Synthesis of fully substituted dispirocyclohexanes by organocatalytic [2 + 2 + 2] annulation strategy between 2-arylideneindane-1,3-diones and aldehydes

Article abstract of DOI:10.1021/ol4011689

An interesting organocatalytic reaction between 2-arylideneindane-1,3- diones and aldehydes has been developed that gives fully substituted cyclohexanes that bear two all-carbon quaternary centers. The dispirocyclohexanes were obtained in reasonable-to-good chemical yields and with high stereoselectivities (>95:5 d.r. and up to 99% ee) using a catalytic amount of commercially available α,α-l-diphenylprolinol trimethylsilyl ether (5 mol %) and DABCO (20 mol %) in DMF at -20 °C. The reaction proceeds through a unique Michael/Michael/aldol reaction that requires 2 equiv of the 2-arylideneindane-1,3-dione.

Full text of DOI:10.1021/ol4011689

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Fully Substituted
Dispirocyclohexanes by Organocatalytic
[2 þ 2 þ 2] Annulation Strategy between
2‑Arylideneindane-1,3-diones and Aldehydes
Hsuan-Hao Kuan, Chung-Han Chien, and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
kchen@ntnu.edu.tw
Received April 30, 2013
ABSTRACT
An interesting organocatalytic reaction between 2-arylideneindane-1,3-diones and aldehydes has been developed that gives fully substituted
cyclohexanes that bear two all-carbon quaternary centers. The dispirocyclohexanes were obtained in reasonable-to-good chemical yields and
with high stereoselectivities (>95:5 d.r. and up to 99% ee) using a catalytic amount of commercially available R,R-L-diphenylprolinol trimethylsilyl
ether (5 mol %) and DABCO (20 mol %) in DMF at ꢀ20 °C. The reaction proceeds through a unique Michael/Michael/aldol reaction that requires
2 equiv of the 2-arylideneindane-1,3-dione.
Six-membered carbocycles are important structural motifs
of many biologically active and pharmaceutical products.1
The stereoselective formation of a six-membered ring system
with multiple stereogenic centers from its acyclic precursors
has attracted substantial attention for its usefulness in the
total synthesis of natural products.2 Among the developed
methodologies, the cascade reaction is especially appealing
owing to such decisive synthetic advantages as synthetic
efficiency, atom economy, operational simplicity, and the
minimal need for the isolation and purification process.3
In the past few years, newly developed organocascade strategies
have emerged as promising protocols for the synthesis of
various structural complex molecules4 with diverse structur-
al substituents including cyclohexanes,5 cyclohexenes,6 and
cyclohexanones.7 Melchiorre,8 Gong,9 Wang,10 and Chen11
have discussed the use of 3-olefinic oxindoles to give a
(4) For review articles, see: (a) Moyano, A.; Rios, R. Chem. Rev. 2011,
111, 4703–4832 and reference therein. (b) Albrecht, Ł.; Jiang, H.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2011, 50, 8492–8509. (c) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167–178. (d) Vaxelaire, C.; Winter, P.;
Christmann, M. Angew. Chem., Int. Ed. 2011, 50, 3605–3607. (e) Enders,
D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870. For selected
examples, see: (f) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051–15053. (g) Austin, J. F.; Kim,
S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5482–5487.
(5) For selected examples, see: (a) Hayashi, Y.; Okano, T.; Aratake, S.;
Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922–4925. (b) Ishikawa, H.;
Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304–1307. (c)
Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2007, 46, 9202–9205. (d) Wang, Y.; Han, R.-G.;
Zhao, Y.-L.; Yang, S.; Xu, P.-F.; Dixon, D. J. Angew. Chem., Int. Ed. 2009,
48, 9834–9838. (e) Varga, S.; Jakab, G.; Drahos, L.; Holczbauer, T.;
(1) (a) Jacobsen, E. N. In Comprehensive Asymmetric Catalysis IꢀIII;
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Kobayashi, S. In
Cycloaddition Reaction in Organic Synthesis; Jørgensen, K. A., Ed.; Wiley-
VCH: Weinheim, 2002; Chapter 1. (c) Ogura, A.; Yamada, K.; Yokoshima,
S.; Fukuyama, T. Org. Lett. 2012, 14, 1632–1635.
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23, 207–213. (b) Trost, B. M.; Corte, J. R.; Gudiksen, M. S. Angew.
Chem., Int. Ed. 1999, 38, 3662–3664. (c) Schwartz, K. D.; White, J. D.
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442–524. (b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38,
2993–3009. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
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r
10.1021/ol4011689
XXXX American Chemical Society

spiro[cyclohexanone-oxindole] scaffold. Organocascade re-
actions using oxindole derivatives have been demonstrated
to be effective in constructing spirocyclic oxindoles.12
Central to the organocascade process is the identification
of suitable Michael acceptors. Several electron-deficient
alkenes have been employed in organocascade reactions that
involve enones, enals, and nitroalkenes.
The use of 1,3-indanedione and its derivatives in organo-
catalytic reactions for the synthesis of spirocyclic compounds
has been documented in the literature.13 However, to the best
of our knowledge, the asymmetric synthesis of fully sub-
stituted dispirocyclohexanes by an organocascade-based
method has not been reported. We present here an efficient
synthesis of highly strained dispirocyclohexane derivatives
from 2-arylideneindane-1,3-diones and aldehydes using a
[2 þ 2 þ 2] annulation strategy.
R,R-L-Diphenylprolinol trimethylsilyl ether is now re-
cognized as one of most useful catalysts in organocatalytic
reactions.14 Many organocascade reactions have been
developed around this catalyst. Our research into the
Michael/Michael/aldol reaction began using 2-arylide-
neindane-1,3-dione and propionaldehyde as model sub-
strates in the presence of catalytic quantities of the R,R-L-
diphenylprolinol organocatalyst at 0 °C with various
solvents (Table 1). The reaction proceeded smoothly in
MeOH to afford the desired product in 43% chemical yield
but with only 11% enantioselectivity (Table 1, entry 1).
The chemical yield and enantioselectivity were drastically
improved when the reaction was carried out in DMF and
CH3CN (Table 1, entries 2 and 3). High chemical yield
(72%) and diastereoselectivity (>95:5), but poor enantio-
selectivity (9% ee), were observed in CH2Cl2 (Table 1,
entry 4). The reactivity was significantly lower when
CHCl3 was used (Table 1, entry 5). Although the stereo-
selectivity was retained, the reactivity fell markedly when
the reaction was carried out in THF (Table 1, entry 6).
Moderate chemical yields and unsatisfactory enantioselec-
tivity were observed when the reaction was performed in
ethyl acetate (Table 1, entry 7).
€
(6) For selected examples, see: (a) Enders, D.; Huttl, M. R. M.;
Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. (b) Li, J.-L.; Kang,
T.-R.; Zhou, S.-L.; Li, R.; Wu, L.; Chen, Y.-C. Angew. Chem., Int. Ed.
2010, 49, 6418–6420. (c) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li,
Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem.
Soc. 2011, 133, 5053–5061. (d) Jia, Z.-J.; Zhou, Q.; Zhou, Q.-Q.; Chen,
P.-Q.; Chen, Y.-C. Angew. Chem., Int. Ed. 2011, 50, 8638–8641. (e)
Hong, B.-C.; Nimje, R. Y.; Sadani, A. A.; Liao, J.-H. Org. Lett. 2008, 10,
2345–2348. (f) Hong, B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje, R. Y.; Liao,
J.-H.; Lee, G.-H. Org. Lett. 2009, 11, 5246–5249. (g) Carlone, A.;
Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2007, 46, 1101–1104. (h) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli,
M.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2008, 14,
4788–4791. (i) Enders, D.; Narine, A. A.; Benninghaus, T. R.; Raabe, G.
Synlett 2007, 1667–1670.
The desired product was obtained in an extremely
low chemical yield in toluene (Table 1, entry 8), and no
reaction proceeded in either hexanes or ether (Table 1,
entries 9 and 10).
(7) For selected examples, see: (a) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272–1277. (b)
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Cabrera, S.; Aleman, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2008, 47, 121–125. (c) Marigo, M.; Bertelsen, S.; Landa,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475–5479. (d)
Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahderon Lett. 2004, 45,
9185–9188. (e) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11,
5654–5657. (f) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Synthesis 2008, 3967–
3973. (g) Li, X.-M.; Wang, B.; Zhang, J.-M.; Yan, M. Org. Lett. 2011,
13, 374–377. (h) Wu, L,-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti,
A.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196–
7199.
Table 1. Solvent Effects of the Cascade Reaction in the Presence
of Catalyst 3 at 0 °Ca
(8) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli,
F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 7200–7203.
(9) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008–1011.
(10) Lan, Y.-B.; Zhao, H.; Liu, Z.-M.; Liu, G.-G.; Tao, J.-C.; Wang,
X.-W. Org. Lett. 2011, 13, 4866–4869.
(11) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.;Eur.
J. 2010, 16, 2852–2856.
(12) For a review article, see: (a) Dalpozzo, R.; Bartoli, G.; Bencivenni,
G. Chem. Soc. Rev. 2012, 41, 7247–7290. For selected examples, see: (b)
Wang, L.-L.; Peng, L.; Bai, J.-F.; Jia, L.-N.; Luo, X.-Y.; Huang, Q.-C.; Xu,
entry
solvent
MeOH
time/d
% yieldb
drc
% eed
1
2
5
2
3
5
7
5
5
7
7
7
43
72
85
72
28
32
31
14
ꢀ
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
ꢀ
11
44
49
9
DMF
ꢀ
X.-Y.; Wang, L.-X. Chem. Commun. 2011, 47, 5593–5595. (c) Companyo,
X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano, A.; Rios, R. Chem.
Commun. 2010, 46, 6953–6955. (d) Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang,
Q.-C.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2010, 46, 8064–8066. (e)
Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z.J. Am. Chem. Soc.
2009, 131, 13819–13825.
(13) For a review article, see: (a) Singh, G. S.; Desta, Z. Y. Chem. Rev.
2012, 112, 6104–6155. For selected examples, see: (b) Hu, F.; Wei, Y.; Shi,
M. Tetrahedron 2012, 68, 7911–7919. (c) Dai, B.; Song, L.; Wang, P.; Yi, H.;
Cao, W.; Jin, G.; Zhu, S.; Shao, M. Synlett 2009, 11, 1842–1846. (d) Li, M.;
Yang, W.-L.; Wen, L.-R.; Li, F.-Q. Eur. J. Org. Chem. 2008, 2751–2758. (e)
Pizzirani, D.; Roberti, M.; Recanatini, M. Tetraheron Lett. 2007, 48, 7120–
7124. (f) Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.; Barbas,
C. F., III. J. Org. Chem. 2004, 69, 5838–5849.
(14) For recent review articles on the use of R,R-L-diarylprolinol
trimethylsilyl ether, see: (a) Mielgo, A.; Palomo, C. Chem.;Asian J.
2008, 3, 922–948. (b) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal.
2010, 352, 243–279. (c) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht,
Ł.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248–264. See also: (d)
Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794–797. (e) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215.
3
CH3CN
CH2Cl2
CHCl3
4
5
7
6
THF
47
21
1
7
ethyl acetate
toluene
hexanes
ether
8
9
ꢀ
10
ꢀ
ꢀ
ꢀ
a Unless otherwise specified, the reaction was carried out with
2-arylideneindane-1,3-dione 1a (0.1 mmol), propionaldehyde 2a
(0.2 mmol), and R,R-L-diphenylprolinol trimethylsilyl ether 3 (5 mol %)
in the solvent indicated (0.2 mL) at 0 °C. b Yield of the isolated products.
c Determined by 1H NMR. d Determined by chiral HPLC analysis.
The Michael/Michael/aldol reaction conditions were
further optimized by screening various acidic and basic
B
Org. Lett., Vol. XX, No. XX, XXXX

additives. The desired product was not obtained in the
presence of strong acid additives such as TsOH and TFA
(data not shown), perhaps, because protonation of the
secondary amine hampered formation of the enamine. The
reactivity increased with comparable stereoselectivity
when the reaction was carried out in the presence of an
acidic additive such as PhCOOH or acetic acid (Table 2,
entries 1ꢀ2). Adding a basic additive to the reaction
significantly improved the reactivity and chemical yields
(96ꢀ99%) while maintaining stereoselectivities (Table 2,
entries 3ꢀ5). In general, the stereoselectivity was improved
when the reaction was carried out at ꢀ20 °C, regardless of
whether an acidic or basic additive was used (Table 2,
entries 6ꢀ9). The cooperative catalytic conditions were
examined and failed to improve the stereochemical out-
come in the cascade reaction (Table 2, entry 11). Finally, to
our satisfaction, the stereoselectivity was further improved
when the reaction was carried out in DMF in the presence
of DABCO (Table 2, entry 12). The water content in this
cascade reaction might be crucial to the observed reactivity
and stereoselectivity.
smoothly with propionaldehyde to give the desired fully
substituted cyclohexanes with high stereocontrol (Table 3,
entries 1ꢀ6). The enantioselectivity dropped slightly when
a 3-nitro substituent analogue was used (Table 3, entry 7).
On the other hand, it decreased when an electron-releasing
substituent in the Michael acceptor was present (Table 3,
entries 8ꢀ9). When a heterocyclic substituted Michael
acceptor was used, the desired product was isolated with
52% chemical yield with good stereoselectivity (>95:5
dr and 80% ee) (Table 3, entry 11). Other nucleophilic
partners were tolerated in the cascade reaction (Table 3,
entries 12ꢀ15). The chemical structures of the dispirocy-
clohexanes were determined by IR, 1H NMR, 13C NMR,
1
and HRMS analyses. Examination of the 500 MHz H
NMR spectrum of 4f (CDCl3) reveals that the four
methine protons are located at the axial positions in the
cyclohexane ring [H1: 4.10 ppm (dd, 10.5, 7.0 Hz); H2: 3.85
ppm (ddq, 12.5, 10.5, 6.5 Hz); H3: 3.15 ppm (d, 12.5 Hz);
and H5: 3.94 ppm (s)]. The absolute stereochemistry was
tentatively assigned by single crystal X-ray analyses of
representative substituted products (4k).15
Using the optimized reaction conditions, the scope and
generality of this interesting cascade reaction was studied.
The results are presented in Table 3. For all the substrates
studied, various substituted 2-arylideneindane-1,3-diones
that included electron-withdrawing and -donating substi-
tutents were well tolerated under these conditions.
Table 3. Substrate Scope of the Cascade Reactiona
Withanelectron-withdrawing groupinthe 4-substituted
2-arylideneindane-1,3-diones, the reaction proceeded
Table 2. Optimization of the Cascade Reactiona
time
%
%
entry
1 (R1-)
4-NO2
2 (R2-)
CH3
product (d) yieldb drc eed
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
2
4
4
2
4
4
3
4
4
4
3
4
5
3.5
6
55
46
42
57
41
45
54
40
40
48
52
54
30
17
45
>95:5 96
>95:5 95
>95:5 92
>95:5 93
>95:5 91
>95:5 90
>95:5 85
>95:5 83
>95:5 76
>95:5 75
>95:5 80
>95:5 90
>95:5 82
>95:5 83
>95:5 99
4-CO2Me CH3
4-CF3
4-CN
4-Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-Br
3-NO2
4-OAc
4-Me
4-H
thiophene CH3
4-NO2
4-CN
entry
additive
solvent time/d % yieldb
drc
% eed
9
1
2
3
4
PhCOOH CH3CN
2
2
0.5
0.5
0.5
6
4
7
3
3
46
56
96
97
99
53
51
37
53
64
57
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
54
58
65
67
67
82
79
66
81
82
77
10
11
12
13
14
15
AcOH
DMAP
DABCO
CH3CN
CH3CN
CH3CN
CH2CH3
CH2CH3
CH(CH3)2
Ph
5
Imidazole CH3CN
PhCOOH CH3CN
6e
7e
8e
9e
10e
11e
4-NO2
4-NO2
2-FBA
AcOH
DABCO
DABCO
CH3CN
CH3CN
CH3CN
CH3CN
a Unless otherwise specified, the reaction was carried out with
2-arylideneindane-1,3-dione 1aꢀk (0.1 mmol), aldehyde 2aꢀd (0.2 mmol),
R,R-L-diphenylprolinol trimethylsilyl ether 3 (5 mol %), and DABCO
(20 mol %) in DMF (0.5 mL) at ꢀ20 °C. b Yield of the isolated products.
c Determined by 1H NMR. d Determined by chiral HPLC analysis.
PhCOOH CH3CN
DABCO
3
12e
DABCO
DMF
2
55
>95:5
96
a Unless otherwise specified, the reaction was carried out with
2-arylideneindane-1,3-dione 1a (0.1 mmol), propionaldehyde 2a (0.2 mmol),
R,R-L-diphenylprolinol trimethylsilyl ether 3 (5 mol %), and additives
(20 mol %) in the solvent indicated (0.2 mL) at 0 °C. b Yield of the
isolated products. c Determined by 1H NMR. d Determined by chiral
HPLC analysis. e The reaction was carried out at ꢀ20 °C. 2-FBA:
2-Fluorobenzoic acid.
(15) In our early study of this work, we tried to crystallize the product
for structure determination and moderate enantiomeric products were
used. Interestingly, cocrystal structures of (þ)/(ꢀ)-4f (recrystallized
from 60% ee solution of hexanes/dichloromethane) were obtained.
Many attempts of crystallization failed when high optical purity 4f
(90% ee) was used. Preliminary X-ray crystallographic data for com-
pounds 4f and 4k can be found in the Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

dispirocyclohexanes. The development of highly selective
sequential transforming protocols is of significant impor-
tance in chiral nonracemic materials preparation. Various
2-arylideneindane-1,3-dione and aldehyde condensations
were catalyzed by R,R-L-diphenylprolinol trimethylsilyl
ether (5 mol %) and DABCO (20 mol %) in DMF
at ꢀ20 °C to form functionalized dispirocyclohexanes with
moderate chemical yields and high-to-excellent stereose-
lectivities (>95:5 dr and up to 99% ee). The organocas-
cade construction of three CꢀC bonds to generate a
cyclohexane scaffold via a [2 þ 2 þ 2] annulation strategy,
by one-pot sequential catalysis, is interesting. Other orga-
nocascade protocols are being studied in our laboratory.
Scheme 1. Proposed Mechanism of the Cascade Reaction
The aforementioned organocascade reaction can be ex-
plained by the mechanism that is presented in Scheme 1.
The R,R-L-diphenylprolinol catalyst reacts with the alde-
hydes to form the nucleophilic enamine (A) which under-
goes Michael addition with the 2-arylideneindane-1,3-
diones from the si face to give intermediate B. The presence
of DABCO shifts the reaction toward the nucleophilic enol
species, which then reacts with the second 2-arylidene-
indane-1,3-dione to afford diindane 1,3-dione aldehyde C.
Subsequently, the intramolecular aldol reaction affords
the desired multisubstituted dispirocyclohexanes.
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC 99-2113-M-003-
002-MY3) forfinancialsupportof ourwork. Ourgratitude
extends to the Academic Paper Editing Clinic at NTNU.
Supporting Information Available. Experimental pro-
1
cedures and copies of H, 13C NMR spectra and HPLC
chromatographs for all new products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
In summary, an efficient Michael/Michael/aldol reac-
tion has been developed for synthesizing multisubstituted
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX