Modular synthesis of 3,6-disubstituted-1,2,4-triazines via the cyclodehydration of β-keto- N -acylsulfonamides with hydrazine salts

Article abstract of DOI:10.1021/acs.joc.8b00254

A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of β-keto-N-acylsulfonamides with hydrazine salts is described. Two approaches for synthesizing the requisite β-keto-N-acylsulfonamides are presented, which allow for the late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or α-bromoketones, respectively. The scope of this methodology includes primary and secondary sp³-linked substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of sensitive functionalities.

Full text of DOI:10.1021/acs.joc.8b00254

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Modular Synthesis of 3,6-Disubstituted-1,2,4-triazines via the
Cyclodehydration of #-Keto-N-acylsulfonamides with Hydrazine Salts
Matthew S. Dowling, Wenhua Jiao, Jie Hou, Yuchun Jiang, and Shangsheng Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00254 • Publication Date (Web): 07 Mar 2018
Downloaded from http://pubs.acs.org on March 8, 2018
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Modular Synthesis of 3,6ꢀDisubstitutedꢀ1,2,4ꢀtriazines via the Cyclodehydration of βꢀKetoꢀNꢀ
acylsulfonamides with Hydrazine Salts
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Matthew S. Dowling,*† Wenhua Jiao,† Jie Hou,‡ Yuchun Jiang,‡ and Shangsheng Gong‡
†Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
‡WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
Corresponding Author:
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*Eꢀmail: matthew.s.dowling@pfizer.com
Abstract: A straightforward method for preparing 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazines through a redoxꢀ
efficient cyclodehydration of βꢀketoꢀNꢀacylsulfonamides with hydrazine salts is described. Two
approaches for synthesizing the requisite βꢀketoꢀNꢀacylsulfonamides are presented, which allow for the
late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or αꢀ
bromoketones, respectively. The scope of this methodology includes primary and secondary sp3ꢀlinked
substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of
sensitive functionality.
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The incorporation of nitrogen atoms into aromatic rings is a powerful medicinal chemistry design tactic
for improving physicochemical properties and modulating potency.1 In this context the 1,2,4ꢀtriazine
motif is notable as one of the most prevalent triazine heterocycles within medicinal chemistry, and has
been demonstrated to improve physicochemical properties relative to a pyridine comparator2 and
inhibition of MAOꢀB relative to a diazine comparator.3 Indeed, this heterocycle is present in numerous
bioactive compounds including those targeting adenosine A2A,4 mGluR5,2 mPGESꢀ15 as well as the
marketed drug lamictal.6 1,2,4ꢀTriazines have also found applications as ligands for metals,7 in
agrochemical research, and as clickable bioꢀorthogonal probes.8 Additionally, this heterocycle has been
extensively employed as a starting material for preparing highly substituted pyridines using inverse
electron demand heteroꢀDiels–Alder chemistry.9
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Due to the widespread utility of 1,2,4ꢀtriazines, numerous strategies have been reported for their
synthesis. One of the most widely used strategies involves the condensation between amidrazones and
either 1,2ꢀdiketones or ꢀketoaldehydes (Figure 1, strategy A).10 This chemistry is most often used for
preparing 1,2,4ꢀtriazines for which the 5ꢀ and 6ꢀ substituents are identical; unsymmetrical 1,2ꢀdiketones
often produce regioisomeric mixtures,11 while 1,2ꢀketoaldehydes favor formation of the 3,5ꢀdisubstituted
1,2,4ꢀtriazine.12 Reported approaches for accessing 3,6ꢀdisubstituted 1,2,4ꢀtriazines include the coupling
between two equivalents of an acyl hydrazine and an αꢀbromoketone,13 (strategy B, Figure 1) and
between an αꢀketoꢀoxime, hydrazine and an aldehyde with subsequent dehydration.14 (strategy C, Figure
1). Almost all examples that employ strategy B involve aryl substitution at C6, while examples of
strategy C are limited to 2ꢀ and 4ꢀ pyridyl substituents at C6.
Several new approaches for preparing 1,2,4ꢀtriazines have been reported in the last two years (Figure 1).
For example, Krasavin recently described a method for accessing this heterocycle via hydrohydrazination
of propargylamides 4 with bocꢀhydrazine followed by in situ oxidation.15 While reasonable scope was
demonstrated at C3, the C6 position is limited to a methyl substituent. Ley et al. recently reported
chemistry for the regioselective construction of 3,6ꢀ and 3,5,6ꢀsubstituted 1,2,4ꢀtriazines through the
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coupling of tosyl hydrazones 2 and tosyl aziridines 3 followed by cyclization and in situ oxidation.16 In
this case, the scope at C6 is limited to aryl and a single example with alkyl substitution at C3 resulted in
an 8% yield. Finally, Deng et al. recently described an approach to 3,6ꢀdisubstituted triazines via the
coupling of tosyl triazoleꢀderived rhodium carbenoids 7 with hydrazones of type 6.17 Subsequent
treatment with catalytic pꢀTsOH led to hydrolysis of the terminal hydrazone and cyclization to the triazine
10 via intermediate 9. However, the scope of this methodology was also limited to aryl substituents at
both C3 and C6 positions.
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Figure 1. Relevant precedent for the preparation of substituted 1,2,4ꢀtriazines.
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In an effort to support medicinal chemistry and fragmentꢀbased screening campaigns, we sought to
develop a new method for preparing 1,2,4ꢀtriazines. Particular importance was placed on the ability to
incorporate sp3ꢀlinked substituents onto the heterocycle, which is known to generally provide access to
more developable physicochemical space18 and is a limitation of many of the existing methods for
preparing 1,2,4ꢀtriazines (vide supra). Other goals were to identify mild reaction conditions that enable
the incorporation of sensitive functionality, to employ readily available starting materials in a modular
manner, achieve complete regioselectivity, and to avoid a terminal oxidation step. Along these lines we
took note of the chemistry developed by Deng17 (Figure 1). This chemistry is postulated to proceed
through the intermediacy of tosyl amidrazone 9, which undergoes cyclodehydration with concomitant
sulfinate elimination to afford the 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazine product. We postulated that a more
direct approach to access an intermediate related to 9 could be achieved through condensation of
hydrazine with an acylsulfonamide of type 11 (Figure 1). Acylsulfonamide 11 was expected to undergo
initial condensation of hydrazine with the ketone functionality, followed by an analogous reaction
pathways consisting of cyclization and elimination of sulfinate.19 Proceeding through a sulfonamide
intermediate provides two advantages: firstly, the need for a subsequent oxidation step is eliminated; and,
secondly, the sulfonamide enables the preparation of βꢀketoꢀNꢀacylsulfonamide 11 from readily available
starting materials via either alkylation using an αꢀbromoketone or acylation using an acid chloride.
Therefore, the incorporation of either the C3 or C6 substituent should be possible in two steps from
available starting materials in a modular manner. At the outset, our primary concern associated with this
approach was competitive initial reaction of hydrazine with the acylsulfonamide, which is a known
process that may lead to nonproductive cleavage of the acylsulfonamide.20
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Scheme 1. Preparation of βꢀketoꢀNꢀacylsulfonamide 16.
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Table 1. Optimization of the synthesis of 1,2,4ꢀtriazine 17 from 16.
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Entry
R
Hydrazine Source (1.5 equiv.)
Solvent
Temp. (°C) %yielda
1
CH3
NH2NH2· H2O
EtOH
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0
2
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4
CH3
4ꢀCH3Ph
CH3
NH2NH2· HCl
NH2NH2· HCl
EtOH
EtOH
EtOH
67
60[52]
74[70]
NH2NH2·1.16 HCl
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6
CH3
CH3
NH2NH2·1.16 HCl
NH2NH2·1.16 TsOH
EtOH
EtOH
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45
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4ꢀCH3Ph
CH3
NH2NH2·1.16 HCl
NH2NH2·1.33 HCl
EtOH
EtOH
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65
62
9
CH3
CH3
NH2NH2·1.5 HCl
NH2NH2·2.0 HCl
EtOH
EtOH
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11
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13
CH3
CH3
CH3
NH2NH2·1.16 HCl
NH2NH2·1.16 HCl
NH2NH2·1.16 HCl
EtOH/(5% H2O)
DMSO
45
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73
0
0
1,4ꢀdioxane
aDetermined by analysis of crude 1H NMR spectra using 2,6ꢀdimethoxytoluene as an internal standard. Yield in parentheses
refers to isolated yield after column chromatography.
In order to evaluate the feasibility of this approach, Nꢀacylsulfonamide 16 was prepared in two steps from
benzoyl chloride and methanesulfonamide (Scheme 1). Initial attempts to alkylate Nꢀacylsulfonamide 14
by first deprotonating with strong bases (e.g. sodium hydride, potassium tꢀbutoxide) followed by
treatment with various αꢀbromoketones were not successful. However, this transformation was
successfully accomplished in 70% yield in the presence of N,Nꢀdiisopropylethylamine in DMF at 45 °C.
Treatment of 16 with 1.5 equivalents of hydrazine monohydrate in ethanol at 45 °C afforded a complex
mixture of products (Table1, entry 1). Full consumption of the starting material 16 was observed under
these conditions, however none of the desired 1,2,4ꢀtriazine product was detected; LCMS analysis of the
crude reaction mixture showed major byproducts consistent with acyl group cleavage. In contrast,
treatment of 16 with 1.5 equivalents of hydrazine monohydrochloride under otherwise identical
conditions afforded the desired 1,2,4ꢀtriazine as the major product in 67% yield by 1H NMR (entry 2);
none of the deacylated material was detected by LCMS analysis of the crude reaction mixture. The yield
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of 17 was improved to 74% by using a 1.16 fold excess of HCl relative to hydrazine (entry 4). Notably,
attempts to improve the yield by increasing the reaction temperature (entry 5), using the analogous tosyl
starting material (entry 7) or using the tosyl hydrazine salt in place of hydrazine hydrochloride (entry 6)
were unsuccessful. Further increasing the amount of HCl relative to hydrazine afforded substantially
reduced yields (entries 8ꢀ10). The use of wet (5% water) ethanol had little impact on the yield of the
reaction (entry 11), however using DMSO or 1,4ꢀdioxane21 as solvent afforded no desired product (entry
12,13).
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Scheme 2. Scope of 1,2,4ꢀtriazine synthesis at the C3 position.
With the optimized conditions identified, the scope of this transformation at the C3 position of the 1,2,4ꢀ
triazine product was evaluated (Scheme 2). The βꢀketoꢀNꢀacylsulfonamide starting materials (19aꢀm)
were prepared through acylation of sulfonamide 18. A variety of functional groups are tolerated at the C3
position in this twoꢀstep sequence. For example, electron neutral (20h), rich (20d) and deficient (20g)
aromatic systems all worked well in this transformation. Several heteroꢀaromatic systems that would be
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difficult to prepare using standard transitionꢀmetal mediated crossꢀcoupling methodologies were also
found to be readily prepared using this approach (20e, 20i, 20j, 20k). Additionally, both primary and
secondary alkyl substituents were well tolerated, and the mild reactions conditions are compatible with
sensitive functionality including esters (20f), bocꢀprotected amines (20c, 20e), and alkyl nitriles (20m).
The scalability of this 1,2,4ꢀtriazine synthesis was demonstrated through the preparation of the pyrazoleꢀ
substituted 1,2,4ꢀtriazine 20i on 2.4 g scale from 19i with no loss in isolated yield (81%).
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Scheme 3. Scope of 1,2,4ꢀtriazine synthesis at the C6 position.
aAlternate reaction conditions were used. See experimental section for details.
The scope of this reaction with regards to the C6 position of the 1,2,4ꢀtriazine was also evaluated
(Scheme 3). In this case the starting materials 21aꢀg were prepared in one step through alkylation of Nꢀ
acylsulfonamide 14 with available αꢀbromoketones using N,Nꢀdiisopropylethylamine in 1,4ꢀdioxane or
DMF (see experimental section for details). Unexpectedly, the effectiveness of the optimized conditions
disclosed in Table 1 is dependent on the steric environment adjacent to the ketone. For example, applying
the optimized conditions from Table 1, entry 4 to the isopropyl substrate 21a produced only 3% of the
corresponding 1,2,4ꢀtriazine 22a by analysis of crude 1H NMR (the remaining material balance
constituted starting material). After optimization of the reaction parameters, the isolated yield of the
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isopropylꢀsubstituted 1,2,4ꢀtriazine 22a was improved to 60% through the use of four equivalents of the
hydrazine tosylate salt,22 with heating at 60 °C in the presence of powdered 4Å molecular sieves (see
supporting information for full optimization details). As shown in Scheme 3, a variety of primary and
secondary alkyl substituents are tolerated at the C6 position of the heterocycle. The chemoselectivity of
this transformation is demonstrated though the preparation of phthalimides 22f and 22g. The only C3
substituent that has been examined in this sequence is phenyl. Unfortunately, aryl substituents are not
tolerated at the C6 position of the heterocycle using these conditions, presumably due to the decreased
reactivity of the aryl ketone precursor. However, many of the existing methods for preparing C6ꢀ
substituted 1,2,4ꢀtriazines have only been demonstrated to provide products with aryl substituents at this
position.14,16,17 By providing access to primary and secondary alkyl substituents at the C6 positions this
methodology is complementary to many of the existing methods for preparing C6ꢀsubstituted 1,2,4ꢀ
triazines.
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A possible mechanistic pathway leading to the formation of the 1,2,4ꢀtriazine product is highlighted in
Scheme 4. Because the rate of the reaction is highly sensitive to the steric environment adjacent to the
ketone, the mechanism likely involves initial condensation of hydrazine with the ketone as the rateꢀ
limiting step to give hydrazone 23. Intermediate 24, produced by cyclization of hydrazone 23 onto the
adjacent acyl sulfonamide, likely undergoes direct dehydration and elimination of sulfinate to give the
1,2,4ꢀtriazine product (10). In order to test for the possible intermediacy of 25, ketone 18 and acyl
hydrazine 26 were exposed to pꢀTsOH in ethanol at 50 °C. The corresponding 1,2,4ꢀtriazine product was
not detected by 1H NMR analysis of the crude reaction mixture. This result suggests that intermediate 25,
if produced during the course of the reaction, is not an intermediate leading to the 1,2,4ꢀtriazine product.
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Scheme 4. Possible mechanistic pathways.
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In summary, a strategy for preparing 3,6ꢀdisubstitutedꢀ1,2,4ꢀtriazines through the cyclodehydration of Nꢀ
acylsulfonamides of type 11 is reported. Unlike many existing methods for preparing this heterocycle,
this approach is suitable for preparing 1,2,4ꢀtriazines with a variety of sp3ꢀlinked substituents at both the
C3 and C6 positions, which is highlighted by the fact that twenty out of the twentyꢀone triazine products
shown in Schemes 2 and 3 were unknown in the chemical literature prior to this disclosure.
Experimental Section
General. Sulfonamide 18 was purchased from ChemBridge. tertꢀButyl 3ꢀ(chlorocarbonyl)ꢀ1Hꢀindoleꢀ1ꢀ
carboxylate was prepared using a literature procedure.23 6ꢀMethoxyꢀ2ꢀpyridinecarbonyl chloride was
prepared using a literature procedure.24 3ꢀIsoxazolecarbonyl chloride was prepared using a literature
procedure.25 5ꢀCyanopentanoyl chloride was prepared using a literature procedure.26 6ꢀHeptanoyl
chloride was prepared using a literature procedure.27 2ꢀ(7ꢀBromoꢀ6ꢀoxoheptyl)ꢀ1Hꢀisoindoleꢀ1,3(2H)ꢀ
dione was prepared using a literature procedure.28 All other chemicals and reagents were purchased from
commercial sources and used without further purification. Reactions were monitored by thin layer
chromatography (TLC) using preꢀcoated 250 ꢁm silica gel plates and visualized by fluorescence
quenching under UV light or staining with iodine, pꢀanisaldehyde or potassium permanganate. Unless
1
otherwise indicated, yields refer to isolated compounds. H NMR spectra were recorded at 25 °C with a
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spectrometer equipped with an AutoX ID 600ꢀ5 probe at 600 MHz or an AVIII spectrometer at 400 MHz.
13C NMR spectra were recorded at 25 °C with a spectrometer equipped with a 5 mm BBO cryoprobe
equipped with a Zꢀaxis gradient at 100 MHz. Chemical shifts are reported in part per million (PPM)
using the internal solvent residual of CD3OD or CDCl3 as an internal standard. Signals are listed as
follows: chemical shift in ppm (multiplicity identified as s = singlet, br = broad, d = doublet, t = triplet, q
= quartet, p = pentet, sx = sextet, m = multiplet; integration; coupling constants in Hz). The HRMS
analysis was conducted on a hybrid quadrupoleꢀorbitrap mass spectrometer in positive electrospray mode.
The sample was separated on a UPLC system prior to mass spectrometric analysis. The resulting spectra
was automatically lockmass corrected and the target mass ions and the confirming adduct (H+) were
extracted and combined as a chromatogram. The mass accuracy was calculated for all observed isotopes
against the theoretical mass ions derived from the chemical formula. Melting points are reported in °C
and were uncorrected.
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N-(Methylsulfonyl)-N-(2-oxobutyl)benzamide (16). A mixture of N,Nꢀdiisopropylethylamine (1.97 mL,
11.3 mmol) and Nꢀacylsulfonamide 1429 (1.5 g, 7.5 mmol) in DMF (10 mL) was stirred at rt for 5 min
then treated with 1ꢀbromoꢀ2ꢀbutanone 15 (1.54 mL, 15.1 mmol) and stirred at 45 oC for 18 h. The
reaction mixture was concentrated under reduced pressure. Heptane (40 mL) was added to the crude
reaction mixture and evaporated under reduced pressure. The residue was dissolved in dichloromethane
(150 mL) and washed with 1N HCl (50 ml). The aqueous phase was backꢀextracted with
dichloromethane (2 x 100 mL) and the combined organic layers were dried over sodium sulfate, filtered
and evaporated. The residue was purified using column chromatography, eluting with heptane/ethyl
1
acetate (100:0 to 1:1) to give 16 (1.42 g, 70%) as a white solid. mp = 102ꢀ104 °C; H NMR (400 MHz,
CDCl3) δ 7.41ꢀ7.52 (m, 5H), 4.62 (s, 2H), 3.50 (s, 3H), 2.27 (q, 2H, J = 7.3), 0.98 (t, 3H, J = 7.3); 13C
NMR (100 MHz, CDCl3) δ 205.1, 171.4, 133.9, 131.5, 128.7, 127.1, 56.1, 42.3, 32.8, 7.3; HRMS (ESI)
m/z: [M + H]+ Calcd for C12H16NO4S 270.0795; Found 270.0793.
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6-Ethyl-3-phenyl-1,2,4-triazine (17). A suspension of 16 (300 mg, 1.11 mmol) in ethanol (5.5 mL) was
treated with hydrazine monohydrochoride (95.5 mg, 1.39 mmol) and hydrazine dihydrochloride (29.3 mg,
0.28 mmol). The vial was sealed, evacuated and backfilled three times with nitrogen. The suspension
was stirred at 45 °C for 39 h. The reaction mixture was concentrated under reduced pressure, and the
residue was poured into halfꢀdiluted saturated sodium bicarbonate solution (7 mL) and extracted with
ethyl acetate (5 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 9:1 heptane/ethyl
acetate) to give triazine 17 (144 mg, 70%) as a light amber oil. 1H NMR (600 MHz, CD3OD) δ 8.78 (d,
1H, J = 2.9), 8.47 (d, 2H, J = 7.0), 7.53ꢀ7.60 (m, 3H), 3.07 (qd, 2H, J = 7.6, 1.7), 1.44 (t, 3H, J = 7.6); 13C
NMR (100 MHz, CD3OD) δ 163.7, 162.5, 151.5, 136.3, 132.7, 130.0, 129.0, 27.6, 13.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C11H12N3 186.1026; Found 186.1024.
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N-(Methylsulfonyl)-N-(2-oxopropyl)tetrahydro-2H-pyran-4-carboxamide (19a). A solution of
sulfonamide 18 (300 mg, 1.98 mmol), DMAP (24.2 mg, 0.19 mmol) and triethylamine (0.554 mL, 3.97
mmol) in dichloromethane (6 mL) was treated with the tetrahydroꢀ2Hꢀpyranꢀ4ꢀcarbonyl chloride (324
mg, 2.18 mmol) dropwise at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was
diluted with dichloromethane (30 mL) and washed with 1N HCl (2 x 15 mL) and brine (15 mL). The
organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified
using column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate) to afford 19a (380 mg, 73%)
as a white solid. mp = 103ꢀ107 °C; 1H NMR (400 MHz, CDCl3) δ 4.66 (s, 2H), 3.99ꢀ4.09 (m, 2H), 3.45
(td, 2H, J = 11.7, 2.3), 3.37 (s, 3H), 3.12ꢀ3.21 (m, 1H), 2.23 (s, 3H), 1.90 (qd, 2H, J = 11.7, 4.3), 1.78 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 201.8, 174.8, 66.8, 54.8, 43.0, 41.2, 29.3, 26.9; HRMS (ESI) m/z: [M
+ H]+ Calcd for C10H17NO5S 264.0900; Found 264.0898.
N-(Methylsulfonyl)-N-(2-oxopropyl)-3-phenylpropanamide (19b). A solution of sulfonamide 18 (300
mg, 1.98 mmol), DMAP (24.2 mg, 0.19 mmol) and triethylamine (0.533 mL, 3.97 mmol) in
dichloromethane (6 mL) was treated with benzenepropanoyl chloride (368 mg, 2.18 mmol) dropwise at 0
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°C. The reaction mixture was stirred at rt for 16h. The reaction mixture was diluted with
dichloromethane (30 mL) and washed with 1N HCl (2 x 15 mL) followed by brine (15 mL). The
combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was
purified using column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate) to afford 19b (441
mg, 78%) as a colorless gum. 1H NMR (400 MHz, CDCl3) δ 7.31 (t, 2H, J = 7.5), 7.19ꢀ7.25 (m, 3H), 4.64
(s, 2H), 3.33 (s, 3H), 2.98ꢀ3.04 (m, 2H), 2.92ꢀ2.98 (m, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.8, 172.1, 140.1, 128.6, 128.4, 126.5, 54.8, 42.5, 37.6, 30.7, 26.9; HRMS (ESI) m/z: [M + H]+ Calcd
for C13H18NO4S 284.0951; Found 284.0949.
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tert-Butyl 4-[(methylsulfonyl)(2-oxopropyl)carbamoyl]piperidine-1-carboxylate (19c). A solution of
sulfonamide 18 (250 mg, 1.65 mmol), DMAP (20.2 mg, 0.16 mmol) and triethylamine (0.46 mL, 3.31
mmol) in dichloromethane (5 mL) was cooled to 0 °C and treated with a solution of tertꢀbutylꢀ4ꢀ
(chlorocarbonyl)piperidineꢀ1ꢀcarboxylate (492 mg, 1.98 mmol) in dichloromethane (1 mL) dropwise at 0
°C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with 1N HCl (30
mL) and extracted with dichloromethane (30 mL). The organic layer was washed with brine (15 mL),
dried over sodium sulfate, filtered and evaporated. The crude product was purified using column
chromatography (petroleum ether/ethyl acetate, 1:1) to give 19c (360 mg, 74%) as a yellow gum. 1H
NMR (400 MHz, CDCl3) δ 4.66 (s, 2H), 4.16 (br. s, 2H), 3.36 (s, 3H), 3.02ꢀ3.10 (br. m, 1H), 2.71ꢀ2.85
(br. m, 2H), 2.22 (s, 3H), 1.85 (br. d, 2H, J = 12.4), 1.71 (qd, 2H, J = 12.4, 3.9), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 201.8, 175.0, 154.6, 79.8, 54.8, 43.1, 42.8, 42.1, 28.7, 28.4, 27.0; HRMS (ESI) m/z:
[M + H]+ Calcd for C15H26N2O6S 363.1584; Found 363.1577.
4-Methoxy-N-(methylsulfonyl)-N-(2-oxopropyl)benzamide (19d). A solution of sulfonamide 18 (250
mg, 1.65 mmol), DMAP (20.2 mg, 0.16 mmol) and triethylamine (0.461 mL, 3.31 mmol) in
dichloromethane (5 mL) was treated with a solution of 4ꢀmethoxybenzoyl chloride (492 mg, 1.98 mmol)
in dichloromethane (1 mL) dropwise at 0 °C. The reaction mixture was stirred at rt for 16h. The reaction
mixture was diluted with dichloromethane (30 mL) and washed with 1N HCl (2 x 15 mL) and brine (15
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mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude
product was purified using column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate) to afford
19d (350 mg, 74%) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 2H, J = 8.6), 6.93 (d, 2H, J =
8.6), 4.68 (s, 2H), 3.86 (s, 3H), 3.51 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.0, 171.1,
162.3, 129.7, 125.6, 114.0, 57.2, 55.4, 42.6, 26.7; HRMS (ESI) m/z: [M + H]+ Calcd for C12H16NO5S
286.0744; Found 286.0741.
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tert-Butyl 3-[(methylsulfonyl)(2-oxopropyl)carbamoyl]-1H-indole-1-carboxylate (19e). A solution of
sulfonamide 18 (150 mg, 1.00 mmol), DMAP (12.1 mg, 0.09 mmol) and triethylamine (0.29 mL, 1.98
mmol) in dichloromethane (5 mL) was cooled to 0 °C and treated with a solution of tertꢀbutyl 3ꢀ
(chlorocarbonyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (280 mg, 1.00 mmol) in dichloromethane (5 mL) dropwise at 0
°C. The reaction mixture was stirred at 0 °C for 1h. The reaction mixture was diluted with water (2 mL)
and 2N HCl (1 mL) and stirred for 5 min. The organic layer was separated and the aqueous layer was
backꢀextracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine
(5 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified using column
chromatography (DCM) to give 19e (288 mg, 74%) as a white solid. mp = 132ꢀ136 °C; 1H NMR (400
MHz, CDCl3) δ 8.19 (d, 1H, J = 7.4), 8.05 (s, 1H), 7.77 (d, 1H, J = 7.4), 7.42 (t, 1H, J = 7.4), 7.36 (t, 1H,
J = 7.4), 4.83 (s, 2H), 3.56 (s, 3H), 2.12 (s, 3H), 1.67 (s, 9H); 13C NMR (100 MHz, CD3OD) δ 202.2,
165.9, 148.7, 134.9, 129.7, 127.1, 125.8, 124.3, 120.5, 115.5, 113.6, 85.5, 56.7, 42.7, 28.1, 26.9; HRMS
(ESI) m/z: [M + H]+ Calcd for C18H22N2O6S 395.1271; Found 395.1268.
Ethyl 4-[(methylsulfonyl)(2-oxopropyl)amino]-4-oxobutanoate (19f). A solution of sulfonamide 18 (200
mg, 1.32 mmol), DMAP (16.2 mg, 0.13 mmol) and triethylamine (0.38 mL, 2.65 mmol) in
dichloromethane (10 mL) was treated with a solution of ethyl succinyl chloride (261 mg, 1.59 mmol) in
dichloromethane (2 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2h. The reaction
mixture was diluted with water (2 mL) and 2N HCl (1 mL) and stirred for 5 min. The organic layer was
separated and the aqueous layer was backꢀextracted with dichloromethane (3 x 15 mL). The combined
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organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The
crude product was purified using column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate) to
afford 19f (317 mg, 86%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.7 (s, 2H), 4.15 (q, 2H, J =
7.0), 3.44 (s, 3H), 2.98 (t, 2H, J = 6.2), 2.70 (t, 2H, J = 6.2), 2.22 (s, 3H), 1.26 (t, 3H, J = 7.0); 13C NMR
(100 MHz, CDCl3) δ 201.4, 172.2, 171.8, 60.9, 54.8, 42.5, 31.0, 28.9, 26.8, 14.1; HRMS (ESI) m/z: [M +
H]+ Calcd for C10H18NO6S 280.0849; Found 280.0845.
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N-(Methylsulfonyl)-4-nitro-N-(2-oxopropyl)benzamide (19g). A solution of sulfonamide 18 (400 mg,
2.64 mmol), DMAP (32.3 mg, 0.26 mmol) and triethylamine (0.46 mL, 3.30 mmol) in dichloromethane
(15 mL) was cooled to 0 °C and treated with 4ꢀnitrobenzoyl chloride (589 mg, 3.17 mmol) dropwise at 0
°C. The reaction mixture was stirred at 0 °C for 1.5h. The reaction mixture was diluted with water (2
mL) and 2N HCl (1 mL) and stirred for 5 min. The organic layer was separated and the aqueous layer
was backꢀextracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with
brine (5 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified using
column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate). The crude product was suspended
in petroleum ether/ethyl acetate (1:1, 15 mL), stirred for 15 min, and the resulting solids were collected by
filtration and dried under reduced pressure to give 19g (370 mg, 47%) as a white solid. mp = 185ꢀ187 °C;
1H NMR (400 MHz, CDCl3) δ 8.31 (d, 2H, J = 8.2), 7.68 (d, 2H, J = 8.2), 4.65 (s, 2H), 3.43 (s, 3H), 2.14
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.5, 169.3, 149.2, 139.8, 128.2, 123.9, 56.4, 42.5, 26.8; HRMS
(ESI) m/z: [M + H]+ Calcd for C11H13N2O6S 301.0489; Found 301.0489.
N-(Methylsulfonyl)-N-(2-oxopropyl)benzamide (19h). A solution of sulfonamide 18 (300 mg, 1.98
mmol), DMAP (24.2 mg, 0.19 mmol) and triethylamine (0.533 mL, 3.97 mmol) in dichloromethane (6
mL) was treated with benzoyl chloride (335 mg, 2.38 mmol) dropwise at rt. The reaction mixture was
stirred at rt for 16 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with
1N HCl (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The
crude product was purified using column chromatography (100:0 to 1:1 petroleum ether/ethyl acetate) to
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afford 19h (371 mg, 73%) as a white solid. mp = 110ꢀ113 °C; 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.56
(m, 5H), 4.64 (s, 2H), 3.51 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.9, 171.4, 133.8,
131.5, 128.7, 127.0, 57.0, 42.4, 26.7; HRMS (ESI) m/z: [M + H]+ Calcd for C11H14NO4S 256.0638;
Found 256.0636.
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1-Methyl-N-(methylsulfonyl)-N-(2-oxopropyl)-1H-pyrazole-3-carboxamide (19i). A solution of
sulfonamide 18 (2.89 g, 19.1 mmol), DMAP (234 mg, 1.91 mmol) and 1ꢀmethylꢀ1Hꢀpyrazoleꢀ3ꢀcarbonyl
chloride (3.90 g, 26.9 mmol) in dichloromethane (47.8 mL) was treated with triethylamine (7.97 mL,
57.3 mmol) dropwise and stirred at rt for 18h. The reaction mixture was diluted with water (5 mL) and
saturated ammonium chloride solution (5 mL) and extracted with dichloromethane (3 x 120 mL). The
combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was
purified using column chromatography (100:0 to 90:10 dichloromethane/methanol) to afford 19i (3.15 g,
63%) as a white solid. mp = 115ꢀ117 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, 1H, J = 2.3), 6.89 (d, 1H,
J = 2.3), 5.29 (s, 2H), 3.89 (s, 3H), 3.54 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.6,
162.7, 145.4, 131.2, 111.4, 56.0, 41.8, 39.6, 26.3; HRMS (ESI) m/z: [M + H]+ Calcd for C9H14N3O4S
260.0700; Found 260.0695.
6-Methoxy-N-(methylsulfonyl)-N-(2-oxopropyl)pyridine-2-carboxamide (19j). A solution of
sulfonamide 18 (200 mg, 1.32 mmol), DMAP (16.2 mg, 0.13 mmol) and 6ꢀmethoxyꢀ2ꢀpyridinecarbonyl
chloride (617 mg, 4.27 mmol) in dichloromethane (7.5 mL) was treated with triethylamine (0.552 mL,
3.97 mmol) dropwise at rt. The reaction mixture was stirred at rt for 16h. The reaction mixture was
diluted with water (5 mL) and saturated ammonium chloride (5 mL) and the product was extracted with
ethyl acetate (4 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 1:1 petroleum
ether/ethyl acetate) to afford 19j (225 mg, 60%) as a white solid. mp = 109ꢀ111 °C; 1H NMR (400 MHz,
CDCl3) δ 7.71 (t, 1H, J = 7.4), 7.46 (d, 1H, J = 7.4), 6.89 (d, 1H, J = 7.4), 5.13 (s, 2H), 3.91 (s, 3H), 3.58
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(s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.0, 167.8, 162.5, 148.8, 139.8, 118.6, 114.4, 56.2,
53.9, 42.4, 26.7; HRMS (ESI) m/z: [M + H]+ Calcd for C11H14N2O5S 287.0696; Found 287.0690.
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N-(Methylsulfonyl)-N-(2-oxopropyl)-1,2-oxazole-3-carboxamide (19k). A solution of sulfonamide 18
(170 mg, 1.12 mmol), DMAP (13.7 mg, 0.11 mmol) and 3ꢀisoxazolecarbonyl chloride (222 mg, 1.69
mmol) in dichloromethane (7.5 mL) was treated with triethylamine (0.47 mL, 3.37 mmol) dropwise and
stirred at rt for 18h. The reaction mixture was diluted with water (5 mL) and saturated ammonium
chloride solution (5 mL) and extracted with ethyl acetate (4 x 15 mL). The combined organic layers were
dried over sodium sulfate, filtered and evaporated. The crude product was purified using column
chromatography (100:0 to 1:1 heptane/ethyl acetate) to afford 19k (231 mg, 83%) as a white solid. mp =
dec 150 °C; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 6.86 (s, 1H), 5.20 (s, 2H), 3.57 (s, 3H), 2.25 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 201.7, 160.7, 159.2, 157.6, 106.7, 55.7, 42.1, 26.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C8H11N2O5S 247.0383; Found 247.0383.
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N-(Methylsulfonyl)-N-(2-oxopropyl)hept-6-ynamide (19l). A solution of sulfonamide 18 (380 mg, 2.51
mmol), DMAP (30.7 mg, 0.25 mmol) and triethylamine (0.73 mL, 5.00 mmol) in dichloromethane (10
mL) was cooled to 0 °C and treated with a solution of 6ꢀheptanoyl chloride (363 mg, 2.51 mmol) in
dichloromethane (4 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1.5h. The
reaction mixture was diluted with water (2 mL) and 2N HCl (1 mL) and stirred for 5 min. The organic
layer was separated and the aqueous layer was backꢀextracted with dichloromethane (3 x 10 mL). The
combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 1:1 petroleum
ether/ethyl acetate) to give 19l (320 mg, 49%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.70 (s,
2H), 3.40 (s, 3H), 2.68 (t, 2H, J = 7.0), 2.19ꢀ2.26 (m, 5H), 1.96 (t, 1H, J = 2.7), 1.77ꢀ1.86 (m, 2H), 1.55ꢀ
1.63 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 201.9, 172.5, 83.8, 68.8, 54.8, 42.5, 35.1, 27.5, 26.9, 23.6,
18.2; HRMS (ESI) m/z: [M + H]+ Calcd for C11H18NO4S 260.0951; Found 260.0948.
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5-Cyano-N-(methylsulfonyl)-N-(2-oxopropyl)pentanamide (19m). A solution of sulfonamide 18 (431
mg, 2.85 mmol), DMAP (34.8 mg, 0.28 mmol) and triethylamine (0.79 mL, 5.70 mmol) in
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dichloromethane (10 mL) was cooled to 0 °C and treated with a solution of 5ꢀcyanopentanoyl chloride
(415 mg, 2.85 mmol) in dichloromethane (5 mL) dropwise at 0 °C. The reaction mixture was stirred at 0
°C for 1.5h. The reaction mixture was diluted with water (10 mL) and stirred for 5 min. The organic
layer was separated and the aqueous layer was backꢀextracted with dichloromethane (3 x 10 mL). The
combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 1:1 petroleum
ether/ethyl acetate) to give 19m (500 mg, 67%) as an offꢀwhite solid. mp = 90ꢀ96 °C; 1H NMR (400
MHz, CDCl3) δ 4.66 (s, 2H), 3.34 (s, 3H), 2.72 (t, 2H, J = 7.0), 2.37 (t, 2H, J = 7.0), 2.23 (s, 3H), 1.80ꢀ
1.88 (m, 2H), 1.68ꢀ1.76 (m, 2H) ; 13C NMR (100 MHz, CDCl3) δ 201.8, 172.0, 119.3, 54.8, 42.5, 34.6,
26.9, 24.5, 23.6, 17.0; HRMS (ESI) m/z: [M + H]+ Calcd for C10H17N2O4S 261.0904; Found 261.0901.
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General procedure for the cyclodehydration of Nꢀacylsulfonamides (19aꢀ19m) to give 1,2,4ꢀtriazines
(20aꢀ20m) from Scheme 2.
In a vial a mixture of the βꢀketoꢀNꢀacylsulfonamide 19 (1 equiv.), hydrazine monohydrochloride (1.25
equiv.) and hydrazine dihydrochloride (0.25 equiv.) in ethanol (0.2 M) is sealed, evacuated and backꢀ
filled with nitrogen three times. The reaction mixture is stirred for 18 h at 45 °C. The reaction mixture is
then poured into saturated sodium bicarbonate (5 mL) and extracted with ethyl acetate (5 x 15 mL). The
combined organic layers are dried over sodium sulfate, filtered and evaporated. The crude product is
purified using column chromatography (100:0 to 4:1 heptane/ethyl acetate) to give the triazine product.
6-Methyl-3-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine (20a). General procedure performed on 0.532
mmol scale to give 20a (74 mg, 78%) as a light yellow solid. mp = 73ꢀ75 °C; 1H NMR (400 MHz,
CD3OD) δ 8.70 (s, 1H), 4.06ꢀ4.12 (m, 2H), 3.60ꢀ3.68 (m, 2H), 3.29ꢀ3.39, (m, 1H), 2.71 (s, 3H), 1.95ꢀ2.07
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(m, 4H); 13C NMR (100 MHz, CD3OD) δ 170.6, 158.4, 152.3, 68.7, 43.3, 32.3, 19.2; HRMS (ESI) m/z:
[M + H]+ Calcd for C9H14N3O 180.1131; Found 180.1130.
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6-Methyl-3-(2-phenylethyl)-1,2,4-triazine (20b). General procedure performed on 0.529 mmol scale to
give 20b (87 mg, 82%) as a light yellow solid. mp = 128ꢀ130 °C; 1H NMR (400 MHz, CD3OD) δ 8.65 (s,
1H), 7.13ꢀ7.27 (m, 5H), 3.40 (t, 2H, J = 7.4), 3.17 (t, 2H, J = 7.4), 2.66 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 168.4, 158.1, 152.2, 142.1, 129.61, 129.57, 127.3, 39.4, 35.3, 19.2; HRMS (ESI) m/z: [M +
H]+ Calcd for C12H14N3 200.1182; Found 200.1180.
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tert-Butyl 4-(6-methyl-1,2,4-triazin-3-yl)piperidine-1-carboxylate (20c). General procedure performed
on 0.497 mmol scale to give 20c (72 mg, 52%) as a light red solid. mp = 57ꢀ60 °C; 1H NMR (400 MHz,
CD3OD) δ 8.69 (s, 1H), 4.21 (br. d, 2H, J = 13.2), 3.27 (tt, 1H, J = 11.7, 3.9), 2.93ꢀ3.07 (br. m, 2H), 2.68
(s, 3H), 2.04 (br d, 2H, J = 10.9), 1.83 (qd, 2H, J = 12.1, 4.3), 1.50 (s, 9H) ; 13C NMR (100 MHz, CDCl3)
δ 170.7, 158.4, 156.6, 152.3, 81.2, 45.1, 44.3, 31.6, 28.9, 19.2; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H23N4O2 279.1816; Found 279.1813.
3-(4-Methoxyphenyl)-6-methyl-1,2,4-triazine (20d). General procedure performed on 0.526 mmol scale
to give 20d (87 mg, 82%) as a light yellow solid. mp = 98ꢀ100 °C; 1H NMR (400 MHz, CD3OD) δ 8.68
(s, 1H), 8.39 (d, 2H, J = 9.0), 7.07 (d, 2H, J = 9.0), 3.90 (s, 3H), 2.69 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 164.2, 163.3, 157.4, 152.0, 130.7, 128.5, 115.4, 56.1, 19.2; HRMS (ESI) m/z: [M + H]+ Calcd
for C11H12N3O 202.0975; Found 202.0973.
tert-Butyl 3-(6-methyl-1,2,4-triazin-3-yl)-1H-indole-1-carboxylate (20e). General procedure performed
on 0.355 mmol scale to give 20e (61 mg, 55%) as a yellow solid. mp = 132ꢀ133 °C; 1H NMR (400 MHz,
CDCl3) δ 8.66ꢀ8.69 (m, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.26ꢀ8.28 (m, 1H), 7.37ꢀ7.45 (m, 2H), 2.75 (s,
3H), 1.72 (s, 9H) ; 13C NMR (100 MHz, CDCl3) δ 160.9, 155.1, 149.2, 148.9, 136.3, 129.3, 127.6, 125.1,
123.7, 122.9, 117.0, 115.1, 84.6, 28.2, 19.5; HRMS (ESI) m/z: [M + H]+ Calcd for C17H19N4O2 311.1503;
Found 311.1498.
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Ethyl 3-(6-methyl-1,2,4-triazin-3-yl)propanoate (20f). General procedure performed on 0.537 mmol
scale to give 20f (89 mg, 85%) as a light yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 4.13 (q,
2H, J = 7.0), 3.39 (t, 2H, J = 7.0), 2.95 (t, 2H, J = 7.0), 2.69 (s, 3H), 1.24 (t, 3H, J = 7.0); 13C NMR (100
MHz, CD3OD) δ 174.3, 167.7, 158.2, 152.0, 61.8, 32.4, 32.3, 19.2, 14.6; HRMS (ESI) m/z: [M + H]+
Calcd for C9H14N3O2 196.1081; Found 196.1080.
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6-Methyl-3-(4-nitrophenyl)-1,2,4-triazine (20g). General procedure performed on 0.450 mmol scale to
give 20g (67 mg, 69%) as an offꢀwhite solid. mp = dec. 201 °C; 1H NMR (400 MHz, CDCl3) δ 8.72 (d,
2H, J = 8.9), 8.62 (s, 1H), 8.39 (d, 2H, J = 8.9), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 157.4,
149.8, 149.4, 140.6, 128.9, 124.0, 19.6; HRMS (ESI) m/z: [M + H]+ Calcd for C10H9N4O2 217.0720;
Found 217.0718.
6-Methyl-3-phenyl-1,2,4-triazine15,30 (20h). General procedure performed on 0.548 mmol scale to give
20h (69 mg, 73%) as a light yellow solid. mp = 68ꢀ70 °C; 1H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H),
8.41ꢀ8.47 (m, 2H), 7.51ꢀ7.57 (m, 3H), 2.72 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 163.5, 158.3, 152.1,
136.2, 132.7, 130.0, 129.0, 19.3; HRMS (ESI) m/z: [M + H]+ Calcd for C10H10N3 172.0869; Found
172.0867.
6-Methyl-3-(1-methyl-1H-pyrazol-3-yl)-1,2,4-triazine (20i). General procedure performed on 9.52 mmol
scale to give 20i (1.33 g, 82%) as a yellow solid. General produced performed on 0.791 mmol scale to
give 20i (112 mg, 81%) as a yellow solid. mp 143ꢀ148 °C; 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H),
7.74 (d, 1H, J = 2.3), 7.08 (d, 1H, J = 2.3), 4.03 (s, 3H), 2.72 (s, 3H); 13C NMR (100 MHz, CD3OD) δ
159.7, 158.7, 152.1, 149.0, 134.1, 108.0, 39.7, 19.4; HRMS (ESI) m/z: [M + H]+ Calcd for C8H10N5
176.0931; Found 176.0931.
3-(6-Methoxypyridin-2-yl)-6-methyl-1,2,4-triazine (20j). General procedure performed on 0.310 mmol
scale to give 20j (44 mg, 69%) as a light yellow solid. mp 74ꢀ78 °C; 1H NMR (400 MHz, CD3OD) δ 8.81
(s, 1H), 8.10 (d, 1H, J = 7.4), 7.87 (t, 1H, J = 7.4), 6.98 (d, 1H, J = 7.4), 4.08 (s, 3H), 2.78 (s, 3H); 13C
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NMR (100 MHz, CD3OD) δ 166.1, 162.6, 159.5, 152.1, 151.5, 141.0, 118.2, 114.6, 54.5, 19.5; HRMS
(ESI) m/z: [M + H]+ Calcd for C10H11N4O 203.0927; Found 203.0925.
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6-Methyl-3-(1,2-oxazol-3-yl)-1,2,4-triazine (20k). General procedure performed on 0.487 mmol scale to
give 20k (42 mg, 53%) as an offꢀwhite solid. mp = dec. 163 °C; 1H NMR (400 MHz, CDCl3) δ 8.95 (s,
1H), 8.85 (s, 1H), 7.25 (s, 1H), 2.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 159.6, 158.6, 156.4,
149.8, 104.4, 19.7; HRMS (ESI) m/z: [M + H]+ Calcd for C7H7N4O 163.0614; Found 163.0613.
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3-(Hex-5-yn-1-yl)-6-methyl-1,2,4-triazine (20l). General procedure performed on 1.06 mmol scale to
give 20l (149 mg, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 3.11 (t, 2H, J = 7.6),
2.69 (s, 3H), 2.22ꢀ2.28 (m, 2H), 1.92ꢀ1.04 (m, 3H), 1.58ꢀ1.68 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
167.7, 156.0, 149.2, 84.0, 68.5, 36.2, 27.9, 27.3, 19.2, 18.2; HRMS (ESI) m/z: [M + H]+ Calcd for
C10H14N3 176.1182; Found 176.1181.
5-(6-Methyl-1,2,4-triazin-3-yl)pentanenitrile (20m). General procedure performed on 1.27 mmol scale to
give 20m (160 mg, 71%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 3.15 (t, 2H, J = 7.4),
2.70 (s, 3H), 2.42 (t, 2H, J = 7.4), 2.00ꢀ2.08 (m, 2H), 1.73ꢀ1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
166.9, 156.3, 149.3, 119.4, 35.6, 26.9, 24.7, 19.2, 17.0; HRMS (ESI) m/z: [M + H]+ Calcd for C9H13N4
177.1135; Found 177.1135.
N-(3-Methyl-2-oxobutyl)-N-(methylsulfonyl)benzamide (21a). A mixture of N,Nꢀdiisopropylethylamine
(0.59 mL, 3.39 mmol) and Nꢀacylsulfonamide 14 (450 mg, 2.26 mmol) in DMF (3.01 mL) was stirred at
rt for 5 min, then treated with 1ꢀbromoꢀ3ꢀmethylbutanꢀ2ꢀone (615 mg, 3.61 mmol) and stirred at 45 °C for
24 h. Additional 1ꢀbromoꢀ3ꢀmethylbutanꢀ2ꢀone (200 mg, 1.2 mmol) was added and the reaction was
stirred for an additional 18 h at 45 °C. The reaction mixture was poured into 0.5 N HCl (20 mL) and
extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate,
filtered and evaporated. The crude product was purified using column chromatography (100:0 to 1:1
heptane/ethyl acetate) to give 21a (450 mg, 70%) as a white solid. mp = 119ꢀ121 °C; 1H NMR (400 MHz,
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CDCl3) δ 7.48ꢀ7.53 (m, 1H), 7.40ꢀ7.47 (m, 4H), 4.70 (s, 2H), 3.53 (s, 3H), 2.46 (sx, 1H, J = 7.0), 0.93 (d,
6H, J = 7.0); 13C NMR (100 MHz, CDCl3) δ 208.2, 171.5, 134.0, 131.5, 128.7, 127.1, 55.2, 42.3, 38.0,
17.7; HRMS (ESI) m/z: [M + H]+ Calcd for C13H18NO4S 284.0951; Found 284.0948.
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N-(2-Cyclopropyl-2-oxoethyl)-N-(methylsulfonyl)benzamide (21b). A mixture of N,Nꢀ
diisopropylethylamine (0.65 mL, 3.76 mmol), and Nꢀacylsulfonamide 14 (500 mg, 2.51 mmol) in DMF
(3.3 mL) was stirred at rt for 5 min then treated with 2ꢀbromoꢀ1ꢀcyclopropylethanꢀ1ꢀone (614 mg, 3.76
mmol) and stirred at 45 oC for 18 h. The reaction mixture was concentrated under reduced pressure.
Heptane (40 mL) was added to the crude reaction mixture and evaporated under reduced pressure. The
residue was dissolved in ethyl acetate (40 mL) and washed with 1N HCl (20 ml). The aqueous phase was
backꢀextracted with dichloromethane (2 x 20 mL) and the combined organic layers were dried over
sodium sulfate, filtered and evaporated. The residue was purified using column chromatography, eluting
with heptane/ethyl acetate (100:0 to 1:1) to give 21b (440 mg, 62%) as a white solid. mp = 149ꢀ152 °C;
1H NMR (400 MHz, CDCl3) δ 7.49ꢀ7.54 (m, 1H), 7.41ꢀ7.48 (m, 4H), 4.81 (s, 2H), 3.50 (s, 3H), 1.70ꢀ1.77
(m, 1H), 0.96ꢀ1.03 (m, 2H), 0.88ꢀ0.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 204.3, 171.5, 134.0,
131.4, 128.7, 127.1, 57.0, 42.2, 18.1, 11.5; HRMS (ESI) m/z: [M + H]+ Calcd for C13H16NO4S 282.0795;
Found 282.0790.
N-[4-(4-Bromophenyl)-3-methyl-2-oxobutyl]-N-(methylsulfonyl)benzamide (21c). A solution of Nꢀ
acylsulfonamide 14 (200 mg, 1.00 mmol) in 1,4ꢀdioxane (3.01 mL) was treated with N,Nꢀ
diisopropylethylamine (0.262 mL, 1.51 mmol) and stirred at rt for 5 min. 1ꢀBromoꢀ4ꢀ(4ꢀbromophenyl)ꢀ3ꢀ
methylbutanꢀ2ꢀone (482 mg, 1.51 mmol) was added to the reaction mixture and the reaction was stirred
at 60 °C for 18h. The cooled reaction mixture was poured into 1N HCl (5 mL) and extracted with ethyl
acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 1:1 heptane/ethyl
acetate) to give 21c (225 mg, 51%) as an offꢀwhite solid. mp = 117ꢀ120 °C; 1H NMR (400 MHz, CDCl3)
δ 7.48ꢀ7.52 (m, 1H), 7.37ꢀ7.40 (m, 4H), 7.33 (d, 2H, J = 8.2), 6.88 (d, 2H, J = 8.2), 4.71 (d, 1H, J = 19.3),
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4.44 (d, 1H, J = 19.3), 3.48 (s, 3H), 2.78 (dd, 1H, J = 13.5, 7.0), 2.67 (sx, 1H, J = 7.0), 2.46 (dd, 1H, J =
13.5, 7.0) 0.94 (d, 3H, J = 7.0); 13C NMR (100 MHz, CDCl3) δ 207.3, 171.4, 137.6, 133.7, 131.6, 131.5,
130.4, 128.7, 127.0, 120.4, 56.1, 45.1, 42.3, 37.6, 16.2; HRMS (ESI) m/z: [M + H]+ Calcd for
C19H21BrNO4S 438.0369; Found 438.0370.
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N-(Methylsulfonyl)-N-(2-oxo-4-phenylbutyl)benzamide (21d). A solution of Nꢀacyl sulfonamide 14 (450
mg, 2.26 mmol) in DMF (3.0 mL) was treated with N,Nꢀdiisopropylethylamine (0.59 mL, 3.39 mmol)
and stirred at rt for 5 min. The reaction mixture was treated with 1ꢀbromoꢀ4ꢀphenylbutanꢀ2ꢀone (821 mg,
3.61 mmol) and stirred at 45 oC for 18 h. The reaction mixture was evaporated under reduced pressure
and suspended in 0.5N HCl (5 mL). The product was extracted with ethyl acetate (5 x 7 mL) and the
combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was
purified on the isco combiflash (100:0 to 4:1 heptane/ethyl acetate) to give 21d (461 mg, 64%) as a white
solid. mp = 118ꢀ122 °C; 1H NMR (400 MHz, CDCl3) δ 7.74ꢀ7.53 (m, 1H), 7.37ꢀ7.45 (m, 4H), 7.17ꢀ7.27
(m, 3H), 7.08 (d, 2H, J = 7.1), 4.65 (s, 2H), 3.49 (s, 3H), 2.82 (t, 2H, J = 7.4), 2.60 (t, 2H, J = 7.4); 13C
NMR (100 MHz, CDCl3) δ 203.6, 171.4, 139.9, 133.8, 131.5, 128.7, 128.6, 128.1, 127.0, 126.4, 56.5,
42.3, 41.0, 29.1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H20NO4S 346.1108; Found 346.1102.
N-(Methylsulfonyl)-N-[2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzamide (21e). A solution of Nꢀ
acylsulfonamide 14 (300 mg, 1.51 mmol) in 1,4ꢀdioxane (3.01 mL) was treated with N,Nꢀ
diisopropylethylamine (0.446 mL, 2.56 mmol) and stirred at rt for 5 min. 2ꢀBromoꢀ1ꢀ(tetrahydroꢀ2Hꢀ
pyranꢀ4ꢀyl)ethanone (530 mg, 2.56 mmol) was added and the reaction mixture was stirred at 60 °C for
18h. The cooled reaction mixture was poured into 1N HCl (8 mL) and extracted with dichloromethane (3
x 15 mL). The combined organic layers were washed with saturated sodium bicarbonate (8 mL), dried
over sodium sulfate, filtered and evaporated. The crude product was purified using column
chromatography (100:0 to 1:1 heptane/ethyl acetate) to give 21e (295 mg, 60%) as a white solid. mp =
149ꢀ150 °C; 1H NMR (400 MHz, CDCl3) δ 7.49ꢀ7.54 (m, 1H), 7.41ꢀ7.48 (m, 4H), 4.71 (s, 2H), 3.90 (dt,
2H, J = 11.7, 3.5), 3.51 (s, 3H), 3.30ꢀ3.38 (m, 2H), 2.43ꢀ2.51 (m, 1H), 1.49ꢀ1.55 (m, 4H); 13C NMR (100
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MHz, CDCl3) δ 205.6, 171.3, 133.9, 131.5, 128.7, 127.1, 66.7, 55.0, 44.7, 42.3, 27.4; HRMS (ESI) m/z:
[M + H]+ Calcd for C15H20NO5S 326.1057; Found 326.1053.
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N-[7-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxoheptyl]-N-(methylsulfonyl)benzamide (21f). A
mixture of Nꢀacylsulfonamide 14 (150 mg, 0.753 mmol), 2ꢀ(7ꢀbromoꢀ6ꢀoxoheptyl)ꢀ1Hꢀisoindoleꢀ
1,3(2H)ꢀdione (764 mg, 2.26 mmol) and N,Nꢀdiisopropylethylamine (0.197 mL, 1.13 mmol) in 1,4ꢀ
dioxane (2.0 mL) was stirred at 50 °C for 18h. The reaction mixture was diluted with 1N HCl (10 mL)
and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium
sulfate, filtered and evaporated. The crude product was purified using column chromatography (100:0 to
1:1 heptane/ethyl acetate) to give 21f (270 mg, 78%) as an off white solid. mp = 141ꢀ143 °C; 1H NMR
(400 MHz, CDCl3) δ 7.82ꢀ7.86 (m, 2H), 7.70ꢀ7.74 (m, 2H), 7.49ꢀ7.53 (m, 1H), 7.41ꢀ7.47 (m, 4H), 4.61
(s, 2H), 3.63 (t, 2H, J = 7.4 ), 3.49 (s, 3H), 2.24 (t, 2H, J = 7.6), 1.61 (p, 2H, J = 7.4), 1.49 (p, 2H, J =
7.6), 1.21 (p, 2H, J = 7.6); 13C NMR (100 MHz, CDCl3) δ 204.3, 171.4, 168.4, 134.1, 133.8, 132.1, 131.5,
128.7, 127.1, 123.2, 56.5, 42.3, 39.2, 37.5, 28.2, 26.0, 22.8; HRMS (ESI) m/z: [M + H]+ Calcd for
C23H25N2O6S 457.1413; Found 457.1428.
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N-[4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxobutyl]-N-(methylsulfonyl)benzamide (21g). A
solution of Nꢀacylsulfonamide 14 (300 mg, 1.51 mmol) in 1,4ꢀdioxane (3.01 mL) was treated with N,Nꢀ
diisopropylethylamine (0.393 mL, 2.26 mmol) and stirred at rt for 5 min. 1ꢀBromoꢀ4ꢀNꢀphthalimidoꢀ2ꢀ
butanone (669 mg, 2.26 mmol) was added to the reaction mixture and the reaction was stirred at 50 °C for
18h. The reaction mixture was treated with additional 1ꢀbromoꢀ4ꢀNꢀphthalimidoꢀ2ꢀbutanone (200 mg,
0.67 mmol) and stirred at 60 °C for an additional 3h. The cooled reaction mixture was then poured into
1N HCl (7 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were
washed with water (8 mL), dried over sodium sulfate, filtered and evaporated. The crude product was
purified using column chromatography (100:0 to 1:1 heptane/ethyl acetate) to give 21g (280 mg, 45%) as
a white solid. mp = 189ꢀ191 °C; 1H NMR (600 MHz, CDCl3) δ 7.82ꢀ7.86 (m, 2H), 7.72ꢀ7.76 (m, 2H),
7.37ꢀ7.51 (m, 5H), 4.65 (s, 2H), 3.91 (t, 2H, J = 7.0), 3.49 (s, 3H), 2.73 (t, 2H, J = 7.0); 13C NMR (100
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MHz, CDCl3) δ 201.8, 171.3, 167.9, 134.1, 133.7, 131.9, 131.6, 128.7, 127.1, 123.4, 56.4, 42.4, 37.6,
32.3; HRMS (ESI) m/z: [M + H]+ Calcd for C20H19N2O6S 415.0958; Found 415.0950.
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NH2NH2·1.16 TsOH. A solution of pꢀtoluenesulfonic acid monohydrate (2.22 g, 11.7 mmol) in methanol
(20 mL) was treated with hydrazine monohydrate (500 mg, 9.99 mmol) and stirred at rt for 5 min. The
reaction mixture was concentrated under reduced pressure and the residue was azeotroped from toluene (3
x 20 mL) and dried under high vacuum to give NH2NH2·1.16 TsOH (2.1 g, 90%) as a white solid that was
used directly in the reactions described below.
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3-Phenyl-6-(propan-2-yl)-1,2,4-triazine (22a). A vial containing a mixture of 21a (178 mg, 0.62 mmol),
NH2NH2·1.16 TsOH (505 mg, 2.47 mmol) and 4Å molecular sieves (150 mg) in ethanol (3.0 mL) was
evacuated and backꢀfilled with nitrogen, then heated at 60 °C for 88h. The cooled reaction mixture was
poured into halfꢀdiluted saturated sodium bicarbonate (4 mL) and extracted with ethyl acetate (5 x 15
mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude
product was purified using column chromatography (100:0 to 4:1 heptane/ethyl acetate) to give triazine
22a (74 mg, 59%) as an amber oil.1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.45ꢀ8.49 (m, 2H), 7.53ꢀ
7.62 (m, 3H), 3.36 (sx, 1H, J = 7.0), 1.47 (d, 6H, J = 7.0); 13C NMR (100 MHz, CD3OD) δ 165.8, 163.9,
150.7, 136.6, 132.7, 130.1, 129.1, 33.9, 22.2; HRMS (ESI) m/z: [M + H]+ Calcd for C12H14N3 200.1182;
Found 200.1179.
6-Cyclopropyl-3-phenyl-1,2,4-triazine (22b). A suspension of NH2NH2·1.16 TsOH (331 mg, 1.42 mmol),
21b (100 mg, 0.35 mmol) and 4Å molecular sieves (100 mg) in ethanol (1.78 mL) was evacuated and
backꢀfilled with nitrogen, then stirred at 60 °C for 66h. The reaction mixture was poured into halfꢀdiluted
saturated sodium bicarbonate (4 mL) and extracted with ethyl acetate (5 x 15 mL). The combined organic
layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using
column chromatography (100:0 to 4:1, heptane/EtOAc) to give 22b (44 mg, 63%) as an oil. 1H NMR (400
MHz, CD3OD) δ 8.70 (s, 1H), 8.40ꢀ8.50 (m, 2H), 7.51ꢀ7.58 (m, 3H), 2.30 (p, 1H, J = 6.3), 1.25ꢀ1.31 (m,
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4H); 13C NMR (100 MHz, CD3OD) δ 163.3, 162.8, 150.2, 136.4, 132.4, 130.0, 128.9, 14.3, 11.6; HRMS
(ESI) m/z: [M + H]+ Calcd for C12H12N3 198.1025; Found 198.1023.
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6-[1-(4-Bromophenyl)propan-2-yl]-3-phenyl-1,2,4-triazine (22c). A suspension of NH2NH2·1.16 TsOH
(280 mg, 1.37 mmol), 21c (150 mg, 0.342 mmol) and 4Å molecular sieves (150 mg) in ethanol (1.71 mL)
was evacuated and backꢀfilled with nitrogen, then stirred at 60 °C for 115h. The cooled reaction mixture
was poured into halfꢀdiluted saturated sodium bicarbonate (3 mL) and extracted with ethyl acetate (5 x 20
mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude
product was purified using column chromatography (100:0 to 4:1, heptane/EtOAc) to give 22c (28 mg,
23%) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.49ꢀ8.55 (m, 2H), 8.30 (s, 1H), 7.51ꢀ7.57 (m, 3H), 7.37 (d,
2H, J = 8.2), 6.99 (d, 2H, J = 8.2), 3.40 (sx, 1H, J = 7.0), 3.19 (dd, 1H, J = 13.6, 7.8), 3.03 (dd, 1H, J =
13.6, 7.8), 1.48 (d, 3H, J = 6.6); 13C NMR (100 MHz, CDCl3) δ 162.5, 162.2, 148.4, 138.1, 134.7, 131.6,
131.5, 130.8, 128.9, 128.0, 120.3, 42.0, 39.9, 19.8; HRMS (ESI) m/z: [M + H]+ Calcd for C18H17BrN3
354.0600; Found 354.0598.
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3-Phenyl-6-(2-phenylethyl)-1,2,4-triazine (22d). A mixture of hydrazine dihydrochloride (9.12 mg, 0.08
mmol), hydrazine hydrochloride (65.4 mg, 0.955) and 21d (120 mg, 0.347 mmol) was suspended in 1,2ꢀ
dichloroethane (0.2 mL) and ethanol (1.6 mL) was evacuated and backꢀfilled with nitrogen, then stirred at
50 °C for 48 h. The cooled reaction mixture was poured into saturated sodium bicarbonate (10 mL) and
extracted with ethyl acetate (5 x 10 mL). The combined organic layers were dried over sodium sulfate,
filtered and evaporated. The crude product was purified using column chromatography (100:0 to 9:1
heptane/EtOAc) to give 22d (55 mg, 61%) as a white solid. mp = 85ꢀ88 °C. 1H NMR (600 MHz, CD3OD)
δ 8.67 (s, 1H), 8.44ꢀ8.47 (m, 2H), 7.53ꢀ7.60 (m, 3H), 7.29 (t, 2H, J = 7.0), 7.18ꢀ7.25 (m, 3H), 3.36 (t, 2H,
J = 7.0), 3.18 (t, 2H, J = 7.0); 13C NMR (100 MHz, CDCl3) δ 162.3, 158.8, 149.0, 140.0, 134.8, 131.4,
128.8, 128.7, 128.5, 128.0, 126.5, 35.1, 35.0; HRMS (ESI) m/z: [M + H]+ Calcd for C17H16N3 262.1339;
Found 262.1333.
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3-Phenyl-6-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine (22e). A suspension of NH2NH2·1.16 TsOH (440
mg, 2.15 mmol), 21e (175 mg, 0.618 mmol) and 4Å molecular sieves (150 mg) in ethanol (2.69 mL) was
evacuated and backꢀfilled with nitrogen, then stirred at 60 °C for 88h. The cooled reaction mixture was
poured into halfꢀdiluted saturated sodium bicarbonate (4 mL) and extracted with ethyl acetate (5 x 15
mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude
product was purified using column chromatography (100:0 to 4:1, heptane/EtOAc) to give 22e (67 mg,
52%) as a white solid. mp = 117ꢀ118 °C; 1H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 8.50ꢀ8.56 (m, 2H),
7.52ꢀ7.58 (m, 3H), 4.17 (dd, 2H, J = 11.7, 3.5), 3.63 (td, 2H, J = 11.7, 2.3), 3.26 (tt, 1H, J = 11.7, 3.9),
2.08 (qd, 2H, J = 11.3, 3.9), 1.96ꢀ2.03 (m, 2H) ; 13C NMR (100 MHz, CDCl3) δ 162.7, 161.4, 147.9,
134.7, 131.5, 128.9, 128.0, 67.7, 39.5, 31.5; HRMS (ESI) m/z: [M + H]+ Calcd for C14H16N3O 242.1288;
Found 242.1285.
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2-[5-(3-Phenyl-1,2,4-triazin-6-yl)pentyl]-1H-isoindole-1,3(2H)-dione (22f). A mixture of Nꢀ
acylsulfonamide 21f (150 mg, 0.329 mmol), hydrazine hydrochloride (90 mg, 1.31 mmol) and hydrazine
dihydrochloride (8.6 mg, 0.08 mmol) in ethanol (1.3 mL) and 1,2ꢀdichloroethane (0.3 mL) was stirred at
50 °C for 66h. The cooled reaction mixture was poured into saturated sodium bicarbonate (5 mL) and
extracted with ethyl acetate (5 x 15 mL). The combined organic layers were dried over sodium sulfate,
filtered and evaporated. The crude product was purified using column chromatography (100:0 to 9:1
heptane/ethyl acetate) to give triazine 22f (74 mg, 60%) as a yellow solid. mp = 128ꢀ131 °C; 1H NMR
(400 MHz, CDCl3) δ 8.53 (s, 1H), 8.49ꢀ8.53 (m, 2H), 7.81ꢀ7.86 (m, 2H), 7.68ꢀ7.73 (m, 2H), 7.51ꢀ7.57
(m, 3H), 3.72 (t, 2H, J = 7.0), 3.02 (t, 2H, J = 7.4), 1.92 (p, 2H, J = 7.4), 1.78 (p, 2H, J = 7.4), 1.50 (p,
2H, J = 7.4); 13C NMR (100 MHz, CDCl3) δ 168.4, 162.5, 159.4, 149.0, 134.8, 133.9, 132.1, 131.4, 128.8,
128.0, 123.2, 37.6, 33.1, 28.4, 28.2, 26.3; HRMS (ESI) m/z: [M + H]+ Calcd for C22H21N4O2 373.1659;
Found 373.1652.
2-[2-(3-Phenyl-1,2,4-triazin-6-yl)ethyl]-1H-isoindole-1,3(2H)-dione (22g). A mixture of Nꢀ
acylsulfonamide 21g (100 mg, 0.241 mmol) and NH2NH2·1.16 TsOH (168 mg, 0.724 mmol) in ethanol
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(1.5 mL) and 1,4ꢀdioxane (1.5 mL) was stirred at 60 °C for 18h. The reaction mixture was then treated
with additional NH2NH2·1.16 TsOH (60 mg, 0.26 mmol) and stirred at 60 °C for an additional 24h. The
cooled reaction mixture was poured into saturated sodium bicarbonate (5 mL) and extracted with ethyl
acetate (5 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and
evaporated. The crude product was purified using column chromatography (100:0 to 9:1 heptane/ethyl
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acetate) to give triazine 22g (34 mg, 43%) as a yellow solid. mp = 174ꢀ175 °C; H NMR (400 MHz,
CDCl3) δ 8.60 (s, 1H), 8.47ꢀ8.53 (m, 2H), 7.80ꢀ7.85 (m, 2H), 7.69ꢀ7.74 (m, 2H), 7.49ꢀ7.56 (m, 3H), 4.24
(t, 2H, J = 7.0), 3.41 (t, 2H, J = 7.0); 13C NMR (100 MHz, CDCl3) δ 168.0, 162.6, 156.4, 149.1, 134.6,
134.1, 131.9, 131.6, 128.8, 128.1, 123.4, 36.7, 32.2; HRMS (ESI) m/z: [M + H]+ Calcd for C19H15N4O2
331.1190; Found 331.1183.
Associated Content
The supporting information is available free of charge on the ACS publication website. DOI: xxx
1H and 13C NMR spectra for all new compounds.
Table S1. Optimization of the synthesis of 22a from 21a
Author Information:
Corresponding Author:
*Eꢀmail: matthew.s.dowling@pfizer.com
Notes
The authors declare no competing financial interest.
Acknowledgments
We thank Dr. Kevin Hesp and Dr. Jeremy Starr for helpful discussions.
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21 Hydrazine HCl and 16 exhibited low solubility in 1,4ꢀdioxane.
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22 The hydrazine tosylate salt appeared to be more soluble than the hydrazine hydrochloride salt in
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30 Konno, S.; Ohba, S.; Sagi, M.; Yamanaka, H. Heterocycles, 1986, 24, 1243–1246.
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