Alternative approach toward the generation of benzylic zinc reagent: Direct oxidative addition of active zinc into the carbon-oxygen bond of benzyl mesylates

Article abstract of DOI:10.1055/s-0034-1379880

The use of highly active zinc, prepared by the Rieke method, for the direct preparation of benzylic zinc mesylate was investigated. The oxidative addition of highly active zinc to benzyl mesylate was easily completed under mild conditions. The resulting benzylic zinc mesylates were employed in subsequent cross-coupling reactions with a broad range of electrophiles, and the formation of the corresponding products was successful.

Full text of DOI:10.1055/s-0034-1379880

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 666–670
letter
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H.-S. Jung, S.-H. Kim
Letter
Synlett
Alternative Approach toward the Generation of Benzylic Zinc
Reagent: Direct Oxidative Addition of Active Zinc into the Car-
bon–Oxygen Bond of Benzyl Mesylates
Hye-Soo Jung
OMs
Zn*
E+
ZnOMs
E
Seung-Hoi Kim*
FG
FG
FG
THF, r.t.
Department of Chemistry, Dankook University, 119 Dandaero,
Cheonan, 330-714, South Korea
kimsemail@dankook.ac.kr
FG = H, Cl, OMe,
CN, CO2Et
Received: 06.10.2014
Accepted after revision: 24.11.2014
Published online: 07.01.2015
zylic zinc reagents has attracted great attention. In general,
benzyl halides have been the most widely used substrates
for this purpose, along with zinc metal, and the resulting
benzylic zinc reagents were mostly achieved via the direct
addition of zinc metal to the carbon–halogen bond.
Considering the exceptional reactivity of highly active
zinc (Zn*) prepared by the Rieke method, we sought to fur-
ther investigate its potential capability. Our first journey
was to attempt insertion into the carbon–oxygen bond. To
accomplish this goal, benzyl mesylate was chosen from
among the suitable candidates, as such mesylates can be
easily prepared from the corresponding alcohols using the
standard procedure in the literature.7 To date, there have
been very limited examples of zinc-metal insertion to ben-
zyl mesylate, as reported by Knochel et al.8 In their study,
zinc dust was used exclusively in the presence of lithium
salt in DMPU at elevated temperature.
We now have found an alternative synthetic route for
the direct formation of benzylic zinc mesylate from the di-
rect oxidative addition of highly active zinc to benzyl
mesylate. To the best of our knowledge, it is the first exam-
ple of the direct oxidative addition of active zinc (Zn*) to a
carbon–oxygen bond.9
The preparation and coupling reaction of benzylic zinc
mesylates is presented in Scheme 1. Treatment of the highly
active zinc (Zn*)10 with benzyl mesylates gave the corre-
sponding organozinc reagent, benzylic zinc mesylates I in
high yield. The zinc insertion was completed in four hours
at room temperature in THF, and a very small amount (less
than 1%) of the homocoupled product (dibenzyl, confirmed
by GC–MS) was formed during the reaction. The resulting
organozinc reagents were then coupled with various elec-
trophiles, and the corresponding products were obtained in
moderate to good isolated yields.11
DOI: 10.1055/s-0034-1379880; Art ID: st-2014-u0839-l
Abstract The use of highly active zinc, prepared by the Rieke method,
for the direct preparation of benzylic zinc mesylate was investigated.
The oxidative addition of highly active zinc to benzyl mesylate was easi-
ly completed under mild conditions. The resulting benzylic zinc
mesylates were employed in subsequent cross-coupling reactions with
a broad range of electrophiles, and the formation of the corresponding
products was successful.
Key words benzylic zinc, benzyl meslate, active zinc, oxidative addi-
tion, cross-coupling
Organozinc metallic reagents are pronounced to be ef-
fective reaction intermediates for organic synthesis, mainly
due to their excellent functional-group tolerance.1 There-
fore, a variety of organozinc reagents have been prepared
and used to provide complex organomolecules, which have
shown a wide range of chemical uniqueness. Among the
many valuable organozinc reagents, benzylic zinc reagents
have been considered as critical intermediates for the
preparation of diaryl methane derivatives which have
found use over the broad areas of pharmaceutical and su-
pramolecular chemistry.2 Other than benzylic zinc re-
agents,3 lithium,4 Grignard,5 aluminum,6 and calcium met-
als are also available for the preparation of benzylic metal
complexes. To obtain these benzylic metal reagents, direct
or indirect methods using an appropriate metal and a ben-
zyl derivative have been employed.
As mentioned above, the excellent functional-group tol-
erance of the organozinc reagents has provided the diverse
applicability of such reagents in organic synthesis. There-
fore, the development of novel synthetic methods for ben-
OMs
Zn*
E+
ZnOMs
E
FG
FG
FG
THF, r.t.
FG = H, Cl, OMe
Scheme 1 Preparation of benzylic zinc mesylates and subsequent coupling reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 666–670

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H.-S. Jung, S.-H. Kim
Letter
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Table 1 Coupling Reaction of I with Aromatic Acid Chlorides
CuCN (10 mol%)
LiCl (20 mol%)
Ar
X
COCl
ZnOMs
+
X
O
THF
0 °C, 2 h
(0.8 equiv)
I (1.0 equiv)
1a–h
Entry
X
Product
Yield (%)a
1
2
3
4
5
6
7
8
H
1a
1b
1c
1d
1e
1f
77
70
61
60
81
72
81
70
4-Br
3-Cl
4-Cl
2-I
4-F
4-OMe
4-t-Bu
1g
1h
a Isolated yield (based on acid chloride).
The utilities of the resulting organozinc reagent I were
first examined by a typical copper-catalyzed cross-coupling
reaction with acid chlorides, the results of which are sum-
marized in Table 1. Of the copper catalysts, the use of CuCN
showed an advantage over CuI. The coupling reaction with
acid chlorides bearing both electron-withdrawing and elec-
tron-donating groups provided the corresponding ketones
(1a–h, Table 1) with good isolated yields, regardless of the
substituent on the aromatic acid chlorides, under the con-
ditions depicted below.
With the promising results above in hand, the same re-
action environment was adapted to the coupling of I with
heteroaromatic acid chlorides, resulting in the formation of
the corresponding products (2a–c) in moderate yields (Ta-
ble 2).
The coupling reaction with acid chlorides was then ex-
panded to alkyl acid chlorides. To our delight, all reactions
proceeded smoothly at 0 °C in the presence of catalytic
amounts of copper catalyst in THF, providing the ketones
(3a–c, Table 3) in moderate isolated yields.
Table 2 Coupling Reaction of I with Heteroaromatic Acid Chlorides
Table 3 Coupling Reaction of I with Alkyl Acid Chlorides
CuCN (10 mol%)
CuCN (10 mol%)
acid
chloride
I
+
product
I
product
+
HetArCOCl
(0.8 equiv)
LiCl (20 mol%)
0 °C, 2 h
THF
LiCl (20 mol%)
0 °C, 2 h
THF
2a–c
3a–c
(1.0 equiv)
(1.0 equiv)
(0.8 equiv)
Entry Acid chloride
Product
Yield (%)a
Entry
1
Product 3
Yield (%)
N
N
Cl
COCl
1
60
40
Cl
N
O
O
O
O
2a
3a
3b
3c
Cl
COCl
2
3
60
42
2
3
50
65
N
O
Cl
O
O
2b
2c
O
COCl
a Isolated yield (based on acid chloride).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 666–670

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H.-S. Jung, S.-H. Kim
Letter
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With the positive results obtained from the cross-cou-
pling reaction with acid chlorides, further diversity of the
strategy was then explored. This was accomplished by at-
tempting the traditional palladium(II)-catalyzed cross-cou-
pling reaction with various aryl and heteroaryl halo com-
pounds. Treatment of I with aryl halides were found to give
rise to the formation of the carbon–carbon bond in the
presence of a catalytic amount of palladium(II) catalyst at
refluxing temperature in three hours. Diaryl methane de-
rivatives 4a–g were obtained in moderate to good isolated
yields. The results are summarized in Table 4.
lides described in Table 4, no desired product was obtained
from the Pd(PPh3)2Cl2-catalyzed coupling reaction with he-
teroaryl halides. Surprisingly, the Ni(PPh3)2Cl2 catalyst
proved very effective to complete the coupling under the
conditions described in Table 5, with moderate to good iso-
lated yields observed for most of the coupling reactions.
With the pyridine substrate bearing two halogens, a selec-
tive coupling was found to give 5b in 46% isolated yield (Ta-
ble 5, entry 2).
Table 5 Palladium-Catalyzed Carbon–Carbon Coupling of I with Het-
eroaryl Halides
Table 4 Palladium-Catalyzed Carbon–Carbon Coupling of I with Aryl
Halides
Ni(PPh3)2Cl2 (2 mol%)
I
+
(Het)ArX
product
THF
reflux, 24 h
Pd(PPh3)2Cl2 (2 mol%)
(2.0 equiv)
(1.0 equiv)
5a–f
I
+
ArX
product
THF
Entry
1
ArX
Product
Yield (%)a
reflux, 3 h
(2.0 equiv)
(1.0 equiv)
4a–g
N
N
Entry
ArX
Product
Yield (%)a
69
I
N
Br
Br
N
CN
5a
1
72
Br
4a
CN
2
3
4
46
73
50
Br
I
N
5b
5c
I
2
3
4
5
66
60
68
51
N
OMe
Cl
MeO
4b
4c
4d
N
I
N
OMe
Cl
Br
MeO
Br
5d
5e
5f
I
Br
Br
5
6
51
68
S
S
Br
S
Cl
Ph
Ph
4e
4f
Cl
Br
S
I
a Isolated yield [based on(Het)ArX)].
6
7
81
56
To investigate the generality of this strategy, more ex-
amples of benzylic zinc mesylates were prepared and then
coupled with several different electrophiles. As described in
Scheme 2, 4-chloro- and 4-methoxybenzylic zinc mesylates
(II and III) were easily prepared utilizing the same condi-
tions as above. Once again, only small amounts (1–2%) of
homocoupled products were observed during the oxidative
addition of active zinc. The functionalized benzylic zinc re-
agents (II and III) were also successfully utilized in the vari-
ous cross-coupling reactions with acid chlorides, and the
results with relatively low yields appear in detail in Scheme
2 below.
Br
4g
a Isolated yield (based on ArX).
The applicability of I was further examined by reaction
with various heteroaryl compounds possessing a halogen
atom, and the results are summarized in Table 5. Interest-
ingly, it was found that the use of nickel(II) catalyst showed
a dramatic difference from palladium(II) catalyst for this
coupling. Unlike the coupling reactions with simple aryl ha-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 666–670

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H.-S. Jung, S.-H. Kim
Letter
Synlett
acid
chloride
(0.5 equiv)
Zn*
(2.0 equiv)
OMs
(1.0 eq)
ZnOMs
ketones
THF
reflux, 24 h
catalyst
X
X
6a–i
X = 4-Cl (II), 4-OMe (III)
4-CN (IV), 4-CO2Et (V)
N
Cl
O
O
O
Cl
Cl
Cl
6c (33%)
6a (38%)
6b (35%)
N
Cl
O
O
O
MeO
MeO
MeO
6d (45%)
6e (44%)
6f (38%)
O
O
O
NC
NC
EtO2C
6g (49%)
6h (41%)
6i (35%)
Scheme 2 Reagents and conditions: CuCN (10 mol%), LiCl (20 mol%), 0 °C, 4 h.
In summary, this new method offers the additional ad-
vantage of the flexibility to use benzyl alcohols as starting
materials. More importantly, this study demonstrated the
direct oxidative addition of active zinc to the carbon–oxy-
gen bond of benzyl mesylate under mild conditions. By use
of this methodology, halide-free benzylic zinc reagents
have been prepared, and the resulting organozinc reagents
have been successfully utilized in subsequent cross-cou-
pling reactions with a variety of electrophiles giving rise to
the corresponding products in moderate to good yield.
(3) (a) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10,
1107. (b) Metzger, A.; Schade, M. A.; Manolikakes, G.; Knochel,
P. Chem. Asian J. 2008, 3, 1678. (c) Metzger, A.; Piller, F. M.;
Knochel, P. Chem. Commun. 2008, 5824. (d) Rottlander, M.;
Knochel, P. Tetrahedron Lett. 1997, 38, 1749. (e) Hinkle, R. J.;
Leri, A. C.; David, G. A.; Erwin, W. M. Org. Lett. 2000, 11, 1521.
(f) Gosmini, C.; Rollin, Y.; Gebehenne, C.; Lojou, E.;
Ratovelomanana, V.; Perichon, J. Tetrahedron Lett. 1994, 35,
5637. (g) Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A. J. Org.
Chem. 1997, 62, 8966. (h) Stadtmüller, H.; Greve, B.; Lennick, K.;
Chair, A.; Knochel, P. Synthesis 1995, 70.
(4) (a) Reed, J. N. In Science of Synthesis; Vol. 8a; Snieckus, V., Ed.;
Thieme: Stuttgart, 2006, 329. (b) Hargreaves, S. L.; Pilkington, B.
L.; Russell, S. E.; Worthington, P. A. Tetrahedron Lett. 2000, 41,
1653.
References and Notes
(5) (a) Burns, T. P.; Rieke, R. D. J. Org. Chem. 1987, 52, 3674.
(b) Benkeser, R. A.; Snyder, D. C. J. Org. Chem. 1982, 47, 1243.
(c) Baker, K. V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton,
A. J. Org. Chem. 1991, 56, 698. (d) Harvey, S.; Junk, P. C.; Raston,
C. L.; Salem, G. J. Org. Chem. 1998, 53, 3134. (e) Stoll, A. H.;
Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 606.
(6) Blumke, T. D.; Groll, K.; Karaghisoff, K.; Knochel, P. Org. Lett.
2011, 13, 6440.
(7) Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195.
(8) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5425.
(9) One example showed the direct oxidative addition of active
manganese to benzyl mesylates: Kim, S. H.; Rieke, R. D. J. Org.
Chem. 2000, 65, 2322.
(1) (a) Knochel, P. In Handbook of Functionalized Organometallics;
Wiley-VCH: New York, 2005. (b) Knochel, P.; Millot, N.;
Rodriguez, A. L.; Tucker, C. E. Org. React. 2001, 58, 417.
(c) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.
Int. Ed. 2000, 39, 4414.
(2) (a) Lednicer, D.; Mitscher, L. A. Organic Chemistry of Drug Syn-
thesis; Wiley: New York, 1977. (b) Ueoka, R.; Fujita, T.;
Matsunaga, S. J. Org. Chem. 2009, 74, 4396. (c) Hassan, W.;
Edrada, R.; Ebel, R.; Wray, V.; Berg, A.; van Soest, R.;
Wiryowidagdo, S.; Proksch, P. J. Nat. Prod. 2004, 67, 817.
(d) Molander, G. A.; Elia, M. D. J. Org. Chem. 2006, 71, 9198.
(e) Kaila, N.; Janz, K.; Huang, A.; Moretto, A.; DeBernardo, S.;
Bedard, P. W.; Tam, S.; Clerin, J.; Keith, J. C.; Schaub, R. G.; Wang,
Q. J. Med. Chem. 2007, 50, 40.
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(10) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56,
1445.
(11) Representative Procedures
1-(4-bromophenyl)-2-phenylethanone (1b) in 70% isolated
yield as a white solid (mp 103–104 °C). 1H NMR (500 MHz,
CDCl3): δ = 7.86 (d, J = 8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H), 7.34–
7.24 (m, 5 H), 4.25 (s, 2 H). 13C NMR (125 MHz, CDCl3):
δ = 196.65, 135.25, 134.15, 131.99, 131.96, 130.18, 129.40,
128.80, 127.08, 45.55.
Preparation of Benzylic Zinc Mesylate (I)
In an oven-dried 250 mL round-bottomed flask equipped with a
stir bar was added 4.70 g of active zinc (Zn*, 72.0 mmol) in 100
mL of THF. Benzyl mesylate (11.2 g, 60.0 mmol) was cannulated
neat into the flask at r.t. The resulting mixture was stirred for
4.0 h at r.t. The whole mixture was settled down, and then the
supernatant was used for the subsequent coupling reactions.
Copper-Catalyzed Cross-Coupling Reaction
Into a 25 mL round-bottomed flask were placed CuCN (0.02 g,
10 mol%) and LiCl (0.02 g, 20 mol%). Benzylic zinc mesylate (I,
5.0 mL, 0.5 M in THF, 2.5 mmol) was added into the flask under
an argon atmosphere. Next, 4-bromobenzoyl chloride (0.44 g,
2.0 mmol) was slowly added via a syringe while being stirred at
0 °C. The resulting mixture was at 0 °C for 2 h, quenched with
3.0 M HCl solution, then extracted with Et2O (3 × 10 mL),
washed with sat. NaHCO3, Na2S2O3 solution and brine, and then
dried over anhydrous MgSO4. Purification by column chroma-
tography on silica gel (EtOAc–heptane, 2:98) afforded 0.38 g of
Palladium-Catalyzed Cross-Coupling Reaction
Into a 25 mL round-bottomed flask were added Pd(PPh3)2Cl2
(0.028 g, 2.0 mol%), 2-iodobenzonitrile (0.22 g, 1.0 mmol), and I
(4.0 mL, 0.5 M in THF, 2.0 mmol) under an argon atmosphere at
r.t. The resulting mixture was stirred at r.t. for 1.0 h, quenched
with 3 M HCl solution, then extracted with Et2O (3 × 10 mL),
washed with sat. NaHCO3, Na2S2O3 solution and brine, and then
dried over anhydrous MgSO4. Purification by column chroma-
tography on silica gel (EtOAc–heptane, 10:90) afforded 0.14 g of
4a in 72% isolated yield as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 7.53–7.46 (m, 3 H), 7.43–7.35 (m, 3 H), 7.31–7.29
(m, 1 H), 7.25–7.21 (m, 2 H), 4.04 (s, 2 H). 13C NMR (125 MHz,
CDCl3): δ = 142.71, 139.54, 133.53, 132.40, 129.99, 129.34,
129.01, 128.87, 126.76, 119.03, 112.51, 41.45.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 666–670

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