Azide Radical Initiated Ring Opening of Cyclopropenes Leading to Alkenyl Nitriles and Polycyclic Aromatic Compounds

Article abstract of DOI:10.1002/anie.202013516

We report herein a radical-mediated amination of cyclopropenes. The transformation proceeds through a cleavage of the three-membered ring after the addition of an azide radical on the strained double bond and leads to tetrasubstituted alkenyl nitrile derivatives upon loss of N₂. With 1,2-diaryl substituted cyclopropenes, this methodology could be extended to a one-pot synthesis of highly functionalized polycyclic aromatic compounds (PACs). This transformation allows the synthesis of nitrile-substituted alkenes and aromatic compounds from rapidly accessed cyclopropenes using only commercially available reagents.

Full text of DOI:10.1002/anie.202013516

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Accepted Article
Title: Azide Radical Initiated Ring Opening of Cyclopropenes Leading
to Alkenyl Nitriles and Polycyclic Aromatic Compounds
Authors: Bastian Muriel and Jerome Waser
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013516
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Azide Radical Initiated Ring Opening of Cyclopropenes Leading
to Alkenyl Nitriles and Polycyclic Aromatic Compounds
Bastian Muriel and Jerome Waser*[a]
Abstract: We report herein
a
radical-mediated amination of
alkyl-substituted cyclopropenes, followed by trapping of the
radical by dimethyl zinc (Scheme 1, b) 1.).[14a] Landais and co-
workers developed a radical-mediated dicarbofunctionalization of
cyclopropenes, followed by a base-mediated fragmentation of the
in situ formed cyclopropane (Scheme 1, b) 2.).[17]
cyclopropenes. The transformation proceeds through a cleavage of
the three-membered ring after the addition of an azide radical on the
strained double bond and leads to tetrasubstituted alkenyl nitrile
derivatives upon loss of N2. With 1,2-diaryl substituted cyclopropenes,
this methodology could be extended to a one pot synthesis of highly
functionalized polycyclic aromatic compounds (PACs). This
transformation allows the synthesis of nitrile-substituted alkenes and
aromatic compounds from rapidly accessed cyclopropenes using only
commercially available reagents.
Alkenyl nitriles and polycyclic aromatic compounds (PACs) are
important scaffolds in organic chemistry, material sciences and
medicine.[1] Alkenyl nitriles are key structural motifs in
pharmaceuticals such as Entacapone used in the treatment of
Parkinson’s disease,[2] or the reverse transcriptase inhibitor
Rilpivirine.[3] In addition, they are valuable synthetic intermediates
that have been used as electrophilic partners in conjugate
additions.[4] PACs are also present in biologically active
compounds,[5] and have found many applications as organic
materials for semiconductors[6] and light-emitting diodes.[7]. For
these reasons, developing new methods for the synthesis of
PACs has been the focus of intensive research.[8] Nevertheless,
there is still a strong demand for modular methods to access
selectively polysubstituted PACs.
Cyclopropenes have emerged in the past decades as important
three-carbon building blocks, due to efficient methods for their
synthesis combined with a versatile reactivity.[9] Reaction at the
double bond with organometallic intermediates or transition metal
catalysts gives access to either functionalized cyclopropanes[10]
or substituted alkenes after ring-opening via vinyl carbene
intermediates[11] (Scheme 1, a). The formation of a reactive
cyclopropyl radical intermediate upon the addition of a radical
onto the alkene has been less explored. Nakamura and co-
workers
reported
in
1994
the
hydrostannation
of
cyclopropenes.[12] Several reports have later described the
addition of carbon-centered radicals, with a functionalization of
the resulting cyclopropyl radical through C-S bond formation,[13]
H-abstraction,[14] or a second C-C bond forming event.[15] We
recently developed a photoredox-mediated (3+2) annulation with
cyclopropylanilines to access bicyclo[3.1.0]hexanes.[16] In
contrast, examples of a radical functionalization of cyclopropenes
leading to a cleavage of the three-membered ring are scarce
(Scheme 1, b). Miyata and co-workers reported a ring opening
rearrangement after the addition of a trichloromethyl radical to
Scheme 1. Synthetic strategies towards functionalized cyclopropanes and
substituted alkenes from cyclopropenes (a). Previous reports leading to a
cleavage of the three-membered ring after
a radical functionalization of
cyclopropenes (b). This work: radical amination of cyclopropenes with an azide
radical for the synthesis of alkenyl nitriles and substituted PACs (c).
Although examples of amination reactions of cyclopropenes have
been reported in the presence of transition metals or lanthanides
combined with electrophilic,[18] or nucleophilic sources of
nitrogen,[19] the addition of N-centered radicals has not been
reported to date. We report herein a ring-opening reaction initiated
by the addition of an azide radical (Scheme 1, c). This
transformation led to the formation of alkenyl nitriles after the
rearrangement of a putative azido-cyclopropyl radical (I). With
1,2-diaryl substituted cyclopropenes we developed a one-pot
radical amination / oxidative photocyclization to access highly
substituted PACs. While azide radicals have already been used
for the synthesis of alkenyl nitriles through C-H or C-C bond
cleavage of alkenes and alkynes, these processes were limited to
[*]
B. Muriel, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique
Fédérale de Lausanne, EPFL, SB ISIC LCSO, BCH 4306
1015 Lausanne (Switzerland)
Email: jerome.waser@epfl.ch
Homepage : http://lcso.epfl.ch/
Supporting information for this article is given via a link at the end of
the document. Raw data for NMR, IR and MS is available at
zenodo.org, DOI: 10.5281/zenodo.4279268
1
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the synthesis of trisubstituted olefins and cyclopropenes were not
reported as substrates.[20]
yield, with 14 isolated in 84% yield on a 1.6 mmol scale, albeit
with almost no stereoselectivity.
Our investigations started with cyclopropene 1 employing ABZ (3)
as safe azidation reagent under mild photoredox-catalyzed
conditions known to generate azide radicals (Table 1).[21] Under
green LED irradiation with Cu(dap)2Cl as photocatalyst, alkenyl
nitrile 2 was formed in 82% yield (entry 1). When reducing the
equivalents of ABZ from 2.0 to 1.4, 2 was obtained in 78% yield
(entry 2). In the presence of inexpensive CuCl2 and ABZ (3)
without irradiation, 2 was formed in 62% yield (entry 3). Employing
2 equivalents of PIDA and TMS-N3 as commercial reagents,[22]
2
was obtained in 56% yield after 30 minutes of reaction (entry 4).
Adding 10 mol% of CuCl2 led to a high yield of 94% (entry 5).[23]
While going from 2.0 to 1.5 equivalent led to a decrease in yield
to 85% (entry 6), we found 1.8 equivalent to be optimal combined
with a reduced loading of CuCl2 to 5 mol% (entry 7). Under these
conditions, 2 could be isolated in 88% yield.
Table 1. Discovery and optimization of the radical amination.[a]
Scheme 2. Preliminary scope investigations of the radical amination. Reaction
conditions: 0.3 mmol scale. [a] Yield on 1.6 mmol scale.
Azide Source
(equiv.)
Cat.
(mol%)
Oxidant
(equiv.)
Entry
Time
Yield[b]
Alkenyl nitrile 2 could be obtained in 92% yield on gram scale
(Scheme 3). Taking advantage of the electrophilic nature of 2, it
was successfully engaged in several transformations. A Corey–
Chaykovsky cyclopropanation led to 15 in 54% yield.[26] Alkene 2
underwent a (3+2) annulation with allenoate 16, delivering
cyclopentene 17 in 89% yield.[27] 2 could also be engaged in a
Diels-Alder cycloaddition with Danishefsky's diene 18,[28] leading
to cyclohexenone 19 after acidic deprotection in 64% yield. We
then investigated the possibility to engage cyano-stilbene
derivatives such as 14 into an oxidative photocyclization.[29] Under
irradiation, E to Z isomerization would occur, allowing converting
both isomers to the product. While straightforward methods now
exist for the synthesis of simple disubstituted stilbenes,[30]
accessing tetrasubstituted stilbenes with four different
substituents as obtained in our work still constitutes an important
challenge.[31] In the presence of 1.1 equivalent of DDQ in
acetonitrile (0.05 M) under UV irradiation (365 nm) for 20 hours,
cyano-phenanthrene 20 could be isolated in 74% yield.
A one-pot process from 1,2-diaryl substituted cyclopropenes
allowed to directly access the corresponding PACs (Scheme 4,
see SI for details). On a 0.3 mmol scale, 20 could be isolated in
80% yield. A tert-butyl ester, a ketone and a trifluoromethyl group
in position 1 of the cyclopropene led to phenanthrenes 21, 22 and
23 in 51-75% yields. Both electron-donating and -withdrawing
substituents in para position of both aromatic groups were well
tolerated, delivering products 24-27. Substitutions in ortho and
meta positions were also tolerated (28-31). A 1-thienyl substituted
cyclopropene gave heteroaromatic product 32 in 61% yield.
1[c]
2[c]
3
ABZ (2)
ABZ (1.4)
Cu(dap)2Cl (1)
Cu(dap)2Cl (1)
CuCl2 (10)
-
-
-
-
O/N
O/N
O/N
82%
78%
62%
56%
94%
85%
90%
ABZ (1.4)
4
TMS-N3 (2)
TMS-N3 (2)
TMS-N3 (1.5)
PIDA (2) 30 min
PIDA (2) 30 min
PIDA (1.5) 30 min
5
CuCl2 (10)
CuCl2 (10)
6
7
TMS-N3 (1.8)
CuCl2 (5)
PIDA (1.8) 30 min
(88%[d]
)
[a] Reaction conditions: 0.1 mmol scale, O/N: overnight. dap = 2,9‐bis(para-
anisyl)‐1,10‐phenanthroline. [b] Yields determined by 1H NMR using CH2Br2
as internal standard. [c] Reaction performed under Green LED irradiation. [d]
Isolated yield on 0.1 mmol scale.
With optimized conditions in hands, we carried some preliminary
scope investigations (Scheme 2). On a 0.3 mmol scale,
cyclopropene 1 delivered alkenyl nitrile 2 in 91% yield. Dibenzyl-
and ditrifluoroethyl-ester substituted cyclopropenes gave
products 4 and 5 in 74% and 72% yield, respectively. Both
electron-donating and -withdrawing groups in para-position on the
aromatic substituent of the cyclopropene were compatible with
the reaction (products 6 and 7).[24] Meta-substitution was also
tolerated (product 8, 81% yield). The reaction proceeded as well
with a 2-naphthyl substituent, delivering 9 in 94% yield. For 9, an
X-Ray structure could be obtained.[25] An ortho-CF3 substituted
cyclopropene led to the formation of 10 in 77% yield. As shown
with examples 11, 12 and 13 for which only traces of the alkenyl
nitriles were observed, having an aryl-substituent on the
unsaturated bond was essential. With aryl groups both in position
1 and 2 of the cyclopropene ring, the reaction proceeded in high
2
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most probably by hypervalent iodine reagent intermediates I or II,
would give the nitrile product.[39]
The role of the copper catalyst is still unclear. When the reaction
was performed with cyclopropene 39 in absence of CuCl2
(Scheme 5B), alkenyl nitrile 14 could be still isolated in 30% yield,
but quinoline 40 was also obtained in 34%. Quinoline 40 may be
formed by addition of the iminyl radical in intermediate VIII onto
the benzene ring, followed by oxidation and rearomatization. Its
formation therefore further support path b of the proposed
mechanism. One role for copper may be to recombine with the
imine radical, preventing cyclization and facilitating formation of
the nitrile via deprotonation, eventually after oxidation by the
hypervalent iodine reagent.[40]
Scheme 3. Gram-scale synthesis of 2 and further functionalizations of alkenyl
nitriles 2 and 14. [a] Isolated as a 4.2:1 mixture of regioisomers, major
regioisomer drawn.
We then investigated the synthesis of extended PACs.
Cyclopropenes substituted with 2-naphthyl groups gave
functionalized [4]helicenes 33-35 in good yields. Chrysene and
benzo[g]chrysene derivatives could also be accessed (products
36 and 37). Substituted picene 38 was obtained in a slightly lower
yield of 54%. For all the substrates, full conversion of the starting
material towards the corresponding alkenyl nitriles was observed.
Hence when lower yields were obtained, the oxidative
photocyclization was the limiting step.
Based on experimental observations and literature precedence in
the use of azides to generate nitrile-containing compounds,[32]
a
speculative mechanism can be proposed (Scheme 5A). The
reaction of PIDA with TMS-N3 would lead to the formation of
unstable hypervalent iodine compounds I and II, which will
dissociate into a iodanyl and an azide radical III and IV.[22, 33] IV
would most likely add onto the C-C double bond of the
cyclopropene to generate azido-cyclopropyl radical V.[34] Two
different paths can then be proposed. In path A, cyclopropyl
radical V would be oxidized to cyclopropyl cation VI, probably by
an hypervalent iodine intermediate. From the latter a ring-opening
rearrangement initiated by the azide group would occur, leading
to the formation of VII. From VII, a base-mediated (azide or
acetate)[35] fragmentation would then lead to the alkenyl nitrile
upon loss of nitrogen.[36] Another possibility from intermediate V
would be a direct rearrangement triggered by the azide group with
loss of nitrogen to give iminyl radical VIII (path b).[37] The
rearrangement of cyclopropyl to allyl radicals is a relatively easy
process, with an energy barrier of only 22 kcal/mol for the
cyclopropyl radical.[38] In this case, coupling it with nitrogen
release may even lower further the activation energy, although
this remains highly speculative. From this intermediate, oxidation,
Scheme 4. Scope of the one-pot radical amination / oxidative photocyclization.
Reaction conditions: 0.3 mmol scale.
In conclusion, we have developed a radical amination/ring-
opening of cyclopropenes using azides as nitrogen source. This
transformation constitutes the first example of addition of an N-
centered radical onto cyclopropenes and is one of the few reports
of a ring-opening event after a radical functionalization of the
unsaturated bond. The obtained tetrasubstituted alkenyl nitriles
could be further engaged in several transformations. In the case
of 1,2-diaryl-substituted cyclopropenes, a one-pot process could
be developed to access highly functionalized PACs. This
methodology therefore provides a new way to use cyclopropenes
as starting materials for the synthesis of valuable nitrile-containing
scaffolds using commercially available reagents.
3
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Scheme 5. Speculative mechanism and control experiment in absence of
copper catalyst with cyclopropene 39.
Acknowledgements
We thank the Swiss National Science Foundation (SNSF, grant
no. 200020-182798) and EPFL for financial support. We thank Dr
R. Scopelliti and Dr F. F. Tirani from ISIC at EPFL for X-ray
analysis.
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Keywords: cyclopropenes • amination • radicals • nitriles •
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[40] We thank a reviewer for suggesting us this pathway for the conversion
of the imine radical to the nitrile product.
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10.1002/anie.202013516
Angewandte Chemie International Edition
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A radical amination of cyclopropenes has been developed. The transformation proceeds through a cleavage of the three-membered
ring and provides access to alkenyl nitriles, without the need of an external cyanide source. With 1,2-diaryl substituted cyclopropenes,
a one-pot process could be developed to access a wide range of highly functionalized polycyclic aromatic compounds.
Institute and/or researcher Twitter usernames: @LcsoLab, @EPFL_CHEM_Tweet.
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