Alkylation of 3,5-dichloro-2(1H)-pyrazinones using malonate esters

Article abstract of DOI:10.1016/j.tetlet.2012.06.080

An efficient base-promoted 3-alkylation of 3,5-dichloro-2(1H)-pyrazinones with various malonate esters is described. The method constitutes a simple example of a C-C bond forming process at the 3-position of the pyrazinone core allowing to attain 3-substituted pyrazinones in good to high yields. 3-Alkylation of 3,5-dichloro-2(1H)-pyrazinones with acetoacetic ester was accompanied by further retro-Claisen fragmentation.

Full text of DOI:10.1016/j.tetlet.2012.06.080

Tetrahedron Letters 53 (2012) 4676–4678
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Alkylation of 3,5-dichloro-2(1H)-pyrazinones using malonate esters
⇑
Nigam M. Mishra, Vsevolod A. Peshkov, Olga P. Pereshivko, Sachin G. Modha, Erik V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient base-promoted 3-alkylation of 3,5-dichloro-2(1H)-pyrazinones with various malonate esters
is described. The method constitutes a simple example of a C–C bond forming process at the 3-position of
the pyrazinone core allowing to attain 3-substituted pyrazinones in good to high yields. 3-Alkylation of
3,5-dichloro-2(1H)-pyrazinones with acetoacetic ester was accompanied by further retro-Claisen
fragmentation.
Received 20 May 2012
Accepted 15 June 2012
Available online 26 June 2012
Keywords:
Heterocycles
Ó 2012 Elsevier Ltd. All rights reserved.
3,5-Dichloro-2(1H)-pyrazinones
Malonate ester
Acetoacetic ester
Since the first efficient synthesis1 in 1983 by the Hoornaert
group, 3,5-dichloro-2(1H)-pyrazinones (1) have proven to be highly
versatile scaffolds.2 The extensive synthetic elaboration of 1 pro-
vided an easy access to a wide range of important heterocycles such
as asymmetrically substituted pyrazines,3 furo[2,3-b]pyrazines,4
fused pyridones, and pyridines.5 Furthermore, dichloropyrazinones
1 have found broad application in drug6 and peptidomimetic7 de-
sign. It is well established that there is a considerable difference
in reactivity of the two chlorine atoms at the 3- and 5-position of
the pyrazinone core (Fig. 1). Thus, in general, functionalization of
1 starts with the most active 3-chlorine atom, being part of an
imidoyl chloride system.8
Most of to date reported methodologies for C–C bond formation
at the 3-position require the use of Pd-catalyst and harsh reaction
conditions,9 making the elaboration of novel mild procedures of
interest. De Borggraeve and co-workers reported an efficient
one-pot, two-step process for the synthesis of 2(1H)-pyrazinone
3-carboxamides applying a strong base-promoted reaction of 1
with 2-(4,5-dichloro-1H-imidazol-1-yl)acetonitrile (nucleophilic
substitution of the 3-chlorine) as the key step.10 We have recently
described an N-heterocyclic carbene-catalyzed 3-aroylation of
3,5-dichloro-2(1H)-pyrazinones with various aromatic aldehydes
which occurs through the nucleophilic attack of a Breslow interme-
diate on the imidoylchloride system.11 In continuation of this
research we envisaged that the 3-chlorine could easily undergo
nucleophilic substitution by enolates generated from active methy-
lene compounds. Herein, we wish to present a simple and efficient
base-promoted 3-alkylation of 3,5-dichloro-2(1H)-pyrazinones (1)
with various malonate esters. It should be noted that reactions of
R1
N
R6
O
1
Cl
inactive
N
Cl
active
Figure 1. 3,5-Dichloro-2(1H)-pyrazinones.
heterocycles comprising an imidoyl chloride system with acetoace-
tic or malonate esters are well known.12 However there is only a
limited number of focused studies on the scope of this process.13
At the start of this study we found that 3,5-dichloro-2(1H)-pyr-
azinone 1a could be efficiently coupled with diethyl malonate ester
(2a) in the presence of 2 equiv of a mild inorganic base such as
K3PO4. Carrying out the reaction at 80 °C in dry THF for 5 h, we
were able to isolate alkylated pyrazinone 3a in a good yield of
79% (Table 1, entry 1).14 Next we extended the scope of this proto-
col to the use of various 3,5-dichloro-2(1H)-pyrazinones 1b–i in
combination with 2a. In all cases good yields of the corresponding
3-substituted pyrazinones 3b–i were obtained ranging from 72 to
88% (Table 1, entries 2–9). In addition 1a and 1c were successfully
coupled with dimethyl malonate ester (2b) delivering 3-substi-
tuted pyrazinones 3j and 3k in 81% and 95% yields, respectively
(Table 1, entries 10 and 11). However, when ethyl 2-(diethoxy-
phosphoryl)acetate (2c) was used as active methylene component
in the reaction with 1a, the efficiency of the process significantly
dropped (Table 1, entry 12). Complete consumption of 1a was
achieved only after 3 days. On the other hand a significant part
of 2c remained unreacted, hampering the isolation of pure alkyl-
ated pyrazinone 3l via column chromatography. Reaction of 1a
with ethyl 2-cyanoacetate (2d) provided 3-substituted pyrazinone
⇑
Corresponding author. Tel.: +32 16 32 74 06; fax: +32 16 32 79 90.
E-mail address: erik.vandereycken@chem.kuleuven.be (E.V. Van der Eycken).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.080

N. M. Mishra et al. / Tetrahedron Letters 53 (2012) 4676–4678
4677
Table 1
Alkylation of 3,5-dichloro-2(1H)-pyrazinonesa
R1
N
R1
N
R6
Cl
O
R6
Cl
O
Z'
K3PO4, THF
80 °C, 5-12 h
+
Z'
Z''
N
N
Cl
3
1
2
Z''
Entry
Dichloropyrazinone 1
Malonate ester 2
Product 3
Yieldb (%)
1
2
3
4
R1 = Ph, R6 = Me (1a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOEt (2a)
Z0 = Z00 = COOMe (2b)
Z0 = Z00 = COOMe (2b)
3a
3b
3c
3d
3e
3f
3g
3h
3i
79
74
87
88
76
74
72
73
77
81
95
21e
80
R1 = PMB, R6 = H (1b)
R1 = PMP, R6 = H (1c)
R1 = Bn, R6 = H (1d)
5
R1 = Me, R6 = Ph (1e)
R1 = Me, R6 = Me (1f)
R1 = PMP, R6 = PMP (1g)
R1 = PMB, R6 = PMP (1h)
6c
7
8
9
10
11
12d
13
R1 = 2-MeOC6H4, R6 = Ph (1i)
R1 = Ph, R6 = Me (1a)
R1 = PMP, R6 = H (1c)
R1 = Ph, R6 = Me (1a)
R1 = Ph, R6 = Me (1a)
3j
3k
3l
Z0 = COOEt, Z00 = PO(OEt)2 (2c)
Z0 = COOEt, Z00 = CN (2d)
3m
PMB = p-methoxybenzyl, PMP = p-methoxyphenyl.
a
The reactions were carried out on a 0.4 mmol scale in dry THF (4 mL) with 1.1 equiv of 2 relative to 1, in the presence of 2 equiv of K3PO4 for 5–12 h. Completion of the
reaction was determined by TLC.
b
Isolated yields.
The reaction was continued for 1 day.
c
d
The reaction was continued for 3 days.
e
Determined by 1H NMR (from the mixture with 2c). An analytical sample was prepared by preparative HPLC.
R1
N
R1
N
R1
N
O
R6
Cl
O
R6
Cl
O
R6
Cl
O
6a; R1=Ph, R6=Me; 66%
6b; R1=PMB, R6=H; 58%
K3PO4, THF
80 °C, 6h
treatment
with silica
O
+
+
COOEt
N
N
N
1a,b
Cl
COOEt
COOEt
4
5a,b
6a,b
Scheme 1. Synthesis of 3-substituted pyrazinones 6a,b via alkylation/retro-Claisen sequence.
3m in a good yield of 80% (Table 1, entry 13). Interestingly, for
compound 3m, in contrast to other products, a high tautomeriza-
tion rate was observed.15
a doctoral scholarship. V.A.P. is grateful to the EMECW (Triple I) for
obtaining a doctoral scholarship. The authors thank Ir. B. Demarsin
for valuable help with HRMS.
Then we turned our attention to the investigation of reactions
with acetoacetic ester (4). Application of our protocol to 1a and
1b in combination with 4 resulted in the formation of inseparable
mixtures of products [5a+6a] and [5b+6b], respectively (Scheme
1). Analysis of the 1H NMR spectra of these mixtures revealed that
in both cases product 5 is formed through alkylation, while the
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
080.
second product
6 is a result of an alkylation/retro-Claisen
sequence.13,16 Increasing the reaction time from 6 to 16 h or switch-
ing from dry to wet THF did not facilitate complete conversion of 5
into 6.17 However, when these mixtures were treated with silica,
retro-Claisen fragmentation of 5 into 6 was successfully accom-
plished, allowing isolation of 6a and 6b as sole products.18
In conclusion, we have developed a simple and efficient C–C
bond forming methodology for the functionalization of the
pyrazinone core at the 3-position. The scope of the process was
demonstrated through the use of different 3,5-dichloro-2(1H)-pyr-
azinones in combination with various active methylene
compounds.
References and notes
1. (a) Vekemans, J.; Pollers-Wieërs, C.; Hoornaert, G. J. Heterocycl. Chem. 1983, 20,
919–923. for
a recent microwave-assisted synthesis, see:; (b) Gising, J.;
Örtqvist, P.; Sandström, A.; Larhed, M. Org. Biomol. Chem. 2009, 7, 2809–2815.
2. (a) Pawar, V. G.; De Borggraeve, W. M. Synthesis 2006, 2799–2814; (b) Mehta, V.
P.; Appukkuttan, P.; Van der Eycken, E. Curr. Org. Chem. 2011, 15, 265–283.
3. (a) Mehta, V. P.; Sharma, A.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E.
J. Org. Chem. 2008, 73, 2382–2388; (b) Modha, S. G.; Trivedi, J. C.; Mehta, V. P.;
Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem. 2010, 76, 846–856.
4. (a) Ermolat’ev, D. S.; Mehta, V. P.; Van der Eycken, E. V. Synlett 2007, 3117–
3122; (b) Mehta, V. P.; Modha, S. G.; Ermolat’ev, D.; Van Hecke, K.; Van
Meervelt, L.; Van der Eycken, E. V. Aust. J. Chem. 2009, 62, 27–41; (c) Ermolat’ev,
D. S.; Mehta, V. P.; Van der Eycken, E. V. QSAR Comb. Sci. 2007, 26, 1266–1273.
5. (a) Tutonda, M.; Vanderzande, D.; Hendrickx, M.; Hoornaert, G. Tetrahedron
1990, 46, 5715–5732; (b) Buysens, K. J.; Vandenberghe, D. M.; Toppet, S. M.;
Hoornaert, G. J. Tetrahedron 1995, 51, 12463–12478; (c) Buysens, K. J.;
Vandenberghe, D. M.; Hoornaert, G. J. Tetrahedron 1996, 52, 9161–9178; (d)
Tahri, A.; De Borggraeve, W.; Buysens, K.; Van Meervelt, L.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 1999, 55, 14675–14684; (e) Govaerts, T. C.; Vogels,
I.; Compernolle, F.; Hoornaert, G. Tetrahedron Lett. 2002, 43, 799–802.
Acknowledgements
Support was provided by the Fund for Scientific Research
(FWO), Flanders and by the Research Fund of the University of
Leuven (KU Leuven). N.M.M. is grateful to EMECW13 (Erasmus
Mundus External Cooperation Window Lot 13 India) for obtaining
6. (a) Reiner, J. E.; Siev, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J. Z.; Reddy, K. M.;
Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K.; Gibson, T. S.; Anderson, S.

4678
N. M. Mishra et al. / Tetrahedron Letters 53 (2012) 4676–4678
M.; Bradbury, A. E.; Nolan, T. G.; Semple, J. E. Bioorg. Med. Chem. Lett. 2002, 12,
water and brine, dried over Na2SO4 and concentrated under reduced pressure.
The crude product was subjected to column chromatography yielding pure 3a
(120 mg, 79%). 1H NMR (300 MHz, CDCl3): d 7.63–7.42 (m, 3H), 7.22–7.10 (m,
1203–1208; (b) South, M. S.; Case, B. L.; Wood, R. S.; Jones, D. E.; Hayes, M. J.;
Girard, T. J.; Lachance, R. M.; Nicholson, N. S.; Clare, M.; Stevens, A. M.;
Stegeman, R. A.; Stallings, W. C.; Kurumbail, R. G.; Parlow, J. J. Bioorg. Med.
Chem. Lett. 2003, 13, 2319–2325; (c) Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton,
R. L.; Hayes, M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.;
Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens, A. M.;
Stallings, W. C.; Kurumbail, R. G.; South, M. S. J. Med. Chem. 2003, 46, 4050–
4062; (d) Breslin, M. J.; Duggan, M. E.; Halczenko, W.; Fernandez-Metzler, C.;
Hunt, C. A.; Leu, C. T.; Merkle, K. M.; Naylor-Olsen, A. M.; Prueksaritanont, T.;
Stump, G.; Wallace, A.; Rodan, S. B.; Hutchinson, J. H. Bioorg. Med. Chem. Lett.
2003, 13, 1809–1812; (e) Hopkins, C.; Neuenschwander, K.; Scotese, A.;
Jackson, S.; Nieduzak, T.; Pauls, H.; Liang, G.; Sides, K.; Cramer, D.; Cairns, J.;
Maignan, S.; Mathieu, M. Bioorg. Med. Chem. Lett. 2004, 14, 4819–4823.
7. (a) De Borggraeve, W. M.; Rombouts, F. J. R.; Van der Eycken, E. V.; Toppet, S.
M.; Hoornaert, G. J. Tetrahedron Lett. 2001, 42, 5693–5695; (b) De Borggraeve,
W. M.; Verbist, B. M. P.; Rombouts, F. J. R.; Pawar, V. G.; Smets, W. J.; Kamoune,
L.; Alen, J.; Van der Eycken, E. V.; Compernolle, F.; Hoornaert, G. J. Tetrahedron
2004, 60, 11597–11612; (c) Claerhout, S.; Sharma, S.; Sköld, C.; Cavaluzzo, C.;
Sandström, A.; Larhed, M.; Thirumal, M.; Parmar, V. S.; Van der Eycken, E. V.
Tetrahedron 2012, 68, 3019–3029.
8. (a) Alen, J.; Robeyns, K.; De Borggraeve, W. M.; Meervelt, L. V.; Compernolle, F.
Tetrahedron 2008, 64, 8128–8133; (b) Alen, J.; Dobrzan´ ska, L.; De Borggraeve,
W. M.; Compernolle, F. J. Org. Chem. 2007, 72, 1055–1057.
9. (a) Azzam, R.; De Borggraeve, W.; Compernolle, F.; Hoornaert, G. J. Tetrahedron
Lett. 2004, 45, 1885–1888; (b) Azzam, R.; De Borggraeve, W. M.; Compernolle,
F.; Hoornaert, G. J. Tetrahedron 2005, 61, 3953–3962; (c) Kaval, N.; Bisztray, K.;
Dehaen, W.; Kappe, C. O.; Van der Eycken, E. Mol. Divers. 2003, 7, 125–134.
10. Pawar, S. V.; Pawar, V. G.; Dehaen, W.; De Borggraeve, W. M. Org. Lett. 2008, 10,
4473–4476.
2H), 5.02 (s, 1H), 4.28 (q, J = 7.1 Hz, 4H), 2.10 (s, 3H), 1.30 (t, J = 7.1 Hz, 6H); 13
C
NMR (75 MHz, CDCl3): d 166.1, 154.8, 149.3, 136.8, 136.1, 130.2, 129.8, 127.1,
125.5, 62.1, 56.1, 18.2, 14.0; HRMS (EI) for C18H19ClN2O5, calcd 378.0982, found
378.0999.
15. See Supplementary data for details.
16. For relevant transformations involving transition metal-catalyzed arylation of
active methylene compounds followed by retro-Claisen fragmentation, see: (a)
Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607–2619; (b) Zeevaart, J. G.;
Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett. 2004, 45, 4261–4264; (c)
Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett. 2007, 48, 3289–
3293; (d) He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273–
8275; (e) Rout, L.; Regati, S.; Zhao, C.-G. Adv. Synth. Catal. 2011, 353, 3340–
3346.
17. The 5:6 ratio was not significantly affected. On the other hand slight
fluctuations in 5:6 ratio could be observed even for two independent runs
under standard conditions.
18. Representative procedure for the 3-alkylation/retro-Claisen sequence.
Preparation of ethyl 2-(6-chloro-5-methyl-3-oxo-4-phenyl-3,4-dihydropyrazin-2-
yl)acetate (6a): To a suspension of K3PO4 (170 mg, 0.8 mmol) in dry THF (4 mL)
3,5-dichloro-2(1H)-pyrazinone 1a (102 mg, 0.4 mmol) and acetoacetic ester 4
(57 mg, 0.44 mmol) were added. The resulting mixture was stirred for 6 h at
80 °C in a sealed screw cap vial. Upon completion of the reaction the mixture
was diluted with ethyl acetate (50 mL) and concentrated with silica gel (ca. 3 g)
under reduced pressure at 50 °C. The crude [5+6] mixture adsorbed on silica
was again diluted with ethyl acetate (50 mL) and then concentrated to dryness.
This was repeated 5 times. We presume that accomplishment of the retro-
Claisen fragmentation (5?6) occurs during this adsorption process through
the reaction with a silica surface.
11. Mehta, V. P.; Sharma, A. K.; Modha, S. G.; Sharma, S.; Meganathan, T.; Parmar,
V. S.; Van der Eycken, E. J. Org. Chem. 2011, 76, 2920–2925.
12. For some representative examples, see: (a) Thompson, W. J.; Jones, J. H.; Lyle, P.
A.; Thies, J. E. J. Org. Chem. 1988, 53, 2052–2055; (b) Colbon, P. J. J.; Foster, A. C.;
Giles, M. E.; Patel, Z.; Singleton, J. T. J. Heterocycl. Chem. 2008, 45, 1451–1456;
(c) Montalbetti, C. A. G. N.; Coulter, T. S.; Uddin, M. K.; Reignier, S. G.; Magaraci,
F.; Grånäs, C.; Krog-Jensen, C.; Felding, J. Tetrahedron Lett. 2006, 47, 5973–5975;
(d) Morgentin, R.; Jung, F.; Lamorlette, M.; Maudet, M.; Menard, M.; Plé, P.;
Pasquet, G.; Renaud, F. Tetrahedron 2009, 65, 757–764.
13. Qu, G.-R.; Mao, Z.-J.; Niu, H.-Y.; Wang, D.-C.; Xia, C.; Guo, H.-M. Org. Lett. 2009,
11, 1745–1748.
14. Representative procedure for the 3-alkylation of 3,5-dichloro-2(1H)-
pyrazinones with active methylene compounds.
silica
O
surface
R1
N
R1
N
O
Si
O
OH
Si
R6
Cl
O
R6
Cl
O
O
+
+
O
O
O
O
O
N
N
COOEt
COOEt
5
6
Preparation of diethyl 2-(6-chloro-5-methyl-3-oxo-4-phenyl-3,4-dihydropyrazin-
2-yl)malonate (3a): To a suspension of K3PO4 (170 mg, 0.8 mmol) in dry THF
(4 mL) 3,5-dichloro-2(1H)-pyrazinone 1a (102 mg, 0.4 mmol) and diethyl
malonate 2a (70 mg, 0.44 mmol) were added. The resulting mixture was
stirred for 5 h at 80 °C in a sealed screw cap vial. Upon completion of the
reaction the mixture was diluted with ethyl acetate (50 mL), washed with
Finally, pure 6a (81 mg, 66%) was isolated via column chromatography. 1H NMR
(300 MHz, CDCl3): d 7.61–7.44 (m, 3H), 7.22–7.12 (m, 2H), 4.18 (q, J = 7.1, 2H),
3.81 (s, 2H), 2.10 (s, 3H); 1.26 (t, J = 7.1, 3H). 13C NMR (75 MHz, CDCl3): d 169.1,
155.5, 151.0, 137.0, 135.1, 130.2, 129.7, 127.1, 125.3, 61.2, 39.7, 18.1, 14.1;
HRMS (EI) for C15H15ClN2O3, calcd 306.0771, found 306.0772.