Table 1. Optimization of the Yb(OTf)3-mediated Castagnoli–Cushman reaction to the CPG-bound hexT-isoquinolonic acid conjugate 16a ^a .

Entry	Yb(OTf)3 [equiv.]	t 1 [h]	t 2 [h]	Solvent	Conversion b [%]
1 c	100	4	2	CH2Cl2	<5
2	100	4	2	CH2Cl2	72
3	100	4	1	CH2Cl2	73
4	100	4	0.5	CH2Cl2	68
5	100	3	1	CH2Cl2	69
6	100	2	1	CH2Cl2	68
7	100	1	1	CH2Cl2	65
8	100	16	1	CH2Cl2	73
9 d	100	4	1	CH2Cl2	7
10	50	4	1	CH2Cl2	70
11	25	4	1	CH2Cl2	54
12	0	4	1	CH2Cl2	38
13 e	50	4	1	CH2Cl2	65
14 f	50	4	1	CH2Cl2	63
15 g	50	4	1	CH2Cl2	51
16	50	4	1	THF	56
17	50	4	1	DCE	58
18	50	4	1	ACN	52
19	50	4	1	MeOH	68
20	50	4	1	Toluene	50
21	50	4	1	1,4-Dioxane	52
22	50	4	1	DMF	31
23	50	4	1	EtOAc	40

^aCPG-bound oligonucleotide conjugate 13a (20 nmol) and aniline 14a (500 equiv., 10 μmol) in 36 μL of solvent/triethyl orthoformate (2 : 1) at ambient temperature for t₁, then Yb(OTf)₃ (X equiv., 1 μmol) and anhydride 15a (500 equiv., 10 μmol) both suspended in 30 μL of solvent, at ambient temperature for t₂. Afterwards, with AMA (30% aqueous ammonia/40% aqueous methylamine, 1 : 1 (vol/vol)) at ambient temperature for 0.5 h.

^bDetermined by analytical RP-HPLC analysis.

^cWashing of the CPG-bound hexT-conjugate after imine formation.

^dImine formation performed without triethyl orthoformate.

^e1000 equiv. of aniline 14a and anhydride 15 were used.

^f1500 equiv. of aniline 14a and anhydride 15a were used.

^g2000 equiv. of aniline 14a and anhydride 15 were used.