Sorry for the nomenclature error, this should be HEXAhydrobenzodipyran
[Edited on 17-2-2010 by Ozonelabs]Jor - 17-2-2010 at 10:02
Amazing synthesis. how did you transfer the n-butyllithium?
I know that t-butyllithium catches fire in air spontaneously. Is this not the case with n-butyllithium?
What uses does the compound you made compound have?Magpie - 17-2-2010 at 10:20
Very nice. Your safe and successful use of BuLi demonstrates a high level of sophistication in organic synthesis.
How does the BuLi accomplish ring closure, ie, what is the mechanism? DJF90 - 17-2-2010 at 10:34
Mechanism is Br-Li exchange, followed by arylation of the primary chloride.
EDIT: I have an issue with the last sentence; "The oil
was recrystallised from 40ml Et2O.", as you cannot RE-crystallise an oil.
[Edited on 17-2-2010 by DJF90]
[Edited on 17-2-2010 by DJF90]Ozonelabs - 17-2-2010 at 10:44
Hi Jor,
Thankyou for the comments.
It is probably worthy of mention that all glass was flame dried and Nitrogen flushed. The n-BuLi was actually poured from the bottle, this was done
under a Nitrogen flush mind. The only reason that we didn't take further precautions (ie. cannula) is that the nature of the 2.5M solution is such
that it doesn't ignite in air. We did double (and triple) check this fact with several specialist chemists who have used BuLi in all of its wonderful
forms and concentrations!
The compound is essentially a chemical curiosity, no record of this exact compound is available in literature (to our knowledge, anyway).
Magpie,
Again, thankyou for your comments.
Regarding the mechanism, DJF90 has it right.
Yes yes, the last sentence is incorrect. It should read 'the oil was CRYSTALLISED' not re-crystallised. Sorry about that! woelen - 17-2-2010 at 10:59
I am just amazed at seeing you do all these things in an amateur setting and I want to express my respect for this. Keep up the good work!!
I have browsed the tour of your lab and it looks really great. Especially the gas bottles and lecture bottles are really fun to have in your lab. UnintentionalChaos - 17-2-2010 at 11:25
Not a new compound, but not a ton of references. See the following:
"Intramolecular double or triple Suzuki coupling reaction of substituted di- or tribromobenzenes. An easy synthesis of fused tri- or tetracycles with
a benzene core" Ma, Shengming et al, Journal of Organometallic Chemistry, 690(23), 5389-5395; 2005
"Studies of Claisen rearrangement of bispropargyl ethers. Synthesis of naphthodipyrans, naphthodifurans and naphthofuropyrans" Venugopalan,
Bindumadhavan and Balasubramanian, Kalpattu Kuppuswamy, Heterocycles, 23(1), 81-92; 1985
"Substituted hexahydrobenzodipyrans as 5-HT2A/2C receptor probes" Whiteside, Michael S.; Kurrasch-Orbaugh, Deborah; Marona-Lewicka, Danuta; Nichols,
David E.; Monte, Aaron, Bioorganic & Medicinal Chemistry (2002), 10(10), 3301-3306
"Studies on pyrones and pyridones. 60. Tetrahydrobenzodipyrandiones and tetrahydrobenzodipyrans" Eiden, Fritz; Schmiz, Claus, Archiv der Pharmazie
(Weinheim, Germany) (1976), 309(7), 529-37
"Claisen rearrangements. Claisen rearrangement of bispropargyl ethers" Balasubramanian, K. K.; Venugopalan, B., Tetrahedron Letters (1973), (29),
2707-10
I can't get to all of them, but that third one uses exactly the same reaction you have, except with bromines replacing the chlorines. The last two may
or may not have the same compound in the text, but they turned up with a search.
[Edited on 2-17-10 by UnintentionalChaos]Ozonelabs - 17-2-2010 at 11:34
Many thanks Unintentional Chaos- Admittedly we hadn't done a huge amount of searching, but it is interesting to note that it has been made previously.
You also raise an interesting point, I believe we have a nomenclature issue- this should be HEXAhydrobenzodipyran, not TETRAhydrobenzodipyran.
[Edited on 17-2-2010 by Ozonelabs]Bolt - 17-2-2010 at 14:21
close, it should be hexahydrobenzodiPYRANOzonelabs - 17-2-2010 at 14:30
I really must not have my head screwed on right today, I even called it pyran in the PDF and all the posts previous to that one. I'll go correct it.
Thanks Bolt! scribbler - 8-3-2010 at 12:34
An NMR would be awesome as soon as you get around to it!...Ozonelabs - 1-5-2010 at 03:18
Since you're actually holding the NMR instead of looking at a somewhat fuzzy photo, how are each of those peaks split? dean stark - 8-4-2011 at 06:25
Can anyone comment on the likelyhood of using magnesium exchange via isopropylmagnesium halide instead of lithium to complete this reaction?Nicodem - 9-4-2011 at 00:17
Magnesium-halogen methathesis in practice works well mostly on aryl iodides. There are cases where it works on aryl bromides, but I doubt it would
work in this particular case. You can always try and let us know. If I remember correctly, and I probably don't, there is at least one example where a
homologous cyclization (to the benzobisfuran) is done by the reaction with magnesium metal, but the yields were much lower than using n-BuLi (but
check the literature as I might have confused something). I assume the mechanism involves an intramolecular Mg-Br exchange, as the magnesium would be
expected to insert faster in the alkyl-Br bond forming alkyl-Mg, compared to the insertion into aryl-Br bond forming the required aryl-Mg (only the
aryl-Mg form can cyclize). In such case you would at least have an intramolecular precedence to the Mg-Br methathesis (which still is no proof that
the intermolecular reaction is viable).smuv - 9-4-2011 at 08:49
But with metallic magnesium the mechanism could be different, it could be a Wurtz coupling.dean stark - 11-4-2011 at 02:19
I think I found the paper you were talking about Nicodem - "The Synthesis of 5-Substituted 2,3-Dihydrobenzofurans" (see attached).
It's similar to this procedure with Br on the ring and Cl on the alkyl ether.
They exchange the ring Br using Mg metal (not iPrMgBr!), which apparently happens quicker than the alkyl Cl. Yields are between 60-80%.
They state that the method was devised as an alternative to Li based Parham cyclization, in order to avoid some of the by-products of alkyl
lithiation.
It looks promising. iPrMgBr would probably work as well. I wonder if other metals could be used...
why butyl lithium? i know you got balls the size of mars but would'nt sonication in lithium work just as well without having to handle one of the most
pyrophoric compounds known to man?Methyl.Magic - 12-3-2014 at 12:49
Hi,
I have some problem doing your procedure.
I've done the etherification with 1-bromo-3-chloropropane in methanol and got a pure perfect white powder. Very good method, mush better than
refluxing in acetone with K2CO3.
But when I tried to brominate I got some incertitude because there is a lack of infomration concerning your procedure. I used 0.05 eq of AlCl3 instead
of iron powder and I used Small excess of Br2 (2.1 eq) in chloroform but I let stirred for 24h to ensure complete reaction.
When the reaction is over I was surpised of the necessairy amount of thiosulfate needed to neutralise the bromine excess. When I checked the compound
with TLC (hexane:toluene 7:3) I got no starting material (RF = 0.3), a big spot (RF = 0.45) and a small/tiny spot (RF = 0.85). At first I thought the
tiny spot can be the tribromo product but I am afraid if its only the dibromo and the big spot the monobromo...
Could you please give me the Rf and the solvent system for each product ? And also the melting points.
EtOH seems to dissolve much easily dibromo>monobromo>non-bromo in that order, meaning that its quite tricky to remove the eventual monobromo
unless using the precristallisation method to separate the monobromo and finally cooling down to get the product.
I dont want to pay an NMR, so I really need to know the mp to be sure before doing the next step.
Did you checked the reaction with TLC during the process ? because it seems really fast. I used AlCl3 as the catalyst which is stonger than FeBr3 so I
think the reaction must be completed before yours, so I don't know why I still have a lot of bromine even after 24 h ...
Concerning the future,
Have you tried to formylate it ? There is a really good method is deprotoning the Ar-H with BuLi/TMEDA with the help of the ether helping deprotonate
the ortho position (anyway you have only hydrogen in the ortho position in this case...) and quenching the organolithium with DMF to get the aldehyde
in high yield. I think the reaction is done at 0°C but maybe lower temperature are necessairy here to not destroy the THP ring by removing the more
acid benzilic proton.smaerd - 23-3-2014 at 14:13
NMR looks good, great work as always ozone labs. Don't know about the phenol OH being that far up field. Interesting how tall your aromatic peak is in
comparison to the 'pyran' protons, then again it is pretty skinny. Wondering if those are peaks(~1.3,~1.5,~2.0ppm) from the intermolecular
etherification. Neat. Does your soft-ware toss out TMS peaks?
