Chemo- and regioselective assembly of polysubstituted pyridines and isoquinolines from isocyanides, arynes, and terminal alkynes

Article abstract of DOI:10.1021/jo300072x

We have disclosed a general and efficient synthetic strategy for polysubstituted pyridines and isoquinolines with high chemo- and regioselectivity. In this methodology, 1-alkynyl imines act as the key compound to undergo a sequential alkynyl imine-allenyl

Full text of DOI:10.1021/jo300072x

Article
pubs.acs.org/joc
Chemo- and Regioselective Assembly of Polysubstituted Pyridines
and Isoquinolines from Isocyanides, Arynes, and Terminal Alkynes
Feng Sha,† Luling Wu,†,* and Xian Huang†,‡,§
†Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: We have disclosed a general and efficient
synthetic strategy for polysubstituted pyridines and isoquino-
lines with high chemo- and regioselectivity. In this method-
ology, 1-alkynyl imines act as the key compound to undergo a
sequential alkynyl imine−allenyl imine isomerization/aza-
Diels−Alder reaction/aromatization. In the first place, 1-
alkynyl imines were formed in situ by a highly selective
multicomponent reaction of isocyanides, arynes, and terminal
alkynes and reacted with another molecule of arynes or
terminal alkynes to furnish target heterocyclic products in a
highly efficient and atom-economic manner. On the other hand, we attempted to prepare 1-alkynyl imines by other approaches
to undergo a similar reaction sequence to afford polysubstituted pyridines and isoquinolines with a wider range. Different from
the first approach, the second approach utilized the preprepared 1-alkynyl imines to introduce the related different substitutents
into the final products: arynes or terminal alkynes bearing substituents different from those of 1-alkynyl imines have been
successfully applied for the synthesis a wide variety of pyridines and isoquinolines with diversity.
pyridine or isoquinolines (eq 2, Scheme 1). With this new
approach, various substituents could be introduced into the
different location of the final heterocyclic products, which may
increase the diversity dramatically. Herein, we report full details
of these studies.
INTRODUCTION
■
Pyridines are a class of important heterocycles and appear in
many naturally occurring bioactive compounds, pharmaceutical
molecules, and chiral ligands in polysubstituted form.1−3
Examples include the well-known alkaloids lycodine,2a the A3
adenosine receptor antagonist,2b and N,N-dimethylaminopyr-
idine (DMAP) analogue2c commonly applied in organic
synthesis (Figure 1). In addition, isoquinoline skeleton
possesses interesting bioactivities and acts as the fundamental
part of numerous natural products and synthetic pharmaceut-
icals (Figure 1).1a−c,2a,3 Because of their wide range of activities,
the syntheses of pyridines and isoquinolines remain a topic of
current interest.4,5 However, some of the approaches have
significant disadvantages, including harsh conditions and
lengthy or complicated procedures.4−6
We have previously reported an efficient and highly chemo-
and regioselective approach to polysubstituted pyridines and
isoquinolines through a strategy of multicomponent/isomer-
ization/aza-Diels−Alder/aromatization sequential reactions
from the multicomponent reaction of aryne, isocyanide, and
terminal alkyne: in situ generated intermediate A could
isomerize to N-allenyl imine B after 1,5-hydride shift in the
presence of CsF (eq 1, Scheme 1). Imine B further underwent
aza-Diels−Alder reaction with another molecule of aryne or
alkyne, which was followed by subsequent aromatization to
afford the target heterocyclic products.7 Therefore, we
envisioned that 1-alkynyl imines A may be preprepared and
reacted with other substituted arynes or alkynes to construct
RESULTS AND DISCUSSION
■
The reaction of 2-(trimethylsilyl)phenyl triflate 1a8a (1.3
equiv), benzyl isocyanide 2a (1.0 equiv), and phenylacetylene
3a (1.0 equiv) was conducted in the presence of CsF (2.0
equiv) in MeCN at room temperature (Table 1, entry 1). As
originally observed, N-benzyl 1-alkynyl imine 4a was obtained
in 81% yield, together with isoquinoline 5a and pyridine 6a in
6% and 2% yields, respectively. Thus, we then focused on
optimizing the conditions to control the selectivity of the
reaction to afford one single product 5a or 6a. When 2.5 equiv
of 1a was employed, the reaction conducted at 40 °C afforded
the desired product 5a in 49% yield (Table 1, entry 3); 26% of
4a remained. As reported by Larock et al., the employment of
toluene in the reaction system could reduce the solubility of
CsF so that the generation rate of benzyne would be slowed
down.9 Thus, toluene was added to MeCN to control the
generation of the benzyne to a proper rate to react with 4a.
Luckily, the yield of 5a was greatly improved to 74% when the
reaction was carried out in toluene/MeCN (1:3, Table 1, entry
Received: January 11, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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Figure 1. Application of Polysubstituted Pyridines and Isoquinolines.
Scheme 1. Strategy for the Construction of Pyridines and Isoquinolines via 1-Alkynyl Imines
a
Table 1. Optimization of Conditions for the Multicomponent Reactions of Aryne, Isocyanide, and Terminal Alkyne
b
yield (%)
entry
1a/2a/3a (equiv)
solvent toluene/MeCN (v)
time (h)
T (°C)
4a
5a
6
6a
c
1
2
3
4
5
6
7
8
9
1.3:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
1.3:1.0:2.0
1.3:1.0:2.5
1.3:1.0:3.0
1.3:1.0:3.0
0:1
0:1
0:1
1:5
1:3
1:1
4:1
4:1
5:1
37
37
10
13
18
22
48
48
40
rt
81
72
26
12
2
2
3
c
rt
13
40
40
40
75
75
75
85
49
68
74
16
6
3
1
0.6
57
69
76
70
0
0
0
0.4
0.3
0
a
The reactions were conducted using 1a, 2a (1.0 mmol), 3a, and CsF (2.0 equiv, based on 1a) in 5 mL of solvent. Tf = trifluoromethanesulfonyl,
b
c
TMS = trimethylsilyl. Yield of isolated product based on the isocyanide 2a used. rt = room temperature.
5) and the yield of 6a was reduced to 0.6% and only 2% of 4a
left. We reasoned that increasing the amount of alkyne could
disfavor the addition of a second equivalent of benzyne, and
therefore promote the formation of pyridine 6a. Then, the
reactions with a larger portion of toluene and alkyne were
checked. To our pleasure, by using 3.0 equiv of 3a, the yield of
product 6a was dramatically increased to 76% at 75 °C in
toluene/MeCN (4:1, Table 1, entry 8); the yield of 5a was
0.4%, and no 4a was detected. Furthermore, the 1-alkynyl imine
4a was isolated to react with benzyne precursor 1a or alkyne 3a
under the optimized conditions (Table 1, entries 5 and 8). As
predicted, these two procedures all went smoothly; isoquino-
line 5a and pyridine 6a could be furnished in 75% and 77%
yields, respectively (eq 3).
To examine the scope of the multicomponent reaction, we
then employed a variety of aryne precursors 1,8 isocyanides 2,
and terminal alkynes 3 under the optimized conditions (Table
1, entry 5) to generate substituted isoquniolines 5. As indicted
in Table 2, the phenyl acetylene derivatives 3 with an electron-
withdrawing group or an electron-donating group on the
phenyl ring could be smoothly employed (Table 2, entries 1−
6). Moreover, ethyl propiolate 3d was also applicable in the
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Table 2. Multicomponent Reactions for the Synthesis of
Isoquinolines 5
Table 3. Multicomponent Reactions for the Synthesis of
a
a
Pyridines 6
c
entry
1, R1
2, R2
Ph (2a)
3, R3
Ph (3a)
yield of 5 (%)
b
entry
1, R1
2, R2
Ph (2a)
3, R3
Ph (3a)
yields of 6 (%)
1
2
3
4
5
6
H (1a)
1a
74 (5a)
75 (5b)
67 (5c)
79 (5d)
72 (5e)
76 (5f)
71 (5g)
64 (5h)
57 (5i)
77 (5j)
79 (5k)
2a
p-ClC6H4 (3b)
1
2
3
4
5
6
H (1a)
1a
76 (6a)
65 (6b)
73 (6c)
81 (6d)
70 (6e)
77 (6f)
31 (6g)
43 (6h)
53 (6i)
1a
2a
p-EtC6H4 (3c)
2a
p-EtC6H4 (3c)
3a
1a
p-Tol (2b)
3a
1a
p-Tol (2b)
1a
1-naphthyl (2c)
3b
1a
2b
p-ClC6H4 (3b)
3b
Me (1b)
1a
p-FC6H4 (2d)
3b
Me (1b)
1b
2b
b
7
2a
CO2Et (3d)
p-FC6H4 (2d)
3b
b
c
8
1b
2b
3d
3d
3d
3d
7
1a
2a
2a
2a
n-C6H13 (3e)
c-C3H5 (3f)
p-FC6H4CO (3g)
b
d
9
1a
2c
8
1a
b
e
10
1a
p-BrC6H4 (2e)
9
1a
b
a
11
1b
2d
Unless otherwise specified, the reactions were conducted using 1
a
(0.65 mmol), 2 (0.5 mmol), 3 (1.5 mmol), and CsF (1.3 mmol) in 0.5
Unless otherwise specified, the reactions were conducted using 1
(1.25 mmol), 2 (0.5 mmol), 3 (0.5 mmol), and CsF (2.5 mmol) in
b
mL of MeCN and 2 mL of toluene at 75 °C for 2 d. Yield of isolated
c
b
product based on the isocyanide 2 used. The reaction was conducted
1.88 mL of MeCN and 0.63 mL of toluene at 40 °C overnight. The
reactions were conducted using 1 (1.25 mmol), 2 (0.5 mmol), 3d (0.5
mmol), [18]-crown-6 (3.0 mmol), and KF (2.5 mmol) in 2.5 mL of
THF at 0 °C overnight. Yield of isolated product based on the
isocyanide 2 used.
d
in 0.25 mL of MeCN and 2.25 mL of toluene for 91 h. The reaction
e
was carried out in a sealed tube with a screw cap. The reaction was
c
conducted in 2.5 mL of MeCN at rt overnight.
deficient alkyne 3g afforded corresponding product 6i in
moderate yield (Table 3, entry 9).
reaction and afforded corresponding products 5g−k in
moderate to good yields (Table 2, entries 7−11). In addition
to benzyl and p-methyl benzyl isocyanides, naphth-1-ylmethyl-,
p-fluoro-, and p-bromo-substituted benzyl isocyanides also
participated in the reaction to afford the desired products
(Table 2, entries 5, 6, and 9−11). However, it should be noted
that this reaction is not applicable to the alkyl-substituted
terminal alkynes.
It should be noted that two possible regioisomers 6 and 6′
could be generated, in principle, when terminal alkynes reacted
with N-allenyl imines (Figure 3, TS and TS′); however, the
reactions showed an excellent regioselectivity referring to
alkynes to give 3-substituted pyridines 6 as the single
regioisomer, which was established by the NOESY study of
6c and 6e−i. The regioselectivity may be rationalized as the
steric effect between R3 group of the alkynes and the linear
structure of the allene moiety in TS′, thus, TS is favored,
generating polysubstituted pyridines 6.
The structure of the product 5g was further established by
the X-ray diffraction studies (Figure 2).10
It is interesting to observe that when alkyl isocyanide 2f was
used, the reaction stopped at the stage of the 1-alkynyl imine 4b
(eq 4), indicating the aryl group (R2) is vital for the
isomerization from A to B (Scheme 1). Similar multi-
component couplings have been reported.11
Figure 2. ORTEP representation of 5g with thermal ellipsoids at the
30% probability level.
In addition to symmetric arynes, various nonsymmetric
arynes were also applicable in these reactions. When 4-fluoro-2-
(trimethylsilyl)phenyl triflate 1c was employed, it was
surprising to observe the regioisomer 6j was produced
exclusively in 82% yield (Scheme 2). This was probably due
to the strong electron-withdrawing effect of the fluoro
substituent which causes the meta position bears more negative
charge than the para position (Scheme 2); thus, nucleophilic
attack of isocyanide to aryne occurred preferentially at the para
position to give the electronically favored product.12b,13,14
For contrast, 4-methyl-2-(trimethylsilyl)phenyl triflate 1d
was applied as the benzyne precursor, and a 1:1 mixture of two
Further experiments were conducted to extend the multi-
component reaction to generate substituted pyridines under the
optimized conditions (Table 1, entry 8). The results are
presented in Table 3. When terminal aryl alkynes were
employed, the reaction proceeded smoothly to give the
corresponding polysubstituted pyridines 6a−f in good yields
(Table 3, entries 1−6); the reaction afforded the products 6g
and 6h in lower yields while employing terminal alkyl alkynes
(Table 3, entries 7 and 8); the reaction employing electron-
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Figure 3. Rationale for the exclusive formation of pyridines 6.
Scheme 2
nucleophilic addition of an isocyanide to o-methyl aryne.
Owing to the electron-donating character of the methyl group,
7a (bearing the anionic moiety at the meta position of the
methyl group) would be thermodynamically more stable
among two possible zwitterions. In contrast, formation of the
other zwitterion (7b) should be kinetically favored because of
less steric repulsion between the methyl group and the
incoming isocyanide.8c,12 In this reaction, the thermodynami-
cally stable zwitterion 7a was favored, therefore leading to the
final product 6l. Similar result was observed when using 1f as
aryne precursor and the sole isomer 6m was afforded in 78%
yield. The structures of 6l and 6m were confirmed by their
NOESY analyses (Scheme 3).
Moreover, aryne precursor 1e was also employed in the
reaction to afford isoquinolines. Similarly, the nucleophilic
attack of isocyanide to aryne selectively occurred at the ortho
position, and the Diels−Alder reaction of another molecule of
nonsymmetric aryne proceeded with good selectivity to afford
two regioisomers 5la and 5 lb in 55% combined yield (eq 6).
The major isomer 5la was isolated and confirmed by the
NOESY analysis.
1
regioisomers 6ka and 6kb was formed as determined by H
NMR analysis (eq 5).12,13
In the case of using 6-methyl-2-(trimethylsilyl)phenyl triflate
1e as the benzyne precursor, two regioisomers may be
generated in principle. Interestingly, the reaction occurred
with a perfect regioselectivity to furnish 6l as the only product
in good yield (Scheme 3). The different regioselectivities would
be ascribable to the reversibility of the zwitterions in the
Scheme 3
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One of the most attractive features of the above multi-
component reaction is that four molecules could be directly
assembled into the target heterocyclic compounds in a highly
efficient, regioselective, and atom-economical manner. How-
ever, we also realized that at least two substituents in the
product 5 or 6 were always identical, which seriously limited
the diversity of the current transformation. This inspired us to
further explore an approach for the synthesis of pyridines and
isoquinolines with a much better diversity. According to the
mechanistic studies (eq 3), the reaction intermediate 1-alkynyl
imine 4a could be isolated and utilized to generate pyridine 6a
or isoquinoline 5a. Thus, polysubstituted pyridines or
isoquinolines may be constructed by introducing differently
substituted alkynes or arynes to react with preprepared 1-
alkynyl imines by known methods.15 Therefore, we started to
develop a novel and efficient strategy to synthesize pyridine
derivatives with different susbstituents with 1-alkynyl imines as
the starting material.
Ti(OBu-n)4 was also used to generate 1-alkynyl imines 4k−m
(Scheme 4).15
Scheme 4. Condensation Reaction for the Synthesis of 1-
Alkynyl Imines 4
Initially, 1-alkynyl imines 4 were synthesized via the
previously explored multicomponent reaction of arynes,
isocyanides, and terminal alkynes (Table 4).7 By using CsF as
By using this method, a variety of different substitutents
could be introduced into the alkynyl imines, not limited by the
reported synthetic methods of aryne precursors.8 On the other
hand, compared with the multicomponent reaction (Scheme
3), the condensation strategy would not give regioisomers.
Efforts were then made to choose the proper base for the
reaction to synthesize pyridines 6 (Table 5). CsF was first
Table 4. Multi-component Reaction for the Synthesis of 1-
Alkynyl Imines 4
a
d
Table 5. Base Effect on the Synthesis of Pyridines 6 from 1-
Alkynyl Imines 4
yields of 4
a
entry
1, R1
2, R2
3, R3
Ph (3a)
p-MeOC6H4 (3h) 62 (4d)
(%)
b
c
1
2
3
4
5
6
7
H (1a)
1a
p-Tol (2b)
72 ; 71 (4c)
c
2b
c
1a
p-FC6H4 (2d)
p-ClC6H4 (3b)
n-C4H9 (3i)
c-C3H5 (3f)
3f
73 (4e)
b
c
1a
2b
22 ; 40 (4f)
c
1a
2b
49 (4g)
b
c
1a
1-naphthyl (2c)
25 ; 41 (4h)
b
entry
base
CsF
base (equiv)
yield of 6 (%)
c
Me (1b)
2b
3a
68 (4i)
1
2
3
4
5
3.0
3.0
2.0
2.0
2.0
2.0
2.0
72 (6n)
79 (6n)
78 (6n)
22 (6y)
54 (6y)
35 (6aa)
46 (6aa)
a
The reactions were conducted using 1 (1.5 mmol), 2 (1.0 mmol),
and 3 (1.2 mmol). The reaction was conducted with CsF (3.0 mmol)
in 5 mL of MeCN at rt. The reaction was conducted with KF (3.0
mmol) and [18]-crown-6 (3.5 mmol) in 5 mL of THF at 0 °C to rt
overnight. Yield of isolated product based on the isocyanide 2 used.
Cs2CO3
Cs2CO3
CsF
b
c
d
Cs2CO3
CsF
c
6
c
7
Cs2CO3
the fluoride anion source, the yields were rather low when R3
was an alkyl group (Table 4, entries 4 and 6). Notably,
pyridines and isoquinolines could always be produced in the
presence of CsF, thus leading to the relatively low yields of 1-
alkynyl imines. When a combination of KF and [18]-crown-6
was employed as the fluoride anion source, the yields of 4 were
improved (Table 4, entries 4 and 6).
As shown in Table 4, differently substituted 1-aryl-1-alkynyl
imines could be furnished in moderate to good yields via this
multicomponent reaction. For the terminal alkynes substituted
with either aryl or alkyl groups, the reactions afforded expected
products smoothly. The reaction also showed good regiose-
lectivity when nonsymmetric aryne precursor 1c was employed
to produce p-fluoro-substituted 4j as the only product (eq 7),
which was inconsistent with the regioselectivity of the previous
reaction (Scheme 2).
a
The reactions were conducted using 1-alkynyl imines 4 (0.5 mmol)
and alkynes (1.5 mmol) in 2 mL of toluene and 0.5 mL of MeCN at
b
75 °C. Yield of isolated product based on the 1-alkynyl imine 4 used.
c
The reaction was conducted using alkyne (2.5 mmol) in a sealed tube
with a screw cap.
introduced as the base according to the result presented in
Tables 2 and 3.7 When R3 or R4 was alkyl group, the yields of
6y and 6aa were rather low (Table 5, entries 4 and 6). By
applying Cs2CO3, the yields of 6 were improved (Table 5,
entries 5 and 7).
With the optimized conditions (Table 5, entry 3), we next
synthesized a series of polysubstituted pyridines from these
preprepared 1-alknyl imines. When R1, R2, R3, and R4 were all
aryl groups, the expected products 6n−v could be obtained
smoothly in moderate to good yields (Table 6, entries 1−9).
Alkynes 3 and 1-alkynyl imines 4 bearing alkyl groups were also
applicable in the reaction. In the case that R3 is the cyclopropyl
On the other hand, the condensation reaction of 1-alkynyl
ketones and substituted benzyl amines in the presence of
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a
Table 6. Synthesis of Pyridines 6 from 1-Alkynyl Imines 4
4
3
b
entry
R1
R2
p-Tol
R3
Ph (4c)
R4
yield of 6 (%)
1
Ph
Ph
Ph
p-ClC6H4 (3b)
78 (6n)
58 (6o)
74 (6p)
80 (6q)
62 (6r)
76 (6s)
73 (6t)
81 (6u)
83 (6v)
69 (6w)
68 (6x)
54 (6y)
38 (6z)
46 (6aa)
2
p-Tol
p-FC6H4
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
1-naphthyl
p-Tol
Ph
p-MeOC6H4 (4d)
p-ClC6H4 (4e)
Ph (4j)
3b
3
Ph (3a)
4
p-FC6H4
p-ClC6H4
p-MeOC6H4
3,4-MeC6H3
3,4-MeC6H3
3,4-MeC6H3
Ph
p-EtC6H4 (3c)
5
Ph (4k)
3c
6
Ph (4m)
3b
7
Ph (4i)
3b
8
Ph (4i)
m-NO2C6H4 (3j)
9
Ph (4i)
2-Py (3k)
10
11
12
13
c-C3H5 (4g)
c-C3H5 (4h)
n-C4H9 (4f)
n-C4H9 (4l)
Ph (4c)
3a
Ph
3a
Ph
3a
p-BrC6H4
Ph
3b
c
14
p-Tol
c-C3H5 (3f)
a
The reactions were conducted using 1-alkynyl imines 4 (1.0 equiv), alkynes 3 (3.0 equiv), and Cs2CO3 (2.0 equiv) in toluene/MeCN (4:1) at 75
b
c
°C. Yield of isolated product based on the 1-alkynyl imine 4 used. The reaction was conducted using 1-alkynyl imine 4c (1.0 equiv) and alkyne 3f
(5.0 equiv) in a sealed tube with a screw cap.
group, products 6w and 6x were afforded in 69% and 68% yield,
respectively (Table 6, entries 10 and 11). Nevertheless, by
employing n-butyl group as R3 (Table 6, entries 12, 13) or
cyclopropyl group as R4 (Table 6, entry 14), the reactions gave
the corresponding products in relatively low yields. It should be
noted that product 6v bears two pyridine rings, indicating its
potential to be developed as useful ligands.1c,f
Table 7. Synthesis of Isoquinolines 5 from 1-Alkynyl Imines
4
a
Moreover, we tested the reactivity of internal alkynes 1,2-
diphenylethyne and oct-1-ynylbenzene in this reaction (Scheme
5). However, the reactions did not give pyridine product.
4
R2
1
R4
b
entry
R1
R3
yield of 5 (%)
1
2
3
4
5
Ph
Ph
Ph
Ph (4a)
c-C3H5 (4g)
Ph (4i)
Me (1b)
H (1a)
1a
48 (5m)
51 (5n)
56 (5o)
72 (5p)
57 (5q)
Scheme 5. Reactions with Internal Alkynes
p-Tol
p-Tol
p-Tol
p-Tol
3,4-MeC6H3
p-FC6H4
Ph (4j)
1a
p-ClC6H4
Ph (4k)
1b
a
The reactions were conducted using 4 (1.0 equiv), 1 (2.0 equiv), CsF
(4.0 equiv), and Cs2CO3 (2.0 equiv) in toluene/MeCN (1:3) at 40 °C.
b
Yield of isolated product based on the 1-alkynyl imine 4 used.
be introduced into the following transformations by either in
the in situ generated form (path i) or isolated from the
multicomponent reaction or the condensation reaction of 1-
alkynyl ketone and substituted benzyl amine (path ii). In the
presence of CsF or Cs2CO3, 4 might isomerize to form 1-
allenyl imine intermediate 9 which then undergo aza-Diels−
Alder reaction with aryne or alkyne to form 10a or 10b.18
Subsequent aromatization gives isoquinoline 5 or pyridine 6.
Starting from 1-alkynyl imines, a variety of poly substituted
isoquinolines 5m−q could also be synthesized by introducing
arynes in the presence of Cs2CO3 in moderate to good yields
(Table 7). A satistafctory result was observed even when an
alkyl group, i.e. cyclopropyl, was introduced (5n, Table 7, entry
2).
On the basis of our studies above, a plausible mechanism is
illustrated in Scheme 6. First, isocyanide 2 attacks aryne
nucleophilically to generate the zwitterion 8.10,12,16 After
protonation with terminal alkyne 3,17 subsequent nucleophilic
addition of the in situ generated alkynyl anion occurs, affording
1-alkynyl imine 4 as the pivotal intermediate. Notably, 4 could
CONCLUSION
■
In conclusion, we have developed a novel procedure for the
efficient and diversified assembly of polysubstituted pyridines
and isoquinolines from the multicomponent reaction of arynes,
isocynides, and terminal alkynes, which included 1-alkynyl
imines as the key intermediate, followed by alkynyl imine−
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Scheme 6
126.2, 126.1, 125.8, 125.2, 123.5, 120.9, 61.2, 35.7, 14.2; IR (KBr)
2981, 1719, 1244, 1216, 1179, 1024, 775 cm−1; MS m/z 417 (M+, 89),
416 (100), 342 (70); HRMS (EI) calcd for C29H23NO2 417.1729,
found 417.1725.
allenyl imine isomerization/aza-Diels−Alder reaction/aromati-
zation sequence. Moreover, we synthesized a series of 1-alkynyl
imines through other approaches, which have been successfully
employed in the similar sequential reactions. By the newly
developed strategy, the diversity of pyridines and isoquinolines
has been greatly enriched.
Ethyl 2-(1-(4-Bromophenyl)-3-phenylisoquinolin-4-yl)acetate
(5j). Following the procedure for the preparation of 5i, the reaction
of 1a (395 mg, 1.25 mmol), 2e (98 mg, 0.5 mmol), 3d (49 mg, 0.5
mmol), KF (145 mg, 2.5 mmol), and [18]-crown-6 (792 mg, 3.0
mmol) in 2.5 mL of anhydrous THF afforded 171 mg (77%) of 5j: mp
101−103 °C; 1H NMR (400 MHz, CDCl3) 8.09 (d, J = 8.4 Hz, 1H),
7.99 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.66−7.59 (m, 6H),
7.56 (t, J = 8.4 Hz, 1H), 7.48−7.40 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H),
4.09 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
171.7, 158.5, 152.7, 140.7, 138.5, 136.8, 131.8, 131.4, 130.7, 129.6,
128.3, 128.0, 127.9, 126.8, 125.6, 123.7, 123.0, 120.7, 61.2, 35.6, 14.2;
IR (KBr) 2980, 1720, 1488, 1187, 1070, 1011, 795 cm−1; MS m/z 447
(M+, 67), 445 (M+, 67), 372 (100), 169 (90); HRMS (EI) calcd for
C25H20NO2Br(79) 445.0677, found 445.0686.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under a
purified N2 atmosphere. Anhydrous solvents were distilled prior to
use: THF, Et2O, and toluene were distilled from sodium
benzophenone; MeCN was distilled from P2O5; CH2Cl2 was distilled
from CaH2. Petroleum ether refers to the fraction with boiling point in
the range 60−90 °C. All 1H NMR and 13C NMR spectra were
measured in CDCl3 with TMS as the internal standard. Chemical shifts
are expressed in ppm, and J values are given in Hz. Melting points are
uncorrected. 2-(Trimethylsilyl)aryl triflates 1 were prepared according
to the known methods.8a,13,19 The characterization data for
compounds 4a,b, 5a−h,la,lb, 6a−j,l,m have been reported in the
Supporting Information of our previous communication.7
Ethyl 2-(3-(3,4-Dimethylphenyl)-1-(4-fluorophenyl)-6,7-dimethy-
lisoquinolin-4-yl)acetate (5k). Following the procedure for the
preparation of 5i, the reaction of 1b (408 mg, 1.25 mmol), 2d (68
mg, 0.5 mmol), 3d (49 mg, 0.5 mmol), KF (145 mg, 2.5 mmol), and
[18]-crown-6 (792 mg, 3.0 mmol) in 2.5 mL of anhydrous THF
General Procedure for the Synthesis of Isoquinolines 5i−k.
Under nitrogen atmosphere, KF (145 mg, 2.5 mmol) was added to a
solution of 2-(trimethylsilyl)phenyl triflate 1a (395 mg, 1.25 mmol),
isocyanide 2c (84 mg, 0.5 mmol), propiolate 3d (49 mg, 0.5 mmol),
and [18]-crown-6 (792 mg, 3.0 mmol) in 2.5 mL of anhydrous THF.
The reaction mixture was then stirred at 0 °C overnight. When the
reaction was complete as monitored by TLC, the reaction mixture was
filtered through a short column of silica gel eluted with Et2O. The
filtrate was concentrated under reduced pressure to afford the residue,
which was separated by silica gel chromatography (petroleum ether/
ethyl acetate = 15/1) to afford 5i (119 mg, 57%).
1
afforded 174 mg (79%) of 5k: mp 82−84 °C; H NMR (400 MHz,
CDCl3) 7.80 (s, 1H), 7.70−7.67 (m, 3H), 7.40 (s, 1H), 7.34 (d, J = 8.4
Hz, 1H), 7.20−7.14 (m, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H),
2.47 (s, 3H), 2.37 (s, 3H), 2.29 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 171.9, 162.8 (JC−F = 246.7 Hz), 157.3,
152.0, 140.7, 138.5, 136.3, 136.2, 136.0, 136.0, 135.7 (JC−F = 1.8 Hz),
131.8 (JC−F = 8.4 Hz), 130.8, 129.2, 127.1, 126.9, 124.5, 123.2, 119.5,
115.0 (JC−F = 21.4 Hz), 60.8, 35.6, 20.7, 20.2, 19.7, 19.4, 14.1; IR
(KBr) 2977, 1732, 1508, 1225, 1050, 842 cm−1; MS m/z 441 (M+,
95), 440 (73), 368 (100); HRMS (EI) calcd for C29H28NO2F
441.2104, found 441.2108.
Ethyl 2-(1-(naphthalen-1-yl)-3-phenylisoquinolin-4-yl)acetate
1
(5i): mp 115−117 °C; H NMR (400 MHz, CDCl3) 8.04 (d, J =
8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.76 (t,
J = 8.4 Hz, 1H), 7.69−7.61 (m, 5H), 7.51−7.34 (m, 7H), 4.28 (q, J =
7.2 Hz, 2H), 4.17 (s, 2H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) 171.8, 159.4, 152.7, 140.7, 136.9, 136.4, 133.7, 132.5,
130.8, 129.7, 128.8, 128.6, 128.2, 128.2, 127.9, 127.9, 127.3, 126.7,
Multicomponent Reaction of 1c, 2a, and 3a Leading to Pyridines
6ka and 6kb. Under nitrogen atmosphere, CsF (198 mg, 1.3 mmol)
was added to a solution of 4-methyl-2-(trimethylsilyl)phenyl triflate 1d
(203 mg, 0.65 mmol), benzyl isocyanide 2a (59 mg, 0.5 mmol), and
phenyl ethyne 3a (153 mg, 1.5 mmol) in 0.5 mL of anhydrous MeCN
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and 2 mL of anhydrous toluene. The reaction mixture was then stirred
at 75 °C for 2 days. When the reaction was complete as monitored by
TLC, the reaction mixture was filtered through a short column of silica
gel eluted with Et2O. The filtrate was concentrated under reduced
pressure to afford the residue, which was separated by silica gel
chromatography (petroleum ether/ethyl acetate = 20/1) to afford 6ka
MHz, CDCl3) 8.08−8.06 (m, 2H), 7.39−7.37 (m, 3H), 7.29 (d, J =
8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 4.98 (s, 2H), 2.53 (t, J = 7.2 Hz,
2H), 2.33 (s, 3H), 1.67−1.62 (m, 2H), 1.54−1.49 (m, 2H), 0.96 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 151.5, 137.8, 137.1, 136.1,
130.2, 129.0, 128.1, 127.9, 127.6, 101.4, 74.1, 59.6, 30.4, 22.0, 21.1,
19.1, 13.5; IR (neat) 2930, 2209, 1568, 1448, 1280, 1026 cm−1; MS m/
z 288 [(M − 1)+, 15], 246 (100), 105 (77); HRMS (EI) calcd for
C21H23N 289.1830, found 289.1825.
1
and 6kb (1:1, 150 mg, 73%): oil; H NMR (400 MHz, CDCl3) 7.53
(d, J = 6.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), [7.41−7.32 (m), 7.41−
7.32 (m), 6H], [7.31−7.13 (m), 7.31−7.13 (m), 26H], [7.11−7.06
(m), 7.11−7.06 (m), 4H], 4.12 (s, 2H), 4.09 (s, 2H), 2.38 (s, 3H),
2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) 157.7, 157.5, 154.5, 154.5,
140.8, 140.8, 140.4, 140.4, 140.1, 140.0, 139.8, 139.8, 137.7, 137.4,
134.4, 134.3, 132.2, 132.0, 130.1, 130.1, 130.0, 129.6, 129.5, 129.2,
128.8, 128.8, 128.7, 128.6, 128.5, 128.5, 128.2, 128.2, 127.9, 127.9,
127.7, 127.7, 127.5, 127.5, 127.0, 127.0, 126.2, 126.2, 38.2, 38.2, 21.4,
21.2; IR (KBr) 3023, 1539, 1425, 769 cm−1; MS m/z 411 (M+, 55),
410 (70), 55 (100); HRMS (EI) calcd for C31H25N 411.1987, found
411.1992.
General Procedure for the Preparation of 1-Alkynyl Imines
4c−j. Under nitrogen atmosphere, KF (174 mg, 3.0 mmol) was added
to a solution of 2-(trimethylsilyl)phenyl triflate 1a (447 mg, 1.5
mmol), 4-methylbenzyl isocyanide 2b (131 mg, 1.0 mmol), phenyl
ethyne 3a (122 mg, 1.2 mmol), and [18]-crown-6 (924 mg, 3.5 mmol)
in 5 mL of anhydrous THF. The reaction mixture was stirred at 0 °C
for 2 h and then at room temperature overnight. When the reaction
was complete as monitored by TLC, the reaction mixture was filtered
through a short column of silica gel eluted with Et2O. The filtrate was
concentrated under reduced pressure to afford the residue, which was
separated by silica gel chromatography (petroleum ether/ethyl acetate
= 30/1) to afford 4c (219 mg, 71%).
N-(3-Cyclopropyl-1-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4g). Following the procedure for the preparation of
4c, the reaction of 1a (447 mg, 1.5 mmol), 2b (131 mg, 1.0 mmol), 3f
(80 mg, 1.2 mmol), KF (174 mg, 3.0 mmol), and [18]-crown-6 (924
mg, 3.5 mmol) in 5 mL of anhydrous THF afforded 134 mg (49%) of
1
4g: oil; H NMR (400 MHz, CDCl3) 8.04−8.02 (m, 2H), 7.39−7.35
(m, 3H), 7.28 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 4.94 (s,
2H), 2.33 (s, 3H), 1.56−1.53 (m, 1H), 1.00−0.96 (m, 2H), 0.93−0.89
(m, 2H); 13C NMR (100 MHz, CDCl3) 151.3, 137.8, 137.1, 136.1,
130.2, 129.0, 128.1, 127.9, 127.6, 104.9, 69.5, 59.6, 21.1, 9.5, 0.2; IR
(neat) 3016, 2211, 1594, 1567, 1280, 1027, 917 cm−1; MS m/z 272
[(M − 1)+, 45], 141 (100), 105 (90); HRMS (EI) calcd for C20H19N
273.1517, found 273.1519.
N-(3-Cyclopropyl-1-phenylprop-2-ynylidene)(naphthalen-1-yl)-
methanamine (4h). Following the procedure for the preparation of
4c, the reaction of 1a (447 mg, 1.5 mmol), 2c (167 mg, 1.0 mmol), 3f
(80 mg, 1.2 mmol), KF (174 mg, 3.0 mmol), and [18]-crown-6 (924
mg, 3.5 mmol) in 5 mL of anhydrous THF afforded 127 mg (41%) of
4h: oil; 1H NMR (400 MHz, CDCl3) 8.17 (d, J = 8.0 Hz, 1H), 8.07−
8.04 (m, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.58−
7.37 (m, 7H), 5.40 (s, 2H), 1.58−1.55 (m, 1H), 1.02−0.98 (m, 2H),
0.94−0.90 (m, 2H); 13C NMR (100 MHz, CDCl3) 151.7, 137.8,
136.1, 133.8, 131.9, 130.3, 128.6, 128.1, 127.6, 127.4, 125.8, 125.6,
125.6, 125.5, 124.0, 105.6, 69.5, 57.7, 9.6, 0.2; IR (neat) 3060, 2212,
1690, 1593, 1567, 1282, 920 cm−1; MS m/z 308 [(M − 1)+, 95], 141
(100), 280 (48); HRMS (EI) calcd for C23H19N 309.1517, found
309.1520.
N-(1-(3,4-Dimethylphenyl)-3-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4i). Following the procedure for the preparation of 4c,
the reaction of 1b (489 mg, 1.5 mmol), 2b (131 mg, 1.0 mmol), 3a
(122 mg, 1.2 mmol), KF (174 mg, 3.0 mmol), and [18]-crown-6 (924
mg, 3.5 mmol) in 5 mL of anhydrous THF afforded 229 mg (68%) of
4i: mp 49−51 °C; 1H NMR (400 MHz, CDCl3) 7.94 (s, 1H), 7.88 (d,
J = 7.6 Hz, 1H), 7.57−7.55 (m, 2H), 7.34−7.30 (m, 5H), 7.16−7.12
(m, 3H), 5.10 (s, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H); 13C
NMR (100 MHz, CDCl3) 151.1, 139.3, 136.9, 136.3, 136.1, 135.2,
132.0, 129.5, 129.4, 129.0, 128.4, 128.3, 127.9, 125.4, 121.5, 98.3, 81.9,
59.8, 21.0, 19.7, 19.6; IR (neat) 2958, 2928, 2211, 1725, 1270, 1122,
1071 cm−1; MS m/z 337 (M+, 100), 105 (36); HRMS (EI) calcd for
C25H23N 337.1830, found 337.1829.
N-(1-(4-Fluorophenyl)-3-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4j). Following the procedure for the preparation of 4c,
the reaction of 1c (395 mg, 1.25 mmol), 2b (109 mg, 0.83 mmol), 3a
(102 mg, 1.0 mmol), KF (145 mg, 2.5 mmol), and [18]-crown-6 (792
mg, 3.0 mmol) in 4.2 mL of anhydrous THF afforded 190 mg (70%)
of 4j: oil; 1H NMR (400 MHz, CDCl3) 8.16−8.12 (m, 2H), 7.61−7.58
(m, 2H), 7.41−7.38 (m, 3H), 7.33 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0
Hz, 2H), 7.08 (t, J = 8.0 Hz, 2H), 5.07 (s, 2H), 2.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) 164.3 (JC−F = 248.2 Hz), 149.8, 136.8,
136.4, 133.7 (JC−F = 2.3 Hz), 132.2, 129.8, 129.6 (JC−F = 8.3 Hz),
129.1, 128.6, 128.0, 121.3, 115.2 (JC−F = 21.8 Hz), 98.9, 81.4, 59.9,
21.1; IR (neat) 2921, 2202, 1597, 1497, 1475, 1221, 1124 cm−1; MS
m/z 327 [M+, 35], 196 (100), 129 (80), 224 (65); HRMS (EI) calcd
for C23H18NF 327.1423, found 327.1426.
Condensation of Alkyn-1-ones with Arylmethanamine in
the Presence of Ti(OBu-n)4 Leading to 1-Alkynyl Imines 4k−
m.15a A solution of 4-methylbenzylamine (423 mg, 3.49 mmol) in 1.0
mL of anhydrous THF was added dropwise to a solution of 1-(4-
chlorophenyl)-3-phenylprop-2-yn-1-one (420 mg, 1.75 mmol) and
titanium(IV) butoxide (1.0 g, 2.94 mmol) in 9 mL of anhydrous THF
under nitrogen atmosphere. The resulting yellow mixture was stirred
at room temperature for 3.5 h. The mixture was poured into water (30
N-(1,3-Diphenylprop-2-ynylidene)(p-tolyl)methanamine (4c): oil;
1H NMR (400 MHz, CDCl3) 8.17−8.14 (m, 2H), 7.60−7.57 (m, 2H),
7.41−7.33 (m, 8H), 7.15 (d, J = 8.0 Hz, 2H), 5.11 (s, 2H), 2.32 (s,
3H); 13C NMR (100 MHz, CDCl3) 151.0, 137.4, 136.8, 136.2, 132.1,
130.4, 129.6, 129.1, 128.5, 128.2, 127.9, 127.6, 121.4, 98.7, 81.7, 59.9,
21.1; IR (neat) 2924, 2202, 1593, 1565, 1445, 1316, 1059, 1027 cm−1;
MS m/z 309 [M+, 100], 191 (78), 105 (79); HRMS (EI) calcd for
C23H19N 309.1517, found 309.1515.
N-(3-(4-Methoxyphenyl)-1-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4d). Following the procedure for the preparation of
4c, the reaction of 1a (447 mg, 1.5 mmol), 2b (131 mg, 1.0 mmol), 3h
(158 mg, 1.2 mmol), KF (174 mg, 3.0 mmol), and [18]-crown-6 (924
mg, 3.5 mmol) in 5 mL of anhydrous THF afforded 210 mg (62%) of
4d: mp 79−81 °C; 1H NMR (400 MHz, CDCl3) 8.16−8.14 (m, 2H),
7.53 (d, J = 8.4 Hz, 2H), 7.41−7.39 (m, 3H), 7.34 (d, J = 7.6 Hz, 2H),
7.15 (d, J = 7.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H), 3.77
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) 160.7, 151.3,
137.6, 137.0, 136.2, 133.8, 130.3, 129.0, 128.1, 127.9, 127.6, 114.2,
113.4, 99.3, 81.0, 59.8, 55.2, 21.0; IR (neat) 2924, 2200, 1601, 1563,
1508, 1289, 1248, 1169, 1023, 833 cm−1; MS m/z 339 [M+, 100], 324
(43); HRMS (EI) calcd for C24H21NO 339.1623, found 339.1618.
N-(3-(4-Chlorophenyl)-1-phenylprop-2-ynylidene)(4-
fluorophenyl)methanamine (4e). Following the procedure for the
preparation of 4c, the reaction of 1a (447 mg, 1.5 mmol), 2d (135 mg,
1.0 mmol), 3b (163 mg, 1.2 mmol), KF (174 mg, 3.0 mmol), and
[18]-crown-6 (924 mg, 3.5 mmol) in 5 mL of anhydrous THF
afforded 253 mg (73%) of 4e: oil; 1H NMR (400 MHz, CDCl3) 8.12
(d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.44−7.36 (m, 7H), 7.03
(t, J = 8.4 Hz, 2H), 5.06 (s, 2H); 13C NMR (100 MHz, CDCl3) 161.9
(JC−F = 242.9 Hz), 151.2, 137.2, 136.1, 135.5 (JC−F = 3.1 Hz), 133.4,
130.7, 129.4 (JC−F = 8.9 Hz), 129.0, 128.3, 127.6, 119.7, 115.2 (JC−F
=
21.1 Hz), 97.7, 82.3, 59.3; IR (neat) 2918, 2203, 1588, 1508, 1488,
1220, 1091, 1027 cm−1; MS m/z 347 (M+, 36), 240 (67), 212 (100),
163 (76); HRMS (EI) calcd for C22H15NFCl 347.0877, found
347.0872.
N-(1-Phenylhept-2-ynylidene)(p-tolyl)methanamine (4f). Follow-
ing the procedure for the preparation of 4c, the reaction of 1a (447
mg, 1.5 mmol), 2b (131 mg, 1.0 mmol), 3i (98 mg, 1.2 mmol), KF
(174 mg, 3.0 mmol), and [18]-crown-6 (924 mg, 3.5 mmol) in 5 mL
1
of anhydrous THF afforded 116 mg (40%) of 4f: oil; H NMR (400
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mL), and the water layer was extracted by CH2Cl2 (20 mL × 2). The
organic layer was combined and dried over MgSO4. After evaporation,
the residue was separated by silica gel chromatography (petroleum
ether/ethyl acetate = 30/1) to afford 4k (456 mg, 76%).
N-(1-(4-Chlorophenyl)-3-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4k): oil; 1H NMR (400 MHz, CDCl3) 8.08 (d, J = 8.0
Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.39−7.31 (m, 7H), 7.15 (d, J = 8.0
Hz, 2H), 5.07 (s, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3)
149.8, 136.6, 136.5, 136.4, 135.9, 132.1, 129.8, 129.1, 128.9, 128.6,
128.4, 128.0, 121.2, 99.0, 81.3, 60.0, 21.1; IR (neat) 2918, 2200, 1586,
1486, 1309, 1091, 1012, 837 cm−1; MS m/z 343 [M+, 15], 129 (100),
212 (94), 240 (64); HRMS (EI) calcd for C23H18NCl 343.1128, found
343.1126.
4-(Cyclopropylmethyl)-3-phenyl-1-p-tolylisoquinoline (5n). Fol-
lowing the procedure for the preparation of 5m, the reaction of 4g
(130 mg, 0.48 mmol), 1a (283 mg, 0.95 mmol), CsF (289 mg, 1.9
mmol), and Cs2CO3 (310 mg, 0.95 mmol) in 1.8 mL of anhydrous
MeCN and 0.6 mL of anhydrous toluene afforded 85 mg (51%) of 5n:
oil; 1H NMR (400 MHz, CDCl3) 8.25 (d, J = 8.4 Hz, 1H), 8.16 (d, J =
8.4 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.63−7.56 (m, 4H), 7.51 (t, J =
7.6 Hz, 1H), 7.44−7.23 (m, 5H), 3.07 (d, J = 6.4 Hz, 2H), 2.43 (s,
3H), 1.03−0.97 (m, 1H), 1.43−1.39 (m, 2H), 0.07−0.05 (m, 2H); 13C
NMR (100 MHz, CDCl3) 158.3, 151.6, 141.9, 138.1, 137.0, 136.5,
130.1, 130.0, 129.7, 128.9, 128.3, 127.9, 127.4, 127.3, 126.1, 125.9,
124.4, 32.4, 21.3, 12.0, 5.5; IR (KBr) 2924, 1573, 1445, 1218, 1211
cm−1; MS m/z 349 (M+, 100), 320 (59), 272 (40); HRMS (EI) calcd
for C26H23N 349.1830, found 349.1833.
N-(1-(4-Bromophenyl)hept-2-ynylidene)(phenyl)methanamine
(4l). A solution of benzylamine (373 mg, 3.49 mmol) in 1.0 mL of
anhydrous THF was added dropwise to a solution of 1-(4-
bromophenyl)hept-2-yn-1-one (462 mg, 1.75 mmol) and titanium(IV)
butoxide (1.0 g, 2.94 mmol) in 9 mL of anhydrous THF under
nitrogen atmosphere. The resulting yellow mixture was heated to
reflux for 1.5 h and then cooled to room temperature. The mixture was
poured into water (30 mL), and the water layer was extracted by
CH2Cl2 (20 mL × 2). The organic layer was combined and dried over
MgSO4. After evaporation, the residue was separated by silica gel
chromatography (petroleum ether/ethyl acetate = 30/1) to afford 4l
(556 mg, 90%): oil. 1H NMR (400 MHz, CDCl3) 7.94 (d, J = 8.4 Hz,
2H), 7.51 (d, J = 8.4 Hz, 2H), 7.40−7.32 (m, 4H), 7.27−7.24 (m,
1H), 4.98 (s, 2H), 2.54 (t, J = 7.2 Hz, 2H), 1.67−1.63 (m, 2H), 1.53−
1.48 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
150.6, 139.9, 136.6, 131.2, 129.2, 128.4, 127.9, 126.7, 124.8, 102.0,
73.7, 59.9, 30.3, 22.0, 19.1, 13.5; IR (neat) 2957, 2930, 2209, 1587,
1483, 1280, 1069, 1009 cm−1; MS m/z 353 [M(Br79)+, 10], 91 (100);
HRMS (EI) calcd for C20H20NBr(79) 353.0779, found 353.0785.
N-(1-(4-Methoxyphenyl)-3-phenylprop-2-ynylidene)(p-tolyl)-
methanamine (4m). Following the procedure for the preparation of
4l, the reaction of 4-methylbenzylamine (423 mg, 3.49 mmol), 1-(4-
methoxyphenyl)-3-phenylprop-2-yn-1-one (413 mg, 1.75 mmol), and
titanium(IV) butoxide (1.0 g, 2.94 mmol) in 10 mL of anhydrous THF
4-Benzyl-3-(3,4-dimethylphenyl)-1-p-tolylisoquinoline (5o). Fol-
lowing the procedure for the preparation of 5m, the reaction of 4i
(169 mg, 0.5 mmol), 1a (298 mg, 1.0 mmol), CsF (304 mg, 2.0
mmol), and Cs2CO3 (326 mg, 1.0 mmol) in 1.88 mL of anhydrous
MeCN and 0.62 mL of anhydrous toluene afforded 116 mg (56%) of
5o: mp 73−75 °C; 1H NMR (400 MHz, CDCl3) 8.16 (d, J = 8.8 Hz,
1H), 7.89 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6
Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.33−7.24 (m, 5H),
7.20−7.08 (m, 4H), 4.52 (s, 2H), 2.45 (s, 3H), 2.26 (s, 3H), 2.22 (s,
3H); 13C NMR (100 MHz, CDCl3) 159.2, 152.6, 141.3, 138.8, 138.2,
137.1, 137.0, 136.1, 136.0, 130.9, 130.2, 129.9, 129.2, 128.9, 128.5,
128.2, 128.2, 126.8, 126.1, 125.9, 125.8, 124.9, 124.3, 35.1, 21.3, 19.8,
19.5; IR (KBr) 2920, 1727, 1456, 1271, 1123 cm−1; MS m/z 412 [(M
− 1)+, 100], 57 (87); HRMS (EI) calcd for C31H27N 413.2144, found
413.2147.
4-Benzyl-3-(4-fluorophenyl)-1-p-tolylisoquinoline (5p). Following
the procedure for the preparation of 5m, the reaction of 4j (164 mg,
0.5 mmol), 1a (298 mg, 1.0 mmol), CsF (304 mg, 2.0 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in 1.88 mL of anhydrous MeCN and
0.62 mL of anhydrous toluene afforded 145 mg (72%) of 5p: mp 90−
92 °C; 1H NMR (400 MHz, CDCl3) 8.18 (d, J = 8.4 Hz, 1H), 7.89 (d,
J = 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.60−7.48 (m, 4H), 7.34 (d,
J = 7.6 Hz, 2H), 7.27−7.24 (m, 3H), 7.11 (d, J = 7.6 Hz, 2H), 7.05 (t,
J = 8.0 Hz, 2H), 4.50 (s, 2H), 2.46 (s, 3H); 13C NMR (100 MHz,
CDCl3) 162.5 (JC−F = 244.5 Hz), 159.4, 151.2, 140.8, 138.4, 137.2
(JC−F = 3.6 Hz), 136.9, 136.8, 131.2 (JC−F = 8.8 Hz), 130.1, 130.1,
129.0, 128.6, 128.2, 128.1, 126.4, 126.1, 125.9, 124.8, 124.4, 114.9
(JC−F = 21.2 Hz), 35.0, 21.3; IR (KBr) 2921, 1604, 1509, 1385, 1224,
1182 cm−1; MS m/z 402 [(M − 1)+, 100], 388 (21); HRMS (EI)
calcd for C29H22NF 403.1736, found 403.1733.
1
afforded 303 mg (51%) of 4m: mp 63−65 °C; H NMR (400 MHz,
CDCl3) 8.10 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.42−7.39
(m, 3H), 7.33 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 6.93 (d, J
= 8.8 Hz, 2H), 5.07 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) 161.6, 150.4, 137.1, 136.2, 132.2, 130.5, 129.6,
129.2, 129.1, 128.6, 128.0, 121.6, 113.5, 98.3, 81.8, 59.8, 55.4, 21.1; IR
(neat) 2928, 2202, 1604, 1510, 1310, 1253, 1167, 1031 cm−1; MS m/z
339 [M+, 73], 208 (100), 236 (97), 193 (84); HRMS (EI) calcd for
C24H21NO 339.1623, found 339.1627.
4-Benzyl-3-(4-chlorophenyl)-6,7-dimethyl-1-p-tolylisoquinoline
(5q). Following the procedure for the preparation of 5m, the reaction
of 4k (172 mg, 0.5 mmol), 1b (326 mg, 1.0 mmol), CsF (304 mg, 2.0
mmol), and Cs2CO3 (326 mg, 1.0 mmol) in 1.88 mL of anhydrous
MeCN and 0.62 mL of anhydrous toluene afforded 127 mg (57%) of
General Procedure for the Synthesis of Isoquinolines 5m−q.
Under nitrogen atmosphere, CsF (304 mg, 2.0 mmol) and Cs2CO3
(326 mg, 1.0 mmol) were added at room temperature to a stirred
solution of 1b (326 mg, 1.0 mmol) in 0.47 mL of anhydrous MeCN
and 0.16 mL of anhydrous toluene. The reaction mixture was heated at
40 °C. A solution of 4a (148 mg, 0.5 mmol) in 1.41 mL of anhydrous
MeCN and 0.47 mL of anhydrous toluene was injected into the
reaction mixture by a microinfusion pump at the rate of 0.1 mL/h.
When the injection was over, the mixture was stirred at 40 °C for an
additional 1 h. Then the reaction mixture was filtered through a short
column of silica gel eluted with Et2O. The filtrate was concentrated
under reduced pressure to afford the residue, which was separated by
silica gel chromatography (petroleum ether/ethyl acetate = 20/1) to
afford 5 m (96 mg, 48%).
1
5q: mp 171−173 °C; H NMR (400 MHz, CDCl3) 7.90 (s, 1H),
7.66−7.64 (m, 3H), 7.48 (d, J = 7.6 Hz, 2H), 7.34−7.17 (m, 7H), 7.10
(d, J = 7.6 Hz, 2H), 4.44 (s, 2H), 2.46 (s, 3H), 2.36 (s, 3H), 2.35 (s,
3H); 13C NMR (100 MHz, CDCl3) 158.5, 150.3, 140.9, 140.5, 139.9,
138.2, 137.1, 136.5, 135.8, 133.5, 130.9, 130.0, 129.0, 128.6, 128.1,
128.1, 127.5, 126.0, 125.0, 124.4, 123.8, 34.8, 21.4, 20.8, 20.3; IR
(KBr) 2918, 1493, 1451, 1087, 1014, 907 cm−1; MS m/z 447 (M+,
100), 432 (45); HRMS (EI) calcd for C31H26NCl 447.1754, found
447.1750.
General Procedure for the Synthesis of Pyridines 6n−z and
6aa. Under nitrogen atmosphere, Cs2CO3 (326 mg, 1.0 mmol) was
added at room temperature to a stirred solution of 3b (205 mg, 1.5
mmol) in 0.13 mL of anhydrous MeCN and 0.5 mL of anhydrous
toluene. The reaction mixture was heated at 75 °C. A solution of 4c
(155 mg, 0.5 mmol) in 0.37 mL of anhydrous MeCN and 1.5 mL of
anhydrous toluene was injected into the reaction mixture by a
microinfusion pump at the rate of 0.1 mL/h. When the injection was
over, the mixture was stirred at 75 °C for an additional 1 h. Then the
reaction mixture was filtered through a short column of silica gel
eluted with Et2O. The filtrate was concentrated under reduced
pressure to afford the residue, which was separated by silica gel
4-Benzyl-6,7-dimethyl-1,3-diphenylisoquinoline (5m): mp 100−
1
102 °C; H NMR (400 MHz, CDCl3) 7.87 (s, 1H), 7.77−7.75 (m,
2H), 7.66 (s, 1H), 7.56−7.46 (m, 5H), 7.34−7.23 (m, 5H), 7.18 (t, J =
7.2 Hz, 1H), 7.12 (d, J = 7.2 Hz, 2H), 4.48 (s, 2H), 2.35 (s, 3H), 2.35
(s, 3H); 13C NMR (100 MHz, CDCl3) 158.2, 151.6, 141.4, 141.2,
140.4, 140.1, 136.3, 135.8, 130.2, 129.5, 128.5, 128.2, 128.2, 128.0,
127.8, 127.5, 127.4, 125.9, 124.9, 124.4, 124.0, 34.9, 20.8, 20.2; IR
(KBr) 2920, 1551, 1494, 1448, 1406, 1025, 909 cm−1; MS m/z 398
[(M − 1)+, 100], 237 (38); HRMS (EI) calcd for C30H25N 399.1987,
found 399.1992.
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chromatography (petroleum ether/ethyl acetate = 20/1) to afford 6n
(173 mg, 78%).
reaction of 4m (170 mg, 0.5 mmol), 3b (205 mg, 1.5 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0
mL of anhydrous toluene afforded 181 mg (76%) of 6s: mp 150−152
3-Benzyl-5-(4-chlorophenyl)-2-phenyl-6-p-tolylpyridine (6n): mp
1
1
144−146 °C; H NMR (400 MHz, CDCl3) 7.59−7.56 (m, 2H), 7.48
°C; H NMR (400 MHz, CDCl3) 7.53 (d, J = 8.4 Hz, 2H), 7.45 (s,
(s, 1H), 7.43−7.38 (m, 3H), 7.30−7.18 (m, 7H), 7.11−7.02 (m, 6H),
4.11 (s, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) 157.7, 154.5,
140.7, 140.3, 140.1, 138.4, 137.6, 136.8, 133.1, 132.0, 130.8, 129.9,
129.2, 128.8, 128.6, 128.6, 128.5, 128.2, 128.1, 128.0, 126.3, 38.1, 21.2;
IR (KBr) 2924, 1494, 1433, 1092, 1015 cm−1; MS m/z 444 [(M − 1)+,
65], 430 (40), 57 (100); HRMS (EI) calcd for C31H24NCl 445.1597,
found 445.1595.
1H), 7.30−7.19 (m, 7H), 7.09 (d, J = 8.4 Hz, 4H), 7.03 (d, J = 8.4 Hz,
2H), 6.94 (d, J = 8.4 Hz, 2H), 4.12 (s, 2H), 3.82 (s, 3H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) 159.6, 157.3, 154.4, 140.8, 140.4, 138.5,
137.5, 136.9, 133.1, 132.8, 132.6, 131.8, 130.8, 130.6, 129.9, 128.8,
128.6, 128.6, 128.4, 126.3, 113.6, 55.3, 38.2, 21.2; IR (KBr) 2918,
1508, 1432, 1248, 1175, 907 cm−1; MS m/z 474 [(M − 1)+, 100], 55
(10); HRMS (EI) calcd for C32H26NOCl 475.1703, found 475.1697.
3-Benzyl-5-(4-chlorophenyl)-2-(3,4-dimethylphenyl)-6-p-tolylpyr-
idine (6t). Following the procedure for the preparation of 6n, the
reaction of 4i (169 mg, 0.5 mmol), 3b (205 mg, 1.5 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0
mL of anhydrous toluene afforded 173 mg (73%) of 6t: mp 140−142
3-(4-Chlorophenyl)-5-(4-methoxybenzyl)-6-phenyl-2-p-tolylpyri-
dine (6o). Following the procedure for the preparation of 6n, the
reaction of 4d (140 mg, 0.41 mmol), 3b (164 mg, 1.2 mmol), and
Cs2CO3 (261 mg, 0.8 mmol) in 0.4 mL of anhydrous MeCN and 1.6
mL of anhydrous toluene afforded 113 mg (58%) of 6o: mp 151−153
1
1
°C; H NMR (400 MHz, CDCl3) 7.60−7.56 (m, 2H), 7.46 (s, 1H),
°C; H NMR (400 MHz, CDCl3) 7.44 (s, 1H), 7.35 (s, 1H), 7.30−
7.43−7.37 (m, 3H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H),
7.10 (d, J = 8.4 Hz, 2H), 7.04−6.97 (m, 4H), 6.80 (d, J = 8.4 Hz, 2H),
4.04 (s, 2H), 3.76 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.0, 157.6, 154.4, 140.6, 140.1, 138.5, 137.5, 136.8, 133.1, 133.1,
132.4, 132.3, 130.8, 129.9, 129.8, 129.3, 128.6, 128.5, 128.1, 128.0,
114.0, 55.2, 37.2, 21.2; IR (KBr) 2954, 1511, 1433, 1248, 1092, 1035
cm−1; MS m/z 474 [(M − 1)+, 15], 416 (86), 302 (100), 233 (95);
HRMS (EI) calcd for C32H26NOCl 475.1703, found 475.1706.
3-(4-Chlorobenzyl)-6-(4-fluorophenyl)-2,5-diphenylpyridine (6p).
Following the procedure for the preparation of 6n, the reaction of 4e
(101 mg, 0.29 mmol), 3a (91 mg, 0.9 mmol), and Cs2CO3 (195 mg,
0.6 mmol) in 0.3 mL of anhydrous MeCN and 1.2 mL of anhydrous
toluene afforded 97 mg (74%) of 6p: mp 133−135 °C; 1H NMR (400
MHz, CDCl3) 7.54−7.51 (m, 3H), 7.45−7.36 (m, 6H), 7.30−7.27 (m,
4H), 7.24−7.21 (m, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.90−6.85 (m,
3H), 4.08 (s, 2H); 13C NMR (100 MHz, CDCl3) 162.5 (JC−F = 245.1
Hz), 157.6, 153.7, 140.8, 140.0, 139.5, 138.6, 135.9 (JC−F = 4.1 Hz),
133.8, 131.8 (JC−F = 8.0 Hz), 130.4, 130.1, 129.5, 129.1, 128.7, 128.4,
128.3, 128.2, 127.5, 127.3, 114.8 (JC−F = 21.3 Hz), 29.7; IR (KBr)
2918, 2849, 1491, 1217, 1157, 1015, 842 cm−1; MS m/z 448 [(M −
1)+, 100], 57 (39); HRMS (EI) calcd for C30H21NFCl 449.1347,
found 449.1350.
3-Benzyl-5-(4-ethylphenyl)-2-(4-fluorophenyl)-6-p-tolylpyridine
(6q). Following the procedure for the preparation of 6n, the reaction
of 4j (164 mg, 0.5 mmol), 3c (195 mg, 1.5 mmol), and Cs2CO3 (326
mg, 1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0 mL of
anhydrous toluene afforded 183 mg (80%) of 6q: mp 160−162 °C; 1H
NMR (400 MHz, CDCl3) 7.56−7.53 (m, 3H), 7.30 (d, J = 8.0 Hz,
2H), 7.27−7.22 (m, 2H), 7.20−7.17 (m, 1H), 7.10−7.05 (m, 8H),
7.02 (d, J = 8.0 Hz, 2H), 4.08 (s, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.29
(s, 3H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) 162.7
(JC−F = 245.4 Hz), 156.2, 154.7, 143.2, 141.1, 140.2, 137.4, 137.2,
137.1, 136.4 (JC−F = 3.2 Hz), 134.5, 131.7, 131.1 (JC−F = 8.8 Hz),
129.9, 129.4, 128.7, 128.6, 128.5, 127.8, 126.3, 115.0 (JC−F = 21.3 Hz),
38.2, 28.5, 21.2, 15.4; IR (KBr) 3027, 1602, 1508, 1433, 1224, 1156,
1016, 909 cm−1; MS m/z 456 [(M − 1)+, 100], 91 (10); HRMS (EI)
calcd for C33H28NF 457.2206, found 457.2205.
7.23 (m, 5H), 7.20−7.14 (m, 4H), 7.09−7.07 (m, 4H), 7.02 (d, J = 8.0
Hz, 2H), 4.10 (s, 2H), 2.28 (s, 6H), 2.27 (s, 3H); 13C NMR (100
MHz, CDCl3) 157.9, 154.4, 140.5, 140.5, 138.6, 137.7, 137.4, 136.9,
136.4, 136.3, 133.0, 132.8, 131.9, 130.8, 130.5, 130.0, 129.3, 128.8,
128.6, 128.5, 128.4, 126.6, 126.2, 38.2, 21.2, 19.8, 19.5; IR (KBr) 2971,
1496, 1434, 1090, 1018 cm−1; MS m/z 472 [(M − 1)+, 8], 279 (95),
167 (100), 149 (100); HRMS (EI) calcd for C33H28NCl 473.1910,
found 473.1907.
3-Benzyl-2-(3,4-dimethylphenyl)-5-(3-nitrophenyl)-6-p-tolylpyri-
dine (6u). Following the procedure for the preparation of 6n, the
reaction of 4i (133 mg, 0.4 mmol), 3j (176 mg, 1.2 mmol), and
Cs2CO3 (261 mg, 0.8 mmol) in 0.4 mL of anhydrous MeCN and 1.6
mL of anhydrous toluene afforded 157 mg (81%) of 6u: mp 87−89
1
°C; H NMR (400 MHz, CDCl3) 8.10−8.07 (m, 2H), 7.51 (s, 1H),
7.42−7.36 (m, 3H), 7.30−7.17 (m, 7H), 7.11 (d, J = 7.6 Hz, 2H), 7.02
(d, J = 7.6 Hz, 2H), 4.14 (s, 2H), 2.30 (s, 3H), 2.28 (s, 6H); 13C NMR
(100 MHz, CDCl3) 158.7, 154.6, 148.2, 141.9, 140.5, 140.3, 137.8,
137.4, 136,7, 136.4, 136.3, 135.8, 132.2, 131.6, 130.5, 130.0, 129.3,
129.0, 128.8, 128.8, 128.6, 126.5, 126.3, 124.2, 121.9, 38.1, 21.2, 19.8,
19.6; IR (KBr) 2920, 1531, 1440, 1348, 1101, 1022, 909 cm−1; MS m/
z 484 (M+, 100), 437 (36); HRMS (EI) calcd for C33H28N2O2
484.2151, found 484.2150.
5′-Benzyl-6′-(3,4-dimethylphenyl)-2′-p-tolyl-2,3′-bipyridine (6v).
Following the procedure for the preparation of 6n, the reaction of
4i (169 mg, 0.5 mmol), 3k (155 mg, 1.5 mmol), and Cs2CO3 (326 mg,
1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0 mL of anhydrous
1
toluene afforded 183 mg (83%) of 6v: mp 124−126 °C; H NMR
(400 MHz, CDCl3) 8.61 (d, J = 1.1 Hz, 1H), 7.84 (s, 1H), 7.35−7.29
(m, 5H), 7.22 (t, J = 7.2 Hz, 2H), 7.16−7.06 (m, 5H), 7.03−6.97 (m,
3H), 4.13 (s, 2H), 2.27 (s, 6H), 2.25 (s, 3H); 13C NMR (100 MHz,
CDCl3) 158.5, 158.0, 154.5, 149.5, 140.7, 140.4, 137.7, 137.4, 137.0,
136.3, 136.1, 135.4, 133.1, 131.8, 130.4, 129.8, 129.1, 128.7, 128.5,
128.3, 126.5, 126.0, 125.1, 121.6, 38.1, 21.1, 19.7, 19.4; IR (KBr) 2918,
1589, 1497, 1428, 907 cm−1; MS m/z 439 [(M − 1)+, 12], 84 (100);
HRMS (EI) calcd for C32H28N2 440.2252, found 440.2255.
3-(Cyclopropylmethyl)-2,5-diphenyl-6-p-tolylpyridine (6w). Fol-
lowing the procedure for the preparation of 6n, the reaction of 4g (134
mg, 0.49 mmol), 3a (150 mg, 1.47 mmol), and Cs2CO3 (319 mg, 0.98
mmol) in 0.5 mL of anhydrous MeCN and 2.0 mL of anhydrous
toluene afforded 127 mg (69%) of 6w: mp 92−94 °C; 1H NMR (400
MHz, CDCl3) 7.88 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.52−7.47 (m,
2H), 7.43 (t, J = 7.6 Hz, 1H), 7.38−7.31 (m, 7H), 7.06 (d, J = 7.6 Hz,
2H), 2.72 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H), 1.05−0.90 (m, 1H), 0.56
(q, J = 8.0 Hz, 2H), 0.20−0.17 (m, 2H); 13C NMR (100 MHz,
CDCl3) 157.1, 154.1, 140.6, 140.4, 139.5, 137.3, 137.1, 134.2, 133.2,
130.0, 129.6, 129.3, 128.4, 128.2, 128.0, 127.7, 126.9, 36.6, 21.2, 11.3,
4.9; IR (KBr) 3002, 1427, 1181, 1019, 908 cm−1; MS m/z 374 [(M −
1)+, 100], 298 (17); HRMS (EI) calcd for C28H25N 375.1987, found
375.1991.
3-Benzyl-2-(4-chlorophenyl)-5-(4-ethylphenyl)-6-p-tolylpyridine
(6r). Following the procedure for the preparation of 6n, the reaction of
4k (172 mg, 0.5 mmol), 3c (195 mg, 1.5 mmol), and Cs2CO3 (326
mg, 1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0 mL of
anhydrous toluene afforded 147 mg (62%) of 6r: mp 127−129 °C; 1H
NMR (400 MHz, CDCl3) 7.53−7.49 (m, 3H), 7.37 (d, J = 8.0 Hz,
2H), 7.30 (d, J = 8.0 Hz, 2H), 7.28−7.24 (m, 3H), 7.09−7.06 (m,
6H), 7.02 (d, J = 8.0 Hz, 2H), 4.08 (s, 2H), 2.63 (q, J = 7.2 Hz, 2H),
2.29 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
155.9, 154.8, 143.2, 141.2, 140.2, 138.8, 137.4, 137.1, 137.1, 134.7,
134.0, 131.7, 130.7, 129.9, 129.4, 128.8, 128.6, 128.5, 128.3, 127.8,
126.3, 38.2, 28.5, 21.2, 15.4; IR (KBr) 2965, 1490, 1433, 1091, 1014,
908, 834 cm−1; MS m/z 472 [(M − 1)+, 100], 57 (31); HRMS (EI)
Calcd for C33H28NCl 473.1910, found 473.1916.
3-(Cyclopropylmethyl)-6-(naphthalen-1-yl)-2,5-diphenylpyridine
(6x). Following the procedure for the preparation of 6n, the reaction
of 4h (127 mg, 0.41 mmol), 3a (125 mg, 1.23 mmol), and Cs2CO3
(267 mg, 0.82 mmol) in 0.4 mL of anhydrous MeCN and 1.6 mL of
3-Benzyl-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-p-tolylpyri-
dine (6s). Following the procedure for the preparation of 6n, the
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anhydrous toluene afforded 115 mg (68%) of 6x: mp 168−170 °C; 1H
NMR (400 MHz, CDCl3) 8.01 (s, 1H), 7.86−7.73 (m, 3H), 7.60 (d, J
= 7.6 Hz, 2H), 7.45−7.25 (m, 7H), 7.14−7.09 (m, 5H), 2.74 (d, J =
6.8 Hz, 2H), 1.09−0.95 (m, 1H), 0.59−0.55 (m, 2H), 0.21−0.18 (m,
2H); 13C NMR (100 MHz, CDCl3) 157.1, 154.2, 140.4, 139.5, 139.0,
138.0, 136.2, 134.0, 133.7, 132.2, 129.3, 129.0, 128.4, 128.1, 128.1,
128.0, 127.9, 127.8, 126.9, 126.1, 125.8, 125.4, 124.9, 36.8, 11.2, 5.0; IR
(KBr) 3056, 1428, 1380, 1021, 909 cm−1; MS m/z 410 [(M − 1)+,
100], 105 (20); HRMS (EI) calcd for C31H25N 411.1987, found
411.1981.
§Prof. Huang passed away on March 6, 2010. He was fully in
charge of this project. Prof. Luling Wu is finishing Prof. Huang's
projects with assistance from Prof. Shengming Ma.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Project Nos. 20732005, 20872127, and J0830431) and
the National Basic Research Program of China (973 Program,
2009CB825300) for financial support.
3-Pentyl-2,5-diphenyl-6-p-tolylpyridine (6y). Following the proce-
dure for the preparation of 6n, the reaction of 4f (145 mg, 0.5 mmol),
3a (153 mg, 1.5 mmol), and Cs2CO3 (326 mg, 1.0 mmol) in 0.5 mL of
anhydrous MeCN and 2.0 mL of anhydrous toluene afforded 105 mg
(54%) of 6y: mp 96−98 °C; 1H NMR (400 MHz, CDCl3) 7.60−7.58
(m, 3H), 7.46−7.37 (m, 3H), 7.31−7.22 (m, 7H), 7.00 (d, J = 8.4 Hz,
2H), 2.71 (t, J = 8.0 Hz, 2H), 2.27 (s, 3H), 1.65−1.53 (m, 2H), 1.28−
1.24 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
157.1, 153.9, 140.7, 140.3, 139.9, 137.3, 137.2, 134.2, 133.8, 130.0,
129.6, 129.2, 128.5, 128.2, 128.0, 127.7, 126.9, 32.0, 31.6, 30.7, 22.3,
21.2, 13.9; IR (KBr) 2956, 2927, 2863, 1428, 1021, 829 cm−1; MS m/z
391 (M+, 3], 167 (100), 57 (100); HRMS (EI) calcd for C29H29N
391.2300, found 391.2304.
2-(4-Bromophenyl)-5-(4-chlorophenyl)-3-pentyl-6-phenylpyri-
dine (6z). Following the procedure for the preparation of 6n, the
reaction of 4l (177 mg, 0.5 mmol), 3b (205 mg, 1.5 mmol), and
Cs2CO3 (326 mg, 1.0 mmol) in 0.5 mL of anhydrous MeCN and 2.0
mL of anhydrous toluene afforded 93 mg (38%) of 6z: mp 113−115
°C; 1H NMR (400 MHz, CDCl3) 7.60−7.57 (m, 3H), 7.47 (d, J = 8.4
Hz, 2H), 7.37−7.35 (m, 2H), 7.27−7.22 (m, 5H), 7.15 (d, J = 8.4 Hz,
2H), 2.70 (t, J = 8.0 Hz, 2H), 1.65−1.50 (m, 2H), 1.34−1.25 (m, 4H),
0.88−0.83 (m, 3H); 13C NMR (100 MHz, CDCl3) 156.3, 154.1,
139.8, 139.6, 139.3, 138.3, 134.2, 133.5, 133.3, 131.3, 130.8, 130.8,
130.0, 128.5, 128.0, 127.8, 122.2, 32.0, 31.6, 30.7, 22.3, 13.9; IR (neat)
2919, 2852, 1491, 1432, 1092, 1011, 908 cm−1; MS m/z 490 [(M −
1)+ or (M + 1)+, 88], 352 (45), 57 (100); HRMS (EI) calcd for
C28H25NClBr(79) 489.0859, found 489.0862; C28H25NClBr(81)
491.0838, found 491.0841.
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(m, 3H), 7.28−7.19 (m, 6H), 7.06−7.02 (m, 3H), 4.03 (s, 2H), 2.39
(s, 3H), 2.10−1.90 (m, 1H), 0.91−0.87 (m, 2H), 0.64−0.62 (m, 2H);
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ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data for compounds 4a, 4b, 5a−h, 5la, 5 lb,
and 6a−j,l,m have been reported in the Supporting Information
of our previous communication.7 Copies of 1H/13C NMR
spectra of all new compounds; 2D H−1H NOESY spectra of
1
6o,s,u,w,y. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) (a) Lui, Z. J.; Larock, R. C. J. Org. Chem. 2007, 72, 223.
(b) Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2009, 74, 9132.
(10) Crystal data for compound 5g: C25H21NO2, MW 367.43,
monoclinic, space group P2(1)/n, Mo Kα, final R indices [I > 2σ(I)],
R1 = 0.0529, wR2 = 0.1244, a = 18.1979(13) Å, b = 11.8241(9) Å, c =
20.1682(14) Å, α = 90°, β = 114.8350(10)°, γ = 90°, V = 3938.3(5)
Å3, T = 293(2) K, Z = 8, reflections collected/unique 22603/8547
(Rint = 0.0514), parameters 508. Supplementary crystallographic data
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wululing@zju.edu.cn.
Notes
The authors declare no competing financial interest.
3764
dx.doi.org/10.1021/jo300072x | J. Org. Chem. 2012, 77, 3754−3765

The Journal of Organic Chemistry
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