Synthesis of 2,5-diiodopyrazine by deprotonative dimetalation of pyrazine

Article abstract of DOI:10.1055/s-0028-1083218

The deproto-metalation reactions of pyrimidine and pyrazine were regioselectively carried out using lithium tris(2,2,6,6-tetramethylpiperidino) cadmate in tetrahydrofuran at room temperature. This result was demonstrated by subsequent trapping with iodine to afford 4-iodopyrimidine and 2-iodopyrazine in 71% and 63% yields, respectively. The same reaction performed on pyridazine afforded a mixture of the 3- and 4-iodo derivatives (55% and 41% yields, respectively). From pyrazine, access to the 2,5-diiodo derivative (40% on a 25 mmol scale) proved possible using a larger amount of base (1 equiv instead of 0.33). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083218

PRACTICAL SYNTHETIC PROCEDURES
4033
Synthesis of 2,5-Diiodopyrazine by Deprotonative Dimetalation of Pyrazine
S
ynthesis
e
of 2,5-Diio
a
dopyrazinen-Martial L’Helgoual’ch,a Ghenia Bentabed-Ababsa,a,b Floris Chevallier,a Aïcha Derdour,b Florence Mongin*a
a
Chimie et Photonique Moléculaires, UMR 6510 CNRS, Université de Rennes 1, Bâtiment 10A, Case 1003,
Campus Scientifique de Beaulieu, 35042 Rennes, France
Fax +33(223)236955; E-mail: florence.mongin@univ-rennes1.fr
Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences de l’Université,
Université d’Oran Es-Senia, BP 1524 Es-Senia, Oran 31000, Algeria
b
PSP
Received 29 July 2008; revised 17 August 2008
No141
Abstract: The deproto-metalation reactions of pyrimidine and pyrazine were regioselectively carried out using lithium tris(2,2,6,6-tetra-
methylpiperidino)cadmate in tetrahydrofuran at room temperature. This result was demonstrated by subsequent trapping with iodine to
afford 4-iodopyrimidine and 2-iodopyrazine in 71% and 63% yields, respectively. The same reaction performed on pyridazine afforded a
mixture of the 3- and 4-iodo derivatives (55% and 41% yields, respectively). From pyrazine, access to the 2,5-diiodo derivative (40% on a
25 mmol scale) proved possible using a larger amount of base (1 equiv instead of 0.33).
Key words: metalations, cadmium, lithium, heterocycles, iodine
1) CdCl2⋅TMEDA (1 equiv)
LiTMP (3 equiv)
THF, r.t., 2 h
2) I2
N
N
I
N
N
I
1 58% 2 mmol scale
40% 25 mmol scale
Scheme 1
More recently, RnMLi type compounds (M = nonalkali
metal) have been developed. These species, present in
Introduction
The preparation of functionalized diazines is an important stoichiometric6 or catalytic7 amounts in the reaction mix-
synthetic goal because of the multiple applications of ture, display a large panel of reactivity depending on both
these molecules.1
the metal M and the groups connected to it.
Deprotonative metalation has been widely used as a pow- By combining soft organometallic compounds with alkali
erful method for the regioselective metalation of aromatic additives such as lithium 2,2,6,6-tetramethylpiperidide
rings and various strong bases, such as alkyllithiums and (LiTMP) or lithium chloride, bases [t-Bu2Zn(TMP)Li8
lithium dialkylamides, have been employed for this pur- and (TMP)2Zn·2 MgCl2·2 LiCl;7b TMP = 2,2,6,6-tetra-
pose.2 Even with the latter, either extremely low reaction methylpiperidino] have been prepared and used for the
temperatures or in situ electrophilic trapping are required deproto-metalation of sensitive aromatic substrates.
for aromatics bearing reactive functions (e.g., ester or cy-
ano groups) or sensitive p-deficient heterocycles due to
the high reactivity of the corresponding (hetero)aryllithi-
The metalation of diazines is a difficult challenge due to
very facile nucleophilic addition reactions in relation with
the low LUMO energy levels of these substrates. Re-
course to hindered dialkylamides such as lithium diiso-
ums.
The use of additives for lithium compounds in order to propylamide and lithium 2,2,6,6-tetramethylpiperidide
modify their behavior (‘synergy’) is a challenging field. allowed numerous substituted diazines to be deprotonat-
Various RnMLi type compounds have been prepared, with ed.9 Without substituents, reactions are less obvious. Met-
such species exhibiting properties that cannot be attained alation of pyrazine and pyridazine was found possible
by the homometallic compounds on their own.
using excess lithium 2,2,6,6-tetramethylpiperidide and
very short reaction times at very low temperatures, while
metalation of pyrimidine could only be accomplished us-
ing the in situ trapping technique.10 Kondo described in
2003 the unprecedented regioselective functionalization
of pyridazine and pyrimidine at positions 4 and 5, respec-
tively, using hindered phosphazene t-BuP4 base and
zinc(II) iodide as an additive in toluene, and in the pres-
ence of a carbonylated compound as electrophile.11
Well-known examples are the powerful mixtures of orga-
nolithiums and alkoxides (M = alkali metal) described by
Schlosser,3 Lochmann,4 and Caubère.5
SYNTHESIS 2008, No. 24, pp 4033–4035
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.11.2008
DOI: 10.1055/s-0028-1083218; Art ID: Z18208SS
© Georg Thieme Verlag Stuttgart · New York

4034
J.-M. L’Helgoual’ch et al.
PRACTICAL SYNTHETIC PROCEDURES
I
I
TMEDA (5 equiv)
reflux
2a 66%
I
N
N
N
I
+
N
N
N
N
1) ZnCl2⋅TMEDA (0.5 equiv)
LiTMP (1.5 equiv), THF, 2 h
conditions
2a 55%
2b 41% (x = 1)
r.t.
1) CdCl2⋅TMEDA (x equiv)
LiTMP (3x equiv)
THF, r.t., 2 h
I
N
N
3 57%
2) I2
N
N
N
3 71% (x = 0.5)
N
N
2) I2
N
N
r.t.
4 59%
N
I
4 63% (x = 0.33)
Scheme 2
N
I
Scheme 3
Knochel has reported, since 2006, the use of mixed lithi-
um–magnesium amides, such as (TMP)MgCl·LiCl, for
the deprotonation of diazines;7a,12 the method is powerful,
but it still requires low temperatures, and has not been
used for unsubstituted substrates.
2-Iodopyrazine (4) was isolated in 63% yield using
cadmium(II) chloride–N,N,N¢,N¢-tetramethylethylenedi-
amine (x = 0.33) (0.33 equiv) and lithium 2,2,6,6-
tetramethylpiperidide (1 equiv). If the amounts of cadmi-
um(II) chloride–N,N,N¢,N¢-tetramethylethylenediamine
and lithium 2,2,6,6-tetramethylpiperidide are increased to
0.5 equivalent and one equivalent, respectively, 2,5-di-
iodopyrazine (1) concomitantly forms (20% yield) to the
detriment of 2-iodopyrazine (4) (59% yield).
We recently observed that the metalation of all the unsub-
stituted diazines could be performed at room temperature
or more in tetrahydrofuran using a mixture of bis(2,2,6,6-
tetramethylpiperidino)zinc and lithium 2,2,6,6-tetrameth-
ylpiperidide (0.5 equiv each) [prepared in situ from
ZnCl2·TMEDA13 (0.5 equiv) and LiTMP (1.5 equiv)] a re-
sult evidenced by trapping with iodine (Scheme 2).14
The formation of dimetalated species has been described
using zincate18 or manganate19 type bases; hence, the use
of one equivalent of cadmium(II) chloride–N,N,N¢,N¢-tet-
ramethylethylenediamine and three equivalents of lithium
2,2,6,6-tetramethylpiperidide was used to deprotonate
pyrazine. Under the same reactions conditions, the diio-
dide 1 was isolated in 58% yield when the reaction was
performed on a 2-mmol scale. The protocol could be suc-
cessfully transposed to a 25-mmol scale, albeit providing
compound 1 in a lower yield of 40% (Scheme 1).
In order to seek out a more efficient reagent to deproto-
metalate diazines, we focused on the reaction using the
corresponding mixture with cadmium instead of zinc.15
Indeed, Wittig and co-workers observed in 1951 that the
efficiency of deprotonation reactions of fluorene using
different Ph3MLi reagents was in relation to the size of the
central metal M. In particular, quenching with carbon di-
oxide and subsequent acidic work-up afforded diphenyl-
eneacetic acid in a low 16% yield after ten days reaction
time using lithium triphenylzincate (Ph3ZnLi) as a base
whereas a satisfying 64% yield was obtained after three
days using lithium triphenylcadmate (Ph3CdLi).16
To our knowledge, the synthesis of 2,5-diiodopyrazine (1)
has not been reported by other methods. Similar com-
pounds such as 2-bromo-5-iodopyrazine20 and 2,5-
dibromopyrazine21 have previously been prepared by dia-
zotization of 5-bromopyrazinamine (41% and 66% yield,
respectively), the latter being accessible by bromination
of pyrazinamine (75% yield).22
In contrast to the corresponding Zn–Li base, the in situ
prepared mixture of cadmium(II) chloride–N,N,N¢,N¢-tet-
ramethylethylenediamine (CdCl2·TMEDA)17 and lithium
2,2,6,6-tetramethylpiperidide (3 equiv) seems to provide a
lithium ‘ate’ compound.15
Such compounds can find application as substrates for the
synthesis of molecules endowed with biological23 or
photophysical24 properties.
Scope and Limitations
Reactions were performed under an argon atmosphere. THF was
distilled over sodium/benzophenone. Liquid chromatography sepa-
rations were achieved on silica gel Merck Geduran Si 60 (40–63
Attempts to metalate pyridazine, pyrimidine, or pyrazine
indicated that the Cd–Li base was suitable for an efficient
reaction in tetrahydrofuran at room temperature. Indeed,
subsequent trapping with iodine after two hours afforded
substituted derivatives in satisfying yields. Whereas 4-io-
dopyrimidine (3) was regioselectively formed from pyri-
midine (x = 0.5), a mixture of 3-iodopyridazine (2a) and
4-iodopyridazine (2b) was obtained from pyridazine
(x = 1) in a ~60:40 ratio (Scheme 3).
1
mm). Melting points were measured on a Kofler apparatus. H and
13C NMR were recorded at 200 and 50 MHz, respectively, on a
Bruker ARX-200 spectrometer. Chemical shifts are given in ppm
relative to the solvent residual peak (1H) and the central peak of the
solvent signal (13C).25 IR spectra were taken on a Perkin-Elmer
Spectrum 100 spectrometer. HRMS measurements and elemental
analyses were performed at the CRMPO in Rennes (Centre Régional
de Mesures Physiques de l’Ouest) using a Micromass MS/MS
ZABSpec TOF instrument in EI mode and a Thermo-Finnigan
Flash EA 1112 CHNS analyzer, respectively.
Synthesis 2008, No. 24, 4033–4035 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of 2,5-Diiodopyrazine
4035
Gram-Scale Synthesis of 2,5-Diiodopyrazine (1)
Kondo, Y.; Morokuma, K. J. Am. Chem. Soc. 2008, 130,
472.
To a stirred, cooled (0 °C) soln of 2,2,6,6-tetramethylpiperidine (13
mL, 75 mmol) in THF (25 mL) were successively added 1.6 M BuLi
in hexanes (75 mmol) and CdCl2·TMEDA (7.5 g, 25 mmol). The
mixture was stirred at 0 °C for 15 min before introduction of pyra-
zine (2.0 g, 25 mmol). After 2 h at r.t., a soln of I2 (14 g, 75 mmol)
in THF (25 mL) was added. The mixture was stirred overnight be-
fore addition of sat. aq Na2S2O3 (40 mL) and extraction with EtOAc
(3 × 40 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. Purification by
flash chromatography (silica gel, heptane–CH2Cl2, 100:0 to 80:20)
gave 2,5-diiodopyrazine (3.3 g, 40%) as a yellow powder; mp 141
°C.
(9) (a) Quéguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J.
Adv. Heterocycl. Chem. 1991, 52, 187. (b) Godard, A.;
Turck, A.; Plé, N.; Marsais, F.; Quéguiner, G. Trends
Heterocycl. Chem. 1993, 3, 16. (c) Turck, A.; Plé, N.;
Quéguiner, G. Heterocycles 1994, 37, 2149. (d) Turck, A.;
Plé, N.; Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57,
4489. (e) Chevallier, F.; Mongin, F. Chem. Soc. Rev. 2008,
37, 595.
(10) Plé, N.; Turck, A.; Couture, K.; Quéguiner, G. J. Org. Chem.
1995, 60, 3781.
(11) Imahori, T.; Kondo, Y. J. Am. Chem. Soc. 2003, 125, 8082.
(12) (a) Boudet, N.; Reddy Dubbaka, S.; Knochel, P. Org. Lett.
2008, 10, 1715. (b) Mosrin, M.; Knochel, P. Org. Lett. 2008,
10, 2497.
IR (ATR): 3048, 1431, 1421, 1384, 1267, 1121, 1104, 1004, 886
cm–1.
1H NMR (CDCl3): d = 8.63 (s, 2 H).
13C NMR (CDCl3): d = 116.6 (C2 and C5), 154.1 (C3 and C6).
(13) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett.
1977, 679.
(14) (a) Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F.
J. Org. Chem. 2007, 72, 6602. See also: (b) Seggio, A.;
Lannou, M.-I.; Chevallier, F.; Nobuto, D.; Uchiyama, M.;
Golhen, S.; Roisnel, T.; Mongin, F. Chem. Eur. J. 2007, 13,
9982. (c) L’Helgoual’ch, J.-M.; Seggio, A.; Chevallier, F.;
Yonehara, M.; Jeanneau, E.; Uchiyama, M.; Mongin, F.
J. Org. Chem. 2008, 73, 177.
HRMS: m/z [M] calcd for C4H2I2N2: 331.8307, found: 331.8297.
Anal. Calcd for C4H2I2N2: C, 14.48; H, 0.61; N, 8.44. Found: C,
14.31; H, 0.69; N, 8.48.
Acknowledgment
(15) L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Chevallier, F.;
Yonehara, M.; Uchiyama, M.; Derdour, A.; Mongin F.;
Chem. Commun.; 2008, in press.
(16) Wittig, G.; Meyer, F. J.; Lange, G. Justus Liebigs Ann.
Chem. 1951, 571, 167.
The authors gratefully acknowledge the financial support of Région
Bretagne (to J.-M.L.), MESRS of Algeria (to G.B.) and Rennes
Métropole.
(17) Kedarnath, G.; Kumbhare, L. B.; Jain, V. K.; Phadnis, P. P.;
Nethaji, M. J. Chem. Soc., Dalton Trans. 2006, 2714.
(18) (a) Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.;
Honeyman, G. W.; Mulvey, R. E.; O’Hara, C. T. Angew.
Chem. Int. Ed. 2006, 45, 6548. (b) Armstrong, D. R.; Clegg,
W.; Dale, S. H.; Graham, D. V.; Hevia, E.; Hogg, L. M.;
Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. Chem.
Commun. 2007, 598.
(19) (a) Garcia-Álvarez, J.; Kennedy, A. R.; Klett, J.; Mulvey, R.
E. Angew. Chem. Int. Ed. 2007, 46, 1105. (b) Carrella, L.
M.; Clegg, W.; Graham, D. V.; Hogg, L. M.; Kennedy, A.
L.; Klett, J.; Mulvey, R. E.; Rentschler, E.; Russo, L. Angew.
Chem. Int. Ed. 2007, 46, 4662.
References
(1) (a) Katritzky, A. R. Handbook of Heterocyclic Chemistry,
1st ed.; Pergamon: New York, 1985. (b) Eicher, T.;
Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles,
2nd ed.; Wiley-VCH: Weinheim, 2003, Chap. 6.
(2) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979,
26, 1. (b) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15,
306. (c) Snieckus, V. Chem. Rev. 1990, 90, 879. (d) Gant,
T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(e) Schlosser, M. Organometallics in Synthesis, 2nd ed.;
Wiley: New York, 2002, Chap. I.
(3) Schlosser, M. J. Organomet. Chem. 1967, 8, 9.
(4) Lochmann, L. Eur. J. Inorg. Chem. 2000, 7, 1115.
(5) Caubère, P. Chem. Rev. 1993, 93, 2317.
(6) For reviews, see: (a) Mulvey, R. E. Organometallics 2006,
25, 1060. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.;
Kondo, Y. Angew. Chem. Int. Ed. 2007, 46, 3802.
(20) Pieterse, K.; Lauritsen, A.; Schenning, A. P. H. J.;
Vekemans, J. A. J. M.; Meijer, E. W. Chem. Eur. J. 2003, 9,
5597.
(21) Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 71,
2798.
(7) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958. See also: (b)Wunderlich,S.
H.; Knochel, P. Angew. Chem. Int. Ed. 2007, 46, 7685.
(8) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T.
J. Am. Chem. Soc. 1999, 121, 3539. (b) Uchiyama, M.;
Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada,
T.; Kondo, Y. J. Am. Chem. Soc. 2002, 124, 8514.
(22) Itoh, T.; Kato, S.; Nonoyama, N.; Wada, T.; Maeda, K.;
Mase, T.; Zhao, M. M.; Song, J. Z.; Tschaen, D. M.;
McNamara, J. M. Org. Process Res. Dev. 2006, 10, 822.
(23) See, for example: (a) Tonsiengsom, F.; Miyake, F. Y.;
Yakushijin, K.; Horne, D. A. Synthesis 2006, 49. (b) Garg,
N. K.; Stoltz, B. M. Tetrahedron Lett. 2005, 46, 2423.
(24) For recent examples, see: (a) Saito, R.; Machida, S.; Suzuki,
S.; Katoh, A. Heterocycles 2008, 75, 531. (b) Kojima, T.;
Nishida, J.-i.; Tokito, S.; Tada, H.; Yamashita, Y. Chem.
Commun. 2007, 1430. (c) Marcaccio, M.; Paolucci, F.;
Fontanesi, C.; Fioravanti, G.; Zanarini, S. Inorg. Chim. Acta
2007, 360, 1154. (d) Tsubomura, T.; Enoto, S.; Endo, S.;
Tamane, T.; Matsumoto, K.; Tsukuda, T. Inorg. Chem.
2005, 44, 6373.
(c) Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.;
Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. Angew.
Chem. Int. Ed. 2005, 44, 6018. (d) Clegg, W.; Dale, S. H.;
Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew. Chem.
Int. Ed. 2006, 45, 2370. (e) Clegg, W.; Dale, S. H.;
Harrington, R. W.; Hevia, E.; Honeyman, G. W.; Mulvey, R.
E. Angew. Chem. Int. Ed. 2006, 45, 2374. (f) Clegg, W.;
Dale, S. H.; Drummond, A. M.; Hevia, E.; Honeyman, G.
W.; Mulvey, R. E. J. Am. Chem. Soc. 2006, 128, 7434.
(g) Uchiyama, M.; Matsumoto, Y.; Nobuto, D.; Furuyama,
T.; Yamaguchi, K.; Morokuma, K. J. Am. Chem. Soc. 2006,
128, 8748. (h) Uchiyama, M.; Kobayashi, Y.; Furuyama, T.;
Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, T.;
(25) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
Synthesis 2008, No. 24, 4033–4035 © Thieme Stuttgart · New York