FULL PAPER
– product was used for catalytic diazotransfer without further
purification.
with MeOH (3x) and used for quantification. 2×15 mg of the
resin was cleaved using 50% TFA in DCM for 1 hour and then
dried using a stream of nitrogen. Samples were dissolved in
HPLC MeCN (1 mL) and the loading was determined by
UPLC-MS using Fmoc-β-Ala (0.25 mg/mL) as an external
standard. Calculated loading of the resin was in the range 0.6–
0.7 mmol/g.
Catalytic Diazotransfer
First, NaN3 (176 mmol; 11.5 g) was dissolved in water (53 mL)/
DCM (80 mL) and the flask was placed into ice bath, Tf2O
(6 mL; 35 mmol) was then added in small portions using
addition funnel (over 20 minutes). Reaction mixture was stirred
for 15 minutes in the ice bath and then for 2 hours at rt.
Aqueous layer turned pink/light brown. Then, layers were
separated in a funnel and aqueous layer was extracted 2x with
DCM (2×50 mL). Organic layers were combined and added as
a last reagent to the solution B. Solution B contained starting
material (6 g) after Hofmann rearrangement in a mixture of
MeOH (100 mL)/water (33 mL), NaHCO3 (15 g; 176 mmoL)
and CuSO4.H2O (43 mg; 176 μmol). Reaction mixture slowly
turned green – brown after addition of TfN3 solution (solution
A). Reaction mixture was stirred overnight at rt under N2
atmosphere. Next day, all volatile solvents were removed using
RVO. Pale green suspension was then acidified using conc. HCl
to pH=2. Pale yellow precipitate was formed. EtOAc was then
added to the flask and the mixture was then quantitatively
transferred to the funnel. Extraction with EtOAc was repeated
3x. Organic layers were combined and dried over Na2SO4,
filtrated and evaporated to dryness. Yellow-light brown oily
residue was obtained. Product was isolated using column
chromatography (Tol:EtOAc:AcOH 1.5:1:0.1) with a purity of
90% as white-pale yellow solid. Yield 5.8 g (94%). Measured
data (1D-NMR, HRMS) are consistent with published data.[23]
Nosylation with 4-Nitrobenzenesulfonyl Chloride 2
{R1}
Resin 1{R1} (1 g) was treated with 20% piperidine in DMF
(10 mL) for 15 minutes and subsequently washed with DMF
(3x) and DCM (5x). A solution of 4-NsCl (3 mmol; 640 mg)
and 2,6-lutidine (3 mmol; 380 μL) in DCM (10 mL) was added
to the resin and reaction mixture was shaken overnight. Resin
was washed with DCM (5x).
Fukuyama-Mitsunobu Alkylation 3{R1,R2}
Resin 2{R1} (500 mg) was washed with DCM (3x), dry DMF
(3x) and dry THF (3x). Then, a solution of PPh3 (2.2 mmol;
590 mg) and alcohol (2.2 mmol) in dry THF (2.5 mL) was
added to the resin. A solution of DIAD (2.2 mmol, 444 μL) in
dry THF (2.5 mL) was added to the second syringe and both
syringes were connected with a joint and put in a freezer for
15 minutes. Both solutions were then combined. Reaction
mixture was shaken overnight at rt, washed with THF (3x) and
DCM (5x).
Deprotection of 4-Nosyl Group 4{R1,R2}
Alcohols for Fukuyama-Mitsunobu Alkylation
Resin 3{R1,R2} (for all resins except 3{2,5}) (500 mg) was
washed with DMF (3x). Then, a solution of mercaptoethanol
(7 mmol; 500 μL) and DBU (0.8 mmol; 120 μL) in DMF
(5 mL) was added to the resin and reaction mixture was shaken
at rt for various time (see Table 2). In the case of 3{2,5}, a
solution of thiophenol (4 mmol; 420 μL) and DBU (4 mmol;
600 μL) in DMF (5 mL) was added to the resin (500 mg) and
reaction mixture was shaken for 30 minutes at rt. After reaction,
the resin was washed with DMF (5x) and DCM (5x).
Aryliodide (6.5 mmol) was dissolved in degassed TEA
(13 mL). Then, CuI (0.53 mmol; 100 mg) and Pd(PPh3)2Cl2
(5 mol.%, 230 mg) were added and pale brown suspension was
formed. When propargylalcohol (7.8 mmol; 450 μL) was added,
the suspension changed color to yellow and then to pale brown
and dark precipitate was formed. The reaction mixture was
vigorously stirred under N2 atmosphere . After 6.5 hours, small
sample was extracted with DCM/sat. NH4Cl in eppendorf tube.
DCM layer was analyzed using TLC (H/E 7:3 – Rf of product
is 0.4, ArI 0.9). After completion, the reaction mixture was
quenched with sat.NH4Cl (10 mL), diluted with sat.NH4Cl and
extracted with DCM (3x). Organic layers were combined, dried
over MgSO4, filtered and concentrated. Product was then sorbed
to SiO2 and purified using column chromatography with DCM
as the mobile phase. Product was isolated as yellow solid after
lyophilization of residual solvents. Analytical data were
consistent with published data.[27,28]
Acylation with Fmoc-Azidoalanine 5{R1,R2}
After washing of the resin 4 (500 mg) with DMF (3x), a
solution of Fmoc-azidoalanine (2.2 mmol; 796 mg) and DIC
(2.2 mmol; 356 μL) in DMF (5 mL) was added to the resin and
the reaction mixture was shaken overnight at rt. (for resins 4{4-
6,2} the reaction was repeated twice). Next day, resins were
washed with DMF (3x) and DCM (3x).
Preparation of Triazolodiazepinones
Immobilization of Fmoc-Amino Acids 1{R1}
Cyclization to Triazolodiazepinones 6{R1,R2} and
their Cleavage from the Resin
2
°
A solution of Fmoc-amino acid (3 mmol), HOBt×0.5 H2O
(3 mmol; 430 mg), DMAP (0.75 mmol; 92 mg) and DIC
(3 mmol; 470 μL) in DCM/DMF (1:1, 10 mL) was added to
Wang resin (1.4 mmol; 1 g). Reaction mixture was shaken for
24 hours at rt. Resin was washed with DMF (3x) and DCM
(3x). Small sample of the resin (approx. 30 mg) was washed
Resin 5 was heated in MeCN (10 mL) at 75 C for 24 (R =H)
or 48 hours (R2 =aryl, Me) in a glass vial. After cooling down
to rt, the resin was filtered and washed with DCM (3x). For all
triazoles apart from 7{1-3,1}, 7{2,5}, 7{4,2} and 7{6,2} resin
was then washed with DMF (3x) and a 20% solution of
piperidine in DMF was added to the resin. After 15 minutes,
Adv. Synth. Catal. 2021, 363, 1112–1119
1117
© 2020 Wiley-VCH GmbH
Kriegelsteinová, Patricia
