Metal-free, Regio-, and Stereo-Controlled Hydrochlorination and Hydrobromination of Ynones and Ynamides

Article abstract of DOI:10.1021/acs.joc.7b02257

We developed an atom-economical and metal-free method for the regio- and stereo-selective hydrohalogenation of ynones and ynamides using easy to handle DMPU/HX (X = Br or Cl) reagents. The reaction operates under mild conditions and a range of functional groups is well tolerated. We propose that the hydrohalogenation of ynones gives the anti-addition products via a concerted multimolecular Ad_E3 mechanism and that the hydrohalogenation of ynamides produces the syn-addition products via a cationic keteniminium intermediate.

Full text of DOI:10.1021/acs.joc.7b02257

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Article
Metal free, Regio and Stereo- Controlled Hydrochlorination
and Hydrobromination of Ynones and Ynamides
Xiaojun Zeng, Zhichao Lu, Shiwen Liu, Gerald B. Hammond, and Bo Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02257 • Publication Date (Web): 23 Nov 2017
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The Journal of Organic Chemistry
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Metal free, Regio and Stereo- Controlled Hydrochlorination and Hydrobromination of Ynones and Ynamides
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Xiaojun Zeng,[a] Zhichao Lu,[b] Shiwen Liu,[a] Gerald B. Hammond[b], * and Bo Xu[a], *
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[a]College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai
201620, China; e-mail: bo.xu@dhu.edu.cn
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[b]Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; e-mail: gb.hammond@louisville.edu
ABSTRACT: We developed an atom-economical and metal-free method for the regio- and stereo-selective hydrohalogen-
ation of ynones and ynamides using easy to handle DMPU/HX (X = Br or Cl) reagents. The reaction operates under mild
conditions and a range of functional groups is well tolerated. We propose that the hydrohalogenation of ynones gives the
anti-addition products via a concerted multi-molecular AdE3 mechanism and that the hydrohalogenation of ynamides
produces the syn-addition products via a cationic keteniminium intermediate.
economy. What is needed is a simple, unified,
INTRODUCTION
chemo-and stereo-selective atom-economical hydro-
halogenation method for a wide range of ynones and
ynamides.
Vinylhalides are important targets in medicine and
materials, and they are also important substrates for
cross-coupling reactions.1 More specifically, halogen-
ated vinyl ketones and halogenated N-vinyl amides
(enamides) are especially important targets and syn-
thetic building blocks because they are highly func-
tional sources of vinyl halides.2 The hydrohalogena-
tion of alkynes has provided a uniform approach to-
wards viny halides,1g, 3 and the most straightforward
and atom-economical synthesis of halogenated vinyl
ketones and haloethenamides has been the regio- and
stereo-selective hydrohalogenation of ynones and
ynamides, respectively (Scheme 1, top). For example,
the hydrohalogenation of ynones using HBr/water,4
AlBr3/H2O or LiBr/TFA,4c HCl/water5 SnCl4/H2O5-6
(Scheme 1, a-e) have been reported, but these meth-
ods give poor chemical yields due to side reactions
such as hydration. For the hydrohalogenation of
ynamides, Hsung and coworkers reported an stere-
oselective synthesis of 1-haloenamides using in situ
generated HX from MgX2 in a wet solvent (Scheme
1f).7 Iwasawa and coworkers reported the hydrochlo-
rination of terminal ynamides using HX generated in
situ from TMSX and water (Scheme 1g).8 Sahoo and
coworkers demonstrated a one-pot construction of
haloenamides using a Ph3P/H2O/CX4 system as the
halide source (Scheme 1h).9 Recently, Shin and
coworkers reported a novel benzoic acid-catalyzed
hydrohalogenation of ynamides using N-oxides/di-
halogenated ethane system (Scheme 1d)10 whereas
Thibaudeau and coworkers reported a syn-addition of
HF to the ynamides.11 Although the above mentioned
examples underscore the importance of halogenation
protocols, the reported methods are either too nar-
row in scope, or suffer from complex reaction condi-
tions, low chemical yields and/or poor atom-
Scheme 1. Halogenation of ynones and ynamides.
Recently, we reported a metal-free, hydrogen bond-
ing cluster-enabled addition of sulfonic acids to
haloalkynes.12 We now postulate that a metal-free
and atom-economic hydrochlorination or hydrobro-
mination of ynones 1 and ynamides 4 is possible using
HX. However, hydrogen halides such as hydrogen
chloride and hydrogen bromide are hazardous gases
at room temperature. Although many HX reagents
(e.g.,
Et2O/HCl,
H2O/HCl,
isopropanol/HCl,
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HOAc/HBr, H2O/HBr) are commercially available, With the optimized conditions in hand, we explored
1
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3
4
5
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8
they exist either in low concentration (e.g. Et2O/HCl)
and/or in protic media (H2O, isopropanol, HOAc)
where the protic solvent hampers the nucleophilicity
of HX and also competes with HX in nucleophilic
addition. This effect may explain the low efficiency
when protic solutions of HX are used (Scheme 1). In
this regard, an HX solution in a neutral aprotic medi-
um would be optimal to prevent competitive solvoly-
sis reaction and to achieve high reactivity. Due to its
high hydrogen bond basicity, yet low Brønsted basici-
ty,13, 14 DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone) can form a stable and highly concen-
trated complex with hydrogen chloride (HCl) and
hydrogen bromide (HBr); we have used these com-
plexes in nano-gold catalyzed or non-catalyzed hy-
drohalogenation of alkenes and alkynes.15 We are
now glad to report an atom-economical and metal-
free method for the regio- and stereoselective hydro-
halogenation of ynones and ynamides using easy to
handle DMPU/HX (X = Br or Cl) reagents.
the substrate scope and functional group tolerance
for the hydrochlorination of alkynyl ketones (Table 2,
top). We evaluated the effect of different [R1, R2]
combinations of ynones 1 (Table 2). Combinations of
[R1 = aryl, R2 = alkyl] (Table 2, 2a-l), [R1 = aryl, R2 =
aryl] (Table 2, 2n), [R1 = alkyl, R2 = aryl] (Table 2, 2o
worked very well; good chemical yields and high anti
)
-
-
selectivity were observed. The bulky R2 groups (e.g.
t
Bu, Cy-) did not affect chemical yields (Table 2, 2b
,
,
2c). Equally, the substitution pattern (meta para) or
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the electronic properties of the substituents (electron
deficient or rich) on R1 or R2 played only a small role;
good yields were obtained regardless (Table 2, 2e
2o). Various functional groups such as esters (Table
2, 2e 2k), ether (Table 2, 2i), halides (Table 2, 2f 2h),
-2m,
,
,
nitrile (Table 2, 2l), nitro (Table 2, 2o), and sulfonate
(Table 2, 2j) were well tolerated. Similar conditions
worked very well for the hydrobromination of ynones
when DMPU/HBr was used (Table 2, bottom). In the-
se cases, we observed a very similar reactivity pattern
and functional group tolerance (Table 2, 3a-3j). We
also tested the hydrohalogenation of di-alkyl substi-
tuted ynones. Unfornately we got mostly hydration
products and other by-products. We also attempted
to conduct hydroiodination using DMPU-HI reagent,
but the preparation of DMPU-HI was not successful
(formation of I2 when mixing HI and DMPU).
RESULTS AND DISCUSSION
We carried out the hydrochlorination of 1a as our
model reaction (Table 1). We were delighted to find
that DMPU/HCl gave better yields, higher anti-
selectivity and fewer by-products compared to com-
mercial HCl reagents (Table 1, entries 1-4). Mixing
o
DMPU/HCl with 1a in DCM from 0 C to room tem-
perature produced the desired product, chloro-
unsaturated ketone 2, in 98% yield (Table 1, entry 4).
Screening of other solvents indicated that weakly co-
ordinating solvents like DCM, DCE and toluene were
better than more coordinating solvents such as
CH3CN, THF and DMF (Table 1, entries 5-9).
Table 1. Optimization of the hydrochlorination of alkynyl
ketone.a
O
Ph
O
Cl
O
HCl reagent (2 equiv)
solvent
+
Cl
Ph
Ph
H
H
1a
syn-addition
anti-addition
2a
2a'
/%b (
2a:2a
’)
2
entry
HCl reagent
Et2O/HCl
solvent
DCM
DCM
DCM
DCM
MeCN
Toluene
THF
1
2
3
4
5
6
7
8
9
70 (6:1)
81 (7:1)
92 (3:1)
98 (12:1)
89 (6:1)
88 (7:1)
83 (5:1)
78 (2:1)
97 (8:1)
1,4ꢀdioxane/HCl
Isopropanol/HCl
DMPU/HCl
DMPU/HCl
DMPU/HCl
DMPU/HCl
DMPU/HCl
DMPU/HCl
DMF
DCE
a Reaction conditions: 1a (0.2 mmol), HCl reagent (0.4 equiv)
o
b
in solvent (0.5 mL), 0 C to rt for 8 h. Determined by GCꢀ
MS analysis.
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Table 3. Hydrohalogenation of ynamides.a
Table 2. Hydrohalogenation of ynones.a
1
EWG
2
3
4
5
6
7
8
9
EWG
R1
H
N
R2
DCM
R1
N
+
DMPU/HX
R2
0 oC - rt, 8 h
4
X
5 (X = Br)
6 (X = Cl)
Ms
Ms
Ts
Ph
Ts
Ph
Br
Ph
H
N
Ph
H
N
N Ph
Ph
H
N
H
Br
Br
Br
5a
5c
, 85%
, 82%
5b
, 86%
Ts
5d
, 83%
F
Cl
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Ts
Cl
Ts
N
Ts
N
N
N
Cl
H
Br
H
Br
H
Br
Br
H
5f
, 82%
5e
, 78%
5g
, 79%
5h
, 82%
Br
NC
Ph
Ph
MeO2C
Ts
N
Ms
N
Ms
N
H
Br
Br
H
H
Br
, 82%
5i
, 81%
5k, 64%
5j
Ms
N
Ph Ts
Ph Ts
N
Ph
Ph
Ph
N
Ms
N
Ph
H
H
H
Cl
H
Cl
Cl
Cl
6d
, 95%
6c
, 94%
6a, 95%
6b
, 85%
O
O
Ph Ts
N
Ph Ts
N
Ph
H
N
Ms
N
H
H
H
Cl
Cl
, 92%
Cl
6e
, 95%
6f
, 82%
Cl
6g
6h, 90%
Cl
F
MeO
O2N
Ts
Ts
Ts
N
N
N
Ms
N
H
Cl
H
Cl
H
Cl
H
Cl
6i
, 94%
6j
, 87%
6k
, 92%
6l
, 88%
O
S
Ts
O
Ts
Ts
N
aReaction conditions: ynones
(0.4 mmol) in DCM (0.5 mL), 0 oC to rt for 8 h; trace syn
addition products were also observed in most case, but they
can be easily removed by chromatography.
1
(0.2 mmol), DMPU/HX
N
N
O
H
Cl
ꢀ
Cl
H
H
Cl
6m, 91%
6n
, 90%
6o, 82%
aReaction conditions: ynamide
1
(0.2 mmol), DMPU/HX
(0.4 mmol) in DCM (0.5 mL), 0 oC to rt for 8 h.
Ynamides are readily available compounds that have
found wide applications in organic synthesis.16 We
were glad to find that our protocol can also be used
Next, we investigated the hydrochlorination of yna-
mides 4 using DMPU/HCl as the chlorination reagent
(Table 3, bottom). This protocol also had wide sub-
strate scope and good functional group tolerance
in the hydrohalogenation of ynamides
4 (Table 3).
We first explored the substrate scope and functional
group tolerance in the hydrobromination of yna-
mides 4 (Table 3, top). Despite the strong acidity of
(Table 3 bottom). Ynamides
[EWG = Ts/Ms/carbamate, R2 = alkyl, aryl, allyl,
homoallyl] delivered in good yields as well as in
excellent regio- and stereo control (Table 3, 6a-g).
Interestingly, acid sensitive functional groups such as
alkene, allyl and carbamate survived the reaction
conditions. We also investigated the effects of the
substitution pattern in R1 on the efficiency of reac-
tions. For ynamides with various R1 groups (R1 =
naphthyl, phenyl rings with electron-donating groups
or electron-withdrawing groups, heteroaryls such as
4 with combinations of
6
the DMPU/HBr complex and the fact that ynamides
are acid sensitive compounds, the substrate scope
was broad: both aliphatic and aromatic substituted
ynamides produced syn-addition products exclusively
in good to excellent yields (Table 3): combinations of
-
[EWG = Ts, R2 = Bn], [EWG = Ts, R2 =
n-heptyl],
[EWG = Ms, R2 = methyl], [EWG = Ms, R2 = phenyl]
all gave good yields (Table 3, 5a-d). Also, the substi-
tution pattern (para-, ortho- or -meta) on the aryl
ring of R1 only had a small effect on the efficiency of
the reaction, high yields were obtained regardless
(Table 3, 5e-5i). It should be noted that acid sensitive
functional groups such as nitrile and methyl ester
survived our conditions (Table 1, 5j-5k).
thiophene), high yields of 6 were obtained regardless
(Table 3, 6h ). Remarkably, ynamides featuring a
-
complex cholesterol scaffold furnished the desired
o
chlorinated product in 82% yield (Table 3, 6o).
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Our methodology can be used in larger scale synthe-
tonate C2 preferentially (Scheme 4a). This pathway
eventually leads to the -regioselectivity observed.
Also, DFT geometry optimization of indicates that
the keteniminium intermediate possesses a linear
geometry, with its upper face being sterically hin-
dered by the R1 group, thus favoring the nucleophile
(bromide/chloride) syn approach (formation of the
syn-addition product).11b
1
2
3
4
5
6
7
8
sis without complications. The hydrohalogenation of
ynone 1a (5 mmol scale) gave chlorinated product 2a
and brominated product 3a in 85% and 73% yields,
respectively (Scheme 2a). Ynamide 4a (1.0 gram
scale) was successfully converted to 6a in 93% yield
(Scheme 2b).
α
A
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Scheme 2. Gram scale hydrohalogenations.
Scheme 4. Proposed mechanism. LUMO of keteniminium was
calculated at B3LYP/6ꢀ311+G(2df,2p) level of theory.
For the hydrohalogenation of the electron deficient
Scheme 3. Divergent syntheses from halogenated products.
ynone
so we proposed a different mechanism (Scheme 4b).
The exclusive formation of the -isomer (anti-
1, the direct protonation of 1 is more difficult,
Z
Next, we utilized these halogenated alkene products
in transition metal catalyzed cross-coupling reactions
(Scheme 3). Suzuki coupling of halogenated vinyl ke-
addition) suggested the possibility of an AdE3 mecha-
nism18 because the bromide concentration in the re-
action medium is not low.19 This concerted three-
molecule process should furnish the anti-addition
product. The regio-selectivity found can be rational-
ized by the fact that the NBO charge density of C1 is
significantly higher than C2 because of the resonance
participation of the carbonyl group (Scheme 4b). This
tones
2 and 3 with phenyl boronic acid gave good
yields of the coupling products (Scheme 3a). Similar-
ly, the Pd catalyzed Suzuki coupling of chlorinated
enamide 6a with phenyl boronic acid (Scheme 3b),
and the Sonogashira coupling of brominated enamide
5c with ethynyltrimethylsilane (Scheme 3c) gave
good yields of tri-substituted enamides 8a and 9a
respectively. On the other hand, copper catalysts
such as CuCN was not a good catalyst for coupling of
pathway should eventually lead to the
regioselectivity found.
β-
,
CONCLUSION
5c.
In conclusion, we have developed an atom-
economical and metal-free method for the regio- and
stereo-selective hydrohalogenation of ynones and
ynamides using easily handled DMPU/HX (X = Br or
Cl) reagents. The reaction operates under mild condi-
tions and a range of functional groups are well toler-
ated. Further applications of these new halogenation
reagents are currently underway in our laboratory
and will be reported in due course.
Our proposed mechanism is shown in Scheme 4. For
the hydrohalogenation of ynamides (Scheme 4a), the
high acidity of DMPU/HX facilitates the rate-
determining proton transfer step, which produces the
key intermediate--keteniminium A.17 Because the ni-
trogen atom polarizes the triple bond, the regioselec-
tivity of this protonation is mainly determined by the
charge distribution on C1 and C2 of ynamide 4. Due
to the resonance contribution of the lone pair on the
nitrogen atom, the NBO charge density of C2 is sig-
nificantly higher than C1, so DMPU/HX should pro-
EXPERIMENTAL SECTION
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The Journal of Organic Chemistry
(ESIꢀFTꢀICR) calcd. for C11H8NO[M+H]+: 170.0606,
1H NMR (400 MHz or 500 MHz) and 13C NMR (100
1
2
3
4
5
6
7
8
found:170.0600.
MHz or 125 MHz) spectra were recorded on a Bruker
NMR apparatus. The chemical shifts are reported in δ
(ppm) values (1H and 13C NMR relative to CHCl3, δ
4-(4-Acetylphenyl)but-3-yn-2-one (1m).20 White solid. H NM
R (400 MHz, Chloroformꢀd) δ 7.93 (d, J = 8.2 Hz, 2H), 7.62 (
d, J = 8.2 Hz, 2H), 2.59 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (1
00 MHz, Chloroformꢀd) δ 196.9, 184.2, 138.0, 133.0, 128.3, 1
24.5, 89.9, 88.3, 32.7, 32., 26.64. HRMS (ESIꢀFTꢀICR) calcd.
for C12H11O2[M+H]+:187.0759, found:187.0753.
1
1
13
7.26 ppm for H NMR and δ 77.0 ppm for C NMR).
Or alternatively, H NMR chemical shifts were refer-
1
enced to tetramethylsilane signal (0 ppm). Multiplici-
ties are recorded by s (singlet), d (doublet), t (triplet),
q (quartet), p (pentet), h (hextet), m (multiplet) and
br (broad). Coupling constants (J), are reported in
Hertz (Hz). GC analyses were performed using a
Shimadzu GC-2010 ultra gas chromatography–mass
spectrometry instrument equipped with a Shimadzu
AOC-20s autosampler. Commercial reagents and sol-
vents were obtained from the commercial providers
and used without further purification. The products
were purified using a commercial flash chromatog-
raphy system or a regular glass column. TLC was de-
veloped on silica gel 60 F254 glass plates. The
DMPU/HX reagents were prepared using our published
9
2. Synthesis of ynamides 4
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General procedure. To a mixture of alkynyl bromide (3.0
mmol), 1,10ꢀphenanthroline (0.6 mmol, 108 mg),
CuSO4·5H2O (0.3 mmol,149 mg) and K2CO3 (6.0 mmol, 828
mg) in dry toluene (15.0 mL), amide (3.6 mol) was added. The
reaction mixture was stirred at 70 ºC under the nitrogen atꢀ
mosphere. The progress of the reaction was monitored periodꢀ
ically by TLC. After the completion of the reaction, the reacꢀ
tion mixture was filtered through a pad of celite and the solꢀ
vent was removed in vacuum. The resulting residue was puriꢀ
fied by chromatography on silica gel to give the desired prodꢀ
ucts.
procedures15
.
N-(2-(cyclohex-1-en-1-yl)ethyl)-4-methyl-N-
(phenylethynyl)benzenesulfonamide (4f). Pale yellow oil. 1H
NMR (500 MHz, Chloroformꢀd) δ 7.86 (d, J = 8.3 Hz, 2H),
7.46 – 7.34 (m, 4H), 7.35 – 7.26 (m, 3H), 5.48 (s, 1H), 3.65
– 3.34 (m, 2H), 2.47 (s, 3H), 2.33 (t, J = 7.6 Hz, 2H), 1.99ꢀ
1.94 (m, 4H), 1.73 – 1.59 (m, 2H), 1.57ꢀ1.52 (m,
2H).13C{1H} NMR (100 MHz, Chloroformꢀd) δ 144.5, 134.8,
133.3, 131.3, 129.7, 128.3, 127.7, 124.2, 123.0, 82.5, 70.8,
50.3, 36.4, 28.2, 25.3, 22.8, 22.2, 21.7. HRMS (ESIꢀFTꢀICR)
calcd. for C23H26NO2S [M+H]+: 380.1684, found: 380.1678.
Methyl 3-(3-oxooct-1-yn-1-yl) benzoate (1e).20 White solid. 1H
NMR (400 MHz, Chloroformꢀd) δ 8.23 (s, 1H), 8.10 (d, J =
6.6 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.47 (s, 1H), 3.93 (s,
3H), 2.66 (t, J = 7.2 Hz, 2H), 1.91 – 1.67 (m, 2H), 1.35 (d, J =
3.3 Hz, 4H), 0.91 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (100
MHz, Chloroformꢀd) δ 187.9, 165.8, 136.9, 133.9, 131.3,
130.8, 128.7, 120.6, 88.8, 88.2, 52.5, 45.5, 31.1, 23.8, 22.3,
13.8. HRMS (ESIꢀFTꢀICR) calcd. for C16H19O3 [M+H]+:
259.1334, found: 259.1327.
4-(4-Fluoro-3-methylphenyl)but-3-yn-2-one (1h). Yellow solꢀ
1
(3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-
yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl
id. Mp 42ꢀ43°C. H NMR (400 MHz, Chloroformꢀd) δ 7.61 –
7.33 (m, 2H), 7.00 (t, J = 8.8 Hz, 1H), 2.42 (s, 3H), 2.26 (s,
3H). 19F NMR (376 MHz, Chloroformꢀd) δ ꢀ109.52 – ꢀ112.87
(m). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ 184.4, 162.7
(d, J = 252.4 Hz), 136.5, 132.7 (d, J = 8.9 Hz), 125.9 (d, J =
18.2 Hz), 115.8，115.6, 89.7, 87.9, 32.6 (d, J = 5.3 Hz), 14.3.
HRMS (ESIꢀFTꢀICR) calcd. for C12H10FO [M+H]+: 177.0710
, found: 177.0703.
6-((N,4-
dimethylphenyl)sulfonamido)hex-5-ynoate (4o). White solid.
1
Mp 94–95°C. H NMR (400 MHz, Chloroformꢀd) δ 7.76 (d, J
= 8.3 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 5.35 (d, J = 4.9 Hz,
1H), 4.62 – 4.60 (m, 1H), 2.99 (s, 3H), 2.43 (s, 3H), 2.35 –
2.31 (m, 6H), 2.07 – 1.05 (m, 28H), 1.00 (s, 3H), 0.89 (d, J =
6.5 Hz, 3H), 0.85 (d, J = 1.8 Hz, 3H), 0.83 (d, J = 1.8 Hz, 3H),
0.66 (s, 3H).13C{1H} NMR (100 MHz, ) δ 172.5, 144.5, 139.6,
133.1, 129.7, 127.8, 127.7, 122.6, 75.6, 74.0, 67.4, 56.7, 56.1,
50.0, 42.3, 39.7, 39.5, 38.1, 37.0, 36.6, 36.2, 35.8, 33.4, 31.9,
31.8, 28.2, 28.0, 27.8, 24.2, 23.8, 22.8, 22.5, 21.7, 21.0, 19.3,
18.7, 17.9, 11.8. HRMS (ESI +) calcd. for C41H61NO4S
[M+H]+: 664.4400, found: 664.4385.
3-(3-Oxobut-1-yn-1-yl)phenyl
methanesulfonate
(1j).20
1
White solid. H NMR (400 MHz, Chloroform-d) δ 7.57 –
7.34 (m, 4H), 3.17 (s, 3H), 2.44 (s, 3H). C{1H} NMR (100
13
MHz, Chloroform-d) δ 184.1, 148.8, 131.8, 130.4, 126.2, 124.6,
122.0, 88.9, 87.6, 37.7, 32.7. HRMS(ESI-FT-ICR) calcd. for
C11H11SO4[M+H]+: 239.0378, found:239.0371.
3. Hydrochlorination of ynones 1
Methyl 3-(3-oxobut-1-yn-1-yl)benzoate (1k).20 White solid. 1H
NMR (400 MHz, Chloroformꢀd) δ 8.22 (s, 1H), 8.12 – 8.00
(m, 1H), 7.79 – 7.64 (m, 1H), 7.46 – 7.42 (m, 1H), 3.92 (s,
3H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ
184.2, 165.8, 136.8, 134.0, 131.5, 130.8, 128.8, 120.4, 88.6,
88.5, 52.4, 32.7. HRMS (ESIꢀFTꢀICR) calcd. for
C12H11O3[M+H]+: 203.0708, found:203.0720.
To a solution of ynone 1 (0.2 mmol) in DCM (0.5 mL) was
added DMPU/HCl (43 wt/wt%) (34 mg, 0.4 mmol) at 0 C,
o
then the mixture was warmed to room temperature and was
stirred for 8 h. After completion, the solvent was evaporated
under the reduced pressure and the residue was purified by
silica gel column chromatography (hexanes/EtOAc as elute
solvent) to afford the corresponding products 2.
4-(3-Oxobut-1-yn-1-yl)benzonitrile (1l).20 White solid. 1H
NMR (400 MHz, Chloroformꢀd) δ 7.66 – 7.63 (m, 4H), 2.46
(s, 3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ 183.9,
133.2, 132.2, 124.7, 117.8, 113.9, 90.5, 86.8, 32.7. HRMS
(Z)-4-chloro-4-phenylbut-3-en-2-one (2a).3e Purified by flash
column chromatography (ethyl acetate / hexanes = 1:20)give
the product as colorless oil, 30.2 mg 84% yield. 1H NMR (400
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MHz, Chloroformꢀd) δ 7.86 – 7.55 (m, 2H), 7.58 – 7.31 (m,
(Z)-4-chloro-4-(4-fluoro-3-methylphenyl)but-3-en-2-one (2h).
4H), 6.77 (s, 1H), 2.47 (s, 3H). 13C{1H} NMR (100 MHz,
Chloroformꢀd) δ 196.7, 143.1, 137.3, 130.7, 128.6, 127.3,
124.7, 31.9.
Purified by flash column chromatography (ethyl acetate / hexꢀ
1
2
3
4
5
6
7
8
1
anes = 1:20), yellow oil, 38.1 mg, 90% yield. H NMR (400
MHz, Chloroformꢀd) δ 7.48 – 7.42 (m, 2H), 7.01 (t, J = 8.8 Hz,
1H), 6.69 (s, 1H), 2.44 (s, 3H), 2.28 (s, 3H). 19F NMR (376
MHz, Chloroformꢀd) δ ꢀ101.3 – ꢀ135.0 (m, 1F). 13C{1H} NMR
(100 MHz, Chloroformꢀd) δ 196.4, 162.7 (d, J = 250.8 Hz),
142.1, 133.1 (d, J = 3.8 Hz), 130.7 (d, J = 6.1 Hz), 126.7 (d, J
= 8.7 Hz), 125. 4 (d, J = 17.9 Hz), 124.3, 115.3 (d, J = 23.1
Hz), 31.9, 14.6 (d, J = 3.3 Hz). HRMS (ESIꢀFTꢀICR) calcd.
for C11H11ClFO [M+H]+: 213.0482, found:213.0477.
(Z)-1-chloro-4,4-dimethyl-1-phenylpent-1-en-3-one
(2b).21
Purified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1:20)give the product as yellow oil, 40.8 mg, 92%
yield. 1H NMR (400 MHz, Chloroformꢀd) δ 7.77 – 7.56 (m,
2H), 7.59 – 7.25 (m, 3H), 7.06 (s, 1H), 1.22 (s, 9H).13C{1H}
NMR (100 MHz, Chloroformꢀd) δ 203.6, 143.2, 137.8, 130.4,
128.6, 127.2, 119.9, 44.5, 26.3. HRMS (ESIꢀFTꢀICR) calcd.
for C13H16ClO[M+H]+: 223.0890, found: 223.0885.
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(Z)-4-chloro-4-(3-methoxyphenyl)but-3-en-2-one (2i). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:20), yellow oil, 31.9 mg,76% yield. H NMR (400 MHz,
(Z)-3-chloro-1-cyclohexyl-3-phenylprop-2-en-1-one
(2c).22
1
Purified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1:20)give the product as yellow oil, 42.1 mg, 85% yield.
1H NMR (400 MHz, Chloroformꢀd) δ 7.90 – 7.51 (m, 2H),
7.41ꢀ7.36 (m, 3H), 6.84 (s, 1H), 2.58 – 2.54 (m, 1H), 1.92 –
1.90 (m, 2H), 1.80 – 1.78 (m, 2H), 1.67 – 1.65 (m, 1H), 1.50 –
1.05 (m, 5H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ
201.5, 142.6, 137.55, 130.47, 128.57, 127.24, 122.66, 51.63,
28.35, 25.85, 25.65. HRMS (ESIꢀFTꢀICR) calcd. for
C15H18ClO [M+H]+: 249.1046, found: 249.1039.
Chloroformꢀd) 7.29 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 7.8 Hz,
1H), 7.18 (s, 1H), 7.00 – 6.91 (m, 1H), 6.75 (s, 1H), 3.82 (s,
3H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ
196.6, 159.6, 142.7, 138.7, 129.6, 124.9, 119.6, 116.3, 112.9,
55.4, 31.9. HRMS (ESIꢀFTꢀICR) calcd. for C11H12ClO2
[M+H]+: 211.0526, found: 211.0519.
(Z)-3-(1-chloro-3-oxobut-1-en-1-yl)phenyl methanesulfonate
(2j). Purified by flash column chromatography (ethyl acetate /
1
hexanes = 1:10), pale red oil, 46.5 mg, 85% yield. H NMR
(Z)-1-chloro-1-phenyloct-1-en-3-one (2d). Purified by flash
column chromatography (ethyl acetate / hexanes = 1:20), yelꢀ
low oil, 41.5 mg, 88% yield. 1H NMR (400 MHz, Chloroformꢀ
d) δ 7.67 – 7.75 (m, 2H), 7.50 – 7.30 (m, 3H), 6.78 (s, 1H),
2.68 (t, J = 7.4 Hz, 2H), 1.67ꢀ 1.63 (m, 2H), 1.33 – 1.30 (m,
4H), 0.90 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, Chloꢀ
roformꢀd) δ 199.01, 142.31, 137.44, 130.53, 128.59, 127.26,
123.86, 44.44, 31.38, 23.68, 22.48, 13.92. HRMS (ESIꢀFTꢀ
ICR) calcd. for C14H18ClO [M+H]+: 237.1046, found:
237.1040.
(400 MHz, Chloroformꢀd) δ 7.63 (d, J = 7.9 Hz, 1H), 7.58 (s,
1H), 7.46 (t, J = 8.0 Hz, 1H), 7.36 (ddd, J = 8.1, 2.5, 1.1 Hz,
1H), 6.77 (s, 1H), 3.18 (s, 3H), 2.46 (s, 3H). 13C{1H} NMR
(100 MHz, Chloroformꢀd) δ 196.3, 149.1, 140.6, 139.4, 130.3,
126.1, 125.8, 124.1, 121.1, 37.7, 31.9. HRMS (ESIꢀFTꢀICR)
calcd. for C11H12ClSO4 [M+H]+: 275.0145, found:275.0140.
Methyl (Z)-3-(1-chloro-3-oxobut-1-en-1-yl)benzoate (2k).
Purified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1:15), yellow solid, 40.9 mg, 86% yield. Mp 44ꢀ45°C
1H NMR (400 MHz, Chloroformꢀd) δ 8.31 (s, 1H), 8.08 (d, J =
7.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H),
6.82 (s, 1H), 3.93 (s, 3H), 2.47 (s, 3H). 13C{1H} NMR (100
MHz, Chloroformꢀd) δ 196.4, 166.1, 141.6, 137.6, 131.5,
130.7, 128.9, 128.2, 125.4, 52.4, 31.9. HRMS (ESIꢀFTꢀICR)
calcd. for C12H12ClO3 [M+H]+: 239.0475, found:239.0470.
Methyl (Z)-3-(1-chloro-3-oxooct-1-en-1-yl)benzoate (2e). Puꢀ
rified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1/20), yellow oil. NMR (400 MHz, Chloroformꢀd) δ
8.31 (s, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H),
7.48 (t, J = 7.8 Hz, 1H), 6.83 (s, 1H), 3.93 (s, 3H), 2.68 (t, J =
7.3 Hz, 2H), 1.87 – 1.59 (m, 2H), 1.35ꢀ1.29 (m, 4H), 0.88 (t, J
= 6.6 Hz, 3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ
198.8, 166.2, 140.9, 137.8, 131.5, 131.4, 130.7, 128.8, 128.2,
124.8, 52.4, 44.5, 31.4, 23.6, 22.5, 13.9. HRMS (ESIꢀFTꢀICR)
calcd. for C16H20ClO3 [M+H]+: 295.1101, found: 295.1094.
(Z)-4-(1-chloro-3-oxobut-1-en-1-yl)benzonitrile (2l). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:10), yellow solid, 33.2 mg, 81% yield. Mp 76–78°C. 1H
NMR (400 MHz, Chloroformꢀd) δ 7.77 (d, J = 8.3 Hz, 2H),
7.70 (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 2.47 (s, 3H). 13C{1H}
NMR (100 MHz, Chloroformꢀd) δ 196.1, 141.4, 140.2, 132.4,
127.9, 126.8, 117.9, 114.1, 31.8. HRMS (ESIꢀFTꢀICR) calcd.
for C11H9ClNO [M+H]+: 206.0373, found: 206.0366.
(Z)-4-chloro-4-(4-chlorophenyl)but-3-en-2-one (2f). Purified
by flash column chromatography (ethyl acetate/hexane=
1:20)give the product as pale yellow oil, 35 mg, 82% yield. 1H
NMR (400 MHz, Chloroformꢀd) δ 7.60 (d, J = 8.6 Hz, 2H),
7.37 (d, J = 8.6 Hz, 2H), 6.73 (s, 1H), 2.46 (s, 3H).13C{1H}
NMR (100 MHz, Chloroformꢀd) δ 196.3, 141.6, 136.9, 135.7,
128.9, 128.5, 124.9, 31.9. HRMS (ESIꢀFTꢀICR) calcd. for
C10H9Cl2O [M+H]+: 215.0030, found: 215.0024.
(Z)-4-(4-acetylphenyl)-4-chlorobut-3-en-2-one (2m). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:15), yellow oil, 37.4 mg, 85% yield. 1H NMR (400 MHz,
Chloroformꢀd) 7.97 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.6 Hz,
2H), 6.81 (s, 1H), 2.61 (s, 3H), 2.48 (s, 3H). 13C{1H} NMR
(100 MHz, Chloroformꢀd) δ 197.1, 196.4, 141.3, 138.4, 128.5,
127.5, 126.2, 31.9, 26.7. HRMS (ESIꢀFTꢀICR) calcd. for
C12H12ClO2 [M+H]+: 223.0526, found: 223.0520.
(Z)-4-(4-bromophenyl)-4-chlorobut- 3-en-2-one (2g). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:20), yellow solid, 44.8 mg, 88% yield. Mp 42ꢀ43°C 1H NMR
(400 MHz, Chloroformꢀd) δ 7.53 (s, 4H), 6.74 (s, 1H), 2.45 (s,
3H). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ 196.7, 141.7,
136.1, 131.9, 128.7, 125.2, 124.9, 31.9. HRMS (ESIꢀFTꢀICR)
calcd. for C10H7ClBrO [MꢀH+]: 256.9369, found: 256.9362.
(Z)-3-chloro-1,3-diphenylprop-2-en-1-one (2n). Purified by
flash column chromatography (ethyl acetate / hexanes = 1:20),
yellow oil, 43 mg, 89% yield. 1H NMR (500 MHz, Chloroꢀ
formꢀd) δ 8.02 (d, J = 7.0 Hz, 2H), 7.83 – 7.72 (m, 2H), 7.60 (t,
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The Journal of Organic Chemistry
J = 7.3 Hz, 1H), 7.55 – 7.42 (m, 5H), 7.37 (s, 1H). 13C{1H}
NMR (126 MHz, Chloroformꢀd) δ 189.8, 143.3, 133.4, 130.6,
128.7, 128.7, 128.7, 127.2, 121.5. HRMS (ESIꢀFTꢀICR) calcd.
for C15H12ClO [M+H]+: 243.0577, found: 243.0569.
Methyl (Z)-3-(1-bromo-3-oxooct-1-en-1-yl)benzoate (3e). Puꢀ
1
2
3
4
5
6
7
8
rified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1:15), yellow oil, 54.7 mg, 81% yield. 1H NMR (500
MHz, Chloroformꢀd) δ 8.26 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H),
7.82 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H),
3.94 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 1.86 – 1.52 (m, 2H),
1.34 (dt, J = 7.7, 3.6 Hz, 4H), 0.90 (t, J = 6.8 Hz, 3H). 13C{1H}
NMR (126 MHz, Chloroformꢀd) δ 199.0, 166.2, 139.8, 132.5,
131.7, 131.1, 130.6, 128.9, 128.8, 128.0, 52.4, 44.4, 31.3, 23.5,
22.5, 13.9. HRMS (ESIꢀFTꢀICR) calcd. for C16H20BrO3
[M+H]+: 339.0596, found:339.0589.
(Z)-3-chloro-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one
(2o).3e Purified by flash column chromatography (ethyl acetate
1
/ hexanes = 1:15), yellow oil, 47 mg, 82% yield. H NMR
(500 MHz, Chloroformꢀd) 1H NMR (500 MHz, Chloroformꢀd)
δ 8.34 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H), 7.79 (dt, J
= 6.7, 1.6 Hz, 2H), 7.61 – 7.41 (m, 3H), 7.37 (s, 1H). HRMS
(ESIꢀFTꢀICR) calcd. for C15H11ClNO3 [M+H]+: 288.0427,
found: 288.0419.
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(Z)-4-(4-acetylphenyl)-4-bromobut-3-en-2-one (3f). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:10), yellow oil, 42.5 mg, 80% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 197.05, 196.47, 143.34, 138.15, 131.97,
129.30, 128.45, 128.36, 31.66, 26.73. 13C{1H} NMR (126
MHz, Chloroformꢀd) δ 197.1, 196.5, 143.3, 138.2, 132.0,
129.3, 128.5, 128.4, 31.7, 26.7. HRMS (ESIꢀFTꢀICR) calcd.
for C12H12BrO2 [M+H]+: 267.0012, found: 267.0014.
4. Hydrobromination of ynones 1
To a solution of ynone 1 (0.2 mmol) in DCM (0.5 mL) was
o
added DMPU/HBr (60 wt/wt%) (54 mg, 0.4 mmol) at 0 C,
then the mixture was warmed to room temperature and was
stirred for 8 h. After completion, the solvent was evaporated
under the reduced pressure and the residue was purified by
silica gel column chromatography (hexanes/EtOAc as elute
solvent) to afford the corresponding products 3.
(Z)-4-bromo-4-(4-bromophenyl)but-3-en-2-one (3g). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:20), yellow oil, 43.3 mg, 72% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.54 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.7 Hz,
2H), 6.98 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR (126 MHz,
Chloroformꢀd) δ 196.4, 138.2, 132.4, 131.8, 129.6, 128.2,
124.9, 31.7. HRMS (ESIꢀFTꢀICR) calcd. for C10H9Br2O
[M+H]+: 302.9015, found:302.9013.
(Z)-4-bromo-4-phenylbut-3-en-2-one (3a).23 Purified by flash
column chromatography (ethyl acetate / hexanes = 1:25), pale
1
yellow oil, 33.8 mg, 76% yield. H NMR (400 MHz, Chloroꢀ
formꢀd) δ 7.62 (dd, J = 7.0, 2.6 Hz, 2H), 7.45 – 7.29 (m, 3H),
6.99 (s, 1H), 2.43 (s, 3H).13C{1H} NMR (100 MHz, Chloroꢀ
formꢀd) δ 196.68, 139.30, 133.99, 130.44, 128.55, 128.26,
128.14, 127.90, 31.77.
(Z)-4-bromo-4-(3-methoxyphenyl)but-3-en-2-one (3h). Puriꢀ
fied by flash column chromatography (ethyl acetate / hexanes
= 1:15), yellow oil, 24.9 mg, 49% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.30 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.7 Hz,
2H), 7.16 (s, 1H), 7.00 (s, 1H), 6.96 (d, J = 8.2 Hz, 2H), 3.85
(s, 3H), 2.45 (s, 3H).13C{1H} NMR (126 MHz, Chloroformꢀd)
δ 196.7, 159.5, 140.7, 133.6, 129.5, 128.1, 120.4, 116.0, 113.9,
55.4, 31.7. HRMS (ESIꢀFTꢀICR) calcd. for C11H12BrO2
[M+H]+: 255.0021, found: 255.0013.
(Z)-1-bromo-4,4-dimethyl-1-phenylpent-1-en-3-one (3b). Puriꢀ
fied by flash column chromatography (ethyl acetate / hexanes
= 1:25), yellow oil, 43 mg, 81% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.73 – 7.54 (m, 2H), 7.43ꢀ7.40 (m, 3H), 7.24
(s, 1H), 1.24 (s, 9H). 13C{1H} NMR (126 MHz, Chloroformꢀd)
δ 204.10, 139.83, 134.18, 130.16, 128.52, 128.10, 124.01,
44.38, 26.27. HRMS (ESIꢀFTꢀICR) calcd. for C13H16BrO
[M+H]+: 267.0385, found: 267.0378.
Methyl (Z)-3-(1-bromo-3-oxobut-1-en-1-yl)benzoate (3i). Puriꢀ
fied by flash column chromatography (ethyl acetate / hexanes
= 1:15), yellow oil, 44.9 mg, 80% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 8.27 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.83 (d,
J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H), 3.95 (s,
3H), 2.45 (s, 3H). 13C{1H} NMR (126 MHz, Chloroformꢀd) δ
196.4, 166.2, 139.7, 132.5, 132.4, 131.3, 130.6, 129.0, 128.8,
128.7, 52.4, 31.7. HRMS (ESIꢀFTꢀICR) calcd. for C12H12BrO3
[M+H]+: 282.9970, found: 282.9963.
(Z)-3-bromo-1-cyclohexyl-3-phenylprop-2-en-1-one (3c). Puriꢀ
fied by flash column chromatography (ethyl acetate / hexanes
= 1:25), yellow oil, 46.1 mg, 79% yield. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.74 – 7.57 (m, 2H), 7.52 – 7.30 (m, 3H),
7.07 (s, 1H), 2.57 – 2.52 (m, 1H), 2.06 – 1.90 (m, 2H), 1.85 ꢀ
1.82 (m, 2H), 1.74 – 1.63 (m, 1H), 1.54 – 1.11 (m, 5H).
13C{1H} NMR (126 MHz, Chloroformꢀd ) δ 201.9, 139.6,
133.6, 130.2, 128.5, 128.1, 126.4, 51.7, 28.3, 25.9, 25.6.
HRMS (ESIꢀFTꢀICR) calcd. for C15H18BrO [M+H]+: 293.0541,
found: 293.0534.
(Z)-3-bromo-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one (3j).
Purified by flash column chromatography (ethyl acetate / hexꢀ
anes = 1:20), yellow oil, 51.5 mg, 78% yield. 1H NMR (500
MHz, Chloroformꢀd) δ 8.35 (d, J = 8.9 Hz, 2H), 8.16 (d, J =
8.9 Hz, 2H), 7.79 – 7.68 (m, 2H), 7.55 (s, 1H), 7.51 – 7.43 (m,
3H). 13C{1H} NMR (126 MHz, Chloroformꢀd) δ 188.6, 150.4,
142.04, 138.79, 137.17, 130.91, 129.66, 128.11, 124.15,
123.98. HRMS (ESIꢀFTꢀICR) calcd. for C15H11BrNO3
[M+H]+: 331.9922, found: 331.9914.
(Z)-1-bromo-1-phenyloct-1-en-3-one (3d). Purified by flash
column chromatography (ethyl acetate / hexanes = 1:25), yelꢀ
low oil, 44.8 mg, 80% yield. 1H NMR (500 MHz, Chloroformꢀ
d) δ 7.80 – 7.54 (m, 2H), 7.46 – 7.31 (m, 3H), 7.01 (s, 1H),
2.66 (t, J = 7.4 Hz, 2H), 1.70 – 1.68 (m, 2H), 1.50 – 1.20 (m,
4H), 0.92 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, Chloꢀ
roformꢀd) δ 199.2, 139.5, 133.3, 130.3, 128.5, 128.1, 127.2,
44.4, 31.4, 23.6, 22.5, 13.9. HRMS (ESIꢀFTꢀICR) calcd. for
C14H18BrO [M+H]+: 281.0541, found:281.0535.
5. Hydrobromination of ynamides 4
To a solution of ynamides 4 (0.2 mmol) in DCM (0.5 mL) was
o
added DMPU/HBr (60 wt/wt%) (54 mg, 0.4 mmol) at 0 C,
then the mixture was warmed to room temperature and was
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stirred for 8 h. After completion, the solvent was evaporated
HRMS (ESIꢀFTꢀICR) calcd. for C16H16BrClNO2S [M+H]+:
399.9774, found: 399.9766.
1
2
3
under the reduced pressure and the residue was purified by
silica gel column chromatography (hexanes/EtOAc as elute
solvent) to afford the corresponding products 5.
(E)-N-(1-bromo-2-(4-chlorophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (5g). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), yellow solid,
62.8 mg, 79% yield. Mp 142–143°C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.76 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.6 Hz,
2H), 7.33 – 7.27 (m, 4H), 6.59 (s, 1H), 3.02 (s, 3H), 2.44 (s,
3H).13C{1H} NMR (100 MHz, ) δ 144.6, 134.5, 134.1, 131.6,
131.1, 129.9, 129.5, 128.9, 128.7, 35.7, 21.6. HRMS (ESIꢀFTꢀ
ICR) calcd. for C16H16BrClNO2S [M+H]+: 399.9774, found:
399.9764.
4
5
6
7
8
9
(E)-N-benzyl-N-(1-bromo-2-phenylvinyl)-4-
methylbenzenesulfonamide (5a),1 Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
1
72.4 mg, 82% yield. Mp 142–143°C. H NMR (400 MHz,
Chloroformꢀd) δ 7.86 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz,
2H), 7.33 – 7.27 (m, 2H), 7.24 (dd, J = 6.2, 1.9 Hz, 2H), 7.23
– 7.04 (m, 6H), 6.81 (s, 1H), 4.83 (d, J = 13.1 Hz, 1H), 3.94 (d,
J = 13.1 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, ) δ
144.7, 139.7, 134.3, 133.6, 133.2, 129.9, 129.6, 129.2, 128.7,
128.6, 128.3, 128.1, 128.0, 119.6, 53.3, 21.7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-N-(1-bromo-2-(4-fluorophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (5h). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
62.6 mg, 82% yield. Mp 86ꢀ88°C. 1H NMR (400 MHz, Chloꢀ
roformꢀd) δ 7.77 (d, J = 7.7 Hz, 2H), 7.67 – 7.51 (m, 2H), 7.30
(d, J = 7.9 Hz, 2H), 7.03 (t, J = 8.3 Hz, 2H), 6.81 (s, 1H), 2.97
(s, 3H), 2.43 (s, 3H).19F NMR (376 MHz, Chloroformꢀd) δ ꢀ
111.2 (dq, J = 9.0, 5.0, 4.3 Hz). 13C{1H} NMR (100 MHz,
Chloroformꢀd) δ 162.7 (d, J = 250.0 Hz), 144.7, 135.8, 133.5,
130.7, 130.6, 129.5, 129.0, 121.1, 115.7 (d, J = 21.7 Hz), 36.6,
21.6. HRMS (ESIꢀFTꢀICR) calcd. for C16H16BrFNO2S
[M+H]+: 384.0069, found: 384.0061.
(E)-N-(1-bromo-2-phenylvinyl)-N-heptyl-4-
methylbenzenesulfonamide (5b). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:25), pale yellow
oil, 85 mg, 86% yield. 1H NMR (400 MHz, Chloroformꢀd) δ
7.82 (d, J = 8.2 Hz, 2H), 7.76 – 7.61 (m, 2H), 7.66 – 7.23 (m,
5H), 6.98 (s, 1H), 3.62 – 3.59 (m, 1H), 2.89 – 2.87 (m, 1H),
2.44 (s, 3H), 1.77 – 1.35 (m, 2H), 1.35 – 0.93 (m, 8H), 0.82 (t,
J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, ) δ 144.6, 139.0,
134.0, 133.8, 129.4, 129.2, 129.0, 120.2, 49.7, 31.6, 28.8, 27.4,
26.9, 22.5, 21.7, 14.0. HRMS (ESIꢀFTꢀICR) calcd. for
C22H29BrNO2S [M+H]+: 450.1102, found: 450.1099.
(E)-N-(1-bromo-2-(4-bromophenyl)vinyl)-N-
(E)-N-(1-bromo-2-phenylvinyl)-N-methylmethanesulfonamide
(5c).10 Purified by flash column chromatography (ethyl acetate
/ hexanes = 1:20), pale yellow solid, 49 mg, 85% yield. Mp
phenylmethanesulfonamide (5i). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
69 mg, 81% yield. Mp 121–122°C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.53 (d, J = 8.1 Hz, 2H), 7.44 (q, J = 8.4 Hz,
4H), 7.35 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 6.6 Hz, 2H), 6.99 (s,
1H), 3.14 (s, 3H).13C{1H} NMR (100 MHz, ) δ 138.7, 137.3,
132.2, 131.9, 130.1, 129.6, 127.6, 123.6, 123.3, 118.6, 39.0.
HRMS (ESIꢀFTꢀICR) calcd. for C15H14Br2NO2S [M+H]+:
429.9107, found: 429.9100.
1
90–92°C. H NMR (400 MHz, Chloroformꢀd) δ 7.8 – 7.4 (m,
2H), 7.36 – 7.31 (m, 3H), 6.9 (s, 1H), 3.1 (s, 3H), 3.0 (s, 3H).
13C{1H} NMR (100 MHz, ) δ 137.3, 133.4, 129.2, 128.8,
128.6, 120.5, 37.4, 36.5.HRMS (ESIꢀFTꢀICR) calcd. for
C10H13BrNO2S [M+H]+: 289.9850, found: 289.9842.
(E)-N-(1-bromo-2-phenylvinyl)-N-phenylmethanesulfonamide
(5d).10 White solid, 58 mg, 83% yield. Mp 136–137°C. 1H
NMR (400 MHz, Chloroformꢀd) δ 8.03 – 7.36 (m, 4H), 7.54 –
7.14 (m, 6H), 7.06 (s, 1H), 3.14 (s, 3H). 13C{1H} NMR (100
MHz, ) δ 138.9, 138.5, 133.3, 128.7, 128.6, 127.4, 123.7,
117.9, 39.0. HRMS (ESIꢀFTꢀICR) calcd. for C15H15BrNO2S
[M+H]+: 352.0007, found: 352.0001.
(E)-N-(1-bromo-2-(4-cyanophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (5j). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:15), colorless oil,
64 mg, 82% yield. Mp 131ꢀ134°C. 1H NMR (400 MHz, Chloꢀ
roformꢀd) δ δ 7.75 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 8.0 Hz,
2H), 7.62 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.87 (s,
1H), 2.98 (s, 3H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, ) δ
145.1, 138.2, 135.1, 133.1, 132.4, 129.6, 129.1, 129.0, 124.9,
118.6, 112.0, 36.8, 21.7. HRMS (ESIꢀFTꢀICR) calcd. for
C17H16BrN2O2S [M+H]+: 391.0116, found: 391.0106.
(E)-N-(1-bromo-2-(2-chlorophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (5e). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), yellow solid,
62 mg,78% yield. Mp 82ꢀ83°C. 1H NMR (400 MHz, Chloroꢀ
formꢀd) δ 7.80 (dd, J = 6.7, 2.8 Hz, 1H), 7.71 (dd, J = 8.4, 1.6
Hz, 2H), 7.43 – 7.29 (m, 1H), 7.26 (dd, J = 7.2, 3.4 Hz, 4H),
7.17 (s, 1H), 2.95 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (100
Methyl (E)-3-(2-bromo-2-(N-phenylmethylsulfonamido)vinyl)
benzoate (5k). Purified by flash column chromatography
(ethyl acetate / hexanes = 1:15), colorless oil, 52.4 mg, 64%
yield. 1H NMR (400 MHz, Chloroformꢀd) δ 8.15 (s, 1H), 7.97
(d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1
Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.28
(d, J = 7.1 Hz, 1H), 7.08 (s, 1H), 3.90 (s, 3H), 3.13 (s, 3H).
13C{1H} NMR (100 MHz, ) δ 166.5, 138.9, 137.2, 133.6,
132.5, 130.5, 130.0, 129.9, 129.6, 128.9, 127.7, 124.0, 119.3,
52.2, 39.0. HRMS (ESIꢀFTꢀICR) calcd. for C17H17BrNO4S
[M+H]+: 410.0062, found: 410.0054.
MHz, ) δ 144.6, 133.5, 133.4, 133.3, 132.3, 129.6, 129.5,
+
126.9, 123.5, 36.9, 21.6. HRMS (ESI
) calcd. for
C16H16BrClNO2S[M+H]+: 399.9774, found: 399.9770.
(E)-N-(1-bromo-2-(3-chlorophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (5f). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
65.2 mg, 82% yield. Mp 113ꢀ114°C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.83 – 7.67 (m, 2H), 7.50 (s, 1H), 7.46 (s,
1H), 7.28 (t, J = 6.5 Hz, 4H), 6.79 (d, J = 2.0 Hz, 1H), 2.98 (s,
3H), 2.43 (s, 3H). 13C{1H} NMR (100 MHz, ) δ 144.6, 133.5,
133.4, 133.5, 132.3, 129.6, 129.5, 126.9, 123.5, 36.9, 21.6.
6. Hydrochlorination of ynamides 4
To a solution of ynamides 4 (0.2 mmol) in DCM (0.5 mL) was
o
added DMPU/HCl (43 wt/wt%) (34 mg, 0.4 mmol) at 0 C,
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The Journal of Organic Chemistry
δ 7.81 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.4 Hz, 2H), 7.43 –
then the mixture was warmed to room temperature and was
1
2
3
4
5
6
7
8
stirred for 8 h. After completion, the solvent was evaporated
under the reduced pressure and the residue was purified by
silica gel column chromatography (hexanes/EtOAc as elute
solvent) to afford the corresponding products 6.
7.26 (m, 5H), 6.76 (s, 1H), 5.33 (s, 1H), 3.71 (s, 1H), 3.05 (s,
1H), 2.43 (s, 3H), 2.18 – 2.15 (m, 2H), 1.86 – 1.83 (m, 4H),
1.52 – 1.49 (m, 4H). 13C{1H} NMR (100 MHz, ) δ 144.4,
134.7, 134.5, 133.4, 133.1, 129.5, 129.3, 128.8, 128.4, 127.6,
+
123.9, 47.1, 35.6, 28.1, 25.1, 22.7, 22.1, 21.6. HRMS (ESI )
calcd. for C23H27ClNO2S [M+H]+: 416.1446, found: 416.1441.
(E)-N-(1-chloro-2-phenylvinyl)-N-methylmethanesulfonamide
(6a).10 Purified by flash column chromatography (ethyl acetate
1
/ hexanes = 1:15), white solid, 46.5 mg, 95% yield. H NMR
(E)-3-(1-chloro-2-phenylvinyl)oxazolidin-2-one (6g). Purified
by flash column chromatography (ethyl acetate / hexanes =
1:10), white solid, 41 mg, 92% yield. Mp 124–126°C. 1H
NMR (400 MHz, Chloroformꢀd) 7.31 (s, 5H), 6.73 (s, 1H),
4.42 (t, J = 7.8 Hz, 2H), 3.76 (t, J = 7.9 Hz, 2H).13C{1H}
NMR (100 MHz, ) δ 155.3, 132.9, 130.4, 128.8, 128.7, 127.9,
125.9, 62.8, 44.5. HRMS (ESIꢀFTꢀICR) calcd. for
C11H11ClNO2 [M]+: 224.0448, found: 224.0441.
(400 MHz, Chloroformꢀd) δ 7.56 (d, J = 7.0 Hz, 2H), 7.34 –
7.30 (m, 3H), 6.68 (s, 1H), 3.13 (s, 3H), 3.00 (s, 3H).13C{1H}
NMR (100 MHz, ) δ 132.7, 132.5, 129.1, 128.8, 128.6, 38.1,
35.7. HRMS (ESIꢀFTꢀICR) calcd. for C10H13ClNO2S [M+H]+:
246.0356, found: 246.0350.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-N-(1-chloro-2-phenylvinyl)-N-heptyl-4-
methylbenzenesulfonamide (6b). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), colorless oil,
72.9 mg, 85% yield. 1H NMR (400 MHz, Chloroformꢀd) δ
7.81 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 7.1 Hz, 2H), 7.34 – 7.30
(m, 5H), 6.77 (s, 1H), 3.56 (s, 1H), 3.01 (s, 1H), 2.43 (s, 3H),
1.53 (bs, 2H), 1.55 – 0.94 (m, 8H), 0.82 (t, J = 7.0 Hz, 3H)..
13C{1H} NMR (100 MHz, ) δ 144.4, 134.7, 134.4, 133.1,
129.5, 129.1, 129.0, 128.9, 128.5, 127.9, 48.6, 31.6, 28.8, 27.3,
26.8, 22.4, 21.6, 14.0. HRMS (ESIꢀFTꢀICR) calcd. for
C22H28ClNO2S [M+H]+: 406.1608, found: 406.1599.
(E)-N-(1-chloro-2-(naphthalen-1-yl)vinyl)-N-
methylmethanesulfonamide (6h). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), pale yellow
1
liquid, 53 mg, 90% yield. H NMR (400 MHz, Chloroformꢀd)
δ 7.94 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 9.2 Hz, 2H), 7.76 (d, J
= 7.2 Hz, 1H), 7.62 – 7.43 (m, 3H), 7.32 (s, 1H), 3.02 (s, 3H),
2.81 (s, 3H). 13C{1H} NMR (100 MHz, ) δ 133.4, 131.5, 131.2,
130.1, 130.0, 129.1, 128.7, 126.6, 126.5, 126.1, 125.6, 123.8,
38.5, 36.3. HRMS (ESIꢀFTꢀICR) calcd. for C14H15ClNO2S
[M+H]+: 296.0512, found: 296.0506.
(E)-N-benzyl-N-(1-chloro-2-phenylvinyl)-4-
methylbenzenesulfonamide (6c). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
74.6 mg, 94% yield. Mp 127ꢀ129°C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.86 (d, J = 8.3 Hz, 2H), 7.42 – 7.28 (m, 4H),
7.24 – 7.00 (m, 8H), 6.60 (s, 1H), 4.80 (d, J = 12.3 Hz, 1H),
4.04 (d, J = 12.3 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (100
MHz, ) δ 144.6, 135.0, 134.9, 133.3, 132.8, 129.8, 129.6,
128.9, 128.7, 128.5, 128.3, 128.2, 128.0, 127.5, 52.4, 21.7.
HRMS (ESIꢀFTꢀICR) calcd. for C22H21ClNO2S [M+H]+:
398.0982, found: 398.0980.
(E)-N-(1-chloro-2-(4-fluorophenyl)vinyl)-N,4-
dimethylbenzenesulfonamide (6i).24 Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), pale yellow
1
solid, 63.7 mg, 94% yield. H NMR (400 MHz, Chloroformꢀd)
δ 7.77 (d, J = 8.1 Hz, 2H), 7.64 – 7.54 (m, 2H), 7.30 (d, J =
7.9 Hz, 2H), 7.09 – 6.99 (m, 2H), 6.60 (s, 1H), 3.01 (s, 3H),
2.43 (s, 3H). 19F NMR (376 MHz, Chloroformꢀd) δ ꢀ111.5 – ꢀ
111.6 (m). 13C{1H} NMR (100 MHz, Chloroformꢀd) δ 162.7
(d, J = 249.7 Hz), 144.6, 134.1, 131.1, 130.6 (d, J = 8.3 Hz),
129.5, 129.3, 128.8, 115.7 (d, J = 21.7 Hz), 35.7, 21.6.
(E)-N-(1-chloro-2-phenylvinyl)-N-phenylmethanesulfonamide
(E)-N-(1-chloro-2-(4-chlorophenyl)vinyl)-N-4-
(6d).10 Purified by flash column chromatography (ethyl acetate
dimethylbenzenesulfonamide (6j). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), white solid,
61.7 mg, 87% yield. Mp 108–110°C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.76 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 7.5 Hz,
2H), 7.30 (d, J = 7.6 Hz, 4H), 6.80 (s, 1H), 2.97 (s, 3H), 2.44
(s, 3H). 13C{1H} NMR (100 MHz, ) δ 144.8, 135.7, 134.6,
133.5, 132.3, 129.9, 129.5, 129.0, 128.9, 122.0, 36.7, 21.6.
HRMS (ESIꢀFTꢀICR) calcd. for C16H16Cl2NO2S [M+H]+:
356.0279, found:356.0272.
1
/ hexanes = 1:15), pale yellow liquid , 60.1 mg, 95% yield. H
NMR (400 MHz, Chloroformꢀd) δ 7.83 – 7.41 (m, 4H), 7.46 –
7.07 (m, 6H), 6.84 (s, 1H), 3.13 (s, 3H).13C{1H} NMR (100
MHz, ) δ 138.8, 133.6, 132.6, 129.5, 129.1, 128.7, 128.6,
128.1, 127.6, 124.3, 39.6. HRMS (ESIꢀFTꢀICR) calcd. for
C15H15ClNO2S [M+H]+: 308.0512, found: 308.0506.
(E)-N-allyl-N-(1-chloro-2-phenylvinyl)-4-
methylbenzenesulfonamide (6e).10 Purified by flash column
chromatography (ethyl acetate / hexanes = 1:20), yellow solid,
(E)-N-(1-chloro-2-(4-methoxyphenyl)vinyl)-N-
1
66 mg, 95% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.81
methylmethanesulfonamide (6k). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:15), white solid,
50.6 mg, 92% yield. Mp 125ꢀ127°C 1H NMR (500 MHz,
Chloroformꢀd) δ 7.54 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz,
2H), 6.62 (s, 1H), 3.81 (s, 3H), 3.14 (s, 3H), 3.03 (s,
3H).13C{1H} NMR (125 MHz, ) δ 160.1, 132.0, 130.2, 126.9,
125.4, 114.1, 55.3, 38.0, 35.6. HRMS (ESIꢀFTꢀICR) calcd. for
C11H15ClNO3S [M+H]+: 276.0461, found:276.0453.
(d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 7.50 – 7.18 (m,
5H), 6.74 (s, 1H), 5.72 – 5.71 (m, 1H), 5.24 – 5.23 (m, 1H),
5.12 – 5.10 (m, 1H), 4.28 (s, 1H), 3.64 (s, 1H), 2.44 (s, 3H).
13C{1H} NMR (100 MHz, ) δ 144.5, 134.7, 134.4, 133.2,
130.5, 129.5, 129.0, 128.7, 128.8, 128.5, 127.6, 120.9, 51.5,
21.6. HRMS (ESIꢀFTꢀICR) calcd. for C18H19ClNO2S [M+H]+:
348.0825, found: 348.0817.
(E)-N-(1-chloro-2-phenylvinyl)-N-(2-(cyclohex-1-en-1-
yl)ethyl)-4-methylbenzenesulfonamide (6f). Purified by flash
column chromatography (ethyl acetate / hexanes = 1:25), yelꢀ
(E)-N-(1-chloro-2-(4-nitrophenyl)vinyl)-N-4-
dimethylbenzenesulfonamide (6l). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:15), white solid,
64.4 mg, 88% yield. Mp 154ꢀ157°C. 1H NMR (500 MHz,
1
low oil, 68 mg, 82% yield. H NMR (400 MHz, Chloroformꢀd)
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Chloroformꢀd) δ 8.21 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 7.5 Hz,
7.18 (m, 1H), 6.58 (s, 1H), 1.88 (s, 3H).13C{1H} NMR (100
MHz, Chloroformꢀd) δ 200.2, 154.0, 140.8, 138.9, 129.6,
129.5, 128.8, 128.4, 128.4, 127.7, 30.3.
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4H), 7.33 (d, J = 8.4 Hz, 2H), 3.06 (s, 3H), 2.46 (s, 3H).
13C{1H} NMR (126 MHz, ) δ 147.3, 145.0, 139.6, 133.7,
133.6, 130.1, 129.7, 129.4, 128.7, 123.9, 35.8, 21.6. HRMS
(ESIꢀFTꢀICR) calcd. for C16H16ClN2O4S [M+H]+: 367.0519,
found 367.0512.
A mixture of 4a (73.5 mg, 0.3mmol), phenylboronic acid
(51.2 mg, 4.2 mmol), Pd(OAc)2 (7 mg, 10 mol%) and K2CO3
(82.8 mg, 0.6 mmol) in EtOH/H2O (4/1) (2 mL) was heated at
80 oC for 8 h. After the completion of the reaction, the reaction
mixture was filtered through a pad of celite and removal of the
solvent in vacuum to give the crude product. The resulting
residue was purified by silica gel chromatography to give the
desired products.
(E)-N-(2-(4-acetylphenyl)-1-chlorovinyl)-N-4-
dimethylbenzenesulfonamide (6m). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:10), white solid,
66 mg, 91% yield. Mp 142–143°C. 1H NMR (400 MHz, Chloꢀ
roformꢀd) δ δ 7.93 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.1 Hz,
2H), 7.67 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.68 (s,
1H), 3.03 (s, 3H), 2.59 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR
(100 MHz, ) δ 197.3, 144.7, 137.7, 136.7, 133.9, 132.1, 131.2,
129.6, 128.8, 128.7, 128.6, 35.6, 26.6, 21.6. HRMS (ESIꢀFTꢀ
ICR) calcd. for C18H19ClNO3S [M+H]+: 364.0774, found:
364.0766.
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(Z)-N-(1,2-diphenylvinyl)-N-methylmethanesulfonamide (Z-
8a). Purified by flash column chromatography (ethyl acetate /
hexanes = 1:40), colorless oil, 40.2 mg, 47% yield. 1H NMR
(500 MHz, Chloroformꢀd) δ 7.57 (d, J = 8.8 Hz, 2H), 7.52 (d,
J = 7.2 Hz, 2H), 7.45 – 7.41 (m, 5H), 7.33 (d, J = 7.4 Hz, 1H),
6.83 (s, 1H), 3.12 (s, 3H), 2.50 (s, 3H). 13C{1H} NMR (126
MHz, ) δ 139.6, 137.7, 135.7, 128.9, 128.8, 128.7, 128.7,
128.1, 127.0, 40.0, 37.1. HRMS (ESIꢀFTꢀICR) calcd. for
C16H17NO2S [M+H]+: 288.1058, found: 288.1050.
(E)-N-(1-chloro-2-(thiophen-3-yl)vinyl)-N,4-
dimethylbenzenesulfonamide (6n). Purified by flash column
chromatography (ethyl acetate / hexanes = 1:15), white solid,
58.8 mg, 90% yield. Mp 139ꢀ141°C. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.84 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 4.4 Hz,
1H), 7.34 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 3.5 Hz, 1H), 7.00 (t,
J = 3.9 Hz, 1H), 6.88 (s, 1H), 3.05 (s, 3H), 2.46 (s, 3H).
13C{1H} NMR (126 MHz, ) δ 144.6, 135.9, 134.1, 129.9,
129.5, 129.1, 128.3, 127.0, 126.7, 126.4, 35.5, 21.7. HRMS
(ESIꢀFTꢀICR) calcd. for C14H15ClNO2S2 [M+H]+: 328.0233,
found: 328.0225.
(E)-N-(1,2-diphenylvinyl)-N-methylmethanesulfonamide (E-
8a). Purified by flash column chromatography (ethyl acetate /
hexanes = 1:40), white solid, 37.2 mg, 43% yield. Mp 113ꢀ
115°C 1H NMR (500 MHz, Chloroformꢀd) δ 7.37 (dd, J = 7.1,
2.8 Hz, 2H), 7.32 (dd, J = 5.2, 1.9 Hz, 3H), 7.16 – 7.12 (m,
3H), 7.06 – 6.98 (m, 2H), 6.75 (s, 1H), 3.13 (s, 3H), 2.99 (s,
3H). 13C{1H} NMR (125 MHz, ) δ 140.0, 135.4, 135.2, 129.8,
129.2, 128.8, 128.7, 128.1, 127.5, 127.3, 39.2, 37.1. HRMS
(ESIꢀFTꢀICR) calcd. for C16H18NO2S [M+H]+: 288.1058,
found: 288.1051.
(3S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-
yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl
(E)-6-chloro-6-((N,4-
dimethylphenyl)sulfonamido)hex-5-enoate (6o). Purified by
A mixture of 5c (87 mg, 0.3 mmol), ethynyltrimethylsilane
(41.2 mg, 4.2 mmol), Pd(PPh3)Cl2 (10 mg, 5 mol%), and CuI
(5 mg, 8 mol%re) in Et3N/THF (1/1; 1.5 mL) was stirred at
room temperature for 8 h. After the completion of the reaction,
the reaction mixture was filtered through celite and removal of
the solvent in vacuum gave the crude product. The crude
product was purified by silica gel chromatography (ethyl aceꢀ
tate / hexanes = 1:30) to give the desired product 9a as a paleꢀ
yellow oil (87 mg, 95% yield). Major isomer: 1H NMR (400
MHz, Chloroformꢀd) δ 7.84 (dd, J = 7.6, 2.0 Hz, 2H), 7.42 –
7.27 (m, 3H), 7.05 (s, 1H), 3.12 (s, 3H), 2.94 (s, 3H), 0.26 (s,
9H).13C{1H} NMR (125 MHz, ) δ 140.3, 133.5, 129.5, 129.3,
128.3, 118.4, 104.3, 99.0, 35.7, ꢀ0.4. Minor isomer: 1H NMR
(400 MHz, Chloroformꢀd) δ 7.70 (d, J = 8.1 Hz, 2H), 6.80 (s,
1H), 3.05 (s, 3H), 3.01 (s, 3H), 0.23 (s, 8H).13C{1H} NMR
(126 MHz, ) δ 139.0, 133.6, 129.9, 128.7, 119.9, 101.0, 97.1,
36.4, ꢀ0.3. HRMS (ESIꢀFTꢀICR) calcd. for C15H22NO2SSi
[M+H]+: 308.1141, found: 308.1133.
flash column chromatography (ethyl acetate / hexanes = 1:20),
1
white solid, 114 mg, 82% yield. Mp 88ꢀ89°C. H NMR (500
MHz, Chloroformꢀd δ 7.76 (d, J = 8.2 Hz, 2H), 7.32 (d, J =
8.0 Hz, 2H), 5.79 (t, J = 7.5 Hz, 1H), 5.38 (d, J = 5.1 Hz, 1H),
4.64 (dq, J = 11.9, 7.0, 5.6 Hz, 1H), 2.92 (s, 3H), 2.44 (s, 3H),
2.36 – 2.32 (m, 6H), 2.05 – 1.93 (m, 2H), 1.92 – 1.79 (m, 3H),
1.68 – 1.06 (m, 23H), 1.03 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H),
0.88 (d, J = 2.3 Hz, 3H), 0.87 (d, J = 2.3 Hz, 3H), 0.68 (s,
3H).13C{1H} NMR (126 MHz, ) δ 172.6, 144.3, 139.7, 134.3,
134.0, 129.5, 129.0, 128.5, 122.6, 74.0, 56.7, 56.1, 50.0, 42.3,
39.7, 39.5, 38.1, 37.0, 36.6, 36.2, 35.9, 35.8, 34.1, 31.9, 31.9,
28.6, 28.2, 28.0, 27.8, 24.3, 23.9, 23.8, 22.8, 22.6, 21.6, 21.0,
19.3, 18.7. HRMS (ESIꢀFTꢀICR) calcd. for C41H63ClNO4S
[M+H]+: 700.4166, found: 700.4158.
7. Further transformations of halogenated alkene products
A mixture of 2a (0.2mmol), phenylboronic acid (36.5 mg, 0.3
mmol), Pd(PPh3)2Cl2 (7 mg, 5 mol%) and Cs2CO3 (652 mg, 2
mmol) was added 1,4ꢀdioxane/H2O (4/1, 2 mL) heated at 60
℃ for 8h. After the completion of the reaction, the reaction
mixture extracted with EtOAc, the combined organic layers
dried over Na2SO4 and removal of the solvent by rotary evapoꢀ
ration the resulting residue was purified by chromatography
on silica gel to give the desired products.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/
Copies of NMR spectra (PDF).
4,4-Diphenylbut-3-en-2-one (7a).25 1H NMR (400 MHz, Chloꢀ
roformꢀd) δ 7.50 – 7.36 (m, 3H), 7.39 – 7.27 (m, 5H), 7.23 –
AUTHOR INFORMATION
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The Journal of Organic Chemistry
A.; Bachmann, C.; Marrot, J.; Evano, G.; Thibaudeau, S. J. Org.
Chem. 2015, 80, 3397ꢀ3410.
Corresponding Author
1
2
3
4
5
6
7
8
* Email: bo.xu@dhu.edu.cn；
12.
Zeng, X.; Liu, S.; Shi, Z.; Xu, B. Org. Lett. 2016, 18,
gb.hammond@louisville.edu
4770ꢀ4773.
13.
(a) Okoromoba, O. E.; Hammond, G. B.; Xu, B. Org.
Lett. 2015, 17, 3975ꢀ3977; (b) Okoromoba, O. E.; Han, J.;
Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2014, 136, 14381ꢀ
14384; (c) Okoromoba, O. E.; Li, Z.; Robertson, N.; Mashuta, M.
S.; Couto, U. R.; Tormena, C. F.; Xu, B.; Hammond, G. B. Chem.
Commun. 2016, 52, 13353ꢀ13356.
ACKNOWLEDGMENT
We are grateful to the National Science Foundation
of China for financial support (NSFC-21672035) and
China Recruitment Program of Global Experts for
financial support. G.B.H. is grateful to the National
Institutes of Health (1R01GM121660). X.Z is grateful to
the China Scholarship Council for financial support.
14.
J.ꢀY.; Renault, E. J. Med. Chem. 2009, 52, 4073ꢀ4086.
15. (a) Liang, S.; Ebule, R.; Hammond, G. B.; Xu, B. Org.
Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel,
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Lett. 2017, 19, 4524ꢀ4527; (b) Li, Z.; Ebule, R.; Kostyo, J.;
Hammond, G. B.; Xu, B. Chem. Eur. J. 2017, 23, 12739ꢀ12743.
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(a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.;
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TOC
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EWG
H
X
DMPU/HX
(X = Br, Cl)
DG =
N
R2
R1
DG
6
rt
anti-addition -regioselectivity
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26 examples, up to 95%
R1
DG
X
O
DG = directing
rt
DG
R1
DG =
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R2
group
DMPU/HX
(X = Br, Cl)
H
syn-addition -regioselectivity
25 examples, up to 92%
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