Rapid synthesis of 3-aminoisoquinoline-5-sulfonamides using the buchwald-hartwig reaction

Article abstract of DOI:10.1055/s-0028-1083336

A rapid synthesis of previously unreported 3-aminoiso- quinoline-5- sulfonamides related to known kinase inhibitors was achieved by a two-step sequential reaction of 3-chloro-5-isoquino- linesulfonyl chloride with amines. Palladium-catalysed C-N bond form

Full text of DOI:10.1055/s-0028-1083336

PAPER
561
Rapid Synthesis of 3-Aminoisoquinoline-5-sulfonamides Using the
Buchwald–Hartwig Reaction
R
apid Synthesis of
i
3-A
m
c
o
line-5-sulfon
l
amide
s
as Proisy, Stephen Taylor, Andrew Nelson, Ian Collins*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
Fax +44(208)7224216; E-mail: ian.collins@icr.ac.uk
Received 19 August 2008
Dedicated to Professor Andrew B. Holmes on the occasion of his 65th birthday
O2
S
O2
Abstract: A rapid synthesis of previously unreported 3-aminoiso-
quinoline-5-sulfonamides related to known kinase inhibitors was
achieved by a two-step sequential reaction of 3-chloro-5-isoquino-
linesulfonyl chloride with amines. Palladium-catalysed C–N bond
formation was used to introduce arylamine, alkylamine, and unsub-
stituted amino groups at C-3 of the isoquinoline.
S
R
N
NH
N
N
H
1, fasudil
N
Key words: palladium catalysis, amination, isoquinolines, sulfon-
amides
N
H
Br
Cl
2, H-89
H
N
O
Isoquinolines are an important class of heterocyclic com-
pounds widely represented in natural products, and which
show a range of biological activities.1 The isoquinoline bi-
cycle has been widely used in the design of biologically
active molecules. In particular, isoquinoline-5-sulfon-
amides have been researched as a scaffold for new inhib-
itors of kinase enzymes for the treatment of human
disease.2 For example, the rho kinase inhibitor fasudil (1,
Figure 1) is approved for the treatment of cerebral vaso-
spasm.3 Other isoquinoline-5-sulfonamides have been in-
vestigated as inhibitors of kinases involved in the
deregulated intracellular signalling leading to cancer, for
example, H-89 (2).2,4,5 We have described the preparation
of isoquinoline-5-sulfonamide inhibitors of protein kinase
B, such as 3, as potential anticancer agents.5 As part of a
program to develop novel kinase inhibitors, we required a
straightforward parallel synthesis6 of previously unreport-
ed 3-(alkylamino)- and 3-(arylamino)isoquinoline-5-sul-
fonamides. The introduction of amino functionality at C-
3 of isoquinolines related to 1–3 is of particular interest as
hydrogen bonding to the kinase active site by this region
of the inhibitors is a key determinant of their biological
activity.7
NH
3, CCT077933
Figure 1 Representative isoquinoline-5-sulfonamide kinase inhibi-
tors
best of our knowledge, palladium-catalysed C–N bond
formation has not previously been reported for the intro-
duction of a range of substituted amines at C-3 of 3-ha-
loisoquinolines. In contrast, C–C bond formation to 3-
haloisoquinolines through palladium-catalysed Suzuki,
Stille, or Sonogashira reactions is better precedented.12 In
this paper, we describe the synthesis of various substituted
3-aminoisoquinoline-5-sulfonamides by sequential reac-
tion of the useful bifunctional intermediate 3-chloroiso-
quinoline-5-sulfonyl chloride (5) with cyclic amines,
followed by Buchwald–Hartwig amination13 at C-3 of the
isoquinoline.
The synthesis of our isoquinoline derivatives started with
the introduction of the chlorosulfonyl group at the C-5 po-
sition of 3-chloroisoquinoline (4) (Scheme 1). The start-
ing material 4 was prepared in good yield by selective
reduction of 1,3-dichloroisoquinoline14 with red phospho-
rous.15 Regioselective sulfonylation of 4 was achieved by
high temperature reaction with neat chlorosulfonic acid.16
Depending on the functionalities present on the isoquino-
line, isoquinoline-5-sulfonic acids or isoquinoline-5-sul-
fonyl chlorides have been obtained from this reaction.16 In
the case of 3-chloroisoquinoline (4), the novel chlorosul-
fonyl derivative 5 was obtained in good yield without any
formation of the hydrolysed product.
Various synthetic routes have been developed to access
polysubstituted isoquinolines.8 However, while nucleo-
philic substitution of halides by amines at the C-1 position
of isoquinolines has been extensively reported, the equiv-
alent introduction of amines at the C-3 position has fewer
examples. Existing strategies involve intramolecular cy-
clisation,9 or intermolecular reactions requiring the pres-
ence of a strongly activating 2-substituent on the
isoquinoline10 and harsh reaction conditions.10,11 To the
Preparation of the 3-chloroisoquinoline-5-sulfonamides
6–8 using various cyclic amines proceeded in satisfactory
yields, allowing a first degree of substitution to be intro-
duced. The amines (morpholine, piperidine, and N-Boc-
piperazine) were chosen in order to assess their compati-
SYNTHESIS 2009, No. 4, pp 0561–0566
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083336; Art ID: P10108SS
© Georg Thieme Verlag Stuttgart · New York

562
N. Proisy et al.
PAPER
O2
S
Table 1 Screen of Reagents for Buchwald–Hartwig Coupling of
Aniline to 6
R
N
b
X
Entry Reagentsa
Conversion
to 9ab
69–84%
Cl
N
N
Cl
1
2
Pd(OAc)2, BINAP, t-BuONa
100%
4 R = H
6 X = O
7 X = CH2
8 X = NBoc
a
78%
Pd(OAc)2,biphenyl-2-yl-di-tert-butylphosphine, 0%
t-BuONa
5 R = SO2Cl
Scheme 1 Reagents and conditions: a) ClSO3H, 160 °C; b) amine,
Et3N, CH2Cl2, r.t.
3
4
Pd2(dba)3, BINAP, LiHMDS
Pd2(dba)3, Xantphos, Cs2CO3
100%
0%
a All reactions conducted in toluene at 130 °C (microwave) for 30
min.
bility with subsequent reaction at the C-3 position of the
isoquinoline, and for their similarity to preferred substitu-
ents in kinase inhibitors related to 1.2–5 The regiochemis-
try of the initial sulfonylation was confirmed from the 1H
NMR spectrum of sulfonamide 6 (Figure 2). The distinc-
tive singlet at d = 9.18 for H-1 of the isoquinoline showed
an NOE to H-8, while the singlet at d = 8.59 correspond-
ing to H-4 showed an NOE to the protons adjacent to ni-
trogen on the morpholine ring.
b Determined by HPLC-MS analysis of the crude reaction mixture.
O2
S
O2
S
R1
Cl
R1
R2NH2, t-BuONa
Pd(OAc)2, BINAP
R2
130 °C, 30 min
(MW)
N
N
N
H
3–74%
6–8
9–11
O
O
Equation 1 C–N bond formation to 3-chloroisquinoline-5-sulfon-
amides 6–8. See Table 2 for products and yields.
O
N
S
Ha
Ha
δ 8.24, d
J = 8.2 Hz
H4
H8
Table 2 Buchwald–Hartwig Coupling of Alkyl and Aryl Amines to
the 3-Chloroisoquinoline-5-sulfonamides 6–8a
δ 8.59, s
Cl
H1
N
δ 9.18, s
6
6 → 9a–f
7 → 10a–f
8 → 11a–fb
Figure 2 Regiochemistry of sulfonylation reaction confirmed by 1H
NMR and NOE determination
O
NH
R1
R2
N
N
N
While intramolecular cyclisation of amines to 3-chloro-
isoquinolines has been achieved in good yields,9 harsh
reaction conditions are generally needed when no addi-
tional activating functionality is present on the heterocy-
clic aromatic ring, for example, 150 °C, 72 hours.11a We
first attempted nucleophilic substitution of the 3-chloro-
isoquinoline-5-sulfonamides 6–8 with aniline using var-
ious bases with heating, for example, Et3N, NMP, 150 °C
(microwave), 30 minutes; NaH, DMF, 60 °C (micro-
wave), 120 minutes. Under these conditions, no formation
of product was observed and the starting materials were
recovered unchanged. However, a limited catalyst and
ligand screen of potential Buchwald–Hartwig
conditions13 to achieve the introduction of aniline to 6 was
successful (Table 1). Some sensitivity to the catalyst and
base combination was observed. Although Pd2(dba)3,
BINAP [2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl], and
LiHMDS (entry 3) gave complete conversion of starting
material, the product 9a proved more difficult to isolate
from this mixture. Thus, palladium acetate, BINAP, and
sodium tert-butoxide (entry 1) were selected as the most
suitable reagent combination, and these conditions were
used for the functionalisation of 6–8 with a set of aryl and
alkyl amines (Equation 1, Table 2).
Ph
9a 15%
9b 54%
9c 61%
9d 3%
10a 25%
10b 61%
10c 68%
10d 74%
10e 35%
10fc 33%
11a 18%
11b 53%
11c 60%
11d 62%
11e 18%
11fc 30%
4-MeOC6H4
4-NO2C6H4
PhCH2
n-Bu
9e 4%
H
9fc 48%
a Yields refer to isolated and purified material.
b Yields of free amine following deprotection of piperazine N-Boc us-
ing CF3CO2H in CH2Cl2.
c From coupling of benzophenone imine followed by hydrolysis with
aq HCl.
products were further purified by chromatography as nec-
essary. As shown in Table 2, the yields for the formation
of the disubstituted isoquinolines 9–11 were variable, but
in all cases the standard procedure was successful. Isola-
tion of the morpholine sulfonamides 9d and 9e was
achieved in substantially lower yields than for the corre-
sponding piperidine and piperazine derivatives. This was
principally a result of poor solubility of the morpholine
derivatives 9d and 9e, which led to a reduced efficiency of
isolation and purification. The N-Boc protecting group of
the piperazine derivatives was removed by treatment with
trifluoroacetic acid in dichloromethane following the C–
Reactions were conducted in parallel in an automated mi-
crowave reactor and the crude products were isolated by
solid-phase extraction using acidic resin cartidges. The
Synthesis 2009, No. 4, 561–566 © Thieme Stuttgart · New York

PAPER
Rapid Synthesis of 3-Aminoisoquinoline-5-sulfonamides
563
1H NMR (500 MHz, CDCl3): d = 3.15–3.17 (m, 4 H, CH2), 3.72–
3.74 (m, 4 H, CH2), 7.3 (dd, J = 7.5, 8.2 Hz, 1 H, CH), 8.24 (dd,
J = 8.2, 0.9 Hz, 1 H, CH), 8.39 (d, J = 7.5 Hz, 1 H, CH), 8.59 (br s,
1 H), 9.18 (s, 1H).
13C NMR (125 MHz, CDCl3): d = 45.6, 66.2, 117.3, 126.0, 127.8,
131.3, 133.9, 134.0, 135.2, 148.6, 153.3.
N bond formation and the products 11a–f were isolated as
the free amines. Representative electron-rich and elec-
tron-poor anilines gave satisfactory yields for the C–N
bond formation, as did benzylamine. The introduction of
n-butylamine to the three scaffolds, while lower yielding,
showed the sequence could accommodate nonaromatic
amines. An unsubstituted 3-amino group was introduced
into the molecules through the coupling of benzophenone
imine as an ammonia equivalent,17 followed by hydrolysis
in situ with hydrochloric acid prior to isolation.
HRMS-TOF: m/z [M + H]+ calcd for C13H14ClN2O3S: 313.04082;
found: 313.04106.
3-Chloro-5-(piperidin-1-ylsulfonyl)isoquinoline (7)
Yield: 73%; mp 157–159 °C; HPLC: tR = 4.56 min.
1H NMR (500 MHz, CDCl3): d = 1.46–1.64 (m, 6 H, CH2), 3.17–
3.19 (m, 4 H, CH2), 7.71 (dd, J = 7.4, 8.1 Hz, 1 H), 8.21 (d, J = 8.2
Hz, 1 H), 8.40 (dd, J = 1.2, 7.4 Hz, 1 H), 8.59 (br s, 1 H), 9.17 (s, 1
H).
13C NMR (125 MHz, CDCl3): d = 23.5, 25.4, 46.3, 117.6, 126.0,
127.8, 132.6, 133.4, 133.8, 134.8, 148.3, 153.2.
In summary, the straightforward parallel synthesis of a
small set of previously unreported 3-aminoisoquinoline-
5-sulfonamides related to known kinase inhibitors was
achieved by a two-step sequential reaction of 3-chloro-5-
isoquinolinesulfonyl chloride with various amines. Palla-
dium-catalysed C–N bond formation was used to intro-
duce arylamine, alkylamine, and unsubstituted amino
groups to C-3 of the isoquinoline.
HRMS-TOF: m/z [M + H]+ calcd for C14H16ClN2O2S: 311.0615;
found: 311.0616.
tert-Butyl 4-(3-Chloroisoquinolin-5-ylsulfonyl)piperazine-1-
carboxylate (8)
Yield: 69%; mp 163–165 °C; HPLC: tR = 4.88 min.
1H NMR (500 MHz, CDCl3): d = 1.42 (s, 9 H, CH3), 3.14–3.16 (m,
4 H, CH2), 3.49–3.56 (m, 4 H, CH2), 7.73 (dd, J = 7.1, 8.1 Hz, 1 H),
8.24 (d, J = 8.1 Hz, 1 H), 8.40 (dd, J = 1.2, 8.1 Hz, 1 H), 8.59 (br s,
1 H), 9.19 (s, 1H).
13C NMR (125 MHz, CDCl3): d = 28.3, 43.0, 45.5, 80.6, 117.3,
126.0, 127.8, 131.6, 133.6, 134.0, 135.1, 148.7, 153.4, 154.1.
HRMS-TOF: m/z [M + H]+ calcd for C18H23ClN3O4S: 412.10923;
found: 412.10902.
Reagents and anhyd solvents were obtained from commercial sup-
pliers and used without further purification, unless otherwise noted.
Flash column chromatography was carried out on Merck silica gel
60 (0.015–0.040 mm). Preparative TLC was performed on Mach-
1
erey-Nagel or Analtech precoated silica plates. H and 13C NMR
spectra were recorded at 500 MHz and 126 Hz, respectively, on
Bruker AMX500 spectrometers using an internal deuterium lock.
HPLC-MS analyses were performed on a Micromass LCT/Waters
Alliance 2795 HPLC with a Discovery column from Supelco at a
temperature of 22 °C. A solvent gradient of 10–90% MeOH in 0.1%
aq formic acid was run over 6 min. UV detection was at 254 nm.
Ionisation was by positive or negative ion electrospray and the mo-
lecular weight scan range was 50–1000 Da. HRMS were recorded
on an Agilent 6210 (ToF) mass spectrometer.
Palladium-Catalysed Aminations of Sulfonamides 6,7; N-Phe-
nyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10a); Typi-
cal Procedure
3-Chloroisoquinoline-5-sulfonyl Chloride (5)
A mixture of 7 (0.100 g, 0.320 mmol), Pd(OAc)2 (0.007 g, 0.032
mmol), BINAP (0.060 g, 0.096 mmol), t-BuONa (0.092 g, 0.959
mmol) in toluene (2.1 mL) was stirred under N2 for 5 min at r.t.
Aniline (0.070 mL, 0.735 mmol) was added and the mixture was
heated at 130 °C for 30 min under microwave irradiation. The mix-
ture was purified by ion exchange on SCX-II acidic resin (0.5 g)
eluting with MeOH–CH2Cl2 (1:1), then 2 M NH3 in MeOH. The ba-
sic fractions were combined and concentrated. The crude product
was purified by preparative TLC, eluting with EtOAc–hexanes
(3:7), to give 10a as a yellow solid (0.029 g, 25%); mp 182–183 °C;
HPLC: tR = 4.97 min (Table 1).
3-Chloroisoquinoline (4;15 1.00 g, 6.11 mmol) and ClSO3H (3.6
mL) were stirred at 160 °C under reflux for 22 h. The mixture was
cooled to r.t. and ice was added portionwise to the stirred solution
until effervescence ceased. The mixture was diluted with H2O (20
mL) and stirred at 0 °C for 10 min. The resulting precipitate was
collected and dried in vacuo to give 5 as a tan solid (1.254 g, 78%);
mp 138–139 °C.
1H NMR (500 MHz, CDCl3): d = 7.79 (dd, J = 7.6, 8.1 Hz, 1 H),
8.39 (d, J = 8.1 Hz, 1 H), 8.60 (dd, J = 7.6, 1.1 Hz, 1 H), 8.62 (d,
J = 1.1 Hz, 1 H), 9.27 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 116.4, 125.9, 127.7, 132.3, 134.1,
1H NMR (500 MHz, CDCl3): d = 1.42–1.50 (m, 6 H, CH2), 3.10 (t,
J = 5.5 Hz, 4 H, CH2), 7.05 (s, 1 H, NH), 7.11–7.14 (m, 1 H, CH),
7.29–7.35 (m, 1 H, CH), 7.38–7.41 (m, 4 H, CH), 7.92 (s, 1 H, CH),
8.01 (d, J = 8.1 Hz, 1 H, CH), 8.24 (dd, J = 7.3, 1.2 Hz, 1 H, CH),
9.00 (s,1 H, CH).
136.3, 138.1, 149.7, 153.6.
HRMS-TOF: m/z [M + H]+ calcd for C9H5Cl2NO2S: 261.94908;
found: 261.94894.
13C NMR (125 MHz, CDCl3): d = 23.6, 25.2, 46.1, 96.3, 120.9,
121.4, 123.6, 124.8, 129.4, 130.6, 133.8, 134.7, 135.0, 140.0, 152.9,
153.7.
HRMS-TOF: m/z [M + H]+ calcd for C20H22N3O2S: 368.14272;
found: 368.14235.
Sulfonamides 6–8; 4-(3-Chloroisoquinolin-5-ylsulfonyl)mor-
pholine (6); Typical Procedure
Morpholine (0.150 mL, 1.71 mmol) was added dropwise to a mix-
ture of 5 (0.300 g, 1.14 mmol) and Et3N (0.240 mL, 1.71 mmol) in
CH2Cl2 (4 mL). The mixture was stirred at r.t. for 30 min, and then
left to stand for a further 30 min. The crude mixture was partitioned
between aq NaHCO3 (15 mL) and CH2Cl2 (15 mL). The organic
layer was dried (MgSO4) and the solvent was evaporated in vacuo.
The crude product was purified by flash chromatography on silica
gel, eluting with EtOAc–hexanes (3:7), to give 6 as a colourless sol-
id (0.301 g, 84%); mp 189–190 °C; HPLC: tR = 3.94 min.
5-(Morpholinosulfonyl)-N-phenylisoquinolin-3-amine (9a)
Mp 232–233 °C; HPLC: tR = 2.40 min.
1H NMR (500 MHz, CDCl3): d = 2.94–3.17 (m, 4 H), 3.50–3.66 (m,
4 H, CH2), 6.84 (s, 1 H, CH), 7.36 (dd, J = 7.7, 15.1 Hz, 1 H, CH),
7.38–7.46 (m, 4 H, CH), 7.87 (s, 1 H, CH), 8.04 (d, J = 8.3 Hz, 1 H,
CH), 8.25 (d, J = 8.3 Hz, 1 H, CH), 9.03 (s, 1 H, CH).
Synthesis 2009, No. 4, 561–566 © Thieme Stuttgart · New York

564
N. Proisy et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 45.3, 66.1, 95.7, 121.3, 121.4,
J = 8.8 Hz, 2 H, CH), 7.25–7.36 (m, 3 H, CH), 7.65 (s, 1 H, CH),
7.98 (d, J = 8.1 Hz, 1 H, CH), 8.22 (d, J = 7.3 Hz, 1 H, CH), 8.96 (s,
1 H, CH).
13C NMR (125 MHz, CDCl3): d = 23.6, 25.2, 46.1, 55.6, 95.3,
114.7, 121.0, 124.5, 124.6, 130.5, 132.6, 133.8, 134.8, 135.0, 152.8,
155.0, 156.9.
123.9, 124.8, 129.3, 129.4, 134.4, 134.7, 135.4, 139.8, 153.2, 153.9.
HRMS-TOF: m/z [M + H]+ calcd for C19H20N3O3S: 370.12199;
found: 370.11665.
N-(4-Methoxyphenyl)-5-(morpholinosulfonyl)isoquinolin-3-
amine (9b)
Mp 208–209 °C; HPLC: tR = 2.36 min.
HRMS-TOF: m/z [M + H]+ calcd for C21H24N3O3S: 398.15329;
found: 398.15398.
1H NMR (500 MHz, CDCl3): d = 3.07–3.08 (m, 4 H, CH2), 3.60–
3.61 (m, 4 H, CH2), 3.84 (s, 3 H, CH3), 6.73 (s, 1 H, NH), 6.97 (d,
J = 8.9 Hz, 2 H, CH), 7.22–7.40 (m, 3 H, CH), 7.59 (s, 1 H, CH),
8.01 (d, J = 8.1 Hz, 1 H, CH), 8.23 (d, J = 7.3 Hz, 1 H, CH), 8.98 (s,
1 H, CH).
13C NMR (125 MHz, CDCl3): d = 45.3, 55.6, 66.1, 94.8, 114.8,
120.9, 124.5, 125.0, 129.2, 132.4, 134.4, 134.8, 135.4, 153.1, 155.3,
157.0.
N-(4-Nitrophenyl)-5-(piperidin-1-ylsulfonyl)isoquinolin-3-
amine (10c)
Mp 155–156 °C; HPLC: tR = 2.78 min.
1H NMR (500 MHz, DMSO-d6): d = 1.35–1.53 (m, 6 H, CH2),
3.10–3.12 (m, 4 H, CH2), 7.57 (t, J = 7.7 Hz, 1 H, CH), 7.85–7.92
(m, 2 H, CH), 8.05 (s, 1 H, CH), 8.12-8.21 (m, 3 H, CH), 8.35 (d,
J = 7.7 Hz, 1 H, CH), 9.31 (s, 1 H, CH), 10.34 (s, 1 H, NH).
HRMS-TOF: m/z [M + H]+ calcd for C20H22N3O4S: 400.13255;
found: 400.13286.
13C NMR (125 MHz, DMSO-d6): d = 22.8, 24.9, 46.1, 101.7, 112.3,
116.6, 122.9, 124.8, 125.3, 126.3, 133.5, 134.6, 134.8, 139.5, 152.7,
155.6.
5-(Morpholinosulfonyl)-N-(4-nitrophenyl)isoquinolin-3-amine
(9c)
Mp 269–270 °C; HPLC: tR = 2.64 min.
HRMS-TOF: m/z [M + H]+ calcd for C20H21N4O4: 413.12780;
found: 413.10969.
1H NMR (500 MHz, DMSO-d6): d = 3.08–3.09 (m, 4 H, CH2),
3.60–3.61 (m, 4 H, CH2), 7.58 (t, J = 7.8 Hz, 1 H, CH), 7.89 (d,
J = 9.2 Hz, 2 H, CH), 8.03 (s, 1 H, CH), 8.19–8.24 (m, 3 H, CH),
8.38 (d, J = 7.8 Hz, 1 H, CH), 9.32 (s, 1 H, CH), 10.33 (s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): d = 45.5, 65.4, 101.5, 116.7,
122.9, 124.8, 125.3, 128.9, 133.5, 134.8, 138.2, 139.5, 148.2, 152.0,
152.8.
N-Benzyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10d)
Mp 166–168 °C; HPLC: tR = 4.45 min.
1H NMR (500 MHz, CDCl3): d = 1.34–1.48 (m, 6 H, CH2), 2.91 (t,
J = 5.5 Hz, 4 H, CH2), 4.59 (d, J = 5.6 Hz, 2 H, CH2), 5.44 (t, J = 5.6
Hz, 1 H, NH), 7.23–7.30 (m, 3 H, CH), 7.36–7.37 (m, 2 H, CH),
7.43–7.45 (m, 2 H, CH), 7.94 (d, J = 8.2 Hz, 1 H, CH), 8.19 (dd,
J = 7.2, 1.0 Hz, 1 H, CH), 8.91 (s, 1 H, CH).
HRMS-TOF: m/z [M + H]+ calcd for C19H19N4O5S: 415.10707;
found: 415.10702.
13C NMR (125 MHz, CDCl3): d = 23.5, 25.3, 46.3, 46.8, 93.9,
120.4, 124.1, 127.2, 127.4, 128.7, 129.8, 133.9, 134.8, 135.1, 138.3,
153.0, 156.4.
N-Benzyl-5-(morpholinosulfonyl)isoquinolin-3-amine (9d)
Mp 148–150 °C; HPLC: tR = 4.45 min.
HRMS-TOF: m/z [M + H]+ calcd for C21H24N3O2S: 382.15451;
found: 382.15500.
1H NMR (500 MHz, CDCl3): d = 2.77–2.79 (m, 4 H, CH2), 3.49–
3.51 (m, 4 H, CH2), 4.60 (d, J = 4.4 Hz, 2 H, CH2), 5.53 (br s, 1 H,
NH), 7.25–7.30 (m, 3 H, CH), 7.34–7.37 (m, 2 H, CH), 7.44–7.45
(m, 2 H, CH), 7.98 (dt, J = 8.2, 1.0 Hz, 1 H, CH), 8.13 (dd, J = 7.6,
1.3 Hz, 1 H, CH), 8.93 (br s, 1 H, CH).
13C NMR (125 MHz, CDCl3): d = 45.4, 46.7, 66.1, 93.7, 120.4,
124.0, 127.0, 127.3, 128.5, 128.7, 134.5, 135.1, 135.2, 138.2, 153.1,
156.4.
N-Butyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10e)
Mp 118–119 °C; HPLC: tR = 4.54 min.
1H NMR (500 MHz, CDCl3): d = 0.97 (t, J = 7.5 Hz, 3 H, CH3),
1.43–1.72 (m, 10 H, CH2), 3.17 (t, J = 5.3 Hz, 4 H, CH2), 3.00–3.33
(m, 2 H, CH2), 5.01 (s, 1 H, NH), 7.20 (t, J = 7.5 Hz, 1 H, CH), 7.29
(s, 1 H, CH), 7.91 (d, J = 8.2 Hz, 1 H, CH), 8.16 (dd, J = 7.5, 1.2 Hz,
1 H, CH), 8.86 (s, 1 H, CH).
HRMS-TOF: m/z [M + H]+ calcd for C20H22N3O3S: 313.04082;
found: 313.04106.
13C NMR (125 MHz, CDCl3): d = 13.8, 20.2, 23.6, 25.4, 31.2, 42.5,
46.4, 93.1, 120.0, 123.8, 129.7, 134.1, 134.8, 135.1, 153.0, 156.8.
HRMS-TOF: m/z [M + H]+ calcd for C18H26N3O2S: 348.17402;
found: 348.17492.
N-Butyl-5-(morpholinosulfonyl)isoquinolin-3-amine (9e)
Mp 121–122 °C; HPLC: tR = 4.54 min.
1H NMR (500 MHz, CDCl3): d = 1.00 (t, J = 7.4 Hz, 3 H, CH3),
1.48–1.74 (m, 4 H, CH2), 3.17–3.19 (m, 4 H, CH2), 3.33 (t, J = 7.4
Hz, 2 H, CH2), 3.72 (t, J = 4.7 Hz, 4 H, CH2), 4.99 (s, 1 H, NH),
7.23–7.25 (m, 1 H, CH), 7.32 (s, 1 H, CH), 7.97 (dt, J = 7.5, 1.1 Hz,
1 H, CH), 8.18 (dd, J = 7.5, 1.1 Hz, 1 H, CH), 8.90 (s, 1 H, CH).
13C NMR (125 MHz, CDCl3): d = 13.8, 20.2, 31.2, 42.5, 45.7, 66.3,
92.8, 120.0, 123.8, 128.3, 134.7, 135.3, 135.4, 153.1, 156.8.
Palladium-Catalysed Aminations of Sulfonamide 8; N-Phenyl-
5-(piperazin-1-ylsulfonyl)isoquinolin-3-amine (11a); Typical
Procedure
A mixture of 8 (0.060 g, 0.1460 mmol), Pd(OAc)2 (0.003 g, 0.015
mmol), BINAP (0.027 g, 0.044 mmol), t-BuONa (0.042 g, 0.437
mmol) in toluene (1.2 mL) was stirred under N2 at r.t. for 5 min.
Aniline (0.031 mL, 0.340 mmol) was added and the mixture was
heated at 130 °C for 30 min under microwave irradiation. The mix-
ture was purified by ion exchange on SCX-II acidic resin (2 g), elut-
ing with MeOH–CH2Cl2 (1:1), and then with 2 M NH3 in MeOH.
The basic fractions were combined and concentrated. The residue
was dissolved in CH2Cl2 (2 mL) and CF3CO2H (0.10 mL) was add-
ed. The mixture was stirred at r.t. for 20 min. The mixture was con-
centrated and purified by preparative TLC, eluting with EtOAc–
hexanes (6:4), to give 11a as a yellow solid (0.009 g, 18%); mp
172–173 °C; HPLC: tR = 1.84 min (Table 1).
HRMS-TOF: m/z [M + H]+ calcd for C17H24N3O3S: 350.15329;
found: 350.15310.
N-(4-Methoxyphenyl)-5-(piperidin-1-ylsulfonyl)isoquinolin-3-
amine (10b)
Mp 173–175 °C; HPLC: tR = 2.59 min.
1H NMR (500 MHz, CDCl3): d = 1.44–1.46 (m, 6 H, CH2), 3.04–
3.06 (m, 4 H, CH2), 3.85 (s, 3 H, CH3), 6.73 (s, 1 H, NH), 6.97 (d,
Synthesis 2009, No. 4, 561–566 © Thieme Stuttgart · New York

PAPER
Rapid Synthesis of 3-Aminoisoquinoline-5-sulfonamides
565
1H NMR (500 MHz, MeOD): d = 2.79–2.94 (m, 4 H, CH2), 3.11–
3.23 (m, 4 H, CH2), 7.09 (t, J = 7.4 Hz, 1 H, CH), 7.36–7.41 (m, 3
H, CH), 7.49–7.50 (m, 2 H, CH), 7.83 (s, 1 H, CH), 8.18 (d, J = 8.1
Hz, 1 H, CH), 8.25 (dd, J = 7.4, 1.2 Hz, 1 H, CH), 9.07 (s, 1 H, CH).
13C NMR (125 MHz, MeOD): d = 45.5, 46.2, 97.8, 121.8, 122.4,
124.0, 125.9, 130.2, 130.5, 135.8, 135.9, 136.7, 142.2, 154.3, 155.8.
Benzophenone imine (0.107 mL, 0.639 mmol) was added and the
mixture was heated at 130 °C for 30 min under microwave irradia-
tion. The mixture was cooled, aq 1 M HCl (0.1 mL) was added and
stirred for 30 min. The mixture was concentrated and purified by ion
exchange on SCX-II acidic resin (2 g), eluting with MeOH–CH2Cl2
(1:1), and then with 2 M NH3 in MeOH. The basic fractions were
combined and concentrated. The crude product was purified by pre-
parative TLC, eluting with MeOH–CH2Cl2 (1:19), to give 9f as a
yellow solid (0.045 g, 48%); mp 235–237 °C; HPLC: tR = 2.85 min
(Table 1).
1H NMR (500 MHz, MeOD): d = 3.14–3.16 (m, 4 H, CH2), 3.65–
3.67 (m, 4 H, CH2), 7.31 (dd, J = 8.0, 7.4 Hz, 1 H, CH), 7.50 (s, 1
H, CH), 8.11 (d, J = 8.0 Hz, 1 H, CH), 8.19 (dt, J = 7.4, 1.3 Hz, 1 H,
CH), 8.90 (br s, 1 H, CH).
HRMS-TOF: m/z [M + Na]+ calcd for C19H21N4O2S: 371.15122;
found: 371.13244.
N-(4-Methoxyphenyl)-5-(piperazin-1-ylsulfonyl)isoquinolin-3-
amine (11b)
Mp 202–203 °C; HPLC: tR = 1.95 min.
1H NMR (500 MHz, MeOD): d = 2.70–2.72 (m, 4 H, CH2), 3.04–
3.06 (m, 4 H, CH2), 3.83 (s, 3 H, CH3), 6.97–7.00 (m, 2 H, CH),
7.33–7.37 (m, 3 H, CH), 7.60 (s, 1 H, CH), 8.13 (d, J = 8.1 Hz, 1 H,
CH), 8.20 (dd, J = 7.3, 1.2 Hz, 1 H, CH), 9.00 (s, 1 H, CH).
13C NMR (125 MHz, MeOD): d = 45.8, 46.8, 56.0, 96.6, 115.6,
121.9, 125.4, 125.7, 130.5, 134.8, 135.8, 136.0, 136.7, 154.3, 156.9,
158.00.
13C NMR (125 MHz, DMSO-d6): d = 45.4, 65.5, 94.3, 119.5, 122.8,
127.4, 134.3, 134.7, 134.9, 153.9, 157.9.
HRMS-TOF: m/z [M + H]+ calcd for C13H16N3O3S: 292.11142;
found: 292.11148.
5-(Piperidin-1-ylsulfonyl)isoquinolin-3-amine (10f)
Mp 225–226 °C; HPLC: tR = 2.85 min.
1H NMR (500 MHz, DMSO-d6): d = 1.39–1.54 (m, 6 H, CH2),
3.07–3.09 (m, 4 H, CH2), 6.42 (s, 2 H, NH2), 7.25 (t, J = 7.4 Hz, 1
H, CH), 7.29 (s, 1 H, CH), 8.03 (d, J = 7.4 Hz, 1 H, CH), 8.09 (d,
J = 7.4 Hz, 1 H, CH), 8.94 (s, 1 H, CH).
13C NMR (125 MHz, DMSO-d6): d = 22.9, 24.9, 46.2, 94.5, 119.5,
122.8, 128.7, 134.1, 134.2, 134.4, 153.2, 157.8.
HRMS-TOF: m/z [M + H]+ calcd for C14H18N3O2S: 293.10667;
found: 293.10635.
HRMS-TOF: m/z [M + H]+ calcd for C20H23N4O3S: 399.14854;
found: 399.14784.
N-(4-Nitrophenyl)-5-(piperazin-1-ylsulfonyl)isoquinolin-3-
amine (11c)
Mp 285–287 °C; HPLC: tR = 2.09 min.
1H NMR (500 MHz, DMSO-d6): d = 2.71–2.72 (m, 4 H, CH2),
3.02–3.04 (m, 4 H, CH2), 6.60 (d, J = 9.1 Hz, 1 H), 6.69 (s, 1 H),
7.58 (t, J = 7.7 Hz, 1 H, CH), 8.06 (s, 1 H, CH), 8.19–8.21 (m, 3 H,
CH), 8.37 (d, J = 8.2 Hz, 1 H, CH), 9.32 (s, 1 H, CH), 10.30 (s, 1 H,
NH).
5-(Piperazin-1-ylsulfonyl)isoquinolin-3-amine (11f)
Mp 134–135 °C; HPLC: tR = 1.49 min.
1H NMR (500 MHz, MeOD): d = 2.99–3.01 (m, 4 H, CH2), 3.27–
3.29 (m, 4 H, CH2), 7.29 (t, J = 8.0 Hz, 1 H, CH), 7.47 (s, 1 H, CH),
8.09 (d, J = 8.0 Hz, 1 H, CH), 8.19 (dd, J = 8.0, 1.2 Hz, 1 H, CH),
8.89 (s, 1 H, CH).
13C NMR (125 MHz, DMSO-d6): d = 44.6, 46.0, 101.7, 112.3,
116.6, 122.9, 124.8, 125.3, 129.4, 133.5, 139.5, 148.2, 151.9, 152.7,
155.7.
HRMS-TOF: m/z [M + H]+ calcd for C19H20N5O4: 414.12305;
found: 414.12294.
N-Benzyl-5-(piperazin-1-ylsulfonyl)isoquinolin-3-amine (11d)
Mp 142–143 °C; HPLC: tR = 3.83 min.
13C NMR (125 MHz, MeOD): d = 45.3, 45.7, 97.3, 121.5, 124.9,
129.7, 136.2, 136.3, 136.8, 154.2, 158.8.
1H NMR (500 MHz, MeOD): d = 2.83–2.99 (m, 8 H, CH2), 4.60 (s,
2 H, CH2), 7.24–7.33 (m, 3 H, CH), 7.37 (t, J = 7.6 Hz, 2 H, CH),
7.46–7.48 (m, 2 H, CH), 8.12–8.17 (m, 2 H, CH), 8.97 (s, 1 H, CH).
HRMS-TOF: m/z [M + H]+ calcd for C13H17N4O2S: 293.10667;
found: 293.10358.
13C NMR (125 MHz, MeOD): d = 44.8, 47.1, 49.1, 94.7, 121.4,
125.2, 128.1, 129.0, 129.7, 136.2, 136.4, 136.9, 140.5, 154.8, 158.2.
Acknowledgment
This work was supported by Cancer Research UK [CUK] grant
numbers C309/A8274 and C19524/A7614, and by The Institute of
Cancer Research Community Outreach Fund (S.T.).
HRMS-TOF: m/z [M + H]+ calcd for C20H23N4O2S: 383.15362;
found: 383.15363.
N-Butyl-5-(piperazin-1-ylsulfonyl)isoquinolin-3-amine (11e)
Mp 103–104 °C; HPLC: tR = 1.95 min.
1H NMR (500 MHz, MeOD): d = 1.00 (t, J = 7.4 Hz, 3 H, CH3),
1.45–1.68 (m, 4 H, CH2), 3.27–3.34 (m, 6 H, CH2), 3.37–3.49 (m, 4
H, CH2), 7.26–7.30 (m, 2 H, CH), 8.11 (d, J = 7.4 Hz, 1 H, CH),
8.21 (dd, J = 7.4, 1.2 Hz, 1 H, CH), 8.92 (s, 1 H, CH).
13C NMR (125 MHz, MeOD): d = 14.2, 21.3, 32.4, 43.0, 43.8, 44.4,
94.7, 119.4, 121.5, 128.9, 136.1, 136.7, 137.1, 154.4, 162.9
HRMS-TOF: m/z [M + H]+ calcd for C17H23N3O3S: 349.16927;
found: 349.16819.
References
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444.
(b) Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249.
(2) Ono-Saito, N.; Niki, I.; Hidaka, H. Pharmacol. Ther. 1999,
82, 123.
(3) Shirotani, M.; Hattori, R.; Kawai, C.; Sasayama, S.; Yui, Y.
Cardiovasc. Drug Rev. 1992, 10, 333.
(4) Reuveni, H.; Livnah, N.; Geiger, T.; Klein, S.; Ohne, O.;
Cohen, I.; Benhar, M.; Gellerman, G.; Levitzki, A.
Biochemistry 2002, 41, 10304.
(5) Collins, I.; Caldwell, J.; Fonseca, T.; Donald, A.; Bavetsias,
V.; Hunter, L. K.; Garrett, M. D.; Rowlands, M. G.; Aherne,
G. W.; Davies, T. G.; Berdini, V.; Woodhead, S. J.; Davis,
D.; Seavers, L. C. A.; Wyatt, P. G.; Workman, P.;
McDonald, E. Bioorg. Med. Chem. 2006, 14, 1255.
Introduction of a Primary Amine to Sulfonamides 6–8; 5-(Mor-
pholinosulfonyl)isoquinolin-3-amine (9f); Typical Procedure
A mixture of 6 (0.100 g, 0.320 mmol), Pd(OAc)2 (0.007 g, 0.032
mmol), BINAP (0.060 g, 0.096 mmol), t-BuONa (0.092 g, 0.959
mmol) in toluene (2.1 mL) was stirred under N2 at r.t. for 5 min.
Synthesis 2009, No. 4, 561–566 © Thieme Stuttgart · New York

566
N. Proisy et al.
PAPER
(6) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
(7) (a) Engh, R. A.; Girod, A.; Kinzel, V.; Huber, R.;
Bossemeyer, D. J. Biol. Chem. 1996, 271, 26157.
(b) Collins, I.; Workman, P. Curr. Signal Transduction Ther.
2006, 13.
(8) Keller, P. A. In Comprehensive Heterocyclic Chemistry, 3rd
ed., Vol. 7; Black, D. St. C., Ed.; Elsevier: Oxford, 2008,
217.
(9) (a) Volovnenko, T. A.; Tarasov, A. V.; Turov, A.;
Volovenko, Y. M. Ukr. Khim. Zh. 2007, 73, 44; Chem.
Abstr. 2008, 148, 449584. (b) Volovnenko, T. A.; Tarasov,
A. V.; Volovnenko, Y. M. Ukr. Khim. Zh. 2006, 72, 108;
Chem. Abstr. 2006, 145, 471448. (c) Bakke, J. M.; Riha, J.
J. Heterocycl. Chem. 2001, 38, 99.
(10) (a) Bartmann, W.; Konz, E.; Rueger, W. Heterocycles 1989,
29, 707. (b) Konz, E.; Rueger, W. Heterocycles 1989, 29,
691. (c) Renger, B.; Konz, E.; Rueger, W. Synthesis 1988,
683.
(12) (a) Franceschin, M.; Frasca, S.; Alvino, A.; Bianco, A. Lett.
Org. Chem. 2007, 4, 86. (b) Oertqvist, P.; Peterson, S. D.;
Aakerblom, E.; Gossas, T.; Sabnis, Y. A.; Fransson, R.;
Lindeberg, G.; Danielson, U. H.; Karlen, A.; Sandstroem, A.
Bioorg. Med. Chem. 2007, 15, 1448. (c) Zhu, G.; Gong, J.;
Claiborne, A.; Woods, K. W.; Gandhi, V. B.; Thomas, S.;
Luo, Y.; Liu, X.; Shi, Y.; Guan, R.; Magnone, S. R.;
Klinghofer, V.; Johnson, E. F.; Bouska, J.; Shoemaker, A.;
Oleksijew, A.; Stoll, V. S.; De Jong, R.; Oltersdorf, T.; Li,
Q.; Rosenberg, S. H.; Giranda, V. L. Bioorg. Med. Chem.
Lett. 2006, 16, 3150. (d) Sweetman, B. A.; Mueller-Bunz,
H.; Guiry, P. J. Tetrahedron Lett. 2005, 46, 4643.
(e) Brunner, H.; Olschewski, G.; Nuber, B. Synthesis 1999,
429. (f) Shiraiwa, M.; Sakamoto, T.; Yamanaka, H. Chem.
Pharm. Bull. 1983, 31, 2275.
(13) Janey, J. M. In Name Reactions for Functional Group
Transformations; Li, J. J.; Corey, E. J., Eds.; Wiley:
Hoboken, 2007, 564.
(11) (a) Bartmann, W.; Konz, E.; Rueger, W. J. Heterocycl.
Chem. 1987, 24, 677. (b) Audrain, H.; Bender, D.; Scheel-
Krueger, J.; Nielsen, E. O.; Olsen, G. M.; Peters, D.;
Cumming, P. J. Labelled Compd. Radiopharm. 2003, 873.
(14) Robison, M. M. J. Am. Chem. Soc. 1958, 80, 5481.
(15) Haworth, R. D.; Robinson, S. J. Chem. Soc. 1948, 777.
(16) Lai, J. Y. Q.; Ferguson, Y.; Jones, M. Synth. Commun. 2003,
33, 3427.
(17) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367.
Synthesis 2009, No. 4, 561–566 © Thieme Stuttgart · New York