Synthesis of aminoindolizine and quinoline derivatives via Fe(acac)TBAOH-catalyzed sequential cross-coupling-cycloisomerization reactions

Article abstract of DOI:10.1055/s-0030-1260305

Fe(acac)TBAOH-catalyzed three-component coupling-cycloisomerization reaction of aldehydes, terminal alkynes, and amines provides a diverse range of heterocyclic compounds such as aminoindolizines and quinoline derivatives. Georg Thieme Verlag Stuttgart -

Full text of DOI:10.1055/s-0030-1260305

LETTER
2379
Synthesis of Aminoindolizine and Quinoline Derivatives via Fe(acac)3/TBA-
OH-Catalyzed Sequential Cross-Coupling–Cycloisomerization Reactions
Synthesis of
A
a
minoindoli
c
zine
a
nd Q
u
inoline
D
erivative
sn S. Patil, Sachin V. Patil, Vivek D. Bobade*
Department of Chemistry, HPT Arts and RYK Science College, Nasik 422005, India
Fax +91(253)2574682; E-mail: v_bobade31@rediffmail.com
Received 23 June 2011
Abstract: Fe(acac)3/TBAOH-catalyzed three-component cou-
pling–cycloisomerization reaction of aldehydes, terminal alkynes,
and amines provides a diverse range of heterocyclic compounds
such as aminoindolizines and quinoline derivatives.
R1
N
CHO
Fe(acac)3
R2
N
N
NR1R2
[Fe]
R3
1
+
Key word: aminoindolizines, quinoline derivatives, tetrabutylam-
monium hydroxide (TBAOH), Fe(acac)3 catalyst, cross-coupling,
cycloisomerization
N
TBAOH
R1
DMSO
R2
N
R3
H
2
4
+
R3
The ongoing interest for developing new versatile and ef-
ficient syntheses of heterocycles has always been a com-
mon thread in the synthetic community. In the past decade
the concepts of multicomponent processes, domino reac-
tions, and sequential transformations, where complex and
highly diverse structures are created in a one-pot fashion,
have considerably stimulated both academia and indus-
try.1,2 As diversity-oriented syntheses,3 particularly multi-
component reactions (MCR), focus on synthetic
efficiency and reaction design, mastering unusual combi-
nations and sequences of elementary organic reactions un-
der similar conditions is a major challenge in engineering
novel types of MCR. In the past decade, transition-metal-
catalyzed MCR involving cascade C–C and C–N bond
formations have been widely used in the synthesis of het-
erocycles such as indolizines,4 imidazo[1,2-pyridines],5
quinolines,6 benzo[b]furans,7 aminoindolines, and ami-
noindoles.8,9 However, these processes required expen-
sive transition-metal catalysts such Au, Ag, Rh and high
temperatures. Iron salts have been explored as effective,
alternative, and promising transition-metal catalysts and
have received attention in recent years because they are
inexpensive, readily available, and are environmentally
benign.
3
Scheme 1
action of heteroaryl aldehydes, amines, and terminal
alkynes in DMSO (Scheme 1).
We first examined the coupling reaction of pyridine-2-
carboxaldehyde, piperidine, and phenylacetylene, with
TBAOH as base and Fe(acac)3 as catalyst, to optimize re-
action conditions, and representative results are summa-
rized in Table 1.
Table 1 Coupling Reaction of Pyridine-2-carboxaldehyde, Piperi-
dine, and Phenylacetylene
Fe(acac)3
N
+
+
Ph
TBAOH
DMSO
N
H
N
CHO
N
1
2
3
Ph
4a
Entry
Iron catalyst
(mol%)a
TBAOH
(mol%)
Solvent
Yield (%)
Recently, we reported the TBAOH-catalyzed synthesis of
propargylpyridine.10 During the course of reaction a
byproduct (3-phenyl-1-piperidin-1-yl)indolizine was
formed due to cycloisomerization of the propargylpyri-
dine. Inspired by this result, we became interested in de-
veloping a direct route to indolizines from readily
available precursors. Herein, we report the synthesis of 3-
substituted indolizines involving Fe(acac)3/TBAOH-cata-
lyzed three-component coupling–cycloisomerization re-
1
2
3
4
5
6
7
A (10)
A (5)
A (2)
B (5)
A (5)
A (5)
A (5)
10
10
10
10
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
82
85
36
80
40
0
–
10
25
a Pyridine-2-carboxaldehyde (1 mmol), piperidine (1.1 mmol), phen-
ylacetylene (1.2 mmol) in DMSO until completion of reaction.
A = Fe(acac)3, B = Fe(ClO4)3.
SYNLETT 2011, No. 16, pp 2379–2383
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260305; Art ID: D19911ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2380
S. S. Patil et al.
LETTER
The three-component coupling–cycloisomerization reac- As can be seen from Scheme 2, this multicomponent pro-
tion proceeded smoothly in DMSO to afford the desired cess can be readily diversified through combinations of
product 4a in up to 82% yield after 2.5 hours at room tem- heteroaryl aldehydes, amines, and alkynes. Regarding al-
perature (Table 1, entry 1). The loading of iron catalyst dehydes, pyridine-2-carboxaldehyde and 2-quinolinecar-
was optimized from a range of 2–10 mol% and 5 mol% boxaldehyde undergo three-component coupling reaction
was found to be most effective for this conversion to give products in good yields (products 4a–n). With re-
(Table 1, entry 2). Lowering the catalyst to 2 mol% re- spect to the amine component, cyclic amines (e.g., piperi-
duced the yield to 36% (Table 1, entry 3) In the absence dine, pyrrolidine, and morpholine) afforded products with
of TBAOH no reaction was observed, (Table 1, entry 6), moderate to excellent yields (products 4a–i and 4k,l).
indicating that TBAOH plays a crucial role for this three- Dibenzylamine also gave product in excellent yield (prod-
component coupling reaction. DMSO was found to be a uct 4j). The use of piperazine afforded a bridged indoliz-
better reaction solvent than DMF (Table 1, entry 7). With ine in 57% yield (product 4k). Aryl acetylenes with
these optimized conditions, we examined the scope of this electron-donating groups at the para position (OMe and
multicomponent reaction, and the results are summarized Me) afforded products in 90% and 83% yield, respective-
in Scheme 2.
ly (products 4b,g) while the presence of an electron-with-
NR1R2
R2
R1
Fe(acac)3
N
R3
+
+
H
N
CHO
TBAOH, DMSO
N
R3
N
N
N
N
N
N
N
N
4d
86%
Cl
4a
85%
OMe
4b
90%
4c
72%
O
O
O
O
N
N
N
N
N
N
N
N
N
4e
4f
59%
4h
80%
4g
83%
83%
NO2
Me
O
N
NBn2
N
N
N
N
N
N
N
4k
57%
4i
74%
4j
80%
O
N
N
N
N
N
N
N
S
4m
70%
4l
63%
4n
71%
Scheme 2 Multicomponent reaction under optimized reaction conditions
Synlett 2011, No. 16, 2379–2383 © Thieme Stuttgart · New York

LETTER
Synthesis of Aminoindolizine and Quinoline Derivatives
2381
R2
R2
N
R1
N
+
CHO
N
H
N
1
R1
[Fe]
R3
Fe(acac)3
[Fe]II
R2
R1
N
TBOH
DMSO
N
H
R3
2
i
ii
+
–H
R3
3
[Fe]
R2
R2
R1
N
R1
N
[Fe]II
N
N
+H
R3
R3
4
iii
Scheme 3
drawing substituent (NO2) gave only 59% yield (product catalyst enhances the electrophilicity of the alkyne, and
4f). Alkynes substituted with a six-membered heteroaro- subsequent nucleophilic attack of the nitrogen lone pair
matic ring provided good yields of product (products 4h,i) would produce the cation ii, which undergoes deprotona-
while a five-membered heterocyclic substituent on the tion followed by demetalation of iii to afford indolizines 4
alkyne gave lower yield of product (product 4l). The reac- (Scheme 3).
tion fails with aliphatic alkynes.
Using our optimized protocol, we also studied the cou-
We propose the following mechanism for the formation of pling of aldehydes and primary amines with terminal
aminoindolizines, similar to the mechanism described in alkynes to give 2,4-disubstituted quinoline derivatives in
literature using gold-catalyzed reaction.4a First,
a
good yields (Table 2).
TBAOH-catalyzed three-component coupling of pyri-
dine-2-carboxaldehyde, amine, and alkyne occurrs to af-
ford NR1R2-substituted propargylic pyridine 4 via a
Mannich reaction. Coordination of the alkyne i to the iron
It was found that aldehydes bearing a wide range of sub-
stituents undergo coupling reaction to afford the desired
products in good yield (Table 2, entries 1–10). The reac-
Table 2 Synthesis of 2,4-Disubstituted Quinoline Derivatives
R3
R5
R5
Fe(acac)3
R3
H
R4CHO
+
TBAOH
NH2
N
R4
5
6
Product
8a
7
8
Entry
R3
Ph
Ph
R4
R5
H
H
Cl
H
H
H
H
H
H
H
Yield (%)a
Mp (lit.)b
1
2
4-FC6H4
4-CNC6H4
Ph
73
64
81
62
61
78
84
86
56
61
67–69 (68–69)11
152–155 (154–156)11
87–88 (87–88)11
107–110 (108–109)11
265–269 (268–270)11
99–101 (102)12
oil13
8b
3
8c
4-MeC6H4
4
8d
4-MeC6H4
Naph
5
8e17
8f
4-MeOC6H4
Naph
6
Ph
Ph
Ph
Ph
Ph
Ph
7
8g
4-MeOC6H4
thienyl
n-Bu
8
8h
89–92 (83–85)14
oil15
9
8i
10
8j
Cy
oil11
a Yield is based on aniline (7).
b Literature compounds have been previously reported; physical and spectral data were comparable.
Synlett 2011, No. 16, 2379–2383 © Thieme Stuttgart · New York

2382
S. S. Patil et al.
LETTER
tion of an aromatic aldehyde bearing electron-donating
groups provided a higher yield (Table 2 entry 7), while an
aldehyde with an electron-withdrawing substituent result-
ed in lower yield (Table 2 entry 2). The sterically hindered
1-naphthaldehyde also reacted under optimized condi-
tions (Table 2, entries 4 and 5), and thiophene-2-carbox-
aldehyde aldehyde afforded a good yield of product 8h
(Table 2 entry 8), while aliphatic aldehydes gave lower
yields (Table 2, entries 9 and 10).
References and Notes
(1) (a) Zhu, J.; Bienayme, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (b) Dömling, A. Chem. Rev.
2006, 106, 17. (c) Dömling, A.; Ugi, I. Angew. Chem. Int.
Ed. 2000, 39, 3168.
(2) (a) Tietze, L. F.; Brasche, G.; Gericke, G. M. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
2006. (b) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed.
1993, 32, 131. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(3) (a) Arya, A.; Chou, D. T. H.; Baek, M. G. Angew. Chem. Int.
Ed. 2001, 40, 339. (b) Burke, M. D.; Berger, E. M.;
Schreiber, S. L. Science 2003, 302, 613. (c) Cox, B.;
Denyer, J. C.; Binnie, A.; Donnelly, M. C.; Evans, B.; Green,
D. V. S.; Lewis, J. A.; Mander, T. H.; Merritt, A. T.; Valler,
M. J.; Watson, S. P. Prog. Med. Chem. 2000, 37, 83.
(d) Schreiber, S. L. Science 2000, 287, 1964. (e) Schreiber,
S. L.; Burke, M. D. Angew. Chem. Int. Ed. 2004, 43, 46.
(4) (a) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (b) Kel’in, A.
V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001,
123, 2074. (c) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4,
4697. (d) Kim, J. T.; Butt, J.; Gevorgyan, V. J. Org. Chem.
2004, 69, 5638. (e) Kim, J. T.; Gevorgyan, V. J. Org. Chem.
2005, 70, 2054. (f) Seregin, I. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 12050. (g) Smith, C. R.; Bunnelle, E.
M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169.
(h) Liu, Y. H.; Song, Z. Q.; Yan, B. Org. Lett. 2007, 9, 409.
(i) Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, X. W.
J. Comb. Chem. 2010, 12, 696.
Ph
Ph
(O)
N
Ph
N
viii
Ph
8
Ph
Ph
H
B–
FeII
Ph
BH
N
N
H
vii
Ph
Ph
FeIII
Ph
Ph
NH
HN
PhCHO
+ PhNH2
Ph
(5) Chernyak, N.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010,
Ph
FeIII
v
49, 2743.
(6) (a) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. Tetrahedron 2008,
64, 2755. (b) Zhang, Y.; Li, P.; Wang, L. J. Heterocycl.
Chem. 2011, 48, 153. (c) Sakai, N.; Uchida, N.; Konakahar,
T. Synlett 2008, 1515.
vi
Scheme 4 Postulated reaction mechanism
(7) Li, H.; Liu, J.; Yan, B.; Li, Y. Tetrahedron Lett. 2009, 50,
2353.
A plausible pathway involves Fe(acac)3/TBAOH-cata-
lyzed three-component reaction of aldehyde, amine, and
alkyne to lead to formation of propargylamine vi.10 The
triple bond of propargylamine vi is activated by Lewis
acidic Fe(III) to promote an intramolecular nucleophilic
attack through the aniline aromatic-ring nitrogen. The re-
sulting Fe(III) vinyl ate complex vii subsequently under-
goes decomposition to give the dihydroquinoline
intermediate viii and regenerates Fe(III) catalyst for fur-
ther reactions (Scheme 4). In the presence of air, the gen-
erated dihydroquinoline could be further oxidized to
afford quinoline 8.
(8) (a) Martin, R.; Fürstner, A. Angew. Chem. Int. Ed. 2004, 43,
3955. (b) Sapountzis, I.; Lin, W.; Kofink, C. C.;
Despotopoulou, C.; Knochel, P. Angew. Chem. Int. Ed.
2005, 44, 1654. (c) Komeyama, K.; Morimoto, T.; Takaki,
K. Angew. Chem. Int. Ed. 2006, 45, 2938. (d) Plierker, B.
Angew. Chem. Int. Ed. 2006, 45, 6053. (e) Egami, H.;
Katsuki, T. J. Am. Chem. Soc. 2007, 129, 8940. (f) Cahiez,
G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem. Soc.
2007, 129, 13788. (g) Hatakeyama, T.; Nakamura, M.
J. Am. Chem. Soc. 2007, 129, 9844. (h) Gurinot, A.;
Reymond, S.; Cossy, J. Angew. Chem. Int. Ed. 2007, 46,
6521. (i) Li, Z.; Cao, L.; Li, C. J. Angew. Chem. Int. Ed.
2007, 46, 6505. (j) Li, Z.; Yu, R.; Li, H. Angew. Chem. Int.
Ed. 2008, 47, 7497. (k) Volla, C. M. R.; Vogel, P. Angew.
Chem. Int. Ed. 2008, 47, 1305. (l) Carril, M.; Correa, A.;
Bolm, C. Angew. Chem. Int. Ed. 2008, 47, 4862.
(m) Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.;
Katsuki, T. J. Am. Chem. Soc. 2010, 132, 13633.
(9) Chernyak, D.; Chernyak, N.; Gevorgyan, V. Adv. Synth.
Catal. 2010, 352, 961.
In summary, we have described effective Fe(acac)3/
TBAOH system for the three-component coupling–cy-
cloisomerization reactions of aldehydes, terminal alkynes,
and amines for synthesis of aminoindolizines and quino-
lines.
(10) Patil, S. S.; Patil, S. V.; Bobade, V. D. Synlett 2011, 1157.
(11) Kulkarni, A.; Török, B. Green Chem. 2010, 12, 875.
(12) Martínez, R.; Ramón, D. J.; Yus, M. J. Org. Chem. 2008, 73,
9778.
Acknowledgment
The authors wish to thank UGC, New Delhi, India, for financial
support.
(13) Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.; Verdecchia,
M. Synlett 2006, 3218.
(14) Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F.
J. Org. Chem. 1992, 57, 1842.
Synlett 2011, No. 16, 2379–2383 © Thieme Stuttgart · New York

LETTER
Synthesis of Aminoindolizine and Quinoline Derivatives
2383
(15) Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.;
Konishi, H. Tetrahedron 2004, 60, 11639.
(16) General Procedure for the Synthesis of Aminoindolizine
Derivatives
131.7, 159.0. IR (neat): 2933, 1522, 1245, 1034, 835, 738
cm–1.
(17) General Procedure for the Preparation of Quinoline
Derivatives
To a solution of TBAOH (0.1 mmol) in DMSO (5 mL),
pyridine-2-carboxaldehyde (1.0 mmol), phenyl acetylene
(1.2 mmol), morpholine (1.2 mmol), and Fe(acac)3 (0.05
mmol) were added successively. The resulting mixture was
stirred at r.t. until the reaction was complete as indicated by
TLC. The mixture was then diluted with EtOAc (5 mL),
washed with H2O (2 × 5 mL), and the aqueous phase was
extracted with EtOAc (3 × 5 mL). The combined organic
phases were washed with sat. aq NaCl, dried over anhyd
Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash chromatography on Al2O3 to
afford the target product as a yellow oil.
A mixture of aldehyde (1 mmol) and aniline (1.4 mmol) was
dissolved in DMSO (10 mL) and heated at 60 °C for 2 h. It
was cooled to r.t., TBAOH (10 mol%), phenylacetylene (1.2
mmol), and Fe(acac)3 were added, and the mixture stirred at
r.t. overnight. The reaction mixture was poured into H2O,
and extracted with EtOAc (or CH2Cl2). The organic layer
was washed with H2O and dried over anhyd Na2SO4. The
solvent was removed in vacuo. The product was purified by
column chromatography on silica gel eluting with EtOAc–
hexane (10:90).
4-(4-Methoxyphenyl)-2-(naphthalen-2-yl)quinoline
(Table 3, Entry 5)
4-(Methoxyphenyl)-1-(piperidin-1-yl) indolizine4a (Table
2, Product 4b)
Pale yellow solid, mp 265–269 °C (lit.11 268–270 °C). 1H
NMR (300 MHz, CDCl3): d = 3.93 (s, 3 H), 7.10 (d, J = 8.4
Hz, 2 H), 7.26 (s, 1 H), 7.54 (m, 5 H), 7.75 (t, J = 8.1 Hz, 1
H), 7.96 (m, 4 H), 8.28 (d, J = 8.1 Hz, 1 H), 8.41 (d, J = 9 Hz,
1 H), 8.64 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 55.4.
114.0, 119.4, 125.0, 125.7, 126.6, 127.1, 127.7, 128.5,
128.8, 129.5, 130.0, 130.8, 131.3, 133.4, 136.2, 147.6,
149.8, 156.6, 164.2.
Pale yellow liquid. 1H NMR (300 MHz, C6D6): d = 1.40–
1.48 (m, 2 H), 1.66–1.74 (m, 4 H), 3.01 (dd, J = 5.4 Hz, 4 H),
3.33 (s, 3 H), 6.04–6.09 (m, 1 H), 6.35 (dd, J = 9.0, 6.3 Hz,
1 H), 6.76 (s, 1 H), 6.78–6.83 (m, 2 H), 7.27–7.32 (m, 2 H),
7.58 (d, J = 9.3 Hz, 1 H), 7.91 (d, J = 7.5 Hz, 1 H). 13C NMR
(75 MHz, C6D6): d = 24.8, 27.0, 54.8, 55.7, 106.0, 110.8,
114.0, 114.6, 118.4, 121.6, 122.5, 125.3, 125.6, 129.6,
Synlett 2011, No. 16, 2379–2383 © Thieme Stuttgart · New York

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