Visible light sensitization of benzoyl azides: Cascade cyclization toward oxindoles: Via a non-nitrene pathway

Article abstract of DOI:10.1039/c7cc04852a

Visible light sensitization of benzoyl azides was examined in reaction with N-phenylmethacrylamides to afford biologically important oxindoles and spirooxindoles via a cascade cyclization under mild reaction conditions. Mechanistic studies suggested a non-nitrene pathway, where triplet benzoyl azides act as the reactive intermediate.

Full text of DOI:10.1039/c7cc04852a

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DOI: 10.1039/C7CC04852A
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Visible light sensitization of benzoyl azides: cascade cyclization
toward oxindoles via a non‐nitrene pathway
Dattatraya B. Bagal, Sung‐Woo Park, Hyun‐Ji Song* and Sukbok Chang*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Visible light sensitization of benzoyl azides was examined in much diminished reaction efficiency (Yoon’s study with benzoyl
reaction with N-phenylmethacrylamides to afford biologically azide).4
important oxindoles and spirooxindoles via a cascade cyclization
Continuing our efforts on the C-H amidation reactions,5 we
under mild reaction conditions. Mechansitic studies suggested a envisioned that the diradical character of triplet acyl azides could
non-nitrene pathway, where triplet benzoyl azides act as the be deployed for developing a versatile synthetic methodology.
reactive intermediate.
Considerably long lifetime6 and low quantum yields in the
decomposition of triplet benzoyl azide7 were especially
noteworthy for realizing our hypothesis. Visible light
photocatalysis8 was chosen as a tool for the mild and selective
Ubiquity of aminated molecules in natural products and synthetic
materials allured generations of organic chemists to develop
efficient amination methodologies.1 Utilizing acyl azides as an
efficient and environment-friendly amino source has long been
pursued because the only stoichiometric by-product is N2.
However, thermal or photochemical activation of acyl azides
often leads to unwanted by-products such as isocyanates (via the
Curtius rearrangement)2 and solvent adducts of acyl nitrenes (via
N2 dissociation of activated acyl azides).
energy
transfer.
For
the
reaction
substrate,
N-
phenylmethacrylamides were selected based on their well-
documented reactivity as an excellent radical acceptor, thus
furnishing biologically relevant oxindole products (Scheme 1c).9
Recently, mild and selective activation of carbonyl azides
was achieved by the visible light triplet sensitization. In 2015,
König and coworkers reported amidation of electron-rich
heteroarenes in reaction with benzoyl azides (Scheme 1a).3
Importantly, undesired reactions of neutral acyl nitrene were
effectively inhibited by generating nitrenium species through the
combined transfer of triplet energy and proton. Yoon and
coworkers’ study of olefin aziridination with triplet
carbethoxynitrenes is also a compelling illustration of the
efficacy of visible light triplet sensitization for the mild and
selective activation of carbonyl azides (Scheme 1b).4 However,
in both studies, photosensitization of benzoyl azide still gave rise
to either undesired products (König’s study without H3PO4)3 or
a. Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science
(IBS), Daejeon 34141 (Republic of Korea). E‐mail: songhyunji@kaist.ac.kr
sbchang@kaist.ac.kr
b. Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon 34141 (Republic of Korea)
† Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, characterization of new compounds, details of computational studies
and X‐ray analysis. CCDC 1505485 and 1505486. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/x0xx00000x
Scheme 1 Visible light activation of carbonyl azide
s
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The prospective photocatalytic reaction of 1a and 2a were
Journal Name
Under the optimized reaction conditions, we VeiexwpAlroticrleedOntlhinee
DOI: 10.1039/C7CC04852A
N-arylmethacrylamides (1) and benzoyl azides (2)
scrutinized with visible light irradiation applied by 20 W scope of
household compact fluorescent lamp (CFL) (Table 1). (Table 2). Both electron-donating and electron-withdrawing
Photocatalyst optimization unveiled the highest reactivity with groups on the benzoyl azides were compatible, thus furnishing
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 which has the highest singlet- the corresponding oxindole products equally in good to excellent
triplet energy difference (EST = 60.8 kcal/mol) and the longest yields (3a
–
3j).15 Importantly, a broad range of functional groups
triplet excited-state lifetime (τ= 2300 ns) among those tested.8a such as halo (3d
–
3e), ester (3f), or cyano (3h) were well tolerated.
From the solvent screening, acetonitrile turned out to be most Benzoyl azides bearing multiple substituents at sites other than
effective. The most notable observation with various solvents the para-position were also highly facile in the current
was the absence of by-products typically derived from transformation
isocyanate or acyl nitrene. In fact, no ylides were detected from substituents on the
reactions in DMSO,10 and pyridine.11 Likewise, 1,3,4-oxadiazole For
-substituents, ethyl (3k), benzyl (3l) and phenyl (3m) were
(3i
–
3j). Electronic and steric effects of
N
-arylmethacrylamides were also studied.
N
was not formed in acetonitrile.7a, 12 In addition, no O-H insertion tested to reveal good reactivity. Also, methacrylamides with
product was observed in a reaction using methanol solvent,7c, 13 various phenyl ring substituents underwent the current
while a significant amount (47%) of benzamide by-product was cyclization without difficulty to afford the desired products in
attributed to the hydrogen atom abstraction by triplet benzoyl good to moderate yields (3n–3v).
azide7c from methanol.14 All of these results clearly indicate that
the generation of benzoyl nitrene as the reactive intermediate can
be excluded at the present stage.
While a molecular scaffold of spirooxindoles is embedded in
number of biologically active natural alkaloids, its
straightforward synthesis has been a highly challenging task.16
We envisioned that our present method can be extended to the
synthesis of spirooxindoles by using cyclic α,β-unsaturated
a
Table 1 Optimization of the reaction conditions
amides (4, Table 3). Indeed, various substituted benzoyl azides
(
2
) were readily reacted with 4 to furnish spirooxindoles (5a–
5k).15 Surprisingly, all spirooxindoles products were obtained as
single diastereomers and this stereoselectivity is attributed to the
sterically much favoured reaction on the convex-face of
(Figure 1).
4
Table 2 Scope of benzoyl azides and N‐arylmethacrylamidesa
Entry
Photocatalyst
Solvent
Yield (%)a,b
1
2
3
4
5
6
7
8c
9
[Cu(dap)2]Cl
[Ru(bpy)3]Cl2
[Ir(dtbbpy)(ppy)2]PF6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
MeOH
pyridine
CH2Cl2
CH3CN
0
0
11
42
79
69
42
50
56
74
96
fac‐Ir(ppy)3
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
10
11d
Changes from entry 11
12
13
14
15
16
No photocatalyst or light at 25 oC
No light at 60 oC
with NEt3 or EtN(i‐Pr)2 (3 equiv.)
with Hantzsch ester (3 equiv.)
with TEMPO (3 equiv.) or O2 (1 atm)
0
0
0
0
0
a
1a (0.2 mmol), 2a (0.3 mmol), photocatalyst (2.5 mol %), solvent (1.5 mL), Ar
atmosphere, visible light irradiation with 20 W CFL at 25 oC for 24 h. b Determined
by 1H-NMR analysis using 1,1,2,2,-tetrachloroethane as an internal standard. c 47%
of 4-methoxybenzamide was obtained as side product. d Reaction for 36 h at 25 oC.
a 1 (0.2 mmol), 2 (0.3 mmol), photocatalyst (2.5 mol %), CH3CN (1.5 mL), Ar
atmosphere, visible light irradiation with 20 W CFL at 25 oC for 36 h. All yields
refer to isolated products (3a-3v) by column chromatography.
2 | J. Name., 2012, 00, 1‐3
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Table 3 Substrate scope for aminated spirooxindolesa
Me
(a)
NH
COAr
View Article Online
O
DOI: 10.1039/C7CC04852A
O
Ar
N3
N
O
*Ir3+
R
2
3
Ar
Ar
N
visible
light
1,4-hydrogen
atom transfer
triplet
sensitization
O
Ir3+
O
N
Me
H
3
benzoyl
nitrene
N
Ar
O
O
Ar
N3
N
R
IM1
IM4
Me
5-exo-trig
radical
cyclization
N
R
O
path A
1
O
O
Me
Me
N
Ar
N
Ar
N2
N2
N
R
O
N
R
O
IM2
IM3
O
additives (2 equiv.)
(b)
O
NH2
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
(2.5 mol %)
N3
Cl
CH3CN, Ar, 25 o
C
yield (%)a
a
additives
none
4 (0.2 mmol), 2 (0.3 mmol), photocatalyst (2.5 mol %), CH3CN (1.5 mL), Ar
Cl
visible light (20 W CFL)
o
no reaction
atmosphere, visible light irradiation with 20 W CFL at 25 C for 36 h. All yields
>95
(Me3Si)3SiH
refer to isolated products (5a-5k) by column chromatography.
additives (2 equiv.)
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
(2.5 mol %)
yield (%)a
additives
Me
N
CH3CN, Ar, 25 o
visible light (20 W CFL)
C
none
no reaction
no reaction
O
(Me Si) SiH
3
3
Me
a Yields were determined by 1H-NMR analysis using 1,1,2,2,-tetrachloroethane
as an internal standard. In all cases, no side product was detected.
O
(c)
O
Me
N3
Me
N
N
Cl
Cl
D
D5
Cl
D4
O
O
O
N
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6
(2.5 mol %)
Me
Me
O
Me
CH3CN , Ar, 25 o
visible-light (20 W CFL)
C
N
Cl
Cl
Me
N
H
O
N
Me
Me
no H/D srambling observed
Scheme 2 Mechanistic aspects of the photocatalytic reaction
Figure 1 Origin of the observed diastereoselectivity
The energy transfer to benzoyl azide was supported by the
Stern-Volmer quenching experiment20 and photocatalytic
reactions with the hydrogen atom donor (Scheme 2b). While N-
Based on the observations in Table 1 and Scheme 2b–2c, we
proposed the reaction pathway as illustrated in Scheme 2a. The
first step would be the triplet energy transfer from the excited
photocatalyst to benzoyl azide to generate the triplet benzoyl
arylmethacrylamide remained completely unreacted under the
optimized photocatalytic conditions with and without the
hydrogen atom donor, 4-chlorobenzoyl azide efficiently reacted
with the hydrogen atom donor to afford the corresponding
benzamide in quantitative yield. The reversibility of triplet
sensitization and deactivation of benzoyl azide (Scheme 2a)
could be inferred from the complete recovery of unreacted
benzoyl azide in the reaction without the hydrogen atom donor
(Scheme 2b).
azide (IM1). Next, bimolecular reaction between IM1 and
1
must precede N2 dissociation (path A) because none of the
12
benzoyl nitrene-derived side products (oxadiazole7a,
and
aziridine6, 7c) was detected. The resulting diradical intermediate17
(
IM2) may undergo N2 release and cascade cyclization leading
to a cyclohexadienyl radical intermediate9 (IM4). Finally, an
intramolecular 1,4-hydrogen atom transfer (1,4-HAT)18 will
bring out the product (3
) with concomitant rearomatization.19
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8
(a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
While the stability of the excited azide might be seen counter-
intuitive, there are multiple previous studies implying the
stability of triplet-sensitized azides. In many cases, quantum
yields for the decomposition of triplet-sensitized azides were
very low and the non-zero conversion had been attributed to the
View Article Online
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inadvertent direct irradiation from high energy UV light
21
sources.7,
Also, non-nitrene reaction mechanism had been
proposed for the intermolecular reactions of triplet-sensitized
azides with molecular oxygen22 or hydrogen atom donors.7c
The final step, hydrogen atom transfer, had been examined
9
with a 1:1 mixture of deuterated and non-deuterated
N-
10 (a) C. P. Hadjiantonioumaroulis, A. J. Maroulis, A. Terzis and
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arylmethacrylamide subjected to the photocatalytic reaction with
benzoyl azide (Scheme 2c). As a result, no H/D scrambling was
observed, indicating an intramolecular hydrogen atom transfer in
the last step. In an experiment with repeated on-off cycling of
visible light irradiation, a complete quenching of reactivity was
observed in the absence of light.20 Although this result may not
be a definitive evidence in excluding a radical chain pathway,
any chain propagation process, if there is, must be short-lived.23
In conclusion, we have developed a mild and efficient
synthetic route to biologically important oxindole and
spirooxindole scaffolds enabled by the visible light
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15 The structures of the isolated products, 3a (CCDC 1505485)
and 5d (CCDC 1505486), were unambiguously confirmed by
an X-ray crystallographic analyses. For details, please see the
supporting information.
16 (a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F.
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photocatalytic reaction of benzoyl azides and
N-
arylmethacrylamides. A triplet energy transfer process was
proposed to operate by visible light photocatalysis with
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6. The cyclization proceeds
smoothly over a broad range of substrates and reactants without
involving a competitive decomposition side pathway. The
observed stability and reactivity of the presumed reactive
intermediate, triplet benzoyl azides, would be a promise for
further synthetic studies of acyl azides.
This research was supported by the Institute for Basic
Science (IBS-R010-D1) in the Republic of Korea. The authors
are thankful to Dr. Jung Hee Yoon (IBS) and Dr. Ha Jin Lee (the
Western Seoul Center of Korea Basic Science Institute) for XRD
crystallographic analysis.
,
19 DFT calculation studies for the proposed reaction pathway
(Scheme 2a) had been performed and the results agree with the
proposed mechanism. For details, please see the supporting
information.
20 For details, please see the supporting information.
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