Tandem Olefin Isomerization/Cyclization Catalyzed by Complex Nickel Hydride and Br?nsted Acid

Article abstract of DOI:10.1021/acs.joc.0c02033

We disclose a nickel/Br?nsted acid-catalyzed tandem process consisting of double bond isomerization of allyl ethers and amines and subsequent intramolecular reaction with nucleophiles. The process is accomplished by [(Me3P)4NiH]N(SO2CF3)2 in the presence of triflic acid. The methodology provides rapid access to tetrahydropyran-fused indoles and other oxacyclic scaffolds under very low catalyst loadings.

Full text of DOI:10.1021/acs.joc.0c02033

pubs.acs.org/joc
Article
Tandem Olefin Isomerization/Cyclization Catalyzed by Complex
Nickel Hydride and Brønsted Acid
Prasad M. Kathe, Alexandru Caciuleanu, Andreas Berkefeld,* and Ivana Fleischer*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c02033
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We disclose a nickel/Brønsted acid-catalyzed tandem process
consisting of double bond isomerization of allyl ethers and amines and
subsequent intramolecular reaction with nucleophiles. The process is
accomplished by [(Me3P)4NiH]N(SO2CF3)2 in the presence of triflic acid.
The methodology provides rapid access to tetrahydropyran-fused indoles and
other oxacyclic scaffolds under very low catalyst loadings.
strategies based on base metal catalysts and our experience
with isomerizing transformations10 and nickel catalysis11 gave
us an impetus to address this shortcoming. The application of a
homogeneous nickel catalyst in this chemistry complements
the portfolio of nickel catalyzed isomerizations12 and
corresponding tandem processes,13 providing robust and
economical synthetic routes toward libraries of versatile N-
and O-containing heterocyclic building blocks. The disadvant-
age of some of the tandem isomerization nickel catalysts is the
need to employ stoichiometric amounts of additives and
activators. A relatively simple isomerization catalyst was
reported by Tolman in 197214 who explored the generation
of complex nickel hydrides from readily available phosphine
stabilized zero-valent nickel precursors such as ((EtO)3P)4Ni
and Brønsted acid. The in situ generated nickel hydride
catalyzes the isomerization of simple alkenes such as 1-butene.
Mechanistic studies pointed to a migratory insertion, β-hydride
elimination pathway for the isomerization which requires the
presence of free coordination sites on a metal center. Further
insights by Maschmeyer et al. revealed [L3NiH]+ as the
catalytically active species.15
INTRODUCTION
■
The metal-catalyzed positional isomerization of a double bond
is an emerging synthetic transformation1 that can be combined
with follow-up reactions in tandem processes.2 Such reaction
sequences allow for an efficient construction of complex
structures in a simple manner from a diverse range of readily
available starting materials. The combination of these two (or
more) reactions enables functionalization of an otherwise
unreactive carbon atom.
Allyl ethers and amines are excellent and straightforward to
synthetize substrates for tandem isomerizations. In their
seminal work, Terada and co-workers reported the use of
complex ruthenium hydride in conjunction with a Brønsted
acid for the sequential generation of enamines by isomerization
of allyl amines and subsequent acid-catalyzed generation of
iminium intermediates and Friedel−Crafts alkylation of
electron-rich arenes.3 The intramolecular version of this
reaction provides an efficient route toward synthetically
valuable and structurally diverse heterocyclic compounds
(Scheme 1a).4 This was further explored by Scheidt and co-
workers5 in transformation of indole-containing allyl ethers via
isomerization/oxa-Pictet-Spengler cyclization.6 They employed
a catalyst system comprising an in situ generated complex
iridium hydride and bismuth triflate to give a range of
tetrahydropyran-fused indoles. Further extension was reported
by groups of Nielsen and Saa who developed a ruthenium-
catalyzed synthesis of acetals.7
Notwithstanding the ready availability of reactive complex
nickel hydrides, no practical applications of related Ni(0)
complexes or corresponding hydrides have been reported.
Herein, we disclose the use of the complex
16
[(Me3P)4NiH]N(SO2CF3)2 (Ni−H), easily synthesized
Received: August 23, 2020
While a great variety of catalysts has been reported for the
cyclization step, including enantioselective versions,8 the
isomerization so far has relied only on precious metals such
as Ru and Ir. A mechanistically distinct radical cyclo-
isomerization9 of related substrates using a cobalt catalyst
was reported by Shenvi and co-workers.9d The lack of
https://dx.doi.org/10.1021/acs.joc.0c02033
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 1. Tandem Isomerization/Cyclization of Allyl Ethers and Amines
DPPA = dkiphenylphosphoric acid.
from Ni(PMe3)4 and HN(SO2CF3)2, as an efficient isomer-
ization precatalyst. Moreover, this acidic nickel hydride could
also work synergistically with a strong Brønsted acid to result
in tandem isomerizing cyclizations of allyl ethers and amines
(Scheme 1b).
underwent rapid olefin isomerization at room temperature
regardless of the electronic nature of functional group, giving
the corresponding β-methylstyrenes exclusively as the E-
isomers. Notably, the double bond in 4-phenyl-1-butene
(1g) migrated selectively over a single carbon atom, since
only traces of the regioisomer were found. Both geometrical
isomers were initially present with E/Z = 51:49, but conversion
of (Z) into (E) isomer occurred on prolonged reaction times,
typically overnight. A selective one bond isomerization was
also observed with 1-octene. Substrates with an internal double
bond or a terminal disubstituted double bond did not undergo
positional isomerization, but the reaction of (Z)-2-octene with
1 mol % of catalyst led to 79:21 mixture of E- and Z-isomers
after 22 h. Possibly, the reason is kinetic control of the
reaction.
RESULTS AND DISCUSSION
■
Following the mentioned reports, we sought to investigate the
capability of Ni−H to catalyze olefin isomerization in allyl
benzenes. As depicted in Scheme 2, the allyl benzenes 1a−f
a
Scheme 2. Olefin Isomerization Catalyzed by Ni−H
With the established isomerization procedure in hand, we
proceeded to investigate the follow-up cyclization of indole-
substituted allylether 3aa. We chose to use Bi(OTf)3 as a
cocatalyst and a source of triflic acid owing to its superior
activity in Friedel−Crafts type reactions as compared to other
triflates.17 Unlike the initially investigated alkenes, it was
observed that incomplete isomerization of 3aa to 4aa occured
(57:43 after 2 h), providing an equilibrium mixture eventually.
Addition of a fresh aliquot of Ni−H neither led to any further
isomerization nor to any cyclization. The addition of equimolar
amounts of Bi(OTf)3 after 4 h resulted in formation of 5aa in
30−60% yield (Table 1, entries 1−2). Since the addition of all
reaction components at the onset of reaction appears to result
in incomplete conversion to product, a sequential addition was
tested, in which the reactant was stirred with Ni−H for the
given amount of time (t1) followed by addition of the acid and
prolonged stirring (t2). Still, the use of Bi(OTf)3 did not give
a
Reaction conditions: alkene (0.25 mmol), Ni−H (1 mol %), THF
b
(0.16 M), isolated yield; GC yield using pentadecane as an internal
standard; CH2Cl2 (0.16 M); E/Z ratio after 15 h; Ni-H (0.17 mol
%), isolated yield.
c
d
e
B
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
yield (entries 4, 5). At room temperature, no reaction occurred
in the absence of either Ni−H precatalyst or the Brønsted acid.
Notably, using only Ni−H under forcing reaction conditions
afforded product 5aa in 41% yield (entry 6).
Table 1. Optimization of Reaction Conditions for Tandem
Olefin Isomerization/Oxa-Pictet Spengler Cyclization
a
We tested the scope of the developed methodology by
subjecting a number of O-allylated indole derivatives to
isomerization/cyclization (Scheme 3). The C-3 substituted
indoles with methoxy and bromo substituents smoothly
underwent cyclization to give products 5ab and 5ad in yields
of 86% and 66%, respectively. In an effort to display the
robustness of this catalytic system at a preparative scale, the
loading of Ni−H could be lowered to 0.075 mol % and the
TfOH to 1.5 mol % for the synthesis of 5ab at a 4 mmol scale
in 59% yield (>98% purity, see Supporting Information) and
hence without a major loss in catalytic activity (TOF = 1190
h−1).
time
yield
e
entry Ni−H (mol %)
acid (mol %)
(t1;t2/h) T (°C)
(%)
b
1
2
3
4
5
6
7
5
5
5
5
1
5
1
Bi(OTf)3 (5)
Bi(OTf)3 (5)
TfOH (5)
TfOH (15)
TfOH (4)
None
4/4
4/4
0.5/0.5
0.3/0.3
0.3/0.3
18
r.t
r.t
r.t
r.t
r.t
130
120
31
62
80
12
80
41
78
c
d
(PhO)2P(O)OH
(4)
0.5/18
C-3 substituted unprotected indoles could also undergo
cyclization albeit giving a moderate 53% yield (5ae). A
substrate possessing a phenyl ring adjacent to the O-allyl tether
was tested and the product 5ac could be isolated with a high
d.r. of 20:1 in 65% yield. Incomplete conversion was observed
when the optimized conditions were used for synthesis of 5af
with a methyl group on the allyl chain. For the purpose of
enabling complete conversion, higher loadings of precatalysts
and elevated temperatures were employed to give 5af in 44%
yield. We went on to test selected N-substituted indoles in
catalysis. Substrates without a substituent in the 3-position
a
Reaction conditions: 3aa (0.25 mmol), Ni−H, acid, THF (0.16 M).
b
c
Solvent: CH2Cl2. Solvent: xylene, 130 °C, determined by
d
e
quantitative GC-FID analysis. Solvent: toluene. Isolated yield.
reproducible results, and triflic acid (TfOH) was used instead.
We were pleased to find that with 5 mol % Ni−H and 5 mol %
TfOH, product 5aa was formed in 80% yield (entry 3). While a
high excess of acid (15 mol %) was detrimental, the reaction
time could be shortened to overall 40 min with concurrent
lowering of catalyst loading to 1 mol % without any loss of
a
Scheme 3. Isomerizing Friedel−Crafts Cyclization for Synthesis of Various Pyran-Fused Heterocycles
a
Reaction conditions: substrate (0.25 mmol), Ni−H (1 mol %), CF3SO3H (4 mol %), THF (1.5 mL), r.t., 40 min; b3ab (4.0 mmol), Ni−H (0.075
mol %) CF3SO3H (1.5 mol %) cNi-H (4 mol %), CH3SO3H (16 mol %), THF (1.5 mL), 60 °C, 60 min; dNi-H (2 mol %), CH3SO3H (8 mol %),
THF (1.5 mL), 40 °C, 60 min; Ni-H (0.05 mol %), CF3SO3H (1 mol %).
e
C
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
resulted in the formation of oligomers under acid catalysis.
Also in this case, various 5-substituted indoles reacted to the
corresponding products 5ba−be in good yields. N-substituted
indole with an extra carbon in the N−O bridge resulted in
product 5bf in 47% yield. Furthermore, we tested two polar
substituents on the C-3 position. The presence of a thioether
function was tolerated but resulted in a lower yield. The
presence of thiocyanate function on C-3 position failed to
afford any cyclized product but isomerization of the double
bond was observed.
Scheme 4. Synthesis of Cyclic Acetals
The optimized reaction conditions were further put to test
for synthesis of oxacyclic scaffolds based on electron rich
phenyl and thiophenyl rings using a low Ni−H loading of 0.05
mol %. The reaction of 2-(3-methoxyphenyl)ethylallylether
afforded isochroman derivative 7a in 92% yield. However,
substitution at the 4-position resulted mainly in deallylation. A
lower yield was obtained for the dimethoxy substituted
substrate. Substitutions on the thiophene ring at 2- and 3-
positions were also tolerated to furnish the products 9a and 9b
in 72 and 36% yield, respectively, and a remarkable TOF of
2170 h−1 for 9a.
a
Conditions: 10 (0.25 mmol), Ni−H (4 mol %, (PhO)2P(O)OH (15
mol %), toluene (1.5 mL), 115 °C.
In order to extend the scope of the methodology and to
broaden the variability of oxacylic scaffolds, we aimed at the
intramolecular cyclization of in situ generated electrophiles
with pendant nucleophilic heteroatoms. First, we tested the
synthesis of 1,3-oxazines as cyclic hemiaminal ethers.7a The
alternative synthetic strategy toward related structures through
Mannich condensation of phenols can be limited by the
competitive formation of dimers.18 Considering the lack of
examples of 3d-metal catalyzed transformations using this
particular class of substrates, we capitalized on the ability of
Ni−H to engage in tandem processes to achieve the desired
outcome using 10a as the substrate. The instability of the
reaction product (Table 2) necessitates the use of a weaker
Brønsted acid but harsher reaction conditions (115 °C) and a
higher amount of precatalyst (4 mol %) were required.
membered analogue 11d and the corresponding O,O-acetals
11e−f was accomplished in good yields. Moreover, two 1,3-
dioxolane derivates 11g−h were obtained in 54% and 61%
yields, respectively.
CONCLUSIONS
■
This report describes a methodology, which exploits readily
available complex nickel hydride working in tandem with a
Brønsted acid to enable the synthesis of O-containing
heterocycles by a isomerization/cyclization strategy. The
employed nickel precatalyst performs selectively in migrating
a double bond in allyl arenes and other terminal olefins over
one bond. This reactivity serves as a platform to open new
avenues in nickel hydride/Brønsted acid co-catalyzed tandem
transformations. Our methodology has advantages over state-
of-the art catalyst systems that require either refluxing
conditions and high catalyst loadings (Ru) or a preactivation
and catalyst addition (Ir) in portions. Moreover, we report
unusually low catalyst loadings for nickel in general.
Table 2. Optimization of Reaction Conditions for the
a
Synthesis of Mixed Acetals
EXPERIMENTAL SECTION
■
General Experimental Information. Solvents and Reagents. All
solvents were distilled and dried before use or purchased from the
respective supplier as dry solvents. Reactions with oxygen- or
moisture-sensitive reagents were carried out under argon using
standard Schlenk techniques. Other chemicals were purchased from
Acros Organics, Chem-Pur, Sigma-Aldrich, ABCR, TCI Chemicals,
Fluka Chemicals, Alfa Aesar and were used as received. Used
abbreviations of reagents: THF (tetrahydrofuran). The complexes
[(Me3P)4NiH]N(SO2CF3)2, Ni(PMe3)4, and Ni(PPh3)4 were synthe-
sized according to the procedure reported in the literature.16b,19
Column chromatography was carried out using silica gel (60 Å) as the
stationary phase, either using gravity flow conditions under isocratic
elution or flash column chromatography under gradient elution.
Gradients were set up depending on the solvent ratios found ideal via
thin layer chromatography (TLC). TLC was performed with
aluminum plates coated with silica gel 60 F254 (layer thickness: 0.2
mm) and analyzed under UV-light (254 nm) or stained with a
potassium permanganate solution. Gas Chromatography (GC-FID)
analysis was carried out on a HP6890 GC-System with injector 7683B
and Agilent 7820A system. Dry hydrogen was used as the carrier gas,
and for the measurements, the following method was used: Heating
from 50 to 280 °C within 15 min. Pentadecane was added as the
b
Ni−H (mol %)
acid (mol %)
time (h)
yield (%)
1
2
3
4
1
2
4
4
8
15
15
20
15
42
55
83
81
2.5
2.5
2.5
a
Conditions: 10a (0.25 mmol), Ni−H, (PhO)2P(O)OH, toluene (1.5
b
mL), 115 °C. Isolated yield.
Upon optimizing the reaction conditions for the synthesis of
O,N-acetals, we turned our attention to evaluate the generality
and robustness of these conditions (Scheme 4). Another 6-
membered O,N-acetal with a single substituent on the benzylic
position (11b) could be obtained in 68% yield. However, the
presence of two methyl groups was detrimental for the
transformation and did not lead to complete conversion (11c).
Acetal formation may be kinetically challenged owing to the
steric hindrance by the methyl groups, and formal deallylation
was observed instead. Contrary to 11c, the synthesis of the 7-
D
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
internal standard. For the calibration, samples with different amounts
of substrate and standard (pentadecane) were measured with GC-
FID, and the obtained data were used to plot A(standard)/
A(substrate) against m(standard)/m(substrate). The resulting slope
computed from linear regression is equivalent to the response factor
R, which can be used to quantify unknown samples. Gas
chromatography−mass spectrometry was performed on an Agilent
7820A GC system in combination with an Agilent 5977 B using an EI
source and a quadrupole analyzer. Samples were diluted in an organic
solvent and passed through aluminum oxide prior to GC−MS
analysis. Crude samples were additionally stirred with QuadraSil
scavengers for several minutes prior to analysis. For all analyses, the
following method was used: Heating from 50 to 280 °C within 15
min. “Synkam S1121” chiral HPLC was used for determination of
enantiomeric ratios. Reprosil Chiral-OM (5 μm) was used as a
column (125 × 4 mm) with a 206 PHD UV detector from Linear.
NMR spectra were recorded using a Bruker AVANCE 400 (1H: 400
MHz, 13C: 101 MHz) or Bruker AVANCE 300 (1H: 300 MHz, 13C:
75 MHz). All 13C NMR spectra were recorded with proton
decoupling. All measurements were done at ambient temperature.
Chemical shifts δ are reported in parts per million relative to the
residual 1H and natural abundance 13C NMR resonances of the
solvents: CDCl3, δH/C = 7.26/77.0; THF-d8, δH/C = 3.58/67.6.
Coupling constants J are given in Hertz [Hz]. 1H NMR splitting
patterns are indicated as follows: s = singlet; d = doublet; t = triplet; q
= quartet; quin = quintet; and m = multiplet. Infrared spectra were
recorded on an Agilent Technologies Cary 630 FTIR spectrometer,
equipped with an ATR system. Absorption bands are given in wave
tube was washed with 2 mL CH2Cl2, and the solvent was again passed
through the Pasteur pipette. Careful rotary evaporation of the solvent
(owing to the volatility of the products) was done followed by
recording NMR spectra of the reaction mixture.
General Procedure (AA). Synthesis of Substrates 6a, 6b, 8a,
and 8b by O-Allylation. In a flame-dried 3-neck round bottom flask
fitted with reflux condenser, NaH (60% dispersion in mineral oil, 1.5
equiv) was added. This was followed by addition of dry THF (0.1 M).
The corresponding alcohol (1 equiv) was then added, and the mixture
was heated to 50 °C (oil bath) for 1 h. The mixture was then cooled
to 0 °C before the addition of allyl bromide (2 equiv). The reaction
mixture was stirred at ambient temperature overnight and then
quenched with 50 mL of sat. NH4Cl solution. The aqueous phase was
extracted with EtOAc (2 × 40 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude mixture was purified by
column chromatography (mixture of n-hexane and ethyl acetate).
General Procedure (AB). Synthesis of Indole Derivatives
3aa−3af. 1. Fischer indole synthesis of tryptophol: Phenyl-
hydrazine·HCl (1 equiv) was dissolved in a 1:1 mixture of 4%
aqueous H2SO4 solution (0.69 M) and dimethylacetamide (0.69 M).
Past heating it to 100 °C (oil bath), 2,3-dihydrofuran (1 equiv) was
added drop-wise. After 2 h, the reaction mixture was cooled to
ambient temperature and extracted with ethyl acetate. The organic
phases were dried over anhydrous MgSO4, filtered, and concentrated
by rotary evaporation at 12 mmHg and 50 °C. The crude tryptophol
was purified by column chromatography (n-hexane/ethyl acetate 1:1)
and used as such for the Appel reaction. 2. Appel reaction: In a dry 3-
neck round-bottom flask, tryptophol was dissolved in dry CH2Cl2 and
cooled to 0 °C. After that, triphenylphosphine (1.1 equiv), imidazole
(2.2 equiv), and iodine (1.1 equiv) were added in that order. The
mixture was stirred at ambient temperature till completion. The
reaction was diluted with CH2Cl2 and washed with water, and the
aqueous phase was extracted with CH2Cl2. The organic phases were
dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
crude mixture was purified by column chromatography. 3. O-
Allylation of the iodide: The product of Apple reaction (1 equiv)
and freshly distilled allyl alcohol (30 equiv) were heated to 90 °C (oil
bath). Cesium carbonate (2 equiv) was added, and the yellow mixture
was heated further for 2 h at 100 °C (oil bath). The mixture was then
cooled to ambient temperature and quenched with 10 mL of sat.
NH4Cl solution. The aqueous phase was extracted with dichloro-
methane. The organic phases were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude product was obtained
as red oil. 4. N-Substitution with benzyl group: The substrate was
dissolved in N,N-dimethyl formamide and cooled to 0 °C. Freshly
crushed KOH (3 equiv) was added, and the reaction mixture was
warmed to ambient temperature. After 1 h, the mixture was cooled to
0 °C before adding benzyl chloride (1.5 equiv) dropwise. The
reaction was then warmed to ambient temperature and allowed to stir
till reaction completion before quenching with H2O. This was
followed by extraction with ethyl acetate. The organic phases were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude mixture was purified by column
chromatography.
numbers ν
by the mass spectrometry department of the Institute of Organic
Chemistry, University of Tubingen.
̃
(cm−1). HRMS (ESI, APCI, EI) analysis was carried out
̈
General Procedure (A). Tandem Olefin Isomerization/Oxa-
Pictet Spengler Cyclization and Synthesis of Oxacyclic
Scaffolds. To a flame-dried 20 mL Schlenk tube inside a glove box
was added [(Me3P)4NiH]N(SO2CF3)2 (0.05−1 mol %). Outside the
box, dry THF (0.16 M) was added under Ar counterflow, and a
yellow colored solution formed. After the addition of the substrate
(0.25 mmol), the reaction mixture was stirred for 20 min at room
temperature. This was followed by the addition of triflic acid (0.8−4
mol %), and the reaction mixture was stirred further for 20 min. The
reaction mixture was then diluted with 5 mL ethyl acetate and washed
with water and brine (2 × 5 mL). The aqueous phase was extracted
with ethyl acetate (2 × 5 mL). The combined organic phases were
dried over magnesium sulfate. Organic solvents were removed by
rotary evaporation. This was followed by column chromatography
using dry loading.
General Procedure (B). Synthesis of O,O/O,N-Acetals. To a
flame-dried 20 mL Schlenk tube inside a glove box was added
[(Me3P)4NiH]N(SO2CF3)2 (4 mol %). Outside the box, dry toluene
(0.16 M) was added under Ar counterflow affording a yellow solution.
After the addition of the substrate (0.25 mmol), the reaction mixture
was stirred for 30 min at room temperature. This was followed by
addition of diphenyl phosphate (8−16 mol %), and the reaction
mixture was heated (oil bath) further for the time specified for every
substrate. The reaction mixture was then diluted with 5 mL EtOAc
and washed with water and sat. NaCl (2 × 5 mL). The aqueous phase
was extracted with CH2Cl2 (2 × 5 mL). The combined organic phases
were dried over magnesium sulfate. Organic solvents were removed
by rotary evaporation. This was followed by column chromatography
using dry loading.
General Procedure (C). Olefin Isomerization by [Ni-
(PMe3)4H]Tf2N. For a typical experiment to test olefin isomerization,
the pre-catalyst [(Me3P)4NiH]N(SO2CF3)2 (1 mol %) was added to
a Schlenk tube in a glove box. The Schlenk tube was taken outside the
glove box, evacuated, and backfilled with argon. This was followed by
addition of dry CH2Cl2 (0.16 M), affording a yellow colored solution
to which the substrate was added. The progress of alkene
isomerization was monitored by GC-FID. For the purpose of isolation
of the isomerized product, the reaction mixture was passed through a
Pasteur pipette with cotton plug and aluminum oxide. The Schlenk
General Procedure (AC). Synthesis of 3-Phenyl Substituted
Indoles. 1. Fischer-indole synthesis of 3-substituted indole. In a
three neck flask was added N,N-dimethylurea and L-(+)-tartaric acid.
The mixture was heated at 70 °C (oil bath) till no solid was present
and a “melt” was formed. To this melt was added the corresponding
phenyl hydrazine hydrochloride followed by the aldehyde. The
mixture was stirred until consumption of the reactants. While still hot,
water was added to the mixture. This was followed by extraction with
ethyl acetate (3 × 25 mL). The excess solvent was taken off by rotary
evaporation. The compound was then purified by column
chromatography (n-hexane and ethyl acetate). 2. N-Alkylation of
indole. The purified indole was then added to a Schlenk tube
followed by dry N,N-dimethyl formamide (1 M). The reaction
mixture was cooled to 0 °C, and crushed KOH (3 equiv) was added.
The reaction mixture was allowed to attain room temperature and
stirred for 1 h. The reaction mixture was then again cooled to 0 °C
E
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
followed by dropwise addition of freshly distilled 2-bromoethanol (1.5
equiv). The reaction was stirred at room temperature until
completion. The reaction was quenched by addition of sat. NH4Cl
followed by extractive work-up with ethyl acetate. The crude product
obtained after rotary evaporation was then taken to the next step
without purification. 3. O-Allylation of −OH. The crude alcohol was
added to a Schlenk tube under Ar and dissolved in 1 M dry N,N-
dimethyl formamide. The reaction mixture was cooled to 0 °C
followed by addition of NaH (60% dispersion in mineral oil) (3
equiv). This was followed by addition of freshly distilled allyl bromide
(1.5 equiv). The reaction mixture was allowed to attain room
temperature and stirred till completion.
General Procedure for Optimization of Reaction Con-
ditions. To a flame-dried 20 mL Schlenk tube inside a glove box
was added [(Me3P)4NiH]N(SO2CF3)2 (0.05−1 mol %). Outside the
box, dry THF (0.16 M) was added under Ar counterflow affording a
yellow colored solution. After the addition of the substrate (0.25
mmol), the reaction mixture was stirred for X h (please see
Supporting Information) at room temperature. This was followed
by addition of acid, and the reaction mixture was stirred further for Y
h (please see Supporting Information) at the indicated temperature.
Following this, the standard pentadecane was added (100 μL). To
monitor the reaction, 0.1 mL was taken from the reaction mixture,
and the sample was diluted with 1 mL of ethyl acetate, passed through
a Pasteur pipette fitted with cotton containing basic aluminum oxide,
and transferred into a GC vial. Through GC calibration (shown in
following sections), the quantity of analyte was determined. Please see
Supporting Information for table of optimization.
following the procedure C outlined for olefin isomerization. The
compound was obtained as colorless oil (28 mg, 0.21 mmol, 85%).
The spectral data matches with the one reported in the literature.22
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.1 Hz, 1H), 7.20−
7.08 (m, 3H), 6.60 (dd, J = 15.7, 1.8 Hz, 1H), 6.19−6.04 (m, 1H),
2.33 (s, 4H), 1.91 (dd, J = 6.6, 1.8 Hz, 4H); 13C{1H} NMR (101
MHz, CDCl3): δ = 137.0, 134.7, 130.1, 128.8, 126.9, 126.7, 126.0,
125.3, 19.8, 18.8.
(E)-2-(Prop-1-en-1-yl)phenol (2e). Compound 2e was synthe-
sized from 2-allylphenol (33.5 mg, 0.25 mmol) and [(Me3P)4NiH]-
N(SO2CF3)2 (1.6 mg, 2.48 μmol) in CH2Cl2 (0.16 M) following the
procedure C outlined for olefin isomerization. The compound was
obtained as colorless oil: (88%, 29.4 mg, 0.22 mmol). The spectral
data matches with the one reported in the literature.23 1H NMR (400
MHz, CDCl3): δ = 7.31 (dd, J = 7.7, 1.7 Hz, 1H), 7.14−7.06 (m,
1H), 6.95−6.85 (m, 1H), 6.83−6.75 (m, 1H), 6.66−6.54 (m, 1H),
6.28−6.15 (m, 1H), 1.92 (dd, J = 6.6, 1.7 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ = 152.3, 128.3, 127.9, 127.4, 125.2, 125.0,
120.9, 115.6, 18.9.
(E)-1-Bromo-2-(prop-1-en-1-yl)benzene (2f). Compound 2f
was synthesized from 2-allylbromobenzene (48 mg, 0.25 mmol) using
[(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol) in CH2Cl2 (0.16 M)
following the procedure C outlined for olefin isomerization. The
compound was obtained as colorless oil: 43.2 mg, 0.22 mmol, 90%.
The spectral data matches with the one reported in the literature.24
1H NMR (300 MHz, CDCl3): δ = 7.58−7.43 (m, 2H), 7.28−7.20 (m,
1H), 7.10−7.02 (m, 1H), 6.74 (dd, J = 15.7, 1.8 Hz, 1H), 6.19 (dq, J
= 15.6, 6.7 Hz, 1H), 1.93 (dd, J = 6.6, 1.8 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ = 137.7, 132.8, 129.9, 128.8, 128.0, 127.3, 126.8,
123.0, 18.7.
But-2-en-1-ylbenzene (2g). Compound 2g was synthesized
from but-3-en-1-ylbenzene (33 mg, 0.25 mmol) using [(Me3P)4NiH]-
N(SO2CF3)2 (1.6 mg, 2.48 μmol) in CH2Cl2 (0.16 M) following the
procedure C outlined for olefin isomerization. The compound was
obtained as colorless oil: 23.7 mg, 0.18 mmol, 72%, E/Z: 80:20. This
value of E/Z ratio is in agreement with the one obtained from
quantitative GC-FID analysis: 82:18, traces of other regioisomers
were detected. The spectral data matches with the one reported in the
literature.25 1H NMR (300 MHz, CDCl3): δ = 7.36−7.24 (m, 3H),
7.24−7.16 (m, 4H), 5.70−5.46 (m, 2H), 3.43 (d, J = 5.3 Hz, 1H),
3.34 (d, J = 5.5 Hz, 1H), 1.79−1.70 (m, 1H), 1.71 (dd, J = 4.8, 1.2
Hz, 3H). Note: Protons corresponding to the minor (Z) isomer are
displayed in bold where possible. Due to close overlap of peaks in
aromatic region, the exact assignment of peaks to major/minor
isomers was not done.; 13C{1H} NMR (75 MHz, CDCl3): δ = 141.0,
130.0, 129.0, 128.48 (corresponds to two 13C nuclei), 128.41, 128.3
(corresponds to two 13C nuclei), 126.3, 125.87, 125.82, 124.8, 39.0,
33.1, 17.9, 12.8. Note: 13C nuclei corresponding to the minor (Z)
isomer are displayed in bold where possible. Close overlap
complicates the spectral assignment.
(E)-1-Methoxy-4-(prop-1-en-1-yl)benzene (2a). Compound
2a was synthesized from 1-allyl-4-methoxybenzene (37.05 mg, 0.25
mmol) and [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol) in
CH2Cl2 (0.16 M) following the procedure C outlined for olefin
isomerization. The compound was obtained as colorless oil: 91%, 33.7
mg, 0.22 mmol. The spectral data matches with the one reported in
the literature.20 1H NMR (400 MHz, CDCl3): δ = 7.21−7.15 (m,
2H), 6.79−6.73 (m, 2H), 6.27 (dd, J = 15.8, 1.7 Hz, 1H), 6.08−5.95
(m, 1H), 3.72 (s, 3H), 1.78 (dd, J = 6.6, 1.7 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ = 158.5, 130.8, 130.3, 126.8, 123.5, 113.8, 55.2,
18.4.
(E)-1-(Prop-1-en-1-yl)-4-(trifluoromethyl)benzene (2b).
Compound 2b was synthesized from 1-allyl-4-(trifluoromethyl)-
benzene (46.5 mg, 0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2
(1.6 mg, 2.48 μmol) in CH2Cl2 (0.16 M) following the procedure C
outlined for olefin isomerization. The compound was obtained as
colorless oil: 30.69 mg, 0.16 mmol, 66%. The spectral data matches
with the one reported in literature.21 1H NMR (400 MHz, CDCl3): δ
= 7.54 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 6.49−6.29 (m,
2H), 1.92 (dd, J = 6.2, 1.2 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 141.3, 129.9, 128.5 (d, 2JC−F = 32.3 Hz), 125.9, 125.4 (q,
1
3JC−F = 3.8 Hz), 124.3 (d, JC−F = 271.7 Hz), 18.5; 19F NMR (376
MHz, CDCl3): δ = −62.39. Note: Owing to the lack of enhancement
by NOE, the peaks corresponding to quaternary carbons in the 13C
NMR spectrum do not have a good signal to noise ratio.
2-Octene (2h). Compound 2h was synthesized from 1-octene
(559.4 mg, 4.99 mmol) and [(Me3P)4NiH]N(SO2CF3)2 (5.46 mg,
9.17 μmol) in THF (8.3 M) following the procedure C outlined for
olefin isomerization. The product was obtained as colorless oil: 369
mg, 3.29 mmol, 66%, E/Z = 80:20. 1H NMR (300 MHz, CDCl3): δ =
5.50−5.33 (m, 2H), 2.09−1.89 (m, 2H), 1.69−1.56 (m, 3H), 1.41−
1.21 (m, 6H), 0.89 (td, J = 7.0, 2.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ = 131.6, 124.5, 32.5, 31.4, 29.3, 22.5, 17.9, 14.0.
3-(2-(Allyloxy)ethyl)-1-benzyl-1H-indole (3aa). Compound
3aa was synthesized from 3-(2-(allyloxy)ethyl)-1H-indole (1.3 g,
9.6 mmol, 1 equiv) following the general procedure AB for N-
benzylation. The crude mixture was purified by column chromatog-
raphy (n-hexane/ethyl acetate 93:7) and obtained as colorless oil:
821.4 mg, 2.8 mmol, 62% over two steps. The spectral data matches
with the one reported in the literature.5 1H NMR (400 MHz,
CDCl3): δ = 7.62 (d, J = 4.7 Hz, 1H), 7.35−7.22 (m, 4H), 7.21−7.06
(m, 4H), 6.97 (s, 1H), 6.00−5.85 (m, 1H), 5.30−5.21 (m, 3H),
5.20−5.11 (m, 1H), 4.07−4.00 (m, 2H), 3.82−3.68 (m, 2H), 3.12−
3.01 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ = 137.7, 136.5,
(E)-1,2,3,4,5-Pentafluoro-6-(prop-1-en-1-yl)benzene (2c).
Compound 2c was synthesized from allylpentafluorobenzene (52.0
mg, 0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48
μmol) in CH2Cl2 (0.16 M) following the procedure C outlined for
olefin isomerization. The compound was obtained as colorless oil:
1
45.7 mg, 0.22 mmol, 88%. H NMR (300 MHz, CDCl3): δ = 6.67−
6.48 (m, 1H), 6.28 (dq, J = 16.2, 1.7 Hz, 1H), 2.01−1.91 (m, 3H);
3
13C{1H} NMR (75 MHz, CDCl3): δ = 135.9 (td, JC−F, = 7.5 Hz,
4JC−F = 2.3 Hz), 115.2, 19.7; 19F NMR (376 MHz, CDCl3): δ =
−144.1, −158.1, −163.6. Note: Solvent peak of residual CH2Cl2
1
detected at 5.3 ppm in H NMR. Owing to the lack of enhancement
by NOE, the peaks corresponding to quaternary and F-substituted
carbons in the 13C NMR spectrum do not have a good signal to noise
ratio.
(E)-1-Methyl-2-(prop-1-en-1-yl)benzene (2d). Compound 2d
was synthesized from 2-allylphenol (33.5 mg, 0.25 mmol) and
[(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol) in CH2Cl2 (0.16 M)
F
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
134.9, 128.7, 128.2, 127.5, 126.8, 126.1, 121.7, 119.0, 118.9, 116.8,
112.1, 109.6, 71.9, 70.7, 49.9, 25.8.
1330, 1174, 1088, 924, 734, 697; HRMS (ESI) m/z [M + H]+: calcd
for C21H24NO, 306.1856; found, 306.1853.
3-(2-(Allyloxy)ethyl)-1-benzyl-5-methoxy-1H-indole (3ab).
Compound 3ab was synthesized from 3-(2-(allyloxy)ethyl)-5-
methoxy-1H-indole (1.91 g, 8.3 mmol, 1 equiv) following the general
procedure AB followed for N-benzylation. The crude mixture was
purified by column chromatography (n-hexane/ethyl acetate 90:10)
and obtained as yellow oil: 1.97 g, 6.10 mmol, 74%. The spectral data
matches with the one reported in the literature.5 1H NMR (400 MHz,
CDCl3): δ = 7.26−7.15 (m, 3H), 7.04−6.98 (m, 4H), 6.89 (s, 1H),
6.78−6.72 (m, 1H), 5.96−5.79 (m, 1H), 5.25−5.06 (m, 4H), 3.96
(dt, J = 5.7, 1.4 Hz, 2H), 3.78 (s, 3H), 3.65 (t, J = 7.3 Hz, 2H), 2.96
(t, J = 7.4, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ = 153.8, 137.8,
134.9, 131.8, 128.7, 128.5, 127.5, 126.8, 126.7, 116.8, 111.8, 111.6,
110.4, 100.9, 71.9, 70.7, 55.9, 50.1, 25.8.
1-(2-(Allyloxy)ethyl)-3-phenyl-1H-indole (3ba). Compound
3ba was synthesized from 2-(3-phenyl-1H-indol-1-yl)ethan-1-ol
(300 mg, 1.26 mmol, 1 equiv) and allyl bromide (162 μL, 1.89
mmol, 1.5 equiv) following general procedure AC for O-allylation.
The crude compound was purified by column chromatography (n-
hexane/ethyl acetate 95:5) and obtained as colorless oil: 200 mg, 0.72
mmol, 56%. The spectral data matches with the one reported in the
literature.5 1H NMR (300 MHz, CDCl3): δ = 8.02−7.88 (m, 1H),
7.74−7.61 (m, 2H), 7.52−7.32 (m, 4H), 7.33−7.13 (m, 3H), 5.93−
5.73 (m, 1H), 5.29−5.08 (m, 2H), 4.34 (t, J = 5.7 Hz, 2H), 3.99−
3.89 (m, 2H), 3.79 (t, J = 5.7 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3): δ = 136.9, 135.6, 134.3, 128.7, 127.3, 126.3, 126.2, 125.7,
121.9, 119.9, 117.2, 116.9, 109.6, 72.2, 68.9, 46.3.
3-(2-(Allyloxy)-2-phenylethyl)-1-methyl-1H-indole (3ac).
Compound 3ac was synthesized from 2-(1-methyl-1H-indol-3-yl)-1-
phenylethan-1-ol (1.1 g, 4.3 mmol, 1 equiv) and allyl bromide (557
μL, 779 mg, 6.45 mmol, 2 equiv) using the procedure reported by
Scheidt et al.9 The compound was purified by column chromatog-
raphy (n-hexane/ethyl acetate 9:1) and obtained as yellow oil: 910
mg, 3.12 mmol, 73%. The spectral data matches with the one reported
in the literature.5 1H NMR (300 MHz, CDCl3): δ = 7.57−7.50 (m,
1H), 7.36−7.27 (m, 6H), 7.23−7.17 (m, 1H), 7.11−7.04 (m, 1H),
6.72 (s, 1H), 5.96−5.79 (m, 1H), 5.27−5.08 (m, 2H), 4.61−4.53 (m,
1H), 3.99−3.89 (m, 1H), 3.84−3.74 (m, 1H), 3.70 (s, 3H), 3.29 (dd,
J = 14.6, 7.3 Hz, 1H), 3.06 (dd, J = 14.6, 6.0 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3): δ = 142.5, 136.7, 135.0, 128.2, 127.6, 127.4,
126.8, 121.2, 119.0, 118.5, 116.5, 111.1, 109.0, 99.9, 82.0, 69.7, 34.3,
32.5.
3-(2-(Allyloxy)ethyl)-1-benzyl-5-bromo-1H-indole (3ad).
Compound 3ad was synthesized from 3-(2-(allyloxy)ethyl)-5-
bromo-1H-indole (610 mg, 2.17 mmol) following the general
procedure AB for N-benzylation. The crude mixture was purified by
column chromatography (12 g SiO2, stepwise elution: 1. n-hexane/
ethyl acetate 93:7 for 5 CV followed by n-hexane/ethyl acetate 9:1)
and obtained as colorless oil: 452 mg, 1.22 mmol, 56%. The spectral
data matches with the one reported in the literature.5 1H NMR (400
MHz, THF-d8): δ = 7.75 (s, 1H), 7.27−7.18 (m, 4H), 7.17−7.12 (m,
3H), 7.11−7.04 (m, 2H), 5.96−5.82 (m, 1H), 5.30 (s, 2H), 5.23 (d, J
= 17.3 Hz, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.02−3.92 (m, 2H), 3.64
(t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (101
MHz, THF-d8): δ = 138.0, 135.5, 135.3, 130.2, 128.3, 127.8, 127.1,
126.5, 123.8, 121.4, 114.9, 112.5, 111.1, 71.3, 70.4, 49.4, 25.5.
3-(2-(Allyloxy)ethyl)-1H-indole (3ae). Compound 3ae was
synthesized from 3-(2-iodoethyl)-1H-indole (500 mg, 1.84 mmol, 1
equiv) following the general procedure AB for O-allylation. The crude
mixture was purified by column chromatography (n-hexane/ethyl
acetate 90:10) and obtained as yellow oil: 210 mg, 1.04 mmol, 57%.
The spectral data matches with the one reported in the literature.5 1H
NMR (300 MHz, CDCl3): δ = 7.98 (s, 1H), 7.68−7.58 (m, 1H),
7.40−7.31 (m, 1H), 7.26−7.07 (m, 2H), 7.06 (d, J = 2.2 Hz, 1H),
6.06−5.86 (m, 1H), 5.37−5.14 (m, 2H), 4.10−4.00 (m, 2H), 3.77 (t,
J = 7.3 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3): δ = 136.1, 134.9, 127.5, 121.9, 119.2, 118.8, 116.8, 113.0,
111.0, 71.9, 70.6, 25.8.
1-(2-(Allyloxy)ethyl)-5-bromo-3-phenyl-1H-indole (3bb).
Compound 3bb was synthesized from 2-(5-bromo-3-phenyl-1H-
indol-1-yl)ethan-1-ol (1.3 g, 4.11 mmol, 1 equiv) and allyl bromide
(545 μL, 6.16 mmol, 1.5 equiv) following general procedure AC for
O-allylation. The crude compound purified by column chromatog-
raphy (n-hexane/ethyl acetate 95:5) and obtained as yellow oil: 420
mg, 1.17 mmol, 29%. The spectral data matches with the one reported
in the literature.5 1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 2.6
Hz, 1H), 7.58−7.48 (m, 2H), 7.43−7.31 (m, 2H), 7.31−7.14 (m,
4H), 5.83−5.64 (m, 1H), 5.19−5.01 (m, 2H), 4.23 (t, J = 5.5 Hz,
2H), 3.90−3.81 (m, 2H), 3.70 (t, J = 5.5 Hz, 2H); 13C{1H} NMR (75
MHz, CDCl3): δ = 135.6, 134.9, 134.1, 128.8, 127.9, 127.3, 127.2,
126.1, 124.7, 122.4, 117.2, 116.7, 113.4, 111.2, 72.2, 68.9, 46.6.
1-(2-(Allyloxy)ethyl)-5-methoxy-3-phenyl-1H-indole (3bc).
Compound 3bc was synthesized from 2-(5-methoxy-3-phenyl-1H-
indol-1-yl)ethan-1-ol (710 mg, 2.65 mmol, 1 equiv) and allyl bromide
(352 μL, 3.97 mmol, 1.5 equiv) following general procedure AC for
O-allylation. The crude compound purified by column chromatog-
raphy (n-hexane/ethyl acetate 90:10) and obtained as colorless oil:
350 mg, 1.13 mmol, 43%. The spectral data matches with the one
reported in literature.5 1H NMR (400 MHz, CDCl3): δ = 7.70−7.61
(m, 2H), 7.51−7.41 (m, 2H), 7.44−7.37 (m, 1H), 7.36−7.26 (m,
3H), 6.99−6.90 (m, 1H), 5.93−5.77 (m, 1H), 5.28−5.12 (m, 2H),
4.32 (t, J = 5.6 Hz, 2H), 3.99−3.91 (m, 2H), 3.89 (s, 3H), 3.79 (t, J =
5.6 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ = 154.5, 135.8,
134.3, 132.2, 128.8, 127.2, 126.8, 126.5, 125.6, 117.2, 116.5, 112.1,
110.4, 101.7, 72.2, 69.0, 56.0, 46.5.
1-(2-(Allyloxy)ethyl)-5-fluoro-3-phenyl-1H-indole (3bd).
Compound 3bd was synthesized from 2-(6-fluoro-3-phenyl-1H-
indol-1-yl)ethan-1-ol (620 mg, 2.43 mmol, 1 equiv) and allyl bromide
(323 μL, 3.64 mmol, 1.5 equiv) following general procedure AC for
O-allylation. The compound was purified by column chromatography
(n-hexane/ethyl acetate 9:1) and isolated as colorless oil: 314 mg,
1
1.06 mmol, 44%. H NMR (400 MHz, CDCl3): δ = 7.65−7.55 (m,
3H), 7.48−7.37 (m, 3H), 7.33−7.24 (m, 2H), 7.00 (td, J = 9.0, 2.5
Hz, 1H), 5.82 (ddt, J = 17.1, 10.3, 5.5 Hz, 1H), 5.24−5.11 (m, 2H),
4.33 (t, J = 5.5 Hz, 2H), 3.94 (dt, J = 5.5, 1.5 Hz, 2H), 3.79 (t, J = 5.5
1
Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ = 158.3 (d, JC−F
=
=
3
234.5 Hz), 135.2, 134.2, 133.5, 128.8, 127.7, 127.1, 126.5 (d, JC−F
9.8 Hz), 125.9, 117.2, 116.9 (d, 4JC−F = 4.7 Hz), 110.4 (d, 4JC−F = 2.0
Hz), 110.1, 104.9 (d, JC−F = 24.0 Hz), 72.2, 68.9, 46.7; 19F NMR
2
1-Benzyl-3-(2-(but-3-en-2-yloxy)ethyl)-1H-indole (3af).
Compound 3af was prepared from 3-(2-(but-3-en-2-yloxy)ethyl)-
1H-indole (370 mg, 1.71 mmol) and following general procedure AB
for N-benzylation. The compound was isolated as yellow oil after
purification by flash column chromatography (12 g SiO2, stepwise
elution, n-hexane/ethyl acetate 97.5:2.5 followed by n-hexane/ethyl
acetate 95:5). The product was obtained as colorless oil (260 mg, 0.85
mmol, 50%). 1H NMR (300 MHz, CDCl3): δ = 7.63 (m, 1H), 7.33−
7.24 (m, 4H), 7.23−7.05 (m, 1H), 6.98 (s, 1H), 5.85−5.67 (m, 1H),
5.28 (s, 2H), 5.23−5.05 (m, 2H), 3.95−3.79 (m, 1H), 3.83−3.68 (m,
1H), 3.68−3.53 (m, 1H), 3.10−2.99 (m, 2H), 1.26 (dd, J = 6.4, 1.1
Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ = 140.5, 137.7, 136.5,
128.7, 128.3, 127.5, 126.8, 126.1, 121.6, 119.1, 118.9, 115.6, 112.3,
(376 MHz, CDCl3): δ = −124.55; IR: ν = 3075, 2933, 2978, 2858,
̃
1602, 1543, 1438, 1345, 1110, 991, 857, 793, 760; HRMS (ESI) m/z
[M + Na]+: calcd for C19H18FNONa, 318.1265; found, 318.1266.
1-(2-(Allyloxy)ethyl)-5-chloro-3-phenyl-1H-indole (3be).
Compound 3be was synthesized from 2-(5-chloro-3-phenyl-1H-
indol-1-yl)ethan-1-ol (583 mg, 2.15 mmol, 1 equiv) and allyl bromide
(283 μL, 396 mg, 3.19 mmol 1.5 equiv) following general procedure
AC for O-allylation.23 The compound was purified by column
chromatography (n-hexane/ethyl acetate 93:7) and obtained as
1
yellow oil: 278 mg, 0.89 mmol, 42%. H NMR (400 MHz, CDCl3):
δ = 7.80 (d, J = 2.0 Hz, 1H), 7.54−7.49 (m, 2H), 7.35 (dd, J = 8.4, 7.0
Hz, 2H), 7.25 (s, 1H), 7.22−7.17 (m, 1H), 7.15−7.08 (m, 2H),
5.79−5.65 (m, 1H), 5.15−5.01 (m, 2H), 4.20 (t, J = 5.5 Hz, 2H),
3.83 (dt, J = 5.5, 1.5 Hz, 2H), 3.66 (t, J = 5.5 Hz, 2H); 13C{1H} NMR
109.6, 68.6, 49.8, 26.0, 21.3; IR: ν = 3056, 2974, 2926, 2855, 1464,
̃
G
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(101 MHz, CDCl3): δ = 135.3, 134.9, 134.2, 128.8, 127.4, 127.3,
127.2, 126.0, 125.8, 122.2, 119.4, 117.3, 116.7, 110.7, 72.2, 68.9, 46.6;
mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) by general procedure A
for catalysis. The crude product was purified by column
chromatography (12 g SiO2, static elution, n-hexane/ethyl acetate
95:5) and obtained as colorless oil: 45 mg, 0.15 mmol, 62%, d.r. >
20:1 (computed from 1H−1H NOESY data). The spectral data
matches with the one reported in the literature.5 1H NMR (400 MHz,
CDCl3): δ = 7.47−7.39 (m, 3H), 7.36−7.29 (m, 2H), 7.28−7.21 (m,
2H), 7.18−7.11 (m, 1H), 7.08−7.00 (m, 1H), 5.10 (dd, J = 5.8, 2.7
Hz, 1H), 4.87 (dd, J = 10.7, 2.8 Hz, 2H), 4.62 (dd, J = 10.5, 3.0 Hz,
1H), 3.63 (s, 3H), 3.04−2.92 (m, 1H), 2.90−2.77 (m, 1H), 2.22−
2.06 (m, 1H), 1.99−1.86 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). Note:
The chemical shift displayed in bold above refers to the minor
diastereomer; 13C{1H} NMR (101 MHz, CDCl3): δ = 142.8, 137.7,
135.6, 128.3, 127.4, 126.3, 125.9, 121.3, 119.2, 118.0, 109.3, 108.8,
76.6, 74.0, 31.0, 30.8, 28.1, 8.6.
9-Benzyl-6-bromo-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]-
indole (5ad). The compound 5ad was synthesized from 3-(2-
(allyloxy)ethyl)-1-benzyl-5-bromo-1H-indole (0.25 mmol, 92.5 mg)
using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5
mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) by general procedure A
for catalysis. The crude product was purified by column
chromatography (12 g SiO2, static elution, n-hexane/ethyl acetate
95:5) and obtained as yellow oil: 61 mg, 0.16 mmol, 66%. The
spectral data matches with the one reported in the literature.5 1H
NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 1.9 Hz, 1H), 7.30−7.14
(m, 4H), 7.01−6.88 (m, 3H), 5.29−5.10 (m, 2H), 4.73−4.64 (m,
1H), 4.15−4.01 (m, 1H), 3.91−3.79 (m, 1H), 2.86−2.73 (m, 1H),
1.88−1.61 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ = 137.6, 136.9, 135.8, 128.8, 128.6, 127.5, 125.8,
124.2, 120.8, 112.7, 111.1, 107.7, 72.6, 61.1, 47.4, 27.0, 22.3, 9.8.
1-Ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (5ae). The
compound 5ae was synthesized from 3-(2-(allyloxy)ethyl)-1H-indole
(0.25 mmol, 50 mg) using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48
μmol) and TfOH (1.5 mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) by
general procedure A for catalysis. The crude product was purified by
column chromatography (12 g SiO2, static elution, n-hexane/ethyl
acetate 85:15) and obtained as yellow oil: 27 mg, 0.13 mmol, 53%.
The spectral data matches with the one reported in the literature.5 1H
NMR (300 MHz, CDCl3): δ = 7.65 (s, 1H), 7.48−7.37 (m, 1H),
7.29−7.20 (m, 1H), 7.13−6.98 (m, 2H), 4.79−4.64 (m, 1H), 4.26−
4.13 (m, 1H), 3.82−3.67 (m, 1H), 2.96−2.78 (m, 1H), 2.70−2.56
(m, 1H), 1.95−1.65 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ = 135.8, 134.7, 127.2, 121.6, 119.6, 118.1, 110.8,
108.3, 73.8, 64.5, 27.5, 22.40, 9.3.
IR: ν = 2903, 2862, 2981, 1602, 1546, 1438, 1371, 1237, 1043, 1095,
̃
797, 760; HRMS (ESI) m/z [M + Na]+: calcd for C19H18ClNONa,
334.0969; found, 334.0971.
1-(3-(Allyloxy)propyl)-3-phenyl-1H-indole (3bf). Compound
3bf was synthesized from 3-(3-phenyl-1H-indol-1-yl)propan-1-ol
(778.4 mg, 3.1 mmol, 1 equiv) and allyl bromide (400 μL, 4.6
mmol, 1.5 equiv) following the general procedure AB for O-allylation,
purified by column chromatography n-hexane/ethyl acetate 9:1 and
isolated as yellow oil: 274.2 mg, 0.94 mmol, 30%. The spectral data
matches with the one reported in the literature.5 1H NMR (300 MHz,
CDCl3): δ = 7.94 (dd, J = 8.4, 1.4 Hz, 1H), 7.71−7.61 (m, 2H),
7.49−7.36 (m, 3H), 7.30−7.12 (m, 4H), 6.03−5.82 (m, 1H), 5.38−
5.14 (m, 2H), 4.30 (t, J = 6.7 Hz, 2H), 3.98−3.89 (m, 2H), 3.37 (t, J
= 5.8 Hz, 2H), 2.19−2.06 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 137.0, 135.8, 134.8, 128.9, 127.4, 126.3, 126.0, 125.8,
122.0, 120.1, 120.0, 117.2, 116.9, 109.9, 72.1, 66.7, 43.1, 30.4.
1-(2-(Allyloxy)ethyl)-3-(phenylthio)-1H-indole (3bg). Com-
pound 3bg was synthesized from 2-(3-(phenylthio)-1H-indol-1-
yl)ethan-1-ol (680.1 mg, 2.5 mmol, 1 equiv) and allyl bromide
(328 μL, 3.79 mmol, 1.5 equiv) following the general procedure AB
for O-allylation, purified by column chromatography n-hexane/ethyl
1
acetate 9:1 and isolated as yellow oil: 539.3 mg, 1.74 mmol, 69%. H
NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H),
7.43 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.21−7.11 (m, 3H), 7.14−7.07
(m, 2H), 7.09−7.00 (m, 1H), 5.89−5.75 (m, 1H), 5.25−5.10 (m,
2H), 4.36 (t, J = 5.5 Hz, 2H), 3.99−3.91 (m, 2H), 3.80 (t, J = 5.5 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ = 139.6, 136.9, 134.9,
134.1, 129.9, 128.6, 125.7, 124.6, 122.5, 120.5, 119.8, 117.3, 109.8,
100.8, 72.2, 68.6, 46.6; IR ν = 3052, 2933, 2855, 1580,
(cm−1): ν
̃ ̃
1505, 1457, 1349, 1244, 1207, 1155, 1103, 991, 924, 734, 689; HRMS
(ESI) m/z [M + Na]+: calcd for C19H19NOSNa, 332.1080; found,
332.1079.
9-Benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole
(5aa). The compound 5aa was synthesized from 3-(2-(allyloxy)-
ethyl)-1-benzyl-1H-indole (72 mg, 0.25 mmol, 1 equiv) using
[(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5 mg,
0.88 μL, 0.01 mmol) and THF (1.5 mL) by general procedure A for
catalysis. The crude product was purified by column chromatography
(12 g SiO2, static elution, n-hexane/ethyl acetate 95:5) and obtained
as colorless oil: 57.6 mg, 0.19 mmol, 80%. The spectral data matches
with the one reported in the literature.5 1H NMR (300 MHz,
CDCl3): δ = 7.52 (dd, J = 5.7, 2.9 Hz, 1H), 7.28−7.17 (m, 3H),
7.14−7.06 (m, 3H), 6.98−6.92 (m, 2H), 5.33−5.09 (m, 2H), 4.74−
4.65 (m, 1H), 4.14−4.02 (m, 1H), 3.92−3.78 (m, 1H), 2.92−2.78
(m, 2H), 1.91−1.64 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ = 137.5, 137.2, 136.3, 128.8, 127.4, 126.9,
125.9, 121.6, 119.4, 118.1, 109.7, 108.1, 72.8, 61.3, 47.3, 27.1, 22.5,
9.8.
9-Benzyl-1-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-
indole (5af). The compound 5af was synthesized from 1-benzyl-3-
(2-(but-3-en-2-yloxy)ethyl)-1H-indole (0.25 mmol, 76.3 mg) using
the general procedure A for catalysis. Following changes were made to
the standard procedure. [(Me3P)4NiH]N(SO2CF3)2 (5 mol %,
0.0125 mmol, 8.0 mg), CH3SO3H (20 mol %, 3.2 μL, 0.049
mmol), THF (0.16 M). Following the initial 30 min of room
temperature stirring with the precatalyst, the reaction mixture was
heated to 60 °C (oil bath) for additional 30 min. The crude product
was purified by flash column chromatography on silica gel (12 g SiO2,
stepwise elution n-hexane/ethyl acetate 97:3 for 5 CV (column
volume) and then 95:5) and obtained as colorless oil: 34 mg, 0.11
9-Benzyl-1-ethyl-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-
b]indole (5ab). Compound 5ab was synthesized from 3-(2-
(allyloxy)ethyl)-1-benzyl-5-methoxy-1H-indole (1.29 g, 4.0 mmol),
[(Me3P)4NiH]N(SO2CF3)2 (1.9 mg, 3.0 μmol), triflic acid (5 μL,
0.06 mmol) in THF (0.16 M) using general procedure A for catalysis.
The crude product obtained after work-up was purified by
recrystallization with n-hexane/ethyl acetate (20:3). The final product
was obtained as an off-white solid: 763 mg, 2.37 mmol, 59%, with
1
mmol, 44%. H NMR (400 MHz, CDCl3): δ = 7.51−7.44 (m, 1H),
7.22−7.10 (m, 3H), 7.07−6.94 (m, 3H), 6.84 (d, J = 9.1 Hz, 2H),
5.32 (s, 2H), 4.01−3.82 (m, 2H), 2.88−2.69 (m, 2H), 1.90 (dq, J =
14.7, 7.4 Hz, 1H), 1.69 (dq, J = 14.6, 7.3 Hz, 1H), 1.39 (s, 3H), 0.70
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 138.9,
137.8, 137.0, 128.6, 127.1, 126.6, 125.6, 121.6, 119.4, 118.1, 110.0,
108.7, 75.2, 59.9, 48.0, 32.9, 25.2, 22.8, 7.9. IR: 2967, 2862, 2929,
1464, 1345, 1308, 1151, 1080, 907, 726, 697; HRMS (ESI) m/z
[M]+: calcd for C21H23NO, 305.1774; found, 305.1775.
1
>98% purity as determined by H NMR spectroscopy. The spectral
data matches with the one reported in the literature.5 1H NMR (400
MHz, CDCl3): δ = 7.23−7.14 (m, 4H), 6.96−6.86 (m, 4H), 6.70 (dd,
J = 8.8, 2.5 Hz, 1H), 5.13 (q, J = 17.2 Hz, 2H), 4.65−4.59 (m, 1H),
4.08−3.97 (m, 1H), 3.79 (s, 3H), 2.85−2.67 (m, 2H), 1.85−1.57 (m,
2H), 0.89 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ =
154.1, 137.5, 137.0, 132.3, 128.7, 127.3, 127.2, 125.9, 111.2, 110.2,
107.6, 100.4, 72.8, 61.3, 55.9, 47.4, 27.1, 22.5, 9.8.
1-Ethyl-10-phenyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]-
indole (5ba). This compound 5ba was synthesized from 1-(2-
(allyloxy)ethyl)-3-phenyl-1H-indole (69.4 mg, 0.25 mmol) using
[(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5 mg,
0.88 μL, 0.01 mmol) in THF (0.16 M) following general procedure A
1-Ethyl-9-methyl-3-phenyl-1,3,4,9-tetrahydropyrano[3,4-
b]indole (5ac). The compound 5ac was synthesized from 3-(2-
(allyloxy)-2-phenylethyl)-1-methyl-1H-indole (0.25 mmol, 72.7 mg)
using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5
H
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
for catalysis. Purification by flash column chromatography (12 g SiO2,
static elution. n-hexane/ethyl acetate 95:5) gave the compound as a
white solid: 47.9 mg, 0.17 mmol, 69%. The spectral data matches with
Hz, 1H), 4.11−3.88 (m, 3H), 1.70−1.46 (m, 2H), 0.71 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 134.8, 133.8, 133.6,
129.4, 128.7, 128.4, 126.5, 126.0, 121.6, 118.5, 111.43, 109.5, 75.0,
5
1
62.0, 41.9, 26.2, 9.2; IR: ν = 2967, 2873, 2933, 1602, 1453, 1341,
̃
the one reported in the literature. mp = 81−83 °C; H NMR (400
MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 1H), 7.45−7.38 (d, 4H),
7.28−7.18 (m, 2H), 7.16 (d, J = 5.8 Hz, 1H), 7.07 (d, J = 6.9 Hz,
1H), 5.22 (dd, J = 7.5, 3.3 Hz, 1H), 4.29−4.19 (m, 1H), 4.14−3.98
(m, 2H), 3.99−3.88 (m, 1H), 1.69−1.48 (m, 2H), 0.72 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 135.5, 135.4, 132.2,
129.5, 128.5, 127.4, 126.1, 121.4, 120.3, 119.0, 111.6, 108.5, 75.1,
62.1, 41.9, 26.3, 9.3.
8-Bromo-1-ethyl-10-phenyl-3,4-dihydro-1H-[1,4]oxazino-
[4,3-a]indole (5bb). This compound 5bb was synthesized from 1-
(2-(allyloxy)ethyl)-5-bromo-3-phenyl-1H-indole (89 mg, 0.25 mmol)
using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5
mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) by following general
procedure A for catalysis. Purification by flash column chromatog-
raphy (12 g SiO2, static elution. n-hexane/ethyl acetate 90:10) gave
the compound asyellow oil: 57 mg, 0.16 mmol, 64%. The spectral data
matches with the one reported in the literature.5 1H NMR (400 MHz,
CDCl3): δ = 7.73−7.70 (m, 1H), 7.49−7.37 (m, 4H), 7.35−7.28 (m,
2H), 7.19 (d, J = 8.6 Hz, 1H), 5.27 (dd, J = 7.5, 3.3 Hz, 1H), 4.33 (dt,
J = 11.5, 3.8 Hz, 1H), 4.19−3.98 (m, 3H), 1.74−1.55 (m, 2H), 0.80
(t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 134.7,
134.0, 133.4, 129.4, 129.0, 128.7, 126.5, 124.2, 121.5, 113.6, 111.3,
109.9, 75.0, 61.9, 41.9, 26.2, 9.2.
1-Ethyl-8-methoxy-10-phenyl-3,4-dihydro-1H-[1,4]oxazino-
[4,3-a]indole (5bc). This compound 5bc was synthesized from 1-(2-
(allyloxy)ethyl)-5-methoxy-3-phenyl-1H-indole (76 mg, 0.25 mmol)
using [(Me3P)4NiH] N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5
mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) by general procedure A
for catalysis. Purification by flash column chromatography (12 g SiO2,
static elution. n-hexane/ethyl acetate 95:5) gave the compound as
colorless oil: 53.9 mg, 0.175 mmol, 70%. The spectral data matches
with the one reported in the literature.5 1H NMR (400 MHz,
chloroform-d): δ = 7.42 (d, J = 4.4 Hz, 4H), 7.32−7.26 (m, 1H), 7.19
(dd, J = 8.8, 0.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8,
2.4 Hz, 1H), 5.25 (dd, J = 7.5, 3.3 Hz, 1H), 4.27 (dt, J = 11.4, 3.8 Hz,
1H), 4.15−3.94 (m, 3H), 3.78 (s, 3H), 1.74−1.53 (m, 2H), 0.78 (t, J
= 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 154.9, 135.7,
132.9, 130.7, 129.4, 128.6, 127.6, 126.1, 111.6, 111.3, 109.2, 100.8,
75.0, 62.0, 56.0, 41.9, 26.3, 9.3.
1062, 1088, 965, 730, 790; HRMS (ESI) m/z [M]+: calcd for
C19H18ClNO, 311.1071; found, 311.1070.
1-Ethyl-11-phenyl-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-
a]indole (5bf). Compound 5bf was synthesized from 1-(3-
(allyloxy)propyl)-3-phenyl-1H-indole (72.8 mg, 0.25 mmol) using
[(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5 mg,
0.88 μL, 0.01 mmol) in THF (0.16 M) following the general
procedure A for catalysis. The crude product was purified by flash
column chromatography on silica gel (12 g SiO2, stepwise elution n-
hexane/ethyl acetate 97:3 for 5 CV (column volume) and then 95:5)
and obtained as yellow oil: 34.5 mg, 0.118 mmol, 47%. The spectral
data matches with the one reported in literature.5 1H NMR (300
MHz, CDCl3): δ = 7.50 (d, J = 7.9 Hz, 1H), 7.44−7.37 (m, 4H),
7.35−7.27 (m, 2H), 7.25−7.18 (m, 1H), 7.12−7.00 (m, 1H), 4.98
(dd, J = 8.9, 5.3 Hz, 1H), 4.53−4.28 (m, 2H), 4.14−3.99 (m, 1H),
3.85−3.71 (m, 1H), 2.12−1.86 (m, 3H), 1.84−1.67 (m, 1H), 0.86 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ = 137.2, 136.1,
135.1, 130.3, 128.4, 127.4, 126.3, 122.0, 119.6, 119.5, 116.1, 108.6,
76.1, 65.0, 42.3, 30.6, 27.1, 10.5.
1-Ethyl-10-(phenylthio)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]-
indole (5bg). Compound 5bg was synthesized from 1-(2-(allyloxy)-
ethyl)-3-(phenylthio)-1H-indole (0.25 mmol, 77.3 mg) using
[(Me3P)4NiH]N(SO2CF3)2 (3.2 mg, 4.96 μmol), MeSO3H (1.9
mg, 1.12 μL, 0.012 mmol) in THF (0.16 M) following the general
procedure A for catalysis. The compound was purified by column
chromatography (n-hexane/ethyl acetate 95:5) and obtained as
yellow oil: 0.087 mmol, 27.05 mg, 35%. The isomerization was
carried out for 30 min, and the cyclization with acid was carried out at
40 °C (oil bath) for 30 min. 1H NMR (400 MHz, CDCl3): δ = 7.64−
7.55 (m, 1H), 7.42−7.33 (m, 1H), 7.32−7.24 (m, 1H), 7.22−7.11
(m, 3H), 7.04 (d, J = 7.0 Hz, 3H), 5.06 (dd, J = 8.5, 3.3 Hz, 1H),
4.37−4.26 (m, 1H), 4.23−4.08 (m, 2H), 4.05−3.92 (m, 1H), 2.30−
2.02 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 141.1, 139.0, 136.1, 128.7, 125.3, 124.5, 122.0, 121.1,
119.1, 108.9, 94.8, 74.6, 61.0, 42.0, 26.7, 9.5; HRMS (APCI) m/z [M
+ H]+: calcd for C19H20NOS, 310.1260; found, 310.1267; IR ν
̃
=
3053, 2967, 2929, 2874, 1737, 1580, 1472, 1364, 1312, 1237, 1114,
1081, 734, 689.
1-(2-(Allyloxy)ethyl)-3-methoxybenzene (6a). Following the
general procedure AA, the reaction of 2-(3-methoxyphenyl)ethan-1-ol
(593.0 mg, 3.9 mmol, 1 equiv), NaH (60% dispersion in mineral oil,
312.0 mg, 7.8 mmol, 2 equiv), and allyl bromide (0.7 mL, 7.8 mmol, 2
equiv) gave after 24 h and purification by chromatography (n-hexane/
ethyl acetate 98:2) the product as colorless oil: 227 mg, 1.2 mmol,
30%. The spectral data matches with the one reported in the
literature.7b 1H NMR (400 MHz, CDCl3): δ = 7.21 (t, J = 7.4 Hz,
1H), 6.85−6.74 (m, 3H), 5.99−5.86 (m, 1H), 5.24 (dd, J = 15.5, 1.7
Hz, 1H), 5.16 (dd, J = 10.3, 1.8 Hz, 1H), 4.01 (d, J = 5.2 Hz, 1H),
3.80 (s, 3H), 3.66 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ = 159.7, 140.6, 134.9, 129.4,
121.4, 117.0, 114.7, 111.6, 72.0, 71.2, 55.2, 36.5.
4-(2-(Allyloxy)ethyl)-1,2-dimethoxybenzene (6b). Following
the general procedure AA, the reaction of 2-(3,4-dimethoxyphenyl)-
ethan-1-ol (500.0 mg, 2.74 mmol, 1 equiv), NaH (60% dispersion in
mineral oil, 220 mg, 5.5 mmol, 2 equiv), and allyl bromide (0.47 mL,
5.5 mmol, 2 equiv) gave after 36 h and purification by
chromatography (n-hexane/ethyl acetate 9:1) the product as colorless
oil: 227.0 mg, 1.2 mmol, 30%. The spectral data matches with the one
reported in the literature.7b 1H NMR (300 MHz, CDCl3): δ = 6.82−
6.73 (m, 3H), 6.01−5.81 (m, 1H), 5.31−5.13 (m, 2H), 3.99 (dt, J =
5.6, 1.4 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.63 (t, J = 7.1 Hz, 2H),
2.85 (t, J = 7.1 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ = 148.7,
147.4, 134.8, 131.6, 120.7, 116.8, 112.2, 111.2, 71.8, 71.4, 55.9, 35.9.
1-Ethyl-6-methoxyisochromane (7a). The compound 7a was
synthesized from 1-(2-(allyloxy)ethyl)-3-methoxybenzene (0.25
mmol, 48 mg) using [(Me3P)4NiH]N(SO2CF3)2 (0.08 mg, 1.24
1-Ethyl-8-fluoro-10-phenyl-3,4-dihydro-1H-[1,4]oxazino-
[4,3-a]indole (5bd). Compound 5bd was synthesized from 1-(2-
(allyloxy)ethyl)-5-fluoro-3-phenyl-1H-indole (73.8 mg, 0.25 mmol)
using [(Me3P)4NiH]N(SO2CF3)2 (1.6 mg, 2.48 μmol), TfOH (1.5
mg, 0.88 μL, 0.01 mmol) in THF (0.16 M) following general
procedure A for catalysis. The compound was purified by flash
column chromatography (12 g SiO2 static elution, n-hexane/ethyl
acetate 95:5) and obtained as a white solid: 46 mg, 0.15 mmol, 62%.
1
mp: 104−106 °C. H NMR (300 MHz, CDCl3): δ = 7.41−7.29 (m,
4H), 7.27−7.11 (m, 3H), 6.89 (m, 1H), 5.20 (dd, J = 7.4, 3.5 Hz,
1H), 4.24 (dt, J = 11.3, 3.7 Hz, 1H), 4.14−3.88 (m, 3H), 1.74−1.46
(m, 2H), 0.72 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz,
1
CDCl3): δ = 158.6 (d, JC−F = 234.9 Hz), 135.0, 133.9, 132.0, 129.3,
3
4
128.6, 127.7 (d, JC−F = 9.8 Hz), 126.3, 111.7 (d, JC−F = 4.8 Hz),
109.7 (d, 2JC−F = 26.5 Hz), 109.1 (d, 3JC−F = 9.7 Hz), 104.0 (d, 2JC−F
= 24.1 Hz), 75.0, 62.0, 41.9, 26.2, 9.2; 19F NMR (282 MHz, CDCl3):
δ = −123.8; HRMS (ESI) m/z [M]+: calcd for C19H18FNO,
295.1367; found, 295.1369.
8-Chloro-1-ethyl-10-phenyl-3,4-dihydro-1H-[1,4]oxazino-
[4,3-a]indole (5be). Compound 5be was synthesized from 1-(2-
(allyloxy)ethyl)-5-chloro-3-phenyl-1H-indole (0.32 mmol, 100 mg)
using [(Me3P)4NiH]N(SO2CF3)2 (2.06 mg, 2.48 μmol), TfOH (1.9
mg, 1.12 μL, 0.012 mmol) in THF (0.16 M) by general procedure A
for catalysis. The product was purified by flash column chromatog-
raphy (12 g SiO2, stepwise elution n-hexane/ethyl acetate 9:1)
isolated as colorless oil: 60 mg, 0.19 mmol, 61%. 1H NMR (400 MHz,
CDCl3): δ = 7.50−7.44 (m, 1H), 7.40−7.27 (m, 4H), 7.27−7.18 (m,
1H), 7.18−7.04 (m, 2H), 5.24−5.14 (m, 1H), 4.23 (dt, J = 11.5, 4.0
I
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
μmol) and TfOH (0.22 μL, 2.5 μmol) in THF (0.16 M) by general
procedure A for catalysis. The crude product was purified by column
chromatography (−4 μmol) and TfOH (0.22 μL, 2.5 × 10−3 mmol) in
THF (0.16 M) by general procedure A for catalysis. The crude
product was purified by column chromatography (12 g SiO2, static
elution, 12 g SiO2, static elution, n-hexane/ethyl acetate 98:2) and
obtained as colorless oil: 44 mg, 0.22 mmol, 92%. The spectral data
matches with the one reported in the literature.7b 1H NMR (300
MHz, CDCl3): δ = 7.04−6.95 (m, 1H), 6.76 (dd, J = 8.6, 2.7 Hz,
1H), 6.69−6.61 (m, 1H), 4.72−4.61 (m, 1H), 4.20−4.07 (m, 1H),
3.79 (s, 3H), 3.78−3.72 (m, 1H), 3.07−2.89 (m, 1H), 2.72−2.59 (m,
1H), 2.06−1.70 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ = 157.7, 135.4, 130.5, 125.8, 113.3, 112.3, 76.7, 63.1,
55.2, 29.5, 28.7, 9.5.
1-Ethyl-6,7-dimethoxyisochromane (7b). The compound 7b
was synthesized from 4-(2-(allyloxy)ethyl)-1,2-dimethoxybenzene
(0.25 mmol, 48 mg) using [(Me3P)4NiH]N(SO2CF3)2 (0.08 mg,
1.24 μ−4 mmol), TfOH (0.22 μL, 2.5 μmol) in THF (0.16 M) by
general procedure A for catalysis. The crude product was purified by
column chromatography (12 g SiO2, static elution, n-hexane/ethyl
acetate 93:7) and obtained as colorless oil: 32 mg, 0.14 mmol, 58%.
The spectral data matches with the one reported in the literature.7b
1H NMR (300 MHz, CDCl3): δ = 6.59 (s, 1H), 6.55 (s, 1H) 4.63
(dd, J = 7.9, 2.7 Hz, 1H), 4.17−4.06 (m, 1H), 3.85 (s, 3H), 3.84 (s,
3H), 3.78−3.66 (m, 1H), 2.97−2.82 (m, 1H), 2.59 (dt, J = 15.9, 3.6
Hz, 2H), 2.03−1.86 (m, 1H), 1.76 (dd, J = 14.6, 7.5 Hz, 1H), 0.98 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ = 147.4, 130.1,
126.2, 111.4, 107.9, 76.5, 63.2, 56.0, 55.8, 28.8, 28.7, 9.5.
3-(2-(Allyloxy)ethyl)thiophene (8a). Following the general
procedure AA, the reaction of 2-(thiophen-3-yl)ethan-1-ol (1.32
mL, 11.7 mmol, 1 equiv), NaH (60% dispersion in mineral oil, 0.94 g,
23.4 mmol, 2 equiv), and allyl bromide (2.0 mL, 23.4 mmol, 2 equiv)
gave after 24 h and purification by column chromatography (n-
hexane/ethyl acetate 98:2) the product as colorless oil: 1.0 g, 6.1
mmol, 52%. The spectral data matches with the one reported in the
literature.7b 1H NMR (400 MHz, CDCl3): δ = 7.26−7.24 (m, 1H),
7.04−7.02 (m, 1H), 6.98 (d, J = 4.9 Hz, 1H), 5.98−5.87 (m, 1H),
5.29 (dd, J = 17.0, 2.1 Hz, 1H), 5.16 (dd, J = 10.2, 1.2 Hz, 1H), 4.0
(m, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 7.1 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ = 139.3, 134.9, 128.6, 125.3, 121.1,
117.0, 72.0, 70.5, 30.8.
2-(2-(Allyloxy)ethyl)thiophene (8b). Following the general
procedure AA, the reaction of 2-(thiophen-2-yl)ethan-1-ol (900 mg,
7.02 mmol, 1 equiv), NaH (60% dispersion in mineral oil, 220 mg,
14.0 mmol, 2 equiv), and allyl bromide (0.47 mL, 14.04 mmol, 2
equiv) gave after 24 h and purification by chromatography (n-hexane/
ethyl acetate 98:2) the product as colorless oil. The spectral data
matches with the one reported in the literature.7b 1H NMR (400
MHz, CDCl3): δ = 7.14 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1,
3.4 Hz, 1H), 6.89−6.83 (m, 1H), 6.01−5.86 (m, 1H), 5.35−5.24 (m,
1H), 5.23−5.15 (m, 1H), 4.02 (dt, J = 5.6, 1.4 Hz, 2H), 3.68 (t, J =
6.9 Hz, 2H), 3.12 (t, J = 6.9 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 141.2, 134.7, 126.6, 125.1, 123.6, 117.0, 71.9, 70.8, 30.5.
7-Ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran (9a). The com-
pound 9a was synthesized from 3-(2-(allyloxy)ethyl)thiophene
(0.25 mmol, 42.3 mg) using [(Me3P)4NiH]N(SO2CF3)2 (0.08 mg,
1.24 × 10−4 mmol), TfOH (0.22 μL, 2.5 μmol) in THF (0.16 M) by
general procedure A for catalysis. The crude product was purified by
column chromatography (12 g SiO2, static elution, n-hexane/ethyl
acetate 95:5) and obtained as colorless oil: 30 mg, 0.18 mmol, 72%.
The spectral data matches with the one reported in the literature.7b
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 5.0, 0.9 Hz, 1H), 6.81
(d, J = 5.0 Hz, 1H), 4.76−4.66 (m, 1H), 4.21 (ddd, J = 11.4, 5.7, 2.1
Hz, 1H), 3.75 (ddd, J = 11.3, 10.6, 3.8 Hz, 1H), 2.96−2.79 (m, 1H),
2.64−2.53 (m, 1H), 1.98−1.71 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ = 137.5, 133.4, 127.1, 122.4,
76.2, 64.4, 30.2, 26.3, 9.5.
(0.16 mg, 0.25 μmol), TfOH (0.57 μL, 6.5 μmol) in THF (0.16 M)
by general procedure A for catalysis. The crude product was purified
by column chromatography (12 g SiO2, static elution, n-hexane/ethyl
acetate 98:2) and obtained as colorless oil (30 mg, 0.17 mmol, 36%).
The spectral data matches with the one reported in the literature.7b
1H NMR (400 MHz, CDCl3): δ = 7.09 (d, J = 4.5 Hz, 1H), 6.76 (d, J
= 5.2 Hz, 1H), 4.62 (m, 1H), 4.21 (m, 1H), 3.77 (m, 1H), 3.07−2.91
(m, 1H), 2.79−2.68 (m, 1H), 2.01−1.87 (m, 1H), 1.80−1.67 (m,
1H), 0.99 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ =
137.3, 133.0, 123.9, 122.3, 76.7, 63.7, 28.3, 25.7, 9.5.
N-Allyl-N-(2-(hydroxymethyl)phenyl)-4-methylbenzenesul-
fonamide (10a). Compound 10a was synthesized from N-(2-
(hydroxymethyl)phenyl)-4-methylbenzenesulfonamide (2 g, 7.2
mmol, 1 equiv) and allyl benzene (0.858 mL, 10 mmol, 1.38 equiv)
as per the reported procedure.7a The final product was obtained as a
brown flaky solid (1.5 g, 4.71 mmol, 66%). Some of the product could
be recrystallized from boiling n-hexane (oil bath) to give a white
crystalline solid; however, the recovery of the product was poor (<500
mg). The crude product was purified by column chromatography (n-
hexane/ethyl acetate 7:3) and obtained as a white solid (445 mg, 1.40
1
mmol, 20%). mp = 81−83 °C; H NMR (400 MHz, CDCl3): δ =
7.64−7.50 (m, 3H), 7.38−7.24 (m, 3H), 7.13 (td, J = 7.7, 1.6 Hz,
1H), 6.44 (dd, J = 8.0, 1.2 Hz, 1H), 5.71 (ddt, J = 17.0, 10.1, 6.9 Hz,
1H), 5.06−4.90 (m, 3H), 4.50 (dd, J = 13.0, 5.8 Hz, 2H), 3.73 (dd, J
= 13.9, 8.2 Hz, 1H), 2.88 (br s, 1H), 2.46 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ = 144.0, 142.3, 137.0, 134.6, 131.8, 131.1,
129.6, 129.0, 128.3, 128.1, 127.5, 120.0, 61.2, 55.1, 21.6; IR: ν = 3507,
̃
2955, 2888, 1453, 1593, 1334, 1401, 1058, 1289, 1115, 1010, 872,
820, 663; HRMS (ESI) m/z [M + Na]+: calcd for C17H19NO3SNa,
340.0978; found, 340.0981.
N-Allyl-N-(2-(1-hydroxyethyl)phenyl)-4-methylbenzenesul-
fonamide (10b). Compound 10b was synthesized as per the
reported procedure.7a N-(2-acetylphenyl)-N-allyl-4-methylbenzene-
sulfonamide (2 g, 6.07 mmol, 1 equiv) was dissolved in 100 mL
methanol, and the solution was then cooled at 0 °C and NaBH4 (689
mg, 18.21 mmol, 3 equiv) was added in portions. After the complete
addition, the solution was warmed at room temperature, and the
mixture was stirred for 4 h. The reaction was then quenched by the
addition of 40 mL of acetone, and the solvents were evaporated under
reduced pressure. The crude product was dissolved in ethyl acetate
and washed three times with water and brine (3 × 30 mL). The
organic phase was dried over Na2SO4 and filtered, and the solvent was
evaporated under reduced pressure. The product was isolated by
column chromatography (n-hexane/ethyl acetate 4:1) as a yellow
1
solid: 1.21 g, 3.65 mmol, 60%. mp = 106−109 °C; H NMR (400
MHz, CDCl3): δ = 7.69−7.57 (m, 1H), 7.55−7.48 (m, 2H), 7.40−
7.27 (m, 4H), 7.18−7.03 (m, 1H), 6.46 (ddd, J = 8.1, 1.3 Hz, 1H),
5.77−5.65 (m, 1H), 5.47 (q, J = 6.7 Hz, 1H), 5.06−4.94 (m, 1H),
4.53 (ddt, J = 13.8, 5.5, 1.4 Hz, 1H), 3.71 (ddt, J = 13.9, 8.3, 0.8 Hz,
1H), 2.46 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3): δ = 200.8, 143.9, 141.9, 136.6, 135.1, 132.4, 131.2,
129.6, 129.3, 128.7, 128.3, 128.1, 120.1, 54.6, 30.4, 21.7; HRMS (ESI)
m/z [M + Na]+: calcd for C18H21NO3SNa, 354.1134; found,
354.1136; IR ν = 3533, 2974, 2929, 1595, 1490, 1449, 1397, 1330,
̃
1282, 1155, 1088, 1039, 995, 931, 894, 857, 812, 749, 704.
N-Allyl-N-(2-(hydroxymethyl)benzyl)-4-methylbenzenesul-
fonamide (10d). The compound 10d was synthesized according to
the reported procedure.7a N-(2-(hydroxymethyl)benzyl)-4-methyl-
benzenesulfonamide (1.17 g, 4.0 mmol, 1 equiv), allyl bromide (960
mg, 8 mmol, 2 equiv) and potassium carbonate (1.105 g, 8.0 mmol, 2
equiv) were dissolved in N,N-dimethyl formamide and stirred for 16 h
at 75 °C (oil bath). Then, ethyl acetate (30 mL) and water (30 mL)
were added to the mixture, and the aq phase was extracted five times
with ethyl acetate (5 × 20 mL). The combined organic phases were
washed with water and brine (3 × 30 mL), dried over Na2SO4 and
filtered, and the solvent was evaporated under reduced pressure. The
desired product was isolated from the crude mixture by column
chromatography (n-hexane/ethyl acetate 7:3) as a yellow solid: 0.341
g, 1.02 mmol, 26%. mp = 154−156 °C; 1H NMR (400 MHz, CDCl3):
δ = 7.79−7.72 (m, 2H), 7.38−7.28 (m, 4H), 7.28−7.24 (m, 3H), 5.39
4-Ethyl-6,7-dihydro-4H-thieno[3,2-c]pyran (9b). The com-
pound 9b was synthesized from 2-(2-(allyloxy)ethyl)thiophene
(0.50 mmol, 84.1 mg, 1 equiv) using [(Me3P)4NiH]N(SO2CF3)2
J
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 5.02−4.86 (m, 2H), 4.78 (s, 2H),
4.45 (s, 2H), 3.72 (dt, J = 6.7, 1.3 Hz, 2H), 2.46 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ = 143.8, 139.6, 136.6, 133.8, 132.2,
130.3, 130.2, 129.9, 129.4, 128.4, 128.1, 127.6, 127.5, 119.5, 63.2,
50.1, 48.8, 21.7; HRMS (ESI) m/z [M + Na]+: calcd for
̃
C18H21NO3SNa, 354.1134; found, 354.1138; IR ν = 3511, 3063,
2922, 2870, 1595, 1490, 1453, 1334, 1215, 1155, 1088, 1036, 902,
892, 812, 734.
NMR (400 MHz, CDCl3): δ = 7.34−7.28 (m, 2H), 7.25−7.21 (m,
3H), 6.02−5.79 (m, 1H), 5.39−5.11 (m, 2H), 4.08−4.00 (m, 3H),
3.47 (dd, J = 9.5, 3.4 Hz, 1H), 3.35 (dd, J = 9.5, 7.1 Hz, 1H), 2.81
(dd, J = 6.7, 2.8 Hz, 2H), 2.07 (br s, 1H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 138.1, 134.6, 129.5, 129.4, 128.7, 128.6, 126.6, 117.4,
73.6, 72.4, 71.5, 40.0.
1-(Allyloxy)-2-methyl-1-phenylpropan-2-ol (10h). The com-
pound 10h was synthesized according to the reported procedure.7b In
a flame-dried round-bottom flask NaH (60% dispersion in oil) (0.149
g, 6.22 mmol, 1.15 equiv) was dissolved in 10 mL dry THF and the
solution was cooled at 0 °C. A 2-methyl-1-phenylpropane-1,2-diol
(0.9 g, 5.4 mmol, 1 equiv) solution in THF (10 mL) was added
dropwise, and the resulting mixture was stirred for 15 min at 0 °C.
Then, allyl bromide (0.52 mL, 5.95 mmol, 1.1 equiv) was added
dropwise to the mixture, and the reaction was heated to room
temperature and stirred for 6 h. After this period, the reaction was
quenched by the addition of 10 mL of saturated NH4Cl aq solution
and 20 mL of water. The aq phase was extracted three times with
ethyl acetate (3 × 30 mL), and the combined organic phases were
washed three times with brine (3 × 30 mL), dried over Na2SO4, and
filtered, and the solvent was evaporated under reduced pressure. The
desired product was separated by column chromatography (n-hexane/
ethyl acetate 5:1) as colorless oil: 0.212 g, 1.02 mmol, 19%. Spectral
data conforms to the literature report.7b 1H NMR (400 MHz,
CDCl3): δ = 7.40−7.26 (m, 5H), 5.96−5.85 (m, 1H), 5.29−5.11 (m,
2H), 4.17 (s, 1H), 4.01−3.95 (m, 1H), 3.82−3.74 (m, 1H), 2.56 (br
s, 1H), 1.17 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 138.3, 134.8, 128.4, 128.3, 128.2, 128.1, 128.0, 116.9,
88.1, 73.0, 70.1, 26.2, 24.4.
2-Ethyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (11a).
Compound 11a was synthesized from N-(2-(hydroxymethyl)-
phenyl)-4 methylbenzenesulfonamide (79.2 mg, 0.25 mmol) using
[(Me3P)4NiH]N(SO2CF3)2 (0.01 mmol, 6.6 mg) and diphenyl
phosphate (0.04 mmol, 9.35 mg) in toluene (0.16 M) following
general procedure B for catalysis; however, following changes were
made. Reaction time after addition of diphenyl phosphate: 2.5 h. The
compound was purified by flash column chromatography (12 g SiO2
static elution, n-hexane/ethyl acetate 95:5) and obtained as a white
solid: 65 mg, 0.2 mmol, 83%. mp = 83−85 °C; 1H NMR (300 MHz,
CDCl3): δ = 7.71 (dd, J = 8.1, 1.2 Hz, 1H), 7.39−7.30 (m, 2H),
7.26−7.13 (m, 1H), 7.09−6.97 (m, 3H), 6.78−6.71 (m, 1H), 5.64−
5.60 (m, J = 7.1 Hz, 1H), 4.51 (d, J = 15.6 Hz, 1H), 4.03 (d, J = 15.6
Hz, 1H), 2.27 (s, 3H), 1.69−1.52 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ = 143.5, 135.6, 132.5, 129.0,
2-(2-(Allyloxy)phenyl)ethan-1-ol (10e). The compound 10e
was synthesized according to the reported procedure.7b In a flame-
dried round-bottom flask 2-(2-hydroxyethyl)phenol (2 g, 14.5 mmol,
1 equiv) was dissolved under Ar in 20 mL of dry THF. The solution
was cooled to 0 °C, NaH (60% dispersion in oil) (0.36 g, 15.2 mmol,
1.05 equiv) was added in portions, and the mixture was stirred for 10
min at 0 °C. Then, allyl bromide (1.03 mL, 14.5 mmol, 1 equiv) was
added, and the reaction mixture was stirred at room temperature.
After 5 h, the reaction was quenched by the slow addition of 30 mL of
saturated NH4Cl aq solution and 50 mL of water at 0 °C and the
mixture was stirred for another 30 min at r.t. The aqueous phase was
extracted three times with ethyl acetate (3 × 40 mL), and the
combined organic phases were washed three times with water and
brine (3 × 25 mL), dried over Na2SO4 and filtered, and the solvent
was evaporated under reduced pressure. The desired compound was
isolated by flash chromatography (12g silica, gradient elution: 1. n-
hexane/ethyl acetate 95:5 for elution of relatively non polar impurities
2. n-hexane/ethyl acetate 70:30 for elution of product). The product
1
was isolated as colorless oil: 0.78 g, 4 mmol, 28%. H NMR (400
MHz, CDCl3): δ = 7.23−7.16 (m, 2H), 6.94−6.84 (m, 2H) 6.12−
6.01 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.45−5.39 (m, 1H), 5.31−5.26
(m, 1H) 4.56 (dt, J = 5.2, 1.6 Hz, 2H), 3.91−3.80 (m, 2H), 1.62−
1.58 (m, 1H). Note: Water signal overlaps with the −OH signal in the
above compound, giving rise to an integral of 2H; 13C{1H} NMR
(101 MHz, CDCl3) δ = 156.6, 133.2 131.0, 127.8, 127.3, 120.9, 117.4,
111.7, 68.8, 62.9, 34.2; HRMS (ESI) m/z [M + Na]+: calcd for
C11H14O2Na, 201.0880; found, 201.0888; IR ν = 3336, 2926, 2873,
̃
1599, 1490, 1453, 1423, 1289, 1237, 1189, 1017, 924, 749.
(2-(Allyloxy)phenyl)methanol (10f). Compound 10f was
synthesized according to the reported procedure.7b In a round
bottom flask fitted with condenser was added 2-hydroxy benzylalco-
hol (1g, 8.05 mmol, 1 equiv). This was dissolved in 16 mL of acetone.
To this solution was added K2CO3 (2.8 g, 20 mmol, 2.48 equiv) and
freshly distilled allyl bromide (0.842 mL, 9.8 mmol, 1.2 equiv). The
reaction mixture was refluxed (oil bath) overnight. After the
completion of the reaction the contents in the flask were allowed to
cool down. The reaction mixture was diluted with 20 mL ethyl acetate
and 20 mL water. This was followed by separation of phases. The
aqueous phase was extracted thrice with ethyl acetate (3 × 30 mL).
The combined organic phases were dried over MgSO4 and filtered,
and the solvent was evaporated under reduced pressure. The desired
product was purified by column chromatography over silica gel (n-
hexane/ethyl acetate 85:15) and obtained as colorless oil: 803 mg,
4.89 mmol, 61%. The spectral data matches with the one reported in
literature.7b 1H NMR (300 MHz, CDCl3): δ = 7.34−7.25 (m, 1H),
7.26−7.22 (m, 1H), 7.00−6.84 (m, 1H), 6.17−5.97 (m, 1H), 5.49−
5.35 (m, 1H), 5.36−5.25 (m, 1H), 4.72 (s, 2H), 4.60 (dt, J = 5.2, 1.6
Hz, 2H), 2.26 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ = 156.4,
133.0, 129.3, 128.7, 120.8, 117.6, 111.4, 68.7, 62.1.
1-(Allyloxy)-3-phenylpropan-2-ol (10g). The compound 10g
was synthesized according to the reported procedure.7b Freshly cut
Na (77 mg, 3.3 mmol, 0.3 equiv) was dissolved in 8 mL allylalcohol.
Then, 2-benzyloxirane (1.5 g, 11 mmol, 1 equiv) was added dropwise,
and the reaction was stirred at reflux (oil bath) until full conversion.
The reaction was then cooled to 0 °C and the reaction was quenched
by the addition of 30 mL of saturated NH4Cl aq solution and 20 mL
of water. The aq phase was extracted with diethyl ether (3 × 25 mL),
and the combined organic phases were dried over Na2SO4 and
filtered, and the solvent was evaporated under reduced pressure. The
desired compound was isolated by column chromatography (n-
hexane/ethyl acetate 4:1) as colorless oil: 1.73 g, 9 mmol, 80%. The
spectral data matches with the one reported in the literature.7b 1H
127.7, 127.2, 127.1, 126.0, 124.2, 85.2, 60.8, 24.6, 21.5, 9.4; IR ν =
̃
2967, 2877, 1595, 1490, 1457, 1375, 1047, 991, 1207, 1162, 760, 793,
823, 685; HRMS (ESI) m/z [M + Na]+: calcd for C17H19NO3SNa,
340.0978; found, 340.9791.
2-Ethyl-4-methyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]-
oxazine (11b). Compound 11b was synthesized from N-allyl-N-(2-
(1-hydroxyethyl)phenyl)-4-methylbenzenesulfonamide (84.5 mg,
0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2 (0.01 mmol, 6.6 mg)
and diphenyl phosphate (0.04 mmol, 9.35 mg) in toluene (0.16 M)
by the general procedure B for catalysis; however, following changes
were made. Reaction time after addition of diphenyl phosphate: 3 h.
The product was purified by flash column chromatography (12 g
SiO2, static elution, n-hexane/ethyl acetate 92:8) isolated as colorless
oil: 57.4 mg, 0.17 mmol, 68%. Note: A mixture of diastereomers was
isolated in ratio 2:1. The resonances for major isomer are reported
1
below. H NMR (400 MHz, CDCl3): δ = 7.64 (dd, J = 8.1, 1.3 Hz,
1H), 7.38−7.33 (m, 1H), 7.32−7.24 (m, 2H), 7.05 (dd, J = 8.1, 4.8
Hz, 2H), 6.91 (dt, J = 7.8, 1.3 Hz, 1H), 5.44 (t, J = 6.1 Hz, 1H), 3.52
(q, J = 6.6 Hz, 1H), 2.28 (s, 3H), 1.71−1.53 (m, 3H), 1.23 (d, J = 6.6
Hz, 3H), 0.88 (dt, J = 14.7, 7.4 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ = 143.6, 136.4, 133.2, 131.9, 129.2, 128.2, 127.8, 127.5,
127.3, 126.5, 124.70, 123.6, 86.5, 68.3, 29.2, 21.5, 20.5, 9.2; IR ν =
̃
2933, 2967, 2873, 1595, 1487, 1453, 1080, 1371, 1162, 816, 682;
HRMS (ESI) m/z [M + Na]+: calcd for C18H21NO3SNa, 354.1134;
found, 354.1137.
K
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3-Ethyl-4-tosyl-1,3,4,5-tetrahydrobenzo[e][1,3]oxazepine
(11d). Compound 11d was synthesized from N-allyl-N-(2-
(hydroxymethyl)benzyl)-4-methylbenzenesulfonamide (82.7 mg,
0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2 (0.01 mmol, 6.6 mg)
and diphenyl phosphate (0.04 mmol, 9.35 mg) in toluene (0.16 M)
by the general procedure B for catalysis. Reaction time after addition
of diphenyl phosphate: 3 h. The product was purified by flash column
chromatography (12 g SiO2, static elution, n-hexane/ethyl acetate
93:7) isolated as a white solid: 52 mg, 0.17 mmol, 65%. mp: 72−74
°C; 1H NMR (400 MHz, CDCl3): δ = 7.36−7.29 (m, 2H), 7.19−7.13
(m, 2H), 7.08−7.02 (m, 1H), 6.94 (dd, J = 8.3, 1.0 Hz, 2H), 6.63 (d,
J = 7.5 Hz, 1H), 5.07−4.98 (m, 1H), 4.79−4.60 (m, 3H), 3.91 (dt, J =
15.4 Hz, 1.2 Hz, 1H), 2.27 (s, 3H), 1.96−1.67 (m, 2H), 1.03 (t, J =
7.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ = 142.8, 137.0,
136.8, 135.2, 128.8, 128.1, 127.0, 126.9, 125.7, 91.1, 71.5, 45.6, 27.8,
21.4, 9.6; HRMS (ESI) m/z [M + Na]+: calcd for C18H21NO3SNa,
in toluene (0.16 M) by general procedure B for catalysis, and the
following changes apply. Reaction time after addition of diphenyl
phosphate: 8 h. The product was purified by flash column
chromatography (12 g SiO2, static elution, n-hexane/ethyl acetate
98:2) isolated as colorless oil: 31 mg, 0.15 mmol, 61%. The spectral
data matches with the one reported in the literature.7b 1H NMR (300
MHz, CDCl3): δ = 7.37−7.28 (m, 5H), 5.05 (t, J = 4.5 Hz, 1H), 4.64
(s, 1H), 1.83−1.67 (m, 2H), 1.36 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H),
0.71 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ = 137.6, 128.1,
127.7, 126.0, 102.9, 86.7, 80.7, 27.5, 26.0, 24.8, 8.0.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02033.
354.1134; found, 354.1136; IR ν = 2978, 2862, 1449, 1494, 1379,
̃
1293, 1174, 1098, 1043, 916, 834, 749, 887, 808.
Experimental details and characterization data for the
synthetized compounds (PDF)
2-Ethyl-4,5-dihydrobenzo[d][1,3]dioxepine (11e). Com-
pound 11e was synthesized from 2-(2-(allyloxy)phenyl)ethan-1-ol
(44.5 mg, 0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2 (0.01 mmol,
6.6 mg) and diphenyl phosphate (0.04 mmol, 9.35 mg) in toluene
(0.16 M) by general procedure B for catalysis. Reaction time after
addition of diphenyl phosphate: 15 h. The product was purified by
flash column chromatography (12 g SiO2, static elution, n-hexane/
ethyl acetate 98:2) isolated as colorless oil: 21 mg, 0.11 mmol, 44%.
1H NMR (300 MHz, CDCl3): δ = 7.23−7.08 (m, 2H), 7.05−6.96 (m,
2H), 4.48 (dd, J = 6.0, 4.8 Hz, 1H), 4.27−4.14 (m, 1H), 3.59−3.44
(m, 1H), 3.39−3.22 (m, 2H), 2.75−2.62 (m, 1H), 2.02−1.73 (m,
2H), 1.06 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ =
158.7, 132.8, 130.3, 127.6, 123.6, 121.0, 108.1, 68.5, 37.3, 29.1, 9.0; IR
AUTHOR INFORMATION
Corresponding Authors
■
Andreas Berkefeld − Faculty of Science and Mathematics,
Eberhard Karls University Tübingen, 72076 Tübingen,
Germany; orcid.org/0000-0002-2757-7841;
Email: andreas.berkefeld@uni-tuebingen.de
Ivana Fleischer − Faculty of Science and Mathematics,
Eberhard Karls University Tübingen, 72076 Tübingen,
Germany; orcid.org/0000-0002-2609-6536;
Email: ivana.fleischer@uni-tuebingen.de
ν = 1487, 1353, 1453, 1379, 1237, 1118, 936, 1036, 760, 670; HRMS
̃
Authors
(EI) m/z [M]+: calcd for C11H14O2, 178.0988; found, 178.0996.
2-Ethyl-4H-benzo[d][1,3]dioxine (11f). Compound 11f was
synthesized from (2-(allyloxy)phenyl)methanol (41.05 mg, 0.25
mmol) [(Me3P)4NiH]N(SO2CF3)2 (2.4 μmol, 1.6 mg) and diphenyl
phosphate (0.02 mmol, 5 mg) in toluene (0.16 M) by general
procedure B for catalysis. Reaction time after addition of diphenyl
phosphate: 10 h. The product was purified by flash column
chromatography (12 g SiO2, static elution, n-hexane/ethyl acetate
Prasad M. Kathe − Faculty of Science and Mathematics,
Eberhard Karls University Tübingen, 72076 Tübingen,
Germany
Alexandru Caciuleanu − Faculty of Science and Mathematics,
Eberhard Karls University Tübingen, 72076 Tübingen,
Germany
1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02033
98:2) isolated as colorless oil: 25.4 mg, 0.16 mmol, 64%. H NMR
(300 MHz, CDCl3): δ = 7.21−7.12 (m, 1H), 7.02−6.82 (m, 3H),
5.06−4.94 (m, 2H), 4.85 (d, J = 14.6 Hz, 1H), 1.95−1.79 (m, 2H),
1.07 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ =
Author Contributions
153.0, 127.9, 124.8, 120.9, 120.9, 116.6, 100.7, 66.5, 27.6, 7.9; IR ν =
̃
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
2933, 2970, 2851, 1461, 1487, 1401, 1244, 1051, 1107, 939, 992, 749;
HRMS (EI) m/z [M]+: calcd for C10H12O2, 164.0832; found,
164.0851.
Notes
4-Benzyl-2-ethyl-1,3-dioxolane (11g). Compound 11g was
synthesized from 1-(allyloxy)-3-phenylpropan-2-ol (48 mg, 0.25
mmol) using [(Me3P)4NiH]N(SO2CF3)2 (0.01 mmol, 6.6 mg) and
diphenyl phosphate (0.04 mmol, 9.35 mg) in toluene (0.16 M)
following the general procedure B for catalysis and the following
changes apply. Reaction time after addition of diphenyl phosphate: 12
h reaction temperature. The product was purified by flash column
chromatography (12 g SiO2, static elution, n-hexaneethyl acetate
98:2) isolated as colorless oil: 26 mg, 0.13 mmol, 54%. The spectral
data matches with the one reported in the literature.10 Note: The
product was isolated as a mixture of diastereomers (d.r. 2:1). The
resonances for the major diastereomer are mentioned below. 1H
NMR (300 MHz, CDCl3): δ = 7.37−7.27 (m, 2H), 7.28−7.14 (m,
3H), 4.89 (t, J = 4.6 Hz, 1H), 4.39−4.22 (m, 1H), 3.92−3.82 (m,
1H), 3.70−3.54 (m, 1H), 3.04 (ddd, J = 13.7, 6.4, 2.7 Hz, 1H), 2.85−
2.71 (m, 1H), 1.79−1.60 (m, 2H), 0.97 (q, J = 7.7 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ = 137.5, 129.1, 128.5, 126.5, 105.7, 77.1,
69.2, 40.1, 39.5, 27.3, 27.2, 7.9.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from DAAD (Deutscher Akademischer
Austauschdienst, fellowship P. K.) and the University of
■
Tu
̈
bingen is gratefully acknowledged.
REFERENCES
■
(1) For recent reviews on isomerization, see: (a) Massad, I.; Marek,
I. Alkene Isomerization through Allylmetals as a Strategic Tool in
Stereoselective Synthesis. ACS Catal. 2020, 10, 5793−5804.
(b) Molloy, J. J.; Morack, T.; Gilmour, R. Positional and Geometrical
Isomerisation of Alkenes: The Pinnacle of Atom Economy. Angew.
Chem., Int. Ed. 2019, 58, 13654−13664. (c) Liu, Q.; Liu, X.; Li, B.
Base-Metal-Catalyzed Olefin Isomerization Reactions. Synthesis 2019,
51, 1293−1310. (d) Larionov, E.; Li, H.; Mazet, C. Well-defined
transition metal hydrides in catalytic isomerizations. Chem. Commun.
2014, 50, 9816−9826.
2-Ethyl-4,4-dimethyl-5-phenyl-1,3-dioxolane (11h). Com-
pound 11h was synthesized from 1-(allyloxy)-2-methyl-1-phenyl-
propan-2-ol (51.5 mg, 0.25 mmol) using [(Me3P)4NiH]N(SO2CF3)2
(0.01 mmol, 6.6 mg) and diphenyl phosphate (0.04 mmol, 9.35 mg)
(2) For recent reviews on isomerization-based tandem reactions, see:
(a) Kathe, P.; Fleischer, I. Cooperative Use of Brønsted Acids and
L
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Metal Catalysts in Tandem Isomerization Reactions of Olefins.
isomerization and Hydrogenation Ratios. ACS Catal. 2019, 9, 10294−
10298. (d) Matos, J. L. M.; Green, S. A.; Chun, Y.; Dang, V. Q.;
Dushin, R. G.; Richardson, P.; Chen, J. S.; Piotrowski, D. W.; Paegel,
B. M.; Shenvi, R. A. Cycloisomerization of Olefins in Water. Angew.
Chem., Int. Ed. 2020, 59, 12998−13003.
́
ChemCatChem 2019, 11, 3343−3354. (b) Sommer, H.; Julia-
́
Hernandez, F.; Martin, R.; Marek, I. Walking Metals for Remote
Functionalization. ACS Cent. Sci. 2018, 4, 153−165. (c) Vasseur, A.;
Bruffaerts, J.; Marek, I. Remote functionalization through alkene
isomerization. Nat. Chem. 2016, 8, 209. (d) Goldbach, V.; Roesle, P.;
Mecking, S. Catalytic Isomerizing ω-Functionalization of Fatty Acids.
ACS Catal. 2015, 5, 5951−5972.
(10) Kathe, P. M.; Fleischer, I. Palladium-Catalyzed Tandem
Isomerization/Hydrothiolation of Allylarenes. Org. Lett. 2019, 21,
2213.
̌
(3) Sorimachi, K.; Terada, M. Relay Catalysis by a Metal-Complex/
Bronsted Acid Binary System in a Tandem Isomerization/Carbon-
Carbon Bond Forming Sequence. J. Am. Chem. Soc. 2008, 130,
14452−14453.
(11) (a) Gehrtz, P. H.; Geiger, V.; Schmidt, T.; Srsan, L.; Fleischer,
I. Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing
a Ni(0)-Precatalyst. Org. Lett. 2019, 21, 50−55. (b) Gehrtz, P. H.;
Kathe, P.; Fleischer, I. Nickel-Catalyzed Coupling of Arylzinc Halides
with Thioesters. Chem.Eur. J. 2018, 24, 8774−8778.
(4) (a) Ishoey, M.; Nielsen, T. E. Synthesis of Heterocycles through
Transition-Metal-Catalyzed Isomerization Reactions. Chem.Eur. J.
2014, 20, 8832−8840. (b) Toda, Y.; Terada, M. Relay Catalysis by a
Ruthenium Complex−Chiral Brønsted Acid Binary Sytem for Ternary
Reaction Sequence Involving Enantioselective Pictet−Spengler-Type
Cyclization as the Key Step. Synlett 2013, 24, 752−756. (c) Hansen,
C. L.; Clausen, J. W.; Ohm, R. G.; Ascic, E.; Le Quement, S. T.;
Tanner, D.; Nielsen, T. E. Ruthenium Hydride/Brønsted Acid-
Catalyzed Tandem Isomerization/N-Acyliminium Cyclization Se-
quence for the Synthesis of Tetrahydro-β-carbolines. J. Org. Chem.
2013, 78, 12545−12565.
(12) For recent examples of Ni-catalyzed isomerization, see:
(a) Kapat, A.; Sperger, T.; Guven, S.; Schoenebeck, F. E-Olefins
through intramolecular radical relocation. Science 2019, 363, 391−
̈
396. (b) Weber, F.; Schmidt, A.; Rose, P.; Fischer, M.; Burghaus, O.;
Hilt, G. Double-Bond Isomerization: Highly Reactive Nickel Catalyst
Applied in the Synthesis of the Pheromone (9Z,12Z)-Tetradeca-9,12-
dienyl Acetate. Org. Lett. 2015, 17, 2952−2955. (c) Wang, L.; Liu, C.;
Bai, R.; Pan, Y.; Lei, A. Easy access to enamides: a mild nickel-
catalysed alkene isomerization of allylamides. Chem. Commun. 2013,
49, 7923−7925. (d) Wille, A.; Tomm, S.; Frauenrath, H. A Highly Z-
Selective Isomerization (Double-Bond Migration) Procedure for Allyl
Acetals and Allyl Ethers Mediated by Nickel Complexes. Synthesis
1998, 305−308.
(5) Lombardo, V. M.; Thomas, C. D.; Scheidt, K. A. A Tandem
Isomerization/Prins Strategy: Iridium (III)/Brønsted Acid Coopera-
tive Catalysis. Angew. Chem., Int. Ed. 2013, 52, 12910−12914.
(6) (a) Cox, E. D.; Cook, J. M. The Pictet-Spengler condensation: a
new direction for an old reaction. Chem. Rev. 1995, 95, 1797−1842.
(13) For Ni-catalyzed isomerizing tandem reactions, see: (a) Jans-
̈
sen-Muller, D.; Sahoo, B.; Sun, S.-Z.; Martin, R. Tackling Remote sp3
̈
(b) Pictet, A.; Spengler, T. Uber die Bildung von Isochinolin-
C−H Functionalization via Ni-Catalyzed “chain-walking” Reactions.
Isr. J. Chem. 2020, 60, 195−206. (b) Zhang, Y.; Xu, X.; Zhu, S.
Nickel-catalysed selective migratory hydrothiolation of alkenes and
alkynes with thiols. Nat. Commun. 2019, 10, 1752. (c) He, J.; Song,
P.; Xu, X.; Zhu, S.; Wang, Y. Migratory Reductive Acylation between
Alkyl Halides or Alkenes and Alkyl Carboxylic Acids by Nickel
Catalysis. ACS Catal. 2019, 9, 3253−3259. (d) Gaydou, M.; Moragas,
̈
derivaten durch Einwirkung von Methylal auf Phenyl-athylamin,
Phenyl-alanin und Tyrosin. Ber. Dtsch. Chem. Ges. 1911, 44, 2030−
2036.
́
́
́
(7) (a) Bernardez, R.; Suarez, J.; Fananas-Mastral, M.; Varela, J. A.;
̃
́
Saa, C. Tandem Long Distance Chain-Walking/Cyclization via
RuH2(CO)(PPh3)3/Bronsted Acid Catalysis: Entry to Aromatic
Oxazaheterocycles. Org. Lett. 2016, 18, 642−645. (b) Ascic, E.;
Ohm, R. G.; Petersen, R.; Hansen, M. R.; Hansen, C. L.; Madsen, D.;
Tanner, D.; Nielsen, T. E. Synthesis of Oxacyclic Scaffolds via Dual
Ruthenium Hydride/Brønsted Acid-Catalyzed Isomerization/Cycliza-
tion of Allylic Ethers. Chem.Eur. J. 2014, 20, 3297−3300.
́
́
T.; Julia-Hernandez, F.; Martin, R. Site-Selective Catalytic Carbox-
ylation of Unsaturated Hydrocarbons with CO2 and Water. J. Am.
Chem. Soc. 2017, 139, 12161−12164. (e) Weber, F.; Ballmann, M.;
Kohlmeyer, C.; Hilt, G. Nickel-Catalyzed Double Bond Transposition
of Alkenyl Boronates for in Situ syn-Selective Allylboration Reactions.
Org. Lett. 2016, 18, 548−551. (f) Buslov, I.; Song, F.; Hu, X. An
Easily Accessed Nickel Nanoparticle Catalyst for Alkene Hydro-
silylation with Tertiary Silanes. Angew. Chem., Int. Ed. 2016, 55,
12295−12299. (g) Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.;
Eisenstein, O.; Hartwig, J. F. Linear-Selective Hydroarylation of
Unactivated Terminal and Internal Olefins with Trifluoromethyl-
Substituted Arenes. J. Am. Chem. Soc. 2014, 136, 13098−13101.
(h) Lee, W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G.
Tandem Isomerization and C−H Activation: Regioselective Hydro-
heteroarylation of Allylarenes. Org. Lett. 2013, 15, 5358−5361.
(i) Richmond, E.; Khan, I. U.; Moran, J. Enantioselective and
Regiodivergent Functionalization of N-Allylcarbamates by Mechanis-
tically Divergent Multicatalysis. Chem.Eur. J. 2016, 22, 12274−
12277.
(8) For recent selected reports on Pictet-Spengler-type cyclizations,
see: (a) Maskeri, M. A.; O’Connor, M. J.; Jaworski, A. A.; Davies, A.
V.; Scheidt, K. A. A Cooperative Hydrogen Bond Donor−Brønsted
Acid System for the Enantioselective Synthesis of Tetrahydropyrans.
Angew. Chem., Int. Ed. 2018, 57, 17225−17229. (b) Zheng, C.; Xia,
Z.-L.; You, S.-L. Unified Mechanistic Understandings of Pictet-
Spengler Reactions. Chem 2018, 4, 1952−1966. (c) Fan, W.-T.; Li,
N.-K.; Xu, L.; Qiao, C.; Wang, X.-W. Organo-Catalyzed Asymmetric
Michael−Hemiketalization−Oxa-Pictet−Spengler Cyclization for
Bridged and Spiro Heterocyclic Skeletons: Oxocarbenium Ion as a
Key Intermediate. Org. Lett. 2017, 19, 6626−6629. (d) Das, S.; Liu,
L.; Zheng, Y.; Alachraf, M. W.; Thiel, W.; De, C. K.; List, B. Nitrated
Confined Imidodiphosphates Enable a Catalytic Asymmetric Oxa-
Pictet−Spengler Reaction. J. Am. Chem. Soc. 2016, 138, 9429−9432.
(e) Larghi, E. L.; Kaufman, T. S. Synthesis of Oxacycles Employing
the Oxa-Pictet−Spengler Reaction: Recent Developments and New
Prospects. Eur. J. Org. Chem. 2011, 5195−5231. (f) Yamada, H.;
Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.; Nakagawa,
M. Chiral Lewis Acid-Mediated Enantioselective Pictet−Spengler
Reaction of Nb-Hydroxytryptamine with Aldehydes. J. Org. Chem.
1998, 63, 6348−6354.
(14) (a) Tolman, C. A. Chemistry of tetrakis(triethyl phosphite)-
+
nickel hydride, HNi[P(OEt)3]4 . IV. Mechanism of olefin isomer-
ization. J. Am. Chem. Soc. 1972, 94, 2994−2999. (b) Tolman, C. A.
Chemistry of tetrakis(triethyl phosphite) nickel hydride, HNi[P-
+
(OEt)3]4 . I. Nickel hydride formation and decay. J. Am. Chem. Soc.
1970, 92, 4217−4222.
(15) Bartlett, S. A.; Badiola, K. A.; Arandiyan, H.; Masters, A. F.;
Maschmeyer, T. The Autocatalytic Isomerization of Allylbenzene by
Nickel(0) Tetrakis(triethylphosphite). Eur. J. Inorg. Chem. 2018,
3384−3387.
(9) For selected reports on cycloisomerization, see: (a) Crossley, S.
́
W. M.; Barabe, F.; Shenvi, R. A. Simple, Chemoselective, Catalytic
Olefin Isomerization. J. Am. Chem. Soc. 2014, 136, 16788−16791.
(b) Li, G.; Kuo, J. L.; Han, A.; Abuyuan, J. M.; Young, L. C.; Norton,
J. R.; Palmer, J. H. Radical Isomerization and Cycloisomerization
Initiated by H• Transfer. J. Am. Chem. Soc. 2016, 138, 7698−7704.
(c) Lorenc, C.; Vibbert, H. B.; Yao, C.; Norton, J. R.; Rauch, M. H·
Transfer-Initiated Synthesis of γ-Lactams: Interpretation of Cyclo-
(16) (a) Neary, M. C.; Quinlivan, P. J.; Parkin, G. Zerovalent Nickel
Compounds Supported by 1,2-Bis(diphenylphosphino)benzene: Syn-
thesis, Structures, and Catalytic Properties. Inorg. Chem. 2018, 57,
374−391. (b) Koch, F.; Berkefeld, A. Reactant or reagent? Oxidation
of H2 at electronically distinct nickel-thiolate sites [Ni2(μ-SR)2]+ and
M
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
[Ni−SR]+. Dalton Trans. 2018, 47, 10561−10568. (c) Tolman, C. A.
Electronic effects of phosphorus ligands on the protonation of NiL4
complexes. Inorg. Chem. 1972, 11, 3128−3129.
(17) Bouguerne, B.; Hoffmann, P.; Lherbet, C. Bismuth Triflate as a
Safe and Readily Handled Source of Triflic Acid: Application to the
Oxa−Pictet−Spengler Reaction. Synth. Commun. 2010, 40, 915−926.
(18) (a) Botla, V.; Pilli, N.; Koude, D.; Misra, S.; Malapaka, C.
Molecular Engineering of Tetracyclic 2,3-Dihydro-1H-benzo[2,3]-
benzofuro[4,5-e][1,3]oxazine Derivatives: Evaluation for Potential
Anticancer Agents. Arch. Pharm. 2017, 350, 1700169. (b) Higham, C.
S.; Dowling, D. P.; Shaw, J. L.; Cetin, A.; Ziegler, C. J.; Farrell, J. R.
Multidentate aminophenol ligands prepared with Mannich con-
densations. Tetrahedron Lett. 2006, 47, 4419−4423. (c) Issa, S.;
Walchshofer, N.; Kassab, I.; Termoss, H.; Chamat, S.; Geahchan, A.;
Bouaziz, Z. Synthesis and antiproliferative activity of oxazinocarbazole
and N,N-bis(carbazolylmethyl)amine derivatives. Eur. J. Med. Chem.
2010, 45, 2567−2577.
(19) Schunn, R. A.; Ashby, E. C.; Dilts, J. Tetrakis-
(triphenylphosphine)nickel(0). Inorg. Synth. 1972, 13, 124−126.
(20) Kumar, R.; Sharma, A.; Sharma, N.; Kumar, V.; Sinha, A. K.
Neutral Ionic Liquid [hmim]Br as a Green Reagent and Solvent for
the Mild and Efficient Dehydration of Benzyl Alcohols into (E)-
Arylalkenes Under Microwave Irradiation. Eur. J. Org. Chem. 2008,
5577−5582.
(21) Rauf, W.; Brown, J. M. Catalytic Amide-Mediated Methyl
Transfer from Silanes to Alkenes in Fujiwara−Moritani Oxidative
Coupling. Angew. Chem., Int. Ed. 2008, 47, 4228−4230.
(22) Tiecco, M.; Tingoli, M. Regiochemistry and Stereochemistry of
Nickel-Promoted, Carbon-Carbon Bond-Forming Reactions of Cyclic
Sulfur Compounds. J. Org. Chem. 1985, 50, 3828−3831.
(23) Gregg, Z. R.; Griffiths, J. R.; Diver, S. T. Conformational
Control of Initiation Rate in Hoveyda−Grubbs Precatalysts. Organo-
metallics 2018, 37, 1526−1533.
(24) Albright, H.; Vonesh, H. L.; Schindler, C. S. Superelectrophilic
Fe(III)−Ion Pairs as Stronger Lewis Acid Catalysts for (E)-Selective
Intermolecular Carbonyl−Olefin Metathesis. Org. Lett. 2020, 22,
3155−3160.
(25) Lamb, J. R.; Hubbell, A. K.; MacMillan, S. N.; Coates, G. W.
Carbonylative, Catalytic Deoxygenation of 2,3-Disubstituted Epoxides
with Inversion of Stereochemistry: An Alternative AlkeneIsomeriza-
tion Method. J. Am. Chem. Soc. 2020, 142, 8029−8035.
N
https://dx.doi.org/10.1021/acs.joc.0c02033
J. Org. Chem. XXXX, XXX, XXX−XXX