Preparation of highly functionalized heterocyclic zinc organometallics via a Li(acac)-catalysis of the I/Zn-exchange reaction

Article abstract of DOI:10.1055/s-2004-837206

The reaction of i-Pr₂Zn in the presence of catalytic amount of Li(acac) in NMP with various functionalized heterocyclic iodides provides new polyfunctional diheteroarylzincs, which undergo smooth Negishi cross-coupling reactions and CuCN-2LiCl-

Full text of DOI:10.1055/s-2004-837206

LETTER
267
Preparation of Highly Functionalized Heterocyclic Zinc Organometallics via a
Li(acac)-Catalysis of the I/Zn-Exchange Reaction
Preparation of
H
i
ighly
u
Functionalize
-
d Heter
o
Z
cyclic
Z
inc
O
r
h
ganometallic
u
s
Gong,1 Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 13 October 2004
i-Pr2Zn, Li(acac) (10 mol%)
Abstract: The reaction of i-Pr2Zn in the presence of catalytic
amount of Li(acac) in NMP with various functionalized hetero-
cyclic iodides provides new polyfunctional diheteroarylzincs,
which undergo smooth Negishi cross-coupling reactions and
CuCN·2LiCl-catalyzed allylation reactions under mild conditions.
Remarkably, even an aldehyde function can be present in the di-
organozinc reagents.
ArI
Ar2Zn
Et2O, NMP, r.t.
1
4
Li(acac)
O
Zn
O
Ar
ArZni-Pr
Li
Key words: polyfunctional heterocycles, iodine–zinc exchange
reaction, diorganozinc reagent, catalysis, cross-coupling
i-Pr
2
3
Scheme 1 Li(acac)-catalysis of the iodine-zinc exchange
The preparation of polyfunctionalized heterocycles is a
major synthetic task since many heterocycles are biologi-
cally active compounds.2 The use of metalated hetero- CuCN·2LiCl (20 mol%),8 it reacts with 3-iodo-cyclohex-
cyclic building blocks for the preparation of complex 2-enone to give 7c in 60% yield (entry 2). Only a mono-I/
heterocycles has been a very successful approach.3 Mostly Zn-exchange takes place with 3,5-diiodo-4-methoxypyri-
lithiation or magnesiation reactions have been performed, dine (5b), leading to the zinc reagent 6b. Its reaction with
which precludes the presence of sensitive functionalities ethyl (2-bromomethyl)acrylate9 in the presence of
like a ketone or an aldehyde.4 Recently, we have found CuCN·2LiCl8 leads to the allylated product 7d in 61%
that the addition of catalytic amount of Li(acac) catalyzes yield (entry 4). The bis-allylated 5-iodouracil (5c) pro-
the I/Zn-exchange reaction and allows the preparation of vides under our typical conditions the diorganozinc 6c,
diarylzincs bearing various sensitive functionalities in- which reacts under Pd(0)-catalysis with methyl 4-iodo-
cluding an aldehyde, a ketone or an isothiocyanate.5 In the benzoate giving the arylated uracil 7e in 58% yield (entry
absence of Li(acac), the reaction of i-Pr2Zn with an aryl 5). Electron-rich hetereocycles such as indole derivatives
iodide (ArI, 1) produces only the mixed diorgano zinc react smoothly. Thus, 3-iodo-1-phenylsulfonylindole
species ArZni-Pr (2). In the presence of Li(acac), an inter- (5d)10 furnishes the diorganozinc 6d, which is allylated to
mediate zincate 3 is formed allowing the transfer of the furnish the 3-allylindole 7f in 70% yield (entry 6). A
second isopropyl rest and leading to the diarylzinc product selective mono-I/Zn exchange is also observed with 2,3-
Ar2Zn (4), see Scheme 1.
diiodo-1-phenylsulfonylindole11 providing selectively12
the 2-zincated 3-iodoindole derivative 6e, which after al-
lylation provides the 3-iodoindole derivative 7g in 84%
yield (entry 7). Similarly, 3-iodoindazoles13 are readily
converted to the corresponding diorganozincs 6f–i and re-
act with typical electrophiles leading to the products 7h–
k in 69–78% yields (entries 8–11). Of special interest is
the Pd-catalyzed cross-coupling of 6f with methyl 5-bro-
mo-2-furoate leading to the heterocycle 7h in 78% yield.14
The LiBH4 reduction of 7h provides an NO-independent,
superoxide-sensitive activator of soluble guanylate cyclax
(YC-1).14
Herein, we wish to report that this catalyzed I/Zn-ex-
change reaction can be successfully applied for the prepa-
ration of a broad range of heterocyclic diorganozincs
bearing sensitive functional groups including an alde-
hyde.
We have first examined electron-deficient heterocycles
such as 3-iodopyridine (5a). Its reaction with i-Pr2Zn
(0.55 equiv) in the presence of Li(acac) (10 mol%) in
NMP (N-methylpyrrolidine) at room temperature (12 h)
provides the desired diheteroarylzinc 6a. Its reaction with
various aryl iodides (1.5 equiv) in the presence of
Pd(dba)2 (2.5 mol%) and tri(o-furyl)phosphine (5 mol%)6
leads to the cross-coupling products7 7a,b in 76–83%
yields (entries 1, 2 of Table 1). In the presence of
Interestingly, 5-iodothienyl-2-aldehyde (8) and 5-iodo-2-
furaldehyde (11) are converted under our standard condi-
tions to the zinc reagents 9 and 12 which were respective-
ly allylated with ethyl (2-bromomethyl)acrylate and
cross-coupled with methyl 4-iodobenzoate, leading to the
functionalized aldehydes 10 and 13, respectively, in 71%
and 70% yields (Scheme 2).
SYNLETT 2005, No. 2, pp 0267–0270
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837206; Art ID: G41404ST
0
1.
0
2.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

268
L.-Z. Gong, P. Knochel
LETTER
Table 1 Preparation of Heterocyclic Diorganozincs of Type 6 and their Reaction with Electrophiles
Entry
1
Zinc reagent of type 6
Electrophile
Product of type 7
Yield (%)a
Zn
CO2Me
83b
CO2Me
2
N
6a
N
I
7a
2
3
76b
60c
Zn
CHO
2
N
I
CHO
O
6a
N
7b
Zn
O
2
N
I
6a
N
7c
4
5
61c
58b
CO2Et
Br
OMe
OMe
N
I
Zn
I
2
CO2Et
N
6b
7d
CO2Me
O
CO2Me
O
Allyl
Zn
N
Allyl
N
2
O
N
O
N
I
Allyl
Allyl
6c
7e
6
70c
Br
Zn
2
N
N
SO2Ph
SO2Ph
6d
7f
7
8
84c
CO2Et
Br
I
I
CO2Et
Zn
2
N
N
SO2Ph
SO2Ph
6e
6f
7g
78b
OMe
O
Br
Zn
2
O
O
N
MeO2C
N
Bn
N
N
Bn
7h
7i
9
69c
Br
Zn
2
N
N
N
N
Bn
Bn
6g
Synlett 2005, No. 2, 267–270 © Thieme Stuttgart · New York

LETTER
Preparation of Highly Functionalized Heterocyclic Zinc Organometallics
269
Table 1 Preparation of Heterocyclic Diorganozincs of Type 6 and their Reaction with Electrophiles (continued)
Entry
10
Zinc reagent of type 6
Electrophile
Product of type 7
Yield (%)a
78b
CO2Me
MeO
CO2Me
MeO
Zn
2
N
N
I
N
N
Bn
6h
Bn
7j
11
76b
CO2Me
NC
CO2Me
NC
Zn
2
N
N
I
N
N
Bn
6i
Bn
7k
a Isolated yield of analytically pure product.
b In the presence of 2.5 mol% Pd(dba)2 and 5 mol% tfp.
c In the presence of 20 mol% CuCN·2LiCl.
CO2Et
Br
O
O
H
O
i-Pr2Zn (0.55 equiv)
S
S
H
S
H
Zn
I
2
Li(acac) (10 mol%)
NMP, r.t., 12 h
CuCN·2LiCl (20 mol%)
r.t., 12 h
EtO2C
10: 71%
9
8
CO2Me
O
O
O
i-Pr2Zn (0.55 equiv)
O
H
I
O
H
O
H
Zn
2
I
Li(acac) (10 mol%)
NMP, r.t., 12 h
Pd(dba)2 (2.5 mol%)
tfp (5 mol%)
CO2Me
r.t., 24 h
11
12
13: 70%
Scheme 2 Preparation and reactions of heteroarylzincs bearing an aldehyde function
In summary, we have shown that a range of new function-
(3) (a) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2293.
alized hetereocyclic diorganozincs can be prepared by a
Li(acac)-catalyzed I/Zn exchange reaction. Extensions of
this method are currently underway in our laboratory.15
(b) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V.
Org. Lett. 2003, 5, 1899. (c) Chauder, B.; Larkin, A.;
Snieckus, V. Org. Lett. 2002, 4, 815. (d) Chauder, B.;
Green, L.; Snieckus, V. Pure Appl. Chem. 1999, 71, 1521.
(e) Audoux, J.; Plé, N.; Turck, A.; Quéguiner, G.
Tetrahedron 2004, 60, 6353. (f) Rebstock, A.-S.; Mongin,
F.; Trécourt, F.; Quéguiner, G. Tetrahedron 2004, 60, 2181.
(g) Dumouchel, S.; Mongin, F.; Trécourt, F.; Quéguiner, G.
Tetrahedron 2003, 59, 8629. (h) Quéguiner, G. J.
Heterocycl. Chem. 2000, 37, 615.
Acknowledgment
We thank the Fonds der Chemischen Industrie and the DFG (KN
34716-1) for financial support. We thank Humboldt foundation for
a fellowship to L.-Z. G. We also thank BASF (Ludwigshafen) and
Chemetall (Frankfurt), for the generous gift of chemicals.
(4) For the preparation of some Grignard reagents with a keto
group, see: Kneisel, F. F.; Knochel, P. Synlett 2002, 1799.
(5) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int.
Ed. 2004, 43, 1017.
References
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Synlett 2005, No. 2, 267–270 © Thieme Stuttgart · New York

270
L.-Z. Gong, P. Knochel
LETTER
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(15) Typical Procedure for the Preparation of 4-Pyridin-3-yl-
benzoic Acid Methyl Ester (7a):
To a solution of 3-iodopyridine 5a (205 mg, 1.0 mmol) and
Li(acac) (11 mg, 0.1 mmol) in anhydrous and degassed NMP
(1 mL) was added i-Pr2Zn (5.0 M, 0.11 mL, 0.55 mmol)
dropwise at r.t. under argon. The reaction mixture was
stirred at r.t. for 12 h. The complete conversion of 3-
iodopyridine to the zinc reagent was monitored by GC
analysis. The zinc reagent 6a was treated with a solution of
Pd(bda)2 (14 mg, 0.025 mmol), tri(2-furyl)phosphine (12
mg, 0.05 mmol) and methyl 4-iodobenzoate (393 mg, 1.5
mmol) in THF (2 mL). The resulting mixture was stirred at
r.t. for 12 h, and was quenched with sat. aq NH4Cl. The
aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine and dried
(Na2SO4). After removal of the solvent, the residue was
purified by column chromatography on silica gel (EtOAc–
pentane = 1:2) to give the desired product 7a (176 mg, 83%)
as a yellow solid; mp 102.0–102.8 °C. 1HMNR (300 MHz,
CDCl3): d = 3.93 (s, 3 H), 7.31–7.42 (m, 1 H), 7.63 (d,
J = 8.4 Hz, 2 H), 7.90 (td, J = 7.9, 2.2, 1.8 Hz, 1 H), 8.12 (d,
J = 8.8 Hz, 2 H), 8.62 (dd, J = 1.3, 4.9 Hz, 1 H), 8.86 (dd,
J = 0.9, 2.2 Hz, 1 H) ppm. 13C NMR (75 MHz): d = 52.2,
123.7, 127.1, 129.8, 130.4, 134.7, 135.7, 142.0, 148.0,
148.9, 166.7. IR (KBr): 2951, 1721, 1608, 1285, 1107, 767
cm–1. HRMS (EI): m/z calcd for C13H11NO2: 213.0790;
found: 213.0795.
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Synlett 2005, No. 2, 267–270 © Thieme Stuttgart · New York