Aqueous Tetrahydrofuran

Comparison of the Effect of Organic Modifiers on Analytes with log P — 3 

The selectivity of a number of organic modifiers was examined using the predicted log k values of the log P — 3 models from each group in different organic modifier-water mixtures. The composition of the eluent was adjusted so that either the solubility parameter,1 polarity (Po), proton acceptor (Xa), proton donor (Xd), or dipole moment (Xn) values were kept constant to determine which parameter affected the selectivity. The results are summarized in Table 4.3. 

Chromatographic Behaviour of log P = 3 Compounds in Aqueous Tetrahydrofuran. For analytes whose log P = 3, in 40% aqueous THF the predicted log A values of the model alkanols (ROH), polycyclic hydrocarbons (PAH), alkyl-benzenes (RB), and alkyl benzoates (ROB) are 0.64, 0.77, 0.90, and 0.79, respectively. The polarity of 40% aqueous THF is 7.72. The same polarity can be obtained in 56% aqueous acetonitrile. As noted earlier, in aqueous aceto- 

Po Polarity, Xe proton acceptor, Xd proton donor, Xn dipole moment, THF tetrahydrofuran, ACN acetonitrile, MeOH methanol, ATN acetone, DMF dimethylformamide, nc cannot be calculated. 

If the proton donor value Xd) is fixed at 2.58, the equivalent eluent is 54% aqueous acetonitrile and the predicted log/ value for the logP = 3 compounds should be 0.46, which is again different from any of the log/ values in 40% aqueous THF. The dipole moment Xn) of 40% aqueous THF was 2.20 however, such a value cannot be obtained with any proportion of aqueous acetonitrile. To obtain the same log k values as in 40% aqueous THF, a 

---

NaBH4 is soluble in water, alcohols, pyridine, dioxane, dimethoxyethane, diglyme and triglyme. All these solvents, as well as aqueous tetrahydrofuran and aqueous dimethylformamide, have been used for reductions. The reductions go very slowly in di- and triglyme so these solvents are not suitable for preparative work. In some reductions in dry pyridine and dry dimethyl sulfoxide, reaction only takes place on aqueous work-up. This... 

The 20-ketone of an 11,20-dione has been protected as a A -enol acetate while the 11-ketone is reduced with NaBH4 in aqueous tetrahydrofuran for 9 days at room temperature. The presence of the 17(20)-double bond made possible the later introduction of a 17a-substituent. " r... 

Two hydrogen-transfer systems have been developed that also give good yields of hydroxylamines. One uses 5% palladium-on-carbon in aqueous tetrahydrofuran with phosphinic acid or its sodium salt as hydrogen donor the other uses 5% rhodium-on-carbon in aqueous tetrahydrofuran and hydrazine as donor. These systems are complementary and which is the better may depend on the substrate (36). The reductions cannot be followed by pressure drop, and both require analysis of the product to determine when the reduction should be terminated. 

To a suspension of 35.2 grams (0.2 mol) of L-cysteine hydrochloride monohydrate stirred in a reaction vessel containing 87 ml of 91% aqueous tetrahydrofuran under a nitrogen... 

After cooling the resulting solution, aqueous tetrahydrofuran is added to destroy the excess reducing agent and the solution is filtered. Tetrahydrofuran is distilled off and the residue is recrystallized from acetone petroleum ether. 

In the laboratory, alkenes are often hydrated by the oxymercuration procedure. When an alkene is treated with mercury(II) acetate Hg(02CCH3)2, usually abbreviated Hg(OAc)2l in aqueous tetrahydrofuran (THF) solvent, electrophilic addition of Hg2+ to the double bond rapidly occurs. The intermediate orgnnomercury compound is then treated with sodium borohydride, NaBH4, and an alcohol is produced. For example ... 

Step 4 With the coupling accomplished, the phosphite product is oxidized to a phosphate by treatment with iodine in aqueous tetrahydrofuran in the presence of 2,6-dimethylpyridine. The cycle (1) deprotection, (2) coupling, and (3) oxidation is then repeated until an oligonucleotide chain of the desired sequence has been built. 

The next major obstacle is the successful deprotection of the fully protected palytoxin carboxylic acid. With 42 protected functional groups and eight different protecting devices, this task is by no means trivial. After much experimentation, the following sequence and conditions proved successful in liberating palytoxin carboxylic acid 32 from its progenitor 31 (see Scheme 10) (a) treatment with excess 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in ie/t-butanol/methylene chloride/phosphate buffer pH 7.0 (1 8 1) under sonication conditions, followed by peracetylation (for convenience of isolation) (b) exposure to perchloric acid in aqueous tetrahydrofuran for eight days (c) reaction with dilute lithium hydroxide in H20-MeOH-THF (1 2 8) (d) treatment with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran first, and then in THF-DMF and (e) exposure to dilute acetic acid in water (1 350) at 22 °C. The overall yield for the deprotection sequence (31 —>32) is ca. 35 %. 

The photolysis of aryl azides in water or aqueous tetrahydrofuran provides access to 1 //-azepin-2(37/)-ones. 136.197.199.202... 

Azido-l, 4-benzodiazepin-2-ones 43 arc obtained from 1,4-benzodiazepin-2-ones by treatment with potassium bis(trimethylsilyl)amide, followed by 2,4,6-triisopropylbenzencsulfonyl azide. The azides are reduced to the corresponding amino compounds 44 by the action of triphenyl-phosphane in aqueous tetrahydrofuran. No further details were reported.429... 

Giese and Kretzschmar7j found the rate of addition of hexenyl radicals to methyl acrylate increased 2-fold between aqueous tetrahydrofuran and aqueous ethanol, Salikhov and Fischer74 reported that the rate constant for /-butyl radical addition to acrylonitrile increased 3.6-fold between tetradecane and acetonitrile. Bednarek et al75 found that the relative reactivity of S vs MMA towards phenyl radicals was ca 20% greater in ketone solvents than it was in aromatic solvents. 

Reaction under solvolytic conditions such as in ethanol or aqueous tetrahydrofuran caused exclusive C-14—N bond cleavage and introduction of an ethoxyl or hydroxyl group at C-14, giving 30 in excellent yields (34). Addition of a base such as magnesium oxide to the reaction mixture was found to be useful to avoid the recovery of the starting material as the hydrobromide (35). The reaction was used for a synthesis of protopine alkaloids (Section V,E,5). 

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

Ozonolysis of alkene 446 in the presence of acetaldehyde afforded diketone 448 through the intermediacy of 447. Ring expansion through Beckmann rearrangement took place when bis-oxime 449 was mesylated and warmed in aqueous tetrahydrofuran (THF). The bis-lactam so formed gave piperidinediol 450 on reduction with lithium aluminium hydride, and this compound was transformed into ( )-sparteine by treatment with triphenylphosphine, CCI4, and triethylamine (Scheme 105) <20050BC1557>. 

A suspension of 414 in aquoeus dioxane was treated with proline 433a and iV-phenyl isatin 432a and the reaction mixture was heated at 80-90 °C overnight. The resin-containing cycloaddition product was reduced in aqueous tetrahydrofuran with lithium borohydride for 12 h at room temperature to afford a mixture of mainly 437 and a trace of 438 unlike in solution phase where in equal amount of 437 and 438 were produced (Scheme 99). 

Figure 4.2 Predicted chromatographic behaviour in aqueous acetonitrile and tetrahydro-furan of model compounds whose log P values are 1, 3, and 5. Column, 5 pm octadecyl-bonded silica gel (LiChrosorb LC-7), 25 cm x 4.1 mm i.d. Compounds and eluent , polycyclic aromatic hydrocarbons and alkanols in aqueous acetonitrile, O, alkanols in aqueous tetrahydrofuran and O, polycyclic aromatic hydrocarbons in aqueous tetrahydrofuran.

However, the effects on the rates in nonpolar solvent systems is dramatically larger and often of apparent contradiction. For example, the Hammett rho value for the oxidation of substituted methyl cinnamates and cinnamic acids by tetrabutylammonium permanganate in methylene chloride solutions is positive (33,49). See Figure lb. However, a rho value of converse sign (-0.6) is obtained from a Taft plot (Figure Ic) for the oxidation of vinyl ethers in aqueous tetrahydrofuran (33,50). For many other compounds the Hammett relationships are no longer linear, but concave upward ... 

Reductive carbonylation of isopropylallylamine catalyzed by RhCb.aq or [RhCl(CO)(PPh3)2] in aqueous tetrahydrofuran afforded the corresponding y-lactam (Scheme 5.9) [31]. With the former catalyst at 91 % conversion 75 % lactam yield was observed. PPh3 and 1,2-, 1,3- and 1,4-diphosphines all led to somewhat higher conversions (95-100 %) but to diminished yield of the y-lactam product (45-61 %). 

Molybdenum trichloride is generated in situ from molybdenum pentachlor-ide and zinc dust in aqueous tetrahydrofuran. It is used for conversion of sulfoxides to sulfides [216]. 

Chemical deoxygenation of sulfoxides to sulfides was carried out by refluxing in aqueous-alcoholic solutions with stannous chloride (yields 62-93%) [186 Procedure 36, p. 214), with titanium trichloride (yields 68-91%) [203], by treatment at room temperature with molybdenum trichloride (prepared by reduction of molybdenyl chloride M0OCI3 with zinc dust in tetrahydrofuran) (yields 78-91%) [216], by heating with vanadium dichloride in aqueous tetrahydrofuran at 100° (yields 74-88%) [216], and by refluxing in aqueous methanol with chromium dichloride (yield 24%) [190], A very impressive method is the conversion of dialkyl and diaryl sulfoxides to sulfides by treatment in acetone solutions for a few minutes with 2.4 equivalents of sodium iodide and 1.2-2.6 equivalents of trifluoroacetic anhydride (isolated yields 90-98%) [655]. 

The problem of selective hydrolysis of the acetonlde was studied next. The most practical method consisted of a treatment with acetic acid In aqueous tetrahydrofuran at 65°C which gave a mixture of dlol 103 (major) and trlol 104 (minor) In 77 and 15% yields respectively. Trlol 104 could be converted to 103 by a sequence Involving formation of a 2 3 -orthoester, conversion to the corresponding dl-BOM derivative, then mild hydrolysis. 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

A study was conducted into the regioselectivity of the reactions of cyclic sulfate galactopyranoside 49. Under aqueous tetrahydrofuran (THE) conditions and using the hard nucleophile, hydroxide anion, consistently low regioselectivity was... 

Indium-promoted organometallic reactions are greatly accelerated in water, especially when the coreactant carbonyl compound also has good water solubility. Otherwise, aqueous tetrahydrofuran can be used. To date, indium is the most effective metal for promoting Barbier-type reactions under aqueous conditions. As illustrated here, this is of particular value where formaldehyde is concerned, since the need to generate monomeric formaldehyde by thermal cracking is avoided. 

The presence of bromine at C-12 does not affect the selectivity 12a-bromo-3a-hydroxy-5/J-pregnane-ll,20-dione is reduced to the 20/ -alcohol by NaBH4 in either aqueous tetrahydrofuran or 2-propanol.72 Similarly, a 17-bromo substituent has no effect.239 LiBH4 has also been used for selective reductions of a 20-ketone in the presence of an 11-ketone.92... 

Starch can be vinylated with acetylene in the presence of potassium hydroxide in an aqueous tetrahydrofuran medium.1 1 The mechanism possibly involves the addition of the potassio derivative of starch across the carbon-carbon triple bond of acetylene, with subsequent hydrolysis of the organometallic intermediate to give the vinyl ether. Such a mechanism has been postulated for the formation of vinyl ethers from monohydric alcohols and acetylene, in the presence of an alkali metal base as catalyst.1 2 The vinylation of amylose is very similar to the vinylation of amylopectin, except for the relative ratio of mono- to di-substitution. With amylopectin, the proportion of disubstitution is greater. In both starches, the hydroxyl group on C-2 is slightly more reactive than the hydroxyl group on C-6 there is little substitution at the hydroxyl group on C-3. 

A mild and highly convenient procedure for the hydration of a carbon-carbon double bond involves the initial reaction of an alkene with mercury(n) acetate in aqueous tetrahydrofuran, the resulting mercurial intermediate is reduced in situ by alkaline sodium borohydride solution. The yields of alcohols which are... 

This reaction was extended to prepare 7-nitro- and 9-nitro derivatives of pyrido[l,2-a]pyrimidinone 119 (R = N02, R1 = H R = H, R1 = N02) when the appropriate starting material 118 was heated in boiling dichloro-methane in the presence of triethylamine or when it was stirred in aqueous sodium hydroxide at 20°C (92AJC1825) or treated with sodium azide in aqueous tetrahydrofuran (92AJC2037). Semiempirical molecular orbital calculations (AMI) indicated that the 2-hydroxy-4-oxo tautomeric forms 119 are more stable than the alternative 4-hydroxy-2-oxo tautomeric forms. 

---