Domino reaction of arylaldehydes and 1-acetylcyclopropanecarboxamides: One-pot access to highly functionalized spiropiperidine-2,4-diones

Article abstract of DOI:10.1016/j.tetlet.2010.09.133

A domino reaction based on arylaldehydes and 1- acetylcyclopropanecarboxamides has been developed, which allows one-pot and efficient synthesis of structurally complex piperidine-2,4-diones with multiple functionalities under mild conditions. The overall

Full text of DOI:10.1016/j.tetlet.2010.09.133

Tetrahedron Letters 51 (2010) 6349–6352
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Domino reaction of arylaldehydes and 1-acetylcyclopropanecarboxamides:
one-pot access to highly functionalized spiropiperidine-2,4-diones
⇑
Jing Liu, Shaoxia Lin, Hongqian Ding, Ying Wei, Fushun Liang
Department of Chemistry, Northeast Normal University, Changchun 130024, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A domino reaction based on arylaldehydes and 1-acetylcyclopropanecarboxamides has been developed,
which allows one-pot and efficient synthesis of structurally complex piperidine-2,4-diones with multiple
functionalities under mild conditions. The overall transformation involves tandem aldol/intramolecular
aza-Michael/(aldol)/Michael sequences.
Received 22 August 2010
Revised 18 September 2010
Accepted 29 September 2010
Available online 7 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Arylaldehydes
b-Ketoamides
Michael addition
Piperidine-2,4-diones
Creation of molecular complexity and diversity1 from simple
substrates in an environmentally benign and atom-economic fash-
ion2 constitutes a great challenge in modern organic chemistry,
both from academic and industrial points of view.3,4 In these
contexts, the development of domino reactions5 have emerged as
extremely powerful and popular. Domino processes allow multiple
bond-forming events to occur in a single vessel and, as a conse-
quence, significantly increase resource efficiency during the
cascade.5
gen heterocycles, are important motifs in many biologically and
pharmaceutically interesting compounds,9 as well as useful
intermediates in organic synthesis.10 Although several ap-
proaches for the synthesis of this system have been presented,
development of simple and convenient synthetic procedures for
such nitrogen-containing heterocycles represents an attractive
and interesting area of research in synthetic organic and medic-
inal chemistry.11 Herein, we wish to report our recent results.
The substrates, 1-acetylcyclopropanecarboxamides 2, were pre-
pared following the procedure described in the literature.6a With
substrates 2 in hand, optimization of the reaction conditions was
conducted (Table 1). It was found that no matter at room temper-
ature in t-BuOK/t-BuOH, NaOH/DMF, NaOH/CH3CN, NaH/DMSO, or
at 70 °C in NaOH/EtOH, the reactions of phenylaldehyde 1a and
1-acetyl-N-phenylcyclopropanecarboxamide 2a could not give
satisfactory results (entries 1, 2, 4–6). However, to our delight,
the model reaction between 1a (1.1 mmol) and 2a (1.0 mmol)
could proceed efficiently with NaOH/EtOH at room temperature
In our research on the syntheses of useful cyclic compounds
via domino reactions,6 the utilization of
a
,
a
-disubstituted
b-ketoamides bearing both electrophilic and nucleophilic centers
has been demonstrated in the construction of variety of
a
oxa- and aza-heterocycles including furoquinolines,6a furo[2,3-
b]furans,6b spiroindan-2,20-pyrrolidine,6c and fully functionalized
pyridin-2(1H)-ones.6d More recently, the intramolecular Michael/
anti-Michael addition reactions of N-aryl/alkyl-cinnamoylaceta-
mides in relation to the remote electronic effect has been re-
ported in our group (Scheme 1).7 In conjunction with these
studies and our continued interest regarding the synthetic po-
tential of b-ketoamides,8 we explored the aldol-initiated domino
reaction of arylaldehydes 1 and b-ketoamides 2 containing car-
bonyl, carbamoyl, and cyclopropyl functionalities. As a result of
the research, a one-pot domino reaction leading to highly substi-
tuted spiropiperidine-2,4-diones 3 were developed under mild
conditions. Piperidine-2,4-diones, as typical six-membered nitro-
(entry 3).
A white solid was obtained in 65% yield after
workup and purification by column chromatography, which was
characterized as 5-phenyl-5-azaspiro[2.5]octane-4,8-dione 3a on
O
O
O
NaH, DMSO
NaOH, EtOH
Bn
O
70 oC
N
Bn
r.t.
(R = Bn)
Ph HN
R
O
Ph
N
Ph
O
(R = Ph)
⇑
Corresponding author.
E-mail address: liangfs112@nenu.edu.cn (F. Liang).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.133

6350
J. Liu et al. / Tetrahedron Letters 51 (2010) 6349–6352
Table 1
Table 2
Optimization of the reaction conditions of phenylaldehyde 1a with 1-acetylcyclo-
Domino reactions of arylaldehydes with 1-acetylcyclopropanecarboxamides leading
propanecarboxamide 2aa
to spiropiperidine 2,4-diones 3a
O
Ph
O
O
O
Ar
O
O
O
O
O
O
NaOH, EtOH
r.t.
base
R
NHPh
N
H
+
+
PhCHO
ArCHO
NHPh
NHR
solvent
O
N
Ph
Ph
O
N
R
Ar
1a
2a
3a
1
2
3
Entry
1
Ar
C6H5
2-OMeC6H4
4-OMeC6H4
3,4-CH2O2C6H3
4-MeC6H4
4-ClC6H4
4-FC6H4
2-Thienyl
C6H5
2
R
3b (Yield %)c
Entry
Base
Solvent
T (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1a
1a
1a
1a
2a
2a
2a
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-MeC6H4
2-ClC6H4
Bn
3a (65)
3b (71)
3c (56)
3d (63)
3e (58)
3f (52)
3g (45)
3h (54)
3i (65)
3j (52)
3k (46)
1
2
3
4
5
6
t-BuOK
NaOH
NaOH
NaOH
NaOH
NaH
t-BuOH
DMF
EtOH
EtOH
CH3CN
DMSO
rt
rt
rt
70
rt
rt
12
12
5.5
8
6
4.5
No reaction
Trace
65
0
2a
2a
2a
2a
2a
2b
2c
2d
2e
23
Complicated
a
Reactions were carried out on a 1.0-mmol scale in 5.0 mL of solvent with 1a
(1.1 equiv), 2a (1.0 equiv), and a base (1.0 equiv).
9
b
Yield of isolated product.
10
11
12
C6H5
C6H5
C6H5
d
3l (89)
a
Reactions were carried out on a 1.0-mmol scale in 5 mL of EtOH with 1
(1.1 equiv), 2 (1.0 equiv), and NaOH (1.0 equiv).
b
The stereochemistry of 3 was assigned by the single crystal structure of 3a.
Yield of isolated product.
Only the corresponding aldol condensation product was obtained.
c
d
NO2
O
O
CHO
NO2
NaOH, EtOH
r.t.
+
NHPh
O
O
1j
NHPh
4
(95%)
Figure 1. ORTEP drawing of 3a.
O
CHO
2a
NaOH, EtOH
r.t.
+
N
N
N
the basis of its spectral and analytical data.12 It was noteworthy
that compound 3a was formed in a diastereospecific manner based
on its 1H and 13C NMR spectra. The structure of 3a and its stereo-
chemistry were further confirmed by the X-ray single crystal
diffraction (Fig. 1).13
Ph
O
1k
5
(82%)
Scheme 2. Reactions of strong electron-withdrawing arylaldehydes with 2a.
Having established optimal reaction conditions, we next exam-
ined the scope and limitation of the reactions based on arylalde-
hydes 1 and 1-acetylcyclopropanecarboxamides 2.14 First of all, a
series of arylaldehydes 1 (1.1 mmol) were reacted with 1-acetyl-
N-phenylcyclopropanecarboxamide 2a (1.0 mmol) under the
optimized conditions (EtOH/NaOH, rt) and some of the results
are summarized in Table 2. Consequently, all the reactions with
phenylaldehyde (entry 1), electron-rich arylaldehydes (entries
2–5), less electron-deficient arylaldehydes (entries 6–7), and
heteroarylaldehyde (entry 8) proceeded smoothly to afford the
corresponding highly functionalized spiropiperidine-2,4-diones
3a–h in good yields (45–71%).15 However, for strong electron-
withdrawing arylaldehydes like 2-nitrobenzaldehyde and pyri-
dine-4-carboxyaldehyde, the corresponding products 3 could not
been obtained. Similar to the results reported, only the aldol con-
densation product 4 was separated in 95% yield for 2-nitrobenzal-
dehyde and the aldol/aza-anti-Michael addition product 5 was
obtained in 82% yield for pyridine-4-carboxyaldehyde (Scheme
2).7 Then the reaction scope with respect to the amide motif was
examined. When the substituent on nitrogen was aryl, such as
4-MeOPh, 4-MePh, or 2-ClPh, the desired piperidine-2,4-diones
3i–k were obtained in moderate yields of 46–65% (Table 1, entries
9–11).16 As for N-alkyl substituted b-ketoamides like 1-acetyl-N-
benzylcyclopropanecarboxamide 2e, the reaction could not give
the spiropiperidine-2,4-dione product (entry 12). It was found that
products 3a–k were produced in high efficiency and in a highly
regio- and diastereoselective manner. In all cases, three adjacent
stereocenters were created simultaneously and no diastereoiso-
mers were observed. The procedures involve two molecular of 1
and two molecular of 2, giving rise to complex structures with
multiple functionalities, three continuous chiral carbon atoms
and two separate cyclopropanes. In the domino process, up to four
consecutive bonds including one C–N bond and three C–C bonds
were established.
When excessive arylaldehydes were employed in the above-
mentioned reactions, spiropiperidine-2,4-diones
6 would be
obtained (Table 2). Specifically, upon treatment of 1a (3.0 equiv)
with 2b (1.0 mmol) in the presence of NaOH (2.0 equiv) in EtOH
(5 mL) at room temperature for 3 h, the reaction afforded 7-benzyl-
idene-5,6-diphenyl-5-azaspiro[2.5]octane-4,8-dione 6a in a mod-
erate yield of 41% (Table 3, entry 1). Selected arylaldehydes 1
were reacted with 1-acetylcyclopropanecarboxamides 2 to give
spiropiperidine-2,4-diones 6b–d under otherwise identical condi-
tions (entries 2–4). The structure of 6 was established based on
the spectral and analytical data. It was noteworthy that the yields
of products 6 were not fairly high, which was attributed to the
formation of certain amount of compounds 3 in the reactions.17
The one-pot reaction provides a direct and convenient route to
spiro compound of type 6 with one cyclopropanyl ring, one chiral
carbon atom, and an exocyclic double-bond. During this cascade,
three consecutive bonds including one C–N bond and two C–C

J. Liu et al. / Tetrahedron Letters 51 (2010) 6349–6352
6351
O
Table 3
Domino reactions of arylaldehydes with 1-acetylcyclopropanecarboxamides leading
NaOH
to spiropiperidine 2,4-diones 6a
3a
ð1Þ
EtOH
r.t.
Ph
O
HN
Ph
7a
O
O
O
NaOH, EtOH
r.t.
Ar
+
ArCHO
NHAr'
21 %
O
N
Ar
In conclusion, a concise and efficient synthesis of fully function-
Ar'
alized piperidine-2,4-diones 3 and 6 has been developed based on
the one-pot domino reaction of arylaldehydes and 1-acetylcyclo-
propanecarboxamides. The overall transformation involves tan-
dem aldol/intramolecular aza-Michael/(aldol)/Michael sequences.
This protocol is associated with readily available starting materials,
mild conditions, dense and flexible substitution patterns, and
potential synthetic utility of the final products.
1
2
6
Entry
1
Ar
2
Ar0
6 (Yield %)b,c
1
2
3
4
1a
1a
1e
1e
C6H5
C6H5
2b
2c
2c
2e
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
6a (41)
6b (35)
6c (38)
6d (44)
4-MeC6H4
4-MeC6H4
a
Reactions were carried out on a 1.0-mmol scale in 5 mL of EtOH with
(3.0 equiv), 2 (1.0 equiv), and NaOH (2.0 equiv).
Yield of isolated product.
1
b
c
Acknowledgments
The formation of compounds 3 was observed on TLC.
Financial support by NSFC (20972027), and Training Fund of
NENU’S Scientific Innovation Project (NENU-STC08013 and
STB07007), is greatly acknowledged.
bonds were created. Indeed, spiro compounds 3 and 6 could be
synthesized, respectively, with different mole ratio of reactants.
The richness of the functionality on the piperidine-2,4-diones of
types 3 and 6 may render them extremely versatile as synthons
in further synthetic transformations.18
Based on all the results mentioned above, a possible mechanism
for the highly efficient one-pot transformation into spiropiperi-
dine-2,4-diones 3 was proposed, as depicted in Scheme 3. A tan-
dem aldol condensation and intramolecular aza-Michael addition
of arylaldehyde and b-ketoamides take place first, giving the key
enolate intermediate II (7 ? I ? II).19 Then, the spiropiperidine-
2,4-diones 3 would be produced via a second aldol condensation
of II with 1 giving piperidine-2,4-diones 6 with an exocyclic dou-
ble-bond and a second Michael addition between 6 and 2 (Path
A).20
There is an alternative pathway to form spiro compounds 3,
that is, an intermolecular Michael addition between II and 7
(Path B), which can not be completely ruled out. In order to further
elucidate the possible mechanism, the condensation product 7a
was subjected to the reactions under otherwise identical condi-
tions (Eq. 1). Consequently, compound 3a was obtained in ꢀ21%
yield. The observation supports the possibility of Path B, in which
a tandem aldol/aza-Michael/Michael sequence was involved start-
ing from the substrates 1 and 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.133.
References and notes
1. Schreiber, S. L. Science 2000, 287, 1964.
2. (a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 258; (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
3. Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134.
4. For reviews, see: (a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem., Int.
Ed. 2007, 46, 1570; (b) MacMillan, D. W. C.; Walji, A. M. Synlett 2007, 1477.
5. For reviews on domino reactions: (a) Tiete, L. F. Chem. Rev. 1996, 96, 115; (b)
Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137; (c) Malacria, M. Chem.
Rev. 1996, 96, 289; (d) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996,
96, 195; (e) Neuschütz, K.; Velker, J.; Neier, R. Synthesis 1998, 227; (f) Poli, G.;
Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959; (g) McCarroll, A. J.;
Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224; (h) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131; (i) Bunce, A. Tetrahedron 1995, 51,
13103; (j) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551; (k) de Meijere, A.; von Zezschwitz, P.; Bräse, S. Acc. Chem. Res. 2005, 38,
413.
6. (a) Cheng, X.; Liang, F.; Shi, F.; Zhang, L.; Liu, Q. Org. Lett. 2009, 11, 93; (b) Liang,
F.; Cheng, X.; Liu, J.; Liu, Q. Chem. Commun. 2009, 3636; (c) Liang, F.; Zhang, J.;
Tan, J.; Liu, Q. Adv. Synth. Catal. 2006, 348, 1986; (d) Liang, F.; Li, D.; Zhang, L.;
Gao, J.; Liu, Q. Org. Lett. 2007, 9, 4845; (e) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org.
Chem. 2006, 71, 8006.
7. Li, Y.; Xu, X.; Tan, J.; Liao, P.; Zhang, J.; Liu, Q. Org. Lett. 2010, 12, 244.
8. For selected representative reactions from b-ketoamides, see: (a) Jiang, B.; Tu,
S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660; (b) Liéby-
Muller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176; (c)
Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129, 5828; (d) Lu, B.; Ma, D. Org.
Lett. 2006, 8, 6115; (e) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong, D. Org. Lett.
2008, 10, 345; (f) Ramanjulu, J. M.; DeMartino, M. P.; Lan, Y.; Marquis, R. Org.
Lett. 2010, 12, 2270.
O
O
O
O
NaOH
aldol
NaOH
+
NHR
ArCHO
Ar HN
O
Ar
N
R
I
O
R
7
1
2
9. For pharmacuetical application of piperidine-2,4-diones, see: (a) 3,3-diethyl-5-
methyl-piperidine-2,4-dione (methyprylon) is used for insomnia and daytime
tension, which is categorized under the following by the FDA: Sedatives and
Hypnotics; ATC code: N05CE02; (b) N-arylpiperidine-2,4-dione derivatives
may be used as abnormal cannabidiols agents for lowering intraocular
pressure, Eur. Pat. Appl. EP 2 123 264 A1.
10. For examples of piperidine-2,4-diones as intermediates in organic synthesis,
see: (a) Asahia, K.; Nishinob, H. Tetrahedron 2005, 61, 11107; (b) Asahia, K.;
Nishinob, H. Tetrahedron Lett. 2006, 47, 7259.
11. For recent examples towards piperidine-4-dione and piperidine-2,4-dione
synthesis, see: (a) Cui, L.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394; (b)
Palillero, A.; Teran, J. L.; Gnecco, D.; Juarez, J. R.; Orea, M. L.; Castro, A.
Tetrahedron Lett. 2009, 50, 4208; (c) Davis, F. A.; Chao, B.; Andemichael, Y. W.;
Mohanty, P. K.; Fang, T.; Burns, D. M.; Rao, A.; Szewczyk, J. M. Heteroat. Chem.
2002, 13, 486.
12. Spiro compounds represent an important class of naturally occurring
substances characterized by highly pronounced biological properties. For a
review on the stereo-controlled synthesis of spiro compounds, see: (a)
Sannigrahi, M. Tetrahedron 1999, 55, 9007; Spirocyclopropanes are present in
O
1
Ar
aldol
A
B
Path
Path
O
O
N
R
Ar
6
Ar
N
R
II
O
2
Michael
Ar
aza-Michael
O
O
O
7
R
N
Michael
H
O
N
R
Ar
3
(one of the enantiomers)
Scheme 3. Possible mechanism for the domino reactions leading to spiropiperi-
dine-2,4-diones 3.

6352
J. Liu et al. / Tetrahedron Letters 51 (2010) 6349–6352
a
number of pharmacologically interesting natural products, such as the
2.66–2.71 (m, 1H), 3.10–3.13 (m, 1H), 4.12 (t, J = 6.0 Hz, 1H), 4.64 (s, 1H), 7.05
(d, J = 7.5 Hz, 2H), 7.05–7.14 (m, 3H), 7.16–7.19 (m, 2H), 7.20–7.23 (m, 2H),
cytotoxic illudins. For selected papers see: (b) Pirrung, M. C.; Liu, H. Org. Lett.
2003, 5, 1983; (c) Rasool, N.; Rashid, M. A.; Adeel, M.; Görls, H.; Langer, P.
Tetrahedron Lett. 2008, 49, 2254; (d) Rasool, N.; Rashid, M. A.; Reinke, H.;
Fischer, C.; Langer, P. Tetrahedron 2008, 64, 3246; (e) Bose, G.; Langer, P.
Tetrahedron Lett. 2004, 45, 3861.
7.24–7.25 (m, 2H), 7.27–7.34 (m, 7H), 7.57 (d, J = 8.0 Hz, 2H), 10.80 (s, 1H). 13
C
NMR (CDCl3, 125 MHz) d = 19.0, 19.7, 25.3, 26.0, 34.5, 34.9, 40.6, 42.1, 62.5,
63.1, 120.1, 124.1, 125.3, 125.7, 126.6, 127.9,128.0,128.1, 128.9, 128.9, 129.1,
129.4, 138.0,139.6, 140.4, 142.4, 166.7, 169.5, 206.5, 206.8. MS calcd m/z 582.2,
found 583.2.2 [(M+1)]+. Anal. Calcd for C38H34N2O4: C, 78.33; H, 5.88; N, 4.81;
found: C, 78.30; H, 5.89; N, 4.79.
13. CCDC 771686 (3a) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
14. Typical procedure for the preparation of 3 (3a as an example): To a solution of
1-acetylcyclopropanecarboxamide 2a (203 mg, 1.0 mmol) in EtOH (5 mL) was
added phenylaldehyde 1 (0.12 mL, 1.1 mmol) and NaOH (40 mg, 1.0 mmol).
The mixture was stirred at room temperature. After the starting material 2a
was consumed as indicated by TLC, the reaction mixture was poured into water
(20 mL) and extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic phase
was washed with water (3 ꢁ 10 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether:diethyl ether = 4:1) to give 3a
(378 mg, 65%) as a white solid. 1-((R)-3-((6R,7S)-4,8-dioxo-5,6-diphenyl-5-
azaspiro[2.5]octan-7-yl)-3-phenylpropanoyl)-N-
15. For synthetic details, see Supplementary data.
16. The yields corresponding to products 3 could not be further improved after
several trials.
17. It was observed in our experimental that even though excessive arylaldehyde
was introduced to the reaction system, there is a strong tendency for the
formation of compounds 3.
18. An example for further transformation, see: Alper, P. B.; Meyers, C.; Lerchner,
A.; Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186.
19. For a recent review on organo-catalytic asymmetric aza-Michael addition, see:
(a) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058; For selected
papers, see: (b) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan, B.; Zhong, G. Angew. Chem.,
Int. Ed. 2008, 47, 10187; (c) Zhu, D.; Lu, M.; Chua, P.; Tan, B.; Wang, F.; Yang, X.;
Zhong, G. Org. Lett. 2008, 10, 4585.
phenylcyclopropanecarboxamide (3a): White solid. mp 188–190 °C. 1H NMR
(CDCl3, 500 MHz) d = 1.27–1.32 (m, 1H), 1.54–1.58 (m, 1H) , 1.60–1.64 (m, 1H),
1.68–1.76 (m, 3H), 1.87–1.90 (m, 1H), 2.30–2.34 (m, 1H), 2.49–2.53 (m, 1H),
20. For a minireview on conjugate additions-triggered tandem transformation,
see: Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354.