Preparation and reactions of functionalized arylmagnesium reagents

Article abstract of DOI:10.1055/s-2002-20955

Functionalized magnesium reagents have been prepared via an iodine-magnesium exchange. These reagents can be either trapped directly with aldehydes or transmetallated to copper or zinc to participate in cross-coupling reactions. The iodine-magnesium exchange, represent a unique method for the preparation of aryl and heteroaryl magnesium reagents.

Full text of DOI:10.1055/s-2002-20955

PRACTICAL SYNTHETIC PROCEDURES
565
Preparation and Reactions of Functionalized Arylmagnesium Reagents
P
reparation of
F
un
n
ctionalized A
n
rylmagnesiu
e
m
Reagents Eeg Jensen, Wolfgang Dohle, Ioannis Sapountzis, David M. Lindsay, Viet Anh Vu,
Paul Knochel*
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstr. 5-13, Haus F,
81377 München, Germany
E-mail: Paul.Knochel@cup.uni-muenchen.de
PSP
Received 9 October 2001
No
1
Abstract: Functionalized magnesium reagents have been prepared via an iodine-magnesium exchange. These reagents can be either
trapped directly with aldehydes or transmetallated to copper or zinc to participate in cross-coupling reactions. The iodine-magnesium ex-
change, represent a unique method for the preparation of aryl and heteroaryl magnesium reagents.
Key words: functionalized magnesium reagents, iodine-magnesium exchange, cross-coupling, palladium
CHO
OH
I
MgBr
3
i-PrMgBr
NC
Procedure 1
-20 °C, 1 h
-20 °C, 0.5 h
CN
MeO2C
CO2Me
CO2Me
2
1
4: 83%
N
N
N
1) CuCN·2LiCl
-20 °C, 15 min
i-PrMgBr
MgBr
I
Procedure 2
CO2Et
-20 °C, 1 h
CO2Et
2)
Br
CO2Et
CO2Et
CO2Et
8: 81%
7
-20 - 25 °C, 12 h
6
5
Ph
Ph
Ph
CN
N
N
N
I
MgBr
1) ZnBr2, -20 °C, 15 min
i-PrMgBr
Procedure 3
-20 °C, 1h
2) Pd(dba)2 (10 mol%)
tfp (20 mol%)
25 °C, 16 h
CO2Et
CO2Et
CO2Et
I
9
10
12: 74%
11
NC
Scheme 1
bine a good functional group tolerance with an intrinsic
high reactivity. By performing various stoichiometric or
Introduction
Polyfunctional organometallic reagents are important catalytic transmetallations, this reactivity can be fine-
building blocks for the synthesis of complex target mole- tuned, allowing optimum reaction conditions with numer-
cules.1 In particular, organozinc reagents are known to tol- ous classes of electrophiles.
erate a wide range of functional groups.1,2 Recently, we
have shown that a halogen-magnesium exchange3 allows
the preparation of arylmagnesium halides bearing sensi- Scope and limitations
tive functional groups such as an ester4, nitrile, or imine5
function. These unsaturated organometallic reagents com- The mild conditions required for performing the iodine- or
bromine-magnesium exchange6,7 are compatible with sev-
eral sensitive functionalities on the aryl halide. Thus, an
ester or nitrile group is compatible with the generation of
an arylmagnesium reagent via an iodine-magnesium ex-
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
1437-210X,E;2002,0,04,0565,0569,ftx,en;E50101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

566
A. E. Jensen et al.
PRACTICAL SYNTHETIC PROCEDURES
change, which is complete at –20 °C within a few hours. the ring increases to such an extent that no second ex-
Under these mild conditions, no attack on the ester or ni- change occurs (Scheme 2).
trile group occurs (Scheme 1).
1) i-PrMgBr
I
I
I
Br
THF : NBP (5 : 1)
-35 °C, 1 h
HO
c-Hex
MgBr
I
N
N
N
N
CH2OEt
CH2OEt
i-PrMgBr
2) (BrCl2C)2
c-HexCHO
Me
Me
85 %
-35 °C, 1.5 h
THF, -20 °C
30 min
CO2Me
CO2Me
CO2Me
72 %
1) i-PrMgBr
Br
Br
Br
-10 °C, 1.5 h
CH2OEt
O
Br
Et
O
NMe2
N
N
2) CuCN•2LiCl cat.
Br
NMe2
N
N
78 %
i-PrMgCl
Mg
CuCN•2 LiCl
Br
O
OCH2OEt
-30 °C, 2 h
NC
NC
Scheme 3 Selective chelate directed halogen-magnesium
NC
exchange.
80 %
Scheme 2 Low temperature halogen-magnesium exchange.
Polyfunctional aryl- and heteroaryl-magnesium reagents
may readily undergo cyclization reactions9 with suitable
electrophiles, allowing the preparation of polyfunctional
heterocycles (Scheme 4). Remarkably, the iodine-magne-
sium exchange can be extended to the preparation of func-
tionalized alkenylmagnesium10 or cyclopropylmag-
nesium11 species (Scheme 5).
The rate of the iodine-magnesium exchange is significant-
ly slower than the iodine-lithium exchange,8 and it is ob-
served that the nature of the aromatic or heteroaromatic
ring strongly influences the rate of the exchange. The
more electron-poor the aromatic ring, the faster is the ex-
change reaction. Also, the presence of chelating groups
ortho- to the carbon-halogen bond strongly accelerates the
exchange and allows the bromine-magnesium exchange
to take place under milder conditions than usual. In gener-
al, iodine-magnesium exchange reactions are consider-
ably faster than the corresponding bromine-magnesium
exchange (Scheme 2). Selective mono-halogen-magne-
sium exchanges are observed with diiodo- or dibromo-ar-
omatics. After the first exchange, the electron density of
Functionalized arylmagnesium reagents readily partici-
pate in various transition metal catalyzed cross-coupling
reactions.12,13 Thus, 2-chloropyridines undergo exception-
ally fast Pd(0)-catalyzed cross-couplings with functional-
ized arylmagnesium compounds. The high reaction rate
may be explained by the formation of intermediate palla-
dates.13 Benzylic bromides and primary alkyl iodides un-
dergo Cu(I)-mediated cross-couplings under mild
conditions (Scheme 6).12
COOMe
COOMe
I
COOMe
i-PrMgBr
Ph
N C O
Cl
Cl
MgX
N
Ph
-30 °C, 1 h
-10 °C to rt
O
75 %
Me
Ph
Ph
N
N
1) i-PrMgBr
THF, -10 °C, 3h
N
N
NH2
I
THF, HCl concd
rt, 16h
OMe
2) CuCN·2 LiCl
OMe
N
H
3)
Br
71 %
68 %
Ph
Ph
Scheme 4 Selective synthesis of functionalized heterocycles using functionalized Grignard-reagents.
CO2Et
CO2Et
I
CO2Et
MgBr
CuCN·2LiCl
i-PrMgBr
CO2Et
Br
-20 °C, 0.5 h
NC
CO2Et
NC
NC
70 %; E : Z > 99 : 1
H
H
H
H
H
H
1) CuCN·2 LiCl
i-PrMgCl
Et
Et
2) PhCOCl
I
EtO2C
-40 °C, 15 min
Mg
Ph
O
Cl
O
O
O
O
73 %
Scheme 5 Preparation of functionalized alkenyl- and cyclopropyl-magnesium reagents.
Synthesis 2002, No. 4, 565–569 ISSN 0039-7881 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Preparation of Functionalized Arylmagnesium Reagents
567
with magnesium turnings (10.8 g, 450 mmol), which were covered
with anhyd THF (50 mL). Then 2-bromopropane (18.5 g, 150
mmol) was added dropwise at r.t. in THF (200 mL). After stirring
overnight, the dropping funnel was replaced by a rubber septum. To
separate the reagent from the remaining magnesium turnings, the
Grignard solution was transferred via a transfer-needle into another
dry, argon flushed, 500 mL Schlenk flask equipped with a rubber
septum. For storage of the iso-propylmagnesium bromide solution,
the rubber septum was replaced by a glass stopper. The concentra-
tion of i-PrMgBr was determined by the method of Paquette.19
COOEt
COOEt
COOMe
Cl
N
N
Pd(dba)2 cat.
dppf cat.
MeOOC
MgCl
MgBr
95 %
-40 °C, 6 h
CuCN·2LiCl
(20 mol%)
CO2Me
Ethyl 4-(N,N-Diallylamino)-3-iodobenzoate (5)16
-5 °C, 24 h
CF3
A 250 mL round-bottom flask, equipped with a magnetic stirring
bar and a reflux condenser, was charged with ethyl 4-aminoben-
zoate (5.8 g, 20 mmol), allyl bromide (14.3 mL, 160 mmol) and
Na2CO3 (8.5 g, 80 mmol). DMF (150 mL) was added and the reac-
tion mixture was heated to 100 °C. After completion (6 h, moni-
tored by TLC analysis) the reaction mixture was cooled to r.t. and
poured into water (100 mL), extracted with Et2O (3 100 mL),
dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by flash chromatography (pentane–Et2O, 20:1, 200 g
Merck Silica 60, 0.040–0.060 mm) to yield 7 as a pale yellow oil
(5.6 g, 76%).
CF3
CO2Me
71 %
CH2Br
Scheme 6 Pd(0) and Cu(I)-mediated cross-coupling of functionali-
zed arylmagnesium reagent.
In summary, the iodine- or bromine-magnesium exchange
considerably expands the scope of the preparation of func-
tionalized organomagnesium compounds. A range of new
Grignard reagents bearing various electron-withdrawing
groups can be obtained by these methods. Many of these
reagents are excellent precursors for performing ring clo-
sure reactions. Increasingly, applications in both complex
natural product synthesis14 and industrial processes are
being reported in the literature.15
IR (KBr): 2980 (m), 1716 (s), 1590 (s), 1285 (s), 1252 (s), 1112 (m)
cm–1.
1H NMR (300 MHz, CDCl3): = 8.44 (d, J = 1.8 Hz, 1 H), 7.86 (dd,
J = 1.8, 8.4 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 5.77–5.68 (m, 2 H),
5.13–5.04 (m, 4 H), 4.24 (q, J = 7.1 Hz, 2 H), 3.64–3.61 (m, 4 H),
1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 165.4, 141.0, 135.1, 130.2, 127.1,
123.2, 118.6, 97.7, 61.6, 55.8, 14.7.
MS (EI, 70 eV): m/z (%) = 371 (41), 326 (21), 244 (100), 130 (44).
Procedures
Anal. Calcd for C15H18O2NI: C, 48.53; H, 3.77; N, 4.89. Found: C,
48.15; H, 3.69; N, 4.80.
Herein, we describe three typical synthetic procedures
demonstrating the synthetic scope of functionalised orga-
nomagnesium compounds. In Procedure 1, we report the
preparation of p-carbomethoxyphenylmagnesium bro-
mide 1 starting from commercially available methyl 4-io-
dobenzoate (2) and its direct addition to a functionalized
aromatic aldehyde, 4-cyanobenzaldehyde (3) leading to
the polyfunctional benzhydryl alcohol 4 in 83% yield. In
the second procedure (Procedure 2) the iodoaniline
derivative16 5, having the amino group protected as a dial-
lyl derivative, is converted to the corresponding aminated
Grignard reagent 6. This magnesium reagent is then trans-
metallated to the corresponding copper derivative and al-
lylated with ethyl (2-bromomethyl)acrylate17 (7), leading
to the polyfunctional aniline 8 in 81% yield. In the last
procedure (Procedure 3), a different amino protecting
group (imine) is used in the substrate and a subsequent
palladium(0)-catalyzed cross-coupling is described. The
iodoimine18 9 is readily converted to the magnesium de-
rivative 10, transmetallated to the corresponding zinc re-
agent and coupled in the presence of Pd(0) with 4-
iodobenzonitrile 11, leading to the functional biaryl 12 in
74% yield.
Ethyl 4-Amino-3-iodobenzoate20
To a 250 mL round-bottom flask, equipped with a magnetic stirring
bar, charged with iodine (5.0 g, 20 mmol) and silver sulfate (6.22 g,
20 mmol) EtOH (100 mL) was added. Ethyl 4-aminobenzoate (3.30
g, 20 mmol) was then added and the reaction mixture was vigorous-
ly stirred until complete conversion (30 min, monitored by TLC
analysis). The reaction mixture was filtered through a glass sinter
and concentrated in vacuo. The residue was then taken up in CH2Cl2
(100 mL), washed twice with 5% NaOH solution (75 mL), dried
over Na2SO4, and concentrated in vacuo. The crude product was pu-
rified by flash chromatography (pentane–Et2O, 9:1, 200 g Merck
Silica 60, 0.040–0.060 mm) yielding ethyl 4-amino-3-iodobenzoate
as an off-white powder (5.5 g, 94% yield); mp 83 °C.
IR (KBr): 3661 (m), 1687, (s), 1612 (s), 1590 (m), 1286 (s), 1248
(s) cm–1.
1H NMR (300 MHz, CDCl3): = 8.25 (d, J = 1.8 Hz, 1 H), 7.73 (dd,
J = 1.8, 8.4 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 4.43 (br s, 2 H), 4.24
(q, J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 165.7, 151.0, 141.3, 131.3, 121.9,
113.5, 82.5, 61.1, 14.8.
MS (EI, 70 eV): m/z (%) = 291 (80), 263 (31), 246 (100), 218 (9),
91 (16).
Anal. Calcd for C9H10O2NI: C, 37.14; H, 3.46; N, 4.81. Found: C,
37.11; H, 3.45; N, 4.81.
Ethyl 3-Iodo{[(E)-phenylmethylidene]amino}benzoate (9)18
Ethyl 4-amino-3-iodobenzoate (8.73 g, 30 mmol) was dissolved in
anhyd toluene (60 mL), then benzaldehyde (3.82 g, 36 mmol) and
iso-Propylmagnesium Bromide
A dry, argon flushed, 500 mL round-bottom flask, equipped with a
magnetic stirring bar and a 200 mL dropping funnel, was charged
Synthesis 2002, No. 4, 565–569 ISSN 0039-7881 © Thieme Stuttgart · New York

568
A. E. Jensen et al.
PRACTICAL SYNTHETIC PROCEDURES
concd H2SO4 (a few drops) were added and the mixture heated to re-
flux with a Dean–Stark head and condenser until no more water was
separated (approx. 2 h). The solution was filtered and concentrated
in vacuo. Excess benzaldehyde was distilled off at 100 °C under
vacuum using an oil pump, the resulting yellow oil crystallized
upon standing. Recrystallization from Et2O yielded the product as
yellow needles. Yield (9.98 g, 87%); mp 73 °C.
0.040–0.060 mm) yielding the amine 8 as a pale yellow oil (868 mg,
81%).
IR (KBr): 2981 (w), 1715 (s), 1605 (m), 1250 (m) cm–1.
1H NMR (300 MHz, CDCl3): = 7.78–7.72 (m, 2 H), 6.98 (d,
J = 8.4 Hz, 1 H), 6.18 (d, J = 1.5 Hz, 1 H), 5.71–5.62 (m, 2 H), 5.27
(d, J = 1.5 Hz, 1 H), 5.11–5.01 (m, 4 H), 4.26 (q, J = 7.1 Hz, 2 H),
4.12 (q, J = 7.1 Hz, 2 H), 3.67 (s, 2 H), 3.54 (s, 2 H), 3.52 (s, 2 H),
1.28 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 166.9, 166.5, 154.4, 139.9, 134.4,
133.7, 132.2, 128.2, 125.9, 124.9, 121.9, 177.4, 60.6, 60.5, 55.6,
33.1, 14.3, 14.1.
IR (KBr): 3436 (m), 1702 (s), 1626 (s), 1578 (s), 1290 (s), 1252 (s)
cm–1.
1H NMR (CDCl3, 300 MHz): = 8.46 (d, J = 1.8 Hz, 1 H), 8.19 (s,
1 H), 7.91 (dd, J = 1.8, 8.1 Hz, 1 H), 7.87 (m, 2 H), 7.44 (m, 3 H),
6.89 (d, J = 8.1 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 1.31 (t, J = 7.1
Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 357 (4), 316 (100), 286 (79), 242 (44),
168 (25), 115 (18).
13C NMR (CDCl3, 75 MHz): = 165.3, 162.2, 157.4, 140.7, 135.8,
132.6, 131.3, 129.7, 129.2, 127.5, 118.5, 94.0, 61.6, 14.8.
Anal. Calcd for C21H27O4N: C, 70.56; H, 7.61; N, 3.92. Found: C,
70.42; H, 7.68; N, 3.86.
MS (EI, 70 eV): m/z (%) = 379 (100), 350 (19), 334 (40), 178 (17).
Anal. Calcd for C16H14O2NI: C, 50.68; H, 3.72; N, 3.69. Found: C,
50.60; H, 3.76; N, 3.65.
Ethyl 4 -Cyano-6-{[(E)-phenylmethylidene]amino}[1,1’-biphe-
nyl]-3-carboxylate (12)
A dry, argon flushed 25 mL round-bottom flask, equipped with a
magnetic stirring bar was charged with the imine 9 (1.11 g, 3 mmol)
in anhyd THF (3 mL) and cooled to –20 °C. i-PrMgBr (3.0 mL, 1.3
M in THF, 3.9 mmol) was slowly added. After 1 h the exchange was
complete (monitored by TLC analysis) and ZnBr2 (2.0 mL, 1.5 M
in THF (3 mmol)) was added. The reaction mixture was allowed to
warm to r.t. Another dry, argon flushed 25 mL flask, equipped with
Methyl 4-[(4 -Cyanophenyl)(hydroxy)methyl]benzoate (4)
A dry and argon flushed 50 mL round-bottom flask, equipped with
a magnetic stirring bar, was charged with methyl 4-iodobenzoate (2:
788 mg, 3 mmol) in anhyd THF (6 mL) and cooled to –20 °C. i-
PrMgBr (6.2 mL, 0.54 M in THF, 3.3 mmol) prepared as described
above, was slowly added. After 1 h, the exchange was complete (as
indicated by GC analysis of reaction aliquots) and 4-cyanobenzal-
dehyde (3: 584 mg, 4.5 mmol) was added as a solution in THF (4
mL). The reaction mixture was allowed to warm to room tempera-
ture over 30 min. The reaction mixture was quenched with MeOH
(3 mL), poured into water (150 mL) and extracted with EtOAc
(3 100 mL). The combined organic fractions were washed with
brine (100 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (pentane–
EtOAc, 70:30, 50 g Merck Silica 60, 0.040–0.063 mm) yielding the
alcohol 5 as a white solid. Yield (668 mg, 83%); mp: 153 °C.
21
a magnetic stirring bar, was charged with Pd(dba)2 (87 mg, 0.15
mmol) and tfp21 (69 mg, 0.30 mmol) in anhyd THF (3 mL). After
formation of the active catalyst (indicated by a slight colour change
of the solution from red to yellow) 4-iodobenzonitrile (11; 481 mg,
2.1 mmol) was added followed by the zinc reagent, via syringe. The
reaction mixture was stirred at r.t. for 16 h, quenched with NH4Cl (5
mL), poured into water (50 mL) and extracted with Et2O (3 100
mL). The combined organic fractions were washed with brine (70
mL), dried over Na2SO4 and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (pentane–EtOAc–TEA,
20:1:1, 70 g Merck Silica 60, 0.040–0.060 mm) to yield the imine
12 as a pale yellow powder (581 mg, 74%); mp: 102 °C.
IR (KBr): 3514 (s), 2955 (w), 2227 (s), 1712 (s), 1604 (m), 1434
(m), 1294 (s), 1190 (m) cm–1.
IR (KBr): 3433 (m), 2229 (w), 1710 (s), 1627 (m), 1595 (s), 1578
(m), 1242 (s) cm–1.
1H NMR (CDCl3, 300 MHz): = 8.35 (s, 1 H), 8.00 (m, 2 H), 7.67
(m, 2 H), 7.54 (m, 4 H), 7.38 (m, 3 H), 7.03 (d, J = 9.0 Hz, 1 H),
4.31 (q, J = 7.1 Hz, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): = 166.4, 162.2, 153.8, 143.9, 136.1,
133.8, 132.5, 132.0, 131.8, 131.4, 131.2, 129.5, 129.3, 128.6, 119.6,
119.4, 111.3, 61.6, 14.8.
1H NMR (300 MHz, CDCl3): = 7.73 (d, J = 8.4 Hz, 2 H), 7.39 (d,
J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2
H), 5.63 (s, 1 H), 5.08 (bs, 1 H), 3.67 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 166.0, 149.1, 148.4, 131.5, 129.1,
128.6, 126.7, 126.0, 118.2, 110.2, 73.8, 51.4.
MS (EI, 70 eV): m/z (%) = 267 (9), 252 (4), 236 (19), 208 (28), 190
(20), 163 (42), 137 (100), 130 (52), 104 (31), 77 (25).
Anal. Calcd for C16H13O3N: C, 71.90; H, 4.90; N, 5.24. Found: C,
71.81; H, 4.74; N, 5.12.
MS (EI, 70 eV): m/z (%) = 354 (41), 277 (100), 249 (46), 177 (12).
HRMS calcd for C23H18O2N2: 354.1368. Found: 354.1357.
Ethyl 4-(N,N-Diallylamino)-3-[2-(ethoxycarbonyl)-2-prope-
nyl]-benzoate (8)
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A dry, argon flushed 25 mL round-bottom flask, equipped with a
magnetic stirring bar, was charged with amine 5 (1.11 g, 3 mmol) in
anhyd THF (3 mL) and cooled to –20 °C. i-PrMgBr (3 mL, 1.3 M
in THF, 3.9 mmol) was slowly added. After 1 h, the exchange was
complete (as indicated by TLC analysis). CuCN 2LiCl (3.0 mL,
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concentrated in vacuo. The crude product was purified by flash
chromatography (pentane–EtOAc, 95:5, 70 g Merck Silica 60,
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(7) For alternative preparations of functionalized
arylmagnesium reagents: (a) Lee, J.; Velarde-Ortiz, R.;
Guijairo, A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000,
65, 5428. (b) Kitagawa, K.; Inoue, A.; Shinokubo, H.;
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(8) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404;
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(9) Delacroix, T.; Bérillon, L.; Cahiez, G.; Knochel, P. J. Org.
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(10) Sapountzis, I.; Dohle, W.; Knochel, P. Chem. Commun.
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Synthesis 2002, No. 4, 565–569 ISSN 0039-7881 © Thieme Stuttgart · New York