The document summarizes research towards developing a chemoselective, regioselective, and enantioselective haloazidation reaction. Inspired by a previous method for bromochlorination, the researchers screened conditions to catalyze haloazidation of allylic alcohols using an azide source and halonium electrophile. After exploring various solvents, halonium sources, temperatures, and catalyst loadings, optimized conditions were discovered using TMSN3 and NBS. This new reaction provides access to trifunctional synthons containing a halogen, azide, and alcohol group with potential applications in synthesis.

1. Difunctional Synthons: Progress Towards A
Chemo-, Regio-, and Enantioselective Haloazidation
Jovan A. Lopez, Fritz J. Seidl, and Prof. Noah Z. Burns
Department of Chemistry, Stanford University, Stanford, CA, 94305
Background
Experimental Design
Conclusions and Future Directions
1) Why Halogens and Azide?
The role and importance of halogenated building blocks in organic
synthesis is established and undisputed, owing to the wealth of reactions
they can easily undergo. Moreover, newer methods for C–C bond
formation, such as the Suzuki-Miyaura, Stille, or Sonogashira coupling,
have generated a constant need for readily available halides as synthons.
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442
Lang, K.; Chin, J. W. ACS Chem. Biol. 2014, 9, 16−20
2) Existing Methods
Recently, the Burns lab developed a method to catalytically chemo-, regio-,
and enatioselectively bromochlorinate allylic alcohols. The catalyst is a
chiral ligand, (S,R)-Ln, that binds titanium, allowing for bromochlorination.
Inspired Design
Experimental Goal
In this project, a chemo-, regio-, and enantioselective bromo- and
chloroazidation was developed, derived from a selective bromochlorination
method created previously in the lab. The haloazidation reaction was
optimized, exploring a variety of conditions; the substrate scope and
limitations were also examined in detail.
Results
Substrate Scope
Acknowledgements
I would like to sincerely thank Fritz J. Seidl for being my mentor and friend,
as well as Noah Z. Burns for being an amazing P.I. and supportive advisor.
I owe a big thank you to the entirety of the Burns Research Group for
challenging my abilities and encouraging my growth as a chemist. Without
their guidance, patience, and willingness to teach, this project would not
have been possible.
I would also like to thank Stanford Undergraduate Advising and Research
for providing the opportunity to participate in this enriching program.
R1 = alkyl, aryl, vinyl
R2 = aryl, benzyl, vinyl
X = Br, Cl, I, OTf
Azides on the other hand, recently have found importance in the emerging
field of Bioorthogonal Chemistry. It is a unique functionality in the context of
the cell, providing orthogonal reactivity, useful for site specific labeling or
delivery.
C. R. Chimie. 2012, 15, 688–692
Tetrahedron Letters 2006, 47, 7017–7019
Org. Biomol. Chem., 2016, 14, 853
Org. Biomol. Chem., 2016, 14, 7463
Hu, D. X.; Seidl, F. J.; Bucher, C.; Burns, N. Z. J. Am. Chem. Soc., 2015, 137, 3795
Using the above reaction as a starting point, extensive screening was
undertaken to find ideal conditions that allowed Ti-complex formation with
azide as a nucleophile and either Br or Cl as electrophiles. Temperature,
solvent, azide source, bromine source, and catalyst loading were
systematically varied to find conditions that afforded high yield and
selectivity with cinnamyl alcohol (1) and phenethylprenol (2) as model
substrates. Once suitable conditions were found, the reaction was carried
out on a variety of substrates to explore scope and limitations.
Though several designed conditions allowed for haloazidation to occur,
they proceeded in low yield, and with low but promising selectivity. This
encouraged us to pursue further conditions until serendipity granted us a
near fully optimized procedure.
In an attempt to progress beyond the initial hit, instead of continuing to
explore solvent and halonium source screens that only resulted in failure,
we switched the azide source to TMSN3. Since the bis-azidotitanium species
had a low solubility in hexanes, we hypothesized that the nonpolar
trimethylsilylazide would more readily dissolve in solution, increasing the
equivalents of azide available to interact with substrate.
However, the theoretical reactive species in our system is the
monoazidotitanium complex. Since only the azide-free Ti(Oi-Pr)4 is added
to the reaction, the active Ti complex must be formed in situ; but, the rate of
Ti ligand exchange at -15 oC is slow and poses a threat to the overall
reactivity. In an effort to circumnavigate this problem, the reaction vessel
was initially charged with neat TMSN3 and Ti(Oi-Pr)4 and left to “age” at
room temperature.
Conditions have been discovered that allow for the enatioselective
anti(bromo-, chloro-)azidation of a diversity of allylic alcohols. This reaction
yields trifunctional synthons – halogen, azide, alcohol – that are readily
converted to an array of products by existing techniques. The abundance of
allylic systems and myriad of natural products bearing stereocenters with
these functional groups, make apparent the enormous potential and utility
of this transformation.
Despite the low yield, the first attempt produced a promising hit with a very
respectable 78% ee. Though it seems like the system is already partially
optimized, 1 is a model substrate that introduces an electronic bias. 2 is
more representative of typical substrates.
An identical reaction screen was ran using tBuOCl as the halonium source
in place of NBS. However, the relatively unstable chloroazide quickly
decomposed to junk and elimination products. Neither 1 nor 2 proceeded in
a manner that allowed for even crude yields to be obtained.
Results Continued
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