Directed magnesiation of polyhaloaromatics using the tetramethylpiperidylmagnesium reagents TMP2Mg×2 LiCl and TMPMgCl×LiCl

Article abstract of DOI:10.1002/adsc.201300185

A convenient and efficient functionalization of polyhaloaromatics via regioselective magnesiation has been developed. Starting from simple, inexpensive but structurally challenging arenes, metallation by magnesium amide bases was achieved under mild conditions. The desired Grignard reagents were stable towards aryne formation, were obtained in good yields within short reaction times and could be reacted with a variety of typical electrophiles, providing attractive, functionalized building blocks in good to excellent yields. As an application we have prepared the antimicrobial natural product 2,6-dichloro-3-phenethylphenol isolated from the New Zealand liverwort Riccardia marginata. This synthesis involves a mixed bimetallic compound prepared via metallation of a phenylboronic acid pinacol ester derivative and subsequent selective cross-coupling. Copyright

Full text of DOI:10.1002/adsc.201300185

FULL PAPERS
DOI: 10.1002/adsc.201300185
Directed Magnesiation of Polyhaloaromatics using the
Tetramethylpiperidylmagnesium Reagents TMP2Mg·2LiCl and
TMPMgCl·LiCl
Andreas Unsinn,a Christoph J. Rohbogner,a and Paul Knochela,*
a
Department Chemie, Ludwig Maximilians-Universitꢀt Mꢁnchen, Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen,
Germany
Fax : (+49)-089-2180-77680; phone: (+49)-089-2180-77680; e-mail: paul.knochel@cup.uni-muenchen.de
Received: February 28, 2013; Revised: April 16, 2013; Published online: May 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300185.
Abstract: A convenient and efficient functionaliza- tion we have prepared the antimicrobial natural
tion of polyhaloaromatics via regioselective magne- product 2,6-dichloro-3-phenethylphenol isolated
siation has been developed. Starting from simple, in- from the New Zealand liverwort Riccardia margina-
expensive but structurally challenging arenes, metal- ta. This synthesis involves a mixed bimetallic com-
lation by magnesium amide bases was achieved pound prepared via metallation of a phenylboronic
under mild conditions. The desired Grignard re- acid pinacol ester derivative and subsequent selective
agents were stable towards aryne formation, were cross-coupling.
obtained in good yields within short reaction times
and could be reacted with a variety of typical elec- Keywords: acylation; cross-coupling; Grignard reac-
trophiles, providing attractive, functionalized build- tions; metallation; natural products; synthetic meth-
ing blocks in good to excellent yields. As an applica- ods
Introduction
building blocks,[9] for example, diclofenac or propanil.
Also these halogenated aromatics are found in many
The metallation of aromatics is a convenient approach natural products. Thus, for example, the chlorinated
to the functionalization of these unsaturated scaf- bibenzylphenol 4 isolated from the New Zealand liv-
folds.[1] Besides the conventional lithium bases, such erwort Riccardia marginata[10] displays antimicrobial
as LDA,[2] TMPLi (TMP=2,2,6,6-tetramethylpiperid- activity against Bacillus subtilus, Candida albicans and
yl),[2] BuLi,[2] the Schlosser base (LIC-KOR=BuLi·t- Trichophyton mentagrophytes.
BuOK)[3] or the Fort base (BuLi–LiDMAE;
Recently, we have reported the preparation of
LiDMAE=lithium 2-N,N-dimethylaminoethoxide),[4] highly reactive magnesium TMP amides such as
a range of bimetallic ate-bases has been introduced TMP2Mg·2LiCl (5)[11] and TMPMgCl·LiCl (6)[12]
by Kondo, Mulvey, Mongin and Uchiyama.[5] Al- which proved able to magnesiate various aromatics
though the lithiation of polyhalogenated benzenes under mild conditions.
1 has been well studied,[6] the practicability of this
Herein, we wish to report the use of magnesium
method is very limited by the stability of the resulting amides 5 and 6 for the magnesiation of various poly-
ortho-halophenyllithium of type 2a. These compounds haloaromatics and subsequent reactions with electro-
decompose usually between À908C and À408C de- philes leading to polyfunctional halogenated arenes.
pending on the nature of the halogen leading to the Furthermore, we demonstrate the utilility of our pro-
corresponding arynes[7] 3, which undergo further reac- cedure by preparing the antimicrobial natural product
tions. The corresponding magnesium derivatives of 4 in 4 steps and 59% overall yield.
type 2b display a much better stability and undergo
aryne formation only at higher temperatures (50–
808C). Actually, they have to be heated for the exten- Results and Discussion
sive formation of arynes[8] (Figure 1).
Especially polyfunctional aryl halides are of high We have first examined the magnesiation of all three
importance as agrochemicals, pharmaceuticals and isomers of dichlorobenzene[13] (7–9). With these sub-
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Figure 1.
strates
a
regioselective
magnesiation
using functionalized dichlorobiphenyl derivatives 13a, 14a
TMP2Mg·2LiCl (5) is achieved at 08C within 15– and 15a are obtained in excellent yields (Scheme 2).
60 min, leading to the expected Grignard reagents 10– A broad range of electrophiles react with the di-
12 in >95% yield. Less active TMP bases, such as chlorophenylmagnesium reagents 10–12 leading to the
TMP2Mn·2MgCl2·4LiCl,[14] TMP2Zn·2MgCl2·2LiCl[15] expected products 13b–e, 14b, c and 15b–h in moder-
or TMPZnCl·LiCl[16] proved not to be suitable for ate to excellent yields (Table 1). It should be noticed
such metallations. Side reactions like Wurtz cou- that this type of products can also be prepared via
pling,[17] halogen dance[18] or elimination of HCl[19] are a Br/Mg exchange with i-PrMgCl·LiCl[22] starting,
not observed in the course of the magnesiation however, from the incomparably more expensive cor-
(Scheme 1).
responding bromides.
These Grignard reagents can be transmetallated to
the corresponding organozinc reagents which undergo
at room temperature readily a Negishi cross-cou-
ACTHNUTRGNEUNG
pling[20] using 2 mol% Pd(dba)2 and 4 mol% tfp[21]
[tfp=triACHTUNGTRENNUNG(2-furyl)phosphine] as catalyst. The desired
Scheme 2. Negishi cross-coupling of the metallated dichloro-
benzenes 10-12.
Scheme 1. Magnesiation of dichlorobenzenes 7-9.
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Directed Magnesiation of Polyhaloaromatics using the Tetramethylpiperidylmagnesium Reagents
Table 1. Products obtained after directed magnesiation of dichlorobenzenes 7–9.
Entry
Substrate
E+
Product: Yield[a]
1
I2
7
7
13b: 78%
2
3
PhCHO
13c: 94%
7
7
13d: 87%[b]
13e: 81%[c]
14b: 90%
14c: 74%
4
5
6
ClCO2Et
PhCHO
PhCH2Br
8
8
7
I2
9
9
15b: 78%
15c: 54%
15d: 89%
15e: 74%
15f: 88%[c]
8
Br2
9
9
9
9
PhCHO
DMF
ClCO2Et
10
11
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Product: Yield[a]
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Table 1. (Continued)
Entry
Substrate
E+
12
9
PhCOCl
15g: 97%[c]
15h: 58%[c]
13
9
[a]
Isolated yield of analytically pure product.
A transmetallation with ZnCl2 (1.1 equiv.) and CuCN·2LiCl (1.1 equiv.) was performed.
A transmetallation with ZnCl2 (1.1 equiv.) and 2 mol% PdACTHNUGTRNEUNG(PPh3)4-catalyzed acylation were performed.
[b]
[c]
Thus, the iodolysis of Grignard reagent 10 produces
1,2-dichloro-3-iodobenzene (13b) in 78% (Table 1,
entry 1). Addition of 10 to benzaldehyde gives the ex-
pected alcohol 13c in 94% yield (Table 1, entry 2).
After a transmetallation using CuCN·2LiCl[23] and
acylation with 4-fluorobenzoyl chloride the desired
ketone 13d is obtained in 87% yield (Table 1,
entry 3). Whereas, after
a transmetallation with
ZnCl2, Negishi acylation[24] with ethyl chloroformate
furnishes the desired ethyl ester 13e in 81% yield
(Table 1, entry 4). Similarly the Grignard reagent 11
reacts with benzaldehyde or benzyl bromide yielding
the corresponding alcohol 14b or diphenylmethane
14c in respective yields of 90 and 74% (Table 1, en-
tries 5 and 6). In the same way, the arylmagnesium
species 12 reacts with a range of electrophiles, like
iodine, bromine, benzaldehyde, dimethylformamide
or after transmetallation to zinc with various acid
chlorides under palladium catalysis. The desired prod-
ucts 15b–h are obtained in 54–97% (Table 1, en-
tries 7–13). Remarkably, the reactions can also be run
Scheme 3. Metallation of 1,3,5-trichlorobenzene 16.
conveniently on a larger scale, as the reaction de- gen substituents attached to the aromatic ring. Re-
scribed in entry 8 was performed on a 40-mmol scale. markably, all these bromofluoroarenes are selectively
If the benzene ring is more electron-poor, like in metallated under mild conditions without any subse-
1,3,5-trichlorobenzene (16) magnesiation is best ach- quent halogen dance, Wurtz coupling or elimination
ieved using TMPMgCl·LiCl (6, 08C, 1 h), again degra- of HX. Thus, 1-bromo-3-fluorobenzene (19) is magne-
dation products have not been observed during the siated at À208C using TMP2Mg·2LiCl (5) within 1 h.
reaction course. In this case the use of Subsequent reaction with benzaldehyde provides the
TMP2Mg·2LiCl (5) is not required due to the higher diphenylmethanol 20 in 88% yield. The more elec-
activity of 16. Furthermore whereas TMP2Mg·2LiCl tron-deficient 1,3-dibromo-5-fluorobenzene (21) is
(5) has only limited thermal stability, TMPMgCl·LiCl metallated regioselectively by TMPMgCl·LiCl (6) at
(6) is indefinitely stable at 258C and therefore more À208C within 1 h. The resulting Grignard reagent
practical. The resulting phenylmagnesium derivative reacts with ethyl cyanoformate yielding ethyl 2,4-di-
17 reacts smoothly with electrophiles like 4-cyanoben- bromo-6-fluorobenzoate (22) in 90% yield. Also 1-
zaldehyde, providing alcohol 18 in 89% yield bromo-3,5-difluorobenzene (23) is metallated regiose-
(Scheme 3)
lectively by TMPMgCl·LiCl (6) at À208C within 1 h.
Similarly mixed bromofluoroarenes[25] are regiose- After transmetallation to zinc and palladium-cata-
lectively magnesiated with TMP2Mg·2LiCl (5) or lyzed cross-coupling the desired biphenyl 24a is ob-
TMPMgCl·LiCl (6) depending on the number of halo- tained in 89% yield (Scheme 4).
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Directed Magnesiation of Polyhaloaromatics using the Tetramethylpiperidylmagnesium Reagents
Furthermore, the Grignard reagent derived from 23
reacts with various other electrophiles. Quenching
with iodine or S-methyl methanesulfonothioate af-
fords 5-bromo-1,3-difluoro-2-iodobenzene (24b) and
(4-bromo-2,6-difluorophenyl)ACTHUNTGRNEUNG(methyl)sulfane (24c) in
respective yields of 61 and 88% (Table 2, entries 1
and 2). Similarly, the desired ethyl ester 24d is ob-
tained in 72% by an addition reaction to ethyl cyano-
formate (Table 2, entry 3). Copper-catalyzed acylation
provides the ketones 24e and 24f in 63–71% (Table 2,
entries 4 and 5). After transmetallation to zinc and
Negishi cross-coupling with 1-chloro-4-iodobenzene
the polyhalogenated biphenyl 24g is obtained in 84%
yield (Table 2, entry 6).
We noticed that the magnesiation of 1,4-dibromo-
benzene[26] (25) with TMP2Mg·2LiCl (5) leads mainly
to aryne formation. This can be avoided by the fol-
lowing experimental protocol using ZnCl2 in situ.[27]
.
Thus, 1,4-dibromobenzene was dissolved in ZnCl2 so-
lution (1M in THF) and then treated with
TMP2Mg·2LiCl (5), furnishing full metallation after
12 h at room temperature. The resulting zincate can
Scheme 4. Metallation of various bromofluorobenzenes with
the TMP-magnesium bases 5 and 6.
Table 2. Products obtained after directed magnesiation of 1-bromo-3,5-difluorobenzene (23).
Entry
Substrate
E+
Product: Yield[a]
1
I2
23
23
24b: 61%
24c: 88%
24d: 72%
24e: 71%[b]
24f: 63%[c]
2
3
4
5
MeSO2SMe
NCCO2Et
PhCOCl
23
23
23
6
23
24g: 84%[c]
[a]
Isolated yield of analytically pure product.
[b]
[c]
A transmetallation with ZnCl2 (1.1 equiv.) and CuCN·2LiCl (1.1 equiv.) was performed.
A transmetlalation with ZnCl2 (1.1 equiv.) and Pd-catalyzed cross-coupling using 2 mol% Pd
performed.
AHCTUNGRTEG(NNNU dba)2 4 mol% and tfp were
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Conclusions
We have shown that various polyhaloaromatics can
be regioselectively metallated by using
TMP2Mg·2LiCl (5) or TMPMgCl·LiCl (6) under mild
conditions. The resulting Grignard reagents can be
combined with a large number of electrophiles to pro-
vide attractive new building blocks, particularly func-
tionalized derivatives, in good to excellent yields.
We also succeeded in preparing a mixed bimetallic
zinc-boron reagent by metallation of a phenylboronic
acid pinacol ester derivative and have successfully ap-
Scheme 5. Functionalization of 1,4-dibromobenzene (25).
be cross-coupled with ethyl 4-iodobenzoate in the plied this method in the first preparation of 2,6-di-
presence of 2% Pd(dba)2 and 4% tfp yielding the de- chloro-3-phenethylphenol (4), a antimicrobial natural
sired functionalized unsymmetrical dibromobiphenyl product isolated from the New Zealand liverwort Ric-
26 in 65% yield (Scheme 5). cardia marginata. Further studies on the preparation
AHCTUNGTRENNUNG
To demonstrate the synthetic potential of our meth- of mixed bimetallic reagents via metallation are cur-
odology, we have prepared the antimicrobial biben- rently underway.
zylphenol 4 found in the New Zealand liverwort Ric-
cardia marginata.
Thus, we have performed a metallation of 1,3-di-
Experimental Section
chlorobenzene (8) with TMP2Mg·2LiCl (5) in the
presence of isopropoxyboronic acid pinacol ester[28]
yielding 2,6-dichlorophenylboronic acid pinacol ester
(27) in 93%. Subsequent metallation following the
procedure for 1,4-dibromobenzene (25) yielded the
bimetallic zincate 28 that could be selectively cross-
coupled with (E)-(2-iodovinyl)benzene under Pd-
Synthesis of Ethyl 2’,5’-Dichloro-[1,1’-biphenyl]-4-
carboxylate (15a)
A flame-dried and argon-flushed Schlenk tube equipped
with a rubber septum and a magnetic stirring bar was
charged with a solution of 1,4-dichlorobenzene (294 mg,
2.0 mmol) in dry THF (2 mL) as well as 50 mL of tetrade-
cane (internal standard for GC analysis). The mixture was
cooled to 08C, then TMP2Mg·2LiCl (0.7M in THF, 3.14 mL,
2.2 mmol) was added dropwise through a syringe and the
mixture was stirred at 08C for 0.25 h. Complete metallation
was detected by GC analysis of reaction aliquots quenched
with I2 in dry THF. Then ZnCl2 (2.4 mL, 1M in THF,
2.4 mmol, 1.2 equiv.) was added at 08C. The reaction mix-
ACHTUNGTRENNUNG(PPh)4 catalysis to afford the diphenylstyrene 29. The
latter was used without purification in the following
steps and oxidized under basic conditions with hydro-
gen peroxide. Then the resulting styrylphenol was di-
rectly reduced with molecular hydrogen, providing
the natural product 2,6-dichloro-3-phenethylphenol
(4) in 63% over 3 steps (Scheme 6).
Scheme 6. Total synthesis of 2,6-dichloro-3-phenethylphenol (4).
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Directed Magnesiation of Polyhaloaromatics using the Tetramethylpiperidylmagnesium Reagents
ture was stirred for 10 min before Pd
(dba)2 (23 mg,
Ababsa, F. Chevallier, M. Yonehara, M. Uchiyama, A.
Derdour, F. Mongin, Chem. Commun. 2008, 5375; f) L.
Balloch, J. A. Garden, A. R. Kennedy, R. E. Mulvey, T.
Rantanen, S. D. Robertson, V. Snieckus, Angew. Chem.
2012, 124, 7040; Angew. Chem. Int. Ed. 2012, 51, 6934;
g) R. E. Mulvey, V. L. Blair, W. Clegg, A. R. Kennedy,
J. Klett, L. Russo, Nat. Chem. 2010, 2, 588; h) D. R.
Armstrong, V. L. Blair, W. Clegg, S. H. Dale, J. Garcꢄa-
ꢅlvarez, G. W. Honeyman, E. Hevia, R. E. Mulvey, L.
Russo, J. Am. Chem. Soc. 2010, 132, 9480.
2 mol%), P(o-furyl)3 (19 mg, 4 mol%) and ethyl 4-iodoben-
ACHTUNGTRENNUNG
zoate (497 mg, 1.8 mmol) were added. Then the solution
was warmed to room temperature over 3 h. The reaction
mixture was quenched by the addition of a saturated aque-
ous NH4Cl solution (30 mL), extracted with diethyl ether
(3ꢃ50 mL) and dried over anhydrous MgSO4. After filtra-
tion, the solvent was evaporated under vacuum. The crude
product was purified by column chromatography (pentane:-
diethyl ether=20:1) to give 15a as a colorless solid; yield:
513 mg (97%).
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Acknowledgements
The research leading to these results has received funding
from the European Research Council under the European
Communityꢀs Seventh Framework Programme (FP7/2007-
2013) ERC grant agreement No. 227763. We thank the Fonds
der Chemischen Industrie for financial support. We also
thank BASF SE (Ludwigshafen), Heraeus Holding GmbH
(Hanau) and Rockwood Lithium GmbH (Frankfurt) for the
generous gift of chemicals.
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