SO2F2-Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes

Article abstract of DOI:10.1021/jacs.8b10069

Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO₂F₂-promoted dehydration and dehydrogenation process. This straightforward transformation of sp³-sp³ (C-C) bonds to sp-sp (C=C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN₃ to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).

Full text of DOI:10.1021/jacs.8b10069

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Article
SO2F2 Mediated Oxidative Dehydrogenation
and Dehydration of Alcohols to Alkynes
Gao-Feng Zha, Wan-Yin Fang, You-Gui Li, Jing Leng, Xing Chen, and Hua-Li Qin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10069 • Publication Date (Web): 27 Nov 2018
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Journal of the American Chemical Society
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SO2F2 Mediated Oxidative Dehydrogenation and Dehydration of
Alcohols to Alkynes
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Gao-Feng Zha‡†, Wan-Yin Fang‡†, You-Gui Li⊥, Jing Leng‡, Xing Chen‡, Hua-Li Qin‡*
‡
State Key Laboratory of Silicate Materials for Architectures; and School of Chemistry, Chemical Engineering and Life
Sciences, Wuhan University of Technology, 205 Luoshi Road, Wuhan, 430070, P. R. China
⊥ School of Chemistry and Chemical Engineering, Hefei University of Technology, 193 Tunxi Road, Hefei 230009, P. R. China
KEYWORDS: Alkynes, Alcohols, Dehydration, Dehydrogenation, Sulfuryl fluoride
ABSTRACT: Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40
examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation. This straightforward transformation of
sp3-sp3 (C−C) bonds to sp-sp (C−C) bonds requires only inexpensive and readily available reagents (no transition metals) under
mild condition. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations as illustrated by
regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to
92% yield) and Sonogashira couplings (10 examples, up to 77% yield).
silylvinyltriflates derived from cyclic ketones were recently
used to generate strained alkynes when treated with CsF;21
hydrazones derived from ketones were used to synthesize
alkynes by Cu-catalyzed oxidation.22 Alternatively, alcohols
can be transformed to alkynes via a three-step procedure
(Scheme 1c): dehydration to alkene,23 halogenation to vicinal
dihalides24 and subsequent elimination,25 which typically
requires harsh conditions in every single step. Herein, we
1. INTRODUCTION
Alkyne is a privileged motif prevalent in pharmaceuticals,
agrochemicals, natural products, catalyst architectures, ligands,
and materials.1 It has been widely applied as one of the most
versatile building blocks in the fields of organic chemistry,2
fuel science and technology,3 materials science,4 chemical
biology,5 and drug discovery.5b, 6 Alkynes also participate in a
large number of important chemical transformations such as
report
a
SO2F2-promoted direct dehydrative and
the “click” reaction (azide-alkyne 1,3-dipolar cycloaddition
dehydrogenative conversion of alcohols to alkynes under mild
condition without any transition metals (Scheme 1d).
reactions),7 Sonogashira
and Glaser couplings,9 Pauson–
8
Khand carbonylation,10 metathesis,11 cycloaddition and
cyclization reactions for synthesis of aromatic and
heterocyclic compounds,12 aminations,13 and often play key
roles in natural products synthesis.14 Therefore, the
development of novel and practical methods for construction
of alkynes is extremely important. To date, numerous
protocols have been reported such as Corey-Fuchs,15
Wittig/Horner-Emmons,16 and Gilbert-Seyferth reactions17 and
their modifications.18
Scheme 1. Strategies for Transformation of Alcohols to
Alkynes
Previous work 1: alcohols to carbonyl compounds, then to alkynes
(a) Formation a
C
C
triple bond by introducing an addidional carbon:
H
R
H
OH
oxidation
R
H
strong bases
R
H
C
C
R
H
C
O
X
X
X = Br, Cl
C
C
(b) Formation a
triple bond without introducing an addidional carbon:
With the aim of developing powerful, sustainable, and cost-
effective methods for synthesis of alkynes, we became
interested in the potential use of alcohols, inexpensive and
abundant industrial chemicals, some of which can be obtained
from renewable resources (biomass).19 Traditionally, alcohols
have to be oxidized to aldehydes or ketones before subsequent
conversion to alkynes (Scheme 1a, b, c, d). The alkynes
synthe- sized by Corey-Fuchs reaction and modifications
Y
H
H
H
H
C
steps
oxidation
strong bases
H
H
X
C
O
R
R
R
R
OH
X = OTf, OMs, Br, Cl, H
Y= H, OTf, OMs, Br, Cl
(c) Previous work 2: alcohols to alkenes, then to alkynes
X
H
H
R1
R1
R1
halogenation
dehydration
elimination
strong base
OH
R1
R
R
R
R
harsh conditions
H
X
X= Cl, Br
18
thereof15, add an additional carbon to the skeleton of the
(d) This work: direct dehydration and dehydrogenation of alcohols to alkynes in one operation
direct dehydration
original carbon yl compounds (Scheme 1a). On the other hand,
acetylenes obtained by elimination from vinyl sulfonates and
halides promoted by strong bases maintain the same number
of carbons (Scheme 1b).20 Besides the above methods, 2-
R1
H
R = aryl, hetero
akenyl, alkynyl
R1 = H, alkyl,aryl
and dehydrogenation
transition metal free
DMSO,mild conditions
H
OH
R1
+
SO2F2
R
R
H
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Scheme 2. Proposed Direct Conversion of Alcohols to Table 1 Assessment of the Feasibility of Transformation of
1
2
3
4
5
6
7
8
Alkynes Mediated by SO2F2
Alcohol 1a to Alkyne 3a and Optimization of Reaction
conditionsa
O
O
Cl
VS
OSO2F
+
F
S
F
OH
Cl
Base I / DMSO / SO2F2, r.t. 2 h
O
O
then Base II, 80 o
C
Ph
Ph
Ph
3a
SO2F2
DMSO
2a
1a
H
H
SO2F2
DMSO
H
R1
H
H
OSO2F
O
DMSO
base
OH
R1
R
R
R
Base I
Conversion Yield
Yield
R
base
base
Base II
(equiv.)
H
R1
R1
Entry
(equiv.)
(1a, %)b (2a, %)b (3a, %)b
9
Developing efficient and practical methods using greener,
Et3N
(2.0)
1c
2
/
98
96
41
0
56
0
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cheaper, and more-readily available substrates without
unnecessary steps, or energy waste has been a major target in
modern sustainable chemistry.26 Besides the cheap and
abundance of alcohols, SO2F2 is also an inexpensive (about
1$/kg),27a relatively inert starting material (stable up to 400 ºC
when dry) which has recently attracted significant attention as
a reactive electrophile.27 We envisioned (Scheme 2) that SO2F2
would perform the role of an electrophilic activator similar to
oxalyl chloride under basic conditions, leading to oxidation of
the alcohols to aldehydes or ketones by DMSO (Swern
oxidation).28 Under the same basic conditions, the carbonyl
intermediates would further react with SO2F2 to generate vinyl
fluorosulfates, which will subsequently undergo fluorosulfonic
ester elimination to give alkynes.20, 21
Et3N
(5.0)
/
/
100
100
K2CO3
(1.5)
3c
>99
K2CO3
(5.0)
4
5
6
/
/
100
85
1
73
59
49
KF (5.0)
20
30
K2CO3 Bu4NF.3H2O
(1.5)
100
(3.0)
K2CO3
(1.5)
7
8
KF (3.0)
100
100
100
100
35
0
59
84
2. RESULTS AND DISCUSSION
K2CO3
(1.5)
CsF (3.0)
CsF (3.0)
CsF (3.0)
To achieve the direct transformation of alcohols to alkynes
(Scheme 2), several challenges need to be addressed. First,
SO2F2 have to be sufficiently reactive to activate DMSO for
alcohol oxidation. However, Swern-type of oxidations
typically require low temperatures (-78 ºC) to avoid
deleterious Pummerer rearrangement and generation of highly
reactive H2C=S(+)-CH3 that consumes the starting alcohols in
a non-productive manner.29 Such low reaction temperatures
will significantly decrease the reactivity of SO2F2. Second, a
strong base is generally required to generate the corresponding
enolate from the carbonyl group in situ for further reaction
with SO2F2. This may be accompanied by undesirable side
reactions. Third, DMSO is the ideal solvent for this reaction as
it also serves as the oxidant in the first step. Therefore, all
steps must proceed well in DMSO so that no intermediates
need to be isolated and purified. However, DMSO has rarely
been successfully used as the solvent for Swern-type of
oxidations, because solvents of low polarity (for example,
CH2Cl2) are essential to minimize the formation of
methylthioalkyl ethers.28, 29
K2CO3
(1.5)
9d
0
90
K2CO3
(1.5)
10d, e
0
95(88)
aReaction conditions: 2-(4-Biphenyl)ethanol (1a, 0.2 mmol), base
I, DMSO (1.5 mL) and SO2F2 balloon, r.t., 2 h.; then 80 oC, 12 h.
Base II was added just before the heating commenced, when
applicable. bThe yields and conversion were determined by HPLC
using 1a, 2a, or 3a as external standards (t1a = 4.0 min, λmax = 252
nm; t2a = 9.6, 10.6 min, λmax = 278, 276 nm; t3a = 7.6 min, λmax
=
270 nm, respectively). cThe reaction was quenched before heating.
dBefore base II was added, the reaction mixture was degassed
under vacuum to remove the remaining SO2F2. eReaction was
operated at 100 oC for 2 h.
ention to inorganic bases, which have rarely been employed in
Swern-type oxidation but have advantages over organic bases
such as low total organic carbon (TOC) in the waste, and easy
work-up and purification. Excitingly, when K2CO3 (1.5 equiv.)
was used, 1a again cleanly converted to 2a in quantitative
yield at room temperature (Table 1, entry 3). When the loading
of K2CO3 was increased to 5.0 equivalent and the reaction
temperature was raised to 80 ºC, after a period of 12 h, we
were pleased to find that the main product was the desired
alkyne 3a (73% yield; Table 1, entry 4). KF (5.0 eq.) was less
effective (Table 1, entry 5). Our subsequent investigations
focused on using two bases to maximize the formation of
acetylene product while using K2CO3 for vinyl sulfofluoridate
generation. With both Bu4NF.3H2O and KF (3.0 eq.), a
mixture of vinyl sulfurofluoridate 2a and alkyne 3a resulted
The feasibility of the proposed reaction sequence was
assessed using 2-(4-biphenyl)ethanol 1a as a representative
substrate (Table 1; see SI for more detailed account on
conditions optimization). To our delight, 98% of 1a was
consumed under SO2F2 atmosphere at room temperature when
Et3N (2 equiv.), the most commonly used base for Swern type
of oxidation was employed. The proposed β-stiryl
sulfurofluoridate (2a) was formed in nearly quantitative yield
(96% Table 1, entry 1). When the reaction was performed at
80 ºC with 5 equiv. of Et3N, a mixture of 2a (41% yield) and
the proposed final product 4-ethinylbiphenyl (3a; 56% yield)
resulted (Table 1, entry 2). Encouraged by these initial results,
we turned our att-
o
after heating at 80 C for 12 h (Table 1, entries 6 and 7).
Gratifyingly, CsF gave alkyne 3a in 84% yield with complete
2
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consumption of 2a (Table 1, entry 8). When the reaction oxidative process well to provide their product 3k, 3m and 3n
1
2
3
4
5
6
7
8
mixture was degassed to remove excess of SO2F2 before
adding CsF, the yield of 3a was improved to 90%, indicating
that the remaining SO2F2 hampers the conversion of 2a to 3a
(Table 1, entry 9). Finally, elevating the reaction temperature
in 58%, 49% and 60% yield, respectively. The corresponding
1-naphthyl (1s) and 2-naphthyl (1t) analogues were also
smoothly transformed into alkynes 3s and 3t in 83% and 60%
yields, respectively. This method was also applicable to
alcohols possessing heteroarenes to generate products 3ac,
3ad and 3ae in 85%, 89% and 49% isolated yield, respectively.
Finally, substrate possessing two ethanol groups gave the bis-
acetylene 3n in 40% yield.
o
to 100 C increased the efficiency of the alkyne formation to
provide 3a in 95% HPLC yield and 88% isolated yield (Table
1, entry 10), this being the optimal set of conditions for the
preparative runs described hereafter.
9
Table 2 Scope of Dehydration and Dehydrogenation of 2-
Arylethanols to Arylalkynes
Scheme 3 Direct Dehydrative Dehydrogenation of Homo-
propargyl and Homoallylic Primary Alcohols to Alkynes
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60
K2CO3 (1.5 eq.)
DMSO / SO2F2 (balloon), r. t, 2 h
OH
K2CO3 (1.5 eq.)
OH
DMSO / SO2F2 (balloon), r.t., 2 h
Ar
Ar
then CsF, 100 oC, 2 h
then CsF, 100 oC, 2 h
3a
4a
1
5a
, 67%
OH
K2CO3 (1.5 eq.)
DMSO / SO2F2 (balloon), r.t., 2 h
Ph
PhO
BnO
O
then CsF, 100 oC, 2 h
3a
3b
3g
3c,
3d
3e
, 88%
, 92%
73%
, 95%
, 80%
5b
, 71%
4b
Homopropargyl (4a) and homoallylic (4b) alcohols also
gave the conjugated alkynes 5a and 5b in 67% and 71% yields,
respectively (Scheme 3).
Cl
Br
I
NC
3f
3h
3i
, 63%
3j
, 68%
, 79%
, 72%
, 74%
Table 3 Direct Dehydrative Dehydrogenation of Aliphatic
Alcohols to Alkynes
S
AcHN
OBn
3o
b
3n
, 60%
40%c
3k
3l, 78%
3m, 44%
, 58%
1) K2CO3 (1.5 eq.)
DMSO / SO2F2 (balloon), r.t., 12 h
, 78%
49%b
OH
R
R
Cl
2) DBU (6.0 eq.), SO2F2, r.t., 12 h;
then CsF (5.0 eq.), 100 oC, 12 h
7a, b
6
Cl
d
3p
3r
3s
3t
, 60%
, 66%
, 84%
, 83%
3q
, 35%
O
Cl
Ph
O
O
O
BnO
BnO
7a
, 76%
7b
7c
, 56%
, 72%
O
Cl
3u
3v
3w
3x
3y
, 75%
, 69%
, 60%
, 50%
, 66%
O
Cl
Cl
O
7d
7e
, 61%
, 47%
O
N
O
aReaction conditions: the alcohol (6, 1.0 mmol), K2CO3 (208 mg,
1.5 mmol), DMSO (7.5 mL) and SO2F2 balloon, r.t., 12 h; then
DBU (914 mg, 6.0 mmol), r.t., 12 h.; Next, CsF (760 mg, 5 mmol)
100 C, 12 h. The yields were based on the amounts of isolated
products.
O
O
S
3z
3aa
3ab
3ac
3ad,
3ae
, 49%
, 74%
, 69%
, 85%
, 85%
89%
aReaction conditions: 2-arylethanol (1, 2.0 mmol), K2CO3 (415
o
b
mg, 3.0 mmol), DMSO (15 mL) and SO2F2 balloon, r.t., 2 h; then
o
CsF (914 mg, 6.0 mmol), 100 C, 2 h. The yields were based on
b
the amounts of isolated products. Et3N (405 mg, 4.0 mmol) was
We subsequently examined direct conversion of aliphatic
alcohols 6 to the corresponding alkynes 7. After extensive
screening (see SI for details), we were pleased to find that
vinyl sulfurofluoridates were generated from the aldehydes
derived from alcohols 6a-e through DMSO-promoted
oxidation by the use of a second base, DBU. The vinyl
sulfurofluoridates were subsequently transformed to alkynes
7a-e through β-elimination promoted by CsF (Table 3; 56-
76% yields). Notably the original triple bond functionality of
6d tolerated well during the process of transforming to 7d.
used as the base in the first step and DBU (1.22 g, 8 mmol) was
used instead of CsF during the elimination process. 2,2'-(1,4-
c
phenylene)bis(ethan-1-ol) was served as the starting material and
K2CO3 (830 mg, 6.0 mmol) and CsF (1.83 g, 12.0 mol) were used.
dIsolated yield was 35%, HPLC yield was 85% (due to the volatile
properties of some low-boiling-point alkynes, their HPLC yields
were typically much higher than the isolated yield).
As illustrated in Table 2, a variety of structurally and
electronically diverse homobenzylic primary alcohols (2-
arylethanols; 1) were successfully transformed to their
corresponding phenylacetylenes (3) in moderate to excellent
yields (35%-95%) under the optimized conditions. Both
electron-donating and electron-withdrawing aryl substituents
were well tolerated. It is worth noting that the thioether moiety
in 1k, vinyl moiety in 1m and acetenyl moiety in 1n which are
fragile to many oxidation conditions, are tolerable the
Next, we extended the SO2F2 mediated direct
dehydration/dehydrogenation process to secondary alcohols.
As illustrated in Table 4, secondary alcohols with adjacent
methyl 8a, or phenyl 8b, groups were successfully converted
to the corresponding disubstituted acetylenes 9a and 9b
employing
meth-
3
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Table 4 Direct Dehydrative Dehydrogenation of Secondary Alcohols to Disubstituted alkynes
1
2
3
4
R2
OH
SO2F2 (balloon)/ DMSO
R2
R1
Conditions
R1
8
9a
5
6
7
8
Yieldb
(%)
Entry
Substrate
Method
Product
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
41
35
1
8a
8b
A
9a
9b
OH
Ph
Ph
OH
2
3
4
A
B
B
O
OH
O
N
51
39
45
8c
8d
8e
9c
9d
9e
N
O
O
OH
N
N
O
O
O
OH
O
N
N
5
B
Cl
Cl
O
OH
O
H3C
N
51
52
54
6
7
8
8f
8g
8h
B
B
B
9f
9g
9h
H3C
N
O
OH
O
N
N
O
OH
O
N
N
O
OH
O
N
Ph
50
9
8i
B
9i
N
Ph
Ph
Ph
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aReaction conditions: alcohol (8, 1.0 mmol), K2CO3 (208 mg, 1.5 mmol), DMSO (7.5 mL) and SO2F2 balloon, r.t., 2 h; then CsF
(456 mg, 3.0 mmol), 100 oC, 2 h. (Method A); alcohol (8, 1.0 mmol), DBU (761 mg, 5 mmol), DMSO (7.5 mL) and SO2F2 balloon,
r.t., 5 h. (Method B). bThe yields were based on the amounts of isolated products.
1
2
3
4
5
6
7
8
9
od A (Table 4, entries 1 and 2), albeit in lower yields (41%
and 35% yield, respectively). On the other hand, DBU alone
(5.0 eq.) was sufficiently effective to promote the oxidation,
enolization and elimination for alcohols 8c-8i carrying a β-
substituted acylamino groups, furnishing the corresponding
alkynes 9c-9i in moderate yields, due to the competing
formation of the analogous E-alkenes generated by strong
base-promoted dehydration of the starting alcohols in the
presence of SO2F2.30
well tolerated (10g, 85%; 10h, 78%). Triazoles from 2-
heteroaryl ethanol and 2-(1-napthyl)ethanol were also isolated
in high yields (10k-n, 63-81%). Finally, the homopropargyl
alcohol 4a and homoallylic alcohol 4b were also transformed
into 1,2,3-triazole 10p and 10o in 79% and 53% yields,
respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
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34
35
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40
41
42
43
44
45
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48
49
50
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Table 6 Direct Transformation of 2-Arylethanols to
Diarylalkynes by One-pot Dehydrogenation/Dehydration
and Sonogashira Couplinga
Table 5 Direct, Regioselective Transformation of 2-
Substituted Ethanols to 1,4-Diaryl-1,2,3-triazoles by One-
pot Dehydration/Dehydrogenation and Huisgen alkyne-
azide cycloaddition reactionsa
1. K2CO3 (1.5 eq.), DMSO, SO2F2 (balloon), r. t., 2 h
then CsF (3.0 eq.), 100 oC, 2 h
OH
R
R
2. PhI (1.1 eq), Pd(PPh3)2Cl2 (5 mol%)
CuI (10 mo%), Et3N, Ar, r.t., 12 h
1
11a
ONE-POT
R
1. K2CO3 (1.5 eq.), DMSO, SO2F2 (balloon), r.t., 2 h
then CsF (3.0 eq.), 100 oC, 2 h
OH
N
N
2. PhN3 (1.0 eq.), CuSO4.5H2O (10 mol%),
Na ascorbate (10 mol%), PPh3 (10 mol%),
DMSO-H2O (1:1) r.t. 12 h
R
N
BnO
Br
MeO
Ph
NC
1
11a, 58%
11b, 59%
11e, 65%
11d, 63%
11c, 71%
10
ONE-POT
R2
MeO
O
O
O
O
R1
Cl
O
O
Cl
O
OMe
OBn
11f, 69%
N
11g, 68%
11h, 66%
11i, 51%
11j, 77%
N
N
N
N
N
N
, R1 = H, 85%
, R1 = PhO, 77%
, R1 = OBn, 66%
, R = Ph, 75%
, R = Me, 77%
N
N
N
10a
10b
10c
10d
10e
N
N
aReaction conditions: 2-arylethanol (1, 1.0 mmol), K2CO3 (207
N
N
N
mg, 1.5 mmol), DMSO (8.0 mL) and SO2F2 balloon, r.t., 2 h; then
,
R2 = OBn, 86%
, R2 = Cl, 85%
10f
10h
10i
10j
, 78%
, 92%
N
, 60%
o
10g
CsF (456 mg, 3.0 mmol), 100 C, 2 h; [Pd(PPh3)Cl2] (35 mg, 5
N
Ph
N
O
O
mol%), CuI (19 mg, 10 mol%), iodobenzene (248 mg, 1.1 mmol),
and Et3N (2.0 mL), r.t.,12 h. The yields were based on the amount
of isolated products.
N
N
O
N
S
Ph
N
N
N
5
N
N
N
N
Ph
N
Ph
N
N
N
Ph
Ph
, 81%
N
10k
10l
10m
10n
10o
10p
, 79%
, 74%
, 63%
, 64%
, 53%
Another powerful and useful synthetic method using
terminal alkynes is the Sonogashira reaction.8 For further
demonstrating the usefulness of our method, a one-pot
Sonogashira couplings following the protocol developed by
aReaction conditions: 2-arylethanol (1, 1.0 mmol), K2CO3 (207
mg, 1.5 mmol), DMSO (8.0 mL) and SO2F2 balloon, r.t., 2 h; then
CsF (456 mg, 3.0 mmol), 100 oC, 2 h; Next, H2O (8.0 mL),
sodium ascorbate (20 mg, 10 mol%), CuSO4·5H2O (25 mg, 10
mol%), PPh3 (26 mg, 10 mol%) and PhN3 (119 mg, 1.0 mmol), r.t.,
12 h. The yields were based on the amount of isolated products.
32
Krause et al. using the crude alkynes obtained by direct
dehydrogenation/dehydration of alcohols was successfully
integrated into a one-pot procedure (Table 6). 2-Arylethanols
possessing both electron-donating (OBn, OMe, Ph) and
electron-withdrawing groups (Br, CN) afforded the
unsymmetrical diarylalkynes 11a-i in 51%-71% yields upon
coupling with iodobenzene. Notably, Br (11d) and Cl (11g)
substituents were tolerated well. 2-(1- naph- thyl)ethanol 1o
also afforded the Sonogashira coupling product 11j in 77%
yield.
The direct dehydration and dehydrogenation method
employs only inorganic reagents thus producing alkyne
solutions in DMSO of high purity. Hence, further
transformations using the crude alkynes resulting in highly
efficient, step-economical one-pot become feasible.
Regioselective, Cu-catalyzed azide-alkyne 1,3-dipolar
cycloaddition reaction to 1,4-disubstituted 1,2,3-triazoles7 (the
'Huisgen alkyne-azide cycloaddition reaction') is one of the
most powerful and useful alkyne transformations in various
research fields. After a considerable number of reported
Huisgen alkyne-azide cycloaddition reaction conditions7 were
evaluated, the procedure reported by Feringa,31 employing
CuSO4·5H2O and PPh3 as ligand provided 1,4-diaryl-1,2,3-
triazoles in moderate to excellent yields (53%-92%; Table 5)
directly from primary homobenzylic alcohols without tedious
isolation of any intermediates. Generally, homobenzylic
primary alcohols carrying electron-rich substituents (OPh,
OBn, Ph, Me) gave high yields (10a-e, 10f, 10i-k; 60-92%).
Electron-withdrawing substituents on para positions generally
led to lower yields, similarly to the trend observed in alkyne
synthesis (Table 2). However, a m- or p-chloro substituent was
To demonstrate the utility of our developed SO2F2 mediated
direct dehydration/dehydrogenation process in natural
products, biologically active molecules and drugs synthesis,
some extended work has been conducted. Excitingly, the
synthesis of drug Erlotinib (a tyrosine kinase inhibitor) from
alcohol 12 in 1.0 mmol scale was accomplished through a
two-step sequence of
a nucleophilic addition and an
oxidatively dehydrative dehydrogenation process in 52%
overall yield. Furthermore, the synthesis of carbonic
anhydrases (CAs) inhibitor, the 1,4-substituted triazole 17 was
also achieved33 by using the developed “one-pot” process of
oxidation,
enolization,
elimination
and
1,3-dipolar
cycloaddition in 57% yield.
5
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Journal of the American Chemical Society
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followed by removing SO2F2, adding of 1a and K2CO3, all the
cases resulted in very low yield of enolate 2a (Scheme 6c-6f).
1
Scheme 4 Applications of the developed method for the
synthesis complicated biologically active molecules
2
3
4
These
Scheme 6 Mechanism Studies of the Oxidative Enolating
Process.
Cl
5
6
7
Pyridine, i-PrOH
HN
OH
O
O
(a)
O
O
N
+
K2CO3 (1.5 eq.), SO2F2,
18OH
O
O
16O
N2, reflux, 4 h
H2
N
OH
O
O
N
(a)
SO2F
Ph
Ph
N
16O
DMS
, r.t., 2 h
N
2af
16O > 99%, 18O < 1%
OSO2F
12
13
14, 96%
1af
8
9
OH
K2CO3 (2.0 eq.), DMSO,
SO2F2 (balloon), r.t. 3 h
K2CO3
rt. 2 h
(b)
HN
N
SO2F2
DMSO
+
+
O
then CsF (3.0 eq.), 100 oC, 2 h
Ph
O
N
Ph
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
1 mmol scale
O
2a
1a
, 0.2 mmol
O
> 99% HPLC yield
15 (Erlotinib), 54%
rt. 2 h
(c)
(d)
SO2F2
SO2F2
DMSO
DMSO
2a
+
+
+
+
1a
O
S
<1%
1. K2CO3 (1.5 eq.), DMSO, SO2F2 (balloon), r.t. 2 h
then CsF (3.0 eq.), 100 oC, 2 h
2. R-N3 (1.0 eq), CuSO4.5H2O (10 mol%),
Na ascorbate (10 mol%), PPh3 (10 mol%),
DMSO-H2O (1:1) r.t. 12 h
Ph
NH2
OH
(b)
O
N
R =
Ph
1) rt. 2 h
N
N
R
1a
2a
2) degass,
16
1 mmol scale
17, 57%
<5%
K2CO3, rt. 2 h
ONE-POT
1) K2CO3, 2 h
2) degass,
2a
(e)
(f)
SO2F2
SO2F2
DMSO
DMSO
+
+
As illustrated in Scheme 5, a plausible mechanism involves
<5%
1a
, 2 h
the initial base-promoted formation of a fluorosulfate ester A
of the corresponding alcohol and SO2F2. Subsequent SN2-
displacement by DMSO acting as the nucleophile generates
cationic intermediate C.34 The fate of C, being identical to the
key intermediate in Swern-type oxidations, follows the
latterpathway giving the sulfur ylide D upon deprotonation
with the base. D undergoes intramolecular deprotonation-
elimination of Me2S to provide the aldehyde (ketone) E. From
E, the corresponding vinyl sulfurofluoridate 2 is successfully
obtained from one more equivalent of the base and SO2F2.
Finally, base-assisted β-elimination furnishes the final alkyne
3 as the major product. However, the alkene B could also be
observed as a by-product when the fluorosulfate ester A
undergoes β-elimination directly prior to SN2-displacement by
DMSO.
1) 2 h
2a
2) degass,
K2CO3,
1a
<5%
(a) Oxidation of an 18O labeled substrate. (b-f) Control
experiments for the roles of the base.
experiments further suggested that the current oxidative
process, in which bases can be added without pre-activation of
DMSO, was different from the conventional Swern-type of
oxidations where the bases were required to be added after
pre-activation of DMSO.
3. CONCLUSION
In conclusion, a novel and practical method for direct
dehydration/dehydrogenation of alcohols to alkynes under
mild conditions was developed. This protocol employs cheap
and readily available reagents, solvent and inorganic bases
without transition metals. Excess SO2F2 was used to activate
DMSO for oxidative conversion of alcohols to alkenyl
sulfofluoridates under basic conditions at room temperature,
which is the first report in the literature to the best of our
knowledge. Direct access to 1,4-disubstituted-1,2,3-triazoles
or diarylalkynes by one-pot Cu/phosphine-catalyzed
regioselective Huisgen alkyne-azide cycloaddition reaction or
Pd-catalyzed Sonogashira coupling, respectively, were
enabled through the high purity of crude alkyne products.
Further applications of this method for discovery of new drug
candidates and functional materials are ongoing in our
laboratory.
Scheme 5 A plausible mechanism for direct dehydration
and dehydrogenation of alcohols to alkynes mediated by
SO2F2.
OSO2
F
OH
H
R2
R1
R2
H
SO2F2 (balloon)
DMSO, Bases
ß-Elimination
Base
R1
R2
R1
3
H
2
1
Base
SO2F2
Base
HF
O
S
SO2F2
Base
H
H
H
H3
C
CH2
FSO2
O
H3
C
S
S
H
O
O
S
H
H
ß-Elimination
O
OSO2
F
O
H
H
H
R2
R1
R2
R1
R1
R1
R2
Base
R1
H
H
R2
S
H
R2
FSO2OH
Me
Me
B
A
C
E
D
The proposed mechanism was examined by experimental
studies, the results revealed that unlike the conventional
swern-type oxidations where the oxygens of aldehydes were
adopted from the original alcohols, the oxygens of the
oxidative enolates were provided by DMSO, because the 18O-
labeled arylethanol 1af generated enolate 2af with greater than
99% 16O-labeled purity (Scheme 6a). Further experiments
indicated that mixing of the reactants without K2CO3 (similar
to Table 1, entry 3); mixing of the reactants before adding
K2CO3 followed by removal of SO2F2; pre-mixing SO2F2,
K2CO3, and DMSO over 2 h, before removing SO2F2and
adding 1a; and pre-mixing SO2F2, and DMSO over 2 h,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
6
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Journal of the American Chemical Society
Fully Functionalized Small-Molecule Probes for Integrated
*qinhuali@whut.edu.cn
Phenotypic Screening and Target Identification. J. Am. Chem. Soc.
2012, 134, 10385-10388. (h) Tully, S. E.; Cravatt, B. F. Activity-
Based Probes That Target Functional Subclasses of Phospholipases in
Proteomes. J. Am. Chem. Soc. 2010, 132, 3264-3265.
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chemistry on drug discovery. Drug Discov. Today. 2003, 8, 1128-
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Rev. 2010, 39, 1252-1261. (c) Kacprzak, K.; Skiera, I.; Piasecka, M.;
Paryzek, Z. Alkaloids and Isoprenoids Modification by Copper(I)-
Catalyzed Huisgen 1,3-Dipolar Cycloaddition (Click Chemistry):
Toward New Functions and Molecular Architectures. Chem. Rev.
2016, 116, 5689-5743.
(7) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry:
Diverse Chemical Function from a Few Good Reactions. Angew.
Chem., Int. Ed. 2001, 40, 2004-2021. (b) Rostovtsev, V. V.; Green, L.
G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition
Process: Copper(I)‐Catalyzed Regioselective “Ligation” of Azides
and Terminal Alkynes. Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
(c) Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on
Solid Phase:ꢁ [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed
1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org.
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growing applications of click chemistry. Chem. Soc. Rev. 2007, 36,
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(8) (a) Eckhardt, M.; Fu, G. C. The First Applications of Carbene
Ligands in Cross-Couplings of Alkyl Electrophiles:ꢁ Sonogashira
Reactions of Unactivated Alkyl Bromides and Iodides. J. Am. Chem.
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advances in Sonogashira reactions. Chem. Soc. Rev. 2011, 40, 5084-
5121.
1
2
3
4
5
6
7
8
ORCID
Hua-Li Qin: 0000-0002-6609-0083
Author Contributions
† These two authors contributed equally.
Notes
The authors declare no competing financial interest.
9
10
11
12
13
14
15
16
17
18
19
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21
22
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34
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36
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60
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), and Wuhan University of
Technology for their continuous encouragement towards the
research and financial support.
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(23) (a) Pagan-Torres, Y. J.; Wang, T.; Gallo, J. M. R.; Shanks, B.
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Lifetime, IR Spectrum, and Global Warming Potential. Environ. Sci.
Technol. 2009, 43, 1067-1070. For recent reviews of using SO2F2 gas,
see: (b) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B.
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vendors
world
widely:
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http://synquestlabs.com/product/id/51619.html.;
andhttps://www.fishersci.com/shop/products/NC0715470/nc0715470
#?keyword=Sulfuryl+Fluoride. (f) SO2F2 is a neurotoxin and a potent
greenhouse gas, please handle with care in fume hoods, and SO2F2 is
stable up to 400 °C when dry, it hydrolyses very slowly in water
under neutral conditions, and a little more rapidly under basic
conditions to produce fluorosulfate and fluoride ions.
1
2
3
4
5
Note, Sulfuryl fluoride is a neurotoxic gas that is also a particularly
potent greenhouse gas, please handle with care in fume hoods.
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2480-2482. (b) Mancuso, A. J.; Swern, D. Activated Dimethyl
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Tidwell, T. T. Oxidation of Alcohols by Activated Dimethyl
Sulfoxide and Related Reactions: An Update. Synthesis 1990, 857-
870.
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formation of fluorosulfonic ester with SO2F2 and subsequent β-
elimination: Stang P. J.; Hanack, M.; Subramanian, L. R.
Perfluoroalkanesulfonic Esters: Methods of Preparation and
Applications in Organic Chemistry. Synthesis 1982, 85-126.
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(33) Salmon, A. J.; Williams, M. L.; Wu, Q. K.; Morizzi, J.; Gregg,
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5506−5517.
(34) Alder, R. W. Methyl fluorosulfate as a methylating agent.
Chem. Ind. (London) 1973, 983-985.
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TOC:
sp3-sp3 to sp-sp
R
8
9
H
one-pot dehydration
PhN3
N
and dehydrogenation
N
N
Ph
H
1,3-dipolar
cycloaddition
reaction
transition metal free
>40 examples
up to 95% isolated yield
16 examples, up to
92% isolated yield
from alcohols
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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R1
H
R1
OH
in situ
R1 = H
R
R
PhI
S
R
Ph
R = aryl, hetero
akenyl, alkynyl
R1 = H, alkyl,aryl
H
2 H2O
+
Sonogashira
reaction
O
10 examples, up to
77% isolated yield
from alcohols
S
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