Platinum/scandium-cocatalyzed cascade cyclization and ring-opening reaction of tertiary amines with substituted salicylaldehydes to synthesize 3-(aminoalkyl)coumarins

Article abstract of DOI:10.1021/jo102219z

The synthesis of 3-(aminoalkyl)coumarins starting with a platinum/scandium-cocatalyzed oxidative dehydrogenation of α,β- C(sp³)-H bonds of tertiary amines in the presence of ambient oxygen followed by reactions with substituted salicylaldehydes is revealed. The in situ formed enamines reacted with various salicylaldehydes, which resulted in the development of a one-pot synthetic protocol involving aldol reaction, cyclization, and then ring-opening.

Full text of DOI:10.1021/jo102219z

pubs.acs.org/joc
warfarin (1) and acenocoumarol (2) which are clinically used
Platinum/Scandium-Cocatalyzed Cascade
Cyclization and Ring-Opening Reaction of Tertiary
Amines with Substituted Salicylaldehydes to
Synthesize 3-(Aminoalkyl)coumarins
as anticoagulants and rodenticides, have attracted the inter-
est of synthetic chemists (Figure 1).1a Thus far, a variety of
useful and efficient synthetic methods have been explored for
their synthesis. The major synthetic methods for the prep-
aration of coumarins include the Pechmann reaction,2 the
Knoevenagel condensation,3 the Wittig reaction,4 the Claisen
rearrangement,5 the Vilsmeier-Haack and Suzuki cross-
coupling reactions,6 the Pd-catalyzed site-selective cross-
coupling reaction,7 the ring-closing metathesis,8 and so on.
However, these conventional methods are frequently restricted
to relatively harsh conditions and cannot be used for sub-
strates with sensitive groups. Thus, an effective method for
the straightforward synthesis of 3-(aminoalkyl)coumarins
from simple, easily available, and cheap starting materials is
still in high demand in modern organic synthesis.
Xiao-Feng Xia,† Xing-Zhong Shu,† Ke-Gong Ji,†
Ali Shaukat,† Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, People’s Republic of
China, and ‡State Key Laboratory of Solid Lubrication,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Science, Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
Received November 11, 2010
Our group is persistently interested in the oxidation of
tertiary amines to prepare various functionalized heterocy-
clic compounds.9 We recently reported a mild platinum-
catalyzed oxidative dehydrogenation of R and β-C(sp3)-H
bonds adjacent to the nitrogen of tertiary amines to synthesize
trisubstituted enamines and chromano[2,3-b]piperidines,
highlighting the power of Pt catalysis in the oxidation of
tertiary amines (Scheme 1a).9b Herein, we report a platinum/
scandium-cocatalyzed oxidative dehydrogenation of R,
β-C(sp3)-H bonds of tertiary amines with substituted salicylal-
dehydes giving 3-(aminoalkyl)coumarins, which are reported
to have anthelmintic, hypnotic, and insecticidal properties.10
Tertiary amines are dehydrogenated to give enamines, which
react in situ with various salicylaldehydes, resulting in the
development of a one-pot synthetic protocol involving aldol
reaction, cyclization, and ring-opening (Scheme 1b).
Our study began with the reaction of 1.0 equiv of
N-phenylpiperidine 1a, 1.5 equiv of salicylaldehyde 2a, 0.1
equiv of PtCl2 as catalyst, and 1,4-dioxane/H2O (2:1) as solvent
at 80 °C. To our delight, the desired 3-(aminoalkyl)coumarin
3a was isolated in 22% yield as a solid. In an attempt to
optimize the reaction conditions, other commonly used plati-
num catalysts were tested in this reaction. Among the platinum
catalysts, K2PtCl4 gave the best result (Table 1, entry 3). To
optimize the yield of the product further, we studied the
influence of different reaction media (Table 1, entries 4-6).
The synthesis of 3-(aminoalkyl)coumarins starting with a
platinum/scandium-cocatalyzed oxidative dehydrogena-
tion of R,β-C(sp3)-H bonds of tertiary amines in the
presence of ambient oxygen followed by reactions with
substituted salicylaldehydes is revealed. The in situ
formed enamines reacted with various salicylaldehydes,
which resulted in the development of a one-pot synthetic
protocol involving aldol reaction, cyclization, and then
ring-opening.
The development of novel methods for the annulation of
coumarins is very important in the field of synthetic organic
chemistry because coumarins are privileged structures in
biological chemistry as well as important structural units
found in natural and artificial products.1 For example,
(3) (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999, 64,
1033. (b) Song, A.;Wang, X.; Lam, K. S. Tetrahedron Lett. 2003, 44, 1755
and references cited therein.
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893. (b) Estevez-Craun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997, 465. (c)
Ngameni, B.; Touaibia, M.; Patnam, R.; Belkaid, A.; Sonna, P.; Ngadjui,
B. T.; Annabi, B.; Roy, R. Phytochemistry 2006, 67, 2573. (d) Chun, K.; Park,
S.-K.; Kim, H. M.; Choi, Y.; Kim, M.-H.; Park, C.-H.; Joe, B.-Y.; Chun,
T. G.; Choi, H.-M.; Lee, H.-Y.; Hong, S. H.; Kim, M. S.; Nam, K.-Y.; Han,
G. Biorg. Med. Chem. 2008, 16, 530. (e) Jana, R.; Trivedi, R.; Tunge, J.-A.
Org. Lett. 2009, 11, 3434.
(4) (a) Takeuchi, Y.; Ueda, N.; Uesugi, K.; Abe, H.; Nishioka, H.;
Harayama, T. Heterocycles 2003, 59, 217. (b) Maes, D.; Vervisch, S.;
Debenedetti, S.; Davio, C.; Mangelinckx, S.; Giubellina, N.; De Kimpe, N.
Tetrahedron 2005, 61, 2505.
(5) (a) Chattopadhyay, S. K.; Biswas, T.; Neogi, K. Chem. Lett. 2006, 35,
376. (b) Majumdar, K. C.; Debnath, P.; Maji, P. K. Tetrahedron Lett. 2007,
48, 5265. (c) Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem.
Commun. 1986, 16, 1264.
(2) (a) Sharghi, H.; Jokar, M. Heterocycles 2007, 71, 2721. (b) Tyagi, B.;
Mishra, M. K.; Jasra, R. V. J. Mol. Catal. A: Chem. 2007, 276, 47. (c) Laufer,
(6) Hesse, S.; Kirsch, G. Tetrahedron Lett. 2002, 43, 1213.
(7) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 7279.
(8) Nguyen Van, T.; Debenedetti, S.; De Kimpe, N. Tetrahedron Lett.
2003, 44, 4199–4201.
(9) (a) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2009, 74, 7464. (b) Xia, X.-F.; Shu, X.-Z.; Ji, K.-G.;
Yang, Y.-F.; Shaukat, A.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2010, 75,
2893.
€
M. C.; Hausmann, H.; Holderich, W. F. J. Catal. 2003, 218, 315. (d) Potdar,
M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285. (e)
Sharma, G. V. M.; Reddy, J.; Sree Lakshmi, P.; Radha Krishna, P. Tetra-
hedron Lett. 2005, 46, 6119. (f) Manhas, M. S.; Ganguly, S. N.; Mukherjee,
S.; Jain, A. K.; Bose, A. K. Tetrahedron Lett. 2006, 47, 2423. (g) Romanelli,
G. P.; Bennardi, D.; Ruiz, D. M.; Baronetti, G.; Thomas, H. J.; Autino, J. C.
Tetrahedron Lett. 2004, 45, 8935.
(10) Mitra, A. K.; Misra, S. K.; Patra, A. Synth. Commun. 1980, 10, 915.
342 J. Org. Chem. 2011, 76, 342–345
Published on Web 12/09/2010
DOI: 10.1021/jo102219z
r
2010 American Chemical Society

Xia et al.
JOCNote
From the results obtained, 1,4-dioxane/H2O was chosen to
be the best solvent (Table 1, entry 3). Then, we screened a
variety of additives9,11 (Table 1, entries 7-10). Among all the
additives, Sc(OTf)3 gave the best result. A controlled experi-
ment employing 10 mol % Sc(OTf)3 as the sole catalyst did
not lead to product (Table 1, entry 12). After this, we
screened the amount of catalyst and additive. When using
5 mol % of K2PtCl4 as the catalyst and 5 mol % of Sc(OTf)3
as the cocatalyst, a 71% yield was obtained (Table 1, entry 13).
With a series of detailed investigations mentioned above, the
optimized reaction conditions were found to be the following
(entry 13): 5 mol % K2PtCl4 as catalyst, 5 mol % Sc(OTf)3
as cocatalyst, 1,4-dioxane/H2O (2:1) as mixed solvent,
After having established optimized conditions, we extended
the scope of this transformation to a wide range of electron-
ically and structurally diverse tertiary amines and substituted
salicylaldehydes. The results of these studies are listed in
Table 2. Various substituted N-phenylpiperidines reacted
efficiently with salicylaldehyde, affording 3a-k in 40-71%
yields (Table 2, entries 1-11). The protocol is tolerant of
both electron-withdrawing and electron-donating substituents
in the phenyl moiety of 1. Sterically demanding ortho substit-
uents can also participate in this reaction, albeit giving lower
yields (Table 2, entries 4 and 5). To confirm the structural
assignment of products, the relative configuration of the
product 3h was unambiguously assigned by single-crystal
X-ray crystallography (see the Supporting Information).12
Salicylaldehydes 2l-q bearing a variety of substituents on
the benzene ring reacted smoothly to afford the correspond-
ing coumarins 3l-q in 40-53% yields, indicating that the
substituents on the aromatic ring of 2 did not have significant
influence on the reaction. Salicylaldehydes possessing sev-
eral functional groups such as methoxyl, methyl, chloro, and
tert-butyl were also tolerated in this reaction, and moderate
yields of corresponding products were obtained. When
4-methyl-1-phenylpiperidine was subjected to the reaction,
the corresponding product 3r was obtained in 53% yield.
Under the optimum conditions, 1-(naphthalen-1-yl)piperidine
and 1-(naphthalen-2-yl)piperidine were smoothly converted
to 3-(aminoalkyl)coumarins 3s and 3t in 66% and 49%
yields, respectively (Table 2, entries 19 and 20). The size of
the ring of the reactant 1 was also tested. N-Phenylpyrroli-
dine exhibited a low reactivity to form 3u (27%) (Scheme 2).
When enantiomerically pure substrate 1v was used, the
cyclization reaction was observed at the 4,5-position of 1v
and desired product 3v was isolated in a 37% yield with
hydroxyl group tolerated and chirality remaining intact. This
observation reveals that complex chiral alkamine can be
obtained from simple chiral alkamine by using our method.
N-Phenyl-L-prolinol bearing a benzyl as the protecting group
1w underwent this transformation with salicylaldehyde,
leading to 3w in 40% yield (Scheme 2).
˚
5 A molecular sieves as additive, at 80 °C under oxygen
atmosphere.
FIGURE 1. Biologically active 3-alkyl coumarins.
SCHEME 1. Design of a Domino Process
TABLE 1. Optimization of Reaction Conditionsa
entry
catalyst (mol %)
additive (mol %)
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
PtCl2 (10)
PtCl4 (10)
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
DMF/H2O = 2:1
THF/H2O = 2:1
DME/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
1,4-dioxane/H2O = 2:1
22
12
38
26
15
24
53
33
33
45
40
0
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
K2PtCl4 (10)
Sc(OTf)3 (5)
Cu(OTf)2 (10)
5 μL of 6 N HCl
PhCOOH (20)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (5)
K2PtCl4 (5)
K2PtCl4 (5)
K2PtCl4 (5)
71c
38
46d
Sc(OTf)3 (5)
Sc(OTf)3 (5)
˚
All reactions were carried out by using N-phenylpiperidine (0.25 mmol), salicylaldehyde (0.375 mmol), catalyst (0.025 mmol), solvent (2.0 mL), and 5 A
molecular sieves (50 mg) at 80 °C for 20 h; MS = molecular sieves. bYield of isolated product 3a after column chromatography. c1a:2a = 1:2. d1a:2a = 1:3.
J. Org. Chem. Vol. 76, No. 1, 2011 343

Xia et al.
JOCNote
TABLE 2. Scope of the Cascade Cyclization and Ring-Opening Reactiona
aAll reactions were carried out by using 1 (0.25 mmol), 2 (0.5 mmol), 5 mol % K2PtCl4 (0.0125 mmol), 5 mol % Sc(OTf)3 (0.0125 mmol), 1,4-dioxane/
b
˚
H2O (2:1, 2.0 mL) and 5 A molecular sieves (50 mg) at 80 °C under oxygen atmosphere. Isolated yield after column chromatography.
SCHEME 2. Platinum/Scandium-Cocatalyzed Cascade Cycli-
zation and Ring-Opening Reaction of Substituted Tertiary
Amines with Salicylaldehyde
SCHEME 3. Proposed Mechanism
A tentative mechanism for the product formation is proposed
in Scheme 3. Analogous to pathways for the oxidation of
tertiary amines by electrochemical process,13 metals,14 and
oxidants,9a,15 the intermediate iminium ion B is involved. (1)
Platinum coordinates to nitrogen and then goes through
activation of the sp3 C-H adjacent to nitrogen in the
presence of oxygen to form an imine-type intermediate B.
(2) Through β-hydrogen elimination, B is converted to R,
β-unsaturated compound C. (3) The aldol reaction of salicy-
laldehyde with C takes place to give D, followed by cycliza-
tion leading to intermediate E. (4) E, when activated by
Lewis acids, undergoes dehydration to produce F, which is
oxidized in the presence of platinum catalyst, oxygen, and
water to give H. (5) Finally, H undergoes hydrolysis and
ring-opening to yield the product 3a.
(11) (a) Kobayashi, S. Chem. Lett. 1991, 2187. (b) Kobayashi, S. Synlett
1994, 689–701. (c) Kobayashi, S. Eur. J. Org. Chem. 1999, 15 and references
cited therein. See also: (d) Marshman, R. W. Aldrichim. Acta 1995, 28, 77. (e)
Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993, 472.
(12) The crystallographic coordinates for 3h have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. CCDC-798779.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.
ccdc.cam.ac.uk/conts/retrieving.html. The crystallographic data and CIF of
3h can be also obtained in the Supporting Information.
(13) (a) Shono, T.; Matsumura, Y.; Onomura, O.; Ogaki, M.; Kanazawa,
T. J. Org. Chem. 1987, 52, 536. (b) Shono, T.; Matsumura, Y.; Tsubata, K.
Org. Synth. 1985, 206. (c) Shono, T. Tetrahedron 1984, 40, 811. (d) Shono, T.;
Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264. (e)
Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31, 4058.
In summary, we have developed a platinum/scandium-
cocatalyzed cascade cyclization and ring-opening reaction of
tertiary amines with substituted salicylaldehydes to synthe-
size 3-(aminoalkyl)coumarins, which are common structural
motifs found in many natural products and biologically
(14) (a) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337. (b)
Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb, S. M. J. Org. Chem.
1996, 61, 9483.
(15) (a) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
344 J. Org. Chem. Vol. 76, No. 1, 2011

Xia et al.
JOCNote
active compounds. On the other hand, this strategy provides
a useful approach to synthesize complex chiral alkamine
from simple starting material. A plausible mechanism has
also been proposed.
a solid: mp 74-76 °C; 1H NMR (400 MHz, CDCl3) δ 7.40-7.46
(m, 3 H), 7.31 (d, J=8 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.15-7.19
(m, 2 H), 6.69 (t, J=7.4 Hz, 1 H), 6.60-6.62 (m, 2 H), 3.78 (s, 1
H), 3.21 (t, J=6.8 Hz, 2 H), 2.69 (t, J=7.4 Hz, 2 H), 1.94-2.01
(m, 2 H); 13C NMR (100 MHz, CDCl3) δ 161.8, 153.1, 148.2,
138.9, 130.7, 129.2, 129.1, 127.2, 124.3, 119.4, 117.3, 116.4, 112.7,
43.2, 28.4, 27.9; IR (neat, cm-1) 3408, 3055, 2925, 2854, 1713,
1605, 1505, 1456, 1361, 1266, 1222, 1181, 1086, 1035, 738, 702,
530, 456; HRMS (ESI) m/z calcd for C18H17NO2 (M þ H)
280.1332, found 280.1331.
Experimental Section
General Procedure for the Preparation of 3-(Aminoalkyl)-
coumarins 3a. To a test tube were added N-phenylpiperidine
(0.25 mmol), K2PtCl4 (8.3 mg, 10 mol %), salicylaldehyde (0.50
˚
mmol), and powdered 5 A molecular sieve (50 mg). The test tube
was purged under vacuum and then refilled with oxygen 3 times.
1,4-Dioxane/H2O = 2/1 (2.0 mL) was then injected, and the
mixture was allowed to stir at 80 °C. When the reaction was
considered complete as determined by TLC analysis, ethyl
acetate (20 mL) and water (20 mL) were then added to the
reaction mixture. The organic layer was extracted with ethyl
acetate (2 ꢀ 20 mL). The combined organic phases were washed
with brine and dried over sodium sulfate. The residue was
purified by flash chromatography on alkalescence silica gel to
afford corresponding products 3a of the indicated compound as
Acknowledgment. We thank the National Science Foun-
dation (NSF-20732002, NSF-20090443, NSF-20872052, and
NSF 21072080) for financial support.
Supporting Information Available: The detailed experimen-
tal procedure and copies of 1H NMR and 13C NMR spectra of
all compounds and crystallographic data and CIF of 3h This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 1, 2011 345