Zn-, Mg-, and Li-TMP Bases for the Successive Regioselective Metalations of the 1,5-Naphthyridine Scaffold (TMP=2,2,6,6-Tetramethylpiperidyl)

Article abstract of DOI:10.1002/chem.201703638

A set of successive regioselective metalations and functionalizations of the 1,5-naphthyridine scaffold are described. A combination of Zn-, Mg-, and Li-TMP (TMP=2,2,6,6-tetramethylpiperidyl) bases and the presence or absence of a Lewis acid (BF₃?OEt₂) allows the introduction of up to three substituents to the 1,5-naphthyridine core. Also, a novel “halogen dance” reaction was discovered upon metalation of an 8-iodo-2,4-trifunctionalized 1,5-naphthyridine allowing a fourth regioselective functionalization. Additionally, reactions leading to key 1,5-naphthyridines for the preparation of OLED materials and a potential antibacterial agent were performed.

Full text of DOI:10.1002/chem.201703638

A Journal of
Accepted Article
Title: Zn-, Mg-, and Li-TMP Bases for the Successive Regioselective
Metalations of the 1,5-Naphthyridine Scaffold
Authors: Moritz Balkenhohl, Robert Greiner, Ilya S. Makarov, Benjamin
Heinz, Konstantin Karaghiosoff, Hendrik Zipse, and Paul
Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.201703638
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Zn-, Mg-, and Li-TMP Bases for the Successive Regioselective
Metalations of the 1,5-Naphthyridine Scaffold
Moritz Balkenhohl, Robert Greiner, Ilya S. Makarov, Benjamin Heinz, Konstantin Karaghiosoff, Hendrik
Zipse, and Paul Knochel*
Abstract: A set of successive regioselective metalations and
functionalizations of the 1,5-naphthyridine scaffold are described. A
combination of Zn-, Mg-, and Li-TMP bases and the presence or
absence of a Lewis acid (BF3·OEt2) allows the introduction of up to
three substituents to the 1,5-naphthyridine core. Also, a novel
“halogen dance” reaction was discovered upon metalation of an 8-
found that the precomplexation[13] of 1 with the magnesium amide
TMP2Mg·2LiCl (7; 1.1 equiv)[10b] at -78 °C in THF induces a
magnesiation at position C(4) within 5 min leading to the
magnesiated heterocycle 8, which, after quenching with several
electrophiles (E1-X), leads to 4-substituted 1,5-naphthyridines of
type 2 (Table 1). When the magnesium species 8 was treated with
iodine and 1,2-dibromotetrachloroethane, the 4-halo-1,5-
naphthyridines 2a-b were isolated in 49-62% yield (entries 1-2).
Transmetalation of 8 with ZnCl2 and subsequent acylation with
pivaloyl chloride in the presence of 2 mol % Pd(PPh3)4 gave the
4-acyl-1,5-naphthyridine 2c in 63% yield (entry 3).
Transmetalation of 8 to the corresponding copper derivative using
CuCN·2LiCl[14] and reaction with 3-bromocyclohexene or ethyl 2-
iodo-2,4-trifunctionalized 1,5-naphthyridine allowing
a
fourth
regioselective functionalization. Additionally, reactions leading to key
1,5-naphthyridines for the preparation of OLED materials and a
potential antibacterial agent were performed.
Heterocyclic structures are ubiquitous in pharmaceutical and
agrochemical research, and the discovery of new medicinal
targets requires the functionalization of always less common
heterocycles.[1] Naphthyridines certainly belong to the
heterocycles of the future[2] and their functionalization via
metalation is still in its infancy.[3] Especially 1,5-naphthyridines
have been identified as suitable candidates for antimalarial,[4]
antibacterial,[5] anti-Alzheimer,[6] antiparasitic,[7] or anticancer[8]
drugs. Also, their applicability for OLED materials has been
demonstrated.[9] Recently, we[10] and others[11] have reported, that
various metallic TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl)
are powerful metalating reagents, and, that Lewis acids such as
BF3·OEt2 may enhance their metalation power and/or improve
regioselective metalations.[12]
(bromomethyl)acrylate[15]
provided
the
allylated
1,5-
naphthyridines 2d-e in 53-60% yield (entries 4-5). Arylation of the
magnesium species 8 was performed by transmetalation with
ZnCl2 and Negishi cross-coupling[16] with electron rich, neutral,
and poor aryl iodides in the presence of either 3 mol % Pd(dba)2
and 6 mol % tfp (tri(2-furyl)phosphine)[17] or 5 mol % Pd(PPh3)4
Table 1. Metalation and functionalization of 1,5-naphthyridine (1) in the C(4)
position using TMP2Mg·2LiCl (7).
Herein, we report a convenient regioselective metalation and
functionalization of the 1,5-naphthyridine scaffold (1) and show,
that, by using a combination of Zn-, Mg-, and Li-TMP bases with
or without BF3·OEt2, it is possible to regioselectively metalate the
1,5-naphthyridine scaffold providing mono-, di-, tri-, or tetra-
substituted naphthyridines of type 2-6 (Scheme 1). Thus, it was
entry
electrophile
product
yield[a]
1
2
3
I2
2a: X = I; 62%
(BrCCl2)2
tBuCOCl
2b: X = Br; 49%
2c: X = COtBu; 63%[b]
4
5
2d: 60%[c]
2e: 53%[c]
Scheme 1. Regioselective functionalization of the 1,5-naphthyridine scaffold (1)
using Zn-, Mg-, and Li-TMP bases.
6
7
8
X = H
X = OMe
X = CN
2f: X = H; 63%[d]
2g: X = OMe; 75%[d]
2h: X = CN; 48%[e]
[*]
M.Sc. M. Balkenhohl, M.Sc. R. Greiner, Dr. I. S. Makarov, B.Sc. B.
Heinz, Prof. Dr. K. Karaghiosoff, Prof. Dr. H. Zipse, Prof. Dr. P.
Knochel
[a] Isolated yield. [b] 2 mol % Pd(PPh3)4 after transmetalation with a 1 M ZnCl2
solution was used [c] A 1 M CuCN·2LiCl solution was used for transmetalation.
[d] 3 mol % Pd(OAc)2 and 6 mol % SPhos after transmetalation with a 1 M ZnCl2
solution was used. [e] 5 mol % Pd(PPh3)4 after transmetalation with a 1 M ZnCl2
solution was used.
Ludwig-Maximilians-Universität München, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201703638
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leading to 1,5-naphthyridines 2f-h in 48-75% yield (entries 6-8).
The presence of a substituent E1 in the naphthyridine 2 at
position C(4) prevents further complexation of a metallic amide at
N(5) and favors the precomplexation of TMPMgCl·LiCl (9)[18] or
TMPZnCl·LiCl (10)[19] at N(1). This favors a directed magnesiation
(or zincation) at C(8) providing, after quenching with several
electrophiles (E2-X) the regioselectively defined 4,8-substituted
1,5-naphthyridines of type 3. Alternatively, the naphthyridine 2
can be treated with BF3·OEt2 which has two consequences: (1)
BF3 hampers a metalation at position C(8), since no efficient
complexation of the magnesium base (9) is possible; (2) the BF3-
complexation dramatically enhances the acidity at C(2). This
naphthyridine 2g furnished after acylation or cross-coupling the
expected naphthyridines 4d-e in 56-70% yield (entries 11-12).
Finally, 4-phenyl-1,5-naphthyridine (2f) was submitted to the
Table 2. Metalation and functionalization of 1,5-naphthyridines of type 2 in
the C(8)- and C(2)-position using TMPMgCl·LiCl (9) or TMPZnCl·LiCl (10).
entry
substrate
electrophile
product, yield[a]
results in
a
regioselective magnesiation at C(2) using
1
3a: 59%[b][c]
2b
TMPMgCl·LiCl (9). After quenching with an electrophile (E2-X),
2,4-disubstituted 1,5-naphthyridines of type 4 are obtained
(Scheme 2).
(BrCCl2)2
2
3
2g: p-An = p-C6H4OMe
3b: 60%[b]
2g
3c: 60%[b][d]
4
3d: 71%[e]
2c
Scheme 2. Metalation and functionalization of 4-substituted 1,5-naphthyridines
(2) using TMPMgCl·LiCl (9) or TMPZnCl·LiCl (10).
Thus, the naphthyridine 2b was metalated with TMPMgCl·LiCl (9,
1.2 equiv, -40 °C, 1 h) to give the magnesiated species 11.
Reaction of 11 after transmetalation to zinc with 1-chloro-4-
iodobenzene under standard Negishi cross-coupling conditions[16]
resulted in the formation of the biaryl 3a in 59% yield (Table 2,
entry 1). Magnesiation of naphthyridine 2g and quenching with
1,2-dibromotetrachloroethane gave the 8-bromo-naphthyridine
3b in 60% yield (entry 2). Allylation of the magnesium species 11
with 3-bromocyclohexene after transmetalation to copper
afforded the naphthyridine 3c in 60% yield (entry 3). Zincation of
naphthyridine 2c with TMPZnCl·LiCl[19] (10, 1.5 equiv, R.T., 1 h)
led to the formation of the heteroarylzinc halide 12, which was
iodolyzed to give the 4,8-disubstituted naphthyridine 3d in 71%
yield (entry 4). Cross-coupling of 12 with 1-iodo-4-
trifluoromethylbenzene or 1-(3-iodophenyl)-2-methylpropan-1-
one yielded naphthyridines 3e-f in 97-98% yield (entries 5-6).
Allylation of 12 with allyl bromide gave naphthyridine 3g in 80%
yield (entry 7).
A regioselectivity switch was possible as mentioned above by
adding BF3·OEt2 followed by TMPMgCl·LiCl (9).[18] Both reagents
are compatible with each other at temperatures below -40 °C.[12a]
Thus, the 1,5-naphthyridines 2a,g and 2f were treated with
BF3·OEt2 (1.1 equiv, 0 °C, 10 min) followed by TMPMgCl·LiCl (9,
1.2 equiv, -40 °C, 1 h) providing the corresponding magnesium
species 13 (Scheme 2). Subsequent acylation or halogenation
provided 2,4-substituted 1,5-naphthyridines 4a-c in 53-74% yield
(entries 8-10). Applying a similar metalation protocol on the
3e: X = p-CF3; 98%[c][e]
2c
2c
5
6
X = p-CF3
X = m-COiPr
3f: X = m-COiPr; 97%[c][e]
7
2c
3g: 80%[d][e]
4a: X = I; 74%[f]
2a
2a
2a
8
9
10
I2
(BrCCl2)2
PhCOCl
4b: X = Br; 72%[f]
4c: X = COPh; 53%[d][f]
11
12
4d: 70%[d][f]
2g
2g
p-Tol-I
p-Tol = p-C6H4Me
4e: 56%[c][f]
4f: X = I; 58%[f]
2f
2f
2f
13
14
15
I2
(BrCCl2)2
MeSSO2Me
4g: X = Br; 89%[f]
4h: X = SMe; 52%[f]
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Table 2. (continued)
entry
16
substrate
electrophile
product, yield[a]
2f
4i: 59%[d][f]
17
2f
4j: 63%[d][f]
[a] Isolated yield. [b] TMPMgCl·LiCl (1.3 equiv, -40 °C, 1 h) was used. [c]
4 mol % Pd(dba)2 and 8 mol % tfp after transmetalation with a 1 M ZnCl2
Scheme 4. Performance of the “halogen dance” rearrangement leading to
2,4,7,8-tetrafunctionalized 1,5-naphthyridines 6a-e.
solution was used. [d]
A 1 M CuCN·2LiCl solution was used for
transmetalation. [e] TMPZnCl·LiCl (1.5 equiv, R.T., 1 h) was used. [f]
BF3·OEt2 (1.1 equiv, 0 °C, 10 min) and TMPMgCl·LiCl (1.2 equiv, -40 °C,
1 h) were used.
standard metalation protocol and subsequent reaction with
various electrophiles including S-methyl methanethiosulfonate
gave naphthyridines 4f-j in 52-89% yield (entries 13-17).
0 THF
0.0
0
1 THF
2 THF
3 THF
A third functionalization of 2,4-disubstituted 1,5-naphthyridines of
type 4 was not possible using TMPMgCl·LiCl (9) or TMP2Mg·2LiCl
(7), presumably due to a too weak precomplexation of these
sterically hindered Mg-bases and a too low kinetic basicity.[10e]
However, the stronger lithium amide TMPLi (14)[20] readily
complexes N(1) and lithiates the closest C-H bond at C(8). Thus,
the treatment of 4g with TMPLi (1.2 equiv, -78 °C, 30 min)
afforded the 8-lithionaphthyridine of type 15 which was trapped by
several electrophiles including methyl iodide and benzaldehyde
providing 2,4,8-trifunctionalized naphthyridines 5a-f in 70-99%
yield. Addition of TMPLi to 4h followed by 1,2-
dibromotetrachloroethane gave the bromonaphthyridine 5g in
47% yield (Scheme 3).
A fourth functionalization was achieved using a lithium-mediated
“halogen dance” rearrangement.[21] Thus, the reaction of the
trifunctionalized naphthyridine 5a with TMPLi (1.2 equiv, -78 °C,
90 sec) followed by quenching with water gave the corresponding
regioisomer 6a in 78% yield (Scheme 4). The formation of 6a was
explained by a lithiation at position C(7) leading to the lithium
intermediate 16 followed by a very fast “halogen dance” providing
the more stable C(8)-lithiated naphthyridine (17). Reaction of 17
-10
-18.5
-20
-26.5
-30
-39.2
-40
-40.0
-47.4
-51.8
-54.5
-50
-60
Figure 1A. Relative Gibbs free energy diagram for naphthyridines 16 and 17
solvated with a number of explicit THF molecules.
Figure 1B. Lowest-energy conformers of the disolvated 1,5-naphthyridine 16
and 17 including C-Li bond lengths in 16 and 17, and the N(1)-Li atom distance
in 17.
Scheme 3. Metalation and functionalization of 2,4-functionalized 1,5-
naphthyridines (4) in the C(8) position using TMPLi (14).
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with various electrophiles (E-X) gave the 2,4,7,8-tetrasubstituted
1,5-naphthyridines 6b-e in 62-74% yield. This iodine migration
was also proven by an X-ray structure of 6b.[22] In order to shed
some light upon the unexpected halogen dance rearrangement,
quantum chemical calculations on the aryllithium species 16 and
17 were performed at the doublehybrid DFT B2PLYP-D3/def2-
TZVP//B3PW91-D3/def2-SVP level.[23] Solvation energies were
included through the SMD continuum solvation model for THF.[24]
In the absence of explicit THF molecules the rearranged
aryllithium species 17 is 26.5 kJ·mol-1 more stable than 16. This
is in large part due to the coordination of lithium to the N(1)
nitrogen atom in 17. Additional consideration of explicitly solvating
THF molecules lead to a general lowering of the overall free
energies of the systems as shown in Figure 1A. The positioning
of the solvating THF molecules was guided by initial
conformational searches at force field level and subsequent
optimization by quantum chemical methods. While addition of the
first and the second explicit THF molecule lowers the overall free
energy of the systems, addition of a third THF molecule increases
the free energy. We thus conclude, that the complex with two
explicitly solvating THF molecules most closely reflects the
situation in solution with a free energy difference between 16 and
17 of 14.5 kJ·mol-1. Even in the presence of two explicitly solvating
THF molecules this is largely due to a strong interaction between
the lithium atom and the N(1) nitrogen atom (Figure 1B).
To demonstrate the utility of these naphthyridine
functionalizations, a precursor for OLED materials 18[9c] as well
as a precursor for an antibacterial drug candidate 19[5a] were
prepared. Thus, 1,5-naphthyridine (1) was treated with
TMPMgCl·LiCl (9, 3 equiv, -40 to -20 °C, 4 h) affording the 4,8-
dimagnesiated naphthyridine 20[25], which was subsequently
quenched with 1,2-dibromotetrachloroethane to give the desired
dibrominated naphthyridine 18 in 53% yield on gram scale.
Additionally, the reaction of 1,5-naphthyridine (1) with
TMP2Mg·2LiCl (7, 0.6 equiv) and subsequent transmetalation with
ZnCl2 followed by Negishi cross-coupling[16] with 1-iodo-4-tert-
butylbenzene yielded the substituted naphthyridine 21 in 88%
yield. Subsequent directed lithiation using TMPLi (14) and
quenching with methyl trifluoromethanesulfonate gave the
naphthyridine 19 in 53% yield (Scheme 5).
In summary,
a
set of regioselective metalations and
functionalizations of the 1,5-naphthyridine scaffold using Zn-, Mg-,
and Li-TMP bases is reported. A regioselectivity switch was
achieved, when the metalation of
naphthyridine was performed in the presence or absence of
BF3·OEt2. A novel “halogen dance” rearrangement allowed the
a
C(4)-functionalized
introduction of
a
fourth substituent. Finally, two key
naphthyridines for the synthesis of OLED materials and an anti-
bacterial agent were prepared. Further extensions of this work are
currently underway in our laboratories.
Acknowledgements
We would like to thank the DFG (SFB749) and the DIP (German-
Israeli Project Cooperation) for financial support. We also thank
Albemarle (Hoechst, Germany) for the generous gift of chemicals.
Conflict of interest
The authors declare no conflict of interest.
Keywords: halogen dance • metalation • naphthyridine •
nitrogen heterocycles • TMP bases
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[25] After iodolysis and GC-analysis (at 4 h, -20 °C) the ratio between the di-
iodo and mono-iodo naphthyridine was 6:1.
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10.1002/chem.201703638
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
Step
by
step:
Successive
Moritz Balkenhohl, Robert Greiner, Ilya
S. Makarov, Benjamin Heinz, Prof. Dr.
Konstantin Karaghiosoff, Prof. Dr.
regioselective metalations of the 1,5-
naphthyridine scaffold are achieved by
using a combination of Zn-, Mg-, and
Li-TMP bases in the presence or
absence of BF3·OEt2 allowing the
introduction of up to three substituents.
Hendrik Zipse, Prof. Dr. Paul Knochel*
Page No. – Page No.
Zn-, Mg-, and Li-TMP Bases for the
Successive Regioselective
Metalations of the 1,5-Naphthyridine
Scaffold
A
novel
rearrangement allows the introduction
of fourth substituent leading to
2,4,7,8-tetrafunctionalized 1,5-
“halogen
dance”
a
naphthyridines. Also, two key 1,5-
naphthyridines for the synthesis of
OLED materials and an anti-bacterial
agent were prepared.
This article is protected by copyright. All rights reserved.