Access to 3-(2-Oxoalkyl)-azaspiro[4.5]trienones via Acid-Triggered Oxidative Cascade Reaction through Alkenyl Peroxide Radical Intermediate

Article abstract of DOI:10.1002/adsc.201801203

Azaspiro[4.5]trienones bearing ketone side chains at the 3-position are prepared from N-alkyl-arylpropiolamides and ketones via oxidative 1,2-difunctionalization of alkynes. The cascade sequence starts with the generation of alkenyl peroxide intermediates

Full text of DOI:10.1002/adsc.201801203

Title: Access to 3-(2-Oxoalkyl)-azaspiro[4.5]trienones via Acid-
Triggered Oxidative Cascade Reactions through Alkenyl Peroxide
Radical Intermediate
Authors: Chang-Sheng Wang, Thierry Roisnel, Pierre H. Dixneuf, and
Jean-Francois Soulé
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801203
Link to VoR: http://dx.doi.org/10.1002/adsc.201801203

10.1002/adsc.201801203
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Access to 3-(2-Oxoalkyl)-azaspiro[4.5]trienones via Acid-
Triggered Oxidative Cascade Reaction through Alkenyl
Peroxide Radical Intermediate
Chang-Sheng Wang, Thierry Roisnel, Pierre H. Dixneuf and Jean-François Soulé*
Univ Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France. Email: jean-francois.soule@univ-rennes1.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Azaspiro[4.5]trienones bearing ketone side
chains at the 3-position are prepared from N-alkyl‐
arylpropiolamides and ketones via oxidative 1,2-
difunctionalization of alkynes. The cascade sequence
starts with the generation of alkenyl peroxide
intermediates, which are obtained by addition of tert-
butyl hydroperoxide to ketones in presence of a catalytic
amount of a strong acid. Then, the ketone radical adds
to alkynes, followed by spirocyclization and
dearomatization process. This method represents a new
example of difunctionalization of alkynes with
simultaneous formation of two carbon–carbon single
bonds and one carbon–oxygen double bond in one step.
are only few reports focusing on the use of carbon-
centered radicals, albeit it offers a direct synthesis of
polycyclic compounds with the construction of two
C–C single bonds. As examples, Liu and Liang have
successfully employed Langlois’ reagent (CF3SO2Na)
as trifluoromethyl radical precursor in the synthesis
of 3-trifluoromethylated azaspiro[4.5]trienones.[10]
Alkyl radicals –generated by hydrogen abstraction
process of ether[11] or cycloalkane C(sp3)–H bonds[12]
using Cu catalyst with tert-butyl hydroperoxide
(tBuOOH)– have been also employed in those
cascade reactions (Scheme 1).
Keywords: Radical reaction; Cascade; Heterocycles;
Ketones; Peroxides
O
Ar
Ar
Cat.
R4
R
R4
3 N
R
Additive
R
precursors
N
O
R3
O
Spirocyclic compounds are important motifs
embedded in many natural products, bioactive
ref 4
ref 5
ref 6
ref 8
ref 7
compounds
and
functional
molecules.[1]
H SiR3
ArSe SeAr
H2NHN SO2R
H SAr
tBu
N
O
O
CuI or
Spiro[4.5]trienones, which are also valuable
intermediates in organic synthesis, are often prepared
via multi-steps synthesis.[2] One of the most efficient
strategy for the construction of multiple bonds in a
single operation involves 1,2-difunctionalization of
unsaturated molecules,[3] including photoredox
radical process.[4] Among them oxidative radical-
mediated spirocyclization of N-arylpropiolamides has
proven to be an attractive and straightforward method
to access spiro[4.5]trienones in a single step (Scheme
1). For example, radical oxidation of thiols,[5]
sulfonylhydrazides,[6] diaryl diselenide,[7] nitrite,[8] or
silanes[9] gave formation of heteroatom-centered
radicals, which added to alkynes followed by
spirocyclization and dearomatization (Scheme 1).
This procedure allowed the 1,2-difunctionalization of
activated alkynes through the one-pot formation of
C–heteroatom and C–C single bonds. However, there
AgCl
H2O
I2O5
Blue LEDs
O2
TEMPO
H2O
Fe(acac)2
tBuOOH
tBuOOH
ref 9
ref 10 and 11
C(sp3)
CuCl
NaO2S CF3
CuCl
H
tBuOOH
tBuOOH
Scheme 1. Previous Syntheses of Functionalized
spiro[4.5]trienones via Oxidative Radical-Mediated
Spirocyclization of N-Arylpropiolamides.
In 2014, Klussmann and co-workers reported acid-
mediated 1,2-difunctionalization of alkenes with
ketones and tert-butyl hydroperoxide (tBuOOH)
(Scheme 2a).[13] The reaction involves the generation
of ketone radical via the decomposition of alkenyl
peroxide A –generated by the addition of tBuOOH to
1
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
obtained in a poor yield (entry 1). When the reaction
is carried out without acid catalyst or peroxide, no
reactions occurred (entries 2 and 3). The presence of
oxygen has a deleterious effect on this cascade
reaction (entry 4). The use of a larger amount of
ketone (10 equiv.) allowed to improve the yield in 1
to 23% (entry 5). A better yield of 52% in 1 is
obtained using pinacolone as reactant and solvent
(0.2 mol/L) (entry 6). Aqueous solution of tBuOOH
and other oxidants such as (tBuO)2 or PhI(OAc)2 are
not successful (entries 7-9). p-TsOH outperformed
other catalyst such as H2SO4, AcOH and Cu(OTf)
(entries 10-12). A lower catalyst loading resulted in a
lower yield, whereas a higher loading of 20 mol%
failed to improve the yield (entries 13 and 14).
Finally, a prolonged reaction time allowed to improve
the yield up to 76% after 48 h (entries 14-16). The
structure of 1 has been confirmed by X-ray
analysis.[18] Interestingly, previous method to access
azaspiro[4.5]trienones bearing ketone side chains at
the 3-position involves oxidative ipso-annulation of
ketone catalyzed by acid– through homolytic bond
O–O cleavage.[14] Independently, Klussmann’s and
Xia’s groups have employed ketone radicals in
cascade reaction. Indeed, after addition of ketone
radical to alkene unit of N-aryl acrylamides, a radical
cyclization affords oxindoles in good yields (Scheme
2b).[15] Xia and coworkers also reported a similar
procedure for the preparation of isoquinolinonediones
(Scheme 2c).[16]
To the best of our knowledge,
alkenyl peroxide intermediates have never been
employed in addition of ketone radicals into alkynes,
yet. In our continuous efforts to employ carbon-
centered radicals in C–H bond functionalizations,[17]
we decided to investigate the reactivity of ketones in
presence of tBuOOH and activated alkynes such as
N-arylpropiolamides in order to introduce at least two
different functional groups into unsaturated
molecules (Scheme 2d).
specific
substrates
(i.e.
N-(p-
a. Acid-Catalyzed Oxidative Radical Addition of Ketones to Alkenes
(Klussmann)[13]
methoxyaryl)propiolamides with α-carbonyl alkyl
bromides).[19]
p-TsOH
(cat.)
OtBu
O
O
OtBu
O
O
R3
R1
R1
R1
Table 1. Optimization of the Reaction Conditions
tBuOOH
CH3CN, 50 ºC
R2
R2 R3
R2
via A
O
Ph
b. Acid-Catalyzed Oxidative Radical Cascade Addition of Ketones to
Alkenes for Synthesis of Oxindoles (Klussmann)[15a] and (Xia)[15b]
R1
Acid (x mol%)
Ph
tBuOOH (5 eq.)
solvent, 60 ºC, 16 h
N
O
tBu
N
Me
(0.2 mmol)
O
p-TsOH
or MsOH
(cat.)
R2
O
x (equiv or mL)
O
O
tBu
O
R4
R1
1
R4
tBuOOH
50 or 60 ºC
O
N
R3
O
R2
N
R3
c. Acid-Catalyzed Oxidative Radical Cascade Addition of Ketones to
Alkenes for Synthesis of Isoquinolinonediones (Xia)[16]
R1
O
X-ray structure of 1
R2
O
MsOH
(cat.)
O
Entry
x
Acid (x)
Solvent
Yield in
O
1 (%)a)
R4
R1
N
tBuOOH
60 ºC
O
N
R3
R3
R2
1
2
3b)
4c)
5
5 eq
5 eq
5 eq
5 eq
p-TsOH (10) CH3CN
CH3CN
16
O
–
NR
NR
NR
23
d. Acid-Triggered Oxidative Radical Cascade Addition of Ketones to
Alkynes for Synthesis of Azaspiro[4.5]trienones (This work)
p-TsOH (10) CH3CN
p-TsOH (10) CH3CN
O
10 eq p-TsOH (10) CH3CN
Ph
6
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
1 mL
p-TsOH (10) –
p-TsOH (10) –
p-TsOH (10) –
p-TsOH (10) –
52
8
p-TsOH
(cat.)
O
Ph
R4
7d)
8e)
9f)
10
11
12
13
14
15g)
16h)
R1
R4
R2
R1
3 N
R
NR
NR
40
NR
6
44
52
68
82 (76)
tBuOOH
R2
N
R3
O
O
O
H2SO4 (10)
AcOH (10)
Cu(OTf)2
–
–
–
–
Scheme 2. Application of Alkenyl Peroxide Intermediates
in Organic Synthesis.
p-TsOH (5)
p-TsOH (20) –
p-TsOH (10) –
p-TsOH (10) –
We selected N‐methyl‐N,3‐diphenylpropiolamide and
pinacolone as model substrates (Table 1). In the
presence of 10 mol% p-TsOH and tBuOOH (in
decane solution) in acetonitrile at 60 ºC, 3-(3,3-
dimethyl-2-oxobutyl)-1-methyl-4-phenyl-1-
a) Determined by GC-analysis using n-dodecane as internal
standard and isolated yield was shown in parentheses.
Reaction carried out without tBuOOH. Reaction carried
b)
c)
d)
out under air atmosphere. tBuOOH in water solution
azaspiro[4.5]deca-3,6,9-triene-2,8-dione
(1)
is
used instead of tBuOOH in decane. e) (tBuO)2 used instead
2
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
f)
of tBuOOH in decane.
PhI(OAc)2 used instead of
group as from N‐methyl‐N,3‐diphenylpropiolamide
and methyl levulinate, a bio-sourced ketone, the
cyclized product 12 is isolated in 52% yield.
However, no reaction occurred when (substituted)
acetophenones are employed as reactants owing such
ketones have more pronounced radical cation
characters (see supporting information for more
details).[20]
tBuOOH in decane. g) 24 h. h) 48 h.
With the best conditions in hand, we then studied the
effect of the nitrogen substituent on this acid-
mediated oxidative radical cascade reaction (Scheme
3). From, non-substituted N,3-diphenylpropiolamide,
no reaction occurred. The replacement of N-methyl
by N-ethyl substituent has almost no effect as the
azaspiro[4.5]trienones 3 is isolated in 79% yield.
N,3‐diphenylpropiolamide bearing a removal N-
protecting group, e. g., N-allyl or N-benzyl, also
reacted with pinacolone to give the corresponding 3-
O
Ph
Ph
p-TsOH (10 mol%)
R2
N
R2
R1
R
tBuOOH (5 eq.)
N
O
R1
(1 mL)
O
60 ºC, 48 h
O
(3,3-dimethyl-2-oxobutyl)-azaspiro[4.5]trienones
and 5 in 53% and 71% yield, respectively without the
cleavage of the N-protecting group.
4
R
O
(0.2 mmol)
O
O
O
Ph
Ph
Ph
N
O
N
N
R
Ph
O
p-TsOH
(10 mol%)
O
O
O
Ph
O
O
tBu
R = Me 6 81%
R = Et 7 86%
O
N
R
8 49%
9 68%
tBuOOH (5 eq.)
60 ºC, 48 h
O
N
R
O
O
O
O
(1 mL)
tBu
NR
79%
53%
71%
O
2
3
4
5
R = H
(0.2 mmol)
Ph
Ph
Ph
R = Et
R = All
R = Bn
N
N
N
CO2Me
O
O
O
nBu
nDec
11 63%
O
O
O
Scheme 3. Effect of the N-Substituent of N-
arylpropiolamides in Acid-Triggered Oxidative Cascade
Addition – Spirocyclization – Dearomatization Process
10 76%
12 52%
Scheme 4. Scope of the Ketones in Acid-Triggered
Oxidative Radical Cascade Addition – Spirocyclization –
Dearomatization Process.
Then, we investigated the reactivity of other ketones
in this acid-mediated oxidative radical cascade
reaction (Scheme 4). Acetone underwent cascade
reaction with N‐methyl‐N,3‐diphenylpropiolamide or
N‐ethyl‐N,3‐diphenylpropiolamide to afford the
azaspiro[4.5]trienones 6 and 7 in good yields. Going
from primary to secondary ketones, a decrease of
reactivity is observed as the spirocyclization with
diethyl ketone afforded the product 8 in only 49%
yield. This lack of reactivity could be attributed to
steric factors. Unsymmetrical 1-cyclopropylethan-1-
one showed a preference for radical formation at the
primary carbon, giving the corresponding cyclized
product 9 in 68% yield. It is important to note that
even under these radical conditions the cyclopropyl
group remains intact at the end of the reaction. This
observation, suggested that the formation of carbon-
centered radical via the decomposition of alkenyl
peroxide is faster at primary carbon than tertiary
carbon. Other unsymmetrical ketones such as hexan-
2-one or dodecan-2-one displayed the same trend of
reactivity and selectively reacted at the primary
carbon yielding the targeted compounds 10 and 11 in
To further explore the scope of this radical cascade
spirocyclization reaction, various substituted N-
arylpropiolamides are investigated under the
optimized reaction conditions with pinacolone as
radical precursor (Scheme 5). Firstly, the impact of
ortho-substituents on aniline unit of N-
arylpropiolamide is investigated. When the cascade
reaction is performed with ortho-C–halo (halo = F, Cl,
Br) substituted substrates, the azaspiro[4.5]trienones
13-15 are obtained in moderate to good yields
without cleavage of the C–halo bonds allowing
further transformations.
From ortho-phenyl
substituted N-phenylpropiolamide the cascade
reaction, 16 is obtained in 77% yield. The reaction is
slightly sensitive to the steric effect. Indeed, from N-
arylpropiolamides, in which the aniline moiety bears
two electron-donating groups (e. g., Et or iPr) at both
ortho-positions, the corresponding cyclized products
17 and 18 are obtained in 42% and 54% yield,
respectively. Bromo or even iodo atom at the meta-
position of the aniline unit are also tolerated affording
the desired products 19 and 20 in good yields.
Notably, when the reaction is performed using a
substrate with a methyl group attached to the triple
bond, N-methyl-N-phenylbut-2-ynamide, the acid-
76% and 63% yield, respectively.
This
spirocyclization cascade reaction is tolerant to ester
3
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
mediated radical cascade spirocyclization with
pinacolone failed to deliver the corresponding
azaspiro[4.5]trienone 21. However, substituent on
the aryl group attached to the triple bond are well-
tolerated. As example p-hexyloxy substituted aryl
alkyne delivered 22 in 62% yield, and o-phenyl-
substituted aryl alkynes gave the corresponding
product 23 in 57% yield. Naphthalen-1-yl alkyne was
also viable to furnish 24.
MeOH, and HX, respectively, prior to final
elimination of tBuOH to afford the desired products
(Scheme 8).
O
Ph
p-TsOH
(10 mol%)
R
O
tBu
Ph
tBuOOH (5 eq.)
60 ºC, 48 h
R =
(1 mL)
N
N
O
OMe
F
Cl
Br
Me
57%
56%
16%
24%
NR
O
(0.2 mmol)
tBu
O
1
R4
R3
R5
O
R5
R4
p-TsOH
(10 mol%)
R2
R3
N
Scheme 6. Reactivity of N-Arylpropiolamides Bearing a
para-Substituent on the Aniline Unit in Acid-Triggered
Oxidative Radical Cascade Addition – Spirocyclization –
Dearomatization Proces.
O
tBu
R1
O
tBuOOH (5 eq.)
60 ºC, 48 h
N
R2
O
O
(1 mL)
R3
O
tBu
tBu
O
(0.2 mmol)
O
Ph
Ph
Ph
Several control experiments are carefully carried out
to gain deep insight into the reaction pathway. Firstly,
azaspiro-[4.5]trienone (1) is not observed when 2
equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), a radical scavenger, is added into the
F
Cl
Br
N
N
N
O
O
O
tBu
tBu
O
O
O
13 52%
O
14 59%
15 75%
O
O
reaction system.
adduct 22 is detected by GC-MS analysis. This
observation confirms that the cascade
However, the ketone-TEMPO
Et
Ph
i-Pr
Ph
Ph
Ph
Et
i-Pr
N
N
O
N
spirocyclization involves ketone radical species
(Scheme 7a). From (d6)-acetone KIE values of 1.50-
1.06 are determined from intermolecular competition
reaction and from two parallel reactions.[21] These
results indicate that the formation of carbon-centered
radical via the decomposition of alkenyl peroxide is
not the rate-determining step (Scheme 7b). Finally,
in the presence of 1 equivalent of water-18O, the
azaspiro-[4.5]trienone (1) is obtained in only 45%
O
O
tBu
tBu
tBu
O
O
O
16 77%
17 42%
18 54%
O
O
O
Br
I
Ph
Ph
Me
N
N
N
O
O
O
O
tBu
tBu
tBu
O
O
21 0%
19 82%
20 74%
18
n-Hex
yield an no O-labeled product was detected by GC-
O
O
O
O
MS analysis (Scheme 7c). This labeling experiment
indicated that the oxidation of aniline moiety mostly
occurred via the action of tert-butylperoxy radical
(tBuOO•) rather than a water attack.[10]
Ph
tBu
N
N
N
O
O
tBu
O
O
O
tBu
a)
Ph
O
22 62%
23 57%
24 52%
p-TsOH
(10 mol%)
N
O
+
1
trace
O
tBu
Scheme 5. Scope of the N-arylpropiolamides in Acid-
Triggered Oxidative Radical Addition – Spirocyclization –
Dearomatization Process
tBuOOH (5 eq.)
TEMPO (2 eq.)
60 ºC, 48 h
N
O
(1 mL)
O
tBu
22[a]
O
(0.2 mmol)
Ph
b)
Ph
p-TsOH
(10 mol%)
CH3/CD3
CH3/CD3
Interestingly, the reaction with N-arylpropiolamides
containing an aniline unit substituted by a para-
methoxy or a para-fluoro group afforded 1 in
moderate yields (Scheme 6). Moreover, the reaction
with substrates bearing a para-chloro or para-bromo
substituent to the amide moiety also give 1, albeit in a
poor yield (16-24%). Whereas, no reaction occurred
with substrates bearing a para-methyl substituent.
We attributed these results to the addition of the tert-
butylperoxy radical to the para-position of the phenyl
group, forming a C–O bond and leading to cleavage
of the C–OMe, or C–X (X = F, Cl, Br) bonds to yield
N
O
tBuOOH (5 eq.)
N
O
60 ºC, 48 h
O
(1 mL)
CH3/CD3
O
(0.2 mmol)
1 KIE = 1.50 - 1.06
O
c)
Ph
Ph
p-TsOH
(10 mol%)
N
O
tBu
tBuOOH (5 eq.)
H218O (1 eq.)
60 ºC, 48 h
N
O
(1 mL)
O
tBu
O
(0.2 mmol)
1 45%
(no 18O)
[a] Observed by GC-MS analysis
4
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
Experimental Section
Scheme 7. Control Experiments
General Procedure for Acid-Triggered Oxidative
Radical Addition Spirocyclization
On the basis of this study and previous reports,[4-11]
a
–
–
plausible mechanism is proposed (Scheme 8). Firstly,
in the presence of a strong acid (p-TsOH), alkenyl
peroxide intermediate B, is formed after addition of
tBuOOH to the ketone and dehydration. Then, the
decomposition of alkenyl peroxide B through
homolytic bond cleavage leads to ketone radical D
and tBuO•, which latter reacts with tBuOOH to give
t-BuOO• and tBuOH.[13a] A subsequent radical
addition of C into the alkyne at the α-position of the
C=O bond of N-arylpropiolamide generates vinyl
radical E, which undergoes an intramolecular radical
cyclization at the ipso-position to give F. F is then
trapped by the tert-butylperoxy radical (tBuOO•) to
afford G. Finally, H undergoes deprotonation and
the elimination of tBuOH to afford the desired
azaspiro-[4.5]trienone derivative and tBuOH.
Dearomatization Process: In an oven-dried 15 mL
Schlenk tube, N, 3-diarylpropiolamide (0.2 mmol, 1.0
equiv.) and TBHP (1 mmol, 5.0 equiv.) (TBHP: 5.5M
in the dodecane solution) were dissolved in degassed
ketone (1 mL). Then, 4-methylbenzenesulfonic acid
(0.02 mmol, 0.1 equiv.) was added under a stream of
argon, and the reaction mixture was stirred at 60 ºC
over 48 h. After evaporation of solvent, the product
was purified using flash column chromatography on
silica gel to afford desired azaspiro[4.5]trienone
products.
Acknowledgements
We acknowledge the China Scholarship Council (CSC) for a
grant to CSW.
a) Generation of Ketone Radical
[H+]
tBu
O
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tBuOOH
O
O
R
tBu
O
R
O
R
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- tBuOH
O
O
R
O
R
O
G
H
Scheme 8. Proposed Mechanism for Acid-Triggered
Oxidative Radical Addition
Dearomatization Process
–
Spirocyclization
–
In summary, we have developed metal-free
conditions for the diflunctionalization of activated
alkynes with ketones. The reaction enables radical
cascade addition – spirocyclization – dearomatization
process initiated by the formation of ketone radicals
formation from ketones and tert-butyl hydroperoxide
under acidic conditions.
reaction give a straightforward access to 3-(2-
oxoalkyl)azaspiro-[4.5]trienones, incorporating
This one-pot cascade
a
spirocycle unit that is a common structural motif in
many natural products and pharmaceuticals.
5
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201801203
Advanced Synthesis & Catalysis
COMMUNICATION
Access to 3-(2-Oxoalkyl)-azaspiro[4.5]trienones
via Acid-Triggered Oxidative Cascade Addition –
Spirocyclization – Dearomatization Process
through Alkenyl Peroxide Intermediate
Adv. Synth. Catal. Year, Volume, Page – Page
C.-S. Wang, T. Roisnel, P. H. Dixneuf and J.-F.
Soulé*
7
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