Ultrasound promoted one-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione

Article abstract of DOI:10.1016/j.ultsonch.2009.08.012

One-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione from 1,5-diaryl-1,4-pentadien-3-one can be carried out in good yields at 50 °C under ultrasound irradiation. This method provided several advantages such as simple work-up procedur

Full text of DOI:10.1016/j.ultsonch.2009.08.012

Ultrasonics Sonochemistry 17 (2010) 356–358
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound promoted one-pot synthesis
of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione
a
a
Ji-Tai Li a,b, , Xin-Li Zhai , Guo-Feng Chen
*
a College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding 071002, PR China
b Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, Baoding 071002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Received in revised form 23 August 2009
Accepted 24 August 2009
Available online 28 August 2009
One-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione from 1,5-diaryl-1,4-pentadi-
en-3-one can be carried out in good yields at 50 °C under ultrasound irradiation. This method provided
several advantages such as simple work-up procedure, shorter reaction time and higher yield.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
3-Aza-6,10-diaryl-2-oxa-spiro[4.5]decane-
1,4,8-trione
Synthesis
One-pot reaction
Ultrasound irradiation
1. Introduction
yield, shorter reaction time or milder conditions under ultra-
sonic irradiation [5–10]. Herein, we wish to report an efficient
Spiro compounds having cyclic structures fused at a central
carbon are of recent interest due to their interesting conforma-
tional features and their structural implications on biological sys-
tems [1]. The title compound was prepared via two-step reactions
in classical method, bischalcone was converted into the corre-
sponding dimethyl 2,6-diaryl-4-ketocyclohexane-1,1-dicarboxyl-
ate at first, which was then reacted with hydroxylamine
hydrochloride [2–4]. Reddy et al. reported that the synthesis of
2,6-diaryl-4-ketocyclohexane-1,1-dicarboxylate was carried out
in 66–80% yield under refluxing via the condensation of bischal-
cone with dimethyl malonate, which was reacted with hydroxyl-
amine hydrochloride to form 3-aza-6,10-diaryl-2-oxa-spiro
[4.5]decane-1,4,8-trione in 65–76% yield in methanol in the pres-
ence of sodium methoxide [3], but the reaction needed a long
reaction time (14–22 h). Compared with two-step strategies,
one-pot reaction provides useful products without isolation of
any intermediate, and thus reduces time, saves both energy and
raw materials.
one-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-
1,4,8-trione from bischalcones, dimethyl malonate and hydroxyl-
amine hydrochloride catalyzed by sodium hydroxide under
ultrasound irradiation (Scheme 1).
2. Method
2.1. Apparatus and analysis
Dimethyl malonate was purified by distillation prior to use.
1,5-Diaryl-1,4-pentadien-3-one were prepared according to the
literature [11]. Melting points were uncorrected. The 1H NMR
and 13C NMR spectra were recorded on a Bruker AVANCE 400
(400 MHz) spectrometer using TMS as internal standard. MS
were determined on VG70E-HF spectrometer (EI, 70 eV) or SHI-
MADZU GCMS-QP2010 spectrometer (ESI). Sonication was per-
formed in Shanghai Branson BUG25-06 (or 40-06) ultrasonic
cleaner (with a frequency of 25 or 40 kHz and a nominal power
250 W), the total acoustic power injected into the sample
solution was found to be 0.63 (or 1.53) W by calorimetry
[12]. The reaction flasks were immersed in every place of the
cleaner in such way that the surface of reactants is slightly
lower than water in the cleaner, and the temperature of the
water bath was controlled by the addition or removal of circu-
lated water.
Ultrasound irradiation has been considered as a clean and
useful protocol in organic synthesis in the last three decades.
A large number of organic reactions can be carried out in higher
* Corresponding author. Address: College of Chemistry and Environmental
Science, Hebei University, Wusi East Road No. 180, Baoding 071002, PR China.
Fax: +86 312 5079628.
E-mail address: lijitai@hbu.cn (J.-T. Li).
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.08.012

J.-T. Li et al. / Ultrasonics Sonochemistry 17 (2010) 356–358
357
O
33.9, 43.6, 44.4, 52.4, 64.1, 125.8, 128.2, 129.8, 143.3, 154.3,
168.9, 170.0 ppm.
O
Ar
Ar
O
1.NaOH,CH3OH,u.s
2.NH2OH.HCl,u.s.
+
CH2(COOMe)2
.
O
3. Results and discussion
Ar
Ar
HN
O
1
2
The effect of the reaction conditions on the condensation of 1,5-
diphenyl-1,4-pentadien-3-one, dimethyl malonate and hydroxyl-
amine hydrochloride under ultrasound was shown in Table 1. From
the results in Table 1, we can see that the amount of sodium
hydroxide had a significant effect on the yield of 3-aza-6,10-diphe-
nyl-2-oxa-spiro[4.5]decane-1,4,8-trione (2a). When the amount of
sodium hydroxide was 10% mmol, 15% mmol, 30% mmol and
50% mmol, the yield of 2a was 22% (Entry 1), 43% (Entry 2), 68%
(Entry 3) and 61% (Entry 4) respectively.
As shown in Table 1, when increasing the temperature, the yield
also increased. For example, when the molar ratio of 1,5-diphenyl-
1,4-pentadien-3-one and sodium hydroxide was 1:0.15, the 3-aza-
6,10-diphenyl-2-oxa-spiro[4.5]decane-1,4,8-trione (2a) was ob-
tained in 43% yield at 30 °C for 6 h (Entry 2). When increasing
the temperature to 40 °C or 50 °C, the yield of 2a was 52% and
73%, respectively (Entries 5, 6).
We also observed the effect of frequency of ultrasound irradia-
tion on the reaction. The yield with 25 kHz irradiation for 6 h (En-
try 6) was better than that with 40 kHz irradiation for 6 h (Entry 7)
when the molar ratio of 1,5-diphenyl-1,4-pentadien-3-one and so-
dium hydroxide was 1:0.15 at 50 °C. It is shown that lower fre-
quency of ultrasound irradiation improved the yield. The reason
may be that the lower frequency irradiation produces the better
cavitations [5,13]. We also did the experiments in the absence of
ultrasound, the condensation of 1,5-diphenyl-1,4-pentadien-3-
one with dimethyl malonate and hydroxylamine hydrochloride
was carried out in 36% yield (Entry 9) using refluxing for 6 h at
the same conditions. It is apparent that the reaction can be finished
in shorter reaction time to give better yield under ultrasound
irradiation.
Scheme 1. One-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-
trione.
2.2. General procedure for the synthesis of 3-aza-6,10-diaryl-2-oxa-
spiro[4.5]decane-1,4,8-trione
Dimethyl malonate (132 mg, 1 mmol), 1,5-diaryl-1,4-pentadi-
en-3-one (1, 1 mmol), sodium hydroxide (12 mg, 0.3 mmol), meth-
anol (2 mL) were added into a 25 mL round bottomed flask. The
reaction mixture was irradiated in the water bath of the ultrasonic
cleaner at 50 °C for a appropriate period (the reaction was moni-
tored by TLC). Hydroxylamine hydrochloride (69 mg, 1 mmol)
was then added in the above mixture and continued to irradiate.
After the completion of the reaction (the reaction was followed
by TLC), the solvent was evaporated under reduced pressure. The
further purification was accomplished by column chromatography
on silica on (200–300 mesh), eluted with petroleum ether or a mix-
ture of petroleum ether and ethyl acetate (10:1–5:1). The authen-
ticity of compounds 2a–d was established by comparing their
melting points with data reported in literatures. The others (2e–
i) were established by their 1H NMR, 13C NMR and MS.
2.2.1. Compound 2e
White solid, m.p. 237–239 °C; 1H NMR (DMSO), d: 3.31–3.34 (d,
J = 14.2 Hz, 2H, COCH2), 3.34–3.39 (d, 2H, COCH2), 3.53–3.86 (m,
2H, 2PhCH), 7.13–7.45 (m, 8H, Ph-H), 10.62 (s, 1H, N–H); m/z
(ESI): 492 [MÀ1]+; 13C NMR (DMSO): 27.4, 33.9, 43.5, 44.1, 52.7,
63.9, 121.2, 131.5, 131.9, 141.0, 154.8, 170.0, 170.1 ppm.
From the results above, the reaction conditions we chose were
as follows: 1,5-diphenyl-1,4-pentadien-3-one (1 mmol), sodium
hydroxide (0.30 mmol), CH3OH (2 mL), dimethyl malonate
(1 mmol), hydroxylamine hydrochloride (1 mmol). Using this reac-
tion system, we did a series of experiments for one-pot synthesis of
2.2.2. Compound 2f
White solid, m.p. 186–188 °C; 1H NMR (DMSO), d: 3.31–3.34 (d,
J = 10.5 Hz, 2H, COCH2), 3.42–3.45 (d, J = 10.0 Hz, 2H, COCH2),
3.54–3.58 (t, J = 14.0 Hz, 1H, PhCH), 3.86–3.89 (t, J = 12.5 Hz, 1H,
PhCH), 7.19–7.45 (m, 8H, Ph-H), 7.62 (s, 1H, N-H); m/z (ESI):
493 M+; 13C NMR (DMSO): 27.2, 33.9, 43.6, 44.4, 52.6, 64.1,
121.8, 128.8, 130.9, 132.7, 143.6, 154.6, 169.0, 170.1 ppm.
3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione
under
25 kHz ultrasound irradiation. The results are summarized in Table
2.
As shown in Table 2, the reaction of bischalcone with dimethyl
malonate and hydroxylamine hydrochloride catalyzed by sodium
hydroxide was carried out in good yields under ultrasound irradi-
ation. The dramatic improvement observed was with regard to a
short reaction time. According to the method reported in the liter-
2.2.3. Compound 2g
White solid, m.p. 212–214 °C; 1H NMR (DMSO), d: 3.24–3.31 (m,
4H, 2COCH2), 3.89–3.93 (t, J = 13.6 Hz, 2H, PhCH), 4.03–4.06 (t,
J = 17.5 Hz, 2H, PhCH), 7.18–7.45 (m, 8H, Ph-H), 10.66 (s, 1H, N-
H); m/z (ESI): 404 [M+1]+; 13C NMR (DMSO): 22.0, 36.6, 44.8,
45.6, 53.0, 55.9, 127.9128.5, 129.2, 129.5, 134.0, 157.2, 168.3,
168.7 ppm.
Table 1
The effect of reaction conditions on one-pot synthesis of 3-aza-6,10-diphenyl-2-oxa-
spiro[4.5]decane-1,4,8-trione under ultrasound irradiation.*
Entry
Amount of NaOH,
mmol
Frequency,
kHz
Temperature,
°C
Isolated yield, %
2.2.4. Compound 2h
White solid, m.p. 236–238 °C;1H NMR (DMSO), d: 3.22–3.23 (d,
J = 4.84 Hz, 2H, COCH2), 3.31–3.33 (d, J = 9.12 Hz, 2H,COCH2), 3.84–
3.88 (dd, J = 13.2, 3.48 Hz, 1H, PhCH), 3.97–4.00 (dd, J = 13.2,
3.72 Hz, 1H, PhCH), 7.19–7.61 (m, 6H, Ph-H), 10.71 (s, 1H, N-H);
m/z (ESI): 473 M+; 13C NMR (DMSO): 26.8, 33.6, 44.0, 45.4, 58.3,
65.0, 124.8, 126.9, 128.3, 129.6, 132.5, 178.6, 209.7, 209.9 ppm.
1
2
3
4
5
6
7
8
9
0.10
0.15
0.30
0.50
0.15
0.15
0.15
0.30
0.30
25
25
25
25
25
25
40
25
–
30
30
30
50
40
50
50
50
22
43
68
61
52
73
69
91
36
Reflux
2.2.5. Compound 2i
White solid, m.p.196–198 °C; 1H NMR (CDCl3), d: 3.38–3.54 (m,
4H, 2COCH2), 3.56–4.04 (m, 2H, 2PhCH), 7.08–7.25 (m, 8H, Ph-H),
7.69 (s, 1H, N–H); m/z (EI): 402 [MÀ1]+; 13C NMR (DMSO): 27.2,
*
Substrate: 1,5-diphenyl-1,4-pentadien-3-one, 1 mmol; CH3OH, 2 mL; dimethyl
malonate, 1 mmol; hydroxylamine hydrochloride, 1 mmol. Reaction time: addition:
2 h, cyclocondensation: 4 h.

358
J.-T. Li et al. / Ultrasonics Sonochemistry 17 (2010) 356–358
Table 2
One-pot synthesis of 3-aza-6,10-diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione at 50 °C under ultrasound irradiation.
Entry
Ar
Time (reflux), h
Products
Isolated yield (reflux), %
M.p., °C
M.p., °C [Lit]
a
b
c
d
e
f
g
h
i
C6H5
6(6)
5(5)
7(7)
8(8)
6
6
6
6
6(6)
2a
2b
2c
2d
2e
2f
2g
2h
2i
91(36)
88(26)
86(49)
79(42)
73
55
68
49
76(24)
172–174
222–224
214–216
215–217
237–239
186–188
212–214
236–238
196–198
172–174 [3]
223–224 [3]
213–214 [3]
218–219 [3]
–
–
–
–
–
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
4-BrC6H4
3-BrC6H4
2-ClC6H4
2,4-Cl2C6H3
3-ClC6H4
ature [3], the reaction time was 14–22 h, whereas under ultrason-
ication, the reaction time was reduced to half or more. For exam-
ple, compound 2a was previously prepared in 74% yield under
refluxing as reported in the literature [3], while under ultrasound
irradiation, 2a was obtained in 91% yield (Table 2, Entry a) within
6 h catalyzed by sodium hydroxide. Compound 2b was obtained in
76% yield, whereas present procedure resulted in 88% yield within
5 h (Table 2, Entry b). In the absence of ultrasound under refluxing
alone, 2a–d, 2i were obtained in 36% (Table 2, Entry a), 26% (Table
2, Entry b), 49% (Table 2, Entry c), 42% (Table 2, Entry d), 24% (Table
2, Entry i) yield at the other reaction conditions consistent respec-
tively, while under ultrasound irradiation, the yields of 2a–d, 2i
were 91%, 88%, 86%, 79%, 76% respectively. It is apparent that the
ultrasound can accelerate the reaction significantly.
Sonochemistry can be defined as chemistry in a liquid medium
in presence of pressure waves. The increasing interest for sono-
chemistry is due to the positive chemical and mechanical effects
when ultrasonic waves propagate in a liquid medium. Cavitation
is the origin of sonochemistry. Liquids irradiated with ultrasound
can produce bubbles. Under the proper conditions these bubbles
can undergo a violent collapse, which generates localized ‘‘hot
spots” with a transient high temperature and pressures, inducing
molecular fragmentation, and highly reactive species are locally
produced, which are responsible for the chemical effects of ultra-
sound on homogeneous solutions. In the some case, sonication
can probably provide more efficient stirring [5a,14]. All of these
can cause the reaction to take place rapidly.
reported method, this method provided several advantages such
as simple work-up procedure, shorter reaction time and higher
yield.
Acknowledgement
Natural Science Foundation of Hebei Province (B2006000969),
China, supported the project.
References
[1] R. Pradhan, M. Patra, A.K. Behera, B.K. Mishra, R.K. Behera, Tetrahedron 62
(2006) 779.
[2] D.B. Reddy, M.V. Ramana, V. Padmavathi, Indian J. Chem. 37B (1998) 167.
[3] D.B. Reddy, V. Padmavathi, B. Seenaiah, M.V.R. Reddy, Org. Prep. Proc. Int. 24
(1992) 21.
[4] V. Padmavathi, S.M. Basha, D.R. Chinna, V. Subbaiah, T.V.R. Reddy, A. Padmaja,
J. Heterocycl. Chem. 42 (2005) 797.
[5] (a) T.J. Mason, D. Peters, Practical Sonochemistry, second ed., Ellis Horwood,
London, 2002;
(b) J.L. Luche, Synthetic Organic Sonochemistry, Plenum Press, New York,
1998;
(c) J.T. Li, S.X. Wang, G.F. Chen, T.S. Li, Curr. Org. Synth. 2 (2005) 415.
[6] L. Pizzuti, L.A. Piovesan, A.F.C. Flores, F.H. Quina, C.M.P. Pereira, Ultrason.
Sonochem. 16 (2009) 728.
[7] M. Mamaghani, S. Dastmard, Ultrason. Sonochem. 16 (2009) 445.
[8] T.S. Saleh, N.M.A. EL-Rahman, Ultrason. Sonochem. 16 (2009) 237.
[9] H. Mehrabi, Ultrason. Sonochem. 15 (2008) 279.
[10] G.H. Mahdavinia, S. Rostamizadeh, A.M. Amani, Z. Emdadi, Ultrason.
Sonochem. 16 (2009) 7.
[11] G.F. Chen, J.T. Li, H.Y. Duan, T.S. Li, Chem. J. Int. 6 (2004) 7.
[12] T. Kimura, T. Sakamoto, J.M. Leveque, H. Sohmiya, M. Fujita, S. Ikeda, T. Ando,
Ultrason. Sonochem. 3 (1996) 157.
4. Conclusion
[13] (a) M.H. Entezari, A.A. Keshavarzi, Ultrason. Sonochem. 8 (2001) 213;
(b) N.S. Nandurkar, M.J. Bhanushali, S.R. Jagtap, B.M. Bhanage, Ultrason.
Sonochem. 14 (2007) 41;
(c) M.L. Wang, V. Rajendran, Ultrason. Sonochem. 14 (2007) 46.
[14] O. Dahlem, J. Reisse, V. Halloin, Chem. Eng. Sci. 54 (1999) 2829.
An efficient one-pot synthesis of some 3-aza-6,10-diaryl-2-oxa-
spiro[4.5]decane-1,4,8-trione from 1,5-diaryl-1,4-pentadien-3-one
has been developed under ultrasound irradiation. Compared with