Copper promoted synthesis of substituted quinolines from benzylic azides and alkynes

Article abstract of DOI:10.1039/c5ra23065a

A novel copper promoted synthesis of substituted quinolines from various benzylic azides and internal alkynes has been demonstrated. The reaction features a broad substrate scope, high product yields and excellent regioselectivity. In contrast to the known two-step process of acid promoted [4 + 2] cycloaddition reaction and oxidation, the present methodology allows the synthesis of quinolines in a single step under neutral reaction conditions and can be applied to the synthesis of biologically active 6-chloro-2,3-dimethyl-4-phenylquinoline (antiparasitic agent) and 3,4-diphenylquinolin-2(1H)-one (p38αMAP kinase inhibitor). A plausible reaction mechanism involves rearrangement of benzylic azide to N-arylimine (Schmidt reaction) followed by intermolecular [4 + 2] cycloaddition with internal alkynes.

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Journal Name
PAPER
Copper Promoted Synthesis of Substituted Quinolines from
Benzylic Azides and Alkynes
Ching-Zong Luo, Parthasarathy Gandeepan, Yun-Ching Wu, Wei-Chen Chen and Chien-Hong
Cheng*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A novel copper promoted synthesis of substituted quinolines from various benzylic azides and internal alkynes has been
demonstrated. The reaction features a broad substrate scope, high product yields and excellent regioselectivity. In contrast
to the known two-step process of acid promoted [4+2] cycloaddition reaction and oxidation, the present methodology
allows the synthesis of quinolines in a single step under neutral reaction conditions and can be applied to the synthesis of
biologically active 6-chloro-2,3-dimethyl-4-phenylquinoline (antiparasitic agent) and 3,4-diphenylquinolin-2(1H)-one
(p38αMAP kinase inhibitor). A plausible reaction mechanism involves rearrangement of benzylic azide to N-arylimine
(Schmidt reaction) followed by intermolecular [4+2] cyclo addition with internal alkynes.
www.rsc.org/
Introduction
Quinoline and its derivatives are potential heterocyclic scaffold
found in many natural products1-3, and bio-active molecules.4-10
They are also key structures in materials, agrochemicals,
dyestuffs, and pharmaceuticals.11-15 In particular, the use of
quinoline derivatives as ligands for transition metal complexes
for organic synthesis and organic light-emitting materials has
attracted great attention for their synthesis (Fig. 1).16-21
Regardless of many classical methods, such as Pfitzinger,
Skraup, Friedlander, Doebner von Miller, Conrad–Limbach, and
Combes reactions known for the synthesis of quinolines, most
are limited by harsh reaction conditions, limited substrate scope
and low yields.22 Among the various synthetic strategies,23-24
Lewis acid promoted tandem cyclization reaction of N-aryl
imines with terminal alkynes under oxidative condition allows
the access to a variety of 2,4-disubstituted quinolines.25-28 The
proposed reaction mechanism involves the nucleophilic addition
of a terminal alkyne to imine to form propargylamine
intermediate, which undergoes intramolecular cyclization,
followed by oxidation to afford quinoline products. Similar
cyclization reactions using internal alkynes are difficult and
hardly achieved.29 These reactions are not suitable for the
synthesis of quinolines without substitution at C-2 position
(Scheme 1a).
Fig. 1 Examples of useful quinoline cored compounds.
Recently, the in situ generation of N-aryliminium ions from
benzylic azides by means of strong acids has been utilized for the
synthesis of tetrahydroquinoline scaffolds, which can be
oxidized to quinolines by 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ).30-31 The drawbacks of these reactions are
Department of Chemistry, National Tsing Hua University, Hsinchu 30013,
Taiwan. E-mail: chcheng@mx.nthu.edu.tw; Fax: +886-3-5724698; Tel: +886-3-
5721454
Electronic Supplementary Information (ESI) available: General experimental
procedures, characterization details and 1H and 13C NMR spectra of new compounds.
CCDC 1419576–1419579. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/x0xx00000x
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(i) lower product yields, (ii) use of strong acid, (iii) poor and 2a from 1.2:1 to 1:1.2, 3aa was obtained in 63% yield (entry
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DOI: 10.1039/C5RA23065A
regioselectivity and (iv) a two-step process (cyclization and 7). The yield of 3aa further increased to 77%, as the amount of
oxidation) (Scheme 1b). Because of the useful applications of 2a was raised to 2 equiv. (entry 8). We then optimized the
quinolines and the lack of simple and high yielding method for amount of Cu(OTf)2, reaction time and temperature. The
their synthesis, the search for new synthetic methodologies are optimized reaction conditions with 1a (0.28 mmol), 2a (0.56
still highly sought after. Our continuing interests in the quinoline mmol), and Cu(OTf)2 (0.70 mmol) in MeNO2 (2 mL) at 80 C
synthesis32-33 lead us to envision that the in situ generation of N- for 24 h provided 3,4-diphenylquinoline (3aa) in 93% isolated
aryliminium ion from benzylic azide using a Lewis acid catalyst yield. The choice of solvent is crucial to obtain a high product
which is also an oxidant under acid free condition provides a yield. Among the several solvents tested, MeNO2 afforded the
good opportunity to avoid the above mentioned problems at least highest product yield, while PhNO2 and CF3CH2OH also gave
in part. In this report, we disclose a simple and a novel method 3aa in 60 and 75% yields, respectively (Table 1). The attempt to
for the synthesis of various substituted quinolines from benzylic use Cu(OTf)2 as catalyst by employing 0.5 equivalent of
azides and internal alkynes under neutral reaction conditions Cu(OTf)2 with a stoichiometric amount of K2S2O8 or (NH4)2S2O8
using Cu(OTf)2 as both a Lewis acid and oxidant (Scheme 1c).
as oxidants gave the quinoline product in about 50% yield (See
Table 1).
Table 1 Optimization studies for the synthesis of 3,4-diphenylquinoline from benzyl azide
and diphenylacetylene
Temp.(C)/ Yield
Entry
Lewis acid (equiv)
Solvent
Time (h)
100/24
100/24
100/24
100/24
100/24
100/24
100/24
100/24
100/24
100/24
80/24
(%)a
--
1
2
Cu(OAc)2 (2)
Cu(OTf)2 (2)
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
EtOAc
DCE
36
3
Cu(OCOCF3)2 H2O (2)
Cu(BF4)2·6H2O (2)
CuCl2 (2)
trace
33
4
5
--
6
CuF2 (2)
--
7
Cu(OTf)2 (2)
63b
77c
92c
87c
89c
80c
93c
72c
45c
36c
22c
60c
75c
49c,d
52c,d
8
Cu(OTf)2 (2)
9
Cu(OTf)2 (3)
10
11
12
13
14
15
15
16
17
18
19
Cu(OTf)2 (4)
Cu(OTf)2 (3)
Cu(OTf)2 (3)
60/24
Cu(OTf)2 (2.5)
Cu(OTf)2 (2.5)
Cu(OTf)2 (1), 1 atm O2
Cu(OTf)2 (3)
80/24
80/15
80/24
80/24
Scheme 1 Synthetic strategies for substituted quinolines.
Cu(OTf)2 (3)
80/24
Cu(OTf)2 (3)
PhNO2
TFE
80/24
Cu(OTf)2 (3)
80/24
Results and discussion
Cu(OTf)2 (0.5), K2S2O8
MeNO2
MeNO2
100/24
100/24
Initially, several CuII-salts were screened for the reaction of
benzyl azide (1a) and diphenylacetylene (2a) to form 3,4-
diphenylquinoline (3aa) (Table 1). Treatment of 1a (0.34 mmol),
and 2a (0.28 mmol) in the presence of Cu(OTf)2 (0.56 mmol) in
MeNO2 at 100 C for 24 h gave 3aa in 36% yield (Table 1, entry
20 Cu(OTf)2 (0.5), (NH4)2S2O8
aUnless otherwise mentioned, all reactions were performed with 1a (0.34 mmol,),
2a (0.28 mmol, limiting reagent), and Lewis acid (as given in the table) in MeNO2
(2 mL) at 100 C for 24 h. Isolated yields based on the limiting reagents were given.
Yield given in the parenthesis was isolated yield. DCE: 1,2-dichloroethane; TFE:
2,2,2-Trifluoroethanol.. b1a (0.28 mmol, limiting reagent), and 2a (0.34 mmol) were
used. cReactions were performed using 1a (0.28 mmol, limiting reagent), 2a (0.56
mmol), and Lewis acid (as given in the table) in MeNO2 (2 mL) at the given
temperature and time. dCu(OTf)2 (0.14 mmol) was used along with K2S2O8 or
(NH4)2S2O8 (0.32 mmol).
2). The product was unambiguously confirmed by its 1H and 13
C
NMR, HRMS, and X-ray structure analysis.34 Among the Cu(II)-
salts and other Lewis acids tested, only Cu(BF4)2·6H2O showed
considerable potency to give 3aa in 33% yield (See, Table SI for
the detailed optimization studies). By reversing the ratio of 1a
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Scheme 2 Scope of benzylic azides in the synthesis of substituted quinolines. Conditions: 1 (0.28 mmol), 2a (0.56 mmol), and Cu(OTf)2 (0.70 mmol) in MeNO2 (2 mL) at
80 C for 24 h. Isolated yields were determined based on 1.
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Next, we applied the optimized reaction conditions to a variety
of benzylic azides to probe the generality of the reaction (Scheme
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2). First, we tested the para substituted benzylic azides 1b-l
.
Both electron-donating-group (EDG) and electron-withdrawing-
group (EWG) substituted substrates were effectively
transformed into the respective quinoline products. Thus, the
EDG, 4-Me and 4-iPr substituted substrates offered products 3ba
and 3ca in 92% and 90% yields, respectively, but the very
electron-donation 4-methoxy substituted benzyl azide (1d
)
yielded only 36% of product 3da. Halo-substituted benzylazides
1e-h are compatible under the reaction conditions to give the
expected products 3ea-ha in good yields. EWGs containing
benzylic azides 1i-1 provided the respective substituted
quinolines 3ia-la in 44-90% yields. The steric hindrance of ortho
substitution at benzylic azides does not show consistent
influence on the yield of this cyclization reaction. We studied the
reactions of benzylic azides possessing different ortho
substituents such as Me, OMe, Ph, Br, and I with alkyne 2a. The
results reveal that most of the reactions afforded the respective
quinolines in high yields (Scheme 2, products 3ma-qa). Tetra
substituted quinolines 3ra-ta were obtained in good yields by
employing disubstituted benzylic azides 1r-t. The reaction of 3-
methylbenzylic azide gave an inseparable mixture of
regioisomeric quinoline products 3ua + 3ua’ (6:4) in 72% yield.
Synthesis of substituted benzo[h]quinoline
(
3va
)
and
benzo[f]quinoline (3wa) were achieved from 1v and 1w in 74
and 84% yields, respectively. The structure of 3va was further
confirmed by X-ray analysis.34 It is worth to mention that the
halo substituted quinoline products 3ea-ha, 3pa-qa are useful for
further functionalization via cross couplings.
This copper(II) promoted quinoline synthesis was further
expanded to a range of symmetrical and unsymmetrical internal
alkynes (Scheme 3). Thus, the reaction of p-ditolylacetylene (2b
)
with 1a gave the expected product 3ab in 87% yield. Similarly,
p-F, p-Cl, p-Br substituted diarylacetylenes 2c-e reacted with 1a
to provide the corresponding quinolines 3ac-ae in moderate
yields. Di(2-thienyl)acetylene also underwent the cyclization
reaction to provide 3af in 33% yield. Next, we tested a number
of unsymmetrical alkynes 2g-l with 1a and found that the
reactions are highly regioselective giving exclusively a single
regioisomeric product for each of these reactions. Under the
reaction conditions, 1-phenylpropyne (2g) and 1-butynylbenzene
(
2h) provided the respective quinolines 3ag and 3ah in 87 and
96% yields, respectively. The regioselectivity of the products
were confirmed by X-ray structure analysis.34 Electron-deficient
alkyne such as ethyl phenylpropiolate (2i) is also active affording
the expected quinoline product 3ai in 62% yield. Moreover, 3-
tolylpropargyl alcohol (2j), benzyl phenyl acetylene (2k) and 3-
tolylpropargyl amine derivative (2l) also operative to produce
quinoline derivatives 3aj - 3al in good to excellent yields.
Scheme 3 Scope of alkynes in the synthesis of substituted quinolines. Conditions: 1a
(0.28 mmol), 2 (0.56 mmol), and Cu(OTf)2 (0.70 mmol) in MeNO2 (2 mL) at 80 C for 24
h. aCu(BF4)2·6H2O (0.70 mmol) was used instead of Cu(OTf)2.
To demonstrate the synthetic utility of the present copper
promoted cyclization reaction, we synthesize biologically active
compound 6-chloro-2,3-dimethyl-4-phenylquinoline (4) by the
4 | J. Name., 2012, 00, 1-3
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present method. The quinoline compound is known to show
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effectiveness against Leishmania donovani, Trypanosoma cruzi,
T. b. rhodesiense.35 As shown in Scheme 4, compound
4 was
conveniently synthesized from 1f and 2g in two steps with 62%
overall yield.
Scheme 6 Plausible reaction mechanism.
Scheme 4 Synthesis of biologically active 6-chloro-2,3-dimethyl-4-phenylquinoline 4.
Conclusions
We also demonstrated the synthesis of 3,4-diphenylquinolin-
2(1H)-one (
5
) from 3,4-diphenylquinoline (3aa) (Scheme 5).
The copper(II)-promoted synthesis of 3,4-disubstituted
quinolines by the intermolecular cyclization reaction of benzylic
azides and internal alkynes have been demonstrated. It has been
shown that the effectiveness of CuII-salt in the rearrangement of
benzylic azide into N-arylimine (Schmidt reaction) which has
previously only been achieved by strong acids. The catalytic
reaction is highly efficient with a wide range of substituted
benzylic azides. Excellent regioselectivity was observed for the
Compound 5 is known to be a potential p38αMAP kinase
inhibitor.36,37
reaction with unsymmetrical alkyne giving
a
single
regioisomeric product in high yield. The present reaction system
is further applied to the synthesis of two biologically active
compounds.
Scheme 5 Synthesis of 3,4-diphenylquinolin-2(1H)-one 5.
A plausible reaction mechanism for the copper promoted
intermolecular cyclization of benzylic azides and internal
alkynes is shown in Scheme 6. The reaction is initiated by CuII
assisted rearrangement of benzylic azide into N-aryliminium ion
II by the loss of N2 and the migration of the phenyl group.38,39
Next, the intermolecular nucleophilic attack of alkyne to II forms
a vinyl cation intermediate III. An intramolecular electrophilic
aromatic substitution of intermediate III followed by oxidation
afford the final quinoline product. It is worth to mention that the
reaction offer high regioselectivity for unsymmetrical alkynes
2h-i (Scheme 2) and good yields for electron withdrawing group
substituted benzylic azides (Scheme 1). Presumably, the high
regioselectivity is due to the better stabilization of the vinyl
cation intermediate III by the phenyl ring than the alkyl or ester
group on the alkyne substrate. During this copper promoted
cyclization, substituted benzylic azides are turned into an
electron-rich substituted aryl amine (see intermediate III). As a
result, an electron withdrawing substituent on the phenylamide
Experimental section
General procedure for the synthesis of benzyl azides40
Substituted benzylic bromide (1.0 equiv) and sodium azide (1.5
equiv) were dissolved in DMF (2.0 mL/mmol) and stirred at 30
C for 12 h. At the end of the reaction, the mixture was diluted
with water and extracted with diethyl ether. The combined
solution was concentrated in vacuo and the mixture was purified
by a silica gel column (hexane/EtOAc, 90:10) to afford benzylic
azide.
Typical procedure for the synthesis of substituted quinoline
3aa
A sealed tube containing Cu(OTf)2 (254 mg, 0.70 mmol) and
diphenylacetylene 2a (100 mg, 0.56 mmol) was evacuated and
purged with nitrogen gas three times. Then, a solution of benzyl
azide 1a (38 mg, 0.28 mmol) in MeNO2 (2.0 mL) was added to
the system by syringe under a nitrogen atmosphere and the
reaction was stirred at 80 C for 24 h. At the end of the reaction,
the mixture was diluted with CH2Cl2 (10 mL), filtered through a
Celite pad, which was then washed three times with CH2Cl2 (3
ring will not completely stop the electrophilic cyclization of III
.
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X 20 mL). The combined filtrate was concentrated in vacuo and silica gel column using hexane/EtOAc (95:5) as eluent to afford
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the mixture was purified by a silica gel column using the desired pure product
5 in 52% (55 mg) yield.
hexane/EtOAc (95:5) as eluent to afford the desired pure product Yellow solid: m.p. 173-175 °C; 1H NMR (400 MHz, d6-DMSO):
3aa in 91% (71 mg) yield. δ 12.0 (bs, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1
Yellow solid: m.p. 135-137 °C; 1H NMR (400 MHz, CDCl3): δ H), 7.32-7.22 (m, 3 H), 7.18-7.04 (m, 8 H), 6.99 (d, J = 8.0 Hz,
8.99 (s, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 7.74-7.64 (m, 2 H), 7.49- 1 H); 13C NMR (100 MHz, d6-DMSO): δ 161.2 (C), 148.1 (C),
7.43 (m, 1 H), 7.37-7.30 (m, 3 H), 7.23-7.14 (m, 7 H); 13C NMR 138.2 (C), 136.1 (C), 135.7 (C), 131.9 (C), 130.6 (2 CH), 130.1
(100 MHz, CDCl3): δ 151.8 (CH), 147.5 (C), 145.5 (C), 138.1 (CH), 129.5 (2 CH), 127.9 (2 CH), 127.5 (CH), 127.1 (2 CH),
(C), 136.3 (C), 133.1 (C), 130.5 (2 CH), 130.1 (2 CH), 129.5 126.8 (CH), 126.5 (CH), 121.7 (CH), 119.9 (C), 115.1 (CH);
(CH), 129.1 (CH), 128.1 (2 CH), 128.0 (2 CH), 127.7 (CH), HRMS (ESI) [M+H]+ cal for C21H16ON 298.1232, found
127.2 (C), 127.0 (CH), 126.8 (CH), 126.6 (CH); HRMS (FAB) 298.1225; IR (KBr): 3162, 1727, 1643, 1596, 1481, 1442, 1288,
cal for C21H15N [M+] 281.1204, found 281.1204; IR (KBr): 705 and 701 cm-1.
2923, 2854, 1727, 1565, 1488, 1442, 1380, 1272, 1072, 1025,
763 and 701 cm-1.
Procedure for the synthesis of biologically active compound
441
Acknowledgements
We thank the Ministry of Science and Technology of the
Republic of China (MOST-103-2633-M-007-001) for support of
this research.
Compound 3fg was synthesized in 75% yield from 1-
(azidomethyl)-4-chlorobenzene (1f) and phenylpropyne (2g
using a procedure similar to that for the synthesis of quinoline
3aa
)
.
Compound 3fg (110 mg, 0.43 mmol) was dissolved in THF (4.0
mL) and MeLi/LiBr (0.40 mL (2.2 M in Et2O, 0.87 mmol) was
added to the solution at -78 C. The mixture was allowed to warm
to room temperature for 24 h. At the end of the reaction, iodine
(328 mg, 1.29 mmol) was added to the mixture at 0 C and stirred
for 1 h at the same temperature. The mixture was then quenched
with a saturated sodium thiosulfate solution (10 mL). The
resulted biphasic solution was extracted with EtOAc (3 X 30
mL). The combined organic solution was concentrated in vacuo
and the mixture was purified by a silica gel column using
hexane/EtOAc (95:5) as eluent to afford the desired pure product
Notes and references
1
2
3
4
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in 82% (94 mg) yield.
Yellow solid: m.p. 125-127 °C; 1H NMR (400 MHz, CDCl3): δ
7.93 (d, J = 8.8 Hz, 1 H), 7.54-7.44 (m, 4 H), 7.25 (d, J = 2.4 Hz,
1 H), 7.21-7.18 (m, 2 H), 2.72 (s, 3 H), 2.15 (s, 3 H); 13C NMR
(100 MHz, CDCl3): δ 159.3 (C), 145.5 (C), 144.4 (C), 136.9 (C),
131.2 (C), 130.1 (CH), 129.3 (2 CH), 128.9 (CH), 128.7 (2 CH),
128.5 (C), 128.0 (CH), 127.6 (C), 124.8 (CH), 24.5 (CH3), 17.0
(CH3); HRMS (ESI) [M+H]+ cal for C17H15ClN 268.0893, found
268.0885; IR (KBr): 3062, 2923, 2854, 1727, 1666, 1589, 1481,
1373, 1172, 1072, 948, 825 and 701 cm-1
57-75.
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Compound 3aa (100 mg, 0.36 mmol) was dissolved in CH2Cl2
(4.0 mL) and meta-chloroperoxybenzoic acid (134 mg, 0.54
mmol) was added to the solution at 0 C and stirred for 4 h at the
same temperature. After that the reaction was quenched with
saturated sodium bicarbonate solution (5 mL). The resulted
biphasic solution was extracted with CH2Cl2 (3 X 10 mL) and
the combined organic layer was dried over MgSO4 and
concentrated by rotary evaporation. The crude product was
dissolved in Ac2O (3.0 mL) and heated at 75 C for 18 h. At the
end of the reaction, the mixture was quenched with saturated
sodium bicarbonate solution and extracted with CH2Cl2 (3 X 10
mL). The combined solution was dried over MgSO4 and
concentrated in vacuo and the resulted residue was purified by a
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DOI: 10.1039/C5RA23065A
Graphical Abstract:
Copper Promoted Synthesis of Substituted Quinolines from
Benzylic Azides and Alkynes
Ching-Zong Luo, Parthasarathy Gandeepan, Yun-Ching Wu, Wei-Chen Chen and Chien-Hong
Cheng*
A novel method for the synthesis of substituted quinolines from benzylic azides and internal
alkynes using Cu(OTf)2 is described. The reaction features a broad substrate scope, high
product yields and excellent regioselectivity.