Visible-Light-Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition

Article abstract of DOI:10.1002/anie.202009704

The [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N-acryloyl heterocycles with blue LED light (440 nm) in the presence of an Ir^III complex leads to efficient and high yielding fused γ-lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4-diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.

Full text of DOI:10.1002/anie.202009704

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Visible light mediated heterocycle functionalization via a
geometrically interrupted [2+2] cycloaddition
Authors: Mihai Popescu, Aroonroj Mekareeya, Juan Alegre-Requena,
Robert Paton, and Martin Derwyn Smith
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009704
Link to VoR: https://doi.org/10.1002/anie.202009704

10.1002/anie.202009704
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Photocyclization
Visible Light Mediated Heterocycle Functionalization
via Geometrically Interrupted [2+2] Cycloaddition**
Mihai V. Popescu,1Aroonroj Mekereeya,1 Juan V. Alegre-Requena,2 Robert S. Paton1,2*
and Martin D. Smith1*
Previous work: Triplet energy transfer (TET) mediated indole [2+2] cycloadditions
Abstract: The [2+2] photocycloaddition is the most valuable and
intensively investigated photochemical process. Here we demonstrate
that irradiation of N-acryloyl heterocycles with blue LED light
(440 nm) in the presence of an Ir(III) complex leads to efficient and
high yielding fused g-lactam formation across a range of
differentially substituted heterocycles. Quantum calculations show
that the reaction proceeds via cyclization in the triplet excited state
to yield a 1,4-diradical; intersystem crossing leads preferentially to
the closed shell singlet zwitterion. This is geometrically restricted
from undergoing recombination to yield a cyclobutane by the
planarity of the amide substituent. A prototropic shift leads to the
observed bicyclic products in what can be viewed as an interrupted
[2+2] cycloaddition.
Z
Z
Z
Ir(III)
R
Blue LED
R
N
N
N
R
H
H
H
Z = C(COOR)2, NBoc
R1
R1
R1
Ir(III)
NR
O
Blue LED
N
N
N
2 O
N
N
R2
2 O
R
R
R
R
This work: Heterocycle functionalization via an interrupted [2+2] cycloaddition
R1
R1
F
F
Ir(dFppy)3
N
N
N
Ir
R2
base
Blue LED
O
O
F
R2
F
T
he [2+2] photocycloaddition is arguably the most important
-H+/+H+
photochemical transformation in synthetic chemistry.1 In recent years,
a number of visible light [2+2] processes that operate by electron or
energy transfer have been disclosed. Elegant approaches by the
groups of Bach and Yoon have enabled efficient construction of
polycyclic cyclobutane architectures and have also led to advances in
the enantioselective catalysis of such reactions.2 Within this field, the
visible light enabled [2+2] photocycloaddition of indole substrates
has received significant recent attention. You demonstrated that
indoles bearing a C-3 tethered alkene could undergo efficient and
diastereoselective cycloaddition in the presence of an iridium
N
F
TET
N
F
H
ISC
R1
R1
N
N
Ir(dFppy)3
R2
R2
O
O
Scheme 1. Previous work and approach to visible light mediated heterocycle
functionalization
sensitizer to yield fused cyclobutanes (Scheme 1).3 In a related
transformation disclosed by Oderinde,4 alkenes tethered through an
indole C-2 amide were demonstrated to be viable substrates for the
[2+2] cycloaddition under similar visible light conditions. We
reasoned that distinct reactivity could be attained through N-
functionalization of heterocycles (such as indole) with an a-aryl
acryloyl derivative.5 This would provide an alkene with a triplet
energy of ≈ 50 kcal mol-1, similar in magnitude to the triplet energies
of a number of excited state photocatalysts. We envisaged that
excitation to the triplet (T1) state via triplet energy transfer (TET)
from an appropriate sensitizer and addition to the indole alkene would
generate a 1,4-diradical intermediate, which in a conventional [2+2]
process would generate cyclobutane products via intersystem
crossing (ISC) to the singlet state. Once in the singlet state, this
intermediate may adopt an open shell diradical or zwitterionic closed
shell electronic configuration. Both types of electronic configuration
have been recognised in thermal and photochemical cyclobutane
formation and in other processes.6 However, the geometry of the 5,5-
bicyclic lactam ring system means that this route is challenging and
hence can be interrupted via proton transfer to afford the
functionalized aromatic heterocycle.7 Due to the electron-
withdrawing nature of the amide group, we envisioned that this
reaction intermediate could possess significant zwitterionic character,
further facilitating the proposed proton transfer event.
[1]
Mihai V. Popescu, Dr Aroonroj Mekareeya, Prof. Dr Martin D. Smith
Chemistry Research Laboratory
University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk
[2]
Dr Juan V. Alegre-Requena, Prof. Dr Robert S. Paton
Department of Chemistry
Colorado State University,
1301 Center Ave, Ft. Collins,
CO 80523-1872, USA
E-mail: robert.paton@colostate.edu
[**] We are grateful for support from EPSRC for a postdoctoral fellowship
to A. M. (EP/R005826/1) and a studentship (to M.V.P.) via the Centre
for Doctoral Training in Synthesis for Biology and Medicine (EP/
L015838/1). We acknowledge the Extreme Science and Engineering
Discovery Environment (XSEDE) allocation TG-CHE190111.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202009704
Angewandte Chemie International Edition
Table 1. Optimization: photocyclization of 2-acryloyl indole derivative.
The resulting pyrrolo[1,2-a]indole scaffold is an important
motif found in numerous natural products.8 Although
photochemically mediated electron transfer processes have been used
in the past to enable generation of these structures, there are, to our
knowledge, no examples employing energy transfer.9 To probe the
feasibility of this approach, we prepared a test acryloyl substrate 1
through N-acylation of 5-cyano indole and examined its reactivity in
the presence of a range of photocatalysts under irradiation with blue
LED light (Table 1). A ruthenium(II) catalyst proved to be ineffective
(Table 1, entry 1), and hence we examined iridium photocatalysts
with increasingly higher triplet energies (entries 2-6).
[Ir(dtbbpy)(ppy)2]PF6 (entry 3) afforded a trace of product 2.
Significantly higher conversion was observed with fac-Ir(ppy)3 (71%
conversion, entry 4) and similar results were obtained using
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (81% yield), while Ir(dFppy)3 gave
complete conversion and an 85% yield of 2. Furthermore, addition of
a catalytic amount of NaOAc further increased the isolated yield to
93%. With a working substrate synthesis and cyclization procedure
in hand, we examined the scope and limitations of this visible light
mediated process (Table 2).
NC
NC
visible light
photocatalyst
N
N
AcOEt (0.1 M)
Ph
O
O
Blue LED, r.t., 18 h
Ph
1
2
Entry[a]
Catalyst
none
1H NMR yield[a]
1
2
0%
0%
Ru(bipy)3(PF6)2
3
[Ir(dtbbpy)(ppy)2]PF6
6%
4
fac-Ir(ppy)3
71%
5
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6
Ir(dFppy)3
81%
6
7[b]
92% (85%)[c]
95% (93%)[c]
Ir(dFppy)3
Reaction conditions: 1 (0.1 mmol), catalyst (1 mol.%), 35W blue LED (440 nm),
AcOEt ([1] = 0.04 mol dm-3), r.t., 18 h; [a] 1H NMR yield measured vs CH2Br2 as
internal standard; [b] AcOEt ([1] = 0.1 mol dm-3), addition of NaOAc (10 mol%).
[c] yields in parentheses are for isolated material. bipy = 2,2'-bipyridine; dtbbpy =
4,4'-di-tert-butyl-2,2'-bipyridine; ppy = 2-phenylpyridine; dF(CF3)ppy = 2-(2,4-
difluorophenyl)-5-(trifluoromethyl)pyridine.
F
F
8
5
9
Ir(dFppy)3 (1 mol%)
N
Ir
7
6
9a
R1
R1
NaOAc (10 mol%)
1
F
F
N
N
AcOEt (0.1 M)
N
F
2
N
F
R2
Blue LED, r.t., 18 h
O
O
R2
Ir(dFppy)3
OMs
OTBS
Cl
Br
F
N
N
N
N
N
N
O
O
O
O
O
O
3. 98%
4. 85%
5. 79%
6. 94%
7. 52%
8. 95%
O
B
Br
I
NC
MeOOC
MeO
O
N
N
N
N
N
O
N
O
O
O
O
O
9. 94%
10. 83%
2. 93%
11. 62%
12. 70%
13. 66%
N
O
N
N
N
O
N
N
N
N
Br
CF3
H
F
O
O
O
O
O
14. 94%
15. 74%
16. 32%
17. 82%
18. 77%
19. 90%
CN
COOMe
CN
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
20. 88%
21. 85%
23. 92%
24. 84%
25. 74%
22. 21%
(1.3:1 rr)
O
HN
N
CN
S
CN
NC
NC
MeO
N
O
N
N
N
N
N
O
O
O
O
O
tBu
CF3
OMe
27. 91%
28. 68%
29. 88%
(1.8:1 dr)
30. 50%
31. 50%
26. 92%
Table 2. Scope of triplet energy transfer mediated heterocycle functionalization. Reaction conditions: 0.3 mmol indole, 0.01 equiv. Ir(dFppy)3, 0.1 equiv. NaOAc, 32 W
blue LED, AcOEt (0.05 M); reaction time 18 h. Yields are for isolated material. Positions around the indole core are indicated in red numerals. d.r. (diasteroisomeric
ratio) determined by 1H NMR spectroscopy. TBS = tert-butyldimethylsilyl; Ms = methanesulfonyl.
2
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10.1002/anie.202009704
Angewandte Chemie International Edition
We initially explored cyclization of substrates with different
substituents on the indole. The parent substrate in which indole is N-
functionalized with 2-phenyl acrylic acid cyclized smoothly to afford
bicyclic lactam 3 in 98% isolated yield. The reaction is remarkably
tolerant of different substituents around the pyrroloindole core.
Substrates with 8-substituents cyclize successfully including electron
donating groups such as O-tert-butyldimethylsilyl (4, 85% yield) and
electron withdrawing groups such as halogens (8-chloro 5, 79% yield;
8-bromo 6, 94% yield). More reactive groups such as 8-O-
methanesulfonyl 7 also cyclize successfully, albeit in lower yield
(52%). Introducing substituents in the 7-position does not have any
deleterious effects on the reaction. Halogen substituted indoles
cyclize in good to excellent yields: 7-fluoro 8 (95% yield), 7-bromo
9 (94% yield) and 7-iodo 10 (83% yield) groups are all well tolerated.
Electron withdrawing groups such as a cyano 2 (93% yield) or a
methyl ester 11 (62% yield) were both tolerated at C-7 without
incident, and electron rich pyrroloindoles were synthesized with
equal facility (12, 70% yield). Pyrroloindoles bearing pinacol boronic
acid esters were also demonstrated to be viable substrates for the
reaction, cyclizing in 66% isolated yield to afford 13. 6-Bromo and
6-trifluoromethyl substituted indole derivatives also cyclized
effectively to afford product in good yields (14, 94% yield and 15,
74% yield respectively). We were also able to demonstrate that
performing the reaction on a substrate bearing an aldehyde in the 6-
position was also possible, albeit affording product 16 in a moderate
yield of 32%; in this case the remaining material is likely consumed
via polymerization of the starting acrylic acid derivative.
5-Substitution on the pyrroloindole core was exemplified through the
synthesis of the 5-fluoro derivative 17 in 82% yield. We were also
able to perform the reaction efficiently on a series of azaindoles: 6-
azaindole derivative 18 (77% yield), 5-azaindole 19 (90% yield) and
4-azaindole 20 were all generated in good to excellent yields. The
transformation is also tolerant of other changes to the backbone of the
heterocycle; bicyclic pyrrole derivatives such as 21 could also be
generated in 83% yield while bicyclic imidazole derivative 22 was
obtained in 21% yield as a mixture of regioisomers. Substitution is
also tolerated in the 9-position of the pyrroloindole as demonstrated
by the successful conversion of substrates bearing cyanomethyl 23
(92% yield) and methyl ester groups (24, 84% yield). We also probed
the potential to make changes to the substrate via modification of the
N-acyl portion of the molecule. Replacement of the a-phenyl group
on the N-acyl moiety by a methoxy ether was well tolerated and led
to the desired photo-cyclised product in high yield (25, 74%), while
modification of the phenyl group itself by the addition of a p-OMe
substituent also gave an excellent yield (26, 92%). Similarly, addition
of a p-tBu (27, 91%) and p-CF3 (28, 68%) are well tolerated. Addition
of an alkyl substituent at the terminal end of the alkene had no
deleterious effect; however, the product was obtained with minimal
control over diastereoselectivity (29, 88%, 1.2:1 dr). Finally, we
turned our attention to modifying more complex products containing
indoles. Camalexin, a simple alkaloid that is cytotoxic against
aggressive prostate cancer,10 and melatonin, an important sleep-
regulating hormone,11 were acylated and found to be compatible with
the photochemical transformation, leading to the formation of their
corresponding pyrrolo[1,2-a]indole containing products 30 (50%
yield) and 31 (50% yield) respectively.
A. Summarized mechanism
3Ir(III)*
N
F
F
ISC
O
3A
N
Ir
Ph
5-exo-trig
-H+/+H+
1Ir(III)*
TET
F
F
ISC
N
N
N
TS-3B
TS-C
N
F
N
F
Ph
Ph
Ph
ISC
O
O
O
C
N
3B
1B
1Ir(III)
hυ
O
1A
Ph
Retrocyclization
1Ir(III)
C. Mechanistic investigations
B. Energy profile and zwitterion trapping
D
>95%
Ir(dFppy)3
blue LED
H2O (20 eq.)
80
17%
D
TS-3B
TS-C (MeOAc) ΔG‡ = 7.6
TS-C (H2O) ΔG‡ = 5.7
TS-C (NaOAc) ΔG‡ = 3.3
C9a
C9a
N
ΔG‡ = 10.6
N
Ph
91% yield
C2
D
O
60
Ph
O
5%
3A
33
34
TS-C
NC
Ir(dFppy)3
blue LED
D2O (20 eq.)
(53.1)
ISC
ΔG‡ = 5.7
NC
ΔG‡ = 3.2
40
3Ir(III)*
N
O
N
Ph
92% yield
C2
TET
3B
(32.4)
1B
(32.5)
D
Ph
O
80%
20
0
1
35
1Ir(III)
O
1.00
1.65
2.23
C9a
Trapping
agent
1.45
1.27
0.98
2.12
1A
(0.0)
Retrocyclization
ΔG‡ = 9.7
NC
C9a
C2
N
O
Ph
OH
C2
32
11% yield
-20
C
(-18.6)
TS-3B
TS-C (H2O)
Figure 1. A Summary of the proposed reaction mechanism. B Reaction energy profile of the main pathway and retro-cyclization using Boltzmann weighted G values
in kcal·mol-1, along with the trapping experiment carried out with acetone (Conditions: Ir(dFppy)3 (1 mol%), corresponding indole (0.1 M in AcOEt), blue LEDs, r.t., 16
h., acetone (0.4M)). C Top: Deuteration experiments (Conditions: Ir(dFppy)3 (1 mol%), corresponding indole (0.1 M in AcOEt), blue LEDs, r.t., 16 h). Bottom: calculated
transition structures of the carbon-carbon bond forming cyclization, and the water-assisted H shuttle mechanism (distances shown in Å).
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202009704
Angewandte Chemie International Edition
kcal·mol-1 (Figure S6, C). We also discovered an alternative lower
energy pathway that could operate in the presence of water (5.7
kcal·mol-1, Figure 1C). In this scenario, the water co-solvent acts to
shuttle a proton from C9a to C2 leading to the product. However, when
a base such as AcONa is used or the concentration of water as a
cosolvent is low, other pathways might become the preferred routes
to promote this 1,3-shift (Figure S6, C and D).
In conclusion, we have discovered an operationally simple and
functional group tolerant synthesis of pyrroloindoles that proceeds in
the presence of visible light and an iridium(III) sensitizer. The
reaction proceeds via cyclization in the triplet excited state to yield a
1,4-diradical; intersystem crossing leads preferentially to a closed
shell singlet zwitterion that is geometrically restricted from
undergoing recombination to yield a cyclobutane, leading to the
preferential formation of a 5,5-bicyclic lactam ring system.
To probe the practical utility of this transformation, a gram
scale synthesis of 6-bromo substrate 14 was performed. By starting
with 4.6 mmol of the appropriate precursor, 1.39 g of 14 were
obtained (93%), thus demonstrating that the reaction is scalable
without affecting the overall yield.
In order to probe the mechanistic profile of this transformation,
we carried out computational studies with density functional theory
(DFT,12 M06-2X-D3/Def2-QZVPP//M06-2X-D3/6-31++G(d,p);13-15
in SMD ethyl acetate)16 in conjunction with experimental techniques
(Figure 1). The calculated energy required to promote N-acyl 1A from
the singlet (S0) to p-p* triplet (T1) state is 52.2 kcal·mol-1. This is
well matched with the emissive energy of the Ir(dFppy)3 (60.1
kcal·mol-1)17, [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (61.8 kcal·mol-1)17 and
fac-Ir(ppy)3 (55.2 kcal·mol-1)17 catalysts. To exclude an alternative
photoredox catalytic cycle, we turned our attention to electrochemical
studies. Square voltammetry performed on substrate 1 indicated a
reduction potential of -1.62 V and an oxidation potential of 1.91 V
(vs SCE in MeCN). Both reduction and oxidation potentials are
outside the redox capabilities of the optimal Ir(dFppy)3 catalyst
(E1/2(M+/M*) = -1.27 V; E1/2(M*/M-) = 0.35 V vs SCE in MeCN).17
Furthermore, Stern-Volmer quenching experiments showed a clear
substrate catalyst interaction, thus making energy transfer the most
probable mechanistic candidate.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: visible light • photochemistry • mechanism • energy
transfer • catalyst • DFT
Our proposed mechanism is pictured in Figure 1. After singlet-
to-triplet excitation of the initial substrate by the excited state catalyst
[1] S. Poplata, A. Tröster, Y.-Q. Zou, T. Bach, Chem. Rev. 2016, 116,
9748–9815.
3
(1A to A), an intramolecular 5-exo-trig cyclization takes place to
[2] (a) J. Zheng, W. B. Swords, J. Jung, K. L. Skubi, J. B. Kidd, G. J. Meyer,
M. -H. Baik, T. P. Yoon, J. Am. Chem. Soc. 2019, 141, 13625–13634.
(b) Z. D. Miller, B. J. Lee, T. P. Yoon, Angew. Chem. Int. Ed. 2017, 56,
11891–11895. (c) K. L. Skubi, J. B. Kidd, H. Jung, I. A. Guzei, M. -H.
Baik, T. P. Yoon, J. Am. Chem. Soc. 2017, 139, 17186–17192. (d) T.
R. Blum, Z. D. Miller, D. S. Bates, I. A. Guzeri. T. P. Yoon, Science,
2016, 354, 1391–1395. (e) X. Li, C. Jandl, T. Bach, Org. Lett. 2020, 22,
3618–3622. (f) F. M. Hörmann, C. Kerzig, T. S. Chung, A. Bauer, O.
S. Wenger, T. Bach, Angew. Chem. Int. Ed. 2020, 59, 9659–9668. (g)
F. Pecho, Y.‐Q. Zou, J. Gramüller, T. Mori, S. M. Huber, A. Bauer,R.
M. Gschwind, T Bach, Chem. Eur. J., 2020, 26, 5190–5194. (h) L.-M.
Mohr, A. Bauer, C. Jandl, T. Bach, Org. Biomol. Chem. 2019, 17, 7192–
7203. (i) S. Stegbauer, C. Jandl, T. Bach, Angew. Chem. Int. Ed. 2018,
57, 14593–14596. (j) F. M. Hörmann, T. S. Chung, E. Rodriguez, M.
Jakob, T. Bach, Angew. Chem. Int. Ed. 2018, 57, 827–831. (k) L.-M.
Mohr, T. Bach, Synlett, 2017, 28, 2946–2950. (l) C. Brenninger, A.
Pöthig, T. Bach, Angew, Chem. Int. Ed. 2017, 56, 4337–4341. (m) A.
Tröster, R. Alonso, A. Bauer, T. Bach, J. Am. Chem. Soc. 2016, 138,
7808–7811. (n) F. Mayr, R. Brimioulle, T. Bach, J. Org. Chem. 2016,
81, 6965–6971.
produce intermediate 3B. 3B undergoes an intersystem crossing (ISC)
1
and generates the corresponding singlet species B; this species is
better described as a closed-shell singlet zwitterion rather than a
singlet diradical (⟨ Ŝ2 ⟩ = 0 in the wavefunction stability checks). This
zwitterionic species undergoes a proton transfer to form final product
C. The reaction activation barriers of the main pathway, which range
from 3.2 to 10.6 kcal·mol-1 (Figure 1B) are easily accessible at room
temperature. The barrier to ISC is particularly low due to the small
structural reorganization needed from 3B to reach the geometry
observed in the ISC (Figure S7). The calculated energy profile also
indicates the presence of a retrocyclization process (from 1B back to
1A) with an activation barrier of 9.7 kcal·mol-1; this is somewhat
higher than the barrier required to form the reaction product C (3.3 to
7.6 kcal·mol-1). When we performed the reaction on substrate 1 in the
presence of acetone, the adduct 32 was isolated (11% yield), along
with the pyrroloindole product, consistent with the presence of an
enolate-like intermediate. The last step of the proposed mechanism
involves transformation of the zwitterion 1B into the final product C.
We reasoned initially that this could occur via stepwise
deprotonation/reprotonation events or by a direct hydrogen shift from
C9a of 1B to C2. To probe this, we subjected deuterated substrate 33
to the reaction conditions in the presence of 20 equivalents of H2O
(Figure 1C). Under these conditions only a small amount of
deuterium in the C2 position was observed in 34. This result implies
that the H atom from C9a is not directly transferred to the C2 position,
which agrees with the prohibitively high calculated barrier of the
intramolecular H-shift (31.7 kcal·mol-1, Figure S6, A). We did,
however, observe 17% incorporation of deuterium at C9, which is
consistent with a minor 1,2-shift pathway; this was also observed
computationally (8.9 kcal·mol-1, Figure S6, B). Conversely, when
using D2O as co-solvent with a non-deuterated indole 1, the C2
position of product 35 showed significant deuterium incorporation
(80%); control experiments also demonstrated that the pyrroloindole
2 is unreactive under these conditions and no deuterium incorporation
is observed. This is consistent with a pathway whereby the C2
hydrogen comes from solvent. We probed this with further
calculation and found that the stepwise solvent mediated
deprotonation/reprotonation pathway is feasible with a barrier of 7.6
[3] (a) M. Zhu, C. Zheng, X. Zhang, S.-L. You, J. Am. Chem .Soc. 2019,
141, 2636–2644. (b) M. Zhu, X. Zhang, C. Zheng, S. -L. You,
doi.org/10.26434/chemrxiv.12623504.v1.
[4] M. S. Oderinde, E. Mao, A. Ramirez, J. Pawluczyk, C. Jorge, L. A. M.
Cornelius, J. Kempson, M. Vetrichelvan, M. Pitchai, A. Gupta, A. K.
Gupta, N. A. Meanwell, A. Mathur, T. G. M. Dhar, J. Am. Chem. Soc.
2020, 142, 3094–3103.
[5] A. A. Festa, L. G. Voskressensky, E. V. Van der Eycken, Chem. Soc.
Rev. 2019, 48, 4401–4423.
[6] (a) L. Salem, C. Rowland, Angew. Chem. Int. Ed. 1972, 11, 92–111. (b)
G. Gryn’ova, M. L. Coote, C. Corminboeuf, WIRES Comput. Mol. Sci.
2015, 5, 440–459. (c) P. W. Peterson, R. K. Mohamed, I. V. Alabugin,
Eur. J. Org. Chem. 2013, 2505–2527. (d) R. K. Mohamed, P. W.
Peterson, I. V. Alabgin, Chem. Rev. 2013, 113, 7089–7129.
[7] D. Becker, N. Haddad, Y. Sahali, Tetrahedron Lett. 1989, 30, 2661–
2664.
[8] For some related natural products see: (a) D. A. Okorie, Phytochemistry,
1981, 20, 2575–2578. (b) I. Ngantchou, B. Nyasee, C. Denier, C.
Blonski, V. Hannaert, B. Schneider, Bioorg. Med. Chem. Lett. 2010, 20,
3495–3498. (c) C. M. Hasan, T. M. Healey, P. G. Waterman, J. Chem.
Soc. Perkin Trans. 1, 1982, 2807–2812. (d) L. S. Fernandez, M. L.
Sykes, K. T. Andrews, V. M. Avery, Int. J. Antimicrob. Agents, 2010,
36, 275–279. (e) F. Tillequin, M. Koch, Phytochemistry, 1979, 18,
4
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1559–1561. (f) L. S. Fernandez, M. S. Buchanan, A. R. Carroll, Y. J.
Feng, R. J. Quinn, V. M. Avery, Org. Lett. 2009, 11, 329–332.
[9] (a) J. W. Tucker, J. M. R. Narayanam, S. W. Krabbe, C. R. J.
Stephenson, Org. Lett. 2010, 12, 368–371. (b) H. Huang, M. Yu, X. Su,
P. Guo, J. Zhao, J. Zhao, Y. Li, J. Org. Chem. 2018, 83, 2425–2437. (c)
T. Saget, B. König, Chem. Eur. J. 2020, 26, 7004–7007.
[10] (a) L. M. Browne, K. L. Conn, W. A. Ayert, J. P. Tewari, Tetrahedron,
1991, 47, 3909–3914. (b) B. A. Smith, C. L. Neal, M. Chetram, B. Vo,
R. Mezencev, C. Hinton, V. A. Odero-Marah, J. Nat. Med. 2013, 67,
607–618.
[11] (a) A. B. Lerner, J. D. Case, Y. Takahashi, J. Biol. Chem., 1960, 235,
1992–1997. (b) J. Arendt, D. J. Skene, Sleep Med. Rev. 2005, 9, 25–39.
[12] (a) Gaussian 16, Revision C.01, Gaussian, Inc., Wallingford CT, 2016
(full reference available in the ESI). (b) G. Luchini, J. V. Alegre-
Requena, I. Funes-Ardoiz, R. S. Paton, F1000Research 2020, 9(Chem.
Inf. Sci.), 291.
[13] For M06-2X-D3 basis set: (a) Y. Zhao, D. G. Truhlar, Theor. Chem.
Acc. 2008, 120, 215–241. (b) S. Grimme, J. Antony, S. Ehrlich, H.
Krieg, J. Chem. Phys. 2010, 132, 154104–154119.
[14] For 6-31++G(d,p) basis set: (a) W. J. Hehre, R. Ditchfield, J. A. Pople,
J. Chem. Phys. 1972, 56, 2257–2261. (b) P. C. Hariharan, J. A. Pople,
Theoret. Chim. Acta 1973, 28, 213–222. (c) R. Krishnan, J. S. Binkley,
R. Seeger, J. A. Pople, J. Chem. Phys. 1980, 72, 650–654. (d) A. D.
McLean, G. S. Chandler, J. Chem. Phys. 1980, 72, 5639–5648. (e) M.
M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, M. S. Gordon, D. J.
DeFrees, J. A. Pople, J. Chem. Phys. 1982, 77, 3654–3665.
[15] For Def2-QZVPP basis set: (a) F. Weigend, R. Ahlrichs, Phys. Chem.
Chem. Phys. 2005, 7, 3297−3305. (b) F. Weigend, Phys. Chem. Chem.
Phys. 2006, 8, 1057−1065.
[16] (a) E. Cancès, B. Mennucci, J. J. Tomasi, Chem. Phys. 1997, 107, 3032–
3041. (b) B. Mennucci, E. Cancès, J. J. Tomasi, Phys. Chem. B. 1997,
101, 10506–10517. (c) B. Mennucci, J. J Tomasi, Chem. Phys. 1997,
106, 5151–5158. (d) J. J. Tomasi, B. Mennucci, E. Cancès, J. Mol.
Struct. THEOCHEM 1999, 464, 211–226. (e) G.; Scalmani, M. J.
Frisch, J. Chem. Phys. 2010, 132, 114110–114115. (f) A. V. Marenich,
C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B. 2009, 113, 6378–6396.
[17] A. Singh, K. Teegardin, M. Kelly, K. S. Prasad, S. Krishnan, J. D.
Weaver, J. Organomet. Chem. 2015, 776, 51–59.
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Photocyclization
F
F
Mihai V. Popescu, Aroonroj Mekereeya,
Juan V. Alegre-Requena, Robert S.
Paton* and Martin D. Smith*
N
Ir
R1
R1
Ir(dFppy)3
F
N
N
F
R2
base
Blue LED
N
F
N
F
O
O
R2
__________ Page – Page
Visible light mediated heterocycle
functionalization via geometrically
interrupted [2+2] cycloaddition
Irradiation of N-acryloyl heterocycles with blue LED light (440 nm) in the presence of
an Ir(III) complex leads to efficient and high yielding fused g-lactam formation.
Quantum calculation demonstrates that the reaction proceeds via cyclization in the
triplet excited state to yield a 1,4-diradical; intersystem crossing leads preferentially
to the closed shell singlet zwitterion. This is geometrically restricted from undergoing
recombination to yield a cyclobutane and hence proton transfer leads to the observed
products in what can be viewed as an interrupted [2+2] cycloaddition.
6
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