Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies

Article abstract of DOI:10.1002/asia.201901251

Demonstrated herein is an Au^I-catalyzed annulation of sulfonyl-protected ynamides with substituted 1,2-benzisoxazoles for the synthesis of E-benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold-activated ynamide, ring expansion of the benzisoxazole fragment to provide an α-imino vinylic gold intermediate, and 1,2-migration of the sulfonamide motif to the masked carbene center to deliver the respective ring-expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α-imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.

Full text of DOI:10.1002/asia.201901251

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles
with Ynamides: Experimental and Theoretical Studies
Authors: Akhila Kumar Sahoo, Rajeshwer Vanjari, Shubham Dutta, B.
Prabagar, and Vincent Gandon
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201901251
Link to VoR: http://dx.doi.org/10.1002/asia.201901251
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles
with Ynamides: Experimental and Theoretical Studies
Rajeshwer Vanjari, [a] Shubham Dutta, [a] B. Prabagar,[a] Vincent Gandon*[b],[c] and Akhila K. Sahoo*[a]
Abstract: Demonstrated herein is a Au(I)-catalyzed annulation of
sulfonyl-protected ynamides with substituted 1,2-benzisoxazoles for
the synthesis of
E
benzo[e][1,3]oxazine derivatives. The
transformation involves the addition of benzisoxazole to the gold-
activated ynamide, ring expansion of the benzisoxazole fragment to
provide an α-oximino gold carbene, and the 1,2-migration of the
sulfonamide motif to the carbene center to deliver the respective ring
expanded benzo[e][1,3]oxazine of predominant E configuration. A
trapping experiment justifies the participation of the α-oximino gold
carbene. DFT computations also support the hypothesized
mechanism and rationalize the product stereoselectivity.
Introduction
Homogeneous gold-catalyzed cascade oxidative cyclization
processes have largely been used for the fabrication of complex
heterocyclic frameworks.1 In this context, the direct application of
gold-carbenoid species for diverse cyclization methods have
undoubtedly been significant. The Au-catalyzed N-oxide
assisted alkyne oxidation and the cycloisomerization of 1,n‐
enynes are
particularly
notable
gold carbene-based
transformations.2,3 In addition, the nucleophilic nitrenoid
equivalents, for example, azides,4 pyridium ylides,5 2H-azirines,6
and others7 have been used in the generation of gold carbene
species. The formation of Au-carbenes from ynamides occurs
via the elimination of a counter ion or a leaving group after
electron back donation of the metal center (Scheme 1a). In this
regard, Ye,8 Hashmi,9 and Liu10 groups independently reported
the annulation of Au-carbene species, obtained in-situ from
ynamides11 and anthranils or isoxazoles in presence of Au(I)-
catalyst, to provide substituted pyrrole and indole derivatives. By
contrast, the generation of ,’-disubstituted Au-carbenes from
ynamides could also be envisaged with the assistance of a 1,2-
di-heteroatom species that would undergo an internal cleavage
of the YX bond (Scheme 1b). Intrigued by this idea, we
envisaged the Au-catalyzed regioselective attack of
Scheme 1. Generation and trapping of ynamide-derived gold carbenes
[a]
[b]
[c]
Rajeshwer Vanjari, Shubham Dutta, B. Prabagar, Prof. Dr. Akhila K.
Sahoo
School of Chemistry, University of Hyderabad, Hyderabad,
Telangana, India-500046.
E-mail: akhilchemistry12@gmail.com; akssc@uohyd.ac.in.
Prof. Dr. Vincent Gandon
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO),
CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay,
Bâtiment 420, 91405 Orsay cedex, France.
benzisoxazoles to ynamides (Scheme 1c). We anticipated that
the attack of substituted benzisoxazoles to the α-position of an
Au-activated ynamide would first provide the vinyl-gold species
V (Scheme 1c). Next, the electron back donation of gold atom
and the electron-delocalization would trigger the cleavage of the
benzisoxazole ON bond resulting in ring expansion to give the
intermediate VI. Meanwhile, the cleavage of NO bond (IX)
through the electron delocalization of aryl motif would produce X
(supported by DFT study). Finally, 1,2-sulfonamide migration
and dissociation of gold would lead to the desired
benzo[e][1,3]oxazine derivative (Scheme 1c). As shown below,
our strategy proved successful in providing products with a
E-mail: vincent.gandon@u-psud.fr
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole
Polytechnique, Institut Polytechnique de Paris, route de Saclay,
91128 Palaiseau cedex, France.
Supporting information for this article is given via a link at the end of
the document.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
pronounced E stereoselectivity. During the preparation of this
solvent, providing 3a in 89% yield (E/Z = 88:12; entry 6). The
product yield was greatly affected when IPrAuNTf2 (24%, entry
7) and IMesAuNTf2 (21%, entry 8) were used, while the reaction
in the presence of XPhosAuNTf2 was satisfactory (E/Z = 88:12;
entry 9).
manuscript, R. S. Liu[12a] and Y. Liu[12b] group have
independently reported the synthesis of
Z
and
E
benzo[e][1,3]oxazines, respectively, from ynamide and
benzoisoxazole derivatives when exposed to Au(I) catalysts.
Such
a
diverse stereochemical outcome required further
The effective reaction conditions for the ring expansion and
migration cascade between 1a and 2a (Table 1, entry 6) were
then used to probe the reaction generality for the construction of
benzo[e][1,3]oxazines (Schemes 3, 4, and 5). In addition to the
previously discussed product 3a (89%, E/Z 88:22), the desired
benzo[e][1,3]oxazines 3b (87%, p-Ph, E/Z 73:27), 3c (88%, m-
OMe, E/Z 83:17), and 3d (90%, p-OMe, E/Z 72:28) were
obtained in high yields from the electron-rich aryl-substituted
ynamides. By contrast, moderate to good yields were obtained
from electron-poor aryl bearing ynamides, leading to 3e (37%, p-
F, E/Z 58:42) and 3f (80%, m-F, E/Z 84:16). The thiophenyl
substituted benzo[e][1,3]oxazine 3g was obtained in 61% yield
with an E/Z of 15:85. Benzo[e][1,3]oxazine 3h was accessed in
32% yield from a dimethyl-substituted aryl-bearing ynamide. The
robustness of the catalytic system was tested through the
synthesis of 3a (0.6 g) from the mixture of 1a (0.5 g, 1.75 mmol)
and 2a (0.47 g) in presence of the Au-catalyst (5.0 mol%).
examination. The Liu’s[12b] pioneering demonstration leads to E
benzo[e][1,3]oxazines, however, the reaction involves a gold
carbene intermediate; whereas the participation of the vinylic
gold carbene intermediate (IX) validates the formation of E-
isomer benzo[e][1,3]oxazines (major, current work).
We herein discuss the Au(I)-catalyzed annulation of ynamides
with substituted benzisoxazoles for the synthesis of
benzo[e][1,3]oxazine
configuration and examine a detailed density functional theory
(DFT) computations to establish the mechanism.
derivatives
predominantly
of
E
Results and Discussion
The investigation was initiated by performing a reaction between
ynamide 1a and 3-methylbenzisoxazole 2a in presence of
various gold catalysts (Table 1). The reaction proved successful
when conducted with JohnPhosAu(MeCN)SbF6 in 1,4-dioxane;
3a was isolated in 47% yield with the major E configuration (E/Z
= 83:17; entry 1). The structure of E-3a was unambiguously
confirmed by X-ray crystallographic analysis (Scheme 3). The
reaction did not take place in DMF (entry 2), whereas 3a was
obtained in 68% (E/Z = 89:11) and 79% yield (E/Z = 86:14)
when carried out in acetone or 1,2-dichloroethane (DCE),
respectively (entries 3 and 4). The reaction was also effective in
toluene (84%; entry 5), but CHCl3 was found to be the best
Table 1. Optimization of the Reaction Conditions[a]
Yield, 3a
Entry
Catalyst
Solvent
E/Z[b]
(%)[c]
47
0
1
2
3
4
5
6
7
8
9
JohnPhosAu(MeCN)SbF6
JohnPhosAu(MeCN)SbF6
JohnPhosAu(MeCN)SbF6
JohnPhosAu(MeCN)SbF6
JohnPhosAu(MeCN)SbF6
JohnPhosAu(MeCN)SbF6
IPrAuNTf2
1,4-dioxane
DMF
83:17
-
acetone
1,2-DCE
toluene
CHCl3
89:11
86:14
87:13
88:12
85:15
88:12
88:12
68
79
84
89
24
21
81
CHCl3
IMesAuNTf2
CHCl3
XPhosAuNTf2
CHCl3
[a] Reaction conditions: 1a (1.0 equiv, 0.3 mmol), 2a (2.0 equiv), Au-cat (5.0
mol %), solvent (1.0 M) at rt for 4 h. [b] Determined by 1H NMR via integration
of methyl peak. [c ] Isolated yield.
Scheme 3. Reaction of Ynamides (1) with 3-Methylbenzisoxazole (2a).
Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (0.6 mmol, 2.0 equiv), Au-
cat (5.0 mol%), CHCl3 (1.0M) at rt for 4 h. E:Z ratio determined by 1H NMR
integrating methyl peak.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
We next explored the scope of the migrating group using various
N-sulfonyl protected ynamides with 2a (Scheme 4). The reaction
of 2a with N-Bn-sulfonamide (N-Bn-SO2Ar) ynamides furnished
the desired benzo[e][1,3]oxazines [3i (electron-neutral N-Bn-
SO2Ph, 47%, E/Z 77:23), 3j (electron-rich N-Bn-SO2C6H4-p-Ph,
42%, E/Z 75:25), and 3k (electron-poor N-Bn-SO2C6H4-p-Cl,
32%, E/Z 85:15). Likewise, the N-Me-sulfonamide bearing
products [3l (N-Me-SO2C6H4-p-Br, E/Z 85:15), 3m (N-Me-
SO2C6H4-p-NO2, E/Z 81:19), and 3n (N-Me-SO2C6H3-3,4-di-OMe,
E/Z 85:15)] were accessed in good yields. The N-Me
sulfonamide reacted with 2a to provide the respective oxazine
product 3o (89%, E/Z 85:15). The migration was unaffected
when N-Me-SO2camphor bearing ynamide reacted with 2a; the
product 3p (E/Z 84:16) was isolated in 88% yield (Scheme 4).
Lower yields were observed in case of BnNSO2R' due to the
possible deleterious effect of the benzyl group.
Scheme 5. Scope of Benzisoxazole (2). Reaction conditions: 1a (1.0 equiv,
0.3 mmol), 2a (2.0 equiv), Au-cat (5.0 mol%), CHCl3 (1.0 M) at rt for 4 h. E:Z
ratio determined by 1H NMR integrating methyl peak.
Scheme 6. Carbene Trapping
The involvement of a gold carbene intermediate was supported
by the outcome of the coupling of the alkyl-substituted ynamide
1q with 2a (Scheme 6). These substrates provided a non-
migratory product 5, obtained likely via dearomatization and gold
carbene CH bond insertion.
To explore the mechanistic details, DFT computations were
Scheme 4. Scope of Migrating Group. Reaction conditions: 1a (1.0 equiv, 0.3
mmol), 2a (2.0 equiv), Au-cat (5.0 mol%), CHCl3 (1.0M) at rt for 4 h. E:Z ratio
determined by 1H NMR integrating methyl peak.
executed
at
the
M06/def2-QZVP(Au)-6-31
+G(2d,p)//B3LYP/LANL2DZ(Au)-6-31G(d,p) level of theory.
Optimization of the model ynamide shown in Scheme 7 and the
[LAu]+ fragment (L = biphenyl-2-yl-di-methylphosphine) led to the
keteniminium complex A with the release of 17 kcal/mol of Gibbs
free energy. For the rest of the discussion, the carbon center
adjacent to nitrogen of ynamide is denoted C1 and the other -
carbon center is denoted C2. In the following energy profiles, the
keteniminium complex A and 3-methylbenzisoxazole or
The generality of the ring expansion by reacting various
benzisoxazoles (irrespective of the substituents present at
different positions of the arene periphery) with 1a was next
examined (Scheme 5). The reaction between 6-F/6-Cl/6-OMe
substituted 2-methylbenzisoxazoles and 1a delivered the
respective highly-substituted benzo[e][1,3]oxazines 4a4c [E/Z =
6776:3324].
Similarly,
5-OMe
substituted
2-
methylbenzisoxazoles participated in the ring expansion
cascade, producing 4d in 88% yield with better E/Z ratio of 84:16.
Compound 4e (31%; E/Z = 63:37) was isolated from the reaction
of 3-phenyl substituted benzisoxazole with 1a. Likewise, the
reaction of 1a and 5,6-disubstituted benzisoxazole led to 4f, in
excellent yield (91%, E/Z = 86:14).
Scheme 7. Free energy for the formation of the keteniminium gold complex A
(L = biphenyl-2-yl-di-methylphosphine).
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
Scheme 8. Free energy profile (G298, kcal/mol) for the anti-addition of B to A with two Me groups on the same side; geometry of key intermediates and transition
states.
Scheme 9. Free energy profile (G298, kcal/mol) for the anti-addition of B to A with two Me groups on opposite sides.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
Scheme 10. Free energy profiles (G298, kcal/mol) for the syn addition of B to A.
benzisoxazole have been taken as reference for the free
energies. The investigation started with the anti-addition of the
methyl-substituted benzisoxazole B relative to the gold atom in
A. The first option in this anti addition series is an approach in
which the-methyl group of A and that of B are on the same side
(Scheme 8). Optimization of A and B in this orientation led to
adduct [AB]1, located at 4.8 kcal/mol on the energy surface.
The C1-N bond is formed through TS[AB]1C1, lying at 15.1
kcal/mol and yields the iminium complex C1, whose relative free
energy is 1.4 kcal/mol. In agreement with Liu’s proposal, a
transition state corresponding to the cleavage of NO bond
produces D1 at 3.9 kcal/mol. This step requires 15.3 kcal/mol of
free energy of activation relatively to [AB]1. Of note, the C1C2
axis is chiral in D1, yet the steric hindrance did not allow its
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
inversion. No attack of the oxygen carbonyl to C2 could be found. through TSF1G1 lying at 2.0 kcal/mol, to yield the final complex
Instead, a 6-electrocyclization through TSD1E1 lying at 10.8
kcal/mol takes place to provide intermediate E1, located at 8.2
kcal/mol. This attack pushes the gold fragment in the opposite
direction. Again, -no rotation around the C1C2 axis could be
computed because of the high steric demand. Next, attack of the
sulfonylated nitrogen to C2 via TSE1F1 at 4.7 kcal/mol led to
aziridinium F1 at 2.9 kcal/mol. The C1-N+ bond is then cleaved
G1 found at 36.5 kcal/mol. The LAu fragment moves in the
opposite direction of the incoming R2N+ electrophile during the
C2-Au cleavage. Complex G1 corresponds to the experimentally
observed product with right stereochemistry (Scheme 8). In the
second option, the approach of B to A with the two Me groups
on opposite sides is computed (Scheme 9). This route is
Scheme 11. Free energy profiles (G298, kcal/mol) for the anti addition of B’ to A.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
Scheme 12. Free energy profiles (G298, kcal/mol) for the syn addition of B’ to A.
slightly less facile than the previous one depicted in Scheme 8,
since the highest-lying transition state, TSC1’D1’, is 1.0 kcal/mol
less stable than TSC1D1 (16.3 vs 15.3 kcal/mol respectively). In
addition, the aziridinium complex does not converge. TSE1’F1’
directly leads to the final complex G1’. This is not surprising
since the energy difference between F1 and TSF1G1 is only 0.9
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
-kcal/mol (observed in the previous case, Scheme 8). Thus, the
1,2-N shift is concerted (shown in Scheme 9) instead of being a
stepwise process. The structure G1′ differs from G1, as a syn-
interaction of both gold and the sulfonyl group oxygen is
observed for G1′. Nevertheless, the free energy of G1′ is
virtually the same as that of G1 (-36.0 vs -36.5 kcal/mol,
respectively). Importantly, the attack of O to C1 imposes a
rotation around the C1C2 axis; so gold becomes opposite to the
oxygen. Since B had a different orientation from the beginning,
this route leads to the same diastereomer, with two nitrogen on
the right as depicted for G1′. To model the formation of the
unobserved diastereomer (having the two nitrogen atoms in
trans-relationship), the C1C2 chiral axis has to be inverted; but,
as mentioned above, this looks unworkable for steric reasons.
The only other way would be through a syn-attack of B to A with
respect to gold, which is again possible in two ways (Scheme
10). Once more, no aziridinium complex could be found.
Interestingly, the formation of complexes E2 and E2′ from D2
and D2′, respectively is kinetically facile than in the anti-series.
The syn-attack of B to A is however kinetically disfavored over
the anti-attack. TS[AB]2C2 and TS[AB]2’C2’ were located at 19.6 and
20.7 kcal/mol (Scheme 10), respectively on the energy surface,
while the previous TS[AB]1C1 and TS[AB]1’C1’ were found at 15.1
and 14.5 kcal/mol (Schemes 8 and 9), respectively. In the syn-
series, the first step clearly is rate determining, while the second
step in the anti-series is rate determining.
These results are perfectly in line with the experimental results,
but do not provide an explanation to the inversion of
diastereoselectivity when R = H. Liu and co-workers indeed
reported product with a trans-relationship between the two
nitrogen around the C1C2 bond.12a The four energy profiles
shown above were thus recomputed with benzisoxazole itself.
The results are summarized in Schemes 11 and 12. Among the
two options for anti-attack of benzisoxazole (B') to A (Scheme
11), the [AB']3 to D3 pathway is preferred over the [AB']3' to
D3', as the corresponding free energies of activation are
17.2/16.9 vs 18.5/18.1 kcal/mol. Again, inversion of the C1C2
chiral axis was not possible; thus, 1,2-nitrogen shift was found to
be concerted. The structure G3′ is different from the previous
cases, as the exocyclic double bond does not serve as ligand
anymore. This point is further discussed below.
Scheme 13. Relative free energy of the diastereomers of the final products.
Scheme 14. Relative free energy of the diastereomers of the final G-type complexes (G298, kcal/mol).
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
reaction mixture was diluted with CH2Cl2 (10 mL). The crude mixture was
filtered through a small pad of Celite and concentrated under the reduced
pressure. The crude residue was purified through column
chromatography on neutral alumina using ethylacetate and hexane to
provide 3.
In the case of the syn-attack of benzisoxazole (B') to A (Scheme
12), the [AB']4 to D4 pathway is preferred over [AB']4' to D4';
this is concluded from the comparison of the free energies of
activation of the second steps (17.7 vs 19.6 kcal/mol). The other
features are similar to those previously discussed.
Thus, the anti-attack of benzisoxazole to ynamide seems
predominant, but it does not rationalize the formation of the
experimentally observed products. To explain this apparent
discrepancy, we then focused on the relative stability of the final
products and the final complexes involved for the G series. With
both R = H or Me, the products showing a cis relationship of the
nitrogen atoms are more stable (Scheme 13).
Acknowledgements
We thank UoH, CEFIPRA (Grant no. 5505-2), UPE-II, and
PURSE for financial support. R.V. thanks SERB-NPDF,
S.D. and B.P. thank CSIR India for fellowships. VG thanks
CNRS, UPS and Ecole Polytechnique for financial support.
For the G-type complexes, G4 is the most stable at 37.0
kcal/mol (Scheme 14). It corresponds to the experimentally
observed product by Liu and co-workers. Of note, G4 can be
connected to G3′, lying at -36.0 kcal/mol, via the C1C2 rotation
transition state TSG4G3′. If G3′ is formed preferentially as shown
above, it may then undergo a stereo-mutation through this
transition state. This would require a reasonable free energy of
activation of 22.3 kcal/mol from G3′. We modeled complexes
similar to G4 and G3′ in the R = Me series. Interestingly, the
most stable isomer is G6 at -40.2 kcal/mol. It also corresponds
to the experimentally observed product. Its conversion into the
unobserved isomer G5 would coincidently require 22.3 kcal/mol
of free energy of activation but it would be endergonic by 3.0
kcal/mol.13 From the above DFT computations, we can predict a
similar mechanism with 3-methylbenzo[d]isoxazole (R = Me) and
benzo[d]isoxazole (R = H), which corresponds to Schemes 8
and 11 (upper part). The reason for the different
diastereoisomers obtained could be due to a post-isomerization
since the final complexes have different stability depending on
the substitution pattern.
Keywords: Au-carbene • ynamide • benzisoxazole • 1,2-
migration • ring expansion
[1]
a) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; b) D. Qian, J. Zhang,
Chem. Soc. Rev. 2015, 44, 677; c) D. Pflästerer, A. S. K. Hashmi,
Chem. Soc. Rev. 2016, 45, 1331; d) E. Jiménez‐Núñez, A. M.
Echavarren, Chem. Rev. 2008, 108, 3326; e) A. Corma, A. Leyva‐
Perez, M. J. Sabater, Chem. Rev. 2011, 111, 1657; f) A. Fürstner, P. W.
Davies, Angew. Chem. Int. Ed. 2007, 46, 3410; g) R. Dorel, A. M.
Echavarren, Chem. Rev. 2015, 115, 9028; h) J. Miró, C. del Pozo,
Chem. Rev. 2016, 116, 11924; i) R. Vanjari, S. Dutta, M. P. Gogoi, V.
Gandon, A. K. Sahoo, Org. Lett. 2018, 20, 8077; j) B. Prabagar, R. K.
Mallick, R. Prasad, V. Gandon, A. K. Sahoo, Angew. Chem. Int. Ed.
2019, 58, 2365; k) B. Prabagar, Nayan Ghosh, A. K. Sahoo, Synlett
2017, 28, 2539; l) E. Aguilar, J. Santamaría, Org. Chem. Front. 2019, 6,
1513; m) F. Hu, M. Szostak, Adv. Synth. Catal. 2015, 357, 2583.
a) N. D. Shapiro, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 4160; b) G.
Li, L. Zhang, Angew. Chem. Int. Ed. 2007, 46, 5156; c) L. Zhang, Acc.
Chem. Res. 2014, 47, 877; d) H.‐S. Yeom, S. Shin, Acc. Chem. Res.
2014, 47, 966.
[2]
[3]
a) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115, 9028; b) S.
López, E. Herrero-Gómez, P. Pérez-Galán, C. Nieto-Oberhuber, A. M.
Echavarren, Angew. Chem. Int. Ed. 2006, 45, 6029; c) B. P. Taduri, S.
M. A. Sohel, H.-M. Cheng, G.-Y. Lin, R.-S. Liu, Chem. Commun. 2007,
2530; d) A. Escribano-Cuesta, V. López-Carrillo, D. Janssen, A. M.
Echavarren, Chem. Eur. J. 2009, 15, 5646; e) P. Pérez-Galán, N. J. A.
Martin, A. G. Campaña, D. J. Cárdenas, A. M. Echavarren, Chem.
Asian J. 2011, 6, 482; f) R. E. M. Brooner, T. J. Brown, R. A.
Widenhoefer, Angew. Chem. Int. Ed. 2013, 52, 6259.
Conclusions
In summary, a synthetic manifestation for the construction of
benzo[e][1,3]oxazine derivatives from the Au(I)-catalyzed
annulation of ynamide and substituted-benzisoxazole has been
developed. The transformation involves an α-oximino gold
carbene intermediate, obtained through the attack of the
benzisoxazole to the α-position of Au-activated ynamide
followed by the electron-back donation and delocalization
cleaving the benzisoxazole ON bond and then ring expansion
cascade. Finally 1,2-sulfonamide migration and deauration leads
to benzo[e][1,3]oxazine derivatives (major E-isomer). The
reaction is general, featuring a broad scope. The detailed DFT
studies rationalize the dichotomy of product selectivities.
[4]
a) D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
11260; b) A. Wetzel, F. Gagosz, Angew. Chem. 2011, 123, 7492; c) C.
Shu, Y.-H. Wang, B. Zhou, X.-L. Li, Y.-F. Ping, X. Lu, L.-W. Ye, J. Am.
Chem. Soc. 2015, 137, 9567; d) B. Lu, Y. Luo, L. Liu, L. Ye, Y. Wang, L.
Zhang, Angew. Chem. Int. Ed. 2011, 50, 8358; e) Z. Y. Yan, Y. Xiao, L.
Zhang, Angew. Chem. Int. Ed. 2012, 51, 8624; f) J. Matsuoka, Y.
Matsuda, Y. Kawada, S. Oishi, H. Ohno, Angew. Chem. Int. Ed. 2017,
56, 7444; g) B. W. Shen, Q. Sun, L. Li, X. Liu, B. Zhou, J. Z. Yan, L. W.
Ye, Nat. Commun. 2017, 8, 1748.
[5]
[6]
a) C. Li, L. Zhang, Org. Lett. 2011, 13, 1738; b) P. W. Davies, A.
Cremonesi, L. Dumitrescu, Angew. Chem. Int. Ed. 2011, 50, 8931; c)
H.-H. Hung, Y.-C. Liao, R.-S. Liu, J. Org. Chem. 2013, 78, 7970; d)
Tian, X.; Song, L.; Rudolph, M.; Rominger, F.; Oeser, T.; Hashmi, A. S.
K. Angew. Chem., Int. Ed. 2019, 58, 3589.
Experimental Section
General Procedure for Regioselective Annulation of Ynamides (1)
with Benzo[d]isoxazole (2): To the solution of ynamide 1 (1.0 equiv, 0.3
mmol), benzo[d]isoxazole 2 (2.0 equiv, 0.6 mmol) in CHCl3 (0.3 mL for
0.3 mmol) in the reaction tube was added JohnPhosAu(MeCN)SbF6 (5.0
mol %). The resulting mixture was stirred at rt for 4 h. Progress of the
reaction was monitored periodically by TLC. Upon completion, the
a) A. Prechter, G. Henrion, P. F. D. Bel, F. Gagosz, Angew. Chem. Int.
Ed. 2014, 53, 4959; b) L. Zhu, Y. Yu, Z. Mao, X. Huang, Org. Lett. 2015,
17, 30.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
[7]
[8]
a) J. González, J. Santamaría, Á. L. Suárez-Sobrino, A. Ballesteros,
Adv. Synth. Catal. 2016, 358, 1398; b) M. Chen, N. Sun, H. Chen, Y.
Liu, Chem. Commun. 2016, 52, 6324.
a) A.-H. Zhou, Q. He, C. Shu, Y.-F. Yu, S. Liu, T. Zhao, W.Zhang, X. Lu,
L.-W. Ye, Chem. Sci. 2015, 6, 1265; b) X.-Y. Xiao, A.-H. Zhou, C. Shu,
F. Pan, T. Li, L.-W. Ye, Chem. Asian J. 2015, 10, 1854; c) W.-B. Shen,
X.-Y. Xiao, Q. Sun, B. Zhou, X.-Q. Zhu, J.-Z. Yan, X. Lu, L.-W. Ye,
Angew. Chem. Int. Ed. 2017, 56, 605; d) L. Li, T. -D. Tan, Y. -Q. Zhang,
X. L. L. -W. Ye, Org. Biomol. Chem. 2017,15, 8483.
[9]
a) H. Jin, L. Huang, J. Xie, M. Rudolph, F. Rominger, A. S. K. Hashmi,
Angew. Chem. Int. Ed. 2016, 55, 794; b) H. Jin, B. Tian, X. Song, J. Xie,
M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed.
2016, 55, 12688.
[10] a) L. Sahani, R.-S. Liu, Angew. Chem. Int. Ed. 2017, 56, 1026; b) S. S.
Giri, R. –S. Liu, Chem. Sci. 2018, 9, 2991; c) B. D. Mokar, P. D. Jadhav,
Y. B. Pandit, R. –S. Liu, Chem. Sci. 2018, 9, 4488; d) R. L. Sahani, R.-
S. Liu, Angew. Chem. Int. Ed. 2017, 56, 12736.
[11] a) B. Zhou, T. -D. Tan, X. -Q. Zhu, M. Shang, L. -W. Ye, ACS Catal.
2019, 9, 6393; b) F. Pan, C. Shu, L. W. Ye, Org. Biomol. Chem.
2016,14, 9456; c) G. Evano, C. Theunissen, M. Lecomte, Aldrichimica
Acta 2015, 48, 59; d) X . -N. Wang, H. -S. Yeom, L.. -C. Fang, S. He, Z.
-X. Ma, B. L. Kedrowski, R. P. Hsung, Acc. Chem. Res. 2014, 47, 560;
e) K. A. De-Korver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang, R.
P. Hsung, Chem. Rev. 2010, 110, 5064; f) G. Evano, A. Coste, K.
Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840.
[12] a) P. D. Jadhav, X. Lu, R.–S. Liu, ACS Catal. 2018, 8, 9697; b) W. Xu,
J. Zhao, X. Li, Y. Liu, J. Org. Chem. 2018, 83, 15470.
[13] Note that the isomerization of G3 into the enantiomer of G4’ is also
possible in both series, but the corresponding transition states have
free energy about 5 kcal/mol higher than those discussed.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201901251
Chemistry - An Asian Journal
FULL PAPER
FULL PAPER
Rajeshwer Vanjari, [a] Shubham Dutta, [a]
B. Prabagar[a] Vincent Gandon*[b],[c] and
Akhila K. Sahoo*[a]
Page No. – Page No.
Title
Demonstrated herein is a Au(I)-catalyzed annulation of sulfonyl-protected ynamides
with substituted 1,2-benzisoxazoles for the synthesis of E benzo[e][1,3]oxazine
derivatives. The transformation involves the addition of benzisoxazole to the gold-
activated ynamide, ring expansion of the benzisoxazole fragment to provide an α-
oximino gold carbene, and the 1,2-migration of the sulfonamide motif to the carbene
center to deliver the respective ring expanded benzo[e][1,3]oxazine of predominant
E configuration.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.