Photoredox Decarboxylative Alkylation/(2+2+1) Cycloaddition of 1,7-Enynes: A Cascade Approach Towards Polycyclic Heterocycles Using N-(Acyloxy)phthalimides as Radical Source

Article abstract of DOI:10.1002/adsc.201900657

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Full text of DOI:10.1002/adsc.201900657

Title: Photoredox Decarboxylative Alkylation/(2+2+1) cycloaddition
of 1,7-enynes: A Cascade Approach Towards Polycyclic
Heterocycles Using N-(acyloxy)-Phthalimides as Radical Source
Authors: Márcio Paixão, José Tiago , Gustavo Silva, and Elias André
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900657
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Photoredox Decarboxylative Alkylation/(2+2+1) Cycloaddition
of 1,7-Enynes: A Cascade Approach Towards Polycyclic
Heterocycles Using N-(Acyloxy)phthalimides as Radical Source
José Tiago Menezes Correia,†a Gustavo Piva da Silva,†a Elias André a and Márcio
Weber Paixão a*
a. Center of Excellence for Research in Sustainable Chemistry (CERSusChem), Department of Chemistry, Federal
University of São Carlos – UFSCar, Rodovia Washington Luís, km 235 - SP-310 - São Carlos - São Paulo - Brazil -
13565-905. E-mail: mwpaixao@ufscar.br † These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The visible-light-mediated radical cascade reaction of 1,7-enynes towards the access of densely decorated
polyheterocyclic scaffolds is disclosed. The key sp3-hybridized carbon-centered radical intermediates are promptly
generated upon an oxidative quenching of the photocatalyst with a range of N-(acyloxy)alkylphthalimides. This strategy
features mild reaction conditions, broad substrate scope and high functional group tolerance affording polycyclic
heterocycles in generally good chemical yields.
Keywords: Photocatalysis; 1,7-Enynes; N-(acyloxy)phthalimides; cycloaddition
generation involves an oxidative quenching
Introduction
process (catalyst quenching), which is initiated by
an electron-transfer event from the photocatalyst
to the N-(acyloxy)phthalimides moiety, leading
after carbon dioxide and phthalimide anion
extrusion to a C-centered radical.[4]
The development of a milder and straightforward
methodology towards structurally diverse and
complex target molecules through highly
controlled multiple bond-forming processes has
been a long-standing goal pursued by synthetic
chemists.[1] In this regard, radical cascade
strategies are among the most powerful protocols
to assemble complex poly carbo(hetero)cyclic
skeletons.[2]
The strategy allows the one-pot construction of
multiple C-C bonds that are often elusive or
currently would require sequential manipulations
and the insertion of directing or protecting groups
to be achieved through the classical polar
chemistry.[2] Therefore, redox-neutral radical
cascade process has a strong impact when
Inspired by the seminal work of Okada and
Oda,[6] in 2013 Reiser disclosed an elegant
approach for the synthesis of (spiro)anellated
furans through the visible-light reductive-
decarboxylation of N-(acyloxy)phthalimides
mediated by iridium complex in the presence of
water.[7] Likewise, the Glorius group revisited this
strategy for the straightforward photoredox
synthesis of benzylic alcohols and ethers through
radical oxy-alkylation of styrenes.[5a] Besides, it
was reasoned that a hydrogen bond interaction is
responsible for phthalimide reduction potential
increment, allowing, therefore, its ready reduction
by the photoexcited catalyst. Recent reports have
expanded the scope of the reductive-
decarboxylative functionalization using a similar
strategy.[5b,c,w]
economic
and
sustainable
aspects
are
considered.[1a]
Among
the
carbon-triggered
cascade
methodologies previously developed, those in
which the alkyl radicals are generated through a
decarboxylative event has attracted special
attention.[3] Recently, research efforts in many
laboratories have explored the application of
In light of these previous reports, we envisioned
the application of this approach on the radical
addition/annulation of 1,7-enynes (Scheme 1),
which are recognized as formidable building
blocks for the preparation of densely
redox-active
N-(acyloxy)phthalimides
in
photoredox decarboxylative alkylation reactions,[4,
functionalized
polycyclic
carbo-
and
5a-r]
heterocycles.[2b,d] Most of the previous reports on
including
chemoselective
cascade
cyclizations.[5s-x] Mechanistically, the alkyl radical
1
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
radical alkylating cascade usually required harsh
reaction conditions and stoichiometric radical
initiators which would limit their practical
protocol, having cyclohexyl carboxylic acid N-
(acyloxy)phthalimide derivative 2a and the 1,7-
enyne 1a as model substrates (Table 1). Thereby,
application (Scheme 1a).[3,8] On the other hand, inspired by Xiao’s elegant work,[5w] we have
only three examples of visible-light-induced chosen to conduct the photocatalytic reaction in
redox-neutral cascade alkylations of 1,6- and 1,7- the presence of 1 mol% of [Ir(dtbbpy)(ppy)2]PF6,
enynes have been reported so far. Particularly, 1.2 equiv. of pyridine as the base, 10 equiv. of
those strategies employed bromomalonates and
bromo-ketones as radical precursors which
intrinsically limited structural diversification of
water as hydrogen-donor and CH3CN as solvent
under blue LED irradiation (34W Kessil Lamp -
max= 456nm). Delightfully, desired product 3a
the compound libraries (Scheme 1b).[9] Therefore, was produced in 55% chemical yield after 20h
we thought that a complementary practical (Table 1, entry 1). In an initial set of optimization
approach for the preparation of this interesting
experiments, distinct photoredox-catalysts were
class of scaffold is highly desirable. As part of our evaluated. Nonetheless, these seemingly modest
studies on photocatalytic radical cyclizations,[10] changes completely ceased the photochemical
we report herein,
reductive decarboxylation
a
visible-light-mediated reactions (entries 2-4). We further considered
of N- whether a higher amount of water could be
(acyloxy)phthalimides and the trapping of beneficial to this protocol - however, no
respective resulting alkyl radicals by 1,7-enynes, improvement was observed when 20 equiv. of
furnishing
spirocyclopenta[c]quinolones through
skeletally
diverse water has been added to the reaction system (entry
a
cascade
5). Furthermore, the solvent screening indicated
that DMSO was optimal to deliver 3a in 74% yield
Table 1. Optimization of the reaction conditions[a]
Entry
Deviation from standard conditions
3a (%)
55
Traces
n.r.
n.r.
51
1
2
3
4
5
6
7
8
9
none
II instead of
III instead of
IV instead of
I
I
I
20 eq. of H2O instead of 10 eq.
DMF instead of CH3CN
DMSO instead of CH3CN
2,6-Lutidine instead of Pyridine
DMSO/2,6-Lutidine instead of
CH3CN/Pyridine
40
74
72
75
10
11
NaHCO3 instead of Pyridine
No base
59
37
12[b]
13[b]
No water
Air atmosphere
31
n.r.
Scheme 1. Previous reports on radical cascade
alkylations of 1,6 and 1,7-enynes and presented
methodology.
[a]
Standard reaction conditions: 0.10 mmol scale
using 2.5 equiv. of 2a, 1.2 equiv. of the base and
10 equiv. of H2O and 1.0 mol% of photocatalyst.
process (Scheme 1c).
[b] Using entry 8 as the standard condition.
(entry 7).
Results and Discussion
In a parallel attempt to increase reaction
efficiency, we then examined the influence of base
in the reaction outcome. To this, in combination
We began our endeavors by identifying suitable
reaction conditions for the outlined cascade
2
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
with the standard reaction parameters and, also
using DMSO as the solvent, 2,6-Lutidine showed
the best reaction performance (entries 8 and 9).
Subsequently, the presence of a weaker inorganic
base (NaHCO3) also delivered the desired product
3a in a reduced yield (entry 10). Conducting the
cascade protocol in the absence of base or water
led to significant erosion in the reaction yield,
showing that the presence of such additives is
crucial for the reaction outcome (entries 11 and
12). Afterward, the reaction was also shown to be
sensitive to the presence of oxygen - showing
therefore that a freeze-pump-thaw procedure is
indispensable to the success of this transformation
(entry 13).
Table 2. Scope of 1,7-enynes.[a]
With suitable reaction conditions in hand, we
next turned our attention to evaluating the
generality of this new cascade reaction
methodology.[11] As shown in Table 2, the
presence of a range of substituents is compatible
with the annulation reaction. Firstly, the effect of
electronic distinct substitution patterns on the
phenyl ring of the aniline moiety has been
evaluated. Interestingly, 1,7-enynes carrying
[a] Reaction conditions: 1b-p (0.10 mmol), 2a (0.25
mmol), 1,6-lutidine (1.2 equiv.), H2O (10 equiv.) and 1.0
mol% of Ir(ppy)2(dtbbpy)PF6, CH3CN (1.0 mL) in a sealed
Schlenk flask, under argon atmosphere and at room
temperature.
electron-donating
groups
showed
similar
reactivity than those with electron-withdrawing
counterparts (Table 2, products 3b-e). Moreover,
we investigated the influence of substituents on the
aromatic moiety of the alkyne. Gratifyingly, the
cascade reaction tolerates electron-withdrawing
(e.g., fluorine, methyl ester) and electron-donating
(e.g., methyl, methoxy) functional groups,
affording the desired products in moderate to good
yields (Table 2, products 3f-i). On the other hand,
a 1,7-enyne derivative bearing an alkyl side chains
(aliphatic alkynes) was shown to be a limitation of
this protocol, as only traces of products were
observed under the standard reaction conditions
(Table 2, products 3j and 3k). A nitrogen-
containing heteroaryl moiety, which is among the
most prevalent scaffold present in bioactive
molecules, has also been evaluated under this
carbon-triggered cascade manifold. Notably, the
reaction of the 1,7-enyne involving the
alkynylpyridine derivative delivered the desired
product 3l in 44% yield.
[b] 3 mmol scale
We next sought to explore the generality of this
methodology with respect to the N-
(acyloxy)phthalimides (Table 3). This mild,
radical-based method exhibits broad functional
group tolerance. First, the reactivity of cyclic
secondary carbon-centered radicals was evaluated
- the results revealed a considerable decrease in the
chemical yield as the size of the cyclic alkyl ring
decreases (Table 3, compounds 4a and 4b). These
observations would probably be related to the
lower stability and, therefore, the difficult
generation of strained cyclic alkyl radicals through
the single electron transfer event.[12] Further, we
are pleased to observe that less bulky acyclic
secondary carbon-centered radical was well-
accommodated, being the desired product 4c
obtained in 55% yield. Then, a non-symmetrical
We were pleased to find that different N-
protecting groups were also tolerated in our
reaction. Both N-benzyl- and N-tosyl-protected
1,7-enynes were smoothly converted to their
spirocyclic cyclopenta[c]quinoline congeners in
moderate yields (Table 2, compounds 3m and 3n).
We then evaluated the protocol towards oxygen-
containing heterocycle synthesis. Accordingly,
cyclopenta[c]chromene 3o was assembled in an
acceptable chemical yield. Furthermore, this
selective and straightforward protocol was also
applied for the construction of a densely
functionalized dihydroquinoline derivative in high
yield (Table 2, compound 3p).
acyclic
derivative,
2-methyl-butyl
N-
(acyloxy)phthalimide, was subjected to the
standard conditions affording 4d in 64% yield as a
1:1 mixture of diastereoisomers. Nonetheless, the
silyl ether derivative containing phthalimide ester
- NHP ester 2e – gave rise to product 4e in 34%
yield with a diastereoselectivity of 4:1. The
observed lower yield could be attributed to the
lability of tert-butyldimethylsilyl protecting group
under the reaction conditions. Moreover, sterically
hindered
secondary
alkyl-N-
(acyloxy)phthalimides underwent alkyl radical
cascade reaction in good yield and high
3
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
Table 3. Scope of N-(acyloxy)phthalimides
[a] Standard optimized conditions: 1 (0.10 mmol), 2 (0.25 mmol), 1,6-lutidine (1.2 equiv.), H2O (10 equiv.) and 1.0 mol%
of Ir(ppy)2(dtbbpy)PF6, CH3CN (1.0 mL) in a sealed Schlenk flask, under Argon atmosphere and at room temperature.
[b] 2.0 mol% of catalyst was used.
[c] 1 (0.2 mmol), 2 (0.1 mmol), 1,6-lutidine (1.2 equiv.), H2O (10 equiv.) and 1.0 mol% of Ir(ppy)2(dtbppy)PF6, CH3CN
(1.0 mL) in a sealed Schlenk flask, under Argon atmosphere and at room temperature.
diastereoselectivity. However, longer reaction however, under slightly modified reaction
time is required (Table 3, compound 4f). conditions products 4n and 4o were both obtained
Medicinally privileged saturated cyclic secondary
amines e.g. pyrrolidine and piperidine derivatives
have both proven to be viable substrates for this
methodology. Thus, under the optimized reaction
in only 22% chemical yield. The current method
also exhibits limitations when secondary benzylic-
and cyclopropyl N-(acyloxy)phthalimides have
been submitted to the optimized reaction
conditions, N-Boc and N-Cbz protected proline- conditions (4p and 4q – Table 3).
derivatives afforded the products 4g and 4h in 50%
yield with 3:2 d.r. and 35% yield with 1:1 d.r.
To gain additional information regarding the
functional-group tolerance of this new
respectively (Table 3). Additionally, visible-light- photocatalytic cascade process, we have examined
mediated radical cascade reaction of N-Boc- and the reaction of 1a with 2a in the presence of five
N-tosyl-isonipecotic-N-(acyloxy)phthalimides
afforded the expected products in good yields
(Table 3, compounds 4i and 4j).
additives under the standard reaction condition.
To further demonstrate the versatility of this
protocol, we decided to investigate the behavior of
1,7-enyne 2o in the presence of secondary
carbocyclic-N-(acyloxy)phthalimides.
As
observed previously, chemical efficiency
decreased as the ring strain increase (Table 3,
compound 4k vs 4l). Besides, N-Boc-isonipecotic-
N-(acyloxy)phthalimide also reacted smoothly in
the presence of substrate 1o, giving product 4m in
48% yield.
Moreover, the reactivity of primary alkyl N-
(acyloxy)phthalimides were also examined –
Scheme 2 – Functional group tolerance study.
4
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
Conclusion
Accordingly,
the
additive-based
reaction
screening showed that the indole, aldehyde, ketone
or cyanoarene moieties were well tolerated under
the reaction conditions. Moreover, with the
exception of the cyanoarene, the aforementioned
additives could be largely recovered at the end of
the process. In contrast, the presence of a chalcone
significantly inhibited the cascade, indicating that
the presence of an additional Michael acceptor
moiety is harmful to the transformation.
In summary, we have demonstrated a redox-
neutral photocatalytic alkylating cascade process
for the construction of skeletally diverse
spirocyclopenta[c]quinolones. Although there are
some limitations, this protocol shows broad
substrate scope – with respect to both the alkyl
phthalimide and the 1,7-enyne – and high
functional group tolerance. This mild and versatile
strategy offers a complementary alternative to the
previously reported methodologies. Furthermore,
we also observed that the activation of N-
Base on the above observations and literature
precedents, a plausible reaction mechanism was
proposed (Scheme 3).[3,5a,8,9] Upon excitation with
visible light, the ground-state photocatalyst (Ir(III)
)
(acyloxy)phthalimides by water through
a
hydrogen-bond interaction showed a pivotal role
in lengthy radical cascades. Given the prevalence
of nitrogen heterocycles in bioactive molecules
and the challenges associated with accessing
densely substituted fused-ring systems, this
protocol opens the possibility to access a wide
number of structurally diverse polycyclic N-
heterocycles in a simple and efficient manner.
is promoted to its highly reducing excite stated
1/2
(*Ir(III), Ered = – 0.96 V),[13] which undergoes a
single electron transfer step with the activated
alkyl N-(acyloxy)phthalimide
2
(Ered1/2 < – 1.28 V
vs. SCE in MeCN)[7] affording the reduced N-
(acyloxy)phthalimide along with the oxidized
form of the photocatalyst (IrIV). According to a
seminal study by Glorius and co-workers, this
process is enabled through the hydrogen-bonding
interaction between
2
and water.[5a] Further, the
Experimental Section
reduced N-(acyloxy)phthalimide decomposes
readily, releasing CO2, phthalimide anion and the
General procedure for the photoredox decarboxylative
alkylation/(2+2+1)-cycloaddition of 1,7-enines (products
3a-3o, 4a-4h, 4l and 4m).
alkyl radical intermediated
addition of to the C=C bond of the 1,7-enyne
starts a regioselective radical cascade process, that
generates the vinyl radical intermediated
Subsequently, the radical undergoes an
intramolecular 1,5-hydrogen atom transfer (1,5-
HAT) leading to intermediate , which upon
cyclization generates intermediate . To complete
the catalytic cycle, is easily oxidized by the
ground-state iridium catalyst (IrIV) accessing the
carbocation , that after deprotonation (by the
5. Next, the radical
5
1,
6
.
In a Schlenk tube at r.t., iridium catalyst I (1 mol%), N-
(acyloxy)phthalimide (2.5 equiv.), enyne (1 equiv.), were
dissolved in 1.0 mL of acetonitrile, following by the
addition of 2,6-lutidine (1.2 equiv) and H2O (10 equiv.). The
reaction mixture was carefully degassed via freeze-pump
thaw (three times), and the vessel refilled with argon. The
Schlenk tube was stirred and irradiated with a blue LED
positioned approximately at 3 cm distance from the reaction
vessel. After 20-48 h of irradiation, the solvent was removed
under vacuum to give the crude product. Column
chromatography on silica (hexanes/ethyl acetate = 9:1 or
hexanes/dichloromethane = 6:4 or 4:6) afforded pure
compounds.
6
7
8
8
9
basic additive or the phthalimide anion) gives the
desired product and the ground-state photocatalyst
(IrIII).
General procedure for the photoredox decarboxylative
alkylation/(2+2+1)-cycloaddition of 1,7-enines (products
4g, 4h, 4i and 4j).
In a Schlenk tube at r.t., iridium catalyst I (1 mol%), N-
(acyloxy)phthalimide (2.5 equiv.), enyne (1 equiv.), were
dissolved in 1.0 mL of acetonitrile, following by the
addition of 2,6-Lutidine (1.2 equiv.) and H2O (10 equiv.).
The reaction mixture was carefully degassed via freeze-
pump thaw (three times), and the vessel refilled with argon.
The Schlenk tube was stirred and irradiated with a blue LED
positioned approximately at 3 cm distance from the reaction
vessel. After 20-48h of irradiation, the solvent was removed
under vacuum. The mixture was extracted with ethyl acetate,
washing 3 times the system with HCl 10% and NaOH 0.1
M each. The collected organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure to give the
crude product. Column chromatography on silica
(hexanes/ethyl acetate = 9:2) afforded pure compounds.
Scheme 3 – Mechanistic proposal for the decarboxylative
cascade alkylation of 1,7-enynes employing N-
(acyloxy)phthalimides as radical precursors.
5
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
[5] For other recent examples of photocatalytic radical
alkylation strategies using N-(acyloxy)phthalimides
see: a) A. Tlahuext-Aca, R. A. Garza-Sanchez, F.
Glorius, Angew. Chem. Int. Ed. 2017, 13, 3708–3711;
Acknowledgements
We are grateful to CNPq (INCT Catálise), FAPESP (14/50249-8,
15/17141-1 and 17/10015-6) for financial support. GSK is also
acknowledged for the financial support. We are in debit with
CIMED Group for generous support. This study was financed in
part by the Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior - Brasil (CAPES) - Finance Code 001.
b) W. Kong, C. Yu, H. An, Q. Song, Org. Lett. 2018
,
20, 349–352; c) W. Sha, S. Ni, J. Han, Y. Pan, Org.
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Kachkovskyi, D. Rackl, O. Reiser, J. Org. Chem.
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Liang, Org. Lett. 2018, 20, 4824–4827; g) T. C.
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Org. Chem. 2018, 83, 3000–3012; h) G. Z. Wang, R.
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10.1002/adsc.201900657
Advanced Synthesis & Catalysis
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7
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Advanced Synthesis & Catalysis
FULL PAPER
Photoredox Decarboxylative Alkylation/(2+2+1)
cycloaddition of 1,7-enynes:
A
Cascade
Approach Towards Polycyclic Heterocycles
Using N-(acyloxy)phthalimides as Radical
Source
Adv. Synth. Catal. Year, Volume, Page – Page
José Tiago Menezes Correia, Gustavo Piva da
Silva, Elias André and Márcio Weber Paixão
8
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