NHC-catalyzed cascade synthesis of 1-substituted 4-aryl- tetrahydroquinoline-2,5-diones

Article abstract of DOI:10.1016/j.tet.2012.11.052

N-Heterocyclic carbene (NHC)-catalyzed organocascade reactions via redox processes were found to be a simple and flexible procedure for the synthesis of a series of suitably functionalized 1-substituted 4-aryl-tetrahydroquinoline-2, 5-diones. A wide range of potential biologically active quinoline derivatives for biomedical screening were obtained.

Full text of DOI:10.1016/j.tet.2012.11.052

Tetrahedron 69 (2013) 1133e1137
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
NHC-catalyzed cascade synthesis of 1-substituted
4-aryl-tetrahydroquinoline-2,5-diones
,
b
b
b
b
b
Changsheng Yao a , Weihui Jiao , Zhaoxin Xiao , Rui Liu , Tuanjie Li , Chenxia Yu
*
a School of Chemistry and Engineering, Key Laboratory of Biotechnology for Medicinal Plant, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China
b School of Chemistry and Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2012
Received in revised form 14 November 2012
Accepted 16 November 2012
Available online 21 November 2012
N-Heterocyclic carbene (NHC)-catalyzed organocascade reactions via redox processes were found to be
a simple and flexible procedure for the synthesis of a series of suitably functionalized 1-substituted 4-
aryl-tetrahydroquinoline-2,5-diones. A wide range of potential biologically active quinoline derivatives
for biomedical screening were obtained.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbenes
Organocascade reactions
1-Substituted 4-aryl-tetrahydroquinoline-
2,5-diones
Umpolung
Bromoenals
1. Introduction
acylazoliumions formed in the presence of NHC are significantly
effective intermediates. In 2010, Xiao et al. published NHC-cata-
Thequinolonecoreisanindispensablemotifinseveralbiologically
active natural products and their analogues are of great importance in
biochemistry and pharmaceutics.1 Organic chemists paid much at-
tention to studying quinolone derivatives, e.g., substituted
2-quinolones,2 and lots of researches focused on developing 2-
quinolones as anticancers,3 herbicide safeners,4 and antitumor
agents.5 As a result, a great number of 2-quinolones, such as 4-aryl-
quinoline-2(1H)-ones,6 3,4-disubstitutedquinoline-2(1H)-ones,7 and
N-substituted-2-quinolones8 have been successfully synthesized.
Nevertheless, as far as we know, only a few examples of the synthesis
of N-substituted 4-aryl-tetrahydroquinoline-2,5-diones were re-
ported.9 Therefore, developing new approaches to this kind of qui-
nolone are still highly demanded.
lyzed reaction of alkynyl aldehydes with 1,3-ketoesters or 1,3-
diketones (Scheme 1a), in which a,b-unsaturated acylazoliumions
acted as the key intermediate.13 Subsequently, Bode et al. reported
an NHC-catalyzed annulation reaction between conjugated enals
and enamines, in which the key a,b-unsaturated acylazoliumion
intermediate was generated by the reaction of the enal and the NHC
catalyst in the presence of an external oxidant (Scheme 1b).14
Moreover, Ye and our group have independently reported an
NHC-catalyzed redox cyclization of
dinucleophilic reagents. In this reaction, the
lazoliumion intermediate was directly formed from the
moenal and the NHC catalyst without any external oxidant (Scheme
a
-bromoenals with 1,3-
-unsaturated acy-
-bro-
a,b
a
1c), which represented a new redox-neutral pathway for a,b-un-
Over the past decade, organocascade reactions have become an
important field of research in organic, combinatorial, and medicinal
chemistry, due to their advantages of reducing the number of
manual operations, saving time and production costs and so on.10 In
the development of new carbonecarbon and carboneheteroatom
bond-forming cascade reactions, N-heterocyclic carbene (NHC) as
a single organocatalyst has been applied to a large number of
saturated acylazoliumion formation.15 To date, there have been no
reports on the synthetic application of this method to the synthesis
of 1-substituted 4-aryl-tetrahydroquinoline-2,5-diones. This moti-
vated us to develop an NHC-catalyzed cascade approach to these
heterocycles by employing a-bromoenals and enaminones as the
reaction partners via CeC and CeN bond formation (Scheme 1d).
umpolung transformations.11,12 In particular, the
a,b-unsaturated
2. Results and discussion
We initially investigated the reaction between
namic aldehyde (1a) and 5,5-dimethyl-3-(phenylamino)cyclohex-
a-bromocin-
* Corresponding author. Fax: þ86 516 83500365; e-mail addresses: csyao@
xznu.edu.cn, csyao@jsnu.edu.cn, Yao.Changsheng@gmail.com (C. Yao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.052

1134
C. Yao et al. / Tetrahedron 69 (2013) 1133e1137
With the optimized reaction conditions in hand, we turned our
attention to the scope of this reaction with respect to different
enaminones. The results showed that the protocol could be applied
for the enaminones derived from both aryl amines and aliphatic
(a)
amines (Table 2). We then examined different a-bromoenals. The a-
bromoenal bearing either an electron-rich group (e.g., entry 6) or
an electron-deficient aryl group (e.g., entry 14) could participate in
this reaction and afford the desired product in good yield. However,
(b)
this protocol could not be applied to
a
-bromoenal bearing an ali-
phatic
b-substituent (see Table 2, entry 16).
(c)
Table 2
Substrate scope of the NHC-catalyzed annulation
(d)
R1
R2
R3
Product
Yielda [%]
Scheme 1.
Entry
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
CH3
CH3
CH3
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
d
60
64
68
55
70
62
65
63
66
60
71
67
50
48
47
ND
2-enone (2a) catalyzed by a range of NHC precursors AeD. It was
found that the best precatalyst for this transformation was imida-
zolium salt D, which gave the desired tetrahydroquinoline-2,5-
dione product 3a in 45% yield (Table 1, entries 1e4). Next we in-
vestigated the effect of base on this reaction and found that Cs2CO3
was the best among DBU, K2CO3, t-BuOK, and Cs2CO3 (Table 1, en-
tries 4e7). Screening of the solvent showed that was most suited
among others (Table 1, entries 8e10). It was found that a reaction
temperature of 80 ꢀC was most favorable (Table 1, entries 10e13).
Finally, it was worth noting that the use of 1.3 equiv of Cs2CO3 and
0.1 equiv of the precatalyst afforded the best result (Table 1, entries
13e17).
4-MeC6H4
4-ClC6H4
PhCH2
4-BrC6H4
Ph
4-ClC6H4
4-MeOC6H4
Ph
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
Ph
4-MeOC6H4
4-ClC6H4
2-NO2C6H4
2-NO2C6H4
CH3
9
10
11
12
13
14
15
16
Ph
4-MeOC6H4
Ph
Table 1
a
Isolated yield.
Optimization of reaction conditions
A
D
B
C
Our previous communication showed that
hyde could be readilyobtainedthrough the dehydrogenbromination of
-dibromoaldehyde.15b Therefore we attempted to use
-dibro-
moaldehyde as a precursor of -bromoenal in this reaction. The results
a-bromocinnamalde-
a,b
a,b
Entry
Precat. (mol %)
Base (mol %)
Solvent
Temp (ꢀC)
Yielda [%]
a
1
2
3
4
5
6
7
8
A (10)
B (10)
C (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (10)
D (7)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
K2CO3 (130)
DBU (130)
t-BuOK (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (130)
Cs2CO3 (110)
Cs2CO3 (150)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
70
70
70
70
70
70
70
Reflux
70
110
90
50
80
80
80
80
80
ND
ND
ND
45
revealed that the reaction of enaminone with
hyde generated in situ from the corresponding
a
-bromocinnamalde-
a,b-dibromoaldehyde
and Cs2CO3 gave the final products in good yields (Table 3).
Two different postulated mechanistic pathways for the reaction
are suggested for this reaction (Scheme 2). Breslow intermediate F,
20
Trace
Trace
ND
30
50
58
40
60
57
61
generated from the reaction of
a-bromoenal 1 and NHC, was
9
CH3CN
transformed into acylazoliumion E by leaving of the bromide anion.
In this step, the carbonyl carbon atom moved to a higher oxidation
state compared with that of the starting material. Thus this trans-
formation was an NHC-catalyzed internal oxidation, which is sim-
10
11
12
13
14
15
16
17
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
ilar to the reaction of a-halogen substituted aldehyde promoted by
NHC.16 Adduct G is generated by the following reaction of enami-
none 4 with E through a Michael-type 1,4-addition, which fur-
nishes the final product 3 and liberate the NHC catalyst by an
intramolecular acylation reaction.17a,c Alternatively, intermediate G
D (13)
D (10)
D (10)
58
55
a
Isolated yield.

C. Yao et al. / Tetrahedron 69 (2013) 1133e1137
1135
4.1.1. Compound 3a. White solid; mp: 144e145.5 ꢀC (lit.
147e149 ꢀC18); 1H NMR (400 MHz, CDCl3)
7.46e6.96 (m, 10H),
Table 3
NHC-catalyzed reaction of a,b-dibromoaldehydes with enaminones
d
Entry
R1
R2
R3
Product
Yielda [%]
4.50 (d, J¼4 Hz, 1H), 3.10e3.00 (m, 2H), 2.29 (s, 2H), 2.08 (d,
J¼20 Hz, 1H), 2.02 (d, J¼16 Hz, 1H), 1.03 (s, 3H), 0.95 (s, 3H); 13C
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
H
3a
3b
3c
3p
3q
67
70
72
68
70
4-MeC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
NMR (100 MHz, CDCl3) d 195.9, 170.2, 153.1, 141.5, 137.1, 128.8, 126.9,
126.7, 117.6, 50.2, 41.8, 38.4, 33.0, 28.4, 28.2; IR (potassium bromide)
(n
, cmꢁ1): 2931, 1701, 1648, 1617, 1492, 1374, 452; HRMS (ESI) m/z:
calcd for [MþH]þ: C23H24NO2: 346.1807; found: 346.1811.
a
Isolated yield.
4.1.2. Compound 3b. White solid; mp: 127e128 ꢀC; 1H NMR
can be formed by 1,2-addition enaminone 4 to intermediate E,
followed by a Claisen type [3,3]-sigmatropic rearrangement.
(400 MHz, CDCl3)
d
7.30e7.20 (m, 7H), 7.08 (d, J¼8 Hz, 1H), 6.85 (d,
J¼8 Hz, 1H), 4.49 (d, J¼8 Hz, 1H), 3.09e2.99 (m, 2H), 2.40 (s, 3H),
2.29 (s, 2H), 2.10 (d, J¼16 Hz, 1H), 2.03 (d, J¼16 Hz, 1H), 1.03 (s, 3H),
0.96 (s, 3H). IR (potassium bromide) (n
, cmꢁ1): 2884, 1705, 1646,
1613, 1511, 1373, 453; HRMS (ESI) m/z: calcd for [MþH]þ:
C24H26NO2: 360.1964; found: 360.1966.
4.1.3. Compound 3c. White solid; mp: 194e196 ꢀC; 1H NMR
(400 MHz, CDCl3)
7.44e6.89 (m, 9H), 4.50 (t, J¼4 Hz, 1H), 3.04 (d,
J¼8 Hz, 2H), 2.30 (s, 2H), 2.08 (d, J¼20 Hz, 1H), 2.00 (d, J¼16 Hz, 1H),
1.04 (s, 3H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
195.9, 170.2,
152.5,141.2,135.5,134.8,129.9,128.9,127.0,126.6,118.0, 77.4, 77.1, 76.8,
d
d
50.2, 41.9, 38.2, 33.1, 32.9, 28.50, 28.1; IR (potassium bromide) (n,
cmꢁ1):2962,2889,1700,1647,1488,1349,1204,1142,1083,825;HRMS
(ESI) m/z: calcd for [MþH]þ: C23H23ClNO2: 380.1417; found: 380.1417.
4.1.4. Compound 3d. Yellow soil; 1H NMR (400 MHz, CDCl3)
d
7.24e6.90 (m, 10H), 5.37 (d, J¼16 Hz, 1H), 4.58 (d, J¼16 Hz, 1H),
4.44 (d, J¼8 Hz, 1H), 3.08 (dd, J1¼4 Hz, J2¼16 Hz, 1H), 2.90 (dd,
J1¼8 Hz, J2¼16 Hz, 1H), 2.45 (d, J¼16 Hz, 1H), 2.39 (d, J¼20 Hz, 1H),
2.24 (s, 2H), 1.01 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
190.7, 165.2, 147.9, 135.6, 131.7, 123.5, 123.4, 122.2, 121.7, 121.6,
121.3, 113.1, 44.6, 39.5, 34.9, 32.3, 27.49, 26.9, 23.1, 22.8; IR (potas-
sium bromide) (n
, cmꢁ1): 3061, 3029, 2959, 2870, 1694, 1616, 1494,
1452, 1383, 731, 698; HRMS (ESI) m/z: calcd for [MþH]þ:
C24H26NO2: 360.1964; found: 360.1976.
4.1.5. Compound 3e. White solid; mp: 189e189.5 ꢀC; 1H NMR
(400 MHz, DMSO-d6)
Scheme 2. Proposed mechanistic pathway for the cascade reaction.17
d
7.71 (d, J¼8.0 Hz, 2H), 7.35e7.08 (m, 7H),
4.32 (d, J¼4 Hz, 1H), 3.21 (q, J¼8 Hz, 1H), 2.72 (d, J¼16 Hz, 1H), 2.32
(d, J¼16 Hz, 1H), 2.22 (dd, J1¼16 Hz, J2¼20 Hz, 2H), 2.01 (d, J¼16 Hz,
3. Conclusions
1H), 1.00 (s, 3H), 0.95 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 195.1,
169.4, 153.3, 141.6, 136.3, 132.4, 128.7, 126.7, 126.59, 121.6, 115.9,
In this study we have developed a new and flexible organo-
49.5, 32.9, 32.8, 28.4, 27.2; IR (potassium bromide) (
n
, cmꢁ1): 2943,
catalytic cascade reaction between
a-bromo-a,b-unsaturated al-
1706, 1640, 1614, 1486, 1375, 453; HRMS (ESI) m/z: calcd for
[MþH]þ: C23H23BrNO2: 424.0912; found: 424.0917.
dehydes (or -dibromoaldehydes) and enamineones by utilizing
a,b
NHC catalytic system for the synthesis of a family of structurally
closely related quinoline derivatives. This formal [3þ3] reaction
provides a direct and practical method for the construction of
quinoline structure. Further studies on extending the reaction
scope and investigating the reaction mechanism are ongoing.
4.1.6. Compound 3f. White solid; mp: 152e154 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.49e6.92 (m, 7H), 6.82 (d, J¼8 Hz, 2H), 4.45
(d, J¼4 Hz, 1H), 3.77 (s, 3H), 3.08e2.98 (m, 2H), 2.29 (s, 2H), 2.07
(d, J¼20 Hz, 1H), 2.01 (d, J¼16 Hz, 1H); 1.02 (s, 3H), 0.95 (s, 3H); IR
(potassium bromide) (n
, cmꢁ1): 2955, 1696, 1655, 1624, 1510, 1376,
4. Experimental section
453; HRMS (ESI) m/z: calcd for [MþH]þ: C24H26NO3: 376.1913; found:
376.1909.
4.1. General procedure
4.1.7. Compound 3g. White solid; mp: 171e173 ꢀC; 1H NMR
To a round-bottom flask (25 mL) containing a magnetic bar was
(400 MHz, CDCl3)
d
7.43e6.81 (m, 8H), 4.44 (t, J¼4 Hz, 1H), 3.77
added NHC precursor D (34 mg, 0.1 mmol), Cs2CO3 (422 mg, for
dibromoaldehyde, 812 mg of Cs2CO3 was used), and toluene (5 mL).
Adding -bromo- -unsaturated aldehyde/ -dibromoaldehyde
a
,
b-
(s, 3H), 3.01 (d, J¼8 Hz, 2H), 2.30 (s, 2H), 2.06 (d, J¼8 Hz, 1H), 1.99
(d, J¼8 Hz, 1H), 1.03 (s, 3H), 0.96 (s, 3H); IR (potassium bromide)
a
a
,b
a
,b
(n
, cmꢁ1): 2952, 1711, 1621, 1511, 1491, 1377, 452; HRMS (ESI) m/z:
(1.2 mmol) and enamineone (1.0 mmol) after the reaction mixture
was stirred for about 10 min, the reaction system was kept at 80 ꢀC
with stirring until completion (monitored by TLC). After removal of
the solvent under reduced pressure, the crude product was purified
by column chromatography (silica gel, mixtures of ethyl acetate/
petroleum ether, 1:3, v/v).
calcd for [MþH]þ: C24H25ClNO3: 410.1523; found: 410.1521.
4.1.8. Compound 3h. White solid; mp: 167e169 ꢀC; 1H NMR
(400 MHz, CDCl3)
(s, 3H), 3.77 (s, 3H), 3.06e2.97 (m, 2H), 2.29 (s, 2H), 2.08 (d, J¼16 Hz,
1H), 2.03 (d, J¼20 Hz, 1H), 1.03 (s, 3H), 0.95 (s, 3H); IR (potassium
d
7.22e6.81 (m, 8H), 4.43 (d, J¼4 Hz, 1H), 3.84

1136
C. Yao et al. / Tetrahedron 69 (2013) 1133e1137
bromide) (
n
, cmꢁ1): 2996, 2952, 2836, 1706, 1620, 1512, 1465, 1376,
J2¼6.4 Hz, 1H), 3.09e2.98 (m, 2H), 2.44 (t, J¼8 Hz, 2H), 2.26e2.12
(m, 2H), 2.06e1.91 (m, 2H); IR (potassium bromide) (
, cmꢁ1): 2941,
1693, 1643, 1607, 1488, 1369, 1225, 1131, 831, 704; HRMS (ESI) m/z:
calcd for [MþH]þ: C21H19BrNO2: 396.0599; found: 396.0579.
453; HRMS (ESI) m/z: calcd for [MþH]þ: C25H28NO4: 406.2018;
n
found: 406.2019.
4.1.9. Compound 3i. White solid; mp: 132e134 ꢀC (reported
133e135 ꢀC18); 1H NMR (400 MHz, CDCl3)
d 7.48e7.20 (m, 9H), 7.01 (d,
Acknowledgements
J¼4 Hz,1H), 4.51 (d, J¼4 Hz,1H), 3.11e3.00 (m, 2H), 2.43 (t, J¼8 Hz, 2H),
2.24e2.13 (m, 2H), 2.05e1.90 (m, 2H); IR (potassium bromide)
This project was sponsored by Qing Lan Project. We are also
grateful for financial support by NSFC (No. 21242014), A Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions, and the Major Basic Research Project
of the Natural Science Foundation of the Jiangsu Higher Education
Institutions (09KJA430003). We also appreciate Prof. Changsheng
Cao in Jiangsu Normal University for his help on preparation of
catalysts.
(n
, cmꢁ1): 2942,1690,1641,1611,1493,1447,1224,1188, 872, 695; HRMS
(ESI) m/z: calcd for [MþH]þ: C21H20NO2: 318.1494; found: 318.1509.
4.1.10. Compound 3j. White solid; mp: 132e133 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.29e6.94 (m, 9H), 4.50 (d, J¼4 Hz, 1H), 3.83
(s, 3H), 3.09e2.99 (m, 2H), 2.42 (s, 2H), 2.22 (s, 2H), 2.04e1.90 (m,
2H); IR (potassium bromide) (n
, cmꢁ1): 2955, 1709,1636, 1613, 1510,
1379, 1181, 1135; HRMS (ESI) m/z: calcd for [MþH]þ: C22H22NO3:
348.1600; found: 348.1614.
Supplementary data
4.1.11. Compound 3k. White solid; mp: 173e175 ꢀC; 1H NMR
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.11.052.
(400 MHz, CDCl3)
d
7.43e6.93 (m, 9H), 4.50 (d, J¼8 Hz, 1H),
3.09e2.98 (m, 2H), 2.43 (t, J¼8 Hz, 2H), 2.26e2.12 (m, 2H),
2.06e1.90 (m, 2H); IR (potassium bromide) (n
, cmꢁ1): 2944, 1692,
References and notes
1642, 1608, 1490, 1379, 452; HRMS (ESI) m/z: calcd for [MþH]þ:
C
21H19ClNO2: 352.1104; found: 352.1103.
1. (a) Sunassee, S. N.; Davies-Coleman, M. T. Nat. Prod. Rep. 2012, 29, 513e535; (b)
Jacoby, G. A.; Hooper, D. C. In Review of the Quinolone Family Antibiotic Discovery
and Development; Dougherty, T. J., Pucci, M. J., Eds.; Springer: US, 2012;
pp 119e146; (c) Denton, T. T.; Zhang, X. D.; Cashman, J. R. J. Med. Chem. 2005, 48,
224e239; (d) Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.; Asano,
M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47,
2853e2863; (e) Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y. Bioorg. Med. Chem. Lett.
2004, 14, 1193e1196; (f) Ryckebusch, A.; Deprez-Poulain, R.; Maes, L.; Debreu-
Fontaine, M. A.; Mouray, E.; Grellier, P.; Sergheraert, C. J. Med. Chem. 2003, 46,
542e557.
4.1.12. Compound 3l. White solid; mp: 167e169 ꢀC; 1H NMR
(400 MHz, DMSO-d6)
d
7.18e6.87 (m, 8H), 4.23 (d, J¼4 Hz, 1H), 3.79
(s, 3H), 3.72 (s, 3H), 3.10 (dd, J1¼8 Hz, J2¼16 Hz, 1H), 2.66 (d,
J¼16 Hz,1H), 2.37e2.23 (m, 3H), 2.12 (d, J¼16 Hz,1H),1.99e1.90 (m,
2H); IR (potassium bromide) (n
, cmꢁ1): 2971, 1702, 1644, 1617, 1512,
1375, 1251, 1177, 833, 450; HRMS (ESI) m/z: calcd for [MþH]þ:
2. (a) Kumar, N.; Raj, V. P.; Jayshree, B. S.; Kar, S. S.; Anandam, A.; Thomas, S.; Jain,
P.; Rai, A.; Rao, C. M. Chem. Biol. Drug Des. 2012, 80, 291e299; (b) Al-Amiery, A.;
Al-Bayati, R.; Saour, K.; Radi, M. Res. Chem. Intermed. 2012, 38, 559e569; (c) He,
F.; Liu, Z.; Yang, J.; Fu, P.; Peng, J.; Zhu, W. M.; Qi, S. H. Tetrahedron Lett. 2012, 53,
2280e2283.
C
23H24NO4: 378.1705; found: 378.1720.
4.1.13. Compound 3m. White solid; mp: 126e128 ꢀC; 1H NMR
(400 MHz, CDCl3)
7.46e6.91 (m, 9H), 4.47 (d, J¼4 Hz, 1H),
3.09e2.98 (m, 2H), 2.30 (s, 2H), 2.04 (d, J¼1.2 Hz, 2H), 1.03 (s, 3H),
d
~
€
3. (a) Ferrer, P.; Avendano, C.; Sollhuber, M. Liebigs Ann. 1995, 1895e1899; (b) van
Cutsem, E.; van de Velde, H.; Karasek, P.; Oettle, H.; Vervenne, W. L.; Szaw-
lowski, A.; Schoffski, P.; Post, S.; Verslype, C.; Neumann, H.; Safran, H.; Humblet,
Y.; Ruixo, J. P.; Ma, Y.; von Hoff, D. J. Clin. Oncol. 2004, 22, 1430e1438.
4. Wolfgang, G.; Hermann, B.; Christopher, R.; Thomas, K. DE Patent 19 727 410,
1999.
0.94 (s, 3H); IR (potassium bromide) (n
, cmꢁ1): 2955, 1693, 1657,
1626, 1492, 1374, 746, 696, 590; HRMS (ESI) m/z: calcd for [MþH]þ:
C
23H23ClNO2: 380.1417; found: 380.1400.
5. (a) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller, P.;
Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479e486; (b) Andresen, B. M.;
Couturier, M.; Cronin, B.; D’Occhio, M.; Ewing, M. D.; Guinn, M.; Hawkins, J. M.;
Jasys, V. J.; LaGreca, S. D.; Lyssikatos, J. P.; Moraski, G.; Ng, K.; Raggon, J. W.;
Stewart, A. M.; Tickner, D. L.; Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. L. Org.
Process Res. Dev. 2004, 8, 643e650.
6. (a) Sit, S. Y.; Meanwell, N. A. U.S. Patent 5,892,045, 1999; (b) Hewawasam, P.;
Starrett, J. E., Jr.; Swartz, S. G. U.S. Patent 5,972,961, 1999; (c) Hewawasam, P.;
Starrett, J. E., Jr. U.S. Patent 6,184,231, 2001.
7. (a) Sharma, M.; Gupta, V. B. Pharmaceuticals 2010, 3, 3167e3185; (b) Glasnov, T.
N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864e3870; (c) Carling,
R. W.; Leeson, P. D.; Moore, K. W.; Moyes, C. R.; Duncton, M.; Hudson, M. L.;
Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Tricklebank,
M. D.; Saywell, K. L. J. Med. Chem. 1997, 40, 754e765.
4.1.14. Compound 3n. White solid; mp: 226e227 ꢀC; 1H NMR
(400 MHz, CDCl3)
7.96e7.18 (m, 9H), 4.99 (d, J¼8 Hz, 1H), 3.23 (dd,
J1¼12 Hz, J2¼16 Hz, 1H), 3.09 (dd, J1¼4 Hz, J2¼20 Hz, 1H), 2.29e2.08
(m, 4H), 1.04 (s, 3H), 1.00 (s, 3H); IR (potassium bromide) (
, cmꢁ1):
d
n
3067, 3038, 2958, 2888, 1704, 1658, 1627, 1593, 1530, 1376, 1296,
1212, 785, 740, 694; HRMS (ESI) m/z: calcd for [MꢁH]ꢁ:
C
23H21N2O4: 389.1501; found: 389.1496.
4.1.15. Compound 3o. White solid; mp: 206e208 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.96e7.01 (m, 8H), 4.98 (d, J¼8 Hz, 1H), 3.87 (s,
8. (a) Hammouda, M.; Mashaly, M. M.; Afsah, E. M. Pharmazie 1994, 49, 365e366;
(b) Assy, M. G.; Abd-El Motti, F. M. Egypt. J. Chem. 1996, 39, 581e586; (c) Assy,
M. G.; Abd-Ell, M. F. M. Indian J. Chem., Sect. B 1996, 35, 608e610; (d) Assy, M.
3H), 3.22 (dd, J1¼8 Hz, J2¼16 Hz, 1H), 3.09 (dd, J1¼4 Hz, J2¼20 Hz,
1H), 2.28e2.10 (m, 4H), 1.05 (s, 3H), 1.01 (s, 3H); IR (potassium
bromide) (n
, cmꢁ1): 3381, 3067, 2961, 2932, 1705, 1656, 1624, 1514,
ꢀ
G.; Fikry, R. M.; Aouf, N. H. J. Indian Chem. Soc. 1997, 74, 152e153; (e) Dahlen, E.;
1417, 1375, 1341, 1250, 826, 746; HRMS (ESI) m/z: calcd for [MꢁH]ꢁ:
Andersson, M.; Dawe, K.; Tellander, A. C.; Brunmark, C.; Bjork, A.; Hedlund, G.
Autoimmunity 2000, 32, 199e211.
C
24H23N2O5: 419.1607; found: 419.1610.
9. (a) Wang, X. S.; Zhang, M. M.; Jiang, H.; Yao, C. S.; Tu, S. J. Tetrahedron 2007, 63,
4439e4449; (b) Tu, S. J.; Zhu, X. T.; Zhang, J. P.; Xu, J. N.; Zhang, Y.; Wang, Q.; Jia,
R. H.; Jiang, B.; Zhang, J. Y.; Yao, C. S. Bioorg. Med. Chem. Lett. 2006, 16,
2925e2928; (c) Berrino, R.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Org. Chem.
2012, 77, 2537e2542; (d) Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69,
6772e6780.
10. (a) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365e2379; (b)
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167e178.
11. (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606e5655; (b)
Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691e2698; (c) Moore,
J. L.; Rovis, T. Top. Curr. Chem. 2010, 291, 77e144; (d) Cohen, D. T.; Scheidt, K. A.
Chem. Sci. 2012, 3, 53e57.
4.1.16. Compound 3p. White solid; mp: 141e142 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.51e7.16 (m, 9H), 4.53 (d, J¼4 Hz, 1H),
3.15e3.03 (m, 2H), 2.32 (dd, J1¼16 Hz, J2¼20 Hz, 2H), 2.04 (d,
J¼20 Hz, 1H), 1.88 (d, J¼20 Hz, 1H), 1.02 (s, 3H), 0.97 (s, 3H); IR
(potassium bromide) (n
, cmꢁ1): 2957, 1699, 1646, 1476, 1375, 1201,
1141, 754, 701; HRMS (ESI) m/z: calcd for [MþH]þ: C23H23ClNO2:
380.1417; found: 380.1414.
12. Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314e325.
13. Zhu, Z. Q.; Xiao, J. C. Adv. Synth. Catal. 2010, 352, 2455e2458.
14. Wanner, B.; Mahatthananchai, J.; Bode, J. W. Org. Lett. 2011, 13, 5378e5381.
4.1.17. Compound 3q. White solid; mp: 187e188 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
7.59e6.87 (m, 9H), 4.50 (dd, J1¼2.8 Hz,

C. Yao et al. / Tetrahedron 69 (2013) 1133e1137
1137
15. (a) Sun, F. G.; Sun, L. H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134e3138; (b) Yao,
C. S.; Wang, D. L.; Lu, J.; Li, T. J.; Jiao, W. H.; Yu, C. X. Chem.dEur. J. 2012, 18,
1914e1917.
16. For selected examples of NHC-catalyzed redox reactions, see: (a) Reynolds,
N. T.; Read de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518e9519;
(b) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860e2861; (c) Ling, K.
B.; Smith, A. D. Chem. Commun. 2011, 373e375; (d) For recent review, see:
Rong, Z. Q.; Zhang, W.; Yang, G. Q.; You, S. L. Curr. Org. Chem. 2011, 15,
3077e3090.
17. (a) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266e9269; (b) Ryan,
S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176e14177; (c)
Samanta, R. C.; Maji, B.; De Sarkar, S.; Bergander, K.; Froehlich, R.; Muck-Lich-
tenfeld, C.; Mayr, H.; Studer, A. Angew. Chem., Int. Ed. 2012, 51, 5234e5238.
18. Strozhev, M. F.; Lielbriedis, I. Khim. Geterotsikl. Soedin. 1990, 7, 947e949.