Ru(II)-Catalyzed Chemoselective C(sp3)-H Monoarylation of 8-Methyl Quinolines with Arylboronic Acids

Article abstract of DOI:10.1021/acs.joc.0c01603

The transition-metal-promoted C-H activation has become an efficient as well as atom-economic methodology for the synthesis of a wide array of organic molecules, but the cost of the metal catalyst and selectivity remain the major challenges. Herein, the first [Cl2Ru(p-cymene)]2-catalyzed direct monoarylation of unactivated C(sp3)-H bonds of 8-methyl quinolines with arylboronic acids to synthesize diarylmethane compounds is presented. The transformation shows a broad substrate scope with high chemoselectivity for the synthesis of 8-benzyl quinolines. In the preliminary mechanistic studies, control experiments, deuterium labeling experiments, and kinetic studies have been performed.

Full text of DOI:10.1021/acs.joc.0c01603

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Article
Ru(II)-Catalyzed Chemoselective C(sp3)-H Monoarylation
of 8-Methyl Quinolines with Arylboronic Acids
Diksha Parmar, Rohit` Kumar, Rakesh Kumar, and Upendra Sharma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01603 • Publication Date (Web): 19 Aug 2020
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The Journal of Organic Chemistry
Ru(II)-Catalyzed Chemoselective C(sp3)-H Monoarylation of 8-
Methyl Quinolines with Arylboronic Acids
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Diksha Parmar, Rohit Kumar, Rakesh Kumar and Upendra Sharma*
Chemical Technology Division and AcSIR, CSIR- IHBT, Palampur-176061, India
Supporting Information
ABSTRACT: The transition metal promoted C-H activation has grown as an efficient as well as atom economic methodology for
the synthesis of wide array of organic molecules but cost of the metal
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catalyst and selectivity remains the major challenges. Herein, the first
[Cl2Ru(p-cymene)]2-catalyzed direct mono-arylation of unactivated C(sp3)-
H bond of 8-methyl quinolines with aryl boronic acids to synthesize
diarylmethane compounds is presented. The transformation shows broad
substrate substrate scope with high chemoselectivity for the synthesis of 8-
benzyl quinolines. In preliminary mechanistic study- control experiments,
deuterium labelling experiments and kinetic studies have been performed.
KEYWORDS: C-H activation, [Cl2Ru(p-cymene)]2, arylation, 8-methyl quinolines, phenylboronic acids.
with organoboranes where mono-arylation was achieved only
in case of sterically hindered 7-substituted 8-MQs as substrates
and otherwise both mono- and di-arylated products were
obtained in the reaction.10g Although Ru(II)-catalysts have also
contributed immensely towards the discovery of efficient
catalytic systems for the direct C(sp2)-H arylation,11 there are
only few reports on C(sp3)-H arylation.12 Hence, these
considerations led us to search for the cost-effective Ru(II)-
catalyzed regio- and chemo- selective direct C(sp3)-H mono-
arylation of 8-MQ with less expensive and bench stable
arylboronic acids. (Scheme 1b)
Introduction
Over the years, quinoline has gained a huge attraction of the
researchers as it is the most versatile and important N-based
heterocyclic compound found in the nature particularly in
alkaloids.1 Quinoline scaffolds are used as ‘parental moieties’
which are integrated to functionalized molecules with a wide
range of applications in agrochemicals,2 pharmaceuticals1e,3 and
ligands in transition metal catalysts.4 Obeying to the importance
of quinolines, various methods have been developed for their
functionalization mainly by using Pd-catalyst but necessity of
pre-activated substrates, strong bases and stoichiometric
amount of metal catalyst remained the main shortcomings.5
However, development of TM-catalyzed C-H activation
eliminates all these requirements and therefore is a desirable
methodology for the direct functionalization of quinolines.6
The synthesis of C-Caryl bonds are indeed vital in organic
chemistry but these transformations are challenging for the
substrates having no directing group assistance as uncontrolled
regio- and chemo- selectivity leads to the undesired homo- and
Scheme 1. C(sp3)-H arylation of 8-methyl quinoline
hetero- couplings and hence formation of side products.5,7
A
number of reactions have been flourished widely for the direct
C(sp2)-H arylation of quinolines via transition metal catalysts
owing to the availability of pi-orbitals and easy formation of
their metallacycle intermediates.8 Significantly, methodologies
have also been reported for the direct functionalization9 and
particularly for arylation7d,7e, 10 of more challenging C(sp3)-H
bond of 8-methyl quinoline (8-MQ) under expensive Pd(II)-
and Rh(III)-catalysts. (Scheme 1a) In the pioneering studies, M.
S. Sanford,10a,10c O. Daugulisfor,10b W.Y. Yu10d and I. Larrosa7d
groups have independently developed CH-arylation protocols
through costly Pd-catalyst with a limited scope for 8-MQ. In
2015, F. Glorius and co-workers demonstrated a Rh(III)-
catalyzed C(sp3)-H arylation where chemoselectivity remained
an issue as both mono- and di-arylation products were observed
in case of primary C(sp3)-H bond.7e Later, Rh(I)/NHC-
catalyzed site- and enantio- selective direct C(sp3)-H arylation
with aryl bromides10e and Rh(III)-catalyzed C(sp3)-H arylation
with diazonaphthalen-2(1H)-ones/quinonediazides10f have also
been demonstrated but use of costly metal and limited scope
permit further investigation in this direction. Recently, our
group has reported the rhodium-catalyzed C(sp3)-H arylation
Results and Discussion
In order to explore Ru(II)-catalyzed C(sp3)-H arylation of 8-
MQ, we commenced our studies by reacting 8-MQ (1a) with
phenyl boronic acid (2a) in the presence of [Cl2Ru(p-cymene)]2
(5 mol%), AgOTf (20 mol%), Cu(OTf)2 (10 mol%) and Ag2O
(2 equiv.) in THF (Tetrahydrofuran) (0.5 ml) at 100 °C for 12h
under inert atmosphere. Pleasingly, this reaction afforded the
expected 8-benzyl quinoline (3a) in 23% isolated yield (Table
1, entry 6). When [Cl2Ru(p-cymene)]2 was omitted from the
reaction, no product was formed and 1a was recovered as such
(Table 1, entry 2). After extensive optimization of various
solvents, reaction efficiency was improved to 52% when a
combination of solvents (THF : TFE in 1 : 1) was used (Table
1, entry 1, 6). The optimization of additives proved that the
efficiency of the reaction was decreased to 35% in the absence
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of AgOTf (Table 1, entry 3). Also, control reaction without
various para-substituted phenyl boronic acids in moderate
Cu(OTf)2 or Ag2O resulted in decreased product yield (Table 1,
entry 4-5). Under air atmosphere, reaction efficiency was
decreased to 40%. (Table 1, entry 7) No significant
improvement was found with decrease or increase in the
temperature and 21% product yield was obtained at rt. (Table 1,
entry 8, 9) The reaction did not proceed when [Cl2Ru(p-
cymene)]2 was replaced with CoCp*(CO)I2 metal complex.
(Table 1, entry 10) No significant change in reaction efficiency
was observed with increase in time of the reaction. (Table 1,
entry 11, 12)
yields (3za-e). Unfortunately, when the reaction of thiophen-2-
ylboronic acid was conducted with 8-MQ, no arylated product
was obtained and 1a was recovered (3zf) whereas,
benzo[d][1,3]dioxol-5-ylboronic acid provided the desired
product with 7-chloro-8-MQ in low yield (3zg).
Scope of the reaction was further investigated by reacting
different substituted 8-MQs with para-chloro phenylboronic
acid to access diverse functionalized quinoline derivatives
(Table 3). It was observed that substituents like -Cl, -Br, -OMe,
-Me, CF3 at C7 position of 8-MQ were well tolerable and
provided the desired 7-substituted 8-benzyl quinolines in good
yields (3zh-m). However, 2-methyl- and 2-phenyl-8-MQ didn’t
underwent the reaction which might be due to the steric
hindrance (3zn-o). Methyl substituted 8-MQ at C3, C4, C5 and
C6 position reacted smoothly with para-chloro phenyl boronic
acid and afforded the desired products with yields up to 50%
(3zp-s). The reaction of 5-nitro- and 5-bromo-8-MQ with para-
chloro phenyl boronic acid afforded the products in acceptable
yields (3zt-u) and 6-substituted 8-MQ with -Br and styrene
were also amiable to provide the desired arylated products (3zv-
w).
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Table 1. Optimization studya
3a
entry
variation in the standard condition
none
yield (%)
52b (95)
n.r.
35b
31b
9b
23c
40b
32b
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without [Cl2Ru(p-cymene)]2
without AgOTf
Table 2. Substrate scope with phenyl boronic acids
without Cu(OTf)2
without Ag2O
THF instead of THF: TFE (1:1)
air atmosphere
at 120 ˚C instead of 100 ˚C
at rt instead of 100 ˚C
CoCp*(CO)I2 in place of
[Cl2Ru(p-cymene)]2
24 h instead of 12 h
48 h instead of 12h
21b
10
n.r.
43b
42b
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areaction conditions: 1a (0.1 mmol), 2a (2.0 equiv.), [Cl2Ru(p-cymene)]2 (5 mol%),
AgOTf (20 mol%), Cu(OTf)2 (10 mol%), Ag2O (2 equiv.), THF:TFE (1:1) (0.5 mL)
100 ˚C, 24 h under inert atmosphere. bNMR yield (1,1,2,2-tetrachloroethane as an
internal standard). cIsolated Yield. In parenthesis: Yield based on recovered starting
material (brsm).
After establishing the optimal reaction conditions, to assess the
generality of developed strategy several substituted phenyl
boronic acids with 8-MQ were tested (Table 2). A range of
para-substituted phenyl boronic acids with electron donating
and electron withdrawing groups provided the mono-arylated
products in yield up to 95% on the basis of recovered starting
material (3b-i). Also, the ortho- and meta- substituted phenyl
boronic acids furnished products in satisfactory yields and high
selectivity. (3j-m). Therefore, in case of unsubstituted 8-MQ,
selectively mono-arylated products were obtained which was
not feasible in the previously reported protocol (3a-m).10g We
further examined the scope for 7-substituted 8-MQs with
various substituted phenyl boronic acids. When 7-chloro-8-MQ
was reacted with a range of para-substituted phenyl boronic
acids, desired arylated products were obtained in good yields
(3n-u). While ortho- and meta-substituted phenyl boronic acids
also afforded the desired products (3v-3z). Similarly, 7-bromo-
8-MQ also furnished the desired mono-arylated products with
reaction conditions: 1 (0.2 mmol), 2 (2.0 equiv.), [Cl2Ru(p-cymene)]2 (5 mol%),
AgOTf (20 mol%), Cu(OTf)2 (10 mol%), Ag2O (2 equiv.), THF:TFE (1:1) (0.5 mL)
100 ˚C, 24 h under inert atmosphere. bUse of 2,4,6-triphenylboroxin instead of phenyl
boronic acid. In parenthesis: Yield based on recovered starting material (brsm).
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Table 3. Substrate scope with 8-methyl quinoline
deuteration was observed in the recovered reactant as well as in
the product. Both these experiments confirmed the irreversible
nature of CH-activation step as well no formation of diarylated
product (Scheme 2b). Next, competition and parallel
experiments were performed by reacting the equimolar amount
of 1a and deuterated 8-MQ (1a-d3) with 2a for 2h. In both these
experiments KIE value of 1.0 was observed (Scheme 2c-d)
which confirmed that the C-H bond activation is not involved
in the rate limiting step. In order to check the possibility of
formation of Ru(0) nanoparticles, SEM analysis of crude
reaction mixture was carried out however, no NPs were
observed.
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Based on the preliminary experiments we have performed and
precedent literature,13 a tentative mechanistic pathway for this
coupling reaction was proposed (Scheme 3). The initial step
likely involves the conversion of ruthenium catalyst to the
active cationic ruthenium species A in the presence of AgOTf
and Cu(OTf)2. This active catalytic species reacts with 1a to
give intermediate B which undergoes transmetallation with
arylboronic acid to afford the intermediate C. Reductive
elimination from C results in the formation of desired arylated
product and Ru(0) species which undergoes re-oxidation to
generate the active species A for the continuation of the
catalytic cycle.
Scheme 3. Plausible mechanistic cycle
reaction conditions: 1a (0.2 mmol), 2i (2.0 equiv.), [Cl2Ru(p-cymene)]2 (5 mol%),
AgOTf (20 mol%), Cu(OTf)2 (10 mol%), Ag2O (2 equiv.), THF:TFE (1:1) (0.5 mL)
100˚C, 24 h under inert atmosphere. bNMR yield (1,1,2,2-tetrachloroethane as an
internal standard). In parenthesis: Yield based on recovered starting material (brsm)
Scheme 2. Deuterium labelling experiments
Next, the synthetic utility of arylated product 3a was illustrated
by subjecting it to different post transformation reactions
(Scheme 4).14 The reaction of 3a was performed in the presence
of Ni(II)-catalyst and NaBH4 to obtain the corresponding
reduced product (4a),14a whereas secondary C(sp3)-H amidation
was carried out with dioxazolone to obtain the amidated product
(4b).14c Oxidation of 3a was carried out with m-CPBA to
synthesize corresponding N-oxide derivative (4c).14b Also,
secondary C(sp3)-arylation was carried out with phenylboronic
acid to obtain the corresponding triarylmethane (4d).10g
Further, preliminary experiments to understand the mechanistic
pathway of reaction were carried out. When deuterium labelling
experiment was carried out without 2a in the presence of
CD3OD, no deuterium incorporation was observed (Scheme
2a). When the same experiment was repeated with 2a, 0%
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Gram scale experiment was carried out with 8-methyl quinoline
Analytical Information. For heating, IKA magnetic hot plate
(10.0 mmol) and 4-(Trimethylsilyl)phenylboronic acid (2.0
equiv.) using [Cl2Ru(p-cymene)]2 (2.5 mol%), AgOTf (10
mol%), Cu(OTf)2 (5 mol%) and Ag2O (1 equiv.) in THF:TFE
(1:1) 25mL at 100 °C for 24h under inert atmosphere. Arylated
product was isolated in 32% (933 mg) yield. (Scheme 5)
stirrers are used. Bronsted Electro thermal 9100 was used to
record the melting point. For characterization of all the
compounds, 1H NMR, 13C NMR, FTIR, LC-MS & HRMS were
performed. Q-TOF-Micromass and maXis Impact mass
spectrometers were used to perform the mass spectrometry of
1
new compounds. Copies of H, 13C NMR are attached in the
Scheme 4. Synthetic utility of arylated product 3a
NMR supporting information. Shimadzu IR Prestige-21with
ZnSe Single reflection ATR accessory was used to perform the
IR spectroscopy of new compounds. Bruker-Avance 600 MHz
instrument was used to perform the NMR of all the compounds.
All 1H and proton decoupled- 13C NMR spectrums are reported
in parts per million (ppm) units, and measured relative to the
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deuterated chloroform signal- 7.260 (for H NMR) and 77.16
(for 13C{1H}). Optimization studies were carried out with NMR
yields calculated by using TCE (1, 1, 2, 2-tetrachloroethane) as
internal standard.
Synthesis of substituted 8-methyl quinolines: Substituted 8-
methyl quinolines 1n, 1za, 1zk, 1zl, 1zm, 1zs, 1zt, 1zu, and 1zv
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were prepared by following the literature procedure,
compounds 1zn, 1zo, 1zp, 1zq and 1zw were prepared by
following the literature procedure, 16 and 1zr was used from
commercially available source.
General procedure for the arylation of 8-methyl quinolines
with phenyl boronic acid: To a 10 mL oven-dried reaction vial-
8-methylquinoline (0.2 mmol), phenyl boronic acid (0.4 mmol),
[Cl2Ru(p-cymene)]2 (5 mol%), AgOTf (20 mol%), Cu(OTf)2
(10 mol%), Ag2O (2 equiv.) and THF:TFE (1:1) 1.0 mL were
added under argon atmosphere. The crude mixture was stirred
at 100 °C for 12 h. Under reduced pressure, solvent was
evaporated and the reaction mixture was directly purified by
flash chromatography using silica gel (230−400 mesh size) and
EtOAc : n-hexane as the eluent otherwise mentioned in reverse
phase silica using MeOH : H2O as eluent.
Scheme 5. Gram scale experiment
Conclusion
Characterization Data. 8-benzylquinoline (Table 2, Entry
3a)10g White solid, yield = 20 mg (46%). Mp = 51 – 53 ℃.
Purification by flash chromatography (3% 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), 7.69 (dd, J = 7.2, 2.4 Hz, 1H),
7.47 – 7.44 (m, 2H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.35 – 7.33
(m, 2H), 7.30 – 7.28 (m, 2H), 7.21 – 7.20 (m, 1H), 4.70 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 149.7, 146.9, 141.5,
140.3, 136.4, 129.6, 129.52, 129.51, 128.5, 126.5, 126.4, 126.0,
121.1, 36.9.
In summary, a catalytic method has been developed for the
synthesis of 8-benzyl quinolines via direct regio- and chemo-
selective C(sp3)-H arylation with bench stable aryl boronic
acids under cost effective Ru(II)-catalysis. This method
provides access to broad array of 8-benzyl quinolines in
moderate to good yields with easy recovery of the unreacted
starting material.
EXPERIMENTAL SECTION
8-(4-amylbenzyl)quinoline (Table 2, Entry 3b)10g Colourless
Reagent Information. All the reactions were performed under
inert atmosphere in the screw cap reaction vials unless
otherwise stated. All the solvents in sure-seal bottles and
chemicals were bought from TCI and Sigma-Aldrich whereas
silica gel (230-400 mesh) and C-18 reversed phase silica used
for column chromatography were procured from Merck. For
normal phase column chromatography, gradient elution using
ethyl acetate : n-hexane and for reversed phase column
chromatography. methanol : water was performed based on
Merck aluminium TLC sheets (silica gel 60F254 and 60 RP-18
F₂ ₅ ₄ s)
liquid, yield
= 17.3 mg (30%). Purification by flash
chromatography (2% 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), 7.69 – 7.68 (m, 1H), 7.46 – 7.43 (m, 2H), 7.41 (dd, J
= 8.4, 4.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 2H), 7.11 (d, J = 7.8 Hz,
2H), 4.67 (s, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.63 – 1.58 (m, 2H),
1.37 – 1.30 (m, 4H), 0.91 – 0.89 (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, 128.52, 128.50, 126.5, 126.3, 121.1, 36.5, 35.7,
31.7, 31.4, 22.7, 14.2.
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8-(4-(trimethylsilyl)benzyl)quinoline (Table 2, Entry 3c)10g
8-(4-(tert-butyl)benzyl)quinoline (Table 2, Entry 3i) White
solid, yield = 23.1 mg (42%). Mp = 83 – 85 ℃. Purification by
flash chromatography (3% EtOAc/n-hexane). H NMR (600
Yellow solid, yield = 30.2 mg (52%). Mp = 92 – 95 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.98 – 8.97 (m, 1H), 8.15 (dd,
J = 7.8, 1.8 Hz, 1H), 7.71 – 7.68 (m, 1H), 7.46 – 7.45 (m, 4H),
7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 2H), 4.70 (s,
2H), 0.25 (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, 129.0, 128.5,
126.5, 126.4, 121.1, 36.9, -0.91.
8-(4-bromobenzyl)quinoline (Table 2, Entry 3d)10g White solid,
yield = 20.8 mg (35%). Mp = 44 – 46 ℃. Purification by flash
chromatography (3% EtOAc/n-hexane). 1H 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), 7.47 – 7.43 (m, 2H),
7.41 (dd, J = 8.4, 4.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.20 (d,
J = 8.4 Hz, 2H), 4.63 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3,
δ): 149.7, 146.8, 140.6, 139.7, 136.4, 131.5, 131.2, 129.6,
128.6, 126.7, 126.5, 121.2, 119.8, 36.4.
1
MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.12 (dd, J =
8.4, 1.8 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.4 Hz,
1H), 7.40 (dd, J = 7.8, 4.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H),
7.24 – 7.22 (m, 2H), 4.84 (s, 2H), 1.26 (s, 9H). 13C{1H} NMR
(150 MHz, CDCl3, δ): 150.6, 148.5, 147.8, 137.7, 137.3, 136.2,
135.4, 128.6, 128.5, 127.2, 127.1, 125.1, 121.1, 34.4, 33.1, 31.5.
IR (ZnSe) νmax (cm−1) 2954, 2924, 2910, 2866, 1653, 1595,
1498, 800, 788. HRMS (ESI-TOF) (m/z) [M + H]+ calcd for
C20H22N 276.1747; found, 276.1751.
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8-(2-fluorobenzyl)quinoline (Table 2, Entry 3j)10g Colourless
liquid, yield
= 20.8 mg (44%). Purification by flash
chromatography (2% 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), 7.70 (dd, J = 7.2, 2.4 Hz, 1H), 7.46 – 7.44 (m, 2H),
7.41 (dd, J = 8.4 Hz, 4.2 Hz, 1H), 7.28 – 7.26 (m, 1H), 7.21 –
7.18 (m, 1H), 7.09 – 7.06 (m, 1H), 7.05 – 7.02 (m, 1H), 4.74 (s,
2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 161.47 (d, JCF
=
8-(4-methoxybenzyl)quinoline (Table 2, Entry 3e)10g Yellow
244.5 Hz), 149.6, 146.9, 138.8, 136.4, 131.90 (d, JCF = 4.5 Hz),
129.3, 128.5, 128.23 (d, JCF = 16.5 Hz), 127.85 (d, JCF = 7.5
Hz), 126.6, 126.5, 124.05 (d, JCF = 3.0 Hz), 121.1, 115.33 (d,
JCF = 21.0 Hz), 29.91 (d, JCF = 3.0 Hz).
liquid, yield
= 15.9 mg (32%). Purification by flash
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chromatography (7% EtOAc/n-hexane). H NMR (600 MHz,
CDCl3, δ): 9.01 – 8.99 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.69 –
7.67 (m, 1H), 7.46 (d, J = 6.0 Hz, 2H), 7.40 – 7.38 (m, 1H), 7.31
– 7.29 (m, 2H), 6.89 –7 6.8 (m, 2H), 4.69 (s, 2H), 3.78 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3, δ): 157.9, 149.5, 146.7,
140.6, 136.3, 133.4, 130.3, 129.3, 128.4, 126.4, 126.2, 121.0,
113.8, 55.2, 36.0.
8-(2-chlorobenzyl)quinoline (Table 2, Entry 3k) Yellow liquid,
yield = 10.1 mg (20%). Purification by flash chromatography
(2% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 8.98
(dd, J = 4.2, 1.8 Hz, 1H), 8.17 (dd, J = 7.8, 1.8 Hz, 1H), 7.71 (d,
J = 8.4 Hz, 1H), 7.45 – 7.41 (m, 3H), 7.32 (d, J = 7.2 Hz, 1H),
7.21 – 7.14 (m, 3H), 4.82 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 149.7, 146.9, 138.9, 138.5, 136.5, 134.7, 131.7,
129.6, 129.2, 128.5, 127.7, 126.9, 126.6, 126.5, 121.2, 34.5. IR
(ZnSe) νmax (cm−1) : 2953, 2922, 2850, 1653, 1595, 1496, 806,
788, 742. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for
C16H13ClN 254.0731; found, 254.0731.
8-([1,1'-biphenyl]-4-ylmethyl)quinoline (Table 2, Entry 3f)
White solid, yield = 20.6 mg (35%). Mp = 90 – 92 ℃.
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Purification by reverse silica C-18 (80% MeOH/H2O). H NMR
(600 MHz, CDCl3, δ): 9.01 – 8.99 (m, 1H), 8.17 (dd, J = 8.4,
1.8 Hz, 1H), 7.72 (dd, J = 7.8, 1.8 Hz, 1H), 7.60 – 7.57 (m, 2H),
7.54 – 7.46 (m, 4H), 7.44 – 7.40 (m, 5H), 7.34 – 7.31 (m, 1H),
4.75 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.7, 146.9,
141.3, 140.7, 140.2, 138.9, 136.4, 129.9, 129.7, 128.8, 128.6,
127.2, 127.14, 127.10, 126.6, 126.5, 121.2, 36.6. IR (ZnSe) νmax
(cm−1) 2960, 2922, 1689, 1494, 1485, 1469, 806, 792, 758.
HRMS (ESI-TOF) (m/z) [M + H]+ calcd for C22H18N 296.1434;
found, 296.1444.
8-(3,5-dimethylbenzyl)quinoline (Table 2, Entry 3l)10g White
solid, yield = 11.8 mg (24%). Mp = 81 – 84 ℃. Purification by
flash chromatography (3% 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), 7.70 – 7.68 (m, 1H), 7.46 – 7.42 (m, 2H), 7.42
– 7.40 (m, 1H), 6.94 (s, 2H), 6.84 (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, 21.4.
8-(4-nitrobenzyl)quinoline (Table 2, Entry 3g)10g Brown solid,
yield = 12.1 mg (23%). Mp = 84 – 86 ℃. Purification by flash
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chromatography (7% EtOAc/n-hexane). H 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), 8.10 – 8.08 (m, 2H), 7.75 – 7.74 (m, 1H), 7.51 – 7.45
(m, 4H), 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, 123.6, 121.4, 37.1.
8-(4-(trifluoromethyl)benzyl)quinoline (Table 2, Entry 3h)10g
White solid, yield = 24.1 mg (42%). Mp = 52 – 55 ℃.
Purification by flash chromatography (3% 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), 7.73 (dd, J = 6.6, 3.0 Hz, 1H),
7.52 (d, J = 8.4 Hz, 2H), 7.49 – 7.45 (m, 2H), 7.43 – 7.41 (m,
3H), 4.73 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.8,
146.7, 145.8, 139.2, 136.5, 129.7, 129.6, 128.6, 128.30 (q, JCF
= 31.5 Hz), 126.9, 126.5, 125.34 (q, JCF = 3.0 Hz), 124.54 (q,
JCF = 270 Hz), 121.3, 36.9.
8-(3,5-bis(trifluoromethyl)benzyl)quinoline (Table 2, Entry
3m)10g White solid, yield = 14.2 mg (20%). Mp = 49 – 50 ℃.
Purification by flash chromatography (5% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8 Hz, 1H),
8.18 – 8.16 (m, 1H), 7.82 (s, 2H), 7.77 – 7.75 (m, 1H), 7.68 (s,
1H), 7.53 – 7.49 (m, 2H), 7.43 (dd, J = 7.8 Hz, 4.2 Hz, 1H),
4.76 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.9, 146.6,
144.2, 138.2, 136.5, 131.46 (q, JCF = 33.0 Hz), 129.7, 129.52
(q, JCF = 4.5 Hz), 128.8, 127.4, 126.6, 123.61 (q, JCF = 271.5
Hz), 121.5, 120.15 – 120.04 (m), 37.1.
8-benzyl-7-chloroquinoline (Table 2, Entry 3n)10g White solid,
yield = 21.2 mg (42%). Mp = 65 – 68 ℃. Purification by flash
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chromatography (2% EtOAc/n-hexane). H NMR (600 MHz,
CDCl3, δ): 8.99 (d, J = 3.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H),
7.66 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.41 (dd, J =
8.4, 4.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.22 – 7.20 (m, 2H),
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7.14 – 7.12 (m, 1H), 4.89 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 150.5, 147.5, 140.3, 137.3, 136.5, 135.7, 129.0,
128.6, 128.2, 127.3, 127.2, 126.0, 121.1, 33.6.
127.7, 127.3, 125.16 (q, JCF = 3.0 Hz), 124.52 (q, JCF = 270.0
Hz), 121.3, 33.5. IR (ZnSe) νmax (cm−1) 2924, 1606, 1490, 1417,
1321, 1311, 1159, 1109, 1064, 1019, 933. HRMS (ESI-TOF)
(m/z) [M + H]+ calcd for C17H12ClF3N 322.0605; found,
322.0581.
7-chloro-8-(4-amylbenzyl)quinoline (Table 2, Entry 3o)10g
Yellow solid, yield = 18.0 mg (28%). Mp = 40 – 42 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8 Hz, 1H),
8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (d,
J = 9.0 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 1H), 7.24 (d, J = 7.8
Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 4.84 (s, 2H), 2.51 (t, J = 7.8
Hz, 2H), 1.57 – 1.54 (m, 2H), 1.31 – 1.27 (m, 4H), 0.88 – 0.85
(m, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.6, 147.7,
140.4, 137.7, 137.5, 136.2, 135.4, 128.8, 128.5, 128.3, 127.2,
127.1, 121.1, 35.7, 33.2, 31.7, 31.3, 22.7, 14.2.
4-((7-chloroquinolin-8-yl)methyl)phenyl acetate (Table 2,
Entry 3u)10g Yellow solid, yield = 27.3 mg (44%). Mp = 155 –
156 ℃. Purification by flash chromatography (10% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.96 (dd, J = 4.2, 1.8
Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.82 – 7.79 (m, 2H),
7.68 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.42 (dd, J =
8.4, 4.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 4.91 (s, 2H), 2.52 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 198.0, 150.7, 147.6,
146.2, 136.5, 136.3, 135.6, 135.1, 129.2, 128.4, 128.4, 127.6,
127.2, 121.3, 33.7, 26.6.
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7-chloro-8-(4-methoxybenzyl)quinoline (Table 2, Entry 3p)10g
Pale yellow solid, yield = 21.5 mg (38%). Mp = 78 – 80 ℃.
Purification by flash chromatography (6% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.99 (dd, J = 4.2, 1.8 Hz, 1H),
8.10 (dd, J = 8.4, 1.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.53 (d,
J = 9.0 Hz, 1H), 7.39 (dd, J = 7.8, 4.2 Hz, 1H), 7.32 – 7.29 (m,
2H), 6.80 – 6.77 (m, 2H), 4.82 (s, 2H), 3.74 (s, 3H).13C{1H}
NMR (150 MHz, CDCl3, δ): 157.8, 150.6, 147.7 137.8, 136.3,
135.3, 132.5, 130.0, 128.5, 127.2, 127.1, 121.1, 113.7, 55.3,
32.7.
7-chloro-8-(2-fluorobenzyl)quinoline (Table 2, Entry 3v)10g
White sticky, yield = 11.9 mg (22%). Purification by flash
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chromatography (3% EtOAc/n-hexane). H NMR (600 MHz,
CDCl3, δ): 8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.16 (dd, J = 8.4, 1.8
Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42
(dd, J = 8.4, 4.2 Hz, 1H), 7.13 – 7.10 (m, 1H), 7.07 – 7.04 (m,
1H), 6.86 – 6.84 (m, 1H), 6.70 – 6.67 (m, 1H), 4.89 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 161.13 (d, JCF = 243.0
Hz), 150.8, 147.9, 136.3, 136.0, 136.0, 129.74 (d, JCF = 3.0 Hz),
128.4, 127.6, 127.38 (d, JCF = 7.5 Hz), 127.1, 127.06 (d, JCF =
15.0 Hz), 123.80 (d, JCF = 3.0 Hz), 121.3, 115.06 (d, JCF = 22.5
Hz), 26.38 (d, JCF = 4.5 Hz).
7-chloro-8-(3,5-dimethylbenzyl)quinoline (Table 2, Entry
3w)10g White solid, yield = 17.9 mg (32%). Mp = 76 – 78 ℃.
Purification by flash chromatography (3% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.99 – 8.98 (m, 1H), 8.13 – 8.12
(m, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.40
(dd, J = 8.4, 4.2 Hz, 1H), 6.92 (s, 2H), 6.78 (s, 1H), 4.80 (s, 2H),
2.22 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.6, 147.8,
140.1, 137.6, 137.5, 136.2, 135.6, 128.5, 127.7, 127.2, 127.1,
126.7, 121.1, 33.4, 21.5.
8-(4-bromobenzyl)-7-chloroquinoline (Table 2, Entry 3q)10g
White solid, yield = 21.1 mg (32%). Mp = 99 – 101 ℃.
Purification by flash chromatography (3% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.97 (d, J = 4.2 Hz, 1H), 8.12
(d, J = 7.8 Hz, 1H), 7.65 (dd, J = 9.0, 1.8 Hz, 1H), 7.54 (d, J =
8.4 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.22
(d, J = 8.4 Hz, 2H), 4.81 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 150.7, 147.5, 139.4, 136.8, 136.3, 135.4, 131.2,
130.8, 128.4, 127.5, 127.2, 121.2, 119.7, 33.1.
7-chloro-8-(4-methylbenzyl)quinoline (Table 2, Entry 3r)10g
Yellow solid, yield = 24.0 mg (45%). Mp = 72 – 75 ℃.
Purification by flash chromatography (2% 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), 7.64 (d, J = 9.0 Hz, 1H), 7.54 (d,
J = 8.4 Hz, 1H), 7.40 (dd, J = 7.8, 4.2 Hz, 1H), 7.24 (d, J = 7.8
Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 4.84 (s, 2H), 2.27 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3, δ): 150.6, 147.7, 137.7,
137.3, 136.2, 135.4, 135.3, 128.9, 128.9, 128.5, 127.2, 127.1,
121.1, 33.2, 21.1.
8-(3,5-bis(trifluoromethyl)benzyl)-7 chloroquinoline (Table 2,
Entry 3x)10g White solid, yield = 12.4 mg (16%). Mp = 124 –
127 ℃. Purification by flash chromatography (3% EtOAc/n-
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hexane). H NMR (600 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8
Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (d, J = 9.0
Hz, 1H), 7.65 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.45 (dd, J =
8.4, 4.2 Hz, 1H), 4.95 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3,
δ): 150.9, 147.3, 142.9, 136.5, 135.5, 135.4, 131.31 (q, JCF =
33.0 Hz), 129.43 (q, JCF = 3.0 Hz), 128.4, 128.1, 127.3, 123.60
(q, JCF = 271.5 Hz), 121.5, 120.2 – 120.1 (m), 33.4.
7-chloro-8-(4-nitrobenzyl)quinoline (Table 2, Entry 3s)10g Pale
yellow solid, yield = 29.8 mg (50%). Mp = 110 – 112 ℃.
Purification by flash chromatography (6% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.97 – 8.96 (m, 1H), 8.17 (dd,
J = 7.8, 1.8 Hz, 1H), 8.07 – 8.05 (m, 2H), 7.72 (d, J = 9.0 Hz,
1H), 7.57 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 9.6 Hz, 2H), 7.46 –
7.44 (m, 1H), 4.95 (s, 2H) 13C{1H} NMR (150 MHz, CDCl3, δ):
150.9, 148.3, 147.4, 146.4, 136.5, 135.8, 135.6, 129.8, 128.4,
128.0 127.3, 123.5, 121.5, 33.7
7-chloro-8-(4-(trifluoromethyl)benzyl)quinoline (Table 2,
Entry 3t) Brown crystalline solid, yield = 33.3 mg (52%). Mp =
66 – 68 ℃. Purification by flash chromatography (3% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.97 (dd, J = 4.2, 1.8
Hz, 1H), 8.15 (dd, J = 8.4, 1.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H),
7.56 (d, J = 9.0 Hz, 1H), 7.46 – 7.42 (m, 5H), 4.91 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 150.8, 147.6, 144.5,
136.5, 136.4, 135.5, 129.3, 128.4, 128.21 (q, JCF = 31.5 Hz),
N-(3-((7-chloroquinolin-8-yl)methyl)phenyl)acetamide (Table
2, Entry 3y) Brown solid, yield = 18.6 mg (30%). Mp = 130 –
132 ℃. Purification by flash chromatography (25% EtOAc/n-
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hexane). H NMR (600 MHz, CDCl3, δ): 8.98 (dd, J = 4.2, 1.8
Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.54
(d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.8,
4.2 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 7.17 – 7.14 (m, 1H), 7.09
(br s, 1H, NH), 7.06 (d, J = 7.8 Hz, 1H), 4.83 (s, 2H), 2.08 (s,
3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 168.3, 150.7, 147.6,
141.2, 137.9, 137.1, 136.3, 135.6, 128.9, 128.5, 127.4, 127.2,
125.0, 121.2, 120.1, 117.7, 33.5, 24.7. IR (ZnSe) νmax (cm−1):
3288, 3253, 2922, 2852, 1653, 1589, 1489, 800 785. HRMS
(ESI-TOF) (m/z): [M + Na]+ calcd for C18H15ClN2NaO
333.0765; found, 333.0764.
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1-(3-((7-chloroquinolin-8-yl)methyl)phenyl)ethanone (Table 2,
7-bromo-8-(4-amylbenzyl)quinoline (Table 2, Entry 3ze)
Entry 3z)10g White solid, yield = 25.9 mg (44%). Mp = 86 – 88
℃. Purification by flash chromatography (10% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.99 – 8.97 (m, 1H),
8.14 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H),
7.68 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.50 (d, J =
7.8 Hz, 1H), 7.43 – 7.41 (m, 1H), 7.29 – 7.26 (m, 1H), 4.91 (s,
2H), 2.53 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 198.5,
150.7, 147.6, 141.0, 137.2, 136.8, 136.4, 135.5, 133.8, 129.2,
128.5, 127.6, 127.3, 126.1, 121.3, 33.5, 26.8.
Yellow liquid, yield = 29.3 mg (40%). Purification by flash
chromatography (2% EtOAc/n-hexane). 1H NMR (600 MHz,
CDCl3, δ): 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.12 (dd, J = 8.4, 1.8
Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.41
(dd, J = 8.4, 4.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.01 (d, J =
7.8 Hz, 2H), 4.87 (s, 2H), 2.50 (t, J = 7.8 Hz, 2H), 1.56-1.54 (m,
2H), 1.31 – 1.27 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 150.6, 147.9, 140.4, 139.8, 137.3,
136.3, 131.4, 128.8, 128.3, 127.6, 127.3, 126.5, 121.3, 35.9,
35.7, 31.7, 31.3, 22.7, 14.2. IR (ZnSe) νmax (cm−1): 2956, 2924,
2850, 1653, 1602, 1589, 1558, 1485, 1361, 1121, 921, 837, 796.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C21H23BrN
368.1008; found, 368.1012.
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7-bromo-8-(4-methoxybenzyl)quinoline (Table 2, Entry 3za)
Yellow liquid, yield = 20.9 mg (32%). Purification by flash
chromatography (10% EtOAc/n-hexane). 1H NMR (600 MHz,
CDCl3, δ): 8.97 (dd, J = 4.2, 1.8 Hz, 1H), 8.10 (dd, J = 8.4, 1.8
Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40
(dd, J = 7.8, 4.2 Hz, 1H), 7.30 – 7.27 (m, 2H), 6.79 – 6.76 (m,
2H), 4.86 (s, 2H), 3.74 (s, 3H). 13C{1H} NMR (150 MHz,
CDCl3, δ): 157.8, 150.5, 147.7, 139.8, 136.3, 132.3, 131.3,
130.0, 127.6, 127.3, 126.3, 121.2, 113.6, 55.2, 35.4. IR (ZnSe)
νmax (cm−1): 3032, 2964, 2922, 1653. 1600, 1581, 1487, 798,
785. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H15BrNO
328.0332; found, 328.0342.
8-(benzo[d][1,3]dioxol-5-ylmethyl)-7-chloroquinoline (Table
2, Entry 3zg)10g Yellow solid, yield = 11.8 mg (20%). Mp = 84
– 87 ℃. Purification by 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), 7.64 (d, J = 8.4 Hz, 1H),
7.53 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 4.2 Hz, 1H), 6.86 –
6.83 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 5.85 (s, 2H), 4.78 (s,
2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.6, 147.6, 147.4,
145.7, 137.5, 136.3, 135.4, 134.2, 128.5, 127.2, 127.2, 122.0,
121.1, 109.7, 108.0, 100.8, 33.18.
7-bromo-8-(4-(trifluoromethyl)benzyl)quinoline (Table 2,
Entry 3zb) White crystalline, yield = 29.2 mg (40%). Mp = 72
– 74 ℃. Purification by flash chromatography (2% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8
Hz, 1H), 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H),
7.62 (d, J = 8.4 Hz, 1H), 7.47 – 7.41 (m, 5H), 4.96 (s, 2H).
13C{1H} NMR (150 MHz, CDCl3, δ): 150.7, 147.7, 144.4,
138.5, 136.4, 131.3, 129.3, 128.20 (q, JCF = 33.0 Hz), 127.9,
127.6, 126.6, 125.15 (q, JCF = 4.5 Hz), 124.53 (q, JCF = 271.5
Hz), 121.5, 36.2. IR (ZnSe) νmax (cm−1) 3010, 2924, 1612, 1593,
1588, 1489, 1427, 1315, 1163, 1064, 1056, 827, 792. HRMS
(ESI-TOF) (m/z) [M + H]+ calcd for C17H12BrF3N 366.0100;
found, 366.0103.
7-bromo-8-(4-bromobenzyl)quinoline (Table 2, Entry 3zc)
White crystalline solid, yield = 37.7 mg (50%). Mp = 93 – 95
℃. Purification by flash chromatography (80% MeOH/H2O).
1H NMR (600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8 Hz, 1H),
8.13 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.60 (d,
J = 8.4 Hz, 1H), 7.43 (dd, J = 8.4, 4.2 Hz, 1H), 7.32 – 7.30 (m,
2H), 7.19 – 7.18 (m, 2H), 4.84 (s, 2H). 13C{1H} NMR (150
MHz, CDCl3, δ): 150.6, 147.62, 139.2, 138.9, 136.5, 131.4,
131.3, 130.8, 127.7, 127.6, 126.5, 121.4, 119.7, 35.8. IR (ZnSe)
νmax (cm−1) 2924, 2864, 1589, 1485, 1099, 1047, 1010, 800, 786.
HRMS (ESI-TOF) (m/z) [M + H]+ calcd for C16H12Br2N
375.9331; found, 375.9334.
7-bromo-8-(4-(trimethylsilyl)benzyl)quinoline (Table 2, Entry
3zd) Yellow solid, yield = 31.1 mg (42%). Mp = 74 – 76 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8 Hz, 1H),
8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (d,
J = 9.0 Hz, 1H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.37 (d, J = 7.8
Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 4.91 (s, 2H), 0.20 (s, 9H).
13C{1H} NMR (150 MHz, CDCl3, δ): 150.6, 147.9, 140.9,
139.4, 137.4, 136.3, 133.3, 131.3, 128.4, 127.6, 127.4, 126.5,
121.3, 36.3, -0.9. IR (ZnSe) νmax (cm−1) 3064, 3012, 2951, 1653,
1521, 1485, 1396, 1247, 1109, 837, 823, 800, 788, 750, 729.
HRMS (ESI-TOF) (m/z) [M + H]+ calcd for C19H21BrNSi
370.0621; found, 370.0621.
8-(4-chlorobenzyl)quinoline (Table 2, Entry 3zh)10g White
solid, yield = 20.2 mg (40%). Mp = 51 – 53 ℃. Purification by
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flash chromatography (2% EtOAc/n-hexane). H NMR (600
MHz, CDCl3, δ): 8.96 (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), 7.47 – 7.44 (m,
2H), 7.42 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 – 7.22 (m, 4H), 4.65
(s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 149.7, 146.8,
140.1, 139.8, 136.4, 131.8, 130.7, 129.6, 128.6, 128.5, 126.7,
126.5, 121.2, 36.4.
7-chloro-8-(4-chlorobenzyl)quinoline (Table 2, Entry 3zi)10g
White solid, yield = 15.8 mg (55%). Mp = 80 – 82 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.98 – 8.97 (m, 1H), 8.14 (d, J
= 7.8 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H),
7.43 – 7.41 (m, 1H), 7.27 (d, J = 6.6 Hz, 2H), 7.17 (d, J = 7.8
Hz, 2H), 4.82 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ):
150.7, 147.6, 138.9, 137.0, 136.3, 135.4, 131.6, 130.4, 128.5,
128.3, 127.5, 127.2, 121.3, 33.0.
7-bromo-8-(4-chlorobenzyl)quinoline (Table 2, Entry 3zj)
Yellow liquid, yield = 33.2 mg (50%). Mp = 80 – 82 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.98 – 8.97 (m, 1H), 8.15 (d, J
= 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H),
7.46 – 7.45 (m, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.2
Hz, 2H), 4.88 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3, δ):
150.7, 147.7, 139.0, 138.7, 136.4, 131.6, 131.3, 130.4, 128.3,
127.7, 127.6, 126.5, 121.4, 35.7. IR (ZnSe) νmax (cm−1) 2958,
2922, 2852, 1656, 1593, 1487, 1087, 1014, 829, 802. HRMS
(ESI-TOF) (m/z) [M + H]+ calcd for C16H12BrClN 331.9836;
found, 331.9837.
8-(4-chlorobenzyl)-7-methoxyquinoline (Table 2, Entry 3zk)
Brown solid, yield = 9.0 mg (16%). Mp = 99 – 101 ℃.
Purification by flash chromatography (10% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.92 (dd, J = 4.2, 1.8 Hz, 1H),
8.09 – 8.07 (m, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 9.0
Hz, 1H), 7.29 – 7.25 (m, 3H), 7.14 – 7.12 (m, 2H), 4.64 (s, 2H),
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3.95 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3, δ): 157.5, 150.6,
145.0, 143.7, 140.3, 139.8, 135.9, 131.6, 131.5, 130.7, 128.6,
147.6, 140.8, 136.2, 131.1, 130.4, 128.1, 127.5, 124.7, 123.8,
119.0, 113.9, 56.5, 29.1. IR (ZnSe) νmax (cm−1) 2995, 2958,
2924, 2837, 1612, 1595, 1570, 1502, 1487, 1259, 1082, 823.
HRMS (ESI-TOF) (m/z) [M + Na]+ calcd for C17H14ClNaNO
306.0656; found, 306.0656.
128.5, 122.1, 121.6, 36.6, 22.1, 19.1. IR (ZnSe) νmax (cm−1)
2927, 2850, 1653, 1589, 1570, 1489, 1433, 1085, 1016, 866.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H17ClN
282.1044; found, 282.1045.
8-(4-chlorobenzyl)-5-methylquinoline (Table 2, Entry 3zs)
Brown crystalline solid, yield = 24.0 mg (45%). Mp = 60 – 62
℃. Purification by flash chromatography (2% EtOAc/n-
8-(4-chlorobenzyl)-7-methylquinoline (Table 2, Entry 3zl)
Yellow liquid, yield = 17.1 mg (32%). Purification by flash
chromatography (2% EtOAc/n-hexane). 1H NMR (600 MHz,
CDCl3, δ): 8.93 (dd, J = 4.2, 1.8 Hz, 1H), 8.13 (dd, J = 7.8, 1.8
Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.36
(dd, J = 8.4, 4.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.06 (d, J =
8.4 Hz, 2H), 4.75 (s, 2H), 2.44 (s, 3H). 13C{1H} NMR (150
MHz, CDCl3, δ): 149.9, 147.3, 139.7, 138.2, 136.3, 136.2,
131.3, 130.1, 129.9, 128.4, 126.9, 126.2, 120.3, 32.1, 20.6. IR
(ZnSe) νmax (cm−1) 2947, 2924, 2858, 2837, 1614, 1598, 1570,
1502, 1489, 1454, 108, 1014, 827, 796, 788. HRMS (ESI-TOF)
(m/z) [M + H]+ calcd for C17H15ClN 268.0888; found, 268.0886.
8-(4-chlorobenzyl)-7-(trifluoromethyl)quinoline (Table 2,
Entry 3zm) Yellow solid, yield = 31.4 mg (49%). Mp = 48 – 50
℃. Purification by reverse silica C-18 (80% MeOH/H2O). 1H
NMR (600 MHz, CDCl3, δ): 8.99 – 8.97 (m, 1H), 8.20 (d, J =
8.4 Hz, 1H), 7.88 – 7.82 (m, 2H), 7.51 – 7.49 (m, 1H), 7.13 (d,
J = 7.8 Hz, 2H), 7.00 (d, J = 7.8 Hz, 2H), 4.91 (s, 2H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 151.0, 147.0, 139.7, 139.1, 136.3,
131.4, 129.82, 129.6, 128.88 (q, JCF = 16.5 Hz), 128.2, 127.5,
124.60 (q, JCF = 273.0 Hz), 123.05 – 122.9 (m), 122.92, 32.3.
19F NMR (565 MHz, CDCl3) δ 58.28 IR (ZnSe) νmax (cm−1):
2951, 2924, 2852, 1653, 1602, 1489, 1319, 1300, 1107, 837,
798. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H22ClF3N
322.0605; found, 322.0601.
8-(4-chlorobenzyl)-3-methylquinoline (Table 2, Entry 3zp)
Yellow solid, yield = 26.7 mg (50%). Mp = 70 – 72 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.80 (s, 1H), 7.91 (s, 1H), 7.63
(d, J = 8.4 Hz, 1H), 7.43 – 7.40 (m, 1H), 7.36 (d, J = 7.2 Hz,
1H), 7.26 – 7.21 (m, 4H), 4.62 (s, 2H), 2.52 (s, 3H). 13C{1H}
NMR (150 MHz, CDCl3, δ): 151.7, 145.0, 140.1, 139.4, 135.1,
131.7, 130.7, 130.6, 128.6, 128.5, 128.4, 126.6, 126.1, 36.4,
18.8. IR (ZnSe) νmax (cm−1) 2923, 2852, 1602, 1485, 1467,
1435, 1411, 812, 771. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd
for C17H14ClNaN 290.0707; found, 290.0706.
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hexane). H NMR (600 MHz, CDCl3, δ): 8.95 (dd, J = 4.2, 1.8
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Hz, 1H), 8.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.45 – 7.43 (m, 1H),
7.23 (dd, J = 22.2, 7.2 Hz, 2H), 7.25 – 7.21 (m, 4H), 4.61 (s,
2H), 2.66 (s, 3H) 13C{1H} NMR (150 MHz, CDCl3, δ): 149.2,
147.0, 140.3, 137.7, 133.2, 132.8, 131.6, 130.7, 129.2, 128.5,
127.9, 126.9, 120.8, 36.6, 18.7. IR (ZnSe) νmax (cm−1): 3032,
2964, 2927, 2845, 1653, 1598, 1489, 1471, 1082, 1014, 800,
785. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H15ClN
268.0888; found, 268.0887.
8-(4-chlorobenzyl)-5-nitroquinoline (Table 2, Entry 3zt)
Yellow crystalline solid, yield = 17.9 mg (30%). Mp = 88 – 90
℃. Purification by flash chromatography (2% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 9.06 – 9.03 (m, 2H),
8.29 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 9.0, 4.2 Hz, 1H), 7.52 (d,
J = 7.8 Hz, 1H), 7.26 – 7.23 (m, 4H), 4.70 (s, 2H) 13C{1H} NMR
(150 MHz, CDCl3, δ): 150.7, 148.1, 146.3, 138.4, 132.44,
132.38, 130.8, 128.9, 127.5, 124.7, 124.0, 121.5, 37.1. IR
(ZnSe) νmax (cm−1) 2920, 2850, 1595, 1514, 1492, 1400, 1336,
1089, 1014, 769, 788. HRMS (ESI-TOF) (m/z): [M + H]+ calcd
for C16H12ClN2O2 299.0582; found, 299.0597.
5-bromo-8-(4-chlorobenzyl)quinoline (Table 2, Entry 3zu)
White crystalline solid, yield = 37.2 mg (56%). Mp = 76 – 78
℃. Purification by flash chromatography (2% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.96 (dd, J = 4.2, 1.8
Hz, 1H), 8.55 (dd, J = 8.4, 1.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H),
7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.23 (t,
J = 9.6 Hz, 4H), 4.59 (s, 2H) 13C{1H} NMR (150 MHz, CDCl3,
δ): 150.3, 147.4, 140.0, 139.5, 135.9, 132.0, 130.7, 130.3,
129.9, 128.6, 127.8, 122.4, 120.3, 36.3. IR (ZnSe) νmax (cm−1)
3035, 2927, 2852, 1656, 1591, 1558, 1489, 1031, 1014, 800,
786. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H12BrClN
331.9836; found, 331.9836.
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6-bromo-8-(4-chlorobenzyl)quinoline (Table 2, Entry 3zv)
White crystalline solid, yield = 38.5 mg (58%). Mp = 84 – 86
℃. Purification by flash chromatography (2% EtOAc/n-
8-(4-chlorobenzyl)-4-methylquinoline (Table 2, Entry 3zq)
Yellow crystalline solid, yield = 18.7 mg (35%). Mp = 67 – 69
℃. Purification by flash chromatography (2% EtOAc/n-
hexane). 1H NMR (600 MHz, CDCl3, δ): 8.81 (d, J = 4.2 Hz,
1H), 7.90 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.42 (d,
J = 7.2 Hz, 1H), 7.26 – 7.21 (m, 5H), 4.65 (s, 2H), 2.71 (s, 3H)
13C{1H} NMR (150 MHz, CDCl3, δ): 149.4, 146.4, 140.22,
140.17, 137.9, 131.7, 130.7, 129.3, 128.6, 128.5, 126.2, 122.6,
122.1, 36.7, 19.1. IR (ZnSe) νmax (cm−1): 3037, 2954, 2922,
2852, 1653, 1600, 1489, 1082, 1010, 839, 758. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C17H15ClN 268.0888; found,
268.0887.
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hexane). H NMR (600 MHz, CDCl3, δ): 8.95 – 8.94 (m, 1H),
8.05 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.43 (dd, J
= 7.8, 4.2 Hz, 2H), 7.25 (s, 4H), 4.59 (s, 2H) 13C{1H} NMR
(150 MHz, CDCl3, δ): 150.0, 145.4, 142.2, 139.1, 135.4, 132.8,
132.1, 130.7, 129.7, 128.7, 128.6, 122.1, 120.5, 36.1. IR (ZnSe)
νmax (cm−1) 2939, 2924, 2854, 1656, 1587, 1558, 1483, 1429,
1359, 1089, 1016, 864, 846, 810, 785. HRMS (ESI-TOF) (m/z):
[M + Na]+ calcd for C16H11BrClNaN 353.9656; found,
353.2714.
(E)-8-(4-chlorobenzyl)-6-styrylquinoline (Table 2, Entry 3zw)
White solid, yield = 28.4 mg (32%). Mp = 140 – 142 ℃.
Purification by flash chromatography (2% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 8.89 (dd, J = 4.2, 1.8 Hz, 1H),
8.13 (dd, J = 7.8, 1.8 Hz, 1H), 7.73 – 7.70 (m, 2H), 7.55 (d, J =
7.2 Hz, 2H), 7.41 – 7.37 (m, 3H), 7.30 – 7.25 (m, 5H), 7.23 –
7.16 (m, 2H), 4.66 (s, 2H) 13C{1H} NMR (150 MHz, CDCl3, δ):
149.5, 146.6, 139.9, 137.1, 136.3, 135.4, 131.8, 130.7, 130.2,
8-(4-chlorobenzyl)-4,6-dimethylquinoline (Table 2, Entry 3zr)
Yellow crystalline solid, yield = 21.4 mg (38%). Mp = 80 – 82
℃. Purification by flash chromatography y (2% EtOAc/n-
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1H), 7.65 (s, 1H), 7.26 – 7.20 (m, 6H), 4.61 (s, 2H), 2.68 (s,
3H), 2.49 (s, 3H) 13C{1H} NMR (150 MHz, CDCl3, δ): 148.5,
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129.0, 128.9, 128.6, 128.96, 128.89, 127.6, 126.8, 124.7, 121.7,
yield = 35.3 mg (75%). Purification by flash chromatography
36.5. IR (ZnSe) νmax (cm−1) 3026, 2964, 2821, 1510, 1489,
1375, 1226, 1217, 1043, 9568, 889, 806. HRMS (ESI-TOF)
(m/z): [M + Na]+ calcd for C24H18ClNNa 378.1020; found,
378.1019.
(100% EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 8.43
(d, J = 6.0 Hz, 1H), 7.71 (dd, J = 17.4, 7.8 Hz, 2H), 7.50 (t, J =
7.8 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.28 – 7.26 (m, 2H), 7.22
– 7.20 (m, 3H), 7.17 (t, J = 7.2 Hz, 1H), 5.08 (s, 2H) 13C{1H}
NMR (150 MHz, CDCl3, δ): 142.0, 140.8, 138.0, 135.7, 134.3,
132.8, 129.1, 128.5, 128.3, 127.8, 127.1, 125.9, 120.8, 41.9. IR
(ZnSe) νmax (cm−1) 3059, 3024, 2922, 1653, 1600, 1570, 1558,
1492, 1421, 1382, 1300, 1270750, 696. HRMS (ESI-TOF)
(m/z): [M + Na]+ calcd for C16H13NNaO 258.0889; found,
258.0887.
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General procedure for the synthesis of 1a-d3: To a 10 mL
reaction vial- [Cl2RhCp*]2 (2.5 mol%) Cu(OAc)2 (2.0 equiv.) &
AcOD (1.0 equiv.), 8-methylquinoline (0.1 mmol), D2O were
added and stirred at 100 °C for 20 h. The crude mixture was
extracted with EtOAc and purified using flash chromatography,
silica gel (230−400 mesh size) and EtOAc : n-hexane as eluent.
Product with 92% deuteration on the benzylic C(sp3)-H of 8-
methyl quinoline was obtained.
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General procedure for the synthesis of 8-((3,5-
bis(trifluoromethyl)phenyl)(phenyl)methyl)quinoline (Scheme
4, entry 4d):10g To a 10 mL reaction vial- 8-benzyl quinoline
(0.2 mmol), 3,5-bis(trifluoromethyl)phenyl boronic acid (3.0
equiv.), [Cp*RhCl2]2 (5 mol%), Tf2O (10 mol%) were added in
DCE (1.0 mL) with stirring at 100 °C for 24h. The arylated
product was purified using flash chromatography, silica gel
(230−400 mesh size), (2% EtOAc/n-hexane) as eluent. Yellow
General procedure for the synthesis of 8-benzyl-1,2,3,4-
tetrahydroquinoline (Scheme 4, entry 4a):14a To a 10 mL
reaction vial- 8-benzyl quinoline (0.2 mmol) NiCl2.6H2O (10
mol%) in MeOH (1.0 mL), followed by the addition of NaBH4
(40 equiv.) in portions with stirring at 0 °C for 0.5 h. The stirring
was continued further for another 2h. The crude mixture was
filtered through the celite pad and filterate was purified using
flash chromatography, silica gel (230−400 mesh size), (2%
EtOAc/n-hexane) as eluent. White solid, yield = 38 mg (85%).
Mp = 55 – 57 ℃. Purification by flash chromatography (2%
EtOAc/n-hexane). 1H NMR (600 MHz, CDCl3, δ): 7.33 – 7.30
(m, 2H), 7.27 – 7.20 (m, 3H), 6.93 (d, J = 7.2 Hz, 1H), 6.87 (d,
J = 7.2 Hz, 1H), 6.65 – 6.62 (m, 1H), 3.84 (s, 2H), 3.62 (s, 1H),
3.25 (t, J = 5.4 Hz, 2H), 2.82 – 2.80 (m, 2H), 1.93 – 1.90 (m,
2H) 13C{1H} NMR (150 MHz, CDCl3, δ): 142.8, 139.6, 129.7,
128.7, 128.74, 128.70, 128.5, 128.2, 126.4, 124.0, 121.8, 116.6,
42.4, 37.8, 27.5, 22.1. IR (ZnSe) νmax (cm−1) 2924, 2835, 1597,
1492, 1475, 1444, 1431, 1375, 1315, 1265, 765, 734, 698.
HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C16H18N 224.1434;
found, 224.1433.
General procedure for the synthesis of (S)-N-(phenyl(quinolin-
8-yl)methyl)benzamide (Scheme 4, entry 4b):14c To a 10 mL
reaction vial- 8-benzyl quinoline (0.2 mmol), dioxazolone (1.2
equiv.), [Cp*RhCl2]2 (4 mol%), AgSbF6 (16 mol%), H2-BHTL
(8 mol%) were added in DCM (1.0 mL) with stirring at 80 °C
for 5 h. The product was purified using flash chromatography,
silica gel (230−400 mesh size), (2% EtOAc/n-hexane) as eluent.
White solid, yield = 26.4 mg (39%). Mp = 185 – 187 ℃.
Purification by flash chromatography (8% EtOAc/n-hexane).
1H NMR (600 MHz, CDCl3, δ): 10.03 (d, J = 9.0 Hz, 1H), 8.91
(dd, J = 4.2, 1.2 Hz, 1H), 8.21 (dd, J = 8.4, 1.2 Hz, 1H), 7.89
(d, J = 7.2 Hz, 2H), 7.87 (d, J = 7.2 Hz, 1H), 7.81 (dd, J = 0.6,
7.8 Hz, 1H), 7.58 – 7.56 (m, 1H), 7.50 –7.47 (m, 1H), 7.44 –
7.42 (m, 3H), 7.38 (d, J = 7.8 Hz, 2H), 7.22 (t, J = 7.8 Hz, 2H),
7.16 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H).13C{1H} NMR
(150 MHz, CDCl3, δ): 166.4, 149.3, 146.6, 143.0, 137.7, 137.2,
135.0, 131.4, 130.6, 129.5, 128.6, 128.3, 128.2, 127.3, 127.0,
126.9, 126.7, 121.2, 57.9. IR (ZnSe) νmax (cm−1) 1714, 1651,
1512, 1481, 1467, 1346, 804, 790, 763, 717, 694. HRMS (ESI-
TOF) (m/z): [M + H]+ calcd for C23H19N2O 339.1492; found,
339.1497.
liquid, yield
= 64.7 mg (75%). Purification by flash
chromatography (3% EtOAc/n-hexane). 1H NMR (600 MHz,
CDCl3, δ): 8.89-8.87 (m, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.78 (d,
J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J = 3.0 Hz, 2H), 7.53 –
7.50 (m, 1H), 7.41 (d , J = 8.4, 4.2 Hz, 1H), 7.35 – 7.32 (m, 2H),
7.30 – 7.26 (m, 2H), 7.22 (d, J = 3.0 Hz, 1H), 7.17 – 7.15 (m,
2H). 13C{1H} NMR (150 MHz, CDCl3, δ): 150.0, 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.
Deuterium Labelling Experiment with 8-Methylquinoline
(1a) (Scheme 2a). To a 10 mL reaction vial- [Cl2Ru(p-
cymene)]2 (5 mol%), AgOTf (20 mol%), Cu(OTf)2 (10 mol%)
& Ag2O (2.0 equiv.) were added followed by the addition of 8-
methylquinoline (0.1 mmol), CD3OD (10 equiv.), THF (0.5
mL) under argon atmosphere and stirred at 100 °C for 12h. The
crude reaction mixture was analyzed by 1H NMR. 0%
deuteration was observed.
Deuterium Labelling Experiment with 8-Methylquinoline
(1a) and phenyl boronic acid (2a) (Scheme 2b). To a 10 mL
reaction vial- phenylboronic acid (2.0 equiv.), [Cl2Ru(p-
cymene)]2 (5 mol%) AgOTf (20 mol%), Cu(OTf)2 (10 mol%)
& Ag2O (2.0 equiv.) were added followed by the addition of 8-
methylquinoline (0.1 mmol), CD3OD (10.0 equiv.), THF (0.5
mL) under argon atmosphere and stirred at 100 °C for 12h. The
crude reaction mixture was analyzed by 1H NMR. No
deuteration was observed on the benzylic C(sp3)-H of 8-methyl
quinoline and benzylic C(sp3)-H of 8-benzyl quinoline.
Parallel Reaction for KIE Study (Scheme 2c). To a 10 mL
reaction vial- [Cl2Ru(p-cymene)]2 (5 mol%) AgOTf (20 mol%),
Cu(OTf)2 (10 mol%) & Ag2O (2.0 equiv.) were added followed
by the addition of 8-methylquinoline (0.1 mmol), THF (0.5 mL)
under argon atmosphere. In another reaction vial 8-methyl
quinoline-d3 (0.1 mmol) was used instead of 8-methyl
quinoline. The two-reaction mixtures were allowed to stir at
100 ℃ for 2 h. Both reaction mixtures were analyzed through
1HNMR using TCE (0.10 mmol) as an internal standard and the
calculated kinetic isotope effect value (kH/kD) equal to 1.0 was
found.
General procedure for the synthesis of 8-benzylquinoline 1-
oxide (Scheme 4, entry 4c):14b To a 10 mL reaction vial- 8-
benzyl quinoline (0.2 mmol) and m-CPBA (3.0 equiv.) were
added in (1.0 mL) DCM with stirring at rt for 24h. The product
was purified using flash chromatography, silica gel (230−400
mesh size), (90% EtOAc/n-hexane) as eluent. Sticky brown,
Competition Reaction for KIE Study (Scheme 2d). To a 10
mL reaction vial- phenylboronic acid (0.4 mmol), [Cl2Ru(p-
9
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Based Hydrazone Derivatives as Insecticidal Agents. RSC Adv. 2016,
cymene)]2 (5 mol%) AgOTf (20 mol%), Cu(OTf)2 (10 mol%)
& Ag2O (2.0 equiv.) were added followed by the addition of 8-
methylquinoline (0.1 mmol), 8-methyl quinoline-d3 (0.1 mmol),
THF (1.0 mL) under argon atmosphere and stirred at 100 °C for
2h. Firstly, 1H NMR of the crude mixture was performed and
then it was purified by flash chromatography to obtain the
arylated product using silica gel (230−400 mesh size) and
EtOAc : n-hexane as the eluent. The kinetic isotope effect value
(PH/PD) equal to 1.0 was found.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, details of optimization studies,
1
characterization data for all synthesized compounds including H
and 13C spectra. FAIR Data is available as Supporting Information
for Publication and includes the primary NMR FID files for
compounds 3a-3z, 3za-3zw, 4a-4d.
AUTHOR INFORMATION
Corresponding
Author:
*upendra@ihbt.res.in;
upendraihbt@gmail.com
Web address: http://www.ihbt.res.in/en/staff/scientificstaff?
chronoform=sctdetailandtask=detailandid=41
Notes
The authors declare no competing financial interests
ACKNOWLEDGMENT
We are thankful to the Director, CSIR-IHBT for continuous
inspiration. The work described in this manuscript is financially
supported by CSIR (MLP0154/MLP0159). DP and RK
acknowledge UGC and CSIR for scholarship. Communication no.
provided by CSIR-IHBT for this manuscript is 4610.
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