Tuning the Annulation Reactivity of Vinyl Azides and Carbazates: A Divergent Synthesis of Aza-pyrimidinones and Imidazoles

Article abstract of DOI:10.1021/acs.orglett.5b02180

A divergent cascade annulation has been developed using readily available vinyl azides and carbazates with a wide range of substituents. Vinyl azides were successfully applied as bifunctional partners to prepare aza-pyrimidinones via 6-ring closure with c

Full text of DOI:10.1021/acs.orglett.5b02180

Letter
pubs.acs.org/OrgLett
Tuning the Annulation Reactivity of Vinyl Azides and Carbazates: A
Divergent Synthesis of Aza-pyrimidinones and Imidazoles
Jiaan Shao, Xingyu Liu, Ke Shu, Pai Tang, Jing Luo, Wenteng Chen,* and Yongping Yu*Zhejiang Province
Key Laboratoryof Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University,
Hangzhou 310058, P. R.China
S
* Supporting Information
ABSTRACT: A divergent cascade annulation has been developed using
readily available vinyl azides and carbazates with a wide range of
substituents. Vinyl azides were successfully applied as bifunctional
partners to prepare aza-pyrimidinones via 6-ring closure with carbazates
as well as to construct polyfunctionalized imidazoles via 5-ring closure
with N-substituted carbazates. The aza-heterocycles were obtained with
high levels of chemoselectivity and excellent yields.
Table 1. Optimization of the Reaction Conditions
za-heterocycles are present as core scaffolds in many
A
natural products with a wide spectrum of biological
activity. Consequently, the efficient and selective construction
of these heterocycles is of importance.1 The divergent synthesis
strategy appears to be popular and useful in the construction of
aza-heterocycles, requiring an understanding of the reactivity
and chemoselectivity of intermediates and substrates.2,3 Vinyl
azides possess unique chemical reactivity and serve as versatile
synthons for the synthesis of various aza-heterocycles.4,5
Recently, our group has been interested in exploring the
potential reactivity of vinyl azides with a range of reactive
partners.6
a
b
entry
conditions
LG
yield [%]
1
2
3
4
5
6
7
8
Dioxane, 130 °C, 6 h
MeCN, 130 °C, 6 h
Toluene, 130 °C, 6 h
MeCN, 120 °C, 6 h
MeCN, 80 °C, 6 h
MeCN, 80 °C, 24 h
MeCN, 130 °C, 6 h
MeCN, 130 °C, 6 h
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
OEt
85
89
20
86
40
Carbazates, namely as “blocked” hydrazines, bear unique
functionalities.7 Carbazates could in situ generate amino
isocyanates via thermolysis, which possess the electrophilic
nature of isocyanates and the nucleophilicity of the only
nitrogen atom.7b In the above-mentioned case, the reactivity of
carbazates has shifted from ambident molecules8 to amphoteric
reagents. While pioneering work showed that vinyl azides and
carbazates favorably undergo a thermal reaction to form the
reactive intermediates 2H-aziridines and amino isocyanates
respectively, the efficiency of their cascade reactions remained
speculative.
Our efforts toward this putative reactivity initiated using vinyl
azides 1a and various carbazates 2. Gratifyingly, we observed
the formation of aza-pyrimidinone 3a with an acceptable yield
(85%) in dioxane at 130 °C (Table 1, entry 1). The aza-
pyrimidinone derivatives are reported to have valuable
pharmacological properties, such as being Gpr119 agonists9a
and a modulator of the Edg-2 receptor.9b Further studies found
that the solvent and temperature of the reaction have a
significant impact on the efficiency for the formation of 3a.
When the reaction was carried out at 130 °C in MeCN, the
yield of 3a slightly improved to 89% (Table 1, entry 2). While
the reaction yield (Table 1, entry 3, 20%) significantly
decreased in toluene under the identical reaction conditions.
Lowering the temperature to 80 °C for 6 or 24 h reduced the
45
<10
92
OPh
a
Unless otherwise noted, the reactions were carried out with vinyl
azides 1a (0.3 mmol) and carbazates 2 (0.33 mmol) heating in
solvents (0.5 M, sealed tubes). Isolated yields.
b
yields below 50% (Table 1, entries 5−6). Screening of the
leaving groups (LG) revealed that the tert-butoxy (Ot-Bu) and
phenoxyl (OPh) groups worked efficiently, thus leading to 3a
in 86% and 92% yields, respectively (entries 4 and 8). In
contrast, the ethoxy (EtO) group in 2 suppressed the formation
of 3a (Table 1, entry 7).
With the optimal reactivity defined at 130 °C in MeCN, the
generality of this aza-pyrimidinone synthesis was next explored
using a series of vinyl azides 1 and carbazates 2 (Scheme 1). β-
Aryl substituted vinyl azides reacted smoothly with carbazates 2
in excellent yields (80%−95%), allowing the introduction of
electron-rich and -deficient benzene rings as the substituent R1
(for 3b−3g), as well as the sterically hindered 2-chlorophenyl
group (for 3h). However, the reaction with a strongly electron-
Received: July 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02180
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Scheme 1. Scope of Aza-pyrimidinone from Vinyl Azides 1
a
and Carbazates 2
Figure 1. X-ray Crystal Structure of Product 3e (CCDC 1406472).
Scheme 2. Further Structural Elaboration of Aza-
pyrimidinones 3
And this extension would significantly broaden the applicability
of this approach.
We next investigated the scope of N-substituted carbazates 2′
instead of carbazates 2. The results turned out to be rather
challenging (Scheme 3). In the case of N-methyl carbazate 2′-a
Scheme 3. Cascade Reactions with N-Substituted Carbazates
2′
a
Reaction conditions: vinyl azides 1 (1.0 mmol), carbazates 2 (1.1
mmol) in MeCN (0.5 M) heated in a sealed tube (130 °C, 6 h). Yields
shown are those of the isolated products.
deficient vinyl azide having a 4-nitrobenzene ring as R1 resulted
in no formation of the desired product 3i. A β-alkyl substituted
vinyl azide was also capable of coupling with carbazate 2 to
yield the product 3k in 79%, while a β-hydrogen substituted
vinyl azide failed to obtain the product 3l. This may be due to
the instability of 2H-azirdine generated. We next examined the
compatibility of various α-substituted vinyl azides 1 in this
synthesis. Installation of aryl groups as the substituent R2
favored the reactions to deliver aza-pyrimidone 3m−3o in
excellent yields (75%−84%). Likewise, replacement of
substituents R2 with the aryl carbonyl or 6-morpholinyl
carbonyl group could also be realized in this reaction, albeit
in moderate yields (for 3p, 54%; for 3q, 64%).
and N-phenyl carbazate 2′-b, the reactions resulted in a
complex mixture without the formation of desired aza-
pyrimidinone product 3 under the reaction conditions stated
above (Scheme 3). In the case of N-benzyl carbazate 2′-c, the
cyclization led to the selective formation of a five-membered
imidazole 5c over the six-membered aza-pyrimidinone 3
(Scheme 3).
The structure of product 5c has been conclusively confirmed
by single crystal X-ray analysis (Figure 2). The results
unambiguously showed the special chemical reactivity of N-
substituted carbazates 2′ in this present transformation, rather
than via putative amino isocyanate intermediates reported in
Scheme 1.
Based on the observed reactivity feature in this reaction, we
further explored the generality of this cascade reactions. β-Aryl
substituted vinyl azides reacted efficiently with N-substituted
carbazates 2′ in excellent yields (75%−90%), allowing the
introduction of electron-rich and -deficient benzene rings as the
substituent R1 (for 5a−5d and 5f−5g), as well as a heterocyclic
substituent at the R1 position (for 5e). However, a β-hydrogen
substituted vinyl azide failed to result in the desired product
(for 5i). When varying the groups on the Ar substituent of N-
1
Products 3a−3q were characterized by H and 13C NMR
spectra as well as HRMS analysis. The structure of one
representative product 3e was further confirmed by X-ray
analysis (Figure 1).
The so-obtained aza-dihydropyrimidinones could be further
elaborated to oxidative dehydrogenation (Scheme 2). For
example, a solution of 3a in the presence of a catalytic amount
of Cu(OAc)2, K2CO3, and 2.0 equiv of TBHP10 afforded ethyl
3-hydroxy-5-phenyl-1,2,4-triazine-6-carboxylate 4a in 90% yield.
B
DOI: 10.1021/acs.orglett.5b02180
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Scheme 5. Proposed Reaction Pathways Leading to Aza-
pyrimidinone and Imidazoles
Figure 2. X-ray crystal structure of product 5c (CCDC 1406473).
substituted carbazates 2′, both electron-rich and -deficient
benzene rings were tolerated by the present method and
proceed efficiently with N-benzyl substituted carbazates 2′ in
good to excellent yields (for 5a, 5c, and 5h) (Scheme 4).
Scheme 4. Scope of Polyfunctionalized Imidazoles from
a
Vinyl Azides 1 and N-substituted Carbazates 2′
intermediate E undergoes a facile ring expansion to G. Finally,
the product 5 is achieved through aromatization of G.
In summary, we have developed an efficient divergent
approach for the controlled construction of aza-pyrimidinones
or imidazoles from readily available vinyl azides and carbazates.
The products were obtained with high levels of chemo-
selectivity and excellent yields. The broad applicability of the
reaction sequence is remarkable for the rapid synthesis of a
number of pharmaceutical agents.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02180.
Crystallographic data for 3e (CCDC 1406472) (CIF)
a
Reaction conditions: vinyl azides 1 (1.0 mmol), N-substituted
Crystallographic data for 5c (CCDC 1406473) (CIF)
Experimental procedures, characterization, and spectral
data of the final products (PDF)
carbazates 2′ (1.1 mmol) in MeCN (0.5 M) heated in a sealed tube
(130 °C, 6 h). Yields shown are those of the isolated products.
AUTHOR INFORMATION
Corresponding Authors
On the basis of the above results, a plausible mechanism is
outlined in Scheme 5. In the stated reaction conditions, vinyl
azide 1 is converted to 2H-aziridine I by thermal decom-
position. Subsequently, nucleophilic attack takes place between
I and carbazates 2 leading to the adduct product II. In the case
of H as substituent R3 (pathway a), the resulting adduct A
undergoes subsequent removal of HLG leading to amino-
isocyanate intermediate C. Then, the intramolecular nucleo-
philic attack of the nitrogen of the aziridine to isocyanate gives
the adduct D. Ring opening of the strained three-membered
ring in adduct D affords aza-pyrimidinone 3. An alternative 5-
ring closure pathway leading to polyfunctionalized imidazoles
was observed in the case of the benzyl group as substituent R3
(pathway b). Nucleophilic attack similarly takes place between I
and the benzyl substituted nitrogen atom of carbazates.
Concomitant loss of a carbamate residue by cleavage of the
N−N bond of adduct B affords imine intermediate E.11 Then,
■
*E-mail: wentengchen@zju.edu.cn.
*E-mail: yyu@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (Nos. 81273356 and 81473074), National
Science & Technology Major Projects for “Major New Drugs
Innovation and Development” of China (2014ZX09304002-
007), the Program for Zhejiang Leading Team of S&T
Innovation Team (2011R50014), and Arthritis & Chronic
Pain Research Institute, USA to Y.Y.; National Natural Science
Foundation of China (No. 81402778) and the Fundamental
C
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Research Funds for the Central Universities (No.
2015QNA7029) to W.C.; and the China Postdoctoral Science
Foundation Funded Project (2015M570520) to J.S.
REFERENCES
(1) Trost, B. M. Science 1983 219, 245.
(2) (a) Schreiber, S. L. Science 2000 287, 1964. (b) Kuruvilla, F. G.;
Shamji, A. F.; Sternson, S. M.; Hergenrother, P. J.; Schreiber, S. L.
Nature 2002 416, 653.
■
(3) (a) Dixon, D. D.; Lockner, J. W.; Zhou, Q.; Baran, P. S. J. Am.
Chem. Soc. 2012 134, 8432. (b) Dai, H.-X.; Stepan, A. F.; Plummer,
M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011 133, 7222.
(4) Selected reactions with vinyl azides: (a) Xiang, L.; Niu, Y.; Pang,
X.; Yan, R. Chem. Commun. 2015 51, 6598. (b) Hu, B.; DiMagno, S.
G. Org. Biomol. Chem. 2015 13, 3844. (c) Wang, Y.-F.; Lonca, G.
H.; Chiba, S. Angew. Chem., Int. Ed. 2014 53, 1067. (d) Zhu, X.;
Wang, Y.-F.; Zhang, F.-L.; Chiba, S. Chem. - Asian J. 2014 9, 2458.
(e) Donthiri, R. R.; Pappula, V.; Reddy, N. N.; Bairagi, D.;
Adimurthy, S. J. Org. Chem. 2014 79, 11277. (f) Jung, N.; Brase, S.
̈
Angew. Chem., Int. Ed. 2012 51, 12169. (g) Sajna, K. V.; Kumara
Swamy, K. C. J. Org. Chem. 2012 77, 8712. (h) Wang, Y. F.; Toh, K.
K.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011 133, 6411.
(i) Wang, Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int.
Ed. 2011 50, 5927.
́
(5) (a) Timen, Å. S.; Risberg, E.; Somfai, P. Tetrahedron Lett. 2003
44, 5339. (b) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K.
Org. Lett. 2008 10, 313.
(6) Selected reactions with vinyl azides: (a) Zhang, G.; Chen, B.;
Guo, X.; Guo, S.; Yu, Y. Adv. Synth. Catal. 2015 357, 1065. (b) Liu,
S.; Chen, W.; Luo, J.; Yu, Y. Chem. Commun. 2014 50, 8539.
(c) Zhang, G.; Ni, H.; Chen, W.; Shao, J.; Liu, H.; Chen, B.; Yu, Y.
Org. Lett. 2013 15, 5967. (d) Shao, J.; Yu, W.; Shao, Z.; Yu, Y.
Chem. Commun. 2012 48, 2785. (e) Chen, W.; Hu, M.; Wu, J.; Zou,
H.; Yu, Y. Org. Lett. 2010 12, 3863.
(7) (a) Vincent Rocan, J.-F.; Clavette, C.; Leckett, K.; Beauchemin,
A. M. Chem. - Eur. J. 2015 21, 3886. (b) Clavette, C.; Vincent Rocan,
J.-F.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2013 52, 12705.
(c) Clavette, C.; Gan, W.; Bongers, A.; Markiewicz, T.; Toderian,
A. B.; Gorelsky, S. I.; Beauchemin, A. M. J. Am. Chem. Soc. 2012
134, 16111. (d) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky,
S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc. 2009 131,
8740.
(8) Nigst, T. A.; Ammer, J.; Mayr, H. Angew. Chem., Int. Ed. 2012 51,
1353.
(9) (a) Grauert, M.; Barker, R.; Breitfelder, S.; Buettner, F.;
Eickelmann, P.; Fox, T.; Grundl, M.; Lehmann-Lintz, T.
WO2011138427. (b) Shankar, G.; Solow-Cordero, D.; Spencer, J.
V.; Gluchowski, C. WO2003062392.
(10) Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005 7,
4673.
(11) Attanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.;
Moscatelli, G.; Prati, F. Org. Lett. 2007 9, 3461.
D
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