Direct addition of functionalized organozinc reagents to carbon dioxide, ketones, and aldehydes in the presence of MgCl2

Article abstract of DOI:10.1055/s-0030-1258314

A variety of functionalized organozinc reagents undergo smooth addition reactions at ambient temperature to carbon dioxide, ketones, and aldehydes in the presence of stoichiometric amounts of MgCl₂. Several reactions were performed on a 20 mmol scale. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258314

3802
PRACTICAL SYNTHETIC PROCEDURES
Direct Addition of Functionalized Organozinc Reagents to Carbon Dioxide,
Ketones, and Aldehydes in the Presence of MgCl2
Sebastian Bernhardt, Albrecht Metzger, Paul Knochel*
Ludwigs-Maximilians-Universität München, Department Chemie, Butenandtstraße 5-13, Haus F,
81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 22 September 2010; revised 6 October 2010
PSP
No196
Abstract: A variety of functionalized organozinc reagents undergo smooth addition reactions at ambient temperature to carbon dioxide,
ketones, and aldehydes in the presence of stoichiometric amounts of MgCl2. Several reactions were performed on a 20 mmol scale.
Key words: organozinc reagents, magnesium chloride, carbon dioxide, phenylacetic acid derivatives, addition reactions
procedure 1
Mg (2.5 equiv)
LiCl (0.75 equiv)
ZnCl2 (0.55 equiv)
Br
Zn·2MgX2·LiCl
X = Cl, Br
2
THF, 25 °C, 2 h
MeO
MeO
1a
2a: 90% (20 mmol scale)
procedure 2
Mg (2.5 equiv)
LiCl (0.75 equiv)
ZnCl2 (0.55 equiv)
Br
Zn·2MgX2·LiCl
2
THF, 25 °C, 2 h
TIPSO
TIPSO
X = Cl, Br
1b
2b: 86% (16 mmol scale)
procedure 3
O
Zn·2MgX2·LiCl
X = Cl, Br
CO2 (1 bar)
2
OH
THF, 25 °C, 3 h
MeO
MeO
2a (0.6 equiv)
4a: 94% (10 mmol scale)
95% (2 mmol scale)
procedure 4
F
CHO
OH
F
Zn·2MgX2·LiCl
3a (1.0 equiv)
2
THF, 25 °C, 6 h
TIPSO
TIPSO
X = Cl, Br
2b (0.6 equiv)
4b: 89% (8 mmol scale)
Scheme 1 Typical procedures for the preparation of organozinc reagents by direct magnesium insertion into the corresponding organic halides
in the presence of LiCl and ZnCl2 (procedures 1 and 2) and their addition reactions to carbon dioxide (procedure 3) or aldehydes (procedure 4)
at room temperature.
SYNTHESIS 2010, No. 22, pp 3802–3810
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Advanced online publication: 22.10.2010
DOI: 10.1055/s-0030-1258314; Art ID: T19210SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Reaction of Functionalized Organozinc Reagents with Carbonyl Substrates 3803
gous manner, substituted diarylzinc reagents 2c and 2d re-
acted with functionalized benzaldehydes 3c,d providing
Introduction
The addition reactions of organometallic reagents to ke- the corresponding alcohols 4d and 4e in 85–95% yield
tones, aldehydes, and carbon dioxide are essential trans- (entries 2 and 3). Furthermore, a direct addition of bis(4-
formations in organic synthesis as they provide a chlorophenyl)zinc·2MgX2 (2d) to 4-fluorobenzoyl chlo-
convenient access to various types of alcohols or carbox- ride (3e) furnished the benzophenone derivative 4f within
ylic acids.1 Among the different classes of organometallic 12 hours at 25 °C (81% yield; entry 4) without the need of
reagents, organozincs display a high functional group tol- using stoichiometric amounts of copper(I) salts. More-
erance.2 Their moderate reactivity towards various elec- over, heteroarylzinc reagents underwent addition
trophiles can be dramatically increased in the presence of reactions to benzaldehydes. Thus, the bis(5-pyra-
catalytic amounts of transition metal salts.3 Alternatively, zolyl)zinc·2MgX2 (2e) as well as the bis(1,2-oxazol-4-
it would be more economical to use inexpensive main- yl)zinc·2MgX2 (2f) added to aldehydes 3f and 3g provid-
group metal centered Lewis acids for the activation of car- ing the secondary alcohols 4g and 4h in 76–80% yield
bonyl functions towards the addition reaction of zinc re- (entries 5 and 6). Bis(hexylzinc)·2MgX2 (2g) was suc-
agents. Recently, we reported the preparation of cessfully used for the addition to 3-chlorobenzaldehyde
functionalized aryl-,4 benzyl-5 and alkylzinc6 reagents by (3f) and the desired secondary alcohol 4i was obtained af-
the direct magnesium insertion into the corresponding ha- ter 14 hours in 87% yield (entry 7). Bis-benzylic zinc re-
lides in the presence of LiCl and ZnCl2. Furthermore, we agents of type 2 [(ArCH2)2Zn·2MgCl2] as well as benzylic
have shown that these zinc reagents undergo smooth addi- zinc chlorides of type 5 (ArCH2ZnCl·MgCl2) can also be
tion reactions to various carbonyl derivatives and carbon used for efficient addition reactions. Thus, the electron-
dioxide at room temperatures without the use of polar co- poor bis[3-(ethoxycarbonyl)benzyl]zinc·2MgCl2 (2h) and
solvents.7 The increased reactivity of these organozincs the electron-rich bis(3-methoxybenzyl)zinc·2MgCl2 (2i)
can be assigned to the presence of stoichiometric amounts were used for the addition reactions to various ketones
of the Lewis acid MgCl2, which is usually formed during 3h,i and the desired alcohols 4j,k were isolated in 68 and
the preparation of the reagent.4–6 Herein, we wish to report 84% yield, respectively (entries 8 and 9). Furthermore, 4-
typical practical procedures illustrating these methods and methoxybenzylzinc chloride·MgCl2 (5a) added to 4-N,N-
their scale-up.
dimethylaminobenzaldehyde (3j) within one hour and the
alcohol 4l was obtained in 99% yield on a 10 mmol scale
(entry 10). Moreover, the reaction of 4-fluorobenzylzinc
chloride·MgCl2 (5b) with the acetophenone 3b and the
benzophenone 3k led to the tertiary alcohols 4m,n in 80
Scope and Limitations
The organozinc reagents were accessible under mild and 78% yield, respectively (entries 11 and 12).
conditions starting from the corresponding aryl and alkyl
Remarkably, these new zinc reagents reacted with carbon
bromides or benzyl chlorides. Thus, bis(4-methoxyphen-
dioxide without the need of a polar cosolvent and transi-
yl)zinc·2MgX2 (2a; X = Cl, Br) was prepared on a
tion metal catalysis. Thus, bis(benzylzinc)·2MgCl2 (2j)
20 mmol scale from 4-bromoanisole (1a) by oxidative ad-
and bis[3-methoxybenzyl]zinc·2MgCl2 (2i) were readily
dition of 2.5 equivalents of magnesium turnings in the
converted to the phenylacetic acids 4o and 4p at ambient
temperature in 76 and 98% yield, respectively (Table 2,
presence of 0.5 equivalent of ZnCl2 and 1.5 equivalents of
LiCl in 90% yield (procedure 1 of Scheme 1). The reac-
entries 1 and 2). Furthermore, the 2-chloro-substituted
tion proceeds smoothly in two hours at room temperature.
bis-benzylzinc reagent 2k was treated with carbon dioxide
and the functionalized phenylacetic acid derivative 4q
was obtained in 80% yield (entry 3) on a 10 mmol scale.
In an analogous manner bis(4-TIPSO-phenyl)zinc·2MgX2
(2b) was prepared from (4-bromophenoxy)(triisopro-
pyl)silane (1b) in 86% yield on a 16 mmol scale
Finally, bis(hexylzinc)·2MgX2 (2g) smoothly led to hep-
(procedure 2). Bis(4-methoxyphenyl)zinc·2MgX2 (2a;
tanoic acid (4r) after reaction with CO2 for 12 hours.
X = Cl, Br) added to carbon dioxide at 25 °C in THF and
In summary, efficient addition reactions of functionalized
organozinc reagents to various carbonyl derivatives in the
the corresponding benzoic acid 4a was obtained within
three hours in 94% yield on a 10 mmol scale (procedure 3
presence of MgCl2 were demonstrated. We have extended
of Scheme 1). Furthermore, the reaction of bis(4-TIPSO-
our previous work and have reported herein readily scal-
able experimental procedures (10–20 mmol scale). These
reactions can be performed with standard laboratory
phenyl)zinc·2MgX2 (2b) with 3-fluorobenzaldehyde (3a)
led to the secondary alcohol 4b in 89% on a 8 mmol scale
(procedure 4 of Scheme 1). Remarkably, both aryl groups
glassware and do not require the use of expensive chemi-
were transferred in this addition reaction. Similarly, bis(4-
cals. Further studies are currently underway in our labora-
tories to extend this method.
methoxyphenyl)zinc·2MgX2 (2a) added within one hour
to 4-cyanoacetophenone (3b) and the desired alcohol 4c
was isolated in 62% yield (Table 1, entry 1). In an analo-
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

3804
S. Bernhardt et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Addition Reactions of Functionalized Organozinc Reagents to Various Carbonyl Derivatives at 25 °C
Entry
1
Zinc reagenta
Electrophile
Time (h)b Product
Yield (%)c
62
O
HO
Zn·2MgX2
2
1
X = Cl, Br
MeO
MeO
CN
NC
2a (0.6 equiv)
3b (1.0 equiv)
4c
OH
O
Zn·2MgX2
2
2
3
4
5
3
4d
10
93
H
NMe2
X = Cl, Br
NMe2
CF3
F3C
2c (0.6 equiv)
3c (1.0 equiv)
95%
(10 mmol scale)
85%
OH
O
Zn·2MgX2
2
O
O
O
O
H
X = Cl, Br
(1.5 mmol scale)
Cl
Cl
Br
Br
2d (0.6 equiv)
3d (1.0 equiv)
4e
O
O
2d (0.6 equiv)
12
81
80
Cl
F
Cl
F
3e (1.0 equiv)
4f
OH
Ph
O
Cl
Cl
6
N
H
Zn·2MgCl2
2
N
N
N
Ph
2e (0.6 equiv)
3f (1.0 equiv)
4g
O
OH
Zn·2MgX2
2
H
6
14
76
N
N
O
O
N
N
N
N
X = Cl, Br
N
N
2f (0.6 equiv)
3g (1.0 equiv)
4h
OH
O
Zn·2MgX2
Cl
Cl
7
8
9
14
24
1
87
2
H
X = Cl, Br
2g (0.6 equiv)
3f (1.0 equiv)
4i
F
O
EtO2C
2
68d
Zn·2MgCl2
EtO2C
HO
F
2h (1.2 equiv)
3h (1.0 equiv)
4j
OH
O
MeO
MeO
Zn·2MgCl2
84
2
2i (0.6 equiv)
3i (1.0 equiv)
4k
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Reaction of Functionalized Organozinc Reagents with Carbonyl Substrates 3805
Table 1 Addition Reactions of Functionalized Organozinc Reagents to Various Carbonyl Derivatives at 25 °C (continued)
Entry
Zinc reagenta
Electrophile
Time (h)b Product
Yield (%)c
NMe2
O
99
ZnCl·MgCl2
10
1
H
(10 mmol scale)
MeO
OH
Me2N
MeO
5a (1.2 equiv)
3j (1.0 equiv)
4l
CN
O
ZnCl·MgCl2
11
12
15
80
78
F
HO
NC
F
5b (1.2 equiv)
3b (1.0 equiv)
4m
Cl
F
O
Cl
5b (1.2 equiv)
48
OH
Cl
Cl
3k (1.0 equiv)
4n
a Complexed LiCl is omitted for the sake of clarity.
b The reaction time for the addition reaction at 25 °C is given.
c Yield of isolated analytically pure product.
d The addition reaction was performed at 50 °C.
Table 2 Addition Reactions of Functionalized Organozinc Reagents to Carbon Dioxide at 25 °C
Entry
1
Zinc reagenta
Time (h)b
Product
Yield (%)c
76
OH
Zn·2MgCl2
2.5
2
O
2j
4o
MeO
MeO
OH
Zn·2MgCl2
2
3
4
25
12
12
98
2
O
2i
4p
OH
80
Zn·2MgCl2
2
Cl
(10 mmol scale)d
O
Cl
2k
2g
4q
4r
OH
86d
Zn·2MgX2
2
X = Cl, Br
O
a Complexed LiCl is omitted for the sake of clarity.
b The reaction time for the addition reaction to carbon dioxide at 25 °C is given.
c Yield of isolated analytically pure product.
d The addition reaction was performed at 50 °C.
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

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S. Bernhardt et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (400 MHz, DMSO-d6): d = 12.59 (s, 1 H), 7.91–7.85 (m,
All reactions were carried out under argon atmosphere in dried
glassware. All starting materials were purchased from commercial
suppliers and used without further purification unless otherwise
stated. THF was continuously refluxed and freshly distilled from
sodium benzophenone ketyl under N2. Yields refer to isolated com-
pounds estimated to be >95% pure as determined by 1H NMR spec-
troscopy and capillary GC analyses.
2 H), 7.03–6.96 (m, 2 H), 3.81 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 166.9, 162.8, 131.3, 122.9,
113.8, 55.4.
MS (EI, 70 eV): m/z (%) = 152 (M+, 100), 135 (86), 107 (10), 92
(16), 77 (25), 63 (12).
HRMS: m/z calcd for C8H8O3: 152.0473; found: 152.0468.
Mixed ZnCl2/LiCl Solution
ZnCl2/LiCl solution (1.1/1.5 M in THF) was prepared by drying
ZnCl2 (37.5 g, 275 mmol) and LiCl (15.9 g, 375 mmol) together in
a Schlenk flask under high vacuum (1 mbar) at 150 °C for 5 h under
vigorous stirring. After cooling to 25 °C, anhyd THF (250 mL) was
added and stirring was continued until all salts were dissolved.
(3-Fluorophenyl){4-[(triisopropylsilyl)oxy]phenyl}methanol
(4b); Typical Procedure 4
A 50 mL Schlenk flask, equipped with a magnetic stirring bar and a
septum, was flame-dried under high vacuum. After cooling to
25 °C, 3-fluorobenzaldehyde (3a; 1.05 g, 8.44 mmol) was added
and dissolved in THF (5 mL). Bis{4-[(triisopropylsilyl)oxy]phe-
nyl}zinc·2MgX2 (2b; X = Cl, Br; 22.2 mL, 5.1 mmol, 0.23 M in
THF) was added dropwise over a period of 5 min and the reaction
mixture was stirred for 6 h at 25 °C (GC-analysis of a reaction ali-
quot quenched with sat. aq NH4Cl showed complete conversion).
Then, the reaction mixture was cooled to 0 °C and quenched with
sat. aq NH4Cl (30 mL) and extracted with EtOAc (3 × 60 mL). The
combined organic phases were dried (MgSO4). Evaporation of the
solvents in vacuo and purification by flash chromatography (silica
gel, isohexane–Et2O, 5:1) afforded the alcohol 4b (2.81 g, 89%) as
a colorless oil.
Bis(4-Methoxyphenyl)zinc (2a); Typical Procedure 1
A 50 mL Schlenk flask, equipped with a magnetic stirring bar and a
septum, was flame-dried under high vacuum. Mg turnings (1.22 g,
50.0 mmol) were added followed by ZnCl2/LiCl solution (10.0 mL,
11.0 mmol/15.0 mmol, 1.1/1.5 M in THF). Then, 4-bromoanisole
(1a; 3.74 g, 20.0 mmol) was added dropwise as a solution in anhyd
THF (13.0 mL) using a water bath to keep the temperature below
30 °C. The reaction mixture was stirred for 2 h (GC analysis of a re-
action aliquot quenched with sat. aq NH4Cl showed complete con-
version). Then, the supernatant solution was carefully cannulated to
a new dry and argon-flushed 50 mL Schlenk flask through a syringe
filter. Iodometric titration of the zinc reagent 2a indicated a concen-
tration of 0.39 M, corresponding to a yield of 90%.8
IR (Diamond-ATR, neat): 3329 (w), 2866 (m), 1606 (m), 1507 (vs),
1263 (vs), 1011 (w), 911 (s), 881 (vs), 762 (s), 712 (m), 681 cm–1
(s).
1H NMR (300 MHz, CDCl3): d = 7.31–7.24 (m, 1 H), 7.19–7.16 (m,
2 H), 7.12–7.07 (m, 2 H), 6.96–6.90 (m, 1 H), 6.86–6.81 (m, 2 H),
5.75 (br s, 1 H), 2.19 (br s, 1 H), 1.29–1.16 (m, 3 H), 1.09 (d, J = 7.1
Hz, 18 H).
Bis(4-TIPSO-phenyl)zinc (2b); Typical Procedure 2
A 50 mL Schlenk flask, equipped with a magnetic stirring bar and a
septum, was flame-dried under high vacuum. Mg turnings (1.03 g,
42.5 mmol) were added followed by ZnCl2/LiCl solution (7.9 mL,
8.7 mmol/11.9 mmol, 1.1/1.5 M in THF). Then, (4-bromophen-
oxy)(triisopropyl)silane (1b; 5.19 g, 15.8 mmol) was added drop-
wise as a solution in anhyd THF (23.0 mL) using a water bath to
keep the temperature below 30 °C. The reaction mixture was stirred
for 2 h (GC analysis of a reaction aliquot quenched with sat. aq
NH4Cl showed complete conversion). Then, the supernatant solu-
tion was carefully cannulated to a new dry and argon-flushed 50 mL
Schlenk flask through a syringe filter. Iodometric titration of the
zinc reagent 2b indicated a concentration of 0.23 M, corresponding
to a yield of 86%.8
13C NMR (75 MHz, CDCl3): d = 162.9 (d, 1JC,F = 246.0 Hz), 155.8,
3
3
146.6 (d, JC,F = 6.7 Hz), 135.8, 129.8 (d, JC,F = 8.1 Hz), 127.9,
122.0 (d, 4JC,F = 3.1 Hz), 119.9, 114.1 (d, 2JC,F = 21.3 Hz), 113.3 (d,
2JC,F = 22.2 Hz) 75.3, 18.1, 15.2.
MS (EI, 70 eV): m/z (%) = 374 (M+, 29), 331 (100), 303 (22), 275
(26), 207 (12), 183 (14), 151 (20), 137 (25), 125 (28), 123 (18), 97
(30), 77 (12), 59 (10).
HRMS: m/z calcd for C22H31FO2Si: 374.2077; found: 374.2076.
Preparation of the Zinc Reagents of Type 2
Bis[2-(dimethylamino)phenyl]zinc (2c)
4-Methoxybenzoic Acid (4a); Typical Procedure 3
A 50 mL Schlenk flask, equipped with a magnetic stirring bar and a
septum, was flame-dried under high vacuum. After cooling to
25 °C, the flask was filled with gaseous CO2 generated from dry ice
and predried by streaming through a tube filled with solid CaCl2.
Then, bis(4-methoxyphenyl)zinc (2a; X = Cl, Br; 12.8 mL, 5.0
mmol, 0.39 M in THF) was added and dry CO2 was bubbled through
the reaction mixture for 5 min until a balloon attached to the reac-
tion flask by a short length rubber tubing and a needle adapter was
inflated. The reaction mixture was stirred for 3 h at 25 °C until the
zinc reagent had been completely consumed (GC analysis of a reac-
tion aliquot quenched with I2 showed complete conversion). The re-
action mixture was diluted with Et2O (20 mL) and sat. aq NaHCO3
(10 mL) was added. After filtration, the organic phase was separat-
ed and extracted with sat. aq NaHCO3 (3 × 50 mL). The combined
aqueous phases were carefully acidified with 5 M HCl until pH <5
and extracted with Et2O (3 × 100 mL). The combined organic phas-
es were dried (Na2SO4). Evaporation of the solvents in vacuo pro-
vided 4-methoxybenzoic acid (4a; 1.47 g, 94%) as a white solid; mp
185–186 °C.
According to TP1/2, (2-bromophenyl)dimethylamine (2.00 g,
10.0 mmol) in THF (6.7 mL) was treated with Mg turnings (608
mg, 25.0 mmol) in a THF solution (5.0 mL) of ZnCl2 (5.5 mmol)
and LiCl (7.5 mmol) at 25 °C for 2 h. After subsequent cannulation
to another argon-flushed Schlenk flask, iodometric titration of the
zinc reagent 2c indicated a concentration of 0.29 M.
Bis(4-chlorophenyl)zinc (2d)
According to TP1/2, 1-bromo-4-chlorobenzene (3.83 g, 20.0 mmol)
in THF (4.0 mL) was treated with Mg turnings (1.22 g, 50.0 mmol)
in a THF solution (10 mL) of ZnCl2 (11.0 mmol) and LiCl (15.0
mmol) at 25 °C for 1.5 h. After subsequent cannulation to another
argon-flushed Schlenk flask, iodometric titration of the zinc reagent
2d indicated a concentration of 0.71 M.
Bis(3-ethyl-1-phenyl-1H-pyrazol-5-yl)zinc (2e)
According to TP1/2, 5-chloro-3-methyl-1-phenyl-1H-pyrazole
(2.70 g, 14.0 mmol) in THF (9.3 mL) was treated with Mg turnings
(851 mg, 34.9 mmol) in a THF solution (7 mL) of ZnCl2 (7.7 mmol)
and LiCl (10.5 mmol) at 25 °C for 4 h. After subsequent cannula-
tion to another argon-flushed Schlenk flask, iodometric titration of
the zinc reagent 2e indicated a concentration of 0.34 M.
IR (Diamond-ATR, neat): 2842 (w), 2542 (w), 1678 (vs), 1602 (s),
1426 (m), 1260 (vs), 1166 (s), 1024 (s), 924 (s), 844 (s), 772 (s), 614
cm–1 (s).
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Reaction of Functionalized Organozinc Reagents with Carbonyl Substrates 3807
Bis(3,5-dimethylisoxazol-4-yl)zinc (2f)
Preparation of the Title Compounds of Type 4
According to TP1/2, 4-bromo-3,5-dimethylisoxazole (3.52 g,
20.0 mmol) in THF (10.0 mL) was treated with Mg turnings
(1.22 mg, 50.0 mmol) in a THF solution (10 mL) of ZnCl2 (11.0
mmol) and LiCl (15.0 mmol) at 25 °C for 1 h. After subsequent can-
nulation to another argon-flushed Schlenk flask, iodometric titra-
tion of the zinc reagent 2f indicated a concentration of 0.20 M.
4-[1-Hydroxy-1-(4-methoxyphenyl)ethyl]benzonitrile (4c)
According to TP4, bis(4-methoxyphenyl)zinc·2MgX2 (2a; X = Cl,
Br; 2.31 mL, 0.90 mmol, 0.39 M in THF) was added to 4-acetylben-
zonitrile (3b; 218 mg, 1.50 mmol) in THF (0.5 mL) and the reaction
mixture was stirred for 1 h at 25 °C. Purification by flash chroma-
tography (silica gel, pentane–Et2O, 9:1 + 1 vol% Et3N) afforded the
alcohol 4c (236 mg, 62%) as a white solid; mp 77–79 °C.
Bis(hexyl)zinc (2g)
IR (Diamond-ATR, neat): 3494 (m), 2231 (m), 1504 (s), 1448 (m),
1403 (m), 1245 (vs), 1194 (m), 1178 (s), 1028 (vs), 840 (s), 816
cm–1 (s).
1H NMR (400 MHz, C6D6): d = 7.13–7.07 (m, 4 H), 7.05–7.00 (m,
2 H), 6.76–6.70 (m, 2 H), 3.30 (s, 3 H), 1.70 (br s, 1 H), 1.50 (s, 3 H).
13C NMR (100 MHz, C6D6): d = 159.3, 153.7, 139.5, 131.8, 127.4,
126.6, 118.9, 113.8, 111.0, 75.2, 54.8, 30.5.
MS (EI, 70 eV): m/z (%) = 253 (M+, 12), 235 (100), 220 (27), 190
(9), 151 (8), 130 (21), 43 (5).
According to TP1/2, hexyl bromide (3.30 g, 20.0 mmol) in THF
(10.0 mL) was treated with Mg turnings (1.22 mg, 50.0 mmol) in a
THF solution (10.0 mL) of ZnCl2 (11.0 mmol) and LiCl (15.0
mmol) at 25 °C for 2 h. After subsequent cannulation to another ar-
gon-flushed Schlenk flask, iodometric titration of the zinc reagent
2g indicated a concentration of 0.31 M.
Bis(3-ethoxycarbonyl)benzylzinc (2h)
According to TP1/2, 3-(ethoxycarbonyl)benzyl chloride (2.71 g,
13.6 mmol) in THF (12 mL) was treated with Mg turnings (826 mg,
34.0 mmol) in a THF solution (6.80 mL) of ZnCl2 (7.45 mmol) and
LiCl (10.2 mmol) at 25 °C for 1.5 h. After subsequent cannulation
to another argon-flushed Schlenk flask, iodometric titration of the
zinc reagent 2h [premix of an aliquot with excess ZnCl2 solution
(1.00 M in THF)] indicated a concentration of 0.33 M.
HRMS: m/z calcd for C16H15NO2: 253.1103; found: 253.1094.
[2-(Dimethylamino)phenyl][4-(trifluoromethyl)phenyl]metha-
nol (4d)
According to TP4, bis[2-(dimethylamino)phenyl]zinc·2MgX2 (2c;
X = Cl, Br; 3.00 mL, 0.90 mmol, 0.30 M in THF) was added to 4-
(trifluoromethyl)benzaldehyde (3c; 261 mg, 1.5 mmol). The reac-
tion mixture was stirred for 3 h at 25 °C. Purification by flash chro-
matography (silica gel, pentane–EtOAc, 8:1 + 1 vol% Et3N)
afforded the alcohol 4d (413 mg, 93%) as a yellow oil.
Bis(3-methoxybenzyl)zinc (2i)
According to TP1/2, 3-methoxybenzyl chloride (2.35 g, 15.0 mmol)
in THF (8.0 mL) was treated with Mg turnings (608 mg, 25.0
mmol) in a THF solution (7.5 mL) of ZnCl2 (8.25 mmol) and LiCl
(11.3 mmol) at 25 °C for 2 h. After subsequent cannulation to an-
other argon-flushed Schlenk flask, iodometric titration of the zinc
reagent 2i [premix of an aliquot with excess ZnCl2 solution (1.00 M
in THF)] indicated a concentration of 0.31 M.
IR (Diamond-ATR, neat): 2945 (w), 2833 (w), 1618 (w), 1489 (m),
1322 (vs), 1160 (s), 1110 (s), 1065 (s), 1016 (s), 936 (m), 859 (m),
768 cm–1 (m).
1H NMR (400 MHz, DMSO-d6): d = 7.63 (d, J = 8.2 Hz, 2 H), 7.52
(d, J = 8.4 Hz, 2 H), 7.32–7.26 (m, 1 H), 7.24–7.18 (m, 2 H), 7.09–
7.02 (m, 1 H), 6.27 (d, J = 4.3 Hz, 1 H), 6.01 (d, J = 4.9 Hz, 1 H),
2.61 (s, 6 H).
Bis(benzyl)zinc (2j)
According to TP1/2, benzyl chloride (1.27 g, 10.0 mmol) in THF
(2.0 mL) was treated with Mg turnings (608 mg, 25.0 mmol) in a
THF solution (5.0 mL) of ZnCl2 (5.5 mmol) and LiCl (7.5 mmol) at
25 °C for 1 h. After subsequent cannulation to another argon-
flushed Schlenk flask, iodometric titration of the zinc reagent 2j
[premix of an aliquot with excess ZnCl2 solution (1.00 M in THF)]
indicated a concentration of 0.42 M.
4
13C NMR (100 MHz, DMSO-d6): d = 151.6, 150.7 (q, JC,F = 1.5
Hz), 139.7, 128.0, 128.0, 127.0 (q, 2JC,F = 31.9 Hz), 126.8, 124.8 (q,
3JC,F = 3.8 Hz), 124.4 (q, 1JC,F = 271.7 Hz), 124.1, 120.3, 68.3, 45.4.
MS (EI, 70 eV): m/z (%) = 295 (M+, 94), 280 (100), 276 (20), 262
(65), 242 (69), 173 (16), 145 (12), 106 (9), 91 (10), 77 (11).
HRMS: m/z calcd for C16H16F3NO: 295.1184; found: 295.1178.
Bis(2-chlorobenzyl)zinc (2k)
According to TP1/2, 2-chlorobenzyl chloride (3.22 g, 20.0 mmol) in
THF (5.0 mL) was treated with Mg turnings (1.22 g, 50.0 mmol)
and a THF solution (10 mL) of ZnCl2 (11.0 mmol) and LiCl (15.0
mmol) at 25 °C for 1 h. After subsequent cannulation to another
argon-flushed Schlenk flask, iodometric titration of the zinc reagent
2k [premix of an aliquot with excess ZnCl2 (1.00 M in THF)] indi-
cated a concentration of 0.54 M.
(6-Bromo-1,3-benzodioxol-5-yl)(4-chlorophenyl)methanol (4e)
According to TP4, bis(4-chlorophenyl)zinc·2MgX2 (2d; X = Cl, Br;
6.00 mL, 0.90 mmol, 0.15 M in THF) was added to 6-bromo-1,3-
benzodioxole-5-carbaldehyde (3d; 344 mg, 1.50 mmol) in THF
(1.0 mL). The reaction mixture was stirred for 10 h at 25 °C. Puri-
fication by flash chromatography (silica gel, pentane–Et2O, 6:1 + 1
vol% Et3N) afforded the alcohol 4e (438 mg, 85%) as pale yellow
oil.
4-Methoxybenzylzinc Chloride (5a)
According to TP1/2, 4-methoxybenzyl chloride (1.10 g, 7.00 mmol)
in THF (1.0 mL) was treated with Mg powder (425 mg, 17.5 mmol)
in a THF solution (7.0 mL) of ZnCl2 (7.7 mmol) and LiCl (10.5
mmol) at 25 °C for 2 h. After subsequent cannulation to another ar-
gon-flushed Schlenk flask, iodometric titration of the zinc reagent
5a indicated a concentration of 0.72 M.
IR (Diamond-ATR, neat): 3316 (w), 2896 (w), 1471 (vs), 1407 (m),
1388 (m), 1231 (s), 1103 (m), 1035 (vs), 1013 (s), 931 (s), 845 (s),
780 cm–1 (m).
1H NMR (400 MHz, acetone-d6): d = 7.44–7.38 (m, 2 H), 7.35–7.30
(m, 2 H), 7.12 (s, 1 H), 7.02 (s, 1 H), 6.07 (s, 1 H), 6.05 (d, J = 1.0
Hz, 1 H), 6.01 (d, J = 1.0 Hz, 1 H), 2.83 (br s, 1 H).
13C NMR (100 MHz, acetone-d6): d = 148.8, 148.7, 143.7, 138.0,
4-Fluorobenzylzinc Chloride (5b)
According to TP1/2, 4-fluorobenzyl chloride (2.17 g, 15.0 mmol) in
THF (7.5 mL) was treated with Mg turnings (911 mg, 37.5 mmol)
in a THF solution (15 mL) of ZnCl2 (16.5 mmol) and LiCl (22.5
mmol) at 25 °C for 45 min. After subsequent cannulation to another
argon-flushed Schlenk flask, iodometric titration of the zinc reagent
5b indicated a concentration of 0.39 M.
133.2, 129.3, 129.0, 112.9, 112.7, 108.8, 103.0, 73.6.
MS (EI, 70 eV): m/z (%) = 342 (100), 340 (M+, 76), 229 (48), 209
(13), 201 (10), 149 (14), 139 (50), 122 (35), 110 (10), 77 (18), 63
(8).
HRMS: m/z calcd for C14H10BrClO3: 339.9502; found: 339.9504.
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

3808
S. Bernhardt et al.
PRACTICAL SYNTHETIC PROCEDURES
1-(3-Chlorophenyl)heptan-1-ol (4i)
(4-Chlorophenyl)(4-fluorophenyl)methanone (4f)
According to TP4, bis(4-chlorophenyl)zinc·2MgX2 (2d; X = Cl, Br;
2.90 mL, 0.90 mmol, 0.31 M in THF) was added to 4-fluoroben-
zoylchloride (3e; 238 mg, 1.5 mmol) and the reaction mixture was
stirred for 12 h at 25 °C. Purification by flash chromatography (sil-
ica gel, pentane–Et2O, 8:1) afforded the benzophenone 4f (286 mg,
81%) as a colorless solid mp 118–119 °C.
According to TP4, bis(hexyl)zinc·2MgX2 (2g; X = Cl, Br; 2.90 mL,
0.90 mmol, 0.31 M in THF) was added to 3-chlorobenzaldehyde
(3f; 211 mg, 1.5 mmol) and the reaction mixture was stirred for 14
h at 25 °C. Purification by flash chromatography (silica gel, pen-
tane–Et2O, 3:1) afforded the alcohol 4i (295 mg, 87%) as a colorless
oil.
IR (Diamond-ATR, neat): 1648 (s), 1591 (s), 1504 (m), 1400 (m),
1271 (s), 1227 (s), 1155 (s), 1145 (s), 1085 (s), 853 (vs), 838 (s), 757
(vs), 672 cm–1 (s).
1H NMR (400 MHz, DMSO-d6): d = 7.84–7.79 (m, 2 H), 7.75–7.72
(m, 2 H), 7.63–7.60 (m, 2 H), 7.41–7.35 (m, 2 H).
IR (Diamond-ATR, neat): 3334 (w), 2927 (s), 1574 (w), 1432 (m),
1198 (m), 1044 (m), 882 (m), 783 (vs), 696 cm–1 (s).
1H NMR (400 MHz, DMSO-d6): d = 7.35–7.34 (m, 1 H), 7.32–7.30
(m, 1 H), 7.26–7.23 (m, 2 H), 5.25 (d, J = 4.7 Hz, 1 H), 4.52–4.48
(m, 1 H), 1.61–1.48 (m, 2 H), 1.34–1.16 (m, 8 H), 0.84–0.81 (m, 3
H).
13C NMR (100 MHz, DMSO-d6): d = 193.7, 164.8 (d, 1JC,F = 251.8
4
3
Hz), 137.6, 135.6, 133.2 (d, JC,F = 3.1 Hz), 132.6 (d, JC,F = 9.6
13C NMR (100 MHz, DMSO-d6): d = 149.2, 132.7, 129.8, 126.4,
125.6, 124.5, 71.6, 39.2, 31.3, 28.6, 25.1, 22.1, 13.9.
Hz), 131.4, 128.7, 115.7 (d, 2JC,F = 22.9 Hz).
MS (EI, 70 eV): m/z (%) = 234 (M+, 44), 199 (15), 141 (20), 138
MS (EI, 70 eV): m/z (%) = 226 (M+, 4), 143 (37), 141 (100), 113
(59), 123 (100), 111 (21), 95 (28), 75 (19).
(22), 77 (29).
HRMS: m/z calcd for C13H8ClFO: 234.0248; found: 234.0246.
HRMS: m/z calcd for C13H19ClO: 226.1124; found: 226.1119.
(3-Chlorophenyl)(3-methyl-1-phenyl-1H-pyrazol-5-yl)meth-
anol (4g)
Ethyl 3-[2-(4-Fluorophenyl)-2-hydroxypropyl]benzoate (4j)
According to TP4, 1-(4-fluorophenyl)ethanone (3h; 276 mg,
According to TP4, 3-chlorobenzaldehyde (3f; 211 mg, 1.50 mmol)
was added to bis(3-methyl-1-phenyl-1H-pyrazol-5-yl)zinc·2MgCl2
(2e; 2.65 mL, 0.90 mmol, 0.34 M in THF). The reaction mixture
was stirred for 6 h at 25 °C. Purification by flash chromatography
(silica gel, pentane–Et2O, 1:1 + 1 vol% Et3N) afforded the alcohol
4g (358 mg, 80%) as a white solid; mp 100–102 °C.
2.0 mmol)
was
added
to
bis(3-(ethoxycarbonyl)ben-
zyl)zinc·2MgCl2 (2h; 6.67 mL, 2.2 mmol, 0.33 M in THF). The re-
action mixture was stirred for 24 h at 50 °C. Purification by flash
chromatography (silica gel, pentane–EtOAc, 4:1 + 1 vol% Et3N) af-
forded the alcohol 4j (444 mg, 68%) as a pale yellow oil.
IR (Diamond-ATR, neat): 3480 (w), 1699 (s), 1603 (m), 1508 (s),
1277 (vs), 1223 (s), 1199 (s), 1160 (m), 1106 (s), 1088 (s), 836 (s),
755 (s), 720 cm–1 (s).
1H NMR (400 MHz, C6D6): d = 8.07–8.01 (m, 1 H), 7.95–7.92 (m,
1 H), 7.02–6.95 (m, 3 H), 6.95–6.91 (m, 1 H), 6.82–6.74 (m, 2 H),
4.17–4.08 (m, 2 H), 2.76 (d, J = 13.3 Hz, 1 H), 2.69 (d, J = 13.3 Hz,
1 H), 1.23 (s, 1 H), 1.16 (s, 3 H), 1.03 (t, J = 7.1 Hz, 3 H).
IR (Diamond-ATR, neat): 1504 (m), 1437 (m), 1370 (m), 1194 (m),
1146 (w), 1130 (w), 1050 (m), 1032 (s), 797 (vs), 772 (vs), 726 (s),
697 cm–1 (vs).
1H NMR (400 MHz, C6D6): d = 7.53–7.47 (m, 2 H), 7.28–7.25 (m,
1 H), 7.07–6.94 (m, 4 H), 6.87–6.83 (m, 1 H), 6.74 (t, J = 7.7 Hz, 1
H), 5.78 (s, 1 H), 5.45 (s, 1 H), 2.92 (s, 1 H), 2.16 (s, 3 H).
13C NMR (100 MHz, C6D6): d = 149.0, 145.8, 144.9, 140.3, 134.4,
13C NMR (100 MHz, C6D6): d = 166.4, 162.0 (d, 1JC,F = 244.4 Hz),
143.6 (d, 4JC,F = 3.1 Hz), 137.8, 135.1, 132.2, 130.8, 128.0, 128.0,
127.1 (d, 3JC,F = 8.0 Hz), 114.8 (d, 2JC,F = 21.0 Hz), 73.9, 60.8, 50.5,
29.2, 14.2.
MS (EI, 70 eV): m/z (%) = 302 (M+, <1), 184 (15), 257 (23), 211
(13), 196 (11), 164 (100), 139 (88), 136 (42), 118 (11), 91 (18), 43
(36).
129.6, 129.1, 127.8, 127.7, 126.9, 125.5, 124.8, 107.3, 67.3, 13.5.
MS (EI, 70 eV): m/z (%) = 298 (M+, 100), 221 (5), 204 (7), 185 (12),
159 (48), 139 (9), 116 (4), 77 (11).
HRMS: m/z calcd for C17H15ClN2O: 298.0873; found: 298.0869.
(3,5-Dimethylisoxazol-4-yl)[4-(1H-1,2,4-triazol-1-yl)phe-
nyl]methanol (4h)
HRMS: m/z calcd for C18H19FO3: 302.1318; found: 302.1306.
According to TP4, bis(3,5-dimethylisoxazol-4-yl)zinc·2MgX2 (2f;
X = Cl, Br; 3.64 mL, 1.20 mmol, 0.33 M in THF) was added to 4-
(1H-1,2,4-triazol-1-yl)benzaldehyde (3g; 346 mg, 2.00 mmol) in
THF (1.0 mL). The reaction mixture was stirred for 14 h at 25 °C.
Purification by flash chromatography (silica gel, EtOAc + 1 vol%
Et3N) afforded the alcohol 4h (413 mg, 76%) as a white solid; mp
129–130 °C.
1,1-Dicyclopropyl-2-(3-methoxyphenyl)ethanol (4k)
According to TP4, dicyclopropylmethanone (3i; 156 mg,
1.50 mmol) was added to bis(4-methoxybenzyl)zinc·2MgCl2 (2i;
2.90 mL, 0.90 mmol, 0.31 M in THF). The reaction mixture was
stirred for 1 h at 25 °C. Purification by flash chromatography (silica
gel, pentane–Et2O, 9:1 + 1 vol% Et3N) afforded the alcohol 4k (292
mg, 84%) as a colorless oil.
IR (Diamond-ATR, neat): 3328 (m), 1608 (m), 1522 (vs), 1424 (s),
1274 (s), 1154 (s), 1032 (s), 982 (s), 958 (m), 862 (s), 792 (vs), 674
cm–1 (vs).
1H NMR (400 MHz, acetone-d6): d = 9.01 (s, 1 H), 8.08 (s, 1 H),
7.89–7.81 (m, 2 H), 7.62–7.55 (m, 2 H), 5.93 (s, 1 H), 2.91 (br s, 1
H), 2.36 (s, 3 H), 2.03 (s, 3 H).
13C NMR (100 MHz, acetone-d6): d = 166.4, 159.4, 153.2, 144.0,
142.4, 137.1, 128.0, 120.2, 117.7, 66.2, 11.3, 10.8.
MS (EI, 70 eV): m/z (%) = 270 (M+, 29), 253 (8), 211 (7), 172 (9),
146 (100), 124 (13), 82 (7), 43 (9).
IR (Diamond-ATR, neat): 1601 (m), 1488 (s), 1453 (m), 1437 (m),
1312 (m), 1260 (vs), 1167 (s), 1153 (s), 1043 (s), 1022 (s), 994 (s),
778 (s), 703 cm–1 (s).
1H NMR (300 MHz, C6D6): d = 7.16–7.08 (m, 1 H), 7.02–6.98 (m,
1 H), 6.94–6.88 (m, 1 H), 6.78–6.71 (m, 1 H), 3.39 (s, 3 H), 2.80 (s,
2 H), 0.67–0.55 (m, 3 H, incl. OH), 0.44–0.32 (m, 4 H), 0.27–0.06
(m, 4 H).
13C NMR (75 MHz, C6D6): d = 159.9, 139.7, 129.0, 123.5, 117.2,
111.8, 70.6, 54.7, 49.4, 19.0, 1.3, –0.2.
MS (EI, 70 eV): m/z (%) = 232 (M+, <1), 214 (11), 185 (10), 122
(40), 111 (100), 91 (18), 77 (13), 69 (77), 57 (11), 41 (26).
HRMS: m/z calcd for C14H14N4O4: 270.1117; found: 270.1115.
HRMS: m/z calcd for C15H20O2: 232.1463; found: 232.1453.
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Reaction of Functionalized Organozinc Reagents with Carbonyl Substrates 3809
1-[4-(Dimethylamino)phenyl]-2-(4-methoxyphenyl)ethanol (4l)
According to TP4, 4-methoxybenzylzinc chloride·MgCl2 (5a; 36.1
mL, 13.0 mmol, 0.36 M in THF) was added to 4-(dimethylami-
no)benzaldehyde (3j; 1.49 g, 10.0 mmol) in THF (5 mL) and the re-
action mixture was stirred for 1 h at 25 °C. Purification by flash
chromatography (silica gel, pentane–Et2O, 2:5) afforded the alcohol
4l (2.68g, 99%) as a yellow solid; mp 113–115 °C.
Phenylacetic Acid (4o)
According to TP3, bis(benzyl)zinc·2MgCl2 (2j; 2.38 mL, 1.00
mmol, 0.42 M in THF) was treated with dry gaseous CO2 at 25 °C
for 2.5 h. After purification, phenylacetic acid (4o; 208 mg, 76%)
was obtained as a white solid; mp 80–82 °C.
IR (Diamond-ATR, neat): 2921 (w), 1692 (s), 1407 (m), 1336 (m),
1228 (m), 1186 (m), 892 (m), 839 (m), 751 (m), 699 (vs), 676 cm–1
(s).
IR (Diamond-ATR, neat): 1614 (m), 1522 (s), 1508 (s), 1440 (m),
1354 (m), 1243 (s), 1204 (m), 1184 (m), 1175 (m), 1156 (m), 1106
(m), 1045 (m), 1027 cm–1 (s).
1H NMR (400 MHz, C6D6): d = 7.27–7.22 (m, 2 H), 7.04–6.99 (m,
2 H), 6.76–6.71 (m, 2 H), 6.63–6.58 (m, 2 H), 4.75–4.70 (m, 1 H),
3.30 (s, 3 H), 3.06 (dd, J = 13.5, 7.4 Hz, 1 H), 2.98 (dd, J = 13.5, 5.7
Hz, 1 H), 2.53 (s, 6 H), 1.66 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 12.29 (br s, 1 H), 7.33–7.28
(m, 2 H), 7.27–7.20 (m, 3 H), 3.56 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 172.7, 135.0, 129.3, 128.2,
126.5, 40.7.
MS (EI, 70 eV): m/z (%) = 136 (M+, 72), 91 (100), 65 (12), 44 (5).
13C NMR (100 MHz, C6D6): d = 158.7, 150.4, 133.0, 131.0, 130.9,
HRMS: m/z calcd for C8H8O2: 136.0524; found: 136.0509.
127.3, 114.0, 112.7, 75.6, 54.7, 45.7, 40.3.
(3-Methoxyphenyl)acetic Acid (4p)
MS (EI, 70 eV): m/z (%) = 271 (M+, 2), 253 (58), 238 (27), 165 (6),
150 (100), 122 (7), 120 (6).
According to TP3, bis(3-methoxybenzyl)zinc·2MgCl2 (2i; 3.13 mL,
1.0 mmol, 0.32 M in THF) was treated with dry gaseous CO2 at
25 °C for 2 h. After purification, (3-methoxyphenyl)acetic acid (4p)
(326 mg, 98%) was obtained as a slightly red solid; mp 67–68 °C.
HRMS: m/z calcd for C17H21NO: 271.1572; found: 271.1570.
4-[2-(4-Fluorophenyl)-1-hydroxy-1-methylethyl]benzonitrile
(4m)
IR (Diamond-ATR, neat): 2920 (m), 1692 (s), 1492 (m), 1258 (s),
1212 (s), 1167 (s), 1035 (s), 996 (m), 893 (m), 792 (s), 756 cm–1
(vs).
1H NMR (400 MHz, DMSO-d6): d = 7.21 (t, J = 8.0 Hz, 1 H), 6.83–
6.79 (m, 3 H), 3.72 (s, 3 H), 3.52 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 172.6, 159.2, 136.5, 129.3,
121.6, 115.1, 112.0, 55.0, 40.7.
According to TP4, 4-fluorobenzylzinc chloride·MgCl2 (5b; 4.62
mL, 1.80 mmol, 0.39 M in THF) was added to 4-acetylbenzonitrile
(3b; 218 mg, 1.50 mmol) in THF (0.5 mL) and the reaction mixture
was stirred for 15 h at 25 °C. Purification by flash chromatography
(silica gel, pentane–Et2O, 1:1 + 1 vol% Et3N) afforded the alcohol
4m (305 mg, 80%) as yellowish solid; mp 93–95 °C.
MS (EI, 70 eV): m/z (%) = 166.1 (M+ 100), 121.1 (87), 91.1 (21).
HRMS: m/z calcd for C9H10O3: 166.0630; found: 166.0630 (M+).
IR (Diamond-ATR, neat): 3468 (m), 2234 (m), 1606 (m), 1404 (m),
1220 (s), 1144 (m), 1098 (m), 1075 (m), 1018 (m), 933 (m), 836
(vs), 821 (s), 770 (m), 709 cm–1 (m).
,
1H NMR (300 MHz, C6D6): d = 7.07–7.01 (m, 2 H), 6.91–6.85 (m,
2 H), 6.73–6.64 (m, 2 H), 6.61–6.53 (m, 2 H), 2.54 (d, J = 13.6 Hz,
1 H), 2.49 (d, J = 13.6 Hz, 1 H), 1.22 (br s, 1 H), 1.05 (s, 3 H).
(2-Chlorophenyl)acetic Acid (4q)
According to TP3, bis(2-chlorobenzyl)zinc·2MgCl2 (2k; 1.85 mL,
1.0 mmol, 0.52 M in THF) was treated with dry gaseous CO2 at
50 °C for 12 h. After purification, (2-chlorophenyl)acetic acid (4q)
(272 mg, 80%) was obtained as a white solid; mp 92–93 °C.
1
13C NMR (75 MHz, C6D6): d = 162 (d, JC,F = 244.8 Hz), 152.5,
3
4
132.2 (d, JC,F = 7.9 Hz), 132.2 (d, JC,F = 3.1 Hz), 131.7, 125.9,
2
5
118.9, 115.0 (d, JC,F = 21.0 Hz), 111.0, 73.9 (d, JC,F = 1.4 Hz),
IR (Diamond-ATR, neat): 2916 (w), 1699 (s), 1402 (m), 1238 (s),
1055 (m), 926 (m), 761 (vs), 733 (s), 687 cm–1 (s).
1H NMR (400 MHz, DMSO-d6): d = 7.45–7.36 (m, 2 H), 7.30–7.26
(m, 2 H), 3.70 (s, 2 H).
49.3, 28.8.
HRMS (ESI): m/z calcd for C16H14FNO: 273.1403 ([M + NH4]+);
found: 273.1397 ([M + NH4]+).
13C NMR (101 MHz, DMSO-d6): d = 171.5, 133.7, 133.3, 132.2,
1-(2-Chlorophenyl)-1-(4-chlorophenyl)-2-(4-fluorophenyl)eth-
anol (4n)
129.0, 128.8, 127.1, 38.7.
MS (EI, 70 eV): m/z (%) = 170 (M+, 40), 135 (76), 125 (100), 91
(50), 63 (10).
HRMS: m/z calcd for C8H7ClO2: 170.0135; found: 170.0133 (M+).
According to TP4, 4-fluorobenzylzinc chloride·MgCl2 (5b; 4.62
mL, 1.80 mmol, 0.39 M in THF) was added to (2-chlorophenyl)(4-
chlorophenyl)methanone (3k; 377 mg, 1.50 mmol) in THF
(0.5 mL) and the reaction mixture was stirred for 48 h at 25 °C. Pu-
rification by flash chromatography (silica gel, pentane–Et2O–
CH2Cl2, 18:1:1) afforded the alcohol 4n (422 mg, 78%) as yellow
solid; mp 90–92 °C.
Heptanoic Acid (4r)
According to TP3, bis(hexyl)zinc·2MgX2 (2g; X = Cl, Br; 3.22 mL,
1.00 mmol, 0.31 M in THF) was treated with dry gaseous CO2 at
50 °C for 12 h. After purification, heptanoic acid (4r) (223 mg,
86%) was obtained as a colorless oil.
IR (Diamond-ATR, neat): 1510 (s), 1488 (m), 1433 (m), 1224 (s),
1159 (m), 1092 (m), 1035 (m), 1014 (m), 1002 (m), 822 (vs), 756
(vs), 748 cm–1 (s).
1H NMR (400 MHz, C6D6): d = 7.39 (dd, J = 7.8, 1.8 Hz, 1 H),
7.07–7.00 (m, 3 H), 6.88–6.63 (m, 8 H), 3.70 (d, J = 13.1 Hz, 1 H),
3.04 (d, J = 13.1 Hz, 1 H), 2.31 (br s, 1 H).
IR (Diamond-ATR, neat):2928 (m), 1704 (vs), 1412 (m), 1283 (m),
1237 (m), 1206 (w), 1106 (w), 934 cm–1 (w).
1H NMR (400 MHz, DMSO-d6): d = 11.95 (s, 1 H), 2.17 (t, J = 7.4
Hz, 2 H), 1.50–1.43 (m, 2 H), 1.30–1.19 (m, 6 H), 0.86–0.83 (m, 3
H).
13C NMR (101 MHz, DMSO-d6): d = 174.5, 33.7, 31.0, 28.2, 24.5,
22.0, 13.9.
MS (EI, 70 eV): m/z (%) = 130 (M+, 1), 101 (10), 87 (30), 73 (60),
60 (100), 55 (16), 43 (16), 41 (23).
13C NMR (100 MHz, C6D6): d = 161.8 (d, 1JC,F = 244.2 Hz), 144.3,
3
4
142.2, 132.9, 132.2 (d, JC,F = 7.8 Hz), 132.0, 132.0 (d, JC,F = 3.3
Hz), 130.8, 128.6, 128.5, 128.0, 127.9, 126.1, 114.1 (d, 2JC,F = 21.0
Hz), 77.3 (d, 1JC,F = 1.4 Hz), 43.7.
HRMS (ESI): m/z calcd C20H15Cl3FO: 405.0466 ([M + HCO2]+);
found: 405.0462 ([M + HCO2]+).
HRMS: m/z calcd for C7H14O2: 130.0994; found: 130.0987 (M+).
Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York

3810
S. Bernhardt et al.
PRACTICAL SYNTHETIC PROCEDURES
(3) For selected examples, see: (a) Shi, J.; Zeng, X.; Negishi, E.
Org. Lett. 2003, 5, 1825. (b) Gavryushin, A.; Kofink, C.;
Manolikakes, G.; Knochel, P. Org. Lett. 2005, 7, 4871.
(c) Yeh, M. C. P.; Knochel, P.; Santa, L. E. Tetrahedron Lett.
1988, 29, 3887. (d) Reddy, C. K.; Knochel, P. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1700. (e) Kazmierski, I.;
Bastienne, M.; Gosmini, C.; Paris, J.-M.; Périchon, J. J. Org.
Chem. 2004, 69, 936. (f) Dong, Z.; Manolikakes, G.; Li, J.;
Knochel, P. Synthesis 2009, 681. (g) Monzon, G.; Knochel,
P. Synlett 2010, 304. (h) Tamaru, Y.; Nakamura, T.;
Sakaguchi, M.; Ochiai, H.; Yoshida, Z. J. Chem. Soc., Chem.
Commun. 1988, 610. (i) Metzger, A.; Gavryushin, A.;
Knochel, P. Synlett 2009, 1433. (j) Seebach, D.; Beck, A.
K.; Schmidt, B.; Wang, Y. M. Tetrahedron 1994, 50, 4363.
(4) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(b) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. H.;
Gavryushin, A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
(5) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun.
2008, 5824.
Acknowledgment
We thank the DFG and the European Research Council (ERC) for
financial support. We also thank Chemetall GmbH (Frankfurt) and
BASF SE (Ludwigshafen) for the generous gift of chemicals.
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Synthesis 2010, No. 22, 3802–3810 © Thieme Stuttgart · New York