Preparation of pyrazine carboxamides: A reaction involving N-heterocyclic carbene (NHC) intermediates

Article abstract of DOI:10.1021/ol402200x

In the reactions of 2,3-pyrazinedicarboxylic anhydride with amines and anilines, pyrazine carboxamides are formed in good to excellent yields. A mechanism is proposed involving ring opening of the anhydride and decarboxylation of the heterocyclic ring. Based on other similar heterocyclic decarboxylations, this suggests the involvement of an N-heterocyclic carbene intermediate leading to the product.

Full text of DOI:10.1021/ol402200x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Preparation of Pyrazine Carboxamides:
A Reaction Involving N‑Heterocyclic
Carbene (NHC) Intermediates
Rajasekhar Reddy Naredla, Barada P. Dash, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb,
Illinois 60115, United States
dkllumpp@niu.edu
Received August 2, 2013
ABSTRACT
In the reactions of 2,3-pyrazinedicarboxylic anhydride with amines and anilines, pyrazine carboxamides are formed in good to excellent yields. A
mechanism is proposed involving ring opening of the anhydride and decarboxylation of the heterocyclic ring. Based on other similar heterocyclic
decarboxylations, this suggests the involvement of an N-heterocyclic carbene intermediate leading to the product.
Since Breslow proposed the involvement of a stable
N-heterocyclic carbene (NHC) in biosynthetic reactions,1
this area of chemistry has seen extensive growth. This
pioneering work was soon followed by Wanzlick’s pre-
paration of an imidazole-2-ylidene carbene,2 Arduengo’s
isolation of a stable NHC,3 and the development of numer-
ous NHC scaffolds.4 The NHCs have been the subject of
many recent studies, research largely driven by the use of
NHCs as organocatalysts and ligands in metal complexes.4
Other than the organocatalytic conversions with NHCs
however, there are very few examples of synthetic chemical
reactions that occur through NHCs as one of the primary
reactive intermediates. In the following Letter, we describe
an efficient route to pyrazine carboxamides and a mechan-
ism is proposed which involves an NHC as a key reactive
intermediate.
Among the known routes to NHC structures, one is the
decarboxylation of pyridinium carboxylates and related
heterocyclic betaine species.5 For example, it has been
shown that N-methylpyridinum 2-carboxylate 1 (homarine,
a marine natural product found in the tissues of shellfish
and invertebrates) undergoes thermal decarboxylation to
give the corresponding NHC 2 (eq 1).5a Subsequent trap-
ping reactions by electrophiles or
transition metals provide respective routes to pyridinum
salts and NHCÀmetal complexes.5b,6,7 In a similar
(1) Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762–1763.
(2) Wanzlick, H.-W.; Schikora, E. Chem. Ber. 1960, 72, 494.
(3) Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361–363.
(4) (a) Fevre, M.; Pinaud, J.; Gnanou, Y.; Vignolle, J.; Taton, D.
Chem. Soc. Rev. 2013, 42, 2142–2172. (b) Crabtree, R. H. Coord. Chem.
Rev. 2013, 257, 755–766. (c) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686–11698. (d)
Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522.
(5) (a) Haake, P.; Mantecon, J. J. Am. Chem. Soc. 1964, 86, 5230–
5234. (b) Katritsky, A. R.; Awartani, R.; Patel, R. C. J. Org. Chem. 1982,
47, 498–502. (c) Lavorato, D.; Terlouw, J. K.; Dargel, T. K.; Koch, W.;
McGibbon, G. A.; Schwarz, H. J. Am. Chem. Soc. 1996, 118, 11898–
€
11904. (d) Schmidt, A.; Snovydovych, B.; Habeck, T.; Drottboom, P.;
Gjikaj, M.; Adam, A. Eur. J. Org. Chem. 2007, 4909–4916.
(6) Katritzky, A. R.; Faid-Allah, H. M. Synthesis 1983, 149–151.
(7) Rosello-Merino, M.; Diez, J.; Conejero, S. Chem. Commun. 2010,
46, 9247–9249.
r
10.1021/ol402200x
XXXX American Chemical Society

process, Harrington described the synthesis of nicotina-
mides from 2,3-pyridinedicarboxylic anhydride 3 (eq 2).8
The conversions involve heating anhydride 3 with ani-
lines in
Table 1. Products and Yields from the Reactions of Anilines and
Amines with 2,3-Pyrazinedicarboxylic Anhydride (8)a
acetic acid. Nicotinamides (i.e., 4) and pyridine-2,3-
dicarboximides (i.e., 5) are formed as products. Product
4 is clearly the result of a decarboxylation reaction, sug-
gesting the cleavage of 6 to the NHC intermediate 7 (eq 3).
Protonation at the ring carbon then leads to the nicotina-
mide 4. As a synthetic route to nicotinamides, Harrington’s
study was limited to only anilines.
Given the value of heterocyclic amides and the impor-
tance of NHC species, we have sought to extend this decar-
boxylation chemistry to reactions involving 2,3-pyrazine-
dicarboxylic anhydride (8). Pyrazinecarboxylic acids are
known to undergo thermal decarboxylations,9 suggesting
the possibility of forming pyrazine carboxamides by reac-
tions with the anhydride with amines and anilines. As a
class of compounds showing varied biological activities,10
pyrazine carboxamides are desirable synthetic targets.
Our studies began with the reaction of aniline with 2,3-
pyrazinedicarboxylic anhydride (8, eq 4). An optimized
procedure involved the
a Reaction conditions: 1.0 mmol of anhydride 8, 1.0 mmol of the
amine, 15 mL of toluene refluxed for 12 h. b Isolated yield of pure
product. c Amide product accompanied by pyrazine-2,3-dicarboximide
byproduct (see Supporting Information).
reaction in refluxing toluene (or xylene) and the expected
pyrazine carboxamide (9) is formed in excellentyield. Other
anilines were converted to the respective pyrazine carbox-
amides (Table 1). Pyrazine carboxamides 10À15 were
formed in good to excellent yields by reactions with anhy-
dride 8 and the respective anilines. With primary aliphatic
amines, the product amides (16À21) were isolated in low to
excellent yield. In some cases, significant quantities of the
pyrazine-2,3-dicarboximides were also isolated from the
product mixtures (see Supporting Information). Several
amino acids are also shown to give the pyrazine carbox-
amides. Thus, valine, proline, methionine, and leucine
derivatives give the respective heterocyclic amides
(22À25) in fair to excellent yields (Figure 1). The highest
yields have been obtained with valine and leucine deriva-
tives, suggesting a possible link between reaction yield and
the relative size or bulk of the amino acid nucleophile.
The conversion of anhydride 8 to the pyrazine carbox-
amides occurs in a reaction accompanied by decarboxyla-
tion. By analogy to the decarboxylation of homarine and
related systems, carboxamide formation likely involves a
pyrazine-based carbene (Scheme 1). Thus, a mechanism is
proposed in which the amine reacts with the anhydride (8)
to initially give the zwitterionic species 26. Ring opening of
(8) Harrington, P. M. Heterocycles 1993, 35, 683–687.
(9) (a) Heinisch, G.; Loetsch, G. Synthesis 1988, 119–121. (b) Rao,
A. V. R.; Yadav, J. S.; Ravichandran, K.; Sahasrabudhe, A. B.;
Chaurassia, S. S. Ind. J. Chem., Sec. B: Org. Chem. Incl. Med. Chem.
1984, 23B, 850.
(10) (a) Berg, S.; Bergh, M.; Hellberg, S.; Hoegdin, K.; Lo-Alfredsson,
Y.; Soederman, P.; von Berg, S.; Weigelt, T.; Ormoe, M.; Xue, Y.; Tucker,
J.; Neelissen, J.; Jerning, E.; Nilsson, Y.; Bhat, R. J. Med. Chem. 2012, 55,
9107–9119. (b) Scanio, M. J. C.; Shi, L.; Drizin, I.; Gregg, R. J.; Atkinson,
R. N.; Thomas, J. B.; Johnson, M. S.; Chapman, M. L.; Liu, D.; Krambis,
M. J.; Liu, Y.;Shieh, C.-C.; Zhang, X. F.; Simler, G. H.;Joshi, S.;Honore,
P.;Marsh, K. C.;Knox, A.;Werness, S.; Antonio, B.;Krafte, D. S.;Jarvis,
M. F.; Faltynek, C. R.; Marron, B. E.; Kort, M. E. Bioorg. Med. Chem.
2010, 18, 7816–7825. (c) Chiurato, M.; Boulahjar, R.; Routier, S.; Troin,
Y.; Guillaumet, G. Tetrahedron 2010, 66, 4647–4653.
B
Org. Lett., Vol. XX, No. XX, XXXX

by considering the principle of least motion,12 there are
several factors that argue against it. First, decarboxylation
of 30 would need to occur faster than proton transfer
leading to the carboxylic acid intermediate (27). This
seems unlikely considering the very high acidity of the
NÀH protons on the protonated amide. Second, rapid
decarboxylation of 30 would also preclude formation
of the pyrazine-2,3-dicarboximide byproducts (eq 5).
Although the carboxylic acid intermediate 27 was not
isolated from our product mixtures, similar products
have been isolated as major products in the reactions of
2,3-pyridinedicarboxylic anhydride (3).8
Figure 1. Products and yields for the reactions of 2,3-pyrazine-
dicarboxylic anhydride (8) with amino acids.
Scheme 1. Proposed and Alternative Mechanisms
In order to test our mechanistic proposal, we conducted
NMR experiments with 2,3-pyrazinedicarboxylic anhy-
dride (8) and 1-adamantylamine. The reaction between
these two compounds was shown to be an exceptionally
efficient route to the amide (16, Table 1). The amine and
anhydride (8) were dissolved in d8-toluene, and the solu-
tion was heated to 90 °C. Acquisition of 13C spectra was
doneat regular intervals, and the results are consistent with
the proposed mechanism (Figure 2). Thus, anhydride 8 has
three 13C resonances (spectrum A): δ, 157.5 (CdO), 149.6
(CH), and 145.3 (C). Upon heating the mixture (spectrum
B), two prominent new carbonyl resonances appear at δ,
163.8 and 162.6. A smaller carbonyl resonance also begins
to appear at about δ, 161.3. We believe that these peaks
arise from the formation of primarily the carboxylic acid
27 and a small amount of the final amide product 16. Thus,
intermediate 27 shows peaks in the aromatic region at δ,
147.4 (C), 145.4 (CH), 143.3 (C), 142.2 (CH). The remain-
ing peaks in the aromatic region can be assigned to the final
amide product (16), based on comparison with the 13C
NMR spectrum of the purified amide 16 (spectrum F). It
could also be argued that the two carbonyl resonances at δ,
163.8 and 162.6, might arise from the zwitterionic inter-
mediate 30. However, this seems unlikely given that the
carboxylate anion 13C resonance generally occurs down-
field from analogous carboxylic acid signals. While acetic
acid exhibits a carbonyl resonance at δ, 178.1 (D2O), a
tetramethylammonium acetate resonance is found at δ,
182.6 (D2O).13 In the case of pyrazines, pyrazinecarboxylic
the tetrahedral intermediate provides the pyrazine car-
boxylic acid 27. In some case, the intermediate pyrazine
carboxylic acids undergo dehydration to give pyrazine-2,3-
dicarboximides (vide supra). Subsequent formation of the
zwitterion 28 then leads to the decarboxylation step. The
resulting pyrazine-based carbene (29) gives the carboxa-
mide product by a final proton transfer or migration.
Several attemptsweremade totraptheNHC intermediates
(i.e., 29) in organometallic complexes, but these efforts
were unsuccessful.11
acid and the zwitterionic amino acid exhibit respective 13
C
resonances at δ, 165.1 and 167.8 (DMSO).14 These data
suggest intermediate 30, if formed,
An alternative mechanism can be imagined in which
decarboxylation of zwitterion 30 directly provides the
carbanion 31 and proton transfer then gives the observed
pyrazine carboxamide. While this mechanism is appealing
(11) Under varied conditions, the reactions were done in the presence
of [Cu(MeCN)4]BF4 and [IrClCOD]2 in an effort to trap the NHC
intermediate.
(12) Hine, J. Adv. Phys. Org. Chem. 1978, 15, 1–61.
(13) Hagen, R.; Roberts, J. D. J. Am. Chem. Soc. 1969, 91, 4504–
4506.
would exhibit a 13C resonance further downfield than the
(14) The Aldrich/ACD Library of FT NMR Spectra; Sigma-Aldrich.
observed δ, 163.8 and 162.6.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 2. 13C NMR spectra (d8-toluene) of 2,3-pyrazinedicarboxylic anhydride (spectrum A), purified amide 16 (spectrum F), and
reaction mixtures of 2,3-pyrazinedicarboxylic anhydride with 1-adamantylamine. Reactions were done at 90 °C, and analyses were
taken at 105 min (spectrum B), 180 min (spectrum C), 360 min (spectrum D), and 540 min (spectrum E). 2,3-Pyrazinedicarboxylic
anhydride (v); proposed intermediates: carboxylic acid 27 (*) and NHC 29 or unknown intermediate (Δ); amide 16 is unmarked.
With more time, the signals assigned to compound 27
dissipate and an increasing amount of the final product 16
is seen (spectra D and E). Interestingly, a new set of peaks
arise from a low concentration intermediate. This species is
found to have a single carbonyl resonance at δ, 162.1 and
four other peaks in the aromatic region of the spectrum.
These signals are consistent with the proposed NHC struc-
ture 29, although the presence of an unknown intermediate
cannot be rigorously excluded. As expected, the peaks as-
signed to 29 also dissipate and the final product 16 is the
main component of the mixture (spectrum E).
In summary, we have found that the pyrazine carbox-
amides may be prepared in fair to excellent yields by the
reactions of anilines and amines with 2,3-pyrazinedicar-
boxylic anhydride. The conversions involve a novel dec-
arboxylation step, and a mechanism is proposed which
invokes the formation of an N-heterocyclic carbene inter-
mediate. This chemistry represents a rare example of an
NHC as a primary reactive intermediate in a synthetic
conversion.
Acknowledgment. This material is based on work sup-
ported by the National Science Foundation under CHE-
1300878. We also thank Northern Illinois University for a
Great Journeys Fellowship (R.R.N.).
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H and 13C NMR spec-
tra of new compounds. Full NMR spectra from Figure 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
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