Metal-free spirocyclization of N-arylpropiolamides with glyoxylic acids: Access to complex azaspiro-fused tricycles

Article abstract of DOI:10.1039/d0cc04800c

A metal-free oxidative cascade acylation and dearomatization of N-(p-methoxyaryl)propiolamides was achieved via K2S2O8 mediated decarboxylation of a-oxocarboxylic acids under operationally simple conditions to access azaspiro[4,5]-trienones in good to excellent yields. Furthermore, the utility of the protocol was illustrated in a one-pot reaction sequence consisting of Ugi-reaction/spirocyclization/ aza-Michael transformation for the construction of complex tricyclic cores having quaternary spirocenters.

Full text of DOI:10.1039/d0cc04800c

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DOI: 10.1039/D0CC04800C
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Metal-free Spirocyclization of N-Arylpropiolamides with Glyoxylic
Acids: Access to Complex Azaspiro-fused Tricycles
Received 00th January
20xx,
Akshay M. Nair, Anand H. Shinde, Shreemoyee Kumar, Chandra M. R. Volla*a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract:
A
metal-free oxidative cascade acylation and have been employed in a variety of elegant alkyne addition-
dearomatization of N-(p-methoxyaryl)propiolamides was achieved cyclization cascades.7 However these protocols suffer from the
via K2S2O8 mediated decarboxylation of -oxocarboxylic acids requirement of expensive and non-sustainable silver catalysts,
under operationally simple conditions to access azaspiro[4,5]- thereby limiting their large scale applications. In the recent
trienones in good to excellent yields. Furthermore, the utility of the years, K2S2O8 has emanated as a cheap, non-toxic and readily
protocol was illustrated in a one-pot reaction sequence consisting available oxidant for carrying out a plethora of C−C and C−X
of Ugi-reaction/spirocyclization/aza-Michael transformation for bond forming reaction.8 In this regard, metal-free generation of
the construction of complex tricyclic cores having quaternary acyl radicals via persulfate mediated decarboxylation of a-
spirocenters.
oxocarboxylic acid is gaining rapid interest.9 Despite these
elegant reports, metal free decarboxylative ipso-
spirocyclization with glyoxylic acids to access azaspiro-
[4,5]trienones remains yet elusive.10 Recently, we
Functionalized spirocyclohexadienones have drawn much
attention recently because of their excellent biological activities
and their widespread applications in the synthesis of complex
molecular frameworks.1 Consequently, there is a growing
demand for developing new methods for the construction of
these spirocycles. Dearomatization of easily available phenol
derivatives and transition-metal catalysed intramolecular
nucleophilic ipso-carbocyclization of alkenes/alkynes were
found to be versatile strategies for the generation of
spirocyclohexadienone system.2,3 Furthermore, cascade ipso-
spirocyclization of N-arylpropiolamides involving either
electrophilic activation4 or radical addition5 have emerged as
fascinating synthetic protocols for constructing functionalized
azaspiro[4,5]-trienones. Following these strategies, a variety of
functional groups were introduced onto the azaspiro[4,5]-
trienone framework.
demonstrated
a metal free sulfonylative spirocyclization
strategy towards sulfonylated azaspiro-[4,5]trienones.5n In
continuation of this interest, herein we report an efficient
metal-free, and facile route towards acylated azaspiro-
[4,5]trienones via a persulfate mediated decarboxylative ipso-
spirocyclization of N-arylpropiolamides with aryl glyoxylic acids.
The strategy was further illustrated in a one-pot reaction
sequence consisting of Ugi-reaction/spirocyclization/aza-
Michael reaction for the synthesis of complex acylated azaspiro
tricycles (Scheme 1b).
a) Metal-free decarboxylative spirocyclization
Ar'
O
Ar'
O
O
Ar
MeO
HO
K2S2O8
+
Ar
N
O
R
N
R
O
O
Of late, a-oxocarboxylic acids (glyoxylic acids) being widely
abundant and non-toxic, were extensively utilized as
environmentally benign acyl surrogates.6 Acyl radicals
generated by silver catalysed decarboxylation of glyoxylic acids
Facile
Upto 89%
Metal free
b) One-pot route towards acylated azaspiro tricycles
O
O
OMe
R
O
HO
Ar
R'
H2N
O
Ph
O
HN
K2S2O8
CO2H
N
Me
Me
NC
O
Ar
Ph
R
R'
O
Me
Upto 78%
6-New bonds
Quick & facile access to molecular complexity
aDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-
400076, India. E-mail: chandra.volla@chem.iitb.ac.in
Scheme 1: Overview of the work
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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We commenced our investigation with N-(4-methoxyphenyl)-N- electron-donating or electron-withdrawing groups in the ortho, meta
View Article Online
DOI: 10.1039/D0CC04800C
methyl-3-phenylpropiolamide 1a and phenylglyoxylic acid 2a as or para-positions of the aryl ring were well tolerated, generating the
the model substrates. Initially, the reaction was carried out corresponding products 3b-3k in good yields (67-88%). Strong
using 20 mol% of AgNO3 as a catalyst in 1:1 mixture of acetone electron-withdrawing NO2 group failed to give the desired product
and water at 80 oC employing K2S2O8 as the stoichiometric 3h. Captivatingly, benzodioxolone, 1-napthyl as well as 2-napthyl
oxidant and we were delighted to observe the formation of glyoxylic acids reacted smoothly with 1a delivering the respective
target spiro[4,5]-trienone 3a in 28% NMR yield within 12 h spirocyclic trienones 3l, 3m and 3n in good yields (80, 75 and 78%).
(entry 1). To evaluate the roles of the silver salt and the oxidant,
Table 2. Scope of the decarboxylative ipso-spirocyclization.a
initial control experiments were carried out. While in the
absence of K2S2O8, as expected no reaction was observed (entry
2). Interestingly, the control experiment without AgNO3
afforded 3a in a much better yield of 43% (entry 3). Encouraged
by this, various parameters like solvents, concentration and
temperature were screened to improve the yield. As evident
from entries 4-7, other solvents led to inferior yields. Increasing
the amount of the oxidant K2S2O8 led to slightly improved yields
of 52% (3.0 equiv.) and 48% (4.0 equiv.) (entries 8-9). When the
reaction was carried out at 100 oC using 3.0 equiv. of K2S2O8, 3a
was observed in 63% yield (entry 10). Further increasing the
temperature to 120 oC drastically improved the reaction
efficiency and the product 3a was formed in 91% NMR yield
(89% isolated) (entry 11). Reduction of the stoichiometry of 2a
and use of other oxidants like (NH4)2S2O8, Na2S2O8 or oxone
instead of K2S2O8 led to inferior yields (entries 12-15).
Ar
O
Ar
O
MeO
O
K2S2O8 (3 eq.)
HO
+
Ar'
Acetone: H2O (1:1)
N
R
O
N
3
Ar'
O
120 o
C
R
O
2
1
O
Ph
H, 3a, 89% (87%)b
Me, 3b, 86%
Ph, 3c, 88%
O
Ph
F, 3e, 81%
Cl, 3f, 83%
Br, 3g, 82%
O
O
OMe
N
N
NO2, 3h, Traces
Me
OMe, 3d, 85%
O
Me
O
R
3i, 67%
3a-3h
Ph
O
O
Ph
O
Ph
O
O
O
Cl
N
N
O
N
Me
Me
O
O
Me
F
O
O
Cl
3j, 79%
3k, 84%
3l, 80%
O
O
O
Ph
O
O
Ph
Ph
O
O
O
N
N
N
R
Me
Me
O
O
O
Table 1. Optimization of reaction conditions.a
Bn, 3o, 79%
Ac, 3p, Traces
H, 3q, Traces
Ph
3m, 75%
3n, 78%
O
Ph
O
O
MeO
O
R
Cl
HO
Oxidant (2 equiv.)
+
O
Ph
O
Ph
R
O
Ph
O
N
O
Solvent,
temp, overnight
N
Ph
O
O
Me
Me
1a
O
N
2a
3a
Me
N
N
Me
Me
O
Sr.no
Cat.
Oxidant
Solvent
Temp
(oC)
80
Yield
(%)b
28
O
R= Me, 3u, 82%
OMe, 3v, 79%
R= 4-Me, 3r, 86%
4-Cl, 3s, 80%
3-CF3, 3t, 79%
3w, 81%
1
2
AgNO3
K2S2O8
-
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
DMF:H2O (1:1)
OMe
AgNO3
80
ND
OMe
Ph
H
O
O
O
Ph
O
3
-
-
-
-
-
-
-
-
-
-
-
-
-
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
80
43
O
N
Cl
MeO
4
80
16
N
Me
N
O
Me
Me
O
O
5
DCM:H2O (1:1)
80
Traces
38
3x, 78%
3y, 84%
3z, Traces
6
MeCN:H2O (1:1)
THF:H2O (1:1)
80
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol, 2 equiv.), K2S2O8 (3 equiv.),
120 oC, 12 h. bIsolated yield from 1.0 g (3.8 mmol) of 1a.
7
80
7
52c
48d
63c
91 (89)c,e
70f
68c
74c
32c
8
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
Acetone:H2O (1:1)
80
9
80
Subsequently, we turned our attention to explore the scope of
various N-(p-methoxyaryl)propiolamides 1 against phenylglyoxylic
acid 2a. Initially the effect of protecting group on the nitrogen atom
of 1 was investigated. While N-benzyl protection on nitrogen atom
delivered the desired product 3o in 79%, reaction of 2a with
substrate having the N-acyl or free N-H groups met with no success
(3p and 3q). We then explored the effect of substituent on the
aromatic ring of the internal alkyne and were pleased to find that
methyl, chloro and trifluoromethyl substituted arylalkynes provided
the desired products 3r-3t in good yields. Substrates bearing o-
methyl, o-methoxy, or m-chloro on the aromatic ring of N-aryl moiety
also reacted smoothly with 2a and afforded the corresponding
products in good yields 3u-w (79-82 %). Moreover, trisubstituted N-
arylalkynamides (one methoxy and one chloro or two methoxy
groups) were also found to be consistent with the optimal conditions
3x & 3y. The terminal alkyne bearing N-arylpropiolamide failed to
10
11
12
13
14
15
100
120
120
120
120
120
(NH4)2S2O8
Na2S2O8
Oxone
Reaction conditions: a) unless mentioned, 1a (0.2 mmol), 2a (0.4
mmol, 2 equiv.), AgNO3 (20 mol%), K2S2O8 (2 equiv.). b) Yield based
on 1H NMR using 1,3,5-trimethoxybenzene as internal standard. c)
3.0 equiv. of K2S2O8. d) 4.0 equiv. of K2S2O8. e) Yield in parenthesis
refers to isolated yield after column chromatography. f) 1.5 equiv.
of 2a.
Having the optimized reaction conditions in hand, the scope and
limitation of this strategy were studied with 1a against a variety of
arylglyoxylic acids (Table 2). Arylglyoxylic acids bearing either
2 | J. Name., 2012, 00, 1-3
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deliver the corresponding product 3z. To our delight the reaction was treated with acid in DCE and heated to 60 oC. We wVeierweAdreticlliegOhntleinde
DOI: 10.1039/D0CC04800C
found to be scalable where in 1 g of 1a yielded 1.12 g of 3a in 87%.
to observe the formation of the desired acylated tricycle 8a in
75% as a single diastereomer, significantly increasing the value
of the protocol. Indeed, high diastereoselectivities were also
observed in related acid-catalyzed cyclization reported by
Srivastava and co-workers and the stereochemical assignment
of azaspiro tricycles 8 was done in analogy with the results of
Srivastava and co-workers.12 Remarkably, the overall sequence
consists of formation of six new bonds and three stereocenters.
Various benzaldehydes 5 were compatible with the one-pot
sequence 8b & 8c. To our delight, we found that aldehydes
could be replaced with ketones, wherein acetone was also
found to be viable furnishing 8d in 71%. Pleasingly,
cyclopentanone and 4-ethyl cyclohexanone delivered the
corresponding tetracyclic bis-spiro derivatives 8e-g in good
yields. Substituted glyoxylic acids 2 furnished the corresponding
products in moderate to good yields 8h-8j. Pleasingly, 3,4,5-
trimethoxyaniline 4 and 3,4,5-trimethoxy benzaldehyde 5 were
found to be compatible in the sequence affording the complex
well functionalized derivatives 8k in 61% (5:1 dr).
Table 3: One pot synthesis of acylated tricyclic azaspirotrienones.
O
OMe
R
O
DCE
1).
rt, overnight
R'
5
2).
Ph
H2N
2 (2 eq.)
O
HN
4
6
K2S2O8 (3.0 eq.)
Acetone/ H2O (1:1)
N
CO2H
O
Me
Me
NC
120 o
C
R
8
R'
O
Ar
Ph
Me
3). H2SO4 (2.0 eq.)
7
DCE, 60 o
C
3rd step
1st step
O
N
OMe
Me
Me
Me
Me
2nd step
Me
Me
Ph
O
NH
NH
Ph
N
O
O
R
R'
Ar
O
R
R'
O
B
A
O
O
O
Ph
Ph
O
O
HN
HN
Ph
O
HN
N
N
O
O
N
O
O
O
Me Me
O
S
H, 8a, 75%
Cl, 8b, 75%
R=
8d, 71%
8c, 70%
R
O
O
O
a) Radical quenching experiment
Ph
O
Ph
O
Ph
Ph
Ph
O
O
O
O
HN
HN
MeO
K2S2O8 (3 eq.)
HN
O
HO
+
N
N
N
Acetone: H2O (1:1)
N
O
O
O
120 o
C
N
O
Me
O
O
O
O
2a
Me
TEMPO (2 eq.)
3a (Traces)
1a
Me
R
Et
(b) Investigation of other leaving groups
R= H, 8e, 78%
Me, 8f, 73%
8h, 72%
8g, 75%
Ph
O
Ph
O
O
K2S2O8 (3 eq.)
R
HO
O
O
O
Acetone: H2O (1:1)
120 o
MeO
OMe
Ph
N
O
C
N
O
Me
O
Me
R = F (57%)
SMe (82%)
Me (Traces)
H (52%)
3a
O
Ph
Ph
O
HN
O
1
2a
O
HN
O
HN
N
O
F
N
N
(c) Studies with heavy water
Ph
O
18
O
O
O
Ph
O
O
MeO
K2S2O8 (3 eq.)
MeO
OMe
HO
Cl
+
Acetone: H2O18 (1:1)
OMe
8k, 61% (5:1 dr)
8i, 69%
N
8j, 58%
O
120 o
C
N
O
Me
O
Me
(82%)
2a
3a-O18
1a
Reaction conditions: 1) 4 (0.1 mmol), 5 (0.1 mmol), 6 (0.1 mmol), 7 (0.1
mmol), DCE, rt. 12 h. 2) 2 (0.2 mmol), K2S2O8 (0.3 mmol), Acetone:H2O (1:1),
120 oC, 12 h. 3) H2SO4 (0.2 mmol), DCE, 60 oC, 6 h.
Scheme 2. Preliminary mechanistic studies.
In order to gain some insights on the mechanism of the reaction,
preliminary studies were carried out. Addition of a radical
scavenger like 2,2,6,6-tetrametyl-1-piperidinyloxy (TEMPO) in
2.0 equiv. was found to inhibit the reaction indicating that the
cascade acylation might proceed via a radical pathway.
Interestingly, under the optimized conditions, p-fluoro
substituted N-phenylpropiolamide gave the desired 3-acyl
azaspiro[4,5]-trienone 3a in 57% yield while methylmercapto
substitution led to the formation of 3a in 82%. Furthermore,
unsubstituted N-phenylpropiolamide also furnished 3a, albeit in
lower yield (52%). No product formation was observed with the
p-methyl derivative. Since p-methoxy, p-fluoro, p-
methylmercapto and unsubstituted N-phenylpropiolamides
were able to deliver the spirotrienone 3a, we sought to explore
the source of oxygen atom of the newly formed carbonyl group
by O18-labelling experiment. Using a mixture of acetone and
H2O18 (1:1) as a solvent, spirotrienone 3a-O18 containing
predominantly O18 was obtained in 82% NMR yield. These
findings suggest that new carbonyl oxygen originates from
water.
Azaspiro-fused tricyclic motifs form the core of a variety of
medicinally active naturally occurring alkaloids like,
cylindricines C, lepadiformine, and fasicularin.11 To broaden the
utility of the developed protocol, we envisaged to gain facile
access to novel acylated azaspiro-fused tricyclic skeletons in a
one-pot
manner
employing
the
decarboxylative
spirocyclization. We envisioned that a four-component Ugi
reaction of p-methoxy aniline 4, carbonyl compounds 5,
phenylpropiolic acid 6 and tert-butyl isonitrile 7 would furnish
the propiolamide A, which would be similar to propiolamide 1
and poised to undergo metal free decarboxylative ipso-
cyclization providing the key intermediate B, which on acid
mediated aza-Michael addition would furnish novel acylated
tricycles 8 having quaternary spirocenters. To realize the same
aniline 4 was reacted with benzaldehyde 5a, propiolic acid 6 and
t-Bu isonitrile 7 in DCE over night after which the solvent was
evaporated and the crude mixture was then subjected to our
optimized conditions with the glyoxylic acid 2a. Following this
the solvents were removed again and the crude mixture was
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2. (a) D. Magdziak, S. J. Meek and T. R. R. Pettus, Chem. Rev. 2004, 104,
A plausible mechanism for the metal-free acylation ipso-
cyclization was proposed based on the previous reports and
control experiments (Scheme 3).9 Homolytic cleavage of
persulfate under thermal condition produces the reactive
sulfate radical anion intermediate A. Single electron oxidation
of glyoxylic acid 2 by A generates acyl radical B after extrusion
of carbon dioxide. The acyl radical B reacts with the
propiolamide 1 generating the radical intermediate C, which on
ipso-spirocyclization would form intermediate D. The radical
intermediate D is oxidized by a second sulfate radical anion to
generate intermediate E. Nucleophilic attack of water and
subsequent hydrolysis of the hemiketal furnishes the acylated
azaspiro-[4,5]trienone 3 via the intermediate F.
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4, 350; (j) H.-L. Hua, Y.-T. He, Y.-F. Qiu, Y.-X. Li, B. Song, P. Gao, X.-R.
Song, D.-H. Guo, X.-Y. Liu and Y.-M. Liang, Chem. Eur. J., 2015, 21, 1468;
(k) W.-T. Wei, R.-J. Song, X.-H. Ouyang, Y. Li, H.-B. Li and J.-H. Li, Org.
Chem. Front., 2014, 1, 484; (l) X.-H. Ouyang, R.-J. Song, B. Liu and J.-H.
Li, Chem. Commun., 2016, 52, 2573; (m) W. Wei, H.-H. Cui, D.-S. Yang,
H.-L. Yue, C.-L. He, Y.-L. Zhang and H. Wang, Green Chem., 2017, 19,
5608; (n) A. M. Nair, I. Halder, S. Khan and C. M. R. Volla, Adv. Synth.
Catal., 2020, 362, 224.
O
S
2-
Ph
O
SO4
MeO
Ph
O
O
MeO
O
Ar
O
+
O
A
O
1
Ar
N
Ar
N
O
Me
O
Me
C
B
OH
D
O
S
Ar
Spirocyclization
CO2
O
O
A
O
2
O
Generation of acyl radical
2-
SO4
MeO
O
Ph
O
Ph
MeO
H2O
Ph
HO
O
O
N
Ar
N
Ar
N
Ar
Me
O
Me
Me
O
O
3
F
E
Scheme 3. Proposed mechanism.
Conclusions
In summary, a simple and versatile strategy for furnishing a
wide variety of acylated azaspiro[4,5]-trienones from N-
arylpropiolamides and -oxocarboxylic acids has been
developed under operationally simple conditions. This
methodology offers a concise approach to this class of
molecules under metal-free conditions and requires
inexpensive and readily available K2S2O8 as oxidant. Additionally
complex tricyclic spirocycles were synthesized efficiently in a
single pot by extension of the protocol. Preliminary mechanistic
studies indicated that the cascade cyclization proceeds via a
radical pathway and the oxygen atom of the newly formed
carbonyl group originates from water.
6. F. Penteado, E. F. Lopes, D. Alves, G. Perin, R. G. Jacob and E. J. Lenardão,
Chem. Rev., 2019, 119, 7113.
7. (a) C. R. Reddy, R. C. Kajare and N. Punna, N. Chem. Commun. 2020, 56,
3445; (b) M. Meng, G. Wang, L. Yang, K. Cheng, and C. Qi, Adv. Synth.
Catal. 2018, 360, 1218; (c) W.-C. Yang, P. Dai, K. Luo, Y.-G. Ji, and L. Wu,
Adv. Synth. Catal. 2017, 359, 2390. (d) K. Yan, D. Yang, W. Wei, F. Wang,
Y. Shuai, Q .Li, and H. Wang, J. Org. Chem. 2015, 80, 1550. (e) T. Liu, Q.
Ding, Q. Zong and G. Qiu, Org. Chem. Front. 2015, 2, 670.
Conflicts of interest
There are no conflicts to declare.
8. S. Mandal, T. Bera, G. Dubey, J. Saha and J. K. Laha, ACS Catal., 2018, 8,
5085.
9. (a) H. Wang, L.-N. Guo, S. Wang and X.-H. Duan, Org. Lett., 2015, 17,
3054; (b) J. K. Laha and K. V. Patel, Chem. Commun., 2016, 52, 10245–
10248; (c) J. K. Laha, M. K. Hunjan, S. Hegde and A. Gupta, Org. Lett.,
2020, 22, 1442.
Acknowledgements
This activity is supported by Department of Science and Technology,
Government of India (TMD/CERI/BEE/2016/098). A.H.S. thanks IIT
Bombay and S.K. thanks University Grants Commission (U.G.C.) for
the fellowship.
10. During the submission of this manuscript, Reddy and co-workers
reported
a silver-catalyzed decarboxylative ipso-cyclization of N-
arylpropiolamides using glyoxylic acids: C. R. Reddy, D. H. Kolgave, M.
Subbarao, M. Aila and S. K. Prajapti, Org. Lett., 2020, 22, 5342.
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Aoyagi, C. Kibayashi and K. S. Gates, J. Am. Chem. Soc., 2005, 127, 15004;
(c) H. Abe, S. Aoyagi, and C. Kibayashi, J. Am. Chem. Soc., 2000, 122,
4583.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04800C
TOC Graphic
Metal-free Spirocyclization of N-Arylpropiolamides with Glyoxylic Acids: Access to Complex
Azaspiro-fused Tricycles
A. M. Nair, A. H. Shinde, S. Kumar, C. M. R. Volla*
An efficient K2S2O8-mediated oxidative cascade spirocyclization of N-arylpropiolamides with aryl glyoxylic
acids was demonstrated for constructing azaspiro[4,5]-trienones and complex azaspiro-fused
architectures.
Ar'
O
N
Ar'
O
O
O
O
MeO
HO
K2S2O8
+
Ar
Ph
N
Ar
O
HN
O
R
N
R
O
O
CO2
Ph
Upto 89%
O
>
Metal free > Good to excellent yields > Broad substrate scope
> Six new bonds in
one-pot
> Scalable
> Opeationally facile > Cheap and easily available oxidant