Preparation of an Arenylmethylzinc Reagent with Functional Groups by Chemoselective Cross-Coupling Reaction of Bis(iodoazincio)methane with Iodoarenes

Article abstract of DOI:10.1055/s-0034-1381044

Palladium-catalyzed cross-coupling reaction of bis(iodozincio)methane with iodoarenes carrying various functionalities such as ester, boryl, cyano, and halo groups proceeded chemoselectively to give the corresponding arenylmethylzinc species efficiently. The moderate reactivity of the gem-dizinc reagent imparted functional group tolerance to the process. The transformations from iodoheteroarenes were also performed; in the case of iodopyridine derivatives, the nickel-catalyzed reaction gave the corresponding organozinc species efficiently. The obtained arenylmethylzinc species underwent the copper-mediated coupling reaction with a range of organic halides.

Full text of DOI:10.1055/s-0034-1381044

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© Georg Thieme Verlag Stuttgart · New York
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Preparation of an Arenylmethylzinc Reagent with Functional
Groups by Chemoselective Cross-Coupling Reaction of Bis(iodo-
zincio)methane with Iodoarenes
Yukako Shimada
Ryosuke Haraguchi
Seijiro Matsubara*
CH2(ZnI)2
R–Ar–CH2ZnI
R–Ar–I
Pd or Ni cat.
R–Ar: XC6H4, EtOCOC6H4, Bpin-C6H4, etc. >76% (Pd cat., 9 examples)
R–Ar: Py, X-Py >30% (Ni cat., 5 examples)
Department of Material Chemistry, Graduate School of Engi-
neering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo,
615-8510 Kyoto, Japan
matsubara.seijiro.2e@kyoto-u.ac.jp
Received: 06.04.2015
Accepted after revision: 25.06.2015
Published online: 22.07.2015
bis(iodozincio)methane (1),6,7 which can be used to intro-
duce the iodozinciomethyl group directly, we tried to devel-
op a shorter route from aryl iodide 2 to arenylmethylzinc
reagent 3. As shown in Scheme 1, the cross-coupling reac-
tion of 1 with 2 was examined in the presence of a transi-
tion-metal catalyst.8
DOI: 10.1055/s-0034-1381044; Art ID: st-2015-s0246-c
Abstract Palladium-catalyzed cross-coupling reaction of bis(iodozin-
cio)methane with iodoarenes carrying various functionalities such as
ester, boryl, cyano, and halo groups proceeded chemoselectively to
give the corresponding arenylmethylzinc species efficiently. The mod-
erate reactivity of the gem-dizinc reagent imparted functional group
tolerance to the process. The transformations from iodoheteroarenes
were also performed; in the case of iodopyridine derivatives, the nickel-
catalyzed reaction gave the corresponding organozinc species efficient-
ly. The obtained arenylmethylzinc species underwent the copper-medi-
ated coupling reaction with a range of organic halides.
E+ (4)
CH2(ZnI)2 (1)
Ar-I
Ar-CH2ZnI
Ar-CH2E
cat.
5
2
3
Scheme 1 Zinciomethylation of iodoarene
To find an appropriate catalyst for the cross-coupling re-
action, treatment of iodoanisole (2a) with bis(iodozin-
cio)methane (1) was examined in the presence of palladi-
um catalyst (5 mol%) with various ligands (Table 1). The ob-
tained arenylmethylzinc species 3a was quenched with 1 M
aqueous HCl and its yield was estimated by the amount of
4-methoxytoluene (5aa). A use of the electron-deficient li-
gand, tris[3,5-bis(trifluoromethyl)phenyl]phosphine, gave
good results. As the migrating iodozinciomethyl group can
be regarded as an electron-rich moiety, the electron-with-
drawing ligand might be necessary for the transmetalation
and the reductive elimination.9 The use of Pd2dba3 as a pal-
ladium source resulted in satisfactory yield (entries 5 and
6). Further tuning of the reaction temperature and the ratio
of the ligand gave the product in excellent yields (entries 6–
10). The further cross-coupling product, bis(4-methoxy-
phenyl)methane, was not identified in the reaction mix-
ture.10
Keywords arenylmethylzinc, organozinc, cross-coupling, palladium,
nickel
Aromatic components are important structures for
pharmaceuticals and materials, and their insertion has
been studied intensively in order to synthesize many mole-
cules.1 Nucleophilic introduction of arene moieties is often
performed by using the corresponding arenylmetals.
Schlosser developed an approach for the preparation of
highly functionalized arenyllithium through the oriented
deprotonation method.2 In addition, the formation of a
functionalized arenylmagnesium from the magnesium am-
ide is also an efficient route.3 Compared with the estab-
lished route for the preparation of highly functionalized
arenylmetals, the homologous arenylmethylmetals with
several functional groups have not been well studied, al-
though they can also play a crucial role in the introduction
of an aromatic skeleton. Recently, Knochel and co-workers
reported an efficient route to heteroarenylmethylzinc re-
agents from iodoheteroarenes through magnesium–iodine
exchange, chloromethylation, and reduction with Zn-LiCl.4,5
Given that highly functional iodoarenes had been estab-
lished by the oriented deprotonation method, this ho-
mologative method was considered to be an easily accessi-
ble and reasonable route. Since we have studied the use of
As shown in Scheme 2, the functional group tolerance of
this coupling reaction was examined. Halo, cyano, trifluoro-
methyl, boryl, and ester groups did not disturb the transfor-
mation; however, 4-nitro-1-iodobenzene afforded the cor-
responding zinc reagent in only 12% yield. The zinciometh-
ylation of 3-iodopyridine under the Pd catalyst also gave
the corresponding coupling product in low yield.
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Table 1 Optimization of Zinciomethylation of 2aa
To achieve high yield in the cross-coupling reaction of 3-
iodopyridine, the use of nickel catalyst instead of a palladi-
um catalyst was shown to be effective (Table 2). Especially,
the catalyst prepared from NiCl2 (5 mol%) and Ph3P (10
mol%) gave the cross-coupling product in 99% yield (entry
8).
I
CH2ZnI
Me
H3O+ (4a)
catalyst
+ CH2(ZnI)2
THF, T °C
0.5 h
1
OMe
OMe
OMe
2a
5aa
3a
Ligand
Table 2 Optimization of Zinciomethylation of 2ja
Entry
1
Temp Metal
5aab
(%)
N
N
N
H3O+ (4a)
(equiv) (°C)
(mol%)
(mol%)
catalyst
+ CH2(ZnI)2
THF, T °C
0.5 h
1
2
3
4
5
6
7
8
9
10
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.0
25
25
25
25
25
25
40
40
40
40
PdCl2 (5)
Ph3P (10)
<5
<5
<5
19
45
50
22
91
99
93
Me
5ja
I
1
CH2ZnI
PdCl2 (5)
(EtO)3P (10)
2j
3j
PdCl2 (5)
(2-furyl)3P (10)
Entry
Catalyst [metal (mol%), ligand (mol%)]
5ja (%)b
PdCl2 (5)
(3-CF3C6H4)3P (10)
[3,5-(CF3)2C6H3]3P (10)
[3,5-(CF3)2C6H3]3P (10)
[3,5-(CF3)2C6H3]3P (10)
[3,5-(CF3)2C6H3]3P (20)
[3,5-(CF3)2C6H3]3P (20)
[3,5-(CF3)2C6H3]3P (12)
1
2
3
4
5
6
7
8
Pd2dba3 (2.5), [3,5-(CF3)2C6H3]3P (20)
Pd2dba3 (2.5), (2-furyl)3P (20)
NiCl2dppp (5)
20
10
40
38
76
2
PdCl2 (5)
Pd2dba3 (2.5)
Pd2dba3 (2.5)
Pd2dba3 (2.5)
Pd2dba3 (2.5)
Pd2dba3 (1.5)
NiCl2dppe (5)
NiCl2(PPh3)2 (5)
NiCl2 (5), [3,5-(CF3)2C6H3]3P (10)
NiCl2 (5), (2-furyl)3P (10)
NiCl2 (5), Ph3P (10)
a Reaction conditions: 1 (0.36 M in THF, 0.7 mmol), 2a (0.7 mmol).
38
99
b Yield determined by GC analysis using dodecane as internal standard.
a Reaction conditions: 1 (0.36 M in THF, 0.7 mmol) and 2j (0.7 mmol).
b Yield determined by GC analysis using decane as internal standard.
Pd2dba3
(1.5 mol%)
P[3,5-(CF3)2C6H3]3
As shown in Scheme 3, a range of iodopyridines were
examined as substrate for the cross-coupling reaction with
gem-dizinc 1 in the presence of nickel catalyst. Fluoro and
chloro groups did not disturb the reaction (5ma, 5na).
H3O+ (4a)
(12 mol%)
+ CH2(ZnI)2
Ar-Me
Ar-I
THF, 40 °C
0.5 h
2
1 (1.0 equiv)
5
NiCl2
(5.0 mol%)
Ph3P
Br
Br
NC
H3O+ (4a)
(10 mol%)
Ar-I + CH2(ZnI)2
Ar-Me
Me
Me
Me
THF, 40 °C
2j–n 1 (1.0 equiv)
5
5ba (92%)
5ca (86%)
5da (87%)
Cl
N
F3C
Bpin
EtO2C
N
N
F
N
N
Me
Me
Me
Me
Me
Me
5la (71%)
Me
Me
5ea (76%)
5fa (99%)
5ga (89%)
5ja (95%) 5ka (74%)
5ma (45%) 5na (30%)
O2N
N
S
Scheme 3 Zinciomethylation of iodopyridines
Me
Me
Me
5ha (12%)
5ha (73%)
5ia (20%)
The copper-mediated reactions of the arenylmethylzinc
reagents, which had been prepared from iodoarenes (2a,j)
and gem-dizinc 1, with various electrophiles are shown in
Table 3. Allyl- and propargyl bromide gave the coupling
compounds regioselectively. The use of benzoyl cyanide
gave arenylmethyl phenyl ketones in good yields. Instead of
benzoyl cyanide, the use of benzoyl chloride resulted in the
formation of 4-benzoyloxy-1-halobutane, which was
formed by a ring-opening of THF.
N
N
N
H3O+ (4a)
catalyst
+ CH2(ZnI)2
THF, T °C
0.5 h
Me
5ja
I
1
CH2ZnI
2j
3j
Scheme 2 Zinciomethylation of iodoarenes bearing a functional group
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2395–2398

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Table 3 Sequential Reaction of Arenylmethylzinc with Electrophiles
1) CH2(ZnI)2 (1.0 equiv)
Pd2dba3 (1.5 mol%)
Mediated by Copper Salta
I
R
P[3,5-(CF3)2C6H3]3 (12 mol%)
E+
CuCN⋅2LiCl
Bpin
Bpin
2) CuCN⋅2LiCl (1.0 equiv)
E+ (4, 0.9 equiv)
3) sat. NH4Cl (aq)
•
(1.0 equiv)
–30 °C
(4, 0.9 equiv)
catalyst
2f
5fb, 5fe, 5ff
Ar-I
Ar–CH
+ CH2(ZnI)2
2–E
THF, 40 °C
0.5 h
–30 to 25 °C
9 h
2a, j
1 (1.0 equiv)
5
Ph
O
Entry
2
Catalyst (mol%) Electrophile
5 (%)b
Bpin
Bpin
Bpin
1
2
2a
2a
2a
2a
2a
2j
Pd (3)
Pd (3)
Pd (3)
Pd (3)
Pd (3)
Ni (5)
Ni (5)
Ni (5)
Ni (5)
Ni (5)
allyl bromide (4b)
cinnamyl bromide (4c)
91 (5ab)
68 (5ac)
81 (5ad)
91 (5ae)
91 (5af)
65 (5jb)
75 (5jc)
59 (5jd)
61 (5je)
55 (5jf)
5fb (97%)
5fe (63%)
5ff (52%)
Scheme 4 Reaction of the pinacol ester of 4-iodophenylboronic acid
3
prenyl bromide (4d)
proprargyl bromide (4e)
benzoyl cyanide (4f)
allyl bromide (4b)
4
catalyzed cross-coupling reaction, so the higher functional
tolerance compared with the existing methods was demon-
strated.
5
6
7
2i
cinnamyl bromide (4c)
prenyl bromide (4d)
proprargyl bromide (4e)
benzoyl cyanide (4f)
8
2j
Acknowledgment
9
2j
This work was supported financially by the Japanese Ministry of Edu-
cation, Culture, Sports, Science and Technology.
10
2i
Me
Me
Ph
References and Notes
MeO
•
MeO
MeO
5ac
5ab
5ad
5jb
(1) (a) Schlosser, M. In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; Wiley: Chichester, 2002, 1–352. (b) Boudier,
A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem. Int. Ed.
2000, 39, 4414.
(2) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376.
(3) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(4) Barl, N. M.; Sansiaume-Dagousset, E.; Monzón, G.; Wagner, A. J.;
Knochel, P. Org. Lett. 2014, 16, 2422.
Ph
N
O
MeO
N
MeO
5ae
5af
N
(5) (a) Murakami, K.; Yorimitsu, H.; Oshima, K. Chem. Eur. J. 2010,
16, 7688. (b) Braendvang, M.; Bakken, V.; Gundersen, L.-L.
Bioorg. Med. Chem. 2009, 17, 6512. (c) Baba, Y.; Toshimitsu, A.;
Matsubara, S. Synlett 2008, 2061.
Ph
N
Me
5jd
Me
N
Ph
•
5jc
O
(6) Nishida, Y.; Hosokawa, N.; Murai, M.; Takai, K. J. Am. Chem. Soc.
2015, 137, 114.
5jf
5je
(7) (a) Sada, M.; Uchiyama, M.; Matsubara, S. Synlett 2014, 25,
2831. (b) Sada, M.; Komagawa, S.; Uchiyama, M.; Kobata, M.;
Mizuno, T.; Utimoto, K.; Oshima, K.; Matsubara, S. J. Am. Chem.
Soc. 2010, 132, 17452. (c) Haraguchi, R.; Matsubara, S. Synthesis
2014, 46, 2272.
(8) Yoshino, H.; Toda, N.; Kobata, M.; Ukai, K.; Oshima, K.; Utimoto,
K.; Matsubara, S. Chem. Eur. J. 2006, 12, 721.
(9) (a) Kanemoto, S.; Matsubara, S.; Oshima, K.; Utimoto, K.;
Nozaki, H. Chem. Lett. 1987, 16, 5. (b) Goliaszewski, A.;
Schwartz, J. Organometallics 1985, 4, 417.
(10) To perform the cross-coupling between the formed arenyl-
methylzinc iodide and iodoarene by Pd catalyst, we found that
LiCl (1.0 equiv) plays a crucial role. As shown in Scheme 5, 4-
methoxyphenylmethylzinc iodide, which was prepared from 4-
methoxy-1-iodobenzene and bis(iodozincio)methane in the
presence of Pd catalyst, was treated with p-tolyl iodide in the
presence of a stoichiometric amount of LiCl and an additional
Pd catalyst (PEPPSI-IPr) to afford 1-methoxy-4-(4-methylben-
zyl)benzene in 81% yield. Without the addition of LiCl, no cross-
coupling product was observed, see: Shimada, Y.; Matsubara, S.;
a Reaction conditions: 1 (0.36 M in THF, 1.0 mmol), 2 (1.0 mmol),
CuCN·2LiCl (1.0 mmol), electrophile (0.9 mmol).
b Isolated yield.
As described above, the merit of the present method is
the functional group tolerance. As shown in Scheme 4, the
Bpin group remained intact throughout the whole transfor-
mation. Starting from the pinacol ester of 4-iodophenylbo-
ronic acid 2f, the iodozinciomethylation and the copper-
mediated coupling with a range of halides afforded various
organoboronic acid esters.11 These products can be trans-
formed into various aromatic compounds through the
Suzuki–Miyaura coupling reaction.
In conclusion, we have shown a novel method that can
be used to prepare the arenylmethylzinc reagent bearing
functional groups. The introduction of the C–Zn bond was
performed by zinciomethylation through transition-metal-
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Proceedings of the 95th CSJ Annual Meeting, Chiba, Japan,
March 26–29, 2015; The Chemical Society of Japan: Tokyo,
2015; 2EA-46.
at the same temperature and the mixture was stirred for 10 h at
25 °C. Aqueous work-up (sat. aq NH4Cl) followed by extraction
with Et2O gave the crude product. Purification by silica gel
column chromatography (5 wt% boric acid) gave the title com-
pound (168 mg, 52%). 1H NMR (CDCl3): δ = 8.00 (d, J = 8.0 Hz,
2 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.54 (dd, J = 8.0, 8.0 Hz, 1 H), 7.44
(dd, J = 8.0, 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 4.30 (s, 2 H),
1.33 (s, 12 H). 13C NMR (CDCl3): δ = 197.4, 137.7, 136.4, 135.1,
133.1, 130.1, 128.8, 128.6, 128.4, 83.7, 45.8, 24.8. HRMS (ESI):
m/z [M + K]+ calcd for C20H23O3B: 361.1372; found: 361.1359.
2-[4-(But-3-en-1-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (5fb): 1H NMR (CDCl3): δ = 7.78 (d, J = 8.5 Hz, 2 H),
7.23 (d, J = 8.5 Hz, 2 H), 5.9–5.8 (m, 1 H), 5.06 (ddt, J = 17.0, 1.5,
1.0 Hz, 1 H), 5.00 (dd, J = 10, 1.5, 1.0 Hz, 1 H), 2.75 (t, J = 7.5 Hz,
2 H), 2.40 (dtt, J = 7.5, 7.5, 1.0 Hz, 2 H), 1.36 (s, 12 H). 13C NMR
(CDCl3): δ = 145.2, 137.9, 134.8, 127.9, 114.9, 83.6, 35.5, 35.3,
24.8. HRMS (ESI): m/z [M + Na]+ calcd for C16H23O2B: 281.1683;
found: 281.1683.
p-Tol-I (0.9 equiv)
PEPPSI-IPr (0.05 equiv)
LiCl (1.0 equiv)
H2
C
CH2ZnI
25 °C, 18 h
MeO
Me
MeO
81%
Scheme 5
(11) Preparation of 1-Phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl]ethan-1-one (5ff) To a mixture of
Pd2dba3 (0.015 mmol, 13.7 mg) and P(3,5-(CF3)2C6H3)3
(0.12 mmol, 74.4 mg) in THF (2 mL), a solution of 2f (1.0 mmol,
330 mg) in THF (2.0 mL) was added. The mixture was stirred for
5 min at 25 °C, then a solution of bis(iodozincio)methane (0.36
M in THF, 1.0 mmol, 2.8 mL) was added. The resulting mixture
was stirred for 1 h at the same temperature. The mixture was
cooled to –30 °C, then a solution of CuCN·2 LiCl (1.0 M in THF,
1.0 mmol, 1.0 mL) was added and the resulting mixture was
stirred for 15 min at the same temperature. A solution of
benzoyl cyanide (0.9 mmol, 118 mg) in THF (0.5 mL) was added
2-[4-(Buta-2,3-dien-1-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (5fe): 1H NMR (CDCl3): δ = 7.76 (d, J = 8.5 Hz,
2 H), 7.26 (d, J = 8.5 Hz, 2 H), 5.27 (dt, J = 7.0, 7.0 Hz, 1 H), 4.73
(dt, J = 7.0, 3.0 Hz, 2 H), 3.38 (dt, J = 7.0, 3.0 Hz, 2 H), 1.35 (s,
12 H). 13C NMR (CDCl3): δ = 143.6, 135.2, 134.9, 128.0, 127.8,
89.2, 83.6, 75.2, 35.2, 24.8. HRMS (ESI): m/z [M + Na]+ calcd for
C
16H21O2B: 279.1527; found: 279.1515.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2395–2398