Regioselective metalations of pyrimidines and pyrazines by using frustrated Lewis pairs of BF3×OEt2 and hindered magnesium- and zinc-amide bases

Article abstract of DOI:10.1002/anie.201301694

Born of frustration: Using the frustrated Lewis pairs TMP-metal and BF ₃×OEt₂ allows the regioselective metalation of pharmaceutically relevant diazines, such as pyrimidines, purines, and pyrazines. These metalations are often complementary to prior deprotonations performed without BF₃×OEt₂. Especially attractive is a new sequential regioselective full functionalization of the pyrazine scaffold with a bulky (TMS)₂CH substituent. Copyright

Full text of DOI:10.1002/anie.201301694

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DOI: 10.1002/anie.201301694
Frustrated Lewis Pairs
Regioselective Metalations of Pyrimidines and Pyrazines by Using
Frustrated Lewis Pairs of BF3·OEt2 and Hindered Magnesium– and
Zinc–Amide Bases**
Klaus Groll, Sophia M. Manolikakes, Xavier Mollat du Jourdin, Milica Jaric, Aleksei Bredihhin,
Konstantin Karaghiosoff, Thomas Carell, and Paul Knochel*
The functionalization of diazines is of great importance,
because these N-heterocycles are present in numerous natural
products, pharmaceuticals, and agrochemicals.[1] They also
find applications in materials science and polymer chemis-
try.[2] The directed metalation and further functionalization of
these electron-deficient N-heterocycles can be realized with
ate bases[3] and in some cases with lithium bases.[4] However,
low temperature and carefully designed reaction conditions
are required owing to the low stability of the resulting
Scheme 1. Switchable, regioselective metalation of the pyrimidine 1a.
À
lithitated N-heterocycles. Recently, the C H activation of
various N-heteroaromatics has also been reported.[5] More-
over, a range of LiCl-solubilized TMP–metal bases (TMP =
2,2,6,6-tetramethylpiperidyl) are known.[6] They display
a high kinetic basicity and give access to several metalated
diazines[7] and purines.[8] It was also found that these metallic
amide bases are compatible with a strong Lewis acid, such as
BF3·OEt2.[9] Thus, the reactivity of the sterically hindered
TMP base is not annihilated by BF3·OEt2, but on the contrary,
a synergetic effect is observed (dual activation). This effect
allows a regioselective metalation of various substituted
pyridines and derivatives,[10] which is not possible without
the use of this Lewis pair combination. This compatibility of
a strong Lewis acid with a Lewis base as a result of steric
hindrance corresponds directly to the concept of frustrated
Lewis pairs.[11] Herein, we report a new BF3-assisted regiose-
lective metalation of biologically relevant pyrimidine deriv-
atives and purines. As an application, we developed a new
strategy for the BF3-mediated regioselective full functional-
ization of pyrazines.
expected iodide 3a is isolated in 85% yield. In contrast, the
reaction of the pyrimidine 1a with BF3·OEt2 (1.1 equiv, 08C,
15 min) then TMPZnCl·LiCl (4, 1.5 equiv, THF, À208C, 1 h)
leads to a quantitative metalation at position 2. After
a copper-mediated allylation with 3-bromocyclohexene (5a),
the desired 2-functionalized pyrimidine 3b was isolated in
92% yield (Scheme 1). This behavior might be explained by
an increased acidity at position 2 owing to the complexation
of BF3 with the pyrimidine ring rather than with the sterically
hindered Lewis base TMPZnCl·LiCl, allowing a complete
switch of regioselectivity.[12]
The zincated intermediate derived from 1a undergoes
a smooth Negishi cross-coupling[13] with 4-iodoanisole (5b)
using 2% [Pd(dba)2] (dba = dibenzylideneacetone) and 4%
tfp (tfp = tri-(2-furyl)phosphine),[14] affording the 2-arylated
pyrimidine 3c in 89% yield (Table 1, entry 1). This regiose-
lective metalation is quite general, the pyrimidines 1b–d are
also selectively zincated in position 2 regardless of their
substitution pattern. After allylation, iodolysis, or cross-
coupling, the expected 2-functionalized pyrimidines 3d–i are
obtained in 66–71% yield (entries 2–7).
More complex pyrimidine derivatives, such as the thieno-
pyrimidines[15] 6a and 6b, display a similar regioselectivity
switch (Scheme 2). Thus, the treatment of 6a (R = NMe2)
with TMPZnCl·LiCl (4) leads to a smooth deprotonation of
the most acidic proton of 6a (i.e. position 6) giving, after
cross-coupling, the 6-arylated product 7a in 83% yield.
Alternatively, addition of BF3·OEt2 to 6a,b followed by
TMPZnCl·LiCl (4) leads to a regioselective zincation at
position 2 (over 10:1) of the pyrimidine ring. Palladium-
catalyzed cross-coupling or copper-mediated allylation fur-
nishes the 2-functionalized thienopyrimidines 8a and 8b in
70–77% yield (Scheme 2).
Thus, we have found that the use of BF3·OEt2 allows the
orthogonal metalation of the pyrimidine scaffold. Treating
4,6-dimethoxypyrimidine (1a) with TMPMgCl·LiCl (2,
1.1 equiv, THF, 08C, 40 min) provides a regioselective mag-
nesiation at position 5 (Scheme 1). After iodolysis, the
[*] K. Groll, S. M. Manolikakes, Dr. X. M. du Jourdin, Dr. M. Jaric,
Dr. A. Bredihhin, Prof. Dr. K. Karaghiosoff, Prof. Dr. T. Carell,
Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the SFB 749 and the
Alexander von Humboldt Foundation for financial support. We also
thank BASF SE (Ludwigshafen), W. C. Heraeus GmbH (Hanau), and
Rockwood Lithium GmbH (Frankfurt) for the generous gift of
chemicals.
As a metalation of purines at position 2 is only reported
by a lithiation-mediated stannyl transfer,[16] we have inves-
tigated the magnesiation of functionalized purine derivatives
in this position. Whereas, purine 9 is reluctant to undergo
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301694.
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Table 1: Regioselective zincation of pyrimidine derivatives 1 in posi-
tion 2.
metalation using various TMP bases in the absence of a Lewis
acid, we found that a prior addition of BF3·OEt2 (1.1 equiv)
allows a magnesiation at position 2 with TMPMgCl·LiCl (2,
1.5 equiv), leading after bromination to the 2-bromopurine
derivative 10 in 55% yield (Scheme 3).
Entry
Substrate
Electrophile
E-X
Product,
Yield[a]
Scheme 3. BF3-assisted metalation of purine 9 in position 2.
1
2
3
4
1a
1b
1b
1b
5b
5b
5c
5a
3c: 89%[b]
3d: 70%[b]
3e: 69%[b]
3 f: 71%[c]
We have also applied the frustrated Lewis pair
[TMP2Mg·2LiCl and BF3·OEt2] to a sequential regioselective
full functionalization of the pyrazine scaffold. We attached
a bulky (TMS)2CH substituent to the pyrazine ring, an
approach pioneered in selective lithiations on aromatics by
Snieckus.[17] Recently, the bis(trimethylsilyl)methyl group[18]
has also been used for Wittig rearrangements and Prins
cyclizations.[19] Attached to the pyrazine core, this silylated
substituent together with BF3·OEt2 as a metalation activator
À
allows a full differentiation of the three remaining C H
bonds, mainly using steric effects.[20] Thus, the Kumada–
Corriu cross-coupling[21] of commercially available 2-chloro-
pyrazine (11) with (TMS)2CHMgBr·LiCl[22] provides 2-(bis-
(trimethylsilyl)methyl)pyrazine (12) in 65% yield (Scheme 4).
5
6
7
1c
1d
1d
5d
3g: 66%[b]
3h: 66%
3i: 67%[b]
I2
5c
[a] Yield of isolated analytically pure product. [b] Obtained by Pd-
catalyzed cross-coupling. [c] Obtained by Cu-mediated allylation.
Scheme 4. New strategy for a regioselective full functionalization of
pyrazines.
The bulky (TMS)2CH substituent causes, after addition of
BF3·OEt2 (1.1 equiv), a selective complexation at the least
hindered heterocyclic N-atom to give the Lewis adduct 13
(Scheme 4).[23] Using TMP2Mg·2LiCl (14, 1.1 equiv) at
À788C allows a selective magnesiation at position 5 as this
is the most accessible activated proton. Position 3 is not an
option for the metalation because of steric hindrance by the
bulky (TMS)2CH group.[24] Likewise, no metalation occurs at
position 6, as this position is less activated by the Lewis acid
Scheme 2. Switchable, regioselective metalation of the thienopyrimi-
dines 6a and 6b.
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(inductive effect). The resulting metalated pyrazine reacts
with various electrophiles E1-X, such as (BrCl2C)2,
PhSO2Cl,[25] I2, or Ar-I, producing the 5-functionalized
pyrazines 15a–e in 61–89% yield (Table 2, entries 1–5).[26]
A second metalation of the pyrazines of type 15 with
TMP2Mg·2LiCl (14, 1.1 equiv, À408C, 30 min) results in
a regioselective magnesiation at the least sterically hindered
position, 6 (Scheme 4). The quenching with various electro-
philes (E2-X = I2, (BrCl2C)2, thiosulfonate, allyl bromide, or
aryl iodide) provides the trisubstituted pyrazines 16a–f in 70–
93% yield (Table 2, entries 6–11). The remaining position of
the pyrazine core bearing a proton is then magnesiated with
TMP2Mg·2LiCl (14, 1.1–1.5 equiv, À40–08C, 1–3.5 h) leading,
Table 2: Regioselective full functionalization of 2-(bis(trimethylsilyl)methyl)pyrazine (12) [An=p-MeO-C6H4].
Entry Substrate
Electrophile
Product,
Yield[a]
Entry Substrate
Electrophile
Product,
Yield[a]
(BrCl2C)2
1
12[b]
15a: 89%
9
15a[d]
5g
16d: 74%[c]
PhSO2Cl
2
3
12[b]
15b: 61%
15c: 65%
10
11
15a[d]
5h
16e: 70%[c]
16 f: 93%
I2
(BrCl2C)2
12[b]
15b[d]
TMS-CN
4
12[b]
5b
15d: 81%[c]
12
16a[f]
17a: 72%
5
6
12[b]
5e
15e: 74%[c]
13
14
16a[f]
5a
17b: 59%[e]
I2
I2
15a[d]
16a: 86%
16b[g]
17c: 78%
7
8
15a[d]
5a
16b: 88%[e]
16c: 70%
15
16
17
16b[g]
16c[h]
16 f[i]
5b
17d: 59%[c]
17e: 72%
17 f: 83%
PhSO2S-An
I2
15a[d]
5 f
I2
[a] Yield of isolated analytically pure product. [b] 1) BF3·OEt2 (1.1 equiv), 08C, 15 min; 2) TMP2Mg·2LiCl (14, 1.1 equiv), À788C, 15 min. [c] Obtained by
Pd-catalyzed cross-coupling after Zn transmetalation. [d] TMP2Mg·2LiCl (14, 1.1 equiv), À408C, 30 min. [e] Obtained by Cu-mediated allylation after Zn
transmetalation. [f] TMP2Mg·2LiCl (14, 1.1 equiv), À408C, 3.5 h. [g] TMP2Mg·2LiCl (14, 1.3 equiv), 08C, 1 h. [h] TMP2Mg·2LiCl (14, 1.5 equiv), À208C,
3.5 h. [i] TMP2Mg·2LiCl (14, 1.1 equiv), À408C, 2 h.
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after quenching with standard electrophiles, to the pyrazines
17a–f in 59–83% (entries 12–17).
The (TMS)2CH group can be further manipulated and
converted to useful functionalities, as previously shown by
Palomo et al. Thus, the treatment of the pyrazine 17d with
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Scheme 5. Transformations of the regioselectively obtained pyrazine
derivatives [An=p-MeO-C6H4].
Peterson olefination of 15d with benzaldehyde in the
presence of 10% TBAF[29] furnishes the stilbene derivative
20 in 93%. Finally, the (TMS)2CH group is compatible with
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In summary, we have shown that the combination of
BF3·OEt2 with TMP–Mg or TMP–Zn bases allows a regiose-
lective functionalization of various diazines, such as pyrimi-
dines, purines, and pyrazines.[34] More importantly, the use of
BF3·OEt2 together with TMP–Mg or TMP–Zn bases allows
metalation of positions which are not available in the absence
of the Lewis acid. In combination with a bulky group such as
bis(trimethylsilyl)methyl, this strategy allows a regioselective
full functionalization of the pyrazine core. Afterwards, this
substituent can be transformed into various useful function-
alities. Further study of the use of Lewis acids for triggering
the metalation of N-heterocycles is underway.
[12] In the absence of BF3·OEt2 no zincation of 1a was observed at
À208C (under 5% conversion). However, the use of 2.0 equiv of
TMPZnCl·LiCl (4) at 258C for 30 min affords an unselective
metalation (1:1) and only 25% conversion. The combination of
BF3·OEt2 with TMPMgCl·LiCl (2, 2.0 equiv) mostly led to
decomposition of 1a at À788C and only 20% of the 2-metalated
pyrimidine derivative was detected.
Received: February 27, 2013
Revised: April 2, 2013
Published online: May 23, 2013
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Keywords: frustrated Lewis pairs · magnesium · metalation ·
N-heterocycles · zinc
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