Copper-catalyzed oxidative diamination of terminal alkynes by amidines: Synthesis of 1,2,4-trisubstituted imidazoles

Article abstract of DOI:10.1021/ol400560m

An efficient copper-catalyzed synthesis of 1,2,4-trisubstituted imidazoles using amidines and terminal alkynes has been developed. Overall, the oxidative process, which involves Na₂CO₃, pyridine, a catalytic amount of CuCl₂

Full text of DOI:10.1021/ol400560m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Oxidative Diamination
of Terminal Alkynes by Amidines:
Synthesis of 1,2,4-Trisubstituted
Imidazoles
Jihui Li and Luc Neuville*
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Laboratoire
ꢀ
International Associe, CNRS, 91198 Gif-sur-Yvette Cedex, France
luc.neuville@icsn.cnrs-gif.fr
Received February 28, 2013
ABSTRACT
An efficient copper-catalyzed synthesis of 1,2,4-trisubstituted imidazoles using amidines and terminal alkynes has been developed. Overall, the
oxidative process, which involves Na2CO3, pyridine, a catalytic amount of CuCl2 2H2O, and oxygen (1 atm), consisted of a regioselective
diamination of alkynes allowing the synthesis of diverse imidazoles in modest to good yields.
3
Metal promoted transformations involved in carbonꢀ
heteroatom bond formation hold a central place in organic
chemistry. This field has been especially productive allow-
ing the functionalization of a broad variety of nitrogen
nucleophiles through Pd- and Cu-catalyzed reactions.1 In
addition to single event (CꢀN bond formation), strategies
involving multiple bond formation have appeared in the
literature including strategies for the synthesis of useful
heterocycles.2 Diamination belongs to this area of research
and hasbeenactively pursued.3 While this strategy has been
essentially devoted to the functionalization of alkenes,
related reactions involving alkynes are limited.4
Amidines are important units found in various drugs
or natural products and play an important role as pre-
cursors for the synthesis of diverse heterocycles such as
benzimidazoles, quinazolines, imidazoles, or pyrimidines.5
Given the importance of N-arylated amidines, a number
of transition-metal-catalyzed N-arylative procedures have
been described.6 Among these, Cu-catalyzed oxidative
(1) For a recent review, see: (a) Beletskaya, I. P.; Cheprakov, A. V.
Organometallics 2012, 31, 7753–7808. For copper, see: (b) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (c)
Monnier, F.; Taillefer Angew. Chem., Int. Ed. 2009, 48, 6954–6971.
For reviews involving palladium, see: (d) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534–1544. (e) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2,
27–50. (f) Hickman, A. J.; Sanford, M. Nature 2012, 484, 177–185. For
general reviews, see: (g) Fischer, C.; Koenig, B. Beilstein J. Org. Chem.
2011, 7, 59–74. (h) Sadig, J. E. R.; Willis, M. C. Synthesis 2011, 43, 1–22.
(2) (a) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873–6894. (b)
Liu, T.; Fu, H. Synthesis 2012, 44, 2805–2824. (c) Ball, C. J.; Willis, M. C.
Eur. J. Org. Chem. 2013, 425–441.
(5) For recent examples: (a) Chao, B.; Lin, S.; Ma, Q.; Lu, D.; Hu, Y.
Org. Lett. 2012, 14, 2398–2401. (b) Yang, X.; Jin, Y.; Liu, H.; Jiang, Y.;
Fu, H. RSC Adv. 2012, 2, 11061–11066. (c) Xu, L.; Jiang, Y.; Ma, D.
Org. Lett. 2012, 14, 1150–1153. (d) McGowan, M. A.; McAvaoy, C. Z.;
Buchwald, S. L. Org. Lett. 2012, 14, 3800–3803. (e) Li, S.; Li, Z.; Yuan,
Y.; Li, Y.; Zhang, L.; Wu, Y. Chem.;Eur. J. 2013, 19, 1496–1501. (f) Li,
B.; Samp, L.; Sagal, J.; Hayward, C. M.; Yang, C.; Zhang, Z. J. Org.
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2463–2497. See also: (b) McGowan, M. A.; McAvoy, C. Z.; Buchwald,
S. L. Org. Lett. 2012, 14, 3800–3803 and references therein.
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1932–1934. (b) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen,
J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15, 7292–7296. (c) He,
H.-F.; Wang, Z.-J.; Bao, W. Adv. Synth. Catal. 2010, 352, 2905–2912. (d)
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Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008,
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Leow, M. L.; Liu, X.-W. Org. Lett. 2012, 14, 4386–4389.
r
10.1021/ol400560m
XXXX American Chemical Society

conditions have allowed direct CꢀH functionalization.7,8
N-Alkyl and N-alkenyl amidines were also recently shown
to be versatile units giving access to various azahetero-
cycles under aerobic oxidativeconditions, as demonstrated
by Chiba in a series of publications.9
Scheme 1. Cu-Catalyzed Aerobic Process Involving Amidines
We have been interested in tandem metal-catalyzed
transformation for the synthesis of a heterocyclic structure10
including strategies involving CꢀNandCꢀH bond functional-
ization.11 Recently, we became involved in the development of
Cu-catalyzed aerobic oxidative transformation to build a
CꢀN bond.12 In this context, we extended the ChanꢀLamꢀ
Evans reaction13 to the selective N-arylation of amidines and
the direct synthesis of benzimidazoles (Scheme 1A).14 Given
the proximity of imidazoles with such heterocycles and the
interest associated to their broad applications,15 we reasoned
that they could be prepared following a similar transform-
ation.16 Unfortunately, attempts to react amidines with
vinylboronic acid derivatives, instead of arylboronic acid,
under similar reaction conditions were unsuccessful.
could be formed according to a tandem sequence involving
a direct N-alkynylation followed by a cyclizative hydro-
amination (Scheme 1B).17 Support for the feasibility of the
N-alkynylation was based on the work of Sthal, describing
a Cu-catalyzed aerobic oxidative synthesis of N-alkynyl-
heterocycles and N-alkynylamides, recently extended to
the synthesis of yninines.18,19 In addition, Fujii and Ohno
demonstrated that N-arylated amidines could react with
1-triisopropylsilethynyl benziodoxolone under Cu-catalyzed
reaction conditions to afford quinazolines and that the
reaction could rely on the formation of an N-alkylynated
species.20
Herein, we report conditions that allow trisubstituted
imidazoles tobeformedfrom easilyavailable amidines and
terminal alkynes. The new Cu-catalyzed process used
oxygen as a co-oxidant and consisted of the regioselective
addition of two distinct N-atoms across the alkyne.
To explore the reactivity of amidines toward acetylenes,
we followed Stahl’s work.19a In that event, N-tolyl benzimi-
damide (1a) and ethynylbenzene 2a (2 equiv) were reacted in
As an alternative to the boronic acid residue, we thought
to use a terminal alkyne, reasoning that the imidazole
(8) For general reviews dealing with CꢀH functionalization, see: (a)
CꢀH activation. In Topics in Current Chemistry; Yu, J.-Q., Shi, Z., Eds.;
€
Springer, 2010; Vol. 292, pp 1ꢀ380. (b) Wencel-Delord, J.; Droge, T.; Liu,
F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (c) Cho, S.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. (d) Stokes,
B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 39, 4071–4088. (e)
Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960–9009. (f) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord,
J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236–10254.
(9) (a) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
3679–3679. (b) Toh, K. K.; Sanjaya, S.; Sahnoun, S.; Chong, S. Y.;
Chiba, S. Org. Lett. 2012, 14, 2290–2292. (c) Sanjaya, S.; Chua, H. S.;
Chiba, S. Synlett 2012, 23, 1657–1661. (d) Wang, Y.-F.; Chen, H.;
Chiba, S. J. Am. Chem. Soc. 2012, 134, 11980–11983. (e) Sanjaya, S.;
Chiba, S. Org. Lett. 2012, 14, 5342–5345. (f) Chen, H.; Sanjaya, S.;
Wang, Y.-F.; Chiba, S. Org. Lett. 2013, 15, 212–215.
(10) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.;Eur. J. 2007,
13, 961–967. (b) Salcedo, A.; Neuville, L.; Rondot, C.; Retailleau, P.;
Zhu, J. Org. Lett. 2008, 10, 857–860. (c) Jaegli, S.; Vors, J.-P.; Neuville,
L.; Zhu, J. Synlett 2009, 2997–2999. (d) Jaegli, S.; Vors, J.-P.; Neuville,
L.; Zhu, J. Tetrahedron 2010, 66, 8911–8921. Reaction involving CꢀH
functionalizations: (e) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org.
Lett. 2006, 8, 4927–4930. (f) Pinto, A.; Neuville, L.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 3291–3295. (g) Piou, T.; Neuville, L.; Zhu, J.
Org. Lett. 2012, 14, 3760–3763. (h) Piou, T.; Neuville, L.; Zhu, J. Angew.
Chem., Int. Ed. 2012, 51, 11561–11565.
(11) (a) Pinto, A.; Neuville, L.; Zhu, J. Tetrahedron Lett. 2009, 50,
3602–3605. (b) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 572–577. (c) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.;
Neuville, L.; Zhu, J. Chem.;Eur. J. 2010, 16, 5863–5867. (d) Jaegli, S.;
Dufour, J.; Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors, J.-P.; Neuville, L.;
Zhu, J. Org. Lett. 2010, 12, 4498–4501.
the presence of CuCl2 2H2O (20 mol %), pyridine (2 equiv),
3
and Na2CO2 (2 equiv) under oxygen (1 atm), with gentle
heating (70 °C) (Table 1, entries 1 and 2). Interestingly, we
found that the reaction furnished imidazole 4a as the major
compound and the oxidized quinazoline 7a as a minor
byproduct.
Based on this result, we undertook an optimization
study presented in Table 1.21 The following observations
weremadeduring these trials: Formationof quinazoline7a
could not be suppressed, but yields remained low whatever
the conditions (<13%). The formation of 1,4-diphenyl-
buta-1,3-diyne resulting from a GlaserꢀHay dimerization
(12) For reviews, see: (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S.
Angew. Chem., Int. Ed. 2011, 50, 11062–11087. (b) Campbell, A. N.;
Stahl, S. S. Acc. Chem. Res. 2012, 45, 851–863. (b) Shi, Z.; Zhang, C.;
Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381–3429.
(17) For reviews dealing with hydroamination, see: (a) Severin, R.;
€
Doye, S. Chem. Soc. Rev. 2007, 36, 1407–1420. (b) Muller, T. E.;
(13) For recent reviews, see: (a) Qiao, J. X.; Lam, P. Y. S. Synthesis
2011, 829–856. (b) Rao, K. S.; Wu, T.-S. Tetrahedon 2012, 68, 7735–
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3705–3892. Cu(II) promoted cyclization: (c) Hiroya, K.; Itoh, S.;
Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. (d) See reference 9b.
(18) For reviews, see: (a) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840–2859. (b) DeKorver, K. A.; Li, H.; Lohse,
A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064–5106. (c) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45,
17–26.
(19) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833–835. (b) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.;
Couty, F.; Evano, G. Org. Lett. 2012, 14, 6–9.
(20) Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett.
2010, 12, 3963–3965.
(21) See the Supporting Information for additional data.
ꢀ
7754. Our recent contribution: (c) Benard, S.; Neuville, L.; Zhu, J.
J. Org. Chem. 2008, 73, 6441–6444. (d) Benard, S.; Neuville, L.; Zhu, J.
Chem. Commun. 2010, 46, 3393–3395.
ꢀ
(14) Li, J.; Benard, S.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 5980–
5983.
(15) (a) Xi, N.; Huang, Q.; Liu, L. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 5, pp 143ꢀ364. (b) Pastor, I.;
Yus, M. Curr. Chem. Biol. 2009, 3, 385–408. (c) Bellina, F.; Cauterucio,
S.; Rossi, R. Tetrahedron 2007, 63, 4571–4624 and references cited
therein.
(16) For an alternative Cu-promoted aerobic synthesis of imidazoles,
see: Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2012, 14, 6068–6071.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Survey of Reaction Conditions
Scheme 2. Scope of Cu-Catalyzed Synthesis of Imidazoles:
N-Substituted Amidines
additive
(equiv)
addition time,
yield
(%)b
entry
temp (°C)
solvent
1
Na2CO3 (2)/pyridine (2)
0 h, 70
toluene 14 (5)
toluene 60 (9)
toluene 34 (13)
toluene 34 (11)
toluene 27 (6)
toluene 0 (0)
2
Na2CO3 (2)/pyridine (2)
10 h, 70
10 h, 100
10 h, 70
10 h, 70
10 h, rt
10 h, 70
10 h, 70
10 h, 70
10 h, 70
5 h, 70
3
Na2CO3 (2)/pyridine (2)
4c
5c
6
Na2CO3 (2)
pyridine (2)
ꢀ
7
ꢀ
toluene 60 (nd)
8
ꢀ
DCE
65 (9)
9
Na2CO3 (2)
dioxane 13 (nd)
10
11
12
13
14
15
Na2CO3 (2)/pyridine (2)
DMF
THF
0 (0)
0 (0)
ꢀ
ꢀ
10 h, 70
5 h, 70
DMSO 35 (8)
toluene 54 (11)
ꢀ
Ph3PO (0.2)
10 h, 70
10 h, 70
DCE
DCE
68 (nd)
71 (7)
Na2CO3 (2)/pyridine (2)
a CuCl2 2H2O (0.2 equiv), amidine (1.0 equiv) (C = 0.2 M), additive,
3
O2 (1 atm), 24 h; ethynylbenzene (2.0 equiv) (C = 0.2 M) was added
dropwise for the indicated time. b Isolated yield; yield in parentheses
refers to 7a; nd = not determined but present. c Under air.
process of the alkyne22 could be minimized by applying a
10 h slow addition of the acetylenide to the reaction
(Table 1, entries 1, 2, and 12). Solvents greatly influence
the reaction, which was best performed in toluene or
dichloroethane (DCE) (Table 1, entries 8 to 12). Gentle
heating (70 °C) was required to effect the desired transfor-
mation, but higher temperatures proved to be deleterious
(Table 1, entries 2, 3, and 6). Additive-free conditions
furnished good results (Table 1, entry 8) but, as noted
later, were not general.23 Among the additives/ligands that
were evaluated [tetramethylethylenediamine (TMEDA),
bipyridine (Bipy), triphenylphosphine oxide, tributylpho-
sphine, 1,2-bis(diphenylphosphine)ethane, N,N-diisopropy-
lethylamine, triethylamine, cesium carbonate, potassium
tert-butoxide], the combination of sodium carbonate and
pyridine provided the best outcome.21
1,4-diphenylbuta-1,3-diyne, but the reaction was successfully
extended to various N-substituted amidines (Scheme 2).
The reaction tolerated functional groups such as alkyl,
ether, ester, nitro, chloro, or bromo, and overall, the
expected 1,2,4-triarylimidazoles were obtained in modest
to good yields ranging between 39% and 74%. The
electronic nature of the residue found at either the C- or
N-position of N-arylated benzamidines did not substan-
tially impact the reaction outcome, as seen with the synth-
esis of 5f and 5g or 5l and 5m. The reaction was however
found to be sensitive to steric hindrance, even if imidazoles
5d and 5k could be obtained in useful yields. The reaction
was not limited to N-arylated benzamidines, as C- or
N-alkyl imidazoles 824 and 9 were isolated in reasonable
yields. Interestingly, in the case of N-methylbenzamide,
the chlorinated imidazole 10 was also isolated in 11%
yield.25
With suitable conditions in hand [CuCl2 2H2O(0.2equiv),
3
amidine (1.0 equiv) (C = 0.2 M in DCE), pyridine (2 equiv),
Na2CO3 (2 equiv), O2 (1 atm), 24 h; dropwise addition of
ethynylbenzene (2.0 equiv) (C = 0.2 M in DCE) over 10 h],
the scope of this new Cu-catalyzed reaction was examined.
Benzamidine itself was not compatible with the present
reaction, leading exclusively to the formation of
(22) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422–424. (b) Hay,
A. S. J. Org. Chem. 1962, 27, 3320–3321. (c) Siemsen, P.; Livingston,
R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632–2657.
(23) Amidines are known a ligand for copper: (a) Barker, J.; Kilner,
M. Coord. Chem. Rev. 1994, 133, 219–300. (b) Oakley, S. H.; Soria,
D. B.; Coles, M. P.; Hitchcock, P. B. Dalton Trans. 2004, 537–546.
(24) Because of the instability of N-phenylbutyrimidamide under the
conditions, addition and overall time were 4 and 6 h, respectively.
(25) When N-methylbenzamide was reacted with 1.1 equiv of
CuCl2 H2O under otherwise identical conditions, 9 and 10 were isolated
3
in 6% and 34% yields, respectively. For a related haloamination
process, see: Too, P. C.; Chiba, S. Chem. Commun. 2012, 48, 7634–7636.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of the Copper-Catalyzed Synthesis of
Imidazoles Using Various Terminal Alkynes
Scheme 4. Possible Mechanism
buta-1,3-diyne or chlorinated imidazole 10 possibly
deriving from complex A or D through the activation of
a second equivalent of alkyne or an oxidative process,25
respectively. Regioisomeric alkynylacetimidamides C0
could be involved in the formation of quinazoline 7
following an aerobic carbooxygenation.27
In summary, we have developed an efficient and regio-
selective access to 1,2,4-trisubstitued imidazoles from
terminal alkynes and amidines. The process, which used
copper as the catalyst and oxygen as the co-oxidant,
involves the selective addition of two distinct N-atoms
across the triple bond, making the process particularly
cheap and atom efficient. Further studies aimed at gaining
mechanistic insights, as well as expanding the process to
other heterocycles, are being pursued.
We finally evaluated the scope of the reaction with
respect to the alkyne coupling partner. As illustrated in
Scheme 3, the reaction was found to be compatible with
various terminal alkynes such as aryl, primary and tertiary
alkyl, cyclopropyl, and silyl-substitued alkynes. The elec-
tronic nature of the substituent of the alkyne had no
significant impact on the reaction, as both 1-ethynyl-4-
methoxybenzene and methyl propiolate provided the cor-
responding imidazoles 5q and 5r in comparable yields. The
reaction was however restricted to terminal alkynes, as,
with diphenylacetylene or ethyl 3-phenylpropiolate, no
reaction occurred.
A proposed catalytic cycle for the reaction is shown in
Scheme 4. The reaction would be initiated by a Cu-
promoted activation of the alkyne and the amidine to
deliver complex A. Oxidation of complex A, followed by
reductive elimination, would form the Cu-bounded alky-
nylacetimidamidesC.26 Complex C wouldnextundergo an
intramolecular 5-endo-dig-cyclization onto the activated
alkyne thereby forming, after deprotonation, imidazolyl-
copper(I) complex D. Finally, protonolysis would liberate
imidazole 5 and the reoxidation of the Cu(I) complex tothe
Cu(II) complex would close the catalytic cycle. The me-
chanism is consistent with the formation of 1,4-diphenyl-
Acknowledgment. Financial support from ICSN,
CNRS. J.L. thanks the Government of China for a
National Graduate Student Program of Building World-
Class Universities.
Supporting Information Available. Experimental proce-
dures, product characterization, and copies of the 1H and 13C
NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(27) N-(2-Alkynylphenyl)amidine could also be a precursor; see
refs 9b and 20.
(26) We were not able to identify intermediate 6. Even if internal
alkynes did not react, alternatives mechanisms, such as amino-cupra-
tion/CꢀN bond formation (ref 4c/4e) or [3 þ 2] annulation of a nitrene
(ref 9b), cannot be excluded.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX