Lewis Acid Directed Regioselective Metalations of Pyridazine

Article abstract of DOI:10.1002/anie.201903839

Mono- or bidentate boron Lewis acids trigger a regioselective magnesiation or zincation of pyridazine in position C3 (ortho product) or C4 (meta product). The regioselectivity of the metalation was rationalized with the help of calculated pK_a values of both pyridazine and pyridazine/Lewis acid complexes.

Full text of DOI:10.1002/anie.201903839

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Accepted Article
Title: Lewis Acid Directed Regioselective Metalations of Pyridazine
Authors: Moritz Balkenhohl, Harish Jangra, Tobias Lenz, Marian
Ebeling, Hendrik Zipse, Konstantin Karaghiosoff, and Paul
Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903839
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10.1002/anie.201903839
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Lewis Acid Directed Regioselective Metalations of Pyridazine
Moritz Balkenhohl, Harish Jangra, Tobias Lenz, Marian Ebeling, Hendrik Zipse, Konstantin
Karaghiosoff, and Paul Knochel*
In memory of Friedhelm Balkenhohl
Abstract: Mono- or bidentate boron Lewis acids trigger
a
ortho-regioselectivity was only 83%.[2b] Earlier metalations were
found to proceed in moderate yields (16-32%).[2a] Kondo has
shown, that a C4-functionalization of 1 could be achieved using
an excess of a bulky Schwesinger base.[6] Previously, we have
reported that magnesium and zinc organometallics are
compatible with strong Lewis acids including BF3·OEt2.[7] These
frustrated Lewis pairs[8] proved to be exceptional reagents for the
regioselective metalation of various N-heterocycles.[9] So far,
directed ortho-metalations (DoM) of N-heterocycles have been
the privileged strategy for performing regioselective
metalations.[10] Meta-metalations of arenes have been achieved
using mixed alkali-metal-mediated metalations in which the
second metal sodium plays a pivotal role in the stability of the
formed organometallic species.[11] Remote lithiations are also
feasible on sterically hindered silylated arenes.[12] That Lewis
acids strongly acidify the protons of pyridazine (1) was
demonstrated by calculations,[13] showing that the ease of
deprotonation may increase by mono-complexation (see 2)[14] and
further by a bis-complexation as shown in 3 (Scheme 1). These
calculations led us to examine the metalation of 1 using mono- or
bidentate Lewis acids. Herein, we wish to report, that the
appropriate choice of a Lewis acid further facilitates a metalation
and, combined with steric effects, allows the regioselective
metalation of the pyridazine scaffold (1) either in position C3
(ortho-product) or in position C4 (meta-product; Scheme 1).
regioselective magnesiation or zincation of pyridazine in position C3
(ortho-product) or C4 (meta-product). The metalation regioselectivity
was rationalized with the help of calculated pKa values of both
pyridazine and pyridazine-Lewis acid complexes.
N-Heterocycles are invaluable scaffolds in pharmaceutical and
material research.[1] Whereas the functionalization of pyridines is
well established, other diazines such as pyrimidines and
pyrazines are much less investigated and the regioselective
functionalization of the pyridazine scaffold (1) is still in its
infancy.[2] Pyridazines are especially important N-heterocycles
since they are present in various pharmaceuticals and
agrochemicals.[3] Also, they play the role of bioisosteres of
pyridines and are therefore important in drug design.[4] They
belong to the so-called heterocycles of the future.[5] Although a
metalation of pyridazine (1) using TMPLi (TMP = 2,2,6,6-
tetramethylpiperidyl) in the presence of ZnCl2·TMEDA (TMEDA =
tetramethylethylenediamine) has been reported by Mongin, the
Table 1. Optimization of the reaction conditions for the directed ortho-metalation
of pyridazine (1).
time
[h]
ratio
entry
TMP base
BF3·OEt2
-
yield[a]
(6:7)[b]
1
2
3
4
5
6
TMPMgCl·LiCl (4)[c] (1.05 equiv)
0.25
12%
1%
32:68
96:4
60:40
96:4
n.d.
TMPMgCl·LiCl (4)[c] (1.05 equiv) 1.1 equiv 0.25
TMPZnCl·LiCl (5) (1.10 equiv)
-
2
2
6
6
45%
45%
64%
Scheme 1. Calculated pKa values of pyridazine (1), the pyridazine-BF3 adduct
(2), and a bidentate Lewis acid-pyridazine adduct (3), and the directed ortho-
and meta-metalation of pyridazine (1) using TMPZnCl·LiCl.
TMPZnCl·LiCl (5) (1.30 equiv) 1.1 equiv
TMPZnCl·LiCl (5) (1.30 equiv) 1.1 equiv
TMPZnCl·LiCl (5) (1.50 equiv) 1.1 equiv
72% (57%)[d] 97:3
[*]
M. Balkenhohl, H. Jangra, T. Lenz, M. Ebeling, Prof. Dr. H. Zipse
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
[a] NMR yield using trimethoxybenzene as standard. [b] Determined by NMR
analysis. [c] The reaction was run at -78 °C. [d] Isolated yield of 6.
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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Thus, we have examined the metalation of pyridazine (1) with
TMPMgCl·LiCl (4)[15] in THF in the absence or presence of
BF3·OEt2. In both cases, yields were low due to instability of the
magnesium species, and a regioselective metalation could only
be achieved in the presence of the Lewis acid (Table 1, entries 1-
2). Higher yields were obtained, using the more covalent metal
amide TMPZnCl·LiCl (5, entries 3-6).[16] A low regioselectivity of
the zincation was observed in the absence of BF3·OEt2 (entry 3).
However, in the presence of BF3·OEt2 (1.1 equiv), a room
temperature metalation of 1 proceeds within 2 h reaction time
(entry 4). A crude NMR-determination showed a 96:4 ratio
between 3-iodopyridazine (6) and 4-iodopyridazine (7). By using
1.5 equiv of TMPZnCl·LiCl (5) and extending the reaction time to
6 h a maximum conversion and excellent regioselectivity (6:7 =
97:3) was obtained, leading, after iodolysis, to pure 3-
iodopyridazine (6) in 57% isolated yield. Further functionalizations
were performed and an arylation using palladium-catalyzed
Negishi cross-couplings[17] with various electron-rich and -poor
aryl iodides, provided 3-arylated pyridazines 6a-f in 53-72% yield
(Scheme 2).
Scheme 3. Directed ortho-metalation of 3-phenylpyridazine (6a) using TMPLi
(8).
almost completely regioselective lithiation at position C6 (9:10
ratio = 96:4), providing, after iodolysis and isolation, the pure
iodopyridazine 9 in 72% yield (Table 2, entry 1). These conditions
were used for further reactions of the lithiated pyridazine 6a with
D2O, (Cl3C)2, MeSSO2Me, PhSSO2Ph, and N-formylmorpholine,
as well as allylic bromides, to give various 3,6-disubstituted
pyridazines 9a-g in 44-79% yield (Scheme 3).
Alternatively, using TMPMgCl·LiCl (4, 1.1 equiv) in the presence
of BF3·OEt2 (1.1 equiv) led to an unselective deprotonation. In this
case, after iodolysis, a 44:56 ratio between the iodides 9 and 10
was obtained (Table 2, entry 2). Interestingly, increasing the
amount of 4 (2.0 equiv) led to an improved regioselectivity of
27:73 (Table 2, entry 3). This result may be explained by
assuming that 1.0 equiv of 4 is used up to activate the heterocycle
in addition to BF3·OEt2, also playing the role of a Lewis acid.[19]
The additional equivalent of 4 acts as deprotonating agent.
Further increase of the amount of 4 did not improve this
regioselectivity (entry 4). This enhanced selectivity proved to be
sufficient for preparative applications. Thus, the treatment of
various 2-arylpyridazines (6a,c,e) with TMPMgCl·LiCl (4) in the
presence of BF3·OEt2 led, after iodolysis or thiolation, to the
regiomerically pure products 10 and 10a in 38-58% yield
(Scheme 4).
Scheme 2. BF3·OEt2 mediated ortho-zincation and arylation of pyridazine (1).
tfp = tri-(2-furyl)phosphine.[18]
In order to expand the scope of such metalations,
3-phenylpyridazine (6a, prepared according to Scheme 2) was
submitted to various metalation conditions (Table 2). The very
strong and kinetically active base TMPLi (8, 0.95 equiv) led to an
Table 2. Optimization of the reaction conditions for the directed C5- and C6-
metalation of 3-phenylpyridazine (6a).
ratio
(9:10)[a]
entry
TMP base (equiv)
BF3·OEt2 time
yield
1
2
3
4
TMPLi (8) (0.95 equiv)
-
5 min
72%[b]
65%[c]
96:4
TMPMgCl·LiCl (4) (1.1 equiv) 1.1 equiv 20 min
44:56
TMPMgCl·LiCl (4) (2.0 equiv) 1.1 equiv 20 min 82%[c] (58%)[b] 27:73
TMPMgCl·LiCl (4) (3.0 equiv) 1.1 equiv 20 min 26:74
45%[c]
[a] Determined by NMR analysis. [b] Isolated yield of the main regioisomer.
[c] NMR yield using trimethoxybenzene as standard.
Scheme 4. Directed meta-metalation of 3-arylpyridazines 6a,c,e using
BF3·OEt2 and TMPMgCl·LiCl (4).
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Table 3. Optimization of the reaction conditions for the Lewis acid directed
C4-metalation of pyridazine (1).
yield (Table 3, entries 3-4; Scheme 5). According to the
calculations,[13] H1 is the most acidic proton (pKa(H1) = 23.2).
However, due to steric effects combined with a high acidity
(pKa(H2) = 25.8), exclusively H2 is deprotonated.
Finally, to prove the synthetic utility of these regioselective
metalations, the herbicide credazine (14)[23] was prepared. Thus,
3-iodopyridazine (6) was dissolved in toluene and mixed with o-
cresol (1.2 equiv), Pd(OAc)2 (2 mol%), tBuXPhos (3 mol%) and
potassium phosphate (2.0 equiv).[24] After stirring at 100 °C for
14 h, credazine (14) was obtained in 93% yield (Scheme 6).
entry
equiv
1.3
temperature
0 °C
yield[a]
40%[c]
ratio (C4:C3)[b]
99:1
1
2
3
4
1.3
-78 °C
52%
99:1
1.7
-78 °C
86% (63%)[c]
69%
99:1
2.0
-78 °C
99:1
[a] NMR yield using trimethoxybenzene as standard. [b] Determined by NMR
analysis. [c] Isolated yield.
Scheme 6. Synthesis of the herbicide credazine (14) starting from 3-
iodopyridazine (6).
Interestingly, replacing the 3-phenyl substituent of 6a with a para-
anisyl or para-chlorophenyl substituent, led, with the same base
system, to an almost perfectly regioselective metalation
(regioisomeric ratio = 98:2 (10b) and 99:1 (10c)). After iodolysis,
the pyridazines 10b and 10c were obtained in 50% yield
(Scheme 4). To confirm the regioselectivity, an X-ray
measurement of 10c was performed.[20]
These results led us to examine further possibilities for a Lewis
acid directed C4-metalation (meta-product). After several
experiments, we chose the bidentate diboroanthracene 11 first
reported by Kaufmann.[21] Thus, mixing equimolar amounts of 11
and 1 at 0 °C led to a yellow solution, indicating the formation of
a 1:1 complex. The structure of this complex 12 was confirmed by
NMR-studies.[22] Treatment of 12 with TMPZnCl·LiCl (5) at 0 °C
led to the formation of the zincated pyridazine 13, which, after
iodolysis, exclusively gave 4-iodopyridazine (7) in 40% yield
(Table 3, entry 1). Lowering the temperature to -78 °C resulted in
an increased yield of 52% (entry 2). An additional variation of
stoichiometry showed, that with 1.7 equiv of 5, the optimal
reaction conditions were obtained, leading to 7 in 63% isolated
In summary, we have developed a highly regioselective Lewis
acid directed C3- and C4-metalation and functionalization of
pyridazine. The choice of the Lewis acid is key for the success
and the regioselectivity of the reaction, allowing the first Lewis
acid directed meta-metalation using
a
TMP-base. This
unprecedented reactivity opens up new perspectives for the
metalation of heterocycles using metal amide bases. Further
extensions of this work are currently underway in our laboratories.
Acknowledgements
We thank the DFG (SFB749) for financial support. We also thank
Albemarle (Hoechst, Germany) for the generous gift of chemicals.
Keywords: frustrated Lewis pairs • magnesiation • pyridazine •
TMP-bases • zincation
[1]
a) S. A. K. Anttila, E. V. J. Leinonen, CNS Drug Reviews 2001, 7, 249-
264; b) X.-Q. Li, T. B. Andersson, M. Ahlström, L. Weidolf, Drug Metab.
Dispos. 2004, 32, 821-827; c) P. N. W. Baxter, R. Dali-Youcef, J. Org.
Chem. 2005, 70, 4935-4953; d) E. Vitaku, D. T. Smith, J. T. Njardarson,
J. Med. Chem. 2014, 57, 10257-10274; e) D. Chen, S.-J. Su, Y. Cao, J.
Mater. Chem. C 2014, 2, 9565-9578; f) P. Martins, J. Jesus, S. Santos,
L. R. Raposo, C. Roma-Rodrigues, P. V. Baptista, A. R. Fernandes, 2015,
20, 16852; g) K. Dinesh, J. Subheet Kumar, Curr. Med. Chem. 2016, 23,
4338-4394; h) A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C.
Blakemore, L. H. Jones, O. Fadeyi, Org. Biomol. Chem. 2016, 14, 6611-
6637.
[2]
a) N. Plé, A. Turck, K. Couture, G. Quéguiner, J. Org. Chem. 1995, 60,
3781-3786; b) A. Seggio, F. Chevallier, M. Vaultier, F. Mongin, J. Org.
Chem. 2007, 72, 6602-6605; c) J.-M. L’Helgoual’ch, G. Bentabed-
Ababsa, F. Chevallier, M. Yonehara, M. Uchiyama, A. Derdour, F.
Mongin, Chem. Commun. 2008, 5375-5377; d) M. Mosrin, P. Knochel,
Org. Lett. 2009, 11, 1837-1840; e) S. H. Wunderlich, M. Kienle, P.
Knochel, Angew. Chem. Int. Ed. 2009, 48, 7256-7260; Angew. Chem.
2009, 121, 7392-7396.
Scheme 5. Directed meta-metalation and functionalization of pyridazine using
the bidentate Lewis acid 11 and TMPZnCl·LiCl (5).
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[3]
a) J. P. Chambon, J. Brochard, A. Hallot, M. Heaulme, R. Brodin, R.
Roncucci, K. Biziere, J. Pharmacol. Exp. Ther. 1985, 233, 836-844; b) A.
Perio, J. P. Chambon, R. Calassi, M. Heaulme, K. Biziere, J. Pharmacol.
Exp. Ther. 1986, 239, 542-547; c) M. Asif, Curr. Med. Chem. 2012, 19,
2984-2991; d) H. Abou-Hamdan, L. Désaubry, J. Org. Chem. 2018, 83,
2954-2958.
[14] A crystal structure of the pyridazine-BF3 adduct 2 was obtained:
[4]
[5]
[6]
[7]
a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529-2591; b) C. G.
Wermuth, MedChemComm 2011, 2, 935-941.
R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
5845-5859.
For further details, see the Supporting Information.
a) T. Imahori, Y. Kondo, J. Am. Chem. Soc. 2003, 125, 8082-8083; b) T.
Imahori, K. Suzawa, Y. Kondo, Heterocycles 2008, 76, 1057-1060.
a) M. Jaric, B. A. Haag, A. Unsinn, K. Karaghiosoff, P. Knochel, Angew.
Chem. Int. Ed. 2010, 49, 5451-5455; Angew. Chem. 2010, 122, 5582-
5586; b) S. Duez, A. K. Steib, S. M. Manolikakes, P. Knochel, Angew.
Chem. Int. Ed. 2011, 50, 7686-7690; Angew. Chem. 2011, 123, 7828-
7832; c) Q. Chen, X. M. du Jourdin, P. Knochel, J. Am. Chem. Soc. 2013,
135, 4958-4961; d) K. Groll, S. M. Manolikakes, X. M. du Jourdin, M.
Jaric, A. Bredihhin, K. Karaghiosoff, T. Carell, P. Knochel, Angew. Chem.
Int. Ed. 2013, 52, 6776-6780; Angew. Chem. 2013, 125, 6909-6913.
D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2015, 54, 6400-6441;
Angew. Chem. 2015, 127, 6498-6541.
[15] For reviews, see: a) B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Knochel,
Angew. Chem. Int. Ed. 2011, 50, 9794-9824; Angew. Chem. 2011, 123,
9968-9999; b) T. Klatt, J. T. Markiewicz, C. Sämann, P. Knochel, J. Org.
Chem. 2014, 79, 4253-4269; c) M. Balkenhohl, P. Knochel, SynOpen
2018, 02, 78-95; d) S. D. Robertson, M. Uzelac, R. E. Mulvey, Chem.
Rev. 2019, DOI: 10.1021/acs.chemrev.9b00047.
For recent examples, see: d) M. Balkenhohl, C. François, D. Sustac
Roman, P. Quinio, P. Knochel, Org. Lett. 2017, 19, 536-539; e) D. S.
Ziegler, R. Greiner, H. Lumpe, L. Kqiku, K. Karaghiosoff, P. Knochel, Org.
Lett. 2017, 19, 5760-5763; f) L. A. Bozzini, J. H. C. Batista, M. B. M. de
Mello, R. Vessecchi, G. C. Clososki, Tetrahedron Lett. 2017, 58, 4186-
4190; g) M. Balkenhohl, B. Heinz, T. Abegg, P. Knochel, Org. Lett. 2018,
20, 8057-8060.
[8]
[9]
For recent examples, see: a) T. Klatt, V. Werner, M. G. Maximova, D.
Didier, Y. Apeloig, P. Knochel, Chem. Eur. J. 2015, 21, 7830-7834; b) M.
Balkenhohl, R. Greiner, I. S. Makarov, B. Heinz, K. Karaghiosoff, H.
Zipse, P. Knochel, Chem. Eur. J. 2017, 23, 13046-13050; c) M.
Balkenhohl, B. Salgues, T. Hirai, K. Karaghiosoff, P. Knochel, Org. Lett.
2018, 20, 3114-3118.
[16] For recent examples, see: a) M. A. Ganiek, M. R. Becker, M. Ketels, P.
Knochel, Org. Lett. 2016, 18, 828-831; b) B. V. Lam, Y. Berhault, S.
Stiebing, C. Fossey, T. Cailly, V. Collot, F. Fabis, Chem. Eur. J. 2016, 22,
4440-4446; c) Y.-H. Chen, M. Ellwart, G. Toupalas, Y. Ebe, P. Knochel,
Angew. Chem. Int. Ed. 2017, 56, 4612-4616; Angew. Chem. 2017, 129,
4683-4687; d) M. E. Dalziel, P. Chen, D. E. Carrera, H. Zhang, F.
Gosselin, Org. Lett. 2017, 19, 3446-3449; e) L. Klier, D. S. Ziegler, R.
Rahimoff, M. Mosrin, P. Knochel, Org. Process Res. Dev. 2017, 21, 660-
663.
[10] For literature on directed ortho-metalation, see: a) V. Snieckus, Chem.
Rev. 1990, 90, 879-933; b) The Directed ortho Metalation Reaction: A
Point of Departure for New Synthetic Aromatic Chemistry. In Modern
Arene Chemistry; C. G. Hartung, V. Snieckus, Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 330−367; c) S. Usui, Y. Hashimoto, J. V.
Morey, A. E. H. Wheatley, M. Uchiyama, J. Am. Chem. Soc. 2007, 129,
15102-15103; d) Y. Kondo, J. V. Morey, J. C. Morgan, H. Naka, D.
Nobuto, P. R. Raithby, M. Uchiyama, A. E. H. Wheatley, J. Am. Chem.
Soc. 2007, 129, 12734-12738; e) J. Board, J. L. Cosman, T. Rantanen,
S. P. Singh, V. Snieckus, Platinum Met. Rev. 2013, 57, 234-258.
[11] a) P. C. Andrikopoulos, D. R. Armstrong, D. V. Graham, E. Hevia, A. R.
Kennedy, R. E. Mulvey, C. T. O'Hara, C. Talmard, Angew. Chem. Int. Ed.
2005, 44, 3459-3462; Angew. Chem. 2005, 117, 3525-3528; b) D. R.
Armstrong, W. Clegg, S. H. Dale, E. Hevia, L. M. Hogg, G. W. Honeyman,
R. E. Mulvey, Angew. Chem. Int. Ed. 2006, 45, 3775-3778; Angew.
Chem. 2006, 118, 3859-3862; c) A. J. Martínez-Martínez, A. R. Kennedy,
R. E. Mulvey, C. T. O’Hara, Science 2014, 346, 834-837.
[17] a) A. O. King, N. Okukado, E.-i. Negishi, J. Chem. Soc., Chem. Commun.
1977, 683; b) D. Haas, J. M. Hammann, R. Greiner, P. Knochel, ACS
Catal. 2016, 6, 1540.
[18] V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585-9595.
[19] We propose, that the first equivalent of TMPMgCl·LiCl, BF3·OEt2 and
pyridazine form a complex, in which both reagents act as Lewis acids.
The second equivalent of TMPMgCl·LiCl may then deprotonate the C5-
position.
[20] CCDC 1906337 (10c), CCDC 1906338 (9c), CCDC 1906339 (6a), and
CCDC 1906340 (2) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[21] W. Schacht, D. Kaufmann, J. Organomet. Chem. 1987, 331, 139-152.
[22] For further details, see the Supporting Information and: S. N. Kessler, H.
A. Wegner, Org. Lett. 2010, 12, 4062-4065.
[12] a) M. Schlosser, C. Heiss, E. Marzi, R. Scopelliti, Eur. J. Org. Chem.
2006, 4398-4404; b) A. B. Bellan, P. Knochel, Angew. Chem. Int. Ed.
2019, 58, 1838-1841; Angew. Chem. 2019, 131, 1852-1856.
[23] M. Nakagawa, M. Ando, Agric. Biol. Chem. 1977, 41, 1975-1984.
[24] a) C. H. Burgos, T. E. Barder, X. Huang, S. L. Buchwald, Angew. Chem.
Int. Ed. 2006, 45, 4321-4326; Angew. Chem. 2006, 118, 4427-4432; b)
L. Salvi, N. R. Davis, S. Z. Ali, S. L. Buchwald, Org. Lett. 2012, 14, 170-
173.
[13] For further details, see the Supporting Information.
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COMMUNICATION
Moritz Balkenhohl, Harish Jangra,
Tobias Lenz, Marian Ebeling, Hendrik
Zipse, Konstantin Karaghiosoff, and
Paul Knochel*
Page No. – Page No.
Lewis Acid Directed Regioselective
Metalations of Pyridazine
Chelation is key: By chelating the diazine pyridazine with
a bidentate
diboroanthracene Lewis acid, a rare C4-metalation was achieved. Additionally, a
highly regioselective ortho-metalation was obtained when the monodentate Lewis
acid BF3·OEt2 was employed. A rationalization of the regioselectivity was possible
using calculated pKa values of the pyridazine-Lewis acid complexes.
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