Iodination via NIS -- various conditions

[Guinea Pig]

GP didn't like the title of that other thread, so he started a new one, hope no one minds.

First of all, GP would like to clairify the DMF/Acetone @ 4C.  The reference is:
J. CHEM. SOC. Perkin Trans I, 1985 p2521

Now at first this seems like an odd reference as it's title has nothing to do with what we want, but upon further investigation we find that they needed an Iodo derivative of their multiple ringed compound, catechin.  They did work with both OH and OMe substituted catechin, using NIS to Iodinate their intermediate.  This procedure was applied to various phenols in GP's research group, with varied success.  It would seem as though the more electron rich the ring, the easier iodination occurs.  Attempts with methoxy derivatives were not attempted by GP, so he don't know for sure on those.  It DOES work for phenols, some better than others.

Another procedure:
Tetrahedron Lett. Vol. 37, No. 23, pp. 4081-4084, 1996
This paper is titled:
"Mild and Regiospecific Nuclear Iodination of Methoxybenzenes and Naphthalenes with N-Iodosuccinimide in Acetonitrile"

They apply NIS in MeCN to a good number of Methoxy derivatives, all giving high yields (85+) of the iodinated products.   GP has not seen success with phenols, but that's not what we are concerned with here now is it..dumb GP.

Next..Tetrahedron Lett., Vol 33, No 20, pp. 2883-2886, 1992

This one is a bit 'out there' but this statement caught GP's eye:
"Halogenated salicylic acid derivatives were prepared by direct halogenation of salicylic acids in DMF at ambient temp. using NBS or NIS"
They are sticking that Iodine on the ring, so it couldn't hurt investigation.

One more NIS ref:
J. Am. Chem. Soc. Vol 105, No. 9, 1983
This one is strange.  They use NIS and NBS on coumarin, which is another big molecule.  This one uses glacial acetic acid as the solvent.

And FINALLY, GP would like to restate:
Tetrahedron Lett. vol 40 (1999) 6051-6054

Now THIS one is probably the best, but it does not use NIS.  GP posted this but never got much reply, anyhow, here it is (PAY ATTENTION!  )
Titled "A Practical Iodination of Aromatic Compounds using Tetrabutylammonium Peroxydisulfate and Iodine"

They apply the title peroxide as a source of tetrabutylammonium sulfate radical, which is one mamma of an oxidizer, to generate the I+ in situ which attacks the ring.  They apply this to a whole slew of Methoxy compounds, some of them seem VERY suspicious to GP... And these people get GRANTS to do this shit.. GP loves it the most.  This method seems to work with short chain substituents along with the Methoxys. (hint, hint)  They claim high yields of 85+%.  The title peroxide can be *EASILY* generated in only a days work from... Tetrabutyl ammonium persulfate and...?? damn.. don't have that paper here.  The Ref for the peroxide is:  Synlett, 1995, 207-208.

Can't remember the other reagent, but believe GP, it's NOT something that would be watched by any means, and the peroxide preparation is easy shmeezy (isn't all inorganic chemistry that way?)

GP hopes this helps..  around the lab GP is known as the "iodination guy"...he hopes to live up to this.

GP out..

[Guinea Pig]

quick clairification:

The peroxide in the last reference is produced by reacting Tetrabutyl ammonium hydrogen sulfate (TBAHS) with Potassium peroxydisulfate.  Neither of which should be any problem to order. 

[rev drone]

Out of curiosity, how did you find these ref's?

[Guinea Pig]

How did GP get the refs?  By simply searching Chem Abstracts for a certain compound GP needed to iodinate for research purposes,  Most any paper will have some kind of introduction which cites other methods which have been attempted.  Following these footnotes, one is able to collect as many related papers as one wishes.

Library skills, my friend, library skills.

[rev drone]

GP,

Thanks much again for the ref's. The reason I ask abut your literary research techniques is that I've discovered everybody has their own, and its always good to exchange efficient methods. If you take a look around, you'll see I've submitted my fair share of bibliographic information -- don't worry about the 'ol reverend's library skills. You relied more on the CA, while others prefer searching for book reviews, while still others live-and-die by the big electronic databases. Since Current contents and Beilstein haven't been checked, I imagine these would be an even better (not to mentinon faster) means of getting even more info. I'll be back.

[Rhodium]

While you're at it Drone, check if N-chlorosuccinimide can be used to chlorinate activated rings with the same ease...

[rev drone]

Wow, there are more halogenations involving NIS and NCS than you'd ever imagine -- sifting through the mess is a bigger task than I originally estimated. While I go to task on that, I submit for your amusement a couple tastey ref's, practically facilitating all the major DOX's:

JOC 58, 27 (1993) 7906-7912

A modification of the Duff reaction, producing 4-chloro-2,5-dimethoxybenzaldehyde from chloro-para-dimethoxybenzene. This method uses hexamine as the carbonyl source, TFAA as the solvent, 12 h. reflux, and gets 75% yields. Looks like the method of choice fo subsequent DOC/2C-C synthetic preparations, IMHO.

Org. Prep. Proc. Int'l 23(4), (1991) 419-424

A procedure yielding 87% 4-bromo-2,5-dimethoxybenzaldehyde from 2,5-dimethoxybenzaldehyde using Br2 in AcOH. 72 hours, ambient temp -- looks readily scaleable. Translation: a HUGE leap in yields over the traditional route of employing bromination as the last step. Somewhere, there are commercial labs awaiting the use of this procedure in a custom synthesis for their visionary clientel..

Tet. Lett. 34, 39 (1993) 6223-6224

78% Yields, explicitly producing DOI from DOH, using nothing mor than I2, Ag2SO4 in EtOH. 17 h. Ambient temps. A little heavy on the solvent, but how else are you gonna get those reagents to dissolve effectively?

I think these might be already mentioned, but they're so good, they're worth a second gander.

------------------
-the good reverend drone

Ipsa scientia potestas est

[Rhodium]

This procedure was cited in

Post 106226

(Guinea Pig: "Iodination via NIS -- various conditions", Chemistry Discourse) (the first post in this thread), and FYI, "the other thread" mentioned in that post is

Post 105991 (missing)

(psyloxy: "2C-H freebase --> 2C-C.HCl in one step", Chemistry Discourse).

Catechin is a complex molecule, whose aromatic portion is a substituted methoxybenzene. Thus this method should be suitable for iodination of 2C-H, 2,5-DMA, 1,4-Dimethoxybenzene and similar compounds.

Iodination of (+)-Catechin with N-Iodosuccinimide (NIS)
J. Chem. Soc. Perkin. Trans. 1, 2521-2527 (1985)

(+)-Catechin (2 mmol) dissolved in dimethylformamide (DMF) was treated at 4°C with NIS (450 mg, 2 mmol) dissolved in dry acetone (20 ml) by dropwise addition over 30 min. The reaction effected the quantitative conversion of (+)-catechin. The product was extracted with ethyl acetate and the solution was washed successively with 0.1M HCI and NaHCO₃ solutions and finally dried (Na₂SO₄).
The product obtained after evaporation was methylated and separated by p.l.c. eluting with hexane-acetone-ethyl acetate (60:25:15 v/v). The following fractions were obtained: R_f 0.76 (10 mg), 0.65 (16 mg), 0.54 (250 mg), 0.49 (25 mg), and 0.27 (8 mg).


This German article is mentioned as reference #3, #18 & #35 (of 43) in

Post 106011 (missing)

(rev drone: "Re: 2C-H freebase --> 2C-C.HCl in one step", Chemistry Discourse), which is a Beilstein printout of bromination of 1,4-Dimethoxybenzene without elemental bromine.

As can be seen, it is about brominating the three dimethoxybenzenes (1,4-MeO-, 1,2-MeO- and 1,3-MeO-Benzene) by heating with with N-Bromosuccinimide in carbon tetrachloride on a boiling water bath for a few hours. After cooling, the solution is diluted with more CCl₄, filtering off the precipitated succinimide and washing the organic solution with dilute NaOH to remove the last traces of NBS and succinimide. The product is isolated by evaporating the solvent and distillation of the residue.

Bromierung der Diphenol-dialkyläther
Ann. Chem. 556, 1-9 (1944)

Hydrochinon-dimethyläther
9 g N-Brom-succinimid wurden mit 15 g des Dimethyläthers und etwas CCl₄ versetzt und 12 Stunden erhitzt. Es wurden 8 g Brom-hydrochinon-dimethyläther in Gestalt eines hellgelben Öls vom Siedep. 252-258°C erhalten. Noelting und Werner gaben Siedep. 262-263°C au.) Höhersiedende Produkte waren nicht zu fassen.

Veratrol
8 g Brom-succinimid worden vorsichtig in 15 g mit 10 ccm CCl₄ verdünntes Veratrol eingetragen. Das Gemisch erwärmte sich erheblich unter Auflösung des Bromimids. Es wurde anschließend noch 6 Stunden auf dem Wasserbad erhitzt, und man erhielt 6 g Brom-veratrol vom Siedep.= 157-158°C/30mmHg (Grignard und Mitarb. geben Siedep. = 131°C/12mmHg an).

Resorcin-dimethyläther
Man verfährt genau wie im vorigen Beispiel: Man erhält 8 g Bromresorcin-dimethyläther in Gestalt eines hellgelben Öles vom Siedep = 155-159°C/30mmHg, das im Kältegemisch zu fast farblosen Krystallen erstarrt (nach Rice, Chem. Ber. 23, 3250, 1890 Siedep. 152°C/25mmHg und Schmelzp. 24-26°C). Es war bei diesen Bromierungen kein Zeichen einer Entmethylierung festzustellen.

[demorol]

Halogenation of Aromatic Compounds by N-chloro-, N-bromo-, and N-iodosuccinimide

Chemistry Letters, Vol. 32, No. 10, pp. 932-933 (2003)
DOI:

10.1246/cl.2003.932

Abstract

An efficient and mild method for the halogenation of aromatic compounds using N-chloro-, N-bromo-, and N-iodosuccinimide in the presence of NH₄NO₃ of FeCl₃ in acetonitrile was developed.



Halogenation of aromatic compounds is one of the most important reactions in organic synthesis. The most commonly used reagents for this purpose are bromine and chlorine in the presence of iron halide. In terms of ease of handling in laboratories, N-bromo- (NBS), and N-chlorosuccinimide (NCS) will be superior halogenating reagents if benzylic halogenation is suppressed. Schmid reported that benzene and toluene gave nuclear brominated derivatives in good yields by the reactions with NBS and AlCl₃ without solvents under long reflux using a large amount of the catalyst (>1 equiv.), but in unsatisfactory yields (21-61%) of products together with te polysubstituted products by the reactions using H₂SO₄, FeCl₃, and ZnCl₂.¹ Lambert et al. Reported that nuclear substituted derivatives were obtained in good yields from the reactions of aromatic compounds with NBS in 50% aqueous H₂SO₄, ² however this method requires considerably acidic conditions. Thus, there is a need to develop a practical procedure for the halogenation of aromatic compounds.

In this paper, we report that aromatic compounds react with NBS, NCS, or N-iodosuccinimide (NIS) in the presence of NH₄NO₃ or FeCl₃ in CH₃CN to give the corresponding nuclear substituted products.



…

Experimental

A typical experimental procedure is as follows: A mixture of 1,4-dimethoxybenzene (1.38g, 10 mmol), NBS (1.78g, 10 mmol), and NH₄NO₃ (80mg, 1 mmol) in dry CH₃CN (5 mL) was stirred at 25°C for 10 min. The reaction mixture was poured into water (50 mL) and extracted with ether. The extracts were washed with water, dried and evaporated. The residue was chromatographed (hexane-acetone = 10:1) on silica gel to give 2-bromo-1,4-dimethoxbenzene (2.04g, 94%).




References:
¹ H. Schmid, Helv. Chim. Acta, 29, 1144 (1946).
² L. Lambert, W. D. Ellis, and R. J. Parry, J. Org. Chem., 30, 304 (1965).
³ S. D. Ross, M. Finkelstein, and R. C. Petersen, J. Am. Chem. Soc., 80, 4327 (1958)
⁴ C. M. Suter, J. Am. Chem. Soc., 51, 2585 (1929).
⁵ E. Campaigne and W. M. LeSuer, J. Am. Chem. Soc., 70, 416 (1948).

[Rhodium]

It's an odd thing that N-iodosuccinimide (NIS) is only mentioned in the title/abstract, and not together with any experimental results... But other than that, a very nice article!

[Lego]

Preparation of Functionalized Juglone Acetates and Juglones via 1,4-Dimethoxynaphthalene Derivatives:
Synthesis of Anthraquinones Related to Rhein and Aloe Emodin

James L. Bloomer, Kenneth W. Stagliano, and Joseph A. Gazzillo

J. Org. Chem., 1993, 58, 7906-7912

[...]

4-Chloro-2,5-dimethoxybenzaldehyde (1b)
Trifluoroacetic acid (450 mL, 5.84 mol) was added to a mixture of 1-chloro-2,5-dimethoxybenzene (51.8 g, 300 mmol) and hexamethylenetetramine (42.0 g, 300 mmol). The solution was immediately placed in a preheated oil bath (90-95 °C) and refluxed for 12 h. The hot solution was poured onto 600 g of crushed ice and the resultant dark orange mixture rapidly stirred for 30 min, After the ice had melted, the solution was made basic with a large excess of solid NaHCO₃ until a yellow precipitate formed. Water (300 mL) was added and the mixture stirred until the paste solidified. The solid was filtered through a large Buchner funnel and washed with water (500 mL). The yellow mass was air dried and then recrystallized from high-boiling petroleum ether yielding 1b (46.1 g, 75%) as a fluorescent yellow solid mp = 106 °C; Rf = 0.45 (3:1 CHCl₃/pentane).


For aromatic chlorination:

Post 321599 (missing)

(Rhodium: "Aromatic para-chlorination with KCl/Oxone", Novel Discourse)

Additional Keywords: 4-Chloro-2,5-DMBA, TFA, HMTA, DOC, synthesis, 2C-C

[Nicodem]

Lego that is just great!

The only drawback is that damn trifluoroacetic acid. But 75% yield with a Duff formilation! That is worth trying. I wonder what yield would the usual Duff with in boric acid give. I still have a gram or two of some dirty 1-chloro-2,5-dimethoxybenzene to play with. Anybody thinks it is worth checking?

[dioulasso]

Sounds promising.

Im wondering how well would a Duff formylation work on:
2,5-Dimethoxyphenol
or possibly
2,5-Dimethoxytiophenol

The original one w/ Glyceroboric a. works for Syringaldehyde though nor with the best of yields.

http://www.orgsyn.org/orgsyn/cdxgif/CV4P0866.gif

Also for alkane-substituted phenols Duff seems to work in aq. AcOH (w/ surprisingly high yields)

Post 208298 (missing)

(Antoncho: "Duff formylation in aq. AcOH - 90% yield ", Chemistry Discourse)

Post 425391

(ylid: "Another Duff Formylation in aqueous AcOH", Novel Discourse)

How about using other stronger acids?
e.g.
Trichloroacetic acid
Methanesulfonic acid
p-Toluenesulfonic acid
Sulfamic acid
etc.

[Vitus_Verdegast]

The original Duff with glyceroboric acid generally gives yields between 10-30% if I remember correctly.. It is overall lower than what the Reimer-Tiemann gives.

Is there no-one then with access to the journal Chemistry Express ?

Post 295499 (not existing)

Chem. Express (1991), 6(1), p37-40 (CAN 114:184910) claims high yields using a mixture of AcOH and Ac₂O.
Could be interesting..