Radical/Polar Annulation Reactions (RPARs) Enable the Modular Construction of Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.8b02968

An annulation process for the construction of 1,1-disubstituted cyclopropanes via a radical/polar crossover process is described. The cyclopropanation proceeds by the addition of a photocatalytically generated radical to a homoallylic tosylate. Reduction of the intermediate radical alkylation adduct (via single electron transfer) furnishes an anion that undergoes an intramolecular substitution. The process displays excellent functional group tolerance, characteristic of proceeding through odd-electron intermediates, and occurs under mild conditions with visible light irradiation.

Full text of DOI:10.1021/acs.orglett.8b02968

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Radical/Polar Annulation Reactions (RPARs) Enable the Modular
Construction of Cyclopropanes
John A. Milligan, James P. Phelan, Viktor C. Polites, 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
2
§
3284-9069, United States
Medicines for All Institute, Virginia Commonwealth University, Biotech 8 737 North 5th Street, Richmond, Virginia 23219-1441,
United States
*
S Supporting Information
ABSTRACT: An annulation process for the construction of 1,1-
disubstituted cyclopropanes via a radical/polar crossover process is
described. The cyclopropanation proceeds by the addition of a
photocatalytically generated radical to a homoallylic tosylate.
Reduction of the intermediate radical alkylation adduct (via single
electron transfer) furnishes an anion that undergoes an intramolecular
substitution. The process displays excellent functional group tolerance,
characteristic of proceeding through odd-electron intermediates, and
occurs under mild conditions with visible light irradiation.
nnulation reactions are prized for their ability to increase
molecular complexity rapidly. The synthetic importance
The revival of visible-light photoredox catalysis has resulted
1
A
in the discovery of novel single-electron processes that, in
contrast to traditional stoichiometric radical generation
methods, are facilitated by selective and sequential photo-
of cyclization reactions is additionally driven by the broad
applicability of carbocyclic rings in fields such as medicinal
chemistry, where structural rigidity (particularly in three- and
four-membered rings) can impart unique binding and
6
catalytic oxidization/reduction events. This paradigm enables
reactive odd-electron species to be catalytically generated
under mild conditions, providing access to previously
challenging modes of single electron reactivity with broad
functional group tolerance. Indeed, an array of novel “single-
2
metabolic properties (Figure 1). The crux of annulation
from a synthetic standpoint, specifically for carbocyclic rings, is
forging C−C bonds. Although this is typically accomplished
3
4
7
8
through pericyclic processes or anionic cyclizations, numer-
ous ring-closing radical cyclizations have been developed, most
electron” paradigms for cross-coupling, cycloaddition, and
radical/polar crossover processes have been developed in
9
of which are mediated by stoichiometric Bu SnH or similar
recent years. With such a rapid influx of new synthetic
3
5
halogen abstractors.
strategies, it comes as no surprise that photoredox catalysis is
quickly being adopted in both the academic and industrial
sectors to overcome the challenges associated with two-
10
electron processes in complex molecule synthesis.
To facilitate implementation of the rapidly expanding
toolbox of photoredox reactivity, we and others have
developed various radical feedstocks [e.g., organotrifluoro-
borates, carboxylic acids, bis(catecholato)silicates, 4-alkyl
dihydropyridines] that provide a palette of potential C−C
7
,11
bond connections through alkyl cross-coupling.
The innate
functional group tolerance of odd electron carbon nucleophiles
enables these precursors to be used in the presence of
functional groups typically not tolerated by two-electron
pathways. However, realizing that the chemistry of many of
Figure 1. Examples of therapeutic agents containing a 1,1-
disubstituted cyclopropane unit.
Received: September 17, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
6
these feedstocks was poorly explored within other radical-
based manifolds, we initiated a program to apply them in
radical/polar crossover processes that lead to carbocyclic ring
structures. Recent investigations along these lines have yielded
a mechanistically distinct cyclopropanation method that
proceeds via a photocatalytically generated halomethyl radical
in substitution processes than the iodide; (2) the unlike-
lihood of tosylates to engage in S 2-type processes would
ensure that cyclization would occur by an anionic pathway;
(3) aryl sulfonate esters have tunable reactivity; and (4)
sulfonate esters are generally less light-sensitive than alkyl
halides.
H
17
12
(Scheme 1, Previous Work). Computational analysis and
The conditions previously established for our aforemen-
12a
tioned cyclopropanation process were adapted with styrene
1 and diisopropylammonium bis(catecholato)(3-acetoxy-
propyl)silicate to develop this new cyclopropanation reaction.
High-throughput screening experiments revealed that polar,
aprotic solvents are optimal, with DMSO being the best of the
solvents investigated (Table 1, entries 1, 6−9).
Scheme 1. Comparison of Cyclopropanation Strategies and
Implications of the Envisioned Approach
Table 1. Screening of Conditions for the Cyclopropanation
Process
a
,
b c
entry
deviation from standard conditions
none
under air
yield (%)
1
2
3
4
5
6
7
8
9
87 (74)
44
94
88
0
50
4
[Ir{dF(CF )ppy} (bpy)]PF (5 mol %)
3
2
6
[Ru(bpy) ](PF ) (5 mol %)
3
6 2
+
MesAcr (5 mol %)
DMF (0.05 M)
dioxane (0.05 M)
MeCN (0.05 M)
experimental evidence revealed that Giese-type addition of this
halomethyl radical to an olefin is followed by single electron
transfer (SET) from the photocatalyst, which converts the
resulting radical adduct to an anion that undergoes anionic 3-
exo-tet ring closure.
3
0
PhCF (0.05 M)
3
1
1
1
1
1
0
1
1
2
3
DMSO (0.10 M)
DMSO (0.025 M)
no photocatalyst
no light
83
81
0
0
(66)
In considering the mechanism of this process, we realized
that a more general strategy for cyclopropanation may exist.
That is, if the electrophilic component was built into the olefin-
containing species, any photocatalytically generated radical
may be able to induce cyclization upon radical addition and
single-electron reduction (Scheme 1). This approach would be
conceptually related to Michael addition-mediated anionic
MsO instead of TsO
a
Unless otherwise noted, reactions were run using alkene 1 (0.025
mmol, 1 equiv), diisopropylammonium bis(catecholato)(3-acetoxy-
propyl)silicate (0.038 mmol, 1.5 equiv), 4CzIPN (0.0013 mmol, 5
mol %), and DMSO (0.5 mL, 0.05 M). Yield determined by UPLC
b
c
using 4,4′-dimethylbiphenyl as a standard. Isolated yield in
1
3
cyclization, but with distinctly greater tolerance of structural
diversity in the nucleophilic partner and without the need for a
strongly polarized olefin such as an enone or acrylate. Although
canonical cyclopropanation strategies such as the Simmons−
parentheses.
Photocatalyst variation revealed that either 4CzIPN or Ir- or
Ru-based photocatalysts were effective (entries 1, 3, 4).
Importantly, the former organic dye can be prepared at a
significantly lower cost and therefore was favored. Reaction
concentration proved to be critical. Decreasing the concen-
tration to 0.05 M improved the isolated yield, likely by
reducing the rate of competitive polymerization of the styryl
radical intermediate (compare entries 1, 10, and 11). A “zero-
precautions” reaction demonstrated that the described process
is rather robust; conducting the reaction with an air
atmosphere and nonrigorously dried DMSO still afforded the
product, albeit in reduced yield (entry 2). Control studies
confirmed that this was indeed a photocatalytic process; both
light and the photocatalyst were necessary for reactivity
(entries 11−12). The mesylate analog of 1 also underwent
cyclization in comparable (66%) isolated yield and can
presumably be used interchangeably with the tosylate
derivative (entry 13).
1
4
Smith reaction have been used to access similar cyclopropane
structures, the photocatalytic method envisioned would allow a
modular assembly of diverse 1,1-disubstituted cyclopropane
derivatives without the need to prepare an array of alkene or
carbene precursors. Additionally, the size and substitution
patterns of the carbocylic ring can potentially be modulated by
modifying the substrate prior to annulation. Collectively, these
advantages poise radical/polar annulation reactions (RPARs)
to be a powerful approach to carbocyclic ring construction via
15
carbodifunctionalization of olefins.
Exploration of this process began with an examination of
tosylate 1 as a model system for RPAR-type reactivity.
Substrates of this class can be readily prepared in two steps
from commercially available materials [see Supporting
Information (SI)]. Although the iodide analog of 1 also
showed effective annulation reactivity, the tosylate leaving
group was preferred because (1) the tosylate is more reactive
B
DOI: 10.1021/acs.orglett.8b02968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of the Annulative Process via Radical/Polar Crossover
a
b
Unless otherwise noted, the reactions were carried out on a 0.3 mmol scale at 35 °C; isolated yields after purification. Reaction carried out in
c
d
e
DMSO for 2 h. Reaction conducted on 1 mmol scale. Reaction carried out in DMSO for 16 h. Reaction carried out in DMA for 4 h.
1
8
The generality of the cyclopropantion process was assessed
on a series of 1,1-disubstituted alkenes. Overall, radical
alkylation/cyclization proceeded smoothly across an array of
different styryl systems, faring best with electron-deficient
arenes. In contrast, 1,1-dialkyl olefins did not react with the
radical species, an observation that is consistent with our
A UPLC-based robustness screen confirmed that the
representative RPAR cyclopropanation of tosylate 1 to afford
cyclopropane 2 can be carried out in the presence of a variety
of additives containing functional groups such as unprotected
phenols and alcohols. Lewis basic heterocycles and free amines,
which are incompatible with the electrophilic carbenoid
14
12a
species used in the Simmons−Smith cyclopropanation, are
also tolerated (see the SI for details on this screen).
previous studies.
The reaction nonetheless permits the
installation of an array of functionalized alkyl fragments onto
the styrene precursor. Alkylsilicates are ideal for generating
primary, nonstabilized alkyl radical partners for this cyclo-
propanation because of their low, relatively uniform redox
Given that the success of RPAR cyclopropanation should be
independent of the radical source, the transformation was
conducted with other classes of radical precursors. In doing so,
radicals with a range of stereoelectronic environments and
whose corresponding silicates would be challenging to prepare
were incorporated. Potassium alkyltrifluoroborates, for exam-
ple, served as competent precursors in the cyclopropanation.
Secondary, tertiary, benzylic, and α-heteroatom C-centered
radicals were generated from their corresponding trifluorobo-
rate reagents and engaged in the cyclopropanation. The radical
structure appeared to have minimal effect on the reaction
success and allowed an array of motifs to be incorporated. For
example, chromanone 25 demonstrates the potential of RPAR
to construct cyclopropanes containing medicinally relevant
fragments. 4-Alkyldihydropyridines (DHPs), a class of radical
precursors that are readily prepared from the corresponding
1
1a
potentials.
The breadth of silicate reagents employed demonstrates that
RPAR cyclopropanation tolerates traditionally electrophilic
subunits both on the arene and on the radical itself. These
moieties can be readily diversified through classical two-
electron processes (e.g., hydrolysis of 2 or acylation of 16). In
addition, this cyclization strategy is insensitive to the presence
of protic groups (11, 16, 17) and demonstrates olefin
selectivity (15) (Scheme 2). The rather general nature of
this process can likely be attributed to the mild conditions
under which RPAR occurs (room temperature, near-neutral
pH, and absence of any additives) in addition to the general
7
11b
benefits associated with odd-electron intermediates.
aldehydes, showed similar trends in reactivity.
C
DOI: 10.1021/acs.orglett.8b02968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The cyclopropanation process is consistent across the
various radical precursors. Cyclopentylmethyl cyclopropane
through a competition study. Several analogs of tosylate 1
bearing either π- or σ-electron-withdrawing groups were
subjected to the reaction conditions, and UPLC analyses
were conducted during the initial period of the reaction (∼10
min; see SI for data). These studies suggested that the
electron-deficient arene promotes the overall transformation.
This could be due to either accelerating the initial Giese-type
addition or by stabilizing the transient anion intermediate VII.
More comprehensive computational studies of these particular
mechanistic aspects are ongoing.
The method described herein allows the rapid and efficient
assembly of a diverse array of 1,1-disubstituted cyclopropanes
from readily accessible homoallylic tosylates and various
radical precursors. This modular process is compatible with
an array of stereoelectronically distinct radicals and tolerates a
variety of functional groups. Further applications of RPAR
reactivity for the preparation of more diverse and highly
substituted carbocyclic rings are underway and will be reported
in due course.
1
4, for example, was obtained from cyclopentylsilicate,
-trifluoroborate, and -dihydropyridine radical precursors in
very similar yields (61%, 68%, and 61%, respectively).
Pyrrolidine 21 was also prepared from either the correspond-
ing trifluoroborate or by decarboxylative fragmentation of Boc-
7
b
proline in high yield (Scheme 3). In addition, pyrrolidine 33
Scheme 3. Synthesis of Pyrrolidine 21 from Various Radical
Precursors
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02968.
Experimental procedures, details regarding mechanistic
1
experiments and high-throughput screening, and H,
C, and F NMR spectra for all compounds (PDF)
was activated using H-atom transfer (HAT) chemistry to form
1
3
19
19
a stabilized α-amino radical, which successfully underwent
cyclopropanation. Aside from demonstrating the fidelity of
RPAR cyclization toward C-centered radicals, the versatility of
this process suggests that it may be amenable toward merger
with catalytic processes beyond those examined here.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: g molandr@sas.upenn.edu.
*E-mail: cbkelly@vcu.edu.
ORCID
Regardless of the origin of the radical, we suggest the
following sequence of mechanistic events for the cyclo-
propanation process: (1) visible light-mediated photoexcita-
tion of 4CzIPN I to its excited state II; (2) reductive
quenching of II by any of the radical precursors IV whose
oxidation potentials fall below that of 4CzIPN (E [PC*/
James P. Phelan: 0000-0002-0058-0653
Viktor C. Polites: 0000-0001-7034-400X
Christopher B. Kelly: 0000-0002-5530-8606
Gary A. Molander: 0000-0002-9114-5584
Notes
1
/2
20
PC]: 1.35 V vs SCE ); (3) after homolytic fragmentation of
the precursor, Giese-type addition by an alkyl radical V into
the olefin to generate VI; (4) SET reduction of VI by the
reduced state of 4CzIPN III; (5) anionic cyclization resulting
in assembly of the carbocyclic ring by displacement of the
sulfonate ester (Figure 2). To aid in a clearer mechanistic
understanding, the role of arene electronics was probed
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.). J.P.P. and C.B.K. are
grateful for NIH NRSA fellowships (F32 GM125241 and F32
GM117634, respectively). C.B.K. acknowledges start-up funds
from Virginia Commonwealth University. We thank Dr.
Charles W. Ross, III (University of Pennsylvania) for obtaining
HRMS data. We thank Frontier Scientific, Gelest Inc., and
Johnson Matthey for donation of some of the fine chemicals
used in this work. In addition, we thank Kessil Lighting for the
generous donation of a prototype PR160 Rig.
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