Enantioselective synthesis of indole-fused dihydropyranones via catalytic cycloaddition of ketenes and 3-alkylenyloxindoles

Article abstract of DOI:10.1021/jo101318u

Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [4+2] cycloaddition reaction of alkyl(aryl)ketenes and 3-alkylenyloxindoles to give the corresponding 3,4-dihydropyrano[2,3-b]indol-2- ones in excellent yields with good di

Full text of DOI:10.1021/jo101318u

pubs.acs.org/joc
Enantioselective Synthesis of Indole-Fused
Dihydropyranones via Catalytic Cycloaddition of
Ketenes and 3-Alkylenyloxindoles
Hui Lv, Xiang-Yu Chen, Li-hui Sun, and Song Ye*
CAS Key Laboratory of Molecular Recognition and Function,
Beijing National Laboratory for Molecular Sciences, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190,
People’s Republic of China
FIGURE 1. Indole-fused dihydropyranones.
biologically active natural products and pharmaceutical
agents.2 Consequently, great efforts have been devoted to
the synthesis of various fused indoles, and many efficient
approaches have been documented.3 In the meantime, dihydro-
pyranones also present a wide range of biologically active
compounds.4 Thus a hybrid of these two motifs could poten-
tially lead to a series of structurally and biologically interesting
compounds (Figure 1). Although the synthesis and application
of indole-fused pyranones and their derivatives have been
reported sporadically,5 to the best of our knowledge, the direct
asymmetric synthesis of these compounds remains a challenge.
N-Heterocyclic carbenes (NHCs) are useful reagents for
synthesis of heterocyclic compounds,6 excellent ligands for
organometallic catalysts,7 and versatile organocatalysts for
varied reactions.8,9 In this context, we, simultaneously with
songye@iccas.ac.cn
Received July 5, 2010
(5) (a) Bestmann, H. J.; Schmid, G. Tetrahedron Lett. 1984, 25, 1441.
(b) Ohnuma, T.; Kasuya, H.; Kimura, Y.; Ban, Y. Heterocycles 1982, 17, 377.
(c) Amiet, R. G.; Eastwood, F. W.; Rae, I. D. R. Aust. J. Chem. 1972, 25,
1473. (d) Nakagawa, M.; Sodeoka, M.; Yamaguchi, K.; Hino, T. Chem.
Pharm. Bull. 1984, 32, 1373. (e) Fritz, H.; Losacker, P. Justus Liebigs Ann.
Chem. 1967, 709, 135. (f ) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2004, 6,
2849. (g) Kam, T. S.; Tan, S. J.; Ng, S. W.; Komiyama, K. Org. Lett. 2008, 10,
3749. Feldman, K. S.; Vidulova, D. B.; Karatjas, A. D. J. Org. Chem. 2005,
70, 6429. (h) Reh, S.; Bergman, J. Tetrahedron 2005, 61, 3115.
(6) (a) Bourissou, D.; Guerret, O.; Gabbaı, F. P.; Bertrand, G. Chem. Rev.
2000, 100, 39. (b) Cheng, Y.; Meth-Cohn, O. Chem. Rev. 2004, 104, 2507.
(c) Cheng, Y.; Wang, B.; Wang, X.-R.; Zhang, J.-H.; Fang, D.-C. J. Org.
Chem. 2009, 74, 2357. (d) Cheng, Y.; Peng, J. H.; Li, J. Q. J. Org. Chem. 2010,
75, 2382. (e) Cheng, Y.; Liu, M.-F; Fang; Lei, X.-M. Chem.;Eur. J. 2007, 13,
4282. (f ) Ding, H. F.; Zhang, Y. P.; Bian, M.; Yao, W. J.; Ma, C. J. Org.
Chem. 2008, 73, 578. (g) Ma, C.; Yang, Y. W. Org. Lett. 2005, 7, 1343.
(h) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003, 5, 665.
(7) (a) N-Heterocyclic Carbenes in Transition Metal Catalysis; Glorius,
F., Ed.; Topics in Organometallic Chemistry, Vol. 28; Springer-Verlag:
Berlin, 2007. (b) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.;
Wiley-VCH: Weinheim, 2006.
Chiral N-heterocyclic carbenes were found to be efficient
catalysts for the formal [4þ2] cycloaddition reaction of
alkyl(aryl)ketenes and 3-alkylenyloxindoles to give the corre-
sponding 3,4-dihydropyrano[2,3-b]indol-2-ones in excel-
lent yields with good diastereo- and enantioselectivities.
Convenient methods for constructing molecules with two
separate biologically interesting scaffolds that are fused are
of great value for both organic and medicinal chemists.1 The
indole ring is regarded as a privileged structure in many
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893. (b) Gil, C.; Brase, S. J. Comb. Chem. 2009, 11, 175.
(8) For reviews, see: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. (c) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534.
(2) For reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Saki, N.; Annaka,
K.; Fujita, A.; Sato, A. J. Org. Chem. 2008, 73, 4160. (e) Bandini, M.;
Eichholzer, A. Angew. Chem. In. Ed. 2009, 48, 9608.
(9) (a) Ugai, T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63, 296.
( Chem. Abstr. 1951, 45, 5148). (b) Breslow, R. J. Am. Chem. Soc. 1958, 80,
3119. (c) Stetter, H.; Schreckenberg, M. Angew. Chem. 1973, 85, 89. Angew.
Chem., Int. Ed. 1973, 12, 81. (d) Burstein, C.; Glorius, F. Angew. Chem., Int.
Ed. 2004, 43, 6205. (e) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 14370. (f ) Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 9518. (g) Fischer, C.; Smith, S. W.; Powell, D. A.; Fu,
G. C. J. Am. Chem. Soc. 2006, 128, 1472. (h) He, L.; Jian, T.-Y.; Ye, S. J. Org.
Chem. 2007, 72, 7466. (i) Du, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949.
( j) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. Adv. Synth. Catal. 2008, 350,
1258. (k) Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008,
130, 17266. (l) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334.
(m) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740. (n) Vora,
H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2680. (o) Nair, V.; Vellalath, S.;
Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507. (p) Biju, A. T.;
Wurz, N. E.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 5970. (q) Enders, D.;
Henseler, A. Adv. Synth. Catal. 2009, 351. (r) Ye, W.; Cai, G.; Zhuang, Z.;
Jia, X.; Zhai, H. Org. Lett. 2005, 7, 3769. (s) Liu, Y. K.; Li, R.; Yue, L.; Li,
B. J.; Chen, Y. C.; Wu, Y.; Ding, L. S. Org. Lett. 2006, 8, 1521. (t) Sun, X. Y.;
Ye, S. Q.; Wu, J. Eur. J. Org. Chem. 2006, 4787.
(3) For examples, see: (a) Pudlo, M.; Csanyi, D.; Moreau, F.; Riedl, Z.;
Sapi, J. Tetrahedron 2007, 63, 10320. (b) Majumdar, K. C.; Taher, A.; Ponra,
S. Tetrahedron Lett. 2010, 51, 147. (c) Barluenga, J.; Tudela, E.; Ballesteros,
A.; Tomas, M. J. Am. Chem. Soc. 2009, 131, 2096. (d) Singh, V.; Hutait, S.;
Biswas, S.; Batra, S. Eur. J. Org. Chem. 2010, 531. (e) John, J.; Indu, U.;
Suresh, E.; Radhakrishnan, K. V. J. Am. Chem. Soc. 2009, 131, 5042.
(f ) Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920. (g) Li, G. J.;
Wang, E.; Chen, H.; Li, H. F.; Liu, Y. H.; Wang, P. G. Tetrahedron 2008, 64,
9033. (h) Halim, R.; Scammells, P. G.; Flynn, B. Org. Lett. 2008, 10, 1967.
(4) (a) Hamilton, H. W.; Tait, B. D.; Gajda, C.; Hagen, S. E.; Ferguson,
D.; Lunney, E. A.; Pavlovsky, A.; Tummino., P. J. Bioorg. Med. Chem. Lett.
1996, 6, 719. (b) Krishna, P. R.; Srinivas, R. Tetrahedron: Asymmetry 2007,
18, 2197. (c) Narasimhulu, M.; Krishna, A. S.; Rao, J. R.; Venkateswarlu, Y.
ꢀ
Tetrahedron 2009, 15, 2989. (d) Kasaplar, P.; Yilmazer, O.; Cagir, A. Bioorg.
Med. Chem. 2009, 1, 311. (e) Mohapatra, D. K.; Das, P. P.; Reddy, D. S.;
Yadav, J. S. Tetrahedron Lett. 2009, 43, 5941. (f ) Krishna, P. R.; Srinivas, R.
Tetrahedron Lett. 2007, 48, 2013. (g) Das, B.; Laxminarayana, K.; Krishnaiah,
M.; Kumar, D. N. Bioorg. Med. Chem. Lett. 2009, 22, 6396.
DOI: 10.1021/jo101318u
r
Published on Web 09/15/2010
J. Org. Chem. 2010, 75, 6973–6976 6973
2010 American Chemical Society

Lv et al.
JOCNote
SCHEME 1. NHC-Catalyzed Synthesis of Spirocyclic Oxindole-
β-lactones
TABLE 1. Screening of N-Heterocyclic Carbenes
Smith et al.,10 demonstrated that NHCs were efficient cata-
lysts for the [2þ2] and [4þ2] formal cycloaddition of ketenes
with imines, enones, etc., to give the corresponding cycload-
ducts in good yields with excellent enantioselectivties.11,12
Especially, Bode et al. reported an interesting synthesis of
dihydropyranones via the NHC-catalyzed [4þ2] cycloaddi-
tion reaction of oxodienes and R-chloroaldehydes in 2006.13
Later, we successfully developed the NHC-catalyzed [4þ2]
cycloaddition of oxodienes and ketene to give dihydropyra-
nones14-16 and recently the [2þ2] cycloaddition of isatin and
ketenes to give spirocyclic oxindole-β-lactones (Scheme 1).17
Herein we report an NHC-catalyzed formal cycloaddition
of ketenes with alkylenyloxidoles for the direct asymmetric
synthesis of indole-fused dihydropyranones. The reaction
of phenyl(ethyl)ketene 2a with 3-alkylenyloxindole 1a was
investigated as the model reaction (Table 1). It was found
that NHC 4a0, generated freshly from the precursor 4 and
Cs2CO3, could catalyze the reaction of 1a and 2a to give the
corresponding indole-fused dihydropyranone 3aa in 61%
yield with 2:1 ratio of trans/cis-isomer and 38% ee for the
trans-isomer (entry 1).
entry
cat.a
3aa
yield (%)b
trans:cisc
ee (%)d
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
(-)-3aa
(-)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(þ)-3aa
(-)-3aa
(þ)-3aa
61
78
99
91
98
93
90
95
94
86
73
67
2:1
2:1
4:1
4:1
4:1
3:1
3:1
3:1
3:1
2:1
1:1
4:1
38
40
1
71
54
60
60
66
59
15
12
13
9
10
11
12
5a
5b
6
aNHCs 40-60 were generated from their precursors 4-6 (10 mol %) in
the presence of Cs2CO3 (10 mol %) in the noted solvent at room
Then a series of NHC precurors 4b-i,11,18 derived from
L-pyroglutamic acid, were tested as the catalysts. It was found
that the reaction catalyzed by NHC 4b0, with an N-2-iso-
propylphenyl group, gave the product in 78% yield and 40%
ee (entry 2).
b
temperature for 30 min and used immediately. Total yield of the cis-
and trans-isomer. cDetermined by 1H NMR of the reaction mixture.
dDetermined by chiral HPLC. PMP = p-methoxyphenyl, Mes = 2,4,6-
trimethylphenyl.
Recently, we found that the NHCs with a proximal
hydroxyl group show a promising enantioselectivity in the
aza-Morita-Baylis-Hillman reaction and the dimerization
of ketenes.19 Considering the possible H-bonding between
the hydroxyl group of the NHC and the substrate, NHCs
with a proximal free hydroxyl group were tested. NHC 4c0,
with a diphenylmethylhydroxyl group, resulted in excellent
yield but very low and reversed enantioselectvity (entry 3). In
order to increase the H-bond-donating ability of the hydroxyl
group, strong electron-withdrawing substituents were intro-
duced into the diarylmethyl group, which led to NHCs 4d0-g0.
It was found that the reactions catalyzed by these catalysts
gave the desired product in high yields with good enantio-
selectivities (entries 4-7).
As shown in our previous report, an N-bulky group, such
as mesityl, also benefits the reversed enantioselectivities,20 so
NHCs 4h0,i0, with an N-mesityl group, were tested. While
both NHCs 4h0 and 4i0 showed good and reversed ennatio-
selectivities compared to NHC 4a0, it is unexpected that no
better result was observed for the reaction catalyzed by NHC
4i0, which bears a better H-bonding donor group than 4h0
(10) (a) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org.
ꢁ
Biomol. Chem. 2008, 6, 1108. (b) Concellon, C.; Duguet, N.; Smith, A. D.
Adv. Synth. Catal. 2009, 351, 3001.
(11) (a) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008,
10, 277. (b) He, L.; Lv, H.; Zhang, Y.-R.; Ye, S. J. Org. Chem. 200, 73, 8101.
(12) For reviews of catalytic reactions of ketenes, see: (a) Orr, R. K.;
Calter, M. A. Tetrahedron 2003, 59, 3545. (b) Tidwell, T. T. Angew. Chem.,
Int. Ed. 2005, 44, 5778. (c) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(d) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771.
(e) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(13) (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088.
(b) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817.
(14) Evans et al. reported a copper-catalyzed synthesis of dihydropyrone
from silylketene: Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125.
(15) For the pioneering enantioselective [4þ2] cycloaddition of ketenes
catalyzed by cinchona alkaloid, see: (a) Bekele, T.; Shah, M. H.; Wolfer, J.;
Abraham, C. J.; Weatherwax, A.; Lectka, T. J. Am. Chem. Soc. 2006, 128,
1810. (b) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.;
Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370. (c) Wolfer, J.; Bekele, T.;
Abraham, C. J.; Dogo-Isonagie, C.; Lectka, T. Angew. Chem., Int. Ed. 2006,
45, 7398. (d) Alden-Danforth, E.; Scerba, M. T.; Lectka, T. Org. Lett. 2008,
10, 4951.
(16) (a) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.;Eur. J. 2008, 14,
8473. (b) Lv, H.; You, L.; Ye, S. Adv. Synth. Catal. 2009, 351, 2822.
(17) Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth. Catal. 2010, 352,
1892.
(19) (a) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825.
(b) Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal. 2008, 350,
(18) (a) Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367.
(b) Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. Org. Chem. 2009,
74, 9214.
2715.
(20) Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed.
2009, 48, 192.
6974 J. Org. Chem. Vol. 75, No. 20, 2010

Lv et al.
JOCNote
TABLE 2. Optimization of the Reaction Conditionsa
entry
solvent
T
yieldb
trans:cisc
ee (%)d
1
2
3
4
5
6
7
THF
ether
rt
rt
rt
rt
rt
rt
rt
rt
rt
91
93
89
91
65
95
83
86
trace
91
93
88
4:1
5:1
1:1
4:1
6:1
10:1
1:1
6:1
71
78
4
70
86
90
4
DME
toluene
CHCl3
DCM
DMF
DCM
DCM
DCM
DCM
DCM
8e
9f
10
11
12g
79
-20 °C
-60 °C
rt
7:1
5:1
3:1
83
78
57
aNHC precursor 4d (0.03 mmol), Cs2CO3 (0.03 mmol), alkylenylox-
indole 1a (0.3 mmol), and ketene 2a (0.45 mmol) were used. bTotal yields
of the cis- and trans-isomer. Determined by H NMR of the reaction
c
1
f
mixture. dee of trans-(þ)-3aa. etBuOK was used as the base. DBU was
used as the base. g5 mol % of NHC precursor (0.015 mmol) and Cs2CO3
(0.015 mmol) were utilized.
FIGURE 2. Possible catalytic cycle.
TABLE 3. Catalytic Enantioselective Synthesis of 3,4-Dihydropyrano-
[2,3-b]indol-2-ones via NHC-Catalyzed [4þ2] Cycloaddition of 3-Alkyl-
enyloxindoles and Ketenes
to 5 mol % resulted in a descrease in diastereo- and enantios-
electivity (entry 12).
With the optimal reaction conditions in hand, the scope of
the substrate was then investigated (Table 3). While phenyl-
(alkyl)ketenes 2a-d with a linear chain (R = Me, Et, n-Pr, n-
Bu) worked well, the yields and selectivities decreased some-
what when the chain was enlongated (entries 1-4). Although
the yields are very good for reactions of both aryl(alkyl)-
ketenes with electron-donating groups (2e,f: Ar
=
4-MeC6H4, 4-MeOC6H4) and electron-withdrawing groups
(2g,h: Ar = 4-ClC6H4, 4-BrC6H4), the enantioselectivities
decreased somewhat for ketenes 2g,h (entries 5-8). It also
should be noted that ketenes with sterically demanding aryl
groups (2i,j: Ar = 2-chlorophenyl, 2-naphthyl) did not work
for the reaction (entries 9 and 10).23
Other 3-alkylenyloxindoles, such as 1b and 1c, with
5-fluoro and 5-methyl substituents, respectively, also worked
for the reaction. Although good enantioselectivities were
found for both reactions, the diastereoselectivities varied
from a ratio of 3:1 to 10:1(entries 11 and 12).
entry
1
2 (Ar, R)
3
yield (%)a trans:cisb ee (%)c
1
2
3
4
5
6
7
8
1a 2a (Ph, Et)
3aa
3ab
3ac
3ad
3ae
95
97
92
88
92
98
99
97
10:1
8:1
6:1
6:1
6:1
7:1
9:1
6:1
90
83
87
83
88
89
70
69
1a 2b (Ph, Me)
1a 2c (Ph, n-Pr)
1a 2d (Ph, n-Bu)
1a 2e (4-MeC6H4, Et)
1a 2f (4-MeOC6H4, Et) 3af
1a 2g (4-ClC6H4, Et)
1a 2h (4-BrC6H4, Et)
1a 2i (2-ClC6H4, Et)
1a 2j (2-naphthyl, Et)
1b 2a
3ag
3ah
3ai
3aj
3ba
3ca
9
trace
trace
91
10
11
12
3:1
10:1
87
83
The structure and absolute stereochemistry of dihydro-
pyranoindolone (þ)-(3S,4R)-3ag were established by the
X-ray analysis of its crystal.24
1c 2a
92
aTotal yields of the cis- and trans-isomer. bDetermined by 1H NMR of
the reaction mixture. cDetermined by chiral HPLC.
(entries 8 and 9). Other NHCs, such as the tetracyclic NHCs
21
5a0,b0 and bistriazolium NHC 60,22 can also catalyze the
reaction efficiently but with low enantioselectivities (entries
10-12).
The optimization of other reaction conditions is summa-
rized in Table 2. Solvent screening revealed that DCM is the
solvent of choice, in which good yield (95%) and high
diastereoselectivity and enantioselectivity (trans:cis = 10:1,
90% ee) were achieved (entry 6). It was found that the base of
Cs2CO3 led to better results than KOtBu and DBU (entries 8
and 9). Reactions at low temperatures (-20, -60 °C) went
well but showed somewhat low diastereo- and enantioselec-
tivities (entries 10, 11). Reducing the loading of the catalyst
The benzoyl protective group of the cycloadduct 3aa could
be easily removed to give the corresponding indole-fused
dihydropyranone 4aa in good yield (eq 1).
The possible catalytic cycle is depicted in Figure 2. The
addition of NHC to ketenes gives the enolates I, which react
with 3-alkylenyloxindoles via [4þ2] cycloaddition to give
adducts II, followed by fragmentation to furnish the final
dihydropyranoindolones 3 and regenerate the NHC.
(21) Kerr, M. S.; Alaniz, J.; Read de Alaniz, J.; Rovis, T. J. Org. Chem.
2005, 70, 5725.
(22) Ma, Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Liu, J.; Yang, S.; You, J.-S.
Adv. Synth. Catal. 2008, 350, 2645.
(23) Monosubstituted ketenes such as phenylketene and chloromethyl-
ketenes, generated in situ from the corresponding acyl chlorides, did not
work under the current reaction conditions.
(24) See Supporting Information for details.
J. Org. Chem. Vol. 75, No. 20, 2010 6975

Lv et al.
JOCNote
In conclusion, a high enantioselective synthesis of 3,4-
dihydropyrano[2,3-b]indol-2-ones was realized by the chiral
NHC-catalyzed formal [4þ2] cycloaddition of ary(alkyl)-
ketenes and 3-alkylenyloxindoes. The ready availability of
the catalyst, mild reaction condition, and good selectivities
make this direct formal cycloaddition reaction highly poten-
tially useful in the synthesis of the fused indole compounds.
acetate) to give the corresponding 3,4-dihydropyrano[2,3-b]-
indol-2-ones as white solids.
3aa: 133.7 mg (95%), Rf = 0.65 (petroleum ether/ethyl
acetate, 5:1); mp 169 °C; [R]25 þ242.4 (c 0.5, CH2Cl2);
D
1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 1H), 7.62 (d,
J = 7.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.29-7.40 (m, 5H),
7.18-7.28 (m, 4H), 7.11 (d, J = 7.2 Hz, 2H), 4.59 (s, 1H),
4.09-4.24 (m, 2H), 2.20-2.32 (m, 1H), 1.90-2.1 (m, 1H), 1.22
(t, J = 7.2 Hz, 3H), 0.74 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.2, 167.4, 166.6, 143.2, 135.5, 133.8, 133.0, 132.3,
129.4, 128.8, 128.2, 128.1, 126.9, 125.0, 124.2, 124.0 117.3, 114.9,
93.5, 62.0, 52.6, 41.9, 29.6, 14.0, 7.5; IR (KBr) ν 1786, 1734, 1698
cm-1; HRMS (EI) calcd for C29H25NO5 [M]þ 467.1733, found
467.1738. HPLC analysis: 90% ee (trans) [Daicel CHIRALPAK
AD-H column; 20 °C; 1.0 mL/min; solvent system: i-PrOH/
hexanes, 10:90; retention times: 13.9 min (minor), 16.0 min (major)].
Experimental Section
General Procedure for Synthesis of 3,4-Dihydropyrano[2,3-
b]indol-2-ones via NHC-Catalyzed Cycloaddition of Ketenes
and 3-Alkylenyloxindoles. An oven-dried 50 mL Schlenk tube
equipped with a stir bar was charged with the NHC precursor 4d
(22 mg, 0.03 mmol) and Cs2CO3 (9.8 mg, 0.03 mmol). The tube
was closed with a septum, evacuated, and backfilled with argon.
To this mixture was added distilled solvent DCM (2 mL); then
the mixture was stirred for 30 min at room temperature.
3-Alkylenyloxindole 1 (0.3 mmol) and ketene 2 (0.45 mmol)
were added. The reaction mixture was stirred at room tempera-
ture and monitored by TLC until the 3-alkylenyloxindole was
fully consumed. The reaction mixture was passed through a pad
of silica gel and washed with ethyl acetate. Several drops of the
Acknowledgment. Financial support from National Science
Foundation of China (20872143, 20932008), the Ministry of
Science and Technology of China (2009ZX09501-018), and the
Chinese Academy of Sciences is greatly acknowledged.
1
solution were collected and concentrated for the H NMR to
Supporting Information Available: Experimental proce-
dures, compound characterizations (PDF), and crystal structure
data of indolodihydropyranone 3ag (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
determine the ratio of the trans/cis-isomers. The solvent was
removed under reduced pressure, and the residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl
6976 J. Org. Chem. Vol. 75, No. 20, 2010