Gold-Catalyzed Formal [3 + 2] Cycloaddition of Ynamides with 4,5-Dihydro-1,2,4-oxadiazoles: Synthesis of Functionalized 4-Aminoimidazoles

Article abstract of DOI:10.1021/acs.orglett.7b01469

A gold-catalyzed formal [3 + 2] cycloaddition of ynamides with 4,5-dihydro-1,2,4-oxadiazoles has been developed. The reaction provides a concise and regioselective access to highly functionalized 4-aminoimidazoles likely via the formation of an α-imino go

Full text of DOI:10.1021/acs.orglett.7b01469

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Formal [3 + 2] Cycloaddition of Ynamides with
4,5‑Dihydro-1,2,4-oxadiazoles: Synthesis of Functionalized
4‑Aminoimidazoles
Wei Xu, Gaonan Wang, Ning Sun, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A gold-catalyzed formal [3 + 2] cycloaddition of
ynamides with 4,5-dihydro-1,2,4-oxadiazoles has been developed.
The reaction provides a concise and regioselective access to highly
functionalized 4-aminoimidazoles likely via the formation of an α-
imino gold carbene intermediate followed by cyclization. 4,5-
Dihydro-1,2,4-oxadiazole was found to act as an efficient N-
iminonitrene equivalent in these reactions.
midazole rings constitute core structures of a wide range of
biologically active substances, natural products, and synthetic
derivatives such as aminoacetonitrile with the thioiminoether
hydrochloride salts.11d However, these methods usually suffer
from limited substrate scope. Therefore, the development of
highly efficient methods for the synthesis of 4-aminoimidazoles
from easily available starting materials under mild reaction
conditions is highly desirable.
I
organic compounds.1 They have also found many applications in
marketed drugs,2 ionic liquids,3 agrochemical industries,4
coordination chemistry as unique ligands,5 and functional
materials.6 4-Aminoimidazoles are highly attractive due to their
significant biological activities. For example, 1-methyl-4-amino-
imidazole derivative A is a novel Jak2 inhibitor, which might be
used for the treatment of myeloproliferative neoplasms
(MPNs).7 Imidazole B with a 4-[(2-sulfobenzoyl)amino]
group represents a novel class of potent nonpeptide angiotensin
II receptor antagonists, which may serve as a useful therapeutic
agents for the treatment of hypertension.8 4-Pyridin-2(1H)-one-
linkered imidazole C was discovered to be a potent inhibitor of
human cytomegalovirus (HCMV).9 In addition, 4-amino-
imidazole D with a cyclobutyl ring was found to be an inhibitor
of cyclin-dependent kinase 5/p25 for the treatment of
Alzheimer’s disease10 (Figure 1). Although a large number of
imidazole syntheses have been developed in recent years, few of
these procedures are capable of being used for the synthesis of 4-
aminoimidazoles.11 These compounds are usually synthesized
via reduction of 4-nitroimidazoles or cyclization of nitrile
On the other hand, gold-catalyzed cyclization or cycloaddition
reactions involving α-imino gold carbenes as the key synthetic
intermediates have gained much attention due to their high
efficiency for the synthesis of nitrogen-containing heterocycles.12
A series of nitrene-transfer reagents such as azides,13a 2H-
azirines,13b N-iminopyridium ylides,13c isoxazoles,13d benzoisox-
azoles,13e and triazapentalene13f have been developed to induce
the generation of these highly reactive α-imino gold−carbene
species. Recently, we discovered that 1,4,2-dioxazoles can be
used as an efficient N-acylnitrene equivalent to trigger a facile
generation of α-imino gold−carbene intermediate in gold-
catalyzed nitrene-transfer reactions to ynamides.14 The reaction
offers a novel approach to highly functionalized oxazoles under
mild reaction conditions (Scheme 1, A). Inspired by this work
and our continuous interests on the chemistry of ynamides,14,15
we envisioned that 4,5-dihydro-1,2,4-oxadiazoles might act as a
new type of nitrene-transfer reagent because these substrates
might also undergo the N−O bond cleavage reactions under the
appropriate reaction conditions. For example, the N−O bond in
4,5-dihydro-1,2,4-oxadiazoles can be reductively cleaved through
H2/Raney nickel or under basic conditions.16 The development
of such transformations would be of great interest for the
synthesis of functionalized 4-aminoimidazoles from ynamides
and easily available heterocyclic substrates (Scheme 1, B). To
date, transformations of 4,5-dihydro-1,2,4-oxadiazoles in catal-
ysis are quite rare. During the preparation of our manuscript,
Received: May 15, 2017
Figure 1. Biologically active 4-aminoimidazole derivatives.
© XXXX American Chemical Society
A
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Scheme 1. Gold-catalyzed [3 + 2] Cycloaddition of Ynamides
with Nitrene Precursors
Table 1. Optimization of the Reaction Conditions
Hashmi et al. reported an elegant gold-catalyzed cyclization of
ynamides with saturated 1,2,4-oxadiazoles to N-acyl-substituted
4-aminoimidazoles (Scheme 1, C).17 Compared with this work,
our method utilizes 4,5-dihydro-1,2,4-oxadiazole, an unsaturated
heterocycle, as the nucleophilic nitrene equivalent, which allows
the access to N-H-, alkyl-, and aryl-substituted 4-amino-
imidazoles. The method serves as a highly attractive complement
to Hashmi’s work for the synthesis of a wider diversity of 4-
aminoimidazoles.
To test the feasibility of our hypothesis, we initially
investigated the cyclization reaction of mesylamide-derived
ynamide 1a with 3,5-diphenyl-4,5-dihydro-1,2,4-oxadiazole 2a
bearing a free N-H moiety (Table 1). We anticipated that the 4-
aminoimidazole 3a with a free N-H group would result, which
can be readily functionalized via N-substitution reactions. To our
delight, the expected product 3a was formed in 66% yield in the
presence of 5 mol % of Johnphos(MeCN)AuSbF6 (catalyst A) in
DCE at 80 °C for 6 h (Table 1, entry 1). The results implied that
the desired [3 + 2] cycloaddition of ynamide with 4,5-dihydro-
1,2,4-oxadiazole could proceed with concomitant elimination of
benzaldehyde. Since the steric and electronic effects of the
ligands could have a large influence on the selectivity and
efficiency of the reactions, we expected that the yield of 3a might
be improved through variation of the different ligands on gold
catalyst. Then the effects of phosphine ligands on gold catalysts
were examined (entries 2−4). Gratifyingly, it was found that gold
catalyst B with a bulky tBuXphos as the ligand was highly efficient
for this transformation, leading to 3a in 98% yield (entry 2). In
addition, benzaldehyde was formed quantatively according to 1H
NMR analysis of the crude reaction mixture. BrettPhosAu-
(MeCN)SbF6 (catalyst D) with a highly crowded biphenyl ligand
also afforded 3a in a good yield of 85% (entry 4). The use of N-
heterocyclic carbene gold(I) complex E (IPrAuNTf2) or F
(IPrAu(MeCN)SbF6) (IPr = 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene) as the catalysts only afforded moderate
yields of 3a (entries 5 and 6). PPh3-ligated gold catalysts led to 3a
in 64−65% yields (entries 7 and 8). A gold(III) complex such as
PicAuCl2 or AuCl3 could also catalyze the reaction, furnishing 3a
in 56% and 83% yield, respectively (entries 9 and 10). When the
reactions were carried out in other solvents such as THF, DCM,
MeCN, or toluene, 3a was formed in lower yields of 30−68%
(entries 11−14). Decreasing the amount of 2a to 1.0 equiv gave a
lower yield of 3a (78%, entry 15). The use of tBuXphosAuCl as
the catalyst afforded only 10% of 3a (entry 16). Employing
AgSbF6, TfOH, or HNTf2 as the catalyst afforded enamine 4a as
the major product derived from the attack of imino nitrogen of 2a
to the ynamide (entries 17−19). Increasing the amount of
HNTf2 to 1.0 equiv resulted in the formation of the complex
reaction mixture.18
Having established an effective catalytic system for this novel
cascade annulation reaction, we turned our attention to
investigate the generality of this reaction. The scope of ynamides
1 was first studied using 2a as the reaction partner under the
reaction conditions given in Table 1, entry 2. As illustrated in
Scheme 2, a wide variety of ynamides 1 participated well in the
target reaction. The effects of the electron-withdrawing groups
on nitrogen were examined. Compared with mesyl-protected
substrate 1a, tosyl-protected substrate 1b afforded 3b in a much
lower yield of 70% with a longer reaction time. The results reveal
that N-alkyl ynamides bearing mesyl protecting group display
higher reactivity for this transformation. In addition, N-aryl-
substituted ynamides, whenever bearing a mesyl or tosyl group
on nitrogen, resulted in lower products yields and longer reaction
time (3c and 3d). Next, we examined the effects of the R1 group
on the alkyne terminus. When R1 was an aryl group, generally,
both electron-donating (p-Me, p-OMe) and electron-with-
drawing substituents (p-F, p-CO2Et) on the aryl rings were
well compatible, leading to 3e−h in 79−91% yields. Ynamide
B
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a
a
Scheme 2. Scope of Ynamides
Table 2. Scope of the 4,5-Dihydro-1,2,4-oxadiazoles
a
Isolated yields.
bearing a NO2-substituted aryl ring could also undergo the
desired cyclization, albeit with a lower product yield (3i, 40%). A
sterically demanding 1-naphthyl group was well suited, furnish-
ing 3j in 77% yield. Interestingly, ynamide with an 1,3,5(10)-
estratrien-3-ol-17-one derivative also reacted efficiently to afford
3k in 94% yield.
The reactivity of alkyl-substituted ynamides were also
evaluated (Scheme 3). Interestingly, the reaction of phenethyl-
Scheme 3. Reactions of Alkyl-Substituted Ynamides with 2a
a
b
substituted ynamide 1l with 2a afforded enamine 4b in 17% yield
with high Z-stereoselectivity catalyzed by 5 mol % of catalyst B.
The yield of 4b could be improved to 46% using PPh3AuNTf2 as
the catalyst. Under these conditions, N-tosylynamide 1m
afforded 4c in 40% yield. It was likely that Z-4b was formed by
gold-catalyzed isomerization of the initially generated E-4b or
from the reaction of 2a with keteniminium ion intermediate 5′
(vide infra) directly. The results indicate that the imino nitrogen
attacks the ynamide preferentially, and ring-opening of 4,5-
dihydro-1,2,4-oxadiazole does not occur in these cases, possibly
due to the lower stability of the gold−carbene intermediate
formed in the fragmentation step. These results also strongly
supported our assumption that a vinyl gold intermediate was
formed during the process. The structures of 4-aminoimidazole
3f and 4a, 4c were unambiguously confirmed by X-ray
crystallography.19
We next investigated the scope of 4,5-dihydro-1,2,4-
oxadiazoles 2 using ynamide 1a as the reaction partner (Table
2). To our delight, both of the N-H- and N-substituted20 4,5-
dihydro-1,2,4-oxadiazoles 2 worked very well under the standard
reaction conditions, furnishing the corresponding 4-amino-
imidazoles in generally good to excellent yields (70−94%). In the
cases of substrates 2b−d with a free N-H group, the reaction
efficiency was not affected by the nature of leaving groups
(R5COR6): R5 = Et, R6 = H (3a, 84%) R5 = R6 = Me (3a, 82%),
R5 = Ph, R6 = Me (3a, 87%). Alkyl (R3)-substituted 4,5-dihydro-
1,2,4-oxadiazoles such as butyl-, benzyl-, cyclopropyl-, or
Isolated yields. 1.8 equiv of 4,5-dihydro-1,2,4-oxadiazole was used.
cyclohexyl-substituted ones were also well suited for this
reaction, furnishing 3l−o in 70−92% yields. The effects of N-
substituents R4 were also investigated. N-Aryl-, benzyl-, and
butyl-substituted substrates 2i−l also turned out to be perfect
substrates, leading to 3p−s with a phenyl group as R3 in high
yields of 79−94%. N-Phenyl-substituted 4,5-dihydro-1,2,4-
oxadiazole 2m with an alkyl substituent as R3 worked also
efficiently (3t). These results further demonstrated the diversity
and flexibility of this method.
On the basis of the above results and our previous work, a
possible reaction mechanism is given in Scheme 4. Initially, the
imino nitrogen attacks on the gold-coordinated ynamide 5 or
Scheme 4. Possible Reaction Mechanism
C
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Letter
Read, J. A.; Costa, C. R.; Shi, J.; Su, M.; Ye, M.; Zinda, M. J. Med. Chem.
2014, 57, 144.
keteniminium ion intermediate 5′ regioselectively due to the
polarity of the ynamide to afford vinyl gold intermediate 6 or 6′
with an iminium ion moiety. Intermediate 6/6′ fragmentizes into
the α-imino gold carbene 7 and benzaldehyde via N−O and C−
N bond cleavage reaction. Nucleophilic attack of the imino
nitrogen in 7 to gold−carbene followed by elimination of the
gold catalyst leads to the products 3.
In conclusion, we have developed a gold-catalyzed formal [3 +
2] cycloaddition of ynamides with 4,5-dihydro-1,2,4-oxadiazoles.
The reaction provides a concise and regioselective access to
highly functionalized 4-aminoimidazoles likely via the formation
of an α-imino gold carbene intermediate followed by cyclization.
4,5-Dihydro-1,2,4-oxadiazole was found to act as an efficient N-
imino nitrene equivalent in these reactions. The method offers
several advantages such as easily accessible starting materials,
high efficiency, and wide functional group tolerance. Further
extensions of this reaction to the synthesis of other heterocycles
such as sulfur-containing heterocycles are currently underway.
(8) Palkowitz, A. D.; Steinberg, M. I.; Thrasher, K. J.; Reel, J. K.;
Hauser, K. L.; Zimmerman, K. M.; Wiest, S. A.; Whitesitt, C. A.; Simon,
R. L.; Pfeifer, W.; Lifer, S. L.; Boyd, D. B.; Barnett, C. J.; Wilson, T. M.;
Deeter, J. B.; Takeuchi, K.; Riley, R. E.; Miller, W. D.; Marshall, W. S. J.
Med. Chem. 1994, 37, 4508.
(9) Fader, L.; Brault, M.; Desjardins, J.; Dansereau, N.; Lamorte, L.;
Tremblay, S.; Bilodeau, F.; Bordeleau, J.; Duplessis, M.; Gorys, V.;
Gillard, J.; Gleason, J. L.; James, C.; Joly, M.-A.; Kuhn, C.; Llinas-Brunet,
M.; Luo, L.; Morency, L.; Morin, S.; Parisien, M.; Poirier, M.; Thibeault,
C.; Trinh, T.; Sturino, C.; Srivastava, S.; Yoakim, C.; Franti, M. ACS
Med. Chem. Lett. 2016, 7, 525.
(10) Helal, C. J.; Kang, Z.; Lucas, J. C.; Gant, T.; Ahlijanian, M. K.;
Schachter, J. B.; Richter, K. E. G.; Cook, J. M.; Menniti, F. S.; Kelly, K.;
Mente, S.; Pandit, J.; Hosea, N. Bioorg. Med. Chem. Lett. 2009, 19, 5703.
(11) (a) Rossi, E.; Pini, E. Tetrahedron 1996, 52, 7939. (b) Rolfs, A.;
Liebscher, J. J. Org. Chem. 1997, 62, 3480. (c) Marwaha, A.; Singh, P.;
Mahajan, M. P.; Velumurugan, D. Tetrahedron Lett. 2004, 45, 8945.
(d) Bader, H.; Downer, J. D. J. Chem. Soc. 1953, 1636.
(12) For a review, see: Davies, P. W.; Garzon
2015, 4, 694.
́
, M. Asian J. Org. Chem.
ASSOCIATED CONTENT
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(13) For selected papers, see: (a) Gorin, D. J.; Davis, N. R.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 11260. (b) Prechter, A.; Henrion, G.;
Faudot dit Bel, P.; Gagosz, F. Angew. Chem., Int. Ed. 2014, 53, 4959.
(c) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem., Int. Ed.
2011, 50, 8931. (d) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao,
T.; Zhang, W.; Lu, X.; Ye, L.-W. Chem. Sci. 2015, 6, 1265. (e) Jin, H.;
Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01469.
Experimental details, spectroscopic characterization of all
new compounds, and X-ray crystallographic data for
compounds 3f, 4a, and 4c (PDF)
X-ray crystallographic data for compound 3f (CIF)
X-ray crystallographic data for compound 4a (CIF)
X-ray crystallographic data for compound 4c (CIF)
Chem., Int. Ed. 2016, 55, 794. (f) Gonzal
Sobrino, A. L.; Ballesteros, A. Adv. Synth. Catal. 2016, 358, 1398.
́
ez, J.; Santamaría, J.; Suar
́
ez-
́
(14) Chen, M.; Sun, N.; Chen, H.; Liu, Y. Chem. Commun. 2016, 52,
6324.
(15) (a) Liu, J.; Chen, M.; Zhang, L.; Liu, Y. Chem. - Eur. J. 2015, 21,
1009. (b) Wang, G.; You, X.; Gan, Y.; Liu, Y. Org. Lett. 2017, 19, 110.
(16) (a) Chavan, N. L.; Naik, N. H.; Nayak, S. K.; Kusurkar, R. S.
ARKIVOC 2010, 248. (b) Aitken, R. A.; Raut, S. V. Synlett 1991, 1991,
189.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhliu@sioc.ac.cn.
ORCID
(17) Zeng, Z.; Jin, H.; Xie, J.; Tian, B.; Rudolph, M.; Rominger, F.;
Hashmi, A. S. K. Org. Lett. 2017, 19, 1020.
Yuanhong Liu: 0000-0003-1153-5695
Notes
(18) Very recently, Wan et al. reported that HNTf2 could catalyze the
[3 + 2] cycloaddition of ynamides with dioxazoles or N-alkyl-substituted
oxadiazolones to oxazoles or 4-aminoimidazoles, respectively. See:
(a) Zhao, Y.; Hu, Y.; Wang, C.; Li, X.; Wan, B. J. Org. Chem. 2017, 82,
3935. (b) Zhao, Y.; Hu, Y.; Li, X.; Wan, B. Org. Biomol. Chem. 2017, 15,
3413. However, in their work, when free N-H oxadiazolone was
employed, only N-vinylimidazole derived from [3 + 2] cycloaddition
followed by the addition with ynamide was obtained in low yield (ref
18b.). Our results indicated that the use of HNTf2 as the catalyst only
afforded a trace amount of the desired imidazole 3 when substrate 2 with
a N-H group was employed. In addition, 3a was not observed by
treatment of 4a with 5 mol % of catalyst B at 80 °C, indicating that our
reaction does not proceed via 4a. When 4a was treated with 10 mol % of
HNTf2 at 80 °C, only a trace amount of 3a was observed. A good yield of
the imidazole product could be observed in the presence of 1.0 equiv of
HNTf2 when the substrate 2 with a N-R group was used. See ref 20.
(19) See the Supporting Information.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development Program
(2016YFA0202900), the National Natural Science Foundation
of China (Grant Nos. 21372244, 21572256, and 21421091), and
the Strategic Priority Research Program of the Chinese Academy
of Sciences (Grant No. XDB20000000) for financial support.
REFERENCES
■
(1) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon Press: New
York, 1984; Vol. 5, pp 457−497.
(2) Heravi, M. M.; Daraie, M.; Zadsirjan, V. Mol. Diversity 2015, 19,
577.
(3) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667.
(4) Choi, J.-H.; Abe, N.; Tanaka, H.; Fushimi, K.; Nishina, Y.; Morita,
A.; Kiriiwa, Y.; Motohashi, R.; Hashizume, D.; Koshino, H.; Kawagishi,
H. J. Agric. Food Chem. 2010, 58, 9956.
(20) The reaction of 1a with 2j bearing an N-R group was also
investigated in the presence of HNTf2. The yields of the desired 3q were
obtained in 28% and 69% at 80 °C in DCE using 15 mol % or 1.0 equiv of
HNTf2, respectively.
(5) Konishi, H.; Ueda, T.; Muto, T.; Manabe, K. Org. Lett. 2012, 14,
4722.
(6) Lin, W.; Long, L.; Yuan, L.; Cao, Z.; Chen, B.; Tan, W. Org. Lett.
2008, 10, 5577.
(7) Su, Q.; Ioannidis, S.; Chuaqui, C.; Almeida, L.; Alimzhanov, M.;
Bebernitz, G.; Bell, K.; Block, M.; Howard, T.; Huang, S.; Huszar, D.;
D
DOI: 10.1021/acs.orglett.7b01469
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