Selective 7- endo -Cyclization of 3-Aza-5-alkenols through Oxidative Pd(II)-Catalyzed Olefin Oxyarylation

Article abstract of DOI:10.1055/s-0036-1590939

3-Aza-5-alkenols undergo selective 7- endo - trig cyclization when treated with a catalytic Pd(II) species, CuCl ₂ and ArSnBu ₃ giving 7-aryl-substituted oxazepanes. The intramolecular alkoxylation occurs with formation of a seven-me

Full text of DOI:10.1055/s-0036-1590939

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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en
S. Gazzola et al.
Letter
Synlett
Selective 7-endo-Cyclization of 3-Aza-5-alkenols through
Oxidative Pd(II)-Catalyzed Olefin Oxyarylation
Silvia Gazzolaa
6-exo-trig-cyclization
7-endo-trig-cyclization
Egle M. Beccallib
Tea Borellia
Carlo Castellanoc
Daria Diamantea
Gianluigi Broggini*a
Pg
Pg
Pg
R
Pd(II)
Pd(II)
N
X
N
N
Ar
CuCl2, ArSnBu3
R = H, iPr, iBu
oxidant
R = H
O
OH
O
R
5 examples of different reactions
X = CO2Me, Cl, OCOH, OCOMe
7 examples
24–80%
a Dipartimento di Scienza e Alta Tecnologia, Università dell’Insubria,
Via Valleggio 11, 22100, Como, Italy
gianluigi.broggini@uninsubria.it
b DISFARM, Sezione di Chimica Generale e Organica ‘A. Marchesini’
Università degli Studi di Milano, Via Venezian 21, 20133 Milano,
Italy
c Dipartimento di Chimica, Università degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
Received: 31.08.2017
Accepted after revision: 04.10.2017
Published online: 08.11.2017
we describe the development of an oxidative palladium-
catalyzed procedures for the cyclization of 3-aza-5-alkenols
in the presence of various nucleophiles, mainly focused on
oxyarylation reactions.
DOI: 10.1055/s-0036-1590939; Art ID: st-2017-d0658-l
Abstract 3-Aza-5-alkenols undergo selective 7-endo-trig cyclization
when treated with a catalytic Pd(II) species, CuCl2 and ArSnBu3 giving 7-
aryl-substituted oxazepanes. The intramolecular alkoxylation occurs
with formation of a seven-membered ring only when associated with an
arylating step. Otherwise, 6-exo-trig reactions, providing morpholine
derivatives, were observed.
In our continuing interest in intramolecular transition-
metal-catalyzed reactions to provide access to heterocyclic
systems,7 we have reported a molecular oxygen-promoted
6-exo-trig Pd(II)-catalyzed cyclization that affords 1,4-ox-
azine derivatives from 3-aza-5-alkenols under mild condi-
tions with molecular oxygen as the sole oxidant (Scheme 1,
path a).8 During our investigation, we observed that the 7-
endo-cyclization was preferred to the most common 6-exo
one when R3SnAr was used as the arene source (Scheme 1,
path b).
Key words palladium, heterocycles, domino reactions, Wacker reac-
tion, homogeneous catalysis, cyclization, oxyarylation
Transition-metal-catalyzed reactions involving C–H
bond functionalization can provide a variety of cyclic scaf-
folds, not easily obtained by conventional synthetic meth-
ods, from readily available starting materials.1 In this field,
oxidative palladium-catalyzed reactions have proven to be
fruitful in accessing a wide range of compounds with a
range of molecular architectures.2 Indeed, obtaining molec-
ular complexity through the formation of more than one
bond in a single step presents a powerful synthetic tool.3 To
this purpose, the palladium(II)/copper(II) combination, as
catalyst and oxidizing agent respectively, has been demon-
strated to be productive in developing new procedures for
the synthesis of functionalized (poly)heterocyclic systems.4
In this context, intramolecular Pd-catalyzed processes in-
volving a C–O bond formation starting from alcohols, phe-
nols, or carboxylic acids as well as from secondary amides,
ureas, and carbamates to build oxygen-containing hetero-
cycles are known in the literature.5 The formation of a C–O
bond as one step of domino processes can be successfully
combined with C–C, C–N, or to another C–O bond-forming
step in reactions with alkenes, alkynes, or allenes.6 Herein,
Pg
N
Nu
O
R
R
Pg
Pg
Pd(II)
O2
Pd(II)
N
N
Nu = Ar
OH
Cu(II)
Nu
O
Pg
R
N
R
Nu
path a
ref. 8
path b
or this work
O
Nu = Ar
Scheme 1 Possible Pd-catalyzed exo and endo cyclization of 3-aza-5-
alkenols
Optimal oxyarylation conditions were explored using a
Pd(II) catalyst, copper(II) salt as oxidant, and an aryl or-
ganometallic compound as the aryl source. Taking a lead
from the procedure for the alkene arylation by coupling
with aryl stannanes,9 the 3-aza-5-alkenol 1a was treated
with 10 mol% of PdCl2(MeCN)2 (2), a stoichiometric amount
of Bu3SnPh, an excess of CuCl2 and NaOAc in tetrahydrof-
uran at room temperature for 24 hours. In this way, com-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
S. Gazzola et al.
Letter
Synlett
plete conversion of the substrate led to the 4-tosyl-7-
phenyl-oxazepane 3a being isolated in 75% yield as sole
product (Scheme 2). A COSY experiment was essential to
confirm the structure, allowing us to exclude the possible
formation of a 6-benzyl-morpholine arising from a 6-exo-
trig cyclization process.
oxazepane 3a in 78% yield (Table 1 entry 2). The same sev-
en-membered ring was isolated when a smaller amount of
2 was used, although in lower yield (Table 1 entry 3). The
palladium catalyst was essential for the successful outcome
of the reaction (Table 1 entry 4). However, the oxyarylation
process could be promoted either by Pd(OAc)2 or
Pd(O2CCF3)2 even in the less effective manner (Table 1 en-
tries 5 and 6). In addition to THF as solvent of choice, DMF
and dioxane were likewise suitable as reaction solvents,
whereas the process remained incomplete after 24 hours
using CH2Cl2 (Table 1 entries 7–9). An improvement of the
conversion was achieved when the reaction was carried out
in DMF at 100 °C, which afforded the product in 86% yield
(Table 1 entry 10). The use of Cu(OAc)2 or catalytic CuCl2
under oxygen atmosphere as oxidants supplied the exclu-
sive or prevalent formation of the 6-methyl-4-tosyl-3,4-di-
hydro-2H-1,4-oxazine (4a), arising from an alkoxylation re-
2 (10 mol%)
CuCl2 (1 equiv)
PhSnBu3 (1 equiv)
Ts
Ts
N
N
Ph
OH
O
NaOAc (2 equiv)
THF, r.t., 24 h
1a
3a (75%)
Scheme 2 Oxyarylation reaction of 3-aza-5-alkenol 1a
To improve the yield of the reaction, we examined fur-
ther conditions by changing catalyst, oxidant, solvent, and
temperature (Table 1). The cyclization also proceeded with
the above catalytic system in the absence of base giving the
Table 1 Optimization Conditions for 7-endo-trig Oxyarylation Reactiona
Pd-catalyst
oxidant
Ts
Ts
Ts
Ts
N
N
N
N
Ph
Ph
+
+
OH
O
OH
5a
O
arylating agent
1a
3a
4a
Entry
Catalyst
Oxidant
Arylating agent
Solvent
Temp (°C)
Product (%)b
1c
2
2
CuCl2
Bu3SnPh
THF
THF
THF
THF
THF
THF
DMF
25
3a (75)
3a (78)
3a (62)
SM
2
CuCl2
Bu3SnPh
25
3d
4
2
CuCl2
Bu3SnPh
25
–
CuCl2
Bu3SnPh
25
5
Pd(OAc)2
CuCl2
Bu3SnPh
25
3a (64)
3a (67)
3a (61)
3a (49)
3a (13)
3a (86)
4a (47)
3a (8) + 4a (42)
SM
6
Pd(O2CCF3)2
CuCl2
Bu3SnPh
25
7
2
CuCl2
Bu3SnPh
25
8
2
CuCl2
Bu3SnPh
dioxane
CH2Cl2
DMF
THF
25
9
2
CuCl2
Bu3SnPh
25
10e
11
12f
13
14
15
16h
17i
18j
2
CuCl2
Bu3SnPh
100
25
2
Cu(OAc)2
CuCl2/O2
CuCl2
Bu3SnPh
2
Bu3SnPh
THF
25
2
PhB(OH)2
4-tolylB(OH)2
PhB(OH)2
4-tolylB(OH)2
4-tolylB(OH)2
4-tolylB(OH)2
THF
25
2
CuCl2
THF
25
SM
g
2
CuCl2
THF
reflux
100
100
reflux
–
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
DMF
MeCN
5a (36)
5a (40)
5a (44)
2
2
a Reaction conditions: 1a (0.4 mmol), catalyst (10 mol%), oxidant (1 equiv), arylating agent (1 equiv), solvent (5 mL) for 24 h, unless otherwise noted.
b Yield of isolated products.
c Reaction performed in the presence of NaOAc (2 equiv).
d 5 mol% of 2 instead of 10 mol%.
e The reaction was completed after 8 h.
f CuCl2 (10 mol%).
g A complex mixture of polymeric products was obtained.
h Reaction conditions: 1a (0.4 mmol), Pd(OAc)2 (10 mol%), Cu(OAc)2 (2 equiv), 4-tolylB(OH)2 (1 equiv), LiOAc (3 equiv), DMF (10 mL) at 100 °C for 18 h.
i Conditions (h) with 2 (10 mol%) as catalyst.
j Reaction conditions: 1a (0.4 mmol), 2 (10 mol%), Cu(OAc)2 (3 equiv), 4-tolylB(OH)2 (0.6 mmol), Et3N (2 equiv), MeCN (5 mL) at reflux for 24 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
S. Gazzola et al.
Letter
Synlett
action followed by migration of the first-formed exo-cyclic
C–C double bond inside the ring (Table 1 entries 11 and 12).
Using literature data on the Pd-catalyzed coupling of orga-
noboron reagents and olefin in oxidative conditions as a
precedent, we considered testing organoboron compounds
as the aryl source.10 Firstly, we used 2 as catalyst, CuCl2 as
oxidant and phenylboronic acid, and 4-tolylboronic acid as
arylating agents at room temperature but, in both cases,
only unreacted starting material was recovered (table 1 en-
tries 13 and 14). Performing the reaction at reflux also
failed to provide the desired oxyarylation product (Table 1
entry 15). Following the conditions successfully employed
for the functionalization of alkenes reported by Mori and
co-workers,10c we treated the substrate 1a with 4-tolylbo-
ronic acid in the presence of Pd(OAc)2 as catalyst, Cu(OAc)2,
and LiOAc in DMF at 100 °C (Table 1 entry 16). After 18
hours, the crude mixture revealed only the arylation prod-
uct 5a, isolated in 36% yield. The same outcome was ob-
served using 2 as catalyst instead of Pd(OAc)2 (Table 1 entry
17). Finally, we tested the conditions exploited for the ary-
lating cyclization of alkenyl amines, utilizing 2 as catalyst
with Cu(OAc)2, 4-tolylboronic acid, and Et3N as additive in
MeCN at reflux (Table 1 entry 18).11 However, despite the
complete conversion of the substrate, the desired product
5a was only isolated in 44% yield from the crude mixture.
The totally selective 7-endo-trig cyclization, which al-
lows easy access to the oxazepane ring, prompted us to ex-
tend the oxyarylating conditions to other 3-aza-5-alkenols
in order to provide evidence for a general behavior of this
catalytic system (Scheme 3).12 The reactions on the O-allyl
derivatives 1b–e were carried out using 10 mol% of 2, 1
equivalent of CuCl2, and Bu3SnPh in THF. As with 1a, all the
substrates gave seven-membered ring products. In this case
milder conditions were found to be sufficient for cyclization
because reactions were complete at room temperature in
shorter reaction times (see Table 1, entry 10).
tively, also underwent cyclization, affording two diastereo-
isomeric seven-membered ring products (cis/trans-3d and
cis/trans-3e). Thus, although the reaction was unselective
from a stereochemical viewpoint, with the enantiopure
chiral alkenols the 7-endo approach was solely operating. X-
ray crystal-structure analysis of the trans-3e allowed the
confirmation of the oxazepane structure with two inde-
pendent molecules in the asymmetric unit as well as as-
signment of the S-configuration to the new stereocenter
(Figure 1).14 Assignment of the absolute configuration to all
1
the products was then based on their similar H NMR and
13C NMR spectra.
Figure 1 ORTEP drawing of compound trans-3e at 25% probability level
This general oxyarylation outcome affording only the 7-
endo product with total selectivity is intriguing and, in one
sense, unexpected. Wondering whether this regioselectivi-
ty depends on the substrate or on the reaction conditions,
we decided to investigate other palladium-catalyzed proce-
dures that typically occur by exo-cyclization. Firstly, we ex-
amined carbonylative conditions on the alkenols 1a,b with
a catalytic amount of 2 (5 mol%) and a stoichiometric
amount of CuCl2 in methanol under CO (1 atm) at room
temperature for 24 hours.15 In both cases, the reactions led
to the 2-[(methoxycarbonyl)methyl]-morpholines (6a and
6b) as the sole products, isolated in 65% and 74% yield, re-
spectively, confirming that those conditions are able to pro-
mote an alkoxylation/carboalkoxylation reaction (Scheme
4, eq. 1). An alkoxychlorination process was subsequently
investigated under two different conditions based on the
presence of 2 as catalyst (Scheme 4, eq. 2 and 3).16,17 Work-
ing either with an excess of CuCl2 in THF at room tempera-
ture or NCS as the chlorine source in CH2Cl2 at room tem-
perature, the cyclization occurred with formation of the 5-
chloromethyl-morpholine 7. We also attempted an alkoxyl-
ation/esterification sequence on substrate 1a using analo-
gous conditions to our previous work focused on an aryla-
tion/esterification procedure of indolyl allylamides.18 The
best result was obtained by use of 2 as catalyst and 3 equiv-
R
R
2 (10 mol%)
O
N
CuCl2 (1 equiv)
O
N
S
S
O
O
Ph
PhSnBu3 (1 equiv)
THF, r.t., 24 h
OH
O
3b: R = NO2 (62%)
3c: R = NH2 (67%)
1b: R = NO2
1c: R = NH2
2 (10 mol%)
CuCl2 (1 equiv)
PhSnBu3 (1 equiv)
Ts
R
Ts
Ts
N
N
N
Ph
+
Ph
OH
O
O
R
THF, r.t., 18 h
R
1d,e
cis-3d (44%)
cis-3e (47%)
trans-3d (24%)
trans-3e (38%)
d: R = i-Pr;
e: R = s-Bu
Scheme 3 Oxyarylation process on 3-aza-5-alkenols 1b–d
For instance, 3-aza-5-alkenols 1b,c provided the oxa-
zepanes 3b13 and 3c in similarly good yields, excluding any
issues arising from different protecting groups. Compounds
1d,e, deriving from (+)-valinol and (+)-isoleucinol, respec-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
S. Gazzola et al.
Letter
Synlett
alents of CuCl2 in DMF as well as DMA at 150 °C. These con-
ditions furnished formic and acetic esters (8 and 9, respec-
tively) as well as the chloro derivative 7 (Scheme 4, eq. 4). It
is noteworthy that, despite the low selectivity, the outcome
of the reaction also supplied only six-membered ring prod-
ucts. Finally, the established conditions to carry out the Pd-
catalyzed amino- or oxyacetoxylation of alkenes in the
presence of PhI(OAc)2 as oxidant via Pd(IV) intermediates
were tested.19 The treatment of 1a with Pd(OAc)2 (10 mol%),
PhI(OAc)2 (2 equiv), Bu4NOAc (1 equiv) in acetonitrile at
60 °C for 24 hours, selectively yielded the 5-acetoxymethyl-
morpholine 9 (Scheme 4, eq. 5). On the whole, all the Pd-
catalyzed reactions represented in Scheme 4 resulted in the
6-exo-trig cyclization, confirming that the oxyarylation is
the sole procedure that occurs with 7-endo-trig cyclization.
2 (10 mol%)
CuCl2 (1 equiv)
Ts
Bn
N
O
Bn
O
O
Bu3Sn
(1 equiv)
10 (80%)
Ts
N
THF, r.t., 18 h
OH
2 (10 mol%)
CuCl2 (1 equiv)
1a
Bu3SnR (1 equiv)
THF, r.t., 18 h
R = 2-furyl, 2-thienyl, vinyl, ethynyl
Scheme 5 Oxidative alkoxylation reactions of 3-aza-alkenol 1a with
organotin derivatives
At this point, some experiments were performed in or-
der to elucidate the mechanistic basis of the oxyarylation
reaction. In order to exclude the participation of a chloro-
phenyl derivative as a possible first-formed intermediate,
followed by cyclization,21 we investigated the behavior of
compound 11, obtained carrying out the reaction at 0 °C
(Scheme 6, eq. 1). Under the standard conditions (Table 1
entry 2) no conversion of the substrate was observed. The
intramolecular displacement of the chlorine atom of 11 by
the hydroxyl group, giving the desired oxazepane ring 3a,
was only achieved solely by working at 120 °C in DMSO as
solvent. On the other hand, a hydroalkoxylation process on
the first-formed product of olefin arylation was ruled out
due to the unproductive oxidative Pd(II)-catalyzed cycliza-
tion performed on derivative 5a (Scheme 6, eq. 2).
2 (5 mol%)
CuCl2 (1 equiv)
Pg
Pg
N
N
CO2Me
(eq. 1)
MeOH, CO
r.t., 24 h
OH
O
Pg = Ts: 1a
Pg = Ns: 1b
Pg = Ts: 6a (65%)
Pg = Ns: 6b (74%)
2 (10 mol%)
CuCl2 (3 equiv)
(eq. 2)
(eq. 3)
THF, r.t., 24 h (51%)
Ts
Ts
N
Cl
N
2 (10 mol%)
O
OH
NCS (1.2 equiv)
1a
7
CH2Cl2, N2
r.t., 24 h (42%)
2 (10 mol%)
Ts
Ts
N
OCOH
+
CuCl2 (3 equiv)
Ph
7 (38%)
O
2 (10 mol%)
Ts
DMF, 150 °C, 18 h
Ts
Ts
N
Ts
CuCl2 (1 equiv)
N
N
Cl
8 (35%)
Ph
N
(eq. 1)
+
(eq. 4)
OH
2 (10 mol%)
OH
11 (30%)
O
PhSnBu3 (1 equiv)
THF, 0 °C, 6 h
OH
CuCl2 (3 equiv)
N
OCOMe
1a
3a (15%)
1a
+
7 (42%)
O
DMA, 150 °C, 18 h
2 (10 mol%)
CuCl2 (1 equiv)
THF, r.t., 24 h
DMSO
120 °C, 18 h
9 (29%)
Pd(OAc)2 (10 mol%)
PhI(OAc)2 2 (equiv)
Bu4NOAc (1 equiv)
Ts
Ts
3a (21%)
N
N
OCOMe
2 (10 mol%)
(eq. 5)
OH
O
Ts
CuCl2 (1 equiv)
N
Ph
MeCN, 60 °C, 24 h
(eq. 2)
1a
9 (91%)
OH
THF, 0 °C, 6 h
Scheme 4 Different synthetic transformation performed on alkenols
1a and 1b
5a
Scheme 6 Experimental attempts for mechanism elucidation
To shed light on the central role of the organotin reagent
for the success of the endo-cyclization process, other or-
ganotin derivatives were tested. The overall obtained re-
sults suggest that only arylstannanes are suitable substrates
for domino intramolecular oxylation reactions. The use of
4-benzyloxyphenyl-(tributyl)stannane was found to be ef-
fective for the 7-endo-trig process, providing the oxazepane
1020 in 80% (Scheme 5); conversely, heteroaryl substrates
such as 2-furyl and 2-thienyl (tributyl)stannanes, vinyl and
ethynyl (tributyl)stannanes gave only complex mixtures of
degradation compounds.
The results depicted in Scheme 6 suggest that the for-
mation of the aryl-substituted seven-membered products
involves a cyclization step on a palladium intermediate. The
proposed mechanism to rationalize the selective 7-endo-
trig reaction is outlined in Scheme 7. Initially, olefin inser-
tion in the Pd–aryl bond of the Pd(II) complex I, arising from
transmetalation with Bu3SnAr,22 generates the σ-alkyl–
Pd(II) intermediate II. This latter is susceptible to reversible
β-hydride elimination followed by olefin insertion with op-
posite regiochemistry, involving the benzylic position se-
lectively.23 The resulting favored Pd–benzyl complex III is
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E
S. Gazzola et al.
Letter
Synlett
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Nishikawa, T.; Yoshida, Y.; Kameda, S.; Ide, M.; Saikawa, Y.;
Nakata, M. J. Org. Chem. 2010, 75, 5573. For selected examples of
analogous reactions on allenes, see: (g) Le Bras, J.; Muzart, J.
Chem. Soc. Rev. 2014, 43, 3003. (h) Alcaide, B.; Almendros, P.;
Rodriguez-Acebes, R. J. Org. Chem. 2006, 71, 2346.
Ts
1a
N
OH
I
II
X
LnPdII
H
LnPdIIX
Ts
Ts
β-H elim.
N
Ar
N
+
Ar
OH
OH
III
Ts
N
LnPd0
HX
+
Ar
O
3a
Scheme 7 Proposed mechanism for the 7-endo-trig cyclization
depicted on substrate 1a
A possible alternative and competitive mechanistic
pathway, based on an initial intramolecular formation of
the C–O bond followed by transmetalation of the σ-alkyl–
Pd(II) intermediate with Bu3SnAr, was reasonably ruled out
due to the results of the reactions performed with non-aryl
nucleophiles that afforded 1,4-oxazine derivatives through
6-exo-trig cyclization.
In conclusion, we have developed a direct oxyarylation
of unactivated 3-aza-5-alkenols under oxidative palladium-
catalyzed conditions that occurs selectively by a 7-endo-trig
process. The ability of the catalytic system to promote this
reaction under mild conditions at room temperature opens
up the possibility to develop a stereoselective procedure us-
ing chiral ligands.
Funding Information
Università degli Studi dell’Insubria and Università degli Studi di
Milano are acknowledged for financial support. Support through
CMST COST Action, CA15106 (CHAOS) is also gratefully acknowl-
edged.
C
M
S
T
C
O
S
T
Aocitn
C(
A
1
5
1
0
6)
Supporting Information
Supporting information for this article is available online at
(7) (a) Borelli, T.; Brenna, S.; Broggini, G.; Oble, J.; Poli, G. Adv. Synth.
Catal. 2017, 359, 623. (b) Gazzola, S.; Beccalli, E. M.; Borelli, T.;
Castellano, C.; Chiacchio, M. A.; Diamante, D.; Broggini, G. J. Org.
Chem. 2015, 80, 7226. (c) Broggini, G.; Poli, G.; Beccalli, E. M.;
Brusa, F.; Gazzola, S.; Oble, J. Adv. Synth. Catal. 2015, 357, 677.
(d) Broggini, G.; Barbera, V.; Beccalli, E. M.; Chiacchio, U.;
Fasana, A.; Galli, S.; Gazzola, S. Adv. Synth. Catal. 2013, 355,
1640. (e) Broggini, G.; Borsini, E.; Fasana, A.; Poli, G.; Liron, F.
https://doi.org/10.1055/s-0036-1590939.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
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Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
S. Gazzola et al.
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(20) Spectroscopic Data of 7-[4-(Benzyloxy)phenyl]-4-(4-methyl-
benzenesulfonyl)-1,4-oxazepane (10)
(11) Zheng, J.; Huang, L.; Huang, C.; Wu, W.; Jiang, H. J. Org. Chem.
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(12) General Procedure for the 7-endo-trig Oxyarylation process
A mixture of N-allylaminoalcohol 1 (1.0 equiv), PdCl2(CH3CN)2
(0.1 equiv), CuCl2 (1.0 equiv), and PhSnBu3 (1.0 equiv) in THF
(0.2 M) was stirred at room temperature for 18–24 h. Then the
solvent was evaporated under reduced pressure, and water (10
mL) was added. The aqueous layer was extracted with CH2Cl2 (3
× 10 mL), and the organic layers were dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude
product was purified by silica column chromatography to afford
the corresponding oxazepane 3.
1H NMR (400 MHz, CDCl3): δ = 1.93–1.99 (m, 1 H), 2.16–2.21 (m,
1 H), 2.37 (s, 3 H), 3.15–3.19 (m, 1 H), 3.23–3.29 (m, 1 H), 3.48–
3.54 (m, 1 H), 3.58–3.70 (m, 2 H), 3.99 (dt, J = 12.8, 2.9 Hz, 1 H),
4.54 (dd, J = 5.6, 9.6 Hz, 1 H), 4.97 (s, 2 H), 6.85 (d, J = 8.1 Hz, 2
H), 7.12 (d, J = 8.1 Hz, 2 H), 7.24–7.35 (m, 7 H), 7.63 (d, J = 8.1 Hz,
2 H). 13C NMR (100 MHz, CDCl3): δ = 21.5 (q), 37.6 (t), 46.2 (t),
51.7 (t), 69.8 (t), 70.0 (t), 81.1 (d), 114.8 (d), 126.9 (d), 127.0 (d),
127.4 (d), 127.9 (d), 128.6 (d), 129.8 (d), 135.3 (s), 135.9 (s),
136.9 (s), 143.4 (s), 158.1 (s). MS: m/z = 437 [M+]. Anal. Calcd for
(13) Spectroscopic Data of 7-Phenyl-4-(4-nitrobenzenesulfonyl)-
1,4-oxazepane (3b)
1H NMR (400 MHz, CDCl3): δ = 1.92–2.03 (m, 1 H), 2.24–2.31 (m,
1 H), 3.27 (ddd, J = 13.2, 10.0, 2.8 Hz, 1 H), 3.35–3.42 (m, 1 H),
3.54–3.59 (m, 1 H), 3.67 (dt, J = 13.6, 2.8 Hz, 1 H), 3.73 (ddd, J =
12.4, 7.6, 4.4 Hz, 1 H), 4.08 (dt, J = 13.2, 3.2 Hz, 1 H), 4.62 (dd, J =
9.6, 4.4 Hz, 1 H), 7.14–7.28 (m, 5 H), 7.94 (d, J = 8.4, 2 H), 8.33 (d,
J= 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 37.9 (t), 46.3 (t),
51.7 (t), 69.9 (t), 81.6 (d), 124.5 (d), 125.5 (d), 127.6 (d), 128.1
(d), 128.5 (d), 142.4 (s), 149.9 (s), 150.0 (s). MS: m/z = 362 [M+].
Anal. Calcd for C17H18N2O5S: C, 56.34; H, 5.01; N, 7.73. Found: C,
56.11; H, 5.27; N, 7.48.
C
25H27NO4S: C, 68.63; H, 6.22; N, 3.20. Found: C, 68.74; H, 5.98;
N, 3.47.
(21) (a) Kalyani, D.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 2150.
(b) Kalyani, D.; Satterfield, A. D.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 8419.
(22) For the transmetalation process between Bu3SnAr and palla-
dium(II) species, see: Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508.
(23) (a) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z.-I. Angew.
Chem. Int. Ed. Engl. 1986, 25, 735. (b) Gligorich, K. M.;
Cummings, S. A.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129,
14193. (c) Urkalan, K. B.; Sigman, M. S. Angew. Chem. Int. Ed.
2009, 48, 3146. (d) Werner, E. W.; Urkalan, K. B.; Sigman, M. S.
Org. Lett. 2010, 12, 2848. (e) Satterfield, A. D.; Kubota, A.;
Sanford, M. S. Org. Lett. 2011, 13, 1076.
(14) CCDC 1519865 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F