Copper-catalyzed aerobic intramolecular carbo- and amino-oxygenation of alkynes for synthesis of azaheterocycles

Article abstract of DOI:10.1021/ol3007106

A synthetic method of highly substituted quinolines has been developed from N-(2-alkynylaryl)enamine carboxylates under Cu-catalyzed aerobic conditions via intramolecular carbo-oxygenation of alkynes. This strategy was further applied for N-alkynylamidine

Full text of DOI:10.1021/ol3007106

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2290–2292
Copper-Catalyzed Aerobic Intramolecular
Carbo- and Amino-Oxygenation of
Alkynes for Synthesis of Azaheterocycles
Kah Kah Toh, Stephen Sanjaya, Sophian Sahnoun, Sin Yee Chong, and
Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received March 21, 2012
ABSTRACT
A synthetic method of highly substituted quinolines has been developed from N-(2-alkynylaryl)enamine carboxylates under Cu-catalyzed aerobic
conditions via intramolecular carbo-oxygenation of alkynes. This strategy was further applied for N-alkynylamidines for amino-oxygenation of
alkynes, leading to imidazole and quinazoline derivatives.
Aromatic azaheterocycles are an omnipresent com-
ponent of numerous natural alkaloids and potent
pharmaceutical drugs.1 While diverse synthetic ap-
proaches toward azaheterocycles have been exploited,2
there remains a demand of conceptually novel and
versatile methodologies for chemical synthesis of aro-
matic azaheterocycles from readily available building
blocks.
aerobic conditions using enamine carboxylates,3 N-H
imines,4 and amidines5to construct azaheterocyclic frame-
works (Scheme 1).6 In this context, we became interested in
oxidative functionalizationofcarbonÀcarbontriplebonds
(alkyne)7 under copper-catalyzed aerobic reaction condi-
tions. As shown in Scheme 2, a sequence of intramolecular
carbo(or amino)-cupration8 of alkynes followed by oxy-
genative carbonylation could be envisioned to occur in an
We have studied copper-mediated oxidative functiona-
lization of carbonÀcarbon unsaturated bonds under
(5) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
3679.
(6) For recent reviews on copper-catalyzed aerobic oxidative trans-
formation, see: (a) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, in
press (DOI: 10.1039/c2cs15323h). (b) Shi, Z.; Zhang, C.; Tang, C.; Jiao,
N. Chem. Soc. Rev. 2012, 41, 3381. (c) Wendlandt, A. E.; Suess, A. M.;
Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
(1) For recent reviews, see: (a) Thomas, G. L.; Johannes, C. W. Curr.
Opin. Chem. Biol. 2011, 15, 516. (b) Tohme, R.; Darwiche, N.; Gali-
Muhtasib, H. Molecules 2011, 16, 9665. (c) Dandapani, S.; Marcaurelle,
L. A. Curr. Opin. Chem. Biol. 2010, 14, 362. (d) Welsch, M. E.; Snyder,
S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347. (e) Carey,
J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem.
2006, 4, 2337.
(7) For recent reviews on transition-metal-catalzyed functionaliza-
tion of alkynes, see: (a) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50,
€
7226. (b) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358. (c) Furstner, A.
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-
Blackwell: 2010. (b) Progress in Heterocyclic Chemistry; Gribble, G. W.,
Joule, J. A., Eds.; Elsevier: Oxford, 2008; Vol. 20 and others in this series.
(c) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon: Oxford, 2008. (d)
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. A.,
Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon: Oxford, 1996. (e) Eicher,
T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-VCH: Weinheim,
2003.
Chem. Soc. Rev. 2009, 38, 3208. (d) Kirsch, S. F. Synthesis 2008, 3183. (e)
Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917. (f) Li, Z.; Brouwer, C.;
He, C. Chem. Rev. 2008, 108, 3239. (g) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Rev. 2008, 108, 3326. (h) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395. (i) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (j)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
ꢀ
ꢀ~
(8) For a review on addition of metal enolates to carbonÀcarbon
ꢀ ꢁ
unsaturated bonds (carbometallation), see: Denes, F.; Perez-Luna, A.;
ꢀ
Chemla, F. Chem. Rev. 2010, 110, 2366.
(3) Toh, K. K.; Wang, Y.-F.; Ng, E. P. J; Chiba, S. J. Am. Chem. Soc.
2011, 133, 13942.
(4) (a) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12, 3682.
(b) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010, 132, 7266.
(9) As a prelminary result, we have found that the reactions of
N-propargyl enamine carboxylates provided 4-benzoylpyrroles via carbo-
oxygenation of alkynes under copper-catalyzed aerobic conditions; see
ref 3h.
r
10.1021/ol3007106
Published on Web 04/10/2012
2012 American Chemical Society

unprecedented mode of oxo functionalization of alkynes,
resulting in various acylated cyclic compounds.9,10 Herein,
we report copper-catalyzed aerobic synthesis of aza-aro-
matic heterocycles such as quinolines, imidazoles, and
quinazolines from N-(2-alkynylaryl)enamine carboxylates
and N-alkynylamidines.
CuBr•SMe2 (entries 2À4). The highest yield of 2a was
achieved using 1,10-phenanthroline (1,10-phen) (entry 4).
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Cu-Catalyzed Aerobic Functionalization of Alkenes
and Benzene Rings
Cu salts
[mol %]
ligands
[mol %]
time yield
entry
additive
[h]
[%]b
c
1
CuBr•SMe2 (20)
À
K2CO3
0.3
1
57
2
CuBr•SMe2 (20) DABCO (20)
CuBr•SMe2 (20) DMAP (20)
CuBr•SMe2 (20) 1,10-phen (20)
CuBr•SMe2 (10) 1,10-phen (20)
À
À
À
À
(60)
(55)
(62)
(76)
83
3
2
4
0.5
2
5
6
CuBr•SMe2 (10) 1,10-phen (30) MS 4 Ad 1.5
7e
8
CuBr•SMe2 (10) 1,10-phen (30) MS 4 Ad 4.5
83
CuBr2 (10)
Cu(OAc)2 (10)
FeCl3 (10)
1,10-phen (30) MS 4 Ad 1.5
1,10-phen (30) MS 4 Ad 24
1,10-phen (30) MS 4 Ad 24
1,10-phen (30) MS 4 Ad 24
1,10-phen (30) MS 4 Ad 24
(70)
(60)
0
9
10
11
12
CoBr2 (10)
Pd(OAc)2 (5)
(26)
0
a The reactions were carried out using 0.3 mmol of enamine 1a in
DMF at 60 °C under an O2 atmosphere. b Isolated yields are recorded.
NMR yields were shownin parentheses. c 1.1 equiv of K2CO3 was added.
d 100 wt % with 1a. e The reaction was conducted under an air atmo-
sphere. DABCO = 1,4-diazabicyclo[2.2.2]octane; DMAP = N,N-di-
methyl-4-aminopyridine; 1,10-phen = 1,10-phenanthroline.
Scheme 2. Cu-Catalyzed Aerobic Oxo Functionalization of
Alkynes (This Work)
The catalytic loading of CuBr•SMe2 could be reduced to
10 mol % (entries 5 and 6), and quinoline 2a was obtained
in 83% yield with 30 mol % of 1,10-phen (entry 6), where
addition of molecular sieves 4 A (MS 4 A) made the
reaction more reproducible in terms of the reaction rate.13
Using 18O2 as an atmosphere, incorporation of the oxygen
atom from O2 wasobservedintheresultingcarbonylgroup
of 2a-18O (see Supporting Information for details). Re-
duction of the oxygen partial pressure under an air atmo-
sphere (0.21 atm of O2) did not affect the product yield of
2a, while the reaction rate became slightly longer (entry 7).
It is noted that the reaction under a N2 atmosphere did not
give any cyclized product at all, which suggested that the
presence of molecular oxygen might be indispensable for
initial CÀC bond forming cyclization.14 Copper(II) species
also showed the catalytic reactivity toward the present
quinoline formation (entries 8 and 9). It is noted that other
metals such as Fe(III), Co(II), and Pd(II) were not viable
for this transformation (entries 10À12).
Our study was commenced with the reactions of N-(2-
alkynylaryl)enamine carboxylate 1a under copper-cata-
lyzed aerobic conditions (Table 1). When 1a was treated
with 20 mol % of CuBr•SMe2 in the presence of K2CO3 in
DMF at 60 °C under an O2 atmosphere, an intramolecular
carbo-oxygenation11 product, 4-benzoylquinoline 2a was
isolated in 57% yield (entry 1).12 The yield of product 2a
was improved by the addition of nitrogen bases/ligands to
(10) Li recently reported copper-catalyzed aerobic carbo-oxygena-
tion of alkynes of 1,6-enynes to synthesize 1,4-naphthoquinones; see:
Wang, Z.-Q.; Zhang, W.-W.; Gong, L.-B.; Tang, R.-Y.; Yang, X.-H.;
Liu, Y.; Li, J.-H. Angew. Chem., Int. Ed. 2011, 50, 8968.
(11) For recent selected reports on carbo-oxygenation of alkynes
using other oxygen sources, see: (a) Gronnier, C.; Kramer, S.;
Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2012, 134, 828. (b) Qian,
D.; Zhang, J. Chem. Commun. 2011, 47, 11152. (c) Hachiya, H.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 3076. (d) Li, C.-W.; Pati,
K.; Lin, G.-Y.; Hung, H.-H.; Liu, R.-S. Angew. Chem., Int. Ed. 2010, 49,
9891. (e) Yeom, H.; Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J.; Lee, S.;
Shin, S. Angew. Chem., Int. Ed. 2010, 49, 1611. (f) Cui, L.; Peng, Y.;
Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394. (g) Cui, L.; Zhang, G.;
Peng, Y.; Zhang, L. Org. Lett. 2009, 11, 1225. (h) Shapiro, N. D.; Toste,
F. D. J. Am. Chem. Soc. 2007, 129, 4160. (i) Zhang, D.; Ready, J. M. Org.
Lett. 2005, 7, 5681.
(13) Addition of 2 equiv of H2O rendered the reaction of 1a (using
10 mol % CuBr•SMe2 and 30 mol % 1,10-phen) slow, giving quinoline
2a in 85% yield after 24 h.
(12) The structure of 2a was secured by X-ray crystallographic
analysis (CCDC-872056); see Supporting Information.
(14) A proposed reaction mechanism is discussed in the Supporting
Information.
Org. Lett., Vol. 14, No. 9, 2012
2291

Scheme 3. Substrate Scope for Synthesis of Quinolinesa,b
Table 2. Cu-Catalzyed Aerobic Reactions of
N-Alkynylamidinesa
a Reactions were carried out using 0.3À0.6 mmol of enamines 1 with
CuB•SMe2 (10 mol %) and 1,10-phenanthroline (30 mol %) in the
presence of MS 4 A (100 wt %) at 60 °C under an O2 atmosphere.
c
bIsolated yields are recorded. The yield was obtained from the corre-
sponding aryl iodide via Pd-catalyzed Sonogashira coupling followed by
the present Cu-catalyzed aerobic quinoline formation; see Supporting
Information for more details.
a The reactions were carried out using 0.5À0.6 mmol of amidines 3
with Cu(OAc)2 (10 mol %) and 1,10-phenanthroline (10 mol %) at 80 °C
under an O2 atmosphere. b Isolated yields are recorded.
With the optimized conditions in hand, we next exam-
ined the substrate scope for the synthesis of highly sub-
stituted quinolines (Scheme 3). By varying substituents R1
of enamines 1, it was shown that both electron-rich and -
deficient benzene rings could be introduced, and a bromine
substituent was tolerated while keeping the CÀBr bond
intact (for 2bÀ2f). Several alkyl groups (for 2gÀ2i) aswellasa
methoxycarbonyl group (for 2j, 2k) were all installed in good
yields. At the C(6)-position of quinoline frameworks, halogen
atoms as well as a cyano group could be introduced (for
2lÀ2o). As for R3 on the alkyne moiety, several substituted
benzenes could be used (for 2pÀ2r), while no cyclization was
observed when substituents R3 were alkyl groups.
Stimulated by the structural analogy of amidines with
enamine carboxylates, amino-oxygenation of alkynes15
could be envisioned to occur by Cu-catalyzed aerobic
reactions of N-alkynylamidines (Table 2). As expected,
the aerobic reactions of N-benzyl-N-propargylamidine
3a with 10 mol % of Cu(OAc)2 and 10 mol % of 1,10-
phenanthroline in DMF at 80 °C provided 4-benzoylimi-
dazole 4a in good yield (entry 1).16 This amino-oxygena-
tion showed an interesting chemoselectivity in the reaction
of N-allyl-N-propargylamidine 3c (entry 3). The cycliza-
tion exclusively selected the alkyne tether to afford
N-allyl-4-benzoylimidazoles 4c. Moreover, 4-benzoylqui-
nazoline 4d could be synthesized in good yield from
N-(2-alkynylphenyl)amidine 3d (entry 4).17
In summary, we have developed Cu-catalyzed aerobic oxo-
functionalization of alkynes that could deliver a variety of aza-
aromatic heterocycles. Further investigation for the scope,
detailed mechanisms, and synthetic applications of the present
strategy to other azaheterocycles is currently underway.
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education. We thank Dr. Yongxin Li and Dr.
Rakesh Ganguly (Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University) for assistance in
X-ray crystallographic analysis.
(15) For recent selected reports on amino-oxygenation of alkynes
using other oxygen sources, see: (a) Mukherjee, A.; Dateer, R. B.;
Chaudhuri, R.; Bhunia, S.; Narayan Karad, S.; Liu, R.-S. J. Am. Chem.
Soc. 2011, 133, 15372. (b) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc.
2011, 133, 8482. (c) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed.
2011, 50, 3236. (d) Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13,
2395. (e) Yeom, H.-S.; So, E.; Shin, S. Chem.;Eur. J. 2011, 17, 1764.
(16) The reaction of 3a with CuB•SMe2 (10 mol%) and 1,10-phenan-
throline (30 mol %) at 60 °C under an O2 atmosphere for 4 h provided 4a
in 46% yield.
(17) Zhang and Zhu reported copper-catalyzed aerobic reactions of
N-allyl amidines, that afforded formylimidazoles via carbo-oxygenation
of the alkene; see: Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.;
Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678.
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
2292
Org. Lett., Vol. 14, No. 9, 2012