Inexpensive Radical Methylation and Related Alkylations of Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.8b00190

A simple method for the introduction of a methyl and higher aliphatic group to various heteroarenes using very inexpensive reagents is described. It is based on the radical addition of a carboxylic xanthate followed by decarboxylation. Depending on the heteroarene structure, the decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave oven.

Full text of DOI:10.1021/acs.orglett.8b00190

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Inexpensive Radical Methylation and Related Alkylations of
Heteroarenes
Qi Huang and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, Palaiseau, 91128 Cedex, France
S
* Supporting Information
ABSTRACT: A simple method for the introduction of a
methyl and higher aliphatic group to various heteroarenes
using very inexpensive reagents is described. It is based on the
radical addition of a carboxylic xanthate followed by
decarboxylation. Depending on the heteroarene structure, the
decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave
oven.
he need by pharmaceutical and agrochemical laboratories
stimulant but a weak bronchodilator and diuretic.6a In the case
Tfor rapid optimization of the biological activity profile of of desogestrel, a third-generation oral contraceptive, the extra
methyl on C-13 (i.e., an ethyl group instead of methyl)
increases the potency by 50-fold.9
promising leads through late-stage structural modification has
rekindled the interest of the community in the possibilities of
radicals.1 Older chemistries, such as the various Minisci
reactions,2 have been revived,3 and newer methods are being
developed.4 In this respect, the introduction of a methyl and
possibly other alkyl groups has acquired a special prominence
and urgency.5 Nature has elaborated over the eons highly
sophisticated machineries for methylating biological molecules
using both radical and ionic mechanisms.6 Methylation is thus
involved in many fundamental biological phenomena such as
replication, transcription, and epigenetics, and cell differ-
entiation. One fundamental example is the methylation of
uracil present in RNA leading to tymine, one of the four DNA
bases.6a Nature has evolved receptors exquisitely capable of
detecting the presence of this simplest but ubiquitous
functional group. Disruptions in the recognition of methylated
DNA, for instance, can cause debilitating diseases.7 Rett
Syndrome, a serious neurodevelopmental disorder, is caused
by a mutation in the methyl-CpG-binding protein 2 (MECP2)
gene, which modifies its ability to bind to methylcytosine
bearing DNA.8
The introduction of a methyl group into various hetero-
aromatic molecules at a late stage to better map the structure−
activity profile remains therefore an important research goal. In
addition to the recently revived Minisci-type reactions, Baran
and collaborators described a two-step route based on the
addition of sulfonylmethyl radicals to heteroarenes followed by
desulfonylation.10 We now describe an alternative approach
allowing the introduction of both acetic acid and methyl
groups. It is inexpensive and, in some cases, sufficiently efficient
and selective to be useful as a preparative tool. It can also be
extended to higher groups.
We have reported extensively on the unique properties of the
degenerate addition−exchange of xanthates.11 However, the
direct formation of reactive and unstabilized methyl radicals is
problematic. The reason is inherent to the addition−
fragmentation mechanism, where intermediate adduct radical
6 derived from S-methyl xanthate 5 does not fragment to
produce xanthate 7 and the desired but high energy methyl
radical (Scheme 1). An indirect route was therefore developed
involving xanthate 8 which, upon addition−fragmentation
initiated by dilauroyl peroxide (DLP), readily gives rise to
stabilized radical 9.12 A normal chain reaction can now be
sustained. Thus, addition of xanthate 8 to N-allylacetanilide
gives adduct 10, and further exposure to stoichiometric DLP
induces ring closure onto the aromatic ring. Finally, reductive
desulfurization of intermediate 11 with Raney nickel furnishes
indoline 12 with the requisite methyl group.
One vivid illustration of the influence of a methyl group on
the activity profile can be seen in theophylline 1, theobromine
2, and caffeine 3 (Figure 1), three molecules that are present in
coffee beans, tea leaves, and cocoa and ingested daily by a large
fraction of the human population. Theophylline is not an
excitant, but it is the strongest diuretic and bronchodilator of
the three, whereas the most lipophilic, caffeine, is a CNS
While it is possible to consider xanthate 8 as a reagent for the
introduction of a methyl group onto hetereoarenes, a much
better solution emerged in the guise of xanthate 13. This nicely
crystalline compound is made on a large scale by mixing
Received: January 18, 2018
Figure 1. Examples of biologically active methylated products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
observed such addition/decarboxylation with a few other
heteroarenes, such as pyrazine 22, quinoxaline 24, and purine
26. In the last case, the reaction furnished an inseparable 1:1.1
mixture of starting material 26 and mono- and dimethylated
products 27 and 28. The ratio of 27 and 28 was 7:1 (NMR).
The yield of methylated pyrazine 23 was modest (32%), but
only one regioisomer was observed. The reaction with 3-
chloroquinoxaline 24 furnished a low yield of product 25 in
poor yield (6%), with a large amount of returned starting
material (72%).
Scheme 1. Indirect Radical Methylation
With most of the other heteroarenes, incomplete or no
decarboxylation was observed (Scheme 4). Thus, 1-methyl-4-
Scheme 4. Formation of Heteroareneacetic Acids
bromoacetic acid and potassium O-ethyl xanthate in water and
filtering the product (Scheme 2). Indeed, a >100 g batch could
thus be completed in one afternoon. The bulk cost of goods is
practically insignificant, at less than $10 (US) per kg!
Scheme 2. Carboxymethyl Radical as a Methyl Radical
Equivalent
Xanthate 13 readily acts as the precursor of the relatively
stabilized carboxymethyl radical 14.13 Addition of the latter to a
heteroarene 15 would give adduct radical 16 which, upon
oxidation by electron transfer to the peroxide and aromatization
of the resulting cationic species 17, would afford addition
product 18.14 Finally, thermal elimination of CO2 would
produce methylated heteroarene 19 (Scheme 2).
Indeed, heating a solution of caffeine, 3, and excess xanthate
13 (3 equiv) in refluxing ethyl acetate with portionwise
addition of stoichiometric DLP resulted in the smooth
formation of methylcaffeine 21 (Scheme 3). In this example,
the decarboxylation of the initial carboxymethyl adduct 20
occurred spontaneously under the reaction conditions. We
nitroimidazole 29 gave rise to 1-methyl-4-nitro-5-imidazole-
acetic acid 30, which precipitated from the reaction mixture and
could be isolated by simple filtration in 40% yield. A small yield
(4%) of 1,5-dimethyl-4-nitroimidazole 31 was also isolated. A
higher yield (68%) of acid 30 and a product of better quality
was obtained by lowering the reaction temperature to 60 °C.
No decarboxylation occurred with imidazole 32, which gave
adduct 33, or with pyrrole 34 and indole substrates 36 and 38.
In the case of indole 2-carboxylate 36, we noted a significant
increase in the yield of adduct 37 (57%) and a cleaner reaction
when ethyl acetate was replaced with 1,2-dichloroethane
(DCE). The yield was comparable on a 10 mmol scale (∼2
g). With indole 3-carboxylate 38, the yield of product 39 was
rather poor but could be improved somewhat by operating at
60 °C. Addition without decarboxylation took place with 1,3-
dimethyluracil 40 and flavone 42 to give the corresponding
carboxylic acids 41 and 43, respectively.
Scheme 3. Radical Methylation of Various Heteroarenes
Interestingly, the regiochemistry was not the same with
benzothiazoles 44 and 46. Whereas the former gave the 7-
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Letter
substituted product, the latter reacted at the 4-position. It
appears that in the latter case the regioselectivity is dictated by
the ethoxy group on C-6, and in the former case, it is the
acetamido group on C-2 that directs the addition (radical 14 is
electrophilic in character and will add preferentially to electron-
rich positions on the heteroarene). Because of the insolubility
of benzothiazole 44, the unusual methyl benzoate had to be
used as solvent.
substituted carboxylic acid xanthates allow the introduction of
various groups that cannot be installed directly. The use of
propionic acid derived xanthate 66 thus leads to the attachment
of an ethyl group. Some examples are collected in Scheme 6. In
Scheme 6. Introduction of an Ethyl Group
Imidazopyridine 49, imidazopyrimidine 51, and imidazopyr-
idazine 53 behaved similarly and furnished carboxylic acids 50,
52, and 54. Imidazopyridine 49 proved to be the best substrate
in the whole series, giving product 50 in 90% yield after direct
filtration from the reaction mixture. The introduction of the
acetic acid group increases the crystallinity and decreases the
solubility of the product. In the favorable cases where the
product actually precipitates during the reaction, it (the
product) finds itself shielded from further attack by any radical
species in the medium. Moreover, this simplifies the
purification immensely and allows for practical large-scale
syntheses. Indeed, compounds 37, 50, and 56 were readily
prepared on a gram scale.
The decarboxylation proved more problematic than ex-
pected. Thermolysis of carboxylic acid 50, neat or in an inert
high boiling solvent such as tert-butylbenzene, gave rather
modest yields (ca. 30−35%) of the methyl imidazopyridine 57.
Similar results were obtained upon heating in DMF at 170−190
°C in a sealed tube in the presence of potassium fluoride,
according to the recent method of Amii.15 A much better yield
(88%) was obtained by heating in a microwave oven in N,N-
dimethylacetamide (DMA), a thermally more stable solvent
(Scheme 5). Methylheteroarenes 31 and 58−60 were cleanly
prepared using similar conditions.
the first four examples, decarboxylation occurred spontaneously
under the reaction conditions (in the case of compound 72, 1.2
equiv of trifluoroacetic acid was added). For the others, heating
in DMA or NMP in a microwave oven proved necessary. The
ability to introduce directly a propionic acid motif is not devoid
of interest, since arylpropionic acids constitute an important
class of nonsteroidal anti-inflammatory substances in clinical
use.16 Some members have also found application as
herbicides.17
Scheme 5. Decarboxylation of Heteroareneacetic Acids
Another interesting extension is the introduction of the
valuable fluoromethyl group, accomplished by starting with
fluoroacetic acid xanthate 89. Attempts to access this reagent by
substitution of bromofluoroacetic acid 87 failed; however, ester
88 is accessible18 and could be selectively cleaved with acid to
give reagent 89 (Scheme 7). Reaction with caffeine 3 indeed
gave fluoromethylcaffeine 90, albeit in significantly lower yield
(29%) than for the corresponding methylation. This is probably
due, at least in part, to a polarity mismatch, but more work is
needed to clarify the various factors involved.
Scheme 7. Introduction of Other Alkyl Chains
The decarboxylation of carboxylic acids 37 and 56 required
even higher temperatures, which led to the unwanted
concomitant formation of carboxamides 62 and 64, obviously
derived from reaction with DMA. We therefore switched to the
even more robust N-methylpyrrolidone (NMP). In this
manner, compounds 61 and 63, as well as pyrrole carboxylate
65, were produced in good yield without complication from
amide formation. This represents a practical and apparently
general method for decarboxylating heteroarylacetic acids.
The present approach for the introduction of a methyl group
into heteroarenes is of much greater generality. More
C
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xanthate-substituted carboxylic acids. A more direct route is by
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compound 92 from chloropyridylmethyl xanthate 91.19 The
yield is modest because of the tendency of acrylic acid to
polymerize. Nevertheless, the reaction with pyrazine 22
proceeded nicely with spontaneous decarboxylation to furnish
addition product 93 in 52% yield.
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biologically active substances in order to rapidly optimize
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this method has significant preparative value in many instances.
We have also uncovered some limitations. A number of
heteroarenes could not be functionalized in this manner,
including the particularly important pyridines.20 Further work
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ASSOCIATED CONTENT
■
S
* Supporting Information
(11) For reviews, see: (a) Quiclet-Sire, B.; Zard, S. Z. Pure Appl.
Chem. 2011, 83, 519. (b) Quiclet-Sire, B.; Zard, S. Z. Isr. J. Chem.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00190.
Experimental procedures, full spectroscopic data, and 1H
and 13C NMR for all new compounds (PDF)
(14) For earlier addition of xanthates to heteroarenes, see:
(a) Coppa, F.; Fontaria, F.; Minisci, F.; Pianese, G.; Tortoreto, P.;
Zhao, L. Tetrahedron Lett. 1992, 33, 687. (b) Osornio, Y. M.; Cruz-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samir.zard@polytechnique.edu.
ORCID
Almanza, R.; Jimen
2003, 18, 2316. (c) Reyes-Gutier
Martínez, R.; Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388.
(d) Florez-Lopez, E.; Gomez-Perez, L. B.; Miranda, L. D. Tetrahedron
Lett. 2010, 51, 6000. (e) Guerrero, M. A.; Miranda, L. D. Tetrahedron
Lett. 2006, 47, 2517. (f) Chay, C. I.; Cansino, R. G.; Pinzon, C. I.;
́
ez-Montano, V.; Miranda, L. D. Chem. Commun.
̃
́
rez, P. E.; Torres-Ochoa, R. O.;
́
́
́
Samir Z. Zard: 0000-0002-5456-910X
Notes
́
Torres-Ochoa, R. O.; Martínez, R. Mar. Drugs 2014, 12, 1757.
(g) Wang, S.; Huang, X.; Ge, Z.; Wang, X.; Li, R. RSC Adv. 2016, 6,
The authors declare no competing financial interest.
́ ́
63532. (h) Perez, V. M.; Fregoso-Lopez, D.; Miranda, L. D.
ACKNOWLEDGMENTS
We thank Ecole Polytechnique for a scholarship to Q.H. and
Tetrahedron Lett. 2017, 58, 1326. (i) Braun, M.-G.; Castanedo, G.;
Qin, L.; Salvo, P.; Zard, S. Z. Org. Lett. 2017, 19, 4090.
(15) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560.
■
Dr. Bea
of xanthate 89.
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trice Sire (Ecole Polytechnique) for a first preparation
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(17) Wenger, J.; Niderman, T.; Mathews, C. Herbicides. In Modern
DEDICATION
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Crop Protection Compounds; Kramer, W., Schirmer, U., Jeschke, P.,
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Witschel, M., Eds.; Wiley-VCH: Weinheim, 2012; Vol. 1, pp 447−478.
(18) Jean-Baptiste, L.; Yemets, S.; Legay, R.; Lequeux, T. J. Org.
Chem. 2006, 71, 2352.
This paper is dedicated with respect to the memory of
Professor Francesco Minisci (Politecnico di Milano).
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(20) See the SI for a list of heteroarenes that reacted poorly or not at
all. In addition to unreacted starting material, unidentified side
products, and products from direct reaction with radicals from the
peroxide were observed.
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DOI: 10.1021/acs.orglett.8b00190
Org. Lett. XXXX, XXX, XXX−XXX