Aluminum bases for the highly chemoselective preparation of aryl and heteroaryl aluminum compounds

Article abstract of DOI:10.1002/anie.200804966

Selective C H activation with a series of neutral aluminum trisamide bases led to a wide range of polyfunctional aryl and heteroaryl aluminum reagents. Ester and cyano groups are stable under the reaction conditions for this direct alumination, and donor

Full text of DOI:10.1002/anie.200804966

Angewandte
Chemie
DOI: 10.1002/anie.200804966
Directed Alumination
Aluminum Bases for the Highly Chemoselective Preparation of Aryl
and Heteroaryl Aluminum Compounds**
Stefan H. Wunderlich and Paul Knochel*
Organoaluminum reagents have found numerous ap-
plications in synthetic organic chemistry,[1] for example,
in carbo- and hydroalumination reactions. The Lewis
acidic character of the aluminum metal center enables
reactions with unique chemo-, regio-, and enantiose-
lectivity to be carried out.[2,3] In general, aryl aluminum
species are generated by transmetalation of aryl lithium
reagents with various aluminum(III) sources[4] or in
some cases through aluminum–tin or aluminum–boron
exchange reactions.[5] The deprotonation of aromatic
rings with an aluminum base is a very convenient
Scheme 1. Preparation of the aluminum trisamide bases 1 and 4.
method for the preparation of unsaturated organo-
aluminum compounds. Recently, Uchiyama, Wheatley,
and co-workers reported directed alumination reactions
with the powerful aluminate base iBu3Al(TMP)Li (TMP =
2,2,6,6-tetramethylpiperidyl).[6] Owing to the ate character of
this base, several aromatic and heteroaromatic compounds
were metalated readily. Herein, we report new neutral
aluminum trisamide bases inspired by recent structural
investigations[7] that undergo highly regioselective metalation
reactions.
Thus, the treatment of LiTMP with a solution of AlCl3 in
THF (0.33 equiv)[8] at À788C leads to a solution of Al-
(TMP)3·3LiCl (1; Scheme 1). An additional sterically hin-
dered aluminum base was prepared by treating the imine 2[9]
with tBuLi (1.0 equiv) in THF[10] at À788C to give the lithium
amide 3, followed by transmetalation with AlCl3 (0.33 equiv)
in THF. The corresponding aluminum trisamide base 4 was
obtained in quantitative yield (Scheme 1).[11] These bases
display excellent reactivity and good solubility (0.3m in
THF).[12]
with ZnCl2 to give the corresponding zinc reagents, and after
copper-mediated acylation[14] or a palladium-catalyzed cross-
coupling reaction[15] with [Pd(dba)2] (5 mol%) and P(o-furyl)3
(10 mol%), the products 6a–c were obtained in 70–79% yield
(Table 1, entries 1–3).
Similarly, complete alumination was observed with the
aluminum trisamide 4 (1.0 equiv) within 3–5 h at À5 to
À108C, and the biaryl compounds 6a–c were isolated in 71–
77% yield (Table 1, entries 1–3). These results indicate that
both bases, 1 and 4, show similar metalation rates. However,
the practical and economical synthesis of 4 led us to use this
base for further experiments. The metalation of difluoroben-
zenes 5d–f is especially challenging and requires a low
reaction temperature.[16] However, with the aluminum base 4,
a smooth regioselective alumination proceeded at À408C
within 1.5–3 h. After transmetalation to the corresponding
zinc derivatives and Negishi cross-coupling, the functional-
ized biphenyls 6d–f were obtained in 79–89% yield (Table 1,
entries 4–6). Moreover, the metalation of the corresponding
dichlorobenzenes 5g–i proceeded within 3–4.5 h under sim-
ilar conditions at À608C to give the functionalized aromatic
compounds 6g–i in 78–85% yield after transmetalation and
cross-coupling (Table 1, entries 7–9).
Electron-rich aromatic compounds are generally difficult
to metalate. Thus, aromatic ethers are poor ortho-directing
groups for lithiation reactions.[17] Monometallic magnesium
and zinc amides are unable to metalate such substrates at
all.[18] However, aluminum amides are powerful reagents for
the metalation of aromatic ethers, probably as a result of a
strong coordination of the ether oxygen atom to the
aluminum center. Thus, the metalation of anisole (5j) with 4
was complete within 9 h at 258C,[19] and a copper-mediated
acylation gave the substituted benzophenone 6j in 79% yield
(Table 1, entry 10). A substantially lower metalation rate was
observed with 1 (11 h at 258C; Table 1, entry 10). Interest-
ingly, the substituted anisoles 5k and 5l, as well as the
naphthalene derivative 5m, were also metalated regioselec-
First, we investigated the alumination of various function-
alized aromatic compounds, such as benzonitrile (5a), tert-
butyl benzoate (5b), and tert-butyl 1-naphthoate (5c). These
substrates all underwent complete metalation with Al-
(TMP)3·3LiCl (1, 1.0 equiv)[13] within 3–6 h at À5 to À108C.
The resulting aryl aluminum compounds were transmetalated
[*] S. H. Wunderlich, Prof. Dr. P. Knochel
Department Chemie and Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council for an advanced investigator grant, and the
Deutsche Forschungsgemeinschaft (DFG) for financial support. We
also thank Evonik AG (Hanau), BASF AG (Ludwigshafen), and
Chemetall GmbH (Frankfurt) for the generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804966.
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Table 1: Products of type 6 obtained by the alumination of aromatic and heteroaromatic compounds
with 4, transmetalation with ZnCl2, and subsequent transformation with electrophiles (E+).
tively at the ortho position to the
methoxy group. Copper-mediated
trapping reactions or a palladium-
catalyzed cross-coupling reaction
then furnished the products 6k–m
Entry Substrate
T [8C], t [h][a] E+
Product/Yield [%][b]
in
73–78%
yield
(Table 1,
entries 11–13). Additionally, phene-
tole (5n) was aluminated within
10 h at 258C, whereas the metal-
ation of trifluoromethoxybenzene
(5o) proceeded within 3 h at 08C.
The subsequent reactions with
chlorobenzoyl chlorides in the pres-
ence of CuCN·2LiCl (1.1 equiv) led
to the benzophenones 6n and 6o in
85 and 81% yield, respectively
(Table 1, entries 14 and 15). Fur-
thermore, 2-methoxypyridine (5p)
1
5a
À10, 4 (4)
6a: 71 (70)[c]
2
3
5b
5c
À5, 3 (3)
À5, 5 (6)
6b: 77 (79)[d]
6c: 76 (78)[c]
and
6-chloro-2-methoxypyridine
4
5
6
5d: p
5e: m
5 f: o
À40, 2
À40, 1.5
À40, 3
p-IC6H4CO2Et 6d: p; Ar=p-CO2EtC6H4: 79[d]
m-IC6H4NO2
o-IC6H4Cl
(5q) were aluminated within 3 h at
25 and 08C, respectively. After
CuCN·2LiCl-mediated
6e: m; Ar=m-NO2C6H4: 88[d]
6 f: o; Ar=o-ClC6H4: 89[d]
acylation
reactions, the ketones 6p and 6q
were obtained in 85 and 90% yield
(Table 1, entries 16 and 7). Interest-
ingly, the use of aromatic or hetero-
aromatic ethers as substrates ena-
bles the alumination reactions to be
carried out at very convenient tem-
peratures (0 or 258C), possibly as a
consequence of the complexation of
the aluminum center with the ether
oxygen atom.
7
8
9
5g: p
5h: m
5i: o
À60, 3
p-IC6H4Me
o-IC6H4OMe
m-IC6H4Me
6g: p; Ar=p-MeC6H4: 85[d]
6h: m; Ar=o-OMeC6H4: 78[d]
6i: o; Ar=m-MeC6H4: 81[d]
À60, 4.5
À60, 4.5
10
11
5j: X=H
5k: X=Cl
25, 9 (11) p-ClC6H4COCl 6j: X=H; R=COC6H4-p-Cl: 79 (74)[c]
25, 4
p-IC6H4CN
6k: X=Cl; R=p-CNC6H4: 78[d]
6l: X=I; R=(2-EtO2C)allyl: 73[e]
12
5l: X=I
25, 8
The highly regioselective alumi-
nation can be used to create unusual
substitution patterns on heteroaro-
matic compounds. Thus, 2-(triiso-
propylsilyl)benzothiazole (7a) and
2-(triethylsilyl)benzothiazole (7b)
may be metalated either at the
ortho position to the nitrogen
atom (position a) or at the ortho
position to the sulfur atom (posi-
tion b; Scheme 2). Interestingly,
both substrates were aluminated
exclusively at position a with the
base 4 (1.0 equiv; 258C, 12 h). After
transmetalation to form a zinc com-
pound, followed by a copper-medi-
ated acylation or palladium-cata-
lyzed cross-coupling reaction, the
functionalized benzothiazoles 8a
and 8b were isolated in 83 and
81% yield, respectively. Similar
regioselectivity is observed when
metalation both a to an oxygen
atom and a to a sulfur atom is
possible. Thus, phenoxathiine (9)
underwent a smooth regioselective
13
5m
25, 8
6m: 77[c]
14
15
5n
5o
25, 10
0, 3
6n: 85[c]
6o: 81[c]
16
17
5p
5q
25, 3 (3.5)
6p: 85 (81)[c]
0, 3
6q: 90[c]
[a] The metalation times with TMP3Al·3LiCl (1) are given in parentheses. [b] Yield of the analytically pure
isolated product. Yields in brackets are for the use of 1 in place of 4. [c] The organozinc intermediate was
transmetalated with CuCN·2LiCl (1.1 equiv). [d] The product was obtained by palladium-catalyzed
cross-coupling with [Pd(dba)2] (5 mol%) and P(o-furyl)3 (10 mol%). In products 6d–6f and 6g–6i, the
aryl substituent is located between the two halogen atoms. [e] CuCN·2LiCl (0.25 equiv) was used.
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In conclusion, we have reported a new
directed alumination that enables the regiose-
lective functionalization of various aromatic and
heteroaromatic compounds. A number of func-
tional groups are tolerated, including ester and
cyano groups, as well as halogen atoms. Owing to
the strong Lewis acidic character of aluminum,
remarkable regioselectivity was observed with
oxygen-substituted aromatic substrates. These
substrates are difficult to metalate with other
amide bases. The high regioselectivity enables
the preparation of compounds with uncommon
substitution patterns. We are currently investi-
gating the scope of application of these new
aluminum bases.
Experimental Section
Scheme 2. Regioselective alumination of the benzothiazoles 7a and 7b and phenoxa-
thiine (9) with the aluminum base 4 and subsequent transmetalation with ZnCl2,
followed by copper-mediated acylation or palladium-catalyzed cross-coupling. dba=
dibenzylideneacetone, TES=triethylsilyl, TIPS=triisopropylsilyl.
Preparation of (C12H26N)3Al·3LiCl (4): tert-Butyliso-
butylideneamine[10] (2; 7.63 g, 60.0 mmol) was dis-
solved in THF (60 mL) in an argon-flushed Schlenk
flask. This solution was cooled to À788C, tBuLi (1.5m
in pentane, 40 mL, 60.0 mmol) was added dropwise,
and the resulting mixture was stirred at this temper-
ature for 4 h. A freshly prepared solution of AlCl3 (20 mmol, 2.67 g)
in THF was then added, and the mixture was stirred at À608C for
15 h. The solvents were then reduced in vacuo. The fresh solution of 4
was titrated prior to use at 08C with menthol[21] or 2-propanol, and
with 4-(phenylazo)diphenylamine[18] as an indicator. A concentration
of 0.3m in THF was found.
alumination within 12 h at 258C at the ortho position to the
oxygen atom. Subsequent transmetalation and a copper-
mediated acylation with p-chlorobenzoyl chloride (1.0 equiv)
provided the ketone 10 in 77% yield (Scheme 2).
Few examples of the metalation of substrates containing
partly saturated rings have been described.[20] However, the
metalation of 2,3-dihydrobenzofuran (11) with 4 proceeded
smoothly within 12 h at 258C, and a palladium-catalyzed
cross-coupling reaction furnished the compound 12 in 85%
yield (Scheme 3). Furthermore, the treatment of benzo-
Synthesis of 12: (C12H26N)3Al·3LiCl (4; 0.3m solution in THF,
7 mL, 2 mmol) was added dropwise to a solution of 2,3-dihydroben-
zofuran (11; 240 mg, 2.0 mmol) in dry THF (2 mL) under argon in a
50 mL Schlenk tube equipped with a magnetic stirring bar, and the
resulting mixture was stirred at 258C for 12 h. After transmetalation
with ZnCl2, a palladium-catalyzed cross-coupling reaction with 4-
iodoanisole was carried out at 258C for 2 h. After aqueous workup
and purification by column chromatography, 12 (385 mg, 85%) was
obtained as a colorless solid.
[1,3]dioxole (13a) or benzo[1,4]dioxane (13b) with
4
(1.0 equiv) led to an aluminated intermediate within 12 h at
258C. A subsequent transmetalation with ZnCl2 and palla-
dium-catalyzed cross-coupling or copper-mediated acylation
provided the products 14a and 14b in 75 and 78% yield,
respectively (Scheme 3).
Received: October 10, 2008
Published online: January 13, 2009
Keywords: aluminum · copper · cross-coupling ·
.
homogeneous catalysis · lithium
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