Protocol for Stereoselective Construction of Highly Functionalized Dienyl Sulfonyl Fluoride Warheads

Article abstract of DOI:10.1021/acs.joc.0c01877

A pyrrolidine-mediated Knoevenagel-type reaction for highly stereoselective construction of novel α-halo-1,3-dienylsulfonyl fluorides was achieved in up to 100% Z-selectivity and high yields at room temperature from condensation of the readily available aldehydes and halomethanesulfonyl fluorides. This protocol provided a class of unique α-halo-1,3-dienylsulfonyl fluorides with wide scope and excellent functional group compatibility. The α-halo-1,3-dienylsulfonyl fluorides were used as versatile building blocks in sulfur fluoride exchange click chemistry, Suzuki reaction, and Sonogashira reaction for the assembly of highly functionalized dienyl sulfonyl fluoride derivatives to be applied as covalent warheads for the discovery of new drugs.

Full text of DOI:10.1021/acs.joc.0c01877

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Article
A protocol for stereoselective construction of highly
functionalized dienyl sulfonyl fluoride warheads
Zai-Wei Zhang, Shi-Meng Wang, Wan-Yin Fang, Ravindar Lekkala, and Hua-Li Qin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01877 • Publication Date (Web): 22 Sep 2020
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A protocol for stereoselective construction of highly functionalized
dienyl sulfonyl fluoride warheads
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Zai-Wei Zhanga, Shi-Meng Wangb, Wan-Yin Fanga, Ravindar Lekkalaa, and Hua-Li
Qina, *
a
School of Chemistry, Chemical Engineering and Life Science, Wuhan University
of Technology, 205 Luoshi Road, Wuhan, 430070, China
b School of Life Science, Wuchang University of Technology, Wuhan, 430223, P.R.
China
*E-mail: qinhuali@whut.edu.cn.
TOC:
SO2F
Suzuki
R1
9 examples
49~83% yields
SO2F
X
SO2F
X= Cl, Br, I
Sonogashira
SO2F
R
R
O
THF, r.t., 20 minutes
X
R2
R= aryl, heteroaryl, alkenyl
10 examples
62~87% yields
38 examples
up to grams scales
up to 100% Z-selectivity
first access to highly fuctionalized dienyl sulfonyl fluorides
mild conditions and high yields
SO2N3
NaN3
X
a protocol with great potential for drug discovery
5 examples
88~99% yields
Abstract:
A pyrrolidine-mediated Knoevenagel-type reaction for highly stereoselective
construction of novel α-halo-1,3-dienylsulfonyl fluorides was achieved in up to
100% Z-selectivity and high yields at room temperature from condensation of the
readily available aldehydes and halomethanesulfonyl fluorides. This protocol
provided a class of unique α-halo-1,3-dienylsulfonyl fluorides with wide scope and
excellent functional group compatibility. The α-bromo-1,3-dienylsulfonyl fluorides
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were used as versatile building blocks in SuFEx click chemistry, Suzuki reaction
and Sonogashira reaction for assembly of highly functionalized dienyl sulfonyl
fluoride derivatives to be applied as covalent warheads for discovery of new drugs.
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Introduction
Covalent drugs, exerting pharmacological effects by covalently binding to
biological targets, exhibit several advantages in pharmacodynamics and drug
resistance comparing to their non-covalent counterparts (Figure 1a).1 The alkenes
conjugated with electron-withdrawing groups have played a significant role for
discovery of covalent drugs that undergo irreversible Michael additions with a
unique cysteine residue of a specific protein.2 Meanwhile, sulfonyl fluorides are
among the most prominent electrophiles for addressing the ε-amino group of lysine,
the hydroxyl groups of tyrosine, serine, or threonine residues and they are somewhat
reactive toward cysteine and histidine side chains as well.3 Vinyl sulfonyl fluoride
derivatives, as a representative class of novel scaffolds containing both olefin
“Michael” acceptors and sulfonyl fluorides, have been widely applied in searching
for covalent inhibitors, fluorogenic probes (Figure 1b), and discovery of new drugs.4
In addition, with the development of sulfur fluoride exchange (SuFEx) click
chemistry, sulfonyl fluorides have also garnered immense interest in organic
synthesis, drug discovery, material science and many other fields.5 The exploration
of novel and practical methods for construction of diverse vinyl sulfonyl fluoride
scaffolds is highly desirable and of great significance.
On the other hand, the functionalized 1,3-dienes6 and conjugated polyenes7 are
the core motifs in biologically active molecules and natural products (Figure 1c). As
for an efficient Z-selective diene synthesis, the convenience of starting materials
should also be fully considered along with the aim of gaining a unique
stereoselectivity. The Knoevenagel condensation is a well-established C=C double
bond-forming reaction in organic synthesis.8 A broad range of catalytic systems9
have been exploited for the Knoevenagel condensation reaction. However,
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stereoselectivity control is still difficult to achieve for this synthetic strategy.
Herein, we report a pyrrolidine-mediated Knoevenagel–type condensation reaction
for highly Z-selective C=C double bonds formation, as a novel method for the
synthesis of valuable α-halo-1,3-dienylsulfonyl fluorides, using the inexpensive and
highly abundant starting materials.
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N
O
H
O
O
N
N
MeO
O
H
NMe2
O
N
N
O
NH2
N
N
Cl
NH2
N
N
N
Me2
N
N
(a)
Me
N
N
H
N
Me
HN
N
CN
N
NH
O
NH
O
N
O
HN
Me2
N
N
N
F
N
Cl
O
O
afatinib
ibrutinib
osimertinib
acalabrutinib
neratinib
NH2
N
4-tol
Ph
O
OMe
NH
O
OMe
O
S
O
O
O
O O
S
O
H
O
S
O
H
N
S
R
O
N
O
N
N
Ph
N
N
(b)
F
N
O
H
S
MeN
O
Ph
MeO
OMe
rigosertib
NaO2C
iPr
O
PL-SO2
(Schreiber 2012)
HO
O
N-methyl-Pip-F-hF-VSf
Chagas' disease
(late preclinical)
peptido-VSF
myelodisplastic syndrome
(Phase III)
kinase inhibitors
(Taunton 2012)
Sug.O
O
O
N
O
O
(c)
OH
OH
O
HO
O
OH
MeO
O
CH2OMe
(Sug)2
NH2
HO
O
OH
O
Callystatin A
Inthomycin A
Vitamin D2
Apoptolidin
OH
Figure 1. (a) Representative “Michael acceptor” covalent drugs; (b) Fluorogenic
probes and drug candidates containing sulfonyl fluoride and vinyl sulfone motifs;
(c) Natural products containing dienes and polyenes
There are two major challenges for achieving pyrrolidine-mediated synthesis of
vinyl sulfonyl fluorides. The first challenge is that because the vinyl sulfonyl
fluorides are very reactive “perfect” Michael acceptors, the secondary amine,
pyrrolidine catalyst, may undergo Michael addition to destroy the newly generated
olefin with simultaneous devitalizing catalytic activities.10 The second challenge is
that because the sulfonyl fluoride moieties are sensitive to bases, and the reaction of
amine with sulfonyl fluoride may occur even under very mild conditions to form
sulfonyl amide, which will consume both the amine catalyst and the sulfonyl
fluoride products.11
A
cursory index of the literature indicated the
Knoevenagel-type condensation of sulfonyl fluoride compounds are still
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considerably rare and only one report involving the condensation reaction between
methanedisulfonyl fluoride (MDSF) and 4-(dimethylamino)benzaldehyde in the
presence of Ac2O.12 Accordingly, the relative studies on the Knoevenagel-type
condensation of sulfonyl fluoride-containing molecules with aldehydes have been in
high demand for the construction of highly functionalized dienyl sulfonyl fluorides.
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Results and Discussion
Table 1 Optimization of the reaction conditionsa.
SO2F
pyrrolidine
O
+
Br
SO2F
solvent, r.t.
Br
1a
2a
3aa
Entry
1c
2c
3c
4c
5
pyrrolidine (mol%)
2a (eq.)
Solvent
Acetonitrile
DMF
Conversion/%b
Yield/%b
62
30
30
30
30
30
60
100
60
60
3
3
81
75
63
3
DCM
THF
97
69
3
93
88
3
THF
93
89
6
3
THF
100
100
100
100
95
7
3
THF
88
8
2.0
3.5
THF
82
9
THF
95
aReaction conditions: cinnamaldehyde (1a, 0.5 mmol) and pyrrolidine were dissolved in solvent (0.2
M, 2.5 mL) and the mixture was stirred for 5 minutes before the subsequent addition of 2a. Then the
b
stirring lasted for 20 minutes at room temperature. The yield was determined by HPLC using 1a,
3aa as the external standards respectively (t1a = 2.4 min, λmax, 1a = 284.4 nm; t3aa = 4.1 min, λmax, 3aa
=
322.5 nm; acetonitrile / water = 80 : 20 (v / v)). c1.1 equiv. KF was added as additive and the mixture
was stirred overnight at room temperature.
To test the feasibility of the proposed method, we initially examined
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cinnamaldehyde (1a) and bromomethanesulfonyl fluoride (2a) as the model
substrates for the construction of α-bromo-1,3-dienylsulfonyl fluoride (3aa) (Table
1). Pyrrolidine was found to be the optimal catalyst for this transformation (see
Supporting Information for a more detailed account of optimization conditions).
The investigation of solvent effect revealed that, despite some good results achieved
in MeCN, DMF and DCM, THF was found to be the best choice (Table 1, entries
1-4). The comparable yield of 3aa was also obtained without the addition of KF
(Table 1, entry 4 vs entry 5). Elevating the catalyst loading to 60 mol%, the
conversion of aldehyde 1a and yield of product 3aa was improved obviously (Table
1, entry 6). And further increasing the pyrrolidine amount to 100 mol%, the reaction
efficiency was deteriorated slightly, owing to the aforementioned side reactions
occurring under strong alkaline conditions (Table 1, entry 7). In addition, the use of
an excess amount of bromomethanesulfonyl fluoride (2a) (3.0 equivalents) was
found to be essential, and a significantly decreased yield was observed when 2a was
reduced to 2.0-fold-excess (Table 1, entries 7-9). Therefore, the entry 6 of Table 1
was eventually selected as the optimized conditions for the following preparative
runs.
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With the optimized reaction conditions in hand, we next evaluated the generality
of this Knoevenagel-type condensation employing various aldehydes 1 to react with
bromomethanesulfonyl fluorides (2a) for the formation of dienylsulfonyl fluorides
(Table 2). A wide range of aryl vinyl aldehydes decorated with both
electron-withdrawing and electron-donating groups on aryl rings (1a-1p) were
efficiently converted to the corresponding α-bromo-1,3-dienylsulfonyl fluorides
(3aa-3pa) in 70-96% yields. Furthermore, naphthalene aldehyde, heterocyclic
aldehydes containing oxygen, sulfur, and nitrogen atoms on aryl rings (1q-1u) were
smoothly transformed into the corresponding α-bromo-1,3-dienylsulfonyl fluorides
(3qa-3ua) in 64-88% yields. In addition, dienal (1v) substrate was also successfully
converted into its corresponding product (3va) in 90% yield. Besides, the derivative
of drugs Ozagrel (1w) and Acrivastine (1x) turned out to be suitable substrates,
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resulting in the expected transformation with 74% and 63% yields, respectively.
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Table 2. Condensation of aldehydes with halomethylsulfonyl fluorides (2)a.
9
SO2F
Pyrrolidine (60 mol%)
O
+
R
X
SO2F
R
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X
THF, r.t., 20 minutes
2
1
3
2a,
X = Br
, X = Cl
, X = I
2b
2c
SO2F
SO2F
SO2F
SO2F
SO2F
X
X
X
X
X
, 93% (X = Br)
3cbb
O
F
Cl
3aa,
3abb
3acb
96% (X = Br)*
, 80% (X = Cl)
,75% (X = I)**
3ba
3bbb
, 94% (X = Br)
3ca
3da
3ea
, 82% (X = Br)
, 86% (X = Br)
3dbb
3ecb
, 91% (X = Cl)
, 83% (X = Cl)
3ccb
, 81% (X = Cl)
3dcb
, 71% (X = I)
, 79% (X = I)
, 67% (X = I)
*10 mmol scale, 88%
**10 mmol scale, 62%
O
SO2F
SO2F
SO2F
SO2F
SO2F
X
X
X
, 81% (X = Br)
X
X
O2N
Ph
Br
3ga
3ha
3ia
, 92% (X = Br)
, 65% (X = Br)
3fa
3fcb
, 76% (X = Br)
3ja
, 93% (X = Br)
, 56% (X = I)
O
Br
F3C
SO2F
Cl
SO2F
SO2F
SO2F
SO2F
X
X
X
X
X
3ka
3kbb
3la
3ma
3na
, 84% (X = Br)
, 69% (X = Br)
, 72% (X = Br)
, 80% (X = Br)
3oa
, 84% (X = Br)
3nbb
, 56% (X = Cl)
3kcb
, 89% (X = Cl)
3ncb
, 64% (X = I)
, 77% (X = I)
SO2F
O
SO2F
NO2
N
SO2F
SO2F
S
SO2F
X
X
Cl
X
X
X
3ra
3rbb
, 86% (X = Br)
3ta
, 64% (X = Br)
3qab
, 85% (X = Cl)
3pa
3sa
, 70% (X = Br)
, 80% (X = Br)
, 88% (X = Br)
SO2F
X
SO2F
X
SO2F
SO2F
N
N
N
X
X
N
N
Ts
3vab
, 90% (X = Br)
3wac
, 74% (X = Br)
3uab
, 77 % (X = Br)
3xac
, 63% (X = Br)
a Reaction conditions: aldehyde (1, 1.0 mmol), THF (5.0 mL), pyrrolidine (60 mol%, 50.0 μL),
b
and halomethylsulfonyl fluoride (2, 3.0 mmol) were added in sequence, r.t., 20 minutes. 0.5
mmol scale. c 0.2 mmol scale.
Subsequently, the chloromethanesulfonyl fluoride (2b) was also applied to the
condensation process with aldehydes for preparing α-chloro-1,3-dienylsulfonyl
fluorides. And the experiment results indicated that a series of aldehydes containing
different substituents at ortho, meta or para position of aryl ring worked smoothly
to generate their corresponding α-chloro-1,3-dienylsulfonyl fluorides (3ab-3db, 3kb
and 3nb) in moderate to excellent yields (56% to 91%). O-heterocycle substrate
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(1r) also underwent the condensation smoothly, furnishing its anticipated product
(3rb) in 85% yield.
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To further examine the scope of this protocol, we also explored the reaction of
iodomethanesulfonyl fluoride (2c) with enals. Notably, electron-withdrawing and
electron-donating groups substituted α-iodo-1,3-dienylsulfonyl fluorides (3ac,
3cc-3fc, 3kc, 3nc) were efficiently obtained from the condensation of aldehydes
with iodomethanesulfonyl fluoride (2c) in moderate to good yields (56% to 79%)
under the standard conditions. Nevertheless, the aryl aldehydes were not amenable
for the fabrication of corresponding α-halogen arylethenesulfonyl fluorides when
reacting with halomethylsulfonyl fluorides (2) under the standard conditions
resulted in very low conversions together with generating a mixture of E/Z
configuration of aryl vinyl bromines instead of the desired dienyl sulfonyl fluorides.
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Table 3. Suzuki reaction of the α-bromo-1,3-dienylsulfonyl fluoride (3aa) with
boronic acids
PdCl2(PPh3)2 (5 mol%)
SO2F
OH
OH
SO2F
tri–o–tolylphosphine (10 mol%)
R
B
+
K2CO3 (2 eq.), argon,
toluene, 50 oC, 24 h
Br
R
3aa
4
SO2F
SO2F
SO2F
SO2F
SO2F
O
Et
O
4a
, 83%
Ph
4b
4d
, 65%
, 63%
4c
, 72%
O
SO2F
SO2F
SO2F
SO2F
4e
, 49%
S
Br
4h
4g
, 63%
4i
, 59%
, 68%
4f
, 62%
Reaction conditions: (1Z,3E)-1-bromo-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3aa, 0.5
mmol), phenylboronic acid (1.5 eq.), tri-o-tolylphosphine (10 mol%), PdCl2(PPh3)2 (5 mol%),
K2CO3 (2.0 eq.), toluene (5.0 mL), 50 oC, 24 h, under argon atmosphere.
The previous successful Pd-catalyzed Suzuki coupling of arylboronic acids with
1-bromoethene-1-sulfonyl fluoride (1-Br-ESF)13 drove us to examine similar
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reactions of α-bromo-1,3-dienylsulfonyl fluoride (3aa). Satisfyingly, the expected
Suzuki coupling reaction proceeded smoothly under the catalysis of PdCl2(PPh3)2,
affording a series of novel dienylsulfonyl fluorides (Table 3). Para-substituted
boronic acids were smoothly converted under Suzuki reaction condition to give the
desired products (4a-4g) in moderate to good yields (49% to 83%). 1-Naphthal and
2-naphthal boronic acids also successfully provided the corresponding products (4h
and 4i) in 63% and 59% yields, respectively.
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Table 4. Sonogashira reaction of the α- iodo-1,3-dienylsulfonyl fluoride (3ac)
with alkynes
PdCl2(Cy3P)2 (5 mol%)
CuI (10 mol%)
SO2F
SO2F
+
R
I
Et3N/toluene, under Argon, r.t., 12 h
3ac
5
R
SO2F
SO2F
SO2F
SO2F
SO2F
Br
80%
SO2F
Br
5d,
5a,
74%
SO2F
5e,
5b,
75%
SO2F
78%
5c,
83%
SO2F
SO2F
F
N
S
5f,
5g,
5i,
5j,
87%
62%
75%
81%
5h,
77%
Reaction conditions: (1Z, 3E)-1-iodo-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3ac, 0.5
mmol), alkyne (1.5 eq.), CuI (10 mol%), PdCl2(Cy3P)2 (5 mol%), Et3N (0.5 mL.), toluene (1.5
mL), 50 oC, 12 h, under argon atmosphere.
In addition, α-bromo-1,3-dienylsulfonyl fluoride (3ac) was further tested for
Sonogashira reaction with alkynes to access another class of highly functionalized
vinyl sulfonyl fluorides (Table 4).
A
range of alkynes with both
electron-withdrawing and electron-donating groups on aryl ring were efficiently
converted to the corresponding products (5a-5f) in 62% to 83% yields. Furthermore,
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the alkynes contain N-, and S-heterocycles were smoothly transformed to their
desired products (5g and 5h) in 75% and 77% yields, respectively. Besides, the
cyclic and long chain alkynes were also efficiently provided the corresponding
products (5i and 5j) in 81% and 87% yields, respectively.
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Table
5.
Synthesis
of
α-halo-1,3-dienesulfonyl
azides
from
α-halo-1,3-dienylsulfonyl fluorides
NaN3 (2 eq.)
R
SO2N3
SO2F
R
H2O/Acetone, 35 oC, 12 h
X
X
6
X = Br,Cl
SO2N3
SO2N3
SO2N3
Br
, 97%
Br
Br
, 99%
O
6a
6c
SO2N3
6b
, 88%
SO2N3
Cl
Br
, 99%
6d
6e
, 99%
Reaction conditions: α-halo-1,3-dienylsulfonyl fluoride (0.25 mmol), Sodium azide (2.0 eq.),
acetone (2.0 mL), H2O (0.5 mL), 35 oC, 12 h.
In our final investigation, α-halo-1,3-dienylsulfonyl fluorides efficiently reacted
with sodium azide in H2O/Acetone co-solvent to give the corresponding
α-halo-1,3-dienesulfonyl azides 6 in good to quantitative yields (Table 5). Under
standard reaction conditions, diverse α-bromo-1,3-dienesulfonyl azides containing
substituents at ortho and para-position (6a-6d) were obtained smoothly in 88-99%
yields
from
the
α-bromo-1,3-dienylsulfonyl
fluorids.
Besides,
α-chloro-1,3-dienesulfonyl azide containing methyl substituent at para-position (6e)
was also formed efficiently in quantitative yield.
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O
O
Cs2CO3 (1.0 eq.)
OH
O
SO2F
CH3CN
r.t., 1h
S
+
O
Br
O
Br
7
8
9
1.1 eq
3aa
0.5 mmol
7
, 100%
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Scheme 1. SuFEx reaction of the new dienylsulfonyl fluoride (3aa)
The sulfonyl fluoride (-SO2F) group was regarded as a robust connector in SuFEx
chemistry. The utilization of the new α-bromo-1,3-dienylsulfonyl fluoride (3aa) for
further SuFEx click reaction with phenol (Scheme 1) was also accomplished. With
the aid of Cs2CO3 as a base, SuFEx reaction of 3aa with the 4-methoxyphenol in
acetonitrile at room temperature afforded the desired compound 7 in quantitative
yield. It has to be noticed that the SuFEx reactions of 3aa with amines including
pyrrolidine, piperidine, morpholine for the synthesis of corresponding sulfamide
were unsuccessful due to the various competitive reactions occurring
simultaneously.
N
H
SO2F
60 mol%
O
Br
SO2F
2a
+
(a)
Br
THF, r.t.
3aa
96% yield
1a
1 eq.
3 eq.
N
N
SO2F
SO2F
SO2F
Br
Br
THF
r.t.
8
+
(b)
9
N
H
Br
O
S
1 eq.
N
N
3aa
SO2F
O
Br
Br
10
11
O
O
THF
r.t.
Br
S
(c)
Br
SO2F
2a
1 eq.
+
N
N
H
2 eq.
12
89% yield
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Scheme 2. (a) Desired Knoevenagel-type condensation. (b) Various competitive
reaction of dienylsulfonyl fluoride 3aa with pyrrolidine. (c) SuFEx reaction of
bromomethanesulfonyl fluoride 2a and pyrrolidine
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In theory, the aldehyde, halomethylsulfonyl fluoride and dienylsulfonyl fluoride
in the reaction system were all reactive to the strong nucleophilie pyrrolidine,
resulting in a variety of transformations. Knoevenagel-type condensation
distinguished itself from other competitors and become the leading reaction in our
system. In order to uncover the process of this developed transformation, some
control experiments were carried out in the Scheme 2. The reaction of
cinnamaldehyde 1a with bromomethanesulfonyl fluoride 2a under the standard
condition delivered the dienylsulfonyl fluoride 3aa in nearly quantitative yield
(Scheme 2a). The several reactive sites existing on the dienylsulfonyl fluoride 3aa
led to the reaction with pyrrolidine without regioselectivity and a mixture of
Michael addition and nucleophilic substitution products were formed (Scheme 2b),
which exactly accounted for the failure of SuFEx reaction of dienylsulfonyl
fluorides with amines. Simply stirring the bromomethanesulfonyl fluoride 2a with
pyrrolidine
in
THF
provided
the
SuFEx
product
1-((bromomethyl)sulfonyl)pyrrolidine 12 as a white solid (Scheme 2c). Based on
these control experiment results, we postulated that the aldehyde 1 preferentially
combined with pyrrolidine to form an active intermediate, which participated in the
subsequent condensation with halomethylsulfonyl fluoride 2 to generate the
dienylsulfonyl fluoride 3. After the completion of desired Knoevenagel-type
reaction, the catalyst pyrrolidine remaining in the system was captured by excess of
halomethylsulfonyl fluoride 2 via SuFEx reaction, which obviated aforementioned
side reactions occurring with organocatalyst to stabilize the dienylsulfonyl fluoride
3 (Scheme 3).
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5
6
SO2F
Ph
Br
3aa
Ph
O
N
7
H
1a
8
9
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11
12
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N
N
SO2F
Br
Ph
Ph
OH
H
13
16
Base
-OH
Br
SO2F
2a
Br
SO2F
15
N
Ph
14
Scheme 3. Proposed mechanism
Conclusion
In conclusion,
a
pyrrolidine-mediated Knoevenagel-type stereoselective
construction of novel α-halo-1,3-dienylsulfonyl fluorides was developed. The
transformations of a broad range of abundant, easily accessible, and inexpensive
aldehydes into α-halo-1,3-dienylsulfonyl fluorides were conducted under mild
conditions with up to 100% Z-selectivity. The desired α-halo-1,3-dienylsulfonyl
fluorides were converted to two class of highly functionalized novel dienyl sulfonyl
fluorides using Suzuki reaction and Sonogashira reaction. Further examinations of
these scaffolds in drug discovery and chemical biology are ongoing in our
laboratory.
Experimental section
General Information. All reactions were carried out under air atmosphere, unless
otherwise specified. Oil bath was used for heating the reaction flasks. NMR spectra
1
19
were recorded in CDCl3 on a 500 MHz (for H), 471 MHz (for F), and 126 MHz
13
(for C) spectrometer. All chemical shifts were reported in ppm relative to TMS
(1H NMR, 0 ppm) as internal standards. Melting points of the products were
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measured on a micro melting point apparatus (SGW X-4) and uncorrected. MS
experiments were performed on a TOF-Q ESI or CI/EI instrument. Reagents and
solvents used in the reactions were all purchased from commercial sources and used
without further purification, unless otherwise noticed. The HPLC experiments were
carried out on a Waters e2695 instrument (column: J&K, RP-C18, 5 μm, 4.6 × 150
mm), and the yields of the products were determined by using the corresponding
pure compounds as the external standards. The coupling constants were reported in
Hertz (Hz). The following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
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Procedure for the synthesis of bromomethanesulfonyl fluoride (2a).
Step 1: A mixture of CH2Br2 (343.7 g, 2 mol), Na2SO3 (252.1 g, 2 mol),
tetrabutylammonium hydrogen sulfate (10.0 g, 0.03 mol), and H2O (400 mL) /
EtOH (200 mL) was refluxed for 36 h with vigorous stirring. The solvent was
evaporated under vacuum and the resulting solid residue dissolved in a warm
mixture of H2O (320 mL) and EtOH (1800 mL). After filtration of some insoluble
materials, the filtrate was cooled at -20 °C. The crystalline sodium salt was
collected by filtration: 301.7 g (77% yield).
Step 2: The sulfonate was placed in a 500-ml, three-necked flask equipped with a
stirrer, a glass stopper and a reflux condenser, and cooled with an ice bath.
Phosphorus pentachloride (218.6 g, 1.05 mole) was added cautiously to the
sulfonate (195.9 g, 1 mol) with vigorous stirring. It liquified immediately and the
reddish brown solution was heated at 130 °C for 45 min and then at 70 °C for 30
min. The solution was then poured into 500 mL of ice-water and allowed to stand
for 1 h in order to hydrolyze the phosphorus oxychloride. Bromomethanesulfonyl
chloride was extracted with three 150-mL portions of methylene chloride. The
combined methylene chloride extracts were washed with 200 mL of water, two
200-mL portions of 5% sodium bicarbonate, and finally with 150 mL of water. The
solvent was evaporated to give crude bromomethanesulfonyl chloride which was
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used directly in the next step.
5
6
7
8
Step 3: KHF2 (156.2 g, 2 mol) was added to 400 mL water and a nearly saturated
KHF2 solution formed after 1 h, when the solution approached to room temperature.
At this point, the crude bromomethanesulfonyl chloride generated from previous
step was all added to KHF2 solution. With continued stirring, the mixture was
stirred for 2 h at room temperature. The stationary mixture separates into two
phases. The upper phase is an aqueous solution of salts, and the lower phase is
bromomethanesulfonyl fluoride. Bromomethanesulfonyl fluoride was extracted with
three 100-mL portions of methylene chloride, the combined organic phase was
washed with brine, dried over anhydrous Na2SO4 and concentrated by rotary
evaporator to give crude bromomethanesulfonyl fluoride (slightly yellow liquid).
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o
Further distillation at 100 C under reduced pressure with water-pump helped to
remove the impurities and gave pure bromomethanesulfonyl fluoride as colorless
liquid (105.5 g, 60% yield over two steps).
1
Bromomethanesulfonyl fluoride. (2a). Colorless liquid. H NMR (500 MHz,
CDCl3) δ 4.70 (d, J = 4.4 Hz, 2H) 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 49.7 (m,
1F). 13C{1H} NMR (126 MHz, CDCl3) 36.8 (d, J = 29.1 Hz). HRMS (EI) m/z: [M]+
calcd for CH2BrFO2S 175.8943; found 175.8932.
Procedure for the synthesis of chloromethanesulfonyl fluoride (2b)
Step 1: A mixture of CH2Cl2 (25.4 g, 0.3 mol, 20 mL), Na2SO3 (25.2 g, 0.2 mol),
tetrabutylammonium hydrogen sulfate (1.0 g, 3 mmol), and H2O (100 mL) was
refluxed for 36 h with vigorous stirring. The solvent was evaporated in vacuo and
the resulting solid residue dissolved in a warm mixture of H2O (32 mL) and EtOH
(180 mL). After filtration of some insoluble materials, the filtrate was cooled at
-20 °C. The crystalline sodium salt was collected by filtration: 17.0 g (56% yield).
Step 2: The sulfonate was placed in a 250-ml, three-necked flask equipped with a
stirrer, a glass stopper and a reflux condenser, and cooled with an ice bath.
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Phosphorus pentachloride (1.2 eq., 27.6 g, 133 mmol) was added cautiously to the
sulfonate with vigorous stirring. It liquified immediately and the reddish brown
solution was heated at 130 °C for 45 min and then at 70 °C for 30 min. The solution
was then poured into 100 mL of ice-water and allowed to stand for 1 h in order to
hydrolyze the phosphorus oxychloride. Chloromethanesulfonyl chloride was
extracted with three 50-mL portions of methylene chloride. The combined
methylene chloride extracts were washed with 50 mL of water, two 50-mL portions
of 5% sodium bicarbonate, and finally with 50 mL of water. The solvent was
evaporated to give crude product chloromethanesulfonyl chloride which was used
directly in the next step.
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Step3: The crude chloromethanesulfonyl chloride generated from previous step
was all added to saturated KHF2 solution [KHF2 (15.6 g, 0.2 mol) was added to 40
mL water and a nearly saturated KHF2 solution formed after 1 h].With continued
stirring, the mixture was stirred for 2 h at room temperature. The stationary mixture
separates into two phases. The upper phase is an aqueous solution of salts, and the
lower phase is chloromethanesulfonyl fluoride. Chloromethanesulfonyl fluoride was
extracted with three 50-mL portions of methylene chloride, the combined organic
phase was washed with brine, dried over anhydrous Na2SO4 and concentrated by
rotary evaporator to give crude chloromethanesulfonyl fluoride (slightly yellow
liquid). Further distillation at 85 oC under reduced pressure with water-pump helped
to remove the impurities and gave pure chloromethanesulfonyl fluoride as colorless
liquid (7.1 g, 48% yield over two steps).
Chloromethanesulfonyl fluoride (2b). Colorless liquid. 1H NMR (500 MHz, CDCl3)
δ 4.85 (d, J = 4.9 Hz, 2H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 48.3 (t, J = 5.7
Hz, 1F). 13C{1H} NMR (126 MHz, CDCl3) 53.4 (d, J = 28.2 Hz). HRMS (EI) m/z:
[M]+ calcd for CH2ClFO2S, 131.9448; found 131.9445.
Procedure for the synthesis of iodomethanesulfonyl fluoride (2c)
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Step 1: A mixture of CH2I2 (107.1 g, 0.4 mol), Na2SO3 (50.4 g, 0.4 mol),
tetrabutylammonium hydrogen sulfate (2.0 g, 7.5 mmol), and H2O (400 mL) / EtOH
(200 mL) was refluxed for 36 h with vigorous stirring. The solvent was evaporated
under vacuum and the resulting solid residue dissolved in a mixture of acetic acid
(400 mL) and ethyl acetate (200 mL), and the mixture was heated to 100 °C for 1 h.
The hot mixture was filtered, and another 1,000 mL ethyl acetate was poured into
the filtrate. The sodium salt was collected by filtration: 52.7g (54% yield).
Step 2: The sulfonate was placed in a 500-ml, three-necked flask equipped with a
stirrer, a glass stopper and a reflux condenser, and cooled with an ice bath.
Phosphorus pentachloride (58.5 g, 1.3 eq.) was added cautiously to the sulfonate
with vigorous stirring. It liquified after heating and the reddish brown solution was
heated at 130 °C for 45 min and then at 70 °C for 30 min. The solution was then
poured into 300 mL of ice-water and allowed to stand for 1 h in order to hydrolyze
the phosphorus oxychloride. Iodomethanesulfonyl chloride was extracted with three
75-mL portions of methylene chloride. The combined methylene chloride extracts
were washed with 200 mL of water, two 200-mL portions of 5% sodium
bicarbonate, and finally with 150 mL of water. The solvent was evaporated to give
crude product iodomethanesulfonyl chloride which was used directly in the next
step.
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Step3: The crude iodomethanesulfonyl chloride generated from previous step was
all added to saturated KHF2 solution [KHF2 (31.2 g, 0.4 mol) was added to 80 mL
water and a nearly saturated KHF2 solution formed after 1 h]. With continued
stirring, the mixture was stirred for 2 h at room temperature. The stationary mixture
separates into two phases. The upper phase is an aqueous solution of salts, and the
lower phase is iodomethanesulfonyl fluoride. Iodomethanesulfonyl fluoride was
extracted with three 75-mL portions of methylene chloride. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4 and concentrated by
rotary evaporator to give crude iodomethanesulfonyl fluoride (red-brown liquid).
o
Further distillation at 135 C under reduced pressure with oil-pump gave pure
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iodomethanesulfonyl fluoride as red-brown liquid (35.3 g, 73% yield).
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7
8
1
Iodomethanesulfonyl fluoride (2c). Red-brown liquid. H NMR (500 MHz, CDCl3)
9
19
13
δ 4.69 (d, J = 3.7 Hz, 2H). F{1H, C} NMR (471 MHz, CDCl3) δ 51.4 (m, 1F).
13C{1H} NMR (126 MHz, CDCl3) 3.5 (d, J = 26.3 Hz). HRMS (EI) m/z: [M]+ calcd
for CH2FIO2S, 223.8804; found 223.8809.
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Preparation of Substrates.
1a-1f, 1k, 1n, 1p, 1r were purchased from commercial sources. 1g and 1o were
prepared according to the literature31. 1h and 1l were prepared according to the
literature32. 1i, 1m, 1q and 1s were prepared according to the literature33. 1j was
prepared according to the literature34. 1v was prepared according to the literature35.
1u was prepared according to the literature36.
Preparation of (E)-3-(6-chloropyridin-3-yl)acrylaldehyde (1t). An oven-dried
reaction flask was charged with 6-chloronicotinaldehyde (6 mmol, 2 eq.), 2-
(triphenylphosphoranylidene) acetaldehyde (3 mmol, 1 eq.) and dry toluene (20 mL)
o
under argon atmosphere, and the resulting mixture was stirred at 40 C overnight.
The reaction mixture was cooled to room temperature and the solvent was
concentrated to dryness. The residue was purified through silica gel
chromatography
to
afford
the
desired
product
(E)-3-(6-chloropyridin-3-yl)acrylaldehyde (1t) as white solid (266 mg, 53 % yield).
Preparation of (E)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)acrylaldehyde (1w).
Step 1: To a solution of Ozagrel (500 mg, 2.19 mmol 1 equiv) dissolved in
o
ethanol (10 mL) was added Me3SiCl (5.0 eq.) in portion wise at 50 C under
nitrogen atmosphere. The resulting white turbidity slowly disappeared to form a
yellow transparent solution. The stirring was lasted until the Ozagrel was
completely consumed (monitored by TLC). Then solvent was removed under
reduced pressure to get a white solid which was used directly in the next step.
Step 2: An oven-dried round bottom flask was charged with crude ethyl
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(E)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)acrylate and DCM (10 mL) under
nitrogen atmosphere before cooling to -10oC (ice-methanol bath), then DIBAL (2.0
eq., 4.4 mL, 1.0 M solution in hexane) was slowly added via a syringe. Once the
reaction was complete (monitored by TLC), the solution was concentrated to
dryness and purified through silica gel chromatography using MeOH/DCM (5:95)
as eluent to obtain the target alcohol as white solid. (356mg, 76 % yield, over two
steps).
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Step 3: To a solution of alcohol in DCM (10 mL) at 0 °C was added Dess-Martin
periodinane (1.2 eq., 2 mmol) portion wise over 10 min. The reaction mixture was
stirred at 0 °C for 30 minutes before warmed to room temperature for another 30
minutes. The mixture was concentrated to dryness and purified through silica gel
chromatography
using
MeOH/DCM
(5:95)
as
eluent
to
obtain
(E)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)acrylaldehyde (1w) as light yellow
solid (226mg, 64 % yield).
Preparation of (E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)
pyridine-2-yl)acrylaldehyde (1x).
Step 1: To a solution of Acrivastine (349 mg, 1 mmol 1 equiv) dissolved in
o
ethanol (10 mL) was added Me3SiCl (5.0 eq.) in portion wise at 50 C under
nitrogen atmosphere. The resulting white turbidity slowly disappeared to form a
yellow transparent solution. The stirring was lasted until the Avastin was
completely consumed (monitored by TLC). Then solvent was removed under
reduced pressure to get a white solid which was used directly in the next step.
Step 2: An oven-dried round bottom flask was charged with crude ethyl
(E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)pyridin-2-yl)acrylate and
DCM (10 mL) under nitrogen atmosphere before cooling to -10oC (ice-methanol
bath), then DIBAL (2 equiv, 2 mL, 1.0 M solution in hexane) was slowly added via
a syringe. Once the reaction was complete (monitored by TLC), the solution was
concentrated to dryness and purified through silica gel chromatography using
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MeOH/DCM (5:95) as eluent to obtain the target alcohol as white solid. (291mg,
87 % yield, over two steps).
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Step 3: To a solution of alcohol in DCM (10 mL) at 0 °C was added Dess-Martin
periodinane (1.2 eq., 1.0 mmol) portion wise over 10 min. The reaction mixture was
stirred at 0 °C for 30 minutes before warmed to room temperature for another 30
minutes. The mixture was concentrated to dryness and purified through silica gel
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chromatography
using
MeOH/DCM
(5:95)
as
eluent
to
obtain
(E)-3-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)pyridin-2-yl)acrylaldehy
de (1x) as white solid (170mg, 59 % yield).
General procedures for the synthesis of 3.
To an oven-dried reaction tube was added aldehyde (1, 1.0 mmol, 1.0 eq.),
pyrrolidine (60 mol%, 50 μL) and THF (0.2 M, 5 mL). And the stirring was lasted
for 5 minutes before the subsequent addition of halomethylsulfonyl fluoride (2, 3.0
mmol, 3.0 eq.). Then the resulting mixture was allowed to stir at room temperature
for about 20 minutes, until the aldehyde was completely consumed monitored by
TLC. The mixture was diluted with DCM (10 mL) and concentrated to dryness
under reduced pressure. The residue was purified by column chromatography on
silica gel using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to
obtain the desired products (3aa-3ga, 3ia-3oa, 3qa-3sa and 3va), petroleum ether /
ethyl acetate = 7:1 (v/v) as eluent to obtain the desired products (3ha and 3pa),
MeOH/DCM = 5:95 (v/v) as eluent to obtain the desired product (3ta, 3ua, 3wa and
3xa).
(1Z,3E)-1-bromo-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3aa). White solid,
278 mg, 96% yield. Mp: 76-78 °C. 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 10.6
Hz, 1H), 7.59-7.57 (m, 2H), 7.44-7.43 (m, 3H), 7.26 (d, J = 15.5 Hz, 1H), 7.01 (dd,
J1 = 15.6 Hz, J2 = 10.7 Hz, 1H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.1.
13C{1H} NMR (126 MHz, CDCl3) δ 148.1, 145.3, 134.9, 131.1, 129.3, 128.3, 122.0,
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109.7 (d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd for C10H8BrFO2S, 289.9412;
found 289.9417.
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(1Z,3E)-1-bromo-4-(4-methoxyphenyl)buta-1,3-diene-1-sulfonyl fluoride (3ba).
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Yellow solid, 301 mg, 94% yield. Mp: 93-95 °C. H NMR (500 MHz, CDCl3) δ
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7.89 (d, J = 10.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 15.6 Hz, 1H), 6.94
(d, J = 8.7 Hz, 2H), 6.87 (dd, J1 = 15.5 Hz, J2 = 10.7 Hz, 1H), 3.87 (s, 3H). 19F{1H,
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13C} NMR (471 MHz, CDCl3) δ 53.4. C{1H} NMR (126 MHz, CDCl3) δ 162.2,
148.0, 145.9, 130.2, 127.8, 119.7, 114.8, 107.7 (d, J = 33.6 Hz), 55.6. HRMS (ESI)
m/z: [M + H]+ calcd. for C11H11BrFO3S, 320.9591; found 320.9588.
(1Z,3E)-1-bromo-4-(p-tolyl)buta-1,3-diene-1-sulfonyl fluoride (3ca). Yellow solid,
1
283 mg, 93% yield. Mp: 109-110 °C. H NMR (500 MHz, CDCl3) δ 7.90 (d, J =
10.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.24-7.21 (m, 3H), 6.96 (dd, J1 = 15.6 Hz, J2
= 10.7 Hz, 1H), 2.40 (s, 3H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.2.
13C{1H} NMR (126 MHz, CDCl3) δ 148.2, 145.7(d, J = 2.7 Hz), 141.8, 132.3,
130.0, 128.4, 121.0, 108.8 (d, J = 33.6 Hz), 21.7. HRMS (EI) m/z: [M]+ calcd for
C11H10BrFO2S, 303.9569; found 303.9561.
(1Z,3E)-1-bromo-4-(4-fluorophenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3da).
1
Yellow solid, 265 mg, 86% yield. Mp: 80-82 °C. H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 10.7 Hz, 1H), 7.59-7.55 (m, 2H), 7.22 (d, J = 15.5 Hz 1H), 7.14-7.10
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(m, 2H), 6.92 (dd, J1 = 15.6 Hz, J2 = 10.5 Hz, 1H). F{1H, C} NMR (471 MHz,
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CDCl3) δ 53.1, -107.9 (m, 1F). C{1H} NMR (126 MHz, CDCl3) δ 164.4 (d, J =
253.4 Hz), 146.6, 145.2, 131.2 (d, J = 2.7 Hz) ,130.3 (d, J = 8.2 Hz), 121.7, 116.5
(d, J = 22.7 Hz), 109.7 (d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd. for
C10H7BrF2O2S, 307.9318; found 307.9299.
(1Z,3E)-1-bromo-4-(4-chlorophenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3ea).
1
Yellow solid, 266 mg, 82% yield. Mp: 125-127 °C. H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 10.6 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.20 (d,
J = 15.6 Hz, 1H), 6.97 (dd, J1 = 15.6 Hz, J2 = 10.6 Hz, 1H). 19F{1H, 13C} NMR (471
MHz, CDCl3) δ 53.1. 13C{1H} NMR (126 MHz, CDCl3) δ 146.4, 144.9, 137.0,
133.4, 129.6, 129.4, 122.4, 110.3 (d, J = 33.6 Hz). HRMS (EI) m/z: [M-H]+ calcd.
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for C10H6BrClFO2S, 322.8950; found 322.8970.
(1Z,3E)-1-bromo-4-(4-bromophenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3fa).
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Yellow solid, 280 mg, 76% yield. Mp: 146–148 °C. 1H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 10.5 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.19 (d,
J = 15.6 Hz, 1H), 6.99 (dd, J1 = 15.5 Hz, J2 = 10.5 Hz, 1H). 19F{1H, 13C} NMR (471
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MHz, CDCl3) δ 53.1. C{1H} NMR (126 MHz, CDCl3) δ 146.4, 144.9 (d, J = 1.8
Hz), 133.8, 132.6, 129.6, 125.4, 122.5, 110.5 (d, J = 33.6 Hz). HRMS (EI) m/z:
[M]+ calcd for C10H7Br2FO2S, 367.8518; found 367.8512.
(1Z,3E)-4-([1,1'-biphenyl]-4-yl)-1-bromobut a-1,3-diene-1-sulfonyl fluoride (3ga).
1
Yellow solid, 296 mg, 81% yield. Mp: 150-152 °C. H NMR (500 MHz, CDCl3) δ
7.94 (d, J = 10.5 Hz, 1H), 7.69-7.62 (m, 6H), 7.50-7.47 (m, 2H), 7.42-7.39 (m, 1H),
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7.29 (d, J1 = 15.4 Hz, 1H), 7.04 (dd, J1 = 15.5 Hz, J2 = 10.7 Hz, 1H). F{1H, C}
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NMR (471 MHz, CDCl3) δ 53.2. C{1H} NMR (126 MHz, CDCl3) δ 147.6, 145.4
(d, J = 1.9 Hz), 143.8, 140.0, 133.8, 129.1, 128.9, 128.3, 127.9, 127.2, 121.8, 109.4
(d, J = 32.7 Hz). HRMS (EI) m/z: [M]+ calcd. for C16H12BrFO2S, 365.9725; found
365.9707.
(1Z,3E)-1-bromo-4-(4-nitrophenyl)buta-1,3-diene-1-sulfonyl fluoride (3ha). Brown
solid, 218 mg, 65% yield. Mp: 158-160 °C. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J
= 8.8 Hz, 2H), 7.95 (d, J = 10.5 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 15.5
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Hz, 1H), 7.13 (dd, J1 = 15.7 Hz, J2 = 10.5 Hz, 1H). F{1H, C} NMR (471 MHz,
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CDCl3) δ 52.9. C{1H} NMR (126 MHz, CDCl3) δ 148.8, 144.3, 143.9(d, J = 1.8
Hz), 140.8, 128.8, 125.8, 124.5, 113.2 (d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd
for C10H7BrFNO4S, 334.9263; found 334.9268.
(1Z,3E)-1-bromo-4-(m-tolyl)buta-1,3-diene-1-sulfonyl fluoride(3ia). Yellow solid,
280 mg, 92% yield. Mp: 69-71 °C. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 10.7
Hz, 1H), 7.37 (m, 2H), 7.34-7.30 (m, 1H), 7.26-7.21 (m, 2H), 6.99 (dd, J1 = 15.6
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Hz, J2 = 10.7 Hz, 1H), 2.41 (s, 3H). F{1H, C} NMR (471 MHz, CDCl3) δ 53.1.
13C{1H} NMR (126 MHz, CDCl3) δ 148.4, 145.5 (d, J = 1.8 Hz), 139.0, 134.9,
132.0, 129.2, 128.9, 125.6, 121.7, 109.3 (d, J = 32.7 Hz), 21.4. HRMS (EI) m/z:
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[M]+ calcd. for C11H10BrFO2S, 303.9569; found 303.9551.
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(1Z,3E)-1-bromo-4-(3-methoxyphenyl)buta-1,3-diene-1-sulfonyl fluoride (3ja).
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Yellow solid, 298 mg, 93% yield. Mp: 54-56 °C. H NMR (500 MHz, CDCl3) δ
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7.91 (d, J = 10.6 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 15.5 Hz, 1H) , 7.17
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(d, J = 7.6 Hz, 1H), 7.07 (m, 1H), 7.00-6.95 (m, 2H), 3.86 (s, 3H). F{1H, C}
NMR (471 MHz, CDCl3) δ 53.1. 13C{1H} NMR (126 MHz, CDCl3) δ 160.2, 148.0,
145.3 (d, J = 1.8 Hz), 136.3, 130.3, 122.2, 121.0, 116.7, 113.5, 109.8 (d, J = 33.6
Hz), 55.5. HRMS (EI) m/z: [M]+ calcd for C11H10BrFO3S, 319.9518; found
319.9513.
(1Z,3E)-1-bromo-4-(3-(trifluoromethyl)phenyl)buta-1,3-diene-1-sulfonyl fluoride
1
(3ka). Yellow solid, 247 mg, 69% yield. Mp: 71-73 °C. H NMR (500 MHz,
CDCl3) δ 7.91 (d, J = 10.5 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H) , 7.65 (d,
J = 7.7 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.03 (dd, J1 = 15.5 Hz, J2 =
10.5 Hz, 1H). F{1H, C} NMR (471 MHz, CDCl3) δ 52.9, -62.9. C{1H} NMR
(126 MHz, CDCl3) δ 145.8, 144.5, 135.6, 131.9 (q, J = 32.7 Hz), 131.2, 129.9,
127.3 (q, J = 3.6 Hz), 124.8 (q, J = 3.6 Hz), 123.8 (q, J = 273.4 Hz), 123.6, 111.6
(d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd. for C11H7BrF4O2S, 357.9286; found
357.9267.
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(1Z,3E)-1-bromo-4-(3-chlorophenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3la).
1
Yellow solid, 233 mg, 72% yield. Mp: 65-67 °C. H NMR (500 MHz, CDCl3) δ
7.90 (d, J = 10.5 Hz, 1H), 7.55-7.54 (m, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.41-7.35 (m,
2H), 7.18 (d, J = 15.7 Hz, 1H), 6.99 (dd, J1 = 15.6 Hz, J2 = 10.5 Hz, 1H). F{1H,
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13C} NMR (471 MHz, CDCl3) δ 53.0. C{1H} NMR (126 MHz, CDCl3) δ 146.0,
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144.7 (d, J = 1.8 Hz), 136.7, 135.4, 130.8, 130.5, 127.9, 126.5, 123.2, 111.1 (d, J =
32.7 Hz). HRMS (EI) m/z: [M]+ calcd for C10H7BrClFO2S, 323.9023; found
323.9029.
(1Z,3E)-1-bromo-4-(o-tolyl)buta-1,3-diene-1-sulfonyl fluoride (3ma). Yellow solid,
1
243 mg, 80% yield. Mp: 103-105 °C. H NMR (500 MHz, CDCl3) δ 7.96 (d, J =
10.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 15.4 Hz, 1H) ,7.33 (td, J1 = 7.4
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Hz, J2 = 1.1 Hz, 1H), 7.29-7.23 (m, 2H), 6.95 (dd, J1 = 15.4 Hz, J2 = 10.7 Hz, 1H),
2.44 (s, 3H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.1. 13C{1H} NMR (126
MHz, CDCl3) δ 145.6. 145.6, 137.9, 133.8, 131.2, 130.9, 126.8, 126.5, 122.9, 109.5
(d, J = 32.7 Hz), 19.9. HRMS (EI) m/z: [M]+ calcd for C11H10BrFO2S, 303.9569;
found 303.9561.
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(1Z,3E)-1-bromo-4-(2-methoxyphenyl)buta-1,3-diene-1-sulfonyl fluoride (3na).
1
Yellow solid, 269 mg, 84% yield. Mp: 78-80 °C. H NMR (500 MHz, CDCl3) δ
7.93 (d, J = 10.7 Hz, 1H), 7.63-7.58 (m, 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.07 (dd, J1 =
15.6 Hz, J2 = 10.7 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.92
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(s, 3H). F{1H, C} NMR (471 MHz, CDCl3) δ 53.3. C{1H} NMR (126 MHz,
CDCl3) δ 158.5, 146.5, 143.6, 132.5, 128.6, 123.9, 122.3, 121.1, 111.5, 108.3 (d, J =
32.7 Hz), 55.8. HRMS (EI) m/z: [M]+ calcd. for C11H10BrFO3S, 319.9518; found
319.9498.
(1Z,3E)-1-bromo-4-(2-bromophenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3oa).
1
Yellow solid, 309 mg, 84% yield. Mp: 112-114 °C. H NMR (500 MHz, CDCl3) δ
8.09 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 10.5 Hz, 1H), 7.81-7.70 (m, 3H), 7.60 (t, J =
7.6 Hz 1H), 6.94 (dd, J1 = 15.4 Hz, J2 = 10.5 Hz 1H) 19F{1H, 13C} NMR (471 MHz,
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CDCl3) δ 52.9. C{1H} NMR (126 MHz, CDCl3) δ 148.2, 144.2 (d, J = 2.7 Hz),
142.4, 133.9, 130.9, 130.8, 129.1, 126.4, 125.4, 112.9 (d, J = 33.6 Hz). HRMS (EI)
m/z: [M]+ calcd for C10H7Br2FO2S, 367.8518; found 367.8511.
(1Z,3E)-1-bromo-4-(2-nitrophenyl)buta-1,3-diene-1-sulfonyl fluoride (3pa). Yellow
solid, 234 mg, 70% yield. Mp: 109-111 °C. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J
= 8.3 Hz, 1H), 7.98 (d, J = 10.5 Hz, 1H), 7.81-7.70 (m, 3H), 7.59 (t, J = 7.9 Hz,
1H), 6.94 (dd, J1 = 15.5 Hz, J2 = 10.6 Hz, 1H) 19F{1H, 13C} NMR (471 MHz,
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CDCl3) δ 52.9. C{1H} NMR (126 MHz, CDCl3) δ 148.2, 144.2 (d, J = 2.7 Hz),
142.4, 133.9, 130.9, 130.8, 129.1, 126.4, 125.4, 112.9 (d, J = 33.6 Hz). HRMS (EI)
m/z: [M]+ calcd. for C10H7BrFNO4S, 334.9263; found 334.9245.
(1Z,3E)-1-bromo-4-(naphthalen-2-yl)buta-1,3-diene-1-sulfonyl fluoride (3qa).
1
Yellow solid, 0.5mmol scale, 150 mg, 88% yield. Mp: 129–131 °C. H NMR (500
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MHz, CDCl3) δ 7.97-7.93 (m, 2H), 7.90-7.85 (m, 3H), 7.72 (d, J = 8.5 Hz, 1H),
7.58-7.53 (m, 2H), 7.38 (d, J = 15.4 Hz, 1H), 7.10 (dd, J1 = 15.5 Hz, J2 = 10.6 Hz,
1H) 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.3. 13C{1H} NMR (126 MHz,
CDCl3) δ 148.1, 145.4, 134.6, 133.4, 132.4, 130.5, 129.1, 128.8, 128.0, 127.9,
127.2, 123.4, 122.0, 109.5 (d, J = 32.7 Hz). HRMS (EI) m/z: [M]+ calcd for
C14H10BrFO2S, 339.9569; found 339.9565.
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(1Z,3E)-1-bromo-4-(furan-2-yl)buta-1,3-diene-1-sulfonyl fluoride (3ra). White
solid, 241 mg, 86% yield. Mp: 70–72 °C. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J =
10.8 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 15.3 Hz, 1H), 6.87 (dd, J1 = 15.2
Hz, J2 = 10.8 Hz, 1H), 6.70 (d, J = 3.3 Hz, 1H), 6.53 (dd, J1 = 3.3 Hz, J2 = 1.7 Hz,
1H) 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.3. 13C{1H} NMR (126 MHz,
CDCl3) δ 151.4, 145.9, 144.9 (d, J = 2.7 Hz), 133.2, 119.9, 116.2, 113.1, 109.1 (d, J
= 32.7 Hz). HRMS (EI) m/z: [M]+ calcd. for C8H6BrFO3S, 279.9205; found
279.9186.
(1Z,3E)-1-bromo-4-(thiophen-2-yl)buta-1,3-diene-1-sulfonyl fluoride (3sa). Brown
solid, 237 mg, 80% yield. Mp: 89–91 °C. 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J =
10.6 Hz, 1H), 7.48 (d, J = 5.0 Hz, 1H), 7.36 (d, J = 15.2 Hz, 1H), 7.31 (d, J = 3.5
Hz, 1H), 7.10 (dd, J1 = 4.9 Hz, J2 = 3.7 Hz, 1H), 6.76 (dd, J1 = 15.3 Hz, J2 = 10.7
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Hz, 1H) F{1H, C} NMR (471 MHz, CDCl3) δ 53.4. C{1H} NMR (126 MHz,
CDCl3) δ 145.0 (d, J = 2.7 Hz), 140.4, 140.0, 131.7, 130.0, 128.7, 121.0, 108.7 (d, J
= 33.6 Hz). HRMS (EI) m/z: [M]+ calcd for C8H6BrFO2S2, 295.8977; found
295.8981.
(1Z,3E)-1-bromo-4-(6-chloropyridin-3-yl)buta-1,3-diene-1-sulfonyl fluoride (3ta).
1
White solid, 208 mg, 64% yield. Mp: 149–151 °C. H NMR (500 MHz, CDCl3) δ
8.53 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 10.5 Hz, 1H), 7.88 (dd, J1 = 8.3 Hz, J2 = 2.5
Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 15.7 Hz, 1H), 7.03 (dd, J1 = 15.7 Hz,
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J2 = 10.5 Hz, 1H). F{1H, C} NMR (471 MHz, CDCl3) δ 53.0. C{1H} NMR
(126 MHz, CDCl3) δ 153.3, 149.7, 144.0 (d, J = 2.7 Hz), 142.1, 136.5, 129.7, 125.0,
124.3, 112.2 (d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd. for C9H6BrClFNO2S,
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324.8975; found 324.8951.
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(1Z,3E)-1-bromo-4-(1-tosyl-1H-indol-3-yl)buta-1,3-diene-1-sulfonyl fluoride (3ua).
Yellow solid, 0.5 mmol scale, 186 mg, 77% yield. Mp: 154–156 °C. 1H NMR (500
MHz, CDCl3) δ 8.02 (d, J = 8.1 Hz, 1H), 7.92-7.90 (m, 2H), 7.83 (d, J = 8.4 Hz,
2H), 7.79 (d, J = 7.8 Hz, 1H), 7.44-7.27 (m, 5H), 7.04 (dd, J1 = 15.6 Hz, J2 = 10.7
Hz, 1H), 2.37 (s, 3H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 53.5. 13C{1H} NMR
(126 MHz, CDCl3) δ 146.0, 145.7 (d, J = 1.8 Hz), 138.8, 135.7, 134.7, 130.3, 128.8,
127.8, 127.2, 126.0, 124.6, 122.2, 120.6, 119.0, 114.1, 108.6 (d, J = 32.7 Hz), 21.8.
HRMS (EI) m/z: [M]+ calcd for C19H15BrFNO4S2, 482.9610; found 482.9618.
(1Z,3E,5E)-1-bromo-6-phenylhexa-1,3,5-triene-1-sulfonyl fluoride (3va). Yellow
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solid, 0.5 mmol scale, 142 mg, 90% yield. Mp: 78–80 °C. H NMR (500 MHz,
CDCl3) δ 7.83 (d, J = 10.9 Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.41-7.34 (m, 3H),
7.05 (dd, J1 = 14.1 Hz, J2 = 9.6 Hz, 1H), 7.01-6.92 (m, 2H), 6.56 (dd, J1 = 14.3 Hz,
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J2 = 10.9 Hz, 1H). F{1H, C} NMR (471 MHz, CDCl3) δ 53.4. C{1H} NMR
(126 MHz, CDCl3) δ 148.1, 145.1 (d, J = 1.8 Hz), 141.6, 135.9, 129.7, 129.1, 127.6,
127.3, 125.5, 108.9 (d, J = 33.6 Hz). HRMS (EI) m/z: [M]+ calcd for
C12H10BrFO2S, 315.9569; found 315.9574.
(1Z,3E)-4-(4-((1H-imidazol-1-yl)methyl)phenyl)-1-bromobuta-1,3-diene-1-sulfonyl
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fluoride (3wa). Gum, 0.2 mmol scale, 55 mg, 74% yield. H NMR (500 MHz,
CDCl3) δ 7.90 (d, J = 10.7 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.23 (d, J
= 15.6 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 6.98 (dd, J1 = 15.6 Hz, J2 =
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10.5 Hz, 1H), 6.91 (s, 1H), 5.17 (s, 2H). F{1H, C} NMR (471 MHz, CDCl3) δ
53.1. 13C{1H} NMR (126 MHz, CDCl3) δ 146.8, 145.0 (d, J = 1.8 Hz), 138.9, 137.5,
135.0, 129.5, 128.8, 128.1, 122.5, 119.5, 110.3 (d, J = 32.7 Hz), 50.6. HRMS (EI)
m/z: [M]+ calcd. for C14H12BrFN2O2S, 369.9787; found 369.9764.
(1Z,3E)-1-bromo-4-(6-((E)-3-(pyrrolidin-1-yl)-1-(p-tolyl)prop-1-en-1-yl)pyridin-2-
yl)buta-1,3-diene-1-sulfonyl fluoride (3xa). 0.2 mmol scale, gum, 62 mg, 63%
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yield. H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 10.9 Hz, 1H), 7.63-7.58 (m, 2H),
7.28-7.24 (m, 4H), 7.20 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 8.0
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Hz, 1H), 3.45 (d, J = 7.0 Hz, 2H), 2.83 (m, 4H), 2.41 (s, 3H), 1.91-1.89 (m, 4H).
19F{1H, 13C} NMR (471 MHz, CDCl3) δ 52.8. 13C{1H} NMR (126 MHz, CDCl3) δ
157.8, 152.1, 145.9, 144.4 (d, J = 1.8 Hz), 137.9, 137.4, 134.3, 129.6, 129.6, 126.0,
123.3, 123.2, 112.5 (d, J = 32.7 Hz), 54.2, 53.7, 23.6, 21.4. HRMS (ESI) m/z: [M]+
calcd. for C23H24BrFN2O2S, 490.0726; found 490.0708.
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(1Z,3E)-1-chloro-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3ab). 0.5 mmol scale.
Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to obtain
yellow solid, 98 mg, 80% yield. Mp: 70-72 °C. 1H NMR (500 MHz, CDCl3) δ 7.71
(d, J = 10.7 Hz, 1H), 7.58-7.56 (m, 2H), 7.44-7.42 (m, 3H), 7.20 (d, J = 15.7 Hz,
1H), 7.05 (dd, J1 = 15.8 Hz, J2 = 10.9 Hz, 1H). 19F{1H, 13C} NMR (471 MHz,
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CDCl3) δ 52.6. C{1H} NMR (126 MHz, CDCl3) δ 147.4, 141.6 (d, J = 1.8 Hz),
134.9, 131.0, 129.3, 128.3, 121.1 (d, J = 33.6 Hz), 119.8. HRMS (EI) m/z: [M]+
calcd for C10H8ClFO2S, 245.9918; found 245.9914.
(1Z,3E)-1-chloro-4-(4-methoxyphenyl)buta-1,3-diene-1-sulfonyl fluoride (3bb). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
1
to obtain yellow solid, 126 mg, 91% yield. Mp: 62-64 °C. H NMR (500 MHz,
CDCl3) δ 7.68 (d, J = 10.9 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 15.6 Hz,
1H), 6.95-6.88 (m, 3H), 3.86 (s, 3H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 52.8.
13C{1H} NMR (126 MHz, CDCl3) δ 162.1, 147.3, 142.2 (d, J = 2.7 Hz), 130.1,
127.8, 119.3 (d, J = 32.7 Hz), 117.5, 114.8, 55.6. HRMS (EI) m/z: [M-H]+ calcd. for
C11H9ClFO3S, 274.9950; found 274.9962.
(1Z,3E)-1-chloro-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3cb). 0.5 mmol scale.
Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to obtain
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yellow solid, 108 mg, 83% yield. Mp: 104-106 °C. H NMR (500 MHz, CDCl3) δ
7.69 (d, J = 10.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.17 (d,
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J = 15.6 Hz, 1H), 7.00 (dd, J1 = 15.5 Hz, J2 = 10.7 Hz, 1H), 2.40 (s, 3H). F{1H,
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13C} NMR (471 MHz, CDCl3) δ 52.7. C{1H} NMR (126 MHz, CDCl3) δ 147.5,
141.9 (d, J = 1.8 Hz), 141.7, 132.2, 130.0, 128.3, 120.3 (d, J = 33.6 Hz), 118.8,
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21.7. HRMS (EI) m/z: [M]+ calcd for C11H10ClFO2S, 260.0074; found 260.0079.
(1Z,3E)-1-chloro-4-(4-fluorophenyl)buta-1,3-diene-1-sulfonyl fluoride (3db). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
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to obtain yellow solid, 107 mg, 81% yield. Mp: 80-82 °C. H NMR (500 MHz,
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CDCl3) δ 7.69 (d, J = 10.7 Hz, 1H), 7.57-7.55 (m, 2H), 7.16 (d, J = 15.7 Hz, 1H),
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7.14-7.10 (m, 2H), 6.97 (dd, J1 = 15.6 Hz, J2 = 10.8 Hz, 1H). F{1H, C} NMR
(471 MHz, CDCl3) δ 52.5, -108.1 (m, 1F). 13C{1H} NMR (126 MHz, CDCl3) δ
164.3 (d, J = 253.5 Hz), 145.9, 141.4 (d, J = 1.8 Hz), 131.2 (d, J = 2.7 Hz), 130.2
(d, J = 8.2 Hz), 121.2 (d, J = 31.8 Hz), 119.6 (d, J = 2.7 Hz), 116.5 (d, J = 21.8 Hz).
HRMS (EI) m/z: [M-H]+ calcd. for C10H6ClF2O2S, 262.9751; found 262.9760.
(1Z,3E)-1-chloro-4-(3-(trifluoromethyl)phenyl)buta-1,3-diene-1-sulfonyl fluoride
(3kb). 0.5 mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1
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(v/v) as eluent to obtain yellow solid, 88 mg, 56% yield. Mp: 72-75 °C. H NMR
(500 MHz, CDCl3) δ 7.78 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 10.6 Hz,
1H), 7.67 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 15.7, 1H), 7.11
(dd, J1 = 15.6 Hz, J2 = 10.6 Hz, 1H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 52.4,
-62.9. 13C{1H} NMR (126 MHz, CDCl3) δ 145.1, 140.7 (d, J = 2.7 Hz), 135.7,
131.9 (q, J = 32.7 Hz), 131.1, 129.9, 127.2 (q, J = 3.6 Hz), 124.7 (q, J = 3.6 Hz),
123.8 (q, J = 273.4 Hz), 123.0, 121.5. HRMS (EI) m/z: [M]+ calcd for
C11H7ClF4O2S, 313.9791; found 313.9798.
(1Z,3E)-1-chloro-4-(2-methoxyphenyl)buta-1,3-diene-1-sulfonyl fluoride (3nb). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
1
to obtain yellow solid, 123 mg, 89% yield. Mp: 62-64 °C. H NMR (500 MHz,
CDCl3) δ 7.72 (d, J = 10.9 Hz, 1H), 7.59-7.54 (m, 2H), 7.41-7.38 (m, 1H), 7.11 (dd,
J1 = 15.6 Hz, J2 = 10.8 Hz, 1H). 7.01 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),
3.91 (s, 3H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ 52.7. 13C{1H} NMR (126
MHz, CDCl3) δ 158.5, 142.9, 142.7 (d, J = 2.7 Hz), 132.4, 128.6, 123.9, 121.1,
120.2, 119.9 (d, J = 32.7 Hz), 111.5, 55.7. HRMS (EI) m/z: [M-H]+ calcd. for
C11H9ClFO3S, 274.9950; found 274.9961.
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(1Z,3E)-1-chloro-4-(furan-2-yl)buta-1,3-diene-1-sulfonyl fluoride (3rb). 0.5 mmol
scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to
obtain yellow solid, 100 mg, 85% yield. Mp: 65-67 °C. 1H NMR (500 MHz, CDCl3)
δ 7.66-7.59 (m, 1H), 7.55 (d, J = 1.1 Hz, 1H), 6.95-6.88 (m, 2H), 6.68 (d, J = 3.4
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Hz, 1H), 6.52 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 1H). F{1H, C} NMR (471 MHz,
CDCl3) δ 52.7. C{1H} NMR (126 MHz, CDCl3) δ 151.4, 145.8, 141.2 (d, J = 2.8
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Hz), 132.6, 120.6 (d, J = 33.6 Hz), 117.8, 116.0, 113.0. HRMS (EI) m/z: [M]+ calcd
for C8H6ClFO3S, 235.9710; found 235.9719.
(1Z,3E)-1-iodo-4-phenylbuta-1,3-diene-1-sulfonyl fluoride (3ac). 0.5 mmol scale.
Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to obtain
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yellow solid, 127 mg, 75% yield. Mp: 103-105 °C. H NMR (500 MHz, CDCl3) δ
7.88 (d, J = 10.3 Hz, 1H), 7.59-7.57 (m, 2H), 7.45-7.43 (m, 3H), 7.31 (d, J = 15.4
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Hz, 1H), 6.89 (dd, J1 = 15.5 Hz, J2 = 10.5 Hz, 1H). F{1H, C} NMR (471 MHz,
CDCl3) δ 53.8. C{1H} NMR (126 MHz, CDCl3) δ 151.8 (d, J = 1.9 Hz), 148.7,
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134.9, 131.2, 129.3, 128.4, 125.9, 82.5 (d, J = 30.9 Hz). HRMS (EI) m/z: [M]+
calcd for C10H8FIO2S, 337.9274; found 337.9279.
(1Z,3E)-1-iodo-4-(p-tolyl)buta-1,3-diene-1-sulfonyl fluoride (3cc). 0.5 mmol scale.
Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent to obtain
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yellow solid, 139 mg, 79% yield. Mp: 107-109 °C. H NMR (500 MHz, CDCl3) δ
7.85 (d, J = 10.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 15.4 Hz, 1H), 7.24
(d, J = 8.1 Hz, 2H), 6.84 (dd, J1 = 15.4 Hz, J2 = 10.4 Hz, 1H), 2.40 (s, 3H). 19F{1H,
13C} NMR (471 MHz, CDCl3) δ 53.9. 13C{1H} NMR (126 MHz, CDCl3) δ 152.1 (d,
J = 2.7 Hz), 148.9, 141.9, 132.2, 130.0, 128.4, 124.9, 81.4 (d, J = 30.9 Hz), 21.7.
HRMS (EI) m/z: [M]+ calcd for C11H10FIO2S, 351.9430; found 351.9427.
(1Z,3E)-4-(4-fluorophenyl)-1-iodobuta-1,3-diene-1-sulfonyl fluoride(3dc). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
1
to obtain yellow solid, 119 mg, 67% yield. Mp 84-86 °C. H NMR (500 MHz,
CDCl3) δ 7.86 (d, J = 10.6 Hz, 1H), 7.59-7.56 (m, 2H), 7.27 (d, J = 15.6 Hz, 1H),
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7.14-7.11 (m, 2H), 6.81 (dd, J1 = 15.4 Hz, J2 = 10.4 Hz, 1H). F{1H, C} NMR
(471 MHz, CDCl3) δ 53.8, -107.8 (m, 1F). 13C{1H} NMR (126 MHz, CDCl3) δ
164.4 (d, J = 253.4 Hz), 151.6 (d, J = 1.8 Hz), 147.2, 131.2 (d, J = 3.6 Hz), 130.3
(d, J = 8.2 Hz), 125.6, 116.5 (d, J = 22.7 Hz), 82.6 (dd, J1 = 30.9 Hz, J2 = 1.8 Hz).
HRMS (EI) m/z: [M]+ calcd for C10H7F2IO2S, 355.9179; found 355.9173.
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(1Z,3E)-4-(4-chlorophenyl)-1-iodobuta-1,3-diene-1-sulfonyl fluoride(3ec). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
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to obtain white solid, 132 mg, 71% yield. Mp: 130-132 °C. H NMR (500 MHz,
CDCl3) δ 7.86 (d, J = 10.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.5 Hz,
2H), 7.25 (d, J = 15.4 Hz, 1H), 6.85 (dd, J1 = 15.4 Hz, J2 = 10.4 Hz, 1H). F{1H,
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13C} NMR (471 MHz, CDCl3) δ 53.8. 13C{1H} NMR (126 MHz, CDCl3) δ 151.4 (d,
J = 2.7 Hz), 147.0, 137.1, 133.4, 129.6, 129.5, 126.4, 83.3 (d, J = 30.9 Hz). HRMS
(EI) m/z: [M]+ calcd for C10H7ClFIO2S, 371.8884; found 371.8887.
(1Z,3E)-4-(4-bromophenyl)-1-iodobuta-1,3-diene-1-sulfonyl fluoride(3fc). 0.5
mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1 (v/v) as eluent
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to obtain yellow solid, 116 mg, 56% yield. Mp: 132-134 °C. H NMR (500 MHz,
CDCl3) δ 7.86 (d, J = 10.4 Hz, 1H), 7.56 (dt, J1 = 8.4 Hz, J2 = 2.5 Hz, 2H), 7.43 (dt,
J1 = 8.4 Hz, J2 = 2.3 Hz, 2H), 7.23 (d, J = 15.6 Hz, 1H), 6.87 (dd, J1 = 15.5 Hz, J2 =
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10.5 Hz, 1H). F{1H, C} NMR (471 MHz, CDCl3) δ 53.7. C{1H} NMR (126
MHz, CDCl3) δ 151.4 (d, J = 2.7 Hz), 147.1, 133.8, 132.6, 129.6, 126.5, 125.5, 83.4
(d, J = 30.8 Hz). HRMS (EI) m/z: [M]+ calcd for C10H7BrFIO2S, 415.8379; found
415.8376.
(1Z,3E)-1-iodo-4-(3-(trifluoromethyl)phenyl)buta-1,3-diene-1-sulfonyl
fluoride
(3kc).0.5 mmol scale. Using a mixture of petroleum ether / ethyl acetate = 40:1
(v/v) as eluent to obtain white solid, 130 mg, 64% yield. Mp: 78-80 °C. 1H NMR
(500 MHz, CDCl3) δ 7.89 (d, J = 10.4 Hz, 1H), 7.79 (s, 1H), 7.76 (d, J = 7.9 Hz,
1H), 7.68 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 15.6 Hz, 1H),
6.94 (dd, J1 = 15.4 Hz, J2 = 10.4 Hz, 1H). 19F{1H, 13C} NMR (471 MHz, CDCl3) δ
53.6, -62.9. 13C{1H} NMR (126 MHz, CDCl3) δ 151.0 (d, J = 1.8 Hz), 146.4, 135.6,
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