A convenient alumination of functionalized aromatics by using the frustrated Lewis pair Et3Al and TMPMgCl·LiCl

Article abstract of DOI:10.1002/chem.201301869

A straightforward and efficient alumination of functionalized arenes by using the frustrated Lewis pair Et₃Al and TMPMgCl×LiCl (TMP=2,2,6,6-tetramethylpiperidyl) has been developed. In particular, halogenated electron-rich aromatics can be smoothly functionalized by using the frustrated Lewis pair Et₃Al and TMPMgCl×LiCl. Compared with previously described alumination methods, this procedure avoids extensive cooling and the need for an excess of base. This in situ procedure has proven to be most practical and allows for regio- and chemoselective metalation of a wide range of aromatics with sensitive functional groups (CONEt₂, CO ₂Me, CN, OCONMe₂) or halogens (F, Cl, Br, I). The resulting aromatic aluminates, which were characterized by using NMR spectroscopy, were subjected to allylations, acylations, and palladium-catalyzed cross-coupling reactions after transmetalation to zinc. It was shown that the nature of the Zn salt used for transmetalation is crucial. Thus, compared with ZnCl₂ (2equiv), the use of Zn(OPiv)₂ (2equiv; OPiv=pivalate) allows the subsequent quenching reactions to be performed with only a slight excess of electrophile (1.2equiv) and provides interesting functionalized aromatics in good yields.

Full text of DOI:10.1002/chem.201301869

FULL PAPER
DOI: 10.1002/chem.201301869
A Convenient Alumination of Functionalized Aromatics by Using the
Frustrated Lewis Pair Et3Al and TMPMgCl·LiCl
Andreas Unsinn,[a] Stefan H. Wunderlich,[a, b] Anukul Jana,[a]
Konstantin Karaghiosoff,[a] and Paul Knochel*[a]
Abstract: A straightforward and effi-
cient alumination of functionalized
arenes by using the frustrated Lewis
base. This in situ procedure has proven
to be most practical and allows for
regio- and chemoselective metalation
of a wide range of aromatics with sensi-
tive functional groups (CONEt2,
CO2Me, CN, OCONMe2) or halogens
(F, Cl, Br, I). The resulting aromatic
aluminates, which were characterized
by using NMR spectroscopy, were sub-
jected to allylations, acylations, and
palladium-catalyzed cross-coupling re-
actions after transmetalation to zinc. It
was shown that the nature of the Zn
salt used for transmetalation is crucial.
Thus, compared with ZnCl2 (2 equiv),
pair
Et3Al
and
TMPMgCl·LiCl
(TMP=2,2,6,6-tetramethylpiperidyl)
has been developed. In particular,
halogenated electron-rich aromatics
can be smoothly functionalized by
using the frustrated Lewis pair Et3Al
and TMPMgCl·LiCl. Compared with
previously described alumination meth-
ods, this procedure avoids extensive
cooling and the need for an excess of
the use of Zn
ACHTUNGTRENNUNG
pivalate) allows
quenching reactions to be performed
with only a slight excess of electrophile
(1.2 equiv) and provides interesting
functionalized aromatics in good yields.
À
Keywords: aluminum · C C cou-
pling · Lewis pairs · metalation · re-
gioselectivity
Introduction
needed to achieve full conversion. Recently, we have
prepared the related non-ate base [(tBuCH(iPr))-
N
ACHTUNGTRENNUNG
Organoaluminum reagents are useful intermediates for the
formation of new carbon–carbon bonds.[1] Compared with
other main-group metals, aluminum is fairly inexpensive and
nontoxic, and its recovery is possible through aluminum hy-
droxide precipitation.[2] Furthermore, aluminum exhibits
useful reactivity due to its Lewis acid properties.[3] In partic-
ular, the alumination of electron-rich aromatics is of great
synthetic interest because the corresponding lithiation can
require extensive cooling, whereas the metalation with
standard Mg and Zn bases is sluggish with such aromatics.
However, for an efficient metalation of these scaffolds lithi-
um bases or bimetallic bases are generally required.[4]
ACHTUNGTERN(NNUG tBu)N]3Al·3LiCl, which proved to regioselectively alumi-
nate a range of aromatic and heteroaromatic scaffolds.[8] Its
metalation power and regioselectivity was complementary
to other TMP bases, such as TMPMgCl·LiCl (1),[9]
TMP2Mg·2LiCl
Zn·2MgCl2·2LiCl[12] and TMP2Mn·2MgCl2·4LiCl.[13] Where-
as most of these TMP-bases react readily with aromatics
that have electron-withdrawing substituents, [(tBuCH(iPr))-
(tBu)N]3Al·3LiCl is able to metalate electron-rich oxygen-
substituted aromatics. Unfortunately, solutions of [(tBuCH-
(iPr))(tBu)N]3Al·3LiCl in THF display only limited stability
(2),[10]
TMPZnCl·LiCl,[11]
TMP2-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(2–3 d at À508C). Therefore, we looked for a more practical
alternative, which is described herein. We report the use of
the frustrated Lewis pair[14] Et3Al–TMPMgCl·LiCl (3) for
the alumination of various functionalized aromatics. The
dual catalysis of the Lewis acid Et3Al and the Lewis base
TMPMgCl·LiCl has several preparative advantages. Also,
Lewis pair 3 displays good metalating power and convenient
practical handling. In contrast to previous reports, this new
system and its in situ preparation avoids the problem of
using an excess of the aluminum base in the metalation step.
The pioneering work of Uchiyama has shown that alumi-
ACTHNUTRGNEUNG
num ate bases[5] such as iBu3Al(TMP)Li[6] (TMP=2,2,6,6-
tetramethylpiperidyl) proved to be very useful for the di-
rected alumination of various aromatics and some hetero-
ACHTUNGTRENNUNG
cycles.[7] Nevertheless, an excess of base (2.2 equiv) was
[a] Dipl.-Chem. A. Unsinn, Dr. S. H. Wunderlich, Dr. A. Jana,
Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
Department Chemie
Furthermore, we reveal that the use of ZnACTHNURTGNENG(U OPiv)2 (OPiv=
pivalate) allows the excess of electrophile to be minimized
in subsequent reactions.
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F
81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[b] Dr. S. H. Wunderlich
New address: AlzChem AG, Trostberg (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301869.
Chem. Eur. J. 2013, 00, 0 – 0
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Table 1. Conversion of 4a to aluminate species 5a in the course of the metalation
Results and Discussion
with in situ prepared bases, using various aluminum sources.[a]
In the first optimization step of this new directed
alumination procedure, we searched for the most
convenient aluminum source. 4-Chloroanisole (4a),
which was used as a model aromatic substrate, was
treated at 08C with various aluminumACTHNUGRTENUNG(III) reagents
Conversion [%]
(1.1 equiv) followed by the addition of
TMPMgCl·LiCl (1; 1.2 equiv) and then warming to
258C.
Entry
AlY3
1 h
2 h
3 h
4 h
7 h
10 h
22 h
1
2
3
4
5
6
7
–
17
19
20
21
23
25
30
AlCl3
<5
<5
<5
32
38
31
<5
<5
<5
44
55
45
<5
<5
<5
58
62
57
<5
<5
<5
61
<5
<5
<5
69
<5
<5
<5
74
82
76
<5
<5
<5
76
90
81
When 4-chloroanisole (4a) was treated with 1 for
22 h at ambient temperature, 30% ortho metalata-
tion was obtained. However, the reaction did not
proceed further. In the presence of aluminum re-
agents AlCl3, MeAlCl2, and Me2AlCl, conversion to
corresponding ortho-metalated compound 5a drop-
ped to less than 5%. This was not surprising be-
cause a standard transmetalation of 1 to a tricoordi-
nated aluminum compound is
MeAlCl2
Me2AlCl
Me3Al
Et3Al
iBu3Al
68
78
62
69
[a] The conversion to the corresponding metal species was monitored by using GC
analysis of aliquots of the reaction mixture quenched with allyl bromide in the pres-
ence of CuCN·2LiCl, with tetradecane as the internal standard.
expected.[15a]
The
tentative
structure of the resulting alumi-
num reagents is MenCl2ÀnAl-
ACHTUNGTRENNUNG(TMP) (n=0–2), and no metal-
ation activity is expected for
these reagents. However, the
use of trialkylaluminum re-
agents, such as Me3Al, Et3Al,
and iBu3Al, greatly increased
the metalation rate of 4a. The
observed rates proved to be
comparable, but the combina-
tion of 1 with Et3Al led to more
complete conversions (Table 1).
One possible mechanism that
could account for better conver-
sion with R3Al additives com-
pared with R2AlX additives
is the initial formation of
the aluminate species Et3Al-
ACHTUNGTRENNUNG(TMP)MgCl·LiCl, similar to
Figure 1. 13C NMR spectra recorded in THF for TMPMgCl·LiCl (1), Et3Al–TMPMgCl·LiCl (3), and Et3Al
with LiCl; *: TMPMgCl·LiCl, ꢅ: TMPH, +: new species.
iBu3AlACHTUNGTRENNUNG(TMP)Li as reported by
Uchiyama et el.[4c] This species
could effectively deprotonate
anisole 4a. However, seminal
studies by the groups of Hevia, Garcꢃa-ꢄlvarez, Robertson,
and Mulvey demonstrated that solvent-separated ion-pair
species and a dismutation process have to be considered for
such aluminates. In addition, ligand exchanges have been
observed on such aluminates.[5] This prompted us to perform
a multinuclear NMR spectroscopy study to clarify the
nature of the species formed from 3. Thus, mixing equimolar
amounts of Et3Al with 1 at 258C in THF (0.5m) gave ap-
proximately 80% unchanged 1 along with two new species
(Figure 1).
(Figure 1). The formation of Et4AlACTHNGUTERNNU(G MgCl) along with a new
TMP-containing compound in solution proves that an equili-
bration process took place. Furthermore, the existence of
only one new TMP-containing compound in solution implies
that there is no Et3Al
cause the observed formation of Et4Al
explained in connection with the two Et2Al
Et2Al
(TMP)2MgCl·LiCl[16] species (Scheme 1).
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
One of these species was identified as Et4AlACTHNUTRGNE(NUG MgCl) by
using 1H, 13C, and 27Al NMR spectroscopy,[15] whereas the
second species clearly contains at least one TMP moiety
Scheme 1. Putative equilibria of 3 in THF.
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A Convenient Alumination of Functionalized Aromatics
FULL PAPER
ACTHNGUTRENNUaG ACHTUNGTRENNtUNG ion of the corresponding (5-
chloro-2-methoxyphenyl)mag-
nesium iodide Grignard reagent
with Et3Al (Figures 2 and 3).
The Grignard reagent was
prepared through oxidative in-
sertion of magnesium in the
presence of LiCl in 4-chloro-2-
iodo-1-methoxybenzene
(Scheme 2).[18] Thus, it can be
concluded that the alumination
of 4a proceeds through depro-
tonation by the TMP anion
rather than by an alkyl ligand.
In particular, the absence of
the13C NMR signals of the
Grignard reagent and genera-
tion of the same species simply
by adding Et3Al to the
Grignard reagent supports the
identity of these organoalumi-
num species. Further evidence
is provided by the 27Al NMR
spectrum (Figure 2). It shows a
new broad signal at d=
153 ppm, which is attributed to
Figure 2. 27Al NMR spectra recorded in THF for 3 and arylaluminate 5a prepared by deprotonation or Mg in-
*
*
sertion followed by transmetalation; ꢅ: Et4AlACHUTNGTRNENU(G MgCl), : arylaluminates 5a and 5aa, : Et3Al.
Unfortunately, 27Al NMR spectroscopy does not allow
these species to be distinguished between due to similar ex-
pected chemical shifts (Figure 2a).[17] However, comparison
with control 27Al NMR spectra proved that Figure 2a shows
the expected broad signal for Et3Al centered at d=175 ppm
along with the very sharp signal of Et4AlACHTUNGTRENN(UNG MgCl) at d=
159 ppm.
Note that, as shown in Table 1, Me2AlTMP is not active
in the metalation of 4a. A similar result is expected for
Et2AlTMP·THF (Scheme 1), whereas the formation of
Et2AlACHTUNGTRENNUNG(TMP)2MgCl·LiCl is less favored for steric reasons.
Furthermore, the groups of Hevia, Garcꢃa-ꢄlvarez, Robert-
son, and Mulvey have shown that iBu4Al(Li) is not active in
metalations.[5] Therefore, we conclude that the active species
in our system must be Lewis pair 3. In fact, 1 and Et3Al rep-
resent 80% of the reaction mixture. This coexistence of
Lewis acid Et3Al and Lewis base 1 during the course of the
reaction implies that 3 may be regarded as a frustrated
Lewis pair. There is a very slow and incomplete reaction
taking place between 1 and Et3Al (Scheme 1 and Figure 1).
To shed some light on the organometallic species pro-
duced after metalation, we deprotonated 4a with a stoichio-
metric mixture of 3 at ambient temperature. After a
reaction time of 24 h, we investigated the reaction mixture
by using 1H, 13C, 27Al, and 7Li NMR spectroscopy. The
13C NMR spectrum recorded at 258C clearly shows the pres-
ence of three organoaluminum species, which are identified
Scheme 2. Postulated equilibrium of arylaluminate 5a.
two organoaluminum species 5a and 5aa. Due to the similar
environment of Al in these compounds (surrounded by four
carbon atoms) similar chemical shifts are anticipated, and
due to the expected broadness of the signals they cannot be
resolved. In all these reactions Li+ obviously did not change
its environment. All solutions in which Li+ is present
7
showed the same signal in Li NMR spectroscopy, that is, a
singlet at d=3.2 ppm.
Further preliminary experiments proved that in situ gen-
eration of 3 was advantageous because 3 slowly decomposes
in THF. Additionally, the conversion of 4a to the aluminate
species (5a) is slightly higher for the in situ preparation
(Scheme 3 and Table 1).
as 5a, 5aa, and Et4Al
same three species are formed independently by trans
A
In the next step, the stoichiometry of Et3Al was opti-
mized. Compound 4a was treated with various amounts of
N
ACHTUNGTRENNUNG
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P. Knochel et al.
ics and reacted the resulting
aluminates with various electro-
philes, for example, addition to
aldehydes, acylations, allyla-
tions, and cross-couplings with
aryl iodides (Table 2). Thus, 4a
was smoothly metalated within
24 h at 258C. Resulting aryltrie-
thylaluminate 5a subsequently
reacted with p-anisaldehyde to
give desired alcohol 6a in 75%
yield (Scheme 5).
This new procedure proved
to be quite general. By treating
a variety of aromatics of type 4
with Et3Al followed by 1, a
range of functionalized alumi-
nates was prepared in a conven-
ient temperature range (À5–
258C). After quenching with
typical electrophiles, expected
products of type 6 were isolated
in 70 to 83% yield (Table 2).
Accordingly, aluminate 5a
could also be smoothly trans-
metalated to zinc by using
ZnCl2, and underwent a Pd-cat-
alyzed Negishi cross-coupling[19]
Figure 3. 13C NMR spectra of arylaluminate 5a prepared by deprotonation or Mg insertion followed by trans-
metalation and the corresponding Grignard reagent; +: arylaluminate 1, ꢅ: arylaluminate 2, *: Grignard re-
*
agent, : hydrolysis (4a).
with
trile (2.5 equiv) with 2% [Pd-
(dba)2] (dba=dibenzylidene-
acetone) and 4% TFP (TFP=
tri
(2-furyl)phosphine),[20] which
led to desired biphenyl 6b in
2-chloro-4-iodobenzoni-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Scheme 3. Alumination of 4-chloroanisole (4a) with preformed 3.
Et3Al
and
reacted
with
1.1 equivalents of 1 for 22 h at
258C. If Et3Al was used in sub-
stoichiometric amounts, only
low conversions (51–65%) were
obtained, whereas an excess of
Scheme 5. Regioselective functionalization of 4a by alumination.
Et3Al did not further improve
the metalation rate (Scheme 4).
Thus, the best conditions require the use of stoichiometric
amounts of Et3Al.
With these optimized reaction conditions, we were able to
aluminate a broad range of electron-rich and -poor aromat-
70% yield (Table 2, entry 1). 4-Fluoroanisole (4b) and 4-
bromoanisole (4c) were also completely metalated within 15
and 28 h, respectively, at 258C. After transmetalation with
ZnCl2 (2.2 equiv), the corresponding organometallics react-
ed with ethyl 4-iodobenzoate (2.5 equiv) under Pd catalysis
or with 4-chlorobenzoyl chloride (2.5 equiv) mediated by
CuCN·2LiCl[21] (1.1 equiv) to give biphenyl 6c and ketone
6d in 77 to 79% yield (Table 2, entries 2 and 3). Because 3-
fluoroanisole (4d) is prone to undergoing b-elimination, it is
metalated at lower temperature (À58C). Under these condi-
tions, full metalation is achieved within 20 min. Following
transmetalation to zinc, a copper-catalyzed allylation with 3-
Scheme 4. Metalation of 4a by using various amounts of Et3Al.
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A Convenient Alumination of Functionalized Aromatics
FULL PAPER
Table 2. Alumination of aromatics and subsequent quenching with elec-
trophiles (2.5 equiv).
tained in 73% yield (Table 2, entry 6). meta-Substituted
ester 4g and amide 4h were metalated within 1 h at 08C,
and the resulting arylaluminates were allylated or reacted
with 4-cyanobenzaldehyde to give 2-allylated products 6h
and 6i and lactone 6j in 74 to 83% yield (Table 2, entries 7–
9).
However, this smooth alumination still has a drawback.
To achieve high yields, it was necessary to use an excess of
the electrophile (2.5 equiv). Preliminary results showed that
a direct cross-coupling of the intermediate aluminates by
Entry Substrate t [8C],
T [h]
Electrophile
Product
Yield[a]
[%]
1
25, 24
70[b]
4a
6b
using [PdACHTNUGTRNEUNG(tmpp)2Cl2] (tmpp=tris(2,4,6-trimethoxyphenyl)-
2
3
25, 15
25, 28
77[b]
phosphine) leads only to low yields of the desired biphenyl
(15%). Therefore, we screened the nature and amount of
zinc reagent used for the transmetalation (Table 3). If two
4b
4c
6c
6d
79[c]
Table 3. Screening of various Zn-salts for the transmetalation step.
4
5
À5, 0.3
87[d]
4d
4e
6e
6 f
25, 1
85
Entry
ZnX2
n [equiv]
Yield of 7 [%]
1
2
3
4
5
6
ZnCl2
ZnCl2
ZnCl2·2LiCl
ZnCl2·2LiCl
2
5
2
5
2
5
38
58
<5
<5
70
6
0, 3
73
ZnACHTUNTGERN(UNG OPiv)2
ZnG(OPiv)2
67
4 f
4g
4h
6g
6h
6i
7
8
0, 1
0, 1
81
74
equivalents of ZnCl2 were used for the transmetalation, bi-
phenyl 7 was isolated in 38% yield, whereas with five equiv-
alents of ZnCl2, the yield increased to 58% (Table 3, en-
tries 1 and 2). In contrast, the use of two or five equivalents
of ZnCl2·2LiCl[22] gave mainly 4-ethylbenzonitrile and only
small amounts of 7 (Table 3, entries 3 and 4). Lastly,
Zn(OPiv)2 provided the best results; remarkably, two equiv-
9
0, 1
83
alents of ZnACTHUNRGTNEUNG(OPiv)2 were sufficient to provide 7 in 70%
yield, whereas the use of five equivalents did not further im-
prove the yield of 7 (Table 3, entries 5 and 6)
4h
6j
In the next step, we further optimized the stoichiometry
of ZnACTHNURGTEN(UGN OPiv)2 and the electrophile. We attempted to reduce
[a] Isolated yield of analytically pure product. [b] Obtained after trans-
metalation with ZnCl2 (2.2 equiv) by palladium-catalyzed cross-coupling
with 2% [PdACHTUNGTRENNUNG(dba)2] and 4% TFP. [c] A transmetalation with ZnCl2
(2.2 equiv) and CuCN·2LiCl (1.1 equiv) was performed. [d] Obtained
after transmetalation with ZnCl2 (2.2 equiv) and allylation catalyzed by
5% CuCN·2LiCl.
the amount of Zn(OPiv)2 used and investigated whether the
use of an excess of electrophile still had an impact on the re-
action yield (Table 4). Interestingly, a large excess of ethyl
4-iodobenzoate did not significantly improve the yield of 8
in the Negishi cross-coupling, whereas the amount of
Zn(OPiv)2 greatly influenced the reaction yield. The best re-
bromocyclohexene provided desired product 6e in 87%
yield (Table 2, entry 4). In contrast, 3-chloroanisole (4e) was
metalated at 258C within 1 h, and subsequent allylation with
methallyl bromide gave anisole derivative 6 f in 85% yield
(Table 2, entry 5). Electron-poor arenes 4 f–h were metalat-
ed at slightly lower temperatures. para-Substituted amide 4 f
was aluminated within 3 h at 08C, and after Negishi cross-
sults were obtained with 2.2 equiv of Zn
1.2 equiv of the electrophile (Table 4, entry 3).
ACHTUNGTERNN(UNG OPiv)2 and
With these optimized conditions in hand, metalations of
various electron-rich substrates were carried out and gave
products 9a–k in yields of 51 to 91% (Table 5). Under these
conditions, 4a was metalated within 24 h at 258C. After
coupling with 3-iodo
G
transmetalation with ZnACTHNGUTER(NNUG OPiv)2 a Negishi cross-coupling
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P. Knochel et al.
Table 4. Influence of the stoichiometry of Zn
phile.
ACHTUNGTERN(NUGN OPiv)2 and the electro-
within 28 h at 258C and a subsequent CuCN·2LiCl-mediat-
ed acylation gave ketone 7c in 68% (Table 5, entry 3). 4-Io-
doanisole (4i) was iodolyzed and allylated after alumination
to give diiodoarene 9d and 2-allylated anisole 9e in 83 to
89% yield (Table 5, entries 4 and 5). Furthermore, 3-chlor-
oanisole (4e) was smoothly aluminated and allylated to give
anisole derivative 9 f in 77% yield (Table 5, entry 6). Also,
dioxygenated substrates were readily metalated by following
this procedure. 5-Bromo-1,3-benzodioxole (4j) is aluminated
within 30 min at 08C. Subsequent allylation with 3-bromocy-
clohexene or benzoylation gave expected arenes 9g and 9h
in 51 to 91% yield (Table 5, entries 7 and 8). Similarly, 6-
bromo-2,3-dihydro-1,4-benzodioxine (4k) and 6,7-bromo-
2,3-dihydro-1,4-benzodioxine (4l) were efficiently aluminat-
ed at 08C and readily allylated under CuCN·2LiCl catalysis
to give desired functionalized dihydrobenzodioxines 9i and
9j in 72 to 80% yield (Table 5, entries 9 and 10). Interest-
ingly, dimethylcarbamate-protected phenols 4m and 4n
Entry
n [equiv]
x [equiv]
Yield of 8 [%]
1
2
3
4
1.1
1.1
2.2
2.2
1.2
2.4
1.2
2.4
47
51
78
75
with ethyl 4-bromobenzoate and 2-bromoquinoxaline led to
desired products 9a and 9b in 71 to 73% yield (Table 5, en-
tries 1 and 2). Similarly, 4-bromoanisole (4c) was metalated
Table 5. Metalation of electron-rich aromatics and reaction with electrophiles (1.2 equiv) after transmetalation with ZnACTHUNRGTNEUNG(OPiv)2 (2.2 equiv).
Entry Substrate t [8C],
T [h]
Electrophile
Product
Yield[a]
[%]
Entry Substrate
t [8C],
T [h]
Electrophile Product
Yield[a]
[%]
1
25, 24
73[b]
7
0, 0.5
91[e]
4a
9a
4j
9g
2
3
25, 24
25, 28
71[b]
8
0, 0.5
0, 0.5
PhCOCl
51[e]
4a
4c
9b
9c
4j
9h
69[c]
9
80[d]
4k
9i
9j
4
5
25, 30
25, 30
I2
83
10
0, 0.5
0, 0.5
72[e]
4i
9d
4l
89[e]
11
74[d]
4i
9e
9 f
4m
9k
6
25, 1
77[e]
12
0, 2
77[b]
4e
4n
9l
(OPiv)2 (2.2 equiv) by palladium-catalyzed cross-coupling by using 2%
(OPiv)2 (2.2 equiv) by palladium-catalyzed cross-coupling with 2% [Pd(PPh3)4]. [d] Transme-
(OPiv)2 (2.2 equiv) and CuCN·2LiCl (1.1 equiv) was performed. [e] Obtained after transmetalation with Zn(OPiv)2 (2.2 equiv) and allylation cat-
alyzed by 5% CuCN·2LiCl.
[a] Isolated yield of analytically pure product. [b] Obtained after transmetalation with Zn
[Pd(dba)2] and 4% TFP. [c] Obtained after transmetalation with Zn
talation with Zn
ACHTUNGTRENNUNG
G
A
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
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A Convenient Alumination of Functionalized Aromatics
FULL PAPER
were smoothly aluminated without undergoing anionic
ortho-Fries rearrangement[23] to give biphenyls 9k and 9l in
74 to 77%, respectively, after Pd-catalyzed cross-coupling
(Table 5, entries 11 and 12).
Furthermore, selective cross-couplings can be performed.
The choice of the Pd catalyst is essential for achieving a che-
moselective reaction. Use of 2% [PdACHTNUTRGEN(UNG PPh3)4] as the catalyst
left the bromo substituent in the para position untouched
during a cross-coupling with 4-iodobenzonitrile that gave bi-
phenyl 10 at 258C. On addition of 1.2 equivalents of (3,4-
methylenedioxy)phenylmagnesium bromide to the same re-
action vessel, a second cross-coupling took place at 508C to
give polyfunctional terphenyl 11 in 70% yield (Scheme 6).
Scheme 8. Metalation of 4-methoxybenzonitrile (4o).
cross-couplings with ethyl 4-bromobenzoate or 4-bromo-
phenyl dimethylcarbamate to give biphenyls 13c–d in 67 to
75% yield (Table 6, entries 2 and 3). Isomeric 3-methoxy-
benzonitrile (4o) and ethyl 4-
methoxybenzoate (4p) were
correspondingly metalated and
cross-coupled to give highly
functionalized biphenyls 13e
and 13 f in 62 to 73% yield
(Table 6, entries 4 and 5). Car-
bamate 4 f, ethyl ester 4q, and
methyl ester 4r were smoothly
aluminated at 08C and after
Pd-catalyzed
cross-coupling
Scheme 6. One-pot preparation of a polyfunctional terphenyl (11) through two consecutive selective cross-cou-
plings.
gave arenes 13g–i in 65 to 82%
yield (Table 6, entries 6–9). This
methodology is also applicable
In contrast, use of [1,3-bis(2,6-diisopropylphenyl)imida-
zol-2-ylidene](3-chloropyridyl)palladium(II) dichloride
to heteroarenes. Benzothiophene (4s) was metalated within
1 h at 258C and underwent Pd-catalyzed cross-coupling after
(PEPPSI-iPr)[24] led selectively first to the formation of the
desired bromobiphenyl at 258C, which directly underwent a
second cross-coupling with an ethyl group from the alumi-
num reagent Et3Al to give alkylated biphenyl 12 in 41%
yield (Scheme 7).
transmetalation with Zn
phthalate to give 2-arylated benzothiophene 13j in 74%
yield (Table 6, entry 10).
ACHTUNGERTN(NUNG OPiv)2 with diethyl 4-bromoiso-
AHCTUNGTRENNUNG
The method can also be extended to the alumination of
more electron-rich arenes, such as 2-methoxynaphthalene
(14), by replacing 1 with TMP2Mg·2LiCl (2). In the metala-
tion of 14 with in situ prepared 3, only low conversions to
the corresponding arylaluminate species were obtained.
Thus, naphthalene derivative 14 was smoothly metalated by
Et3Al and 2 within 12 h at 258C. Resulting aluminate 15 un-
dergoes a Pd-catalyzed Negishi cross-coupling or acylation
after transmetalation with ZnACHTNUGRTENUNG(OPiv)2 to give desired prod-
ucts 16a and 16b in 57 to 62% yield (Scheme 9).
Finally, homocoupling[25] of the aluminate derived from 5-
bromo-2,2-difluorobenzoACTHUNRGTNE[NUG 1,3]dioxole (17) proceeded readily
in the presence of p-chloranil (2.4 equiv, À788C, 2 h) to
afford bis-naphthol 18, a known precursor for Difluor-
phos,[26] the electron-deficient analogue of SEGPHOS[27]
(Scheme 10).
Scheme 7. Selective one-pot arylation and alkylation.
This methodology was also applied to arenes with elec-
tron-withdrawing groups and heterocycles. 4-Methoxybenzo-
nitrile (4o) was readily aluminated at 258C, and subsequent
cross-coupling with 5-bromo-1,3-benzodioxole afforded de-
sired biphenyl 13a in 74% yield (Scheme 8).
Conclusion
Under the same reaction sequence, alumination of 4o and
transmetalation with ZnACTHNUTRGNE(UGN OPiv)2 afforded 2-zincated 4-me-
thoxybenzonitrile, which was acylated in the presence of
CuCN·2LiCl to give functionalized ketone 13b in 72%
yield (Table 6, entry 1). Similarly, it underwent Pd-catalyzed
We have reported a new alumination procedure involving
the in situ preparation of 3 through sequential addition of
Et3Al and TMPMgCl·LiCl. This method combines chemo-
and regioselective metalation with good functional group
tolerance and storable reagents, and overcomes the need for
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P. Knochel et al.
Table 6. Metalation of electron poor substrates and reaction with electrophiles
(1.2 equiv) after transmetalation with Zn(OPiv)2 (2.2 equiv).
AHCTUNGTRENNUNG
Entry Substrate t [8C],
T [h]
Electrophile
Product
Yield[a]
[%]
1
2
25, 3
25, 3
PhCOCl
72[b]
4o
4o
13b
13c
67[c]
3
4
5
25, 3
25, 2
25, 2
75[c]
62[c]
73[c]
4o
4p
13d
13e
Scheme 9. Metalation of 2-methoxynaphthalene (14) by using Et3Al and
2.
tions at a convenient temperature range and provides new
efficiently functionalized aromatic building blocks in high
yields. Extensions of this method are currently under inves-
tigation in our laboratories.
4q
13 f
6
7
0, 3
0, 1
82[c]
Experimental Section
4 f
4r
13g
13h
4-(4-Cyanophenyl)benzo
ACHTUNGTREN[NGNU 1,3]dioxol-5-yl dimethylcarbamate (9k): A solu-
tion of benzo[1,3]dioxol-5-yl dimethylcarbamate (4m; 418 mg, 2.0 mmol)
AHCTUNGTRENNUNG
65[d]
in dry THF (2 mL) was placed in a flame-dried and argon-flushed
Schlenk tube equipped with a rubber septum and a magnetic stirring bar
and tetradecane (internal standard for GC analysis; 50 mL) was added.
The mixture was cooled to and maintained at 08C, then Et3Al (251 mg,
2.2 mmol, 1.1 equiv) was added and the mixture was stirred for 10 min.
TMPMgCl·LiCl (1; 1.2m in THF, 2.0 mL, 2.4 mmol) was then added
dropwise at 08C and the reaction mixture was stirred for 30 min. Com-
plete metalation was detected by GC analysis of aliquots of the reaction
mixture quenched with allyl bromide in the presence of CuCN·2LiCl in
dry THF, with tetradecane as the internal standard. The reaction mixture
8
9
0, 1
73[c]
4s
4t
13i
13j
25, 1
74[c]
was cooled to À208C, then Zn
the mixture was stirred for 15 min. The mixture was allowed to warm to
258C, then a solution of [Pd(PPh3)4] (46 mg, 2 mol%) in THF (2 mL)
ACHTUNGTNER(NUNG OPiv)2 (1.18 g, 4.4 mmol) was added and
AHCTUNGTRENNUNG
[a] Isolated yield of analytically pure product. [b] Transmetalation with Zn(OPiv)2
(2.2 equiv) and CuCN·2LiCl (1.1 equiv) was performed. [c] Obtained after trans-
metalation with Zn(OPiv)2 (2.2 equiv) by palladium-catalyzed cross-coupling with
2% [Pd(PPh3)4]. [d] Obtained after transmetalation with Zn(OPiv)2 (2.2 equiv) by
palladium-catalyzed cross-coupling with 2% [Pd(dba)2] and 4% TFP.
was added, followed by 4-bromobenzonitrile (437 mg, 2.4 mmol), and the
mixture was stirred for 12 h. The reaction was quenched with a mixture
of saturated aqueous NH4Cl (30 mL) and aqueous HCl (2m, 10 mL), ex-
tracted with diethyl ether (3ꢅ50 mL), and dried over anhydrous MgSO4.
After filtration, the solvent was evaporated in vacuo. The crude product
an excess of base and electro-
phile. This practical procedure
gives access to new organome-
tallics not readily available by
halogen/metal-exchange reac-
tions or previously reported
metalation procedures by using
TMP bases. It allows alumina- Scheme 10. Preparation of a Difluorphos precursor by using in situ prepared 3.
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A Convenient Alumination of Functionalized Aromatics
FULL PAPER
was purified by column chromatography (eluent: pentane/diethyl ether
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Acknowledgements
The research leading to these results received funding from the European
Research Council under the European Communityꢆs Seventh Framework
Programme (FP7/2007-2013) ERC grant agreement no. 227763. We thank
the Fonds der Chemischen Industrie and the Deutsche Forschungsge-
meinschaft (DFG) for financial support. A.J. thanks the Humboldt Foun-
dation for a fellowship. We also thank BASF SE (Ludwigshafen), Her-
aeus Holding GmbH (Hanau), and Rockwood Lithium GmbH (Frank-
furt) for generous gifts of chemicals.
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Received: May 15, 2013
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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A Convenient Alumination of Functionalized Aromatics
FULL PAPER
À
C C Coupling
A. Unsinn, S. H. Wunderlich, A. Jana,
K. Karaghiosoff,
P. Knochel* ................... &&&& — &&&&
A Convenient Alumination of Func-
tionalized Aromatics by Using the
Frustrated Lewis Pair Et3Al and
TMPMgCl·LiCl
The power of frustration: A wide
range of polyfunctional aryltriethylalu-
minate reagents were prepared at a
convenient temperature range (À5 to
258C) by in situ preparation of the
frustrated Lewis pair Et3Al–
TMPMgCl·LiCl (TMP=2,2,6,6-tetra-
methylpiperidyl). The protocol toler-
ates a wide range of functional groups
and an efficient alumination proceeds
without a large excess of base (see
scheme).
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!