A transition-metal-free & diazo-free styrene cyclopropanation

Article abstract of DOI:10.1039/c9sc02749a

An operationally simple and broadly applicable novel cyclopropanation of styrenes using gem-diiodomethyl carbonyl reagents has been developed. Visible-light triggered the photoinduced generation of iodomethyl carbonyl radicals, able to cyclopropanate a wide array of styrenes with excellent chemoselectivity and functional group tolerance. To highlight the utility of our photocyclopropanation, we demonstrated the late-stage functionalization of biomolecule derivatives.

Full text of DOI:10.1039/c9sc02749a

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A transition-metal-free & diazo-free styrene
cyclopropanation†
ab
Cite this: DOI: 10.1039/c9sc02749a
a
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Ana G. Herraiz
and Marcos G. Suero
An operationally simple and broadly applicable novel cyclopropanation of styrenes using gem-diiodomethyl
carbonyl reagents has been developed. Visible-light triggered the photoinduced generation of iodomethyl
carbonyl radicals, able to cyclopropanate a wide array of styrenes with excellent chemoselectivity and
functional group tolerance. To highlight the utility of our photocyclopropanation, we demonstrated the
late-stage functionalization of biomolecule derivatives.
Received 5th June 2019
Accepted 17th August 2019
DOI: 10.1039/c9sc02749a
rsc.li/chemical-science
activated alkenes and showed an excellent functional group
tolerance and chemoselectivity, however, the process was
Introduction
exclusively evaluated for methylene transfer via (c)CH2I.
Moreover, Charette and co-workers developed a radical bor-
ocyclopropanation enabled by ow techniques, UVA light and
xanthone as photocatalyst.11 This reaction involved the gener-
ation of (c)CH(Bpin)I and provided valuable cyclo-
propylboronates as mixtures of diastereoisomers.12
The novel photoredox-catalyzed radical cyclopropanations
represent a clear advance in the synthesis of cyclopropane rings
and a more practical approach to strategies based on diazo
reagents and metal-carbenoids.13,14 However, it is clearly an
underdeveloped methodology and challenges associated with
alkene scope, reagent diversity or efficiency of the process
(reagent equivalents) should be solved. In addition, the
Over the last few decades, one of the main challenges in the
synthesis of cyclopropane rings1 – a prevalent structural motif
in pharmaceutical agents2 and natural products3 – has been to
develop robust and general alkene cyclopropanations that avoid
the use of explosive, highly toxic, pyrophoric or water-sensitive
carbene transfer reagents (diazo reagents and organometallic
carbenoids). However, although important advances have been
made in this direction,4 a major limitation remaining is the
broad tolerance to functional groups and consequently, the
cyclopropanation of complex molecules.5
In 2017, our group reported a new methodology for the
stereoconvergent cyclopropanation of E/Z isomeric styrene
mixtures and Michael acceptors6 by means of photoredox
catalysis (Scheme 1A).7 The key to these studies was the use of
the well-known [Ru(bpy)3][PF6]2 photocatalyst and photo-
reducible diiodomethane8 as a methylene source that enabled
the generation of a carbenoid-like radical (c)CH2I termed
radical carbenoid, as a reactive cyclopropanating species.
Although the method showed a broad functional group toler-
ance and excellent chemoselectivity, severe limitations in the
styrene scope were found and an excess of diiodomethane (5
equivalents) had to be used. Aer this, rstly the group of
Molander9 and secondly the group of Li10 reported two
complementary redox-neutral cyclopropanations using photo-
oxidizable bis(catecholato)iodomethylsilicate reagents and
4CzIPN or Ir[dF(CF3)ppy]2(dtbbpy)PF6 as photocatalysts. The
Molander reaction was demonstrated in a wide variety of
aInstitute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science
¨
and Technology, Av. Paısos Catalans 16, Tarragona, 43007, Spain. E-mail: mgsuero@
iciq.es
b
´
´
´
`
Departament de Quımica Analıtica i Quımica Organica, Universitat Rovira i Virgili,
´
Calle Marcel. lı Domingo, 1, Tarragona, 43007, Spain
Scheme 1 New radical cyclopropanations enabled by visible-light:
a valuable alternative to methods employing diazo reagents or metal-
carbenoids (A and B).
† Electronic supplementary information (ESI) available. CCDC 1915890. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9sc02749a
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development of novel methodologies that avoid the use of (Scheme 2A). 2a is a white solid that can be prepared on a 12
precious Ru/Ir photocatalysts and permit late-stage functional- gram scale from 3-(adamantan-1-yloxy)-3-oxopropanoic acid
ization of complex molecules would be highly appreciated. and N-iodosuccinimide (NIS). Importantly, 2a features great
Here, we report the rst general photocatalyst-free cyclo- stability in comparison with the analogue ethyl 2,2-diiodoace-
ꢁ
propanation of styrenes that use underexploited gem-diiodo- tate (2b), which has to be stored in a freezer (<ꢀ20 C) and in
methyl carbonyl compounds as cyclopropanating reagents and solution (0.5 M CH3CN). Differential scanning calorimetry
a simple compact uorescence lamp (CFL) as a visible-light (DSC) studies were performed with reagent 2a and did not show
source (Scheme 1B). The process generates valuable cyclopropyl relevant exothermic decompositions, which are commonly
carboxylates that could be diversied by well-documented found for diazo compounds (see ESI†).16
decarboxylative strategies.15 Its excellent functional group
Aer this, we evaluated reagent 2a (1 equiv.) for the cyclo-
tolerance and chemoselectivity have enabled access to cyclo- propanation of (E)-anethole (1a) with and without the [Ru(bpy)3]
propyl carboxylates that are not possible to obtain in a direct [PF6]2 photocatalyst. We were delighted to nd that both reac-
manner by current catalytic strategies relying on metal-carbe- tions led to the expected tri-substituted cyclopropane 3a in
ne(carbenoid) (this is because of the preference of the latter moderate yields (63–60% yield, Scheme 2B) as an equimolar
species to react with more nucleophilic functionalities than isomeric mixture of diastereoisomers. To explain the formation
a styrene double bond).
of 3a we propose the initial generation of iodomethyl radical
ester int-I as a cyclopropanating species. Aer this, an unbiased
attack of the pyramidal sp3-hybridized radical int-I on 1a would
generate benzylic radicals int-II and int-III,17 which would
evolve to the corresponding cyclopropane 3a by a radical
homolytic substitution (SH2) 3-exo-tet cyclization. Radical
homolytic substitutions are common elementary steps in
radical chemistry and in terms of frontier molecular orbitals,
this cyclization involves the interaction between the high-
energy singly occupied molecular orbital (SOMO) of the benzylic
radical, and the lowest unoccupied molecular orbital (LUMO) of
the C–I bond. A similar cyclization has been observed previously
by Curran and Togo in cyclopropane synthesis using 1,3-diha-
loalkanes and radical initiators/reductants.18
Results and discussion
During the development of our photoredox-catalyzed cyclo-
propanation, control experiments revealed that excluding the
[Ru(bpy)3][PF6]2 photocatalyst in the reaction resulted in a poor
yield of the corresponding cyclopropanes (15–18% yield, 18
hours).6 These interesting results encouraged us to question
whether gem-diiodomethyl carbonyl reagents – activated alkyl
iodides with more absorbance in the visible region ꢀ could
provide an efficient photocatalyst-free cyclopropanation and
deliver valuable carbonyl-substituted cyclopropane rings. Our
investigations started by synthesizing 1-adamantanyl 2,2-diio-
doacetate (2a) as a potential new cyclopropanating reagent
Aer these preliminary investigations, we evaluated other
solvents, amines and visible-light sources and found that the
best reaction conditions involve only 2 equiv. of reagent 2a, i-
Pr2EtN (4 equiv.), CH3CN (1 mL), an aqueous solution of NaCl
(1.25 M, 0.5 mL) and degasication of the reaction mixture prior
Table 1 Optimization studiesa
Entry
Deviation of the reaction conditions
Yieldb 3a, %
1
2
3
4
5
6
None
91c(75)d
Without NaCl (H2O)
Without NaCl
Under air
Without i-Pr2EtN
In the dark
17
48
10
0
0
a
Reaction conditions: 1a (0.10 mmol), 2a (0.10 mmol), i-PrEt2N (0.20
mmol), CH3CN (1 mL), NaCl (1.25 M in H2O, 0.5 mL). Reactions were
degassed prior to irradiation. b 1H-NMR yields calculated using 1,2-
c
dimethoxyethane as the internal standard. Yield of the isolated
product adding additional 2a (0.10 mmol, 1 equiv.) and i-PrEt2N (0.20
d
mmol, 2 equiv.) aer 4 hours. Yield of the isolated product using 1
gram of (E)-1a and 1 equiv. of 2a. See the ESI for the evaluation of
other solvents, amines, or visible-light sources.
Scheme 2 Synthesis of gem-diodomethyl carboxylate reagents 2a,b
(A) and discovery of a photocatalyst-free cyclopropanation. Ad ¼ 1-
adamantyl (B).
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to irradiation (91% yield, Table 1, entry 1). We were glad to nd under air (10% yield, entry 4). No conversion to 3a was observed
that these reaction conditions were also suitable for a 1 gram without i-Pr2EtN or the CFL (entries 5 and 6).
scale reaction using only 1 equiv. of 2a (75% yield). However,
With the optimized reaction conditions in hand, we evaluated
poorer efficiency was observed when reactions were carried out the scope of the new photocyclopropanation using 46 styrene
without NaCl (H2O) or H2O (17–48% yield, entries 2 and 3)19 or derivatives and reagents 2a, b.20 As shown in Table 2, our protocol
was effective for a variety of diversely substituted styrenes (3b–r),
Table 2 Scope of the styrene photocyclopropanationa
a
Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), i-PrEt2N (0.80 mmol), CH3CN (2 mL), NaCl (1.25 M in H2O, 1 mL); yields of the isolated
product. Diastereomeric ratios were between 1 : 1 and 1.5 : 1 and determined by 1H NMR analysis. E/Z-alkene mixtures 1 are shown in
b
brackets. c Reaction conditions 1 (0.40 mmol), 2 (0.20 mmol), i-PrEt2N (0.40 mmol), CH3CN (2 mL), NaCl (1.25 M in H2O, 1 mL).
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substituted at the b position with methyl (3b, c) or alkyl groups
functionalized with an olen (3d), phthalimide (3e), alcohol (3f–
g) and phenyl (3h) or cyclobutyl rings (3i). We were glad to nd
that our photocyclopropanation worked well for stilbenes (3j, k),
cyclic (3l, q) and a-substituted styrenes (3m–q), which failed in
our previous photoredox cyclopropanation.6a In addition,
whereas the more substituted acyclic and cyclic trisubstituted
styrenes were well tolerated (3q, r), our process did not work for
styrenes with a sterically demanding b carbon center (3s, t). It is
worth highlighting that although the reaction generates mixtures
of diastereoisomers at the a-carbonyl center, which are easily
separable by column chromatography, the reaction proceeded
with absolute stereoconvergence for E/Z isomeric mixtures of di
and tri-substituted styrenes (1c, d, h, i, r).
We then decided to investigate the scope of terminal (hetero)
styrenes (3u–as). These substrates provided poor conversion to
the cyclopropane in our methylenation reaction,6a and instead
open-chain dimeric products were found from the homocou-
pling of benzylic radical intermediates. We were delighted to
nd that the new photocatalyst-free cyclopropanation was able
to cyclopropanate a broad variety of styrenes functionalized with
amine (3u), alkoxide (3v–x), sulde (3z), halogen (3aa–3ac, 3ae),
alkyl (3af, ag), phenyl (3ah), allyl (3ai), aldehyde (3aj), carboxylic
acid (3ak), pinacol boronic ester (3al), unsubstituted (3am) or
naphthalene (3an) groups. Unfortunately, styrenes substituted
with strong electron-withdrawing groups such as CF3 did not
yield the desired cyclopropane 3ad. Furthermore, we observed
that while our protocol was able to functionalize heterostyrenes
containing imidazole (3ao), benzofurane (3ap), indole (3aq, 3ar),
benzothiophene (3as) and thiophene (3at), no cyclopropanation
reaction was found for pyridine derivatives (3au).
Scheme 3 Reagent scope (A), late-stage functionalization (B) and
radical trapping experiments (C). Diastereomeric ratios of cyclopro-
panes were between 1 : 1 and 1.5 : 1 and determined by 1H NMR
The excellent functional group tolerance and chemoselectivity
observed towards the styrene double bond are in sharp contrast
to current catalytic methods that cyclopropanate styrenes analysis.
involving electrophilic metal-carbenes from diazoacetates. These
methods may suffer from chemo- and site-selectivity in chal-
explained involving abstraction of a hydrogen atom with int-I.
lenging substrates bearing additional alkenes (3d, w, ai),21 or
functionalities able to intercept the corresponding metal-carbene
intermediate such as alcohol (3f, g),22 aldehyde (3aj),23 alkyne
(3x),24 carboxylic acid (3ak)25 or sulde (3e, z) groups.26
An additional experiment carried out with the classic cyclo-
propyl radical probe 8 also supports the formation of int-I as an
intermediate by forming an atom-transfer radical addition
(ATRA) product 9.
On the other hand, although our process was successfully
extended to other gem-diiodomethyl esters (3au, av) or ketone
reagents (4a–c, Scheme 3A), the corresponding analogues
substituted with amides (4d) or other electron-withdrawing
groups did not provide the expected cyclopropane ring (5a–c).
The synthetic potential of our photocyclopropanation was
further illustrated with the late-stage functionalization of
biomolecule derivatives (Scheme 3B). Our process was able to
functionalize styrenes derived from estrone (6a), L-valine (6b)
and b-D-glucose pentaacetate (6c).27 In addition, we were
delighted to nd that the process could also work with the
unprotected glucose derivative (6d).28 This nal example clearly
highlights the potential of our methodology to be applicable in
alternative complex scenarios.29
Moreover, we wanted to prove the formation of radical int-I.30
Firstly, an experiment carried out without styrene resulted in
Scheme 4 Mechanistic hypotheses for the photogeneration of int-I (A
the isolation of iodoacetate 7 (Scheme 3C). Its formation can be and B).
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Finally, our current hypotheses for the photogeneration of
Chemical Science
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radical carbenoid int-I are depicted in Scheme 4. Considering
that our reagent 2a absorbs in the visible region (tail of
absorption: 460 nm at 0.1 M, see ESI†), we believe that one of
the possible scenarios could involve the photogeneration of the
excited state [2a]* and its evolution to int-I and I(c) by homolysis
(Scheme 4A).31 In this particular case, i-Pr2EtN might be acting
as a quencher of the iodine species, I(c) or I2, formed during the
reaction.32 Recently, the group of Aggarwal hypothesized
a homolytic cleavage of the C–I bond in a-iodo ketones by
visible light as a suitable pathway for the generation of elec-
trophilic alkyl radicals, analogous to int-I.33
On the other hand, another possible scenario involves the
formation of a short-lived exciplet [i-Pr2EtN$2a]* that undergoes
photoinduced electron transfer and generates int-I.34 Exciplet
analogues have been proposed recently in the generation of
radicals from inactivated alkyl iodides.35
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¨
The quantum yield measured for the model photo-
cyclopropanation of (E)-1a with 2a was found to be 1.5 (l ¼ 410
nm in CH3CN/H2O, using potassium ferrioxalate as the acti-
nometer), suggesting that if a radical-chain is operating, it is
very inefficient. At this point, this result does not allow us to
discriminate between one of the two mechanistic hypotheses
depicted in Scheme 4.
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Conclusions
In summary, we have developed a robust, scalable, and safe
photochemical cyclopropanation reaction with gem-diiodomethyl
carbonyl reagents. Our new cyclopropanation features an excel-
lent functional group tolerance that permitted the functionaliza-
tion of a broad range of functionalized styrenes and biomolecules.
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Conflicts of interest
A patent application describing the results presented in this
manuscript has been lled.
6 (a) A. M. del Hoyo, A. G. Herraiz and M. G. Suero, Angew.
Chem., Int. Ed., 2017, 56, 1610; Angew. Chem., 2017, 129,
1632; (b) A. M. del Hoyo and M. G. Suero, Eur. J. Org.
Chem., 2017, 2017, 2122.
7 M. H. Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem.,
2016, 81, 6898.
Acknowledgements
The ICIQ Starting Career Programme, Agencia Estatal de Inves-
´
´
tigacion (AEI) of the Ministerio de Ciencia, Innovacion y Uni-
versidades (CTQ2016-75311-P, AEI/FEDER-EU), the CELLEX
Foundation through the CELLEX-ICIQ high-throughput experi-
mentation platform and the CERCA Programme (Generalitat de
Catalunya) are gratefully acknowledged for nancial support. We
thank the CELLEX Foundation for the pre-doctoral fellowship (to
A. G. H.) and the ICIQ Research support area. We also thank Y.
8 For pioneering examples in photoredox carbon–halogen
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R. Ramırez-Contreras, M. E. Muratore, M. J. Johansson and
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´
a
pi-system: (a) J. L. Jeffrey, F. R. Petronijevic and
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charge-transfer complex between i-Pr2EtN and 2a may be
excluded: UV/vis absorption analysis of an equimolar
mixture of i-Pr2EtN and 2a did not show the characteristic
bathochromic shi expected for a charge-transfer complex
(see ESI†).
´
´
19 We believe that the role of aqueous NaCl is to quench 35 (a) Y. Shen, J. Cornella, F. Julia-Hernandez and R. Martin, ACS
possible water-soluble sub-products formed during the
reaction, whose absorption reduces the number of
Catal., 2017, 7, 409. For related photochemical generation of
radical species with activated alkyl halides via charge-transfer
or electron donor–acceptor complexes see: (b) E. Arceo,
available
photons
and
the
progress
of
the
´
´
photocyclopropanation. The sub-products could come
I. D. Jurberg, A. Alvarez-Fernandez and P. Melchiorre, Nat.
Chem., 2013, 5, 750; (c) X. Sun, W. Wang, Y. Li, J. Ma and
S. Yu, Org. Lett., 2016, 18, 4638; (d) Y. Wang, J. Wang, G. X. Li,
G. He and G. Chen, Org. Lett., 2017, 19, 1442; and ref. 19.
¨
from the decomposition of Hunig's base.
A similar
observation has been recently found by Bach et al.:
¨
A. Bohm and T. Bach, Chem.–Eur. J., 2016, 22, 15921.
Chem. Sci.
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