17. A. L. Millard et al., Clin. Exp. Immunol. 130, 245–255 (2002).
18. B. Wang, A. Morinobu, M. Horiuchi, J. Liu, S. Kumagai, Cell.
Immunol. 253, 54–58 (2008).
19. P. V. Chang, L. Hao, S. Offermanns, R. Medzhitov, Proc. Natl.
Acad. Sci. U.S.A. 111, 2247–2252 (2014).
20. K. Atarashi et al., Science 331, 337–341 (2011).
21. N. Arpaia et al., Nature 504, 451–455 (2013).
22. Y. Furusawa et al., Nature 504, 446–450 (2013).
23. P. M. Smith et al., Science 341, 569–573 (2013).
24. N. Singh et al., Immunity 40, 128–139 (2014).
25. L. Peyrin-Biroulet et al., Proc. Natl. Acad. Sci. U.S.A. 107,
We acknowledge the Host-Microbe Systems Biology Core
(HMSB Core) at the University of California at Davis School of
Medicine for expert technical assistance with microbiota
sequence analysis. The data reported in the manuscript are
tabulated in the main paper and the supplementary materials.
M.X.B. and A.J.Bä. filed invention report number 0577501-16-
0038 at iEdison.gov for a treatment to prevent postantibiotic
expansion of Enterobacteriaceae. This work was supported
by Public Health Service grants AI060555 (S.A.C.), TR001861
(E. E. O.), AI112241 (C.A.L.), DK087307 (C. G.), AI109799 (R. M. T.),
AI112258 (R.M. T.), AI112949 (A.J.Bä. and R.M. T.), AI096528
(A.J.Bä.), AI112445 (A.J.Bä.), AI112949 (A.J.Bä.), and AI114922
(A.J.Bä.). K.L.L. was supported by an American Heart Association
Predoctoral Fellowship (15PRE21420011).
Materials and Methods
Figs. S1 to S7
15 February 2017; accepted 22 June 2017
diazidation of alkenes
Niankai Fu, Gregory S. Sauer, Ambarneil Saha, Aaron Loo, Song Lin*
Vicinal diamines are a common structural motif in bioactive natural products, therapeutic
agents, and molecular catalysts, motivating the continuing development of efficient,
selective, and sustainable technologies for their preparation. We report an operationally
simple and environmentally friendly protocol that converts alkenes and sodium azide—
both readily available feedstocks—to 1,2-diazides. Powered by electricity and catalyzed by
Earth-abundant manganese, this transformation proceeds under mild conditions and
exhibits exceptional substrate generality and functional group compatibility. Using
standard protocols, the resultant 1,2-diazides can be smoothly reduced to vicinal diamines
in a single step, with high chemoselectivity. Mechanistic studies are consistent with metal-mediated azidyl radical transfer as the predominant pathway, enabling dual carbon-nitrogen bond formation.
Vicinal diamines are frequently found in pharmaceuticals and medicinally relevant natural products, as well as in privileged molecular catalysts for stereoselective syn- thesis (1). Despite substantial advances, a
broadly applicable methodological approach to
their synthesis remains elusive (2). The direct addition of two nitrogen-based functional groups to
alkenes—a family of abundant, readily accessible,
and structurally diverse feedstocks—is a particularly powerful approach to 1,2-diamine synthesis.
Although several methods are available for the
oxidative transformation of alkenes into 1,2-diols
(3), the analogous extension of this synthetic logic
to vicinal diamines remains underdeveloped. Existing methods frequently require stoichiometric
heavy metals (e.g., osmium or palladium) or esoteric nitrogenous reagents (e.g., nitrogen oxides,
diaziridinones, or N-activated sulfamides) and generally exhibit limited substrate scope (Fig. 1A) (4–10).
In this context, alkene diazidation is an attractive alternative route to vicinal diamine synthesis
(11–13), because the resulting 1,2-diazides can readily
be reduced to the corresponding diamines (Fig. 1B).
Furthermore, organic azides can participate in 1,3-
dipolar cycloaddition (14), the aza-Wittig reaction
(15), Staudinger ligation (16), and C–H bond amination (17), making them highly versatile intermediates for synthetic, materials, and biological
applications (18). However, existing protocols
uniformly require stoichiometric quantities of
reagents including peroxydisulfates (11), high-valent metal salts (11, 12), or hypervalent iodines
(13). The use of strong and indiscriminate oxidizing agents precludes the use of substrates with
oxidatively labile functionalities, such as alcohol,
aldehyde, sulfide, and amine groups. In addition,
these oxidants produce environmentally deleterious by-products and present an explosion hazard
when used alongside an azide source. An elegant
catalytic protocol was recently developed to address these conventional issues with reaction selectivity and substrate generality (13). Nonetheless,
both azidotrimethylsilane (TMSN3, a toxic and volatile reagent) and hypervalent iodine derivatives—
compounds that are difficult to handle on a
practical scale—remain necessary to drive the
Electrochemistry offers a mild and efficient al-
ternative to conventional chemical approaches for
redox transformations (19–21). With sufficient po-
tential bias, common organic starting materials
can lose or gain electrons at the electrode surface,
readily producing highly reactive intermediates.
Electrochemistry allows for precise, external
control of chemoselectivity and the flux of re-
active intermediates by regulating the applied
potential. Such control also maximizes energy
efficiency, making electrosynthesis one of the
most sustainable approaches for the prepa-
ration of complex organic molecules (21). More-
over, because the driving force derives solely from
electricity, electrosynthesis can be easily coupled
with renewable energy sources such as solar
light (22, 23). Recent studies have demonstrated
electrochemistry’s distinctive capability to engen-
der bond-forming reactions that challenge or-
thodox methods (24–36). Here we present an
electrochemical protocol for the diazidation of
alkenes as a general, efficient, and atom-economical
approach to vicinal diamine synthesis (Fig. 1C).
Anodic generation of azidyl radical (N3·) from
sodium azide (NaN3), followed by successive
additions of N3· to the alkene C=C bond and
the incipient carbon radical adduct (I), forms
two new C–N bonds, furnishing a vicinal diazide.
Hydrogen gas (H2) generated from cathodic
proton reduction—as evidenced by gas chro-
matography analysis of the reaction headspace—
and sodium acetate are the only by-products.
Our catalytic system shows an unusual combina-
tion of high reactivity and excellent chemose-
lectivity. As such, it is applicable to the diazidation
of a substantially greater variety of alkenes
than existing methods, specifically with respect
to substitution pattern and functional group
Our early efforts demonstrated that electrochemically generated azidyl radical could induce
the homolysis of C=C p-bonds. To establish proof
of concept, we carried out electrolysis experiments
using 4-(tert-butyl)styrene (1a) as the archetypal
substrate, oxidatively robust graphite as the anode
(working electrode), and platinum (Pt), with its
low overpotential for proton reduction, as the cathode (counter electrode). We chose NaN3 as the
azide source, because it is readily available and
exhibits markedly lower toxicity and volatility
compared with other azide derivatives. With
as a radical scavenger to trap carbon radical intermediate I, azidooxygenated product 1c formed
in high yield and with complete regioselectivity
(Fig. 2). However, efforts to trigger diazidation by
directly trapping I with another equivalent of
azidyl radical proved unsuccessful; only traces of
Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, NY 14853, USA.
*Corresponding author. Email: email@example.com