Enantioenriched α-Vinyl 1,4-Benzodiazepines and 1,4-Benzoxazepines via Enantioselective Rhodium-Catalyzed Hydrofunctionalizations of Alkynes and Allenes

Article abstract of DOI:10.1021/acs.joc.1c01268

Benzofused seven-membered heterocycles such as 1,4-benzo[e]diazepines (1,4-BZDs) and 1,4-benzo[e]oxazepines (1,4-BZOs) were efficiently synthesized by Rh-catalyzed hydrofunctionalization of internal alkynes and allenes in good to excellent yields. The asy

Full text of DOI:10.1021/acs.joc.1c01268

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Note
Enantioenriched α‑Vinyl 1,4-Benzodiazepines and 1,4-
Benzoxazepines via Enantioselective Rhodium-Catalyzed
Hydrofunctionalizations of Alkynes and Allenes
́
́
Alvaro Velasco-Rubio, Rodrigo Bernárdez, Jesus A. Varela, and Carlos Saá*
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ABSTRACT: Benzofused seven-membered heterocycles such as 1,4-
benzo[e]diazepines (1,4-BZDs) and 1,4-benzo[e]oxazepines (1,4-BZOs)
were efficiently synthesized by Rh-catalyzed hydrofunctionalization of
internal alkynes and allenes in good to excellent yields. The asymmetric
hydroamination of (aminomethyl)anilines gave rise to 3-vinyl-1,4-BZDs
with excellent enantioselectivities. Orthogonal N-deprotection of 1,4-
BZDs allowed an easy entry to an advanced pyrrolobenzodiazepine
metabolite of the V2-receptor antagonist Lixivaptan.
enzofused seven-membered rings containing two heter-
oatoms (N, O) comprise the structural core of a
transfer cyclization reactions.16 Although all of these strategies
could be considered very useful to build the azaheterocycle
skeleton, they lack the capacity to introduce stereodefined
Csp3 formation in C-3, e.g., a chiral allylic/homoallylic amine
(Figure 1)
B
privileged family of drugs employed to treat several
indications.1 1,4-Benzo[e]diazepines (1,4-BZDs) are known
to interact with a variety of human receptors2 and have been
extensively used to treat Central Nervous System (CNS)
illnesses,3 cancer,4 or HIV virus.5 In addition, several drugs and
advanced metabolites possess a stereodefined chiral Csp3 in C-
3 (1,4 benzodiazepine numbering), which enhances their
biological activity,6 e.g., the pyrrolobenzodiazepines (PBZDs),7
bearing a [7,5] ring fusion with an N-bridgehead (Figure 1).
On the other hand, 1,4-benzo[e]oxazepines (1,4-BZOs)
possess recognized pharmacological activity in the treatment
of Alzheimer disease8 and as tranquilizers.9
These highly relevant biological activities of 1,4-BZDs have
inspired chemists over the years to develop a variety of
synthetic approaches based on Friedel−Crafts reactions,10 ring
expansions,11 aza-Michael cyclizations,12 click chemistry,13
heteroannulations,14 Ugi condensations,15 or 1,5-hydride
In this regard, transition metal-catalyzed asymmetric hydro-
functionalization/cyclization of allenes/internal alkynes has
been used as an eco-friendly strategy to afford enantioenriched
five- and six-membered heterocycles from achiral starting
materials.17 The combination with a catalytic amount of
Brønsted acids allows the π-allyl intermediate formation that
can be subsequently trapped with N- and O-nucleophiles to
afford the corresponding chiral allylic amine or allyl ether
(Scheme 1).17 This methodology was pioneered by Yamamoto
(Scheme 1a),18 who was able to obtain a racemic five-
membered ring in a Pd-catalyzed hydroamidation of allenes,18a
and later the enantioenriched five- and six-membered rings in a
Pd-catalyzed hydroamidation of internal alkynes.18b The
groups of Toste, Liu, and Widenhoefer were working
successfully on catalytic Au and Bronsted acid heterocycliza-
tions of allenes (Scheme 1b).19 Recently, the group of Breit20
has developed an intensive study of the Rh-catalyzed
hydrofunctionalizations to afford enantioenriched α-vinylated
five- and six-membered azaheterocycles (through NTs
nucleophiles)20e,f and tetrahydropyrans (Scheme 1c).20g
However, only a single benzofused seven-membered azahetero-
cycle, 4-vinyl-tetrahydrobenzo[b][1,5]-benzoxazepine, could
Received: May 31, 2021
Published: July 14, 2021
Figure 1. Bioactive 1,4-benzodiazepines and 1,4-benzoxazepines.
https://doi.org/10.1021/acs.joc.1c01268
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© 2021 American Chemical Society
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Note
To accomplish our synthetic goal, we then proceeded to
evaluate the Rh-catalyzed asymmetric hydroamination of 1d
(Table 1), with a slight modification of our previous conditions
regarding reactants loadings and temperature.
Scheme 1. Rh-Catalyzed Hydrofunctionalizations of Alkynes
and Allenes to α-Vinylated Heterocycles
Table 1. Optimization of Rh-Catalyzed Asymmetric
Hydroamination of Internal Alkynes 1d and 1e
chiral ligand
Brønsted
acid
1,4-BDZ 2
yield (%)
a
entry alkyne 1
(L*)
er
1
1d
Josiphos-SL-
J002−1
rac-BNP
acid
<5
2
3
1d
1d
(R)-BINAP
(R)-BINAP
PPTS
rac-BNP
acid
rac-BNP
acid
rac-BNP
acid
rac-BNP
acid
TFA
TFA
traces
19
57:43
57:43
57:43
67:33
80:20
60:40
b
4
5
6
7
8
1d
1d
1d
1e
1e
(R)-BINAP
58
73
81
50
60
(R)-DTBM-
Segphos
(S)-DTBM-
Garphos
(R)-DTBM-
Garphos
(R)-DTBM-
Garphos
be synthesized in low chemical yield but good ee using the
same protocol.21 Herein, we report a Rh-catalyzed hydro-
functionalization of internal alkynes and allenes to benzofused
seven-membered heterocycles employing substrates bearing
N−Ar groups as nitrogenated nucleophiles.21g The enantiose-
lective hydroamination to 3-vinyl-1,4-BZDs and hydroalkox-
ylation to 3-vinyl-1,4-BZO is conveniently disclosed (Scheme
1).
c
d
a
Reaction conditions: 4 mol % [Rh(cod)Cl]2, 10 mol % L*, 10 mol %
Brønsted acid, DCE (0.4 M). 5 days. The (S)-2d was observed as a
major enantiomer. Reaction performed at 70 °C. PMP = p-
b
c
We began our study exploring the virtually unknown
intramolecular Rh-catalyzed hydrofunctionalizations of internal
alkynes to seven-membered heterocycles (Scheme 2). Gratify-
d
(methoxyphenyl).
Scheme 2. Rh-Catalyzed Hydrofunctionalizations of
Internal Alkynes 1a−d to Seven-Membered Heterocycles
2a−d
Using Josiphos-SL-J002−1, a member of the typical family
of chiral ligands for intramolecular asymmetric hydroamina-
tions,20e only gave traces of 2d (Table 1, entry 1). When (R)-
BINAP was used as chiral ligand, 3-vinyl-1,4-benzodiazepine
2d could only be obtained in a low 19% yield and 57:43 er in
the presence of rac-BNP as Brønsted acid (Table 1, entries 2
and 3). The yield increased to 58%, without any erosion of
enantioselectivity, when the reaction was run for 5 days at the
same temperature (Table 1, entry 4). Pleasingly, when chiral
biaryl phosphine ligands (R)-DTBM-Segphos and (S)-DTBM-
Garphos were used (Table 1, entries 5 and 6), good yields and
promising enantioselectivities of 2d (73−81%, 14−34% ee)
were obtained.24 We reasoned that a more rigid N-protecting
group (e.g., tosyl group) might help to increase the
enantioselectivity of the hydroamination. In fact, when 1e
(PG = Ts) was used in the presence of (R)-DTBM-Garphos as
chiral ligand and TFA as Brønsted acid (pKa = 0.52), the
corresponding 3-vinyl-1,4-benzodiazepine 2e was obtained in
50% yield and 80:20 er (Table 1, entry 7).25 Unfortunately,
reaction at a higher temperature, 70 °C, had limited effect in
yield with quite considerable erosion of enantioselectivity
(Table 1, entry 8).24
ingly, benzylic alcohol 1a (X = O, Z = NTs) smoothly cyclized,
under standard conditions,20a to the corresponding 3-vinyl-1,4-
benzoxazepine 2a in very good yield. On changing the nature
of the heteroatoms, using oxygen as alkyne tether and PMP-
protected amine as a nucleophile,22 1b (X = NPMP, Z = O),
the heterocyclization efficiency to 2b dropped to 41% yield. In
this case, partial depropargylation of starting material was
detected, whereas when the carbon-tethered alkynylamine 1c
(X = NPMP, Z = CH2) was used, the corresponding α-vinyl-2-
benzazepine 2c was isolated in a moderate 57% yield.23 To our
delight, when both the nucleophile and the alkyne tether were
nitrogen atoms, 1d (X= NPMP, Z = NBoc), the hydro-
amination smoothly occurred to give the desired 3-vinyl-1,4-
BDZ 2d in fairly good yield.
The fact that the best result regarding the enantioselectivity
was 60% made us wonder about the influence of the Brønsted
acid in the isomerization process of the internal alkyne to the
terminal allene. So, we decided to directly synthesize allenes 3d
and 3e to make them react under the optimized conditions
(Table 2). Unfortunately, when using chiral biaryl phosphine
ligands (R)-DTBM-Segphos and (R)-DTBM-Garphos, allene
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Table 2. Optimization of Rh-Catalyzed Asymmetric
Hydroamination of Allenes 3d and 3e
Scheme 3. Scope of the Asymmetric Rh-Catalyzed
Hydrofunctionalizations of Allenes 3
chiral ligand
1,4-BDZ 2
yield (%)
a
entry allene 3
(L*)
Brønsted acid
er
1
3d
3d
3d
3e
3e
3e
3e
(R)-DTBM-
rac-BNP acid
50
76
70
80
70
90
60
74:26
Segphos
2
(R)-DTBM-
Garphos
(R)-DTBM-
Garphos
(R)-DTBM-
Segphos
(R)-DTBM-
Garphos
(R)-DTBM-
Garphos
(R)-DTBM-
Garphos
rac-BNP acid
rac-BNP acid
PPTS
75:25
78:22
90:10
95:5
b
3
4
5
6
PPTS
ClCH2CO2H
PPTS
91:9
c
7
95:5
a
a
b
Reaction conditions: 4 mol % [Rh(cod)Cl]2, 10 mol % L*, 10 mol %
PPTS. ClCH2CO2H
b
c
Brønsted acid, DCE (0.4 M). 0.2 M instead of 0.4 M. 70 °C. PMP =
p-(methoxyphenyl).
hydroxylated allene 3a smoothly cyclized to the 3-vinyl-1,4-
benzoxazepine 2a (90% yield) but with a moderate 78:22 er.
From the literature28 and our own observations/results
during the screening of the reaction conditions, we cannot
anticipate which one of the two competing pathways typically
proposed for Rh-catalyzed hydrofunctionalizations based on
“inner” (reductive elimination) or “outer” (external nucleo-
phile attack) is operating.19,20 The nature of the nucleophile
plays a crucial role in the last C−X (N, O) bond formation
(hydroamination vs hydroalkoxylation). Thus, when NHPMP
acts as a nucleophile, an SN2 attack over the Rh-π-allyl complex
may occur (“outer sphere”).29 On the other hand, alcohols
typically follow a reductive elimination when they act as a
nucleophile (“inner sphere”), and this may cause the low
enantioselectivity found in the cyclization of benzylic alcohol
3a.30
We next turned toward derivatization of the enantioenriched
3-vinyl-1,4-benzodiazepine obtained (Scheme 4). Orthogonal
N-deprotection of the PMP group of 2e was carried under
typical oxidative cleavage conditions (CAN in a mixture of
MeCN/H2O) to give rise to the desired benzylammonium salt
4 in 85% yield.31 On the other hand, removal of the Ts group
of 2e could be achieved using mild reducing conditions (Na,
naphthalene, rt) to afford the aniline 5 in 85% yield.32 The
benzylammonium salt 4 reacted smoothly with acryloyl
chloride to afford amide 6 in 65% yield. Finally, an RCM
(Hoveyda−Grubbs catalyst second G, 87%) gave rise to the
pyrrol-2-one ring 7, which is an advanced metabolite of
Lixivaptan, a vasopressin V2-receptor antagonist to treat
congestive heart failure and liver cirrhosis.7a,33 The derivatiza-
tion process occurred without erosion of enantioselectivity
(94:6 er).
3d gave rise to 3-vinyl-1,4-benzodiazepine 2d in moderate to
good yields with modest enantioselectivities (Table 2, entries
1−3). Interestingly, hydroaminations occurred more efficiently
in terms of chemical yields and enantioselectivities with the
more rigid tosylated allene 3e. Under standard conditions with
PPTS as Brønsted acid (pKa = 5.21) and (R)-DTBM-Segphos
as chiral ligand, the 3-vinyl-1,4-benzodiazepine 2e could be
obtained in 80% yield and 90:10 er (Table 2, entry 4).26 To
our delight, upon changing the nature of the chiral ligand to
(R)-DTBM-Garphos, the 1,4-BDZ 2e could be obtained in
70% yield with an excellent 95:5 er (Table 2, entry 5).
Curiously, the employment of chloroacetic acid (pKa = 2.87)
favors the reaction to give an excellent yield (90%) but with
slight erosion of enantioselectivity (91:9 er, Table 2, entry 6).
Conversely, when the reaction was performed at a higher
temperature, 70 °C, a lower chemical yield was obtained
(60%) but without loss of enantioselectivity (95:5 er, Table 2,
entry 7).24 This result contrasts with the drop of ee when using
the alkyne 1e at 70 °C (Table 1, entry 8). We speculate that
the nature of the Brønsted acid is crucial (PPTS vs TFA) to
favor a cationic intermediate (with PPTS) that would evolve
via an “outer sphere” mechanism rather than a more neutral-
like intermediate (with TFA) that might favor competitive
mechanisms that would erode the enantioselectivity of the
process.
Having established the optimized conditions, a series of N-
benzylamino N-tosyl allenes 3 bearing different substituents on
the benzene ring were screened (Scheme 3).27 All of the tested
substrates bearing strong EDG and EWG (OMe, CF3),
halogens (F, Cl, Br), or alkyl (Me) groups in any position of
the ring are well tolerated to give the corresponding 3-vinyl-
1,4-BDZs 2f−2n in rather good yields and excellent
enantiomeric ratios, indicating that the electronic properties
of the aromatic moiety have little influence on the reactivity
and enantioselectivity. By contrast, the asymmetric reaction
was very sensitive to the nature of the nucleophile since the
In summary, we have developed an intramolecular Rh-
catalyzed hydrofunctionalization of internal alkynes and allenes
to benzofused seven-membered heterocycles. The asymmetric
hydroamination of (aminomethyl)aniline derivatives afforded
chiral 3-vinyl-1,4-benzodiazepines (1,4-BZDs) with good to
excellent yields and enantioselectivities. Orthogonal N-
deprotection of 1,4-BZDs allowed an easy manipulation that
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Note
a
X-ray crystallographic analysis was performed at the CACTUS
facility of the University of Santiago de Compostela.
Scheme 4. Derivatization of 3-Vinyl-1,4-benzodiazepine 2e
General Procedure for the Preparation of Alkynes 1a, 1d,
and 1e. PG-Amine Protection. Boc2O (9.3 g, 42 mmol, 1.7 equiv),
DMAP (0.92 g, 7.5 mmol, 0.3 equiv), and Et3N (3.5 mL, 25 mmol, 1
equiv) were added at rt to a solution of ethyl 2-aminobenzoate (4.13
g, 25 mmol, 1 equiv) in 250 mL of dry THF (0.1 M), and the reaction
mixture was then stirred at 60 °C in an oil bath for 24 h. Then the
reaction was quenched at rt with H2O, and both layers were
separated. The aqueous layer was extracted with Et2O (3 × 50 mL),
and the combination of organic layers was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The compound S1a was
purified by silica gel column chromatography with hexane/EtOAc
(39:1) as the eluent.
The Ts-derivative S1b was synthesized according to the
literature.34
Ethyl 2-((tert-Butoxycarbonyl)amino)benzoate (S1a): 70% yield
1
(5.57 g, 21 mmol); amorphous white solid; H NMR (300 MHz,
CDCl3) δ 10.30 (s, 1H), 8.47−8.41 (m, 1H), 8.01 (dd, J = 8.1, 1.7
Hz, 1H), 7.55−7.46 (m, 1H), 6.99 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H),
4.37 (q, J = 7.2 Hz, 2H), 1.53 (d, J = 0.9 Hz, 8H), 1.44−1.37 (m,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.0, 152.8, 142.3, 134.3,
130.8, 120.9, 118.6, 114.5, 80.3, 61.1, 28.3, 14.2; MS (CI), m/z (%)
266 (M+ + 1, 100).
a
Conditions: (a) 2.5 equiv of CAN, MeCN/H2O, then HCl (1 M) in
Et2O, 85% yield; (b) 6 equiv of Na, 0.2 equiv of naphthalene, THF, rt,
16 h, 85% yield; (c) 2 equiv of acryloyl chloride, 2 equiv of Et3N, 0.1
equiv of DMAP, DCM, 0 °C to rt, 2 h, 65% yield; (d) 10 mol %
Hoveyda−Grubbs catalyst second G, DCM, reflux, 36 h, 87% yield.
N-Alkylation.35 A round-bottomed flask equipped with a stirring
magnetic bar was flamed-dried under a vacuum and backfilled with
argon. Then, it was charged with NaH (1.2 equiv), put under a
vacuum, and backfilled with argon for three times. Then DMF (0.33
M) was added, and the mixture was cooled to 0 °C. A solution of N-
protected aniline S2 (1 equiv) in DMF (2 mL) was then added
slowly, and the mixture was stirred at 0 °C for 2 h. Afterward, a
propargyl bromide derivative (1.3 equiv) was added, and the reaction
was allowed to warm slowly to rt and stirred for 16 h. The reaction
was quenched with a saturated solution of NH4Cl (aq) and extracted
with EtOAc. The aqueous layer was extracted with EtOAc, and the
combination of organic layers was washed with a saturated solution of
NH4Cl (aq) (3 × 100 mL). The combination of organic layers was
dried over Na2SO4 and concentrated in vacuo. The residue was then
purified by silica gel column chromatography with hexanes/EtOAc
(8:2) as the eluent to give the desired products S2.
led to an enantioenriched advanced metabolite of the V2-
receptor antagonist Lixivaptan. Mechanistic investigations are
currently underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under an
inert atmosphere of argon and with anhydrous solvents in a glassware
oven or flame-dried at 80 °C unless otherwise stated. All chemicals
were purchased from Acros Organics Ltd., Aldrich Chemical Co. Ltd.,
Alfa Aesar, Strem Chemicals Inc., Fluorochem Ltd., or TCI Europe
N.V. chemical companies and used without further purification, unless
otherwise stated. Analytical thin-layer chromatography was carried out
on silica-coated aluminum plates (silica gel 60 F254 Merck) or on
aluminum sheets (aluminum oxide 60 F254 neutral Merck) using UV
light as a visualizing agent (254 nm) and KMnO4 (solution of 1.5 g of
potassium permanganate, 10 g of potassium bicarbonate and 1.25 mL
of 10% sodium hydroxide in 200 mL of water) with heat as
developing agents. Flash column chromatography was performed on
silica gel 60 (Merck, 230−400 mesh) with the indicated eluent. All
other reagents and solvents (acetonitrile, dichloromethane, dichloro-
ethane, tetrahydrofuran, toluene, and methanol) were used dry, unless
otherwise indicated.
Ethyl 2-(But-2-yn-1-yl(tert-butoxycarbonyl)amino)benzoate
1
(S2d): 93% yield (2.95 g, 9.3 mmol); colorless oil; H NMR (300
MHz, CDCl3), δ (ppm): 7.91 (d, J = 7.7 Hz, 1H), 7.58−7.22 (m,
3H), 4.69 (d, J = 17.5 Hz, 1H), 4.41−4.20 (m, 2H), 3.96 (d, J = 17.4
Hz, 1H), 1.75 (s, 3H), 1.51 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.28 (s,
6H); 13C{1H} NMR (75 MHz, CDCl3) δ 163.2, 133.0, 132.4, 131.6,
131.0, 130.3, 129.8, 128.8, 127.1, 80.3, 74.9, 61.1, 39.5, 28.0, 14.1, 3.6;
MS (CI), m/z (%) 318 (M+ + 1, 100).
Ethyl 2-((N-(But-2-yn-1-yl)-4-methylphenyl)sulfonamido)-
benzoate (S2e): 90% yield (3.34 g, 9 mmol); amorphous off-white
solid; 1H NMR (300 MHz, CDCl3) δ 7.89−7.81 (m, 1H), 7.64−7.56
(m, 2H), 7.45−7.36 (m, 2H), 7.26−7.19 (m, 2H), 7.17−7.10 (m,
1H), 4.54 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.69 (t, J =
2.4 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 166.1, 143.1, 137.9, 137.4, 133.0, 131.8, 131.5, 131.1, 129.1,
128.7, 127.8, 81.5, 74.0, 61.4, 42.0, 21.5, 14.1, 3.4; MS (CI), m/z (%)
372 (M+ + 1, 100).
Enantiomeric ratio (er) values were determined on an Agilent
HPLC 1100 Series or on a Jasco SFC 4000 series using commercially
available chiral columns.
1H NMR, 13C NMR, and DEPT experiments were carried out
using a Varian Inova 500, Varian Inova 400 MHz or Varian Mercury
300 MHz. All NMR experiments were recorded at 298 K otherwise
stated. All chemical shifts are reported in parts per million (ppm) and
referenced to residual solvent peaks. Coupling constants (J) are given
in hertz (Hz). Multiplicities are reported as follows: s = singlet; d =
doublet; t = triplet; q = quartet, m = multiplet or as a combination of
them. The proton signals corresponding to NH and OH groups may
Ester Reduction.36 DIBAL-H (1 M in DCM, 2.2 equiv) was added
dropwise to a stirred solution of the ester S2 (1 equiv) in DCM (0.3
M) at −78 °C. The reaction was then stirred at that temperature for 3
h. Afterward, MeOH (5 mL) was added followed by a saturated
solution of the Rochelle Salt at −78 °C. The reaction was then
warmed up to rt and stirred for 1 h. The mixture was extracted with
DCM (3 × 30 mL), and the combination of organic layers was
washed with a saturated solution of NaCl (aq), dried over Na2SO4,
and concentrated in vacuo. The residue was then purified by silica gel
column chromatography with hexanes/EtOAc (9:1 to 7:3) as the
eluent to afford the desired product S3d/1a.
1
not appear in the H NMR spectra due to deuterium exchange.
Reactions were followed using a GC Agilent HP-6890N with a
mass spectroscopy HP-5973N using DB-35MS and HP-5MS columns
for the GC and a chemical ionization font for the MS. Mass
spectrometry analysis was carried out using a Micromass Autospec, a
TRACE MS, or a HP-5988-A with chemical ionization and a Bruker
Microtof APCI using chemical ionization spectrometers at the
CACTUS Facility (Universidade de Santiago de Compostela).
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1
tert-Butyl But-2-yn-1-yl(2-(hydroxymethyl)phenyl)carbamate
(S3d): 99% yield (2.53 g, 9.2 mmol); amorphous white solid. It was
used in the next step without further purification.
N-(But-2-yn-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methylbenze-
nesulfonamide (1a): 91% yield (2.8 g, 8.5 mmol); amorphous off-
white solid; 1H NMR (300 MHz, CDCl3) δ 7.64−7.55 (m, 3H), 7.37
(td, J = 7.5, 1.3 Hz, 1H), 7.33−7.23 (m, 2H), 7.15 (td, J = 7.7, 1.7 Hz,
1H), 6.65 (dd, J = 8.0, 1.3 Hz, 1H), 4.93 (s, 1H), 4.60 (s, 1H), 4.33
(s, 2H), 3.00−2.89 (m, 1H), 2.45 (s, 3H), 1.65 (t, J = 2.4 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 144.0, 142.2, 137.3, 135.2, 131.0,
mmol); yellow oil; H NMR (300 MHz, CDCl3) δ 7.32 (d, J = 7.4
Hz, 1H), 7.25 (td, J = 7.9, 7.5, 1.5 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H),
6.95 (td, J = 7.4, 0.9 Hz, 1H), 6.81−6.73 (m, 2H), 6.68−6.61 (m,
2H), 4.72 (q, J = 2.3 Hz, 2H), 4.32 (s, 2H), 3.74 (s, 3H), 1.87 (t, J =
2.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 152.3, 148.6, 139.2,
125.6, 124.8, 124.6, 117.7, 111.3, 111.0, 108.5, 80.1, 70.7, 53.0, 52.2,
40.8, 0.0; HRMS (MM: ESI-APCI+) m/z calcd for C18H20NO2 [M +
H]+ 282.1489, found 282.1492.
Preparation of Alkyne 1c. 1-(Diethoxymethyl)-2-iodobenzene
(S5). Synthesized according to the literature.37
3-(2-(Diethoxymethyl)phenyl)propanal (S6). Iodide S5 (5.73 g,
18.7 mmol, 1 equiv) and the allylic alcohol (3.18 mL, 46.8 mmol, 2.5
equiv) were added to a solution of Pd(OAc)2 (168 mg, 0.75 mmol, 4
mol %), NaHCO3 (7.54 g, 89.8 mmol, 4.8 equiv), and Bu4NCl (5.2 g,
18.7 mmol, 1 equiv) in DMF (35 mL). The mixture was stirred at 50
°C in an oil bath for 4 h, and the reaction was filtered through a short
plug of silica gel. Then, H2O (30 mL) was added to the filtrate and
then extracted with EtOAc (2 × 50 mL). The combination of organic
layers was washed with H2O (2 × 50 mL) and brine (50 mL), dried
over Na2SO4, and concentrated in vacuo. The product was purified by
silica gel column chromatography with hexanes/EtOAc (19:1) as the
eluent to give the aldehyde S6: 86% yield (3.8 g, 16.1 mmol); yellow
oil; 1H NMR (300 MHz, CDCl3) δ 9.83 (t, J = 1.4 Hz, 1H), 7.55 (dd,
J = 7.3, 2.0 Hz, 1H), 7.30−7.20 (m, 2H), 7.17 (dd, J = 7.0, 1.6 Hz,
1H), 5.56 (s, 1H), 3.70−3.42 (m, 6H), 3.07 (t, J = 7.7 Hz, 2H),
2.84−2.73 (m, 2H), 1.22 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (75
MHz, CDCl3) δ 201.8, 138.7, 136.5, 129.6, 128.6, 127.1, 126.1, 100.6,
61.7, 45.4, 24.5, 15.2; MS (CI), m/z (%) 237 (M+ + 1, 100).
1-(But-3-yn-1-yl)-2-(diethoxymethyl)benzene (S7).38 nBuLi (7.73
mL, 19.32 mmol, 1.2 equiv) was added dropwise to a solution of
DIPA (2.71 mL, 19.32 mmol, 1.2 equiv) in THF (130 mL) at −78
°C. The reaction mixture was warmed to 0 °C and stirred for 15 min.
Then the reaction was cooled to −78 °C, and trimethylsilyldiazo-
methane (8.05 mL, 16.1 mmol, 1 equiv) was added. The reaction was
stirred at −78 °C for 30 min. Then a solution of aldehyde S6 (3.8 g,
16.1 mmol, 1 equiv) in THF (33 mL) was added. The mixture was
stirred for 1 h, and then the reaction was heated to reflux for 3 h. The
reaction was quenched with H2O (100 mL), and the aqueous layer
was extracted with Et2O (2 × 60 mL). The combination of organic
layers was washed with H2O (100 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography with hexanes/EtOAc (99:1) as the eluent to give S7:
129.4, 129.3, 128.3, 128.3, 128.2, 82.0, 72.8, 61.3, 42.6, 21.6, 3.4;
HRMS (MM: ESI-APCI+) m/z calcd for C18H18N2O2S [M − H2O]+
312.1053, found 312.1059.
Alcohol Oxidation. DMP (1.1 equiv) was added to a stirred
solution of the alcohol S3d/1a (1 equiv) in DCM (0.25 M) at rt. The
mixture was stirred for 30 min. The reaction was quenched with a 1 M
solution of NaOH (aq) and extracted with DCM (2 × 30 mL). The
combination of organic layers was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was used in the next
step without further purification.
Reductive Amination. p-Anisidine (1.5 equiv) was added to a
stirred solution of the aldehyde previously synthesized in MeOH
(0.25 M) or (1:1 MeOH/DCM) under an argon atmosphere. The
reaction was stirred at room temperature for 18 h. Then the reaction
was cooled to 0 °C, and NaBH4 (1.1 equiv) was added portionwise.
The reaction was then allowed to warm up to rt and stirred for 2 h.
The reaction was quenched with water and extracted with DCM. The
combination of organic layers was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was then purified by
silica gel column chromatography with hexanes/EtOAc (9:1 to 8:2)
as the eluent to give the desired products 1d/1e.
tert-Butyl But-2-yn-1-yl(2-(((4-methoxyphenyl)amino)methyl)-
1
phenyl)carbamate (1d): 80% yield; amorphous off-white solid; H
NMR (300 MHz, DMSO-d6, 80 °C) δ 7.46−7.35 (m, 1H), 7.31−7.18
(m, 3H), 6.7 (d, J = 8.9 Hz, 2H), 6.5 (d, J = 8.9 Hz, 2H), 5.46 (bs,
1H), 4.30 (bs, 2H), 4.21 (bs, 2H), 3.64 (s, 3H), 1.75 (t, J = 2.4 Hz,
3H), 1.39 (s, 9H); 13C{1H} NMR (75 MHz, DMSO-d6, 80 °C) δ
153.0, 150.7, 142.7, 139.5, 137.6, 127.5, 127.1, 126.9, 126.8, 114.5,
113.0, 79.5, 79.4, 75.0, 55.2, 43.3, 39.3, 27.6, 2.5; HRMS (MM: ESI-
APCI+) m/z calcd for C23H29N2O3 [M + H]+ 381.2173, found
381.2171.
N-(But-2-yn-1-yl)-N-(2-(((4-methoxyphenyl)amino)methyl)-
1
phenyl)-4-methylbenzenesulfonamide (1e): 70% yield (2 g, 4.8
51% yield (1.92 g, 8.26 mmol); colorless oil; H NMR (300 MHz,
1
mmol); amorphous off-white solid; H NMR (300 MHz, CDCl3) δ
CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.33−7.17 (m, 3H), 5.61 (s, 1H),
3.70−3.43 (m, 4H), 2.98 (t, J = 7.7 Hz, 2H), 2.51 (td, J = 7.7, 2.7 Hz,
12H), 1.99 (t, J = 2.7 Hz, 1H), 1.24 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 138.6, 136.5, 129.8, 128.4, 126.8, 126.2,
100.3, 84.1, 68.8, 61.7, 20.2, 15.2; MS (CI), m/z (%) 233 (M+ + 1,
100).
7.64 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.1 Hz,
3H), 7.13 (t, J = 7.7 Hz, 1H), 6.76 (t, J = 7.1 Hz, 3H), 6.62 (d, J = 8.4
Hz, 2H), 4.52 (s, 2H), 4.33 (s, 2H), 4.08−4.01 (m, 1H), 3.74 (s, 3H),
2.45 (s, 3H), 1,65 (t, J = 2.4 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 152.1, 143.8, 142.6, 141.1, 137.7, 135.8, 129.4, 129.3, 129.1,
128.4, 127.4, 114.9, 114.3, 81.8, 73.0, 55.8, 45.4, 42.3, 21.6, 3.5;
HRMS (MM: ESI-APCI+) m/z calcd for C25H27N2O3S [M + H]+
435.1737, found 435.1730.
1-(Diethoxymethyl)-2-(pent-3-yn-1-yl)benzene (S8). nBuLi (3.2
mL, 8 mmol, 1.1 equiv) was added dropwise at −78 °C to a solution
of S7 (1.7 g, 7.3 mmol, 1 equiv) in THF (0.3 M). The mixture was
stirred for 50 min at −78 °C, then MeI (2.27 mL, 36.5 mmol, 5
equiv) was added, and the reaction was stirred at rt for 16 h. The
reaction was quenched with a saturated solution of NH4Cl (aq). The
aqueous layer was extracted with EtOAc (40 mL), and the
combination of organic layers was washed with brine (100 mL),
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography with hexanes/EtOAc
(99:1) as the eluent to give S8: 92% yield (1.65 g, 6.7 mmol);
colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J = 7.9, 1.8 Hz,
1H), 7.35−7.16 (m, 3H), 5.63 (s, 1H), 3.67−3.45 (m, 4H), 2.92 (t, J
= 7.7 Hz, 2H), 2.55−2.33(m, 2H), 1.78 (t, J = 2.6 Hz, 3H), 1.23 (t, J
= 7.1 Hz, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 139.1, 136.5,
129.6, 128.3, 126.6, 126.0, 100.1, 78.8, 76.0, 61.6, 31.7, 20.6, 15.2, 3.5;
MS (CI), m/z (%) 247 (M+ + 1, 100).
Preparation of Alkyne 1b. 2-(But-2-yn-1-yloxy)benzaldehyde
(S4). To a suspension of K2CO3 (1 g, 7.2 mmol, 1.2 equiv) in DMF (3
mL) at rt was added salicylaldehyde (0.63 mL, 6 mmol, 1 equiv)
followed by 1-bromo-2-butyne (0.58 mL, 6.6 mmol, 1.1 equiv). The
mixture was then stirred at rt for 16 h. The reaction was quenched
with water (10 mL). The aqueous layer was extracted with AcOEt (3
× 10 mL), and the combination of organic layers was washed with
water (3 × 10 mL), brine (2 × 10 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography with hexanes/EtOAc (19:1) as the eluent to give S6:
1
83% yield (870 mg, 5 mmol); colorless oil; H NMR (300 MHz,
CDCl3) δ 10.46 (s, 1H), 7.82 (dd, J = 7.6, 1.9 Hz, 1H), 7.53 (td, J =
7.3, 1.8 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.06−7.00 (m, 1H), 4.76
(q, J = 2.3 Hz, 2H), 1.83 (t, J = 2.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 189.7, 160.1, 135.7 128.3, 125.4, 121.2, 113.4, 84.7,
73.3, 57.1, 3.6; MS (CI), m/z (%) 175 (M+ + 1, 100).
2-(Pent-3-yn-1-yl)benzaldehyde (S9). A mixture of S8 (1.65 g, 6.7
mmol, 1 equiv) and PPTS (505 mg, 2.01 mmol, 0.3 equiv) in acetone
(260 mL) and H2O (7 mL) was heated to reflux in an oil bath for 15
h. The volatiles were removed under a vacuum, the residue was
N-(2-(But-2-yn-1-yloxy)benzyl)-4-methoxyaniline (1b). used the
general procedure for reductive amination, 70% yield (983 mg, 3.5
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Note
dissolved in DCM (30 mL), and the solution was washed with H2O
(30 mL). The aqueous layer was extracted with DCM (3 × 20 mL),
and the combination of organic layers was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography with hexanes/EtOAc (98:2) as the
NMR mixture of isomers (300 MHz, CDCl3) δ 7.15−7.02 (m, 4H
isom 1, 4H isom 2), 6.91−6.82 (m, 2H isom 1, 2H isom 2), 6.82−
6.74 (m, 2H isom 1, 2H isom 2), 5.49−5.22 (m, 1H isom 1, 1H isom
2), 4.55 (dt, J = 8.8, 4.4 Hz, 1H isom 2), 4.41−4.31 (m, 1H isom 2),
4.27 (d, J = 15.5 Hz, 1H isom 1, 1H isom 2), 4.20 (d, J = 15.6 Hz, 1H
isom 1, 1H isom 2), 3.71 (s, 3H isom 1, 3H isom 2), 3.17 (dd, J =
15.8, 5.4 Hz, 1H isom 1, 1H isom 2), 2.77 (dd, J = 15.8, 3.1 Hz, 1H
isom 1), 2.70 (dd, J = 15.9, 4.3 Hz, 1H isom 2), 1.55 (dd, J = 6.8, 1.6
Hz, 3H isom 2), 1.46 (dt, J = 6.0, 1.1 Hz, 3H isom 1); 13C{1H} NMR
(75 MHz, CDCl3) δ 153.7, 152.8, 144.5, 144.1, 134.4, 134.3, 133.6,
133.5, 129.8, 129.3, 128.8, 128.7, 127.4, 126.3, 126.2, 125.9, 125.8,
119.3, 117.5, 114.5, 114.4, 56.9, 55.6, 55.6, 53.0, 49.9, 48.1, 35.3, 34.4,
17.8, 13.4; HRMS (MM: ESI-APCI+) m/z calcd for C19H22NO [M +
H]+ 280.1696, found 280.1695.
1
eluent to give S9: 94% yield (1.08 g, 6.3 mmol); colorless oil; H
NMR (300 MHz, CDCl3) δ 10.26 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H),
7.51 (t, J = 7.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.6 Hz,
1H), 3.19 (t, J = 7.2 Hz, 2H), 2.58−2.29 (m, 2H), 1.71 (t, J = 2.5 Hz,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 192.0, 143.3, 134.1, 133.7,
131.6, 131.2, 126.9, 77.8, 77.4, 31.5, 21.0, 3.4; MS (CI), m/z (%) 173
(M+ + 1, 100).
4-Methoxy-N-(2-(pent-3-yn-1-yl)benzyl)aniline (1c): used general
procedure for reductive amination, 85% yield (1.5 g, 5.4 mmol);
amorphous off-white solid; 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J
= 7.2 Hz, 1H), 7.32−7.19 (m, 3H), 6.89−6.80 (m, 2H), 6.71−6.60
(m, 2H), 4.31 (s, 2H), 3.79 (s, 3H), 3.69 (bs, 1H), 2.94 (t, J = 7.5 Hz,
2H), 2.51 (ddt, J = 7.5, 5.1, 2.6 Hz, 2H), 1.82 (t, J = 2.6 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 152.2, 142.7, 139.3, 137.1, 129.5,
tert-Butyl 4-(4-Methoxyphenyl)-3-vinyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-1-carboxylate (2d). 70% yield, amorphous
1
off-white solid; H NMR (300 MHz, DMSO-d6, 80 °C) δ 7.43−7.30
(m, 1H), 7.29−7.09 (m, 3H), 6.70 (d, J = 9.1 Hz, 2H), 6.62 (d, J =
9.1 Hz, 2H), 6.03 (ddd, J = 17.2, 10.5, 4.7 Hz, 1H), 5.42−5.19 (m,
2H), 4.81−4.60 (m, 1H), 4.68 (d, J = 17.3 Hz, 1H), 4.39 (d, J = 17.3
Hz, 1H), 4.07 (dd, J = 14.6, 5.2 Hz, 1H), 3.62 (s, 3H), 3.48 (dd, J =
14.6, 9.9 Hz, 1H), 1.22 (s, 9H); 13C{1H} NMR (75 MHz, DMSO-d6,
80 °C) δ 152.5, 151.2, 143.8, 140.7, 135.3, 132.8, 127.8, 126.9, 125.7,
124.9, 115.4, 114.3, 113.9, 79.3, 59.4, 55.2, 51.3, 48.1, 27.3; HRMS
(MM: ESI-APCI+) m/z calcd for C23H28N2O3Na [M + Na]+
403.1992, found 403.1990.
128.9, 127.6, 126.7, 115.0, 114.0, 78.7, 76.5, 55.8, 46.9, 31.7, 20.6, 3.6;
HRMS (MM: ESI-APCI+) m/z calcd for C19H22N2O [M + H]+
280.1696, found 280.1701.
General Procedure for the Racemic Cyclization of Alkynes 1. A 5
mL sealed tube equipped with stirring magnetic bar was flamed-dried
under a vacuum, cooled to rt, and backfilled with argon. Then it was
charged with [Rh(cod)Cl]2 (4 mg, 8 μmol, 0.04 equiv), rac-BNP acid
(5.6 mg, 16 μmol, 0.08 equiv), and rac-BINAP (10 mg, 16 μmol, 0.08
equiv). Afterward, it was put in a vacuum and backfilled with argon
three times. Then 0.5 mL of DCE was added, and the mixture was
stirred for 10 min at rt. Finally, the alkyne 1 (0.2 mmol, 1 equiv) was
added under a flow of argon, and the mixture was stirred at 70 °C in
an oil bath for 24 h. After cooling at rt, the solvent was evacuated in
vacuo, and the residue was purified by silica gel column
chromatography with EtOAc/Hexanes (1:9) as the eluent to give
the desired seven-membered heterocycle 2.
1-Tosyl-3-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine (2a):
85% yield, colorless oil (amorphous off-white solid at 4 °C); 1H
NMR (300 MHz, CDCl3) δ 7.65−7.58 (m, 2H), 7.40−7.34 (m, 1H),
7.32−7.18 (m, 5H), 5.74 (ddd, J = 17.4, 10.7, 5.3 Hz, 1H), 5.37 (t, J =
1.5 Hz, 1H), 5.31 (t, J = 1.5 Hz, 1H), 5.22 (t, J = 1.4 Hz, 1H), 5.19 (t,
J = 1.5 Hz, 1H), 4.49 (d, J = 13.4 Hz, 1H), 4.38 (dd, J = 15.1, 1.9 Hz,
1H), 4.27−4.13 (m, 1H), 4.17 (d, J = 13.4 Hz, 1H), 2.98 (dd, J =
15.1, 10.3 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
143.7, 139.7, 138.5, 138.2, 135.1, 129.8, 129.6, 128.9, 128.8, 128.0,
127.1, 117.2, 80.7, 72.2, 55.6, 21.6; HRMS (MM: ESI-APCI+) m/z
calcd for C18H19NO3S [M + H]+ 330.1158, found 330.1158.
4-(4-Methoxyphenyl)-3-vinyl-2,3,4,5-tetrahydrobenzo[f ][1,4]-
oxazepine (2b): 41% yield, colorless oil; 1H NMR (300 MHz,
CDCl3) δ 7.23 (dd, J = 7.3, 1.7 Hz, 1H), 7.14 (td, J = 8.0, 1.8 Hz,
1H), 6.99 (td, J = 7.4, 1.3 Hz, 1H), 6.86 (dd, J = 8.1, 1.3 Hz, 1H),
6.75 (d, J = 9.2 Hz, 2H), 6.67 (d, J = 9.2 Hz, 2H), 5.90 (ddd, J = 17.2,
10.4, 4.1 Hz, 1H), 5.44 (dt, J = 17.2, 1.8 Hz, 1H), 5.33 (dt, J = 10.4,
1.8 Hz, 1H), 4.93 (d, J = 17.1 Hz, 1H), 4.61−4.50 (m, 1H), 4.36−
4.24 (m, 3H), 3.71 (s, 3H).13C{1H} NMR (75 MHz, CDCl3) δ 158.4,
151.9, 144.6, 133.4, 129.3, 128.1, 127.9, 122.2, 119.4, 116.9, 114.7,
114.3, 72.8, 64.0, 55.8, 48.2; HRMS (MM: ESI-APCI+) m/z calcd for
C18H20NO2 [M + H]+ 282.1489, found 282.1493.
General Procedure for the Asymmetric Cyclization of Alkynes 1.
A 5 mL sealed tube equipped with stirring magnetic bar was flamed-
dried under a vacuum, cooled to rt, and backfilled with argon. Then, it
was charged with [Rh(cod)Cl]2 (4 mg, 8 μmol, 0.04 equiv), Brønsted
acid (16 μmol, 0.08 equiv), and chiral ligand (16 μmol, 0.08 equiv).
Afterward, it was put in a vacuum and backfilled with argon three
times. Then, 0.5 mL of DCE was added, and the mixture was stirred
for 10 min at rt. Finally, the alkyne 1 (0.2 mmol, 1 equiv) was added
under a flow of argon, and the mixture was stirred at 50 °C in an oil
bath for 24 h. After cooling at rt and stripping off the solvent, the
resulting residue was purified by silica gel column chromatography
with EtOAc/Hexanes (1:9) as the eluent to give the desired seven-
membered heterocycle 2.
General Procedure for the Preparation of Allenes 3d−3f, 3h−3j,
and 3n. Tosyl derivatives S 1f,39 S1h,40 S1i,41 S1j,42 and S1n43 were
synthesized according to literature procedures.
See the general procedure for N-alkylation of alkynes.
Ethyl 2-((tert-Butoxycarbonyl)(prop-2-yn-1-yl)amino)benzoate
1
(S10d). 94% yield (2.85 g, 9.4 mmol), colorless oil; H NMR (300
MHz, CDCl3) δ 7.96 (dd, J = 7.7, 1.8 Hz, 1H), 7.65−7.33 (m, 3H),
4.82 (dd, J = 17.7, 2.5 Hz, 1H), 4.34 (dtd, J = 9.7, 7.1, 3.4 Hz, 2H),
4.03 (dd, J = 17.7, 2.5 Hz, 1H), 2.33−2.15 (m, 1H), 1.60 (s, 2H),
1.39 (t, J = 7.2 Hz, 3H), 1.31 (s, 8H); 13C{1H} NMR (75 MHz,
CDCl3) δ 166.0, 154.0, 153.7, 141.6, 141.1, 132.6, 132.5, 131.0, 129.8,
129.5, 129.1, 127.3, 81.0, 80.4, 80.0, 79.8, 72.2, 71.8, 61.1, 60.9, 40.2,
39.1, 28.2, 28.0, 14.1; MS (CI), m/z (%) 304 (M+ + 1, 100).
Ethyl 2-((4-Methyl-N-(prop-2-yn-1-yl)phenyl)sulfonamido)-
benzoate (S10e). 90% yield (3.2 g, 9 mmol); amorphous yellow
solid; 1H NMR (300 MHz, CDCl3) δ 7.94−7.83 (m, 1H), 7.66−7.54
(m, 2H), 7.51−7.35 (m, 2H), 7.30−7.13 (m, 3H), 5.02−4.35 (m,
2H), 4.28 (s, 2H), 2.42 (s, 3H), 2.21 (t, J = 2.5 Hz, 1H), 1.37 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.0, 143.4, 137.4,
137.1, 132.9, 132.1, 131.9, 131.3, 129.3, 129.0, 127.7, 73.6, 61.5, 41.3,
21.6, 14.1; MS (CI), m/z (%) 358 (M+ + 1, 100).
2-(4-Methoxyphenyl)-3-vinyl-2,3,4,5-tetrahydro-1H-benzo[c]-
azepine (2c): 57% yield, colorless oil; 1H NMR (300 MHz, CDCl3) δ
7.29 (d, J = 6.9 Hz, 1H), 7.24−7.12 (m, 2H), 7.09 (d, J = 6.9 Hz,
1H), 6.75(d, J = 9.2 Hz, 2H), 6.65 (d, J = 9.2 Hz, 2H), 5.99 (ddd, J =
17.2, 10.4, 3.6 Hz, 1H), 5.28−5.15 (m, 2H), 4.75 (d, J = 17.1 Hz,
1H), 4.36−4.25 (m, 1H), 4.24 (d, J = 17.0 Hz, 1H) 3.72 (s, 3H),
3.04−2.80 (m, 2H), 2.36−2.21 (m, 1H), 2.15−1.96 (m, 1H);
13C{1H} NMR (75 MHz, CDCl3) δ 151.1, 144.9, 139.8, 139.4, 137.4,
Methyl 4-Methyl-2-((4-methyl-N-(prop-2-yn-1-yl)phenyl)-
sulfonamido)benzoate (S10f). 90% yield (3.21 g, 9 mmol);
1
amorphous off-white solid; H NMR (300 MHz, CDCl3) δ 7.73 (d,
J = 7.9 Hz, 1H), 7.60−7.50 (m, 2H), 7.20 (dd, J = 8.1, 4.0 Hz, 3H),
7.01 (d, J = 1.7 Hz, 1H), 4.64 (s, 1H), 3.69 (s, 3H), 2.38 (s, 3H), 2.28
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.1, 143.3, 143.2,
137.5, 137.2, 133.0, 131.3, 129.7, 129.3, 129.0, 128.9, 127.9, 127.6,
78.9, 73.4, 52.1, 41.3, 21.5, 21.3; MS (CI), m/z (%) 358 (M+ + 1,
100).
130.2, 127.8, 126.7, 126.0, 114.8, 114.4, 112.9, 62.0, 55.8, 49.3, 32.5,
32.4; HRMS (MM: ESI-APCI+) m/z calcd for C19H22NO [M + H]+:
280.1696, found 280.1695.
2-(4-Methoxyphenyl)-3-(prop-1-en-1-yl)-1,2,3,4-tetrahydroiso-
quinoline (2c′): 20% yield, colorless oil (mixture of isomers); 1H
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Note
Methyl 2-((4-Methyl-N-(prop-2-yn-1-yl)phenyl)sulfonamido)-4-
13C{1H} NMR (75 MHz, CDCl3) δ 209.6, 166.3, 143.2, 142.9, 137.9,
(trifluoromethyl)benzoate (S10h). 84% yield (1.8 g, 4.5 mmol);
137.2, 132.5, 131.4, 129.4, 129.1, 129.1, 127.5, 86.8, 75.9, 51.9, 51.0,
1
21.5, 21.3; MS (CI), m/z (%) 372 (M+ + 1, 100).
amorphous yellow solid; H NMR (300 MHz, CDCl3) δ 8.0 (d, J =
8.1 Hz, 1H), 7.7 (d, J = 8.1 Hz, 1H), 7.6 (d, J = 8.0 Hz, 2H), 7.4 (s,
1H), 7.3−7.1 (m, 2H), 4.6 (s, 2H), 3.9 (s, 3H), 2.4 (s, 3H), 2.2 (d, J
= 2.5 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.5, 144.2,
138.3, 136.5 (d, J = 8.1 Hz), 133.9 (q, J = 33.6 Hz), 131.8, 129.6,
129.1 (d, J = 3.8 Hz), 127.9, 125.8 (d, J = 3.9 Hz), 124.8, 121.2, 74.5,
52.9, 41.3, 21.7; 19F NMR (282 MHz, CDCl3) δ −63.2; MS (CI), m/
z (%) 412 (M+ + 1, 100).
Methyl 5-Methoxy-2-((4-methyl-N-(prop-2-yn-1-yl)phenyl)-
sulfonamido)benzoate (S10i). 83% yield (0.62 g, 1.7 mmol); yellow
oil; 1H NMR (300 MHz, CDCl3) δ 7.6 (d, J = 7.9 Hz, 2H), 7.3 (d, J =
3.0 Hz, 1H), 7.2 (d, J = 7.9 Hz, 2H), 7.1 (d, J = 8.7 Hz, 1H), 6.9 (dd,
J = 8.8, 3.1 Hz, 1H), 4.9 (s, 1H), 4.3 (s, 1H), 3.8 (d, J = 13.9 Hz, 6H),
2.4 (s, 3H), 2.2 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.3,
159.6, 143.2, 137.3, 133.54, 133.4, 129.9, 129.4, 127.8, 117.8, 116.0,
79.1, 73.6, 55.8, 52.5, 41.5, 21.6; MS (CI), m/z (%) 423 (M+ + 1,
100).
Methyl 2-((N-(Buta-2,3-dien-1-yl)-4-methylphenyl)sulfonamido)-
4-(trifluoromethyl)benzoate (S11h): 70% yield (1.3 g, 3 mmol);
brown oil; H NMR (500 MHz, CDCl3) δ 8.0 (dd, J = 8.2, 1.0 Hz,
1
1H), 7.6 (ddd, J = 8.2, 1.8, 0.8 Hz, 1H), 7.5−7.5 (m, 2H), 7.3−7.2
(m, 2H), 7.1 (d, J = 1.8 Hz, 1H), 5.2 (ddd, J = 7.4, 6.6, 0.9 Hz, 1H),
4.6 (dt, J = 6.6, 2.3 Hz, 2H), 4.3 (dt, J = 7.4, 2.3 Hz, 3H), 3.9 (s, 4H),
2.4 (s, 4H); 13C{1H} NMR (126 MHz, CDCl3) δ 210.2, 165.7, 144.0,
138.7, 133.7 (q, J = 33.2 Hz), 131.8, 129.8, 128.0 (q, J = 3.6 Hz),
127.6, 125.1 (q, J = 3.7 Hz), 123.1 (q, J = 272.8 Hz), 86.1, 76.2, 52.8,
50.9, 21.6; 19F NMR (282 MHz, CDCl3) δ −63.0; MS (CI), m/z (%)
426 (M+ + 1, 100).
Methyl 2-((N-(Buta-2,3-dien-1-yl)-4-methylphenyl)sulfonamido)-
5-methoxybenzoate (S11i): 70% yield (0.45 g, 1.16 mmol); brown
oil; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 7.34 (d,
J = 2.6 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 6.94−6.90 (m, 2H), 5.22
(q, J = 6.9 Hz, 1H), 4.60 (d, J = 6.5 Hz, 2H), 4.34 (s, 1H), 4.21 (s,
1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 209.8, 166.4, 159.1, 143.2, 137.3, 133.5, 132.8, 130.3,
129.5, 127.6, 117.9, 115.9, 86.8, 75.9, 55. 8, 52.4, 51.7, 21.6; MS (CI),
m/z (%) 388 (M+ + 1, 100).
Methyl 5-Bromo-2-((4-methyl-N-(prop-2-yn-1-yl)phenyl)-
sulfonamido)benzoate (S10j). 70% yield (2.95 g, 7 mmol);
1
amorphous off-white solid; H NMR (300 MHz, CDCl3) δ 7.90 (d,
J = 2.5 Hz, 1H), 7.48 (dd, J = 8.3, 6.3 Hz, 3H), 7.16 (d, J = 8.1 Hz,
2H), 6.98 (d, J = 8.3 Hz, 1H), 4.49 (s, 1H), 3.71 (s, 3H), 2.33 (s,
3H), 2.16 (t, J = 2.3 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
164.9, 143.8, 136.8, 136.6, 135.3, 134.2, 134.1, 133.6, 129.5, 127.7,
123.1, 78.5, 74.1, 52.7, 41.2, 21.6.MS (CI), m/z (%) 374 (M+ + 1,
100).
Methyl 4,5-Dimethoxy-2-((4-methyl-N-(prop-2-yn-1-yl)phenyl)-
sulfonamido)benzoate (S10n). 99% yield (0.8 g, 1.98 mmol);
white foam; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 2H),
7.36 (s, 1H), 7.23 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 4.88 (s, 1H), 4.27
(s, 1H), 3.90 (s, 3H), 3.70 (d, J = 2.9 Hz, 6H), 2.40 (s, 3H), 2.23 (t, J
= 2.5 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.7, 151.5,
148.8, 143.5, 137.4, 131.5, 129.3, 127.9, 123.9, 115.4, 113.2, 79.3,
73.5, 56.2, 56.0, 52.2, 41.4, 21.6; MS (CI), m/z (%) 404 (M+ + 1,
100).
Homologation of Alkynes to Allenes. CuI (0.5 equiv), (CHO)n
(2.5 equiv), and Cy2NH (1.8 equiv) were added to a stirred solution
of the alkyne S10 (1 equiv) in dioxane (0.2 M). The reaction was
then heated to reflux in an oil bath for 6 h. Then, the reaction was
cooled to rt, and the solvent was removed in vacuo. The residue was
dissolved in CHCl3 (50 mL) and washed with 10% NH4OH (2 × 50
mL) and H2O (2 × 50 mL). The combination of organic layers was
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography with hexanes/EtOAc
(8:2) as the eluent to give the allenes S11.
Ethyl 2-(Buta-2,3-dien-1-yl(tert-butoxycarbonyl)amino)-
benzoate (S11d): 82% yield (2.44 g, 7.7 mmol); yellow oil; 1H
NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6
Hz, 1H), 7.35−7.17 (m, 2H), 5.30 (p, J = 6.6 Hz, 1H), 4.78−4.60 (m,
2H), 4.58−4.41 (m, 1H), 4.38−4.21 (m, 2H), 3.94−3.79 (m, 1H),
1.50 (s, 3H), 1.36; 13C{1H} NMR (75 MHz, CDCl3) δ 209.1, 166.3,
153.9, 141.9, 132.3, 131.0, 129.2, 126.7, 87.4, 80.0, 75.8, 61.1, 49.1,
28.0, 14.2; MS (CI), m/z (%) 318 (M+ + 1, 100).
Methyl 5-Bromo-2-((N-(buta-2,3-dien-1-yl)-4-methylphenyl)-
sulfonamido)benzoate (S11j): 80% yield (2.44 g, 5.6 mmol);
1
amorphous white solid; H NMR (300 MHz, CDCl3) δ 7.96 (d, J
= 2.4 Hz, 1H), 7.50 (dd, J = 11.0, 8.3 Hz, 3H), 7.22 (d, J = 8.0 Hz,
2H), 6.85 (d, J = 8.5 Hz, 1H), 5.19 (p, J = 7.0 Hz, 1H), 4.58 (dd, J =
6.6, 2.4 Hz, 2H), 4.25 (dd, J = 7.4, 2.4 Hz, 2H), 3.75 (s, 3H), 2.38 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 209.8, 165.1, 143.6, 136.9,
136.6, 135.0, 134.3, 134.2, 132.79, 129.6, 127.5, 122.3, 86.4, 76.1,
52.5, 50.9, 21.5; MS (CI), m/z (%) 437 (M+1, 100).
Methyl 2-((N-(Buta-2,3-dien-1-yl)-4-methylphenyl)sulfonamido)-
4,5-dimethoxybenzoate (S11n): 56% yield (0.46 g, 1.1 mmol);
brown foam; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.3 Hz, 2H),
7.37 (s, 1H), 7.31−7.18 (m, 3H), 6.52 (s, 1H), 5.26 (t, J = 6.9 Hz,
1H), 4.61 (s, 2H), 4.40 (s, 1H), 4.15 (s, 1H), 3.92 (s, 4H), 3.75 (s,
4H), 3.66 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
209.8, 165.9, 151.5, 148.5, 143.2, 137.5, 132.0, 129.4, 127.7, 124.0,
115.0, 113.4, 87.0, 76.0, 56.2, 56.2, 52.1, 51.4, 21.6; MS (CI), m/z
(%) 418 (M+ + 1, 100).
See the general procedure for the ester reduction of alkynes.
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methyl-
benzenesulfonamide (3a): 94% yield (2.5 g, 7.6 mmol); amorphous
1
white solid; H NMR (300 MHz, CDCl3) δ 7.63−7.50 (m, 3H),
7.39−7.24 (m, 3H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 6.46 (dd, J = 8.0,
1.3 Hz, 1H), 5.10−4.93 (m, 2H), 4.66−4.38 (m, 4H), 3.84 (dd, J =
13.8, 8.3 Hz, 1H), 3.09−2.97 (m, 1H), 2.45 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 209.9, 144.0, 142.4, 136.9, 134.8, 131.0, 129.6,
129.1, 128.3, 128.1, 127.7, 85.3, 76.1, 61.2, 51.4, 21.6; HRMS (MM:
ESI-APCI+) m/z calcd for C18H18NO2S [M − H2O]+: 312.1053,
found 312.1059.
tert-Butyl Buta-2,3-dien-1-yl(2-(hydroxymethyl)phenyl)-
1
carbamate (S12d): 88% yield; colorless oil; H NMR (300 MHz,
DMSO-d6, 80 °C) δ 7.52 (d, J = 7.1 Hz, 1H), 7.34−7.17 (m, 2H),
7.12 (dd, J = 7.4, 1.7 Hz, 1H), 5.26 (p, J = 6.6 Hz, 1H), 4.90−4.69
(m, 3H), 4.45 (d, J = 5.3 Hz, 2H), 4.06 (bs, 2H), 1.35 (s, 9H);
13C{1H} NMR (75 MHz, DMSO-d6, 80 °C) δ 208.2, 153.2, 139.4,
Ethyl 2-((N-(Buta-2,3-dien-1-yl)-4-methylphenyl)sulfonamido)-
benzoate (S11e): 90% yield (3 g, 8.1 mmol); amorphous white
solid; 1H NMR (300 MHz, CDCl3) δ 7.88−7.80 (m, 1H), 7.52−7.44
(m, 2H), 7.36 (hept, J = 5.3 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.97−
6.88 (m, 1H), 5.21 (p, J = 7.0 Hz, 1H), 4.55 (dt, J = 6.6, 2.3 Hz, 2H),
4.38−4.15 (m, 5H), 2.36 (s, 4H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 209.6, 166.18, 143.3, 137.7, 136.9, 133.1,
131.8, 131.3, 130.9, 129.4, 128.4, 127.5, 86.6, 75.9, 61.3, 50.9, 21.5,
14.1; MS (CI), m/z (%) 372 (M+ + 1, 100).
139.0, 127.5, 127.1, 126.6, 126.5, 86.6, 78.9, 75.7 58.7, 48.3, 27.5; MS
(CI), m/z (%) 276 (M+ − [OH], 100).
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)-5-methylphenyl)-4-
methylbenzenesulfonamide (S12f): 90% yield (2.37 g, 6.9 mmol);
1
amorphous white solid; H NMR (300 MHz, CDCl3) δ 7.56 (d, J =
8.0 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.16
(d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 5.09−4.97 (m, 1H), 4.93 (d, J =
11.9 Hz, 1H), 4.61 (d, J = 7.1 Hz, 1H), 4.57−4.37 (m, 3H), 3.88−
3.73 (m, 1H), 2.46 (s, 3H), 2.16 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 209.9, 144.1, 139.2, 138.3, 136.9, 134.8, 130.9, 129.9, 129.5,
128.3, 128.2, 85.5, 76.2, 61.1, 51.4, 21.7, 20.9; MS (CI), m/z (%) 326
M+ − [OH], 100).
Methyl 2-((N-(Buta-2,3-dien-1-yl)-4-methylphenyl)sulfonamido)-
4-methylbenzoate (S11f): 85% yield (2.84 g, 7.65 mmol);
1
amorphous white solid; H NMR (300 MHz, CDCl3) δ 7.74 (d, J
= 7.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 14.1, 7.9 Hz,
3H), 6.86 (s, 1H), 5.37−5.08 (m, 1H), 4.58 (dt, J = 5.8, 2.4 Hz, 2H),
4.27 (s, 2H), 3.68 (d, J = 1.1 Hz, 3H), 2.39 (s, 3H), 2.30 (s, 3H);
10895
https://doi.org/10.1021/acs.joc.1c01268
J. Org. Chem. 2021, 86, 10889−10902

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)-5-(trifluoromethyl)-
phenyl)-4-methylbenzenesulfonamide (S12h): 64% yield (0.7 g,
1.86 mmol); amorphous yellow solid; 1H NMR (500 MHz, CDCl3) δ
7.8 (d, J = 8.0 Hz, 1H), 7.6 (d, J = 8.1 Hz, 1H), 7.5 (dd, J = 8.2, 1.7
Hz, 2H), 7.3 (d, J = 7.8 Hz, 2H), 6.6 (s, 1H), 5.1−5.0 (m, 2H), 4.7−
4.6 (m, 2H), 4.5 (q, J = 10.1 Hz, 2H), 3.8 (dd, J = 13.6, 8.5 Hz, 1H),
2.5 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 210.5, 146.8, 144.8,
137.5, 134.0, 130.4 (q, J = 33.0 Hz), 129.9, 128.2, 125.8 (q, J = 3.7
Hz), 125.0 (q, J = 3.7 Hz), 123.4 (1, J = 272.3 Hz), 85.0, 76.4, 61.0,
51.4, 21.7; MS (CI), m/z (%) 380 M+ − [OH], 100).
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)-4-methoxyphenyl)-
4-methylbenzenesulfonamide (S12i): 54% yield (0.23 g, 0.663
mmol), brown oil; 1H NMR (500 MHz, CDCl3) δ 7.6−7.5 (m, 2H),
7.3−7.3 (m, 2H), 7.1 (d, J = 3.0 Hz, 1H), 6.6 (dd, J = 8.8, 3.0 Hz,
1H), 6.4 (d, J = 8.8 Hz, 1H), 5.1−5.0 (m, 1H), 4.9 (d, J = 12.2 Hz,
1H), 4.6 (dddd, J = 11.2, 6.6, 2.9, 1.6 Hz, 1H), 4.6−4.4 (m, 3H), 3.8
(s, 4H), 3.0 (s, 1H), 2.4 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3)
δ 210.0, 159.8, 144.0, 143.9, 135.1, 129.7, 129.4, 128.9, 128.2, 115.0,
114.6, 85.5, 76.2, 61.6, 55.6, 51.7, 21.7; MS (CI), m/z (%) 342 (M+ −
[OH], 100).
1H), 3.74 (s, 3H), 2.45 (s, 3H), 2.18 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 210.0, 152.2, 143.9, 142.6, 137.9, 137.4, 137.3, 135.6,
129.7, 129.5, 129.4, 128.9, 128.3, 114.9, 114.5, 85.8, 76.1, 55.9, 51.4,
45.2, 21.7, 20.9; HRMS (MM: ESI-APCI+) m/z calcd for
C26H29N2O3S [M + H]+ 449.1893, found 449.1896.
N-(Buta-2,3-dien-1-yl)-N-(2-(((4-methoxyphenyl)amino)methyl)-
5-(trifluoromethyl)phenyl)-4-methylbenzenesulfonamide (3h): 73%
1
yield, (0.7 g, 1.4 mmol), brown oil; H NMR (500 MHz, CDCl3) δ
7.7 (d, J = 8.0 Hz, 1H), 7.6−7.5 (m, 3H), 7.3 (d, J = 8.0 Hz, 2H), 6.8
(d, J = 8.6 Hz, 2H), 6.7 (s, 1H), 6.6 (d, J = 8.6 Hz, 2H), 5.2−5.1 (m,
1H), 4.7 (d, J = 16.3 Hz, 1H), 4.6 (t, J = 8.8 Hz, 1H), 4.6−4.4 (m,
3H), 3.9−3.8 (m, 1H), 3.7 (s, 3H), 2.5 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 210.5, 152.4, 146.3, 144.6, 142.1, 138.0, 134.5, 129.9,
129.6, 129.6 (q, J = 32.9 Hz), 125.5 (q, J = 3.7 Hz), 125.2 (q, J = 3.7
Hz), 123.6 (q, J = 272.2 Hz), 114.4, 85.2, 76.3, 55.9, 51.4, 45.4, 21.7;
19F NMR (282 MHz, CDCl3) δ −62.5; HRMS (MM: ESI-APCI+)
m/z calcd for C26H26F3N2O3S [M + H]+ 503.1649, found 503.1639.
N-(Buta-2,3-dien-1-yl)-N-(4-methoxy-2-(((4-methoxyphenyl)-
amino)methyl)phenyl)-4-methylbenzenesulfonamide (3i): 50%
yield, (0.26 g, 0.56 mmol), brown oil; 1H NMR (500 MHz,
CDCl3) δ 7.7−7.5 (m, 2H), 7.3 (dt, J = 10.8, 5.3 Hz, 2H), 7.1 (d, J =
3.1 Hz, 1H), 6.8−6.7 (m, 2H), 6.7−6.6 (m, 3H), 6.6−6.5 (m, 1H),
5.2−5.0 (m, 1H), 4.7−4.5 (m, 3H), 4.5−4.3 (m, 2H), 4.0−3.8 (m,
1H), 3.7 (d, J = 2.7 Hz, 6H), 2.5−2.4 (m, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 210.0, 159.6, 152.2, 143.8, 142.8, 142.6, 135.6, 129.7,
129.6, 129.3, 128.1, 114.9, 114.5, 114.0, 113.0, 85.8, 77.4, 76.0, 55.8,
55.4, 51.5, 45.6, 21.6; HRMS (MM: ESI-APCI+) m/z calcd for
C26H29N2O4S [M + H]+ 465.1843, found 465.1840.
N-(4-Bromo-2-(hydroxymethyl)phenyl)-N-(buta-2,3-dien-1-yl)-4-
methylbenzenesulfonamide (S12j): 90% yield (2 g, 5 mmol);
1
amorphous white solid; H NMR (300 MHz, CDCl3) δ 7.79 (d, J =
2.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.39−7.17 (m, 3H), 6.33 (d, J
= 8.5 Hz, 1H), 5.09−4.91 (m, 2H), 4.70−4.35 (m, 5H), 3.88−3.75
(m, 1H), 2.48 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 210.0,
144.7, 144.4, 135.8, 134.4, 133.6, 131.2, 129.8, 129.2, 128.0, 123.0,
85.2, 76.41, 60.8, 51.3, 21.7; MS (CI), m/z (%) 391 (M+ − [OH],
100).
N-(4-Bromo-2-(((4-methoxyphenyl)amino)methyl)phenyl)-N-
(buta-2,3-dien-1-yl)-4-methylbenzenesulfonamide (3j): 65% yield
(1.28 g, 2.5 mmol), amorphous white solid; 1H NMR δ 7.7 (d, J = 2.4
Hz, 1H), 7.6 (d, J = 8.3 Hz, 2H), 7.4−7.2 (m, 3H), 6.75 (d, J = 8.9,
2H), 6.6 (d, J = 8.9, 2H), 6.4 (d, J = 8.4 Hz, 1H), 5.1 (q, J = 7.0 Hz,
1H), 4.7−4.5 (m, 3H), 4.4 (d, J = 15.6 Hz, 2H), 3.8 (dd, J = 9.3, 4.4
Hz, 1H), 3.7 (s, 3H), 2.5 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
210.2, 152.4, 144.2, 144.0, 132.3, 130.6, 129.8, 129.6, 128.2, 115.0,
114.5, 85.9, 76.4, 55.9, 51.4, 45.4, 21.7; HRMS (MM: ESI-APCI+)
m/z calcd for C25H26BrN2O3S [M + H]+ 513.0842, found 513.0851.
N-(Buta-2,3-dien-1-yl)-N-(4,5-dimethoxy-2-(((4-methoxyphenyl)-
amino)methyl)phenyl)-4-methylbenzenesulfonamide (3n): 64%
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)-4,5-dimethoxy-
phenyl)-4-methylbenzenesulfonamide (S12n): 57% yield (0.24 g,
0.61 mmol), amorphous white solid; 1H NMR (500 MHz, CDCl3) δ
7.6−7.5 (m, 2H), 7.3 (d, J = 7.9 Hz, 2H), 7.0 (s, 1H), 5.8 (s, 1H), 5.0
(dt, J = 7.9, 6.6 Hz, 1H), 4.9 (d, J = 11.9 Hz, 1H), 4.7−4.6 (m, 1H),
4.5 (ddt, J = 9.4, 6.5, 2.3 Hz, 1H), 4.5 (ddt, J = 13.5, 5.9, 2.8 Hz, 1H),
4.4 (d, J = 12.0 Hz, 1H), 3.9 (s, 3H), 3.8 (ddt, J = 13.7, 8.2, 1.7 Hz,
1H), 3.5 (s, 3H), 2.4 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
210.1, 149.4, 148.4, 144.2, 135.4, 135.1, 129.7, 128.9, 128.4, 112.9,
110.5, 85.6, 76.3, 61.2, 56.1, 55.8, 51.6, 21.7; MS (CI), m/z (%) 382
(M+ − [OH], 100).
1
yield (0.18 g, 0.36 mmol), amorphous white solid; H NMR (500
See the general procedure for the oxidation and reductive
amination of alkynes.
MHz, CDCl3) 7.6 (dt, J = 8.2, 2.0 Hz, 2H), 7.3−7.2 (m, 2H), 7.1−7.0
(m, 1H), 6.8 (dt, J = 8.8, 2.0 Hz, 2H), 6.6 (dq, J = 6.7, 2.1 Hz, 2H),
6.1−5.9 (m, 1H), 5.2−5.0 (m, 1H), 4.7−4.5 (m, 2H), 4.5−4.3 (m,
3H), 3.9 (dd, J = 13.7, 8.6 Hz, 1H), 3.8 (t, J = 1.9 Hz, 3H), 3.8−3.7
(m, 3H), 3.6−3.5 (m, 3H), 2.4 (d, J = 2.6 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 210.0, 152.3, 149.2, 147.7, 143.9, 142.7, 135.7,
133.8, 129.5, 129.1, 128.3, 114.9, 114.8, 111.7, 111.2, 85.8, 76.1, 55.9,
55.8, 55.7, 51.5, 45.4, 21.6; HRMS (MM: ESI-APCI+) m/z calcd for
C27H31N2O5S [M + H]+ 495.1948, found 495.1951.
tert-Butyl Buta-2,3-dien-1-yl(2-(((4-methoxyphenyl)amino)-
methyl)phenyl)carbamate (3d): 70% yield (1.8 g, 4.8 mmol); yellow
1
oil; H NMR (300 MHz, DMSO-d6, 80 °C) δ 7.45−7.36 (m, 1H),
7.30−7.14 (m, 3H), 6.68 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 8.9 Hz,
2H), 5.46 (bs, 1H), 5.33 (p, J = 6.6 Hz, 1H), 4.87−4.76 (m, 2H),
4.25 (bs, 1H), 4.15 (s, 2H), 3.97 (bs, 1H), 364 (s, 3H), 1.40 (s, 9H);
13C{1H} NMR (75 MHz, DMSO-d6, 80 °C) δ 208.2, 153.2, 150.8,
142.6, 140.0, 137.3, 127.8, 127.3, 126.7, 114.5, 113.0, 86.7, 79.2, 75.9,
55.2, 48.4, 43.4, 27.6; HRMS (MM: ESI-APCI+) m/z calcd for
C23H29N2O3 [M + H]+: 381.2173, found 381.2176.
Preparation of Allenes 3: General Procedure. Tosylamides
S13 were synthesized according to literature.44
N-Alkylation. A round-bottomed flask equipped with a stirring
magnetic bar was flamed-dried under a vacuum and backfilled with
argon. Then, it was charged with K2CO3 (2 equiv), and the
corresponding tosylamide S13 was put under a vacuum and backfilled
with argon three times. Then DMF (0.25 M) was added, and the
mixture was stirred for 30 min at rt. Afterward, a propargyl bromide
derivative (1.5 equiv) was added, and the reaction was warmed to 80
°C in an oil bath for 16 h. The reaction was quenched with a saturated
solution of NH4Cl (aq) and extracted with EtOAc. The aqueous layer
was extracted with EtOAc, and the combination of organic layers was
washed with a saturated solution of NH4Cl (aq) (3 × 100 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was then
purified by silica gel column chromatography with hexanes/EtOAc
(7:3) as the eluent to give the propargylated products S14.
N-(Buta-2,3-dien-1-yl)-N-(2-(((4-methoxyphenyl)amino)methyl)-
phenyl)-4-methylbenzenesulfonamide (3e): 70% yield (1.5 g, 3.5
mmol); amorphous white solid; 1H NMR (500 MHz, CDCl3) δ
7.62−7.57 (m, 2H), 7.53 (dd, J = 7.7, 1.6 Hz, 1H), 7.28 (dd, J = 10.4,
7.2 Hz, 3H), 7.12 (td, J = 7.7, 1.6 Hz, 1H), 6.80−6.74 (m, 2H), 6.64−
6.56 (m, 3H), 5.12 (p, J = 6.9 Hz, 1H), 4.70−4.32 (m, 5H), 3.90 (dd,
J = 13.7, 8.4 Hz, 1H), 3.74 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 210.0, 152.1, 143.8, 142.6, 141.3, 137.3, 135.5, 129.7,
129.6, 129.3, 128.8, 128.2, 127.9, 127.4, 114.9, 114.3, 85.6, 76.0, 55.8,
51.4, 45.3, 21.6; HRMS (MM: ESI-APCI+) m/z calcd for
C25H27N2O3S [M + H]+: 435.1737, found 435.1738.
N-(Buta-2,3-dien-1-yl)-N-(2-(((4-methoxyphenyl)amino)methyl)-
5-methylphenyl)-4-methylbenzenesulfonamide (3f): 80% yield
1
(716 mg, 1.6 mmol), amorphous white solid; H NMR (300 MHz,
CDCl3) δ 7.60 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.29 (d, J
= 8.0 Hz, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 9 Hz, 2H), 6.62
(d, J = 9 Hz, 2H), 6.41 (s, 1H), 5.11 (p, J = 6.9 Hz, 1H), 4.69−4.48
(m, 2H), 4.37 (dd, J = 16.7, 6.7 Hz, 3H), 3.88 (dd, J = 13.6, 8.5 Hz,
N-(5-Chloro-2-(hydroxymethyl)phenyl)-4-methyl-N-(prop-2-yn-
1-yl)benzenesulfonamide (S14g): 60% yield (1 g, 3 mmol); 1H
NMR (300 MHz, CDCl3) δ 7.67−7.53 (m, 3H), 7.31 (s, 2H), 7.11
(dd, J = 8.5, 2.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.89 (s, 1H), 4.60
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Note
(s, 1H), 4.36 (d, J = 2.5 Hz, 2H), 2.86 (d, J = 7.7 Hz, 1H), 2.45 (s,
3H), 2.17 (t, J = 2.5 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
144.6, 144.4, 135.6, 135.3, 134.8, 130.8, 129.8, 129.6, 128.5, 128.4,
128.3, 77.2, 74.5, 60.9, 41.9, 21.7; MS (CI), m/z (%) 332 (M+ −
[OH], 100).
See the general procedure for oxidation and reductive amination.
N-(Buta-2,3-dien-1-yl)-N-(5-chloro-2-(((4-methoxyphenyl)-
amino)methyl)phenyl)-4-methylbenzenesulfonamide (3g): 57%
1
yield (330 mg, 0.71 mmol); H NMR (300 MHz, CDCl3) δ 7.5 (d,
J = 7.9 Hz, 2H), 7.4 (d, J = 8.3 Hz, 1H), 7.2 (d, J = 8.0 Hz, 2H), 7.1
(dd, J = 8.4, 2.2 Hz, 1H), 6.7 (d, J = 9 Hz, 2H), 6.5−6.4 (m, 3H), 5.0
(p, J = 7.0 Hz, 1H), 4.6−4.2 (m, 5H), 3.8−3.7 (m, 1H), 3.6 (s, 3H),
2.4 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 210.2, 152.3, 144.3,
142.3, 140.3, 138.5, 134.9, 132.3, 130.3, 129.8, 129.0, 128.3, 128.2,
115.0, 114.4, 85.4, 76.3, 55.9, 51.3, 45.0, 21.7; HRMS (MM: ESI-
APCI+) m/z calcd for C25H26ClN2O3S [M + H]+ 469.1347, found
469.1351.
N-(4-Chloro-2-(hydroxymethyl)phenyl)-4-methyl-N-(prop-2-yn-
1
1-yl)benzenesulfonamide (S14k): 60% yield (1 g, 2.8 mmol); H
NMR (300 MHz, CDCl3) δ 7.66−7.50 (m, 3H), 7.34 (t, J = 8.8 Hz,
3H), 6.61 (t, J = 1.7 Hz, 1H), 4.96−4.48 (m, 2H), 4.40−4.29 (m,
2H), 2.91 (s, 1H), 2.46 (s, 3H), 2.24−2.14 (m, 1H); 13C{1H} NMR
(75 MHz, DMSO-d6) δ 144.8, 141.1, 137.9, 134.5, 133.4, 131.9,
130.0, 129.9, 129.8, 129.6, 128.5, 128.3, 77.0, 74.6, 60.7, 41.9, 21.7;
MS (CI), m/z (%) 332 (M+ − [OH], 100).
N-(3-Fluoro-2-(hydroxymethyl)phenyl)-4-methyl-N-(prop-2-yn-
1-yl)benzenesulfonamide (S14l): 53% yield (600 mg, 1.8 mmol); 1H
NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.38−7.24 (m,
3H), 7.22−7.09 (m, 2H), 6.53−6.44 (m, 1H), 4.82 (s, 2H), 4.40 (d, J
= 2.5 Hz, 2H), 3.07 (t, J = 6.9 Hz, 1H), 2.46 (s, 3H), 2.18 (t, J = 2.5
Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.12, 160.8, 144.6,
138.9, 134.7, 129.7, 129.3 (d, J = 9.8 Hz), 128.5, 124.2, 124.1, 117.2,
116.9, 77.1, 74.5, 54.8, 54.8, 42.3, 21.8; 19F NMR (282 MHz, CDCl3)
δ −113.1; MS (CI), m/z (%) 316 (M+ − [OH], 100).
N-(2-(Hydroxymethyl)-3-methylphenyl)-4-methyl-N-(prop-2-yn-
1-yl)benzenesulfonamide (S14m): 53% yield (600 mg, 1.82 mmol);
1H NMR (300 MHz, CDCl3) δ 7.57 (dd, J = 8.3, 1.5 Hz, 2H), 7.35−
7.18 (m, 3H), 7.02 (t, J = 7.8 Hz, 1H), 6.43 (d, J = 7.9 Hz, 1H), 4.98
(d, J = 11.6 Hz, 1H), 4.59 (t, J = 11.3 Hz, 1H), 4.38 (t, J = 1.9 Hz,
2H), 2.99 (dd, J = 10.8, 3.1 Hz, 1H), 2.52 (s, 3H), 2.43 (d, J = 3.6 Hz,
3H), 2.15 (q, J = 2.1 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ
144.3, 140.7, 140.5, 137.5, 135.0, 131.6, 129.6, 128.5, 128.2, 125.6,
74.2, 57.9, 42.3, 21.7, 19.6; MS (CI), m/z (%) 312 (M+ − [OH],
100).
N-(Buta-2,3-dien-1-yl)-N-(4-chloro-2-(((4-methoxyphenyl)-
amino)methyl)phenyl)-4-methylbenzenesulfonamide (3k): 56%
1
yield (530 mg, 1.13 mmol); H NMR (300 MHz, CDCl3) δ 7.62−
7.50 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.09 (dd, J = 8.5, 2.6 Hz, 1H),
6.77 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 6.51 (d, J = 8.5 Hz,
1H), 5.11 (p, J = 7.0 Hz, 1H), 4.72−4.48 (m, 3H), 4.41 (d, J = 15.5
Hz, 2H), 3.83 (dd, J = 13.9, 8.3 Hz, 1H), 3.74 (s, 3H), 2.45 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 210.2, 152.4, 144.2, 143.8, 142.3,
135.9, 135.3, 134.9, 129.8, 129.4, 129.3, 128.2, 127.5, 115.0, 11447.5,
85.5, 76.3, 55.9, 51.4, 45.4, 21.7; HRMS (MM: ESI-APCI+) m/z
calcd for C25H26ClN2O3S [M + H]+ 469.1347, found 469.1348.
N-(Buta-2,3-dien-1-yl)-N-(3-fluoro-2-(((4-methoxyphenyl)-
amino)methyl)phenyl)-4-methylbenzenesulfonamide (3l): 52%
1
yield (210 mg, 0.47 mmol); H NMR (300 MHz, CDCl3) δ 7.59
(d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.21−7.04 (m, 2H),
6.81 (d, J = 9.0 Hz, 2H), 6.77−6.67 (m, 2H), 6.47 (d, J = 7.7 Hz,
1H), 5.03 (p, J = 6.9 Hz, 1H), 4.67−4.45 (m, 3H), 4.41−4.21 (m,
2H), 3.97−3.84 (m, 1H), 3.76 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 210.0, 162.3 (d, J = 248.7 Hz), 152.6, 144.2,
142.8, 139.8 (d, J = 6.3 Hz), 135.2, 129.7, 128.9, 128.6 (d, J = 9.9
Hz), 128.4, 128.2, 124.5 (d, J = 3.4 Hz), 116.2 (d, J = 22.8 Hz), 115.2,
114.9, 85.5, 76.2, 55.9, 51.7, 39.8, 21.7; 19F NMR (282 MHz, CDCl3)
δ −113.1 (t, J = 7.8 Hz); HRMS (MM: ESI-APCI+) m/z calcd for
C25H26FN2O3S [M + H]+ 453.1643, found 453.1645.
See the general procedure for homologation of alkynes to allenes.
N-(Buta-2,3-dien-1-yl)-N-(5-chloro-2-(hydroxymethyl)phenyl)-4-
methylbenzenesulfonamide (S15g): 54% yield (450 mg, 1.24
1
mmol); H NMR (300 MHz, CDCl3) δ 7.55 (dd, J = 8.3, 1.8 Hz,
3H), 7.34 (d, J = 8.0 Hz, 3H), 6.43 (t, J = 1.6 Hz, 1H), 5.10−4.88 (m,
2H), 4.72−4.33 (m, 4H), 3.79 (d, J = 10.8 Hz, 1H), 2.87 (t, J = 6.5
Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 210.3,
144.6, 141.3, 138.2, 134.4, 133.4, 132.1, 129.9, 129.5, 128.2, 128.0,
85.2, 76.5, 60.8, 51.4, 21.7; MS (CI), m/z (%) 346 (M+ − [OH],
100).
N-(Buta-2,3-dien-1-yl)-N-(4-chloro-2-(hydroxymethyl)phenyl)-4-
methylbenzenesulfonamide (S15k): 72% yield (750 mg, 2 mmol);
1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 2.6 Hz, 1H), 7.54 (d, J =
8.1 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.10 (dd, J = 8.5, 2.5 Hz, 1H),
6.40 (d, J = 8.5 Hz, 1H), 5.09−4.82 (m, 2H), 4.70−4.36 (m, 4H),
3.87−3.75 (m, 1H), 2.86 (s, 1H), 2.46 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 210.2, 144.6, 144.4, 135.5, 135.0, 134.7, 130.9, 129.9,
129.1, 128.4, 128.2, 85.3, 76.4, 61.0, 51.5, 21.7; MS (CI), m/z (%)
346 (M+ − [OH], 100).
N-(Buta-2,3-dien-1-yl)-N-(3-fluoro-2-(hydroxymethyl)phenyl)-4-
methylbenzenesulfonamide (S15l): 50% yield (310 mg, 0.9 mmol);
1H NMR (300 MHz, CDCl3 δ 7.55 (d, J = 8.0 Hz, 2H), 7.31 (d, J =
N-(Buta-2,3-dien-1-yl)-N-(2-(((4-methoxyphenyl)amino)methyl)-
3-methylphenyl)-4-methylbenzenesulfonamide (3m): 58% yield
1
(330 mg, 0.74 mmol); H NMR (300 MHz, CDCl3) δ 7.60 (d, J =
8.1 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.08
(t, J = 7.7 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H),
6.48 (d, J = 7.8 Hz, 1H), 5.05 (dq, J = 8.0, 6.6 Hz, 1H), 4.68−4.46
(m, 2H), 4.46−4.20 (m, 3H), 3.90 (ddt, J = 13.8, 8.2, 1.8 Hz, 1H),
3.77 (s, 3H), 2.47 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 209.8, 152.3, 143.8, 143.4, 140.2, 138.8, 138.2, 135.6, 131.0,
129.6, 128.2, 127.6, 125.9, 114.9, 114.6, 85.6, 76.0, 55.9, 51.6, 42.6,
21.6, 19.5; HRMS (MM: ESI-APCI+) m/z calcd for C26H29N2O3S
[M + H]+: 449.1893, found 449.1896.
General Procedure for the Asymmetric Cyclization of Allenes 3.
A 5 mL sealed tube equipped with a stirring magnetic bar was flamed-
dried under a vacuum, cooled to rt, and backfilled with argon. Then it
was charged with [Rh(cod)Cl]2 (3 mg, 6 μmol, 0.04 equiv), PPTS (4
mg, 15 μmol, 0.1 equiv) or ClCH2CO2H (1.4 mg, 15 μmol, 0.1
equiv), and (R)-DTBM-Garphos (19 mg, 15 μmol, 0.1 equiv).
Afterward, it was put in a vacuum and backfilled with argon for three
times. Then 0.4 mL of DCE was added, and the mixture was stirred
for 10 min at rt. Finally, the allene 3 (0.15 mmol, 1 equiv) was added
under a flow of argon, and the mixture was stirred at 50 °C in an oil
bath for 24 h. After the mixture was cooled at rt and the solvent was
stripped off, the resulting residue was purified by silica gel column
chromatography with hexanes/EtOAc (9:1) as the eluent to give the
desired seven-membered heterocycle 2.
8.0 Hz, 2H), 7.13 (qd, J = 8.3, 6.3 Hz, 2H), 6.30 (dd, J = 7.0, 2.2 Hz,
1H), 5.04 (q, J = 7.0 Hz, 1H), 4.94−4.39 (m, 5H), 3.82 (t, J = 10.9
Hz, 1H), 3.25−3.13 (m, 1H), 2.46 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 210.0, 164.1, 160.8, 144.3, 134.4, 129.7, 129.0 (d, J = 9.9
Hz), 128.1, 123.5 (d, J = 3.4 Hz), 116.5, 116.2, 85.2, 76.3, 54.8, 54.8,
51.5, 21.6; 19F NMR (282 MHz, CDCl3) δ −113.5; MS (CI), m/z
(%) 330 (M+ − [OH], 100).
N-(Buta-2,3-dien-1-yl)-N-(2-(hydroxymethyl)-3-methylphenyl)-4-
methylbenzenesulfonamide (S15m): 70% yield (435 mg, 1.27
1-Tosyl-3-vinyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine (2a):
used the general procedure with PPTS as Bronsted acid, 90%, 56%
ee, [α]2D5 −7.54 (c 1, CHCl3). SFC conditions: 30% MeOH,
Phenomenex Amylose 1 at 40 °C, (CO2/MeOH = 70:30, 1 mL/
min), λ = 210 nm, tR (min): major = 5.98, minor = 6.96). See other
spectroscopic data of 2a in the racemic cyclization of alkyne 1a.
(R)-4-(4-Methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine (2e): PPTS as Brønsted acid, 70% yield,
1
mmol); H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 2H),
7.37−7.26 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H),
6.27 (d, J = 8.0 Hz, 1H), 5.15−4.98 (m, 2H), 4.72−4.36 (m, 4H),
3.89−3.75 (m, 1H), 3.09 (dd, J = 11.0, 2.8 Hz, 1H), 2.54 (s, 3H),
2.45 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 210.0, 144.1, 140.6,
137.6, 134.9, 131.1, 129.7, 128.3, 128.0, 125.1, 85.6, 76.2, 58.0, 51.6,
21.7, 19.6; MS (CI), m/z (%) 326 (M+ − [OH], 100).
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Note
amorphous off-white solid, 90% ee, [α]2D5 −22.4 (c 0.5, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 1H), 7.22−7.03 (m,
5H), 6.64 (d, J = 8 Hz, 2H), 6.51 (d, J = 9 Hz, 2H), 6.25 (d, J = 9 Hz,
2H), 5.75 (ddd, J = 17.3, 10.6, 3.9 Hz, 1H), 5.16 (dd, J = 28.1, 13.9
Hz, 2H), 4.57−4.36 (m, 3H), 4.04 (d, J = 17.2 Hz, 1H), 3.65 (s, 3H),
3.47 (q, J = 13.4, 12.7 Hz, 1H), 2.08 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 152.1, 144.0, 143.0, 139.5, 136.2, 133.6, 129.9, 129.1,
128.5, 127.7, 126.8, 126.5, 126.4, 117.2, 114.8, 114.4, 60.3, 55.7, 54.3,
51.3, 21.4; HRMS (MM: ESI-APCI+) m/z calcd for C25H27N2O3S
[M + H]+ 435.1737, found 435.1738. SFC conditions: 30% MeOH,
Phenomenex Amylose-1 at 40 °C (CO2/MeOH = 70:30, 1 mL/min),
λ = 210 nm, tR (min): major = 19.26, minor = 22.02).
(R)-4-(4-Methoxyphenyl)-8-methyl-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2f): ClCH2CO2H as a Brønsted
acid, 86% yield, amorphous off-white solid, 86% ee, [α]2D5 −70.17 (c 1,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.20 (d, J = 8.3
Hz, 2H), 7.08−6.91 (m, 2H), 6.72 (d, J = 8.1 Hz, 2H), 6.60 (d, J = 9
Hz, 2H), 6.30 (d, J = 9 Hz, 2H), 5.82 (ddd, J = 16.9, 10.9, 3.5 Hz,
1H), 5.31−5.14 (m, 2H), 4.61−4.37 (m, 3H), 4.07 (d, J = 17.1 Hz,
1H), 3.73 (d, J = 2.1 Hz, 3H), 3.61−3.43 (m, 1H), 2.34 (s, 3H), 2.16
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 152.05, 144.0, 143.0,
139.4, 137.6, 136.2, 133.7, 130.6, 129.1, 128.3, 127.2, 126.9, 126.8,
117.1, 114.9, 114.4, 60.3, 55.7, 54.3, 51.1, 21.5, 21.3; HRMS (MM:
ESI-APCI+) m/z calcd for C26H29N2O3S [M + H]+ 449.1893, found
449.1896. SFC conditions: 30% MeOH, Phenomenex Amylose-1 at
40 °C (CO2/MeOH = 70:30, 1 mL/min), λ = 210 nm, tR (min):
major = 33.15, minor = 30.60).
(R)-8-Chloro-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2g): ClCH2CO2H as a Brønsted
acid, 55% yield, amorphous off-white solid, 92% ee, [α]2D5 −17.20 (c 1,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.8 (d, J = 2.2 Hz, 1H), 7.16
(d, J = 7.9 Hz, 1H), 7.07 (dd, J = 8.2, 2.1 Hz, 1H), 7.00 (d, J = 8.1 Hz,
1H), 6.68 (d, J = 8.0 Hz, 2H), 6.58−6.48 (m, 2H), 6.23 (d, J = 8.5
Hz, 2H), 5.75 (ddd, J = 17.2, 10.5, 3.8 Hz, 1H), 5.27−5.11 (m, 2H),
4.57−4.38 (m, 3H), 4.03 (d, J = 17.4 Hz, 1H), 3.66 (s, 4H), 3.52−
3.38 (m, 1H), 2.10 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
152.3, 143.9, 143.5, 140.7, 135.4, 133.1, 130.1, 129.5, 129.3, 127.0,
126.4, 126.1, 117.4, 114.9, 114.5, 60.5, 55.8, 54.1, 50.9, 21.5; HRMS
(MM: ESI-APCI+) m/z calcd for C25H26ClN2O3S [M + H]+
469.1347, found 469.1348. SFC conditions: 30% MeOH, Phenom-
enex Amylose-1 at 40 °C (CO2/MeOH = 70:30, 1 mL/min), λ = 210
nm, tR (min): major = 19.78, minor = 16.24).
(R)-4-(4-Methoxyphenyl)-1-tosyl-8-(trifluoromethyl)-3-vinyl-
2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (2h): ClCH2CO2H as
a Brønsted acid, 99% yield, amorphous off-yellow solid, 90% ee, [α]D25
−37.40 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.1 (s, 1H), 7.4
(d, J = 7.9 Hz, 1H), 7.3 (d, J = 8.0 Hz, 1H), 7.2 (d, J = 7.9 Hz, 2H),
6.7 (d, J = 8.0 Hz, 2H), 6.6 (d, J = 8.5 Hz, 2H), 6.3 (d, J = 8.4 Hz,
2H), 5.8 (ddd, J = 17.2, 10.3, 3.5 Hz, 1H), 5.3−5.2 (m, 2H), 4.6 (d, J
= 17.5 Hz, 1H), 4.6−4.5 (m, 2H), 4.2 (d, J = 17.5 Hz, 1H), 3.7 (d, J =
1.3 Hz, 3H), 3.5 (s, 1H), 2.2 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 152.4, 143.8, 143.6, 140.2, 137.3, 135.6, 133.3, 129.3, 127.2,
123.8 (q, J = 272.5 Hz), 123.0−122.9 (m), 117.4, 115.0, 114.9, 114.6,
60.5, 55.8, 54.0, 51.1, 21.5; 19F NMR (282 MHz, CDCl3) δ −62.4;
HRMS (MM: ESI-APCI+) m/z calcd for C26H26F3N2O3S [M + H]+
504.1689, found 504.1683. SFC conditions: 20% MeOH, Phenom-
enex Amylose-1 at 40 °C (CO2/MeOH = 80:20, 1 mL/min), λ = 210
nm, tR (min): major = 15.05, minor = 12.15).
conditions: 20% MeOH, Phenomenex Amylose-1 at 40 °C (CO2/
MeOH = 80:20, 1 mL/min), λ = 210 nm, tR (min): major = 15.71,
minor = 16.97).
1
(R)-7-Bromo-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2j): ClCH2CO2H as Brønsted
acid, 70% yield, amorphous off-white solid, 88% ee, [α]2D5 −11.69 (c 1,
CHCl3); 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3)
δ 7.8 (d, J = 8.7 Hz, 1H), 7.3 (dd, J = 8.7, 2.4 Hz, 1H), 7.3 (d, J = 2.4
Hz, 1H), 7.2 (d, J = 8.0 Hz, 2H), 6.7 (d, J = 8.0 Hz, 2H), 6.60 (d, J =
9.0 Hz, 2H), 6.25 (d, J = 9.0 Hz, 2H), 5.8 (ddd, J = 17.2, 10.5, 3.7 Hz,
1H), 5.3−5.1 (m, 2H), 4.7−4.4 (m, 3H), 4.1 (d, J = 17.5 Hz, 1H),
3.74 (s, 3H), 3.5 (dd, J = 14.8, 10.6 Hz, 1H), 2.2 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 152.3, 143.7, 143.4, 138.8, 135.8, 133.2
131.2, 130.6, 130.0, 129.3, 128.0, 126.9, 119.6, 117.43, 114.8, 114.5,
60.2, 55.7, 54.2, 50.9, 21.5; HRMS (MM: ESI-APCI+) m/z calcd for
C25H26BrN2O3S [M + H]+ 513.0842, found 513.0851. SFC
conditions: 30% MeOH, Phenomenex Amylose-1 at 40 °C (CO2/
MeOH = 70:30, 1 mL/min), λ = 210 nm, tR (min): major = 24.37,
minor = 21.15).
(R)-7-Chloro-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2k): ClCH2CO2H as a Brønsted
acid, 72% yield, amorphous off-white solid, 94% ee, [α]2D5 −17.20 (c 1,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.7 Hz, 1H),
7.18−7.00 (m, 4H), 6.65 (d, J = 7.9 Hz, 2H), 6.55 (d, J = 8.8 Hz,
2H), 6.23 (d, J = 8.8 Hz, 2H), 5.74 (ddd, J = 17.3, 10.5, 4.0 Hz, 1H),
5.25−5.07 (m, 2H), 4.55−4.36 (m, 3H), 3.98 (d, J = 17.4 Hz, 1H),
3.66 (s, 3H), 3.40 (d, J = 15.6 Hz, 1H), 2.09 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 152.4, 143.8, 143.3, 138.3, 135.9, 135.6, 133.3,
131.7, 129.3, 128.3, 127.7, 127.6, 126.9, 117.4, 114.9, 114.5, 60.3,
55.7, 54.3, 51.1, 21.5; HRMS (MM: ESI-APCI+) m/z calcd for
C25H26ClN2O3S [M + H]+ 469.1347, found 469.1348. SFC
conditions: 30% MeOH, Phenomenex Amylose-1 at 40 °C (CO2/
MeOH = 70:30, 1 mL/min), λ = 210 nm, tR (min): major = 20.09,
minor = 17.33).
(R)-6-Fluoro-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2l): ClCH2CO2H as a Brønsted
acid, 60% yield, amorphous off-white foam, 90% ee, [α]2D5 −6.50 (c 1,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 1H),
7.23−7.05 (m, 3H), 6.84 (t, J = 8.8 Hz, 1H), 6.66 (d, J = 7.8 Hz, 2H),
6.55 (d, J = 8.4 Hz, 2H), 6.26 (d, J = 8.4 Hz, 2H), 5.77 (ddd, J = 17.3,
10.5, 3.7 Hz, 1H), 5.27−5.12 (m, 2H), 4.56 (d, J = 17.8 Hz, 1H), 4.46
(dd, J = 10.7, 5.4 Hz, 2H), 4.29 (d, J = 17.8 Hz, 1H), 3.66 (s, 3H),
3.55−3.41 (m, 1H), 2.09 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3)
δ 159.9 (d, J = 244.3 Hz), 152.1, 143.7, 143.2, 141.4 (d, J = 5.0 Hz),
135.8, 133.2, 129.1, 127.8 (d, J = 10.0 Hz), 126.8, 121.5, 121.4, 117.3,
114.6, 114.4, 112.8 (d, J = 23.0 Hz), 60.1, 55.6, 54.10 42.7, 21.4; 19F
NMR (282 MHz, CDCl3) δ −116.32 (t, J = 8.3 Hz); HRMS (MM:
ESI-APCI+) m/z calcd for C25H26FN2O3S [M + H]+ 453.1643, found
453.1643. SFC conditions: 20% MeOH, Phenomenex Amylose-1 at
40 °C (CO2/MeOH = 80:20, 1 mL/min), λ = 210 nm, tR (min):
major = 19.08, minor = 17.66).
(R)-4-(4-Methoxyphenyl)-6-methyl-1-tosyl-3-vinyl-2,3,4,5-tetra-
hydro-1H-benzo[e][1,4]diazepine (2m): ClCH2CO2H as a Brønsted
acid, 86% yield, brown oil, 94% ee, [α]2D5 −20.65 (c 1, CHCl3); H
1
NMR (500 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 1H), 7.18 (s, 2H),
7.03 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 7.9 Hz,
2H), 6.58−6.50 (m, 2H), 6.25 (d, J = 8.6 Hz, 2H), 5.71 (ddd, J =
17.2, 10.6, 4.5 Hz, 1H), 5.21−5.11 (m, 2H), 4.49−4.36 (m, 2H), 4.25
(q, J = 17.3 Hz, 2H), 3.66 (s, 3H), 3.36 (dd, J = 14.7, 10.8 Hz, 1H),
2.19 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
152.6, 144.7, 142.9, 140.0, 136.5, 136.1, 134.1, 131.7, 129.2, 128.7,
126.9, 124.6, 119.4, 117.4, 116.3, 114.4, 60.4, 55.7, 54.6, 48.5, 21.5,
20.3; HRMS (MM: ESI-APCI+) m/z calcd for C26H29N2O3S [M +
H]+ 449.1893, found 449.1896. SFC conditions: 20% MeOH,
Phenomenex Amylose-1 at 40 °C (CO2/MeOH = 80:20, 1 mL/
min), λ = 210 nm, tR (min): major = 20.98, minor = 19.36).
(R)-7-Methoxy-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-tet-
rahydro-1H-benzo[e][1,4]diazepine (2i): ClCH2CO2H as a Brønsted
acid, 86% yield, amorphous off-yellow solid, 90% ee, [α]2D5 −66.28 (c
1
1, CHCl3); H NMR (500 MHz, CDCl3) δ 7.8 (d, J = 8.9 Hz, 1H),
7.2 (d, J = 7.9 Hz, 2H), 6.8−6.7 (m, 3H), 6.7 (d, J = 3.0 Hz, 1H),
6.55 (d, J = 8.5 Hz, 2H), 6.3 (d, J = 8.5 Hz, 2H), 5.8 (ddd, J = 17.3,
10.6, 4.0 Hz, 1H), 5.3−5.1 (m, 2H), 4.6−4.4 (m, 3H), 4.0 (d, J = 17.1
Hz, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 3.5 (s, 1H), 2.2 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 157.9, 152.3, 144.0, 142.9, 136.4, 135.8,
133.8, 132.4, 129.1, 128.2, 126.7, 117.2, 115.4, 114.3, 113.9, 112.2,
60.3, 55.7, 55.6, 54.5, 51.8, 21.5; HRMS (MM: ESI-APCI+) m/z
calcd for C26H29N2O4S [M + H]+ 465.1843, found 465.1858. SFC
(R)-7,8-Dimethoxy-4-(4-methoxyphenyl)-1-tosyl-3-vinyl-2,3,4,5-
tetrahydro-1H-benzo[e][1,4]diazepine (2n): ClCH2CO2H as a
Brønsted acid, 78% yield, amorphous off-white foam, 96% ee, [α]D25
1
−76.38 (c 1, CHCl3); H NMR (500 MHz, CDCl3) δ 7.5−7.4 (m,
10898
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J. Org. Chem. 2021, 86, 10889−10902

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
1H), 7.2 (d, J = 7.9 Hz, 2H), 6.7 (d, J = 7.9 Hz, 2H), 6.6−6.5 (m,
3H), 6.3 (d, J = 8.4 Hz, 2H), 5.8 (ddd, J = 17.1, 10.5, 4.1 Hz, 1H),
5.3−5.1 (m, 2H), 4.5 (d, J = 17.0 Hz, 2H), 4.4 (dd, J = 10.6, 4.8 Hz,
1H), 4.0 (d, J = 17.1 Hz, 1H), 3.9 (d, J = 2.6 Hz, 6H), 3.7 (s, 3H), 3.5
(d, J = 14.6 Hz, 1H), 2.2 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3)
δ 152.3, 147.7, 147.2, 144.0, 143.0, 136.2, 133.8, 132.3, 129.2, 126.8,
126.0, 122.2, 117.2, 115.3, 114.3, 110.7, 60.5, 56.2, 56.1, 55.7, 54.6,
51.4, 21.5; HRMS (MM: ESI-APCI+) m/z calcd for C27H31N2O5S
[M + H]+ 495.1948, found 495.1958. SFC conditions: 20% MeOH,
Phenomenex Amylose-1 at 40 °C (CO2/MeOH = 80:20, 2 mL/min),
λ = 210 nm, tR (min): major = 11.50, minor = 12.90).
to give the desired product 6: 65% yield (30 mg), amorphous off-
white solid, [α]2D5 − 8.90 (c 0.7, CHCl3); 1H NMR (300 MHz,
DMSO-d6, 80 °C) δ 7.62 (d, J = 7.9 Hz, 2H), 7.40−7.09 (m, 6H),
6.54 (dd, J = 16.7, 10.5 Hz, 1H), 5.99 (ddd, J = 16.4, 13.8, 3.5 Hz,
2H), 5.63 (dd, J = 10.4, 2.3 Hz, 1H), 5.24 (dd, J = 22.5, 14.0 Hz, 2H),
4.60 (d, J = 132.9 Hz, 3H), 4.11−4.00 (m, 2H), 2.35 (s, 3H);
13C{1H} NMR (75 MHz, DMSO-d6, 80 °C) δ 165.4, 143.3, 139.3,
137.1, 133.7, 132.1, 129.5, 129.0, 128.0, 127.2, 127.1, 126.5, 125.7,
124.1, 116.6, 52.0, 44.7, 39.8, 20.6; HRMS (MM: ESI-APCI+) m/z
calcd for C21H24N2O3S [M + H]+ 383.1424, found 383.1422.
(R)-10-Tosyl-5,10,11,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-a]-
[1,4]diazepin-3-one (7).45 A flame-dried Schlenk was charged with
the Hoveyda−Grubbs second generation catalyst (2.5 mg, 0.004
mmol, 0.1 equiv), and it was put under a vacuum and backfilled with
argon. Afterward, a solution of 5 (15 mg, 0.04 mmol, 1 equiv) in dry
DCM (1.5 mL) was added, and the reaction was refluxed in an oil
bath for 36 h. Then, the reaction crude was purified by silica gel
column chromatography with a gradient of hexanes/EtOAc (60:40)
to 100% EtOAc as the eluent to give the desired product 7: 87% yield
Derivatization of (R)-4-(4-Methoxyphenyl)-1-tosyl-3-vinyl-
2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (2e). (R)-1-Tosyl-3-
vinyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-4-ium chloride
(4).31 A solution of PMP-protected amine 2e (110 mg, 0.25 mmol)
in 8.0 mL of MeCN was cooled in an ice bath and treated with a
solution of CAN (275 mg, 0.5 mmol, 2.5 equiv) in water (8 mL)
dropwise. The reaction allowed to warm to 25 °C and stirred for 3 h.
The crude reaction was diluted with water and washed with Et2O, and
the organic layer was discarded. The aqueous layer was basified to pH
10 with a saturated Na2CO3 solution and extracted with Et2O. The
combined organic layers were dried with MgSO4 and treated with a 1
M HCl solution in Et2O and concentrated to afford the hydrochloride
salt of the product as an amorphous white solid: 77 mg, 85% yield,
1
(12 mg), white foam, 88% ee, [α]2D5 −8.10 (c 0.5, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.70−7.58 (m, 2H), 7.39 (dd, J = 7.3, 1.8 Hz,
1H), 7.32−7.21 (m, 4H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 6.93 (dd, J =
6.0, 1.7 Hz, 1H), 6.19 (dd, J = 6.0, 1.7 Hz, 1H), 4.84 (d, J = 14.9 Hz,
1H), 4.72 (dd, J = 14.5, 3.4 Hz, 1H), 4.67−4.55 (m, 1H), 3.83 (d, J =
14.9 Hz, 1H), 2.73 (dd, J = 14.5, 11.3 Hz, 1H), 2.44 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 169.1, 144.3, 142.8, 139.8, 138.3, 137.1,
130.2, 130.1, 129.6, 129.5, 129.1, 129.0, 127.3, 64.7, 53.8, 44.0, 21.7;
HRMS (MM: ESI-APCI+) m/z calcd for C19H19N2O3S [M + H]+
355.1111, found 355.1111. SFC conditions: 40% MeOH, Phenom-
enex Amylose-1 at 40 °C (CO2/MeOH = 60:40, 1 mL/min), λ = 210
nm, tR (min): major = 9.12, minor = 11.06).
[α]2D5 122.7 (c 0.70, MeOH); H NMR (300 MHz, methanol-d4) δ
1
7.77 (d, J = 7.8 Hz, 2H), 7.56 (dd, J = 5.8, 3.2 Hz, 1H), 7.45 (dd, J =
8.5, 4.5 Hz, 4H), 7.31−7.17 (m, 1H), 5.86 (ddd, J = 17.4, 10.5, 7.0
Hz, 1H), 5.73−5.54 (m, 2H), 4.51 (dd, J = 15.7, 2.6 Hz, 1H), 4.31 (d,
J = 14.1 Hz, 1H), 4.25−4.15 (m, 1H), 4.09 (d, J = 14.0 Hz, 1H),
3.44−3.29 (m, 2H), 2.48 (s, 3H); 13C{1H} NMR (75 MHz,
methanol-d4) δ 148.8, 144.4, 141.2, 135.5, 135.3, 134.6, 133.9,
133.7, 132.8, 132.2, 131.1, 126.3, 66.2, 54.8, 52.8, 24.1; HRMS (MM:
ESI-APCI+) m/z calcd for C18H21ClN2O2S [M − Cl + H]+ 329.1324,
found 329.1320.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01268.
■
sı
(R)-4-(4-Methoxyphenyl)-3-vinyl-2,3,4,5-tetrahydro-1H-benzo-
[e][1,4]diazepine (5).32 To a solution of naphthalene (4 mg, 0.02
mmol, 0.2 equiv) in anhydrous THF (1 mL) in an oven-dried Schlenk
flask under a stream of argon were added hexane-rinsed sheets of
sodium metal (21.2 mg, 0.885 mmol, 6 equiv). The mixture was then
sonicated at rt until a green color persisted when a solution of 2e (62
mg, 0.143 mmol) in THF (4 mL) was added, resulting in a rapid loss
of the green color. The turbid yellow reaction mixture was removed
from the sonicator and stirred at rt for 15 h. Afterward, the reaction
was cooled to 0 °C, and 10 mL of MeOH was slowly added to quench
the Na followed by the addition of a saturated solution of NaHCO3
(only after consumption). The reaction was diluted with Et2O and
washed with NaHCO3 and H2O. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The product was purified by silica
gel column chromatography with hexanes/EtOAc (8:2) as the eluent
to give the desired product 5: 85% yield (34 mg), colorless oil, [α]D25
−50.1 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J = 7.4
Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.88−6.55 (m, 5H), 6.50 (d, J = 7.9
Hz, 1H), 5.90 (ddd, J = 17.0, 10.3, 3.9 Hz, 1H), 5.29 (dd, J = 25.6,
13.9 Hz, 2H), 5.01 (d, J = 17.1 Hz, 1H), 4.50−4.37 (m, 1H), 4.19 (d,
J = 17.1 Hz, 1H), 3.9 (bs, 1H), 3.70 (s, 3H), 3.67−3.58 (m, 1H), 3.40
(dd, J = 14.3, 5.4 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 151.3,
147.8, 145.0, 135.4, 129.4, 127.4, 124.8, 119.0, 116.6, 115.5, 114.7,
113.1, 64.8, 55.8, 50.2, 48.5; HRMS (MM: ESI-APCI+) m/z calcd for
C18H21ClN2O2S [M + H]+ 281.1648, found 281.1647.
Optimization procedures, X-ray crystallographic data,
chiral HPL, and NMR spectra for all new compounds
(PDF)
Accession Codes
CCDC 1983304 contains the supplementary 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 contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Carlos Saá − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CiQUS), Departamento
de Química Orgánica, Universidade de Santiago de
Compostela, 15782 Santiago de Compostela, Spain;
orcid.org/0000-0003-3213-4604; Email: carlos.saa@
usc.es
(R)-1-(1-Tosyl-3-vinyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4] diaze-
pin-4-yl) prop-2-en-1-one (6). To a suspension of 4 (45 mg, 0.123
mmol) and DMAP (1.5 mg, 0.012 mmol, 0.1 equiv) in DCM (0.1 M)
cooled in an ice-bath was added Et3N (60 μL, 0.5 mmol, 4 equiv).
After the mixture was stirred for 5 min, acryloyl chloride (20 μL,
0.247 mmol, 2 equiv) was added dropwise. The reaction was allowed
to warm to rt and stirred for 2 h. The crude reaction was diluted with
H2O and extracted with DCM. The organic layer was washed with an
aqueous solution of 5% HCl, brine, dried over Na2SO4, and
concentrated in vacuo. The resulting product was purified by silica
gel column chromatography with hexanes/EtOAc (7:3) as the eluent
Authors
́
Alvaro Velasco-Rubio − Centro Singular de Investigación en
Química Biolóxica e Materiais Moleculares (CiQUS),
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Rodrigo Bernárdez − Centro Singular de Investigación en
Química Biolóxica e Materiais Moleculares (CiQUS),
Departamento de Química Orgánica, Universidade de
10899
https://doi.org/10.1021/acs.joc.1c01268
J. Org. Chem. 2021, 86, 10889−10902

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Decarboxylative Asymmetric Allylic Alkylation of 1,4-Diazepan-5-
ones. Org. Lett. 2019, 21, 9158−9161.
Santiago de Compostela, 15782 Santiago de Compostela,
Spain
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Dou, H.; Williamson, T.; Treanor, J.; Liu, H.; Jin, L.; Xu, G.; Ma, J.;
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Methods for the Synthesis of 1,4-Oxazepanes and their Benzo-
Derivatives. In Synthetic Approaches to Nonaromatic Nitrogen Hetero-
cycles; Wiley, 2020; pp 437−500.
́
Jesus A. Varela − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CiQUS), Departamento
de Química Orgánica, Universidade de Santiago de
Compostela, 15782 Santiago de Compostela, Spain;
orcid.org/0000-0001-8499-4257
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01268
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work received financial support from MINECO (project
CTQ2017-87939R and ORFEO−CINQA network RED2018-
102387-T), the Xunta de Galicia (project ED431C 2018/04
and Centro singular de investigación de Galicia accreditation
2019-2022, ED431G 2019/03), and the European Union
(European Regional Development Fund, ERDF). A.V.-R.
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