Harnessing the Polarizability of Conjugated Alkynes toward [2 + 2] Cycloaddition, Alkenylation, and Ring Expansion of Indoles

Article abstract of DOI:10.1021/acs.orglett.8b02230

Reported is the utilization of electronically biased conjugated alkynes in the development of highly diastereo- and regioselective dearomative [2 + 2] cycloadditions, alkenylations, and ring expansions of electron-rich indoles. Regioselective protonations of cross- and linear-conjugated alkynes were found to be crucial for accessing various cyclobutene-fused indoline and alkenylated indole derivatives. Furthermore, the facile ring expansion of [2 + 2] keto adducts, which were successfully synthesized from ynones, provided 1H-benzo[b]azepine scaffolds.

Full text of DOI:10.1021/acs.orglett.8b02230

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Harnessing the Polarizability of Conjugated Alkynes toward [2 + 2]
Cycloaddition, Alkenylation, and Ring Expansion of Indoles
Tapas R. Pradhan, Hong Won Kim, and Jin Kyoon Park*
The Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 46241, Korea
S
* Supporting Information
ABSTRACT: Reported is the utilization of electronically biased conjugated alkynes in the development of highly diastereo-
and regioselective dearomative [2 + 2] cycloadditions, alkenylations, and ring expansions of electron-rich indoles. Regioselective
protonations of cross- and linear-conjugated alkynes were found to be crucial for accessing various cyclobutene-fused indoline
and alkenylated indole derivatives. Furthermore, the facile ring expansion of [2 + 2] keto adducts, which were successfully
synthesized from ynones, provided 1H-benzo[b]azepine scaffolds.
been systematically studied, particularly for electron-rich
wing to the degree of unsaturation associated with them,
Oconjugated enynes have been utilized for the development indoles. For instance, while electron-rich ynamides are known
to undergo Ficini-type [2 + 2] cycloadditions with electron-
deficient alkenes,6c,8 they undergo hydroarylation9 with
electron-rich indoles in the presence of a gold catalyst (top,
Scheme 1A). Conversely, electron-deficient symmetric alkynes
(e.g., dimethyl acetylenedicarboxylate) were known to react
with electron-rich indoles in Lewis acid mediated10a and
photochemical reactions10b in the early 1980s (bottom, Scheme
1A); however, complete control toward cycloaddition over
alkenylation11 has been elusive since then. Moreover, the
cycloadducts are reversibly converted into 1H-benzazepines,
ring-expanded products, due to heat and light.10
As part of our recent research on regio- and stereoselective
C−H annulation using branched ynenamides12 and selective
synthesis of linear ynenamides,13 we hypothesized that
electronically perturbed cross- and linear-conjugated alkynes
could be selectively activated by an acid to provide a practical
solution to the above-mentioned problems, consequently
leading to the development of divergent intermolecular coupling
reactions with indoles. Gratifyingly, while cross-conjugated
alkynes provided cyclobutene-fused indolines, linear-conjugated
alkynes gave C2-alkenylated indoles, regio- and stereoselectively
(top, Scheme 1B). Additionally, the recognition of potential ring
expansion of cyclobutenes14 led us to focus on the synthesis of
of novel synthetic routes to valuable structurally diversified
compounds.1 An electronic switch around unsaturated C−C
bonds is an essential event that underpins their site-selective
reactivities either with metals or under metal-free conditions.2 A
pertinent strategy for selective reactions is to alter the highest
occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) through suitably tethered electron-
donating/withdrawing substituents or the conjugation length.3
Additionally, broken or continuous electron flow driven by cross
and linear conjugation4 may perturb the electron density around
the reaction sites and result in site-selective interception by
nucleophiles through an activator, such as a Brønsted or Lewis
acid. It is, therefore, of interest to study such electronic events in
order to obtain a powerful, yet undiscovered, switchable vector
for divergent manipulations and more general control of regio-
and stereoselectivity.
Despite the diversity of alkynes tailored toward [2 + 2]
cycloadditions with alkenes (inter- or intramolecular), many of
them operate through combinations of precious metal catalysts
and supporting ligands.5 Directed intermolecular cycloadditions
using Au,5a Ni,5e and Co5h utilizing the distinct reactivity of
conjugated enynes are some examples. When an acid is used,
proper electronic balance between the two coupling partners is
required,6 a characteristic that has been exploited in numerous
methods, with some exceptions.7 However, to date, reactions
between electron-rich alkynes and electron-rich alkenes have not
Received: July 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02230
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Comparison between Previous Work and Our
Work
Scheme 2. Scope of Branched Ynenamides 2 with Substituted
Indoles 1
a b
,
fused N-heterocycles; serendipitously, we found reagent-free
ring expansion conditions for the dearomative cycloadducts,
obtained from conjugated ynones, to access pharmaceutically
privileged 1H-benzazepine scaffolds (bottom, Scheme 1B).15
To test the feasibility of the proposed reaction, we began our
investigation by reacting 1a with a 1:10 stereoisomeric mixture
of 2a (Table S1 and S2), from which the optimum conditions
were found, and TfOH (1.2 equiv) was determined to be the
best activator in 0.4 M DCE using 4 Å molecular sieves (entry 6,
Table S1).16 With these optimized conditions, first, the scope
and generality of the intriguing [2 + 2] cycloaddition process
were investigated, and the results for 25 different cross-
conjugated ynenamides and six indole derivatives are displayed
(Scheme 2). The cycloaddition of indole 1a with ynenamide
substrates bearing electronically different aryl groups on the
enamide terminus furnished the corresponding [2 + 2]
cycloadducts. Changing the substituents on the aryl ring at the
yne terminus is also possible, but a CF3 group at the ortho
position reduced the reactivity and resulted in no observed
cycloadduct 3ap. Further study on the electronic effects of the
aryl rings suggested that the substituents could be either
electron-rich or poor in positions affecting the electron density
around the phenyl nuclei. Cycloadduct 3at was recrystallized,
and its single-crystal X-ray structure was unequivocally assigned.
Unfortunately, no traces of 3av were observed, possibly owing to
electronic and steric effects. Then, we examined the effect of
changing the substituents on neighboring reaction sites of indole
and found similar cycloadducts with comparable yields. An alkyl
substituted cis-ynenamide reacted in a similar fashion to provide
corresponding cycloadduct 3bx, the structure of which was
confirmed using single-crystal X-ray diffraction. However,
indoles with electron-withdrawing substituents were not
a
All reactions were carried out under the optimized conditions (0.15
mmol of 1 and 0.1 mmol of ynenamide 2 using 1.2 equiv of TfOH in
0.4 M DCE with MS 4 Å). Isolated yield. Reaction was conducted
for 3 h. Both starting materials were recovered.
b
c
d
successful to provide cycloadducts (3fa and 3ga). The reactivity
of the other ynenamides, comprising sterically and electronically
differentiable groups on the N-atom as well as 2,3-substituted
indole, was tested (Table S3). It is of note that an unexpected [4
+ 2] cycloaddition pathway was followed by 2,3-dimethyl indole
with decent yield, which may be ascribed to the steric hindrance
promoting the nucleophilic enamide addition to iminum.
When 3a was replaced with linear ynenamide 4a under the
optimized conditions for [2 + 2] cycloaddition (entry 6, Table
S1),16 an appreciable amount of nondearomative alkenylation
product 5a was obtained (68%). The yield of 5a was improved to
78% by using bistriflimide (entry 3, Table S5). It is worth
mentioning here that the alkenylation process also proceeds
through cis−trans isomerization of the enamide unit. Next, we
turned our attention to generalizing the alkenylation reaction
between various indole derivatives 1 and linear ynenamides 4
under the optimized conditions (Scheme 3). Substrates 4
bearing various electron-withdrawing and donating aromatic
groups at the alkynyl terminus generated the desired coupling
products, 5a−f, in comparable yields and regioselectivities. An
alkyl terminated ynenemide also did not deviate to afford the
desired alkenylation product 5g. Furthermore, the reaction
exhibited excellent functional group compatibility with respect
to functionalized indoles 1 bearing isopropyl, allyl, propargyl,
and benzyl groups under our current reaction conditions, giving
the desired products in good yields. Unfortunately, alkenylation
B
DOI: 10.1021/acs.orglett.8b02230
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Organic Letters
Letter
Scheme 3. Scope of Branched Ynenamides 4 with Substituted
Indoles 1
Scheme 4. Scope of Ynones 6 for One-Pot [2 + 2]
a b c
a b
,
, ,
Cycloaddition and Ring Expansion
a
All reactions were carried out under the optimized conditions (0.15
mmol of 1 and 0.1 mmol of ynenamide 4 using 1.2 equiv of HNTf2 in
b
c
0.4 M DCE). Isolated yield. Reaction was conducted for 12 h.
was limited for an indole with an electron-withdrawing
substituent (1l) at the 3-position. An ynenamide derived from
a substituted allenamide was also suitable for this trans-
formation, selectively providing 5m.
a
All reactions were carried out with 0.15 mmol of 1 and 0.1 mmol of
ynone 6 using 1.2 equiv of BF3·OEt2 in 0.4 M DCE for 0.5 h at rt
Realizing that there is ring strain associated with a cyclobutene
ring, we attempted the ring expansion of cyclobutene-fused
indole 3aa, as a showcase of its synthetic applicability. An earlier
report on thermal and Ag-catalyzed ring expansion was
unsuitable17a,b for our substrate, 3aa (box, in Scheme 4).
Inspired by the recent report by Hsung et al. on the carbonyl-
group-assisted ring opening of fused cyclobutenamides14a and
thermal ring opening of cyclobutene-fused indolines,10 we
reasoned that the hydrolyzed product could undergo the same to
afford highly substituted benzazepines. To our delight, the ring
expansion of 7a occurred without any catalyst or reagent.
Because the yields from ynenamides were disappointing (25−
32%, Table S6; top, Scheme 4), we envisaged an alternative
synthetic route to 7 using ynone 6. A short optimization study
revealed that the Lewis acid BF3·OEt2 gave the best results,
providing isolable [2 + 2] cycloadduct 7a in 92% yield.16
Furthermore, owing to internal Lewis acids, mild heating of the
reaction mixtures accelerated the ring expansion, giving highly
functionalized benzazepines in quantitative yields, thus provid-
ing a transition-metal-free approach, complementing the
previous metal-catalyzed precedents.15 The scope of the
reaction was excellent for both enolizable and nonenolizable
ynones, for yne-terminus alkyl moieties, and for neighboring
sensitive and hindered functionalities on the indole ring
(Scheme 4). Remarkably, installation of benzazepine moieties
into natural products such as cholesterol and ursodeoxycholic
acid derivatives was also possible (8l and 8m), highlighting the
synthetic utility of the present transformation. However,
attempts to synthesize fully substituted and bridge-head
benzazepines were unfruitful; instead, the corresponding
cycloadducts (7n−p) were obtained in high yields (91%−94%).
To determine a mechanism for the [2 + 2] cycloaddition, we
gathered some experimental results obtained during optimiza-
tion and scope examination. A single E isomer was detected in
the Z/E mixture (1:2.5) (Scheme 5A) as well as major cis-
b
followed by 3 h at 50 °C. Isolated yields obtained under one-pot
c
conditions from 6. Quantitative conversion of 7 to 8, as indicated by
d
1H NMR. Ring expansion was performed by heating at 100 °C for 2
e
h. Only cycloadducts 7n−p were isolated.
Scheme 5. Observations for Mechanistic Insights for [2 + 2]
Cycloaddition
isomeric ynenamide 2x (Scheme 5B), which attest the dual role
of the Brønsted acid in alkyne activation and enamide
isomerization to the more stable E isomer. Meanwhile, a control
experiment without indole suggested that the isomerization18
occurs prior to cycloaddition (Scheme 5C). The lack of D-
incorporation of 2a (Scheme 5D) and nonerosion of D-content
of 2a-D (Scheme 5E) rule out enamide protonation.
On the basis of the above studies, a possible mechanism for
the [2 + 2] cycloaddition is proposed in Scheme 6A. Following
isomerization, chemoselective protonation of the alkyne (path
C
DOI: 10.1021/acs.orglett.8b02230
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Organic Letters
Letter
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Proposed Mechanisms
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pjkyoon@pusan.ac.kr.
ORCID
Jin Kyoon Park: 0000-0001-6768-2788
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a two-year research grant from
Pusan National University.
■
REFERENCES
(1) For general reviews, see: (a) Wessig, P.; Mu
2008, 108, 2051. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
■
̈
ller, G. Chem. Rev.
2901.
(2) For some selected examples: (a) Xiao, Y.; Lin, J.-B.; Zhao, Y.-N.;
Liu, J.-Y.; Xu, P.-F. Org. Lett. 2016, 18, 6276. (b) Yao, Q.; Liao, Y.; Lin,
L.; Lin, X.; Ji, J.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2016, 55, 1859.
(c) Gurubrahamam, R.; Gao, B.-F.; Chen, Y. M.; Chan, Y. T.; Tsai, M.-
K.; Chen, K. Org. Lett. 2016, 18, 3098. (d) Li, W.; Yu, X.; Yue, Z.;
Zhang, J. Org. Lett. 2016, 18, 3972. (e) Li, W.; Yu, X.; Yue, Z.; Zhang, J.
Org. Lett. 2016, 18, 3972. (f) Verrier, C.; Melchiorre, P. Chem. Sci. 2015,
6, 4242. (g) Zhou, L.; Zhang, M.; Li, W.; Zhang, J. Angew. Chem., Int. Ed.
2014, 53, 6542. (h) Qian, H.; Yu, X.; Zhang, J.; Sun, J. J. Am. Chem. Soc.
2013, 135, 18020. (i) Rauniyar, V.; Wang, Z. J.; Burks, H. E.; Toste, F.
D. J. Am. Chem. Soc. 2011, 133, 8486. (j) Zhang, W.; Zheng, S. Q.; Liu,
N.; Werness, J. B.; Guzei, I. A.; Tang, W. P. J. Am. Chem. Soc. 2010, 132,
3664. (k) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 12865. (l) Belot, S.; Vogt, K. M.; Besnard, C.;
Krause, N.; Alexakis, A. Angew. Chem., Int. Ed. 2009, 48, 8923. (m) Xiao,
Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903. (n) Hayashi, T.;
Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305. (o) Yao, T.; Zhang, X.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (p) Han, J. W.;
Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915.
(3) (a) Fukui, K. In Molecular Orbitals in Chemistry, Physics, and
Biology; Lowdin, P.-O., Pullman, B., Ed.; Academic Press: New York,
1964; p 513. (b) Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc.
1965, 87, 4388. (c) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int.
Ed. Engl. 1969, 8, 781. (d) Houk, K. N. Acc. Chem. Res. 1975, 8, 361.
(e) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley:
London, 1976. (f) Geittner, J.; Huisgen, K. Tetrahedron Lett. 1977, 10,
881. (g) Padwa, A.; Carlsen, P. H. J. J. Org. Chem. 1978, 43, 3757.
(h) Sustmann, R. Pure Appl. Chem. 2009, 40, 569. (i) Chen, L.; Chen,
K.; Zhu, S. Chem. 2018, 4, 1208.
(4) (a) Gorman, C. B.; Marder, S. R. Proc. Natl. Acad. Sci. U. S. A.
1993, 90, 11297. (b) Ricks, A. B.; Solomon, G. C.; Colvin, M. T.; Scott,
A. M.; Chen, K.; Ratner, M. A.; Wasielewski, M. R. J. Am. Chem. Soc.
2010, 132, 15427.
(5) For selected precedents of alkene-alkyne [2 + 2] cycloaddition:
(a) Elena de Orbe, M.; Echavarren, A. M. Eur. J. Org. Chem. 2018, 2018,
2740. (b) Bai, Y.-B.; Luo, Z.; Wang, Y.; Gao, J.-M.; Zhang, L. J. Am.
Chem. Soc. 2018, 140, 5860. (c) Garcia-Morales, C. G.; Ranieri, B.;
Escofet, I.; Lopez-Suarez, L.; Obradors, C.; Konovalov, A. I.;
Echavarren, A. M. J. Am. Chem. Soc. 2017, 139, 13628. (d) Kossler,
D.; Perrin, F. G.; Sul-eymanov, A. A.; Kiefer, G.; Scopelliti, R.; Severin,
K.; Cramer, N. Angew. Chem., Int. Ed. 2017, 56, 11490. (e) Nishimura,
A.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2012, 134, 15692. (f) Li, Y.;
Liu, X.; Jiang, H.; Liu, B.; Chen, Z.; Zhou, P. Angew. Chem., Int. Ed.
a) over the enamide (path b) gives vinyl cation intermediate A.
Regioselective Friedel−Crafts alkenylation of an indole by A
produces B. Subsequent ring closure of the alkene at the indole
iminium ion gives 3 via addition−elimination (C). The
proposed mechanism for alkenylation (Scheme 6B) involves
the selective protonation of the -yne unit at the δ-position to
produce isomerized intermediate D, which is likely formed
through a continuous electron flow sequence. Nucleophilic
attack of the indole on the more electrophilic γ-carbon of D
affords cyclopropyl carbocation F via bond rearrangement of the
ipso-carbon as shown in E. Finally, rearomatization through
simultaneous loss of a proton and cyclopropane ring opening
affords alkenylation product 5 from F.
In conclusion, we have developed robust acid-mediated
protocols for the dearomative cycloaddition and alkenylation of
electron-rich indoles with electronically biased ynenamides for
the first time. An irreversible and chemoselective protonation of
the conjugated ynenamide allowed us to achieve divergent site-
selective functionalizations regio- and stereoselectively. More
importantly, the reagent-free ring expansion of the correspond-
ing isolable hydrolyzed cycloadducts extended our interests to
the investigation of the reactivity of conjugated ynones, enabling
expedient access to ubiquitous 1H-benzo[b]azepines. This work
also contributes new knowledge on the behavior of a new class of
alkynes tailored for indole chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02230.
Screening of reaction conditions, experimental proce-
1
dures, X-ray diffraction data, and H and 13C NMR
spectra of all compounds (PDF)
Accession Codes
CCDC 1863503, 1863504, and 1856321 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
́
2011, 50, 6341. (g) Lopez-Carrillo, V.; Echavarren, A. M. J. Am. Chem.
Soc. 2010, 132, 9292. (h) Hilt, G.; Paul, A.; Treutwein, J. Org. Lett.
2010, 12, 1536. (i) Takenaka, Y.; Ito, H.; Hasegawa, M.; Iguchi, K.
Tetrahedron 2006, 62, 3380. (j) Fu
̈
rstner, A.; Davies, P. W.; Gress, T. J.
D
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Am. Chem. Soc. 2005, 127, 8244. (k) Narasaka, K.; Hayashi, Y.;
Shimadzu, H.; Niihata, S. J. Am. Chem. Soc. 1992, 114, 8869.
(l) Dzhemilev, U. M.; Khusnutdinov, R. I.; Muslimov, Z. S.;
Tolstikov, G. A. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.)
1987, 36, 977.
(6) For selected examples: (a) Kang, T.; Ge, S.; Lin, L.; Lu, Y.; Liu, X.;
Feng, X. Angew. Chem., Int. Ed. 2016, 55, 5541. (b) Okamoto, K.;
Shimbayashi, T.; Tamura, E.; Ohe, K. Org. Lett. 2015, 17, 5843. (c) Li,
H. Y.; Hsung, R. P.; Dekorver, K. A.; Wei, Y. G. Org. Lett. 2010, 12,
3780. (d) Ishihara, K.; Fushimi, M. J. Am. Chem. Soc. 2008, 130, 7532.
(e) Takenaka, Y.; Ito, H.; Hasegawa, M.; Iguchi, K. Tetrahedron 2006,
62, 3380. (f) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005,
127, 3668. (g) Ito, H.; Takenaka, Y.; Kobayashi, T.; Iguchi, K. J. Am.
Chem. Soc. 2004, 126, 4520. (h) Sweis, R. F.; Schramm, M. P.; Kozmin,
S. A. J. Am. Chem. Soc. 2004, 126, 7442. (i) Snider, B. B.; Rodini, D. J.;
Conn, R. S. E.; Sealfon, S. J. Am. Chem. Soc. 1979, 101, 5283.
(7) (a) Shen, L.; Zhao, K.; Doitomi, K.; Ganguly, R.; Li, Y.-X.; Shen,
Z.; Hirao, H.; Loh, T.-P. J. Am. Chem. Soc. 2017, 139, 13570. (b) Liang,
R. X.; Jiang, H. F.; Zhu, S. F. Chem. Commun. 2015, 51, 5530.
(8) (a) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072.
(b) Enomoto, K.; Oyama, H.; Nakada, M. Chem. - Eur. J. 2015, 21,
2798.
(9) Pirovano, V.; Negrato, M.; Abbiati, G.; Dell’Acqua, M.; Rossi, E.
Org. Lett. 2016, 18, 4798.
(10) (a) Augusto, J.; Rodriguez, R.; Verardo, L. I. J. Heterocyclic Chem.
1983, 20, 1263. (b) Davis, P. D.; Neckers, D. C. J. Org. Chem. 1980, 45,
456. (c) Davis, P. D.; Neckers, D. C. J. Org. Chem. 1980, 45, 462.
(11) For typical C2-alkenylation of indoles, suitable directing groups
are required. For carboximide group, see: (a) Schipper, D. J.;
Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6910.
(b) Sharma, S.; Han, S.; Shin, Y.; Mishra, N. K.; Oh, H.; Park, J.; Kwak,
J. H.; Shin, B. S.; Jung, Y. H.; Kim, I. S. Tetrahedron Lett. 2014, 55, 3104
For pyrimidyl groups, see:. (c) Ding, Z.; Yoshikai, N. Angew. Chem., Int.
Ed. 2012, 51, 4698 For imine group, see:. (d) Fallon, B. J.; Derat, E.;
Amatore, M.; Aubert, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A.; Petit,
M. Org. Lett. 2016, 18, 2292.
(12) For the synthesis of branched ynenamide, see: (a) Liu, G.; Kong,
W.; Che, J.; Zhu, G. Adv. Synth. Catal. 2014, 356, 3314. (b) Dwivedi, V.;
Babu, M. H.; Kant, R.; Reddy, M. S. Chem. Commun. 2015, 51, 14996
For C−H annulation using ynenamide, see:. (c) Alam, K.; Hong, S. W.;
Oh, K. H.; Park, J. K. Angew. Chem., Int. Ed. 2017, 56, 13387.
(13) Pradhan, T. R.; Kim, H. W.; Park, J. K. Angew. Chem., Int. Ed.
2018, 57, 9930.
(14) (a) Wang, X. N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.;
Hsung, R. P. J. Am. Chem. Soc. 2015, 137, 5596. (b) Frebault, F.;
Luparia, M.; Oliveira, M. T.; Goddard, R.; Maulide, N. Angew. Chem.,
Int. Ed. 2010, 49, 5672.
(15) For the synthesis of 1H-benzo[b]azepine, see: (a) Undeela, S.;
Ravikumar, G.; Nanubolu, J. B.; Singarapu, K. K.; Menon, R. S. Chem.
Commun. 2016, 52, 4824. (b) Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.;
Prabhakar, A.; Jagadeesh, B. Chem. Commun. 2004, 2124 and for their
importance, see the references cited therein.
(16) The details of optimization study are described in the Supporting
Information
(17) (a) Ikeda, H.; Obno, R.; Una, T.; Tamura, P. Tetrahedron Lett.
1980, 21, 3403. (b) A 3:1 cis-trans mixture of 3aa was observed in the
crude NMR of the reaction mixture.
(18) No D-incorporation was observed with TfOD, and E/Z
isomerization was also found with a catalytic amount of TfOH.
E
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