Direct 1,4-difunctionalization of isoquinoline

Article abstract of DOI:10.1016/j.tetlet.2009.07.125

The synthesis of 1,4-disubstituted isoquinoline derivatives was achieved in one step starting from isoquinoline. The process involved a nucleophilic addition in 1-position followed by an electrophilic trapping in 4-position. Interesting features were noted when C₂Cl₆ was used as the electrophile since different compounds could be isolated selectively only by adjusting the reaction parameters.

Full text of DOI:10.1016/j.tetlet.2009.07.125

Tetrahedron Letters 50 (2009) 5716–5718
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct 1,4-difunctionalization of isoquinoline
*
Frédéric Louërat, Yves Fort, Victor Mamane
Laboratoire SRSMC-SOR, UMR CNRS-UHP 7565, Nancy Université, BP 70239, Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1,4-disubstituted isoquinoline derivatives was achieved in one step starting from iso-
quinoline. The process involved a nucleophilic addition in 1-position followed by an electrophilic trap-
ping in 4-position. Interesting features were noted when C2Cl6 was used as the electrophile since
different compounds could be isolated selectively only by adjusting the reaction parameters.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 June 2009
Revised 17 July 2009
Accepted 22 July 2009
Available online 26 July 2009
Keywords:
Isoquinoline
Functionalization
‘One-pot’ reaction
Isoquinoline derivatives play an important role in organic
chemistry, not only as key structural units in many natural prod-
ucts,1 but also as building blocks in important pharmaceuticals.2
Furthermore, they are utilized as chiral ligands for transition metal
catalysis,3 and their iridium complexes are used in organic light-
emitting diodes.4 For these reasons, the efficient synthesis of iso-
quinoline derivatives is of considerable interest to synthetic and
medicinal chemists.5 For fine-tuning of the biological and/or phys-
ical properties of these compounds for final application, a general
and flexible functionalization method that allows a rapid access
to diversely substituted compounds from the inexpensive and
readily available isoquinoline is highly desirable.
was accelerated by adding a stoichiometric amount of a lithium
coordinating compound such as DME (dimethoxyethane).11,12
Duringtheir work, they observedthat, when using methyl chlorofor-
mate as the electrophile, along with the expected N-acylation prod-
uct, a non-separable by-product incorporating two ester groups was
also observed, probably resulting from the initial C-acylation fol-
lowed by N-acylation (Fig. 1).
On the basis of these considerations and pursuing our efforts
toward the synthesis and functionalization of polyheterocyclic
systems,13 we report herein our results concerning the 1,4-difunc-
tionalizion of isoquinoline. The undesired N-addition to 2N was
avoided by using electrophiles such as alkyl halides or hexachloro-
The 2,5-difunctionalization of pyridine through a nucleophilic
attack at C-2 followed by an electrophilic trapping at C-5 was first re-
ported nearly four decades ago.6 Thereafter, several groups showed
the utility of this reaction by the synthesis of different substituted
pyridines7 and particular interest was directed on the isolation and
characterization of the dihydropyridine intermediate involved in
this reaction.8 Curiously, there is no report concerning this reaction
with isoquinoline although it would represent a rapid way of func-
tionalization of the isoquinoline core. Indeed, the direct addition
on isoquinoline is too slow and the resulting dihydro derivative re-
aromatizes rapidly by loss of LiH9 before it can react with an electro-
phile. In order to facilitate the nucleophilic addition, one way could
be electrophilic N-activation.10 However the dihydro intermediates
would be too stable to react with an electrophile. We then reasoned
that the best way to succeed in the 1,4-difunctionalization of
isoquinoline could be via activation of the nucleophile. Alexakis
and co-workers observed that the reaction of MeLi with isoquinoline
E
E
[O]
N
N
N
1
R
R
3
RLi
EX
Li
this work
NLi
N
2N
2C
R
R
N-acylation
C-acylation
CO2Me
Alexakis et al.
CO2Me
N
H
N
N
OMe
O
CO2Me
CO2Me
R
R
R
Cl
* Corresponding author. Tel.: +33 3 83 68 43 20; fax: +33 3 83 68 47 85.
E-mail address: victor.mamane@srsmc.uhp-nancy.fr (V. Mamane).
Figure 1. Addition—Electrophilic trapping sequence on isoquinoline.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.125

F. Louërat et al. / Tetrahedron Letters 50 (2009) 5716–5718
5717
ethylene (C2Cl6) (Table 1).14,15 The reaction of 1 with 1.2 equiv of
n-BuLi in the presence of 1 equiv of DME resulted in clean C1-addi-
tion after 3 h in diethyl ether at 30 °C under argon. After addition of
MeOH (2 equiv), the mixture was opened to air producing com-
pound 3a in 82% yield (entry 1).The dihydro intermediate 2C could
be trapped by iodomethane followed by addition of MeOH and air
oxidation to give 3b in 68% yield (entry 2). Trapping with allylbro-
mide afforded a mixture containing the expected product along
with products of the double bond isomerization. Nevertheless,
compound 3c could be isolated in 31% yield (entry 3). When
C2Cl6 was added to the reaction mixture, instead of the expected
product 3e, dimer 3d was obtained in a good yield of 72% (entry
4).16 Probably, compound 4 resulting from reaction of the dihydro
intermediate 2C/2N with C2Cl6, was trapped immediately by
remaining 2C/2N to give 3d (Fig. 2).17 However, compound 3e
could be obtained in 54% yield by performing a reverse addition
of the reaction mixture to a solution of C2Cl6 in Et2O following by
MeOH addition (entry 5).18 We then tested the reactivity of 4 to-
ward different nucleophiles but the chlorine displacement was ob-
served only when H2O was used giving 3-hydroxyquinoline 3f in a
moderate yield of 58% (entry 6).19 It is worth noting that 3f and re-
lated compounds were already observed by Uno and co-workers
after air oxidation of the hydrolyzed dihydro derivative 2C/2N for
2 days in benzene.10 MeLi was then used as the nucleophile and
we observed the same reactivity toward isoquinoline 1 compared
to n-BuLi. However, it was noted that the resulting dihydro inter-
mediates were not completely re-aromatized after addition of
MeOH under air thus requiring the addition of DDQ (2,3-di-
chloro-5,6-dicyano-p-benzoquinone) in order to achieve reaction
completion. Under these conditions, compound 3g was isolated
in 74% yield (entry 7). The dimer 3h20 could be obtained in 64%
yield by adding C2Cl6 to the reaction mixture before DDQ oxidation
(entry 8). The reverse addition procedure allowed the isolation of
compound 3i in 42% yield (entry 9). Finally, the reaction of PhLi
was performed under the standard conditions allowing the synthe-
sis of products 3j and 3k with respective yields of 74% and 73% (en-
tries 10 and 11).
Table 1
Functionalized isoquinoline derivatives
3 produced via the sequence shown in
Figure 1a
Entry
1
RLi
EX
Product
Yield (%)
82
N
n-BuLi
MeOH
n-Bu
3a
2
3
4
5
6
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
MeI
68
31
72
54
58
N
n-Bu
3b
Br
N
n-Bu
3c
C2Cl6
n-Bu
n-Bu
N
N
3d
Cl
b
C2Cl6
N
n-Bu
OH
3e
3f
b,c
C2Cl6
N
n-Bu
In conclusion, we have described a straightforward access to
1,4-disubstituted isoquinoline compounds by a simple addition—
electrophilic trapping sequence. The use of DME during the addi-
tion of RLi (n-BuLi, MeLi and PhLi) was important to accelerate
the reaction and to allow electrophilic trapping before rearomati-
zation. Among the electrophiles tested, C2Cl6 was very interesting
because it allowed the selective formation of three different com-
pounds depending on the order of addition (normal or reverse)
and on the quenching method (H2O instead of MeOH). It is inter-
esting to note that in case of 3i, the presence of a methyl group
and a chlorine atom should allow for further transformations to
occur.13b,21
N
7
8
MeLi
MeLi
MeLi
PhLi
PhLi
MeOHd
74
64
42
74
73
3g
d
C2Cl6
N
N
3h
Cl
b
9
C2Cl6
N
3e, 3i, 3k
3i
3j
R
[O]
N
N
Cl
N
10
MeOH
C2Cl6
2
[O]
Ph
Cl
3d, 3h
2
N
air, 2 days
benzene
Uno (ref 10)
4
R
b
H2O
R
11
C2Cl6
N
OH
Ph
3k
[O]
a
3f
Reaction conditions: (i) 1.2 equiv RLi, 1 equiv DME, Et2O, 30 °C, 3 h. (ii) 1.5 equiv
N
EX, 2 h. (iii) MeOH (2 equiv), air oxidation.
b
Reverse addition.
Addition of H2O at the end of the reaction.
Oxidation with DDQ (1 equiv).
R
c
d
Figure 2. Different pathways for the evolution of intermediate 4.

5718
F. Louërat et al. / Tetrahedron Letters 50 (2009) 5716–5718
8. (a) Marsais, F.; Granger, P.; Quéguiner, G. J. Org. Chem. 1981, 46, 4494–4497; (b)
Acknowledgment
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9. (a) Abramovitch, R. A.; Poulton, G. A. Chem. Commun. 1967, 274–275; (b)
Fraenkel, G.; Copper, J. C. Tetrahedron Lett. 1968, 8, 1825–1830.
10. Uno, H.; Okada, S.; Suzuki, H. J. Heterocycl. Chem. 1991, 28, 341–346.
11. Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 2117–2122.
12. Nichols, M. A.; Williard, P. G. J. Am. Chem. Soc. 1993, 115, 1568–1572.
13. (a) Mamane, V.; Louërat, F.; Iehl, J.; Abboud, M.; Fort, Y. Tetrahedron 2008, 64,
10699–10705; (b) Mamane, V.; Aubert, E.; Fort, Y. J. Org. Chem. 2007, 72, 7294–
7300; (c) Mamane, V.; Fort, Y. Tetrahedron Lett. 2006, 47, 2337–2340; (d)
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We gratefully acknowledge the CNRS and Nancy Université for
financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.125.
14. The use of TMSCl or aldehydes as electrophiles resulted in inseparable complex
mixtures.
15. General experimental procedure: preparation of 1-methyl-4-chloro-isoquinoline
References and notes
3i. To
a solution of isoquinoline 1 (1 g, 7.75 mmol) and DME (0.8 mL,
7.75 mmol) in degassed Et2O (40 mL) at 30 °C, under argon, was added MeLi
(1.6 M in Et2O, 5.8 mL, 9.3 mmol) and the mixture was stirred for 3 h before it
was transferred to a degazed solution of C2Cl6 (3.7 g, 11.62 mmol) in Et2O
(10 mL) at 30 °C. After 2 h of stirring, MeOH (15 mmol, 0.6 mL) was added and
the mixture was stirred under open air for 30 min (complete aromatization
was observed by performing 1H NMR of the crude mixture). The reaction
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42%).1H NMR (200 MHz, CDCl3) d 8.37 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.99 (d,
J = 8.4 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 2.87 (s, 3H); 13C
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123.5, 21.9. MS (EI) m/z 177 (M+, 100%), 142 (26), 115 (45). HRMS m/z calcd for
C10H8ClN: 177.0345, found: 178.0418 (MH+). For analytical data of all other
compounds, see the Supplementary data.
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