NH₄H₂PO₄/SiO₂: a recyclable, efficient heterogeneous catalyst for crossed aldol condensation reaction

Abstract

Crossed aldol condensation of aromatic aldehydes with cyclic ketones in the presence of catalytic amount of NH₄H₂PO₄/SiO₂ (as a safe, green, and cheap heterogeneous catalyst) under solvent-free condition afforded α,ά-bis(substituted-benzylidene) cycloalkanones in high yields. This method is general with respect to all types of aromatic aldehydes and is an eco-friendly procedure. And the catalyst is easily prepared, stable, reusable, and efficient under the reaction conditions.

Keywords:

• aromatic aldehydes
• α,ά-Bis(substituted-benzylidene) cycloalkanones
• crossed aldol condensation
• cyclic ketones
• NH4H2PO4/SiO2

Introduction

Cross-aldol condensation of aromatic aldehydes with cyclic ketones is an important protocol for the synthesis of α,ά-bis(substituted-benzylidene)cycloalkanones, which are very important precursors to potentially bioactive pyrimidine derivates 1, intermediates for agrochemical, pharmaceuticals and perfumes 2, new organic material for nonlinear optical applications 3, cytotoxic analogous 4, bis-spiropyrrolidines 5, and the units of liquid crystalline polymers 6. Usually, this condensation process is catalyzed by strong acid or base, however, suffers from side reactions (such as self-condensation of ketones and aldehydes) giving the corresponding products in low yields 7 8. Therefore, numerous studies in the literature to improve the performance of the reaction have existed; the main progress was the following: (1) The aldol reaction was catalyzed by organometallic complexes but the yields were not satisfactory 9 or required long reaction time 10, (2) Lewis acid such as RuCl₃ 11, SmI₃ 12, BF₃Et₂O 13 14, FeCl₃ 6H₂O 15, Mg(HSO₄)₂ 16, KHSO₄ 17, Yb(OTf)₃ 18, Cu(II) trifluoroacetate 19, InCl₃ 4H₂O 20, LiClO₄ 21, NKC-9 (polymer-supported sulfonic acid) 22, SiO₂–Pr–SO₃H 23 were used to promote the aldol reaction, and (3) I₂ 24, TMSCl/NaI 25, LiOH 26, KF/Al₂O₃ 27, [(Me₃Si)₂N]₃Ln(µ-Cl)Li(THF)₃ 28, Silica Chloride 29, BMPTO(bis(p-ethoxyphenyl)telluroxide) 30, TCT(2,4,6-trichloro[1,3,5]triazine) 31 NaOH in micellar medium 32, KOH 33, Na-HAP 34, and animal bone meal 35 were also found to accelerate this type of reaction. However, the use of toxic reagents, long reaction time, low yields, formation of a mixture of products, and tedious separation procedures is among the drawbacks of the reported methods. It is therefore important to find a more convenient method for the preparation of these compounds.

Silica gel and silica-supported reagents has been used as catalyst in organic synthesis because it is easily available, inexpensive, and nontoxic. Use of such a heterogeneous catalyst benefits several potential catalyst reuses and waste production minimizations 36–38.

Among of many silica-supported catalysts employed, NH₄H₂PO₄/SiO₂, one of the solid supported catalysts has already been prepared by our research group 39 and approved to be a potential green catalyst with several advantages such as low toxicity, low cost, ease of handling, and high catalytic activity. In continuation of our work to develop new and eco-friendly synthetic methodologies, herein we report a novel, green, facile, and efficient one-pot method for the synthesis of α,ά-bis(substituted-benzylidene) cycloalkanones catalyzed by NH₄H₂PO₄/SiO₂ under solvent-free condition (Scheme 1).

short-legendScheme 1. 

Results and discussion

Initially, the reaction was performed by reacting cyclohexanone (1 equiv) and benzaldehyde (2 equiv) in the presence of 0.05 g of NH₄H₂PO₄/SiO₂ as a catalyst under solvent-free condition at 80°C. Under these conditions, only a trace amount of product was obtained after 150 min. The conditions for this transformation were optimized and the results are shown in Table 1. No product was obtained in the absence of the catalyst (Table 1, entry 1) even when the reaction time was extended to 180 min., thus demonstrating the importance of NH₄H₂PO₄/SiO₂. The amount of the catalyst required for the transformation was investigated by the use of 0.05–0.15 g. of catalyst. Under these conditions, the yields were in a range of 10–90% (Table 1). The use of 0.15 g of NH₄H₂PO₄/SiO₂ gave the best result (Table 1, entry 9). The reaction worked well with electron-withdrawing (NO₂, Cl) as well as electron-donating (Me, MeO, N(CH₃)₂) groups, giving various α,ά-bis(substituted-benzylidene) cycloalkanones in 85–94% yields. As it is shown in Table 2, the method is general and encompasses a variety of aromatic aldehydes with excellent yields. The reaction worked with aliphatic aldehydes but did not react well.

Table 1. Reaction of benzaldehyde and cyclohexanone under solvent-free conditions.

Entry	NH4H2PO4/SiO2 (g)	Temperature (°C)	Time (min)	Yield (%)
1	0.00	80–110	180	–
2	0.05	80	150	Trace
3	0.05	80	120	Trace
4	0.05	110	60	10
5	0.1	80	30	10
6	0.1	110	30	20
7	0.15	80	30	85
8	0.15	110	20	90
9	0.15	110	15	90

Table 2. Preparation of α,ά-bis(substituted benzylidene)cycloalkanones catalyzed by NH₄H₂PO₄/SiO₂ at 110°C under solvent-free conditions.

Entry	Ar	Z	Time (min)	Product	Yield (%)	Mp (°C)	Lit. Mp (°C)
1	C6H5	CH2	15	3a	90	188–189	188–190 (18)
2	p-MeC6H4	CH2	10	3b	85	242–243	243–244 (18)
3	p-MeOC6H4	CH2	8	3c	90	211–212	211–212 (18)
4	p-ClC6H4	CH2	10	3d	92	228–229	228–229 (18)
5	p-NO2C6H4	CH2	15	3e	90	229–230	229–231 (18)
6	p-Me2NC6H4	CH2	15	3f	85	271–273	270–273 (18)
7	C6H5CH=CH	CH2	20	3g	85	222–223	215–216 (18)
8	o-ClC6H4	CH2	12	3h	85	154–156	152–153 (10)
9	C6H5	CH2CH2	10	3i	90	116–117	117–118 (18)
10	p-MeC6H4	CH2CH2	10	3j	92	170–171	164–165 (18)
11	p-MeOC6H4	CH2CH2	10	3k	90	162–164	161–163 (18)
12	p-ClC6H4	CH2CH2	12	3l	90	146–148	147–148 (11)
13	p-NO2C6H4	CH2CH2	10	3m	94	160–162	161–162 (18)
14	p-Me2NC6H4	CH2CH2	20	3n	92	250–252	250–252 (18)
15	C6H5CH=CH	CH2CH2	20	3o	90	179–180	177–178 (18)
16	o-ClC6H4	CH2CH2	20	3p	85	103–104	102–104 (31)
17	C6H5	CH(Me)CH2	15	3q	90	99–100	97–99 (31)
18	p-MeC6H4	CH(Me)CH2	15	3r	90	125–127	125–127 (31)
19	p-MeOC6H4	CH(Me)CH2	15	3s	92	137–139	137–139 (31)
20	p-ClC6H4	CH(Me)CH2	15	3t	94	158–160	156–160 (31)

Experimental

Preparation of NH₄H₂PO₄/SiO₂

The catalyst was prepared by mixing silica gel (1.5 g, Merck grade 60, 230–400 mesh) with a solution of NH₄H₂PO₄ (0.6 g, 5 mmol) in distilled water (10 mL). The resulting mixture was stirred for 30 min to absorb NH₄H₂PO₄ on surface of silica gel (Scheme 2). After removal of water in a rotary evaporator, the solid powder was dried at 120°C for 2–3 h under reduced pressure. The drying temperature was maintained below the decomposition temperature of the salt.

short-legendScheme 2. 

Infrared spectras of silica gel and catalyst, before and after using it, were shown in Figure 1. Frequency comparison of IR spectras show the appearance of absorption in region 1400 cm⁻¹. This absorption is due to the P=O stretching vibrations of –OPO₃H₂ groups presence that was shown in Scheme 2.

Figure 1.  (A) Infrared spectra of SiO₂ (Silica gel only). (B) Infrared spectra of catalyst (NH₄H₂PO₄/SiO₂) before using it. (C) Infrared spectra of catalyst (NH₄H₂PO₄/SiO₂) after using it.

Synthesis of α,ά-bis(substituted-benzylidene) cycloalkanones: general procedure

A mixture of aromatic aldehyde (2 mmol), cyclic ketones (1 mmol), and NH₄H₂PO₄/SiO₂ (0.15 g) was stirred for 2 min at room temperature and then the temperature was raised to 110°C and maintained for the appropriate time (Table 2). After completion of the reaction (monitored by TLC), the reaction mixture was diluted with hot ethanol and the catalyst was filtrated off, the residue was kept at room temperature and the resulting crystal product was collected by filtration and washed with ethanol. The product was found to be pure and no further purification was necessary.

The ¹H-NMR data of some compounds are given below:

Compound 3q. ¹H-NMR (300 MHz, CDCl₃): δ 7.81 (dbr, 2H, J = 1.6 Hz), 7.32–7.49 (10H, Ar), 3.10 (ddbr, 2H, J = 3.5, 15.8 Hz), 2.52 (ddd, 2H, J = 2.6, 11.4, 15.8 Hz), 1.89 (m, 1H), and 1.10 (d, 3H, J = 6 Hz).

Compound 3r. ¹H-NMR (300 MHz, CDCl₃): δ 7.79 (dbr, 2H, J = 1.6 Hz), 7.21–7.39 (8H, Ar), 3.10 (ddbr, 2H, J = 3.5, 15.7 Hz), 2.50 (ddd, 2H, J =2.4, 11.3, 15.7 Hz), 2.39 (s, 3H), 1.87 (m, 1H), and 1.08 (d, 3H, J = 6.3 Hz).

Compound 3s.¹H-NMR (300 MHz, CDCl₃): δ 7.77 (dbr, 2H, J = 1.6 Hz), 6.92–7.47 (8H, Ar), 3.85 (s, 3H), 3.06 (ddbr, 2H, J =3.5, 15.7 Hz), 2.50 (ddd, 2H, J =2.4, 11.3, 15.7 Hz), 1.88 (m, 1H), and 1.10 (d, 3H, J = 6.5 Hz).

Compound 3t. ¹H-NMR (300 MHz, CDCl₃): δ 7.73 (dbr, 2H, J = 1.6 Hz), 7.38 (8H, Ar), 2.99 (ddbr, 2H, J = 3.5, 15.7 Hz), 2.48 (ddd, 2H, J = 2.6, 11.2, 15.7 Hz), 1.88 (m, 1H), and 1.08 (d, 3H, J = 6.5 Hz).

Reusability of catalyst

Next, we investigated the reusability and recycling of NH₄H₂PO₄/SiO₂. A mixture of p-cholorobenzaldehyde, cyclopentanone, and H₄H₂PO₄/SiO₂ was stirred at 110°C in solvent-free condition. After completion of the reaction, the reaction mixture was diluted with hot ethanol and the catalyst was separated by simple filtration and recovered NH₄H₂PO₄/SiO₂ was reused in subsequent reactions without significant decrease in activity even after five runs (Table 3).

Table 3. The recycling of NH₄H₂PO₄/SiO₂ in synthesis of 3d.

Entry	Time (min)	Yield (%)
1	40	92
2	40	92
3	60	90
4	60	90
5	90	85

Conclusions

We described herein an ammonium dihydrogen phosphate adsorbed on silica gel (NH₄H₂PO₄/SiO₂) catalyzed highly efficient, one-pot, green protocol for the synthesis of α,ά-bis(substituted-benzylidene) cycloalkanones by the condensation of aromatic aldehydes and cyclic ketones under solvent-free condition in very good to excellent yields. The present methodology offers several advantages such as simple procedure, low cost, easy work-up, short reaction time, and milder condition.

Acknowledgements

We thank the faculty of chemistry of K.N. Toosi University of Technology and Islamic Azad University-Marvdasht Branch for supporting this work.

Appendix A: Supporting information for