Directed manganation of functionalized arenes and heterocycles using tmp2Mn·2MgCl2·4LiCl

Full text of DOI:10.1002/anie.200903505

Communications
DOI: 10.1002/anie.200903505
Directed Manganation
Directed Manganation of Functionalized Arenes and Heterocycles
Using tmp2Mn·2MgCl2·4LiCl**
Stefan H. Wunderlich, Marcel Kienle, and Paul Knochel*
The metalation of arenes and heterocycles is of considerable
interest, since it allows direct functionalization of an unac-
À
tivated C H bond by the stoichiometric formation of an
organometallic intermediate. Whereas the lithiation of unsa-
turated organic substrates has been extensively used,[1] the
search for metalation procedures that are compatible with
more functional groups and proceed at close to room
temperature has been the subject of considerable efforts. In
this regard, the development of various “ate” bases has been
very promising.[2,3] Also, the use of sterically hindered
metallic amides complexed by LiCl of the type
tmpnM1·xM2Xm·yLiCl (tmp = 2,2,6,6-tetramethylpiperidyl;
M1 = Mg,[4] Zn,[5] Al;[6] M2 = Mg) has led to highly chemo-
and regioselective metalations. The presence of LiCl was
essential since it increases the solubility of these metallic
Scheme 1. Preparation and reactivity of 3 compared to 2.
bases and enhances their kinetic basicity by lowering their
aggregation states.[7]
The preparation of transition-metal amides has been
envisioned, as transition metals display reactivity patterns not
accessible for main-group elements.[8] Especially manganese,
owing to its low price, moderate toxicity, and versatile
reactivity, is of synthetic interest.[9] Herein, we report a new
manganese base[10] that shows a unique chemoselectivity and
metalation with 3 furnishes cleanly the corresponding dihe-
teroaryl manganese reagent, which smoothly adds to benzal-
dehyde, thus providing the alcohol 5 in 77% yield (Scheme 1).
Remarkably, we found that a range of functionalized
aromatic substrates are readily manganated under convenient
reaction conditions (0–258C). Thus, methyl 4-bromobenzoate
(6a) reacts with 3 (0.6 equiv) within 3.5 h at 258C, furnishing
the diaryl manganese reagent 7a without cleavage of the
sensitive methyl ester function. Copper(I)-catalyzed acylation
using CuCN·2LiCl[12] (20 mol%) and 2-thienoyl chloride
(1.2 equiv) provides the ketone 8a in 77% yield. The highly
functionalized benzophenone derivative 6b is converted to
the corresponding manganese species 7b by the reaction with
3 (0.6 equiv, 258C, 2 h). CuI-catalyzed allylation with 3-
bromocyclohexene (1.2 equiv) provides the polyfunctional
benzophenone 8b in 74% yield (Scheme 2).
Subsequent palladium-catalyzed arylations are also read-
ily accomplished. The reaction of methyl 3-chlorobenzoate
(6c) with 3 (0.6 equiv, 258C, 2 h) provides a diaryl manganese
intermediate that undergoes a Pd-catalyzed cross-coupling[13]
([Pd(PPh3)4] (2.5 mol%), 258C, 12 h) with 1-iodo-3-trifluoro-
methylbenzene (1.1 equiv) to give the ortho,ortho’-disubsti-
tuted biphenyl 8c in 77% yield (Table 1, entry 1). Similarly,
the manganation of methyl 4-chlorobenzoate (6d) and cross-
coupling with 3-iodotoluene furnishes the biphenyl 8d in 80%
yield (Table 1, entry 2).
À
À
reactivity, allowing the efficient formation of C C and C N
bonds. Furthermore, the convenient metalation conditions
make it a very practical base for synthetic applications. Thus,
the addition of commercially available tmmpMgCl·LiCl (2;
2.0 equiv) to MnCl2·2LiCl[11] (1 equiv) at 08C with subsequent
stirring at 258C for 3 h provides the manganese amide 3 as a
0.5m solution in THF (Scheme 1). The base 3 has an excellent
thermal stability and can be stored at 258C for more than
eight weeks without appreciable decomposition. Preliminary
experiments show immediately that the new Mn base has a
very different reactivity than the Mg base 2. Thus, whereas the
reaction of 2 with 2-phenyl-1,3,4-oxadiazole (4) provides only
ring fragmentation products (PhCN and NCOMgCl), its
[*] S. H. Wunderlich, M. Kienle, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen
Department Chemie & Biochemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-776-80
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank Evonik AG
(Hanau), BASF AG (Ludwigshafen), W. C. Heraeus GmbH (Hanau),
and Chemetall GmbH (Frankfurt) for the generous gift of chemicals.
tmp=2,2,6,6-tetramethylpiperidyl.
The diaryl manganese intermediates also react well with
aldehydes.[14] Thus, the manganation of methyl 3-bromoben-
zoate 6e with 3 (0.6 equiv, 258C, 2 h) provides a manganese
reagent that adds to 4-methoxybenzaldehyde (1.2 equiv),
leading to the lactone 8e in 81% yield (Table 1, entry 3).[15]
A
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903505.
range of substituted benzene derivatives bearing an ester or
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Table 1: Manganation of aromatic substrates (6c–j) and heterocyclic rings (9a–d) with 3 and reactions with electrophiles.
No.
Substrate[a]
Electrophile
Product[b]
No.
Substrate[a]
Electrophile
Product[b]
1
6c (25, 2)
8c (77)
7
6i (0, 0.5)
8i (83)
8j (77)
À
NC CO2Et
2
6d (25, 3)
8d (80)
8
6j (25, 10)
3
4
6e (25, 2)
8e (81)
8 f (88)
9
9a (0, 0.5)
10a (77)
10b (71)
PhCOCl
6 f (0, 0.75)
10
9b (0, 0.75)
5
6g (25, 30)
8g (73)
11
9c (0, 0.5)
10c (88)
6
6h (0, 3.5)
8h (78)
12
9d (0, 0.5)
10d (84)
[a] The reaction conditions for the metalation with 3 are given in parentheses (T [8C], t [h]). [b] Yield [%] of isolated analytically pure product is given in
parentheses.
nitrile (6 f–i) are converted with the base 3 to the correspond-
ing diaryl manganese compounds and undergo smooth Cu-
catalyzed allylations with various allylic bromides in 73–88%
yield (Table 1, entries 4–7). 4-Trifluoromethoxy-substituted
bromobenzene (6j) was also manganated with 3 (0.6 equiv;
258C, 10 h) at the ortho-position to the CF3O group. A
À
subsequent acylation with NC CO2Et provides the disubsti-
tuted ethyl benzoate 8j in 77% yield (Table 1, entry 8).
A range of functionalized heterocycles have been man-
ganated as well. Thus, the nicotinic ester 9a undergoes a
complete manganation with 3 (0.6 equiv; 08C, 0.5 h), provid-
ing the expected manganese reagent, which undergoes a Pd0-
catalyzed cross-coupling ([Pd(PPh3)4] (2.5 mol%); 08C, 5 h)
with p-TIPSOC6H4I (1.1 equiv; TIPS = triisopropylsilyl),
leading to the polyfunctional pyridine 10a in 77% yield
(Table 1, entry 9). Similarly, the cyano-substituted pyridine
9b and pyrazine 9c undergo a complete metalation with 3
(0.6 equiv) at 08C (30–45 min). After CuI-catalyzed acylation,
the ketones 10b and 10c are obtained in 71 and 88% yield,
respectively (Table 1, entries 10 and 11). The electron-rich
heterocycle N-benzylbenzimidazole 9d smoothly reacts with
3 (08C, 30 min). Addition to 4-iPrC6H4CHO furnishes the
expected alcohol 10d in 84% yield (Table 1, entry 12).
The functionalization of the benzothiadiazole scaffold is
especially important because of potential applications in the
Scheme 2. Manganation of functionalized arenes with 3 and subse-
quent acylation or allylation.
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preparation of new materials.[16] A novel functionalization of
3,6-dibromobenzothiadiazole (9e) in the 4-position is readily
achieved by treating 9e with 3 (0.6 equiv; 08C, 2.5 h). The
resulting diheteroaryl manganese reagent is quenched with
pivaldehyde to give the alcohol 10e in 78% yield. Alter-
natively, a Pd-catalyzed benzoylation gives the ketone 10 f in
77% yield (Scheme 3).[17]
Scheme 3. Manganation of 3,6-dibromobenzothiadiazole (9e) with 3
and reactions with electrophiles.
Scheme 4. Oxidative aminations of a manganated arene or heterocycle
leading to polyfunctional amines 12a,b. TMS=trimethylsilyl. TBAF=
tetrabutylammonium fluoride.
Recently, we reported an oxidative amination of organo-
magnesium reagents[18] using chloranil and copper amides.[19]
We have found that aryl copper reagents prepared from diaryl
manganese reagents obtained by directed manganation with 3
give superior yields in this amination procedure compared
with those prepared from aryl magnesium reagents obtained
by metalation with 2. Thus, the reaction of 3-bromo-4-
fluorobenzonitrile (6k) with 3 (0.55 equiv, 08C, 30 min) and
subsequent reaction with CuCl·2LiCl (1.1 equiv, À508C,
30 min) and addition of LiN(SiMe3)2 (2.0 equiv, À508C, 1 h)
provides the lithium amidocuprate 11a, which by reaction
with chloranil (1.1 equiv, À788C, 1 h) furnishes the trimethyl-
silyl-protected aniline 12a in 86% yield (Scheme 4). Perfor-
mance of the same sequence with the corresponding aryl
magnesium reagents provides a 10% lower yield of the
aniline 12a.[20] A similar amination was performed starting
with the functionalized pyridine 9b. The same sequence leads
to the lithium amidocuprate 11b, which undergoes an
oxidative amination mediated by chloranil and, after depro-
tection with TBAF (2.0 equiv, 258C, 10 min), furnishes the
deprotected 4-aminopyridine 12b in 75% yield (Scheme 4).
This reaction sequence proved to be general, and various
aminated arenes and pyridines have been prepared (Table 2).
Thus, the treatment of the benzonitrile 6k with several
lithium amides affords after oxidative amination the aryl
amines 12c–f in 66–73% yields (Table 2, entries 1–4). The
related functional benzonitrile 6l and the nicotinate 9a are
oxidatively aminated, leading to the aniline 12g (75%,
Table 2, entry 5) and to the amines 12h and 12i in 65 and
81% yield (Table 2, entries 6–7).
cycles. This metalation procedure tolerates several functional
groups (methyl ester, ketone, nitrile) and proceeds at
convenient temperatures (0–258C), in contrast to
tmpMgCl·LiCl (2), which requires lower metalation temper-
atures. The resulting new functionalized diaryl manganese
intermediates react with various electrophiles using Pd or Cu
catalysis. Finally, these diaryl manganese reagents proved to
be especially well-suited for oxidative aminations, thus
allowing the preparation of polyfunctional amines. Exten-
sions of these manganations to more complex unsaturated
substrates are currently underway in our laboratories.
Experimental Section
5: An argon-flushed 25 mL Schlenk tube equipped with a magnetic
stirring bar and septum was charged with a solution of 4 (290 mg,
2 mmol) in dry THF (1 mL) and cooled to 08C. A solution of 3 (0.5m
in THF, 2.4 mL, 2.4 mmol) was added dropwise, and the reaction
mixture was stirred at 08C for 30 min. Then, PhCHO (254 mg.
2.4 mmol) was added at 08C and the mixture was stirred for another
1 h at 08C. After standard workup (addition of sat. NH4Cl solution
followed by extraction with diethyl ether), the solvent was evaporated
in vacuo. The crude product was purified by column chromatography
(pentane/diethyl ether 1:1) to give 5 (390 mg, 77%) as a colorless
solid.
Received: June 29, 2009
Published online: August 28, 2009
In summary, we have reported a convenient directed
manganation of various polyfunctional arenes and hetero-
Keywords: amide bases · cross-coupling · directed metalation ·
manganese · oxidative amination
.
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Y. Kobayashi, T. Furuyama, S. Nakamura, Z. Kajihara, T.
Table 2: Polyfunctional amines of type 12 obtained by the oxidative
amination of diaryl manganese reagents with lithium amides mediated
by chloranil.
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Lithium amide
Product[b]
LiNPh2
1
6k (0, 0.5)
12c (66, 59[c])
2
3
6k (0, 0.5)
6k (0, 0.5)
12d (73, 62[c])
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12e (66)
4
5
6k
(0, 0.5)
12 f (66[d])
LiN(SiMe3)2
6l (25, 2)
12g (75[e])
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9a (0, 0.5)
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