Efficient synthesis of functionalized organozinc compounds by the direct insertion of zinc into organic iodides and bromides

Article abstract of DOI:10.1002/anie.200601450

(Chemical Equation Presented) Insider dealing: A wide range of poly-functional (hetero)aromatic and aliphatic zinc reagents can be easily prepared in THF. The compounds are formed by a Zn insertion reaction mediated by the addition of LiCl (see scheme; All = allyl).

Full text of DOI:10.1002/anie.200601450

Communications
Organozinc Compounds
DOI: 10.1002/anie.200601450
Efficient Synthesis of Functionalized Organozinc
Compounds by the Direct Insertion of Zinc into
Organic Iodides and Bromides**
Arkady Krasovskiy, Vladimir Malakhov,
Andrei Gavryushin, and Paul Knochel*
Organozinc compounds are important intermediates in
organic chemistry because of their compatibility with many
functional groups.[1] The direct insertion of zinc into organic
halides is the most attractive and simplest method for the
preparation of functionalized organozinc halides.[1] Whereas
several polar solvents such as dimethylacetamide, hexame-
thylphosphoramide, N,N-dimethylformamide, dimethylsulf-
oxide, acetonitrile, and tetramethylurea can be used,[2] the
most common and convenient is tetrahydrofuran.[3] The
preparation of arylzinc iodides in THF from aryl iodides
can only be achieved by using Rieke-zinc[1b,4] or requires the
presence of electron-accepting substituents in the ortho po-
sition of the aryl iodides as well as elevated reaction
temperatures.[3] The use of Rieke-zinc also allows the
preparation of alkylzinc reagents starting from alkyl bromides
instead of alkyl iodides.[5] Since the activity of Rieke-zinc
decreases with time, the development of a practical procedure
for zinc insertion using commercially available zinc dust
would be highly desirable.
Recently, we have found that the Br/Mg exchange
reaction can be accelerated by adding LiCl.[6] Herein, we
report a new protocol for the preparation of functionalized
aryl-and alkylzinc compounds by the direct insertion of
commercially available Zn powder[7] in the presence of LiCl
in THF. Thus, when iodobenzene (1a) was treated with
commercial zinc powder (3 equiv, 150 mesh, activated by the
addition of 1,2-dibromoethane (5 mol%) and TMSCl
(1 mol%))[7] only 5% conversion could be reached after
24 h at 508C. However, in the presence of 1.5 equivalent of
LiCl, full conversion into phenylzinc iodide (1b) was
observed after 7 h at 508C. Ketone 1c was obtained in 90%
yield after reaction with pivaloyl chloride in the presence of
CuCN·2LiCl. The presence of an electron-withdrawing group
at the ortho (see 2a) or para positions (see 3a) considerably
increases the rate of insertion, and the corresponding arylzinc
[*] Dr. A. Krasovskiy, V. Malakhov, A. Gavryushin, Prof. Dr. P. Knochel
Ludwig Maximilians-Universität München
Department Chemie & Biochemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-218-077-680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) and the DFG for financial support. We also
thank Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen)
for the generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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iodides can be efficiently prepared at room temperature
(> 98% conversion; Scheme 1). The insertion of zinc in the
absence of LiCl can only be accomplished at 708C with a low
compounds (13a, entry 10, Table 1). A stepwise insertion into
2,5-diiodothiophene (14a) allows the introduction of two
different electrophiles (Scheme 2). Thus, the reaction of
diiodide 14a with Zn/LiCl followed by a copper(I)-catalyzed
Scheme 1. Insertion of Zn in the presence and absence of LiCl. The
specified yields by the formula numbers 1b–3b were determined by
titration; the yields >98% were determined by GC analysis.
Scheme 2. Chemoselective zinc insertion into diiodides.
yield for ortho-trifluoromethylphenyl iodide (2a) and no
insertion occurs with ethyl 4-iodobenzoate (3a; 708C, 24 h,
conversion < 5%). The organozinc iodides 2b and 3b react
cleanly with electrophiles such as tetramethylthiuram disul-
fide[8] and allyl bromide to afford the corresponding products
2c and 3c in yields of 91 and 94%, respectively (Scheme 1).
4-Anisylzinc iodide (4a) can be prepared in 93% yield by
the insertion of Zn in the presence of LiCl at 508C in THF
(entry 1, Table 1).[9] A broad range of functionalized arylzinc
iodides bearing an ester, a nitrile, or an amide group such as
5a–8a can be easily prepared in good yields (92–95%) and
treated with electrophiles (entries 2–5, Table 1). A sensitive
methyl ketone functionality is also compatible with the mild
insertion conditions. 4-Acetylphenylzinc iodide (9a) was
formed in 87% yield after 3 h at 258C and a copper-catalyzed
acylation led to the diketone 9b in 88% yield (entry 6,
Table 1). Interestingly, even an aldehyde group can be
tolerated. Thus, aryl-and heteroarylzinc iodides bearing a
formyl group (10a and 11a) were obtained in good yields by a
direct zinc insertion reaction at room temperature (entries 7
and 8, Table 1). Transition-metal-catalyzed coupling reactions
with ethyl 4-iodobenzoate (1 mol% [Pd(PPh3)4]) and ethyl 2-
bromomethyl acrylate (0.4 mol% of CuCN·2LiCl) led to the
desired functionalized aldehydes 10b and 11b in yields of 85
and 81%, respectively (entries 7 and 8, Table 1).
acylation led to the ketone 14b, which can be further
functionalized through a zinc insertion/allylation sequence
to afford the disubstituted thiophene 14c in 82% overall
yield. Alternatively, the formation of a bismetallic species can
be achieved.[10] Thus, 2,2’-diiodobiphenyl (15a) reacts
smoothly with Zn/LiCl (5 equiv) at 508C to furnish bis(iodo-
zincio)biphenyl (15b) in 94% yield. The corresponding
biphenyl derivative 15c was obtained in 77% yield after a
copper(I)-catalyzed coupling with allyl bromide.
A smooth zinc insertion is also observed for heterocyclic
iodides. Thus, various iodopyridines and 1-iodoisoquinoline
react readily with Zn powder to afford the corresponding
heteroarylzinc iodides 16a–19a at RT in yields of greater than
90% (entries 11–14, Table 1). The resulting organozinc com-
pounds were efficiently quenched with a wide range of
electrophiles under transition-metal catalysis to give the
functionalized aza-heterocycles 16b–19b in yields of 83–90%.
À
The insertion of Zn into a C Br bond is also possible in
the case of activated aryl-and heteroaryl compounds. Thus, in
the presence of LiCl, the functionalized zinc reagent 20bwas
formed at room temperature in 91% yield starting from the
bromodiester 20a. Quenching with allyl bromide leads to the
allylated diester 20c in 90% yield. Similarly, the reaction of
ethyl 5-bromo-2-furoate (21a) with Zn/LiCl furnishes the
corresponding furylzinc reagent 21b in 92% yield after 12 h
at 258C. This compound was successfully coupled with 4-
iodobenzonitrile in the presence of [Pd(PPh3)4] (1 mol%;
Scheme 3).[11]
The insertion reaction displays an excellent chemoselec-
tivity. Thus, treating 4-bromophenyl iodide (508C, 6 h) with
À
Zn/LiCl resulted only in insertion into the C I bond to give
the zinc reagent 12a (96%). Subsequent allylation provides
the aryl bromide 12b in 96% yield (entry 9, Table 1).
Moreover, a selective formation of the corresponding mono-
metalated compound is possible in the case of diiodoaryl
For the first time, the use of Zn powder in the presence of
LiCl allows the expedient preparation of functionalized
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Table 1: Preparation and reactions of functionalized aryl- and heteroarylzinc reagents.
Entry Zinc reagent,
yield [%][a]
T [8C], Electrophile
t [h]
Product, yield [%][b]
Entry Zinc reagent,
yield [%][a]
T [8C], Electrophile Product, yield [%][b]
t [h]
1
8
4a: 93
50, 90 AllBr[c]
4b: 94
5b: 90
11a: 83
25, 2.5
11b: 81
12b: 96
2
9
5a: 92
25, 1
AcCl[d]
12a: 96
50, 6
AllBr[c]
3
10
6a: 95
50, 3
50, 6
6b: 89
7b: 88
13a: 90
50, 120 AllBr[c]
13b: 89
16b: 87
4
11[e]
7a: 93
PhCOCl[d]
16a: 92
25, 8
5
12
8a: 93
25, 24 AllBr[c]
8b: 96
9b: 88
17a: 90
25, 24 CH3COCl[d]
17b: 83
18b: 85
6
13
9a: 87
25, 3
PhCOCl[d]
18a: 91
25, 12 AllBr[c]
7[e]
14
10a: 82
25, 12
10b: 85
19a: 96
25, 12 PhCOCl[d]
19b: 90
[a] Yield estimated after titration withI 2. [b] Yield of isolated analytically pure product based on the molarity of the zinc reagent. [c] 2 mol% of CuCN·2LiCl was
added. [d] 20 mol% of CuCN·2LiCl was added. [e] 1 mol% of [Pd(PPh3)4] was added.
alkylzinc reagents 22a–30a starting from alkyl bromides
(Table 2). Thus, unactivated n-octylbromide and 1-bromo-5-
chloropentane react cleanly with Zn·LiCl to afford the
corresponding alkylzinc reagents in yields of greater than
92%. The reaction with PhCOCl in the presence of catalytic
amounts of Pd0 provides ketones 22b and 23b in 89% yield
(Table 2).[11] The formation of cyclobutylmethylzinc bromide
24aproceeds without the formation of ring-opening products,
thus leading after allylation to the unsaturated ester 24b.
Functionalized alkylzinc compounds such as 25a–27acan also
be prepared in high yields. The Pd-catalyzed coupling of these
zinc reagents with different ethyl iodobenzoates lead to
difunctionalized benzenes 25b–27bin good yields (entries 4–
6, Table 2). The insertion reaction is also efficient in the case
of secondary alkyl bromides and provides alkylzinc reagents
28a and 29a in yields of 96 and 93%, respectively. Adaman-
tylzinc bromide (30a) is obtained in 83% yield by the direct
insertion of Zn in the presence of LiCl. Secondary alkylzinc
reagents 28a–30a show good reactivity towards electrophiles
(entries 7–9, Table 2). Finally, zinc insertion in the presence of
LiCl allows the smooth preparation of the alkenylzinc reagent
31b starting from a-bromostyrene (31a). Copper(I)-cata-
lyzed acylation with benzoyl chloride leads to the unsaturated
ketone 31c in 81% yield (Scheme 4).
The nature of the activation of the zinc dust with LiCl is
speculative. However, it can be envisioned that the role of
LiCl is to rapidly remove the formed organozinc reagent from
the metal surface by generating highly soluble RZnX·LiCl
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Table 2: Preparation and reaction of aliphatic zinc reagents.
Entry Zinc reagent,
yield [%][a]
T [8C] Electrophile
t [h]
Product,
yield [%][b]
1
2
3
n-C8H17ZnBr·LiCl
22a: 92
50, 24 PhCOCl[c]
50, 12 PhCOCl[c]
50, 50
22b: 89
23b: 89
24b: 82
Cl(CH2)5ZnBr·LiCl
23a: 93
24a: 86
4
5
AcO(CH2)4ZnBr·LiCl
25a: 96
50, 3
50, 1
25b: 83
Scheme 3. LiCl-mediated zinc insertion into aryl and heteroaryl
bromides.
EtO2C(CH2)3ZnBr·LiCl
26a: 95
26b: 93
27b: 88
6
7
NC(CH2)4ZnBr·LiCl
27a: 95
50, 6
PhCOCl[c]
50, 24
28a: 96
28b: 94
8
9
PhCOCl[c]
Scheme 4. Insertion of Zn into a-bromostyrene.
29a: 93
30a: 83
50, 18
29b: 90
30b: 79
complexes, thus allowing a rapid reaction of a further
À
molecule of R X and thereby avoiding the competitive
50, 24
deactivation of the active metal sites.
In conclusion, we have shown that the use of Zn powder in
the presence of LiCl in THF allows a simple, high-yielding
preparation of a broad range of functionalized aryl-and
heteroarylzinc reagents. The synthesis of the alkylzinc
reagents was performed from inexpensive and readily avail-
able alkyl bromides. All reactions proceed within a practical
temperature range (25–508C), and can be extended to large-
scale preparation. Extensions of this work are currently
underway.[12]
[a] Yield determined by titration withI . [b] Yield of isolated analytically pure
2
product based on the molarity of the zinc reagent. [c] 0.1 mol% of [Pd(dba)2]
(dba=trans,trans-dibenzylideneacetone) and 0.2 mol% of S-phos[14] were
added. [d] 1 mol% of CuCN·2LiCl was added.
iodine[13] showed that the concentration of 3b in THF was 0.83m. The
solution of 3b (3 mmol, 3.61 mL) was carefully separated from the
remaining zinc powder by using a syringe and transferred to another
dry and Ar-flushed flask. Allyl bromide (3.3 mmol) was added at
À208C, followed by CuCN·2LiCl (one drop of a 1.0m solution in
THF, ca. 0.02 mmol, ca. 0.4 mol%). The reaction mixture was stirred
for 1 h at 08C and was then quenched with saturated aqueous NH4Cl
solution (5 mL). The aqueous phase was extracted with ethyl acetate
(3 ” 5 mL) and concentrated in vacuo. The crude residue was purified
by flash chromatography (CH2Cl2) and yielded 3c (2.82 mmol,
504 mg, 94%) as a colorless oil.
Experimental Section
Typical procedure. Preparation of 3c (Scheme 1): Anhydrous LiCl
(5 mmol) was placed in an Ar-flushed flask and dried for 20 min at
150–1708C under high vacuum (1 mbar). Zinc powder (7 mmol,
1.4 equiv, 150 mesh, Chemetall, or 325 mesh, Strem) was added under
Ar and the heterogeneous mixture of Zn and LiCl was dried again for
10–20 min at 150–1708C under high vacuum (1 mbar). The reaction
flask was evacuated and refilled with argon three times. THF (5 mL)
was added and the Zn was activated with BrCH2CH2Br (5 mol%) and
Me3SiCl (1 mol%).[7] 3a (5 mmol) was then added neat at room
temperature. The insertion reaction was complete after 24 h (checked
by GC analysis of reaction aliquots, the conversion was higher than
98%). Titration of an aliquot (1 mL) of the organozinc reagent with
Received: April 12, 2006
Published online: August 10, 2006
Keywords: coupling · homogeneous catalysis · insertion ·
.
organozinc compounds · zinc
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[12] A patent application was filed.
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