RES EARCH

ORGANIC CHEMISTRY the handful of other ring-contraction reactions

of azepines that have been reported (24–34).
Aromatic nitrogen scanning by ipso-selective Whereas in certain instances this may be de-
sirable, such skeletal rotation precludes straight-
nitrene internalization forward structure-activity interrogation and
complicates retrosynthetic analysis. We rea-
Tyler J. Pearson, Ryoma Shimazumi, Julia L. Driscoll, Balu D. Dherange, Dong-Il Park, Mark D. Levin* soned that selective ipso-carbon deletion of
azepines would instead allow direct formation
Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current of a single pyridine isomer (2) with neither
strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack skeletal nor functional group perturbation. This
of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N would also enable nitrogen scanning because
replacement reaction allowing unified access to various pyridine isomers through a nitrene- the site selectivity of azide installation would, in
internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted a predictable and straightforward manner, guide
to 3H-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion the final site of nitrogen placement. In effect,
through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso the net transformation would be internalization
carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without of the nitrene nitrogen, replacing the carbon
perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated atom to which it was formerly attached. We re-
synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan. port the successful realization of such an ipso-
selective nitrene-internalization reaction.

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S
hape complementarity between a ligand theses can often limit the viability of the strat- Development of an oxidative carbon extrusion
and its target strongly influences bind- egy altogether. Our design centered on the hypothesis that
ing phenomena in medicinal chemistry. Accordingly, the development of synthetic oxidation of the azepine would lead to an
Consequently, isoteric atom replacements methods that can enable the direct interro- azaheptatriene species (I) from which chele-
that retain the three-dimensional con- gation of such C-to-N replacements has at- tropic extrusion of the ipso carbon could be
tour of the molecule figure prominently in the tracted substantial interest (10–12). The reverse achieved through the corresponding azanor-
discovery process. Within this class, the re- reaction (pyridine to benzene) has been re- caradiene isomer (II) (Fig. 2A). In this regard,
placement of an aromatic carbon atom with a ported with the use of stoichiometric tita- we were guided by precedent in the analogous
nitrogen to afford the corresponding pyridine nium alkylidynes, and other atom-swapping benzenoid systems; whereas decarbonylation
(or higher azaarene) is privileged for its ability approaches (for example, O to N) have been of tropone requires temperatures >400°C, spi-
to impart critical drug-like properties through demonstrated in aliphatic systems (13–15). We rocyclic diamido-aminal derivatives have been
the modulation of physicochemical properties, recently reported a C2 selective carbon dele- shown to extrude benzene at or near room
introduction of hydrogen-bond acceptors, and tion of quinolines, which when paired with temperature (Fig. 2B) (35–37). This difference
management of oxidative metabolic liabilities nitrogen insertion into the resulting indole, af- in reactivity can be attributed to the change in
(1–3). This effect has been so frequently ob- fords the corresponding replacement product, angle strain of the differently hybridized aza-
served by medicinal chemists that it has be- a cinnoline (16, 17). This sequence, however, is norcaradiene intermediates. Accordingly, we
come known colloquially as the “necessary currently limited to specific heterocyclic scaf- envisioned that introduction of a second pen-
nitrogen effect” (4, 5). With drug discovery folds and can only afford a single C-to-N replace- dant donor to the amine nucleophile would
still a largely empirical practice, the identifi- ment isomer. enable spirocyclization and thereby facilitate
cation of such necessary nitrogens frequently In the search for a strategy that would en- carbene elimination through a similar reduc-
requires the examination of each isomeric able arbitrary site-directable C-to-N replace- tion of angle strain. Initial attempts with 1,
permutation—a practice referred to in discov- ment, we took inspiration from the literature n-diamines (which would lead to N-heterocyclic
ery chemistry as a “nitrogen scan” (Fig. 1A). of 2-amino-3H-azepines, synthesis of which carbene leaving groups) provided detectable
Specific nitrogen scans that were involved in from aryl azides (1) and protic nucleophiles quantities of pyridine but were consistently
the identification of three recently Food and dates back to Doering’s seminal 1966 report plagued by the oxidative sensitivity of the free
Drug Administration (FDA)–approved phar- (Fig. 1C) (18–21). Specifically, Sundberg’s sub- amine. Consequently, we turned our attention
maceuticals are shown in Fig. 1B (6–8). sequent finding that photolysis in the presence to the aminoalcohol-substituted azepine deriv-
Although a nitrogen scan is conceptually sim- of air leads to a mixture of pyridine products, ative 3a. On the basis of prior reports of non-
ple, its practice is divorced from this ideal by a including those featuring the formal “para”– destructive oxidation of azepines through the
conspicuous lack of direct atom-replacement carbon deletion products, suggested that oxi- use of N-bromosuccinimide, we initially hy-
techniques. Conducting a nitrogen scan there- dation of the azepines could serve as a poten- pothesized that similar oxidants would facili-
fore almost invariably requires bottom-up syn- tial path forward (22). In a further development, tate oxidation and spirocycle formation in our
thesis of each azine isomer (9). Each of the Burns recently reported that singlet oxygen system (38). However, treatment of 3a with an
analogs shown in Fig. 1B followed this tem- acts on the 3H-azepines to induce formal organic base and N-bromosuccinimide led to
plate, requiring iterative syntheses to identify “meta”-carbon deletion (23). Both of these ap- the exclusive formation of the succinimide-
the final clinical candidate. This need for syn- proaches are problematic in that the nitrogen trapped oxidation product 4a (Fig. 2C). Having
thetic iteration represents a substantial bottle- insertion and carbon deletions are conducted observed the noninnocence of the liberated
neck in the discovery of new medicines, and with differing selectivity, leading to an overall conjugate anion upon formal Br+ transfer, we
the availability of appropriate heterocycle syn- sequence that produces multiple products (in hypothesized that further modulation of the
the case of nonsymmetric starting aryl azides), oxidant could allow productive reactivity. Upon
removes distal functional groups, retains the subsequent examination of N-bromocaprolactam,
incoming amine nucleophile, and thereby pro- a less-oxidizing Br+ equivalent, we observed
Department of Chemistry, University of Chicago, Chicago, IL
60637, USA. motes rearrangement of the arene skeleton. the formation of the desired spirocyclic N,O-
*Corresponding author: Email: marklevin@[Link] Indeed, such rearrangements are the norm in ketal 5a (39). Heating of this species to 80°C

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Fig. 1. Background and motivation. (A) General outline of the nitrogen scan strategy. (B) Examples of nitrogen scans examined in the discovery of recently approved
pharmaceuticals. (C) Outline of relevant precedent for formal nitrene internalization, emphasizing drawbacks associated with the prior art. EP2, prostaglandin E2 receptor;
RET, rearranged during transfection proto-oncogene; K-Ras G12C, Kirsten rat sarcoma protein with glycine 12 to cysteine mutation; iPr, isopropyl; Me, methyl.

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Fig. 2. Design and mechanism. (A) Design hypothesis for ipso-carbon deletion of azepines. (B) Precedent in benzenoid systems, demonstrating hybridization effects.
(C) Discovery of oxidant-dependent cyclization and thermolytic extrusion of pyridine, with optimized conditions and control experiments lacking a pendant alcohol.
(D) Computed mechanism for carbene extrusion from spirocyclic azahexatriene. NBS, N-bromosuccinimide; NBC, N-bromocaprolactam; decomp., decomposition;
conv., conversion; DBU, diazabicycloundecene; OTBS, tert-butyldimethylsilyloxy.

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Fig. 3. Scope and selectivity. (A) Scope of the reaction. Standard conditions: (i) 0.3 mmol aryl azide, 0.3 mmol ethylaminoethanol, 3 ml MeCN, and 427-nm
light-emitting diode (LED); (ii) 0.3 mmol DBU, 3 ml dioxane heated to 80°C, and 0.6 mmol N-bromocaprolactam added dropwise at 80°C. Isolated yield of pyridine
from aryl azide (black). Proton NMR (1H-NMR) yield of photolysis (blue) and interpolated yield of pyridine based on azepine yield (purple), shown in parentheses.
Asterisk indicates NMR yield. (B) Demonstration that nonsymmetric substrates form only one pyridine isomer.

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Fig. 4. Applications of nitrene

internalization. (A) Synthesis
of an azasteroid from estrone
and comparison with published
route from nortestosterone.
(B) Demonstration of a
prototypical nitrogen scan
leveraging an unselective
C–H borylation.

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resulted in the liberation of the corresponding pathways were found to be similar in energy, and 3tb both yielded pyridine, they proceeded
pyridine in moderate yield, whereas thermol- converging at INT2. with differing yields, suggesting that the spe-
ysis of 4a led only to nonspecific decomposi- cific steric profile of the azepine does influence
tion. Because further oxidation of 5a begins to Reaction scope and applications the oxidation efficiency.
compete with 3a as the reaction proceeds, if In seeking to translate these observations to a Limitations manifest in both steps of the
the oxidation reaction is instead conducted at synthetic protocol starting from the aryl azide, reaction. For example, functionalities in the
80°C with slow addition of the oxidant, much we found that the crude photolysate from the ortho position that can competitively react with
higher yields of the desired pyridine can be initial azepine synthesis could be effectively the photogenerated nitrene (for example,
obtained. Although the putative carbene by- carried forward to pyridine without interme- Cadogan cyclization) are not well tolerated
product (6) could not be detected, we could diate purification, avoiding yield losses asso- during photolysis (supplementary materials)
observe its oxidation product, N-ethyl oxazoli- ciated with purification of the azepine. This (40, 41). Some substrates also have limitations
dinone, with both nuclear magnetic resonance two-stage, one-pot transformation was found inherent to their photophysics. For example,
(NMR) and mass spectrometry. This oxidation to be readily applicable to a range of aryl 4-azidobiphenyl undergoes facile intersystem
can occur either from adventitious dioxygen azides (Fig. 3). Various alkyl, aryl, and hetero- crossing relative to ring expansion and there-
or the Br+ reagent, with the latter forming the aryl groups were compatible in a number of fore generates substantial quantities of triplet
oxazolidinone through hydrolysis upon aque- different substitution patterns (2a to 2c, 2j, nitrene products such as azobiphenyl and
ous workup. 2k, 2n, 2o, and 2r). Electron-rich arenes (2b, 4-phenylaniline (42). Furthermore, resonance
Control experiments with aminoazepines 2j, and 2r) and those bearing both resonance donors such as alkoxy and amine substituents
that lacked the pendant alcohol function (7a) (2d to 2f, 2l, and 2m) and inductive (2h) ac- in the ortho and para positions of the aryl ring
or in which the alcohol was silylated (8a) did ceptors were all viable for nitrene internaliza- favor the formation of quinone-type resonance
not afford any detectable pyridine under anal- tion. The reaction also tolerates protected amines forms upon nitrene generation, which we have
ogous conditions, supporting the critical role (2p and 2s), allowing conversion of amino- found not to productively form azepines. The
of spirocyclization in the carbon-deletion pro- glutethimide into rogletimide and alcohols oxidation carries a different set of limitations.
cess. Computational assessment of the forma- (2 g, 2h, and 2i), even those with delicate pro- Free alcohols and amines do not productively
tion of 2a from 5a at the BP86/def2-SVP/D3BJ/ tecting groups such as silyl ethers. Strained and react with N-bromocaprolactam, even in the
CPCM(THF)//wB97XD3/def2-TZVP/CPCM(THF) fused rings were also compatible (2p and 2r). presence of excess base, necessitating their
level of theory revealed an energetic landscape A critically important feature of our protocol protection. In some instances, overoxidation
roughly in line with our experimental obser- is that in cases in which two different azepine of the intermediate azepine leads instead to
vations (THF, tetrahydrofuran). The extru- isomers are formed during photolysis, both bromopyridines or bipyridines as prominent
sion was predicted to proceed with an overall converge to a common product. Indeed, for by-products. In this regard, we found that
barrier of 21.5 kcal/mol through a stepwise substrate 1t, we could observe the formation substrates bearing sterically demanding groups
carbene extrusion by means of a zwitterionic of both azepine isomers in a 1:1 ratio. Treat- in the para position tended to avoid these side
intermediate (INT2) (37). Although various ment of these azepines, either as a mixture reactions (compare 2l versus 2m; 2a versus
levels of theory disagreed on the rate-determining (Fig. 3B) or upon separation (supplementary 2t) and as such served as the most general
step, all functionals that we examined afforded materials), led to the formation of the ipso- substrate class.
an energy surface with three similarly energetic substitution product 2t as the exclusive pyri- To further demonstrate the applications
transition states (details provided in supple- dine product, with no detectable formation of this protocol, we examined its use in a
mentary materials). The two diastereomeric of its isomeric pyridines. Although isomers 3ta more complex setting (Fig. 4A). Estrone can be

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can be conducted, enabling nitrogen scan ope- data are available in the supplementary materials. License
(2022).
rations that serve as a direct chemical analog information: Copyright © 2023 the authors, some rights reserved;
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