A facile synthesis of 1,3,4-trisubstituted isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2009.04.040

A facile and versatile approach to 1,3,4-trisubstituted isoquinoline derivatives from commercially available 1,3-dichloroisoquinoline is described.

Full text of DOI:10.1016/j.tetlet.2009.04.040

Tetrahedron Letters 50 (2009) 3081–3083
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of 1,3,4-trisubstituted isoquinolines
*
Hanbiao Yang
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94034, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and versatile approach to 1,3,4-trisubstituted isoquinoline derivatives from commercially avail-
able 1,3-dichloroisoquinoline is described.
Received 16 March 2009
Revised 1 April 2009
Accepted 8 April 2009
Available online 14 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The isoquinoline ring system is frequently found in alkaloids,1
and it has also been widely used as a scaffold in drug discovery
programs.2 In addition, various isoquinoline derivatives have
gained popularity as ligands for transition-metal catalysis.3 There-
fore, the synthesis of isoquinoline derivatives is of considerable
interest to synthetic and medicinal chemists.4
Although much information concerning the synthesis of iso-
quinoline and congeners thereof is available in the literature,5
the generation of 1,3,4-trisubstituted isoquinolines is still a chal-
lenging problem. Several approaches to such compounds have
been described in the literature,2b,c,4b,c,6 but the need for highly
functionalized intermediates and/or harsh reaction conditions
indicates that alternative syntheses of such entities are still re-
quired. It occurred to us that the direct C-4 lithiation of commer-
cially available 1,3-dichloroisoquinoline 1 (Scheme 1) ought to be
possible,7 and this, coupled with the well-known difference in
reactivity of the chloro groups at C-1 and C-3,2d,3 in 1 should pro-
vide access to a wide variety of 1,3,4-trisubstituted isoquinolines 4.
This work describes the successful realization of such a synthetic
strategy.
Li
Cl
Cl
Lithiation
N
N
Cl
R
Cl
2
3
1
Electrophile
R
R2
Cl
N
N
R1
Cl
4
Scheme 1. A proposed 1,3,4-trisubstituted isoquinoline synthesis.
The reaction of the 4-lithioisoquinoline derivative 2 with vari-
ous electrophilic reagents was then examined. Thus, 15 min after
the lithiated species had been generated, the solution thereof
was cannulated into a THF solution of the electrophilic reagent
(3 equiv) at room temperature. Whereas allyl bromide gave only
a very minor amount of the desired product 3a, the much more
reactive allyl iodide gave 3a in nearly 90% yield (Table 1, entries
1 and 2). The homologous compound 3b was generated equally
efficiently from methallyl iodide. In contrast, the reaction with
methyl iodide was surprisingly inefficient (entry 4), but it was dra-
matically improved with methyl triflate, giving 3c in 90 % yield,
even when only 1.1 equiv of the electrophile was used (entry 5).
The reaction of the lithiated species 2 with benzoyl chloride, io-
dine, and benzenesulfonyl chloride was also studied. Whereas
the expected products 3d and 3e were obtained from benzoyl chlo-
ride and iodine, respectively (entries 6 and 7), quenching with ben-
zenesulfonyl chloride gave a complex mixture without even traces
of 3f, as determined by LC–MS analysis.
The first phase of this work involved a study of the lithiation of
1. Thus, addition of lithium diisopropylamide (LDA) to a THF solu-
tion of 1 at ꢀ78 °C generated an orange-colored solution. After 2 h
at this temperature, the solution was cannulated into 20% DCl in
D2O at room temperature. The monodeuterated compound 5,
determined to contain <5% hydrogen at C-4 by the absence of the
d 7.67 ppm singlet found in the 1H NMR spectrum of 1, was iso-
lated in high yield.
D
Cl
Cl
LDA, THF, -78 ºC, 2 h
ð1Þ
N
N
then 20% DCl in D2O
88%
Cl
Cl
It is well established for 1,3-dichloroisoquinoline derivatives
that both nucleophilic displacement and transition metal-cata-
lyzed cross-coupling reactions occur preferentially at C-1.2d,3
Therefore, compounds 3a–d could, in principle, be converted into
a variety of 1,3,4-trisubstituted isoquinolines. It appeared to us,
however, that the iodo compound 3e would be an even more
5
* Tel.: +1 650 855 5697; fax: +1 650 855 6585.
E-mail address: hanbiao.yang@roche.com
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.040

3082
H. Yang / Tetrahedron Letters 50 (2009) 3081–3083
Table 1
Unfortunately, all attempts to prevent the formation of 1 failed
(e.g., through rigorous exclusion of moisture). In addition, separa-
tion of 6a and 1 by silica gel chromatography was not successful.
Therefore, further study of the Negishi coupling was curtailed.
The Suzuki cross-coupling with phenylboronic acid in aqueous
dioxane (4:1) was then studied (reagent quantities shown in Table
2), examining the effect of the reaction temperature and time on
the course of the reaction. Thus, after 40 min of microwave irradi-
ation at 80 °C, the reaction ceased, but the product consisted of a
1.8:1 mixture of 6a and the bis-coupling product 7 (entry 2).
Effecting the reaction at lower temperatures had a pronounced ef-
fect on the 6a/7 ratio. For example, at 65 °C it improved to 7:1 (en-
try 3), and at 60 °C, and at a 20-min reaction period, only 6a was
formed, but consumption of the starting material was not complete
(entry 4). The optimum cross-coupling conditions turned out to in-
volve conventional heating at 55 °C for 12 h, which resulted in
complete consumption of the starting material and a 21:1 ratio
of 6a/7a (entry 5).
Synthesis of 4-substituted-1,3-dichloroisoquinoline via lithiation/electrophilic trap-
ping sequencea
R
Cl
Cl
LDA, THF, -78 ºC
N
N
then Electrophile, rt
Cl
Cl
1
3a: allyl
3b: methallyl
3c: methyl 3d: benzoyl
3e: iodide 3f: benzenesulfonyl
Entry
Electrophile
Conversionb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
Allyl bromide
Allyl iodide
5
87
87
66
91
100
95
100
NDd
87e
87e
NDd
80e
61
Methallyl iodide
Methyl iodide
Methyl triflate
Benzoyl chloride
Iodine
90
0
Benzenesulfonyl chloride
The scope of the Suzuki cross-coupling reaction with several
aryl- and heteroarylboronic acids was then examined (Table 3).
Phenylboronic acids bearing electron donating or accepting
substituents at the meta or para positions gave good to excellent
results, both in terms of product yields and mono:bis coupling
product ratios. The coupling reaction failed with o-meth-
oxyphenylboronic acid (entry 4). Satisfactory results were also
obtained with 3-furyl- and 4-pyridylboronic acids, although a
higher reaction temperature (up to 75 °C) was required (entries 7
and 8, respectively). No coupling occurred with 2-furlyboronic acid
at 75 °C, and at 95 °C an inseparable 3:1 mixture of the desired
product 6i and l was obtained (entry 9).
The utility of the processes and intermediates described herein
was demonstrated by the synthesis of climiqualine 86c (Scheme 2),
a compound with hypolipemic and hypoglycemic activities in rats
and rabbits, from 6a and the sodium salt of imidazole. Further-
more, under the conditions reported by Buchwald,10 compound 8
a
Reagents and conditions: 1.2 equiv of LDA, THF, ꢀ78 °C, 15 min; 3 equiv of
electrophile, rt.
b
Determined by absorption at 240–320 nM range after separation of the crude
reaction mixture by LC.
c
Isolated yield after silica gel chromatography.
ND: not determined.
The product was isolated as a mixture with starting material 1. The yield was
d
e
based on the amount of desired product in the mixture.
versatile precursor of 1,3,4-trisubstituted isoquinoline derivatives
given that the C-4 iodo group should readily and selectively partic-
ipate in transition metal-catalyzed cross-coupling reactions. This
route to such trisubstituted isoquinoline congeners became even
more attractive when it was found that we were unable to gain ac-
cess to 4-aryl or 4-heteroaryl-1,3-dichloroisoquinlines from the
lithio compound 2.8
A series of cross-coupling reactions with 3e were then carried
out and the product mixtures were analyzed by UV spectroscopy
in the 240–320 nM region, after separation of the crude reaction
mixtures by liquid chromatography on an Xterra C18 column.
The Negishi cross-coupling reaction with phenylzinc chloride was
the first studied process under the conditions shown in Table 2
(entry 1). Compound 6a was indeed obtained as the major product
(49%), but it was contaminated with significant amounts of the
starting material 3e (18%) and 1,3-dichloroisoquinoline 1 (33%).9
Table 3
Substrate scope for the Suzuki cross-coupling reaction of 4ea
I
R
Cl
Cl
R-B(OH)2
N
N
Cl
Cl
3e
6a: phenyl
6b: 4-MeOC6H4
6c: 3,4,5-triMeOC6H2 6d: 2-MeOC6H4
6e: 4-FC6H4 6f: 4-NCC6H4
6g: 3-furanyl 6h: 4-pyridyl
6i: 2-furanyl
Table 2
Optimization of cross-coupling reactions of 3e
Ph
Ph
I
Ph
Cl
Cl
Cl
Entry
R–B(OH)2
Ph
Prod.
Ratiob (mono/bis)
Yield (%)
+
N
N
N
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
21/1
87
4-MeOC6H4
3,4,5-TriMeOC6H2
2-MeOC6H4
4-FC6H4
32/1
93c
89
Cl
Cl
7
6a
d
3e
NDe
Trace
97
Entry
Conditionsa
Temp (°C)
Time (min)
Conversionb (%)
Ratiob
(6a/7/3e)
11/1
d
4-NCC6H4
3-Furanyl
4-Pyridyl
2-Furanyl
92
85e
80d
65d
60d
55e
720
40
40
20
720
82
100
100
72
1.5:0:1
1.8:1:0
7:1:0
1:0:0
21:1:0
6g
6h
6i
20/1
89f
1
2
3
4
5
A
B
B
d
71g
40%f,h
d
B
a
Bc
100
Reagents and conditions: R–B(OH)2 (1.1 equiv), K2CO3 (3 equiv), PdCl2(dppf)
(10 mol %), 1,4-dioxane/H2O (4/1), 55 °C, 12 h.
Mono//bis-coupling product ratio was determined from the absorption at 240–
320 nM , after separation of the crude reaction mixture by LC.
a
b
A: phenylzinc chloride (1.8 equiv), Pd(PPh3)4 (10 mol %), THF. B: phenylboronic
acid (1.3 equiv), PdCl2(dppf) (10 mol %), K2CO3 (3 equiv), 1,4-dioxane/H2O (4:1).
b
c
Determined from the absorption intensity at 240–320 nM , after separation of
Isolated as a mixture with 6 by silica gel chromatography.
Bis-coupling product was not observed.
ND: not determined.
Performed at 75 °C.
Performed at 70 °C.
An inseparable 3:1 mixture of 6i/1.
d
the crude reaction mixture by LC.
c
e
1.1 equiv of phenylboronic acid was used.
Microwave heating.
Conventional heating.
d
f
e
g
h

H. Yang / Tetrahedron Letters 50 (2009) 3081–3083
3083
4. For recent examples, see: (a) Yang, Y.-Y.; Shou, W.-G.; Chen, Z.-B.; Hong, D.;
Wang, Y.-G. J. Org. Chem. 2008, 73, 3928–3930; (b) Gilmore, C. D.; Allan, K. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558–1559; (c) Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 4764–
4766; (d) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179–5182.
5. Alvarez, M.; Joule, J. A. Sci. Synth. 2005, 15, 661–838.
6. (a) Bartmann, W.; Konz, E.; Rueger, W. Synthesis 1988, 9, 680–683; (b) Renger,
B.; Konz, E.; Rueger, W. Synthesis 1988, 9, 683–685; (c) Lerch, U.; Granzer, E.
Ger. Offen. DE 2314985, Mar 26, 1973; Chem. Abstr. 1975, 82, 16836.
7. For an excellent review on lithiation of halogenated aryl and heteroaryl
compounds, see: Schlosser, M. Eur. J. Org. Chem. 2001, 21, 3975–3984.
8. Palladium catalyzed cross-coupling reactions of 2, or its zinc derivative, with
iodobenzene were not successful.
OCH3
Ph
N
Ph
N
Ph
Cl
Cl
Cl
b
a
N
N
92%
N
73%
6a
9
8
N
N
Scheme 2. Synthesis of climiqualine 8 and its derivative. Reagents and conditions:
(a) NaH, imidazole, DMF, 60 °C; (b) Pd(OAc)2, XPHOS, K3PO4, 4-methoxyphenylbo-
ronic acid, THF, 85 °C.
9. The identity of the major product was confirmed by comparison with an
authentic sample of 4a.
10. Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818–
11819.
readily participated in Suzuki cross-coupling reaction with 4-
methoxyphenyl boronic acid to afford 9 in excellent yield (92%).
Similarly, this nucleophilic aromatic substitution/Suzuki cross-
coupling sequence could be applied to 3a–d, 6a–c, and 6e–h to
prepare a variety of other 1,3,4-trisubstituted isoquinolines.
In summary, we report a facile route to 1,3,4-trisubstituted iso-
quinolines from commercially available 1,3-dichloroisoquinoline 1.
A key step in the process is the direct lithiation of 1 at C-4, and the
reaction of the so-produced lithium species 2 with various electro-
philic reagents to produce diverse 4-substituted-1,3-dichloroiso-
quinolines.11 The 4-iodo compound 3e obtained in this way,
readily participated in Suzuki cross-coupling reactions to produce
various 4-aryl-1,3-dichloroisoquinolines,12 which could be trans-
formed into 4-aryl-isoquinoline derivatives bearing different sub-
stituents at C-1 and C-3.
11. A representative procedure—The preparation of compound 3e: To a solution of
1,3-dichloroisoquinoline 1 (5 g, 25.3 mmol) in THF (400 mL) at ꢀ78 °C was
added LDA (1 M in THF, 27.5 mL, 27.5 mmol) drop-wise. The resulting orange
solution was stirred at ꢀ78 °C for 15 min and quenched by cannulating to a
solution of iodine (12.7 g, 50 mmol) in THF (100 mL) at room temperature. The
reaction mixture was stirred at room temperature overnight and then
quenched with 10% aqueous Na2S2O3. The mixture was further diluted with
saturated aqueous NaHCO3. The organic layer was separated and the aqueous
layer was extracted with EtOAc (3ꢁ). The combined organic layers were dried
(MgSO4), filtered, and concentrated. The residue was dissolved in CH2Cl2,
filtered through a short pad of silica gel with 25% EtOAc in hexane as eluent to
give crude 3e as a pale yellow powder, which upon trituration from CH2Cl2/
hexane afforded 7.3 g of 3e (containing about 5% of 1, 85% yield,) as a off-white
powder. The product was further purified by recrystallization from 8/1 hexane/
CH2Cl2 to give an analytically pure sample. Mp: 129–131 °C; 1H NMR (CDCl3,
500 MHz): d 8.27 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.83 (t, J = 7.0 Hz,
1H), 7.72 (t, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d 151.4, 148.1, 141.2,
133.6, 132.5, 129.4, 127.1, 125.7, 97.2; IR (KBr film): 3431, 1609, 1535, 1478,
1432, 1349, 1297, 1248, 1183, 1150, 1128, 1035, 982, 897, 848, 769, 757, 713,
649, 616 cmꢀ1; HRMS calcd for C9H5Cl2IN [M+H]+: 323.8838. Found: 323.8835.
Anal. Calcd for C9H4Cl2IN: C, 33.37; H, 1.24; N, 4.32. Found: C, 33.61; H, 1.15; N,
4.27.
Acknowledgments
The author thanks Eric Sjogren for his inspiration and encour-
agement of this work, Joseph Muchowski for helpful discussions
and revision of this manuscript, and Kate Comstock for high-reso-
lution mass spectroscopy measurement.
12. Selected spectroscopic data—Compound 6a: Mp: 93–95 °C; 1H NMR (CDCl3,
400 MHz): d 8.40–8.35 (m, 1H), 7.70–7.64 (m, 2H), 7.57–7.46 (m, 4H), 7.36–
7.33 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 149.9, 142.0, 138.9, 134.9, 131.9,
131.4, 130.1, 128.7, 128.5, 128.3, 126.5, 126.0, 125.8; IR (KBr film): 3430, 1653,
1615, 1560, 1547, 1502, 1436, 1384, 1322, 1265, 1146, 1117, 984, 861, 771,
;
703, 631, 620 cmꢀ1 MS calcd for C15H9Cl2N [M+H]+: 274. Found: 274.
References and notes
Compound 8: Mp: 166–169 °C; 1H NMR (CDCl3, 300 MHz): d 8.14 (t, J = 1 Hz,
1H), 8.11–8.07 (m, 1H), 7.72–7.51 (m, 7H), 7.40–7.37 (m, 2H), 7.32 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 147.1, 142.4, 139.9, 137.8, 135.0, 131.9, 131.8, 130.1,
128.8, 128.6, 128.4, 126.3, 124.5, 121.3, 120.3; IR (KBr film): 3138, 1614, 1552,
1503, 1480, 1414, 1333, 1259, 1235, 1172, 1144, 1103, 1074, 1035, 972, 863,
828, 764, 702, 684, 672, 660, 615 cmꢀ1; HRMS calcd for C18H13ClN3 [M+H]+:
306.0793. Found: 306.0790; Anal. Calcd for C18H12ClN3: C, 70.71; H, 3.96; N,
13.74. Found: C, 70.05; H, 3.87; N, 13.68. Compound 9: Mp: 170–172 °C; 1H
NMR (DMSO-d6, 300 MHz): d 8.33 (t, J = 1.1 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H),
7.87 (t, J = 1.2 Hz, 1H), 7.85–7.72 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.52–7.43 (m,
3H), 7.34–7.30 (m, 4H), 7.25 (t, J = 1.0 Hz, 1H), 6.80–6.74 (m 2H), 3.60 (s, 3H);
13C NMR (DMSO-d6, 125 MHz) d 158.7, 147.7, 147.0, 138.1, 138.0, 136.5, 131.6,
131.5, 131.4, 130.8, 130.2, 129.0, 128.7, 128.3, 127.8, 125.5, 124.2, 121.0, 120.6,
113.0, 55.0; IR (KBr film): 3052, 1607, 1569, 1515, 1471, 1409, 1331, 1297,
1. Bentley, K. W.. In The Isoqunoline Alkaloids; Hardwood Academic: Amsterdam,
1998; Vol. 1.
2. For recent examples, see: (a) Vasdev, N.; LaRonde, F. J.; Woodgett, J. R.; Garcia,
A.; Rubie, E. A.; Meyer, J. H.; Houle, S.; Wilson, A. A. Bioorg. Med. Chem. 2008, 16,
5277–5284; (b) Yoon, T.; De Lombaert, S.; Brodbeck, R.; Gulianello, M.;
Chandrasekhar, J.; Horvath, R. F.; Ge, P.; Kershaw, M. T.; Krause, J. E.; Kehne, J.;
Hoffman, D.; Doller, D.; Hodgetts, K. J. Bioorg. Med. Chem. Lett. 2008, 18, 891–
896; (c) Trotter, B. W.; Nanda, K. K.; Kett, N. R.; Regan, C. P.; Lynch, J. J.; Stump,
G. L.; Kiss, L.; Wang, J.; Spencer, R. H.; Kane, S. A.; White, R. B.; Zhang, R.;
Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.; Hartman, G. D.;
Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954–6957; (d) Örtqvist, P.; Peterson, S.
D.; Åkerblom, E.; Gossas, T.; Sabnis, Y. A.; Fransson, R.; Lindeberg, G.; Danielson,
U. H.; Karlén, A.; Sandström, A. Bioorg. Med. Chem. 2007, 15, 1448–1474.
3. (a) Durola, F.; Sauvage, J. P.; Wenger, O. S. Chem. Commun. 2006, 171–173; (b)
Sweetman, B. A.; Müller, H.; Guiry, P. J. Tetrahedron Lett. 2005, 46, 4643–4646;
(c) Ford, A.; Sinn, E.; Woodward, S. J. Chem. Soc., Perkin Trans. 1 1997, 927–934.
1248, 1176, 1072, 1033, 968, 839, 774, 707, 672 cmꢀ1
; HRMS calcd for
C25H20N3O [M+H]+: 378.1601. Found: 378.1595. Anal. Calcd for C25H19N3O: C,
79.55; H, 5.07; N, 11.13. Found: C, 79.22; H, 5.00; N, 11.16.