Radical Cation Cyclopropanations via Chromium Photooxidative Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b01095

The chromium photocatalyzed cyclopropanation of diazo reagents with electron-rich alkenes is described. The transformation occurs under mild conditions and features specific distinctions from traditional diazo-based cyclopropanations (e.g., avoiding β-hydride elimination, chemoselectivity considerations, etc.). The reaction appears to work most effectively using chromium catalysis, and a number of decorated cyclopropanes can be accessed in generally good yields.

Full text of DOI:10.1021/acs.orglett.7b01095

Letter
pubs.acs.org/OrgLett
Radical Cation Cyclopropanations via Chromium Photooxidative
Catalysis
Francisco J. Sarabia and Eric M. Ferreira*
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
S
* Supporting Information
ABSTRACT: The chromium photocatalyzed cyclopropana-
tion of diazo reagents with electron-rich alkenes is described.
The transformation occurs under mild conditions and features
specific distinctions from traditional diazo-based cyclopropa-
nations (e.g., avoiding β-hydride elimination, chemoselectivity
considerations, etc.). The reaction appears to work most
effectively using chromium catalysis, and a number of
decorated cyclopropanes can be accessed in generally good
yields.
yclopropanes are important structures in organic chem-
Scheme 1. Approaches to Cyclopropane Synthesis Using
Photocatalysis
C
istry.1 Their rigidstructure provides awell-definedspatiality
that can be decorated with features that can impart function, and
they are prevalent in natural and unnatural bioactive molecules.2
The cyclopropane ring strain also allows them to serve as useful
3C components in the construction of larger ring systems.3 There
are several synthetic methods toward accessing cyclopropanes
from alkenes,4 including the transition-metal catalyzed reaction
with diazo compounds.5 This method, most commonly using Rh
or Cu catalysis, has proven widely effective. That said, orthogonal
approaches using these reactants may present strategic synthetic
alternatives.
Theuseofphotocatalysis6 fortheformationofcyclopropanesis
relatively underexplored (Scheme 1). For UV-light-mediated
diazo decomposition, alkene cyclopropanation can be favorable
using triplet sensitization.7 Per
́
ez-Prieto and Stiriba have
described diarylketone catalysts for sensitized cyclopropana-
tions.8 In terms of metal catalyst systems, Stephenson and co-
workers described an atom-transfer process of bromomalonate
across analkenevia iridiumcatalysis, whichupontreatment witha
base affords a cyclopropane product.9 Guo et al. reported a
Ru(bpy)32+-catalyzed method that combines dibromomalonates
and benzylidenemalononitriles;10 this process occurs via the
formation of the α-bromomalonate anion in situ. A Ru-catalyzed
method using diiodomethane to achieve radical additions to
styrene derivatives was recently described by Suero et al.11
Bauld had previously shown that aminium oxidants were
capable of inducing radical cation-based cyclopropanations
between alkenes and diazo reagents.12 We were curious whether
this transformation could be achieved using photocatalytic
oxidative systems. Toward the design of sustainable synthetic
methods, we have been interested in the application of
photocatalysts based on first-row transition metals to supplant
the traditionally employed Ru and Ir systems. We have recently
reported on the use of polypyridinyl and -phenanthrolinyl ligated
Cr photocatalysts for mediating (4 + 2)-cycloadditions.13 Herein,
wedescribea(2+1)-cycloaddition between electron-rich alkenes
anddiazoreagentspromotedbytheseCrcomplexes. Importantly,
we highlight the orthogonality of catalytic activation of this
process (alkene oxidation vs diazo decomposition), which we
anticipate will render this method useful in synthetic chemistry.
We began our studies by investigating the proposed cyclo-
addition between trans-stilbene and ethyl diazoacetate using the
catalysts in Figure 1. We first utilized the reaction conditions
developed in the original Cr-catalyzed report (1 mol %
[Cr(Ph2phen)3](BF4)3, NUV irradiation, CH3NO2) with 5
equiv of the diazoacetate (Table 1, entry 1). To our delight, the
Received: April 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01095
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(entries 16−18) confirmed the importance of both the light and
the photocatalyst to reactivity.
With optimized conditions for cyclopropanation in hand, we
established the alkene scope (Scheme 2). A range of stilbenes
Scheme 2. Cyclopropanation: Alkene Scope
Figure 1. Photocatalysts evaluated.
Table 1. Optimization of Cr-Catalyzed Cyclopropanation
a
NMR yield (%)
2a
time
(h)
entry
cat. (mol %)
Cr1 (1)
solvent
(equiv)
3aa 4aa 5aa
b
1
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
5
24
24
40
40
40
40
24
14
21
60
61
60
5
8
10
8
7
8
a
b
Gram scale experiment. Reaction performed with needle outlet open
2
3
4
5
6
7
8
9
Cr1 (1)
Cr1 (1)
Cr2 (1)
Cr3 (1)
Cr4 (1)
Ru1 (1)
Ru1 (1)
5
c
d
to air. Product observed in 3.0:1 dr. Product observed in 4.1:1 dr.
1.1
1.1
1.1
1.1
1.1
5
11
1
1
40
50
3
8
7
were competent reactants, and the products were accessed in
generally high yields. Aryl alkyl alkenes were also participatory in
this cycloaddition. Although the yields were overall good, there
wasingenerallittlediastereoselectivity, asthecyclopropaneswere
observed as approximately 1:1 mixtures with a couple of
exceptions. For compounds 3ia−3ma, the reactivity pattern
somewhat mirrors that of the (4 + 2)-cycloaddition; the pendant
oxygenated group if electron-rich (i.e., alcohol or ether) will
hamper reactivity due to donation into the presumed radical
cation intermediate.15 Curiously, an alkyl tosylate also rendered
the reaction unproductive (3na).16 Gratifyingly, trisubstituted
alkenes were reactive in this chemistry (e.g., 3sa, 3ta), which had
not been the case for the (4 + 2) process. Tetrasubstituted olefins
unfortunately proved unreactive.
9
8
0
0
9
4
5
Ru2 (5) + MV
5
12
2
2
c
(15)
10
11
12
13
14
15
16
17
Ru2 (5)
Cr1 (1)
Cr1 (1)
Cr1 (1)
Cr1 (1)
Cr1 (1)
none
CH3NO2
CHCl3
acetone
CH2Cl2
CH3CN
DCE
5
21
24
24
24
24
24
14
49
49
0
18
57
73
67
73
0
0
1
5
2
8
0
0
0
0
0
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
8
7
10
5
DCE
0
CrCl3 (10)
Cr1 (1)
DCE
0
0
d
18
DCE
0
0
a
b
The alkene reactivity observed appears to correlate well with
respective reduction potentials. As seen in Figure 2, a window of
competent reactivity was observed for alkenes with reduction
potentials in the range E1/2 = +1.11 − 1.80 V (vs SCE).17,18
Stilbene derivatives 1v (E1/2 = +0.99 V) and 1w (E1/2 = +1.94 V)
were both unproductive in the cycloaddition. This spectrum of
reactivity is reflective of the presumed radical cation mechanism
Determined using veratraldehyde as a standard. Near-UV light
c
(bulbs at 300, 350, and 419 nm) used instead of 23 W CFL. MV:
d
methyl viologen2+·(PF6)2. Reaction performed in dark (foil wrapped).
cycloaddition occurred, and cyclopropane 3aa was formed in
good yield, validating the hypothesis that these oxidizing catalysts
could induce this process. Byproducts 4aa and 5aa were also
detected in small quantities. We found that lowering the
equivalents of the diazoacetate to 1.1 equiv and using visible
light were comparably effective to the original conditions. Other
photooxidizing chromium catalysts we have explored were able to
promote the transformation, albeit in lower yields (entries 4−6).
Additionally, when oxidizing systems based on Ru(II) photo-
catalysts were employed, the yields were poor (entries 7−10). A
range of solvents were evaluated, and we ultimately found that
dichloroethane was optimal for the transformation, affording the
highest yield of cyclopropane 3aa with minimal formation of
byproducts 4aa and 5aa (entry 15).14 Control experiments
Figure 2. Alkene reactivity range based on reduction potential.
B
DOI: 10.1021/acs.orglett.7b01095
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Letter
pathway, necessitating an appropriate oxidation capacity in order
to achieve proper activity.
A different outcome was observed in the reaction between
trans-anethole and diazopropionate 2f. Expected cyclopropane
3ff was indeed the main product, but byproduct dihydrofuran 9ff
was also observed in measurable yield (Scheme 5). Resubjecting
The chemoselectivity of the cycloaddition, dictated by
electronics, is a unique and important attribute of this
transformation. The more commonly employed cyclopropana-
tions of diazo compounds using metal catalysis (i.e., Rh or Cu
catalysts) may be governed by other factors, such as favorable
intramolecularity. Scheme 3 is illustrative. trans-Anethole (1f)
Scheme 5. Cyclopropanation and Rearrangement
Scheme 3. Alkene Chemoselectivity
the cyclopropane product to the photocatalyst conditions also
generated the dihydrofuran in high yield.23 Control experiments
indicated that the chromium catalyst and light were both required
for this rearrangement to occur.24
Additionally, when a competition experiment was performed
withbothdiazoacetate2aanddiene10, thecyclopropane product
was the predominant observed species, highlighting the increased
nucleophilicityof2aininterceptingtheradicalcation(Scheme6).
and diazoacetate 2b were combined under both Cu-catalyzed
cyclopropanation conditions and our standard Cr photocatalytic
conditions. The Cu-catalyzed reaction19 afforded a mixture of
both possible cyclopropane products (3fb and 6) in low
conversion.20 Alternatively, with Cr catalysis the intermolecular
additionproduct(3fb)wasobservedexclusively.Additionally, the
cyclopropanation ofcompound 7 wassuccessful, establishing that
intramolecular processes can occur on the condition that it is
electronically feasible. We anticipate this type of chemoselectivity
can be strategically employed in complex synthetic settings, a
distinguishing feature of this Cr-catalyzed cyclopropanation.
Different diazo esters and arylketones were also generally
effective (Scheme 4). Notably, α-alkyl diazo esters were
Scheme 6. Competition Experiment between Diazo and Diene
Our proposed mechanism for the cycloaddition is consistent
withthepreviousprocessesdescribedbyBauld(Scheme7, shown
Scheme 4. Cyclopropanation: Diazo Scope
Scheme 7. Proposed Mechanism
for formation of cyclopropane 3aa).12b The excited state Cr(III)
catalyst induces alkene single electron oxidation.25 The resulting
radical cation undergoes nucleophilic attack by the diazo
compound. Loss of N2 affords a “long-bonded” radical cation
intermediate 14.12b At this stage, electron transfer from either the
reduced-state Cr complex or another equivalent of alkene yields
the cyclopropane product. Turnover occurs either via reentry of
the Cr complex into the photocatalytic cycle, or through radical
propagation by the electron transfer from the alkene
component.26 Byproducts 4aa and 5aa would arise from
intermediate 13whenN2 islostviaphenylorhydrogen migration,
respectively.27 Theobservation ofdifferential reactivities between
this process and our reported (4 + 2)-cycloadditions (alkene
competencies, O2 dependencies) indicate that a more thorough
analysis of the mechanism will be necessary for full elucidation.
a
b
Product observed in 1.4:1 dr. Product observed in 1.5:1 dr.
competent partners, with no observation of β-hydride elimi-
nation, typically a common phenomenon in diazo decomposition
cyclopropanations.21 The mechanistic pathway differentiation of
this process enables cyclopropanation to predominate. Addition-
ally, the mechanism ensures that diazo dimerization is avoided,
and thus no slow addition protocols were necessary.22
C
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828. (c) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (d) Angnes, R. A.; Li,
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Insummary, aradicalcationcycloadditionbetweenalkenesand
diazo species using Cr catalysis and visible light is described. The
formation of polysubstituted cyclopropanes via this process may
offeranattractivealternativetothemorecommonlyemployedRh
or Cu complexes. The chemoselectivity aspects are a distinguish-
ing characteristic of this transformation, and by virtue of this no
syringe pump mode of addition is necessary. Current efforts are
dedicated toward enriching our mechanistic understanding and
expanding the suite of cycloadditions mediated by these Cr
photocatalysts; these endeavors will be later disclosed.
(8) (a) Pastor-Per
Chem. 2007, 72, 1541. (b) Pastor-Per
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(11) del Hoyo, A. M.; Herraiz, A. G.; Suero, M. G. Angew. Chem., Int. Ed.
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(12) (a) Stufflebeme, G.; Lorenz, K. T.; Bauld, N. L. J. Am. Chem. Soc.
1986, 108, 4234. (b) Bauld, N. L.; Stufflebeme, G. W.; Lorenz, K. T. J.
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01095.
■
S
Experimental procedures, compound characterization
data, and spectra (PDF)
(13) (a) Stevenson, S. M.; Shores, M. P.; Ferreira, E. M. Angew. Chem.,
Int. Ed. 2015, 54, 6506. (b) Higgins, R. F.; Fatur, S. M.; Shepard, S. G.;
AUTHOR INFORMATION
■
Stevenson, S. M.; Boston, D. J.; Ferreira, E. M.; Damrauer, N. H.; Rappe,
́
Corresponding Author
*E-mail: emferr@uga.edu.
ORCID
A. K.; Shores, M. P. J. Am. Chem. Soc. 2016, 138, 5451. (c) Stevenson, S.
M.; Higgins, R. F.; Shores, M. P.; Ferreira, E. M. Chem. Sci. 2017, 8, 654.
(14) The alkene byproducts were only observed in the diaryl alkene-
based cyclopropanations in <10% yield and were readily removed by
column chromatography.
Eric M. Ferreira: 0000-0001-9412-0713
Notes
(15) (a) Gassman, P. G.; Bottorff, K. J. Tetrahedron Lett. 1987, 28, 5449.
(b) Gassman, P. G.; Bottorff, K. J. J. Am. Chem. Soc. 1987, 109, 7547.
(c) Mizuno, K.; Tamai, T.; Nishiyama, T.; Tani, K.; Sawasaki, M.; Otsuji,
Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 2113. (d) Asaoka, S.; Kitazawa,
T.; Wada, T.; Inoue, Y. J. Am. Chem. Soc. 1999, 121, 8486. (e) Hamilton,
D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134, 18577.
(16) For this specific reaction, sulfonyloxy transfer to the diazoacetate
was observed instead.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was carried out by the Catalysis Collaboratory for
Light-activated Earth Abundant Reagents (C-CLEAR), which is
supported by the NSF and EPA through the Network for
Sustainable Molecular Design and Synthesis program (NSF-
CHE-1339674). F.J.S. is supported by the NSF Graduate
Research Fellowship Program under Grant No. 038550-02. Any
opinions, findings, and conclusions or recommendations ex-
pressed in this material are those of the authors and do not
necessarily reflect the views of the NSF. We acknowledge
collaborators Niels Damrauer (Univ. Colorado), Anthony Rappe
(Colorado St. Univ.), and Matthew Shores (Colorado St. Univ.)
and their groups for enriching discussions.
(17) (a) Kubota, T.; Uno, B.; Matsuhisa, Y.; Miyazaki, H.; Kano, K.
Chem. Pharm. Bull. 1983, 31, 373. (b) Reference 12b.
(18) The reduction potential of [Cr(Ph2phen)3]3+ (E*1/2 = + 1.33 V vs
SCE in CH3NO2) is within a viable range for alkene oxidation
competency. We note that these values should only be used as a general
guide, as they are sensitive to the conditions of measurement (solvent,
etc.).
́
(19) (a) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559.
(b) Sacconi, L.; Ciampolini, M. J. Chem. Soc. 1964, 276.
(20) Attempts at Rh catalysis were less effective than those with Cu.
(21) For an elegant solution using Rh catalysis, see: Panne, P.;
DeAngelis, A.; Fox, J. M. Org. Lett. 2008, 10, 2987.
(22) Other potential carbene precursors, such as tosylhydrazones,
triazoles, sulfur and iodonium ylides, as well as donor−donor and
acceptor−acceptor diazo species, were ineffective.
(23) Although this ring expansion (acylcyclopropane → dihydrofuran)
is more commonly observed with ketones and aldehydes, there are
isolated reports of this process with donor−acceptor based cyclo-
propylesters promoted by a Lewis acid and/or heat. See: (a) Abdallah,
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