Access to cyclobutene-fused azepines through au-catalyzed cycloisomerization of stable alkyne tethered ketene N,N -acetals

Article abstract of DOI:10.1021/ol501125r

A base promoted reaction between N-protected propargyl amines and 3-bromopropiolate readily provides an array of novel stable alkyne-tethered ketene N,N-acetals in good yields. A wide range of structurally complex cyclobutene-fused azepine heterocycles are synthesized through the gold-catalyzed intramolecular cycloisomerization of ketene N,N-acetals for the first time. A plausible reaction pathway is deduced on the basis of the ¹H NMR studies.

Full text of DOI:10.1021/ol501125r

Letter
pubs.acs.org/OrgLett
Access to Cyclobutene-Fused Azepines through Au-Catalyzed
Cycloisomerization of Stable Alkyne Tethered Ketene N,N-Acetals
Sanatan Nayak, Nayan Ghosh, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad-500046, India
S
* Supporting Information
ABSTRACT: A base promoted reaction between N-protected
propargyl amines and 3-bromopropiolate readily provides an
array of novel stable alkyne-tethered ketene N,N-acetals in
good yields. A wide range of structurally complex cyclobutene-
fused azepine heterocycles are synthesized through the gold-
catalyzed intramolecular cycloisomerization of ketene N,N-
1
acetals for the first time. A plausible reaction pathway is deduced on the basis of the H NMR studies.
old-catalyzed cycloisomerization has emerged as a
powerful tool for the fabrication of complex cyclic
moieties in the ketene aminal assist in increasing the
nucleophilicity at C-2 due to the inherent delocalization of
the nitrogen lone pair over the double bond. Disappointingly,
the exceptional reactivity of the ketene aminal made its
synthesis and storage difficult,4,5 thereby limiting its synthetic
potential. Interestingly, the introduction of N-protecting groups
and electron-withdrawing groups at C-2 contributes to the
stability of the ketene aminals.5a−e A detailed literature survey
revealed that there are no reports on the synthesis of stable
alkyne tethered ketene N,N-acetals so far.
We thus envisaged that the hydroamidation of N-protected
propargyl amine 1a to the activated ynamide A, obtained from
1a and 2a, would produce 3a (Scheme 1). We further
presumed that the inherent delocalization of the nitrogen lone
pair in ketene N,N-acetals would assist the 6-endo-dig attack of
C-2 to the Lewis acid (LA)-activated alkyne unit with the
formation of iminium species. Subsequent cleavage of the C−N
bond followed by a [2 + 2]-intramolecular cycloaddition6 with
a pendant alkyne would afford an unusual cyclobutene-fused
azepine skeleton 4a (Scheme 1). The construction of
cyclobutane fused heterocycles has been a particularly
fascinating challenge for synthetic chemists.2e,f Of note, the
synthetic methods for cyclobutene-fused azepine structural
entities have remained elusive so far.
G
architectural entities with remarkably high efficiency.1,2 The
cyclization and isomerization sequence contributes significantly
toward building complexity, introducing numerous function-
alities and substituents, and constructing novel cyclic molecular
entities from readily accessible precursors.1 For instance, the
gold-catalyzed cycloisomerization of 1,n-diynes and 1,n-enyne
enables the synthesis of various novel carbo- and hetero-
cycles.1,2
Recently, we have demonstrated the Au-catalyzed, p-TSA·
H2O triggered hydrative cyclization of alkyne tethered ynamide
A for the synthesis of dihydropyridinone C (Scheme 1).3a The
Scheme 1. Current Work
Herein we report a K3PO4 base promoted one-step method
for the synthesis of stable alkyne tethered ketene N,N-acetals
from easily accessible N-protected propargyl amines and 3-
bromopropiolates. We further demonstrate the Au-catalyzed
cycloisomerization of alkyne-tethered ketene N,N-acetals for
the synthesis of cyclobutene-fused azepines.
To our delight, K3PO4 base assisted conjugate addition−
elimination of TsN-propargyl amine (1a) to 3-bromopropiolate
(2a) followed by the hydroamidation sequence successfully
provided the desired alkyne-teth-ered ketene N,N-acetal 3a in
78% yield (Scheme 2).7,8 The reaction proved to be general,
transient alkyne-tethered ketene N,O-acetal B, obtained via the
attack of p-TSA on an activated ynamide, presumably
participates in the cyclization to form C (Scheme 1).3a Since
the isolation of ketene N,O-acetal B was not successful in our
hands, we envisioned the synthesis of an analogous alkyne-
tethered ketene N,N-acetal 3 and examined its reactivity to Au-
catalysts.
The ketene N,N-acetals are also known as ketene aminals or
1,1-enediamines; these compounds are useful for a wide range
of applications in organic synthesis.4,5 The two enamine
Received: April 18, 2014
© XXXX American Chemical Society
A
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Letter
Scheme 2. Substrate Scope for the Preparation of Stable
a
,b
Alkyne Tethered Ketene N,N-Acetals 3
Figure 1. ORTEP plots for X-ray crystal structure of 4a.
Scheme 3. Synthesis of Cyclobutene-Fused Azepines 4,
a
,b
Substrate Scope I
a
Reactions were carried out using 1 (1.0 mmol), 2 (0.5 mmol), K3PO4
b
(2.5 equiv) in toluene (4.0 mL) at 70 °C. Isolated yields.
and a wide variety of stable alkyne tethered ketene N,N-acetals
3b−w were prepared in moderate to good yields (Scheme 2).
The electron-rich (Me, OMe, di-Me, and methylenedioxy) and
-poor (CF3) aryl substituted TsN-propargyl amines were
reacted well with 2a. The halo and other functional groups
(F, Cl, Br, I, NO2, ester, keto, and CN) on the aryl moiety in 1
did not affect reaction outcome. The X-ray crystallography
analysis further elucidates the structure of 3l.8 Interestingly, the
reaction was found to be compatible with the formation of
thienyl-substituted aminal 3s. The methyl or benzyl 3-
bromopropiolates with 1 produced 3t−v in moderate yields.
The N−Ms protected propargyl amine was also no exception
delivering 3w in 71% yield.
Having a wide array of stable alkyne tethered ketene N,N-
acetals 3 in hand, we then investigated the Au-catalyzed
cycloisomerization of 3.8 A careful screening of various Au-
catalysts and solvents revealed that the compound 3a
transformed to 4a (80%) under the optimized conditions
shown in eq 1; the X-ray crystallography analysis established
the structure of 4a (Figure 1).8
a
Reactions were carried out using 3 (0.2 mmol), catalyst A (3.0 mol
b
c
%) in DCE (3.0 mL) at room temperature for 4 h. Isolated yields.
Reaction continued for 20 h.
The keto, ester, nitro, and cyano functional groups on arenes in
the ketene N,N-acetals 3i−l did not affect the cycloisomeriza-
tion; however, the reaction proceeded sluggishly, justifying the
poor activation by the Au-complex to the electron-deficient
alkynes, and the products 4i−l were obtained in moderate to
good yields. The cycloisomerization of m-Me, m-CF3, and m-
NO2 on aryl-ring containing ketene aminals 3m−o led to the
desired products 4m−o. The products 4p and 4q having two
methyl or chloro groups on arenes in m-/p-positions were
isolated in 67% and 61% yields, respectively. Similarly, 4r
(58%) was produced from 3r. Gratifyingly, the 2-thienyl
substituted ketene aminal 3s underwent cycloisomerization
delivering 4s in 82% yield. The methyl and benzyl ester groups
did not show pronounced effect to the efficiency and reactivity;
The essence of the optimized cycloisomerization conditions
is examined assessing the reactivity as well as the scope of this
transformation (Scheme 3). The compounds 3b and 3c having
electron donating p-Me and p-OMe groups on the aryl ring
underwent cycloisomerization efficiently, furnishing 4b and 4c
(X-ray structure) in 74%, 75% yields, respectively.8 The desired
products 4d−g were isolated in excellent yields from the
corresponding halo group (F, Cl, Br, and I) bearing precursors
3d−g. The CF3-bearing product 4h was obtained in 75% yield.
B
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Letter
the products 4t and 4u were produced in 77% and 81% yields,
respectively. A moderate yield of 4v is the consequence of the
electron-deficient m-NO2-phenyl substituted alkyne moiety on
3v; recovering 26% of 3v after performing the reaction for 24 h.
Gratifyingly, the N-mesyl protected compound 3w efficiently
cycloisomerized to result in 4w in good yield.
We next looked into the cycloisomerization of the unsym-
metrical alkyne-tethered ketene N,N-acetal. Interestingly, the
reaction of ynamide 5a,3a with 1m in the presence of K3PO4,
delivered a nonseparable E/Z (3/1) mixture of 3x and 3x′ in
60% yield. Gratifyingly, the cycloisomerization of 3x and 3x′
under the optimized conditions led to a nonseparable mixture
of cyclobutene-fused azepines 4x and 4x′ (3:1, 82%) (Scheme
4). The regioselective attack of the C-2 enediamine to the
Scheme 4. Cycloisomerization of Unsymmetrical 3
1
Figure 2. H NMR Experiment.
Scheme 5. Plausible Mechanistic Cycle
electron-rich substituted alkyne possibly allows the formation of
major product 4x.8 This preliminary observation needs detailed
investigations.
To probe the occurrence of the intramolecular attack of an
enamine nucleophile to the Au-activated alkyne moiety for the
conversion of 3 to 4, a reaction between an electron-rich and
-deficient aryl moiety bearing ketene aminals 3b and 3h was
performed under the optimized conditions for 4 h.8 The
compounds 4b (72%) and 4h (51%) were exclusively isolated.8
We did not even observe a trace of the crossover products. It is
thus clear that the intramolecular cyclization of 3 led exclusively
to 4.
Although the mechanism details are yet to be established, the
plausible mechanistic cycle is sketched in Scheme 5.1f The
reaction begins with the activation of the triple bond of ketene
N,N-acetal by the Au-catalyst, triggering the regioselective 6-
endo-dig attack of the olefin C-2 of enediamine. The inherent
participation of the nitrogen lone pair assists this cyclization3a
and allows the rapid formation of a six-membered iminium-
To understand the probable path of the reaction, we
performed a series of 1H NMR measurements. The compound
3f (spectrum I) was thus subjected to the optimized catalytic
1
gold-vinyl species I; the H NMR experiment study supports
this fact (Figure 2). The cleavage of the C−N bond in I would
then generate the vinyl-gold-allyl-cation species II in situ. The
removal of the Au-species from II readily forms the transient
allene-species III. Finally, [2 + 2]-cycloaddition between the
reactive allene and Au-activated alkyne produces the azabicyclo-
[5.2.0]nona-1(9),5-diene-5-carboxylate heterocycles with the
release of the Au-complex.6 Although we could not detect the
allene intermediate in the 1H NMR experiment, the
participation of an allene intermediate suitably explains the
formation of an unusually strained cyclobutene-fused azabicy-
clic moiety.
In conclusion, we have demonstrated a synthetically viable
strategy for the preparation of a wide array of bench-stable
alkyne-tethered ketene-N,N-acetals for the first time, from
easily accessible N-Ts/Ms protected propargyl amines and 3-
bromopropiolates under the influence of the K3PO4 base. The
gold-catalyzed cycloisomerization of alkyne-tethered ketene
aminals delivered the rather unusual cyclobutene-fused azepine
skeletons; the reaction exhibits a good substrate scope and
tolerates various functional groups. The 1H NMR studies
allowed deducing a plausible reaction pathway. These
1
conditions in CDCl3 in the NMR tube (Figure 2). The H
NMR spectrum of the crude mixture was recorded in regular
time intervals. Surprisingly, we observed an instant shift of
vinyl-Ha (5.76 ppm, s) in 3f to (6.32 ppm, t) in 5 min
(spectrum II). The two propargyl −CH2 protons in 3f [4.50 (s)
and 4.63 (s) ppm] are shifted to [4.91 (dd) and 5.29 (bt) ppm]
with finer splitting, reflecting the chemically nonequivalent
nature of one of the −CH2 groups; the two Me-groups of N-Ts
are also moved from 2.40 and 2.37 ppm to 2.44 and 2.52 ppm
along with minor relevant changes found in the aryl-ring and
CO2Et protons (spectrum II). These observations support the
rapid formation of a transient six-membered N-heterocycle. As
the time proceeds, the intensity of relevant peaks of the
transient species (spectrum II) slowly reduced with the
appearance of the corresponding peaks related to 4f (spectrum
III); this transition was noticed from 15 min. As observed from
the crude 1H NMR spectrum, the reaction was complete in 105
min (spectrum IV) with the disappearence of the peaks in
spectrum II. These studies truly witness the cycloisomerization
of 3 to 4.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
(u) Jimenez-Nunez, E.; Claverie, C. K.; Nieto-Oberhuber, C.;
́
́
̃
Detailed experimental procedures and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5452.
(3) (a) Ghosh, N.; Nayak, S.; Sahoo, A. K. Chem.Eur. J. 2013, 19,
9428. (b) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.;
Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560.
(4) For a review, see: Huang, Z. T.; Wang, M. X. In The Chemistry of
Enamines; Rappoport, Z., Ed.; John Wiley: New York, 1994; pp 1303−
1363.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: akhilchemistry12@gmail.com; akssc@uohyd.ernet.in.
Notes
(5) For selected recent examples on ketene N,N-acetal, see: (a) Shi,
Y.; Zhang, J.; Grazier, N.; Stein, P. D.; Atwal, K. S.; Traeger, S. C.;
Callahan, S. P.; Malley, M. F.; Galella, M. A.; Gougoutas, J. Z. J. Org.
Chem. 2004, 69, 188. (b) Yu, C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang,
Z.-T. Synlett 2006, 1825. (c) Naito, H.; Hata, T.; Urabe, H.
Tetrahedron Lett. 2008, 49, 2298. (d) Yaqub, M.; Yu, C.-Y.; Jia, Y.-
M.; Huang, Z.-T. Synlett 2008, 1357. (e) Coste, A.; Couty, F.; Evano,
G. Org. Lett. 2009, 11, 4208.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This manuscript is dedicated to Prof Ganesh Pandey on the
occasion of his 60th birthday. We thank UoH for financial
support. S.N and N.G thank CSIR, India for a fellowship. Mr.
R. Goud, Sudalai, A. Sudheer Kumar, and Krishna Chari, UoH
are thanked for the X-ray crystallographic analysis.
(6) For allene [2 + 2] cycloaddition, see: Aubert, C.; Fensterbank, L.;
Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954
and references cited therein.
(7) For introduction of a nucleophile at the α-position of ynamides,
see: (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(b) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis,
A. Org. Lett. 2005, 7, 1047. (c) Kramer, S.; Dooleweerdt, K.;
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