Preparation of functionalized organoaluminiums by direct insertion of aluminium to unsaturated halides

Article abstract of DOI:10.1038/nchem.590

The preparation of polyfunctional organometallics is important in organic synthesis as these reagents are very popular nucleophiles. The preparation of functionalized aluminium reagents by direct insertion of aluminium powder is in general not possible. Such a reaction would be of special importance owing to the low price of aluminium compared with magnesium (it is half the price), the low toxicity of this metal and the chemoselectivity of the resultant organoaluminium reagents. We have now found that by adding catalytic amounts of selected metallic chlorides (TiCl₄, BiCl₃, InCl ₃ or PbCl₂) in the presence of LiCl, aluminium powder inserts into various unsaturated iodides and bromides under mild conditions. These resulting new organoaluminium reagents undergo smooth Pd-catalysed cross-coupling and acylation reactions, as well as copper-catalysed allylic substitutions, affording various interesting products for pharmaceutical and material science applications.

Full text of DOI:10.1038/nchem.590

ARTICLES
PUBLISHED ONLINE: 24 MARCH 2010 | DOI: 10.1038/NCHEM.590
Preparation of functionalized organoaluminiums
by direct insertion of aluminium to
unsaturated halides
¨
Tobias Blumke, Yi-Hung Chen, Zhihua Peng and Paul Knochel
*
The preparation of polyfunctional organometallics is important in organic synthesis as these reagents are very popular
nucleophiles. The preparation of functionalized aluminium reagents by direct insertion of aluminium powder is in general not
possible. Such a reaction would be of special importance owing to the low price of aluminium compared with magnesium (it
is half the price), the low toxicity of this metal and the chemoselectivity of the resultant organoaluminium reagents. We
have now found that by adding catalytic amounts of selected metallic chlorides (TiCl4, BiCl3, InCl3 or PbCl2) in the presence
of LiCl, aluminium powder inserts into various unsaturated iodides and bromides under mild conditions. These resulting new
organoaluminium reagents undergo smooth Pd-catalysed cross-coupling and acylation reactions, as well as copper-catalysed
allylic substitutions, affording various interesting products for pharmaceutical and material science applications.
rganometallic compounds, which are molecules containing a
Preliminary results showed that aluminium powder did not insert
carbon–metal bond, are widely adopted for carbon–carbon into various organic halides in the presence of LiCl or other lithium
bond-forming reactions. The insertion of metals to unsatu- salts. We envisaged that additional metallic salts could be beneficial
O
rated halides is the most straightforward method to prepare aromatic as the preparation of allylic aluminium reagents is accelerated by the
and heteroaromatic organometallics1. For example, the preparation of addition of InCl3 (refs 33–36). We therefore screened the influence
organomagnesium reagents (Grignard reagents) is conducted by of several additives on the insertion rate of aluminium powder
adding an organic halide to a suspension of magnesium turnings in (3 equivalents) in the presence of LiCl (3 equivalents) to a typical
a polar nonprotic solvent such as THF or diethyl ether2. However,
many unsaturated organometallic reagents (for example, from zinc,
indium, manganese or aluminium) are difficult to generate from
commercial metal powders. The surface layers of the metals mostly
consist of hydroxides and oxides (that is, they are passivated), thus
making the metal unreactive towards the organic halide. In particular,
the highly oxophilic aluminium is passivated very easily3. Metal acti-
vation is therefore essential for the success of such direct insertions,
and several procedures including the use of Rieke-metals4–6 have
been developed7–9. However, preparation methods of arylaluminium
reagents are scarce10. A recent directed alumination11–14 using an alu-
minium base allows the generation of arylaluminium compounds by
a deprotonation reaction. The transmetallation15–18 of organolithium
and organomagnesium reagents using aluminium salts also provides
a convenient route to arylaluminium derivatives.
Although the reaction of metallic aluminium with organic
halides has been known since the pioneering work of Hallwachs19
and Schaferik in 1859 only very few examples of aromatic halides
undergo this reaction20,21. In recent years, we have shown that
several metals such as zinc22–24, indium25,26 and magnesium27,28
can be activated in the presence of stoichiometric amounts of
LiCl, which solubilizes and removes the resulting organometallic
species from the metal surface, therefore allowing a further insertion
to occur on the clean metal surface. Extensions of such an inexpen-
sive activation to aluminium powder would be highly desirable
owing to the low toxicity, very low price and potential high chemos-
electivity of the organoaluminium reagents29–32. Herein, we report a
new preparation of various unsaturated organoaluminium reagents
by a direct metal insertion in the presence of LiCl and catalytic
amounts of selected metallic salts.
Table 1 | Catalyst screening for the preparation of
arylaluminium reagent from aryl iodide*.
Al (3 equiv.)
F3C
F3C
LiCl (3 equiv.)
TMSCl (3 mol%)
Catalyst (5 mol%)
THF, 25°C
I
Al2/3
X=I or Cl†
X
1
2
Entry
Catalyst
Insertion
time (h)
Yield
(%)‡
1
2
3
4
5
6
7
8
ZnCl2
FeCl3
MnCl2
ZrCl4
Cp2ZrCl2
HfCl4
PbCl2
VCl4
8
8
8
8
8
8
4
4
Traces§
Traces§
Traces§
Traces§
Traces§
Traces§
77k,}
47
0#
87
85
85
9
NiCl2
InCl3
SnCl2
BiCl3
5
2.5
8
4.5
0.5
10
11
12
13
TiCl4
62**
*The reactions were carried out with 1-iodo-4-(trifluoromethyl)benzene (2 mmol) and THF (4 ml).
†
The arylaluminum reagents prepared by oxidative addition of metallic aluminum exist in a complex
equilibrium. The sesquihalide structure (Ar3Al2X3 ¼ ArAl2/3X, 2)3 is one possibility among others;
there may also be structures such as Li[ArAlX3] present in solution. ‡Yield was determined by
iodolysis in THF. §Below 3%. kWithout activation with TMSCl the yield dropped to 60%. }In the
absence of LiCl no insertion was observed. #Homodimer was formed quantitatively. **More than
20% of homodimer was found.
Department Chemie und Biochemie, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstrasse 5-13, Haus F. 81377 Mu¨nchen, Germany.
e-mail: paul.knochel@cup.uni-muenchen.de
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.590
ARTICLES
Table 2 | TiCl4-catalysed insertion of aluminium to aryl bromides and subsequent cross coupling reaction.
Al (3 equiv.)
LiCl (1.5 equiv.)
TiCl4 (3 mol%)
i-Pr
i-Pr
(i) Zn(OAc)2 (1.5 equiv.)
N
N
(ii) 5: R-X' (0.7 equiv.)
FG
FG
FG
PEPPSI-iPr (1.4 mol%)
Al2/3X
THF, 30-50°C
i-Pr
i-Pr
Br
R
X' = leaving group
Cl Pd Cl
N
3
4
6
X = Br or Cl
Cl
PEPPSI-iPr
Entry
Substrate
Conditions
Electrophile
Product (Yield, %)*
(Temperature,
time)
Br
1
30 8C
3.5 h
Br
CO Me
2
F
F
CO Me
2
5a
5b
3a
6a (93)
Br
2
3
50 8C
20 h
Br
NO
2
OMe
OMe
NO
2
3b
6b (80)
Cl
CN
Cl
CN
50 8C
6 h
S
Br
O
OMe O
6c (70)
OMe
3c
Cl
5c
Cl
CF
Cl
3
4
50 8C
Br
CF
†
3
5 h
Br
OMe
5d
OMe
3d
6d (79)
Br
5
6
7
50 8C
16 h
Br
OBoc
SMe
SMe
6e (68)
OBoc
5e
3e
†
I
50 8C
4 h
F C
3
Br
F C
3
3f
COMe
O
5f
6f (82)
Cl
I
CO Et
2
Cl
50 8C
CO Et
2
14 h
Br
5g
3g
†
6g (91)
*Isolated yield of analytically pure product (.95% pure). †0.6 equivalents of electrophile used.
substrate like 1-iodo-4-(trifluoromethyl)benzene (1) in THF. A BiCl3 were quite effective and provided 2 in 85–87% yield. In addition,
number of metallic salts such as ZnCl2, FeCl3, MnCl2, ZrCl4, inexpensive TiCl4 (5 mol%) led to the aluminium reagent 2 in 62%
Cp2ZrCl2 and HfCl4 have proved ineffective, affording less than 3% yield within 30 min (Table 1, entry 13). In this case, dimerization of
of the desired arylaluminium reagent (2) (Table 1, entries 1–6); 1, which led to 4,40-ditrifluoromethylbiphenyl, was responsible for
however, some metal chlorides dramatically accelerated the alu- the lower yield.
minium insertion (Table 1, entries 7–13). The addition of PbCl2
These preliminary experiments have demonstrated that several
(5 mol%)37 along with LiCl led to the desired aluminium reagent additives (PbCl2, VCl4, InCl3, SnCl2, BiCl3, TiCl4) allow the direct
2 in 60% yield after 3 h at 30 8C, whereas no product was obtained insertion of aluminium powder in the presence of Me3SiCl
in the absence of LiCl. Additional activation of the aluminium suspen- (3 mol%) and LiCl (3 equivalents). Further experimentation has
sion in THF with Me3SiCl (3 mol%)38–40 yielded 2 in 77% (Table 1, shown that the choice of the appropriate additive depends on the
entry 7). The addition of VCl4 (5 mol%) afforded the desired alu- structure and the nature of the organic halide. Thus, for the prep-
minium reagent 2 at 30 8C in 4 h in 47% yield, but the addition of aration of arylaluminium reagents starting from aryl bromides, the
NiCl2 provided only a homodimer (Table 1, entries 8–9). addition of TiCl4 (3 mol%) was found to be optimum. The treatment
Interestingly other chlorides such as InCl3 (refs 41–43), SnCl2 and of 1-bromo-2-fluorobenzene (3a) with Al powder (3 equivalents),
314
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.590
ARTICLES
Table 3 | InCl3- and BiCl3-catalysed insertion of aluminium to unsaturated iodides and subsequent reaction with electrophiles.
Al (3 equiv.)
LiCl (1.5 equiv.)
MCl3 (3 mol%)
(i) Zn(OAc)2 (1.5 equiv.)
(ii) 9: R-X' (0.7 equiv.)
FG
Substrate
Me
FG
FG
PEPPSI (1.4 mol%)
or CuCN·2LiCl (7 mol%)
X' = leaving group
I
Al2/3
X
THF, 30–50 °C
M = In or Bi
R
7
8
10
X = I or Cl
Entry
Conditions
(Catalyst,
temperature,
time)
Electrophile
Product (Yield, %)*
Br
Me
1
InCl3
50 8C
24 h
Br
S
Me
I
O
Me
Cl
O
7a
7b
9a
10a (89)
CO Et
2
CO2Et
2
3
InCl3
50 8C
3 h
Br
Cl
I
Cl
9b
10b (91)
Me
Me
InCl3
50 8C
24 h
Br
S
O
I
9c
S
7c
COMe
10c (75)
CN
Br
Br
4
InCl3
50 8C
24 h
I
CN
9d
7d
7e
10d (54)
CO Et
2
5
6
7
BiCl3
50 8C
3 h
CO Et
2
F
I
F
N
9e
N
10e (82)
Br
CN
BiCl3
50 8C
12 h
CN
F CO
3
I
F CO
3
N
N
7f
9f
10f (75)
F C
3
CO Et
F C
2
3
CO Et
2
BiCl3
30 8C
4.5 h
I
OMe
OMe
I
N
N
N
N
1
OMe
OMe
9g
10g (73)
*Isolated yield of analytically pure product (.95% pure).
LiCl (1.5 equivalents) and TiCl4 (3 mol%) at 30 8C for 3.5 h furnished converted to the corresponding organoaluminium reagent (4c),
the corresponding aluminium reagent (4a), which underwent a which after transmetallation with Zn(OAc)2 (1.5 equivalents) readily
smooth Pd-catalysed cross-coupling in the presence of Zn(OAc)2 underwent a Liebeskind-Srogl46,47 cross-coupling with the thioester
(1.5 equivalents) and PEPPSI-iPr (¼[1,3-bis(2,6-diisopropylphenyl)imi- 5c to afford the functionalized benzophenone derivative 6c in 70%
dazol-
2-ylidene](3-chloropyridyl)palladium(II)
dichloride; yield (Table 2, entry 3). Variously substituted aryl bromides such as
1.4 mol%)44,45 with methyl 4-bromobenzoate (5a, 0.7 equivalents) 3d–g, bearing substituents such as a chloride, trifluoromethyl or thio-
leading to the biphenyl ester 6a in 93% yield (Table 2, entry 1). methyl group, were readily converted to the intermediate aluminium
Remarkably, the intermediate 2-fluoroarylaluminium reagent (4a) reagents at 50 8C within 4–16 h. Subsequent transmetallation and
did not undergo elimination to an aryne under the preparation and highly chemoselective Pd-catalysed cross-coupling with various aryl
cross-coupling conditions.
bromides or iodides bearing a carbonate, an acetyl or an ester furn-
It is not onlyelectron-poorarylaluminium reagentsthat can be pre- ished the expected polyfunctional biphenyl adducts in 68–91% yield
pared; electron-rich aryl bromides also reacted smoothly. Aluminium (Table 2, entries 4–7).
inserted into 1-bromo-2-methoxybenzene (3b) at 50 8C within 20 h to
In the case of aryl iodides as substrates, InCl3 and BiCl3 were
give the aluminium reagent 4b, which was converted to the biphenyl used as additives (3 mol%) and led to the best conversions and
derivative 6b in 80% yield by a cross-coupling as described above yields. Thus, the reaction of 1-iodo-3,5-dimethylbenzene (7a)
(Table 2, entry 2). Similarly, the 4-chloro-2-bromoanisole (3c) was with Al powder (3 equivalents) in the presence of LiCl (1.5
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.590
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Table 4 | PbCl2-catalysed insertion of aluminium to aryl and heteroaryl halides bearing ester and amide functionalities and
subsequent reaction with electrophiles.
Al (3 equiv.)
LiCl (1.5 equiv.)
PbCl2 (3 mol%)
(i) Zn(OAc)2 (1.5 equiv.)
O
O
O
(ii) 13: R-X' (0.7 equiv.)
R1
PEPPSI (1.4 mol%)
or CuCN·2LiCl (7 mol%)
X' = leaving group
R1
Al2/3
X
R2
R1
THF, 50°C
X
11
12
14
R1 = OEt or NEt2
X = I or Br
Entry
Substrate
Conditions
Electrophile
Product (Yield %)*
(Temperature,
time)
Br
1
50 8C
6 h
EtO C
EtO C
2
Br
2
S
S
CHO
CHO
11a
14a (92)
13a
Br
2
3
50 8C
25 h
I
I
EtO C
2
EtO C
2
11b
11b
13b
14b (88)
I
50 8C
25 h
EtO C
EtO C
2
2
O
O
13c
14c (78)
Br
4
30 8C
4 h
I
13d
CO Et
2
CO Et
2
14d (80)
11c
Br
5
6
50 8C
24 h
EtO C
2
EtO C
2
Br
O
O
NC
11d
NC
13e
14e (83)
Me
Br
Me
50 8C
30 h
Et N
Et N
2
2
I
O
O
F
F
11e
13f
14f (91)
*Isolated yield of analytically pure product (.95% pure).
equivalents) and InCl3 (3 mol%) afforded the arylaluminium or BiCl3. However in the presence of PbCl2 (3 mol%) a smooth
halide 8a within a 24 h reaction time at 50 8C. After treatment insertion proceeds at 50 8C allowing for the first time the direct prep-
with Zn(OAc)2 (1.5 equivalents), a Pd-catalysed acylation with a aration of ester- or amide-functionalized aryl and heteroarylalumi-
bromo-substituted thioester (9a, 0.7 equivalents)48 provided the nium halides. Thus, the reaction of 5-bromo-thiophene-2-
benzophenone 10a in 89% yield with excellent chemoselectivity carboxylic acid ethyl ester (11a) with Al powder in the presence of
(Table 3, entry 1). A similar reaction of 3-chloro-1-iodobenzene LiCl (1.5 equivalents) and PbCl2 (3 mol%) after 6 h at 50 8C led
(7b) with Al powder (3 equivalents), LiCl (1.5 equivalents) and to the corresponding aluminium reagent (12a). A Pd-catalysed
InCl3 (3 mol%) led to the aluminium organometallic 8b within cross-coupling with 4-bromobenzaldehyde (13a, 0.7 equivalents)
3 h at 50 8C. After the successful transmetallation with produced the 2,5-disubstituted thiophene 14a in 92% yield after
Zn(OAc)2 (1.5 equivalents) a copper(I)-catalysed allylation with prior transmetallation with Zn(OAc)2 (1.5 equivalents) (Table 4,
ethyl (2-bromomethyl)acrylate (9b)49 in the presence of entry 1). Remarkably, the sensitive formyl functionality was perfectly
.
CuCN 2LiCl (ref. 50) at 0 8C furnished the acrylate 10b in 91% compatible with the cross-coupling conditions. Ethyl 3-iodobenzo-
yield after 30 min (Table 3, entry 2). Several functionalized unsa- ate (11b) was also converted to the corresponding aluminium
turated substrates (1,7c–f) including a cycloalkenyl iodide (7d) reagent 12b (50 8C, 25 h). After the preceding transmetallation
readily underwent an Al insertion with InCl3 or BiCl3 as a catalyst, with Zn(OAc)2 (1.5 equivalents), the copper-catalysed allylation
followed by transmetallation and Pd-catalysed cross-coupling, to with 3-bromocyclohexene (13b, 0.7 equivalents) with catalytic
.
generate the desired products 10c–g in 54–82% yield (Table 3, amounts of CuCN 2LiCl (7 mol%) at 0 8C over 30 min generated
entries 3–7). the allylated product 14b in 88% yield (Table 4, entry 2). In addition,
The aluminium insertion in the presence of an ester or an amide a Pd-catalysed cross-coupling with 1-(4-iodophenyl)-2-methylpro-
functional group did not lead to satisfactory yields with TiCl4, InCl3 pan-1-one (13c, 0.7 equivalents) afforded the biphenyl 14c in 78%
316
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.590
ARTICLES
10. Saito, S. in Comprehensive Organometallic Chemistry III (ed. Knochel, P.) Vol. 9
(Elsevier, 2007).
yield (Table 4, entry 3). Related iodo- and bromo-unsaturated sub-
strates bearing an ester (11c–d) or an amide (11e) were smoothly
converted to the corresponding aluminium reagents. After Cu-cata-
lysed allylation or Pd-catalysed cross-coupling in the presence of
Zn(OAc)2 the expected adducts 14d–f were obtained in 80–91%
yield (Table 4, entries 4–6).
The mechanism of aluminium powder activation by the additives
MXn (Table 1) is certainly complex. It seems that the combination of
catalytic amounts of MXn (whose role may be to activate the alu-
minium by forming new reactive M–Al entities) and stoichiometric
amounts of LiCl (whose role is to solubilize the resulting organome-
tallic) results in continuous activation of the aluminium.
Interestingly Pb and Bi did not insert into 1 under the standard
reaction conditions. Also, the addition of a stoichiometric amount
of PbCl2 or low-valent salts like TiCl2 or InCl to 1 did not lead to
the formation of an organometallic species.
In summary, we have shown that metallic chlorides such as
TiCl4, InCl3, BiCl3 and PbCl2 allow for the first time a convenient
generation of functionalized arylaluminium halides, which
undergo Pd-catalysed cross-coupling or Cu-catalysed allylations
after successful transmetallation with Zn salts. The conversion of
aryl bromides to the corresponding arylaluminium halides using
Al powder may be of industrial relevance owing to the low price
of aluminium and low toxicity of the aluminium hydroxides
obtained after aqueous workup. Further studies of the reaction
scope and mechanism are currently underway in our laboratories.
11. Uchiyama, M., Naka, H., Matsumoto, Y. & Ohwada, T. Regio- and chemoselective
direct generation of functionalized aromatic aluminum compounds using
aluminum ate base. J. Am. Chem. Soc. 126, 10526–10527 (2007).
12. Naka, H. et al. An aluminum ate base: Its design, structure, function, and
reaction mechanism. J. Am. Chem. Soc. 129, 1921–1930 (2007).
13. Naka, H. et al. Mixed alkylamido aluminate as a kinetically controlled base.
J. Am. Chem. Soc. 130, 16193–16200 (2008).
14. Wunderlich, S. & Knochel, P. Aluminum bases for the highly chemoselective
preparation of aryl and heteroaryl aluminum compounds. Angew. Chem. Int. Ed.
48, 1501–1504 (2009).
15. Ishikawa, T., Ogawa, A. & Hirao, T. A novel oxovanadium(V)-induced oxidation
of organoaluminum compounds. Highly selective coupling of organic
substituents on aluminum. J. Am. Chem. Soc. 120, 5124–5125 (1998).
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conjugate addition of aryl aluminum reagents to trisubstituted enones:
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8211–8214 (2008).
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1,4-addition of aryl groups to enones using arylalkylaluminum compounds.
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18. Gao, H. & Knochel, P. New preparation and reactions of arylaluminum reagents
using barbier conditions. Synlett 1321–1325 (2009).
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organischen Radicalen. Liebigs Ann. Chem. 109, 206–209 (1859).
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and organic halogen derivatives. J. Am. Chem. Soc. 93, 1827–1833 (1908).
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preparation. J. Org. Chem. 5, 106–121 (1940).
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Methods
General procedure for aluminium insertion and subsequent cross-coupling:
Preparation of 14a. LiCl (127 mg, 3 mmol, 1.5 equivalents) and PbCl2 (17 mg,
0.06 mmol, 3 mol%) were placed in an argon-flushed flask and dried for 10 min at
380 8C (heat gun) on high vacuum (1 mbar). Aluminium powder (162 mg, 6 mmol,
3.0 equivalents) was added under argon and the flask was evacuated and refilled with
argon three times. After the addition of THF (1.5 ml), aluminium powder was
activated by treatment with Me3SiCl (2 mol%). Ethyl 5-bromothiophene-2-
carboxylate (11a, 470 mg, 2 mmol, 1.0 equivalents), along with heptadecane
(0.12 ml) as an internal standard, was added in THF (1 ml) at 25 8C and the
resulting solution was stirred at 50 8C for 5.5 h. Gas chromatography analysis of
hydrolysed reaction aliquots showed full conversion. The organoaluminium solution
was separated from the remaining aluminium powder and canulated to an argon-
flushed flask containing anhydrous Zn(OAc)2 (556 mg, 3 mmol, 1.5 equivalents).
The resulting suspension was stirred for 20 min at 25 8C. 4-bromobenzaldehyde
(13a, 262 mg, 1.4 mmol, 0.7 equivalents) was added as a solution in THF (2 ml)
followed by the addition of PEPPSI-iPr (19 mg, 0.028 mmol, 1.4 mol%). The
reaction mixture was then stirred at 30 8C for 2 h and quenched with saturated NH4Cl
solution (1 ml) and water (2 ml). The aqueous layer was extracted three times with
ether. The combined organic extracts were dried with MgSO4 and concentrated
in vacuo. The crude residue was purified by flash column chromatography
(pentane/ether ¼ 4:1) to afford 14a as a colourless oil (335 mg, 92% yield).
28. Metzger, A., Piller, F. M. & Knochel, P. Polyfunctional benzylic zinc chlorides by
the direct insertion of magnesium into benzylic chlorides in the presence of LiCl
and ZnCl2. Chem. Commun. 5824–5826 (2008).
29. Negishi, E.-i., Takahashi, T., Baba, S., Van Horn, D. E. & Okukado, N.
Palladium- or nickel-catalyzed reactions of alkenylmetals with unsaturated
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Received 22 September 2009; accepted 29 January 2010;
published online 24 March 2010
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Acknowledgements
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Author contributions
T.B. and Y.-H.C. contributed equally to this work. Z.P. assisted in conducting and
analysing the chemical experiments. P.K. designed and directed the project and wrote the
manuscript with contributions from Y.-H.C. and T.B. All authors contributed
to discussions.
Additional information
The authors declare no competing financial interests. Supplementary information
and chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to P.K.
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