Preparation of non-symmetrical 2,3-bis-(2,2'-oligopyridyl)pyrazines via 1,2-disubstituted ethanones

Article abstract of DOI:10.1055/s-1999-2800

Sequential oxidation of the condensation products between alkyl 2,2'- oligopyridyl carboxylates and 6-methyl pyridine homologues with m-CPBA, then iodine affords the corresponding mixed α-diketones. These compounds are readily transformed into the respective mixed bis-oligopyridyl pyrazines, a class of compounds of interest for supramolecular chemistry.

Full text of DOI:10.1055/s-1999-2800

LETTER
1203
Preparation of Non-Symmetrical 2,3-Bis-(2,2’-oligopyridyl)pyrazines via 1,2-
Disubstituted Ethanones
Fenton R. Heirtzler
Department of Chemistry, University of Basel, CH-4056 Basel, Switzerland
Fax +41 (0)61 267 1020; E-mail: heirtzler@ubaclu.unibas.ch
Received 10 May 1999
with excess trimethylsilyl cyanide and benzoyl chloride
Abstract: Sequential oxidation of the condensation products be-
according to Fife’s procedure8 to afford nitriles 5a–b
tween alkyl 2,2’-oligopyridyl carboxylates and 6-methyl pyridine
(Scheme 1).9 Basic methanolysis of 5a–c,10 followed by
homologues with m-CPBA, then iodine affords the corresponding
mixed a-diketones. These compounds are readily transformed into
acidic hydrolysis of the intermediate methyl imidates
the respective mixed bis-oligopyridyl pyrazines, a class of com- gave esters 6a–c in good overall yields.11 This simple pro-
pounds of interest for supramolecular chemistry.
cedure is superior to the known preparations of related ni-
triles and related esters in terms of yields and number of
Key words: pyrazine, pyridine, C-C coupling, enol, oxidation
synthetic steps.12
The supramolecular chemistry of substances incorporat-
ing the pyrazine ring is limited to a handful of oligohetero-
cyclic compounds.1,2 The arrangement of that ring’s donor
atoms and p-electron system, as well as the presence of p-
stacking effects orthogonal to the ring plane,3 make com-
pounds which contain it and their metallosupramolecular
complexes attractive candidates for electronic delocaliza-
tion studies. We are interested in the preparation, charac-
terization and supramolecular chemistry of oligo-2,2’-
pyridyloligopyrazines having the general formula 1.4-6
The 2,3-disubstitution pattern about the pyrazine ring dic-
tates that the steric interaction of appended groups will
also contribute to their topology and supramolecular
chemistry. In view of this multi-faceted behaviour, the un-
der-representation of such compounds from the literature
is possibly due to the paucity of methods for their prepa-
ration.
Simpler substances serving as both model substances and
eminent retrosynthetic candidates are 2,3-bis(2,2’-oli-
gopyridyl)pyrazines 2, bearing dislike oligopyridyl sub-
stituents. In analogy to our earlier synthesis of some
symmetrical oligopyridyl pyrazines,5 we reasoned that ac-
cess to the non-symmetrical compounds could be gained
through the corresponding a-diketones 3. We have al-
ready described a simple preparation of one such com-
pound based on the mixed benzoin condensation of
appropriate aldehydes.4 However, the anticipated chro-
matographic separation of larger bis-oligopyridyl precur-
sors constitutes a drawback to this method’s extension to
larger homologues. Thus, we sought a preparatory method
by which two arbitrary oligopyridyl fragments are cou-
pled to afford a crude reaction mixture containing a single
bis-oligopyridyl product and in which the aforementioned
junction can later be transformed into a pyrazine ring.
Scheme 1 Preparation of Tautomeric 1,2-Bis(2,2’-oligopirydyl)etha-
nones 8
Slow addition of the esters 6a–d to solutions of the 6-me-
thyl oligopyridine derivatives 7a–d and 2 equivalents of
base in Et2O or 1,2-dimethoxyethane (DME) at low tem-
perature furnished the keto-enol tautomeric condensation
products 8a–g after work-up and column chromatography
(Scheme 1 and Table 1). The use of sterically hindered
lithium tetramethylpiperidide (LTMP) instead of lithium
diisopropylamide (LDA) was in some cases necessary to
prevent reaction of the base with the esters. Products con-
taining unsubstituted oligopyridyl ring systems (e.g., 8a–
Our approach used the Claisen-type condensation of oli-
gopyridyl-6-carboxylate esters with appropriate active
hydrogen compounds. The ester starting materials were
prepared by treatment of the oligopyridyl-N-oxides 4a–b7
Synlett 1999, No. 8, 1203–1206 ISSN 0936-5214 © Thieme Stuttgart · New York

1204
F. R. Heirtzler
LETTER
Table 1 Condensation of Esters 6a-d with 6-Methylpyridine Derivatives
7a-d Affording Ethanones 8
d) could be recrystallized and characterized as pure, crys- The preference of 8 for a novel reactivity mode analogous
talline materials.13 Hot solutions of those chromatograph- to the Rubottom oxidation of silyl enol ethers,16 as op-
ically pure derivatives containing methyl substituents posed to that in the Baeyer-Villiger reaction,17 is illustrat-
(8e–g) invariably precipitated poorly-soluble dark-red co- ed by the absence of ester side products from the crude
1
loured films, which according to H NMR spectroscopic dihydroxyolefin reaction mixtures according to 1H NMR
analysis, consisted of polymeric materials. In the case of spectroscopic analysis. Other oxidizing reagents gave
8f, no crystalline material could be isolated. Thus, these only poorly characterizable mixtures.18 The position of
three compounds were employed without further purifica- the tautomeric equilibria in 8 did not exert any clear influ-
tion in the following reaction step.
ence on the isolated yields of 3. Except for compound 3e,
all a-diketones were obtained as pure, crystalline solids.
Although 3f could be recrystallized following column
chromatography, significant material loss due to partial
decomposition on silica gel resulted in its being employed
in a synthetically pure state for the next reaction step.
The oxidation of 8 to the a-diketones 3 was the key step
to this synthetic pathway. Here, we sought an alternative
reaction sequence to the classical selenium dioxide
method14 which would provide the products in more reli-
able yields. This was possible by treatment of 8 with 1
equivalent of m-CPBA in a mixture of dichloromethane Condensation of 3a–g with 1,2-diaminoethane, followed
and aqueous sodium bicarbonate solution, giving the non- by chloranil oxidation in xylene under reflux afforded the
symmetrical 1,2-dihydroxyolefins (not shown) already pyrazine derivatives 2a–g after column chromatography
containing various amounts of 3. Complete oxidation of on deactivated alumina/CH2Cl2 - EtOAc and/or silica gel/
this material was achieved using a solution of 1 equivalent Et2HN - hexanes (Scheme 2).19 The variation in isolated
of iodine per dihydroxyolefin, and afforded clean 3 after yields (Table 2) for these compounds partially reflects the
work-up and column chromatography (Scheme 2).15
instability of some precursors (8e–g) and the low solubil-
ity of a few of the products (e.g., 2b–c; solubility of 2c:
less than 1 mg/mL). However, all pyrazine derivatives 2
were stable materials whose identity and purity was attest-
ed to by either satisfactory analytical data or the combina-
tion of clean spectra and high resolution mass
spectroscopy.
Some properties of compounds 2a–g deserve preliminary
comment. Inspection of molecular models shows that the
minimization of dipole-dipole interactions within the sep-
arate oligopyridyl chains,20 as well as steric effects both
within and between them, would result in a double-helical
twisting of the oligopyridyl units about one another. Proof
of this is seen in the 1H NMR spectrum of e.g., bipyridyl
pyridyl 2a (see Ref.19). On the terminal pyridyl substituent
in the bipyridyl fragment, H-3"’absorbs at an abnormally
high field position. NOE effects observed between H-3"’
and H-3"/H-6" of the solitary pyridine ring leads us to as-
cribe this to edge-on-surface shielding effects between the
two terminal pyridine rings.21
This phenomenon, the origins of the comparatively low
solubility and high melting point of symmetrical deriva-
tive 2c, and the scope and limitations of this reaction se-
quence will be addressed in upcoming papers.
Scheme 2 Synthesis of Pyrazine Target Molecules 2
Synlett 1999, No. 8, 1203–1206 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparation of Non-symmetrical 2,3-Bis-(2,2’-oligopyridyl)pyrazines via 1,2-Disubstituted Ethanones
1205
(9) 5a: To an ice-cooled solution of 4a (8.41 g, 48.9 mmol) and
trimethylsilyl cyanide (31 mL, 240 mmol) in ca. 130 mL dry
CH2Cl2 under N2 was carefully added benzoyl chloride (11
mL, 98 mmol). After stirring overnight at r.t., 10% aq Na2CO3
was carefully added to the chilled reaction mixture and it was
concentrated at 200 mbar to complete crude product
precipitation. This was collected by filtration, washed with
water, dried in vacuum over P4O10 and repeatedly
Table 2 Bis(oligopyridiyl)pyrazines 2 Synthesized
recrystallized from hexane to give 5a (6.71 g) as fluffy
colourless needles, mp 132-133° C (Lit.:12b 130-131° C); 5b:
see procedure for 5a. Purification by column chromatography
(15:85 - EtOAc:CH2Cl2, silica gel) and recrystallization
(heptane-CH2Cl2), mp 152-153° C; Anal. Calcd for C16H10N4:
C, 74.41; H, 3.90; N, 21.69. Found: C, 73.82; H, 4.10; N,
21.00.
(10) 5c: Baxter, P. N. W.; Connor, J. A.; Joseph, A.; Schweizer, W.
B.; Wallis, J. D. J. Chem. Soc., Dalton Trans. 1992, 3015.
(11) Typical procedure: 6a: A solution of 5a (5.71 g, 31.5 mmol)
and sodium methoxide (55 mmol) in dry MeOH (100 mL) was
stirred overnight under N2 at r. t. Then, AcOH (3.2 mL, 55
mmol) and solid NaHCO3 were added, and solvent removed in
vacuo. The remaining material was dissolved in EtOAc/sat.
aq. NaHCO3 (80/20 mL), the phases separated, the aq layer
extracted with EtOAc and the combined organic extracts
washed with sat. aq NaHCO3, water and brine. After drying
(MgSO4) and solvent removal in vacuo, the resulting oily
methyl imidate ester was stirred in MeOH (50 mL) and water
(50 mL), acidified to ca. pH 1 with 5% aq. H2SO4, at r t. (2 h).
Then, the chilled mixture was brought to pH 9 with 2 M aq.
NaOH, EtOAc (80 mL) added, and after brief agitation, the
phases separated. The aq. layer was extracted with EtOAc, the
combined organic solutions washed with water and brine,
dried (MgSO4) and concentrated under vacuum to give a pale
yellow solid. Hot filtration and repeated recrystallization
(hexanes) afforded 6a (5.85 g) as colourless crystals, mp 82-
83° C; Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N,
13.08. Found: C, 67.23; H, 4.88; N, 12.88.
Acknowledgement
Support by the University of Basel, Novartis AG, Dow Elanco/U.
K. and the Treubel Fond/Basel is gratefully acknowledged. Dr. K.
Kulike is thanked for the measurement of NMR spectra.
(12) (a) Buhleier, E.; Wehner, W.; Vögtle, F. Chem. Ber. 1978,
111, 201; Potts, K. T. Bull. Soc. Chim. Belg. 1990, 99, 741;
König, B. Chem. Ber. 1995, 128, 1141; (b) Case, F. H. J. Org.
Chem. 1966, 31, 2398.
References and Notes
(13) Typical procedure: 8a: a solution of 7a (0.43 g, 4.7 mmol) in
dry Et2O (9 mL) was added to LDA (9.8 mmol) in Et2O (40
mL) at -70 to -65° C under N2. After ca. 30 min at -65° C, 6a
(1.0 g, 4.7 mmol) in Et2O (15 mL) was added dropwise to the
yellow solution. The stirred mixture was warmed to 25° C (4
h), sat. aq NH4Cl (50 mL), then EtOAc (50 mL) added. The
phases were separated, the aqueous phase extracted with
EtOAc, the combined organic extracts washed with water,
dried (MgSO4) and solvent removed in vacuo. Column
chromatography (7:93 - EtOAc:CH2Cl2, alumina activity III)
of the resulting red oil and recrystallization (MeOH), afforded
8a (0.58 g) as yellow needles, mp 115-116° C; Anal. Calcd for
C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C, 74.42; H,
5.26; N, 14.52.
(1) Chan, C.-W.; Mingos, D. M. P.; White, A. J. P.; Williams, D.
J. Chem. Commun. 1996, 81; Ferigo, M.; Bonhôte, P.; Marty,
W.; Stoeckli-Evans, H. J. Chem. Soc., Dalton Trans. 1994,
1549; Neels, A.; Stoeckli-Evans, H.; Escuer, A.; Vicente, R.
Inorg. Chem. 1995, 34, 1846; Campagna, S.; Denti, G.;
Serroni, S.; Juris, A.; Venturi, M.; Ricevuto, V.; Balzani, V.
Chem. Eur. J. 1995, 1, 21; Brauns, E.; Jones, S. W.; Clark, J.
A.; Molnar, S. M.; Kawanishi, Y.; Brewer, K. J. Inorg. Chem.
1997, 36, 2861.
(2) Schnebeck, R.-D.; Randaccio, L.; Zangrando, E.; Lippert, B.
Angew. Chem. Int. Ed. 1998, 37, 119.
(3) Carlucci, L.; Ciani, G.; Proserpio, D. M.; Sironi, A. J. Am.
Chem. Soc. 1995, 117, 4562.
(4) Bark, T.; Weyhermüller, T.; Heirtzler, F. Chem. Commun.
1998, 1475.
(5) Heirtzler, F. R.; Neuburger, M.; Zehnder, M.; Constable, E. C.
Liebigs Ann./Recueil 1997, 297.
(14) Newkome, G. R.; Roper, J. M.; Robinson, M. J. J. Org. Chem.
1980, 45, 4380; Rabjohn, N. Org. React. (N.Y.); Dauben, W.
G., Ed.; 1976, 24, 261.
(15) Typical procedure: 3a: a solution of 8a (0.70 g, 2.6 mmol) in
CH2Cl2 (25 mL) and 0.5 M aq. NaHCO3 (7 mL) was treated
with m-CPBA (85%, 0.52 g, 2.6 mmol) over 20 min. After
stirring overnight, the mixture was extracted with sat. aq.
NaHCO3 and H2O dried (Na2SO4) and the solvent removed in
vacuo to leave an orange solid (0.68 g). A suspension of this
material in dry CH2Cl2 (20 mL) was then added to a solution
of I2 (0.46 g, 1.8 mmol) in CH2Cl2 (50 mL) and stirred at r.t.
(2.5 h). A brown oil precipitated during this time. Sat. aq
(6) Heirtzler, F.; Weyhermüller, T. J. Chem. Soc., Dalton Trans.
1997, 3653; Heirtzler, F. R.; Neuburger, M.; Zehnder, M.;
Bird, S. J.; Orrell, K. G.; Sik, V. J. Chem. Soc., Dalton Trans.
1999, 565; Heirtzler, F.; Jones, P. G.; Neuburger, M.;
Zehnder, M. Polyhedron 1999, 18, 601.
(7) Thummel, R. P.; Jahng, Y. J. Org. Chem. 1985, 50, 3635;
Wenkert, D.; Woodward, R. B. J. Org. Chem. 1983, 48, 283.
(8) Fife, W. K. J. Org. Chem. 1983, 48, 1375.
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1206
F. R. Heirtzler
LETTER
NaHCO3 was then added, and the mixture was vigorously
stirred and decanted. The residual oil was dissolved in
CH2Cl2/sat. aq NaHCO3 in an ultrasonic cleaning bath. The
combined organic extracts were washed with water, dried
(Na2SO4) and solvent removed in vacuo. Column
chromatography (30:70 - EtOAc:CH2Cl2 on silica gel)
afforded 3a (0.42 g) as a crystalline mass, recrystallized (abs.
EtOH) for elemental analysis, mp 129.5-130° C; EI-MS (70
eV): m/z (relative intensity) = 289 (M+, 45), 261 (48), 233
(54), 155 (100); Anal. Calcd for C17H11N3O2: C, 70.58; H,
3.83; N, 14.53. Found: C, 70.30; H, 3.86; N, 14.43.
filtering of the supernatant solution (3 x 10 mL, each). The
combined organic phases were washed with 2 M aq NaOH,
then water and extracted into 3 M aq HCl. The combined
aqueous extracts were washed with Et2O, rendered basic by
addition of ice-cold 2 M aq. NaOH and extracted with CH2Cl2.
The combined organic extracts were washed with water, dried
(Na2SO4), concentrated in vacuo and the resulting viscous oil
purified by column chromatography (3:97 - EtOAc:CH2Cl2,
alumina activity III) to afford 2a (0.32 g) as a pale yellow
crystalline solid, recrystallized (CH2Cl2 - heptane) for
elemental analysis; 1H NMR (300 MHz, CDCl3): d = 8.71 (s,
2H, H-5; H-6), 8.58 (br d, J = 4 Hz, 1H, H-6"'), 8.42 (dt, J =
1.3; 4.7 Hz, 1H, H-6"), 8.36 (dd, J = 1.0; 7.9 Hz, 1H, H-5'),
8.12 (dd, J = 1.0; 7.7 Hz, 1H, H-3'), 7.96 (t, J = 7.8 Hz, 1H, H-
4'), 7.79-7.82 (m, 2H, H-3", H-4"), 7.52 (dt, J = 7.8; 1.7 Hz,
1H, H-4"'), 7.22 (br d, J = 6.8 Hz, 1H, H-3"'), 7.17-7.21 (m,
2H, H-5"; H-5"'); EI-MS (70 eV): m/z (relative intensity) =
311 (M+, 70), 310 (100), 283 (7), 233 (20), 155 (8); Anal.
Calcd for C19H13N5: C, 73.30; H, 4.21; N, 22.49. Found: C,
73.17; H, 4.36; N, 22.84.
(16) Rubottom, G. M.; Juve, H. D. J. Org. Chem. 1983, 48, 422.
(17) Krow, G. R. Org. React. (N.Y.); Paquette, L. A., Ed.; 1993, 43,
251.
(18) E.g., bromine, iodine, magnesium monoperoxyphthalic acid,
peracetic acid, Davis's oxirane, Brederick's reagent and
pyridinium chlorochromate. See: Bonadies, F.; Bonini, C.
Synth. Commun. 1988, 18, 1573; Davis, F. A.; Sheppard, A. C.
J. Org. Chem. 1987, 52, 954; Wasserman, H. H.; Ives, J. L. J.
Org. Chem. 1985, 50, 3573; Eistert, B.; Endres, E. Liebigs
Ann. 1970, 734, 56; Vogel, E.; Klug, W.; Breuer, A. Organic
Syntheses, Coll. Vol. 6; Noland, W. E. Ed.; Wiley: New York,
1988.
(20) Constable, E. C. Tetrahedron 1992, 48, 10013; Bassani, D.
M.; Lehn, J.-M.; Baum, G.; Fenske, D. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1845.
(19) Typical procedure: 2a: A solution of 3a (0.42 g, 1.4 mmol)
and 1,2-diaminoethane (0.097 mL, 1.4 mmol) in EtOH (10
mL) was heated under reflux (2 h). After solvent evaporation
in vacuo, the residual red solid and chloranil (0.36 g, 1.4
mmol) in xylene (10 mL) were heated under reflux (6 h). The
cooled reaction mixture was filtered through a celite pad, the
residual insoluble material treated with PhMe and then 2 M
aq. NaOH in an ultrasonic cleaning bath with repeated
(21) See: Boyd, D. R.; Evans, T. A.; Jennings, W. B.; Malone, J.
F.; O'Sullivan, W.; Smith, A. J. Chem. Soc., Chem. Commun.
1996, 2269.
Article Identifier:
1437-2096,E;1999,0,08,1203,1206,ftx,en;G13899ST.pdf
Synlett 1999, No. 8, 1203–1206 ISSN 0936-5214 © Thieme Stuttgart · New York