A Palladium-Catalyzed Oxa-(4+4)-Cycloaddition Strategy towards Oxazocine Scaffolds

Article abstract of DOI:10.1055/s-0040-1706038

A Pd-catalyzed oxa-(4+4)-cycloaddition between 1-azadienes and (2-hydroxymethyl)allyl carbonates is described. Aurone-derived azadienes furnished polycyclic 1,5-oxazocines in good yields. Interestingly, linear azadienes have also been involved and yielded monocyclic heterocycles with complete regioselectivity. DFT calculations were carried out to gain insight on this observation.

Full text of DOI:10.1055/s-0040-1706038

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 981–986
letter
981
en
A. Scuiller et al.
Letter
Synlett
A Palladium-Catalyzed Oxa-(4+4)-Cycloaddition Strategy Towards
Oxazocine Scaffolds
Anaïs Scuillera
Xueyang Liua
Marie Cordierb,1
Julian Garrec*c
Alexis Archambeau*a
Pd(0)-catalyzed
(4+4) cycloaddition
R'O2S
NSO2R'
N
+
BocO
OH
O
24 examples
43–89%
R
R
DFT calculations
mono- and polycyclic
1,5-oxazocines
0
0
0
0-0
0
0
2
-1
3
1
1
-
5
0
3
X
a Laboratoire de Synthèse Organique, UMR 7652, Ecole Polytechnique,
ENSTA Paris, CNRS, IP Paris, 91128 Palaiseau, France
alexis.archambeau@polytechnique.edu
b Laboratoire de Chimie Moléculaire, UMR 9168, Ecole Polytechnique,
CNRS, IP Paris, 91128 Palaiseau, France
c Unité Chimie et Procédés, ENSTA Paris, IP Paris, 91120 Palaiseau,
France
julian.garrec@ensta-paris.fr
Corresponding Authors
Received: 16.03.2021
Accepted after revision: 17.04.2021
Published online: 19.05.2021
Me
Me
N
HO
Me
N
O
DOI: 10.1055/s-0040-1706038; Art ID: st-2021-v0101-l
Me
O
O
HO
Me
Ph
Me
Otonecine
Helianane
(cytotoxic activity)
Nefopam
(analgesic)
Abstract
A Pd-catalyzed oxa-(4+4)-cycloaddition between 1-aza-
(hepatotoxic activity)
dienes and (2-hydroxymethyl)allyl carbonates is described. Aurone-de-
rived azadienes furnished polycyclic 1,5-oxazocines in good yields. In-
terestingly, linear azadienes have also been involved and yielded
monocyclic heterocycles with complete regioselectivity. DFT calcula-
tions were carried out to gain insight on this observation.
CF3
Me
O
OH
Me
N
O
Me
N
CF3
N
N
O
NH
OPh
N
N
N
O
Me
AcN
O
Key words cycloaddition, catalysis, heterocycles, medium-sized rings,
oxazocines, azadienes
KRP-103
ML341
(tachykinin NK1 receptor antagonist)
(trypanocidal activity)
Figure 1 Examples of oxygenated and nitrogenated eight-membered
rings with biological activities
Medium-sized heterocycles are constituents of several
biologically active natural products and pharmaceuticals
and were successfully incorporated in several drug leads2 as
their structure confers them with favorable pharmacoki-
netic properties.3 However, their tedious preparation4–6
hampers a more thorough investigation of these scaffolds in
medicinal chemistry and the development of new methods
for their synthesis is of foremost importance (Figure 1).
Cycloadditions of 1,n-dipoles have recently emerged as
an efficient tool towards medium-sized rings. These trans-
formations involve at least one stable partner and aurone-
derived azadienes have been exploited in numerous (n+4)
cycloadditions as an electrophilic 1,4-dipole (Scheme 1a).7–
the C=C or the C=O bond) and spiro compounds have also
been prepared via (1+2)13 and (3+2) cycloadditions.14
Linear azadienes, derived from chalcones, display a dif-
ferent reactivity. While they also operate as a 1,4-electro-
philic dipole in several (1+4)15 and in a wide variety of (2+4)
cycloadditions (hetero-Diels–Alder),16 they generally act as
an activated alkene (1,2-dipole with the C=C bond) when
opposed to nucleophilic 1,n-dipole (n ≥3) to afford the cor-
responding (n+2) cycloadducts.17–19 (Scheme 1a). Our group
recently reported a Pd-catalyzed (5+4) cycloaddition be-
tween azadienes and vinylcyclopropanes highlighting the
difficulty to involve linear 1-azadienes with complete re-
giocontrol as (3+2) side cycloadducts were also obtained
(Scheme 1b).11c In this context, we became interested in nu-
cleophilic oxa-1,4-dipoles generated in situ from (2-hy-
droxymethyl) allyl carbonates and a Pd0 catalyst.20 Herein
we report a regioselective palladium-catalyzed (4+4)-cy-
cloaddition process involving these intermediates and cy-
12
Several catalyzed cycloadditions relying on -allyl PdII
chemistry employed these electrophiles and Trost de-
scribed the reactivity of a palladium-trimethylenemethane
derivative in a (3+4) cycloaddition.9c Zhao reported the for-
mation of medium-sized nine- and ten-membered hetero-
cycles using vinyl carbonate11a and vinyl oxetanes12 as 1,5-
and 1,6-dipoles, respectively (Scheme 1b). Aurone-derived
azadienes can also behave as an electrophilic 1,2-dipole (via
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

982
A. Scuiller et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa
a. General reactivity of azadienes
as a
as a
as a
as a
1,4-dipole
1,2-dipole
1,4-dipole 1,2-dipole
NTs
NTs
Pd2(dba)3 (5 mol%)
P ligand (10 mol%)
R2
[1+4] [4+4]
[2+4] [5+4]
[3+4] [6+4]
[1+2]
[3+2]
[1+4]
[2+4]
[3+4]
[3+2]
[4+2]
NTs
TsN
O
solvent, rt, 16 h
R1
C3
+
O
R
O
RO2CO
OH
2a
R = Me 2b
O
Ph
R = t-Bu
b. Azadienes in Tsuji–Trost chemistry for the synthesis of medium-sized rings
Ph
1a
3a
R = Et 2c
Oxa-1,5-dipoles - Zhao - 2017
Ar
O
NTs
TsN
O
Pd0 cat. [5+4]
Entry
Substrate
R
Ligand
Solvent
Yield (%)b
O
O
+
O
O
R
O
1
2
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
t-Bu
Me
dppe
dppe
dppe
PPh3
toluene
toluene
toluene
toluene
toluene
toluene
benzene
CH2Cl2
THF
81
77
74
–
Ar
R
PdII
Ar
Previous work from our group - 2021
3
Et
Ar2
NTs
TsN
Ar2
TsN
NC
CN
Pd0 cat. [5+4]
CN
CN
+
4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
+
CN
Ar2
CN
CN
Ar1
5
XantPhos
dppbz
dppe
dppe
dppe
dppe
12
80
92 (86)
25
61
–
CN
Ar1
Ar1
PdII
6
c. This work: Formation of 1,5-oxazocines
7
NTs
PdII
8
TsN
Pd0
R
chemoselective [4+4]
9
O
BocO
OH
10
–
O
with acyclic azadienes
R
a Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd2(dba)3 (0.005
mmol), ligand (0.01 mmol) in solvent (1 mL) for 16 h at room temperature.
b NMR yields; isolated yield in parentheses.
Scheme 1 General reactivity of acyclic and aurone-derived azadienes
clic or acyclic 1-azadienes (Scheme 1c). During the prepara-
tion of this manuscript, Yao and Lin reported a similar study
focusing on aurone-derived azadienes.10c
formation as cycloadduct 3b (86%) and 3c (72%) were isolat-
ed in good yields. The behavior of several aurone-derived 1-
azadienes with different aryl group at the C4 position was
then interrogated. Oxazocines bearing electron-rich p-me-
thoxyphenyl (3d) and 3,4-dimethoxphenyl (3e) rings were
generated smoothly under the previously optimized set of
conditions. The steric hindrance occasioned by an o-methyl
or a 1-naphthyl group did not alter the cycloaddition pro-
cess which afforded smoothly eight-membered rings 3f and
3g, respectively. Electron-deficient aryl groups are also tol-
erated: azadiene 1h derived from m-cyanobenzaldehyde
proved to be a suitable substrate. However, the introduction
of the strong inductive electron-withdrawing p-trifluoro-
methyl group came with a slight yield decrease as our cata-
lytic process furnished 3i (42%) in moderate yield. The pres-
ence of an aromatic halogen atom was also examined and
oxazocine 3j bearing an o-chlorine substituent, suitable for
further functionalization, was prepared in good yield (85%).
Gratifyingly, a heteroaromatic moiety such as 2-thiophenyl
was also introduced and the (4+4) cycloaddition proceeded
smoothly to furnish oxazocine 3k. We tackled the challenge
of introducing an alkyl group at the C4 position. While this
study was limited by the instability of the corresponding
starting material, we were delighted to prepare oxazocine
3l bearing a tert-butyl group in 72% yield. Finally, the sul-
fonamide moiety was also modified and oxazocine 3m
(80%) with a 2-nitrosulfonamide was efficiently generated
(Scheme 2).
To conduct this study, we selected aurone-derived aza-
diene 1a and allyl tert-butyl carbonate 2a as our test sub-
strates. Using dppe as a diphosphine ligand in the presence
of Pd2(dba)3 as the palladium(0) source, we were delighted
to observe, at room temperature (toluene), the efficient for-
mation of eight-membered oxazocine 3a as the sole prod-
uct of the (4+4) cycloaddition (81% yield). Methyl and ethyl
carbonates 2b and 2c, respectively, displayed a similar be-
havior under the same conditions but furnished 3a in a
slightly lower yield. The optimization was then pursued,
and an array of phosphine ligands was examined. While
PPh3 and XantPhos failed to generate efficiently the expect-
ed cycloadduct (Table 1, entries 4 and 5), 1,2-bis(diphenyl-
phosphino)benzene (dppbz) also proved to be suitable for
this transformation. We selected dppe for economic reasons
and performed a screening of solvents which revealed ben-
zene as the solvent of choice in our case as 1,4-oxazocine 3a
was isolated in 86% yield (Table 1, entry 7). The structure of
this new medium-sized heterocycle was then confirmed by
XRD analysis.21
With these optimized conditions in hand, an evaluation
of the scope of this transformation was then carried out.
We demonstrated that the presence of an electron-donating
group on the benzofuran moiety of azadienes 1b and 1c
seems to have little influence on the outcome of this trans-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986

983
A. Scuiller et al.
Letter
Synlett
allowed us to further review the scope of this monocyclic
oxazocine synthesis. Under the previously described reac-
tion conditions, azadienes 4c and 4d, bearing electron-do-
nating substituents (3-OMe; 3,4-OCH2O) on the Ar1 group,
were readily converted into the expected cycloadducts. An
electron-rich heteroaromatic 2-furane was well-tolerated
and our method furnished oxazocine 5e (89%) in very good
yield. Electron-withdrawing substituent (p-F, p-CF3) on Ar1
did not alter the reaction outcome as oxazocines 5f (63%)
and 5g (63%) were obtained from the corresponding aza-
dienes. Various substitutions are also tolerated on the Ar2
ring as 1,5-oxazocines 5h, 5i, and 5j bearing an electron-do-
nating p-methyl, a 2-naphthyl, or an electron-withdrawing
p-fluoro substituent, respectively, were generated in mod-
erate to good yields (Scheme 4).
Pd2(dba)3 (5 mol%)
dppe (10 mol%)
R'O2S
NSO2R'
N
BocO
OH
+
O
benzene (0.1 M), rt, 16 h
O
R
O
R
1b–m
2a
3b–m
TsN
TsN
TsN
O
O
O
O
O
O
Me
3b (86%)
MeO
3c (72%)
3d (66%)
OMe
TsN
TsN
O
TsN
O
O
O
O
O
Me
O
O
3f (63%)
3g (65%)
3e (59%)
OMe
OMe
TsN
TsN
TsN
Pd2(dba)3 (5 mol%)
dppe (10 mol%)
RO2S
Ar2
NSO2R
N
Ar2
O
O
O
4
2
+
BocO
OH
O
Cl
O
O
O
toluene, 50 °C, 1–24 h
Ar1
4a–j
2a
5a–j
3i (42%)
3j (85%)
Ar1
3h (63%)
CN
CF3
2-Ns
N
TsN
TsN
TsN
(4-Ns)N
Ph
O
Ph
O
O
O
O
O
5a (77%)
(13%)a
5b (61%)
S
Ph
Ph
3l (72%)
3m (80%)
3k (63%)
TsN
TsN
TsN
Scheme 2 Formation of benzofuran-fused oxazocines
O
O
O
O
5c (62%)
5d (66%)
5e (89%)
The reactivity of chromanone-derived azadiene 1n was
then questioned. It was here necessary to work at higher
temperature (toluene, 50 °C) to isolate the expected polycy-
clic oxazocine 3n (49%). A putative (4+4) cycloaddition does
not come with a concurrent aromatization, unlike the pre-
vious case of aurone-derived azadienes (Scheme 3).
O
OMe
TsN
O
TsN
O
O
5f (63%)
5g (63%)
F
CF3
NTs
Pd2(dba)3 (5 mol%)
dppe (10 mol%)
TsN
TsN
TsN
TsN
Ph
BocO
OH
O
toluene, 50 °C, 3 h
49%
O
O
O
Me
F
O
1n
O
Ph
2a
3n
Ph
Ph
Ph
5j (43%)
5h (60%)
5i (55%)
Scheme 4 Formation of monocyclic oxazocines. a Reaction run at rt.
Scheme 3 General reactivity of acyclic and aurone-derived azadienes
This encouraging result prompted us to investigate the
behavior of acyclic 1-azadienes derived from chalcones un-
der our (4+4)-cycloaddition conditions. Azadiene 4a was
prepared from benzylideneacetophenone and selected as
our test substrate. An elevation of the temperature (50 °C,
toluene) was also required to achieve a smooth (4+4) cy-
cloaddition towards the corresponding monocyclic 1,5-ox-
azocine 5a (77%), whose structure has been confirmed by
XRD analysis.22 The azadiene 4b, bearing a p-nitrobenzene
sulfonamide moiety, was a suitable substrate under the
same reaction conditions and led to the corresponding me-
dium-sized heterocycle 5b (61%). The ease of preparation of
acyclic 1-azadienes bearing different aryl group at C2 and C4
A mechanism was proposed to illustrate this (4+4) pro-
cess. After complexation (not shown) with the alkene moi-
ety of 2a followed by an oxidative addition to generate PdII-
-allyl complex A, the in situ generated tert-butanolate can
deprotonate the alcohol moiety and lead to the 1,4-dipole
B. An oxa-Michael addition into azadiene 4a then generates
the key PdII--allyl complex intermediate C. The eight-
membered ring 5a could result from pathway (a) after addi-
tion of the sulfonamide anion to the -allyl-PdII. As carbon
C3 is not highly congested, one could imagine an alternative
pathway (b) involving a (4+2) cycloaddition leading to tet-
rahydropyran 6. While this product could never be ob-
served, a fast aza-Claisen rearrangement could also lead to
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986

984
A. Scuiller et al.
Letter
Synlett
oxazocine 5a but this reaction pathway has been ruled as
DFT calculations showed a very high energy barrier of
about 45 kcal/mol (Scheme 5).23
that the two structures have almost the same free energy:
reaching the transition state requires a minimal amount of
structural reorganization that comes together with only a
small increase in cycle tension. It is also worth stressing
that there is a stabilizing electrostatic attraction between
the negatively charged nitrogen atom and the carbocation
in Ra which is exacerbated by the low dielectric constant of
the solvent. A competitive (4+2) pathway (b) could occur
from reactant conformer Rb (GRb = ca. GRa). However, its
chemical step is associated with a higher activation barrier
(GTSb − GRb = ca. 10 kcal/mol). This is due to the boat confor-
mation of TSb, which typically requires more energy to be
formed from the reactant. A chair transition state TSc can be
reached following another (4+2) pathway (c) with a much
lower free-energy barrier (GTSc − GRc = ca. 3 kcal/mol). How-
ever, the overall free-energy landscape of this pathway is
much higher than the two others due to the high free ener-
gy of Rc with respect to Ra and Rb. As highlighted in the gray
box, this is due to a strong steric conflict between the sulfo-
nyl group and the oxygen atom to which the carbocation is
attached in Rc. Finally, the free energy of the eight-mem-
bered ring is only slightly higher than that of the most sta-
ble six-membered ring that we obtained (GPa – GPb = ca. 4
kcal/mol). The overall picture that emerges from our calcu-
lations is that the system gets kinetically trapped into the
free energy basin corresponding to Pa (Figure 2).
2a
Pd0L2
Ts
N
L2 = dppe
(a)
CO2
O
Ph
t-BuO
5a
(a)
Ph
PdIIL2
PdIIL2
Ts
N
aza-Claisen
rearrangement
(b)
(b)
O
Ph
A
(b)
C
HO
ΔG = +45 kcal/mol
C3
Ph
PdIIL2
TsN
NTs
Pd0L2
Ph
O
t-BuOH
Ph
B
O
Ph
6
4a
Ph
zwitterionic 1,4-dipole
Scheme 5 Proposed mechanism
In order to shed some light on the observed, regioselec-
tivity favoring a (4+4) cycloaddition, we explored the mi-
croscopic details of the reaction using density functional
theory (DFT) calculations. We identified three reactant con-
formers, namely Ra, Rb and Rc, which are in thermal equilib-
rium (represented with dashed line in Figure 2). It turns out
that the (4+4) cycloaddition is virtually barrierless (GTSa
=
ca. GRa). Taking a closer look at the structures of Ra and TSa,
we notice that they are very similar, which, by virtue of the
Hammond principle, provides an explanation for the fact
Figure 2 Free energy profiles of the cyclization reactions following a (4+4)-cycloaddition mechanism (pathway (a) in green), a (4+2)-cycloaddition
mechanism involving a boat conformation at the TS (pathway (b) in blue) and a (4+2)-cycloaddition mechanism involving a chair conformation at the TS
(pathway (c) in red). Each free energy is defined relative to the most stable conformer of the reactant, namely Rb. Conformational transitions and chem-
ical steps are represented with dashed and plain lines, respectively. For the sake of clarity, the full molecular structure is represented only for Rb. For all
the other stationary states, only key backbone atoms involved in the cyclization process are represented (hydrogen atoms are removed from the repre-
sentation too). More detailed representations of the same structures are provided in the Supporting Information. For each reaction pathway, the nucle-
ophilic attack is represented with an orange arrow and the corresponding forming bond at the TS is depicted with orange dots. The lower gray box
provides additional representations of the reactive backbone of Rb and Rc in order to emphasize the steric conflict between the sulfonyl group (plain
spheres) and the endocyclic oxygen atom (transparent magenta sphere).
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986

985
A. Scuiller et al.
Letter
Synlett
In this study, we have disclosed an original pathway to
benzofuran-fused [1,5]-oxazocines via a palladium-cata-
lyzed (4+4) cycloaddition with (2-hydroxymethyl)allyl car-
bonates.24 Acyclic azadienes have also been involved in this
process and monocyclic eight-membered rings were ob-
tained with complete regioselectivity and DFT calculations
were carried out to rationalize this peculiar finding.
(7) For a (1+4) cycloaddition, see: Wang, C.-S.; Li, T.-Z.; Cheng, Y.-C.;
Zhou, J.; Mei, G.-J.; Shi, F. J. Org. Chem. 2019, 84, 3214.
(8) For (2+4) cycloadditions, see: (a) Rong, Z.-Q.; Wang, M.; Chow,
C. H. E.; Zhao, Y. Chem. Eur. J. 2016, 22, 9483. (b) Gu, Z.; Wu, B.;
Jiang, G.-F.; Zhou, Y.-G. Chin. J. Chem. 2018, 36, 1130. (c) Fan, T.;
Zhang, Z.-J.; Zhang, Y.-C.; Song, J. Org. Lett. 2019, 21, 7897. (d) Li,
X.; Yan, J.; Qin, J.; Lin, S.; Chen, W.; Zhan, R.; Huang, H. J. Org.
Chem. 2019, 84, 8035. (e) Marques, A.-S.; Duhail, T.; Marrot, J.;
Chataigner, I.; Coeffard, V.; Vincent, G.; Moreau, X. Angew.
Chem. Int. Ed. 2019, 58, 9969.
Conflict of Interest
(9) For (3+4) cycloadditions, see: (a) Chen, J.; Jia, P.; Huang, Y. Org.
Lett. 2018, 20, 6715. (b) Gao, Z.-H.; Chen, K.-Q.; Zhang, Y.; Kong,
L.-M.; Li, Y.; Ye, S. J. Org. Chem. 2018, 83, 15225. (c) Trost, B. M.;
Zuo, Z. Angew. Chem. Int. Ed. 2020, 59, 1243. (d) Kumari, P.; Liu,
W.; Wang, C.-J.; Dai, J.; Wang, M.-X.; Yang, Q.-Q.; Deng, Y.-H.;
Shao, Z. Chin. J. Chem. 2020, 38, 151. (e) Liu, Y.-Z.; Wang, Z.;
Huang, Z.; Zheng, X.; Yang, W.-L.; Deng, W.-P. Angew. Chem. Int.
Ed. 2020, 59, 1238. (f) Yan, R.-J.; Liu, B.-X.; Xiao, B.-X.; Du, W.;
Chen, Y.-C. Org. Lett. 2020, 22, 4240.
(10) For (4+4) cycloadditions, see: (a) Ni, H.; Tang, X.; Zheng, W.;
Yao, W.; Ullah, N.; Lu, Y. Angew. Chem. Int. Ed. 2017, 56, 14222.
(b) Jiang, B.; Du, W.; Chen, Y.-C. Chem. Commun. 2020, 56, 7257.
(c) Li, Q.; Pan, R.; Wang, M.; Yao, H.; Lin, A. Org. Lett. 2021, 23,
2292.
(11) For (5+4) cycloadditions, see: (a) Yang, L.-C.; Rong, Z.-Q.; Wang,
Y.-N.; Tan, Z. Y.; Wang, M.; Zhao, Y. Angew. Chem. Int. Ed. 2017,
56, 2927. (b) Rong, Z.-Q.; Yang, L.-C.; Liu, S.; Yu, Z.; Wang, Y.-N.;
Tan, Z. Y.; Huang, R.-Z.; Lan, Y.; Zhao, Y. J. Am. Chem. Soc. 2017,
139, 15304. (c) Scuiller, A.; Karnat, A.; Casaretto, N.;
Archambeau, A. Org. Lett. 2021, 23, 2332.
(12) For a (6+4) cycloaddition, see: Wang, Y.-N.; Yang, L.-C.; Rong, Z.-
Q.; Liu, T.-L.; Liu, R.; Zhao, Y. Angew. Chem. Int. Ed. 2018, 57,
1596.
The authors declare no conflict of interest.
Funding Information
This work was supported by the Agence Nationale de la Recherche
(JCJC grant CycloSyn, ANR-18-CE07-0008). X.L. thanks the Agence Na-
tionale de la Recherche for a M2 grant. A.S. thanks Labex CHARMM-
MAT (ANR-11-LABX-0039) for a M2 grant and the Agence Nationale
de la Recherche for a PhD fellowship.
A
g
e
n
c
e
N
ati
o
n
a
l
e
d
el
a
Re
c
herc
h
e
(A
N
R-18-C
E
0
7-0
0
0
8
)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706038.
S
u
p
p
orti
n
gInform
a
ti
o
nS
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) Current address: Univ Rennes, CNRS ISCR-UMR 6226, 35000
Rennes, France.
(2) (a) Bodireddy, M. R.; Krishnaiah, K.; Babu, P. K.; Bitra, C.; Gajula,
M. R.; Kumar, P. Org. Process Res. Dev. 2017, 21, 1745.
(b) Audouze, K.; Nielsen, E. Ø.; Peters, D. J. Med. Chem. 2004, 47,
3089. (c) Dandapani, S.; Germain, A. R.; Jewett, I.; Le Quement,
S.; Marie, J.-C.; Muncipinto, G.; Duvall, J. R.; Carmody, L. C.;
Perez, J. R.; Engel, J. C.; Gut, J.; Kellar, D.; Siqueira-Neto, J. L.;
McKerrow, J. H.; Kaiser, M.; Rodriguez, A.; Palmer, M. A.; Foley,
M.; Schreiber, S. L.; Munoz, B. ACS Med. Chem. Lett. 2014, 5, 149.
(d) Tanioka, A.; Deguchi, T. Drug. Res. 2017, 67, 302.
(3) (a) Khan, A. R.; Parrish, J. C.; Fraser, M. E.; Smith, W. W.; Bartlett,
P. A.; James, M. N. G. Biochemistry 1998, 37, 16839. (b) Taylor, R.
D.; Maccoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.
(c) Rezai, T.; Yu, B.; Millhauser, G. L.; Jacobson, M. P.; Lokey, R. S.
J. Am. Chem. Soc. 2006, 128, 2510. (d) Kwon, Y.-U.; Kodadek, T.
Chem. Biol. 2007, 14, 671.
(13) Fang, Q.-Y.; Yi, M.-H.; Wu, X.-X.; Zhao, L.-M. Org. Lett. 2020, 22,
5266.
(14) (a) Verma, K.; Taily, I. M.; Banerjee, P. Org. Biomol. Chem. 2019,
17, 8149. (b) Trost, B. M.; Zuo, Z. Angew. Chem. Int. Ed. 2021, 60,
5806.
(15) (a) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org. Chem. 2011,
76, 2374. (b) Yang, M.; Wang, T.; Cao, S.; He, Z. Chem. Commun.
2014, 50, 13506. (c) Zheng, P.-F.; Ouyang, Q.; Niu, S.-L.; Shuai, L.;
Yuan, Y.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. J. Am. Chem. Soc. 2015,
137, 9390. (d) Li, H.; Luo, J.; Li, B.; Yi, X.; He, Z. Org. Lett. 2017,
19, 5637. (e) Wang, L.; Li, S.; Blümel, M.; Puttreddy, R.;
Peuronen, A.; Rissanen, K.; Enders, D. Angew. Chem. Int. Ed.
2017, 56, 8516.
(16) (a) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517.
(b) Esquivias, J.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc.
2007, 129, 1480. (c) Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen,
Y.-C. Angew. Chem. Int. Ed. 2008, 47, 9971. (d) Jiang, X.; Shi, X.;
Wang, S.; Sun, T.; Cao, Y.; Wang, R. Angew. Chem. Int. Ed. 2012,
51, 2084. (e) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M.
Z.; O’Riordan, T. J. C.; Smith, A. D. Angew. Chem. Int. Ed. 2013, 52,
11642.
(4) For books on medium-sized-ring synthesis, see: (a) Newkome,
G. R. Eight-Membered and Larger Rings, In Progress in Heterocy-
clic Chemistry; Suschitzky, H.; Scriven, E. F. V., Ed.; Elsevier:
Amsterdam, 1991, 319. (b) Quirke, J. M. E. Eight-Membered and
Larger Rings Systems, In Heterocyclic Chemistry; Suschitzky, H.,
Ed.; Royal Society of Chemistry: London, 1986, 455.
(5) For reviews on medium-sized rings, see: (a) Molander, G. A. Acc.
Chem. Res. 1998, 31, 603. (b) Yet, L. Chem. Rev. 2000, 100, 2963.
(c) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073.
(d) Roxburgh, C. J. Tetrahedron 1993, 49, 10749. (e) Donald, J. R.;
Unsworth, W. P. Chem. Eur. J. 2017, 23, 8780. (f) Clarke, A. K.;
Unsworth, W. P. Chem. Sci. 2020, 11, 2876. (g) Choury, M.;
Basilio Lopes, A.; Blond, G.; Gulea, M. Molecules 2020, 25, 3147.
(6) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(b) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117.
(17) (a) Verma, K.; Banerjee, P. Adv. Synth. Catal. 2017, 359, 3848.
(b) Bai, D.; Yu, Y.; Guo, H.; Chang, J.; Li, X. Angew. Chem. Int. Ed.
2020, 59, 2740.
(18) Burlow, N. P.; Howard, S. Y.; Saunders, C. M.; Fettinger, J. C.;
Tantillo, D. J.; Shaw, J. T. Org. Lett. 2019, 21, 1046.
(19) For a recent exception, see this (4+3) cycloaddition: Yuan, C.;
Zhang, H.; Yuan, M.; Xie, L.; Cao, X. Org. Biomol. Chem. 2020, 18,
1082.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986

986
A. Scuiller et al.
Letter
Synlett
(20) (a) Gao, R.-D.; Xu, Q.-L.; Zhang, B.; Gu, Y.; Dai, L.-X.; You, S.-L.
Chem. Eur. J. 2016, 22, 11601. (b) Yuan, Z.; Pan, R.; Zhang, H.; Liu,
L.; Lin, A.; Yao, H. Adv. Synth. Catal. 2017, 359, 4244. (c) Mao, B.;
Liu, H.; Yan, Z.; Xu, Y.; Xu, J.; Wang, W.; Wu, Y.; Guo, H. Angew.
Chem. Int. Ed. 2020, 59, 11316. (d) Song, X.; Xu, L.; Ni, Q. Org.
Biomol. Chem. 2020, 18, 6617. (e) Dai, W.; Li, C.; Liu, Y.; Han, X.;
Li, X.; Chen, K.; Liu, H. Org. Chem. Front. 2020, 7, 2612.
0.015 mmol, 0.05 equiv) and dppe (12.0 mg, 0.03 mmol, 0.1
equiv) were added in benzene (3 mL, 0.1 M) and stirred for 15
min at rt. Carbonate 2a (84.7 mg, 0.45 mmol, 1.5 equiv) and
azadiene 1a (113 mg, 0.30 mmol) were then added, the reaction
mixture was stirred at rt for 16 h, filtered over silica, and con-
centrated under reduced pressure to afford the crude product.
The residue was purified by flash column chromatography on
silica gel (petroleum ether/EtOAc = 85:15) to afford 3a (109 mg,
81%) as a yellow solid; mp 46 °C.
(21) CCDC 2040269 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
IR (neat): 2922, 1597, 1494, 1452, 1384, 1346, 1180, 1157,
www.ccdc.cam.ac.uk/structures
1095, 1069, 747 cm–1 1H NMR (400 MHz, CDCl3, –20 °C):  =
.
(22) CCDC 2040268 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
7.86 (d, J = 8.2 Hz, 2 H), 7.61–7.58 (m, 1 H), 7.41–7.12 (m, 10 H),
5.45 (s, 1 H), 5.24 (s, 1 H), 5.02 (s, 1 H), 4.91 (d, J = 13.5 Hz, 1 H),
4.58 (d, J = 12.6 Hz, 1 H), 4.24 (d, J = 12.6 Hz, 1 H), 4.10 (d, J =
13.5 Hz, 1 H), 2.44 (s, 3 H). 13C NMR (101 MHz, CDCl3, –20 °C): 
= 154.4, 153.0, 143.5, 139.3, 138.1, 136.4, 129.3 (2 C), 128.5,
128.4 (2 C), 127.8 (2 C), 127.6 (2 C), 126.6, 124.6, 123.1, 122.7,
120.0, 116.0, 111.3, 79.0, 75.9, 54.7, 21.6. HRMS (ESI+): m/z [M +
H]+ calcd for C26H24NO4S+: 446.1421; found: 446.1410.
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/structures
(23) See the Supporting Information.
(24) Typical Procedure for the Pd-Catalyzed (4+4) Cycloadditions
of 2a with 1a (Benzene, rt)
In a screw-cap SVL tube filled with argon, Pd2(dba)3 (13.7 mg,
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 981–986