Synthesis and reactivity of lithium tri(quinolinyl)magnesates

Article abstract of DOI:10.1016/j.tet.2003.06.001

2-, 3- and 4-Bromoquinolines were converted to the corresponding lithium tri(quinolinyl)magnesates at -10°C when exposed to Bu₃MgLi in THF. The resulting organomagnesium derivatives were quenched with various electrophiles or involved in metal-catalyzed coupling reactions with heteroaryl halides to afford functionalized quinolines.

Full text of DOI:10.1016/j.tet.2003.06.001

Tetrahedron 59 (2003) 8629–8640
Synthesis and reactivity of lithium tri(quinolinyl)magnesates
*
Sylvain Dumouchel, Florence Mongin, Franc¸ois Trecourt and Guy Queguiner
´
´
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08,
´
76131 Mont-Saint-Aignan Cedex, France
Received 9 April 2003; revised 22 May 2003; accepted 16 June 2003
Abstract—2-, 3- and 4-Bromoquinolines were converted to the corresponding lithium tri(quinolinyl)magnesates at 2108C when exposed to
Bu3MgLi in THF. The resulting organomagnesium derivatives were quenched with various electrophiles or involved in metal-catalyzed
coupling reactions with heteroaryl halides to afford functionalized quinolines.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
tributylmagnesate (Bu3MgLi); the lithium tri(quinolinyl)-
magnesates, thus obtained were either trapped with electro-
philes9 or involved in transition metal-catalyzed cross-
couplings.10
Interest in azine (pyridine, quinoline…) and diazine
products either for pharmaceuticals or as building blocks
for various applications within materials science and
supramolecular chemistry has led to extensive efforts
devoted to a variety of synthetic methodologies.1 Notably,
the uses of organolithium,1b–d organoboron,2 organotin,2b,c,3
organozinc2b,c,4 and organomagnesium2b,c compounds
allow many functionalizations, either by trapping with
electrophiles or cross-coupling reactions.
Herein, the details of our investigations on the elaboration
and the reactivity of such magnesium intermediates are
recorded. In situ IR spectroscopy was used to monitor their
formation and consumption.
2. Results and discussion
In the quinoline series, where the compounds are particu-
larly prone to nucleophilic addition due to their low LUMO
levels, the lithiation1b,c and halogen–lithium exchange5
reactions used require low temperatures, which can be
difficult to realize on an industrial scale. The uses of
Since a magnesium ate complex (R3MgLi) was first
published in 1951,11 several investigations on its structure
have been reported.12 However, synthetic applications of
magnesate reagents remained seldom explored until very
recently.13 Oshima published in 2001 the first halogen–
magnesium exchanges via organomagnesium ate complexes
in the benzene, pyridine and thiophene series.13i,l The
same year, the mono-exchange of dibromobenzenes and
dibromoheteroarenes (pyridine and thiophene series) was
developed by Iida and Mase using Bu3MgLi.13m
6
7
`
superbases by Caubere or zincates by Kondo could help to
bias the reactions in favour of deprotonation, however, they
are limited to the syntheses of 2- or 8-substituted quinolines.
An access to pyridinylmagnesium halides, through halo-
gen–metal exchange of bromopyridines, was developed
using isopropylmagnesium chloride in tetrahydrofuran
(THF).8 Nevertheless, when bromoquinolines were
involved in the protocol, the corresponding quinolinyl-
magnesium halides were not obtained. Due to the lower
LUMO levels of such substrates, the nucleophilic attack of
the base to the quinoline ring was favoured over the
exchange reaction. We had, therefore, to turn our attention
to other magnesium species.
Our initial experiments were conducted using Bu3MgLi,
prepared by mixing BuMgCl and BuLi in a 1:2 ratio.13m The
formation of the magnesate was monitored using the in situ
infrared spectroscopy. The spectra were recorded with a
ReactIRe 4000 fitted with an immersible DiComp ATR
probe.14 The experiment was conducted as follows: BuLi
was added to BuMgCl at 2758C and the temperature was
slowly allowed to reach 2108C. The absorbance associated
with BuMgCl (1034, 1068 and 1494 cm21) rapidly
decreased upon addition of BuLi, while the absorbance
associated with Bu2Mg (1467 cm21) increased15 at low
temperatures (between 275 and 2408C). Next, the
disappearance of Bu2Mg (1467 cm21) and the appearance
We recently accomplished the bromine–magnesium
exchange of 2-, 3- and 4-bromoquinolines using lithium
Keywords: quinolines; ate complexes; in situ IR; cross-coupling.
*
Corresponding author. Tel.: þ33-2-35-52-24-82; fax: þ33-2-35-52-29-
62; e-mail: florence.mongin@insa-rouen.fr
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.06.001

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S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
being the most efficient (entries 6–8). The attempted use
of Bu2iPrMgLi16 gave greater amounts of alkylated side
products (entries 9–10).
The reaction proceeded well when 0.35 equiv. of Bu3MgLi
was used, with all three alkyl groups in the base participate
in the magnesium–bromine exchange. As the species
formed is rather stable in toluene, even at reflux (entry 5),
a complex 1a (assumed to be lithium tri(3-quinolinyl)mag-
nesiate) rather than a mixture of bis(3-quinolinyl)mag-
nesium and 3-quinolinyllithium was postulated. This was
supported by IR spectroscopic experiments. Indeed, when
Bu3MgLi was treated with 3-bromoquinoline (1) at 2108C,
the disappearance of the base (699 and 733 cm21) was
associated with the appearance of the complex 1a (1270 and
1336 cm21),17 which was next consumed by benzaldehyde
(Fig. 1), while 3-quinolinyllithium18 (1065 and 1254 cm21),
3-quinolinylmagnesium bromide19 (1262 cm21) and
Scheme 1.
Table 1. Optimization of the bromine–magnesium exchange of 1
Entry
Base (equiv.)
Solvent
Conditions
Yield (%)
1
2
3
Bu3MgLi (0.35)
Bu3MgLi (0.66)
Bu3MgLi (1.0)
Toluene
Toluene
Toluene
Toluene
Toluene
THF
MTBE
Et2O
Toluene
THF
2108C, 2.5 h
2108C, 2.5 h
2108C, 2.5 h
rt, 2.0 h
Reflux, 30 min
2108C, 2.5 h
2108C, 2.5 h
2108C, 2.5 h
2108C, 2.5 h
2108C, 2.5 h
65
8
0
48
42
89
71
56
53
61
4
5
6
7
8
9
10
Bu3MgLi (0.35)
Bu3MgLi (0.35)
Bu3MgLi (0.35)
Bu3MgLi (0.35)
Bu3MgLi (0.35)
Bu2iPrMgLi (0.35)
Bu2iPrMgLi (0.35)
of Bu3MgLi (699 and 733 cm21) were observed, at higher
temperatures (between 240 and 2108C). As observed by
Iida and Mase through 1H and 13C NMR,13m the IR
experiment showed the existence of a single species,
distinctly different from either BuMgCl or BuLi.
Scheme 2.
The reaction of commercial 3-bromoquinoline (1) using
Bu3MgLi (0.35 equiv.) in toluene at 2108C, as described
for the bromine–magnesium exchange of 2,6-dibromo-
pyridine,13m followed by trapping with benzaldehyde (1 h at
2108C and 18 h at rt) generated, after hydrolysis, the
alcohol 2a in 65% yield. The first step of the reaction was
then optimized using other solvents and bases, under
different conditions (Scheme 1, Table 1).
Table 2. Quenching of 1a
Entry
1
Electrophile
PhCHO
E
Product
Yield (%)a
89, 65b
CH(OH) Ph
2a
2
2b
44
It was noted that the yields largely depend on the amount of
base used. Whereas 65% of 2a was obtained on exposure to
0.35 equiv. of Bu3MgLi, very poor yields were observed
using 0.66 and 1.0 equiv. In the latter cases, quinolines
butylated at C2 and C4 were formed, due to nucleophilic
addition reactions of residual butylmagnesium species to the
ring (entries 1–3). Obviously, accurate charges of BuMgCl
and BuLi are necessary to obtain reliable yields. The
exchange reaction is still feasible at rt or at reflux instead of
2108C, however greater amounts of butylated quinolines
are obtained (entries 4–5). Performing the reaction in other
environments showed polar solvents such as THF, methyl
tert-butyl ether (MTBE), and diethyl ether can be used; THF
3
4
5
6
DMF
CO2
I2
PhSSPh
CHO
CO2H
I
2c
2d
2e
2f
75b
46
81, 76b
44b
SPh
7
2g
55b
a
Isolated yields based on 1.
Using toluene instead of THF.
b
Figure 1. Three-dimensional infrared profile for the formation and consumption of 1a.

S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
8631
Scheme 5.
Scheme 3.
Table 4. Quenching of 4a
bis(3-quinolinyl)magnesium20 (1073 cm21) show different
absorbances.
Entry
Electrophile
E
Product
Yield (%)a
1
2
3
4
PhCHO
CO2
I2
PhSSPh
CH(OH)Ph
6a
6b
6c
6d
28
39
57
47
The procedure being optimized, a series of electrophiles was
used to quench the compound 1a. Benzaldehydes, dimethyl-
formamide, carbon dioxide, iodine, diphenyl disulfide and
menthyl 4-toluenesulfinate afforded the alcohols 2a–b, the
aldehyde 2c, the carboxylic acid 2d, the iodide 2e, the
sulfide 2f and the sulfoxide 2g, respectively (Scheme 2,
Table 2).
CO2H
I
SPh
a
Isolated yields based on 4.
sulfide 5d, respectively, in low to medium yields
(Scheme 4, Table 3).
Since the reaction with benzaldehyde (entry 1) proceeds
well, a steric hindrance effect could explain the lower yield
obtained with 2-tolualdehyde (entry 2). Enolizable carbonyl
compounds such as acetaldehyde, acetone and 3-pentanone
did not furnish the corresponding alcohols (only quinoline
was isolated). The reaction with ketones such as benzo-
phenone failed too; quinoline and benzhydrol were isolated,
probably through a reduction in the presence of 1a.
Dimethylformamide (entry 3) readily reacts, as observed
by Iida and Mase in the pyridine series.13m The yield
obtained for the amino acid 2d (entry 4) largely depends on
the isolation process. Iodine (entry 5), diphenyl disulfide
(entry 6) and menthyl 4-toluenesulfinate (entry 7) could also
be used. Of particular importance to rationalize the variable
results, the reaction conducted in THF without electrophile
(except bromobutane generated in the exchange step) gave
3-butylquinoline (2h) in 60% yield (Scheme 3).
The bromine–magnesium exchange step being slower,22
more side products are formed through addition reactions of
unreacted butylmagnesium species to the quinoline ring.23
Interestingly, the enolizable 3-pentanone (entry 2) gave the
expected alcohol, albeit in a low yield of 33%, while
hexanal and benzophenone failed.
The behaviour of 4-bromoquinoline (4) is similar, as
exemplified by trapping 4a with electrophiles to produce
the expected alcohol 6a, the carboxylic acid 6b, the iodide 6c
and the sulfide 6d in moderate yields (Scheme 5, Table 4).
Thus, the lithium tri(quinolinyl)magnesates 1a, 3a and 4a,
derived from 2-, 3- and 4-bromoquinolines (1, 3 and 4),
were prepared and intercepted with various electrophiles.
It was then interesting to study whether an access to
arylquinolines via these species was possible. To this end,
the intermediates 1a, 3a and 4a were each subjected to
transition metal-catalyzed couplings with heteroaromatic
halides. A survey of the literature revealed that lithium
arylzincates have been involved in palladium catalyzed
couplings with aryl iodides in modest yields.7 Conversely,
to our knowledge, studies concerning the use of lithium
arylmagnesates have not been reported. The reactions of
arylmagnesium halides with aryl chlorides, bromides or
iodides are possible at rt under palladium catalysis.24
Nickel, which is harder than palladium, was most often
chosen for chlorides24f,25 and fluorides,26 which are harder
than bromides and iodides. Recently, iron has been found to
be efficient for coupling reactions with chlorides.27
The bromine–magnesium exchange reaction was then
carried out on 2- and 4-bromoquinolines (3–4)21 using
THF as a solvent, under the same conditions. The reaction of
2-bromoquinoline (3) and subsequent quenching of the
intermediate 3a with benzaldehyde (entry 1), 3-pentanone
(entry 2), iodine (entry 3) and diphenyl disulfide (entry 4)
provided the alcohols 5a–b, the iodide 5c and the
Indeed, the coupling experiments conducted under nickel
catalysis between 1a, prepared in THF, and heteroaromatic
bromides were unsuccessful. On the other hand, the
reactions could be achieved when 5 mol% of bis(d0ibenzyl-
ideneacetone)palladium(0) (Pd(dba)2) and 1,1 -bis(di-
phenylphosphino)ferrocene (dppf) were used,24e – g,28
and the 3-arylquinolines 7a–k were obtained (Scheme 6,
Table 5).
Scheme 4.
Table 3. Quenching of 3a
Entry
Electrophile
E
Product
Yield (%)a
1
2
3
4
PhCHO
EtCOEt
I2
CH(OH)Ph
C(OH)Et2
5a
5b
5c
5d
39, 18b
33
49
I
SPh
PhSSPh
15
a
As the step to provide 1a proceeds in 85–90% yield, the low
to modest yields observed are mainly due to the coupling
Isolated yields based on 3.
Using toluene instead of THF.
b

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S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
Table 5 (continued)
Entry
Bromide
Product
Yield (%)a
9
7j:
24
Scheme 6.
Table 5. Coupling of 1a with bromides
10
7k:
15
Entry
Bromide
Product
Yield (%)a
a
Isolated yields based on 1.
b
c
d
Using PPh3 10 mol% instead of dppf.
Using PdCl2 instead of Pd(dba)2.
Using 0.5 equiv. of 2,6-dibromopyridine.
1
7a:
7b:
56, 39,b 25c
step. It can be mentioned, as pointed out by Kumada,28a that
dppf is a more convenient ligand than PPh3 (entries 1, 8);
dba was also found to play an important role (entry 1).28b
More importantly, the reactivity of the halide involved
is crucial since the formation of 3-butylquinoline (2h)
competes with the cross-coupling reaction.29 The best
results were observed with p-deficient substrates such as
bromopyridines and bromoquinolines, for which the
oxidative addition step is easier (entries 1–7). The position
of the bromine atom on the ring too has a pronounced effect
on the yields, the results being better for 2-bromo substrates,
as noted by Pridgen for Kharasch cross-couplings in the
pyridine series.30 Consequently, the reaction with 2,5-di-
bromopyridine is 100% regioselective at C2 (entry 3). With
symmetrical dibromopyridines, a single coupling was
observed for 3,5-dibromopyridine (entry 5), whereas the
mono- and bis-coupled products were obtained for the more
reactive 2,6-dibromopyridine (entry 4). Lower yields were
obtained with less activated substrates of the benzene (entry
8) and the thiophene (entries 9, 10) series.
2
3
4
35
7c:
7d:
7e:
7f:
53
29, 10d
22, 37d
12
The reactions with aryl chlorides were then investigated.
Since our first experiments with iron-catalyzed cross-
couplings did not appear promising (only homocoupling
was observed under the conditions described by Fu¨rstner27b),
we turned our attention to nickel catalysis. The tandem
bis(acetylacetonate)nickel(II) (Ni(acac)2)–1,3-bis(diphe-
nylphosphino)propane (dppp) allowed the 3-arylquinolines
7a,b,g,l,m to be synthesized (Scheme 7, Table 6).
5
6
7
8
One complication being that the lithium tri(quinolinyl)-
magnesate 1a reacts with bromobutane, the results reflect
the lower reactivity of chlorides, when compared to
bromides. The use of nickel in the presence of dppp
3
1
7g:
7h:
7i:
51
45
29, 16b
Scheme 7.

S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
8633
Table 6. Coupling of 1a with chlorides
Entry Chloride
Product
Yield (%)a
1
7a
7b
7g
18, 21,b 0c
Scheme 9.
2
3
8
Table 8. Coupling of 4a with bromides
Entry
Bromide
Product
Yield (%)a
0
1
9a:
43
4
7l:
32
2
9b:
48
5
7m:
24
a
Isolated yields based on 1.
After reflux for 3 h.
Using 1,2-bis(diphenylphosphino)ethane or dppf instead of dppp.
b
c
3
4
9c:
,5
4
9d:
23
Scheme 8.
a
Isolated yields based on 4.
Table 7. Coupling of 3a with bromides
(found to be the best ligand, as observed for the Karasch
cross-couplings)2b,24c,e–g,25,28a,30,31 could help to favour the
insertion step, but the yields of the whole process remain
modest. The importance of the substrate used (better yields
with diazines (entries 4, 5) than azines (entries 1–3)) and
the position of the chlorine atom on the ring (entries 1, 2)
was clearly evidenced.
Entry
Bromide
Product
Yield (%)a
1
8a:
28
To evaluate the scope of this reaction, it was applied to the
lithium tri(quinolinyl)magnesates 3a (Scheme 8, Table 7)
and 4a (Scheme 9, Table 8).
2
3
1
8b:
27
Lower yields were observed for the syntheses of 7g, 8a,b
and 9a–d, mainly due to the preparation step of the
intermediates 3a and 4a. A steric hindrance effect can be put
forward in some cases (e.g. Table 8, entry 3), as already
evoked in Kharasch cross-couplings.30
3
7g
11, 13b
a
Isolated yields based on 3.
After reflux for 5 h.
b

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S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
4. Experimental
4.1. General
Melting points were measured on a Kofler apparatus. NMR
spectra were recorded in CDCl3 or DMSO-d6 with a Bruker
AM 300 spectrometer (1H at 300 MHz and 13C at 75 MHz).
Mass spectra were recorded with a Jeol JMS-AX500
spectrometer, and the molecular peak is given. IR spectra
were taken on a Perkin–Elmer FT IR 205 spectrometer, and
main IR absorptions are given in cm21. Elemental analyses
were performed on a Carlo Erba 1106 apparatus.
Scheme 10.
Starting materials. THF was distilled from benzophenone/
Na. Toluene was dried over P2O5. The water content of the
solvents was estimated to be lower than 45 ppm by the
modified Karl Fischer method.34 Reactions were carried out
under dry N2. Silica gel (Geduran Si 60, 0.063–0.200 mm)
was purchased from Merck. BuMgCl (2.0 M) in Et2O and
BuLi (1.6 M) in hexane were purchased from Aldrich. 2-
and 4-Bromoquinolines (3, 4) were prepared from 2- and
4-hydroxyquinolines, respectively.21 1-Bromoisoquinoline
was prepared from isoquinoline N-oxide.35 3-Bromoquino-
line (1), Pd(dba)2 and Ni(acac)2 were supplied by Acros,
The reaction was performed in the pyridine and benzene
series under the same conditions. Starting from 3-bromo-
pyridine, ‘one pot’ bromine–magnesium exchange, fol-
lowed by coupling of the lithium tri(pyridinyl)magnesate
generated with 2-bromopyridine, afforded the bipyridine 10
in a yield comparable to those obtained for the Kharasch
cross-couplings of 3-pyridinylmagnesium chlorides24f
(Scheme 10).
The procedure was similarly effected starting from bromo-
benzene, to afford the phenyl azines 7i and 11, albeit in a
poor yield due to the conditions used for the preparation of
the lithium magnesate32 (Scheme 11).
36
dppf by Avocado and dppp by Lancaster. Pd(PPh3)4 was
prepared according to described procedures. Petrol refers to
petroleum ether (bp 40–608C).
Unless otherwise noted, the reaction mixture was diluted
with AcOEt (50 mL) after the reaction. The organic layer
was dried over MgSO4, the solvents were evaporated under
reduced pressure, and the crude compound was chromato-
graphed on a silica gel column (eluent is given in the
product description).
4.2. General procedure 1: 3-substituted quinolines 2a–g
by bromine–magnesium exchange of 1 and subsequent
trapping with electrophiles
To the solvent (2 mL) at 2108C were added BuMgCl
(0.63 mmol) and BuLi (1.3 mmol). After 1 h at 2108C, a
solution of 3-bromoquinoline (1, 0.23 mL, 1.7 mmol) in the
solvent (2 mL) was introduced at 2308C, and the mixture
was stirred at 2108C for 2.5 h. The electrophile (1.7 mmol)
was then added at 2108C; the mixture was stirred at this
temperature for 1 h and at rt for 18 h before addition of
water (0.5 mL).
Scheme 11.
3. Conclusion
We have demonstrated that a magnesium ate complex,
Bu3MgLi, induces the bromine–magnesium exchange of 2-,
3- and 4-bromoquinolines, giving the corresponding lithium
tri(quinolinyl)magnesates. These were either intercepted
with various electrophiles or involved in metal-catalyzed
coupling reactions with aromatic halides in a one pot
procedure. Though the yields are not high, this method is
interesting since it avoids a preliminary synthesis of the
‘organometallic’ substrate, usually at low temperatures via
its corresponding lithio compound. Another advantage of
this methodology is the relative stabilities of these
organometallic species: the bromine–lithium exchange5
has to be performed at low temperatures to prevent side
reactions whereas the bromine–magnesium exchange
proceeds at 2108C. The yields obtained are often
analogous to those observed during bromine–lithium
exchange reactions5 or cross-couplings through quinolinyl-
boranes.33
4.2.1. a-Phenyl-3-quinolinemethanol (2a). The general
procedure 1, using PhCHO (0.17 mL), gave 89% (solvent:
THF) of 2a (eluent: CH2Cl2/AcOEt 90:10): mp 138–1408C
(lit.5d 136–1388C); the IR and NMR data are in accordance
with those of the literature.5d
4.2.2. a-(2-Methylphenyl)-3-quinolinemethanol (2b).
The general procedure 1, using 2-methylbenzaldehyde
(0.20 g), gave 44% (solvent: THF) of 2b (eluent: CH2Cl2/
AcOEt 90:10): mp 1348C; 1H NMR (CDCl3) d 2.13 (s, 3H,
Me), 4.20 (s, 1H, OH), 6.05 (s, 1H, CH(OH)), 7.03 (m, 1H,
0
0
0
0
H5 ), 7.12 (m, 2H, H3 ,4 ), 7.38 (m, 1H, H6 ), 7.43 (m, 1H,
H6), 7.55 (m, 1H, H7), 7.62 (d, 1H, J¼8.3 Hz, H5), 7.92
(d, 1H, J¼8.3 Hz, H8), 7.95 (d, 1H, J¼1.9 Hz, H4), 8.57 (d,
1H, J¼1.9 Hz, H2); 13C NMR (CDCl3) d 19.8 (Me), 71.5

S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
8635
0
0
(CH(OH)), 126.8 (C3), 127.1 (C6 ), 127.2 (C6), 128.1 (C4 ),
128.3 (C5), 129.1 (Cb), 129.9 (C7), 130.0 (C8), 131.1 (C4),
4.3. General procedure 2: 2-substituted quinolines 5a–d
by bromine–magnesium exchange of 3 and subsequent
trapping with electrophiles
0
0
0
0
134.1 (C5 ), 135.8 (C3 ), 136.5 (C1 ), 141.1 (C2 ), 147.4 (Ca),
150.7 (C2); IR (KBr) n 3147, 2832, 1457, 1331, 1231, 819,
699 cm21. Anal. calcd for C17H15NO (249.32): C, 81.90; H,
6.06; N, 5.62. Found: C, 81.63; H, 6.04; N, 5.43%.
To THF (2 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, a solution of
2-bromoquinoline (3, 0.35 g, 1.7 mmol) in THF (2 mL) was
introduced at 2308C, and the mixture was stirred at 2108C
for 2 h. The electrophile (1.7 mmol) was then added at
2108C; the mixture was stirred at this temperature for 1 h
and at rt for 18 h before addition of water (0.5 mL).
4.2.3. 3-Quinolinecarboxaldehyde (2c). The general
procedure 1, using DMF (0.13 mL), gave 75% (solvent:
toluene) of 2c (eluent: CH2Cl2/AcOEt 90:10). The physical
and spectral data are analogous to those obtained for a
commercial sample (Aldrich).
4.3.1. a-Phenyl-2-quinolinemethanol (5a). The general
procedure 2, using PhCHO (0.17 mL), gave 39% of 5a
(eluent: CH2Cl2/AcOEt 90:10): mp 968C; the 1H NMR data
are in accordance with those of the literature;6 13C NMR
(CDCl3) d 75.6 (CH(OH)), 119.7 (C3), 127.8 (C8), 127.9
4.2.4. 3-Quinolinecarboxylic acid (2d). The general
procedure 1, using an excess of freshly crushed dry ice (in
this case, the aqueous phase obtained after evaporation of
the residue to dryness and addition of water (3 mL) was
washed with CH2Cl2 (10 mL) and acidified to pH 1 using a
5% aqueous solution of hydrochloric acid; 2d was then
recovered after filtration and drying under vacuum), gave
46% (solvent: THF) of 2d. The physical and spectral data
are analogous to those obtained for a commercial sample
(Aldrich).
0
(Cb), 128.0 (C3 ,5 ), 128.4 (C5), 129.0 (C2 ,6 ), 129.2 (C6),
0
0
0
0
0
129.7 (C7), 130.2 (C4 ), 137.4 (C4), 141.4 (C1 ), 146.4 (Ca),
160.9 (C2); IR (KBr) n 3053, 1664, 1599, 1445, 1318, 1293,
1168, 967, 784, 754, 690, 621 cm21. Anal. calcd for
C16H13NO (235.29): C, 81.68; H, 5.57; N, 5.95. Found: C,
81.46; H, 5.43; N, 5.67%.
4.2.5. 3-Iodoquinoline (2e).37 The general procedure 1,
using a solution of I2 (0.43 g) in THF (3 mL) (in this case,
the reaction mixture was treated with 0.3 g of Na2S2O3),
gave 81% (solvent: THF) of 2e (eluent: petrol/AcOEt
4.3.2. a,a-Diethyl-2-quinolinemethanol (5b). The general
procedure 2, using an excess of EtCOEt (2 mL), gave 33%
of 5b (eluent: CH2Cl2/AcOEt 90:10); the physical and
spectral data are in accordance with those of the literature.39
Anal. calcd for C14H17NO (215.30): C, 78.10; H, 7.96; N,
6.51. Found: C, 78.34; H, 7.81; N, 6.67%.
1
90:10): mp 488C; H NMR (CDCl3) d 7.7 (m, 3H, H5,6,7),
7.98 (d, 1H, J¼7.5 Hz, H8), 8.46 (d, 1H, J¼1.9 Hz, H4),
8.96 (d, 1H, J¼1.9 Hz, H2); 13C NMR (CDCl3) d 90.2 (C3),
127.2 (C6), 130.2 (C5), 130.4 (C8), 137.6 (Cb), 144.1 (C7),
146.7 (C4), 151.8 (Ca), 156.0 (C2); IR (KBr) n 1573, 1489,
1348, 1312, 1122, 1071, 937, 885, 778, 745 cm21. Anal.
calcd for C9H6IN (255.06): C, 42.38; H, 2.37; N, 5.49.
Found: C, 42.61; H, 2.37; N, 5.61%.
4.3.3. 2-Iodoquinoline (5c).40 The general procedure 2,
using a solution of I2 (0.43 g) in THF (3 mL) (in this case,
the reaction mixture was treated with 0.3 g of Na2S2O3),
gave 49% of 5c (eluent: CH2Cl2/AcOEt 90:10): mp 52–
1
538C; H NMR (CDCl3) d 7.45 (m, 1H, H6), 7.6 (m, 4H,
H3,4,5,7), 7.95 (d, 1H, J¼8.7 Hz, H8); 13C NMR (CDCl3) d
119.4 (C2), 127.5 (Cb), 128.2 (C6), 129.2 (C5), 130.3 (C8),
130.6 (C3), 132.3 (C7), 137.4 (C4), 149.9 (Ca); IR (KBr) n
1579, 1495, 1347, 1343, 1116, 1049, 937 cm21. Anal. calcd
for C9H6IN (255.06): C, 42.38; H, 2.37; N, 5.49. Found: C,
42.46; H, 2.64; N, 5.64%.
4.2.6. 3-(Phenylthio)quinoline (2f). The general procedure
1, using a solution of PhSSPh (0.37 g) in toluene (3 mL),
gave 44% (solvent: toluene) of 2f (eluent: petrol/AcOEt
1
90:10): mp 888C (lit.38 79–808C); the H NMR data are in
accordance with those of the literature;38 13C NMR (CDCl3)
0
d 127.6 (C2 ,6 ), 127.7 (C3), 128.1 (C6), 128.1 (C3 ,5 ), 128.6
0
0
0
0
0
(C1 ), 129.9 (C4 ), 130.0 (C5), 130.4 (Cb), 131.7 (C7), 134.7
(C8), 137.5 (C4), 147.0 (Ca), 152.6 (C2); IR (KBr) n 3055,
2926, 1577, 1475, 1073, 910, 785, 743, 689 cm21. Anal.
calcd for C15H11NS (237.33): C, 75.92; H, 4.67; N, 5.90; S,
13.51. Found: C, 75.94; H, 4.84; N, 5.96; S, 13.38%.
4.3.4. 2-(Phenylthio)quinoline (5d). The general procedure
2, using a solution of PhSSPh (0.37 g) in THF (3 mL), gave
15% of 5d (eluent: CH2Cl2/AcOEt 90:10). The physical and
spectral data are analogous to those obtained for a
commercial sample (Acros).
4.2.7. 3-((4-Methylphenyl)sulfinyl)quinoline (2g). The
general procedure 1, using (1R,2S,5R)-(2)-menthyl (S)-4-
toluenesulfinate (0.50 g), gave 55% (solvent: toluene) of 2g
(eluent: CH2Cl2/Et2O 90:10): mp 1268C; 1H NMR (CDCl3)
d 2.30 (s, 3H, Me), 7.21 (m, 2H, Ph), 7.55 (m, 3H, H6 and
Ph), 7.8 (m, 2H, H5,7), 8.05 (d, 1H, J¼8.7 Hz, H8), 8.53 (d,
1H, J¼2.2 Hz, H4), 8.76 (d, 1H, J¼2.2 Hz, H2); 13C NMR
4.4. General procedure 3: 4-substituted quinolines 6a–d
by bromine–magnesium exchange of 4 and subsequent
trapping with electrophiles
To THF (2 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, a solution of
4-bromoquinoline (4, 0.35 g, 1.7 mmol) in THF (2 mL) was
introduced at 2308C, and the mixture was stirred at 2108C
for 2.5 h. The electrophile (1.7 mmol) was then added at
2108C; the mixture was stirred at this temperature for 1 h
and at rt for 18 h before addition of water (0.5 mL).
0
0
(CDCl3) d 21.8 (Me), 125.6 (C2 ,6 ), 127.7 (C3), 128.3 (Cb),
0
128.8 (C6), 129.9 (C3 ,5 ), 130.7 (C5), 131.7 (C7), 133.2 (C4),
0
0
0
139.5 (C8), 141.7 (Ca), 142.9 (C1 ), 146.2 (C2), 149.1 (C4 );
IR (KBr) n 2919, 1493, 1358, 1086, 1045, 1015, 956, 808,
752, 631 cm21. Anal. calcd for C16H13NOS (267.35): C,
71.88; H, 4.90; N, 5.24; S, 11.99. Found: C, 71.89; H, 4.93;
N, 5.24; S, 11.72%.
4.4.1. a-Phenyl-4-quinolinemethanol (6a).41 The general
procedure 3, using PhCHO (0.17 mL), gave 28% of 6a

8636
S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
(eluent: CH2Cl2/AcOEt 90:10): mp 1188C; 1H NMR
(CDCl3) d 3.50 (s, 1H, OH), 6.42 (s, 1H, CH(OH)), 7.18
1567, 1495, 1407, 1344, 1303, 1095, 992, 959, 927, 710,
738, 619 cm21. Anal. calcd for C14H10N2 (206.25): C,
81.53; H, 4.89; N, 13.58. Found: C, 81.28; H, 4.71; N,
13.53%.
0
0
0
0
0
(d, 1H, J¼4.5 Hz, H3), 7.3 (m, 5H, H2 ,3 ,4 ,5 ,6 ), 7.55 (m, 1H,
H6), 7.60 (d, 1H, J¼7.5 Hz, H5), 7.83 (m, 1H, H7), 7.99 (d,
1H, J¼8.7 Hz, H8), 8.73 (d, 1H, J¼4.5 Hz, H2); 13C NMR
(CDCl3) d 73.0 (CH(OH)), 118.9 (C3), 124.2 (C5), 126.1
4.5.2. 3-(3-Pyridinyl)quinoline (7b). The general pro-
cedure 4, using 3-bromopyridine (0.16 mL), gave 35% of
7b (eluent: CH2Cl2/Et2O 80:20): mp 1278C (lit.33a 128–
0
(Cb), 126.3 (C7), 126.7 (C6), 126.9 (C8), 127.7 (C2 ,6 ), 129.2
0
0
0
0
0
(C3 ,5 ), 129.5 (C1 ), 130.3 (C4 ), 142.5 (Ca), 149.1 (C4),
150.5 (C2); IR (KBr) n 3058, 2817, 1437, 1325, 1198,
787 cm21. Anal. calcd for C16H13NO (235.29): C, 81.68; H,
5.57; N, 5.95. Found: C, 81.39; H, 5.46; N, 5.79%.
1
1298C); the H NMR data are in accordance with those of
the literature;33a 13C NMR (CDCl3) d 124.3 (C6), 127.7
0
(C3), 127.8 (C5 ), 128.0 (Cb), 128.1 (C7), 128.2 (C3 ), 128.5
0
0
(C8), 129.6 (C4), 129.7 (C5), 130.4 (Ca), 134.1 (C4 ), 135.1
0
0
4.4.2. 4-Quinolinecarboxylic acid (6b). The general
procedure 3, using an excess of freshly crushed dry ice (in
this case, the aqueous phase obtained after evaporation of
the residue to dryness and addition of water (3 mL) was
washed with CH2Cl2 (10 mL) and acidified to pH 1 using a
5% aqueous solution of hydrochloric acid; 6b was then
recovered after filtration and drying under vacuum), gave
39% of 6b. The physical and spectral data are analogous to
those obtained for a commercial sample (Aldrich).
(C2), 148.8 (C6 ), 149.6 (C2 ); IR (KBr) n 3041, 2924, 2853,
1567, 1495, 1338, 1186, 1022, 952, 815, 758, 700 cm21
.
4.5.3. 3-(5-Bromo-2-pyridinyl)quinoline (7c). The general
procedure 4, using 2,5-dibromopyridine (0.40 g), gave 53%
of 7c (eluent: CH2Cl2/Et2O 80:20): mp 1508C; H NMR
(CDCl3) d 7.46 (m, 1H, H6), 7.75 (m, 2H, H5,7), 7.79 (m, 2H,
1
0
0
H8,4 ), 8.03 (d, 1H, J¼8.3 Hz, H3 ), 8.58 (d, 1H, J¼2.2 Hz,
13
0
H4), 8.68 (d, 1H, J¼3.2 Hz, H6 ), 9.34 (d, 1H, J¼2.2 Hz,
0
0
H2); C NMR (CDCl3) d 120.5 (C5 ), 122.1 (C3 ), 126.9
4.4.3. 4-Iodoquinoline (6c).42 The general procedure 3,
using a solution of I2 (0.43 g) in THF (3 mL) (in this case,
the reaction mixture was treated with 0.3 g of Na2S2O3),
gave 57% of 6c (eluent: CH2Cl2/AcOEt 90:10): mp 908C;
1H NMR (CDCl3) d 7.48 (m, 1H, H6), 7.61 (m, 1H, H7), 7.84
(d, 1H, J¼4.3 Hz, H3), 7.88 (d, 1H, J¼8.3 Hz, H8), 7.92 (d,
1H, J¼7.1 Hz, H5), 8.32 (d, 1H, J¼4.3 Hz, H2); 13C NMR
(CDCl3) d 112.4 (C3), 127.1 (Cb), 128.5 (C5), 130.5 (C6),
130.7 (C8), 132.1 (C7), 132.9 (C4), 148.5 (Ca), 150.1 (C2);
IR (KBr) n 3398, 3066, 1627, 1575, 1568, 1413, 1197, 1056,
965, 837, 663 cm21. Anal. calcd for C9H6IN (255.06): C,
42.38; H, 2.37; N, 5.49. Found: C, 42.34; H, 2.34; N, 5.18%.
(C6), 127.6 (C5), 128.2 (Cb), 129.6 (C7), 129.8 (C8), 131.0
0
(C3), 134.1 (C4), 139.9 (C4 ), 148.6 (Ca), 150.8 (C2 ), 151.5
0
0
(C6 ), 153.5 (C2); IR (KBr) n 3053, 1573, 1494, 1355, 1122,
1092, 1005, 844, 789, 760, 621 cm21. Anal. calcd for
C14H9BrN2 (285.15): C, 58.97; H, 3.18; N, 9.82. Found: C,
58.83; H, 3.16; N, 9.54%.
4.5.4. 3-(6-Bromo-2-pyridinyl)quinoline (7d) and 2,6-bis-
(3-quinolinyl)pyridine (7e). The general procedure 4,
using 2,6-dibromopyridine (0.40 g), gave 29% of 7d
(eluent: CH2Cl2/Et2O 80:20): mp 1778C; 1H NMR
0
(CDCl3) d 7.43 (d, 1H, J¼7.9 Hz, H5 ), 7.52 (m, 1H, H4),
0
7.65 (m, 2H, H6,7), 7.79 (d, 1H, J¼7.5 Hz, H3 ), 7.87 (d, 1H,
4.4.4. 4-(Phenylthio)quinoline (6d). The general procedure
3, using a solution of PhSSPh (0.37 g) in THF (3 mL), gave
47% of 6d (eluent: CH2Cl2/AcOEt 90:10); the physical and
spectral data are in accordance with those of the literature;43
J¼7.7 Hz, H5), 8.08 (d, 1H, J¼8.0 Hz, H8), 8.74 (d, 1H, J¼
1.7 Hz, H4), 9.40 (d, 1H, J¼1.7 Hz, H2); 13C NMR (CDCl3)
0
0
d 119.7 (C3 ), 127.6 (C6), 127.6 (C5), 128.1 (C5 ), 129.1 (Cb),
0
129.7 (C7), 130.8 (C8), 134.8 (C4), 130.5 (C3), 139.7 (C4 ),
0
IR (KBr) n 3048, 2933, 1537, 1466, 1071, 832, 689 cm21
.
143.1 (C6 ), 148.0 (Ca), 149.1 (C2), 156.3 (C2); IR (KBr) n
0
3061, 579, 1439, 1123, 984, 797, 729 cm21. Anal. calcd for
C14H9BrN2 (285.15): C, 58.97; H, 3.18; N, 9.82. Found: C,
58.87; H, 3.26; N, 9.53%, and 22% of 7e (eluent: CH2Cl2/
4.5. General procedure 4: 3-substituted quinolines 7a–k
by bromine–magnesium exchange of 1 and subsequent
cross-coupling with bromides and iodides
1
Et2O 50:50): mp 2208C; H NMR (CDCl3) d 7.55 (m, 2H,
0
0
H6 ), 7.72 (m, 2H, H7 ), 7.90 (m, 5H, H3,4,5,5 ), 8.12 (d, 2H,
0
0
0
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, 3-bromoquino-
line (1, 0.23 mL, 1.7 mmol) in THF (2 mL) was introduced
at 2308C, and the mixture was stirred at 2108C for 2 h. A
solution of the halide (1.7 mmol) in THF (3 mL), Pd(dba)2
(48 mg, 83 mmol) and dppf (47 mg, 83 mmol) were
successively added at 2108C; the mixture was stirred for
1 h at this temperature and for 18 h at rt before addition of
an aqueous saturated NH4Cl solution (0.5 mL).
J¼8.3 Hz, H8 ), 8.86 (d, 2H, J¼2.1 Hz, H4 ), 9.66 (d, 2H,
J¼2.1 Hz, H2 ); 13C NMR (CDCl3) d 120.3 (C3,5), 127.5
0
0
(2C6 ), 127.8 (2C5 ), 128.9 (2Cb ), 129.3 (2C7 ), 129.7 (2C8 ),
0
0
0
0
0
0
0
130.5 (2C3 ), 134.4 (2C4 ), 138.6 (C4), 148.7 (2Ca ), 149.8
0
(2C2 ), 155.3 (C2,6); IR (KBr) n 3050, 2923, 1586, 1334,
949, 812 cm21. Anal. calcd for C23H15N3 (333.40): C,
80.86; H, 4.54; N, 11.60. Found: C, 80.58; H, 4.83; N,
11.32%.
4.5.5. 3-(5-Bromo-3-pyridinyl)quinoline (7f). The general
procedure 4, using 3,5-dibromopyridine (0.40 g), gave 12%
4.5.1. 3-(2-Pyridinyl)quinoline (7a). The general pro-
cedure 4, using 2-bromopyridine (0.16 mL), gave 57%
of 7a (eluent: CH2Cl2/Et2O 80:20): mp 1008C (lit.33a
99–1008C); the 1H NMR data are in accordance with
1
of 7f (eluent: CH2Cl2/Et2O 80:20): mp 1638C; H NMR
(CDCl3) d 7.58 (t, 1H, J¼8.3 Hz, H6), 7.74 (m, 1H, H7),
0
7.85 (d, 1H, J¼8.3 Hz, H5), 8.10 (m, 2H, H8,6 ), 8.27 (t, 1H,
those of the literature;33a 13C NMR (CDCl3) d 121.1 (C3 ),
J¼1.9 Hz, H4 ), 8.68 (d, 1H, J¼2.4 Hz, H4), 8.82 (d, 1H,
0
0
0
0
123.2 (C5 ), 127.4 (C6), 128.2 (C5), 128.9 (Cb), 129.6 (C7),
0
130.3 (C8), 132.2 (C3), 134.2 (C4), 137.4 (C4 ), 148.5 (Ca),
J¼1.9 Hz, H2 ), 9.06 (d, 1H, J¼2.4 Hz, H2); 13C NMR
0
(CDCl3) d 121.5 (C5 ), 127.9 (C6), 128.0 (C5), 128.5 (Cb),
0
149.6 (C6 ), 150.5 (C2), 155.1 (C2 ); IR (KBr) n 3040, 1591,
0
0
129.5 (C8), 129.7 (C7), 130.7 (C3), 134.4 (C4), 135.5 (C3 ),

S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
8637
0
0
0
137.4 (C6 ), 146.8 (Ca), 148.2 (C2 ), 149.2 (C2), 150.5 (C4 );
IR (KBr) n 3058, 1587, 1493, 1107, 1088, 857, 789,
760 cm21. Anal. calcd for C14H9BrN2 (285.15): C, 58.97;
H, 3.18; N, 9.82. Found: C, 58.74; H, 3.43; N, 9.74%.
and BuLi (1.3 mmol). After 1 h at 2108C, 3-bromoquino-
line (1, 0.23 mL, 1.7 mmol) in THF (2 mL) was introduced
at 2308C, and the mixture was stirred at 2108C for 2 h. A
solution of the chloride (1.7 mmol) in THF (3 mL),
Ni(acac)2 (21 mg, 83 mmol) and dppp (34 mg, 83 mmol)
were successively added at 2108C; the mixture was stirred
for 1 h at this temperature and for 18 h at rt before addition
of an aqueous saturated NH4Cl solution (0.5 mL).
4.5.6. 2,30-Biquinoline (7g). The general procedure 4, using
2-bromoquinoline (3, 0.35 g), gave 51% of 7g (eluent:
CH2Cl2/Et2O 80:20): mp 1738C (lit.33a 175–1768C); the 1H
NMR data are in accordance with those of the literature;33a
13
0
C NMR (CDCl3) d 119.1 (C3 ), 127.5 (Cb ), 128.0 (C6),
0
128.0 (C6 ), 129.0 (C5), 129.0 (C5 ), 129.7 (Cb), 130.2 (C7),
0
130.2 (C7 ), 130.5 (C8), 130.5 (C8 ), 130.6 (C3), 137.6 (C4 ),
0
4.6.1. 3-(2-Pyrimidinyl)quinoline (7l). The general pro-
cedure 5, using 2-chloropyrimidine (0.19 g), gave 32% of 7l
(eluent: CH2Cl2/AcOEt 60:40): mp 1138C; 1H NMR
0
0
0
0
0
0
(CDCl3) d 7.18 (d, 1H, H5 ), 7.50 (m, 1H, H7), 7.69 (m,
137.7 (C4), 147.4 (Ca ), 148.0 (Ca), 150.2 (C2), 154.7 (C2 );
IR (KBr) n 3051, 1595, 1506, 1494, 1434, 1406, 1320, 1305,
1289, 1195, 1122, 1045, 1012, 968, 938, 837, 787, 746, 649,
622 cm21. Anal. calcd for C18H12N2 (256.31): C, 84.35; H,
4.72; N, 10.93. Found: C, 84.11; H, 4.53; N, 10.67%.
1H, H6), 7.88 (d, 1H, J¼7.0 Hz, H5), 8.09 (d, 1H, J¼8.0 Hz,
0
0
H8), 8.78 (d, 2H, J¼1.5 Hz, H4 ,6 ), 9.12 (d, 1H, J¼1.0 Hz,
H4), 9.85 (d, 1H, J¼1.0 Hz, H2); 13C NMR (CDCl3) d 115.7
0
(C5 ), 128.0 (C6), 128.1 (C5), 129.3 (Cb), 129.6 (C8), 130.5
(C7), 131.0 (C3), 136.3 (C4), 149.4 (Ca), 150.5 (C2), 160.7
4.5.7. 3,30-Biquinoline (7h). The general procedure 4, using
3-bromoquinoline (1, 0.23 mL), gave 45% of 7h (eluent:
CH2Cl2/Et2O 80:20): mp 2708C (lit.44 2708C); the 1H NMR
data are in accordance with those of the literature;44 13C
(C4 ,6 ), 163.4 (C2 ); IR (KBr) n 3043, 1560, 1423, 1345, 810,
747 cm21. Anal. calcd for C13H9N3 (207.24): C, 75.35; H,
4.38; N, 20.28. Found: C, 75.08; H, 4.26; N, 19.98%.
0
0
0
0
NMR (CDCl3) d 127.8 (C6,6 ), 128.3 (C5,5 ), 128.5 (Cb,b ),
0
0
4.6.2. 3-(2-Pyrazinyl)quinoline (7m). The general pro-
cedure 5, using 2-chloropyrazine (0.15 mL), gave 24% of
0
129.8 (C7,7 ), 130.4 (C8,8 ), 131.1 (C3,3 ), 134.3 (C4,4 ), 148.0
0
0
0
1
0
0
(Ca,a ), 149.9 (C2,2 ); IR (KBr) n 3042, 2947, 1884, 1573,
1493, 1353, 1320, 1197, 1127, 940, 926, 754, 624 cm21
7m (eluent: CH2Cl2/AcOEt 60:40): mp 1468C; H NMR
(CDCl3) d 7.55 (m, 1H, H7), 7.75 (m, 1H, H6), 7.89 (d, 1H,
J¼8.3 Hz, H5), 8.10 (d, 1H, J¼8.0 Hz, H8), 8.55 (d, 1H, J¼
.
Anal. calcd for C18H12N2 (256.31): C, 84.35; H, 4.72; N,
10.93. Found: C, 84.06; H, 4.63; N, 10.82%.
0
0
2.5 Hz, H4), 8.66 (d, 1H, J¼1.5 Hz, H6 ), 8.73 (s, 1H, H3 ),
9.14 (d, 1H, J¼1.5 Hz, H5 ), 9.51 (d, 1H, J¼2.5 Hz, H2); 13C
0
4.5.8. 3-Phenylquinoline (7i). The general procedure 4,
using iodobenzene (0.19 mL), gave 29% of 7i (eluent:
CH2Cl2/Et2O 80:20): mp 528C (lit.33a 51–538C); the NMR
data are in accordance with those of the literature;45 IR
(KBr) n 3058, 1493, 902, 786, 761, 696 cm21. Anal. calcd
for C15H11N (205.26): C, 87.77; H, 5.40; N, 6.82. Found: C,
87.58; H, 5.54; N, 6.69%.
NMR (CDCl3) d 126.3 (C6), 127.8 (C7), 128.0 (C3), 128.9
(C8), 129.8 (C4), 131.0 (Cb), 134.7 (C5), 140.4 (Ca), 142.7
0
0
0
0
(C3 ), 144.1 (C2), 145.0 (C5 ), 149.0 (C2 ), 149.1 (C6 ); IR
(KBr) n 3038, 2922, 1574, 1495, 1311, 1127, 1071, 1013,
853, 786, 750 cm21. Anal. calcd for C13H9N3 (207.24): C,
75.35; H, 4.38; N, 20.28. Found: C, 75.11; H, 4.53; N,
20.02%.
4.5.9. 3-(2-Thienyl)quinoline (7j). The general procedure
4, using 2-bromothiophene (0.14 g), gave 24% of 7j (eluent:
CH2Cl2/Et2O 50:50): mp 668C; the 1H NMR data are
in accordance with those of the literature;31b 13C NMR
4.7. General procedure 6: 2-substituted quinolines 8a–b
by bromine–magnesium exchange of 3 and subsequent
cross-coupling with bromides
0
(CDCl3) d 124.8 (C3 ), 126.5 (C5 ), 126.9 (C6), 127.6 (C4 ),
127.9 (C5), 128.2 (Cb), 129.5 (C7), 129.7 (C8), 129.7 (C3),
0
134.5 (C4), 141.1 (C2 ), 147.6 (Ca), 149.0 (C2); IR (KBr) n
0
0
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, a solution of
2-bromoquinoline (3, 0.35 g, 1.7 mmol) in THF (2 mL) was
introduced at 2308C, and the mixture was stirred at 2108C
for 2 h. A solution of the bromide (1.7 mmol) in THF
(3 mL), Pd(dba)2 (48 mg, 83 mmol) and dppf (47 mg,
83 mmol) were successively added at 2108C; the mixture
was stirred for 1 h at this temperature and for 18 h at rt
before addition of an aqueous saturated NH4Cl solution
(0.5 mL).
2930, 2365, 1492, 1430, 1345, 1327, 1280, 1124, 1078, 913,
860, 782, 749, 691 cm21
.
4.5.10. 3-(3-Thienyl)quinoline (7k). The general procedure
4, using 3-bromothiophene (0.14 g), gave 15% of 7k
(eluent: CH2Cl2/Et2O 50:50): mp 86–888C (lit.33a 88–
898C); the 1H NMR data are in accordance with those of the
literature;33a 13C NMR (CDCl3) d 122.0 (C2 ), 126.5 (C4 ),
0
0
0
126.9 (C6), 127.7 (C5), 128.3 (C5 ), 128.5 (Cb), 129.1 (C7),
0
129.5 (C8), 129.6 (C3), 134.5 (C4), 139.3 (C3 ), 147.6 (Ca),
4.7.1. 2-(2-Pyridinyl)quinoline (8a). The general pro-
cedure 6, using 2-bromopyridine (0.16 mL), gave 28% of
1
149.8 (C2); IR (KBr) n 3064, 2955, 1667, 1602, 1571, 1494,
1463, 1422, 1378, 1330, 1126, 1087, 1015, 788, 752, 700,
8a (eluent: CH2Cl2): mp 988C (lit.33a 98–998C); the H
NMR data are in accordance with those of the literature;33a
13
660, 623 cm21
.
0
C NMR (CDCl3) d 119.6 (C3), 120.5 (C5 ), 122.4 (C3 ),
0
124.9 (Cb), 126.3 (C6), 127.6 (C5), 129.1 (C7), 129.2 (C8),
0
0
0
4.6. General procedure 5: 3-substituted quinolines 7l–m
by bromine–magnesium exchange of 1 and subsequent
cross-coupling with chlorides
126.9 (C4 ), 140.9 (C4), 148.3 (Ca), 150.0 (C6 ), 157.4 (C2 ),
157.6 (C2); IR (KBr) n 3050, 3000, 1610, 1595, 1480, 1452,
1324, 1292, 1242, 1091, 1039, 782, 625 cm21. Anal. calcd
for C14H10N2 (206.25): C, 81.53; H, 4.89; N, 13.58. Found:
C, 81.34; H, 4.76; N, 13.87%.
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)

8638
S. Dumouchel et al. / Tetrahedron 59 (2003) 8629–8640
4.7.2. 2,20-Biquinoline (8b). The general procedure 6, using
2-bromoquinoline (3, 0.35 g), gave 27% of 8b (eluent:
CH2Cl2/Et2O 80:20). The physical and spectral data are
analogous to those obtained for a commercial sample
(Fluka).
4.9. 2,30-Bipyridine (10)
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, 3-bromopyridine
(0.16 mL, 1.7 mmol) was introduced at 2308C, and the
mixture was stirred at 2108C for 2 h. A solution of
2-bromopyridine (0.16 mL, 1.7 mmol) in THF (3 mL),
Pd(dba)2 (48 mg, 83 mmol) and dppf (47 mg, 83 mmol)
were successively added at 2108C; the mixture was stirred
for 1 h at this temperature and for 18 h at rt before addition
of an aqueous saturated NH4Cl solution (0.5 mL) to afford
62% of 10 (eluent: CH2Cl2/Et2O 50:50, and then MeOH/
AcOEt 50:50). The physical and spectral data are analogous
to those obtained for a commercial sample (Acros).
4.8. General procedure 7: 4-substituted quinolines
9a–b,d by bromine–magnesium exchange of 4 and
subsequent cross-coupling with bromides
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, a solution of
4-bromoquinoline (4, 0.35 g, 1.7 mmol) in THF (2 mL) was
introduced at 2308C, and the mixture was stirred at 2108C
for 2 h. A solution of the bromide (1.7 mmol) in THF
(3 mL), Pd(dba)2 (48 mg, 83 mmol) and dppf (47 mg,
83 mmol) were successively added at 2108C; the mixture
was stirred for 1 h at this temperature and for 18 h at rt
before addition of an aqueous saturated NH4Cl solution
(0.5 mL).
4.10. 1-Phenylisoquinoline (11)
To THF (4 mL) at 2108C were added BuMgCl (0.63 mmol)
and BuLi (1.3 mmol). After 1 h at 2108C, bromobenzene
(0.26 g, 1.7 mmol) was introduced at 2308C, and the
mixture was stirred at 2108C for 2.5 h. A solution of
1-bromoisoquinoline (0.35 g, 1.7 mmol) in THF (3 mL),
Pd(dba)2 (48 mg, 83 mmol) and dppf (47 mg, 83 mmol)
were successively added at 2108C; the mixture was stirred
for 1 h at this temperature and for 18 h at rt before addition
of an aqueous saturated NH4Cl solution (0.5 mL) to afford
24% of 11 (eluent: CH2Cl2/AcOEt 90:10): mp 858C (lit.27b
88–898C); the spectral data are in accordance with those of
the literature.27b
4.8.1. 4-(2-Pyridinyl)quinoline (9a). The general pro-
cedure 7, using 2-bromopyridine (0.16 mL), gave 43% of
9a (eluent: CH2Cl2/AcOEt 80:20): mp 668C; 1H NMR
0
(CDCl3) d 7.40 (m, 4H, H5,7,3 ,5 ), 7.66 (m, 1H, H6), 7.79
0
0
(t, 1H, J¼7.6 Hz, H4 ), 8.05 (d, 1H, J¼4.4 Hz, H3), 8.11 (d,
0
1H, J¼8.5 Hz, H8), 8.74 (d, 1H, J¼4.3 Hz, H6 ), 8.92 (d, 1H,
J¼4.4 Hz, H2); 13C NMR (CDCl3) d 119.4 (C3), 121.8 (C5 ),
0
0
123.6 (C3 ), 125.3 (C6), 125.9 (Cb), 127.5 (C5), 129.9 (C7),
0
130.2 (C8), 137.2 (C4 ), 146.9 (C4), 148.6 (Ca), 149.1 (C6 ),
0
0
150.3 (C2), 157.4 (C2 ); IR (KBr) n 3048, 2997, 1650, 1598,
4.11. IR spectroscopic analyses
1367, 1294, 1237, 1101, 786, 623 cm21. Anal. calcd for
C14H10N2 (206.25): C, 81.53; H, 4.89; N, 13.58. Found: C,
81.34; H, 4.61; N, 13.46%.
Samples were recorded using a ReactIRe 4000 from ASI
Applied Systems fitted with an immersible DiComp ATR
probe optimized for maximum sensitivity. The spectra were
acquired in 64 scans per spectrum at a gain of 1 and a
resolution of 8 using system ReactIRe 2.21 software. A
representative reaction was carried out as follows: The IR
probe was inserted through a nylon adapter and O-ring seal
into an oven-dried, cylindrical adjustable-volume ReactIRe
microcell46 fitted with magnetic stir bar under N2 atmos-
phere. Following the recording of a background spectrum
(1024 scans), the flask was charged with BuMgCl. IR
spectra were collected at 2 min intervals over the course of
the reaction. BuLi was added at 2758C, and the temperature
was slowly raised to 2108C. 3-Bromoquinoline was then
introduced at 2608C, and the temperature was slowly raised
to rt before addition of PhCHO.
4.8.2. 4-(5-Bromo-2-pyridinyl)quinoline (9b). The general
procedure 7, using 2,5-dibromopyridine (0.40 g), gave 48%
1
of 9b (eluent: CH2Cl2/Et2O 80:20): mp 1268C; H NMR
0
(CDCl3) d 7.42 (d, 1H, J¼4.4 Hz, H3), 7.50 (m, 2H, H7,3 ),
0
7.68 (m, 1H, H6), 7.95 (dd, 1H, J¼8.3, 2.1 Hz, H4 ), 8.02
(d, 1H, J¼7.7 Hz, H5), 8.12 (d, 1H, J¼8.3 Hz, H8), 8.82
13
0
(d, 1H, J¼2.1 Hz, H6 ), 8.93 (d, 1H, J¼4.4 Hz, H2);
0
C NMR (CDCl3) d 121.1 (C5 ), 121.7 (C3), 125.7
0
(C3 ), 126.1 (C6), 126.4 (Cb), 127.7 (C5), 130.0 (C8),
0
130.4 (C7), 139.9 (C4 ), 145.3 (C4), 149.3 (Ca), 150.4 (C2),
151.4 (C6 ), 155.4 (C2 ); IR (KBr) n 3068, 2937, 1583,
1494, 936, 621 cm21. Anal. calcd for C14H9BrN2 (285.15):
C, 58.97; H, 3.18; N, 9.82. Found: C, 58.76; H, 3.44; N,
9.57%.
0
0
4.8.3. 4-(2-Pyrazinyl)quinoline (9d). The general pro-
cedure 7, using 2-bromopyrazine (0.27 g), gave 23% of 9d
(eluent: CH2Cl2/Et2O 80:20): mp ,508C; 1H NMR (CDCl3)
d 7.51 (d, 1H, J¼4.5 Hz, H3), 7.56 (d, 1H, J¼7.5 Hz, H5),
7.74 (t, 1H, J¼7.5 Hz, H6), 8.06 (t, 1H, J¼8.5 Hz, H7), 8.18
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0
(d, 1H, J¼8.5 Hz, H8), 8.66 (d, 1H, J¼1.8 Hz, H6 ), 8.76 (d,
´
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