(Master Searcher)
11-21-02 03:19
No 381740
      Gabriel sythesis patents
(Rated as: excellent)

Patent US4544755 cleavage
Patent US5780645 alkyl carbonates

The hardest thing to explain is the obvious
(Master Whacker)
11-23-02 03:00
No 382445
      Thank you kind Sir!!!  Bookmark   


Thank you very much for sharing that amazing find, you just made my day.  I have searched for a better hydrolysis than the standard hydrazine route and have found nothing in the journal literature other than the NaBH4/2-propanol method.  All of the real chemists here need to check the patent on cleavage.

It uses simple ethanolamine at 80'C to hydrolyze alkyl pthalimides in excellent yields.  Simply fantasticsmile
(Hive Bee)
11-23-02 05:39
No 382479
      also I am no real chemist  Bookmark   

also being no real chemist I recognized the worth of this.

thanks Sam!

I will come back on this with questions for the real chemists. Hope they will lend me their ear.


now or never
(Master Searcher)
11-23-02 16:38
No 382594
      You're welcome. Does bromosafrole have a chance?  Bookmark   

You're welcome.  Does bromosafrole have a chance?
See also Post 305357 (hsark: "gabriel synthesis", Methods Discourse)

The hardest thing to explain is the obvious
(Hive Addict)
01-30-03 01:24
No 402482
      great  Bookmark   

Sam you are the greatest.  The question i have though.  The patent says that proscess will work with compounds with independantly substituted rings.  Say  4iodo-2,5dimethoxyphenylethylphlactamide.  I was just worried about possibly the monoethanolamine reacting with the I on the ring in a fashion similar to the halosafrole procedures.  Can anyone recommend a good way to work up this reaction.  I was thinking Flood with water. Basifyingextract with Ethylacetate and distillation of the freebase. 

He who holds the LSD holds the keys.
(Chief Bee)
01-30-03 04:52
No 402539
      Ethanolamine will not react with aromatic...  Bookmark   

Ethanolamine will not react with aromatic halides.
(Hive Addict)
01-31-03 23:03
No 403082
      WOrkup  Bookmark   

Does the work up seem suitable??  Also will a Bromination  using KBr+Oxone(aq) work in the same way as the KI+Oxone?  Will the  oxone react negatively with the phlactamide group.

He who holds the LSD holds the keys.
(Chief Bee)
02-02-03 11:35
No 403563
      Aromatic Bromination with Oxone/KBr
(Rated as: excellent)

Aromatic Bromination with Oxone/KBr
Synthetic Communications 32(15), 2313-2318 (2002)

Halogenated aromatic compounds are a useful class of intermediates as they are precursors to a number of organometallic species useful in the synthesis of natural products and pharmaceutically important compounds. The manufacture of a range of bulk and fine chemicals, including flame retardants, disinfectants and antibacterial and antiviral drugs, involves bromination. (1)  Bromo aromatics are widely used as intermediates in the manufacture of pharmaceuticals, agrochemicals and other specialty chemical products. Consequently, a variety of methods for the bromination of aromatics have been reported in the literature. (2-13)

Traditional methods of aromatic bromination involve the use of non-selective hazardous acidic reagents such as mineral acids and metal halides, which can lead to separation difficulties and unacceptable levels of toxic and corrosive waste. Conventional bromination methods typically use elemental bromine, a pollutant and a safety and health hazard. To overcome these difficulties some researchers have utilized a combination of hydrobromic acid and suitable oxidant such as tert-butylhydroperoxide or hydrogen peroxide. (13-15) The replacement of such reagents by non-toxic and more selective reagents is very desirable and represents an important goal in the context of clean synthesis. We report a highly para selective method for bromination of aromatic compounds based on the use of KBr as a bromine source and oxone® as an oxidant.

(1) ArH + KBr + 2 KHSO5·KHSO4·K2SO4 ArBr + KOH + K2S2O8·KHSO4·K2SO4 + H2O
(2) 2 KHSO5·KHSO4·K2SO4 + KBr KOH + HOBr + K2S2O8·KHSO4·K2SO4
(3) 2 HOOSO3K 2 ·OH + 2 ·OSO3K
(4) KBr + 2 ·OH + ·OSO3K KOH + HOBr + K2S2O8
(5) ArH + HOBr ArBr + H2O

Potassium peroxymonosulfate is an inexpensive and readily accessible oxidizing agent. It is commonly used as oxone® (2KHSO5.KHSO4.K2SO4) and is a versatile oxidant for the transformation of a wide range of functional groups. (16)

A number of different aromatic substrates were subjected to the bromination reaction to test the generality of this method and the results are summarized in Table 1 . Efficient bromination of aromatic substrates with good yields and regioselectivity observed with acetonitrile, methanol as solvents (Table 1 ). As Table 1 shows that the reaction gives high yields and para-selectivity for a range of substituted benzenes of high activity. The results in Table 1 indicate that activated aromatic compounds are more selective for nuclear bromination. Introduction of an electron-withdrawing group on the aromatic ring substantially decreases the rate of ring bromination (Table 1 , Entry 8) while on electron donating group increases it. These system yield selectively para brominated aromatics unless the para-position (Table 1 , Entry 7) is substituted. The para substituted aromatics were brominated in the ortho-position. 2-Methoxy naphthalene gives 1-bromo-2-methoxy naphthalene. When the less reactive aromatics such as bromobenzene, nitrobenzene, benzoic acid failed to undergo bromination under the same reaction conditions.

A wide range of solvents have been employed in these reactions including, carbon tetrachloride, hexane, dichloromethane, methanol and acetonitrile. The best results were obtained when acetonitrile, methanol were used as solvents compared to others (Table 2 ). The reaction is very fast in methanol compared to acetonitrile.

We surveyed the oxybromination with various oxidants such as oxone®, tert-butylhydroperoxide, hydrogen peroxide and molecular O2. Reactions were conducted with anisole as a probe-substrate at room temperature in acetonitrile. However, oxone® is far superior to the other reagents. The role of oxone® was confirmed by conducting a blank experiment where the formation of bromo compound was not observed.

Oxybromination of an aromatic compound in the presence of oxone® proceeds according to the stoichiometry of Eq. 1 . It is believed that the bromination proceeds via the formation of hypobromous acid. The hypobromous acid has higher instability due to pronounced ionic nature and thus more reactivity towards the aromatic nucleus.

Oxone®, in direct comparison, has a higher onset of decomposition than hydrogen peroxide and liberates less energy. This reaction is performed at lower temperature, which provides a larger margin of safety. Additionally oxone® is a solid, allowing for the addition of precisely weighed amounts of reagent to be used in the reaction.

In conclusion, we have developed a practical method using oxone® as an interesting alternative to hydrogen peroxide in the oxidative bromination of aromatic compounds. The commercial availability of the reagent, simple reaction conditions, no evaluation of hydrogen bromide and excellent yields of monobrominated products make our method valuable from a preparative point of view.

General Procedure for the Bromination of Aromatic Compounds: Oxone® (2.2 mmol) was added to a well stirred solution of KBr (2.2 mmol) and substrate (2.0 mmol) in methanol (10 mL) and the reaction mixture was allowed to stir at room temperature. The reaction was monitored by thin layer chromatography (TLC). After the completion of the reaction. The mixture was filtered and solvent evaporated under reduced pressure. The products were purified by column chromatography over silica gel and confirmed by 1H NMR and Mass spectra.


1  Ulmann's Encyclopedia of Industrial Chemistry, 6th Ed.,  Wiley-VCH, Weinheim, 1998.  Electronic Release.
2  Schmid H., Helv. Chim. Acta, 29 (1946) 1144.
3  Lambert F.L., Ellis W.D., Parry R.J., J. Org. Chem., 30 (1965) 304.
4  Konishi H., Aritomi K., Okano T., Kiji J., Bull. Chem. Soc., Jpn., 62 (1989) 591.
5  Bovonsombat P., McNelis E., Synthesis, (1993) 237.
6  Smith K., Bahzad D., J. Chem. Soc. Chem. Commun., (1996) 467.
7  Paul V., Sudalai A., Daniel T., Srinivasan K.V., Tetrahedron Lett., 35 (1994) 7055.
8  Choudary B.M., Sudha Y., Reddy P.N., Synlett., (1994) 450.
9  Auerbach J., Weissman S.A., Blacklock T.J., Angelss M.R., Hoogsteen K., Tetrahedron Lett., 34 (1993) 931.
10 Oberhauser T., J. Org. Chem., 62 (1997) 4504.
11 Singh A.P., Mirajkar S.P., Sharma S., J. Mol. Cat. A, 150 (1999) 241.
12 Goldberg Y., Alper H., J. Mol. Cat. A, 88 (1994) 377.
13 Barhate N.B., Gajare A.S., Wakharkar R.D., Badekar A.V., Tetrahedron Lett., 39 (1998) 6349.
14 Dakka J., Sassa Y., J. Chem. Soc., Chem. Commun., (1987) 1421.
15 Lubbecke H., Boldt P., Tetrahedron., 34 (1978) 1577.
16 Webb K.S., Levy D., Tetrahedron Lett., 36 (1995) 5117.  and References Cited Therein.
(Hive Addict)
02-03-03 02:47
No 403791
      Thanks  Bookmark   

It seems like  ask and you shall recieve these days.  You guys are great.  TeeHee Thank you
Can triethanolamine be used in place of the ethanolamine.

He who holds the LSD holds the keys.
(Chief Bee)
02-03-03 09:19
No 403895
      No, the prep requires plain ethanolamine.  Bookmark   

No, the prep requires plain ethanolamine.
(Hive Addict)
02-03-03 23:27
No 404107
      US Patent 5780645 Alkylation of Imides  Bookmark   

US Patent 5780645

Procedure for Alkylation of Imides


A process for the alkylation of imides wherein the imides are reacted with dialkyl carbonate in the liquid state at a temperature between 100-250*C and at a pressure of between 0-60 atm in the presence of a basic catalyst.  The carbonate reagents are not very toxic and thermally stable and their use as alkylation agents makes it possible to produce waste products with a negligible saline content.

Example 1:

A stainless steel autoclave with a capacity of 250ml is equipped as above.  15g of phthalimide is loaded with 92.5g of dimethylcarbonate, 33g of methanol and 0.35g of potassium carbonate.  The stirrer is turned on and the reactor is heated on an oil bath until the internal temperature reaches 170*C.  As the reaction proceeds, CO2 is produced and the internal pressure builds up to a maximum value of 25.5 atm.  After approximately 1 hour of reaction at a temperature of 170*C, more than 99% of the phthalimide is converted and the selectivity in N-methyl phthalimide is total.  The autoclave is allowed to cool to RT and the mix is transferred to a flask and the methanol and dimethyl carbonate remaining are recovered by distillation at 1 atm.  The residue is taken up in 250ml of dimethyl carbonate and is filtered to eliminate the catalyst.  The solvent is taken away by distillation to give 16.4g of N-methyl phthalimide. Yield: 99%

Example 2:


A stainless steel autoclave with a capacity of 250ml equipped as above is loaded with 11g of succinimide, 100g of dimethylcarbonate, 35.5g of methanol and 0.38g of potassium carbonate.  The stirrer is switched on and the autoclave is heated to 170*C.  During the reaction, CO2 is evolved causing the pressure to rise to 25 atm.  After approximately 50minutes at 170*C, 99.5% of the succinimide has been converted and the selectivity to N-methylsuccinimide is 95%./[red]  Once the reaction period has finished the autoclave is cooled to RT.  The methanol and dimethyl carbonate are distilled off and the catalyst is filtered.  [red]Solvent removal gives 12.5g of N-methylsuccinimide.  This is recrystallized using chloroform and hexane mixtures.

Example 3:

N,N-dimethylimide of tetracarboxyl perylene acid

The apparatus as above but with 100ml capacity is loaded with 5.4g of the di-imide of the tetracarboxy perylene acid 3,4,9,10 with 25g of dimethylcarbonate, 20g of N,N-dimethylformamide, 0.27g of trimethylcetylammonium chloride and 0.21g of potassium carbonate.  The stirrer is switched on and the autoclave is heated with a thermostatic oil bath until the temperature inside the reactor reaches 170*C.  As the reaction proceeds, carbon dioxide is produced and the internal pressure of the reactor builds to a max value of 18 atm.  After 7 hours of reaction, the autoclave is allowed to cool to environmental temperature, the mix is transferred to a flask and the methanol and dimethylcarbonate are removed at 110*C at 1 atm.  Afterwards, when the internal pressure has fallen, the dimethylformamide is removed for distillation.  The residue is suspended in 100ml of distilled water, filtered, washed with 2x50ml of distilled water ad dried at 100*C.  After drying, 5.4g of N,N-dimethylimide of the acid is obtained. 

Example 4:


A vessel as in Example 1 is loaded with 12g of phthalimide, 58g of diethylcarbonate, 84g of N,N-dimethylformamide and 0.284g of potassium carbonate.  The stirrer is turned on and the autoclave heated to 200*C for 2 hours.  The max pressure reaches 15 atm.  At this time, at least 99% of the imide has been converted.  The yield is 98% (13g) and selectivity is greater than 99%.

The ethanol and and other liquid components are removed via distillation.  The residue is taken up in 150ml of DCM, washed with water, dried on sodium sulfate and filtered.  This is purified with chloroform/hexane.

References Cited:

French Patent 2533558
German Patent 1963728
German Patent 2726682

(Hive Addict)
02-04-03 17:19
No 404393
      Will the ring of the phlactamide group also...  Bookmark   

Will the ring of the phlactamide group also get halogenated by the KX Oxone? 

Proposed synth(Note) I went ahead and calculated the Kbr to brominate the phlactamide ring too.)

15 gms(.048m) of N-(2-(2,5-Dimethoxyphenyl)ethyl)phthalimide is placed into 50ml MEOH with 1.02gms(.01m)KBR
Then the solution is stirred while .01m of Oxone(aq) is added. The solution is stirred till completeion.  2ml of (aq)Sodiumbisulfite is added then the rxn is basified with 25%NaOH and extracted 3x50ml of DCM.  Dcm extracts are washed with Bisulfate again then once with NaHCO2.  The Dcm is removed under vaccume to give N-(2-(4 bromo-2,5-Dimethoxyphenyl)ethyl)phthalimide.

(.048m) 15 gms N-(2-(4 Bromo-2,5-Dimethoxyphenyl)ethyl)phthalimide Is refluxed in ethanolamine for 20 mins.  Then the rxn is flooded with water.  The amine is extractred with 3x50ml of dcm and the residue distilled under N2 to give 2CB.  2CB freebase is then treated with .045m of 20% HCL.

WOuld it be okay with this compound to do the clevage in just the amine without an additional solvent.

He who holds the LSD holds the keys.
(Chief Bee)
02-04-03 21:41
No 404456
      Phtalimide  Bookmark   

Will the ring of the phlactamide group also get halogenated by the KX Oxone?

It's "Phtalimide". You managed to spell it in your synth proposal.

That ring can be halogenated, but not without a good excess of halogenated agent, as it is far less activated than 2C-H.
(Hive Addict)
02-04-03 23:18
No 404480
      HeeHaw  Bookmark   

My shitty spelling really bothers you doesn't it.
For any one wondering.
The preperation of this compound I speak of is in Phikal in the 2CI entry.   

He who holds the LSD holds the keys.
(Chief Bee)
02-04-03 23:29
No 404484
      badd speling  Bookmark   

Yup, spelling is important in chemistry, and also to be able to find stuff in TFSE.
(Chief Bee)
07-05-03 04:08
No 444604
      Cleavage of phthalimides to amines w/ Ethanolamine
(Rated as: excellent)

Cleavage of phthalimides to amines
Patent US4544755


Phthalimides of the formula I where R is a substituent and the ring A can be further substituted, are cleaved by a process in which a compound of the formula I is treated with an alkanolamine. The compounds prepared according to the invention are useful intermediates for the preparation of dyes, drugs and plastics.

Introduction and Prior Art

The compounds of the formula I can be prepared by a conventional method, for example by reacting a halogen compound with potassium phthalimide by the Gabriel method.

The cleavage of the phthalimides to give amines and phthalic acids or derivatives thereof is frequently very difficult in practice. Acidic hydrolysis with 20-30% strength hydrochloric acid generally requires prolonged refluxing (Liebig Ann. Chem. 1949, 22) or has to be carried out at 200°C. under superatmospheric pressure (Chem. Ber. 20 (1887), 2224). Alkaline hydrolysis with an aqueous alkali does not in general proceed any further than the phthalamic acid stage. For complete hydrolysis, a downstream treatment with a mineral acid is necessary (Chem. Ber. 37 (1904), 1038). Although the cleavage of the phthalimides of the formula I by means of hydrazine presents scarcely any problems on the laboratory scale, considerable difficulties are encountered on an industrial scale. The sparingly soluble salt of the cyclic phthalic hydrazide is formed in the reaction (Nature (London) 158 (1946), 514) and separates out as a bulky precipitate, the handling of which requires large amounts of solvents and large reaction kettles. The acute toxicity and the high price of hydrazine are also obstacles to the economical use of this method.

It was therefore extremely surprising that cleavage of phthalimides can be carried out readily in accordance with the invention.

Description of the Invention

The cleavage of the phthalimide of the formula I is carried out simply by heating the compound in an alkanolamine. This acts both as a solvent and as a reactant. Examples of suitable alkanolamines are monoethanolamine, monoisopropanolamine, 3-aminopropanol and aminoethylethanolamine. Monoethanolamine is preferably used. The reaction temperatures are from 40 to 140°C., preferably from 60 to 100°C. The method of working up the reaction mixture depends on the nature of the amine liberated, and is as a rule very simple. For example, water-insoluble, solid amines can usually be precipitated by adding water. Water-soluble amines can be isolated by extraction with a solvent, such as methylene chloride, ethyl acetate or toluene. The phthalic acid alkanolamides liberated in the reactions remain in the aqueous phase and can therefore be separated off without difficulty.

The cleavage can of course also be carried out in the presence of an additional solvent, this being done in particular where the cleavage products are capable of reacting with the alkanolamines, so that an excess of alkanolamine over and above the stoichiometric amount is disadvantageous. For example, where exchangeable halogen atoms are present, it is advisable to carry out the reaction only with about the stoichiometric amount of the alkanolamine.

Examples of solvents which can be used in the cleavage are alkanols, glycols, glycol ethers, ketones, halohydrocarbons or hydrocarbons, specific examples being methanol, ethanol, propanol, butanol, glycol, methyl glycol, ethyl glycol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, methylene chloride, chlorobenzene and toluene.

As a rule, the phthalimido radical serves as a protective group, i.e. its presence permits reactions which are impossible in the presence of a free amino group. For example, when the amino group is protected it is possible to carry out alkylations, acylations, nitrations, halogenations, chlorosulfonations or oxidations.



100 g of 2-cyanomethyl-N-phenylphthalimide were introduced, a little at a time, into 100 g of monoethanolamine at 80°C. After 10 minutes, the mixture was cooled to 20°C., and 400 g of ice water were added dropwise. The precipitated product was filtered off under suction and washed neutral with ice water.

Yield: 40 g (80% of theory); m.p. 70°C.



30 g of 2-(1-imidazolylmethyl)-N-phenylphthalimide in 60 g of monoethanolamine were stirred for 1 hour at 70°C. The mixture was cooled to 20°C., after which 200 g of ice water were added dropwise and the mixture was extracted with three times 150 g of ethyl acetate. The combined extracts were dried, and evaporated down under reduced pressure.

Yield: 13 g (75% of theory); m.p. 42°C.