Direct magnesiation of polyfunctionalized arenes and heteroarenes using (tmp)2Mg·2 LiCl

Article abstract of DOI:10.1002/anie.200701487

(Chemical Equation Presented) Outstripping lithium bases: A wide range of polyfunctional aryl and heteroaryl magnesium reagents were efficiently prepared in THF by direct magnesiation with (tmp)₂Mg·2 LiCl, an exceptionally active base. These co

Full text of DOI:10.1002/anie.200701487

Angewandte
Chemie
DOI: 10.1002/anie.200701487
Synthetic Methods
Direct Magnesiation of Polyfunctionalized Arenes and Heteroarenes
Using (tmp)2Mg·2LiCl**
Giuliano C. Clososki, Christoph J. Rohbogner, and Paul Knochel*
Dedicated to Professor Herbert Mayr on the occasion of his 60th birthay
Directed lithiations are important reactions for the function-
alization of arenes and heterocycles.[1] In contrast, directed
magnesiation with magnesium bases has been used much less
at 08C for 0.5 h. Whereas with (tmp)MgCl·LiCl no significant
deprotonation of 2a was observed, the use of magnesium
bisamides complexed with two equivalents of LiCl such as
3a–c led to excellent results (Scheme 1).
[3]
often.[2] The pioneering workof Eaton et al. demonstrated
the potential of this approach using magnesium bis(2,2,6,6-
tetramethylpiperamide), (tmp)2Mg. However, the limited
solubility of such bases in common organic solvents as well
as the requirement for an excess of the magnesium bases (2–
7 equiv) to achieve high conversions has precluded their
general use. Recently, we have reported that mixed Li/Mg
amides of the type R2NMgCl·LiCl and in particular
(tmp)MgCl·LiCl (1) are highly soluble magnesium bases
readily able to deprotonate a broad range of unsaturated
substrates.[4] However, some moderately activated arenes
such as tert-butyl benzoate (2a) gave unsatisfactory results
(Scheme 1). Therefore, we have developed a new class of
mixed Li/Mg bases: magnesium bisamides complexed with
lithium chloride, (R2N)2Mg·2LiCl (3). The reagents 3a–c
were readily prepared by reacting R2NLi with MgCl2 in THF
In general (tmp)2Mg·2LiCl (3a) proves to be the most
powerful and selective base,[5] and the best results were
obtained when it was freshly prepared. We have found that
this base can also be conveniently made by reacting
(tmp)MgCl·LiCl (1) with lithium 2,2,6,6-tetramethylpipera-
mide[6] for 30 min at 08C. Since 1 can be stored in THF at
258C for months, this alternative method appears to be the
best for routine experiments. Moreover, this procedure can
also be applied successfully for the preparation of 3a in situ.
On the other hand, [tBu(iPr)N]2Mg·2LiCl (3c) can be stored
in THFat 48C for three weeks with no significant reduction of
activity.
A number of aromatic and heterocyclic substrates were
cleanly metalated with 3a (Table 1). Thus, tert-butyl benzoate
(2a) was converted to the ortho-magnesiated intermediate by
reaction with 3a within 1 h at 258C. After transmetalation
with CuCN·2LiCl,[7] the reaction with benzoyl chloride
provided the ketoester 4b in 93% yield (entry 1, Table 1).
Remarkably, the magnesiated intermediates of the type
ArMg(tmp)·2LiCl obtained after the magnesiation with 3a
were smoothly transmetalated with ZnCl2 (1.2 equiv) and
underwent a Negishi cross-coupling[8] with ethyl 4-iodoben-
zoate (1.5 equiv) in the presence of [Pd(dba)2] (2 mol%), and
P(o-furyl)3 (4 mol%) at 258C for 12 h, leading to the biphenyl
derivative 4c in 82% yield (entry 2, Table 1).
Similarly, the magnesiation of PhCO2iPr (2b) with 3a
(258C, 1 h) gave after copper(I)-mediated acylation with
propionyl chloride the ketone 4d in 78% yield (entry 3,
Table 1). Additionally, the reactions of 3a and 3c (1.2 equiv)
with ethyl naphthoate (2c) led to the corresponding ortho-
magnesiated intermediates within 3 h at O8C. Iodolysis,
bromolysis with (BrCl2C)2, or Negishi cross-coupling with 4-
iodo benzonitrile afforded the corresponding functionalized
derivatives 4e–g in 81–83% yield (entries 4–6, Table 1). The
presence of an electron-withdrawing group such as a bromine
substituent in the case of tert-butyl 4-bromobenzoate (2d)
accelerated the metalation, furnishing the magnesiated prod-
uct within 1 h at À208C. Quenching with iodine afforded tert-
butyl 4-bromo-2-iodobenzoate (4h) in 71% yield (entry 7,
Table 1). A copper(I)-mediated benzoylation with benzoyl
chloride gave the corresponding tert-butyl 2-benzoyl-4-bro-
mobenzoate (4i) in 77% yield (entry 8, Table 1). Although
benzonitriles are metalated sluggishly with 1, the use of 3a
(1.2 equiv) led to a complete magnesiation of benzonitrile 2 f
Scheme 1. Comparison between magnesium amide 1 and magnesium
bisamides 3a–c.
[*]Dr. G. C. Clososki, Dipl.-Chem. C. J. Rohbogner, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**]We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) for financial support. G.C.C.
thanks the Humboldt Foundation for a fellowship. We also thank
Chemetall GmbH (Frankfurt), Degussa GmbH (Hanau), and BASF
AG (Ludwigshafen) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Products of type 4 obtained by the magnesiation of arenes with (tmp)2Mg·2 LiCl (3a) and reactions with electrophiles.
+
Entry
Substrate
T [oC],t [h]E
Product
Yield [%][a]
1
2
3
2a: R=tBu
2a: R=tBu
2b: R=iPr
25, 1
25, 1
25, 1
PhCOCl
p-IC6H4CO2Et
EtCOCl
4b: E=COPh, R=tBu
4c: E=p-C6H4CO2Et, R=tBu
4d: E=COEt, R=iPr
93[b]
82[c]
78[b]
4
5
6
2c
2c
2c
0, 3
0, 3
0, 3
I2
4e: E=I
4 f: E=Br
4g: E=p-C6H4CN
83
(BrCl2C)2
p-IC6H4CN
83
81[c]
7
8
2d
2d
À20, 1
À20, 1
I2
4h: E=I
4i: E=COPh
71
PhCOCl
77[b]
9
2e
À30, 3
p-IC6H4CO2Et
4j
70[c]
94
10
11
12
13
14
2 f: R=tBu,X=CH 0, 1
2 f: R=tBu, X=CH 0, 1
2g: R=Et, X=N
2g: R=Et, X=N
2g: R=Et, X=N
I2
4k: E=I, X=CH, R=tBu
p-C6H4CO2Et
I2
(BrCl2C)2
p-IC6H4CN
4l: E=p-IC6H4CO2Et,X=CH, R=tBu 88[c]
À40, 3
4m: E=I, X=N, R=Et
4n: E=Br, X=N, R=Et
4o: E=p-C6H4CN, X=N, R=Et
77
À40, 3
À40, 3
70
73[c]
15
2h
À40, 12
I2
4p
66
[a]Yield of analytically pure product. [b]Transmetalation with CuCN·2LiCl (0.2 mol%) was performed. [c]Obtained by palladium-catalyzed cross-
coupling after transmetalation with ZnCl2 (1.2 to 1.3 equiv).
at À308C within 3 h. After Negishi cross-coupling with ethyl
4-iodobenzoate, the corresponding functionalized biphenyl
derivative 4j was obtained in 70% yield (entry 9, Table 1). A
1,3-diester such as 2 f was magnesiated regioselectively with
3a in position 4 and not in position 2 as a result of steric
hindrance, providing after iodolysis or Negishi cross-coupling
reaction with ethyl 4-iodobenzoate the corresponding deriv-
atives 4k and 4l in 94% and 88% yield, respectively
(entries 10 and 11, Table 1). The directed metalation of
pyridines is of great importance.[9] Ester-substituted pyridines
are also excellent substrates for base 3a, and the diester 2g
was converted to the corresponding 2-magnesiated pyridine
(À408C), which provided after iodolysis, bromolysis with
(BrCl2C)2, or Negishi cross-coupling with 4-iodobenzonitrile
the expected polyfunctional pyridines 4m–o in 70–77% yield
(entries 12–14, Table 1). Similarly 4-carbethoxypyridine (2h)
reacted smoothly with 3a (À408C, 12 h) leading after
iodolysis to the 3-iodopyridine 4p in 66% yield (entry 15,
Table 1).
directing group was converted to the magnesiated intermedi-
ate 6 (À208C, 4 h) leading, after a copper(I)-mediated
benzoylation with benzoyl chloride to the 1,2-diketone 7 in
72% yield. Similarly, the Boc-protected ethyl benzoate 8 was
selectively converted to the magnesium intermediate 9 within
2 h at 08C, providing after iodolysis the corresponding 2-
iodobenzoate 10 in 78% yield. The role of the Boc group is to
direct the magnesiation and to enhance the rate of metalation.
Interestingly, the powerful and more bulky bis(dimethylami-
no)phosphonate directing group allows a magnesiation of 11
within 1 h at 08C. Remarkably, the OP(O)(NMe)2 group
selectively directs the metalation to position 4 leading to the
magnesiated reagent 12 (Scheme 2). Quenching of 12 with I2
provided the aryl iodide 13 in 91% yield.
The magnesiation of electron-rich aromatic rings is
especially difficult. However, such metalations can be per-
formed successfully with the highly active bases of type 3. For
example, dimethyl-1,3-benzodioxan-4-one (14)[10] was con-
verted to the corresponding magnesium reagent 15 within
10 min at À408C. After a transmetalation with ZnCl2 and Pd-
catalyzed cross-coupling with (E)-1-hexenyl iodide[11] (16)
(1.5 equiv, 258C, 12 h), the 6-substituted benzodioxane (17)
was isolated in 77% yield. Hydrogenation of the double bond
followed by cleavage of the dioxanone with excess of KOH
The new class of mixed Mg/Li bases of type 3 also
tolerates sensitive functional groups such as a ketone, a
carbonate (OBoc; Boc = tert-butoxycarbonyl), or a bis(dime-
thylamino) phosphonate group (OP(O)(NMe2)2). Thus, the
unsymmetrical benzophenone 5 bearing a Boc group as a
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nBuLi (2.4m in Hexane, 12.5 mL, 30 mmol)
was added dropwise. After the addition was
complete, the reaction mixture was warmed
to 08C and stirred at this temperature for
30 min. Freshly titrated 1[4] (1.0m in THF,
30 mL, 30 mmol) was then added dropwise to
the reaction mixture. The reaction mixture
was stirred at 08C for 30 min, warmed to
258C, and stirred for 1 h. The solvents were
then removed under vacuum affording a
yellowish solid. Freshly distilled THF was
then slowly added under vigorous stirring
until the salts were completely dissolved. The
resulting solution of 3a solution was
titrated[13] prior to use at 08C with benzoic
acid using 4-(phenylazo)diphenylamine as
the indicator. A concentration of 0.7m in
THF was obtained.
4c: A dry and nitrogen-flushed 10 mL
Schlenkflaskequipped with
a magnetic
Scheme 2. Chemoselective directed magnesiation using 3a.
stirring bar and a septum was charged with
a solution of 2a (0.178 g, 1.0 mmol) in dry
provided the 6-hexylsalicylic acid (18), a natural product
found in the essential oil of Pelargonium sidoides DC,[12] in
89% yield (Scheme 3).
THF (1 mL). Freshly prepared 3a (0.70m in THF, 1.57 mL, 1.1 mmol)
was added dropwise, and the reaction mixture was stirred at this
temperature for 1 h. The completion of the metalation was checked
by GC analysis of reaction aliquots quenched with a solution of I2 in
anhydrous ether. The mixture was then cooled to À408C, ZnCl2 (1m
solution in THF, 1.2 mL, 1.2 mmol) was added, and the reaction
mixture stirred for 15 min. [Pd(dba)2] (11 mg, 2 mol%) and P(o-
furyl)3 (9 mg, 4 mol%) dissolved in THF (0.5 mL) were then trans-
ferred by cannula to the reaction mixture, and then ethyl 4-
iodobenzoate (0.414 g, 1.5 mmol) dissolved in THF (0.5 mL) was
added. The reaction mixture was slowly warmed to 258C and stirred
for 12 h. The reaction mixture was quenched with sat. aq. NH4Cl
solution, extracted with diethyl ether (3 ” 15 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was removed in
vacuo. Purification by flash chromatography (n-pentane/diethyl
ether, 10:1) furnished compound 4c (0.267 g, 82%) as a colorless oil.
Received: April 5, 2007
Revised: May 29, 2007
Published online: July 30, 2007
Keywords: copper · cross-coupling · homogeneous catalysis ·
.
lithium chloride · organomagnesium compounds
Scheme 3. Preparation of 6-hexylsalicylic acid (18), a compound found
in the essential oil of Pelargonium sidoides DC.
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7683

Communications
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