Synthesis of N-arylated 1,2-dihydroheteroaromatics through the three-component reaction of arynes with N-heteroaromatics and terminal alkynes or ketones

Article abstract of DOI:10.1002/asia.200900324

The reaction of benzynes with N-heteroaromatics including quinolines, isoquinolines, and pyridines and various terminal alkynes or ketones with an a-hydrogen in the presence of KF and 18-crown-6 in THF at room temperature for 8 h gave various N-arylated 1,2-dihydroheteroaromatics in good to moderate yields. Some of these product structures are found in various naturally occurring and biologically active heterocyclic compounds. The reaction involves an unusual multiple construction of new C - C, C - N, and C - H bonds and the cleavage of a C - H bond in one pot. It is likely that the three-component coupling proceeds through the nucleophilic addition of quinoline to benzyne, which generates a zwitterionic species. The latter then attracts a proton from terminal alkyne (or ketone) to generate an N-arylated quinolinium cation and an acetylide anion. Further reaction of these two ions provides the final substituted 1,2-dihydroquinolines. In the reaction, the terminal alkyne acts first as a proton donor and then as a nucleophile. The application of a three-component coupling reaction product, 1,2-dihydro-2-pyridinyl alkyne in a stereospecific [4+2] Diels-Alder cycloaddition reaction with N-phenyl maleimide to give an isoquinuclidine derivative, an important core present in various natural products, is demonstrated.

Full text of DOI:10.1002/asia.200900324

DOI: 10.1002/asia.200900324
Synthesis of N-Arylated 1,2-Dihydroheteroaromatics Through the Three-
Component Reaction of Arynes with N-Heteroaromatics and Terminal
Alkynes or Ketones
Masilamani Jeganmohan, Sivakolundu Bhuvaneswari, and Chien-Hong Cheng*[a]
À
À
Abstract: The reaction of benzynes
with N-heteroaromatics including qui-
nolines, isoquinolines, and pyridines
and various terminal alkynes or ke-
tones with an a-hydrogen in the pres-
ence of KF and 18-crown-6 in THF at
room temperature for 8 h gave various
N-arylated 1,2-dihydroheteroaromatics
in good to moderate yields. Some of
these product structures are found in
various naturally occurring and biologi-
cally active heterocyclic compounds.
The reaction involves an unusual multi-
C H bonds and the cleavage of a C H
bond in one pot. It is likely that the
three-component coupling proceeds
through the nucleophilic addition of
quinoline to benzyne, which generates
a zwitterionic species. The latter then
attracts a proton from terminal alkyne
(or ketone) to generate an N-arylated
quinolinium cation and an acetylide
anion. Further reaction of these two
ions provides the final substituted 1,2-
dihydroquinolines. In the reaction, the
terminal alkyne acts first as a proton
donor and then as a nucleophile. The
application of a three-component cou-
pling reaction product, 1,2-dihydro-2-
pyridinyl alkyne in
a stereospecific
[4+2] Diels–Alder cycloaddition reac-
tion with N-phenyl maleimide to give
an isoquinuclidine derivative, an impor-
tant core present in various natural
products, is demonstrated.
Keywords: arynes · cycloaddition ·
heteroaromatics · quinolines · zwit-
terions
À
À
ple construction of new C C, C N, and
Introduction
drogen.[12] Our continued interest in benzyne chemis-
try[11c–f,13] prompted us to explore the possibility of trapping
the N-heteroaromatic/benzyne zwitterion by pronucleo-
philes including terminal alkynes or alkyl ketones that have
an a-hydrogen. Herein, we wish to report the reaction of
benzynes with N-heteroaromatics including quinolines, iso-
quinolines, and pyridines with terminal alkynes or ketones.
The reaction involves an unusual multiple construction of a
The addition of nucleophiles to benzynes to generate zwit-
terionic species which can then be trapped by electrophiles
is an attractive method for the construction as well as the
functionalization of heterocyclic compounds.[1–12] Arising
from the low-lying LUMO of benzyne, even neutral nucleo-
philes such as pyridines,[1] pyrroles,[2] aziridines,[3] imida-
zoles,[4] amides,[5] amines,[6] isocyanides,[7] alcohols,[8] and
imines[9] readily react with benzyne to generate zwitterionic
species. The resulting zwitterionic species can be trapped by
various electrophiles. Up to now, the electrophiles used
were protons, imines, aldehydes, and CO2. Recently, we
have demonstrated a new method of trapping N-heteroaro-
matic/benzyne zwitterionic species by nitrile having an a-hy-
À
À
À
À
new C C, C N, and C H bond and cleavage of a C H
bond in one pot, which provides various substituted N-ary-
lated 1,2-dihydro-N-heteroaromatics. It is important to note
that some of these product structures such as 1,2-dihydro-
quinoline and 1,2-dihydroisoquinoline skeletons are found
in various naturally occurring and biologically active hetero-
cyclic compounds. We have also demonstrated the applica-
tion of a three-component coupling reaction product, 1,2-di-
hydro-2-pyridinyl alkyne, in a stereospecific [4+2] Diels–
Alder cycloaddition reaction with N-phenyl maleimide to
give an isoquinuclidine derivative, which is known to be an
important core present in various natural products.[14]
[a] Dr. M. Jeganmohan, Dr. S. Bhuvaneswari, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu 30013, Taiwan
Fax : (+886)3-572-4698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
Chem. Asian J. 2010, 5, 153 – 159
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153

FULL PAPERS
Table 1. Results of the three-component coupling reaction of various
benzynes with quinoline and terminal alkynes.[a]
Results and Discussion
The reaction of benzyne precursor 2-(trimethylsilyl)phenyl
triflate (1a) with quinoline (2a) and phenyl acetylene (3a)
in the presence of KF (2.0 equiv) and 18-crown-6 (2.0 equiv)
in THF at room temperature for 8 h gave the product 4a in
85% yield (Table 1, entry 1). In the reaction, benzyne was
generated in situ from the reaction of a fluoride ion with 1a.
In the absence of 18-crown-6, no generation of 4a and ben-
zyne was observed. It is likely that the crown ether increases
the solubility of KF in the THF solution.[15] The reaction is
highly regioselective with the phenylethynyl group adding
exclusively to the C-2 carbon of the quinoline ring.
Entry
1
1
3
Product 4
Yield [%][b]
3a
85
In addition to 1a, several other substituted benzyne pre-
cursors 1b–g were tested (Table 1). Thus, 2a and 3a reacted
smoothly with 4,5-dimethylbenzyne generated from precur-
sor 1b under the reaction conditions to afford 4b in 87%
yield (entry 2). Other disubstituted benzyne precursors 1c
and 1d also afforded 4c and 4d in 84 and 79% yields, re-
spectively (entries 3 and 4). However, the reaction of elec-
tron-deficient 4,5-diflurobenzyne generated from precursor
1e with 2a and 3a gave the corresponding three-component
product 4e in moderate 61% yield (entry 5). We next stud-
ied the regioselectivity of unsymmetrical benzynes in the re-
action. 4-Methyl-2-trimethylsilylphenyl triflate (1 f) provided
two regioisomeric products 4 f and 4 f’ in a 50:50 ratio in
83% combined yields (entry 6). Whereas, 3-methoxyben-
zyne generated from precursor 1g reacted with 2a and 3a
or 3b to afford single regioisomeric products 4g and 4h
with the methoxy substituent meta to the amino group ex-
clusively in 77 and 79% yields, respectively (entries 7 and
8).[10c,16]
The three-component coupling reaction was successfully
extended to various terminal alkynes (Table 2). Methyl
propargyl ether (3b) and 2-ethynyl-6-methoxynaphthalene
(3c) reacted effectively with quinoline (2a) and benzyne
precursor 1a to give 4i and 4j in 75 and 76% yields, respec-
tively (entries 1 and 2). An heterocycle substituted alkyne,
2-ethynylthiophene (3d), also efficiently participated in the
reaction to provide 4k in 78% yield (entry 3). tert-Butyl
acetylene (3e) and propargyl acrylate (3 f) gave the expect-
ed products 4l and 4m in 76 and 80% yields, respectively
(entries 4 and 5). Dipropargyl ether (3g) furnished product
4n in 74% yield (entry 6). Only one of the terminal alkynyl
groups of 3g participated in the three-component coupling
reaction; the other terminal alkyne remained intact. The
present protocol can be further applied to substituted
enynes 3h and 3i to afford the corresponding addition prod-
ucts 4o and 4p in good yields, respectively (entries 7 and 8).
2
3
4
3a
3a
3a
87
84
79
5
6
3a
3a
61
83
7
8
3a
3b
77
79
1g
[a] Reaction conditions: benzyne precursors 1a–g (1.2 mmol), quinoline
(2a) (1.0 mmol), alkynes 3a–b (1.3 mmol), KF (2.0 mmol), and 18-crown-
6 (2.0 mmol) in THF at room temperature for 8 h. [b] Yield of isolated
product.
Abstract in Chinese:
Under similar reaction conditions, other substituted qui-
nolines 2b–f that have substituents, OMe, Cl, and CO2Me at
C-6 position, Me at C-4 position, and Br at C-3 position also
154
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Chem. Asian J. 2010, 5, 153 – 159

Synthesis of N-Aryl Heteroaromatic Compounds
Table 2. Results of the three-component reaction of benzynes with different terminal alkynes and different
quinolines.[a]
reacted efficiently with 1a and
3a or 3b to provide coupling
products 4q–u, respectively in
62-83% yields (entries 9–13).
These results showed that an
electron-donating
substituent
on the quinoline moiety favors
product formation, while an
electron-withdrawing
group
considerably hinders the reac-
tion.
In addition to quinolines 2a–
f, other N-heteroaromatics in-
cluding isoquinolines 2g–i and
pyridines 2j–l were also exam-
ined (Table 3). The treatment
of isoquinoline (2g) with ben-
zyne precursors 1a or 1b and
3a in the presence of KF
(2.0 equiv) and 18-crown-6
(2.0 equiv) in THF at room
temperature for 8 h gave prod-
ucts 5a and 5b in 82 and 85%
yields, respectively (Table 3, en-
tries 1 and 2). Similarly, 3-meth-
ylisoquinoline (2h) and 4-bro-
moisoquinoline (2i) reacted
with 1a and 3b and 1a and 3a,
respectively, to give products 5c
and 5d in 79 and 71% yields
(entries 3 and 4). The reaction
of pyridine (2j) with benzyne
precursor 1a and phenyl acety-
lene (3a) proceeded smoothly
to provide the product 5e in
72% yield (Table 3, entry 5).
Similarly, methyl propargyl
ether (3b), 2-ethynyl-6-methox-
ynaphthalene (3c) and proparg-
yl acrylate (3 f) reacted with 1a
and 2j to give products 5 f–h in
Entry
1
1
2
3
Product 4
Yield [%][b]
1a
2a
75
2
3
1a
1b
2a
2a
76
78
4
5
6
1a
1a
1a
2a
2a
2a
76
80
74
good
yields
(entries 6–8).
Under similar reaction condi-
tions, the treatment of 2-phenyl
pyridine (2k) with 1a and 3a or
3b afforded the products 5i and
5j in a highly regioselective
manner in 72 and 71% yields
(entries 9 and 10). On the other
hand, the reaction of 3-phenyl
pyridine (2l) with 1a and 3a af-
forded the regioisomeric prod-
ucts 5k and 5k’ in an 85:15
ratio in 75% combined yield
(entry 11).
7
1b
2a
77
8
9
1a
1a
2a
2b
75
83
3a
The three-component cou-
pling reaction can be further
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155

C.-H. Cheng et al.
FULL PAPERS
alkynes has been proposed in
Scheme 2. The benzyne precur-
sor 1a first reacts with KF and
18-crown-6 to generate benzyne
10.[14] Quinoline (2a) then un-
dergoes nucleophilic addition to
benzyne 10 to give quinoline/
benzyne zwitterionic species 11.
The negative charge of the
zwitterionic species abstracts a
proton from the terminal
alkyne to give intermediate 12
and the terminal alkyne anion
13. Further nucleophilic addi-
tion of anion 13 to the C=N
double bond of the quinolinium
cation 12 gives product 4. This
mechanism also accounts for
the coupling of benzynes with
isoquinoline and RCOMe.
Table 2. (Continued)
Entry
1
2
3
Product 4
Yield [%][b]
10
1a
2c
3a
74
11
12
13
1a
1a
1a
2d
2e
2f
3a
3b
3b
62
78
70
[a] Reaction conditions: benzyne precursors 1a–b (1.2 mmol), quinolines 2a–f (1.0 mmol), alkynes 3a–i
(1.2 mmol), KF (2.0 mmol), and 18-crown-6 (2.0 mmol) in THF at room temperature for 8 h. [b] Yield of iso-
lated product.
Conclusions
We have demonstrated a three-
component coupling of arynes
extended to alkyl ketones having an a-hydrogen as a third
component to trap the isoquinoline/benzyne zwitterion spe-
cies. When benzyne precursor 1a was treated with isoquino-
line (2g) and acetone (6a) in the presence of KF (2.0 equiv)
and 18-crown-6 (2.0 equiv) in THF at 608C for 8 h, a three-
component coupling product 7a was observed in 81% iso-
lated yield (Table 4, entry 1). If the reaction was carried out
at room temperature, no product could be isolated. Similar
to acetone, acetophenone (6b) and 2-acetothiophene (6c)
also efficiently participated in the reaction to give products
7b and 7c in good yields, respectively (entries 2 and 3). a,b-
Unsaturated enone 6d also reacted smoothly to provide the
coupling product 7d in 67% yield (entry 4). Under similar
reaction conditions, other benzyne precursors 1b, 1d, and
1g also underwent three-component coupling reaction with
2g and acetone (6a) to afford the products 7e–g in 87, 81,
and 77% yields, respectively (entries 5–7). Finally, 4-bromoi-
soquinoline (2i) reacted with 1a and 6a to provide 7h in
71% yield (entry 8).
with N-heteroaromatics including quinolines, isoquinolines,
and pyridines and terminal alkynes. This method provides
À
À
À
the construction of new C C, C N, and C H bonds and
À
cleavage of a C H bond in one pot and allows the efficient
synthesis of various N-arylated 1,2-dihydroaromatics-2-qui-
nolinyl, 1,2-dihydro-1-isoquinolinyl, and 1,2-dihydro-2-pyri-
dinyl alkynes in good to moderate yields. In addition to ter-
minal alkynes, ketones with an a-hydrogen can also be used
as a third component to trap the isoquinoline/benzyne zwit-
terion species. The application of 1,2-dihydro-2-pyridinyl
alkyne in a stereospecific [4+2] Diels–Alder cycloaddition
reaction with N-phenyl maleimide has been demonstrated.
Experimental Section
General procedure for the three-component reaction of benzynes with
N-heteroaromatics and terminal alkynes or ketones: A 25 mL round-bot-
tomed flask containing KF (2.00 mmol) and 18-crown-6 (2.00 mmol) was
evacuated and purged with nitrogen gas three times. Freshly distilled
THF (9.00 mL), benzyne precursor (1.20 mmol), N-heteroaromatics
(1.00 mmol), and terminal alkyne (1.30 mmol) were sequentially added to
the system and the reaction mixture was stirred at room temperature for
8 h. The mixture was concentrated and the residue was purified on a neu-
tral silica gel column using hexanes-ethyl acetate as eluent to afford
product 4 or 5. A similar procedure was followed for the reaction of ben-
zynes with N-heteroaromatics and ketones, but the reaction was carried
at 608C for 8 h.
The application of 1,2-dihydropyridine in the [4+2] Diels–
Alder cycloaddition reaction is shown in Scheme 1.[12,17a] The
reaction of 1,2-dihydropyridine (5e) with N-phenyl malei-
mide (8) in toluene at 808C for 8 h gave the isoquinuclidine
derivative 9 in 87% isolated yield. The cycloaddition reac-
tion is highly stereospecific and only one diastereoisomer
was isolated. The stereochemistry of product 9 was deter-
mined by NOE experiments.[12,17b] 2-Azabicyclo
ACHTNUTRGNE[NUG 2.2.2]octane
1,2-Dihydro-1-phenyl-2-(2-phenylethynyl)quinoline (4a). Pale green oil;
1H NMR (400 MHz, CDCl3): d=7.57–7.54 (m, 2H), 7.44–7.37 (m, 4H),
7.31–7.26 (m, 3H), 7.21 (t, J=7.2 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 7.06
(t, J=6.0 Hz, 1H), 6.89–6.81 (m, 2H), 6.61 (d, J=8.0 Hz, 1H), 5.95 (dd,
J=8.0, 6.0 Hz, 1H), 5.34 ppm (d, J=6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=145.5, 141.5, 131.7, 129.3, 128.4, 128.2, 128.1, 127.2, 125.8,
(isoquinuclidine) is an important core present in various nat-
ural products that show biological activities.[17c]
A possible reaction mechanism of the three-component
coupling of benzynes with N-heteroaromatics and terminal
156
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Chem. Asian J. 2010, 5, 153 – 159

Synthesis of N-Aryl Heteroaromatic Compounds
Table 3. Results of the reaction of benzyne precursors with various iso-
quinolines or pyridines and terminal alkynes.[a]
Table 3. (Continued)
Entry
1
2
3
Product 5
Yield [%][b]
Entry
1
2
3
Product 5
Yield [%][b]
7
1a 2j
1a 2j
1a
3c
69
1
1a
3a
82
8
3f
78
72
71
2
3
1b 2g
3a
3b
85
79
9
3a
3b
1a
10
1a 2k
4
1a
3a
71
11
1a
3b
75
5
6
1a
3a
3b
72
67
[a] Reaction conditions: benzyne precursors 1a–b (1.2 mmol), isoquino-
lines, or pyridines 2 (1.0 mmol), alkynes 3 (1.3 mmol), KF (2.0 mmol),
and 18-crown-6 (2.0 mmol) in THF at room temperature for 8 h.
[b] Yield of isolated product.
1a 2j
122.3, 122.5, 121.2, 117.9, 115.1, 87.5, 85.7, 51.1, 29.2, 25.7, 22.2, 21.5 ppm;
HMRS: m/z (%) calcd for C25H25N: 339.1987; found: 339.1986.
124.1, 123.9, 123.3, 122.8, 121.8, 119.4, 116.1, 80.1, 84.7, 50.9 ppm; HMRS:
m/z (%) calcd for C23H17N: 307.1361; found: 307.1354.
2-(3-Methoxyprop-1-ynyl)-4-methyl-1-phenyl-1,2-dihydroquinoline (4t).
Pale green oil; H NMR (400 MHz, CDCl3): d=7.58–7.52 (m, 3H), 7.42–
1-(3-Methoxyphenyl)-2-(3-methoxyprop-1-ynyl)-1,2-dihydroquinoline
(4h). Pale green oil; 1H NMR (400 MHz, CDCl3): d=7.23 (d, J=7.2,
4.0 Hz, 1H), 7.06–7.00 (m, 4H), 6.90 (d, J=6.8 Hz, 1H), 6.80 (t, J=
6.4 Hz, 1H), 6.67 (d, J=6.4 Hz, 1H), 6.52 (d, J=6.8 Hz, 1H), 5.86 (dd,
J=4.8, 1.6 Hz, 1H), 5.13 (dd, J=4.8, 1.2 Hz, 1H), 4.05 (s, 2H), 3.77 (s,
3H), 3.26 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=160.4, 146.7,
141.1, 129.9, 128.4, 127.2, 125.8, 123.5, 121.9, 119.7, 116.6, 115.7, 109.6,
109.1, 85.2, 80.4, 59.9, 57.4, 55.3, 50.3 ppm; HMRS: m/z (%) calcd for
C20H19NO2: 305.1416; found: 305.1411.
1
7.28 (m, 5H), 7.20–7.16 (m, 2H), 7.12 (t, J=6.8 Hz, 1H), 7.07 (t, J=
6.8 Hz, 1H), 6.95–6.87 (m, 2H), 5.79 (t, J=6.0 Hz, 1H), 5.29 (t, J=
6.0 Hz, 1H), 2.17 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=145.7,
141.5, 136.3, 131.7, 130.9, 130.5, 129.2, 128.1, 127.8, 124.1, 123.9, 123.6,
119.3, 118.9, 116.3, 88.5, 84.2, 50.8, 18.7 ppm; HMRS: m/z (%) calcd for
C20H19NO: 289.1467; found: 289.1458.
3-Bromo-2-(3-methoxyprop-1-ynyl)-1-phenyl-1,2-dihydroquinoline (4u).
Pale yellow oil; 1H NMR (400 MHz, CDCl3): d=7.42–7.38 (m, 4H), 7.19
(t, J=6.8 Hz, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.91–6.87 (m, 3H), 5.21 (s,
1H), 4.09 (s, 2H), 3.30 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
144.9, 139.3, 129.3, 128.6, 127.8, 126.6, 124.3, 123.6, 123.0, 120.3, 116.9,
113.2, 83.1, 81.3, 58.8, 57.5, 57.4 ppm; HMRS: m/z (%) calcd for
C19H16BrNO: 353.0415; found: 353.0410.
2-((6-Methoxynaphthalen-2-yl)ethynyl)-1-phenyl-1,2-dihydroquinoline
(4j). Pale yellow oil; 1H NMR (400 MHz, CDCl3): d=7.82 (s, 1H), 7.65–
7.58 (m, 4H), 7.44–7.38 (m, 3H), 7.20–7.12 (m, 3H), 7.09–7.05 (m, 2H),
6.91 (d, J=8.0 Hz, 1H), 6.83 (t, J=7.6 Hz, 1H), 6.62 (d, J=9.2 Hz, 1H),
6.96 (dd, J=9.2, 6.0 Hz, 1H), 5.38 (d, J=6.0 Hz, 1H), 3.89 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=158.2, 145.6, 141.5, 134.1, 131.4, 129.3,
129.2, 129.0, 128.4, 128.3, 127.2, 126.6, 125.8, 124.1, 123.9, 123.3, 121.8,
119.5, 119.2, 117.6, 116.1, 105.7, 87.7, 85.9, 55.2, 51.0 ppm; HMRS: m/z
(%) calcd for C28H21NO: 387.1623; found: 387.1632.
1,2-Dihydro-2-(3,4-dimethylphenyl)-1-(2-phenylethynyl)isoquinoline
(5b). Pale green oil; 1H NMR (400 MHz, CDCl3): d=7.33–7.31 (m, 2H),
7.24–7.09 (m, 10H), 6.62 (d, J=8.0 Hz, 1H), 5.91 (s, 1H), 5.87 (d, J=
8.0 Hz, 1H), 2.29 (s, 3H), 2.23 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=143.4, 137.8, 132.0, 131.7, 130.6, 130.5, 130.3, 128.4, 128.3,
128.1, 126.2, 126.0, 124.0, 123.1, 118.5, 114.5, 103.8, 88.2, 85.1, 51.9, 20.5,
19.2 ppm; HMRS: m/z (%) calcd for C25H21N: 335.1674; found: 335.1667.
1,2-Dihydro-2-(3-methylbut-3-en-1-ynyl)-1-(3,4-dimethylphenyl)quinoline
(4o). Pale green oil; 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=8.0 Hz,
2H), 7.35 (t, J=7.2 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.04 (d, J=8.0 Hz,
1H), 6.97 (t, J=7.2 Hz, 1H), 6.81–6.78 (m, 2H), 6.50–6.48 (d, J=8.0 Hz,
1H), 6.01–5.99 (m, 1H), 5.82 (dd, J=9.6, 4.8 Hz, 1H), 5.19 (d, J=4.8 Hz,
1H), 2.04–2.01 (m, 4H), 1.59–1.53 ppm (m, 4H); 13C NMR (100 MHz,
CDCl3): d=143.0, 142.2, 137.0, 132.4, 129.7, 128.1, 126.9, 126.5, 125.5,
1-Phenyl-2-(phenylethynyl)-1,2-dihydropyridine (5e). Pale green oil;
1H NMR (400 MHz, CDCl3): d=7.44–7.19 (m, 9H), 7.04 (t, J=7.2 Hz,
1H), 6.56 (d, J=8.0 Hz, 1H), 6.14 (dd, J=8.0, 6.4 Hz, 1H), 5.52–5.47 (m,
2H), 5.36 ppm (t, J=6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
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C.-H. Cheng et al.
FULL PAPERS
Table 4. Results of the three-component coupling reaction of benzyne
precursors with isoquinolines and ketones 6a–d.[a]
Entry
1
2
6
Product 7
Yield [%][b]
1
1a
2g
81
Scheme 1.
eimide.
ACHTUNGTREN[NUNG 4+2] cycloaddition of 1,2-dihydropyridine with N-phenyl mal-
2
3
1a
1a
2g
2g
78
75
4
1a
2g
67
5
6
7
1b
1d
1g
2g
2g
2g
6a
6a
6a
87
81
77
Scheme 2. Proposed mechanism for the three-component reaction of ben-
zyne with quinoline and terminal alkynes.
J=7.6 Hz, 1H), 6.21 (dd, J=8.8, 5.6 Hz, 1H), 5.89 (d, J=5.6 Hz, 1H),
5.45 (d, J=8.4, 5.6 Hz, 1H), 5.32 (d, J=6.4 Hz, 1H), 4.14 (d, J=2.0 Hz,
2H), 3.36 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=146.1, 140.5,
137.6, 128.7, 128.4, 128.2, 127.5, 123.9, 122.1, 121.9, 114.8, 108.8, 85.9,
78.9, 60.1, 57.5, 51.7 ppm; HMRS: m/z (%) calcd for C21H19NO:
301.1467; found: 301.1469.
1-(2-Phenyl-1,2-dihydroisoquinolin-1-yl)propan-2-one (7a). Pale yellow
oil; 1H NMR (400 MHz, CDCl3): d=7.33 (t, J=7.6 Hz, 2H), 7.20–7.17
(m, 1H), 7.10–7.03 (m, 5H), 6.98 (t, J=6.0 Hz, 1H), 6.64 (d, J=6.0 Hz,
1H), 5.89 (d, J=7.6 Hz, 1H), 5.64 (dd, J=7.6, 2.0 Hz, 1H), 3.20 (dd, J=
16.0, 9.6 Hz, 1H), 2.72 (dd, J=16.0, 3.6 Hz, 1H), 1.97 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=207.3, 144.3, 131.0, 130.4, 129.5, 128.8,
127.7, 126.0, 125.9, 123.6, 121.1, 115.5, 105.1, 55.2, 46.1, 31.7 ppm; IR
8
1a
2i
6a
71
(KBr): n˜ =3062, 3039, 1712ACHTNUGRTNEUNG
(nCO), 1565, 943 cmÀ1; HMRS: m/z (%) calcd
[a] Reaction conditions: benzyne precursors 1 (1.2 mmol), isoquinolines
2g and 2i (1.0 mmol), acetone (6a) (1.5 mmol) and other ketones 6b–d
(1.0 mmol), KF (2.0 mmol), and 18-crown-6 in THF (2.0 mmol) at 608C
for 8 h. [b] Yield of isolated product.
for C18H17NO: 263.1310; found: 263.1306.
1-Cyclohexenyl-2-(2-phenyl-1,2-dihydroisoquinolin-1-yl)ethanone (7d).
Pale yellow oil; 1H NMR (400 MHz, CDCl3): d=7.30 (t, J=7.6 Hz, 2H),
7.14 (t, J=8.0 Hz, 1H), 7.06–7.01 (m, 5H), 6.94 (t, J=7.2 Hz, 1H), 6.62
(d, J=4.8 Hz, 1H), 6.55 (s, 1H), 5.86 (d, J=7.2 Hz, 1H), 5.62 (dd, J=7.2,
3.2 Hz, 1H), 3.44 (dd, J=16.6, 7.6 Hz, 1H), 2.78 (dd, J=16.4, 4.0 Hz,
1H), 2.26 (s, 2H), 2.11–2.00 (m, 2H), 1.50–1.44 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=199.4, 144.4, 141.6, 139.8, 131.1, 130.5, 129.4,
128.9, 127.5, 126.3, 125.7, 123.4, 120.9, 115.6, 105.1, 56.4, 39.5, 26.1, 23.9,
145.1, 131.8, 129.6, 129.2, 128.2, 128.1, 123.4, 122.8, 121.8, 116.5, 113.5,
102.1, 87.5, 84.1, 50.8 ppm; HMRS: m/z (%) calcd for C19H15N: 257.1204;
found: 257.1195.
3-(1-Phenyl-1,2-dihydropyridin-2-yl)prop-2-ynyl acrylate (5h). Pale green
oil; 1H NMR (400 MHz, CDCl3): d=7.32 (t, J=7.6 Hz, 2H), 7.09 (d, J=
8.0 Hz, 2H), 7.03 (t, J=7.6 Hz, 1H), 6.49 (d, J=10.2 Hz, 1H), 6.43 (d,
J=17.2 Hz, 1H), 6.15–6.07 (m, 2H), 5.84 (d, J=10.4 Hz, 1H), 5.38–5.77
(3H), 4.77 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=165.3, 144.8,
131.6, 129.6, 129.4, 127.7, 123.6, 121.9, 116.4, 112.9, 102.0, 85.1, 77.7, 52.5,
21.8, 21.3 ppm; IR (KBr): n˜ =3062, 1658
HMRS: m/z (%) calcd for C23H23NO: 329.1780; found: 329.1771.
(nCO), 1565, 794, 763 cmÀ1
ACHTUNGTERNNUNG ;
1-(4-Bromo-2-phenyl-1,2-dihydroisoquinolin-1-yl)propan-2-one (7h). Pale
yellow oil; 1H NMR (400 MHz, CDCl3): d=7.45 (d, J=7.6 Hz, 1H),
7.40–7.27 (m, 3H), 7.17–6.95 (5H), 6.90 (s, 1H), 5.63 (dd, J=9.2, 3.2 Hz,
1H), 3.16 (dd, J=16.8, 9.2 Hz, 1H), 2.77 (dd, J=16.4, 3.6 Hz, 1H),
1.97 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=206.6, 143.5, 130.7,
129.9, 129.8, 129.6, 128.0, 127.4, 125.8, 123.5, 121.9, 115.8, 99.4, 55.6, 46.9,
47.2 ppm; IR (KBr): n˜ =3046, 1673ACHTUNGTRNEUNG
(nCO), 1556 cmÀ1; HMRS: m/z (%)
calcd for C17H15NO2: 265.1103; found: 265.1095.
2-(3-Methoxyprop-1-ynyl)-1,6-diphenyl-1,2-dihydropyridine (5j). Pale
green oil; 1H NMR (400 MHz, CDCl3): d=7.34 (dd, J=8.0, 1.6 Hz, 2H),
7.20–7.18 (m, 3H), 7.17–7.07 (m, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.85 (t,
31.6 ppm; IR (KBr): n˜ =3185, 3062, 3008, 1712
HMRS: m/z (%) calcd for C18H16BrNO: 341.0415; found: 341.0421.
(nCO), 1591, 794 cmÀ1
ACHTUNGTERNNUNG ;
158
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Chem. Asian J. 2010, 5, 153 – 159

Synthesis of N-Aryl Heteroaromatic Compounds
Spectral data of the remaining compounds and the 1H and 13C NMR
spectra of all the compounds are given in the Supporting Information.
Am. Chem. Soc. 2008, 130, 1558; c) U. K. Tambar, B. M. Stoltz, J.
Am. Chem. Soc. 2005, 127, 5340.
[10] Selected recent reviews on aryne reactions: a) D. PeÇa, D. Perez, E.
Guitian, Angew. Chem. 2006, 118, 3659; Angew. Chem. Int. Ed.
2006, 45, 3579; b) A. M. Dyke, A. J. Hester, G. C. Lloyd-Jones, Syn-
thesis 2006, 24, 4093; c) H. Pellissier, M. Santelli, Tetrahedron 2003,
59, 701.
Acknowledgements
[11] Selected references for metal-catalyzed aryne involving three-com-
ponent coupling reactions: a) J. L. Henderson, A. S. Edwards, M. F.
Greaney, J. Am. Chem. Soc. 2006, 128, 7426; b) J. L. Henderson,
A. S. Edwards, M. F. Greaney, Org. Lett. 2007, 9, 5589; c) M. Jegan-
mohan, C.-H. Cheng, Org. Lett. 2004, 6, 2821; d) T. T. Jayanth, M.
Jeganmohan, C.-H. Cheng, Org. Lett. 2005, 7, 2921; e) S. Bhuvanes-
wari, M. Jeganmohan, C.-H. Cheng, Org. Lett. 2006, 8, 5581; f) S.
Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Chem. Commun.
2008, 5013; g) C. Xie, L. Liu, Y. Zhang, P. Xu, Org. Lett. 2008, 10,
2393.
We thank the National Science Council (NSC-96-2113M-007-020-MY3)
of Republic of China for the support of this research. We would also like
to express our appreciation to Dr. Kanniyappan Parthasarathy for his as-
sistance in acquiring some of the spectral data.
[1] a) E. K. Fields, S. Meyerson, J. Org. Chem. 1966, 31, 3307; b) N.
Dennis, A. R. Katritzky, S. K. Parton, J. Chem. Soc. Perkin Trans. 1
1976, 2285; c) D. K. Rayabarapu, K. K. Majumdar, T. Sambaiah, C.-
H. Cheng, J. Org. Chem. 2001, 66, 3646; d) E. Ihara, A. Kurokawa,
T. Koda, T. Muraki, T. Itoh, K. Inoue, Macromolecules 2005, 38,
2167.
[2] a) G. Wittig, W. Behnisch, Chem. Ber. 1958, 91, 2358; b) G. Wittig,
B. Reichl, Chem. Ber. 1963, 96, 2815; c) L. A. Carpino, D. E. Barr, J.
Org. Chem. 1966, 31, 764; d) G. Kaupp, J. Perreten, R. Leute, H.
Prinzbach, Chem. Ber. 1970, 103, 2288; e) L. J. Kricka, J. M. Vernon,
Adv. Heterocycl. Chem. 1974, 16, 87.
[3] V. Nair, K. H. Kim, J. Org. Chem. 1975, 40, 3784.
[4] a) M. Yoshida, S. Sugiura, A. Kunai, Org. Lett. 2002, 4, 2767; b) C.
Xie, Y. Zhang, Org. Lett. 2007, 9, 781.
[5] a) Z. Liu, R. C. Larock, J. Am. Chem. Soc. 2005, 127, 13112; b) H.
Yoshida, E. Shirakawa, Y. Honda, T. Hiyama, Angew. Chem. 2002,
114, 3381; Angew. Chem. Int. Ed. 2002, 41, 3247.
[6] a) Z. Liu, R. C. Larock, Org. Lett. 2003, 5, 4673; b) H. Yoshida, T.
Morishita, J. Ohshita, Org. Lett. 2008, 10, 3845.
[12] M. Jeganmohan, C.-H. Cheng, Chem. Commun. 2006, 2454.
[13] T. T. Jayanth, M. Jeganmohan, C.-H. Cheng, J. Am. Chem. Soc.
2006, 128, 2232.
[14] Selected references: a) Y. Luo, Z. Li, C. Li, Org Lett. 2005, 7, 2675,
and references therein; b) I. N. Nesterova, L. M. Alekseeva, S. M.
Golovira, V. G. Granik, Khim.-Farm. Zh. 1995, 29, 31; I. N. Nestero-
va, L. M. Alekseeva, S. M. Golovira, V. G. Granik, Chem. Abstr.
1996, 124, 117128t; c) N. Yamada, S. Kadowaki, K. Takahashi, K.
Umezu, Biochem. Pharmacol. 1992, 44, 1211; d) K. Faber, H.
Stueckler, T. Kappe, J. Heterocycl. Chem. 1984, 21, 1177; e) E.
Lukevics, I. Segal, A. Zablotskaya, S. Germane, Molecules 1997, 2,
180; f) H.-J. Knçlker, S. T. L. Agarval, Tetrahedron Lett. 2005, 46,
1173; g) A. Frisch, L. Landa, S. Saaby, K. A. Jorgensen, Angew.
Chem. 2005, 117, 6212; Angew. Chem. Int. Ed. 2005, 44, 6058, and
references therein.
[15] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
[16] P. P. Wickham, K. H. Hazan, H. Guo, G. Jones, K. H. Reuter, W. J.
Scott, J. Org. Chem. 1991, 56, 2045.
[17] a) M. Saunders, E. H. Gold, J. Org. Chem. 1962, 27, 1439; b) C.
Chen, B. Munoz, Tetrahedron Lett. 1999, 40, 3491; c) H. Nakano, N.
Tsugawa, R. Fujita, Tetrahedron Lett. 2005, 46, 5677, and references
therein.
[7] a) H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, A. Angew.
Chem. 2004, 116, 4025; Angew. Chem. Int. Ed. 2004, 43, 3935;
Angew. Chem. Int. Ed. 2004, 43, 3935; b) H. Yoshida, H. Fukushima,
J. Ohshita, A. Kunai, Tetrahedron Lett. 2004, 45, 8659; c) F. Sha, X.
Huang, Angew. Chem. 2009, 121, 3510; Angew. Chem. Int. Ed. 2009,
48, 3458.
[8] a) Z. Liu, R. C. Larock, Org. Lett. 2004, 6, 99; b) J. Zhao, R. C.
Larock, Org. Lett. 2005, 7, 4273; c) C. Raminelli, Z. Liu, R. C.
Larock, J. Org. Chem. 2006, 71, 4689.
Received: July 29, 2009
Published online: December 10, 2009
[9] a) H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, J. Am. Chem.
Soc. 2006, 128, 11040; b) G. D. Gilmore, K. M. Allan, B. M. Stoltz, J.
Chem. Asian J. 2010, 5, 153 – 159
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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