Page 3 of 4
Journal Name
ChemComm
DOI: 10.1039/C5CC04813C
and 78% yield respectively). Moreover, we were surprised to find formation of the diaziridine product is also viable given the
that 3-hydroxybenzaldehyde furnished the diaziridine product in experimental results.
good yield as well (Entry 9, 80%). We further extended the scope of
this reaction to heterocyclic aromatic aldehydes and found that the
respective heterocyclic diaziridine was obtained in high yield (Entry
Conclusions
We have created a proficient and general method for the synthesis of
substituted diaziridines. This reaction constructs three stereocenters
in one step from achiral substrates. Furthermore, this method
efficiently provides the desired heterocycle for a wide variety of
aromatic and aliphatic aldehydes, ketones and amines. We will
continue to focus on further understanding the reaction pathway
leading to these diaziridines. Moreover, the substituted diaziridines
made through these efforts will be assayed as potential cytochrome
P450 2B6 inhibitors to gain insight into the pharmacological profile
of this scaffold.
10, 85%).
We also wanted to investigate the scope by changing the amine
component of the reaction (Table 3). We initially tested the
diaziridination of hydrocinnamaldehyde with alkyl amines (allyl and
propyl amine), and we found that they also provide the diaziridine in
good yields and as single diastereomers (Entries 2 and 5 with 78 and
94% respectively). Bulky alkyl amines like t-butyl and cyclopentyl
amine were also successful at furnishing the desired diaziridines
(Entries 1 and 3, 89 and 76% yield respectively). We were also
interested in testing amines with pharmacophoric properties for the
generation of a library for high-throughput-screening of their
biological properties. Piperonylamine reacted to efficiently provide
the respective diaziridine in high yield (Entry 4, 85% yield).
Acknowledgements
The Donors of the American Chemical Society Petroleum
Research Fund financially supported these research efforts. We
are also thankful to Mr Steven M. Ruggiero for his
participation.
Notes and references
§
Department of Chemistry and Biochemistry, Rowan University, 201
Mullica Hill Rd, Glassboro, New Jersey, USA. E-mail: moura-
Electronic Supplementary Information (ESI) available: [Experimental
protocols and spectroscopic data for each diaziridine are provided]. See
DOI: 10.1039/c000000x/
1
2
3
Asymmetric Synthesis of Nitrogen Heterocycles, Ed. J. Royer, Wiley-
Figure 1. Reaction progression by NMR at 4 different times.
VCH: Wienheim, 2009.
The diaziridine ring shares a particular set of properties. It is a
hydrazine and aminal at the same time. Moreover, due to ring strain
and lone-pair repulsion; both N atoms are configurationally stable.15
We clearly observe this particular phenomenon in the diaziridination
of cyclohexanone. The respective diaziridine is only chiral at the N
The Chemistry of Heterocycles; Ed. Eicher, T.; Hauptmann, S.
Wiley-VCH: 2005.
For reviews, see: (a) H. Chuang-Yang and A. G. Doyle, Chem. Rev.
2014, 114, 8153. (b) R. A. Moss, Acc. Chem. Res. 2006, 39, 267. (c)
Y. Zhu, R. C. Cornwall, H. Du, B. Zhao and Y. Shi, Acc. Chem. Res.
2014, 47, 3665. (d) Liu, Ed. Chemistry of Diazirines, Ed. M. T. H.
Liu, CRC Press: Boca Raton, FL, 1987.
1
atoms and its benzylic protons in the H-NMR were shown to be
diastereotopic (Supporting Information). Thus, all the diaziridines
obtained as single isomers were obtained as a single diastereomers.
We then turned our attention to further understanding the mechanism
for this reaction. Although it has been postulated that this reaction
undergoes imine formation followed by diaziridination, we sought to
determine if the diaziridination step was concerted or stepwise.16
Thus, we designed an experiment to follow the reaction completion
at low temperature by NMR (Figure 1).17 This experiment shows
that imine 1b benzylic protons form immediately upon mixing the
aldehyde with the amine (singlet at 4.55 ppm, reaction time = 5 min,
red spectrum), with trace amounts of diaziridine 1a diastereotopic
benzylic protons (doublet of doublets at 3.55 ppm). As the reaction
moves forward (spectrum in green, blue and purple), the ratio of
these benzylic protons shifts to the complete disappearance of imine
1b benzylic protons after 3.5 h. The new resonance corresponds to
the benzylic protons in the diaziridine ring in a trans stereochemical
relationship to the alkyl chain from the aldehyde substrate.18
Throughout the duration of this experiment, we did not observe the
formation of non-chiral intermediates. These results indicate that the
diastereoselective step may be a concerted step; however, a pathway
going through a highly organized ionic transition state towards the
4
5
6
7
H. Ishihara, K. Hori, H. Sugihara, Y. N. Ito and T. Katsuki, Helv.
Chim. Acta, 2002, 85, 4272.
Y. Schneider, J. Prevost, M. Gobin and C. Y. Legault, Org. Lett.
2014, 16, 596.
(a) H. Du, B. Zhao and Y. Shi, J. Am. Chem. Soc. 2007, 129, 762. (b)
B. Zhao, H. Du and Y. Shi, J. Am. Chem. Soc. 2008, 130, 7220.
(a) D. A. Capretto, C. Brouwer, C. B. Poor and C. Hue, Org. Lett.
2011, 13, 5842. (b) A. V. Shevtsov, V. V. Kuznetsov, A. A.
Kislukhin, V. Y. Petukhova, Y. A. Strelenko and N. N. Makhova, J.
Heterocycl. Chem., 2006, 43, 881. (c) H. Du, B. Zhao and Y. Shi, J.
Am. Chem. Soc., 2007, 129, 762. (d) B. Zhao, H. Du, S. Cui and Y.
Shi, J. Am. Chem. Soc., 2010, 132, 3523. (e) B. Zhao, X. Peng, S. Cui
and Y. Shi. J. Am. Chem. Soc., 2010, 132, 11009.
8
(a) Y. Kobayashi, C. Sridar, U. M. Kent, S. G. Puppali, J. M.
Rimoldi, H. Zhang, L. Waskell and P. F. Hollenberg, Drug Met. And
Dispos., 2006, 34, 2102. (b) C. Sridar, Y. Kobayashi, H. Brevig, U.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3