at the C7
position (Table 2).
2[e]
3[e,f]
4[f]
AgSbF6 in place of Tf2O
AgSbF6 + Cu(OTf)2 in place of Tf2O
Cu(OTf)2 in place of Tf2O
AgOTf in place of Tf2O
37
52
53
62
54
5[d,g]
6
DME in place of DCE
7
8
9
10
11
12
13
14
15
TFE in place of DCE
1,4 dioxane in place of DCE
Ag2CO3 in place of Ag2O
Without Tf2O
Without Ag2O
At rt
CoCp*COI2/ AgOTf
MnO2 instead of Ag2O
CuO instead of Ag2O
36
35
56
<5
<5
56
nd
10
nd
Table 3. Substrate scope with 8-methylquinolines[a]
[a] reaction conditions: 1 (0.10 mmol), 2 (0.20 mmol), inert atmosphere. [b] Yield
based on NMR analysis of crude reaction mixture using tetrachloroethane as an
internal standard. [c] Isolated yield in parentheses, [d] 2.5 equiv of 2, [e] AgSbF6
(20 mol%), [f] Cu(OTf)2 (20 mol%), [g] AgOTf (10 mol%). nd: not detected.
After having the optimized conditions in hand, the substrate scope
was examined by reacting different phenylboronic acids with 1a
(Table 2).
Table 2. Substrate scope with arylboronic acids[a]
[a] reaction conditions: 1 (0.30 mmol), 2 (0.60 mmol), [RhCp*Cl2]2 (5 mol%),
Tf2O (10 mol%), Ag2O (2 equiv), DCE (0.2 M), 80 oC, 24 h under inert
atmosphere. [b] 2 (2.5 equiv) at 100 oC. [c] Use 2 (1.2 equiv). [d] Use of AgOTf
instead of Tf2O. In parenthesis ratio of mono and diarylated product.
To get selectively the mono-arylated product, the reaction
conditions were optimized further and at 80 ℃ with 2.0 equiv of
2a, the monoarylated product was obtained in 20:1 selectivity with
[a] reaction conditions: 1 (0.30 mmol), 2 (0.75 mmol), [RhCp*Cl2] (5 mol%), Tf2O
(10 mol%), Ag2O (2 equiv), DCE (0.2 M), 100 oC, 24 h, under inert atmosphere.
-
[b] (PhBO)3 as arylating source. [c] PhBF3 K+ as arylating source. [d] 2n (1.2
equiv) at 80 oC. [e] Use of AgOTf instead of Tf2O.
2
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a minor decrease in yield (3q). Next, different substituted 8-
methylquinolines were reacted with 2a (2.0 equiv) at 80 ℃ of
reaction temperature. Methyl substituent at C7, C6, C5, C4, and
C3 position of 8-methylquinolines were well tolerated under the
reoptimized condition and afforded the desired monoarylated
products with high selectivity (3r, 3t-v, 40-64%, 13:1-20:1). The
halogen-substituted 8-methylquinoline also afforded the
monoarylated products in moderate yield (3s, 3x-y). 5-Nitro-8-
methylquinoline and 4-phenyl-8-methylquinoline also reacted
successfully with 2a and gave the desired monoarylated products
in 20% and 40% yields, respectively (3z & 3za). Further, olefin
substituents at C6 of 8-methylquinolines also gave the products
in good yields (3zb-zc). Other substrates such as 2-ethyl pyridine
also found compatible under present reaction conditions affording
the mono-arylated products with complete chemoselectivity albeit
in low yields (3zd-ze).[11a]
substituted at para-position with electron-donating groups and
meta-position with electron-withdrawing groups favour the
product formation.
Table 5. Substrate scope for symmetrical diarylation[a]
Next, 8-methylquinoline (1q) was also reacted with different
substituted phenylboronic acids (Table 4). Different functional
groups at the ortho, meta or para position of phenylboronic acid
were well tolerated and provided the desired mono-arylated
products with high selectivity in moderate yields (3ze-zp). The
reaction of 8-methylquinoline with thiophene-2-ylboronic acid also
gave the product (3zq) in 25% yield. Further, the 5-substituted 8-
methylquinolines with electronically different groups afforded the
desired products (3zr-3zs) in moderate yield.
Table 4. Substrate scope with arylboronic acids[a]
[a] reaction conditions: 1 (0.30 mmol), 2 (1.80 mmol), [RhCp*Cl2]2 (5 mol%),
Tf2O (10 mol%), Ag2O (2 equiv), DCE (0.2 M), 100 oC, 24 h under inert
atmosphere.
The unsymmetrical diarylation was achieved by reacting
mono-arylated products (3) with different arylboronic acids (3
equiv) (Table 6).
Table 6. Substrate scope for unsymmetrical diarylation[a]
[a] reaction conditions: 1q (0.30 mmol), 2 (0.36 mmol), [RhCp*Cl2]2 (5 mol%),
triflic anhydride (10 mol%), Ag2O (2 equiv), DCE (0.2 M), 80 oC, 24 h under inert
atmosphere. [b] 2 (2 equiv). In parenthesis ratio of mono and diarylated product.
Further to extend the scope of the current reaction, symmetrical
as well as unsymmetrical double arylation of C(sp3)-H bond of 8-
methyquinoline was carried out (Table 5 and 6). Firstly, one-pot
symmetrical double arylation was attempted (Table 5). We were
pleased to note that the chemoselectivity can be switched towards
the symmetrical diarylated product by reacting 8-methyl
quinolines with an increased quantity of arylboronic acids (6
equiv) under same reaction conditions as applied for
monoarylation (Table 5). Various meta- and para-substituted
arylboronic acids were reacted with 8-methyl quinoline to afford
diarylated products in good yield and chemoselectivity (3’zi, 3’zl
& 3’zo). Substituted 8-methylquinolines also reacted successfully
to give the diarylated product along with the formation of the minor
monoarylated product (3’zt-3’zw). The phenyboronic acids
[a] reaction conditions: 1 (0.30 mmol), 2 (0.9 mmol), [RhCp*Cl2]2 (5 mol%), Tf2O
(10 mol%), Ag2O (2 equiv), DCE (0.2 M), 100 oC, 24 h under inert atmosphere.
[b] NMR yield using TCE as an internal standard.
In the case of 7-substituted 8-methylquinolines very low yield of
double arylated product (4a) was observed, which further
confirmed that the high chemoselectivity for the monoarylation is
sterically controlled. The unsymmetrical diarylated products (4b-
d) were obtained in 45-60% yields when 8-benzylquinoline (3zf)
3
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was reacted with 4-substituted phenylboronic acids (2) under the
optimized
reaction
conditions.
The
3,5-
trifluoromethylphenylboronic acid was also well compatible under
the developed reaction condition (4e). Further, the effect of the
electronic nature of substituents on para-position of benzyl and 5-
position of the quinoline ring of 8-benzylquinoline was studied.
The reaction of 4-chlorophenylbornoic acid with 8-(4-
methoxybenzyl)quinoline (3zl) afforded the diarylated product (4f)
in higher yield whereas reaction with 8-(4-nitrobenzyl)quinoline
(3zm) provided a lower yield (4g) as compared to 4c. No reaction
was observed in the case of 5-nitro-8-benzylquinoline (4i)
whereas 5-methyl-8-benzylquinoline reacted successfully to
afford 40% of the corresponding diarylated product (4h). These
reactions indicated that electron-donating group on para-position
of a benzyl ring and 5-position of quinoline ring of 3zf favour the
unsymmetrical diarylated product formation (4).
Scheme 5. Deuterium labelling experiments
Next, a five-membered rhodacycle (A) was synthesized[6d] and
applied as a catalyst to afford 41% of the arylated product
(Scheme 6). This experiment confirms that rhodacycle (A) is an
intermediate in the catalytic cycle of the developed reaction.
Furthermore, late-stage arylation of the oxime derivative of
santonin (5a) was carried out with 4-methoxyphenylboronic acid
(Scheme 2). Complete regioselectivity was observed for
monoarylation with
a
very low yield of corresponding
monoarylated product (6a).
Scheme 6. Intermediate study
Further, a kinetic study was also performed to demonstrate the
order of the reaction by initial rate method at room temperature,
which revealed an overall second-order reaction, first order with
respect to 7-chloro-8-methylquinoline as well as 4-
amylphenylboronic acid (Figure 1). Therefore, the rate of the
monoarylation reaction depends upon the concentration of both
the reactants.
Scheme 2. Late-stage C(sp3)-H arylation
Subsequently, scalability of the developed protocol was
demonstrated by synthesizing 3h up to 1.50 g from reaction of 1a
with 2h (Scheme 3).
Scheme 3. Gram scale reaction
Figure 1. Kinetic study
Current reaction conditions are also applicable for C(sp3)-
alkylation of 8-methylquinoline (Scheme 4). The reaction of 8-
methyl quinoline with MeBF3K and nBuBF3K salt provided the
methylated and alkylated product (8a-b) in 42% and 20% yields,
respectively (Scheme 4), while the aliphatic boronic acids failed
to provide the desired products.
Scheme 4: Alkylation of primary C(sp3)-H bond.
Various experiments were carried out to understand the reaction
mechanism (Scheme S1-S5).[19] Under arylation condition 10% d-
incorporation was observed in the absence of phenylboronic acid
(2d) whereas no d-incorporation was observed in the presence of
2d, signifying that C-H activation step is slower than the
subsequent steps (Scheme 5a). The C-H bond cleavage might be
the rate-determining step as revealed by the KIE value for the
competition and parallel experiments (Scheme 5b).
Scheme 7. Plausible mechanistic cycle
4
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Characterization Data 7-chloro-8-(4-pentylbenzyl)quinoline (Table 2,
Entry 3a). Yellow solid, yield = 66.1 mg (68%). Mp = 40-42 ℃. Isolated
from flash chromatography (3% EtOAc/n-hexane). H NMR (600 MHz,
A catalytic cycle was proposed on the basis of preliminary
experiments and literature reports (Scheme 7).[11a] Initially, Rh(III)-
precursor in the presence of AgSbF6 or AgOTf/Tf2O is converted
into active Rh-species which react with 8-methyquinoline to form
rhodacycle A. Rhodacycle A undergo ligand exchange with aryl
organoboron reagent to give B which on reductive elimination
provided the desired arylated product along with Rh(I) species.
Active catalytic species is regenerated from Rh(I) species in the
presence of oxidant to continue the catalytic cycle.
1
CDCl3, δ): 8.98-8.99 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz,
1H), 7.54 (d, J = 8.4 Hz, 1H), 7.39-7.41 (m, 1H), 7.24 (d, J = 7.2 Hz, 2H),
7.02 (d, J = 7.2 Hz, 2H), 4.84 (s, 2H), 2.50-2.53 (m, 2H), 1.53-1.58 (m, 2H),
1.27-1.31 (m, 4H), 0.86-0.88 (m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ):
150.6, 147.8, 140.4, 137.7, 137.5, 136.2, 135.4, 128.9, 128.5, 128.3, 127.2,
127.1, 121.1, 35.7, 33.2, 31.7, 31.3, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2922,
2855, 2338, 1948, 1913, 1605, 1587, 1510, 1489, 1308, 1234, 1117, 1038,
1020, 928, 856, 827, 808, 795, 764, 602, 496. HRMS (ESI-TOF) (m/z): [M
+ H]+ calcd for C21H23ClN, 324.1514; found 324.1510.
7-chloro-8-(4-ethylbenzyl)quinoline (Table 2, Entry 3b). Yellow liquid, yield
= 56.6 mg (67%). Isolated from flash chromatography (3% EtOAc/n-
hexane). 1H NMR (300 MHz, CDCl3, δ): 8.99 (dd, J = 4.2, 1.8 Hz, 1H), 8.11
(dd, J = 8.1, 1.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H),
7.39 (dd, J = 8.1, 4.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 8.1 Hz,
2H), 4.87 (s, 2H), 2.56-2.63 (m, 2H), 1.18-1.23 (m, 3H). 13C{1H} NMR (150
MHz, CDCl3, δ): 150.6, 147.7, 141.7, 137.7, 137.6, 136.2, 135.4, 128.9,
128.4, 127.7, 127.19, 127.1, 121.1, 33.2, 28.5, 15.6. IR (ZnSe) νmax (cm−1):
2963, 2336, 1605, 1589, 1512, 1489, 1422, 1362, 1314, 1125, 1040, 953,
928, 851, 829, 808, 795, 660, 627, 602, 534, 473. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C18H17ClN, 282.1044; found 282.1041.
Conclusion
In summary, we have disclosed
a
Cp*Rh(III)-catalyzed
regioselective and chemoselective C-H arylation of 8-
methylquinolines with organoboron reagents through C(sp3)-H
activation. In addition to the selective mono-functionalization,
one-step symmetrical and two-step unsymmetrical diarylation of
C(sp3)-H has also been carried out. Further, the developed
method is also applicable for the arylation of oxime derivative and
2-ethylpyridine. The kinetic study revealed an overall second-
order reaction for the monoarylation. The developed protocol is
also applicable for the gram-scale synthesis of arylated products.
7-chloro-8-(4-methylbenzyl)quinoline (Table 2, Entry 3c). Yellow solid,
yield = 40.2 mg (50%). Mp = 73-76 ℃. Isolated from flash chromatography
(3% EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8
Hz, 1H), 8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.54 (d, J
= 9.0 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 7.02
(d, J = 7.8 Hz, 2H), 4.83 (s, 2H), 2.26 (s, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 150.6, 147.7, 137.7, 137.3, 136.2, 135.4, 135.3, 129.0, 128.9,
128.5, 127.2, 127.1, 121.1, 33.2, 21.2. IR (ZnSe) νmax (cm−1): 2961, 2932,
2855, 2338, 1892, 1605, 1589, 1512, 1489, 1447, 1422, 1362, 1310, 1125,
1105, 1040, 976, 926, 851, 826, 808, 793, 750, 660, 627, 602, 519. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C17H15ClN, 268.0888; found 268.0881.
Experimental Section
Reagent information. Unless otherwise stated, all reactions were carried
out under inert atmosphere in screw cap reaction vials. Solvents were
bought from Aldrich in sure-seal bottle and used as such. Chemicals were
bought from Sigma Aldrich, Alfa-aesar and TCI. For column
chromatography, silica gel (230-400 mesh) and C-18 reverse silica from
Merck was used. A gradient elution using n-hexane and ethyl acetate was
performed based on Merck aluminium TLC sheets (silica gel 60F254).
8-benzyl-7-chloroquinoline (Table 2, Entry 3d). White solid, yield = 49.5
mg (65%). Mp = 66-68 ℃. Isolated from flash chromatography (3%
EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 8.99 (dd, J = 4.2, 1.8 Hz,
1H), 8.11 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J =
8.4 Hz, 1H), 7.40 (dd, J = 7.8, 4.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 2H), 7.22-
7.24 (m, 2H), 7.14-7.16 (m, 1H) 4.90 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 150.6, 147.7, 140.4, 137.4, 136.2, 135.5, 129.0, 128.4, 128.2,
127.2, 127.2, 125.9, 121.1, 33.6. IR (ZnSe) νmax (cm−1): 3059, 3026, 2976,
2941, 2328, 1601, 1589, 1489, 1452, 1422, 1368, 1312, 1169, 1121, 1032,
935, 907, 822, 783, 758, 708, 694, 665, 602, 577, 517, 476. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C16H13ClN, 254.0731; found, 254.0736.
Analytical information. The melting points were recorded on a Bronsted
Electro thermal 9100. All isolated compounds are characterized by 1H
NMR, 13C NMR, LC-MS and IR. In addition, all the compounds are further
characterized by HRMS. Mass spectra were recorded on Water Q-ToF-
Micro Micromass, high-resolution 6560 Ion Mobility Q-TOF LC/MS (Agilent,
Santa Clara,USA) and maXis Impact mass spectrometers. Copies of 1H,
13C NMR can be found in the NMR supporting information. IR was
analyzed by Shimadzu IR Prestige-21with ZnSe Single reflection ATR
accessory. Nuclear magnetic resonance spectra were recorded either on
a Bruker-Avance 600 or 300 MHz instrument. All 1H NMR experiments are
reported in units, parts per million (ppm) and were measured relative to the
signals for residual chloroform (7.26) in the deuterated solvents. All 13C
NMR spectra were reported in ppm relative to deuterated chloroform
(77.16) and all were obtained with 1H decoupling. Optimization studies
were done by NMR by using TCE as internal standard.
7-chloro-8-(4-methoxybenzyl)quinoline (Table 2, Entry 3e). Yellow solid,
yield = 52 mg (61%). Mp = 79-80 ℃. Isolated from flash chromatography
(5% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 8.99 (dd, J = 4.2, 1.8
Hz, 1H), 8.11 (dd, J = 8.4, 1.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54 (d, J
= 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.77
(d, J = 8.4 Hz, 1H), 4.81 (s, 2H), 3.73 (s, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 157.8, 150.6, 147.6, 137.8, 136.2, 135.3, 132.5, 130.0, 128.5,
127.2, 127.1, 121.1, 113.6, 55.3, 32.7. IR (ZnSe) νmax (cm−1): 3007, 2839,
2336, 1607, 1508, 1487, 1296, 1234, 1179, 1121, 1032, 930, 827, 816,
795, 752, 598, 523. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H15ClNO,
284.0837; found 284.0830.
Preparation of starting materials. Substituted 8-methyl quinolines 1w,
1zb and 1zc were synthesized according to the literature procedure,[20]
compound 1r, 1s, 1t, 1u, 1x, 1y and 1z were synthesized according to the
literature procedure,[7a] compound 1za was synthesized according to the
literature procedure,[21] and all other substituted 8-methyl quinolines were
used from commercially available sources. The compound 5a was
synthesized according to the literature procedure.[22]
7-chloro-8-(4-nitrobenzyl)quinoline (Table 2, Entry 3f). Yellow solid, yield
= 31.3 mg (35%). Mp = 100-112 ℃. Isolated from flash chromatography
1
(6% EtOAc/n-hexane). H NMR (300 MHz, CDCl3, δ): 8.97 (dd, J = 4.2,
1.8 Hz, 1H), 8.17 (dd, J = 8.4, 1.8 Hz, 1H), 8.06 (d, J = 8.7 Hz, 2H), 7.72
(d, J = 8.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.43-7.48 (m, 3H), 4.94 (s,
2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.9, 148.3, 147.5, 146.5, 136.5,
135.9, 135.6, 129.8, 128.5, 128.0, 127.3, 123.5, 121.5, 33.7. IR (ZnSe)
νmax (cm−1): 3057, 2924, 2855, 2336, 1597, 1520, 1489, 1341, 1314, 1261,
1171, 1111, 930, 854, 831, 810, 756, 716, 691, 669, 596, 482. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C16H12ClN2O2, 299.0582; found 299.0586.
General procedure for the functionalization of 7-chloro-8-methyl
quinolines with arylboronic acids and characterization data. To an
oven-dried screw cap reaction vial charged with a spin vane magnetic stir-
bar, 7-chloro-8-methylquinoline (0.3 mmol), arylboronic acid (0.75 mmol),
[RhCp*Cl2]2 (5 mol %) and Ag2O (2.0 equiv) were added under argon
atmosphere, followed by the addition of dichloroethane (1.5 mL) and triflic
anhydride (10 mol%). The subsequent reaction mixture was stirred at
100 °C for 24 h. On completion of reaction, the solvent was evaporated
under reduced pressure to get the crude reaction mixture. The crude
mixture was purified by flash chromatography using silica gel (230−400
mesh size) and n-hexane: EtOAc as the eluent.
8-(4-bromobenzyl)-7-chloroquinoline (Table 2, Entry 3g). White solid, yield
= 89.8 mg (90%). Mp = 99-101 ℃. Isolated from flash chromatography (3%
EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 8.97 (dd, J = 4.2, 1.5 Hz,
1H), 8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.54 (d, J =
8.7 Hz, 1H), 7.41 (dd, J = 8.1, 4.2 Hz, 1H), 7.30-7.35 (m, 2H), 7.22 (d, J =
8.4 Hz, 2H), 4.81 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.7, 147.6,
139.4, 136.9, 136.3, 135.4, 131.3, 130.9, 128.5, 127.5, 127.3, 121.3, 119.8,
33.1. IR (ZnSe) νmax (cm−1): 3048, 2963, 2943, 2924, 2851, 1605, 1585,
5
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10.1002/chem.201905591
Chemistry - A European Journal
FULL PAPER
1483, 1422, 1260, 1123, 1101, 1067, 1042, 1009, 932, 835, 827, 802, 777,
592, 517, 492. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H12BrClN,
331.9836; found 331.9836.
6.71(m, 1H), 4.89 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 161.17 (d, J
= 243.8 Hz), 150.8, 148.0, 136.3, 136.04, 136.03, 129.79 (d, J = 4.5 Hz),
128.5, 127.6, 127.38 (d, J = 7.5 Hz), 127.11, 127.10 (d, J = 15.0 Hz),
123.80 (d, J = 3.0 Hz), 121.3, 115.06 (d, J = 21.8 Hz), 26.40 (d, J = 3.8
Hz). IR (ZnSe) νmax (cm−1): 3032, 2997, 2957, 2926, 2326, 1967, 1902,
1603, 1483, 1449, 1422, 1223, 1126, 1092, 1055, 1038, 953, 930, 860,
827, 814, 758, 449. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H12ClFN,
272.0637; found 272.0639.
7-chloro-8-(4-chlorobenzyl)quinoline (Table 2, Entry 3h). White solid, yield
= 75.2 mg (87%). Mp = 80–82 ℃. Isolated from flash chromatography (3%
EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 8.97 (dd, J = 4.2, 1.8 Hz,
1H), 8.12 (dd, J = 8.1, 1.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.54 (d, J =
8.7 Hz, 1H), 7.41 (dd, J = 8.4, 4.2 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.15 –
7.19 (m, 2H), 4.83 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.7, 147.6,
138.9, 137.0, 136.3, 135.4, 131.7, 130.4, 128.4, 128.3, 127.5, 127.2, 121.2,
33.0. IR (ZnSe) νmax (cm−1): 3028, 2936, 2336, 1929, 1595, 1487, 1360,
1179, 1126, 1088, 1042, 1015, 934, 829, 802, 494. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C16H12Cl2N, 288.0341; found 288.0345.
8-(benzo[d][1,3]dioxol-5-ylmethyl)quinoline (Table 2, Entry 3p). Use of
AgOTf (10 mol%) instead of Tf2O. Yellow solid, yield = 66.1 mg (74%). Mp
= 85–86 ℃. Isolated from flash chromatography (5% EtOAc/n-hexane). 1H
NMR (600 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.12 (dd, J = 7.8,
1.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.40 (dd, J
= 7.8, 4.2 Hz, 1H), 6.86 (s, 1H), 6.83-6.85 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H),
5.85 (s, 2H), 4.78 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.7, 147.6,
147.4, 145.7, 137.5, 136.3, 135.4, 134.2, 128.5, 127.3, 127.2, 122.0, 121.2,
109.7, 108.1, 100.8, 33.2. IR (ZnSe) νmax (cm−1): 2922, 2904, 2852, 2335,
1602, 1485, 1438, 1423, 1363, 1247, 1232, 1035, 792, 609, 474. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C17H13ClNO2, 298.0629; found
298.0624.
7-chloro-8-(4-(trimethylsilyl)benzyl)quinoline (Table 2, Entry 3i). White
sticky, yield = 74.3 mg (76%). Isolated from flash chromatography (3%
EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 9.00 (dd, J = 4.2, 1.8 Hz,
1H), 8.11 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.56 (d, J =
9.0 Hz, 1H), 7.38-7.45 (m, 5H), 4.92 (s, 2H), 0.26 (s, 9H). 13C{1H} NMR (75
MHz, CDCl3, δ): 150.6, 147.8, 141.0, 137.4, 136.2, 135.5, 133.4, 128.5,
128.4, 127.2, 121.1, 33.6, -0.9. IR (ZnSe) νmax (cm−1): 3012, 2949, 2326,
1597, 1489, 1247, 1107, 931, 835, 823, 800, 790, 765, 731, 640, 592, 489.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H21ClNSi, 326.1126; found
326.1121.
4-((7-chloroquinolin-8-yl)methyl)phenyl acetate (Table 2, Entry 3j). Yellow
solid, yield = 18.7 mg (20%). Mp = 154-156 ℃. Isolated from flash
chromatography (10% EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ):
8.97 (dd, J = 3.9, 1.8 Hz, 1H), 8.13 (dd, J = 8.1, 1.5 Hz, 1H), 7.66 (d, J =
8.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.1, 4.2 Hz, 1H), 7.36
(d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.84 (s, 2H), 2.24 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3, δ): 169.7, 150.6, 148.9, 147.7, 138.0, 137.3,
136.3, 135.4, 130.1, 128.5, 127.3, 127.3, 121.2, 121.2, 33.0, 21.3. IR
(ZnSe) νmax (cm−1): 3053, 2924, 2336, 1746, 1595, 1506, 1489, 1373, 1227,
1192, 1171, 1016, 920, 835, 797, 764, 627, 598, 525, 507, 473, 428.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H15ClNO2, 312.0786; found
312.0780.
General procedure for the arylation of 8-methyl quinolines with
arylboronic acid and characterization data. To an oven-dried screw cap
reaction vial charged with a spin vane magnetic stir-bar, arylboronic acid
(0.6 mmol or 0.36 mmol), [RhCp*Cl2]2 (5 mol %) and Ag2O (2 equiv) were
added under argon atmosphere, followed by the addition of 8-
methylquinoline (0.3 mmol), dichloroethane (1.5 mL) and triflic anhydride
(10 mol%). The subsequent reaction mixture was stirred at 80 °C for 24 h.
On completion of reaction, the solvent was evaporated under reduced
pressure to get the crude reaction mixture. The crude mixture was purified
by flash chromatography using silica gel (230-400 mesh size) and n-
hexane: EtOAc as the eluent.
8-(4-pentylbenzyl)quinoline (Table 3, Entry 3q). Colourless liquid, yield =
34.7 mg (40%). Isolated from flash chromatography (5% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.99 (dd, J = 4.2, 1.8 Hz, 1H), 8.14-8.16 (m,
1H), 7.69 (t, J = 4.8 Hz, 1H), 7.45 (d, J = 5.4 Hz, 2H), 7.41 (dd, J = 7.8, 4.2
Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H),
2.59 (t, J = 7.8 Hz, 2H), 1.60-1.65 (m, 2H), 1.33-1.37 (m, 4H), 0.91-0.93
(m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.6, 146.9, 140.6, 140.5,
138.5, 136.4, 129.5, 129.3, 128.5, 128.5, 126.5, 126.3, 121.1, 36.5, 35.7,
31.7, 31.4, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 3005, 2926, 2855, 2336, 1595,
1512, 1497, 1466, 1369, 1319, 1074, 1022, 818, 789, 754, 606. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C21H24N, 290.1903; found 290.1905.
1-(3-((7-chloroquinolin-8-yl)methyl)phenyl)ethanone (Table 2, Entry 3l).
White solid, yield = 31.1 mg (35%). Mp = 86-88 ℃. Isolated from flash
chromatography (10% EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ):
8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.14 (dd, J = 8.1, 1.8 Hz, 1H), 8.01 (s, 1H),
7.73 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H),
7.51 (d, J = 7.2 Hz, 1H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 – 7.31 (d, J =
7.8 Hz, 1H) 4.91 (s, 2H), 2.53 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ):
198.5, 150.7, 147.6, 141.0, 137.3, 136.8, 136.4, 135.5, 133.8, 129.2, 128.5,
127.6, 127.3, 126.1, 121.3, 33.5, 26.8. IR (ZnSe) νmax (cm−1): 3063, 3028,
2920, 2851, 2336, 1672, 1603, 1584, 1489, 1358, 1269, 1125, 1082, 1040,
835, 812, 797, 600, 590, 478. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C18H15ClNO, 296.0837; found 296.0832.
7-methyl-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3r). Yellow liquid,
yield = 58.3 mg (64%). Isolated from flash chromatography (3% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.94-8.95 (m, 1H), 8.11 (d, J = 7.8
Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33-7.36 (m,
1H), 7.06 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.2 Hz, 2H), 4.78 (s, 2H), 2.53 (t,
J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.54-1.59 (m, 2H), 1.28-1.34 (m, 4H), 0.87-
0.90 (m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.8, 147.6, 140.1,
138.3, 138.1, 137.2, 136.1, 130.1, 128.5, 128.3, 126.9, 125.9, 120.2, 35.6,
32.3, 31.7, 31.3, 22.7, 20.6, 14.1. IR (ZnSe) νmax (cm−1): 3005, 2955, 2926,
2855, 2336, 1614, 1503, 1460, 1362, 1317, 1070, 1020, 829, 797, 658,
610. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C22H26N, 304.2060; found
304.2058.
7-chloro-8-(3,5-dimethylbenzyl)quinoline (Table 2, Entry 3m). White solid,
yield = 42.3 mg (50%). Mp = 76-78 ℃. Isolated from flash chromatography
1
(3% EtOAc/n-hexane). H NMR (300 MHz, CDCl3, δ): 8.99 (dd, J = 4.2,
1.8 Hz, 1H), 8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.55
(d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 1H), 6.93 (s, 2H), 6.79 (s,
1H), 4.82 (s, 2H), 2.23 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.6,
147.8, 140.1, 137.6, 136.2, 135.6, 128.5, 127.7, 127.2, 127.1, 126.8, 121.1,
33.5, 21.5. IR (ZnSe) νmax (cm−1): 2916, 2851, 2336, 1599, 1487, 1422,
1360, 1314, 1121, 1040, 920, 843, 827, 799, 698, 592. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C18H17ClN, 282.1044; found 282.1041.
7-fluoro-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3s). Use 4-
amylboronic acid (2.5 equiv) at 100 ℃. Yellow liquid, yield = 46.1 mg (50%).
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (600
MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.11 (dd, J = 8.4, 1.8 Hz,
1H), 7.68 (dd, J = 9.0, 6.0 Hz, 1H), 7.32-7.37 (m, 2H), 7.31 (d, J = 8.4 Hz,
2H), 7.04 (d, J = 7.8 Hz, 2H), 4.66 (d, J = 1.8 Hz, 2H), 2.52 (t, J = 7.8 Hz,
2H), 1.53-1.58 (m, 2H), 1.27-1.33 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3, δ): 160.87 (d, JCF = 246.0 Hz), 150.6, 147.78 (d, JCF
= 10.5 Hz), 140.5, 138.1, 136.3, 128.8, 128.36, 127.61 (d, JCF = 10.5 Hz),
125.66, 124.67 (d, J = 15.0 Hz), 120.24, 120.23, 117.13 (d, J = 27.0 Hz),
35.7, 31.7, 31.3, 28.8, 28.8, 22.7, 14.1. IR (ZnSe) νmax (cm−1): 2926, 2855,
2349, 2326, 1620, 1501, 1462, 1431, 1364, 1319, 1248, 1217, 1065, 993,
829, 797, 773, 746, 694, 664, 611, 534, 500, 457. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C21H23FN, 308.1809; found 308.1832.
8-(3,5-bis(trifluoromethyl)benzyl)-7-chloroquinoline (Table 2, Entry 3n).
Use of (3,5-bis(trifluoromethyl)phenyl)boronic acid (1.2 equiv) at 80 ℃.
White solid, yield = 76.0 mg (65%). Mp = 124-126 ℃. Isolated from flash
chromatography (3% EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ):
8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz, 1H), 7.87 (s, 2H),
7.71 (d, J = 8.7 Hz, 1H), 7.66 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.44 (dd, J
= 8.4, 4.2 Hz, 1H), 4.95 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.9,
147.4, 143.0, 136.5, 135.6, 135.5, 131.37 (q, JCF = 33.0 Hz), 129.46 (d,
JCF = 3.8 Hz), 128.4, 128.1, 127.4, 123.64 (d, JCF = 270.8 Hz), 121.5,
120.03-120.24 (m), 33.45. IR (ZnSe) νmax (cm−1): 3032, 2997, 2940, 2334,
1607, 1489, 1377, 1283, 1157, 1115, 947, 895, 829, 800, 683. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C18H11ClF6N, 390.0479; found 390.0475.
6-methyl-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3t). Yellow liquid,
yield = 38.2 mg (42%). Isolated from flash chromatography (5% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.90 – 8.91 (m, 1H), 8.05 (dd, J =
8.4, 1.2 Hz, 1H), 7.44 (s, 1H), 7.36-7.38 (m, 1H), 7.29 (s, 1H), 7.23 (d, J =
7.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.62 (s, 2H), 2.55-2.58 (m, 2H), 2.46
(s, 3H), 1.58-1.63 (m, 2H), 1.31-1.34 (m, 4H), 0.88-0.90 (m, 3H). 13C{1H}
7-chloro-8-(2-fluorobenzyl)quinoline (Table 2, Entry 3o). White sticky, yield
= 19.6 mg (24%). Isolated from flash chromatography (3% EtOAc/n-
hexane). 1H NMR (300 MHz, CDCl3, δ): 8.94 (dd, J = 4.2, 2.1 Hz, 1H), 8.16
(dd, J = 8.1, 1.8 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H),
7.42 (dd, J = 8.1, 4.2 Hz, 1H), 7.02-7.15 (m, 2H), 6.83-6.88 (m, 1H), 6.66-
6
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10.1002/chem.201905591
Chemistry - A European Journal
FULL PAPER
NMR (150 MHz, CDCl3, δ): 148.8, 145.5, 140.5, 140.1, 138.7, 136.3, 135.7,
131.9, 129.3, 128.6, 128.5, 125.2, 121.1, 36.4, 35.7, 31.7, 31.4, 22.7, 21.8,
14.2. IR (ZnSe) νmax (cm−1): 2955, 2924, 2855, 2328, 1597, 1512, 1493,
1454, 1369, 1115, 1036, 862, 804, 781, 611, 536. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C22H26N, 304.2060; found 304.2054.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C21H23N2O2, 335.1754; found
335.1748.
8-(4-pentylbenzyl)-4-phenylquinoline (Table 3, Entry 3za). Use 4-
amylboronic acid (1.2 equiv). Sticky yellow liquid, yield = 32.9 mg (30%).
Isolated from flash chromatography (3% EtOAc/n-hexane). 1H NMR (300
MHz, CDCl3, δ): 9.00 (d, J = 4.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.49-
7.55 (m, 5H), 7.45 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.34-7.36
(m, 1H), 7.27 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 4.71 (s, 2H),
2.55-2.60 (m, 2H), 1.56-1.66 (m, 2H), 1.32-1.35 (m, 4H), 0.88-0.92 (m, 3H).
13C{1H} NMR (75 MHz, CDCl3, δ): 149.0, 148.8, 147.3, 140.9, 140.6, 138.7,
138.7, 129.7, 129.5, 129.4, 128.6, 128.5, 128.4, 127.0, 126.5, 124.4, 121.4,
36.9, 35.7, 31.8, 31.4, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2955, 2926, 2855,
1566, 1508, 1489, 1464, 1445, 1431, 1395, 1350, 1275, 1182, 1115, 1074,
849, 812, 764, 700, 600, 577, 556, 544, 519, 488, 446. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C27H28N, 366.2216; found 366.2216.
5-methyl-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3u). Brown liquid,
yield = 36.4 mg (40%). Isolated from flash chromatography (5% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.97 (dd, J = 4.2, 1.8 Hz, 1H), 8.32
(d, J = 9.0 Hz, 1H), 7.42-7.44 (m, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.27 (d, J
= 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 4.62 (s,
2H), 2.65 (s, 3H), 2.55-2.58 (m, 2H), 1.58-1.62 (m, 2H), 1.38-1.24 (m, 4H),
0.88-0.90 (m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.1, 147.1, 140.5,
138.8, 138.5, 132.8, 132.7, 129.3, 129.2, 128.5, 127.8, 127.0, 120.7, 36.5,
35.7, 31.7, 31.4, 22.7, 18.7, 14.2. IR (ZnSe) νmax (cm−1): 2955, 2924, 2855,
2326, 1599, 1501, 1468, 1356, 1022, 824, 812, 787, 557. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C22H26N, 304.2060; found 304.2056.
(E)-8-(4-pentylbenzyl)-6-styrylquinoline (Table 3, Entry 3zb). Use 4-
4,6-dimethyl-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3v). Colourless
liquid, yield = 51.4 mg (54%). Isolated from flash chromatography (5%
EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 8.77 (d, J = 4.5 Hz, 1H),
7.63 (s, 1H), 7.28 (s, 1H), 7.20-7.24 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 4.64
(s, 2H), 2.68 (s, 3H), 2.57 (t, 7.8 Hz, 2H), 2.49 (s, 3H), 1.56-1.66 (m, 2H),
1.31-1.35 (m, 4H), 0.88-0.92 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ):
148.4, 145.2, 143.6, 140.6, 140.4, 138.9, 135.8, 131.5, 129.3, 128.5, 128.5,
122.0, 121.2, 36.7, 35.7, 31.7, 31.3, 22.7, 22.1, 19.1, 14.2. IR (ZnSe) νmax
(cm−1): 2955, 2924, 2855, 2326, 1595, 1510, 1501, 1433, 1377, 1022, 856,
841, 829, 800, 519. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C23H28N,
318.2216; found 318.2211.
amylboronic acid (1.2 equiv). Yellow liquid, yield = 32.9 mg (28%). Isolated
from flash chromatography (5% EtOAc/n-hexane). H NMR (300 MHz,
1
CDCl3, δ): 8.92 (d, J = 3.6 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.71 (s, 2H),
7.54 (d, J = 7.8 Hz, 2H), 7.36-7.42 (m, 3H), 7.26-7.31 (m, 3H), 7.11-7.19
(m, 4H), 4.68 (s, 2H), 2.56-2.61 (m, 2H), 1.57-1.67 (m, 2H), 1.32-1.36 (m,
4H), 0.87-0.92 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 149.4, 146.9,
140.8, 140.6, 138.5, 137.3, 136.3, 135.4, 130.1, 129.3, 128.92, 128.87,
128.6, 128.3, 128.0, 127.6, 126.8, 124.4, 121.5, 36.6, 35.7, 31.7, 31.4,
22.7, 14.2. IR (ZnSe) νmax (cm−1): 3022, 2955, 2926, 2855, 1589, 1491,
1375, 1117, 959, 881, 835, 783, 746, 691, 556, 480. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C29H30N, 392.2373; found 392.2370.
3-methyl-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3w). Yellow liquid,
yield = 31.9 mg (40%). Isolated from flash chromatography (5% EtOAc/n-
hexane). 1H NMR (300 MHz, CDCl3, δ): 8.81 (d, J = 2.1 Hz, 1H), 7.90 (dd,
J = 2.4 Hz, 1H), 7.60 (dd, J = 7.8, 1.8 Hz, 1H), 7.33-7.42 (m, 2H), 7.21 (d,
J = 7.8 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 4.63 (s, 2H), 2.52-2.58 (m, 5H),
1.56-1.61 (m, 2H), 1.29-1.33 (m, 4H), 0.86-0.90 (m, 3H). 13C{1H} NMR (75
MHz, CDCl3, δ): 151.6, 145.3, 140.5, 140.4, 138.7, 135.1, 130.4, 129.3,
128.6, 128.5, 128.4, 126.6, 125.7, 36.5, 35.7, 31.8, 31.4, 22.7, 18.8, 14.2.
IR (ZnSe) νmax (cm−1): 2955, 2924, 2855, 1605, 1512, 1491, 1466, 1373,
1076, 961, 881, 804, 766, 611. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C22H26N, 304.2060; found 304.2055.
(E)-methyl 3-(8-(4-pentylbenzyl)quinolin-6-yl)acrylate (Table 3, Entry 3zc).
Use 4-amylboronic acid (1.2 equiv). Yellow liquid, yield = 44.8 mg (40%).
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (300
MHz, CDCl3, δ): 8.97 (dd, J = 4.2, 1.8 Hz, 1H), 8.15 (dd, J = 8.1, 1.8 Hz,
1H), 7.75-7.80 (m, 2H), 7.61 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.4, 4.2 Hz,
1H), 7.23 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.45 (d, J = 16.2 Hz,
1H), 4.63 (s, 2H), 3.81 (s, 3H), 2.55-2.60 (m, 2H), 1.55 – 1.65 (m, 2H),
1.29-1.34 (m, 4H), 0.86-0.91 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ):
167.4, 150.6, 147.8, 144.4, 141.6, 140.8, 138.0, 136.8, 132.4, 129.3, 128.6,
128.5, 127.7, 127.4, 121.9, 118.9, 51.9, 36.5, 35.7, 31.7, 31.3, 22.7, 14.2.
IR (ZnSe) νmax (cm−1): 3009, 2951, 2926, 2855, 1707, 1632, 1587, 1514,
1493, 1433, 1310, 1285, 1256, 1192, 1165, 1126, 1038, 1018, 1001, 980,
930, 885, 856, 835, 804, 785, 773, 729, 561, 484, 436. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C25H28NO2, 374.2115; found 374.2118.
5-bromo-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3x). Use 4-
amylboronic acid (1.2 equiv). Yellow solid, yield = 42.0 mg (38%). Mp =
42-45 ℃. Isolated from flash chromatography (5% EtOAc/n-hexane). 1H
NMR (300 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.55 (dd, J = 8.7,
1.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.30
(d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 4.61
(s, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.55-1.65 (m, 2H), 1.30-1.35 (m, 4H), 0.88-
0.92 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.2, 147.6, 140.9, 140.8,
138.0, 135.8, 130.3, 129.9, 129.3, 128.6, 127.7, 122.2, 119.9, 36.4, 35.7,
31.7, 31.3, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2955, 2926, 2855, 2336, 1591,
1564, 1512, 1491, 1460, 1383, 1346, 1207, 1146, 1034, 920, 907, 856,
822, 806, 789. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C21H23BrN,
368.1008; found 368.1002.
2-(4-pentylphenethyl)pyridine (Table 3, Entry 3zd). Use AgOTf (10 mol%)
instead of Tf2O. Yellow liquid, yield = 15.2 mg (20%). Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
8.56 (d, J = 4.2 Hz, 1H), 7.57 (td, J = 7.2, 1.8 Hz, 1H), 7.08-7.13 (m, 6H),
3.07-3.09 (m, 2H), 3.00-3.03 (m, 2H), 2.56 (t, J = 7.8 Hz, 2H), 1.57-1.62
(m, 2H), 1.29-1.33 (m, 4H), 0.88-0.90 (m, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 161.6, 149.4, 140.7, 138.9, 136.4, 128.5, 128.5, 123.1, 121.3,
40.5, 35.8, 35.7, 31.7, 31.4, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2955, 2924,
2855, 2326, 1589, 1514, 1474, 1435, 814, 746, 556. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C18H24N, 254.1903; found 254.1903.
6-bromo-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3y). Use 4-
amylboronic acid (1.2 equiv). Colourless liquid, yield = 38.7 mg (35%).
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (300
MHz, CDCl3, δ): 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.04 (dd, J = 8.1, 1.8 Hz,
1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.42 (dd, J = 8.1, 4.2 Hz, 1H), 7.22 (d, J =
7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.61 (s, 2H), 2.57 (t, J = 7.8 Hz, 2H),
1.56-1.65 (m, 2H), 1.30-1.35 (m, 4H), 0.87-0.91 (m, 3H). 13C{1H} NMR (75
MHz, CDCl3, δ): 149.9, 145.6, 143.1, 140.9, 137.7, 135.4, 132.8, 129.7,
129.3, 128.7, 128.3, 122.0, 120.6, 36.2, 35.7, 31.7, 31.3, 22.7, 14.2. IR
(ZnSe) νmax (cm−1): 2955, 2926, 2855, 1589, 1570, 1512, 1487, 1466, 1425,
1360, 1319, 1234, 1182, 1115, 1090, 1030, 1022, 864, 845, 802, 781, 725,
648, 606, 594, 559, 530, 503, 488, 461. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C21H23BrN, 368.1008; found 368.1011.
2-(4-chlorophenethyl)pyridine (Table 3, Entry 3ze). Use AgOTf (10 mol%)
instead of Tf2O. Brown liquid, yield = 9.8 mg (15%). Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
8.56 (d, J = 4.2 Hz, 1H), 7.56 (td, J = 7.8, 1.8 Hz, 1H), 7.22 (d, J = 8.4 Hz,
2H), 7.09-7.13 (m, 3H), 7.05 (d, J = 7.8 Hz, 1H), 3.01-3.08 (m, 4H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 160.9, 149.5, 140.1, 136.5, 131.8, 130.0, 128.6,
123.2, 121.4, 40.1, 35.4. IR (ZnSe) νmax (cm−1): 3011, 2924, 2855, 2326,
1591, 1568, 1491, 1474, 1433, 1092, 1015, 816, 748, 627, 523, 490, 403.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C13H13ClN, 218.0721; found
218.0731.
8-benzylquinoline (Table 4, Entry 3zf).[23] White solid, yield = 30.2 mg
(46%). Mp = 50-52 ℃. Isolated from flash chromatography (4% EtOAc/n-
hexane).1H NMR (600 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.15-
8.16 (m, 1H), 7.69 (dd, J = 7.2, 1.8 Hz, 1H), 7.41-7.47 (m, 3H), 7.33 (d, J
= 7.2 Hz, 2H), 7.28-7.30 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H) 4.70 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 149.6, 146.8, 141.5, 140.3, 136.4,
129.6, 129.5, 128.5, 128.4, 126.5, 126.4, 126.0, 121.1, 36.9. IR (ZnSe)
νmax (cm−1): 3028, 2961, 2924, 1599, 1574, 1491, 1391, 1360, 1314, 1260,
1153, 1080, 1028, 872, 810, 787, 758, 700, 606, 571, 515, 438. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C16H14N, 220.1121; found 220.1120.
5-nitro-8-(4-pentylbenzyl)quinoline (Table 3, Entry 3z). Use 4-amylboronic
acid (1.2 equiv). Yellow solid, yield = 20.1 mg (20%). Mp = 101-103 ℃.
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (300
MHz, CDCl3, δ): 9.03-9.08 (m, 2H), 8.28 (d, J = 7.8 Hz, 1H), 7.65 (dd, J =
8.7, 4.2 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (d,
J = 7.8 Hz, 2H), 4.71 (s, 2H), 2.54-2.60 (m, 2H), 1.55-1.65 (m, 2H), 1.29-
1.34 (m, 4H), 0.86-0.91 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 150.6,
149.2, 146.5, 144.1, 141.3, 137.0, 132.3, 129.4, 128.8, 127.5, 124.8, 123.9,
121.4, 37.2, 35.7, 31.7, 31.3, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2953, 2922,
2855, 2326, 1595, 1518, 1499, 1400, 1323, 1153, 1119, 835, 795, 737.
7-chloro-8-(4-ethylbenzyl)quinoline (Table 4, Entry 3zg). Yellow liquid,
yield = 29.7 mg (40%). Isolated from flash chromatography (5% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.98-8.99 (m, 1H), 8.14-8.16 (m,
7
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10.1002/chem.201905591
Chemistry - A European Journal
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1H), 7.68-7.69 (m, 1H), 7.44-7.46 (m, 2H), 7.41 (dd, J = 7.8, 4.2 Hz, 1H),
7.26 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 4.67 (s, 2H), 2.61-2.65
(m, 2H), 1.23 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.6, 146.9,
141.8, 140.6, 138.6, 136.4, 129.5, 129.4, 128.5, 128.0, 126.5, 126.3, 121.1,
36.5, 28.6, 15.7. IR (ZnSe) νmax (cm−1): 2963, 2326, 1597, 1512, 1497,
1369, 1319, 1246, 1074, 1022, 851, 818, 789, 758, 604, 534. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C18H18N, 248.1434; found 248.1434.
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (600
MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.2 Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz,
1H), 7.68-7.69 (m, 1H), 7.41-7.46 (m, 3H), 6.94 (s, 2H), 6.85 (s, 1H), 4.62
(s, 2H), 2.27 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.6, 146.9,
141.3, 140.5, 137.9, 136.4, 129.6, 128.5, 127.7, 127.4, 126.5, 126.3, 121.1,
36.6, 21.5. IR (ZnSe) νmax (cm−1): 3019, 2965, 2916, 2851, 1595, 1497,
1431, 1319, 1069, 851, 827, 793, 758, 727, 692, 588. HRMS (ESI-TOF)
(m/z): [M + H]+ calcd for C18H18N, 248.1434; found 248.1433.
8-(4-bromobenzyl)quinoline (Table 4, Entry 3zh).[13e] Use arylboronic acid
(1.2 equiv). White solid, yield = 31.3 mg (35%). Mp = 45-46 ℃. Isolated
8-(3,5-bis(trifluoromethyl)benzyl)quinoline (Table 4, Entry 3zo). Use
arylboronic acid (1.2 equiv). White solid, yield = 33.1 mg (31%). Mp = 49-
50 ℃. Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR
(600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.16 (dd, J = 8.4, 1.8
Hz, 1H), 7.83 (s, 2H), 7.76 (dd, J = 7.8, 1.8 Hz, 1H), 7.69 (s, 1H), 7.49-
7.53 (m, 2H), 7.43 (dd, J = 7.8, 4.2 Hz, 1H), 4.77 (s, 2H). 13C{1H} NMR
1
from flash chromatography (5% EtOAc/n-hexane). H NMR (600 MHz,
CDCl3, δ): 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz, 1H),
7.70 (dd, J = 7.8, 1.8 Hz, 1H), 7.41-7.47 (m, 3H), 7.38 (d, J = 8.4 Hz, 2H),
7.20 (d, J = 8.4 Hz, 2H), 4.63 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ):
149.8, 146.7, 140.6, 139.6, 136.4, 131.5, 131.2, 129.6, 128.6, 126.7, 126.5,
121.3, 119.8, 36.4. IR (ZnSe) νmax (cm−1): 3041, 2929, 1595, 1573, 1485,
1435, 1404, 1388, 1361, 1070, 1010, 850, 819, 796, 761, 655, 617, 590,
472, 439. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H13BrN, 298.0226;
found 298.0229.
(150 MHz, CDCl3, δ): 149.9, 146.6, 144.2, 138.2, 136.5, 131.46 (q, JCF
=
33.0 Hz), 129.7, 128.8, 129.5 (q, JCF = 4.5 Hz), 127.4, 126.6, 123.62 (d,
JCF = 271.5 Hz), 121.5, 120.04 – 120.15 (m), 37.1. IR (ZnSe) νmax (cm−1):
3055, 2924, 2326, 1501, 1375, 1273, 1175, 1128, 1113, 1103, 1072, 1053,
1028, 891, 870, 841, 827, 793, 758, 702. HRMS (ESI-TOF) (m/z): [M + H]+
calcd for C18H12F6N, 356.0868; found 356.0861.
8-(4-chlorobenzyl)quinoline (Table 4, Entry 3zi).[11b] Use arylboronic acid
(1.2 equiv). White solid, yield = 35.0 mg (46%). Mp = 50–52 ℃. Isolated
1
from flash chromatography (5% EtOAc/n-hexane). H NMR (300 MHz,
8-(2-fluorobenzyl)quinoline (Table 4, Entry 3zp). Colourless liquid, yield =
14.2 mg (20%). Isolated from flash chromatography (5% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.98 (d, J = 3.6 Hz, 1H), 8.15 (d, J = 7.8 Hz,
1H), 7.70 (d, J = 8.4 Hz, 1H), 7.41-7.46 (m, 3H), 7.28 (t, J = 7.2 Hz, 1H),
7.18-7.21 (m, 1H), 7.06-7.09 (m, 1H), 7.02-7.05 (m, 1H) 4.74 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 161.45 (d, JCF = 244.5 Hz), 149.6,
146.9, 138.8, 136.4, 131.9 (d, JCF = 4.5 Hz), 129.3, 128.5, 128.22 (d, JCF
= 16.5 Hz), 127.85 (d, JCF = 9.0 Hz), 126.6, 126.5, 124.05 (d, J = 3.0 Hz),
121.15, 115.33 (d, JCF = 22.5 Hz), 29.91 (d, JCF = 4.5 Hz). IR (ZnSe) νmax
(cm−1): 3040, 2326, 1584, 1489, 1454, 1369, 1319, 1225, 1094, 1032, 827,
791, 772, 750, 696, 583, 496, 447. HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C16H13FN, 238.1032; found 238.1029.
CDCl3, δ): 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.14-8.17 (m, 1H), 7.71 (dd, J =
6.9, 2.4 Hz, 1H), 7.40-7.49 (m, 3H), 7.21-7.28 (m, 4H), 4.65 (s, 2H). 13C{1H}
NMR (75 MHz, CDCl3, δ): 149.7, 146.8, 140.1, 139.8, 136.4, 131.8, 130.8,
129.6, 128.6, 128.5, 126.7, 126.5, 121.2, 36.4. IR (ZnSe) νmax (cm−1): 3003,
2951, 2920, 2853, 2336, 1595, 1576, 1491, 1393, 1090, 1074, 1016, 800,
787, 758, 727, 694, 665, 598, 550, 517, 476, 434. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C16H13ClN, 254.0731; found 254.0734.
8-(4-(trifluoromethyl)benzyl)quinoline (Table 4, Entry 3zj).[13e] Use
arylboronic acid (1.2 equiv). White solid, yield = 15.5 mg (18%), Mp = 53-
55 ℃. Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR
(600 MHz, CDCl3, δ): 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.16 (dd, J = 7.8, 1.8
Hz, 1H), 7.72-7.73 (m, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.46-7.49 (m, 2H),
7.42-7.44 (m, 3H), 4.73 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.8,
146.8, 145.8, 139.2, 136.5, 129.7, 129.6, 128.7, 128.3 (q, JCF = 31.5 Hz),
126.9, 126.5, 121.3, 125.30-125.37 (q, JCF = 4.5 Hz), 124.64 (q, JCF = 270
Hz), 36.9. IR (ZnSe) νmax (cm−1): 3046, 2934, 2334, 1614, 1499, 1418,
1319, 1161, 1126, 1107, 1063, 1016, 953, 854, 824, 806, 791, 764, 750,
739, 698, 658, 598, 513. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C17H13F3N, 288.0995; found 288.0991.
8-(thiophen-2-ylmethyl)quinoline (Table 4, Entry 3zq). Transparent
crystalline solid, yield = 16.9 mg (25%). Mp = 71-73 ℃. Isolated from flash
chromatography (5% EtOAc/n-hexane). 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.15
(dd, J = 8.4, 1.8 Hz, 1H), 7.71 (dd, J = 7.8, 1.2 Hz, 1H), 7.57 (d, J = 6.6 Hz,
1H), 7.48 (dd, J = 7.8, 7.2 Hz, 1H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.12-
7.13 (m, 1H), 6.92-6.93 (m, 2H), 4.87 (s, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 149.7, 146.5, 144.2, 139.5, 136.4, 129.3, 128.5, 126.8, 126.8,
126.6, 125.6, 123.9, 121.3, 31.25. IR (ZnSe) νmax (cm−1): 2955, 2924, 1591,
1497, 1427, 1393, 1366, 1072, 826, 799, 760, 745, 700, 642, 613, 577,
513, 440. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C14H12NS, 226.0685;
found 226.0685.
8-(4-(trimethylsilyl)benzyl)quinoline (Table 4, Entry 3zk). Use arylboronic
acid (1.2 equiv). Brown solid, yield = 38.5 mg (44%). Mp = 92–94 ℃.
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (600
MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz,
1H), 7.68-7.70 (m, 1H), 7.45-7.46 (m, 4H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H),
7.34 (d, J = 7.8 Hz, 2H), 4.70 (s, 2H), 0.26 (s, 9H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 149.7, 146.9, 142.1, 140.2, 137.5, 136.4, 133.6, 129.6, 128.9,
128.5, 126.5, 126.4, 121.1, 36.9, -0.91. IR (ZnSe) νmax (cm−1): 2953, 2911,
2336, 1595, 1497, 1396, 1260, 1248, 1105, 835, 816, 791, 758, 727, 696,
665, 635, 613, 588, 519, 478, 440. HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C19H22NSi, 292.1516; found 292.1511.
8-benzyl-5-methylquinoline (Table 4, Entry 3zr). Yellow liquid, yield = 30.8
mg (44%). Isolated from flash chromatography (5% EtOAc/n-hexane).8.98
(dd, J = 4.2, 1.8 Hz, 1H), 8.33 (dd, J = 8.4, 1.8 Hz, 1H), 7.44 (dd, J = 8.4,
4.2 Hz, 1H), 7.31-7.33 (m, 2H), 7.25-7.30 (m, 3H), 7.18-7.21 (m, 2H), 4.66
(s, 3H), 2.66 (s, 4H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.1, 147.1,
141.8, 138.3, 132.9, 132.7, 129.8, 129.5, 129.2, 128.4, 126.9, 125.9, 120.7,
36.9, 18.7. IR (ZnSe) νmax (cm−1): 3024, 2920, 2326, 1601, 1580, 1493,
1470, 1452, 1356, 1346, 1315, 1150, 1072, 1030, 1003, 968, 847, 816,
802, 785, 770, 750, 725, 698, 687, 619, 594, 552, 503, 473. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C17H16N, 234.1277; found 234.1277.
8-(4-methoxybenzyl)quinoline (Table 4, Entry 3zl). Yellow liquid, yield =
29.9 mg (40%). Isolated from flash chromatography (5% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.96-8.97 (m, 1H), 8.14-8.16 (m, 1H), 7.68
(d, J = 7.8 Hz, 1H), 7.40-7.46 (m, 3H), 7.24-7.26 (m, 2H), 6.83 (dd, J = 8.4,
1.2 Hz, 2H), 4.63 (s, 2H), 3.78 (d, J = 1.2 Hz, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 157.9, 149.5, 146.7, 140.6, 136.3, 133.4, 130.3, 129.4, 128.4,
126.4, 126.2, 121.0, 113.8, 55.2, 36.0. IR (ZnSe) νmax (cm−1): 3001, 2907,
2833, 2326, 1611, 1508, 1497, 1464, 1439, 1300, 1242, 1175, 1105, 1034,
816, 791, 760, 746, 725, 602, 525. HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C17H16NO, 250.1226; found 250.1223.
8-benzyl-5-nitroquinoline (Table 4, Entry 3zs). Yellow solid, yield = 9.5 mg
(12%). M.pt. = 69-71 ℃. Isolated from flash chromatography (5% EtOAc/n-
hexane). 9.07 (dd, J = 4.2, 1.8 Hz, 1H), 9.05 (dd, J = 9.0, 1.8 Hz, 1H), 8.28
(d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.4, 4.2 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H),
7.30-7.32 (m, 4H), 7.22-7.25 (m, 1H), 4.75 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 150.7, 148.8, 146.4, 144.1, 139.9, 132.3, 129.5, 128.8, 127.6,
126.6, 124.7, 123.9, 121.4, 37.6. IR (ZnSe) νmax (cm−1): 2924, 2853, 1518,
1489, 1398, 1317, 1263, 1234, 1153, 864, 835, 802, 766, 739, 708, 698,
575, 503. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H13N2O2,
265.0972; found 265.0972.
8-(4-nitrobenzyl)quinoline (Table 4, Entry 3zm). Yellow solid, yield = 8.7
mg (11%). Mp = 85-87 ℃. Isolated from flash chromatography (5%
EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 8.93 (dd, J = 4.2, 1.8 Hz,
1H), 8.16 (dd, J = 8.4, 1.8 Hz, 1H), 8.08-8.11 (m, 2H), 7.74-7.75 (m, 1H),
7.47-7.51 (m, 2H), 7.45-7.46 (m, 2H), 7.43 (dd, J = 8.4, 4.2 Hz, 1H), 4.75
(s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.9, 149.7, 146.6, 146.4,
138.4, 136.5, 130.0, 129.9, 128.7, 127.3, 126.5, 123.7, 121.4, 37.1. IR
(ZnSe) νmax (cm−1): 2926, 1595, 1497, 1339, 1107, 851, 806, 716, 592, 515
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H13N2O2, 265.0972; found
265.0972.
General procedure for the symmetrical diarylation of 8-
methylquinoline with arylboronic acids and characterization data. To
an oven-dried screw cap reaction vial charged with a spin vane magnetic
stir-bar, phenylboronic acid (6 equiv), [RhCp*Cl2]2 (5 mol %) and Ag2O (2
equiv) were added under argon atmosphere, followed by the addition of 8-
methylquinoline (0.3 mmol), dichloroethane (1.5 mL) and triflic anhydride
(10 mol%). The subsequent reaction mixture was stirred at 100 °C for 24
h. On completion of reaction, the solvent was evaporated under reduced
pressure to get the crude reaction mixture. The crude mixture was purified
either by flash chromatography using silica gel (230-400 mesh size) and
8-(3,5-dimethylbenzyl)quinoline (Table 4, Entry 3zn).[13e] Use arylboronic
acid (1.2 equiv). White solid, yield = 25.2 mg (34%). Mp = 80-82 ℃.
8
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10.1002/chem.201905591
Chemistry - A European Journal
FULL PAPER
n-hexane: EtOAc as the eluent or by column chromatography using
reverse silica C-18 and H2O: MeOH as eluent.
6.80 (d, J = 9.0 Hz, 4H), 3.77 (s, 6H), 2.67 (s, 3H), 2.47 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 157.8, 148.4, 143.4, 140.8, 137.2, 135.6, 132.3,
132.2, 130.6, 128.5, 122.0, 121.5, 113.6, 55.3, 48.6, 22.3, 19.2. IR (ZnSe)
νmax (cm−1): 3007, 2922, 2830, 1607, 1508, 1452, 1439, 1244, 1169, 1036,
833, 814, 584, 517. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C26H26NO2,
384.1958; found 384.1960.
8-(bis(4-chlorophenyl)methyl)quinoline (Table 5, Entry 3'zi). White solid,
yield
= 72.1 mg (66%). Mp = 147-149 ℃. Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (300 MHz, CDCl3, δ):
8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.15 (dd, J = 8.1, 1.8 Hz, 1H), 7.74 (dd, J =
8.1, 1.5 Hz, 1H), 7.45-7.50 (m, 1H), 7.39 (dd, J = 8.1, 4.2 Hz, 1H), 7.22-
7.26 (m, 5H), 7.07 (d, J = 8.7 Hz, 4H), 7.01 (s, 1H). 13C{1H} NMR (75 MHz,
CDCl3, δ): 150.0, 146.3, 142.7, 142.0, 136.4, 132.2, 131.0, 130.2, 128.6,
127.2, 126.3, 121.4, 49.1. IR (ZnSe) νmax (cm−1): 3040, 2999, 1950, 1898,
1886, 1595, 1487, 1466, 1402, 1385, 1090, 1074, 1011, 854, 820, 787,
766, 754, 694, 681, 615, 538, 519, 494, 444. HRMS (ESI-TOF) (m/z): [M
+ H]+ calcd for C22H16Cl2N, 364.0654; found 364.0654.
General procedure for the secondary C(sp3)-H bond arylation of 8-
benzylquinoline with arylboronic acids and characterization data. To
an oven-dried screw cap reaction vial charged with a spin vane magnetic
stir-bar, 8-benzylquinoline (0.3 mmol), arylboronic acid (3 equiv),
[RhCp*Cl2]2 (5 mol %) and Ag2O (2 equiv) were added under argon
atmosphere, followed by the addition of dichloroethane (1.5 mL) and triflic
anhydride (10 mol%). The subsequent reaction mixture was stirred at
100 °C for 24 h. On completion of reaction, the solvent was evaporated
under reduced pressure to get the crude reaction mixture. The crude
mixture was purified either by flash chromatography using silica gel (230-
400 mesh size) and n-hexane: EtOAc as the eluent or by column
chromatography using reverse silica C-18 and H2O: MeOH as eluent.
8-(bis(4-methoxyphenyl)methyl)quinoline
(Table
5,
Entry
3'zl).
Transparent Crystalline solid, yield = 68.2 mg (64%). Mp = 131-133 ℃.
Isolated from flash chromatography (4% EtOAc/n-hexane). 1H NMR (600
MHz, CDCl3, δ): 8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.12-8.14 (m, 1H), 7.69-
7.71 (m, 1H), 7.45-7.48 (m, 1H), 7.36 (dd, J = 8.4, 4.2 Hz, 1H), 7.33 (dd, J
= 7.2, 0.6 Hz, 1H), 7.07-7.09 (m, 4H), 6.98 (s, 1H), 6.79-6.82 (m, 4H), 3.77
(s, 6H). 13C{1H} NMR (150 MHz, CDCl3, δ): 157.9, 149.8, 146.5, 143.5,
137.1, 136.3, 130.6, 130.3, 128.5, 126.5, 126.2, 121.1, 113.7, 55.3, 48.5.
IR (ZnSe) νmax (cm−1): 3055, 3003, 2963, 2833, 1607, 1582, 1506, 1495,
1302, 1246, 1173, 1107, 1030, 835, 816, 797, 773, 760, 577, 515. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C24H22NO2, 356.1645; found 356.1645.
8-((4-pentylphenyl)(phenyl)methyl)quinoline (Table 6, Entry 4b). Yellow
liquid, yield = 49.3 mg (45%). Isolated from flash chromatography (1%
EtOAc/n-hexane). 1H NMR (300 MHz, CDCl3, δ): 8.89 (dd, J = 4.2, 1.8 Hz,
1H), 8.13 (dd, J = 8.4, 1.8 Hz, 1H), 7.70 (dd, J = 8.1, 1.5 Hz, 1H), 7.45-
7.50 (m, 1H), 7.34-7.38 (m, 3H), 7.24-7.29 (m, 2H), 7.16-7.20 (m, 3H), 7.09
(s, 5H), 2.57 (t, J = 7.8 Hz, 2H), 1.56-1.66 (m, 2H), 1.30-1.35 (m, 4H), 0.87-
0.92 (m, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 149.8, 146.5, 144.9, 143.2,
141.7, 140.7, 136.3, 130.5, 129.8, 129.6, 128.5, 128.3, 128.2, 126.6, 126.3,
126.0, 121.1, 49.7, 35.7, 31.8, 31.2, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2955,
2926, 2855, 2336, 1597, 1510, 1495, 1466, 1450, 1366, 1186, 1078, 820,
793, 758, 727, 698, 610. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C27H28N, 366.2216; found 366.2208.
8-(bis(3,5-bis(trifluoromethyl)phenyl)methyl)quinoline (Table 5, Entry 3'zo).
White solid, yield = 105.5 mg (62%). Mp = 118-120 ℃. Isolated from flash
1
chromatography (4% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.84 (dd, J =
8.4, 1.2 Hz, 1H), 7.79 (s, 2H), 7.61 (s, 4H), 7.55 (dd, J = 7.8, 7.2 Hz, 1H),
7.46 (dd, J = 8.4, 4.2 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J = 7.2, 1.2 Hz, 1H).
13C{1H} NMR (150 MHz, CDCl3, δ): 150.3, 145.8, 145.3, 139.4, 136.7,
131.09 (q, JCF = 33.0 Hz), 130.0, 129.59 (q, JCF = 3.0 Hz), 128.9, 128.4,
126.5, 123.34 (d, JCF = 273.0 Hz), 122.0, 121.18-121.29 (m), 49.81. IR
(ZnSe) νmax (cm−1): 2322, 1501, 1371, 1273, 1167, 1119, 1109, 1084, 899,
799, 704, 681. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C26H14F12N,
568.0929; found 568.0930.
8-((4-chlorophenyl)(phenyl)methyl)quinoline (Table 6, Entry 4c). White
solid, yield = 69.3 mg (70%). Mp = 149-151 ℃. Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (300 MHz, CDCl3, δ):
8.88 (dd, J = 3.9, 1.5 Hz, 1H), 8.15 (dd, J = 8.1, 1.5 Hz, 1H), 7.73 (dd, J =
8.1, 1.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (dd, J = 8.4, 4.2 Hz, 1H),
7.21-7.31 (m, 6H), 7.15-7.18 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.07 (s, 1H).
13C{1H} NMR (75 MHz, CDCl3, δ): 149.9, 146.4, 144.1, 143.2, 142.5, 136.4,
131.9, 131.1, 130.4, 129.7, 128.6, 128.4, 126.9, 126.4, 126.3, 121.3, 49.6.
IR (ZnSe) νmax (cm−1): 3065, 3028, 3001, 1597, 1485, 1173, 1086, 1011,
824, 800, 783, 754, 729, 700, 694, 606, 486. HRMS (ESI-TOF) (m/z): [M
+ H]+ calcd for C22H17ClN, 330.1044; found 330.1044.
8-(bis(4-chlorophenyl)methyl)-5-methylquinoline (Table 5, Entry 3'zt).
Light yellow solid, yield = 70.4 mg (62%). Mp = 139-142 ℃. Isolated from
flash chromatography (4% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3,
δ): 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.46 (dd, J =
8.4, 4.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 4H), 7.16 (d,
J = 7.2 Hz, 1H), 7.08 (d, J = 8.4 Hz, 4H), 7.01 (s, 1H), 2.68 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 148.9, 145.5, 142.5, 139.4, 133.8, 133.6, 132.1,
130.9, 130.4, 128.4, 127.9, 126.9, 120.8, 48.9, 18.6. IR (ZnSe) νmax (cm−1):
2326, 1599, 1487, 1086, 1011, 818, 791, 768, 602, 583, 498. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C23H18Cl2N, 378.0811; found 378.0810.
8-((4-methoxyphenyl)(phenyl)methyl)quinoline (Table 6, Entry 4d). White
solid, yield = 58.6 mg (60%). Mp = 163-167 ℃. Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.71 (dd, J =
7.8, 1.2 Hz, 1H), 7.47 (dd, J = 8.4, 7.2 Hz, 1H), 7.37 (dd, J = 8.4, 4.2 Hz,
1H), 7.32 (dd, J = 7.2, 1.8 Hz, 1H), 7.24-7.27 (m, 2H), 7.19 (d, 7.2 Hz, 1H),
7.16 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.81 (d, J =
8.4 Hz, 2H), 3.77 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 158.0, 149.8,
146.5, 145.0, 143.2, 136.7, 136.3, 130.7, 130.4, 129.7, 128.5, 128.3, 126.6,
126.2, 126.1, 121.2, 113.7, 55.3, 49.3. IR (ZnSe) νmax (cm−1): 3030, 2957,
1609, 1582, 1508, 1493, 1441, 1302, 1248, 1173, 1109, 1026, 1011, 839,
818, 795, 787, 766, 756, 733, 704, 662, 631, 608, 581, 513, 420. HRMS
(ESI-TOF) (m/z): [M + H]+ calcd for C23H20NO, 326.1539; found 326.1545.
8-(bis(4-chlorophenyl)methyl)-6-bromoquinoline (Table 5, Entry 3'zu).
White solid, yield = 95.7 mg (72%). Mp = 178-179 ℃. Isolated from reverse
silica C-18 (20% H2O/MeOH). 1H NMR (600 MHz, CDCl3, δ): 8.85 (dd, J =
4.2, 1.8 Hz, 1H), 8.05 (dd, J = 8.4, 1.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H),
7.40 (dd, J = 7.8, 4.2 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.25-7.27 (m, 4H),
7.07 (d, J = 8.4 Hz, 4H), 6.96 (s, 1H). 13C{1H} NMR (150 MHz, CDCl3, δ):
150.2, 144.8, 144.4, 141.8, 135.4, 133.4, 132.5, 130.9, 129.7, 129.2, 128.7,
122.3, 120.4, 49.0. IR (ZnSe) νmax (cm−1): 2920, 2851, 2326, 1593, 1487,
1433, 1402, 1371, 1088, 1011, 864, 833, 822, 804, 795, 756, 725, 683,
646, 519, 500, 478, 415. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C22H15BrCl2N, 441.9759; found 441.9757.
8-((3,5-bis(trifluoromethyl)phenyl)(phenyl)methyl)quinoline (Table 6, Entry
4e). Yellow liquid, yield
= 97.1 mg (75%). Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.16-8.18 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H),
7.73 (s, 1H), 7.64-7.65 (m, 2H), 7.50-7.53 (m, 1H), 7.41 (dd, J = 8.4, 4.2
Hz, 1H), 7.33 (td, J = 7.8, 2.4 Hz, 2H), 7.27-7.30 (m, 2H), 7.22 (d, J = 4.2
Hz, 1H), 7.15-7.17 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.1,
147.3, 146.1, 142.6, 141.1, 136.5, 131.45 (q, JCF = 33 Hz), 131.3, 130.3,
129.71-129.75 (m), 129.7, 128.8, 128.7, 127.5, 127.0, 126.4, 123.57 (q,
JCF = 270 Hz), 121.6, 120.38-120.45 (m), 50.03. IR (ZnSe) νmax (cm−1):
2326, 1497, 1371, 1275, 1167, 1125, 1109, 1078, 941, 899, 849, 795, 783,
762, 727, 700, 681, 669. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C24H16F6N, 432.1181; found 432.1183.
8-(bis(4-chlorophenyl)methyl)-4,6-dimethylquinoline (Table 5, Entry 3'zv).
Pale yellow solid, yield = 82.4 mg (70%). Mp = 174-176 ℃. Isolated from
flash chromatography (4% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3,
δ): 8.64 (d, J = 4.2 Hz, 1H), 7.68-7.69 (m, 1H), 7.21-7.24 (m, 4H), 7.17-
7.18 (m, 1H), 7.05-7.07 (m, 5H), 7.00 (s, 1H), 2.67 (s, 3H), 2.47 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3, δ): 148.7, 144.5, 143.7, 142.9, 142.0,
135.6, 132.1, 132.0, 131.0, 128.6, 128.5, 122.3, 122.1, 49.2, 22.3, 19.1.
IR (ZnSe) νmax (cm−1): 2920, 2851, 2326, 1593, 1487, 1433, 1402, 1371,
1088, 1011, 864, 833, 822, 804, 795, 756, 725, 683, 646, 519, 500, 478,
415. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C24H20Cl2N, 392.0967;
found 392.0964.
8-((4-chlorophenyl)(4-methoxyphenyl)methyl)quinoline (Table 6, Entry 4f).
Yellow solid, yield = 64.8 mg (60%). Mp = 117-119 ℃. Isolated from
reverse silica C-18 (20% H2O/MeOH). 1H NMR (600 MHz, CDCl3, δ): 8.87
(dd, J = 4.2, 1.8 Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (dd, J = 7.8,
1.2 Hz, 1H), 7.47 (dd, J = 7.8, 7.2 Hz, 1H), 7.38 (dd, J = 7.8, 4.2 Hz, 1H),
7.28-7.30 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.05-7.07 (m, 4H), 6.98 (s, 1H),
6.82 (d, J = 9.0 Hz, 2H), 3.77 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ):
8-(bis(4-methoxyphenyl)methyl)-4,6-dimethylquinoline (Table 5, Entry
3'zw). Yellow solid, yield = 55.2 mg (48%). Mp = 182-185 ℃. Isolated from
flash chromatography (4% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3,
δ): 8.67 (d, J = 4.2 Hz, 1H), 7.65 (s, 1H), 7.20-7.15 (m, 1H), 7.17 (d, J =
4.2 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 4H), 6.97 (s, 1H),
9
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10.1002/chem.201905591
Chemistry - A European Journal
FULL PAPER
158.1, 149.9, 146.3, 143.6, 142.7, 136.4, 136.2, 131.8, 131.0, 130.7, 130.3,
128.6, 128.4, 126.9, 126.3, 121.4, 113.8, 55.3, 48.8. IR (ZnSe) νmax (cm−1):
2953, 2920, 2851, 1709, 1508, 1491, 1460, 1369, 1300, 1246, 1173, 1155,
1132, 1105, 1090, 1072, 1026, 1015, 795, 773, 758, 719, 619, 577, 538,
463, 446, 422. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C23H19ClNO,
360.1150; found 360.1151.
[5d]
Synthesis of 1a-d3 To an oven-dried screw cap reaction vial charged
with a spin vane magnetic stir-bar, 8-methylquinoline (1a) (0.3 mmol),
[RhCp*Cl2]2 (2.5 mol %), CD3COOD (1 equiv.) and Cu(OAc)2 (2 equiv.)
were added in D2O (1 mL) under air at room temperature subsequent
reaction mixture was stir at 100 ℃ for 20 h. The reaction mixture was
extracted with EtOAc and the organic layer was dried over Na2SO4. The
solvent was evaporated under reduced pressure and the crude mixture
was purified by flash chromatography using silica gel (230-400 mesh size)
and n-hexane: EtOAc as eluent and 97%-D of 1a-d3 was obtained.
8-((4-chlorophenyl)(4-nitrophenyl)methyl)quinoline (Table 6, Entry 4g).
yellow sticky, yield = 41.6 mg (37%). Isolated from reverse silica C-18
(20% H2O/MeOH). 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J = 8.4, 1.8 Hz,
1H), 8.10-8.12 (m, 2H), 7.78 (dd, J = 8.4, 1.2 Hz, 1H), 7.49 (dd, J = 8.4,
7.2 Hz, 1H), 7.41 (dd, J = 8.4, 4.2 Hz, 1H), 7.27-7.31 (m, 4H), 7.23 (dd, J
= 7.2, 1.2 Hz, 1H), 7.11 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (150
MHz, CDCl3, δ): 152.0, 150.1, 146.6, 146.1, 141.5, 141.0, 136.5, 132.7,
131.1, 130.4, 130.2, 128.9, 128.7, 127.6, 126.3, 123.7, 121.6, 49.7. IR
(ZnSe) νmax (cm−1): 2924, 2853, 2326, 1597, 1516, 1489, 1342, 1089, 1012,
821, 790, 518. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C22H16Cl N2O2,
375.0895; found 375.0894.
Rhodacycle synthesis
A Rhodacycle intermediate A synthesised
according to the literature procedure.[6a] Yellow solid, 1H NMR (600 MHz,
CDCl3, δ): 8.94 (dd, J = 5.4, 1.2 Hz, 1H), 8.09 (dd, J = 8.4, 1.2 Hz, 1H),
7.62 (dd, J = 6.6, 1.2 Hz, 1H), 7.42-7.47 (m, 2H), 7.36 (dd, J = 8.4, 4.8 Hz,
1H), 3.95-3.98 (m, 1H), 3.68-3.71 (m, 1H), 1.62 (s, 15H). 13C{1H} NMR
(150 MHz, CDCl3, δ): 153.7, 151.8, 151.5, 136.7, 130.1, 128.8, 128.1,
123.1, 122.1, 93.99, 93.95, 33.8, 33.7, 9.3.
8-((4-chlorophenyl)(phenyl)methyl)-5-methylquinoline (Table 6, Entry 4h).
White solid, yield = 41.3 mg (40%). Mp = 116-118 ℃. Isolated from flash
1
chromatography (5% EtOAc/n-hexane). H NMR (600 MHz, CDCl3, δ):
Acknowledgements
8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.41 (dd, J =
8.4, 4.2 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24-7.28 (m, 2H), 7.19-7.22 (m,
3H), 7.14-7.17 (m, 3H), 7.09 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 2.67 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3, δ): 149.3, 146.6, 144.3, 143.4, 140.5,
133.5, 132.7, 131.8, 131.1, 130.0, 129.8, 129.7, 128.4, 128.2, 126.7, 126.3,
120.9, 49.6, 18.8. IR (ZnSe) νmax (cm−1): 3026, 2920, 2851, 1740, 1599,
1487, 1086, 1011, 827, 797, 779, 733, 698, 577. HRMS (ESI-TOF) (m/z):
[M + H]+ calcd for C23H19ClN, 344.1201; found 344.1203.
Authors
thanks Director, CSIR-IHBT for continuous
encouragement and providing necessary facilities. R.K. and D. P.
acknowledges UGC, New Delhi, for the Research Fellowship. D.
C. and A. K. D. acknowledges DST-INSPIRE, New Delhi, and
CSIR, New Delhi, respectively for research fellowship. Financial
support from CSIR (MLP0203/HCP0019) is also acknowledged.
CSIR-IHBT communication number for this manuscript is 4544.
(3S,3aS,5aS,9bS,E)-9-(4-methoxybenzyl)-8-(methoxyimino)-3,5a-
dimethyl-3a,4,5,5a,8,9b-hexahydronaphtho[1,2-b]furan-2(3H)-one
(Scheme 2, Entry 6a). Use of 4-methoxyphenylboronic acid (2.5 equiv.) at
80 ℃. Yellow solid, yield = 14.9 mg (13%). Mp = 122-125 ℃. Isolated from
flash chromatography (10% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3,
δ): 7.16 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 9.6 Hz, 1H), 6.74-6.76 (m, 2H),
5.97 (d, J = 10.2 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1H), 4.19 (d, J = 14.4 Hz,
1H), 4.00 (d, J = 14.4 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 2.23-2.29 (m, 1H),
1.92-1.95 (m, 1H), 1.72-1.75 (m, 1H), 1.59-1.63 (m, 2H), 1.46-1.51 (m, 1H),
1.26 (s, 3H), 1.12 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ):
177.9, 157.4, 148.9, 145.0, 139.5, 134.5, 129.6, 126.6, 113.3, 113.2, 82.1,
62.2, 55.3, 53.2, 41.1, 41.0, 38.8, 29.2, 25.9, 24.1, 12.7. IR (ZnSe) νmax
(cm−1): 2934, 2324, 1773, 1508, 1240, 1157, 1057, 1032, 984, 893, 874,
802, 523. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C23H28NO4, 382.2013;
found 382.2016.
Notes
The authors declare no competing financial interest.
Keywords: Rhodium catalyst, arylation, di-arylation, 8-methyl
quinolines and organoboron reagents.
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8-pentylquinoline (Scheme 4, Entry 8b).[24] Use of nBuBF3K (3 equiv.)
instead of boronic acid salt at 100 ℃. Yellow liquid, yield = 6.0 mg (10%).
Isolated from flash chromatography (5% EtOAc/n-hexane). 1H NMR (600
MHz, CDCl3, δ): 8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.13 (dd, J = 7.8, 1.8 Hz,
1H), 7.66 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.45-7.48 (m, 1H),
7.38 (dd, J = 8.4, 4.2 Hz, 1H), 3.27 (t, J = 7.8 Hz, 2H), 1.77-1.82 (m, 2H),
1.36-1.46 (m, 4H), 0.89-0.91 (m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ):
149.4, 147.1, 141.9, 136.5, 128.8, 128.6, 126.4, 125.9, 120.9, 32.1, 31.5,
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TOF) (m/z): [M + H]+ calcd for C14H18N, 200.1434; found, 200.1433.
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ml) charged with a spin vane magnetic stir-bar, 7-chloro-8-methylquinoline
(8.0 mmol, 1.42 g), 4-chlorophenylboronic acid (20.0 mmol, 3.13 g),
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under argon atmosphere, followed by the addition of dichloroethane (40
mL) and triflic anhydride (5 mol%, 67.2 μl). The subsequent reaction
mixture was stirred at 100 °C for 24 h. Solvent was evaporated under
reduced pressure, and the crude mixture was purified by column
chromatography using silica gel (230−400 mesh size) and 3% EtOAc: n-
hexane as the eluent. Product 3h was isolated (1.50 g, 65%).
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11
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R. Kumar, D. Parmar, S. S. Gupta, D. Chandra, A. K. Dhiman
and U. Sharma*
Cp*Rh(III)-Catalyzed
Sterically
Controlled
C(sp3)-H
Selective Mono- and Diarylation of 8-Methylquinolines with
Organoborons
Arylation: Monoarylation of C(sp3)-H of 8-methylquinolines is disclosed along with symmetrical and unsymmetrical diarylation of 8-
methylquinolines in one-pot and sequential manner, respectively. Order of reaction with respect to each reactant is first order.
12
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