Photoredox Radical/Polar Crossover Enables Construction of Saturated Nitrogen Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b00602

Photoredox-mediated radical/polar crossover (RPC) processes offer new avenues for the synthesis of cyclic molecules. This process has been realized for the construction of medium-sized saturated nitrogen heterocycles. Photocatalytically generated alkyl ra

Full text of DOI:10.1021/acs.orglett.9b00602

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoredox Radical/Polar Crossover Enables Construction of
Saturated Nitrogen Heterocycles
Loïc R. E. Pantaine,† John A. Milligan,† Jennifer K. Matsui,† Christopher B. Kelly,*,‡,§
and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, P.O. Box 842006, Richmond, Virginia
23284-9069, United States
§Medicines for All Institute, Virginia Commonwealth University, Biotech 8 737 North Fifth Street, Richmond, Virginia 23219-1441,
United States
S
* Supporting Information
ABSTRACT: Photoredox-mediated radical/polar crossover
(RPC) processes offer new avenues for the synthesis of cyclic
molecules. This process has been realized for the construction
of medium-sized saturated nitrogen heterocycles. Photo-
catalytically generated alkyl radicals possessing pendant leaving
groups engage imines in C−C bond formation, and
subsequent reduction of the intermediate nitrogen-centered
radical triggers anionic ring closure. With the aid of visible
light irradiation, substituted pyrrolidines, piperidines, and
azepanes can be prepared under mild, redox-neutral
conditions.
eterocyclic compounds comprise 87% of known small
H
molecule therapeutics.1 Nitrogen-based heterocycles in
particular are among the most common subunit in drug
molecules.2 These structures also serve as the backbone of
ligands and appear in numerous natural and designed
molecules.1,2 In the context of drug development, the improved
pharmacological properties of compounds with higher fractions
of sp3-hybridized centers3 has sparked an increasing interest in
incorporating saturated nitrogen heterocycles in bioactive
molecules.4 Piperidines are the most prominent saturated
nitrogen heterocycles in therapeutic compounds, followed
closely by piperazines and pyrrolidines.2 The popularity and
utility of these heterocycles motivate the pursuit of novel
synthetic methods to prepare these cyclic systems in a mild and
modular fashion.
Figure 1. Bioactive nitrogen-containing heterocycles.
The most common approaches to introduce saturated
nitrogen heterocycles are C−N bond-forming processes
through SNAr chemistry, cross-coupling strategies such as
Buchwald−Hartwig amination, or peptide coupling.1,5 How-
ever, many medicinally relevant compounds possess α-
substitution (often aryl, Figure 1), which poses challenges to
these methods (Figure 2). A classical method for the synthesis of
α-arylated nitrogen heterocycles is a lithiation followed by
treatment with an electrophile or conversion into a suitable
nucleophile (i.e., cuprate or zincate) for cross-coupling.6
Another class of increasingly popular reactions are single-
electron variants of the lithiation approach, initiated through
either hydrogen-atom transfer (HAT)7 or photoredox-induced
oxidation of radical precursors (such as a carboxylic acids or
trifluoroborates).8 Although powerful, these strategies are
contingent on having a preconstructed saturated N-heterocycle
that is subsequently functionalized with the group of interest.
A less common approach to α-arylated nitrogen heterocycles
is the construction of the ring from acyclic precursors through an
annulation process. The most obvious way to accomplish such a
process, reductive amination, is notoriously challenging,
Received: February 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Comparison of related developments to this work.
radical alkylation of an imine using an oxidizable, bifunctional
radical precursor. Subsequent reduction of the resulting
nitrogen-centered radical would furnish an amide anion that
could engage a distal leaving group in an intramolecular
displacement. A series of annulation processes (5-, 6-, or even
7-exo-tet ring closures) can be envisioned using this improved
radical/polar crossover approach. Indeed, typical methods to
accomplish this type of process require a combination of
stoichiometric Mn2(CO)10, InCl3, and UV irradiation.20
The proposed annulation makes use of a small set of easily
accessible bis(catecholato)silicate radical precursors.21 These
reagents have previously been effective for the radical alkylation
of imines22 and the cyclopropanation of olefins19a (Figure 3).
Motivated by these previous successes, a preliminary screen was
conducted wherein imine 1 was irradiated with a series of 3-
halopropylsilicates (Cl, Br, I) in the presence of a photocatalyst
[Ru(bpy)3(PF6)2] in DMF (Table 1, entries 1−3). Although
Figure 2. Typical approaches to saturated nitrogen heterocycles.
considering that the cyclic imine intermediate is prone to
polymerization/dimerization.9 Recently, a resurgence in meth-
̈
ods based on the Hofmann−Loffler−Freytag (HLF) reaction
have yielded elegant approaches to pyrrolidines from amines
with distal olefins.10 Likewise, PCET has allowed lactams to be
prepared from cyclization of an amidyl radical containing a
pendant olefin.11
Recently, Bode and co-workers have developed a copper-
mediated annulation process using “SnAP” reagents.12 This
strategy involves condensation of an organotin-tethered amine
with an aldehyde to generate an aldimine. Subsequent oxidative
generation of a heteroatom-stabilized primary carbon-centered
radical via destannylative fragmentation triggers 6-endo-trig
cyclization. Reduction of the aminyl radical provides the desired
nitrogen heterocycle (e.g., thiomorpholine, oxazepane, 3-
alkoxypyrrolidine). A silicon variant of the annulation paradigm
has also been developed using “SLAP” reagents and transitioned
to continuous flow.13
a
Table 1. Optimization of the Annulation Process
The identification of various precursors that furnish alkyl
radicals under photoredox conditions, such as Bode’s SLAP
reagents, has led to the discovery of previously nonviable
reactions and allowed new synthetic disconnections to be
realized.14 Visible-light photoredox catalysis provides a means to
tap the synthetic potential of radicals in a way not possible when
using stoichiometric radical generation techniques, while still
retaining the benefits associated with odd-electron reactivity.
These hallmarks of photoredox processes have precipitated their
rapid uptake in both academia and industry, especially for late-
stage functionalization.15 Visible-light-mediated approaches
have revolutionized an array of different reaction classes,
including cross-coupling,16 cycloaddition,17 and, recently,
radical/polar crossover (RPC)18 processes.
In the context of the latter, our group has initiated a program
to apply various radical precursors in RPC processes that lead to
annulation reactions, including the cyclopropanation of alkenes
(Figure 3).19 Inspired by the successes of these annulation
processes and the SLAP/SnAP paradigm,13,14 a novel approach
to the synthesis of saturated nitrogen-based heterocycles from
acyclic species was considered. The crux of this approach is the
a
b
c
entry
X
photocat.
solvent
time (h)
yield (%)
1
2
3
Cl
Br
I
[Ru]
[Ru]
[Ru]
[Ru]
[Ru]
[Ir]
DMF
DMF
DMF
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
16
16
16
48
16
16
16
16
0.5
16
16
8
20
10
46
46
54
35
60
59
−
d
4
Br
Br
Br
Br
Br
Br
Br
Br
e
5
e
6
7
e
4CzIPN
[Ir]
f
8
f
9
10 ,
[Ir]
[Ir]
−
f g
f
h
11
17
a
Conditions unless otherwise noted: silicate (5 equiv, 1.5 mmol),
imine (1.0 equiv, 0.3 mmol), photocatalyst (2 mol %), DMSO (0.1
M), irradiating with 21 W CFL. Photocatalyst: [Ru] = [Ru(bpy)3]-
(PF6)2 and [Ir] = [Ir{dF(CF3)2ppy}2(bpy)]PF6. Isolated yield after
purification. 2 equiv of silicate used. A 1:2 silicate/imine ratio used
along with 4 W blue LEDs. A 1:2 silicate/imine ratio used along with
30 W blue LEDs. Reaction conducted in the dark. NMR yield of
crude reaction mixture.
b
c
d
e
f
g
h
B
DOI: 10.1021/acs.orglett.9b00602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 1. Scope of the Radical Alkylation/Cyclization Processes with Imines
a
Reaction conditions unless otherwise noted: alkylsilicate (1 equiv, 0.3 mmol), imine (2.0 equiv, 0.6 mmol), photocatalyst (2 mol %), DMSO (0.1
b
c
M), irradiating with 30 W blue LEDs at 35 °C for 30 min; all yields are isolated yields after purification. Reaction run for 16 h. Reaction
conducted on 1 mmol scale with 1 mol % photocatalyst. Reaction conducted on 2 mmol scale with 1 mol % of photocatalyst.
d
annulation was observed in all cases, the reaction generally
proceeded slowly and gave poor conversion to the desired
pyrrolidine 2. Interestingly, of this series, the 3-bromopropyl-
silicate proved best. Speculatively, the 3-bromopropyl radical
provides a good compromise of stability (3-iodopropyl radical is
prone to SH2 3-exo-tet cyclization23) and reactivity (some
addition without cyclization was observed when using 3-
chloropropylsilicate). Reducing the loading of the 3-bromo-
propylsilicate and extending the reaction time led to more than
doubling the yield of 2 (entry 4). High throughput
experimentation (HTE) techniques revealed that using a 2-
fold excess of the imine reagent provided a higher yield (see
Supporting Information). However, excess imine could be
recovered upon chromatographic purification in cases where the
imine is valuable (such as late-stage derivatization scenarios).
Scale up of these conditions gave the identical yield in a much
shorter period (entry 5). Evaluation of alternative photocatalysts
revealed that Ir[dF(CF3)ppy]2(bpy)PF6 was superior (entries
6−7). Using this photocatalyst and a more powerful light source,
the reaction time was reduced to a mere 30 min (entry 9).
Various additives were screened, but gave either similar or
diminished yields (see Supporting Information for details).
Control studies confirmed irradiation was necessary for
reactivity (entry 10), but the reaction could proceed (albeit in
poor yield) in the absence of a photocatalyst (entry 11). Given
that alkylsilicates are known to fragment when irradiated with
UV-A/UV-B light, an electron donor−acceptor complex24
between the highly conjugated imine and the bis(catecholato)
moiety may form, facilitating light-mediated radical generation.
With suitable conditions established, the scope of the
annulation process was examined (Scheme 1). In general,
when using 3-bromopropylsilicate, a variety of N-phenyl
aldimines were amenable to the RPC cyclization process to
provide the corresponding pyrrolidines. In some cases,
extending the reaction time to 16 h was necessary to give
improved yields. The reaction tolerated imines derived from
both electron-rich and electron-poor benzaldehydes, including a
free phenol (5). The cyclization of benzothiophene, isoxazole,
and pyridine-containing imines successfully provided pyrroli-
dines 10−12. Substituents with a variety of steric and electronic
characteristics were tolerated on either of the aryl rings on the
imine substrate. In particular, replacement of the N-phenyl
C
DOI: 10.1021/acs.orglett.9b00602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
group with a p-methoxyphenyl (PMP) group gave a comparable
yield of pyrrolidine product (2 vs 19). Given the ability to
oxidatively cleave PMP groups, these species would be suitable
for further derivatization. Additionally, other cleavable groups
were compatible with the RPC annulation process. Both p-
toluenesulfonyl and N,N-dimethylsulfamidyl aldimines under-
went the cyclization process to provide 22 and 23, respectively,
but in diminished yields. Unfortunately, the process could not be
extended to unprotected (NH) imines, N-Boc-imines, or
hydrazones. Using a 4-bromobutylsilicate and identical reaction
conditions, piperidines were accessible from aldimines in
comparable yields (24−27). Attempts using either a 5-
bromopentylsilicate or 5-iodopentylsilicate reagent did provide
azepane 28, although in low yield. The major product observed
was the uncyclized alkyl halide. In these cases, the rate of
protonation by the acidic ammonium counterion of the
alkylsilicate likely exceeds the rate of 7-exo-tet cyclization.
Smaller rings could not be obtained through this method; only
traces of the corresponding aziridine were observed. The
inability to access the requisite 2-bromoethylsilicate (likely
because of facile β-silyl elimination) prevented any attempts at
preparing azetidines.
Figure 4. Plausible mechanism for the annulation process.
benign conditions of this strategy make it ideal for the late-stage
introduction of saturated N-containing heterocycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00602.
Ketimines were also amenable to the reaction, allowing
pyrrolidines with α-quaternary centers to be assembled rapidly.
In general, ketimines derived from benzophenones fared best.
Various aryl ring substituents had minimal effect on yield (29−
32), an observation consistent with that seen in aldimines.
Mixed aryl-alkyl ketimines could be used, albeit with diminished
yields. Subjecting a ketimine derived from an α-CF3 ketone
enabled synthesis of α-CF3-substituted pyrrolidine 33. Similarly,
an acetophenone-derived ketimine was competent in the
annulation process (34). Ketimines also provide opportunities
for bicyclic ring construction, as demonstrated by the
preparation of benzopyrrolizidine 35. This bicyclic structure
bears resemblance to the core of recently reported anticancer
candidates.25 Piperidines bearing α-quaternary centers are also
accessible using this RPC approach. Aryl ketiminoacetates and
ketimidates, however, were not amenable to this process. The
formation of piperidines from ketimines using the analogous 4-
bromobutylsilicate reagent was not as effective as piperidine
formation, and in some cases unexpected side products were
observed.
Experimental procedures, details of high-throughput
1
screening, and H, 13C, and 19F NMR spectra for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gmolandr@sas.upenn.edu.
*E-mail: cbkelly@vcu.edu.
ORCID
Jennifer K. Matsui: 0000-0003-0693-0404
Christopher B. Kelly: 0000-0002-5530-8606
Gary A. Molander: 0000-0002-9114-5584
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
NIGMS (R01 GM 113878 to G.M.). C.B.K. is grateful for an
NIH NRSA fellowship (F32 GM117634) and acknowledges
start-up funds from Virginia Commonwealth University. J.K.M.
is grateful for a BMS graduate Fellowship in Synthetic Organic
Chemistry. We thank Dr. Charles W. Ross, III (University of
Pennsylvania) for obtaining HRMS data. We acknowledge
Johnson Matthey for fine chemicals donations and Kessil
Lighting for donation of a prototype PR160 Rig.
Based on the prior art18−21 and our own observations during
the course of this study, the following sequence of events
constitute a plausible mechanistic path for the annulation
process: (1) Visible-light-mediated photoexcitation of I to its
excited state II; (2) Reductive quenching of II (E1/2 [P*/P]:
1.35 V vs SCE) by the bifunctional alkylsilicate (E1/2 = +0.4−0.7
vs SCE for most alkylsilicates); (3) Homolytic fragmentation of
oxidized IV to furnish alkyl radical V, which readily adds to
imine VI, giving the N-centered radical VII; (4) SET reduction
of VII by the reduced state of III to provide amide anion VIII;
(5) C−N bond formation and ring closure by way of anionic
cyclization, giving IX (Figure 4).
The radical/polar annulation process described herein
enables the rapid construction of saturated nitrogen hetero-
cycles from acyclic precursors. This RPC reaction accommo-
dates numerous functional groups, occurs under mild
conditions, and can be completed in as little as 30 min.
Furthermore, its modular nature allows various medium-sized
rings to be assembled from a single imine by adjusting the
alkylsilicate used, and it also permits quaternary centers to be
established α to nitrogen with ease. The inherent flexibility and
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