02-24-04 08:31
No 490756
I seem to stumble upon a lot of neat stuff these days. Yesterday i came into possession of quite an amount of 3,4,5-trimethoxybenzoylchloride. Happily not nociting that damned "o" i sang a little song and did a little dance. After some time i did notice that someone actually had been blasphemic enough to attach an oxygen to this otherwise wonderfull molecule.
Not, this stuff seems so close to the obvious end material that i could cry. Anr bright ideas on how to turn this into something usefull? The only this i could come up with is to reduce the acidchloride to the benzylalcohol, and turn this into the benzylchloride using thionylchloride or something similar, and then proceed with making the benzylnitrile.
Any brilliant ideas folks?
Regards
Bandil
Nuke the whales!
(Hive Bee)
02-24-04 09:49
No 490761
To convert the Bezoylchloride into Benzaldehyde see:
Patent DE333154
roger2003
(The Archetypical "Good Guy")
02-24-04 10:00
No 490764
Thanks Roger!
The platinium / palladium catalysts does not pose a problem. I do not have access to hydrogenation apparatus unfortunately, so any ideas that does not involve hydrogenation?
Regards
Bandil
Nuke the whales!
(Wonderful Personality)
02-24-04 10:29
No 490770
The procedure in the patent doesnt involve pressure, so no Parrshaker would be needed, only Pt-catalyst and hydrogen with (boiling) toluene as solvent. But the chloride might have to get converted to the bromide as yields with the chloride suck (10-25%). With the bromide 90%+ are possible. I believe this is related to catalyst poisoning here.
ADDON:
perhaps this way:
Condensation of the benzoyl chloride with diethyl ethoxymagnesiummalonate, followed by hydrolysis of the ester.
Organic Syntheses, CV 4, 573
Preparation of o-methoxyphenylacetone
(Hive Bee)
02-24-04 20:41
No 490838
1.) Maybe the most practical reduction to the benzaldehide would be with the Rosenmund catalyst (http://themerckindex.cambridgesoft.com/
3,4,5-Trimethoxybenzaldehyde. (../rhodium /mescal
To a solution of 200 g. of 3,4,5-trimethoxy benzoyl chloride in 1000 cc of xylene freshly distilled over sodium, there is added 60 g. of a 5 % palladium-barium sulfate catalyst. The mixture is heated in an oil bath maintained at 150 deg C and a vigorous stream of hydrogen is introduced into the boiling solution. The hydrogen should be washed with aqueous permanganate and the dried with sulfuric acid. After 60-80 hours the reaction is complete. The solution is filtered and the aldehyde conveniently isolated as its bisulfite compound. Yield 120 g. (70.6 % of theory), m.p. 74 deg C.
2.) The use of selective hydride reagents like DIBAL-H, RED-AL, LiAlH(OBut)3 usually requires low temperatures (<-70°C) and is more often done on the esters or amides (but getting an ester of your acylchloride is no sweat). But even if you make this reagents in situ from LiAlH4 it is still not cheap, safe and easy besides being unpractical (or unavailable) working at such low temperatures.
3.) Another somewhat more accessible reduction might be the McFadyen-Stevens reaction (http://themerckindex.cambridgesoft.com/
P.S. Does anybody knows if NaBH4 can reduce benzoylchlorides to benzylalcohols in aprotic solvents? I saw this slightly mentioned in a book, but there were no references.
“The real drug-problem is that we need more and better drugs.” – J. Ott
(The Archetypical "Good Guy")
02-25-04 08:19
No 490958
Thank you all for your nice ideas!
I just really really resent the idea of playing with hydrogen without the correct equipment. I think i'll just go for the reduction to the benzylalcohol and follow the standard route from there. Nothing like a good old challenge eh'?
Regards
Bandil
Nuke the whales!
(Stranger)
02-25-04 08:32
No 490961
this was the precursor for the original mescaline synthesis, using the Rosenmund reduction mentioned. you can turn it into many useful things that have been used to make PEA's, but its a long road from anything besides CHO and CH2OH. captain obvious strikes again. im sure you know and am sure you will have anhydrous conditions anyways, but just know i ought to post this:
-if this 3,4,5 cpd is anything like the unsubbed cpd it hydrolyzes easy to the benzoic acid, especially when you dont want it to. its a lot of steps from benzoic acid to PEA if you dont have a hydride.
on that note, anyone know if Na alkoxide reduces benzoic esters to alcohol like it does other esters? and what are the yields with NaBH4/benzoic ester? who wants to read for me?
yeah, i saw the acyl halide to aldehyde via NaBH4 in DMF/THF too, and dont know if it applies either. but i do know that LAH or NaBH4 would be very handy for you to arrive at the benzyl OH, as you know. and benzyl alcohols can be turned in to benzyl Cl at RT w/HCl alone. tho its usually done cold. i assume this has something to do with ether cleavage.
hopefully this will get everyone to get some Pd, LAH, or at least NaBH4. even basic chemistry like this sucks without them.
(Moderator)
02-25-04 11:04
No 490980
Think Grignard...
(The Archetypical "Good Guy")
02-25-04 11:51
No 490982
Hmm... yes?
As far as i can see a grignard reactant will add twice to give an alcohol with two new alkyl groups attached. How is this usefull?
Lithium dialkylcuprate could be used, which would add once to form a ketone with one alkyl chain attached. Maybe something far out could be made with that compound, but it's not as "attractive" as a single LAH reduction followed by the usual route...
Regards
Bandil
Nuke the whales!
(Hive Bee)
02-25-04 15:59
No 491005
If you were to make the acetophenone or propiophenone via an organometallic compound, you could then brominate to give the alpha-bromoketone, followed by the addition of sodium azide. Reduce the formed azidoketone to the azidoalcohol, acetylate and CTH to the amine.
Based on experience, the transformation of the acetophenone/propiophenone to the azidoalcohol should be very high yielding. I have yet to test the next two steps, but they are based on a combination of Preparation of amphetamines from phenylpropanolamine (../rhodium /amph.c
There are also many ways of reducing the benzoylchloride to the benzyl alcohol, using various borohydrides, often in very high yield. I use the example below because the yield is so impressive, but there are 25 other refs for the same transformation, most of which use less exotic reagents:
Reaction Classification: Preparation
Yield: 100 percent (BRN=878307)
Reagent: (i-PrO)2TiBH4
Solvent: CH2Cl2
Time: 8 minutes
Temperature: -20oC
Ref. 1: Ravikumar, K. S.; Chandrasekaran, Srinivasan; J.Org.Chem.; 61; 3; 1996; 826-830.
I'll post some refs for the same reduction using NaBH4 (though in slightly lower yield) if anyone's interested.
(Hive Bee)
02-25-04 18:30
No 491036
I'll post some refs for the same reduction using NaBH4 (though in slightly lower yield) if anyone's interested.
I'm interested. It sounds much better than using LAH (not to mention more accesible).
“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
02-25-04 21:36
No 491054
(Rated as: good read)
All the following refs are for the unsubstituted benzoyl chloride -> benzyl alcohol transformation, but aryl alkyl ethers are stable to borohydrides so the procedures should be just as applicable to 3,4-5-trimethoxybenzoyl chloride:
Reductions with plain sodium borohydride:
Reaction Classification: Preparation
Yield: 78 percent
Reagent: NaBH4
Solvent: various solvent(s)
Time: 3 hour(s)
Temperature: 80oC
Ref. 1: Santaniello, Enzo; Fiecchi, Alberto; Manzocchi, Ada; Ferraboschi, Patrizia; J.Org.Chem.; 48; 18; 1983; 3074-3077.
Reaction Classification: Preparation
Reagent: NaBH4
dioxane
Ref. 1: Chaikin; Brown; J.Amer.Chem.Soc.; 71; 1949; 122, 124.
Reaction Classification: Preparation
Reagent NaBH4
dioxane
Ref. 1: Schlessinger; Brown; Patent US2683721; 1952.
Reductions using modified sodium borohydride:
Reaction Classification: Preparation
Reagent: NaBH4
AlCl3
O,O'-dimethyl-diethylene glycol
Ref. 1: Brown; Subba Rao; J.Amer.Chem.Soc.; 78; 1956; 2582, 2587.
With sodium trimethoxyborohydride:
Reaction Classification Preparation
Reagent: sodium trimethoxy borate
diethyl ether
Ref. 1: Brown; Mead; J.Amer.Chem.Soc.; 75; 1953; 6263.
Sodium trimethoxyborohydride can be made from sodium hydride and methyl borate as in the equation:
NaH + B(OCH3)3 -> NaBH(OCH3)3
And finally with LAH/SiO2 in quantitative yield:
Reaction Classification: Preparation
Yield: 100 percent
Reagent: LiAlH4/SiO2
Solvent: hexane
Time: 3 hour(s)
Temperature: 25oC
Ref. 1: Kamitori, Yasuhiro; Hojo, Masaru; Masuda, Ryoichi; Izumi, Tatsuo.; Inoue, Tatsuro; Synthesis; 5; 1983; 387-388.
Edit: On page 3 of the linked patent there is some nice information:
The hydrogenation of benzoyl chloride
In a 1-liter round-bottom flask fitted with a condenser, stirrer and dropping funnel is placed 200ml of anhydrous ethyl ether and 128g (1.00 mole) of sodium trimethoxyborohydride. To the stirred suspension is added a solution of 70g benzoyl chloride dissolved in anhydrous ethyl ether. A vigorous reaction ensues. The acid chloride should be added to the hydrogenation agent slowly, at such a rate that the ether refluxes gently. After the acid chloride has been added, the mixture is permitted to stand for 1 hour and 200ml water is added. The reaction mixture is then poured into a separatory funnel, the ether layer is separated and dried with calcium hydride. The ether is removed on a steam cone and the benzyl alcohol is obtained by distilation under vacuum. The product yield is 49g., B.P. 93-96o at 11mm., nD25 1.5375. The yield is 90% of the theoretical. By addition of sodium trimethoxyborohydride (1.00 mole) to benzoyl chloride (1.00 mole) in ether at 0o, benzaldehyde is formed. The benzaldehyde is conveniently recovered as its bisulfite addition compound. It was converted into the phenylhydrazone, M.P. 154-156o.
(Stranger)
02-25-04 22:52
No 491073
(Rated as: good read)
acyl Cl=>(benz)aldehydes:
Reduction of Acid Chlorides with NaBH4 in DMF...
Babler & Invergo, Tetrahedron Letters 22(1), 11-14 (1981)
Post 306703 (PEYOTE: "Acid Chlorides to Aldehydes w/o Rosenmund", Chemistry Discourse)
All of these NaBH4 reductions seem to use THF/DMF to make the borate, but JCS Perkin Trans. 1, 27, 1980 uses CH3CN and Cd salt i guess.
a way that looks better than these reacts the COCl at RT 24 hrs. with NaBH4 in THF/DMF(1:1) then the borate/solvents reacts with PCC in CH2Cl2 at RT 24 hrs. for high yield of the aldehyde:
Reductive Oxidation of Acid Chlorides to Aldehydes with Sodium Borohydride and Pyridinium Chlorochromate
Jin Soon Cha and Dae Yon Lee
Bull. Korean Chem. Soc. Vol. 21(12), 1260-1263 (2000) (http://journal.kcsnet.or.kr/publi/bul/b
(The Archetypical "Good Guy")
02-26-04 13:26
No 491218
Ahhh, sweet! Borohydride will do the job
Guess that's settled then. Thanks folks!
Regards
Bandil
Nuke the whales!
(Hive Addict)
02-29-04 18:06
No 491806
(Rated as: excellent)
This is related to the article posted in Post 389178 (demorol: "Acid chlorides -> aldehydes", Novel Discourse), but here the authors substituted NaBH4 for LAH with equally good results, as was mentioned in Post 491073 (gsus: "acyl Cl=>(benz)aldehydes", Chemistry Discourse).
Reductive Oxidation of Acid Chlorides to Aldehydes with Sodium Borohydride and Pyridinium Chlorochromate
Jin Soon Cha* and Dae Yon Lee Department of Chemistry and Institute of Natural Science, Yeungnam University, Kyongsan 712-749, Korea Received July 19, 2000
Bull. Korean Chem. Soc. (2000) Vol. 21, No. 12
Full-text PDF: http://journal.kcsnet.or.kr/publi/bul/bu
The establishment of a simple, general and practical method to get aldehydes from acid chlorides is one of the most desirable objects in organic synthesis. Recently, we reported that the oxidation of alkoxyaluminum intermediates, which are formed by reduction of acid chlorides with aluminum hydride, with pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC), affords aldehydes in excellent yields.1 But this method did not provide a really simple and practical procedure. The reducing agent, aluminum hydride, exhibits a very strong reducing power which results in attacking almost all of the organic functional groups.2 In addition to this, the reagent should be prepared just prior to use.2a Recently, we successfully applied sodium borohydride, a very mild and economical reducing agent, to the reductive oxidation for conversion of carboxylic acids to aldehydes.3 On the basis of these results, we decided to utilize sodium borohydride as a reducing agent to carry out reductive oxidation to convert acid chlorides to aldehydes. Herein, we introduce a new method, which effects the transformation of acid chlorides to aldehydes in excellent yields.
Although there has already been reported that sodium borohydride reduces acid chlorides to alcohols readily,4 we re-examined such reductions in THF or THF-DMF. The reagent reduce both aromatic and aliphatic acid chlorides to the corresponding alcohols in refluxing THF (Procedure A) or in THF-DMF (1 : 1) at 25° (Procedure B) both in 24h : the yields of alcohols from both procedures were higher than 98%. We applied such procedures to reduction of acid chlorides to the corresponding alkoxyborates stage, and the resultant borates are then subjected to the oxidation procedure with PCC. As shown in Table 1, this procedure provides a clean and convenient conversion of acid chlorides to aldehydes. Both aliphatic and aromatic acid chlorides are readily converted to the corresponding aldehydes in excellent yields. The oxidation of aliphatic borates requires 2.5 equivalents of PCC, while the oxidation of aromatic borates needs only 10% excess. However, the oxidation in THF-DMF-CH2Cl2 (1 : 1 : 2) appears to be more effective than the procedure in THF-CH2Cl2 (1 : 1). Therefore, it appears that the reduction of acid chlorides in THF-DMF (1 : 1) at 25° (Procedure B) followed by oxidation of the resultant alkoxyborates with PCC in THF-DMF-CH2Cl2 (1 : 1 : 2) is recommendable for conversion of acid chlorides to aldehydes.
This reaction is broadly applicable as many substituents, such as chloro, methoxy, nitro and alkenyl groups are tolerated. The tolerance of sodium borohydride toward a wide variety of functional groups as well as its ease of handling and low cost, combined with the mild nature of PCC as an oxidizing agent, makes this method simple, general and practical. It is noteworthy that the use of sodium borohydride can provide more selective reactions than the use of aluminum hydride, because sodium borohydride is milder and hence more selective than aluminum hydride.2 Moreover, we are now free from preparing a solution of aluminum hydride prior to use. Consequently, this method provides another useful procedure for direct conversion of acid chlorides to the corresponding aldehydes.5,6
Experimental
All glassware used was dried thoroughly in a drying oven at 130°, assembled hot, and cooled under a stream of dry nitrogen prior to use. All reactions and manipulations of air and moisture-sensitive materials were carried out under a dry nitrogen atmosphere. All chemicals were commercial products of the highest purity which were carefully purified by standard methods before use. The acid chlorides were commercial products and purified by distillation. Tetrahydrofuran (THF) was distilled from benzophenone-sodium ketyl. Sodium borohydride (NaBH4) and pyridinium chlorochromate (PCC) were used as received from Aldrich Chemical Co. Yields reported in all cases are of analytically pure compounds. GC analyses were carried out on a Varian 3300 FID chromatograph equipped with a Varian 4400 integrator using Carbowax 20M capillary column.
Reduction of Acid Chlorides (Formation of Alkoxyborate Intermediates). The following two different procedures for the reduction of acid chlorides to alkoxyborate intermediates are listed in Table 1.
Procedure A: Into on oven-dried, 100-mL, round-bottomed flask with a side-arm, fitted with a silicon rubber cap, a magnetic stirring bar, and a reflux condenser connected to a mercury bubbler was introduced 0.38 g (10 mmol) of sodium borohydride, followed by 18 mL of THF. To this slurry, 1.40 g (10 mmol) of benzoyl chloride was added. The reaction mixture was then brought to a gentle reflux for 24h with vigorous stirring. The reaction mixture was subjected to oxidation (vide infra). Procedure B: Into a 100-mL flask equipped as described above (Procedure A), was added 0.38 g (10 mmol) of sodium borohydride, followed by 9 mL of THF and 9 mL of DMF. Finally, 1.40 g (10 mmol) of benzoyl chloride was added to this solution of sodium borohydride with stirring. The reaction mixture was stirred for 24h at room temperature, and then subjected to oxidation (vide infra).
Oxidation of Alkoxyborate Intermediate. To a wellstirred suspension of PCC (2.4 g, 11 mmol) in methylene chloride (18 mL) taken in a 100-mL flask, was added dropwise the above reaction mixture (from procedure A or B) using a cannula. The mixture was stirred for 24h at room temperature. GC analysis of an aliquot using tridecane as an internal standard indicated a yield of 99%.
Isolation of Product Aldehydes. The procedure for the isolation of benzaldehyde in the reaction mixture is illustrative. In the usual setup, 60 mmol of benzoyl chloride was reduced with 60 mmol of sodium borohydride in a THF-DMF (1 : 1) mixture solvent (108 mL) at room temperature for 24h, the same as the procedure B described above. The reaction mixture was then oxidized with PCC (14.3 g, 66 mmol) in methylene chloride (108 mL) at room temperature for 24h. The mixture was diluted with ethyl ether (200 mL) and the supernatant liquid was filtered through Florisil (110 g) contained in a 300-mL sintered glass funnal. The solid residue was triturated with ethyl ether (3 x 50 mL) and passed through the same Florisil column. The filterate was then concentrated and distilled under reduced pressure to give 5.16 g (81%) of pure benzaldehyde, bp. 63-65o (16 mm). The 1H NMR spectrum agreed with that of an authentic sample.
Acknowledgment. This work was supported by Korea Research Foundation Grant (KRF-99-005-D00054). The 1H NMR spectra were recorded on a Bruker AMX 300 spectrometer at the Yeungnam University Instrumental Analysis Center.
Table 1. Conversion of Acid Chlorides to Aldehydes by Reductive Oxidation with Sodium Borohydride (NaBH4) and Pyridinium Chlorochromate (PCC)
| Acid Chloride | Product | Reduction Procedurea,b (A or B) | Oxidationc,d Time (h) | Yield (%)e |
| Butyryl | Butyraldehyde | B | 6 | 95 |
| Isobutyryl | Isobutyraldehyde | B | 6 | 96 |
| Hexanoyl | Hexanal | A/(B) | 6, 24/(6) | 92, 94/(71f, 97(80)) |
| Trimethylacetyl | Trimethylacetaldehyde | A/(B) | 6/(6) | 93/(61f, 96) |
| Trichloroacetyl | Trichloroacetaldehyde | B | 6 | 95 |
| Cyclopropanecarbonyl | Cyclopropanecarboxaldehyde | B | 6 | 97 |
| Cyclohexanecarbonyl | Cyclohexanecarboxaldehyde | B | 6 | 98 |
| Cinnamoyl | Cinnamaldehyde | B | 6 | 97 |
| Benzoyl | Benzaldehyde | A/(B) | 6, 24/(6, 24) | 98, 99/(94, 99f, 99(81)) |
| 1-Naphthoyl | 1-Naphthaldehyde | B | 6 | 98 |
| 2-Naphthoyl | 2-Naphthaldehyde | B | 6 | 97 |
| o-Toluoyl | o-Tolualdehyde | B | 6 | 96 |
| p-Toluoyl | p-Tolualdehyde | A/(B) | 6/(6) | 94/(99) |
| 2-Chlorobenzoyl | 2-Chlorobenzaldehyde | A/(B) | 6/(6) | 91/(97) |
| 4-Chlorobenzoyl | 4-Chlorobenzaldehyde | A/(B) | 6/(6) | 90/(98) |
| o-Anisoyl | o-Anisaldehyde | A/(B) | 6/(6) | 90/(97) |
| p-Anisoyl | p-Anisaldehyde | A/(B) | 6/(6) | 90/(98) |
| 4-Nitrobenzoyl | p-Nitrobenzaldehyde | A/(B) | 6/(6) | 92/(97) |
a Treated with 1 equiv NaBH4. b Procedure A: reacted for 24h in refluxing THF; Procedure B: reacted for 24h at 25° in a THF-DMF (1 : 1) mixture solvent. c In a THF-CH2Cl2 (1 : 1) or THF-DMF-CH2Cl2 (1 : 1 : 2) mixture solvent. d Reacted with 2.5 equiv PCC for aliphatic acid chlorides and 1.1 equiv for aromatic acid chlorides at room temperature. e GC yields; the values in parentheses are isolated yields. f Reacted with 2 equiv PCC at room temperature.
References
1. Cha, J. S.; Kim, J. M.; Chun, J. H.; Kwon, O. O.; Kwon, S. Y.; Han, S. W. Org. Prep. Proced. Int. (1999) 31, 204.
2. (a) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. (1966) 88, 1464.
(b) Cha, J. S.; Brown, H. C. J. Org. Chem. (1993) 58, 4732.
3. Cha, J. S.; Lee, D. Y.; Kim, J. M. Org. Prep. Proced. Int. (1999) 31, 694
4. (a) Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. (1949) 71, 122.
(b) Babler, J. H.; Invergo, B. J. Tetrahedron Lett. (1981) 22, 11.
(c) Babler, J. H. Syn. Commun. (1982) 12, 839.
5. For reviews: (a) Mosettig, E.; Mozingo, R. Org. React. (1948) 4, 362.
(b) Cha, J. S. Org. Prep. Proced. Int. (1989) 21, 451.
6. Cha, J. S.; Brown, H. C. J. Org. Chem. (1993) 58, 4732 and references cited therein.
http://www.movieconnection.it/schede/nos
(Hive Bee)
03-14-04 18:47
No 495069
(Rated as: good idea!)
Bandil or anybee else that have at his disposition a nicely substituted benzoylhalide, benzoic anhydride or methyl benzoate might want to check the following idea of general bee-interest.
I was reading a nitroalkane reactions review* when I saw the following general reaction:
R-CH=NO2- + R’-CO-X ==> R’-CO-CHR-NO2 + X-
and realized I actually already tried something similar only that I used it the “other way”. I acylated the sodium salt of nitrotoluene with acetanhydride to get 2- and 4-nitro-P2P. I don’t know why I didn’t realize its further use for the opposite reaction.
The R-CH=NO2- is off course the nitronate salt produced from a nitroalkane and a base, for example of nitromethane or preferably nitroethane with sodium ethoxyde or hydroxide. X is a halide or other groups that activate the carboxylic acid.
By having the R=H for the PEA’s (or R=Me for the amphetamines) and R’=aryl (in Bandil’s case it is 3,4,5-trimethoxyphenyl) you get an alpha-nitro-3,4,5-trimethoxy-acetophenon
CH2=NO2- + {3,4,5-triMeO-phenyl}-CO-X ==> {3,4,5-triMeO-phenyl}-CO-CH2-NO2
The alpha-nitro-acetophenones can presumably be reduced with NaBH4/EtOH to the 1-phenyl-2-nitro-etanoles which on acidification/dehydration turn into the appropriate beta-nitrostyrenes:
{3,4,5-triMeO-phenyl}-CO-CH2-NO2 ={NaBH4/EtOH}=> {3,4,5-triMeO-phenyl}-CH(OH)-CH2-NO2
{3,4,5-triMeO-phenyl}-CH(OH)-CH2-NO2 ={H+}=> {3,4,5-triMeO-phenyl}-CH=CH-NO2 + H2O
Both of these two reactions can probably bee done in a one pot procedure.
I guess there is no need to explain the further use of the nitrostyrene. This might bee a better alternative to the reduction of benzoylhalides to alcohols, their oxidations to the aldehyde and the Henry condensation. After all many substituted benzoic acids are readily avaible and the method might work also with their methyl esters (from a simple Fisher esterification).
Sorry if I posted this before doing a literature search but I would need Beilstein for that and I won’t bee having access to it in the next days. So, maybe some interested bee could find some references to similar reactions with preparation details.
* Rosini and Ballini. Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion Synthons. SYNTHESIS (1988) 833-847.
“The real drug-problem is that we need more and better drugs.” – J. Ott