Fe(OTf)3-catalyzed tandem Meyer-Schuster rearrangement/intermolecular hydroamination of 3-aryl propargyl alcohols for the synthesis of acyclic β-Aminoketones

Article abstract of DOI:10.1016/j.tet.2017.02.030

Fe(OTf)₃-catalyzed synthesis of acyclic β-aminoketones from 3-aryl propargyl alcohols and nitrogen nucleophiles were investigated. Results showed that propargyl alcohols without bulky groups α to the hydroxyl group underwent the transformation smoothly. Sulphonamides exhibited the higher reactivity than amides as the nitrogen nucleophiles and the transformation of acyclic β-aminoketones were finished in shorter reaction time and higher yields. Finally, racemic fluoxetine was efficiently accessed with the present reaction as the first step. This novel synthesis of acyclic β-aminoketones probable proceeded a Fe(OTf)₃-catalyzed Meyer-Schuster rearrangement of 3-aryl propargyl alcohols, followed by a intermolecular hydroamination between nitrogen nucleophiles and α, β-unsaturated ketones.

Full text of DOI:10.1016/j.tet.2017.02.030

Accepted Manuscript
Fe(OTf) -catalyzed tandem Meyer-Schuster rearrangement/intermolecular
3
hydroamination of 3-aryl propargyl alcohols for the synthesis of acyclic β-
Aminoketones
Ruiheng Tao, Yan Yin, Yongbin Duan, Yuxing Sun, Yue Sun, Fengkai Cheng,
Jinpeng Pan, Cheng Lu, Yuan Wang
PII:
S0040-4020(17)30162-X
10.1016/j.tet.2017.02.030
TET 28471
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 January 2017
Revised Date: 13 February 2017
Accepted Date: 14 February 2017
Please cite this article as: Tao R, Yin Y, Duan Y, Sun Y, Sun Y, Cheng F, Pan J, Lu C, Wang Y,
Fe(OTf) -catalyzed tandem Meyer-Schuster rearrangement/intermolecular hydroamination of 3-aryl
3
propargyl alcohols for the synthesis of acyclic β-Aminoketones, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.02.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Fe(OTf) -Catalyzed Tandem Meyer-Schuster
3
Rearrangement/Intermolecular
Hydroamination of 3-Aryl Propargyl
Alcohols for the Synthesis of Acyclic β-
Aminoketones
a
a, b,
a
a
a
a
a
a
Ruiheng Tao , Yan Yin *, Yongbin Duan , Yuxing Sun , Yue Sun , Fengkai Cheng , Jinpeng Pan , Cheng Lu ,
a
and Yuan Wang
a
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd.,
Shanghai, 201418, P. R. China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Ling Ling Rd., Shanghai, 200032, P. R. China
HO R4
R3
O
R
3
R
4
H
N
R2
Fe(OTf)
3
(20mol%)
Ar
N
R1
R1
R2
Ar
1
2 or 3
5 samples, up to 94% yields
2

1
ACCEPTED MANUSCRIPT
Click he
Tetrahedron
journal homepage: www.elsevier.com
Fe(OTf) -Catalyzed Tandem Meyer-Schuster Rearrangement/Intermolecular
3
Hydroamination of 3-Aryl Propargyl Alcohols for the Synthesis of Acyclic β-
Aminoketones
a
a, b,
a
a
a
a
a
Ruiheng Tao , Yan Yin ∗ , Yongbin Duan , Yuxing Sun , Yue Sun , Fengkai Cheng , Jinpeng Pan ,
a
a
Cheng Lu , and Yuan Wang
a
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai, 201418, P. R. China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Rd., Shanghai, 200032, P.
b
R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3
Fe(OTf) -catalyzed synthesis of acyclic β-aminoketones from 3-aryl propargyl alcohols and
nitrogen nucleophiles were investigated. Results showed that propargyl alcohols without bulky
groups α to the hydroxyl group underwent the transformation smoothly. Sulphonamides
exhibited the higher reactivity than amides as the nitrogen nucleophiles and the transformation
of acyclic β-aminoketones were finished in shorter reaction time and higher yields. Finally,
racemic fluoxetine was efficiently accessed with the present reaction as the first step. This novel
Available online
Keywords:
3
synthesis of acyclic β-aminoketones probable proceeded a Fe(OTf) -catalyzed Meyer-Schuster
Meyer-Schuster rearrangement
intermolecular hydroamination
propargyl alcohols
rearrangement of 3-aryl propargyl alcohols, followed by a intermolecular hydroamination
between nitrogen nucleophiles and α, β-unsaturated ketones.
2
009 Elsevier Ltd. All rights reserved.
Fe(OTf)
β-aminoketones
3
—
——
∗
Corresponding author: Tel.: +86 21 60877220; Fax: +86 21 60877331; E-mail address: yinyan@sit.edu.cn (Y. Yin)

2
Tetrahedron
ACCEPTED MANUSCRIPT
Ph
1
. Introduction
PhCOR1
+
a
Ph
(A)
(B)
Ph
OH
R1
1
β-Aminoketone is an important building block in organic
R3
R
3
synthesis, which can easily be converted to α, β-unsaturated
ketone, 1, 3-amino alcohol and other functionalized ketone, and
b
Ar
1
+
Ar-X
OH
OH
R4
R4
1
β-amino carbonyl compounds exhibit numerous biological
O
Scheme 1.Synthesis of 1. Reagents and conditions: (a) n-BuLi, THF, -78 C-rt,
(b) PdCl (PPh ) , CuI, Et N, 80 C.
2 3 2 3
activities including anti-inflammatory, anticancer, anti-
O
2
tuberculosis, antibacterial, analgesic and antitussive activities.
For the efficient access to acyclic β-aminoketones, the
reaction conditions between 3-phenyl-prop-2-yn-1-ol 1a and
TsNH were firstly optimized (Table 1). Catalyzed with 20 mol%
As a result, various methods for the preparation of β-
3
aminoketone have been developed. Mannich-type reaction might
2
be the most popular methodology for the one-pot construction of
of acids including TfOH, AgOTf, Cu(OTf) , or Sc(OTf) , 4-
2
3
β-aminoketone with substitution at nitrogen which has been
4
methyl-N-(3-oxo-3-phenyl-propyl)-benzenesulfonamide 2a were
separated in moderate yields (entries 1-4). Treating with 20
or Fe(OTf) , 2a were obtained in 92% and
4% yields after 16 hours, respectively (entries 5-6). While 20
studied by organic chemists for decades. Copper(II) acetate
catalyzed ring-opening cross-coupling of cyclopropanols with
5
mol% of Bi(OTf)
3 3
sulfonylazide is an alternative strategy. Aminobromination of α,
9
β-unsaturated ketones with sulfonamide and NBS afforded the
corresponding halo acyclic β-aminoketones in excellent yields
mol% of FeCl was added, unanticipated N-(3-chloro-3-phenyl-
3
6
allyl)-4-methyl-benzenesulfonamide was separated (entry 7).
Then dioxane, DCE, benzene, THF and toluene were compared
as solvents, dioxane exhibited to be the best solvent among them
and unconsumed 1a was recovered (entries 6, and 8-11). Catalyst
loading studies showed that 10 mol% of Fe(OTf) cause very low
yield of 2a and 30 mol% of Fe(OTf) had the similar yield and
reaction time as 20 mol% of Fe(OTf) (entries 12 and 13 vs. 6).
Out of our expectation, dimeric diketone was separated while
decreasing TsNH to 1 equivalence (entries14), and increasing
TsNH to 3 equivalence had no effect on the yield compared with
and selectivities. Morken reported a one-pot synthesis of β-
amidoketones from allenes in good yields and high
7
enantioselectivities. Convenient access to heterocycle-containing
β-aminoketones through a direct N-methylation reaction using8
3
DMSO as the one-carbon bridge was exlporated by Sun.
3
Recently, Shi reported a direct oxidation of the aliphatic C-H
bonds of primary amines and amino acids as well as dipeptides to
3
9
the corresponding oxo products. Although much attention has
2
been paid to construct theβ-aminoketone unit, development of
new synthetic methodology for this privileged structure is still an
important and challenging task for the chemistry community.
2
2
equivalence of TsNH (entries 15 vs. 6). So the optimized
reaction conditions for this transformation were 20 mol% of
Fe(OTf) as the catalyst, 2 equivalence of nitrogen nucleophile,
2
Recently, Yanada demonstrated that electron-rich primary
3
propargyl alcohols undergo Bi(OTf) -catalyzed Meyer-Schuster
and dioxane as solvent.
3
rearrangement and successive 1,4-addition of alcohol to give β-
a
Table 1.Optimization of the reaction conditions.
alkoxyketones, they also extend this tandem reaction to a one-pot
O
10
Acid
dihydroquinolone synthesis (Figure 1, Scheme A). Our group
developed a superacid-catalyzed intramolecular cyclization of o-
aniliopropargy alcohols to the synthesis of 2,3-dihydro-4(1H)-
TsNH
2
NHTs
OH
1a
2a
11
quinolone (Figure 1, Scheme B). The transformation in both
Scheme A and Scheme B was accessed through rearrangement of
propargyl alcohols to the corresponding α, β-unsaturated
aldehydes, and the intramolecular hydroamination of nitrogen to
olefins. In this work, we would like to investigate the acid-
catalyzed reaction between 3-aryl propargyl alcohols and
nitrogen nucleophiles for the synthesis of acyclic β-aminoketones
Catalyst
loading
Temp.
TsNH
2
Time
(h)
2a
Entry
Catalyst
Solvent
O
b
(
C)
(equiv.)
(%)
(mol%)
α, α, α,-
Trifluorotol
uene
1
TfOH
110
20
2
6
50
(
Figure 1, Scheme C).
2
3
AgOTf
Dioxane
Dioxane
110
110
20
20
2
2
31
20
62
59
1. Yanada's work
OH
R2
Cu(OTf)
R2
1
CO Et
2
R1
N
2
Bi(OTf)3
R
Scheme A
4
5
6
7
8
9
Sc(OTf)
3
3
Dioxane
Dioxane
Dioxane
Dioxane
THF
110
110
110
110
70
20
20
20
20
20
20
20
20
10
30
20
2
2
2
2
2
2
2
2
2
2
1
33
16
16
11
48
48
18
13
48
14
17
51
92
94
50
Up to 87% yields
NHCO
2
Et
O
O
2
. Our previous work
Bi(OTf)
O
OH
R
TfOH
R
+
R
Scheme B
Fe(OTf)3
NHSO
2
R1
N
H
N
SO
R1
2
Up to 85% yields
FeCl
3
3
. Present work
c
OH
1
2
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
Fe(OTf)
3
3
3
3
3
3
3
9
R
NR R
1
2
Acid
+
R R NH
Scheme C
R
c
c
c
c
O
DCE
90
39
34
42
42
Figure 1 Tandem Meyer-Schuster rearrangement/hydroamination
1
0
1
Benzene
Toluene
Dioxane
Dioxane
Dioxane
90
2
. Results and discussion
1
110
110
110
110
2
-Substituted 1,3-diphenyl-prop-2-yn-1-ols were accessed
through the nucleophilic addition of phenylacetylen to phenyl
carbonyl compounds (Scheme 1, A). Other 3-aryl substituted
propargyl alcohols were synthesized through Pd -catalyzed
Sonogashina coupling reaction of Ar-X and commercial available
12
1
2
2
+
13
94
85
14
13
prop-2-yn-1-ols (Scheme 1, B).

3
O
1
5
Fe(OTf)
3
Dioxane
110
20
3
ACCE14PTE
9
D
4
MANUSCRIPT
9
OH
NHTs
12
21
91
85
a
b
c
OCH3
Reaction conditions: 1a (0.2 mmol), solvent (1 mL).
Isolated yield after flash chromatography.
The unconsumed 1a was recovered.
1i
1j
OCH
3
2i
O
NHTs
10
OH
3
H CO
2j
OCH
3
In Yanada's investigation, only 3-phenyl-prop-2-yn-1-ol
derivatives with electronic donating group on the phenyl ring
underwent Bi(OTf) -catalyzed tandem Meyer-Schuster
rearrangement and 1, 4-addition to the resulting vinyl ketone.
O
11
H
3
C
OH
NHTs
15
9
89
92
84
91
3
1k
10
H C
2k
3
O
We then explored the scope of 3-aryl propargyl alcohols under
the optimized reaction conditions (Table 2). Propargyl alcohols
Ph
NHTs
1
1
1
2
3
4
OH
OH
1l
1
Ph
2l
(1a-1p) with different Ar groups on the triple bond were prepared
O
according to Scheme 1, which may alter the electron density of
the triple bond. The difference of substitutions in the phenyl ring
had obvious effects on the reaction times and yields (entries 1-
NHTs
10
17
m
2m
O
OH
NHTs
1
1). There were no transformation for 3-aryl propargyl alcohols
S
1
n
S
2n
with very electronic withdrawing groups (NO and CN), and the
2
a
Reaction conditions: Alcohol (0.2 mmol), TsNH
0.04 mmol), dioxane (1 mL), 110 C.
2
(0.4 mmol), Fe(OTf)
3
starting materials (1b and 1c) were recovered (entries 2 and 3). 3-
Aryl propargyl alcohols with weaker electronic withdrawing
O
(
b
group (4-CF and 4-Cl) underwent the transformation slowly and
Isolated yield after flash chromatography.
3
low yields were obtained (entries 4 and 5). To our surprise 2f was
formed in 80% yield after 21 hours from 1f with 4-Br-substituion
and 85% yield for 2g after 10 hours from 1g with 4-F-substituion
c
Unconsumed 1 was recovered.
We then turned our attention to secondary and tertiary
(
entries 6 and 7). The similar results as Yanada's investigation
were obtained, electronic donating substitutions, such as 4-OCH3,
-OCH , 3-OCH , and 4-Ph, were benefit for this reaction (93%
alcohols (Table 3). The reactions of the more sterically hindered
alcohols resulted in hardly proceeding to this tandem reaction
and almost could not obtain the corresponding β-aminoketones.
Secondary alcohols (1o and 1p) transferred to β-aminoketones in
30% and 10% yields after 6 hours, respectively, and by-products
were separated (entries 1 and 2). Only a complex mixture was
detected and no β-aminoketones were separated with tertiary
alcohols (1q and 1r) as the starting materials (entries 3 and 4).
2
3
3
yield for 1h with 4-OCH after 3 hours, 91% yield for 1i with 2-
3
OCH after 12 hours, 85% yield for 1j with 3-OCH after 29
3
3
hours, 89% yield for 1k with 4-CH after 15 hours, and 92%
3
yield for 1l with 4-Ph after 9 hours, entries 8-12). Expanding
phenyl ring to naphthalenyl and thiophenyl rings, products 2o
and 2p were obtained in high yields (entries 13 and 14).
However, replacement of aromatic ring to alkyl group including
CH and CH CH led to no reaction.
a
Table 3.Scope of 3-arylpropargyl alcohols 1.
3
O
R3 R4
R
4
R
Fe(OTf)
3
3
2
3
+ TsNH2
NHTs
OH
dioxane, reflux
a
Table 2.Scope of 3-aryl propargyl alcohols 1.
1
2
Fe(OTf)
3
O
+
TsNH2
Ar
OH
Ar
NHTs
dioxane, reflux
b
Entry
1
Alcohol
Product
Time(h) Yield(%)
1
2
O
Yield
NHTs
6
6
6
6
30
10
0
OH
Entry
1
Alcohol
Product
Time(h)
16
1o
b
2o
(%)
O
O
OH
OH
NHTs
94
2
3
4
1a
2
a
OH
NHTs
1
p
2p
O
2
N
c
c
O
2
3
-
-
72
72
NR
NR
1
b
OH
NHTs
1q
NC
2q
OH
1
c
O
NHTs
O
F
3
C
c
0
4
5
OH
72
72
10
NHTs
NHTs
1
d
HO
1r
F
3
C
2r
2
d
O
a
Reaction conditions: Alcohol (0.2 mmol), TsNH
0.04 mmol), dioxane (1mL), 110 C.
2
(0.4 mmol), Fe(OTf)
3
Cl
O
OH
OH
47
(
1
e
Cl
2e
b
Isolated yield after flash chromatography.
O
O
Br
F
NHTs
6
7
8
21
10
3
80
85
93
Subsequently, we examined the scope of nitrogen
1
f
Br
2f
nucleophiles with 1a as the propargyl alcohol, and the results
were summarized in Table 4. Sulfonamides were well tolerated
and afforded the corresponding β-aminoketones in high isolated
yields (entries 1-5). Increasing the nucleophilicity of
benzenesulfonamides resulted in higher rate and yield of the
reaction (entries 1-3). Secondary benzenesulfonamide could be
OH
OH
NHTs
1
g
F
2
g
O
H
3
CO
NHTs
1
h
H
3
CO
2h
employed for this reaction, and TsNHCH gave 3c in 81% yield
3
(entry 4). Benzamide showed low reactivity and only 8% yields
of 3e were obtained after 16 hours (entry 6). Trifluoroacetamide

4
Tetrahedron
es MANUSCRIPTFe(OTf)
and aniline could not give the correspondin
A
g
C
β-a
C
m
E
in
P
ok
T
et
E
on
D
O
O
3
due to the low nucleophilicity (entries 7 and 8).
OH Dioxane, reflux
(A)
a
Table 4.Scope of the nitrogen nucleophiles.
1
a
6
b
Entry
1
Nucleophile
Product
Time(h) Yield(%)
18O
16
O
O
O18
2
16OH + TsNH
Fe(OTf)
3
, H
O
O
2
NHTs
(B)
NHTs
S
NH
2
N
H
S
O
22
16
91
94
95
92
81
Dioxane, reflux
+
O
1a
18O-2a
16O- 2a
3a
O
Scheme 3. Mechanistic evidences
Based on the knowledge of the transformation of propargyl
alcohols into α, β-unsaturatedketones and the mechanistic
O
S
O
S
2
NH
2
N
O
H
O
15
2a
O
O
evidences in Scheme 3, we proposed a possible mechanism of
present reaction (Scheme 4). Propargylic alcohols easily lost a
H O and added a H O in the presence of catalytic amounts of
O
O
S
O
3
4
5
6
O
S
NH
2
N
14
18
19
16
H
O
3b
2
2
Fe(OTf) . Then keto-enol tautomerism afforded α, β-unsaturated
ketones. Coordination of the carbonyl group to Fe(OTf)3
O
3
O
O
S
S
N
N
H
O
O
followed by nucleophilic addition of TsNH afforded coordinated
enol intermediate. Protonation of enol intermediate provided
2
3
c
O
O
O
S
S
O
products 2 and regenerated catalyst Fe(OTf)3.
NH
2
N
H
O
O
3
d
OH
+
H
2
O
HO
Ar
Fe(OTf)3
O
O
Ar
Ar
unsaturated ketones
O
2
- H O
N
H
c
1
NH
2
8
3
e
Fe(OTf)
O
3
Fe(OTf)
2
O
O
Ar
NHTs
c
c
+ TsNH
TfOH
2
+ TfOH
7
8
-
16
16
NR
NR
F
3
C
NH
2
Ar
Ar
NHTs
-
- Fe(OTf)3
O
2
NH
2
-
Scheme 4. Plausible mechanism
a
Reaction conditions: Alcohol (0.2 mmol), Nucleophile (0.4 mmol), Fe(OTf)
0.04 mmol), dioxane (1mL), 110 C.
3
O
(
3. Conclusion
b
Isolated yield after flash chromatography.
In summary, we developed a Fe(OTf) -catalyzed tandem
3
c
Unconsumed 1a was recovered.
Meyer-Schuster rearrangement/1,4-addition of 2-aryl propargyl
alcohols with nitrogen nucleophiles to give acyclic β-
aminoketones, and this methodology was successfully used in the
Fluoxetine, marketed under the trade name Prozac, offers the
treatment of anxiety, alcoholism, chronic pain, headache,
obsessive disorders, sleepdisorders, and bulimia.There have been
several reports on the synthesis of racemic fluoxetine and optical
fluoxetine. As shown in Figure 2, racemic fluoxetine was
successfully accomplished by reduction of compound 3c with
synthesis of racemic fluoxetine. The Fe(OTf) catalyst probably
3
played a dual role in the rearrangement of propargyl alcohols to
the corresponding unsaturated ketones and intermolecular
hydroamination of nucleophiles to unsaturated ketones. Our
studies indicated a low catalyst loading and high yield reaction,
making it a potentially attractive method in organic synthesis of
acyclic β-aminoketones. More reactions between propargyl
alcohols and nucleophiles were underway in our lab and will be
published in due course.
14
NaBH in methanol, etherification with 4-chlorobenzotrifluoride
4
and sodium hydride in dimethylsulfoxide, and subsequent
deprotection with Na/Naphthalene. Finally, an easy and novel
approach for the total synthesis of racemic fluoxetine were
discovered, and the total yield was 59% from 1a after 4 steps.
4
. Experimental section
CF
3
CF
3
O
OH
a
b
O
c
O
N
Ts
N
Ts
4.1. General information
N
Ts
N
H
Commercially available reagents and anhydrous solvents were
used without further purification unless otherwise specified. Thi-
n layer chromatography (TLC) analyses were performed with H-
uanghai TLC plates. All the products were purified by column
chromatography on silica gel with ethyl acetate-hexane in an
3
c
4
5
Fluoxetine
Scheme 2.Synthesis of racemic Fluoxetine. Reagents and conditions: (a)
NaBH , MeOH; (b) NaH, 1-chloro-4-trifluoromethyl-benzene, DMSO; (c) Na,
naphthalene, glycol dimethyl ether.
Additional experiments shed some light on the reaction
mechanism. Treatment of 1a with stoichiometric amounts of
Fe(OTf)3 led to dimeric diketone 6, which was reported by
Yanada previously (Scheme 3, A). Refluxing 1a with 20 mol%
of Fe(OTf) , 2 equivalences of TsNH , 1 equivalence of H O,
and dioxane led to both O-2a and O-2a detected by HRMS
Scheme 3, B), which meant that the removal of O in 1a and the
4
1
13
appropriate ratio as the eluent. H and C NMR spetra were
recorded at Bruker 500- or 400-MHz instrument with TMS as an
internal standard. IR spectra (KBr) were recorded on a FT-IR
10
−1
18
spectrometer in the range of 400-4000cm .The melting points
were measure on a SGWX-4 instrument. High-resolution mass
spectrographic (HRMS) experiments were performed with
Thermo Finnigan Orbitrap mass analyzer.
3
2
2
18
16
16
(
18 18
addition of O in H2 O were took place during the reaction.
4
.2. Preparation of 1a-1o and 1q
To a mixture of aryl halide (1 mmol) in Et N (4 mL),
3
PdCl (PPh ) (0.1 mmol), CuI (0.05 mmol), and propargyl
2
3 2
O
alcohol (1.2 mmol) were added. The mixture was stirred at 80 C
under nitrogen until the starting halide disappeared completely
monitored by TLC. Then the reaction was quenched by saturated

5
[
18]
NH Cl solution and extracted with ethyl aceta
organic phases were washed with brine, dried over anhydrous
A
te.
C
T
C
he
E
c
P
om
T
b
E
in
D
ed MA
3
N
-(p
U
-T
S
o
C
lyl
R
)p
I
r
P
op
T
-2-yn-1-ol (1k) : 78% yield; brown solid;
4
O
1
m.p. 33-34 C; H NMR (500MHz, CDCl ) δ 7.35 (d, J = 8.0 Hz,
3
Na SO4 and concentrated under reduced pressure to give a
2H), 7.14 (d, J = 8.0 Hz, 2H), 4.51 (s, 2H), 2.37 (s, 3H), 1.96 (br,
OH, 1H); IR (KBr, cm ) 3364, 3025, 2923, 2854, 1713, 1605,
1508, 1456, 1377, 1029, 817, 525.
2
-
1
residue. Finally the residue was purified through column
chromatography on silica gel (200-300 mesh) with
hexane/EtOAc as eluent to afford the products 1a-1o and 1q.
[22]
3
-Biphenyl-4-yl-prop-2-yn-1-ol (1l) : 81% yield; brown solid;
[
16]
1
O
1
3
-Phenyl-prop-2-yn-1-ol (1a)
: 94% yield; brown oil; H
m.p. 122-123 C; H NMR (500MHz, CDCl ) δ 7.61 (d, J = 7.0
3
NMR (500MHz, CDCl ) δ 7.47-7.44 (m, 2H), 7.35-7.32(m, 3H),
Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.47
(t, J = 7.0 Hz, 2H), 7.40-7.37 (m, 1H), 4.55 (d, J = 5.5 Hz, 2H),
1.77(t, J = 5.5 Hz, 1H); IR (KBr, cm ) 3319, 3051, 3032, 2958,
2922, 2857, 1483, 1446, 1405, 1260, 1030, 1016, 952, 839, 800,
764, 722, 695, 668, 558.
3
-
1
4
2
.50 (s, 2H), 1.75 (br, OH, 1H); IR (KBr, cm ) 3355, 3057, 2920,
863, 1597, 1489, 1442, 1032, 952, 756, 691, 524.
-
1
[
16]
3
-(4-Nitro-phenyl)-prop-2-yn-1-ol (1b) : 91% yield; brown
O 1
solid; m.p. 95-96 C; H NMR (500MHz, CDCl ) δ 8.21 (d, J =
3
[
23]
8
1
1
.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 4.56 (s, 2H), 1.83 (br, OH,
H); IR (KBr, cm ) 3314, 3107, 3074, 2917, 2848, 1594, 1515,
346, 1108, 1023, 949, 853, 748, 686.
3-Naphthalen-2-yl-prop-2-yn-1-ol (1m) : 78% yield; yellow
-
1
O
1
solid; m.p. 59-60 C; H NMR (500MHz, CDCl ) δ 7.99 (s, 1H),
3
7.84-7.79 (m, 3H), 7.52-7.49 (m, 3H), 4.58 (s, 2H), 1.80 (br, OH,
-
1
[
17]
1H); IR (KBr, cm ) 3308, 3053, 2917, 2861, 1593, 1497, 1428,
1357, 1263, 1220, 1027, 977, 861, 820, 741, 479.
4
-(3-Hydroxy-prop-1-ynyl)-benzonitrile (1c) : 86% yield;
O 1
light yellow solid; m.p. 95-96 C; H NMR (500MHz, CDCl ) δ
3
[
24]
7
.62 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 4.54 (d, J = 5.0
3-Thiophen-3-yl-prop-2-yn-1-ol (1n) : 65% yield; brown oil;
-
1
1
Hz, 2H), 1.96 ((t, J = 5.0 Hz, 1H); IR (KBr, cm ) 3456, 3124,
065, 2236, 1712, 1604, 1503, 1424, 1362, 1032, 840, 554.
H NMR (500MHz, CDCl ) δ 7.47-7.46 (m, 1H), 7.28-7.26 (m,
3
3
1H), 7.13-7.12 (m, 1H), 4.49 (s, 2H), 2.16 (br, OH, 1H); IR (KBr,
-1
[
18]
cm ) 3377, 3106, 2923, 2854, 1456, 1359, 1028, 987, 858, 783,
626.
3
-(4-Trifluoromethyl-phenyl)-prop-2-yn-1-ol (1d)
:
83%
O
1
yield; brown solid; m.p.39-40 C; H NMR (500MHz, CDCl ) δ
3
[
25]
1
7
2
2
5
.60 (d, J = 8.5, 2H), 7.56 (d, J = 8.5, 2H), 4.54 (d, J = 6.0 Hz,
4-Phenyl-but-3-yn-2-ol (1o) :92% yield; orange oil; H NMR
-
1
H), 1.72 (t, J = 6.0 Hz, 1H); IR (KBr, cm ) 3322, 3050, 2925,
867, 1616, 1406, 1324, 1168, 1127, 1068, 1018, 954, 842, 713,
97, 521.
(500MHz, CDCl ) δ 7.46-7.44 (m, 2H), 7.33-7.32 (m, 3H), 4.79-
3
4.76 (m, 1H), 2.09-2.08 (m, 1H), 1.58-1.57 (m, 3H); IR (KBr,
-
1
cm ) 3346, 3081, 3057, 2981, 1489, 1106, 1072, 1037, 1024, 932,
756, 691.
[
19]
3
-(4-Chloro-phenyl)-prop-2-yn-1-ol (1e) : 81% yield; yellow
O 1
[26]
solid; m.p. 77-78 C; H NMR (500MHz, CDCl ) δ 7.36 (d, J =
2-Methyl-4-phenyl-but-3-yn-2-ol (1q) : 88% yield; yellow
3
O
1
8
2
2
.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.50 (d, J = 5.5 Hz, 2H),
.51 (t, J = 5.5 Hz, 1H); IR (KBr, cm ) 3355, 3081, 3056, 2981,
931, 1598, 1489, 1443, 1362, 1271, 1162, 962, 906, 755, 691.
solid; m.p. 52-53 C; H NMR (500MHz, CDCl ) δ 7.44-7.43 (m,
3
-
1
2H), 7.33-7.32 (m, 3H), 2.07 (br, OH, 1H), 1.64 (s, 6H); IR (KBr,
-
1
cm ) 3362, 3081, 3056, 2981, 2931, 2868, 1598, 1573, 1489,
1443, 1362, 1271, 1162, 1070, 962, 906, 808, 755, 691, 560, 518.
[
20]
3
-(4-Bromo-phenyl)-prop-2-yn-1-ol (1f) : 81% yield; brown
O 1
solid; m.p.79-80 C; H NMR (500MHz, CDCl ) δ 7.46 (d, J =
4.3. Preparation of 1p and 1r
3
8
1
1
.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 4.50 (s, 2H), 1.94 (br, OH,
H); IR (KBr, cm ) 3320, 3235, 3057, 2919, 2861, 1584, 1485,
361, 1222, 1030, 1011, 950, 822, 738, 525.
-1
To a solution of phenylacetylen (4 mmol) in dry THF (10 mL),
O
n-BuLi solution (4.4 mmol) was added at -78 C. The solution
O
O
was allowed to warm to 0 C over 1 hour and stirred at 0 C for
[
19]
O
3
-(4-Fluoro-phenyl)-prop-2-yn-1-ol (1g)
:
82% yield;
30 minutes. Then the solution was cooled to -78 C again and
1
colorless oil; H NMR (500MHz, CDCl ) δ 7.43 (d, J = 9.0 Hz,
ketone or aldehyde (4.0 mmol) was added. The reaction mixture
was allowed to warm to room temperature over 1 hour and stirred
at room temperature until the ketone or aldehyde disappeared
completely monitored by TLC. Then the reaction was quenched
3
2
5
1
H), 7.02 (t, J = 9.0 Hz, 2H), 4.50 (d, J = 5.5 Hz, 2H), 1.86 (t, J =
-1
.5 Hz, 1H); IR (KBr, cm ) 3362, 3046, 3025, 2922, 2866, 1601,
507, 1231, 1156, 1027, 953, 836, 550.
[
16]
by saturated NH Cl solution and extracted with ethyl acetate. The
4
3
-(4-Methoxy-phenyl)-prop-2-yn-1-ol (1h) : 59% yield;
O
1
combined organic phases were washed with brine, dried over
anhydrous Na SO and concentrated under reduced pressure to
orange solid; m.p. 61-62 C; H NMR (500MHz, CDCl ) δ 7.39 (d,
J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 4.50 (d, J = 5.5 Hz,
H), 3.83 (s, 3H), 1.69 (t, J = 5.5 Hz, 1H); IR (KBr, cm ) 3393,
071, 3003, 2933, 2837, 1606, 1508 ,1291, 1248, 1173, 1032,
32, 525.
3
2
4
-
1
give a residue. Finally the residue was purified through column
chromatography on silica gel (200-300 mesh) with
hexane/EtOAc as eluent to afford the products 1p and 1r.
2
3
8
[
27]
[
21]
1,3-Diphenyl-prop-2-yn-1-ol (1p) : 79% yield; white solid;
O 1
3
-(2-Methoxy-phenyl)-prop-2-yn-1-ol (1i)
: 75% yield;
O
1
m.p. 62-63 C; H NMR (500MHz, CDCl ) δ 7.65 (d, J = 7.5 Hz,
3
yellow solid; m.p.48-49 C; H NMR (500MHz, CDCl ) δ 7.43 (d,
J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 6.94-6.89 (m, 2H), 4.57
d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 1.79 (t, J = 6.0 Hz, 1H); IR
KBr, cm ) 3381,3074, 3006, 2935, 2837, 1596, 1492, 1463,
434, 1262, 1116, 1048, 1023, 795, 752.
3
2
H), 7.52-7.50 (m, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.39 (d, J = 7.5
Hz, 1H), 7.36-7.34 (m, 3H), 5.72 (s, 1H), 2.51 (br, OH, 1H); IR
(
(
1
-
1
-1
(KBr, cm ) 3362, 3062, 3031, 1598, 1489, 1455, 1443, 1030,
97, 961, 756, 719, 691.
9
[
28]
[
18]
2,4-Diphenyl-but-3-yn-2-ol (1r) : 70% yield; white solid;
O 1
3
-(3-Methoxy-phenyl)-prop-2-yn-1-ol (1j)
: 70% yield;
1
m.p. 91-92 C; H NMR (500MHz, CDCl ) δ 7.76 (d, J = 8.0 Hz,
3
brown oil; H NMR (500MHz, CDCl ) δ 7.24-7.21 (m, 1H),7.06-
.04 (m, 1H), 6.99 (s, 1H), 6.91-6.89 (m, 1H), 4.51 (d, J = 5.0 Hz,
H), 3.80 (s, 3H), 2.20 (t, J = 5.0 Hz, 1H); IR (KBr, cm ) 3392,
072, 3003, 2938, 2835, 1603, 1575, 1488, 1289, 1204, 1174,
164, 1042, 971, 854, 782, 686.
3
2
H), 7.52-7.50 (m, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.36-7.33 (m,
7
2
3
1
-1
-1
4H), 2.55 (br, OH, 1H), 1.90 (s, 3H); IR (KBr, cm ) 3389, 3083,
3
1
059, 3030, 2982, 2930, 2860, 1598, 1489, 1444, 1367, 1266,
211, 1138, 1087, 1027, 939, 756, 699, 606, 582.
4
.4. Preparation of 2a, 2d-2p, and 3a-3e

6
Tetrahedron
13
To a mixture of propargyl alcohol 1 (0.2 mm
A
o
C
l)
C
in
E
di
P
ox
T
an
E
e
D
(1 MA3H
NU
),
3.
S
32
C
-3
R
.28IP(m
T
, 2H), 3.25 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H); C
mL), Fe(OTf) (0.04 mmol) and nucleophile (0.4 mmol) were
NMR (125MHz, CDCl ) 200.40, 159.19, 143.22, 137.29, 134.39,
3
3
added. The mixture was stirred at refluxing temperature until 1
disappeared completely monitored by TLC. Then the reaction
130.47, 129.69, 127.04, 126.78, 120.71, 111.69, 55.49, 43.53,
-
1
38.81,21.50; IR (KBr, cm ) 3279, 3069, 2957, 2923, 2852, 1663,
1595, 1484, 1463, 1435, 1324, 1286, 1243, 1156, 1091, 1018,
918, 813, 756, 660, 549. HRMS calcd for C H NNaO S
was quenched by saturated NaHCO solution and extracted with
3
ethyl acetate. The combined organic phases were washed with
17
19
4
+
brine, dried over anhydrous Na SO4 and concentrated under
[M+Na] :356.0927, found: 3356.0932.
2
reduced pressure to give a residue. Finally the residue was
purified through column chromatography on silica gel (200-300
mesh) with hexane/EtOAc as eluent to afford the products 2a,
N-[3-(3-Methoxy-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2j) : yellow solid; m.p. 121-122 C; H
[29]
O
1
NMR (500MHz, CDCl ) δ 7.78 (d, J = 8.0 Hz, 2H), 7.46 (d, J =
3
2
d-2p, and 3a-3e.
8
.0 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (d, J =
4
-Methyl-N-(3-oxo-3-phenyl-propyl)-benzenesulfonamide
8.0 Hz, 2H), 7.15-7.12 (m, 1H), 5.29 (t, J = 6.0 Hz, 1H), 3.87 (s,
3H), 3.37-3,33 (m, 2H), 3.22 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H); IR
(KBr, cm ) 3274, 3065, 3031, 2955, 2923, 2853, 1683, 1597,
1521, 1472, 1456, 1327, 1259, 1158, 1093, 1018, 913, 799, 679,
551.
[
5]
O
1
(
7
2a) : yellow solid; m.p.86-87 C; H NMR (500MHz, CDCl ) δ
.89 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.5
Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 7.5 Hz, 2H), 5.27 (t,
J = 6.5 Hz, 1H), 3.37-3.34 (m, 2H), 3.24 (t, J = 6.0 Hz, 2H), 2.42
s, 3H); IR (KBr, cm ) 3288, 3062, 2923, 1682, 1597, 1449,
3
-
1
-
1
(
1
4
-Methyl-N-(3-oxo-3-p-tolyl-propyl)-benzenesulfonamide
[5] O 1
325, 1217, 1158, 1092, 814, 774, 689, 665, 550.
(
2k) : brown solid; m.p.96-97 C; H NMR (500MHz, CDCl ) δ
3
4
-Methyl-N-[3-oxo-3-(4-trifluoromethyl-phenyl)-propyl]-
7.79-7.77 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz,
2H), 5.25 (t, J = 6.5 Hz, 1H), 3.36-3.32 (m, 2H), 3.21 (t, J = 6.0
Hz, 2H), 2.43 (s, 3H), 2.42 (s, 3H); IR (KBr, cm ) 3275, 3062,
3030, 2923, 2868, 1678, 1607, 1418, 1324, 1287, 1181, 1160,
1093, 814, 663, 550.
O
1
benzenesulfonamide (2d): brown solid; m.p.105-106 C;
NMR (500MHz, CDCl ) δ 8.00 (d, J = 8.0 Hz, 2H), 7.77 (d, J =
.0 Hz, 2H),7.74 (d, J = 8.0 Hz, 2H),7.31 (d, J = 8.0 Hz, 2H),
.21-5.18 (m, 1H), 3.40-3.37 (m, 2H), 3.27-3.25 (m, 2H), 2.42 (s,
H); C NMR (125MHz, CDCl ) δ 197.90, 143.54, 138.77,
37.13, 135.08, 134.80, 129.80, 128.35, 127.03, 125.78, 38.76,
6.13, 21.47; IR (KBr, cm ) 3292, 3067, 2960, 2925, 2855, 1686,
410, 1324, 1260, 1162, 1127, 1066, 1016, 814, 661, 550. HRMS
H
-
1
3
8
5
3
1
3
1
13
3
N-(3-Biphenyl-4-yl-3-oxo-propyl)-4-methyl-
benzenesulfonamide (2l): light yellow solid; m.p. 131-132 C;
O
-
1
1
H NMR (500MHz, CDCl ) δ 7.97 (d, J = 8.0 Hz, 2H), 7.80 (d, J
3
+
= 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H),
calcd for C H F NNaO S [M+Na] :394.0695, found:394.0701.
17
16
3
3
7
.50 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8.0
N-[3-(4-Chloro-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2e) : brown solid; m.p. 86-87 C; H
Hz, 2H), 5.27 (t, J = 6.0 Hz, 1H), 3.38 (t, J = 5.5 Hz, 2H), 3.27 (t,
[
29]
O
1
13
J = 5.5 Hz, 2H), 2.43 (s, 3H); C NMR (125MHz, CDCl ) δ
3
NMR (500MHz, CDCl ) δ 7.83 (d, J = 8.5 Hz, 2H), 7.78 (d, J =
196.54, 146.40, 143.43, 139.65, 137.19, 134.86, 129.80, 129.02,
128.62, 128.42, 127.33, 127.28, 127.05, 38.42, 38.27, 21.52; IR
3
8
5
2
1
.0 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
.21 (t, J = 6.5 Hz, 1H), 3.38-3.34 (m, 2H), 3.21 (t, J = 6.0 Hz,
H), 2.43 (s, 3H); IR (KBr, cm ) 3288, 3091, 3064, 2924, 2855,
682, 1589, 1401, 1326, 1215, 1158, 1091, 1013, 814, 661, 551.
-
1
(KBr, cm ) 3290, 3062, 3030, 2922, 1674, 1602, 1403, 1327,
1156, 1091, 918, 841, 762, 726, 696, 661, 548. HRMS calcd for
-
1
+
C H NNaO S [M+Na] :402.1134, found:402.1139.
22
21
3
N-[3-(4-Bromo-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2f) : brown solid; m.p. 122-123 C; H
4-Methyl-N-(3-naphthalen-2-yl-3-oxo-propyl)-
benzenesulfonamide(2m): brown solid; m.p. 118-119 C; H
[
5]
O
1
O
1
NMR (500MHz, CDCl ) δ 7.78-7.75 (m,4H), 7.62 (d, J = 8.5 Hz,
NMR (500MHz, CDCl ) δ 8.39 (s, 1H), 7.98-7.95 (m, 2H), 7.92-
3
3
2
H), 7.32 (d, J = 8.5 Hz, 2H), 5.19 (t, J = 5.5 Hz, 1H), 3.37-3.34
7.89 (m, 2H), 7.85 (d, J = 8.5 Hz, 2H),7.66-7.64 (m, 1H), 7.63-
7.59 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H), 5.29 (t, J = 6.0 Hz, 1H),
-
1)
(m, 2H), 3.21 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H); IR (KBr, cm
13
3
1
290, 3089, 3063, 2923, 1682, 1585, 1485, 1397, 1326, 1215,
158, 1093, 1070, 1009, 814, 661, 550.
3.42 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 2.38 (s, 3H);
C
NMR (125MHz, CDCl ) δ 196.81, 143.39, 137.30, 135.83,
3
1
33.54, 132.41, 129.99, 129.77, 129.62, 128.81, 128.60, 127.82,
N-[3-(4-Fluoro-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2g) : light yellow solid; m.p. 107-108 C;
-1
[
29]
O
127.04, 126.99, 123.40, 38.50, 38.27, 21.43; IR (KBr, cm ) 3287,
3059, 2922, 2870, 1676, 1626, 1596, 1468, 1436, 1411, 1374,
1
1
H NMR (500MHz, CDCl ) δ 7.92 (d, J = 8.5 Hz, 2H), 7.77 (d, J
3
327, 1214, 1159, 1092, 924, 814, 661, 550; HRMS calcd for
=
8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H),
+
C H NNaO S [M+Na] :376.0978, found:376.0984.
20
19
3
5
2
1
.31 (t, J = 6.0 Hz, 1H), 3.36-3.32 (m, 2H), 3.21 (t, J = 6.0 Hz,
-
1
H), 2.42 (s, 3H); IR (KBr, cm ) 3287, 3109, 3069, 2924, 1682,
597, 1507, 1410, 1326, 1226, 1158, 1093, 844, 815, 662, 551.
4-Methyl-N-(3-oxo-3-thiophen-3-yl-propyl)-
O
1
benzenesulfonamide(2n): light yellow solid; m.p. 99-100 C; H
NMR (500MHz, CDCl ) δ 8.02 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H),
7.50-7.49 (m, 1H), 7.36-7.33 (m, 1H),7.32 (d, J = 8.0 Hz, 2H),
3
N-[3-(4-Methoxy-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2h) : light yellow solid; m.p. 123-124 C;
[
15]
O
1
5.24 (t, J= 6.5 Hz, 1H), 3.36-3.32 (m, 2H), 3.15 (t, J = 6.0 Hz,
H NMR (500MHz, CDCl ) δ 7.87 (d, J = 8.5, 2H), 7.78 (d, J =
13
3
2
1
H), 2.43 (s, 3H); C NMR (125MHz, CDCl ) δ 193.10, 143.43,
3
7
(
5
2
1
.5, 2H), 7.31 (d, J = 7.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 5.31
41.52, 137.17, 132.62, 129.78, 127.04, 126.69, 126.58, 39.30,
38.31, 21.51; IR (KBr, cm ) 3280, 3104, 2954, 2923, 2853, 1670,
t, J = 6.0 Hz, 1H), 3.89 (s, 3H), 3.36-3.32 (m, 2H), 3.18 (t, J =
-1
-
1
.5 Hz, 2H), 2.42 (s, 3H); IR (KBr, cm ) 3274, 3065, 2958, 2922,
851, 1670, 1599, 1508, 1418, 1323, 1259, 1221, 1158, 1091,
026, 814, 667, 550.
1
597, 1510, 1413, 1326, 1229, 1157, 1092, 871, 813, 661, 550;
+
HRMS calcd for C H NNaO S [M+Na] : 332.0386, found:
14
15
3 2
3
32.0392.
N-[3-(2-Methoxy-phenyl)-3-oxo-propyl]-4-methyl-
benzenesulfonamide (2i): light yellow solid; m.p. 94-95 C; H
O
1
4-Methyl-N-(1-methyl-3-oxo-3-phenyl-propyl)-
benzenesulfonamide (2o) : yellow solid; m.p.93-94 C;
[30]
O
1
H
NMR (500MHz, CDCl ) δ 7.78 (d, J = 8.0, 2H), 7.74 (d, J = 8.0,
3
NMR (500MHz, CDCl ) δ 7.84 (d, J = 7.5 Hz, 2H), 7.76 (d, J =
3
1
(
H), 7.52-7.49 (m,1H), 7.31 (d, J = 8.0 Hz, 2H), 7.03-7.00
m,1H), 6.98 (d, J = 8.0 Hz, 1H), 5.23 (t, J = 6.0 Hz, 1H), 3.91 (s,
8
=
.0 Hz, 2H), 7.60-7.57(m, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.26 (d, J
8.0 Hz, 2H), 5.32-5.30 (m, 1H); 3.87-3.82 (m, 1H), 3.24-3.20

7
-
P
1
(
m, 1H), 3.10-3.05 (m, 1H), 2.39 (s, 3H); IR
A
(K
C
Br
C
, c
E
m
)
T
3
E
28
D
4, MA
w
N
as
U
qu
S
en
C
ch
R
edIPby
T
saturated NH Cl solution and extracted with
4
3
1
6
062, 2958, 2925, 2871, 1682, 1597, 1580, 1495, 1449, 1378,
ethyl acetate. The combined organicphases were washed with
brine, dried over anhydrous Na SO4 andconcentrated under
reduced pressure to give a residue. Finally the residue was
purified through column chromatography on silica gel (200-300
mesh) with hexane/EtOAc as eluent to afford 5 in 72% yield after
321, 1304, 1288, 1213, 1160, 1091, 1001, 901, 884, 815, 754,
89, 666, 584, 551.
2
4
-Methyl-N-(3-oxo-1,3-diphenyl-propyl)-
[31]
O
1
benzenesulfonamide (2p) : white solid; m.p. 106-107 C; H
NMR (500MHz, CDCl ) δ 7.82 (d, J = 7.5 Hz, 2H), 7.63 (d, J =
2
steps.
3
7
7
1
.5 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 2H),
.36 (s, 1H), 7.19-7.17 (m, 6H), 5.72-5.71 (m, 1H); 4.90-4.85 (m,
H), 3.63-3.58 (m, 1H), 3.50-3.45 (m, 1H), 2.38 (s, 3H); IR (KBr,
To a dried three neck round bottom flash sodium metal (21.5
mmol), naphthalene (28 mmol) and dry glycol dimethyl ether (10
mL) were added and the reaction mixture was stirred at room
temperature for 2 hours. Then the naphtalenide mixture was
added slowly to a solution of 5 (0.72 mmol) in dry glycol
dimethyl ether (4 mL). The reaction was stirred at room
temperature until 5 disappeared completely monitored by TLC.
The reaction was quenched with couple drops of water and
extracted with ethyl acetate. The combined organic phases were
-
1
cm )3280, 3062, 3032, 2957, 2923, 2853, 1683, 1596, 1492,
448, 1328, 1260, 1157, 1090, 1018, 812, 749, 700, 668, 540.
1
[
32]
N-(3-Oxo-3-phenyl-propyl)-benzenesulfonamide
(3a)
:
O
1
brown solid; m.p.100-101 C; H NMR (500MHz, CDCl ) δ 7.91-
7
=
3
.89(m, 4H), 7.62-7.57(m, 2H), 7.53 (t, J = 7.0 Hz, 2H), 7.48 (t, J
7.0 Hz, 2H), 5.35 (br, NH, 1H), 3.38-3.36 (m, 2H), 3.26-3.24
-
1
washed with brine, dried over anhydrous Na
2
SO
4
and
(m, 2H); IR (KBr, cm ) 3288, 3063, 2957, 2920, 2850, 1682,
concentrated under reduced pressure to give a residue. Finally,
the residue was purified through column chromatography on
silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford
1
6
596, 1580, 1447, 1324, 1217, 1157, 1092, 1000, 914, 819, 754,
88, 583.
[
14]
4
-Methoxy-N-(3-oxo-3-phenyl-propyl)-benzenesulfonamide
racemic fluoxetine in 88% yield. Racemic fluoxetine : brown
[
5]
O
1
O 1
(3b) : yellow solid; m.p.77-78 C; H NMR (500MHz, CDCl ) δ
solid; m. p. 157-158 C; H NMR (500MHz, CDCl ) δ 7.44 (d, J
3
3
7
.99 (d, J = 7.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 7.5
= 8.5 Hz, 2H), 7.40-7.37 (m, 4H), 7.33-7.32 (m, 2H), 6.70 (d, J =
Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 5.30
8.5 Hz, 2H), 4.78-4.76 (m, 1H), 3.56-3.53 (m, 2H), 3.00 (s, 3H),
-
1
(d, J = 6.0 Hz, 1H), 3.86 (s, 3H), 3.38-3.33 (m, 2H), 3.23 (t, J =
2.05-2.01 (m, 2H); IR (KBr, cm ) 3365, 3064, 3031, 2923, 2853,
1616, 1533, 1457, 1328, 1199, 1107, 1069, 818, 701, 592.
-
1
6
1
7
.0 Hz, 2H); IR (KBr, cm ) 3281, 3062, 2925, 2852, 1681, 1596,
578, 1497, 1448, 1325, 1260, 1217, 1153, 1093, 1025, 913, 833,
44, 689, 560.
4
.6. Procedure for the synthesis of 6
To a mixture of propargyl alcohol 1a (0.2 mmol) in dioxane (1
4
,N-Dimethyl-N-(3-oxo-3-phenyl-propyl)-
[33]
O
1
mL), Fe(OTf) (0.2 mmol) was added, and the reaction was
3
benzenesulfonamide (3c) : yellow solid; m.p.81-82 C; H
NMR (500MHz, CDCl )δ 7.96 (d, J = 7.5 Hz, 2H),7.71 (d, J =
stirred at refluxing temperature until 1a disappeared completely
monitored by TLC. Then the reaction was quenched by saturated
3
8
7
2
3
1
.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H),
.49 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.5 Hz, 2H), 3.48-3.45 (m,
H), 3.37-3.34 (m, 2H), 2.83 (s, 3H), 2.45 (s, 3H); IR (KBr, cm )
062, 3030, 2956, 2924, 2870, 1682, 1596, 1448, 1338, 1305,
251, 1159, 1088, 953, 815, 728, 717, 690, 548.
NaHCO solution and extracted with ethyl acetate. The combined
3
-
1
organic phases were washed with brine, dried over anhydrous
Na SO4 and concentrated under reduced pressure to give a
2
residue. Finally the residue was purified through column
chromatography on silica gel (200-300 mesh) with
hexane/EtOAc as eluent to give 6. 2-Methylene-1,5-diphenyl-
[
5]
N-(3-Oxo-3-phenyl-propyl)-methanesulfonamide
yellow solid; m.p.106-107 C; H NMR (500MHz, CDCl ) δ 7.96
(3d) :
O
1
[35]
O
1
3
pentane-1,5-dione (6) : yellow solid; m.p.56-57 C; H NMR
(d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz,
(400MHz, CDCl ) δ 7.91 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.2 Hz,
3
2
3
1
H), 5.12 (br, NH, 1H), 3.57-3.54 (m, 2H), 3.36-3.32 (m, 2H),
.01 (s, 3H); IR (KBr, cm ) 3294, 3060, 3025, 2920, 2850, 1682,
596, 1448, 1391, 1217, 1148, 970, 755, 690, 521.
2H), 7.50-7.45 (m, 2H), 7.41-7.34 (m, 4H), 5.89 (s, 1H), 5.61 (s,
-
1
1H), 3.17 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H); IR (KBr,
-
1
cm ) 3083, 3059, 3026, 2960, 2921, 2850, 1684, 1653, 1595,
1447, 1261, 1206, 1095, 1023, 1001, 799, 750, 708, 690.
[
34]
N-(3-Oxo-3-phenyl-propyl)-benzamide (3e) : yellow solid;
O
1
m.p.92-93 C; H NMR (500MHz, CDCl ) δ 7.99 (d, J = 7.5 Hz,
3
Acknowledgments
2
7
3
3
1
H), 7.78 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.51-
.48(m, 3H), 7.43 (t, J = 7.5 Hz, 2H), 6.98 (br, NH, 1H), 3.93-
-
1
The work was supported by National Natural Science
Foundation of China (Grant No.21502117), and Shanghai
Municipal Education Commission (Plateau Discipline
Construction Program). Support from Prof. Guanjun Wang and
Prof. Gang Zhao was also greatly appreciated.
.90 (m, 2H), 3.39-3.35 (m, 2H); IR (KBr, cm ) 3337, 3061,
029, 2956, 2926, 2854, 1682, 1643, 1578, 1535, 1488, 1448,
326, 1307, 1215, 1076, 1001, 971, 801, 712, 690.
4
.5. Procedure for the synthesis of racemic Fluoxetine
To a mixture of 3c (1 mmol) in methanol (3 mL) NaBH (1.2
mmol) was added, and the mixture was stirred at room
4
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Supplementary Material
1
13
H NMR spectra, C NMR spectra of new compounds, and
HRMS spectra of new compounds associated with this article can
be found, in the online version, at http://dx.doi.org.