Author Topic: Benzodioxin MDA analogue?  (Read 8871 times)

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Benzodioxin MDA analogue?
« on: April 06, 2004, 10:01:00 AM »
I understand how easy it is for any chemical novice to sit on chemdraw and draw up *new* exciting possible drugs but just thought I would throw this chemical into discussion. 

2,3-Dihydro-1,4-benzodioxin-6-aminopropane (?think thats correct)

The benzaldehyde appears to be available...

CAS = 29668-44-8

Pubmed showed that the aminoethanol analogue might have beta-blocking ability but thats all I could find...

2-Benzodioxinylaminoethanols: a new class of beta-adrenergic blocking and antihypertensive agents.

Lalloz L, Loppinet V, Coudert G, Guillaumet G, Loubinoux B, Labrid C, Beaughard M, Dureng G, Lamar JC.

Various 2-benzodioxinylaminoethanol derivatives were synthetized and investigated for beta-adrenergic blocking activity. Most compounds demonstrated a beta-blocking activity of a competitive type when evaluated in guinea pig atrial and tracheal preparations. Three compounds were more potent than practolol and propranolol. All compounds demonstrated antihypertensive properties in spontaneously hypertensive rats. The most active compound was 1-(1,4-benzodioxin-2-yl)-2-[N4-(2-methoxyphenyl)piperazino]ethanol (11), which at 2.5 mg/kg iv lowered blood pressure by 41%.

PMID: 6120237 [PubMed - indexed for MEDLINE]

Anyway, just wondered if anyone had any thoughts?

- OL


  • Guest
Possible, but not very likely
« Reply #1 on: April 06, 2004, 10:29:00 AM »


Pihkal #110


This substance is rather similar, but has been shown to be relatively ineffective. I do not think that the MDA analog you drew up would show any MDMA-like action either, as anything more bulky added to the methylenedioxy ring has been shown to be rather ineffective. This is what Shulgin has to say on a similar topic:


  • Guest
Looks like those compound releases formaldeyde
« Reply #2 on: April 06, 2004, 12:01:00 PM »
Looks like those compound releases formaldeyde on contact with acidic medium... Doesn't sound very healthy  :)


  • Guest
A more interesting possibility?
« Reply #3 on: April 07, 2004, 01:37:00 PM »
The MDA/IAP 'hybrid' 5-(2-aminopropyl)-2,3-dihydrobenzofuran pictured below has been made by the Nichols research group but has recieved little attention here (save for

Post 476448

(Rhodium: "5-(2-aminopropyl)-benzofuran", Novel Discourse)
and a couple of other posts), although it has been touted as a 'non-neurotoxic MDMA analogue' (according to psychokitty in

Post 108607 (missing)

(dormouse: "Better than honey?  -Bella*****", Novel Discourse)
). Here it is:


Non-neurotoxic MDMA analogue ("NC(C)Cc2ccc1OCCc1c2")

The benzaldehyde is not commercially available and the 2,3-dihydrobenzofuran precursor (which can then be formylated to the benzaldehyde) is expensive. But consider the following scheme:


Dibromination of phenol ("c1ccccc1O>>c1cc(Br)cc(Br)c1O")

This appears to give the majority of the desired isomer best upon treatment of phenol with molecular bromine. The dibrominated phenol can then be alkylated with 1,2-dibromoethane and a base:


Etherification ("c1cc(Br)cc(Br)c1O.BrCCBr>>c1cc(Br)cc(Br)c1OCCBr")

The next step is my favourite: A one-pot intramolecular (Parham) cyclisation followed by formylation upon treatment with DMF. The compound is first treated with 2-3 equivalents of ethylmagnesiumbromide. Because the aromatic ring gives a more stable Grignard than the ethylmagnesiumbromide, the Mg cation migrates, and the resulting aryl Grignard displaces the bromide on the end of its connected ethyl chain. The Mg cation from the other equivalent of Grignard then inserts between the C-Br bond para to the oxygen, which after treatment with DMF and hydrolysis gives the benzaldehyde. I've drawn it as two steps so it can be seen properly:


Benzaldehyde formation part I ("c1cc(Br)cc(Br)c1OCCBr.[Mg++]Br.>>Br[Mg++]c2ccc1OCCc1c2")


Benzaldehyde formation part II ("Br[Mg++]c2ccc1OCCc1c2.C(=O)N(C)(C)>>C(=O)c2ccc1OCCc1c2")

References for the dibromination:

Benzyltrimethylammonium tribromide in DCM/methanol, 87% yield: Bull.Chem.Soc.Jpn.; 60; 11; 1987; 4187-4189.

Bromine in CCl4: J.Prakt.Chem.; 332; 6; 1990; 1093-1098.

Bromine in GAA: J.Chem.Soc.; 85; 1904; 1228.

For the etherification:

Dibromophenol, dibromoethane, NaOH (aq.), 59% after 22h heating: J.Org.Chem.; 46; 7; 1981; 1384-1388.

For the benzaldehyde formation:

Tetrahedron Letters 41 (2000) 2269–2273

J.Org.Chem. 1981, 46, 1384-1388

Once you get the benzaldehyde it should be plain sailing with the usual Knoevenagel and reduction to the amine. It's likely that the yield of the etherification can be increased by using a more modern PTC method (and a large excess of dibromoethane: see

Post 196477 (missing)

(hest: "Re: New Amph.  more potent than LSD", Serious Chemistry)

When I get my hands on the remaining reagents required I'll give the above proposal a go. I've already tried the cyclisation/formylation but my vacuum isn't working and the impure benzaldehyde has been waiting for weeks already. Plus I'm pretty certain there will be some 4-ethoxybenzadehyde which will be difficult to separate. I'll probably distill to get an idea of the yield and then discard whatever I get back. I don't fancy ending up with a lot of 4-ethoxyamphetamine by accident.


Looks like those compound releases formaldeyde on contact with acidic medium... Doesn't sound very healthy  :)

Won't the same apply to MDMA? The 'acetal' between the oxygens is the same in both cases. I was wondering about this as a possible explanation for the far greater instability of the dioxole ring to Lewis/protic acids in comparison to the plain aryl ethers. Anisole, for example, is stable to standard Friedel-Crafts conditions whereas benzodioxole is entirely demethylated (AlCl3/acid chloride/DCM at 0oC).


  • Guest
« Reply #4 on: April 07, 2004, 04:53:00 PM »
Kinetic: Do you have those refs handy, so that you could post a suggested experimental?


  • Guest
Unsure why it's active
« Reply #5 on: April 07, 2004, 09:20:00 PM »
Hi Kinetic,

I’m a little puzzled as to the activity of the dihydrobenzofuran deriv that you mentioned in your post above. The reason being that in a previous paper (1), Nichols, investigated the activity of MMAI (5-methoxy-6-methyl-2-aminoindane) and MMA (3-methoxy-4-methylamphetamine) and found that they both substituted for MDMA in rats trained to discriminate MDMA activity. MMA has the methyl group in the para position and the methoxy group in the meta position with respect to the isopropylamine side chain (as MMAI has the isopropyl side chain formed into a symmetrical 5 membered ring, you cant really refer to para and meta orientation of the ring substituents), which makes sense, as it is effectively DOM with one of the methoxy groups removed. What puzzles me is that with the dihydrobenzofuran deriv you mention, the oxygen atom is in the para position (equates to para methoxy) to the sidechain, and the direct attachment of the carbon atom is in the meta position (equates to meta methyl), which has the orientation of the ring substituents the other way around; after checking, I cannot find any reports of 4-methoxy-3-methylamphetamine being active at all, nevermind substituting for MDMA in trained rats. As such, I would have thought that the benzofuran with the structure given below would be the compound with activity similar to MMA (and hence MDMA)

ref (1): Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA)
Johnson MP, Frescas SP, Oberlender R, Nichols DE
J Med Chem, 1991; 34(5):1662-8


  • Guest
An interesting possiblilty
« Reply #6 on: April 08, 2004, 08:54:00 AM »
Hi Fastandbulbous: :)

The Nichols research group made both isomers of the dihydrobenzofuran analogue. The one I depicted is compound 5 in

Synthesis and Pharmacological Examination of Benzofuran, Indan, and Tetralin Analogues of 3,4-( Methyenedioxy)amphetamine

(, and your analogue is compound 4. I chose the former as it's much easier to make. Here is the quote from the paper on the pharmacology:

The results of the drug-discrimination studies are shown in Table I and II. Benzofurans 4 and 5 fully substituted in (S)-lc-trained and 3-trained rata with ED508 not significantly higher than those of the training drugs and potencies comparable to one another. Both 4 and 5 were potent in producing disruption in (S)-amphetamine-trained and LSD-trained rata, and neither compound substituted in (S)-amphetamine-trained or LSD-trained rata which were not disrupted (data not shown). These results indicate that, behaviorally, 4 and 5 resemble (S)-1c and 3, and have neither amphetamine-like nor LSD-like properties. Furthermore, these data indicate that the position of the oxygen atom in relation to the alkylamine side chain is not particularly significant in producing lc- or 3-like behavioral responses. Thus, both 4 and 5 might be expected to exhibit human psychopharmacology similar to one another, to 1c and 3, and, possibly, to the related entactogens la and lb [Kinetic's voice: 1a and 1b are MDA and MDMA, respectively]. This prediction is based on our previous observations that both la and lb fully substitute for the training drug lc.8,27 Since 4 and 5 also substitute for 1c, it seems highly likely that these compounds must produce a behavioral cue similar to that produced by la and lb.


I made the 2-(2',4'-dibromophenoxyethyl)bromide by dibromination of 2-phenoxyethylbromide with 2 eq. bromine in GAA. I didn't use a Lewis acid catalyst (as Nichols does in the similar procedure:

Post 364601 (missing)

(Barium: "Another way of inserting the aminopropyl", Serious Chemistry)) so I'm worried that there may have been some ring-monobrominated contaminant. The yield after recrystalisation from 1:1 methanol:acetonitrile (an excellent combination) was around 70%. I want to try the ring bromination on the more activated phenol before I take the procedure any further, to ensure the maximum amount of dibrominated ring product.

The ring-bromination of a phenol with molecular bromine is a pretty standard procedure but I can go to the library and type up the experimental from the Bull Chem Soc Japan article as well as the old J Chem Soc article (though I may have to order this one).

Here is the smaller of the two cyclisation articles (the other file hasn't taken kindly to the new upload feature). BuLi isn't necessary; Nichols manages a similar cyclisation with the Grignard:

A practical approach to highly functionalized benzodihydrofurans
Michael Plotkin, Sanyou Chen and P. Grant Spoors
Tetrahedron Letters 41 (2000) 2269–2273


A number of aromatic dibromides have been treated with 2–3 equivalents of n-butyllithium in order to initiate two sequential chemical events, a Parham cyclization and an intermolecular reaction with DMF.

And the abstract and selected experimental from the second article:

Oxygen Heterocycles by the Parham Cyclialkylation
Charles K. Bradsher and David C. Reames
J.Org.Chem. 1981, 46, 1384-1388


The addition of butyllithium at -100oC to w-bromoalkyl ethers of o-bromophenol (and its congeners) led to preferential exchange of the aryl bromine at position 2. The resulting organolithium reagents, under suitable conditions, cyclized to afford 2,3-dihydrobenzofurans (6), 3,4-dihydro-2H-l-benzopyrans (13), or 2,3,4,5-tetra-hydro-1-benzoxepins (16) in good yields, but less satisfactory reaults were obtained with the intermediate expected to produce 8-methyl-3,4,5,6-tetrahydro-2H-benzoxocin (19). w-Bromoethy1 and w-bromopropyl ethers of suitable dibromophenols were treated successively with 2 equiv. of butyllithium and an electrophile to yield derivatives of 6 and 13.


Phenoxyethyl Bromides (4).

These were prepared in yields of 47-61% by refluxing and stirring for 6-22h a mixture containing 0.120 mol of the phenol, 30.1 g (0.160 mol) of the ethylene bromide, 5.20 g of sodum hydroxide, and 90mL of water, esentially as described by Marvel and Tannenbaum6

(b) 5-Methyl-2,3-dihydro-2-benzofurancarboxyaldehyde (8).

Two successive equivalents of butyllithium were added to 4f at -100oC as described in the preceding experiment. Thirty minutes after the addition of the second equivalent of butyllithium, a solution of 1.61 g (22mmol) of dimethylformamide was added over 3 min. The solution was held at -100oC for 30 min and was then allowed to warm slowly to room temperature. Stirring of the suspension at room temperature was continued for 1 h. The reaction mixture was poured into 5% hydrochloric acid, the phases were separated, and the aqueous phase was extracted with ether (3x150mL). The organic materials were dried, concentrated, and distilled under reduced pressure. The yield of aldehyde 8 was 1.80 g (81%): bp 72-75.5oC (0.08 torr)

(c) 2,3-Dihydro-5-benzofurancarboxylic Acid (10).

(2,4-Dibromophenoxy)ethyl bromide (4e; 8.97g, 25mmol) was dissolved in dry THF (165 mL) and hexane (40 mL). The solution was placed in a 500-mL flask equipped for low-temperature lithiation and was cooled to -100oC. Butyllithium (27mmol) was added at such a rate that the temperature did not rise above -95oC. The solution was stirred at -100oC for 30min, and then 27 mmol of butyllithium was added at -100oC. A sample was taken after 30 min and processed, and examination by 1H NMR showed exchange to be complete. One hour (at -100oC) after the second addition of butyllithium, the mixture was poured into a slurry of solid CO2 in ether (150 mL). After the mixture had come to room temperature, the layers were separated. The organic phase was extracted with saturated sodium bicarbonate solution (3 X 150 mL). The combined bicarbonate solutions were washed once with ether and then acidified with hydrochloric acid. The resulting precipitate was recrystallized from ethanol, giving 2.50g (61%) of 7 as shiny colorless plates: mp 184-188oC; mp (pure).

6: Marvel, C. S.; Tannenbaum, A. L. Organic Syntheses; 1941; Vol. I, p 435.


  • Guest
Cmpd 4 is a much better bet than cmpd 5
« Reply #7 on: April 12, 2004, 06:30:00 PM »
Hi Kinetic

On your last post on this subject, you quoted a part of Nichols paper that said that both benzofuran compounds (4 and 5) substituted for compounds 1c and 3 in drug discrimination trials using trained rats. By extension, the paper went on to say that as compounds 1a and 1b also substituted for 1c and 3. From this, it went on to say that both 4 and 5 might be expected to exhibit human pharmacology similar to 1c and 3, and possibly, to the related entactogens 1a and 1b.
Indeed, 1a, 1b, 4 and 5 do substitute for 1c and 3, and this is due to the fact that all the aforementioned compounds are potent inhibitors of 5-HT uptake, but later on in the paper, it is stated that 1a and 1b are also inhibitors of dopamine and noradrenaline (norepinephrine) uptake

It is our hypothesis that 6, which possesses a significant catecholaminergic component, behaviorally lies closer to the la end of a spectrum However, 6 caused disruption in a large percentage of 3-trained rats, indicating that the behavioral effects of 1c and 3 may actually be slightly different. The explanation for this discrepancy may lie in the fact that 3 is highly selective for affecting serotonin uptake/release, and its behavioral cue probably reflects a more "purely serotoneric" response. In moving from 3 to Ic to la, an increased ability to affect catecholamine uptake/release is observed, and behavioral responses may reflect this change in the ratio of catecholamine to 5-HT effect.of behavioral effects than it does to the pure serotonin releasing, or 3, end. Thus, the compounds in this series can be ranked in order their ratio of catecholamine/5-HT effect such that la > 6 > lc > 3. These ratios of effects may significantly alter the behavioral pharmacology, since we have recently shown that 5-HT-releasing agents can markedly potentiate the effects of an indirectly acting dopaminergic drug.

Later in the same paper, it goes on to say that the compounds ability to inhibit the uptake of dopamine and noradrenaline plays a significant role in the psychopharmacology of said compounds, their being a spectrum of activity dependant upon the ratio of 5HT to catchecolamine uptake inhibition, compounds 1a and 1b also being potent inhibitors of catchecolamine uptake.

it is clear that all the compounds of this class have in common their ability to simultaneously release both 5-HT and the catecholamines DA and NE, albeit to varying degrees. Certain nuances of behavioral effect, however, seem to arise from shifts in the potency ratio in affecting catecholamine and 5-HT release. Thus, agents which have a lower potency in catecholamine systems, such as 5, behaviorally resemble agents like 3, while compounds with greater effects on catecholamine systems would be expected to elicit behavioral responses more similar to those produced by la.

From the data given in table III of that paper (see below), the relative values of 5HT to dopamine/noradrenaline inhibition can be calculated.

As can be seen from section c of the table (part a is present in paper, parts b and c are my calculations taken from data given in part a), the higher the relative inhibition of catchecolamines to 5HT, the closer the profile is to that of 1a (MDA) and the less like it is to the purely serotonergic 3 (MMAI). This places the order of how like 1a (and thereby unlike 3) the compounds are:-

                     1a > 4 > 6 > 5 > 3

As compound 6 is IAP, which has some similarity to MDA, but does not produce the extreme euphoria and feeling of closeness that MDA/MDMA does (from personal experience with IAP), it can be seen that whereas compound 4 is more like MDA than IAP, compound 5 is less like MDA than IAP, of the two, compound 4 is the most likely to have an overall activity like that MDA.

One other option is open to try to produce an activity profile like that of MDA/MDMA, and that is to use an indirectly acting catocholinergic compound (eg. amphetamine) with one of the above, in order to produce a 5HT to dopamine/noradrenaline uptake inhibition ratio more like that of MDA. As no data is given regarding the ability of any of the above to inhibit the enzyme monoamine oxidase (MAO), such an undertaking would have to proceed with great caution.

I have tried very small doses of amphetamine (aprox 2mg) taken in conjunction with 25mg of IAP, which did not result in any changes in pulse rate/ blood pressure that were different to 25mg of IAP taken on its own. I will eventually try a dose of aprox 20mg of amphetamine with 25mg of IAP, but as the neurotoxicity also seems to increase as the levels of dopamine increase, it may be some time before I can give a description of the action of said combination (it seems the neurotoxicity goes hand in hand with the ability to produce an MDA/MDMA type experience)

Structure of compounds 1a, 4, 5 and 6 (discussed above)

If Nichols (or anyone else) has taken that research any further, and someone has the appropriate references, I would be grateful for any more info.


  • Guest
A success, a failure, and an alternative proposal
« Reply #8 on: May 28, 2004, 09:05:00 AM »
I decided to try the first two steps of the proposal I made above. Even if the compound turns out to be inactive, the chemstry is still very interesting, and some of it could be applied to the bis-benzodifuranyl analogue made by Nichols.

The first step was the dibromination of 2-phenoxyethyl bromide, which went very nicely:


200mmol 2-phenoxyethyl bromide
420mmol bromine
440mmol zinc chloride
Acetic acid

A solution of 40.2g 2-phenoxyethyl bromide and 60g zinc chloride in 100ml acetic acid was cooled to 10oC. Over 1.5 hours a solution of 21.6ml bromine in 25ml acetic acid was added, keeping the temperature at 10-15oC throughout. Stirring was continued without further cooling for 3 hours, then all was added to 500ml water. The precipitated solid was taken up in 100ml DCM followed by 2x50ml DCM. The combined extracts were washed with 250ml water, 2x100ml 1M potassium carbonate solution1, 100ml brine and dried over MgSO4. Removal of the solvent gave a brown solid weighing 70.7g (197mmol, crude yield 98%) which, after recrystallisation from 80ml 1:1 methanol:acetonitrile2, filtering and drying under vacuum, gave the title product a sparkling, light coloured solid.

Yield: 67.6g (188mmol, 94%)

1 The potassium carbonate washes should be omitted as they caused significant darkening of the organic layer.
2 100ml pure methanol should be an even better recrystallisation solvent.

The second step (one-pot cyclisation and formylation) gave a product which seems to be 5-ethyl-2,3-dihydrobenzofuran, judging by it's boiling point and apparent inability to react with semicarbazide. At higher temperatures it appears the aryl Grignard reacts more rapidly with the formed ethyl bromide than I had hoped, in a reaction reminiscent of Wurtz coupling.

To overcome the problem, a lower temperature could be used (the temperature reached 45oC during addition of the 2,4-dibromo-1-(2-bromo-ethoxy)-benzene to the excess of ethylmagnesiumbromide). Inverse addition - i.e. addition of 1 equivalent ethylmagnesiumbromide to 2,4-dibromo-1-(2-bromo-ethoxy)-benzene to form the ring, then cooling and addition of the rest of the ethylmagnesiumbromide, followed by DMF, is probably the best way. This is what I will try next time, though I doubt that will be soon.

But what seems more promising to me is the following proposal:

Starting from 4-hydroxybenzaldehyde is almost as innocuous as starting from phenol, with the advantage of having the formyl group already in place. Treatment of this with 1,2-dibromoethane, much like hest's work in

Post 196477 (missing)

(hest: "Re: New Amph.  more potent than LSD", Serious Chemistry)
, will give the ether:


Etherification ("c1cc(C=O)ccc1O.BrCCBr>>c1cc(C=O)ccc1OCCBr")

Bromination in acetic acid should work just as well as the bromination of the phenol derivative above, as there is essentially only one position the bromine can take up. There are numerous examples in the literature for the similar bromination of 4-methoxybenzaldehyde:


Bromination ("c1cc(C=O)ccc1OCCBr>>c1cc(C=O)cc(Br)c1OCCBr")

Now, the above compound is treated with 2 equivalents of ethylmagnesiumbromide. The first equivalent will add to the carbonyl, and the second will cause a Parham cyclisation as explained in the above post

Post 499568

(Kinetic: "A more interesting possibility?", Novel Discourse)
. This gives the phenyl-1-propanol derivative:


Grignard addition followed by Parham cyclisation ("c1cc(C=O)cc(Br)c1OCCBr>>CCC(O)c2ccc1OCCc1c2")

The phenyl-1-propanol is of course readily dehydrated to the propenylbenzene, which can be though of as a safrole analogue:


Dehydration ("CCC(O)c2ccc1OCCc1c2>>CC=Cc2ccc1OCCc1c2")

The propenylbenzene is then oxidised to the phenylacetone by the Hive's favourite Wacker oxidation, and from this the amphetamine or methamphetamine is made via any one of the usual methods.


For the bromination (the related 4-methoxybenzaldehyde -> 3-bromo-4-methoxybenzaldehyde transformation):

With bromine and iodine in CCl4: J. Amer. Chem. Soc., 39, 1917, 1711
With bromine in CCl4: Justus Liebigs Ann. Chem., 460?, 1928, 135
With bromine in acetic acid: J. Chem. Soc. Perkin Trans. 1, 1979, 829-837.

For the related Grignard addition of ethylmagnesiumbromide to 4-methoxybenzaldehyde:

Chem. Ber., 38, 1905, 1679
Tetrahedron Lett., 37 (48), 1996, 8767-8770.

For the Parham cyclisation:

Articles dealt with given in the above post

Post 499729

(Kinetic: "An interesting possiblilty", Novel Discourse)

For the dehydration of phenyl-1-propanols to propenylbenzenes:

Propenylbenzenes from propiophenones


Propenylbenzene from phenyl-1-propanol



  • Guest
Parham my mistake
« Reply #9 on: May 31, 2004, 06:46:00 AM »
Many thanks to azole for pointing out a mistake I had made, and for his suggestions on a workaround for the problem. His advice undoubtedly saved me a lot of time trying to work out why I had had so many failures.

The mistake, which I incorporated into my proposals throughout the thread, was the assumption that the ethylmagnesiumbromide used by Nichols in J. Med. Chem., 2001, 44 (6), 1003-1010 - article posted in

Post 364601 (missing)

(Barium: "Another way of inserting the aminopropyl", Serious Chemistry)
- was a catalyst; i.e., I assumed it metalated the aryl bromide, itself then forming ethyl bromide, which could then react with the Mg powder to reform ethylmagnesium bromide, which would again metalate the ring.

In fact, this is not the case: its role is simply as an activating agent (much like I2 is often used), to ensure the direct oxidative insertion of the Mg between the Ar-Br bond, which then displaces the chloride from the end of the connected side-chain, closing the ring. A reasonably thorough literature search indicates that metalation with Grignards only occurs in the presence of a catalyst (e.g. a Cu salt).

It's therefore unlikely I made 5-ethyl-2,3-dihydrobenzofuran as speculated in my above post; it also seems unlikely I could have made the benzaldehyde, or even closed the ring. There was however definitely a reaction; there was a temperature rise from 20oC to 45oC during addition of a THF solution of 2,4-dibromo-1-(2-bromo-ethoxy)-benzene to a THF solution of 2.5 equivalents of ethylmagnesiumbromide, as well as appreciable lightening of the dark 'metallic' Grignard colour.

At higher temperatures and with the heavier halides attached to the ethyl chain of the substituted 2-phenoxyethyl bromide, metalation of the side-chain, followed by elimination of ethene from the unstable product, is an increasingly prevalent side-reaction:


Ethene elimination ("c1cccc(Br)c1OCCBr.CC[Mg++]Br.>>c1cccc(Br)c1O.C=C")

This could explain why the Nichols group chose to use 1,4-bis(2-chloroethoxy)benzene rather than 1,4-bis(2-bromoethoxy)benzene, and could also explain the reaction I observed.

Fortunately, the problem should be readily overcome. Starting from 4-hydroxybenzaldehyde, it would probably be best to use 1,2-dichloroethane in the etherification, to limit any unwanted metalation followed by elimination during the next step. The ring-bromination step will not be affected by the change of halogen.

Treatment of this brominated product with a slight excess of ethylmagnesiumbromide, which should react with the more electrophilic carbonyl (rather than the chloroethoxy group), will give an intermediate alcoholate:


Intermediate alcoholate formation ("c1cc(C=O)cc(Br)c1OCCCl>>c1cc(C([O-])CC)cc(Br)c1OCCCl")

This intermediate is then added directly to a stirred suspension of Mg powder in THF; the excess ethylmagnesiumbromide acting as an initiator of the aryl Grignard formation and subsequent cyclisation in the same way Nichols uses it in the cyclisation of 1,4-bis(2-chloroethoxy)2,5-dibromobenzene. This leads us to the same product as before, 1-(2,3-dihydrobenzofuran-5-yl)-1-propanol:


Ring closure ("c1cc(C([O-])CC)cc(Br)c1OCCCl>>CCC(O)c2ccc1OCCc1c2")

Note the two caveats: the ethylmagnesium must first react with the carbonyl, and not the chloroethoxy group (however, alkyl chlorides aren't particularly electrophilic); also, the intermediate alcoholate must be soluble in THF. Using sufficient solvent should overcome this problem - the horrible white goo which can precipitate during a Grignard reaction can often be overcome by using sufficient solvent. It may also be possible to use a better donor solvent, such as dimethoxyethane.

I've included the original article on the Parham cyclisation. There is nothing on the formation of dihydrobenzofuran analogues, but it's interesting nonetheless. The first thing that came to my mind was the applicability to aminoindanes and aminotetralins, as the 1-indanones and 1-tetralones (cyclised propiophenone/butyrophenone derivatives) can be made readily by this route:

Selective Lithiation of Bromoarylalkanoic Acids and Amides at Low Temperature. Preparation of Substituted Arylalkanoic Acids and Indanones
William E. Parham,* Lawrence D. Jones, and Yousry Sayed
J. Org. Chem., 40 (16), 1975

Edit: When synthesising 2,4-dibromo-1-(2-bromo-ethoxy)-benzene - as in the previous post, the flask was encased in aluminium foil throughout the reaction. Whether this is necessary I don't know, but the synthesis should read: 'A solution of 40.2g 2-phenoxyethyl bromide and 60g zinc chloride in 100ml acetic acid was cooled to 10oC. The flask was then encased in aluminium foil to exclude light. Over 1.5 hours...'


  • Guest
Related PIHKAL entry
« Reply #10 on: May 31, 2004, 03:54:00 PM »
The first step from Shulgin's synthesis of


( - addition of propylmagnesiumbromide to piperonal - should be adaptable for the Grignard addition of ethylmagnesiumbromide to 3-bromo-4-(2-chloroethoxy)benzaldehyde. The crude yield is 96%:


The Grignard reagent of propyl bromide was made by the dropwise addition of 52g 1-bromopropane to a stirred suspension of 14g magnesium turnings in 50mL anhydrous Et2O. After the addition, stirring was continued for 10min, and then a solution of 50g piperonal in 200mL anhydrous Et2O was added over the course of 30min. The reaction mixture was heated at reflux for 8h, then cooled with an external ice bath. It was quenched with the addition of a solution of 75mL cold, saturated aqueous ammonium chloride. The formed solids were removed by filtration, and the two-phase filtrate separated. The organic phase was washed with 3x200mL dilute HCl, dried over anhydrous MgSO4, and the solvent removed under vacuum. The crude 62.2g of 1-(3,4-methylenedioxyphenyl)-2-butanol [Kinetic's voice: this should read 1-(3,4-methylenedioxyphenyl)-1-butanol], which contained a small amount of the olefin that formed by dehydration, was distilled at 98°C at 0.07mm/Hg to give an analytical sample, but the crude isolate served well in the next reaction. Anal. (C11H14O3) C,H.

Graphical abstract:


Grignard addition to piperonal ("C(=O)c2ccc1OCOc1c2.CCC[Mg++]Br>>CCCC(O)c2ccc1OCOc1c2")

The next step in the synthesis is the dehydration of 1-(3,4-methylenedioxyphenyl)-1-butanol to 1-(3,4-methylenedioxyphenyl)-1-butene, which should be adaptable for the dehydration of 1-(2,3-dihydrobenzofuran-5-yl)-1-propanol to 1-(2,3-dihydrobenzofuran-5-yl)-1-propene. The yield is 93%, making the overall yield from piperonal 89%:


A mixture of 65g crude 1-(3,4-methylenedioxyphenyl)-2-butanol [Kinetic's voice: again, this should read 1-(3,4-methylenedioxyphenyl)-1-butanol] and 1g finely powdered potassium bisulfate was heated with a soft flame until the internal temperature reached 170°C and H2O was no longer evolved. The entire reaction mixture was then distilled at 100-110°C at 0.8mm/Hg to give 55g of 1-(3,4-methylenedioxyphenyl)-1-butene as a colorless oil. Anal. (C11H12O2) C,H.

Graphical abstract:


Dehydration to 1-(3,4-methylenedioxyphenyl)-1-butene ("CCCC(O)c2ccc1OCOc1c2>>CCC=Cc2ccc1OCOc1c2")


  • Guest
reactivity of RMgX towards RX
« Reply #11 on: June 01, 2004, 04:50:00 AM »
To use more accessible Grignard reagents instead of RLi is a very attractive idea. However, the reactivity of RMgX may differ greatly from the reactivity of RLi. The mechanism of the reported* cyclization of 2,5-dibromohydroquinone bis(2-chloroethyl) ether with Mg/EtMgBr probably doesn't include metallation by EtMgBr. There are at least two articles to support this point of view.

Factors influencing the course and mechanism of Grignard reactions. XVII. Interchange of radicals in the reaction of Grignard reagents and organic halides in the presence of metallic halides.
M. S. Kharasch and C. F. Fuchs
J. Org. Chem.
, 10, 292-297 (1945).

   Unlike RLi, organomagnesium compounds typically do not react with organic halides (R'Hal) to form R'MgX. However, there are exceptions, e.g. alpha-haloketones (


( ) and haloacetylenes (see below). In the presence of CoCl2 the halogen-metal exchange does take place to some extent, and various coupling products are formed.

Factors determining the course and mechanism of Grignard reactions. XVIII. The effect of metallic halides on the reactions of Grignard reagents with 1-chloro-3-phenylpropane, cinnamyl chloride, and phenylethynyl bromide.
M. S. Kharasch, F. L. Lambert, and W. H. Urry
J. Org. Chem.
, 10, 298-306 (1945).

   In the absence of transition metal halides, 1-chloro-3-phenylpropane does not react with Grignard reagents; cinnamyl bromide enters "normal" Wurtz-type coupling reactions, and phenylethynyl bromide undergoes halogen-metal exchange. The situation is completely altered on addition of CoCl2 or other metal catalysts.

   The reactions of halogen-magnesium exchange were reviewed recently. Shame on me, I didn't know.

Highly Functionalized Organomagnesium Reagents Prepared through Halogen-Metal Exchange
P. Knochel et al.,
Angew.Chem. Int. Ed. Engl.
, 42(36), 4302-4320 (2003).


  It appears that arylbromides bearing electron-withdrawing substituents (or a chelating group ortho- to the halogen) do react with RMgX. Thus, 2,4-dibromoanisole is converted into 2-MeO-5-Br-PhMgCl by treatment with 2 eq. of i-PrMgCl in THF at 40° for 5 h. Subsequent reaction with CO2 affords the corresponding carboxylic acid in 90% yield (see the following ref.).

Metal-halogen exchange between polybromoanisoles and aliphatic Grignard reagents: a synthesis of cyclopenta[b]benzofurans
H. Nishiyama et. al.,
J. Org. Chem.
, 57, 407 (1992).

No DOI found.


Post 185131 (missing)

(hest: "New Amph.  more potent than LSD", Serious Chemistry)


  • Guest
2,3-Dihydrobenzofurans without BuLi
« Reply #12 on: June 01, 2004, 07:03:00 AM »
Great azole!

Here is another very interesting article: on the synthesis of 5-substituted 2,3-dihydrobenzofurans from 2-(2-bromophenoxy)ethyl chlorides, using only Mg in the cyclisation. The article also has a high-yielding PTC alkylation of bromophenols, referenced in

Post 196477 (missing)

(hest: "Re: New Amph.  more potent than LSD", Serious Chemistry)

The Synthesis of 5-Substituted 2,3-Dihydrobenzofurans
Ramon J. Alabaster, Ian F. Cottrell, Hugh Marley, Stanley H. B. Wright*
, 12, 1988, 950-952.


The preparation of 2,3-dihydrobenzofurans 6 from 2-(2-bromophenoxy)ethyl chlorides 3 by reaction with magnesium in a development of the Parham cyclialkylation reaction is described. A high yielding procedure using phase-transfer catalysis has also been developed for the preparation of the intermediate chloroethyl ethers 3 from bromophenols 2. The 5-hydroxy derivative 15 may be obtained from 2,3-dihydrobenzofuran (6a) by reaction with electrophilic agents followed by oxidation.

Edit: Commenting on your edit: So if 2,4-dibromoanisole reacts with 2eq. of i-propylmagnesiumchloride in THF at 40°C, it seems likely that 2,4-dibromo-1-(2-bromoethoxy)benzene would react with 2.5eq. ethylmagnesiumbromide at 20-45°C. So maybe I did cyclise the ring after all! But still, it's impossible to say without further analysis.


  • Guest
Grignard formylation article
« Reply #13 on: June 11, 2004, 12:53:00 PM »
The following article - part of which has been posted in

Post 60192 (missing)

(yellium: "Another route to 2C-[BDE]", Chemistry Discourse)
- has a high-yielding and simple formylation of phenylmagnesiumbromide, which should be readily adaptable to suit the in-situ prepared 5-(2,3-dihydrobenzofuranyl)magnesiumbromide, as well as other interesting substituted aryl systems (such as 5-bromo-1,3-benzodioxole):

Synthetic Methods and Reactions; Part 109. Improved Preparation of Aldehydes and Ketones From N,N-Dimethylamides and Grignard Reagents
George A. Olah, G. K. Surya Prakash, Massoud Arvanaghi
, 3, 1984, 228-230


  • Guest
3-Br-4-(2-chloroethoxy)BA failed to cyclize
« Reply #14 on: July 28, 2004, 09:32:00 AM »
SWIM has made some synthetic studies along the route proposed by Kinetic (

Post 510530

(Kinetic: "Parham my mistake", Novel Discourse)

1) 4-Hydroxybenzaldehyde was successfully alkylated. SWIM managed to get a 69% yield of a pure product using 1,2-dichloroethane in a non-optimized procedure. The published1 procedure deals with 1-bromo-2-chloroethane, a more reactive alkylator, and only a 30% yield is achieved.

2) Bromination of the above aldehyde gave 40% of the monobromo product. The optimum reaction conditions are yet to be found.

3) The reaction of 3-bromo-4-(2-chloroethoxy)benzaldehyde with 4 eq. of EtMgBr in THF gave no cyclization product after a 2.5 h reflux, as can be inferred from the NMR spectra. Apparently, only addition of EtMgBr has occurred.

   Of course, one can make a dimethyl acetal from 3-bromo-4-(2-chloroethoxy)benzaldehyde and cyclize it with Mg/THF as described above (

Post 510718

(Kinetic: "2,3-Dihydrobenzofurans without BuLi", Novel Discourse)

Experimental part


Bu4NBr FW 322.36
1,2-Dichloroethane FW 98.96, d 1.256, bp 83°
4-Hydroxybenzaldehyde FW 122.12
K2CO3 FW 138.21
Na2SO3 FW 126.04

   A 250 ml RBF equipped with a magnetic stirrer, a reflux condenser, and a gas bubbler connected to the top of the condenser was charged with 4-hydroxybenzaldehyde (18.06 g, 0.148 mol), anhydrous sodium sulfite (~0.2 g, 1.6 mmol), tetrabutylammonium bromide (2.39 g, 7.41 mmol, 5 mol. %), potassium carbonate (21.5 g, 0.156 mol), 1,2-dichloroethane (60 ml), and ethylene glycol (40 ml). The mixture was stirred at reflux for 24 h (at 17 h point gas evolution still continued, and TLC showed incomplete reaction). Then the mixture was cooled; water was added to dissolve the precipitated KCl,  followed by toluene (60 ml). The contents of the flask were transferred to a separatory funnel, the flask was rinsed with toluene (10 ml), and the rinsings also were added to the separatory funnel. After shaking, the organic (upper) layer was separated and washed with 10% aq. KOH (4×25 ml). The aqueous layer was extracted with toluene (15 ml), and the extract was also washed with KOH solution (4×10 ml).

   The combined organic phases were filtered* through a mixture of silica gel (height 2 cm) and anhyd. Na2SO4 (height 0.5 cm) placed on a glass filter (diam. 4 cm); the adsorbed product was eluted with a mixture of toluene (80 ml) and ethyl acetate (20 ml), and the combined solutions were evaporated under reduced pressure to give a crude product (27.7 g) as a yellow oil, which solidified on standing in a refrigerator.

   TLC (Merck F254 SiO2 plates, visualisation in UV light and with 0.5% 2,4-dinitrophenylhydrazine soln. in dil. H2SO4; eluent : CHCl3 - Me2CO 19:1 v/v) showed 2 major spots: Rf 0.65 (4-(2-chloroethoxy)benzaldehyde) and Rf 0.53 (presumably (OHCC6H4OCH2)2, since it was not detected in the product upon distillation), along with traces of 4-hydroxybenzaldehyde, Rf 0.24,  and another aldehyde byproduct, Rf 0.19.

   Distillation in a vacuum of an oil pump gave two fractions : bp 100-108 °C (1.83 g) and bp 108-115 °C (lit. bp 110 °C (0.1 mm Hg)1; 138-142 °C (2 mm Hg)2) . These were combined and redistilled. After a small forerun (0.96 g), the product was collected (18.83 g, 69%; lit.1 yield 30% from 1-bromo-2-chloroethane), which solidified on standing (mp 29-30 °C; lit.1 mp 31°C). The smell is similar to that of anisaldehyde, but not so intense. TLC showed a small admixture of 4-hydroxybenzaldehyde. The forerun solidified below 20 °C.

   1H NMR (200 MHz, CDCl3): ? (ppm) 9.85 (s, 1H, CHO), 7.80 (m (AA'BB'), 2H, H-2, H-6), 6.98 (m (AA'BB'), 2H, H-3, H-5), 4.27 (t, 2H, J = 5.7 Hz, -OCH2CH2Cl), 3.82 (t, 2H, J = 5.7 Hz, -OCH2CH2Cl).

   13C NMR (50 MHz, CDCl3): ? (ppm) 190.56 (CHO), 162.94, 131.80, 130.21, 114.67 (benzene ring), 67.97 (-CH2O-), 41.48 (-CH2Cl).

*This step (actually, a short-column chromatography) was originally designed to get rid of Bu4NBr and the byproduct having lower Rf value, presumably 4-(2-hydroxyethoxy)benzaldehyde. Instead, the solution can be simply dried with Na2SO4.


Br2 FW 159.82, d 3.119
4-(2-Chloroethoxy)benzaldehyde FW 184.62, d25 1.22462
ZnCl2 FW 136.28

   A solution of bromine (1.8 ml, 35 mmol) in glacial AcOH (5 ml) was added to a solution of 4-(2-chloroethoxy)benzaldehyde (~5 ml, 6.18 g, 33.5 mmol) and zinc chloride (0.91 g, 6.7 mmol) in glacial AcOH (15 ml) dropwise with magnetic stirring over the course of 8 min (slight exothermy). The reaction flask was protected from light with aluminum foil. The mixture was allowed to stand at rt for 2 h 15 min. The product has virtually the same Rf value as the starting aldehyde in a number of eluents tested (CHCl3 - Me2CO 19:1, petroleum ether - EtOAc 7:3, benzene - EtOAc 9:1 v/v), so TLC appeared to be useless.

   Another portion of Br2 (0.4 ml, 7.8 mmol) was added (obviously, this was a mistake, see below), and the mixture was allowed to stand for 1.5 h. Then 2% aq. Na2SO3 was added with stirring until the bromine color disappeared; the volume of the mixture was brought to ~100 ml with water, the organic layer separated, and the aqueous layer extracted with CHCl3 (3×10 ml).

   The combined organic phases were washed with water (60 ml), 5% aq. NaOH containing 0.5% Na2SO3 (2×60 ml), dried (Na2SO4), and evaporated to give a colorless oil (7.75 g), which solidified on standing in a refrigerator. This was dissolved in a mixture of petroleum ether (20 ml), CCl4 (10 ml) and PhMe (7 ml) at ~50 °C. On cooling to rt, crystals formed. The mixture was cooled to +4 °C; petroleum ether (10 ml) was gradually added to complete crystallization; the crystals were filtered off, washed with cold CCl4, then with a 1 : 3 mixture of CCl4 with petroleum ether, and dried. Yield 3.585 g (40%) of white crystals, mp 84-85 °C, with a "pesticide" smell. Rf 0.37 (petr. ether - EtOAc 7:3 v/v).

   The mother liquors and washings were evaporated to dryness. Low-temperature crystallization of the residue from methanol gave 1.95 g of white crystals with mp 50-53 °C, probably a dibrominated product, with Rf 0.57 (petr. ether - EtOAc 7:3 v/v). The melting point was raised to 53-54 °C after recrystallization from CCl4 - petroleum ether. The solubility of the byproduct in CCl4 is much higher than that of the main product. After standing at rt for several days, the crystals turned to a yellow liquid.

   1H NMR (200 MHz, CDCl3): ? (ppm) 9.84 (s, 1H, CHO), 8.06 (d, 1H, J = 1.9 Hz, H-2), 7.79 (dd, 1 H, J = 1.9 Hz, J = 8.5 Hz, H-6), 6.98 (d, 1H, J = 8.5 Hz, H-5), 4.36 (t, 2H, J = 5.9 Hz, -OCH2CH2Cl), 3.89 ((t, 2H, J = 5.9 Hz, -OCH2CH2Cl).

   13C NMR (50 MHz, CDCl3): ? (ppm) 189.43 (CHO), 159.21, 134.64, 131.08, 130.92, 113.01, 112.55 (benzene ring), 69.14 (-CH2O-), 41.11 (-CH2Cl).


3-Bromo-4-(2-chloroethoxy)benzaldehyde FW 263.52
EtBr FW 108.97, d 1.460
Mg FW 24.31

   To a solution of EtMgBr prepared from EtBr (4.0 ml,  54 mmol) and Mg (1.93 g, 79 mmol) in abs. THF (50 ml) under argon was added a solution of 3-bromo-4-(2-chloroethoxy)benzaldehyde (3.48 g, 13.2 mmol) in abs. THF (20 ml) dropwise with stirring and cooling in a water bath (30-35 °C, internal temperature). The addition took 13 min. No precipitate has formed. The mixture was refluxed for 2.5 h (after 0.5 h TLC showed a single spot of the product, Rf 0.46 in CHCl3 - Me2CO 19 : 1 v/v; no changes were noted on further heating) and cooled to 0 °C. A saturated aq. solution of NH4Cl (50 ml) was carefully added to the reaction mixture (Caution: ethane evolution!), followed by PhMe (50 ml). The organic layer was separated; the aqueous layer was extracted with PhMe (2×20 ml), and the combined extracts were washed with 10% aq. NaOH (3× 25 ml), dried (Na2SO4) and evaporated. The resulting product (viscous yellowish oil) gave a positive Beilstein test, and its NMR spectra were consistent with the title structure (cf. 3 and 4).

   1H NMR (200 MHz, CDCl3): ? (ppm) 7.50 (s, 1H, H-2), 7.17 (d, 1H, J = 8.6 Hz, H-6), 6.84 (d, 1H, J = 8.6 Hz, H-5), 4.46 (t, 1H, J = 6.4 Hz, CHOH), 4.25 (t, 2H, J = 6.0 Hz, -OCH2CH2Cl), 3.83 (t, 2H, J = 6.0 Hz,  -OCH2CH2Cl), 2.54 (br. s, 1H, OH), 1.69 (m, 2H, -CHOH-CH2CH3), 0.86 (t, 3H, J = 7.3 Hz, CH3).

   13C NMR (50 MHz, CDCl3): ? (ppm) 153.7, 139.2, 131.0, 127.2, 126.0, 114.4, 113.7, 112.3 (arom. ring; note the signals of admixtures), 74.6 (CHOH), 69.3 (-CH2O-), 41.5 (-CH2Cl), 31.7 (-CHOHCH2CH3), 9.9 (CH3).

1 J. Org. Chem., 18, 1380 (1953).


Patent US2568579


3   The 13C NMR spectrum of 1-phenyl-1-propanol, found in

NMRShiftDB - NMR web database

(, is as follows: 140.50, 126.53, 128.33, 127.76 (arom. ring), 77.30 (CHOH), 29.24 (CH2), 9.84 (CH3).

4   In the patent application

some 13C spectra of dihydrobenzofurans are presented. Thus, in 5-bromo-2,3-dihydrobenzo[b]furan-7-carboxylic acid the chemical shift of C-2 is 71.78 ppm; that of C-3 is 27.88 ppm.
   Nichols didn't publish the 13C NMR spectra of the benzofurans obtained by his group. In 1H spectra the chemical shifts of the benzylic CH2 groups of dihydrobenzofurans were at ~3.2 ppm.


  • Guest
« Reply #15 on: July 28, 2004, 01:29:00 PM »
Wow azole, what a post!

Thankyou so very much for trying this out! Although it's a shame the cyclisation doesn't work as hoped, your post was certainly an inspirational way in which to let us know. If only alkyllithiums were more accessible; ethyllithium would hopefully still do the trick.

It's interesting that you noted the smell of 3-Bromo-4-(2-chloroethoxy)benzaldehyde as pesticide-like; that was the first thing I thought when I smelled 2-phenoxyethyl bromide/chloride.

I made some 2-phenoxyethyl chloride using the procedure in Synthesis, 1988, 12, 950-952 (article posted above in

Post 510718

(Kinetic: "2,3-Dihydrobenzofurans without BuLi", Novel Discourse)
. I first modified the procedure, using less 1,2-dichloroethane and water, and half the amount of PTC. The 65% yield was lower than the expected 90%, so I tried it again, following the procedure almost to the letter (only using TBAB as PTC, and sodium metabisulfite instead of bisulfite). The yield was again 65%. After distillation the (pesticide-smelling, but rather pleasant to me) product was a solid in the fridge and slowly melted when removed, so had a melting point slightly below room temperature. The pure product should melt around 25oC.

The third time I tried the procedure I got only 39% yield, after using only two equivalents of NaOH. I inferred from this that the amount of 1,2-dichloroethane (80ml or 125ml for a 100mmol reaction gave the same yield) was not critical, nor was the amount or type of PTC (5mol% aliquat 336 or 10mol% TBAB). Only decreasing the amount of NaOH seems to lower the yield. This may be useful for anyone wanting to try hest's work in

Post 196477 (missing)

(hest: "Re: New Amph.  more potent than LSD", Serious Chemistry)

As the cyclisation doesn't work on the alkoxide, I hope that the original idea (treatment of 2-(2,4-dibromophenoxy)ethyl chloride with 2 equivalents of Mg, followed by treatment with DMF1) can still be made to work, as very similar work has been reported in the literature. The stabilising effect of the aryl ether oxygen in the ortho-position should ensure the cyclisation occurs before the para position reacts, so this should not interfere with the cyclisation as the alkoxide seems to. Hopefully we will soon see.

I feel inspired enough by your post to set off another synthesis of 2-phenoxyethyl chloride. I will then have enough to dibrominate it - using bromine and a catalytic amount of zinc chloride this time - and then attempt my yet-untested proposal of cyclisation with Mg (probably initiating the reaction with a small amount of ethylmagnesiumbromide1).

1 I know for certain that both the formlyation procedure and the initiation of aryl Grignards by ethylmagnesiumbromide occurs readily: see

Post 517404

(Kinetic: "Two formylation procedures", Novel Discourse)

TFSE is full of 5-year old threads ending with "I'll report back tomorrow!", but I feel the least I can do is try this again. I will report back in due course (but not tomorrow, though).


  • Guest
Why must we insist on doing things the hard...
« Reply #16 on: July 29, 2004, 12:07:00 AM »
Why must we insist on doing things the hard way?  It's not as if benzofuran itself is difficult or expensive to obtain..  Nichols has already found that the tetrahydrobenzodifuran (5a) analog of 2,5-DMA is much weaker than the benzodifuran analog (6a, which just so happens to be as potent as the DOX-series of psychedelic amphetamines [1]).  Here are the compounds I am talking about:

Thus, I would put a good wager on the fact that the monobenzofuran, pictured above, would have considerably higher potency than the corresponding dihydro analogue.  Here's what Nichols had to say about the reasoning behind this:

"An additional trend that can be observed in Tables 1 and 2 is that the benzo[1,2-b;4,5-b']difuran-containing compounds (series 6) bind with higher affinity and exhibit increased potency relative to the corresponding tetrahydrobenzo[1,2-b;4,5-b']difurans (series 5), indicating that the compounds in series 6 posses more favorable interactions with the agonist binding site.  This may be due to the increased hydrophobicity of the extended tricyclic aromatic nucleus in 6a-c relative to the tetrahydro congeners 5a-c and a resulting greater tendency to partition into the hydrophobic receptor binding site.  It is also possible that the exteneded aromaticity of the benzo[1,2-b;4,5-b']difurans (series 6) may result in enhanced affinity by increasing the effective aromatic surface area on the ligand available for for favorable pi-stacking interactions with the agonist binding site, while still maintaining some (albeit weaker) hydrogen-bond acceptor properities of the furan oxygen atoms.  It is interesting to note that although potency is generally increased for the aromatic compounds 6a-c relative to the tetrahydro compounds 5a-c, the intrinsic activity of these compounds remaines largely unchanged. [1]"

If you are still set on dihydrobenzofuran, reduction of benzofuran still seems like a much more viable option taking into account both difficulty and economic factors.  However, that's just my opinion..

[1] J. Med. Chem. 2001, 44, 1003-1010


  • Guest
Reactive in the wrong position
« Reply #17 on: July 29, 2004, 05:18:00 AM »
Why must we insist on doing things the hard way?  It's not as if benzofuran itself is difficult or expensive to obtain.

No, but it is difficult to manipulate - the 3-position on the furan ring is more reactive than any of the benzene ring positions (similar to indole), so therefore it is difficult to turn it into a benzofuranyl-aminopropane.


  • Guest
d'oh.. I completely overlooked that.
« Reply #18 on: July 29, 2004, 05:20:00 PM »
d'oh.. I completely overlooked that.  Instead, let me propose these two steps from p-hydroxybenzaldehyde to a desired aldehyde:

The only possible problem I see here is perhaps obtaining chloroacetaldehyde, but it *is* available if you look hard enough.  250g of a 45% aqueous solution is available commercially for around $10..

p-formyl-phenoxyacetaldehyde when refluxed with GAA and a lewis acid *should* close the ring, forming the wanted aldehyde in good yield.


  • Guest
Total Synthesis of Benzofuran
« Reply #19 on: July 29, 2004, 07:09:00 PM »

Total Synthesis of Benzofuran


Equip a 1-litre three-necked flask with an efficient double surface reflux condenser, a mechanical stirrer and a thermometer, the bulb of which is within 2cm of the bottom of the flask. Place a warm solution of 80g of sodium hydroxide in 80 ml of water in the flask, add a solution of 25g (0.266 mol) of phenol in 25 ml of water and stir. Adjust the temperature inside the flask to 60-65°C (by warming on a water bath or by cooling, as may be found necessary); do not allow the crystalline sodium phenoxide to separate out. Introduce 60g (40.5 ml, 0.5 mol) of chloroform in three portions at intervals of 15 minutes down the condenser. Maintain the temperature of the well-stirred mixture at 60-70°C during the addition by immersing the flask in hot or cold water as may be required. Finally heat on a boiling water bath for 1 hour to complete the reaction. Remove the excess of chloroform from the alkaline solution by steam distillation. Allow to cool, acidify the orange-colored liquid cautiously with dilute sulfuric acid and again steam distill the almost colorless liquid until no more oily drops are collected. Extract the distillate at once with ether, remove most of the ether from the extract by distillation on a water bath using a rotary evaporator. Transfer the residue, which contains phenol as well as salicylaldehyde, to a small glass-stoppered flask, add about twice the volume of saturated sodium metabisulfite solution, and shake vigorously (preferably mechanically) for at least half an hour, and allow to stand for 1 hour. Filter the paste of bisulfite compound at the pump, wash it with a little alcohol, and finally with a little ether (to remove the phenol). Decompose the bisulfite compound by warming in a round-bottomed flask on a water bath with dilute sulfuric acid, allow to cool, extract the salicylaldehyde with ether and dry the extract with anhydrous magnesium sulfate. Remove the ether by flash distillation and distill the residue collecting the salicylaldehyde (a colorless liquid) at 195-197°C. The yield is 12g (37%).

o-Formylphenoxyacetic acid

To a mixture of 35 ml (40 g, 0.33 mol) of salicylaldehyde, 31.5 g (0.33 mol) of chloroacetic acid and 250 ml of water contained in a 500-ml, two-necked round-bottomed flask fitted with a stirrer unit, add slowly with stirring a solution of 26.7 g (0.66 mol) of sodium hydroxide in 700 ml of water. Heat the mixture to boiling with stirring and reflux for 3 hours. The solution acquires a red-brown color. Cool and acidify the solution with 60 ml of concentrated hydrochloric acid and steam distill to remove unreacted salicylaldehyde; 12ml (14g) are thus recovered. Cool the residual liquor which first deposits some dark red oil which then solidifies; on standing, almost colorless crystals appear in the supernatant solution. Decant the supernatant solution and crystals and filter off the crystals, and air dry; the yield of almost pure product, m.p. 132-133°C, is 21 g. The solidified red oil may be extracted with small quantities of hot water, the extracts treated with decolorizing charcoal and cooled, to yield a further 6g of product; total yield 27g.


Heat under reflux for 8 hours a mixture of 20 g (0.11 mol) of o-formylphenoxyacetic acid, 40g of anhydrous sodium acetate, 100 ml of acetic anhydride and 100ml glacial acetic acid. Pour the light brown solution into 600 ml of iced water, and allow to stand for a few hours with occasional stirring to aid the hydrolysis of acetic anhydride. Extract the solution with three 150 ml portions of ether and wash the combined ether extracts with 5 per cent aqueous sodium hydroxide until the aqueous layer is basic; the final basic washing phase acquires a yellow color. Wash the ether layer with water until the washings are neutral, dry the ethereal solution over anhydrous calcium chloride and remove the ether on a rotary evaporator. Distil the residue and collect the benzofuran as a fraction of b.p. 170-172°C. The yield of colourless product is 9.5g (91%).

Reference: A. I. Vogel, Textbook of Practical Organic Chemistry, 5th Ed., Longman (1989)