New preparation and reactions of arylaluminum reagents using Barbier conditions

Article abstract of DOI:10.1055/s-0028-1088127

The reaction of various aryl bromides with magnesium turnings, LiCl and R₂AlCl (R = Et, i-Bu) provides at room temperature arylaluminum reagents in high yields. These organometallic species undergo readily 1,4-additions, acylations, allylations, and Pd-catalyzed cross-couplings with various aryl iodides and bromides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088127

LETTER
1321
New Preparation and Reactions of Arylaluminum Reagents Using Barbier
Conditions
P
reparationand Re
o
actions of
A
n
rylaluminum
g
R
eagents jun Gao, Paul Knochel*
Department Chemie & Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 20 January 2009
Thus, the treatment of 4-bromoanisole (1.0 equiv) with
Abstract: The reaction of various aryl bromides with magnesium
magnesium turnings (2.5 equiv) activated with DIBAL-H
turnings, LiCl and R2AlCl (R = Et, i-Bu) provides at room temper-
ature arylaluminum reagents in high yields. These organometallic
species undergo readily 1,4-additions, acylations, allylations, and
(1%),9 LiCl (1.25 equiv), and Et2AlCl (1.0 M solution in
hexane, 1.1 equiv) at 25 °C provides the corresponding
Pd-catalyzed cross-couplings with various aryl iodides and bro- arylaluminum reagent 1a within 3 hours as indicated by
mides.
GC analysis of hydrolyzed reaction aliquots. The crude
arylaluminum reagent is cannulated to a solution of
CuCN·2LiCl (0.1 equiv)9 at –10 °C followed by cyclo-
hex-2-enone (0.6 equiv) and TMSCl (1.1 equiv).5b After
acidic workup, the 3-arylated cyclohexanone 4a is isolat-
ed in 72% yield (entry 1 of Table 1). This Michael addi-
tion was extended to arylaluminum reagents bearing a
chlorine substituent (1b,c, entries 2 and 3) leading to the
3-substituted cyclohexanones 4b,c in 71–77% yield. The
ortho-tolylaluminum species 1d also reacts smoothly with
cyclohex-2-enone affording the 1,4-adduct 4d in 76%
yield (entry 4). Finally, amino-substituted arylaluminum
species such as 1e can be readily prepared with our meth-
od providing after the addition to ethyl acrylate the b-aryl-
ated ester 4e in 66% yield (entry 5). The competitive
transfer of an ethyl group was never observed in these
copper-catalyzed 1,4-additions. However, this was the
case for Pd-catalyzed cross-couplings. Therefore, in these
cases, Et2AlCl (4a) was replaced by i-Bu2AlCl (4b) which
transfer only the aryl moiety to the organic electrophile. A
range of Pd-catalyzed cross-couplings could be per-
formed with various aryl bromides or iodides of type 6 us-
ing PEPPSI-i-Pr (7) as the catalyst (2 mol%).10 In all
cases, the arylaluminum reagents 1 undergo directly the
desired cross-coupling without the need of a further trans-
metalation.11 Thus, the reaction of the aluminum reagent
4-MeOC6H4Ali-Bu2 (1f) with 4-BrC6H4CO2Et (0.8 equiv,
25 °C, 4 h) in the presence of PEPPSI-i-Pr (7) provides the
biphenyl derivative 8a in 89% yield (entry 1 of Table 2).
The cross-coupling with 2-BrC6H4CO2Et is complete
within one hour at 25 °C and furnishes the biphenyl ester
(8b) in 95% yield (entry 2). Chlorine- and methyl-substi-
tuted arylaluminum reagents 1g and 1h react with the aryl
bromides 6b and 6c leading to the biphenyls 8c and 8d in
81–83% yield (entries 3 and 4). Amino-substituted aryl-
aluminum reagents, such as 1i and 1j, react smoothly with
aryl bromides 6c and 6d (1 h, 25 °C) affording the biphe-
nyls 8e and 8f in 68–91% yield (entries 5 and 6). Further
CF3-, MeO-, and trimethoxy-substituted arylaluminums
1k–m undergo cross-couplings under similar reaction
conditions in 76–87% yield (entries 7–9). Finally, thio-
methyl-substituted arylaluminums (1n and 1o) give the
Key words: organoaluminum, cross-coupling, 1,4-addition, acyla-
tion, Barbier reaction
The preparation of main-group organometallics for appli-
cations in organic synthesis is one of the most active
research areas in organic chemistry since these organome-
tallics readily form new carbon–carbon bonds. Previously
unrecognized high chemoselectivity of zinc and magne-
sium reagents led to an increased research activity in this
field.1 The preparation of organoaluminum derivatives is
of special interest due to the potentially broad functional-
group tolerance of organoalanes, the low cost of alumi-
num reagents, and their low toxicity. Surprisingly, general
preparations of arylaluminum reagents are rare.2 The most
important syntheses of arylaluminum compounds are di-
rected aluminations,3,4 transmetalation reactions.5 Most
transmetalations from highly reactive organolithium re-
agents have to be performed at low temperature.5 Recent-
ly, we have found that the insertion of various metals (Zn,6
In,7 Mg8) is dramatically accelerated by the addition of
LiCl. Also, the use of Barbier reaction conditions allows
to generate sensitive organozinc reagents via reactive in-
termediate magnesium reagents which are trapped in situ
with ZnCl2.8 Using a similar approach, we wish to report
herein a new preparation method of arylaluminum re-
agents of type 1 (Scheme 1) which proceeds at room tem-
perature via an in situ generated organomagnesium
species of type 2 obtained by the reaction of aryl bromides
3 with magnesium turnings in the presence of LiCl and a
dialkylaluminum chloride (R2AlCl; 4a: R = Et; 4b: R = i-
Bu).
Mg (2.5 equiv)
LiCl (1.25 equiv)
R2AlCl (4a,b)
ArAlR2
ArBr
ArMgX⋅LiCl
25 °C, 1–3 h
3
2
1 (R = Et or i-Bu)
Scheme 1
SYNLETT 2009, No. 8, pp 1321–1325
x
x.
x
x.
2
0
0
9
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088127; Art ID: G02309ST
© Georg Thieme Verlag Stuttgart · New York

1322
H. Gao, P. Knochel
LETTER
Table 1 Copper-Catalyzed Michael Additions of Arylaluminum Reagents 1 to Enones
O
O
(0.6 equiv)
AcOH
ArAlEt2
–10 to 25 °C, 15 min
TMSCl (1.1 equiv)
CuCN⋅2 LiCl (0.1 equiv)
–10 °C to r.t., 4 h
THF, hexane
Ar
1
4
Entry
1
Arylaluminum reagent
Enone
Product 4
Yield (%)a
O
1a
1b
1c
4-MeOC6H4AlEt2
3-ClC6H4AlEt2
4-ClC6H4AlEt2
cyclohex-2-enone
4a
4b
4c
72
77
71
OMe
Cl
O
O
O
2
3
cyclohex-2-enone
cyclohex-2-enone
Cl
Me
4
5
1d
1e
2-MeC6H4AlEt2
cyclohex-2-enone
ethyl acrylate
4d
4e
76
66
CO2Et
3-Me2NC6H4AlEt2
Me2N
a Isolated yields of analytically pure products.
CF3
cross-couplings with aryl iodides (6g and 6h) affording
the desired biphenyls in 83–84% yield (entries 10 and 11).
CF3
CuCN⋅2 LiCl (0.1 equiv)
Br
–10 to 25 °C , 3 h
CO2Et
+
THF, heptane
The arylaluminum reagents of type 1 undergo also smooth
copper(I)-catalyzed acylations with acid chlorides of type
10 leading to aryl ketones of type 11. The reaction of 4-
MeOC6H4Ali-Bu2 (1f) with benzoyl chloride (10a, 0.8
equiv) between –10 °C to 25 °C in the presence of
CuCN·2LiCl9 (0.1 equiv) furnishes the desired benzophe-
CO2Et
(0.8 equiv)
Al(i-Bu2)
1k
12 85%
Scheme 2
none (11a) in 72% yield (entry 1 of Table 3). Similarly, In summary, we have shown that the generation of aryl-
the substituted arylaluminum reagents 1h, 1n, 1p, and 1g aluminums (ArAlR2) prepared from aryl bromides using
react in the presence of CuCN·2LiCl (0.1 equiv) with magnesium turnings in the presence of LiCl and R2AlCl
pivaloyl chloride (10b), benzoyl chloride (10a), or 4-bromo- (R = Et or i-Bu) can tolerate several functional groups.
benzoyl chloride (10c) within 3 hours providing the ke- However, a ketone, a nitrile, or an ester group are not
tones 11b–d in 77–87% yield (entries 2–4). The reaction compatible with this procedure. The aluminum reagents
of 3-F3CC6H4Ali-Bu2 (1k) with ethyl 2-(bromometh- of type 1 were shown to undergo smooth Pd-catalyzed
yl)acrylate12 in the presence of CuCN·2LiCl9 (0.1 equiv) cross-couplings and Cu-catalyzed Michael additions,
furnishes the allylation product 12 in 85% yield acylations, and allylations. Further reactivity studies of
(Scheme 2). Thus, a copper-catalyzed allylation can be these arylaluminum derivatives and extension of this
also realized conveniently with the arylaluminum re- method are currently under way in our laboratory.
agents.13–16
Synlett 2009, No. 8, 1321–1325 © Thieme Stuttgart · New York

LETTER
Preparation and Reactions of Arylaluminum Reagents
1323
Table 2 Pd-Catalyzed Cross-Couplings of Arylaluminum Reagents 1 with Aryl Bromides and Iodides of Type 6 Leading to Biphenyls of
Type 8
Ar2X (6, 0.8 equiv)
PEPPSIi-Pr (7; 2 mol%)
Ar1–Ar2
Ar1Al(i-Bu)2
25 °C, 1–12 h
THF, heptane
1
8
Entry
1
Arylaluminum reagent
Ar1X
Product 8
Yield (%)a
89
CO2Et
1f
1f
4-MeOC6H4Ali-Bu2
6a
6b
4-BrC6H4CO2Et
2-BrC6H4CO2Et
8a
8b
MeO
MeO
2
4-MeOC6H4Ali-Bu2
95
EtO2C
EtO2C
Cl
3
4
1g
1h
3-ClC6H4Ali-Bu2
2-MeC6H4Ali-Bu2
6b
6c
2-BrC6H4CO2Et
2-BrC6H4OMe
8c
81
83
Me
8d
MeO
NMe2
5
6
1i
1j
3-Me2NC6H4-AliBu2
4-Me2NC6H4Ali-Bu2
6d
6e
4-BrC6H4OMe
4-BrC6H4Cl
8e
8f
68
91
OMe
Cl
Me2N
CF3
7
8
9
1k
1l
3-F3CC6H4-Ali-Bu2
6a
6f
4-BrC6H4CO2Et
2-BrC6H4Me
8g
8d
8h
76
87
79
CO2Et
OMe
Me
2-MeOC6H4-Ali-Bu2
3,4,5-(MeO)3C6H2Ali-Bu2
CO2Et
MeO
1m
6a
4-BrC6H4CO2Et
MeO
MeS
OMe
10
11
1n
1o
4-MeSC6H4Ali-Bu2
2-MeSC6H4Ali-Bu2
6g
6h
2-IC6H4CO2Et
4-IC6H4CO2Et
8i
8j
84
83
EtO2C
CO2Et
SMe
a Isolated yields of analytically pure products.
Synlett 2009, No. 8, 1321–1325 © Thieme Stuttgart · New York

1324
H. Gao, P. Knochel
LETTER
Table 3 Copper(I)-Catalyzed Acylations of Arylaluminum Reagents 1 with Acid Chlorides of Type 10 Leading to Aryl Ketones of Type 11
RCOCl (10; 0.8 equiv)
0.1 CuCN⋅2 LiCl
O
ArAl(i-Bu)2
Ar
R
–10 to 25 °C , 3 h
THF, heptane
1
11
Entry
1
Arylaluminum reagent
RCOCl
Product 11
Yield (%)a
72
1f
4-MeOC6H4Ali-Bu2
10a
10b
10a
10a
PhCOCl
t-BuCOCl
PhCOCl
PhCOCl
11a
MeO
MeS
COPh
COPh
Me
2
3
4
1h
1n
1p
2-MeC6H4Ali-Bu2
4-MeSC6H4Ali-Bu2
2-F3CC6H4Ali-Bu2
11b
11c
11d
77
87
85
COt-Bu
CF3
COPh
O
C
Cl
5
1g
3-ClC6H4Ali-Bu2
10c
4-BrC6H4COCl
11e
85
Br
a Isolated yields of analytically pure products.
(8) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(b) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun.
2008, 5824.
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
Acknowledgment
H.G. thanks the Humboldt Foundation for financial support. We
thank the Fonds der Chemischen Industrie, the European Research
Council (ERC), Chemetall GmbH (Frankfurt), and BASF AG (Lud-
wigshafen) for financial support.
(10) Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev,
E. A. B.; O’Brien, C. J.; Valente, C. Chem. Eur. J. 2006, 12,
4749.
References and Notes
(11) (a) King, A. O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc.,
Chem. Commun. 1977, 683. (b) Negishi, E.-i.; Okukado, N.;
King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am. Chem.
Soc. 1978, 100, 2254. (c) Negishi, E.; Luo, F.-T. J. Org.
Chem. 1983, 48, 1560. (d) Negishi, E.-i.; Bagheri, V.;
Chatterjee, S.; Luo, F.-T. Tetrahedron Lett. 1983, 24, 5181.
See also: (e) Manolikakes, G.; Schade, M. A.;
Munoz Hernandez, C.; Mayr, H.; Knochel, P. Org. Lett.
2008, 10, 2765.
(12) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
(13) Typical Procedure: Preparation of Aluminum Reagent
1f
A dry argon-flushed Schlenk flask equipped with a magnetic
stirrer and a rubber septum was charged with anhyd LiCl
(106 mg, 2.5 mmol), and the flask was dried with a heating
gun for 3–5 min on high vacuum (1 mbar). To this flask was
added the magnesium turnings (122 mg, 5.0 mmol), and the
flask was evacuated and refilled with argon. After the
addition of freshly distilled THF (3 mL), magnesium
turnings were activated with DIBAL-H (0.2 mL, 0.1 M
solution in THF, 0.02 mmol). After heating for about 1 min
and then cooling to 25 °C, i-Bu2AlCl soln (2.2 mmol, 0.8 M
in heptane) was added. Finally, 4-bromoanisole (374 mg, 2.0
mmol) was added in one portion at 25 °C. After 3 h at this
temperature, the reaction mixture was cannulated to a new
Schlenk flask for the trapping reaction with an electrophile.
(14) The 27Al NMR spectra of 1a obtained by our method and by
the reaction of p-lithioanisole and 4a give the same chemical
shift (d = 178.16 ppm, in THF and Et2O).
(1) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.
Int. Ed. 2003, 42, 4302.
(2) Saito, S. Comprehensive Organometallic Chemistry III, Vol.
9; Knochel P., Amsterdam: Elsevier, 2007, 245–296.
(3) (a) Uchiyama, M.; Naka, H.; Matsumoto, Y.; Ohwada, T.
J. Am. Chem. Soc. 2004, 126, 10526. (b) Naka, H.;
Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.;
McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc.
2007, 129, 1921. (c) Naka, H.; Morey, J. V.; Haywood, J.;
Eisler, D. J.; McPartlin, M.; Garcia, F.; Kudo, H.; Kondo, Y.;
Uchiyama, M.; Wheatley, A. E. H. J. Am. Chem. Soc. 2008,
130, 16193.
(4) Wunderlich, S. H.; Knochel, P. Angew. Chem. Int. Ed. 2009,
48, 1501.
(5) (a) Ishikawa, T.; Ogawa, A.; Hirao, T. J. Am. Chem. Soc.
1998, 120, 5124. (b) Hawner, C.; Li, K.; Cirriez, V.;
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Eur. J. Inorg. Chem. 1998, 295.
(6) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel,
P. Angew. Chem. Int. Ed. 2006, 45, 6040. (b) Boudet, N.;
Sase, S.; Sinha, P.; Liu, C.-Y.; Krasovskiy, A.; Knochel, P.
J. Am. Chem. Soc. 2007, 129, 12358.
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Synlett 2009, No. 8, 1321–1325 © Thieme Stuttgart · New York

LETTER
Preparation and Reactions of Arylaluminum Reagents
1325
(15) Typical Procedure: Preparation of 3-(4-Methoxy-
phenyl)cyclohexanone (4a)
(16) Typical Procedure: Preparation of Ethyl 4¢-Methoxy-
biphenyl-2-carboxylate (8b)
The freshly made aluminum reagent 1a was cannulated into
a dry argon-flushed Schlenk flask equipped with a magnetic
stirrer and a rubber septum at –10 °C. To this was added
CuCN·2LiCl (0.2 mL, 1 M in THF, 0.2 mmol), and the
reaction mixture was stirred for 5 min. After the addition of
cyclohex-2-enone (115 mg, 1.2 mmol) and then TMSCl (239
mg, 2.2 mmol), the cooling bath was removed and the
mixture was stirred for 4 h at 25 °C. The reaction was
quenched with AcOH (360 mg, 6.0 mmol) at –30 °C and
then kept at 25 °C for 15 min. The mixture was extracted
three times with EtOAc, washed with aq sat. NaHCO3, H2O,
and sat. NaCl soln. The combined organic layers were dried
over Na2SO4, and the solvents were removed under reduced
pressure to furnish the crude product, which was further
purified by column chromatography (SiO2) to obtain a light
yellow oil (72% yield, 176 mg).
A dry Schlenk flask equipped with a magnetic stirrer and a
rubber septum was charged with ethyl 2-bromobenzoate
(366 mg, 1.6 mmol), PEPPSIi-Pr (13.6 mg, 2 mol%). The
flask was thoroughly flushed with argon, and freshly
distilled THF (0.5 mL) was added to it through the rubber
septum. The resultant mixture was stirred at 25 °C for 5 min
before the aluminum reagent 1f was slowly cannulated into
the flask. After 1 h, the reaction was quenched with aq 2 N
HCl at –30 °C and then kept at 25 °C for 10 min. The mixture
was extracted three times with EtOAc, washed with aq sat.
NaHCO3, H2O, and sat. NaCl soln. The combined organic
layers were dried over Na2SO4, and the solvents were
removed under reduced pressure to furnish the crude
product, which was further purified by column chromatog-
raphy (SiO2) to obtain a light yellow oil (95% yield, 389
mg).
Synlett 2009, No. 8, 1321–1325 © Thieme Stuttgart · New York

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