Synthesis and reactivity of aryl- and heteroaryl-magnesium reagents bearing keto groups

Article abstract of DOI:10.1055/s-2002-34865

The reaction of iodophenyl ketones with neo-pentylmagnesium bromide in THF or THF:NMP or THF:DMAC mixtures allows the first preparation of aryl- and heteroarylmagnesium species bearing a ketone. Under appropriate conditions, these new reagents react with

Full text of DOI:10.1055/s-2002-34865

LETTER
1799
Synthesis and Reactivity of Aryl- and Heteroaryl-Magnesium Reagents
Bearing Keto Groups
A
F
ryl- and
H
ete
l
roaryl
o
r
R
eagent
i
s
with
a
eto
G
roup
n
s
Felix Kneisel, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
Fax +49(89)21807680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 8 August 2002
as S-methyl methanethiosulfonate, chlorotrimethylstan-
nane or ethyl (2-bromomethyl)acrylate, to give the de-
sired product (3b–d) in 57–81% yield (entries 2–4).
Abstract: The reaction of iodophenyl ketones with neo-pentylmag-
nesium bromide in THF or THF:NMP or THF:DMAC mixtures
allows the first preparation of aryl- and heteroarylmagnesium
4
species bearing a ketone. Under appropriate conditions, these Although satisfactory yields were obtained, the need to
new reagents react with a range of electrophiles, leading to poly- use an excess of NpMgBr for performing the iodine-mag-
functional products.
nesium exchange due to very long reaction times encour-
Key words: functionalised organomagnesium reagents, iodine- aged us to examine alternative experimental conditions.
magnesium exchange, cross-coupling, palladium catalysis
We found that the use of a polar co-solvent like N-meth-
ylpyrrolidinone (NMP) or N,N-dimethylacetamide
(
DMAC) strongly accelerates the iodine-magnesium ex-
change and allowed the performance of this reaction with-
in several minutes, using stoichiometric amounts of
NpMgBr. Thus, the reaction of the ketone 1b with NpMg-
Br (1.1 equiv) in THF in the presence of NMP (10 equiv)
between –45 °C and –25 °C, led within 60 min to the com-
The preparation of functionalised organometallics is an
important synthetic task, since it allows expeditious ac-
cess to polyfunctional molecules upon reaction with vari-
ous electrophiles. Recently, we have found that various
functionalised organomagnesium compounds bearing an
1
ester, halide, amide or cyano group can be readily pre- plete formation of Grignard reagent 2b. Its treatment with
pared via an iodine-magnesium exchange mediated by i- ZnBr
(1.2 equiv) followed by the addition of methyl 4-io-
2
2
PrMgBr in THF. Herein, we wish to report an extension dobenzoate (0.9 equiv; 20 °C; overnight) in the presence
5
of this method to the preparation of aryl- and heteroaryl- of palladium(bis-benzylideneacetone) [Pd(dba) , 2.5
2
6
magnesium compounds bearing a keto group. Whereas 2- mol%] and tris-orthofurylphosphine (tfp, 5 mol%) gave
7
iodophenyl phenyl ketone (1a), upon treatment with i- the expected Negishi cross-coupling product (3e) in 60%
yield (entry 5). Using a similar procedure (Method B), the
Grignard reagent 2b was reacted with diphenyl disulfide,
affording the thioether 3f in 74% yield (entry 6). Interest-
ingly, this procedure can also be applied to aryl ketones
bearing an acidic proton at the -position. Thus cyclohex-
yl 2-iodophenyl ketone (1c) reacted cleanly with NpMgBr
PrMgBr, gave mainly the reduction product (2-iodophe-
nyl)phenylmethanol by hydride transfer, the use of neo-
3
pentylmagnesium bromide (NpMgBr) allowed the de-
sired iodine-magnesium exchange to take place. Thus, the
treatment of 1a with NpMgBr (2.25 equiv) in THF at –55
°
C resulted in the formation of the corresponding Grig-
nard reagent (2a) after 3 d at –50 °C (Method A; see (1.1 equiv) in THF–NMP (4:1) between –45 °C and –25
Scheme 1). Its treatment with S-methyl methanethiosul- °C during 60 min, affording the corresponding arylmag-
fonate (2.5 equiv; –50 °C to 20 °C; overnight) led to the nesium reagent 2c. Its transmetallation with ZnBr7
(1.2
2
expected 2-methylthiophenyl phenyl ketone (3a) in 63% equiv) and Pd(0)-catalyzed Negishi cross-coupling with
yield (entry 1 of Table 1).
methyl 4-iodobenzoate (0.9 equiv; 20 °C; overnight) fur-
nished the corresponding polyfunctional biphenyl 3g in
Similarly, reaction of 1-(2-iodophenyl)-2,2-dimethylpro-
pan-1-one (1b) provided the corresponding Grignard re-
agent (2b) which reacted with different electrophiles, such
6
4% yield (entry 7). Remarkably, this reaction can also be
used with the aromatic iodide 4, which is converted under
our standard conditions [Method B, THF–NMP (10
Br
I
O
E
O
Mg
O
NpMgBr (2.25 equiv)
E
R
R
R
THF, -55 °C to -50 °C, 3 d
(Method A)
1
2
3: 46-81 %
see Table 1)
(
Scheme 1
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1799,1802,ftx,en;G22002ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
©

1
800
F. F. Kneisel, P. Knochel
LETTER
O
O
O
i
ii
MeO2C
I
MeO2C
MgBr
MeO2C
CO2Et
4
5
6: 77 %
Scheme 2 Reagents and conditions: i) NpMgBr (1.1 equiv); THF–NMP (10 equiv), –50 °C to –40 °C, 0.5 h (Method B). ii) 1) ZnBr ; 2) ethyl
2
(
2-bromomethyl)acrylate (1.5 equiv); CuCN 2LiCl (20 mol%).
1
) NpMgBr (1.1 equiv)
THF:DMAC
80 °C, 1 h
O
O
O
-
S
S
S
I
D
+
2) AcOD, -78 °C
D
8a
8b
7
8a : 8b (92:8); 78 %
Scheme 3
equiv); NpMgBr (1.1 equiv); –50 °C to –40 °C; 30 min) References
to the polyfunctional magnesium reagent 5. After trans-
(
1) (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 4415. (b) Knochel, P.;
Millot, N.; Rodriguez, A. L.; Tucker, C. E. Organic
Reactions, Vol. 58; Overman, L. E., Ed.; Wiley & Sons Ltd.:
New York, 2001, 417.
2) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu,
V. A.; Knochel, P. Synthesis 2002, 565.
3) (a) Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.;
Fournioux, X. Synlett 2001, 927. (b) Yuan, T.-M.; Yeh, S.-
M.; Hsieh, Y.-T.; Luh, T.-Y. J. Org. Chem. 1994, 59, 8192.
metallation to the corresponding zinc reagent with ZnBr2
(
1.2 equiv), allylation with ethyl (2-bromometh-8
4
yl)acrylate (1.5 equiv) in the presence of CuCN·2LiCl
20 mol%; –25 °C to 20 °C; 3 h) led to the ketone 6 in 77%
(
(
(
yield (Scheme 2). The extent of enolate formation is neg-
ligible in this case.
However, in the case of 2-acetyl-5-iodothiophene (7) a
significant amount of the magnesium enolate is formed.
Thus, the reaction of 7 with NpMgBr (1.1 equiv) in THF
containing DMAC (10 equiv) at –80 °C for 60 min led, af-
ter deuteration with AcOD, to a 92:8 mixture of the two
deuterated thiophene isomers (8a,b) in 78% isolated yield
(c) Tuckmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber.
1986, 119, 1581. (d) Tamura, M.; Kochi, J. K. Bull. Chem.
Soc. Jpn. 1971, 44, 3063.
(
(
4) Villieras, J.; Rambaud, M. Synthesis 1982, 11, 924.
5) Takahashi, Y.; Ito, T.; Sakai, S.; Ishii, Y. Chem. Comm.
(
Scheme 3).
1970, 1065.
(
(
6) Allen, D. W.; Hutley, B. G.; Mellor, M. T. J. J. Chem. Soc.,
Perkin Trans. 2 1972, 63.
7) (a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Negishi,
E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
Nevertheless, 2-acyl-5-iodothiophenes and 2-butyryl-5-
iodothiophene (9), as well as 2-butyryl-5-iodofurane (10)
were converted to the corresponding Grignard reagent 11
and 12 (entries 8 and 9) and reacted respectively with
chlorotrimethylstannane and ethyl (2-bromo-meth-
yl)acrylate in the presence of CuCN·2LiCl, leading to
the desired products 13 and 14 in 60% and 46% yields (en-
tries 8 and 9).
102, 3298. (c) Kobayashi, M.; Negishi, E. J. Org. Chem.
1980, 45, 5223. (d) Tamaru, Y.; Ochiai, H.; Nakamura, T.;
Yoshida, Z. Tetrahedron Lett. 1986, 27, 955. (e) Klement,
I.; Rottländer, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.;
Venegas, P.; Cahiez, G. Tetrahedron 1996, 52, 7201.
8) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
4
8
(
In summary, we have developed a method allowing the
preparation of arylmagnesium species bearing a keto
group. Extensions of this method are currently underway.9
(9) Typical procedures: (a) Preparation of 2-[2-(2,2-
dimethylpropionyl)-benzyl]-acrylic acid ethyl ester (3d)
using Method A (entry 4 of Table 1):
A dry and argon flushed 50 mL Schlenk tube, equipped with
a septum and a magnetic stirrer was charged with 1-(2-
iodophenyl)-2,2-dimethylpropan-1-one(1b) (288 mg, 1.0
mmol) in dry THF (0.5 mL). The solution was cooled to –50
Acknowledgement
We thank the Fonds der Chemischen Industrie for a Kekulé
scholarship to F. F. K. We thank the BASF AG, Degussa AG and
Chemetall GmbH for generous gifts of chemicals.
°
C and NpMgBr (3.6 mL, 0.6 M in THF, 2.25 mmol) was
slowly added. The pale yellow mixture was stirred for 3 d at
40 °C until GC-analysis of a reaction aliquot indicated
complete iodine-magnesium exchange. Then CuCN 2LiCl
2.3 mL, 1.0 M in THF, 2.3 mmol) was slowly added. After
–
8
(
Synlett 2002, No. 11, 1799–1802 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Aryl- and Heteroaryl-Magnesium Reagents Bearing Keto Groups
1801
Table 1 Products of Type 3 and 13,14 Obtained by the Reaction of the Magnesium Species 2, Generated with NpMgBr from the Aryl- or
Heteroaryl- Iodides 1 or 11,12 in THF (Method A), or in THF–NMP or THF–DMAC (Method B)
Entry
1
Grignard Reagent 2
Methoda Electrophile
Product of Type 3
Yield (%)b
63
BrMg
BrMg
2b
O
2a
2b
A
A
A
A
MeSSO Me
2
MeS
MeS
3
O
3a
3b
3c
3d
Ph
Ph
2
3
4
O
MeSSO Me
O
63
57
81
2
t-Bu
t-Bu
Me SnCl
Me Sn
O
3
t-Bu
2b
CO Et
2
CO Et
2
Br
O
t-Bu
5
2b
B
I
CO2Me
3e
60
O
CO2Me
t-Bu
6
7
2b
B
B
PhSSPh
PhS
O
3f
74
64
t-Bu
BrMg
O
2c
I
CO Me
2
3g
O
CO2Me
8
9
11
12
B
B
Me SnCl
13
60
46
3
n-Pr
n-Pr
n-Pr
MgBr
MgBr
SnMe3
S
S
O
O
CO Et
2
14
n-Pr
Br
CO2Et
O
O
O
O
a
Method A: NpMgBr (2.25 equiv), THF, –50 °C to –40 °C, 3 d; Method B: NpMgBr (1.1 equiv), THF–NMP or THF–DMAC (4:1), –80 °C to
–
40 °C, 0.5 h to 1 h.
b
Yield of analytically pure product.
4
1
2
5 min, ethyl (2-bromomethyl)acrylate (500 mg, 0.35 mL,
.5 mmol) was added and the reaction mixture was allowed
benzyl]acrylic acid ethyl ester (3d) as a clear oil (215 mg,
81%). (b) Preparation of 2,2-dimethyl-1-(2-phenylthio-
phenyl)-propan-1-one (3f) using Method B (entry 6 of
Table 1):
to warm up to room temperature overnight. After quenching
with sat. aq NH Cl (5 mL), the aqueous phase was extracted
4
with dichloromethane (3 30 mL) and the combined organic
phases were dried with sat. aq. NaCl and concentrated in
vacuo. The residue was purified by flash chromatography
A dry and argon flushed 10 mL Schlenk flask, equipped with
a septum and a magnetic stirrer, was charged with 1-(2-
iodophenyl)-2,2-dimethylpropan-1-one (1b) (145 mg, 0.5
mmol) in dry THF (0.5 mL). The solution was cooled to
(
95:5 pentane/ether) yielding 2-[2-(2,2-dimethylpropionyl)-
Synlett 2002, No. 11, 1799–1802 ISSN 0936-5214 © Thieme Stuttgart · New York

1
802
F. F. Kneisel, P. Knochel
LETTER
–
45 °C and NpMgBr (1.0 mL, 0.6 M in THF, 0.6 mmol),
A dry and argon flushed 50 mL Schlenk tube, equipped with
a septum and a magnetic stirrer, was charged with 2-butyryl-
5-iodothiophene (9) (280 mg, 1.0 mmol) in dry THF (5 mL)
and DMAC (1.0 mL). The reaction mixture was cooled to
–90 °C and NpMgBr (2.0 mL, 0.6 M in THF, 1.2 mmol) was
slowly added. The mixture was rapidly stirred for 1 h at –78
°C with formation of a white precipitate.
then NMP (0.5 mL) were slowly added. The yellow mixture
was rapidly stirred and warmed up to –25 °C within 15 min,
with formation of a sticky, brownish precipitate. At this
temperature, GC-analysis of a reaction aliquot indicated
complete iodine-magnesium exchange. Diphenyl disulphide
(220 mg, 1.0 mmol) was added. The reaction mixture was
stirred for 8 h and slowly warmed up to room temperature.
GC-analysis indicated complete conversion. After
Chlorotrimethylstannane (2.0 mL, 1.0 M in THF, 2.0 mmol)
was slowly added and the reaction mixture was allowed to
warm up to room temperature over 12 h. The reaction
quenching with sat. aq NH Cl (3 mL), the aqueous phase
4
was extracted with dichloromethane (3 20 mL) and the
combined organic phases were dried with sat. aq. NaCl and
concentrated in vacuo. The residue was purified by flash
chromatography (95:5 pentane/ether), yielding 2,2-
dimethyl-1-(2-phenylthiophenyl)-propan-1-one (3f) as a
clear oil (99 mg, 74%). (c) Preparation of 1-(5-
trimethylstannylthiophen-2-yl)-butan-1-one (13) using
Method B (entry 8 of Table 1):
mixture was quenched by the addition of sat. aq. NH Cl (5
4
mL). The aqueous phase was extracted with
dichloromethane (3 30 mL) and the combined organic
phases were dried with sat. aq NaCl and concentrated in
vacuo. The residue was purified by flash chromatography
(95:5 pentane/ethyl acetate), yielding 1-(5-trimethylstannyl-
thiophen-2-yl)-butan-1-one (13) as a clear liquid (190 mg,
60%).
Synlett 2002, No. 11, 1799–1802 ISSN 0936-5214 © Thieme Stuttgart · New York