Scaleable preparation of functionalized organometallics via directed ortho metalation using Mg- and Zn-amide bases

Article abstract of DOI:10.1021/op9002888

A range of aryl and heteroaryl organometallics are efficiently prepared in THF Wia directed ortho metalation by using the previously reported amide bases tmpMgCl · LiCl (tmp ) 2,2,6,6-tetramethylpiperidyl), tmp₂Mg · 2LiCl and tmp₂Zn

Full text of DOI:10.1021/op9002888

Organic Process Research & Development 2010, 14, 339–345
Scaleable Preparation of Functionalized Organometallics via Directed Ortho
Metalation Using Mg- and Zn-Amide Bases
Stefan H. Wunderlich, Christoph J. Rohbogner, Andreas Unsinn, and Paul Knochel*
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Department Chemie und Biochemie, Butenandtstrasse 5-13, Haus F,
81377 Mu¨nchen, Germany
Abstract:
is a drawback for its larger scale application. Compared to earlier
reported neutral Mg-amides,8 the corresponding tmp2Mg ·2LiCl
(2) also reacts in a stoichiometric manner resulting in products
of the type ArMgtmp ·2LiCl. Additionally, the metalation of
more sensitive substrates can be accomplished by using the zinc
base tmp2Zn ·2MgCl2 ·2LiCl (3).9 Both MgCl2 and LiCl are
essential for the high kinetic basicity and good solubility of this
A range of aryl and heteroaryl organometallics are efficiently
prepared in THF Wia directed ortho metalation by using the
previously reported amide bases tmpMgCl ·LiCl (tmp ) 2,2,6,6-
tetramethylpiperidyl), tmp2Mg ·2LiCl and tmp2Zn ·2MgCl2 ·
2LiCl. These metalation reactions are carried out at 80-100
mmol scale. The unsaturated organometallic compounds
undergo smooth reactions with various electrophiles, e.g.
additions to carbonyl groups, Pd-catalyzed cross-coupling
reactions or Cu-catalyzed acylations. In all cases, the
metalation rates have been compared with corresponding
small-scale reactions (1-2 mmol). Moreover, a procedure
for the recovery of the valuable tmp-H from the aqueous
layer is reported.
(3) (a) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.;
McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129,
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Angew. Chem., Int. Ed. 2007, 46, 3802. (c) Naka, H.; Morey, J. V.;
Haywood, J.; Eisler, D. J.; McPartlin, M.; Garcia, F.; Kudo, H.; Kondo,
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Chevallier, F.; Yonehara, M.; Jeanneau, E.; Uchiyama, M.; Mongin,
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47, 731. (k) Blair, V. L.; Carrella, L. M.; Clegg, W.; Conway, B.;
Harrington, R. W.; Hogg, L. M.; Klett, J.; Mulvey, R. E.; Rentschler,
E.; Russo, L. Angew. Chem., Int. Ed. 2008, 47, 6208. (l) Blair, V. L.;
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Introduction
Over the last few decades, the directed ortho metalation for
the functionalization of unsaturated substrates has become more
and more important.1 The use of lithium reagents for performing
such transformations has been thoroughly investigated, but the
tolerance towards functional groups (especially esters) was
unsatisfactory.2 In addition to this pioneering work of Snieckus
and Beak, several ate-bases for the selective metalation of arenes
and heteroarenes under mild conditions have been reported by
Kondo, Mongin, Mulvey and Uchiyama.3 Recently, we found
that the LiCl-complexed and solubilized amide base tmpMgCl ·
LiCl (1) allows the smooth magnesiation of various activated
aromatics and heteroaromatics.4 The presence of LiCl is
essential since it leads to monomeric metallic amides reacting
in a stoechimometric manner (e.g., no excess of magnesium
amide is required in contrast to previously reported magnesium
bases5). Also, the high kinetic basicity of tmpMgCl ·LiCl results
due to the presence of LiCl.6 This commercially available
reagent can be stored under inert gas atmosphere at 25 °C for
at least 6 months without significant loss of activity. For the
metalation of less activated aromatic substrates, the highly
reactive tmp2Mg ·2LiCl (2) proved to be a powerful metalation
agent.7 The only drawback is the stability of tmp2Mg ·2LiCl
(2) since it is only stable for a maximum of 24 h at 25 °C which
´
L.; Clegg, W.; Garc´ıa-Alvarez, P.; Kennedy, A. R.; Klett, J.; Mulvey,
R. E.; Rentschler, E.; Russo, L. Angew. Chem., Int. Ed. 2009, 48,
3317. (n) Blair, V. L.; Carrella, L. M.; Clegg, W.; Klett, J.; Mulvey,
R. E.; Rentschler, E.; Russo, L. Chem.sEur. J. 2009, 15, 856.
(4) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Boudet, N.; Lachs, J. R.; Knochel, P. Org. Lett.
2007, 9, 5525. (d) Boudet, N.; Dubbaka, S. R.; Knochel, P. Org. Lett.
2008, 10, 1715. (e) Stoll, A. H.; Knochel, P. Org. Lett. 2008, 10, 113.
(f) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497.
(5) (a) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. J. Org. Chem. 1995,
60, 8414. (b) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. Liebigs
Ann. 1995, 1441. (c) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J.
Synthesis 1995, 1225.
(6) Garc´ıa-Alvarez, P.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Klett,
J.; Mulvey, R. E.; O’Hara, C. T.; Weatherstone, S. Angew. Chem.,
Int. Ed. 2008, 47, 8079.
(7) (a) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 7681. (b) Rohbogner, C. J.; Clososki, G. C.; Knochel,
P. Angew. Chem., Int. Ed. 2008, 47, 1503. (c) Rohbogner, C. J.;
Wagner, A. J.; Clososki, G. C.; Knochel, P. Org. Synth. 2009, 86,
374.
(8) (a) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111,
8016. (b) Zhang, M.-X.; Eaton, P. E. Angew. Chem., Int. Ed. 2002,
41, 2169. (c) Eaton, P. E.; Lukin, K. A. J. Am. Chem. Soc. 1993, 115,
11375. (d) Kondo, Y.; Yoshida, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1996, 2331.
* Author to whom correspondence may be sent. Fax: (+49) 089 2180 77680.
E-mail: paul.knochel@cup.uni-muenchen.de.
(1) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Chinchilla, R.; Na´jera,
C.; Yus, M. Chem. ReV. 2004, 104, 2667.
(2) (a) Whisler, M. C.; MacNeil, S.; Beak, P.; Snieckus, V. Angew. Chem.,
Int. Ed. 2004, 43, 2206. (b) Schlosser, M. Angew. Chem., Int. Ed.
2005, 44, 376. (c) Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G.
Tetrahedron 2001, 57, 4489. (d) Mongin, F.; Que´guiner, G. Tetra-
hedron 2001, 57, 4059.
(9) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
7685. (b) Wunderlich, S. H.; Knochel, P. Org. Lett. 2008, 10, 4705.
(c) Wunderlich, S. H.; Knochel, P. Chem. Commun. 2008, 47, 6387.
(d) Dong, Z.; Clososki, G. C.; Wunderlich, S. H.; Unsinn, A.; Li, J.;
Knochel, P. Chem.sEur. J. 2009, 15, 457.
10.1021/op9002888  2010 American Chemical Society
Published on Web 02/01/2010
Vol. 14, No. 2, 2010 / Organic Process Research & Development
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339

Scheme 1. Preparation of the amide bases 1-3
Scheme 2. Metalation of ethyl 3-chlorobenzoate (4),
isoquinoline (6) and 2,6-dichloropyridine (8) using
tmpMgCl·LiCl (1) and subsequent reactions with
electrophiles
long-term stable reagent (6 months). This zincation method
tolerates sensitive functionalities such as aldehydes or nitro
groups as well as heterocycles which are prone to undergo ring
opening. The zincations usually occur at close to room tem-
perature, but elevated temperature (up to 120 °C) can be used
for unreactive substrates. The tolerance towards functional
groups still remains excellent at these temperatures. Usually,
the optimization of these metalation procedures was carried out
in 1-2 mmol scale. Herein, we report the extension of these
metalation reagents to larger-scale experiments (80-100 mmol).
Results and Discussion
For the experiments described in this paper, the amide bases
were prepared on a larger scale than previously described in
the literature. Therefore, tmpMgCl ·LiCl (1) is obtained by the
reaction of iPrMgCl·LiCl (1.31 M in THF, 850 mL) with
tmp-H (161 g, 194 mL, 1.02 equiv) under inert gas atmosphere
(N2) at 25 °C for 48 h with purging to remove the formed
propane.10 A concentration of 1.15 M in THF (>95% yield) is
obtained. Due to the high reactivity of tmp2Mg ·2LiCl (2), this
base is prepared separately for each reaction by reacting
tmpMgCl·LiCl (1; 1.15 M in THF; 87 mL,) with freshly
prepared tmpLi (100 mL, 1 M in hexane/THF).11 After
evaporation of all solvents and redissolution of the residue in
THF, the concentration of tmp2Mg ·2LiCl (2) was found to be
0.7 M in THF (94% yield). For the preparation of
tmp2Zn ·2MgCl2 ·2LiCl (3), tmpMgCl ·LiCl (1; 1.15 M in THF;
348 mL) is cooled to 0 °C and ZnCl2 (1.0 M in THF, 200 mL,
0.5 equiv) is added over a period of 15 min. After stirring this
mixture for 2 h at 0 °C, the solution of tmp2Zn ·2MgCl2 ·2LiCl
(3) is concentrated in Vacuo. A concentration of 0.44 M in THF
(>95% yield) is obtained (Scheme 1).
reactions with electrophiles. Ethyl 3-chlorobenzoate (4;
18.5 g. 100 mmol) was added to a solution of tmpMgCl · LiCl
(1; 1.15 M in THF, 96 mL, 1.1 equiv), and metalation is
performed at 0 °C for 6 h (same metalation rate as for
reactions performed at a 2 mmol scale; metalation progress
checked by iodolysis of reaction aliquots and gas chro-
matographical analysis).4b The resulting mixture is cooled
to -40 °C, and reacted with PhCOCl (14.2 g, 1.0 equiv)
in the presence of CuCN · 2LiCl (1 M in THF, 10 mL).12
After a slow warming of the reaction mixture to 25 °C
within 3 h, the benzophenone 5 is obtained in 86% yield
We have carried out several larger-scale metalations
using tmpMgCl · LiCl (1; Scheme 2) and subsequent
(10) Tmp-H can be added at once to iPrMgCl·LiCl at 25 °C; a slight
exothermic reaction was observed. For the preparation in 1.1 mol scale,
no external cooling was necessary.
(11) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. J. Org. Chem. 1987, 52,
448.
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Scheme 3. Metalation of ethyl benzoate (10),
di-tert-butylisophthalate (12) and ethyl 1-naphthoate (14)
using tmp2Mg·2LiCl (2) and subsequent reactions with
electrophiles
Scheme 4. Metalation of coumarin (16), quinoxaline (18)
and ethyl 4-cyanobenzoate (20) using tmp2Zn·2MgCl2 ·2LiCl
(3) and subsequent reactions with electrophiles
Pd-catalyzed cross-coupling14 reaction with 4-bromotoluene (1.0
equiv) using Pd(OAc)2 (0.5 mol %) and RuPhos (1 mol %) as
catalytic system15 leads to the biaryl ester 11 in 71% yield. The
magnesiation of di-tert-butylisophthalate (12; 22.2 g) using
tmp2Mg ·2LiCl (2; 128 mL, 1.1 equiv) is complete within 45
min at 25 °C (compared to 1 h for 2 mmol scale). Subsequently,
after transmetalation with ZnCl2 (90 mL, 1.1 equiv) a Pd-
catalyzed cross-coupling14 reaction with 4-bromobenzonitrile
(1.0 equiv) using Pd(OAc)2 (0.5 mol %) and RuPhos (1 mol
%) as catalytic system15 provides the functionalized biaryl 13
in 75% yield. Additionally, the full metalation of ethyl 1-naph-
thoate (14; 18.0 g) is obtained within 45 min at 25 °C using
tmp2Mg ·2LiCl (2; 143 mL, compared to 1 h for 2 mmol scale
reactions)7a by applying this large-scale protocol. After quench-
ing with Boc2O (1.4 equiv), the desired mixed diester 15 is
isolated in 69% yield.16
Finally, we report larger-scale zincations (Scheme 4). Thus,
a 250 mL Schlenk-flask is charged with tmp2Zn ·2MgCl2 ·2LiCl
(3; 0.44 M in THF, 114 mL), and coumarin (16; 14.6 g) is
added to the zinc base 3 in one portion at 25 °C. After 2 h
(compared to 4 h for the 2 mmol scale reaction9a), the metalation
of coumarin is complete (indicated by iodolysis of reaction
aliquots and gas chromatographical analysis), and the resulting
mixture is cooled to -20 °C. Then, CuCN ·2LiCl (10 mL, 10
mol %) is added, followed by benzoyl chloride (14.2 g, 1.0
equiv).12 The acylation reaction proceeds while the reaction
(81% in 2 mmol scale4b). Isoquinoline (6; 12.9 g,) is
regioselectivelymetalatedinposition2usingtmpMgCl · LiCl
(1; 1.15 M in THF, 104 mL, 1.2 equiv) within 1 h
(compared to 2 h for 2 mmol scale) and the addition of
the metalated species to a solution of I2 in THF (1 M in
THF, 110 mL, 1.1 equiv) at -78 °C furnishes the expected
heterocyclic iodide 7 after 1 h in 76% yield.13 Similarly,
2,6-dichloropyridine (8; 14.8 g) is converted into the fully
magnesiated species within 15 min at 25 °C (same
metalation rate compared that of to 2 mmol scale
reactions) using tmpMgCl · LiCl (1; 1.15 M in THF, 96
mL, 1.1 equiv). The alcohol 9 is obtained in 92% yield
after the reaction with 4-methoxybenzaldehyde (1.0 equiv).
Furthermore, the larger-scale magnesiation of unactivated
aromatics was performed by using the more reactive
tmp2Mg ·2LiCl (2) under the optimized conditions as shown
in Scheme 3. Thus, a 500 mL Schlenk-flask is charged with
freshly prepared tmp2Mg ·2LiCl (2; 143 mL). Ethyl benzoate
(10; 13.5 g) is added at 25 °C to the magnesium base 2 in one
portion. After 45 min of metalation time (compared to 1 h for
2 mmol scale; metalation progress checked by iodolysis of
reaction aliquots and gas chromatographical analysis) and
subsequent cooling to -40 °C, ZnCl2 (100 mL, 1.1 equiv) is
added, and the resulting mixture is stirred for 15 min. Then, a
(12) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390. (b) Knochel, P.; Rao, S. A. J. Am. Chem. Soc. 1990,
112, 6146.
(14) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(15) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 7509.
(13) In a 1 mmol scale, a yield of 92% was observed (ref 4a). The order
and the rate of addition of iodine are important for larger scales.
Different conditions than the ones reported in the Experimental Section
lead even to lower yields.
(16) Rohbogner, C. J.; Wunderlich, S. H.; Clososki, G. C.; Knochel, P.
Eur. J. Org. Chem. 2009, 1781.
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mixture is slowly warmed to reach 25 °C over 5 h. The desired
benzoylated coumarin 17 is obtained in 69% yield (compared
to 75% in 2 mmol scale). Accordingly, the zincation of
quinoxaline (18; 13.5 g) is achieved within 3 h (compared to
6 h for the 2 mmol scale reaction9d) using tmp2Zn ·2MgCl2 ·
2LiCl (3; 0.44 M in THF, 114 mL). Subsequently, a Pd-
catalyzed cross-coupling reaction with 4-iodoanisole (1.0 equiv)
using Pd(dba)2 (0.5 mol %) and (o-fur)3-P (1 mol %) as catalytic
system furnishes the arylated quinoxaline 19 in 82% yield
(compared to 85% for 2 mmol scale reaction). Interestingly,
the metalation of coumarin (16) and quinoxaline (18) proceeds
twice as fast when carried out in 100 mmol scale. In contrast,
the metalation of ethyl 4-cyanobenzoate (20; 17.5 g, 100 mmol)
using tmp2Zn ·2MgCl2 ·2LiCl (3; 0.44 M in THF, 114 mL) takes
48 h at 25 °C (compared to 24 h for the 2 mmol scale reaction).
A subsequent Pd-catalyzed cross-coupling14 with iodobenzene
(1.0 equiv) using Pd(dba)2 (0.5 mol %) and (o-fur)3-P (1 mol
%) as catalytic system leads to the biaryl 21 in 84% yield
(compared to 85% for the 2 mmol scale reaction).
solution in dry THF, then shaken with NH4Cl (1 mL) and sat.
aq Na2S2O3 solution (1 mL) and extracted with 1 mL diethyl
ether (1 mL)).
Preparation of tmpMgCl ·LiCl (1). A dried and nitrogen-
flushed 2 L Schlenk-flask, equipped with a magnetic stirring
bar and rubber septum, is charged with iPrMgCl·LiCl (1.31
M in THF, 850 mL, 1.11 mol). Then 2,2,6,6-tetramethylpip-
eridine (161 g, 194 mL, 1.14 mol, 1.02 equiv) is added at once,
and the mixture is stirred until gas evolution ceases (48 h).
Titration with benzoic acid using 4-(phenylazo)diphenylamine
as indicator prior to use shows a concentration of 1.15 M.
Preparation of tmp2Mg ·2LiCl (2). A flame-dried and
nitrogen-flushed 500 mL Schlenk-flask, equipped with a
magnetic stirring bar and rubber septum, is charged with 100
mL of dry THF cooled in a -40 °C cooling bath and stirred
for 15 min at this temperature. Then n-BuLi (45.5 mL, 2.22 M
in hexanes, 100 mmol, 1.1 equiv) is added at once via syringe.
After stirring for 15 min at -40 °C, 2,2,6,6-tetramethylpiperi-
dine (14.1 g, 100 mmol, 1.1 equiv) is added at once via syringe.
The resulting mixture is stirred at -40 °C for 5 min and stirred
at 0 °C for further 30 min. Then, tmpMgCl ·LiCl (87 mL, 1.15
M in THF, 100 mmol, 1.1 equiv.) is added via syringe in one
portion (addition time <1 min.). The mixture is stirred at 0 °C
for 30 min and at 25 °C for another 1 h. The solvents are
removed in Vacuo. The resulting pale-brown solid is redissolved
in dry THF (100-120 mL) and stirred for 10 min at 25 °C.
Titration with benzoic acid using 4-(phenylazo)diphenylamine
as indicator prior to use shows a concentration of 0.70 M.
Preparation of tmp2Zn ·2MgCl2 ·2LiCl (3). A flame-dried
and nitrogen-flushed 500 mL Schlenk-flask, equipped with a
magnetic stirring bar and rubber septum, is charged with a
solution of tmpMgCl ·LiCl (1; 348 mL, 400 mmol) and cooled
to 0 °C. Then, ZnCl2 (1.0 M in THF, 200 mL, 200 mmol, 0.5
equiv) is added over a period of 15 min. After stirring this
mixture for 2 h at 0 °C, the solution of tmp2Zn ·2MgCl2 ·2LiCl
(3) is concentrated in Vacuo. Titration with benzoic acid using
4-(phenylazo)diphenylamine as indicator prior to use shows a
concentration of 0.44 M.
Preparation of ethyl 2-benzoyl-3-chlorobenzoate (5). A
flame-dried and nitrogen-flushed 250 mL Schlenk-flask, equipped
with a magnetic stirring bar and rubber septum, is charged with
a solution of tmpMgCl ·LiCl (1; 96 mL, 110 mmol) and cooled
to 0 °C. Then, ethyl 3-chlorobenzoate (4; 18.5 g, 100 mmol) is
added and the mixture is stirred for 6 h at 0 °C. The resulting
mixture is cooled to -40 °C and PhCOCl (14.2 g, 100 mmol,
1.0 equiv) and CuCN ·2LiCl (1 M in THF, 10 mL, 10 mmol)
were added. After slow warming to 25 °C within 3 h, the
reaction mixture is quenched with a mixture of a sat. aqueous
NH4Cl solution (300 mL) and conc. aqueous NH3-solution (50
mL) and extracted with Et2O (3 × 250 mL). The combined
organic layers are washed with brine (250 mL) and dried over
anhydrous MgSO4. After filtration, the solvent is removed in
Vacuo. The crude product is purified by recrystallization (n-
heptane/ethyl acetate) to give 5 as a colourless solid (24.8 g,
86%).
To regenerate 2,2,6,6-tetramethylpiperidine (tmp-H), the
aqueous layers of the above-described reaction mixtures are
collected and treated with NaOH (pH ) 12-13) until tmp-H
separates as its own layer above the aqueous phase. Then, tmp-H
can easily be separated and is recovered after distillation from
CaH2 in up to 75% yield.
Summary and Outlook
In conclusion, we have shown that metalation processes
using tmpMgCl ·LiCl (1), tmp2Mg ·2LiCl (2) and tmp2Zn ·
2MgCl2 ·2LiCl (3) can readily and safely be carried out at
multigram scale with comparable yields as obtained for small
scales. Interestingly, the metalation steps occur usually with an
enhanced rate. Remarkably, acylation reactions can be carried
out with only 10 mol % CuCN ·2LiCl (in general 20-100%
CuCN·2LiCl for small scales), and the catalyst loading of cross-
coupling reactions can be decreased to 0.5% of Pd.
Experimental Section
General Considerations. All reactions were carried out
under air and moisture exclusion. All glassware was oven-dried
(80 °C) overnight (min 12 h), evacuated in high vacuum
(1 ·10-3mbar) and backfilled with nitrogen (this procedure was
repeated three times). Syringes which were used to transfer
anhydrous solvents or reagents were purged with nitrogen prior
to use. THF was continuously refluxed and freshly distilled from
sodium benzophenone ketyl under nitrogen. Yields refer to
isolated yields of compounds estimated to be >95% pure as
1
determined by H NMR (25 °C) and capillary GC analysis.
NMR spectra were recorded on solutions in deuterated chlo-
roform (CDCl3) with residual chloroform (δ 7.25 ppm for 1H
NMR and δ 77.0 ppm for 13C NMR) or d6-DMSO (δ 2.49 ppm
for 1H NMR and δ 39.5 ppm for 13C NMR). Column
chromatographical purifications were performed using SiO2
(0.040-0.063 mm, 230-400 mesh ASTM) from Merck if not
indicated otherwise. tmpH, liquid aldehydes and acid chlorides
were distilled prior to use. The completion of the metalation
reaction was checked by GC analysis of reaction aliquots
(reaction aliquots were quenched with 0.2 mL of a 0.5 M I2
mp: 108.6-109.6 °C.
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1H NMR (300 MHz, CDCl3) δ: 8.08 (m, 1 H), 7.81 (m, 2
H), 7.44-7.68 (m, 5 H), 4.17 (q, 3J ) 7.1 Hz, 2 H), 1.10 (t, 3J
) 7.1 Hz, 3 H).
1H NMR (600 MHz, CDCl3) δ. 7.26 (d, J ) 0.75 Hz, 2 H),
7.21-7.18 (m, 2 H), 6.88-6.86 (m, 2 H), 5.67 (s, 1 H), 3.78
(s, 3 H), 2.67 (br s, 1 H).
13C NMR (150 MHz, CDCl3) δ. 159.88, 158.75, 150.48,
133.62, 128.22, 120.33, 114.45, 73.88, 55.32.
13C NMR (75 MHz, CDCl3) δ: 194.52, 164.82, 140.65,
136.91, 134.15, 133.63, 131.97, 130.89, 130.11, 129.24, 128.93,
62.09, 13.84.
MS (70 eV, EI) m/z. 285 (55), 283 (35) [M+], 176 (13), 174
(20), 137 (100), 135 (12), 109 (69), 94 (17), 77 (19).
IR (ATR) ν˜ (cm-1). 3340, 3100, 3000, 2835, 1739, 1584,
1554, 1544, 1508, 1464, 1426, 1378, 1362, 1303, 1240, 1167,
1150, 1113, 1098, 1069, 1030, 993, 920, 834, 828, 813, 774,
768, 736, 680, 666, 630, 610.
MS (70 eV, EI) m/z (%): 290 (19), 288 (43) [M+], 242 (32),
211 (73), 211 (26), 185 (32), 183 (100), 152 (10), 151 (13),
105 (87), 77 (31).
IR (ATR) ν˜ (cm-1): 1706, 1672, 1584, 1564, 1430, 1366,
1284, 1202, 1152, 1074, 1028, 928, 866, 764, 744, 734, 702,
652, 618.
HRMS (EI): for C13H11Cl2NO2 (283.0167) 283.0164.
Preparation of Ethyl 4′-methylbiphenyl-2-carboxylate
(11). In a flame-dried and nitrogen-flushed 500 mL Schlenk-
flask, equipped with a magnetic stirring bar and rubber septum,
the freshly prepared solution of tmp2Mg ·2LiCl (2; 110 mL,
100 mmol) is provided; ethyl benzoate (10; 13.5 g, 90 mmol)
is added, and the reaction mixture is stirred for 45 min at 25
°C. The resulting solution is cooled to -40 °C, and ZnCl2 (100
mL, 100 mmol, 1.1 equiv) is added, and the resulting mixture
is stirred for 15 min. Then, Pd(OAc)2 (0.5 mol %), RuPhos (1
mol %) and 4-bromotoluene (16.2 g, 95 mmol, 1.05 equiv) are
added. After warming to 25 °C and stirring for 12 h at 25 °C,
the reaction is quenched with a sat. aq NH4Cl solution (250
mL) and extracted with Et2O (3 × 250 mL). The combined
organic layers are washed with brine (250 mL) and dried over
anhydrous MgSO4. After filtration, the solvent is removed in
Vacuo. The crude product is purified by column chromatography
(pentane/diethyl ether ) 9:1) to give 11 as pale-yellow oil (15.4
g, 71%).
HRMS (EI): for C16H13ClO3 (288.0553) 288.0569.
Preparation of 2-Iodoisoquinoline (7). A flame-dried and
nitrogen-flushed 250 mL Schlenk-flask, equipped with a
magnetic stirring bar and rubber septum, is charged with a
solution of tmpMgCl·LiCl (1; 104 mL, 120 mmol). Isoquinoline
(6; 12.9 g, 100 mmol) is added, and the mixture is stirred for
1 h at 25 °C. Then, the reaction mixture is cannulated slowly
to a solution of I2 in THF (1 M in THF, 110 mL, 110 mmol,
1.1 equiv) at -78 °C. The resulting mixture is stirred for 1 h at
-78 °C and then quenched with a sat. aq Na2S2O3 solution
(250 mL) and extracted with Et2O (3 × 250 mL). The combined
organic layers are washed with brine (250 mL) and dried over
anhydrous MgSO4. After filtration, the solvent is removed in
Vacuo. The crude product is purified by column chromatography
(pentane/diethyl ether ) 9:1) to give 7 (19.4 g, 76%) as a
yellowish solid.
mp: 73.9-75.8 °C.
1H NMR (300 MHz, CDCl3) δ: 7.88 (m, 1 H), 7.53 (m, 1
H), 7.44 (m, 2 H), 7.29 (m, 4 H), 4.21 (q, J ) 7.0 Hz, 2 H),
2.47 (s, 3 H), 1.12 (t, J ) 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3) δ: 8.23 (d, J ) 5.6 Hz, 1 H),
8.08 (d, J ) 8.4 Hz, 1 H), 7.72-7.62 (m, 3 H), 7.54 (d, J )
5.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3) δ: 168.89, 142.48, 138.63,
136.84, 131.45, 131.10, 130.69, 129.69, 128.79, 128.37, 126.98,
60.91, 21.23, 13.82.
13C NMR (75 MHz, CDCl3) δ: 142.96, 136.14, 132.82,
131.91, 131.06, 128.98, 127.44, 127.22, 121.29.
MS (70 eV, EI) m/z: 255 (39) [M+], 129 (10), 128 (100),
127 (5), 101 (17), 77 (7), 75 (8), 51 (5).
MS (70 eV, EI) m/z: 240 (51) [M+], 213 (10), 212 (10), 196
(18), 195 (100),167 (23), 166 (18), 165 (51), 153 (10), 152 (48),
82 (8).
IR (ATR) ν˜ (cm-1): 3047, 1992, 1904, 1834, 1774, 1619,
1576, 1539, 1490, 1443, 1363, 1316, 1302, 1251, 1219, 1173,
1136, 1038, 954, 871, 822, 808, 787, 776, 751, 654, 637.
HRMS (EI): for C9H6IN (254.9545) 254.9535.
IR (ATR) ν˜ (cm-1): 3060, 3024, 2981, 2924, 2870, 1713,
1600, 1518, 1445, 1365, 1286, 1276, 1241, 1172, 1125, 1112,
1085, 1047, 1016, 1006, 854, 819, 758, 730, 709, 656.
HRMS (EI): for C16H16O2 (240.1150)240.1142.
Preparation of (2,6-Dichloropyridin-4-yl)(4-methoxyphe-
nyl)methanol (9). A flame-dried and nitrogen-flushed 250 mL
Schlenk-flask, equipped with a magnetic stirring bar and rubber
septum, is charged with a solution of tmpMgCl ·LiCl (1; 96
mL, 110 mmol). 2,6-Dichloropyridine (8; 14.8 g, 100 mmol)
is added, and the mixture is stirred for 15 min at 25 °C. The
resulting mixture is cooled to -40 °C, and 4-methoxybenzal-
dehyde (13.6 g, 100 mmol, 1.0 equiv) is added. The resulting
mixture is stirred for 1 h at -78 °C and then quenched with
brine (250 mL) and extracted with Et2O (3 × 250 mL). The
combined organic layers are washed with brine (250 mL) and
dried over anhydrous MgSO4. After filtration, the solvent is
removed in Vacuo. The crude product is purified by recrystal-
lization (n-heptane/ethyl acetate) to give 9 as a colourless solid
(26.1 g, 92%).
Preparation of Di-tert-butyl 4′-cyanobiphenyl-2,4-dicar-
boxylate (13). In a flame-dried and nitrogen-flushed 500 mL
Schlenk-flask, equipped with a magnetic stirring bar and rubber
septum, the freshly prepared solution of tmp2Mg ·2LiCl (2; 100
mL, 90 mmol) is provided; di-tert-butylisophthalate (12; 22.2 g,
80 mmol) is added, and the reaction mixture is stirred for 45
min at 25 °C. The resulting solution is cooled to -40 °C, and
ZnCl2 (90 mL, 90 mmol, 1.1 equiv) is added; the resulting
mixture is stirred for 15 min. Then, Pd(OAc)2 (0.5 mol %),
RuPhos (1 mol %) and 4-bromobenzonitrile (15.3 g, 84 mmol,
1.05 equiv) are added. After warming to 25 °C and stirring for
12 h at 25 °C, the reaction mixture is quenched with a sat. aq
NH4Cl solution (250 mL) and extracted with Et2O (3 × 250
mL). The combined organic layers are washed with brine (250
mL) and dried over anhydrous MgSO4. After filtration, the
mp: 90.6-93.8 °C.
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solvent is removed in Vacuo. The crude product is purified by
recrystallization (n-heptane/ethyl acetate) to give 13 as a yellow
solid (22.8 g, 75%).
Et2O (3 × 250 mL). The combined organic layers are washed
with brine (250 mL) and dried over anhydrous MgSO4. After
filtration, the solvent is removed in Vacuo. The crude product
is purified by recrystallization (n-heptane/ethyl acetate) to give
17 as a yellowish solid (17.8 g, 71%).
mp: 158.5-158.8 °C.
1H NMR (300 MHz, CDCl3) δ: 8.44 (d, J ) 1.5 Hz, 1 H),
8.13 (dd, J ) 8.0, 1.9 Hz, 1 H), 7.72 (d, J ) 8.5 Hz, 2 H), 7.43
(d, J ) 8.5 Hz, 2 H), 7.35 (d, J ) 8.0 Hz, 1 H), 1.61 (s, 9 H),
1.37 (s, 9 H).
mp: 136.0-137.1 °C.
1H NMR (300 MHz, CDCl3) δ: 8.1 (s, 1 H), 7.90 (d, J )
8.4 Hz, 2 H), 7.67-7.57 (m, 3 H), 7.51-7.44 (m, 2 H), 7.40
(d, J ) 8.5 Hz, 1 H), 7.34 (d, J ) 7.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3) δ: 166.31, 164.51, 145.98,
143.92, 132.60, 132.01, 131.83, 131.73, 131.13, 130.33, 129.23,
118.67, 111.40, 82.21, 81.84, 28.16, 27.64.
13C NMR (75 MHz, CDCl3) δ: 191.6, 158.4, 154.8, 145.3,
136.2, 133.8, 133.6, 129.5, 129.2, 128.6, 127.0, 125.0, 118.2,
116.9.
MS (70 eV, EI) m/z: 323 (19) [M+ - tBu], 306 (17), 268
(53), 267 (100), 266 (11), 250 (50), 177 (22), 166 (10), 57 (76),
56 (17).
MS (70 eV, EI) m/z: 251 (13), (250) (100) [M+], 222 (24),
221 (59), 173 (21), 105 (98), 77 (61), 51 (11).
IR (ATR) ν˜ (cm-1): 2972, 2933, 2228, 1722, 1711, 1604,
1477, 1368, 1324, 1302, 1276, 1254, 1250, 1158, 1146, 1121,
1089, 838, 775, 754, 740.
IR (ATR) ν˜ (cm-1): 3061, 1712, 1656, 1607, 1595, 1580,
1563, 1487, 1453, 1449, 1445, 1363, 1318, 1305, 1297, 1264,
1237, 1214, 1182, 1164, 1144, 1120, 1073, 1041, 1026, 1000,
962, 952, 946, 937, 920, 865, 857, 816, 793, 769, 759, 754,
736, 696, 681.
HRMS (EI): for C23H25NO4 (379.1784) 379.1785.
Preparation of 2-tert-Butyl 1-Ethyl naphthalene-1,2-
dicarboxylate (15). In a flame-dried and nitrogen-flushed 500-
mL Schlenk flask, equipped with a magnetic stirring bar and
rubber septum, the freshly prepared solution of tmp2Mg ·2LiCl
(2; 110 mL, 100 mmol) is added followed by ethyl 1-naphthoate
(14; 18.0 g, 90 mmol), and the reaction mixture is stirred for
45 min at 25 °C. Boc2O (28.0 g, 130 mmol, 1.44 equiv) is
added in one portion at 25 °C, and the reaction mixture was
stirred for 2 h. A sat. aq NH4Cl solution (250 mL) is added,
and the mixture is extracted with Et2O (3 × 250 mL). The
combined organic layers are washed with brine (250 mL) and
dried over anhydrous MgSO4. After filtration, the solvent is
removed in Vacuo. The crude product is purified by recrystal-
lization (n-heptane/ethyl acetate) to give 15 as a colourless solid
(12.4 g, 69%).
HRMS (EI): for C16H10O3 (250.0630) 250.0605.
Preparation of 2-(4-Methoxyphenyl)quinoxaline (19). A
flame-dried and nitrogen-flushed 250 mL Schlenk-flask, equipped
with a magnetic stirring bar and rubber septum, is charged with
a solution of tmp2Zn ·2MgCl2 ·2LiCl (3; 114 mL, 100 mmol).
Quinoxaline (18; 13.0 g, 100 mmol) is added and the mixture
is stirred for 3 h at 25 °C. Then, Pd(dba)2 (280 mg; 0.5 mol
%), (o-fur)3-P (230 mg; 1 mol %) and 4-iodoanisole (23.4 g,
100 mmol, 1.00 equiv) are added and the reaction mixture is
stirred for 2 h at 25 °C. The reaction mixture is quenched with
a sat. aqueous NH4Cl solution (250 mL) and extracted with
Et2O (3 × 250 mL). The combined organic layers are washed
with brine (250 mL) and dried over anhydrous MgSO4. After
filtration, the solvent is removed in Vacuo. The crude product
is purified by recrystallization (n-heptane/ethyl acetate) to give
19 as a colourless solid (19.4 g, 82%).
mp: 70.5-70.9 °C.
1H NMR (300 MHz, CDCl3) δ; 7.92 (m, 4 H), 7.59 (m, 2
H), 4.58 (q, J ) 7.3 Hz, 2 H), 1.64 (s, 9 H), 1.46 (t, J ) 7.2
Hz, 3 H).
mp: 100.2-101.9 °C.
1H NMR (600 MHz, CDCl3) δ: 9.28 (s, 1 H), 8.16 (d, J )
8.8 Hz, 2 H), 8.12 (t, J ) 8.1.Hz, 2 H), 7.77-7.67 (m, 2 H),
7.11 (d, J ) 8.8 Hz, 2 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3) δ: 169.03, 165.07, 134.85,
134.30, 129.38, 129.25, 128.07, 127.52, 127.03, 125.93, 125.24,
82.23, 61.73, 28.13, 14.14.
13C NMR (150 MHz, CDCl3) δ: 161.52, 151.41, 143.00,
142.26, 141.11, 130.27, 129.36, 129.20, 129.13, 129.02, 114.62,
55.47.
MS (70 eV, EI) m/z: 300 (16) [M+], 244 (41), 227 (10), 216
(11), 200 (20), 199 (100), 198 (10), 172 (21), 155 (29), 154
(14), 127 (25), 126 (30), 57 (15).
MS (70 eV, EI) m/z: 236 (100) [M+], 233 (14), 221 (17),
209 (12), 166 (8), 118 (8), 57 (8).
IR (ATR) ν˜ (cm-1): 3058, 2982, 2939, 1720, 1708, 1365,
1294, 1269, 1238, 1168, 1139, 1116, 1036, 1014, 860, 848,
833, 798, 790, 764, 733.
IR (ATR) ν˜ (cm-1): 3057, 3005, 2930, 2833, 1602, 1576,
1536, 1488, 1427, 1291, 1270, 1246, 1226, 1181, 1130, 1030,
957, 847, 810, 795, 758, 728, 670, 655, 630, 609.
HRMS (EI): for C15H12N2O (236.0950) 236.0945.
Preparation of Ethyl 5-cyanobiphenyl-2-carboxylate (21).
A flame-dried and nitrogen-flushed 250 mL Schlenk-flask,
equipped with a magnetic stirring bar and rubber septum, is
charged with a solution of tmp2Zn·2MgCl2 ·2LiCl (3; 114 mL,
100 mmol). Ethyl 4-cyanobenzoate (20; 17.5 g, 100 mmol) is
added, and the mixture is stirred for 48 h at 25 °C. Then,
Pd(dba)2 (280 mg; 0.5 mol %), (o-fur)3-P (230 mg; 1 mol %)
and iodobenzene (20.4 g, 100 mmol, 1.00 equiv) are added,
and the reaction mixture is stirred for 5 h at 25 °C. The reaction
mixture is quenched with a sat. aq NH4Cl solution (250 mL)
HRMS (EI): for C13H11O2 (300.1362) 300.1358.
Preparation of 3-Benzoyl-2H-chromen-2-one (17). A
flame-dried and nitrogen-flushed 250 mL Schlenk-flask, equipped
with a magnetic stirring bar and rubber septum, is charged with
a solution of tmp2Zn ·2MgCl2 ·2LiCl (3; 114 mL, 100 mmol).
Coumarin (16; 14.6 g, 100 mmol) is added neatly, and the
mixture is stirred for 2 h at 25 °C. The resulting mixture is
cooled to -20 °C, then PhCOCl (14.2 g, 100 mmol, 1.0 equiv)
and CuCN ·2LiCl (1 M in THF, 10 mL, 10 mmol) were added.
After slow warming to 25 °C within 5 h, the reaction mixture
is quenched with a mixture of a sat. aq NH4Cl solution (300
mL) and conc. aq NH3-solution (50 mL) and extracted with
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and extracted with Et2O (3 × 250 mL). The combined organic
layers are washed with brine (250 mL) and dried over anhydrous
MgSO4. After filtration, the solvent is removed in Vacuo. The
crude product is purified by column chromatography (pentane/
ether 7:1) to give 21 as a yellowish oil (21.1 g, 84%).
1H NMR (300 MHz, CDCl3) δ: 8.13-8.17 (m, 1 H),
7.89-7.91 (m, 1 H), 7.70-7.77 (m, 2 H), 7.40-7.47 (m, 2 H),
7.29-7.34 (m, 2 H), 4.10 (q, J ) 7.3 Hz, 2 H), 0.98 (t, J ) 7.2
Hz, 3 H).
HRMS (EI): for C16H13NO2 (251.0946) 251.0941.
Acknowledgment
We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC) and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank Evonik AG
(Hanau), BASF AG (Ludwigshafen), W.C. Heraeus GmbH
(Hanau) and Chemetall GmbH (Frankfurt) for the generous gift
of chemicals.
13C NMR (75 MHz, CDCl3) δ: 167.4, 143.2, 139.1, 135.5,
134.0, 132.2, 130.2, 130.1, 128.4, 128.2, 116.3, 114.8, 61.6,
13.6.
MS (70 eV, EI) m/z; 251 (35) [M+], 223 (11), 207 (16), 206
(100), 178 (16), 177 (16), 151 (15).
Supporting Information Available
Copies of 1H- and 13C NMR. This material is available free
of charge via the Internet at http://pubs.acs.org.
IR (ATR) ν˜ (cm-1): 3098, 3052, 2990, 2980, 2938, 2904,
2232, 1712, 1674, 1602, 1578, 1568, 1558, 1504, 1480, 1472,
1444, 1398, 1366, 1350, 1318, 1280, 1250, 1186, 1158, 1138,
1124, 1106, 1076, 1048, 1020, 968, 920, 902, 872, 854, 842,
788, 764, 710, 696, 668, 642, 630, 614, 604, 580, 566.
Received for review November 4, 2009.
OP9002888
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