An improved synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-b]pyrazines by palladium catalyzed amidation using xantphos in a 1,4-dioxane:tert-amyl alcohol solvent system

Article abstract of DOI:10.1002/adsc.201400465

Herein an improved protocol for the synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-b]pyrazines using a palladium-catalyzed amidation that utilizes Xantphos as an ancillary phosphine ligand is reported. The use of a binary solvent system comprised of

Full text of DOI:10.1002/adsc.201400465

UPDATES
DOI: 10.1002/adsc.201400465
An Improved Synthesis of Imidazo[4,5-b]pyridines and
U
Imidazo[4,5-b]pyrazines by Palladium Catalyzed Amidation using
A
Xantphos in a 1,4-Dioxane:tert-Amyl Alcohol Solvent System
Adam J. Rosenberg,a Ijaz Ahmed,a Robert J. Wilson,a Theresa M. Williams,a
Lauren Kaminsky,a and Daniel A. Clarka,*
a
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, New York 13244,
USA
Fax : (+1)-315-443-4070; phone: (+1)-315-443-2127; e-mail: daclar01@syr.edu
Received: May 8, 2014; Published online: September 26, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400465.
Abstract: Herein an improved protocol for the syn-
thesis of imidazo[4,5-b]pyridines and imidazo[4,5-
(IPb) and their derivatives represents a useful proto-
col for obtaining these sought-after compounds. Due
to our ongoing interest in this class of heterocy-
cles,[12–13] further improvements were desired for IPb
synthesis.
The goal of the current study was to obtain IPb in
high yield using readily available starting materials,
including the pre-catalyst and ligand.[14,15] Our previ-
ous methodology utilized commercial 3-amino-2-
G
ACHTUNGTRENNUNG
b]pyrazines using a palladium-catalyzed amidation
that utilizes Xantphos as an ancillary phosphine
ligand is reported. The use of a binary solvent
system comprised of 1,4-dioxane and tert-amyl alco-
hol was crucial in eliminating unwanted by-prod-
ucts.
chloropyridines and amides, and Pd2ACTHUNTRGNE(UGN dba)3·CHCl3 as
Keywords: nitrogen heterocycles; P ligands; palladi-
um
our precatalyst of choice.[12,16] However, the method
relied on biarylphosphine ligands, a potential limiting
factor in wide-spread use of this methodology.[16]
While recent progress has been achieved in address-
ing the cost of these ligands,[17,18] they remain, in our
Imidazopyridines are an important class of structures mind, prohibitively expensive.
commonly utilized in pharmaceuticals due to their
Thus, we pursued the use of alternate phosphine-
many beneficial qualities including solubility and hy- based ligands which were financially more viable. Ad-
drogen bonding capabilities (Figure 1).[1–11] We recent- ditionally, expanded scope with regard to substrates
ly reported a method of preparing these moieties and amide coupling partners was desired. In particu-
using a palladium-catalyzed coupling between an lar, the use of electron-deficient benzyl moieties was
amide and substituted 3-amino-2-chloropyridines.[12] ineffective using our previous protocol. Substrates
This method of preparing imidazoACTHNUTRGNEU[GN 4,5-b]pyridines that had unhindered chlorides (i.e., 4-chlorobenzyl)
were also not compatible with our previous method.
Finally, we sought to incorporate additional function-
ality on the amide partner. Here, we discuss further
investigations which address these previous limita-
tions.
In our initial report, various ligands were screened
and only biaryl ligands (i.e., Me4-t-Bu-XPhos) dis-
played acceptable reactivity (Scheme 1).[12]
The non-proprietary BippyPhos ligand gave a mod-
erate yield, while related 4-MeBippyPhos gave com-
parable yields to the biaryl ligands. Unfortunately, the
high cost and difficult preparation of 4-methylpyra-
zole, needed for the synthesis of the 4-MeBippyPhos,
led us to explore other options.
Figure 1. Selected imidazoACTHUNTGRNEUNG[4,5-b]pyridines.
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UPDATES
Adam J. Rosenberg et al.
phosphine ligands required the use of aprotic solvents
for positive outcomes with little to no conversion ob-
served in alcoholic solvents.[12,25–29] Re-examination of
our reaction revealed that XantPhos and DPEPhos in
aprotic solvents produced the desired cyclization
product 2a along with reduced pyridine 3 (entries 1–5,
Table 1). The identity of 3 was confirmed through in-
dependent synthesis from 3-aminopyridine. It is be-
lieved that formamide acts as the reductant in the for-
mation of pyridine 3 (vide infra). Furthermore, when
formamide is exchanged for other amides 3 was not
observed.
Having not observed the formation of 3 in previous
studies (Scheme 1), alternative solvents were screened
in order to eradicate this unwanted by-product. No
reaction was observed using DMF or NMP (entries 6
and 7); while the reaction in diglyme showed moder-
Scheme 1. Previous work.
1
ate conversion with no observable 3 by H NMR (en-
In our previous study we observed no reaction tries 8 and 9). These results combined with our previ-
when Xantphos was used in tert-butyl alcohol. A ous success using tert-butyl alcohol suggested a protic
À
survey of the literature revealed that Pd-catalyzed C
solvent would minimize formation of pyridine 3. Un-
N amide bond formation had been accomplished fortunately, as aforementioned, protic solvents were
using Xantphos in aprotic solvents.[19–24] Further scru- deleterious to the reaction when bidentate ligands
tiny of the literature revealed an interesting trend; al- were utilized (entry 1). To overcome these difficulties
coholic solvents were used with ancillary ligands bear- we examined mixed solvent systems using aprotic sol-
ing a biarylphosphine motif. Conversely, bidentate vents and tert-amyl alcohol (t-AmOH).[30–32] The
Table 1. Reaction optimization.[a]
Entry
Ligand
Solvent
Yield [%] 2a (3)[b]
Conversion [%][b]
Reaction time
1
2
3
4
5
6
7
8
XantPhos
XantPhos
XantPhos
DPEPhos
XantPhos
XantPhos
XantPhos
DPEPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
DPEPhos
dppb
t-BuOH
toluene
1,4-dioxane
1,4-dioxane
DME
DMF
NMP
diglyme
NR
–
18 h
18 h
18 h
18 h
18 h
18 h
18 h
18 h
18 h
6 h
6 h
18 h
6h
18 h
18 h
18 h
18 h
22 (42)
83 (15)
37 (46)
22 (31)
NR
79
100
87
53
–
NR
–
36 (0)
33 (0)
11 (79)
13 (29)
84 (0)
93%[c]
27 (35)
trace (45)
23 (19)
4 (36)
56
51
100
42
85
100
71
48
50
40
9
diglyme
10
11
12
13
14
15
16
17
toluene:t-AmOH (10:1)
toluene:t-AmOH (1:1)
dioxane:t-AmOH (1:1)
dioxane:t-AmOH (10:1)
dioxane:t-AmOH (10:1)
dioxane:t-AmOH (10:1)
dioxane:t-AmOH (10:1)
dioxane:t-AmOH (10:1)
dppf
rac-BINAP
[a]
Reaction conditions: 2a (0.4 mmol), Pd2ACHTNUTRGNE(UNG dba)3·CHCl3 (0.004 mmol, 1 mol%), ligand (0.02 mmol, 5 mol%), formamide
(0.6 mmol), K3PO4 (0.6 mmol), solvent (0.2M), 1108C.
Based on crude H NMR using mesitylene as an internal standard.
Isolated yield. NR=no reaction.
[b]
[c]
1
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An Improved Synthesis of ImidazoACTHNUTRGENNU[G 4,5-b]pyridines and ImidazoACHTUTGNREN[NUGN 4,5-b]pyrazines
choice of additive was determined based on previous terestingly, no reduction was observed in isopropyl al-
literature precedents demonstrating the effectiveness cohol, suggesting that it does not participate as a re-
of binary solvent systems.[31,33,34] The Fu group has ducing agent in this reaction.[34,41–45] Based on these re-
also demonstrated the advantage of mixed protic and sults, we posited that the reaction mandates the use of
aprotic solvent systems.[35–37]
a sterically hindered protic co-solvent to give high
First, mixtures of toluene and t-AmOH were exam- conversion of 1a and provide 2a in high yield, while
ined. While excellent conversion was obtained in avoiding the reduction to 3. The exact nature of the
a 10:1 mixture, pyridine 3 was the primary product co-solvent and the role it plays in inhibiting the for-
(entries 10 and 11). Switching to 1,4-dioxane, which mation of 3 is currently being investigated.
demonstrated promise as the sole solvent, gave posi-
With optimal conditions in hand, we turned our at-
tive results (entries 12–14). In a 1:1 1,4-dioxane:t- tention toward the scope of the reaction. As shown in
AmOH mixture using XantPhos, little change was ob- Table 3, the new reaction conditions provided the de-
served from solely 1,4-dioxane. XantPhos in a 10:1 di- sired IPb 2 in good to excellent yields with substituted
oxane:t-AmOH solvent system gave a 93% yield in benzylic derivatives (entries 1–15). Electron-donating
only six hours with no observable 3 in the crude substituents (entries 1–4), as well as halogenated sub-
1H NMR (entry 13). Other bidentate ligands, with strates (entries 5–8) performed well, giving 79–94%
bite angles similar to XantPhos (1118), such as DPE- yields. Notably, using our previous conditions, the
Phos (1028), dppb (998), dppf (968), and BINAP (858), ortho-chlorobenzyl subtrate 1g provided 2g in 51%
proved inferior (entries 15–17).[38]
yield; this new protocol provided a much improved
With the ligand and solvent ratio selected, we ex- 79% yield of 2g (entry 7). In contrast to 1g, the para-
plored alternatives to tert-amyl alcohol as the co-sol-
vent to determine their effect on the reaction
(Table 2). Water resulted in rapid consumption of 1a,
however, pyridine 3 was the sole product observed
(Table 2, entry 2). We attribute this to the hydrolysis
of formamide to furnish ammonium formate.[39,40]
Changing the co-solvent to methanol provided mini-
mal amounts of desired IPb 2a and poor conversion
(entry 3). Switching to the more hindered isobutyl al-
cohol and isopropyl alcohol offered a higher degree
of conversion (entries 4 and 5). Isobutyl alcohol gave
30% yield of 2a with 20% 3, while isopropyl alcohol
provided 69% of 2a at 78% conversion after 24 h. In-
Table 3. Substrate scope.[a]
Entry
R
Yield [%][b]
Product
1
2
3
4
1a CH2(4-MeOC6H4)
1b CH2(2,4-MeOC6H3)
1c CH2(2,5-MeOC6H3)
1d CH2(4-Me2NC6H4)
93
81
85
94
94
96
79
94
70
85
96
71
95
57
70
94
77
63
85
91
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
5
6
7
8
1e CH
1f CH
1g CH
1h CH
1i CH CHTGNUTRENNUNG
1j CH2Ph
G
CHTUNGTRENNUNG
Table 2. Co-solvent screen.[a]
9[c]
10
11
12[c,d]
13
14[e]
15[c,d]
16
17
18[c]
19
20
1k (R)-CH
1l CH2(3,5-MeOC6H3)
1m CH2(4-CF3C6H4)
1n CH2(3-NO2C6H4)
1o CH
1p Ph
1q CH
1r Cy
Entry
Co-solvent
Yield [%]
Conversion
2a (3)[b]
of 2a [%][b]
1
2
3
4
5
t-AmOH
H2O
MeOH
i-BuOH
i-PrOH
93 (0)
0 (74)
13 (18)
30 (20)
69 (0)
100
100[c]
31
84
78
1s Cyp
1t i-Pr
2s
2t
[a]
Reaction conditions:
1 (0.4 mmol), Pd2CAHTUNTGRNUEGN(dba)3·CHCl3
(0.004 mmol, 1 mol%), XantPhos (0.02 mmol, 5 mol%),
formamide (0.6 mmol), K3PO4 (0.6 mmol), solvent
(0.2M), 1108C, 6.5 h.[b] Isolated yields.
[a]
Reaction conditions: 1a (0.4 mmol), Pd2ACTHNUTRGNEG(NU dba)3·CHCl3
(0.004 mmol, 1 mol%), ligand (0.02 mmol, 5 mol%), for-
mamide (0.6 mmol), K3PO4 (0.6 mmol), solvent (0.2M),
1108C, 24 h.
Based on crude H NMR using mesitylene as an internal
standard.
[c]
1
90% conversion based on crude H NMR using mesity-
lene as an internal standard.
2 mol% Pd2ACHTUNGTERNU(GNN dba)3·CHCl3 and 10 mol% XantPhos.
65% conversion based on crude H NMR using mesity-
lene as an internal standard.
[b]
[c]
1
[d]
[e]
1
Full conversion was observed at 1 h.
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UPDATES
Adam J. Rosenberg et al.
Table 4. Amide scope.[a]
chlorobenzyl substrate 1h was not amenable to our
previous conditions and resulted in multiple coupling
events followed by decomposition of 1h. Under the
current conditions 2h was formed in 94% yield
(entry 8). Benzyl and 4-biphenylbenzyl substrates
were also well tolerated under the reaction conditions
(entries 9 and 10). As anticipated, chiral subtrate 1k
showed no racemization and provided 2k in excellent
96% yield (entry 11). Another important improve-
ment was the greater propensity for electron-deficient
benzyl groups to participate in the reaction. Com-
pound 1l bearing inductively withdrawing methoxy
groups provided 2l in 71% yield (97% conversion
1
with a trace of dechlorination observed by H NMR
of the crude reaction mixture) (entry 12).
Pyridine 1m bearing a trifluoromethyl group afford-
ed 95% yield of 2m (entry 13). In addition, meta-ni-
trobenzyl 1n and para-cyano 1o gave 2n and 2o in
1
57% (65% conversion by H NMR) and 70% (90%
conversion by 1H NMR) yields, respectively (en-
tries 14 and 15). Nitro groups previously proved detri-
mental to the reaction and substantial decomposition
of the starting material and extremely poor yields
were observed for 2n. Under the current conditions,
decomposition of the starting material was not ob-
served by 1H NMR in the crude reaction mixture.
Aryl subsituents continue to perform well, with 1p
giving a 94% yield of 2p (entry 16). N-Alkyl sub-
strates were again well tolerated. Substrate 1q and 1r
with the sterically encumbered cyclohexylmethyl and
cyclohexyl gave 2q and 2r in 77% and 63% yields, re-
spectively (entries 17 and 18). Pyridines 1s and 1t
bearing cyclopentyl (Cyp) and isopropyl moieties af-
forded 2s in 85% and 2t in 91% yield (entries 19 and
20).
[a]
Reaction conditions: 1–6 (0.4 mmol), Pd2ACTHNUTRGNEG(NU dba)3·CHCl3
(0.004 mmol, 1 mol%), Xantphos (0.02 mmol, 5 mol%),
amide (0.6 mmol), K3PO4 (0.6 mmol), solvent (0.2M),
1108C. All yields are isolated.
[b]
Amide used as limiting reagent.
the success of this approach. These conditions allowed
One of the goals of this endeavor was to broaden the efficient coupling of chlorinated benzyl deriva-
the scope of amide coupling partners. Previously, only tives, and substrates with electron-poor benzyl func-
benzamide and acetamide were utilized to afford IPb tionality including nitro and cyano groups. Addition-
7 in 65% and 8 60% yield, respectively (Table 4). Sig- ally, we were able to expand the scope of the amide
nificantly improved 78% yield of 7 and 83% yield of coupling partner granting access to a wider selection
8 were obtained in this study. Previously, no reaction of C-2 substituted imidazoACTHNUTRGNE[NUG 4,5-b]pyridines. We are
or incomplete conversion was observed with cyclohex- currently working to expand this methodology to re-
anecarboxamide and trans-cinnamamide. Here, yields gioselectively couple multi-chlorinated aminopyri-
of 96% for 9 and 79% for 10 were achieved. Addi- dines, as well as exploring the mechanism of the for-
tionally, 2-furanamide also performed well giving 11 mamide-mediated reduction of chloropyridines.
in 97% yield. Substitution at the four position of the
pyridine was well tolerated providing substituted IPb
12 in 70% yield albeit with extended reaction time
Experimental Section
(24 h). In agreement with our previous report, pyra-
zines performed exceedingly well giving 13 in 83%
and 14 in 95% yield; with reduced reaction times
(1 h).
Typical Procedure for the Palladium-Catalyzed
Amide Coupling and Dehydration of 3-Amino-2-
chloropyridines: Synthesis of Imidazo
2a
ACHTUNGTREN[NGNU 4,5-b]pyridine
In summary, we have developed an improved pro-
tocol for the synthesis of imidazo
imidazo[4,5-b]pyrazines. A palladium-catalyzed ami-
dation procedure using readily available XantPhos as
a ligand in a binary solvent system proved crucial to 0.004 mmol), XantPhos (11.6 mg, 0.02 mmol), K3PO4
ACHTUNGTREN[NUNG 4,5-b]pyridines and
ACHTUNGTRENNUNG
To an oven-dried 25-mL Schlenk tube equipped with a mag-
netic stir bar were added Pd2A(dba)3·CHCl3 (4.1 mg,
CTHUNGTRENNUNG
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UPDATES
An Improved Synthesis of ImidazoACTHNUTRGENNU[G 4,5-b]pyridines and ImidazoACHTUTGNREN[NUGN 4,5-b]pyrazines
(128 mg, 0.6 mmol) and the chloropyridine 1a (100 mg,
0.4 mmol). The reaction vessel was evacuated and refilled
with argon gas. 1,4-Dioxane and t-AmOH (10:1, 2 mL) were
then added via syringe followed by formamide (24 mL,
0.6 mmol) and the reaction mixture was degassed by three
vacuum/argon(g) purge cycles. The reaction vessel was then
equipped with a cold-finger condenser and immersed in
a pre-heated (1108C) oil-bath and the content stirred for
6 h. Upon consumption of the pyridine (as judged by TLC
analysis) the reaction mixture was allowed to cool to room
temperature, diluted with methanol (10 mL), and passed
through a Celiteꢁ plug, rinsing with additional methanol.
The crude mixture was concentrated under vacuum and ap-
plied to a silica gel column, eluting with 3% MeOH in
CH2Cl2 to afford product 2a as an off-white solid; yield:
89 mg (93%).
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Acknowledgements
We thank Syracuse University for generous financial support
of this research. We thank the Chisholm and Totah research
groups for sharing of chemicals, use of instrumentation, and
helpful discussions.
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