A Facile Route to Substituted Bidentate and

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SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 1408–1412 letter

Syn lett

1408

Letter

A. K. Pal et al.

A Facile Route to Substituted Bidentate and Tridentate Ligands Capable of Forming Six-membered Chelate Rings with TransitionMetal Ions Amlan K. Pala Pavan Kumar Mandalia,b Dillip Kumar Chand*b

R

R

Garry S. Hanan*a

Z

a

Département de Chimie, Université de Montréal, Montréal, Québec H3T 1J4, Canada [email protected] b Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India [email protected]

Received: 05.12.2014 Accepted: 30.03.2015 Published online: 04.05.2015 DOI: 10.1055/s-0034-1380654; Art ID: st-2014-s0665-l

Abstract A facile one-pot synthesis of mono(hpp)- or di(hpp)-substituted N-heterocyclic ligands from halogenated N-heterocycles and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (H-hpp) is presented. N,N-Bidentate and N,N,N-tridentate ligands incorporating electron-donating and electron-withdrawing substituents can also be readily synthesized using this method.

Key words palladium, catalysis, C–N bond-forming reactions, N-heterocyclic ligands, one-pot synthesis

Transition-metal complexes of polypyridyl ligands continue to attract considerable attention due to their potential applications as photoluminescent chemo- and biosensors,1 redox mediators,2 photocatalysts,3 and photosensitizers in light-harvesting devices (LHD) and dye-sensitized solar cells (DSSC).4 The most employed ligands in these fields remain the archetypical N,N-bidentate 2,2′-bipyridine (bpy) and N,N,N-tridentate 2,2′:6′,2′′-terpyridine (tpy), that bond to metal centers forming five-membered chelate rings.5 Although polymetallic complexes containing bpy as the chelating ligand are usually less stereochemically appealing due to diastereomer formation, complexes composed of tpy ligands are synthetically more readily accessible due to their inherent achiral nature, which render them useful for incorporation into larger supramolecular assemblies. However, complexes containing tpy as ligands are usually devoid of exciting photophysical properties due to the deviation from octahedral geometry around the metal center compared to that of the complexes composed of bpy or substituted bpy ligands.6

N

Y

Pd(OAc)2, BINAP

N

X + N

H-hpp R = H, EDG, EWG X = Br, Cl; Y, Z = CH, N

N H

KOt-Bu toluene, Δ

Z

Y

hpp

N 60–96%

A fruitful approach to improve the photophysical properties of the metal complexes [or more specifically ruthenium(II) complexes] containing tridentate ligands includes the complexation of tridentate ligands that chelate to a metal center forming six-membered chelate ring; thus improving the octahedral geometry around the metal center.7 Recently, the photophysical and redox properties of these bidentate and tridentate ligands containing N-heterocycles have also begun to attract interest due to their potential application as organic light-emitting diodes (OLED).5g,8 Thus, methodologies available for the synthesis of bidentate and tridentate ligands that exhibit larger bite angles around metal ions are of considerable interest with respect to many of the applications as discussed above. Triazabicyclodecene {1,5,7-triazabicyclo[4.4.0]dec-5ene or TBD} is used (a) as an organocatalyst in aminolysis of esters,9 (b) as a base in C–N cross-coupling reactions,10 (c) and also in various organic transformations, such as Michael reactions, Wittig reactions, ring-opening polymerizations, Knoevenagel condensations, and deprotection reactions.11 Coles et al. recently reported that hpp moieties can be linked with methylene linkers to form H2C(hpp)2 {where TBD is abbreviated as its IUPAC name H-hpp in this work; H-hpp = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine} and used as bidentate ligand with transition metals12 or as a hydrogen-bonding motif.13 To the best of our knowledge, except these reports and our group efforts, H-hpp has never been used as a synthon to synthesize chelating ligands. Theoretically, the larger bite angle formed by these chelating ligands upon coordination to a metal center improves the photophysical properties of the complexes by inducing a larger ligand-field strength which destabilizes the antibonding metal-centered excited states.7

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1408–1412

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In this context, we present herein the facile one-pot synthesis of a library of bidentate and tridentate chelating ligands with electronically and sterically hindered substituents at different positions of the N-heterocycles (Scheme 1). R

R Z

Y

X +

KOt-Bu

N H

N

N

toluene, Δ

H-hpp

R = H, EDG, EWG

Z

Pd(OAc)2, BINAP

N

Y

hpp

N 1–3, 7–13

X = Br, Cl; Y, Z = CH or N X2

X2 Y

X1

Y

KOt-Bu

N H

N

N

Pd(OAc)2, BINAP

N

+

hpp

N

toluene, Δ

4–6

X1, X2 = Br, Cl Y = CH, N hpp

X2 Z

Y

X1

+

N

Pd(OAc)2, BINAP

N

KOt-Bu

N H

N

toluene, Δ

X1, X2 = Br, Cl Y, Z = CH, N

Z

Y

hpp

N 14–16

Scheme 1 Syntheses of bidentate and tridentate ligands via C–N bondforming reactions

The characterization of the newly reported compounds by 1H NMR and 13C NMR spectroscopy and HR mass spectrometry is also reported. In a typical procedure, the reaction involves a one-pot C–N bond formation using mono- or dihalo-substituted pyridine, pyrimidine, pyrazine, and H-hpp in the presence of 2 mol% of Pd(OAc)2 and a phosphine source, for example, (±)-BINAP in hot toluene.14 The formation of the precatalyst by premixing of the phosphine and Pd(OAc)2 in toluene was found to be advantageous for the progress of the reaction.15 The halogenated N-heterocycle was then added at 60 °C under inert N2 atmosphere, where a visual color change from dark-red to pale-yellow was observed. The product was obtained by subsequent addition of the H-hpp and KOt-Bu, followed by heating the solution at 90–130 °C for the time mentioned in Table 1.22 While the synthesis of hpp-substituted pyridyl substrate (1)23 provided a satisfactory yield, the analogue containing the pyrimidyl ring (2) was obtained in a modest yield, presumably due to poor oxidative addition at the 2-position of the pyrimidyl ring.16 Although the chlorine atom is a poorer leaving group compared to a bromine atom, the poorer basicity of pyrazine compared to that of pyrimidine (3) facilitates the oxidative addition to furnish the corresponding product in 89% yield.20 Under mild reaction conditions, 2 mol% of Pd(OAc)2 and 1.1 equivalents of H-hpp per dihalo-substituted starting materials (4–6)24 provided the exclusive formation of mono-hpp-substituted products, leaving the opportunity for further reactivity with suitable coupling reagents.16

Table 1 Syntheses of N-Heterocyclic Ligandsa Compd

Halogenated N-heterocycle

1

Reaction conditions

Yield (%)b

Product

90 °C, 3 h N

N

Br N

2 N

N

Br

90

16

60

16

89

16

86

new

96

16

92

16

hpp N

130 °C, 1 h

Ref.

hpp

N

N 3

90 °C, 3 h N

N

Cl

4

hpp

120 °C, 4 h Br

N

Br

Br

N

hpp

N

hpp

Br

Br 5

90 °C, 3 h N

Br

Cl

Cl

6

Cl

hpp

120 °C, 4 h N

N

N

N


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Table 1 (continued) Compd

Halogenated N-heterocycle

7

Reaction conditions

Yield (%)b

Product

120 °C, 3.5 h Me

N

Me

Br

8

N

N

MeO

Br

new

N

hpp

92

new

N

hpp

87

new

71

new

96

new

94

new

15c

new

83

17

72

18

93

19

MeO

MeO 9

120 °C, 5 h N

Br

OMe

OMe 10

120 °C, 16 h N

93 hpp

120 °C, 4 h MeO

Ref.

N

Br

hpp

O2N

O2N 11

120 °C, 3 h N

N

Br

hpp

Ac

Ac 12

120 °C, 3 h N

N

Br

hpp

HOOC

HOOC 13

120 °C, 24 h N

N

Br

14

hpp

90 °C, 3.5 h Br

N

hpp

Br

N

hpp

N

N 15

90 °C, 16 h Cl

N

hpp

Cl

Cl

Cl

16

N

hpp

hpp

hpp

120 °C, 24 h N

N

N

N

a

Conditions: halogenated N-heterocycle (ca. 1 mmol), Pd(OAc)2 (2 mol%), (±)-BINAP (3 mol%), H-hpp and KOt-Bu (1.1 and 2.5 equiv with respect to halogenated N-heterocycle, for mono-hpp substitution and 2.2 and 5 equiv with respect to halogenated N-heterocycle, for di-hpp substitutions, respectively) in dry toluene for specified time and temperature as mentioned in column 3. b Isolated yields for new syntheses. Literature yields are similar for reported syntheses as found in ref. 16–19. c Conversion with respect to 6-bromonicotinic acid as observed by 1H NMR spectroscopy.

The efficiency of the coupling reactions were also tested with electron-donating substituents on the halogenated Nheterocycles (8–10).26–28 Although the rate of oxidative addition to the C–X bond (where X = Br, Cl) becomes slower in the presence of electron-donating substituents compared to that of electron-withdrawing groups, good to excellent yields (71–92%) were obtained using the aforementioned methodology. The relatively lower yield for compound 10 is presumably due to the electron-donating nature of the methoxy group at the 2-position of the C–Br bond that negatively influences the oxidative addition at the C–Br bond.

The C–N bond-forming reactions were found to be efficient for substrates containing electron-withdrawing groups (11 and 12),29,30 while the corresponding C–N coupled products were obtained in satisfactory yield. The notably poor yield for compound 1331 is probably due to the favorable protonation of the strong amine base H-hpp (pKa = 26.03 in MeCN)21 by the carboxylic acid group present in one of the starting materials over KOt-Bu (pKa = ca. 17) even though excess KOt-Bu was used.


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The dibromo- or dichloro-substituted N-heterocycles were found to undergo double substitutions at both of the halogen positions in the presence of 2.2 equivalents of Hhpp and 5 equivalents of KOt-Bu under these reaction conditions (14–16). Due to the presence of extra ring-nitrogen atoms (15 and 16), the chloro-substituted N-heterocycles provided good to excellent yields. The newly synthesized C–N coupled products were characterized by 1H NMR and 13C NMR spectroscopy and HRMS (Supporting Information). A common feature in the 1 H NMR spectra of the coupled products vs. H-hpp is the splitting of the signals of the hpp moiety due to the fact that attaching a heterocycle to the guanidine NH position of Hhpp renders the six annular methylene units nonequivalent by both 1H NMR and 13C NMR spectroscopy in contrast to free H-hpp. In conclusion, a general C–N bond-forming methodology has been established and was successfully employed with different functionalized N-heterocycles to give the products in good to satisfactory yields. The formation of homocoupled product was not observed. Using proper stoichiometry of H-hpp, this powerful methodology allows substitution onto dihalo-substituted N-heterocycles to give rise to mono-hpp-substituted product leaving opportunity for further substitution at the other C–X (X = Br, Cl) position. Using only 2 mol% of catalyst loading, the di-hpp-substituted products could also be synthesized in good yields. A variety of designed ligands could be prepared using the strategy established in this communication.

Acknowledgment A.K.P. and G.S.H. are grateful to the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Centre for Self Assembled Chemical Structures for financial support. P.K.M. and D.K.C. thank Shastri Indo-Canadian Institute for a fellowship and research grant, respectively. The authors thank M. Carolina Chaves for help with one of the experiments.

Supporting Information Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1380654. SuponritIgfmanSuponritIgfman

References and Notes (1) Gill, M. R.; Garcia-Lara, J.; Foster, S. J.; Smythe, C.; Battaglia, G.; Thomas, J. A. Nat. Chem. 2009, 1, 662; and references cited therein. (2) Thompson, D. W.; Ito, A.; Meyer, T. J. Pure Appl. Chem. 2013, 85, 1257. (3) Eisenberg, R. Science 2009, 324, 44; and references cited therein. (4) Bomben, P. G.; Robson, K. C. D.; Koivisto, B. D.; Berlinguette, C. P. Coord. Chem. Rev. 2012, 256, 1438; and references cited therein.

(5) (a) Hofmeier, H.; Schubert, U. S. Chem. Soc. Rev. 2004, 33, 373. (b) Brown, D. G.; Sanguantrakun, N.; Schulze, B.; Schubert, U. S.; Berlinguette, C. P. J. Am. Chem. Soc. 2012, 134, 12354. (c) Pal, A. K.; Laramée-Milette, B.; Hanan, G. S. RSC Adv. 2014, 4, 21262. (d) Pal, A. K.; Laramée-Milette, B.; Hanan, G. S. Inorg. Chim. Acta 2014, 418, 15. (e) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553. (f) Schubert, U. S.; Hofmeier, H.; Newkome, G. R. Modern Terpyridine Chemistry 2006. (g) Wang, J.; Hanan, G. S. Synlett 2005, 1251. (h) Polson, M. I. J.; Medlycott, E. A.; Hanan, G. S.; Mikelsons, L.; Taylor, N. J.; Watanabe, M.; Tanaka, Y.; Loiseau, F.; Passalacqua, R.; Campagna, S. Chem. Eur. J. 2004, 10, 3640. (i) Medlycott, E. A.; Hanan, G. S.; Loiseau, F.; Campagna, S. Chem. Eur. J. 2007, 13, 2837. (6) (a) Pal, A. K.; Hanan, G. S. Chem. Soc. Rev. 2014, 43, 6184. (b) Medlycott, E. A.; Hanan, G. S. Chem. Soc. Rev. 2005, 34, 133. (c) Medlycott, E. A.; Hanan, G. S. Coord. Chem. Rev. 2006, 250, 1763. (7) (a) Abrahamsson, M.; Jäger, M.; Österman, T.; Eriksson, L.; Persson, P.; Becker, H.-C.; Johansson, O.; Hammarström, L. J. Am. Chem. Soc. 2006, 128, 12616. (b) Jäger, M.; Kumar, R. J.; Görls, H.; Bergquist, J.; Johansson, O. Inorg. Chem. 2009, 48, 3228. (c) Abrahamsson, M.; Jäger, M.; Kumar, R. J.; Österman, T.; Persson, P.; Becker, H.-C.; Johansson, O.; Hammarström, L. J. Am. Chem. Soc. 2008, 130, 15533. (d) Hammarström, L.; Johansson, O. Coord. Chem. Rev. 2010, 254, 2546; and references cited therein. (8) (a) Goodall, W.; Williams, J. A. G. Chem. Commun. 2001, 2514. (b) Roberto, D.; Tessore, F.; Ugo, R.; Bruni, S.; Manfredi, A.; Quici, S. Chem. Commun. 2002, 846. (9) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron Lett. 2007, 48, 3863. (10) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2006, 71, 430. (11) (a) Huczynski, A.; Brzezinski, B. 1,5,7-Triazabicyclo[4.4.0]dec-5ene, In e-EROS Encyclopedia of Reagents for Organic Synthesis; John Wiley and Sons: New York, 2008, doi: 10.1002/047084289X.rn00786. (b) Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts; Ishikawa, T., Ed.; John Wiley and Sons: Chichester, 2009. (12) Oakley, S. H.; Coles, M. P.; Hitchcock, P. B. Inorg. Chem. 2004, 43, 7564. (13) Coles, M. P. Chem. Commun. 2009, 3659. (14) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338. (c) Shrestha, R.; Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 9303. (15) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413. (16) Pal, A. K.; Nag, S.; Ferreira, J. M.; Brochery, V.; Ganga, G. L.; Santoro, A.; Serroni, S.; Campagna, S.; Hanan, G. S. Inorg. Chem. 2014, 53, 1679. (17) (a) Pal, A. K.; Zaccheroni, N.; Campagna, S.; Hanan, G. S. Chem. Commun. 2014, 50, 6846. (b) Pal, A. K.; Serroni, S.; Zaccheroni, N.; Campagna, S.; Hanan, G. S. Chem. Sci. 2014, 5, 4800. (18) Pal, A. K.; Hanan, G. S. Dalton Trans. 2014, 43, 11811. (19) (a) Pal, A. K.; Dauphin, P. D.; Hanan, G. S. Chem. Commun. 2014, 50, 3303. (b) Pal, A. K.; Hanan, G. S. Dalton Trans. 2014, 43, 6567. (20) Joule, J. A.; Mills, K. In Heterocyclic Chemistry; Wiley-Blackwell: Oxford, 2013. (21) Sooväli, L.; Kaljurand, I.; Kütt, A.; Leito, I. Anal. Chim. Acta 2006, 566, 290.


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(22) General Procedure In a typical procedure, for mono-hpp substitution reactions, a 100 mL oven-dried round-bottomed flask was charged with (±)-BINAP (3 mol% with respect to N-haloheterocycle) and dissolved in dry toluene (5 mL) under an inert N2 atmosphere at ca. 60 °C to give a clear colorless solution. To this solution was added Pd(OAc)2 (2 mol% with respect to the halogenated N-heterocycle), and the reaction mixture was stirred at ambient temperature under N2 atmosphere to give a clear dark red solution. To this solution was added the halogenated N-heterocycle (1 mmol), and the reaction was heated to 60 °C under N2 atmosphere for 15–20 min, with a concomitant color change from dark-red to yellow. To the resulting clear yellow solution was added H-hpp (1.1 equiv with respect to starting halogenated Nheterocycle), followed by the addition of KOt-Bu (2.5 equiv with respect to halogenated N-heterocycle), and the resulting brownish-red solution was heated at elevated temperature and for the time indicated in Table 1. After this time, the reaction mixture was cooled to r.t., and the solvent was evaporated to dryness. To the resulting brownish-green solid was added an aliquot of a mixture of toluene and Et2O (10:60, v/v), and the mixture was filtered. The pale-yellow filtrate was evaporated to dryness. The desired product was isolated as colorless or yellow solid by trituration with acetone (1–2 mL). Subsequent drying under vacuum afforded the compound in the yield as indicated in Table 1. (23) Except for compounds 4 and 7–13, all of the C–N coupled products are known compounds.11–14 The yields reported in Table 1 for existing compounds were found to be similar to those of the literature reports, and their characterization data were found to be in good agreement to those mentioned in the literature reports. (24) 1-(6-Bromopyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (4) White solid. 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 3.86 (t, J = 6.0 Hz, 2 H), 3.39 (t, J = 4.8 Hz, 2 H), 3.22 (m, 4 H), 2.0 (quin, J = 6.0 Hz, 2 H), 1.87 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.05, 148.91, 140.69, 137.76, 119.21, 115.78, 48.46, 48.30, 43.58, 43.07, 23.03, 22.32 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C12H15N4Br: 295.0558; found: 295.0631. (25) 1-(6-Methylpyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (7) White solid. 1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 5.6 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 6.53 (d, J = 7.2 Hz, 1 H), 3.75 (t, J = 6.0 Hz, 2 H), 3.27 (t, J = 5.6 Hz, 2 H), 3.10 (m, 4 H), 2.29 (s, 3 H), 1.89 (quin, J = 6.0 Hz, 2 H), 1.76 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.45, 155.35, 149.51, 135.75, 115.68, 115.16, 48.16, 47.95, 43.24, 43.07, 23.85, 22.98, 22.07 ppm. ESIHRMS (CHCl3): m/z [M + H]+ calcd for C13H18N4: 231.1610; found: 231.1671. (26) 1-(6-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (8) Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.44 (t, J = 8.0 Hz, 1 H),

(27)

(28)

(29)

(30)

(31)

7.27 (m, 1 H), 6.24 (dd, J = 12.0 Hz, 1 H), 3.92 (t, J = 6.0 Hz, 2 H), 3.85 (s, 3 H), 3.45 (t, J = 5.6 Hz, 2 H), 3.26 (m, 4 H), 2.04 (quin, J = 6.0 Hz, 2 H), 1.92 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.27, 154.04, 149.67, 138.61, 109.14, 100.96, 52.86, 48.26, 48.17, 43.23, 43.05, 23.15, 22.18 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C13H18N4O: 247.1559; found: 247.1632. 1-(5-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (9) White solid. 1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 2.8 Hz, 1 H), 7.46 (d, J = 9.2 Hz, 1 H), 7.12 (dd, J = 12.0 Hz, 1 H), 3.76 (s, 3 H), 3.72 (t, J = 6.0 Hz, 2 H), 3.32 (t, J = 5.6 Hz, 2 H), 3.19 (m, 2 H), 2.03 (quin, J = 6.0 Hz, 2 H), 1.85 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.54, 150.39, 150.20, 132.90, 122.82, 120.71, 55.81, 48.55, 48.33, 44.68, 43.37, 23.22, 22.44 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C13H18N4O: 247.1559; found: 247.1631. 1-(3-Methoxypyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (10) White solid. 1H NMR (400 MHz, CD3CN): δ = 7.93 (d, J = 3.0 Hz, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.17 (dd, J = 12.0 Hz, 1 H), 3.79 (s, 3 H), 3.50 (t, J = 6.0 Hz, 2 H), 3.24 (m, 6 H), 2.06 (quin, J = 6.0 Hz, 2 H), 1.83 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.89, 150.62, 150.15, 139.84, 119.95, 118.48, 56.0, 48.28, 48.19, 46.76, 45.9, 24.52, 22.91 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C13H18N4O: 247.1559; found: 247.1635. 1-(5-Nitropyridin-2-yl)-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (11) Yellow solid. 1H NMR (400 MHz, CDCl3): δ = 9.02 (d, J = 4.0 Hz, 1 H), 8.13 (dd, J = 12.0 Hz, 1 H), 7.86 (d, J = 10.0 Hz, 1 H), 4.01 (t, J = 6.0 Hz, 2 H), 3.44 (t, J = 6.0 Hz, 2 H), 3.25 (m, 4 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.90 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 148.34, 144.28, 137.10, 130.70, 114.68, 48.19, 48.14, 43.46, 42.95, 23.29, 21.93 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C12H15N5O2: 262.1304; found: 260.1348. 1-[6-(2,3,4,6,7,8-Hexahydro-1H-pyrimido[1,2-a]pyrimidin1-yl)pyridin-3-yl]ethanone (12) White solid. 1H NMR (400 MHz, CDCl3): δ = 8.76 (dd, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.8 Hz, 1 H), 7.75 (dd, J = 8.8 Hz, 1 H), 3.97 (t, J = 5.6 Hz, 2 H), 3.42 (t, J = 6.0 Hz, 2 H), 3.24 (m, 4 H), 2.47 (s, 3 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.89 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.74, 158.58, 148.87, 135.23, 115.54, 48.28, 48.19, 43.37, 42.89, 26.09, 23.34, 22.08 ppm. ESIHRMS (CHCl3): m/z [M + H]+ calcd for C14H18N4O: 259.1559; found: 259.1614. 6-{2,3,4,6,7,8-Hexahydro-1H-pyrimido[1,2-a]pyrimidin-1yl}nicotinic Acid (13) White solid. 1H NMR (400 MHz, CDCl3): δ = 8.82 (dd, J = 2.0 Hz, 1 H), 8.14 (dd, J = 8.0 Hz, 1 H), 7.01 (dd, J = 6.4 Hz, 1 H), 3.77 (t, J = 6.0 Hz, 2 H), 3.39 (t, J = 6.0 Hz, 2 H), 3.31 (m, 4 H), 2.01 (quin, J = 6.0 Hz, 2 H), 1.89 (quin, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.43, 154.8, 150.2, 149.20, 139.13, 124.05, 116.23, 48.08, 47.76, 45.41, 40.12, 21.80, 20.47 ppm. ESI-HRMS (CHCl3): m/z [M + H]+ calcd for C13H16N4O2: 261.1352; found: 261.1420.
