Platinum-catalyzed michael addition and cyclization of tertiary amines with nitroolefins by dehydrogenation of α,β-sp3 C-H bonds

Article abstract of DOI:10.1021/jo100133z

A mild platinum-catalyzed oxidative dehydrogenation of α,β- C(sp³)-H bonds of tertiary amines in the presence of ambient oxygen is revealed, and the in situ formed enamines subsequently reacting with various nitroolefins resulted in the development of two one-pot synthetic protocols involving Michael addition-elimination and Michael addition-cyclization. By using different functionalized nitroolefins compatible with the current oxidative conditions, two types of structurally divergent products, trisubstituted enamines and chromano[2,3-b]piperidines, could be expediently accessed, respectively.

Full text of DOI:10.1021/jo100133z

pubs.acs.org/joc
Platinum-Catalyzed Michael Addition and Cyclization of Tertiary
Amines with Nitroolefins by Dehydrogenation of r,β-sp3 C-H Bonds
Xiao-Feng Xia,† Xing-Zhong Shu,† Ke-Gong Ji,† Yan-Fang Yang,† 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 January 25, 2010
A mild platinum-catalyzed oxidative dehydrogenation of R,β-C(sp3)-H bonds of tertiary amines in the
presence of ambient oxygen is revealed, and the in situ formed enamines subsequently reacting with
various nitroolefins resulted in the development of two one-pot synthetic protocols involving Michael
addition-elimination and Michael addition-cyclization. By using different functionalized nitroolefins
compatible with the current oxidative conditions, two types of structurally divergent products,
trisubstituted enamines and chromano[2,3-b]piperidines, could be expediently accessed, respectively.
SCHEME 1. General Strategies for Enamine Formation
Introduction
Michael addition is one of the most fundamental carbon-
carbon bond forming reactions in organic chemistry, wherein
enolates or stabilized carbanions are among the nucleophiles
usually used for such a case.1,2 Enamines as enolate equivalents
are employed extensively for the selective formation of C-Cand
C-N bonds in the Michael addition and Diels-Alder reaction,
as well as a wide range of other reactions.3 In the synthetic
chemistry of enamines, the condensation between an amine and
a carbonyl compound constitutes the classical method for the
formation of enamines (route a of Scheme 1),3 in which acidic,
basic, and/or azeotropic conditions are usually required. As an
alternative synthetic route, enamines can also be generated from
dehydrogenation of tertiary amines mediated by transition
metals as reported by Goldman, Henbest, Wickberg, and co-
workers (route b of Scheme 1).4 However, these methods are
frequently restricted to relatively harsh reaction conditions.
(1) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Comprehensive
Asymmetric Catalysis, 1st ed.; Springer: Berlin, Germany, 1999. (b) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701.
(2) (a) Yang, X.; Zhou, X.; Lin, L.; Chang, L.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2008, 47, 7079. (b) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc.
2006, 128, 9624. (c) Corey, E. J.; Zhang, F. Y. Org. Lett. 2000, 2, 4257. (d)
Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418.
(3) (a) List, B. Synlett 2001, 1675. (b) List, B. Acc. Chem. Res. 2004, 37, 548. (c)
Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am.
Chem. Soc. 1963, 85, 207. (d) Stork, G.; Saccomano, N. A. Tetrahedron Lett. 1987,
28, 2087. (e) The Chemistry of Enamines; Rappoport, Z., Ed.; Wiley: New York,
1994. (f) Mukherjee, S.; Yang, J.-W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471. (g) Adams, J. P.; Robertson, G. Contemp. Org. Synth. 1997, 4, 183. (h)
Adams, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 125. (i) Whitesell, J. K. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
UK, 1991; Vol. 6. (j) Fang, P.; Hou, X.-L. Org. Lett. 2009, 11, 4612. (k) Kumar,
V.; Kaur, S.; Kumar, S. Tetrahedron Lett. 2006, 47, 7001. (l) Herndon, J. W.;
Zhang, Y.; Wang, K. J. Organomet. Chem. 2001, 634, 1. (m) Belmont, P.; Belhadj,
T. Org. Lett. 2005, 7, 1793. (n) Tiano, M.; Belmont, P. J. Org. Chem. 2008, 73,
4101. (o) Facoetti, D.; Abbiati, G.; Rossi, E. Eur. J. Org. Chem. 2009, 2872.
(4) (a) Enamines: synthesis, structure, and reactions, 2nd ed.; Cook, A. G.,
Ed.; Marcel Dekker: New York, 1988. (b) Buckley, D.; Dunstan, S.; Henbest, H. B.
J. Chem. Soc. 1957, 4901. (c) Hansson, C.; Wickberg, B. J. Org. Chem. 1973, 38,
3074. (d) Zhang, X.-W.; Fried, A.; Knapp, S.; Goldman., A. S. Chem. Commun.
2003, 2060.
DOI: 10.1021/jo100133z
r
Published on Web 03/26/2010
J. Org. Chem. 2010, 75, 2893–2902 2893
2010 American Chemical Society

Xia et al.
JOCArticle
SCHEME 2. Platinum-Catalyzed Reaction of Tertiary Amines with Nitroolefins
Thus, a mild method for the straightforward synthesis of
enamines is still of high demand in modern organic synthesis.
Recently, the activation of the hydrogen located at the R-
position of the nitrogen atom represents a useful method for
the construction of complex molecules.5 Of them, the cross-
dehydrogenative coupling (CDC) constitutes one of such
important synthetic transformations involving R C-H oxi-
dative activation of tertiary amines.6-11 Murahashi,6
Doyle,7 Li,8 and others9 have developed this kind of oxida-
tive coupling reaction via transition metal catalysis in the
presence of oxidants. Beyond these interesting results, Todd
and we recently disclosed a metal-free CDC protocol using
DDQ10 and hypervalent iodine(III) reagents11 as oxidants,
respectively. However, simultaneous activation of both R
and β hydrogens of an amine nitrogen atom is rarely reported
for the generation of enamines. In this relevant area of
research, there are two preceding examples, which were
recently reported by Weng, Wang, and co-workers,12,13
demonstrating the in situ formation of enamine intermedi-
ates via R,β-dehydrogenation of tertiary amines, but the
expected C-H bond activation depends significantly on
the use of tertiary aliphatic amines as well as on the use
of stoichiometric amounts of diethyl azodicarboxylate
(DEAD) or FeCl3.
Our group is persistently interested in the oxidation of
tertiary amines to prepare various functionalized heterocyc-
lic compounds. During the course of the study of platinum-
catalyzed tandem reactions,14 we interestingly discovered
that tertiary amines could react with nitroolefins in the
presence of oxygen under platinum catalysis (Scheme 2), in
which two one-pot synthetic protocols involving Michael
addition-elimination and Michael addition-cyclization
were developed on the basis of the reaction of the in situ
generated enamines with different functionalized nitroole-
fins. To our knowledge, this mild synthesis of enamine
intermediates provides a pathway in one-pot manner to the
synthetically useful trisubstituted enamines and chromano-
[2,3-b]piperidines, which have received increased attention
due to their medicinal potentials, especially as antiallergic
and antiulcer drugs.15 Herein we report our results for the
synthesis of a series of functionalized substituted enamines
and chromano[2,3-b]piperidines from readily available sim-
ple starting materials.
(5) (a) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008,
73, 3961. (b) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813.
(c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (d) Li, Z.; Li, C.-J. Eur.
J. Org. Chem. 2005, 15, 3173. (e) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
6968. (f) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556. (g) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (h) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810. (i) Brown, S. H.; Crabtree, R. H. J. Am. Chem.
Soc. 1989, 111, 2935. (j) Ngouansavanh, T.; Zhu, J.-P. Angew. Chem., Int. Ed.
2007, 46, 5775.
(6) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005. (b) Murahashi, S.; Komiya, N.; Terai, H. Angew.
Chem., Int. Ed. 2005, 44, 6931. (c) Murahashi, S.; Komiya, N.; Terai, H.;
Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
Results and Discussion
Michael Addition-Elimination. Our study began with the
reaction of 1.0 equiv of N-phenylpiperidine (1a), 1.5 equiv of
(E)-2-nitrostyrene (2a), and 0.1 equiv of PtCl2 as catalyst,
and 1,4-dioxane/H2O (2:1) as solvent at 80 °C. To our
delight, the desired trisubstituted enamine 3a as a solid was
isolated in 26% yield (entry 1 of Table 1). Addition of
hexafluoroisopropanol (HFIP) as a weak Brønsted acid
increased the reaction yield to about 50% (entries 2-3). To
improve the reaction efficiency, the effect of acids was then
(7) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem.
Soc. 2006, 128, 5648.
˚
(8) For select examples, see: (a) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed.
2008, 47, 7075. (b) Basle, O.; Li, C.-J. Org. Lett. 2008, 10, 3661. (c) Basle, O.;
Li, C.-J. Green Chem. 2007, 9, 1047. (d) Li, Z.; Bohle, D. S.; Li, C.-J. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (e) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 3672. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (g) Li,
Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 15, 3173. (h) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810. (i) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997.
(9) (a) Sud, A.; Sureshkumarz, D.; Klussmann, M. Chem. Commun. 2009,
3169. (b) Chu, L. L.; Zhang, X. G.; Qing, F.-L. Org. Lett. 2009, 11, 2197. (c)
Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701. (d) Xu, X.-L.; Li, X.-N.
Org. Lett. 2009, 11, 1027. (e) Shen, Y.-M.; Li, M.; Wang, S.-Z.; Zhan, T.-G.;
Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 8, 953. (f) Zhang, Y.; Fu, H.;
Jiang, Y.; Zhao, Y.-F. Org. Lett. 2007, 19, 3813.
investigated. It was found that the weakly acidic 5 A molec-
ular sieves (MS) as additive gave the best result (entry 4),
whereas strong acids were less active or ineffective (entries
5-7). In addition to PtCl2, other platinum catalysts were also
(14) (a) Ji, K.-G.; Shu, X.-Z.; Chen, J.; Zhao, S.-C.; Zheng, Z.-J.; Lu, L.;
Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2008, 10, 3919. (b) Shu, X.-Z.; Ji, K.-G.;
Zhao, S.-C.; Zheng, Z.-J.; Chen, J.; Lu, L.; Liu, X.-Y.; Liang, Y.-M. Chem.;
Eur. J. 2008, 14, 10556.
(15) (a) Isoda, Y.; Fujiwara, H.; Hosogami, T. Chem. Abstr. 1991, 115,
183264z. (b) Nohara, A.; Ishiguro, T.; Ukawa, K.; Sugihara, H.; Maki, Y.;
Sanno, Y. J. Med. Chem. 1985, 28, 559. (c) Nohara, A.; Kuriki, H.; Sajio, T.;
Sugihara, H.; Kanno, M.; Sanno, Y. J. Med. Chem. 1977, 20, 141. (d)
Nohara, A.; Sugihara, H.; Ukawa, K. Chem. Abstr. 1981, 94, 192310m. (e)
Ukawa, K.; Ishiguro, T.; Kuriki, H.; Nohara, A. Chem. Pharm. Bull. 1985,
33, 4432. (f) Singh, G.; Singh, R.; Girdhar, N. K.; Ishar, M. P. S. Tetrahedron
2002, 58, 2471. (g) Langer, P.; Apple, B. Tetrahedron Lett. 2003, 44, 5133.
(10) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
(11) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2009, 74, 7464.
(12) Xu, X.; Li, X.; Ma, L.; Ye, N.; Wang, B. J. Am. Chem. Soc. 2008, 130,
14048.
(13) Wang, S.-J.; Wang, Z.-Y.; Zheng, X.-Q. Chem. Commun. 2009, 47,
7372.
2894 J. Org. Chem. Vol. 75, No. 9, 2010

Xia et al.
JOCArticle
TABLE 1. Optimization of Reaction Conditionsa
as oxidant was also examined, and it was interestingly found
that a higher yield of 70% could be obtained even at lower
temperature under oxygen atmosphere (entry 18), clearly
demonstrating that oxygen can speed up this oxidative
transformation of tertiary amines. Furthermore, the catalyst
loading was investigated (entries 19-21). Lowering the
catalyst loading led to a slow conversion with the decreased
yield of 3a (entries 19 and 20), and even no expected product
was observed in the absence of platinum catalyst (entry 22).
Surprisingly, increasing the amount of catalyst to 15 mol %
gave the considerably decreased yield of 45% (entry 21).
With the series of detailed investigations mentioned above,
the reaction conditions were eventually optimized (entry 18):
10 mol % of K2PtCl4 as catalyst, 1,4-dioxane/H2O (2:1) as
entry
catalyst (mol %)
PtCl2 (10)
conditionsb
yield (%)
1
2
1, 4-dioxane/H2O (2:1) 80 °C
1, 4-dioxane/H2O (2:1)
1 equiv HFIP, 80 °C
1, 4-dioxane/H2O (2:1)
2 equiv HFIP, 80 °C
1, 4-dioxane/H2O (2:1)
26
50
PtCl2 (10)
PtCl2 (10)
PtCl2 (10)
PtCl2 (10)
PtCl2 (10)
PtCl2 (10)
PtCl4 (10)
K2PtCl4 (10)
3
4
5
6
7
8
9
52
57
˚
˚
mixed solvent, 5 A molecular sieves as additive, at 60 °C, and
under oxygen atmosphere.
5 A MS, 80 °C
1, 4-dioxane/H2O (2:1)
2equiv HOAc, 80 °C
1, 4-dioxane/H2O (2:1)
2 equiv HBF4, 80 °C
1, 4-dioxane/H2O (2:1)
2 equiv HSbF6, 80 °C
1, 4-dioxane/H2O (2:1)
40
Having established the optimal reaction conditions, we
next explored the scope of the reaction. This reaction was
successfully extended to a series of substituted N-aryl piper-
idines and nitroolefins. The corresponding results are listed
in Table 2. Under the optimized conditions, N-phenyl piper-
idine reacted with various substituted (E)-nitrostyrenes,
providing 3a-h in 40-70% yields (Table 2, entries 1-8).
From these results, it can be seen that this reaction tolerated
a variety of functional groups at the ortho, meta, and para
positions of the phenyl moiety in substituted (E)-nitrostyr-
enes, indicating that the steric effect had little impact on this
one-pot transformation. Nevertheless, a relatively lower
yield was obtained while using the aromatic nitroolefin with
a strongly electron-donating substituent in the phenyl ring
(enrty 8), which could be ascribed to the fact that the
electron-donating substituent decreased the electrophilic
reactivity of nitroolefin. The nitroolefin possessing a hetero-
cyclic ring, such as furan nucleus, can also participate in this
reaction to give the desired product 3i in 41% yield (entry 9).
Noteworthily, the substrate scope of the present platinum-
catalyzed Michael addition-elimination reaction can be
further extended to the aliphatic nitroolefin albeit in very
low yield (entry 10).
The property of the substituent on the aryl group of N-aryl
piperidines also influences the yield of the product. From
entries 11-17 of Table 2, it can be seen that an electron-
donating substituent at the N-aryl piperidine favors product
formation (entries 11-14), while an electron-withdrawing
group (e.g., Cl and Br) slightly hinders the reaction (entries
15-17). This might be due to the fact that the electron-
donating substituent increases the nucleophilic oxidative
reactivity of tertiary amines. The reaction of N-aryl piper-
idine possessing a benzyl group at the 2-position with (E)-
nitrostyrene 2a, as shown in eq 1 of Scheme 3, proceeded
smoothly to give the product 3u in a lower yield even at
slightly elevated temperature. Additionally, the size of the
ring of cyclic tertiary amine was also tested. N-Phenylaze-
pane exhibited a lower reactivity to form 3v (20% yield, eq 2
of Scheme 3) and N-phenyl pyrrolidine did not undergo the
expected reaction. It is worth mentioning that N-aryl mor-
pholine could also participate in this reaction although a
lower yield was obtained (eq 3 of Scheme 3).
trace
trace
58
˚
5 A MS, 80 °C
1, 4-dioxane/H2O (2:1)
5 A MS, 80 °C
65
˚
10 PtCl2 (10), COD (20) 1, 4-dioxane/H2O (2:1) 80 °C
11 PtCl2 (10), CO (1 atm) 1, 4-dioxane/H2O (2:1) 80 °C
12 K2PtCl4 (10)
13 K2PtCl4 (10)
14 K2PtCl4 (10)
trace
trace
39
DME/H2O (2:1)
˚
5 A MS, 80 °C
THF/H2O (2:1)
30
45
˚
5 A MS, 80 °C
DMF/H2O (2:1)
5 A MS, 80 °C
H2O, 5 A MS, 80 °C
1, 4-dioxane/H2O (2.5:1)
5 A MS, 80 °C
1, 4-dioxane/H2O (1.5:1)
5 A MS, 80 °C
1, 4-dioxane/H2O (2:1)
5 A MS, 60 °C, O2
1, 4-dioxane/H2O (2:1)
5 A MS, 60 °C, O2
1, 4-dioxane/H2O (2:1)
˚
˚
15 K2PtCl4 (10)
16 K2PtCl4 (10)
21
52
˚
17 K2PtCl4 (10)
18 K2PtCl4 (10)
19 K2PtCl4 (2.5)
20 K2PtCl4 (5)
21 K2PtCl4 (15)
42
70
36
60
45
0
˚
˚
˚
˚
5 A MS, 60 °C, O2
1, 4-dioxane/H2O (2:1)
5 A MS, 60 °C, O2
1, 4-dioxane/H2O (2:1)
˚
22
-
˚
5 A MS, 60 °C, O2
aAll reactions were carried out by using N-phenylpiperidine (0.2
mmol), (E)-2-nitrostyrene (0.3 mmol), catalyst (0.02 mmol), and solvent
(2 mL) for 14 h. bHFIP = hexafluoroisopropanol; MS = molecular
sieves.
tested in this reaction (entries 8-11). Among the platinum
catalytic systems examined, K2PtCl4 as catalyst delivered the
desired product 3a with the improved yield of 65% (entry 9),
demonstrating the fact that only hypervalent platinum cat-
alysts could activate R-hydrogen of the nitrogen atom in this
case. With an attempt to optimize the yield of the product, we
further studied the influence of different reaction media
(entries 12-14). From the results obtained, it can be seen
that 1,4-dioxane/H2O was the best solvent of choice (entry
9), and the reaction media investigated (e.g., DME/H2O,
THF/H2O, DMF/H2O, and H2O) gave 3a only in 21-45%
yields (entries 12-15). It should be noted that the best ratio
of 1,4-dioxane/H2O was 2:1, and the yields of 3a were
lowered when the ratio of water was either increased or
decreased (entries 16 and 17). Moreover, the effect of oxygen
Michael Addition-Cyclization. During the course of the
study of the mechanism of aforementioned Michael addition-
elimination, we envisioned that the enamine A reacted
with electrophiles Eþ (e.g., nitroolefins) to form putative
J. Org. Chem. Vol. 75, No. 9, 2010 2895

Xia et al.
JOCArticle
TABLE 2. Platinum-Catalyzed Michael Addition-Elimination of N-Aryl Piperidines with Nitroolefinsa
entry
R1
R2
product
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
H
H
H
H
phenyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
13
14
16
14
16
19
16
14
14
21
15
14
15
15
15
14
15
14
14
14
70
65
61
46
56
54
67
40
41
20b
55
58
71
52
43
32
40
61
68
47
4-methylphenyl
3-methylphenyl
2-methylphenyl
4-chlorophenyl
3-chlorophenyl
2-chlorophenyl
4-methoxyphenyl
2-furyl
cyclohexyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
4-chlorophenyl
2-chlorophenyl
4-methylphenyl
3j
3k
3l
4-methyl
3-methyl
4-methoxyl
3,4-dimethyl
4-chloro
3m
3n
3o
3p
3q
3r
3s
3t
3-chloro
4-bromo
4-methyl
4-methyl
4-methyl
aAll reactions were carried out by using 1 (0.2 mmol), nitroolefins 2 (0.3 mmol), K2PtCl4 (0.02 mmol), 1, 4-dioxane/H2O (2:1, 2 mL), and 5 A
˚
molecular sieves (50 mg) at 60 °C under oxygen atmosphere. bThe reaction was carried out at 80 °C.
SCHEME 3. Platinum-Catalyzed Michael Addition Reaction
intermediary iminium ion B, which can be readily trapped by
nucleophiles (Scheme 4).16 Phenol is one of the nucleophiles
that often is used for this purpose. To further explore the
scope of the reaction involving the in situ formation of
enamines, we extended our study to the substituted nitro-
vinylphenols 4 instead of simple aromatic nitroolefins 2
used in Michael addition-elimination sequence. As des-
cribed in Table 3, a variety of chromano[2,3-b]piperidine
derivatives were produced smoothly in the presence of
catalytic amounts of PtCl2 in 1,4-dioxane/H2O (2:1) at
SCHEME 4. Michael Addition-Cyclization
80 °C under 1 atm of O2, although the longer reaction
period and higher temperature were necessary to complete
this Michael addition-cyclization initiated by catalytic
oxidative dehydrogenation of tertiary amines. From the
results of Table 3, it was found that the electronic effects
and the positions of the substitutents in 1 did not show
(16) (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367.
(b) Zhang, X.-S.; Zhang, S.-L.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1.
2896 J. Org. Chem. Vol. 75, No. 9, 2010

Xia et al.
JOCArticle
TABLE 3. Platinum-Catalyzed Michael Addition-Cyclization of N-Aryl Piperidines with Nitrovinylphenolsa
entry
R1
R3
product
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
a
H
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
19
19
22
22
19
22
25
22
21
20
21
22
65
57
62
52
59
52
48
56
65
62
50
29
4-methoxyl
4-methyl
4-bromo
3,4-dimethyl
3-methyl
3-chloro
4-chloro
2-benzyl
H
5-methoxyl
5-methyl
3-methyl
5j
5k
5l
H
H
˚
All reactions were carried out by using 1 (0.3 mmol), 4 (0.2 mmol), PtCl2 (0.02 mmol), 1, 4-dioxane/H2O (2:1, 2 mL) and 5 A molecular sieves (50 mg)
at 80 °C under oxygen atmosphere.
SCHEME 5. Platinum-Catalyzed Michael Addition-Cyclization
obvious influences on the reaction efficiency. How-
ever, when employing the substituted nitrovinylphenol 4
bearing the substituent R3 ortho to the hydroxyl, the
unfavorable steric effect was observed remarkably and
the reaction yield is quite low (entry 12). It should be noted
that several functional groups such as methoxy, chloro,
and bromo were also compatible with this reaction.
In addition, N-(1-naphthyl)piperidine was also tolerated in this
reaction (Scheme 5). To further confirm the structural assign-
ment of products in the present Michael addition-cyclization,
the relative configuration of the product 5i was unambiguously
assigned by X-ray crystallography.
Proposed Mechanism. A tentative mechanism for the
product formation is proposed in Scheme 6. Analogous to
pathways for the oxidation of tertiary amines by electro-
chemical process,17 metals,18 and oxidants,10,11 the inter-
mediate iminium ion C is formed in the presence of platinum
catalyst, oxygen, and water. First, the platinum catalyst [Pt]
coordinates to the nitrogen and then goes through the
activation of C (sp3)-H adjacent to the nitrogen in the
presence of oxygen, affording an iminium ion intermediate
C.19 Second, the subsequent β-hydrogen elimination in C
produces the enamine D, which undergoes Michael addition
with nitroolefins 2a and 4a to give the Michael adduct
intermediates E (path A) and F (path B), respectively. By
further hydrogen elimination in iminium ion moiety of E, the
trisubstituted enamine product 3a could be delivered readily.
Contrarily, the iminium ion moiety in F was intramolecularly
attacked by the nucleophilic hydroxyl group, smoothly
giving the structurally different product 5a.20
Conclusions
In conclusion, a mild platinum-catalyzed dehydrogena-
tion of R,β-sp3 C-H bonds adjacent to the nitrogen of
tertiary amines was successfully established, and the in
situ formed enamines initially serving as carbon-nucleo-
philes reacted with various nitroolefins, leading to the
development of two one-pot protocols involving Michael
(19) As for the plausible process concerning the generation of iminium ion
C, please see the scheme below.
The platinum catalyst first coordinated to the nitrogen atom, followed by
insertion into the R C-H bond, leading to an iminium ion coordinated to a
platinum metal hydride C0 (see: Anguille, S.; Brunet, J.-J.; Chu, N.-C.;
Diallo, O.; Pages, C.; Vincendeau, S. Organometallics 2006, 25, 2943). The
platinum hydride was then oxidized by oxygen to regenerate the platinum
catalyst with release of water (see: Chen, L.; Davies, J. A. Inorg. Chim. Acta
1990, 175, 41).
(17) (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.
(18) (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.
(20) Stevens, R. V.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5580.
J. Org. Chem. Vol. 75, No. 9, 2010 2897

Xia et al.
JOCArticle
SCHEME 6. Proposed Mechanism
addition-elimination and Michael addition-cyclization.
This platinum-catalyzed reaction provided an effective
access to structurally divergent heterocyclic compounds.
Additionally, the present reaction can tolerate a large num-
ber of substrates, including aromatic and aliphatic nitro-
olefins as Michael acceptors as well as various functionalized
(E)-nitrovinylphenols as Michael acceptors/donors with
significant structural variation.
EtOAc to afford 57.2 mg (65%) of the indicated compound as
a solid after 14 h: mp 82-84 °C; 1H NMR (400 MHz, CDCl3)
δ 7.22-7.28 (m, 2 H), 7.09-7.14 (m, 4 H), 6.83-6.87 (m, 3 H),
6.55 (s, 1 H), 4.81-4.86 (m, 1 H), 4.68-4.73 (m, 1 H),
4.12-4.16 (m, 1 H), 3.40-3.43 (m, 2 H), 2.32 (s, 3 H),
1.95-2.04 (m, 1 H), 1.83-1.91 (m, 3 H); 13C NMR (100
MHz, CDCl3) δ 146.6, 136.9, 135.8, 129.4, 129.2, 127.2,
127.1, 119.6, 115.1, 109.6, 78.1, 48.9, 45.1, 22.5, 22.2, 20.9;
IR (neat, cm-1) 3027, 2923, 2845, 1733, 1657, 1597, 1551,
1499, 1376, 1319, 1261, 1200, 1163, 995, 875, 816, 752, 695,
658, 520; HRMS (ESI) m/z calcd for C20H22N2O2 (M þ H)
323.1754, found 323.1748.
3c was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 46.1 mg (61%) of the indicated compound as
an oil after 16 h: 1H NMR (400 MHz, CDCl3) δ 7.19-7.28 (m, 3
H), 7.00-7.08 (m, 3 H), 6.83-6.87 (m, 3 H), 6.56 (s, 1 H),
4.82-4.88 (m, 1 H), 4.69-4.73 (m, 1 H), 4.12-4.16 (m, 1 H),
3.41-3.43 (m, 2 H), 2.33 (s, 3 H), 1.84-2.05 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 146.6, 138.7, 138.4, 129.2, 128.6, 128.2,
128.1, 127.1, 124.3, 119.7, 115.1, 109.5, 77.9, 49.3, 45.1, 22.5,
22.2, 21.4; IR (neat, cm-1) 3033, 2923, 2844, 1733, 1657, 1597,
1551, 1498, 1377, 1319, 1261, 1199, 1171, 995, 873, 788, 751, 698,
662, 523; HRMS (ESI) m/z calcd for C20H22N2O2 (M þ H)
323.1754, found 323.1761.
Experimental Section
General Procedure for the Preparation of 5-(2-Nitro-1-aryl-
ethyl)-1-aryl-1,2,3,4-tetrahydropyridine, 3a-w. To a Schlenk
tube were added N-phenyl piperidine (0.20 mmol), K2PtCl4
(8.3 mg, 10 mol %), 2-nitrovinylbenzene (0.30 mmol), and
˚
powdered 5 A molecular sieves (50 mg). The Schlenk tube was
purged under vacuum and then refilled with oxygen 3 times. A
mixed solvent of 1,4-dioxane/H2O (2:1, 2.0 mL) was added by
syringe, and then the mixture was stirred at 60 °C. When the
reaction was considered complete as determined by TLC ana-
lysis, 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 the corresponding products.
3d was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 31.0 mg (46%) of the indicated compound as
an oil after 14 h: 1H NMR (400 MHz, CDCl3) δ 7.14-7.23 (m, 5
H), 7.10-7.13 (m, 1 H), 6.81-6.87 (m, 3 H), 6.49 (s, 1 H),
4.83-4.89 (m, 1 H), 4.66-4.71 (m, 1 H), 4.39-4.44 (m, 1 H),
3.37-3.48 (m, 2 H), 2.40 (s, 3 H), 1.81-2.04 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 146.6, 136.6, 136.5, 131.1, 129.2, 127.8,
127.1, 126.1, 125.7, 119.7, 115.1, 108.3, 77.8, 45.1, 22.8, 22.3,
19.5; IR (neat, cm-1) 3063, 2927, 2842, 1924, 1734, 1655, 1597,
1550, 1498, 1376, 1319, 1262, 1161, 1036, 995, 909, 875, 753, 694,
658, 619, 571, 523; HRMS (ESI) m/z calcd for C20H22N2O2
(M þ H) 323.1754, found 323.1757.
3a was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 48.5 mg (70%) of the indicated compound as
a solid after 13 h: mp 94-96 °C; 1H NMR (400 MHz, CDCl3) δ
7.31-7.35 (m, 2 H), 7.21-7.28 (m, 5 H), 6.84-6.87 (m, 3 H),
6.56 (s, 1 H), 4.83-4.88 (m, 1 H), 4.71-4.75 (m, 1 H), 4.16-4.20
(m, 1 H), 3.41-3.44 (m, 2 H), 1.96-2.05 (m, 1 H), 1.84-1.91 (m,
3 H); 13C NMR (100 MHz, CDCl3) δ 146.6, 138.8, 129.2, 128.8,
127.4, 127.3, 119.7, 115.2, 109.4, 77.9, 49.3, 45.1, 22.5, 22.2; IR
(neat, cm-1) 3056, 2924, 2848, 1950, 1709, 1657, 1596, 1551,
1497, 1377, 1340, 1319, 1263, 1200, 1162, 1080, 1030, 996, 877,
738, 700, 659, 615, 528; HRMS (ESI) m/z calcd for C19H20N2O2
(M þ H) 309.1598, found 309.1595.
3e was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 40.8 mg (56%) of the indicated compound as
a solid after 16 h: mp 68-70 °C; 1H NMR (400 MHz, CDCl3) δ
3b was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
2898 J. Org. Chem. Vol. 75, No. 9, 2010

Xia et al.
JOCArticle
7.23-7.31 (m, 4 H), 7.15-7.17 (m, 2 H), 6.85-6.88 (m, 3 H),
6.54 (s, 1 H), 4.79-4.85 (m, 1 H), 4.68-4.72 (m, 1 H), 4.14-4.18
(m, 1 H), 3.42-3.43 (m, 2 H), 1.82-1.99 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 146.5, 137.4, 133.2, 129.2, 128.9, 128.7,
127.6, 119.9, 115.2, 108.8, 77.7, 48.6, 45.1, 22.6, 22.2; IR (neat,
cm-1) 3062, 2926, 2844, 1732, 1656, 1597, 1551, 1496, 1376,
1340, 1319, 1262, 1200, 1163, 1090, 1013, 995, 875, 752, 694, 660,
570, 532; HRMS (ESI) m/z calcd for C19H19ClN2O2 (M þ H)
343.1208, found 343.1201.
3f was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 28.2 mg (54%) of the indicated compound as
a solid after 19 h: mp 60-62 °C; 1H NMR (400 MHz, CDCl3) δ
7.21-7.29 (m, 5 H), 7.10-7.13 (m, 1 H), 6.86-6.89 (m, 3 H),
6.56 (s, 1 H), 4.81-4.86 (m, 1 H), 4.69-4.74 (m, 1 H), 4.14-4.18
(m, 1 H), 3.43-3.45 (m, 2 H), 1.82-2.01 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 146.5, 141.0, 134.6, 130.0, 129.2, 127.7,
127.6, 125.5, 119.9, 115.3, 108.5, 77.6, 48.9, 45.1, 22.4, 22.1; IR
(neat, cm-1) 3062, 2926, 2843, 1939, 1709, 1656, 1596, 1551,
1498, 1376, 1340, 1319, 1262, 1199, 1165, 1081, 996, 878, 787,
752, 696, 662, 566, 525; HRMS (ESI) m/z calcd for
C19H19ClN2O2 (M þ H) 343.1208, found 343.1202.
NMR (100 MHz, CDCl3) δ 146.5, 129.1, 128.6, 119.4, 115.0,
107.6, 77.8, 51.0, 45.3, 37.5, 31.5, 31.0, 30.9, 26.2, 26.1, 22.3,
20.7; IR (neat, cm-1) 3034, 2926, 2850, 1713, 1658, 1597, 1549,
1499, 1445, 1379, 1325, 1260, 1194, 1165, 995, 869, 750, 693, 661,
576, 522; HRMS (ESI) m/z calcd for C19H26N2O2 (M þ H)
315.2067, found 315.2062.
3k was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 36.5 mg (55%) of the indicated compound as
a solid after 15 h: mp 102-104 °C; 1H NMR (400 MHz, CDCl3)
δ 7.30-7.34 (m, 2 H), 7.21-7.27 (m, 3 H), 7.05-7.07 (m, 2 H),
6.75-6.77 (m, 2 H), 6.51 (s, 1 H), 4.82-4.87 (m, 1 H), 4.70-4.75
(m, 1 H), 4.15-4.19 (m, 1 H), 3.36-3.43 (m, 2 H), 2.27 (s, 3 H),
1.84-2.03 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 144.5,
138.9, 129.7, 129.1, 128.7, 127.7, 127.4, 127.3, 115.4, 108.6, 77.9,
49.3, 45.4, 22.5, 22.2, 20.4; IR (neat, cm-1) 3061, 3028, 2983,
2930, 2848, 1885, 1738, 1657, 1614, 1571, 1553, 1516, 1448, 1375,
1320, 1243, 1203, 1163, 1046, 937, 847, 810, 702, 635, 607, 528;
HRMS (ESI) m/z calcd for C20H22N2O2 (M þ H) 323.1754,
found 323.1752.
3l was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 35.8 mg (58%) of the indicated compound as
a solid after 14 h: mp 76-78 °C; 1H NMR (400 MHz, CDCl3) δ
7.31-7.35 (m, 2 H), 7.21-7.27 (m, 3 H), 7.13-7.17 (m, 1 H),
6.66-6.69 (m, 3 H), 6.56 (s, 1 H), 4.84-4.89 (m, 1 H), 4.72-4.76
(m, 1 H), 4.16-4.20 (m, 1 H), 3.41-3.43 (m, 2 H), 2.33 (s, 3 H),
1.83-2.04 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 146.6,
139.0, 138.9, 129.0, 128.7, 127.5, 127.4, 127.3, 120.7, 115.9,
3g was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 51.8 mg (67%) of the indicated compound as
a solid after 16 h: mp 80-82 °C; 1H NMR (400 MHz, CDCl3) δ
7.39-7.41 (m, 1 H), 7.18-7.28 (m, 5 H), 6.83-6.87 (m, 3 H),
6.58 (s, 1 H), 4.70-4.85 (m, 3 H), 3.43-3.46 (m, 2 H), 1.88-2.05
(m, 4 H); 13C NMR (100 MHz, CDCl3) δ 146.6, 136.0, 134.4,
130.3, 129.2, 128.5, 128.3, 127.7, 126.9, 119.8, 115.3, 107.3, 76.7,
45.3, 45.2, 23.1, 22.2; IR (neat, cm-1) 3463, 2984, 2938, 1888,
1740, 1597, 1554, 1466, 1444, 1374, 1242, 1098, 1047, 1001, 937,
918, 847, 786, 756, 694, 634, 608; HRMS (ESI) m/z calcd for
C19H19ClN2O2 (M þ H) 343.1208, found 343.1213.
112.4, 109.1, 77.9, 49.3, 45.1, 22.5, 22.2, 21.7; IR (neat, cm-1
)
3030, 2923, 2845, 1711, 1656, 1601, 1551, 1494, 1448, 1377, 1348,
1318, 1262, 1199, 1161, 1080, 1027, 997, 771, 698, 659, 615, 561,
529; HRMS (ESI) m/z calcd for C20H22N2O2 (M þ H) 323.1754,
found 323.1750.
3h was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 25 mg (40%) of the indicated compound as a
solid after 14 h: mp 74-76 °C; 1H NMR (400 MHz, CDCl3) δ
7.24-7.28 (m, 2 H), 7.13-7.15 (m, 2 H), 6.85-6.87 (m, 5 H),
6.53 (s, 1 H), 4.80-4.85 (m, 1 H), 4.67-4.72 (m, 1 H), 4.11-4.15
3m was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 47 mg (71%) of the indicated compound as a
solid after 15 h: mp 84-85 °C; 1H NMR (400 MHz, CDCl3) δ
7.31-7.34 (m, 2 H), 7.21-7.27 (m, 3 H), 6.79-6.82 (m, 4 H),
6.44 (s, 1 H), 4.83-4.88 (m, 1 H), 4.70-4.75 (m, 1 H), 4.14-4.18
(m, 1 H), 3.76 (s, 3 H), 3.33-3.42 (m, 2 H), 1.82-2.03 (m, 4 H);
13C NMR (100 MHz, CDCl3) δ 153.7, 141.2, 138.9, 128.7, 128.3,
127.4, 127.3, 117.2, 114.6, 108.1, 77.9, 55.6, 49.3, 46.0, 22.4, 22.2;
IR (neat, cm-1) 3027, 2927, 2836, 1711, 1651, 1615, 1577, 1546,
1509, 1428, 1373, 1323, 1262, 1238, 1178, 1033, 988, 817, 745,
699, 638, 549, 525; HRMS (ESI) m/z calcd for C20H22N2O3
(M þ H) 339.1703, found 339.1708.
(m, 1 H), 3.78 (s, 3 H), 3.43 (br, 2 H), 1.86-2.04 (m, 4 H); 13
C
NMR (100 MHz, CDCl3) δ 158.8, 146.6, 130.7, 129.2, 128.5,
127.0, 119.7, 115.1, 114.1, 109.8, 78.2, 55.2, 48.6, 45.1, 22.7, 22.2;
IR (neat, cm-1) 3102, 3034, 2931, 2839, 1731, 1657, 1600, 1550,
1509, 1462, 1377, 1337, 1315, 1256, 1200, 1176, 1115, 1031, 994,
971, 830, 753, 695, 658, 587, 523; HRMS (ESI) m/z calcd for
C20H22N2O3 (M þ H) 339.1703, found 339.1709.
3i was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 28 mg (41%) of the indicated compound as
an oil after 14 h: 1H NMR (400 MHz, CDCl3) δ 7.35-7.36 (m, 1
H), 7.24-7.27 (m, 2 H), 6.85-6.87 (m, 3 H), 6.57 (s, 1 H),
6.32-6.33 (m, 1 H), 6.12-6.13 (m, 1 H), 4.70-4.84 (m, 2 H),
4.25-4.29 (m, 1 H), 3.45-3.48 (m, 2 H), 1.91-2.15 (m, 4 H); 13C
NMR (100 MHz, CDCl3) δ 152.4, 146.5, 142.0, 129.2, 128.9,
119.9, 115.3, 110.4, 106.5, 106.3, 76.5, 45.1, 43.9, 22.2, 21.9; IR
(neat, cm-1) 3062, 2926, 2846, 1711, 1659, 1597, 1552, 1499,
1377, 1321, 1262, 1200, 1167, 1078, 1013, 996, 972, 915, 879, 813,
749, 695, 597, 524; HRMS (ESI) m/z calcd for C17H18N2O3 (M
þ H) 299.1390, found 299.1382.
3n was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 32 mg (52%) of the indicated compound as
an oil after 15 h: 1H NMR (400 MHz, CDCl3) δ 7.30-7.34 (m, 2
H), 7.21-7.27 (m, 3 H), 7.00-7.02 (m, 1 H), 6.67-6.68 (m, 1 H),
6.59-6.63 (m, 1 H), 6.52 (s, 1 H), 4.83-4.88 (m, 1 H), 4.71-4.76
(m, 1 H), 4.15-4.19 (m, 1 H), 3.37-3.40 (m, 2 H), 2.24 (s, 3 H),
2.18 (s, 3 H), 1.84-2.04 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ
144.9, 139.0, 137.3, 130.2, 128.7, 128.0, 127.9, 127.4, 127.3,
116.9, 112.9, 108.4, 78.0, 49.3, 45.4, 22.5, 22.2, 20.1, 18.7; IR
(neat, cm-1) 3026, 2923, 2857, 1877, 1734, 1656, 1610, 1551,
1505, 1450, 1376, 1320, 1262, 1201, 1180, 1045, 996, 852, 807,
761, 701, 642, 608, 586, 527; HRMS (ESI) m/z calcd for
C21H24N2O2 (M þ H) 337.1911, found 337.1909.
3j was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 17 mg (20%) of the indicated compound as
an oil after 21 h: 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (m, 2
H), 6.82-6.84 (m, 3 H), 6.35 (s, 1 H), 4.58-4.62 (m, 1 H),
4.37-4.43 (m, 1 H), 3.45 (br, 2 H), 2.49-2.56 (m, 1 H),
2.06-2.12 (m, 1 H), 1.92-1.93 (m, 3 H), 1.67-1.76 (m, 6 H),
3o was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 30.5 mg (43%) of the indicated compound as
a solid after 15 h: mp 117-119 °C; 1H NMR (400 MHz, CDCl3)
δ 7.32-7.35 (m, 2 H), 7.19-7.29 (m, 5 H), 6.75-6.78 (m, 2 H),
6.49 (s, 1 H), 4.84-4.89 (m, 1 H), 4.71-4.76 (m, 1 H), 4.16-4.20
(m, 1 H), 3.34-3.43 (m, 2 H), 1.83-2.05 (m, 4 H); 13C NMR
1.34-1.42 (m, 1 H), 1.14-1.26 (m, 3 H), 0.95-1.07 (m, 1 H); 13
C
J. Org. Chem. Vol. 75, No. 9, 2010 2899

Xia et al.
JOCArticle
(100 MHz, CDCl3) δ 145.1, 138.6, 129.0, 128.8, 127.4, 127.3,
126.9, 124.6, 116.2, 110.3, 77.9, 49.3, 45.2, 22.3, 22.1; IR (neat,
cm-1) 3029, 2924, 2844, 1657, 1593, 1550, 1495, 1450, 1377,
1346, 1320, 1261, 1199, 1163, 1095, 975, 816, 762, 700, 627, 520;
HRMS (ESI) m/z calcd for C19H19ClN2O2 (M þ H) 343.1208,
found 343.1215.
3p was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 20 mg (32%) of the indicated compound as a
solid after 14 h: mp 92-94 °C; 1H NMR (400 MHz, CDCl3) δ
7.14-7.36 (m, 6 H), 6.81-6.83 (m, 2 H), 6.71-6.74 (m, 1 H),
6.53 (s, 1 H), 4.85-4.91 (m, 1 H), 4.73-4.78 (m, 1 H), 4.17-4.21
(m, 1 H), 3.39-3.42 (m, 2 H), 1.88-2.06 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 147.5, 138.6, 135.0, 130.2, 128.8, 127.5,
127.4, 126.6, 119.5, 115.0, 113.0, 110.9, 77.8, 49.3, 45.1, 22.4,
22.1; IR (neat, cm-1) 3028, 2923, 2850, 1656, 1591, 1550, 1486,
1439, 1377, 1321, 1259, 1199, 1101, 990, 844, 765, 700, 653, 615,
551; HRMS (ESI) m/z calcd for C19H19ClN2O2 (M þ H)
343.1208, found 343.1202.
3q was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 26.5 mg (40%) of the indicated compound as
a solid after 15 h: mp 64-66 °C; 1H NMR (400 MHz, CDCl3) δ
7.32-7.35 (m, 4 H), 7.21-7.29 (m, 3 H), 6.70-6.73 (m, 2 H),
6.49 (s, 1 H), 4.84-4.89 (m, 1 H), 4.71-4.76 (m, 1 H), 4.16-4.20
(m, 1 H), 3.38-3.39 (m, 2 H), 1.85-2.05 (m, 4 H); 13C NMR
(100 MHz, CDCl3) δ 145.6, 138.6, 131.9, 128.8, 127.5, 127.4,
126.7, 116.7, 111.9, 110.4, 77.9, 49.3, 45.1, 22.4, 22.1; IR (neat,
cm-1) 3029, 2952, 2924, 2854, 1710, 1660, 1588, 1551, 1493,
1453, 1377, 1319, 1261, 1198, 1164, 1076, 1002, 816, 761, 701,
678, 623, 525; HRMS (ESI) m/z calcd for C19H19BrN2O2 (M þ
H) 387.0703, found 387.0708.
1551, 1495, 1440, 1376, 1318, 1262, 1199, 1159, 1044, 997, 817,
773, 723, 695, 658, 589, 522; HRMS (ESI) m/z calcd for
C21H24N2O2 (M þ H) 337.1911, found 337.1919.
3u was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 34.0 mg (41%) of the indicated compound as
an oil after 18 h: 1H NMR (400 MHz, CDCl3) δ 7.18-7.33 (m, 5
H), 7.12-7.17 (m, 7 H), 7.00-7.08 (m, 2 H), 6.00 (s, 1 H),
4.64-4.69 (m, 1 H), 4.52-4.57 (m, 1 H), 3.99-4.05 (m, 3 H),
3.16-3.18 (m, 2 H), 1.72-1.97 (m, 4 H); 13C NMR (100 MHz,
CDCl3) δ 147.9, 141.1, 139.3, 135.5, 131.7, 131.5, 128.7, 128.6,
128.3, 127.4, 127.3, 127.2, 125.9, 124.6, 124.5, 107.3, 77.9, 49.0,
48.8, 37.4, 22.6, 22.2; IR (neat, cm-1) 3060, 2923, 2840, 1725,
1655, 1551, 1491, 1450, 1377, 1309, 1258, 1197, 1074, 974, 888,
763, 732, 699, 614, 554; HRMS (ESI) m/z calcd for C26H26N2O
(M þ H) 399.2067, found 399.2077.
3v was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 10.5 mg (20%) of the indicated compound as
an oil after 15 h: 1H NMR (400 MHz, CDCl3) δ 7.24-7.38 (m, 7
H), 6.80-6.83 (m, 3 H), 6.31 (s, 1 H), 4.86-4.91 (m, 1 H),
4.76-4.82 (m, 1 H), 4.23-4.27 (m, 1 H), 3.62-3.75 (m, 2 H),
2.11-2.15 (m, 1 H), 1.99-2.06 (m, 1 H), 1.73-1.79 (m, 2 H),
1.50-1.56 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 146.1,
138.5, 132.3, 129.3, 128.8, 127.5, 127.4, 123.4, 118.6, 113.7, 77.9,
50.1, 48.1, 28.0, 27.2, 24.0; IR (neat, cm-1) 3029, 2926, 2855,
1733, 1650, 1596, 1551, 1498, 1375, 1341, 1199, 1035, 987, 882,
750, 696, 656, 515; HRMS (ESI) m/z calcd for C20H22N2O2 (M
þ H) 323.1754, found 323.1750.
3w was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 9.5 mg (15%) of the indicated compound as
an oil after 15 h: 1H NMR (400 MHz, CDCl3) δ 7.27-7.36 (m, 5
H), 7.22-7.26 (m, 2 H), 6.76-6.84 (m, 3 H), 5.96 (s, 1 H),
4.96-5.01 (m, 1 H), 4.67-4.72 (m, 1 H), 4.09-4.22 (m, 3 H),
3.49-3.58 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 145.2,
137.5, 134.2, 129.3, 128.8, 127.7, 127.6, 119.4, 114.1, 108.5, 77.5,
64.7, 47.3, 44.2; IR (neat, cm-1) 3060, 2923, 2865, 1677, 1594,
1552, 1496, 1462, 1386, 1296, 1211, 1080, 1014, 751, 696, 614,
578, 558, 520; HRMS (ESI) m/z calcd for C18H18N2O3 (M þ H)
311.1390, found 311.1393.
3r was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 52.8 mg (61%) of the indicated compound as
a solid after 14 h: mp 84-86 °C; 1H NMR (400 MHz, CDCl3) δ
7.28-7.31 (m, 2 H), 7.13-7.17 (m, 3 H), 6.66-6.71 (m, 3 H),
6.54 (s, 1 H), 4.79-4.85 (m, 1 H), 4.68-4.73 (m, 1 H), 4.13-4.17
(m, 1 H), 3.40-3.45 (m, 2 H), 2.33 (s, 3 H), 1.80-1.98 (m, 4 H);
13C NMR (100 MHz, CDCl3) δ 146.6, 139.0, 137.5, 133.1, 129.1,
128.9, 128.7, 127.7, 120.9, 116.0, 112.4, 108.6, 77.8, 48.6, 45.1,
22.5, 22.1, 21.7; IR (neat, cm-1) 3029, 2923, 2843, 1711, 1656,
1613, 1551, 1515, 1491, 1439, 1376, 1320, 1261, 1200, 1164, 1091,
1013, 978, 885, 811, 736, 717, 662, 630, 536; HRMS (ESI) m/z
calcd for C20H21ClN2O2 (M þ H) 357.1364, found 357.1370.
3s was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 47.1 mg (68%) of the indicated compound as
a solid after 14 h: mp 100-102 °C; 1H NMR (400 MHz, CDCl3)
δ 7.39-7.41 (m, 1 H), 7.18-7.25 (m, 3 H), 7.12-7.16 (m, 1 H),
6.65-6.69 (m, 3 H), 6.58 (s, 1 H), 4.69-4.85 (m, 3 H), 3.42-3.45
(m, 2 H), 2.32 (s, 3 H), 1.86-2.03 (m, 4 H); 13C NMR (100 MHz,
CDCl3) δ 146.7, 138.9, 136.0, 134.4, 130.3, 129.0, 128.5, 127.7,
126.9, 120.7, 116.1, 112.5, 107.0, 76.7, 45.3, 45.2, 23.1, 22.2, 21.7;
IR (neat, cm-1) 3038, 2923, 2842, 1733, 1711, 1657, 1601, 1584,
1551, 1494, 1376, 1318, 1263, 1199, 1159, 1039, 998, 909, 869,
759, 693, 657, 615, 568, 532; HRMS (ESI) m/z calcd for
C20H21ClN2O2 (M þ H) 357.1364, found 357.1381.
General Procedure for the Preparation of 5-(Nitromethyl)-1-
phenyl-2,3,4,4a,5,10a-hexahydro-1H-chromeno[2,3-b]pyridine,
5a-m. To a Schlenk tube were added N-phenyl piperidine (0.40
mmol), PtCl2 (5.3 mg, 10 mol %), nitrovinylphenol (0.20 mmol),
˚
and powdered 5 A molecular sieves (50 mg). The Schlenk tube
was purged under vacuum and then refilled with oxygen 3 times.
A mixed solvent of 1,4-dioxane/H2O (2:1, 2.0 mL) was added by
syringe, and then the mixture was stirred at 80 °C. When the
reaction was considered complete as determined by TLC ana-
lysis, 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.
5a was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 42.2 mg (65%) of the indicated compound as
a solid after 19 h: mp 98-100 °C; 1H NMR (400 MHz, CDCl3) δ
7.28-7.32 (m, 2 H), 7.14-7.23 (m, 3 H), 7.09 (d, J = 7.2 Hz, 1
H), 6.97 (t, J = 7.2 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1 H), 6.84 (d,
J = 8.0 Hz, 1 H), 5.53 (d, J = 2.0 Hz, 1 H), 4.60 (d, J = 7.6 Hz, 2
H), 3.49 (t, J = 15.2 Hz, 1 H), 3.35-3.38 (m, 2 H), 2.15-2.18 (m,
1 H), 1.83-1.89 (m, 2 H), 1.48-1.64 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ 154.1, 150.2, 129.6, 129.1, 121.6, 120.9, 119.0,
117.5, 117.0, 82.8, 80.3, 44.0, 40.9, 35.4, 24.9, 24.1; IR (neat,
cm-1) 3062, 2930, 2856, 1940, 1710, 1600, 1583, 1550, 1490,
3t was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 28.2 mg (47%) of the indicated compound as
an oil after 14 h: 1H NMR (400 MHz, CDCl3) δ 7.09-7.16 (m, 5
H), 6.66-6.69 (m, 3 H), 6.55 (s, 1 H), 4.81-4.87 (m, 1 H),
4.69-4.74 (m, 1 H), 4.12-4.16 (m, 1 H), 3.40-3.43 (m, 2 H),
2.32 (s, 6 H), 1.83-2.04 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ
146.7, 138.9, 136.9, 135.8, 130.1, 129.4, 129.2, 129.0, 127.3,
127.2, 120.6, 115.9, 112.4, 109.4. 78.1, 48.9, 45.2, 22.5, 22.3,
21.7, 20.9; IR (neat, cm-1) 3026, 2922, 2845, 1734, 1656, 1602,
2900 J. Org. Chem. Vol. 75, No. 9, 2010

Xia et al.
JOCArticle
1454, 1410, 1377, 1300, 1252, 1224, 1170, 1113, 1035, 954, 883,
758, 696, 649, 530; HRMS (ESI) m/z calcd for C19H20N2O3
(M þ H) 325.1547, found 325.1542.
J = 7.2 Hz, 1 H), 5.52 (br, 1 H), 4.59-4.62 (m, 2 H), 3.50 (t, J =
7.6 Hz, 1 H), 3.31-3.37 (m, 2 H), 2.34 (s, 3 H), 2.14-2.17 (m, 1
H), 1.83-1.88 (m, 2 H), 1.58-1.64 (m, 1 H), 1.45-1.55 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ 154.2, 150.2, 138.8, 129.5, 129.1,
128.9, 122.4, 120.9, 119.7, 117.5, 117.1, 116.1, 82.8, 80.4, 44.0,
40.9, 35.4, 24.9, 24.2, 21.7; IR (neat, cm-1) 3038, 2935, 2856,
2728, 1710, 1604, 1583, 1550, 1488, 1453, 1407, 1376, 1301, 1258,
1223, 1168, 1112, 1037, 989, 959, 911, 877, 778, 757, 697, 649,
580, 529; HRMS (ESI) m/z calcd for C20H22N2O3 (M þ H)
339.1703, found 339.1700.
5b was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 42.6 mg (57%) of the indicated compound as
a solid after 19 h: mp 124-126 °C; 1H NMR (400 MHz, CDCl3)
δ 7.08-7.19 (m, 4 H), 6.83-6.91 (m, 4 H), 5.38 (d, J = 1.2 Hz, 1
H), 4.59 (d, J = 8.0 Hz, 2 H), 3.78 (s, 3 H), 3.48 (t, J = 7.6 Hz, 1
H), 3.33-3.39 (m, 1 H), 3.18-3.21 (m, 1 H), 2.16-2.18 (m, 1 H),
1.83-1.89 (m, 2 H), 1.43-1.61 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ 155.0, 154.2, 144.1, 129.5, 129.0, 121.5, 120.9, 117.5,
117.1, 114.3, 83.9, 80.3, 55.5, 44.8, 40.9, 35.5, 25.0, 24.1; IR
(neat, cm-1) 3042, 2928, 2858, 2053, 1608, 1583, 1549, 1510,
1441, 1377, 1293, 1246, 1230, 1167, 1112, 1033, 988, 953, 876,
825, 755, 705, 647, 629, 577, 539; HRMS (ESI) m/z calcd for
C20H22N2O4 (M þ H) 355.1652, found 355.1651.
5g was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 35.7 mg (48%) of the indicated compound as
a solid after 25 h: mp 40-42 °C; 1H NMR (400 MHz, CDCl3) δ
7.16-7.20 (m, 2 H), 7.10-7.12 (m, 2 H), 6.99-7.02 (m, 1 H),
6.89-6.95 (m, 2 H), 6.84-6.86 (m, 1 H), 5.50 (d, J = 2.4 Hz, 1
H), 4.62 (d, J = 8.0 Hz, 2 H), 3.50 (t, J = 7.6 Hz, 1 H), 3.29-3.27
(m, 2 H), 2.13-2.16 (m, 1 H), 1.81-1.88 (m, 2 H), 1.59-1.65 (m,
1 H), 1.46-1.55 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 153.8,
151.4, 134.8, 130.0, 129.5, 129.2, 121.4, 121.2, 118.9, 117.5,
117.0, 116.9, 82.3, 80.3, 44.0, 40.8, 35.2, 24.7, 23.9; IR (neat,
cm-1) 3070, 2937, 2857, 1793, 1710, 1590, 1550, 1484, 1453,
1409, 1377, 1304, 1252, 1223, 1169, 1111, 1038, 990, 960, 887,
848, 803, 759, 717, 690, 648, 615, 580, 532; HRMS (ESI) m/z
calcd for C19H19ClN2O3 (M þ H) 359.1157, found 359.1162.
5h was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 41.7 mg (56%) of the indicated compound as
a solid after 22 h: mp 144-146 °C; 1H NMR (400 MHz, CDCl3)
δ 7.24-7.26 (m, 2 H), 7.15-7.23 (m, 1 H), 7.05-7.11 (m, 3 H),
6.89-6.93 (m, 1 H), 6.82-6.84 (m, 1 H), 5.46 (d, J = 2.0 Hz, 1
H), 4.59-4.62 (m, 2 H), 3.50 (t, J = 7.6 Hz, 1 H), 3.28-3.34 (m,
2 H), 2.14-2.17 (m, 1 H), 1.82-1.89 (m, 2 H), 1.58-1.64 (m, 1
H), 1.45-1.52 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 153.9,
148.8, 129.5, 129.2, 128.9, 126.6, 121.1, 120.4, 117.4, 116.9, 82.7,
80.3, 44.2, 40.8, 35.3, 24.8, 23.9; IR (neat, cm-1) 3040, 2936,
2857, 1881, 1732, 1586, 1551, 1492, 1454, 1410, 1376, 1300, 1249,
1225, 1169, 1112, 1041, 988, 956, 884, 823, 758, 709, 686, 640,
614, 580, 528; HRMS (ESI) m/z calcd for C19H19ClN2O3 (M þ
H) 359.1157, found 359.1160.
5i was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 54.5 mg (65%) of the indicated compound as
a solid after 21 h: mp 144-146 °C; 1H NMR (400 MHz, CDCl3)
δ 7.66-7.68 (m, 1 H), 7.28-7.29 (m, 1 H), 7.21-7.25 (m, 3 H),
7.11-7.18 (m, 5 H), 6.98-7.00 (m, 1 H), 6.81-6.87 (m, 2 H),
4.70 (d, J = 2.0 Hz, 1 H), 4.20-4.25 (m, 1 H), 4.09-4.14 (m, 1
H), 3.98-4.05 (m, 2 H), 3.42-3.49 (m, 1 H), 3.29-3.33 (m, 1 H),
2.71-2.74 (m, 1 H), 1.95-1.99 (m, 1 H), 1.67-1.79 (m, 2 H),
1.38-1.56 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 154.2,
149.3, 141.6, 136.8, 131.3, 129.5, 128.9, 128.4, 128.3, 127.2,
126.1, 125.8, 125.5, 120.6, 117.4, 117.3, 84.6, 80.1, 45.4, 40.7,
37.6, 35.5, 25.1, 24.1; IR (neat, cm-1) 3025, 2933, 2853, 1735,
1602, 1583, 1551, 1488, 1451, 1405, 1375, 1294, 1226, 1169, 1109,
1046, 988, 956, 879, 841, 759, 733, 698, 649, 610, 558, 512;
HRMS (ESI) m/z calcd for C26H26N2O (M þ H) 415.2016,
found 415.2018.
5c was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 43.7 mg (62%) of the indicated compound as
a solid after 22 h: mp 116-118 °C; 1H NMR (400 MHz, CDCl3)
δ 7.05-7.18 (m, 6 H), 6.87-6.90 (m, 1 H), 6.82-6.84 (m, 1 H),
5.48 (d, J = 1.6 Hz, 1 H), 4.59 (d, J = 8.0 Hz, 2 H), 3.49 (t, J =
7.6 Hz, 1 H), 3.27-3.38 (m, 2 H), 2.30 (s, 3 H), 2.14-2.17 (m, 1
H), 1.82-1.91 (m, 2 H), 1.43-1.62 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ 154.2, 147.9, 131.1, 129.6, 129.5, 129.0, 120.9,
119.3, 117.5, 117.1, 83.1, 80.3, 44.2, 40.9, 35.4, 24.9, 24.1, 20.5;
IR (neat, cm-1) 3028, 2934, 2857, 2737, 1732, 1611, 1582, 1550,
1514, 1487, 1454, 1409, 1377, 1298, 1251, 1225, 1170, 1113, 1069,
1036, 988, 955, 910, 882, 841, 816, 757, 736, 648, 593, 530;
HRMS (ESI) m/z calcd for C20H22N2O3 (M þ H) 339.1703,
found 339.1707.
5d was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 44 mg (52%) of the indicated compound as a
solid after 22 h: mp 140-142 °C; 1H NMR (400 MHz, CDCl3) δ
7.37-7.40 (m, 2 H), 7.15-7.19 (m, 1 H), 7.09-7.12 (m, 1 H),
6.99-7.03 (m, 2 H), 6.91 (t, J = 7.2 Hz, 1 H), 6.83 (d, J = 8.0 Hz,
1 H), 5.47 (d, J = 2.0 Hz, 1 H), 4.61 (d, J = 7.2 Hz, 2 H), 3.50 (t,
J = 7.6 Hz, 1 H), 3.30-3.34 (m, 2 H), 2.14-2.16 (m, 1 H),
1.82-1.89 (m, 2 H), 1.46-1.63 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ 153.9, 149.3, 131.9, 129.6, 129.2, 121.2, 120.8, 117.5,
116.9, 114.1, 82.6, 80.3, 44.1, 40.8, 35.3, 24.8, 23.9; IR (neat,
cm-1) 3061, 2925, 2843, 1710, 1657, 1588, 1550, 1493, 1451,
1377, 1347, 1319, 1262, 1199, 1163, 1078, 1029, 996, 975, 908,
878, 814, 762, 700, 678, 622, 518; HRMS (ESI) m/z calcd for
C19H19BrN2O3 (M þ H) 403.0652, found 403.0657.
5e was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 44.3 mg (59%) of the indicated compound as
a solid after 19 h: mp 136-137 °C; 1H NMR (400 MHz, CDCl3)
δ 7.14-7.18 (m, 1 H), 7.05-7.09 (m, 2 H), 6.83-6.94 (m, 4 H),
5.48 (d, J = 1.6 Hz, 1 H), 4.57-4.60 (m, 2 H), 3.48 (t, J = 7.6 Hz,
1 H), 3.28-3.38 (m, 2 H), 2.25 (s, 3 H), 2.20 (s, 3 H), 2.14-2.17
(m, 1 H), 1.81-1.90 (m, 2 H), 1.43-1.61 (m, 2 H); 13C NMR
(100 MHz, CDCl3) δ 154.2, 148.2, 137.1, 130.1, 129.8, 129.5,
129.0, 120.8, 120.7, 117.5, 117.1, 116.7, 83.1, 80.4, 44.1, 40.9,
35.4, 24.9, 24.2, 20.1, 18.9; IR (neat, cm-1) 3407, 3015, 2935,
2857, 2734, 1711, 1611, 1582, 1551, 1505, 1487, 1453, 1412, 1376,
1305, 1255, 1223, 1170, 1114, 1038, 1012, 988, 959, 877, 853, 812,
757, 709, 645, 589, 527; HRMS (ESI) m/z calcd for C21H24N2O3
(M þ H) 353.1860, found 353.1854.
5j was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 44 mg (62%) of the indicated compound as a
solid after 20 h: mp 122-124 °C; 1H NMR (400 MHz, CDCl3) δ
7.30 (t, J = 7.6 Hz, 2 H), 7.12-7.14 (m, 2 H), 6.96 (t, J = 7.6 Hz,
1 H), 6.74-6.79 (m, 2 H), 6.61-6.62 (m, 1 H), 5.48 (d, J = 2.0
Hz, 1 H), 4.61 (d, J = 7.6 Hz, 2 H), 3.74 (s, 3 H), 3.46 (t, J = 7.6
Hz, 1 H), 3.34-3.37 (m, 2 H), 2.11-2.15 (m, 1 H), 1.82-1.88 (m,
2 H), 1.49-1.62 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 153.8,
150.2, 147.9, 129.1, 121.4, 118.9, 118.3, 117.4, 115.6, 113.5, 82.5,
80.4, 55.7, 44.0, 41.2, 35.4, 24.9, 24.2; IR (neat, cm-1) 3060,
5f was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 37.5 mg (52%) of the indicated compound as
a solid after 22 h: mp 110-112 °C; 1H NMR (400 MHz, CDCl3)
δ 7.15-7.21 (m, 2 H), 7.10 (d, J = 7.2 Hz, 1 H), 6.95-6.96 (m, 2
H), 6.89 (t, J = 7.2 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.80 (d,
J. Org. Chem. Vol. 75, No. 9, 2010 2901

Xia et al.
JOCArticle
3033, 2997, 2936, 2856, 1732, 1598, 1550, 1496, 1463, 1408, 1377,
1333, 1280, 1220, 1174, 1159, 1102, 1038, 991, 960, 881, 846, 816,
760, 735, 696, 655, 590, 524; HRMS (ESI) m/z calcd for
C20H22N2O4 (M þ H) 355.1652, found 355.1650.
1105, 1078, 1030, 989, 943, 906, 881, 809, 758, 739, 697, 651, 557,
524; HRMS (ESI) m/z calcd for C20H22N2O3 (M þ H) 339.1703,
found 339.1702.
5m was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 38.4 mg (50%) of the indicated compound as
a solid after 21 h: mp 123-124 °C; 1H NMR (400 MHz, CDCl3)
δ 8.09 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.63-7.65
(m, 2 H), 7.51-7.55 (m, 1 H), 7.43-7.48 (m, 2 H), 7.14-7.18 (m,
1 H), 7.06-7.08 (m, 1 H), 6.85-6.89 (m, 2 H), 5.29 (d, J = 1.6
Hz, 1 H), 4.44-4.53 (m, 2 H), 3.57-3.64 (m, 1 H), 3.47-3.51 (m,
1 H), 3.08-3.12 (m, 1 H), 2.36-2.39 (m, 1 H), 1.99-2.11 (m, 1
H), 1.83-1.86 (m, 1 H), 1.54-1.70 (m, 2 H); 13C NMR (100
MHz, CDCl3) δ 154.2, 147.1, 134.6, 129.6, 129.3, 129.0, 128.4,
125.9, 125.7, 124.7, 123.2, 120.8, 119.4, 117.5, 117.1, 84.9, 80.2,
45.6, 41.1, 35.4, 25.2, 24.4; IR (neat, cm-1) 3052, 2934, 2854,
1709, 1580, 1550, 1487, 1455, 1406, 1376, 1337, 1316, 1291, 1261,
1225, 1169, 1111, 1088, 1032, 987, 954, 910, 883, 849, 801, 776,
758, 736, 704, 646, 579, 549, 513; HRMS (ESI) m/z calcd for
C23H22N2O3 (M þ H) 375.1703, found 375.1707.
5k was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 36.7 mg (50%) of the indicated compound as
a solid after 21 h: mp 104-106 °C; 1H NMR (400 MHz, CDCl3)
δ 7.28-7.32 (m, 2 H), 7.13-7.15 (m, 2 H), 6.95-6.99 (m, 2 H),
6.90 (br, 1 H), 6.73-6.75 (m, 1 H), 5.50 (d, J = 2.0 Hz, 1 H),
4.59-4.63 (m, 2 H), 3.45 (t, J = 7.6 Hz, 1 H), 3.35-3.38 (m, 2
H), 2.26 (s, 3 H), 2.12-2.16 (m, 1 H), 1.83-1.89 (m, 2 H),
1.49-1.63 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 151.8,
150.3, 130.2, 129.8, 129.7, 129.1, 121.5, 119.0, 117.3, 116.7, 82.6,
80.4, 44.1, 40.9, 35.5, 24.9, 24.2, 20.4; IR (neat, cm-1) 3393,
2930, 2856, 1732, 1596, 1550, 1495, 1408, 1376, 1223, 1166, 1122,
1039, 990, 958, 880, 818, 759, 695, 648, 583, 527; HRMS (ESI) m/
z calcd for C20H22N2O3 (M þ H) 339.1703, found 339.1708.
5l was obtained according to the above procedure. The
reaction mixture was chromatographed with 30:1 hexanes/
EtOAc to afford 20 mg (29%) of the indicated compound as
an oil after 22 h: 1H NMR (400 MHz, CDCl3) δ 7.29-7.33 (m, 2
H), 7.19-7.24 (m, 2 H), 6.94-7.05 (m, 3 H), 6.81 (t, J = 7.2 Hz,
1 H), 5.48 (d, J = 1.6 Hz, 1 H), 4.60 (d, J = 7.6 Hz, 2 H), 3.49 (t,
J = 7.6 Hz, 1 H), 3.37-3.43 (m, 2 H), 2.16-2.17 (m, 1 H), 2.14
(s, 3 H), 1.83-1.91 (m, 2 H), 1.59-1.63 (m, 1 H), 1.46-1.54 (m, 1
H); 13C NMR (100 MHz, CDCl3) δ 151.9, 150.6, 130.0, 129.0,
127.0, 126.8, 121.8, 120.4, 119.6, 116.4, 82.9, 80.5, 44.6, 41.0,
35.3, 25.0, 24.1, 15.8; IR (neat, cm-1) 3052, 2924, 2853, 1597,
1551, 1496, 1467, 1408, 1376, 1298, 1261, 1223, 1208, 1170, 1132,
Acknowledgment. We thank the National Science Founda-
tion (NSF-20732002, NSF-20090443, and NSF-20872052) for
financial support.
Supporting Information Available: The detailed experimen-
tal procedure and copies of 1H NMR and 13C NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2902 J. Org. Chem. Vol. 75, No. 9, 2010