N -heterocyclic carbene (NHC)-catalyzed highly diastereo- and enantioselective oxo-Diels-Alder reactions for synthesis of fused pyrano[2,3- b ]indoles

Article abstract of DOI:10.1021/ol301175z

A chiral N-heterocyclic carbene (NHC)-catalyzed Diels-Alder reaction of 2-oxoindolin-3-ylidenes and α-chloroaldehydes was developed for the synthesis of fused pyrano[2,3-b]indoles in good to excellent yields (up to 99%) with high cis-diastereoselectivities (>99:1 dr) and enantioselectivities (up to >99% ee).

Full text of DOI:10.1021/ol301175z

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2894–2897
N-Heterocyclic Carbene (NHC)-Catalyzed
Highly Diastereo- and Enantioselective
Oxo-DielsꢀAlder Reactions for Synthesis
of Fused Pyrano[2,3-b]indoles
Limin Yang,†,‡ Fei Wang,†,‡ Pei Juan Chua,‡ Yunbo Lv,‡ Liang-Jun Zhong,† and
Guofu Zhong*,†
College of Materials, Chemistry & Chemical Engineering and School of Medicine,
Hangzhou Normal University, Hangzhou 310036, China, and Division of Chemistry and
Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological University, 21 Nanyang Link, Singapore 637371, Singapore
zgf@hznu.edu.cn
Received April 30, 2012
ABSTRACT
A chiral N-heterocyclic carbene (NHC)-catalyzed DielsꢀAlder reaction of 2-oxoindolin-3-ylidenes and R-chloroaldehydes was developed for the
synthesis of fused pyrano[2,3-b]indoles in good to excellent yields (up to 99%) with high cis-diastereoselectivities (>99:1 dr) and
enantioselectivities (up to >99% ee).
The unique electronic characteristics of N-heterocyclic
carbenes (NHCs) not only promote development of new
organometallic processes1 but also allow them to act as
catalysts in organocatalytic reactions.2 The NHC-cata-
lyzed DielsꢀAlder reaction,3 an important milestone in
NHC organocatalysis, is different from the traditional
a1-d1 umpolung (benzoin condensation4 and Stetter reaction5)
and a3-d3 umpolung (homoenolate cycloaddition) approaches.6
Veryrecently, we disclosed a chiralNHC-catalyzedhetero-
DielsꢀAlder reaction of oxodiazene and in situ generated
enolate species from R-chloroaldehydes for the synthesis of
highly enantioselective R-amino acid derivatives.7 Our on-
going interest in the NHC-catalyzed hetero-DielsꢀAlder
† Hangzhou Normal University.
‡ Nanyang Technological University.
(1) For reviews on NHC as ligands, see: (a) Bourissou, D.; Guerret,
O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39–91. (b)
Herrmann, W. A.; Weskamp, T.; Bohm, V. P. W. Adv. Organomet.
Chem. 2001, 48, 1–69. (c) Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
41, 1290–1309. (d) Scott, N. M.; Nolan, S. P. Eur. J. Inorg. Chem. 2005,
44, 1815–1828.
(4) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. (b)
Sheehan, J.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666–
3667. (c) Enders, D.; Breuer, K. Comprehensive Asymmetric Catalysis;
Springer-Verlag: Heidelberg, Germany, 1999; Vol. 3, pp 1093ꢀ1102.
(5) (a) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639–647. (b)
Enders, D. Stereoselective Synthesis; Springer-Verlag: Heidelberg,
Germany, 1993; pp 63ꢀ90. (c) Enders, D.; Breuer, K.; Runsink, J.; Teles,
J. H. Helv. Chim. Acta 1996, 79, 1899–1902.
(2) For reviews on NHC as organocatalysts, see: (a) Seebach, D.
Angew. Chem., Int. Ed. 1979, 18, 239–258. (b) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606–5655. (c) Moore, J. L.; Rovis,
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T. Top. Curr. Chem. 2010, 291, 77–144. (d) Marion, N.; Dıez-Gonzalez,
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S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000.
(3) For references of NHC-catalyzed DielsꢀAlder reactions, see: (a)
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418–
8420. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088–15089. (c) Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett.
2008, 10, 957–960. (d) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008,
10, 3817–3820.
(6) (a) Yang, L.; Tan, B.; Wang, F.; Zhong, G. J. Org. Chem. 2009,
74, 1744–1746. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 14370–14371. (c) Burstein, C.; Glorius, F. Angew. Chem.,
Int. Ed. 2004, 43, 6205–6208. (d) He, M.; Bode, J. W. Org. Lett. 2005, 7,
3131–3134. (e) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
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Chem. Soc. 2008, 130, 2416–2417.
r
10.1021/ol301175z
Published on Web 05/18/2012
2012 American Chemical Society

reaction8 of in situ generated enolate species prompted us
to investigate the cycloaddition with R,β-unsaturated
amide to afford dihydropyranone moieties, which are
important building blocks in the synthesis of natural
products, and biologically active compounds.9
The synthesis of an R,β-unsaturated amide could be
classically carried out from commercially available isatins.
Presumably, activation of the isatin C3ꢀO double bond
via a simple one-step WittigꢀHorner reaction results in the
formation of 2-oxoindolin-3-ylidenes in excellent yields.
Moreover, this strategy being based on the annulation of
indoles opens up a new avenue for the synthesis of fused
pyran[2,3-b]indole skeletons, one of the most important
heterocycles and key structural units of biologically active
alkaloids.10 Although significant advances have been
achieved in the development of these derivatives for the
synthesis of biologically important compounds,11 enantio-
selective variants are still very limited.
cis-enolates are thermodynamically more stable than
the trans forms by approximately 3.9ꢀ6.5 kcal/mol.7
In the active cis-enolate, the N-substituted group is
prone to be “trans” to the oxo group and this mode is
reinforced by the presence of the bulky triazolium moiety.
The stereochemistry of 2-oxoindolin-3-ylidenes in this
[4 þ 2] cycloaddition reaction proved to exhibit an
(E)-configuration.14 The cis-diastereoselectivity would
arise from a cis-enolate reacting as the dienophile with
(E)-2-oxoindolin-3-ylidenes via an endo-transition state.
In this transition state mode, the re-face is completely
blocked by the indane moiety of the carbene catalyst,
leaving the si-face more accessible for the [4 þ 2] cycload-
dition withthe 2-oxoindolin-3-ylidene substrate(Figure1).
A study that was carried out by Ye and co-workers
presented a formal [4 þ 2] cycloaddition of ketenes with
oxindoles yielding indole-fused dihydropyranones.12
However, the diastereo- and enantioselectivities obtained
were quite unsatisfactory.
To address the challenge of achieving high optical
purity, N-mesityl-substituted triazolium salt13 (refer to
cat.) was chosen as the catalyst for this reaction and
racemic R-chloroaldehyde 1 was used as the dienophile
precursor to generate in situ the enolate species from
elimination of HCl from the NHC-R-chloroaldehyde ad-
duct. We envisioned that excellent diastereoselectivities
and absolute stereochemistries can be rationalized due to
the highly preferred endo-cis-transition state. The hypoth-
esis was based on DFT calculations that determined that
Figure 1. Proposed transtion state.
To test the concept, we carried out the reaction using 2.0
equiv of R-chloroaldehyde 2a and 3-alkylenyloxindole 1a
with N-mesityl-substituted triazolium salt in the presence
of base. The results were summarized in Table 1. As
expected, 20 mol % of N-mesityl substituted triazolium
salt effectively promoted the reaction in the presence of
Et3N in dichloromethane at room temperature and deliv-
ered the desired product with excellent diastereo- and
enantioselectivity (Table 1, entry 1). Next, the use of
different basesand solvents wasevaluated for thisreaction.
DIPEA was found to slightly decrease the enantioselec-
tivity (entry 2). When DBU was employed, the yield
decreased dramatically even though there was no loss in
diastereo- and enantioselectivity (entry 3). We observed
that the inorganic bases were deemed to be unsuitable for
the reaction, as they led to lowered yields and enantio-
selectivities (entries 4 and 5).
The screening of solvents revealed that toluene was the
most ideal (entry 12), while ethyl acetate gave the worst
result with a 65% yield, 85% ee, and uncompromised
diastereoselectivity (entry 6). n-Hexane afforded compar-
able results to that of toluene with a prolonged reaction
time (18 h, entry 10). When the catalyst loading was
lowered to 10 mol %, similar results were obtained, albeit
with a longer reaction time (entry 13). However, when the
catalyst loading was further decreased to 5 mol %, a
prolonged reaction time (18 h) was required and it resulted
(7) For a computational study regarding NHC-catalyzed oxo-
DielsꢀAlder reaction, see: (a) Kaeobamrung, J.; Kozlowski, M. C.;
Bode, J. W. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20661–20665. (b)
Yang, L.; Wang, F.; Lee, R.; Lv, Y.; Huang, K.-W.; Zhong, G.
Submitted.
(8) Other approaches to NHC-catalyzed oxo-DielsꢀAlder reactions:
(a) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.;Eur. J. 2008, 14,
8473–8476. (b) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu,
I. Org. Lett. 2009, 11, 3934–3937. (c) Fang, X.; Chen, X.; Chi, Y. R. Org.
Lett. 2011, 13, 4708–4711. (d) Ling, K. B.; Smith, A. D. Chem. Commun.
2011, 47, 373–375.
(9) (a) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D. N.
Bioorg. Med. Chem. Lett. 2009, 22, 6396–6398. (b) Kasaplar, P.;
Yilmazer, O.; Cagir, A. Bioorg. Med. Chem. 2009, 1, 311–314. (c)
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, 719–724.
(10) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach, 2nd ed.; Wiley: New York, 2002; pp 189200. (b) Gataullin,
R. R. J. Org. Chem. 2008, 45, 321–354.
(11) (a) Ohnuma, T.; Kasuya, H.; Kimura, Y.; Ban, Y. Heterocycles
1982, 17, 377–380. (b) Nakagawa, M.; Sodeoka, M.; Yamaguchi, K.;
Hino, T. Chem. Pharm. Bull. 1984, 32, 1373–1384. (c) Fritz, H.;
Losacker, P. Justus Liebigs Ann. Chem. 1967, 709, 135–150. (d) Feldman,
K. S.; Karatjas, A. G. Org. Lett. 2004, 6, 2849–2852. (e) Kam, T. S.; Tan,
S. J.; Ng, S. W.; Komiyama, K. Org. Lett. 2008, 10, 3749–3752. (f) Reh,
S.; Bergman, J. Tetrahedron 2005, 61, 3115–3123.
(12) Lv, H.; Chen, X.-Y.; Sun, L.-H.; Ye, S. J. Org. Chem. 2010, 75,
6973–6976.
(13) (a) For review of the chemistry of N-mesityl catalysts, see:
Chiang, P.-C.; Bode, J. W. TCI MAIL 2011, 149, 2–17. (b) For their
syntheses, see: Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362–376.
(c) For mechanistic studies, see: Mahatthananchai, J.; Bode, J. W. Chem.
Sci. 2012, 3, 192–197.
(14) (a) Long, D. R.; Richards, C. G.; Ross, M. S. F. J. Hetereocycl.
Chem. 1978, 15, 633–636. (b) Autrey, R. L.; Tahk, F. C. Tetrahedron
1967, 23, 901–917. (c) Jones, G.; Rae, W. J. Tetrahedron 1966, 22, 3021–
3026.
Org. Lett., Vol. 14, No. 11, 2012
2895

in a slight decrease in both yield and ee (entry 14). So a
10 mol % catalyst loading was chosen for this reaction.
Lowering of the reaction temperature led to a longer
reaction time (10 h) and unsatisfactory results (entry 15).
When the reaction was performed at 30 °C, the reaction
was completed within 10 min, but with a lower yield,
possibly due to the decomposition of R-chloroaldehyde
(Table 1, entry 16). It is particularly noteworthy that, in all
cases, the diastereoselectivity of the reaction was excellent
(>99:1 dr).
Table 2. Substrate Scope of NHC-Catalyzed [4 þ 2] Cycload-
ditiona
t
yield
(%)b
ee
entry
R1 (1)
C6H5 (1a)
(h)
(%)c
drd
Table 1. Optimization of Reaction Conditionsa
1
2
3
4
5
6
7
8
0.6
0.5
14
6
82 (3a)
87 (3b)
70 (3c)
82 (3d)
90 (3e)
92 (3f)
72 (3g)
93 (3h)
97
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4-BrBnOC2H4 (1b)
TBSOC2H4 (1c)
C3H7 (1d)
98
95
98
CH3 (1e)
0.5
0.3
1
>99
>99
82
BnOC2H4 (1f)
BnO (1g)
C6H13 (1h)
0.3
99
a Reaction was performed in 0.2 mmol scale in anhydrous toluene
(2 mL) at rt. b Yields of isolated products. c ee values determined by
HPLC analysis on Chiralcel IA, IB, or IC column (see the Supporting
Information). d dr values determined by 1H NMR.
t
yield
(%)b
ee
(%)c
entry
solvent
base
(h)
drd
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EA
Et3N
6.5
7
64
60
20
43
50
65
80
67
73
80
90
86
90
83
88
85
87
85
94
96
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
very well tolerated with 5-(benzyloxy)-2-chloropentanal
in which optically pure products were obtained quantita-
tively within 30 min (Table 2, entry 6).
DIPEA
DBU
3
5
4
Cs2CO3
t-BuOK
Et3N
3
5
1.5
0.3
4
A wide range of 2-oxoindolin-3-ylidenes was also tested
using 5-(benzyloxy)-2-chloropentanal under the optimized
conditions (Table 3). In most cases, the reactions were
completed within 30 min except in the case of the non-
protected 2-oxoindolin-3-ylidene. Different N-protecting
groups were also investigated in the reaction. The non-
protected counterpart was well tolerated in the reaction,
affording excellent enantio- and diastereoselectivity despite
6
7
Et2O
Et3N
8
THF
Et3N
1
9
CHCl3
n-
Et3N
0.5
18
10
Et3N
hexane
PhCl
11
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
3
60
82
82
75
70
60
87
97
97
92
95
95
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
12
toluene
toluene
toluene
toluene
toluene
0.5
0.6
18
10
0.2
13e
14f
15g
16h
Table 3. Substrate Scope of NHC-Catalyzed [4 þ 2] Cycload-
ditiona
a Unless otherwise specified, the reaction was performed on a
0.2 mmol scale in solvent (2 mL) at rt. b Yields of isolated products. c ee
values determined by HPLC analysis on Chiralcel IA, IB, or IC column
(see the Supporting Information). d dr values determined by 1H NMR.
e Used 10 mol % of catalyst and 1.1 equiv of Et3N. f 5 mol % of catalyst
used. g Performed at 0 °C. h Performed at 30 °C.
With the optimal reaction conditions established, the
scope of this [4 þ 2] cycloaddition was investigated (Tables 2
and 3). The reaction proceeded smoothly for a broad
spectrum of R-chloroaldehydes to afford the desired prod-
ucts in good yields and excellent optical purity (Table 2),
with the exception of 3-(benzyloxy)-2-chloropropanal
(entry 7). The lower enantioselectivity of 3g was presum-
ably due to the easier formation of trans-enolate species by
using 3-(benzyloxy)-2-chloropropanal than other R-chloro-
aldehydes. In general, R-chloroaldehydes derived from
linear aliphatic aldehydes favor the [4 þ 2] cycloaddition
reaction with 3-alkylenyloxindole 2a to deliver good
results (Table 2, entries 4, 5, and 8). The reaction was also
t
yield
(%)a
ee
entry
R2, R3
(h)
(%)a
dra
1
2
3
4
5
6
7
8
Ac, CO2Et (2b)
Ac, CO2Me (2c)
Ac, COMe (2d)
H, CO2Et (2e)
Ac, CO2Bn (2f)
Bz, CO2Et (2g)
Boc, CO2Et (2h)
Ts, CO2Et (2i)
0.3
0.5
0.3
5
95 (3i)
86 (3j)
75 (3k)
61 (3l)
78 (3m)
84 (3n)
99 (3o)
71 (3p)
96
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98
97
>99
97
0.5
0.2
0.2
0.2
98
>99
99
a See corresponding column footnote in Table 2.
2896
Org. Lett., Vol. 14, No. 11, 2012

the lower yield and longer reaction time needed (Table 3,
entry 4). The N-Boc-protected 2-oxoindolin-3-ylidene
gave the best result, affording the corresponding optically
pure product with quantitative yield.
Scheme 1. Proposed Mechanism
acylation completes the catalytic cycle and releases the
enantioenriched pyran[2,3-b]indole and regenerates the
NHC catalyst.
In conclusion, a chiral NHC-catalyzed DielsꢀAlder
reaction of 2-oxoindolin-3-ylidenes and R-chloroalde-
hydes was developed for the synthesis of fused 3,4-
dihydropyrano[2,3-b]indol-2(9H)-ones in good to excel-
lent yields (up to 99%) with high cis-diastereoselectivities
(>99:1 dr) and enantioselectivities (up to 99% ee). This
protocol holds great potential in the synthesis of biologi-
cally active fused pyrano[2,3-b]indole derivatives in high
enantiomeric purity.
Figure 2. X-ray crystal structure of 3b. Thermal ellipsoids were
shown at 50% probability.
To determine the stereochemistry of the 3,4-dihydro-
pyrano[2,3-b]indol-2(9H)-one obtained from the chiral
NHC-catalyzed [4 þ 2] cycloaddition of R-chloroalde-
hydes with 2-oxoindolin-3-ylidenes, the X-ray crystallo-
graphic analysis of the product 3b was performed to
provide the absolute configuration (Figure 2). The chiral
cis-N-mesityl substituted triazolium salt prepared from
(1S,2R)-(þ)-cis-1-aminoindan-2-ol afforded exclusively the
cis-(3R,4S)-3,4-dihydropyrano[2,3-b]indol-2(9H)-one 3b.
Our proposed pathway of this [4 þ 2] cycloaddition
reaction (Scheme 1) first involves the nucleophilic addition
of an NHC organocatalyst to an R-chloroaldehyde afford-
ing adduct I. It is followed by elimination of hydrogen
chloride to provide enolate species II. The enolate species
then participates in the [4 þ 2] cycloaddition with
2-oxoindolin-3-ylidene to give adduct III. Subsequent
Acknowledgment. We are thankful for financial sup-
port for this work provided by the Hangzhou Normal
University and the MOE in Singapore (ARC 12/07
#T206B3225).
Supporting Information Available. Experimental de-
tails and characterization of new compounds. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2897