Catalytic Intramolecular Friedel-Crafts Reaction of Benzyl Meldrum's Acid Derivatives: Preparation of 5,6-Dimethoxy-2-Methyl-1-Indanone
Checked by Maurizio Bernasconi and Andreas Pfaltz.
1. Procedure
A. 5-(3,4-Dimethoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1). An oven-dried 1-L, two-necked, round-bottomed flask equipped with an oval (Note 1) magnetic stir bar, a rubber septum and a two-tap Schlenk adaptor connected to a bubbler and an nitrogen/vacuum manifold (Note 2) is charged with 3,4-dimethoxybenzaldehyde (20.0 g, 120 mmol, 1.0 equiv) (Note 3), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (17.7 g, 123 mmol, 1.0 equiv) (Note 4) and ethanol (250 mL) (Notes (Note 5) and (Note 6)) by temporary removal of the septum. After complete dissolution of the reactants, piperidine (1.2 mL, 12.3 mmol, 0.1 equiv) (Note 7) and acetic acid (0.7 mL, 12.3 mmol, 0.1 equiv) (Note 7) are added sequentially by syringe (Note 8) and the solution is stirred at room temperature for 30 min. Sodium triacetoxyborohydride (52.1 g, 246 mmol, 2.0 equiv) (Note 9) is then added in four equal portions, one after the other on a 30 min interval by temporarily removing the septum. The reaction mixture is stirred for another 60 min at room temperature (Note 10), after which it is cooled using an ice bath and quenched by the addition of saturated ammonium chloride solution (60 mL).
The reaction mixture is then transferred into a 1-L separatory funnel using dichloromethane (3 x 80 mL) and saturated ammonium chloride (3 x 80 mL). Deionized water (50 mL) is added to facilitate the separation of the two layers. The layers are separated and the organic phase is collected into a 2-L Erlenmeyer flask. The aqueous phase is extracted with dichloromethane (2 x 150 mL) and the combined organic layers are dried over MgSO4 (20 g), filtered through a coarse glass frit (Note 11) into a 1-L round-bottomed flask, concentrated by rotary evaporation (35 °C, approximately 2 mmHg) and dried under reduced pressure (room temperature, 0.15 mmHg) over 30 min. The crude product is transferred into a 500-mL round-bottomed flask equipped with an oval (Note 1) stir bar, suspended in methanol (80 mL) (Notes (Note 6) and (Note 12)) and warmed at 55 °C for 20 min (Note 13). After allowing the solution to cool to room temperature (~20 min), the reaction vessel is stored in a freezer at −25 ºC for 17 h. The yellow solid is collected by suction filtration (room temperature, approximately 10 mmHg), through a coarse frit (Note 11), washed with methanol (10 mL, −25 °C), dried for 30 min under reduced pressure (0.15 mmHg, room temperature, 1 h) to yield 29.9 g (85 % yield) of product 1 as pale yellow crystals (Notes (Note 14) and (Note 15)).
B. 5-(3,4-Dimethoxybenzyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione (2). An oven-dried 500-mL, three-necked, round-bottomed flask equipped with an oval (Note 1) magnetic stir bar, a 50-mL addition funnel, a two-tap Schlenk adaptor connected to a bubbler and an nitrogen/vacuum manifold (Note 2) and a rubber septum is charged with 1 (21.9 g, 74.5 mmol, 1.0 equiv) and potassium carbonate (15.4 g, 112 mmol, 1.5 equiv) (Note 16) by temporary removal of the septum. Freshly distilled N,N-dimethylformamide (74 mL) (Note 17) is added into the reaction flask (Note 18). After complete dissolution of the reactants, iodomethane (9.3 mL, 149 mmol, 2.0 equiv) (Note 19) is added via syringe to the addition funnel, and added dropwise to the reaction mixture (Note 20).
After 3.5 h (Note 21), the reaction mixture is transferred with deionized water (2 x 30 mL) and dichloromethane (2 x 30 mL) into a 1-L Erlenmeyer flask equipped with an oval (Note 1) stir bar, filled with deionized water (100 mL) and cooled using an ice bath. After stirring for 5 min, the solution is transferred into a 1-L separatory funnel using deionized water (30 mL) and dichloromethane (30 mL). The layers are partitioned and the organic phase is collected into a 1-L Erlenmeyer flask. The aqueous phase is further extracted with 10% dichloromethane in hexanes (3 x 150 mL). The combined organic layers are washed with water (200 mL) and brine (200 mL), dried over MgSO4 (20 g), filtered through a coarse glass frit (Note 11) into a 1-L round bottom flask, and concentrated by rotary evaporation (40 ºC, approximately 10 mmHg). The crude product is dried under reduced pressure (room temperature, 0.2 mmHg) for 30 min prior being transferred to a 250-mL round-bottomed flask, dissolved in methanol (30 mL) (Notes (Note 6) and (Note 12)) and warmed at 55 °C for 20 min (Note 13). After allowing the solution to cool to room temperature (~20 min), it is stored in the freezer at −25 ºC for 17 h. The crystals are collected by suction filtration through a coarse frit (Note 11) under vacuum (room temperature, approximately 10 mmHg) and washed with methanol (10 mL, −25 °C). Product 2 is then collected into a 250-mL round-bottom flask and dried under reduced pressure (room temperature, 0.15 mmHg) for 30 min to give 20.21 g (88 % yield) of pale yellow crystals (Note 22).
C. 5,6-Dimethoxy-2-methyl-1-indanone (3). An oven-dried 1-L, three-necked, round-bottomed flask equipped with an oval (Note 1) magnetic stir bar, a 500-mL addition funnel, a reflux condenser with a two-tap Schlenk adaptor connected to a bubbler and an nitrogen/vacuum manifold (Note 2) on the top, and a glass stopper is charged with 2 (12.0 g, 38.9 mmol, 1.0 equiv) by temporary removal of the glass stopper. Freshly distilled nitromethane (390 mL) (Notes (Note 23) and (Note 24)) is added into the reaction flask (Note 25) via the addition funnel. When the reaction mixture begins to reflux at 100 °C (Note 13), TMSOTf (0.7 mL, 0.1 equiv) (Note 26) is added via the addition funnel, which is rinsed with nitromethane (approximately 5 mL). After 60 min (Note 27) the reaction mixture is allowed to cool for 15 min before it is placed in an ice bath. After stirring for 5 min, saturated ammonium chloride solution (10 mL) is added.
After 15 min of stirring, the reaction mixture is then transferred into a 1-L round-bottom flask with dichloromethane (100 mL) before it is concentrated by rotary evaporation (45 ºC, approximately 4 mmHg). The resulting crude product is transferred into a 2-L separatory funnel using deionized water (2 x 50 mL) and ethyl acetate (3 x 100 mL). The layers are separated and the organic phase is collected into a 2-L Erlenmeyer flask. The aqueous phase is then extracted with ethyl acetate (2 x 200 mL) and the combined organic phases are washed with brine (200 mL), dried over MgSO4 (20 g), filtered through a coarse glass frit (Note 11) into a 2-L round-bottomed flask and concentrated by rotary evaporation (40 ºC, approximately 4 mmHg). The crude product is transferred using dichloromethane (2 x 50 mL) into a 250-mL round-bottomed flask equipped with an oval (Note 1) magnetic stir bar, then concentrated by rotary evaporation (40 °C, approximately 4 mmHg) and dried under reduced pressure (room temperature, 0.2 mmHg) for 30 min to yield a slightly purple powder. To the solid crude product is added ethanol (30 mL) (Notes (Note 5) and (Note 6)) and the suspension is heated to 90 °C for 20 min (Note 13). The solution is allowed to cool to room temperature for 40 min. The precipitated colorless crystals are filtered off through a coarse frit (Note 11), washed with cold ethanol (5 °C, 10 mL) (Note (Note 5) and (Note 6)) collected into a 250-mL round-bottomed flask and dried under reduced pressure overnight (room temperature, 0.08 mmHg), to give 5.36 g (67 % yield) of white crystals (Notes (Note 28), (Note 29) and (Note 30)).
2. Notes
1.
Length: 4 cm, diameter: 2 cm
2.
A picture of this adaptor can be found in:
Org. Synth. 2008,
85, 64-71.
3.
3,4-Dimethoxybenzaldehyde (99%) was purchased from Aldrich Chemical Company, Inc. and was ground to a fine powder before use.
4.
2,2-Dimethyl-1,3-dioxane-4,6-dione (98%) was purchased from Aldrich Chemical Company and was used as received.
5.
Ethanol (ACS reagent) was obtained from Fluka and was used as received.
6.
The graduated cylinder was oven-dried.
7.
Piperidine (99%, ReagentPlus) and
acetic acid (> 99.7%, ACS reagent) were obtained from Aldrich Chemical Company, Inc. and both reagents were used as received. The rate of addition of those compounds does not influence the outcome of the reaction.
8.
During the condensation, the reaction changed from a clear yellow mixture to a cloudy yellow mixture.
9.
Sodium triacetoxyborohydride (95%) was purchased from Aldrich Chemical Company, Inc. and was used as received.
Caution: After the addition of each portion of the reducing agent (mainly after the first two portions) strong hydrogen gas evolution is observed and the internal temperature of the reaction increases (from 25 °C to 36 °C). The checkers observed in some cases that upon the first addition of the reducing agent the reaction could not be stirred properly due to the increased viscosity of the reaction mixture. In this case an additional
80 mL of
ethanol were added.
10.
The reaction was monitored via TLC with 3:1
n-hexane/ethyl acetate as eluent (R
f value of 0.31). The color of the reaction mixture changed from cloudy yellow to cloudy white as sodium triacetoxyborohydride was added.
11.
A 125-mL filter funnel with a coarse frit, porosity 3, was used.
12.
Methanol (Exceeds ACS Specifications) was obtained from J.T. Baker and used as received.
13.
A silicon oil bath was used.
14.
The product displays the following physicochemical properties: pale yellow crystals; mp 136 °C. Lit. 142-144 °C;
1H NMR
pdf (CDCl
3, 400 MHz) δ: 1.48 (s, 3 H), 1.72 (s, 3 H), 3.45 (d,
J = 4.8 Hz, 2 H), 3.72 (t,
J = 4.8 Hz, 1 H), 3.84 (s, 3 H), 3.86 (s, 3 H), 6.77 (m, 1 H), 6.85-6.87 (m, 2 H);
13C NMR
pdf (CDCl
3, 400 MHz) Δ: 27.6, 28.6, 32.1, 48.5, 56.0 (2 C), 105.4, 111.3, 113.3, 122.2, 129.6, 148.3, 149.0, 165.6 (2 C); IR (ATM): 2993, 2943, 2860, 1782, 1747, 1516, 1447, 1259, 1155, 1020, 862 cm
-1; Anal. Calcd. for C
15H
18O
6: C, 61.20; H, 6.16, found: C, 61.07; H, 6.39.
15.
In some cases the product contained 5-8% of a side product. This side product was identified as the
alkylidene Meldrum's acid (Knoevenagel condensation intermediate). This product has the following analytical data:
1H NMR(CDCl
3, 400 MHz) Δ: 1.79 (s, 6 H), 3.96 (s, 3 H), 3.99 (s, 3 H), 6.96 (d,
J = 8.5 Hz, 1 H), 7.65 (dd,
J = 8.5, 2.0 Hz, 1 H), 8.31 (d,
J = 2.1 Hz, 1H), 8.37 (s, 1 H). The side product does not influence the outcome of the subsequent reactions, and it is removed in the recrystallization in Step B.
16.
Potassium carbonate (> 99.0%, ACS reagent) was purchased from Aldrich Chemical Company, Inc. and used as received.
17.
N,N-Dimethylformamide (certified ACS) was purchased from Aldrich Chemical Company and was freshly distilled over calcium hydride.
18.
The solvent was added using a syringe.
19.
Iodomethane (99%, stabilized with copper, ReagentPlus) was purchased from Aldrich Chemical Company, Inc. and used as received.
20.
Iodomethane was added over a period of 9 min (1 mL/minute). The internal temperature raised from 28 °C to 33 °C.
21.
The reaction was monitored via TLC with 3:1
n-hexane/ethyl acetate as eluent (R
f value of 0.30). The reaction mixture was a cloudy white solution.
22.
The product displays the following physicochemical properties: pale yellow crystals; mp 88-89 °C.
1H NMR
pdf (CDCl
3, 400 MHz) δ: 0.99 (s, 3 H), 1.61 (s, 3 H), 1.73 (s, 3 H), 3.28 (s, 2 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 6.69-6.77 (m, 3 H);
13C NMR
pdf (CDCl
3, 400 MHz) δ: 26.1, 28.7, 29.5, 44.7, 52.6, 56.0 (2 C), 105.4, 111.3, 113.2, 122.5, 128.0, 148.7, 149.1, 170.2 (2 C); IR (ATM): 3006, 2937, 2840, 1774, 1738, 1512, 1379, 1261, 1238, 1201, 1145, 1022, 980, 825, 680 cm
-1. Anal. Calcd for C
16H
20O
6: C, 62.33; H, 6.54. Found: C, 62.33; H, 6.42.
23.
Nitromethane (96%, Reagent Grade) was purchased from Aldrich Chemical Company, Inc. and was freshly distilled under nitrogen over calcium hydride behind a safety shield.
24.
The use of nitromethane gave optimal selectivity, yielding product
3 over its regioisomer,
6,7-dimethoxy-2-methyl-1-indanone (
4)
, in a >20:1 ratio. Since regioisomer
4 is an oil at room temperature, it was easily separated from product
3 through a simple recrystallization. The Friedel-Crafts acylation was also carried out at reflux in acetonitrile (
3:
4 ratio of 9:1), toluene (
3:
4 ratio of 8:1), and chlorobenzene (
3:
4 ratio of 7:1).
25.
The addition funnel was charged with the solvent using a cannula.
26.
TMSOTf (99%) was purchased from Aldrich Chemical Company, Inc. and distilled under vacuum at approximately 10 mmHg and stored in a Schlenk tube protected from light. TMSOTf was added over a period of 2 min (0.35 mL/min).
27.
The reaction was monitored via TLC with 2:1
n-hexane/ethyl acetate as eluent (R
f value of 0.31). The reaction mixture changed from yellow to dark purple over the course of one hour.
28.
The product displays the following physicochemical properties: white crystals; mp 133 °C. Lit. 132-133 °C;
1H NMR
pdf (CDCl
3, 500 MHz) δ: 1.29 (d,
J = 7.4 Hz, 3 H), 2.63 (dd,
J = 16.8, 3.4 Hz, 1 H), 2.69 (ddq,
J = 7.4, 7.4, 3.6 Hz, 1 H), 3.30 (dd,
J = 16.8, 7.4 Hz, 1 H), 3.90 (s, 3 H), 3.96 (s, 3 H), 6.86 (s, 1 H), 7.17 (s, 1 H);
13C NMR
pdf (CDCl
3, 500 MHz) δ: 16.8, 34.9, 42.3, 56.2, 56.3, 104.6, 107.5, 129.1, 148.9, 149.5, 155.6, 208.4; IR (ATM): 2963, 2925, 2838, 1679, 1588, 1496, 1461, 1427, 1364, 1318, 1239, 998, 834 cm
-1; Anal. Calcd. for C
12H
14O
3: C, 69.88; H, 6.84, found: C, 69.83; H, 6.89.
29.
To isolate the regioisomer, the reaction was performed in toluene and regioisomer
4 was purified using flash silica gel chromatography eluting with 2:1
n-hexane/ethyl acetate.
30.
The regioisomer,
6,7-dimethoxy-2-methyl-1-indanone, displays the following physicochemical properties: light yellow oil;
1H NMR CDCl
3, 300 MHz) Δ: 1.27 (d,
J = 7.2 Hz, 3 H), 2.57-2.72 (m, 2 H), 3.27 (dd,
J = 16.3, 7.7 Hz, 1 H), 3.86 (s, 3 H), 3.99 (s, 3 H), 7.04 (d,
J = 8.2 Hz, 1 H), 7.15 (d,
J = 8.2 Hz, 1 H);
13C NMR CDCl
3, 75 MHz) Δ: 16.1, 33.6, 43.0, 58.8, 61.5, 119.9, 120.8, 128.4, 145.9, 146.9, 150.9, 206.6; IR (CH
2Cl
2): 1708 cm
-1; HRMS
m/z calcd for C
12H
14O
3 (M
+): 206.0943. Found: 206.0945.
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
1-Indanones have proven synthetic utility in numerous biologically active natural products and play a major role in medicinal chemistry and the development of pharmaceuticals.
2 Although the intramolecular Friedel-Crafts acylation is the most powerful means of preparing 1-indanones, it suffers from significant drawbacks.
3 Typical procedures rely on the reaction of
carboxylic acids or acid chlorides with stoichiometric amounts of Brønsted or Lewis acids, which poses problems for cyclization precursor preparation, product isolation, and functional group compatibility. Our group has reported that the use of
Meldrum's acid as acylating agent provides a solution that overcomes the problems associated with the
carbocyclization of carboxylic acids or acid chlorides. Furthermore, the cyclization of Meldrum's acid derivatives provides an expedient and efficient entry into
2-substituted 1-indanones.
4 Enolizable benzyl Meldrum's acid derivatives are readily functionalized under mild reactions conditions. Such facile α-alkylations are significantly more difficult for
carboxylic acids and acid chlorides, and therefore synthesis of 2-substituted 1-indanones is typically performed after Friedel-Crafts acylation, where the standard difficulties of mono-alkylating ketones present themselves. In addition, compared to traditional acylation procedures, the generation of volatile and inert side products, acetone and CO
2, simplified product isolation.
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