Exploiting Imine Photochemistry for Masked N-Centered Radical Reactivity

Article abstract of DOI:10.1002/anie.201909492

This report details the development of a masked N-centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1-aminonorbornanes. This process employs the N-centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C?C bonds en route to the norbornane core. Achieving bond-forming reactivity as a function of the N-centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl-fused 1-aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

Full text of DOI:10.1002/anie.201909492

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International Edition: DOI: 10.1002/anie.201909492
German Edition: DOI: 10.1002/ange.201909492
Radical Reactions
Exploiting Imine Photochemistry for Masked N-Centered Radical
Reactivity**
Daryl Staveness, James L. Collins III, Rory C. McAtee, and Corey R. J. Stephenson*
Abstract: This report details the development of a masked N-
centered radical strategy that harvests the energy of light to
drive the conversion of cyclopropylimines to 1-aminonorbor-
nanes. This process employs the N-centered radical character
of a photoexcited imine to facilitate the homolytic fragmenta-
tion of the cyclopropane ring and the subsequent radical
and photophysics research have set the stage for synthetic
chemists to create and invent the technologies of tomorrow
while addressing the major challenges of today. One such
challenge is the need for more efficient syntheses of saturated
building blocks in drug discovery.[4,13,14] Increased saturation
not only offers access to more diverse chemical space[15] but is
also correlated with improved developmental properties,[16]
including a decreased likelihood of CYP450 inhibition and
the associated adverse metabolic events.[17] This work con-
tributes to this need while also expanding our repertoire of
photochemical methodology, demonstrating the ability of a 4-
nitrobenzimine to drive the homolysis of a strained ring and
ultimately facilitate the production of 1-aminonorbornanes
(1-aminoNBs; systems being evaluated as potential aniline
bioisosteres) using nothing other than violet light.
ꢀ
cyclization sequence that forms two new C C bonds en route
to the norbornane core. Achieving bond-forming reactivity as
a function of the N-centered radical character of an excited
state Schiff base is unique, requiring only violet light in this
instance. This methodology operates in continuous flow,
enhancing the potential to translate beyond the academic
sector. The operational simplicity of this photochemical
process and the structural novelty of the (hetero)aryl-fused 1-
aminonorbornane products are anticipated to provide a val-
uable addition to discovery efforts in pharmaceutical and
agrochemical industries.
Our initial strategy for the synthesis of 1-aminoNBs[18]
(see Figure 1A) was informed by our prior efforts leveraging
photoredox catalysis for amine oxidation.[19–22] While the
majority of amine oxidation methods lead to a-amino radicals
through heterolytic decomposition of amine radical cation
intermediates,[10,23] our initial approach operated through
strain-driven homolytic decomposition of oxidized amino-
cyclopropanes, generating a carbon-centered radical that
proceeds to the norbornane core via serialized radical
cyclizations. Unfortunately, this strategy only proved effective
for N,N-dialkylaminocyclopropane starting materials, prohib-
iting our planned applications of C1-NH2 1-aminoNBs.
Circumventing this limitation would require another means
of accessing open-shell character at nitrogen (see Figure 1B).
Nitrogen-centered radicals have drawn a great deal of interest
in recent years, largely driven by photochemical innova-
tion.[24,25] Prominent alternatives to amine radical cations
Introduction
The unique reactivity of excited state species has been
a major driving force for synthetic innovation, both in
classical times and during the modern reinvigoration of
photochemical methodology.[1,2] Importantly, as the pharma-
ceutical industry continues to increase its investment in
photochemistry,[3,4] the field now has an unprecedented
opportunity to translate academic discoveries into disruptive
new technologies. The large-scale production of artemisinin
illustrates this transformative potential,[5] and state-of-the-art
visible light-based methods are also beginning to directly
impact drug development (e.g. elbasvir[6]). The revival of
photoredox catalysis has played a leading role in the rise of
visible light photochemistry,[7,8] largely because the strategy
offers exceedingly mild access to open-shell species (e.g.
carbon-centered radicals,[9] amine radical cations[10]) and can
be paired with additional catalytic protocols (e.g. Ni-based
cross-coupling,[11] enantioselective Lewis acid catalysis[12]).
However, photoredox catalysis is not the only photochemical
technique that is worth exploring. Decades of photochemistry
ꢀ
include amidyl or imidyl radicals arising from oxidation of N
H bonds[26,27] via proton-coupled electron transfer (PCET)[28]
[29–31]
or from N X bonds via homolysis,
reduction,[32] or even
ꢀ
oxidation[33] by employing a-aminoxy carboxylic acid auxil-
iaries popularized by the groups of Leonori[34,35] and Stud-
er.[36,37] Alternatively, it was hypothesized that initiation of
our desired fragmentation-cyclization sequence could be
accomplished not from a discrete N-centered radical but
a temporaneous N-centered radical. More specifically, a cyclo-
propylimine would serve as a masked N-centered radical,
revealing the nitrogen-based radical character only upon
excitation. Directing the focus to aryl aldehydes provided the
potential for selective excitation, as the conjugated imines
were anticipated to absorb at longer wavelengths than
common organic chromophores. As both the introduction
and removal of the Schiff base were expected to be facile and
high-yielding (and could perhaps be accomplished in a cata-
lytic sense in conjunction with the photochemistry; see
[*] Dr. D. Staveness, J. L. Collins III, R. C. McAtee,
Prof. C. R. J. Stephenson
Department of Chemistry, University of Michigan
930 N. University Ave, Ann Arbor, MI 48109 (USA)
E-mail: crjsteph@umich.edu
[**] A previous version of this manuscript has been deposited on
a preprint server (https://doi.org/10.26434/chemrxiv.7390421.v1).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201909492.
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specific rearrangement is the photo-racemization of dihydro-
pyrazine (ꢀ)-3 (see Figure 2A),[42] facilitated by the non-
classical bond structure available to [2.2.1] bicyclic systems
with open-shell character adjacent to the bridgehead position.
Figure 2. Imine-based photochemistry and the design of our masked
N-centered radical strategy: A) Photo-racemization of dihydropyrazine
(ꢀ)-3 with UV light[42] (of note, all necessary electron-pushing arrows
are depicted, but this is not expected to be a concerted process).
B) Design principles behind our masked N-centered radical strategy
for the synthesis of 1-aminoNBs.
Figure 1. 1-Aminonorbornanes through photochemical innovation:
A) Comparison of our photochemical strategies toward 1-aminonor-
bornanes. B) Comparison of existing approaches for the production of
nitrogen-centered radicals with our masked N-centered radical strat-
egy.
This work also represents a rare prior example of a 1-
aminoNB in the literature; of note, the majority of prior 1-
aminoNB preparations generate the bridgehead amine via
a Hofmann or a Curtius rearrangement of terpene-based
materials[43–46] or from downstream products of cyclopenta-
diene-acrylate Diels–Alder reactions[47–50] (only one radical-
based closure[51] existed before our work[18]).
Our approach, as designed to supply 1-aminoNBs (2; see
Figure 2B) from the Schiff base of aminocyclopropanes (1),
distinguishes itself from the decades of prior imine photo-
chemistry by initiating a multi-step radical fragmentation/
Supporting Information), this strategy appeared to offer an
efficient solution to the need for C1-NH2 1-aminoNBs.
Interestingly, the N-centered radical character of excited
state imines has yet to be harnessed as an initiator for radical
cyclization chemistry. Most reports of photoexcited imines
have been designed to follow closely to carbonyl or olefin
photochemistry, but even early investigations appreciated
that this translation is not necessarily a direct one.[38,39] For
instance, photoisomerizations of N-aryl benzimines are prone
to thermal equilibration back to the E-isomer,[38] and aza-
photocycloadditions tend to require specialized systems,
specifically N-acyl imines.[38–40] Similarly, achieving an aza
variant of the Norrish type II cyclization required an
intricately designed oxazolinone from Hoffmann, Abe, and
co-workers.[41] Importantly, despite the discrepancies between
imine and carbonyl photochemistry, the mechanistic rules that
govern excited state reactivity still hold; for example, photo-
chemical electrocyclic ring opening and ring closure reactions
proceed through the 1(p,p*) state in concordance with
Woodward–Hoffmann rules.[38] One example of an imine-
ꢀ
cyclization sequence (forming two new C C bonds in the
process) from the nitrogen-centered radical component of the
excited state diyl. Initiating radical relay reactions from
excited state diyls presents a major challenge: both radicals
must be successfully terminated to generate a stable, closed-
shell product. Our mechanistic design overcomes this factor
by bringing the open-shell character back to the original
atoms involved in the excitation event. While the carbon-
based radical is simply a bystander, the nitrogen-based radical
drives the multi-step formation of the norbornane core only
to return to nitrogen, a unique attribute that is functionally-
analogous to the round-trip radical probes introduced by
Branchaud[52,53] and Eaton.[54] Termination of both radicals is
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thus achieved simultaneously through simple restoration of
the pCN bond. The development of our masked N-centered
radical strategy, performance in continuous flow, mechanistic
proposal, and evaluation of scope is reported herein.
excitation of a given transition. It was anticipated that the
desired cyclopropane fragmentation would operate via
ꢀ
a mechanism analogous to C H abstraction or a-cleavage
reactions of excited state carbonyls (i.e. Norrish-type chemis-
try), as these modes of reactivity clearly rely on open-shell
character at the heteroatom. The excited state species
implicated in that chemistry is the S1(n,p*) state, where the
in-plane association of a nucleophilic s-bond with the
electrophilic singly-occupied lone pair on oxygen drives the
requisite bond scission.[55] Applying this logic to our system,
the singly-occupied nitrogen lone pair (nN) of the S1(n,p*)
state would serve as the electrophilic component, enabling the
homolytic fragmentation of a nucleophilic, in-plane sCC bond
of the adjacent cyclopropane (see Figure 3D). Significantly,
the large bathochromic shift observed for the n!p* tran-
sition for cyclopropylimine 1a (Dlmax ꢁ+ 100 nm relative to
acetaldehyde[56]) allows for excitation near the visible range
(violet light), suggesting a high degree of functional group
tolerance relative to classical UVB/UVC-mediated carbonyl
photochemistry.
Results and Discussion
The initial assessment of our masked N-centered radical
strategy began with UV/Vis spectroscopic analysis of benzo-
fused cyclopropylimine starting material 1a and model 4-
nitrobenzimine 1b (see Figure 3; 1-aminoNB 2a included for
completeness). All three Schiff base systems revealed a strong
absorbance near 300 nm (see Figure 3A) and a second, much
weaker absorbance around 380–385 nm (see Figure 3B);
notably, the styrene functionality of cyclopropylimine 1a is
shown to absorb below 275 nm and is believed to be
ineffectual in this work. These ꢁ 300 nm and ꢁ 385 nm
maxima are assigned as the p!p* and n!p* transitions,
respectively, consistent with the wealth of literature surround-
ing the photochemistry of carbonyl compounds and deriva-
tives thereof (including imines[38,39]). The discrepancy in molar
absorptivities (see Figure 3C) is a function of orbital overlap,
as the ground state species is optimally-aligned for a p!p*
transition but necessitates out-of-plane bending to overcome
the perpendicularity of the n and p* orbitals.[55] Importantly,
the relatively large resolution[39,56] between these maxima (as
measured in acetonitrile) offers the potential for selective
To evaluate the viability of this mechanistic hypothesis,
benzo-fused cyclopropylimine 1a was exposed to a range of
wavelengths to assess conversion to 1-aminoNB 2a (see
Figure 4). As there was no theoretical need for any additional
reagents, the optimization was centered exclusively on light
source. Irradiating degassed solutions of cyclopropylimine 1a
in dry acetonitrile quickly revealed a preference for 390 nm
light, presumably progressing through the S1(n,p*) state to
Figure 3. UV/Vis data and proposed mechanism of cyclopropane fragmentation: A) UV/Vis data for cyclopropylimines 1b and 1a and 1-aminoNB
2a collected at 50 mm in MeCN. B) UV/Vis data collected at 10 mm in MeCN. C) Structures and data summary; [a]molar absorptivities (e)
estimated from peak absorbance at single concentration. D) Depiction of in-plane donation from cyclopropyl sCC to singly-occupied nn orbital in
S1(n,p*) state.
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Figure 4. Optimization of light source for photochemical production of
1-aminoNBs: Reactions were run on ꢁ200 mmol scale and degassed
prior to irradiation via three freeze-pump-thaw cycles; all reactions run
in 2 dram borosilicate vials except entry 2 (quartz tube) and entry 5
(TPFA tubing), see Supporting Information. [a] No product was
isolated, but an estimated 1–2% was detected by crude 1H NMR.
[b] Trial 5 was run in continuous flow (see Supporting Information for
details on flow apparatus). [c] Vial was wrapped in black electrical tape
to exclude light prior to exposure to standard batch conditions.
fully consume starting material and afford the desired product
in 76% yield after 8 hrs of irradiation (entry 1; 200 mmol scale
reaction). In concordance with the above analysis, excitation
of the p!p* transition with 300 nm light (entry 2) did not
proceed to product, and in fact, returned starting material in
nearly quantitative recovery. Light sources less optimally-
aligned with the n!p* transition maxima ( ꢁ 385 nm)
predictably provided less conversion, with the 370 nm light
source outperforming the 440 nm light source as expected
(51% vs. 13% yield, respectively; entries 3 and 4). The utility
of the 390 nm light was further demonstrated in a continuous
flow setting (entry 5); the optimized batch processing yield
was nearly recapitulated (73% vs. 76%) while improving the
rate of production and indicating potential for translation into
an industrial setting, where flow photochemistry has drawn
substantial interest.[57] Significantly, this reactivity definitively
requires light, as evidenced by the near quantitative recovery
of starting material upon excluding light from the reaction or
employing purely thermal conditions at 1208C in a sealed
tube (entries 6 and 7, respectively).
Figure 5. Reaction scope: A) Generic reaction scheme; all reactions
were run on ꢁ200 mmol scale and degassed via three freeze-pump-
thaw cycles prior to exposure to optimized conditions; Ar=4-nitro-
phenyl. B) Arene modifications. C) C7-substitution effects. [a] C7-
CO2Me substrate proceeded in 3.6:1 anti:syn dr based on crude
1H NMR, but was isolated in 48% yield in >20:1 dr (an additional 10–
15% of a 1:5 anti:syn mixture was collected along with minor
impurities). D) Deviations from designed reactivity.
Evaluation of the reaction scope was performed on
a variety of cyclopropylimines with fused aryl and heteroaryl
rings. The (hetero)aryl fusion arose from the chosen approach
for starting material synthesis, which converted commercial-
ly-available 2-halo-(hetero)aryl nitriles to the desired cyclo-
propylimines via a three-step sequence: 1) a modified Ku-
linkovich cyclopropanation,[58–60] 2) Schiff base formation, and
3) Suzuki coupling (see Supporting Information for detailed
synthetic procedures). All cyclopropylimine starting materi-
als were subjected to the optimized 390 nm irradiation
conditions, and the isolated yields of 1-aminoNB products
(isolated as the Schiff base) are provided in Figure 5.
route to fluorinated systems 2d and 2e (isolated in 80% and
83% yield, respectively). The location of the substituent
appeared to be ineffectual. Even a C11-methyl group was
viable (providing 1-aminoNB 2c in 75% yield), despite the
potential for 1,5-H-atom abstraction by the C7-radical
intermediate. In addition to the C10- and C9-fluoro species
mentioned above, C9-chloro and C9-trifluoromethyl 1-
aminoNBs 2 f and 2g were generated in good yield. Interest-
ingly, upon transitioning to an electron-donating methoxy
group, substitution locale played a major role in reaction
progression, affording C9-methoxy 1-aminoNB 2h in good
yield (65%) yet producing only 29% of the C8-methoxy 1-
Starting with the substituted benzene series, both neutral
and electron-withdrawing substituents were well-tolerated
(2c–2g), with the substitution even providing some benefit en
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aminoNB 2i; it is suspected that the C8 functionality inhibits
progression via A1,3 interactions that alter the conformational
preferences of the cyclopropane motif, but electronic factors
could also contribute to the above observation. Heteroarene
fusions were also amenable to the photochemical method-
ology, providing structurally-unique thiophene-fused (2j) and
pyridine-fused (2k) 1-aminoNBs (of note, while 11-aza 1-
aminoNB 2k was produced in 73% yield, the related 8-aza
system was isolated in only 20% yield; see pg. S86 of
Supporting Information for more details). In regards to varied
substitution on the aliphatic portion of the norbornane core,
this methodology tracked with our prior observations with
N,N-dialkylaminocyclopropanes, necessitating functionality
at C7 to stabilize the C7-radical of diyl intermediate. For
mono-substituted systems, the anti:syn ratio of 1-aminoNB
products was consistently close to 2:1 in favor of the anti
isomer for C7-alkyl systems, with steric bulk only minimally
increasing the selectivity for the anti isomer (e.g. C7-tert-butyl
system 2n, 3.0:1 dr); this ratio was also independent of the
original olefin geometry as C7-methyl 1-aminoNB 2l was
formed in a 2.2:1 anti:syn ratio from the Z-isomer, while C7-
propyl 1-aminoNB 2m was isolated in a 1.7:1 anti:syn ratio
from the E-isomer. Similarly to above, the fluorinated systems
2p and 2q were produced in higher yields than the
corresponding benzo-fused 1-aminoNB 2m (58% and 57%
vs. 45%). Interestingly, the C7-carboxylate product 2o was
formed with the highest selectivity for the anti-isomer (48%
yield of anti isomer; 3.6:1 dr in crude reaction mixture),
suggesting that electronic factors can also serve a minor role.
During the course of evaluating the substrate scope,
a number of observations were made that merit discussion. In
regards to the role of the nitro motif in our masked N-
centered radical strategy, it was proven to be necessary, given
that a 3,5-bis(trifluoromethyl)benzimine system was unable
to facilitate the production of 1-aminoNB 2r upon irradiation
at 390 nm or at shorter wavelengths (see Supporting Infor-
mation). Secondly, a 2,3-thiophene-fused cyclopropylimine
1y provided an intriguing cyclohexane byproduct (4) in good
yield (69%) rather than the desired 1-aminoNB ( ꢁ 6%). This
represents the only evidence for premature termination
pathways competing with the desired radical cyclization
sequence; even the closely-related 3,4-thiophene-fused sys-
tem 2j did not produce detectable quantities of this by-
product, suggesting strict electronic requirements for the
undesired termination. It is not known whether the distonic
diyl intermediate progresses to cyclohexane 4 through
electron-transfer or H-atom abstraction pathways at this
time, nor is it known whether or not this pathway is coupled to
the production of the minor pyrroline byproduct ( ꢁ 10%
yield; see pg. 120 of Supporting Information). Of note, the
photochemical cyclopropylimine-pyrroline rearrangement
has been reported[61–63] (and could be achieved, albeit
inefficiently, by irradiating model cyclopropylimine 1b under
standard conditions), but this was not an appreciably com-
petitive pathway. The majority of these transformations
generated the desired 1-aminoNBs as the only detectable
product, speaking to the overall efficiency of the reaction
design despite the implementation of highly-reactive inter-
mediates (i.e. singlet excited states, carbon-centered radicals).
In fact, cyclopropylimine 1y was the only substrate tested that
produced isolable quantities of the pyrroline byproduct; see
pg. S11 for control experiments and further discussion of this
rearrangement as contextualized with our methodology.
As a preliminary means of showcasing the utility of the 1-
aminoNB products and thus the masked N-centered radical
strategy, a number of post-irradiation functionalizations were
performed on the benzo-fused norbornane scaffold 2a. Initial
removal of the Schiff base proceeded cleanly, as anticipated,
to reveal the C1-NH2 1-aminoNB target 2s (see Figure 6A).
Alternatively, coupling the photochemical method with Schiff
base formation and/or removal in a one-pot fashion was
proven to be viable (see pg. S8 of Supporting Information),
though the two-step sequence shown here has thus far led to
the highest yields of 1-aminoNB 2s. Manipulation of the free
amine of 1-aminoNB 2s can be achieved through standard
methods, as demonstrated through acetylation to acetamide
2t. Direct conversion of the Schiff base product 2a to
acetamide 2t proceeded in higher yield than the two-step
deprotection-acetylation sequence, suggesting the potential
to couple the deprotection and N-functionalization proce-
dures together en route to alternative targets. Notably, 1-
aminoNB 2s itself offers a great deal of synthetic flexibility in
addition to standard uses of amine functionality (e.g. nucle-
ꢀ
ophilic aromatic substitution, C N coupling reactions; not
shown). The bridgehead amine can also serve as a precursor
to a bridgehead cation (via the bridgehead diazonium species
5). This methodology was originally developed as a means of
delineating SN1 mechanisms,[64] and variations have been
developed to generate 1-hydroxy, 1-halo, and 1-aryl norbor-
nanes[45,65,66] from these unique cationic species; conditions to
afford the former[44] were recapitulated herein, providing 1-
Figure 6. Post-irradiation functionalization of 1-aminoNBs: A) Bridge-
head manipulations; Reagents and conditions: a) AcOH, H2O, MeCN,
rt; b) Ac2O, NEt3, DMAP, CH2Cl2, rt; c) Ac2O, pTsOH·H2O, DCE, 758C;
d) NaNO2, 2m H2SO4 (aq), 1:1 DMF:H2O, 08C to rt. B) Manipulation
of C7-CO2H 1-aminoNB 2v; Reagents and conditions: e) [Ir(dF-
(CF3)ppy)2(dtbbpy)](PF6) (2.5 mol%), K2HPO4, Two H150 Blue Kessil
lamps, 1:1 iPrOH:DMF, 30–358C (fan-controlled); f) Ir(dF(CF3)ppy)2-
(dtbbpy)](PF6) (2.5 mol%), NiBr2·DME (20 mol%), dtbbpy (25 mol%),
K2CO3, methyl 4-bromobenzoate, Two H150 Blue Kessil lamps, MeCN,
30–358C (fan-controlled); Ar=(4-CO2Me)-C6H4.
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three freeze-pump-thaw cycles. The reaction was irradiated with
hydroxynorbornane 6 in 74% yield. Perhaps the most
significant manipulation was the conversion of C7-CO2Me
1-aminoNB 2o to the C7-methylene 1-aminoNB 2v (see
Figure 6B). The C7-methylene system provides the closest
spatial occupancy to the aniline congener, which could prove
critical for the execution of our 1-aminoNB bioisosterism
goals (outlined in our prior manuscript[18]). This was achieved
through photochemical reductive decarboxylation of a C7-
carboxylic acid species (2u). Given the prevalence of
carboxylic acid manipulations now available, this sequence
indicates the potential for rapid diversification of these 1-
aminoNB scaffolds. One such attempt yielded O-arylated
species 2w via a photochemical IrIII/NiII co-catalyzed trans-
formation inspired by MacMillan lab research. Of note, while
the chosen conditions more closely mimic the decarboxylative
cross-coupling methodology,[67] the reaction yielded the
product previously ascribed to an energy transfer-mediated
transformation.[68] This result communicates the complexity
associated with deconvoluting the reactivity available via
these co-catalytic photochemical processes,[11] further incen-
tivizing rigorous mechanistic evaluation of these reaction sub-
types.[69] Significantly, whether through incorporation of
functionality in the cyclopropylimine starting materials or
post-irradiation manipulations, this methodology enables the
production of a variety of substituted 1-aminoNBs, all of
which are structurally-distinct from building blocks currently
available to the drug discovery community.
390 nm light (Kessil PR-160 model) for 8 hrs (for 200 mmol-scale
reactions), controlling the temperature between 30–358C with a fan.
The mixture was partitioned between 1:1 saturated NaHCO3 (aq.):-
water and ether. Phases were separated, and the aqueous phase was
further extracted with ether three times. Combined organics were
washed with brine, dried over anhydrous magnesium sulfate, filtered
to remove solids, and concentrated in vacuo. The crude residue was
purified via flash chromatography over basic alumina to afford the
desired 1-aminoNB as the Schiff base (2). No unexpected or
unusually high safety hazards were encountered. For detailed
experimental procedures and characterization data for all cyclo-
propylimines and 1-aminoNBs presented above, see the Supporting
Information.
Acknowledgements
The authors acknowledge the financial support for this
research from the NIH NIGMS (R01-GM127774), the
Camille Dreyfus Teacher-Scholar Award Program, and the
University of Michigan. DS was supported by a Postdoctoral
Fellowship, PF-16-236-01–CDD, from the American Cancer
Society. This material is based upon work supported by the
National Science Foundation Graduate Research Fellowship
for RCM (Grant No DGE 1256260). J.L.C. was supported by
the University of Michiganꢀs Rackham Merit Fellowship.
Conflict of interest
Conclusion
The authors declare no conflict of interest.
The work detailed above demonstrates the operational-
simplicity and unique reactivity offered by our masked N-
Keywords: 1-aminonorbornane · cyclopropylimine ·
excited state diyl · imine photochemistry · N-centered radical
ꢀ
centered radical strategy. Initiating a radical C C bond
ꢀ
fragmentation/C C bond-forming cyclization sequence from
the N-centered radical character of an excited state imine is,
to our knowledge, a fundamentally new transformation in
synthetic photochemistry. Terminating the radical processes
via regeneration of the imine obviated the need for any
reagent beyond the light source itself, which conveniently lies
in the violet region of the spectrum and thus avoids unwanted
excitation of common functional groups (cross-reactivity that
can plague the utility of traditional UVB photochemistry).
Importantly, this new mode of reactivity ultimately enabled
the production of the originally-targeted C1-NH2 1-ami-
noNBs, facilitating downstream applications of these satu-
rated buildings blocks. As the Schiff base is both introduced
and removed via simple and mild transformations, it was an
ideal surrogate for the amine radical cation-driven reactivity
previously developed. This new photochemical transforma-
tion thus provides a key motif for our aniline bioisosterism
program while opening new avenues for the modern synthetic
photochemist.
[1] D. Schultz, T. Yoon, Science 2014, 343, 1239176.
[2] M. Kꢁrkꢁs, J. Porco, C. R. J. Stephenson, Chem. Rev. 2016, 116,
9683 – 9747.
[3] J. Douglas, M. Sevrin, C. R. J. Stephenson, Org. Process Res.
Dev. 2016, 20, 1134 – 1147.
[4] D. Blakemore, L. Castro, I. Churcher, D. Rees, A. Thomas, D.
Wilson, A. Wood, Nat. Chem. 2018, 10, 383 – 394.
[5] J. Turconi, F. Griolet, R. Guevel, G. Oddon, R. Villa, A. Geatti,
M. Hvala, K. Rossen, R. Goller, A. Burgard, Org. Process Res.
Dev. 2014, 18, 417 – 422.
[6] H. Yayla, F. Peng, I. Mangion, M. McLaughlin, L. Campeau, I.
Davies, D. DiRocco, R. Knowles, Chem. Sci. 2016, 7, 2066 – 2073.
[7] M. Shaw, J. Twilton, D. MacMillan, J. Org. Chem. 2016, 81, 6898 –
6926.
[8] J. Douglas, J. Nguyen, K. Cole, C. R. J. Stephenson, Aldrichimica
Acta 2014, 47, 15 – 25.
[9] D. Staveness, I. Bosque, C. R. J. Stephenson, Acc. Chem. Res.
2016, 49, 2295 – 2306.
[10] J. Beatty, C. R. J. Stephenson, Acc. Chem. Res. 2015, 48, 1474 –
1484.
[11] J. Twilton, C. Le, P. Zhang, M. Shaw, R. Evans, D. MacMillan,
Nat. Rev. Chem. 2017, 1, 0052.
[12] T. Yoon, Acc. Chem. Res. 2016, 49, 2307 – 2315.
[13] T. Ritchie, S. Macdonald, J. Med. Chem. 2014, 57, 7206 – 7215.
Experimental Section
In a dry vial under inert atmosphere, cyclopropylimine 1 was
dissolved in dry MeCN (0.1m). Reaction mixture was degassed with
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These are not the final page numbers!

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[14] D. Brown, J. Bostrom, J. Med. Chem. 2016, 59, 4443 – 4458.
[15] F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52,
6752 – 6756.
[16] T. Ritchie, S. Macdonald, R. Young, S. Pickett, Drug Discovery
Today 2011, 16, 164 – 171.
[17] F. Lovering, MedChemComm 2013, 4, 515 – 519.
[18] D. Staveness, T. Sodano, K. Li, E. Burnham, K. Jackson, C. R. J.
Stephenson, Chem 2019, 5, 215 – 226.
[19] A. Condie, J. Gonzalez-Gomez, C. R. J. Stephenson, J. Am.
Chem. Soc. 2010, 132, 1464 – 1465.
[43] J. Houben, E. Pfankuch, Justus Liebigs Ann. Chem. 1931, 489,
193 – 223.
[44] P. Bartlett, L. Knox, J. Am. Chem. Soc. 1939, 61, 3184 – 3192.
[45] P. Beak, B. Harris, J. Am. Chem. Soc. 1974, 96, 6363 – 6372.
[46] R. Braslau, H. Kuhn, L. Burrill II, L. Lanham, C. Stenland,
Tetrahedron Lett. 1996, 37, 7933 – 7936.
[47] D. Applequist, J. Klieman, J. Org. Chem. 1961, 26, 2178 – 2182.
[48] J. Wilt, C. Parsons, C. Schneider, D. Schultenover, W. Wagner, J.
Org. Chem. 1968, 33, 694 – 708.
[49] A. Nickon, T. Nishida, Y. Lin, J. Am. Chem. Soc. 1969, 91, 6860 –
6861.
[20] G. Bergonzini, C. Schindler, C. Wallentin, E. Jacobsen, C. R. J.
Stephenson, Chem. Sci. 2014, 5, 112 – 116.
[21] J. Douglas, K. Cole, C. R. J. Stephenson, J. Org. Chem. 2014, 79,
11631 – 11643.
[50] M. Dejmek, H. Hrebabecky, M. Sala, M. Dracinsky, E.
Prochazkova, P. Leyssen, J. Neyts, J. Balzarini, R. Nencka,
Bioorg. Med. Chem. 2014, 22, 2974 – 2983.
[22] J. Beatty, C. R. J. Stephenson, J. Am. Chem. Soc. 2014, 136,
10270 – 10273.
[23] U. Yoon, Z. Su, P. Mariano in CRC Handbook of Organic
Photochemistry and Photobiology, 2nd ed. (Eds.: W. Horspool, F.
Lenci), CRC Press, Boca Raton, FL, 2004, Chap. 101, pp. 101-1 –
101-20.
[24] M. Kꢁrkꢁs, ACS Catal. 2017, 7, 4999 – 5022.
[25] T. Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45, 3069 – 3087.
[26] G. Choi, Q. Zhu, D. Miller, C. Gu, R. Knowles, Nature 2016, 539,
268 – 271.
[27] J. Chu, T. Rovis, Nature 2016, 539, 272 – 275.
[28] E. Gentry, R. Knowles, Acc. Chem. Res. 2016, 49, 1546 – 1556.
[29] V. Schmidt, R. Quinn, A. Brusoe, E. Alexanian, J. Am. Chem.
Soc. 2014, 136, 14389 – 14392.
[51] E. Della, A. Knill, Aust. J. Chem. 1994, 47, 1833 – 1841.
[52] B. Branchaud, A. Glenn, H. Stiasny, J. Org. Chem. 1991, 56,
6656 – 6659.
[53] B. Branchaud, M. Montague-Smith, J. Am. Chem. Soc. 1993, 115,
798 – 800.
[54] P. Eaton, Y. Yip, J. Am. Chem. Soc. 1991, 113, 7692 – 7697.
[55] N. Turro, V. Ramamurthy, J. Scaiano, Principles of Molecular
Photochemistry: An Introduction (Ed.: N. Turro), University
Science Books, Sausalito, CA, 2009, pp. 52 – 66 and 370 – 382.
[56] A. Gordon, R. Ford, The Chemistꢀs Companion: A Handbook of
Practical Data, Techniques, and References (Ed. A. Gordon),
Wiley, New York, 1972, pp. 211 – 220.
[57] D. Cambiꢂ, C. Bottecchia, N. Straathof, N. Hessel, T. Noꢃl,
Chem. Rev. 2016, 116, 10276 – 10341.
[30] W. Czaplyski, C. Na, E. Alexanian, J. Am. Chem. Soc. 2016, 138,
13854 – 13857.
[58] J. Cha, O. Kulinkovich, Organic Reactions, Vol. 77 (Ed. S.
Denmark), Wiley, Hoboken, 2012, pp. 3 – 160.
[31] E. Wappes, K. Nakafuku, D. Nagib, J. Am. Chem. Soc. 2017, 139,
10204 – 10207.
[32] K. Nakafuku, S. Fosu, D. Nagib, J. Am. Chem. Soc. 2018, 140,
11202 – 11205.
[59] P. Bertus, J. Szymoniak, Chem. Commun. 2001, 1792 – 1793.
[60] P. Bertus, J. Szymoniak, J. Org. Chem. 2002, 67, 3965 – 3968.
[61] P. Campos, A. Soldevilla, D. Sampedro, M. Rodriguez, Org. Lett.
2001, 3, 4087 – 4089.
[33] J. Davies, S. Morcillo, J. Douglas, D. Leonori, Chem. Eur. J. 2018,
24, 12154 – 12163.
[62] D. Sampedro, A. Soldevilla, M. Rodriguez, P. Campos, M.
Olivucci, J. Am. Chem. Soc. 2005, 127, 441 – 448.
[63] A. Soldevilla, D. Sampedro, P. Campos, M. Rodriguez, J. Org.
Chem. 2005, 70, 6976 – 6979.
[64] D. Applequist, J. Roberts, Chem. Rev. 1954, 54, 1065 – 1089.
[65] P. Beak, R. Trancik, J. Am. Chem. Soc. 1968, 90, 2714 – 2715.
[66] P. Beak, R. Trancik, D. Simpson, J. Am. Chem. Soc. 1969, 91,
5073 – 5080.
[67] C. Johnston, R. Smith, S. Allmendinger, D. MacMillan, Nature
2016, 536, 322 – 325.
[68] E. Welin, C. Le, D. Arias-Rotondo, J. McCusker, D. MacMillan,
Science 2017, 355, 380 – 385.
[34] J. Davies, N. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2017, 56,
13361 – 13365; Angew. Chem. 2017, 129, 13546 – 13550.
[35] E. Dauncey, S. Morcillo, J. Douglas, N. Sheikh, D. Leonori,
Angew. Chem. Int. Ed. 2018, 57, 744 – 748; Angew. Chem. 2018,
130, 752 – 756.
[36] H. Jiang, A. Studer, Angew. Chem. Int. Ed. 2017, 56, 12273 –
12276; Angew. Chem. 2017, 129, 12441 – 12444.
[37] H. Jiang, G. Seidler, A. Studer, Angew. Chem. Int. Ed. 2019, 58,
16528 – 16532; Angew. Chem. 2019, 131, 16680 – 16684.
[38] A. Pratt, Chem. Soc. Rev. 1977, 6, 63 – 81.
[39] A. Padwa, Chem. Rev. 1977, 77, 37 – 68.
[69] D. Arias-Rotondo, J. McCusker, Chem. Soc. Rev. 2016, 45, 5803 –
5820.
[40] E. Kumarasamy, S. Kandappa, R. Raghunathan, S. Jockusch, J.
Sivaguru, Angew. Chem. Int. Ed. 2017, 56, 7056 – 7061; Angew.
Chem. 2017, 129, 7162 – 7167.
[41] C. Lefebvre, C. Michelin, T. Martzel, V. Djouꢀou Mvondo, V.
Bulach, M. Abe, N. Hoffmann, J. Org. Chem. 2018, 83, 1867 –
1875.
Manuscript received: July 28, 2019
Revised manuscript received: October 7, 2019
[42] D. Farnum, G. Carlson, J. Am. Chem. Soc. 1970, 92, 6700 – 6701.
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Research Articles
Radical Reactions
D. Staveness, J. L. Collins, R. C. McAtee,
C. R. J. Stephenson*
&&&& — &&&&
Exploiting Imine Photochemistry for
Masked N-Centered Radical Reactivity
The N-centered open-shell character of
photoexcited cyclopropylimines is uti-
lized to initiate a radical fragmentation–
cyclization sequence that generates
bridgehead-functionalized norbornanes.
This unique mode of reactivity requires
only violet light to proceed, and the 1-
aminonorbornane products are valuable
building blocks for drug and agrochem-
ical discovery programs.
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&&&&
These are not the final page numbers!