RSC Advances
Paper
tert-butyl phosphorus ligands represented by 3a, 3m, and 3p
were ineffective ligands in our model reactions (Entries 1–3).
Furthermore, the diphenyl phosphorus ligands such as 3w, 3y,
3z, and 3ab showed low to moderate conversions in the model
cross-coupling reactions (Entries 6–9). However, the dicyclo-
hexyl phosphorus ligands shown by 3r and 3t showed greater
than 99% conversions by GC analyses (Entries 4–5). Further
exploration of ligand 3r with K
reaction overnight at room temperature or for 3 h at 80
3
PO
4
as the base, stirring the
ꢀ
C
showed inferior conversions (Entries 10–12). There was no
conversion when a ligand was not used in the model reaction
Scheme 3 Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine
ligands 3m–3ab from 2-iodo-3-iodo(or bromo)imidazo[1,2-a]pyri- (Entry 13).
dines 5 or 6 via palladium-catalyzed Suzuki/phosphination or a phos-
phination/Suzuki cross-coupling reactions sequences.
Furthermore, a Buchwald–Hartwig amination model study
was investigated with our new imidazo[1,2-a]pyridine phos-
phorus ligands 3a–3ab. The Buchwald–Hartwig amination
reaction of 4-chlorotoluene (12) with aniline (13) to give 4-
methyl-N-phenylaniline (14) was screened with our ligands
phospination with diphenylphosphine (method 2) to give
intermediate 8 (X ¼ Br, I becomes PPh
2
) followed by Suzuki
palladium-catalyzed cross-coupling reactions with arylboronic (Table 4). Our screening conditions were exactly as used in the
acids. Note that the change in reactivity of the core when
switching between bromo and iodo at C3 results in a change in
the order of cross-coupling steps.
optimization of the Suzuki cross-coupling reactions of m-
bromo-xylene (9) and 2-methoxyphenylboronic acid (10) to give
2,6-dimethyl-(2-methoxy)biphenyl (11). Tert-butyl phosphine
With our library of functionalized imidazo[1,2-a]pyridine
phosphorus ligands 3a–3ab in hand, we began to screen these
ligands in Suzuki–Miyaura cross-coupling reactions to prepare
sterically-hindered biaryl compounds. We chose the Suzuki–
ligands 3a, 3d, 3g, 3n, and 3p were all ineffective in the ami-
nation reactions (Entries 1–2, 4, 7–8). However, as expected, the
dicyclohexyl phosphorus ligands 3e, 3q, and 3s showed >99%
conversion (Entries 3, 9, and 11) in the model screening reac-
Miyaura cross-coupling reactions of m-bromo-xylene (9) and 2- tion conditions. Phosphorus ligand 3s were screening against
methoxyphenylboronic acid (10) to give 2,6-dimethyl-(2-
methoxy)biphenyl (11) as our model reaction as outlined in
Table 3. Our initial screening conditions included 5.0 mol%
ligand, 2.5 mol% palladium(II) acetate with 2.5 equivalents of
base in 1,4-dioxane at 80 C for 12–24 h. As expected, SPhos and
XPhos were employed as our initial ligands to conrm our GC
other bases such as K PO , K CO , KOt-Bu, and NaOt-Bu
3
4
2
3
(Entries 12–15) where all gave >99% conversions except for
K
2
CO which was ineffective. Finally, ligands 3h and 3k showed
3
moderate conversions (Entries 5–6).
ꢀ
In summary, we have disclosed two complementary
synthetic routes to 3-aryl-2-phosphinoimidazo[1,2-a]pyridine
ligands 3a–3ab from 2-aminopyridine (1). In one method, 2-
analyses of >99% conversion in our chosen model reaction
(Entries 14–15). With the GC conditions validated, we screened aminopyridine (1) underwent
a
copper-catalyzed iodine-
selected ligands from 3a–3ab. It was clearly evident that the di-
mediated cyclization with arylacetylenes followed by
Table 2 Palladium-catalyzed Suzuki/phosphination or phosphination/Suzuki reactions sequences of 2,3-diiodoimidazo[1,2-a]pyridine (5) or 3-
a
bromo-2-iodoimidazo[1,2-a]pyridine (6)
Entry
R
Ar
Method/substrate
Step 1 (% yield)
Step 2 (% yield)
1
2
3
4
5
6
7
8
9
t-Bu
t-Bu
t-Bu
t-Bu
Cy
Cy
Cy
Cy
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2,3-diOMeC
3,4-diOMeC
2,5-diOMeC
6
6
6
H
H
H
3
3
3
1, 5
1, 5
1, 5
1, 5
1, 5
1, 5
1, 5
1, 5
1, 5
2, 6
2, 6
2, 6
2, 6
2, 6
2, 6
2, 6
7a (59)
7b (54)
7c (58)
7d (50)
7a (59)
7e (40)
7b (54)
7f (58)
7d (50)
8 (70)
8 (70)
8 (70)
8 (70)
8 (70)
8 (70)
8 (70)
3m (64)
3n (31)
3o (61)
3p (62)
3q (46)
3r (52)
3s (52)
3t (21)
3u (55)
3v (52)
3w (68)
3x (67)
3y (52)
3z (64)
3aa (40)
3ab (39)
3,4,5-triOMeC
6
H
2
2,3-diOMeC
2,6-diOMeC
3,4-diOMeC
6
6
6
H
H
H
3
3
3
2,3,4-triOMeC
3,4,5-triOMeC
6
H
H
2
2
6
10
11
12
13
14
15
16
2,3-diOMeC
2,5-diOMeC
3,4-diOMeC
6
6
6
H
3
H
H
3
3
2,3,4-triOMeC
3,4,5-triOMeC
6
H
H
2
2
6
4-FC
6
H
4
3-F,5-OMeC
6
H
3
a
Reaction conditions: 5, ArB(OH)
CO
2
, Pd(PPh
3
)
4
(5 mol%), Na
2
CO
3
2 2 2
(2 equiv.), 1,4-dioxane/H O (2 : 1) and HPR (1 equiv.), Pd(OAc) (2.5–5 mol%),
ꢀ
Cs
2
3
(1.2 equiv.), DIPPF (2.5–10 mol%), 1,4-dioxane, 80 C or 6, reverse sequence of reactions.
17780 | RSC Adv., 2019, 9, 17778–17782
This journal is © The Royal Society of Chemistry 2019