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Synthesis of Novel TricyclicAryltriazole‐3‐ThioneCompoundsCuiman Cai a , Janet S. Plummer a , David Connor a ,Daniel D. Holsworth a & Jeremy J. Edmunds aa Pfizer Global Research and Development, MichiganLaboratories, Department of Chemistry, 2800Plymouth Road, Ann Arbor, MI, 48105, USA

Version of record first published: 28 Jul 2007

To cite this article: Cuiman Cai, Janet S. Plummer, David Connor, Daniel D. Holsworth& Jeremy J. Edmunds (2005): Synthesis of Novel Tricyclic Aryltriazole‐3‐ThioneCompounds, Synthetic Communications: An International Journal for RapidCommunication of Synthetic Organic Chemistry, 35:3, 349-356

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Synthesis of Novel Tricyclic Aryltriazole-3-Thione Compounds

Cuiman Cai, Janet S. Plummer, David Connor, Daniel D. Holsworth,

and Jeremy J. Edmunds

Pfizer Global Research and Development, Michigan Laboratories,

Department of Chemistry, Ann Arbor, MI, USA

Abstract:A new synthetic protocol has been developed to provide entry into a series of

novel tricyclic aryltriazole-3-thiones analogs. The classical reaction conditions of sub-

jecting an arylhydrazide with thiophosgene to form the thioisocyanate intermediate and

ultimately the corresponding aryltriazole-3-thione framework were not successful.

However, using a combination of carbon disulfide and 1,8-diazabicyclo[5.4.0]undec-

7-ene (DBU) to form the thioisocyanate intermediate was found to produce the

novel tricyclic aryltriazole-3-thiones (5, 8a–c) in good yield.

Keywords: Aryltriazoles, thioisocyanate

INTRODUCTION

As part of a high throughput screen to discover anti-inflammatory agents and

in particular, agents that would inhibit Mac-1 (Macrophase antigen-1), a series

of aryltriazole-3-thiones compounds were identified. While initial lead

compounds were synthesized by a number of previously known procedures,[1]

a new synthetic process was needed to encompass a series of novel six- and

seven-member tricyclic aryltriazole-3-thiones (5, 8a–c) for further SAR

analysis (Scheme 1).

Received in the USA October 29, 2004

Address correspondence to Daniel D. Holsworth, Pfizer Global Research and

Development, Michigan LaboratoriesDepartment of Chemistry, 2800 Plymouth

Road, Ann Arbor, MI 48105, USA. Fax: 734-622-3909; E-mail: cuiman.cai@pfizer.

com; daniel.holsworth@pfizer.com

Synthetic Communicationsw, 35: 349–356, 2005

Copyright # Taylor & Francis, Inc.

ISSN 0039-7911 print/1532-2432 online

DOI: 10.1081/SCC-200048912

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The first tricyclic compound synthesized in the series was 5,6-dihydro-

2H-[1,2,4]triazolo[3,4-a]isoquinoline-3-thione 5, which originated from the

known 3,4-dihydro-1-(2H)-isoquinolinone 1 (Scheme 2). Generation of the

isoquinolinethione 2 with Lawesson’s reagent followed by activation of

the thioamide by alkylation with methyl iodide afforded the intermediate

thioether 3. Generation of the corresponding hydrazino compound 4 by

subjecting thioether 3 to hydrazine proceeded in excellent yield. It should

be noted that alternative attempts to prepare the hydrazino-isoquinoline 4via the iminochloride or iminotriflate failed due to either inefficient

Scheme 1. Synthetic targets. Six- and seven-member tricyclic aryltriazole-3-thiones.

Scheme 2. Preparation of 5,6-dihydro-2H-[1,2,4]triazolo[3,4a]isoquinoline-3-

thione (5).

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generation of the iminochloride or ring opening of the iminotriflate to generate

the trifluoro-N-[2-(2-hydrazinocarbonyl-phenyl)-ethyl]-methanesulfonamide

upon treatment with hydrazine. Exposure of the hydrazino intermediate 4

with thiophosgene in methylene chloride 08C for 45min followed by reflux

in trichlorobenzene for 4 h, afforded the tricyclic aryltriazole-3-thione 5 in

modest yield.

The thiomethyl analogs 6a–c were synthesized via literature methods

(see experimental). Using the same reaction conditions as for compound 4,hydrazino analogs 7a–c were formed. Interestingly, unlike the synthesis of

compound 5 (Scheme 2), the cycloaddition between hydrazino analogs 7a–

c and thiophosgene did not produce the expected products, but rather

resulted in complex mixtures. Therefore, an alternative synthetic protocol

was devised. Carbon disulfide in the presence of DBU has shown to react

with 20-aminobenzamides to form 4-oxo-2-thio-1,2,3,4-tetrahydroquinazo-

lines via the isothiocyanate intermediate.[2] Further, a mixture of carbon

disulfide and triethylamine has been used to create thioisocyanate intermedi-

ates from primary amines.[2] Using the reaction conditions outlined by

Mizuno, Nishiguchi, and Okushi[3] with hydrazino analogs 7a–c, the pro-

duction of the desired tricyclic aryltriazole-3-thiones 8a–c were obtained in

good yield (Scheme 3).

In summary, both six- and seven-membered novel tricyclic aryltriazole-3-

thiones have been prepared. While the classical triazole-3-thione synthetic

procedure failed[4] the use of carbon disulfide and DBU greatly facilitated

Scheme 3. Synthetic protocol for the production of novel aryltriazole-3-thiones 8a–c.

Synthesis of Novel Tricyclic Aryltriazole-3-Thione Compounds 351

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the formation of the desired products via the thioisocyanate intermediate.

These reaction conditions have provided the synthesis of novel tricyclic aryl-

triazole-3-thiones under mild conditions with vastly improved yields.

EXPERIMENTAL

All starting materials were obtained from commercial sources unless

otherwise specified in the experimental section. Proton NMR spectra were

obtained on a Varian Unity 400MHz or 200MHz spectrometer. Elemental

analyses were determined on a Perkin-Elmer model 240C instrument or

were determined by Robertson Labs. Mass spectral data were obtained on a

VG Analytical 7070 E/HF mass spectrometer using chemical ionization

conditions. Flash column chromatography was performed on silica gel 60,

230–400 mesh, purchased from Mallinckrodt.

3,4-Dihydro-1(2H)-isoquinolinone (1)

Isoquinolinone (5.3 g, 36.5mmol) in acetic acid (100mL) was hydrogenated

over 20% Pd/C (0.5 g) for 20 h at rt. The mixture was filtered through a

pad of celite and evaporated in vacuo. The residue was dissolved in

ethyl acetate, washed with saturated sodium bicarbonate, water, dried over

magnesium sulfate, filtered, and evaporated in vacuo to yield 1 (4.92 g,

92%). M.P. ¼ 57–598C [lit.[5] ¼ 588C]; 1H NMR (d6-DMSO, 200MHz)

d 7.94 (brs, 1H), 7.85–7.81 (m, 1H), 7.47–7.42 (m, 1H), 7.36–7.27

(m, 2H), 3.40–3.32 (m, 2H), 2.92–2.86 (m, 2H); MS ¼ 148 (Mþ 1).

3,4-Dihydro-1(2H)-isoquinolinethione (2)

To 3,4-dihydro-1 (2H)-isoquinolinone (0.44 g, 3.0mmol) in THF (20mL) was

added Lawesson’s reagent (0.51 g, 1.25mmol). The solution was stirred

overnight at rt and then heated to 508C for 60 h. The solution was cooled to

rt and diluted with ethyl acetate. The organic layer was washed with

saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered,

and evaporated in vacuo. The residue was purified by column chromatography

(2% methanol/98% methylene chloride) to give 0.47 g (97%) of 2.

M.P. ¼ 96–978C [lit.[2] ¼ 988C]; 1H NMR (d6-DMSO, 200MHz) d 10.49

(brs, 1H), 8.31 (d, J ¼ 7.69Hz, 1H), 7.52–7.45 (m, 1H), 7.37–7.26

(m, 2H), 3.43–3.48 (m, 2H), 2.95–2.88 (m, 2H); MS ¼ 164 (Mþ 1).

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3,4-Dihydro-1-(methylthio)-isoquinoline (3)

To 3,4-dihydro-1 (2H)-Isoquinolinone (0.30 g, 1.84mmol) in methylene

chloride (5mL) was added methyl iodide (0.34mL, 5.51mmol), and the

solution was stirred overnight at rt. The solvent was evaporated in vacuo

and the resultant residue diluted with ethyl acetate. The organic layer was

washed with saturated sodium bicarbonate, water, dried over magnesium

sulfate, filtered, and evaporated in vacuo to afford 0.28 g (92%) of 3 hydroio-

dide. M.P. ¼ 98–1008C [lit.[2] ¼ 998C]; 1H NMR (CDCl3, 200MHz) d 7.68–

7.63 (m, 1H), 7.36–7.17 (m, 3H), 3.79–3.76 (m, 2H), 2.78–2.70 (m, 2H),

2.45 (s, 3H); MS ¼ 178 (Mþ 1).

3,4-Dihydro-1-(hydroazino)-isoquinoline (4)

To 3,4-dihydro-1-(methylthio)-isoquinoline (0.80 g, 4.52mmol) in aceto-

nitrile (10mL) was added hydrazine [Caution! Highly toxic. Use in a good

fume hood] (1.5mL, 47.7mmol) and the solution heated at reflux for 1.5 h.

The solution was cooled and concentrated in vacuo. The residue was triturated

with hexane to give 0.82 g (92%) of 4. M.P. ¼ 56–588C [lit.[6] ¼ 55–578C];1H NMR (CDCl3, 200MHz): d 8.05–8.00 (m, 1H), 7.36–7.19 (m, 3H), 4.53

(brs, 3H), 3.52–3.46 (m, 2H), 2.96–2.90 (m, 2H); MS ¼ 162 (Mþ 1).

5,6-Dihydro-2H-[1,2,4]triazolo[3,4-a]isoquinoline-3-thione (5)

To thiophosgene [Caution! Highly toxic. Use in a good fume hood] (0.34ml,

4.47mmol) in methylene chloride (5mL) was added drop-wise to a solution

consisting of 3,4-dihydro-1-(hydroazino)-isoquinoline (0.48 g, 2.98mmol)

in methylene chloride (5mL) and triethylamine (1.25mL, 8.94mmol) at

08C over a period of 45min. The solvent was removed and trichlorobenzene

(25mL) added. The solution was refluxed for 4 h, and then the mixture

reduced to a residue in vacuo. Methylene chloride was added and the

organic layer washed with water. The product was extracted into 0.5N

NaOH and upon addition of 10% acetic acid, a precipitate formed. The

precipitate was collected and purified by column chromatography (1 : 1

ethyl acetate/hexane) to provide 0.19 g (30%) of 5. M.P. ¼ 200–2018C;1H NMR (d6-DMSO, 400MHz) d 13.76 (s, 1H), 7.775 (d, J ¼ 7Hz, 1H),

7.40 (m, 3H), 3.98 (t, J ¼ 8Hz, 2H), 3.13 (t, J ¼ 8Hz, 2H); 13C NMR

(d6-DMSO, 100MHz) d 166.17, 147.85, 135.27, 131.72, 129.38, 128.22,

124.29, 122.91, 39.20, 27.54; MS ¼ 204 (Mþ 1); Anal. Calcd. for

C10H9N3S1: C, 59.09; H, 4.46; N, 20.67; found: C, 59.39; H, 4.63; N, 20.67.

Synthesis of Novel Tricyclic Aryltriazole-3-Thione Compounds 353

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(4,5-Dihydro-3H-2-benzazepin-1-yl)-hydrazine (7a)

1-Methylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[C]azepine [6a,[7] 0.82 g,

4.29mmol] in acetonitrile (10mL) was added hydrazine [Caution! Highly

toxic. Use in a good fume hood] (1.0mL, 31.8mmol). The solution was

heated at reflux for 1.5 h and then cooled to rt. A precipitate formed upon

cooling, which was collected and crystallized from acetonitrile to provide

0.62 g (83%) of 7a, which was used immediately in the next step. 1H NMR

(d6-DMSO, 200MHz) d 7.41–7.36 (m, 1H), 7.27–7.12 (m, 3H), 4.72 (brs,

1H), 3.34 (brs, 2H), 2.96–2.90 (m, 2H), 2.74–2.67 (m, 2H), 1.84–1.71

(m, 2H); MS ¼ 176 (Mþ 1).

(2,3-Dihydro-1,4-benzoxazepin-5-yl)-hydrazine (7b)

To 5-Methylsulfanyl-2,3-dihydro-1,4-benzoxazepine [6b,[4] 1.62 g, 8.28mmol]

in acetonitrile (20mL) was added hydrazine [Caution! Highly toxic. Use in a

good fume hood] (5mL). The solution was heated at reflux for 1 h, cooled to

rt, and an additional 3mL of hydrazine was added. The mixture was heated

at reflux for an additional 5 h and then at rt overnight. The mixture was

subjected to column chromatography (85 : 15 CH2Cl2/10% NH4OH in

EtOH) to provide 0.73 g (50%) of 7b, which was used immediately in the

next step. 1H NMR (d6-DMSO, 400MHz) d 8.41 (dd, J ¼ 7.95, 1.69Hz,

1H), 7.36 (ddd, J ¼ 7.95, 6.99, 1.69Hz, 1H), 7.15 (dd, J ¼ 7.95, 8.20Hz,

1H), 7.07 (d, J ¼ 8.19Hz, 1H), 4.45 (m, 2H), 4.34 (m, 2H);MS ¼ 178 (Mþ 1).

(6,7-Dihydro-5-thia-8-aza-benzocyclohepten-9-yl)-hydrazine (7c)

9-Methylsulfanyl-6,7-dihydro-5-thia-8-aza-benzocycloheptene [6c,[8] 0.37 g,

1.74mmol] in acetonitrile (15mL) was added hydrazine [Caution! Highly

toxic. Use in a good fume hood] (5mL) and 4 Angstrom molecular sieves.

The solution was heated at reflux for 6 h, cooled to rt, and an additional

7mL of hydrazine was added. The mixture was stirred at rt overnight. The

reaction mixture was concentrated in vacuo and the residue was subjected

to column chromatography (85 : 15 CH2Cl2: 10% NH4OH/EtOH) to yield

0.16 g (48%) of 7c, which was used immediately in the next step. 1H NMR

(d6-DMSO, 400MHz) d 7.45–7.30 (m, 4H), 6.00 (s, 1H), 4.85 (brs, 2H),

3.21–3.15 (m, 2H), 2.97–2.92 (m, 2H); MS ¼ 194 (Mþ 1).

2,4,5,6-Tetrahydro-1,2,3a-triaza-benzo[e]azulene-3-thione (8a)

To a solution of DMF (3.5mL) carbon disulfide [Caution! Highly toxic. Use in

a good fume hood] (2.1mL, 34.2mmol) and DBU (0.26ml, 1.71mmol) was

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added 7a (0.30 g, 1.71mmol). The solution was refluxed for 40min, cooled to

rt, and diluted with ethyl acetate. The organic layer was washed with saturated

sodium bicarbonate, water, dried with magnesium sulfate, filtered, and evap-

orated in vacuo. The residue was purified by column chromatography (1 : 1

ethyl acetate/hexane) to yield 0.17 g (45%) of 8a. M.P. ¼ 144–1458C;1H NMR (d6-DMSO, 400MHz) d 13.90 (brs, 1H), 7.65–7.63 (m, 1H),

7.50–7.46 (m, 1H), 7.42–7.37 (m, 2H), 3.89 (t, J ¼ 8Hz, 2H), 2.69

(t, J ¼ 4Hz, 2H), 2.13 (q, J ¼ 8Hz, 2H); 13C NMR (d6-DMSO, 100MHz) d

166.98, 152.59, 139.77, 131.75, 130.73, 128.66, 127.86, 109.99, 41.94,

30.54, 28.58; MS ¼ 218 (Mþ 1); Anal. Calcd. for C11H11N3S1: C, 60.80;

H, 5.10; N, 19.34; found: C, 60.97; H, 5.10; N, 20.18.

4,5-Dihydro-2H-6-oxa-1,2,3a-triaza-benzo[e]azulene-3-thione (8b)

To a solution of DMF (1.8mL), carbon disulfide [Caution! Highly toxic. Use

in a good fume hood] (1.8mL, 29.6mmol) and DBU (0.22mL, 1.68mmol)

was added drop-wise to a solution of 7b (0.26 g, 1.48mmol) in DMF

(3.5mL). The mixture was heated at reflux for 2.5 h, then cooled to room

temperature, acidified with 1N HCL, and allowed to sit at rt. A precipitate

formed after 1 hr. Purification of the crude compound by column chromato-

graphy (10% CH3OH/CHCl3) afforded 0.17 g (52%) of 8b. M.P. ¼ 245–

2508C (decomp); 1H NMR (d6-DMSO, 400MHz) d 13.98 (brs, 1H), 8.105

(dd, J ¼ 4, 8Hz, 1H), 7.37 (dddd, J ¼ 4, 8, 12, 16Hz, 1H), 7.10 (dddd,

J ¼ 4, 8, 12, 16Hz, 1H), 7.04 (dd, J ¼ 4, 8Hz, 1H), 4.45 (m, 2H), 4.25

(m, 2H); 13C NMR (d6-DMSO, 100MHz) d 167.61, 157.29, 149.29, 132.62,

129.14, 123.28, 121.71, 114.30, 68.94, 48.64; MS ¼ 220 (M þ1); Anal.

Calcd. for C10H9N3O5: C, 54.78; H, 4.14; N, 19.16; found: C, 54.88; H,

4.10; N, 19.18.

4,5-Dihydro-2H-6-thia-1,2,3a-traza-benzo[e]azulene-3-thione (8c)

To a solution of DMF (1mL), carbon disulfide [Caution! Highly toxic. Use

in a good fume hood] (1mL, 16.6mmol) and DBU (0.12mL, 0.83mmol)

was added drop-wise to a solution of 7c (0.16 g, 0.83mmol) in DMF. The

mixture was heated to reflux for 25min. After cooling to rt, the solution

was acidified with 1N HCL and stirred for 30min to yield a orange sticky

solid. The solid was subjected to column chromatography (1 : 1 ethyl

acetate/hexane) to afford 0.13 g (68%) of 8c. M.P. ¼ 193–1968C; 1H NMR

(d6-DMSO, 400MHz) d 7.71–7.66 (m, 2H), 7.56–7.52 (m, 2H), 4.13

(t, J ¼ 4Hz, 2H), 3.34 (t, J ¼ 4Hz, 2H); 13C NMR (d6-DMSO, 100MHz) d

166.90, 152.23, 135.21, 132.49, 132.04, 131.46, 130.60, 129.98, 42.18,

35.79; MS ¼ 236 (Mþ 1); Anal. Calcd for C10H9N3S2: C, 51.04; H, 3.85;

N, 17.86; found: C, 50.77; H, 4.05; N, 17.51.

Synthesis of Novel Tricyclic Aryltriazole-3-Thione Compounds 355

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