Synthesis of allylated quinolines/isoquinolines via palladium-catalyzed cyclization-allylation of azides and allyl methyl carbonate

Article abstract of DOI:10.1039/c4ob02567a

A novel and efficient strategy for one-step synthesis of allylated quinolines and isoquinolines via palladium-catalyzed cyclization-allylation of azides and allyl methyl carbonate is developed for the first time. The results indicated that the regioselective synthesis of allyl- and diallyl-substituted quinolines/isoquinolines depends on different substituted groups at R¹ and R⁴ positions, such as H or other groups. The reactions proceed smoothly in the presence of Pd(PPh₃)₄ and K₃PO₄ or NaOAc in DMF at 100°C to give the corresponding allyl- and diallyl-substituted quinolines and isoquinolines in good to high yields.

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ARTICLE TYPE
Synthesis of Allylated Quinolines/Isoquinolines via Palladium-Catalyzed
Cyclization-Allylation of Azides and Allyl Methyl Carbonate
Jiang Luo, a Zhibao Huo, * a, Jun Fu, a Fangming Jin, a Yoshinori Yamamoto b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel and efficient strategy for the oneꢀstep synthesis of allylated quinolines and isoquinolines via
palladiumꢀcatalyzed cyclizationꢀallylation of azides and allyl methyl carbonate is first developed. The
results indicated that the regioselective synthesis of allylꢀ and diallylꢀsubstituted quinolines/isoquinolines
depends on the different substituted groups at R1 and R4 positions, such as H or other groups. The
10 reactions proceed smoothly in the presence of Pd(PPh3)4 and K3PO4 or NaOAc in DMF at 100 oC to give
the corresponding allylꢀ and diallylꢀsubstituted quinolines and isoquinolines in good to high yields.
Previous studies
Introduction
[3]
(1) Synthesis of 3-allylquinoline starting f rom the amines
O
O
Isoquinolines and quinolines are two important classes of
heterocyclic compounds because of their wide utility. Substituted
15 isoquinolines and quinolines are often found as structural
framework in many biologically active natural products and
pharmaceuticals, their physical properties make them beneficial
(1) Molecular sieves
Cl
N
Me
OEt (2) Ph2O, 250 ºC
(1)
+
NH2
(3) POCl3
Me
Ph
(2) Synthesis of 4-allylisoquinolines starting from the imines [8-9]
Ph
1
as functional materials . Furthermore, substituted isoquinolines
cat. Pd(0)
X
(2)
(3)
+
and quinolines can also be used as organocatalysts and
20 meaningful tools for the syntheses of chiral molecules with high
enantioselectivity 2. In particular, allylꢀsubstituted quinolines/
isoquionlines are of special interest because the allyl group
sometimes plays an important role in the compound’s
bioactivity3. Besides that, the presence of allyl group makes
25 further cyclization feasible 4.
base
N
t-Bu
N
I
cat. Ru
I
Ph
Allyl
Ph
N
+
R
base, 100 o
C
N
Me
R = OH or OMe
Me
(3) Synthesis of quinolines and isoquinolines starting f rom the azides [10-11]
R2
R2
Owing to their potential usefulness, the synthetic methods for
quinoline/isoquinoline derivatives have been extensively studied
since its discovery by Gerhardt in 1842 5ꢀ6. Currently, one of the
frequently used methods for allylꢀsubstituted quinolines/
30 isoquinolines is the coupling between halogenꢀcontaining
quinolines/isoquinolines and allylic substrates over metalꢀ
catalysts 7. However, a severe drawback of the substitution is that
the reaction only works with halogenꢀcontainin g
quinolines/isoquinolines. Thus, its application is limited.
35 Recently, several new synthetic methods for the synthesis of
allylꢀsubstituted quinolines/isoquionlines were developed as
shown in Scheme 1. Tempone et al. 3 reported a twoꢀstep process
for the synthesis of 3ꢀallylquinolines from the amine and allyl
E
Electrophile
R1
R1
(4)
(5)
R3
CH3NO2, rt
N3
N
R3
E+ = I2, Br2, NBS, NIS, ICl, H+
or AuCl3 and AgNTf2 catalysts
E = H, in the case of AuCl3
and AgNTf2 catalysts
R5
I
R4
R3
X
R4
R3
X
R5
1) I2, base, CH2Cl2, rt
or
N3
N
2) AuCl3, AgSbF6
THF, 100 o
C
R2
R1
R2
R1
X = C, N
This Work
(4) One-step synthesis of mono- and diallyl-substituted isoquinolines and quinolines starting from the azides
R4
R4
R5
Pd(PPh3)4 (10 mol%), base (5 eq)
DMF, 100 o
R3
R2
R3
R2
C
R3
R2
or
(6)
OCO2Me
N
R5
N3
N
3
R5
8
2a
R4
H
4
≠
R4 = H
substrates in 2005 (Eq. 1). Larock et al. reported an efficient
1
40 and practical method for the synthesis of 4ꢀallylisoquinolines
using oꢀ(1ꢀAlkynyl)benzaldimines and allyl halides as starting
materials and gave moderate yield (Eq. 2). More recently,
R5
Pd(PPh3)4 (10 mol%), base (5 eq)
R3
R2
R5
R3
R2
DMF, 100 o
C
R3
R2
R5
or
(7)
N
N3
N
OCO2Me
2a
R1
R1
R1
H
7
9
R1 = H
6
≠
5
Jeganmohan et al. reported the intermolecular synthesis of 4ꢀ
50
allylisoquinolines from the imines in the presence of RuCl2(pꢀ
45 cymene)2 and gave 55% yield (Eq. 3). Although significant
progress has been made in the synthesis of allylꢀsubstituted
Scheme 1 Background and New Reactions
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quinolines/isoquionlines, the reactions hitherto developed still
have some limitations, such as high reaction temperature, long
reaction time. Therefore, the development of efficient methods
for the synthesis of allylꢀsubstituted quinolines/ isoquinolines is
highly desired.
5
Previously, we reported the synthesis of substituted quinolines
via electrophilic cyclization of 1ꢀazidoꢀ2ꢀ(2ꢀpropynyl) benzenes
in the presence of electrophilic reagents or electrophilic catalysts
(Eq. 4) 10. Also we reported metalꢀcatalyzed or nonmetalꢀ
10 catalyzed synthesis of substituted dihydroisoquinolines, and
iodineꢀmediated or goldꢀcatalyzed synthesis of substituted
isoquinolines (Eq. 5) 11. Encouraged by the findings above, we
have developed an effective strategy for the regioselective oneꢀ
step synthesis of allylated quinolines via the palladiumꢀcatalyzed
15 cyclizationꢀallylation reaction of 1ꢀazidoꢀ2ꢀ(2ꢀpropynyl) benzene
1 and allyl methyl carbonate 2a 12. The corresponding 3, 4ꢀ
diallylquinoline 3a in 69% yield in the case of R4 = H and 3ꢀ
allylquinoline 4 in 67% yield in the case of R4 ≠ H were obtained
in the presence of Pd(PPh3)4 and K3PO4 or NaOAc in DMF at
20 100 °C. In addition, we newly found that 1,4ꢀdiallylisoquinolines
6 and 4ꢀallylisoquinolines 7 could also be synthesized from 2ꢀ
alkynyl benzyl azides 5 and allyl methyl carbonate 2a under mild
reaction conditions. To the best of our knowledge, it is the first
time for the oneꢀstep synthesis of 1,4ꢀdiallylisoquinolines 6 and
Table 2 Optimization of the Reaction Conditions a
cat Pd, base
OCO2Me
+
Ph
N3
Solv, Temp, 24 h
N
Ph
25 4ꢀallylisoquinolines
7 via palladiumꢀcatalyzed cyclizationꢀ
1a
2a
3a
allylation of azides and allyl methyl carbonate to date.
Furthermore, this palladiumꢀcatalyzed reaction is mechanistically
interesting, compared to the Au+ꢀcatalyzed and I+ꢀmediated
reactions, as mentioned later. Herein, we report a detailed
30 investigation of these synthetic methods for the allylꢀ and diallylꢀ
substituted quinolines and isoquinolines.
Yield (%) b SM recov. (%) b
Entry
cat Pd
Bases
Solvent
-
K3CO3
K3CO3
K3CO3
K3CO3
-
0
4
1
2
DMF
DMF
0
0
0
0
0
0
0
0
0
0
0
0
0
5
8
11
0
0
8
0
0
0
Pd2(dba)3.CHCl3 (5 mol%)
Pd2(dba)3.CHCl3 (5 mol%) c
Pd2(dba)3.CHCl3 (5 mol%) d
Pd(PPh3)4
8
3
DMF
35
4
DMF
26
5
DMF
Pd(PPh3)4
K2CO3
Na2CO3
NaHCO3
NaOH
(47) e
42
6
DMF
Results and Discussion
Pd(PPh3)4
7
DMF
Pd(PPh3)4
46
8
DMF
Synthesis of 3-allylquinolines and 3,4-diallylquinolines from
azides and allyl methyl carbonate
Pd(PPh3)4
56
9
DMF
Pd(PPh3)4
NaOAc
K3PO4
KH2PO4
Et3N
66
10
11
12
13
14
15
16
17
18
19
20
21
22
DMF
35 Initially, we selected 1ꢀazidoꢀ2ꢀ(3ꢀphenylpropꢀ2ꢀynyl) benzene
1a as a model substrate to screen allyl sources. The results are
summarized in Table 1. When allyl methyl carbonate 2a was used,
the reaction proceeded smoothly and gave the desired 3, 4ꢀ
diallylquinoline 3a in 47% isolated yield (entry 1). Allyl chloride
40 2b produced the desired product 3a in low yield (entry 2). No
desired product was obtained with allyl tributyltin 2c (entry 3).
Allyl acetate 2d, giving the product 3a in 39% isolated yield
together with unidentified products (entry 4). Also, the use of 2a
together with 2d produced 3a in lower yield (entry 5). Thus, allyl
45 methyl carbonate was utilized as an allyl source for further
optimization of reaction conditions.
Pd(PPh3)4
75 (69) e
37
DMF
Pd(PPh3)4
DMF
Pd(PPh3)4
48
DMF
Pd(PPh3)4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4 (3 eq)
27
1,4-dioxane
AcOEt
Benzene
CH3CN
CH3CN+H2O
THF
Pd(PPh3)4
29
Pd(PPh3)4
26
Pd(PPh3)4
66
Pd(PPh3)4
15
Pd(PPh3)4
30
f
Pd(PPh3)4
69 (60) e
63
DMF
Pd(PPh3)4 (5 mol%)
Pd(PPh3)4
DMF
65 (59) e
DMF
a The reactions were performed with 1a (0.05 mmol) and 2a (5 eq) in the presence of Pd catalyst (10 mol%) and base (5
eq) in 1mL DMF at 100 oC for 24 h under a argon atmosphere. b 1H NMR yield was determined by using pꢀxylene as an
Our research focused on the optimization of palladium
catalysts, solvents, bases and temperatures, and the results are
summarized in Table 2. No desired product 3a was obtained in
50 the absence of palladium catalyst (entry 1). A yield of 26% was
f
internal standard. c 5 mol% XantPhos was used. d 10 mol% SꢀPhos was used. e Isolated yield is shown in parentheses.
The reaction temperature was 80 oC .
55 obtained when the reaction was carried out in the presence of
Pd(PPh3)4 but in the absence of base (entry 5). This result
indicated the importance of the combined use of both palladium
catalyst and base. Next we tested two palladium catalysts,
.
Pd2(dba)3 CHCl3 and Pd(PPh3)4, respectively (entries 2ꢀ4 and 6),
60 the latter gave a much better result. The use of ligands, XantPhos
and SꢀPhos, gave 8% and 35% yields in the presence of
2
|
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.
Pd2(dba)3 CHCl3, respectively (entries 3 and 4). Among the
(entry 11). The substrate 1m afforded the desired product 3m in
58% yield with method B. On the basis of the results above, it
clearly indicated that R4 group plays a key role in the selective
synthesis of allylated quinolines.
various bases we investigated (entries 6ꢀ13), the use of K3PO4
and NaOAc afforded 3a in high yields (entries 10 and 11). The
screening of various solvents, such as 1, 4ꢀdioxane, AcOEt,
benzene, CH3CN, CH3CN+H2O, THF and DMF, revealed that
solvents played an important role in the formation of 3a (entries
11, 14ꢀ19). DMF was found to be the most suitable solvent, and
the product 3a was obtained in 69% isolated yield (entry 11). The
decrease in reaction temperature to 80 °C gave the product 3a in
5
45
Pd(PPh3
)4 (10 mol%),
K3PO4 (5 eq)
10 60% isolated yield (entry 20). Decreasing the amounts of base
and catalyst resulted in lower yields (entries 21 and 22).
+
OCO2Et
2e
+
Ph
DMF, 100 o
C
N3
1a
N
Ph
3', 60%
N
Ph
3n,
trace
Table 3 Synthesis of 3,4ꢀdiallylquinolines with various substrates a
Pd(PPh3
K3PO4 (5 eq)
)4 (10 mol%),
R4
R4
Pd(PPh3)4 (10 mol%),
base (5 eq)
R3
R2
R3
R2
+
Ph
OCO2Et
OCO2Me
R3
R2
+
+
or
N3
1a
DMF, 100 o
C
R5
N
Ph
DMF, 100 o
C
N
R5
N3
N
Ph
N
R5
3', 67%
2f
3o, trace
1
3
2a
4
R4 = H
R4
H
Yield (%) b
R2
R3
R4
R5
Entry
Time (h)
Substrate 1
Methods
3 or 4
Other substituted allyl carbonates such as crotyl ethyl
carbonate 2e and ethyl 2ꢀmethylallyl carbonate 2f, instead of allyl
1
2
A
A
A
B
A
A
A
B
A
A
B
5
4
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
3g
3h
3i
69
66
55
38
60
64
42
45
33
n.d c
67
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
pꢀMeꢀPh
3,5ꢀF2ꢀPh
cyclohexyl
3ꢀMeꢀPh
pꢀClꢀPh
pꢀMeꢀPh
Ph
50 methyl carbonate 2a, were also investigated and gave only trace
amounts of the products 3n and 3o. 2ꢀphenylquinoline 3’ as main
product 10 was formed. Next, we investigated the feasibility of the
3
3
H
H
4
24
5
H
H
5
H
H
13
ring closing metathesis reaction of 3a. The reaction of 3a was
6
5
H
H
carried out in CH2Cl2 at reflux for 1 h in the presence of 10 mol%
55 Grubbs’ first generation catalyst and obtained the desired
cyclization product 12 in 90% yield.
7
1g
1h
1i
5
Br
Br
Cl
H
H
8
2
H
9
5
H
Ph
10
1j
-
5
H
H
11
1k
4
5
H
OAc
Ph
a
All the reactions were carried out using 0.05 mmol of 1 and 5 eq of 2 in the presenc of Pd(PPh3)4 (10 mol%) under
argon atomosphere in 1mL DMF at 100 oC; method A, DMF (1 mL), K3PO4 (5 eq); method B, NaOAc (5 eq). b Isolated
yield. c Not determined.
Grubbs 1st gen. catalyst (10 mol%)
CH2Cl2, reflux, 1 h
N
Ph
N
Ph
3a
12, 90%
15
With the optimized conditions in hand, we carried out the
reactions between various 1ꢀazidoꢀ2ꢀ(2ꢀpropynyl) benzenes 1 and
allyl methyl carbonate 2a, and the results are summarized in
Table 3. The substrate 1b, having a methyl at the paraꢀposition of
the aromatic ring, afforded the corresponding cyclized product 3b
60
A
proposed mechanism for the formation of 3,4ꢀ
diallylquinoline 3a via palladiumꢀcatalyzed cyclizationꢀallylation
reaction of 1ꢀazidoꢀ2ꢀ(2ꢀpropynyl) benzene 1a and allyl methyl
carbonate 2a is illustrated in Scheme 2. Initially, Pd(0) reacts
with allyl methyl carbonate 2a to form the πꢀallyl palladium
20 in 66% isolate yield through method A (entry 2). The substrate
1c, bearing fluorine atoms at 3,5ꢀpositions on the aromatic ring,
afforded the desired product 3c in 55% yield (entry 3).
Furthermore, the substrates 1d, having a cyclohexyl group at the
alkyne terminus, gave the expected products 3d in moderate
25 yields with method B (entries 4); Here, a mixture of unidentified
byꢀproducts were formed, but they were easily separated from the
desired quinoline by column chromatography. It is noteworthy
that the method B gave a little higher yield than the method A,
although it took a longer reaction time. The substrates 1e and 1f,
30 having a methyl at the metaꢀposition and a chloro group at paraꢀ
position of the aromatic ring, afforded products 3e and 3f in 60%
and 64% isolate yield through method A (entries 5 and 6). The
substrates 1g, 1h and 1i, in which the aromatic ring was
substituted with bromo and chloro groups, afforded the
35 corresponding products 3g, 3h and 3i in moderate yields,
respectively (entries 7ꢀ9). The reaction led to a mixture and no
products 3 and/or 4 were observed when substrate 1j (R5 = H)
reacted with 2a (entry 10). It is noteworthy that the reaction of
1k, having OAc group at R4 (at the benzylic position), proceeded
40 smoothly and gave the 3ꢀallylquinoline 4 in 67% isolated yield
65 species 8 14, 15 with concomitant evolution of CO2. Deprotonation
of propargylic proton of 1a takes place with methoxide formed.
Then nucleophilic attack of propargylic anion to allylpalladium
cation to result in propargylic allylation 9 and regeneration of
Pd(0). Next, oxidative addition of allyl methyl carbonate 2a
70 occurs again to form 8, the intermediate 9 reacts with 8 again to
generate intermediate 10 and subsequent nucleophilic attack of a
nitrogen atom to the electronꢀdeficient alkyne forms an
intermediate 11. Finally, elimination of N2 and H+, together with
elimination of Pd (0), produces 3,4ꢀdiallylquinoline 3a. It is
75 noteworthy that, for the azideꢀalkyne cyclization, Pd (II) acts
similarly as I+ reagent, Bronsted acid and Au catalyst. Perhaps,
the most important point of the present Pd methodology,
compared to the previous Au+ and I+ methods,13 is that the Pdꢀ
catalyzed azideꢀalkyne cyclization is able to incorporate another
80 organic ligand of Pd (see 9), which is allyl in present, into
quinoline framework.
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Table 4 Synthesis of Allylisoquinolines with Various Substrates a
OCO2Me
R5
Pd(0)
Pd(PPh3)4 (5 mol%),
K3PO4 (5 eq)
N
Ph
3a
2a
R3
R2
R5
R3
R2
R3
R2
R5
OCO2Me
+
or
N
N3
DMF, 100 oC
N
5
R1
2a
R1
CO2
6
7
R1
R1 = H
H
Pd+ -OMe
8
R2
R3
R5
6 or 7
Time (h)
H
Yield (%) b
Entry
R1
Substrate 5
Pd
R5
H
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
5a
5b
5c
5d
5e
5f
Ph
pꢀOMeꢀPh
Ph
5
14
4
86
51
55
41
52
85
93
87
79
81
90
60
93
89
1
2
H
H
H
H
H
H
H
N
+
N2
11
Ph
N3
1a
3
H
Cl
MeOH
Ph
4
1ꢀcyclohexenyl
Ph
5
H
H
O
H
O
Pd+
Ph
CH2
5
5
H
N-
N2
N-
N2
Me
Ph
Ph
Ph
Me
Me
Ph
Me
Ph
H
H
Cl
H
O
H
H
H
H
O
6
Ph
2
+
10
8
+
9
5g
5h
5i
7
Ph
5
8
Ph
5
Scheme 2 A Proposed Mechanism for the Formation of 3a.
9
cyclohexyl
Ph
5
5j
12
5
10
11
12
13
14
CH2
CH2
CH2
5
On the basis of the proposed mechanism in Scheme 2, we
conducted some the experiments under the optimized reaction
conditions to investigate the formation of the intermediates in this
process. Firstly, allylated alkyne 9 as starting material was
prepared in order to investigate the feasibility for the synthesis of
5k
5m
5n
5o
pꢀtolyl
pꢀClꢀPh
pꢀFꢀPh
3ꢀMeꢀPh
O
O
O
O
7g
7h
7i
10
3
H
H
H
H
3
a All the reactions were carried out using 5 (0.05 mmol) and 2a (5 eq) in the presenc of Pd(PPh3)4 (5 mol%)
under argon atomosphere in 1mL DMF at 100 oC; . b Isolated yield.
10 3,4ꢀdiallylquinoline 3a. However, we did not get compound 9 at
all. Next, the substrate 1’ without azide was used to test if the
similar allylation product 9’ would be formed. As a result,
compound 9’ was observed in mixture and gave 7% NMR yield
40
of 4ꢀallylisoquinolines 7 are investigated using more highly
substituted substrates when R1 ≠ H (entries 6ꢀ14). The 5f and 5g
substituted with methyl and phenyl groups at R1 position
1
by H NMR and GCꢀMS. The result suggests that the formation
15 of the intermediates 9 is possible.
45 proceeded without problems and gave products 7a and 7b in 85%
and 93% yields, respectively (entries 6 and 7). The substrate 5h
gave the product 7c in 87% yield (entry 8). The reaction of 5i,
having cyclohexyl group at R5 gave the corresponding product 7d
in 79% yield (entry 9). The substrates 5j, 5k and 5m having 3,4ꢀ
50 diꢀRO substituents on the aromatic ring gave the products 7e, 7f
and 7g in 81%, 90% and 60% yields, respectively (entries 10, 11
and 12). The reactions of 5n and 5o, having methyl and phenyl
groups at R1 position gave the corresponding product 7h and 7i in
93% and 89% yields, respectively (entry 13 and 14). A substrate
55 13, having allyl group at R1 proceeded smoothly and gave
products 6a in 80% yield. From the results above, we found that
the substrates (R1 = H) gave less yields than the more highly
substituted substrates (R2 ≠ H). The observations might indicate
that the palladiumꢀcatalyzed cyclizationꢀallylation reaction is able
60 to incorporate another organic ligand of Pd (see 13 in Scheme 3),
which is allyl in present, into isoquinoline framework.
Pd(PPh3
K3PO4 (5 eq)
)4 (10 mol%),
OCO2Me
+
Ph
DMF, 100 o
C
Ph
1'
2a
9',
7%
Synthesis of 4-allylisoquinolines and 1,4-diallylisoquinolines
from azides and allyl methyl carbonate
20 Encouraged by the successful synthesis of 3ꢀallylquinoline 4 and
3,4ꢀdiallylquinolines 3a, we used 2ꢀalkynyl benzyl azides 5 as
starting materials, instead of 1ꢀazidoꢀ2ꢀ(2ꢀpropynyl) benzene 1a,
to synthesize 4ꢀallylisoquinolines 7 and 1,4ꢀdiallylisoquinolines 6.
The similar reaction conditions in the synthesis of allylated
25 quinoline are also effective for isoquinoline synthesis (see Table
S1 in supporting information).
The scopes of the cyclizationꢀallylation reactions of 2ꢀalkynyl
benzyl azides 5 and allyl methyl carbonate 2a are examined, and
the results are summarized in Table 4. Firstly, the reactions for
30 the synthesis of 1,4ꢀdiallylisoquinolines are carried out when R1 =
H (entries 1ꢀ5). An arylacetylene bearing a methoxy group 5b on
the aromatic ring afforded the corresponding product 6b in 51%
yield (entry 2). The substrates 5c, in which the aromatic ring was
substituted with chloro group, gave the product 6c in 55% yield
35 (entry 3). The reaction of 5d, having 1ꢀcyclohexenyl substituent
at R5 gave the corresponding product 6d in 41% yield (entry 4).
The substrates 5e, having a 3,4ꢀdiꢀRO substituent on the aromatic
ring gave the product 6e in 52% yield (entry 5). Next, synthesis
65
Two substituted allyl carbonates such as crotyl ethyl carbonate
2e and ethyl 2ꢀmethylallyl carbonate 2f, instead of allyl methyl
carbonate 2a, were also investigated. Unfortunately, the allyl
sources 2e and 2f are ineffective for the substrates 5a and 5k, and
only trace amounts of the diallylꢀsubstituted isoquinolines and
70 allylꢀsubstituted isoquinolines were detected in the mixture by 1H
NMR and GCꢀMS analysis.
4
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DOI: 10.1039/C4OB02567A
5k
5a
regioselective
oneꢀstep
synthesis
of
allylated
OCO2Et
OCO2Et
Pd(PPh3)4 (5 mol%)
Pd(PPh3)4 (5 mol%)
2e
2f
40 quinolines/isoquinolines via the palladiumꢀcatalyzed cyclizationꢀ
allylation reaction of azides and allyl methyl carbonate. As a
result, allylated quinolines/isoquinolines were obtained in good to
high yields. R1 and R4 groups play a key role for the
transformation. Diallylꢀsubstituted quinolines/ isoquinolines are
45 achieved when R1 = R4 = H, while allylꢀsubstituted quinolines/
isoquinolines are achieved when R1 ≠ H and R4 ≠ H. The present
studies provide useful methods for the synthesis of allylated
quinolines/isoquinolines with a wide variety of substrates. Further
works to expand the scope and synthetic utility of this
50 methodology to the synthesis of biologically important natural
and unnatural compounds are in progress.
or
6
7
K3PO4 (5 eq)
K3PO4 (5 eq)
DMF, 100 o
DMF, 100 o
C
C
A plausible reaction pathway for the synthesis of 1,4ꢀ
diallylisoquinoline 6a via Pdꢀcatalyzed cyclizationꢀallylation
reaction of 2ꢀalkynyl benzyl azide 5a and allyl methyl carbonate
2a is shown in Scheme 3. Similar to the previous observation in
the synthesis of compounds 3a (see Scheme 2), initially, Pd(0)
reacts with allyl methyl carbonate 2a to form the πꢀallyl
palladium species 8
5
14, 15
with concomitant evolution of CO2.
10 Deprotonation of benzylic proton of 5a takes place with
methoxide formed. Then nucleophilic attack of benzylic anion to
allylpalladium cation to result in benzylic allylation 13 and
regeneration of Pd(0) 16. Next, oxidative addition of allyl
carbonate 2a occurs again to form 8, the intermediate 13 reacts
15 with 8 again to generate intermediate 14 and subsequent
nucleophilic attack of a nitrogen atom to the electronꢀdeficient
alkyne forms an intermediate 15. Finally, elimination of N2 and
H+, together with elimination of Pd (0), produces 1,4ꢀ
diallylisoquinoline 6a.
Experimental Section
General Information
1H and 13C NMR spectra were operated at 400 MHz and 100
55 MHz, respectively. The reactions were monitored by thinꢀlayer
chromatography (TLC). Column chromatography was performed
on neutral silica gel (60N, 45ꢀ75 ꢁm) and hexane/AcOEt (5:1)
was used as an eluent. The Pd(PPh3)4 was prepared according to
the literature procedure. 17 All starting materials used in our study
60 were prepared in the laboratory. Substrates 5a-5o were prepared
according to the reported literatures. 11b, 11d The procedures and
20
Ph
OCO2Me
analytical data of 5a, 5b, 5d, 5f, 5g and 5j-5k should be seen in
Pd(0)
N
2a
[11b, 11d]
our prevous literatures.
Substrate 5a’ was prepared
6a
18
according to the reported literatures. TLC was performed on
65 aluminumꢀprecoated plates of silica gel 60 with an HSGF254
indicator and visualized under UV light or developed by
immersion in the solution of 0.6% KMnO4 and 6% K2CO3 in
water.
CO2
Pd
R5
N2
Pd+ -OMe
8
Ph
N
+
H
N3
15
2-(azidomethyl)-4-chloro-1-(phenylethynyl)benzene
(5c).
H
1
Pd+
70 Yellow oil (883.4 mg, 33%); H NMR (400 MHz, CDCl3) δ 4.61
(s, 2H), 7.33ꢀ7.29 (t, J = 8.2 Hz, 1H), 7.40ꢀ7.34 (m, 3H), 7.41 (s,
1H), 7.50ꢀ7.46 (d, J = 7.2 Hz, 1H), 7.58ꢀ7.54 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ 52.8, 85.5, 95.5, 121.1, 122.5, 128.4, 128.5,
128.5, 128.9, 131.6, 133.5, 134.6, 139.0. IR (KBr) 3058, 2923,
75 2098, 1496, 1259, 1103, 825, 750, 686 cmꢀ1. HRMSꢀESI (m/z)
[M]+ Calcd for C15H11N3Cl [M + H]+ 268.0642; Found 268.0639.
5-(azidomethyl)-6-(phenylethynyl)benzo[d][1,3]dioxole (5e).
Ph
N-
5a
Ph
+
MeOH
N-
+
N2
N2
8
13
14
Scheme 3 A Plausible Reaction Pathway for the Formation of 6a.
25
As mentioned above, the reaction of the compound 13
proceeded smoothly and gave 6a in 80% yield under the
optimized conditons. It showed that the formation of the
intermediate 13 in this process is possible. Next, the reaction of
5a’ was carried out in order to investigate the role of the azide
30 group in this process, no expected compound 13’ was observed in
the absence of azide group. It indicated that the electronꢀ
withdrawing effect of azide moiety is necessary for the allylation
process.
1
Yellow oil (804.1 mg, 29%); H NMR (400 MHz, CDCl3) δ 4.54
(s, 2H), 6.02 (s, 2H), 6.87 (s, 1H), 7.01 (s, 1H), 7.38ꢀ7.33 (m, 3H),
80 7.57ꢀ7.49 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 53.1, 86.7,
93.1, 101.7, 109.1, 111.8, 116.2, 122.9, 128.4, 128.4, 131.5,
132.1, 147.4, 148.3. IR (KBr) 3046, 2902, 2098, 1479, 1375,
1218, 1039, 929, 750 cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for
C16H12N3O2 [M + H]+ 278.0930; Found 278.0931.
85 2-(azido(phenyl)methyl)-4-chloro-1-(phenylethynyl)benzene
1
(5h). Yellow oil (859.5 mg, 25%); H NMR (400 MHz, CDCl3),
δ 6.29 (s, 1H), 7.30ꢀ7.27 (d, J = 8.2 Hz, 1H), 7.40ꢀ7.35 (t, J = 4.2,
Hz, 8H), 7.50ꢀ7.45 (t, J = 8.0 Hz, 3H), 7.51 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ 65.9, 85.0, 95.9, 120.6, 122.5, 127.3, 127.5,
90 128.2, 128.3, 128.5, 128.8, 128.8, 131.5, 133.6, 134.9, 138.3,
143.1. IR (KBr) 3064, 2931, 2098, 1491, 1265, 1103, 814, 756,
35
+
692 cmꢀ1. HRMSꢀESI (m/z) [M] Calcd for C21H15N3Cl [M +
H]+ 344.0955; Found 344.0947.
Conclusion
We have first developed an effective strategy for the
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1-(azido(phenyl)methyl)-2-(cyclohexylethynyl)benzene
colourless oil (504.7 mg, 16%); H NMR (400 MHz, CDCl3) δ
(5i).
removed under reduced pressure, the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate,
1
1.41ꢀ1.28 (m, 3H), 1.63ꢀ1.42 (m, 3H), 1.81ꢀ1.66 (m, 2H), 1.88 (d, 60 30/1~5/1) to provide the product 6a-6e.
J = 12.2, 2H), 2.63 (dd, J = 9.0, 3.5 Hz, 1H), 6.30 (s, 1H), 7.23ꢀ
7.18 (m, 1H), 7.29ꢀ7.25 (m, 2H), 7.36ꢀ7.32 (m, 5H), 7.42 (d, J =
7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 24.9, 25.8, 29.8, 32.5,
65.9, 78.2, 100.3, 123.2, 126.9, 127.3, 127.7, 127.8, 128.0, 128.5,
1,4-diallyl-3-phenylisoquinoline (6a). Yellow oil (12.3 mg,
5
86%); 1H NMR (400 MHz, CDCl3) δ 2.95 (dd, J = 14.1, 6.6 Hz,
2H), 3.12 (dd, J = 14.1, 7.8 Hz, 2H), 5.10ꢀ4.78 (m, 4H), 5.37ꢀ5.22
(m, 2H), 7.49ꢀ7.36 (m, 4H), 7.53 (t, J = 7.7 Hz, 2H), 7.93ꢀ7.85 (m,
132.4, 139.3, 141.0. IR (KBr) 3029, 2925, 2850, 2098, 1485, 65 1H), 8.02ꢀ7.94 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 43.0,
1450, 1247, 750, 692 cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for
71.2, 120.4, 121.2, 123.1, 127.0, 127.7, 127.7, 128.1, 128.3,
128.29, 128.7, 128.9, 128.9, 130.1, 131.5, 137.2, 139.3, 148.1. IR
(KBr) 3075, 2919, 2850, 1641, 1450, 1352, 982, 923, 756, 698
10 C21H22N3 [M + H]+ 316.1814; Found 316.1808.
5-(azido(phenyl)methyl)-6-((4-chlorophenyl)ethynyl)benzo[d]
1
+
+
[1,3]dioxole (5m). Yellow oil (1085.9 mg, 28%); H NMR (400
cmꢀ1. HRMSꢀEI (m/z) [M]
Calcd for C21H18N [M ﹣ H]
MHz, CDCl3) δ 6.05ꢀ5.90 (m, 2H), 6.31 (s, 1H), 6.87 (s, 1H), 70 284.1439; Found 284.1436.
6.97 (s, 1H), 7.34ꢀ7.30 (m, 3H), 7.37ꢀ7.34 (m, 4H), 7.42ꢀ7.38 (m,
15 2H). 13C NMR (100 MHz, CDCl3) δ 65.8, 88.0, 92.3, 101.8,
107.7, 111.5, 115.2, 126.4, 127.1, 127.4, 128.0, 128.8, 132.6,
133.7, 134.5, 139.2, 147.1, 148.7. IR (KBr) 2917, 2845, 2095,
1,4-diallyl-3-(4-methoxyphenyl)isoquinoline (6b). Yellow oil
(8.0 mg, 51%); 1H NMR (400 MHz, CDCl3) δ 2.94 (dd, J = 14.1,
6.6 Hz, 2H), 3.10 (dd, J = 14.2, 7.8 Hz, 2H), 3.88 (s, 3H), 5.03ꢀ
4.82 (m, 4H), 5.44ꢀ5.21 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 7.50ꢀ
1464, 1238, 1029, 869 cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for 75 7.37 (m, 3H), 7.95ꢀ7.80 (m, 3H). 13C NMR (100 MHz, CDCl3) δ
C22H15N3O2Cl [M + H]+ 388.0853; Found 388.0864.
43.1, 55.4, 71.1, 114.3, 120.3, 121.0, 123.1, 124.1, 128.0, 128.0,
128.1, 128.3, 128.4, 128.7, 128.7, 130.2, 139.2, 139.2, 148.0,
159.6. IR (KBr) 3071, 2914, 2848, 1727, 1612, 1503, 1357, 1248,
1030, 915, 828, 769 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for
20 1-(1-azidoethyl)-2-((4-fluorophenyl)ethynyl)benzene
colourless oil (955.0 mg, 36%); H NMR (400 MHz, CDCl3) δ
(5n).
1
1.59 (d, J = 6.8, 3H), 5.26 (q, J = 6.8 Hz, 1H), 7.12ꢀ7.03 (m, 2H),
7.34ꢀ7.28 (m, 1H), 7.42ꢀ7.35 (m, 1H), 7.50ꢀ7.44 (m, 1H), 7.58ꢀ 80 C22H20NO [M﹣H]+ 314.1545; Found 314.1544.
7.50 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 21.0, 58.9, 86.3,
25 93.4, 119.0, 119.0, 121.5, 125.5, 127.7, 129.0, 132.5, 133.4,
133.5, 142.7. IR (KBr) 3066, 2982, 2089, 1506, 1232, 827, 756
cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for C16H13N3F [M + H]+
266.1094; Found 266.1083.
1,4-diallyl-7-chloro-3-phenylisoquinoline (6c). Yellow oil (8.8
mg, 55%); H NMR (400 MHz, CDCl3) δ 2.94 (dd, J = 14.1, 6.6
1
Hz, 2H), 3.12 (dd, J = 14.2, 7.8 Hz, 2H), 5.08ꢀ4.87 (m, 4H), 5.37ꢀ
5.24 (m, 2H), 7.46ꢀ7.37 (m, 3H), 7.53 (t, J = 7.6 Hz, 2H), 7.79 (t,
85 J = 8.1 Hz, 1H), 7.93 (d, J = 7.7 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 42.9, 71.2, 120.9, 122.1, 123.6, 126.4, 127.0, 128.3,
128.5, 129.0, 129.0, 129.1, 129.6, 129.7, 131.2, 134.3, 136.3,
139.4, 149.9. IR (KBr) 3081, 2907, 2844, 1641, 1444, 1346, 982,
774, 692 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for C21H17NCl [M﹣
1-(azido(phenyl)methyl)-2-(m-tolylethynyl)benzene
(5o).
1
30 Yellow oil (1811.0 mg, 56%); H NMR (400 MHz, CDCl3) δ
2.37 (s, 3H), 6.37 (s, 1H), 7.19ꢀ7.16 (m, 1H), 7.31ꢀ7.27 (m, 5H),
7.41ꢀ7.33 (m, 5H), 7.49ꢀ7.45 (m, 1H), 7.57ꢀ7.52 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ 21.3, 66.1, 86.6, 95.1, 122.3, 122.6, 90 H]+ 318.1050; Found 318.1047.
126.7, 127.0, 127.5, 127.8, 128.0, 128.3, 128.6, 128.8, 129.5,
35 132.1, 132.5, 138.1, 139.1, 141.3. IR (KBr) 2917, 2851, 2095,
1470, 869, 750, 691 cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for
C22H18N3 [M + H]+ 324.1501; Found 324.1517.
1,4-diallyl-3-cyclohexenylisoquinoline (6d). Yellow oil (5.9 mg,
41%); H NMR (400 MHz, CDCl3) δ 1.78ꢀ1.70 (m, 2H), 1.88ꢀ
1.79 (m, 2H), 2.35ꢀ2.27 (m, 2H), 2.72ꢀ2.63 (m, 2H), 2.89 (dd, J =
14.0, 6.8 Hz, 2H), 3.05 (dd, J = 14.1, 7.8 Hz, 2H), 5.08ꢀ4.82 (m,
1
1-(1-azidobut-3-enyl)-2-(phenylethynyl)benzene (13). Yellow 95 4H), 5.31ꢀ5.20 (m, 2H), 6.55ꢀ6.43 (m, 1H), 7.45ꢀ7.35 (m, 3H),
oil (519.3 mg, 19%); 1H NMR (400 MHz, CDCl3) δ 2.72ꢀ2.55 (m,
40 2H), 5.21ꢀ5.15 (m, 2H), 5.29ꢀ5.24 (m, 1H), 5.96ꢀ5.80 (m, 1H),
7.35ꢀ7.29 (m, 1H), 7.43ꢀ7.36 (m, 4H), 7.51ꢀ7.45 (m, 1H), 7.62ꢀ
7.54 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 40.2, 63.4, 86.6,
7.78ꢀ7.72 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 22.2, 22.6,
25.6, 27.2, 29.7, 43.1, 70.7, 120.2, 121.5, 122.9, 126.8, 127.8,
128.2, 128.5, 128.6, 129.2, 130.2, 136.2, 139.6, 141.4, 147.9. IR
(KBr) 3075, 2925, 2856, 1727, 1641, 1450, 993, 923, 762 cmꢀ1.
94.7, 118.3, 121.8, 122.8, 126.0, 127.7, 128.4, 128.6, 128.8, 100 HRMSꢀEI (m/z) [M]+ Calcd for C21H22N [M﹣H]+ 288.1752;
131.5, 132.4, 133.8, 141.2. IR (KBr) 2917, 2839, 2095, 1458, 910,
45 744, 685 cmꢀ1. HRMSꢀESI (m/z) [M]+ Calcd for C18H16N3 [M +
H]+ 274.1344; Found 274.1336.
Found 288.1755.
5,8-diallyl-7-phenyl-[1,3]dioxolo[4,5-g]isoquinoline
(6e).
1
Yellow oil (8.6 mg, 52%); H NMR (400 MHz, CDCl3) δ 2.88
(dd, J = 14.1, 6.6 Hz, 2H), 3.07 (dd, J = 14.1, 7.7 Hz, 2H), 5.08ꢀ
105 4.87 (m, 4H), 5.37ꢀ5.26 (m, 2H), 6.08 (s, 2H), 6.88 (s, 1H), 7.30
(s, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.90 (d,
J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 43.1, 70.9, 102.0,
102.2, 104.2, 120.4, 121.3, 126.9, 127.9, 128.9, 128.9, 130.1,
130.1, 131.6, 131.6, 137.1, 138.1, 142.3, 148.1, 148.2. IR (KBr)
110 3081, 2913, 1641, 1467, 1352, 1271, 1039, 918, 779, 692 cmꢀ1.
HRMSꢀEI (m/z) [M]+ Calcd for C22H18NO2 [M﹣H]+ 328.1338;
Found 328.1333.
General Procedure for the Synthesis of 1,4-diallylquinoline (6)
To a 5ꢀmL screwꢀcapped vial equipped with a magnetic stirring
50 bar were added 1ꢀ(azidomethyl)ꢀ2ꢀ(phenylethynyl)benzene 5a-5e
(0.05 mmol), Pd(PPh3)4 (2.9 mg, 0.0025 mmol), K3PO4 (53.1 mg,
0.25 mmol), allyl methyl carbonate 2a (28.4 ꢁL, 0.25 mmol), and
DMF (1 mL). The mixture was stirred at 100 °C. The reaction
progress was monitored by TLC (hexane/ethyl acetate, 5/1). After
55 consumption of the staring material, the reaction mixture was
cooled to room temperature and filtered through a short column
with the use of ethyl acetate as eluent. After the solvent was
General Procedure for the Synthesis of 4-allyl-1-methyl-3-
phenylisoquinoline (7)
6
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To a 5ꢀmL screwꢀcapped vial equipped with a magnetic stirring
bar were added 1ꢀ(azidomethyl)ꢀ2ꢀ(phenylethynyl)benzene 5f-5k 60 25.6, 44.4, 101.9, 102.2, 103.9, 120.3, 120.4, 126.9, 127.9, 128.9,
2H), 7.89 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
(0.05 mmol), Pd(PPh3)4 (2.9 mg, 0.0025 mmol), K3PO4 (53.1 mg,
0.25 mmol), allyl methyl carbonate 2a (28.4 ꢁL, 0.25 mmol), and
DMF (1 mL). The mixture was stirred at 100 °C. The reaction
progress was monitored by TLC (hexane/ethyl acetate, 5/1). After
130.3, 130.4, 131.6, 136.4, 138.3, 144.5, 148.1, 148.3. IR (KBr)
3070, 2913, 2844, 1646, 1467, 1352, 1294, 1033, 698 cmꢀ1.
HRMSꢀEI (m/z) [M]+ Calcd for C20H16NO2 [M﹣H]+ 302.1181;
Found 302.1176.
5
consumption of the staring material 5f-5k, the reaction mixture 65 8-allyl-5-methyl-7-p-tolyl-[1,3]dioxolo[4,5-g]isoquinoline (7f).
1
was cooled to room temperature and filtered through a short
column with the use of ethyl acetate as eluent. After the solvent
10 was removed under reduced pressure, the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate,
30/1~5/1) to provide the product 7a-7f.
Yellow oil (14.3 mg, 90%); H NMR (400 MHz, CDCl3) δ 1.83
(s, 3H), 2.43 (s, 3H), 2.85 (dd, J = 14.0, 6.6 Hz, 1H), 2.99 (dd, J =
14.0, 7.8 Hz, 1H), 5.06ꢀ4.84 (m, 2H), 5.45ꢀ5.28 (m, 1H), 6.06 (s,
2H), 6.88 (s, 1H), 7.36ꢀ7.27 (m, 3H), 7.78 (d, J = 7.9 Hz, 2H).
70 13C NMR (100 MHz, CDCl3) δ 21.3, 25.6, 44.4, 101.9, 102.1,
103.9, 120.2, 120.6, 126.8, 128.7, 129.6, 130.4, 130.4, 136.1,
137.8, 138.3, 144.4, 148.1, 148.1. IR (KBr) 3075, 2982, 2919,
1745, 1601, 1473, 1352, 1294, 1039, 923, 819, 692 cmꢀ1. HRMSꢀ
EI (m/z) [M]+ Calcd for C21H18NO2 [M﹣H]+ 316.1338; Found
4-allyl-1-methyl-3-phenylisoquinoline (7a). Yellow oil (11.0
1
mg, 85%); H NMR (400 MHz, CDCl3) δ 1.88 (s, 3H), 2.92 (dd,
15 J = 14.1, 6.6 Hz, 1H), 3.05 (dd, J = 14.1, 7.9 Hz, 1H), 5.03ꢀ4.87
(m, 2H), 5.39ꢀ5.28 (m, 1H), 7.49ꢀ7.36 (m, 4H), 7.53 (t, J = 7.7 Hz,
2H), 7.88 (t, J = 7.3 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H). 13C NMR 75 316.1341.
(100 MHz, CDCl3) δ 25.5, 44.4, 120.3, 121.2, 122.7, 126.9, 127.1,
128.1, 128.4, 128.7, 128.9, 128.9, 130.4, 131.5, 136.4, 139.5,
20 150.2. IR (KBr) 3070, 2982, 2925, 1641, 1444, 1352, 988, 918,
762, 692 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for C19H16N [M﹣H]+
258.1283; Found 258.1279.
8-allyl-7-(4-chlorophenyl)-5-phenyl-[1,3]dioxolo[4,5 g]isoquin
-oline (7g). Yellow oil (12.0 mg, 60%); 1H NMR (400 MHz,
CDCl3) δ 3.36 (dd, J = 14.1, 6.4 Hz, 1H), 3.55 (dd, J = 14.1, 7.6
Hz, 1H), 5.04ꢀ4.84 (m, 2H), 5.25ꢀ5.14 (m, 1H), 6.13ꢀ6.00 (m,
80 2H), 6.88 (s, 1H), 7.29ꢀ7.26 (m, 1H), 7.39ꢀ7.30 (m, 5H), 7.53ꢀ
7.46 (m, 2H), 7.86 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 43.0, 102.0, 102.1, 105.3, 120.3, 120.9, 126.0, 128.2,
128.6, 129.0, 129.1, 129.2, 129.9, 130.0, 133.8, 137.1, 137.5,
139.0, 143.9, 148.3, 148.6. IR (KBr) 2905, 1470, 1345, 1029, 928,
4-allyl-1,3-diphenylisoquinoline (7b). Yellow oil (14.9 mg,
1
93%); H NMR (400 MHz, CDCl3) δ 3.44 (dd, J = 14.0, 6.4 Hz,
25 1H), 3.59 (dd, J = 14.0, 7.7 Hz, 1H), 5.02ꢀ4.82 (m, 2H), 5.23ꢀ5.12
(m, 1H), 7.49ꢀ7.30 (m, 9H), 7.54 (t, J = 7.5 Hz, 2H), 7.93 (d, J =
7.5 Hz, 1H), 8.01 (d, J = 7.7 Hz 2H). 13C NMR (100 MHz, 85 827, 732 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for C25H17NO2Cl [M
CDCl3) δ 43.2, 120.7, 121.3, 124.2, 126.0, 127.1, 128.2, 128.5,
128.5, 128.8, 128.8, 128.9, 129.0, 130.0, 131.4, 137.4, 139.1,
30 139.5, 139.5, 149.4. IR (KBr) 3058, 2912, 1646, 1491, 1444,
1352, 982, 756, 698 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for
C24H18N [M﹣H]+ 320.1439; Found 320.1441.
﹣H]+ 398.0943; Found 398.0943.
4-allyl-3-(4-fluorophenyl)-1-methylisoquinoline (7h). Yellow
1
oil (12.9 mg, 93%); H NMR (400 MHz, CDCl3) δ 1.88 (s, 3H),
2.92 (dd, J = 14.1, 6.6 Hz, 1H), 3.04 (dd, J = 14.1, 7.9 Hz, 1H),
90 5.04ꢀ4.88 (m, 2H), 5.39ꢀ5.28 (m, 1H), 7.28ꢀ7.17 (m, 2H), 7.49ꢀ
7.40 (m, 3H), 7.83 (t, J = 6.4 Hz, 1H), 7.97ꢀ7.89 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 25.5, 44.3, 120.4, 121.0, 122.7, 122.8,
126.7, 127.7, 127.7, 128.5, 128.7, 128.8, 130.3, 130.3, 136.2,
138.6, 150.1. IR (KBr) 2911, 2845, 1506, 1220, 833, 756, 577
4-allyl-7-chloro-1,3-diphenylisoquinoline (7c). Yellow oil
(15.5 mg, 87%); 1H NMR (400 MHz, CDCl3) δ 3.42 (dd, J = 14.1,
35 6.4 Hz, 1H), 3.58 (dd, J = 14.1, 7.7 Hz, 1H), 5.06ꢀ4.84 (m, 2H),
5.23ꢀ5.13 (m, 1H), 7.47ꢀ7.30 (m, 8H), 7.58ꢀ7.50 (m, 2H), 7.84 (d,
J = 8.2 Hz, 1H), 7.96 (t, J = 7.8 Hz 2H). 13C NMR (100 MHz, 95 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for C19H15NF [M ﹣ H]+
CDCl3) δ 43.0, 121.2, 122.2, 124.6, 125.6, 125.9, 125.9, 127.0,
128.4, 128.8, 128.8, 129.0, 129.1, 129.5, 131.1, 134.6, 136.6,
40 138.5, 139.6, 151.2. IR (KBr) 3064, 2919, 1635, 1496, 1450,
1352, 982, 768, 698 cmꢀ1. HRMSꢀEI (m/z) [M]+ Calcd for
C24H17NCl [M﹣H]+ 354.1050; Found 354.1053.
276.1189; Found 276.1190.
4-allyl-1-phenyl-3-m-tolylisoquinoline (7i). Yellow oil (14.9 mg,
1
89%); H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.37 (dd, J =
14.0, 6.2 Hz, 1H), 3.52 (dd, J = 14.0, 7.7 Hz, 1H), 4.98ꢀ4.74 (m,
100 2H), 5.16ꢀ5.05 (m, 1H), 7.22ꢀ7.14 (m, 1H), 7.44ꢀ7.22 (m, 9H),
7.72 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J = 5.5 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 21.5, 43.1, 120.7, 121.3, 124.1,
124.2, 126.0, 127.1, 127.8, 127.9, 128.5, 128.8, 129.0, 130.0,
131.3, 137.4, 137.5, 138.6, 138.7, 139.2, 139.2, 139.6, 149.4. IR
4-allyl-3-cyclohexyl-1-phenylisoquinoline (7d). Yellow oil
1
(12.9 mg, 79%); H NMR (400 MHz, CDCl3) δ 1.54ꢀ1.30 (m,
45 3H), 1.84ꢀ1.69 (m, 3H), 1.91 (d, J = 12.9 Hz, 2H), 2.15ꢀ2.05 (m,
2H), 3.05 (t, J = 12.0 Hz, 1H), 3.36 (dd, J = 14.0, 6.3 Hz, 1H),
3.49 (dd, J = 14.0, 7.7 Hz, 1H), 4.97ꢀ4.76 (m, 2H), 5.18ꢀ5.06 (m, 105 (KBr) 2911, 2851, 1589, 1446, 1220, 916, 658 cmꢀ1. HRMSꢀEI
1H), 7.36ꢀ7.28 (m, 6H), 7.46ꢀ7.38 (m, 2H), 7.67 (d, J = 7.6 Hz,
1H), 13C NMR (100 MHz, CDCl3) δ 26.1, 26.5, 32.6, 36.3, 43.3,
50 120.4, 121.5, 124.1, 126.0, 127.5, 127.7, 128.3, 128.3, 128.6,
128.9, 130.1, 137.0, 139.4, 144.3, 148.9. IR (KBr) 3064, 2931,
2856, 1641, 1444, 1334, 988, 750, 692 cmꢀ1. HRMSꢀEI (m/z)
[M]+ Calcd for C24H24N [M﹣H]+ 326.1909; Found 326.1911.
8-allyl-5-methyl-7-phenyl-[1,3]dioxolo[4,5-g]isoquinoline (7e).
(m/z) [M]+ Calcd for C25H20N [M ﹣ H]+ 334.1596; Found
334.1592.
General Procedure for the ring closing reaction (12)
110 To a 5ꢀmL screwꢀcapped vial equipped with a magnetic stirring
bar were added 3,4ꢀdiallylquinolines 3a (14.3 mg, 0.05 mmol),
Grubbs I catalyst (4.1 mg, 0.005 mmol), and CH2Cl2 (1 mL). The
mixture was stirred for 1 h at 40 °C. The reaction progress was
monitored by TLC (hexane/ethyl acetate, 10/1). After
115 consumption of the staring material 3a, the reaction mixture was
1
55 Yellow oil (12.3 mg, 81%); H NMR (400 MHz, CDCl3) δ 1.83
(s, 3H), 2.85 (dd, J = 14.0, 6.6 Hz, 1H), 3.00 (dd, J = 14.0, 7.8 Hz,
1H), 5.06ꢀ4.87 (m, 2H), 5.43ꢀ5.28 (m, 1H), 6.07 (s, 2H), 6.88 (s,
1H), 7.31 (s, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.51 (t, J = 7.7 Hz,
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C4OB02567A
4
C. G. Pancote, B. S. de Carvalho, C. V. Luchez, J. P. S. Fernandes,
M. J. Politi, C. A. Brandt, Synthesis 2009, 23, 3964.
R. H. F. Manske, Chem. ReV. 1942, 30, 113ꢀ144.
cooled to room temperature and filtered through a short column
with the use of ethyl acetate as eluent. After the solvent was
removed under reduced pressure, the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate,
30/1~5/1) to provide the product 12 in 90% yield as a yellow oil
(11.6 mg). 1H NMR (400 MHz, CDCl3) δ 2.95ꢀ2.83 (m, 2H),
3.38ꢀ3.25 (m, 2H), 6.17ꢀ6.02 (m, 2H), 7.39ꢀ7.29 (m, 2H), 7.53ꢀ
7.40 (m, 4H), 7.90ꢀ7.82 (m, 3H). 13C NMR (100 MHz, CDCl3) δ
43.8, 47.0, 112.2, 123.3, 126.2, 127.8, 128.0, 128.3, 128.8, 128.9,
5
6
65
70
For quinoline syntheses see: (a) G. Jones, Ed. Comprehensive
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5
10 129.9, 130.0, 130.7, 134.8, 140.0, 144.0, 148.3. IR (KBr) 3058,
2919, 2844, 1635, 1253, 1033, 796 cmꢀ1. HRMSꢀEI (m/z) [M]+
Calcd for C19H14N [M﹣H]+ 256.1126; Found 256.1122.
7
75
Acknowledgements
The authors gratefully acknowledge the financial support from
15 the National Natural Science Foundation of China (No.
21277091); the State key Program of National Nature Science
Foundation of China (No. 21436007); Key Basic Research
Projects of Science and Technology Commission of Shanghai
80
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(14JC1403100); the Program for
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20 Appointment (Eastern Scholar) at Shanghai Institutions of Higher
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Notes and references
a
School of Environmental Science and Engineering, the State Key
25 Laboratory of Metal Matrix Composites , Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, China. Tel/Fax: (86)21-
54742251; E-mail: hzb410@sjtu.edu.cn
95
b
WPI-Advanced Institute for Materials Reaserch (WPI-AIMR), Tohoku
University, Sendai 980-8577, Japan; State Key Laboratory of Fine
30 Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian
116012, China.
† Electronic Supplementary Information (ESI) available: Experimental
details, characterization data, 1H NMR and 13C NMR spectra of newly
synthesized compounds. See DOI: 10.1039/b000000x/
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8
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