Efficient preparation of polyfunctional organometallics via directed ortho -metalation

Article abstract of DOI:10.1055/s-0029-1218845

Highly functionalized organometallics are efficiently prepared in larger quantities (up to 4 g) by directed ortho-metalation using the previously reported amide bases TMP₂Mn2MgCl₂4LiCl (TMP=2,2,6,6-tetramethylpiperidyl), TMP₂Fe2MgCl₂4LiCl and TMP₃La3MgCl₂5LiCl. The resulting organometallics undergo various reactions with electrophiles like acid chlorides, alkyl iodides, or aldehydes and provide the corresponding products in good to excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218845

2670
PRACTICAL SYNTHETIC PROCEDURES
Efficient Preparation of Polyfunctional Organometallics via Directed
ortho-Metalation
P
olyfunctiona
t
O
rgan
e
ometallics
fvia Dire
a
tedortho-M
n
e
talation H. Wunderlich, Tomke Bresser, Cora Dunst, Gabriel Monzon, Paul Knochel*
Ludwig-Maximilians-Universität München, Department Chemie und Biochemie,
Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 22 April 2010
PSP
No190
Abstract: Highly functionalized organometallics are efficiently prepared in larger quantities (up to 4 g) by directed ortho-metalation using
the previously reported amide bases TMP2Mn·2MgCl2·4LiCl (TMP = 2,2,6,6-tetramethylpiperidyl), TMP2Fe·2MgCl2·4LiCl and
TMP3La·3MgCl2·5LiCl. The resulting organometallics undergo various reactions with electrophiles like acid chlorides, alkyl iodides, or
aldehydes and provide the corresponding products in good to excellent yields.
Key words: directed metalation, organometallics, metal amides, catalysis, LiCl
Procedure 1
Br
(1.1 equiv)
CO2Me
MeO2C
CO2Me
Mn
(TMP)2Mn•2MgCl2•4LiCl
(0.60 equiv)
2
CuCN•2LiCl
(5 mol%)
THF, 25 °C, 1 h
F
F
F
0 °C, 1 h
90%
CO2Et
Procedure 2
CO2Et
CO2Et
(TMP)2Fe•2MgCl2•4LiCl
Oct-I
(1.2 equiv)
(0.75 equiv)
C8H17
Fe
2
THF, 25 °C, 18 h
25 °C, 7 h
CN
CN
CN
78%
F
(10 mol%)
COCl
Procedure 3
CO2Me
CO2Me
La
MeO2C
O
(TMP)3La•3MgCl2•5LiCl
(0.35 equiv)
(1.0 equiv)
–5 °C, 1 h
3
THF, 0 °C, 3.5 h
Cl
Cl
Cl
81%
Scheme 1 General procedures for the preparation of highly functionalized organometallics and their reactions with various electrophiles
MnCl2·2LiCl,5 FeCl2·2LiCl6 and LaCl3·2LiCl7 leads to
Introduction
room temperature stable and highly kinetic active metala-
The metalation of functionalized unsaturated substrates tion reagents. The metalations occur under mild condi-
provides useful intermediates in organic synthesis. Be- tions (usually close to 25 °C) and display a high atom
sides traditional and well-investigated lithium reagents,1 a economy since all TMP moieties can be used for the di-
number of mixed ate-bases have been developed and rected metalation. The resulting organometallics can con-
structurally investigated.2 Although these approaches tain a variety of functional groups and they react with a
seemed to be promising, there is still a need for neutral number of electrophiles (in the presence of an appropriate
and easily manageable chemoselective bases for the met- catalyst, if needed). In general, we have shown that chang-
alation of organic substrates tolerating most functional- ing the metal of the amide bases also changes the behavior
ities at ambient temperature. Recently, we reported that of the corresponding organometallic reagent. Usually, the
the treatment of TMPMgCl·LiCl3 (1; TMP = 2,2,6,6-tet- optimization of these metalation procedures was carried
ramethylpiperidyl) with metallic chlorides such as ZnCl2,4 out in 1–2 mmol scale. Herein, we wish to report the ex-
tension of the preparation of functionalized organometal-
lics using the new metalation reagents of Mn, Fe, and La
to the experiments in larger scales (ca. 3–4 g scale)
(Scheme 1).
SYNTHESIS 2010, No. 15, pp 2670–2678
Advanced online publication: 29.06.2010
DOI: 10.1055/s-0029-1218845; Art ID: T09410SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

PRACTICAL SYNTHETIC PROCEDURES
Results and Discussion
Polyfunctional Organometallics via Directed ortho-Metalation
2671
hours at 0 °C using TMP2Mn·2MgCl2·4LiCl (2; 0.6 equiv)
and the ketone 6c is obtained in 70% yield after a
First, the amide bases 2–4 were efficiently prepared by the CuCN·2LiCl mediated acylation10 with 2-furoyl chloride
transmetalation of TMPMgCl·LiCl (1; Scheme 2). Thus, (entry 3).
the reaction of TMPMgCl·LiCl3 (1; 2.0 equiv) with a so-
lution of MnCl2·2LiCl8 (1 M in THF) provides the reagent
MnCl2•2LiCl
(1.0 equiv)
Cl
TMP2Mn·2MgCl2·4LiCl (2) in >95% yield by stirring
the mixture for 30 minutes at 0 °C and further for three
hours at 25 °C. Similarly, the new Fe(II)-base
TMP2Fe·2MgCl2·4LiCl (3) is obtained by the similar re-
action of TMPMgCl·LiCl (1; 2.0 equiv) with a solution of
N Mg
N Mg
N Mg
Li
Li
Li
N
Mn•2MgCl2•4LiCl
2
2
3
THF
0 to 25 °C,
3.5 h
2
Cl
2 TMP2Mn:a 95%; 0.50 M in THF
1
FeCl2·2LiCl
(1
M
in
THF).
Additionally,
FeCl2•2LiCl
(1.0 equiv)
TMP3La·3MgCl2·5LiCl (4) is prepared by the reaction of
TMPMgCl·LiCl (1; 3.0 equiv) with the THF soluble com-
plex LaCl3·2LiCl9 in THF for 12 hours. All three bases
can be stored at 25 °C under inert gas atmosphere for at
least two months without decomposition.
Cl
Cl
N
Fe•2MgCl2•4LiCl
THF
0 to 25 °C,
3.5 h
2
3 TMP2Fe:a 95%; 0.50 M in THF
1
We started these upscaling experiments with the directed
manganations using the manganese amide base 2. Thus,
the metalation of methyl 3-fluorobenzoate (5a) is
complete within one hour at 25 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.6 equiv). A CuCN·2LiCl
catalyzed allylation10 with 3-bromocyclohexene furnishes
the 1,2,3-trisubstituted arene 6a in 90% yield (Table 1, en-
try 1). Furthermore, the manganation of 4-fluorobenzoni-
trile (5b) takes place at 25°C within two hours using
TMP2Mn·2MgCl2·4LiCl (2; 0.6 equiv). A subsequent
CuCN·2LiCl mediated acylation10 with benzoyl chloride
leads to the benzophenone 6b in 68% yield (entry 2). Eth-
yl 4-cyanobenzoate (5c) is fully manganated within 1.25
LaCl3•2LiCl
(1.0 equiv)
Cl
Cl
N
La•3MgCl2•5LiCl
THF
25 °C, 12 h
3
4 TMP3La:a 95%; 0.33 M in THF
1
Scheme 2 Preparation of the bases 2–4. a LiCl and MgCl2 have been
omitted for the sake of clarity
Table 1 Preparation of the Products of Type 6 by Directed Metalation Using the TMP-Bases of Mn, Fe, and La
Entry Substrate (5)
Base
Temp (°C), Electrophile
time (h)
Product (6)
Yield (%)a
CO2Me
Br
MeO2C
1
5a
5b
TMP2Mn (2)
25, 1
6a: 90b
F
F
CN
F
O
CN
COCl
6b: 68c
6c: 70c
Ph
2
TMP2Mn (2)
TMP2Mn (2)
25, 2
F
O
CO2Et
CO2Et
O
3
5c
0, 1.25
COCl
O
CN
CN
CN
CN
Br
F
6d: 96b
F
4
5d
TMP2Mn (2)
0, 0.5
Br
Br
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

2672
S. H. Wunderlich et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Preparation of the Products of Type 6 by Directed Metalation Using the TMP-Bases of Mn, Fe, and La (continued)
Entry Substrate (5)
Base
Temp (°C), Electrophile
time (h)
Product (6)
Yield (%)a
OMe
OMe OH
CHO
N
N
N
5
5e
TMP2Mn (2)
0, 0.5
6e: 94
N
OMe
OMe
CO2Et
CO2Et
Cl
6
5f
TMP2Fe (3)
TMP2Fe (3)
TMP2Fe (3)
TMP2Fe (3)
25, 3
6f: 85
Ph
F
F
CO2Me
CO2Me
7
5a
5g
5g
25, 3
6g: 83d
6h: 78d
6i: 78d
I
F
F
CO2Et
CO2Et
C8H17
CN
8
25, 18
25, 18
I
5
CN
CO2Et
EtO2C
9
I
CN
CN
CN
CN
F
I
10
5b
TMP2Fe (3)
25, 18
6j: 69d
F
O
CO2Me
CHO
O
11
5h
5h
TMP3La (4)
TMP3La (4)
0, 3.5
0, 3.5
6k: 73
6l: 75
Cl
Cl
O
CO2Me
MeO2C
COCl
CHO
12
Ph
Cl
Cl
CN
CN
F
OMe
F
13
5d
TMP3La (4)
–35, 0.5
6m: 80
Br
Br
OMe
O
OH
O
O
CO2Et
Cl
14
15
5i
5j
TMP3La (4)
TMP3La (4)
–20, 0.75
0, 0.5
6n: 80
6o: 87
CO2Et
Cl
O
N
N
O
S
N
HO
S
N
a Isolated yield of analytically pure products.
b CuCN·2LiCl (5 mol%) was used.
c CuCN·2LiCl (20 mol%) was used.
d 4-Fluorostyrene (10 mol%) was used.
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctional Organometallics via Directed ortho-Metalation
2673
Surprisingly, the manganation of 5-bromo-2-fluoroben- In summary, we have demonstrated that the use of the bases
zonitrile (5d) is achieved in position adjacent to the fluo- TMP2Mn·2MgCl2·4LiCl (2), TMP2Fe·2MgCl2·4LiCl (3),
rine substituent within 30 minutes at 0 °C using and TMP3La·3MgCl2·5LiCl (4) leads smoothly to the cor-
TMP2Mn·2MgCl2·4LiCl (2; 0.6 equiv). A CuCN·2LiCl responding organometallics. The reactions are carried out
catalyzed allylation10 with 3-bromocyclohexene gives the in larger amounts and important functional groups like es-
highly functionalized arene 6d in 96% yield (entry 4). ters or cyano groups can be easily tolerated during the
Similarly, the metalation of 3,6-dimethoxypyridazine (5e) metalation protocols. Efficient and atom economical reac-
is accomplished within 30 minutes at 0 °C using tions with electrophiles provide the desired products in
TMP2Mn·2MgCl2·4LiCl (2; 0.6 equiv). The addition of good to excellent yields. The application of these bases to
the metalated species to benzaldehyde provides the alco- more complex systems is currently underway in our labo-
hol 6e in 94% yield (entry 5).
ratories.
Furthermore, the directed ferration and the subsequent
cross-couplings catalyzed by nickel impurities can also be
carried out in larger scales. Thus, the metalation of ethyl
3-fluorobenzoate (5f) leads to the fully ferrated arene
within three hours at 25 °C. The subsequent reaction with
benzyl chloride affords the substituted diphenylmethane
6f in 85% yield (entry 6). Similarly, the ferration of meth-
yl 3-fluorobenzoate (5a) using TMP2Fe·2MgCl2·4LiCl (3;
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes which were used to transfer anhydrous
solvents or reagents were purged with argon prior to use. THF was
continuously refluxed and freshly distilled from sodium benzophe-
none ketyl under N2. Yields refer to isolated yields of compounds
estimated to be >95% pure as determined by 1H NMR spectroscopy
(25 °C) and capillary GC analysis. NMR spectra were recorded on
solutions in CDCl3 with residual CHCl3 (d = 7.25 for 1H NMR and
0.75 equiv) is also finished within three hours at 25 °C. 77.0 for 13C NMR), DMSO-d6 (d = 2.49 for 1H NMR and 39.5 for
13C NMR). Column chromatographical purifications were per-
An adjacent alkylation with 1-iodobutane in the presence
of 4-fluorostyrene11 furnishes the alkylated arene 6g in
formed using SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) from
Merck, unless otherwise indicated. TMPH, liquid acid chlorides and
aldehydes were distilled prior to use. LaCl3·2LiCl was purchased as
83% yield (entry 7). Arenes bearing cyano groups can also
be used for this ferration procedure. Thus, ethyl 3-cy-
a 0.5 M solution in THF from Chemetall GmbH, Frankfurt.
anobenzoate (5g) is metalated regioselectively in position
2 within 18 hours at 25 °C using TMP2Fe·2MgCl2·4LiCl
(3; 0.75 equiv). The subsequent alkylation reactions with
either 1-iodooctane or 2-iodopropane in the presence of 4-
fluorostyrene provide the products 6h,i in 78% yield in
both cases (entries 8 and 9). Additionally, the metalation
of 4-fluorobenzonitrile (5b) is readily finished within
18 hours at 25 °C using TMP2Fe·2MgCl2·4LiCl (3;
0.75 equiv). An alkylation with iodocyclohexane in the
presence of 4-fluorostyrene affords the functionalized
benzonitrile 6j in 69% yield (entry 10).
Reagent MnCl2·2LiCl (1 M in THF)
A dry and argon-flushed 250 mL Schlenk tube, equipped with a
magnetic stirring bar and a glass stopper, was charged with LiCl
(6.8 g, 160 mmol) and heated up to 150 °C under high vacuum for
3 h. After cooling to r.t. under argon, MnCl2 (10.1 g, 80 mmol, 99%
pure) was added under inert atmosphere inside a glove box. The
Schlenk flask was further heated to 130 °C for 3 h under high
vacuum, cooled to r.t., and charged with freshly distilled THF (80
mL) under argon with vigorous stirring. The mixture was stirred for
at least 24 h at 25 °C. The reagent MnCl2·2LiCl (1.0 M in THF) was
obtained as a yellow solution.
Subsequently, the lanthanations were investigated. Thus,
methyl 3-chlorobenzoate (5h) is converted into the fully
lanthanated species within 3.5 hours at 0 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 equiv). The subsequent
additions to electrophiles bearing carbonyl groups like cy-
clohexanecarbaldehyde or benzoyl chloride furnish the
lactone 6k and the benzophenone 6l in 73 and 75% yield,
respectively (entries 11,12). Furthermore, after 30 min-
utes at –35 °C, the metalation of 5-bromo-2-fluoroben-
zonitrile (5d) is complete using TMP3La·3MgCl2·5LiCl
(4; 0.35 equiv) and the adjacent addition to 4-methoxy-
benzaldehyde gives the alcohol 6m in 80% yield (entry
13). Moreover, ethyl 2-chloronicotinate (5i) is fully
metalated after 45 minutes at –20 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 equiv) and a subsequent
acylation with 2,2-dimethylpropanoic anhydride provides
the highly functionalized pyridine 6n in 80% yield (entry
14). Finally, the lanthanation of benzothiazole (5j) is
readily finished after 30 minutes at 0 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 equiv) and the reaction of
the metalated species with a-tetralone leads to the tertiary
alcohol 6o in 87% yield (entry 15).
Reagent FeCl2·2LiCl (1 M in THF)
A dry and argon-flushed 250 mL Schlenk tube, equipped with a
magnetic stirring bar and a glass stopper, was charged with LiCl
(4.7 g, 110 mmol) and heated up to 150 °C under high vacuum for
3 h. After cooling to r.t. under argon, FeCl2 (6.34 g, 50 mmol, 98%
pure) was added under inert atmosphere inside a glove box. The
Schlenk flask was further heated to 130 °C for 5 h under high
vacuum, cooled to r.t., charged with freshly distilled THF (50 mL)
under argon and wrapped in an aluminum foil to protect it from
light. The mixture was vigorously stirred until all solid goes in so-
lution (ca. 6 h). The reagent FeCl2·2LiCl (1.0 M in THF) was ob-
tained as a brown solution.
Reagent TMP2Mn·2MgCl2·4LiCl (2)
In a dry and argon-flushed 250 mL Schlenk flask, freshly titrated
TMPMgCl·LiCl (1; 200 mmol, 1.18 M, 170 mL) was purged and
cooled to 0 °C. Then, MnCl2·2LiCl (1 M in THF, 100 mL,
100 mmol) was added over a period of 5 min. The resulting mixture
was stirred for 30 min at 0 °C, warmed to 25 °C, and stirred for an-
other 3 h. The resulting solution of TMP2Mn·2MgCl2·4LiCl (2) was
concentrated in vacuo and was titrated prior to use at 0 °C with ben-
zoic acid using 4-(phenylazo)diphenylamine as indicator. A con-
centration of up to 0.5 M in THF was obtained.
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

2674
S. H. Wunderlich et al.
PRACTICAL SYNTHETIC PROCEDURES
Manganation of Functionalized Aromatics and Heteroaromat-
ics Using TMP2Mn·2MgCl2·4LiCl (2); General Procedure (GP
1)
After filtration, the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (pentane–
Et2O, 9:1) to give 6a (2.96 g, 90%) as a colorless oil.
In a dry argon-flushed 100 mL Schlenk flask, equipped with a mag-
netic stirring bar and a septum, the starting material was dissolved
in THF (1 mL per mmol). This solution was brought to the given
temperature, then TMP2Mn·2MgCl2·4LiCl (2) was added dropwise
and stirred at this temperature for the indicated time. Complete met-
alation was monitored by GC analysis of reaction aliquots, which
were quenched with allyl bromide in the presence of CuCN·2LiCl
in anhyd THF using tetradecane as internal standard (Table 1).
IR (Diamond-ATR, neat): 3021, 2933, 2860, 2837, 1722, 1651,
1609, 1576, 1452, 1432, 1283, 1254, 1240, 1192, 1169, 1140, 1130,
1072, 1049, 999, 932, 903, 871, 812, 802, 794, 770, 734, 719, 693,
684, 622 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.39 (m, 1 H), 7.28–7.10 (m,
2 H), 5.85–5.77 (m, 1 H), 5.66–5.60 (m, 1 H), 4.12–4.01 (m, 1 H),
3.88 (s, 3 H), 2.22–2.00 (m, 3 H), 1.96–1.83 (m, 2 H), 1.80–1.63 (m,
1 H).
13C NMR (75 MHz, CDCl3): d = 168.5 (d, J = 3.9 Hz), 161.9 (d,
J = 245 Hz), 133.4 (dd, J = 5.2 Hz, J = 44.3 Hz), 129.3 (d, J = 1.3
Hz), 127.2 (d, J = 9.3 Hz), 126.8 (d, J = 2.3 Hz), 124.9 (d, J = 3.4
Hz), 118.5 (d, J = 23.5 Hz), 52.1, 36.2 (d, J = 1.3 Hz), 29.1 (d,
J = 1.6 Hz), 24.6, 22.9.
MS (EI, 70 eV): m/z (%) = 234 (16, [M+]), 202 (100), 184 (34), 159
(16), 146 (23), 133 (21), 73 (16), 69 (17), 40 (18).
Reagent TMP2Fe·2MgCl2·4LiCl (3)
In a dry and argon-flushed 250 mL Schlenk flask, freshly titrated
TMPMgCl·LiCl (1; 100 mmol, 1.18 M, 85 mL) was purged and
cooled to 0 °C. Then, FeCl2·2LiCl (1 M in THF, 50 mL, 50 mmol)
was added over 5 min. The resulting mixture was stirred for 30 min
at 0 °C, warmed to 25 °C, and stirred for another 3 h. The resulting
solution of TMP2Fe·2MgCl2·4LiCl (3) was concentrated in vacuo
and was titrated prior to use at 0 °C with benzoic acid (0.2 M in
THF) using 4-(phenylazo)diphenylamine as indicator. A concentra-
tion of up to 0.5 M in THF was obtained.
HRMS (EI): m/z calcd for C14H15FO2: 234.1056; found: 234.1058.
2-Benzoyl-4-fluorobenzonitrile (6b)
According to GP 1, the metalation of 4-fluorobenzonitrile (5b;
1.94 g, 16 mmol) was complete within 1 h at 25 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.52 M in THF, 16.2 mL, 8.4 mmol).
The reaction mixture was then cooled to –30 °C, CuCN·2LiCl (1 M
solution in THF, 3.2 mL) and benzoyl chloride (2.92 g, 20.8 mmol)
were then added dropwise and was allowed to warm up slowly to
20 °C and stirred at this temperature for 3 h. The resulting mixture
was then quenched with sat. aq NH4Cl (60 mL), extracted with Et2O
(3 × 100 mL), and the combined Et2O layers were dried (Na2SO4).
After filtration, the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (pentane–
Et2O, 5:1) to give 6b (2.48 g, 68%) as a colorless solid; mp 77.8–
88.9 °C.
Ferration of Functionalized Aromatics Using
TMP2Fe·2MgCl2·4LiCl (3); General Procedure (GP 2)
In a dry argon-flushed 100 mL Schlenk flask, equipped with a mag-
netic stirring bar and a septum, the starting material was dissolved
in THF (1 mL per mmol). Then, TMP2Fe·2MgCl2·4LiCl (3) was
added dropwise at 25 °C and stirred at this temperature for the indi-
cated time. The metalation progress was monitored by GC analysis
of the reaction aliquots, which were quenched with allyl bromide in
the presence of CuCN·2LiCl in anhyd THF using tetradecane as in-
ternal standard (Table 1).
Reagent TMP3La·3MgCl2·5LiCl (4)
In a dry and argon-flushed 250 mL Schlenk flask, freshly titrated
TMPMgCl·LiCl (1; 100 mmol, 1.18 M, 85 mL) was purged with N2
and cooled to 0 °C. Then, freshly titrated LaCl3·2LiCl (0.5 M in
THF, 66 mL, 33 mmol) was added over 5 min. The resulting mix-
ture was stirred for 30 min at 0 °C, warmed to 25 °C and stirred for
another 12 h. The resulting solution of TMP3La·3MgCl2·5LiCl (4)
was concentrated in vacuo and was titrated prior to use at 0 °C with
benzoic acid using 4-(phenylazo)diphenylamine as indicator. A
concentration of up to 0.35 M in THF was obtained.
IR (Diamond-ATR, neat): 3348, 3103, 1066, 1049, 2921, 2229,
1963, 1908, 1733, 1652, 1637, 1597, 1578, 1533, 1484, 1449, 1404,
1363, 1316, 1302, 1280, 1230, 1198, 1178, 1134, 1106, 1072, 1024,
1000, 974, 922, 881, 853, 830, 807, 740, 728, 714, 696, 672, 645,
623 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87–7.77 (m, 4 H), 7.67–7.62 (m,
1 H), 7.52–7.17 (m, 2 H), 7.30 (t, J = 8.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 190.8, 161.4 (d, J = 245 Hz),
136.6 (d, J = 9.8 Hz), 136.3, 135.5 (d, J = 4.6 Hz), 134.2, 129.8 (d,
J = 0.8 Hz), 128.8, 117.9 (d, J = 23.5 Hz), 117.2, 109.2 (d, J = 3.9
Hz).
MS (EI, 70 eV): m/z (%) = 225 (29, [M+]), 148 (14), 105 (100), 77
(30), 74 (16), 59 (22), 45 (15)
Lanthanation of Functionalized Aromatics and Heteroaromat-
ics Using TMP3La·3MgCl2·5LiCl (4); General Procedure (GP 3)
In a dry argon-flushed 100 mL Schlenk flask, equipped with a mag-
netic stirring bar and a septum, the starting material (1 equiv) was
dissolved in THF (1 mL per mmol). This solution was brought to the
given temperature, then TMP3La·3MgCl2·5LiCl (4; 0.75 equiv) was
added dropwise and stirred at this temperature for the indicated
time. The metalation progress was monitored by GC analysis of re-
action aliquots, which were quenched with allyl bromide in the
presence of CuCN·2LiCl in anhyd THF using tetradecane as inter-
nal standard (Table 1).
HRMS (EI): m/z calcd for C14H8FNO: 225.0590; found: 225.0589.
4-Cyano-2-(furan-2-carbonyl)benzoic Acid Ethyl Ester (6c)
According to GP 1, the metalation of ethyl 4-cyanobenzoate (5c;
2.45 g, 14.0 mmol) was complete within 75 min at 0 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.48 M in THF, 17.5 mL, 8.4 mmol).
The reaction mixture was then cooled to –30 °C, CuCN·2LiCl (1 M
solution in THF, 15.4 mL, 15.4 mmol) and 2-furoyl chloride (2.19
g, 16.8 mmol) were then added dropwise and allowed to warm up
slowly to 20 °C and stirred at this temperature for 3 h. The resulting
mixture was then quenched with sat. aq NH4Cl (60 mL), extracted
with Et2O (3 × 100 mL), and the combined Et2O layers were dried
(Na2SO4). After filtration, the solvent was evaporated in vacuo. The
crude product was purified by column chromatography (pentane–
Et2O, 65:35) to give 6c (2.64 g, 70%) as a yellowish solid; mp
115.9–117.4 °C.
Methyl 2-Cyclohex-2-en-1-yl-3-fluorobenzoate (6a)
According to GP 1, the metalation of methyl 3-fluorbenzoate (5a;
2.46 g, 16.0 mmol) was complete within 1 h at 25 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.52 M in THF, 16.2 mL, 8.4 mmol).
The reaction mixture was then cooled to –30 °C, CuCN·2LiCl (1 M
solution in THF, 0.8 mL) and 3-bromocyclohexene (2.7 g, 16.8
mmol) were then added dropwise and the mixture was allowed to
warm up slowly to 20 °C overnight. The resulting mixture was then
quenched with a sat. aq NH4Cl (60 mL), extracted with Et2O
(3 × 100 mL) and the combined Et2O layers were dried (Na2SO4).
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctional Organometallics via Directed ortho-Metalation
2675
IR (Diamond-ATR, neat): 3139, 3047, 2996, 2908, 2360, 2234,
2100, 1714, 1654, 1604, 1564, 1468, 1402, 1387, 1364, 1308, 1293,
1278, 1237, 1212, 1166, 1145, 1118, 1080, 1024, 1016, 982, 976,
914, 891, 882, 875, 858, 807, 777, 769, 750, 715, 697, 678, 632, 621
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10 (d, J = 8.3 Hz, 1 H), 7.84 (dd,
J = 6.6, 1.7 Hz, 1 H), 7.76 (d, J = 1.7 Hz, 1 H), 7.60 (s, 1 H), 7.07
(d, J = 3.6 Hz, 1 H), 6.56 (q, J = 1.7 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2
H), 1.12 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 181.6, 164.7, 152.1, 147.6, 140.7,
133.7, 133.6, 131.6, 130.8, 119.6, 117.1, 116.0, 112.8, 62.4, 13.6.
MS (EI, 70 eV): m/z (%) = 269 (44, [M+]), 241 (45), 240 (18), 224
(99), 213 (31), 212 (91), 197 (18), 184 (22), 174 (41), 169 (15), 168
(17), 140 (61), 129 (20), 95 (100), 63 (15).
1H NMR (300 MHz, CDCl3): d = 7.48–7.44 (m, 4 H), 7.43 (d,
J = 5.8 Hz, 1 H), 5.99 (s, 1 H), 4.15 (s, 3 H), 4.11 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 162.7, 159.4, 140.4, 137.3, 128.6,
128.3, 126.9, 117.2, 70.2, 54.6, 54.5.
MS (EI, 70 eV): m/z (%) = 246 (100, [M+]), 245 (43), 231 (41), 155
(41), 153 (34), 105 (15).
HRMS (EI): m/z calcd for C13H14N2O3: 246.1004; found: 246.0981.
2-Benzyl-3-fluorobenzoic Acid Ethyl Ester (6f)
According to GP 2, the metalation of ethyl 3-fluorobenzoate (5f;
2.52 g, 15.0 mmol) was complete within 3 h at 25 °C using
TMP2Fe·2MgCl2·4LiCl (3; 0.53 M in THF, 21.2 mL, 11.25 mmol).
Benzyl chloride (2.28 g, 2.1 mL, 18.0 mmol) was then added drop-
wise and the reaction mixture was allowed to stir at 25 °C overnight.
The resulting mixture was then quenched with a mixture of sat. aq
NH4Cl (60 mL) and aq 2 M HCl (25 mL), extracted with Et2O
(3 × 100 mL) and the combined Et2O layers were dried (Na2SO4).
After filtration, the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (pentane–
Et2O, 10:1) to give 6f (3.3 g, 85%) as a colorless oil.
HRMS (EI): m/z calcd for C15H11NO4: 269.0688; found: 269.0667.
5-Bromo-2-fluoro-1¢,2¢,3¢,4¢-tetrahydro-[1,1¢-biphenyl]-3-car-
bonitrile (6d)
According to GP 1, the metalation of 5-bromo-2-fluorobenzonitrile
(5d; 3.00 g, 15 mmol) was complete within 0.5 h at 0 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.34 M in THF, 26.4 mL, 9.0 mmol).
The reaction mixture was then cooled to –30 °C, CuCN·2LiCl (1 M
solution in THF, 3.0 mL) and 3-bromocyclohexene (1.95 mL, 15.0
mmol) were then added dropwise and the mixture was allowed to
warm up slowly to 20 °C overnight. The resulting mixture was then
quenched with sat. aq NH4Cl (60 mL), extracted with Et2O (3 × 100
mL) and the combined Et2O layers were dried (Na2SO4). After fil-
tration, the solvent was evaporated in vacuo. The crude product was
purified by column chromatography (pentane–Et2O, 50:1) to give
6d (4.03 g, 96%) as a colorless oil.
IR (Diamond-ATR, neat): 3030, 2982, 2938, 1718, 1604, 1583,
1496, 1452, 1391, 1367, 1259, 1215, 1182, 1172, 1159, 1132, 1112,
1096, 1075, 1025, 969, 912, 865, 843, 829, 798, 785, 755, 730, 720,
695, 640 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75–7.72 (m, 1 H), 7.35–7.17 (m,
7 H), 4.48 (d, J = 1.9 Hz, 2 H), 4.34 (q, J = 7.3 Hz, 2 H), 1.33 (t,
J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 186.7 (d, J = 3.4 Hz), 161.5 (d,
J = 245 Hz), 139.9, 132.5 (d, J = 4.1 Hz), 129.0 (d, J = 17.0 Hz),
128.3 (d, J = 1.0 Hz), 128.1, 127.4 (d, J = 8.8 Hz), 126.1 (d, J = 3.6
Hz), 125.8, 118.8 (d, J = 23.7 Hz), 61.1, 30.9 (d, J = 4.6 Hz), 14.1.
IR (Diamond-ATR, neat): 2931, 2862, 2239, 1458, 1448, 1325,
1314, 1294, 1274, 1261, 1248, 1230, 1222, 1199, 952, 925, 920,
870, 775, 766, 742, 723, 700, 681, 636, 614 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.12–8.10 (m, 1 H), 7.66–7.63 (m,
1 H), 6.00–5.95 (m, 1 H), 5.59–5.55 (m, 1 H), 3.73–3.68 (m, 1 H),
2.08–1.90 (m, 3 H), 1.65–1.46 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.9 (d, J = 256.4 Hz), 137.3 (d,
J = 5.7 Hz), 136.1 (d, J = 14.9 Hz), 133.7, 130.3, 126.8, 116.6 (d,
J = 3.8 Hz), 112.9, 102.3 (d, J = 17.3 Hz), 34.1, 29.3, 24.2, 20.2.
MS (EI, 70 eV): m/z (%) = 282 (11), 281 (51), 280 (9, [M+]), 279
(49), 266 (38), 264 (32), 251 (11), 227 (14), 225 (15), 200 (22), 185
(32), 184 (12), 173 (15), 172 (100), 171 (28), 159 (43), 158 (29),
152 (23), 145 (21), 144 (10), 67 (29), 54 (69), 41 (28).
MS (EI, 70 eV): m/z (%) = 258 (3, [M+]), 213 (22), 212 (100), 183
(21), 151 (10).
HRMS (EI): m/z calcd for C16H15FO2: 258.1056; found: 258.1059.
Methyl 2-Butyl-3-fluorobenzoate (6g)
According to GP 2, the metalation of methyl 3-fluorobenzoate (5a;
2.46 g, 16.0 mmol) was complete within 3 h at 25 °C using
TMP2Fe·2MgCl2·4LiCl (3; 0.43 M in THF, 28.0 mL, 12.0 mmol).
1-Iodobutane (3.53 g, 19.2 mmol) and 4-fluorostyrene (370 mg)
were then added dropwise and the reaction mixture was allowed to
stir at 25 °C overnight. The resulting mixture was then quenched
with a mixture of sat. aq NH4Cl (60 mL) and aq 2 M HCl (25 mL),
extracted with Et2O (3 × 100 mL) and the combined Et2O layers
were dried (Na2SO4). After filtration, the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
(pentane–Et2O, 80:1) to give 6g (2.79 g, 83%) as a colorless oil.
HRMS (EI): m/z calcd for C13H11BrFN: 279.0059; found: 279.0055.
(3,6-Dimethoxypyridazin-4-yl)phenylmethanol (6e)
According to GP 1, the metalation of 3,6-dimethoxypyridazine (5e;
2.10 g, 15.0 mmol) was complete within 30 min at 0 °C using
TMP2Mn·2MgCl2·4LiCl (2; 0.48 M in THF, 18.8 mL, 9.0 mmol).
Then, benzaldehyde (1.91 g, 18.0 mmol) was added dropwise and
the reaction mixture was allowed to warm up slowly to 20 °C and
stirred at this temperature for 3 h. The resulting mixture was then
quenched with sat. aq NH4Cl (60 mL), extracted with Et2O (3 × 100
mL) and the combined Et2O layers were dried (Na2SO4). After fil-
tration, the solvent was evaporated in vacuo. The crude product was
purified by column chromatography (pentane–Et2O, 1:1) to give 6e
(3.53 g, 94%) as a white solid; mp 109.3–111.0 °C.
IR (Diamond-ATR, neat): 2956, 2931, 2873, 1724, 1610, 1579,
1456, 1433, 1379, 1360, 1199, 1166, 1141, 1091, 999, 931, 879,
832, 812, 773, 754 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.63–7.6 (m, 1 H), 7.22–7.11 (m,
2 H), 3.88 (s, 3 H), 2.97–2.92 (m, 2 H), 1.60–1.50 (m, 2 H), 1.46–
1.33 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.3 (d, J = 3.6 Hz), 161.5 (d,
J = 245 Hz), 157.8, 132.0, 126.3 (d, J = 8.8 Hz), 126.0 (d, J = 3.6
Hz), 118.5 (d, J = 24.0 Hz), 52.1, 32.7, 25.7 (d, J = 4.1 Hz), 22.8,
13.8.
IR (Diamond-ATR, neat): 3262, 3102, 3057, 3026, 2995, 2951,
2889, 2866, 2590, 1956, 1936, 1885, 1819, 1758, 1700, 1662, 1626,
1600, 1551, 1492, 1468, 1453, 1380, 1302, 1257, 1217, 1191, 1180,
1154, 1136, 1077, 1046, 1029, 1008, 946, 912, 836, 806, 774, 765,
752, 726, 700, 683, 642, 620, 605 cm–1.
MS (EI, 70 eV): m/z (%) = 210 (15, [M+]), 181 (20), 179 (57), 168
(35), 149 (100), 136 (64), 109 (63), 83 (12), 41 (12).
HRMS (EI): m/z calcd for C12H15FO2: 210.1056; found: 210.1043.
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

2676
S. H. Wunderlich et al.
PRACTICAL SYNTHETIC PROCEDURES
3-Cyano-2-octylbenzoic Acid Ethyl Ester (6h)
stir at 25 °C for 2 h. The resulting mixture was then quenched with
a mixture of sat. aq NH4Cl (60 mL) and aq 2 M HCl (25 mL), ex-
tracted with Et2O (3 × 100 mL) and the combined Et2O layers were
dried (Na2SO4). After filtration, the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
(pentane–Et2O, 80:1) to give 6j (2.4 g, 69%) as a colorless solid; mp
56.4–58.7 °C.
According to GP 2, the metalation of ethyl 3-cyanobenzoate (5g;
2.45 g, 14.0 mmol) was complete within 18 h at 25 °C using
TMP2Fe·2MgCl2·4LiCl (3; 0.48 M in THF, 21.9 mL, 10.5 mmol).
1-Iodooctane (3.70 g, 15.4 mmol) and 4-fluorostyrene (171 mg)
were then added dropwise and the reaction mixture was allowed to
stir at 25 °C overnight. The resulting mixture was then quenched
with a mixture of sat. aq NH4Cl (60 mL) and aq 2 M HCl (25 mL),
extracted with Et2O (3 × 100 mL) and the combined Et2O layers
were dried (Na2SO4). After filtration, the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
(pentane–Et2O, 98:2) to give 6h (3.19 g, 78%) as a brown oil.
IR (Diamond-ATR, neat): 2929, 2852, 2226, 1605, 1585, 1489,
1448, 1409, 1372, 1289, 1238, 1183, 1135, 1097, 1011, 945, 926,
914, 890, 811, 778, 735, 687, 607 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (dd, J = 6.7, 4.5 Hz, 1 H),
7.49–7.44 (m, 1 H), 7.11–7.04 (m, 1 H), 2.92–2.80 (m, 1 H), 1.93–
1.71 (m, 5 H), 1.49–1.17 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 163.0 (d, J = 245.0 Hz), 136.4 (d,
J = 16.2 Hz), 132.3 (d, J = 6.7 Hz), 131.6 (d, J = 9.8 Hz), 118.5,
116.5 (d, J = 25 Hz), 108.4 (d, J = 3.9 Hz), 36.9, 32.7, 26.5, 25.9.
IR (Diamond-ATR, neat): 3428, 3079, 2955, 2926, 2856, 2359,
2228, 2180, 2165, 2100, 1964, 1952, 1918, 1723, 1582, 1461, 1445,
1390, 1367, 1271, 1259, 1203, 1176, 1142, 1100, 1084, 1044, 1021,
949, 910, 864, 835, 820, 761, 723, 661, 640 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.99 (dd, J = 8.0, 1.5 Hz, 1 H),
7.70 (dd, J = 7.8, 1.5 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 4.36 (q,
J = 7.0 Hz, 2 H), 3.16–3.11 (m, 2 H), 1.64–1.56 (m, 2 H), 1.43–1.35
(m, 6 H), 1.33–1.25 (m, 7 H), 0.84 (t, J = 6.6 Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 203 (32, [M+]), 160 (13), 148 (19), 147
(100), 135 (12), 134 (33), 41 (15).
HRMS (EI): m/z calcd for C13H14FN: 203.1110; found: 203.1099.
13C NMR (75 MHz, CDCl3): d = 166.3, 148.0, 135.9, 134.6, 131.7,
126.3, 117.6, 114.7, 61.5, 32.7, 31.8, 31.5, 29.8, 29.3, 29.2, 22.6,
14.2, 14.1.
MS (EI, 70 eV): m/z (%) = 287 (39, [M+]), 242 (83), 189 (100),184
(17), 174 (64), 170 (32), 161 (55), 160 (37), 157 (30), 156 (73), 143
(32), 142 (16), 129 (19), 128 (21), 117 (22), 116 (20), 115 (25), 77
(15), 57 (39), 55 (20), 43 (50), 41 (70).
4-Chloro-3-cyclohexyl-2-benzofuran-1(3H)-one (6k)
According to GP 3, the metalation of methyl 3-chlorobenzoate (5h;
2.56 g, 15 mmol) was complete within 3.5 h at 0 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 M in THF, 15 mL, 5.3 mmol). Cy-
clohexanecarbaldehyde (2.24 g, 20.0 mmol) was then added drop-
wise and the reaction mixture was allowed to warm up slowly to
20 °C for 2 h. The resulting mixture was then quenched with brine
(60 mL), extracted with Et2O (3 × 100 mL) and the combined Et2O
layers were dried (Na2SO4). After filtration, the solvent was evapo-
rated in vacuo. The crude product was purified by column chroma-
tography (Al2O3; pentane–Et2O, 9:1) to give 6k (2.74 g, 73%) as a
colorless solid; mp 114.3–119.1 °C.
HRMS (EI): m/z calcd for C18H25NO2: 287.1885; found: 287.1878.
3-Cyano-2-isopropylbenzoic Acid Ethyl Ester (6i)
According to GP 2, the metalation of ethyl 3-cyanobenzoate (5g;
2.45 g, 14.0 mmol) was complete within 18 h at 25 °C using
TMP2Fe·2MgCl2·4LiCl (3; 0.48 M in THF, 21.9 mL, 10.5 mmol).
2-Iodopropane (2.62 g, 15.4 mmol) and 4-fluorostyrene (171 mg)
were then added dropwise and the reaction mixture was allowed to
stir at 25 °C overnight. The resulting mixture was then quenched
with a mixture of sat. aq NH4Cl (60 mL) and aq 2 M HCl (25 mL),
extracted with Et2O (3 × 100 mL) and the combined Et2O layers
were dried (Na2SO4). After filtration, the solvent was evaporated in
vacuo. The crude product was purified by column chromatography
(pentane–Et2O, 90:10) to give 6i (2.35 g, 78%) as a brown oil.
IR (Diamond-ATR, neat): 3503, 3073, 2927, 2856, 1757, 1601,
1585, 1459, 1450, 1373, 1344, 1317, 1307, 1280, 1253, 1205, 1135,
1066, 1050, 976, 958, 925, 897, 862, 844, 819, 790, 769, 741, 689,
658, 619, 603 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74 (d, J = 7.7 Hz, 1 H), 7.57 (dt,
J = 7.7 Hz, J = 1.2 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 1 H), 5.4 (s, 1 H),
2.47–2.33 (m, 1 H), 1.95–1.75 (m, 2 H), 1.69–1.53 (m, 3 H), 1.37–
0.98 (m, 3 H), 0.95–0.74 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 169.4, 145.6, 134.3, 130.5, 128.9,
128.6, 123.8, 84.9, 38.9, 30.4, 26.4, 25.8, 25.6, 23.9.
MS (EI, 70 eV): m/z (%) = 250 (1, [M+]), 170 (27), 168 (100), 83
(4), 41 (2).
IR (Diamond-ATR, neat): 3636, 3546, 3436, 3079, 2970, 2938,
2906, 2878, 2732, 2360, 2226, 2165, 2154, 2086, 2042, 1960, 1918,
1721, 1582, 1460, 1442, 1388, 1367, 1285, 1259, 1210, 1178, 1146,
1136, 1107, 1095, 1054, 1017, 962, 929, 915, 891, 864, 820, 799,
765, 728, 682, 641, 634 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (q, J = 1.5 Hz, 1 H), 7.69 (q,
J = 1.7 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1 H), 4.36 (q, J = 7.0 Hz, 2 H),
3.65–3.55 (m, 1 H), 1.47 (q, J = 7.3 Hz, 6 H), 1.37 (t, J = 7.0 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 168.0, 150.9, 136.8, 133.8, 133.1,
126.2, 118.5, 112.2, 61.8, 31.6, 21.2, 14.1.
MS (EI, 70 eV): m/z (%) = 217 (20, [M+]), 189 (28), 174 (24), 172
(60), 171 (40), 170 (51), 156 (100), 154 (16), 142 (17), 130 (20),
116 (17), 115 (25), 59 (27), 44 (18), 43 (55), 43 (18), 41 (50).
HRMS (EI): m/z calcd for C14H15Cl2O: 250.0761; found: 250.0768.
2-Benzoyl-3-chlorobenzoic Acid Methyl Ester (6l)
According to GP 3, the metalation of methyl 3-chlorobenzoate (5h;
2.39 g, 14.0 mmol) was complete within 3.5 h at 0 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 M in THF, 15.0 mL, 5.3 mmol).
Benzoyl chloride (2.16 g, 15.4 mmol) was then added dropwise and
the reaction mixture was allowed to warm up slowly to 20 °C over-
night. The resulting mixture was then quenched with sat. aq NH4Cl
(60 mL), extracted with Et2O (3 × 100 mL) and the combined Et2O
layers were dried (Na2SO4). After filtration, the solvent was evapo-
rated in vacuo. The crude product was purified by column chroma-
tography (pentane–Et2O, 17:2) to give 6l (2.88 g, 75%) as a white
solid; mp 133.9–135.7 °C.
HRMS (EI): m/z calcd for C13H15NO2: 217.1103; found: 217.1109.
2-Cyclohexyl-4-fluorobenzonitrile (6j)
According to GP 2, the metalation 4-fluorobenzonitrile (5b;
2.1 g, 17 mmol) was complete within 3 h at 25 °C using
TMP2Fe·2MgCl2·4LiCl (3; 0.43 M in THF, 28.0 mL, 12.0 mmol).
Iodocyclohexane (4.28 g, 20.4 mmol) and 4-fluorostyrene (370 mg)
were then added dropwise and the reaction mixture was allowed to
IR (Diamond-ATR, neat): 3068, 3009, 2951, 1920, 1721, 1678,
1674, 1597, 1582, 1567, 1449, 1432, 1313, 1295, 1267, 1205, 1184,
1154, 1111, 1070, 1024, 1001, 996, 978, 972, 939, 927, 850, 820,
794, 766, 746, 733, 727, 717, 705, 668, 654 cm–1.
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Polyfunctional Organometallics via Directed ortho-Metalation
2677
1H NMR (300 MHz, CDCl3): d = 8.03 (dd, J = 8.0, 1.2 Hz, 1 H),
7.79–7.76 (m, 2 H), 7.64 (dd, J = 8.0, 1.2 Hz, 1 H), 7.59–7.54 (m, 1
H), 7.50 (d, J = 8.0 Hz, 1 H), 7.47–7.42 (m, 2 H), 3.69 (s, 3 H).
1-(1,3-Benzothiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ol
(6o)
According to GP 3, the metalation benzothiazole (5j; 1.88 g,
14 mmol) was complete within 0.5
h at 0 °C using
13C NMR (75 MHz, CDCl3): d = 194.4, 165.0, 140.7, 136.6, 134.0,
TMP3La·3MgCl2·5LiCl (4; 0.35 M in THF, 15 mL, 5.3 mmol). a-
Tetralone (2.46 g, 16.8 mmol) was then added dropwise and the re-
action mixture was allowed to warm up slowly to 20 °C for 2 h. The
resulting mixture was then quenched with a mixture of sat. aq
NH4Cl (60 mL) and aq 2 M HCl (25 mL), extracted with Et2O
(3 × 100 mL) and the combined Et2O layers were dried (Na2SO4).
After filtration, the solvent was evaporated in vacuo. The crude
product was purified by column chromatography (pentane–Et2O,
5:1) to give 6o (3.43 g, 87%) as a yellowish solid; mp 107.8–
111.1 °C.
133.4, 131.8, 130.3, 129.9, 128.9, 128.8, 128.7, 52.5.
MS (EI, 70 eV): m/z (%) = 274 (30, [35Cl – M+]), 242 (18), 198 (35),
197 (100), 105 (75), 77 (29).
HRMS (EI): m/z calcd for C15H11ClO3: 274.0397; found: 274.0387.
5-Bromo-2-fluoro-3-[hydroxy(4-methoxyphenyl)methyl]ben-
zonitrile (6m)
According to GP 3, the metalation of 5-bromo-2-fluorobenzonitrile
(5d; 3.00 g, 15 mmol) was complete within 0.5 h at –35 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 M in THF, 13 mL, 4.6 mmol). 4-
Methoxybenzaldehyde (1.77 g, 1.6 mL, 13.0 mmol) was then added
dropwise and the reaction mixture was allowed to warm up slowly
to 20 °C overnight. The resulting mixture was then quenched with
brine (60 mL), extracted with Et2O (3 × 100 mL) and the combined
Et2O layers were dried (Na2SO4). After filtration, the solvent was
evaporated in vacuo. The crude product was purified by column
chromatography (pentane–Et2O, 5:1) to give 6m (4.03 g, 80%) as a
colorless solid; mp 124.5–126.1 °C.
IR (Diamond-ATR, neat): 3319, 3063, 2932, 2873, 2832, 1895,
1595, 1499, 1491, 1455, 1439, 1393, 1333, 1316, 1276, 1238, 1221,
1180, 1168, 1117, 1094, 1042, 1015, 913, 875, 860, 777, 730, 724,
702, 648 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.01–7.87 (m, 2 H), 7.51–7.37 (m,
2 H), 7.28–7.13 (m, 4 H), 3.98–3.93 (m, 1 H), 3.06–2.90 (m, 2 H),
2.57–2.48 (m, 1 H), 2.39–2.31 (m, 1 H), 2.21–1.98 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 180.1, 139.0, 137.3, 135.5, 129.2,
128.6, 128.3, 126.5, 125.9, 124.8, 123.9, 121.6, 75.3, 39.4, 29.4,
19.3.
IR (Diamond-ATR, neat): 3513, 2241, 1608, 1511, 1460, 1440,
1368, 1304, 1284, 1246, 1208, 1191, 1177, 1058, 1024, 866, 843,
829, 820, 786, 758, 718, 665, 644, 634, 627, 614 cm–1.
MS (EI, 70 eV): m/z (%) = 281 (15, [M+]), 263 (81), 262 (100), 136
(24), 135 (14), 91 (15).
1H NMR (400 MHz, DMSO-d6): d = 8.10–8.04 (m, 2 H), 7.26 (d,
J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.30 (d, J = 4.5 Hz,
1 H), 5.90 (d, J = 4.5 Hz, 1 H), 3.70 (s, 3 H).
HRMS (EI): m/z calcd for C17H15NOS: 281.0874; found: 281.0876.
13C NMR (100 MHz, DMSO-d6): d = 158.7, 158.6 (d, J = 257.2
Hz), 136.3 (d, J = 13.8 Hz), 135.5 (d, J = 5.4 Hz), 134.6, 134.3,
127.7, 116.7 (d, J = 3.5 Hz), 113.8, 112.7, 102.3 (d, J = 16.9 Hz),
67.4 (d, J = 1.9 Hz), 55.0.
MS (EI, 70 eV): m/z (%) = 337 (39), 336 (14, [M+]), 335 (41), 228
(16), 226 (18), 137 (63), 135 (11), 109 (100), 77 (10).
References
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HRMS (EI): m/z calcd for C15H11BrFNO2: 334.9957; found:
334.9954.
2-Chloro-4-(2,2-dimethylpropionyl)nicotinic Acid Ethyl Ester
(6n)
(2) (a) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A.
E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem.
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Honeyman, G. W.; Mulvey, R. E.; O’Hara, C. T.; Russo, L.
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Carrella, L.; Clegg, W.; García-Álvarez, P.; Kennedy, A. R.;
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According to GP 3, the metalation of ethyl 2-chloronicotinate (5i;
2.79 g, 15 mmol) was complete within 0.75 h at –20 °C using
TMP3La·3MgCl2·5LiCl (4; 0.35 M in THF, 15 mL, 5.3 mmol). 2,2-
Dimethylpropanoic anhydride (3.04 mL, 15.0 mmol) was then add-
ed dropwise and the reaction mixture was allowed to warm up slow-
ly to 20 °C overnight. The resulting mixture was then quenched
with brine (60 mL), extracted with Et2O (3 × 100 mL) and the com-
bined Et2O layers were dried (Na2SO4). After filtration, the solvent
was evaporated in vacuo. The crude product was purified by column
chromatography (pentane–Et2O 5:1) to give 6n (3.24 g, 80%) as a
yellow oil.
IR (Diamond-ATR, neat): 2977, 727, 1696, 1574, 1538, 1479,
1463, 1449, 1394, 1380, 1364, 1271, 1222, 1185, 1127, 1096, 1065,
1042, 999, 854, 832, 796, 777, 768, 744, 705, 626 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.59 (d, J = 5.07 Hz, 1 H),
7.67 (d, J = 5.07 Hz, 1 H), 4.27 (q, J = 7.21 Hz, 2 H), 1.24 (t,
J = 7.21 Hz, 3 H), 1.19 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 209.3, 164.6, 152.6, 151.7,
150.1, 126.0, 119.8, 62.8, 44.4, 27.2, 14.1.
MS (EI, 70 eV): m/z (%) = 213 (16), 212 (20), 186 (27), 183 (100),
113 (11), 57 (21).
HRMS (EI): m/z calcd for C13H16ClNO3: 269.0819; found:
269.0808.
Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York

2678
S. H. Wunderlich et al.
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Synthesis 2010, No. 15, 2670–2678 © Thieme Stuttgart · New York