Preparation and selective reactions of mixed bimetallic aromatic and heteroaromatic boron-magnesium reagents

Article abstract of DOI:10.1002/anie.200462928

(Chemical Equation Presented) It's all in the mix: The magnesiation of iodoaryl and iodoheteroaryl boronic esters with iPrMgCl·LiCl leads to mixed bimetallic compounds, which react with a variety of electrophiles to provide highly functionalized boronic e

Full text of DOI:10.1002/anie.200462928

Angewandte
Chemie
Boron–Magnesium Reagents
Preparation and Selective Reactions of Mixed
Bimetallic Aromatic and Heteroaromatic Boron–
Magnesium Reagents**
Oliver Baron and Paul Knochel*
Scheme 2. Synthesis of boronic esters of type 6 by the treatment of
magnesiated boronic esters 5 with electrophiles.
Dedicated to Professor Peter Stanetty
on the occasion of his 60th birthday
The selective functionalization of aryl and heteroaryl com-
pounds is an important synthetic task. The resulting poly-
functional (hetero)aryl derivatives are often essential build-
ing blocks in the synthesis of pharmaceuticals, agrochemicals,
and new organic materials.[1] We envisaged that bimetallic[2]
aromatic derivatives of type 1, which bear two metal-centered
substituents of distinctly different reactivity, would be useful
reagents. Their stepwise reaction with two electrophiles E1
and E2 would provide products of type 2 and 3 (Scheme 1).
boronic esters 5a–b also added directly to benzaldehyde to
provide the hydroxy-substituted boronic esters 6e and 6h in
83 and 71% yield, respectively (Table 1, entries 5 and 8). The
boronic ester cuprates underwent a smooth addition–elimi-
nation reaction with 3-iodocyclohexenones to furnish the
expected b-substituted unsaturated ketones 6 f (78%), 6g
(79%), and 6j (76%; Table 1, entries 6, 7, and 10). Prelimi-
nary experiments showed that the ortho-magnesiated phenyl-
boronic ester 5c displayed a lower reactivity towards electro-
philes. However, its allylation gave the boronic ester 6k in
71% yield (Table 1, entry 11).
By using the readily available heterocyclic diiodides 7,[6]
8,[7] and 9,[8] it was possible to prepare the iodoheteroaryl
boronic esters 11 (76%), 12 (76%), and 13 (81%) by an I/Mg
exchange followed by treatment with the dioxaborolane 10
(Scheme 3). These boronic esters were readily converted by
treatment with iPrMgCl·LiCl at ꢀ788C into the related
magnesiated species 14–16, which reacted with various
electrophiles as found for the magnesiated carbocyclic
boronic esters. Thus, the copper(i)-catalyzed allylation of 14
and 16 provided the allylated heterocyclic boronic esters 17a
and 17c in 83 and 91% yield, respectively (Table 2, entries 1
and 3). Transmetalation of the magnesiated 2-indolyl boronic
ester 15 with CuCN·2LiCl, followed by treatment with
Scheme 1. Reactivity of bimetallic aryl derivates.
Unfortunately, the reaction of para-iodoboronic ester 4a[3]
with iPrMgCl afforded only the corresponding isopropylbor-
onate, which results from the attack of the Grignard reagent
at the boronic ester functionality. However, the reaction with
the new reagent iPrMgCl·LiCl[4] (ꢀ788C, 2 h) furnished the
desired magnesiated boronic ester 5a, which reacted with a
variety of electrophiles to provide boronic esters of type 6 in
good yields (Scheme 2, Table 1). Thus, the reaction of 5a with
allylic bromides in the presence of a catalytic amount of
CuCN·2LiCl[5] furnished the expected allylated boronic esters
6a and 6b in 77 and 67% yield, respectively (Table 1,
entries 1 and 2). Acylation reactions proceeded best when the
Grignard reagents 5a and 5b were transmetalated stoichio-
metrically with CuCN·2LiCl. Both aliphatic and aromatic
acid chlorides reacted smoothly to give the keto-substituted
boronic esters 6c, 6d, and 6i in 72, 73, and 71% yield,
respectively (Table 1, entries 3, 4, and 9). The magnesiated
[*] Dipl.-Chem. O. Baron, Prof. Dr. P. Knochel
Department Chemie und Biochemie
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
[**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We also thank Chemetall
and BASF for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 3. Synthesis of iodo-substituted heterocyclic boronic esters
11–13 by I/Mg exchange. Ts=p-toluenesulfonyl.
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DOI: 10.1002/anie.200462928
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 1: Preparation of boronic esters of type 6 by the reaction of the magnesiated aryl boronic esters
5a–c with electrophiles.
the corresponding alcohol directly in 78%
yield (Table 2, entry 4).
Yield [%][a]
All new polyfunctional boronic esters
underwent smooth Suzuki cross-coupling
reactions. Thus, boronic ester 6h (Table 1,
entry 8) reacted readily with 4-bromoben-
zonitrile in the presence of [PdCl2(dppf)]
(5 mol%; dppf = 1,1’-bis(diphenylphospha-
nyl)ferrocene)[9] and K2CO3 (3 equiv) in
THFat 608C (9 h) to give the cross-coupling
product 18 in 92% yield (Scheme 4). In a
convenient one-pot procedure, the iodobor-
onic ester 4a was treated first with
iPrMgCl·LiCl (ꢀ788C, 2 h) and then with
benzaldehyde to provide the magnesium
alcoholate 19, which was submitted directly
to Suzuki cross-coupling conditions.[8] This
sequence afforded the terphenyl derivative
20, which was isolated in 73% yield
(Scheme 4). Similarly, magnesiation of the
meta-substituted iodoboronic ester 4b,
transmetalation with CuCN·2LiCl, and
treatment with 3-iodo-2-methylcyclohexe-
none led to the polyfunctional boronic ester
21, which reacted with 4-bromoisoquinoline
under palladium catalysis to provide the
heterocyclic product 22 in 52% overall yield
(Scheme 4).
Entry
5
Electrophile
6
1
2
5a
5a
R=H
R=CO2Et
6a: R=H
6b: R=CO2Et
77
67
3
4
5a
5a
PhCOCl
BuCOCl
6c: R=Ph
6d: R=Bu
72
73
5
5a
PhCHO[b]
6e
83
6
7
5a
5a
R=H
R=Me
6 f: R=H
6g: R=Me
78
79
In summary, we have prepared magne-
siated aryl and heteroaryl boronic esters by
an I/Mg exchange. These reagents provided
access to a broad array of polyfunctional
boronic esters, which underwent smooth
Suzuki cross-coupling reactions. Further
extensions of this methodology are cur-
rently being studied in our laboratories.
8
9
5b
5b
PhCHO[b]
BuCOCl
6h
71
71
6i
Experimental Section
Typical procedure: Synthesis of 12: iPrMgCl
(1.48 mL, 1.3 mmol, 0.88m in THF) was added
dropwise over 5 min to a solution at ꢀ788C of 8
(0.611 g, 1.2 mmol) in THF (8 mL) in a dry,
argon-flushed 25-mL Schlenk tube equipped with
a
magnetic stirring bar and a septum. The
reaction mixture was stirred at this temperature
for 2 h, until completion of the I/Mg exchange
was detected by GC analysis of reaction aliquots,
then 10 (0.158 g, 1.0 mmol) was added. The
resulting mixture was allowed to warm to room
temperature and stirred until full conversion into
the boronic ester 12 was indicated by GC analysis.
The reaction mixture was then quenched with a
small amount of a saturated, aqueous solution of
NH4Cl and extracted with Et2O (4 ꢀ 10 mL), and
the extracts were dried over Na2SO4. After
filtration, the solvent was evaporated in vacuo.
Recrystallization from CH2Cl2 yielded 12
(387 mg, 76%) as a colorless solid.
10
5b
6j
76
11
5c
6k
71
[a] Yield of analytically pure isolated product. [b] This reaction does not require a transmetalation step
with CuCN·2LiCl.
propionyl chloride, furnished the keto-substituted indolyl
boronic ester 17b in 81% yield (Table 2, entry 2). The
reaction of magnesiated species 16 with benzaldehyde gave
Synthesis of 17b: iPrMgCl·LiCl (1.46 mL, 1.4 mmol, 0.96m in
THF) was added dropwise over 15 min to a solution at ꢀ788C of 12
(0.611 g, 1.2 mmol) in THF (25 mL) in a dry, argon-flushed 100-mL
3134
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Angewandte
Chemie
Schlenk tube equipped with a magnetic stirring bar and a septum. The
Table 2: Synthesis of polyfunctional heterocyclic boronic esters of type
17 by the reaction of magnesiated heterocyclic boronic esters with
electrophiles.
reaction mixture was stirred at this temperature for 1 h, until
completion of the I/Mg exchange was detected by GC analysis of
reaction aliquots, then CuCN·2 LiCl (1.2 mL, 1.2 mmol, 1.0m in THF)
was added, and the resulting mixture was stirred at ꢀ788C for an
additional 20 min. Propionyl chloride (0.093 g, 1.0 mmol) was then
added, and the reaction mixture was allowed to warm to room
temperature and stirred until full conversion into the boronic ester
17b was indicated by GC analysis. The reaction mixture was then
quenched with a small amount of a saturated, aqueous solution of
NH4Cl and extracted with Et2O (4 ꢀ 10 mL) and CH2Cl2 (3 ꢀ 10 mL),
and the extracts were dried over Na2SO4. After filtration, the solvent
was evaporated in vacuo. Recrystallization from CH2Cl2 yielded the
indolyl boronic ester 17b (356 mg, 81%) as a colorless solid.
Entry
Magnesiated
boronic ester
Electrophile
17
Yield[a]
[%]
allyl
bromide
1
83
81
2
3
EtCOCl
Received: December 14, 2004
Published online: April 12, 2005
Keywords: boronic esters · cross-coupling · heterocycles ·
.
magnesium · palladium
allyl
bromide
91
78
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16
PhCHO[b]
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Scheme 4. One-pot magnesiation, reaction with an electrophile, and Suzuki cross-
coupling. DME=1,2-dimethoxyethane.
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