A method for the synthesis of substituted quinolines via electrophilic cyclization of 1-azido-2-(2-propynyl)benzene

Article abstract of DOI:10.1021/jo902603v

(Chemical Equation Presented) A new and efficient strategy for the synthesis of substituted quinolines via electrophilic cyclization is developed. The intramolecular cyclization of 1-azido-2-(2-propynyl)benzene 1 proceeds smoothly in the presence of electrophilic reagents (I₂, Br ₂ , ICl, NBS, NIS, and HNTf₂) in CH₃NO ₂ at room temperature or in the presence of catalytic amounts of AuCl₃/AgNTf₂ in THF at 100 °C to afford the corresponding quinolines 2 in good to high yields. In the case of the electrophilic reagents, E of 2 is either I, Br, orH, depending on the reagent type, while E of 2 is H in the case of the electrophilic catalyst. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902603v

pubs.acs.org/joc
A Method for the Synthesis of Substituted Quinolines via Electrophilic
Cyclization of 1-Azido-2-(2-propynyl)benzene
Zhibao Huo,† Ilya D. Gridnev,‡ and Yoshinori Yamamoto*,†,§
†Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan,
‡Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of
Technology, Tokyo 152-8580, Japan, and WPI-AIMR (WPI-Advanced Institute for Materials Research),
Tohoku University, Katahira 2-1-1, Aobaku, Sendai 980-8577, Japan
§
yoshi@mail.tains.tohoku.ac.jp
Received December 16, 2009
A new and efficient strategy for the synthesis of substituted quinolines via electrophilic cyclization is
developed. The intramolecular cyclization of 1-azido-2-(2-propynyl)benzene 1 proceeds smoothly in
the presence of electrophilic reagents (I2, Br2, ICl, NBS, NIS, and HNTf2) in CH3NO2 at room
temperature or in the presence of catalytic amounts of AuCl3/AgNTf2 in THF at 100 °C to afford the
corresponding quinolines 2 in good to high yields. In the case of the electrophilic reagents, E of 2 is
either I, Br, or H, depending on the reagent type, whileE of2 is H in the case ofthe electrophilic catalyst.
Introduction
Furthermore, quinoline derivatives have been shown to be
outstanding organocatalysts and are recognized as useful tools
for the highly enantioselective syntheses of chiral molecules.5
Because of their importance, much attention has been paid to
development efficient methods for the synthesis of substituted
quinolines. In recent years, a number of syntheses of quinoline
derivatives have been reported.6
Quinolines represent an important class of alkaloids because
of their wide utility. Substituted quinolines are often found as
structural frameworks in a large number of biologically active
natural products and pharmaceuticals.1 Examples include anti-
Alzheimer agents,2 anticancer agents,3 and antimalarial drugs.4
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Published on Web 01/26/2010
DOI: 10.1021/jo902603v
r
2010 American Chemical Society

Huo et al.
We recently reported metal-catalyzed or nonmetal-cata-
JOCArticle
TABLE 1. Optimization of Electrophilic Reagents (I2, Br2, NIS, ICl,
NBS, Hþ) for Cyclization of 1a
lyzed synthesis of substituted dihydroisoquinolines (eqs 1
and 2),7 and an entirely new method for the synthesis of
substituted isoquinolines through iodine-mediated8 or gold-
catalyzed9 cyclization of 2-alkynyl benzyl azides (eq 3).
A novel and practical synthesis of substituted quinolines via a
two-step procedure involving Grignard addition of alkynyl-
magnesium bromides to 2-aminoaryl ketones followed by
regioselective copper- or palladium-catalyzed 6-endo-dig cyclo-
dehydration of the corresponding 1-(2-aminophenyl)-2-yn-
1-ols (eq 4) was reported by Gabriele and co-workers.10 Accor-
dingly, it occurred to us that the electrophilic cyclization of
1-azido-2-(2-propynyl)benzene would give substituted quino-
lines. Herein, we report a new method for the synthesis of
substituted quinolines 2 from 1-azido-2-(2-propynyl)benzene 1
in the presence of I2, Br2, NIS, and ICl in CH3NO2 at room
temperature or in the presence of catalytic amounts of AuCl3/
AgNTf2 and HNTf2 in THF at 100 °C (eq 5).
entry
Eþ
solvent time (h) 2a (%) 3a (%) 1aa (%)
1
2
3
4
5
6
I2
I2
I2
I2
I2
I2
CH2Cl2
DMF
toluene
THF
CH3CN
12
12
12
12
12
56
31
28
23
45
23
0
31
16
18
0
38
6
37
7
CH3NO2 24
74 (69) 13 (7)
0
7b I2
8
CH2Cl2
CH3NO2
CH3NO2 12
12
1
73
(96)
84
11
0
0
0
0
3
Br2
9c Br2
10 NBS
11 ICl
12 NIS
CH3NO2
CH3NO2
CH3NO2 12
0.5 (84)
0.5 (55)
0
0
0
0
0
0
0
0
0
50
81
77
(82)
13
0
13 TfOH (1 equiv)
14 HCl (1 equiv)
15 TsOH H2O
THF
THF
THF
24
24
24
0
3
(1 equiv)
16 HBF4 (1 equiv)
17 TFA (1 equiv)
18 AcOH (1 equiv)
19 HNTf2 (1 equiv) THF
20 HNTf2 (1.2 equiv) THF
21d HNTf2 (1 equiv) THF
THF
THF
THF
24
24
24
24
24
24
0
10
0
54(49)
(62)
37
0
0
37
0
0
76
44
50
7(5)
0
0
0
a1H NMR yield was determined by using CH2Br2 as an internal stan-
dard. Isolated yield is shown in parentheses. bNaHCO3 (2 equiv) as addi-
tive was used. c3 equiv of Br2 was used. dReaction temperature was 120 °C.
promoted by electrophilic reagents, the results are summar-
ized in Table 1. Table 2 outlines the results for the use of
Lewis acids as catalysts. As observed in the case of the
electrophilic cyclization of 1-azido-2-(2-propynyl)benzene
(eq ), the cyclization of 1a produced 2 along with the 1,3-
dipolar adduct 3 under certain conditions. The iodocycliza-
tion with I2 gave 3 as a minor product (Table 1, entries 1 and
3-7), but the bromocyclization with Br2 and NBS and the
iodocyclization with ICl and NIS did not produce 3 at all
(entries 8-12). Especially, the bromocyclization by the use of
Br2 afforded 2 with an excellent yield (96% isolated yield)
(entry 8). The use of Bronsted acids did not afford good
results (entries 13-19). The use of acetic acid gave 3 without
formation of 2. A better result was obtained by the use of
HNTf2 as a protic acid (entry 20).
The electrophilic catalysts, such as AgSbF6, PPh3AuCl,
CuI, and PtCl2, gave 3 as a major product, although the
combined yields of 2 and 3 were low (Table 2, entries 6, 8, 18,
and 21). Among the catalysts examined, AuCl3/AgNTf2
(1:3, 30 mol %) gave 2 in 85% isolated yield without for-
mation of 3 (entry 16). To understand how the regio- and
(7) (a) Asao, N.; Yudha, S.; Nogami, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 5526. (b) Ohtaka, M.; Nakamura, H.; Yamamoto, Y.
Tetrahedron Lett. 2004, 45, 7339. (c) Asao, N.; Iso, K.; Yudha, S. Org. Lett.
2006, 8, 4149.
(8) (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 4764–4766. (b) Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008,
130, 15720–15725. (c) See also: Huo, Z.; Tomeba, H.; Yamamoto, Y.
Tetrahedron Lett. 2008, 49, 5531–5533.
(9) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651–3653.
(10) (a) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P.
J. Org. Chem. 2007, 72, 6873–6877. (b) Gabriele, B.; Mancuso, R.; Salerno,
G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org. Chem. 2008, 73, 4971–4977.
Results and Discussion
Initially, we screened the reaction conditions for the
electrophilic cyclization of substrate 1a. For cyclization,
J. Org. Chem. Vol. 75, No. 4, 2010 1267

Huo et al.
JOCArticle
TABLE 2. Optimization of Electrophilic Catalysts for Cyclization of 1a
TABLE 3. Selected Structural Parameters of the Optimized
Structures of Associates between Diaryl Acetylene 1a and Various
Electrophilic Reagentsa
entry
catalyst
2a (%)
3a (%)
1aa (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18b
19
20
21
AgOTf
AgPF6
AgBF4
AgNTf2
AgClO4
AgSbF6
AgSbF6/TFA (2 equiv)
PPh3AuCl
AuCl
AuCl/AgOTf (1:1)
AuCl/AgSbF6 (1:1)
AuCl/AgNTf2 (1:1)
AuCl3
AuCl3/AgSbF6 (1:3)
AuCl3/AgOTf (1:3)
AuCl3/AgNTf2 (1:3)
PdCl2
CuI
Cu(OTf)2
9
0
0
5
0
11
5
0
0
0
0
0
12
0
45
0
0
0
0
0
0
0
0
0
(31)
0
0
16
45
83
89
33
56
13
53
19
31
24
13
17
61
0
0
0
0
0
11
87
5
ΔH,
˚
˚
entry
electrophile
kcal/mol a, A b, A θ, deg ω, deg
1
2
3
4
5
6
7
8
9
Br2
I2
-6.3 2.759 2.968 169.7 179.1
-5.1 3.029 3.201 170.9 178.6
-7.6 2.905 3.111 168.5 178.7
-3.8 2.782 2.962 173.5 179.7
-3.7 3.058 3.187 177.3 175.6
-4.1 3.185 3.290 170.5 177.7
-23.8 2.317 2.342 167.9 166.8
-28.6 2.300 2.293 167.5 165.6
-34.6 2.037 2.049 165.9 164.2
-41.9 2.022 2.052 163.8 168.3
-36.6 2.213 2.225 163.3 161.2
-40.4 2.208 2.286 161.0 168.2
-51.6 2.192 2.200 163.0 161.7
-37.5 2.307 2.313 166.4 163.7
ICl (coordination by Iþ)
0
ClI (coordination by Clþ
NBS
NIS
AgCl
AgOTf
CuCl
19
35
51
(49)
32
66 (64)
58 (57)
(85)
(50)
(6)
35
0
10 CuOTf
11 AuCl
12 AuNTf2
13 AuOTf
14 AuPPh3
In(OTf)3
PtCl2
aOptimizations were done on the B3LYP/SDD level of theory.
12
a1H NMR yield was determined by using CH2Br2 as an internal stan-
dard. Isolated yield is shown in parentheses. b1.5 equiv of CuI, CH3CN,
110 °C, 60 h.
important for obtaining better chemical yields of 2. The
difference between θ and ω is the largest in the case of
AuNTf2 among the catalysts examined (entry 12). In the
case of AuClPPh3, the chemoselectivity was changed; 3 was
formed as an isolable product and the desired 2 was not
obtained at all (Table 2, entry 8). Accordingly, we carried out
the computation for the AuClPPh3 case, and the result is
shown in entry 14. However, the reason for the switch of the
chemoselectivity is not clear at present.
chemoselectivities depend on the reagents and catalysts, we
carried out a computation study similar to that performed
previously for the case of isoquinoline synthesis.11 Com-
puted enthalpies of formation and selected structural para-
meters of the optimized structures of associates between
diaryl acetylene 1a and various electrophilic reagents/cata-
lysts are shown in the Table 3.
With the optimized conditions in hand, the scope of the
electrophilic cyclization of various substrates, reagents, and
catalysts was studied. The results are summarized in Table 4.
The substrate 1a was cyclized in the presence of 5 equiv of
I2 in CH3NO2 within 24 h to afford a mixture of product 2aa
in 69% yield and the triazole 3 in 7% yield (entry 1). Other
electrophiles such as NIS and ICl were also investigated. The
reactions proceeded smoothly to produce 2aa without for-
mation of 3 (entries 2 and 3). The use of NIS gave 2aa in a
higher yield than ICl. Bromo-substituted quinoline 2ab was
obtained with Br2 or NBS at shorter reaction times in higher
yields as compared to the case of iodo-substituted quinoline
(entries 4 and 5). The quinoline 2ac was obtained in 85% or
62% isolated yield, respectively, in the presence of 30 mol %
of AuCl3/90 mol % of AgNTf2 or in the presence of 1.2 equiv
of HNTf2 (entries 6 and 7). Substrate 1b having methyl at the
para-position of the aromatic ring afforded the correspond-
ing cyclized products 2ba and 2bb with use of NIS and Br2,
respectively, in high yields (entries 8 and 9). The substrate 1c
bearing a 3,5-difluoro group on the aromatic ring afforded
the corresponding cyclized products 2ca-2cc in good to high
yields (entries 10-12). The reactions of substrates 1d and 1e,
having a methyl and a cyclohexyl group at the alkyne
terminus, proceeded smoothly under the standard condition
to give quinolines 2da, 2db, and 2ea-2ec in good yields
(entries 13-17). The cyclization of 1f afforded the bromo-
substituted 2fa and H-substituted 2fb upon treatment with
Comparing the data of Table 3 with the synthetic results,
one can elucidate the structural features of an associate
between the alkyne and the electrophiles that plays a critical
role for the selective cyclization to the corresponding quino-
lines. Thus, it is clear that the strength of the electrophile
binding is not significant for the successful quinoline synth-
esis, since either very strongly binding electrophiles (e.g.
AuNTf2 or AuOTf, entries 12 and 13) or weakly binding
bromine (entry 1) can give selectively high yields of quino-
lines, and vice versa: both strongly binding (e.g. AgOTf,
entry 8) and weakly binding (I2, entry 2) electrophiles can be
poor catalysts and/or provide significant amounts of the side
product 3. On the other hand, one can see a clear correlation
between the performance of the catalyst and its ability to
bind to the triple bond in a nonsymmetrical manner, leaving
the acetylene moiety uninvolved. Thus, the best performing
catalyst, viz. Br2, coordinates to the triple bond only weakly,
but strongly nonsymmetrically (the angle ω is most close to
180°), and the difference between θ and ω (and a and b) is the
largest among the reagents examined (entries 1-6). Similar
values of ω are seen only for NIS and ICl (coordinating
by iodine), which also are nice reagents and can be used
for synthetic purposes. The nonsymmetrical factor is also
(11) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun.
2009, 5075–5087.
1268 J. Org. Chem. Vol. 75, No. 4, 2010

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JOCArticle
TABLE 4. Synthesis of Substituted Quinolines with Various Substrates and Electrophilesa
aThe reaction of 1 (0.2 mmol) was carried out in the presence of 5 equiv of electrophile (I2, ICl, NIS, Br2, or NBS) in CH3NO2 (0.1 M) at
room temperature for the indicated reaction time under argon unless otherwise noted. bIsolated yield. cTriazole was obtained in 7% as
a minor product. dSubstrate 1 (0.2 mmol) was treated with 30 mol % of AuCl3 and 90 mol % of AgNTf2 in THF (2 mL) at 100 °C under argon.
f
eSubstrate 1 (0.2 mol) was treated with 1.2 equiv of HNTf2 in THF (2 mL) at 100 °C under argon. 7 equiv of Br2 was used. g10 equiv of
Br2 was used.
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SCHEME 1. A Plausible Mechanism
Experimental Section
General Procedure for the Electrophilic Cyclization of 1-Azido-
2-(3-phenylprop-2-ynyl)benzene 1a by Br2. To a 5 mL screw capped
vial equipped with a magnetic stirring bar were added 1-azido-
2-(3-phenylprop-2-ynyl)benzene (1a, 46.7 mg, 0.2 mmol) and CH3-
NO2 (1.5 mL) under an argon atmosphere. Bromine (0.052 mL,
1.0 mmol, 5 equiv) in 0.5 mL of CH3NO2 was added dropwise to
the vial with a syringe. The reaction mixture was stirred at room
temperature for 1 h, and the progress of the reaction was
monitored by TLC (hexane/ethyl acetate, 5/1). After complete
consumption of the starting material, saturated aqueous Na2S2O3
was added, and stirring was continued for 5-15 min. The mixture
was extracted with CH2Cl2 (2 ꢀ 10 mL) and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(silica gel, hexane/ethyl acetate; 20/1-10/1) to afford product 2ab
in 96% yield (54.6 mg). 1H NMR (500 MHz, CDCl3) δ 7.61-7.44
(m, 4H), 7.81-7.71 (m, 4H), 8.13 (d, J = 8.5Hz, 1H), 8.51 (s, 1H).
13C NMR (75 MHz, CDCl3) δ 116.8, 126.4, 127.4, 128.0, 128.2,
128.8, 129.3, 129.5, 130.0, 139.8, 139.9, 146.5, 158.1. IR (KBr)
3050, 2921, 1615, 1462, 1078, 743, 689 cm-1. HRMS (EI) calcd for
C15H10BrN (M þ Na) 305.9889, found 305.9888.
Br2 and Au(NTf2)3, respectively, in good to high yields
(entries 18 and 19). The substrates 1g and 1h, in which the
aromatic ring was substituted with chloro and bromo
groups, gave the corresponding quinolines 2ga, 2gb, and
2ha-2hc in good to high yields irrespective of the use of Br2,
NIS, Au(NTf2)3, or HNTf2 as electrophiles (entries 20-25).
In both cases, increased amounts of bromine were used to
obtain good chemical yields. Substitution of the OAc group
at R2 did not exert any significant influence on the cycliza-
tion: the reaction proceeded very smoothly to afford the
products 2ia, 2ib and 2ja, 2jb in good yields (entries 26-29).
The use of NBS, instead of Br2, was also effective for the
formation of quinoline 2jb (entry 29). A biquinoline was
synthesized by the electrophilic cyclization: the substrate 1k
was treated with Br2 at room temperature, leading to the
desired product 2ka in 59% yield (entry 30).
General Procedure for the Electrophilic Cyclization of 1-Azido-
2-(3-phenylprop-2-ynyl)benzene 1a by AuCl3/AgNTf2. To a THF
(2 mL, 0.1 M) solution of AuCl3 (18.2 mg, 0.06 mmol) and
AgNTf2 (70.9 mg, 0.18 mmol), which were weighed in a glovebox,
was added 1-azido-2-(3-phenylprop-2-ynyl)benzene (1a, 46.7 mg,
0.2 mmol) at room temperature under an Ar atmosphere in a
pressured vial. The mixture was stirred at 100 °C for 24 h. The
reaction progress was monitored by TLC (hexane/ethyl acetate,
5/1). After consumption of 1a, the reaction mixture was cooled to
room temperature and filtered through a short Florisil pad with
use of ethyl acetate as eluent. After concentration, the residue was
purified by column chromatography (silica gel, hexane/ethyl
acetate, 20/1-10/1) to afford product 2ac in 85% yield as a white
When 1l (R3 = H) was treated with Br2, the dibromination
of the triple bond took place, leading to the bis-bromine
adduct 4 selectively in 85% yield (eq 9).
1
solid (34.9 mg). H NMR (300 MHz, CDCl3) δ 7.56-7.41 (m,
4H), 7.71 (tt, J = 7.5, 1.5 Hz, 1H), 7.90-7.78 (m, 2H), 8.24-8.11
(m, 4H). 13C NMR (75 MHz, CDCl3) δ 119.0, 126.2, 127.4, 127.4,
127.5, 128.7, 128.8, 128.8, 129.3, 129.6, 129.7, 136.7, 157.3. IR
(KBr) 3054, 3034, 2925, 2119, 1580, 1445, 827, 762, 691 cm-1
.
HRMS (EI) calcd for C15H11N (M þ Na) 228.0784, found
228.0784.
General Procedure for the Electrophilic Cyclization of 1-Azido-
2-(3-phenylprop-2-ynyl)benzene 1a by HNTf2. To a THF (2 mL,
0.1 M) solution of HNTf2 (67.5 mg, 0.24 mmol), which was
weighed in a glovebox, was added 1-azido-2-(3-phenylprop-
2-ynyl)benzene (1a, 46.7 mg, 0.2 mmol) at room temperature
under an Ar atmosphere in a pressured vial. The mixture was
stirred at 100 °C for 24 h. The reaction progress was monitored by
TLC (hexane/ethyl acetate, 5/1). After consumption of 1a, the
reaction mixture was cooled to room temperature and filtered
through a short Florisil pad with use of ethyl acetate as eluent.
After concentration, the residue was purified by column chroma-
tography (silica gel, hexane/ethyl acetate, 20/1-10/1) to afford
product 2ac in 62% yield as a white solid (25.5 mg).
A plausible mechanism for the formation of quinoline 2
via electrophilic cyclization of 1-azido-2-(2-propynyl)benzene 1
is illustrated in Scheme 1. Coordination of the triple bond of 1
to an electrophile Eþ is presumed to generate an intermediate A,
and subsequent nucleophilic attack of a nitrogen atom to
the electron-deficient alkyne would form an intermediate B.
Elimination of N2 and Hþ then results in the formation of qui-
noline 2.
In conclusion, we have developed a new and efficient stra-
tegy for the synthesis of quinolines via electrophilic cycliza-
tion of 1-azido-2-alkynylbenzene derivatives. This reaction
provides a useful method for the synthesis of multisubsti-
tuted quinolines in good to high yields. Particularly, the easy
synthesis of bisquinoline 2ka is interesting and we are now
extending this methodology for the synthesis of polyaromatic
rings.
Supporting Information Available: Characterization data
for all new compounds and details of computation. This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
1270 J. Org. Chem. Vol. 75, No. 4, 2010