Lithium-mediated zincation of pyrazine, pyridazine, pyrimidine, and quinoxaline

Article abstract of DOI:10.1021/jo0708341

(Chemical Equation Presented) Deprotonation of pyrazine, pyridazine, pyrimidine, and quinoxaline using an in situ mixture of ZnCl₂· TMEDA (0.5 equiv) and LiTMP (1.5 equiv) was studied. Pyrazine and pyrimidine were deprotonated in THF at room te

Full text of DOI:10.1021/jo0708341

for the deprotonation of diazines, a method still requiring low
temperatures and not extendable to unsubstituted substrates.5
Lithium-Mediated Zincation of Pyrazine,
Pyridazine, Pyrimidine, and Quinoxaline
Kondo described in 1999 the deprotonation reactions of
functionalized aromatics such as alkyl benzoates, ethyl thiophen-
ecarboxylates, ethyl 2-furancarboxylate, pyridine, quinoline, and
Anne Seggio, Floris Chevallier, Michel Vaultier, and
Florence Mongin*
t
isoquinoline using a zincate, Bu2Zn(TMP)Li.6 The reaction
Synthe`se et ElectroSynthe`se Organiques, UMR 6510 CNRS,
UniVersite´ de Rennes 1, Baˆtiment 10A, Case 1003, Campus
Scientifique de Beaulieu, 35042 Rennes Cedex, France
carried out in THF at rt proved to be chemoselective, but
required 1 or 2 equiv of base, only TMP participating in the
reaction.
Mulvey has reported since 2005 several examples of efficient
deprotonation using lithium or sodium amido-zincates.7 The term
alkali-metal-mediated zincation has been introduced to depict
these reactions since the reactivity (“synergy”) exhibited by the
zincates cannot be replicated by the homometallic compounds
on their own.8
ReceiVed April 20, 2007
Herein, we describe the optimized deprotonation reaction of
diazines using a zinc diamide-lithium amide mixture.
The addition of one molar equivalent (per lithium) of TMEDA
or THF to a bulk nonpolar hydrocarbon in order to increase the
opportunity for crystal growth proved to favor the deprotonation
reactions of N,N-diisopropylcarboxamide7c,d and anisole7g using
lithium amidozincates. We therefore decided to prepare a base
from ZnCl2‚TMEDA,9 much less hygroscopic than ZnCl2, and
to study its ability to deprotonate diazines. We chose to combine
ZnCl2‚TMEDA with 3 equiv of LiTMP10 and first turned to
the deprotonation of pyrazine (1) (Table 1).
Deprotonation of pyrazine, pyridazine, pyrimidine, and
quinoxaline using an in situ mixture of ZnCl2‚TMEDA (0.5
equiv) and LiTMP (1.5 equiv) was studied. Pyrazine and
pyrimidine were deprotonated in THF at room temperature,
a result evidenced by trapping with I2. The competitive
formation of dimer observed in net hexane was reduced by
using cosolvents (TMEDA or THF). Starting from quinoxa-
line, the dimer formation took place in THF also, and
mixtures of mono- and diiodides were obtained whatever
the solvent and conditions used. A similar competitive
formation of a diiodide was noted with pyridazine; the use
of THF at reflux temperature nevertheless afforded the 3-iodo
derivative in good yield.
(3) Ple´, N.; Turck, A.; Couture, K.; Que´guiner, G. J. Org. Chem. 1995,
60, 3781-3786.
(4) Imahori, T.; Kondo, Y. J. Am. Chem. Soc. 2003, 125, 8082-8083.
(5) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. 2006,
118, 3024-3027; Angew. Chem., Int. Ed. 2006, 45, 2958-2961. Concerning
lithium magnesates in the diazine series obtained by iodine-metal exchange,
see: (b) Buron, F.; Ple´, N.; Turck, A.; Marsais, F. Synlett 2006, 1586-
1588.
Substituted diazines are structural units present in many
pharmaceutical synthetic intermediates and natural products.1
Among the methods used to functionalize diazines,1 deproto-
nation reactions using lithiated bases have been developed.2
Metalation of diazines is a difficult challenge due to very facile
nucleophilic addition reactions in relation with the low LUMOs
energy levels of these substrates. Recourse to dialkylamides such
as lithium diisopropylamide (LiDA) and lithium 2,2,6,6-
tetramethylpiperidide (LiTMP) generally allowed substituted
diazines to be deprotonated. Concerning the parent diazines,
metalation of pyrazine and pyridazine was found possible with
an excess of LiTMP and very short reaction times at very low
temperatures, while metalation of pyrimidine could only be
accomplished using the in situ trapping technique.3 More
recently, Kondo described the unprecedented regioselective
functionalization of pyridazine and pyrimidine at positions 4
(6) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539-3540. See also: (b) Imahori, T.; Uchiyama, M.;
Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450-2451. (c) Uchiyama,
M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo,
Y. J. Am. Chem. Soc. 2002, 124, 8514-8515. (d) Uchiyama, M.;
Matsumoto, Y.; Nobuto, D.; Furuyama, T.; Yamaguchi, K.; Morokuma,
K. J. Am. Chem. Soc. 2006, 128, 8748-8750. (e) Uchiyama, M.;
Matsumoto, Y.; Usui, S.; Hashimoto, Y.; Morokuma, K. Angew. Chem.,
Int. Ed. 2007, 46, 926-929.
(7) (a) Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman,
G. W.; Kennedy, A. R.; Mulvey, R. E. Angew. Chem. 2005, 117, 6172-
6175; Angew. Chem., Int. Ed. 2005, 44, 6018-6021. (b) Andrikopoulos,
P. C.; Armstrong, D. R.; Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia,
E.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. J. Am. Chem. Soc.
2005, 127, 6184-6185. (c) Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman,
G. W.; Mulvey, R. E. Angew. Chem. 2006, 118, 2430-2434; Angew. Chem.,
Int. Ed. 2006, 45, 2370-2374. (d) Clegg, W.; Dale, S. H.; Harrington, R.
W.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew. Chem. 2006, 118,
2434-2437; Angew. Chem., Int. Ed. 2006, 45, 2374-2377. (e) Armstrong,
D. R.; Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.; Honeyman, G. W.;
Mulvey, R. E. Angew. Chem. 2006, 118, 3859-3862; Angew. Chem., Int.
Ed. 2006, 45, 3775-3778. (f) Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L.
M.; Honeyman, G. W.; Mulvey, R. E.; O’Hara, C. T. Angew. Chem. 2006,
118, 6698-6700; Angew. Chem., Int. Ed. 2006, 45, 6548-6550. (g) Clegg,
W.; Dale, S. H.; Drummond, A. M.; Hevia, E.; Honeyman, G. W.; Mulvey,
R. E. J. Am. Chem. Soc. 2006, 128, 7434-7435. (h) 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, 598-600.
(8) For reviews, see: (a) Mulvey, R. E. Organometallics 2006, 25, 1060-
1075. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew.
Chem. 2007, 119, 3876-3899; Angew. Chem., Int. Ed. 2007, 46, 3802-
3824.
t
and 5, respectively, using hindered phosphazene Bu-P4 base
and ZnI2 as additive in toluene in the presence of a carbonylated
compound as electrophile.4 Knochel reported in 2006 the use
of mixed lithium-magnesium amides such as (TMP)MgCl‚LiCl
* To whom correspondence should be addressed. E-mail: florence.
mongin@univ-rennes1.fr.
(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, New York, 2003;
Chapter 6.
(9) Concerning the synthesis of a lithium zincate from ZnCl2‚TMEDA,
see: Kjonaas, R. A.; Hoffer, R. K. J. Org. Chem. 1988, 53, 4133-4135.
(10) In the previously described bases of Kondo’s type, Zn is surrounded
by two tert-butyls and one TMP. We thought deprotonation of diazines,
which are prone to nucleophilic addition, would be more likely if the use
of alkyls was avoided.
(2) (a) Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV.
Heterocycl. Chem. 1991, 52, 187-304. (b) Godard, A.; Turck, A.; Ple´, N.;
Marsais, F.; Que´guiner, G. Trends Heterocycl. Chem. 1993, 3, 16-29. (c)
Turck, A.; Ple´, N.; Que´guiner, G. Heterocycles 1994, 37, 2149-2172. (d)
Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489-
4505.
10.1021/jo0708341 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/27/2007
6602
J. Org. Chem. 2007, 72, 6602-6605

at -75 °C.3 In addition, 4 equiv of LiTMP were necessary with
the previously reported procedure to give a 44% yield of 2a,3
against 0.5 equiv of ZnCl2‚TMEDA and 1.5 equiv of LiTMP
with our method to provide 2a in 59% yield. The reason why
the dimer 3 forms more easily when hexane is used instead of
THF could be linked to stronger interactions between the
pyrazine nitrogen and lithium in the absence of chelating solvent,
activating the diazine ring for nucleophilic addition. Such
interactions could be reduced using 5 additional equiv of
TMEDA or 10 equiv of THF.
TABLE 1. Deprotonation of Pyrazine (1) Using an in Situ Pre-
pared Mixture of ZnCl2‚TMEDA (0.5 Equiv) and LiTMP (1.5 Equiv)
cosolvent
(equiv)
1/2/3
compound
(yield %)
entry solvent
electrophile, El
ratioa
When the deprotonation of pyrazine (1) was conducted in
hexane, the dimer 3 was identified along with the expected
iodide 2a. Starting from quinoxaline (4) (Table 2), the formation
of a dimer (compound 7) was also observed at rt (entry 1) or
under reflux (entry 2) but, more importantly, both the monoio-
dide 5 and the diiodide 6 were obtained after trapping with
iodine. This result was not significantly modified in the presence
of 5 additional equiv of TMEDA (entry 3) or 10 equiv of THF
(entry 4). Using bulk THF instead of hexane, the formation of
the iodo derivatives 5 and 6 was favored (entries 5-7) with
yields of 25 and 17%, respectively, under reflux (entry 6).
The formation of dizincated arenes has been described
recently by deprotonation using a zincate: naphthalene was
dideprotonated at both the 2 and 6 positions,7f and benzene at
1
2
3
4
5
6
THF
-
I2, I
I2, I
8/91/1
8/67/25
3/96/1
2/97/1
2/97/1
2a (59b [44c])
hexane
-
-
hexane TMEDA (5) I2, I
hexane THF (10)
THF
THF
-
I2, I
-
TMEDA (5) I2, I
-
2a (46b)
ClPPh2, P(O)Ph2 13/86/1 2b (52)
a Determined by 1H NMR spectroscopy. b Decomposition of compound
2a observed at rt. c Using 4 equiv of LiTMP, -75 °C, 6 min.3
The first experiment was carried out with 0.5 equiv of ZnCl2‚
TMEDA and 1.5 equiv of LiTMP in THF at rt. Trapping with
iodine after 2 h afforded the expected iodide 2a in 59% yield
(entry 1). The observation by Mulvey of a positive effect of a
stoichiometric amount of TMEDA on the efficiency of depro-
tonations using lithium zincates in hexane7c,d,g led us to substitute
THF by hexane. Under the same reaction conditions, the dimer
3 was identified together with the iodide 2a by NMR analysis
of the crude (entry 2). Thus, deprotonation occurred but was
probably followed either by reaction of the zincated pyrazine
with the pyrazine starting material or by 1,2-migration11 of the
pyrazyl group as depicted in Scheme 1. By adding 5 additional
equiv of TMEDA (entry 3) or 10 equiv of THF (entry 4) to
hexane,12 the dimer 3 formation was lowered. A similar
conversion was noted adding TMEDA to THF,13 but the iodide
2a was isolated in a moderate 46% yield (entry 5). With the
use of chlorodiphenylphosphine as electrophile and THF without
cosolvent, the phosphine oxide14 2b was obtained in 52% yield
(entry 6).
t
both the 1 and 4 positions,7h when treated with Bu2Zn(TMP)-
Na‚TMEDA in hexane. Even if dimetalated compounds such
as 1,3- and 1,4-phenylenedisodiums, 2,5-furandiyldisodium, 2,5-
furandiyldilithium, 2,5-thiophenediyldisodium, and 4,6-diben-
zofurandiyldisodium have been evidenced, the generation of
dideprotonated species is generally precluded by using a
stoichiometric amount of base in a solvent of sufficient polarity
such as THF.16 Using polar additives or solvents with quinoxa-
line (4), the formation of the diiodide 6 was still observed (albeit
lowered). Nevertheless, when detected in polar solvents, the
kinetically formed dilithio species revert to the thermodynami-
cally more stable monometal species.16 In contrast, the dizin-
cated substrates are still present after long reaction times, a result
that could be attributed to their relative stability compared to
that of the corresponding bis(alkali metal) compounds.
We next turned to the deprotonation of pyridazine (8) (Table
3) and first used as a deprotonation procedure treatment with
0.5 equiv of ZnCl2‚TMEDA and 1.5 equiv of LiTMP in THF
at rt for 2 h. Under these conditions, a mixture of the 3-iodo 9
and 4-iodo 10 derivatives was obtained after trapping with iodine
(entry 1). Increasing the reaction temperature to reflux resulted
in the concomitant formation of the diiodide 11, which was
SCHEME 1. Proposed Pathway for the Formation of 3
1
identified by its H NMR, 13C NMR, and mass spectra (entry
2). Adding 5 equiv of TMEDA favored the formation of the
3-iodo isomer 9, which was isolated in 66% yield (entry 3).
Replacing THF with hexane resulted in low conversions and
competitive formation of the compound 11 whether the reaction
The degradation of the pyrazylzincate was not observed in
THF at rt after 2 h,15 while lithiopyrazine decomposes rapidly
TABLE 2. Deprotonation of Quinoxaline (4) Using an in Situ Prepared Mixture of ZnCl2‚TMEDA (0.5 equiv) and LiTMP (1.5 equiv)
entry
solvent
cosolvent (equiv)
temp.
4/5/6/7 ratioa
compound yield (%)
1
2
3
4
5
6
7
hexane
hexane
hexane
hexane
THF
-
rt
27/38/25/10b
13/33/31/23b
29/19/18/34b
19/43/22/16
9/58/18/15
-
-
reflux
reflux
reflux
25 °C
reflux
reflux
5 (20); 6 (4)
TMEDA (5)
THF (10)
-
7 (11)
-
-
THF
-
3/61/21/15b
2/43/21/34b
5 (25); 6 (17)
THF
TMEDA (5)
-
1
a Determined by H NMR spectroscopy. b Presence of numerous other products in the crude.
J. Org. Chem, Vol. 72, No. 17, 2007 6603

TABLE 3. Deprotonation of Pyridazine (8) Using an in Situ Prepared Mixture of ZnCl2‚TMEDA (0.5 equiv) and LiTMP (1.5 equiv)
entry
solvent
cosolvent (equiv)
temp.
8/9/10/11 ratioa
compound (yield %)
1
2
3
4
5
6
7
8
THF
-
rt
3/73/24/0
9, (- [16b])
THF
-
reflux
reflux
rt
6/64/21/9
-
THF
TMEDA (5)
-
11/74/8/7
9 (66)
-
hexane
hexane
hexane
hexane
hexane
54/27/8/11
35/41/11/13
17/58/11/14c
24/65/11/0
5/83/12/0
-
reflux
reflux
reflux
reflux
-
TMEDA (5)
PMDTA (5)
THF (10)
-
-
9 (30)
1
a Determined by H NMR spectroscopy. b Using 4 equiv of LiTMP, -75 °C, 6 min.3 c Traces of 3,6-diiodopyridazine (about 3%) were detected on the
spectra of the crude mixture.
TABLE 4. Deprotonation of Pyrimidine (12) Using an in Situ Pre-
was conducted at rt (entry 4) or under reflux (entry 5), with
pared Mixture of ZnCl2‚TMEDA (0.5 equiv) and LiTMP (1.5 equiv)
(entry 6) or without TMEDA. The compound 11 was not
detected, and better regioselectivities were observed by replacing
TMEDA with PMDTA (entry 7) or THF (entry 8), but the iodide
9 was isolated in a moderate 30% yield using the latter.
The degradation of the pyridazylzincate was not observed in
THF or hexane after 2 h at reflux, with or without additives,
while lithiopyridazine decomposes rapidly at -75 °C.3 Our
method gave the iodide 9 in a better yield than using LiTMP
entry temp. (°C) electrophile, El 12/13/14/15 ratioa compound (yield %)
(66% yield after interception with iodine against 16% using the
lithium amide).3 LiTMP being more selective than the more
1
2
3
4
5
0
I2, I
4/75/6/15
0/93/3/4
0/91/4/5
0/71/8/21
0/75/0/15
-
25
I2, I
13a (57 [0b])
-
hindered lithium zincate, the incomplete regioselectivity of the
deprotonation could be in relation with the size of the depro-
tonating agent.3 The formation of the diiodide 11 could be due
to a competitive deprotonation of the iodide 9 or 10 during the
addition of the THF iodine solution. Nevertheless, a faster
addition of the electrophile solution not favoring the monoio-
dides formation,17 the diiodide 11 could rather result from a
dideprotonation, as noted with quinoxaline (4).
The deprotonation of pyrimidine (12) was finally investigated
(Table 4). The reaction was performed in THF at temperatures
ranging from 0 °C to reflux (entries 1-4). After trapping with
iodine, mixtures of the 4-iodo 13a, the 5-iodo 14a, and the 4,4′-
dimer 15 were obtained whatever the temperature. The 4,4′-
dimer formation being minimal at 25 °C, a good 97%
regioselectivity was observed for the iodide 13a, which was
isolated in 57% yield (entry 2). Using the same deprotonation
conditions, the phosphine 13b was produced in 42% yield after
interception with chlorodiphenylphosphine (entry 5). As previ-
ously noted with pyrazine (1), the formation of dimer was
favored in hexane.
40
reflux
25
I2, I
I2, I
ClPPh2, PPh2
13a (16)
13b (42)
1
a Determined by H NMR spectroscopy. b Using LiTMP, whatever the
temperature.
lower conversion and degradation, respectively, we assumed
that the deprotonating species was (TMP)3ZnLi‚TMEDA.18 The
competitive formation of dimers sometimes observed in net
hexane (e.g., with pyrazine) was reduced by adding cosolvents
(TMEDA or THF). Competitive formation of diiodides was
noted with quinoxaline and pyridazine.
The main advantage of this methodology is the relative
stability of the organometallic species formed: hydrogen-
lithium exchange has to be performed at low temperature (-75
°C) in order to prevent side nucleophilic addition while
hydrogen-zinc exchange proceeds at rt or more.
Experimental Section
Whereas 4-pyrimidyllithium could only be generated using
the in situ trapping technique,3 the pyrimidylzincate was
accumulated in THF at 25 °C (4% of the 4,4′-dimer after 2 h).
In conclusion, pyrazine, pyridazine, and pyrimidine were
deprotonated on treatment with 0.5 equiv of ZnCl2‚TMEDA
and 1.5 equiv of LiTMP in THF at rt or reflux, a result
evidenced by trapping with I2. Since (TMP)2Zn and LiTMP give
Deprotonation of Pyrazine. To a stirred, cooled (0 °C) solution
of 2,2,6,6-tetramethylpiperidine (0.53 mL, 3.0 mmol) in THF (3
mL) were successively added BuLi (1.6 M hexanes solution, 3.0
mmol) and ZnCl2‚TMEDA19 (0.25 g, 1.0 mmol). The mixture was
stirred for 10 min at 0 °C before introduction of pyrazine (0.16 g,
2.0 mmol). After 2 h at room temperature, a solution of I2 (0.76 g,
3.0 mmol) in THF (5 mL) was added. The mixture was stirred
overnight before addition of an aq saturated solution of Na2S2O3
(2 mL) and extraction with EtOAc (3 × 15 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure.
(11) Concerning 1,2-migration of zincates, see: Harada, T.; Chiba, M.;
Oku, A. J. Org. Chem. 1999, 64, 8210-8213.
(12) Seggio, A.; Lannou, M.-I.; Chevallier, F.; Nobuto, D.; Uchiyama,
M.; Golhen, S.; Roisnel, T.; Mongin, F. In press.
(13) The effect of TMEDA is generally weakened when used in THF:
Collum, D. B. Acc. Chem. Res. 1992, 25, 448-454.
(14) The oxidation of (diphenylphosphino)pyrazine could not be avoided.
(15) The 1H NMR spectra of the crude only shows the presence of
residual pyrazine.
Iodopyrazine (2a). 2a was obtained according to the pyrazine
deprotonation procedure and isolated after purification by flash
chromatography on silica gel (CH2Cl2) as a pale-yellow powder
(18) The in situ prepared mixture of ZnCl2‚TMEDA (0.5 equiv) and
LiTMP (1.5 equiv) in THF was analyzed by NMR: the 13C spectra showed
that the main species in solution are LiTMP and (TMP)2Zn.
(19) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977,
679-682.
(16) Schlosser, M. Angew. Chem. 2005, 117, 380-398; Angew. Chem.,
Int. Ed. 2005, 44, 376-393.
(17) The reverse addition was not attempted, due to the low solubility
of the pyridazylzincate.
6604 J. Org. Chem., Vol. 72, No. 17, 2007

(0.24 g, 59%); mp 90 °C dec. 1H NMR (CDCl3): δ 8.38 (dd, 1H,
J ) 1.3 and 2.8), 8.50 (d, 1H, J ) 2.8), 8.86 (d, 1H, J ) 1.3).
These values are consistent with the literature.3 13C NMR
(CDCl3): δ 118.6, 143.1, 146.0, 153.4. HRMS: calcd for C4H3N2I
(M+•) 205.9341, found 205.9355.
mL). The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure.
3-Iodopyridazine (9). 9 was obtained according to the pyridazine
deprotonation procedure and isolated after purification by flash
chromatography on silica gel (CH2Cl2/EtOAc, 100:0 to 70:30) as
a yellow powder (0.27 g, 66%); mp 130 °C dec. 1H NMR
(CDCl3): δ 7.16 (dd, 1H, J ) 8.6 and 5.0), 7.88 (dd, 1H, J ) 8.6
and 1.2), 9.14 (dd, 1H, J ) 1.2 and 5.0). These values are consistent
with the literature.3 13C NMR (CDCl3): δ 125.8, 127.3, 137.4,
150.6. HRMS: calcd for C4H3N2I (M+•) 205.9341, found 205.9335.
4-Iodopyridazine (10). 10 was obtained according to the
pyridazine deprotonation procedure and identified in the crude
mixture. 1H NMR (CDCl3): δ 8.20 (dd, 1H, J ) 5.4, 2.2), 8.92 (d,
1H, J ) 5.4), 9.49 (s, 1H). 13C NMR (CDCl3): δ 101.1, 135.6,
151.2, 158.4.
3,5-Diiodopyridazine (11). 11 was obtained according to the
pyridazine deprotonation procedure and identified in the crude
mixture. 1H NMR (CDCl3): δ 8.31 (d, 1H, J ) 1.7), 9.35 (d, 1H,
J ) 1.6). 13C NMR (CDCl3): δ 100.8, 124.3, 145.1, 157.1.
HRMS: calcd for C4H2N2I2 (M+•) 331.8307, found 331.8298.
Deprotonation of Pyrimidine. To a stirred, cooled (0 °C) solu-
tion of 2,2,6,6-tetramethylpiperidine (0.53 mL, 3.0 mmol) in THF
(3 mL) were successively added BuLi (1.6 M hexanes solution,
3.0 mmol) and ZnCl2‚TMEDA19 (0.25 g, 1.0 mmol). The mixture
was stirred for 10 min at 0 °C before introduction of pyrimidine
(0.16 g, 2.0 mmol). After 2 h at 25 °C, a solution of I2 (0.76 g, 3.0
mmol) in THF (5 mL) was added. The mixture was stirred overnight
before addition of an aq saturated solution of Na2S2O3 (2 mL) and
extraction with EtOAc (3 × 15 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure.
Bipyrazine (3). 3 was obtained according to the pyrazine
1
deprotonation procedure and identified in the crude mixture. H
NMR (CDCl3): δ 8.56 (s, 4H), 9.46 (s, 2H). These values are
consistent with the literature.20 HRMS: calcd for C8H6N4 (M+•)
158.0592, found 158.0590.
(Diphenylphosphino)pyrazine Oxide (2b). 2b was obtained
according to the pyrazine deprotonation procedure using ClPPh2
(0.54 mL, 3.0 mmol) instead of I2 as electrophile. The product was
isolated after purification by flash chromatography on silica gel
(pentane/EtOAc, 70:30 to 0:100) as a white powder (0.29 g, 55%);
mp 120 °C. 1H NMR (CDCl3): δ 7.49 (m, 6H), 7.86 (dd, 4H, J )
7.8 and 11.8), 8.69 (m, 2H), 9.40 (s, 1H). 13C NMR (CDCl3): δ
128.7 (d, 4C, JP ) 12), 131.2 (d, 2C, JP ) 105), 132.1 (d, 4C, JP
) 10), 132.5 (d, 2C, JP ) 3), 144.9 (d, JP ) 15), 146.4 (d, JP ) 3),
148.7 (d, JP ) 20), 152.4 (d, JP ) 125). 31P NMR (CDCl3): δ
20.1. HRMS: calcd for C16H13N2OP (M+•) 280.0765, found
280.0753.
Deprotonation of Quinoxaline. To a stirred, cooled (0 °C)
solution of 2,2,6,6-tetramethylpiperidine (0.53 mL, 3.0 mmol) in
THF (3 mL) were successively added BuLi (1.6 M hexanes solution,
3.0 mmol) and ZnCl2‚TMEDA19 (0.25 g, 1.0 mmol). The mixture
was stirred for 10 min at 0 °C before introduction of quinoxaline
(0.26 g, 2.0 mmol). After 2 h at reflux, a solution of I2 (0.76 g, 3.0
mmol) in THF (5 mL) was added. The mixture was stirred overnight
before addition of an aq saturated solution of Na2S2O3 (2 mL) and
extraction with EtOAc (3 × 15 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure.
4-Iodopyrimidine (13a). 13a was obtained according to the
pyrimidine deprotonation procedure and isolated after purification
by flash chromatography on silica gel (CH2Cl2/EtOAc, 100:0 to
80:20) as a yellow powder (0.23 g, 57%); mp 112 °C dec. 1H NMR
(CDCl3): δ 7.76 (dd, 1H, J ) 1.3 and 5.3), 8.21 (d, 1H, J ) 5.3),
8.83 (d, 1H, J ) 1.3). 13C NMR (CDCl3): δ 129.6, 133.1, 156.1,
158.6. HRMS: calcd for C4H3IN2 (M+•) 205.9341, found 205.9335.
5-Iodopyrimidine (14a). 14a was obtained according to the
pyrimidine deprotonation procedure and identified in the crude
2-Iodoquinoxaline (5). 5 was obtained according to the qui-
noxaline deprotonation procedure and isolated after purification by
flash chromatography on silica gel (heptane/CH2Cl2, 50:50 to 0:100)
as a pale-yellow powder (0.13 g, 25%). mp 101 °C. 1H NMR
(CDCl3): δ 7.8 (m, 2H), 8.0 (m, 2H), 8.96 (s, 1H). These values
are consistent with the literature.21 13C NMR (CDCl3): δ 118.2,
128.9, 129.6, 130.5, 131.0, 141.1, 144.9, 152.2. HRMS: calcd for
C8H5N2I (M+•) 255.9497, found 255.9495.
1
mixture. H NMR (CDCl3): δ 8.77 (s, 2H), 8.94 (s, 1H).
4,4′-Bipyrimidine (15). 15 was obtained according to the
pyrimidine deprotonation procedure and identified in the crude
mixture. 1H NMR (CDCl3): δ 8.44 (dd, 2H, J ) 1.5 and 5.0), 8.97
(d, 2H, J ) 5.0), 9.36 (d, 2H, J ) 1.5). These values are consistent
with the literature.3,23 HRMS: calcd for C8H6N4 (M+•) 158.0592,
found 158.0575.
2,5-Diiodoquinoxaline (6). 6 was obtained according to the
quinoxaline deprotonation procedure and isolated after purification
by flash chromatography on silica gel (heptane/CH2Cl2, 50:50 to
0:100) as a pale-yellow powder (0.13 g, 17%); mp 199-200 °C.
1H NMR (CDCl3): δ 7.50 (dd, 1H, J ) 7.3 and 8.3), 8.04 (dd, 1H,
J ) 1.2 and 8.3), 8.37 (dd, 1H, J ) 7.3 and 1.2), 9.02 (s, 1H). 13
C
4-(Diphenylphosphino)pyrimidine (13b). 13b was obtained
according to the pyrimidine deprotonation procedure using ClPPh2
(0.54 mL, 3.0 mmol) instead of I2 as electrophile. The product was
isolated after purification by flash chromatography on silica gel
(heptane/EtOAc, 70:30 to 30:70) as a pale-yellow oil (0.22 g, 42%).
1H NMR (CDCl3): δ 7.02 (dd, 1H, J ) 1.5 and 5.2), 7.41 (m,
10H), 8.53 (dd, 1H, J ) 3.0 and 5.2), 9.22 (br dd, 1H, J ) 1.5 and
3.0). 13C NMR (CDCl3): δ 124.4 (d, 2C, JP ) 12), 129.0 (d, 4C,
JP ) 8), 129.9 (2C), 134.0 (d, JP ) 9), 134.6 (d, 4C, JP ) 20),
156.1, 158.3 (d, JP ) 9), 175.3 (d, JP ) 5). 31P NMR (CDCl3): δ
-3.7. HRMS: calcd for C16H13N2P (M+•) 264.0816, found
264.0811.
Acknowledgment. We gratefully acknowledge the financial
support of Re´gion Bretagne, CNRS, and GlaxoSmithKline
(fellowship given to A.S.). We thank Thierry Roisnel for his
contribution to this study. We thank CRMPO (Universite´ de
Rennes 1) for HRMS analysis.
NMR (CDCl3): δ 102.1, 119.3, 129.8, 132.1, 141.0, 141.3, 145.1,
153.2. HRMS: calcd for C8H4N2I2 (M+•) 381.8464, found 381.8447.
The structure of 6 was elucidated on the basis of HMBC NMR
spectroscopy.
2,2′-Biquinoxaline (7). 7 was obtained according to the qui-
noxaline deprotonation procedure and identified in the crude
1
mixture. H NMR (CDCl3): δ 7.85 (m, 4H), 8.24 (m, 4H), 10.10
(s, 2H). These values are consistent with the literature.22 HRMS:
calcd for C16H10N4 (M+•) 258.0905, found 258.0910.
Deprotonation of Pyridazine. To a stirred, cooled (0 °C)
solution of 2,2,6,6-tetramethylpiperidine (0.53 mL, 3.0 mmol) in
THF (3 mL) were successively added BuLi (1.6 M hexanes solution,
3.0 mmol), ZnCl2‚TMEDA19 (0.25 g, 1.0 mmol), and TMEDA (1.5
mL, 10 mmol). The mixture was stirred for 10 min at 0 °C before
introduction of pyridazine (0.16 g, 2.0 mmol). After 2 h at reflux,
a solution of I2 (0.76 g, 3.0 mmol) in THF (5 mL) was added. The
mixture was stirred overnight before addition of an aq saturated
solution of Na2S2O3 (2 mL) and extraction with EtOAc (3 × 15
Supporting Information Available: General procedures and
copies of the 1H, 13C, and 31P NMR spectra of 2b, 6, 13a, and 13b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Fort, Y.; Becker, S.; Caube`re, P. Tetrahedron 1994, 50, 11893-
11902.
JO0708341
(21) Sugimoto, O.; Mori, M.; Moriya, K.; Tanji, K.-I. HelV. Chim. Acta
2001, 84, 1112-1118.
(22) Sugimoto, O.; Sudo, M.; Tanji, K.-I. Tetrahedron 2001, 57, 2133-
(23) Ioachim, E.; Medlycott, E. A.; Polson, M. I. J.; Hanan, G. S. Eur.
J. Org. Chem. 2005, 3775-3780.
2138.
J. Org. Chem, Vol. 72, No. 17, 2007 6605