Regioselective lithium-halogen exchange and palladium-catalyzed cross-coupling reactions of 2,4-dihaloquinolines

Article abstract of DOI:10.1016/j.tetlet.2005.07.137

Lithium-halogen exchange of 2,4-dibromoquinolines proceeds regioselectively at C-4 and affords 4-substituted quinolines on quenching with electrophiles. Palladium-catalyzed cross-coupling reactions of 2-bromo-4-iodoquinoline provide 4-substituted 2-bromoq

Full text of DOI:10.1016/j.tetlet.2005.07.137

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6697–6699
Regioselective lithium–halogen exchange and palladium-catalyzed
cross-coupling reactions of 2,4-dihaloquinolines
Daniel L. Comins,* Jason M. Nolan and Ibrahim D. Bori
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 30 June 2005; revised 26 July 2005; accepted 26 July 2005
Available online 10 August 2005
Abstract—Lithium–halogen exchange of 2,4-dibromoquinolines proceeds regioselectively at C-4 and affords 4-substituted quinolines
on quenching with electrophiles. Palladium-catalyzed cross-coupling reactions of 2-bromo-4-iodoquinoline provide 4-substituted
2-bromoquinoline derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
We recently published a report on the regioselective
Sonogashira coupling of 2,4-dibromoquinolines.1 Using
HMBC correlations and other NMR data, we proved
that this reaction was general and selective for the C-2
position of the quinolines (Scheme 1).
1. 1.1 n-BuLi
Et2O/THF,
-78 °C
Br
N
Br
N
not
N
Br
2. H2O
Br
8
6
7a
It has been suggested that selectivity of this type is a re-
sult of a mechanism in which the lone pair of the nitro-
gen coordinates to the metal and directs substitution to
the C-2 position.2 It is known that C-2 selectivity is also
general for analogous 2,4-dibromo-3 and 2,5-dibromo-
pyridines.4 Conversely, it has been demonstrated that
Scheme 2.
Owing to the fact that not all pyridine chemistry is
directly applicable to quinolines,7 an investigation of
the reactivity of 2,4-dibromoquinolines toward lith-
ium–halogen exchange was undertaken. Treatment of
2,4-dibromoquinoline with 1.1 equiv of n-BuLi (Et2O/
THF, ꢀ78 °C) provided a lithioquinoline which was
quenched with water (Scheme 2).
2,4-dibromopyridines will undergo
a regioselective
lithium–halogen exchange reaction5 at C-4 to afford
4-substituted 2-bromopyridines on addition of
electrophiles.6
The resulting product was determined to be 2-bromo-
quinoline by comparison8 with authentic samples of 7a
and 8.9 To determine if this reaction was general for
other electrophiles, a study was carried out and the
results are shown in Table 1. The anticipated products
7b–f were obtained in good to high yields.
H
R2
Br
N
Br
N
R1
R1
Br
Pd(PPh3)2Cl2
CuI, HN(i-Pr)2
1,4-dioxane, 23 °C
R2
2
1
In contrast to the reactivity of 2,4-dibromoquinoline,
when 2-bromo-4-iodoquinoline (7b) was subjected to
Sonogashira coupling conditions, the product was deter-
mined to be the 4-substituted quinoline 9 (Scheme 3).
(ref. 1)
Scheme 1.
Keywords: Lithium–halogen exchange; Quinolines; Cross-coupling;
a-Amino alkoxide.
Corresponding author. Tel.: +1 9195152911; fax: +1 9195159371;
The product 9 was afforded in 90% yield after 2 h at
room temperature. To determine if 2-bromo-4-iodo-
quinoline could be selectively substituted at C-4 using
*
e-mail: dan_comins@ncsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.137

6698
D. L. Comins et al. / Tetrahedron Letters 46 (2005) 6697–6699
Table 1. Examples of C-4 substitution of 6a
To establish if additional functionality can be present at
C-3 during the regioselective lithium–halogen exchange,
the known 2,4-dibromo-3-quinolinecarboxaldehyde
(14)1 was protected in situ as an a-amino alkoxide13
and treated with n-BuLi. Addition of iodine to the
resulting dianion 15 provided quinolinecarboxaldehyde
17 in 90% yield. Similarly, the more reactive dianion
16 was treated with MeSSMe to give quinoline deriva-
tive 18. In addition, the dianion 20 was prepared from
alcohol 191 and treated with iodine to give quinoline
21 in high yield (Scheme 4).
1. 1.1 n-BuLi
Br
E
N
Et2O/THF,
-78 °C
2. E+
N
Br
Br
6
7a, E = H, 7b, E = I, 7c, E = Me
7d, E = SiMe3, 7e, E = CHO
7f, E = CH(OH)Ph
Entry
E+
Product
Yieldb (%)
1
2
3
4
5
6
H2O
I2
MeI
TMSCl
DMF
PhCHO
7a
7b
7c
7d
7e
7f
76
87
85c
70
74
82
The Sonogashira reaction on quinolines 17 and 21 was
briefly examined. Trimethylsilylacetylene and 17 gave a
mixture of 4- and 2,4-disubstituted products (22 and
23) along with recovered starting material. The analo-
gous reaction with quinoline 21 afforded an inseparable
mixture of 2- and 4-substituted isomers 24 and 25
(Scheme 5).
a The reactions were performed on a 0.1–1.0 mmol scale.
b All yields are for isolated products after chromatography.
c Purity determined to be 94% by 1H NMR analysis.10
In summary, the lithium–halogen exchange reaction of
2,4-dibromoquinoline provides a method for synthesiz-
ing 4-substituted 2-bromoquinolines with identical regio-
selectivity as found in the pyridine series. This selectivity
is understood to arise from the stability of the lithio-
quinoline intermediate, which is most stable when the
aryl–lithium bond is furthest from the nitrogen lone
pair.14 In this report, we also presented a new method
for regioselective palladium-catalyzed cross-couplings
of 2,4-dihaloquinolines at the C-4 position. This selectiv-
ity is complementary to our previously published work,
in which substitution was selective for the C-2 position.1
With 2-bromo-4-iodoquinoline, the Suzuki, Stille, Sono-
gashira, and Heck reactions all proceeded with excellent
C-4 regioselectivity and is a result of the greater reactiv-
ity of the aryl–iodide bond toward oxidative addition
with palladium relative to the aryl–bromide bond.15
The presence of a formyl or hydroxymethyl group at
C-3 lowers the regioselectivity of the Sonogashira
cross-coupling reaction.
SiMe3
I
H
SiMe3
Pd(PPh3)2Cl2
CuI, TEA,
23 °C, 2 h
N
Br
N
Br
7b
9
I
not
N
SiMe3
10
Scheme 3.
other palladium-catalyzed cross-coupling reactions, a
study was carried out and the results are shown
in Table 2.
Table 2. Various palladium-catalyzed cross-coupling reactions of 7b
Entry
Conditions
Coupling partner
Product
Yielda (%)
33b
CO2Me
Br
1 (Heck)
Pd(PPh3)2OAc2, KOAc, CH3CN, 80 °C, 24 h
CH2@CH–CO2Me
N
11
2 (Stille)
Pd(PPh3)2Cl2, DMF, 80 °C, 18 hc
CH2@CH–SnBu3
63d
55
N
Br
Br
12
Ph
3 (Suzuki)
Pd(PPh3)2Cl2, 2.0 M K2CO3, THF, 20 h, De
Ph–B(OH)2
N
13
a Reported yields are for isolated products and are unoptimized.
b Compound 7b was recovered in 30% yield.
c Ref. 11.
d Compound 7b was recovered in 12% yield.
e Ref. 12.

D. L. Comins et al. / Tetrahedron Letters 46 (2005) 6697–6699
6699
Acknowledgments
N
N
NMR and mass spectra data for new compounds were
obtained at NCSU instrumentation laboratories, which
were established by grants from the North Carolina Bio-
technology Center and the National Science Foundation
(grants CHE-9059532, CHE-0078253).
Br
N
Li
1. Li
N
N
CHO
OLi
Br
N
Br
2. 1.1 n-BuLi, -78 ˚C
14
15
1. Li
N
N
1. I2
Supplementary data
2. 1.1 n-BuLi, -78 ˚C
2. H2O
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tet-
let.2005.07.137. Experimental for the preparation of
7b, 9, and 17, characterization data for compounds
7a–f, 9, 11–13, 17–18, and 21–23.
N
R
N
Li
N
1. MeSSMe
CHO
OLi
Br
2. H2O
N
Br
17, R = I 90%
16
18, R = SMe 50%
References and notes
1. Nolan, J. M.; Comins, D. L. J. Org. Chem. 2003, 68,
3736.
2. Shiota, T.; Yamamori, T. J. Org. Chem. 1999, 64, 453, and
references therein.
3. Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.
4. Chambers, R. D.; Hall, C. W.; Hutchinson, J.; Millar,
R. W. J. Chem. Soc., Perkin Trans. 1 1999, 1705.
5. Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988,
352, 1.
Br
Li
1. MeLi
OH
OLi
N
Br
2. n-BuLi
N
Br
20
19
I2
I
6. Bouillon, A.; Lancelot, J.; Collot, V.; Bovy, P. R.; Rault,
S. Tetrahedron 2002, 58, 4369.
OH
7. Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed; A.W.
Longman: England, 1977, Chapter 5.
N
Br
8. The productÕs structure was determined using mp, 1H- and
89%
13C NMR.
21
9. (a) Both 2-bromoquinoline and 4-bromoquinoline were
synthesized from the corresponding hydroxyquinoline and
their respective data matched the literature values: Sugi-
moto, O.; Mori, M.; Moriya, K.; Tanji, K. Helv. Chim.
Acta 2001, 84, 1112; (b) Ono, I.; Hata, N. Bull. Chem. Soc.
Jpn. 1987, 60, 2891.
Scheme 4.
SiMe3
SiMe3
10. The impurity was determined to be 20-bromo-4-methyl-
H
SiMe3
CHO
Br
1
CHO
[2,40]biquinolinyl by H NMR. For entries 2–4 of Table 1
Pd(PPh3)2Cl2
17
the product is reactive with the lithioquinoline intermedi-
ate, and it is favorable to use inverse addition in those
cases.
CuI, TEA,
23 °C, 2 h
N
N
SiMe3
22 55%
17%
23
11. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic
Chemistry: A Guide for the Synthetic Chemist; Baldwin, J.
E., Williams, F. R. S., Williams, R. M., Eds.; Elsevier
Science Ltd: Oxford, 2000, p 207.
12. Couve-Bonnaire, S.; Carpentier, J.; Mortreux, A.; Casta-
net, Y. Tetrahedron Lett. 2001, 42, 3689.
13. Review: Comins, D. L. Synlett 1992, 615–625.
14. Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
4059.
15. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 1998, p 203.
SiMe3
H
SiMe3
I
Pd(PPh3)2Cl2
OH
OH
21
CuI, TEA,
23 °C, 2 h
N
Br
N
SiMe3
24
25
ratio 1 : 0.7
Scheme 5.