Versatile synthesis of fused tricyclic 1,2,4-triazole derivatives

Article abstract of DOI:10.1080/00397911003707170

(Chemical Equation Presented) The synthesis of a small series of fused tricyclic 1,2,4-triazoles is described. The key reaction is an intramolecular two-stage, one-pot reduction/cyclization sequence of a nitropyridine/oxadiazole substrate to give the key tricyclic triazole. Further standard transformations convert this template into a series of final target compounds. Copyright Pfizer Ltd.

Full text of DOI:10.1080/00397911003707170

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Versatile Synthesis of Fused Tricyclic
1,2,4-Triazole Derivatives
David Ellis a
a Discovery Chemistry , Pfizer Global Research and Development ,
Kent , United Kingdom
Published online: 03 Mar 2011.
To cite this article: David Ellis (2011) Versatile Synthesis of Fused Tricyclic 1,2,4-Triazole Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:7, 963-975, DOI: 10.1080/00397911003707170
To link to this article: http://dx.doi.org/10.1080/00397911003707170
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Synthetic Communications1, 41: 963–975, 2011
Copyright # Pfizer Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707170
VERSATILE SYNTHESIS OF FUSED TRICYCLIC
1,2,4-TRIAZOLE DERIVATIVES
David Ellis
Discovery Chemistry, Pfizer Global Research and Development,
Kent, United Kingdom
GRAPHICAL ABSTRACT
Abstract The synthesis of a small series of fused tricyclic 1,2,4-triazoles is described. The
key reaction is an intramolecular two-stage, one-pot reduction/cyclization sequence of a
nitropyridine/oxadiazole substrate to give the key tricyclic triazole. Further standard trans-
formations convert this template into a series of final target compounds.
Keywords Fused tricyclic ring system; intramolecular reduction cyclization; Suzuki
reaction; 1,2,4-triazole; vicarious nucleophilic substitution
INTRODUCTION
We required tricyclic 1,2,4-triazole derivatives 1 (Fig. 1) as part of an oxytocin
(OT) antagonist program. These were designed as conformationally restricted
analogs of the previously disclosed triazoles 2.[1]
Retrosynthetic Analysis
The synthetic route adopted for previous triazoles utilized the well-precedented
conversion of 1,3,4-oxadiazoles to 1,2,4-triazoles with amines under thermal, acid-
catalyzed conditions[2] (Scheme 1).
Received December 14, 2009.
Address correspondence to David Ellis, Discovery Chemistry, Pfizer Global Research and
Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. E-mail: david.ellis@pfizer.com
963

964
D. ELLIS
Figure 1. Required triazole targets and earlier analogs.
Scheme 1. Precedented oxadiazole to triazole conversion.
This strategy influenced the retrosynthetic analysis of the tricyclic analogs
where an oxadiazole precursor 3 could be cyclized to the required template 4 and
the distal aryl ring attached via a standard Suzuki reaction (Scheme 2).
Oxadiazole 3 then could be further broken down into simpler fragments
(Scheme 3).
Previous in-house work had already shown that chloromethyloxadiazoles such
as 5 could be easily synthesized, which supported this approach. Benzylamine 6 was
Scheme 2. Proposed intramolecular cyclization.
Scheme 3. Key fragments in the retrosynthesis.

FUSED TRICYCLIC 1,2,4-TRIAZOLE DERIVATIVES
965
Scheme 4. Initial vicarious nucleophilic substitution.
chosen as the protected amine fragment, and the pyridine derivative chosen was
6-methoxy-3-nitropyridine-2-carboxaldehyde 7, which was to be accessed from the
known 2-dichloromethyl-6-methoxy-3-nitropyridine[3] 9. Masking the 3-aminopyri-
dine as a nitro group would remove potential protecting group conflicts between
the two amines later on. The aldehyde would also be more stable than the corre-
sponding halomethylpyridine derivative. Therefore, the synthesis relied initially on
obtaining 6-methoxy-3-nitropyridine-2-carboxaldehyde 7. The aldehyde is now com-
mercially available from Anichem.
Synthesis of 6-Methoxy-3-nitropyridine-2-carboxaldehyde 7
This compound is prepared by the vicarious nucleophilic substitution
(VNS)[3,4] reaction of chloroform onto commercial 2-methoxy-5-nitropyridine 8,
followed by hydrolysis of the dichloride to the aldehyde (Scheme 4).
Initial reaction to the dichloro compound 9, though successful, gave poor
yields (45%). The low temperature required to avoid problems resulting from
dichlorocarbene formation also caused solubility problems with the base and start-
ing nitropyridine. Magnetic stirring of the reaction was awkward, and the addition
time of the reactants was also lengthy because of the exothermic nature of the reac-
tion. Hydrolysis of the dichloride was also slow and incomplete under the conditions
shown. This was thought to be due to the difficulty of hydrolysis of the strong C-Cl
bond, a factor that has been noted in the synthesis of other triazole analogs from
their trichloromethyl derivatives.[5]
Substitution of bromoform for chloroform showed problems in the VNS reac-
tion similar to that seen with chloroform, with addition times of ꢀ2 h for a 10-g reac-
tion. However, the yield was much improved, and over two consecutive experiments
65–70% yields of the dibromide 10 were obtained (Scheme 5). These yielded sufficient
material to continue, and the conditions of the VNS reaction were not investigated
further. Scope clearly exists for potential optimization of this step. For reactions
above the 10-g scale, mechanical stirring would be obligatory. During the second
experiment, the temperature was allowed to reach ꢁ50 ꢂC at times, and the yield
of this reaction was not greatly different than the yield obtained in the first reaction,
Scheme 5. Improved vicarious nucleophilic substitution.

966
D. ELLIS
Scheme 6. Key oxadiazole synthesis.
which was maintained at À70 ꢀC. Therefore, it may be possible to raise the tempera-
ture of the reaction somewhat with benefits for solubility and addition times.
The hydrolysis of the dibromide 10 was much more rapid than that of the
dichloro analog as expected and was complete in 1–2 h at reflux. The yields were con-
sistent at ꢁ70%, and thus large quantities of this useful trifunctionalized pyridine
were available for the next stages of the synthesis.
Synthesis of 2-Chloromethyl-5-(4-bromophenyl)-1,3,4-oxadiazole 14
Once again, previous project methodology was used to assemble this key
fragment as shown in Scheme 6.
The commercial ester 11 was readily converted to the hydrazide by heating
with hydrazine hydrate in methanol. Acylation with chloroacetyl chloride was
straightforward and rapid, though the insolubility of the product 12 caused minor
issues during the workup. It was easier to evaporate the solvent and treat the residue
with hot water. Filtration followed by further washes with water successfully
removed the HCl salt of the N-methylmorpholine (NMM) and all other by-products,
furnishing the required hydrazide 12 in good yield. Dehydrative cyclization of the
di-acylhydrazide to the oxadiazole 13 in refluxing POCl3 was also rapid and clean,
giving a good yield of the oxadiazole after a simple aqueous=organic workup.[6] Dis-
placement of the chloride with benzylamine proceeded cleanly at rt, though heating
to 50 ꢀC significantly shortened the reaction time to a few hours. A simple workup
then furnished the desired amino-oxadiazole 14 in 52% yield. No chromatography
was required throughout this sequence.
Assembly of the Tricyclic Template
With large amounts of the key amino-oxadiazole 14 to hand, the crucial joining
of this fragment and the pyridine aldehyde could be attempted by reductive amina-
tion. The use of secondary benzylamine 14 has two benefits in such an approach. It
reduces the tendency for overreaction with the aldehyde to give tertiary amine

FUSED TRICYCLIC 1,2,4-TRIAZOLE DERIVATIVES
967
Scheme 7. Assembly of tricyclic template.
by-products (earlier attempts with the aldehyde and an aminomethyloxadiazole
were not encouraging) and also provides a suitable protecting group to facilitate
late-stage modification of the template.
The reductive amination shown in Scheme 7 was straightforward, and after a
simple workup, the crude product 15 was triturated with ether and filtered to yield
analytically pure material. This nitropyridine substrate was then stirred in acetic acid
at 65 ꢂC in the presence of 5 equivalents of iron powder to effect reduction of the
nitro group to the amine, which cyclized intramolecularly to the desired tricyclic tria-
zole template 16. Once again, after a simple workup, the material was isolated and
analytically pure without the need for chromatography.
Scheme 8. Initial modifications to tricyclic template.

968
D. ELLIS
Scheme 9. Final variation of tricyclic template.
Modification of the Tricyclic Template
With a robust route to multigram quantities of the tricyclic triazole template
16, attention now turned to the late-stage modification to yield final target
compounds.
Previous SAR had indicated just two key variants of the distal aromatic ring
would allow an assessment of the activity of these templates. These were
o-methylphenyl and o-methoxyphenyl. These were installed via a standard Suzuki
coupling reaction.[7] The couplings were straightforward and gave good yields of
the biphenyl products 17a, and b (Scheme 8).
The N-benzyl group was removed via catalytic transfer hydrogenation[8] using
20% Pd(OH)2=C and ammonium formate in ethanol at reflux to yield key amines
18a and b. Alternative hydrogenation conditions as well as the use of 1-chloroethyl-
chloroformate (ACE-Cl)[9] had either failed or given a less clean reaction profile. The
necessity of using hydrogenation to remove the benzyl group confirmed the decision
to react the bromine prior to deprotection as the correct course. It was also gratify-
ing that the hydrogenation had cleaved only the desired N-benzyl group in prefer-
ence to the other two ‘‘pseudo-benzylic’’ bonds.
The final modifications of the tricyclic template were carried out by standard
acylation and alkylation reactions to give a small series of eight analogs for testing
(Scheme 9).
CONCLUSION
A straightforward and versatile synthesis of an interesting tricyclic 1,2,4-
triazole template has been described. The key features of the method include
modification of a VNS reaction using CHBr3 instead of CHCl3 to access a useful

FUSED TRICYCLIC 1,2,4-TRIAZOLE DERIVATIVES
969
trifunctional nitropyridine aldehyde. Furthermore, once this aldehyde is attached to
an amino-oxadiazole via reductive amination, a sequential reduction=cyclization
sequence furnishes the required tricyclic template with two points of diversity. The
reactions used are all straightforward and simple to carry out, and the use of chro-
matography throughout the sequence is minimal.
EXPERIMENTAL
1
All H NMR spectra were obtained on a 400-MHz Varian Mercury spec-
trometer using either CDCl3 or dimethylsulfoxide (DMSO-d6) as solvents. The
chemical shifts are reported in parts per million (ppm) relative to the deuterated sol-
vent. Mass spectra were recorded on an Agilent 1100 series liquid chromatography=
mass spectrometry (LC=MS) instrument in the electrospray and atmospheric
pressure (ES=AP) ionization modes. All chromatography was performed using
Merck silica using a gradient elution profile unless otherwise stated. Thin-layer chro-
matography (TLC) was performed using Merck TLC plates. Solvent systems used
are given with the TLC=Rf data.
Synthesis of 2-Dibromomethyl-6-methoxy-3-nitropyridine 10
Preparation. A solution of bromoform (18.86 g, 74.6 mmol) and 6-methoxy-3-
nitropyridine (10 g, 64.9 mmol) in a mixture of THF (30 mL) and DMF (15 mL) was
added dropwise to a cold (ꢁ70 ꢂC) solution of potassium t-butoxide (29.0 g, 260 mmol)
in THF (100 mL) and DMF (30 mL) under nitrogen while maintaining the internal
temperature between ꢁ60 ꢂC and ꢁ70 ꢂC. The addition takes approximately 2 h.
The resulting dark red mixture was left at ꢁ60 ꢂC for 20 min before quenching the
reaction with acetic acid (30 mL) and allowing it to warm to ambient temperature.
The mixture was poured with stirring onto a mixture of crushed ice and EtOAc
(200 mL). When the ice had melted, the organic layer was separated, and the aqueous
phase was extracted with EtOAc (2 ꢃ 100 mL). The combined organic extracts were
washed with 2 M HCl (4 ꢃ 50 mL), saturated aqueous NaHCO3 solution (50 mL),
and brine (50 mL), dried over MgSO4, filtered, and evaporated. The residue was dis-
solved in MeOH (50 mL) and treated with charcoal at reflux for 5 min. The mixture
was filtered, the filtrate was evaporated, and the resulting solid was triturated with
pentane and filtered to yield the title compound 10 as a fawn solid, which was pure
enough to use directly in the next stage. Yield: 15 g, 70%; amorphous fawn solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 4.20 (s, 3H), 6.85 (d, J ¼ 7.14 Hz, 1H),
7.63 (s, 1H), 8.25 (d, J ¼ 7.14 Hz, 1H). TLC Rf 0.4 (EtOAc=pentane 1:9), Rf 0.79
(DCM=MeOH 98:2).
Synthesis of 6-Methoxy-3-nitropyridine-2-carboxaldehyde 7
Preparation. A solution of AgNO3 (2.34 g, 13.80 mmol) in water (5 mL) was
a
added to
solution of 2-dibromomethyl-6-methoxy-3-nitropyridine (1.5 g,
4.60 mmol) in EtOH (15 mL). The resulting mixture was heated to reflux under nitro-
gen for 2 h. The EtOH was then evaporated, and the aqueous residue was diluted

970
D. ELLIS
with EtOAc (30 mL). The precipitate of AgBr was filtered, and the organic layer then
separated, washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered,
and evaporated. The residue was purified by chromatography eluting with EtOAc=
pentane (5:95–1:3 in 5% stages of EtOAc) to yield the title compound 7, which was
pure enough to use directly in the next stage. Yield: 1.0 g; 71% amorphous pale
yellow solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 4.15 (s, 3H), 7.02 (d, J ¼ 8.6 Hz, 1H),
8.30 (d, J ¼ 8.6 Hz, 1H), 10.35 (s, 1H). MS APCI: m=z 183 [M þ Hþ]. Anal. calcd. for
C7H6N2O4: C, 46.16; H, 3.32; N, 15.38. Found: C, 45.56; H, 3.30; N, 15.14.
Synthesis of 2-Benzylaminomethyl-5-
(4-bromophenyl)-1,3,4-oxadiazole 14
Preparation. Potassium carbonate (5.04 g, 36.55 mmol) was added in one
portion to a solution of 2-chloromethyl-5-(4-bromophenyl)-1,3,4-oxadiazole 13
(5 g, 18.28 mmol) prepared as shown in Scheme 6 by the late Olga Wallace and ben-
zylamine (2.25 g, 21.02 mmol) in CH3CN (50 mL) at room temperature. The result-
ing mixture was heated to 50 ꢂC for 6 h. The CH3CN was evaporated, and the residue
was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc was sepa-
rated, washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and
evaporated. The white residue was triturated with ether and filtered to furnish the
title compound 14. Yield: 3.3 g, 52%; amorphous white solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 2.00 (s, 1H), 3.90 (s, 2H), 4.10 (s, 2H),
7.20–7.40 (m, 5H), 7.68 (d, 2H), 7.80 (d, 2H). MS APCI: m=z 344=346 [M þ Hþ], 1
bromine pattern. Anal. calcd. for C16H14BrN3O: C, 55.83; H, 4.10; N, 12.21. Found:
C, 55.67; H, 4.04; N, 12.10.
Representative Reductive Amination Procedure
Preparation. NaBH(OAc)3 (2.64 g, 12.46 mmol) was added portionwise to a
stirred ice-cold solution of 6-methoxy-3-nitropyridine-2-carboxaldehyde 7 (2.10 g,
11.50 mmol) and 2-benzylaminomethyl-5-(4-bromophenyl)-1,3,4-oxadiazole 14
(3.30 g, 9.59 mmol) in DCM (30 mL) over 5 min. The solution was allowed to warm
to rt. After 18 h, the reaction mixture was washed with NaHCO3 solution
(2 ꢃ 10 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated. The resi-
due was triturated with a mixture of MeOH and ether (1:9) to give a solid, which was
filtered and washed with fresh ether to give 15. Yield: 4.40 g, 90%; amorphous white
solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 3.85–4.00 (br s, 2H), 4.05 (s, 3H), 4.10
(s, 2H), 4.40 (s, 2H), 6.75 (d, J ¼ 10.75 Hz, 1H), 7.18–7.35 (m, 5H), 7.67 (d, 6.90 Hz,
2H), 7.92 (d, J ¼ 8.60 Hz, 2H), 8.12 (d, J ¼ 10.75 Hz, 1H). MS (APCIþve): m=z
(%) ¼ 510=512 (100%) [M þ Hþ], 1 bromine pattern. MS (APCI-ve): m=z (%) ¼
509=511 (100%) [M ꢁ Hþ], 1 bromine pattern. Anal. calcd. for C23H20BrN5O4: C,
54.12; H, 3.95; N, 13.72. Found: C, 53.97; H, 4.00; N, 13.60. TLC Rf 0.69
(EtOAc=pentane 1:1), Rf 0.76 (DCM=MeOH 95:5).

FUSED TRICYCLIC 1,2,4-TRIAZOLE DERIVATIVES
971
Representative Two-Stage, One-Pot Reduction/Cyclization
Procedure
Preparation. Iron powder (1.43 g, 25.57 mmol) was added to a suspension of
15 (4.35 g, 8.52 mmol) in AcOH (45 mL) in one portion. The resulting mixture was
heated to 65 ꢂC under nitrogen for 3 h. The remaining iron powder was filtered
and washed well with fresh AcOH. The filtrate was then evaporated to dryness.
The residue was azeotroped with toluene (2 ꢃ 10 mL) and then partitioned between
EtOAc (60 mL) and saturated NaHCO3 solution (30 mL). This mixture was filtered
through a pad of celite to remove residual iron powder. The organic phase was then
separated; washed with 10% aqueous citric acid solution, water (10 mL), and brine
(10 mL), dried over MgSO4, filtered, and evaporated to give 16. Yield: 2.40 g,
61%; amorphous fawn solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 3.60–4.10 (br m, 6H), 4.05 (s, 3H),
6.70 (d, J ¼ 7.15 Hz, 1H), 7.10 (d, J ¼ 7.15 Hz, 1H), 7.30–7.60 (m, 9H). MS
(APCIþve): m=z (%) ¼ 462=464 (100%) [M þ Hþ], 1 bromine pattern. Anal. calcd.
for C23H20BrN5O: C, 59.74; H, 4.36; N, 15.15. Found: C, 59.52; H, 4.37; N,
14.80. TLC Rf 0.60 (EtOAc), Rf 0.42 (DCM=MeOH 95:5).
Representative Suzuki Coupling Reaction
Preparation. A solution of Na2CO3 (445 mg, 4.20 mmol) in water (3 mL) and
tetrakistriphenylphosphine (100 mg) was added to a stirred and degassed solution of
16 (971 mg, 2.10 mmol) and 2-methoxyphenylboronic acid (478 mg, 3.15 mmol) in
1,2-dimethoxyethane (10 mL). The reaction flask was then immersed in an oil bath pre-
heated to 120 ꢂC. After 5 h, the reaction was evaporated to low volume and diluted
with EtOAc (20 mL) and water (10 mL). The organic phase was separated, washed
with saturated NaHCO3 solution (5 mL) and brine (5 mL), dried over MgSO4, filtered,
and evaporated. The oily residue crystallized readily and was triturated with ether and
filtered to yield the biphenyl product 17a. Yield: 950 mg, 92%; amorphous white solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 3.70–4.10 [m, 10H inc 3.80 (s, 3H) and
4.05 (s, 3H)], 6.65–6.80 (m, 1H), 6.95–7.10 (m, 2H), 7.20–7.65 (m, 12H). MS
(APCIþve): m=z (%) ¼ 490 (100%) [M þ Hþ]. Anal. calcd. for C30H27N5O2 ꢄ 0.4H2O:
O: C, 72.53; H, 5.64; N, 14.10. Found: C, 72.87; H, 5.57; N, 13.73. TLC Rf 0.44
(EtOAc), Rf 0.22 (DCM=MeOH 95:5).
Data for Compound 17b (Ar ¼ 2-Methylphenyl). Yield: 1 g, 98%; amorph-
1
ous white solid. H NMR (400 MHz, CDCl3): d ¼ 2.30 (s, 3H), 3.75–4.05 (m, 6H),
4.05 (s, 3H), 6.70–6.78 (d, J ¼ 8.60 Hz, 1H), 7.20–7.60 (m, 14H). MS (APCIþve):
m=z (%) ¼ 474 (100%) [M þ Hþ]. Anal. calcd. for C30H27N5O ꢄ 0.5H2O: C, 74.67;
H, 5.85; N, 14.51. Found: C, 74.44; H, 5.77; N, 13.58. TLC Rf 0.45 (EtOAc), Rf
0.34 (DCM=MeOH 95:5).
Representative Debenzylation of Biphenyl Products
Preparation. The N-benzyl derivative 17a (Ar ¼ 2-methoxyphenyl) (869 mg,
1.77 mmol) was added to a suspension of 20% Pd(OH)2 = C (50 mg) in EtOH

972
D. ELLIS
(20 mL) under nitrogen. Ammonium formate (1.12 g, 17.75 mmol) was then added,
and then mixture was heated to reflux. After 8 h, the catalyst was filtered, and the
filtrate evaporated. The residue was partitioned between EtOAc (20 mL) and water
(10 mL). The organic phase was separated, washed with NaHCO3 solution (10 mL)
and brine, dried over MgSO4, filtered, and evaporated. The resulting solid was tritu-
rated with ether and filtered to yield the product 18a, which was pure enough to use
in subsequent reactions. Yield: 410 mg, 58%; amorphous white solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 2.20–2.60 (br s, 1H), 3.75 (s, 3H), 3.95
(s, 3H), 3.90–4.10 (br m, 4H), 6.62 (d, J ¼ 8.50 Hz, 1H), 6.90–7.00 (m, 2H), 7.17 (d,
J ¼ 8.50 Hz, 1H), 7.22–7.30 (m, 2H), 7.45–7.55 (m, 4H). MS (APCIþve): m=z
(%) ¼ 400 (100%) [M þ Hþ]. TLC Rf 0.41 (DCM=MeOH=aqueous NH4OH 90:10:1).
Data for compound 18b (Ar ¼ 2-methylphenyl). Yield: 371 mg, 92%; white
1
foam. H NMR (400 MHz, CDCl3): d ¼ 2.00–2.60 (br s, 1H), 2.25 (s, 3H), 4.05 (s,
3H), 4.10–4.25 (m, 4H), 6.70 (d, J ¼ 7.86 Hz, 1H), 7.15–7.30 (m, 5H), 7.37 (d,
J ¼ 8.60 Hz, 2H), 7.57 (d, J ¼ 8.60 Hz, 2H). MS (APCIþve): m=z (%) ¼ 384 (100%)
[M þ Hþ]. TLC Rf 0.22 (DCM=MeOH=aqueous NH4OH 90:10:1).
Representative Methylation Procedure
Preparation. To a stirred solution of 18a (Ar ¼ 2-methoxyphenyl) (100 mg,
0.25 mmol) in DCM (3 mL) was added a 37% aqueous solution of formaldehyde
(81 ml, 1 mmol). The resulting mixture was stirred at rt for 30 mins. Sodium triacetox-
yborohydride 964 mg, 0.30 mmol) was then added. After 1 hr NaHCO3 solution
(3 mL) was added and the stirring continued for 20 mins. The organic layer was then
separated and washed with brine (3 mL), dried over MgSO4 filtered and evaporated
to give the product 22a. Yield: 80 mg, 77%; white foam.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 2.60 (s, 3H), 3.70 (s, 3H), 3.75–3.95
(m, 4H), 4.05 (s, 3H), 6.70 (d, J ¼ 7.20 Hz, 1H), 6.95–7.10 (m, 2H), 7.20–7.40 (m,
3H), 7.50–7.65 (m, 4H). MS (APCIþve): m=z (%) ¼ 414 (100%) [M þ Hþ]. Anal.
calcd. for C24H23N5O2:0.5H2O: C, 68.23; H, 5.73; N, 16.58. Found: C, 68.20; H,
5.64; N, 16.28. TLC Rf 0.15 (DCM:MeOH 95:5).
Data for compound 22b (Ar ¼ 2-methylphenyl). Yield: 83 mg, 89%; white
foam. 1H NMR (400 MHz, CDCl3): d ¼ 2.25 (s, 3H), 2.65–2.75 (br s, 3H), 3.70–4.20
(m, 4H), 4.05 (s, 3H), 6.75 (d, J ¼ 7.15 Hz, 1H), 7.20–7.35 (m, 5H), 7.38 (d,
J ¼ 7.15 Hz, 2H), 7.60 (d, J ¼ 7.15 Hz, 2H). MS (APCIþve): m=z (%) ¼ 398 (100%)
[M þ Hþ]. Anal. calcd. for C24H23N5O ꢄ 0.5H2O: C, 70.92; H, 5.95; N, 17.23. Found:
C, 70.64; H, 5.87; N, 16.95. TLC Rf 0.14 (DCM=MeOH 95:5).
Representative Acylation Procedures
Preparation. Acetyl chloride (21 ml, 23 mg, 0.29 mmol) was added to a stirred
ice-cold solution of 18a (Ar ¼ 2-methoxyphenyl) (90 mg, 0.22 mmol) and
di-isopropylethylamine (41 mg, 0.31 mmol). The resulting solution was allowed to
warm to rt. After 1 h, the solution was diluted with DCM (5 mL); washed with water

FUSED TRICYCLIC 1,2,4-TRIAZOLE DERIVATIVES
973
(3 mL), NaHCO3 solution (3 mL), and brine (3 mL); dried over MgSO4; filtered; and
evaporated to give the product 19a (R ¼ CH3). Yield: 74 mg, 75%; white foam.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 2.30 and 2.40 (2 ꢃ s, 3H, rotamers),
3.80 (s, 3H), 4.00 (s, 3H), 4.60–5.00 (m, 4H), 6.70–6.80 (m, 1H), 6.98–7.10 (m,
2H), 7.25–7.40 (m, 3H), 7.50–7.70 (m, 4H). MS (APCIþve): m=z (%) ¼ 442 (100%)
[M þ Hþ]. Anal. calcd. for C25H23N5O3 ꢄ 0.4H2O: C, 66.92; H, 5.35; N, 15.61. Found:
C, 67.31; H, 5.31; N, 15.45. TLC Rf 0.16 (DCM=MeOH 95:5), Rf 0.27 (DCM=
MeOH=aqueous NH4OH 90:10:1).
Data for compound 19b (Ar ¼ 2-methylphenyl). Yield: 60 mg, 68%; white
1
solid. H NMR (400 MHz, CDCl3): d ¼ 2.30 (s, 3H), 2.38 and 2.40 (2 ꢃ s, 3H, rota-
mers), 4.00 (s, 3H), 4.65–5.00 (m, 4H), 6.70–6.80 (m, 1H), 7.20–7.65 (m, 9H). MS
(APCIþve): m=z (%) ¼ 426 (100%) [M þ Hþ]. Anal. calcd. for C25H23N5O2 ꢄ 0.5H2O:
O: C, 69.11; H, 5.57; N, 16.12. Found: C, 69.14; H, 5.50; N, 15.95. TLC Rf 0.13
(DCM=MeOH 95:5), Rf 0.61 (DCM=MeOH=aqueous NH4OH 90:10:1).
Methylchloroformate (23 ml, 28 mg, 0.29 mmol) was added. to a stirred ice-cold
solution of 18a (Ar ¼ 2-methoxyphenyl) (90 mg, 0.22 mmol) in DCM (3 mL) and
di-isopropylethylamine (41 mg, 0.31 mmol). The resulting solution was allowed to
warm to rt. After 1 h, the solution was diluted with DCM (5 mL), washed with water
(3 mL), NaHCO3 solution (3 mL), and brine (3 mL); dried over MgSO4; filtered; and
evaporated. The residue was triturated with ether and filtered to give the product 20a
(R ¼ OCH3). Yield: 74 mg, 72%; amorphous white solid.
Data. 1H NMR (400 MHz, CDCl3): d ¼ 3.82 (s, 6H), 4.02 (s, 3H), 4.60–4.90
(m, 4H), 6.74 (d, J ¼ 7.15 Hz, 1H), 6.95–7.08 (m, 2H), 7.20–7.40 (m, 3H),
7.50–7.63 (m, 4H). MS (APCIþve): m=z (%) ¼ 458 (100%) [M þ Hþ]. Anal. calcd.
for C25H23N5O4: C, 65.63; H, 5.06; N, 15.31. Found: C, 65.35; H, 5.08; N, 15.10.
TLC Rf 0.24 (DCM=MeOH 95:5), Rf 0.33 (DCM=MeOH=aqueous NH4OH
90:10:1).
Data for compound 20b (Ar ¼ 2-methylphenyl). Yield: 54 mg, 58%;
amorphous white solid. 1H NMR (400 MHz, CDCl3): d ¼ 2.26 (s, 3H), 3.80 (s,
3H), 4.02 (s, 3H), 4.60–4.85 (m, 4H), 6.75 (d, J ¼ 7.15 Hz, 1H), 7.20–7.34 (m, 5H),
7.39 (d, J ¼ 7.15 Hz, 2H), 7.58 (d, J ¼ 7.15 Hz, 2H). MS (APCIþve): m=z
(%) ¼ 442 (100%) [M þ Hþ]. Anal. calcd. for C25H23N5O3 ꢄ 0.4H2O: C, 66.92; H,
5.35; N, 15.61. Found: C, 67.04; H, 5.26; N, 15.52. TLC Rf 0.17 (DCM=MeOH
95:5), Rf 0.77 (DCM=MeOH=aqueous NH4OH 90:10:1).
Representative Sulfonamide Formation
Preparation. Methanesulfonyl chloride (22 ml, 23 mg, 0.29 mmol) was added
to a stirred ice-cold solution of 18a (Ar ¼ 2-methoxyphenyl) (90 mg, 0.22 mmol)
and di-isopropylethylamine (41 mg, 0.31 mmol) in DCM (3 mL). The resulting sol-
ution was allowed to warm to rt. After 1 h, the solution was diluted with DCM
(5 mL); washed with water (3 mL), NaHCO3 solution (3 mL), and brine (3 mL); dried
over MgSO4; filtered; and evaporated. The residue was triturated in ether and filtered
to give the product 21a (R ¼ CH3SO2-). Yield: 76 mg, 70%; amorphous white solid.

974
D. ELLIS
Data. 1H NMR (400 MHz, CDCl3): d ¼ 2.96 (s, 3H), 3.80 (s, 3H), 4.02 (s, 3H),
4.40–4.80 (m, 4H), 6.75 (d, J ¼ 7.15 Hz, 1H), 6.97–7.10 (m, 2H), 7.25–7.40 (m, 3H),
7.55–7.65 (m, 4H). MS (APCIþve): m=z (%) ¼ 478 (100%) [M þ Hþ]. Anal. calcd. for
C24H23N5O4S: C, 60.36; H, 4.85; N, 14.66. Found: C, 59.99; H, 4.98; N, 14.35. TLC
Rf 0.24 (DCM=MeOH 95:5), Rf 0.31 (DCM=MeOH=aqueous NH4OH 90:10:1).
Data for compound 21b (Ar ¼ 2-methylphenyl). Yield: 57 mg, 59%; white
1
foam. H NMR (400 MHz, CDCl3): d ¼ 2.25 (s, 3H), 2.98 (s, 3H), 4.02 (s, 3H),
4.40–4.80 (m, 4H), 6.82 (d, 1H), 7.20–7.35 (m, 5H), 7.41 (d, 2H), 7.58 (d, 2H). MS
(APCIþve): m=z (%) ¼ 462 (100%) [M þ Hþ]. Anal. calcd. for C24H23N5O3S ꢄ H2O:
C, 60.11; H, 5.25; N, 14.60. Found: C, 60.13; H, 5.04; N, 14.13. TLC Rf 0.17
(DCM=MeOH 95:5), Rf 0.75 (DCM=MeOH=aqueous NH4OH 90:10:1).
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