Dimethyl Sulfoxide and N-Iodosuccinimide Promoted 5-exo-dig Oxidative Cyclization of Yne-Tethered Ynamide: Access to Pyrrolidones and Spiro-pyrrolidones

Article abstract of DOI:10.1021/acs.orglett.6b01149

An unprecedented metal-free dimethyl sulfoxide (DMSO) and N-iodosuccinimide mediated regioselective 5-exo-dig oxidative cyclization of an in situ generated enol equivalent of amides from ynamides bearing internal alkynes is demonstrated. The reaction allows easy access to functionalized pyrrolidone skeletons. Pyrrolidones having 3-o-biaryl motifs successfully undergo intramolecular electrophilic cyclization with the α,β-unsaturated olefin, furnishing spiro-pyrrolidone motifs. A one-pot sequential 5-exo-dig cyclization of the yne-tethered ynamides, followed by electrophilic cyclization of the pyrrolidone, is presented. The role of DMSO in the transformation is clarified, and a tentative reaction pathway is proposed.

Full text of DOI:10.1021/acs.orglett.6b01149

Letter
pubs.acs.org/OrgLett
Dimethyl Sulfoxide and N‑Iodosuccinimide Promoted 5-exo-dig
Oxidative Cyclization of Yne-Tethered Ynamide: Access to
Pyrrolidones and Spiro-pyrrolidones
B. Prabagar, Sanatan Nayak, Rangu Prasad, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: An unprecedented metal-free dimethyl sulfoxide (DMSO)
and N-iodosuccinimide mediated regioselective 5-exo-dig oxidative
cyclization of an in situ generated enol equivalent of amides from
ynamides bearing internal alkynes is demonstrated. The reaction allows
easy access to functionalized pyrrolidone skeletons. Pyrrolidones having
3-o-biaryl motifs successfully undergo intramolecular electrophilic
cyclization with the α,β-unsaturated olefin, furnishing spiro-pyrrolidone
motifs. A one-pot sequential 5-exo-dig cyclization of the yne-tethered ynamides, followed by electrophilic cyclization of the
pyrrolidone, is presented. The role of DMSO in the transformation is clarified, and a tentative reaction pathway is proposed.
Scheme 1. Enol Equivalent for Regioselective Cyclization
yrrolidone derivatives are useful building blocks in organic
synthesis, as these motifs are widely distributed in the
P
molecules that show promising antimicrobial, antifungal, anti-
tumor, and antituberculosis activity (Figure 1).1 Furthermore,
Figure 1. Pyrrolidone derivatives containing natural products.
analogous to spiro-N-heterocycles, spiro-pyrrolidone scaffolds
would show superior biological activity.2 Ynamides, the nitrogen-
substituted alkynes, are versatile scaffolds extensively used in the
design and development of novel synthetic transformations.3
They are also used in the preparation of complex N-heterocycles
as well as highly reactive intermediates that are inaccessible by
conventional syntheses.4 In particular, cyclization and cyclo-
isomerization of yne-tethered ynamides would allow for the
construction of a novel molecular framework.5 However, the
6-endo-dig cyclization of yne−ynamide motifs readily afford
6-membered N-heterocycles, while the 5-exo-dig mode cycliza-
tion to yield pyrrolidine scaffolds remains elusive. Given the
aforementioned significance of pyrrolidones and ynamides, the
development of efficient and reliable synthetic routes to highly
functionalized pyrrolidone derivatives from readily accessible
ynamides is desirable.
benzo[f]dihydroisoquinolone frameworks (Scheme 1A, D).5b,c
At this conjecture, we envision to explore the 5-exo-dig oxidative
cyclization of inherently polarized ynamide motifs with a tethered
alkyne to build the pyrrolidone skeleton under metal-free condi-
tions (Scheme 1B). To the best of our knowledge, no such
transformations of yne−ynamides are so far known. A recent
report on the synthesis of pyrrolidone discusses the oxidative
cycloisomerization of Rh(I) carbene, generated from a ynamide
in the presence of pyridine N-oxide and a Rh catalyst, with the
internal alkyne.7 We could therefore visualize 5-exo-dig cyclization
of the ketene N,O-acetal of TS-I, attained through the preferential
attack of polarizable DMSO/N,N-dimethylformamide (DMF)
The preformed enol ethers successfully undergo exo- and endo-
cyclization with tethered alkyne motifs under the influence of metal
catalysis (Scheme 1A, C).6 Interestingly, the p-toluenesulfonic
acid (p-TsOH) promoted Au(I)-catalyzed 6-endo-dig cyclization
of the in situ generated enol equivalent of amides from ynamides
with an internal yne moiety affords novel dihydropyridinone and
Received: April 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01149
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Organic Letters
Letter
on the NIS-activated ynamide,8 with the alkyne motif followed
by oxidation to give pyrrolidone in a single step.9 The steric features
of TS-II would probably rule out the possibility of participation
of the 6-endo-dig cyclization.10 We herein demonstrate a unified
metal-free method for the construction of pyrrolidones and
spiro-pyrrolidones from easily accessible and stable yne-tethered
ynamides at room temperature.
a,b
Scheme 2. Synthesis of Pyrrolidones: Substrate Scope I
To search for the possibility of the projected transformation in
Scheme 1B, investigations were attempted to establish 5-exo-dig
cyclization of 1,5-yne−ynamide 1a to yield 2a (Table 1).
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
“O” source
(2.0 equiv)
electrophile
(2.0 equiv)
a
entry
solvent
2a
2a′
Reactions were carried out using 1 (0.5 mmol), NIS (1.0 mmol), and
DMSO (1.0 mmol) in dioxane (3.0 mL) at rt for 4 h. Isolated yields.
b
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMF
NIS
NCS
NBS
NIS
NIS
NIS
NIS
I2
ClCH2CH2Cl
dioxane
dioxane
dioxane
dioxane
acetone
THF
35
60
40
50
15
92
72
30
25
75
35
ynamide 1f reacted smoothly to yield 2f with a modifiable formyl
moiety on the periphery of the pyrrolidone skeleton. The
o-Br-substituted aryl moiety in the ynamide terminus of 1g did
not affect the reaction efficiency, manufacturing 2g (78%).
Cyclization of 1h (electron-donating and electron-withdrawing
groups bearing aryl moieties on the propargyl and ynamide
terminus, respectively) yielded 2h (83%). Pleasingly, a thiophene-
bearing ynamide 1i effectively underwent cyclization to provide 2i
in high yield. Cyclization of 1 having aliphatic substitution at the
ynamide terminus was next probed. The 3-cyclopropyl 2j (77%)
and 3-butyl-substituted pyrrolidone 2k (79%) were constructed;
the labile cyclopropyl group survived. The pyrrolidone 2l (75%),
having an easily removable NMs moiety, was also prepared. Thus,
stereoelectronic factors at the propargyl and ynamide terminus
of 1 did not show a pronounced impact on the current 5-exo-dig
cyclization of 1, constructing wide arrays of pyrrolidone motifs
in appreciable yields. The robustness of this reaction is validated
through gram-scale reaction of 1a and 1f for the synthesis of 2a
(890 mg, 82%) and 2f (800 mg, 72%), respectively (Scheme 3).
DMF
65
60
20
65
DMF
DMSO
DMSO
DMSO
DMSO
acetone
H2O
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
ICl
c
d
10
Au(I)
e
11
CF3COOAg
NIS
12
13
75
70
NIS
20
a
Reactions were carried out using 1a (0.5 mmol), electrophiles
(1.0 mmol), and O-source (1.0 mmol) in solvent (3.0 mL) at rt for 4 h.
Isolated yields. Complex mixture. XPhosAu(MeCN)SbF6. Unreacted
b
c
d
e
starting material.
To begin, compound 1a was exposed to NIS (2.0 equiv) in the
presence of DMSO (2.0 equiv) in 1,2-dichloroethane (DCE) at
rt. Gratifyingly, the desired 2-pyrrolidone 2a (35%) was obtained
along with 60% monohydration product 2a′ (entry 1). The other
promoters N-chlorosuccinimide (NCS)/N-bromosuccinimide
(NBS) were ineffective (entries 2 and 3). To our delight, 2a
(92%) was exclusively obtained when the reaction was performed
in dioxane at rt (entry 4). DMF also served as a good nucleophile;
however, it provided inferior results (entries 5−7). Iodine
and ICl were also suitable promoters to produce 2a and 2a′
(entries 8 and 9). In contrast, the effective Au(I) and CF3CO2Ag
agents arbitrarily failed (entries 10 and 11). The combinations of
acetone and NIS or water and NIS were not suitable, producing
major amounts of 2a′ (entries 12 and 13). It appears that DMSO
serves as an effective nucleophile in this reaction.
We next surveyed the scope of the 5-exo-dig cyclization of yne-
tethered ynamides 1 for the synthesis of pyrrolidone derivatives
under the optimal reaction conditions in entry 4, Table 1; the
results were detailed in Scheme 2. The compound 1a (0.5 mmol)
readily provided 92% of 2a. The cyclization of 1 having o-Me-,
m-formyl-, or m,p-di-Cl-substituted aryl moieties in the propargyl
terminus reacted efficiently to deliver the desired 2b−d in
excellent yields. Compound 1e with the ethyl group on the
propargyl alkyne terminus was also suitable, constructing 81%
of 2e. Notably, the unsubstituted propargylalkyne terminus
Scheme 3. Gram-Scale Synthesis of 2a and 2f
The olefin in the 3-aryl-substituted pyrrolidone skeleton in
Scheme 2 serves as a Michael acceptor. We speculate that
a 3-biaryl-bearing pyrrolidone would undergo electrophilic
cyclization with the α,β-unsaturated ketone to afford spiro-
pyrrolidones.11 We thus consider introducing an o-biaryl moiety
in the pyrrolidone periphery and examine the electrophilic
cyclization reaction. Accordingly, we tested the NIS-mediated
cyclization of yne-tethered ynamide derivatives 3 having a biaryl
group at the ynamide terminus (Scheme 4). The reaction of 3a
under the optimized conditions (entry 4, Table 1) led to 4a in
excellent yield. X-ray crystallographic analysis data established the
structure of 4a.12 Similarly, the 2-naphthyl-bearing pyrrolidone
derivative 4b was accessed in 82% yield. Electron-donating and
electron-withdrawing groups on the biphenyl ring did not affect
B
DOI: 10.1021/acs.orglett.6b01149
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Organic Letters
Letter
a,b
Screening of various Lewis and Brønsted acids for the electro-
philic cyclization of 4a led to the optimized conditions [TfOH in
CH2Cl2 at rt], affording the unusual spiro-pyrrolidone derivative
5a in 88% yield. Likewise, 4f was readily transformed to 5b
(81%). Interestingly, the reaction of 4a with TfOH (10 equiv) at
rt for 15 h or TfOH (5.0 equiv) at 70 °C for 7 h gave N-Ts-
deprotected spirocylic product 6a in good yield. The structure of
6a was elucidated by X-ray analysis (Scheme 5).12 Similarly, com-
pound 6b (76%) was obtained from 4k. Thus, the current method
allows easy access to build fluorene (spiro-pyrrolidone) scaffolds.
We next performed a one-pot DMSO- and NIS-promoted
5-exo-dig cyclization of 3k followed by the TfOH-assisted electro-
philiccyclization of 4k; surprisingly, a dehydrogenative spirocyclic
product 7 was obtained in 81% yield (Scheme 6). We believe the
Scheme 4. Synthesis of Pyrrolidones: Substrate Scope II
Scheme 6. One-Pot 5-Exo-Dig and Spiro-cyclization of 3k
TfOH-mediated cyclization of 4k in the presence of unreacted
NIS would produce 4-iodospiro-pyrrolidone, which subsequently
undergoes dehydrohalogenation to form 7,13 whereas the
reaction of 5a/6a with NIS and TfOH failed to deliver the
corresponding dehydrgenative spirocyclic product.
To acquire preliminary insight into the mechanism, 1a
was exposed to the optimized conditions in the presence of
18O-DMSO;13a gratifyingly, we observed the formation of
18O-labeled pyrrolidone 2a-18O (confirmed by HRMS)
(Scheme 7).12 By contrast, under the standard conditions,
a
Reactions were carried out using 3a (0.5 mmol), NIS (1.0 mmol), and
b
DMSO (1.0 mmol) in dioxane (3.0 mL) at rt for 4 h. Isolated yields.
the reaction, providing 4c (85%) and 4d (76%). Likewise, pre-
cursors 3e−k (with different aryl and o-biphenyl at the propargyl
and ynamide terminus, respectively) fruitfully underwent
cyclization to deliver the corresponding products 4e−k; formyl,
CF3, F, keto, and Br were compactible. The naphthyl moiety on
the propargyl terminus did not show adverse effects, furnishing
4l (85%). Gratifyingly, heteroaryl-substituted 3-biphenyl-
bearing pyrrolidones 4m (79%) and 4n (72%) were effectively
constructed.
Scheme 7. Mechanistic Investigations
With the 3-o-biaryl-molded pyrrolidone skeletons 4 in hand,
we then performed the acid-mediated electrophilic cyclization of
the aryl motif with the unsaturated ketone in 4 (Scheme 5).11c
a,b
Scheme 5. Synthesis of Spiro-pyrrolidone Derivatives
ynamide 8 without a pendant alkyne exclusively furnished the
corresponding α-keto amide 8” (Scheme 7).8 The α-keto amide
is possibly formed by β-iodination of the ynamide, followed by the
attack of DMSO at the α-position of the transient keteniminium
species, and finally through enolization, iodination, and oxidation
(Scheme 7).13b−d,14 We therefore believe that the reaction
involves a ketene N,O-acetal obtained in situ by the nucleophilic
attack of DMSO to the β-iodoketeniminium species.
Although the mechanism of this cyclization is not yet fully
known, a tentative mechanism is proposed on the basis of the
above-mentioned results (Scheme 8). The reaction begins with
the attack of DMSO onto the transient ketiniminium species I,
obtained from the ynamide and NIS, to deliver ketene N,O-acetal
II,8 which undergoes SN2-type 5-exo-dig cyclization with the
NIS-activated tethered alkyne to give III.15 TS-I preferably
participates in the cyclization favoring the 5-exo mode attack
over the conformationally unfavorable 6-endo-attack in TS II.16
Expulsion of the allylic iodo group via attack of DMSO to the
exocylic double bond then generates IV. Finally, iodide-mediated
a
Reactions were carried out using 4 (0.3 mmol) and TfOH (1.5 mmol)
b
c
in CH2Cl2 (2.0 mL) at rt for 7 h. Isolated yields. TfOH (3.0 mmol)
at rt for 15 h. TfOH (1.5 mmol) at 70 °C for 7 h.
d
C
DOI: 10.1021/acs.orglett.6b01149
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Organic Letters
Letter
(b) Theunissen, C.; Met
́
ayer, B.; Henry, N.; Compain, G.; Marrot, J.;
Scheme 8. Plausible Mechanism
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nucleophilic displacement of the S and O bond of IV provides the
desired product.17,18
In conclusion, a metal-free 5-exo-dig cyclization of yne-
tethered ynamides is showcased for the first time; the reaction
has a broad scope, furnishing peripherally decorated pyrrolidone
and spiro-pyrrolidone derivatives. The 5-exo-dig cyclization of
yne-tethered ynamides in the presence of the [DMSO + NIS]
system is notable, as this species preferably undergoes 6-endo-dig
cyclization under Au catalysis. A one-pot synthesis of spiro-
pyrrolidone from the yne-tethered ynamide is also demonstrated.
The cleavage of the N-Ts bond makes this process synthetically
viable and useful.
(12) See the Supporting Information.
(13) (a) Fenselau, A. H.; Moffatt, J. G. J. Am. Chem. Soc. 1966, 88, 1762.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01149.
(14) (a) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.; Yao, P.-
Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780. (b) Al-Rashid, Z. F.;
Hsung, R. P. Org. Lett. 2008, 10, 661. (c) Santos, M. D.; Davies, P. W.
Chem. Commun. 2014, 50, 6001.
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Kirsch, S. F. J. Org. Chem. 2013, 78, 2780. (c) Wang, A.-F.; Zhu, Y.-L.;
Wang, S.-L.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang, B. J. Org. Chem. 2016, 81,
1099.
Experimental details and spectral data (1H, 13C, and 19F)
(PDF)
HRMS data (PDF)
X-ray crystallographic data for 4a (CIF)
X-ray crystallographic data for 6a (CIF)
(16) (a) Xie, Y.-X.; Yan, Z.-Y.; Wang, D.-Z.; Wu, L.-Y.; Qian, B.; Liu,
X.-Y.; Liang, Y.-M. Eur. J. Org. Chem. 2009, 2009, 2283. (b) Schlemmer,
C.; Andernach, L.; Schollmeyer, D.; Straub, B. F.; Opatz, T. J. Org. Chem.
2012, 77, 10118. (c) Santana, A. S.; Carvalho, D. B.; Cassemiro, N. S.;
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G., Jr; Barbosa, S. L.; Dabdoub, M. J.; Baroni, A. C. M. Tetrahedron Lett.
2014, 55, 52.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: akhilchemistry12@gmail.com, akssc@uohyd.ac.in.
Notes
The authors declare no competing financial interest.
(17) (a) Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; Yuan, J.-J.; Gao, Q.-
H.; Wu, A.-X. Chem. Commun. 2012, 48, 9086.
ACKNOWLEDGMENTS
■
(18) For halo-mediated cyclizations, see: (a) Hessian, K. O.; Flynn, B.
L. Org. Lett. 2006, 8, 243. (b) Ali, S.; Zhu, H.-T.; Xia, X.-F.; Ji, K.-G.;
Yang, Y.-F.; Song, X.-R.; Liang, Y.-M. Org. Lett. 2011, 13, 2598.
(c) Mothe, S. R.; Kothandaraman, P.; Rao, W.; Chan, P. W. H. J. Org.
Chem. 2011, 76, 2521. (d) Kothandaraman, P.; Lauw, S. J. L.; Chan, P.
W. H. Tetrahedron 2013, 69, 7471. (e) Kothandaraman, P.; Koh, B. Q.;
Limpanuparb, T.; Hirao, H.; Chan, P. W. H. Chem. - Eur. J. 2013, 19,
1978.
We thank UoH-UPE-II for financial support. P.B., S.N., and R.P.
thank CSIR India for a fellowship. Dr. K. Nagarjuna, UoH, is
thanked for the X-ray crystallographic analysis.
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DOI: 10.1021/acs.orglett.6b01149
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