An efficient and mild ortho-zincation of aromatics and heterocycles by using TMP2Mg·2LiCl in the presence of ZnCl2

Article abstract of DOI:10.1016/j.jorganchem.2009.12.016

A variety range of functionalized aryl and heteroaryl zinc reagents were efficiently generated by using TMP₂Mg·2LiCl (TMP = 2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl₂. The subsequently functionalization gave after react

Full text of DOI:10.1016/j.jorganchem.2009.12.016

Journal of Organometallic Chemistry 695 (2010) 775–780
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
An efficient and mild ortho-zincation of aromatics and heterocycles by using
TMP2MgÁ2LiCl in the presence of ZnCl2
a
b
a
Zhi-Bing Dong a, , Wei-Hua Zhu , Zhi-Guang Zhang , Min-Zhi Li
*
a School of Chemistry and Chemical Engineering, Jiangsu University, Xuefu Road 301, Zhenjiang 212013, PR China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Weijin Road 94, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety range of functionalized aryl and heteroaryl zinc reagents were efficiently generated by using
TMP2MgÁ2LiCl (TMP = 2,2,6,6-tetramethylpiperamidyl) in the presence of ZnCl2. The subsequently func-
tionalization gave after reaction with electrophiles the expected polyfunctionalized products in good
yields. A detailed study concerned on the point how we found the protocol and how we optimized it
was depicted.
Received 25 September 2009
Received in revised form 14 December 2009
Accepted 15 December 2009
Available online 23 December 2009
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Aromatics
Heterocycles
Zincation
Metalation
Functionalization
1. Introduction
traces, while the major product, the dimeric heterocycle (3) was
isolated in 34% yield (Scheme 1).
The directed ortho-metalation of aromatics and heterocycles is
an efficient method for the functionalization of these compounds
[1–10]. However, deprotonation of some heterocyclic aromatic
rings gave unsatisfactory results due to the high reactivity of the
generated organometallic intermediates [11,12], and it is already
known that the metalation of diazines is challenging since very fac-
ile competitive nucleophilic addition reactions occur [13–16]. To
resolve this problem, recently, we (Knochel and Dong et al.) have
reported a simple method for the zincation of some sensitive aro-
matic and heteroaromatic substrates by using TMP2MgÁ2LiCl
(TMP = 2,2,6,6-tetramethylpiperamidyl) [17,18] in the presence of
ZnCl2 [19]. Thus, with addition of ZnCl2 to the substrates, prior to
the addition of the magnesium base TMP2MgÁ2LiCl, the relatively
active aromatics and heterocycles can be smoothly metalated at
25 °C, after reaction with electrophiles, the expected functionalized
products can be obtained in good yields. Herein, we wish to report
a detailed study of the reaction and an expanded application to fur-
ther illustrate this efficient and mild method.
This is probably due to the relatively high reactivity of the orga-
nomagnesium intermediate, and we speculate that the less reac-
tive organozinc intermediate might not lead to this result. Then,
we first investigated the metalation of 1a by an in situ procedure
via which the less reactive zinc intermediate might be generated.
Thus, 0.5 equivalent of TMP2MgÁ2LiCl was added to the substrate,
subsequently 0.5 equivalent of ZnCl2 was added to the reaction
solution under the setting temperature, the metalation was
checked by iodination and was analyzed by GC machine. To our
disappointment, no matter how the reaction temperature changes,
the metalation always gave a mixture without any favoured selec-
tivity (Scheme 2).
However, when the addition of ZnCl2 to the substrate, prior to
the addition of the magnesium base TMP2MgÁ2LiCl, an exciting re-
sult was obtained: only traces of dimer was observed and quinox-
alyl iodide was isolated in 94% yield (Scheme 3).
The optimal ratio of ZnCl2 to TMP2MgÁ2LiCl (0.5:0.55) was ob-
tained by studying the metalation of pyrazine which is also a reac-
tive heterocycle (Scheme 4). The order of addition of all the
reaction partners (first ZnCl2, then base TMP2MgÁ2LiCl) is essential
for achieving the reported metalation time in this paper, which
indicates a probable precomplexation of the aromatic or heteroar-
omatic substrate facilitates the deprotonation with TMP2MgÁ2LiCl
[19]. Alternatively, base TMP2MgÁ2LiCl reacts first with quinoxaline
affording the organomagnesium intermediate, after a fast trans-
metalation with ZnCl2 (0.5 equiv.), the quinoxalylzinc intermediate
could be formed [19].
2. Results and discussion
During the course of the metalation and the subsequent func-
tionalization of quinoxaline (1a) by using the magnesium base
TMP2MgÁ2LiCl, the desired quinoxalyl iodide (2) was obtained only
* Corresponding author. Tel.: +86 15052934393.
E-mail address: zhibingdong80@yahoo.com.cn (Z.-B. Dong).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.12.016

776
Z.-B. Dong et al. / Journal of Organometallic Chemistry 695 (2010) 775–780
N
N
CO2Et
CO2Et
1) TMP2Mg·2LiCl
I
N
I
N
N
TMP2Mg·2LiCl (0.55 equiv.)
iodination analysis
N
N
(0.55 equiv.), r.t. 2 h
+
2) I2, 0 oC to r.t.
N
1 h
Cl
7a
Cl
7b
1a
2: traces
3: 34%
-50 oC for 30 min.: 40% conversion
then
N
Mg·2LiCl
N
-50 oC for 3 h: 50% conversion
then
-10 oC for 8 h: start decomposing
then
TMP2Mg·2LiCl
r.t. for 30min.: decomposed
Scheme 1. Functionalization of quinoxaline by using TMP2MgÁ2LiCl without ZnCl2.
CO2Et
I
CO2Et
1) ZnCl2 (0.5 equiv.)
2) TMP2Mg·2LiCl (0.55 equiv.)
N
25oC, overnight
1)TMP2Mg·2LiCl (0.5 equiv.)
2) ZnCl2 (0.5 equiv.)
Cl
7b
iodination analysis
Cl
7a
N
N
I
N
N
N
N
N
+
-78 oC to r. t.
iodination analysis
full conversion
3
1a
2
Scheme 5. Metalation of ethyl 4-chlorobenzoate by using TMP2MgÁ2LiCl and the
iodination analysis:
new protocol.
still a mixture without selectivity
Scheme 2. Metalation of quinoxaline by using TMP2MgÁ2LiCl prior to the addition
to decompose when the reaction was performed under a higher
temperature to accelerate the reaction, this made the metalation
of this substrate in a dilemma (Scheme 5). However, by using the
new protocol, we can resolve this problem in a smooth way. Thus,
by using the optimal reaction condition, the metalation of ethyl 4-
chlorobenzoate was accomplished with a full conversion at 25 °C
overnight (Scheme 5).
Further, a variety range of functionalized substrates were
cleanly ortho-deprotonated by using this protocol (Table 1). The
zincated quinoxaline 1a was transmetalated to copper intermedi-
ate which further underwent an allylation [20] to give the func-
tionalized product 1b in 75% yield (entry 1). The metalation of
pyrazine 4a was achieved within 30 min, similarly, a further cop-
per-mediated allylations gave the corresponding functionalized
pyrazines in 70–75% yield (entries 3–4, see 4c in Scheme 4 also).
The zincation of 3-bromoquinoline 5a occurred at position 2 pro-
viding, after the reaction with 3-chloroprop-1-enyl-benzene, the
corresponding product 5b in 78% yield (entry 5). In addition, the
ortho-metalations of the esters 7a, 8a and 9a were accomplished
with a full conversion at r.t., and the functionalized ethyl benzoates
7c–d, 8b and 9b were obtained in 70–86% yields after quenching
with various electrophiles (entries 6–9).
of ZnCl2.
N
1) ZnCl2 (0.5 equiv.)
2) TMP2Mg·2LiCl
N
I
N
N
N
N
N
(0.55 equiv.), r.t. 2 h
+
3) I2, 0 oC to r.t.
N
1 h
3: traces
2: 94%
1a
Scheme 3. Functionalization of quinoxaline by using the new protocol.
1) ZnCl2 (1 equiv.)
2) TMP2Mg·2LiCl (0.55 equiv.)
N
I
N
-40oC, 120 min.
3) iodination analysis
N
N
4b
4a
almost no conversion
1) ZnCl2 (1 equiv.)
2) TMP2Mg·2LiCl (1 equiv.)
N
I
N
-40oC, 120 min.
3) iodination analysis
N
N
4a
By using this methodology, a multiple functionalization of het-
erocycles was also performed under mild condition (Scheme 6). For
example, due to the inductive effect of the extra bromine atom in
position 6, the metalation of 6-bromoquinoxaline 6a (up to
8 mmol) was first occurred at position 5, and the dibromide 6b
was obtained in 70% yield by bromination with (BrCl2C)2. The sec-
ond metalation occurred at position 8, giving after a copper-med-
iated allylation the multifunctionalized product 6c in 70% yield.
We also performed the metalation and the subsequent functional-
ization of 1a scaled-up to 12 mmol, thus, the zincated quinoxaline
underwent a Negishi [21–24] cross-coupling to give the expected
product 1c in 80% yield (Table 1, entry 2). The scaled-up metalation
4b
low conversion
N
1) ZnCl2 (0.5 equiv.)
N
N
Zn
)
2
2) TMP2Mg·2LiCl (0.55 equiv.)
-40oC, 30 min.
N
4a
iodination analysis:
full conversion
N
1) CuCN·2LiCl (1.1 equiv.)
2) CH2=C(CH3)CH2Br (1.5 equiv.)
-40 oC to r.t., 1h
N
4c: 75%
of 1a and 6a illustrates this method in
a typical practical
Scheme 4. Ratio optimization of ZnCl2 to TMP2MgÁ2LiCl.
procedure.
We also studied the metalation of the aromatic substrate 7a
(ethyl 4-chlorobenzoate) to make a further illustration of this
method. As we can see from Scheme 5, the metalation of 7a by
using the powerful base TMP2MgÁ2LiCl under low temperature is
relatively slow while the organomagnesium intermediate started
3. Conclusion
In summary, an efficient ortho-deprotonation and subsequent
functionalization of various sensitive aromatics and heterocycles
by using TMP2MgÁ2LiCl in the presence of ZnCl2 was demonstrated.

Z.-B. Dong et al. / Journal of Organometallic Chemistry 695 (2010) 775–780
Br
777
1. ZnCl2 (0.5 equiv.)
2. TMP2Mg·2LiCl
(0.75 equiv.)
Br
N
N
1. ZnCl2 (0.5 equiv.)
2. TMP2Mg·2LiCl
(0.55 equiv.)
Br
Br
N
N
25 oC, 15 min.
Br
N
N
25 oC, 0.1 h
3. (BrCl2C)2, 0 o
to 25 oC, 1 h
C
3. CuCN·2LiCl
oC
c
-C6H9Br, -40
oC
to 25
, 1 h
6a
6c: 70%
6b: 70%
Scheme 6. Multiple functionalization of heterocycles by using the new protocol.
Table 1
Products obtained by direct ortho-metalation of the substrates with TMP2MgÁ2LiCl at 25 °C in the presence of ZnCl2 (0.5 equiv) followed by the reaction with electrophiles.
Entry
Substrate
t(h)
E–X
Products
Yield (%)a
N
N
E
N
N
1
2
1a
1a
N
2
2
CH2@C(CH3)CH2Br
p-IC6H4CO2Et
1b: E = CH2(CH3)C@CH2
1c: E = p-C6H4CO2Et
75b
80c
N
N
E
N
4a
4a
3
4
0.5
0.5
I2
4b: E = I
4d: E = c-C6H9
71
c-C6H9Br
70b
Br
Br
N
N
E
5
5a
2.5
PhCH@CHCH2Cl
5b: E = CH2CH@CHPh
78b
CO2Et
CO2Et
Cl
7a
7a
Cl
E
6
7
12
12
PhCOCl
(BrCl2C)2
7c: E = COPh
7d: E = Br
86b
74
CO2Et
CO2Et
CO2Et
Br
8a
Cl
Br
E
8
12
CH2@C(CH3)CH2Br
8b: E = CH2(CH3)C@CH2
70b
79
E
Cl
CO2Et
9
9a
2.5
I2
9b: E = I
a
b
c
Isolated yield of analytically pure product.
A transmetalation CuCNÁ2LiCl (1.1 equiv) was performed.
Obtained by a palladium-catalyzed cross-coupling.
All the reactions were carried out under mild conditions with good
yields. A detailed study concerned on the point how we found the
protocol and how we optimized it was depicted. It is noteworthy
that this methodology also allows multiple functionalizations of
heterocyclic substrates.
4.1.1. Bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–Bis(lithium
chloride): TMP2MgÁ2LiCl
In an argon-flushed Schlenk flask, 2,2,6,6-tetramethylpiperidine
(TMPH) (5.07 mL, 30 mmol) was dissolved in THF (30 mL). This
solution was cooled to À40 °C and n-BuLi (2.4 M in Hexane,
12.5 mL, 30 mmol) was added dropwise. After the addition was
complete, the reaction mixture was warmed to 0 °C and stirred
at this temperature for 30 min. Freshly titrated TMPMgClÁLiCl
[25,26] (1.0 M in THF, 30 mL, 30 mmol) was then added dropwise
to the LiTMP solution and the reaction mixture was stirred at
0 °C for 30 min, warmed to 25 °C and stirred for 1 h. The solvents
were then removed in vacuo affording a yellowish solid. Freshly
distilled THF was then slowly added under vigorous stirring, until
the complete dissolution of the salts. The freshly prepared
(TMP)2MgÁ2LiCl solution was titrated prior to use at 0 °C with ben-
zoic acid using 4-(phenylazo)-diphenylamine as indicator [27]. A
concentration of 0.6 M in THF was obtained.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere in
flame-dried glassware. Syringes which were used to transfer anhy-
drous solvents or reagents were purged with argon prior to use. All
starting materials were purchased from commercial suppliers and
used without further purification unless otherwise stated. THF was
continuously refluxed and freshly distilled from Na benzophenone
ketyl under N2. Yields refer to isolated yields of compounds esti-
mated to be >95% pure as determined by 1H NMR (25 °C) and cap-
illary GC. Column chromatography was performed using SiO2
(0.040–0.063 mm, 230–400 mesh ASTM) from Merck if not
indicated.
4.1.2. 1 M ZnCl2 solution in THF
A dry and argon-flushed 500-mL Schlenk flask, equipped with a
magnetic stirrer and a glass stopper, was charged with ZnCl2

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Z.-B. Dong et al. / Journal of Organometallic Chemistry 695 (2010) 775–780
(20.45 g, 150 mmol) and heated to 150 °C under high vacuum for
5 h. After cooling to 25 °C under argon, freshly distilled THF
(150 mmol) was added and the mixture was stirred continuously
until the salts got dissolved. The reagent ZnCl2 (1 M in THF) ap-
pears as a colorless solution.
142.3, 141.8, 131.8, 130.6, 130.3, 130.1, 129.8, 129.2, 127.4, 61.3,
14.4. MS (EI, 70 eV): m/z (%) = 279 (15), 278 (74) [M+], 250 (32),
233 (100), 206 (12), 205 (32), 102 (12), 76 (14). HRMS (EI): m/z
calcd for C17H14O2N2: 278.1055; found: 278.1030.
4.1.7. 2-Iodopyrazine (4b) [12]
4.1.3. 1 M CuCNÁ2LiCl solution in THF
According to TP, the metalation of pyrazine (4a, 160 mg,
2.0 mmol) was completed within 30 min at 25 °C. Iodine
(760 mg, 3 mmol) dissolved in THF (3 mL) was added to the reac-
tion and the reaction mixture was stirred at 25 °C for 1 h and
was quenched with aq. sat. NH4Cl solution (10 mL). After extrac-
tion with diethyl ether (3 Â 20 mL), the combined organic layers
were washed with sat Na2S2O3 solution and brine, dried over
MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (pen-
tane:diethyl ether = 10:1) to give 4b (293 mg, 71%) as a pale yellow
solid. Mp: 90–91 °C, decomposition. IR (ATR): 3433, 2925, 2867,
A dry and argon-flushed 50-mL Schlenk flask, equipped with a
magnetic stirrer and a glass stopper, was charged with LiCl
(848 mg, 20 mmol) and heated to 130 °C under high vacuum for
1 h. After cooling to 25 °C under argon, CuCN (869 mg, 10 mmol)
was added under an inert atmosphere inside a glove box. The
Schlenk flask was further heated to 140 °C for 5 h under high vac-
uum and cooled to 25 °C. It was then charged with freshly distilled
THF (20 mL) under an argon flush and wrapped with aluminum foil
to protect it from light. The mixture was stirred vigorously until all
the solid went into solution to furnish 1.0 M CuCNÁ2LiCl in THF.
1503, 1447 cmÀ1
.
1H NMR (300 MHz, CDCl3): d = 8.87 (d,
4.1.4. Typical procedure for the zincation of polyfunctionalized
aromatics and heterocycles with TMP2MgÁ2LiCl (TP)
J = 1.3 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.39 (dd, J = 1.3, 2.8 Hz,
1H). 13C NMR (75 MHz, CDCl3): d = 118.3, 143.1, 146.1, 153.5. MS
(EI, 70 eV): m/z (%) = 206 (100) [M+], 127 (37), 79 (67), 52 (57).
HRMS (EI): m/z calcd for C4H3N2I: 205.9341; found: 205.9350.
A dry and argon-flushed 25-mL Schlenk flask, equipped with a
magnetic stirrer and
a septum, the given starting material
(1 mmol) was dissolved in THF (2 mL), and ZnCl2 (1 M solution in
THF, 0.5 mL, 0.5 mmol) was added. TMP2MgÁ2LiCl (0.6 m in THF,
0.92 mL, 0.55 mmol) was added dropwise and the reaction mixture
was stirred at 25 °C for the indicated time. Complete metalation
was detected by GC-analysis of reaction aliquots which were
quenched with I2 in dry THF.
4.1.8. 2-(2-Methylallyl)pyrazine (4c)
According to TP, the metalation of pyrazine (4a, 160 mg,
2.0 mmol) was completed within 30 min at 25 °C. The reaction
mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF,
2.2 mL, 2.2 mmol) and 3-bromo-2-methylpropene (406 mg,
3.0 mmol) were added. The mixture was allowed to warm to
25 °C overnight. The reaction mixture was quenched with sat.
NH4Cl solution (10 mL) and extracted with diethyl ether
(3 Â 20 mL). The combined organic layers were washed with brine,
dried over MgSO4 and evaporated the solvent (Caution! The evap-
oration should be done carefully since the product is volatile.)
The residue was purified by flash chromatography on silica gel
(pentane:diethyl ether = 2:1) to give 4c (200 mg, 75%) as a pale yel-
low oil. IR (ATR): 2961, 2923, 1401, 1257, 1084, 1056, 1015, 787,
4.1.5. 2-(2-Methylallyl)quinoxaline (1b) [28]
According to TP, the metalation of quinoxaline (1a, 260 mg,
2 mmol) was completed within 2 h at 25 °C. The reaction mixture
was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF, 2.2 mL,
2.2 mmol) and 3-bromo-2-methylpropene (406 mg, 3.0 mmol)
were added. The mixture was allowed to warm to 25 °C overnight.
The reaction mixture was quenched with sat. NH4Cl solution
(10 mL) and extracted with diethyl ether (3 Â 20 mL). The com-
bined organic layers were washed with brine, dried over MgSO4
and concentrated. The residue was purified by flash chromatogra-
phy on silica gel (pentane:diethyl ether = 5:1) to give 1b (276 mg,
75%) as a colorless oil. IR (ATR): 3020, 2962, 2922, 1404, 1260,
701, 685 cmÀ1 1H NMR (300 MHz, CDCl3): d = 8.50 (s, 2H), 8.42
.
(s, 1H), 4.91 (t, J = 1.5 Hz, 1H), 4.78 (d, J = 0.6 Hz, 1H), 3.54 (s,
2H), 1.73 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 155.5, 144.9,
144.1, 142.5, 142.3, 113.68, 44.2, 22.3. MS (EI, 70 eV): m/z
(%) = 134 (13) [M+], 133 (87), 119 (100), 94 (45). HRMS (EI): m/z
calcd for C8H10N2: 134.0844; found: 134.0831.
1085, 1058, 1017, 882, 787, 758, 723, 701, 685 cmÀ1 1H NMR
.
(300 MHz, CDCl3): d = 8.79 (s, 1H), 8.11–8.03 (m, 2H), 7.79–7.68
(m, 2H), 4.96–4.94 (m, 1H), 4.81–4.80 (m, 1H), 3.76 (s, 2H), 1.81
(s, 3H). 13C NMR (75 MHz, CDCl3): d = 155.0, 145.9, 142.5, 142.1,
141.2, 130.0, 129.2, 129.2, 129.0, 113.9, 45.2, 22.5. MS (EI, 70 eV):
m/z (%) = 184 (27) [M+], 183 (64), 170 (13), 169(100), 168 (17),
144 (32), 102 (11), 76 (11). HRMS (EI): m/z calcd for C12H12N2:
184.1000; found: 184.0973.
4.1.9. 2-(Cyclohex-2-enyl)pyrazine (4d)
According to TP, the metalation of pyrazine (4a, 160 mg,
2.0 mmol) was completed within 30 min at 25 °C. The reaction
mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF, 2.2
mL, 2.2 mmol) and 3-bromocyclohex-1-ene (483 mg, 3.0 mmol)
were added. The mixture was allowed to warm to 25 °C overnight.
The reaction mixture was quenched with sat. NH4Cl solution
(10 mL) and extracted with diethyl ether (3 Â 20 mL). The com-
bined organic layers were washed with brine, dried over MgSO4
and evaporated the solvent (Caution! The evaporation should be
done carefully since the product is volatile.) The residue was puri-
fied by flash chromatography on silica gel (pentane:diethyl
ether = 4:1) to give 4d (224 mg, 70%) as a colorless oil. IR (ATR):
2971, 2934, 1696, 1589, 1567, 1476, 1364, 1210, 1155, 1115,
4.1.6. 4-Quinoxalin-2-yl-benzoic acid ethyl ester (1c) [19]
According to TP, the metalation of quinoxaline (1a, 1560 mg,
12 mmol) was completed within 2 h at 25 °C. A solution of
Pd(dba)2 (180 mg) and P(2-fur)3 (150 mg) in THF (12 mL) was
added, followed by ethyl 4-iodobenzoate (4968 mg, 18 mmol).
The reaction mixture was stirred at 25 °C for 6 h. The reaction mix-
ture was quenched with sat. aq. NH4Cl solution (20 mL), extracted
with diethyl ether (3 Â 30 mL) and dried over anhydrous MgSO4.
After filtration, the solvent was evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel (pen-
tane:diethyl ether = 3:1) to give 1c (2668 mg, 80%) as a colorless
solid. Mp: 88.8–90.9 °C. IR (ATR): 2923, 1713, 1607, 1363, 1271,
1183, 1126, 1099, 1048, 1017, 958, 861, 772, 758, 752, 698, 668,
1082, 1023, 946, 890, 871, 836, 806, 787, 739, 688, 592 cmÀ1 1H
.
NMR (300 MHz, CDCl3): d = 8.45 (d, J = 1.8 Hz, 2 H), 8.35 (d,
J = 1.8 Hz, 1H), 5.95–5.89 (m, 1H), 5.76–5.70 (m, 1H), 3.60–3.54
(m, 1H), 2.08–2.00 (m, 3H), 1.73–1.64 (m, 3H). 13C NMR (75 MHz,
CDCl3): d = 160.6, 144.0, 142.2, 129.7, 127.2, 41.7, 30.2, 24.7, 20.9.
MS (EI, 70 eV): m/z (%) = 160 (49) [M+], 159 (48), 145 (32), 132
(30), 131 (100), 119 (16), 118 (14), 94 (44), 79 (15), 77 (11), 67
615 cmÀ1 1H NMR (300 MHz, CDCl3): d = 9.39 (s, 1H), 8.33–8.16
.
(m, 6H), 7.85–7.80 (m, 2H), 4.46 (q, J = 7.2 Hz, 2H), 1.47 (t,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): d = 166.2, 150.7, 143.1,

Z.-B. Dong et al. / Journal of Organometallic Chemistry 695 (2010) 775–780
779
(10), 53 (10), 52 (12). HRMS (EI): m/z calcd for C10H12N2: 160.1000;
found: 160.0996.
1H), 6.08–6.05 (m, 1H), 5.73(dd, J = 10.2, 2.4 Hz, 1H), 4.72–4.68
(m, 1H), 2.17–2.14 (m, 3H), 1.73–1.66 (m, 2H), 1.58–1.53 (m,
1H). 13C NMR (150 MHz, CDCl3): d = 146.3, 145.5, 144.0, 142.0,
140.7, 132.9, 130.3, 128.5, 128.1, 124.3, 34.7, 31.1, 25.1, 20.7. MS
(EI, 70 eV): m/z (%) = 370 (50), 369 (32), 368 (100) [M+], 367 (48),
366 (53), 365 (22), 342 (14), 341 (34), 340 (31), 339 (63), 338
(16), 337 (31), 329 (37), 328 (20), 327 (75), 326 (27), 325 (40),
324 (12), 315 (12), 313 (22), 311 (11), 303 (10), 302 (18), 301
(17), 290 (11), 289 (66), 288 (15), 287 (70), 261 (19), 260 (11),
259 (21), 235 (14), 233 (17), 208 (18), 207 (22), 206 (11), 205
(10), 193 (11), 192 (12), 180 (24), 179 (29), 167 (35), 166 (26),
154 (15), 153 (46), 152 (19), 151 (10), 140 (12), 127 (15), 126
(19), 77 (13), 76 (11), 75 (12), 67 (20). HRMS (EI): m/z calcd for
C14H14N2Br2: 367.9347; found: 367.9356.
4.1.10. 3-Bromo-2-cinnamylquinoline (5b)
According to TP, the metalation of 3-bromoquinoline (5a,
416 mg, 2 mmol) was completed within 2.5 h at 25 °C. The reaction
mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF,
2.2 mL, 2.2 mmol) and 3-chloroprop-1-enyl-benzene (456 mg,
3 mmol) were added. The mixture was allowed to warm to 25 °C
and stirred overnight. The reaction mixture was quenched with
sat. aq. NH4Cl solution (10 mL), extracted with diethyl ether
(3 Â 20 mL) and dried over anhydrous MgSO4. After filtration, the
solvent was evaporated in vacuo. The crude product was purified
by flash chromatography on silica gel (pentane:diethyl ether =
80:1) to give 5b (505 mg, 78%) as a white solid, Mp: 97.6–
99.9 °C. IR (ATR): 3022, 2860, 1586, 1486, 1448, 1394, 1298,
1196, 1169, 1141, 1122, 980, 970, 956, 930, 905, 857, 798, 778,
4.1.13. Ethyl 2-benzoyl-4-chlorobenzoate (7c)
According to TP, the metalation of ethyl 4-chlorobenzoate (7a;
369 mg, 2.0 mmol) was completed within 12 h at 25 °C. The reac-
tion mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF,
2.2 mL, 2.2 mmol) and benzoyl chloride (0.35 mL, 3 mmol) were
added. The mixture was allowed to warm to 25 °C and stirred over-
night. The reaction mixture was quenched with sat. aq. NH4Cl solu-
tion (10 mL), extracted with diethyl ether (3 Â 20 mL) and dried
over anhydrous MgSO4. After filtration, the solvent was evaporated
in vacuo. The crude product was purified by flash chromatography
silica gel (pentane:diethyl ether = 6:1) to give 7c (500 mg, 86%) as a
yellow solid. Mp: 78.9–80.9 °C. IR (ATR): 2983, 2909, 1712, 1677,
1619, 1590, 1583, 1560, 1490, 1473, 1450, 1445, 1385, 1363,
1319, 1311, 1283, 1267, 1243, 1177, 1153, 1134, 1105, 1089,
1074, 1021, 1001, 979, 966, 954, 942, 899, 875, 860, 843, 815,
746, 714, 693 cmÀ1 1H NMR (600 MHz, CDCl3): d = 8.38 (s, 1H),
.
8.13 (s, 1H), 7.73 (t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.38
(dd, J = 8.4, 1.2 Hz, 2H), 7.28 (t, J = 7.8 Hz, 2H), 7.21–7.18 (m, 1H),
6.63–6.54 (m, 2H), 4.13 (d, J = 4.8 Hz, 2H). 13C NMR (150 MHz,
CDCl3): d = 158.1, 137.3, 128.4, 128.1, 127.2, 126.5, 126.3, 118.4,
41.7. MS (EI, 70 eV): m/z (%) = 326 (11), 325 (59), 324 (50), 323
(63) [M+], 322 (41), 248 (34), 246 (36), 245 (18), 244 (65), 243
(26), 242 (24), 241 (32), 224 (12), 223 (100), 222 (12), 221 (100),
167 (23), 166 (14), 140 (16), 127 (18), 121 (12), 116 (10), 115
(40), 91 (11), 77 (10). HRMS (EI): m/z calcd for C18H14N1Br1:
323.0310; found: 323.0293.
4.1.11. 5,6-Dibromo-quinoxaline (6b) [19]
According to TP, the metalation of 6-bromoquinoxaline (6a;
1672 mg, 8 mmol) was completed within 5 min at 25 °C.
BrCl2CCCl2Br (3900 mg, 12 mmol) was added at 25 °C and the
resulting mixture was stirred for 1 h. The reaction mixture was
quenched with sat. aq. NH4Cl solution (10 mL), extracted with
diethyl ether (3 Â 25 mL) and dried over anhydrous MgSO4. After
filtration, the solvent was evaporated in vacuo. The crude product
was purified by fast chromatography on silica gel (pentane:diethyl
ether = 5:1) to give 6b (1613 mg, 70%) as a colorless solid. Mp:
182.0–184.3 °C, decomposition. IR (ATR): 3076, 3044, 1591, 1548,
1469, 1430, 1352, 1338, 1188, 1112, 1030, 965, 880, 865, 830,
808, 780, 770, 712, 698, 690, 643, 619, 609, 591, 585 cmÀ1 1H
.
NMR (400 MHz, CDCl3): d = 8.02 (d, J = 8.4 Hz, 1H), 7.77–7.73 (m,
2H), 7.57–7.52 (m, 2H), 7.46–7.41 (m, 2H), 7.36 (d, J = 8.4 Hz,
1H), 4.07 (q, J = 7.1 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d = 195.5, 165.2, 143.3, 139.2, 136.7, 133.7,
131.9, 129.9, 129.6, 128.9, 128.0, 127.8, 62.0, 13.8. MS (EI, 70 eV):
m/z (%) = 288 (24) [M+], 245 (16), 244 (15), 243 (35), 213 (11),
211 (36), 183 (56), 152 (21), 105 (100), 77 (45), 57 (13). HRMS
(EI): m/z calcd for C16H13ClO3:288.0553; found: 288.0550.
4.1.14. Ethyl 2-bromo-4-chlorobenzoate (7d)
776, 640, 616 cmÀ1
.
1H NMR (300 MHz, CDCl3): d = 8.99 (d,
According to TP, the metalation of ethyl 4-chlorobenzoate (7a;
369 mg, 2.0 mmol) was completed within 12 h at 25 °C.
BrCl2CCCl2Br (974 mg, 3 mmol) was added at 25 °C and the result-
ing mixture was stirred for 1 h. The reaction mixture was quenched
with sat. aq. NH4Cl solution (10 mL), extracted with diethyl ether
(3 Â 20 mL) and dried over anhydrous MgSO4. After filtration, the
solvent was evaporated in vacuo. The crude product was purified
by flash chromatography on silica gel (pentane:diethyl ether =
160:1) to give 7d (390 mg, 74%) as a semi-solid. IR (ATR): 3089,
2981, 1727, 1582, 1554, 1468, 1366, 1281, 1241, 1100, 1037,
J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 9 Hz, 1H), 8.00
(d, J = 9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d = 146.0, 145.4,
142.6, 142.0, 134.5, 129.7, 128.1, 127.1. MS (EI, 70 eV): m/z
(%) = 290 (50), 289 (10), 288 (100) [M+], 286 (53), 261 (18), 236
(12), 234 (24), 232 (12). HRMS (EI): m/z calcd for C8H6N2Br2:
287.8721; found: 287.8677.
4.1.12. 5,6-Dibromo-8-(cyclohex-2-enyl)quinoxaline (6c)
According to TP, the metalation of 5, 6-dibromoquinoxaline (6b,
144 mg, 0.5 mmol) was completed (treated with 0.5 equiv. of ZnCl2
and 0.75 equiv. of TMP2MgÁ2LiCl) within 15 min at 25 °C. The reac-
tion mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF,
0.55 mL, 0.55 mmol) and 3-bromocyclohex-1-ene (121 mg,
0.75 mmol) were added. The mixture was allowed to warm to
25 °C and stirred overnight. The reaction mixture was quenched
with sat. aq. NH4Cl solution (10 mL), extracted with diethyl ether
(3 Â 10 mL) and dried over anhydrous MgSO4. After filtration, the
solvent was evaporated in vacuo. The crude product was purified
by flash chromatography on silica gel (pentane:diethyl
ether = 10:1) to give 6c (128 mg, 70%) as a pale yellow solid. Mp:
140 °C, decomposition. IR (ATR): 2914, 2854, 1580, 1473, 1453,
1444, 1430, 1356, 1294, 1268, 1214, 1130, 1056, 1032, 1021,
1015, 869, 855, 831, 794, 767, 680, 661 cmÀ1 1H NMR (600 MHz,
.
CDCl3): d = 7.73 (dd, J = 8.4, 0.6 Hz, 1 H), 7.65–7.64 (m, 1H), 7.32–
7.30 (m, 1H), 4.37 (qd, J = 7.2, 0.6 Hz, 2 H), 1.38 (td, J = 7.2,
0.6 Hz, 3H). 13C NMR (150 MHz, CDCl3): d = 165.2, 138.0, 134.0,
132.2, 130.6, 127.4, 122.4, 61.8, 14.2. MS (EI, 70 eV): m/z (%) =
264 (19), 262 (15) [M+], 236 (33), 234 (25), 221 (25), 220 (10),
219 (100), 217 (77), 191 (18), 189 (14), 110 (13), 75 (14), 74
(11). HRMS (EI): m/z calcd for C9H8O2Br1Cl1: 261.9396; found:
261.9389.
4.1.15. Ethyl 4-bromo-2-(2-methylallyl)benzoate (8b)
According to TP, the metalation of ethyl 4-bromobenzoate (8a;
458 mg, 2.0 mmol) was completed within 12 h at 25 °C. The reac-
tion mixture was cooled to À40 °C, then CuCNÁ2LiCl (1 m in THF,
2.2 mL, 2.2 mmol) and 3-bromo-2-methylpropene (406 mg,
.
981, 947, 880, 862, 728, 705, 681, 659 cmÀ1 1H NMR (600 MHz,
CDCl3): d = 8.94 (d, J = 1.8 Hz, 1H), 8.88 (d, J = 1.8 Hz, 1H), 7.84 (s,

780
Z.-B. Dong et al. / Journal of Organometallic Chemistry 695 (2010) 775–780
3.0 mmol) were added. The mixture was allowed to warm to 25 °C
and stirred overnight. The reaction mixture was quenched with sat.
aq. NH4Cl solution (10 mL), extracted with diethyl ether
(3 Â 20 mL) and dried over anhydrous MgSO4. After filtration, the
solvent was evaporated in vacuo. The crude product was purified
by flash chromatography on silica gel (pentane:diethyl ether =
160:1) to give 8b (396 mg, 70%) as a colorless oil. IR (ATR): 3079,
2980, 2937, 1717, 1587, 1561, 1476, 1445, 1390, 1366, 1251,
Acknowledgment
We thank Chinese Scholarship Council (CSC) and Jiangsu Uni-
versity (program code: 09JDG024) for a financial support. Z.B. Dong
would like express the most sincere thanks to Prof. Dr. Paul Kno-
chel for his earnest help during Dr. Dong’s stay in Germany.
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1131, 1092, 1073, 1019, 888, 864, 835, 770, 708 cmÀ1 1H NMR
.
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(300 MHz, CDCl3): d = 7.75 (dd, J = 8.7, 0.9 Hz, 1H), 7.43–7.40 (m,
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239 (86), 238 (31), 237 (44), 236 (26), 223 (10), 158 (44), 157
(45), 131 (12), 130 (67), 129 (100), 128 (63), 127 (21), 116 (11),
115 (39), 89 (15). HRMS (EI): m/z calcd for C13H15O2Br1:
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4.1.16. Ethyl 3-chloro-2-(2-methylallyl)benzoate (9b) [29]
According to TP, the metalation of ethyl 3-chlorobenzoate (9a;
369 mg, 2.0 mmol) was completed within 2.5 h at 25 °C. Iodine
(760 mg, 3 mmol) dissolved in THF (3 mL) was added to the reac-
tion and the reaction mixture was stirred at 25 °C for 1 h and
was quenched with aq. sat. NH4Cl solution (10 mL). After extrac-
tion with diethyl ether (3 Â 20 mL), the combined organic layers
were washed with sat Na2S2O3 solution and brine, dried over
MgSO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (pentane, and then diethyl
ether) to give 9b as a pale yellow oil (491 mg, 79%). IR (ATR):
2963, 2936, 1725, 1576, 1443, 1400, 1366, 1281, 1254, 1191,
1149, 1129, 1088, 1014, 791, 757, 731 cmÀ1 1H NMR (600 MHz,
.
CDCl3): d = 7.56–7.53 (m, 1H), 7.44–7.41 (m, 1H), 7.34–7.31 (m,
1H), 4.40 (qd, J = 7.2, 0.6 Hz, 2H), 1.40 (td, J = 7.2, 0.6 Hz, 3H). 13C
NMR (150 MHz, CDCl3): d = 167.4, 140.8, 140.7, 131.2, 129.1,
127.5, 98.0, 62.2, 14.1. MS (EI, 70 eV): m/z (%) = 312 (17), 310
(52) [M+], 282 (27), 265 (100), 110 (32), 75 (35). HRMS (EI): m/z
calcd for C9H8ClIO2: 309.9258; found: 309.9235.
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