Efficient approach to allylated quinolines via palladium-catalyzed cyclization-allylation of 1-azido-2-(2-propynyl) benzenes with allyl methyl carbonate

Article abstract of DOI:10.1016/j.tetlet.2014.01.068

The palladium-catalyzed cyclization-allylation reaction of ortho-azido propynylbenzenes 1 and allyl methyl carbonate 2d gives the corresponding allylated quinolines in moderate to good yields. The reaction of 1-azido-2-(2-propynyl)benzene 1a proceeds smoo

Full text of DOI:10.1016/j.tetlet.2014.01.068

Tetrahedron Letters 55 (2014) 1552–1556
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Tetrahedron Letters
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Efficient approach to allylated quinolines via palladium-catalyzed
cyclization–allylation of 1-azido-2-(2-propynyl) benzenes with allyl
methyl carbonate
a
a
b
Jiang Luo a, Zhibao Huo a, , Jun Fu , Fangming Jin , Yoshinori Yamamoto
⇑
a School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
b WPI-Advanced Institute for Materials Research, Tohoku University, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed cyclization–allylation reaction of ortho-azido propynylbenzenes 1 and allyl
methyl carbonate 2d gives the corresponding allylated quinolines in moderate to good yields. The reac-
tion of 1-azido-2-(2-propynyl)benzene 1a proceeds smoothly with 10 mol % Pd(PPh3)4 and 5 equiv K3PO4
or NaOAc in DMF at 100 °C to afford 3,4-diallylquinoline 3a in 69% yield in the case of R2 = H and 3-allyl-
quinoline 4 in 67% yield in the case of R2 – H.
Received 30 September 2013
Revised 7 January 2014
Accepted 16 January 2014
Available online 23 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Allylation
Cyclization
Palladium
Synthetic methods
Heterocycles
Introduction
use of strong acids and bases are needed in the coupling procedure.
Therefore, the development of an efficient and environmentally be-
Quinoline skeletons are a major class of compounds which
occur in many natural products and pharmaceuticals. Substituted
quinolines are often used for structural frameworks of many syn-
thetic compounds with bioactive properties such as antimalarial,
antibacterial, antihypertensive, antiasthmatic, and anti-inflamma-
tory agents.1–3 Furthermore, substituted quinolines can be used
as organocatalysts and as meaningful tools for the syntheses of
chiral molecules with high enantioselectivity.4 In particular, allyl-
substituted quinolines are of special interest because the allyl
group sometimes plays an important role in the compound’s bioac-
tivity.5 Besides that, the presence of the allyl group makes further
cyclization feasible.6
Due to their importance, much attention has been paid to the
preparation and functionalization of allyl-substituted quinolines.
A number of regioselective synthetic methods for allyl-substituted
quinolines have been reported, like 2-allylquinolines,7 and 3-allyl-
quinolines.8 A frequently used method for the synthesis of allyl-
substituted quinolines is the metal-catalyzed coupling between
halogen-containing quinolines and allylic substrates.7,8 However,
the use of complex catalysts, prolonged reaction times, and/or
nign protocol for the synthesis of allyl-substituted quinolines is
still desirable. Previously, we reported metal-catalyzed or non-
metal-catalyzed synthesis of substituted dihydroisoquinolines,
and iodine-mediated or gold-catalyzed synthesis of substituted
isoquinolines.9 Also we reported the synthesis of substituted quin-
olines via electrophilic cyclization of 1-azido-2-(2-propynyl) ben-
zenes in the presence of electrophilic reagents or electrophilic
catalysts.10 It occurred to us that the transition-metal catalyzed-
reaction of 1-azido-2-(2-propynyl) benzenes and allyl compounds
might produce allyl-substituted quinolines.
Herein, we report a novel method for the one-step synthesis of
allylated products selectively via palladium-catalyzed cyclization–
allylation reaction of 1-azido-2-(2-propynyl) benzenes 1 with allyl
methyl carbonate 2d. The reaction proceeded smoothly to afford
3,4-diallylquinolines 3 in the case of R2 = H and 3-allylquinolines
4 in the case of R2 – H in moderate to good yields with no by-prod-
ucts (Scheme 1). To the best of our knowledge, it is the first time for
the synthesis of 3,4-diallylquinolines and 3-allylquinolines to date.
Furthermore, this palladium-catalyzed reaction is mechanistically
interesting, compared to the Au+-catalyzed and I+-mediated reac-
tions, as mentioned later.
⇑
Corresponding author. Tel.: +86 21 5474 2251.
E-mail address: hzb410@sjtu.edu.cn (Z. Huo).
http://dx.doi.org/10.1016/j.tetlet.2014.01.068
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. Luo et al. / Tetrahedron Letters 55 (2014) 1552–1556
1553
R2
H
R1
R3
R2
N3
Cat. Pd, base
R2 = H
Cat. Pd, base
1
R1
R1
N
R3
N
R3
R2 ≠ H
+
4
3
OCO2Me
2d
Scheme 1. Pd-catalyzed synthesis of 3,4-diallylquinolines and 3-allylquinolines.
the product 3a was obtained in 69% isolated yield (entry 11). The
decrease in reaction temperature to 80 °C gave the product 3a in
60% isolated yield (entry 20). Decreasing the amounts of base and
catalyst resulted in lower yields (entries 21 and 22).
Results and discussion
Initially, we selected 1-azido-2-(3-phenylprop-2-ynyl) benzene
1a as a model substrate. The results are summarized in Table 1.
When allyl acetate 2a was used, the reaction proceeded smoothly
and gave the desired 3,4-diallylquinoline 3a in 39% isolated yield
(entry 1). Allyl chloride 2b produced the desired product 3a in
low yield (entry 2). No desired product was obtained with allyl tri-
butyltin 2c (entry 3). The best result was obtained with allyl
methyl carbonate 2d, giving the product 3a in 47% 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
methyl carbonate was utilized as an allyl source for further optimi-
zation of reaction conditions.
Our research was focused on the optimization of palladium cat-
alysts, solvents, bases, and temperatures, and the results are sum-
marized in Table 2. No desired product 3a was obtained in the
absence of palladium catalyst (entry 1). A low yield (26%) was ob-
tained when the reaction was carried out in the presence of
Pd(PPh3)4 but in the absence of base (entry 5), indicating the impor-
tance of the combined use of both palladium catalyst and base. Next
we tested two palladium catalysts, Pd2(dba)3ÁCHCl3 and Pd(PPh3)4
(entries 2–4 and 6), the latter gave much better result. The use of
ligands, XantPhos, and S-Phos, gave 8% and 35% yields in the pres-
ence of Pd2(dba)3ÁCHCl3, respectively (entries 3 and 4). Among the
various bases we investigated (entries 6–13), the use of K3PO4
and NaOAc afforded 3a in high yields (entries 10 and 11). The
screening of various solvents, such as 1,4-dioxane, AcOEt, benzene,
CH3CN, CH3CN + H2O, THF, DMF, revealed that the choice of sol-
vents played an important role for the formation of 3a (entries
11, 14–19). DMF was found to be the most suitable solvent, and
With optimized conditions in hand, we carried out the reactions
between various 1-azido-2-(2-propynyl) benzenes 1 and allyl
methyl carbonate 2d, and the results are summarized in Table 3.
The substrate 1b, having a methyl at the para-position of the aro-
matic ring, afforded the corresponding cyclized product 3b in 66%
isolate yield through method A (entry 1). The substrate 1c, bearing
fluorine atoms at 3,5-positions on the aromatic ring, afforded the
desired product 3c in 55% yield (entry 2). Furthermore, the sub-
strates 1d, having a cyclohexyl group at the alkyne terminus, gave
the expected products 3d in moderate yields via the methods A
and B (entries 3 and 4, respectively); here, a mixture of unidenti-
fied by-products was 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,
having a methyl at the meta-position and a chloro group at para-
position of the aromatic ring, afforded products 3e and 3f in 60%
and 64% isolate yield through method A (entries 5 and 6). The sub-
strates 1g, 1h and 1i, in which the aromatic ring was substituted
with bromo and chloro groups, afforded the corresponding prod-
ucts 3g, 3h and 3i in moderate yields, respectively (entries 7–9,
10). The substrate 1j afforded the desired product 3j in 45% yield
with method A and 58% yield with method B (entries 11 and 12).
Other substituted allyl carbonates such as crotyl ethyl carbonate
2e and ethyl 2-methylallyl carbonate 2f, instead of allyl methyl
carbonate 2d, were also investigated and gave only trace amounts
of the products, 2-phenylquinoline as main product10 was formed
(yield 60% for 2e, 67% for 2f).
Table 1
Optimization of the allyl sourcesa
Pd(PPh3)4 (10 mol%),
K3PO4 (5 eq)
+
OCO2Et
2e
Ph
N3
1a
DMF, 100 o
C
Pd(PPh3)4 (10 mol%),
K2CO3 (5 eq)
X
N
Ph
+
Ph
DMF, 100 o C, 24 h
3k (trace)
N3
N
Ph
1a
2
3a
Pd(PPh3)4 (10 mol%),
K3PO4 (5 eq)
Entry
Allyl sources
3a, Yieldb (%)
OCO2Et
+
1
2
3
44 (39)c
OAc
Cl
Ph
N3
1a
DMF, 100 o
C
23
0
N
Ph
2f
3m
SnBu3
(trace)
52 (47)c
OCO2Me
2a + 2d
4
5
21d
a
All the reactions were carried out using 0.05 mmol of 1a and 5 equiv of 2 in the
It is noteworthy that the reaction of 1n, having the OAc group at
R2 (at the benzylic position), proceeded smoothly and gave the
3-allylquinoline 4 in 67% isolated yield (Scheme 2). On the basis
of the results above, it is clearly indicated that R2 group plays a
key role in the selective synthesis of allylated quinolines.
presence of Pd(PPh3)4 (10 mol %), and K2CO3 (5 equiv), in 1 mL DMF at 100 °C for
24 h.
b
1H NMR yield was determined by using p-xylene as an internal standard.
Isolated yield is shown in parentheses.
2.5 equiv 2a and 2.5 equiv 2d were used respectively.
c
d

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J. Luo et al. / Tetrahedron Letters 55 (2014) 1552–1556
Table 2
Optimization of the reaction conditionsa
cat Pd, base
OCO2Me
+
Ph
Solv, Temp, 24 h
N3
N
Ph
1a
2d
3a
Entry
cat Pd
Bases
Solvent
Yieldb (%)
SM recov.b (%)
1
2
3
4
5
6
7
8
—
K3CO3
K3CO3
K3CO3
K3CO3
—
K2CO3
Na2CO3
NaHCO3
NaOH
NaOAc
K3PO4
KH2PO4
Et3N
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0
4
8
35
0
0
0
0
0
0
0
0
0
0
0
0
0
5
8
11
0
0
8
0
0
0
c
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
c,d
c,e
26
(47)f
42
46
56
66
9
10
11
12
13
14
15
16
17
18
19
20
21
22
75 (69)f
37
DMF
48
27
29
26
66
15
30
1,4-Dioxane
AcOEt
Benzene
CH3CN
CH3CN+H2O
THF
DMF
DMF
DMF
69 (60)f
63
g
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
h
65 (59)f
i
a
The reactions were performed with 1a (0.05 mmol) and 2d (5 equiv) in the presence of Pd catalyst (10 mol %) and base (5 equiv) in 1 mL DMF at 100 °C for 24 h under a
argon atmosphere.
b
1H NMR yield was determined by using p-xylene as an internal standard.
c
5 mol % Pd2(dba)3ÁCHCl3 was used.
d
5 mol % XantPhos was used.
e
10 mol % S-Phos was used.
Isolated yield is shown in parentheses.
The reaction temperature was 80 °C.
5 mol % Pd(PPh3)4 was used.
f
g
h
i
3 equiv K3PO4 was used.
Table 3
Sythesis of 3,4-diallylquinolines with various substratesa
Pd(PPh3)4 (10 mol%),
K3PO4 or NaOAc (5 eq)
R1
OCO2Me
+
R3
N3
DMF, 100 o
C
R1
N
R3
1
2d
3
Entry
1
Substrate (1)
Method
A
Time (h)
4
Product (3)
Yieldb (%)
66
1b
1c
3b
N3
N3
Me
F
2
A
3
3c
55
F
1d
3
4
A
B
5
3d
26
38
N3
24
Me
Cl
5
6
A
A
5
5
3e
3f
60
64
1e
1f
N3
N3

J. Luo et al. / Tetrahedron Letters 55 (2014) 1552–1556
1555
Table 3 (continued)
Entry
Substrate (1)
Method
A
Time (h)
5
Product (3)
Yieldb (%)
Br
1g
Me
7
3g
42
N3
Br
1h
8
9
A
B
1
2
3h
36
45
Ph
N3
Cl
1i
1j
10
A
5
3i
3j
33
Ph
Ph
N3
11
A
B
3
5
45
58
N3
12
a
All the reactions were carried out using 0.05 mmol of 1 and 5 equiv of 2 in the presence of Pd(PPh3)4 (10 mol %) under argon atmosphere in 1 mL DMF at 100 °C; method A,
K3PO4 (5 equiv); method B, NaOAc (5 equiv).
b
Isolated yield.
A proposed mechanism for the formation of 3,4-diallylquinoline
3a via palladium-catalyzed cyclization–allylation of 1-azido-2-(2-
propynyl) benzene with allyl methyl carbonate is illustrated in
Scheme 3. Initially, Pd(0) reacts with allyl methyl carbonate 2d
previous Au+ and I+ methods,13 is that the Pd-catalyzed azide–al-
kyne cyclization is able to incorporate another organic ligand of
Pd (see 6), which is allyl in present, into quinoline framework.
to form the p
-allyl palladium species 511,12 with concomitant evo-
Conclusions
lution of CO2. Deprotonation of propargylic proton of 1a takes
place with methoxide formed. Then nucleophilic attack of propar-
gylic anion to allylpalladium cation results in propargylic allylation
6 and regeneration of Pd(0). Next, oxidative addition of allyl car-
bonate 2d occurs again to form 5, the intermediate 6 reacts with
5 again to generate intermediate 7 and subsequent nucleophilic at-
tack of a nitrogen atom to the electron-deficient alkyne forms an
intermediate 8. Finally, elimination of N2 and H+, together with
elimination of Pd(0), produces 3,4-diallylquinoline 3a. It is note-
worthy that, for the azide–alkyne 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
In conclusion, we have developed an effective strategy for the
regioselective synthesis of allylated quinolines via the palladium-
catalyzed cyclization–allylation reaction of 1-azido-2-(2-propynyl)
benzene and allyl methyl carbonate. R2 group (at the propargylic
position) plays a key role for the transformation. This reaction pro-
vides a useful method for the synthesis of allylated quinolines with
a wide variety of substrates. Further works to expand the scope
and synthetic utility of this methodology to the synthesis of biolog-
ically important natural and unnatural compounds are in progress.
Acknowledgments
The authors gratefully acknowledge the financial support from
the Program for Professor of Special Appointment (Eastern Scholar)
at Shanghai Institutions of Higher Learning (ZXDF160002). The
Project was sponsored by SRF for ROCS, SEM (BG1600002).
OAc
OAc
Pd(PPh3)4 (10 mol%),
NaOAc (5 eq)
OCO2Me
+
Ph
DMF, 5 h, 100 oC
N3
1n
N
Ph
(67 %)
2d
4
Supplementary data
Scheme 2. Sythesis of 3-allylquinolines.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
068.
References and notes
OCO2Me
Pd(0)
N
Ph
3a
2d
1. (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543; (b) Balasubramanian, M.; Keay, J.
G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; ; Pergamon Press: Oxford, 1996; Vol. 5, p 245.
2. (a) Chen, Y.; Fang, K.; Sheu, J.; Hsu, S.; Tzeng, C. J. Med. Chem. 2001, 44, 2374; (b)
Camps, P.; Gõmez, E.; Muñoz-Torrero, D.; Badia, A.; Vivas, N. M.; Barril, X.;
Orozco, M.; Luque, F. J. J. Med. Chem. 2001, 44, 4733; (c) Roma, G.; Di Braccio,
M.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000, 35, 1021; (d)
Lamazzi, C.; Leonce, S.; Pfeiffer, B.; Renard, P.; Guillaumet, G.; Rees, C. W.;
Besson, T. Bioorg. Med. Chem. Lett. 2000, 10, 2183; (e) Larsen, R. D.; Corley, E. G.;
King, A. O.; Carroll, J. D.; Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.;
Gauthier, J. Y.; Xiang, Y. B.; Zamboni, R. J. J. Org. Chem. 1996, 61, 3398.
3. (a) Joshi, A. A.; Viswanathan, C. L. Bioorg. Med. Chem. Lett. 2006, 16, 2613; (b)
Perzyna, A.; Klupsch, F.; Houssin, R.; Pommery, N.; Lemoine, A.; Hénichart, J. P.
Bioorg. Med. Chem. Lett. 2004, 14, 2363; (c) Martirosyan, A. R.; Rahim-Bata, R.;
Freeman, A. B.; Clarke, C. D.; Howard, R. L.; Strobl, J. S. Biochem. Pharmacol.
2004, 68, 1729; (d) Charris, J.; Martinez, P.; Dominguez, J.; Lopez, S.; Angel, J.;
Espinoza, G. Heterocycl. Commun. 2003, 9, 251; (e) Dubé, D.; Blouin, M.; Brideau,
C.; Chan, C.; Desmarais, S.; Ethier, D.; Falgueyret, J.; Friesen, R. W.; Girard, M.;
Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N.; Med, B. Chem. Lett.
1998, 8, 1255; (f) Kalluraya, B.; Sreenivasa, S. Il Faemaco 1998, 53, 399.
CO2
H
Pd+ -OMe
5
Pd
R3
H
N
+
N2
8
Ph
N3
1a
MeOH
Pd+
Ph
N-
N2
Ph
N-
N2
+
5
7
+
6
Scheme 3. A proposed mechanism for the formation of 3a.

1556
J. Luo et al. / Tetrahedron Letters 55 (2014) 1552–1556
4. (a) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252; (b) Tan, B.; Shi, Z.;
Chua, P. J.; Zhong, G. Org. Lett. 2008, 10, 3425; (c) Wang, B.; Wu, F.; Wang, Y.;
Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768; (d) Biddle, M. M.; Lin, M.;
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830; (e) Enders, D.; Grondal, C.;
Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (f) Wang, Y.; Liu, X.-F.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
5. Tempone, A. G.; Silva, A. C. M. P.; Brandt, C. A.; Martinez, F. S.; Borborema, S. E.
T.; Silveira, M. A. B.; Andrade, H. F., Jr. Antimicrob. Agents Chemother. 2005, 49,
1076.
6. Pancote, C. G.; de Carvalho, B. S.; Luchez, C. V.; Fernandes, J. P. S.; Politi, M. J.;
Brandt, C. A. Synthesis 2009, 23, 3964.
7. (a) Shoji, W.; Yukihiro, K.; Takashi, T.; Jun-ichi, U.; Shigeru, O. Bull. Chem. Soc.
Jpn. 1989, 62(7), 2338; (b) Gilman, H.; Eisch, J.; Soddy, T. S. J. Am. Chem. Soc.
1959, 81, 4000; (c) Thorsett, E. D.; Stermitz, F. R. J. Heterocyclic Chem. 1973, 10,
243.
Matsumoto, Y.; Tanaka, K. J. Am. Chem. Soc. 2006, 128, 8404; (d) Lee, K.; Kim,
H.; Mo, J.; Lee, P. H. Chem. Asian J. 2011, 6, 2147; (e) Berthiol, F.; Doucet, H.;
Santelli, M. Synthesis 2005, 20, 3589; (f) Ishikura, M.; Kamada, M.; Oda, I.; Ohta,
T.; Terashima, M. J. Heterocyclic Chem. 1987, 24(2), 377.
9. (a) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651; (b) Fischer, D.;
Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc.
2008, 130, 15720; (c) Huo, Z.; Tomeba, H.; Yamamoto, Y. Tetrahedron Lett. 2008,
49, 5531; (d) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 4764; (e) Asao, N.; Yudha, S.; Nogami, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526; (f) Ohtaka, M.; Nakamura,
H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339; (g) Asao, N.; Iso, K.; Yudha, S.
Org. Lett. 2006, 8, 4149.
10. Huo, Z.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266.
11. (a) Busetto, L.; Palazzi, A. Inorg. Chim. Acta 1975, 13, 233; (b) Shaw, B. L.; Shaw,
G. J. Chem. Soc. (A) 1971, 3533.
8. (a) Furuyama, T.; Yonehara, M.; Arimoto, S.; Kobayashi, M.; Matsumoto, Y.;
Uchiyama, M. Chem. Eur. J. 2008, 14, 10348; (b) Seomoon, D.; Lee, P. H. J. Org.
Chem. 2008, 73, 1165; (c) Uchiyama, M.; Furuyama, T.; Kobayashi, M.;
12. (a) Kamijo, S.; Jin, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 9453; (b)
Kamijo, S.; Jin, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 11940.
13. Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075.