Cooperative catalysis with metal and secondary amine: Synthesis of 2-substituted quinolines via addition/cycloisomerization cascade

Article abstract of DOI:10.1021/jo101103a

A cooperative catalytic system, consisting of CuI and pyrrolidine, has been developed for an efficient synthesis of 2-substituted quinolines. A combination of both the catalysts is necessary; the use of either catalyst alone does not give the product.

Full text of DOI:10.1021/jo101103a

pubs.acs.org/joc
wherein soft transition-metal ions2 are employed, would be
Cooperative Catalysis with Metal and Secondary
Amine: Synthesis of 2-Substituted Quinolines via
Addition/Cycloisomerization Cascade
considered a difficult task. Kirsch and co-workers developed a
cooperative catalytic system consisting of a combination of a
Au(I) complex and a secondary amine.3 Dixon et al. found
a mutually compatible combination of pyrrolidine and Cu-
(OTf)2-PPh3 for the synthesis of cyclopentenes.4 Jørgensen et al.
developed a route to cyclopentene carbaldehydes under
cooperative catalysis by Cu(I)/Au(I) and a secondary amine.5
A sequential procedure for the synthesis of substituted cyclic
ether based on a secondary amine and Au(I) complexes has
been reported by Krause and Alexakis.6 Ding and Wu devel-
oped a binary catalytic system, consisting of AgOTf and a
secondary amine, for the synthesis of 1,2-dihydroisoquino-
lines.7
Nitin T. Patil* and Vivek S. Raut
Organic Chemistry Division - II, Indian Institute of Chemical
Technology, Hyderabad 500 607, India
nitin@iict.res.in; patilnitint@yahoo.com
Received June 8, 2010
Keeping in mind the above literature and our recent results on
π-activation,8 we considered a cooperative catalytic system,
consisting of a metal and a secondary amine, as a potentially
useful tool to access 2-substituted quinolines 3 from 2-amino-
benzaldehydes 1 and terminal alkynes 2 (Scheme 1). Notably,
2-substituted quinolines are one of the most ubiquitous struc-
tural motifs found in numerous naturally occurring9 and phar-
macologically important compounds.10Herein, we report our
findings on this study.11
A cooperative catalytic system, consisting of CuI and pyrroli-
dine, has been developed for an efficient synthesis of 2-sub-
stituted quinolines. A combination of both the catalysts is
necessary; the use of either catalyst alone does not give the
product.
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DOI: 10.1021/jo101103a
r
Published on Web 09/21/2010
J. Org. Chem. 2010, 75, 6961–6964 6961
2010 American Chemical Society

Patil and Raut
JOCNote
SCHEME 1. Concept of Cooperative Catalysis for the
Synthesis of 2-Substituted Quinolines
TABLE 2. Scope with 2-Aminobenzaldehydesa
entry
1
3
yieidb (%)
1
2
3
4
5
6
7
8
9
1b, R1 = R2 = R3 = H
3b
3c
3d
3e
3f
3g
3h
3i
94
82
76
78
78
80
90
72
62c
67c
72d
1c, R1 = Me, R2 = R3 = H
1d, R1 = R3 = Me, R2 = H
1e, R1 = OMe, R2 = R3 = H
1f, R1 = R2 = OMe, R3 = H
1g, R1 = R3 = H, R2 = Cl
1h, R1 = Cl, R2 = H, R3 = Me
1i, R1 = Br, R2 = R3 = H
1j, R1 = COOMe, R2 = R3 = H
1k, R1 = R3 = H, R2 = COOMe
1l, R1 = CN, R2 = R3 = H
1m, R1 = NO2, R2 = R3 = H
3j
3k
3l
TABLE 1. Catalysts Screening Studiesa
10
11
12
3m
58e
aA solution of the 1 (0.30 mmol), 1-octyne 2a (0.36 mmol), CuI (10 mol
%), and pyrrolidine (25 mol %) in CH3CN (2 mL) was heated at 100 °C for
c
d
12 h. bIsolated yields. Reaction mixture was heated for 18 h. Reaction
mixture was heated for 36 h. eReaction mixture was heated for 48 h.
entry
M
amine
yieldb (%)
judged from entries 15 and 16, the use of either of catalyst
(CuI or pyrrolidine) alone does not give 3a.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuCl
CuBr
CuI
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
morpholine
piperidine
Et2NH
71
56
85
82
56
82
80
50
c
25
20
70
50
75
c
With the optimized reaction conditions in hand, we then
extended the reaction range to include 2-aminobenzalde-
hydes (Table 2). As illustrated in Table 2, 1-octyne was
reacted with functionalized 2-aminobenzaldehydes bear-
ing ortho, meta, and para substitutions on the aryl ring to
give the corresponding products in moderate to good yields.
Particularly noteworthy is the fact that halo substituents
were well tolerated (entries 6-8); therefore, the products
obtained have potential for further functionalization by
conventional palladium-catalyzed cross-coupling reactions.
Another advantage of this method is that even electron-
withdrawing substituents, such as -COOMe, -CN, and
-NO2, in the 2-aminobenzaldehydes were tolerated,
although longer reaction times were needed for the comple-
tion of the reaction (entries 9-12). It should be noted that the
reaction is not applicable to the ketone, i.e., 2-aminoaceto-
phenone or 2-aminobenzophenone.
[Cu(CH3CN)4]PF6
Cu(OTf)2
CuI
CuI
CuI
CuI
CuI
CuI
iPr2NH
Cy2NH
Bn2NH
pyrrolidine
pyrrolidine
pyrrolidine
AgOTf
AuCl
PPh3AuOTf
Cul
pyrrolidine
c
aA solution of the 1a (0.30 mmol), 1-octyne 2a (0.36 mmol), metal
catalyst (10 mol %), and secondary amine (25 mol %) in CH3CN (2 mL)
was heated at 100 °C for 12 h. bIsolated yields. cRecovery of 1a in
70-80% yield.
Proof of principle studies were carried out using 1a and
1-octyne 2a as model substrates in acetonitrile. At first, we
explored copper-based catalysts because they are highly toler-
ant toward basic amines and they are superior catalysts for
alkynylation. To begin with, 1a and 2a were treated with
10 mol % of CuCl and 25 mol % of pyrrolidine in acetonitrile
at 100 °C. Pleasingly, the reaction proceeded well, and the
desired product 3a was obtained in 71% yield (Table 1, entry
1). Next, various Cu(I) and Cu(II) catalysts were examined
(entries 2-5); among them, CuI proved to be the best (entry 3).
Using CuI as a catalyst, a variety of secondary amines were
examined; however, the outcome turned out to be unsatisfac-
tory (6-11) comparedwiththe resultsdescribedinentry3. The
other metal catalysts such as Ag(I) and Au(I) also gave prod-
ucts, albeit in moderate yields (entries 12-14). As can be
To further explore the generality and scope of this ap-
proach, a variety of terminal alkynes were investigated
(Table 3). The aryl alkynes 2b and 2c on reaction with 1a
gave the expected product 3n and 3o in 61% and 67% yields,
respectively (entries 1 and 2). Interestingly, enynes 2d and 2e
also worked well to afford 3p and 3q in 85% and 60% yields,
respectively (entries 3 and 4). Aliphatic terminal alkynes 2f-i
(entries 5-8) and cycloalkyl acetylenes 2j-k (entries 9 and 10)
were also found to be good substrates, giving the correspond-
ing products 3r-w in moderate to good yields. The reaction of
heteroaromatic alkynes 2l and 2m with 1a under the standard
reaction conditions afforded 3x and 3y in 90% and 86% yields,
respectively (entries 11 and 12).
A mechanistic hypothesis based on the dual activation
concept in which an organocatalyst is combined with π-acid,
is proposed in Figure 1. At first, aldehyde 1 would condense
in situ with the pyrrolidine to give an iminium ion 4.12 The
iminium ion 4 on reaction with CuI and 1-octyne 2a would
(11) A conceptually different process for the synthesis of quinolines has
been reported. However, none of the processes is known to give 2-substituted
(4-unsubstituted) quinolines; see: (a) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che,
C.-M. Org. Lett. 2007, 9, 2645–2648. (b) Jiang, B.; Si, Y.-G. J. Org. Chem.
2002, 67, 9449–9451. (c) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew.
Chem., Int. Ed. 1999, 38, 3222–3225.
(12) 2-Aminoacetophenone and 2-aminobenzophenone might have failed
to undergo this reaction because of their reluctance to form iminium ion
compared to corresponding aldehydes.
6962 J. Org. Chem. Vol. 75, No. 20, 2010

Patil and Raut
JOCNote
TABLE 3. Scope with Terminal Alkynesa
FIGURE 1. Proposed mechanism for cooperative catalysis.
FIGURE 2. Alternative mechanism.
aA solution of the 1a (0.30 mmol), terminal alkynes 2 (0.36 mmol),
CuI (10 mol %), and pyrrolidine (25 mol %) in CH3CN (2 mL) was
heated at 100 °C for 12 h. bIsolated yields. c3 equiv of 2j was used.
FIGURE 3. Application to the synthesis of biologically active
compounds/natural products.
10 mol % of CuI. The reaction afforded the corresponding
three-component coupling product in 90% yield.14
produce intermediate 5 with expulsion of water. A union of
copper acetylide and iminium ion in 5 would then lead to the
formation of copper-coordinated propargylamine deriva-
tive 6.13 The intermediate 6 would then undergo 6-endo-dig
cyclization to form 7. A protonation and aromatization
would then occur to give 3a with the liberation of CuI and
pyrrolidine. To gain insight into the mechanism, an experiment
was conducted using benzaldehyde as a substrate. Accord-
ingly, a solution of benzaldehyde, 1-octyne, and pyrrolidine in
acetonitrile was heated at 100 °C for 12 h in the presence of
Another possible mechanism involving hydroamination
between 1a and 2a, which triggers cycloisomerization (cf. 8
and 9) to form 3a (Figure 2), can be completely ruled out.
None of the reactions produced C-2- and C-3-disubstituted
regioisomeric quinolines, not even in trace amounts.11a In
addition, the reaction between aniline and 1-octyne under
the standard conditions did not afford the corresponding
hydroamination product.
As a further demonstration of the utility of a cooperative
catalytic system, we thought of synthesizing some biologi-
cally active compounds/natural products.9d,e Accordingly,
when 2-aminobenzaldehyde 1b was treated with 2b, 1-
pentyne, 1-heptyne, and 2h independently, under standard
conditions, quinolines 3z, 3aa, 3ab, and 3ac were obtained in
70%, 93%, 94%, and 92% yields, respectively (Figure 3).
Remarkably, 2-propylquinoline 3aa is currently undergoing
clinical trials.10a
(13) Cu(I)-catalyzed three-component coupling reactions of aldehydes,
terminal alkynes, and amines is a well-known process; for selected examples,
see: (a) Nakamura, S.; Ohara, M.; Nakamura, Y.; Shibata, N.; Toru, T.
Chem.-Eur. J. 2010, 16, 2360–2362. (b) Gommermann, N.; Knochel, P.
Chem.-Eur. J. 2006, 12, 4380–4392. (c) Bisai, A.; Singh, V. K. Org. Lett.
2006, 8, 2405–2408. (d) Wei, C.; Mague, J. T.; Li, C. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5749–5754. (e) Shi, L.; Tu, Y. Q.; Wang, M.; Zhang, F. M.;
€
Fan, C. A. Org. Lett. 2004, 6, 1001–1003. (f) Knopfel, T. F.; Aschwanden, P.;
In conclusion, we have developed a practical strategy to
access 2-substituted quinolines from 2-aminobenzaldehyde
Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43,
5971–5973. (g) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763–5766. (h) Wei, C.; Li, C.-J. J. Am.
Chem. Soc. 2002, 124, 5638–5639. (i) Brannock, K. C.; Burpitt, R. D.;
Thweatt, J. G. J. Org. Chem. 1963, 28, 1462–1464.
(14) See the Supporting Information for details.
J. Org. Chem. Vol. 75, No. 20, 2010 6963

Patil and Raut
JOCNote
and terminal alkynes through a tandem addition/cyclo-
isomerization cascade catalyzed by a pyrrolidine and copper(I)
iodide co-operative catalyst system. The developed method
has been found to be applicable for the synthesis of natu-
rally occurring and pharmaceutically important com-
pounds. Since the enantioselective transfer hydrogenation
of 2-substituted quinolines is known in the literature,15 the
present protocol may find use in the preparation of appro-
priately substituted quinolines, which can further be tran-
sformed into enantiopure tetrahydroquinoline natural prod-
ucts and their analogues.16 As far as regioselectivitive
synthesis of 2-substituted quinolines is concerned, the pre-
ethyl acetate and filtered through a plug of silica gel. The filtrate
was concentrated under reduced pressure, and the resulting
residue was purified by column chromatography (silica gel,
hexane/EtOAc) to give the desired products 3.
6-Hexyl[1,3]dioxolo[4,5-g]quinoline (3a): 85% yield; mp =
105-107 °C; pale yellow solid; Rf 0.50 (hexane/EtOAc = 80/20);
1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 1H), 7.29
(s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.96 (s, 1H), 6.06 (s, 2H), 2.85 (t,
J = 7.5 Hz, 2H), 1.77 (pent, J = 7.5 Hz, 2H), 1.45-1.25 (m, 6H),
0.89 (t, J= 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ160.8,150.4,
147.0, 146.0, 135.0, 123.2, 119.4, 105.5, 102.6, 101.4, 39.0, 31.7, 30.1,
29.2, 22.5, 14.0; IR (KBr): νmax 3041, 2920, 1618, 1503, 1462, 1240
cm-1; MS (ESI) m/z 258 (Mþ þ H); HRMS calcd for C16H19NO2
(Mþ þ H) 258.1494, found 258.1506.
sent protocol constitutes an advanced complement to
17
2-Hexylquinoline (3b): 94% yield; pale yellow oil; Rf 0.64
(hexane/EtOAc = 80/20); 1H NMR (300 MHz, CDCl3) δ 8.00
(d, J = 8.3 Hz, 2H), 7.72 (dd, J = 8.3, 1.5 Hz, 1H), 7.64 (td, J =
8.3, 1.5 Hz, 1H), 7.43 (td, J = 8.3, 1.5 Hz, 1H), 7.24 (d, J =
8.3 Hz, 1H), 2.94 (t, J = 7.5 Hz, 2H), 1.81 (pent, J = 7.5 Hz,
2H), 1.46 - 1.23 (m, 6H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 162.9, 147.8, 136.0, 129.1, 128.7, 127.3, 126.6,
125.4, 121.2, 39.3, 31.6, 29.9, 29.1, 22.4, 13.9; IR (film) νmax 3053,
2926, 2857, 1601, 1502 cm-1; MS (ESI) m/z 214 (Mþ þ H);
HRMS calcd for C15H19N (Mþ þ H) 214.1595, found 214.1589.
€
Friedlander synthesis of quinolines.
Experimental Section
General Procedure. To a screw-cap vial containing a stir
bar were added 2-aminobenzaldehydes (0.3 mmol), terminal
alkynes (0.36 mmol, 1.2 equiv), CuI (10 mol %), dry CH3CN
(2 mL), and pyrrolidine (25 mol %). The reaction vial was fitted
with a cap, evacuated, and filled with nitrogen and heated at
100 °C for 12 h. The reaction mixture was allowed to warm to
ambient temperature. The reaction mixture was diluted with
Acknowledgment. We gratefully acknowledge financial
support by the Council of Scientific and Industrial Research,
India. N.T.P. is grateful to Dr. J. S. Yadav, Director, IICT,
and Dr. V. V. N. Reddy, Head, Org-II Division, for their
support and encouragement.
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Supporting Information Available: All experimental proce-
dures, analytical data, and copies of 1H and 13C NMR spectra of
newly synthesized products. This material is available free of
charge via the Internet at http://pubs.acs.org.
€
Chem. Commun. 2001, 2576–2577. For the original report on Friedlander
€
quinoline synthesis, see: (c) Friedlander, P. Ber. 1882, 15, 2572–2575.
6964 J. Org. Chem. Vol. 75, No. 20, 2010