Highly stereoselective synthesis of 1,2,3-trisubstituted indanes via oxidative N-heterocyclic carbene-catalyzed cascades

Article abstract of DOI:10.1021/ol202108a

Three stereocenters are formed in the carbene catalyzed cascade reaction of enals with various β-diketones to give the corresponding indane derivatives with excellent stereoselectivities. The products are readily transformed to the corresponding 1,2,3-tri

Full text of DOI:10.1021/ol202108a

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4966–4969
Highly Stereoselective Synthesis
of 1,2,3-Trisubstituted Indanes
via Oxidative N-Heterocyclic
Carbene-Catalyzed Cascades
€
Anup Biswas, Suman De Sarkar, Roland Frohlich, and Armido Studer*
Organisch-Chemisches Institut, NRW Graduate School of Chemistry,
University of Mu€nster, Corrensstrasse 40, 48149 Mu€nster, Germany
studer@uni-muenster.de
Received August 3, 2011
ABSTRACT
Three stereocenters are formed in the carbene catalyzed cascade reaction of enals with various β-diketones to give the corresponding indane
derivatives with excellent stereoselectivities. The products are readily transformed to the corresponding 1,2,3-trisubstituted indane derivatives,
which represent privileged substructures in medicinal chemistry.
Indenes1 and indanes2 have found widespread appli-
cation as biologically important substructures in med-
icinal chemistry. Despite the high importance of these
substance classes, surprisingly only few methods for
their stereoselective synthesis have been reported.3,4
Herein, we disclose a new approach to the synthesis
of highly enantioenriched 1,2,3-trisubstituted indanes
via oxidative NHC-catalysis (NHC = N-heterocyclic
carbene).5
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r
10.1021/ol202108a
Published on Web 08/24/2011
2011 American Chemical Society

We recently showed that Breslow intermediates, readily
generated by reaction of aldehydes with an NHC,5 can be
oxidized with mild organic oxidants to acylazolium ions,
which react with various O-nucleophiles to the corre-
sponding esters.6ꢀ8 Furthermore, we published that R,β-
unsaturated acylazolium ions, generated by NHC-cata-
lyzed redox activation of enals 1 using oxidant 3, react as
Michael acceptors with β-diketones or β-ketoesters to give
dihydropyranones 2 in good to excellent yields under mild
conditions (Scheme 1, eq 1).9ꢀ11
Table 1. Reaction of enal 3a with 4a under various conditions
Scheme 1. NHC-Catalyzed Oxidative Cascade Reactions
solvent
(time h)
yield
(%)
eeb
entry NHC
base (equiv)
dra5a:5a’ (%)
1
A
A
B
B
B
B
B
B
B
B
C
THF (15)
THF (3)
THF (3)
THF (3)
THF (12)
Et3N (1.2)
DBU (1.1)
DBU (1.1)
DBU (0.3)
Et3N (0.3)
10
30
40
38
30
74
62
1:1
2
<1:99
3
<1:99
<1:99
1:1
89
89
4
5
>99
>99
>99
6
PhMe (16) Et3N (0.1)
PhMe (16) Et3N (1.2)
PhMe (24) KOtBu (1.2)
PhMe (24) DABCO (1.2)
DCM (24) Et3N (1.2)
PhMe (24) Et3N (0.3)
4.2:1
2.7:1
7
8
9
32
26
4:1
>99:1c
>99
>99
10
11
a Determined on isolated separated isomers. b Determined by HPLC
using a chiral column. c Unidentified side product formed.
Encouraged by these results we decided to apply redox
activationof enalsforthe constructionofthe corestructure
of highly substituted indanes (eq 2).4 The planned cascade
reaction comprises two CꢀC-bond forming processes
along with an intramolecular acylation. The challenging
task was the control of the relative as well as absolute
configuration of the 3 newly formed contiguous stereo-
genic centers.
Test reactions were conducted with aldehyde 3a and β-
diketone 4a to give indane derivatives 5a/5a0 at room
temperature under different conditions. Using achiral
triazolium salt A as catalyst precursor and Et3N in THF
provided only a low yield of the targeted product that was
formed as a 1:1 mixture of diastereoisomers (Table 1, entry 1).
With DBU reaction was faster and higher yielding
(entry 2). Interestingly, only isomer 5a0 was isolated in that
case. We then switched to chiral triazolium salt B12 as
precatalyst and noted a further increase in yield (entry 3).
Pleasingly, an acceptable enantioselectivity (89%) was
achieved. A similar result was obtained upon lowering
the amount of base (entry 4). Switching to NEt3 lead to
excellent enantioselectivity (ee >99%, entry 5). Reaction
was slower and both diastereoisomers were isolated with
very high enantioselectivity (the other enantiomer was not
identifiedby HPLCanalysis for bothisomers). The relative
configuration of the major isomer 5a (cis,cis) was unam-
biguously assigned by X-ray analysis and NOE experi-
ments and the relative configuration of 5a0 (trans,cis) was
determined by NOE-experiments (see Supporting
Information). The best yield was achieved in toluene (74%,
entry 6). Diastereoselectivity was moderate but enantios-
electivity was excellent. Increasing the amount of NEt3
further lowered the diastereoselectivity (entry 7). KOtBu
did not work as base whereas with 1,4-diazabicyclo-
[2.2.2]octane (DABCO) a lower yield was achieved, while
(8) NHC catalyzed oxidative esterification using MnO2 as oxidant:
(a) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Tetrahedron
2009, 65, 3102. Using organic oxidants: (b) Noonan, C.; Baragwanath,
L.; Connon, S. J. Tetrahedron Lett. 2008, 49, 4003. (c) Rose, C. A.;
Zeitler, K. Org. Lett. 2010, 12, 4552.
(9) De Sarkar, S.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266.
(10) While preparing this manuscript, two papers on the enantio-
selective version of that process appeared: (a) Rong, Z.-Q.; Jia, M.-Q.;
You, S.-L. Org. Lett. 2011, 13, 4080. (b) Zhu, Z.-Q.; Zheng, X.-L.; Jiang,
N.-F.; Wan, X.; Xiao, J.-C. Chem. Commun. 2011, 47, 8670.
(11) (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc.
2009, 131, 14176. (b) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am.
Chem. Soc. 2011, 133, 4694. Alternative mechanism: (c) Kaeobamrung,
J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010,
132, 8810. (d) Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew.
Chem., Int. Ed. 2011, 50, 1673.
(12) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
Org. Lett., Vol. 13, No. 18, 2011
4967

keeping the excellent enantioselectivity (entries 8, 9). Inter-
estingly, in dichloromethane (DCM) isomer 5a was the
only isomer detectable, however, yield was low (entry 10).
Surprisingly, with triazolium salt C13 as precatalyst, the
reaction did not work (entry 11)
We then tested the substrate scope of the cascade reac-
tion under optimized conditions (toluene, NEt3, B (5 mol
%), 16 h). Since some nucleophiles reacted sluggishly using
0.1 or 0.3 equiv of NEt3, all following experiments were
conducted with 1.2 equiv of base. The enal and also the β-
diketo component were varied and the relative configura-
tion of products 5bꢀk was assigned in analogy to 5a (note
that in the 1H NMR spectrum, the vinylic proton of these
compounds showed a very characteristic chemical shift for
both isomers 5x(cis,cis, around 5.4 ppm) and 5x0 (trans,cis,
around 5.1 ppm)). Reaction of enal 3a with acetylacetone
delivered 5bin 69% yield with high diastereoselectivity and
excellent enantioselectivity (Figure 1). With β-arylenals
bearing a halogen atom at the arene moiety, the cascade
process delivered products 5c and 5d as single diastereoi-
somers in enantiomerically pure form. The trans,trans-
isomers 5c0 and 5d0 were not identified by 1H NMR
spectroscopy in these reactions. A similar result was
obtained using the naphthyl substituted enal (see 5e). Yield
was lower for reaction of acetylacetone with a more
electron rich β-arylenal (38%, 5f). For this compound,
the other enantiomer was also identified (93% ee). The R2-
substituent in the enal (see eq 2 in Scheme 1) can also be
varied. We replaced the methyl group by a phenyl sub-
stituent and noticed a far slower cascade process. Reaction
time had to be extended to 24 h, and 5g was isolated as a
single isomer in 44% yield. As compared to the cascade
conducted with acetylacetone, the ethyl substituted β-
diketone congener reacted with enal 3a with higher selec-
tivity (5h: 54%) but the bis-p-tolyl-β-diketone ketone
provided a moderate diastereoselectivity in a lower yield
(5i). Because of solubility problems, reaction time was
increased to 30 h for this nucleophile.
Figure 1. Compounds 5bꢀk successfully prepared (Conditions:
toluene, NEt3 (1.2 equiv), B (5 mol %), 16 h. a24 h reaction time.
b30 h reaction time. cdr at additional stereocenter = 1.3:1. ddr at
additional stereocenter = 3.6:1).
absolute stereochemistry of the initial CꢀC-bond forma-
tion in our cascade resembles the stereodetermining step in
the formation of 7. Therefore, we assigned the absolute
configuration obtained in our cascades accordingly.
Scheme 2. Reaction of Cinnamaldehyde with 6 and Subsequent
Transformation to Known Ester 8
As expected, in the reaction of 3a with an unsymmetrical
β-diketone, the stereogenic center at the R-position to the
β-diketone was not controlled (dr = 1.3:1, see 5j). β-
Ketoesters turned out to be suitable substrates as shown
for a single example (5k). The cis/trans-selectivity at the
ring was well controlled; however, the additional center R
to the ester functionality was formed with low selectivity.
For assignment of the absolute configuration we studied
the reaction of cinnamaldehyde with β-ketoester 6 under
similar conditions to give dihydropyranone 7 in 69% yield
with 92% ee (Scheme 2). Treatment of 7 with aq. HCl in
refluxing dioxane led to ring-opening of the dihydropyr-
anone; hydrolysis of the ester followed by decarboxylation
gave the corresponding acid. Esterification with TMS-
diazomethane eventually afforded known ester (S)-8 in
We predict that the reaction occurs via the catalytic cycle
as depicted in Scheme 3. Reaction of enal 9 with carbene B0
in the presence of oxidant 3 generates acylazolium ion 10.9
Conjugate addition of the likely deprotonated 1,3-dicar-
bonyl compound to the redox activated Michael acceptor
provides 11. As suggested by Bode, the same intermediate
may also be formed via a Claisen-type rearrangement.11c,d
Enolate 11 can undergo intramolecular 1,4-addition4b,15 to
generate 12 (via 13), which undergoes intramolecular
acylation to eventually afford product 5 and catalyst B0.
88% yield ([R]D = ꢀ23.6° (c = 1.0 in benzene); [R]D =
ꢀ22.4° (c = 2.0 in benzene)14). The step determining the
(13) Vora, H. U.; Lathrop, S. P.; Reynolds, N. T.; Kerr, M. S.;
deAlaniz, J. R.; Rovis, T. Org. Synth. 2010, 87, 350.
(14) Sato, M.; Kano, K.; Kitazawa, N.; Hisamichi, H.; Kaneko, C.
Heterocycles 1990, 31, 1229.
(15) Conjugate addition in NHC-catalyzed cascade reactions: Fang,
X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2011,
50, 1910.
4968
Org. Lett., Vol. 13, No. 18, 2011

Alternatively, enolate 11 can be transformed via an endo-
Hetero-DielsꢀAlder reaction16 (see 14) and subsequent
carbene fragmentation to product 5.17
very good selectivities (80ꢀ93% ee, an example is depicted
in Scheme 2). However, the selectivities achieved for the
cascades far exceed those ee’s. It is therefore likely that the
diastereoisomer of 13 (not shown, diastereomeric at the
newly formed stereogenic center) does not efficiently
further react (mismatched case) to trans,cis-5. In fact, we
never identified that particular isomer in our studies. The
nonproductive isomer of 13 might undergo back reaction
to 10 or might further react to a product different from 5.
By doing so, the “stereochemical error” occurring in the
first CꢀC-bond formation is corrected in the follow up
reaction. Increase of initial selectivity by a subsequent
second stereoselective reaction that funnels the “wrong”
isomer into a product which is not an enantiomer of the
targeted compound is well established in asymmetric
synthesis.18
Scheme 3. Suggested Catalytic Cycle
Finally, we converted the cascade product 5a to the
corresponding indane derivative by methanolysis under
very mild conditions (stirring in MeOH at rt) to provide
1,2,3-trisubstituted indane 15 in a quantitative yield
(Scheme 4).
Scheme 4. Stereospecific Methanolysis of 5a
In conclusion, we presented a new method for the highly
enantioselective synthesis of substituted indane derivatives.
The method uses oxidative carbene catalysis. Starting ma-
terials are readily prepared and products of the cascade
reaction are easily transformed to the corresponding 1,2,
3-trisubstituted indane derivatives. Such indanes are privi-
leged substructures in medicinal chemistry.
The high cis-selectivity for the second CꢀC-bond for-
mation can be understood by considering model 13. The
H-atom of the Michael acceptor points toward the enolate
for steric reasons leading to the observed cis-intermediate
12. If the second bond formation occurs via a Hetero
ꢀDielsꢀAlder reaction, the endo-rule (see 14)16b would
explain the cis-selectivity. The very high enantioselectiv-
ities (>99%) achieved for most of the transformations
need further comments. We have shown that under opti-
mized conditions, CꢀC-bond formation in systems that
lack the second Michael-acceptor occurs with moderate to
Acknowledgment. We thank the DFG and the NRW
Graduate School of Chemistry for funding our work. We
dedicate this paper to Prof. Dieter Enders on the occasion
of his 65th birthday.
Supporting Information Available. Experimental details,
characterization data for the products. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(16) (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088. (b) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418. See also:(c) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett.
201110.1021/ol201917u.
(17) A third mechanistic option suggested by a referee: Reaction
might go via a pathway involving initial ring closure in 13 by the
diketone moiety (as in refs 9,10) followed by Michael reaction and
ring-closing/ring-opening to give 5.
(18) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: Sausalito, 2009; p 563.
Org. Lett., Vol. 13, No. 18, 2011
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