Synthesis of substituted quinolines by the electrophilic cyclization of n-(2-alkynyl)anilines

Article abstract of DOI:10.1016/j.tet.2009.12.012

A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I₂, Br₂, PhSeBr, and p-O₂NC₆H₄SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)₂-catalyzed ring closure of these same alkynylanilines.

Full text of DOI:10.1016/j.tet.2009.12.012

Tetrahedron 66 (2010) 1177–1187
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted quinolines by the electrophilic cyclization
of n-(2-alkynyl)anilines
*
Xiaoxia Zhang, Tuanli Yao, Marino A. Campo, Richard C. Larock
Department of Chemistry, Iowa State University, Ame, IA 50010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the
6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I2, Br2, PhSeBr, and p-O2NC6H4SCl. The
reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the
presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have
been synthesized by the Hg(OTf)2-catalyzed ring closure of these same alkynylanilines.
Published by Elsevier Ltd.
Received 30 September 2009
Received in revised form 30 November 2009
Accepted 3 December 2009
Available online 5 January 2010
Keywords:
Substituted quinolines
Electrophilic cyclization
Alkynes
Hg-catalyzed cyclization
1. Introduction
quinolines have also been synthesized by a photochemical route,7
a modified Skraup quinoline synthesis employing halo-substituted
The quinoline skeleton occurs in numerous natural products,
especially in alkaloids.1 Many quinolines display interesting phys-
iological activities and have found applications as pharmaceuticals
(e.g., antimalarial drugs, such as quinine or chloroquine) and ag-
rochemicals, as well as being general synthetic building blocks.2
Halogen-containing quinolines are of particular interest, because
the halogen atom can play a crucial role in the compound’s bio-
activity and provides an avenue for further structure elaboration.3
The isolation and synthesis of naturally-occurring quinoline de-
rivatives have received considerable attention in the literature due
to their biological and pharmaceutical importance.4 Although
acroleins and anilines,8 and the Friedla¨nder quinoline synthesis.3c
Some of these methods suffer relatively low yields, poor regiose-
lectivity, and/or rather lengthy synthetic sequences.
The cyclization of alkynes containing proximate nucleophilic
centers promoted by electrophiles is currently of great interest and
developing into a very effective strategy for carbo- and heterocyclic
ring construction.9 This chemistry provides a convenient approach
to the synthesis of functionalized cyclic compounds through the
regioselective addition of the nucleophile and the electrophile
across the carbon–carbon triple bond. Successful examples of this
process have been reported for the synthesis of isoquinolines,10
Scheme 1.
simple 3-bromoquinolines can be obtained by the bromination of
quinoline hydrochlorides,5 the site-selective aromatic halogenation
of substituted quinolines remains a synthetic challenge.6 3-Halo-
benzothiophenes,11 polycyclic aromatics,12 indoles,13 furopyr-
idines,14 isoindolin-1-ones,15 isocoumarins,16 isochromenes,17 and
benzofurans.13d,18 However, no one prior to our recent communi-
cation19 had employed this chemistry to synthesize quinolines.
Herein, we wish to report the full details of this successful strategy
for the synthesis of quinolines using very mild reaction conditions
(Scheme 1).
* Corresponding author.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.12.012

1178
X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
2. Results and discussion
3-Iodo-4-phenylquinoline (2) was generated in a good yield
using this approach (Table 1, entry 1). Thus, we have subsequently
employed the reaction conditions developed here on a wide variety
of other triflamides and the results are summarized in Table 1,
entries 2–10. Good yields have been obtained when the group R on
the alkyne is phenyl, as well as relatively electron-rich or electron-
deficient aryl groups (entries 1–4). The cyclization of substrates
During our early efforts to obtain 3-iodoquinolines, a two-step
procedure was first examined (Scheme 2). Triflamide 1 with R¼Ph
was treated with ICl at ꢀ78 ꢁC to afford a dihydroquinoline in-
termediate, which could be subsequently treated with base to
achieve aromaticity.20
Scheme 2.
Table 1
Synthesis of quinolines from N-(2-alkynyl)triflamidesa
Entry
Triflamide
Electrophile
Product
% Overall yield
1
2
R¼Ph
1
3
ICl
ICl
2
4
88
62
3
4
5
7
ICl
ICl
6
8
45
51
5
6
9
9
ICl
10
10
trace
trace
I2/AgClO4
7
8
R¼n-Bu
11
13
ICl
ICl
12
14
25
trace
9
15
18
ICl
ICl
60þ25
10
19
56
11
20
ICl
2
74
a
All reactions were run using 0.30 mmol of the N-(2-alkynyl)sulfonamide and 1.5 equiv of ICl in 3 mL of CH2Cl2 at ꢀ78 ꢁC for 1 h. After work-up, the solvent was removed,
the crude mixture and 10 equiv of NaOMe were directly dissolved in MeOH and stirred overnight.

X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
1179
Table 2
bearing both electron-donating and -withdrawing groups on the
aniline moiety proved no difficulty when R is phenyl group (entries
9 and 10). When the 3-methoxyaniline derivative 15 was utilized,
two isomeric quinoline products were obtained (entry 9). The
product formed from cyclization onto the less sterically hindered
position para to the methoxy group is the major isomer.
The products of addition of ICl to the triple bond of the tri-
flamides 9 and 13 were the major products observed under the
above reaction conditions. These presumably are generated from
the relatively stable cations formed by the electron-releasing MeO
or vinylic groups, followed by trapping by the chloride anion gen-
erated from the ICl (Scheme 3).
Effect of I2 stoichiometry and base on the cyclization of N-(3-phenyl-2-propy-
nyl)aniline (22) (Eq. 1)a
Entry
Equiv of I2
Base (equiv)
% Yield
1
2
3
4
5
6
7
8
3
2
6
6
3
3
3
3
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
d
76
44b
75
56c
72
NaOCO2CH3 (2)
Cs2CO3 (2)
pyridine (2)
Et3N (2)
71
35
45
a
All reactions were run under the following conditions unless otherwise stated:
0.3 mmol of 22, I2 and the base in 3 mL of MeCN were stirred at room temperature
for 12 h.
b
The reaction was not finished after 24 h; 40% of 22 was left.
After 24 h, 25% of 22 was left.
c
0.5 h, the desired iodoquinoline 2 was obtained cleanly in a 76%
yield (Table 2, entry 1). The reaction has also been run on a 2.0 mmol
scale and product 2 was generated in a 75% yield, indicating the
utility of this procedure on a larger scale. A much longer reaction
time was required when decreasing the amount of I2 from 3 to
2 equivand the yield of 2 dropped substantially (entry 2). Essentially
the same yield was obtained when using either 3 or 6 equiv of I2
(compare entries 1 and 3). Thus, we chose to use 3 equiv of I2 in the
rest of our optimization work. The reaction was also dramatically
slowed down when there was no base employed, even in the pres-
ence of 6 equiv of I2 (entry 4). Other carbonate bases, such as Cs2CO3
and NaOCO2CH3, which have been successfully employed in our
related isoquinoline synthesis,10 gave a yield comparable to that of
NaHCO3 (entries 5 and 6). Organic bases, namely triethylamine and
pyridine, actually lowered the yield (entries 7 and 8). The combi-
nation of 0.30 mmol of the N-(2-alkynyl)aniline, 3 equiv of I2 and
2 equiv of NaHCO3 in 3 mL of CH3CN at room temperature was
therefore chosen as our ‘optimal’ reaction conditions and the scope
of this reaction was systematically investigated (Table 3).
First, various substituents on the end of the alkyne were ex-
amined. In general, electron-rich and electron-deficient aryl
groups have generated quinolines in good to excellent yields,
presumably because these substituents are capable of stabilizing
a vinylic cation intermediate (entries 1, 5, and 10; Table 3). The
yield dropped and a much longer reaction time was needed for
the p-acetylphenyl-substituted alkyne 30 to react (24 h vs 0.5 h
for alkyne 22) (entry 11). Substrate 31 with a strong electron-
withdrawing NO2 group on the para-position of the arene failed
to generate any cyclization product (entry 12). The yield of the
pyridine derivative 34 also suffers, which might be the result of
the coordination of Iþ to the nitrogen of the pyridine, further
lowering the electron density of the pyridine ring (entry 13).10
Interestingly, an amino group, generally believed to be a stronger
nucleophile than a phenyl group, ortho to the alkynyl moiety
remains untouched during the cyclization in contrast to our
previously reported indole synthesis employing 2-(1-alkynyl)-
anilines (entry 14).13a This indicates the need for an appropriate
leaving group on the nitrogen in order to effect a successful in-
dole synthesis. In fact, cyclization by I2 proceeds in a decent yield
even when the terminus of the carbon–carbon triple bond bears
an alkyl group. Thus, 4-butyl-3-iodoquinoline (12) can be syn-
thesized in a 43% yield, alongside a 26% yield of 4-butyl-3,6-
diiodoquinoline, which is presumably formed by iodocyclization
of N-(2-heptynyl)-4-iodoaniline formed by prior iodination of the
aniline (entry 15). The desired cyclization did not occur when the
acetylene bears a sterically-hindered silyl or t-Bu group, or
a simple H atom on the triple bond (entries 17–19). Substitution
of a vinylic group on the alkyne presents no problem as the 4-
(1-cyclohexenyl)quinoline 14 was formed cleanly in an 80% yield
Scheme 3.
It appears that the relatively stable iodovinylic cation is re-
luctant to undergo electrophilic attack on the N-substituted aro-
matic ring. Therefore, removal of the trifluoromethanesulfonyl
group might be expected to increase the nucleophilicity of the aro-
matic ring and thus improve the yield of the desired cyclization.
This has indeed proven to be the case. Furthermore, although this is
a convenient and new approach to 3-iodo-1,2-dihydroquinolines,
the failure of the reactions with substrates 9 and 13 and the poor
yield from the reaction of the alkyl-substituted alkyne 11 encour-
aged us to search for a more general and straightforward synthetic
approach to 3-iodoquinolines. Finally, the cyclization of meth-
anesulfonamide 20 was also successful (entry 11). Obviously, one
could obtain dihydroquinolines after the first step without further
base-induced deprotection of the nitrogen if one so desired.
Aniline derivative 21 was next subjected to direct electrophilic
cyclization (Scheme 4). A fair amount of the iodoquinoline 10 was
generated upon reaction with ICl and subsequent treatment by the
oxidizing agents nitrobenzene or DDQ. However, it was later found
that the oxidation step was unnecessary, since 10 was formed in
a good yield upon iodination with ICl plus NaHCO3 without sub-
sequent addition of an oxidant.
Scheme 4.
Figuring that the conversion of 21 to 10 by ICl might not be the
simplest, most convenient and most general of transformations, we
choose to optimize the reaction of aniline 22 using I2 in the pres-
ence of various bases (Eq. 1).
ð1Þ
The results are summarized in Table 2. When a mixture of aniline
22, 3 equiv of I2 and 2 equiv of NaHCO3 in MeCN was stirred at rt for

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X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
Table 3
Synthesis of quinolines by electrophilic cyclization of N-(2-alkynyl)anilines
Entry
Propargylic amine
Electrophile
Product(s)
% Yield
E
I
I
a
1
2
3
4
R¼Ph
22
21
I2
2
2
23
24
76
83
20
0c
IClb
PhSeBrb
NBSb
PhSe
Br
a
5
6
7
I2
I
10
10
25
71
73
74
IClb
I
PhSeBrb
PhSe
b
8
Br2
26
51
9
21
28
p-O2NC6H4SClb
SC6H4NO2-p
27
29
12
78
a
10
I2
I
a,d
11
12
30
31
I2
I
I
8
57
a
I2
32
trace
a
13
33
I2
I
34
25
a
14
35
38
I2
36þ37
55þ0
a
15
16
17
18
R¼n-Bu
I2
I
I
I
I
12
12
40
42
43e
30
IClb
a
R¼SiMe
R¼H
39
41
I2
trace
0
a
I2
a
19
43
I2
44
0

X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
1181
Table 3 (continued)
Entry
Propargylic amine
Electrophile
Product(s)
% Yield
a
20
21
45
46
I2
14
47
80
I2
38f
a
a
22
23
48
48
I2
19
49
63
75
PhSeBrb
a
24
25
50
I2
I
51
52
88
56
PhSeBrb
PhSe
a
26
27
53
55
I2
54
56
79
75
a
I2
a
28
29
57
59
I2
58
58d
a
I2
16þ17
29þ37
a
30
60
I2
61þ62
71þ8
(continued on next page)

1182
Table 3 (continued)
X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
Entry
Propargylic amine
Electrophile
Product(s)
% Yield
75
a
31
63
65
I2
64
66
a
32
I2
trace
a
33
34
35
67
69
71
I2
68
70
72
0
I2
35g
a
IClb
50
,h
a
36
73
I2
74
62
a
37
75
77
I2
76
80
a
38
I2
2
0
a
All reactions were run under the following conditions unless otherwise stated: 0.3 mol of the propargylic aniline, 3 equiv of I2, and 2 equiv of NaHCO3 in 3 mL of CH3CN
were stirred at room temperature for 0.5 h.
b
Two equiv of ICl/Br2/PhSeBr/p-O2NC6H4SCl/NBS in 1 mL of CH3CN were added dropwise to the solution of 0.3 mmol of propargylic aniline and 2 equiv of NaHCO3 in 2 mL of
MeCN over 10 min at rt and the solution was stirred for another 10 min.
c
Only the product formed from bromination of the 4-position of the aniline ring was obtained.
The reaction took 24 h.
The product was obtained together with a 26% yield of 4-n-butyl-3,6-diiodoquinoline.
Compound 2 was also generated in a 25% yield.
7-Amino-3,6-diiodo-8-methyl-4-phenylquinoline was also obtained in a 28% yield.
ICl (4 equiv) in 1 mL of CH2Cl2 was added dropwise to the solution of 0.30 mmol of 71 in 2 mL of CH2Cl2 over 10 min at ꢀ78 ꢁC and the solution was stirred for another
d
e
f
g
h
10 min.
(entry 20). Together with iodoquinoline 2, formed in a 25% yield,
the 2,3,4-trisubstituted quinoline 47 was obtained in a moderate
yield. This quinoline is most likely generated by elimination of
toluene during the aromatization step (entry 21).
An interesting feature of this cyclization is the fact that yields
aren’t significantly affected by the substituents on the aniline ring.
para-Substituents ranging from a weak electron-withdrawing
group, like a Br, to a strong electron-withdrawing group, like a NO2,

X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
1183
along with an electron-donating MeO group, all generate the cor-
responding substituted quinoline derivatives in good yields (entries
22, 24, 26 and 27). A substrate with two methyl groups situated
meta to the amino group also afforded a high yield of the corre-
sponding quinoline, although a longer reaction time was needed
(entry 28).
The regioselectivity of this cyclization has also been in-
vestigated. 3-Methoxyaniline 59 afforded the ortho-cyclization
regioisomer 16 and the para-cyclization isomer 17 in 29% and
37% yields, respectively (entry 29). On the other hand, very in-
terestingly, the 3-nitroaniline 60 afforded regioisomers 61 and
62 in a 79% combined yield with cyclization occurring primarily
ortho to the nitro group (9:1 ratio of ortho to para cyclization) for
reasons that are not obvious (entry 30). Excellent regioselectivity
was achieved in the cyclization of 2-naphthylamine 63, since
only one isomer was observed. The ring closure occurred selec-
tively in the less sterically-hindered 3-position of the naphtha-
lene ring (entry 31). Unfortunately, cyclization onto a pyridine
ring proved unsuccessful using our current reaction conditions
(entry 32).
Other halogen electrophiles have also been successfully
employed in this quinoline synthesis. For example, the stronger
electrophile ICl has been utilized in this cyclization. Our ‘optimal’
ICl reaction conditions are the following: 0.30 mmol of the prop-
argylic aniline, 2 equiv of ICl, and 2 equiv of NaHCO3 in 3 mL of
MeCN are stirred at room temperature. Three equiv of ICl were not
necessary, since all of the alkynes were completely consumed when
2 equiv of ICl were employed. Lowering the temperature to 0 ꢁC or
ꢀ78 ꢁC did not improve the yields. Yields comparable to those
obtained using I2 (compare entry 1 with 2, and entry 5 with 6, Table
3) have been obtained, but the reactions are much faster, being
complete in about 5 min. However, using ICl as the electrophile was
not helpful in improving the yields of the desired monoiodinated
quinolines where I2 only generated a moderate yield, as in entries
15 and 16. When 2 equiv of NBS in MeCN were added dropwise to
a mixture of aniline 22 and 2 equiv of NaHCO3 in MeCN, N-(3-
phenyl-2-propynyl)-4-bromoaniline was obtained in quantitative
yield, and no cyclization to the quinoline was observed after 2 h
(entry 4). The reaction of Br2 with alkynylaniline 22 was messy with
the formation of mono-, di- and tribromoquinolines evident. In the
case of aniline 21, we were able to isolate dibromoquinoline 26 in
a 51% yield (entry 8, Table 3).
Table 4
Effect of organoselenium electrophiles on the cyclization of aniline 21 (Eq. 2)a
Entry
Electrophile
Base (equiv)
% Yield of 25
1
2
3
4
5
6
7
PhSeCl
PhSeSePh
PhSeBr
PhSeBr
PhSeBr
PhSeBr
PhSeBr
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
Na2CO3 (1)
NEt3 (3)
38b
0
74
0
40
48
0c
Pyridine (3)
d
a
Two equivalents of PhSeX in 1 mL of MeCN was added dropwise to a solution of
0.3 mmol of propargylic aniline and the base in 2 mL of MeCN at rt.
b
A 19% yield of 3,6-di(phenylselenyl)quinoline was also obtained.
Compound 21 bearing a PhSe group para to the amino group was obtained in
c
a 42% yield.
When N,N-disubstituted anilines and derivatives were
employed in the reaction with ICl or I2, quinolinium salts can be
obtained (entries 35 and 36, Table 3). Thus, the dipropargylic ani-
line 73 gave a good yield of the isoquinolinium salt 74, when
allowed to react with I2 (Eq. 3). None of the double cyclization
product was observed. In a similar fashion, amide 71 reacted with
ICl to give isoquinolinium salt 72 (Table 3, entry 35).
Although PhSeCl and PhSeBr has been found to be effective
electrophiles in our electrophilic cyclization of alkynes to iso-
quinolines,10 isochromenes,17 isocoumarins,16 benzo[b]thio-
phenes,11 and isoindolin-1-ones,15 PhSeCl is not nearly as effective
as PhSeBr in this current quinoline process (Eq. 2 and entries 1 and
3, Table 4). The reaction of PhSeCl plus 2 equiv of NaHCO3 gave only
a 38% yield of selenium-substituted quinoline (entry 1, Table 4).
This reaction also provided a 19% yield of the 3,6-diselenium-
substituted quinoline. No reaction occurred when using PhSeSePh
(entry 2, Table 4). Interestingly, when PhSeBr was used as the
electrophile, the desired 3-(phenylselenyl)quinoline 25 was
obtained in a 74% yield (entry 3). Surprisingly, simply changing the
base from NaHCO3 to Na2CO3 resulted in a messy reaction and none
of the desired quinoline 25 was observed (entry 4). Organic bases,
such as NEt3 and pyridine, provided lower yields (entries 5 and 6).
The presence of a base to remove the side product HBr is crucial
(entry 7). The reaction of 21 and PhSeBr without any base afforded
none of the desired quinoline. Instead, a 42% yield of aniline 21 with
a PhSe group para to the aniline nitrogen was obtained. It is im-
portant to emphasize that the dropwise addition of ICl and PhSeBr
to the reaction vessel is very important in obtaining a clean re-
action, but this is unnecessary when using I2. Representative ex-
amples of the synthesis of selenium-containing quinolines are
included in entries 3, 7, 23 and 25 in Table 3.
The highly substituted aniline 75 gave an excellent yield of the
highly functionalized quinoline 76 (entry 37). An analogous ap-
proach to quinolines might be to cyclize N-(3-phenyl-2-propyny-
lidene)aniline, which can be easily generated by the condensation
of aniline with 3-phenylpropynal. However, under our standard I2
reaction conditions, none of the desired iodoquinoline 2 was gen-
erated. Instead, the imine starting material decomposed (entry 38,
Table 3).
We propose the following mechanism for this iodocyclization
process (Scheme 5): (1) the carbon–carbon triple bond of the
propargylic aniline coordinates to the iodine cation generating an
iodonium intermediate A, (2) intramolecular nucleophilic attack of
the aromatic ring of the aniline on the activated triple bond forms
dihydroquinoline B, (3) in the presence of I2 or ICl, the dihy-
droquinoline B is oxidized to the corresponding quinoline.20 It is
also possible that the dihydroquinoline is not oxidized to the
quinoline until it is exposed to air during the work-up.

1184
X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
either MeCN or CH2Cl2 as the solvent at rt (entries 13 and 14).
Lowering the amount of Hg(OTf)2 or changing the solvent or ad-
dition of an oxidant are all detrimental to the reaction (entries 8–
12). This reaction is believed to proceed in a stepwise manner,
because compound 79 could be separated from the reaction
mixture after half an hour and it was gradually converted to
compound 78 when stirred in the presence of air, but the absence
of mercury salts (Eq. 5). However, analogous dihydroquinoline
intermediates have not been observed in the iodine-promoted
ring closure process (Table 3).
Scheme 5.
The scope of this metal-catalyzed process using the above ‘opti-
mal’ reaction conditions was subsequently examined. The compati-
bility of substrates is very similar to that of the I2 cyclization process.
With phenyl and p-MeOC6H4 groups on the end of the alkyne, the
desired quinolines were generated in excellent yields (Table 6, en-
tries 1 and 2). An analogous 3,5-dimethylaniline derivative was also
cyclized in good yield (entry 4). Only 4% Hg(OTf)2 was needed for the
cyclization of substrate 59 with a meta-methoxy substituent (entry
5). Regioisomers 83 and 84 were obtained in a 73% overall yield. The
yield of isomer 84 is slightly higher than that of 83. On the other
hand, cyclization of the 2-naphthyl derivative 63 afforded a high
yield of a single product inwhich cyclization occurs exclusively in the
1-position of the naphthalene (entry 6). Note that the regiochemistry
here is completely the opposite of that of the corresponding iodo-
cyclization (Table 3, entry 31). When an electron-withdrawing ester
group was incorporated into the para-position of the aniline, only
a 53% yield of quinoline 86 could be obtained employing 20 mol % of
Hg(OTf)2 (entry 7). The reaction was not as efficient when the distal
Recently, considerable attention has focused on metal catalysts,
which can effectively activate unsaturated bonds toward intra-
molecular electrophilic attack on arenes. Various heterocycles and
carbocycles have been successfully synthesized using this strat-
egy.21–26 However, the direct cyclization of simple propargylic an-
ilines to quinolines has not yet been achieved. Our interest in the
synthesis of quinolines bearing a hydrogen in the 3-position en-
couraged us to first screen those reagents and catalysts previously
reported to be active in this kind of chemistry (Eq. 4). The results
are summarized in Table 5.
Table 5
Metal-catalyzed cyclization of aminoalkyne 22 (Eq. 4)
Entry
Catalyst
Solvent
Temp (ꢁC)
Time (h)
% Yield of 78 (22)
Ref.
1
2
3
4
5
6
7
8
5% AuCl3
EtOH
MeCN
75
70
65
70
80
rt.
rt.
rt.
rt.
50
100
rt.
rt.
rt.
48
72
48
48
48
48
48
24
48
168
48
24
6
10 (75)
15 (70)
8 (90)
38 (51)a
5 (80)
0
21
22
23
24
25
d
d
d
d
d
d
d
d
d
5% AuCl3/ 15% AgOTf
5% RuCl3/ 15% AgOTf
5% PtCl4
5% PtCl2
3% Cu(OTf)2
3% Hg(O2CCF3)2
3% Hg(OTf)2/ 15% TMU
5% Hg(OTf)2
3% Hg(OTf)2
4% Hg(OTf)2
ClCH2CH2Cl
ClCH2CH2Cl
toluene
CH2Cl2
MeCN
MeCN
MeCN
MeCN
DMSO
trace
55 (35)a
50 (45)a
40 (50)a
10 (71)
< 1
9
10
11
12
13
14
5% Hg(OTf)2/ 1.2 MnO2
10% Hg(OTf)2
10% Hg(OTf)2
MeCN
MeCN
CH2Cl2
96
95
24
a
The yield did not improve when the reaction was run a longer time.
AuCl3 and Au(OTf)3, which have been shown to be effective
catalysts for the cyclization of imines derived from carbonyl
compounds and propargylic amines,21 and the hydroarylation of
alkynes22 were ineffective in this quinoline process (Table 5, en-
tries 1 and 2). The reaction of aniline and 3-phenylpropynal was
also messy under the reaction conditions of entry 1. Unsatisfactory
results were also obtained from RuCl3/AgOTf, PtCl4, and PtCl2 salts,
although they have been shown to affect the cyclization of
N-protected anilines to hydroquinolines (entries 3–5).23–25 While
both Cu(OTf)2 and Hg(O2CCF3)2 are inactive (entries 6–8), Hg(OTf)2
was found to be the catalyst of choice. Thus, 10% Hg(OTf)2 pro-
motes the cyclization of 22 to quinoline 78 in a 95–96% yield using
end of the triple bond was substituted by either an alkyl or vinylic
group (entries 3, 8 and 9). However, we were able to efficiently cy-
clize substrates bearing electron-rich aromatic rings and either
a butyl or cyclohexenyl group on the alkyne, and the amount of
catalyst could be reduced to 5 mol % in both cases (entries 8 and 9,
Table 6). It is particularly noteworthy that a C-C double bond is
readily accommodated in this later process.
These functionally-substituted quinolines, particularly the iodo
derivatives, offer considerable potential for further elaboration. For
example, iodoquinoline 29 undergoes a facile Suzuki reaction26 with
styrylboronic acid to afford the styryl-substituted quinoline 93 in
a 73% yield (Scheme 6). Quinoline 93 is an analog of a CHMG-CoA

X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
1185
Table 6
Synthesis of quinolines by the Hg(OTf)2-catalyzed cyclization of N-(2-Alkynyl)anilines in MeCNa
Entry
Substrate
Hg(OTf)2 (mol %)
Time (h)
Product
% Yield
1
2
3
R¼Ph
22
21
38
10
10
15
6
6
78
80
81
96
88
50
R¼
r
-MeOC6H4
R¼n-Bu
12
4
5
57
59
10
4
6
6
82
79
83
35
D84
þ38
6
7
8
63
50
87
10
20
5
12
24
3
85
86
88
65
53
75
9
89
5
5
90
73
10
45
30
24
91
38
11
75
20
12
92
65
a
To a solution of 0.3 mmol of the propargylic aniline in 3 mL of CH3CN was added a catalytic amount of Hg(OTf)2. The reaction mixture was stirred at room temperature for
the indicated time.

1186
X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
reductase inhibitor.3c Iodoquinoline 36 readily undergoes an intra-
molecular palladium-catalyzed Buchwald–Hartwig amination27 to
produce the interesting tetracyclic diamine 94 in a 65% yield.
under reduced pressure. The residue was purified by column
chromatography on a silica gel column.
4.2.1. 3-Iodo-4-(3-methoxyphenyl)quinoline (4). The reaction mix-
ture was chromatographed using 5:1 hexane/EtOAc to afford the
product as a white solid in a 62% yield: 117–118 ꢁC; 1H NMR (CDCl3,
300 MHz)
1H), 7.41–7.50 (m, 3H), 7.68–7.72 (m,1H), 8.08–8.10 (d, J¼6.6 Hz,1H),
9.22 (s, 1H); 13C NMR (CDCl3, 75 Hz)
55.43, 96.11, 114.26, 114.66,
121.40, 126.78, 127.43, 128.90, 129.48, 129.76, 129.86, 141.60, 147.17,
152.24,156.65,159.70; IR (CHCl3) 2837,1613,1513,1483,1246 cmꢀ1
d 3.84 (s, 3H), 6.78 (s,1H), 6.81–6.83 (m,1H), 7.03–7.06 (m,
d
;
HRMS m/z 360.9972 (calcd for C16H12INO, 360.9964); Anal. Calcd for
C16H12INO: C, 53.1; H, 3.3; N 3.9; Found: C, 53.1; H, 3.9; N, 3.5.27
Compounds 38, 39, 41, 43, 46, 48, 53, 55, 59, and 65 were pre-
pared by reaction of the appropriate aniline (2 equiv) and the cor-
responding propargylic mesylate at room temperature in CH3CN.28
4.2.2. N-(2-Heptynyl)aniline (38). To
a solution of the meth-
anesulfonate29 of 2-heptyn-1-ol (950 mg, 5.0 mmol) in 50 mL of
CH3CN was added aniline (930 mg, 10.0 mmol). After being stirred
for 20 h under N2, the reaction was quenched by adding brine. The
reaction mixture was extracted with Et2O (2ꢂ30 mL). The extracts
were dried over MgSO4 and the solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(10:1 hexane/EtOAc) on silica gel to afford 589 mg of the product
(63% yield) as a light yellow oil. The spectral properties were
identical with those previously reported.30
Scheme 6.
3. Conclusions
A wide variety of 3-halogen-, selenium- and sulfur-containing
quinolines have been readily synthesized under mild reaction
conditions by the 6-endo-dig electrophilic cyclization of N-(2-
alkynyl)anilines by ICl, I2, Br2, PhSeBr and ArSCl as electrophiles.
The reaction affords quinolines in moderate to good yields and
various functional groups are readily accommodated. Dihy-
droquinoline derivatives can be obtained when triflamides are used
as the starting materials. Quinolinium salts can be obtained when
N-alkyl-N-(2-alkynyl)anilines are employed. Quinolines bearing
a hydrogen in the 3-position have been synthesized by the
Hg(OTf)2-catalyzed ring closure of these same alkynylanilines. Fi-
nally, further conversion of the iodine moiety in these iodoquino-
lines to other functionally-substituted quinolines has been
illustrated.
4.3. General procedure for the electrophilic cyclization
of N-(2-Alkynyl)anilines by I2
In a vial was placed 0.3 mmol of the propargylic aniline, 3 equiv
of I2, 2 equiv of NaHCO3, and 3 mL of CH3CN. The reaction mixture
was stirred at room temperature, and the reaction was monitored
by TLC to establish completion. When finely ground iodine powder
was employed, all reactions were complete in 0.5 h. The reaction
mixture was then diluted with 25 mL of ether and washed with
20 mL of satd aq Na2S2O3. The organic layer was separated and the
aqueous layer was extracted with another 25 mL of ether. The
combined organic layers were dried over MgSO4 and filtered.
The solvent was evaporated under reduced pressure and the
product was isolated by chromatography on a silica gel column.
4. Experimental section
4.1. General
4.4. General procedure for the electrophilic cyclization
of N-(2-Alkynyl)anilines by ICl, Br2, PhSeBr or p-O2NC6H4SCl
The 1H and 13C NMR spectra were recorded at 300 and 75.5 MHz
or 400 and 100 MHz, respectively. All melting points are un-
corrected. High resolution mass spectra were recorded on
a MS50TC double focusing magnetic sector mass spectrometer
using EI at 70 eV. All reagents were used directly as obtained
commercially unless otherwise noted.
In a vial was placed 0.3 mmol of the propargylic aniline, 2 equiv
of NaHCO3 and 2 mL of CH3CN. Two equivalents of ICl, Br2, PhSeBr
or p-O2NC6H4SCl in 1 mL of CH3CN were added dropwise to the vial.
The reaction mixture was stirred at room temperature for 5 min.
The reaction mixture was then diluted with 25 mL of ether, and
washed with 20 mL of satd aq Na2S2O3 (for the reaction of ICl and
Br2) or satd aq NaCl (for the reactions of PhSeBr and p-O2NC6H4SCl).
The organic layer was separated and the aqueous layer was
extracted with another 25 mL of ether. The combined organic layers
were dried over MgSO4 and filtered. The solvent was evaporated
under reduced pressure and the product was isolated by chroma-
tography on a silica gel column.
4.2. General procedure for the electrophilic cyclization
of n-triflamides by ICl
To a solution of N-phenyl-N-(3-phenylprop-2-ynyl)trifluoro-
methanesulfonamide (102 mg, 0.30 mmol) in CH2Cl2 (3.0 mL) at
ꢀ78 ꢁC was added ICl (58.5 mg, 0.36 mmol) in CH2Cl2 (0.5 mL) and
the resulting solution was stirred at this temperature for 0.5 h. The
reaction mixture was washed with satd aq Na2S2O3 (20 mL) and the
organic layer dried over Na2SO4, filtered, and the solvent removed
under reduced pressure. To the crude solution of 3-iodo-4-phenyl-
1-trifluoromethanesulfonyl-1,2-dihydroquinoline in MeOH (10 mL)
was added NaOMe (3.0 mmol, 162 mg) and the mixture was stirred
at rt in the presence of air for 12 h. The reaction mixture was diluted
with diethyl ether (50 mL) and washed with brine (50 mL). The
organic layer was dried (Na2SO4), filtered, and the solvent removed
4.4.1. 4-(4-Methoxyphenyl)-3-(phenylseleno)quinoline (25). The re-
action mixture was chromatographed using 3:1 hexane/EtOAc to
afford 86 mg (74%) of the product as a yellow solid: mp 93–94 ꢁC;
1H NMR (CDCl3, 300 MHz)
d
3.91 (s, 3H), 7.06 (d, J¼6.0 Hz, 2H),
7.26–7.32 (m, 5H), 7.43–7.57 (m, 3H), 7.63–7.68 (m, 1H), 7.68–7.73
(m, 1H), 8.05 (d, J¼8.4 Hz, 1H), 8.67 (s, 1H); 13C NMR (CDCl3, 75 Hz)
d
55.57, 114.25, 126.23, 127.22, 127.34, 128.44, 128.47, 129.16, 129.61,

X. Zhang et al. / Tetrahedron 66 (2010) 1177–1187
1187
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4.5. General procedure for the Hg(OTf)2-catalyzed cyclization
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To a vial containing a solution of 0.3 mmol of the propargylic
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The reaction mixture was stirred at room temperature, and the
reaction was monitored by TLC to establish completion. The re-
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with 20 mL of satd aq NaI. The organic layer was separated and the
aqueous layer was extracted with another 25 mL of ether. The
combined organic layers were washed further with 25 mL of satd
aq NaCl. The organic layer was dried over MgSO4 and filtered. The
solvent was evaporated under reduced pressure and the product
was isolated by chromatography on a silica gel column.
4.5.1. 4-(4-Methoxyphenyl)quinoline (80). The reaction mixture was
chromatographed using 10:1 hexane/EtOAc to afford 62 mg of the
product (88%) as a light yellow oil: 1H NMR (CDCl3, 400 MHz)
d 3.91
(s, 3H), 7.05–7.08 (d, J¼8.7 Hz, 2H), 7.32–7.33 (d, J¼4.2 Hz, 2H), 7.44–
7.53 (m, 3H), 7.70–7.75 (m, 1H), 7.96–7.99 (d, J¼8.4 Hz, 1H), 8.15–8.18
(d, J¼8.4 Hz, 1H), 8.92–8.93 (d, J¼4.5 Hz, 1H); 13C NMR (CDCl3,
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Acknowledgements
We gratefully acknowledge the National Institute of General
Medical Sciences (GM 070620) for support of this research;
Kawaken Fine Chemicals Co., Ltd., and Johnson Matthey, Inc. for
donations of Pd(OAc)2, and Frontier Scientific and Synthonix for
contributions of boronic acids.
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Supplementary data
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Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2009.12.012.
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consistent for compound 4.
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