Alkali-metal mediated zincation of N-heterocyclic substrates using the lithium zincate complex, (THF)Li(TMP)Zn(tBu)2 and applications in in situ cross coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2011.06.090

This study investigates the ability of the mixed-metal reagent [Li(TMP)Zn(tBu)₂] 1 to promote direct Zn-H exchange reactions (zincations) of a wide range of N-heterocyclic molecules. The generated metallated intermediates from these reactions are intercepted with I₂ and some of them are also employed as precursors in Pd-catalysed Negishi cross-coupling applications. A comparison with recent precedents in metallation chemistry reveals that for some of these heterocycles, 1 allows improved conversions, under milder conditions and in certain cases, even gives unique regioselectivities.

Full text of DOI:10.1016/j.tetlet.2011.06.090

Tetrahedron Letters 52 (2011) 4590–4594
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Alkali-metal mediated zincation of N-heterocyclic substrates using
the lithium zincate complex, (THF)Li(TMP)Zn(tBu)2 and applications
in in situ cross coupling reactions
Victoria L. Blair a, , David C. Blakemore b, Duncan Hay b, Eva Hevia a, , David C. Pryde b
⇑
⇑
a WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, UK
b Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This study investigates the ability of the mixed-metal reagent [Li(TMP)Zn(tBu)2] 1 to promote direct Zn–
H exchange reactions (zincations) of a wide range of N-heterocyclic molecules. The generated metallated
intermediates from these reactions are intercepted with I2 and some of them are also employed as pre-
cursors in Pd-catalysed Negishi cross-coupling applications. A comparison with recent precedents in met-
allation chemistry reveals that for some of these heterocycles, 1 allows improved conversions, under
milder conditions and in certain cases, even gives unique regioselectivities.
Received 22 April 2011
Revised 3 June 2011
Accepted 24 June 2011
Available online 1 July 2011
Keywords:
Metallation
Zincation
Ó 2011 Elsevier Ltd. All rights reserved.
N-Heterocycles
Lithium
Mixed-metal reagents
Nitrogen-containing heteroaromatic ring systems are key struc-
tural units present in a multitude of pharmaceuticals, natural prod-
ucts, agrochemicals and other biologically active molecules,
making methods to enable their selective functionalization of great
value in synthesis.1–3 One of the most important methodologies
which allows the incorporation of these important molecules into
more complex molecular scaffolds is deprotonative metallation,
traditionally using strong bases, such as alkyl lithiums and lithium
diamides.4,5 However, despite their extensive applications, the use
of these reagents (which generate in situ highly reactive (het-
ero)aryllithiums) imposes severe limitations including the need
for cryogenic temperatures, limited functional group tolerance,
restricted regioselectivity and incompatibility with Pd cross-cou-
pling methods.
TMPMgClꢀLiCl13,14 and related salt-supported reagents such as lith-
ium magnesiate Mg(TMP)2ꢀ2LiCl when paired with the halide
ZnCl2.15
Within the context of TMP-dialkyl zincates, the isolation and
structural characterization of key metallation intermediates (prior
to any electrophilic interception) have demonstrated that these
deprotonations are in fact direct zincations (alkali-metal mediated
zincation, AMMZn) as exemplified in Scheme 1 which feature the
structural outcome of the AMMZn of anisole by lithium-zincate
[Li(TMP)Zn(tBu)2] 1.16
Herein we report a reactivity study using the lithium-zincate
base [Li(TMP)Zn(tBu)2] 1 (Scheme 1) with a range of N-containing
heteroaromatic substrates. The intermediate zincated heterocycles
were quenched with I2 to determine the regioselectivity of the
metallation, or cross-coupled with various electrophiles under
Pd-catalysis. Our results are compared and contrasted to related
reactions within the literature.
Zincate 1 was prepared in situ according to the reported litera-
ture procedure (by mixing LiTMP with tBu2Zn using THF as a sol-
vent)9 and reacted with several heteroarenes such as substituted
pyridines, diazines and their benzo derivatives (Table 1).
Thus, 2-methoxypyridine (2) was zincated selectively at the 3-
position with 1 (1 equiv, 25 °C, 2 h), and after I2 addition gave
the 3-iodo product 2a in a 92% yield (entry 1). This metallation reg-
ioselectivity of 2 has been previously reported using the aluminate
base [iBu3Al(TMP)Li]18 however, low temperatures (ꢁ78 °C) and an
excess of base (2.2 equiv) were required to achieve 82% yield of 2a.
Searching for more efficient reagents which can overcome these
important drawbacks, a new generation of multimetallic reagents
have been developed that allows the regioselective metallation of
various functionalised aromatic and heteroaromatic substrates
offering a wider functional group tolerance, and often requiring
milder reaction conditions.6–8 Pioneering work in this area includes
Kondo and Uchiyama’s TMP–zincate complex [Li(TMP)Zn(tBu)2],
9–11
(TMP = 2,2,6,6-tetramethylpiperidide), Mulvey’s sodium re-
lated analogue [(TMEDA)Na(TMP)Zn(tBu)2]6,12 (TMEDA = N,N,N0,N0-
tetramethylethylenediamine), and Knochel’s Turbo-Grignard
⇑
Corresponding authors.
E-mail address: eva.hevia@strath.ac.uk (E. Hevia).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.090

V. L. Blair et al. / Tetrahedron Letters 52 (2011) 4590–4594
4591
OMe
TMP
TMP
tBuH
Zn tBu
Li
O
Zn tBu
+
O
Li
O
C
H3C
CH3
CH3
Me
1
Scheme 1. AMMZn of anisole and molecular structure of the metallated product [(THF)LiZn(TMP)(C6H4-OMe)(tBu)]16 in the solid-state.
In a related reaction Knochel reported the selective acylation of 2
at the 3-position using the LiCl-complexed aluminate base [(tBu)
NCH(iPr)(tBu)]3Alꢀ3LiCl17 (25 °C, 2 h) in 68% yield.
was previously investigated using LiTMP in the presence of either
23
21
ZnCl2 or CdCl2 to give exclusively the 4-iodo products in 57%
and 71% yields, respectively. Contrasting with this, the use of the
phosphazene base, tBu-P4 and zinc iodide on pyrimidine gave
the 5-metallated species exclusively (Scheme 3).33
We hypothesised that these observations could be rationalized
by initial deprotonation at the position next to the nitrogens of the
ring (either the 2- or 4-positions is possible but metallation at the
2-position would give a very high energy species) while subse-
quent migration to the less destabilized 5-position could then oc-
cur; how much of this is seen would depend on the rates of
migration for the different species under the reaction conditions.
This hypothesis will be investigated further.
Similarly the corresponding 3- and 4-methoxypyridines are also
zincated selectively with 1 under mild conditions (0 °C, 2 h) to give
3a and 4a in 71% and 70% yields (entries 2 and 3), respectively, after
I2 quenching. The lithiation of these substrates has been previously
investigated using mesityllithium (ꢁ23 °C, 3 h). Interestingly the
lithiation promotes a different regioselectivity of substrate 3 which
is metallated exclusively at the 2-position19 to give the meth-
ylsulfanyl compound in 82% yield. Our results are more consistent
with studies on 3-substituted pyridyl systems where the directing
ortho group (DoG) is a carboxylate27 or an o-tetrahydropyran-2-
oxyl (O-THP)28 group. In these cases, lithiation occurs at the 4-posi-
tion of the pyridyl system rather than the 2-position (Scheme 2).
In pyridine itself, the relative acidities around the ring are
700:72:1 (4:3:2 positions).29 The position next to the nitrogen is
considered least acidic because the sp2 lone pair on the nitrogen
has an anti-bonding interaction with the C–Li bond. It is conceiv-
able that our results reflect a similar unfavourable interaction with
the C–Zn bond. Viewed in this light, the results of mesityllithium
may be seen as more unusual (it may also be that the 2-position
is the initial site of deprotonation in all cases but the resulting high
energy species migrates to a lower energy 4-metallated species
under our conditions).
The metallation of pyridazine (8) with 1 unfortunately failed as
its reaction at 0 °C in THF gave a black solution with no recoverable
products or starting materials (entry 7). However selective 3-met-
23
allation has been previously reported with LiTMP and ZnCl2 to
give the 3-iodo product in 66% yield. Alternatively, when reacted
with LiTMP and CdCl2ꢀTMEDA, mixtures of the 3-iodo and 4-iodo
products were observed in an approximate 60:40 ratio.21
Reaction of 1 with the substituted pyrazine 2,6-dichloropyr-
azine (9) gave the expected 3-iodinated product (9a) in a moderate
46% yield after I2 quenching. The yield of this reaction may have
been adversely affected by a competing LiCl elimination reaction
which has been noted before in a similar sodium zincate reaction
with chlorobenzene.34 Contrastingly, it is reported that 9 can be
zincated quantitatively with TMPZnClꢀLiCl and quenched with io-
dine to give 9a in 90% yield.24
Direct zincation at the C2 position of quinoxaline (10) and qui-
nazoline (11) can be accomplished by 1 (0 °C, 2 h, entries 9 and 10)
which after trapping with I2 gave the expected products 10a and
11a in 50% and 69% yields, respectively. This compares to the alter-
native precomplexation of 10 with ZnCl2 followed by reaction with
the lithium magnesiate, TMP2Mgꢀ2LiCl, reported by Knochel15 and
Dong22 which afforded 10a in an almost quantitative 94% yield.
However, we have found no other known alternative metallation
procedures to access 11a.
Significantly, like the attempted metallation of 8, zincate 1
failed to metallate cinnoline (12). Reactions performed at low tem-
peratures resulted in black solutions without recovery of the start-
ing material or any iodinated products. 1H NMR analysis of the
metallated intermediates prior to iodine interception showed the
presence of a complicated mixture of products in solution with
several broad multiplets overlapping in the range 5.5ꢁ 4.5 ppm
which suggests that decomposition of the metallated heterocycle
with loss of aromaticity has likely taken place. It is interesting to
contrast this with the use of ZnCl2 and LiTMP which allows this
deprotonation to occur in good yield; similarly, the use of the phos-
phazene base, tBu-P4 and ZnI2 with pyridazine did not lead to
decomposition but gave the 4-metallated species. Again, this may
suggest that initial deprotonation occurs at the 3-position and
the resulting high energy metallated species may transform into
Turning to pyridine (5), Kondo and Uchiyama9 previously
reported the C-2 zincation of 5 with 1 at room temperature, which
gave the 2-iodopyridine product in 76% yield. In our studies,
repeating this reaction at 0 °C with a shorter reaction time of 1 h
gave a different regioselectivity, namely, the 4-iodopyridine (5a)
product in 50% yield after I2 addition, suggesting that the C-4 zin-
cated species is the kinetic product of this deprotonation reaction.
Closely related temperature-dependent regioselectivities have
been reported for the metallation of trifluoromethylbenzene by
the sodium zincate [(TMEDA)Na(TMP)Zn(tBu)2].30
The next class of heteroaromatics we investigated was the dia-
zines31: specifically, pyrazine (6), pyrimidine (7) and pyridazine
(8). While metallation of diazines with lithium bases such as LiT-
MP32 has been previously reported, very low temperatures, short
reaction times and a large excess of base (4 equiv) were required
resulting in low product yields. Using 1, pyrazine could be twofold
deprotonated selectively at positions 2 and 5 affording product 6a
after I2 trapping in 68% yield (0 °C, 2 equiv, 1 h, entry 5). Interest-
ingly, only products of dimetallation were observed even when
1 equiv of base 1 was used. In a previous metallation study of pyr-
azine21,20,23 a less environmentally friendly lithium cadmate base
was found to deprotonate 6 to give both the mono- and di-iodin-
ated products after I2 trapping in 63% and a lower 58% yield,
respectively. A better alternative for the selective mono-metalla-
tion of pyrazine was recently achieved using TMP2Mgꢀ2LiCl in
the presence of ZnCl2 at room temperature to give the mono-iodin-
ated product in 71% yield.
Deprotonation of pyrimidine (7) with 1 (entry 6) performed in
THF at 0 °C provided mixtures of the 4-iodo and 5-iodo compounds
in a 7:3 ratio after trapping with I2. The selective 4-metallation of 7
the more stable 4-position metallated species (an a-effect is in
operation between the two nitrogen lone pairs in this case and this
may increase the destabilization of the metallated species).

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V. L. Blair et al. / Tetrahedron Letters 52 (2011) 4590–4594
Table 1
Range of N-heterocyclic substrate reactions with [Li(TMP)Zn(tBu)2] 1 and quenching with I2, and the corresponding literature methods
Entry
Substrate
Product obtained using ‘Li(TMP)Zn(tBu)2’
Comparative studies using alternative reagents
I
O
I
82%c
OMe
iBu3Al(TMP)Li
Ph
N
OMe
N
OMe
N
68%b
1
2
a
N
OMe
2a 92%
[(tBu)NCH(iPr)(tBu)]3Al.3LiCl
OMe
OMe
I
mesityllithium
OMe
N
3
N
SMe
SMe
82%d
2
3
71%a
N
3a
OMe
OMe
OMe
N
I
mesityllithium
84%d
70%a
N
N
4a
I
4
Li(TMP)(tBu)2Zn
N
5
I
N
73%f
4
5
N
50%e
5a
N
I
CdCl2.TMEDA
+ LiTMP 63%h
I
N
N
N
N
I
CdCl2.TMEDA
+ LiTMP
68%g
N
6
I
I
N
6a
I
N
TMP2Mg2.LiCl
+ ZnCl2 71%i
58%j
I
CdCl2.TMEDA
+ LiTMP 71%h
N
I
N
N
N
N
7
ZnCl2.TMEDA
+ LiTMP 57%l
+
6
7
N
N
N
30:70e,k
mixture
N
N
I
N
I
N
N
N
N
N
66%m
+
I
Decomposition products
ZnCl2.TMEDA
+ LiTMP
41%h
8
55%
CdCl2.TMEDA + LiTMP
Cl
N
Cl
Cl
46%e
I
Cl
N
Cl
Cl
I
N
TMPZnCl.LiCl
90%n
8
9
N
9
N
N
9a
N
I
N
N
I
TMP2Mg.2LiCl + ZnCl2
94%o
50%e
I
N
N
N
N
10
11
10a
N
N
N
N
10
11
12
69%e
11a
N
Decomposition products
12
N
N
N
N
I
MeS
I
TMPMgCl.LiCl
79%q
N
N
N
89%p
13
13a
N
N
N
TMPZnCl.LiCl
98%r
I
N
N
13
14
98%p
N
N
14
N
14a
N
H
N
N
LDA
85%t
N
60-80%s
N
15
R
15a
R = Me, CHO
N
R
R = Me, CHO
COOMe, Ph
COOMe, Ph
(a) Li(TMP)Zn(tBu)2, 1 equiv, 25 °C, 1–2 h,(I2). (b) TMPMgClꢀLiCl + BF3.OEt2, 0 °C 60 h, (I2).17 (c) iBu3Al(TMP)Li, 2.2 equiv, ꢁ78 °C, 1 h, (I2).18 (d) Mesityllithium, ꢁ23 °C, 3 h,
(MeSSMe 3 equiv).19 (e) Li(TMP)(tBu)2Zn, 1 equiv, 0 °C, 1–2 h(I2). (f) Li(TMP)Zn(tBu)2, 1 equiv, 25 °C, 3 h(I2).9 (g) Li(TMP)Zn(tBu)2, 2 equiv, 0 °C, 1 h (I2). (h)CdCl2.TMEDA + LiTMP,
25 °C, 2 h (I2).20,21 (i) TMP2Mgꢀ2LiCl + ZnCl2, 25 °C, (I2).22 (j) CdCl2ꢀTMEDA + LiTMP, 2 equiv, 25 °C, 2 h (I2).21,20 (k) Determined by 1H NMR spectroscopy. (l) ZnCl2ꢀTMEDA + LiTMP,
25 °C, 2 h, (I2).23 (m) ZnCl2ꢀTMEDA + LiTMP, reflux, 2 h, (I2).23 (n) TMPZnClꢀLiCl, 1.1 equiv, 25 °C (I2).24 (o) TMP2Mgꢀ2LiCl + ZnCl2, 25 °C, 2 h (I2).15 (p) Li(TMP)Zn(tBu)2, 2 equiv,
25 °C, 1 h (I2). (q) TMPMgClꢀLiCl, 25 °C, 1 h (MeSSMe).25 (r) TMPZnClꢀLiCl, 1.1 equiv, 25 °C, (I2). (s) Li(TMP)Zn(tBu)2, 1 equiv, ꢁ78 °C to ꢁ40 °C 1–2 h. (t) LDA, 0–5 °C, MeI-78 °C.26

V. L. Blair et al. / Tetrahedron Letters 52 (2011) 4590–4594
4593
the 5-iodo products 13a and 14a (89% and 98% yields, respectively)
after I2 trapping. Previously reported work using TMPMgClꢀLiCl25
has shown similar functionalisation of the C-5 position of 13 to
give the methylsulfanyl product in 79% yield, while reacting 14
with TMPZnClꢀLiCl (25 °C, 2 h) after I2 quenching gives 14a in
excellent 98% yield. In summary for 5-membered heterocycles,
O
O
I
1. n-BuLi, THF, -78 °C
2. I2
O
O
N
N
(88%)
a-lithiation is the preferred outcome of reaction with the lithiation
occurring at the most acidic centre (typically next to the pyrrole-
like nitrogen).
O
1. LiTMP (3 equiv),
-50 °C
D
O
OH
Finally, 1 was reacted with various 1-substituted indazoles in
an attempt to furnish their 3-iodo derivatives (entry 14), however,
instead we isolated the product of ring-opening, the 2-alkylbenzo-
nitrile compounds 15a in 60–80% yields. This result demonstrates
the instability of the metallated intermediate that even at low tem-
peratures (ꢁ78 °C) undergoes ring-opening to the more energeti-
cally stable compound 15a. Precedent exists in the literature for
a similar reaction with 1-methylindazole and LDA that after MeI
quench gave the similar 2-dimethylaminobenzonitrile compound
in 85% yield.26
Overall zincate 1 offers an alternative deprotonation method
that in some cases is more practical (see typical procedure) and
higher yielding than precedented literature methods (Table 1,
entries 1, 5, 12 and 13). In most instances the quenched products
show the same regioselectivity as the reported alternative bases;
however, in a few select occasions a different metallation pattern
is observed (Table 1, entries 2, 4 and 10).
In order to evaluate the full synthetic utility of these zincated
intermediates as precursors in Negishi cross-coupling reactions to
generate unsymmetrical bis-aryls, we carried out test reactions on
five of the metallated substrates. Reactions of 2-, 3- and 4-methoxy-
pyridine were attempted under palladium catalysis using PdCl2
(dppf) (dppf = 1,10-bis(diphenylphosphino)ferrocene) and 2-bro-
mopyridine or 1-bromo-4-chlorobenzene as coupling partners.
The reactions were heated to 100 °C in THF with microwave irradi-
ation to give the bis-aryl compounds 2b, 3b and 4b (Table 2, entries
OH
N
2. D2O
N
(74%)
Scheme 2. Lithiation of 3-O-THP pyridine and quinoline-3-carboxylic acid.
N
ZnI2, tBu-P4 base, THF
-78 °C to rt
N
N
N
I
(66%)
Scheme 3. Reaction of tBu-4P base and ZnI2 with pyrimidine.
The literature precedent for this deprotonation clearly demon-
strates that the generated metallated species are not too unstable
to react without decomposition, so it is not clear to us why, under
our conditions, decomposition occurs. It is possible that in this case
the metallated species generated under our conditions falls apart
rather than rearranging, but it may also be that our system is more
prone to conjugate addition and subsequent further reaction.
Moving on to five-membered heterocycles, both 1-methylpyra-
zole (13) and 1-methyl-1,2,4-triazole (14) were zincated selec-
tively in the expected most acidic C5-position upon reaction with
1 under mild conditions (25 °C, 2 h, entries 12 and 13) to furnish
Table 2
Metallation/cross-coupling results of selected substrates with base 1
Entry
Substrate
Coupling partner
Catalyst/conditions
Product/yielda
N
OMe
N
Br
N
1
PdCl2(dppf), 2.5 mol %, 100 °C, 10 min
75%
2
N
OMe
2b
OMe
Cl
Cl
Cl
Br
Br
N
3
2
3
PdCl2(dppf), 10 mol %, 110 °C, 10 min
OMe
30%
N
3b
OMe
Cl
N
OMe
PdCl2(dppf), 10 mol %, 110 °C, 10 min
N
41%
N
4b
4
Cl
Cl
Cl
N
N
N
4
5
PdCl2(dppf), 2.5 mol %, 100 °C, 10 min
Pd[P(tBu)3]2, 2.5 mol %, 100 °C, 10 min
Br
Br
67%
51%
13
13b
Cl
N
N
N
N
N
N
14b
14
a
Isolated, analytically pure product.

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V. L. Blair et al. / Tetrahedron Letters 52 (2011) 4590–4594
1, 2 and 3) in isolated yields of 75%, 30% and 41%, respectively. Sim-
ilarly the two five-membered ring heterocycles 13 and 14 (Table 2
entries 4 and 5) were also subjected to palladium-catalysed cross-
coupling reactions under similar conditions to give the correspond-
ing bis-aryl products 13b and 14b in 67% and 51% yields,
respectively.
was purified by column chromatography using a 4 g silica cartridge
and EtOAc/heptane 40:60 as eluent to give 5-(4-chlorophenyl)-1-
methylpyrazole (13b) as a light yellow oil (25.9 mg, 67% yield).
1H NMR (400 MHz, CDCl3) d ppm 3.88 (s, 3H) 6.30 (d, J = 1.95 Hz,
1H) 7.33–7.38 (m, 2H) 7.42–7.47 (m, 2 H) 7.51 (d, J = 1.95 Hz, 1H).
In summary, we have quantified the chemoselective deprotona-
tive zincation reactions of a range of N-based heteroaromatic com-
pounds using the known lithium zincate base [Li(TMP)Zn(tBu)2] 1.
In interesting cases it offers routes to different regioselectivity and
higher yielding reactions compared with previous metallation
methods described in the literature (whether using conventional
organolithium reagents or mixed-metal bases). We have also dem-
onstrated that the relative stability of the organometallic interme-
diates formed allows palladium-catalysed cross-coupling reactions
to be performed successfully, without the need for an additional
transmetallation step enabling the synthesis of unsymmetrical
bis-aryl products.
Acknowledgements
We thank the EPSRC and the University of Strathclyde for the
generous sponsorship of this research (through the award of a
Strathclyde Knowledge Transfer Account Research Exploitation
Partnership).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.090.
References and notes
Preparation of [Li(TMP)Zn(tBu)2] 1
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20. L’Helgoual’ch, J. M.; Bentabed-Ababsa, G.; Chevallier, F.; Yonehara, M.;
Uchiyama, M.; Derdour, A.; Mongin, F. Chem. Commun. 2008, 5375.
21. L’Helgoual’ch, J. M.; Bentabed-Ababsa, G.; Chevallier, F.; Derdour, A.; Mongin, F.
Synthesis 2008, 4033.
22. Dong, Z.-B.; Zhu, W.-H.; Zang, Z.-G.; Li, M.-Z. J. Organomet. Chem. 2010, 695, 775.
23. Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F. J. Org. Chem. 2007, 72, 6602.
24. Morsin, M.; Knochel, P. Org. Lett. 2009, 11, 1837.
In a vial under a N2 atmosphere ZnCl2 (54 mg, 0.4 mmol) was
dissolved in THF (1 mL) and cooled to ꢁ50 °C. Next tBuLi
(0.56 mL of a 1.7 M solution in pentane, 0.8 mmol) was added
dropwise and the solution was allowed to stir at ꢁ50 °C for
40 min. In a separate vial containing TMPH (0.68 mL, 0.4 mmol)
and THF (1 mL), nBuLi (0.25 mL of a 1.6 M solution in hexane,
0.4 mmol) was added dropwise at ꢁ50 °C and the solution was
allowed to stir for 40 min reaching room temperature. Next the
LiTMP solution was introduced to the in situ tBu2Zn solution at
ꢁ50 °C and the reaction was allowed to stir for 30 min and warmed
gradually to 0 °C.35 The resultant light yellow solution was further
reacted with various heterocyclic substrates.36
Typical iodination procedure
[Li(TMP)Zn(tBu)2] 1 was prepared on a 0.4 mmol scale in THF.
To this solution 2-methoxypyridine (0.042 mL, 0.4 mmol) was
added and the resultant light orange reaction allowed to stir at
room temperature for 2 h. Next, the solution was cooled to 0 °C
and quenched with I2 (508 mg, in 1 mL THF) and allowed to stir
for 1 h. A 10% solution of Na2S2O3 was added until bleaching and
the product extracted with CH2Cl2 (3 ꢂ 1 mL). The combined
organic extracts were dried over MgSO4 and the solvent removed
under reduced pressure. The residue was purified by SiO2 chroma-
tography using heptane/CH2Cl2 as eluent (20:80 ? 40:60) to give
3-iodo-2-methoxypyridine (2a) as a colourless oil (87.1 mg, 92%
yield). 1H NMR (400 MHz, CDCl3) d ppm 4.00 (s, 3H) 6.65 (dd,
J = 7.61, 4.88 Hz, 1H) 8.03 (dd, J = 7.61, 1.76 Hz, 1H) 8.13 (dd,
J = 4.88, 1.76 Hz, 1H).
25. Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11, 3326.
26. Bunnel, A.; O’Yang, C.; Petrica, A.; Soth, M. J. Synth. Commun. 2006, 36, 285.
27. Rebstock, A. S.; Mongin, F.; Trecourt, F.; Queguiner, G. Tetrahedron Lett. 2002,
43, 767.
Typical cross-coupling procedure
28. Azzouz, R.; Bischoff, L.; Fruit, C.; Marsais, F. Synlett 2006, 1908.
29. Clayden, J. Organolithiums: Selectivity for Synthesis; Elsevier Science Ltd: Oxford,
UK, 2002.
30. Armstrong, D. R.; Blair, V. L.; Clegg, W.; Dale, S. H.; Garcia-Alvarez, J.;
Honeyman, G. W.; Hevia, E.; Mulvey, R. E.; Russo, L. J. Am. Chem. Soc. 2010,
132, 9480.
31. Chevallier, F.; Mongin, F. Chem. Soc. Rev. 2008, 37, 595.
32. Ple, N.; Turck, A.; Couture, K.; Quéguiner, G. J. Org. Chem. 1995, 60, 3781.
33. Imahori, T.; Suzawa, K.; Kondo, Y. Heterocycles 2008, 76, 1057.
34. Armstrong, D. R.; Balloch, L.; Clegg, W.; Dale, S. H.; Garcia-Alvarez, P.; Hevia, E.;
Hogg, L. M.; Kennedy, A. R.; Mulvey, R. E.; O’Hara, C. T. Angew. Chem., Int. Ed.
2009, 48, 8675.
35. Low temperatures (ꢁ50 °C) are required during the preparation of 1 in order to
avoid decomposition of the reactive organolithium reagents employed (tBuLi,
nBuLi and LiTMP) with polar solvent THF.
[Li(TMP)Zn(tBu)2] 1 was prepared on a 0.4 mmol scale in THF.
To this, 1-methylpyrazole (13) (0.017 mL, 0.2 mmol) was added
and the resultant light yellow solution was allowed to stir at room
temperature for 2 h. This solution was then transferred to a THF
(1 mL) solution of PdCl2(dppf) (7.3 mg, 2.5 mol%) and 1-bromo-4-
chlorobenzene (38.3 mg, 0.2 mmol) to give a heterogeneous orange
solution. The mixture was then reacted in a Biotage initiator 8
microwave reactor at 100 °C for 10 min. The reaction was
quenched with saturated NH4Cl solution (2 mL) and extracted with
CH2Cl2 (3 ꢂ 1 mL). The organic fractions were combined and dried
by passing through a phase separator cartridge with a hydrophobic
frit and the solvent removed under reduced pressure. The residue
36. Following the same experimental procedure described for 1, the related n-
butyl lithium zincate [Li(TMP)Zn(nBu)2] was prepared, however, it showed a
much weaker metalating ability than 1.