Rapid Synthesis of 3-Aminoisoquinoline-5-sulfonamides Using the Buchwald-Hartwig Reaction

Abstract

A rapid synthesis 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 amines. Palladium-catalysed C-N bond formation was used to introduce arylamine, alkylamine, and unsubstituted amino groups at C-3 of the isoquinoline.

Isoquinolines are an important class of heterocyclic compounds widely represented in natural products, and which show a range of biological activities. [¹] The isoquinoline bicycle has been widely used in the design of biologically active molecules. In particular, isoquinoline-5-sulfon­amides have been researched as a scaffold for new inhibitors 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 vaso­spasm. [³ ] Other isoquinoline-5-sulfonamides have been investigated 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 synthesis [6] of previously unreported 3-(alkylamino)- and 3-(arylamino)isoquinoline-5-sulfonamides. 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]

Various synthetic routes have been developed to access polysubstituted isoquinolines. [8] However, while nucleophilic substitution of halides by amines at the C-1 position of isoquinolines has been extensively reported, the equivalent introduction of amines at the C-3 position has fewer examples. Existing strategies involve intramolecular cyclisation, [9] or intermolecular reactions requiring the presence of a strongly activating 2-substituent on the isoquinoline [¹0] and harsh reaction conditions. [¹0] [¹¹] To the best of our knowledge, palladium-catalysed C-N bond formation has not previously been reported for the introduction of a range of substituted amines at C-3 of 3-haloisoquinolines. 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 reaction of the useful bifunctional intermediate 3-chloroisoquinoline-5-sulfonyl chloride (5) with cyclic amines, followed by Buchwald-Hartwig amination [¹³] at C-3 of the isoquinoline.

The synthesis of our isoquinoline derivatives started with the introduction of the chlorosulfonyl group at the C-5 position of 3-chloroisoquinoline (4) (Scheme  [¹] ). The starting material 4 was prepared in good yield by selective reduction of 1,3-dichloroisoquinoline [¹4] with red phosphorous. [¹5] Regioselective sulfonylation of 4 was achieved by high temperature reaction with neat chlorosulfonic acid. [¹6] Depending on the functionalities present on the isoquinoline, isoquinoline-5-sulfonic acids or isoquinoline-5-sulfonyl chlorides have been obtained from this reaction. [¹6] In the case of 3-chloroisoquinoline (4), the novel chlorosulfonyl derivative 5 was obtained in good yield without any formation of the hydrolysed product.

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 introduced. The amines (morpholine, piperidine, and N-Boc-piperazine) were chosen in order to assess their compatibility with subsequent reaction at the C-3 position of the isoquinoline, and for their similarity to preferred substituents in kinase inhibitors related to 1. [²-5] The regiochemistry of the initial sulfonylation was confirmed from the ^¹H NMR spectrum of sulfonamide 6 (Figure  [²] ). The distinctive singlet at δ = 9.18 for H-1 of the isoquinoline showed an NOE to H-8, while the singlet at δ = 8.59 corresponding to H-4 showed an NOE to the protons adjacent to nitrogen on the morpholine ring.

While intramolecular cyclisation of amines to 3-chloro­isoquinolines has been achieved in good yields, [9] harsh reaction­ conditions are generally needed when no additional activating functionality is present on the heterocyclic aromatic ring, for example, 150 ˚C, 72 hours. [¹¹a] We first attempted nucleophilic substitution of the 3-chloro­isoquinoline-5-sulfonamides 6-8 with aniline using var­ious bases with heating, for example, Et₃N, NMP, 150 ˚C (microwave), 30 minutes; NaH, DMF, 60 ˚C (microwave), 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 conditions [¹³] 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] ).

Table 2 Buchwald-Hartwig Coupling of Alkyl and Aryl Amines to the 3-Chloroisoquinoline-5-sulfonamides 6-8 ^a

	6 → 9a-f	7 → 10a-f	8 → 11a-f b
Ph	9a 15%	10a 25%	11a 18%
4-MeOC6H4	9b 54%	10b 61%	11b 53%
4-NO2C6H4	9c 61%	10c 68%	11c 60%
PhCH2	9d 3%	10d 74%	11d 62%
n-Bu	9e 4%	10e 35%	11e 18%
H	9f c 48%	10f c 33%	11f c 30%
a Yields refer to isolated and purified material. b Yields of free amine following deprotection of piperazine N-Boc using CF3CO2H in CH2Cl2. c From coupling of benzophenone imine followed by hydrolysis with aq HCl.

Reactions were conducted in parallel in an automated microwave reactor and the crude products were isolated by solid-phase extraction using acidic resin cartidges. The products were further purified by chromatography as necessary. 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. Isolation of the morpholine sulfonamides 9d and 9e was achieved in substantially lower yields than for the corresponding 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-N bond formation and the products 11a-f were isolated as the free amines. Representative electron-rich and electron-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.

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. Palladium-catalysed C-N bond formation was used to introduce arylamine, alkylamine, and unsubstituted amino groups to C-3 of the isoquinoline.

Reagents and anhyd solvents were obtained from commercial suppliers 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 Macherey-Nagel or Analtech precoated silica plates. ^¹H 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 molecular weight scan range was 50-1000 Da. HRMS were recorded on an Agilent 6210 (ToF) mass spectrometer.

3-Chloroisoquinoline-5-sulfonyl Chloride (5)

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): δ = 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): δ = 116.4, 125.9, 127.7, 132.3, 134.1, 136.3, 138.1, 149.7, 153.6.

HRMS-TOF: m/z [M + H]⁺ calcd for C₉H₅Cl₂NO₂S: 261.94908; found: 261.94894.

Sulfonamides 6-8; 4-(3-Chloroisoquinolin-5-ylsulfonyl)morpholine (6); Typical Procedure

Morpholine (0.150 mL, 1.71 mmol) was added dropwise to a mixture 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 solid (0.301 g, 84%); mp 189-190 ˚C; HPLC: t _R = 3.94 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 45.6, 66.2, 117.3, 126.0, 127.8, 131.3, 133.9, 134.0, 135.2, 148.6, 153.3.

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: t _R = 4.56 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 23.5, 25.4, 46.3, 117.6, 126.0, 127.8, 132.6, 133.4, 133.8, 134.8, 148.3, 153.2.

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: t _R = 4.88 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 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.

Palladium-Catalysed Aminations of Sulfonamides 6,7; N -Phenyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10a); Typical Procedure

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 mixture 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 basic 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: t _R = 4.97 min (Table  [¹] ).

^¹H NMR (500 MHz, CDCl₃): δ = 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).

^¹³C NMR (125 MHz, CDCl₃): δ = 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.

5-(Morpholinosulfonyl)- N -phenylisoquinolin-3-amine (9a)

Mp 232-233 ˚C; HPLC: t _R = 2.40 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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).

^¹³C NMR (125 MHz, CDCl₃): δ = 45.3, 66.1, 95.7, 121.3, 121.4, 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: t _R = 2.36 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₂₀H₂₂N₃O₄S: 400.13255; found: 400.13286.

5-(Morpholinosulfonyl)- N -(4-nitrophenyl)isoquinolin-3-amine (9c)

Mp 269-270 ˚C; HPLC: t _R = 2.64 min.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₁₉H₁₉N₄O₅S: 415.10707; found: 415.10702.

N -Benzyl-5-(morpholinosulfonyl)isoquinolin-3-amine (9d)

Mp 148-150 ˚C; HPLC: t _R = 4.45 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₂₀H₂₂N₃O₃S: 313.04082; found: 313.04106.

N -Butyl-5-(morpholinosulfonyl)isoquinolin-3-amine (9e)

Mp 121-122 ˚C; HPLC: t _R = 4.54 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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): δ = 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.

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: t _R = 2.59 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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, 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): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₂₁H₂₄N₃O₃S: 398.15329; found: 398.15398.

N -(4-Nitrophenyl)-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10c)

Mp 155-156 ˚C; HPLC: t _R = 2.78 min.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 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).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₂₀H₂₁N₄O₄: 413.12780; found: 413.10969.

N -Benzyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10d)

Mp 166-168 ˚C; HPLC: t _R = 4.45 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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).

^¹³C NMR (125 MHz, CDCl₃): δ = 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.

HRMS-TOF: m/z [M + H]⁺ calcd for C₂₁H₂₄N₃O₂S: 382.15451; found: 382.15500.

N -Butyl-5-(piperidin-1-ylsulfonyl)isoquinolin-3-amine (10e)

Mp 118-119 ˚C; HPLC: t _R = 4.54 min.

^¹H NMR (500 MHz, CDCl₃): δ = 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).

^¹³C NMR (125 MHz, CDCl₃): δ = 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.

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 mixture was 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 residue was dissolved in CH₂Cl₂ (2 mL) and CF₃CO₂H (0.10 mL) was added. The mixture was stirred at r.t. for 20 min. The mixture was concentrated 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: t _R = 1.84 min (Table  [¹] ).

^¹H NMR (500 MHz, MeOD): δ = 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): δ = 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.

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: t _R = 1.95 min.

^¹H NMR (500 MHz, MeOD): δ = 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): δ = 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.

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: t _R = 2.09 min.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 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).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 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: t _R = 3.83 min.

^¹H NMR (500 MHz, MeOD): δ = 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).

^¹³C NMR (125 MHz, MeOD): δ = 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.

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: t _R = 1.95 min.

^¹H NMR (500 MHz, MeOD): δ = 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): δ = 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.

Introduction of a Primary Amine to Sulfonamides 6-8; 5-(Morpholinosulfonyl)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. Benzophenone imine (0.107 mL, 0.639 mmol) was added and the mixture was heated at 130 ˚C for 30 min under microwave irradiation. 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 preparative TLC, eluting with MeOH-CH₂Cl₂ (1:19), to give 9f as a yellow solid (0.045 g, 48%); mp 235-237 ˚C; HPLC: t _R = 2.85 min (Table  [¹] ).

^¹H NMR (500 MHz, MeOD): δ = 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).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 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: t _R = 2.85 min.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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.

5-(Piperazin-1-ylsulfonyl)isoquinolin-3-amine (11f)

Mp 134-135 ˚C; HPLC: t _R = 1.49 min.

^¹H NMR (500 MHz, MeOD): δ = 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, MeOD): δ = 45.3, 45.7, 97.3, 121.5, 124.9, 129.7, 136.2, 136.3, 136.8, 154.2, 158.8.

HRMS-TOF: m/z [M + H]⁺ calcd for C₁₃H₁₇N₄O₂S: 293.10667; found: 293.10358.

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.).

References

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References

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  Search in Google Scholar
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  Search in Google Scholar
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  CrossrefSearch in Google Scholar
• 3 Shirotani M. Hattori R. Kawai C. Sasayama S. Yui Y. Cardiovasc. Drug Rev.  1992,  10:  333 
  CrossrefSearch in Google Scholar
• 4 Reuveni H. Livnah N. Geiger T. Klein S. Ohne O. Cohen I. Benhar M. Gellerman G. Levitzki A. Biochemistry  2002,  41:  10304 
  CrossrefSearch in Google Scholar
• 5 Collins I. Caldwell J. Fonseca T. Donald A. Bavetsias V. Hunter LK. Garrett MD. Rowlands MG. Aherne GW. Davies TG. Berdini V. Woodhead SJ. Davis D. Seavers LCA. Wyatt PG. Workman P. McDonald E. Bioorg. Med. Chem.  2006,  14:  1255 
  CrossrefSearch in Google Scholar
• 6 Collins I. J. Chem. Soc., Perkin Trans. 1  2002,  1921 
  Crossref
• 7a Engh RA. Girod A. Kinzel V. Huber R. Bossemeyer D. J. Biol. Chem.  1996,  271:  26157 
  Search in Google Scholar
• 7b Collins I. Workman P. Curr. Signal Transduction Ther.  2006,  13 
• 8 Keller PA. In Comprehensive Heterocyclic Chemistry   3rd ed., Vol. 7:  Black D St. C. Elsevier; Oxford: 2008.  p.217 
  Search in Google Scholar
• 9a Volovnenko TA. Tarasov AV. Turov A. Volovenko YM. Ukr. Khim. Zh.  2007,  73:  44 ; Chem. Abstr. 2008, 148, 449584
  Search in Google Scholar
• 9b Volovnenko TA. Tarasov AV. Volovnenko YM. Ukr. Khim. Zh.  2006,  72:  108 ; Chem. Abstr. 2006, 145, 471448
  Search in Google Scholar
• 9c Bakke JM. Riha J. J. Heterocycl. Chem.  2001,  38:  99 
  Search in Google Scholar
• 10a Bartmann W. Konz E. Rueger W. Heterocycles  1989,  29:  707 
  Search in Google Scholar
• 10b Konz E. Rueger W. Heterocycles  1989,  29:  691 
  Search in Google Scholar
• 10c Renger B. Konz E. Rueger W. Synthesis  1988,  683 
• 11a Bartmann W. Konz E. Rueger W. J. Heterocycl. Chem.  1987,  24:  677 
  Search in Google Scholar
• 11b Audrain H. Bender D. Scheel-Krueger J. Nielsen EO. Olsen GM. Peters D. Cumming P. J. Labelled Compd. Radiopharm.  2003,  873 
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  Search in Google Scholar
• 12b Oertqvist P. Peterson SD. Aakerblom E. Gossas T. Sabnis YA. Fransson R. Lindeberg G. Danielson UH. Karlen A. Sandstroem A. Bioorg. Med. Chem.  2007,  15:  1448 
  Search in Google Scholar
• 12c Zhu G. Gong J. Claiborne A. Woods KW. Gandhi VB. Thomas S. Luo Y. Liu X. Shi Y. Guan R. Magnone SR. Klinghofer V. Johnson EF. Bouska J. Shoemaker A. Oleksijew A. Stoll VS. De Jong R. Oltersdorf T. Li Q. Rosenberg SH. Giranda VL. Bioorg. Med. Chem. Lett.  2006,  16:  3150 
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  Search in Google Scholar
• 12e Brunner H. Olschewski G. Nuber B. Synthesis  1999,  429 
• 12f Shiraiwa M. Sakamoto T. Yamanaka H. Chem. Pharm. Bull.  1983,  31:  2275 
  Search in Google Scholar
• 13 Janey JM. In Name Reactions for Functional Group Transformations   Li JJ. Corey EJ. Wiley; Hoboken: 2007.  p.564 
• 14 Robison MM. J. Am. Chem. Soc.  1958,  80:  5481 
  CrossrefSearch in Google Scholar
• 15 Haworth RD. Robinson S. J. Chem. Soc.  1948,  777 
• 16 Lai JYQ. Ferguson Y. Jones M. Synth. Commun.  2003,  33:  3427 
  CrossrefSearch in Google Scholar
• 17 Wolfe JP. Ahman J. Sadighi JP. Singer RA. Buchwald SL. Tetrahedron Lett.  1997,  38:  6367 
  CrossrefPubMedSearch in Google Scholar