Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition–Polar Cyclization Cascade

Article abstract of DOI:10.1002/anie.201808598

Herein, we describe the development of a photoredox-catalyzed decarboxylative radical addition–polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical–polar crossover reactions between aliphatic carboxylic acid

Full text of DOI:10.1002/anie.201808598

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Accepted Article
Title: Synthesis of Functionalized Cyclopropanes from Carboxylic Acids
via a Radical Addition-Polar Cyclization Cascade
Authors: Chao Shu, Riccardo S. Mega, Björn J. Andreassen, Adam
Noble, and Varinder Kumar Aggarwal
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808598
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10.1002/anie.201808598
Angewandte Chemie International Edition
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Synthesis of Functionalized Cyclopropanes from Carboxylic
Acids via a Radical Addition–Polar Cyclization Cascade
Chao Shu,† Riccardo S. Mega,† Björn J. Andreassen, Adam Noble,* and Varinder K. Aggarwal*
Abstract: Herein, we describe the development of a photoredox-
catalyzed decarboxylative radical addition–polar cyclization cascade
approach to functionalized cyclopropanes. Reductive termination of
radical–polar crossover reactions between aliphatic carboxylic acids
and electron-deficient alkenes yielded carbanion intermediates that
were intercepted in intramolecular alkylations with alkyl chlorides
appended to the alkene substrate. The mild conditions, which make
use of a readily available organic photocatalyst and visible light, were
demonstrated to be amenable to a broad range of structurally complex
particularly interested in targeting cyclopropanes, as these
strained carbocycles are highly valuable motifs in drug
development and are common components of bioactive natural
products.[9]
carboxylic acids and
a wide variety of chloroalkyl alkenes,
demonstrating exquisite functional group tolerance.
Over the last decade, photoredox catalysis has been
extensively explored.[1] The mild conditions, high functional group
tolerance, and diversity of compatible carbon-centered radical
precursors, has resulted in numerous synthetically valuable
methodologies,
particularly in
the
area
of
alkene
functionalization.[2] The mechanistic pathways of such reactions
are dependent on the fate of the open-shell intermediate
generated upon addition of a radical to the alkene substrate,
which can undergo a radical-mediated bond-forming process
(Scheme 1A, path 1)[3] or a radical–polar crossover (Scheme 1A,
path 2).[4,5] In the latter case, a single-electron transfer (SET)
event leads to a carbocation (oxidative termination) or a carbanion
(reductive termination), which can then react with a nucleophile or
electrophile, respectively. Whilst both processes have been
extensively reported, in the case of reductive termination the
anion generated has invariably been protonated (Scheme 1A,
path 2, E = H).[5] We were interested in exploring whether the
anion generated could be trapped by a carbon-based electrophile
as this would be much more synthetically useful but has rarely
been reported.[6]
We
recently
reported
a
photoredox-catalyzed
decarboxylative radical addition of carboxylic acids to vinyl
boronic esters, proceeding via a radical–polar crossover with
reductive termination to give an α-boryl anion.[7] We queried
whether the catalytically-generated carbanions could undergo
intramolecular alkylations with alkyl halides, as this would provide
a decarboxylative radical addition–polar cyclization cascade for
the synthesis of cyclic boronic esters (Scheme 1B).[8] We were
Scheme 1. Photoredox-catalyzed alkene difunctionalizations.
Herein, we report the successful development of
a
photoredox-catalyzed radical–polar crossover cyclopropanation,
in which a broad range of readily available carboxylic acids are
directly converted to structurally diverse cyclopropanes through
decarboxylative reactions with chloroalkyl alkenes. During the
preparation of this manuscript, Molander and co-workers reported
a cyclopropanation of styrene-derivatives using iodomethyl
silicates that proceeds via a radical–polar crossover with
intramolecular alkylation of an intermediate β-iodo anion.[10] Our
process represents a fragment coupling approach, which is
distinct from Molander’s, and other, photoredox-catalyzed
[*]
Dr. C. Shu, Mr. R. S. Mega, Mr. B. J. Andreassen, Dr. A. Noble,
Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk, a.noble@bristol.ac.uk
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808598
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COMMUNICATION
cyclopropanations that use carbenoid-like radicals to introduce a
one-carbon unit in a formal [2+1] cycloaddition.[10,11]
were accessed in high yields. Furthermore, the reaction proved to
be relatively insensitive to the electronics of the aromatic ring, with
homoallyl chlorides functionalized with electron-deficient
pyridines or electron-rich benzofurans yielding the corresponding
heteroaromatic-substituted cyclopropanes 4i and 4j in 70% and
68% yield, respectively.
We began our investigation by studying the reaction of (4-
chlorobut-1-en-2-yl)boronic acid pinacol ester 1a (Scheme 2). We
were delighted to discover that irradiation of a mixture of 1a, Boc-
Pro-OH (2), and cesium carbonate in the presence of the iridium
photocatalyst Ir(ppy)2(dtbbpy)PF6 (3) led to the formation of
cyclopropyl boronic ester 4a in 90% yield. Analysis of the crude
reaction mixture confirmed that no hydrofunctionalization product
5 was formed, which highlights the high rate of intramolecular
alkylation of the carbanion intermediate. Remarkably, it was found
that 1 mol% of the more economical cyanobenzene-based
organic photocatalyst 4CzIPN (6) could promote the reaction with
even higher efficiency than 3, providing cyclopropane 4a in
quantitative yield.[12,13]
Table 1. Scope of the chloroalkyl alkenes.[a]
Scheme 2. Optimized conditions.
[a] Reactions were performed using 0.3 mmol of 2 and 1.5–2.0 equiv of 1 or 8.
See Supporting Information for exact experimental procedures. Yields are of
isolated products. Diastereomeric ratios were determined by 1H NMR analysis
of the purified products. [b] Solvent = DMF, temperature ~50 °C. [c] Solvent =
CH2Cl2, temperature ~30 °C (with fan cooling). [d] Number in parenthesis is the
isolated yield on a 2.0 mmol scale. [e] Using 5 mol% 6 and K2CO3 as the base.
Having identified optimal conditions, we began to
investigate the scope of the transformation with respect to other
homoallyl chlorides 1 (Table 1). The reaction was found to be
amenable to a diverse range of electron-withdrawing groups,
including carboxylate esters (4b), nitriles (4c), primary amides
(4d), sulfones (4e), and phosphonate esters (4f), providing the
cyclopropane products in excellent yields. The methodology could
also be applied to the preparation of vicinally disubstituted
cyclopropanes 7 by using allyl chlorides 8. Boronic ester 7a was
formed in moderate yield, which was attributed to the formation of
allyl ester side-products by SN2 displacement of the chloride of 8a
by the carboxylate of 2. For allyl chloride substrates 8, the
enhanced reactivity of the alkyl chloride towards O-alkylation
resulted in ester formation becoming competitive with SET and
decarboxylation. Switching solvents from DMF to CH2Cl2 greatly
reduced the amount of O-alkylation in the case of carboxylate
ester and thioester substrates 8b and 8c, enabling products 7b
and 7c to be generated in high yields. Cyclopropanes 7a–c were
formed in high diastereoselectivity with respect to the vicinal
cyclopropyl substituents but with low stereocontrol at the
pyrrolidine stereocenter, which is in keeping with a radical–polar
crossover process. The reaction was not limited to the use of
homoallyl chlorides bearing electron-withdrawing groups, as
styrene derivatives 1g-j were also capable substrates, with the
stabilized benzylic radical intermediate undergoing efficient
single-electron reduction prior to cyclization. For example,
cyclopropanes containing phenyl (4g) and naphthyl (4h) groups
Next, we turned our attention to determining the generality
of the reaction with respect to the carboxylic acid substrate (Table
2). Initially, we focussed on the reaction of α-amino acids with 1a
due to the potential for rapid access to cyclopropanated γ-amino
boronic acid derivatives. In addition to boronic acid derivatives
being highly valuable synthetic handles in organic synthesis,[14]
they are also finding increased application as novel drug
candidates.[15] We also applied the reactions to 1b to access
cyclopropanated analogues of γ-amino butyric acid (GABA), the
main inhibitory neurotransmitter in the mammalian nervous
system.[16] Structurally diverse α-amino acids reacted efficiently
with 1a to yield the corresponding cyclopropyl boronic esters,
including those possessing various carbamoyl protecting groups
(9a), as well as cyclic (10a) and acyclic (11a) amino acids. By
using an increased catalyst loading of 2 mol%, α-amino acids with
a carbamate N–H group also reacted efficiently (12–23).
Increasing the size of the α-substituent from methyl to iso-propyl
to tert-butyl resulting in a gradual decrease in yield (products 12a,
13a and 14a); however, N-Boc-protected tert-leucine still reacted
to give 14a in synthetically useful yield. Primary and tertiary
α-amino acids, Boc-Gly-OH and Boc-Aib-OH, also gave the
desired products in reasonable yields (15a and 16a). Reaction of
these lower yielding substrates with 1b led to substantially
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Table 2. Scope of the carboxylic acids.[a]
[a] Reactions were performed using 0.3 mmol of the carboxylic acid and 1.2–2.0 equiv of 1a or 1b. The heat generated by the LEDs resulted in reaction temperatures
of ~50 °C. See Supporting Information for exact experimental procedures. Yields are of isolated products. Diastereomeric ratios were determined by 1H NMR
analysis of the purified products.
improved yields of methyl ester cyclopropanes 15b and 16b. The
higher yields obtained with carboxylate ester 1b compared to
boronic ester 1a are in keeping with Carboni’s observations that
acrylates react more rapidly with alkyl radicals than vinyl boronic
esters.[17] Diversely functionalized amino acid substrates were
tolerated, including those with aromatic and heteroaromatic rings,
sulfides, esters, and primary amides (products 17a–21a, 18b and
19b). Dipeptides Z-Gly-Phe-OH and Z-Phe-Leu-OH were also
viable substrates (products 22a, 22b and 23a), demonstrating the
success of this methodology in peptide modification.
dehydroabietic acid underwent efficient reaction with both 1a and
1b to give the 29a and 29b in high yields and good levels of
diastereocontrol. Similarly, other tertiary alkyl carboxylic acids,
including the phenol-containing vitamin E analogue Trolox and
the fibrate drug gemfibrozil, provided the cyclopropane products
30a, 30b, 31a and 31b in good to excellent yields. Furthermore,
the densely functionalized naturally-occurring primary alkyl
carboxylic acids cholic acid and biotin reacted with 1b to give the
structurally complex cyclopropane products 32b and 33b,
respectively.
We then proceeded to investigate a wider range of
carboxylic acids. Tetrahydrofuran-2-carboxylic acid reacted
efficiently with both homoallyl chlorides 1a and 1b, demonstrating
that α-oxy acids also function well under the optimized conditions
(products 24a and 24b). This was also the case for simple
secondary alkyl carboxylic acids, with 2-methylheptanoic acid
yielding cyclopropanes 25a and 25b in good yields. Bis-
cyclopropane product 26b could also be prepared upon reaction
of a cyclopropyl carboxylic acid with 1b. The poor yield of product
26b reflects the challenges associated with the generation and
subsequent addition reactions of cyclopropyl radicals.[18] Indeed,
attempted reaction of the same cyclopropyl carboxylic acid with
the less reactive alkenyl boronic ester 1a[17] only resulted in
recovery of unreacted starting materials. Similarly, primary alkyl
carboxylic acids, including benzylic and non-benzylic, were found
to be unreactive with 1a but reacted efficiently with 1b to give
good yields of cyclopropanes 27b and 28b.
Table 3. Formation of larger rings.[a]
Cyclized
product, yield
Protonated
product, yield
Entry
Substrate
n
X
1
2
3
4
5
6
7
8
34a
34b
34c
35a
35b
35c
36b
36c
2
2
2
3
3
3
4
4
Cl
Br
I
37, 0%
37, 0%
40a, 65%
40b, 62%
40c, 36%
41a, 76%
41b, 25%
41c, trace[b]
42b, 91%
42c, 84%
37, trace[b]
38, 10%
38, 41%
38, 86%
39, trace[b]
39, trace[b]
Cl
Br
I
Br
I
[a] Reactions were performed using 0.2 mmol of 2 and 2.0 equiv of 34–36.
Yields are of isolated products. [b] A trace amount was observed in the crude
product mixture.
We then targeted more complex carboxylic acids as
substrates for our reaction, with the aim of demonstrating its
potential as a valuable method for late-stage diversification of
bioactive natural products and drug molecules. To this end,
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To probe the generality of this cyclization reaction, we also
explored the formation of larger rings using haloalkyl alkenes 34,
35, and 36 (Table 3). Of the substrates explored, only
cyclopentane formation was successful and optimum results were
obtained using iodide 35c (entry 6). Reactions with haloalkyl
alkenes 34 and 36 gave the protonated Giese addition products
40 and 42 instead of the 4- and 6-membered rings. The failure to
generate cyclobutane 37 and cyclohexane 39 reflects the
significantly slower rates of 4- and 6-exo-tet cyclization compared
to 3- and 5-exo-tet, which results in protonation to form 40 or 42
becoming the dominant pathway.[19]
and 4b in comparable yields to those obtained with the homoallyl
chlorides (Scheme 3C). In a related study forming 3-membered
rings, Molander and co-workers compared the activation barriers
of radical and anionic cyclizations with different leaving groups
and also concluded that the cyclization occurred through an
anionic pathway, thereby supporting our observations.[10]
Based on these observations, we propose the mechanism
outlined in Scheme 4. Initially, visible-light irradiation of the
photocatalyst (PC) leads to generation of the excited state
catalyst (PC*). SET with the carboxylate generated from in situ
deprotonation of carboxylic acid 2 results in reduction of the
photocatalyst, to radical anion PC•–, and oxidation of the
carboxylate to a carboxyl radical. Extrusion of CO2 provides
carbon-centered radical 47 that undergoes addition to homoallyl
chloride 1 to form the stabilized alkyl radical 48. A second SET
between radical 48 and the PC•– state of the photocatalyst
completes the photoredox catalytic cycle and results in reductive
termination of the radical process. Finally, the resulting stabilized
carbanion 49 undergoes a polar 3-exo-tet cyclization to give the
cyclopropane product 4. Measurement of a quantum yield (Φ) of
0.65 for the reaction of Boc-Pro-OH (2) with alkenyl boronic ester
1a suggests that alternative radical chain mechanisms are not
operative, thus providing further support for the closed
photoredox catalytic cycle shown in Scheme 4. The remarkable
breadth of the substituents attached to the homoallyl chlorides
that could be employed is especially noteworthy, ranging from
strong electron-withdrawing groups (e.g. carboxylate esters and
nitriles) all the way to electron-rich aromatics (e.g. benzofuran).
This highlights the broad synthetic utility of 4CzIPN, as the
reduced photocatalyst PC•– (E1/2 [4CzIPN/4CzIPN•–] = –1.21 V vs.
SCE in MeCN)[12b] was able to undergo SET with carbon-centered
radicals of vastly different reduction potentials, including
α-carboxylate ester radicals (E1/2 [R•/R–] ≈ –0.6 V vs. SCE in
MeCN)[22] and electron-rich benzylic radicals (E1/2 [R•/R–] < –1.4 V
vs. SCE in MeCN).[23]
Scheme 3. Mechanistic studies.
To gain insight into the mechanism of this radical cascade
process, we conducted several experiments to elucidate the
presence or absence of radical and carbanion intermediates
(Scheme 3). Reaction of cis-pinonic acid, a cyclobutane-
containing primary alkyl carboxylic acid, generated the ring-
opened product 43, confirming the initial formation of a primary
carbon-centered radical, which undergoes ring-opening to
generate the more stable tertiary radical prior to reaction with 1b
(Scheme 3A). The formation of carbanion intermediates was
confirmed by submitting allyl acetate 44 to the standard reaction
conditions, during which elimination of the acetate group occurred
to give alkene 45 in excellent yield (Scheme 3B). Elimination of
the acetate group will only take place after reduction of the
intermediate α-carbonyl radical to the carbanion (enolate).[20]
Although this result supports
a
radical–polar crossover
Scheme 4. Proposed mechanism.
mechanism, possible alternative pathway during the
a
cyclopropanation step is a homolytic substitution reaction (SH2)
between the intermediate α-carbonyl radical and the alkyl halide,
In conclusion, we have developed a photoredox-catalyzed
cyclopropane synthesis proceeding via a decarboxylative radical
addition–polar cyclization cascade. The mild conditions,
catalyzed by an organic photocatalyst, were found to tolerate a
broad range of functional groups on both the carboxylic acid and
the chloroalkyl alkenes substrates. Mechanistic studies confirmed
a
process that has previously been reported for radical
cyclopropanations with alkyl iodides.[11b,c] While this alternative
mechanism is unlikely given that chlorine is a much poorer radical
leaving group than iodine,[21] we gained conclusive evidence for a
polar (SN2) cyclopropanation by carrying out the reaction of 2 with
homoallyl tosylates 46a and 46b, which gave cyclopropanes 4a
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G. Suero, Angew. Chem. Int. Ed. 2017, 56, 1610; c) A. M. del Hoyo, M.
G. Suero, Eur. J. Org. Chem. 2017, 2017, 2122.
that the reaction proceeds via
a radical–polar crossover
mechanism involving reductive termination and subsequent
alkylation of a carbanion intermediate. Given the abundance of
carboxylic acids in sustainable chemical feedstocks, we believe
that this new fragment coupling-based cyclopropanation reaction
provides a valuable, atom-economical methodology for the
expedient preparation of structurally diverse cyclopropanes.
[12] a) H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature 2012,
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Acknowledgements
[18] L. J. Johnston, J. C. Scaiano, K. U. Ingold, J. Am. Chem. Soc. 1984, 106,
4877.
We thank EPSRC (EP/I038071/1) and H2020 ERC (670668) for
financial support. We thank Dr. Daniel Pflästerer for preliminary
work.
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Keywords: Photoredox catalysis • cyclopropanes • carboxylic
acids • radical–polar crossover • decarboxylation
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8312.
[23] B. A. Sim, D. Griller, D. D. M. Wayner, J. Am. Chem. Soc. 1989, 111,
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The development of
coupling-based cyclopropanation
between carboxylic acids and
chloroalkyl alkenes is described. The
reaction involves photoredox-
catalyzed decarboxylative radical
addition–polar cyclization cascade and
uses of a readily available organic
photocatalyst. The mild conditions
a
fragment
C. Shu, R. S. Mega, B. J. Andreassen ,
A. Noble,* V. K. Aggarwal*
Page No. – Page No.
a
Synthesis of Functionalized
Cyclopropanes from Carboxylic
Acids via a Radical Addition–Polar
Cyclization Cascade
provide
access
to
diversely
functionalized cyclopropanes from a
broad range of structurally complex
carboxylic acid and alkene substrates.
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