Organocatalytic synthesis of substituted spirocyclohexane carbaldehydes via [4 + 2] annulation strategy between 2-arylideneindane-1,3-diones and glutaraldehyde

Article abstract of DOI:10.1021/ol501160k

An organocatalytic domino reaction between 2-arylideneindane-1,3-diones and glutaraldehyde has been devised that gives functionalized spirocyclohexane carbaldehydes with an all-carbon quaternary center. The reaction proceeds through a Michael/Aldol sequence in good-to-high chemical yields and with high levels of stereoselectivity (up to >95:5 dr and 99% ee) in the presence of the α,α-l-diphenylprolinol trimethylsilyl ether 3 (20 mol %) and DIPEA (20 mol %) in ether at 0 °C.

Full text of DOI:10.1021/ol501160k

Letter
pubs.acs.org/OrgLett
Organocatalytic Synthesis of Substituted Spirocyclohexane
Carbaldehydes via [4 + 2] Annulation Strategy between
2‑Arylideneindane-1,3-diones and Glutaraldehyde
Shaik Anwar,†,‡ Shao Ming Li,† and Kwunmin Chen*,†
†Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
‡Division of Chemistry, Department of Sciences and Humanities, Vignan’s Foundation for Science, Technology and Research-VFSTR
(Vignan University), Vadlamudi 522 213 Guntur, Andhra Pradesh, India
S
* Supporting Information
ABSTRACT: An organocatalytic domino reaction between 2-
arylideneindane-1,3-diones and glutaraldehyde has been
devised that gives functionalized spirocyclohexane carbalde-
hydes with an all-carbon quaternary center. The reaction
proceeds through a Michael/Aldol sequence in good-to-high
chemical yields and with high levels of stereoselectivity (up to
>95:5 dr and 99% ee) in the presence of the α,α-L-
diphenylprolinol trimethylsilyl ether 3 (20 mol %) and
DIPEA (20 mol %) in ether at 0 °C.
Scheme 1. Domino Michael/Aldol Approach toward
Spirocyclohexane Carbaldehyde
he 1,3-indanedione skeleton is an important component of
many naturally occurring biologically active substances and
T
has served as a substrate in numerous reactions.1 In recent years,
readily accessible 2-arylidene-1,3-indandiones have started
gaining attention in the field of organocatalysis.2 2-Arylidenein-
dane-1,3-diones are highly reactive 1,1-diactivated alkenes that
have been used extensively as acceptors in the synthesis of
symmetric and nonsymmetric spiro[cyclohexane-1,2′-indan]-
1′,3′,4-triones,2a spirocyclopropanation,2b,c asymmetric [3 + 2]
annulations,2d and epoxidation.2e Moreover, 2-arylidene-1,3-
indandiones have been used as dipolarophiles for the synthesis of
spirocyclic3 and dispiroheterocyclic4 skeleta.
raldehyde (25%) in CH2Cl2 at 0 °C. The reaction proceeded
smoothly in 87% chemical yield for the desired product 4a
(Table 1, entry 1). Low diastereomeric ratio (37:63) and high
enantioselectivities were obtained (86 and 99% ee, respectively).
The use of other chlorinated solvents failed to increase the
stereoselectivty in the products (Table 1, entries 2 and 3).
Although comparable reactivity was observed, the use of protic
solvents resulted in poor diastereoselectivities (Table 1, entries
4−6).
The use of polar aprotic solvents such as CH3CN and DMF
lowered the diastereoselectivity and enantioselectivity for
product 4a (Table 1, entries 7 and 8). Next, etheral solvents
were screened in the reaction (Table 1, entries 9−12). Among
these, diethyl ether was found to be the solvent of choice under
the present reaction conditions to give product 4a with a high
chemical yield of 91% and high enantioselectivity of 90% ee
(Table 1, entry 12). A reversal of diastereoselectivity was
observed when THF and Et2O were used (Table 1, entries 10
and 12). The reactivity decreased slightly when nonpolar
On the other hand, the use of aqueous pentane-1,5-dial5 as a
four-carbon unit has been efficiently utilized in the synthesis of
substituted cyclohexanes,6 tetrahydropyrans,7 functionalized
cyclopentenes,8 pyrrolidines,9 piperidines,10 and 3-oxabicyclo-
[3.3.1]nonan-2-ones.11
However, the efficient synthesis of substituted spirocyclic
skeleta using 2-arylideneindane-1,3-diones and glutaraldehyde
remains elusive. Very recently, we reported an interesting
domino synthesis of dispirocyclohexane derivatives 5 between
the reaction of 2-arylideneindane-1,3-diones and aldehydes
(Scheme 1). The desired cyclohexanol derivatives were obtained
in moderate chemical yields and excellent stereoselectivities
(>95:5 dr and up to 99% ee).12 As a further extension of this
work, we envisioned that functionalized 1,3-indanedione-derived
spirocyclohexane carbaldehyde 4 could be readily obtained by
reaction of 2-arylideneindane-1,3-diones with dialdehyde 2
mediated by α,α-L-diphenylprolinol trimethylsilyl ether.13 This
Michael/Aldol sequence would eventually incorporate three
stereocenters.
Toward this, an initial investigation was carried out into the
reaction of 2-arylideneindane-1,3-dione with aqueuous gluta-
Received: April 22, 2014
Published: May 16, 2014
© 2014 American Chemical Society
2993
dx.doi.org/10.1021/ol501160k | Org. Lett. 2014, 16, 2993−2995

Organic Letters
Letter
product 4a in 87% chemical yield and excellent dr of 97:3, with
91% ee (Table 2, entry 3). The chemical yield was further
improved with along enantioselectivity (95% ee) when DIPEA
was added as an additive (Table 2, entry 4). The reactivity
dropped when an inorganic base was used, and the reaction
required a relatively longer reaction time for conversion (Table 2,
entry 5). Finally, the use of DMAP reduced the enantioselectivity
of the reaction (Table 2, entry 6).
With the optimized reaction conditions identified, we next
explored the substrate scope of this domino Michael/Aldol
reaction. Various functional groups were screened in 1a−n to
better understand group tolerance (Table 3).
Table 1. Solvent Screening of Domino Michael/Aldol
Reaction
a
b
c
d
entry
solvent
time (h)
yield (%)
dr
% ee
1
CH2Cl2
CHCl3
DCE
1
87
78
98
87
94
94
88
98
83
99
86
91
81
78
37:63
48:52
29:71
37:63
41:59
44:56
29:71
59:41
45:55
30:70
81:19
82:18
84:16
62:38
86/99
85/99
78/99
72/99
66/93
73/95
72/99
34/87
74/96
72/99
85/97
90/95
89/99
75/98
2
1
3
1
4
MeOH
EtOH
IPA
2
Table 3. Substrate Scope of the Domino Michael/Aldol
5
1.5
1.5
1.5
3
a
Reaction
6
7
CH3CN
DMF
8
9
1,4-dioxane
THF
9
10
11
12
13
14
4.5
2.5
1.5
1.5
4
MTBE
Et2O
toluene
EtOAc
b
time
(h)
yield
(%)
%
c
d
a
entry
1
Ar-
4
dr
ee
Unless otherwise specified, the reaction was carried out with 2-
1
1a
1b
1c
1d
1e
1f
C6H5
4a
4b
4c
4d
4e
4f
6.5
5
99
73
95
98
78
77
78
82
68
89
86
70
95
96
93:7
95:5
95
90
95
83
91
93
90
82
87
80
86
82
95
95
arylideneindane-1,3-dione 1a (0.1 mmol), glutaraldehyde 2 (0.25
mmol), and α,α-L-diphenylprolinol trimethylsilyl ether 3 (20 mol %)
2
4-OAcC6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
b
in the solvent indicated (0.5 mL) at 0 °C. Yield of the isolated
3
24
24
3
95:5
c
d
1
products. Determined by H NMR. Determined by chiral HPLC
analysis.
4
93:7
5
92:8
6
4-FC6H4
4
91:9
7
1g
1h
1i
4-ClC6H4
4g
4h
4i
4
89:11
89:11
89:11
77:23
92:8
solvents such as toluene were used (Table 1, entry 13). Finally,
the use of ethyl acetate as solvent further decreased the reactivity
and stereoselectivity of the reaction (Table 1, entry 14).
The domino sequence was further optimized (Table 2).
Interestingly, the addition of 20 mol % of acidic additives
decreased the stereoselectivity (Table 2, entries 1 and 2).
However, the presence of basic additives significantly improved
the outcome with only one major diastereoisomer being
identified (Table 2, entries 3−6). The use of DABCO gave the
8
4-NO2C6H4
3-NO2C6H4
4-CF3C6H4
4-CNC6H4
4-CO2MeC6H4
2-thiophene
3-thiophene
5
9
4
10
11
12
13
14
1j
4j
4
1k
1l
4k
4l
5
12
12
12
>95:5
>95:5
>95:5
1m
1n
4m
4n
a
Unless otherwise specified, the reaction was carried out with 2-
arylideneindane-1,3-dione 1a−n (0.1 mmol), glutaraldehyde 2 (0.25
mmol), α,α-L-diphenylprolinol trimethylsilyl ether 3 (20 mol %), and
Table 2. Optimization of the Domino Michael/Aldol
b
DIPEA (20 mol %) in diethyl ether (0.5 mL) at 0 °C. Yield of the
a
c
d
1
Reaction
isolated products. Determined by H NMR. Major diastereomer.
Determined by chiral HPLC analysis.
Electron-donating, halo-substituted, electron-withdrawing,
and heterocyclic substitutents were all well tolerated under the
optimized conditions. Acetoxy substituent 1b gave a reasonable
chemical yield with a high stereoselectivity (Table 3, entry 2).
The use of methoxy and methyl substituents in 1c and 1d almost
took 1 day for complete consumption of starting materials (Table
3 entries 3 and 4). This decrease in reactivity may be due to
unfavorable creation of electron density for a nucleophilic
enamine attack at the carbon atom of 2-arylideneindane-1,3-
dione. Halogen substituents 1e−g showed a similar reactivity
profile, with reaction completion in 3−4 h (Table 3, entries 5−
7). The enantioselectivity dropped slightly when 3-nitro
substituent 1i was used (Table 3, entry 9). The stereoselectivity
decreased further when strong electron-withdrawing group 4-
trifluoromethyl substituent 1j was used (77:23 dr and 80% ee,
Table 3, entry 10). This may be due to the rapidly Aldol−retro-
Aldol equilibrating reaction of the spiroindanone framework.14
The heterocyclic substituted Michael acceptors 1m,n gave the
b
c
d
entry
additive
time (h)
yield (%)
dr
% ee
1
2
3
4
5
6
PhCOOH
AcOH
1
92
99
87
99
87
98
70:30
60:40
97:3
93:7
94:6
95:5
82
87
91
95
90
79
1
DABCO
DIPEA
K2CO3
2.5
6.5
9
DMAP
4
a
Unless otherwise specified, the reaction was carried out with 2-
arylideneindane-1,3-dione 1a (0.1 mmol), glutaraldehyde 2 (0.25
mmol), α,α-L-diphenylprolinol trimethylsilyl ether 3 (20 mol %), and
an additive (20 mol %) in diethyl ether (0.5 mL) at 0 °C. Yield of the
isolated products. Determined by H NMR. Major diastereomer.
Determined by chiral HPLC analysis.
b
c
d
1
2994
dx.doi.org/10.1021/ol501160k | Org. Lett. 2014, 16, 2993−2995

Organic Letters
Letter
Notes
desired product with good stereoselectivity (>95:5 dr and 95%
ee) (Table 3, entries 13 and 14).
The authors declare no competing financial interest.
The chemical structures of the spirocyclohexane carbaldehyde
1
4a−n were fully characterized by IR, H NMR, 13C NMR, and
ACKNOWLEDGMENTS
■
HRMS analyses. The absolute configuration was unambiguously
determined by single-crystal X-ray analyses of a representative
bromo-substituted product (4e).15
We thank the Ministry of Science and Technology of the
Republic of China (NSC 102-2113-M-003-005-MY3) for
financial support of our work.
The aforementioned domino reaction can be explained by the
mechanism depicted in Scheme 2. The α,α-L-diphenylprolinol
REFERENCES
■
(1) For a review article, see: (a) Singh, G. S.; Desta, Z. Y. Chem. Rev.
2012, 112, 6104. For selected examples, see: (b) Dai, B.; Song, L.;
Wang, P.; Yi, H.; Cao, W.; Jin, G.; Zhu, S.; Shao, M. Synlett 2009, 11,
1842. (c) Li, M.; Yang, W.-L.; Wen, L.-R.; Li, F.-Q. Eur. J. Org. Chem.
2008, 2751. (d) Pizzirani, D.; Roberti, M.; Recanatini, M. Tetraheron
Lett. 2007, 48, 7120. (e) Roy, S.; Amireddy, M.; Chen, K. Tetrahedron
2013, 69, 8751.
Scheme 2. Proposed Mechanism for the Domino Michael/
Aldol Reaction
(2) For recent examples, see: (a) Ramachary, D. B.; Anebouselvy, K.;
Chowdari, N. S.; Barbas, C. F., III. J. Org. Chem. 2004, 69, 5838.
(b) Russo, A.; Meninno, S.; Tedesco, C.; Lattanzi, A. Eur. J. Org. Chem.
2011, 5096. (c) Das, U.; Tsai, Y.-L.; Lin, W. Org. Biomol. Chem. 2013, 11,
44. (d) Hu, F.; Wei, Y.; Shi, M. Tetrahedron 2012, 68, 7911. (e) Russo,
A.; Lattanzi, A. Org. Biomol. Chem. 2010, 8, 2633.
(3) Li, E.; Huang, Y.; Liang, L.; Xie, P. Org. Lett. 2013, 15, 3138.
(4) (a) Babu, A. R. S.; Raghunathan, R. Tetrahedron Lett. 2006, 47,
9221. (b) Babu, A. R. S.; Raghunathan, R. Tetrahedron 2007, 63, 8010.
(5) (a) Huang, X.-F.; Liu, Z.-M.; Geng, Z.-C.; Zhang, S.-Y.; Wang, Y.;
Wang, X.-W. Org. Biomol. Chem. 2012, 10, 8794. (b) Hong, B.-C.;
Kotame, P.; Liao, J.-H. Org. Biomol. Chem. 2011, 9, 382. (c) Hong, B.-C.;
Nimje, R. Y.; Sadani, A. A.; Liao, J.-H. Org. Lett. 2008, 10, 2345.
(6) (a) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922. (b) Chintala, P.; Ghosh, S. K.; Long, E.; Headley,
A. D.; Ni, B. Adv. Synth. Catal. 2011, 353, 2905. (c) Hong, B.-C.; Nimje,
R. Y.; Wu, M.-F.; Sadani, A. A. Eur. J. Org. Chem. 2008, 1449. (d) Zhao,
catalyst reacts with the dialdehyde 2 to form the nucleophilic
enamine (A). The nucleophilic conjugate attack occurs from the
si face of the enamine to the re facial of the 2-arylideneindane-1,3-
dione to give intermediate (B). Subsequent intramolecular aldol
reaction followed by hydrolysis affords the desired multi-
substituted spirocyclohexane carbaldehyde 4. The stability of
the product 4 can be further explained by the fact that the
hydroxy, aryl, and the aldehyde functionalities all lie in the
equatorial position. One of the carbonyl groups in the 1,3-
indanedione may orient in the pseudoaxial position of the chair
conformation, thereby avoiding 1,3-diaxial interactions.
G.-L.; Dziedzic, P.; Ullah, F.; Eriksson, L.; Cor
2009, 50, 3458.
́
dova, A. Tetrahedron Lett.
(7) Hazelard, D.; Ishikawa, H.; Hashizume, D.; Koshino, H.; Hayashi,
Y. Org. Lett. 2008, 10, 1445.
(8) Yeh, L.-F.; Anwar, S.; Chen, K. Tetrahedron 2012, 68, 7317.
(9) Kumar, I.; Mir, N. A.; Gupta, V. K.; Rajnikant. Chem. Commun.
2012, 48, 6975.
In summary, an efficient organocatalytic domino reaction
between 2-arylideneindane-1,3-diones and glutaraldehyde has
been developed that gives functionalized spirocyclohexane
carbaldehydes with an all-carbon quaternary center. Various
substituted 2-arylideneindane-1,3-dione reacted smoothly with
aqueous glutaraldehyde solution catalyzed by α,α-L-diphenyl-
prolinol trimethylsilyl ether 3 (20 mol %) and DIPEA (20 mol
%) as an additive. The reaction proceeds through a sequential
Michael/Aldol process in high chemical yields and with
stereoselectivities up to >95:5 dr and 95% ee when run in
ether at 0 °C. This one-pot sequential catalysis for construction
of substituted spirocyclohexane carbaldehydes with three
stereocenters via a formal [4 + 2] annulation strategy is
synthetically useful.
(10) (a) Kumar, I.; Ramaraju, P.; Mir, N. A.; Singh, D.; Gupta, V. K.;
Rajnikant. Chem. Commun. 2013, 49, 5645. (b) He, Z.-Q.; Han, B.; Li,
R.; Wu, L.; Chen, Y.-C. Org. Biomol. Chem. 2010, 8, 755.
(11) Hong, B.-C.; Lan, D.-J.; Dange, N. S.; Lee, G.-H.; Liao, J.-H. Eur. J.
Org. Chem. 2013, 2472.
(12) Kuan, H.-H.; Chien, C.-H.; Chen, K. Org. Lett. 2013, 15, 2880.
(13) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. For recent
review articles on the use of α,α-L-diarylprolinol trimethylsilyl ether, see:
(c) Mielgo, A.; Palomo, C. Chem.Asian J. 2008, 3, 922. (d) Xu, L.-W.;
Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243. (e) Jensen, K. L.;
Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A. Acc. Chem. Res.
2012, 45, 248.
(14) (a) Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.;
Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872. (b) Nicolaou, K.
C.; Montagnon, T.; Vassilikogiannakis, G. Chem. Commun. 2002, 2478.
(15) Detailed X-ray crystallographic data are available from the
CCDC,12 Union Road, Cambridge CB2, 1EZ, UK for product 4e
(CCDC 957552).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of H NMR, 13C NMR
1
spectra and HPLC chromatographs for all new products. This
material is available free of charge via the Internet at http://pubs.
acs.org.
NOTE ADDED AFTER ASAP PUBLICATION
The TOC/abstract graphic contained errors and was replaced on
June 6, 2014.
■
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kchen@ntnu.edu.tw.
2995
dx.doi.org/10.1021/ol501160k | Org. Lett. 2014, 16, 2993−2995