Ligand-Free RuCl3-Catalyzed Alkylation of Methylazaarenes with Alcohols

Article abstract of DOI:10.1021/acs.joc.6b03095

RuCl₃ efficiently catalyzes the alkylation of methylquinolines, methylpyridines, 2-methyl-benzooxazoles, and 2-methyl-quinoxalines with alkyl- or aryl-alcohols as alkylating agents. This synthetically useful and atom economical transformation does not require additional ligands. The mechanistic study indicated the alkylation reaction underwent a stepwise transfer hydrogenation, aldol condensation, and hydrogenation reaction pathway.

Full text of DOI:10.1021/acs.joc.6b03095

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Article
Ligand-Free RuCl3-Catalyzed Alkylation of Methylazaarenes with Alcohols
Tong-Yu Feng, Hong-Xi Li, David James Young, and Jian-Ping Lang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03095 • Publication Date (Web): 03 Mar 2017
Downloaded from http://pubs.acs.org on March 3, 2017
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Ligand-Free RuCl3-Catalyzed Alkylation of Methylazaarenes with
Alcohols
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TongꢀYu Feng, †,§ HongꢀXi Li,*,† David James Young,‡ and JianꢀPing Lang*,†,§
†State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials,
College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, Jiangsu, People’s Republic of China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
‡Faculty of Science and Engineering, University of the Sunshine Coast, Maroochydore DC,
Queensland, 4558 Australia
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
__________________________
† Soochow University
§ Shanghai Institute of Organic Chemistry
‡ University of the Sunshine Coast
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______________________________________________________________________________
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RuCl3, t-BuOK
+
R
OH
1,4-dioxane
130 o
N
N
R
C
R = Aryl, Alkyl
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Ligand-free
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ABSTRACT: RuCl3 efficiently catalyzes the alkylation of methylquinolines, methylpyridines,
2ꢀmethylꢀbenzooxazoles and 2ꢀmethylꢀquinoxalines with alkylꢀ or arylꢀalcohols as alkylating
agents. This synthetically useful and atom economical transformation does not require additional
ligand. The mechanistic study indicated the alkylation reaction underwent a stepꢀwise transfer
hydrogenation, aldol condensation and hydrogenation reaction pathway.
______________________________________________________________________________
INTRODUCTION
Metalꢀcatalyzed C(sp3)ꢀH bond functionalization is a useful transformation for the construction
of CꢀC bonds.1 The direct C(sp3)ꢀH bond activation of methylazaarenes provides valuable access
to alkylazaarene derivatives with applications in medicinal chemistry,2 organic catalysis,3 and
material sciences.4 Oxidative functionalization of the benzylic C(sp3)ꢀH bonds of alkylazaarenes
mediated by palladium,5 copper,6ꢀ8 rhodium,9 Lewis acids,10ꢀ13 Brønsted acids,14 iodine,15
microwave irradiation,16 or metalꢀfree catalysts17ꢀ19 have been developed. Once activation is
achieved, the reactive intermediate will add to the C=N bond of aldimines,5a,5c,6c,11b,13a,17a and
imines,17c the C=C bond of olefins,6a,7a methylenemalononitriles,10a α,βꢀunsaturated
carbonyls,10c,12a,15c butꢀ2ꢀeneꢀ1,4ꢀdiones,12a and maleimide,18c the C=O bond of
aldehydes,10b,13b,14b,15b,16a,16b,16c,17c,19a,19c
isatins,15a,16c
1ꢀmethylindolineꢀ2,3ꢀdione,3b,14a
αꢀ
trifluoromethyl carbonyls,11c aldehyde esters,7b,11a aryl glyoxals,19b and ketene,9 the N=N double
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bonds of azodicarboxylates,5b and substitute for the CꢀN bond of amines,6b,8b,17b and the CꢀX
bond of aryl halides,5d and bromoacrylate.3d Many coupling partners are known, but alcohols are
underutilized in this respect, despite being easier to handle, generally less toxic and more readily
available.20 In recent years the αꢀalkylation of methyl aryl ketones,21,22 secondary alcohols,23,24
amides25 and esters26 with primary alcohols as alkylating agents has provided an economical and
efficient method for CꢀC bond formation.27,28 For example, Yus et al. demonstrated that
[Ru(DMSO)4]Cl2 catalyzes αꢀalkylation reactions of ketones and secondary alcohols with
primary alcohols as alkylating agents, respectively.29 To date three papers reported the
introduction of alkylꢀchain moieties onto pyridines or quinolines using alcohols as the alkylating
sources.30ꢀ32 In 2010, Kempe and coꢀworkers investigated the αꢀalkylation of methylꢀNꢀ
heteroaromatic compounds with alcohols catalyzed by [IrCl(cod)]2 coupled with P,Nꢀligand
Py2NP(iPr)2 (Py = pyridinyl, Pr = propyl).30 Obora and coꢀworkers prepared alkylquinolines
from 2ꢀmethylquinoline and alcohols catalyzed by [Ir(OH)(cod)]2/PPh3.31 Shimizu et al.
demonstrated the alkylation of 2ꢀmethylquinoline with alcohols using Pt nanoclusters supported
by γꢀAl2O3 (Pt/Al2O3) at high temperature (170 ºC).32 These reactions required expensive metals
and hard to separate phosphine ligands or high temperatures which limits the substrate scope. We
have a longꢀstanding interested in the hydrogenꢀtransfer reaction33 and have found that alcohol
substrates themselves can act as labile ligands to accelerate the RuCl3ꢀcatalyzed reductive Nꢀ
alkylation of nitroarenes with alcohols. Herein we report a simple and versatile method for the
preparation of various 2ꢀalkylazaarenes from methylazaarenes and alcohols catalyzed by RuCl3,
without the need for additional ligands.
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RESULTS AND DISCUSSION
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The reaction of 2ꢀmethylquinoline (1a) with naphthalenꢀ2ꢀylꢀmethanol (2a) was chosen as a
model reaction (Table 1). Reaction of 1a (2.0 mmol) with 2a (1.0 mmol) in the presence of 2.0
mol% RuCl2(PPh3)3 as the catalyst and tꢀBuOK (0.5 mmol) as base provided the desired
compound 2ꢀ2ꢀ(2ꢀ(naphthalenꢀ2ꢀyl)ethyl)quinoline (3a) in 75% isolated yield (Table 1, entry 1).
The same reaction produced 3a in a lower yield (70%) using Ru(PPh3)2(CO)2Cl2 as the catalyst,
but the product was contaminated with 2ꢀ(2ꢀ(naphthalenꢀ2ꢀyl)vinyl)quinolone (4a) in 6% yield
(entry 2). The addition of PPh3, bisdiphenylphosphinomethane (dppm) or 1,2ꢀ
bis(diphenylphosphino)ethane (dppe) did not increase the activity of [Ru(pꢀcymene)Cl2]2,
Ru3(CO)12 or RuCl3·3H2O (entries 3ꢀ7). Interestingly, RuCl3·3H2O alone gave the best results,
with the yield up to 78% (entry 8). The base tꢀBuOK proved most effective (entry 8), slightly
better than KOH (entry 9) while weak bases K2CO3 and K3PO4 were almost inactive (entries 10
and 11). An increased proportion of tꢀBuOK (60 mol%) led to a slightly higher yield (84%, entry
12), but beyond this amount, the yield actually decreased from 84% to 72% to 54% for
stoichiometries of 60 mol%, 70 mol% and 90 mol%, respectively (entries 12ꢀ14). Higher or
lower 1a/2a molar ratios resulted in a decrease in the yield of 3a (entries 15 and 16). When the
catalyst loading was decreased from 2 mol% to 1 mol%, a lower yield was observed (entry 17)
and a higher catalyst loading (3 mol%) produced 3a in 74% together with a byproduct 2,2'ꢀ(2ꢀ
(naphthalenꢀ2ꢀyl)propaneꢀ1,3ꢀdiyl)diquinoline (5a, in 5% yield, entry 18). A strong solvent
dependence of the coupling reaction was observed. Dioxane proved to be the most suitable
solvent (entry 12). The same reaction gave a 52% yield in toluene, 50% yield in chlorobenzene
and 46% yield in mesitylene (entries 19ꢀ21). At a lower temperature (120 ºC), the reaction
proceeded in a commensurately yield (69%, entry 22), while a higher temperature (140 ºC) did
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not increase the yield. Thus the optimized reaction conditions were found to be 2 mol % of
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RuCl3·3H2O and 60 mol % of tꢀBuOK (as the base) in 1,4ꢀdioxane as solvent at 130 ºC for 24 h.
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Table 1. Optimizing reaction conditions for the alkylation reaction of 1a with 2aa.
Yieldb
Ligand
(mol%)
Entry Cat.
Base (mol%) Solvent
3a
4a
5a
1
2
RuCl2(PPh3)3
tꢀBuOK (50) 1,4ꢀdioxane
tꢀBuOK (50) 1,4ꢀdioxane
75% trace
70% 6%
Ru(PPh3)2(CO)2
Cl2
3
4
Ru3(CO)12
PPh3 (5)
PPh3 (5)
tꢀBuOK (50) 1,4ꢀdioxane
tꢀBuOK (50) 1,4ꢀdioxane
55% 5%
[Ru(pꢀ
68% trace
cymene)Cl2]2
5
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
PPh3 (5)
tꢀBuOK (50) 1,4ꢀdioxane
77%
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dppm (2.5) tꢀBuOK (50) 1,4ꢀdioxane
73%
7
dppe (2.5)
tꢀBuOK (50) 1,4ꢀdioxane
tꢀBuOK (50) 1,4ꢀdioxane
75%
8
78%
9
KOH (50)
K2CO3 (50)
K3PO4 (50)
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
70% trace
trace
trace
84%
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11
12
13
14
15c
tꢀBuOK (60) 1,4ꢀdioxane
tꢀBuOK (70) 1,4ꢀdioxane
tꢀBuOK (90) 1,4ꢀdioxane
tꢀBuOK (60) 1,4ꢀdioxane
72%
54%
74%
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16d
17e
18f
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RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
tꢀBuOK (60) 1,4ꢀdioxane
tꢀBuOK (60) 1,4ꢀdioxane
tꢀBuOK (60) 1,4ꢀdioxane
tꢀBuOK (60) toluene
73%
75%
74%
52%
5%
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tꢀBuOK (60) chlorobenzene 50%
21
tꢀBuOK (60) mesitylene
tꢀBuOK (60) 1,4ꢀdioxane
tꢀBuOK (60) 1,4ꢀdioxane
46% trace
22g
23h
69%
84%
a1a (2.0 mmol, 286 mg), 2a (1.0 mmol, 158 mg), Cat. (2 mol%) and base in solvent (1 mL) at 130 ºC for 24 h.
bIsolated yield. c1a (1.8 mmol) and 2a (1.0 mmol). d1a (2.2 mmol) and 2a (1.0 mmol). e1 mol% RuCl3·3H2O.
f3 mol% RuCl3·3H2O. gat 120 ºC hat 140 ºC.
With the optimized reaction conditions in hand, a variety of benzyl alcohol derivatives bearing
electronꢀrich, ꢀneutral and ꢀwithdrawing substituents were investigated as substrates for this
crossꢀcoupling reaction (Table 2). The electronic nature of the substituents on the phenyl rings of
the alcohols had some effect on the catalytic activity. Benzyl alcohols with electronꢀrich and
electronꢀneutral groups reacted smoothly to produce the desired products in 78ꢀ90% yield (3aꢀ
3j). By contrast, (4ꢀchlorophenyl)methanol with an electronꢀwithdrawing group on phenyl
provided product 3k in 45% isolated yield. Orthoꢀ or metaꢀpositioned substituents did not
hamper the alkylation reaction (entries 3, 4, 6 and 7). It is noteworthy that heteroatomꢀcontaining
alcohols like pyridinꢀ3ꢀylꢀmethanol and thiophenꢀ2ꢀylmethanol reacted smoothly to afford the
corresponding products 2ꢀ(2ꢀpyridinꢀ3ꢀylꢀethyl)ꢀquinoline (3l, 65%) and 2ꢀ(2ꢀthiophenꢀ2ꢀylꢀ
ethyl)ꢀquinoline (3m, 57%), respectively (entries 12 and 13). Nonꢀactivated primary aliphatic
alcohols (heptanꢀ1ꢀol and octanꢀ1ꢀol) required higher alcohol/1a molar ratios to complete the
alkylation reactions in 55% and 56% isolated yields (3n and 3o), respectively.
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Table 2. RuCl3-Catalyzed Reactions of 1a with Primary Alcohol (2).
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RuCl3, t-BuOK
130 oC, 1,4-dioxane
R
OH
+
R
N
N
(3)
(1a)
(2)
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Entrya
Alcohol
Product
Yieldb
1
2
3
4
5
84%
3a
3b
3c
3d
3e
88%
78%
79%
80%
78%
OH
O
6c
7c
8c
3f
3g
3h
N
O
OH
O
79%
85%
N
O
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82%
90%
45%
5
6
7
8
3i
3j
N
CMe3
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3k
12c
13d
65%
57%
3l
3m
CH3(CH2)5CH2OH
CH3(CH2)6CH2OH
14d,e
15d,e
55%
56%
3n
3o
a1a (2.0 mmol), 2 (1.0 mmol), RuCl3·3H2O (2 mol%) and tꢀBuOK (60 mol%) in 1,4ꢀdioxane (1 mL) at 130 ºC
for 24 h. bIsolated yield. ctꢀBuOK (70 mol%). dtꢀBuOK (90 mol%). e1a (1.0 mmol) and 2 (2.0 mmol).
Encouraged by the high efficiency for the reaction of 2ꢀmethylquinoline with alcohols
described above, we investigated other methyl azaarenes as potential substrates (Table 3). This
alkylation reaction was compatible with a variety of 2ꢀ and 4ꢀmethyl analogues including 4ꢀ
methylquinoline, 2ꢀmethylquinoxaline, 2ꢀmethylpyridine, 4ꢀmethylpyridine, and 2ꢀmethylꢀ
benzooxazole under the standard or similar reaction conditions. 2,6ꢀDimethylꢀquinoline and 6ꢀ
methoxyꢀ2ꢀmethylꢀquinoline gave the expected products in high yields (87% (3p), 89% (3q)). 4ꢀ
Methylꢀquinoline reacted to give 3r in 60% yield under standard conditions while 8ꢀ
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methylquinoline was inert. 2ꢀMethylquinoxaline gave the desired methylꢀalkylated product (3s)
in 84% isolated yield (entry 5). The alkylation of 2ꢀ or 4ꢀmethylpyridine in the presence of 100
mol% tꢀBuOK afforded the corresponding products (3t and 3u) albeit in moderate yields (entries
6 and 7). The use of 2ꢀmethylꢀbenzooxazole gave the corresponding methylꢀalkylated product
(3v) in a good yield (entry 8).
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Table 3. RuCl3-Catalyzed Reactions of Methylazaarene (1) with Benzyl Alcohol (2b).
RuCl3, t-BuOK
130 oC, 1,4-dioxane
+
R
OH
N
N
(3)
(1)
(2b)
Entrya
Alcohol
Product
Yieldb
87%
1
2
3p
3q
N
N
O
O
89%
60%
N
N
N
N
N
3
3r
4
5
ꢀ
ꢀ
-
N
N
N
N
84%
3s
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6c,d
34%
3t
N
N
7
8
9
N
7c,d
N
29%
56%
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3u
3v
N
O
N
O
8
a1 (2.0 mmol), 2b (1.0 mmol), RuCl3·3H2O (2 mol%) and tꢀBuOK (60 mol%) in 1,4ꢀdioxane (1 mL) at 130 ºC
for 24 h. bIsolated yield. c1 (3.0 mmol) and 2b (1.0 mmol). dtꢀBuOK (90 mol%).
The coupling of 1a and 2a was monitored over time using HPLC to help elucidating the
reaction mechanism (Figure 1). Intermediates 2ꢀ(2ꢀ(naphthalenꢀ2ꢀyl)vinyl)quinoline (4a) and 2ꢀ
naphthaldehyde (6a) were formed initially, concomitant with a sharp decrease in the
concentration of 1a and 2a, and then replaced by product 3a. In a separate experiment, the
reaction of 6a and 2ꢀmethylquinoline for half an hour in the presence of tꢀBuOK resulted in the
formation of 4a in 27% yield coupled with product 3a in 1.5% yield (Eq. 1), supporting the
hypothesis that 4a is an intermediate in the reaction. Moreover, in another check experiment, the
transfer hydrogenation of 4a by benzyl alcohol with RuCl3/tꢀBuOK (Eq. 2, Scheme 1) gave the
hydrogenated product 3a in 81% yield. Unsaturated intermediate 4a could also be reacted with
1a under the optimized reaction conditions and likewise gave the transfer hydrogenation product
3a (32% yield) together with addition product 5a (28% yield, Eq. 3). However, the transfer
hydrogenation reaction of 4a with 2a is significantly faster than the reaction of 4a with 1a under
the same conditions.
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Figure 1. Timeꢀcourse monitoring of the reaction of 1a with 2a.
t-BuOK
1,4-dioxane
0.5 h
O
+
N
+
N
(1)
N
1.0 mmol
4a, 27%
3a, 1.5%
1.0 mmol
RuCl3
OH
CHO
N
t-BuOK
+
+
(2)
N
1,4-dioxane
24 h
3a, 81%
6a, 91%
0.5 mmol
0.5 mmol
RuCl3
N
t-BuOK
N
+
(3)
N
+
N
1,4-dioxane
24 h
N
0.5 mmol
0.5 mmol
5a, 28%
3a, 32%
These results, coupled with the experimental data from the previous reports30ꢀ32 can be used
to formulate a mechanism for the alkylation of methylazaarenes with alcohols (Scheme 1). Step
1 is the dehydrogenation of alcohol to aldehyde and formation of a rutheniumꢀhydride
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intermediate. This aldehyde undergoes condensation with methylazaarene in Step 2 to produce
an alkenylquinoline intermediate. Step 3 involves the hydrogenation of alkenylquinoline by a
ruthenium hydride complex to generate the alkylated quinoline.
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Scheme 1. Proposed Mechanism for the Alkylation of Methylazaarenes with Alcohols.
R
OH
O
R
R
N
N
[Ru]
[Ru-H]
R
KOBu-t
N
CONCLUSIONS
An efficient and convenient ligandꢀfree RuCl3ꢀcatalyzed alkylation of methylquinoline with
alcohols has been developed. Various benzylic and aliphatic alcohols can be used as the
alkylating agent and this simple catalytic system also promotes the αꢀalkylation of
methylpyridines, 2ꢀmethylꢀbenzooxazole and 2ꢀmethylꢀquinoxaline. The reaction proceeds
through a oneꢀpot sequence of transfer hydrogenation/aldol condensation/hydrogenation steps
and is an easyꢀtoꢀperform and atomꢀeconomical protocol for the synthesis of alkylazaarenes.
EXPERIMENTAL SECTION
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General Procedure
General. 1H and 13C NMR spectra were recorded at 400 and 151 MHz, respectively, in CDCl3 or
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DMSOꢀd6 using a BRUKER AVANCE III HD spectrometer. H and C chemical shifts are
reported in parts per million relative to Me4Si using the residual solvent signal as an internal
reference. High resolution mass spectra (HRMS) were obtained with a GCT Premier (Micromass
UK limited) chemical ionization timeꢀofꢀflight mass spectrometer (CIꢀTOF). The uncorrected
melting points were measured on a MelꢀTemo II apparatus.
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Typical Reaction (Table 2, entry 1). A mixture of RuCl3·3H2O (5 mg, 0.02 mmol), tꢀBuOK
(68 mg, 0.6 mmol), 1a (286 mg, 2 mmol), and 2a (158 mg, 1 mmol) in 1,4ꢀdioxane (1 mL) was
stirred at 130 °C for 24 h under N2. The product 3a was isolated by column chromatography
(300−400 mesh silica gel, petroleum ether/ethyl acetate = 20/1) in 84% yield (240 mg) as a white
solid.
2-(2-(naphthalen-2-yl)ethyl)quinolone (3a).31 Yield: 237 mg (84%), pale yellow solid, mp:
118.3ꢀ119.1 ºC. 1H NMR (400 MHz, DMSOꢀd6): δ 8.25 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz,
1H), 7.92 (d, J = 8.0 Hz, 1H), 7.88–7.76 (m, 4H), 7.72 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.4 Hz,
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1H), 7.51–7.37 (m, 4H), 3.37–3.24 (m, 4H). C NMR (151 MHz, DMSOꢀd6): δ 161.5, 147.3,
139.1, 136.1, 133.1, 131.6, 129.4, 128.4, 127.7, 127.7, 127.4, 127.4, 127.3, 126.5, 126.2, 125.9,
125.7, 125.2, 121.7, 39.7, 34.8. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C21H18N 284.1439;
Found 284.1442.
2-phenethylquinoline (3b).31 Yield: 205 mg (88%), pale yellow liquid. 1H NMR (400 MHz,
DMSOꢀd6): δ 8.25 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 17.6, 8.2 Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H),
7.54 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 3.3 Hz, 4H), 7.21–7.11 (m, 1H),
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3.26–3.18 (m, 2H), 3.14–3.06 (m, 2H). C NMR (151 MHz, DMSOꢀd6): δ 161.4, 147.3, 141.4,
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136.0, 129.2, 128.4, 128.3, 128.2, 127.7, 126.4, 125.8, 125.6, 121.6, 39.9, 34.7. HRMS (CIꢀTOF)
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m/z: [M + H]+ Calcd for C17H16N 234.1283; Found 234.1290.
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2-(2-methylphenethyl)quinolone (3c).31 Yield: 193 mg (78%), pale yellow liquid. 1H NMR
(400 MHz, CDCl3): δ 8.06 (dd, J = 17.6, 8.5 Hz, 2H), 7.78 (dd, J = 8.1, 0.8 Hz, 1H), 7.70 (ddd, J
= 8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.23–7.18 (m, 2H), 7.17–7.07 (m,
3H), 3.29–3.22 (m, 2H), 3.17–3.11 (m, 2H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 162.1,
148.1, 139.8, 136.4, 136.2, 130.3, 129.6, 129.0, 129.0, 127.7, 126.9, 126.3, 126.2, 125.9, 121.6,
39.8, 33.4, 19.5. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C18H18N 248.1439; Found 248.1436.
2-(3-methylphenethyl)quinolone (3d).31 Yield: 195 mg (79%), pale yellow liquid. 1H NMR
(400 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.2, 0.9
Hz, 1H), 7.68 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.47 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.22 (d, J = 8.4
Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.08 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H),
3.27 (dd, J = 10.0, 6.2 Hz, 2H), 3.11 (dd, J = 9.9, 6.4 Hz, 2H), 2.31 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 162.0, 148.0, 141.5, 138.0, 136.3, 129.5, 129.4, 128.9, 128.4, 127.6, 126.9, 126.8,
125.9, 125.6, 121.6, 41.1, 36.0, 21.5. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C18H18N
248.1439; Found 248.1440.
2-(4-methylphenethyl)quinolone (3e).31 Yield: 198 mg (80%), pale yellow liquid. 1H NMR
(400 MHz, DMSOꢀd6): δ 8.24 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 19.5, 8.2 Hz, 2H), 7.71 (t, J =
7.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 7.7 Hz, 2H), 7.06 (d, J
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= 7.6 Hz, 2H), 3.23–3.15 (m, 2H), 3.09–3.01 (m, 2H), 2.24 (s, 3H). C NMR (151 MHz,
DMSOꢀd6): δ 161.5, 147.3, 138.3, 136.1, 134.7, 129.3, 128.8, 128.4, 128.2, 127.7, 126.4, 125.7,
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121.7, 40.0, 34.3, 20.6. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C18H18N 248.1439; Found
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248.1427.
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2-(2-methoxyphenethyl)quinolone (3f).3a Yield: 205 mg (78%), pale yellow liquid. H
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NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.76–7.58 (m,
2H), 7.43 (t, J = 7.4 Hz, 1H), 7.27–7.07 (m, 3H), 6.83 (dd, J = 14.5, 7.6 Hz, 2H), 3.76 (s, 3H),
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3.33–3.21 (m, 2H), 3.19–3.09 (m, 2H). C NMR (151 MHz, CDCl3): δ 162.4, 157.5, 147.9,
136.0, 129.9, 129.8, 129.2, 128.8, 127.4, 127.3, 126.7, 125.6, 121.6, 120.4, 110.1, 55.1, 39.2,
30.6. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C18H18NO 264.1388; Found 264.1377.
2-[2-(3-Methoxy-phenyl)-ethyl]-quinoline (3g). Yield: 208 mg (79%), pale yellow liquid.
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Yield: 79% (208 mg), yellow liquid. H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.4 Hz, 1H),
8.00 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.4 Hz,
1H), 7.20 (dt, J = 10.0, 8.1 Hz, 2H), 6.87–6.78 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 3.73 (s, 3H),
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3.32–3.24 (m, 2H), 3.16–3.08 (m, 2H). C NMR (151 MHz, CDCl3): δ 161.7, 159.7, 148.0,
143.2, 136.3, 129.4, 129.4, 128.8, 127.6, 126.8, 125.8, 121.6, 120.9, 114.1, 111.5, 55.1, 40.9,
36.0. IR (KBr disc): 2955(w), 2930(w), 2833(w), 1637(s), 1617(s), 1600(s), 1584(m), 1491(m),
1426(w), 1384(w), 827(m), 783(w), 745(w) cmꢀ1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for
C18H18NO 264.1388; Found 264.1397.
2-(4-methoxyphenethyl)quinolone (3h).31 Yield: 223 mg (85%), pale yellow solid, mp:
55.1ꢀ56.3 ºC. 1H NMR (400 MHz, DMSOꢀd6): δ 8.24 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 19.3, 8.2
Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.17 (d, J =
8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 3.69 (s, 3H), 3.18 (t, J = 7.8 Hz, 2H), 3.03 (t, J = 7.8 Hz,
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2H). C NMR (151 MHz, DMSOꢀd6): δ 161.6, 157.5, 147.3, 136.1, 133.3, 129.3, 129.3, 128.4,
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127.7, 126.5, 125.7, 121.7, 113.7, 54.9, 40.2, 33.9. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for
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C18H18NO 264.1388; Found 264.1394.
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2-(4-(tert-butyl)phenethyl)quinolone (3i).31 Yield: 237 mg (82%), pale yellow solid, mp:
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68.6ꢀ69.4 ºC. H NMR (400 MHz, DMSOꢀd6): δ 8.25 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz,
1H), 7.92 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 8.4
Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 3.20 (dd, J = 9.4, 6.5 Hz, 2H), 3.11–
3.02 (m, 2H), 1.23 (s, 9H). 13C NMR (151 MHz, DMSOꢀd6): δ 161.6, 148.0, 147.3, 138.4, 136.1,
129.3, 128.4, 128.0, 127.7, 126.5, 125.7, 125.0, 121.6, 40.0, 34.2, 34.0, 31.2. HRMS (CIꢀTOF)
m/z: [M + H]+ Calcd for C21H24N 290.1909; Found 290.1913.
2-(2-(naphthalen-1-yl)ethyl)quinolone (3j).3a Yield: 255 mg (90%), pale yellow liquid. H
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NMR (400 MHz, CDCl3): δ 8.13 (dd, J = 14.8, 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.82 (d, J =
7.8 Hz, 1H), 7.68 (dd, J = 16.1, 8.8 Hz, 3H), 7.52–7.40 (m, 3H), 7.36–7.27 (m, 2H), 7.11 (d, J =
8.4 Hz, 1H), 3.64–3.55 (m, 2H), 3.44–3.35 (m, 2H). 13C NMR (151 MHz, CDCl3): δ 161.9,
148.1, 137.6, 136.2, 133.9, 131.9, 129.4, 129.0, 128.8, 127.6, 126.9, 126.8, 126.1, 125.9, 125.8,
125.6, 125.5, 123.82, 121.6, 40.1, 32.9. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C21H18N
284.1439; Found 284.1443.
2-(4-chlorophenethyl)quinolone (3k).31 Yield: 120 mg (45%), pale yellow solid, mp: 57.2ꢀ
58.1 ºC. 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 23.4, 8.4 Hz, 2H), 7.80–7.66 (m, 2H), 7.49
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(t, J = 7.4 Hz, 1H), 7.19 (dt, J = 13.4, 8.0 Hz, 5H), 3.31–3.21 (m, 2H), 3.18–3.09 (m, 2H). C
NMR (151 MHz, CDCl3): δ 161.3, 148.0, 140.0, 136.3, 131.7, 129.9, 129.5, 128.9, 128.5, 127.6,
126.8, 125.9, 121.5, 40.7, 35.1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C17H15ClN 268.0893;
Found 268.0882.
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2-(2-Pyridin-3-yl-ethyl)-quinoline (3l). Yield: 152 mg (65%), white solid, mp: 70.5ꢀ71.9 ºC.
1H NMR (400 MHz, DMSOꢀd6): δ 8.48 (s, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.27 (d, J = 8.4 Hz,
1H), 7.94 (dd, J = 13.2, 8.3 Hz, 2H), 7.77–7.66 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 8.4
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Hz, 1H), 7.29 (dd, J = 7.5, 4.9 Hz, 1H), 3.29–3.22 (m, 2H), 3.14 (t, J = 7.7 Hz, 2H). C NMR
(151 MHz, DMSOꢀd6): δ 161.0, 149.6, 147.2, 147.1, 136.2, 135.9, 129.4, 128.4, 127.8, 126.5,
125.8, 121.7, 39.2, 31.5. IR (KBr disc): 3049(w), 2922(w), 2859(w), 1617(m), 1598(m), 1562(w),
1574(w), 1425(m), 1400(m), 1384(m), 867(w), 847(w), 827(m), 774(w) cmꢀ1. HRMS (CIꢀTOF)
m/z: [M + H]+ Calcd for C16H15N2 235.1235; Found 235.1232.
2-(2-(thiophen-2-yl)ethyl)quinolone (3m).3a Yield: 136 mg (57%), pale yellow liquid. H
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NMR (400 MHz, CDCl3): δ 8.04 (dd, J = 24.3, 8.4 Hz, 2H), 7.79–7.64 (m, 2H), 7.47 (t, J = 7.4
Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.86 (dd, J = 18.6, 14.2 Hz, 2H), 3.36
13
(dd, J = 14.4, 5.9 Hz, 4H). C NMR (151 MHz, CDCl3): δ 161.0, 147.9, 144.2, 136.3, 129.5,
128.8, 127.6, 126.9, 126.7, 125.9, 124.6, 123.2, 121.5, 41.0, 29.7. HRMS (CIꢀTOF) m/z: [M +
H]+ Calcd for C15H14NS 240.0847; Found 240.0835.
2-octylquinoline (3n).3a Yield: 133 mg (55%), pale yellow liquid. H NMR (400 MHz,
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CDCl3): δ 8.06 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.48 (t, J =
7.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.03–2.92 (m, 2H), 1.87–1.72 (m, 2H), 1.43–1.23 (m,
10H), 0.87 (t, J = 6.2 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 163.2, 147.8, 136.5, 129.5, 128.8,
127.6, 126.8, 125.8, 121.5, 39.4, 32.0, 30.2, 29.7, 29.6, 29.4, 22.8, 14.2. HRMS (CIꢀTOF) m/z:
[M + H]+ Calcd for C17H24N 242.1909; Found 242.1913.
2-nonylquinoline (3o).31 Yield: 143 mg (56%), pale yellow liquid. H NMR (400 MHz,
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CDCl3): δ 8.07 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.48 (t, J =
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12H), 0.87 (t, J = 6.3 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 163.2, 147.7, 136.6, 129.6, 128.7,
127.6, 126.9, 125.9, 121.5, 39.4, 32.0, 30.2, 29.7, 29.7, 29.7, 29.4, 22.8, 14.2. HRMS (CIꢀTOF)
m/z: [M + H]+ Calcd for C18H26N 256.2065; Found 256.2061.
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6-methyl-2-phenethylquinoline (3p).34a Yield: 215 mg (87%), pale yellow liquid. H NMR
(400 MHz, CDCl3): δ 7.94 (dd, J = 16.9, 8.6 Hz, 2H), 7.51 (s, 2H), 7.22 (dt, J = 18.7, 7.6 Hz,
6H), 3.31–3.21 (m, 2H), 3.18–3.08 (m, 2H), 2.50 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 160.9,
146.6, 141.7, 135.7, 135.7, 131.8, 128.6, 128.6, 128.5, 126.9, 126.5, 126.1, 121.6, 40.9, 36.1,
21.6. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C18H18N 248.1439; Found 248.1432.
6-methoxy-2-phenethylquinoline (3q).34b Yield: 234 mg (89%), pale yellow solid, mp:
1
70.1ꢀ70.9 ºC. H NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 14.7, 8.8 Hz, 2H), 7.35 (dd, J = 9.0,
1.7 Hz, 1H), 7.30–7.15 (m, 6H), 7.04 (s, 1H), 3.91 (s, 3H), 3.30–3.20 (m, 2H), 3.18–3.09 (m,
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2H). C NMR (151 MHz, CDCl3): δ 159.3, 157.4, 144.0, 141.7, 135.2, 130.3, 128.6, 128.5,
127.8, 126.1, 122.1, 121.9, 105.3, 55.63, 40.8, 36.2. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for
C18H18NO 264.1388; Found 264.1375.
4-phenethylquinoline (3r).31 Yield: 140 mg (60%), pale yellow solid, mp: 101.2ꢀ102.1 ºC.
1H NMR (400 MHz, DMSOꢀd6): δ 8.77 (d, J = 4.3 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.03 (d, J =
8.3 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 4.2 Hz, 1H), 7.29 (d, J
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= 4.2 Hz, 4H), 7.20 (dd, J = 8.3, 4.1 Hz, 1H), 3.39–3.33 (m, 2H), 3.05–2.97 (m, 2H). C NMR
(151 MHz, DMSOꢀd6): δ 150.1, 147.89, 147.2, 141.0, 129.7, 129.1, 128.4, 128.3, 126.9, 126.5,
126.0, 123.9, 121.0, 35.5, 33.0. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C17H16N 234.1283;
Found 234.1287.
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2-phenethylquinoxaline (3s).31 Yield: 197 mg (84%), pale yellow liquid. H NMR (400
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MHz, DMSOꢀd6): δ 8.85 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.86–7.75 (m, 2H), 7.27 (d, J = 4.2
7
8
9
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Hz, 4H), 7.18 (dd, J = 8.2, 4.2 Hz, 1H), 3.34–3.28 (m, 2H), 3.13 (t, J = 7.8 Hz, 2H). C NMR
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(151 MHz, DMSOꢀd6): δ 156.7, 146.4, 141.4, 140.9, 140.6, 130.1, 129.2, 128.8, 128.5, 128.4,
128.3, 126.0, 37.0, 34.1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C16H15N2 235.1235; Found
235.1224.
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2-phenethylpyridine (3t).31 Yield: 62 mg (34%), pale yellow liquid. H NMR (400 MHz,
CDCl3): δ 8.56 (s, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.23 (dd, J = 25.3, 6.6 Hz, 5H), 7.14–7.00 (m,
2H), 3.08 (d, J = 4.1 Hz, 4H). 13C NMR (151 MHz, CDCl3): δ 161.3, 149.3, 141.6, 136.5, 128.6,
128.5, 126.1, 123.1, 121.3, 40.3, 36.1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C13H14N
184.1126; Found 184.1129.
1
4-phenethylpyridine (3u).34c Yield: 53 mg (29%), pale yellow solid, mp: 68.4ꢀ69.2 ºC. H
NMR (400 MHz, CDCl3): δ 8.48 (d, J = 3.1 Hz, 2H), 7.27 (t, J = 7.0 Hz, 2H), 7.23–7.17 (m, 1H),
13
7.14 (d, J = 7.1 Hz, 2H), 7.07 (d, J = 3.8 Hz, 2H), 2.92 (s, 4H). C NMR (151 MHz, CDCl3): δ
150.6, 149.7, 140.7, 128.5, 128.5, 126.3, 124.0, 37.1, 36.6. HRMS (CIꢀTOF) m/z: [M + H]+
Calcd for C13H14N 184.1126; Found 184.1125.
2-phenethylbenzo[d]oxazole (3v).31 Yield: 48 mg (56%), pale yellow solid, mp: 55.2ꢀ56.1
1
ºC. H NMR (400 MHz, CDCl3): δ 7.63–7.55 (m, 1H), 7.43–7.34 (m, 1H), 7.26–7.09 (m, 7H),
13
3.14 (s, 4H). C NMR (151 MHz, CDCl3): δ 166.3, 150.9, 141.4, 140.2, 128.7, 128.4, 126.6,
124.7, 124.2, 119.7, 110.4, 32.9, 30.6, 1.1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C15H14NO
224.1075; Found 224.1081.
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2-(2-(naphthalen-2-yl)vinyl)quinolone (4a).31 Yield: 125 mg (56%), pale yellow solid, mp:
3
4
5
6
1
165.2ꢀ166.1 ºC. H NMR (400 MHz, DMSOꢀd6): δ 8.38 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.98
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9
13
(ddd, J = 25.4, 14.2, 5.6 Hz, 8H), 7.77 (t, J = 7.4 Hz, 1H), 7.68–7.50 (m, 4H). C NMR (151
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MHz, DMSOꢀd6): δ 155.6, 147.7, 136.5, 134.1, 133.9, 133.2, 133.0, 129.8, 129.2, 128.7, 128.4,
128.1, 127.8, 127.8, 127.6, 127.0, 126.6, 126.5, 126.2, 123.8, 120.0. HRMS (CIꢀTOF) m/z: [M +
H]+ Calcd for C21H16N 282.1283; Found 282.1289.
2,2'-(2-(naphthalen-2-yl)propane-1,3-diyl)diquinoline (5a). A mixture of RuCl3·3H2O (7.5
mg, 0.03 mmol), tꢀBuOK (68 mg, 0.6 mmol), 1a (286 mg, 2 mmol), and 2a (158 mg, 1 mmol) in
1,4ꢀdioxane (1 mL) were stirred at 130 °C for 24 h under N2. The product 5a was isolated by
column chromatography (300−400 mesh silica gel, petroleum ether/ethyl acetate = 5/1) in 5%
1
yield (21 mg) as a white solid, mp: 117.6ꢀ118.9 °C. H NMR (400 MHz, CDCl3): δ 8.04 (d, J =
8.5 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.76–7.58 (m, 8H), 7.41 (ddd, J = 16.7, 12.7, 6.9 Hz, 5H),
13
7.09 (d, J = 8.4 Hz, 2H), 4.25 (p, J = 7.5 Hz, 1H), 3.62–3.48 (m, 4H). C NMR (151 MHz,
CDCl3): δ 160.7, 147.9, 141.4, 135.8, 133.5, 132.3, 129.2, 128.9, 128.0, 127.7, 127.6, 127.5,
126.7, 126.6, 126.4, 125.8, 125.7, 125.3, 122.1, 46.2, 45.8. IR (KBr disc): 3056(w), 2922(w),
2850(w), 1636(s), 1618(s), 1599(s), 1561(m), 1425(m), 1400(m), 1384(m), 855(m), 820(m),
748(m) cmꢀ1. HRMS (CIꢀTOF) m/z: [M + H]+ Calcd for C31H25N2 425.2018; Found 425.2015.
ASSOCIATED CONTENTS
Supporting Information.
Copies of 1H and 13C NMR spectra for all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
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* Eꢀmail: lihx@suda.edu.cn. Tel: 86ꢀ512ꢀ65883569
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* Eꢀmail: jplang@suda.edu.cn. Tel: 86ꢀ512ꢀ65882865, Fax: 86ꢀ512ꢀ65880328
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of China
(21471108, 21373142 and 21531006), the Natural Science Foundation of Jiangsu Province
(BK20161276), the State Key Laboratory of Organometallic Chemistry of Shanghai Institute of
Organic Chemistry (2015kfꢀ07), the Priority Academic Program Development of Jiangsu Higher
Education Institutions, the “Soochow Scholar” Program of Soochow University, and State and
Local Joint Engineering Laboratory for Novel Functional Polymeric Materials. We are grateful
to the useful comments of the editor and reviewers.
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