An efficient synthesis of 1,6- and 1,7-dibromo-3-aminoisoquinolines: versatile templates for the preparation of functionalized isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2006.11.035

An efficient synthetic route to 1,6- and 1,7-dibromo-3-aminoisoquinoline was devised. These intermediates served as ideal templates for the preparation of 3-aminoisoquinoline analogues functionalized at C(6) or C(7).

Full text of DOI:10.1016/j.tetlet.2006.11.035

Tetrahedron Letters 48 (2007) 487–489
An efficient synthesis of 1,6- and
1,7-dibromo-3-aminoisoquinolines: versatile templates
for the preparation of functionalized isoquinolines
Mike Frohn,* Roland W. Burli, Bobby Riahi and Randall W. Hungate
¨
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA
Received 14 October 2006; accepted 6 November 2006
Available online 1 December 2006
Abstract—An efficient synthetic route to 1,6- and 1,7-dibromo-3-aminoisoquinoline was devised. These intermediates served as ideal
templates for the preparation of 3-aminoisoquinoline analogues functionalized at C(6) or C(7).
ꢀ 2006 Elsevier Ltd. All rights reserved.
Isoquinolines are widely known elements in natural
products as well as in agents with potential therapeutic
utility.1 In the context of a medicinal chemistry pro-
gram, we were interested in preparing a series of 1-
oxo-3-amino- and 1,3-diaminoisoquinoline derivatives.
For this, we required efficient access to large quantities
of isoquinolines that could serve as scaffolds amenable
to derivatization at multiple sites, particularly on the
benzene ring. Since electrophilic substitution of isoquin-
olines at positions C(5)–C(8) has proven difficult,2 rela-
tively few 1-oxo-3-amino-, and 1,3-diaminoisoquinoline
derivatives have been reported bearing carbon-based
substituents at these positions.3 Therefore, we focused
on the construction of compounds carrying a single
halide function on the benzene ring, anticipating that
transition-metal catalyzed reactions would render easy
access to these compounds. In particular, dibromoiso-
quinolines 1 and 2 (Fig. 1) were thought to be ideal
intermediates since these would allow diversification at
three separate sites through semi-orthogonal transfor-
mations: nucleophilic aromatic substitution (SNAr) at
C(1), electrophilic functionalization of the 3-amino
group and transition-metal catalyzed reactions at either
C(6) or C(7).
electrophilic
functionalization
R1
R2
NH2
6
7
transition-metal
catalyzed reaction
N
SNAr
1
Br
1: R1 = Br, R2 = H
2: R1 = H, R2 = Br
Figure 1. 1,6- and 1,7-Dibromo-3-aminoisoquinoline templates.
develop a synthetic route to access bromo-substituted
dinitriles 8 and 9 in multigram quantities (Scheme 1).
We first attempted to apply a known route for the
synthesis of similarly substituted compounds.5 Unfortu-
nately, it proved somewhat difficult to produce large
quantities of these particular bromo-substituted di-
nitriles following this method. Benzylic bromination of
4-bromo-2-methylbenzonitrile (3) gave a mixture of
bromide 4 and dibrominated material (LC/MS and
TLC analysis). Because the dibromide side product
was difficult to remove by recrystallization, we were
forced to perform a tedious column chromatography
for purification (48% isolated yield).
Substituted 1-bromo-3-aminoisoquinolines have been
prepared from the corresponding dinitrile by treatment
with HBr in acidic (AcOH) or nonpolar (Et2O or benz-
ene) solvents.4 Therefore, our first objective was to
As this approach seemed impractical for our purposes,
we next focused on installation of the benzylic nitrile
through an SNAr approach. Treatment of 4-bromo-2-
fluorobenzonitrile 5 with the sodium anion of methyl
cyanoacetate at 90 ꢁC proceeded smoothly to give ester
7 in 74% yield.6 Optimization of conditions that
*
Corresponding author. Tel.: +1 805 447 2761; e-mail: mfrohn@
amgen.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.035

488
M. Frohn et al. / Tetrahedron Letters 48 (2007) 487–489
Br
Br
i
Br
CN
CN
3
4
CO2Me
CN
R1
R2
NH2
R1
R2
F
R1
R2
R1
R2
iii
ii
CN
CN
v
N
CN
CN
Br
5: R1 = Br, R2 = H
6: R1 = H, R2 = Br
7: R1 = Br, R2 = H
8: R1 = Br, R2 = H
9: R1 = H, R2 = Br
1: R1 = Br, R2 = H
2: R1 = H, R2 = Br
iv
Scheme 1. Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, CCl4, 48%; (ii) methyl cyanoacetate, NaH, DMSO, 90 ꢁC, 74% for 7;
(iii) 2 equiv H2O, DMSO, 115 ꢁC, 93% for 8; (iv) methyl cyanoacetate, NaH, DMSO, 90 ꢁC; then H2O, reflux (91% for 8, 81% for 9); (v) HBr (g),
dichloroacetic acid, 0 ꢁC to room temperature (59% for 1, 73% for 2).
promoted smooth decarboxylation of 7 to give dinitrile
8 proved elusive; for example, heating the ester in AcOH
to 120 ꢁC resulted in ester hydrolysis exclusively.7 Basic
conditions (NaOH, KOH, LiOH)8 initiated nitrile
hydrolysis competitively with decarboxylation. In
addition, nucleophilic decarboxylation under Krapcho
conditions (NaCN, LiCl, or NaCl in wet DMSO)9 gave
multiple products. Finally, it was found that simply
heating the ester in wet DMSO (2 equiv H2O) at
115 ꢁC for 1 h in the absence of additional salt yielded
decarboxylation to dinitrile 8 in 93% yield.10
by Johnson and Nasutavicus4 for similar intermediates
gave isoquinoline 1. However, we found that the use
of HBr in acetic acid produced inconsistent results.
Most notably, various amounts of a 3-acetamide
byproduct were observed.12 Alternatively, addition of
HBr (g) to a solution of 8 in benzene or Et2O4 was found
to be impractical.13
To solve this problem, we screened a variety of acidic
solvents, which identified HBr (g) in dichloroacetic acid
as a suitable condition to produce 1,6-dibromo-3-
aminoisoquinoline free of acetylated byproduct.14 These
reaction conditions allowed the isolation of 1 (59%) and
2 (73%) on 10–20 g scale.15 Access to such quantities of
dibromoisoquinoline intermediates allowed efficient
synthesis of multifunctional isoquinoline derivatives
(Scheme 2, Table 1).16
Next, we attempted to combine the two steps into a one-
pot procedure. Indeed, we found that upon completion
of the SNAr addition (followed by LC/MS), adding
water as co-solvent and heating to reflux provided clean
decarboxylation, enabling the isolation of 8 in 91% yield
directly from 5.11 Analogous treatment of benzonitrile 6
gave 9 in slightly lower yield (81% yield for the two
chemical steps).
Table 1. Isoquinoline analogues prepared via dibromo- intermediates
1 and 2
With an efficient synthesis of the dinitriles accomplished,
our attention turned to isoquinoline formation. Treat-
ment of dinitrile 8 with 30% HBr in AcOH as described
R3
R4
NHR2
N
R1
Entry R1
1
R2 R3
Ac Ph
R4
H
NH2
NH2
iii or iv
i or ii
Br
Br
N
N
N
N
N
Br
R1
2
3
Ac
H
TMS
NHR2
NHR2
v, vi, or vii
Br
R3
Ac
Ms
Ac
H
Ph
N
N
R1
R1
O
4
5
H
N
Scheme 2. Reagents and conditions: (i) piperidine, 1,4-dioxane,
170 ꢁC, microwave irradiation, 86–90%; (ii) phenethyl alcohol, NaH,
DMF, 42%; (iii) acetic anhydride, NEt3, 89–94%; (iv) methanesulfonyl
chloride, pyridine/CH2Cl2 (1:1), 81%; (v) cat. Pd(PPh3)4, cat. CuI,
TMS–acetylene, NEt3, 80 ꢁC, 94% for both reactions; (vi) cat.
Pd2(dba)3, cat. P(t-Bu)3, KF, boronic acid, 65 ꢁC, 1,4-dioxane, 70–
87%; (vii) cat. Pd2(dba)3, cat. P(t-Bu)3, N,N-dicyclohexylmethylamine,
methyl acrylate, 1,4-dioxane, 80 ꢁC, 87%.
O
O
H
H
TMS
S
O
6
Ac

M. Frohn et al. / Tetrahedron Letters 48 (2007) 487–489
489
11. Procedure for the preparation of 4-bromo-2-(cyano-
methyl)benzonitrile (8). Methyl cyanoacetate (22.1 mL,
250 mmol) was slowly added to a suspension of sodium
hydride (10.0 g, 250 mmol, 60% dispersion in mineral oil)
in DMSO (75 mL) at 0 ꢁC. The mixture was stirred for
30 min at room temperature before 4-bromo-2-fluoro-
benzonitrile (25.0 g, 125 mmol) was added as a solution in
DMSO (125 mL) via cannula. The yellow solution was
heated to 90 ꢁC for 2 h, H2O (450 mL) was added, and the
reaction was heated to reflux for 8 h. The mixture was
cooled to 5 ꢁC and 0.1 N HCl (250 mL) was added. After
stirring at 5 ꢁC for 30 min, the resulting precipitate was
filtered, washed with water and dried to afford 4-bromo-2-
As expected, the C(1) bromide could be selectively dis-
placed via SNAr displacement by an amine (microwave
irradiation, entries 1–4)17 or an alkoxide anion (ambient
temperature, entries 5 and 6).18 Next, the 3-amino group
was converted to an acetamide (Ac, entries 1–3, 5 and 6)
or a methyl sulfonamide (Ms, entry 4).5a,b Finally, the
C(6) and C(7) bromides participated in Sonogashira
(entries 2 and 5),19 Heck (entry 4),20 and Suzuki
couplings (entries 1, 3 and 6)21 to give good yields of
substituted isoquinolines.
In conclusion, an efficient synthetic route for the prepa-
ration of 1,6- and 1,7-dibromo-3-aminoisoquinolines in
multigram quantity is presented. As demonstrated in
Scheme 2 and Table 1, these compounds serve as versa-
tile intermediates for the synthesis of multisubstituted 1-
oxo-3-amino- and 1,3-diaminoisoquinoline derivatives
with various substituents at C(6) and C(7). This general
strategy should be applicable for the preparation of
other multisubstituted 3-aminosoquinolines.
1
(cyanomethyl)benzonitrile (25.17 g, 91% yield). H NMR
(400 MHz, CDCl3) d ppm 7.85 (1H, s), 7.65 (1H, d,
J = 8.4 Hz), 7.57 (1H, d, J = 8.2 Hz), 3.99 (2H, s); 13C
NMR (100 MHz, CDCl3) d ppm 135.21, 134.14, 132.39,
132.34, 128.88, 115.84, 115.25, 110.98, 22.35.
12. In one case, small amounts of nitrile hydrolysis were also
observed (10–15% by LC/MS analysis).
13. Preliminary experiments showed that continuous addition
of HBr (g) was required for the reaction to proceed.
14. Minor amounts of nitrile hydrolysis was also observed.
15. Procedure for the preparation of 1,6-dibromoisoquinolin-
3-amine (1). HBr (g) was bubbled through dichloroacetic
acid (100 mL) at 0 ꢁC for 10 min. 4-Bromo-2-(cyano-
methyl)benzonitrile (25.0 g, 113 mmol) was added and the
mixture was stirred at 0 ꢁC for 15 min, warmed to room
temperature and stirred for 1 h. The yellow suspension was
cooled back to 0 ꢁC and Et2O (100 mL) was added slowly.
After stirring at 0 ꢁC for 30 min, the precipitate was filtered,
washed with Et2O (200 mL) and dried. The solid was taken
up in H2O (100 mL) and 1 N NaOH was added until the pH
reached 12. The resulting suspension was stirred for 15 min,
the solid was filtered and then dried. This solid was
suspended in CHCl3 (2 L) and the resulting white precip-
itate was filtered off. The filtrate was concentrated under
vacuum to give 1,6-dibromoisoquinoline-3-amine as a
yellow solid (20.0 g, 59% yield). 1H NMR (400 MHz,
CDCl3) d ppm 7.89 (1H, d, J = 1.8 Hz), 7.78 (1H, d,
J = 9.0 Hz), 7.34 (1H, dd, J = 9.0, 2.0 Hz), 6.58 (1H, s), 6.49
(2H, s); 13C NMR (100 MHz, CDCl3) d ppm 156.23, 142.71,
141.40, 130.03, 126.62, 126.15, 125.16, 119.73, 96.63.
16. All compounds in Table 1 were characterized by 1H
NMR, 13C NMR and high resolution mass spectrometry
(to within 4.0 ppm). All were >95% pure as analyzed by
LC/MS (Phenomenex, MAX RP, 4 lm, 50 · 2.0 mm,
1 mL/min, (A) 0.1% TFA in H2O, (B) 0.1% TFA in
MeCN, 10–100% B in 10 min).
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´
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