Scaleable preparation of sensitive functionalized aromatics and heteroaromatics via directed metalation using tmpZnCl.LiCl

Article abstract of DOI:10.1021/op1001935

A range of functional aryl and heteroaryl zinc reagents were prepared in THF via directed zincation using the previously reported amide base tmpZnCl.LiCl. These metalation reactions were carried out on 50 mmol scale. Diverse sensitive functional groups su

Full text of DOI:10.1021/op1001935

Organic Process Research & Development 2010, 14, 1299–1303
Scaleable Preparation of Sensitive Functionalized Aromatics and Heteroaromatics
via Directed Metalation Using tmpZnCl · LiCl
Tomke Bresser, Gabriel Monzon, Marc Mosrin, and Paul Knochel*
Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany
Abstract:
prepared the chemoselective base tmp2Zn ·2MgCl2 ·2LiCl7 that
allows the directed zincation of more sensitive aromatics and
heteroaromatics. However, using this reagent with some electron-
poor aromatic and heterocyclic compounds still gives unsatis-
factory results in terms of yields and regioselectivity. Moreover,
several activated aromatics bearing a nitro group or heterocycles
such as pyridazines require metalation temperatures below -50
°C, which is not convenient for reaction upscaling.8 Therefore,
we have studied the preparation of a more selective zinc base,
tmpZnCl·LiCl9 (1), that undergoes the directed regio- and
chemoselective zincation of sensitive aryl and heteroaryl
A range of functional aryl and heteroaryl zinc reagents were
prepared in THF via directed zincation using the previously
reported amide base tmpZnCl ·LiCl. These metalation reactions
were carried out on 50 mmol scale. Diverse sensitive functional
groups such as a nitro group, an aldehyde, an ester, and a nitrile
are tolerated. Furthermore, the resulting zinc intermediates show
excellent reactivity towards various classes of electrophiles, e.g.
Pd-catalyzed cross-coupling reactions or Cu-catalyzed acylations
and allylations. In all cases, the metalation rates have been
compared with those of the corresponding small-scale reactions
(1-2 mmol). Moreover, the recovery of the valuable tmp-H from
the aqueous phase has been demonstrated.
(4) (a) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley, A. E. H.;
McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129,
1921. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y.
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,
Y.; Uchiyama, M.; Wheatley, A. E. H. J. Am. Chem. Soc. 2008, 130,
16193. (d) Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakamura,
S.; Kajihara, Z.; Miyoshi, T.; Sakamoto, T.; Kondo, Y.; Morokuma,
K. J. Am. Chem. Soc. 2008, 130, 472. (e) Usui, S.; Hashimoto, Y.;
Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am. Chem. Soc.
2007, 129, 15102. (f) Chevallier, F.; Mongin, F. Chem. Soc. ReV. 2008,
37, 595. (g) Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F. J.
Org. Chem. 2007, 72, 6602. (h) L’Helgoual’ch, J.-M.; Seggio, A.;
Chevallier, F.; Yonehara, M.; Jeanneau, E.; Uchiyama, M.; Mongin,
F. J. Org. Chem. 2008, 73, 177. (i) Carrella, L. M.; Clegg, W.; Graham,
D. V.; Hogg, L. M.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.;
Rentschler, E.; Russo, L. Angew. Chem., Int. Ed. 2007, 46, 4662. (j)
Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.; Honeyman, G. W.;
Mulvey, R. E.; O’Hara, C. T.; Russo, L. Angew. Chem., Int. Ed. 2008,
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.;
Clegg, W.; Conway, B.; Hevia, E.; Kennedy, A.; Klett, J.; Mulvey,
R. E.; Russo, L. Chem.sEur. J. 2008, 14, 65. (m) Albore´s, P.; Carrella,
Introduction
Directed metalation reactions of unsaturated substrates have
become more significant since they facilitate the functionaliza-
tion of these scaffolds and provide important intermediates in
organic synthesis.1 Functional group tolerance is still a challenge
and makes the preparation of functionalized organometallic
compounds more complicated. For the performance of such
transformations, the use of lithium bases has been carefully
investigated, although the functional group tolerance is only
modest.2 In addition to the pioneering work of Snieckus and
Beak,3 a number of new selective bases for achieving regio-
and chemoselective metalations have already been reported by
Kondo, Uchiyama, Mongin, and Mulvey; especially, mixed -ate
bases have found useful applications.4 Recently, we have shown
that magnesium bases such as tmpMgCl ·LiCl5 (tmp ) 2,2,6,6-
tetramethylpiperidyl) or tmp2Mg ·2LiCl5h,6 proved to be highly
active and selective magnesium bases even though highly
sensitive functionalities such as an aldehyde or a nitro group
are not tolerated with such bases. Additionally, we have also
´
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.
(5) (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) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497.
(d) Mosrin, M.; Bresser, T.; Knochel, P. Org. Lett. 2009, 11, 3406.
(e) Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11,
3326. (f) Thaler, A.; Koch, P.; Del Amo, V.; Knochel, P.; Laufer, S.
Synthesis 2008, 225. (g) Melzig, L.; Rauhut, C. B.; Knochel, P.
Synthesis 2009, 1041. (h) Mosrin, M.; Petrera, M.; Knochel, P.
Synthesis 2008, 3697.
* Author for correspondence. Fax: (+49) 089 2180 77680. E-mail:
paul.knochel@cup.uni-muenchen.de.
(6) (a) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 7681. (b) Mosrin, M.; Boudet, N.; Knochel, P. Org.
Biomol. Chem. 2008, 6, 3237. (c) Mosrin, M.; Petrera, M.; Knochel,
P. Synthesis 2008, 3697. (d) Rohbogner, C. J.; Wirth, S.; Knochel, P.
Org. Lett. 2010, 12, 1984.
(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.
(7) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
7685. (b) Mosrin, M.; Knochel, P. Chem.sEur. J. 2009, 15, 1468.
(c) Despotopoulou, C.; Gignoux, C.; McConnell, D.; Knochel, P.
Synthesis 2009, 3661.
(3) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Leroux, F.; Jeschke,
P.; Schlosser, M. Chem. ReV. 2005, 105, 827. (c) Hodgson, D. M.;
Miles, S. M. Angew. Chem., Int. Ed. 2006, 45, 93. (d) Yus, M.;
Foubelo, F. In Handbook of Functionalized Organometallics; Knochel,
P., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1.
(8) Wunderlich, S. H.; Knochel, P. Chem. Commun. 2008, 6387.
(9) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. TMPZnCl ·LiCl
is commercially available from Chemetall Frankfurt/Germany (contact:
christoph.krinninger@chemetall.com). (b) Monzon, G.; Knochel, P.
Synlett 2010, 304. (c) Crestey, F.; Knochel, P. Synthesis 2010, 1097.
10.1021/op1001935  2010 American Chemical Society
Published on Web 10/04/2010
Vol. 14, No. 6, 2010 / Organic Process Research & Development
•
1299

Scheme 1. Preparation of tmpZnCl ·LiCl 1
Scheme 2. Zincation of aromatics and heteroaromatics 2, 4,
6, 8, 10, and 12 using tmpZnCl ·LiCl (1) and subsequent
reactions with electrophiles
substrates containing functional groups such as an aldehyde or
a nitro group at 25 °C. Its higher selectivity is due to the absence
of magnesium salts (MgCl2) and to the nature of the resulting
zinc organometallic produced: ArZnX instead of Ar2Zn (with
tmp2Zn ·2MgCl2 ·2LiCl). The mild base tmpZnCl·LiCl (1) is
quantitatively prepared by a one-pot procedure, and the THF
solution can be stored under an inert gas atmosphere for several
weeks at 25 °C. The zincations with this base usually proceed
at room temperature. For moderately activated substrates,
increased temperatures have to be used (up to 160 °C). Such
high reaction temperatures are compatible with the stability of
the zinc intermediates and do not reduce the tolerance towards
functional groups.10 Usually, the optimization of these meta-
lation procedures was performed with 1-2 mmol scale. Herein,
we report the extension of this commercially available meta-
lation reagent to larger-scale experiments (50 mmol).
Results and Discussion
For the experiments described in this contribution, the zinc
base 1 was prepared in a larger scale than previously described
in the literature.9 Therefore, a dry and argon-flushed 1.0-L
Schlenk flask, equipped with a magnetic stirring bar and a
rubber septum, was charged with freshly distilled tmp-H (59.5
mL, 350 mmol) dissolved in THF (350 mL). This solution was
cooled to -40 °C, and n-BuLi (2.3 M in hexane, 152.2 mL,
350 mmol) was dropwise added. After the addition was
complete, the reaction mixture was allowed to warm up slowly
to -10 °C for 1 h. Then, ZnCl2 (1.0 M in THF, 368 mL, 368
mmol) was dropwise added, and the resulting solution was
stirred for 30 min at -10 °C and then for 30 min at 25 °C. The
solvents were then removed under high vacuum, affording a
yellowish solid. Freshly distilled THF was then slowly added
under vigorous stirring until the salts were completely dissolved.
The freshly prepared tmpZnCl ·LiCl (1) solution was titrated
prior to use at 0 °C with benzoic acid using 4-(phenylazo)-
diphenylamine as indicator.11 A concentration of 1.35 M in THF
was obtained (Scheme 1).
We have carried out several large-scale experiments using
tmpZnCl·LiCl (1) and further reactions with electrophiles
(Scheme 2).
Thus, 2-bromo-4-fluorobenzonitrile (2; 9.95 g, 50 mmol)
dissolved in THF (50 mL) is reacted with tmpZnCl ·LiCl (1;
40.7 mL, 1.1 equiv) at 25 °C, and the resulting mixture is
warmed to 65 °C for 45 min (same metalation rate as for
reactions performed at 1 mmol scale; metalation progress
checked by iodolysis of reaction aliquots and gas chromato-
graphical analysis). Quenching with benzoyl chloride (9.1 g,
1.3 equiv) (after the addition of CuCN·2LiCl12 (55 mL, 1.1
equiv)) furnishes the new substituted benzonitrile 3 in 90%
yield. Smooth zincations of arenes and heteroarenes bearing
sensitive functionalities such as aldehydes or nitro groups can
also be tolerated on larger scales. Thus, the metalation of
benzothiophene-3-carbaldehyde (4; 8.1 g, 50 mmol) is complete
within 30 min at 25 °C using tmpZnCl ·LiCl (1; 40.7 mL, 1.1
equiv). The corresponding zinc derivative undergoes a Pd-
catalyzed cross-coupling reaction13 with 4-iodoanisole (14.0 g,
1.2 equiv) using Pd(dba)2 (565 mg, 2 mol %) and P(2-furyl)3
(465 mg, 4 mol %)14 to give after 2 h the corresponding
functionalized aldehyde 5 in 85% yield. Similarly, 2,6-dichlo-
(10) (a) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun.
2009, 5615. (b) Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J.
Org. Chem. 2010, 75, 4686.
(11) Hammett, L. P.; Walden, G. W.; Edmonds, S. M. J. Am. Chem. Soc.
1934, 56, 1092.
(12) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
1300
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Vol. 14, No. 6, 2010 / Organic Process Research & Development

ropyrazine (6; 7.45 g, 50 mmol) is converted into the zincated
species within 30 min at 25 °C (same metalation rate compared
to 1 mmol scale reactions) using tmpZnCl ·LiCl (1; 40.7 mL,
1.1 equiv). The trisubstituted pyrazine 7 is obtained in 79%
yield after a Neghishi cross-coupling reaction with ethyl
4-iodobenzoate13 (16.5 g, 1.2 equiv) using Pd(dba)2 (565 mg,
2 mol %) and P(2-furyl)3 (465 mg, 4 mol %).14 The metalation
of 2-chloro-3-nitropyridine (8; 7.91 g, 50 mmol) is complete
within 5 h at 25 °C. Quenching with 4-chlorobenzoyl chloride
(9.63 g, 1.1 equiv) at -30 °C (after transmetalation with
CuCN ·2LiCl12 (55 mL, 1.1 equiv) at -30 °C) provides the
ketone 9 in 77% yield. Although this yield was not quantitative,
the crude GC analysis indicates a clean reaction with few side
products, small amounts of pyridine 8, and acid chloride. The
unreacted pyridylzinc reagent gives the chloropyridine 8 back
after workup. No attempts were made to recover the starting
material to improve the reaction yield further. Other sensitive
heterocycles such as pyrimidines or caffeine are zincated at 25
°C. Thus, the metalation of 2,4-dichloropyrimidine (10; 7.45 g,
50 mmol) is achieved within 1 h at 25 °C. Trapping with
3-bromocyclohexene (9.7 g, 1.2 equiv) provides after the
addition of a catalytic amount of CuCN ·2LiCl12 (5.0 mL, 10
mol %), the allylated pyrimidine 11 in 81%. Remarkably, the
full zincation of caffeine (12; 9.7 g, 50 mmol) is obtained within
10 min at 25 °C. A Pd(0)-catalyzed cross-coupling reaction13
with 4-chloro-iodobenzene (13.1 g, 1.1 equiv) using Pd(dba)2
(850 mg, 3 mol %) and P(2-furyl)3 (700 mg, 6 mol %)14 as
catalytic system furnishes the new functionalized purine 13 in
79% yield. The regeneration of 2,2,6,6-tetramethylpiperidine
(tmp-H) was carried out as was published recently.15
anhydrous solvents or reagents were purged with argon prior
to use. THF was continuously refluxed and freshly distilled from
sodium benzophenone ketyl under argon. Yields refer to isolated
yields of compounds estimated to be >95% pure as determined
by 1H NMR (25 °C) and capillary GC analysis. NMR spectra
were recorded on solutions in deuterated chloroform (CDCl3)
with residual chloroform (δ 7.25 ppm for 1H NMR and δ 77.0
ppm for 13C NMR). Column chromatographical purifications
were performed using SiO2 (0.040-0.063 mm, 230-400 mesh
ASTM) from Merck. tmp-H, 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 solution in dry THF, then shaked NH4Cl (1 mL) and sat.
aq Na2S2O3 solution (1 mL) and extracted with diethyl ether
(1 mL).
Preparation of tmpZnCl ·LiCl (1). A dry and argon-flushed
1.0-L Schlenk flask, equipped with a magnetic stirring bar and
a rubber septum, was charged with 2,2,6,6-tetramethylpiperidine
(59.5 mL, 350 mmol) freshly dissolved in THF (350 mL). This
solution was cooled to -40 °C, and n-BuLi (2.3 M in hexane,
152.2 mL, 350 mmol) was dropwise added. After the addition
was complete, the reaction mixture was allowed to warm up
slowly to -10 °C for 1 h. ZnCl2 (1.0 M in THF, 368 mL, 368
mmol, 1.05 equiv) was dropwise added, and the resulting
solution was stirred for 30 min at -10 °C and then for 30 min
at 25 °C. The solvents were then removed under vacuum,
affording a yellowish solid. Freshly distilled THF was then
slowly added under vigorous stirring until the salts were
completely dissolved. The freshly prepared tmpZnCl ·LiCl (1)
solution was titrated prior to use at 25 °C with benzoic acid
using 4-(phenylazo)diphenylamine as indicator. A concentration
of 1.35 M in THF was obtained.
Preparation of 3-Benzoyl-4-bromo-2-fluorobenzonitrile
(3). To a solution of 2-bromo-4-fluorobenzonitrile (2; 9.95 g,
50 mmol) dissolved in THF (50 mL) was added tmpZnCl ·LiCl
(1; 1.35 M in THF, 40.7 mL, 55 mmol) at 25 °C, and the
resulting mixture was heated for 45 min at 65 °C. The reaction
mixture was then cooled to -30 °C, and CuCN ·2LiCl (1 M
solution in THF, 55 mL, 55 mmol) was added. After 30 min
of stirring at the same temperature, benzoyl chloride (9.1 g, 65
mmol) was added, and the resulting mixture was allowed to
warm up slowly to 25 °C within 3 h. The reaction mixture was
then quenched with a sat. aq NH4Cl solution (300 mL), extracted
with diethyl ether (3 × 250 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (diethyl ether/pentane, 1:4)
furnished the compound 3 (13.6 g, 90%) as a colourless solid.
Mp: 97.5-98.9 °C. 1H NMR (300 MHz, CDCl3) δ: 7.81-7.79
(m, 2 H), 7.70-7.62 (m, 1 H), 7.60-7.59 (m, 2 H), 7.54-7.48
(m, 2 H). 13C NMR (75 MHz, CDCl3) δ: 189.2, 159.5 (d, J )
263.7 Hz), 135.0, 134.9, 134.3, 130.7 (d, J ) 21.0 Hz), 129.7,
129.6, 129.2, 126.4 (d, J ) 5.2 Hz), 112.7, 101.3 (d, J ) 6.1
Hz). MS (70 eV, EI) m/z: 303 (28) [M+], 105 (100), 77 (33),
51 (11). IR (ATR) ν˜˜ (cm-1): 3090, 3073, 2240, 1928, 1740,
1681, 1594, 1578, 1564, 1456, 1449, 1422, 1313, 1284, 1272,
1248, 1171, 1125, 1077, 1001, 987, 966, 938, 886, 832, 789,
Summary and Outlook
In conclusion, we have shown that regioselective zincations
of highly sensitive arenes and heteroaromatics using the mild
base tmpZnCl ·LiCl (1) can safely be carried out on multigram
scales with yields comparable to those obtained for small scales.
Remarkably, chemoselective zincations can be performed at
room temperature and higher temperatures (65 °C), tolerating
sensitive functions such as an aldehyde, a nitro group, an ester,
or a nitrile.
Experimental Section
General Considerations. All reactions were carried out
under air and moisture exclusion. All glassware was oven-dried
(80 °C) overnight (minimun of 12 h), evacuated in high vacuum
(1 × 10-3 mbar) and backfilled with argon (this procedure was
repeated three times). Syringes which were used to transfer
(13) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298. (b) Negishi, E.; Kobayashi, M. J. Org. Chem. 1980, 45,
5223. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340. The relatively
high catalyst loading was used to obtain fast conversions to the arylated
arenes and heteroarenes to afford higher yields. Cross-coupling
reactions with aryl bromides lead to decomposition of the correspond-
ing zinc intermediates.
(14) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (b)
Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J.
Org. Chem. 1994, 59, 5905. (c) Klement, I.; Rottla¨nder, M.; Tucker,
C. E.; Majid, T. N.; Knochel, P.; Venegas, P.; Cahiez, G. Tetrahedron
1996, 52, 7201.
(15) Wunderlich, S. H.; Rohbogner, C. J.; Unsinn, A.; Knochel, P. Org.
Res. Process DeV. 2010, 14, 339.
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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1301

715, 688, 673. HRMS (EI) Calcd for C14H7BrFNO, 302.9695;
Found, 302.9689.
for 5 h. The reaction mixture was cooled to -30 °C,
CuCN·2LiCl (1 M solution in THF, 55.0 mL, 55.0 mmol) was
added dropwise, and the resulting mixture was stirred for 30
min at the same temperature. Then, 4-chlorobenzoyl chloride
(9.63 g, 55.0 mmol) was added dropwise at -30 °C, and the
reaction mixture was allowed to warm up slowly to 25 °C within
3 h. The resulting mixture was then quenched with a sat. aq
NH4Cl solution (300 mL), extracted with diethyl ether (3 ×
250 mL), and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated in vacuo. Purification by flash
chromatography (pentane/CH2Cl2, 65:35) furnished the com-
pound 9 (11.45 g, 77%) as a colorless solid. Mp: 116.5-117.8
Preparation of 2-(4-Methoxyphenyl)-1-benzothiophene-
3-carbaldehyde (5). To a solution of benzothiophene-3-
carbaldehyde (4; 8.1 g, 50 mmol) dissolved in THF (50 mL)
was added tmpZnCl ·LiCl (1; 1.35 M in THF, 40.7 mL, 55
mmol) at 25 °C, and the resulting mixture was stirred for 30
min. Pd(dba)2 (565 mg, 2 mol %) and P(2-furyl)3 (465 mg, 4
mol %) dissolved in THF (20 mL) and mixed with 4-iodoanisole
(14.0 g, 60 mmol) were then transferred via cannula, and the
resulting mixture was stirred at 25 °C for 2 h. The reaction
mixture was then quenched with a sat. aq NH4Cl solution (300
mL), extracted with diethyl ether (3 × 250 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated
in vacuo. Purification by flash chromatography (diethyl ether/
pentane, 15:85) furnished the compound 5 (11.3 g, 85%) as a
1
°C. H NMR (CDCl3, 300 MHz) δ: 8.68 (d, J ) 4.9 Hz, 2
H), 7.72 (d, J ) 8.5 Hz, 2 H), 7.49 (d, J ) 8.3 Hz, 1 H), 7.38
(d, J ) 4.9 Hz, 1 H). 13C NMR (CDCl3, 75 MHz) δ: 188.5,
151.4, 143.8, 143.3, 143.0, 142.0, 132.3, 131.2, 129.6, 121.5.
MS (EI, 70 eV) m/z (%): 296 (8) [35Cl - M+], 169 (14), 141
(28), 139 (100), 129 (23), 127 (77), 111 (24). IR (ATR) ν˜
(cm-1): 3090, 2186, 2162, 1676, 1583, 1568, 1534, 1502, 1486,
1442, 1402, 1382, 1366, 974, 858, 846, 830, 814, 800, 776,
748, 738, 716, 684, 676, 648, 634, 616. HRMS (EI) Calcd
for C12H6Cl2N2O3, 295.9755; Found, 295.9743.
1
yellowish solid. Mp: 81.3-84.9 °C. H NMR (600 MHz,
CDCl3) δ: 10.0 (s, 1 H), 8.77 (d, J ) 8.2 Hz, 1 H), 7.73 (d, J
) 7.9 Hz, 1 H), 7.51-7.45 (m, 3 H), 7.42-7.36 (m, 1 H),
7.01-6.97 (m, 2 H), 3.84 (s, 3 H). 13C NMR (150 MHz,
CDCl3) δ: 186.5, 161.0, 160.8, 137.5, 131.7, 126.0, 125.5,
124.8, 123.7, 121.4, 114.3, 55.3. MS (70 eV, EI) m/z: 268 (100)
[M+], 253 (12), 237 (19), 225 (12), 197 (10). IR (ATR) ν˜
(cm-1): 3295, 3028, 2918, 2848, 2767, 1651, 1620, 1602, 1526,
1493, 1458, 1431, 1397, 1351, 1298, 1254, 1222, 1181, 1176,
1097, 1038, 1019, 826, 817, 751, 729, 697. HRMS (EI) Calcd
for C16H12O2S, 268.0558; Found, 268.0552.
Synthesis of 4,6-Dichloro-5-(cyclohex-2-en-1-yl)pyrimi-
dine (11). 4,6-Dichloropyrimidine (10; 7.45 g, 50.0 mmol)
dissolved in THF (50 mL) was added to a solution of
tmpZnCl·LiCl (1) (1.35 M in THF, 40.7 mL, 55.0 mmol) at
25 °C, and the resulting mixture was stirred at this temperature
for 1 h. The reaction mixture was cooled to -30 °C,
CuCN ·2LiCl (1 M solution in THF, 5.0 mL, 5.0 mmol) was
added and stirred at this temperature for 10 min. Then,
3-bromocyclohexene (9.7 g, 60.0 mmol) was added dropwise
at -30 °C, and the reaction mixture was allowed to warm up
slowly to 25 °C for 3 h. The resulting mixture was then
quenched with a sat. aq NH4Cl solution (300 mL), extracted
with diethyl ether (3 × 250 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/diethyl ether,
95:5) furnished the compound 11 (9.23 g, 81%) as a yellow
oil. 1H NMR (CDCl3, 300 MHz) δ: 8.59 (s, 1 H), 5.91-5.84
(m, 1 H), 5.54-5.49 (m, 1 H), 4.21-4.14 (m, 1 H), 2.14-2.08
(m, 2 H), 2.01-1.83 (m, 2 H), 1.79-1.64 (m, 2 H). 13C NMR
(CDCl3, 75 MHz) δ: 161.7, 155.4, 135.4, 128.6, 126.2, 38.4,
25.7, 24.2, 22.5. MS (EI, 70 eV) m/z (%): 228 (34) [35Cl -
M+], 228 (100), 227 (28), 216 (18), 215 (32), 214 (18), 213
(53), 202 (19), 200 (33), 193 (23), 177 (32), 175 (51), 139 (25),
81 (80), 70 (16), 68 (16), 67 (47), 54 (96). IR (ATR) ν˜ (cm-1):
3025, 2934, 2861, 2835, 1650, 1532, 1510, 1447, 1432, 1408,
1376, 1350, 1329, 1307, 1228, 1215, 1194, 1162, 1127, 1046,
980, 934, 899, 882, 848, 808, 779, 721, 616. HRMS (EI) Calcd
for C10H10Cl2N2, 228.0221; Found, 228.0220.
Preparation of Ethyl 4-(3,5-dichloropyrazin-2-yl)ben-
zoate (7). To a solution of 2,6-dichloropyrazine (6; 7.45 g, 50
mmol) dissolved in THF (50 mL) was added tmpZnCl ·LiCl
(1) (1.35 M in THF, 40.7 mL, 55 mmol) at 25 °C and the
resulting mixture was stirred at this temperature for 30 min. A
solution of Pd(dba)2 (565 mg, 2 mol %) and P(2-furyl)3 (465
mg, 4 mol %) dissolved in THF (50 mL) and mixed with
4-iodoethyl benzoate (16.5 g, 60 mmol) was then transferred
via cannula to the reaction mixture. The resulting mixture was
stirred at 25 °C for 3 h and then quenched with a sat. aq NH4Cl
solution (300 mL), extracted with diethyl ether (3 × 250 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent
was evaporated in vacuo. Purification by flash chromatography
(diethyl ether/pentane, 1:9) furnished the compound 7 (11.7 g,
79%) as a colourless solid. Mp: 88.5-90.0 °C. 1H NMR (300
MHz, CDCl3) δ: 8.59 (s, 1 H), 8.14 (d, J ) 8.6 Hz, 2 H), 7.84
(d, J ) 8.6 Hz, 2 H), 4.40 (q, J ) 7.2 Hz, 2 H), 1.40 (t, J ) 7.0
Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ: 165.8, 150.1, 145.9,
142.0, 139.0, 131.6, 129.4, 61.2, 14.3. MS (70 eV, EI) m/z:
296 (32) [35Cl - M+], 270 (24), 268 (38), 251 (100), 223 (26).
IR (ATR) ν˜ (cm-1): 3086, 3005, 2985, 2359, 1966, 1708, 1611,
1569, 1537, 1507, 1482, 1466, 1446, 1423, 1366, 1310, 1283,
1190, 1175, 1140, 1131, 1114, 1098, 1028, 1021, 1009, 915,
858, 843, 786, 758, 719, 698, 675, 634, 621, 616, 610, 602.
HRMS (EI) Calcd for C13H10Cl2N2O2, 296.0119; Found,
296.0119.
Synthesis of 8-(4-Chlorophenyl)-1,3,7-trimethyl-1H-pu-
rine-2,6(3H,7H) (13). 1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-
dione (12; 9.71 g, 50.0 mmol) dissolved in THF (100 mL) was
reacted with a solution of tmpZnCl ·LiCl (1) (1.35 M in THF,
40.7 mL, 55.0 mmol) at 25 °C, and the resulting mixture was
stirred at this temperature for a maximum 10 min. Solution of
Pd(dba)2 (850 mg, 3 mol %) and P(2-furyl)3 (700 mg, 6 mol
%) dissolved in THF (50 mL) and mixed with 1-chloro-4-
Synthesis of (2-Chloro-3-nitropyridin-4-yl)(4-chlorophe-
nyl)methanone (9). 2-Chloro-3-nitropyridine (8; 7.91 g, 50.0
mmol) dissolved in THF (50 mL) was reacted with a solution
of tmpZnCl ·LiCl (1) (1.35 M in THF, 40.7 mL, 55.0 mmol)
at 25 °C, and the resulting mixture was stirred at this temperature
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iodobenzene (13.11 g, 55.0 mmol, 1.1 equiv) was then
transferred via cannula to the reaction mixture. The resulting
mixture was stirred for 2 h at 40 °C. The reaction mixture was
then quenched with a sat. aq NH4Cl solution (300 mL), extracted
with diethyl ether (3 × 250 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash-chromatography (CH2Cl2/diethyl ether, 1:1)
furnished compound 13 (12.09 g, 79%) as a colourless solid.
614, 606. 601. HRMS (EI) Calcd for C14H13ClN4O2, 304.0727;
Found, 304.0719.
Acknowledgment
We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for their 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.
1
Mp: 198.7-199.5 °C. H NMR (CDCl3, 300 MHz) δ: 7.63
(d, J ) 8.5 Hz, 2 H), 7.47 (d, J ) 8.5 Hz, 2 H), 4.02 (s, 3 H),
3.58 (s, 3 H), 3.39 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ:
155.5, 151.6, 150.8, 148.2, 136.7, 130.4, 129.2, 126.8, 108.7,
33.9, 29.8, 28.0. MS (EI, 70 eV) m/z (%): 304 (100) [35Cl-
M+], 303 (25), 82 (21). IR (ATR) ν˜ (cm-1): 2964, 1695, 1646,
1606, 1570, 1538, 1473, 1454, 1431, 1408, 1375, 1339, 1289,
1230, 1180, 1108, 1091, 1074, 1030, 1008, 978, 835, 803, 760,
749, 739, 730, 708, 685, 672, 650, 645, 639, 632, 625, 620,
Supporting Information Available
1
Copies of H- and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Received for review July 12, 2010.
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