Heterobimetallic Pd-Sn catalysis: Michael addition reaction with C-, N-, O-, and S-nucleophiles and in situ diagnostics

Article abstract of DOI:10.1021/jo302643v

An efficient Michael addition reaction of differently substituted enones with carbon, sulfur, oxygen, and nitrogen nucleophiles has been achieved by a new heterobimetallic "Pd-Sn" catalyst system. The nature of the catalytically relevant species and their

Full text of DOI:10.1021/jo302643v

Article
pubs.acs.org/joc
Heterobimetallic Pd−Sn Catalysis: Michael Addition Reaction with C‑,
N‑, O‑, and S‑Nucleophiles and in Situ Diagnostics
Debjit Das,† Sanjay Pratihar,†,‡ and Sujit Roy*,§
†Organometallics & Catalysis Laboratory, Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
‡Department of Chemical Sciences, Tezpur University, Napaam,784028, Assam, India
§Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
S
* Supporting Information
ABSTRACT: An efficient Michael addition reaction of differently
substituted enones with carbon, sulfur, oxygen, and nitrogen
nucleophiles has been achieved by a new heterobimetallic “Pd−Sn”
catalyst system. The nature of the catalytically relevant species and
their interactions with the enone moiety has been examined by
spectroscopy. The effect of ligand and the coordination mode of
enone with “Pd−Sn” heterobimetallic system have been investigated
by kinetics and DFT studies. A straightforward application of this
methodology is shown in the synthesis of 1,4-oxathiepane core.
Michael addition reaction is widely recognized as one of the
most important C−C, C−O, C−N, and C−S bond-forming
reactions, and the resulting products are of wide importance.8
Various acids/base,9 transition-metal salts,9q,10 and organo-
catalysts9q,11 are known to promote the reaction. Besides this,
various homo- or heterobimetallic catalytic systems efficiently
catalyzes the Michael reaction.3a,5d,7b,12 In an early demon-
stration, Shibasaki and co-workers achieved a highly efficient
Michael addition of 2-hydroxy-1,5-methoxyacetophenone to
α,β-unsaturated ketones promoted by a bimetallic oxo-bridged
ZnII/ZnII homobimetallic catalyst built on a binol scaffold.12b
Subsequently, the group has demonstrated the catalytic use of
oxo-bridged heterobimetallic assemblies built using rare-earth
and alkali metal combination in asymmetric aza-Michael
reaction. Mechanistic studies further established that the
reaction proceeds via a novel Lewis acid−Lewis acid
cooperative mechanism.3a Yet another achievement by the
group is the use of homo- and heterobimetallic TM2 catalysts
(TM is transition metal) built on a Schiff-base scaffold for
various asymmetric Michael reactions.12a,e Lee et al. showed the
utility of a novel tetranuclear ZnII/FeIII heterobimetallic catalyst
in mediating the thia-Michael addition of thiophenols to α,β-
unsaturated enones.12c Jautze and Peters designed ferrocene-
bridged PdII/PdII heterobimetallic catalysts for the asymmetric
Michael reaction between substituted cyanoacetates and vinyl
ketones.12d The authors suggested a cooperative intramolecular
bimetallic mechanism involving activation of substrates at both
INTRODUCTION
■
Activation of an organic functionality by two different types of
catalytic centers, main group (Lewis acids) and transition
metals, is an important theme of research in modern organic
reactions.1 The relative ability of the metals (both main group
and transition) to make a σ- or a π-complex with appropriate
substrates is useful in making the choice of catalysts for the
desired transformations, especially in cases where bi- or
polyfunctional substrates are involved. Over the past decade,
multimetallic catalysis has received much attention since during
substrate activation and coupling steps in the catalytic cycle the
synergistic functions of more than one active centers in the
catalyst can enhance the catalytic activity and selectivity.2
Irrespective of their types, multimetallic catalysts offer superior
results in terms of efficiency and selectivity relative to the
individuals. In this regard, heterobimetallic catalysis constitutes
an important subarea within the broader domain of multi-
metallic catalysis. In cooperative intramolecular heterobimetal-
lic catalysis, the two different metals are linked together by a
metal−metal bond or via a ligand and directly or indirectly the
two metals participate in substrate activation.2f,3,4 Electrophile
and nucleophile can be also activated separately by different
metal complexes as in cooperative dual metal catalysis.5,6
Additionally, dual metal reagents are used to provide a more
active species in situ for substrate activation.6a,b,7 In
continuation of our research program in bimetallic catalysis
involving a transition-metal partner and tin as a main group
metal partner, we present here a new bimetallic (Pd/Sn)
catalyst system for the activation of enone toward Michael
addition with a large spectrum of nucleophiles.4,6
Received: December 4, 2012
© XXXX American Chemical Society
A
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the PdII sites. Gao et al. have demonstrated that a dual reagent
combination of FeCl3 and PdCl2 in acetylacetonate can
efficiently mediate the Michael addition of indoles to
chalcones.7b In situ mass spectral studies confirmed the
formation of a bimetallic Fe−Pd species in the reaction. It
may be mentioned here that Jacobsen and co-workers
pioneered the concept of dual-role catalyst using a combination
of two reagent system to generate the active catalyst for
conjugate addition to α,β-unsaturated imides.5d
systems containing Pd as TM and Sn as Lewis acid partner. The
heterobimetallic Pd−Sn catalysts (A1−A5) have been synthe-
sized via the insertion reaction of SnCl2 across PdCl2(MeCN)2
in the presence of ligand in acetone−dichloromethane (Scheme
2).14,6c
Scheme 2. Preparation of Complexes
Although numerous advances have been made in catalytic
Michael addition reaction, there exists a wide scope to develop
catalytic system capable of forming C−C and C−Z (Z =
heteroatom) bonds directly via Michael reaction with wide
range of substrate scopes. In this context the catalyst loading
(>5 mol %) and the use of additives are of concern in some of
the reported catalytic Michael addition reaction.9b−f,11g−j,13 For
example, Ramachary et al. employed bifunctional amine (30
mol %) as organocatalyst with acid additive (30 mol %) for the
direct addition of a variety of alcohols to enones.13g Xu et al.
achieved the Michael reactions of chalcones with active
methylene compounds using 15 mol % of FeCl3.9d 1,4-
Conjugated addition of indoles/thiols to α,β-unsaturated
ketones mediated by a catalytic amount (10 mol %) of InBr3
was reported by Umani-Ronchi et al.9e In the present work, we
were interested to test the principle of cooperative catalysis in
the Michael reaction using a new heterobimetallic “Pd−Sn”
catalyst to establish the scope of its reactivity and finally to
make initial attempts to understand the nature of substrate
activation.
Initially, we had chosen the model reaction between methyl
vinyl ketone (MVK) 1a and 1,3,5-trimethoxy benzene 2a in the
presence of various “Pd−Sn” heterobimetallic complexes as
catalyst (2 mol %) in dichloromethane (DCM) at room
temperature (Table 1).
a
Table 1. Catalyst Screening
b
entry
complex
time (h)
yield of 3aa (%)
1
2
3
Pd(COD)ClSnCl3 (A1)
Pd(PPh3)2ClSnCl3 (A4)
Pd(dppe)(SnCl3)2 (A5)
1
12
12
75
trace
trace
RESULTS AND DISCUSSION
a
■
A mixture of 2a (0.25 mmol), 1a (0.5 mmol), and catalyst (2 mol %)
b
in 2 mL of DCM was stirred at room temperature (30 °C). 1H NMR
yield using triphenylmethane as external standard.
In general, a borderline soft transition metal (TM) center is
well-known to form a π-complex with soft functional groups
like an alkene or an alkyne. On the other hand, a hard Lewis
acid (LA) center prefers σ-complexation with CY, where Y is
generally a hard center (O, N).1 Since an enone has two
binding sites (soft double bond and relatively hard keto oxygen
atom), they can be concurrently activated across a hetero-
bimetallic system having a TM and a Lewis acidic (LA) center.
Thus, the combination of a hard, electrophilic, and Lewis acidic
metal center with a borderline soft transition metal center may
potentially lead to novel bimetallic reactivity and enhance the
efficiency in Michael reaction of enones with various
nucleophiles (Scheme 1).
The above studies indicated that with respect to catalytic
efficiency, only catalyst A1 bearing a diene ligand (COD) was
promising. The inactivity of other complexes may be due to the
lack of a coordination site for MVK activation. For a better look
on the effect of ligand on catalyst efficiency, we carried out a
kinetic study in the presence of “Pd−Sn” catalysts (Figure 1, for
details see the Supporting Information).15 From the pseudo-
1
first-order rate data (vide H NMR, Figure 1), we noted the
The above idea inspired us to check the reactivity of enone
against various nucleophiles in the presence of heterobimetallic
Scheme 1. Proposed Bimetallic Model for the Activation of
Enone
Figure 1. Comparative reactivity pseudo-first-order rate plot for
different catalysts.
B
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following: (a) a combination of catalytic amounts of
PdCl2(MeCN)2 and SnCl2 showed highest activity; (b)
individually PdCl2(MeCN)2 and SnCl2 were least reactive;
(c) catalysts bearing the diene ligands showed reactivity order
as CHD > NBD > COD.
performed at the B3LYP/LANL2DZ, 6-31G* level of theory.
The study revealed that complex C-3 is more stable than C-2
and C-1 (Scheme 3).
Scheme 3. Relative Complex Formation Energy of Active
The highest reactivity of a combination of PdCl2(MeCN)2
and SnCl2 encouraged us to look for the active species of this
catalytic system. Toward this end, UV−vis study was carried
out in DCM/acetonitrile solvent. Upon addition of SnCl2 (1
equiv) to PdCl2(MeCN)2 (1 equiv), the initial yellow color
changed to reddish-orange. The corresponding spectrum was in
sharp contrast to that of PdCl2(MeCN)2 indicating the
formation of a new species (Figure 2). Addition of 1,5-
Complex between “Pd−Sn” and MVK
We also looked into the ease of formation of intermediate C-
3 from the corresponding precursor complexes (diene)-
PdClSnCl3 (A1−A3). The calculated enthalpy of formation
(ΔHf) and formation energy in terms of electronic energy
shown below indicates that the ease of displacement of a diene
ligand from the corresponding complexes by MVK follows the
order CHD > NBD > COD (Scheme 4).18
Scheme 4. Formation Energy for the Reaction of “Pd−Sn”
Complex A1−A3, MVK, and MeCN
This trend correlates well with the experimentally
determined comparative efficacy of the catalysts in the model
reaction (A3 > A2 > A1; Figure 1).
Figure 2. UV−vis spectrum of (1) PdCl2(MeCN)2; (2) a mixture of
PdCl2(MeCN)2 and SnCl2 (1:1); (3) a mixture of PdCl2(MeCN)2,
SnCl2, and COD (1:1:1). The inset shows the molecular structure of
PdCl(COD)SnCl3 A1.
Equipped with the preliminary understanding on bond
activation as described above, we proposed examination of the
scope and optimization of the reaction conditions of the
bimetallic “Pd−Sn” catalyst. For this purpose we had chosen
the relatively slow reaction between MVK 1a with 2-
methylthiophene 2c. From solvent screening, acetonitrile was
judged as the best solvent for the “Pd−Sn”-catalyzed Michael
addition reaction over DCE, C6H6, or hexane (Table 2). The
optimum catalyst loading was found to be 2 mol %. Reduction
of catalyst loading from 2 to 1 mol % drastically reduced the
yield of the reaction (entry 5, Table 2).
The scope of the present bimetallic Pd−Sn-catalyzed C−C
and C−heteroatom bond forming Michael addition reaction of
enones is illustrated in Tables 3 and 4. The generality of the
reaction was successfully tested in the case of various enones
(1a−e,k,l) with electron-rich arenes (2a,b) and heteroarenes
(2c−h) as the nucleophiles under the optimized conditions and
at room temperature (30 °C) (Chart 1). In most cases, the
corresponding hydroarylated products were obtained in
moderate to excellent yields (Table 3, entries 1−12). In all
cases, only monoadduct product was obtained with the
exception of entry 4. Notably, in the case of free indole, the
reactions were completely C3-selective, with no N-alkyl
product being formed (Table 3, entries 5, 8, 10, and 11).
One may note that the hydroarylation reaction failed with
arenes such as anisole or toluene. Next, we extended the scope
of the reaction by employing cyclic, symmetrical, and
cyclooctadiene (COD) to this solution generated the complex
PdCl(COD)SnCl3 A1 (Figure 2). It is therefore apparent that
the combination of PdCl2(MeCN)2 and SnCl2 leads to the in
situ generation of (MeCN)2PdCl(SnCl3) A6, which we believe
is the catalytically active species.
We also carried out in situ 13C NMR experiments to
understand the binding of enone to complex A6. The 13C NMR
spectrum of a 1:1:1 mixture of PdCl2(MeCN)2, SnCl2, and 1b
in CDCl3/acetonitrile at room temperature revealed that upon
binding to the Pd−Sn motif the carbonyl carbon and the
double bond carbons of enone 1b were downfield shifted as
compared to free 1b.16 A similar observation was made in the
case of binding of chalcone 1i to Pd−Sn (Supporting
Information). The above results establish the activation of the
enone moiety by the bimetallic assembly. However, the relative
extent of such activation at each of the metal centers cannot be
predicted with the given data. Therefore, we wished to derive
further insight on the nature of enone−activation across the
Pd−Sn motif from DFT studies. MVK was chosen as the
representative enone for these studies. The energetically most
stable structure of the MVK-coordinated Pd−Sn complex was
determined from complex formation energy in terms of ΔHf
and ΔEf with zero-point energies (ZPE) and thermal
corrections at 298 K.17 All of the calculations have been
C
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a
Table 2. Solvent Screening and Optimization
Scheme 5. Synthesis of 1,4-Oxathiepane Cores
b
entry
solvent
yield of 3ac (%)
1
2
3
4
MeCN
DCE
87
65
37
35
40
benzene
hexane
MeCN
amines and O-nucleophiles were briefly examined and the
desired products were obtained in excellent yields (Table 4,
entries 11, 12, 16, and 17). The structures of 3ca and 3cp were
established by X-ray crystallographic analysis (Supporting
Information). Here, it is also noted that our attempt to activate
other α,β-unsaturated systems like unsaturated aldehydes,
esters, or cyanides was not successful with the present
bimetallic catalyst system.
c
5
a
Reaction conditions: 1a (0.25 mmol), 2c (0.75 mmol), 2 mol % of
PdCl2(MeCN)2, and 2 mol % of SnCl2 in solvent (1 mL) at room
b
temperature (30 °C). 1H NMR yield using triphenylmethane as
c
external standard. 1 mol % of PdCl2(MeCN)2 and 1 mol % of SnCl2
was used.
Next, a brief study was undertaken employing the present
reaction for the synthesis of less commonly studied 1,4-
oxathiepane core (Scheme 5). Here, the Michael product was
reduced by NaBH4, and then corresponding cyclization was
carried out by 3 mol % of catalyst PdCl(COD)SnCl3 C1 or
C1/AgPF6 for the preparation of substituted 1,4-oxathiepane
4a and 4b (for details, see the Experimental Section).4c,6c
unsymmetrical 1,3-dicarbonyls (2i−l) as the nucleophile for
carbon−carbon bond formation (Table 3, entries 13−17).
Attracted by the direct C−C bond formation via Michael
addition reaction, we next examined the reactivity of the “Pd−
Sn” catalyst in C−heteroatom bond formation with representa-
tive S-, N-, and O-nucleophiles under similar reaction
conditions. Generally sulfur-containing compounds are poten-
tial catalyst poisons because of their strong coordinating
properties.19 However, the addition to various enones was
accomplished smoothly at room temperature with both
aromatic and aliphatic thiols (Table 4, entries 1−8). With an
aliphatic bifunctional nucleophile like 2-mercaptoethanol,
selective C−S bond formation took place (entries 4 and 8).
Similarly, in the case of 2-mercaptophenol 2q, exclusive C−S
bond formation was observed resulting in the formation of 3fq
(Table 4, entry 3). Aromatic amines also showed moderate to
good reactivity with differently substituted α,β-unsaturated
ketones (Table 4, entries 9, 10, 13−15). Weak nucleophilic
substrates such as acetanilides or sulfonamides were inert
toward the transformation. Similar reactions with aliphatic
CONCLUSION
■
We have developed a new heterobimetallic “Pd−Sn” catalyst
system to activate enones for the effective construction of direct
C−C and C−heteroatom bond with a wide range of
nucleophiles via Michael addition reaction. Spectroscopic and
theoretical investigations provided initial insight in to the
nature of activation of enone by the catalyst.
EXPERIMENTAL SECTION
■
General Methods. All preparations and manipulations were
performed under a dry, oxygen-free, argon atmosphere. All solvents
used for the synthesis, were dried and distilled by standard methods.
Precoated silica gel 60F254 was used for thin-layer chromatography,
Chart 1. Electrophiles and Nucleophiles Employed in the Michael Addition Reaction
a
The position of substitution is indicated by the truncated bond.
D
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a
Table 3. Michael Addition of Various Michael Acceptors 1 with C-Nucleophiles 2
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Table 3. continued
a
All of the reactions were carried out in acetonitrile at room temperature with 1.2 equiv of Michael acceptor, 1 equiv of NuH, 2 mol % of SnCl2, and
b
1
2 mol % of PdCl2(MeCN)2 unless otherwise stated. Except entries 2−4 where H NMR yield was calculated using triphenylmethane as external
c
d
e
standard; all others are isolated yield. Carried out with 1 equiv of Michael acceptor and 3 equiv of NuH. Carried out at 60 °C. Carried out with 2.5
f
equiv of Michael acceptor and 1 equiv of NuH. Carried out with 5 mol % of SnCl2 and 5 mol % of PdCl2(MeCN)2.
and silica gel 100−200 mesh was used for column chromatography.
PdCl2, 1,5-cyclooctadiene, and other reagents were purchased from
common commercial sources and were used without further
purification. Dry SnCl2 were prepared from commercially available
intensity data were collected at 293 K using a CCD diffractometer.
UV−vis spectra were recorded using spectrophotometric grade
solvent. High-resolution mass spectra were recorded with a mass
spectrometer (TOF) in positive ion mode. All of the melting points
are uncorrected. Elemental analyses were performed on a CHNS/O
analyzer. IR (4000−500 cm−1; using KBr pellet) spectra were obtained
using an FTIR spectrometer.
Computational Methods. The ground-state geometry optimiza-
tions of all of the probable complexes were performed using
GAUSSIAN 0320 at the B3LYP level of theory. We employed
LANL2DZ effective core potential (ECP) for Pd and Sn, and all other
atoms were treated with the 6-31G(d) basis set. Geometries of all
species studied were fully optimized, and they were characterized as
1
SnCl2,2H2O. H (200, 400 MHz) and 13C (54.6, 100 MHz) NMR
spectra were recorded on 200 and 400 MHz spectrometers. 1H
chemical shifts are reported in ppm from tetramethylsilane with the
solvent resonance as the internal standard (deuterochloroform: δ 7.26
ppm). Data are reported as follows: chemical shifts, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, br = broad, dd = double
doublet, m = multiplet), coupling constant (Hz). 13C chemical shifts
are reported in ppm from tetramethylsilane with the solvent resonance
as the internal standard (CDCl3: δ 77.0 ppm). The X-ray diffraction
F
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a
Table 4. Michael Addition of Various Michael Acceptors 1 with Heteroatom−Nucleophiles 2
G
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Table 4. continued
a
All of the reactions were carried out in acetonitrile at room temperature with 1.2 equiv of Michael acceptor, 1 equiv of NuH, 2 mol % of SnCl2, and
b
1
2 mol % of PdCl2(MeCN)2 unless otherwise stated. Except entries 16 and 17 where H NMR yield was calculated using triphenylmethane as
external standard; all others are isolated yield. Carried out with 2.5 equiv of Michael acceptor and 1 equiv of NuH, NuH was used as a solvent.
c
d
true intermediates on the potential energy surface by the absence of
imaginary frequencies, after frequency calculation on the optimized
geometries. Zero-point energies (ZPE) and thermal corrections at 298
K were calculated by using the frequencies computed at the same level
of theory. The formation energies in the form of ΔHf and ΔEf have
been calculated from the energy difference between product and
reactant from their corresponding enthalpy, electronic energy, and free
energy differences.
Starting Materials. PdCl2(MeCN)2 was prepared following the
literature methods.21 The enones, namely, 1c22a and 1d,22b were
prepared and confirmed according to the literature procedure. Another
set of enones, for example, 1e−j were also prepared according to a
reported procedure.23a The spectral data of 1e,23b 1f,23c 1g,23b 1h,23d
1i,23e and 1j23a were in excellent agreement with the reported data.
Syntheses and Characterization of Complexes.14,6c [Pd-
(COD)Cl(SnCl3)] (A1). The 1,5-cyclooctadiene (55.1 mg, 0.51 mmol)
was dissolved in CH2Cl2 (10 mL) by stirring with a magnetic stirrer,
and a solution of SnCl2 (95 mg, 0.5 mmol) in 0.5 mL of Me2CO was
added, giving a milky suspension. Then solid PdCl2(MeCN)2 (130 mg,
0.50 mmol) was added to this suspension, and stirring was continued
for 10 min. Freshly distilled petroleum ether (30 mL) was added to
the mixture, and stirring was continued for another 10 min. The
precipitate was separated by filtration, washed with petroleum ether,
1
and dried in vacuum to give A1 as a yellow solid (201 mg, 85%). H
NMR (200 MHz, CDCl3): δ 6.31 (br, s, 4H), 2.89−2.95 (m, 4H),
2.50−2.62 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 116.6, 30.9.
DEPT 135: 116.6, 30.9. UV−vis (DCM): (λmax, nm): 325, 390. Anal.
Calcd for C8H12Cl4PdSn: C, 20.22; H, 2.55. Found: C, 20.31; H, 2.48.
[PdCl(PPh3)2(SnCl3)] (A4) was prepared according to the above
procedure by using 2 equiv of triphenylphosphine ligand with respect
to SnCl2. 1H NMR (400 MHz, CDCl3): δ 7.68−7.73 (m, 12H), 7.36−
7.49 (m, 18H). 13C NMR (100 MHz, CDCl3): δ 135, 134.98, 134.92,
130.4, 128.1, 128, 127.9. 31P NMR (CDCl3 + DCM): δ 27.32. Anal.
Calcd for C36H30Cl4P2PdSn: C, 48.50; H, 3.39. Found: C, 48.27; H,
3.28.
Similarly, [Pd(dppe)(SnCl3)2] (A5) was prepared by using 2 equiv
of SnCl2 with respect to ligand dppe or PdCl2(MeCN)2. Anal. Calcd
for C26H24Cl6P2PdSn2: C, 32.70; H, 2.53. Found: C, 32.53; H, 2.67.
Typical Procedure for the Michael Addition of 1,3,5-
Trimethoxybenzene 2a to Methyl Vinyl Ketone 1a Using Pd/
Sn Catalyst. A 10 mL Schlenk flask equipped with a magnetic bar was
charged with [PdCl2(MeCN)2] (2.60 mg, 0.01 mmol), SnCl2 (1.90
H
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mg, 0.01 mmol), methyl vinyl ketone 1a (42 mg, 0.6 mmol), and dry
acetonitrile (2 mL) under an argon atmosphere. Then 1,3,5-
trimethoxybenzene 2a (84 mg, 0.5 mmol) was added, and the
reaction was allowed to continue at room temperature (30 °C).
Following completion of the reaction, solvent was removed under
reduced pressure, and the mixture was subjected to column
chromatography over silica gel (100−200 mesh, eluent: petroleum
ether 60−80 °C/ethylacetate 4:1 v/v) to afford a corresponding
product 3aa as a colorless solid in 92% isolated yield.
115.4, 118.8, 119.4, 121.7, 122.1, 127.3, 128.1, 128.7, 133.1, 136.4,
137.1, 200.2.
1-(2-Bromophenyl)-3-(4-hydroxy-2,6-dimethylphenyl)propan-1-
1
one (3db). Colorless solid (100 mg, 60%). Mp: 62−63 °C. H NMR
(400 MHz, CDCl3): δ 2.27 (s, 6H), 2.95−3.06 (m, 4H), 4.88 (br s,
1H), 6.51 (s, 2H), 7.26−7.37 (m, 3H), 7.60 (d, 1H, J = 7.6 Hz). 13C
NMR (100 MHz, CDCl3): δ 19.8, 23.2, 42.1, 114.9, 118.5, 127.4,
128.1, 129.5, 131.5, 133.5, 137.6, 141.7, 153.4, 204.1. DEPT 135: δ
19.8, 23.2, 42.1, 114.9, 127.4, 128.1, 131.5, 133.5. IR (KBr, cm−1):
3422, 1700, 1595, 1465, 1309, 1140, 1025, 757. Anal. Calcd for
C17H17BrO2: C, 61.28; H, 5.14. Found: C, 61.12; H, 5.33.
Product Data. 4-(2,4,6-Trimethoxyphenyl)butan-2-one (3aa).10h
Colorless solid (109.5 mg, 92%). 1H NMR (200 MHz, CDCl3): δ 2.14
(s, 3H), 2.51−2.58 (m, 2H), 2.79−2.87 (m, 2H), 3.77 (s, 6H), 3.79 (s,
3H), 6.11 (s, 2H). 13C NMR (54.6 MHz, CDCl3): δ 17.5, 29.5, 43.6,
55.3, 55.6, 90.5, 109.6, 158.7, 159.6, 209.6.
3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (3ef).11h Colorless
1
solid (81.2 mg, 50%). H NMR (200 MHz, CDCl3): δ 3.67−3.90
(m, 2H), 5.09 (t, 1H, J = 7.2 Hz), 6.97−7.06 (m, 2H), 7.12−7.55 (m,
11H), 7.95 (d, 2H, J = 7.2 Hz), 8.01 (br s, 1H). 13C NMR (54.6 MHz,
CDCl3): δ 38.4, 45.4, 111.3, 119.4, 119.5, 119.7, 121.6, 122.3, 126.5,
126.8, 128.0, 128.3, 128.6, 128.7, 133.2, 136.8, 137.3, 144.4, 198.8.
3-(1H-Indol-3-yl)cyclohexanone (3kf).11h Colorless oil (65 mg,
61%). 1H NMR (200 MHz, CDCl3): δ 1.78−2.09 (m, 3H), 2.22−2.49
(m, 3H), 2.57−2.70 (m, 1H), 2.76−2.87 (m, 1H), 3.39−3.53 (m, 1H),
6.97 (d, 1H, J = 2.0 Hz), 7.09−7.26 (m, 2H), 7.37 (d, 1H, J = 7.4 Hz),
7.64 (d, 1H, J = 7.6 Hz), 8.13 (br s, 1H). 13C NMR (54.6 MHz,
CDCl3): δ 24.9, 31.7, 36.0, 41.6, 48.1, 111.4, 119.0, 119.4, 119.7, 120.4,
122.2, 126.2, 136.5, 212.0.
4-(5-Methylthiophene-2-yl)butan-2-one (3ac).24 Pale yellow oil
1
(73 mg, 87%). H NMR (200 MHz, CDCl3): δ 2.15 (s, 3H), 2.42 (s,
3H), 2.78 (t, 2H, J = 7.4 Hz), 3.02 (t, 2H, J = 7.4 Hz), 6.52−6.57 (m,
2H). 13C NMR (54.6 MHz, CDCl3): δ 15.2, 24.1, 30.0, 45.2, 124.2,
124.7, 137.7, 141.3, 207.3.
4-(5-Methylfuran-2-yl)butan-2-one (3ad).25 Yellow oil (57.7 mg,
1
76%). H NMR (200 MHz, CDCl3): δ 2.18 (s, 3H), 2.26 (s, 3H),
2.73−2.92 (m, 4H), 5.83−5.88 (m, 2H). 13C NMR (54.6 MHz,
CDCl3): δ 13.4. 22.3, 29.8, 41.9, 105.7, 105.8, 150.5, 152.6, 207.4.
4-(3-Methylthiophene-2-yl)butan-2-one (3ae). Colorless oil (58
mg, 69%). 1H NMR (200 MHz, CDCl3): δ 2.19 (s, 3H), 2.21 (s, 3H),
2.80 (t, 2H, J = 7.6 Hz), 3.04 (t, 2H, J = 7.6 Hz), 6.81 (d, 1H, J = 5.0
Hz), 7.05 (d, 1H, J = 5.0 Hz). 13C NMR (54.6 MHz, CDCl3): δ 13.7,
22.0, 30.2, 45.0, 121.5, 130.2, 133.2, 136.7, 207.6. DEPT 135: δ 13.7,
22.0, 30.2, 45.0, 121.5, 130.2. IR (KBr, cm−1): 2923, 1717, 1363, 1162,
707. Anal. Calcd for C9H12OS: C, 64.25; H, 7.19. Found: C, 64.46; H,
7.27.
2′,4′,6′-Trimethoxybiphenyl-2,5-diol (3la). Pink solid (41 mg,
1
30%). Mp: 208−210 °C. H NMR (200 MHz, DMSO-d6): δ 3.60 (s,
6H), 3.78 (s, 3H), 6.22 (s, 2H), 6.29 (d, 1H, J = 2.8 Hz), 6.42−6.58
(m, 2H), 7.94 (br s, 1H), 8.43 (br s, 1H). 13C NMR (54.6 MHz,
DMSO-d6 + CDCl3): δ 55.6, 56.0, 91.5, 109.4, 114.5, 116.0, 119.4,
122.6, 148.5, 149.5, 158.7, 160.6. IR (KBr, cm−1): 3430, 1468, 1203,
752. Anal. Calcd for C15H16O5: C, 65.21; H, 5.84. Found: C, 65.55; H,
5.75.
4,4′-(3-Methylthiophene-2,5-diyl)dibutan-2-one (3ae′). Colorless
2-Acetyl-2-(4-oxopentan-2-yl)cyclopentanone (3ai). Colorless oil
(36.7 mg, 35%). 1H NMR (400 MHz, CDCl3): δ 0.83 (d, 3H, J = 6.4
Hz), 1.61−1.76 (m, 2H), 1.87−1.97 (m, 1H), 2.09−2.14 (m, 6H),
2.19 (s, 3H), 2.24−2.32 (m, 1H), 2.50−2.58 (m, 1H), 3.01−3.08 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 15.7, 19.4, 25.6, 25.7, 30.4, 32.5,
39.6, 46.1, 73.4, 204.2, 206.5, 215.5. DEPT 135: δ 15.7, 19.4, 25.6,
25.7, 30.4, 32.5, 39.6, 46.1. IR (KBr, cm−1): 2970, 1734, 1701, 1362,
1149, 1120. Anal. Calcd for C12H18O3: C, 68.54; H, 8.63. Found: C,
68.29; H, 8.76.
3-Benzoyl-4-methylheptane-2,6-dione (3bk). Colorless oil (55
mg, 45%). The two diastereomers were obtained, and their ratio (1:1)
was determined by 1H NMR analysis. 1H NMR (200 MHz, CDCl3): δ
0.88 (d, 3H, J = 6.8 Hz), 0.93 (d, 3H, J = 6.8 Hz), 2.03 (s, 3H), 2.05
(s, 3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.19−2.60 (m, 4H), 2.85−3.03 (m,
2H), 4.50 (d, 1H, J = 2.6 Hz), 4.54 (d, 1H, J = 2.2 Hz), 7.38−7.58 (m,
6H), 7.89−7.98 (m, 4H). 13C NMR (54.6 MHz, CDCl3): δ 17.4, 18.3,
28.3, 28.8, 29.7, 29.9, 30.3, 30.5, 47.5, 47.8, 67.3, 67.5, 128.6, 128.8,
128.9, 133.9, 136.7, 137.1, 196.3, 203.9, 207.6. IR (KBr, cm−1): 1640,
1260, 1019, 799. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found:
C, 73.87; H, 7.51.
1
oil (18 mg, 15%). H NMR (200 MHz, CDCl3): δ 2.09 (s, 3H), 2.18
(s, 6H), 2.71−2.79 (m, 4H), 2.90−3.04 (m, 4H), 6.48 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 13.7, 22.0, 24.1, 30.23, 30.24, 45.0, 45.3,
127.8, 132.8, 134.6, 139.5, 207.6, 207.8. DEPT 135: δ 13.7, 22.0, 24.1,
30.23, 30.24, 45.0, 45.3, 127.8. IR (KBr, cm−1): 2921, 1714, 1363,
1162. Anal. Calcd for C13H18O2S: C, 65.51; H, 7.61. Found: C, 65.17;
H, 7.49.
4-(5-Bromo-1H-indol-3-yl)butan-2-one (3ag).26 Colorless solid
(120 mg, 90%). 1H NMR (200 MHz, CDCl3): δ 2.18 (s, 3H), 2.85 (t,
2H, J = 7.0 Hz), 3.02 (t, 2H, J = 7.0 Hz), 6.99 (s, 1H), 7.20−7.32 (m,
2H), 7.74 (s, 1H), 8.34 (br s, 1H). 13C NMR (54.6 MHz, CDCl3): δ
19.2, 30.2, 44.0, 112.6, 112.8, 114.8, 121.3, 123.0, 124.8, 129.1, 135.0,
209.0.
4-(1-Ethyl-1H-indol-3-yl)pentan-2-one (3bh). Colorless oil (96
1
mg, 84%). H NMR (200 MHz, CDCl3): δ 1.43−1.52 (m, 6H), 2.14
(s, 3H), 2.75 (dd, 1H, J = 8.2, 16.0 Hz), 2.99 (dd, 1H, J = 5.8, 16.0
Hz), 3.61−3.78 (m, 1H), 4.15 (q, 2H, J = 7.2 Hz), 6.95 (s, 1H), 7.12−
7.39 (m, 3H), 7.71 (d, 1H, J = 7.8 Hz). 13C NMR (54.6 MHz,
CDCl3): δ 15.5, 21.5, 27.1, 30.4, 40.8, 51.7, 109.5, 118.7, 119.4, 119.6,
121.5, 123.3, 126.9, 136.3, 208.7. DEPT 135: δ 15.5, 21.5, 27.1, 30.4,
40.8, 51.7, 109.5, 118.7, 119.4, 121.5, 123.3. IR (KBr, cm−1): 2971,
2931, 1712, 1462, 1356, 1156, 1013, 740. Anal. Calcd for C15H19NO:
C, 78.56; H, 8.35; N, 6.11. Found: C, 78.76; H, 8.42; N, 6.02.
1-Phenyl-3-(2,4,6-trimethoxyphenyl)propan-1-one (3ca). Color-
less solid (120 mg, 80%). Mp: 80−82 °C. 1H NMR (200 MHz,
CDCl3): δ 2.95−3.16 (m, 4H), 3.78 (s, 6H), 3.82 (s, 3H), 6.14 (s,
2H), 7.41−7.55 (m, 3H), 8.02 (d, 2H, J = 6.8 Hz). 13C NMR (54.6
MHz, CDCl3): δ 18.5, 38.9, 55.6, 55.8, 90.7, 110.0, 128.4, 128.6, 132.9,
137.3, 159.0, 159.8, 201. DEPT 135: δ 18.5, 38.9, 55.6, 55.8, 90.7,
128.4, 128.6, 132.9. IR (KBr, cm−1): 2939, 1683, 1598, 1457, 1204,
1157, 1119, 811, 692. Anal. Calcd for C18H20O4: C, 71.98; H, 6.71.
Found: C, 72.21; H, 6.79.
2-Benzoyl-3-methyl-1-phenylhexane-1,5-dione (3bl). Colorless
1
oil (74 mg, 48%). H NMR (200 MHz, CDCl3): δ 1.08 (d, 3H, J =
7.0 Hz), 2.10 (s, 3H), 2.57 (dd, 1H, J = 7.0, 17.6 Hz), 2.81 (dd, 1H, J
= 5.2, 17.6 Hz), 3.00−3.13 (m, 1H), 5.60 (d, 1H, J = 6.8 Hz), 7.40−
7.59 (m, 6H), 7.94−8.04 (m, 4H). 13C NMR (54.6 MHz, CDCl3): δ
18.0, 30.6, 30.7, 47.9, 59.9, 128.8, 128.9, 129.1, 133.7, 133.8, 136.7,
137.1, 196.2, 196.3, 208.7. IR (KBr, cm−1): 1699, 1671, 1263, 1215,
758, 690. Anal. Calcd for C20H20O3: C, 77.90; H, 6.54. Found: C,
77.63; H, 6.68.
(E)-3-Acetyl-4,8-diphenyloct-7-ene-2,6-dione (3jj).27 Colorless
1
solid (100 mg, 60%). H NMR (200 MHz, CDCl3): δ 1.88 (s, 3H),
2.16 (s, 3H), 2.82−3.06 (m, 2H), 4.08−4.19 (m, 1H), 4.30 (d, 1H, J =
11.0 Hz), 6.55 (d, 1H, J = 16.2 Hz), 7.17−7.47 (m, 11H). 13C NMR
(54.6 MHz, CDCl3): δ 29.8, 29.9, 41.4, 45.2, 74.2, 126.0, 127.4, 128.1,
128.3, 128.8, 128.9, 130.6, 134.3, 140.3, 143.2, 197.6, 202.9, 203.3.
2-(3-Oxocyclohexyl)-1,3-diphenylpropane-1,3-dione (3kl).28 Col-
3-(1H-Indol-3-yl)-1-phenylpropan-1-one (3cf).26 Colorless solid
1
(106 mg, 85%). H NMR (200 MHz, CDCl3): δ 3.23−3.31 (m, 2H),
3.38−3.47 (m, 2H), 7.03 (d, 1H, J = 2.0 Hz), 7.15−7.29 (m, 2H),
7.35−7.62 (m, 4H), 7.68 (d, 1H, J = 7.0 Hz), 8.00 (d, 2H, J = 7.0 Hz),
8.14 (br s, 1H). 13C NMR (54.6 MHz, CDCl3): δ 19.8, 39.4, 111.3,
1
orless oil (88 mg, 55%). H NMR (200 MHz, CDCl3): δ 1.47−1.68
(m, 2H), 1.86−2.03 (m, 2H), 2.13−2.41 (m, 4H), 2.96−3.06 (m, 1H),
I
dx.doi.org/10.1021/jo302643v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5.23 (d, 1H, J = 8.4 Hz), 7.34−7.53 (m, 6H), 7.89−7.97 (m, 4H). 13
C
(E)-5-(2-hydroxyethylthio)-1,5-diphenylpent-1-en-3-one (3jo).
Colorless solid (94 mg, 60%). Mp: 104−106 °C. 1H NMR (400
MHz, CDCl3): δ 2.58 (t, 2H, J = 6.0 Hz), 2.86 (br s, 1H), 3.18−3.32
(m, 2H), 3.62−3.75 (m, 2H), 4.54 (t, 1H, J = 7.2 Hz), 6.71 (d, 1H, J =
16.0 Hz), 7.09−7.54 (m, 11H). 13C NMR (100 MHz, CDCl3): δ 34.4,
43.9, 47.4, 60.7, 125.8, 127.5, 127.7, 128.4, 128.7, 128.9, 130.7, 134.2,
141.9, 143.5, 196.9. DEPT 135: δ 34.4, 43.9, 47.4, 60.7, 125.8, 127.5,
127.7, 128.4, 128.7, 128.9, 130.7, 143.5. IR (KBr, cm−1): 1653, 1609,
1449, 1338, 1072, 750, 699. Anal. Calcd for C19H20O2S: C, 73.04; H,
6.45. Found: C, 73.32; H, 6.57.
NMR (54.6 MHz, CDCl3): δ 24.8, 29.5, 39.5, 41.2, 45.9, 62.3, 128.6,
128.9, 133.8, 136.5, 194.4, 194.6, 209.7.
1-Phenyl-3-(phenylthio)propan-1-one (3cp). Colorless solid (103
mg, 85%). Mp: 72−74 °C. 1H NMR (200 MHz, CDCl3): δ 3.27−3.31
(m, 4H), 7.16−7.56 (m, 8H), 7.89−7.94 (m, 2H). 13C NMR (54.6
MHz, CDCl3): δ 27.9, 38.4, 126.3, 128.1, 128.7, 129.1, 129.4, 133.4,
135.9, 136.5, 198.1. DEPT 135: δ 27.9, 38.4, 126.3, 128.1, 128.7, 129.1,
129.4, 133.4. IR (KBr, cm−1): 1684, 1355, 1181, 974, 743, 727, 688.
Anal. Calcd for C15H14OS: C, 74.34; H, 5.82. Found: C, 74.49; H,
5.77.
4-(4-Nitrophenylamino)butan-2-one (3au).29 Yellow solid (79
mg, 76%). 1H NMR (200 MHz, CDCl3): δ 2.13 (s, 3H), 2.74 (t, 2H, J
= 6.0 Hz), 3.44 (t, 2H, J = 6.0 Hz), 6.46 (d, 2H, J = 9.2 Hz), 7.97 (d,
2H, J = 9.2 Hz). 13C NMR (54.6 MHz, CDCl3): δ 30.2, 37.6, 42.1,
111.0, 126.4, 137.8, 153.1, 207.5.
1,3-Diphenyl-3-(phenylthio)propan-1-one (3ep).9e,11c Colorless
solid (143 mg, 90%). 1H NMR (200 MHz, CDCl3): δ 3.55−3.71
(m, 2H), 5.01 (t, 1H, J = 7.0 Hz), 7.20−7.51 (m, 13H), 7.88 (d, 2H, J
= 7.2 Hz). 13C NMR (54.6 MHz, CDCl3): δ 45.0, 48.5, 127.7, 127.8,
128.1, 128.3, 128.7, 128.9, 129.1, 133.0, 133.5, 134.6, 137.0, 141.5,
197.2.
4-(4-Chlorophenylamino)butan-2-one (3av).30 Colorless solid
1
(69 mg, 70%). H NMR (200 MHz, CDCl3): δ 2.14 (s, 3H), 2.71
(t, 2H, J = 6.0 Hz), 3.34 (t, 2H, J = 6.0 Hz), 3.94 (br s, 1H), 6.50 (d,
2H, J = 8.0 Hz), 7.09 (d, 2H, J = 8. Hz). 13C NMR (54.6 MHz,
CDCl3): δ 30.3, 38.5, 42.3, 114.2, 122.1, 129.1, 146.2, 207.9.
4-Morpholinobutan-2-one (3aw).30 Yellow oil (66.7 mg, 85%). 1H
NMR (200 MHz, CDCl3): δ 2.15 (s, 3H), 2.46 (t, 4H, J = 4.6 Hz),
2.66 (s, 4H), 3.69 (t, 4H, J = 4.6 Hz). 13C NMR (54.6 MHz, CDCl3):
δ 30.1, 40.7, 53.0, 53.5, 66.7, 207.4.
3-(2-Bromophenyl)-3-(2-hydroxyphenylthio)-1-phenylpropan-1-
1
one (3fq). Colorless solid (144 mg, 70%). Mp: 61−63 °C. H NMR
(200 MHz, CDCl3): δ 3.51−3.75 (m, 2H), 5.16 (t, 1H, J = 7.4 Hz),
6.74 (t, 1H, J = 7.4 Hz), 6.98−7.63 (m, 10H), 7.91 (d, 2H, J = 7.8 Hz).
13C NMR (54.6 MHz, CDCl3): δ 43.3, 47.4, 115.4, 116.4, 120.2, 124.4,
127.7, 128.2, 128.8, 129.0, 132.1, 133.2, 133.7, 136.3, 137.1, 139.9,
158.4, 196.8. DEPT 135: δ 43.3, 47.4, 115.4, 120.2, 127.7, 128.2, 128.8,
129.0, 132.1, 133.2, 133.7, 137.1. IR (KBr, cm−1): 3384, 1683, 1469,
1448, 1203, 1024, 752, 688. Anal. Calcd for C21H17BrO2S: C, 61.02; H,
4.15. Found: C, 61.39; H, 4.06.
4,4′-(Benzylazanediyl)dibutan-2-one (3ax). Colorless oil (99 mg,
1
80%). H NMR (200 MHz, CDCl3): δ 2.08 (s, 6H), 2.57 (t, 4H, J =
6.6 Hz), 2.74 (t, 4H, J = 6.6 Hz), 3.54 (s, 2H),.7.22−7.32 (m, 5H). 13C
NMR (54.6 MHz, CDCl3): δ 30.3, 41.6, 48.7, 58.9, 127.3, 128.4. 128.9,
139.0, 208.4. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 73.12; H, 8.47; N, 5.73.
3-(2-Hydroxyethylthio)-1-(4-methoxyphenyl)-3-phenylpropan-1-
1
one (3go). Colorless solid (128 mg, 81%). Mp: 80−82 °C; H NMR
(400 MHz, CDCl3): δ 2.55 (t, 2H, J = 6.0 Hz), 3.39−3.55 (m, 2H),
3.59−3.73 (m, 2H), 3.83 (s, 3H), 4.58 (t, 1H, J = 7.2 Hz), 6.90 (d, 2H,
J = 8.8 Hz), 7.20−7.32 (m, 3H), 7.41 (d, 2H, J = 7.6 Hz), 7.90 (d, 2H,
J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): δ 34.6, 44.0, 45.0, 55.6,
60.7, 113.8, 127.5, 127.8, 128.7, 129.8, 130.5, 142.3, 163.8, 195.6.
DEPT 135: δ 34.6, 44.0, 45.0, 55.6, 60.7, 113.8, 127.5, 127.8, 128.7,
130.5. IR (KBr, cm−1): 3420, 1666, 1604, 1420, 1259, 1173, 1063, 703.
Anal. Calcd for C19H20O2S: C, 73.04; H, 6.45. Found: C, 73.32; H,
6.57. Anal. Calcd for C18H20O3S: C, 68.33; H, 6.37. Found: C, 68.69;
H, 6.49.
4-(p-Tolylamino)pentan-2-one (3bt). Colorless oil (57 mg, 60%).
1H NMR (200 MHz, CDCl3): δ 1.28 (d, 3H, J = 6.4 Hz), 2.19 (s, 3H),
2.28 (s, 3H), 2.56 (dd, 1H, J = 7.2, 16.4 Hz), 2.79 (dd, 1H, J = 5.0,
16.4 Hz), 3.29 (br s, 1H), 3.89−4.02 (m, 1H), 6.58 (d, 2H, J = 8.0
Hz), 7.03 (d, 2H, J = 8.0 Hz). 13C NMR (54.6 MHz, CDCl3): δ 20.5,
20.9, 30.9, 45.8, 49.8, 114.0, 127.1, 130.0, 144.6, 208.2. DEPT 135: δ
20.5, 20.9, 30.9, 45.8, 49.8, 114.0, 130.0. IR (KBr, cm−1): 3393, 2918,
1706, 1146, 808. HRMS (ESI) calcd for C12H17NO + H+ 192.1388,
found 192.1387. Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N,
7.32. Found: C, 75.61; H, 8.84; N, 7.27.
1-(4-Methoxyphenyl)-3-(octylthio)-3-phenylpropan-1-one (3gn).
1-Phenyl-3-(phenylamino)propan-1-one (3cs).31 Yellow solid (91
1
Yellow solid (157 mg, 82%). Mp: 58−60 °C. H NMR (200 MHz,
1
CDCl3): δ 0.79 (t, 3H, J = 7.0 Hz), 1.14 (br s, 10H), 1.35−1.42 (m,
2H), 2.10−2.37 (m, 2H), 3.40 (d, 2H, J = 7.0 Hz), 3.79 (s, 3H), 4.47
(t, 1H, J = 7.0 Hz), 6.83 (d, 2H, J = 7.0 Hz), 7.13−7.37 (m, 5H), 7.83
(d, 2H, J = 7.0 Hz). 13C NMR (54.6 MHz, CDCl3): δ 14.1, 22.7, 28.9,
29.2, 29.3, 31.6, 31.8, 44.6, 45.1, 55.5, 113.8, 127.2, 127.9, 128.5, 130.0,
130.5, 142.5, 163.6, 195.6. DEPT 135: δ 14.1, 22.7, 28.9, 29.2, 29.3,
31.6, 31.8, 44.6, 45.1, 55.5, 113.8, 127.2, 127.9, 128.5, 130.5. IR (KBr,
cm−1): 2919, 2848, 1670, 1600, 1257, 1172, 697. Anal. Calcd for
C24H32O2S: C, 74.95; H, 8.39. Found: C, 75.19; H, 8.28.
mg, 81%). H NMR (200 MHz, CDCl3): δ 3.29 (t, 2H, J = 6.0 Hz),
3.63 (t, 2H, J = 6.0 Hz), 6.65−6.77 (m, 3H), 7.20 (d, 2H, J = 7.8 Hz),
7.42−7.58 (m, 3H), 7.93−7.98 (m, 2H). 13C NMR (54.6 MHz,
CDCl3): δ 37.7, 38.8, 113.1, 117.7, 128.1, 128.7, 129.3, 133.3, 136.7,
147.7, 199.3.
3-(Phenylamino)cyclohexanone (3ks).32 Yellow oil (28.3 mg,
30%). 1H NMR (200 MHz, CDCl3): δ 1.64−1.78 (m, 2H), 1.99−2.39
(m, 5H), 2.81 (dd, 1H, J = 3.2 Hz), 3.70−3.81 (m, 1H), 6.57 (t, 2H, J
= 8.4 Hz), 6.70 (t, 1H, J = 7.2 Hz), 7.12−7.24 (m, 2H). 13C NMR
(54.6 MHz, CDCl3): δ 22.1, 31.1, 41.1, 48.5, 52.3, 113.3, 117.9, 129.4,
146.3, 209.6.
3-(2-Chlorophenyl)-3-(4-methoxyphenylthio)-1-phenylpropan-1-
one (3hr). Colorless oil (168 mg, 88%). 1H NMR (200 MHz, CDCl3):
δ 3.61 (d, 2H, J = 7.2 Hz), 3.72 (s, 3H), 5.29 (t, 1H, J = 7.2 Hz), 6.47
(d, 2H, J = 8.8 Hz), 7.08−7.14 (m, 2H), 7.23−7.55 (m, 7H), 7.87 (d,
2H, J = 8.8 Hz). 13C NMR (54.6 MHz, CDCl3): δ 43.7, 45.4, 55.3,
114.4, 123.6, 126.8, 128.1, 128.3, 128.4, 128.7, 129.8, 133.3, 133.9,
136.5, 138.7, 160.0, 196.6. IR (KBr, cm−1): 2924, 1684, 1591, 1490,
1246, 1030, 752, 688. Anal. Calcd for C22H19ClO2S: C, 69.01; H, 5.00.
Found: C, 69.22; H, 5.09.
3-Propylsulfanyl-1,3-di-p-tolylpropan-1-one (3im). Yellow solid
(109 mg, 70%). Mp: 49−51 °C. 1H NMR (200 MHz, CDCl3): δ 0.89
(t, 3H, J = 7.2 Hz), 1.43−1.61 (m, 2H), 2.19−2.33 (m, 2H), 2.25 (s,
3H), 2.37 (s, 3H), 3.48 (d, 2H, J = 7.0 Hz), 4.52 (t, 1H, J = 7.2 Hz),
7.09 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0
Hz), 7.81 (d, 2H, J = 8.0 Hz). 13C NMR (54.6 MHz, CDCl3): δ 13.7,
21.3, 21.8, 22.8, 33.7, 44.3, 45.6, 127.9, 128.5, 129.4, 129.5, 134.7,
136.9, 139.5, 144.2, 196.9. IR (KBr, cm−1): 2961, 2922, 1684, 1607,
1180, 811. Anal. Calcd for C20H24OS: C, 76.88; H, 7.74. Found: C,
76.53; H, 7.87.
4-Ethoxybutan-2-one (3ay).33 Colorless oil (52 mg, 90%). 1H
NMR (200 MHz, CDCl3): δ 1.12 (t, 3H, J = 7.0 Hz), 2.13 (s, 3H),
2.63 (t, 2H, J = 6.2 Hz), 3.43 (q, 2H, J = 7.0 Hz), 3.65 (t, 2H, J = 6.2
Hz). 13C NMR (54.6 MHz, CDCl3): δ 14.9, 30.3, 43.7, 65.3, 66.4,
207.8.
4-Butoxybutan-2-one (3az).33 Pale yellow oil (60 mg, 83%). H
1
NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 7.2 Hz), 1.24−1.38 (m,
2H), 1.48−1.56 (m, 2H), 2.17 (s, 3H), 2.67 (t, 2H, J = 6.4 Hz), 3.41
(t, 2H, J = 6.4 Hz), 3.66 (t, 2H, J = 6.4 Hz). 13C NMR (54.6 MHz,
CDCl3): δ 13.8, 19.3, 30.4, 31.6, 43.8, 65.7, 70.9, 207.4.
Procedure for the Synthesis of 4a.34 Reduction of (E)-5-(2-
hydroxyethylthio)-1,5-diphenylpent-1-en-3-one 3jo (156 mg, 0.5
mmol) was carried out with sodium borohydride (38 mg, 1 mmol)
in methanol (1 mL) for 1 h at 0−10 °C. After completion of the
reaction, distilled water (10 mL) was added and then the solution was
extracted with ethyl acetate. The organic layer was dried over Na2SO4
and evaporated under vacuum. Compound (E)-5-(2-hydroxyethylth-
J
dx.doi.org/10.1021/jo302643v | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
io)-1,5-diphenylpent-1-en-3-ol 4a was obtained in 88% yield after
column purification.
(E)-5-(2-Hydroxyethylthio)-1,5-diphenylpent-1-en-3-ol (4a). Col-
14.4 Hz), 2.98−3.02 (m, 1HB), 3.09−3.25 (m, 1HA + 1HB), 3.79 (s,
3HA + 3HB), 3.82−3.89 (m, 2HB), 4.02−4.15 (m, 1HA + 1HB), 4.32
(dd, 1HA, J = 6.4, 10.4 Hz), 4.49−4.52 (m, 1HA), 4.61 (d, 1HB, J =
10.4 Hz), 5.21 (dd, 1HA, J = 5.2, 9.6 Hz), 6.87 (d, 2HA + 2HB, J = 8.4
Hz), 7.22−7.41 (m, 7HA + 7HB). 13C NMR (100 MHz, CDCl3): δ
34.4, 37.8, 48.1, 48.9, 50.9, 51.1, 55.5, 69.3, 75.5, 79.2, 82.9, 113.9,
126.9, 127.0, 127.2, 127.5, 127.6, 128.8, 128.9, 135.5, 135.7, 142.6,
143.3, 158.9, 159.0. DEPT δ 34.4, 37.8, 48.1, 48.9, 50.9, 51.1, 55.5,
69.3, 75.5, 79.2, 82.9, 113.9, 126.9, 127.0, 127.2, 127.5, 127.6, 128.8,
128.9. IR (KBr, cm−1): 2926, 1636, 1508, 1246, 1100, 699. ESI-MS for
C18H20O2S [M], [M + K]+ = 339.10. Anal. Calcd for C18H20O2S: C,
71.96; H, 6.71. Found: C, 71.61; H, 6.89.
orless oil (138 mg, 88%); The two diastereomers was obtained and
1
1
their ratio was determined by H NMR analysis; 4aA:4aB = 66:34. H
NMR (400 MHz, CDCl3): δ 2.05−2.23 (m, 2HA + 2HB), 2.46−2.56
(m, 2HA + 2HB), 2.98 (br s, 2HA + 2HB), 3.55−3.72 (m, 2HA + 2HB),
4.09−4.15 (m, 1HA + 2HB), 4.55 (q, 1HA, J = 7.2 Hz), 6.11−6.21 (m,
1HA + 1HB), 6.46−6.55 (m, 1HA + 1HB), 7.18−7.38 (m, 10HA
+
10HB). 13C NMR (100 MHz, CDCl3): δ 34.0, 34.1, 43.7, 43.9, 45.7,
45.8, 60.6, 60.8, 70.4, 70.5, 126.5, 126.6, 127.4, 127.5, 127.8, 128.1,
128.7, 128.8, 130.5, 130.9, 131.5, 131.8, 136.5, 136.6, 141.9, 142.9.
DEPT 135: δ 34.0, 34.1, 43.7, 43.9, 45.7, 45.8, 60.6, 60.8, 70.4, 70.5,
126.5, 126.6, 127.4, 127.5, 127.8, 128.1, 128.7, 128.8, 130.5, 130.9,
131.5, 131.8. Anal. Calcd for C19H22O2S: C, 72.57; H, 7.05. Found: C,
72.17; H, 6.88.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, kinetics plot, UV−vis spectra, DFT
study, spectra for all compounds, and X-ray crystallographic
data for 3ca and 3cP (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Procedure for the Synthesis of 5a. A mixture of 4a (78.5 mg, 0.25
mmol) and 3 mol % [Pd(COD)Cl(SnCl3)] in 2 mL of dry DCE was
stirred at 90 °C for 6 h under an argon atmosphere. Then, the reaction
mixture was evaporated and purified by column chromatography to
give the corresponding 1,4-oxathiepane 5a in 78% yield.
(E)-5-Phenyl-7-styryl-1,4-oxathiepane (5a). Colorless oil (57.7 mg,
AUTHOR INFORMATION
Corresponding Author
*Tel: +91-674-2576021. Fax: +91-674-2306303. E-mail:
sujitroy.chem@gmail.com, sroy@iitbbs.ac.in.
■
78%). The two diastereomers was obtained and their ratio (1:1) was
1
1
determined by H NMR analysis. H NMR (400 MHz, CDCl3): δ
2.40−2.51 (m, 4H), 2.74 (d, 1H, J = 14.4 Hz), 2.91−2.97 (m, 1H),
3.04−3.21 (m, 2H), 3.83 (t, 1H, J = 10.4 Hz), 4.05−4.13 (m, 3H),
4.24−4.33 (m, 2H), 4.51 (dd, 1H, J = 2.4, 12.4 Hz), 4.86 (q, 1H, J =
6.0 Hz), 6.22−6.29 (m, 2H), 6.62−6.68 (m, 2H), 7.22−7.42 (m,
20H). 13C NMR (100 MHz, CDCl3): δ 34.5, 37.8, 46.3, 46.9, 50.60,
50.63, 69.1, 75.3, 77.7, 81.5, 126.60, 126.62, 127.0, 127.3, 127.5, 127.6,
127.7, 127.8, 128.7, 128.8, 128.9, 129.3, 129.7, 130.3, 130.4, 136.9,
137.0, 142.6, 143.3. DEPT 135: δ 34.5, 37.8, 46.3, 46.9, 50.60, 50.63,
69.1, 75.3, 77.7, 81.5, 126.60, 126.62, 127.0, 127.3, 127.5, 127.6, 127.7,
127.8, 128.7, 128.8, 128.9, 129.3, 129.7, 130.3, 130.4. IR (KBr, cm−1):
3025, 2923, 1599, 1493, 1450, 967, 748, 697. HRMS (ESI): calcd for
C19H20OS + H+ 297.1313, found 297.1305. Anal. Calcd for C19H20OS:
C, 76.98; H, 6.80. Found: C, 76.63; H, 6.89.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from DST (to S.R) and CSIR (to D.D and
S.P) is acknowledged. We thank Prof. M. Bhattacharjee and
Prof. D. Mal for support. D.D. thanks Dr. U. K. Roy and
Rajnish Kumar for useful discussions and help.
REFERENCES
■
Procedure for the Synthesis of 4b. Reduction of 3-(2-
hydroxyethylthio)-1-(4-methoxyphenyl)-3-phenylpropan-1-one 3go
(158 mg, 0.5 mmol) was carried out with sodium borohydride (76
mg, 2 mmol) in methanol (1 mL) for 3 h at 30 °C. After completion of
the reaction, distilled water (10 mL) was added and then the solution
extracted with ethyl acetate. The organic layer was dried over Na2SO4
and evaporated under vacuum. Compound 3-(2-hydroxyethylthio)-1-
(4-methoxyphenyl)-3-phenylpropan-1-ol 4b was obtained in 90% yield
after column purification.
3-(2-Hydroxyethylthio)-1-(4-methoxyphenyl)-3-phenylpropan-1-
ol (4b). Colorless oil (143 mg, 90%). The two diastereomers was
obtained and their ratio was determined by 1H NMR analysis; 4bA:4bB
= 62:38. 1H NMR (400 MHz, CDCl3): δ 2.10−2.50 (m, 6HA + 6HB),
3.49−3.62 (m, 2HA + 2HB), 3.77 (3HB), 3.79 (s, 3HA), 3.95−4.05 (m,
1HA + 1HB), 4.42−4.45 (m, 1HB), 4.82−4.86 (m, 1HA), 6.82−6.87
(m, 2HA + 2HB), 7.16−7.34 (m, 7HA + 7HB). 13C NMR (100 MHz,
CDCl3): δ 34.2, 34.3, 45.6, 45.7, 46.2, 46.3, 55.5, 60.7, 60.9, 71.6, 71.7,
114.1, 114.2, 127.2, 127.51, 127.54, 127.6, 127.9, 128.2, 128.8, 128.9,
136.2, 136.5, 142.1, 142.9, 159.3, 159.4. DEPT 135: δ 34.2, 34.3, 45.6,
45.7, 46.2, 46.3, 55.5, 60.7, 60.9, 71.6, 71.7, 114.1, 114.2, 127.2, 127.51,
127.54, 127.6, 127.9, 128.2, 128.8, 128.9. IR (KBr, cm−1): 3419, 2926,
1508, 1244, 1030, 832, 701. Anal. Calcd for C18H22O3S: C, 67.89; H,
6.96. Found: C, 68.16; H, 6.73.
Procedure for the Synthesis of 5b. A mixture of 4b (79.5 mg, 0.25
mmol), 3 mol % of [Pd(COD)Cl(SnCl3)], and 3 mol % of AgPF6 in 2
mL of dry DCE was stirred at 90 °C for 30 min under an argon
atmosphere. Then, the reaction mixture was evaporated and purified
by column chromatography to give the corresponding 1,4-oxathiepane
5b in 72% yield.
7-(4-Methoxyphenyl)-5-phenyl-1,4-oxathiepane (5b). Colorless
oil (54 mg, 72%). The two diastereomers was obtained and their
ratio was determined by 1H NMR analysis; 5bA:5bB = 62:38. 1H NMR
(400 MHz, CDCl3): δ 2.46−2.64 (m, 2HA + 2HB), 2.76 (d, 1HA, J =
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