.

1,1-dicyano-2-methoxy-2-(1′-naphtylmethyl)-ethylene 9.175g (36.95 mmol) and t-Bu-hydrazine hydrochloride 4.65g (37.3 mmol) was suspended in absolute ethanol 0.25L and triethylamine 5.3mL was added dropwise over 7 min period. After stirring at RT for extra 10 min, the mixture was placed on oil bath (90C) and refluxed overnight (18 hours).  The cooled reaction mix was evaporated and the residue was portioned between DCM 150mL and water 100mL. The aqueous phase was re-extracted twice with DCM (2×100mL), the combined extracts were dried (Na2SO4) and evaporated. The residue was purified on a column of silica (250g) in DCM, eluted with straight DCM 0.3L and then 20:1 DCM+EtOAc (v/v; 2L).

The obtained 5-amino-1-tert-butyl-4-cyano-3-(1′-naphtylmethy)-pyrazole (cream-colored crystalline solid, 7.15g, 63.5%Y) was flushed with Ar in a 1L flask, formamide 100mL was added, the flask was equipped with a straight glass tube as air-cooled condenser and the mixture was deoxygenated by a highvac/Ar purge. The mixture was stirred on a 180C oil bath under Ar for 7 hours. The mixture was allowed to cool to R.T., the formed slurry was gradually diluted with water (60mL) and the mix was stirred for additional 30 min. The precipitated product was collected by filtration, thoroughly washed with water, dried by suction and on highvac. The crude product (7.05g) was dissolved in ethanol 0.5L at reflux. One spoon of charcoal was added, the mix was stirred at reflux for additional 10 min then filtered while still warm (the charcoal was washed with additional ethanol) and the filtrate was evaporated to dryness. The obtained foamy residue was re-crystallized from a mix of benzene 30mL and cyclohexane 20mL (RT, overnight). The crystallized product was collected by filtration, washed with 1:1 benzene-cyclohexane mix and then with hexanes, dried by suction and on highvac.
Y=7.788g (57% overall Y) of a cream-colored crystalline solid as a 2:1 co-crystal with benzene.

1H(d6-DMSO, 400MHz): 8.905(very br s, 2H), 8.473(s, 1H), 8.249(m, 1H), 7.936(m, 1H), 7.816(d, 8.2Hz, 1H), 7.555(m, 2H), 7.395(dd, 8.1Hz, 7.2Hz, 1H), 7.153(d, 7.0Hz, 1H), 4.873(s, 2H), 1.654(s, 9H); LC/MS(+ESI): 332(M+1)

Note 1:  1NMPP1 is commercially available but very dear

Note 2:  To remove the benzene trace (the compound is intended for biology use) the purified material was re-dissolved in ethanol 150mL, the solution was carefully concentrated on rotovap from a 50C bath down to about 1/3 volume and the remaining solution was slowly diluted down with water – about 200mL – until cloudy, the crystallization was then induced mechanically (by scratching the solution against the flask joint). The resulting slurry was stirred on ice bath for 1 hour. The precipitate was collected by filtration, washed with ice water, dried by suction and on highvac. This provided 6.012g of pure product free of benzene (Y=49% overall). 1H(d6-DMSO, 400MHz): 8.319(m, 1H), 8.141 (s, 1H), 7.921(m, 1H), 7.793(d, 8.2Hz, 1H), 7.541(m, 2H), 7.391(dd, 8.1Hz, 7.3Hz, 1H), 7.145(d, 7.0Hz, 1H), 7.027(very br s, 2H), 4.875(s, 2H), 1.662(s, 9H)

.

This procedure employs methyl triflate. The final product is a strong irritant. See the notes below.

A slurry of 1-naphtaleneacetic acid 26.00g (140 mmol) in dichloromethane 60mL in a 250mL round flask was placed on ambient water bath and neat oxalyl chloride 13.0mL (150 mmol) was added followed by 5 drops of DMF (not more, else the gas evolution commences too fast). The flask was equipped with a Drierite-filled gas outlet tube and stirred on ambient bath overnight (8h30 min, the gas evolution ceased and the mix became homogennous). The flask was equipped with a vacuum distillation shortpath adaptor, placed on oil bath and the solvent was distilled off at atmospheric pressure from a 80C bath. The residue was then vacuum-distilled at 0.4-0.5 Torr from 80C to 135C bath, the pure acyl chloride distilled at 110C/0.45 Torr. Y=26.11g of a light orange-yellow oily liquid (91%Y)

60% NaH in mineral oil, 5.0g (125 mmol) was loaded into Ar-flushed 1L round flask with a large stirbar. Anhydrous THF 0.5 L (approx) was added via canula and the slurry was cooled on ice bath. Neat CH2(CN)2 4.40g (66.5 mmol) was added in one portion (gas evolution!) [1] and the mix was stirred on ice for 30 min. An addition funnel was charged with benzene 20mL and 1-naphtylacetyl chloride 12.00g (58.63 mmol) and this solution was then dropwise added into vigorously stirred reaction mix on ice bath under Ar (gas evolution) over a 30 min period. The addition funnel was washed with benzene 10mL and the washings were also added to the reaction mix. 10 min after complete addition, the cooling bath was removed and the reaction mix was stirred at RT overnight (7h30min). The reaction mix was then briefly sonicated (1 min) to break few remaining unreacted chunks of NaH, then carefully evaporated to dryness. The obtained foamy residue containing the Na-enolate salt intermediate was suspended in anh MeCN 0.5L (added via canula) and then stirred under Ar and occasionally sonicated  over a 30 min period until all chunks disappeared and a cloudy solution formed. The mixture was placed on ice bath and after 20 min on ice, neat methyl triflate [2] 9.0mL (81.5 mmol) was added by a syringe dropwise over a 10 min period. After additional 10 min stirring on ice, the cooling bath was removed and the mixture was stirred at RT under Ar overnight (15h30 min).  At this point the TLC and HPLC indicated disappearance of the acylmalononitrile intermediate and a formation of two products in about 3:1 ratio.  The reaction was quenched by addition of triethylamine 7.0 mL, stirred for 15 min and then evaporated to dryness. The residue was suspended in toluene (100mL), the slurry was filtered through a medium-porosity glass Buchner funnel (150mL size), the insoluble material was thoroughly washed with additional toluene (150mL) and discarded. The filtrates were evaporated and the residue was dissolved in a mix of DCM and toluene (20+20mL), the mix was applied onto a column of silica (250g) in straight DCM and eluted with DCM. The pure methoxy product migrated first and separated nicely from the sideproduct on silica in DCM. Y=9.200g (63%) of a pale yellow sticky goo that gradually solidified on highvac into a hard white crystalline mass. The product is a potent irritant [3].

1H(CDCl3, 400MHz): 7.932 (m, 1H), 7.912 (m, 1H), 7.864 (d, 8.3Hz, 1H), 7.622 (m, 1H), 7.572 (m, 1H), 7.473 (dd, 8.2Hz, 7.2Hz, 1H), 7.263 (dd, 7.1Hz, 6.2Hz, 1H), 4.448 (s, 2H), 3.935 (s, 3H); 13C(CDCl3, 100MHz): 186.48. 134.05, 131.05, 129.31, 129.12, 127.75, 127.25, 126.53, 125.62, 125.17, 122.28, 113.29, 111.51, 67.83, 59.51, 34.44

Note 1: It is better to add solid malononitrile rather than a warm molten liquid – the liquid tends to solidify in the syringe

Note 2: Methyl triflate is a supremely toxic and dangerous alkylating agent as discussed previously. Use nitrile gloves throughout, keep the triflate in the hood at all times, treat the rotovap and the rotovap waste with a great care until decontaminated with ammonia.

Note 3: The product is completely odorless but a rather creepy irritant – the structure is closely related to CS tear gas commonly used by the police and military. Use gloves, do not spill it outside hood, do not breath vapors (= swollen itchy nose for hours afterwards; certizine pills are a pretty useful thing to have at hand). For the love of God wash your hands with a soap before going to bathroom.  The material is best used right away as a goo – before it solidifies – crushing a hard crystalline solid is no fun with a strong irritant.

To a cooled solution (–78 °C) of 8-bromoquinoline (2.25 g, 10.8 mmol) in THF (70 mL) in a flame-dried flask under N2 was added n-BuLi (2.5 M in hex, 6 mL, 15 mmol) drop-wise. The dark orange mixture was allowed to stir for 10 min. Aldehyde (2.84 g, 16.2 mmol, readily available from salicylaldehyde and 1-chloro-2-methyl-2-propene) was slowly delivered as a solution in THF (3 mL) over a span of 10 min to give a dark cloudy red solution. The reaction was stirred at –78 °C for 20 min, and allowed to warm to room temperature over 2 h. The clear orange solution was quenched with saturated NH4Cl (60 mL), and the layers were separated. The organic layer was washed with water (10 mL), and the combined aqueous washes were extracted with Et2O (2 x 50 mL). The combined organic portions were washed with brine (30 mL), dried over Na2SO4, and concentrated. The resulting orange-yellow residue was taken up in Et2O and a colorless precipitate formed. Collection of this precipitate by vacuum filtration gave the alcohol (1.80 g, 5.9 mmol, 55%), which was carried on directly. The intermediate alcohol (1.53 g, 5 mmol) was dissolved in DMSO (33 mL) and allowed to react with IBX (2.92 g, 10 mmol). The solution was maintained at room temperature for 2 h. Ethyl acetate (20 mL) and water (20 mL) were added, and the resulting colorless precipitate was removed by filtration through Celite. The layers were separated, and the aqueous portion was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4, and concentrated. The yellow-orange oil was purified by column chromatography over silica gel (1:9 EtOAc:Hex) gave 1 as viscous yellow oil (1.20 g, 3.97 mmol, 79%, 43% over the two steps). Rf .23 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.77 (dd, J = 1.8, 4.2 Hz, 1H), 8.13 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.8, 7.5 Hz, 1H), 7.81 (dd, J = 1.5,8.4 Hz, 1H), 7.78 (dd, J = 0.9, 6.6 Hz, 1H), 7.54 (app t, J = 7.8 Hz, 1H) 7.47-7.41 (m, 1H), 7.34 (dd, J = 4.2, 8.1 Hz, 1H), 7.05 (app t, J = 7.5, Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.49-4.36 (m, 2H), 3.97 (s, 2H). 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.8, 158.1, 150.3, 145.9, 141.6, 139.7, 135.7, 133.6, 131.2, 129.8, 129.5, 128.2, 128.0, 125.8, 121.2, 120.5, 112.6, 112.2, 72.0, 18.7; IR (thin film) 3078, 2915, 1645, 1595, 1573, 1485, 1451, 1322, 1294, 1246, 1158, 1109, 1040, 1006, 926, 907, 798, 754, 626; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1329.

A 0.2 M solution of 1 in PhMe was prepared in a N2 atmosphere glove box. RhCl(PPh3)3 (10 mg, 0.01 mmol) catalyst was carefully weighed into a 1 dram vial, and the solution of 1 (0.5 mL, 0.1 mmol) was added followed by toluene (0.5 mL). The vial was capped with a PTFE lined screw-cap and resulting yellow-orange solution was maintained at 130 °C for 48 h. The cloudy brown mixture was removed from the glove box and concentrated onto Celite. Column chromatography (EtOAc:Hex) gave 2 as colorless viscous oil (28.7 mg, 0.095 mmol, 96%).  Rf 0.31 (1:4 EtOAc:Hex)

1H NMR (300 MHz, CDCl3) δ 8.94 (dd, J = 2.1, 4.5 Hz, 1H), 8.18 (dd, J = 1.8, 8.4 Hz, 1H), 7.91 (dd, J = 1.5, 8.4 Hz, 1H). 7.81 (dd, J = 1.8, 7.2 Hz, 1H), 7.56 (dd, J = 7.2, 8.1 Hz, 1H), 7.44 (dd, J = 4.2, 8.4 Hz, 1H), 7.13-7.07 (m, 2H), 6.83-6.78 (m, 2H), 4.72-4.55 (m, 2H), 3.97-3.75 (m, 2H), 1.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.7, 159.1, 150.5, 145.5, 140.1, 136.3, 135.5, 131.2, 129.0, 128.23, 128.2, 126.1, 122.9, 121.5, 120.4, 109.7, 83.0, 54.2, 44.4, 25.9; IR (thin film), 3045, 2961 1681, 1595, 1568, 1479, 1346, 1247, 1216, 970, 831, 792, 750; HRMS (ESI) calcd for [C20H17NO2 + H]+ 304.1332, found 304.1337. The structure was confirmed by HMQC, COSY, and HMBC.

A 1-L 3-neck round bottom flask was equipped with an overhead mechanical stirrer, an internal temperature thermometer, and a dropping funnel. The flask was charged with methanesulfonic acid (250 mL) and warmed with stirring to an internal temperature of 125 °C. 2-Bromoaniline (80.55 g, 0.468 mol) was added portion-wise, followed by meta-nitrobenzenesulfonic acid sodium salt (66.30 g, 0.293 mol) and FeSO4.7H2O (3.90 g, 14 mmol). The addition funnel was charged with glycerol (28.3 mL, 0.39 mol) and the glycerol was added dropwise over 15 min. Two additional portions of glycerol (2 x 28.3 mL, 0.78 mol) were added at three-hour intervals. After the last portion of glycerol was added the brown solution was maintained at 125 °C for 12 hours. The reaction mixture was allowed to cool to RT and water (250 mL) was added. The resulting brown-black solution was transferred to a 4-L beaker with the aid of 100 mL water. The beaker was placed in an ice bath and an aqueous NaOH solution (50% m/v) was added with stirring until the solution was basified to ~ pH 14. The heterogeneous mixture was extracted with Et2O (3 x 500 mL), allowing the emulsion to settle for ~10 min each time. The combined organic extracts were washed with brine (1 x 400 mL), dried over Na2SO4 and filtered through Celite. Concentration of the resulting solution to a viscous brown oil provided the title compound (86.55 g, 0.426 mol, 89%) in ~95% purity as judged by 1H NMR. The crude product was then purified by kugelrohr distillation (0.14 mm Hg; pot temp, 180–205 °C) to give a yellow oil that solidified on standing (83.69 g, 0.402 mol, 86%)

1H NMR (300 MHz, CDCl3): 8.98 (dd, J = 4.2, 1.8, 1H), 8.08 (dd, J = 8.3, 1.7, 1H), 7.98 (dd, J = 7.4, 1.4, 1H), 7.72 (dd, J = 8.1, 1.2, 1H), 7.39 (dd, J = 8.1, 4.2, 1H), 7.32 (t, J = 8.0, 1H); 13C NMR (75 MHz, CDCl3): 151.1, 145.0, 136.5, 133.0, 129.4, 127.7, 126.8, 124.5, 121.8.
This material identical to 8-bromoquinoline prepared by other methods.

The question was: how to perform this reaction in a clean way (no column purifications, no distillations), cheap (if possible, no Ag salts or any other expensive metals), easy (if possible, no Ar and no Schlenk flasks, open air, solvents from bottles), scalable (well, this combines first three I guess), general (yes, I needed a library of these compounds with different functional groups and had no desire to develop different procedures for each of them separately).
Quick look in SciFinder showed two procedures as mostly used and welcomed by scientists; (a) using silver nitrate and NIS (posted on this website some time ago by Chris Douglas  (b) deprotonation with nBuLi in THF or Ether under Ar followed by quench with I2. Obviously, they could not meet my criteria. First approach required using of Ag salts and not so cheap and stable NIS, second one needed anhydrous conditions, cooling, flammable nBuLi and yes – Schlenk flasks and Schlenk line. It is not like I could not do it and I do have Schlenk line under my hood, but… sometimes 10-15 min more in SciFinder can save a lot of pain in the neck.
So, I found procedure from Scott E. Denmark (Tetrahedron 2004, 60, 9695) for the desired iodination in MeOH/H2O using KOH as a base and I2 to deliver I+. Although, this procedure was used only for omega-OH acetylenes, which could be the trick, I decided to give a shot. Reaction worked as a magic – easy, open flask, no cooling or heating, all reactants are cheap and could be found in any lab, water from tap and methanol from bottle. Yields are generally over 80% and no column needed. Below are some selected substrates I did.

Here is the magic procedure:

To a solution of alkyne (50 mmol) in MeOH (50 mL) was slowly added an aqueous solution of KOH (2.5 equiv) in water (10-12 mL) at rt. (I tried recommended 0°C and did not find any difference). After 10 min I₂ (1.5 equiv.) was slowly added within 3-5 min at rt (I tried recommended 1.1 equiv. but could not reach full conversion). The mixture was diluted with H₂O and extracted with pentane. The combined organic layers were concentrated and filtered through 3-5 cm plug of silica gel. Silica gel was washed with pentane till disappearance of spot of product on TLC. Pentane was evaporated and … that’s it. For all substrates I did so far purity of product was >95% by NMR and GC.

Thank you for reading.

Welcome aboard, krest17
_______________________________________________________________________________

Note 1: Thread hijackers and comment-section bandits, watch out:  Now there is two of us [2]
Note 2: Formally, Note 2 serves to remind you about the importance of Note 1 – but in reality it ribs CBC

4-oxo-4,5,6,7-tetrahydroindole 5.15g (38.1 mmol; TCI-US) solution in anh THF 0.45L in a 1L flask was placed on ambient water bath and solid LAH 4.0g was added carefully, portion-wise, into the stirred solution, (4×0.5g then 2×1g – very exothermic, gas evolution!). The mixture was then placed on oil bath and refluxed under Ar on a 75-80C oil bath for 26 hours. The reaction mixture was cooled on ambient water bath, quenched by sequential addition of ethyl acetate 4mL followed by dropwise water addition, 4mL (very slowly – gas evolution), followed by 15% wt NaOH solution 12mL followed by additional water 4mL. The resulting slurry was stirred vigorously for 30 min, the salts were removed by filtration (the cake was washed thoroughly with THF) and the filtrates were concentrated on rotovap. The oily residue was distilled on highvac using a short-path distillation apparatus. (The material distilled pure; no fractionation was necessary, bp 57-60C/0.7 Torr).

Y=3.83g (84%th) of tetrahydroindole as an oily colorless liquid that gradually turns yellowish on light and air.[Note 1]

Anhydrous DMF 20mL in a 250mL flask was cooled on ice bath and neat POCl3 4.6mL (50mmol) was added dropwise (exothermic) under Ar. After 10 min, a solution of tetrahydroindole 3.83g (32.14mmol) in anh DMF 10mL was gradually added over 10min (exothermic) followed by additional anh DMF 2×5mL to wash the flask and the syringe. The cooling bath was replaced with ambient water bath and the reaction was stirred at RT under Ar for 13 hours (overnight). The reaction was quenched by addition of water 20mL followed by 15% wt NaOH solution 40mL. After 10 min, additional 15% NaOH 25mL was added. followed by water 100mL and the mixture was stirred vigorously for 30min on ambient water bath. The precipitated product was collected by filtration, compressed on the Buchner funnel, washed thoroughly with water, dried by suction and on highvac. Y= 4.282g (90.5%) of light tan shiny flakes

1H(d6-DMSO, 400MHz): 11.609(br s, 1H), 9.268(s, 1H), 6.679(s, 1H), 2.557(t, 5.9Hz, 2H), 2.446(t, 5.9Hz, 2H), 1.693(m, 4H)

Note 1: Tetrahydroindole is commercially available but is rather expensive. It has a strong unpleasant indole-like fecal odor – do not spill it outside the hood. Because of the oxidation-related darkening, it is best used within few days.

credit: National Geographic ‘Photo of the day’

The spectacular “NaH catalytic” oxidation recently published in JACS has been thoroughly covered elsewhere. I would like to bring your attention to another jaw-dropping paper that just came out in Org Letters:

http://pubs.acs.org/doi/abs/10.1021/ol901250c

Acetophenones and 1-aryl-ethanols are oxidized to benzamides by heating the material with 3 – 4 equivs of iodine and ammonia in a pressure vessel. There is only a passing reference and footnote that “nitrogen triodide might form in the mix.”

In fact, NI3.NH3 readily precipitates upon mixing iodine with aqueous ammonia. (The products vary; a gradual iodine addition to a large excess of ammonia yields ammonium iodide and nitrogen.) Nitrogen triodide is a notoriously super-sensitive primary explosive. I spent some time hospitalized in eye clinic when I was ten years old – my corneas got burned with iodine and my eardrums ruptured because of playing with a spoonful of nitrogen triodide. (The window pane flew out and I was thrown to the ground by the blast;  it took me half a year to fully recover and this all was from few grams of dry material going poof, unconstrained). I cannot warn strongly enough against mixing iodine with ammonia in a pressure flask and then heating the stuff up!

The authors run these experiments on a 1 mmol scale and they give no details about the order of addition. Since the transformation is pretty useful – with a good substrate scope and it looks simple enough (its done in water) –  sooner or later some innocent person is bound to mix up a big batch in the wrong way – and as he screws on the the pressure vessel cap he is gonna blow himself up into a mauve cloud…

.

A 500mL three-necked round flask equipped with a reflux condenser, internal thermometer, pressure-equalised addition funnel and a large egg-shaped magnetic stirbar was charged with 25% sodium methoxide in methanol 31.55g (Aldrich; 146mmol) and methanol 100mL. The flask was placed on ice slush bath and after 15 min a solution of 1,3-acetonedicarboxylic acid dimethyl ester 25.00g (Acros; 143.55 mmol) in methanol 10mL was added within 15 min, the addition funnel was washed with methanol (2×20mL) and the washings were also added into the mix. The cooling bath was then removed and the flask was placed on a 65C oil bath and stirred for approximately 30 min. (The mixture gradually became homogeneous as the precipitated Na-enolate salt of the di-Me-acetonedicarboxylate re-dissolved with heating). When the internal temperature in the flask has stabilized, a mixture of 40% aqueous glyoxal 12.00g (Alfa; 82.7 mmol, 115% of the theoretic amount) with methanol 30mL was introduced dropwise from the addition funnel – very slowly – over a period of 1h45min, with a vigorous stirring on the 65C oil bath. After the complete addition the funnel was washed with methanol (10mL) and the washings were also added to the mix. The resulting cloudy reaction mixture was stirred for extra 15 min at 65C, then diluted with THF 200mL and the flask was removed from the heating bath. The mixture was stirred at RT overnight (12 hours). The precipitated intermediate (as a disodium salt hydrate) was collected by filtration using a large sintered-glass Buchner funnel. The collected solids were washed thoroughly with THF and then dried by suction for about 2 hours.

This intermediate salt (a cream-colored heavy powder, 27.92g; 90%Y) was dissolved in water 400mL in a 1L flask. 37% concentrated HCl 46 mL was added dropwise with a vigorous stirring (as to limit the formation of dumplings) and the resulting heterogeneous mixture was placed on a 100C oil bath. The mixture was stirred at reflux at 100-120C for 1 hour and at 120C for additional 2 hours – during this time the mixture became homogeneous as the gummy deposits gradually dissolved. The flask was then removed from the heating bath, a large spoon of activated charcoal was added into the stirred mix, the charcoal was removed by filtration while warm (the charcoal was washed with additional water) and sodium chloride 100g was added to the combined filtrates. The mixture was stirred on ambient bath until the complete salt dissolution  (5 min). This mixture was then extracted three times with dichloromethane (3×250mL), the organic extracts were washed with saturated aq. NaHCO3 200mL. The combined extracts were dried with magnesium sulfate and evaporated to dryness from ambient water bath. The obtained crystalline residue was dried on highvac for about 30 min.

Y=7.790g of a white crystalline solid, pure by NMR (78.5% overall from di-Me acetonedicarboxylate) .

1H(CDCl3, 400MHz): 3.048(m, 2H), 2.585(ddd, 19.5Hz, 8.7Hz, 1.8Hz, 4H), 2.156(dd, 19.5Hz, 5.2Hz, 4H)

Note 1: The product is also available commercially [Aldrich 5g/$400]

Note 2: A very slow addition of the glyoxal solution and a careful control of the reaction temperature (65C) by the oil bath during the first step is required for a good yield. The reaction is not very sensitive to moisture so a common-grade MeOH was used from a freshly-opened bottle. (The reflux in the first step was done under Ar but this may be unnecessary). The final product can be re-crystallized from MeOH;  in this preparation NMR-uniform material was obtained directly by evaporating the DCM extracts and drying the residue briefly in vacuo.

Note 3: This preparation was based on a large-scale (1.5 mol) procedure from OrgSyn (Vol 64, p.27, 1986). The medium-scale (140mmol) experiment described here was run in higher dilution, on a stirplate and with the oil bath inplace of a heating mantle. Also the hydrolysis step was simplified at this medium scale, etc – these modifications probably helped to improve the product yield and purity.

Note 4: This preparation provided 80% overall yield when run on twice as large scale (1L flask, 50.1g of di-Me-acetondicarboxylate, 300mL MeOH, 63.2g of 25% NaOMe, 24.25g of 40% glyoxal in 50mL of MeOH, 94mL of conc. HCl). Few minor changes: acetondicarboxylate was added neat by syringe, quite fast (over 10 min at 0C) as there is not much exotherm during the additon. In the second step, the intermediate salt (57.5g) was dissolved first in hot water (800mL) and the solution was placed on oil bath (120C) and conc. HCl (94mL) was added at approx 80C internal temperature with intense stirring, and the resulting emulsion was then stirred at reflux on 115-120C oil bath for additional 150 min. In this way the mix is easier to stir magnetically (as the formation of sticky dumplings is completely prevented).

Evaporating aqueous reaction mixture is a lamentable job –  by weight water has one of the highest evaporation enthalpy values – but with a good rotovap and enough persistence one can even take care of several liters of aqueous mix (if there is no better alternative). The one thing that can turn this into the most frustrating experience is foaming.

I was struggling today; a published homotropanone prep calls for freezing + lyophilizing the entire reaction mix. I scaled that thing by a factor of four and since I did not want to lyophilize a half-liter of the reaction mix, I just put it on the rotavap and suddenly the reasons for the recommended lyophilization became painfully clear…

Desperate people would add n-octanol or even couple of drops of silicone oil to their mix but I did not want to introduce non-volatile impurities into the product. I was dreaming about silanizing the flask glass surface instead (a rinse with Me2SiCl2 and tributylamine in dichloroethane does it) but in the end I just poured 1mL of of hexamethyl disilazane (TMS)2NH straight into my aqueous mixture  - and the foaming ceased like a miracle. It must have been the silicone film on the glass that produced this remarkable effect because when I later transferred the solution into another flask it started foaming crazy anew; and a little more (TMS)2NH and it was calm like a lamb again.