Directed regioselectiveortho,ortho′-magnesiations of aromatics and heterocycles usingsBu2Mg in toluene

Article abstract of DOI:10.1039/d1sc01777b

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium basesBu₂Mg. This new reagent allows mild and regioselectiveortho-magnesiations of variousN-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several doubleortho,ortho′-magnesiations were realized in the case of aryl oxazolines,N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes.

Full text of DOI:10.1039/d1sc01777b

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Directed regioselective ortho,ortho0-magnesiations
of aromatics and heterocycles using sBu2Mg in
toluene†
Cite this: Chem. Sci., 2021, 12, 8424
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Andreas Hess,a Jan P. Prohaska,a Sabrina B. Doerrich,a Florian Trauner,a
c
Ferdinand H. Lutter,a Sebastien Lemaire,b Simon Wagschal,
´
a
Konstantin Karaghiosoffa and Paul Knochel
*
Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost
synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base
sBu2Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated
pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing
groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed
arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides,
acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore,
several double ortho,ortho0-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles
as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence
allowing the preparation of valuable 1,2,3-functionalized arenes.
Received 29th March 2021
Accepted 17th May 2021
DOI: 10.1039/d1sc01777b
rsc.li/chemical-science
While commercially available Bu2Mg contained a 60 : 40
mixture of nBu2Mg and sBu2Mg, we have found only small
Introduction
amounts of the branched coupling side-product Ar-sBu, sug-
gesting that the secondary alkyl moiety was reacting much
slower than the primary one.
The directed magnesiation of arenes and heteroarenes is an
important synthetic tool for the preparation of polyfunctional
aryl- and heteroaryl-magnesium organometallics.1 Mixed
magnesium and lithium amides R2NMgX$LiCl are usually the
most efficient reagents for such metalations.2 Recently, we have
examined the regioselective metalation of various pharmaceu-
tically relevant aryl azoles such as 1.3 We found that standard
metal amides such as LDA or TMPLi (TMP ¼ 2,2,6,6-tetrame-
thylpiperidyl) gave the lithiated products 2 with poor regiose-
lectivity, due to a competitive deprotonation at the 5-position of
the triazole ring of 1. The best result was achieved in toluene4
using the alkylmagnesium amide TMPMgBu5 prepared from
commercial Bu2Mg, which provided aer cross-coupling with
aryl bromides various products of type 3. Although this base was
highly regioselective in toluene, an excess of ArBr was required
to compensate the formation of the Ar-nBu side-product, orig-
inating from a faster cross-coupling of the nBu moiety
compared to the metalated azole 2 (Scheme 1).
a
¨
¨
Ludwig-Maximilians-Universitat Munchen, Department Chemie, Butenandtstrasse
¨
5-13, Haus F, 81377 Munchen, Germany. E-mail: paul.knochel@cup.uni-muenchen.de
bJanssen Pharmaceutica, Chemical Process Research & Development, Turnhoutseweg
30, B-2340 Beerse, Belgium
cJanssen Pharmaceutica, Chemical Process Research & Development, Hochstrasse 201,
8200 Schaausen, Switzerland
Scheme 1 (a) Regioselective magnesiation and subsequent Negishi
cross-coupling of aryl azoles (1) using TMPMgBu in toluene/hexane.
(b) Regioselective magnesiation and ortho,ortho0-functionalization of
arenes and heteroarenes using sBu2Mg in toluene.
† Electronic supplementary information (ESI) available. CCDC 2061336 and
2061337. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1sc01777b
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Herein, we report the preparation of sBu2Mg,6 which avoided
these side reactions and signicantly increased the metalation
scope. Thus, we showed that sBu2Mg was an improved mag-
nesiation reagent, which allowed a highly ortho-regioselective
magnesiation of arenes 4 bearing various directing groups (DG),
leading aer trapping of the resulting diarylmagnesium species
5 with various electrophiles E1 to products of type 6. These
polyfunctional arenes were in several cases magnesiated again
using sBu2Mg producing, aer addition of a second different
electrophile E2, valuable 1,2,3-polyfunctional arenes of type 7.
Results and discussion
The reaction of sBuMgCl in diethyl ether with sBuLi (1.0 equiv.)
in cyclohexane at 25 ꢀC (2 h) gave, aer solvent evaporation
under vacuum, redissolution in toluene and ltration, a 0.43–
0.48 M solution of sBu2Mg in 96% yield.7,8
In preliminary experiments, we have observed a smooth
magnesiation of oxazoline 8a with a toluene solution of 0.6
equiv. of sBu2Mg leading to the diarylmagnesium 9a (Table 1). A
full conversion to the diarylmagnesium species was achieved
within 1 hour and the iodolyzed product 10a was isolated in
80% yield (entry 1). sBu2Mg gave also good results in cyclo-
hexane or THF, albeit in lower yields (entries 2 and 3). cHex2Mg
in toluene delivered the desired product 10a in only 46% yield
and other bases such as Ph2Mg, (TMSCH2)2Mg and tBu2Mg or
sBuMgCl9 did not give any conversion (entries 4–8).
Therefore, a range of oxazolines (8a–d) were magnesiated
selectively on the aryl ring and the resulting diarylmagnesiums
(9a–d) underwent Negishi cross-couplings,10 copper-catalyzed
allylation or acylation,11 in situ Sonogashira cross-coupling12 or
trapping reactions with tetrachlorodibromoethane or dicyclo-
propylketone, leading to the mono–ortho substituted oxazolines
10b–j in 68–98% yield (Scheme 2).
Scheme
2
Regioselective magnesiation of oxazolines 8a–d with
sBu2Mg leading, via diarylmagnesium species 9a–d, to functionalized
oxazolines 10b–j. All yields refer to isolated compounds. Magne-
a
b
c
siation conditions.
The reaction was catalyzed by CuCN$2LiCl
(20 mol%). d Obtained after transmetalation with ZnCl2 (1.1 equiv.) and
a palladium-catalyzed cross-coupling with [PdCl2(dppf)] (5 mol%, dppf
e
¼ diphenylphosphinoferrocene) and an aryl halide (0.83 equiv.).
Obtained after transmetalation with ZnCl2 (1.1 equiv.), subsequent
iodine quench (1.1 equiv.) and Sonogashira cross-coupling with CuI
(4 mol%), Pd(dba)2 (3 mol%, dba ¼ dibenzylideneacetone), tri-(2-furyl)-
phosphine (6 mol%) and phenylacetylene (1.3 equiv.).
Most of the C–H activation methods currently available for
the arylation of aryl azoles were performed by using transition
metal catalysts and suffered from the unwanted formation of
symmetrical bis-arylated products and the selective preparation
of unsymmetrical ortho–ortho0-bis-functionalized13 aryl azoles
remained challenging.14 We have found that various oxazolines
10g–j were again magnesiated at 40–60 ꢀC with sBu2Mg in
toluene (Scheme 3).15 The intermediate diarylmagnesium
species were further functionalized by a copper-catalyzed ally-
lation, Negishi cross-coupling, cobalt-catalyzed electrophilic
amination16 and iodolysis furnishing the desired products 11a–
e in 74–93% yield. Interestingly, magnesiation of 10j followed by
trapping with benzaldehyde and subsequent treatment with
6 M HCl provided lactone 11f in 56% yield.17
Table 1 Magnesiation of oxazoline 8a using various magnesium
reagents in various solvents at 25 ꢀC
Entry
Reagent
Solvent
Yielda
To demonstrate the versatility of the oxazoline directing
group, the strongly sterical hindered ortho,ortho0-functionalized
oxazoline 11b was successfully converted to the corresponding
nitrile 11g using thionyl chloride and DMF18 in 92% yield
(Scheme 4).19
We then turned our attention to the magnesiation of various
N-aryl pyrazoles (12a–c). sBu2Mg proved also to be an excellent
base for the regioselective magnesiation of N-aryl pyrazole 12a,
affording the corresponding bis-arylmagnesium species 13a
1
2
3
4
5
6
7
8
sBu2Mg
sBu2Mg
sBu2Mg
cHex2Mg
tBu2Mg
Toluene
THF
91% (80)c
73%
64%
46%
0%
0%
0%
0%
Cyclohexane
Toluene
Toluene
Toluene
Toluene
Ether/toluene
(TMSCH2)2Mg
Ph2Mg
sBuMgClb
a
Calibrated GC-yield using undecane as internal standard. b 1.2 equiv.
of sBuMgCl were used. c Isolated yield.
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Scheme
3 Regioselective magnesiation of mono-functionalized
Scheme 5 Regioselective magnesiation of N-aryl pyrazoles 12a–c
with sBu2Mg leading, via diarylmagnesium species 13a–c, to func-
oxazolines 10g–j, leading to ortho,ortho0-functionalized oxazolines
a
b
11a–f.
All yields refer to isolated compounds.
Magnesiation
a
tionalized N-aryl pyrazoles 14a–f.
All yields refer to isolated
c
conditions. The reaction was catalyzed by CuCN$2LiCl (20 mol%).
compounds. Magnesiation conditions. c The reaction was catalyzed
by CuCN$2LiCl (20 mol%). d Obtained after transmetalation with ZnCl2
(1.1 equiv.) and a palladium-catalyzed cross coupling with [PdCl2(dppf)]
(5 mol%) and an aryl bromide (0.83 equiv.).
b
d
Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a palla-
dium-catalyzed cross-coupling with [PdCl2(dppf)] (5 mol%) and an aryl
iodide (0.83 equiv.). Obtained after transmetalation with ZnCl2 (1.1
equiv.) and a cobalt-catalyzed electrophilic amination with CoCl2
(5 mol%) and morpholino benzoate (1.2 equiv.). Obtained after
e
f
addition of benzaldehyde (1.2 equiv.) followed by treatment with 6 M
HCl.
The functionalization of less common heterocycles is of key
importance for pharmaceutical applications.21 Thus, the met-
alation of symmetrical 2-aryl-2H-1,2,3-triazoles 16a–b was then
investigated (Scheme 7).22,23 Aer metalation of 16a with 0.6
equiv. of sBu2Mg for 15 min at 40 ꢀC, the resulting bis-
arylmagnesium species 17a was then trapped with furfural,
affording the functionalized 1,2,3-triazole 18a in a 68% yield.
Further trapping reactions such as Negishi cross-coupling,
copper-catalyzed allylation and oxidative alkynylation with
(phenylethynyl)lithium24 lead to 2-aryl-1,2,3-triazoles 18b–d in
52–66% yield. Similarly, 1,2,3-triazole 16b was readily magne-
siated at 25 ꢀC (0.5 h) as shown by the quantitative formation of
a single regioisomer by NMR-analysis of a deuterolyzed reaction
aliquot.20 Further quenching reactions of 17b like thio-
methylation and allylation furnished triazoles 18e–f in 82–91%
yield. A second functionalization was performed on N-aryl
Scheme 4 Transformation of ortho,ortho0-functionalized oxazoline
11b to the corresponding nitrile 11g. a Isolated yield.
aer 0.5 h at 40 ꢀC. Aer addition of benzaldehyde or Weinreb
amide MeCON(OMe)Me, alcohol 14a and ketone 14b were ob-
tained in 74–86% yield (Scheme 5). Copper-catalyzed allylation
with 3-bromocyclohex-1-ene produced the pyrazole 14c (90%
yield). Interestingly, N-aryl pyrazoles 12b and 12c although
bearing relatively acidic protons at the heterocyclic ring were
selectively magnesiated at the ortho-position of the phenyl ring.
In particular, unsubstituted pyrazole 12c was metalated in 94%
yield and >98 : 1 : 1 selectivity, as determined by deuterolysis of
a reaction aliquot.20 These results further conrm the key role of
the coordination at the N(2)-atom of the pyrazole to direct the
metalation selectively on the aryl ring in a non-polar solvent like
toluene. Thus, the functionalized pyrazoles 14d–f were obtained
aer Negishi cross-coupling with 5-bromopyrimidine, 5-bro-
mobenzo[d][1,3]dioxole or addition of furfural in 64–90% yield.
We also achieved an unsymmetrical ortho,ortho0-functionaliza-
tion and mono-substituted pyrazole 14f was selectively magne-
siated at 60 ꢀC (0.5 h) and trapped by Negishi cross-coupling
with 6-iodoquinoline and 4-iododibenzo[b,d]thiophene
providing the products 15a–b in 67–84% yield (Scheme 6).
Scheme 6 Regioselective magnesiation of mono-functionalized N-
aryl pyrazole 14f with sBu2Mg leading to ortho,ortho0-functionalized
N-aryl pyrazoles 15a–b. a All yields refer to isolated compounds.
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standard conditions and the resulting bis-arylmagnesium
species were trapped with a different electrophile (E2) leading
to a range of unsymmetrical functionalized 1,2,3-triazoles 19b–f
in 70–88% yield.
Finally, we examined the metalation of 1-aryl-1H-1,2,3-tri-
azoles such as 20a–e and found that sBu2Mg led to a highly
regioselective magnesiation at the ortho-position of the aryl ring
in toluene (25–40 ꢀC, 0.5–1 h), affording the bis-aryl-magnesium
species 21a in 75% yield and 97 : 3 regioselectivity (Scheme 9).20
This new metalation procedure occurred twice as fast as the
previously reported TMPMgBu base.3 1,2,3-Triazoles 22a and
22b were isolated in 93% and 67% yields respectively aer
Negishi cross-couplings with only 0.83 equiv. of aryl bromide.3
Copper-catalyzed acylation11 with benzoyl chloride lead to
products 22c and 22d in 55–58% yield and quenching with
various aldehydes afforded compounds 22e–h in 69–80% yield.
Remarkably, sBu2Mg was also an excellent base for the
magnesiation of various arenes bearing directing groups such
as a tertiary amide or phosphorodiamidate (23a–j; Scheme 10).25
The addition of sBu2Mg to the aromatic amide 23a in toluene
led to a clean magnesiation within 0.5 h at room temperature.
The resulting diarylmagnesium species 24a was then further
allylated with allyl and cyclohexenyl bromides, leading to 25a
and 25b in 62% and 71% yield respectively. Copper-catalyzed
acylation of 23a with thiophene-2-carbonyl chloride or trap-
ping with furfural furnished the ketone 25c (64% yield) and the
lactone 25d (76% yield).26 Similarly, the amides 23b–f afforded
with the same magnesiation/trapping sequence the polyfunc-
Scheme 7 Regioselective magnesiation of 2-aryl-2H-1,2,3-triazoles
16a–b with sBu2Mg leading, via diarylmagnesium species 17a–b, to
a
functionalized 2-aryl-2H-1,2,3-triazoles 18a–f. All yields refer to
b
c
isolated compounds.
Magnesiation conditions.
Obtained after
transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed
cross-coupling with [PdCl2(dppf)] (5 mol%) and an aryl halide (0.83
d
equiv.). Obtained after transmetalation with CuCN$2LiCl (1.2 equiv.)
and subsequent addition of (phenylethynyl)lithium (2.0 equiv.), fol-
lowed by addition of chloranil (1.3 equiv.). e The reaction was catalyzed
by CuCN$2LiCl (20 mol%).
triazoles 18d–f using again sBu2Mg in toluene, followed by
quench with a different electrophile (E2) (Scheme 8). We
observed a complete magnesiation of 18d with sBu2Mg within
tional
amides
(25e–i)
in
61–72%
yield.
Various
ꢀ
15 min at 40 C and a subsequent reaction with benzaldehyde
produced the mixed bis-functionalized 1,2,3-triazole 19a in 42%
yield. Similarly, 18e and 18f were magnesiated under the
Scheme 8 Regioselective magnesiation of mono-functionalized 2-
aryl-2H-1,2,3-triazoles 18d–f with sBu2Mg leading to ortho,ortho0- Scheme 9 Regioselective magnesiation of 1-aryl-2H-1,2,3-triazoles
a
functionalized 2-aryl-2H-1,2,3-triazoles 19a–f. All yields refer to 20a–e with sBu2Mg leading, via diarylmagnesium species 21a–e, to
a
isolated compounds. b Magnesiation conditions. c The regioselectivity functionalized 1-aryl-2H-1,2,3-triazoles 22a–h. All yields refer to
d
b
c
was determined by crystal structure analysis, see ESI.† The reaction isolated compounds.
Magnesiation conditions.
Obtained after
was catalyzed by CuCN$2LiCl (20 mol%). e The reaction was catalyzed transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed
f
by CuI (10 mol%). Obtained after transmetalation with ZnCl2 (1.1 cross-coupling with [PdCl2(dppf)] (5 mol%) and an aryl halide (0.83
equiv.) and a palladium-catalyzed cross-coupling with [PdCl2(dppf)] equiv.).d The reaction was catalyzed by CuCN$2LiCl (20 mol%). The
e
(5 mol%) and an aryl bromide (0.83 equiv.).
regioselectivity was determined by crystal structure analysis, see ESI.†
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the aldehyde 26a in 90% yield. A two–step transformation
consisting of a reduction with the complex borohydride LiH3-
BPyrr (Pyrr ¼ pyrrolidino)30 followed by a treatment with ethyl
chloroformate31 provided the benzylic chloride 26b in 85%
overall yield (Scheme 11).
Conclusions
In summary, we have developed a new preparation of sBu2Mg in
toluene and showed its utility for the directed magnesiation of
various aromatic and heterocyclic systems including pharma-
ceutically relevant N-arylated pyrazoles as well as N-arylated
1,2,3-triazoles. This method provides a unique access to varius
diarylmagnesium reagents in toluene. Furthermore, a range of
arenes bearing various directing groups such as an oxazoline,
phosphorodiamidate or an amide were magnesiated with
sBu2Mg. Remarkably, a second unsymmetrical ortho,ortho0-
functionalization was achieved in the case of aryl oxazolines, N-
aryl pyrazoles as well as N-aryl triazoles, leading to valuable
synthetic intermediates of potential pharmaceutical relevance.
Further investigations of the use of sBu2Mg as metalating agent
are currently underway in our laboratory.
Author contributions
A. H., J. P. P, S. B. D., F. T. and K. K. performed and analyzed the
experiments. A. H., F. H. L., S. L., S. W. and P. K. designed the
experiments. A. H., S. L., S. W., and P. K. prepared the manu-
script with contributions of all authors.
Scheme 10 Regioselective magnesiation of various arenes bearing an
amide or a phosphorodiamidate directing group as well as 1-propyl-
1,2,4-triazole 23a–k with sBu2Mg leading, via diarylmagnesium species
a
24a–k, to functionalized arenes 25a–o. All yields refer to isolated
b
compounds. Magnesiation conditions. c The reaction was catalyzed
by CuCN$2LiCl (20 mol%). d R ¼ P(O)(NMe2)2. e Obtained after treating
25m with 2 M HCl in dioxane (105 ꢀC, 1 h).
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the Deutsche Forschungsgemeinscha and the Lud-
¨
wig-Maximilians-Universitat for nancial support. We also
thank Albemarle Lithium GmbH (Frankfurt) and the BASF AG
(Ludwigshafen) for the generous gi of chemicals.
Scheme 11 Synthetic transformations of magnesiated product 25b.
a All yields refer to isolated compounds.
Notes and references
phosphorodiamidates (23g–j) were also metalated with sBu2Mg
at 40–60 ꢀC (0.5–1 h) providing the diarylmagnesiums 24g–j,
which were trapped with a range of electrophiles (MeSSO2Me,
I2, cHexCHO and (BrCCl2)2) furnishing the phenol derivatives
25j–m in 68–98% yield. Removal of the phosphorodiamidate
group27 in 25m was achieved with a 2 M HCl treatment in
dioxane (105 ꢀC, 1 h) leading to phenol 25n in 88% yield.
Interestingly, 1-propyl-1,2,4-triazole (23k) was magnesiated with
sBu2Mg and allylated with cinnamyl bromide providing the N-
heterocycle 25o in 86% yield.28
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