Metal-Free Photoinduced Hydroalkylation Cascade Enabled by an Electron-Donor-Acceptor Complex

Article abstract of DOI:10.1021/acs.joc.0c01130

A metal- A nd photocatalyst-free photoinduced radical cascade hydroalkylation of 1,7-enynes has been disclosed. The process is triggered by a single electron transfer (SET) event involving a photoexcited electron-donor-acceptor complex between an NHPI ester and a Hantzsch ester, which decomposes to afford a tertiary radical that is readily trapped by the enyne. The method provides an operationally simple, robust, and step-economical approach toward the construction of diversely functionalized dihydroquinolinones bearing quaternary centers. A sequential one-pot hydroalkylation-isomerization approach is also offered, giving access to a family of quinolinones. A wide substrate scope and high functional group tolerance were observed in both approaches.

Full text of DOI:10.1021/acs.joc.0c01130

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Article
Metal-Free Photoinduced Hydroalkylation Cascade
Enabled by an Electron-Donor-Acceptor Complex
José Tiago Menezes Correia, Gustavo Piva da Silva, Camila M Kisukuri,
Elias André, Bruno Pires, Pablo Silva Carneiro, and Márcio Weber Paixão
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01130 • Publication Date (Web): 26 Jun 2020
Downloaded from pubs.acs.org on June 26, 2020
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Metal-Free Photoinduced Hydroalkylation Cascade
Enabled by an Electron-Donor-Acceptor Complex
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‡
‡
José Tiago M. Correia, Gustavo Piva da Silva, Camila M. Kisukuri, Elias André, Bruno
Pires, Pablo S. Carneiro, Márcio W. Paixão*
Centre of Excellence for Research in Sustainable Chemistry (CERSusChem),
Department of Chemistry - Federal University of São Carlos, São Carlos, São Paulo,
Brazil, 13565-905
Keywords
dihydroquinolinones • hydroalkylation • photochemistry • radical reactions • enynes
Abstract
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A metal- and photocatalyst-free photoinduced radical cascade hydroalkylation of 1,7-
enynes has been disclosed. The process is triggered by a SET event involving a
photoexcited electron-donor-aceptor complex between NHPI ester and Hantzsch ester,
which decomposes to afford a tertiary radical that is readily trapped by the enyne. The
method provides an operationally simple, robust and step-economical approach to the
construction of diversely functionalized dihydroquinolinones bearing quaternary-centers.
A sequential one-pot hydroalkylation-isomerization approach is also allowed giving
access to a family of quinolinones. A wide substrate scope and high functional group
tolerance was observed in both approaches.
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Introduction
The quinolinone and its partially or fully reduced derivatives - dihydroquinolinones and
tetrahydroquinolinones - are among the most privileged N-heterocyclic scaffolds, widely
found in naturally occurring compounds and pharmacologically relevant therapeutic
1
agents (Figure 1). Consequently, substantial efforts have been made towards the
development of straightforward, selective and operationally simple strategies that are
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capable of assembling complex molecular architectures, encompassing these
heterocyclic cores.2 In particular, the preparation of structurally diverse
dihydroquinolinones via radical-based cascade reactions involving 1,7-enynes has drawn
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the attention of chemists in recent years. The growing interest is clearly justified by the
sequential chemo-, regio- and stereoselective multiple-bond formation allowed by this
type of strategy. Beside these synthetic advantages, cascade processes also allow time-
and reactant economy, as well as reduced waste generation by avoiding multiple work-
4
ups and purification steps. Although most reports to date rely on processes triggered by
either stoichiometric radical initiators and/or harsh reaction conditions (Scheme 1a),5
photocatalytic strategies have recently emerged as a powerful synthetic tool to achieve
complex organic scaffolds through milder radical processes (Scheme 1a).6
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O
CF3
OMe
OMe
Cl
O
N
H
N
H
O
N
O
MeO
H
Euodenine A
TLR4 agonist
HIV-1 reverse
transcriptase inhibitor
R1
R2
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R4
OCH3
N
R3
O
O
Ph
NH
N
O
O
CH3
O
O
HO
OCH3
O
N
O
Yaequinolone J2
Insecticidal Antibiotic
P2X7 receptor antagonist
Figure 1. Representative examples of biologically active molecules with 3,4-dihydro-
quinolin-2-one and quinolin-2-one skeletons.
In recent years, N ‐ (acyloxy)-phthalimides (NHPI esters) have been established as
versatile redox-active building blocks, widely employed for C-C and C-X photoredox or
transition-metal-catalyzed couplings.7,8 Earlier examples highlighting the applications of
NHPI esters in photodecarboxylative processes were reported by Okada and co-workers
9
in the late 80s/early 90s (Scheme 1b). Notwithstanding, the great potential of these
molecules was recognized after almost two decades, when Okada´s seminal work was
revisited and adapted by Overman for the construction of congested quaternary centers,
a strategy that was successfully employed in the total synthesis of (-)-Aplyviolene and (-
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)
-Chromodorolide (Scheme 1c).10 These developments set the basis for this currently
expanding field of synthetic chemistry.
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Furthermore, Overman disclosed that slower reactions were observed in the absence
of the photocatalyst and postulated that a direct electron-transfer event from a
photoexcited Hantzsch ester to the NHPI ester would be the driving force for the
process.10d,11 However, this reactivity has not been explored until recently, when Chen
and co-workers reported two elegant allylation strategies based on the photogeneration
of alkoxy and carboxyl radicals through the combination of the respective N-alkoxy and
N-(benzyloxy)-phthalimides with Hantzsch esters in the absence of photocatalysts
12
(Scheme 1d). Mechanistic studies for both transformations indicated the formation of an
Electron-Donor-Acceptor (EDA) complex, which may be crucial for the photo-induced
single electron transfer (SET) event. The development of strategies triggered by the direct
13
photoexcitation of EDA complexes is a field in its golden age. Beyond the success of
photocatalysis using often expensive photocatalysts, the recent discoveries in the
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chemistry of photoactive EDA complexes expands dramatically the boundary of the
application of photochemistry in organic synthesis.
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a) Previous works: Harsh oxidative conditions and photoredox approaches5,6
R4
Fe, Cu / Peroxides
R4
or Ag / K S O
2 2 8
R1
R1
High temperatures
(up to 130ºC)
or
R2
X
O
+
R3
R2
Y
Photocatalyst
Blue LED or CFL
R3
R5
R5
X = H, Br, CO H, CO Phth or CHO
Y
O
2
2
b) Okada and Oda - Photosensitized decarboxylative addition of alkyl-radicals to
electron-deficient olefins9
O
R2
O
[Ru(bpy) ]Cl ,
R3
R1
3
2
O
R1
R2
NH2
BNAH
O
OPhth
+
THF/H O or
2
R4
R5
R4
R5
R3
t-BuOH/H O
N
2
BNAH
Bn
hv > 460 nm
c) Overman - Radical additions for the construction of quaternary centers in natural
product total synthesis10
CO Me
2
TBSO
[
Ru(bpy) ]BF
3
4
CO Me
TBSO
H
H
2
EtO C
CO Et
H
2
2
Me
H
O
Me
Me
+
Me
N
Cl
H
H
H
O
O
DIPEA, Blue LEDs
CH Cl
Cl
Me
Me
2
2
H
OPhth
(_
)-Aplyviolene
d) Chen - Photoinduced radical allylations enabled by EDA complexes12
R
R
R1
=
EtO C
CO Et
2
2
Alk
EtO C
R
R
2
R1 OPhth
N
Alk
H
+
O
R1
=
Blue LEDs
SO Ph
2
CO Et
EtO C
2
2
O
O
Scheme 1. a) Previous reports on cascade alkylation of 1,7-enynes; b) Seminal report on
the use of NHPI esters in a photocatalytic Giese reactions by Okada and co-workers; c)
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Applications of NHPI esters in total synthesis by Overman an co-workers; d) First reports
of photoinduced radical processes involving an EDA complex between the NHPI esters
and Hantzsch ester, by Chen and co-workers.
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Recently, in continuation of our investigations on visible light photocatalytic cascade
processes, we reported a photoredox radical cascade strategy between NHPI esters and
1
,7-enynes (Scheme 2a).6c This mild and versatile methodology afforded a family of
densely functionalized cyclopenta[c]quinolinones in moderate to good yields - however,
no product was detected when tertiary NHPI esters were employed. In this respect, we
anticipated that under suitable, mild conditions, a photoinduced SET event between
NHPI-ester (1a) and the diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (HE)
might take place, leading to the decomposition of 1 into carbon dioxide, phthalimide anion
and the tertiary-radical (4) (Scheme 2b). This photoinduced SET event would be assisted
by the formation of an EDA complex formed between the participating molecules, as
postulated earlier based on visual and spectroscopic evidences (Scheme 2c). Once
formed, 4 would couple with the (metha)acrylamide counterpart of 2a, triggering a radical
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cascade process to deliver the radical intermediate 5, which abstracts a hydrogen atom
from the oxidized Hantzsch ester, with the assistance of base, to afford the
dihydroquinolinone product (3a). Distinct from our previous approach, this new method
would offer a transition-metal- and photocatalyst-free straightforward route to a family of
highly functionalized dihydroquinolinones.15
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a) Limitation of the previous work6c
Ar
not detected
slow 1,6 HAT
ref. 14
O
H
tBu
OPhth
Ir
Ph
N
O
base
+
Ph
H O
H
Ar
2
O
N
O
tBu
N
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not detected
H-donor required
N
O
b) This work - mechanistic rationale
CO Et
HE
2
HN
O
CO Et
2
SET
O
N
N
-
CO2
O
O
O
1a
- Phth
4
2a
EDA Complex
H
N
H
EtO C
CO Et
2
2
CH3
H
CH3
H
tBu
HAT
tBu
DIPEA or Phth
N
O
N
5
O
N
3a
EtO C
CO Et
2
2
c) Evidences of EDA-complex formation
Visual
UV-Vis analysis
1a
HE
1a + HE
NMR traces
Scheme 2. Metal-free cascade hydroalkylation of 1,7-enynes.
Results and Discussion
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Initially, we decided to justify our hypothesis by examining the cascade reaction
between N-(pivaloxy)phthalimide (1a) and 1,7-enyne (2a) as a model (Table 1).
Accordingly, the irradiation of a mixture of 1a (2.0 equiv.), 2a (1.0 equiv.), HE (1.5 equiv.)
and DIPEA (2 equiv.) in THF as solvent delivered 3a in 80% yield (entry 1). Encouraged
by this preliminary result, other reaction parameters were screened to further improve the
reaction efficiency. A comparison study showed that the transformation has not been
drastically affected by degassed conditions (entry 1 vs 2) or increased amounts of NHPI
(entry 3). Moreover, a solvent survey revealed that the use of DMF instead of THF led to
a slightly increased yield, albeit lower selectivity (entry 4). Notably, the presence of base
DIPEA was found to have a significant effect on the cascade process (entry 5). Control
experiments demonstrated the necessity of visible light, base and Hantzsch ester (entries
6 and 7).
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Table 1. Optimization of reaction conditionsa
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EtO C
CO Et
2
2
H
N
CH3
O
O
HE
H
+
O
tBu
tBu
OPhth
DIPEA, THF (1 mL),
34W Blue LED,
24h
N
N
CH3
1a
2a
(Z/E)-3a
3a (%)b Z/E ratioc
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Entry
Deviation from the standard condition
1
2
3
4
5
6
7
none
80
81
82
85
50
20
0
1.5 : 1
1.5 : 1
1: 1
Degassed conditions
3 equiv. of 1a
DMF instead of THF
K CO instead of DIPEA
1 : 1
1 : 1
1.5 : 1
-
2
3
No base
No light or no HE
a
1
a (0.2 mmol.), 2a (0.1 mmol), HE (0.15 mmol), DIPEA (0.2 mmol), THF (1 mL),
under air. b isolated yields. c determined by NMR.
.
With optimal conditions established, the scope and limitation of this metal-free
hydroalkylation cascade protocol was investigated (Table 2). The reaction between 1a
and a wide variety of 1,7-enynes 2a-u has first been evaluated. As shown in Table 2, both
electron-rich as well as electron-poor substituents at meta- and para-positions of both
aromatic parts of the 1,7-enyne were well tolerated. The desired dihydroquinolinones (3b-
i) were obtained in moderate to good yields (Table 2A). An ortho-substitution pattern was
also compatible under the optimized conditions affording 3j in 58% yield. Gratifyingly, the
replacement of the methacrylamide portion by an acrylamide was also well tolerated,
delivering the desired products 3k-3o in 60-75% yield (Table 2B). Moreover, the presence
of heterocyclic moieties has also been evaluated where the 3-ethynyl-pyridine and 3-
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ethynyl-thiophene derivatives were smoothly converted to 3p and 3q in 54% and 60%
yield, respectively (Table 2C). Hereafter, a variety of nitrogen protecting groups were also
investigated to synthesize N-tosyl (3r), N-benzyl (3s) and N-acetyl (3t)
dihydroquinolinones in moderate yields. Interestingly, the developed photochemical
strategy was found to be compatible with an unprotected substrate (3u) isolated in 47%
yield (Table 2D).
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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5
5
5
5
5
5
5
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0
1
2
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4
5
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0
1
2
3
4
5
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2
3
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1
2
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8
9
0
Table 2. Scope of 1,7-enynesa,b
R2
EtO C
CO Et
2
2
R2
R1
H
O
N
HE
O
R3
tBu
H
OPhth+
X
DIPEA, THF, air, r.t.
Blue LED 34W
tBu
R3
X
O
24h
R1
1a
2a-u
3a-u
A - Substituents on the aryl-moieties
R2
H
CH3
H
tBu
CH3
N
O
tBu
R1
N
O
2
3
3
3
3
3
3
e - R = 4-CO Me - 40% (Z/E = 3:1)
2
f - R2 = 4-CH3 - 88% (Z/E = 1:1)
g - R2 = 4-OMe - 61% (Z/E = 3:1)
a - R1 = H - 80% (Z/E = 1.5:1)
3b - R1 = 4-Me - 75% (Z/E = 2.5:1)
c - R1 = 5-Cl - 79% (Z/E = 3:1)
d - R1 = 5-F - 80% (Z/E = 3:1)
3
2
h - R = 4-F - 63% (Z/E = 2:1)
3
3
2
i - R = 3-F - 73% (Z/E = 2.5:1)
j - R2 = 2-CH3 - 58% (Z/E = 3:1)
C - Heterocyclic moieties
B - Acrylic derivatives
R2
H
N
H
3
k - R1 = R2 = H - 63% (Z/E = 1:1)
3l - R1 = 4-Me - 75% (Z/E = 1:1)
Bu 3m - R1 = 5-Cl - 68% (Z/E = 1:1.5)
CH3
R1
H
tBu
t
3n - R1 = 5-F - 60% (Z/E = 1:1.5)
N
O
N
O
3
o - R2 = CH3 - 66% (Z/E = 1:1.5)
D - Substituents on the nitrogen
3r - X = NTs, 55% (Z/E = 3:1)
3
p - 54% (Z/E = 1.5:1)
S
H
H
H
tBu
3s - X = NBn, 52% (Z/E = 2:1)
CH3
tBu 33
t - X = NAc, 59% (Z/E = 3:1)
N
O
1
u - R =F, X = NH, 47 %
R1
X
O
(Z/E = 2:1)
3q - 60% (Z/E = 1:3)
a
1
a (0.2 mmol), 2 (0.1 mmol), HE (0.15 mmol) and DIPEA (0.2 mmol) in 1 mL of THF -
under air atmosphere. b Isolated yields, Z/E ratios determined by 1H NMR.
.
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5
5
5
5
5
5
5
5
5
5
6
To further demonstrate the functional group compatibility of this cascade process,
we explored a plethora of tertiary NHPI-esters (Table 3A – See section 5 of the
supplementary material for the structure of the NHPI esters). Gratifyingly, NHPI-esters
derived from 2-(benzoyloxy)-2-methylpropanoic, 2-methyl-2-(pent-4-enoyloxy)propanoic
and N-Boc-aminoisobutyric acids (1b-1d) were well tolerated, affording the respective
dihydroquinolinones (4a-d) in good yields. Once incorporated onto the dihydroquinolinone
core, these moieties can further be employed as linkers or late-stage interconversion
sites. To our delight, when a scale-up experiment was performed employing 1d (1 mmol),
the desired product 4d could successfully be obtained in 67% yield. Moreover, a slight
modification to the reaction conditions was employed for the sterically hindered 1-
adamantyl NHPI-ester (1e) by increasing both the concentration and temperature (60 ºC),
4e could be furnished in 41% yield. However, when NHPI-esters derived from the 2,2-
dimethyl-butanoic and 1-methyl-1-cycloexanecarboxylic acid (1f and 1g) were evaluated
under the optimized conditions, indistinguishable mixtures of the products were obtained.
To overcome this limitation, a further optimization was carried out, revealing the necessity
of higher amount (4 equiv.) of Hantzsch ester and DMF as solvent. Under this modified
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reaction condition, the dihydroquinolinones (4f) and (4g) were obtained in 54% and 34%
respectively. Surprisingly, only the acrylic enyne (2k) afforded the desired product when
NHPI esters derived from the 3-(benzyloxy)-2,2-dimethylpropanoic (1h) and 2-methyl-1,3-
dioxane-2-carboxylic (1i) acids were subjected to the photochemical conditions. While the
former acid afforded the respective 4h in 55% yield, the latter delivered 4i, after acetal
hydrolysis, in 40% yield (Table 3A). Regarding these transformations, it is noteworthy that
they did not require a high excess of Hantzsch ester, indicating a distinct reactivity of 2k
when compared to 2a (Table 3A).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We then sought to develop a post-modification strategy for the obtained
dihydroquinolinones. The in situ treatment of 3k with DBU (3.0 equiv.) at 60 ºC in THF
resulted in the isomerization product – quinolinone (5a) – in good yield (66%) (Table 3B).
From the outset, we envisioned to expand this approach to a range of functional distinct
acrylic enynes. To our delight, a new family of quinolinones (5b-5f) were obtained.
Different NHPI esters were also tested, affording the desired products (5g-5l) in good to
excellent yields. As earlier, the reaction involving the NHPI ester derived from 2-methyl-
1,3-dioxane-2-carboxylic acid (1i) underwent hydrolysis during the work-up, affording 5m
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in 60% yield. Noteworthy, the NHPI-ester derived from the (R)-(+)-Citronellic acid (1k)
reacted smoothly through a radical-relay process to afford 5n in 62% yield and high
diastereoselectivity (Table 3B).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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2
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4
5
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7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Scope of NHPI esters and one-pot hydroalkylation cascade-isomerization
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1
)
EtO2C
CO2Et
HE
EtO2C
CO2Et
HE
N
H
H
H
N
O
X
DIPEA, THF, r.t.;
Blue LED 36W, 24h
R3
H
R1
O
X
X
R1
+
DIPEA, THF or DMF, r.t. PhthO
Blue LED 36W
R2
2) DBU (3 equiv.),
60ºC, 12h
R1
R2
N
R2
N
O
N
O
R3
24h
one-pot
1
a-l
2a or 2k-q
5a-o
4
a-l
A - Scope of dihydroquinolinonesa,f
B - Scope of quinolinones - R3 = H e,f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
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3
4
4
4
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4
4
4
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5
5
5
5
5
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0
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8
9
0
5
a - R1 = H, R2 = Ph - 66%
5b - R1 = 4-Me; R2 = Ph - 77%
5c - R1 = 5-Cl; R2 = Ph - 60%
d - R1 = 5-F; R2 =Ph - 62%
5e - R1 = H; R2 = 4-CH Ph - 74%
f - R1 = H; R2
H
H
H
R2
H
H
R3
CH3
O
O
CH3
O
O
Ph
O
NHBoc
5
R1
O
3
N
O
N
N
N
O
N
O
5
=
- 60%
a - R3 = CH3, 58% (Z/E = 1:1) 4c - 51% (Z/E = 1.5:1)
b - R3 = H, 50% (Z/E = 1:1.5)
4d - 61% (67%)[b]
5g - 77%
4
4
S
(Z/E = 1:1)
H
H
H
H
H
H
OBn
CH3
O
CH3
O
CH3
X
N
N
N
O
N
O
N
O
N
O
e - 41% (Z/E = 1:1)[c]
4f - 54% (Z/E = 1:1)[d]
4g - 34% (Z/E = 1.5:1)[d]
5h - 60%
5i - X = Et, 70%
5l - 62%
4
5
5
j - X = NHBoc, 85 %
k - X = OBz - 66%
Radical-clock experiment
From (R)-(+)-Citronellic acid
From:
H
H
H
H
OBn
OCH3
O
O
O
O
O
O
O
O
N
N
CH3
O
O
CH3
N
O
N
O
N
O
N
O
O
1i
1k
4
h - 55% (Z/E = 1:1.5)[d]
4i - 40% (Z/E = 1:1.5)
5m - 60%
5n - 62% d.r. > 20:1
C - Commercially available drugs
from Gemfribrozil
H
from Fenofibrate
H
H
R3
O
O
Cl
O
Cl
N
O
N
O
N
O
O
O
4
4
j - R3 = CH3, 40% (Z/E = 1:1)
k - R3 = H, 68% (Z/E = 1:2)
4l - 60 % (Z/E = 1:1.5)[d]
5o - 55%
a
Reactions were conducted as following unless otherwise mentioned: 1 (0.2 mmol), 2 (0.1 mmol), HE (0.15 mmol) and DIPEA (0.2 mmol) in 1 mL of THF - under air atmosphere. b
mmol scale. c0.4M, 60ºC, (without fan). d HE (0.4 mmol) and DMF as solvent. e i. 1 (0.2 mmol), 2 (0.1 mmol), HE (0.15 mmol) and DIPEA (0.2 mmol) in 1 mL of THF - under air
1
atmosphere; ii. DBU (0.3 mmol), 60ºC. f Isolated yields and Z/E ratio measured by 1H NMR.
.
To demonstrate the broad applicability of this photochemical hydroalkylation protocols,
NHPI esters derived from commercially available pharmaceutical ingredients –
Fenofibrate and Gemfibrozil – were further examined. Gratifyingly, the respective
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5
5
5
5
6
dihydroquinolinones (4j-4l) and quinolinone (5o) were readily afforded in good yields
(Table 3C).
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0
This study was further expanded to include secondary alkyl NHPI esters as radical
precursor. Although the previously observed 1,5-HAT pathway may occur – we decided
to evaluate the reaction between 1m and the methacrylic (2a) and acrylic (2k) enynes.
Delightfully, the dihydroquinolinone (4n) was smoothly obtained in 40% yield. In contrast,
the formation of 4m was not detected when 2a was subjected to the established
photochemical condition (Scheme 3a). Regarding to mechanistic aspects, when the
standard reaction was performed in the presence of TEMPO, only traces of product was
obtained (Scheme 3b). This experiment, together with the radical-clock experiment
employing the citronellic acid NHPI ester derivative (1k) (Table 3B), serves as clear
evidence that a radical process is taking place.
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a) Reactivity towards secondary alkyl NHPI ester
H
CH3
O
standard conditions
2a
+
+
OPhth
N
O
N
Ts
4
m - not detected
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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3
4
5
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7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
Ts
H
standard conditions
1m
H
2k
N
N
O
Ts
4
n - 40% (Z/E = 1:1)
b) Radical inhibition experiment
H
CH3
standard conditions
1a
+
2a
TEMPO (2 equiv.)
N
O
3a - not detected
Scheme 3. a) Different reactivities between acrylic and methacrylic 1,7-enynes towards
secondary alkyl NHPI ester. b) Radical inhibition experiment using TEMPO.
Taking advantage of the robustness and practicality of this new method, we envisioned
its translation to the continuous flow conditions. After careful experimentation (see
supporting information), 3a could be obtained in 70% yield (513 mg after 11 hours of
infusion - residence time (t ) = 30 min (Scheme 4).
R
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5
5
5
5
5
5
5
5
6
EtO2C
CO2Et
HE
O
N
H
tBu
DIPEA, DMF,air
r.t., tR = 30 min
Blue LED 36W
OPhth
a
1
H
+
CH3
O
(2 lamps)
O
tBu
1
00 psi
BPR
N
N
0
1
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3
4
5
6
7
8
9
0
1
2
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9
0
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0
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3
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6
7
8
9
0
2a
0.03" id PFE tube
000 
3a - 70% (Z/E = 3:1)
13 mg -46 mg/h
11h of infusion
1
L
5
~
Reaction conditions: 1a (0.2 mol/L), 2a (0.1 mol/L), HE (0.15 mol/L), DIPEA (0.2 mol/L),
r.t, DMF, tR = 30 min, (PBR: PFE tube 0.03'' diameter; 1000 µL), back pack pressure (100
psi) - Injected 25 mL
Scheme 4. Translation to flow conditions
Conclusion
In summary, an efficient metal-free photoinduced cascade hydroalkylation process
between NHPI-esters and 1,7-enynes has been developed. This reaction features mild
reaction conditions, high functional group tolerance and scalability, allowing the
preparation of a library of densely functionalized dihydroquinolinones with quaternary-
carbon centers in moderate to good yields. According to our investigations, the reaction
is triggered by a photoinduced SET process between the NHPI ester and the Hantzsch
ester, which is enabled by the prior formation of an EDA complex. For some cases, an
excess of the Hantzsch ester is required to obtain successful results, which can be related
to the prevention of a plausible 1,6-HAT process, that may lead to several
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indistinguishable side-products observed. Additionally, a better reactivity towards bulkier
tertiary and secondary NHPI esters was observed when acrylic 1,7-enynes were
employed. The dihydroquinolinones derived from acrylic enynes could be converted to
the respective quinolinones, through a one-pot isomerization process. We believe that
these findings may open new avenues in the application of photoinduced cascade
process enabled by EDA complexation. Studies towards the expansion of this concept to
other transformations are ongoing in our laboratory.
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
3
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3
3
3
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4
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4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
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0
1
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4
5
6
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8
9
0
1
2
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9
0
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0
1
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4
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7
8
9
0
EXPERIMENTAL SECTION
Commercially available chemicals and solvents were used without further purification
1
13
unless otherwise noted. H NMR and C NMR spectra were recorded on a Bruker 400
1
MHz and 600 MHz NMR spectrometers (400 or 600 MHz for H and 100 or 150 MHz for
13C, respectively). Chemical shifts (δ) are reported in parts per million relatives to the
residual solvent signals and coupling constants (J) are reported in hertz. High resolution
mass spectra (HRMS) were recorded using electron spray ionization (ESI) (Hybrid linear
ion trap–orbitrap FT-MS /MS – and QqTOF Microtof – QII models). Reagents and
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materials were of the highest commercially available grade and used without further
purification. Flash column chromatography was carried out using silica gel 60 (230-400
mesh) and analytical thin layer chromatography (TLC) was performed using silica gel
aluminum sheets. Visualization of the compounds on TLC was achieved by UV or using
suitable TLC stain. Melting points (MP) were determined by a BUCHI M-560 and are
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uncorrected. A 34W Kessil H150 blue LED (range of emission approximately 380 – 525 nm) was
used as the visible light source for all the photoinduced cascade reactions.
Enynes 2a – 2u and the carboxylic acid precursors for the preparation of NHPI esters 1h,
i, 1m were synthesized according to previous reports in literature.16,17,18,19,20
1
21
General procedure for the synthesis of NHPI esters (1a-1m): A round-bottom flask was
charged with (if solid) carboxylic acid (1.0 equiv.), N-hydroxyphthalimide (1.0 equiv.) and
DMAP (0.1 equiv.). Dichloromethane was added (0.15 M), and the mixture was stirred
vigorously. Carboxylic acid (1.0 equiv.) was added via syringe (if liquid). DIC (1.1 equiv.)
was then added dropwise via syringe, and the mixture was allowed to stir until the acid
was consumed (determined by TLC). Typical reaction times were between 0.5 h and 12
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h. The mixture was filtered (over Celite, SiO , or through a fritted funnel) and rinsed with
2
additional CH Cl . The solvent was removed under reduced pressure, and purification by
2
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column chromatography afforded the corresponding N-(acyloxy)phthalimides. Note:
Some esters are prone to hydrolysis on silica gel during column chromatography and
should be purified as quickly as possible to obtain reasonable separation.
Alternative synthetic route to NHPI esters: The carboxylic acid (1.0 equiv.), oxalyl chloride
(1.1 equiv.), N,N-dimethylformamide (DMF; 5 drops), and anhydrous dichloromethane (to
form a 0.2 M solution of the carboxylic acid) were mixed in an oven-dried round-bottom
flask under nitrogen. The mixture was stirred until gas evolution ceased. Then, all volatiles
were removed under vacuum to yield the desired acid chloride, which was used in the
next step without purification. To a solution of the acid chloride (synthesized or purchased;
1.0 equiv. – 0.2M) in anhydrous dichloromethane under nitrogen was added N-
hydroxyphthalimide (1.1 equiv.). Triethylamine (1.1 equiv.) was then added to the mixture
slowly. The resulting solution was stirred from few hours to overnight at r.t. Next, all
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volatiles were removed under reduced pressure, and the residue was purified via flash
chromatography.
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Full characterization of the NHPI esters reported for the first time (1b, 1d, 1h, 1j and 1l)
are reported below:
1-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-1-oxopropan-2-yl benzoate (1b). 70% yield
(660 mg), white solid, 80.5 – 82.3 °C. The product was obtained after flash
1
chromatography using hexane/ethyl acetate (80:20). H NMR (400 MHz, CDCl ) δ 8.14
3
(d, J = 8.0 Hz, 2H), 7.92 – 7.86 (m, 2H), 7.82 – 7.76 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.48
13
1
(
t, J = 7.6 Hz, 2H), 1.94 (s, 6H). C{ H} NMR (100 MHz, CDCl ) δ 169.1, 165.1, 161.56,
3
1
34.7, 133.4, 130.0, 129.4, 129.0, 128.4, 123.9, 25.0. HRMS (ESI/Q-TOF) m/z: [M + Na]+
Calcd for C H NNaO 376.0792; found 376.0787.
19
15
6
1,3-dioxoisoindolin-2-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (1d). 86%
yield (1200 mg), white solid. The product was obtained after flash chromatography using
hexane/ethyl acetate (80:20 – 70:30). Spectroscopic data match those previously
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reported in the literature. H NMR (400 MHz, CDCl ) δ 7.84 – 7.78 (m, 2H), 7.74 – 7.68
3
13
1
(
m, 2H), 4.97 (s, 1H), 1.64 (s, 6H), 1.44 (s, 9H). C{ H} NMR (100 MHz, CDCl ) δ 171.1,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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0
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61.7, 154.3, 134.7, 129.0, 123.9, 55.8, 42.3, 28.2, 23.4. HRMS (ESI/Q-TOF) m/z: [M +
+
Na] Calcd for C H N NaO 371.1219; found 371.1207.
17
20
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6
1
,3-dioxoisoindolin-2-yl 3-(benzyloxy)-2,2-dimethylpropanoate (1h). 83% yield (630 mg),
white solid. The product was obtained after flash chromatography using hexane/ethyl
1
acetate (80:20). Spectroscopic data match those previously reported in the literature. H
NMR (400 MHz, CDCl ) δ 7.93 – 7.88 (m, 2H), 7.83 – 7.78 (m, 2H), 7.41 (t, J = 7.3 Hz,
3
2
H), 7.37 (d, J = 7.9 Hz, 2H), 7.33 – 7.28 (m, 1H), 4.67 (s, 2H), 3.65 (s, 2H), 1.46 (s, 6H).
13
1
C{ H} NMR (100 MHz, CDCl ) δ 172.7, 162.0, 138.2, 134.7, 129.1, 128.3, 127.6, 127.6,
3
+
1
23.9, 76.1, 73.5, 43.6, 22.4. HRMS (ESI/Q-TOF) m/z: [M + H] Calcd for C H NO
20 20
5
3
54.1336; found 354.1333.
1
,3-dioxoisoindolin-2-yl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate (1j). 80%
yield (1100 mg), pale-yellow solid, 111.9 – 115.2 °C. The product was obtained after flash
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chromatography using hexane/ethyl acetate (70:30). H NMR (400 MHz, CDCl ) δ 7.94 –
3
7
.89 (m, 2H), 7.86 – 7.80 (m, 4H), 7.75 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.14
0
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(
d, J = 8.5 Hz, 2H), 1.89 (s, 6H). C{ H} NMR (100 MHz, CDCl ) δ 194.4, 170.4, 161.7,
3
1
58.6, 138.5, 136.3, 135.0, 132.1, 131.4, 131.3, 128.9, 128.6, 124.1, 118.5, 78.6, 25.7.
+
HRMS (ESI/Q-TOF) m/z: [M + H] Calcd for C H ClNO 464.0895; found 464.0883.
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1
,3-dioxoisoindolin-2-yl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate (1l). 83% yield
(920 mg), pale-yellow solid, 62.8 – 64.1 °C. The product was obtained after flash
1
chromatography using hexane/ethyl acetate (70:30). H NMR (400 MHz, CDCl ) δ 7.94 –
3
7.87 (m, 2H), 7.85 – 7.78 (m, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 6.6 Hz, 2H), 4.04
13
1
(
t, J = 4.9 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.01 – 1.97 (m, 4H), 1.48 (s, 6H). C{ H}
NMR (100 MHz, CDCl ) δ 173.8, 162.1, 157.0, 136.5, 134.7, 130.3, 129.1, 123.9, 123.6,
3
1
20.7, 112.0, 67.7, 42.0, 37.4, 25.1, 25.0, 21.4, 15.8. HRMS (ESI/Q-TOF) m/z:
+
[
M+MeOH+Na] Calcd for C H NNaO 450.1887; found 450.1884.
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General photoinduced cascade procedure: General procedure on 0.1 mmol scale (3a-3u
and 4a-4n): An oven-dried screw-cap 10 mL reaction glass tube equipped with a magnetic
stirring bar was charged with N-(acyloxy)phthalimide 1 (2 equiv.), enyne 2 (1 equiv.),
diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 equiv.) and N,N-
1
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-1
Diisopropylethylamine (2 equiv.). Freshly distilled THF or DMF (0.1 mol L ) was added
under atmospheric air. The tube was caped and placed approximately at 3 cm distance
from the blue LED 34W Kessil lamp and irradiated at room temperature – the temperature
was mantained by placing a fan righ above the reaction tube - for 24 h. After this period,
the solvent was removed under reduced pressure and the crude residue was solubilized
in ethyl acetate and washed with HCl 10% (3x) and NaOH 0.1 M (3x) (Note: When the
solvent is DMF, an alternative work-up was dilute the reaction in ethyl acetate directly).
The collected organic layer was dried over Na SO , filtered and concentrated under
2
4
reduced pressure to give the crude product. Column chromatography on silica afforded
pure compounds.
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EDA photoinduced cascade performed at gram-scale: To a Schlenk tube (50 mL) equipped with
a magnetic stirring bar was charged with enyne 2a (593 mg, 2.15 mmol, 1 equiv.), N-
(acyloxy)phthalimide 1d (1.5 g, 4.3 mmol, 2 equiv.), diethyl 2,6-dimethyl-1,4-dihydropyridine-
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,5-dicarboxylate (817mg, 3.23 mmol, 1.5 equiv.) and N,N-Diisopropylethylamine (555,7 mg, 4.3
-1
mmol, 2 equiv). Anhydrous THF (21.5 mL, 0.1 molL ) was added under atmospheric air. The tube
was placed and irradiated approximately at 3 cm distance from the blue LEDs 34W light for 24 h.
The solvent was removed under reduced pressure and the crude residue 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 Na SO , filtered and concentrated under reduced pressure to give the crude
2
4
product. Column chromatography on silica (hexane/ethyl acetate = 9:2) to afford product 4d (628
mg, 67% yield; Z/E= 1:1) as a pale-yellow oil. The diastereomeric ratio (dr) was determined to be
1
1
:1 by H NMR.
4-benzylidene-1,3-dimethyl-3-neopentyl-3,4-dihydroquinolin-2(1H)-one (3a). 80% yield
(26.7 mg), yellow oil. The product was obtained after flash chromatography using
1
hexane/ethyl acetate (90:10 – 85:15). H NMR (400 MHz, CDCl ) δ 7.42 (d, J = 7.6 Hz,
3
1
H), 7.30 – 7.21 (m, 3H), 7.20 – 7.15 (m, 4H), 7.13 – 7.08 (m, 3H), 7.06 – 7.00 (m, 4H),
.96 – 6.88 (m, 4H), 6.68 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 3.31 (s, 3H), 3.29 (s, 2H), 1.63
6
(s, 3H), 1.59 – 1.47 (m, 2H), 1.43 – 1.29 (m, 2H), 1.20 (s, 3H), 0.79 (s, 9H), 0.76 (s, 8H).
13
1
C{ H} NMR (100 MHz, CDCl ) δ 173.8, 173.6, 139.9, 139.4, 139.2, 138.5, 137.6, 130.8,
3
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30.5, 129.4, 128.7, 128.7, 128.5, 128.4, 128.2, 127.8, 127.0, 126.8, 126.7, 126.2, 124.5,
23.2, 122.1, 114.3, 113.7, 52.9, 49.7, 49.6, 48.9, 33.0, 32.8, 31.1, 30.8, 30.5, 29.7, 25.0,
1
1
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1
0.8. The diastereomeric ratio (dr) was determined to be 1.5:1 by H NMR. HRMS (ESI/Q-
+
TOF) m/z: [M + H] Calcd for C H NO 334.2165; found 334.2165.
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4-benzylidene-1,3,6-trimethyl-3-neopentyl-3,4-dihydroquinolin-2(1H)-one (3b). 75% yield
(26.1 mg), yellow oil. The product was obtained after flash chromatography using
1
hexane/ethyl acetate (90:10 – 85:15). H NMR (400 MHz, CDCl ) δ 7.27 – 7.22 (m, 3H),
3
7.20 – 7.14 (m, 4H), 7.12 – 7.02 (m, 3H), 6.95 (s, 2H), 6.84 – 6.77 (m, 2H), 6.72 (s, 1H),
6.59 (s, 1H), 3.29 (s, 1H), 3.27 (s, 3H), 2.30 (s, 3H), 1.96 (s, 1H), 1.62 (s, 1H), 1.57 – 1.55
(m, 1H), 1.53 (s, 1H), 1.43 – 1.39 (m, 1H), 1.34 – 1.32 (m, 1H), 1.19 (s, 3H), 0.80 (s, 4H),
13
1
0.76 (s, 9H). C{ H} NMR (100 MHz, CDCl ) δ 173.6, 173.5, 140.1, 139.5, 137.7, 136.9,
3
136.2, 132.6, 131.3, 131.0, 130.4, 129.3, 129.2, 129.0, 128.4, 128.0, 127.8, 127.6, 126.7,
126.6, 126.0, 114.2, 113.6, 52.9, 49.7, 49.6, 49.1, 32.9, 32.7, 31.0, 30.8, 30.5, 27.1, 25.1,
1
20.8, 20.5. The diastereomeric ratio (dr) was determined to be 2.5:1 by H NMR. HRMS
+
(ESI/Q-TOF) m/z: [M + H] Calcd for C H NO 348.2322; found 348.2321.
2
4
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