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Synthesis of 1-Indanones from Benzoic Acids Yun-Sheng Huang,* Jian-Qiang Liu, Lang-Jun Zhang, and He-Lin Lu Guangdong Medical College School of Pharmacy, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, 523808, China
bS Supporting Information ABSTRACT: An improved process for the preparation of 1-indanones from various benzoic acids is described. This process involves a FriedelCrafts acylation between a substituted benzoyl chloride and ethylene, followed by an intramolecular Friedel Crafts alkylation in the presence of aluminum chloride. The described process combines three steps into a one-pot process, is scalable, is cost-effective, and thus has a general applicability in manufacturing production of various 1-indanones.
’ INTRODUCTION 1-Indanones are important chemical, pharmaceutical, and agrochemical intermediates.1 Various 1-indanone structures widely exist in many natural products from plants2 and from marine sources.3 Many indanone structures have demonstrated various biological activities,2,4 including antiproliferative activity,5 acetylcholinesterase inhibition as theraputics, such as Donepezil (Aricept), for the treatment of Alzheimer’s disease,6 etc. 5-Chloro-1-indanone is a key intermediate for the synthesis of indoxacarb,7 one of the most widely used insecticides worldwide for pest management. In the past decade, there have been tremendous efforts dedicated to the development of more efficient, cost-effective, and environmentally friendly methods toward the synthesis of 1-indanones. Of all reported methods, they can be summarized into two main synthetic routes for the preparation of 1-indanones (Schemes 1 and 2). The first route is to cyclize the corresponding arylpropionic acids or their acyl chlorides via an intramolecular FriedelCrafts acylation, but the corresponding arylpropionic acids are usually not commercially available. Their preparation normally starts with the substituted benzaldehydes or their equivalents (such as benzyl halides) that condense with diethyl malonate or its equivalents to form the corresponding intermediates that undergo hydrolysis, decarboxylation, hydrogenation, and FriedelCrafts acylation to afford the desired products (Scheme 1).8 This route usually consists of multiple steps and therefore is less favorable for industrial production. The second route is to cyclize the corresponding 3-chloro1-(substituted phenyl)propan-1-one, which can be prepared by reacting substituted benzene with 3-chloropropionyl chloride under the catalysis of aluminum chloride, via an intramolecular FriedelCrafts alkylation to give the desired product (Scheme 2).9 The intramolecular FriedelCrafts alkylation can be mediated by aluminum chloride, sulfuric acid, or other Lewis’ acids, with aluminum chloride offering the best results.10 The drawback of this method is that the acylation step normally gives some ortho-acylate byproduct for the monosubstituted phenyl ring system. Another setback is the purification of 3-chloro-1-(substituted phenyl)propan-1-one, a health hazard (classification codes: H315 and H335), which causes severe skin burns and eye damage and may also cause severe damage to the respiratory system upon exposure.11 r 2011 American Chemical Society
Method 1 (Scheme 1) is more useful for the preparation of 6-substituted 1-indanones, while method 2 (Scheme 2) is better suited for the preparation of 5-substituted 1-indanones. Though some other methods are available, they usually require the use of expensive catalysts (e.g., palladium, Tb(OTf)3, etc.) and are therefore not economically or environmentally useful for industrial purposes.12 Recently, some progress has been made using some less expensive and more environmentally friendly catalysts, such as zeolite,12b heteropoly acid,12c etc., to catalyze the synthesis of 1-indanones. However, the applicability of these catalysts in manufacturing purposes is still not practical due to problems of solubility, yield, and scalability. Despite the available methods mentioned above, an efficient route for the synthesis of more structurally diversified 1-indanones is still lagging. One of the attractive ways to make 1-indanones is to start the corresponding benzoic acids that are readily available commercially. To our surprise, there is only one report identified in the literature to use benzoic acids as starting materials for the preparation of 1-indanones with an overall yield around 30%.13 The reported process included the formation of benzoyl chloride from benzoic acid, acylation with ethylene gas to form the corresponding 3-chloro-1-(substituted phenyl)propan-1-one, and cylization via a FriedelCrafts alkylation in the presence of aluminum chloride to form the desired product. In an effort to develop a more convenient, cost-effective, and environmentally friendly process for the preparation of 1-indanones, we further explored various benzoic acids to the synthesis of various 1-indanones. In this process, we combined three steps into one pot without the workup and purification of any intermediates that are normally highly irritating to human exposure, especially in large scale production. In this report, we wish to describe the results for the synthesis of a series of 1-indanones via this process.
’ RESULTS AND DISCUSSION The current method of synthesizing 1-indanones is largely based on the availability of commercial materials. Both Received: October 16, 2011 Accepted: December 18, 2011 Revised: December 6, 2011 Published: December 18, 2011 1105
dx.doi.org/10.1021/ie202369w | Ind. Eng. Chem. Res. 2012, 51, 1105–1109
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Scheme 1. 1-Indanone Synthesis Based on Arylpropinoic Acid Intramolecular Friedel-Crafts Acylationa
a
Reagents and conditions: (a) NaOEt/diethyl manolate, reflux; (b) NaOH; (c) HCl/reflux; (d) H2/PdC; (e) PPA.
Scheme 2. 1-Indanone Synthesis Based on 3-Chloro-1-phenylpropan-1-one Intramolecular Friedel-Crafts Alkylationa
a Reagents and conditions: (a) 3-chloropropionyl chloride/AlCl3, 0 °C; (b) AlCl3, 160 °C.
(Schemes 1 and 2) methods described above have the limitation that can only be used for preparing certain substituted 1-indanones. In an effort to make more diversified structures of 1-indanones, we designed a one-pot process that involves a benzoic acid reacting with thionyl chloride to form the benzoyl chloride, which reacts with ethylene gas to form the 3-chloro1-(substituted phenyl) propan-1-one that cyclizes under aluminum chloride to form the desired products (Scheme 3). Benzoic acid reacts with thionyl chloride quickly at refluxing temperature. The acylation step between acyl chloride and ethylene carries out between 0 °C and room temperature at atmospheric pressure. The cyclization/intramolecular alkylation requires to be heated at around 140170 °C in order for the reaction to proceed. The one-pot process involved in the production of 1-indanone includes the formation of two intermediates, acyl chloride and 3-chloro-1-phenylpropan-1-one, which are not required to be isolated. The high temperature cyclization step usually results in some polymerization. In order to develop an optimized condition for the one-pot process, we designed a process that uses significantly less amount of solvent compared to the conventional method as mentioned above. A model reaction was conducted in the use of p-toluic acid as the starting material to form the 5-methyl-1-indanone (Table 1). Results from Table 1 indicated that this process requires 2 or more equivalents of aluminum chloride to get good yields. Less than 2 equivalents of it would result in a significant side reaction. Results also showed that 5 runs afforded greater than 75% yields (entries 1, 5, 8, 11, and 14), which used 2.55 equivalents of AlCl3. The minimum amount of AlCl3 required is 2.5 equivalents in order to obtain good yield, with 3 equivalents of AlCl3 offering the optimum overall results. The combination of zeolite and aluminum chloride accelerated the reaction and improved the yields as well (Table 1, entries 2 and 5, 3 and 6). When sodium chloride was used in combination with aluminum chloride, both yield and reaction time were significantly improved in comparison with aluminum chloride alone or the aluminum chloride and zeolite combination (Table 1, entries 815). The amount of aluminum chloride could also be reduced to 23 equivalents with 12 equivalents
of sodium chloride, but less than 2 equivalents of it would slow the reaction and result in a polymerized byproduct (Table 1, entry 4). More than 2 equivalents of sodium chloride resulted in low yields (Table 1, entries 10, 13, 15). The combination of aluminum chloridezeolitesodium chloride also worked in a number of examples with a reduced amount of aluminum chloride (Table 1, entries 1618), but the solubility, workup, and scalability problems make this combination less favorable in large scale synthesis application. On the basis of the model reaction, the optimal condition for this process is to use 1 equivalent of the benzoic acid, 3 equivalents of AlCl3, and 1 equivalent of NaCl. This process includes three steps: to react the benzoic acid with thionyl chloride under reflux, remove the excess of thionyl chloride by distillation, dissolve the residue in dichloromethane (1012 equivalents w/w), add 3 equivalents of AlCl3 and 1 equivalent of NaCl, introduce ethylene gas at 0 °C to room temperature until all the acyl chloride is consumed, remove the dichloromethane to dryness, heat the residue to 140160 °C for 0.51 h, and hydrolyze the mixture at 80 °C with icewater. The above optimized process was applied to synthesize a number of 1-indanone analogues as shown in Table 2. Results in Table 2 indicated that this process afforded relatively good overall yields except for those with methoxy group substituted analogues that usually undergo demethylation partially or completely under the reaction conditions (Table 2, entries 4, 5, 1014, 16, 17). In this process, the ortho and para methoxy groups are more easily demethylated than para-methoxy group. Several analogs 4b, 5b, and 10b (Table 2, entries 4, 5, and 10, respectively) were identified as the major products in the reaction mixture but were not isolated due to difficulty of purification. Instead, they were converted to the corresponding methoxy substituted analogs 4a, 5a, and 10a (Table 2, entries 4, 5, and 10, respectively) for analysis by reacting with dimethyl sulfate. The demethoxylated intermediates may react with the corresponding β-chloropropylphenone intramolecularly or intermolecularly to generate byproduct. Most of the products in Table 2 were produced in the quantities of more than 100 g, of which 7-fluoro-1-indanone was scaled up to 120 kg. However, this process did not work for those electron-deficient benzoic acids (Table 2, entries 7, 8). Compounds 1a, 2a, 3a, 4a, 5a, 6a, 9a, 10a, and 15a (Table 2, entries 1, 2, 3, 4, 5, 9, and 10, respectively) are all known structures. Some of their HNMR spectra were not available in the literature and thus were included in reference 14. Analogs 17a and 17b (Table 2, entry 17) are very close on TLC. Even though their HNMR spectra (based on purified small samples) were different, it is still difficult to assign affirmatively which spectrum belongs to which structure without extra information. There is the same situation for analogs 18a and 18b (Table 2, entry 18). 1106
dx.doi.org/10.1021/ie202369w |Ind. Eng. Chem. Res. 2012, 51, 1105–1109
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Scheme 3. 1-Indanone Synthesis Based on Benzoic Acids as Starting Materials
Table 1. Reaction Conditions and Results for the One-Pot Preparation of 5-Methyl-1-indanone
of preparing structurally more diversified 1-indanones that have been limited by other available methods.
1
1
5
0
0
140160
1.5
83
2
1
3
0
0
140165
2.0
66
3
1
2
0
0
140160
2.5
41
4
1
1
0
0
140160
5
0d
’ EXPERIMENTAL SECTION All reagents purchased commercially were used directly without further purification. Solvents were used directly without prior treatment. Reaction temperatures were recorded using a regular thermometer without correction. 1HNMR spectra were measured at a Bruker AV400D system in CDCl3 solution or otherwise specified. All reactions were carried out in flame-dried glassware connected with a mechanical stirrer, a thermometer, a gas emission and absorption apparatus, and an ethylene gas glass induction pipe.
5 6
1 1
3 2
1 2
0 0
140160 140160
1.5 2
75 57
General Procedure for the Preparation of 5-Methyl-1Indanone (Model Reaction in Table 1). To a four-necked flask
7
1
2
3
0
140160
2
63
8
1
3
0
1
140160
1
86
9
1
2
0
1
140165
0.5
69
10
1
2
0
3
120140
0.5
21e
11
1
3
0
1.5
140160
0.5
76
12
1
3
0
2
140160
0.5
66
13 14
1 1
3 2.5
0 0
3 1.5
120130 140165
0.5 0.5
46 81
15
1
3.5
0
2.5
140160
0.5
49
16
1
3
1
1
140165
0.5
67
17
1
3
2
2
120140
0.5
25e
18
1
2
1
1
140160
0. 5
57
acid
AlCl3
zeolite
NaCl
temp
time
conv
entry (eq)
(eq)
(eq)
(eq)
(°C)a
(h)b
(%)c
a
Data in this column indicate the alkylation temperature; the acylation step runs at 0 °C to room temperature. b Data in this column indicated the alkylation reaction time. c Product was not purified. The conversion rates were determined by dried crude product weight times the corresponding purity (HPLC conditions: Angilent 1100; solvent: MeOH; injection: 2 μL; column: Eclipse XOB-C18 250 mm 4.6 mm; λ = 254 nm; column temp: 30 °C; flow rate: 1.0 mL/min; mobile phase: ACNH2O, 5545%). d No desired product was identified. e Reaction did not go completion due to byproduct formation.
On the basis of molecular geometry and polarity, we assume that both 17b and 18b are more polar than their corresponding analogs 17a and 18a, respectively, to tentatively assign their HNMR spectra to the assumed analog,14 with pending confirmation in the future.
’ CONCLUSIONS In summary, we have developed a process for the synthesis of 1-indanones from benzoic acids that is converted to the benzoyl chloride, then reacts with ethylene, and is followed by a Friedel Crafts akylation with the presence of aluminum chloride. Due to the fact that various structures of benzoic acids are more readily available than arylpropionic acids or the corresponding benzaldehydes, this method has significantly expended the scope
attached to a mechanical stirrer, a thermometer, an ethylene gas inlet, and a condenser was added p-toluic acid (1.4 g, 10 mmol) and thionyl chloride (10 g, 80 mmol), and the resulting solution was heated to reflux under stirring for 3060 min. The excess thionyl chloride was removed by distillation to dryness, and the residue was dissolved in dichloromethane (6 mL), AlCl3 (15 eq according to Table 1), NaCl (03 equiv), and zeolite (03 equiv) and cooled to 0 °C in an ice-bath. Ethylene gas was bubbled into the bottom of the reaction mixture, and the reaction was vigorously stirred until all the benzoyl chloride was consumed (monitored by TLC). The solvent was removed by distillation, and the remaining mixture was heated to 140170 °C for 0.52.5 h until all the intermediate had been converted to the desired 1-indanone product (monitored by TLC). The reaction mixture was cooled to around 80 °C and poured onto icewater. The precipitates were collected by filtration, dried, weighted, and HPLC (conditions: Angilent 1100; solvent: MeOH; injection: 2 μL; column: Eclipse XOB-C18 250 mm 4.6 mm; λ = 254 nm; column temp: 30 °C; flow rate: 1.0 mL/min; mobile phase: ACNH2O, 5545%) analyzed to give conversion rates. General Procedure for the Synthesis of 1-Indanones (Table 2). To a four-necked flask attached to a mechanical stirrer, a thermometer, an ethylene gas inlet, and a condenser was added the corresponding benzoic acid (1 equiv) and thionyl chloride (810 equiv), and the resulting solution was heated to reflux under stirring for 3060 min. The excess thionyl chloride was removed by distillation to dryness, and the residue was dissolved in dichloromethane (1012 eq w/w), AlCl3 (3.0 equiv), and NaCl (1 equiv) and cooled to 0 °C in an ice-bath. Ethylene gas was bubbled into the bottom of the reaction mixture, and the reaction was vigorously stirred until all the benzoyl chloride was consumed (monitored by TLC). The solvent was removed by distillation, and the remaining mixture was heated to 140 160 °C for 0.51 h until all the intermediate had been converted to the desired 1-indanone product (monitored by TLC). The reaction was cooled to around 80 °C and poured onto icewater. The precipitates were collected by filtration and recrystallized 1107
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Table 2. Results for the Preparation of Various 1-Indanones
a Some reactions gave two or more products; only the major one was isolated, purified, and characterized (reference 14). b
