Synthesis of 3-aryl-2-phosphinoimidazo[1,2-: A] pyridine ligands for use in palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1039/c9ra02200g

3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald-Hartwig amination compounds are presented with these ligands.

Full text of DOI:10.1039/c9ra02200g

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Synthesis of 3-aryl-2-phosphinoimidazo[1,2-a]
pyridine ligands for use in palladium-catalyzed
cross-coupling reactions†
Cite this: RSC Adv., 2019, 9, 17778
Ryan Q. Tran, Seth A. Jacoby, Kaitlyn E. Roberts, William A. Swann, Nekoda W. Harris,
Long P. Dinh,
Emily L. Denison and Larry Yet
*
3
-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two
complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated
cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling
reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo
Received 21st March 2019
Accepted 17th May 2019
[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-
catalyzed Suzuki/phosphination or phosphination/Suzuki cross-coupling reactions sequence,
a
DOI: 10.1039/c9ra02200g
respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and
rsc.li/rsc-advances
Buchwald–Hartwig amination compounds are presented with these ligands.
Palladium-catalyzed cross-coupling reactions have revolution- Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonogashira,
ized the formation of C–C and C–X bond formation in the C–X (X ¼ S, O, P) cross-coupling and Buchwald–Hartwig ami-
1
,2
academic and industrial synthetic organic chemistry sectors.
nation reactions (Fig. 1). Preformed catalysts with these ligands
3
Applications such as synthesis of natural products, active attached to the palladium metal center are also recognized as
pharmaceutical ingredients (API), agrochemicals, and mate- well-dened entities in cross-coupling reactions.
rials for electronic applications are showcased. Snieckus
4
5
26
6
The term privileged structure was rst coined by Evans et al.
described in his 2010 Nobel Prize review that privileged ligand in 1988 and was dened as “a single molecular framework able
scaffolds represented the “third wave” in the cross-coupling
reactions where the “rst wave” was the investigation of the
metal catalyst-the rise of palladium and the “second wave” was
1
the exploration of the organometallic coupling partner. In the
last twenty years, it was recognized that the choice of ligand
facilitated the oxidative addition and reductive-elimination
steps of the catalytic cycle of transition metal-catalyzed cross-
coupling reactions, increasing the overall rate of the reaction.
For example, bulky trialkylphosphines facilitated the oxidative
addition processes of electron-rich, unactivated substrates such
7,8
as aryl chlorides. Sterically demanding ligands also provided
enhanced rates of reductive elimination from [(L) Pd(aryl)(R), R
aryl, amido, phenoxo, etc.] species by alleviation of steric
n
¼
9
congestion. Privileged ligands such as Buchwald's biar-
10,11
7,8,12
ylphosphines,
mann's N-heterocyclic carbenes (NHC),
ferrocenes,
aryl(benz)imidazolyl or N-pyrrolylphosphines,
ClickPhos ligands,
phines,
Fu's trialkylphosphines,
Nolan–Her-
1
3–15
Hartwig's
16,17
18,19
Beller's bis(adamantyl)phosphines
and N-
Zhang's
2
0,21
22,23
and Stradiotto's biaryl P–N phos-
24,25
to mention a few, have found wide-spread use in
University of South Alabama, Department of Chemistry, Mobile, AL 36618, USA.
E-mail: lyet@southalabama.edu
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra02200g
Fig.
reactions.
1 Privileged ligands for palladium-catalyzed cross-coupling
1
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to provide ligands for diverse receptors”. In the last three
RSC Advances
27
Phenylacetylene and 2-/3-/4-methoxyphenylacetylenes were
decades, it is clear that privileged structures are exploited as commercially available reagents. With intermediates 2a–d in
28–31
opportunities in drug discovery programs.
For example, hand, we explored several cross-coupling phosphination reac-
imidazo[1,2-a]pyridines are privileged structures in medicinal tions and we found that palladium-catalyzed phosphination
32
chemistry programs (Fig. 2). Imidazo[1,2-a]pyridines are with DIPPF ligand in the presence of cesium carbonate as the
a represented motif in several drugs on the market such as base in 1,4-dioxane under reux provided twelve new ligands
38
zolpidem, marketed as Ambien™ for the treatment of 3a–3l as shown in Table 1. Moderate to good yields were ob-
33
insomnia, minodronic acid, marketed as Bonoteo™ for oral tained under these cross-coupling conditions. There are few
34
treatment of osteoporosis, and olprinone, sold as Coretec™ as commercially available dimethoxyphenylacetylenes, and most
35
a cardiotonic agent.
are prohibitively expensive, and so an alternative synthetic
Our group is interested in a long-term research program strategy was explored.
directed at the use of key privileged structures that are
2-Iodoimidazo[1,2-a]pyridine (4) was conveniently prepared
employed in drug discovery programs as potential phosphorus in three steps from 2-aminopyridine (1) following literature
ligands for cross-coupling reactions. In our entry into the use of procedures, which was then converted into either iodo 5 or
39,40
privileged structures from the medicinal chemistry literature bromo 6 with NIS or NBS, respectively (Scheme 2).
for our investigation into new phosphorus ligands, we have When the phosphorus ligands 3 contained tert-butyl or
developed two complementary synthetic routes for the prepa- cyclohexyl groups, method 1 was followed where 2,3-diiodoi-
ration of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands midazo[1,2-a]pyridine (5) underwent Suzuki cross-coupling
from 2-aminopyridine as our initial substrate.
reactions with arylboronic acids to yield aryl intermediates
Our rst synthetic route for the preparation of 3-aryl-2-phos- 7a–7f, which was followed by palladium-catalyzed cross-
phinoimidazo[1,2-a]pyridine ligands 3a–3l required the copper(II) coupling phosphination reactions with di-tert-butylphosphine
acetate iodine-mediated double oxidative C–H amination of 2- or dicyclohexylphosphine to give C-2 substituted phosphorus
3
8
aminopyridine (1) with arylacetylenes under an oxygen atmosphere ligands 3m–3u in low to moderate yields (Scheme 3, Table 2).
to give 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d (Scheme 1).
36,37
The phosphorus ligands 3v–3ab were prepared from 3-bromo-2-
iodoimidazo[1,2-a]pyridine (6) via palladium-catalyzed
a
Table 1 Palladium-catalyzed phosphination of 3-aryl-2-iodoimidazo
a
[1,2-a]pyridines 2a–2d
Entry
Ar
R
3 (% yield)
1
2
3
4
5
6
7
8
9
Ph (2a)
Ph (2a)
Ph (2a)
t-Bu
Cy
Ph
t-Bu
Cy
Ph
t-Bu
Cy
Ph
t-Bu
Cy
Ph
3a (41)
3b (50)
3c (61)
3d (53)
3e (83)
3f (69)
3g (62)
3h (72)
3i (79)
3j (73)
3k (55)
3l (59)
2-OMeC
2-OMeC
2-OMeC
3-OMeC
3-OMeC
3-OMeC
4-OMeC
4-OMeC
4-OMeC
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
4
4
4
4
4
4
4
4
4
(2b)
(2b)
(2b)
(2c)
(2c)
(2c)
(2d)
(2d)
(2d)
10
11
12
Fig. 2 Imidazo[1,2-a]pyridines as privileged structures in medicinal
chemistry and in our cross-coupling reactions approach.
a
Reaction conditions: 2a–2d (1 equiv.), HPR
CO
2
(1 equiv.), Pd(OAc)
(1.2 equiv.), DIPPF (2.5 mol%), 1,4-dioxane, 80 C.
2
ꢀ
(2 mol%), Cs
2
3
Scheme 1 Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine
ligands 3a–3l from 2-aminopyridine via copper-catalyzed arylacety-
lene cyclizations/palladium-catalyzed phosphination reactions Scheme 2 Preparation of 2,3-diiodoimidazo[1,2-a]pyridine (5) and 3-
sequences.
bromo-2-iodoimidazo[1,2-a]pyridine (6).
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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 conrm 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.
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Table 3 Optimization of conditions for the Suzuki–Miyaura cross- 2-aminopyridine (1) followed by palladium-catalyzed
coupling model reaction
phosphination/Suzuki or Suzuki/phosphination reactions
sequences, respectively. We are currently exploring the scope
and limitations of the 3-aryl-2-phosphinoimidazo[1,2-a]pyri-
dine ligand 3r and 3e in our Suzuki–Miyaura and Buchwald–
Hartwig amination cross-coupling reactions, respectively.
Conflicts of interest
a
Entry
Ligand
Conditions
Conversion (%)
There are no conicts to declare.
1
2
3
4
5
6
7
8
9
3a
3m
3p
3r
3t
3w
3y
3z
3ab
3r
3r
12
20
14 b
>99
>99
21
55
46
11
91
4
39
0
>99
>99
Acknowledgements
We thank the University of South Alabama, Chemistry Depart-
ment for nancial support.
Notes and references
10
11
12
13
14
15
K
3
PO
4
was used as base
reaction was performed at
25 C reaction was stirred
for 3 h no ligand
1
C. C. C. J. Seechurn, M. O. Kitching, T. J. Colacot and
V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062–5085.
Palladium-Catalyzed Coupling Reactions: Practical Aspects and
Future Development, ed. A. Molnar, Wiley-VCH, Weinheim,
Germany, 2013.
ꢀ
3r
—
SPhos
XPhos
2
a
b
Based on GC analyses of consumed 9. Isolated yield of 96% was
3
4
5
6
7
8
9
K. C. Nicolaou, P. G. Bulger and D. Sariah, Angew. Chem., Int.
Ed., 2005, 44, 4442–4489.
J. Magano and J. R. Dunetz, Chem. Rev., 2011, 111, 2177–
obtaisned.
2
250.
C. Torborg and M. Beller, Adv. Synth. Catal., 2009, 351, 3027–
043.
F. Naso, F. Babudri and G. M. Farinola, Pure Appl. Chem.,
999, 71, 1485–1492.
A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41,
176–4211.
C. A. Fleckenstein and H. Plenio, Chem. Soc. Rev., 2010, 39,
94–711.
U. Christmann and R. Vilar, Angew. Chem., Int. Ed., 2005, 44,
66–374.
10 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41,
461–1473.
1 D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2008,
7, 6338–6361.
2 G. C. Fu, Acc. Chem. Res., 2008, 41, 1555–1564.
Table 4 Screening of conditions for the Buchwald–Hartwig amination
cross-coupling model reaction
3
1
4
6
a
Entry
Ligand
Conditions
Conversion (%)
3
1
2
3
4
5
6
7
8
9
3a
3d
3e
3g
3h
3k
3n
3p
3q
3r
3s
3s
3s
3s
3s
38
26 b
>99
29
54
71
0
0
>99
92
>99
83
1
1
1
4
13 N. Marion and S. P. Nolan, Acc. Chem. Res., 2008, 41, 1440–
449.
1
10
11
12
13
14
15
1
1
4 W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41, 1290–1309.
5 G. C. Fortman and S. P. Nolan, Chem. Soc. Rev., 2011, 40,
K
K
3
PO
CO
4
was used as base
was used as base
5151–5169.
2
3
0
>99
>99
KOt-Bu was used as base
NaOt-Bu was used as base
16 J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534–1544.
17 A. Fihri, P. Meunier and J.-C. Hierso, Coord. Chem. Rev.,
a
b
2007, 251, 2017–2055.
Based on GC analyses of consumed 13. Isolated yield of 76% was
obtained.
18 S. Klaus, H. Neumann, A. Zapf, D. Strubing, S. Hubner,
J. Almena, T. Riermeier, P. Groß, M. Sarich,
W.-R. Krahnert, K. Rossen and M. Beller, Angew. Chem.,
Int. Ed., 2006, 45, 154–158.
palladium-catalyzed cross-coupling reactions with phosphines.
In the second protocol, 2,3-diiodoimidazo[1,2-a]pyridine (5) or
19 A. Zapf, A. Ehrentraut and M. Beller, Angew. Chem., Int. Ed.,
3-bromo-2-iodoimidazo[1,2-a]pyridine (6) were prepared from
2000, 39, 4153–4155.
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Paper
20 S. Harkal, F. Rataboul, A. Zapf, C. Fuhrmann, T. Riermeier, 30 S. Bongarzone and M. L. Bolognesi, Expert Opin. Drug
A. Monsees and M. Beller, Adv. Synth. Catal., 2004, 346,
742–1748.
1 A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier, A. Monsees,
Discovery, 2011, 6, 251.
31 L. Yet, Privileged Structures in Drug Discovery-Medicinal
Chemistry and Synthesis, Wiley & Sons, Hoboken, NJ, 2018.
1
2
C. Fuhrmann, N. Shaikh, U. Dingerdissen and M. Beller, 32 C. Enguehard-Gueiffier and A. Gueiffier, Mini-Rev. Med.
Chem. Commun., 2004, 38–39. Chem., 2007, 7, 888.
2 Q. Dai, W. Gao, D. Liu, L. M. Kapes and X. Zhang, J. Org. 33 D. J. Sanger and H. Depoortere, CNS Drug Rev., 1998, 4, 323–
Chem., 2010, 71, 3928–3934. 340.
3 D. Liu, W. Gao, Q. Dai and X. Zhang, Org. Lett., 2005, 7, 4907– 34 T. Makoto, M. Hiroshi, K. Ryoji, O. Yasuo, K. Naoki,
910. Y. Hiroyuki and K. Katsuya, Bone, 2008, 43, 894–900.
4 R. J. Lundgren, B. D. Peters, P. G. Alsabeh and M. Stradiotto, 35 D. Spina, Drugs, 2003, 63, 2575–2594.
2
2
2
2
2
2
4
Angew. Chem., Int. Ed., 2010, 49, 4071–4074.
36 D. Dheer, K. R. Reddy, S. K. Rath, P. L. Sangwan, P. Das and
5 R. J. Lundgren, A. Sappong-Kumankumah and M. Stradiotto,
Chem.–Eur. J., 2010, 16, 1983–1991.
6 H. Li, C. C. C. J. Seechurn and T. J. Colacot, ACS Catal., 2012,
R. Shankar, RSC Adv., 2016, 6, 38033–38036.
37 S. Samanta, S. Jana, S. Mondal, K. Monir, S. K. Chandra and
A. Hajra, Org. Biomol. Chem., 2016, 14, 5073–5078.
38 M. Murata and S. L. Buchwald, Tetrahedron, 2004, 60, 7397–
7403.
2
, 1147–1164.
7 M. G. Bock, R. M. DiPardo, B. E. Evans, K. E. Rittle,
R. M. Freidinger, R. S. L. Chang and V. J. Lotti, J. Med. 39 S. Marhadour, M.-A. Bazin and P. Marchand, Tetrahedron
Chem., 1988, 31, 264. Lett., 2012, 53, 297–300.
8 L. Costantino and D. Barlocco, Curr. Med. Chem., 2006, 13, 40 Heterocyclic derivatives as metabotropic glutamate receptor
2
2
65.
modulators, EP2650284, Merz Pharma GmbH & Co. KGaA,
2013, p. 30.
9 R. W. DeSimone, K. S. Currie, S. A. Mitchell, J. W. Darrow
and D. A. Pippin, Comb. Chem. High Throughput Screening,
2004, 7, 473.
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