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chempyre235
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Nicely done!
Now you can do a transesterification with ethylene glycol to get the cubic analogue of PET! 
Seriously though, good work!
Honestly, I wonder how cubane would affect the properties of polyesters or polyamides.
[Edited on 5/28/2025 by chempyre235]
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Niklas
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That is actually on by bucket list of cubane substances to make, considering my early research was in polymer chemistry and I have all the other
required stuff around (TiPT and Sb2O3) I kinda feel obligated to do it honestly.
Once I scale up the diacid synthesis, aiming to process maybe 100 g of bisketone eventually and leave the rest for the psychedelics, I‘ll most
definitely give cubane PET a shot, but that may still take a while as I‘m currently somewhat procrastinating on making 700 ml of bromine xd
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Niklas
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Some considerations on the synthesis of the cubylethylamine-unit
On the topic of the planned cubane psychedelics, there is one aspect that seems really simple on first sight but turns out to be not nearly as
straightforward on further consideration, and that’s installing the ethylamine / propylamine unit.
Typically one would proceed via a Henry reaction to make the ß-nitrostyrene to then reduce to the amine, generally with lithium aluminumhydride or
sodium borohydride / copper chloride.
There is a couple problems or at least inconveniences with that idea when going from phenyls to cubyls, starting with the least problematic one, cubyl
aldehydes just aren’t nearly as easily accessible by a one step process as aryl aldehydes where you can conveniently perform a Vilsmeier or Rieche
or other formylation of some sorts. As the carboxylates are generally the key intermediates in cubane related synthesis this can be solved by either
selective DIBAL-reduction (this one is kind of inaccessible to do at home) or a LAH-reduction Albright-Goldman-oxidation sequence though.
Now to the actual issues of the Henry approach, most notably the “ß-nitrostyrenes“ (and “nitropropenes“) would likely be exceedingly unstable
as there is no stabilization by the aromatic system and even then most actual ß-nitrostyrenes exhibit at least some level of heat sensitivity. This
would add some considerable difficulty to the whole process, especially as the beta-hydroxy intermediates won‘t eliminate nearly as easily here,
again because of the lack of conjugation with the aromatic system, so one would presumably have to apply heat to get the reaction going which would
lead to degradation and end up in a bad yield at best.
The obvious solution is to first quantitatively make the more stable addition product and then in-situ dehydrate with something like DCC during the
reduction, but I honestly have my doubts whether this will be all too satisfactory either.
So, what alternatives are there to make both cubylethylamines and cubylisopropylamines? One idea I have already proposed in the cubane Ψ-2C-B
synthesis, which is to proceed via the acyl chloride, do a type of Claisen by reaction with the quantitatively deprotonated nitroalkane (nitromethane
on the graph), a kind of enamine equivalent would be preferable but I don’t think that’s a thing for d1 reagents, and then a reduction of both the
nitro group and remaining ketone using alane.
Another pretty intuitive approach only applicable for the ethylamines (it can be extended to make the isopropylamines as shown below but that really
doesn’t seem like the first choice for those) is to make the “benzyl chloride“ from the alcohol, followed by Kolbe nitrile synthesis followed by
typical LAH reduction.
For the cubylethylamines that’s pretty much it, at least I can’t think of anything else that feels particularly viable, as all the other
approaches proceed via a carbonyl intermediate and such aldehydes would come with instability issues on their own, but for the cubylisopropylamines
the corresponding cubylacetones very much seem like viable intermediates. From this the N-alkyl amphetamines could easily be accessed as well, and
while generally not of interest for psychedelic substrates, it may still turn out to be of use.
One of the most promising ideas for that is to proceed by a Darzens-condensation with ethyl 2-bromopropionate (EBP), itself easily available from
alanine in two steps (https://youtu.be/KUOC5fSmejo). As cubane carbaldehyde, just like benzaldehyde, isn’t enolizable, this process should overall work the same as it
would for the aryl equivalents.
The remaining approaches I could imagine all proceed via cubyl bromides (or halides in general, just that the bromides are the easiest to make), which
are accessible from the carboxylic acid either by a one-step Hunsdiecker process with mercury(II)-oxide and bromine or a three-step Barton approach
with NBS as a bromine radical source, second likely being the cleaner and higher yielding one especially for more substituted substrates.
Going from the cubyl bromide to the cubylacetone may be possible by a one-step process, using a reaction Sam has covered for the synthesis of DFMDMA
(https://youtu.be/i43mLFsw6SM?si=z3oOXax3fH25P4zi), and even though the yields appear to not be particularly amazing, it’s still worth to keep in
mind I suppose.
The last approach I wanna mention is to make the Grignard reagent of cubane, react that with propylene oxide to make cubylisopropanol, and then simply
oxidize to the ketone. Now that I think about it doing the Grignard with ethylene oxide followed by halogenation followed by Gabriel synthesis would
also be another path leading to cubylethylamines, but that would be a whole lot of effort and doesn’t at all seem viable compared to the
alternatives.
Overall my personal go-to approaches to use will likely be the modified Claisen approach to make the “phenylethylamines“ and the Darzens approach
to make the “amphetamines“, but to my knowledge Brotato is planning to explore the propylene oxide route as well, and I‘m sure I will try the
acetylacetone route at one point or another too.
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Niklas
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I did a first attempt of the cubane-1,4-diamine synthesis I proposed above, and while it unfortunately failed I think I now have and idea how to do it
properly. So what I did is the following:
A 20 ml vial was charged with 44 mg of hydroxylamine hydrochloride (0,63 mmol), 44 mg of dimethyl cubane-1,4-dicarboxylate (0,2 mmol) and 220 mg
potassium carbonate (1,59 mmol) and the solids taken up in 2 ml of DMF. The vial was loosely capped, and the mixture warmed in a 105 °C silicon
oilbath for 1 h, during which time it turned from a greenish color to a light yellow. 10 ml of dest. water were added resulting in the precipitation
of a white solid which only partly redissolved on acidification with fuming hydrochloric acid, indicating incomplete conversion.
 
The obvious solution to this is to just run the reaction for longer, but cubanes can rearrange to the corresponding cuneanes when extensively heated
especially in atropic solvents so this should better be avoided. Considering the reported reaction time for the Lossen is 5 minutes there definitely
has to be some way to improve the reaction rate, and on reading the paper again they particularly mention that the use of well dried potassium
carbonate accelerates the reaction.
This in itself wouldn’t be an issue, but as my idea was based on generating the hydroxamic acid in-situ using hydroxylamine generated from its
hydrochloride, there would inevitably be at least an equimolar amount of water to hydroxylamine present. So, to get around this, my next attempt will
be to first run the substitution in a solvent like methanol, then remove all the volatiles including water, redissolve the residue of crude hydroxamic
acid in DMF and finally run the Lossen.
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Niklas
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Synthesis of Polyethylene cubane-1,4-dicarboxylate (“Cubane-PET“)
Hello again,
I did a lot of testing regarding the purification of the diester lately, and I will soon put together a post detailing my experiments in that regard.
With some of the resulting material I‘ve decided to already look into some simple synthesis of symmetrical derivatives (I’m still somewhat limited
to what I can do as my mercaptopyridine-N-oxide will take a while to arrive), and will soon hopefully be able to prepare the 1,4-diodo compound and
1,4-diphenyl compound using some lead(IV)-acetate I‘m making at the moment of writing this [1].
One small synthesis I have already successfully (?) executed is based on a suggestion of @chempyre235, and that’s the polyester of
cubane-1,4-dicarboxylic acid and ethylene glycol, which especially considering the hexagonal plane found in cubane resembling benzene (which also
gives it its biosteric properties which will be of relevance to me in the future) can definitely be called “cubane-PET“. To my knowledge this
compound hasn’t been reported before, but I may definitely have missed something, so feel free to call me out on that. In the future I will be
analyzing the product with DSC to get an idea of the glass transition temperature, and of course also get an NMR to check whether I even have the
desired product here at all.
Here a quick overview of the synthetic paths explored, and details as always are given below.
Fig.1 Synthetic paths leading towards “cubane-PET“
Failed direct synthesis according to [2]:
In a 10 ml round bottom flask containing a boiling stone, 250 mg Dimethyl cubane-1,4-dicarboxylate (1,41 mmol) (Note 1) were taken up in 4 ml of
ethylene glycol. A small piece, around 5 mg, of pentane washed sodium (0,2 mmol)was added (Note 2) was added, an air cooled Liebig condenser attached,
and the mixture refluxed for 45 min by warming first in a hot sand bath and later in a hot silicon oil bath. During this period the color slowly
darkened via a red to a dark brown, and then the condenser was quickly switched out for a short path distillation bridge so all the formed methanol is
removed. On reaching 150 °C in the distillation head the heating was stopped, and the mixture cooled in the freezer in hopes of separating the
desired product polymer. This only caused the brown mixture to take on a honey like consistency though, and as no product could be separated on
addition of water either this run was discarded (Note 3).
Note 1: The diester used in this preparation is from the sample prepared in the second run documented here and was used without further purification.
Note 2: In hindsight it likely would have been preferable to first dissolve the sodium in the glycol and then add the ester to avoid a reduction by a
Bouveault-Blanc mechanism, but it’s questionable whether this would really have caused any difference to the final outcome
Note 3: I‘m not entirely sure what went wrong, I suppose the cubane system may not particularly like the temperatures of almost 200 °C, but either
way it’s odd to not get any percipitate at all. The direct synthesis approach may potentially still be successful by using a different catalytic
system like Sb2O3 / TIPT [3], but I deemed that to be somewhat of a pain and therefore went for a more straightforward approach
via the acid chloride.
 
Fig.2-3 Failed synthesis of “cubane-PET“ by base catalyzed transesterification
Synthesis of cubane 1,4-dicarboxylic acid:
In a 250 ml round bottom flask, 917 mg of dimethyl cubane-1,4-dicarboxylate (4,16 mmol) (Note 1) were taken up in around 30 ml of distilled water. 0,5
g of sodium hydroxide (12,5 mmol) and a boiling stone were added, the flask swirled to dissolve the base, and the mixture refluxed for 3,5 h with an
Allihin condenser attached by heating in a heating block. After cooling the yellowish mixture was washed once with 20 ml of MTBE (Note 2), and then
finally acidified by careful addition of 1,2 ml of fuming hydrochloric acid (Note 3). The precipitated solid was collected by gravity filtration,
washed twice with a little more distilled water, and then dried under vacuum, resulting in 705 mg (88,1%) of a crystalline cream colored powder,
decomposing with darkening at 223-224 °C (222-224 °C lit.). By evaporation of the mother liquors to a volume of 10 ml 9 mg of further somewhat more
beige product could be collected, due to the questionable purity and negligible quantity this was discarded though.
Note 1: The diester used in this preparation was made by the typical procedure previously documented and further purified by soxhlet extraction on
silica. This process will soon be explained in a future post of mine.
Note 2: The MTBE washing barely took out any color so it very likely made no difference to the end result. Washing with DCM may be more satisfactory
but overall one can likely just pass on this step.
Note 3: It appears to be of great importance to only add the acid when cooled, as otherwise a considerable amount of salt impurities will get trapped
in the resulting crystals.
 
Fig.4-5 Saponification of the dimethylester and the collected diacid product
Synthesis of Polyethylene cubane-1,4-dicarboxylate [4]:
In a 10 ml round bottom flask 200 mg of cubane-1,4-dicarboxylic acid (1,04 mmol) were suspended in 3 ml of dry dichloromethane. 0,19 ml of
oxalylchloride (2,25 mmol) (Note 1) were added with the help of a syringe, followed by a drop of DMF, causing some instant gas generation and the
solid to gradually start dissolving. The flask was capped with a septum, and from time to time shaken and vented over the course of 45 min (Note 2).
After this period a small quantity of material still hadn’t dissolved, so 3 more ml of DCM and 0,1 ml of oxalylchloride (1,18 mmol, 3,43 mmol in
total) were quickly added and the mixture left to stand for 30 more min. The solvent and other volatiles of the resulting yellow solution were removed
under a 10-20 mbar vacuum without heating (Note 3), and the beige to yellowish residue of crude cubane-1,4-diacylchloride used as such without further
purification or characterization (Note 4).
This solid was redissolved into 5 ml of dry chloroform, and meanwhile in a separate 50 ml round bottom flask 160 μl pyridine (1,98 mmol) and 56 μl
ethylene glycol (1 mmol) were dissolved in 5 ml of chloroform as well (Note 5). The solution of acid chloride was swiftly added to the reaction
mixture minimizing exposure to atmospheric moisture, the flask capped with a stopper, and left to stand for approximately 5 h, during which time a
white solid consisting of pyridine hydrochloride and part of the product polymer precipitated. The solvent was removed by rotary evaporation, the
yellowish residue suspended in 20 ml of half saturated sodium bicarbonate solution, and then collected by gravity filtration. After throughly washing
with dest. water and drying under vacuum 143 mg (63%) of a beige amorphous solid were collected, which for further purification was suspended in 5 ml
of 96% ethanol and again filtered and dried. From this 98 mg (43,2%) of an off-white to grayish powder were collected as the final product (Note
6)(Note 7).
Note 1: The sample of oxalylchloride used was purchased from Sigma Aldrich and had turned somewhat yellow over the course of one year in storage, but
was used in this preparation without further purification potentially explaining why a larger than usual excess had to be used.
Note 2: Especially on larger scales it is quite advisable to use magnetic stirring, I just had no clean stirbars left fitting this flask so this had
to suffice.
Note 3: For reasons unknown to me it’s apparently really important not to heat during the solvent removal as is explicitly noted in countless
papers, though Sam managed to successfully prepare his acid chloride even though he did heat during the vacuum distillation, so it remains an open
question of how relevant it really is.
Note 4: From what I can tell basically all literature regarding the synthesis of cubane-1,4-diacyl chloride is simply refluxing the carboxylic acid in
thionyl chloride [5]. That overall feels like a more convenient procedure for this substrate and likely what I will be employing in the future, I just
didn’t have any thionyl chloride around at the time.
Note 5: The solvent quantity used here is definitely excessive, this was mostly to somewhat help limit mechanical losses at least in this part of the
process.
Note 6: While the yield isn’t particularly amazing it is hardly surprising as mechanical losses, especially for such a generally insoluble material,
will have a huge impact on this scale. On scaling up the whole cubane synthesis I may revisit this polymer synthesis on an overall larger scale, so it
will be interesting to see the difference.
Note 7: An attempt was made to create a type of plastic film by dissolving the solid into benzene and slowly evaporating with the aid of a heatgun,
but the solubility turned out to be too low for this to be a viable process. Hexafluoroisopropanol would likely be required to achieve this which is
well known for being one of the best, if not the best, solvents for dissolving normal PET while still having a reasonable volatility, it is
unfortunately rather pricey though so I don’t know when I‘ll get around to purchasing it to check.
 
Fig.6-7 Synthesis of cubane-1,4-diacyl chloride
 
Fig.8-9 Dried acid chloride and it’s solution in chloroform
 
Fig.10-11 Crude and ethanol washed “cubane-PET“
Sources:
[1] Della, E. W. Head, N. J. (1995). Synthesis and 19F and 13C NMR Studies of a Series of 4-Substituted Fluorocubanes: Resonance Dependence of 19F
Chemical Shifts in a Saturated System. J. Org. Chem., 60/16, 5303–5313
[2] Cammidge, A.N. (1999). An Undergraduate Experiment in Polyester (PET) Synthesis. J. Chem. Educ., 76/2, 236
[3] Cholod, M.S. Shah, N. M. (1982). Catalyst system for a polyethylene terephthalate polycondensation. US4356299A
[4] Fahrenhorst-Jones, T. et al. (2023). 1-Azahomocubane. Chem. Sci., 14/11, 2821-2825
[5] Eaton, P. E. et al. (1995). Barton Decarboxylation of Cubane-1,4-dicarboxylic Acid: Optimized Procedures for Cubanecarboxylic Acid and Cubane.
Synth., 1995/5, 501-502
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Niklas
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Improved one-pot synthesis of endo-2,4-Dibromodicyclopentadiene-1,8-dione diethylene ketal (“Bisketal“)
So I‘ve decided that I would stick to the one-pot procedure I described before (with the modifications stated), as with my 10 l round bottom flask I
now actually have a vessel large enough to execute this reaction with the ~500 ml of ketal left after this second testrun. Doing that will be quite a
task, but I‘m excited, still getting stuff together and should hopefully be able to do things late summer or early autumn. But anyway, considering
the rather bad results of the last run I‘ve decided to do another test following Collin‘s paper more closely, and this is being described below
[1].
In case you are wondering the post regarding the purification of the dimethylester will still follow.
endo-2,4-Dibromodicyclopentadiene-1,8-dione diethylene ketal (“Bisketal“):
In a 1 l three-neck round bottom flask, equipped with an internal thermometer and a 500 ml pressure equalizing addition funnel, 50 g of cyclopentanone
ethylene ketal (0,39 mol) (Note 1) were dissolved into 310 ml of 1,4-dioxane (Note 2) and the resulting solution sparged with argon for 15 min.
Meanwhile the addition funnel was charged with 70 ml of bromine (1,37 mol) (Note 3) and stoppered, and the remaining side neck of the flask connected
to a gas washing bottle filled with concentrated sulfuric acid with an intermediary safety washing bottle in case of suckback. The mixture was cooled
to 5-10 °C with the help of an icebath, and the bromine slowly added over with strong magnetic stirring the course of 3 h making sure to keep the
temperature in the range of 10-15 °C (Note 4). Initially the bromine color instantly disappeared on addition, though towards the end a scarlet
solution remained which was then stirred for 21 h at room temperature (25-30 °C) (Note 5)(Note 6).
Following this the addition funnel was moved to the side neck and a Dimroth attached to the flask. A solution of 121,4 g sodium hydroxide (3,04 mol)
in 610 ml methanol was then gradually added through the addition funnel over the course of 1,75 h, initially causing the mixture to lighten up over an
orange to a light yellow color, but then suddenly darkening again resulting in a light brown suspension of sodium bromide (Note 7). The flask was
moved to a heating mantle and the mixture heated to a mild reflux for 24 h, after which the product was precipitated by pouring into 1,25 l of dest.
water. The reaction flask was washed out twice using 250 ml of dest. water each and once with a little 96% ethanol, and the solid collected by vacuum
filtration after standing in the fridge for 2 h. Things were washed with a total of around 300 ml more dest. water, pulled as dry as possible on the
pump, and finally dried under vacuum till constant weight. From this 66,04 g (83,4%; 88% lit.) of a slightly off-white powder were collected which was
directly forwarded to the deprotection (Note 8).
Note 1: The sample of cyclopentanone ethylene ketal used stems from the synthesis run described in this thread and has a refractive index of 1.448
(1.448 lit.). It was stored over 3Å molecular sieves prior to use.
Note 2: The dioxane used was dried using sodium / benzophenone earlier this year and stored under argon over 3Å molecular sieves ever since.
Note 3: The sample of bromine used was prepared by the oxidation of potassium bromide with sodium persulfate and dried by first washing with
concentrated sulfuric acid, then refluxing over phosphorus pentoxide, and finally redistilling.
Note 4: There is a rather rapid exotherm initially due to the fast mono-bromination, towards the end the temperature is easily controlled though. It
is reported in literature that having the temperature exceed 30 °C even for short periods only results in tars in the following Diels-Alder [2].
Note 5: Temperature has a huge impact on the reaction speed, being finished in a few hours at a temperature of 27 °C while taking days at 15 °C [2].
In case your “room temperature“ is closer to 20 °C it may be advisable to stir for two days rather than just 20 h, even though in [1] a reaction
time of 20 h is reported for regular room temperature.
Note 6: If isolation of the tribromoketal intermediate is desired the solution resulting from this sequence should be poured into diluted sodium
carbonate, the mixture seeded, and the precipitated solid filtered and washed with diluted sodium sulfite to remove trace bromine. A similar approach
has been described in Tom‘s latest video of the cubane series and also in Tsanaktsidis 1997 publication [3][4].
Note 7: It appears that the brown color starts to appear once all the hydrogen bromide has been neutralized. Up until this point there is a
significant exotherm noticeable causing the mixture to boil, unlike believed by many it does not seem to be of relevance to cool during this step
though.
Note 8: I will attempt to isolate some further material from the mother liquors eventually.
Pictures:
Fig.1 Synthesis of the bromine used in the preparation
Fig.2 The apparatus used for the bromination
 
Fig.3-4 The bromination mixture and crystals of bromine-dioxane growing on the sides of the flask
Fig.5 The apparatus used for the Diels-Alder reaction
 
 
Fig.6-9 The reaction mixture during the addition of sodium hydroxide
Fig.10 The final bisketal
Sources:
[1] Collin, D. E. et al. (2021). Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry. Synth., 53/7, 1307-1314
[2] Fluorochem Inc. (1989). CUBANE DERIVATIVES FOR PROPELLANT APPLICATIONS. AD-A210 368
[3] https://youtu.be/BA9dS5_8vkg?si=2CeIWHaoqZI5_fde ; last accessed: 19.06.2025
[4] Tsanaktsidis, J. Bliese, M. (1997). Dimethyl Cubane-1,4-dicarboxylate: A Practical Laboratory Scale Synthesis. Aust. J. Chem., 50/3, 189 - 192
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Niklas
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Improved synthesis of endo-2,4-Dibromodicyclopentadiene-1,8-dione (“Bisketone“)
A 500 ml round bottom flask, equipped with an egg-shaped stirbar, was charged with 205 ml of concentrated sulfuric acid (3,84 mol). With strong
stirring all the previous bisketal intermediate (66,04 g, 162,6 mmol) was added through a powder addition funnel in portions, the funnel quickly
washed down with a couple milliliters of sulfuric acid, and the flask sealed with a ground-glass stopper. After stirring the dark brown solution at
room temperature (20-25 °C) for 31 h things were carefully poured into 1 l of ice water, and the solid collected by vacuum filtration through a
Büchner funnel after standing in the fridge for two hours (Note 1). The solid was throughly washed with dest. water until the washes were no longer
acidic, a majority of the water pulled off on the pump, and the solid finally dried under vacuum (~20 mbar) over silicagel. From this 48,32 g (93,4%)
fine light brown powder were collected as a crude product.
For purification this solid was dissolved into 220 ml (Note 2) of boiling ethyl acetate, 4,8 g of activated charcoal granules were added (Note 3), and
the solution filtered through two layers of filter paper in a Büchner funnel while hot after refluxing for 30 min. After cooling in the freezer the
first fraction of product was collected in a sintered glass funnel and washed down with a minimal amount of additional ethyl acetate to remove traces
of the green mother liquor, from which 35,65 g of a somewhat grayish crystalline solid were collected. The mother liquors were concentrated by rotary
evaporation till the precipitation of further material, which was again collected by vacuum filtration after cooling and the freezer and washed down
with a small quantity of ethyl acetate, resulting in 6,14 g of a slightly off-white, partly crystalline powder. Further evaporation of the dark green
mother liquors yielded a sticky green oil, which could be crystallized by scraping in a mixture of 5 ml ethylacetate and 10 ml heptane, again being
collected by vacuum filtration after cooling and washed with small amounts of ethylaceate to remove traces of a green discoloration, resulting in 4 g
of an again slightly off-white powder. In total 42,79 g of product were collected this way, corresponding to a percent yield of 82,5% (84% lit.) (Note
4).
Note 1: The next day a small amount of further material separated from the mother liquors. While too small of an amount to brother isolating, in
hindsight I would advise to just leave it in the fridge over night.
Note 2: Only around 200 ml are actually required to dissolve the solids, but as the mother liquors will be concentrated anyway it is better to use a
slight excess to minimize things crystallizing and clogging the frit.
Note 3: Less has successfully been used in the last run but the desired product appears to have such a low affinity to the charcoal that more
doesn’t hurt and ensures all of the brown impurity to get removed. If there wouldn’t have been a green impurity this time, which I believe to be
external and stem from the glassware, one may potentially have been able to just fully evaporate the solvent of the filtrate without bothering to take
fractions, minimizing mechanical losses.
Note 4: To remove the slightly grayish color that remained due to activated charcoal particles I decided to filter a hot solution of the product in
acetone through a thin layer of zeolite, doing the mistake of using a sintered glass funnel for that purpose though, leading to crystallization inside
the frit stopping the flow. While I did my best to try to recover all material from this, in the end I only ended up with 33,08 g of an off-white to
slightly yellowish solid, what is rather frustrating considering the material would likely have been fine to use as is.
Now that the previously unsatisfactory sequence has mostly been optimized it’s worth looking at the total yield of things. Taking the 87,5%
for the ketal synthesis, 83,4% for the bromination Diels-Alder sequence, 82,5% for this deprotection and finally 51,2% for the remaining synthesis
(while I reported a 61% yield here before I did not manage to reproduce this value again while yields around 50% seem rather realistic and consistent,
also corresponding to the literature yield of 53%), the total adds up to a very much respectable 30,8% from cyclopentanone to dimethyl
cubane-1,4-dicarboxylate 
Pictures:
Fig.1 The reaction mixture
Fig.2 The crude product
 
Fig.3 The final bisketone, left after the considerably unnecessary extra purification described under Note 4
Sources:
[1] Collin, D. E. et al. (2021). Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry. Synth., 53/7, 1307-1314
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Niklas
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Greetings,
Just as a short update, because I hadn’t posted anything on the project for a while: I‘ve finally constructed a setup for scaling up the UV
reaction and today set up a run with around 35 g of bisketone, so in around a week I will hopefully have a decent amount of diester to finally start
doing some proper chemistry with
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Niklas
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Reaction took a LOT longer than expected, about 300 h until it was complete according to TLC. Definitely gotta change up the setup in the future.. xd
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BromicAcid
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I am just starting to get into preparative UV chemistry. I had a 450 W UV lamp for my reaction, vendor certification said 65% of the energy emitted
as UV light, looked at the spectral emissions for a low pressure mercury lamp. Determined the relative % of each wavelength. Converted to photos.
Determined the amount of time to emit 1 mol of photos. Back of the envelope calculation carried out to see how long the reaction should take at 100%
efficiency. Ended up taking 20 x longer
In short - good luck.
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Metacelsus
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Niklas, this project is really impressive, nice work!
I think the Darzens condensation and Kolbe nitrile synthesis are promising methods for the isopropylamine and ethylamine derivatives, respectively.
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Niklas
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Thank you!
Some notes I forgot to make, while it felt like the most obvious and safest route originally, after having read through a bunch of cubane related
literature I unfortunately believe the Kolbe route may not be too promising after all, as the cubylchloromethane would likely be very prone to
rearrange to a homocubane to release ring strain. This reaction has been demonstrated by Eaton and Yip by simply stirring a solution of
cubylbromomethane in pentane with silica (https://pubs.acs.org/doi/10.1021/ja00020a035).
I‘m sure it could be done with a good amount of experimentation, but yields would likely be far from amazing, overall making this approach rather
unpreferable.
Besides the Darzens route I have quite a bit of fate in the idea of making things via the nitroketone though, so at least for the ethylamines that’s
what I‘ll likely go for first, with the slight modifications compared to the graph of making the Weinreb amide to ensure good yields on the Claisen
and perform the reduction by first making the tosylhydrazone, then adding borohydride to make the alkane (Caglioti-Wolff-Kishner), and finally adding
copper chloride to allow the borohydride to reduce the nitro group to the amine.
[Edited on 24-8-2025 by Niklas]
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Niklas
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One thought I somehow didn’t consider before that is still based on classic Henry chemistry while avoiding an unstable nitroalkene (which in
addition to its instability would likely be fairly low yielding to reduce, as an aromatic ring helps suppress polymerization by a Michael reaction
from the intermediary “nitro-enolate“ on remaining nitroalkene) would be to stay at the addition stage (fairly easy to do in this case as you
don’t have the aromatic conjugation further favoring an elimination), make the tosylate (or convert to some other leaving group like the chloride),
and then reduce.
Again this feels fairly likely to work, but from what I can tell, feel free to correct me if you know of better literature, the reduction of a
tosylate or especially alkyl halides to the alkane usually isn’t super high yielding when not using something like Selectride, which
however can’t reduce the nitro group therefore requiring another step and isn’t something I can get hold of unfortunately.
So I suppose it could be an option, but as aldehydes aren’t as convenient of a precursor in this case anyway (as unlike for aromatics you can’t
just formylate cubane) it’s again not incredibly appealing.
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I should have my notes for the large scale run out in a couple of days, I‘ve already isolated 7 g of product and currently working on collecting the
remaining material.
But on the topic of smaller scale runs, which I would guess some of you would be more interested in as if you are planning to reproduce this synthesis
you may just want to make cubane as a product rather than using it in another synthesis.
I used a 50 ml mantled reaction vessel in my previous runs (both those documented here and my other tests) simply because it happened to be something
I have on hand. This however only allows to make maybe 0,5 g of diester product at best, and isn’t a piece of glassware I would expect much of
anyone to have around. So, what I successfully did for slightly larger scale runs (volume of about 120 ml) was to use a Dimroth condenser, and even
though it seems cursed, it works pretty well.
[Edited on 2-9-2025 by Niklas]
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Larger scale synthesis of dimethyl cubane-1,4-dicarboxylate
Unfortunately this run was quite a bit less successful yield wise than I was hoping, and also took an enormous amount of time (300 h), all due to my
pretty bad and overall quite improvised reactor design. It still produced sufficient material for some first synthesis why I won’t work on improving
this process in the near future, but eventually I‘m definitely going to revisit the scaleup of this step.
To keep the actual writeup more tidy I‘ll quickly explain the reactor design here, a 2 l reactor with a NS45 central joint was equipped with a
custom made central tube 4 cm in internal diameter sealed on the bottom end and jammed against the reactor top with a rubber ring in between to seal
(it‘d obviously be ideal to use a tube with a top male joint to ensure a proper seal and overall make things more stable, but unfortunately this is
impossible with a NS45 joint and the lamp used, as the glass would have to be less than a millimeter thin). A Philips UV-B PL-L 36W/01/4p was placed
in the center, one neck equipped with an electric thermocouple (inside a custom made glass tube 4 mm in internal diameter to protect it from
corrosion), one neck equipped with a gas adapter leading to the argon line, and the remaining necks sealed with stoppers. To allow for stirring a 2,5
cm cylindrical stirbar was added and placed off centered between the central glass tube and reactor wall.
To cool this was placed in a large bucket, lined on the inside with aluminum foil, with two streams of water (from a cheap 15€ aquarium pump)
running over the reaction vessel from opposite sides and a hole being cut into the bottom to allow for the water to recirculate. To keep the water at
a constant temperature a cooling coil connected to my thermostat pump cooled to 5 °C was added to the reservoir.
Attachment: 20250809_124027.mov (3.1MB)
This file has been downloaded 88 times
Fig.1: Video showing the setup and cooling system
Cubane-1,4-dicarboxylic acid (crude) [1]:
In a 2 l wide-neck Erlenmeyer flask 34,65 g of bisketone (109 mmol) were dissolved in a mixture of 900 ml methanol, 160 water, and 1,5 ml of
concentrated sulfuric acid (28,1 mmol) (Note 1) and the resulting light yellow solution sparged with argon for 30 min. It was transferred to the
photoreactor (see above), the vessel flushed out with argon, and things irradiated until full conversion could be observed on analysis with TLC (3:1
heptane / ethylacetate using Seebach‘s stain; bisketone rf=0,36, cage intermediate rf=0,09) (Note 2) while keeping the temperature at 10-15 °C
(Note 3). The resulting light yellow solution (during the reaction it temporarily turned a dark yellow, then lightening up again to an almost
colorless and eventually darkening to a color similar to that of the starting solution) was transferred to a 2 l round bottom flask, the methanol
removed by rotary evaporation, the resulting mixture (150 ml) transferred to a 1 l round bottom flask (NS29) containing a 2,5 cm cylindrical stirbar,
and diluted with 150 ml more water (also used to rinse out the 2 l flask). A Dimroth-condenser (15 °C) was attached and things heated to a reflux in
a heating mantle for 2 h causing the solution to darken to a brownish orange, and finally, after cooling somewhat (Note 4), a solution of 81 g sodium
hydroxide (2,03 mol) in 300 ml of water was added and refluxing continued for 17 h. After cooling the resulting brown-black mixture was acidified with
200 ml of fuming hydrochloric acid (Note 5), the precipitated solid collected by vacuum filtration on a 10 cm Büchner funnel (Note 6), and washed
down with a little more water. After drying under vacuum over phosphorus pentoxide 13,19 g (62,8% yield; 68% lit.) (Note 7) of a brownish grey powder
containing multiple pieces of solid black tar were collected and used as such in the next step.
Note 1: The dissolution is pretty slow and may take half an hour or more.
Note 2: A sample was taken every 50 h, in the end taking 300 h in total. Bartonek reports the reaction time to be no more than 75 h, usually about 50
h, at a similar scale using the same UV source, therefore making it clear that my reactor design is quite awful (only the bottom third of the lamp is
actually sticking into the liquid and the top third isn’t inside the reactor at all so it kind of really isn’t too surprising).
Note 3: There should be no issue with keeping things at room temperature, but as the improvised reactor design meant it wasn‘t particularly well
sealed I was hoping to prevent solvent evaporation this way. Still small amounts of additional methanol had to be added over the course if the
reaction to keep the volume constant.
Note 4: For the small runs I could safely add the sodium hydroxide solution to the still refluxing reaction mixture, in this case an attempt of this
almost caused things to boil over though.
Note 5: I believe this is where significant product loss occurred, as during the small scale experiments I noticed that acidifying while hot resulted
in worse yields pretty consistently, likely because the diacid is actually reasonably water soluble, but when rapidly separating as an amorphous
material when cold it isn’t really able to redissolve to a large extent. When hot it however slowly crystallizes, allowing for it to actually leave
behind a saturated solution. While I did let it cool in this case, I did not consider the significantly stronger exotherm on large scale, causing the
mixture to strongly heat up and resulting in the same negative outcome.
Note 6: The filtration weirdly is awfully slow, I would deem it the worst material I have ever filtered (much worse than the typical bad examples like
iron hydroxide) except for the stuff that just completely blocks the flow.
Note 7: While this yield may not seem too bad, based on the yield of the next step I‘m pretty confident it’s just inflated from having trapped
salts inside the crystals. This is likely also the reason why the product is so light in color, funnily the worse the product looks the better the
total yield usually is.
Fig.2: The solution resulting from the cycloaddition
Fig.3: The mixture after reflux with aqueous sulfuric acid.
Fig.4: Apparatus used for the Faworskii reaction
Fig.5: The crude diacid
Dimethyl cubane-1,4-dicarboxylate [2]:
In a 250 ml round bottom flask (NS29) containing a 2,5 cm cylindrical stirbar all of the above material was taken up in 120 ml of methanol. 1,6 g of
strongly acidic cation exchange resin (Note 1) were added, a mantled Dimroth-condenser attached (r.t), the apparatus flushed out with argon, and
things heated to a reflux in a heating block for 12 h. Initially the mixture turned a black color, later lightening up into a dark brown though, and
after cooling this solution was decanted from the crystallized solids and exchange resin. The residual material was dissolved in DCM, filtered through
some glasswool to remove the catalyst, and the solvent of the pooled mixture removed by rotary evaporation. From this a black solid resulted, which
was extracted in a 250 ml Soxhlet extractor for 48 h (Note 2) using 400 ml of heptane. The solvent was again removed by rotary evaporation, leaving
behind 8,7 g (36,2% yield starting from bisketone, 53,7% lit.) of a light yellow solid (Note 3), which was further purified by recrystallization from
MEK, resulting in 7,03 g (29,3% yield) (Note 4) of white crystals melting at 164-165 °C (161-165 °C lit.).
Note 1: Most literature is using fuming hydrochloric acid as the catalyst which is obviously cheaper and more accessible, it is however definitely of
benefit to minimize the amount of water present though.
Note 2: Completion of the extraction was checked by taking a couple drops of solvent from the extractor and evaporating them on a watchglass. While
this didn’t leave behind any notable residue it appears that the extraction was just very slow at that point, and a few milligrams of additional
material could be isolated by continuing the extraction for 24 h, though the quantity really isn’t worth the time.
Note 3: This material is of sufficient purity for most applications, as the purification can proceed with very few losses it is worth to take this
additional time though. Instead of MEK acetone works equally, I just happened to be out of it.
Note 4: More material of identical purity, from my experience with smaller scale runs at least 1 g and potentially up to 1,5 g, could have been
isolated from the mother liquors, I accidentally overheated things on the hotplate though leading to its decomposition.
Fig.6: Apparatus used for the esterification
Fig.7: The reaction mixture
Fig.8: Purification by Soxhlet extraction
Fig.9: The final product
Sources:
[1] Bartonek, A. et al. (2023). Sensitive 1,4-Disubstituted Nitro-Containing Cubanes: Structures and Properties. J. Org. Chem., 88/18, 12884–12890
[2] Yan, B. et al. (2024). Synthesis of Bishomocubanone Derivatives via Visible-Light-Induced Intramolecular [2+2] Cycloaddition Reaction. Adv. Synth.
Catal., 367/7
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Niklas
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Quote: Originally posted by Niklas  |
Again this feels fairly likely to work, but from what I can tell, feel free to correct me if you know of better literature, the reduction of a
tosylate or especially alkyl halides to the alkane usually isn’t super high yielding when not using something like Selectride, which
however can’t reduce the nitro group therefore requiring another step and isn’t something I can get hold of unfortunately. |
Oh an important note on this, apparently Red-Al works decently well for for the reduction of alkyl tosylates, and I do have 450 ml of a 70% solution
around.
It is kind of less than ideal that one would again proceed via an intermediate with a leaving group alpha to the cubane, again being a fairly likely
candidate to rearrange under many conditions, but I have a procedure in mind that shouldn’t carry this risk. To be precise I would first deprotonate
maybe 1,1 eq of nitroethane with LiH, add the resulting solution to a solution if the cubane carbaldehyde in THF cooled in an icebath, quench with 1,2
eq of TsCl, and directly add the resulting crude mixture to a solution of Red-Al (not sure about the equivalents yet).
While for the unsubstituted amphetamine biostere I will probably proceed via the propylene oxide route as I need cubyl iodide for another synthesis
anyway, for the 4-chloro this isn’t really an option as the chloro will interfere with the Grignard reaction, therefore making the above mentioned
synthesis appealing for it.
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Niklas
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By extraction of the mother liquors of the diacid synthesis with DCM, evaporation, refluxing the brown residue with an excess of methanol with some
strongly acidic cation exchange resin present, evaporating again, and extracting the dark brown sticky residue twice using ~150 ml if boiling heptane
each (the consistency made it impossible to transfer to a Soxhlet) followed by evaporation of the yellow solution a dark yellow crystalline solid
remained, which on recrystallization from MEK made 1,5 g (6,2% yield, 42,4% in total) of white crystals melting at 159-165 °C (161-165 °C).
While this sample is clearly less pure than the previous material, it should still be of sufficient purity for most applications.
As this scaleup overall still can’t be called particularly successful though I‘m currently working on exploring the use of xanthone as a 390 nm
sensitizer, as with these lights there is a lot less of a limit if power you can put in as opposed to the fairly weak 36W UV-B lamp I was using
previously.
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Niklas
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As indicated above, one seemingly promising approach for the scalation of the [2+2]-cycloaddition is a photosensitized approach documented by B. Yan
et al. (https://advanced.onlinelibrary.wiley.com/doi/abs/10.1002/ads...).
Unlike the well known photosensitized approach employing benzophenone, which has been successfully used by Chemiolis and Explosions&fire in the
prepration of dimethyl cubane-1,4-dicarboxylate, is however fairly low yielding (10-20% total yield as opposed to the 30-35% achivable using
unsensitized techniques as I‘ve documented), this one is employing xanthone, and with that claiming a close to quantitative yield on the
cycloaddition (as it‘s the case for the unsensitized approach too, the large losses actually stem from the Faworskii which unfortunately doesn‘t
has much room for improvements). In addition to the yield aspect their claims of dilution (250 g bisketone in about 4 l of volume) and reaction time
(250 g in 12 h) are also extremely impressive, seemingly making it the perfect approach for this reaction, you might even say it‘s too good to be
true.
Well, I tried, and their claims (unfortunately) appear to be complete bs. I performed a run with about 3,7 g of bisketone (so less than 1/50 of the
documented scale) using the same solvent and catalyst ratios as stated, and irradiated using two 50 W 385-395 nm light for 48 h and four 50 W light
for 48 h more hours (cooling performed using a fan), and after this period there appears to be barely any conversion on analysis with TLC (3:1 hexane
/ ethylacetate; Seebach‘s stain). And on evaporating under vacuum, partitioning the residue between water (to dissolve the cage product) and
petroleum ether (to dissolve the xanthone) and filtering most bisketone could be recovered.
A similar run was also performed by Brotato with similar results, and he should soon get a GCMS analysis of the reaction mixture to get a proper idea
of the conversion.
Admittely in the paper it isn‘t stated how many lights were used, however based on the picture of their reactor one can guess ten 40 W lights (40 W
lights used for the small scale runs and ten switches visible on their reactor). The lights used are some fancy “390 nm narrowband“ LEDs, but I
seriously can‘t believe this would make that big of a difference, so I personally have to conclude that the claims in the paper are not
reproducible. Even if it would work this well with those exact LEDs, at that point they‘d be even more financially limiting than the Narrowband UV-B
I‘ve been using for unsensitized irradiation, so this seems to be going nowhere.
[Edited on 3-11-2025 by Niklas]
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Niklas
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Brotato checked things on a 37 g scale and after three days with irradiation using two 200 W lamps on analysis with GCMS only a conversion of 15%
could be achieved. Assuming a linear conversion this would mean 21 days for 37 g, even worse than the already horrendous time I had using the
unsensitized approach (mostly because of the reactor design though, with a better setup 40 g / 50 h should be achievable).
And because the reaction will likely further slow down with time, as is evident by some bisketone initially staying undissolved but dissolving rather
quickly, the reaction not progressing much after that though, 21 days is a very optimistic (and honestly unrealistic) guess.
Another thing indicating this papers claim being more than questionable is the mixture already having turned an orange color even after this amount of
conversion, indicating side reactions similar to those when using benzophenone, so a 99% yield seems pretty unrealistic.
The large peaks are the bisketone, the peak around 12.9 is the xanthone, and the peak around 11.5 is the product.
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Niklas
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Here finally the 1H and 13C NMR of the recrystallized dimethylester from the larger scale run, looks great.
 
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Synthesis of 4-Chlorocubane carboxylic acid
This synthesis is a first step towards the cubane biostere of 4-chloroamphetamine, and I‘ve already managed to process some down to the
corresponding aldehyde (will document that sometime in the near future, once I get around to scaling the procedure). It is achieved in four steps,
with the key step being a Barton decarboxylation using carbon tetrachloride as a „cubyl radical scavenger“ to achieve the chloro substitution [1].
Fig.1: The synthesis of 4-chlorocubane carboxylic acid
Cubane-1,4-dicarboxylic acid monomethylester: In a 250 ml round bottom flask (NS29) containing a 3,5 cm cylindrical stirbar 1,42 g of
dimethyl cubane-1,4-dicarboxylate (6,45 mmol) were dissolved in 60 ml of THF. A solution of 285 mg sodium hydroxide (7,1 mmol) in 3,3 ml of methanol
was dropwise added, the vial rinsed with a little more methanol, and the resulting white suspension stirred for 16 h at room temperature (20-25 °C)
under argon while being protected from light. The solvent of the visually unchanged mixture was removed by rotary evaporation (Note 1), the white
amorphous residue dissolved in about 40 ml of water, and the resulting yellowish solution washed three times using 10 ml DCM each. Things were
acidified by addition of 2 ml of fuming hydrochloric acid, extracted three times using 20 ml DCM each (Note 2), and the pooled extracts washed with 30
ml of water and dried over anhydrous sodium sulfate. After removal of the solvent by rotary evaporation 1,31 g (98,5% yield; 95% lit.) of a white, in
parts slightly yellowish, shiny solid remained, which was used as such without further purification (Note 3).
Note 1: It‘s important for the water bath temperature to stay reasonably low (50 °C or lower), as using a 65 °C water bath resulted in a pinkish
discoloration of the residue, likely due to thermal decomposition.
Note 2: Initially not all of the carboxylic acid dissolves in the organic phase (as it’s solubility in DCM isn’t awfully high), the total quantity
of 60 ml should however be sufficient on this scale.
Note 3: Only for the run mentioned in Note 1 the product was further purified by trituration with heptane due to its fairly significant yellow
discoloration, resulting in the monoester as white shiny flakes in a 86,1% yield.
Fig.2: The collected monomethylester
Methyl 4-chlorocubanecarboxylate (crude): In a 250 ml two-neck round bottom flask (1x NS29, 1x NS14) containing a 2,5 cm cylindrical stirbar
and equipped with a gasadapter 1,16 g of the monoester (5,6 mmol) were suspended in 60 ml of DCM (dried over 3Å molecular sieves). With a flow of
argon running 0,6 ml of oxalyl chloride (7,1 mmol) were added, the flaks capped with a septum, and about 0,05 ml of DMF added using a syringe,
immediately resulting in a gas generation and the slow dissolution of the solid. Things were stirred at room temperature (15-20 °C) over night, at
which point all solids had dissolved, the solvent removed by distillation from a 55 °C water bath, and the residue of crude acid chloride further
dried under vacuum (Note 1).
The resulting beige-yellow solid was dissolved in 15 ml of tetrachloromethane (dried over 3Å molecular sieves) with the aid of a heatgun. Meanwhile
in a 100 ml there-neck round bottom flask (3x NS14) containing a 2,5 cm cylindrical stirbar 1,27 g of 2-mercaptopyridine-N-oxide sodium salt (8,5
mmol) and 10 mg of 4-(N,N-Dimethylamino)pyridine (0,08 mmol) were suspended in 10 ml of tetrachloromethane (dried over 3Å molecular sieves), the
flask equipped with a gasadapter, a Dimroth-condenser and a 100 ml addition funnel, and the apparatus flushed with argon. The addition funnel was
charged with the above prepared solution of the acid chloride (things were rinsed with 5 more ml of carbon tetrachloride), the suspension brought to a
reflux in a sandbath, and the solution dropwise added over their course of 40 min while irradiating with a 500 W lamp, during which time a color
change from white to yellow to greenish to grey could be perceived. Reflux and irradiation were continued for 4 h, the solvent removed by distillation
from a boiling water bath, traces removed under vacuum, and the dark brown oily residue, which crystallized on standing, partitioned between 25 ml of
DCM and 25 ml of 12,5% hydrochloric acid. The organic phase was separated, things extracted twice more using 10 ml of DCM each, and the pooled dark
brown extracts washed with 15 ml water, 15 ml of saturated sodium bicarbonate solution, and finally dried of anhydrous sodium sulfate. The solvent was
removed by rotary evaporation, and the resulting dark brown crystalline residue (Note 1) subjected to kugelrohrdistillation (1-2 mbar, 130 °C),
resulting in 1,17 g (106% yield) (Note 2) of a colorless to slightly yellow crystalline mass, which was used without further purification.
Note 1: Instead of distilling the crude methyl ester one can also process if crude, if instead the final carboxylic acid is further purified by
recrystallization from toluene and soxhlet extraction with heptane. As, at least on a small scale, this generally leads to higher losses (a yield of
39,9% was achieved), the documented procedure is generally superior, however on larger scales one might want to avoid distillation due to a certain
explosion risk these cubane derivatives carry [2].
Note 2: It’s unclear which impurity is causing the apparent increase in yield (I suspect it’s 2-trichloromethylthiopyridine, as I will explain in
my notes on iodocubane soon), it’s however removed in the following step without much difficulty.
Fig.3: Synthesis of the acid chloride
Fig.4: Synthesis of the methyl ester
Fig.5: The collected “crude“ methyl ester
4-Chlorocubane carboxylic acid: In a 50 ml round bottom flaks (NS29) containing a boiling stone all of the crude methyl ester was taken up in
a solution of 1 g sodium hydroxide (25 mmol) in about 30 ml of water. A Dimroth-condenser was attached, and things heated to a reflux in a sandbath
for 4,5 h, causing the mixture to take on a greenish brown color and some brown solid to separate (Note 1). 10 ml of DCM were added, undissolved
material removed by filtration through some glass wool, the aqueous phase separated, and washed twice more using 10 ml DCM each. Traces of DCM were
removed under vacuum, the resulting yellow solution acidified using fuming hydrochloric acid, the solid collected by gravity filtration, washed
throughly with water, and finally dried under vacuum over anhydrous calcium chloride. From this 627 mg (61,3% yield; 55,6% lit. (over three steps)) of
a cream colored powder were collected, appearing pure on analysis with 1H- and 13C-NMR.
Note 1: The tar formation likely stems from a base catalyzed decomposition of the not characterized impurity.
Note 2: Even though things appeared pure on the NMR spectra a slight less polar contamination could be detected on analysis with TLC (3:1 n-Heptane /
ethylacetate, Seebach‘s stain; product rf=0,16, impurity rf=0,42). This is however totally irrelevant for much of any synthetic use of this
substance.
Fig.6: The collected carboxylic acid
Fig.7: 1H-NMR of the carboxylic acid in DMSO-d6 (DMSO and water cut out)
Fig.8: 13C-NMR of the carboxylic acid in DMSO-d6 (DMSO cut out)
Sources:
[1] Benjamin, A. et al. (2016). Validating Eaton‘s hypothesis: Cubane as a Benzene Bioisostere. Angew. Chem., Int. Ed., 55/11, 3580-3585
[2] Fluorochem Inc. (1989). Cubane Derivatives for Propellant Applications. AD-A210 368
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I‘m only now noticing that the picture of the acid chloride synthesis is technically from another test run of this synthesis (why it’s a three
neck rather than two neck flaks like mentioned), but in the end it doesn’t make any difference.
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Synthesis of unsubstituted cubane
The synthesis of unsubstituted cubane is achieved in three steps starting from the dimethylester, by first hydrolizing the esters with sodium
hydroxide, making the diacylchloride by reaction with thionylchloride, and finally decarboxylating by a modified Barton decarboxylation utilizing
chloroform as a hydride source [1]. I‘ve already described the ester hydrolysis in my synthesis of cubane PET (and also the diacylchloride synthesis
however using oxalylchloride and DMF), the run described here was significantly higher yielding though, likely due to the use of a smaller quantity of
water.
Fig.1: Synthesis of unsubstituted cubane
Cubane-1,4-dicarboxylic acid:
In a 50 ml wide-neck Erlenmeyer flask containing a 5 mm cylindrical stirbar 553 mg of dimethyl cubane-1,4-dicarboxylate (2,5 mmol) were suspended in a
solution of 0,4 g of sodium hydroxide (10 mmol) in 15 ml of water and brought to a reflux on the hotplate for two hours. After cooling things were
acidified using fuming hydrochloric acid, left to stand in the fridge for some time, and the precipitate collected by gravity filtration and rinsed
with further water. After drying under vacuum over phosphorus(V)-oxide 456 mg (94,9% yield) of a white shiny powder were collected.
Cubane:
In a 50 ml round bottom flask (NS29) containing a 5 mm cylindrical stirbar 585 mg of cubane-1,4-dicarboxylic acid (3,0r mmol) (Note 1) were suspended
in 3 ml of thionyl chloride (41,4 mmol) (freshly redistilled over 1/5 its weight of quinoline). The flask was flushed out with argon, and things
heated to a reflux in a sand bath with an Allihin condenser attached for five hours, causing things to take on a yellow color. Excess thionylchloride
was removed under vacuum (Note 2), and the resulting partly colorless partly brownish crystalline residue of diacylchloride dissolved in 35 ml of dry
chloroform (Note 3).
Meanwhile in a 100 ml three-neck round bottom flask (1x NS29, 2x NS14) containing a 2,5 cm cylindrical stirbar 1,81 g of 2-Mercaptopyridine-N-oxide
sodium salt (12,1 mmol) and 38 mg if DMAP (0,31 mmol) were taken up in 35 ml of dry chloroform (Note 3), the flask equipped with a gas adapter, an
Allihin condenser and a 50 ml addition funnel, flushed with argon, and the addition funnel charged with the above prepared acid chloride solution.
Things were brought to a reflux in a sand bath, the yellow solution added over the course of 1 h while irradiating with a 500 W lamp, and reflux and
irradiation of the resulting yellowish brown mixture continued for 4 h afterwards. The solvent was removed by rotary evaporation, the brown sticky
residue partitioned between 50 ml of n-pentane and 50 ml of 12,5% hydrochloric acid, the organic phase separated, washed twice more using 30 ml of
water each, and the yellowish solution dried over anhydrous sodium sulfate. The solvent was again removed by rotary evaporation and the partly dark
yellow oily partly white crystalline residue purified by column chromatography using 20 g of 60Å silicagel in a column 1,5 cm in diameter with
n-pentane as the eluent (Note 4). After removal of the solvent by rotary evaporation 223 mg (70,4% yield; 58% lit.) of white slightly waxy needles
were collected, appearing reasonably pure on analysis with 1H- and 13C-NMR.
Note 1: The sample used consists of the material prepared above and an older cream colored diacid sample (223-224 °C decomp.; 224 °C lit.), prepared
by the hydrolysis of the unrecrystallized diester (see cubane PET synthesis).
Note 2: Due to the aggressive nature of the vapor it is advisable to use an aspirator pump for this purpose. A good membrane pump is also suited.
Note 3: As the ethanol commonly added as a stabilizer would react with the acid chloride, the chloroform was washed three times using water, once
using saturated brine, and dried over 3Å molecular sieves beforehand.
Note 4: As cubane, being an alkane, is significantly less polar than any potential impurities, only one large fraction was collected until evaporation
of a couple drops running of the column didn’t leave behind any further solid.
 
Fig.2-3: The diacylchloride synthesis and the collected material
Fig.4: The Barton decarboxylation
 
Fig.5-6: The collected endproduct (4x magnification)
Fig.7: 1H-NMR of the cubane in chloroform-D (chloroform-D and water cut out), the peaks in the range of 0-1,5 ppm are from joint grease
Fig.8: 13C-NMR of the cubane in chloroform-D (chloroform-D cut out)
Sources:
[1] Houston, S. D. et al. (2019). Enantioselective synthesis of (R)-2-cubylglycine including unprecedented rhodium mediated C-H insertion of cubane.
Org. Biomol. Chem., 2019 (17), 1067-1070
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Niklas
Hazard to Others
Posts: 155
Registered: 1-12-2023
Location: Germany
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Mood: Polymerized
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Synthesis of Iodocubane
Iodocubane is an extremely useful precursor in the preparation of mono substituted cubane derivatives as it can be used to undergo Barbier type
reactions by converting to the corresponding butyl zincate reagent [1]. In particular I‘ll soon be using it in the preparation of the cubane
biosteres of amphetamine and deschloroketamine (just have to wait for the butyllithium to arrive).
It is made in four steps from the monomethylester of cubane-1,4-dicarboxylic acid, the synthesis of which I‘ve detailed in my post regarding
4-chlorocubane carboxylic acid, by once again first converting it to the corresponding acyl chloride, decarboxylating using a Barton decarboxylation,
hydrolizing the methyl ester [2], and then finally performing a Kochi decarboxylation of the intermediary cubanemonocarboxylic acid [3], which itself
is an equally useful precursor for the preparation of cubane derivatives.
Fig.1: Synthesis of iodocubane
Methyl cubanemonocarboxlyate:
In a 500 two-neck schlenk flask (1x NS29, 1x NS14) containing an 5 cm triangular stirbar 3 g of the monoester (14,5 mmol) were suspended in 160 ml of
DCM (dried of 3Å molecular sieves). Under a blanket of argon 1,5 ml of oxalylchloride (17,7 mmol) were added, a septum was attached, and about 0,1 ml
of DMF (1,3 mmol) were added using a syringe, instantly resulting in a gas generation and the slow dissolution of the solids. Stirring was continued
at room temperature (20-25 °C) for 1 h, a majority of DCM removed by distillation from a 50 °C water bath, and the beige residue of crude acyl
chloride dried under vacuum.
Meanwhile in a 500 ml three-neck round bottom flask (2x NS29, 1x NS14) containing a 5 cm triangular stirbar, equipped with a Dimroth condenser, a gas
adapter and a 250 ml addition funnel, 3,31 g of 2-mercaptopyridine-N-oxide sodium salt (22,2 mmol) and 20 mg of DMAP were suspended in 120 ml of dry
chloroform (Note 1)(Note 2), the apparatus flushed with argon, and the addition funnel charged with a solution of the above prepared acid chloride in
140 ml of dry chloroform (Note 1)(Note 2). Things were brought to a reflux in a heating mantle, the yellow solution slowly added over the course of 1
h while irradiating with 500 W lamp, and reflux and irradiation continued for 5 more h. The resulting brownish mixture was washed twice with 12,5%
hydrochloric acid (1x 100 ml, 1x 50 ml), once with 50 ml of a saturated sodium carbonate solution, once with 50 ml water and once with 50 ml of
saturated brine, dried over anhydrous magnesium sulfate, and the solvent removed by rotary evaporation. The dark brown oily residue was distilled in a
kugelrohr (2 mbar, 120-140 °C), resulting in 3,3 g of a (139% yield) (Note 3) of a partly liquid partly crystalline colorless substance which was
used as such without further purification.
Note 1: As the ethanol commonly added as a stabilizer would react with the acid chloride, the chloroform was washed three times using water, once
using saturated brine, and dried over 3Å molecular sieves beforehand.
Note 2: Following the literature 155 ml of chloroform each should be used, I however ran out and only had 260 ml left.
Note 3: It‘s unclear which impurity is seemingly increasing the yield, it is however mostly removed in the following ester hydrolysis (also see
cubanemonocarboxylic acid note 1 and note 3).
 
Fig.2-3: Synthesis of the acyl chloride
 
Fig.4-5: The Barton decarboxylation and the collected methyl ester
Cubanemonocarboxylic acid:
The material from the previous step is transferred to a 100 ml round bottom flask (NS29) containing a boiling stone and suspended in a solution of 2 g
sodium hydroxide (50 mmol) in about 30 ml of water. A Dimroth-condenser was attached and things heated to a reflux for 2 h (Note 1), causing things to
take on an orange color and some insoluble tar to separate (Note 2). This mixture was washed three times using 20 ml DCM each, remaining insoluble
junk removed by filtration through some glass wool, and the resulting yellow solution acidified using 10 ml of fuming hydrochloric acid. It was
extracted three times using 20 ml of DCM each, the resulting yellow extracts dried over anhydrous sodium sulfate, and the solvent removed by rotary
evaporation. The residual yellow solid was dissolved in about 60 ml of boiling heptane, things decanted from the small quantity of undissolved junk
and evaporated down to a volume of 10 ml. After cooling in the freezer the precipitate was collected by gravity filtration, rinsed with a little
heptane and dried under vacuum, resulting in 1,68 g (77,7% yield; 79,2% lit. (over three steps)) of light yellow crystals melting at 122-125 °C
(124-125 °C lit.) and appearing of acceptable purity on analysis with 1H- and 13C-NMR (Note 3)(Note 4).
Note 1: A longer reflux time of 4 h or longer might be advisable to result in a purer end product (see note 3 for an explanation).
Note 2: The tar formation likely stems from a base induced decomposition of the uncharacterized impurity, not from the cubane carboxylic acid itself.
Note 3: On both spectra an aromatic impurity is clearly visible, the exact structure, besides an unsymmetrical ortho substitution based on the peak
splitting, however remains unclear. As it could be removed in the following step by washing with hydrochloric acid, one can logically assume this to
be the 2-(trichloromethylthio)pyridine formed as a side product during the Barton decarboxylation, the hydrochloride salt of which might have some
solubility in DCM and chloroform, also explaining the inflated yield of the prior step. As such an impurity wasn’t noted during the
4-chlorocarboxylic acid synthesis, even though the procedure was largely the same, it was likely all decomposed from the 4 h reflux during the ester
hydrolysis, while with the shorter reflux of 2 h traces appear to remain.
Note 4: In the literature procedure the intermediary methyl ester is purified by column chromatography, however the resulting carboxylic acid is still
described as yellow, though an impurity isn’t specified.
Fig.6: Cubane monocarboxylic acid
 
Fig.7-9: 1H-NMR of the monocarboxylic acid in DMSO-d6 (water and DMSO-d6 cut out)
Fig.10: 13C-NMR of the monocarboxylic acid in DMSO-d6 (DMSO-d6 cut out)
Iodocubane:
In a 500 ml three-neck round bottom flaks (2x NS29, 1x NS14) containing a 3,5 cm egg shaped stirbar, equipped with a mantled Dimroth-condenser and a
gas adapter, 1,43 g of cubanemonocarboxylic (9,7 mmol) were dissolved in 190 ml of benzene (dried over 3Å molecular sieves) and the resulting yellow
solution sparged with argon for 30 min. 5,32 g of lead(IV)-acetate (12 mmol) (Note 1) and 5,79 g of iodine (22,8 mmol) were added, the apparatus
flushed with argon, and things refluxed in a heating mantle while irradiating with a 500 W lamp for 3 h. The orangey-yellow precipitate of lead iodide
was removed by filtration through a piece of glass wool, the “permanganate-violet“ solution washed three times using 100 ml of a diluted sodium
sulfite solution each, dried over anhydrous sodium sulfate, and the solvent of the resulting light yellow solution removed by rotary evaporation. The
dark yellow residue was subjected to kugelrohr distillation (10-15 mbar, 140 °C), resulting in 2 g (90% yield) (Note 2) of a light yellow oil,
solidifying to colorless needles slightly below room temperature (Note 3). 2,2 g of this material were dissolved in 15 ml of n-pentane, washed two
times using 25 ml of diluted hydrochloric acid each and once with 25 ml of water, dried over anhydrous sodium sulfate, and the solvent removed by
rotary evaporation. From this 2,1 g (95,4% recov.; 85,9% in total for the run described) of a white to slightly off-white crystalline solid were
collected, melting at 30-32 °C (31-33 °C lit.) and appearing of good purity on analysis with 1H- and 13C-NMR.
Note 1: I have previously described the preparation of the lead(IV)-acetate used in a different thread [4].
Note 2: In a smaller testrun on a scale of 1,5 mmol a crude yield of 86,4% was achieved, likely due to increased mechanical losses from the
distillation.
Note 3: It’s evident from 1H- and 13C-NMR analysis that this “crude product“ still contains the aromatic impurity of the
prior step. In addition to that some undesired peaks are visible in the alkyl region (also for the washed product), mostly from joint grease.
 
Fig.11-13: The Kochi decarboxylation
Fig.14: The distilled iodocubane
 
Fig.15-17: 1H-NMR of the distilled iodocubane in Chloroform-D (water and chloroform-D cut out), the peaks in the range on 0-1,5 ppm are
from joint grease
Fig.18: 13C-NMR of the distilled product in Chloroform-D (chloroform D cut out)
Fig.19: The washed iodocubane
 
Fig.20-21: 1H-NMR of the washed iodocubane in Chloroform-D (water and chloroform-D cut out), the peaks in the range on 0-1,5 ppm are from
joint grease
Fig.22: 13C-NMR of the washed product in Chloroform-D (chloroform D cut out)
Sources:
[1] Kato, Y. et al. (2019). A Protocol for an Iodine–Metal Exchange Reaction on Cubane Using Lithium Organozincates. Org. Lett., 21/2, 473-475
[2] Benjamin, A. et al. (2016). Validating Eaton’s Hypothesis: Cubane as a Benzene Bioisostere. Angew. Chem., Int. Ed., 55/11, 3580-3585
[3] Della, E. W. Head, N. J. (1995). Synthesis and 19F and 13C NMR Studies of a Series of 4-Substituted Fluorocubanes: Resonace Dependence of 19F
Chemical Shifts in a Saturated System. J. Org. Chem., 60/16, 5303-5313
[4] https://www.sciencemadness.org/whisper/viewthread.php?tid=16... ; last accessed: 06.12.2025
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