Angewandte
Communications
Chemie
metal. Furthermore, the study highlights that two-metal
synergistic reactions are not confined to concerted, synchron-
ized processes where the metals belong within the same
reagent, but can be extended to tandem, stepwise processes
involving two separately added reagents that do not form
a co-complex.
The study first established through NMR spectroscopy
that LiTMP and GaR3 remain separate in benzene solution[12]
(Supporting Information). Such separation is essential to
action the lithiation step of TMT because, whereas free
LiTMP is a strong base, combining it with, for example,
iBu3Al to form aluminate LiAl(TMP)(iBu)3 greatly dimin-
ishes deprotonating power.[10a] TMT was then attempted on
three classical naked diazines, pyrazine, pyridazine, and
pyridimine, as well as the related nitrogen–sulfur ring
compound benzothiazole.
Figure 1. Molecular structure of [1-(PMDETA)Li-3-(GaR3)-C4H3N2] (1)
with 50% probability displacement ellipsoids. All H atoms except
those in the C4H3N2 ring have been omitted for clarity.
Pyrazine previously required four molar equivalents of
LiTMP in THF at À758C, but only to afford modest yields of
2-substituted derivatives (39–65%, depending on the electro-
phile) mixed in some cases with 2,5-disubstituted species
(16%).[4] When performed at room temperature in hexane
solution, our new LiTMP-trialkylgallium approach in a 1:1:1
stoichiometry with pyrazine selectively afforded the 2-
monogallated pyrazine manifested in the crystalline complex
[1-(PMDETA)Li-3-(GaR3)-C4H3N2] 1 (isolated yield 61%:
note NMR monitoring of reaction showed 1 is obtained
quantitatively, see the Supporting Information).
The role of PMDETA is to aid crystallization and
stabilization of the sensitive metallo species by chelating to
lithium, but it is added at a later stage to avoid undergoing
a competing TMT deprotonation itself. Stoichiometric con-
trol was also evident when the base:trap:substrate ratio was
doubled to 2:2:1, giving the 2,5-digallated pyrazine [1,4-
{(PMDETA)Li}2-2,5-{(GaR3)}2C4H2N2] 2 cleanly as crystals
isolated in a 44% yield (Scheme 2). However, NMR
monitoring of the reaction revealed 2 forms in a 55% yield,
though a second regioisomer is formed in 33%, which appears
to be the analogous product of 2,6-digallation. This stoichio-
metric control contrasts with the performance of zincate
[(THF)LiZn(TMP)tBu2], which operates through a synchron-
ized bimetallic synergy distinct to that of stepwise TMT, as it
affords only the 2,5-disubstituted pyrazine even with a 1:1,
base:substrate stoichiometry.[8] Previously, excess LiTMP
(1.5 equivalents) dispensed as 0.5ZnCl2·TMEDA/1.5LiTMP
in THF produced 59% of the isolated 2-iodopyrazine that
reportedly decomposes at room temperature, but in hexane
a significant amount of coupled dimer product was also
seen.[7a] Note that a control reaction between pyrazine and
Figure 2. Molecular structure of [1,4-{(PMDETA)Li}2-2,5-
{(GaR3)}2C4H2N2] (2) with 50% probability displacement ellipsoids. All
H atoms except those in the C4H2N2 ring have been omitted for clarity.
Li by tridentate PMDETA, though centrosymmetric 2 is
tetranuclear having two Ga and two Li centers. Notably, 2 is
the more congested structure with its GaR3 units having
proximal dispositions to the (PMDETA)Li units; whereas in
2
À
1 these units have a 1,3-separation. The Ga sp C(diazide)
bond lengths show little variation with each other or with the
3
À
Ga sp C(R group) bonds (see the Supporting Information
for full crystallographic details and supporting NMR charac-
terization).
With its 1,2-placement of N atoms, pyridazine offers
a choice of metalation sites. Site selectivity in its metalation is
exceptionally challenging, as evident from previous work
using excess LiTMP in 0.5ZnCl2·TMEDA/1.5LiTMP/I2,
which in hexane at room temperature achieved only 27% of
the 3-iodo product mixed with the 4-iodo, and 3,6-diiodo
derivatives as well as 54% unreacted pyridazine (note yields
determined from NMR data).[7a] In THF, the yield of the 3-
iodo product rises to 66% but only under extreme reflux
conditions. On its own, LiTMP (4 equivalents) in THF at
À758C produced only 16–32% yields of 3-substituted pyr-
idazines following quenching with different electrophiles.[4]
When run in hexane solution at room temperature, our TMT
reaction afforded a 51% yield of the isolated product [2-
(PMDETA)Li-3-(GaR3)-C4H3N2] 3. Interestingly, 1H NMR
[13]
gallate LiGaR4 did not produce any gallation, but only R
group addition, with concomitant dearomatization of the
heterocycle (Supporting Information).
It may seem surprising that sensitive pyrazinyl mono- and
di-carbanions can be trapped in crystalline form at room
temperature and structurally defined, but this is where the
structures become informative as they show that the hetero-
cyclic units of 1 (Figure 1) and 2 (Figure 2) are cooperatively
stabilized through coordination by both the Li and Ga centers
that tie up the lone pairs of the N and C atoms, respectively.
Both structures are monomeric with aggregation blocked at
2
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!