Wittig reactions of benzaldehydes, alkanals, and cycloalkanals as well as of acetophenones are carried out with alkoxycarbonyl methylidenetriphenylphosphoranes in 10 w% aqueous NaOH, where the cinnamates and alkenoates produced are hydrolysed in situ and the corresponding acids are obtained after mostly simple extractive work-up, often without employing organic solvents. Under the same conditions, benzaldehydes are reacted with alkoxycarbonyl bromomethy-lidenephosphorane to produce 3-arylprop-2-ynoic acids (arylpropiolic acids).
Cinnamic acids and their derivatives have a wide range of uses. They can have antifungal [
Cinnamic acids have been prepared in a number of ways. Among them, the reaction of benzaldehydes with malonic acid is the most common (Knoevenagel reaction with subsequent decarboxylation [
Conventional Wittig reactions with stabilized phosphoranes have been carried under elevated temperature in organic solvents such as THF and benzene, sometimes under acid catalysis (Bestmann variation) [
In the following, a methodology is introduced which involves a one-pot olefination-hydrolysis sequence, where the unsaturated carboxylic acid is the final product, which can be isolated by acidification of the reaction medium, and, in the case of the cinnamic acid products, by simple filtration. The reaction sequence is well- suited for educational laboratories also, and has been shown to give reproducible good yields with our undergraduate students.
Experimental
General Remarks. Melting points were measured on a Stuart SMP 10 melting point apparatus and are uncorrected. Infrared spectra were measured with a Thermo/Nicolet Nexus 470 FT-IR ESP spectrometer. 1H and 13C NMR spectra were recorded with a Varian 400 NMR spectrometer (1H at 395.7 MHz, 13C at 100.5 MHz). The assignments of the carbon signals were aided by DEPT 90 and DEPT 135 experiments (DEPT = Distortionless Enhancement by Polarisation Transfer). The chemical shifts are relative to TMS (solvent CDCl3, unless otherwise noted). Mass spectra were measured with a JMS-01-SG-2 spectrometer, and with an Agilent QTOF 6540 UHD. Column chromatography, where necessary, was performed on silica gel (S, 0.063 mm - 0.1 mm, Riedel de Haen and Merck grade 9385).
2-Methoxybenzaldehyde (1a), 2,4-dimethoxybenzaldehyde (1g) and 4-benzyloxybenzaldehyde (1x) were prepared from the corresponding, commercially available hydroxybenzaldehydes (KOH, DMSO, CH3I or PhCH2Br) [
20 and 22 were prepared by Wittig olefination, starting from 2-benzyloxybenzaldehyde and benzoylmethylidenetriphenylphosphorane and from 2-benzyloxycinnamaldehyde (24) and toluoylmethylidenetriphenylphosphorane.
(E)-Cinnamic acid (3f). To a mixture of benzaldehyde (1f, 1.60 g, 15.1 mmol) and ethoxycarbonylmethylidenetriphenylphosphorane (2a, 6.82 g, 19.5 mmmol) was given an aq. NaOH solution (9.1 w%, 3.5 g (87.5 mmol) NaOH in 35 mL H2O) and the resulting suspension was stirred at 75˚C for 23 h. Triphenylphosphine oxide was filtered off the cooled solution. Thereafter, the filtrate was acidified carefully with 15 w% aq. HCl. The resulting suspension was cooled and filtered. The solid obtained was dried in air to give cinnamic acid (3f, 1.89 g, 77%) as a colorless solid; mp. 132˚C [Lit. 132˚C - 135˚C [
(E)-2-Methoxycinnamic acid (3a) (Procedure A). Colorless solid; mp. 187˚C [Lit. 183˚C - 186˚C [
(E)-4-Methoxycinnamic acid (3b) (Procedure A). Colorless solid; mp. 173˚C [Lit. 173˚C [
(E)-4-Ethoxycinnamic acid (3c) (Procedure A). Colorless solid, mp. 196˚C [Lit. mp. 195˚C - 199˚C [
(E)-4'-Propoxycinnamic acid (3d) (Procedure A). Colorless solid, mp. 155˚C [Lit. 155˚C [
(E)-4'-(N,N-Dimethylamino)cinnamic acid (3e) (Procedure A). Colorless solid, mp. 226˚C; [Lit. 227 - 228˚C [
(E)-2,4-Dimethoxycinnamic acid (3g) (Procedure A). Colorless solid, mp. 191˚C; [Lit. 192˚C - 194˚C [
(E)-2,5-Dimethoxycinnamic acid (3h) (Procedure A). Colorless solid; mp. 149 oC; [Lit. 148˚C - 150˚C [
4-Bromo-2,5-dimethoxycinnamic acid (3i) (Procedure A) as a mixture of E- and Z-isomers (72/28), pale yellow solid, mp. 177˚C - 180˚C (for the E-/Z-mixture); νmax (KBr/cm−1) [E/Z-mixture] 3502 - 2829 (bs, OH), 1687 (C=O), 1677 (C=O), 1629 (C=C), 1565, 1499, 1441, 1392, 1329, 1255, 1207, 1052, 987, 917, 867, 822, 739, 696, 638, 617, 541; (Z)-isomer δH (400 MHz, CDCl3) 3.80 (3H, s, OCH3), 3.84 (3H, s, OCH3), 6.01 (1H, d, 3J = 12.8 Hz), 7.07 (1H, s), 7.23 (1H, d, 3J = 12.8 Hz), 7.39 (1H, s); δC (100.5 MHz, CDCl3) 56.2 (OCH3), 56.3 (OCH3), 113.5 (Cquat), 114.8 (CH), 115.8 (CH), 119.0 (CH), 123.0 (Cquat), 140.4 (CH), 149.3 (Cquat), 151.8 (Cquat), 170.9 (Cquat, CO); (E)-isomer δH (400 MHz, CDCl3) 3.85 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.51 (1H, d, 3J = 16.0 Hz), 7.03 (1H, s), 7.13 (1H, s), 8.00 (1H, d, 3J = 16.0 Hz); δC (100.5 MHz, CDCl3) 56.3 (OCH3), 56.8 (OCH3), 111.6 (CH), 115.3 (Cquat), 116.9 (CH), 118.0 (CH), 122.6 (Cquat), 141.5 (CH), 150.2 (Cquat), 153.0 (Cquat), 172.2 (Cquat, CO); MS (EI, 70 eV) m/z (%) = 288 ([81BrM+, 11), 286 ([79BrM+, 13).
(E)-4-Methylcinnamic acid (3j) (Procedure A). Colorless solid, mp. 195˚C - 199˚C [Lit. 196˚C - 198˚C [
(E)-3-Chlorocinnamic acid (3k) (Procedure A). Colorless crystals, mp. 165˚C; [Lit. 161˚C - 164˚C [
3-Bromocinnamic acid (3L) (Procedure A). Colorless solid; mp. 170˚C [Lit. 177˚C [
(E)-3-Fluorocinnamic acid (3m) (Procedure A).Colorless solid; mp. 168˚C - 169˚C [Lit. 167˚C - 170˚C [
(E)-3,5-Dibromo-4-methoxycinnamic acid (3n) [
(E)-2-Bromo-4,5-dimethoxycinnamic acid (3o) (Procedure A).Colorless solid, mp. 240˚C - 244˚C [Lit. 246˚C - 247˚C [
(2E,4E)-5-Phenylpenta-2,4-dienoic acid (3p) (Procedure A). Pale yellow solid, mp. 165˚C - 166˚C [Lit. mp. 165˚C [
(E)-3-(Thien-2-yl)acrylic acid (3q) (Procedure A). Colorless solid, mp. 145˚C; [Lit. 145˚C - 148˚C [
(E)-5-Bromothien-2-ylacrylic acid (3r) (Procedure A). Colorless solid, mp. 207˚C [Lit. 209˚C - 210˚C [
(E)-3,4-Dimethoxycinnamic acid (3s) (Procedure A). Colorless solid, mp. 183˚C [Lit. 181˚C - 183˚C [
(E)-3,4-Diethoxycinnamic acid (3t) (Procedure A). Colorless solid, mp. 154˚C [Lit. 156˚C [
(E)-3,4-(Methylenedioxy)-cinnamic acid (3u) (Procedure A). Mp. 214˚C [Lit. 242˚C - 244˚C [
(E)-2-Chlorocinnamic acid (3v) (Procedure A). Colorless solid; mp. 200˚C [Lit. mp. 208˚C - 210˚C [
Ethyl (E)-4-nitrocinnamate (3w) and (E)-4-nitrocinnamic acid (3x). A mixture of 4-nitrobenzaldehyde (1w, 1.51 g, 10 mmol) and phosphorane 2a (4.87 g, 14 mmol) in chloroform (0.5 mL) was heated to 120˚C for 45 min. The cooled solution is subjected directly to column chromatography on silica gel (CHCl3/ether/hexane 1:1:1) to give 3w (1.97 g, 89%) as a light yellow solid; mp. 140˚C; [Lit. 138˚C - 140˚C [
(Z)-4-Benzyloxycinnamic acid (3y) (Procedure A). Colorless solid; mp. 168˚C; δH (400 MHz, DMSO-d6) 5.11 (2H, s, OCH2), 5.79 (1H, d, 3J = 12.8 Hz), 6.80 (1H, d, 3J = 12.8 Hz), 6.98 (2H, d, 3J = 8.8 Hz), 7.40 (2H, d, 3J = 8.4 Hz), 7.57 (2H, d, 3J = 8.4 Hz), 7.67 (2H, d, 3J = 8.8 Hz); δC (100.5 MHz, DMSO-d6) 68.8 (OCH2), 114.7 (2C, CH), 118.9, 121.4, 128.0, 129.2, 130.3 (2C, CH), 131.8 (2C, CH), 132.4 (2C, CH), 136.8, 141.2, 159.2 (Cquat), 168.0 (Cquat, CO); MS (Ion trap): m/z 255 (MH+).
Ethyl 3(E)-(9-anthranyl)propenoate (3z-Et). A mixture of 9-anthranylcarbaldehyde (1y, 1.0 g, 4.85 mmol) and ethoxycarbonylmethylidenephosphorane (2a, 2.36 g, 6.79 mmol) is heated at 130˚C for 3h. Thereafter, an additional amount of 2a (348 mg, 1.0 mmol) is added and the reaction mixture heated for another hour at 135˚C. The cooled solution is subjected directly to column chromatography on silica gel (eluent: MtBE/CHCl3/hexane 1:1:7) to give 3z-Et as a yellow-orange solid (1.23 g, 92%), mp. 80˚C [Lit. 80˚C [
Alternatively, to the reaction mixture of 1y and 2a, aq. NaOH (10 w%, 15 mL) was added after 4h, and the resulting solution was kept at reflux for 14 h. Thereafter, the solution was cooled and the precipitate was filtered off. The precipitate which contains both triphenylphosphine oxide and sodium 3(E)-(9-anthranyl)propenoate (3z-Na, see below) was washed diligently with hot water, to dissolve the remainder of the salt. Acidification of the cool filtrate with half conc. aq. HCl provides a precipitate, which was filtered, washed with water and dried to yield 3-(9-anthranyl)propenoic acid (3z) (1.02 g, 85%) as a yellow solid; mp. 242˚C [Lit. mp. 245˚C [
When heated with 10 w% aq. NaOH, 3-(9-anthranyl)propenoic acid (3z) gives sodium 3(E)-(9-anthranyl) propenoate (3z-Na) as golden, shiny leaflets νmax (KBr/cm−1) 3620 - 2850 (bs, OH), 3611 (v), 1635, 1540 (s), 1441, 1392, 1285, 991, 881, 734; δH (400 MHz, CDCl3) 6.14 (1H, d, 3J = 16.0 Hz), 7.50 (4H, m), 7.90 (1H, d, 3J = 16.0 Hz), 8.07 (2H, m), 8.20 (2H, m), 8.50 (1H, s).
4-Nitrobenzoic acid (4) and 4-nitrobenzyl alcohol (5). 4-Nitrobenzaldehyde (1w, 1.51 g, 10 mmol) and phosphorane 2a (4.87 g, 14 mmol) was given to an aq. NaOH solution (9.1 w%, 3.5 g (87.5 mmol) NaOH in 35 mL H2O) and the resulting suspension was stirred at 75˚C for 20 min. With the addition of 4-nitrobenzaldehyde, the solution turned dark-red. The solution was filtered, and the filtrate was extracted with dichloromethane (3 × 25 mL). Then, the aqueous solution was acidified with half-conc. aq. HCl to give 4-nitrobenzoic acid (4) (800 mg, 48%) as a colorless solid, mp. 237˚C [Lit. 237˚C - 240˚C [
(E)-4-Hydroxycinnamic acid (6) [
While general procedure A was used for the preparation of 8b, 8d/8e, and 8f, the E- and Z-isomers of 8b and 8f and compound 8d and 8e were separated by column chromatography on silica gel (CHCl3/ether 10:1) and crystallized from a mixture of CHCl3-hexane (1:4).
(E)-3-Phenylbut-2-enoic acid (8a) (Procedure A). Colorless solid, mp. 129˚C - 131˚C [Lit. 131˚C [
(Z)-3-(4-Chlorophenyl)but-2-enoic acid (Z-8b) [
(E)-3-(4-Bromophenyl)but-2-enoic acid (8c) (Procedure A). Colorless solid, mp. 116˚C [Lit. 116˚C [
(E)-3-(4-Iodophenyl)but-2-enoic acid (8d) (Procedure A) [
(E)-3-Phenylpent-2-enoic acid (E-8f) (Procedure A). Colorless solid, mp. 93˚C [Lit. 95˚C [
(E)-4-Phenylbut-2-enoic acid (8g) (procedure A). Beige solid, mp. 96˚C [Lit. 97˚C [
Ethyl (E)-3-anthran-1-ylbut-2-enoate (10b). A mixture of 1-acetylanthracene (300 mg, 1.36 mmol), phosphorane 2a (760 mg, 2.18 mmol), and benzoic acid (30 mg, 0.25 mmol) in benzene (8 mL) was heated at 80˚C for 12 h. After 3 h, additional 2a (300 mg, 0.87 mmol) was added. The cooled reaction mixture was concentrated in vacuo and subjected to column chromatography on silica gel (ether/CHCl3/hexane 1:3:3) to give 10b (25 mg, 6%) as a colorless oil. ν (neat/cm−1) 1720 (C=O), 1634, 1170; δH (400 MHz, CDCl3) 1.35 (3H, t, 3J = 7.2 Hz), 2.70 (3H, d, 4J = 1.2 Hz), 4.28 (2H, q, 3J = 7.2 Hz), 6.07 (1H, q, 4J = 1.2 Hz), 7.25 (1H, d, 3J = 6.8 Hz), 7.42 (1H, dd, 3J = 8.4 Hz, 3J = 6.8 Hz), 7.47 - 7.48 (1H, m), 7.95 ? 8.00 (3H, m), 8.41 (1H, s), 8.44 (1H, s); δC (100.5 MHz, CDCl3) 14.3 (CH3), 21.6 (CH3), 60.0 (OCH2), 120.6 (CH), 123.5 (CH), 124.2 (CH), 124.6 (CH), 125.6 (CH), 125.8 (CH), 126.8 (CH), 127.3 (Cquat), 127.6 (Cquat), 127.9 (CH), 128.5 (2C, CH), 128.7 (Cquat), 131.5 (Cquat), 131.8 (Cquat), 142.1 (Cquat), 166.8 (Cquat, CO).
For the preparation of 12a - 12c, general procedure A was used. After acidification of the reaction medium after completion of the reaction, the aqueous phase was extracted with CHCl3. The organic phase was dried over MgSO4, concentrated in vacuo and the residue was filtered over a small layer of silica gel (ether/CHCl3 1:1).
5,9-Dimethyldeca-2,8-dienoic acid (12a) [
(E)-Dec-2-enoic acid (12b) [
3-Cyclohexylpropenoic acid (12c). Colorless solid, mp. 53˚C [Lit. 57˚C - 58˚C [
Phenylpropiolic acid (13b). To a mixture of benzaldehyde (1f, 763 mg, 7.2 mmol) and ethoxycarbonylbromomethylidenetriphenylphosphorane (2b, 4.0 g, 9.4 mmol) was given aq. NaOH solution (10 w%, 1.8 g NaOH in 18 mL H2O) and the resulting suspension was stirred at 85˚C for 16 h. Triphenylphosphine oxide was filtered off the cooled solution. Thereafter, the filtrate was acidified carefully with 15 w% aq. HCl. The resulting suspension was cooled and filtered. The solid obtained was dried in air to give phenylpropiolic acid (13b, 589 mg, 56%) as a colorless solid. An analytical sample gave mp. 133˚C [Lit. 135˚C - 137˚C [
4-Methoxyphenylpropiolic acid (13a) (Procedure B). Pale yellow solid, mp. 143˚C [Lit. 144˚C [
3-Chlorophenylpropiolic acid (13c) (Procedure B). Colorless solid, mp. 145˚C [Lit. 144˚C [
3,4-Dimethoxyphenylpropiolic acid (13d) (Procedure B). Colorless solid, mp. 154˚C [Lit. 152˚C - 153˚C [
When a mixture of benzaldehyde 1 and ethoxymethylidenetriphenylphosphorane (2a, 1.3 eq.) is heated in a 10 w% aq. NaOH solution, sodium cinnamates are formed by Wittig olefination and subsequent ester hydrolysis. Upon neutralization of the aqueous solutions with 10 w% - 15w% aq. HCl, cinnamic acids 3 are obtained by easy filtration and drying of the solids in air. With this procedure, cinnamic acids 3 could be synthesized (
Even solid 3e can be filtered off from the neutralized solution easily, as the anilinic nitrogen in 3e is not basic enough to be protonated upon careful neutralization of the reaction mixture. Most of the cinnamic acids are produced in good E-selectivity. However, for phenylpenta-2,5-dienoic acid (3p), 2,4-dimethoxycinnamic acid (3g), 2,5-dimethoxycinnamic acid (3h) and especially 3-bromo-2,5-dimethoxycinnamic acid (3i) anoticable quantity of Z-isomer is formed.
4-Nitrobenzaldehyde (1w) is not an adequate substrate for this one-pot procedure, even though 4-nitroben- zaldehyde (1w) and ethoxymethylidenetriphenylphosphorane (2a) give the Wittig product3wfacilely, when the reaction is performed in chloroform (Scheme 1). Also, the ester hydrolysis of 3w in 10 w% aq. NaOH proceeds
*no additive; **tetramethylammonium bromide (0.15 eq. Bu4NBr) addad.
readily, and 3x is obtained, which can be filtered off and dried after acidification of the reaction solution. Yet, in 10 w% aq. NaOH, 4-nitrobenzaldehyde (1w) undergoes a rapid Cannizzaro reaction, which would be expected to be the general competing pathway for benzaldehydes in aqueous basic media. However, with the exception of the nitro-substituted benzaldehydes, Cannizzaro is not noted to be a main side reaction for the benzaldehydes used. The reason for this may be that the Wittig olefination ensues rapidly in the lipotropic droplets formed by themixture of benzaldehyde and phosphorane, initially suspended in the aqueous solution. In the case of 4-nitrobenzaldehyde (1r) in 10 w% aq. NaOH, a deep red homogeneous solution is produced immediately, from which one of the Cannizzaro products, 4-nitrobenzoic acid (4), can be obtained facilely by extraction of the side product with CH2Cl2 and acidification of the aqueous phase with subsequent extraction of the phase and crystallization of the obtained product [
In the case of 1x (
Scheme 1. Comparison of the sequential Wittig olefination?hydrolysis reaction of 4-nitrobenzaldehyde (1w) leading to cinnamic acid 3x and the reaction under one pot conditions leading to Cannizzaro products 4 and 5.
fraction. The E-isomer could not be detected. At 70˚C, triphenylphosphine oxide and the Wittig product develop liquid hydrophobic micelles. Ester hydrolysis takes place at the micelle boundary, and it may be that the ethyl (E)- p-benzyloxycinnamate, more easily forming intermolecular layers within the micelle, is not as readily accessible as the Z-isomer. It must also be noticed that under the strongly basic conditions, the benzyloxy function is not sufficiently stable and is severed to provide the hydroxy-substituted compound. That micelles play a role in the ester hydrolysis can be seenin alkyl cinnamates with larger residues, such as in ethyl phenylpenta-2,4-dienoate, where the addition of tetramethylammonium bromide [(CH3)4NBr] leads to more yield in phenylpenta-2,4-dienoic acid (3p).
In cases, where the arylcarbaldehydes undergo Wittig reaction with alkoxycarbonylmethylidene phosphoranes slowly and only at higher temperatures at which the phosphoranes are already hydrolysed, a variant of the reaction protocol can be employed. First, the aldehyde is reacted with the phosphorane under solventless conditions at higher temperatures. Thereafter, 10 w% aq. NaOH is added to the reaction mixture, and the reaction is completed. 9-Anthranylcarbaldehyde (1t) represents such a case, where the aldehyde undergoes Wittig olefination only sluggishly due to the steric congestion around the carbaldehyde function. 1t can be reacted with 2a under solventless conditions at 130˚C [
The same solventless procedure was followed, when reacting 4-hydroxybenzaldehyde (1z) with phosphorane 2a at 140˚C for 90 min. Thereafter, the mixture was taken up in 10 w% aq. NaOH and stirred at rt for 30 min., after which the triphenylphosphine oxide was filtered off, and the filtrate acidified with half-conc. aq. HCl to give 4-hydroxycinnamic acid (6, p-coumaric acid) (Scheme 3). Previously, 4-hydroxycinnamic acid had been prepared by Horner Emmons olefination [
Acetophenones 7 have been subjected successfully to the one-pot Wittig olefination-hydrolysis, too (
Scheme 2. Solventless Wittig reactionand subsequent hydrolysis without work-up of 3z.
Scheme 3. Preparation of p-coumaric acid (6) by solventless Wittig-olefination with basic extractive work-up.
E/Z-isomers. The E-isomer could be obtained in pure form by recrystallization from 1:1 v/v CH2Cl2/hexane. In order to obtain both isomers in pure form, the mixture was subjected to chromatography on silica gel (hexane/EtOAc 2:1). The reaction is dependent on the steric bulkiness of the ketone, where bulkiness in the ketone leads to a sterically congested transition state in the Wittig olefination. Thus, 1-acetylanthracene (9) does not react under the conditions to the respective acid at all. 9 reacts with phosphorane 2a sluggishly, and produces butenoate 10b after 12 h in refluxing chloroform in the presence of benzoic acid as acid catalyst only in trace amounts. Under the conditions of the one-pot Wittig olefination?ester hydrolysis, much of the phosphorane 2a hydrolyses before undergoing Wittig olefination with 9 (Scheme 4).
Alkanals and alicyclic carbaldehydes 11 have also been reacted in a one-pot Wittig olefination-hydrolysis reaction. The yields of the corresponding unsaturated acids 12 were slightly lower than for aromatic aldehydes. Also, the obtained carboxylic acids could not be purified simply by crystallization through addition of hydrochloric acid to the reaction mixture. Rather, they have to be extracted after the acidification of the reaction mixture and subjected to column chromatography on silica gel (Scheme 5).
When a mixture of (substituted) benzaldehyde 1 and ethoxybromomethylidenetriphenylphosphorane (2b, 1.3
Scheme 4. Wittig reaction of 1-acetylanthracene (9) with phosphorane.
Scheme 5. One-pot transformation of alkanals and alicyclic aldehydes.
eq.) is heated in a 10 w% aq. NaOH solution, arylpropiolic acids 13 can be isolated upon careful neutralization of the aqueous solution (
We have developed two simple procedures from benzaldehydes to cinnamic acids and to phenylpropiolic acids, respectively, utilizing a modified Wittig-olefination protocol. The reactions and the work-up are performed without any organic solvents in most cases here described. Yields are reproducibly good. The one-pot procedure of olefination and ester hydrolysis can be utilized with alkanals and acetophenones, also. Here, however, chromatographic separation of the products is necessary in some cases.
In former times, the Wittig olefination reaction has not been viewed as a green reaction due to its poor atom- economy. Recently, however, a dedicated effort has seen the development of numerous methods to recycle the toxic triphenylphosphine oxide [
Thies Thiemann,Mohamed W. Elshorbagy,Mostafa H. F. A. Salem,Siraj A. N. Ahmadani,Yosef Al-Jasem,Mariam Al Azani,Mazen A. M. Al-Sulaibi,Bassam Al-Hindawi, (2016) Facile, Direct Reaction of Benzaldehydes to 3-Arylprop-2-Enoic Acids and 3-Arylprop-2-Ynoic Acids in Aqueous Medium. International Journal of Organic Chemistry,06,126-141. doi: 10.4236/ijoc.2016.62014