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Concise synthesis of versatile imidazo[5,1-f][1,2,4]triazin-4(3H)-ones Tuan P. Tran, Ethan L Fisher, Ann S Wright, and Jiao Yang Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00333 • Publication Date (Web): 28 Dec 2017 Downloaded from http://pubs.acs.org on December 28, 2017

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Organic Process Research & Development

Concise synthesis of versatile imidazo[5,1f][1,2,4]triazin-4(3H)-ones Tuan P. Tran,a,* Ethan L. Fisher,a Ann S. Wright,a and Jiao Yangb a

Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, United States

b

WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China

ABSTRACT: The synthesis of a series of imidazo[5,1-f][1,2,4]triazin-4(3H)-ones was developed from starting imidazoles in three linear steps. The synthetic sequence began with an electrophilic amination and thus a rigorous campaign to identify safe reagent and reaction conditions was performed to ensure safety for preparation of these versatile intermediates on large scales. Functionalizations at the key positions on these substrates were exemplified to demonstrate ability to perform latestage diversification for efficient SAR discovery. Keywords: imidazotriazinones; electrophilic amination; aminating reagents; hydroxylamine-O-sulfonic acid, safety.

Introduction In recent years compounds containing the imidazo[5,1f][1,2,4]triazin-4(3H)-one core 1 have become of increasing interest to the pharmaceutical industry. This structural motif is especially well represented in inhibitors of the phosphodiesterase (PDE) family,1 which catalyzes the hydrolysis of cAMP and cGMP to the acyclic derivative (AMP, GMP).2 A very notable example is vardenafil 2 (Levitra), a potent PDE5 inhibitor that is marketed for the treatment of erectile dysfunction,3 which contains an imidazotriazinone nucleus.

of substituents around the imidazotriazinone ring system are generally incorporated early in their syntheses, prior to formation of the bicyclic structure. Scheme 1. Classical synthesis of imidazotriazinones and proposed new method Classical Synthesis: NH O

O

H N

HO

R7

R5

Dakin-West

O

R5

HN

O

O N H

N

N

R2

R5

R7

N H

NH2

5

O

4

3 O

H N

EtO

O

R2

R7

POCl3

R5

HN R2

6

N

N 7

N R7

New Retrosynthetic Plan: H 7

The classical approach to imidazotriazinones begins with the conversion of acylamino acid 3 to acylamino-αketo-ester 4 through a Dakin-West reaction. Condensation with a functionalized amidrazone 5 affords triazinone intermediate 6, then dehydrative cyclization with phosphoryl chloride forms the trisubstituted imidazotriazinone 7 (Scheme 1).4 The issues and limitations of this approach have been discussed in recent reports describing alternative methods to this heterocycle,5 particularly the low purity and difficult isolation of intermediate 4 on large scale, and low conversion to 6, typically 6 steps).5 Moreover, a particular concern for us was that the pattern

HN

N N H 8

R5

R5 N R7

H2 N N 9

N R7

R5 HN

N R7

R5 or R7= Br 10

We sought access to large quantities of a series of imidazotriazinones that will allow for late-stage functionalization at the key vectors (C2, C5, and C7) for efficient structure-activity relationship (SAR) exploration. Closely related to the work of Heim-Riether and Healy,6 which initiated the synthesis of this heterocycle with a carboxyl-containing imidazole, we aimed to build these intermediates from bromo-imidazoles 10, incorporating the C4 carbonyl on amidrazones 8 with a carboxylating reagent. Intermediates 8 can be derived from the

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corresponding N-aminoimidazoles 9 (Scheme 1). Thus, our synthetic plan begins with an electrophilic amination of bromo-imidazoles 10. We envisioned the bromide, which is not accessible through the classical and many of the recent approaches, would provide an advantageous point for diversification through a variety of crosscoupling methodologies. However, we wanted to assuredly address the safety concerns of the electrophilic amination process due to the scale we were aiming to pursue this series. Therefore, we needed to evaluate the suitable aminating reagents and determine the feasibility of obtaining or preparing, then storing and handling of these species. Results and Discussion We first studied the electrophilic amination of imidazole 10a (Scheme 2). We examined four aminating reagents (compounds 11-14) commonly reported in the literature. While they have proven to be effective, there are many concerns associated with this class of reagents, such as their commercial availability, stability, and safety concerns on large scale.7 Our internal safety guidelines recommend a 100 °C separation between the maximum process temperature and the lowest exothermic onset temperature as detected by differential scanning calorimetry (DSC). DSC was performed on reagents 1114 and their data are displayed in Table 1. O-4Nitrophenyl hydroxylamine 11 was the most energetic reagent, with the cumulative 2560 J/g released, more

°C to progress significantly. Additionally, hydroxylamine-O-sulfonic acid 14 is also the least expensive reagent (ca. $0.50/g) and the only one readily available for purchase in large quantity. Under the optimized conditions, a premixed solution of hydroxylamine 14 and sodium bicarbonate in water was added gradually to a cooled (0 °C) solution of the preformed potassium salt of imidazole 10a (Scheme 2). This reaction exhibited an exotherm, but the reaction temperature was contained within our safety guideline by controlling the rate of addition of the hydroxylamine solution. Upon warming to room temperature, the reaction gave an 85% conversion to mixtures of Naminoimidazole isomers, with the desired Naminoimidazole isomer 9a obtained as the major product in approximately three to one ratio, for an effective 64% yield. The amino-imidazole isomers were difficult to separate, and therfore, they were carried onto the next transformation as mixtures. Subsequently, aminoimidazole 9a was coupled with Scheme 2. Three-step synthesis of imidazotriazinone 7a

Table 1. DSC data of aminating reagents and availability/cost

than twice the amounts observed for the other three reagents. The closely related methoxy analog 12 was the least energetic, but its onset point was the lowest of the group at 64 °C. O-(Diphenylphosphinyl)hydroxylamine 13 had a comparable energy profile and a higher onset temperature than 12, at 104 °C. Hydroxylamine-Osulfonic acid 14 emerged as the preferred reagent. Though it had comparable energy profile as 12 and 13, its onset temperature was the highest among all of the reagents at 148 °C, which would allow us to perform the aminating reaction up to about 40 °C. The remaining reagents 11-13 would require maintaining cryogenic conditions for the duration of the aminating process in order to satisfy the recommended safety guideline. However, these aminating transformations require reaction temperature ranges from room temperature to 70

formamidine acetate at around 80 °C to give the ensuing amidrazone 8a in 67% yield (adjusted for the amount of the desired amino-imidazole isomer 9a in the mixtures). Because both intermediates 8a and 9a are nitrogen-rich and low molecular weight species, we also subjected them to DSC analysis. Their onset temperatures were found to be at 206 and 184 °C, respectively, well within our guidelines for working under these conditions. Lastly, amidrazone 8a was treated with carbonyldi(1,2,4-triazole) (CDT) in refluxing tetrahydrofuran to afford the corresponding imidazotriazinone 7a in 64% yield. This triazinone-forming cyclization was initially discovered by our colleagues,8 and otherwise to our best knowledge this transformation has not been reported elsewhere in the literature. Amidrazone 8a tautomerizes to the appropriate form 16 to facilitate its coupling with CDT. Indeed, while we observed mixtures of tautomers in the NMR spectra, effort to obtain x-ray single crystal structure of the mixtures gave crystals of tautomer 16 as the only species isolated (Figure 1). The coupling adduct of 16 with CDT likely undergoes an elimination to generate the isocyanate intermediate, which then readily cyclizes to form the imidazotriazinone. It is notable that the same transformation could not be accomplished with carbonyldiimidazole (CDI). No reaction was observed despite increasing the temperature up to 100 °C in conjunction with a solvent screen. The difference in reactivity between CDI and CDT has been noted in the literature and the triazole urea species were found to be


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Organic Process Research & Development more reactive than its imidazole comparator.9 Hence, our synthetic route provided the intended imidazotriazinone intermediate 7a from a commercial bromo-imidazole in three steps with a 27% overall yield. Using this route, we were able to synthesize more than 100 g of 7a to facilitate our discovery reasearch. Figure 1. X-ray single crystal structure of tautomer 16

Following the above approach, we synthesized several additional imidazotriazinone intermediates (Table 2). Compounds 7b and 7c were made in comparable overall yields using the same starting imidazole 10a. Though the initial formation of 8a above was effected with formamdine, these amidrazone intermediates can also be formed with other substrates such as imidates and nitriles under basic condition.10 In particular, the nitriles are an attractive set as they are a large and easily accessible monomer class and therefore, provide ample opportunity to incorporate a wide range of substituents at C2.

Compounds 7d and 7e were also synthesized from imidazole isomer 10b. N-Amination of isomeric imidazole 10b resulted in both lower conversion (56%) and regio-selectivity (ca. 2:1) as compared to imidazole 10a, for an effective yield of 38%. Similarly, the mixtures of the aminoimidazole products were difficult to separate and so were used as mixtures for the formation of the amidrazone intermediates. As can be deduced from compound 7e, a strategic choice of the reactant nitrile can provide an intermediate with further opportunities for functionalization at C2. Thus, we were able to synthesize a series of imidazotriazinones via an approach that introduces diversity at C2 in the second step. Furthermore, the bromide at C5 or C7 provides opportunity for further elaboration of these imidazotriazinone intermediates. Currently there is very limited examples of transformation performed at C5 and C7 on these structures.6 With the synthesis of the bromoimdazotriazinone templates accomplished, we set out to demonstrate their utility in palladium-catalyzed crosscouplings chemistry. Initially, atttempts to perform a Suzuki coupling on bromide 7a gave yields of less than 40%, along with significant amount of recovered 7a. Postulating that the triazinone moiety could bind to the catalyst and effectively impedes the reaction, we proceeded to protect this moiety as the methoxy-triazene 17a (Scheme 3). Indeed, the initial Suzuki reaction furnished corresponding product 18a in 89%. Having identified the optimized protection strategy, other crosscouplings with 17a and 17b were

Scheme 3. Protection imidazotriazinones.

and

functionalization

of

Table 2. Additional examples of imidazotriazinones 7. R5 H2N N

10a, b

R5

NH2

N

N N

R2

Substrate for Amidrazone 8

O

HN

% Yield from N-aminoimidazole

Product Br

HN

MeCN

Br

7

8

9a, b

Imidazole

N R7

R7

N

N

50

N

N

7b O

10a NC

Br

HN

OMe MeO

N

N

N

36

7c O HN

HN

NH3OAc

N HN

N

Br

7d Br

10b

35

N

N

O NC

O

HN OMe

PMB

O

N 7e

N

N Br

41

also demonstrated and good to excellent yields were obtained for the intended products. The scope of these functionalizations and their yields are illustrated in Scheme 3. Once the desired cross-coupling had been performed, the triazinones can be regenerated by removal of the methoxy protecting group under either acidic or basic conditions in near quantitative yields, as



demonstrated below with compound 18a in Scheme 4. The ability to remove the methoxy protecting group under orthogonal conditions offered flexibility for functional group compatibility or protection strategies elsewhere in these molecules. Scheme 4. Deprotection to regenerate imidazotriazinone

Conclusions In summary, we have successfully developed a short and direct synthesis to a series of substituted imidazotriazinones. These versatile intermediates were made from simple disubstituted imidazoles in three steps. The synthesis starts with an N-amination reaction of the imidazoles, and so we carefully assessed the reagents and conditions to ensure our ability to execute this approach safely on large scales. These pharmaceutically relevant intermediates were also elaborated with a series of crosscoupling transformations to demonstrate their versatility and utility for SAR exploration. Experimental Section General. Starting materials and reagents were obtained from commercial suppliers and were used without further purification. All reactions were performed under an atmosphere of dry nitrogen unless othewise specified. Reported yields of the imidazotriazinones 7b-e refer to yields calibrated with respect to the estimated amount of the corresponding aminoimidazole 9 isomer from the amination reaction. NMR spectra were recorded on a Bruker with field strength of 400 MHz for 1H nuclei and 100 MHz for the 13C nuclei. Analytical data was obtained on representative samples purified by chromatography or trituration. 4-Bromo-2-methyl-1H-imidazol-1-amine (9a). To a solution of KOH (26.1 g, 466 mmol) in H2O (250 mL) was added imidazole 10a (25.0 g, 155 mmol), stirred for approximately 20 min at 0 °C until all solids dissolved. To a solution of NaHCO3 (40.4 g, 466 mmol) in H2O (350 mL) was added hydroxylamine 14 (53.0 g, 466 mmol) portionwise. After all the solids have dissolved and bubbling ceased, this solution was gradually added to the imidazole solution over 30 min. The reaction was gradually warmed to room temperature as the ice melted. After stirring for 18 h, the reaction mixture was filtered, the filtrate was taken up in sat’d K2CO3 solution (500 mL) and extracted three times with CH2Cl2 (500 mL each). The organic layers were combined, dried over Na2SO4, filtered and the filtrate was concentrated. Purification via flash column chromatography on silica gel eluding with 0 to 15% MeOH in CH2Cl2 afforded 23.3 g of mixtures of 9a and 15 in ca. three to one ratio (99.2 mmol, 64%). 1H NMR (400 MHz, CDCl3): δ 6.90 (s, 0.35 H), 6.88 (s, 1

H), 4.67 (br s, 2 H), 4.51 (br s, 0.46 H), 2.44 (s, 1 H), 2.37 (s, 3 H). 2-Bromo-4-methyl-1H-imidazol-1-amine (9b). Reaction as above with 10b (10.0 g, 62.1 mmol) gave 6.12 g of mixtures of 9b with the isomeric by-product in approximately two to one ratio (23.3 mmol, 38%). 1H NMR (400 MHz, CDCl3): δ 6.85 (s, 0.5 H), 6.72 (s, 1 H), 4.67 (br s, 1.1 H), 4.47 (br s, 0.7 H), 2.24 (s, 3 H), 2.17 (s, 1.5 H). N-(4-Bromo-2-methyl-1H-imidazol-1-yl)formimidamide (8a). To a solution of the N-aminoimidazole mixtures containing 9a (55.0 g, ca. 234 mmol) in 2-propanol (1.5 L) was added formamdine acetate (330 g, 3.17 mol), and the reaction mixture was heated to reflux. After 3 h, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated. Purification via flash column chromatography on silica gel eluding with 0 to 5% MeOH in EtOAc gave 31.6 g of intermediate 8a (156 mmol, 67%). 1H NMR (400 MHz, MeOD-d4): δ 7.91 (s, 0.6 H), 7.35 (s, 1 H), 7.07 (s, 0.6 H), 6.92 (s, 1 H), 2.27 (s, 1.9 H), 2.21 (s, 3 H). N-(2-Bromo-4-methyl-1H-imidazol-1yl)formimidamide (8b). Reaction as above with mixtures of 9b and the regioisomer (24.0 g, ca. 91.3 mmol) gave 11.6 g of 8b (30.1 mmol, 63%). 1H NMR (400 MHz, CDCl3): δ 7.99 (br s, 1.1 H), 7.68 (s, 0.4 H), 7.21 (s, 0.5 H), 6.69 (s, 0.4 H), 6.61 (s, 0.5 H), 2.08 (s, 1.7 H), 2.06 (s, 1.3 H). 5-Bromo-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)one (7a). A suspension of compound 8a (86.6 g, 427 mmol) and carbonyldi(1,2,4-triazole) (CDT) (112 g, 847 mmol) in THF (900 mL) was heated to reflux overnight. The reaction mixture was cooled to 10 °C, and the resulting solid was filtered, washed with cold MTBE, and dried under vacuum to furnish 62.5 g of imidazotriazinone 7a (273 mmol, 64%). 1H NMR (400 MHz, DMSO-d6): δ 11.82 (br s, 1 H), 7.88 (d, J= 4.0 Hz, 1 H), 2.46 (s, 3 H). 13 C NMR (100 MHz, DMSO-d6): δ 153.6, 142.6, 141.1, 116.9, 112.9, 11.9. Mass calculated for [M + H]+ (C6H6BrN4O) is m/z = 228.9720 (100%), 230.9699 (97%); found HRMS (ESI) [M+H]+ m/z = 228.9722, 230.9700. Melting point > 270 °C. 5-Bromo-2,7-dimethylimidazo[5,1-f][1,2,4]triazin4(3H)-one (7b). To a solution of the sample containing mixtures of 9a and 16 (3.85 g, ca. 16.4 mmol) in EtOH (30 mL) and MeCN (5.70 mL, 110 mmol) was added NaOEt solution (21% in EtOH, 21 mL, 55.0 mmol) dropwise. The mixture was heated to 85 °C. After heating for 16 h, the reaction mixture mixture was cooled to room temp, then concentrated. The resulting residue was loaded onto silica gel and eluded with 0 to 10% MeOH in CH2Cl2 to remove the baseline impurities. The eluent containing the amidrazone intermediate was concentrated and the semi-crude material was taken onto the next step.


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Organic Process Research & Development A suspension of the above semi-crude intermediate (3.38 g) and CDT (5.12 g, 31.2 mmol) in THF (50 mL) was heated to reflux. After 3 h, the reaction mixture was cooled to room temp and concentrated under vacuum to remove roughly half the solvent volume. To the resulting suspension was added ether (75 mL), stirred rigorously, and filtered. The filtered cake was dried under vacuum to give 1.79g of product 7b as a light grey solid (8.26 mmol, 50%). 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br s, 1 H), 2.44 (s, 3 H), 2.19 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ 153.9, 150.0, 142.0, 115.5, 112.6, 18.7, 11.9. Mass calculated for [M + H]+ (C7H8BrN4O) is m/z = 243 (100%), 245 (97%); found LCMS [M+H]+ m/z = 243, 245. Melting point = 210.5 to 211.1 °C. 5-Bromo-2-(methoxymethyl)-7-methylimidazo[5,1f][1,2,4]triazin-4(3H)-one (7c). To a mixture of the sample containing mixtures of aminoimidazole 9a and 16 (560 mg, ca. 2.39 mmol) and methoxyacetonitrile (270 mg, 3.82 mmol) in EtOH (3mL) was added NaOEt solution (21% in EtOH, 1.42 mL, 3.82 mmol) dropwise. The reaction mixture was heated to reflux. After 90 min, the reaction mixture was cooled to room temp, then concentrated under vacuo. The resulting residue was taken up in sat’d NH4Cl (25 mL), stirred, filtered and dried under vacuum to afford the crude amidrazone intermediate (308 mg). The intermediate above was taken up in THF (5mL), then CDT (410 mg, 2.50 mmol) was added. The mixture was heated to reflux for 3 h, then cooled to room temp. To the reaction solution was added EtOAc (25 mL), and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated. Trituration from ether (30 mL), filtered and dried under vacuum gave 237 mg of imidazotriazinone 7c as a beige solid (0.87 mmol, 36%). 1H NMR (400 MHz, DMSOd6): δ 11.92 (br s, 1 H), 4.22 (s, 2 H), 3.33 (s, 3 H), 2.46 (s, 3 H). Mass calculated for [M + H]+ (C8H10BrN4O2) is m/z = 272.9982 (100%), 274.9962 (97%); found HRMS (ESI) [M+H]+ m/z = 272.9983, 274.9962. 7-Bromo-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)one (7d). Same reaction as for 7a, with mixtures containing 8b and isomeric by-product (20.0 g, ca. 76.1 mmol) gave 6.12 g of 7d (26.7 mmol, 35%). 1H NMR (400 MHz, DMSO-d6): δ 11.86 (br s, 1 H), 7.92 (d, J= 4.0 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ 154.5, 141.4, 139.9, 118.8, 116.1, 14.7. Mass calculated for [M + H]+ (C6H6BrN4O) is m/z = 228.9720 (100%), 230.9699 (97%); found HRMS (ESI) [M+H]+ m/z = 228.9717, 230.9699. Melting point = 201.5 to 201.9 °C. 7-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-5methylimidazo[5,1-f][1,2,4]triazin-4H(3H)-one (7e). To a solution of the sample containing mixtures of 9b and isomeric by-product (3.55 g, ca. 13.5 mmol) and 2-((4methoxybenzyl)oxy)acetonitrile (7.15 g, 40.3 mmol) in EtOH (30 mL) was added NaOEt solution (21% in EtOH, 15.1 mL, 40.3 mmol) dropwise. The reaction mixture was heated to reflux for 4 h, cooled to room temp, and concentrated under vacuo. The resulting residue was

taken up in CH2Cl2 (100 mL) and washed with sat’d NH4Cl solution, H2O, and brine (50 mL each). The organic layer was dried over Na2SO4, filtered and concentrated. Purification via flash column on silica gel eluding with 0 to 5% MeOH in EtOAc afforded 3.45 g of the semi-crude amidrazone intermediate. A suspension of the above amidrazone and CDT (3.21 g, 19.5 mmol) in THF (50 mL) was heated to reflux. After 3 h, the reaction mixture was cooled to room temp, taken up in EtOAc (100 mL), and washed with H2O (50 mL). The aqueous layer was extracted with EtOAc twice more (50 mL each). The combined organic layers was dried over MgSO4, filtered and the filtrate concentrated. Purification via flash column chromatography on silica gel eluding with 50 to 100% EtOAc in heptane furnished 2.08 g of product 7e (5.48 mmol, 41%). 1H NMR (400 MHz, DMSO-d6): δ 11.95 (br s, 1 H), 7.31 (d, J= 8.0 Hz, 2 H), 6.99 (d, J= 8.0 Hz, 2 H), 4.50 (s, 2 H), 4.30 (s, 2 H), 3.72 (s, 3 H), 2.45 (s, 3 H). Mass calculated for [M + H]+ (C15H16BrN4O3) is m/z = 379.0400 (100%), 381.0381 (97%); found HRMS (ESI) [M+H]+ m/z = 379.0393, 381.0373. Melting point = 149.1 to 151.2 °C. 5-Bromo-4-methoxy-7-methylimidazo[5,1f][1,2,4]triazine (17a). To a suspension of 7a (8.00 g, 34.9 mmol) in toluene (100 mL) was added phosphorus oxychloride (9.60 mL, 105 mmol), followed by dropwise addition of TEA (34.1 mL, 244 mmol). The reaction mixture was heated to reflux for 3 h, cooled to room temp, then concentrated under vacuo. The resulting residue was immediately taken up in CH2Cl2 (100 mL), cooled to 0 °C, then MeOH (10 mL, 247 mmol) was added. TEA (24.3 mL, 174 mmol) was added dropwise over 15 min. The reaction mixture was gradually warmed to room temp as the ice bath expired. After 16 h, the reaction mixture was taken up with more CH2Cl2 (100 mL) and washed with sat’d NaHCO3 and H2O (50 mL each). The organic layer was dried over MgSO4, filtered and the filtrate concentrated under vacuo. Trituration from ether and heptane mixture (50 mL each), filtered and dried under vacuum afforded 7.90g of 17a as a light tan solid (32.5 mmol, 93.1%). 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1 H), 4.17 (s, 3 H), 2.68 (s, 3 H). Mass calculated for [M + H]+ (C7H8BrN4O) is m/z = 243 (100%), 245 (97%); found LCMS [M+H]+ m/z = 243, 245. Melting point = 179.4 to 180.2 °C. 7-Bromo-4-methoxy-2(((4-methoxybenzyl)oxy)methyl)5-methylimidazo[5,1-f][1,2,4]triazine (17b). Reaction same as above with 7e (1.01 g, 2.66 mmol) to give 964 mg of 17b (2.45 mmol, 92%). 1H NMR (400MHz, CDCl3): δ 7.36 (d, J= 8.8 Hz, 2 H), 6.88 (d, J= 8.8 Hz, 2 H), 4.66 (s, 2 H), 4.54 (s, 2 H), 4.17 (s, 3 H), 3.80 (s, 3 H), 2.61 (s, 3 H). Mass calculated for [M + H]+ (C16H18BrN4O3) is m/z = 393 (100%), 395 (97%); found LCMS [M+H]+ m/z = 393, 395. 4-Methoxy-7-methyl-5-phenylimidazo[5,1f][1,2,4]triazine (18a). To a degassing solution of 17a (325 mg, 1.34 mmol) in dioxane (5 mL) and H2O (1 mL) was added phenylboronic acid (196 mg, 1.60 mmol), Na2CO3 (429 mg, 4.01 mmol) and Pd(dppf)Cl2.CH2Cl2



(56 mg, 0.067 mmol). The mixture was evacuated with vacuum and filled with N2, repeated twice more, then heated to 85 °C under N2 atmosphere. After 16 h, the reaction mixture was cooled to room temp, filtered through celite, and rinsed with EtOAc (50 mL). The combined filtrate was washed with H2O and brine (25 mL each). The organic layer was dried over MgSO4, filtered, and filtrate concentrated under vacuo. Purification via flash column chromatography on silica gel eluding with 30 to 80% EtOAc in heptane furnished 283 mg of 18a (1.18 mmol, 88%). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1 H), 7.97-7.92 (m, 2 H), 7.47-7.41 (m, 2 H), 7.387.34 (dt, J= 8.0, 1.6 Hz, 1 H), 4.14 (s, 3 H), 2.75 (s, 3 H). 13 C NMR (100 MHz, CDCl3): δ 163.1, 147.7, 141.2, 135.8, 133.1, 129.0, 128.2, 128.0, 54.4, 12.0. Mass calculated for [M + H]+ (C13H13N4O) is m/z = 241; found LCMS [M+H]+ m/z = 241. 4-Mehtoxy-7-methyl-5-vinylimidazo[5,1f][1,2,4]triazine (18b). To a solution of 17a (200 mg, 0.82 mmol) in toluene (3 mL) was added tributyl(vinyl)stannane (313 mg, 0.98 mmol), triphenyl phosphine (33 mg, 0.12 mmol) and Pd2(dba)3 (38 mg, 0.041 mmol). The reaction mixture was heated to 95 °C for 16 h, cooled to room temp, taken up in EtOAc (30 mL) and washed with H2O and brine (15 mL each). The organic layer was dried over MgSO4, filtered and the filtrate was concentrated under vacuo. Purification via flash column chromatography on silica gel eluding with 0 to 50% EtOAc in heptane gave 76 mg of 18b (0.40 mmol, 49%). 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1 H), 7.117.04 (appar q, J= 8.0 Hz, 1 H), 6.23-6.18 (dd, J= 17.6, 1.6 Hz, 1 H), 5.38-5.35 (dd, J= 10.8, 1.6 Hz, 1 H), 4.15 (s, 3 H), 2.68 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 163.6, 147.7, 141.4, 133.3, 127.2, 115.9, 111.2, 54.4, 11.9. Mass calculated for [M + H]+ (C9H11N4O) is m/z = 191.0927; found HRMS (ESI) [M+H]+ m/z = 191.0935. 5-(4-Chlorobenzyl)-4-methoxy-7-methylimidazo[5,1f][1,2,4]triazine (18c). To a dry flask containing 17a (200 mg, 0.82 mmol) and XPhos Pd G2 (32 mg, 0.041 mmol) was added dry dioxane (5 mL). The mixture as evacuated with vacuum then filled with N2, repeated twice more, then 4-chlorobenzylzinc chloride solution (0.5M in THF, 3.29 mL, 1.65 mmol) was added. The reaction was heated to 90 °C. After 16 h, the reaction mixture was cooled to room temp, taken up in EtOAc (50 mL), and filtered over celite. The filtrate was washed with sat’d NaHCO3 and H2O (25 mL each). The organic layer was dried over MgSO4, filtered, and concentrated under vacuo. Purification via flash column chromatography on silica gel eluding with 0 to 50% EtOAc in heptane afforded 163 mg of 18c (0.57 mmol, 69%). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1 H), 7.31-7.24 (m, 4 H), 4.18 (s, 2 H), 4.10 (s, 3 H), 2.53 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 163.4, 147.6, 140.5, 138.3, 135.3, 132.0, 130.0, 128.5, 111.4, 54.3, 34.4, 11.9. Mass calculated for [M + Na]+ (C14H13ClN4ONa) is m/z = 311.0670 (100%), 313.0644 (32%); found HRMS (ESI) [M+H]+ m/z = 311.0676, 313.0632.

4-Methoxy-7-methyl-5-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[5,1-f][1,2,4]triazine (18d). To a solution of 17a (250 mg, 1.03 mmol) in 2-Me-THF (5 mL) was added 3-ethynyl-α,α,α-trifluorotoluene (227 mg, 1.30 mmol), DIEA (0.55 mL, 3.09 mmol), copper (I) The iodide (20 mg, 0.10 mmol), and PdCl2(PPh3)2. mixture as evacuated with vacuum, filled with N2, and repeated twice more. The reaction was heated to reflux. After 16 h, the reaction mixture was cooled to room temp, taken up in EtOAc (50 mL), and washed with sat’d NaHCO3 and H2O (25 mL each). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under vacuo. Purification via flash column chromatography on silica gel eluding with 20 to 60% EtOAc in heptane afforded 214 mg of 18d (0.64 mmol, 63%). 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1 H), 7.83 (s, 1 H), 7.74 (d, J= 7.6 Hz, 1 H), 7.60 (d, J= 8.0 Hz, 1 H), 7.49 (t, J= 7.6 Hz, 1 H), 4.23 (s, 3 H), 2.71 (s, 3 H). 13 C NMR (100 MHz, DMSO-d6): δ 162.9, 148.5, 141.9, 134.6, 130.9 (q, J= 32.5 Hz), 128.9, 128.4 (q, J= 3.9 Hz), 125.1 (q, J= 3.7 Hz), 123.8, 122.3, 116.7, 116.3, 90.9, 83.8, 54.9, 11.9. Mass calculated for [M + H]+ (C16H12F3N4O) is m/z = 333.0958; found HRMS (ESI) [M+H]+ m/z = 333.0971. Methyl 4-methoxy-7-methylimidazo[5,1-f][1,2,4]triazine-5-carboxylate (18e). To a solution of 17a (300 mg, 1.23 mmol) in MeOH (10 mL) was added TEA (0.34 mL, 2.47 mmol) and Pd(dppf)Cl2 (47 mg, 0.062 mmol). The reaction vessel was evacuated with vacuum and filled with N2, evacuated again and filled with CO2 to 45 psi, then heated to 77 °C. After heating for 20 h, the reaction mixture was cooled to room temp, filtered over celite, rinsed with MeOH (10 mL), and the combined filtrate was concentrated under vacuo. The resulting residue was taken up in EtOAc (50 mL), washed with H2O and brine (25 mL each). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated. Purification via flash column chromatography on silica gel eluding with 20 to 60% EtOAc in heptane yielded 227 mg of 18e (1.02 mmol, 83%). 1H NMR (400 MHz, Solvent): δ 8.41 (s, 1 H), 4.12 (s, 3 H), 3.83 (s, 3 H), 2.61 (s, 3 H). Mass calculated for [M + H]+ (C9H11N4O3) is m/z = 223.0826; found HRMS (ESI) [M+H]+ m/z = 223.0825. 4-Methoxy-2-(((4-methoxybenzyl)oxy)methyl)-5methyl-7-phenylimidazo[5,1-f][1,2,4]triazine (18f). To a degassing solution of 17b (250 mg, 0.64 mmol) in 2-MeTHF (5 mL) and H2O (1 mL) was added phenylboronic acid (85 mg, 0.70 mmol), potassium phosphate tribasic (337 mg, 1.27 mmol) and Pd(dppf)Cl2.CH2Cl2 (27 mg, 0.032 mmol). The mixture was evacuated with vacuum and filled with N2, repeated twice more, then heated to 85 °C under N2 atmosphere. After 16 h, the reaction mixture was cooled to room temp, filtered through celite, and rinsed with EtOAc (50 mL). The combined filtrate was washed with H2O and brine (25 mL each). The organic layer was dried over MgSO4, filtered, and the filtrate concentrated under vacuo. Purification via flash column chromatography on silica gel eluding with 0 to 25% EtOAc in heptane furnished 219 mg of 18f (0.56 mmol, 88%). 1H NMR (400 MHz, DMSO-d6): δ 8.44-8.39 (m, 2


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Organic Process Research & Development H), 7.54-7.42 (m, 3 H), 7.34-7.29 (m, 2 H), 6.93-6.87 (m, 2 H), 4.61 (s, 2 H), 4.53 (s, 2 H), 4.12 (s, 3 H), 3.74 (s, 3 H), 2.57 (s, 3 H). Mass calculated for [M + H]+ (C22H23N4O3) is m/z = 391.1765; found HRMS (ESI) [M+H]+ m/z = 391.1762. 7-Methyl-5-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)one (19). A solution of 18a (102 mg, 0.43 mmol) in dioxane (3 mL) and 1 N NaOH (1.3 mL) was heated to 90 °C. After 16 h, the reaction mixture was cooled to room temp and concentrated. The resulting residue was taken up in sat’d NH4Cl (5 mL), stirred, and filtered. The filtered cake was dried under vacuum to afford 93 mg of 19 (0.41 mmol, 97%). Alternatively, 18a (75 mg, 0.31 mmol) was taken up in EtOH (1 mL) and 1 N HCl (1 mL) and heated to reflux. After 16 h, the reaction mixture was cooled to room temp and concentrated. The resulting residue was taken up in sat’d NaHCO3 (5 mL), stirred, filtered, and washed with H2O. The filtered cake was dried under vacuum to afford 69 mg of 19 (0.30 mmol, 98%). 1H NMR (400 MHz, DMSO-d6): δ 11.68 (br s, 1 H), 8.32 (d, J= 8.8 Hz, 2 H), 7.88 (s, 1 H), 741 (t, J= 8.8 Hz, 2 H), 7.32 (t, J= 8.8 Hz, 1 H), 2.54 (s, 3 H). 13C NMR (100 MHz, DMSO-d6): δ 155.14, 142.44, 140.42, 139.81, 133.34, 128.49, 128.46, 128.40, 115.76, 12.29. Mass calculated for [M + H]+ (C12H11N4O) is m/z = 227; found LCMS [M+H]+ m/z = 227. Supporting Information Available. 1H NMR spectra for all compounds. 13C NMR spectra and high resolution mass spectroscopy for selected compounds. X-Ray crystal structure of key structures are provided. DSC data and profiles of aminating reagents 11-14. This material is available free of charge via the Internet at http://pubs.acs.org. Author Information Corresponding Author * E-mail: [email protected]. Telephone: 860-6869100. ORCID Tuan P. Tran: 0000-0001-9578-639X Notes The authors declare no competing financial interest. Acknowledgments We thank Chao Li for conducting and gathering DSC results; Brian Samas and Ivan Samarjian for obtaining the x-ray crystallographic data; and Matthew Teague for collecting HRMS data. Drs. Stephen Wright and Antonia Stepan are acknowledged for helpful discussions and input. References 1. (a) Sanchez-Arias, J. A.; Rabal, O.; CuadradoTejedor, M.; de Miguel, I.; Perez-Gonzalez, M.; Ugarte, A.; Saez, E.; Espelosin, M.; Ursua, S.; Haizhong, T.; Wei, W.; Musheng, X.; Garcia-

Osta, A.; Oyarzabal, J. ACS Chem. Neurosci. 2017, 8, 638-661. (b) Kehler, J.; Rasmussen, L. K.; Langgaard, M.; Jessing, M.; Vital, P. J. V.; Juhl, K. Imidazotriazinones as PDE1 Inhibitors and their preparation. WO 2016174188 A1 20161103. (c) Burdi, D. F.; Tanaka, D.; Fujii, Y.; Kawasumi, M. WO 2016/042775. (d) Helal, C. J.; Chappie, T. A.; Humphrey, J. M.; Verhoest, P. R.; Yang, E. Preparation of Imidazo[5,1-f][1,2,4]triazines for the treatment of Neurological Disorders. US 20120214791 A1 20120823. 2. (a) Beavo, J. A. Physiol. Rev. 1995, 75, 725-748. (b) Jeon, Y. H.; Heo, Y. S.; Kim, C. M.; Hyun, Y. L.; Lee, T. G.; Ro, S.; Cho, J. M. Cell. Mol. Life Sci. 2005, 62, 1198-1220. 3. (a) Haning, H.; Niewohner, U.; Schenke, T.; EsSayed, M.; Schmidt, G.; Lampe, T.; Bischoff, E. Bioorg. Med. Chem. Lett. 2002, 12, 865-868. (b) Niewohner, U.; Es-Sayed, M.; Haning, H.; Schenke, T.; Schlemmer, K.-H.; Keldenich, J.; Bischoff, E.; Perzborn, E.; Dembowsky, K.; Serno, P.; Nowakowski, M. 7-Alkyl and Cycloalkyl substituted Imidazotriazinones. Ger. Offen. DE 19827640 A1 19991223. 4. Charles, I.; Latham, D. W. S.; Hartley, D.; Oxford, A. W.; Scopes, D. I. C. J. Chem. Soc., Perkin Trans. 1 1980, 1139-1146. 5. (a) Werner, D. S.; Dong, H.; Kadalbajoo, M.; Laufer, R. S.; Tavares-Greco, P. A.; Volk, B. R.; Mulvihill, M. J.; Crew, A. P. Tetrahedron Lett. 2010, 51, 3899-3901. (b) Olszewska, T.; Gajewska, E. P. Milewska, M. J. Tetrahedron 2013, 69, 474-480. (c) Mao, Y.; Tian, G.; Liu, Z.; Shen, J.; Shen, J. Org. Process Res. Dev. 2009, 13, 1206-1208. 6. Heim-Riether, A.; Healy, J. J. Org. Chem. 2005, 70, 7331-7337. 7. (a) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1-17. (b) Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley: New York, New York, 1995; Vol. 5, pp 3270. (c) Carpino, L. J. Am. Chem. Soc. 1960, 82, 3133-3135. (d) Boyles, D. C.; Curran, T. T.; Parlett, R. V. Org. Process Res. Dev. 2002, 6, 230-233. (e) Hynes, J.; Doubleday, W. W.; Dyckman, A. J.; Godfrey, J. D.; Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368-1371. 8. Chappie, T. A.; Helal, C. J.; Kormos, B. L.; Tuttle, J. B.; Verhoest, P. R. Imidazotriazine derivatives as PDE10 Inhibitors and their preparation. WO 2014177977 A1 20141106. 9. Ayers, J. S.; Bethell, G. S.; Hancock, W. S.; Hearn, M. T. W. Activated matrix and method of activation. US 4330440 A 19820518. 10. (a) Smith, R. F.; Soelch, R. L.; Feltz, T. P.; Martinelli, M. J.; Geer, S. M. J. Heterocyclic Chem. 1981, 18, 319-325. (b) Khankischpur, M.; Kurz, T. Europ. J. Org. Chem. 2008, 35, 60296033. (c) Volkova, K. A.; Albanov, A. I. Russian J. Org. Chem. 2006, 42, 1730-1731. (d) Wade,



P. C.; Vogt, B. R.; Kissick, T. P.; Simpkins, L. M.; Palmer, D. M.; Millonig, R. C. J. Med. Chem. 1982, 25, 331-333.


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