Regio-and chemoselective zincation of sensitive and moderately activated aromatics and heteroaromatics using TMPZnCl·LiCl

Article abstract of DOI:10.1021/jo100884u

(Figure Presented) A broad range of functionalized aryl- and heteroarylzinc reagents were prepared via directed zincation of sensitive and moderately activated aromatics and heteroaromatics using TMPZnCl·LiCl under various reaction conditions. Diverse sensitive functional groups such as a nitro group, an aldehyde, an ester, and a nitrile are readily tolerated and are compatible with high metalation temperatures. Furthermore, the resulting zinc organometallics display an excellent reactivity toward various classes of electrophiles providing functionalized aromatics and heteroaromatics in high yields.

Full text of DOI:10.1021/jo100884u

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Regio- and Chemoselective Zincation of Sensitive and Moderately
Activated Aromatics and Heteroaromatics Using TMPZnCl LiCl
3
Tomke Bresser, Marc Mosrin, Gabriel Monzon, and Paul Knochel*
€
€
Ludwig-Maximilians-Universitat Munchen Department Chemie Butenandtstrasse 5-13, Haus F,
81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received May 6, 2010
A broad range of functionalized aryl- and heteroarylzinc reagents were prepared via directed
zincation of sensitive and moderately activated aromatics and heteroaromatics using TMPZnCl
3
LiCl under various reaction conditions. Diverse sensitive functional groups such as a nitro group, an
aldehyde, an ester, and a nitrile are readily tolerated and are compatible with high metalation
temperatures. Furthermore, the resulting zinc organometallics display an excellent reactivity toward
various classes of electrophiles providing functionalized aromatics and heteroaromatics in high
yields.
1. Introduction
bases such as TMPMgCl LiCl4 (TMP = 2,2,6,6-tetrame-
3
thylpiperidyl) or TMP2Mg 2LiCl5 proved to be highly active
3
The metalation of aromatics and heteroaromatics is an
important tool since it allows a versatile functionalization of
these molecules. A range of new bases for regio- and chemo-
selective metalation have already been developed.1 In parti-
cular, mixed Zn/Li bases2 and other ate reagents have found
useful applications.3 However, the use of highly reactive
zincates or related ate bases is not always compatible with
sensitive groups. Recently, we have reported that magnesium
and selective bases for the magnesiation of various aromatic
ring systems. Remarkably, these bases are also compatible
with several important functional groups such as an ester, a
nitrile, or an aryl ketone. However, more sensitive function-
alities such as an aldehyde or a nitro group are not tolerated.
Therefore, we have prepared the chemoselective base TMP2-
Zn 2MgCl2 2LiCl6a,b for the direct zincation of sensitive
3
3
aromatics and heteroaromatics. Nevertheless, with this re-
agent some electron-poor functionalized arenes and hetero-
arenes still give unsatisfactory results in terms of yields and
reaction selectivity. Moreover, several activated aromatics
bearing a nitro group or heterocycles like pyridazines require
(1) (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. Handbook of
Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim,
2005; Vol. 1.
(2) (a) Kondo, Y.; Shilai, H.; Uchiyama, M.; Sakamoto, T. J. Am.
Chem. Soc. 1999, 121, 3539. (b) Uchiyama, M.; Miyoshi, T.; Kajihara, Y.;
Sakamoto, T.; Otami, Y.; Ohwada, T.; Kondo, Y. J. Am. Chem. Soc. 2002,
124, 8514.
(3) (a) Mulvey, R. E. Organometallics 2006, 25, 1060. (b) Mulvey, R. E.;
Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46,
3802. (c) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatly, A. E. H.;
McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem. Soc. 2007, 129, 1921.
(d) 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.
(e) Usui, S.; Hashimoto, Y.; Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M.
J. Am. Chem. Soc. 2007, 129, 15102.
(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) 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.
(5) (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) Mosrin, M.; Boudet, N.; Knochel, P. Org.
Biomol. Chem. 2008, 6, 3237. (d) Mosrin, M.; Petrera, M.; Knochel, P.
Synthesis 2008, 3697. (e) Rohbogner, C. J.; Wirth, S.; Knochel, P. Org. Lett.
2010, 12, 1984.
4686 J. Org. Chem. 2010, 75, 4686–4695
Published on Web 06/17/2010
DOI: 10.1021/jo100884u
r
2010 American Chemical Society

Bresser et al.
JOCFeatured Article
SCHEME 1. Preparation of TMPZnCl LiCl (1)
SCHEME 2. Zincation of N-Methylindole-3-carboxyaldehyde
(2) and 6-Nitro-1,3-benzothiazole (4) Using TMPZnCl LiCl (1)
at 25 °C
3
3
metalation temperatures below -50 °C, which is not con-
venient for reaction upscaling.6c Thus, we have developed a
highly selective and mild base TMPZnCl LiCl7,4d that al-
3
lows chemoselective metalations at 25 °C for the directed
zincation of molecules containing sensitive functional groups
such as an aldehyde or a nitro group. Its higher selectivity is due
to the absence of magnesium salts (MgCl2) and to a different
stoichiometry (TMPZnX instead of TMP2ZnX). The mild base
TMPZnCl LiCl (1) is conveniently prepared in a one-pot
3
procedure in quantitative yield as shown in Scheme 1.
Whereas activated arenes and heteroarenes are smoothly
SCHEME 3. Zincation of 4-Fluoro-2-bromobenzonitrile (11)
and 2-Methoxypyrazine (12) Using TMPZnCl LiCl (1) and
Heating
metalated at 25 °C using TMPZnCl LiCl (1), low activated
3
3
systems bearing weak or electron-withdrawing groups do
not react at 25 °C with the base 1. However, they undergo
smooth metalation by heating (65-100 °C) or using micro-
wave irradiation.8 Herein, we give a full report on the zin-
cation of sensitive and moderately activated aromatics and
heteroaromatics at room temperature as well as under thermic
conditions or with microwave activation.
2. Results and Discussion
Thus, the directed zincation of N-methylindole-3-carbox-
yaldehyde (2) provides the desired zinc species 3 at 25 °C
within 30 min (Scheme 2). In the case of 6-nitro-1,3-ben-
zothiazole (4) the metalation to 5 at 25 °C requires only
10 min (Scheme 2). The resulting zinc reagents 3 and 5 readily
undergo an iodination, a copper-mediated allylation,9 as
well as a Neghishi cross-coupling reaction10 leading to new
substituted heteroaromatics 2a,b and 4a, which can be
obtained in 66-84% yield (Table 1, entries 1-3).
zinc species can be acylated with ethyl chloroformate11 in
the presence of catalytic amounts of Pd(PPh3)4 to give the
nitroarene 8a in 63% yield (entry 9). In addition, 2,6- and 2,5-
dichloropyrazine (9) and (10) are smoothly zincated at
25 °C within 30 min. After the reaction mixture was quen-
Similarly, 1-benzofuran-3-carbaldehyde (6) was smoothly
zincated at 25 °C within 30 min leading to a zinc reagent
which undergoes an allylation with 3-bromocyclohexene9 (in
the presence of a catalytic amount of CuCN 2LiCl) leading
3
to the allylated aldehyde 6a in 61% yield (entry 4). A Pd(0)-
catalyzed cross-coupling reaction with 4-iodoanisole10 gives
the benzofuran derivative 6b in 65% yield (entry 5). In the
case of 2,4,6-trichloropyrimidine (7), the metalation is com-
pleted within 45 min at 25 °C. Further iodination, allylation,
and acylation9 give the pyrimidines 7a-c in 83-90% yield
(entries 6-8). 2,4- Difluoronitrobenzene (8) was reacted
with 1 at 25 °C and fully metalated within 1 h. The resulting
ched with allyl bromide (in the presence of CuCN 2LiCl
3
(5 mol %))9 and Negishi10 or Sonogashira12 cross-coupling
reactions, the resulting functionalized heteroarenes 9a-d
and 10a,b were provided in 75-83% yield (entries 10-15).
Aromatics and heteroaromatics which cannot be fully meta-
lated at 25 °C were reacted with TMPZnCl LiCl (1) by heating
3
in an oil bath (65-100 °C). Thus, the treatment of 4-fluoro-2-
bromobenzonitrile (11) with 1 (1.1 equiv, 65 °C, 30 min) leads to
the zincated species which readily undergoes a Neghishi cross-
coupling10 (Scheme 3) or a Cu-catalyzed allylation to the
expected products 11a and 11b in 88-89% yield (Scheme 3 and
Table 2, entry 1). Interestingly, 2-methoxypyrazine (12) can be
(6) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
7685. (b) Mosrin, M.; Knochel, P. Chem.;Eur. J. 2009, 15, 1468. (c)
Wunderlich, S. H.; Knochel, P. Chem. Commun. 2008, 47, 6387.
(7) (a) Mosrin, M; Knochel, P. Org. Lett. 2009, 11, 1837; TMPZnCl LiCl is
3
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.
converted to the corresponding Zn compound with TMPZnCl
3
LiCl (1) at 100 °C within 60 min (Scheme 3). Allylation with
3-bromocyclohexene affords the new pyrazine derivative 12a in
73% yield (Scheme 3). Similarly, 4,6-dichloro-2-(methylthio)-
(8) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun.
2009, 5615.
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988,
53, 2390.
(10) (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.
pyrimidine (13) reacts with TMPZnCl LiCl (1: 1.1 equiv, 65 °C,
3
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 50, 4467. (b) Sonogashira, K. Comprehensive Organic Synthesis;
Pergamon Press: New York, 1991; Vol. 3.
(11) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F. T.; Miller, J. A.; Stoll,
A. T. Tetrahedron Lett. 1983, 24, 5181.
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TABLE 1. Products Obtained by Regio- and Chemoselective Zincation Using TMPZnCl LiCl (1) at 25 °C and Quenching with Electrophiles
3
aYield of analytically pure product. bConditions for the zincation with TMPZnCl LiCl. c5 mol % of CuCN 2LiCl was added. d3 mol % of Pd(dba)2
3
3
and 6 mol % of P(2-furyl)3 were added. e1.1 equiv of CuCN 2LiCl was added. f5 mol % of Pd(PPh3)4 was added.
3
30 min). Acylations and an allylation9 give the functionalized
pyrimidines 13a-c in 88-90% yield (Table 2, entries 2-4).
In cases of less activated substrates, microwave irradiation
turns out to be essential since conventional heating gives
unsatisfactory conversions to the corresponding zinc re-
agents. Therefore, 3,5-dichloro-2-(4-methoxyphenyl)pyrazine
(14) is zincated at 100 °C (200 W) for 1 h (Scheme 4). Acylation
with 2-thienyl chloride and benzoyl chloride (after transmeta-
mediate. Pd(0)-catalyzed cross-coupling reactions10 lead to the
new substituted pyrimidines 15a,b in 86-92% (Scheme 4,
Table 3, entry 2). Interestingly, the use of TMP2Zn 2MgCl2
3
3
2LiCl6 for the zincation of 3-chloro-6-methoxypyridazine (16)
leads to a mixture of regioisomers (metalation in positions
4 and 5). However, by using TMPZnCl LiCl (1; 1.1 equiv,
3
80 °C, 100 W, 1 h), 3-chloro-6-methoxypyridazine (16) is
regioselectively metalated in the ortho-position to the methoxy
group13 (metalation in position 4). The resulting zinc species
lation with CuCN 2LiCl)9 afford the fully substituted pyra-
3
zines 14a and 14b in 78-90% yield (Scheme 4, Table 3,
entry 1). 5-Bromo-2,4-dimethoxypyrimidine (15) is metalated
at 60 °C (100 W) within 30 min to the expected zinc inter-
(13) The regioselectivity has been established by quenching the zinc
organometallic with D2O.
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TABLE 2. Products Obtained by Regio- and Chemoselective Zincation
Using TMPZnCl LiCl (1), Conventional Heating, and Quenching with
Electrophiles
TABLE 3. Products Obtained by Regio- and Chemoselective Zincation
Using TMPZnCl LiCl (1), Microwave Activation, and Quenching with
Electrophiles
3
3
aYield of analytically pure product. bConditions for the zincation
with TMPZnCl LiCl. c5 mol % of CuCN 2LiCl was added. d1.1 equiv
of CuCN 2LiCl was added.
3
3
3
readily undergoes after transmetalation with CuCN 2LiCl9 an
3
acylation with benzoyl chloride or Pd(0)-catalyzed cross-cou-
pling reactions leading to the new substituted pyridazines 16a,b
in 80-89% yield (entries 3 and 4). The zincation of 3,6-
dimethoxypyridazine (17) with TMPZnCl LiCl (1) (90 °C,
3
100 W, 1 h) and subsequent iodination as well as a Neghishi
cross-coupling reaction10 afforded the desired pyridazines 17a,
b in 76-88% yield (entries 5 and 6).
3. Conclusion
In summary, we have reported that aromatic and hetero-
cyclic substrates, bearing electron-withdrawing groups or
several heterocyclic nitrogen atoms, undergo smooth and
selective zincations at room temperature using TMPZnCl
3
LiCl (1). On the other hand, the metalation of moderately
activated arenes and heteroarenes occurs only by conven-
tional heating (65-100 °C) or microwave irradiation, allow-
ing a regio- and chemoselective zincation in excellent yield.
Remarkably, sensitive functionalities like an ester or a nitrile are
tolerated at these high temperatures. Further applications of this
method are currently being investigated in our laboratories.
aYield of analytically pure product. bConditions for the zincation
with TMPZnCl LiCl. c1.1 equiv of CuCN 2LiCl was added. d3 mol %
of Pd(dba)2 and 6 mol % of P(2-furyl)3 were added.
3
3
Typical Procedure for the Preparation of the Reagent
TMPZnCl LiCl (1) (TP1). A dry and argon-flushed 250 mL
3
Schlenk flask equipped with a magnetic stirring bar and a rubber
septum was charged with freshly distilled TMP-H (10.2 mL,
60 mmol) dissolved in THF (60 mL). This solution was cooled
to -40 °C, and n-BuLi (2.4 M in hexane, 25 mL, 60 mmol) was
dropwise added. After the addition was complete, the reaction
mixture was allowed to warm slowly to -10 °C for 1 h. ZnCl2
(1.0 M in THF, 66 mL, 66 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 vacuum
to afford a yellowish solid. Freshly distilled THF was then
slowly added under vigorous stirring until the salts were com-
4. Experimental Section
General Considerations. 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 benzophenone ketyl under
nitrogen. Yields refer to isolated yields of compounds estimated
to be >95% pure as determined by 1H NMR (25 °C) and
capillary GC. 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).
Abbreviations for signal coupling are as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet, br, broad. Column chromato-
graphical purification was performed using SiO2 (0.040-0.063 mm,
230-400 mesh ASTM) if not indicated otherwise. TMPH and
liquid acid chlorides were distilled prior to use. The given watt
numbers refer to the maximum magnetron power output.
pletely dissolved. The freshly prepared TMPZnCl LiCl (1)
3
solution was titrated prior to use at 25 °C with benzoic acid
using 4-(phenylazo)diphenylamine as indicator. A concentra-
tion of 1.3 M in THF was obtained.
Typical Procedure for the Zincation of Polyfunctionalized
Aromatics and Heterocycles with TMPZnCl LiCl (1) at 25 °C
(TP2). A dry and argon-flushed flask equipped with a magnetic
3
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SCHEME 4. Zincation of 3,5-Dichloro-2-(4-methoxyphenyl)pyrazine (14) and 5-Bromo-2,4-dimethoxypyrimidine (15) Using
TMPZnCl LiCl (1) and Microwave Irradiation
3
stirring bar was charged with a solution of the corresponding
arene or heteroarene (1.0 mmol) in dry THF (1-2 mL). The zinc
base (1.1 mmol) was added, and the reaction mixture was stirred
at 25 °C for the indicated times. The completion of the metala-
tion was checked by GC analysis of reaction aliquots quenched
with a solution of I2 in dry THF. The subsequent reactions with
electrophiles were carried out with the indicated conditions.
Typical Procedure for the Zincation of Polyfunctionalized
757, 750, 730, 668, 658; HRMS (ESI) calcd for C16H17NO3
271.1208, found 271.1282.
Ethyl 4-(3-Formyl-1-methyl-1H-indol-2-yl)benzoate (2b). To
a solution of 1-methylindole-3-carboxyaldehyde (2) (159 mg,
1.0 mmol) dissolved in THF (1 mL) was added TMPZnCl LiCl
3
(1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was stirred for 30 min according to TP2.
Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3 (14 mg, 6 mol %)
mixed with ethyl-4-iodobenzoate (360 mg, 1.3 mmol) were then
added via cannula, and the resulting mixture was stirred at 25 °C
for 3 h. The reaction mixture was then quenched with a satd
aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvents were evaporated in vacuo. Purification by flash chro-
matography (Et2O/pentane 1:1) furnished the compound 2b
(224 mg, 73%) as a colorless solid: mp 162.0-163.8 °C; 1H
NMR (CDCl3, 300 MHz) δ 9.72 (s, 1 H), 8.43-8.41 (m, 1 H),
8.22 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 6.8 Hz, 2 H), 7.41-7.32
(m, 3 H), 4.44 (q, d, J = 7.3 Hz, 2 H), 3.68-3.66 (m, 3 H), 1.43 (t,
d, J = 7.1 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 186.0, 165.8,
149.8, 137.5, 133.0, 131.8, 130.9, 129.7, 125.1, 124.4, 123.5,
122.3, 116.0, 109.8, 61.4, 31.1, 14.3; IR (ATR) ν~ (cm-1) 3025,
2978, 2926, 2803, 2768, 2730, 1711, 1649, 1608, 1577, 1568, 1537,
1493, 1466, 1442, 1416, 1372, 1326, 1312, 1278, 1182, 1156, 1127,
1106, 1071, 1029, 1018, 991, 951, 883, 861, 848, 812, 759, 741,
710, 693, 628, 613; HRMS (ESI) calcd for C19H17NO3 307.1208,
found 307.1281.
Aromatics and Heterocycles with TMPZnCl LiCl (1) using
3
Conventional Heating or Microwave Irradation (TP3). A 10-mL
pressurized vial equipped with a magnetic stirring bar was charged
with a solution of the corresponding arene or heteroarene (1.0
mmol) in dry THF (1-2 mL). The zinc base (1.1 mmol) was
added, and the reaction mixture was heated at the corresponding
temperatures by using an oil bath or by using a Discover Bench-
Mate Microwave system under the indicated conditions. After the
desired reaction conditions were set up, the reaction mixture
temperatures were displayed on the microwave screen during
irradiation. The completion of the metalation was checked by
GC analysis of reaction aliquots quenched with a solution of I2
in dry THF. The subsequent reactions with electrophiles were
carried out with the indicated conditions.
Ethyl 2-[(3-Formyl-1-methyl-1H-indol-2-yl)methyl]acrylate
(2a). To a solution of 1-methylindole-3-carboxyaldehyde (2)
(159 mg, 1.0 mmol) dissolved in THF (1 mL) was added
TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at
3
25 °C, and the resulting mixture was stirred for 30 min according
to TP2. The reaction mixture was cooled to -20 °C, and
2-Iodo-6-nitro-1,3-benzothiazole (4a). To a solution of 6-nitro-
1,3-benzothiazole (4) (159 mg, 1.0 mmol) dissolved in THF
(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
CuCN 2LiCl (1 M solution in THF, 0.1 mL, 0.1 mmol) was
3
added. After 5 min of stirring at the same temperature, the
mixture was cooled to -60 °C, ethyl 2-(bromomethyl)acrylate
(290 mg, 1.5 mmol) was added, and the resulting mixture was
allowed to warm slowly to -20 °C within 2 h. The reaction
mixture was then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evapo-
rated in vacuo. Purification by flash chromatography (Et2O/
pentane 3:7) furnished the compound 2a (179 mg, 66%) as a
yellowish solid: mp 121.3-123.0 °C; 1H NMR (CDCl3, 300
MHz) δ 10.12 (s, 1H), 8.30-8.26 (m, 1 H), 7.35-7.38 (m, 3 H),
6.31 (s, 1 H), 5.24 (s, 1 H), 4.30-4.32 (q, J = 7.0 Hz, 2 H), 4.12 (s,
2 H), 3.66-3.65 (m, 3 H), 1.33 (t, J = 7.0 Hz, 3 H); 13C NMR
(CDCl3, 75 MHz) δ 184.1, 166.0, 146.9, 137.2, 136.7, 126.9,
125.6, 123.5, 123.0, 121.1, 115.0, 109.5, 61.4, 29.9, 26.5, 14.2; IR
(ATR) ν~ (cm-1) 3061, 2980, 1912, 1720, 1707, 1631, 1608, 1579,
1533, 1472, 1442, 1420, 1395, 1374, 1328, 1252, 1202, 1186, 1174,
1137, 1095, 1043, 1018, 968, 948, 911, 868, 854, 815, 782, 765,
3
1.1 mmol) at 25 °C, and the resulting mixture was stirred for
10 min according to TP2. Iodine (381 mg, 1.5 mmol) in 2 mL of
THF was then added, and the mixture was stirred for 1 h. The
reaction mixture was then quenched with a satd aq Na2S2O3
(30 mL) and NH4Cl solution (10 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvents were evaporated in vacuo. Purification
by flash chromatography (Et2O/pentane 1:4) furnished the
compound 4a (257 mg, 84%) as a yellowish solid: mp 179.0-
181.0 °C; 1H NMR (300 MHz, CDCl3) δ 8.80 (dd, J = 2.0 Hz,
J = 0.4 Hz, 1 H), 8.31 (dd, J = 6.6 Hz, J = 2.3 Hz, 1 H), 8.13
(dd, J = 8.4 Hz, J = 0.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
157.5, 145.2, 139.5, 122.8, 121.9, 116.9, 112.1; MS (70 eV, EI) m/
z 306 [Mþ] (100), 276 (31), 133 (31), 69 (5); IR (ATR) ν~ (cm-1):
3104, 3054, 1598, 1567, 1505, 1425, 1398, 1332, 1260, 1232, 1120,
1045, 957, 881, 844, 844, 823, 750, 744, 720, 637; HRMS (EI)
calcd for C7H3IN2O2S 305.8960, found 305.8920.
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Bresser et al.
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(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
1.1 mmol) at 25 °C, and the resulting mixture was stirred for
45 min according to TP2. The reaction mixture was cooled to
2-Cyclohex-2-en-1-yl-1-benzofuran-3-carbaldehyde (6a). To
a solution of 1-benzofuran-3-carbaldehyde (6) (146 mg, 1.0
mmol) dissolved in THF (1 mL) was added TMPZnCl LiCl
(1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was stirred for 30 min according to TP2. The
3
3
-20 °C, and CuCN 2LiCl (1 M solution in THF, 0.1 mL, 0.1
3
mmol) was added. After 5 min of stirring at the same tempera-
ture, the mixture was cooled to -60 °C, allyl bromide (240 mg,
2.0 mmol) was added, and the resulting mixture was allowed to
warm slowly to 20 °C within 2 h. The reaction mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvents were evaporated in vacuo. Purifica-
tion by flash chromatography (CH2Cl2/pentane 1:6) furnished
the compound 7b (201 mg, 90%) as a colorless solid: mp
reaction mixture was cooled to -20 °C, and CuCN 2LiCl (1 M
3
solution in THF, 0.1 mL, 0.1 mmol) was added. After 5 min
of stirring at the same temperature, the mixture was cooled to
-60 °C, 3-bromocyclohexene (242 mg, 1.5 mmol) was added,
and the resulting mixture was allowed to warm slowly to -20 °C
within 2 h. The reaction mixture was then quenched with a satd
aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvents were evaporated in vacuo. Purification by flash chro-
matography (Et2O/pentane 5:95) furnished the compound 6a
(138 mg, 61%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ
10.34 (s, 1H), 8.18-8.12 (m, 1 H), 7.49-7.43 (m, 1 H), 7.35-7.29
(m, 2 H), 6.06-6.00 (m, 1 H), 5.78-5.73 (m, 1 H), 4.18-4.10 (m,
1 H), 2.29-2.09 (m, 3 H), 2.04-1.88 (m, 2 H), 1.81-1.67 (m,
1 H). 13C NMR (75 MHz, CDCl3) δ 185.3, 172.3, 153.8, 130.6,
125.2, 124.5, 122.0, 117.3, 111.0, 35.3, 29.1, 24.5, 21.1; MS
(70 eV, EI) m/z 226 [Mþ] (100), 209 (16), 197 (20), 183 (20),
169 (32), 141 (13), 115 (20); IR (ATR) ν~ (cm-1) 3326, 3060,
3024, 2935, 2859, 2835, 2755, 1786, 1667, 1573, 1478, 1451, 1432,
1402, 1377, 1342, 1278, 1251, 1222, 1180, 1150, 1095, 1060, 1044,
1027, 1010, 952, 925, 892, 872, 857, 814, 799, 741, 724, 652, 632;
HRMS (EI) calcd for C15H14O2 226.0994, found 226.0982.
2-(4-Methoxyphenyl)-1-benzofuran-3-carbaldehyde (6b). To a
solution of 1-benzofuran-3-carbaldehyde (6) (146 mg, 1.0
1
39.2-40.3 °C; H NMR (300 MHz, CDCl3) δ 5.75-5.88 (m,
1H), 5.08-5.18 (m, 2H), 3.61 (dt, J = 6.4 Hz, J = 1.4 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 163.0, 157.1, 130.2, 129.3, 118.5,
33.5; MS (70 eV, EI) m/z 222 (100) [35Cl-Mþ], 187 (33), 151 (62),
125 (35), 90 (43); IR (ATR) ν~ (cm-1) 3087, 2934, 1635, 1533,
1501, 1435, 1330, 1287, 1215, 1185, 1123, 1095, 993, 930, 875,
790; HRMS (EI) calcd for C7H5Cl3N2 221.9518, found
221.9494.
1-(2,4,6-Trichloropyrimidin-5-yl)propan-1-one (7c). To a solu-
tion of 2,4,6-trichloropyrimidine (7) (186 mg, 1.0 mmol) dis-
solved in THF (1 mL) was added TMPZnCl LiCl (1) (1.3 M in
3
THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting mixture
was stirred for 45 min according to TP2. The reaction mixture
was cooled to -20 °C, and CuCN 2LiCl (1 M solution in THF,
3
1.1 mL, 1.1 mmol) was added. After 30 min of stirring at the
same temperature, propanoyl chloride (231 mg, 2.0 mmol) was
added, and the resulting mixture was allowed to warm slowly to
25 °C overnight. The reaction mixture was then quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL) and aq NH3, and dried over anhydrous Na2SO4.
After filtration, the solvents were evaporated in vacuo. Purifica-
tion by flash chromatography (CH2Cl2/pentane 1:4) furnished
the compound 7c (201 mg, 84%) as a colorless solid: mp 74.3-
75 °C; 1H NMR (300 MHz, CDCl3) δ 2.83 (q, J = 7.2 Hz, 2 H),
1.19 (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 198.2,
159.2, 158.3, 131.7, 36.8, 7.2; MS (70 eV, EI) m/z 238 (2) [35Cl-
Mþ], 209 (100), 120 (8); IR (ATR) ν~ (cm-1) 2987, 2941, 2894,
1718, 1538, 1501, 1403, 1305, 1210, 1155, 1065, 946, 835, 657;
HRMS (EI) calcd for C7H5Cl3N2O 237.9467, found 237.9482.
Ethyl 2,6-Difluoro-3-nitrobenzoate (8a). To a solution of 2,4-
fluoronitrobenzene (8) (776 mg, 5.0 mmol) dissolved in THF
mmol) dissolved in THF (1 mL) was added TMPZnCl LiCl (1)
3
(1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting
mixture was stirred for 30 min according to TP2. Pd(dba)2 (17 mg,
3 mol %) and P(2-furyl)3 (14 mg, 6 mol %) mixed with 4-iodoa-
nisole (304 mg, 1.3 mmol) were then added via cannula, and the
resulting mixture was stirred at 25 °C overnight. The reaction
mixture was then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evaporated
in vacuo. Purification by flash chromatography (Et2O/pentane
15:85) furnished the compound 6b (164 mg, 65%) as a yellowish
solid: mp 116.3-118.1 °C; 1H NMR (300 MHz, CDCl3) δ 10.31
(s, 1 H), 8.26-8.22 (m, 1 H), 7.83-7.79 (m, 2 H), 7.55-7.49 (m,
1 H), 7.40-7.33 (m, 2 H), 7.08-7.03 (m, 2 H), 3.89 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 186.5, 165.5, 161.2, 152.7, 130.7, 125.6,
124.7, 122.4, 121.0, 116.5, 114.6, 110.9, 55.5; MS (70 eV, EI) m/z
252 [Mþ] (100), 237 (13), 221 (19), 209 (21), 181 (20), 152 (20); IR
(ATR) ν~ (cm-1) 3059, 2915, 2822, 2037, 1948, 1651, 1606, 1578,
1501, 1477, 1446, 1399, 1374, 1342, 1309, 1259, 1247, 1176, 1135,
1107, 1075, 1029, 934, 912, 834, 787, 742; HRMS (EI) calcd for
C16H12O3 252.0786, found 252.0775.
(5 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
3
1.1 mmol) at 25 °C, and the resulting mixture was stirred for 1 h
according to TP2. Pd(PPh3)4 (5 mol %, 290 g) dissolved in THF
(7 mL) and mixed with ethyl chloroformate (1.36 g, 10 mmol)
was then added via cannula to the reaction mixture. The
resulting mixture was allowed to stir at 25 °C overnight. The
reaction mixture was then quenched with a satd aq NH4Cl
solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvents were
evaporated in vacuo. Purification by flash chromatography
(Et2O/pentane 15:85) furnished the compound 8a (728 mg,
63%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ
8.21-8.16 (m, 1H), 7.13-7.07 (m, 1H), 4.48-4.40 (m, 2H),
1.41-1.35 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 164.6 (dd,
J = 266.3 Hz, J = 5.9 Hz), 159.4, 154.4, (dd, J = 274.0 Hz, J =
7.7 Hz), 134.2 (m), 129.15 (d, J = 12.6 Hz), 114.0 (t, J = 20.4
Hz), 112.4 (dd, J = 23.7 Hz, J = 4.7 Hz), 63.0, 14.0; MS (70 eV,
EI) m/z 231 (3) [Mþ], 203 (35), 186 (100), 171 (38), 140 (65), 112
(44), 62 (13); IR (ATR) ν~ (cm-1) 3104, 2988, 1734, 1624, 1599,
1537, 1474, 1449, 1369, 1351, 1291, 1261, 1221, 1174, 1151, 1128,
1036, 1011, 860, 833, 791, 747, 654, 617; HRMS (EI) calcd for
C9H7F2NO4, 231.0343, found 231.0345.
2,4,6-Trichloro-5-iodopyrimidine (7a). To a solution of 2,4,6-
trichloropyrimidine (7) (186 mg, 1.0 mmol) in THF (1 mL) was
added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol)
3
at 25 °C, and the resulting mixture was stirred for 45 min
according to TP2. Iodine (381 mg, 1.5 mmol) in THF (2 mL)
was then added, and the mixture wasstirred for an additional 1 h.
The reaction mixture was then quenched with a satd aq Na2S2O3
(30 mL) and NH4Cl solution (10 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvents were evaporated in vacuo. Purification by
flash chromatography (CH2Cl2/pentane 1:7) furnished the com-
pound 7a (256 mg, 83%) as a colorless solid: mp 97.0-98.0 °C;
13C NMR (75 MHz, CDCl3) δ 167.6, 159.3, 96.5; MS (70 eV, EI)
m/z 308 (100) [35Cl-Mþ], 273 (25), 127 (18), 85 (11); IR (ATR) ν~
(cm-1) 1477, 1270, 1208, 1182, 1009, 851, 806, 752; HRMS (EI)
calcd for C4Cl3IN2 307.8172, found 307.8162.
5-Allyl-2,4,6-trichloropyrimidine (7b). To a solution of 2,4,6-
trichloropyrimidine (7) (186 mg, 1.0 mmol) dissolved in THF
2-Allyl-3,5-dichloropyrazine (9a). To a solution of 2,6-di-
chloropyrazine (9) (149 mg, 1.0 mmol) dissolved in THF
J. Org. Chem. Vol. 75, No. 14, 2010 4691

Bresser et al.
JOCFeatured Article
(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
1.1 mmol) at 25 °C, and the resulting mixture was stirred at this
temperature for 30 min according to TP2. After the mixture was
3,5-Dichloro-2-hex-1-yn-1-ylpyrazine (9d). To a solution of
2,6-dichloropyrazine (9) (149 mg, 1.0 mmol) dissolved in THF
(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
3
3
cooled to -30 °C, CuCN 2LiCl (1 M solution in THF, 5 drops)
1.1 mmol) at 25 °C, and the resulting mixture was stirred at this
temperature for 30 min according to TP2. Iodine (381 mg, 1.5
mmol) dissolved in THF (2 mL) was added dropwise, and the
resulting mixture was stirred for 1 h at 25 °C. To the solution of
freshly generated in situ 2,3-chloro-5-iodopyrazine were succes-
sively slowly added NEt3 (7 mL), CuI (8 mg, 4 mol %), Pd(dba)2
(17 mg, 3 mol %) and P(2-furyl)3 (14 mg, 6 mol %) in THF
(2 mL), and 1-hexyne (115 mg, 1.4 mmol). The reaction mixture
was stirred at 25 °C for 1 h. The resulting mixture was quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvents were evaporated in vacuo. Purification by
flash chromatography (CH2Cl2/pentane 1:5) furnished the com-
pound 9d (189 mg, 83%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 8.40 (s, 1 H), 2.51 (t, J = 7.1 Hz, 2 H), 1.40-1.68 (m,
4 H), 2.51 (t, J = 7.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ
148.7, 144.6, 141.7, 137.5, 101.6, 75.7, 29.9, 21.9, 19.4, 13.5; MS
(70 eV, EI) m/z 228 (47) [35Cl-Mþ], 213 (92), 199 (100), 186 (39),
165 (31), 149 (72), 57 (44), 43 (50); IR (ATR) ν~ (cm-1) 2958,
2932, 2872, 2231, 1494, 1465, 1418, 1308, 1274, 1249, 1166, 1141,
1091, 1051, 1007, 948, 903, 875, 851, 829, 767, 743, 669, 654, 648,
638, 633, 628, 623, 618, 612, 601; HRMS (EI) calcd for
C10H10Cl2N2 228.0221, found 228.0213.
3
was added, and the reaction mixture was then cooled to -60 °C.
Allyl bromide (181 mg, 1.5 mmol) was added dropwise at -60
°C, and the reaction mixture was allowed to warm slowly to 0 °C
for 1.5 h. The resulting mixture was then quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvents were evaporated in vacuo. Purification by flash
chromatography (CH2Cl2/pentane 1:6) furnished the com-
pound 9a (148 mg, 78%) as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 8.44 (s, 1 H), 6.07-5.93 (m, 1 H), 5.22-5.14
(m, 2 H), 3.70 (dt, J = 6.6 Hz, 1.5 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 152.3, 146.8, 145.1, 141.8, 132.2, 118.3, 38.6; MS (70
eV, EI) m/z 188 (36) [35Cl-Mþ], 187 (100), 153 (13), 86 (2); IR
(ATR) ν~ (cm-1) 3453, 3081, 3055, 2985, 2938, 2680, 1722, 1646,
1533, 1516, 1455, 1419, 1377, 1323, 1289, 1250, 1142, 1101, 1058,
1023, 965, 931, 893, 877, 801, 746; HRMS (EI) calcd for
C7H6Cl2N2 187.9908, found 187.9888.
3,5-Dichloro-2-(4-chlorophenyl)pyrazine (9b). To a solution
of 2,6-dichloropyrazine (9) (149 mg, 1.0 mmol) dissolved in THF
(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
3
1.1 mmol) at 25 °C, and the resulting mixture was stirred at this
temperature for 30 min according to TP2. Pd(dba)2 (17 mg,
3 mol %) and P(2-furyl)3 (14 mg, 6 mol %) dissolved in THF
(2 mL) and mixed with 1-chloro-4-iodobenzene (310 mg, 1.3
mmol) were then transferred via cannula to the reaction mixture.
The resulting mixture was stirred at 65 °C for 1 h and then
quenched with a satd aq NH4Cl solution (30 mL), extracted with
diethyl ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvents were evaporated in vacuo. Purifica-
tion by flash chromatography (CH2Cl2/pentane 1:5) furnished
the compound 9b (210 mg, 81%) as a colorless solid: mp
2,5-Dichloro-3-cyclohex-2-en-1-ylpyrazine (10a). To a solu-
tion of 2,6-dichloropyrazine (10) (149 mg, 1.0 mmol) dissolved
in THF (1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF,
0.84 mL, 1.1 mmol) at 25 °C, and the resulting mixture was
stirred at this temperature for 30 min according to TP2. After
3
the mixture was cooled to -30 °C, CuCN 2LiCl (1 M solution
3
in THF, 5 drops) was added, and the reaction mixture was then
cooled to -60 °C. 3-Bromocyclohexene (242 mg, 1.5 mmol) was
then added dropwise, and the reaction mixture was allowed to
warm slowly to -20 °C for 2 h. The resulting mixture was then
quenched with a satd aq NH4Cl solution (30 mL), extracted
with diethyl ether (3 ꢀ 50 mL), and dried over anhydrous
Na2SO4. After filtration, the solvents were evaporated in vacuo.
Purification by flash chromatography (CH2Cl2/pentane 1:3)
furnished the compound 10a (178 mg, 78%) as a colorless oil:
1H NMR (CDCl3, 600 MHz) δ 8.44 (s, 1 H), 5.99-5.95 (m, 1 H),
5.65 (d, J = 10.0 Hz, 1 H), 4.00-3.98 (m, 1H), 2.16-206 (m,
3H), 1.86-1.83 (m, 1 H), 1.71-160 (m, 2H); 13C NMR (CDCl3,
150 MHz) δ 156.6, 146.2, 144.4, 141.7, 129.3, 126.2, 39.1, 27.9,
24.3, 21.0; MS (70 eV, EI) m/z 228 (100) [35Cl-Mþ], 215 (15), 201
(76), 199 (100), 187 (20), 174 (27), 164 (26), 79 (12), 67 (46); IR
(ATR) ν~ (cm-1) 3661, 3319, 3026, 2934, 2860, 2835, 1807, 1656,
1533, 1512, 1446, 1414, 1349, 1330, 1268, 1252, 1145, 1071, 1041,
987, 890, 861, 822, 786, 768, 721, 666, 633, 618, 611, 601; HRMS
(EI) calcd for C10H10Cl2N2 228.0221, found 228.0209.
1
122.6-124.0 °C; H NMR (300 MHz, CDCl3) δ 8.57 (s, 1 H),
7.75 (d, J = 9.0 Hz, 2 H), 7.47 (d, J = 9.0 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 150.0, 145.6, 145.3, 142.0, 136.3, 133.4, 130.8,
128.6; MS (70 eV, EI) m/z 258 (100) [35Cl-Mþ], 225 (39), 223 (55),
137 (22), 85 (8); IR (ATR) ν~ (cm-1) 3075, 2924, 1903, 1656,
1597, 1536, 1500, 1416, 1401, 1312, 1289, 1258, 1173, 1143, 1113,
1103, 1088, 1021, 1007, 959, 912, 865, 834, 825, 772, 737, 712, 657,
631, 620, 615, 602; HRMS (EI) calcd for C10H5Cl3N2 257.9518,
found 257.9353.
3,5-Dichloro-2-[3-(trifluoromethyl)phenyl]pyrazine (9c). To a \
solution of 2,6-dichloropyrazine (9) (149 mg, 1.0 mmol) dis-
solved in THF (1 mL) was added TMPZnCl LiCl (1) (1.3 M in
3
THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting mixture
was stirred at this temperature for 30 min according to TP2.
Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3 (14 mg, 6 mol %)
dissolved in THF (2 mL) and mixed with 3-iodobenzotrifluoride
(354 mg, 1.3 mmol) were then transferred via cannula to the
reaction mixture. The resulting mixture was stirred at 65 °C for
1 h and then quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evapo-
rated in vacuo. Purification by flash chromatography (CH2Cl2/
pentane 1:5) furnished the compound 9c (242 mg, 83%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.61 (s, 1 H), 8.07 (s,
1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.63 (t,
J = 7.8 Hz, 1 H). 13C NMR (CDCl3, 75 MHz) δ 149.6, 146.1,
145.5, 142.2, 135.7, 132.6 (q, J = 2.7 Hz), 131.0 (q, J = 32.6 Hz),
128.9, 126.6 (q, J = 3.9 Hz), 126.5 (q, J = 3.9 Hz), 123.7 (q, J =
272.7 Hz); MS (70 eV, EI) m/z 292 (100) [35Cl-Mþ], 257 (66), 171
(18), 145 (10); IR (ATR) ν~ (cm-1) 2340, 1615, 1534, 1504, 1411,
1332, 1296, 1275, 1256, 1166, 1112, 1094, 1072, 1023, 1002, 903,
867, 807, 793, 772, 705, 697, 662, 653, 646, 620, 610, 604; HRMS
(EI) calcd for C11H5Cl2F3N2 291.9782, found 291.9782.
2,5-Dichloro-3-[3-(trifluoromethyl)phenyl]pyrazine (10b). To
a solution of 2,6-dichloropyrazine (10) (149 mg, 1.0 mmol)
dissolved in THF (1 mL) was added TMPZnCl LiCl (1) (1.3
3
M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting
mixture was stirred at this temperature for 30 min according to
TP2. Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3 (14 mg, 6 mol %)
dissolved in THF (2 mL) and mixed with 3-iodobenzotrifluoride
(354 mg, 1.3 mmol) were then transferred via cannula to the
reaction mixture. The resulting mixture was stirred at 65 °C for 1
h and then quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over anhy-
drous Na2SO4. After filtration, the solvents were evaporated in
vacuo. Purification by flash chromatography (CH2Cl2/pentane
1:9) furnished the compound 10b (219 mg, 75%) as a colorless oil:
1H NMR (CDCl3, 600 MHz) δ 8.61 (s, 1H), 8.07 (s, 1H), 8.01 (d,
J = 7.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.6 Hz,
1H); 13C NMR (CDCl3, 150 MHz) δ 149.6, 146.1, 145.4, 142.1,
4692 J. Org. Chem. Vol. 75, No. 14, 2010

Bresser et al.
JOCFeatured Article
135.8, 132.6 (d, J = 1.1 Hz), 131.5 (q, J = 32.8 Hz), 128.9, 126.5,
(dq, J = 24.4 Hz, J = 3.9 Hz), 123.8 (d, J = 272.3 Hz); MS (70
eV, EI) m/z 292 (100) [35Cl-Mþ], 259 (25), 257 (72), 230 (17), 172
(19), 165 (11), 145 (15); IR (ATR) ν~ (cm-1) 3079, 2357, 1810,
1615, 1534, 1505, 1443, 1411, 1332, 1305, 1296, 1275, 1256, 1221,
1166, 1112, 1094, 1072, 1023, 1002, 903, 867, 807, 793, 772, 734,
705, 697, 662, 653, 646, 635, 629, 625, 617, 608; HRMS (EI) calcd
for C11H5Cl2F3N2 291.9782, found 291.9777.
cooled to -20 °C, and CuCN 2LiCl (1 M solution in THF,
3
0.1 mL, 0.1 mmol) was added. After 15 min of stirring at the
same temperature, 3-bromocyclohexene (209 mg, 1.3 mmol) was
added, and the resulting mixture was allowed to warm slowly to
25 °C within 2 h. The reaction mixture was then quenched with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvents were evaporated in vacuo. Purification by flash
chromatography (CH2Cl2) furnished the compound 12a (139 mg,
73%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
8.05-8.04 (m, 1 H), 7.90-7.89 (m, 1 H), 5.96-5.90 (m, 1 H),
5.75-5.71 (m, 1 H), 3.94 (s, 3 H), 3.92-3.89 (m, 1 H), 2.14-1.99
(m, 3 H), 1.84-1.57 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ
158.1, 150.6, 138.0, 135.7, 128.8, 128.0, 53.4, 37.3, 27.9, 24.8,
21.4; MS (70 eV, EI) m/z 190 (72) [35Cl-Mþ], 189 (26), 175 (25),
162 (26), 161 (100), 149 (11), 124 (61); IR (ATR) ν~ (cm-1) 3052,
3025, 2983, 2934, 1836, 1893, 1787, 1685, 1651, 1574, 1540, 1457,
1444, 1394, 1378, 1345, 1328, 1314, 1266, 1248, 1223, 1184, 1167,
1138, 1127, 1076, 1062, 1043, 1009, 988, 932, 891, 863, 840, 804,
780, 768, 721, 703, 679; HRMS (EI) calcd for C11H14N2O,
190.1106, found 190.1106.
2-Bromo-6-fluoro-40-trifluoromethylbiphenyl-3-carbonitrile
(11a). To a solution of 2-bromo-4-fluorobenzonitrile (11) (200
mg, 1.0 mmol) dissolved in THF (1 mL) was added TMPZnCl
3
LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was heated at 65 °C and for 30 min according
to TP3. Pd(dba)2 (14 mg, 2 mol %), P(2-furyl)3 (10 mg, 4 mol
%), and 4-iodo-benzotrifluoride (353 mg, 1.3 mmol) were then
added, and the resulting mixture was stirred at 25 °C for 2 h. The
reaction mixture was then quenched with a satd aq NH4Cl
solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvents were
evaporated in vacuo. Purification by flash chromatography
(CH2Cl2/pentane 1:3) furnished the compound 11a (305 mg,
1
89%) as a colorless solid: mp 145.3-147.1 °C; H NMR (300
4,6-Dichloro-5-cyclohex-2-enyl-2-methylsulfanylpyrimidine
(13a). To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine
(13) (196 mg, 1.0 mmol) dissolved in THF (1 mL) was added
MHz, CDCl3) δ 7.77-7.71 (m, 3 H), 7.43 (d, J = 8.0 Hz, 2 H),
7.28 (t, J = 8.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 161.8 (d,
J = 259.8 Hz), 136.4 (q, J = 1.6 Hz), 135.3, (d, J = 10.1 Hz),
131.8 (d, J = 19.6 Hz), 131.2 (q, J = 32.7 Hz), 130.2 (d, J = 1.0
Hz), 128.0 (d, J = 3.6 Hz), 123.8 (q, J = 272.5 Hz), 125.5 (q, J =
3.6 Hz), 116.7 (d, J = 1.2 Hz), 116.1 (d, J = 24.5 Hz), 113.3 (d,
J = 3.9 Hz); MS (70 eV, EI) m/z 343 (100) [79Br-Mþ], 264 (10),
244 (30), 195 (35), 168 (7); IR (ATR) ν~ (cm-1) 3065, 2924, 2230,
1921, 1619, 1592, 1569, 1520, 1463, 1408, 1392, 1322, 1278, 1257,
1191, 1160, 1109, 1071, 1053, 1020, 955, 905, 847, 834, 813, 766,
739, 696, 677; HRMS (EI) calcd for C14H6BrF4N 342.9620,
found 342.9610.
TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C,
3
and the resulting mixture was heated at 65 °C for 30 min
according to TP3. The reaction mixture was cooled to -20 °C,
and CuCN 2LiCl (1 M solution in THF, 0.1 mL, 0.1 mmol) was
3
added. After 15 min of stirring at the same temperature,
3-bromocyclohexene (209 mg, 1.3 mmol) was added, and the
resulting mixture was allowed to warm slowly to 25 °C within
2 h. The reaction mixture was then quenched with a satd aq
NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvents were evaporated in vacuo. Purification by flash
chromatography (CH2Cl2/pentane 1:4) furnished the com-
pound 13a (241 mg, 90%) as a colorless solid: mp 99.9-101.
0 °C; 1H NMR (300 MHz, CDCl3) δ 5.87-5.80 (m, 1 H), 5.53-
5.47 (m, 1 H), 4.13-4.03 (m, 1 H), 2.53 (s, 3 H), 2.14-2.06
(m, 2 H), 1.99-1.83 (m, 3 H), 1.76-1.63 (m, 1 H); 13C NMR (75
MHz, CDCl3) δ 170.1, 161.3, 129.0, 128.2, 127.0, 37.9, 26.0,
24.2, 22.6, 14.3; MS (70 eV, EI) m/z 274 (100) [35Cl-Mþ], 248
2-(2-Bromo-3-cyano-6-fluorobenzyl)acrylic Acid Ethyl Ester
(11b). To a solution of 2-bromo-4-fluorobenzonitrile (11) (200
mg, 1.0 mmol) dissolved in THF (1 mL) was added TMPZnCl
3
LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was heated at 65 °C for 30 min according to
TP3. The reaction mixture was cooled to -20 °C, and CuCN
3
2LiCl (1 M solution in THF, 0.1 mL, 0.1 mmol) was added.
After 15 min of stirring at the same temperature, ethyl (2-
bromomethyl)acrylate (250 mg, 1.3 mmol) was added, and the
resulting mixture was allowed to warm slowly to 20 °C within
2 h. The reaction mixture was then quenched with a satd aq
NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration,
the solvents were evaporated in vacuo. Purification by flash
chromatography (CH2Cl2/pentane 1:1) furnished the compound
11b (273 mg, 88%) as a colorless solid: mp 39.8-40.9 °C;
1H NMR (300 MHz, CDCl3) δ 7.63-7.58 (m, 1 H), 7.16 (t,
J = 8.6 Hz, 1 H), 6.22 (t, J = 1.7 Hz, 1 H), 5.07 (t, J = 1.7 Hz,
1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.84 (q, J = 1.9 Hz, 2 H), 1.3 (q,
J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 166.0, 163.3 (d,
J = 259.8 Hz), 135.7, 134.1 (d, J = 10.6 Hz), 129.6 (d, J = 5.4
Hz), 129.2 (d, J = 18.8Hz), 125.6, 116.9 (d, J = 1.3 Hz), 115.6 (d,
J = 24.8 Hz), 113.0 (d, J = 3.9 Hz), 61.1, 31.2 (d, J = 3.1 Hz),
14.1; MS (70 eV, EI) m/z 311 (4) [79Br-Mþ], 268 (19), 232 (100),
205 (26), 204 (62), 176 (63), 159 (96), 158 (67), 133 (22), 132 (17);
IR (ATR) ν~ (cm-1) 3078, 2985, 2938, 2235, 1926, 1704, 1635,
1579, 1469, 1432, 1403, 1369, 1348, 1280, 1256, 1207, 1170, 1136,
1094, 1025, 956, 864, 832, 755, 700, 685; HRMS (EI) calcd for
C13H11BrFNO2 310.9957, found 310.9997.
~
(17), 246 (26), 220 (13), 211 (11), 208 (11), 150 (10); IR (ATR) ν
(cm-1) 2926, 1534, 1480, 1337, 1309, 1258, 1181, 1119, 1043,
979, 882, 856, 825, 803, 769, 757, 717; HRMS (EI) calcd for
C11H12Cl2N2S 274.0098, found 274.0086.
(4,6-Dichloro-2-methylsulfanylpyrimidin-5-yl)thiophene-2-ylme-
thanone (13b). To a solution of 4,6-dichloro-2-methylsulfanyl-
pyrimidine (13) (196 mg, 1.0 mmol) dissolved in THF (1 mL)
was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1
mmol) at 25 °C, and the resulting mixture was heated at 65 °C for
30 min according to TP3. The reaction mixture was cooled to
3
-20 °C, and CuCN 2LiCl (1 M solution in THF, 1.1 mL, 1.1
3
mmol) was added. After 30 min of stirring at the same tempera-
ture, 2-thiophenecarbonyl chloride (293 mg, 2.0 mmol) was
added, and the resulting mixture was allowed to warm slowly
to 25 °C within 2 h. The reaction mixture was then quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL) and aq NH3, and dried over anhydrous
Na2SO4. After filtration, the solvents were evaporated in vacuo.
Purification by flash chromatography (CH2Cl2/pentane 1:2)
furnished the compound 13b (268 mg, 88%) as a colorless solid:
mp 126.1-127.4 °C; 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J =
4.8 Hz, 1 H), 7.49 (d, J = 3.8 Hz, 1 H), 7.17 (t, J = 4.3 Hz, 1 H),
2.60 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 181.0, 174.5, 157.9,
142.1, 137.0, 135.5, 128.8, 125.7, 14.5; MS (70 eV, EI) m/z 304
(78) [35Cl-Mþ], 110 (100); IR (ATR) ν~ (cm-1) 3115, 3088, 2462,
2154, 2161, 1657, 1639, 1540, 1478, 1409, 1356, 1345, 1321, 1283,
2-Cyclohex-2-enyl-3-methoxypyrazine (12a). To a solution of
2-methoxypyrazine (12) (110 mg, 1.0 mmol) dissolved in THF
(1 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
3
1.1 mmol) at 25 °C, and the resulting mixture was heated at
100 °C for 1 h according to TP3. The reaction mixture was
J. Org. Chem. Vol. 75, No. 14, 2010 4693

Bresser et al.
JOCFeatured Article
1245, 1181, 1098, 1086, 1077, 1055, 976, 907, 884, 859, 826, 819,
768, 744, 740, 729, 686; HRMS (EI) calcd for C10H6Cl2N2OS2
303.9299, found 303.9288.
1
14b (347 mg, 90%) as a colorless solid: mp 93.8-95.4 °C; H
NMR (CDCl3, 300 MHz) δ 7.91-7.81 (m, 4 H), 7.68-7.62 (m,
1 H), 7.53-7.48 (m, 2 H), 7.00-6.96 (m, 2 H), 3.85 (s, 3 H); 13
C
(3-Chlorophenyl)[4,6-dichloro-2-(methylthio)pyrimidin-5-yl]me-
thanone (13c). To a solution of 4,6-dichloro-2-methylsulfanylpyr-
imidine (13) (590 mg, 3.0 mmol) dissolved in THF (3 mL) was
NMR (CDCl3, 75 MHz) δ 190.3, 161.3, 150.0, 147.6, 145.3, 141.4,
134.5, 131.2, 130.3, 128.8, 126.4, 113.8, 55.4; MS (70 eV, EI) m/z
358 (16) [35Cl-Mþ], 105 (100), 77 (34); IR (ATR) ν~ (cm-1) 3005,
2356, 1748, 1664, 1605, 1594, 1579, 1512, 1501, 1441, 1420, 1370,
1298, 1266, 1253, 1216, 1179, 1153, 1121, 1087, 1029, 1012, 954,
864, 835, 810, 794, 778, 734, 711, 684, 661; HRMS (EI) calcd for
C18H12Cl2N2O2 358.0276, found 358.0270.
added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at
25 °C, and the resulting mixture was heated at 65 °C for 30 min
accordingtoTP3. Thereactionmixturewascooledto-20 °C,and
3
CuCN 2LiCl (1 M solution in THF, 1.1 mL, 1.1 mmol) was
3
5-Bromo-2,4-dimethoxy-6-(4-methoxyphenyl)pyrimidine (15a).
To a solution of 5-bromo-2,4-dimethoxypyrimidine (15) (219 mg,
1.0 mmol) dissolved in THF (2 mL) was added TMPZnCl LiCl
added. After 30 min of stirring at the same temperature, 2-chlor-
obenzoyl chloride (787 mg, 4.5 mmol) was added, and the
resulting mixture was allowed to warm slowly to 25 °C within
2 h. The reaction mixture was then quenched with a satd aq
NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL)
and NH3, and dried over anhydrous Na2SO4. After filtration, the
solvents were evaporated in vacuo. Purification by flash chroma-
tography (CH2Cl2/pentane 1:4) furnished the compound 13c (880
3
(1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting
mixture was heated at 60 °C (100 W) for 30 min according to TP3.
Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3 (14 mg, 6 mol %)
dissolved in THF (2 mL) and mixed with 1-iodo-4-methoxyben-
zene (257 mg, 1.1 mmol, 1.1 equiv) were then transferred via
cannula to the reaction mixture. The resulting mixture was stirred
at 50 °C for 6 h and then quenched with a satd aq NH4Cl solution
(30 mL), extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evaporated
in vacuo. Purification by flash chromatography (pentane/ether
78:22) furnished the compound 15a (300 mg, 92%) as a white
solid: mp 114.1-115.8 °C; 1H NMR(CDCl3, 300 MHz) δ 7.80 (d,
J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 4.07 (s, 3 H), 4.00 (s,
3 H), 3.85 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 168.1, 165.3,
163.3, 160.8, 131.2, 130.0, 113.3, 96.3, 55.4, 55.3, 55.1; MS (EI,
70 eV) m/z 324 (100) [79Br-Mþ], 323 (47), 310 (14), 309 (15), 297
(22), 296 (39), 295 (26), 294 (36), 265 (12), 215 (38), 158 (16), 157
(12); IR (ATR) (cm-1) 2989, 2940, 2836, 1615, 1583, 1565, 1543,
1519, 1482, 1447, 1416, 1380, 1352, 1309, 1300, 1258, 1201, 1194,
1188, 1177, 1150, 1109, 1030, 1019, 1008, 946, 930, 866, 836, 824,
808, 785, 740, 728, 705, 676, 660, 627; HRMS (EI) calcd for
C13H13BrN2O3 324.0110, found 324.0114.
1
mg, 88%) as a colorless solid: mp 158.4-160.5 °C; H NMR
(CDCl3, 600 MHz) δ 7.82 (s, 1 H), 7.68 (d, J = 8.6 Hz, 1 H),
7.64-7.62 (m, 1 H), 7.47-7.44 (m, 1), 2.62 (s, 3 H); 13C NMR
(CDCl3, 150 MHz) δ 188.4, 175.0, 158.1, 136.7, 135.9, 135.0,
130.7, 129.4, 127.9, 125.3, 14.8; MS (70 eV, EI) m/z 332 (35) [35Cl-
þ
~
M ], 221 (16), 139 (100), 111 (58), 75 (44), 50 (20); IR (ATR) ν
(cm-1) 2955, 2920, 2851, 1728, 1672, 1582, 1569, 1548, 1467, 1399,
1346, 1321, 1286, 1244, 1230, 1218, 1177, 1091, 1077, 1012, 968,
919, 847, 814, 747, 721, 664; HRMS (EI) calcd for C12H7Cl3N2OS
331.9345, found 331.9334.
[3,5-Dichloro-6-(4-methoxyphenyl)pyrazin-2-yl](2-thienyl)metha-
none (14a). To a solution of 3,5-dichloro-2-(4-methoxyphenyl)-
pyrazine (14) (256 mg, 1.0 mmol) dissolved in THF (1 mL) was
added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at
3
25 °C, and the resulting mixture was heated at 100 °C (200 W) for 1
h in the microwave according to TP3. The reaction mixture was
cooled to -20 °C, and CuCN 2LiCl (1 M solution in THF, 1.1 mL,
3
1.1 mmol) was added. After 30 min of stirring at the same
temperature, 2-thiophenecarbonyl chloride (293 mg, 2.0 mmol)
was added, and the resulting mixture was allowed to warm slowly to
25 °C within 2 h. The reaction mixture was then quenched with a
satd aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL) and aq NH3, and dried over anhydrous Na2SO4. After
filtration, the solvents were evaporated in vacuo. Purification by
flash chromatography (CH2Cl2/pentane 1:1) furnished the com-
4-(5-Bromo-2,6-dimethoxypyrimidin-4-yl)benzoic Acid Ethyl
Ester (15b). To a solution of 5-bromo-2,4-dimethoxypyrimidine
(15) (219 mg, 1.0 mmol) dissolved in THF (2 mL) was added
TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C,
3
and the resulting mixture was heated at 60 °C (100 W) for 30 min
according to TP3. Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3
(14 mg, 6 mol %) dissolved in THF (2 mL) and mixed with ethyl
4-iodobenzoate (304 mg, 1.1 mmol, 1.1 equiv) were then trans-
ferred via cannula to the reaction mixture. The resulting mixture
was stirred at 50 °C for 6 h and then quenched with a satd
aq NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ
50 mL), and dried over anhydrous Na2SO4. After filtration, the
solvents were evaporated in vacuo. Purification by flash chro-
matography (pentane/ether 75:25) furnished the compound 15b
(314 mg, 86%) as a white solid: mp 128.9-130.7 °C; 1H NMR
(CDCl3, 300 MHz) δ 8.12 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 8.4
Hz, 2 H), 4.40 (q, J = 7.1 Hz, 2 H), 4.09 (s, 3 H), 4.01 (s, 3 H),
1.40 (t, J = 7.1 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) δ 168.1,
166.1, 165.2, 163.5, 141.8, 131.4, 129.4, 129.1, 97.0, 61.2, 55.4,
55.3, 14.3; MS (70 eV, EI) m/z 366 (90) [79Br-Mþ], 365 (55), 339
(29), 338 (56), 337 (32), 336 (47), 323 (36), 321 (35), 223 (16), 221
(15); IR (ATR) ν~ (cm-1) 2997, 2941, 1943, 1714, 1664, 1560,
1539, 1509, 1481, 1452, 1408, 1379, 1349, 1311, 1282, 1238, 1193,
1178, 1153, 1127, 1112, 1104, 1030, 1022, 1006, 938, 877, 865,
843, 788, 775, 732, 719, 702, 688, 688, 669, 656, 628; HRMS (EI)
calcd for C15H15BrN2O4 366.0215, found 366.0195.
1
pound 14a (284 mg, 78%) as a colorless oil: H NMR (CDCl3,
300 MHz) δ7.91-7.86 (m, 2 H), 7.81-7.78 (m, 2 H), 7.18-7.15 (m,
1 H), 7.03-6.98 (m, 2 H), 3.87 (s, 3 H); 13CNMR(CDCl3, 75MHz)
δ 181.4, 161.3, 149.4, 145.6, 142.1, 140.9, 136.8, 131.3, 128.4, 126.2,
113.9, 55.4; MS (70 eV, EI) m/z 364 (15) [35Cl-Mþ], 111 (100); IR
(ATR) ν~ (cm-1) 3111, 3002, 2944, 2840, 2045, 1737, 1642, 1603,
1513, 1491, 1453, 1414, 1364, 1348, 1301, 1258, 1233, 1183, 1154,
1123, 1114, 1085, 1073, 1048, 1024, 1010, 946, 928, 869, 847, 834,
816, 796, 781, 753, 740, 724, 705, 662, 642, 633, 622, 611, 604;
HRMS (EI) calcd for C16H10Cl2N2O2S 363.9840, found 363.9832.
[3,5-Dichloro-6-(4-methoxyphenyl)pyrazin-2-yl](phenyl)metha-
none (14b). To a solution of 3,5-dichloro-2-(4-methoxyphenyl-
)pyrazine (14) (256 mg, 1.0 mmol) dissolved in THF (1 mL) was
added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at
25 °C, and the resulting mixture was heated at 100 °C (200 W) for
1 h in the microwave according to TP3. The reaction mixture
3
was cooled to -20 °C, and CuCN 2LiCl (1 M solution in THF,
3
1.1 mL, 1.1 mmol) was added. After 30 min of stirring at the same
temperature, benzoyl chloride (280mg, 2.0mmol) wasadded, and
the resulting mixture was allowed to warm slowly to 25 °C within
2 h. The reaction mixture was then quenched with a satd aq
NH4Cl solution (30 mL), extracted with diethyl ether (3 ꢀ 50 mL)
and aq NH3, and dried over anhydrous Na2SO4. After filtration,
the solvents were evaporated in vacuo. Purification by flash
chromatography (CH2Cl2/pentane 1:2) furnished the compound
6-Chloro-3-methoxy-4-[4-(trifluoromethyl)phenyl]pyridazine
(16a). To a solution of 3-chloro-6-methoxypyridazine (16) (145
mg, 1.0 mmol) dissolved in THF (2 mL) was added TMPZnCl
3
LiCl (1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was heated at 80 °C (100 W) for 60 min
according to TP3. Pd(dba)2 (17 mg, 3 mol %) and P(2-furyl)3
(14 mg, 6 mol %) dissolved in THF (2 mL) and mixed with
4694 J. Org. Chem. Vol. 75, No. 14, 2010

Bresser et al.
JOCFeatured Article
1-iodo-4-trifluoromethylbenzene (300 mg, 1.1 mmol, 1.1 equiv)
were then transferred via cannula to the reaction mixture. The
resulting mixture was stirred at 50 °C for 6 h and then quenched
with a satd aq NH4Cl solution (30 mL), extracted with diethyl
ether (3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After
filtration, the solvents were evaporated in vacuo. Purification by
flash chromatography (CH2Cl2) furnished the compound 16a
the solvents were evaporated in vacuo. Purification by flash
chromatography (pentane/ether, 8:2) furnished the compound
1
17a (201 mg, 76%) as a white solid: mp 154.1-156.1 °C; H
NMR (CDCl3, 300 MHz) δ 7.46 (s, 1 H), 4.01 (s, 3 H), 4.06 (s, 3
H); 13C NMR (CDCl3, 75 MHz) δ 161.3, 160.1, 130.8, 93.9, 55.9,
54.9; MS (70 eV, EI) m/z 266 (100) [Mþ], 265 (66), 237 (29), 109
(12), 85 (14), 71 (22), 57 (25), 53 (23); IR (ATR) ν~ (cm-1
)
1
(257 mg, 89%) as a white solid: mp 139.8-141.2 °C; H NMR
3069, 3008, 2996, 2984, 2960, 2948, 2890, 2859, 2667, 2568, 2197,
1996, 1908, 1793, 1576, 1535, 1512, 1458, 1443, 1371, 1346,
1298, 1230, 1186, 1134, 1058, 1019, 1003, 896, 856, 800, 771, 748,
667; HRMS (EI) calcd for C6H7IN2O2 265.9552, found
265.9553.
(CDCl3, 300 MHz) δ 7.76-7.70 (m, 4 H), 7.41 (s, 1 H), 4.17 (s,
3 H); 13C NMR (CDCl3, 75 MHz) δ 161.5, 151.5, 135.9, 131.8 (q,
J = 32.8 Hz), 131.3, 129.5, 128.9, 125.7 (q, J = 3.6 Hz), 123.7 (q,
J = 272.4 Hz), 55.7; MS (70 eV, EI) m/z 288 (36) [35Cl-Mþ], 287
(100), 271 (13), 217 (16), 203 (22); IR (ATR) ν~ (cm-1) 3029, 2991,
2950, 2894, 2863, 2349, 2234, 1928, 1738, 1620, 1574, 1526, 1460,
1454, 1412, 1377, 1324, 1296, 1259, 1236, 1166, 1109, 1070, 1043,
1017, 961, 930, 864, 842, 778, 743, 730, 678; HRMS (EI) calcd for
C12H8ClF3N2O 288.0277, found 288.0250.
4-(4-Chlorophenyl)-3,6-dimethoxypyridazine (17b). To a solu-
tion of 3,6-dimethoxypyridazine (17) (140 mg, 1.0 mmol) dis-
solved in THF (2 mL) was added TMPZnCl LiCl (1) (1.3 M in
3
THF, 0.84 mL, 1.1 mmol) at 25 °C, and the resulting mixture
was heated at 90 °C (100 W) for 1 h according to TP3. Pd(dba)2
(17 mg, 3 mol %) and P(o-furyl)3 (14 mg, 6 mol %) dissolved in
THF (2 mL) and mixed with 1-chloro-4-iodobenzene (262 mg,
1.1 mmol, 1.1 equiv) were then transferred via cannula to the
reaction mixture. The resulting mixture was stirred at 50 °C for
6 h and then quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evapo-
rated in vacuo. Purification by flash chromatography (CH2Cl2)
furnished the compound 17b (220 mg, 88%) as a white solid: mp
117.1-118.7 °C; 1H NMR (CDCl3, 300 MHz) δ 7.50 (dt, J =
6.6, 2.2 Hz, 2 H), 7.38 (dt, J = 6.8, 2.2 Hz, 2 H), 6.87 (s, 1 H), 4.05
(s, 3 H), 4.04 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 162.6, 159.1,
135.6, 132.8, 131.8, 130.3, 128.7, 119.0, 54.8, 54.6; MS (70 eV,
EI) m/z 249 (100) [35Cl-Mþ], 233 (11), 221 (16), 136 (21); IR
(ATR) ν~ (cm-1) 3047, 3023, 2992, 2953, 2865, 1910, 1737, 1657,
1612, 1536, 1494, 1462, 1446, 1405, 1375, 1356, 1302, 1273, 1253,
1221, 1192, 1143, 1108, 1091, 1017, 1013, 995, 963, 909, 876, 835,
827, 821, 774, 769, 744, 718, 669, 658, 629, 612; HRMS (EI)
calcd for C12H11ClN2O2 249.0430, found 249.0428.
(6-Chloro-3-methoxypyridazin-4-yl)phenylmethanone (16b).
To a solution of 3-chloro-6-methoxypyridazine (16) (145 mg,
1.0 mmol) dissolved in THF (2 mL) was added TMPZnCl LiCl
3
(1) (1.3 M in THF, 0.84 mL, 1.1 mmol) at 25 °C, and the
resulting mixture was heated at 80 °C (100 W) for 60 min
according to TP3. The reaction mixture was cooled to -20 °C,
and CuCN 2LiCl (1 M solution in THF, 1.1 mL, 1.1 mmol) was
3
added. After 30 min of stirring at the same temperature, benzoyl
chloride (155 mg, 1.1 mmol) was added, and the resulting
mixture was allowed to warm slowly within 2 h. The reaction
mixture was quenched with a satd aq NH4Cl solution (30 mL),
extracted with diethyl ether (3 ꢀ 50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvents were evapo-
rated in vacuo. Purification by flash chromatography (pentane/
ether 65:35) furnished the compound 16b (200 mg, 80%) as
yellowish white solid: mp 97.1-98.8 °C; 1H NMR (CDCl3, 300
MHz) δ 7.77-7.74 (m, 2 H), 7.68-7.63 (m, 1 H), 7.50 (t, J = 7.7
Hz, 2 H), 7.38 (s, 1 H), 4.07 (s, 3 H); 13C NMR (CDCl3, 75 MHz)
δ 190.4, 160.8, 151.3, 135.0, 134.8, 130.4, 129.7, 128,9, 128.5,
55.7; MS (70 eV, EI) m/z 248 (21) [35Cl-Mþ], 219 (6), 183 (7), 105
(100), 91 (38), 77 (69), 51 (18); IR (ATR) ν~ (cm-1) 3080, 3026,
2955, 1810, 1668, 1595, 1579, 1530, 1489, 1458, 1449, 1371, 1327,
1308, 1287, 1268, 1192, 1173, 1161, 1124, 1096, 1078, 1023, 994,
965, 902, 832, 802, 778, 731, 709, 682, 670, 651, 623, 614; HRMS
(ESI) calcd for C12H9ClN2O2 249.0432, found 249.0425.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
the European Research Council (ERC) for financial support. We
also thank Evonik GmbH, BASF AG, W.C. Heraeus GmbH,
and Chemetall GmbH for the generous gift of chemicals.
4-Iodo-3,6-dimethoxypyridazine (17a). To a solution of 3,6-
dimethoxypyridazine (17) (140 mg, 1.0 mmol) dissolved in THF
(2 mL) was added TMPZnCl LiCl (1) (1.3 M in THF, 0.84 mL,
Note Added after ASAP Publication. There were errors in
the version published ASAP June 17, 2010. The supporting
information and structure 11b in Table 2 have been replaced; the
corrected version reposted on June 23, 2010.
3
1.1 mmol) at 25 °C, and the resulting mixture was heated at 90 °C
(100 W) for 1 h according to TP3. Iodine (381 mg, 1.5 mmol)
dissolved in dry THF (2 mL) was then dropwise added, and the
resulting mixture was stirred for 0.5 h. The reaction mixture was
quenched with a satd aq Na2S2O3 solution (10 mL) and with
a satd aq NH4Cl solution (30 mL), extracted with diethyl ether
(3 ꢀ 50 mL), and dried over anhydrous Na2SO4. After filtration,
Supporting Information Available: NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4695