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All 10 posts Subject: practical alkyl tosylate synth - new approaches Please login to post Down

psyloxy
(Hive Addict)
10-27-03 10:42
No 466982
      practical alkyl tosylate synth - new approaches
(Rated as: excellent)

methyltosylate from tosic acid and...

a)... trimethyl orthoformate

Yield : 99%
Time : 14 h
Temp : ambient
Ref. : Padmapriya, A. A.; Just, G.; Lewis, N. G.; SYNCAV; Synth.Commun.; EN; 15; 12; 1985; 1057-1062.
or a slightly off example with 1% less yield : Patent US2928859

Example 4

20g (0.13 mol) of triethoxymethane was added to 9.5g ( 0.05 mol) of p-toluenesulfonic acid. Heat was immediately evolved and upon its subsidiance the reaction mixture was warmed on a water bath to distill off ethl formate and ethanol boiling between 54 and 79°C. When all distillation had ceased vacuum was applied to the system and the excess triethoxymethane was removed by another distillation. The reaction mixture was then poured into water and extracted three times with ether. The ether layer was washed once with dilute KHCO₃ soln. and the ether evaporated. The crude product thus obtained amounted to 9.8g (0.049 mol) of ethyl p-toluenesulfonate representing a yield of 98% of theoretical and melting at 30-31°C

Post 353838 (Rhodium: "OTC preparation of triethyl orthoformate", Novel Discourse)

b)... trimethyl orthoacetate
Yield : 96%
Solvent : CH2Cl2
Time    : 30 min
Temp    : ambient
Ref : Trujillo, John I.; Gopalan, Aravamudan S.; TELEAY; Tetrahedron Lett.; EN; 34; 46; 1993; 7355-7358.
preparation of trimethoxymethane

a) from chloroform and metal alkoholate

Patent DE919465

Example 1

3.2Kg of a 30% methanolic NaOMe soln. are prewarmed to 30°C. 1065g dry CHCl3 are added dropwise with occasional stirring during 15min. Temp rises to 60 - 75°C and is held there by external cooling. The precipitated NaCl is then redissolved by addition of water and the solution extracted with CHCl3. The CHCl3 soln. is washed with water, dried with NaSO4 and distilled. 550g trimethoxymethane are collected in the range from 95 - 102°C. Yield: 87% (based on methylate used)

Good news is: Mg(OMe)₂, KOMe, NaOMe and Al(OMe)₃ can all be used according to the patent.

Post 257912 (Antoncho: "Alkali metal alkoxides: finally, OTC!", Novel Discourse)
Post 460620 (psyloxy: "magnesium methoxide - Mg alkoxides - Mg, I2, ROH", Chemistry Discourse)

Patent US3274261/Patent DE1217943 : improvements to that process, omitting the extraction/washing but starting with an alkoholate soln. in the product to be made.

b) from formamide, methanol and benzoylchloride

Patent DE2062286

Example 3

To a solution of 140,5g (1mol) benzoylchloride in 600ml DCM are added with stiring at 10°C a mixture of 45g (1 mol) formamide and 100g (3.1 mol) MeOH. Temp is kept at 10°C for 3h, then the rxn mix is heated to 30 - 40°C for another 90 min, which is finally stirred,
together with the precipitated NH4Cl, into 560g of a 13% NaOH soln. The phases are divided and the organic phase dried with 'soda' (NaCO₃?). The soda is filtered and washed with 50ml DCM. When the filtrate is fractionally distilled, in the end with a slight vacuum, 55g trimethoxymethane and 40g methylbenzoate are left, next to some methylchloride (seems like a typo, I think they meant DCM) are left. By using another fractional distillation in vacuo 53g trimethoxymethane can be isolated in pure form, corresponding to a yield of 50%.

1,1,1-trimethoxyethane from acetonitrile Patent US4182910

Example 1

A solution of 845 g (20.61 moles) of acetonitrile and 692 g (21.63 moles) of methanol in 1500 g of o-xylene is chilled to -10° C. and then, over a period of 100 minutes, 789 g (21.62 moles) of anhydrous hydrogen chloride is introduced directly into the solution, with stirring, the temperature rising to +10° C. After the hydrogen chloride introduction is completed, the reaction solution is heated to 30° C.; after about 3 hours the imidomethyl ester hydrochloride crystallizes out; then stirring is continued for 8 hours at 30° C. Then 1530 g (47.8 moles) of methanol is added for the methanolysis, and the excess HCl is neutralized against methyl red with 130 g of a 30 wt.-% methanolic solution of NaOCH₃ After the neutralization, the temperature is raised to 35°C and stirring is continued for another four hours. Then the mixture is cooled down to 10
° C. and the NH₄Cl is removed by centrifugation. The solid substance is washed with o-xylene and the residual content of dissolved NH₄Cl (0.2298 mole) in the combined filtrate is determined by titration with AgNO₃, and then NaOCH₃ is added in an excess (43 g of a 30% solution of NaOCH₃ in methanol). From the filtrate thus treated, fractionation through a packed column yielded 2134 grams Trimethylorthoacetate (17.79 moles= 86.3% yield with respect to the CH₃CN put in, 90% yield with respect to reacted CH₃CN), boiling point 108-109°C.

The o-xylene remaining in the distillation residue contains acetamide as the main impurity, which is removed by azeotropic distillation. The o-xylene thus purified can be reused.

methyltosylate from tosic acid and MeOH / catalyst

Yield : 82%
Catalyst : Fe³⁺-exchanged montmorillonite clay
Solvent : 1,2-dichloro-ethane
Time    : 3h
Temp    : 80°C
Ref.    : Choudary, Boyapati M.; Chowdari, Naidu S.; Kantam, Mannepalli L.; TETRAB; Tetrahedron; EN; 56; 37; 2000; 7291 - 7298.

Abstract

An enviro-economic route for tosylation of alcohols and selective monotosylation of diols in good yield directly using p-toluenesulfonic acid together with metal-exchanged montmorillonite instead of p-toluenesulfonyl chloride or p-toluenesulfonic anhydride is described. The Fe(3+)-montmorillonite clay is the most effective catalyst among metal-exchanged montmorillonites for such tosylation reactions. The activity follows the sequence Fe(3+) > Zn(2+) > Cu(2+) > Al(3+)-montmorillonite > K10 montmorillonite. Regioselective tosylation of diols to monotosylated derivatives is achieved with high purity. In diols having both primary and secondary hydroxy groups, tosylation occurred only at the primary hydroxy group. The solid catalyst displayed consistent activity for several cycles as exemplified in tosylation of cyclohexanol.

--psyloxy--

Rhodium
(Chief Bee)
12-12-03 09:07
No 476352
User Picture       TsOH/CoCl2: Tosylation of alcohols
(Rated as: excellent)

Cobalt(II) catalyzed tosylation of alcohols with p-toluenesulfonic acid
Subbarayan Velusamy, J. S. Kiran Kumar and T. Punniyamurthy
Tetrahedron Letters 45(1), 203-205 (2004) (https://www.rhodium.ws/pdf/cocl2-tsoh.tosylation.pdf)
DOI:10.1016/j.tetlet.2003.10.106

Abstract
Cobalt(II) chloride hexahydrate (CoCl₂·6H₂O) has been found to catalyze the tosylation of both aliphatic and aromatic alcohols with p-toluenesulfonic acid (p-TsOH) in high yields in 1,2-dichloroethane under reflux (ca. 80°C). In the case of aliphatic alcohols, secondary alcohols undergo tosylation chemoselectively in the presence of primary hydroxy groups.

Experimental
Alcohol (3 mmol), p-TsOH (3 mmol) and CoCl₂·6H₂O (5 mol%) were dissolved in ClCH₂CH₂Cl (10 mL) and the solution was stirred under reflux (ca. 80°C) for the appropriate time (see Table 2). The reaction mixture was then allowed to cool to ambient temperature and diethyl ether (50 mL) was added. The catalyst was removed by filtration and the filtrate was washed successively with saturated NaHCO₃ solution (3x10 mL), brine (2x10 mL), and water (1x10 mL). Drying (Na₂SO₄) and evaporation of the solvent on a rotary evaporator afforded a residue, which was passed through a short pad of silica gel using a mixture of ethyl acetate and hexane as eluent to afford the analytically pure tosylate.
____ ___ __ _

Practical and Efficient Methods for Sulfonylation of Alcohols Using Ts(Ms)Cl/Et₃N and Catalytic Me₃N.HCl as Combined Base:
Promising Alternative to Traditional Pyridine
Yoshihiro Yoshida, Yoshiko Sakakura, Naoya Aso, Shin Okada, and Yoo Tanabe
Tetrahedron 55, 2183-2192 (1999) (https://www.rhodium.ws/pdf/tosylation-mesylation.et3n-me3n-hcl.pdf)

Abstract
Several alcohols were smoothly and practically tosylated by two methods A and B. Method A uses the TsCl/Et₃N (1.5-2.5 equiv)/cat. Me₃N.HCl (0.1-1.0 equiv) reagent. Compared with the traditional Py-solvent method, the method A has merits of its much higher reaction rate, operational simplicity, economy in the use of the amine, and circumvention of the undesirable side reaction from R-OTs to R-Cl. Method B uses TsCl/KOH [or Ca(OH)₂]/cat. Et₃N (0.1 equiv)/cat. Me₃N·HCl (0.1 equiv) as the reagent, which will be suited for praclical and large scale production for primary alcohols. On both methods A and B, a clear joint action of Et₃N and Me₃N·HCl catalysts was observed. ¹H-NMR measurements support the proposed mechanism of the catalytic cycle. Related methanesulfonylation using Et₃N and cat. Me₃N·HCl in toluene solvent also successfully proceeded, wherein the clear joint action was also observed.

Experimental

General procedure of Method A
TsCl (1.2-1.5 mmol) in solvent (1.0 ml) was added to a stirred solution of an alcohol (1.0 mmol), Et₃N (1.5-2.5 mmol) and Me₃N·HCl (0.1 or 1.0 mmol) in solvent (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h. To decompose an excess TsCl, N,N-dimethylethylenediamine (ca. 130 mg) was added to the mixture, which was stirred for 10 min. (This procedure is not always necessary, if TsCl is easily separated off by column chromatography). Water was added to the mixture, which was extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂SO₄) and concentrated. The obtained crude product was purified by silica-gel column chromatography (hexane/ether = 30->10:1) to give the desired tosylate.

General procedure of Method B
TsCl (1.5 mmol) in solvent (1.0 ml) was added to a stirred suspension of an alcohol (1.0 mmol), inorganic base (1.5-3.0 mmol), Et₃N (10 mg, 0.1 mmol) and Me₃N·HCl (10 mg, 0.1 mmol) in solvent (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h and at room temp. for 3-5 h. Aqueous 1M HCl was added to the mixture, which was extracted with EtOAc. A similar work up and purification of Method A gave the desired tosylate.
Note: Pellet KOH was refluxed in toluene for ca. 0.5 h to change into dispersion, which was used. High granules Ca(OH)₂ was used.

Mesylation of alcohols using MsCl/Et₃N and cat. Me₃N·HCl
MsCl (172 mg, 1.5 mmol) in toluene (0.5 ml) was added to a stirred solution of an alcohol (1.0 mmol), Et₃N (1.5 or 2.0 mmol), and Me₃N·HCl (0.1 or 1.0 mmol) in toluene (1.0 ml) at 0-5°C, and the mixture was stirred for 1 h. A similar workup and purification by silica-gel column chromatography (hexane/EtOAc = 5:1) gave the desired mesylate.
____ ___ __ _

Tosylation of Alcohols
George W. Kabalka, Manju Varma, and Rajender S. Varma
J. Org. Chem. 51, 2386-2388 (1986) (https://www.rhodium.ws/pdf/tosylation.alcohols.tscl-py.pdf)

We report that the highest yields of pure tosylates based on starting alcohol are obtained using a 2:3:4 ratio of alcohol/tosyl chloride/pyridine in chloroform, whereas secondary alcohols require longer reaction times (~7 h). However, the reaction rate can be increased by using 1:2:3 ratio of alcohol/tosyl chloride/pyridine.

Experimental
The alcohol (10 mmol) was dissolved in chloroform (10 mL) and cooled in an ice bath (0°C). Pyridine (1.62 mL, 20 mmol) was then added, followed by the addition of p-toluenesulfonyl chloride (2.85 g, 15 mmol) in small portions with constant stirring. The reaction was completed in 2.5 h (monitored by TLC). Ether (30 mL) and water (7 mL) were added and the organic layer was washed successively with 2 N HCl, 5% NaHCO₃, and water and then dried (MgSO₄). The solvent was removed under reduced pressure and the crude tosylate was column chromatographed (2% ether/petroleum ether) on a silica gel column to yield the pure tosylate ester in high yield (98%).

The Hive - Clandestine Chemists Without Borders

psyloxy
(Hive Addict)
06-21-04 15:36
No 514615
User Picture       scan
(Rated as: good read)

Synth.Commun. : 15,12.1985;1057-1062

--psyloxy--

Added by Rhodium latest addition (06-21-04):

A New Method for the Esterification of Sulfonic Acids
A. A. Padmapriya, G. Just and N.G. Lewis
Synthetic Communications 15(12), 1057-1062 (1985) (https://www.rhodium.ws/chemistry/sulfonic.esterification.html)

Abstract
Sulfonic acids can be smoothly converted to their methyl and ethyl esters by reaction with trimethyl and triethyl orthoformate, respectively.

psyloxy
(Hive Addict)
06-30-04 22:08
No 516612
User Picture       and another one...

Tetrahedron Lett., 34,46.1993;7355-7358

Alkyl tosylates from trimethylorthoformate and triethylorthoacetate. Easy procedure, excellent yields.

--psyloxy--

psyloxy
(Hive Addict)
07-01-04 00:18
No 516633
User Picture       Did the Japanese do the impossible ?

Trimethylorthoformate from chloroform with NaOH/MeOH ? It just looks like. No NaOMe needed.

Am I the only one that is unable to see more than the first page of this patent ?
(www.espacenet.com doesn't work for me, I get all my patents from www.depatisnet.de)

Patent JP000058225036AA

PURPOSE: The reaction mixture resulting from a reaction between methanol or ethanol, a caustic alkali and chloroform is combined with a specific solvent to effect almost quantitative extraction of the titled compound into the solvent.

CONSTITUTION: Methanol, or ethanol, a caustic alkali, preferably an alcoholic solution of sodium or potassium hydroxide, and chloroform are made to react and the resultant reaction mixture is combined with a solvent which is selected from aliphatic or aromatic hydrocarbons, ethers or their halogenated products, and is low in compatibility with water and capable of separating the product by distillation, in an amount of 1.0W1.5 times the volume of the product. Then, they are vigorously stirred at 20W35°C and separated by standing to effect extraction of the objective orthoformate into the organic solvent layer, while the alkali chloride goes in the aqueous layer. The above solvent can be added at the reaction stage except carbon tetrachloride.

--psyloxy--

psyloxy
(Hive Addict)
07-01-04 22:46
No 516801
User Picture       nothing

EDIT: a complete misunderstanding on my part.

Liebigs Ann.Chem., 9.1990;847-852

Ethyl (S)-2-(4-Tolylsulfonyloxy)propanoate (22): 4-Toluenesulfonyl chloride (6.0 g, 31.5 mmol) was added in portions to a solution of ethyl (S)-2-hydroxypropanoate (21) [2.5 g, 21.1 mmol; commercially available,[a]¹⁴ = -10° (neat); [a]²⁰_D = -24 (c = 8.59, CHCl₃²⁾] with vigorous stirring at - 20°C. Then the temperature was allowed to reach 0°C and stirring continued for 6 h, then for about 12 h at room temp. The mixture was poured into a mixture of ice/hydrochloric acid (1:1, 50 ml) and the organic layer was extracted with ethyl acetate. After drying the solution with sodium sulfate and evaporation of the solvent, 5.34g (93%) of 22 was obtained.

--psyloxy--

azole
(A Truly Remarkable HyperLab Bee)
07-02-04 11:01
No 516946
      W/o catalyst? Really?

Ethyl (S)-2-(4-Tolylsulfonyloxy)propanoate (22): 4-Toluenesulfonyl chloride (6.0 g, 31.5 mmol) was added in portions to a solution of ethyl (S)-2-hydroxypropanoate (21) [2.5 g, 21.1 mmol; commercially available,[a]14 = -10° (neat); [a]20D = -24 (c = 8.59, CHCl32)] with vigorous stirring at - 20°C.

   Well, TsCl was added to a solution of ethyl lactate. A solution in what? Most probably, the authors meant a solution in pyridine, since they treat the reaction mixture with ice - HCl, a step which would be illogical if the reaction is conducted in the absence of a base. With pyridine as the solvent/base it becomes a standard tosylation of an alcohol.

   I'm pretty sure that without a base the reaction of TsCl with a secondary alcohol is very slow, and only traces of the product will be formed after several hours at room temperature.

   In the post Post 417550 (Antoncho: "Methyl tosylate: _finally_ , OTC!!!", Novel Discourse) methyl tosylate is made from TsCl - MeOH - conc. NaOH which form a biphasic system. The reaction takes place in the organic phase which contains almost no water, so the hydrolysis of TsCl is suppressed.

   I don't know if there exists a PTC tosylation method compatible with esters.

psyloxy
(Hive Addict)
07-03-04 18:08
No 517202
User Picture       the recent tosylation literature
(Rated as: excellent)

Bull.Chem.Soc.Jpn., 68,1.1995;297-300 K₂CO₃ / Me₃N^.HCl

preparation of 2-Propynyl p-Toluenesulfonate 2a

To a stirred suspension of propargyl alcohol (5.6 g, 0.1 mol) and K₂CO₃ (15.2 g, 0.12 mol) in MIBK (50 mL) was added Me₃N^.HCl (0.96 g, 0.01 mol) at 0-5°C. After 5 min, p-toluenesulfonyl chloride (20.97 g, 0.12 mol) in MIBK (50 mL) was added at 0-5°C for an hout. After the mixture was stirred for an hour, water (100 g) was added at 20°C. The separated water phase was back extracted with MIBK (20 mL) and the combined organic extracts were first washed with water, and then, saturated aquaeous NaCl, dried (Na₂SO₄), concentrated, and purified by column chromatography (hexane/EtOAc=10:1) giving 19.13 g (91%) of the sulfonate 2a.

MIBK = methyl isobutyl ketone

Here's some other alternatives to Py / Et₃N :

Bull.Chem.Soc.Jpn., 63,4.1990;1260-1262 NaOH / THF

synthesis 1999,9;1633-1636 TMEDA / Me₂N-(CH₂)_n-NMe₂ n=3, n=4, n=6 ;; shitty scan but you get the idea.

Synthesis - 1997;1433-1438 DABCO

Tetrahedron Lett., 42.2001;8781-8783 Ag₂O / KI

--psyloxy--

Rhodium
(Chief Bee)
07-05-04 16:18
No 517576
User Picture       Prep. of Tosylates of Phenols and Acidic Alcohols
(Rated as: excellent)

Preparation of Tosylates of Phenols and Acidic Alcohols
Stanley E. Wentworth and Patrick L. Sciaraffa, Organic Preparations and Procedures 1(4), 225-228 (1969)
_{(Article found by psyloxy & retrieved by azole)}

Although there are many reports of the preparation of the title compounds¹, each one differs somewhat from the next and the yields are variable.

We wish to report a simple preparation of tosylates of phenols and of acidic alcohols. The method involves stirring an acetone solution of tosyl chloride and the alcohol (or phenol) with an excess of aqueous base, removal of the solvent, and isolation of the product. Reaction time is conveniently overnight, but could be reduced to as little as 4 h in the case of phenol without effect on the yield. The yields in many cases were better than those reported and were generally above 90%, except when a non-acidic alcohol such as n-butanol was used². The low yield in this case may be due to further reaction of the tosylate with the excess base, or, as suggested by a referee, competitive hydrolysis of the tosyl chloride. Other compounds prepared by this method are reported in the Table.

Table

Compound Yield mp (Found) mp (lit.)

n-BuOTs 50%^a - -

C₆H₅OTs 98% 94-96 94-95³

p-ClC₆H₄OTs 91% 70-72 79.6-80.6⁴

p-BrC₆H₄OTs 95% 78-80 93-95⁵

p-IC₆H₄OTs 95% 97-99 99⁶

p-NO₂C₆H₄OTs 89% 96-98 97-97.5⁷

CF₃CH₂OTs 95% 40-42 41⁸

C₆H₅CH(CF₃)OTs 94% 113-116 113-116⁹

C₆H₅CH₂CH(CF₃)OTs 91% 89-92 ^b,d

C₇F₁₅CH₂OTs 75% 53-56 ^c,d

TsOCH₂(CF₂)₃CH₂OTs 99% 96-98 92-94¹⁰

a. Crude yield, not isolated.
b. New compound: Anal. Calcd. for C16H15F3O3S: S, 9.31. Found S, 9.19.
c. New compound: Anal. Calcd. for Ci5H9F1503S: C, 32.5; H, 1.63. Found: C, 32.4; H, 1.58.
d. The IR spectra of the new tosylates closely resembled those of the known tosylates (see fig.)

Experimental

Phenyl tosylate

To a stirred solution of 5.0g of tosyl chloride and 2.5g of phenol in 20 ml of acetone was added dropwise 1.28 g. of sodium hydroxide in 8 ml. of water. After having been stirred overnight, the solution was evaporated in vacuo. The resulting semi-solid was partitioned between ether and water. The layers were separated and the aqueous phase washed with a further portion of ether. The combined ethereal extracts were evaporated and the residue recrystallized from a mixture of hexane and acetone to give 6.45g (98%) of phenyl tosylate, mp 94-96°C, lit.³ mp 94-95°C.

References

1. R. B. Wagner and H. D. Zook, "Synthetic Organic Chemistry", John Wiley and Sons, Inc., New York, N. Y., 1953, p. 823.
2. A. T. Roos, H. Gilman, and N. J. Beaber, "Organic Syntheses", Coll. Vol. I, John Wiley and Sons, Inc., New York, N. Y., 1941, p. 145.
3. R. Otto, Ber. 19, 1832 (1886)
4. M. Neeman, A. Modiano, and Y. Shor, J. Org. Chem. 21, 671 (1956)
5. S. E. Hazlet, J. Am. Chem. Soc. 59, 287 (1937)
6. D. Matheson and H. McCombie, J. Chem. Soc. 1103 (1931)
7. E. Bamberger and A. Rising, Ber. 34, 228 (1901)
8. G. Van Dyke Tiers, H. A. Brown, and T. S. Reid, J. Am. Chem. Soc. 75, 5978 (1953)
9. R. A. Shepard and S. E. Wentworth, J. Org. Chem. 32, 3197 (1967)
10. B. S. Marks and G. C. Schweiker, J· Am. Chem. Soc. 80, 5789 (1958)

^{The Hive - Clandestine Chemists Without Borders}

yei
(Stranger)
08-17-04 13:21
No 525886
      I guess it would stand to reason

It would make sense that ROH + CHCl3 + [OH-] would produce orthoformates, to me at least--chloroform + hydroxide produces dichlorocarbene, which could insert into the alcoholic -OH group and produce CHCl2OR. However, when this happens, another HCl can become eliminated, forming another carbene, and inserting again to produce CHCl(OR)2.
The process would repeat a third and last time to yield CH(OR)3, trialkyl orthoformate. As long as the formed carbenes reacted with alcohol better than with the water formed by neutralization of base by the eliminated HCl, it would work.

I guess this is a similar process to how diazomethane inserts itself into hydroxyls. The cool thing is that it doesn't need such a strong base, and there is no competition between substitution and elimination reactions, since both have the same outcome!

_{It's good to bee back! Don't trust your computer!!}

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