Cyclization cascades via N -amidyl radicals toward highly functionalized heterocyclic scaffolds

Article abstract of DOI:10.1021/ja5115858

The addition of a variety of radicals to the double bond of N-(arylsulfonyl)acrylamides can trigger cyclization/aryl migration/desulfonylation cascades via amidyl radical intermediates 2. Herein, we demonstrate the synthetic utility of these intermediates in subsequent C-C and C-X bond-forming events to rapidly build up molecular complexity. First, we describe a regioselective one-pot synthesis of CF₃-, SCF₃-, Ph₂(O)P-, and N₃-containing indolo[2,1-a]isoquinolin-6(5H)-ones from N-[(2-ethynyl)arylsulfonyl]acrylamides through a multi-step radical reaction cascade. The process involves the one-pot formation of four new bonds (one C-X, two C-C, and one C-N), a formal 1,4-aryl migration, and desulfonylation of the starting material. Second, we present a one-pot synthesis of 3,3-disubstituted-2-dihydropyridinones from N-(arylsulfonyl)acrylamides and 1,3-dicarbonyl compounds. In this case, a silver-catalyzed radical cascade process involving the sequential formation of two new C-C bonds and one C-N bond, a formal 1,4-aryl migration, and desulfonylation of the starting material explains the regioselective formation of densely functionalized heterocycles in a straightforward manner. Control experiments have unraveled the key intermediates as well as the sequence of individual steps involved in these transformations.

Full text of DOI:10.1021/ja5115858

Article
pubs.acs.org/JACS
Cyclization Cascades via N‑Amidyl Radicals toward Highly
Functionalized Heterocyclic Scaffolds
Noelia Fuentes, Wangqing Kong, Luis Fernandez-Sanchez, Estíbaliz Merino, and Cristina Nevado*
́
́
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: The addition of a variety of radicals to the
double bond of N-(arylsulfonyl)acrylamides can trigger
cyclization/aryl migration/desulfonylation cascades via amidyl
radical intermediates 2. Herein, we demonstrate the synthetic
utility of these intermediates in subsequent C−C and C−X
bond-forming events to rapidly build up molecular complexity.
First, we describe a regioselective one-pot synthesis of CF3-,
SCF3-, Ph2(O)P-, and N3-containing indolo[2,1-a]isoquinolin-
6(5H)-ones from N-[(2-ethynyl)arylsulfonyl]acrylamides
through a multi-step radical reaction cascade. The process
involves the one-pot formation of four new bonds (one C−X, two C−C, and one C−N), a formal 1,4-aryl migration, and
desulfonylation of the starting material. Second, we present a one-pot synthesis of 3,3-disubstituted-2-dihydropyridinones from
N-(arylsulfonyl)acrylamides and 1,3-dicarbonyl compounds. In this case, a silver-catalyzed radical cascade process involving the
sequential formation of two new C−C bonds and one C−N bond, a formal 1,4-aryl migration, and desulfonylation of the starting
material explains the regioselective formation of densely functionalized heterocycles in a straightforward manner. Control
experiments have unraveled the key intermediates as well as the sequence of individual steps involved in these transformations.
he quest for novel chemical blueprints represents an
endeavor of utmost importance in both academia and
abstraction could take place to give α-aryl-β-functionalized
amides 3 (N-aryl). Alternatively, oxindoles 4 could be
regioselectively obtained by reaction with the aromatic ring in
the case of the N-alkyl-substituted starting materials, as shown
in Scheme 1.
T
industry. Although drug development campaigns continue to
offer useful clinical candidates for a broad array of pathologies,
it is widely accepted that only a small fraction of chemical space
has been explored thus far, and new areas will need to be
examined in order to tackle “undruggable” targets.1 As such,
novel synthetic methods to assemble unprecedented, highly
complex molecular scaffolds are strongly demanded and
continue to attract the attention of the synthetic community.
Alkenes and alkynes are privileged building blocks, as they
allow the simultaneous introduction of different functional
groups via addition across the π-CC2 or -CC3 bond
system. Reactions of substrates endowed with both unsaturated
moieties, namely 1,n-enynes, have enabled the assembly of
elaborate compounds in a highly efficient fashion.4 On the
other hand, radical reaction cascades represent a valuable tool
to access densely functionalized structures, as multiple C−C/
C−X bond-forming reactions can be orchestrated in a highly
selective and functional-group-compatible manner.5 Beautiful
applications of radical reaction cascades can be found in the
total syntheses of complex natural products such as scholarisine
A6 or garcibracteatone,7 to cite some recent examples.
Scheme 1. Previously Developed Radical Reaction Cascades
We hypothesized that the amidyl radical intermediates 2
generated in situ in these transformations could be engaged in
additional bond-forming events in the presence of adequate
partners, thus expanding the synthetic utility of these processes.
Amidyl radicals, generated either by fragmentation of N−X
bonds or by chemical or electrochemical oxidation of amides,
have been previously engaged in radical cyclizations mostly
involving alkene counterparts.9 We thus set out to design
complex cascade reactions based on these intermediates that
Recently, our group reported the addition of a variety of
radicals to the double bond of N-(arylsulfonyl)acrylamide
substrates 1.8 In these transformations, radical addition/aryl
migration/desulfonylation cascades were postulated involving
the participation of an amidyl radical intermediate, 2.
Depending on the nature of the substituents at the nitrogen
atom, different reaction outcomes were observed. Hydrogen
Received: November 18, 2014
Published: January 6, 2015
© 2015 American Chemical Society
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would give access to new structural motifs in a highly controlled
manner.
Table 1. Optimization of the Reaction Conditions
First, we decided to incorporate an alkyne moiety at the ortho
position relative to the arylsulfonyl group in substrates 1. Our
goal was to engage the amidyl radical intermediate 2 in an
additional N−C bond-forming event with the triple bond. The
reaction success would be determined by the chemoselectivity
(alkene vs alkyne) in the addition of the in situ-generated
radicals X·, which could be controlled by the electronic nature
of the substituents installed on each of these unsaturated
moieties (Scheme 2a).
reaction
product, conversion
a
b
entry conditions
additives
(yield, %)
1
A
Cu(MeCN)4PF6 (20%), 2,2′-
7a, <100
Bipy (20%)
c
2
3
4
5
A
A
A
B
Cu2O (25%), 2,2′-Bipy (50%)
Cu2O (40%), 2,2′-Bipy (40%)
Cu2O (25%), 2,2′-Bipy (50%)
K2S2O8 (3 equiv), HMPA
(50%) in CH2Cl2
7a, <100
Scheme 2. Envisaged New Reactivity of N-Amidyl Radicals
7a (64)
7a (70)
5a
6
7
B
B
K2S2O8 (3 equiv), HMPA
(50%) in DMF
8a, <100
d
K2S2O8 (3 equiv), HMPA
(50%) in CH3CN
8a (59)
8
B
B
B
as entry 7, K2S2O8 (1.5 equiv)
as entry 7, HMPA (25%)
8a (64)
8a (66)
9
e
10
K2S2O8 (1.5 equiv), HMPA
(25%) in CH3CN
8a (66)
a
Reaction conditions A: 5a (1 equiv), 6 (1.5 equiv), MeCN (0.05 M),
Second, we speculated that the addition of difunctional C-
centered radicals such as 1,3-dicarbonyl compounds, capable of
simultaneously acting as both radical donors and acceptors, to
the acrylamide moiety could yield additional C−C and C−N
bond-forming reactions with the amidyl radical 2 to produce
densely functionalized heterocycles (Scheme 2b).
80 °C, 20 h. Reaction conditions B: 5a (1 equiv), AgSCF3 (2 equiv),
solvent (0.05 M), 75 °C, 20 h. Isolated yield after column
b
chromatography in silica gel with 100% conversion of the starting
c
d
material. Reaction performed in DMF. Reaction carried out at 0.1 M.
e
AgSCF3 (1.5 equiv)
Herein we present the realization of these concepts via two
different radical reaction cascades which enabled the one-pot
synthesis of two scaffolds, namely, indolo[2,1-a]isoquinolin-
6(5H)-ones and 3,3-disubstituted-dihydropyridinones, with
unprecedented substitution patterns in a completely regio-
selective manner. In addition, to unravel the nature of the
productive reaction intermediates involved in these trans-
formations, control experiments and mechanistic probes were
designed, and the results of these investigations will also be
presented.
Finally, fine-tuning the ratio between catalyst and ligand
allowed us to isolate 7a in 70% yield as shown in Table 1, entry
4. With the optimized conditions in hand for the trifluoro-
methylation reaction, we set out to explore the addition of
trifluoromethylthio radicals using AgSCF3.14 In the presence of
K2S2O8 (3 equiv) and 50 mol% of HMPA in refluxing CH2Cl2
only starting material could be detected (Table 1, entry 5). In
contrast, the reaction in both DMF and acetonitrile showed the
clean formation of 8a, although only with full conversion of the
starting material in the latter case (Table 1, entries 6 and 7).
The reaction proved to be amenable to a decrease of both
K2S2O8 and HMPA, as shown in entries 8 and 9. Finally, 1.5
equiv of AgSCF3 and K2S2O8 and 25 mol% of HMPA sufficed
to produce the desired trifluoromethylthiolated isoquinolinone
8a in an optimal 66% yield (Table 1, entry 10).
Indolo[2,1-a]isoquinolines constitute a privileged scaffold
present in a wide variety of natural compounds and
pharmaceuticals.15 Molecules containing this valuable motif
have been reported to exert tumor inhibition, anti-inflamma-
tory, anti-bacterial, and anti-fungal activities among many
others, but efficient methods to access densely functionalized
forms of this scaffold are scarce.16 Thus, given the efficiency of
our radical cascade to produce highly functionalized derivatives
of this type of compounds, we decided to explore the scope of
this reaction.
RESULTS AND DISCUSSION
■
Reactivity of N-(Aryl)[(2-ethynyl)arylsulfonyl]-
acrylamides. Optimization of the Reaction Conditions. On
the outset, N-(aryl)[(2-ethynyl)arylsulfonyl]acrylamide 5a was
selected as benchmark substrate to explore the addition of
diverse in situ-generated radicals. As the development of
methods to incorporate C−F bonds in relevant building blocks
has recently attracted a lot of attention based on the improved
pharmacological properties observed for F-containing mole-
cules compared to their non-fluorinated analogues, we decided
10
to start our investigation targeting the incorporation of CF3
and SCF311 moieties. As such, the reaction of substrate 5a with
Togni’s reagent 612 in the presence of different copper salts in
acetonitrile as solvent was investigated first.13
Using 20 mol% of both Cu(MeCN)4PF6 and 2,2′-bipyridine
ligand, we were pleased to observe the clean formation of
indolo[2,1-a]isoquinoline 7a together with some unreacted
starting material (Table 1, entry 1). Cu2O did not yield full
conversion of 5a either (Table 1, entry 2). However, an
increased load of both catalyst and ligand delivered trifluoro-
methylated isoquinolinone 7a in 64% yield with full
consumption of the starting material (Table 1, entry 3).
Reaction Scope. With the optimized reaction conditions
for both trifluoromethylation and trifluoromethylthiolation
processes in hand, first we set out to explore the substrate
scope. Acrylamides bearing an electron-donating group (methyl
and methoxy) at the para position of the aromatic ring directly
bound to the N-atom produced the corresponding trifluoro-
methyl- and trifluoromethylthio-substituted indolo[2,1-a]-
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a b
,
Table 2. Reaction Scope
a
b
Unless otherwise stated, Rx = H. Conditions A: Table 1, entry 4. Conditions B: Table 1, entry 10. Conditions C: Togni’s reagent 6 (2 equiv),
c
d
e
nBu4NI (50 mol%), MeCN, 0.05 M, 80 °C, 20 h (ref 8b). Isolated yield after column chromatography. Mixture of regioisomers: 2.6:1. Mixture of
regioisomers: 2.8:1 Reaction performed at 60 °C.
f
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isoquinolin-6(5H)-ones 7b,c and 8b,c in good yields,
respectively (Table 2, entries 3−6).
The presence of electron-withdrawing substituents (fluorine,
trifluoromethyl, methylcarboxylate) at this position seemed to
improve the efficiency of the reaction, as the corresponding
products 7d−f and 8d−f could be isolated in slightly higher
yields (Table 2, entries 7−13). Interestingly, the metal-free
trifluoromethylation reaction of compound 5e delivered 7e in
comparable yield to that of the copper catalyzed one (Table 2,
entry 10).8b An ortho-F substituent was also well tolerated, so
copper and metal-free conditions delivered compound 7g as
single regioisomer in 53 and 56% yield, respectively (Table 2,
entries 14 and 15). Trifluoromethylthiolated product 8g could
also be obtained in 56% yield (Table 2, entry 16). Substrates
bearing substituents at the meta position relative to the N-atom
were also prepared. Thus, m-methyl- and m-fluoro-substituted
substrates 5h,i delivered the trifluoromethyl and trifluoro-
methylthiolated products as a ca. 2.5:1 mixture of regioisomers
as the new C−C bond formation can occur at both ortho and
para positions relative to the methyl or fluorine group,
respectively (Table 2, entries 17−20).
influenced by the substitution pattern in the aromatic ring
directly connected to the N-atom and not so strongly by the
electronic nature of the aromatic substituents in the acetylene
moiety (compare entries 5,6 with entries 7,8 and entries 23,24
with entries 25,26 in Table 2). We thus decided to evaluate the
effect of alkyl substituents at the terminal position of the triple
bond. Interestingly, in the presence of Togni’s reagent 6 under
the standard reaction conditions (Table 1, entry 4), substrates
5p,q delivered the corresponding trifluoromethylated indolo-
[2,1-a]isoquinolines 7p,q in 38 and 28% yield, respectively (eq
3). In these reactions, α-aryl-β-trifluoromethyl amides 12p and
Variations in the substitution pattern of the acryl moiety
were also sought. Substrate 5j bearing a phenyl group at C1 of
the Michael acceptor unit was efficiently transformed into the
corresponding indolo-isoquinolinone derivatives 7j and 8j
(Table 2, entries 21 and 22). The influence of the substituent
at the alkyne moiety was also investigated. Aromatic rings
bearing both electron-donating (methoxy) and electron-with-
drawing groups (methylcarboxylate) in the para position were
well tolerated giving the corresponding trifluoro- and trifluoro-
methylthiolated tetracycles 7k,l and 8k,l in good yields
respectively (Table 2, entries 23−26). Finally, modifications
in the arylsulfonyl moiety (substrates 5m−o) were also studied
proving to be amenable to the above-mentioned conditions as
shown in entries 27−32.
The structure of the product 7a could be confirmed by X-ray
diffraction analysis (Figure 1).17
12q could also be obtained in 15 and 24% yield, respectively. In
contrast, under the standard trifluoromethylthiolation con-
ditions (Table 1, entry 10), 8p and 8q were the only products
observed but the efficiency of the process was diminished
compared to the arylethynyl-substituted substrates presented in
Table 2. Interestingly, a detailed analysis of the reaction mixture
stemming from substrate 5a under the phosphonylation
conditions reported in eq 1 but in the absence of molecular
sieves was also revealing: in addition to the expected product
9a, the corresponding α-aryl-β-phosphonylated amide 12a
could be isolated in 32% yield (eq 4). Amide products 12a,
12p, and 12q seem to confirm the involvement of amidyl
radical intermediates in the transformations yielding the
tetracyclic isoquinoline products 7 and 8.
Finally, the reactions of substrate 5a under the standard
conditions reported in Table 1 (entries 4 and 10) were carried
out in the presence of 2 equiv of TEMPO (eq 5). In both cases,
no conversion to the expected products 7a or 8a was observed,
and only the starting materials were recovered. In addition, in
the first of these reactions, the TEMPO−CF3 adduct could be
detected by both GC-MS (225.16) and 19F NMR (−56 ppm).
Figure 1. X-ray diffraction analysis of product 7a.
To expand the synthetic utility of this methodology, the
introduction of additional heteroatom-centered radicals was
investigated. To our delight, the reaction of substrates 5a, 5b,
5d, and 5l with 30 mol% of AgNO3 and 2.5 equiv of Ph2P(O)H
in acetonitrile at 80 °C in the presence of 4 Å molecular sieves
(reaction conditions previously optimized for the in situ
generation of a phosphonyl radical under silver catalysis)8c
afforded the clean formation of products 9a, 9b, 9d, and 9l in
synthetically useful yields as shown in eq 1. The reaction of
these substrates with 1-azido-1,2-benziodoxol-3-(1H)-one 1018
furnished the corresponding N3-containing products 11a, 11b,
and 11d in 65, 53, and 68% yield, respectively (eq 2).
Control Experiments. The results summarized in Table 2
seemed to indicate that the ability of amidyl radical
intermediates to interact with the alkyne moiety was rather
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TEMPO−SCF3 adduct proved to be more labile and could not
be detected under the reaction conditions.14 These experiments
seem to substantiate the hypothesis of radical intermediates
along the reaction pathway.
Table 3. Optimization of the Reaction Conditions
To gain additional insight into the reaction mechanism, an
o,o-dimethyl-substituted aniline substrate, 5r, was prepared and
submitted to the standard trifluoromethylation and trifluoro-
methylthiolation conditions (eq 6). Although in low yields,13
a
yield of 19a
entry
1
reaction conditions
(%)
TBHP (2 equiv), TsOH or FeCl2 or Cu(OTf)2 (10
complex
mixture
mol %), DCM, 60 °C
2
3
4
5
6
K2S2O8 (2.0 equiv), AgNO3 (10 mol %), MeCN/H2O
60
= 1/1, 50 °C
K2S2O8 (1.5 equiv), AgNO3 (10 mol %), MeCN/H2O
42
= 1/1, 50 °C
b
K2S2O8 (2.0 equiv), AgNO3 (10 mol %), MeCN or
−
H2O, 50 °C
K2S2O8 (2.0 equiv), AgNO3 (10 mol %), MeCN/
73 (70)
H2O = 4/1, 50 °C
(NH4)2S2O8 (2.0 equiv), AgNO3 (10 mol %), MeCN/
66
H2O = 4/1, 50 °C
a
1H NMR yield. In brackets, isolated yield after column chromatog-
b
raphy in silica gel. No conversion was observed in pure MeCN or
pure H2O.
three different scaffolds13,14r, 15,16r, and 17,18rcould
be isolated from the reaction mixtures. X-ray diffraction
analyses of two of these compounds, 13r and 17r,19 and
extensive spectroscopic analysis of 15r and 16r allowed the
unambiguous confirmation of their structure. The formation of
compounds 13r and 14r can be explained by an unusual 1,3-
aryl migration of the o,o-dimethylbenzene ring from the N-
atom to the terminal C-atom of the alkyne.20 In contrast,
compounds 15−18r reflect intriguing additional cyclization
events of the N-atom either onto the arene moiety originally
attached to the alkyne (15r,16r) or onto the o,o-dimethyl-
substituted benzene ring (17r,18r) with concomitant loss of
one of the methyl substituents in the latter case.21
In contrast, treatment of 1a in the presence of AgNO3 (10
mol%) and K2S2O8 (2 equiv) in a mixture MeCN−H2O (1:1)
at 50 °C for 16 h, afforded 3-methyl-3p-tolyl dihydropyridinone
19a in 60% yield (Table 3, entry 2). The structure of 19a could
be confirmed by X-ray diffraction analysis.25 Further control
experiments showed that an excess of K2S2O8 (2 equiv) was
necessary for a productive reaction outcome (Table 3, entry 3).
Single solvent systems (water or MeCN) were also tested;
however, no conversion of the starting material was observed
likely due to the lack of solubility of the substrate and the
oxidant in water and MeCN, respectively (Table 3, entry 4). A
4:1 MeCN−H2O mixture proved to be the best solvent system
furnishing the desired product 19a in 70% yield (Table 3, entry
5). Different oxidants including (NH4)2S2O8 were tested but
they proved to be unable to increase the yield of the product
(Table 3, entries 6).13
Reaction Scope. With the optimized conditions in hand
(Table 3, entry 5), the substrate scope of this transformation
was explored (Tables 4 and 5). First, the substitution pattern
on the aromatic ring directly linked to the N-atom in 1 (R1,
head of Table 4) was evaluated. N-p-Bromophenyl- and p-
methoxyphenyl-substituted arylsulfonamide substrates were
efficiently transformed into the corresponding products 19a
and 19b in 70 and 68% yield, respectively. Ortho-substitution
was well-tolerated and substrates bearing di- and trimethoxy-
substituted aromatic rings afforded the corresponding products
(19c−e) in good yields. Electron-donating substituents
(methoxy or tert-butyl) or the presence of hydrogen at the
para position of the arylsulfonyl group yielded the expected
products (19f−h), with comparable levels of efficiency as single
regioisomers. When both aromatic rings were substituted with
methoxy groups the product 19i was isolated in 63% optimal
yield. o-Bromophenylsulfonyl-substituted substrate 1j, afforded
the corresponding product 19j in 58% yield.
Addition of 1,3-Dicarbonyl Compounds to N-(Aryl)-
(arylsulfonyl)acrylamides. Once the addition of different
radicals onto N-(aryl)[(2-ethynyl)arylsulfonyl]acrylamides 5
had been explored confirming the reactivity of in situ-generated
amidyl radical intermediates toward alkynes, we turned our
attention toward the addition of difunctional C-centered
radicals onto the parent N-(aryl)(arylsulfonyl)acrylamide
substrates 1. We speculated that the use of 1,3-dicarbonyl
compounds, capable of simultaneously acting as both radical
donors and acceptors, could trigger additional C−C and C−N
bond-forming reactions with the postulated amidyl radical
intermediates enabling the synthesis of alternative densely
functionalized heterocycles (Scheme 2b). 1,3-Dicarbonyl
compounds have been previously successfully utilized in
cascade reactions leading to complex molecular scaffolds.22
Metal-free23 as well as transition-metal-mediated24 oxidative
couplings of the methylene Csp3−H bond in 1,3-dicarbonyl
compounds with other partners, have been reported in the past
few years. At the outset of many of these transformations,
radical intermediates were proposed.5c−e,g
Optimization of the Reaction Conditions.13 N-(4-Bromo-
phenyl)-N-tosylmethacrylamide (1a) and pentane-2,4-dione
were used as benchmark substrates to search for the optimal
reaction conditions. Complex mixtures were obtained in the
reaction of these two starting materials with tert-butyl
hydroperoxide (TBHP, 2 equiv) in the presence of catalytic
amounts of protic or Lewis acids (Table 3, entry 1).
When the reaction was carried out with substrate 1k (o-
methyl-substituted), the product 19k could be isolated in 24%
yield. Additionally, amide 20k was also recovered in 26% yield
from the reaction mixture. An efficient transformation was also
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Next, different 1,3-dicarbonyl compounds were tested (Table
5). β-Ketoesters delivered exclusively products 21a, 21d, and
21h stemming from the chemoselective attack of the N-atom
on the keto-carbonyl group. In addition, in the case of non-
symmetrically substituted 1,3-diketone substrates, only one
regioisomer resulting from the attack at the less hindered C
O group was detected in the reaction media (21b and 21i).
When a cyclic 1,3-diketone was used, 22a was exclusively
observed and could be isolated in 60% yield. In this case, likely
due to steric reasons, the formation of an N−H bond is favored
compared to the reaction with the carbonyl group affording α-
aryl-β-functionalized amide 22a.
Table 4. Reaction Scope toward the Synthesis of
Dihydropyridinones 19 from Substituted N-
a b
,
(Arylsulfonyl)acrylamides 1
Control Experiments. Interestingly, the reaction of a 2-N-
phthalimide-substituted substrate 1r afforded the expected
compound 19r, together with oxindole 23r in 31 and 22%
yield, respectively (eq 7). Compound 23r is generated as a
a
b
Reaction conditions: Same as Table 3, entry 5. The value in brackets
shows the isolated yield after column chromatography in silica gel.
c
The corresponding amide, 20k was isolated in 26% yield.
Table 5. Reaction Scope with Different 1,3-Dicarbonyl
ab
,
Compounds
result of a new Csp2−Csp3 bond at the ortho position relative to
the N-atom, a reactivity commonly found in the carbodifunc-
tionalization of N-aryl-substituted acrylamide substrates.26 The
nature of the substituent on the N-atom proved to be crucial to
obtain the desired reactivity. Thus, an N-alkyl-substituted
arylsulfonyl substrate 1s delivered indole 23s in 54% yield in a
complete regioselective manner. In this case, due to the
presence of a more electron-donating alkyl moiety on the N-
atom, the formation of a new N−Csp2 bond is favored over the
reaction of the N-atom with the carbonyl group (eq 8).
When amide 20k was submitted to the standard reaction
conditions no conversion into dihydropyridinone 19k was
observed thus suggesting that amides are not intermediates in
the formation of the observed products (eq 9). Additional
control experiments were conducted to investigate the
mechanism governing these transformations. The reaction
was suppressed upon addition of TEMPO to the reaction
mixture, thus suggesting the intervention of radical inter-
mediates along the reaction pathway. Moreover, no desired
product was observed when stoichiometric amount of base like
NaOH or NaHCO3 were used. These results suggested that the
reaction is favored in slightly acidic medium (eq 10).
a
b
Reaction conditions: Same as Table 3, entry 5. The value in brackets
shows the isolated yield after column chromatography in silica gel.
achieved with more elaborated indane-, 1,4-benzodioxolane-, or
p-phenylbenzene-sulfonyl-substituted substrates (19l−n). Fi-
nally, acrylamides bearing methyl, phenyl, and methoxymethyl
substituents at the internal position of the alkene moiety
afforded the products 19o−q in synthetically useful yields.
Unfortunately, the reaction of substrates bearing trisubstituted
alkenes did not afford the desired dihydropyridinones under the
standard reaction conditions.
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Scheme 3. Mechanistic Proposal
Scheme 4. Mechanistic Proposal To Explain the Formation of Products 13r−18r
Mechanistic Proposal. A mechanistic proposal for the
transformations described above is presented in Scheme 3. At
the outset of these processes, an in situ-generated radical X· (X·
= ·CF3, ·SCF3, ·P(O)Ph2, ·N3, ·CH(COR)2) reacts chemo-
selectively with the acrylic moiety of N-acrylamide substrates 1
and 5, forming a new Csp3−X bond and an α-carbonyl radical
intermediate I. Next, an ipso-cyclization onto the Csp2−SO2
atom takes place, generating a spirocyclic intermediate II in a
new C−C bond-forming event. Upon re-aromatization, SO2 is
expelled, and amidyl radical intermediate III is generated in situ,
involving the concomitant 1,4-migration of the aryl sulfonyl
group27,28 in a Smiles-type rearrangement reaction.29 N-Amidyl
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radicals are considered to be electrophilic, adopting a π-
configuration in its ground state (i.e., single electron located in
a p orbital perpendicular to the plane of the molecule).30
Although addition of amidyl radicals to triple bonds is rare,
experimental and computational evidence points toward a
kinetically feasible reaction.31
individual steps operating in the reactions described in Tables
2, 4, and 5, despite the numerous alternative manifolds.
CONCLUSIONS
■
In summary, two one-pot syntheses of highly functionalized
heterocycles are presented here. Tetracyclic trifluoromethyl-,
trifluoromethylthio-, phosphonyl-, and azidyl-substituted
indolo[2,1-a]isoquinolin-6(5H)-ones can be obtained from N-
[(2-ethynyl)arylsulfonyl]acrylamides. The chemoselective addi-
tion of an in situ-generated radical to the activated double bond
is able to trigger a multi-step radical reaction cascade, yielding
the observed products in an efficient complexity-building
process. The reaction enables a remarkable number of highly
selective bond-forming/breaking events; namely, four new
bonds (Csp3−X, Csp3−Csp2 with concomitant 1,4-aryl
migration and desulfonylation, N−Csp2, and finally a new
Csp2−Csp2) are formed in a single synthetic operation.
A silver-catalyzed radical reaction cascade enabling the
efficient, one-pot, regioselective synthesis of unprecedented
3,3-disubstituted-2-dihydropyridinones from N-(arylsulfonyl)-
acrylamides is also described here. The formation of the
observed products can be explained by sequential formation of
two new C−C bonds and an additional C−N bond triggered by
the initial addition of a C-centered 1,3-dicarbonyl radical onto
the acrylamide moiety of the starting materials. Additionally,
the reaction involves a formal 1,4-aryl migration and a
desulfonylation process, producing the heterocyclic products
in synthetically useful yields.
The presence of a vicinal alkyne moiety in substrates 5 results
in a cyclization of amidyl radical III-a to form a new N−Csp2
bond and a vinyl radical intermediate IV-a. This intermediate
undergoes an additional cyclization to assemble the tetracyclic
product via Csp2−Csp2 bond formation. Upon re-aromatization
of intermediate V-a, the observed indolo[2,1-a]isoquinolin-
6(5H)-one products 7 (X = CF3), 8 (X = SCF3), 9 (X =
P(O)Ph2), and 11 (X = N3) were formed (Scheme 3, left).
When 1,3-dicarbonyl compounds were added to N-
acrylamide substrates 1, initial proton abstraction is proposed
to give a C-centered radical likely involving a Ag(I)−Ag(II)
catalytic cycle in the presence of K2S2O8 as stoichiometric
oxidant. This stabilized C-centered radical undergoes addition
onto the acrylate moiety of 1 to afford an α-keto radical I. The
amidyl radical intermediate III-b (N-aryl) is proposed to react
with the less bulky carbonyl group present in the molecule,
which under the reaction conditions might be present in its
enol form (see compound 22a in Table 5 and control
experiments in eq 10). As a result, intermediate IV-b is
produced, which undergoes elimination of the OH group to
give the desired pyridinones 19 and 21 as shown in the right-
hand side of Scheme 3. Alternatively, intermediate III-b can
evolve via H abstraction (explaining the formation of 20k and
22a) or cyclize onto the vicinal aromatic group (for N-alkyl)
explaining the formation of oxindole 23s respectively.
Nitrogen-centered radicals, including amidyl, iminyl, ami-
nium, and aminyl radicals, have recently emerged as a powerful
synthetic platform for the formation of new C−N bonds.9,36 In
this work we showcase one of the first examples in which
addition of multiple radicals to alkenes produce amidyl radical
intermediates via Smiles rearrangement, evolving additional
radical cyclizations to construct new C−N and C−C bonds.37
We also demonstrate that the reactivity of these key
intermediates can be fine-tuned by electronic as well as steric
factors through a careful choice of the substituents directly
attached to the N-atom (alkyl vs aryl). Investigation of new
reactivity modes for these intermediates and application toward
the synthesis of bioactive molecules is currently underway in
our laboratory.
As already reported,8 different reaction outcomes can arise
depending on the substituents on the N-atom of the amidyl
radical (N-alkyl vs N-aryl). Previous studies on the kinetics of
cyclization of amidyl radicals with alkenes by Newcomb and
Moeller32 reveal an up to 3−4 orders of magnitude lower
reactivity for anilidyl radicals (N-aryl) vs the standard amidyl
(N-alkyl) radical, which might explain why in certain cases, for
anilidyl radicals H abstraction to give the corresponding amides
competes with the cyclization thus yielding compounds 12, 20,
and 22.33 In the case of the more reactive N-alkyl amidyl
radicals, a 5-endo-trig cyclization seems to be favored delivering,
exclusively, oxindole 23s.
Interestingly, the presence of the two methyl groups in ortho-
position of the aniline seems to favor alternative reaction
pathways as shown in eq 6 with the formation of products 13−
18r. As shown in Scheme 4, the α-aryl vinyl radical
intermediate IV′-a, likely existing in linear form,34 can trigger
a 1,4-aryl migration via pathway a,20,27,28 producing two
geometrical isomers of anilidyl radical intermediates VI′-a
and VI″-a. H-abstraction from the reaction media in the former
will deliver compounds 13r and 14r as single stereoisomers.
Alternatively, E-isomer VI″-a can engage in an additional
cyclization with the phenyl group originally attached to the
alkyne unit, delivering, upon re-aromatization, compounds 15r
and 16r. Vinyl radical intermediate IV′-a can also evolve via
pathway b in which cyclization takes place at the methyl-
substituted C-atom of the aniline moiety to produce
intermediate VIII′-a, which upon re-aromatization and a rare
methyl extrusion35 provides compounds 17r and 18r. Although
isolated in low yields, these set of molecules seem to confirm
the proposed radical pathways operating in these trans-
formations and the exquisite control on the selectivity of the
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, additional experiments, character-
ization of all the new compounds, and X-ray data. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
cristina.nevado@chem.uzh.ch
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The European Research Council (ERC Starting grant agree-
ment no. 307948), Swiss National Science Foundation and the
University of Granada are kindly acknowledged for financial
support to W.K., L.F.-S., and N.F. respectively. Dr. Anthony
Linden is acknowledged for the X-ray diffraction analysis
presented here.
971
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J. Am. Chem. Soc. 2015, 137, 964−973

Journal of the American Chemical Society
Article
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