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Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis Jacob M. Ganley, and David L. Waller J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01819 • Publication Date (Web): 11 Oct 2017 Downloaded from http://pubs.acs.org on October 11, 2017
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Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis Jacob M. Ganley and David L. Waller* Manufacturing Process Development, Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, Massachusetts, United States Chemical Commercialization & Technical Operations, Merck & Co., 65 Hayden Avenue, Lexington, Massachusetts, United States
Abstract: A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira couplingcycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 hours. The structure of the heterocyclic ring system was confirmed through single crystal X-ray crystallography. In 1996, Bohacek estimated the universe of organic molecules to contain 1060 structures.1 Among this staggering number, heterocycles occupy a privileged subset due to their importance in the chemistry of living systems and their unique electronic properties.2,3,4,5 Pharmaceutical chemists have long exploited the unique properties of heterocycles in the development of drug candidates, as indicated by surveys of commercially approved drugs.6,7 In the realm of organic synthesis, heterocycles serve as key ligands on metals in numerous catalytic transformations8,9,10,11 and as directing groups for C-H activation.12,13,14 Heterocycles are also receiving increased attention as components of chemical sensors15,16 and innovative materials.17,18 A 2009 report by Pitt estimated the size of the heterocyclic chemical space and concluded that only a small fraction of conceivable heterocycles have been reported.19 Taken together, the field of heterocyclic chemistry appears to be vast, relatively unexplored and full of potential. In this Note, we report our exploration into an uncommon heterocycle, the furo[2,3-c]pyridazine (Scheme 1, top).
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Scheme 1. Structure, numbering and general strategies to prepare the furo[2,3-c]pyridazine ring system.
There are only a handful of reports in the literature describing methods to prepare the furo[2,3-c]pyridazine ring system. In general, these reports rely on one of two approaches: a Dieckmann-type condensation20,21,22 (Scheme 1, eq 1) or a Wittig-based strategy23,24 (Scheme 1, eq 2). While only a few examples of each reaction manifold have been published, these strategies suffer from a tedious starting material preparation and a lack of functional group tolerance. During an investigation of palladium-catalyzed couplings in heterocyclic substrates, we observed that furo[2,3c]pyridazines could be easily accessed through a tandem Sonogashira-cycloisomerization reaction of a bromopyridizinone and an alkyne (Scheme 1, eq 3).25 Given the scarcity of information regarding the synthesis and properties of furo[2,3-c]pyridazines, as well as the single-step access to 2-bromo-3-aminopyridizinones, we sought to optimize this tandem reaction. We initially targeted a Sonogashira coupling on substituted pyridazinone 1 (Scheme 2).26 A brief screen was conducted to identify a catalyst capable of carrying out the desired coupling. Four ligands were selected based on literature precedence indicating their ability to mediate Sonogashira couplings in heterocyclic systems at sterically encumbered positions (P(Cy)3, P(t-Bu)3, P(o-Tol)3 and 1,1'-Bis(diphenylphosphino)ferrocene (DPPF)).27,28,29,30 Of these four ligands, only DPPF showed reactivity, with 43% conversion being observed by UPLCMS. Isolation and characterization of this compound by 1H and
13
C NMR analysis revealed it to be pyridazine 3, the product of the
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desired Sonogashira coupling followed by cycloisomerization of the amide moiety into the alkyne.31,32 While analogous cyclizations have been reported in different substrate classes,33 our interest in the rare furo[2,3c]pyridazine ring system prompted us to optimize this reaction. Scheme 2. Screen of ligands and formation of the furo[2,3-c]pyridazine ring system.a
a
See Experimental Procedures for reaction conditions.
To optimize formation of the furo[2,3-c]pyridazine, we retained the palladium source and base used in the screening reaction, but increased the temperature to 80 °C, which necessitated a switch to dioxane as the solvent (Table 1, entry 1). These conditions provided a sluggish reaction, requiring 24 hours to reach 91% conversion. Switching to PdCl2(PhCN)2 and (i-Pr)2NH dramatically increased the reaction rate and allowed for a reduction in palladium loading, although the conversion abruptly stopped at 80% (entry 2).28 A simple increase in the temperature to 100 °C addressed the reaction stalling, providing 100% conversion to 3 in 2 hours (entry 3). Any efforts to reduce the amount of base, Pd or Cu used in the reaction failed to provide satisfactory outcomes (entries 46). Table 1. Optimization of furo[2,3-c]pyridazine synthesisa
Entry
Pd/Cu Loadingb (mol%)
Temperature (°C)
Time (hr)
Conversionc (%)
1d,e
10/5
80
24
91%
2
5/5
80
4
80%
3
5/5
100
2
100%
4f
5/5
100
4
78%
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a
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5
5/2.5
100
2
52%
6
2.5/5
100
2
85%
Unless indicated otherwise, reactions were performed on a 200 mg scale at 0.2 M in dioxane, with 2 equivalents of
phenylacetylene, 2 equivalents of (i-Pr)2NH and 1.5X equivalents of DPPF, where X is equal to the molar charge of Pd. bThe Pd source was PdCl2(PhCN)2, and the Cu source was CuI, unless indicated otherwise. cConversion was measured by UPLCMS, where conversion = [AUC(product) ÷ AUC(product + starting material)] x 100%. dEt3N was used instead of (i-Pr)2NH. ePdCl2(H3CCN)2 was used instead of PdCl2(PhCN)2. f1 equivalent of (i-Pr)2NH was used instead of 2 equivalents. With optimized conditions in hand, we explored the substrate scope of the alkyne coupling partner in reactions with pyridazinone 1 (Figure 1). Phenyl acetylene and 1-hexyne both cleanly underwent the couplingcycloisomerization reaction to provide their corresponding furopyridazines in good isolated yields (3 and 6, respectively). The presence of a free alcohol in the alkyne fragment was well-tolerated (8, 10 and 12), as was a Bocprotected amine (14) and alkyl chloride (16). Use of t-butylacetylene provided the desired furopyridazine 18 in 80% yield, indicating a high steric tolerance in the reaction. However, ethyl propiolate (19) failed to give any desired product; LCMS analysis indicated rapid addition of diisopropylamine to the alkynoate, thereby preventing further reactivity in this manifold.
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Substrate
Alkyne
Product
NHBn
Yield (%)
NHBn
Br N
N H
Ph O
N
2
1
81%
Ph O
N
3
NHBn n-Bu
1
N
5
n-Bu O
N
81%
6
NHBn CH3 OH CH3
1 7
N
O
N
CH3 OH CH3
8
93%
NHBn OH
OH 1
N 9
O
N
78%
10
NHBn OH 1
N 11
N
O
OH
92%
NHBoc
78%
12
NHBn NHBoc 1 N 13
N
O
14
NHBn (CH2)3 Cl
1
73% N
15
(CH2)3 Cl
N
O 16
NHBn 1
t-Bu N
17
t-Bu N
80%
O 18
O 1 OEt
N/A
N/A
19
Figure 1. Substrate scope of furo[2,3-c]pyridazine formation with 1. Yields reported are isolated yields after purification. We next examined the effect of the β-amino substitution on the coupling-cycloisomerization reaction (Figure 2). When piperidine-substituted pyridizinone 20 was submitted to standard coupling conditions with propargyl alcohol 7 as the coupling partner, the reaction proceeded to only 12% conversion after 2 hours, likely due to the increased steric demand of the piperidine substitution. Increasing the concentration from 0.2 M to 0.5 M dramatically improved the rate, providing 100% conversion in 3 hours and an 82% isolated yield of 21.34 N-Boc propargyl amine also smoothly coupled with pyridizinone 20 at 0.5 M to provide furopyridazine 22 in 94% yield. Ester substitution
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on the pyridizinone was well tolerated, as glycine-substituted 23 underwent the tandem reaction to furnish furopyridazines 24 and 25 in 86 and 95% yields, respectively. Pyridazinone 26, bearing aniline substitution at the β position, cleanly furnished furopyridazines 27 and 28 in excellent yields (89 and 87%, respectively).
Figure 2. Substrate scope of furo[2,3-c]pyridazine with various pyridazinones. Yields reported are isolated yields after purification. While diverse functionality was determined to be suitable in the tandem Sonogashira-cycloisomerization reaction, we did encounter one anomalous substrate during our investigation. When we attempted to couple pyridazinone 1 with TMS-acetylene (29), we observed a typical conversion rate but isolated alkynylpyridazinone 30 in 81% yield instead of the expected bicyclic product 31 (Scheme3). This failure to cyclize was attributed to electronic effects rather than steric effects, given that t-butylacetylene is a competent coupling partner with pyridizinone 1 (see Figure
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1, compound 18). One potential rationale is that the silicon atom decreases the electrophilic character of the α carbon enough to prevent cyclization of the nucleophilic oxygen.35 Scheme 3. Failure of cyclization with TMS-acetylene (29) in the tandem reaction.
To further strengthen our structural assignment of the furo[2,3-c]pyridazine ring system, we characterized the structure of compound 10 (Figure 1) by single crystal X-ray diffraction analysis,36 as shown in Figure S1 of the Supporting Information. In summary, we have reported the development of a rapid and efficient method to prepare the furo[2,3c]pyridazine ring system via a Sonogashira coupling followed by cycloisomerization of the transient αalkynylpyridazinone intermediate. The approach capitalizes on readily available starting materials, is tolerant of a variety of functional groups, and proceeds in good to excellent yields. We envision this protocol enabling investigations of the rare furo[2,3-c]pyridazine ring system and its associated chemistry in applications across multiple disciplines. Experimental Section All starting materials and solvents were purchased and used without further purification. All reactions were monitored by UPLCMS on a Waters Acquity instrument until the starting material was completely consumed. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel 60 F-254 plates (particle size 0.040-0.055 mm, 230-400 mesh) and visualized using UV light. 1H and 13C spectroscopic data were recorded on a Bruker Ascend NMR spectrometer (400 and 100 MHz, respectively) at 23 °C unless otherwise stated. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance (CDCl3: δ 7.26/77.0, 1
H/13C; DMSO-d6: δ 2.49/39.5, 1H/13C). Data are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, sex = sextet, m = multiplet, b = broad, app = apparent), integration and coupling constant(s) (Hz). HRMS data we recorded using a Thermo Fischer Scientific Orbitrap Elite and analyzed using XCalibur 2.2 software. Melting points were determined on a Stanford Research Systems OptiMelt automated
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melting point system and are uncorrected. IR absorptions were recorded on a Thermo Scientific Nicolet 380 FTIR instrument and reported in wavenumbers (cm-1). Ligand screen. 2 mL glass vials equipped with magnetic stir bars were charged with 5-(benzylamino)-4bromopyridazin-3(2H)-one (1; 20 mg, 0.071 mmol, 1 eq), followed by THF (357 µL). Next, triethylamine (20 µL, 0.14 mmol, 2 eq), phenylacetylene (15.7 µL, 0.14 mmol, 2 eq), CuI (1 mg, 0.0071 mmol, 10 mol%), ligand (DPPF (12 mg), P(o-Tol)3 (7 mg), P(t-Bu)3 (4 mg) or P(Cy)3 (6 mg); 0.021 mmol, 30 mol%) and bis(acetonitrile) dichloropalladium (4 mg, 0.014 mmol, 20 mol%) were added. The reaction vials were then degassed by evacuating the vials and backfilling with N2 three times. The reaction mixtures were heated at 60 °C and periodically monitored by UPLCMS for reaction conversion (timepoints = 1 h, 2 h, 4 h, 8 h and 24 h). General Protocol for the Synthesis of Furo[2,3-c]pyridazines: The starting 4-bromo-pyridazin-3(2H)-one (1 eq) was charged to the flask, followed by dioxane (2 mL). Next, diisopropylamine (2 eq), alkyne (2 eq), CuI (5 mol%), bis(benzonitrile) dichloropalladium (5 mol%) and DPPF (7.5 mol%) were added. The reaction mixture was then diluted with dioxane to reach the appropriate concentration (0.2 – 0.5 M, depending on the substrate) and degassed by evacuating the flask and backfilling with N2 three times. Next, the mixture was heated at 100 °C in an aluminum heating mantle until UPLCMS indicated completion of the reaction. The cooled reaction mixture was concentrated to dryness on a rotary evaporator and the residue suspended in EtOAc (30 mL). The organic solution/suspension was washed with aqueous saturated NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated and the residue purified by chromatography on SiO2, unless indicated otherwise. 5-(benzylamino)-4-bromopyridazin-3(2H)-one (1). 4,5-dibromopyridazin-3(2H)-one (10.0 g, 39.4 mmol, 1 eq), benzylamine (8.44 g, 78.8 mmol, 2 eq) and diisopropylethylamine (10.2 g, 78.8 mmol, 2 eq) were dissolved in DMAc (150 mL) and heated at 90 °C for 21 hr. The reaction mixture was then diluted with brine (300 mL), followed by the addition of EtOAc (300 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (200 mL; 3x). The combined organic layers were washed with water (300 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was recrystallized from CH2Cl2 (600 mL) to provide 7.83 g (71%) of 1 as a white solid. mp 200.0 – 202.0 °C (CH2Cl2); IR (film) 3271, 2956, 2774, 1590, 1441, 1298, 701 cm-1; 1H NMR (DMSO-d6) δ 12.51 (br s, 1 H), 7.57 (s, 1 H), 7.37-7.30 (m, 4 H), 7.25 (t, 1 H, J = 8.0 Hz), 7.18
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(t, 1 H, J = 8.0 Hz), 4.58 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 158.1, 146.6, 139.0, 128.6 (2 C), 127.1, 126.9, 126.7 (2 C), 97.0, 45.3; HRMS (ESI) m/z calc’d for C11H11BrN3O [M+H]+ 280.0085, found 280.0078. N-benzyl-6-phenylfuro[2,3-c]pyridazin-4-amine (3). Compound 3 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon dissolution of the concentrated reaction mixture in EtOAc, a light brown solid crystallized from the solution. This solid was filtered and dried to provide 3 (262 mg, 81%). mp 255.5 – 256.8 °C (EtOAc); IR (film) 3174, 3057, 2957, 2864, 1601, 1488, 1455, 1356, 1089, 868, 757 cm-1; 1H NMR (DMSO-d6) δ 8.50 (s, 1 H), 8.00 (t, 1 H, J = 8.0 Hz), 7.89 (d, 2 H, J = 8.0 Hz), 7.56-7.53 (m, 3 H), 7.43-7.48 (m, 3 H), 7.37 (t, 2 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 8.0 Hz), 4.68 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.2, 152.7, 141.2, 138.5, 133.6, 129.6, 129.2 (2 C), 128.7, 128.6 (2 C), 127.4 (2 C), 127.3, 124.8 (2 C), 107.3, 99.3, 45.9; HRMS (ESI) m/z calc’d for C19H16N3O [M+H]+ 302.1293, found 302.1275. N-benzyl-6-butylfuro[2,3-c]pyridazin-4-amine (6). Compound 6 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 6 was isolated as a white solid (244 mg, 81%). mp 139.0 – 140.6 °C (EtOAc); IR (film) 3182, 3064, 2955, 2930, 1567, 1486, 1347, 1177. 860, 696 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.85 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.79 (s, 1 H), 4.60 (d, 2 H, J = 8.0 Hz), 2.77 (t, 2 H, J = 8.0 Hz), 1.66 (p, 2 H, J = 8.0 Hz), 1.36 (m, 2 H), 0.91 (t, 3 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.1, 158.0, 140.8, 138.5, 132.5, 128.5 (2 C), 127.2 (2 C), 127.1, 107.4, 99.4, 45.6, 28.8, 27.2, 21.5, 13.6; HRMS (ESI) m/z calc’d for C17H20N3O [M+H]+ 282.1606, found 282.1589. 2-(4-(benzylamino)furo[2,3-c]pyridazin-6-yl)propan-2-ol (8). Compound 8 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 8 was isolated as a light brown solid (282 mg, 93%). mp 77.0 – 79.2 °C (EtOAc); IR (film) 3327, 3182, 3064, 2980, 1614, 1565, 1346, 1260, 938, 695 cm-1; 1H NMR (1:1 D2O:DMSO-d6) δ 8.37 (s, 1 H), 7.37-7.31 (m, 4 H), 7.25 (t, 1 H, J = 8.0 Hz), 6.84 (s, 1 H), 4.57 (s, 2 H), 1.49 (s, 6 H); 13C NMR (1:1 D2O:DMSO-d6) δ 165.5, 163.2, 141.5, 138.8, 133.0, 129.0 (2 C), 127.6, 127.5 (2 C), 107.3, 97.7, 68.0, 45.8, 28.9 (2 C); HRMS (ESI) m/z calc’d for C16H18N3O2 [M+H]+ 284.1399, found 284.1381. 2-(4-(benzylamino)furo[2,3-c]pyridazin-6-yl)ethan-1-ol (10). Compound 10 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc to 5%
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MeOH/95% EtOAc), 10 was isolated as a light brown solid (225 mg, 78%). mp 135.5 – 135.9 °C (EtOAc); IR (film) 3261, 3186, 2943, 2887, 1619, 1566, 1456, 1053, 729 cm-1; 1H NMR (DMSO-d6) δ 8.40 (s, 1 H), 7.80 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.26 (t, 1 H, J = 8.0 Hz), 6.82 (s, 1 H), 4.85 (t, 1 H, J = 8.0 Hz), 4.59 (d, 2 H, J = 8.0 Hz), 3.75 (q, 2 H, J = 8.0 Hz), 2.91 (t, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.3, 155.6, 140.5, 138.7, 132.7, 128.5 (2 C), 127.2 (2 C), 127.1, 107.2, 100.3, 58.5, 45.6, 31.7; HRMS (ESI) m/z calc’d for C15H16N3O2 [M+H]+ 270.1243, found 270.1227. (4-(benzylamino)furo[2,3-c]pyridazin-6-yl)methanol (12). Compound 12 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 12 was isolated as a white solid (251 mg, 92%). mp 62.5 – 64.2 °C (EtOAc); IR (film) 3315, 3181, 3063, 1615, 1567, 1347, 1025, 696 cm-1; 1H NMR (DMSO-d6) δ 8.44 (s, 1 H), 7.89 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.92 (s, 1 H), 5.59 (t, 1 H, J = 8.0 Hz), 4.61 (d, 2 H, J = 8.0 Hz), 4.56 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.4, 156.8, 141.1, 138.6, 132.9, 128.5 (2 C), 127.13, 127.11 (2 C), 106.5, 100.2, 56.1, 45.5; HRMS (ESI) m/z calc’d for C14H14N3O2 [M+H]+ 256.1086, found 256.1070. tert-butyl ((4-(benzylamino)furo[2,3-c]pyridazin-6-yl)methyl)carbamate (14). Compound 14 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 14 was isolated as a white solid (294 mg, 78%). mp 148.4 – 149.1 °C (EtOAc); IR (film) 3352, 3188, 3065, 1692, 1615, 1248, 1168, 931, 694 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.90 (t, 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.39-7.33 (m, 4 H), 7.26 (t, 1 H, J = 8.0 Hz), 6.86 (s, 1 H), 4.59 (d, 2 H, J = 8.0 Hz), 4.28 (d, 2 H, J = 8.0 Hz), 1.40 (s, 9 H); 13C NMR (DMSO-d6) δ 165.3, 155.5, 154.6, 140.8, 138.5, 132.7, 128.5 (2 C), 127.1 (3 C), 106.7, 100.0, 78.3, 45.5, 37.4, 28.2 (3 C); HRMS (ESI) m/z calc’d for C19H23N4O3 [M+H]+ 355.1770, found 355.1754. N-benzyl-6-(3-chloropropyl)furo[2,3-c]pyridazin-4-amine (16). Compound 16 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 16 was isolated as a light brown solid (235 mg, 73%). mp 150.0 – 151.1 °C (EtOAc); IR (film) 3257, 3062, 2961, 1565, 1355, 947, 753 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.86 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.84 (s, 1 H), 4.60 (d, 2 H, J = 8.0 Hz), 3.71 (t, 2 H, J = 8.0 Hz), 2.92 (t, 2 H, J = 8.0 Hz), 2.13
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(p, 2 H, J = 8.0 Hz);
13
C NMR (DMSO-d6) δ 165.2, 156.2, 140.8, 138.5, 132.7, 128.5 (2 C), 127.2 (2 C), 127.1,
107.1, 100.0, 45.6, 44.4, 29.8, 25.0; HRMS (ESI) m/z calc’d for C16H17ClN3O [M+H]+ 302.1060, found 302.1045. N-benzyl-6-(tert-butyl)furo[2,3-c]pyridazin-4-amine (18). Compound 18 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 18 was isolated as a light brown solid (242 mg, 80%). mp 235.6 – 237.3 °C (EtOAc); IR (film) 3246, 3068, 2974, 2871, 1610, 1563, 1352, 1102, 700 cm-1; 1H NMR (DMSO-d6) δ 8.41 (s, 1 H), 7.77 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.76 (s, 1 H), 4.59 (d, 2 H, J = 8.0 Hz), 1.34 (s, 9 H); 13C NMR (DMSO-d6) (at 333 K) δ 165.1, 164.7, 140.5, 138.3, 132.5, 128.2 (2 C), 127.0 (2 C), 126.8, 106.8, 96.3, 45.6, 32.4, 28.0 (3 C); HRMS (ESI) m/z calc’d for C17H20N3O [M+H]+ 282.1606, found 282.1591. 4-bromo-5-(piperidin-1-yl)pyridazin-3(2H)-one (20). 4,5-dibromopyridazin-3(2H)-one (2.00 g, 7.87 mmol, 1 eq), piperidine (1.35 g, 15.8 mmol, 2 eq) and diisopropylethylamine (4.07 g, 31.5 mmol, 4 eq) were dissolved in DMAc (40 mL) and heated at 70 °C for 4 hr. The reaction mixture was then diluted with brine (100 mL), followed by the addition of EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted EtOAc (30 mL; 3x). The combined organic layers were washed with water (100 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was recrystallized from CH2Cl2 (200 mL) to provide 1.59 g (78%) of 20 as a white solid. mp 182.6 – 183.1 °C (CH2Cl2); IR (film) 3177, 2916, 1622, 1587, 1246, 857, 737 cm-1; 1H NMR (DMSO-d6) δ 12.79 (br s, 1 H), 7.74 (s, 1 H), 3.31 (t, 4 H, J = 8.0 Hz), 1.62-1.60 (m, 6 H); 13C NMR (DMSO-d6) δ 159.0, 151.4, 132.1, 107.5, 50.1 (2 C), 25.5 (2 C), 23.4; HRMS (ESI) m/z calc’d for C9H13BrN3O [M+H]+ 258.0242, found 258.0234. 2-(4-(piperidin-1-yl)furo[2,3-c]pyridazin-6-yl)propan-2-ol (21). Compound 21 was prepared from 20 (300 mg, 1.16 mmol; 0.5 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 21 was isolated as a light brown solid (166 mg, 82%). mp 203.5 – 205.5 °C (EtOAc); IR (film) 3185, 3111, 2937, 1575, 1304, 1187, 941, 654 cm-1; 1H NMR (DMSO-d6) δ 8.68 (s, 1 H), 6.87 (s, 1 H), 5.57 (s, 1 H), 3.60 (t, 4 H, J = 8.0 Hz), 1.64 (m, 6 H), 1.53 (s, 6 H); 13C NMR (DMSO-d6) δ 165.5, 162.8, 142.6, 135.1, 108.1, 98.9, 67.6, 48.5 (2 C), 28.7 (2 C), 25.1 (2 C), 23.6; HRMS (ESI) m/z calc’d for C14H20N3O2 [M+H]+ 262.1556, found 262.1540. tert-butyl ((4-(piperidin-1-yl)furo[2,3-c]pyridazin-6-yl)methyl)carbamate (22). Compound 22 was prepared from 20 (300 mg, 1.16 mmol; 0.5 M) according to the general protocol. Upon purification by chromatography on
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SiO2 (100% EtOAc), 22 was isolated as a white solid (363 mg, 94%). mp 142.0 – 143.8 °C (EtOAc); IR (film) 3199, 3111, 2923, 2844, 1698, 1572, 1168, 1014 cm-1; 1H NMR (DMSO-d6) δ 8.70 (s, 1 H), 7.53 (t, 1 H, J = 8.0 Hz), 6.91 (s, 1 H), 4.30 (d, 2 H, J = 4.0 Hz), 3.59 (d, 4 H, J = 4.0 Hz), 1.61 (m, 6 H), 1.40 (s, 9 H); 13C NMR (DMSO-d6) δ 165.6, 155.5, 154.3, 142.4, 135.2, 107.8, 101.9, 78.3, 48.4 (2 C), 37.3, 28.1 (3 C), 25.0 (2 C), 23.6; HRMS (ESI) m/z calc’d for C17H25N4O3 [M+H]+ 333.1927, found 333.1910. tert-butyl (5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)glycinate (23). 4,5-dibromopyridazin-3(2H)-one (5.00 g, 19.6 mmol, 1 eq), glycine t-butyl ester hydrochloride (4.93 g, 29.4 mmol, 1.5 eq) and diisopropylethylamine (12.7 g, 98.0 mmol, 5 eq) were dissolved in NMP (150 mL) and heated at 100 °C for 14 hr. The reaction mixture was treated with 1 M HCl (aqueous; 300 mL), followed by the addition of EtOAc (500 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (100 mL, 3x). The combined organic layers were washed with water (400 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was purified chromatography on SiO2 (20% Hex/EtOAc to 100% EtOAc) to provide 3.89 g (65%) of 23 as bright yellow solid. mp 143.0 – 146.4 °C (Hex/EtOAc); IR (film) 3361, 3138, 2978, 1731, 1593, 1367, 1147, 843, 742 cm-1; 1H NMR (CDCl3) δ 12.20 (br s, 1 H), 7.42 (s, 1 H), 5.56 (t, 1 H, J = 8.0 Hz), 4.00 (d, 2 H, J = 8.0 Hz), 1.51 (s, 9 H); 13C NMR (CDCl3) δ 167.7, 159.9, 145.9, 126.7, 99.9, 83.9, 45.3, 28.2 (3 C); HRMS (ESI) m/z calc’d for C10H15BrN3O3 [M+H]+ 304.0297, found 304.0291. tert-butyl (6-phenylfuro[2,3-c]pyridazin-4-yl)glycinate (24). Compound 24 was prepared from 23 (200 mg, 0.658 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 24 was isolated as a light brown solid (184 mg, 86%). mp 220.1 – 223.0 °C (EtOAc); IR (film) 3324, 3184, 3079, 2982, 1738, 1616, 1148, 763 cm-1; 1H NMR (DMSO-d6) δ 8.50 (br s, 1 H), 7.91 (d, 2 H, J = 8.0 Hz), 7.73 (t, 1 H, J = 8.0 Hz), 7.55 (t, 2 H, J = 8.0 Hz), 7.51-7.47 (m, 2 H), 4.25 (d, 2 H, J = 8.0 Hz), 1.43 (s, 9 H); 13C NMR (DMSO-d6) δ 169.1, 165.1, 153.1, 141.3, 133.8, 129.6, 129.2 (2 C), 128.6, 124.8 (2 C), 107.5, 98.9, 81.3, 44.7, 27.7 (3 C); HRMS (ESI) m/z calc’d for C18H20N3O3 [M+H]+ 326.1505, found 326.1490. tert-butyl (6-(2-hydroxyethyl)furo[2,3-c]pyridazin-4-yl)glycinate (25). Compound 25 was prepared from 23 (200 mg, 0.658 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 25 was isolated as a waxy brown solid (184 mg, 95%). mp 75.8 – 76.9 °C (EtOAc); IR (film) 3187, 2979, 2931, 1737, 1619, 1150, 1050, 762 cm-1; 1H NMR (DMSO-d6) δ 8.40 (s, 1 H), 7.57 (t, 1 H, J = 8.0 Hz), 6.77 (s, 1
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H), 4.91 (br s, 1 H), 4.14 (d, 2 H, J = 8.0 Hz), 3.76 (t, 2 H, J = 8.0 Hz), 2.93 (t, 2 H, J = 8.0 Hz), 1.42 (s, 9 H); 13C NMR (DMSO-d6) δ 169.2, 165.2, 156.2, 140.8, 132.8, 107.4, 100.1, 81.2, 58.5, 44.5, 31.7, 27.7 (3 C); HRMS (ESI) m/z calc’d for C14H20N3O4 [M+H]+ 294.1454, found 294.1441. 4-bromo-5-(phenylamino)pyridazin-3(2H)-one (26). 4,5-dibromopyridazin-3(2H)-one (5.00 g, 19.7 mmol, 1 eq) and aniline (11.0 g, 118 mmol, 6 eq) were dissolved in DMAc (150 mL) and water (30 mL) and heated at 120 °C for 14 hr. The reaction mixture was then concentrated via rotary evaporation to yield a thick oil. The oil was cooled to 0 °C and treated with water (250 mL). The resulting slurry was filtered, and the solid was dried under vacuum. The crude solid was then recrystallized from EtOAc (100 mL) to give 4.2 g (77%) of 26 as a white solid. mp 233.4 – 234.9 °C (EtOAc); IR (film) 3361, 3213, 3115, 2838, 1603, 1573, 1495, 1413, 1299, 877, 759 cm-1; 1H NMR (DMSO-d6) δ 12.71 (br s, 1 H), 8.55 (br s, 1 H), 7.48 (s, 1 H), 7.41 (t, 2 H, J = 8.0 Hz), 7.27 (d, 2 H, J = 8.0 Hz), 7.21 (t, 1 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 158.4, 144.8, 138.6, 129.4 (2 C), 128.2, 125.2, 124.0 (2 C), 100.6; HRMS (ESI) m/z calc’d for C10H9BrN3O [M+H]+ 265.9929, found 265.9921. (4-(phenylamino)furo[2,3-c]pyridazin-6-yl)methanol (27). Compound 27 was prepared from 26 (300 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 27 was isolated as a light brown solid (241 mg, 89%). mp 199.7 – 200.9 °C (EtOAc); IR (film) 3319, 3252, 3056, 1614, 1564, 1350, 1021, 720 cm-1; 1H NMR (DMSO-d6) δ 9.35 (s, 1 H), 8.75 (s, 1 H), 7.43 (t, 2 H, J = 8.0 Hz), 7.29 (d, 2 H, J = 8.0 Hz), 7.19 (t, 1 H, J = 8.0 Hz), 6.58 (s, 1 H), 5.64 (t, 1 H, J = 8.0 Hz), 4.59 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.8, 157.9, 139.2, 138.0, 134.7, 129.5 (2 C), 124.4, 122.0 (2 C), 108.3, 100.3, 56.2; HRMS (ESI) m/z calc’d for C13H12N3O2 [M+H]+ 242.0930, found 242.0914. 6-(3-chloropropyl)-N-phenylfuro[2,3-c]pyridazin-4-amine (28). Compound 28 was prepared from 26 (300 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon dissolution of the concentrated reaction mixture in EtOAc, a light brown solid crystallized from the solution. This solid was filtered and dried to provide 28 (188 mg, 87%). mp 155.7 – 157.9 °C (EtOAc); IR (film) 3180, 3073, 1610, 1564, 1491, 945, 702 cm-1; 1H NMR (DMSO-d6) δ 9.31 (s, 1 H), 8.72 (s, 1 H), 7.42 (t, 2 H, J = 8.0 Hz), 7.27 (d, 2 H, J = 8.0 Hz), 7.17 (t, 1 H, J = 8.0 Hz), 6.51 (s, 1 H), 3.72 (t, 2 H, J = 8.0 Hz), 2.95 (t, 2 H, J = 8.0 Hz), 2.13 (p, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.8, 157.1, 139.3, 137.5, 134.6, 129.4 (2 C), 124.1, 121.7 (2 C), 108.8, 100.3, 44.4, 29.8, 25.1; HRMS (ESI) m/z calc’d for C15H15ClN3O [M+H]+ 288.0904, found 288.0890.
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5-(benzylamino)-4-((trimethylsilyl)ethynyl)pyridazin-3(2H)-one (30). Compound 30 was prepared from 1 (316 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (50% hexanes/50% EtOAc to 20% hexanes/80% EtOAc), 30 was isolated as a light brown solid (258 mg, 81%). mp 201.4 – 202.6 °C (Hex/EtOAc); IR (film) 3257, 3146, 3027, 2950, 2892, 2151, 1631, 1568, 1347, 835, 694 cm-1; 1H NMR (DMSO-d6) δ 12.36 (br s, 1 H), 7.63 (s, 1 H), 7.38-7.27 (m, 5 H), 7.03 (br s, 1 H), 4.70 (d, 2 H, J = 8.0 Hz), 0.20 (s, 9 H); 13C NMR (DMSO-d6) δ 160.5, 149.9, 139.0, 128.6 (2 C), 128.0, 127.1, 126.7 (2 C), 106.3, 97.7, 93.3, 45.5, 0.01 (3 C); HRMS (ESI) m/z calc’d for C16H20N3OSi [M+H]+ 298.1376, found 298.1363. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1
H and 13C spectra (PDF)
Crystallographic information for 10 (PDF, CIF) AUTHOR INFORMATION Corresponding Author *Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ORCID David L. Waller: 0000-0001-6972-9455 Notes This work was initiated prior to the acquisition of Cubist Pharmaceuticals by Merck & Co., and continued thereafter. The authors declare no competing financial interest. Present Address Present address for DLW: Sage Therapeutics, 215 First Street, Cambridge, Massachusetts, 02142, United States. Present address for JMG: Department of Chemistry, Princeton University, Frick Chemistry Laboratory, Princeton, New Jersey, 08540, United States.
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Acknowledgments The authors thank Dr. Andrew Brunskill (Merck) for X-ray crystallographic analysis of 10. Dr. Zhengzheng Pan (Cubist/Merck) is acknowledged for the acquisition of all mass spectrometry data. The authors would also like to thank Dr. Pamela Tadross (Cubist/Merck) for helpful discussions. References
(1) Bohacek, R. S.; McMartin, C.; Guida, W. C. Med. Res. Rev. 1996, 16, 3. (2) For a discussion of hydrogen-bonding and non-covalent interactions of heterocycles, see: Saenger, J. W. Hydrogen Bonding in Biological Structures; Springer-Verlag: New York, 1991. (3) Frieden, E. J. Chem. Educ. 1975, 52, 754. (4) For a discussion of the roles heterocycles play in biological processes, see: Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications, 2nd ed.; Wiley-VCH: Weinheim, 2011. (5) Dua, R.; Shrivastava, S.; Sonwane, S. K.; Shrivastava, S. K. Adv. Biol. Res. 2011, 5, 120. (6) Vitaku, E.; Smith, D. T.; Njardson, J. T. J. Med. Chem. 2014, 57, 10257. (7) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (8) For a review on N-heterocyclic carbenes in late transition metal catalysis, see: Diez-Gonzalez, S.; Marion, N.; Nolan, S. Chem. Rev. 2009, 109, 3612. (9) For the pioneering use of quinoxalines in metathesis catalysts, see: Barbasiewicz, M; Szadkowska, A.; Bujok, R.; Grela, K. Organometallics 2006, 25, 3599. (10) For a representative application in photoredox catalysis, see: Johnston, C.; Smith, R.; Allmendinger, S.; MacMillan, D. Nature 2016, 536, 322. (11) For an example of the use of a benzimidazole ligand in palladium catalysis, see: Fu, W. C.; Wu, Y.; So, C. M.; Wong, S. M.; Lei, A.; Knowg, F. Y. Org. Lett. 2016, 18, 5300. (12) Wang, P.; Farmer, M.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J.; Wisniewski, S.; Eastgate, M.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269. (13) He, G.; Chen, G. Angew. Chem. Int. Ed. 2011, 50, 5192. (14) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.; Miura, M. Chem. Lett. 2009, 38, 118.
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(15) Cao, W.; Zheng, X.-J.; Sun, J.-P.; Wong, W.-T.; Fang, D.-C.; Zhang, J.-X.; Jin, L.-P. Inorg. Chem. 2014, 53, 3012. (16) Ganjali, M.; Hosseini, M.; Memari, Z.; Faridbod, F.; Norouzi, P.; Goldooz, H.; Badiei, A. Anal. Chim. Acta. 2011, 708, 107. (17) Mason, J.; Oktawiec, J.; Taylor, M.; Hudson, M.; Rodriguez, J.; Bachman, J.; Gonzalez, M.; Cervellino, A.; Guagliardi, A.; Brown, C.; Llewellyn, P.; Masciocchi, N.; Long, J. Nature 2015, 527, 357. (18) Shi, Y.; Yu, G. Chem. Mater. 2016, 28, 2466. (19) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem. 2009, 52, 2952. (20) Shalaby, A. A. J. fuer Prakt. Chemie 1990, 332, 104. (21) Deeb, A.; Bayoumy, B.; Yasine, F.; Fikry, R. Zeitschrift fuer Naturforschung, B Chem. Sci. 1997, 47, 418. (22) Hilpert, K; Hubler, F.; Kimmerlin, T.; Murphy, M; Renneberg, D.; Stamm, S. PCT Int. Appl. WO2013014587A1, 2013. (23) Abdou, W.; Ganoub, N.; Fahmy, A.; Shaddy, A. Heteroat. Chem. 2005, 16, 56. (24) Abdou, W.; Ganoub, N.; Fahmy, A.; Shaddy, A. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 2373. (25) A single example of this type of coupling-cyclization was previously reported as a minor product in a reaction mixture: de Araujo-Junior, J. X.; Schmitt, M., Benderitter, P.; Bourguignon, J.-J. Tetrahedron Lett. 2006, 47, 6125. (26) See the Experimental Procedures for information on the preparation of pyridazinones 1, 20, 23 and 26. Starting pyridazinones 1 and 20 have been previously synthesized: Ball, W. Eur. Pat. Appl. EP0741319A1, 1996. However, in this Note, we provide full analytical characterization of these compounds. (27) Yi, C.; Hua, R. J. Org. Chem. 2005, 71, 2535. (28) Hundertmark, T.; Littke, A.; Buchwald, S.; Fu, G. Org. Lett. 2000, 2, 1729. (29) Sørenson, U.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697. (30) Bosiak, M. ACS Catal. 2016, 6, 2429. (31) We were also cognizant of the potential for in situ cyclization of the benzylamino substituent into the alkyne following Sonogashira coupling. For examples, see: Larock, R.; Yum, E. J. Am. Chem. Soc. 1991, 113, 6689, and reference 32. (32) Cacchi, S.; Frabrizi, G. Chem. Rev. 2005, 105, 2873.
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(33) For examples, see: Jasselin-Hinschberger, A.; Comoy, C.; Chartoire, A.; Fort, Y. Eur. J. Org. Chem. 2015, 2321 and references cited therein. (34) In couplings with substrate 20, UPLCMS indicated 1-5% of a by-product that had a mass consistent with protodebromination of 20. (35) This argument assumes that some degree of electrophilic character must accumulate on the α carbon to initiate the cyclization event, likely by coordination of the alkyne with a metal catalyst. A related failure of silaneterminated alkynes to undergo a related cyclization has been reported: Houpis, I.; Choi, W.; Reider, P.; Molina, A.; Churchill, H.; Lynch, J.; Volante, R. Tet. Lett. 1994, 35, 9355. (36) See the Supporting Information for details concerning the X-ray diffraction study.
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Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis Jacob M. Ganley, and David L. Waller J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01819 • Publication Date (Web): 11 Oct 2017 Downloaded from http://pubs.acs.org on October 11, 2017
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Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis Jacob M. Ganley and David L. Waller* Manufacturing Process Development, Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, Massachusetts, United States Chemical Commercialization & Technical Operations, Merck & Co., 65 Hayden Avenue, Lexington, Massachusetts, United States
Abstract: A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira couplingcycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 hours. The structure of the heterocyclic ring system was confirmed through single crystal X-ray crystallography. In 1996, Bohacek estimated the universe of organic molecules to contain 1060 structures.1 Among this staggering number, heterocycles occupy a privileged subset due to their importance in the chemistry of living systems and their unique electronic properties.2,3,4,5 Pharmaceutical chemists have long exploited the unique properties of heterocycles in the development of drug candidates, as indicated by surveys of commercially approved drugs.6,7 In the realm of organic synthesis, heterocycles serve as key ligands on metals in numerous catalytic transformations8,9,10,11 and as directing groups for C-H activation.12,13,14 Heterocycles are also receiving increased attention as components of chemical sensors15,16 and innovative materials.17,18 A 2009 report by Pitt estimated the size of the heterocyclic chemical space and concluded that only a small fraction of conceivable heterocycles have been reported.19 Taken together, the field of heterocyclic chemistry appears to be vast, relatively unexplored and full of potential. In this Note, we report our exploration into an uncommon heterocycle, the furo[2,3-c]pyridazine (Scheme 1, top).
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Scheme 1. Structure, numbering and general strategies to prepare the furo[2,3-c]pyridazine ring system.
There are only a handful of reports in the literature describing methods to prepare the furo[2,3-c]pyridazine ring system. In general, these reports rely on one of two approaches: a Dieckmann-type condensation20,21,22 (Scheme 1, eq 1) or a Wittig-based strategy23,24 (Scheme 1, eq 2). While only a few examples of each reaction manifold have been published, these strategies suffer from a tedious starting material preparation and a lack of functional group tolerance. During an investigation of palladium-catalyzed couplings in heterocyclic substrates, we observed that furo[2,3c]pyridazines could be easily accessed through a tandem Sonogashira-cycloisomerization reaction of a bromopyridizinone and an alkyne (Scheme 1, eq 3).25 Given the scarcity of information regarding the synthesis and properties of furo[2,3-c]pyridazines, as well as the single-step access to 2-bromo-3-aminopyridizinones, we sought to optimize this tandem reaction. We initially targeted a Sonogashira coupling on substituted pyridazinone 1 (Scheme 2).26 A brief screen was conducted to identify a catalyst capable of carrying out the desired coupling. Four ligands were selected based on literature precedence indicating their ability to mediate Sonogashira couplings in heterocyclic systems at sterically encumbered positions (P(Cy)3, P(t-Bu)3, P(o-Tol)3 and 1,1'-Bis(diphenylphosphino)ferrocene (DPPF)).27,28,29,30 Of these four ligands, only DPPF showed reactivity, with 43% conversion being observed by UPLCMS. Isolation and characterization of this compound by 1H and
13
C NMR analysis revealed it to be pyridazine 3, the product of the
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desired Sonogashira coupling followed by cycloisomerization of the amide moiety into the alkyne.31,32 While analogous cyclizations have been reported in different substrate classes,33 our interest in the rare furo[2,3c]pyridazine ring system prompted us to optimize this reaction. Scheme 2. Screen of ligands and formation of the furo[2,3-c]pyridazine ring system.a
a
See Experimental Procedures for reaction conditions.
To optimize formation of the furo[2,3-c]pyridazine, we retained the palladium source and base used in the screening reaction, but increased the temperature to 80 °C, which necessitated a switch to dioxane as the solvent (Table 1, entry 1). These conditions provided a sluggish reaction, requiring 24 hours to reach 91% conversion. Switching to PdCl2(PhCN)2 and (i-Pr)2NH dramatically increased the reaction rate and allowed for a reduction in palladium loading, although the conversion abruptly stopped at 80% (entry 2).28 A simple increase in the temperature to 100 °C addressed the reaction stalling, providing 100% conversion to 3 in 2 hours (entry 3). Any efforts to reduce the amount of base, Pd or Cu used in the reaction failed to provide satisfactory outcomes (entries 46). Table 1. Optimization of furo[2,3-c]pyridazine synthesisa
Entry
Pd/Cu Loadingb (mol%)
Temperature (°C)
Time (hr)
Conversionc (%)
1d,e
10/5
80
24
91%
2
5/5
80
4
80%
3
5/5
100
2
100%
4f
5/5
100
4
78%
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a
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5
5/2.5
100
2
52%
6
2.5/5
100
2
85%
Unless indicated otherwise, reactions were performed on a 200 mg scale at 0.2 M in dioxane, with 2 equivalents of
phenylacetylene, 2 equivalents of (i-Pr)2NH and 1.5X equivalents of DPPF, where X is equal to the molar charge of Pd. bThe Pd source was PdCl2(PhCN)2, and the Cu source was CuI, unless indicated otherwise. cConversion was measured by UPLCMS, where conversion = [AUC(product) ÷ AUC(product + starting material)] x 100%. dEt3N was used instead of (i-Pr)2NH. ePdCl2(H3CCN)2 was used instead of PdCl2(PhCN)2. f1 equivalent of (i-Pr)2NH was used instead of 2 equivalents. With optimized conditions in hand, we explored the substrate scope of the alkyne coupling partner in reactions with pyridazinone 1 (Figure 1). Phenyl acetylene and 1-hexyne both cleanly underwent the couplingcycloisomerization reaction to provide their corresponding furopyridazines in good isolated yields (3 and 6, respectively). The presence of a free alcohol in the alkyne fragment was well-tolerated (8, 10 and 12), as was a Bocprotected amine (14) and alkyl chloride (16). Use of t-butylacetylene provided the desired furopyridazine 18 in 80% yield, indicating a high steric tolerance in the reaction. However, ethyl propiolate (19) failed to give any desired product; LCMS analysis indicated rapid addition of diisopropylamine to the alkynoate, thereby preventing further reactivity in this manifold.
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Substrate
Alkyne
Product
NHBn
Yield (%)
NHBn
Br N
N H
Ph O
N
2
1
81%
Ph O
N
3
NHBn n-Bu
1
N
5
n-Bu O
N
81%
6
NHBn CH3 OH CH3
1 7
N
O
N
CH3 OH CH3
8
93%
NHBn OH
OH 1
N 9
O
N
78%
10
NHBn OH 1
N 11
N
O
OH
92%
NHBoc
78%
12
NHBn NHBoc 1 N 13
N
O
14
NHBn (CH2)3 Cl
1
73% N
15
(CH2)3 Cl
N
O 16
NHBn 1
t-Bu N
17
t-Bu N
80%
O 18
O 1 OEt
N/A
N/A
19
Figure 1. Substrate scope of furo[2,3-c]pyridazine formation with 1. Yields reported are isolated yields after purification. We next examined the effect of the β-amino substitution on the coupling-cycloisomerization reaction (Figure 2). When piperidine-substituted pyridizinone 20 was submitted to standard coupling conditions with propargyl alcohol 7 as the coupling partner, the reaction proceeded to only 12% conversion after 2 hours, likely due to the increased steric demand of the piperidine substitution. Increasing the concentration from 0.2 M to 0.5 M dramatically improved the rate, providing 100% conversion in 3 hours and an 82% isolated yield of 21.34 N-Boc propargyl amine also smoothly coupled with pyridizinone 20 at 0.5 M to provide furopyridazine 22 in 94% yield. Ester substitution
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on the pyridizinone was well tolerated, as glycine-substituted 23 underwent the tandem reaction to furnish furopyridazines 24 and 25 in 86 and 95% yields, respectively. Pyridazinone 26, bearing aniline substitution at the β position, cleanly furnished furopyridazines 27 and 28 in excellent yields (89 and 87%, respectively).
Figure 2. Substrate scope of furo[2,3-c]pyridazine with various pyridazinones. Yields reported are isolated yields after purification. While diverse functionality was determined to be suitable in the tandem Sonogashira-cycloisomerization reaction, we did encounter one anomalous substrate during our investigation. When we attempted to couple pyridazinone 1 with TMS-acetylene (29), we observed a typical conversion rate but isolated alkynylpyridazinone 30 in 81% yield instead of the expected bicyclic product 31 (Scheme3). This failure to cyclize was attributed to electronic effects rather than steric effects, given that t-butylacetylene is a competent coupling partner with pyridizinone 1 (see Figure
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1, compound 18). One potential rationale is that the silicon atom decreases the electrophilic character of the α carbon enough to prevent cyclization of the nucleophilic oxygen.35 Scheme 3. Failure of cyclization with TMS-acetylene (29) in the tandem reaction.
To further strengthen our structural assignment of the furo[2,3-c]pyridazine ring system, we characterized the structure of compound 10 (Figure 1) by single crystal X-ray diffraction analysis,36 as shown in Figure S1 of the Supporting Information. In summary, we have reported the development of a rapid and efficient method to prepare the furo[2,3c]pyridazine ring system via a Sonogashira coupling followed by cycloisomerization of the transient αalkynylpyridazinone intermediate. The approach capitalizes on readily available starting materials, is tolerant of a variety of functional groups, and proceeds in good to excellent yields. We envision this protocol enabling investigations of the rare furo[2,3-c]pyridazine ring system and its associated chemistry in applications across multiple disciplines. Experimental Section All starting materials and solvents were purchased and used without further purification. All reactions were monitored by UPLCMS on a Waters Acquity instrument until the starting material was completely consumed. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel 60 F-254 plates (particle size 0.040-0.055 mm, 230-400 mesh) and visualized using UV light. 1H and 13C spectroscopic data were recorded on a Bruker Ascend NMR spectrometer (400 and 100 MHz, respectively) at 23 °C unless otherwise stated. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance (CDCl3: δ 7.26/77.0, 1
H/13C; DMSO-d6: δ 2.49/39.5, 1H/13C). Data are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, sex = sextet, m = multiplet, b = broad, app = apparent), integration and coupling constant(s) (Hz). HRMS data we recorded using a Thermo Fischer Scientific Orbitrap Elite and analyzed using XCalibur 2.2 software. Melting points were determined on a Stanford Research Systems OptiMelt automated
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melting point system and are uncorrected. IR absorptions were recorded on a Thermo Scientific Nicolet 380 FTIR instrument and reported in wavenumbers (cm-1). Ligand screen. 2 mL glass vials equipped with magnetic stir bars were charged with 5-(benzylamino)-4bromopyridazin-3(2H)-one (1; 20 mg, 0.071 mmol, 1 eq), followed by THF (357 µL). Next, triethylamine (20 µL, 0.14 mmol, 2 eq), phenylacetylene (15.7 µL, 0.14 mmol, 2 eq), CuI (1 mg, 0.0071 mmol, 10 mol%), ligand (DPPF (12 mg), P(o-Tol)3 (7 mg), P(t-Bu)3 (4 mg) or P(Cy)3 (6 mg); 0.021 mmol, 30 mol%) and bis(acetonitrile) dichloropalladium (4 mg, 0.014 mmol, 20 mol%) were added. The reaction vials were then degassed by evacuating the vials and backfilling with N2 three times. The reaction mixtures were heated at 60 °C and periodically monitored by UPLCMS for reaction conversion (timepoints = 1 h, 2 h, 4 h, 8 h and 24 h). General Protocol for the Synthesis of Furo[2,3-c]pyridazines: The starting 4-bromo-pyridazin-3(2H)-one (1 eq) was charged to the flask, followed by dioxane (2 mL). Next, diisopropylamine (2 eq), alkyne (2 eq), CuI (5 mol%), bis(benzonitrile) dichloropalladium (5 mol%) and DPPF (7.5 mol%) were added. The reaction mixture was then diluted with dioxane to reach the appropriate concentration (0.2 – 0.5 M, depending on the substrate) and degassed by evacuating the flask and backfilling with N2 three times. Next, the mixture was heated at 100 °C in an aluminum heating mantle until UPLCMS indicated completion of the reaction. The cooled reaction mixture was concentrated to dryness on a rotary evaporator and the residue suspended in EtOAc (30 mL). The organic solution/suspension was washed with aqueous saturated NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered, concentrated and the residue purified by chromatography on SiO2, unless indicated otherwise. 5-(benzylamino)-4-bromopyridazin-3(2H)-one (1). 4,5-dibromopyridazin-3(2H)-one (10.0 g, 39.4 mmol, 1 eq), benzylamine (8.44 g, 78.8 mmol, 2 eq) and diisopropylethylamine (10.2 g, 78.8 mmol, 2 eq) were dissolved in DMAc (150 mL) and heated at 90 °C for 21 hr. The reaction mixture was then diluted with brine (300 mL), followed by the addition of EtOAc (300 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (200 mL; 3x). The combined organic layers were washed with water (300 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was recrystallized from CH2Cl2 (600 mL) to provide 7.83 g (71%) of 1 as a white solid. mp 200.0 – 202.0 °C (CH2Cl2); IR (film) 3271, 2956, 2774, 1590, 1441, 1298, 701 cm-1; 1H NMR (DMSO-d6) δ 12.51 (br s, 1 H), 7.57 (s, 1 H), 7.37-7.30 (m, 4 H), 7.25 (t, 1 H, J = 8.0 Hz), 7.18
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(t, 1 H, J = 8.0 Hz), 4.58 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 158.1, 146.6, 139.0, 128.6 (2 C), 127.1, 126.9, 126.7 (2 C), 97.0, 45.3; HRMS (ESI) m/z calc’d for C11H11BrN3O [M+H]+ 280.0085, found 280.0078. N-benzyl-6-phenylfuro[2,3-c]pyridazin-4-amine (3). Compound 3 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon dissolution of the concentrated reaction mixture in EtOAc, a light brown solid crystallized from the solution. This solid was filtered and dried to provide 3 (262 mg, 81%). mp 255.5 – 256.8 °C (EtOAc); IR (film) 3174, 3057, 2957, 2864, 1601, 1488, 1455, 1356, 1089, 868, 757 cm-1; 1H NMR (DMSO-d6) δ 8.50 (s, 1 H), 8.00 (t, 1 H, J = 8.0 Hz), 7.89 (d, 2 H, J = 8.0 Hz), 7.56-7.53 (m, 3 H), 7.43-7.48 (m, 3 H), 7.37 (t, 2 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 8.0 Hz), 4.68 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.2, 152.7, 141.2, 138.5, 133.6, 129.6, 129.2 (2 C), 128.7, 128.6 (2 C), 127.4 (2 C), 127.3, 124.8 (2 C), 107.3, 99.3, 45.9; HRMS (ESI) m/z calc’d for C19H16N3O [M+H]+ 302.1293, found 302.1275. N-benzyl-6-butylfuro[2,3-c]pyridazin-4-amine (6). Compound 6 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 6 was isolated as a white solid (244 mg, 81%). mp 139.0 – 140.6 °C (EtOAc); IR (film) 3182, 3064, 2955, 2930, 1567, 1486, 1347, 1177. 860, 696 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.85 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.79 (s, 1 H), 4.60 (d, 2 H, J = 8.0 Hz), 2.77 (t, 2 H, J = 8.0 Hz), 1.66 (p, 2 H, J = 8.0 Hz), 1.36 (m, 2 H), 0.91 (t, 3 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.1, 158.0, 140.8, 138.5, 132.5, 128.5 (2 C), 127.2 (2 C), 127.1, 107.4, 99.4, 45.6, 28.8, 27.2, 21.5, 13.6; HRMS (ESI) m/z calc’d for C17H20N3O [M+H]+ 282.1606, found 282.1589. 2-(4-(benzylamino)furo[2,3-c]pyridazin-6-yl)propan-2-ol (8). Compound 8 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 8 was isolated as a light brown solid (282 mg, 93%). mp 77.0 – 79.2 °C (EtOAc); IR (film) 3327, 3182, 3064, 2980, 1614, 1565, 1346, 1260, 938, 695 cm-1; 1H NMR (1:1 D2O:DMSO-d6) δ 8.37 (s, 1 H), 7.37-7.31 (m, 4 H), 7.25 (t, 1 H, J = 8.0 Hz), 6.84 (s, 1 H), 4.57 (s, 2 H), 1.49 (s, 6 H); 13C NMR (1:1 D2O:DMSO-d6) δ 165.5, 163.2, 141.5, 138.8, 133.0, 129.0 (2 C), 127.6, 127.5 (2 C), 107.3, 97.7, 68.0, 45.8, 28.9 (2 C); HRMS (ESI) m/z calc’d for C16H18N3O2 [M+H]+ 284.1399, found 284.1381. 2-(4-(benzylamino)furo[2,3-c]pyridazin-6-yl)ethan-1-ol (10). Compound 10 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc to 5%
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MeOH/95% EtOAc), 10 was isolated as a light brown solid (225 mg, 78%). mp 135.5 – 135.9 °C (EtOAc); IR (film) 3261, 3186, 2943, 2887, 1619, 1566, 1456, 1053, 729 cm-1; 1H NMR (DMSO-d6) δ 8.40 (s, 1 H), 7.80 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.26 (t, 1 H, J = 8.0 Hz), 6.82 (s, 1 H), 4.85 (t, 1 H, J = 8.0 Hz), 4.59 (d, 2 H, J = 8.0 Hz), 3.75 (q, 2 H, J = 8.0 Hz), 2.91 (t, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.3, 155.6, 140.5, 138.7, 132.7, 128.5 (2 C), 127.2 (2 C), 127.1, 107.2, 100.3, 58.5, 45.6, 31.7; HRMS (ESI) m/z calc’d for C15H16N3O2 [M+H]+ 270.1243, found 270.1227. (4-(benzylamino)furo[2,3-c]pyridazin-6-yl)methanol (12). Compound 12 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 12 was isolated as a white solid (251 mg, 92%). mp 62.5 – 64.2 °C (EtOAc); IR (film) 3315, 3181, 3063, 1615, 1567, 1347, 1025, 696 cm-1; 1H NMR (DMSO-d6) δ 8.44 (s, 1 H), 7.89 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.92 (s, 1 H), 5.59 (t, 1 H, J = 8.0 Hz), 4.61 (d, 2 H, J = 8.0 Hz), 4.56 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.4, 156.8, 141.1, 138.6, 132.9, 128.5 (2 C), 127.13, 127.11 (2 C), 106.5, 100.2, 56.1, 45.5; HRMS (ESI) m/z calc’d for C14H14N3O2 [M+H]+ 256.1086, found 256.1070. tert-butyl ((4-(benzylamino)furo[2,3-c]pyridazin-6-yl)methyl)carbamate (14). Compound 14 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 14 was isolated as a white solid (294 mg, 78%). mp 148.4 – 149.1 °C (EtOAc); IR (film) 3352, 3188, 3065, 1692, 1615, 1248, 1168, 931, 694 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.90 (t, 1 H, J = 8.0 Hz), 7.56 (t, 1 H, J = 8.0 Hz), 7.39-7.33 (m, 4 H), 7.26 (t, 1 H, J = 8.0 Hz), 6.86 (s, 1 H), 4.59 (d, 2 H, J = 8.0 Hz), 4.28 (d, 2 H, J = 8.0 Hz), 1.40 (s, 9 H); 13C NMR (DMSO-d6) δ 165.3, 155.5, 154.6, 140.8, 138.5, 132.7, 128.5 (2 C), 127.1 (3 C), 106.7, 100.0, 78.3, 45.5, 37.4, 28.2 (3 C); HRMS (ESI) m/z calc’d for C19H23N4O3 [M+H]+ 355.1770, found 355.1754. N-benzyl-6-(3-chloropropyl)furo[2,3-c]pyridazin-4-amine (16). Compound 16 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 16 was isolated as a light brown solid (235 mg, 73%). mp 150.0 – 151.1 °C (EtOAc); IR (film) 3257, 3062, 2961, 1565, 1355, 947, 753 cm-1; 1H NMR (DMSO-d6) δ 8.43 (s, 1 H), 7.86 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.84 (s, 1 H), 4.60 (d, 2 H, J = 8.0 Hz), 3.71 (t, 2 H, J = 8.0 Hz), 2.92 (t, 2 H, J = 8.0 Hz), 2.13
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(p, 2 H, J = 8.0 Hz);
13
C NMR (DMSO-d6) δ 165.2, 156.2, 140.8, 138.5, 132.7, 128.5 (2 C), 127.2 (2 C), 127.1,
107.1, 100.0, 45.6, 44.4, 29.8, 25.0; HRMS (ESI) m/z calc’d for C16H17ClN3O [M+H]+ 302.1060, found 302.1045. N-benzyl-6-(tert-butyl)furo[2,3-c]pyridazin-4-amine (18). Compound 18 was prepared from 1 (300 mg, 1.07 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 18 was isolated as a light brown solid (242 mg, 80%). mp 235.6 – 237.3 °C (EtOAc); IR (film) 3246, 3068, 2974, 2871, 1610, 1563, 1352, 1102, 700 cm-1; 1H NMR (DMSO-d6) δ 8.41 (s, 1 H), 7.77 (t, 1 H, J = 8.0 Hz), 7.40-7.33 (m, 4 H), 7.27 (t, 1 H, J = 8.0 Hz), 6.76 (s, 1 H), 4.59 (d, 2 H, J = 8.0 Hz), 1.34 (s, 9 H); 13C NMR (DMSO-d6) (at 333 K) δ 165.1, 164.7, 140.5, 138.3, 132.5, 128.2 (2 C), 127.0 (2 C), 126.8, 106.8, 96.3, 45.6, 32.4, 28.0 (3 C); HRMS (ESI) m/z calc’d for C17H20N3O [M+H]+ 282.1606, found 282.1591. 4-bromo-5-(piperidin-1-yl)pyridazin-3(2H)-one (20). 4,5-dibromopyridazin-3(2H)-one (2.00 g, 7.87 mmol, 1 eq), piperidine (1.35 g, 15.8 mmol, 2 eq) and diisopropylethylamine (4.07 g, 31.5 mmol, 4 eq) were dissolved in DMAc (40 mL) and heated at 70 °C for 4 hr. The reaction mixture was then diluted with brine (100 mL), followed by the addition of EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted EtOAc (30 mL; 3x). The combined organic layers were washed with water (100 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was recrystallized from CH2Cl2 (200 mL) to provide 1.59 g (78%) of 20 as a white solid. mp 182.6 – 183.1 °C (CH2Cl2); IR (film) 3177, 2916, 1622, 1587, 1246, 857, 737 cm-1; 1H NMR (DMSO-d6) δ 12.79 (br s, 1 H), 7.74 (s, 1 H), 3.31 (t, 4 H, J = 8.0 Hz), 1.62-1.60 (m, 6 H); 13C NMR (DMSO-d6) δ 159.0, 151.4, 132.1, 107.5, 50.1 (2 C), 25.5 (2 C), 23.4; HRMS (ESI) m/z calc’d for C9H13BrN3O [M+H]+ 258.0242, found 258.0234. 2-(4-(piperidin-1-yl)furo[2,3-c]pyridazin-6-yl)propan-2-ol (21). Compound 21 was prepared from 20 (300 mg, 1.16 mmol; 0.5 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 21 was isolated as a light brown solid (166 mg, 82%). mp 203.5 – 205.5 °C (EtOAc); IR (film) 3185, 3111, 2937, 1575, 1304, 1187, 941, 654 cm-1; 1H NMR (DMSO-d6) δ 8.68 (s, 1 H), 6.87 (s, 1 H), 5.57 (s, 1 H), 3.60 (t, 4 H, J = 8.0 Hz), 1.64 (m, 6 H), 1.53 (s, 6 H); 13C NMR (DMSO-d6) δ 165.5, 162.8, 142.6, 135.1, 108.1, 98.9, 67.6, 48.5 (2 C), 28.7 (2 C), 25.1 (2 C), 23.6; HRMS (ESI) m/z calc’d for C14H20N3O2 [M+H]+ 262.1556, found 262.1540. tert-butyl ((4-(piperidin-1-yl)furo[2,3-c]pyridazin-6-yl)methyl)carbamate (22). Compound 22 was prepared from 20 (300 mg, 1.16 mmol; 0.5 M) according to the general protocol. Upon purification by chromatography on
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SiO2 (100% EtOAc), 22 was isolated as a white solid (363 mg, 94%). mp 142.0 – 143.8 °C (EtOAc); IR (film) 3199, 3111, 2923, 2844, 1698, 1572, 1168, 1014 cm-1; 1H NMR (DMSO-d6) δ 8.70 (s, 1 H), 7.53 (t, 1 H, J = 8.0 Hz), 6.91 (s, 1 H), 4.30 (d, 2 H, J = 4.0 Hz), 3.59 (d, 4 H, J = 4.0 Hz), 1.61 (m, 6 H), 1.40 (s, 9 H); 13C NMR (DMSO-d6) δ 165.6, 155.5, 154.3, 142.4, 135.2, 107.8, 101.9, 78.3, 48.4 (2 C), 37.3, 28.1 (3 C), 25.0 (2 C), 23.6; HRMS (ESI) m/z calc’d for C17H25N4O3 [M+H]+ 333.1927, found 333.1910. tert-butyl (5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)glycinate (23). 4,5-dibromopyridazin-3(2H)-one (5.00 g, 19.6 mmol, 1 eq), glycine t-butyl ester hydrochloride (4.93 g, 29.4 mmol, 1.5 eq) and diisopropylethylamine (12.7 g, 98.0 mmol, 5 eq) were dissolved in NMP (150 mL) and heated at 100 °C for 14 hr. The reaction mixture was treated with 1 M HCl (aqueous; 300 mL), followed by the addition of EtOAc (500 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (100 mL, 3x). The combined organic layers were washed with water (400 mL), dried over Mg2SO4, filtered and concentrated via rotary evaporation. The crude product was purified chromatography on SiO2 (20% Hex/EtOAc to 100% EtOAc) to provide 3.89 g (65%) of 23 as bright yellow solid. mp 143.0 – 146.4 °C (Hex/EtOAc); IR (film) 3361, 3138, 2978, 1731, 1593, 1367, 1147, 843, 742 cm-1; 1H NMR (CDCl3) δ 12.20 (br s, 1 H), 7.42 (s, 1 H), 5.56 (t, 1 H, J = 8.0 Hz), 4.00 (d, 2 H, J = 8.0 Hz), 1.51 (s, 9 H); 13C NMR (CDCl3) δ 167.7, 159.9, 145.9, 126.7, 99.9, 83.9, 45.3, 28.2 (3 C); HRMS (ESI) m/z calc’d for C10H15BrN3O3 [M+H]+ 304.0297, found 304.0291. tert-butyl (6-phenylfuro[2,3-c]pyridazin-4-yl)glycinate (24). Compound 24 was prepared from 23 (200 mg, 0.658 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 24 was isolated as a light brown solid (184 mg, 86%). mp 220.1 – 223.0 °C (EtOAc); IR (film) 3324, 3184, 3079, 2982, 1738, 1616, 1148, 763 cm-1; 1H NMR (DMSO-d6) δ 8.50 (br s, 1 H), 7.91 (d, 2 H, J = 8.0 Hz), 7.73 (t, 1 H, J = 8.0 Hz), 7.55 (t, 2 H, J = 8.0 Hz), 7.51-7.47 (m, 2 H), 4.25 (d, 2 H, J = 8.0 Hz), 1.43 (s, 9 H); 13C NMR (DMSO-d6) δ 169.1, 165.1, 153.1, 141.3, 133.8, 129.6, 129.2 (2 C), 128.6, 124.8 (2 C), 107.5, 98.9, 81.3, 44.7, 27.7 (3 C); HRMS (ESI) m/z calc’d for C18H20N3O3 [M+H]+ 326.1505, found 326.1490. tert-butyl (6-(2-hydroxyethyl)furo[2,3-c]pyridazin-4-yl)glycinate (25). Compound 25 was prepared from 23 (200 mg, 0.658 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 25 was isolated as a waxy brown solid (184 mg, 95%). mp 75.8 – 76.9 °C (EtOAc); IR (film) 3187, 2979, 2931, 1737, 1619, 1150, 1050, 762 cm-1; 1H NMR (DMSO-d6) δ 8.40 (s, 1 H), 7.57 (t, 1 H, J = 8.0 Hz), 6.77 (s, 1
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H), 4.91 (br s, 1 H), 4.14 (d, 2 H, J = 8.0 Hz), 3.76 (t, 2 H, J = 8.0 Hz), 2.93 (t, 2 H, J = 8.0 Hz), 1.42 (s, 9 H); 13C NMR (DMSO-d6) δ 169.2, 165.2, 156.2, 140.8, 132.8, 107.4, 100.1, 81.2, 58.5, 44.5, 31.7, 27.7 (3 C); HRMS (ESI) m/z calc’d for C14H20N3O4 [M+H]+ 294.1454, found 294.1441. 4-bromo-5-(phenylamino)pyridazin-3(2H)-one (26). 4,5-dibromopyridazin-3(2H)-one (5.00 g, 19.7 mmol, 1 eq) and aniline (11.0 g, 118 mmol, 6 eq) were dissolved in DMAc (150 mL) and water (30 mL) and heated at 120 °C for 14 hr. The reaction mixture was then concentrated via rotary evaporation to yield a thick oil. The oil was cooled to 0 °C and treated with water (250 mL). The resulting slurry was filtered, and the solid was dried under vacuum. The crude solid was then recrystallized from EtOAc (100 mL) to give 4.2 g (77%) of 26 as a white solid. mp 233.4 – 234.9 °C (EtOAc); IR (film) 3361, 3213, 3115, 2838, 1603, 1573, 1495, 1413, 1299, 877, 759 cm-1; 1H NMR (DMSO-d6) δ 12.71 (br s, 1 H), 8.55 (br s, 1 H), 7.48 (s, 1 H), 7.41 (t, 2 H, J = 8.0 Hz), 7.27 (d, 2 H, J = 8.0 Hz), 7.21 (t, 1 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 158.4, 144.8, 138.6, 129.4 (2 C), 128.2, 125.2, 124.0 (2 C), 100.6; HRMS (ESI) m/z calc’d for C10H9BrN3O [M+H]+ 265.9929, found 265.9921. (4-(phenylamino)furo[2,3-c]pyridazin-6-yl)methanol (27). Compound 27 was prepared from 26 (300 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (100% EtOAc), 27 was isolated as a light brown solid (241 mg, 89%). mp 199.7 – 200.9 °C (EtOAc); IR (film) 3319, 3252, 3056, 1614, 1564, 1350, 1021, 720 cm-1; 1H NMR (DMSO-d6) δ 9.35 (s, 1 H), 8.75 (s, 1 H), 7.43 (t, 2 H, J = 8.0 Hz), 7.29 (d, 2 H, J = 8.0 Hz), 7.19 (t, 1 H, J = 8.0 Hz), 6.58 (s, 1 H), 5.64 (t, 1 H, J = 8.0 Hz), 4.59 (d, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.8, 157.9, 139.2, 138.0, 134.7, 129.5 (2 C), 124.4, 122.0 (2 C), 108.3, 100.3, 56.2; HRMS (ESI) m/z calc’d for C13H12N3O2 [M+H]+ 242.0930, found 242.0914. 6-(3-chloropropyl)-N-phenylfuro[2,3-c]pyridazin-4-amine (28). Compound 28 was prepared from 26 (300 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon dissolution of the concentrated reaction mixture in EtOAc, a light brown solid crystallized from the solution. This solid was filtered and dried to provide 28 (188 mg, 87%). mp 155.7 – 157.9 °C (EtOAc); IR (film) 3180, 3073, 1610, 1564, 1491, 945, 702 cm-1; 1H NMR (DMSO-d6) δ 9.31 (s, 1 H), 8.72 (s, 1 H), 7.42 (t, 2 H, J = 8.0 Hz), 7.27 (d, 2 H, J = 8.0 Hz), 7.17 (t, 1 H, J = 8.0 Hz), 6.51 (s, 1 H), 3.72 (t, 2 H, J = 8.0 Hz), 2.95 (t, 2 H, J = 8.0 Hz), 2.13 (p, 2 H, J = 8.0 Hz); 13C NMR (DMSO-d6) δ 165.8, 157.1, 139.3, 137.5, 134.6, 129.4 (2 C), 124.1, 121.7 (2 C), 108.8, 100.3, 44.4, 29.8, 25.1; HRMS (ESI) m/z calc’d for C15H15ClN3O [M+H]+ 288.0904, found 288.0890.
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5-(benzylamino)-4-((trimethylsilyl)ethynyl)pyridazin-3(2H)-one (30). Compound 30 was prepared from 1 (316 mg, 1.13 mmol; 0.2 M) according to the general protocol. Upon purification by chromatography on SiO2 (50% hexanes/50% EtOAc to 20% hexanes/80% EtOAc), 30 was isolated as a light brown solid (258 mg, 81%). mp 201.4 – 202.6 °C (Hex/EtOAc); IR (film) 3257, 3146, 3027, 2950, 2892, 2151, 1631, 1568, 1347, 835, 694 cm-1; 1H NMR (DMSO-d6) δ 12.36 (br s, 1 H), 7.63 (s, 1 H), 7.38-7.27 (m, 5 H), 7.03 (br s, 1 H), 4.70 (d, 2 H, J = 8.0 Hz), 0.20 (s, 9 H); 13C NMR (DMSO-d6) δ 160.5, 149.9, 139.0, 128.6 (2 C), 128.0, 127.1, 126.7 (2 C), 106.3, 97.7, 93.3, 45.5, 0.01 (3 C); HRMS (ESI) m/z calc’d for C16H20N3OSi [M+H]+ 298.1376, found 298.1363. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1
H and 13C spectra (PDF)
Crystallographic information for 10 (PDF, CIF) AUTHOR INFORMATION Corresponding Author *Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ORCID David L. Waller: 0000-0001-6972-9455 Notes This work was initiated prior to the acquisition of Cubist Pharmaceuticals by Merck & Co., and continued thereafter. The authors declare no competing financial interest. Present Address Present address for DLW: Sage Therapeutics, 215 First Street, Cambridge, Massachusetts, 02142, United States. Present address for JMG: Department of Chemistry, Princeton University, Frick Chemistry Laboratory, Princeton, New Jersey, 08540, United States.
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Acknowledgments The authors thank Dr. Andrew Brunskill (Merck) for X-ray crystallographic analysis of 10. Dr. Zhengzheng Pan (Cubist/Merck) is acknowledged for the acquisition of all mass spectrometry data. The authors would also like to thank Dr. Pamela Tadross (Cubist/Merck) for helpful discussions. References
(1) Bohacek, R. S.; McMartin, C.; Guida, W. C. Med. Res. Rev. 1996, 16, 3. (2) For a discussion of hydrogen-bonding and non-covalent interactions of heterocycles, see: Saenger, J. W. Hydrogen Bonding in Biological Structures; Springer-Verlag: New York, 1991. (3) Frieden, E. J. Chem. Educ. 1975, 52, 754. (4) For a discussion of the roles heterocycles play in biological processes, see: Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications, 2nd ed.; Wiley-VCH: Weinheim, 2011. (5) Dua, R.; Shrivastava, S.; Sonwane, S. K.; Shrivastava, S. K. Adv. Biol. Res. 2011, 5, 120. (6) Vitaku, E.; Smith, D. T.; Njardson, J. T. J. Med. Chem. 2014, 57, 10257. (7) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (8) For a review on N-heterocyclic carbenes in late transition metal catalysis, see: Diez-Gonzalez, S.; Marion, N.; Nolan, S. Chem. Rev. 2009, 109, 3612. (9) For the pioneering use of quinoxalines in metathesis catalysts, see: Barbasiewicz, M; Szadkowska, A.; Bujok, R.; Grela, K. Organometallics 2006, 25, 3599. (10) For a representative application in photoredox catalysis, see: Johnston, C.; Smith, R.; Allmendinger, S.; MacMillan, D. Nature 2016, 536, 322. (11) For an example of the use of a benzimidazole ligand in palladium catalysis, see: Fu, W. C.; Wu, Y.; So, C. M.; Wong, S. M.; Lei, A.; Knowg, F. Y. Org. Lett. 2016, 18, 5300. (12) Wang, P.; Farmer, M.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J.; Wisniewski, S.; Eastgate, M.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269. (13) He, G.; Chen, G. Angew. Chem. Int. Ed. 2011, 50, 5192. (14) Katagiri, T.; Mukai, T.; Satoh, T.; Hirano, K.; Miura, M. Chem. Lett. 2009, 38, 118.
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(15) Cao, W.; Zheng, X.-J.; Sun, J.-P.; Wong, W.-T.; Fang, D.-C.; Zhang, J.-X.; Jin, L.-P. Inorg. Chem. 2014, 53, 3012. (16) Ganjali, M.; Hosseini, M.; Memari, Z.; Faridbod, F.; Norouzi, P.; Goldooz, H.; Badiei, A. Anal. Chim. Acta. 2011, 708, 107. (17) Mason, J.; Oktawiec, J.; Taylor, M.; Hudson, M.; Rodriguez, J.; Bachman, J.; Gonzalez, M.; Cervellino, A.; Guagliardi, A.; Brown, C.; Llewellyn, P.; Masciocchi, N.; Long, J. Nature 2015, 527, 357. (18) Shi, Y.; Yu, G. Chem. Mater. 2016, 28, 2466. (19) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem. 2009, 52, 2952. (20) Shalaby, A. A. J. fuer Prakt. Chemie 1990, 332, 104. (21) Deeb, A.; Bayoumy, B.; Yasine, F.; Fikry, R. Zeitschrift fuer Naturforschung, B Chem. Sci. 1997, 47, 418. (22) Hilpert, K; Hubler, F.; Kimmerlin, T.; Murphy, M; Renneberg, D.; Stamm, S. PCT Int. Appl. WO2013014587A1, 2013. (23) Abdou, W.; Ganoub, N.; Fahmy, A.; Shaddy, A. Heteroat. Chem. 2005, 16, 56. (24) Abdou, W.; Ganoub, N.; Fahmy, A.; Shaddy, A. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 2373. (25) A single example of this type of coupling-cyclization was previously reported as a minor product in a reaction mixture: de Araujo-Junior, J. X.; Schmitt, M., Benderitter, P.; Bourguignon, J.-J. Tetrahedron Lett. 2006, 47, 6125. (26) See the Experimental Procedures for information on the preparation of pyridazinones 1, 20, 23 and 26. Starting pyridazinones 1 and 20 have been previously synthesized: Ball, W. Eur. Pat. Appl. EP0741319A1, 1996. However, in this Note, we provide full analytical characterization of these compounds. (27) Yi, C.; Hua, R. J. Org. Chem. 2005, 71, 2535. (28) Hundertmark, T.; Littke, A.; Buchwald, S.; Fu, G. Org. Lett. 2000, 2, 1729. (29) Sørenson, U.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697. (30) Bosiak, M. ACS Catal. 2016, 6, 2429. (31) We were also cognizant of the potential for in situ cyclization of the benzylamino substituent into the alkyne following Sonogashira coupling. For examples, see: Larock, R.; Yum, E. J. Am. Chem. Soc. 1991, 113, 6689, and reference 32. (32) Cacchi, S.; Frabrizi, G. Chem. Rev. 2005, 105, 2873.
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(33) For examples, see: Jasselin-Hinschberger, A.; Comoy, C.; Chartoire, A.; Fort, Y. Eur. J. Org. Chem. 2015, 2321 and references cited therein. (34) In couplings with substrate 20, UPLCMS indicated 1-5% of a by-product that had a mass consistent with protodebromination of 20. (35) This argument assumes that some degree of electrophilic character must accumulate on the α carbon to initiate the cyclization event, likely by coordination of the alkyne with a metal catalyst. A related failure of silaneterminated alkynes to undergo a related cyclization has been reported: Houpis, I.; Choi, W.; Reider, P.; Molina, A.; Churchill, H.; Lynch, J.; Volante, R. Tet. Lett. 1994, 35, 9355. (36) See the Supporting Information for details concerning the X-ray diffraction study.
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