Since everyone is just *begging* me to type up this paper on the revolutionary OTC methylating agent dimethyl oxalate [sarcasm sarcasm], here it is:
Alkylation with Oxalic Esters. Scope and Mechanism.
Abstract: Alkyl oxalates are well suited for use as standard synthetic reagents in N-, O-, or S- alkylations and often display an interesting regioselectivity. The mechanism seems to be a direct alkylation of the substrate anion.
Introduction:
The alkylating properties of oxalic esters have been known at least since 1960, when Sakakibara alkylated phenols at high temperatures. (1,2) A few more cases can be found in the literature (3-6), but no systematic studies have been made to explore the use of oxalates as standard synthetic reagents. This can be attributed partly to the reaction temperature and the basic conditions which make them unsuitable for sensitive substrates, and also because it does not appear to present much of a mechanistic challenge, i.e. it seems to be a textbook example of an SN2 reaction. In a semi-empirical quantum chemical study we have used this as a probe for criticism of the Frontier Molecular Orbital (FMO) theory and obtained support for the expected SN2 mechanism. (7)
Qing-Hua et al (5) observed that dimethyl oxalate is considerably less toxic than traditional methylating agents. It should therefore be very well suited to large-scale methylations. This fact, together with promising results from our initial study(
, led us to investigate the scope and mechanism for the reaction more closely.
Results and discussion:
The results of the alkylations using dimethyl, diethyl, di-sec-butyl and dibenzyl oxalate are summarized in table 1. When the substrate has more than one nucleophilic center, the position of alkylation is indicated.
Alkylation of o-mercaptoaniline yields the S-alkylated product, as expected. Methylation of 4-nitro imidazole gives an easily purified isomeric mixture, where the 1-alkyl-4-nitro isomer dominates in a ratio of 4:1, as determined by H1 NMR. As comparison, it has been shown that dimethyl sulfate reacts with 4-nitro imidazole in acidic media to give mainly the 1-alkyl-5-nitro isomer in an isomeric ratio of 350:1 (9a) In basic solutions the reaction yields mainly the 1-alkyl-4-nitro product (ratio 3:1)(9b).
Indoles are strongly nucleophilic at the 3 position, and many alkylating agents will alkylate indoles at that site. Oxalic esters selectively monoalkylate various indoles at the 1-nitrogen. Purines were monomethylated at the 9-position.
Methylation of benzotriazole yielded a mixture of 1- and 2-methyl benzotriazole (ratio 2:1) This is to be expected from alkylation of benzotriazole under alkaline conditions, although other alkylation methods may give widely differing ratios (10).
Anthranilonitrile, a primary amine, has been monomethylated in good yield (11). The mechanism in this case seems to involve the alkylation of an intermediate oxalimide, and the subsequent cleavage to the monoalkylated amine (scheme 1). The intermediates have been independently prepared and subjected to the reaction conditions, in all cases yielding the expected N-methylanthranilonitrile. (11)
Scheme 1:
Ph(CN)(NH2) + DiMeOxalate & KO-tBu --> [ Ph(CN)(NH-COOCOMe) --> Ph(CN)(N(Me)-COOCOMe) ] --> Ph(CN)(NH-Me)
*** Note--can we see the conversion of, say, MDA to MDMA? huh?
Lespagnol(3) has shown that phenothiazine is alkylated by oxalate in neutral and acidic media, but the substrates in our study gave only low yields of acylated products in the absence of a base strong enough to deprotonate the substrate.
It can be argued that all alkylations proceed via acylated intermediates as shown in scheme 2.
Scheme 2:
Nu- + R.OCOOCO.R --> (Nu)(R.O)(O-)COCO.R --> NuR + R.OCOOCO-
In order to test this, two acylated indoles, namely methyl 1-oxo-1-(N-indolyl)-acetate (I) and ethyl 1-oxo-1-(N-indolyl)-acetate (II) were prepared by dehydrogenation of the corresponding indolines. (12)
if I or II were intermediates in the alkylation reaction, then reflux with potassium t-butoxide and oxalate in DMF should yield the alkylated indoles. Since indole is methylated in 10 minutes under these reaction times, the acylated indoles ought to react in even less time. The reaction was monitored by TLC for a few hours in both cases. It was noted that if the amount of t-butoxide exceeded the amount of oxalate in the mixture, or if undisolved t-butoxide was present, the reaction yielded alkylated indoles, but if a slight excess of oxalate was present, no alkylation product was formed. Adition of dissolved indole to this unreactive mixture yielded N-alkyl indole almost immediately. Thus we infer that indoles are alkylated under conditions that will not affect the acylated substrates, which consequently are not intermediates in the alkylation reaction. The fact that excess t-butoxide could break down I and II to N-alkyl indoles is attributed to liberation of free indole anion by the base. The inhibition of this liberation by excess oxalate can be explained if t-butoxide and oxalate form a much less nucleophilic complex in solution. Such complexes have been isolated by Adickes(13) To further demonstrate this liberation of indole anion, ethyl 1-oxo-1 (N-indolyl)-acetate II was mixed with a 3-fold excess of DiMeOxalate and 4-fold excess of KOt-Bu in DMF. This mixture was refluxed overnight and then analyzed by GC. Less than 1% of the alkylated indole was N-ethyl indole. As expected, N-methylindole dominated (>99%).
As a final study of the mechanism, di-sec-butyl oxalate and sec-butyl tosylate were prepared from the same optically active (S)-sec-butanol. Both compounds were used to alkylate p-thiocresol using similar conditions. The products were essentially identical, although not enantiomerically pure. Since tosylates are expected to alkylate mainly with inversion, the oxalates obviously alkylate in the same way.
It is notable that the substrate anions can be expected to undergo reversible addition to the acyl carbon of the oxalate in the presence of alkoxides. The alkylations may be dependent on this reversibility to minimize byproducts.
Table 1:
Literature yields are only from alkylation reactions. In several cases there are better non-alkylative methods available for synthesizing these compounds.
Substrate Oxalate Base Where Yield Lit.Yield Ref
Phenol Me Na2CO3 O 79% -
Phenol Et Na2CO3 O 67% -
Phenol Sec-bu K2CO3 O 25% 6 (14)
p-thiocresol Me t-buOK S 76% 81 (15)
" Et Na2CO3 S 66% 91 "
" sec-bu Na2CO3 S 67 48 (16)
o-mercapto Me K2CO3 S 64 54 (17)
aniline
4-Nitroimidazole Me t-BuOK 1 59 - (9b)
Anthanilonitrile Me " N 85 53 (11)
2-Aminobenzophenone " " N 60 70 (24)
Indole Me " N 88 95 (18a)
Indole Bn(?)" N 86 95 "
4-Nitroindole Me EtOK N 91
" Et EtOK N 94
" sec-Bu K2CO3 N 5 . .
7-Et-3-Me-6
Nitroindole Me EtOK N 98
Isatin Me K2CO3 N 61 80 (19a)
5-nitrobenz
imidazole Me t-buOK 1/3 43/40 71/42 (20)
Benzotriazole Me t-buOK 1/2 59/35 69/38 (10a,23)
Purine Me " 9 37 30 (23)
Adenine Me " 9 43 95 (21a)
Carbazole Me " N 95 78 (22)
" Et " N 97 85 "
" Bn(?)" N 86 97 "
Experimental (***Snipped, way too long***)
Anisole:
Phenol (0.94g 10mmol) was boiled with sodium carbonate (4g) in DMF (30mL) for 10 min. after cooling, dimethyl oxalate (2.36g 20mmol) was added, and the mixture was refluxed for 30 min. (ning's note--DMF boils @ 153 deg.) The solution was then poured into aqueous ammonia and extracted with ether. The ether solution was washed with water, dried (MgSO4) and evaporated. Yield 0.85g (79%) Bp 150-1 deg.
Ethyl phenyl ether:
Phenol (0.94g 10mmol), diethyl oxalate (2.92g, 20mmol) and potassium carbonate (4g) were refluxed in DMF(30mL) for 1h. The reaction mixture was poured into aqueous ammonia and extracted with ether. The extract was washed with brine, dried (MgSO4) and evaporated. The product (0.82g 67%) distilled at 62deg/ 8mm Hg.
sec-butyl phenyl ether:
phenol (4.7g 50mmol), sec-butyl oxalate (14.14g 70mmol), potassium carbonate (13g) and pyridine (1mL) were refluxed in DMF (30mL) under N2 for 17h. water (30ml) was added and the solution refluxed for 30 min, the solution was then extracted with light petroleum. The extract was washed with aqueous NaOH and then evaporated. The residue was distilled at 10mm Hg, bp 76-7deg. yield 1.87g (25%)
....blah blah blah
there's more if you want it, but I think this is the most important bit.
Have fun...
Now here is the question....can this methylate hydroquinones, or will it oxidise them instead? I guess wait and see...
Ning especially likes how efficient the ethylation is.
All you lucky guys with dimethylsulfate, great.
But I bet diethylsulfate is a little harder to come by...
Or t-butylsulfate, etc. etc. etc.
By the way, they used just about stoichiometric amounts of oxalate for all the alkylations. If one were to use two times the ethyl-oxalate, could they di-ethylate an amine?
"If you can ester it, you can do it!" seems to be the motto for this type of reagent.
For all who didn't know, oxalic acid can be had from certain types of sink and counter cleaners. It's solubility in water varies by > 100x from 0 to 100 degrees, making it a sucker for large scale recrystalization. Just pour your BKF/zud into a boiling pot calculated for (weight of can)'s worth of acid when boiling hot, let all disolve, decant off hot water into beaker leaving sand and crap behind, put in fridge/freezer, filter out crystals and wash.
The soap should stay in the water, the sand will stay in the pot.
Just ning's 20 won...