Copper(II)/iron(III) co-catalyzed intermolecular diamination of alkynes: Facile synthesis of imidazopyridines

Article abstract of DOI:10.1021/ol301858j

A facile synthesis of imidazo[1,2-α]pyridines has been achieved by copper(II) and iron(III) co-catalyzed C-N bond formation. This reaction involves an intermolecular oxidative diamination of alkynes with high chemoselectivity and regioselectivity.

Full text of DOI:10.1021/ol301858j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper(II)/Iron(III) Co-catalyzed
Intermolecular Diamination of Alkynes:
Facile Synthesis of Imidazopyridines
Jing Zeng, Yu Jia Tan, Min Li Leow, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
xuewei@ntu.edu.sg
Received July 6, 2012
ABSTRACT
A facile synthesis of imidazo[1,2-R]pyridines has been achieved by copper(II) and iron(III) co-catalyzed CꢀN bond formation. This reaction
involves an intermolecular oxidative diamination of alkynes with high chemoselectivity and regioselectivity.
The imidazo[1,2-R]pyridine skeleton is a privileged
structure widely found in many pharmacologically impor-
tant compounds.1 Accompanied by an extensive range of
bioactivitiessuchasantiviral, antibacterial, fungicidal, and
anti-inflammatory properties,2 the significance of the
imidazo[1,2-R]pyridine scaffold in the drug discovery sec-
tor is well appreciated. Because of such appealing benefits,
many commercially available drugs featuring this scaffold
have been developed. Common imidazo[1,2-R]pyridine-
derived drugs (Figure 1) include alpidem3 and zolpidem,4
which are used to treat anxiety and insomnia, necopidem
and saripidem,5 which possess sedative and anxiolytic
effects, and the optically active GSK812397, which is a
candidate for the treatment of HIV infection.6 The ubiqui-
tous emergence of such compounds in the pharmaceutical
Figure 1. Imidazo[1,2-R]pyridine-based drugs.
industry signals huge potential for molecules of this class,
resulting in an ever-growing interest in the synthesis of
imidazo[1,2-R]pyridines.
Although various synthetic methods have been developed
to prepare imidazo[1,2-R]pyridine heterocyclic scaffolds,7
the utility of these methods is often limited by the numerous
steps required to obtain the precursors and their narrow
(1) Couty, F.; Evano, G. In Comprehensive Heterocyclic Chemistry
III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;
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(2) Albrecht, L.; Albrecht, A.; Ransborg, L. K.; Jorgensen, K. A.
Chem. Sci 2011, 2, 1273–1277 and references therein.
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Vadrot, N.; Feldmann, G.; Berthon, B.; Tordjmann, T.; Pessayre, D.
J. Pharmacol. Exp. Ther. 2001, 299, 793–800. (b) Saletu, J.; Grunberger,
B.; Linzmayer, L. Int. Clin. Psychopharmacol. 1986, 1, 145–164.
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(5) (a) Boerner, R. J.; Moller, H. J. Psychopharmakotherapie 1997, 4,
145–148. (b) Sanger, D. J. Behav. Pharmacol. 1995, 6, 116–126.
(6) Gudmundsson, K.; Boggs, S. D. PCT Int. Appl. WO 2006026703,
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(7) For select recent examples, see: (a) Ma, L.; Wang, X.; Yu, W.;
Han, B. Chem. Commun. 2011, 47, 11333–11335. (b) Wang, X. P.; Ma,
L. J.; Yu, W. Synthesis 2011, 2445–2453. (c) Husinec, S.; Markovic, R.;
Petkovic, M.; Nasufovic, V.; Savic, V. Org. Lett. 2011, 13, 2286–2289.
(d) Chunavala, K. C.; Joshi, G.; Suresh, E.; Adimurthy, S. Synthesis
2011, 1319–1319. (e) Wen, L. R.; Jiang, C. Y.; Li, M.; Wang, L. J.
Tetrahedron 2011, 67, 293–302. (f) Sucunza, D.; Samadi, A.; Chioua, M.;
Silva, D. B.; Yunta, C.; Infantes, L.; Carreiras, M. C.; Soriano, E.;
Marco-Contelles, J. Chem. Commun. 2011, 47, 5043–5045.
r
10.1021/ol301858j
XXXX American Chemical Society

Table 1. Optimization of Oxidative Diamination Reactiona
additive
(equiv)
yieldb
entry
catalyst (equiv)
(%)
1
Pd(OAc)2 (0.1), Cu(OAc)2 (0.2)
Pd(OAc)2 (0.1), Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2), PivOH (2)
Cu(OAc)2 (0.5), PivOH (2)
K2CO3 (2)
PivOH (2)
2
21
20
30
49
31
32
34
3
Figure 2. Intra- and intermolecular diamination of alkenes and
alkynes.
4
5
Cu(OAc)2 (0.1), FePO4 4H2O (0.1)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
PivOH (2)
3
6
Cu(acac)2 (0.1), FePO4 4H2O (0.1)
3
7
Cu(nd)2 (0.1), FePO4 4H2O (0.1)
3
substrate scope. Recently, several elegant methods have
been reported for the synthesis of imidazo[1,2-R]pyridines,
including a copper-catalyzed three-component coupl-
ing reaction,8 copper-catalyzed intramolecular CꢀH
amination,9 dehydrogenative amino oxygenation,10 asym-
metric organocatalytic [3 þ 2]-annulation,2 etc. The dearth
of methods means that the continuation of research in this
area is imperative.
Oxidative olefin diamination is rapidly becoming an
active area of research. It provides a powerful entry to
vicinal diamines which exhibit wide utilities in drug dis-
covery, materials, and catalysis.11 To date, olefin diamina-
tion has been largely explored using stoichiometric or
catalytic amounts of palladium,12 nickel,13 gold,14 and
copper15 in an intra- or intermolecular manner (Figure 2,
eq 1).16 However, reports about the intermolecular
8
Cu(TFA)2 (0.1), FePO4 4H2O (0.1)
3
9
CuCl2 (0.1), FePO4 4H2O (0.1)
3
10
11c
12d
13e
14f
15f
16f
17f
18f
CuBr (0.1), FePO4 4H2O (0.1)
3
Cu(OAc)2 (0.1), FePO4 4H2O (0.1)
55
41
67
72
68
54
55
3
Cu(OAc)2 (0.1), FePO4 4H2O (0.1)
3
Cu(OAc)2 (0.1), FePO4 4H2O (0.1)
3
Cu(OAc)2 (0.1), FePO4 4H2O (0.1)
3
Cu(OAc)2 (0.1), Fe(acac)3 (0.1)
Cu(OAc)2 (0.1), Fe(OAc)2 (0.1)
Cu(OAc)2 (0.2)
FePO4 4H2O (0.5)
3
a Unless otherwise specified, all reactions were carried out using 1a
(0.2 mmol, 1 equiv) and 2a (0.3 mmol, 1.5 equiv) with catalyst and
additive in DMF (2 mL) at 110 °C under O2 atmosphere for 24 h.
b Isolated yields of 4a. c Reaction was carried out in DMF and DMSO
(10:1, 2 mL). d Reaction was carried out in DMSO (2 mL). e Reaction
was carried out using 2a (0.2 mmol, 1 equiv), 1a (0.3 mmol, 1.5 equiv) in
DMF, and DMSO (10:1, 2 mL) at 110 °C under O2 atmosphere. f Reaction
was carried out using 2a (0.2 mmol, 1 equiv), 1a (0.3 mmol, 1.5 equiv) in
DMF, and DMSO (10:1, 2 mL) at 130 °C under air. Cu(acac)2
=
(8) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2743–2746.
copper(II) acetylacetonate; Cu(nd)2 = copper(II) neodecanoate; PivOH =
pivalic acid; Cu(TFA)2 = copper(II) trifluoroacetate.
(9) Wang, H. G.; Wang, Y.; Peng, C. L.; Zhang, J. C.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217–13219.
(10) Wang, H. G.; Wang, Y.; Liang, D. D.; Liu, L. Y.; Zhang, J. C.;
diamination of alkynes remain surprisingly limited.17 In
continuation of our interest in the development of novel
methodology for the synthesis of heterocyclic compounds,18
we envisaged that intermolecular diamination of internal
alkynes with 2-aminopyridines might provide a versatile
and an efficient way to synthesize imidazo[1,2-R]pyridines
(Figure 2, eq 2). The successful implementation of this
strategy would imply developing a novel route that bypasses
the difficulties associated with previous methods, providing
an alternative route to imidazopyridines.
We commenced our study by investigating the reaction of
2-aminopyridine 1a (1.0 equiv) with ethyl phenylpropiolate
2a (1.5 equiv) in the presence of Pd(OAc)2 (0.1 equiv) and
Cu(OAc)2 (0.2 equiv) in DMF at 110 °C under O2 atmo-
sphere (Table 1, entry 1). Unfortunately, the reaction did
not proceed under basic conditions, but when PivOH was
Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678–5681.
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2009, 48, 1190–1193. (b) Cardona, F.; Goti, A. Nature Chem. 2009, 1,
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Angew. Chem., Int. Ed. 2010, 49, 8109–8111. (b) Zhao, B. G.; Du, H. F.;
Cui, S. L.; Shi, Y. A. J. Am. Chem. Soc. 2010, 132, 3523–3532.
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(d) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E.
J. Am. Chem. Soc. 2009, 131, 15945–15951. (e) Muniz, K.; Hovelmann,
C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763–773. For intramo-
lecular diamination of alkynes: (f) Yao, B.; Wang, Q.; Zhu, J. Angew.
Chem., Int. Ed. 2012, 51, 5170–5174.
~
€
ꢀ~
(13) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
Chem., Int. Ed. 2007, 46, 7125–7127.
(14) Iglesias, A.; Muniz, K. Chem.;Eur. J. 2009, 15, 10563–10569.
(15) For recent examples, see: (a) Cornwall, R. G.; Zhao, B. G.; Shi,
Y. A. Org. Lett. 2011, 13, 434–437. (b) Sequeira, F. C.; Turnpenny,
B. W.; Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49, 6365–6368.
(c) Zhao, B. G.; Peng, X. G.; Cui, S. L.; Shi, Y. A. J. Am. Chem. Soc.
2010, 132, 11009–11011. (d) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am.
Chem. Soc. 2012, 134, 3679–3682.
(17) (a) Wang, W.; Shen, Y.; Meng, X.; Zhao, M.; Chen, Y.; Chen, B.
Org. Lett. 2011, 13, 4514–4517. (b) Fukudome, Y.; Naito, H.; Hata, T.;
Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820–1821.
(16) For metal-free diamination of alkenes, see: (a) Farid, U.; Wirth,
€
T. Angew. Chem., Int. Ed. 2012, 51, 3462–3465. (b) Roben, C.; Souto,
ꢀ
~
J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz, K. Angew. Chem., Int. Ed.
2011, 50, 9478–9482. (c) Li, H.; Widenhoefer, R. A. Tetrahedron 2010,
66, 4827–4831. (d) Lishchynskyi, A.; Muniz, K. Chem.;Eur. J. 2012, 18,
2212–2216. (e) Chavez, P.; Kirsch, J.; Hovelmann, C. H.; Streuff, J.;
Martinez-Belmonte, M.; Escudero-Adan, E. C.; Martin, E.; Muniz, K.
Chem. Sci. 2012, 3, 2375–2382.
(18) (a) Cai, S.; Xiang, S. H.; Zeng, J.; Gorityala, B. K.; Liu, X.-W.
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J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2011, 13, 1072–1075. (c) Zeng, J.;
Bai, Y.; Cai, S.; Ma, J.; Liu, X.-W. Chem. Commun. 2011, 47, 12855–
12857.
~
B
Org. Lett., Vol. XX, No. XX, XXXX

used as an additive instead of K2CO3 (Table 1, entry 2), the
desired product 3 was obtained in 21% yield (see the
Supporting Information). Interestingly, with only Cu-
(OAc)2 as catalyst, the reaction still proceeded to afford
the desired product, and 0.5 equiv of Cu(OAc)2 was able to
achieve a higher yield as compared to 0.2 equiv (Table 1,
entries 3 and 4). Recent reports on copper/iron co-
catalyzed CꢀH activation and CꢀH amination10,19
prompted us to employ iron in this reaction system. To our
reaction with acetyl-protected substrates gave the desired
product in 28% yield, along with recovered starting mate-
rial, whereas for Boc- or COOEt-protected aminopyri-
dines, better yields were observed as compared to other
protecting groups, but yields were still lower than 50%.
Consolidating the observations on the optimization stud-
ies, we concluded that the best yields was obtained when
the reaction was conducted with 1.5 equiva of unprotected
2-aminopyridine, 1 equiv of alkyne, 0.1 equiv of Cu(OAc)2
delight, the combination of Cu(OAc)2 and FePO4 4H2O
and FePO4 4H2O, and 2 equiv of PivOH in DMF and
DMSO (10:1) at 130 °C under an air atmosphere.
3
3
increased the yield to 49% (Table 1, entry 5). Among the
tested copper salts, Cu(acac)2 and Cu(nd)2 produced lower
yields, while Cu(TFA)2, despite shortening the reaction
time, decreased the yield because of an increased amount
of byproduct (Table 1, entries 6ꢀ8). In addition, copper
halogenides such as CuCl2 and CuBr were found to be
totally inefficient (Table 1, entries 9 and 10). In the in-
vestigation of solvents, we utilized a 10:1 mixture of DMF
and DMSO as solvent to further increase the yield to 55%
(Table 1, entry 11). Interestingly, DMSO alone did not
promotethe reaction(Table1, entry 12). Whenexcessof1a
was added to the reaction mixture (Table 1, entry 13), the
yield of 3 was improved to 67%. The reaction temperature
was increased to 130 °C to further improve the yield to
72% (Table 1, entry 14). In this case, air could be used as
terminal oxidant. Further investigation on a number of
iron salts revealed that Fe(acac)3 gave a slightly lower yield
(Table 1, entry 15). The Fe(II) compound Fe(OAc)2 gave
lower yields even though it might be oxidized to Fe(III) in
the reaction system (Table 1, entry16).When the reaction
was carried out without iron(III) catalyst (Table 1, entry 17),
only 55% of product was obtained. However, a complex
mixture was observed and no desired product was isolated
when the reaction was carried out with only an iron(III)
catalyst (Table 1, entry 18).
The reactivity of N-protected aminopyridine was also
investigated using the optimized conditions above under
an O2 atmosphere (Table 2). It was observed that with
methyl- or tert-butyl-protected aminopyridine, no product
was formed. This could be due to the stabilizing and steric
effects of the protecting groups. On the other hand, the
Figure 3. Substrate scope of the diamination reaction.
With this optimized set of conditions in hand, we further
investigated the substrate scope (Figure 3). Good yields were
obtained when 2-aminopyridine was reacted with isopropyl
or benzyl phenylpropiolate (4 and 5). Smooth progress was
also observed for ynone affording 6 in a reasonable yield.
Ethyl phenylpropiolates substituted with electron-donating
groups proceeded well under the optimized reaction condi-
tions, and acceptable yields were observed (7ꢀ9). However,
the reaction with (3,5-bistrifluoromethyl)phenylpropiolate
gave the resulting product 10 in poor yield. Unfortunately,
the reaction with unactivated alkynes such as diphenylacety-
lene did not proceed to give the desired products under the
current reaction conditions.
Table 2. Optimization of Various N-Protected Aminopyridinesa
yieldb
yieldb
(%)
entry
R
(%) entry
R
1
2
3
1b, R = Me
4
1e, R = Boc
34
42
1c, R = tert-Butyl
1d, R = Ac
5
1f, R = COOEt
28
a Unless otherwise specified, all reactions were carried out using 1
(0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5 equiv), Cu(OAc)2 (0.02 mmol, 0.1
equiv.) and FeSO4•4H2O (0.02 mmol, 0.1 equiv) in DMF and DMSO
(10:1, 2 mL) at 130 °C under O2 for 24 h. b Isolated yields.
(19) Guan, Z. H.; Yan, Z. Y.; Ren, Z. H.; Liu, X. Y.; Liang, Y. M.
Chem. Commun. 2010, 46, 2823–2825. For reviews of Cu/Fe co-cata-
lyzed reactions, see: Su, Y. J.; Jia, W.; Jiao, N. Synthesis 2011, 1678–
1690.
Org. Lett., Vol. XX, No. XX, XXXX
C

2-Aminopyridines substituted at the 3-, 4-, and 5-
positions also underwent this oxidative cyclization reaction
to form the corresponding products (Figure 3). Notably,
the reactions with 3- and 5-methyl substrates (11, 13) gave
much higher yields thanthat of the 4-methyl substrate (12).
Conversely, even with higher temperature and longer
reaction times (140 °C, 48 h), 2-amino-6-methylpyridine
did not afford the expected product (14). This could be due
to the steric hindrance of the 6-methyl group. In addition,
electron-withdrawing groups exerted a negative effect on
the reactivity of 2-aminopyridine, as exemplified when
methoxy carboxylate was placed at the 4-position of
2-aminopyridine (16), which resulted in a lower yield.
Interestingly, when 1-amino-2-isoquinoline was reacted
with ethyl phenylpropiolate or ethyl (4-tertbutyl) phenyl-
propiolate, the reactions were able to produce the corre-
sponding products in good to excellent yields (17 and 18).
The reaction with ethyl (4-nitro)phenylpropiolate also
generated the desired product 19 in an acceptable yield.
Heterocyclic substituted propiolates performed very well,
affording the respective imidazo[1,2-a]isoquinoline in a
reasonable yield (20 and 21).
Although detailed experimental evidence is still pending,
a plausible mechanism for this reaction is outlined in
Scheme 1. It is suggested that copper will coordinate with
the endocyclic nitrogen atom of 2-aminopyridine as de-
picted in A.20 and cis-aminocupration21 will occur (might
through transition state C) to produce Cu(II) intermediate
D. Deprotonation would give intermediate E which can
further be oxidized to a reactive Cu(III) intermediate F.22
Reductive elimination then can take place to deliver the
product 4a,23 with concurrent formation of Cu(I). In the
Scheme 1. Proposed Reaction Mechanism
reaction system, Fe(III) is suggested to oxidize Cu(I) to
Cu(II). Finally, Fe(II) is oxidized to Fe(III) by O2 to close
the catalytic cycle.
In summary, we have documented, for the first time, a
Cu(II) and Fe(III) co-catalyzed diamination of 2-amino-
pyridines and 2-aminoisoquinolines with readily available
alkynes. The strategy allows for the direct synthesis of
imidazo[1,2-a]pyridines and imidazo[1,2-a]isoquinolines
in yields of up to 92%. These structures are ubiquitously
found in a large variety of compounds which possess
important pharmacological properties that are essential
to the biopharmaceutical and chemical sectors. Our dis-
covery provides simple, facile, and straightforward access
to an extensive array of compounds and synergizes the
well-explored intramolecular diamination of alkenes to
alkynes in an intermolecular manner. For aminopyridines
and aminoquinolines, the high levels of chemoselectivity
and regioselectivity of the two nitrogens were demon-
strated for a range of compounds, demonstrating the
flexibility and good reactivity of this strategy. Further
studies into the application of this unique and efficient
methodology to unactivated alkynes and investigations on
the mechanism are currently underway in our laboratory.
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Acknowledgment. We gratefully acknowledge the sup-
port by Nanyang Technological University (RG50/08)
and Ministry of Health, Singapore (NMRC/H1N1R/
001/2009). We thank Dr. Yong-Xin Li and Dr. Rakesh
Ganguly for X-ray analyses.
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(a) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 3694–
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Supporting Information Available. Experimental pro-
cedure, characterization of all of the products, and X-ray
data for compounds 3 and 17. This material is available
free of charge via the Internet at http://pubs.acs.org.
€
€
M. E.; Ciesielski, M.; Gorls, H.; Doring, M. Angew. Chem., Int. Ed.
2002, 41, 2962–2965.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX