Metal-free and selective cleavage of unstrained carbon–carbon single bonds: Synthesis of β-ketosulfones from β-chlorohydrins and sodium sulfinates

Article abstract of DOI:10.1080/00397911.2017.1362439

A metal-free protocol for the selective cleavage of unstrained C–C single bonds was developed. Under the catalysis of KI and in the presence of NaHCO₃, the readily available α-chloro-β-hydroxy ketones underwent bond breaking and sulfonylation smoothly to afford β-ketosulfones with high efficiency and broad substrate scope. Mechanism investigations, both experimental and theoretical, showed that a retro-aldol cleavage/nucleophilic substitution sequence might be involved.

Full text of DOI:10.1080/00397911.2017.1362439

Synthetic Communications
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Metal-free and selective cleavage of unstrained
carbon-carbon single bonds: Synthesis of β-
ketosulfones from β-chlorohydrins and sodium
sulfinates
Yanni Li, Deqiang Liang, Yu Chang, Xiangguang Li, Shaoguang Fu, Yunli Yuan
& Baoling Wang
To cite this article: Yanni Li, Deqiang Liang, Yu Chang, Xiangguang Li, Shaoguang Fu, Yunli
Yuan & Baoling Wang (2017): Metal-free and selective cleavage of unstrained carbon-carbon
single bonds: Synthesis of β-ketosulfones from β-chlorohydrins and sodium sulfinates, Synthetic
Communications, DOI: 10.1080/00397911.2017.1362439
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Date: 21 August 2017, At: 18:55

Metal-free and selective cleavage of unstrained
carbon-carbon single bonds: Synthesis of β-ketosulfones
from β-chlorohydrins and sodium sulfinates
Yanni Li
Department of Chemistry, Kunming University, Kunming, China
Deqiang Liang
Department of Chemistry, Kunming University, Kunming, China
Yunnan Engineering Technology Research Center for Plastic Films, Kunming University,
Kunming, China
Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of
Chemistry, Northeast Normal University, Changchun, China
Yu Chang
Department of Chemistry, Kunming University, Kunming, China
Xiangguang Li
Department of Chemistry, Kunming University, Kunming, China
Shaoguang Fu
1

Department of Chemistry, Kunming University, Kunming, China
Yunli Yuan
Department of Chemistry, Kunming University, Kunming, China
Baoling Wang
Department of Chemistry, Kunming University, Kunming, China
Address correspondence to Deqiang Liang, Department of Chemistry, Kunming University, 2
Puxin Road, Kunming 650214, P. R. China. E-mail: ldq5871@126.com
ABSTRACT
A metal-free protocol for the selective cleavage of unstrained C–C single bonds was
developed. Under the catalysis of KI and in the presence of NaHCO3, the readily available
α-chloro-β-hydroxy ketones underwent bond breaking and sulfonylation smoothly to afford
β-ketosulfones with high efficiency and broad substrate scope. Mechanism investigations, both
experimental and theoretical, showed that a retro-aldol cleavage/nucleophilic substitution
sequence might be involved.
Graphical Abstract
KEYWORDS: C–C bond cleavage, chlorohydrins, metal-free, sulfones
2

Introduction
–
–
Carbon-carbon bond formation[1 5] and cleavage[6 10] are two fundamental transformations
in organic synthesis. However, the efforts of synthetic chemists have mostly been directed towards
bond constructions since the 19th century,[8] and the C–C bond cleavage reaction, which is equally
important particularly in skeletal reorganization and specific fragment utilization, has received far
–
less attention until recently.[6 10] As C–C bonds are the second most abundant feedstocks in
organic molecules, making full use of them is an attractive prospect and would significantly
expand chemists' toolbox.
However, so far it is still of great challenge to selectively cleave an unstrained C–C single
bond,[9],[10] which is among the most inert bonds owing to its large dissociation energy, low degree
of polarization, and the steric hindrance by C–H bonds. To crack such a linkage, the oxidative
addition of a noble metal through chelation-assistance strategy is generally necessary, and such
processes usually proceed in a stoichiometric manner and/or with insufficient selectivity and/or
efficiency.[9],[10] Furthermore, while significant progresses have been made in the cleavage
[17–22]
reactions of relatively active C–C σ bonds, such as Csp2–Csp3,[11–16] Csp2–Csp
and
Csp2–Csp2,[23–27] the examples of unstrained Csp3–Csp3 bond breaking are very rare.[28–30] Therefore,
it is highly desirable to develop metal-free[12–15],[28],[30],[31] Csp3–Csp3 bond cleavage methodologies
of high chemoselectivity and efficiency.
3

Interestingly, the old transformation of retro-aldol condensation falls into this category of
challenging metal-free bond cleavage reaction. Nevertheless, though it has been around since the
1950s,[32–34] the retro-aldol condensation is actually rather under-developed. It is mainly used to
degrade sugars at extremely high temperatures and pressures (i.e., under supercritical
conditions),[35–38] and new tricks from this old dog are very rare.[39] As a result, there is also an
urgent need to develop mild and practical retro-aldol cleavage protocols and to apply them in
useful transformations. In this promising context, a retro-aldol cleavage of -halohydrins is yet to
be revealed.
During our ongoing efforts in the synthesis and application of multi-functionalized
molecules,[40–46] we envisioned that the readily available -chloro--hydroxy ketones[47] might be
versatile synthons owing to their diverse reactivity. Herein, we report a metal-free and selective
C–C bond cleavage reaction of them, which leads to β-ketosulfones and might concern a
retro-aldol condensation mechanism. β-Ketosulfones are a class of highly useful precursors in
organic synthesis.[48],[49] They are also valuable synthetic targets of biological importance,[49–55] for
the sulfonyl functionality is frequently encountered in pharmaceuticals, agrochemicals, and
materials.[56],[57]
Results and Discussion
Our
preliminary
reaction
development
1a and
was
2
conducted
equiv of
with
2-chloro-3-hydroxy-1,3-diphenylpropan-1-one
sodium
4

4-methylbenzenesulfinate 2a as model substrates (Table 1). Surprisingly, in the presence of 30
mol% of KI and 2 equiv of Et3N in tetrahydrofuran (THF) at 50 °C, the Csp3–Csp3 bond cleavage
occurred rapidly and 1-phenyl-2-tosylethan-1-one 3a was afforded in 87% yield within 3.5 h
(entry 1). We subsequently evaluated other bases. The use of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) delivered β-ketosulfone 3a in only a moderate yield after 0.5 h, along with the cyclized
product 4[47] in 50% yield (entry 2). The yield of 1,4-dioxane derivative 4 was further increased to
92% with t-BuOK as the base (entry 3), whereas the employment of KOH led to the decomposition
of the reaction system and no noticeable product was obtained (entry 4). Na2CO3 (entry 5) and
NaHCO3 (entry 6) are both usable for this β-ketosulfone synthesis, and by using NaHCO3 an
excellent yield was achieved within 3.5 h. A control experiment confirmed that no reaction
occurred in the absence of a base (entry 7). Then, we conducted a survey of various solvents.
While sulfone 3a could not be provided using 1,2-dichloroethane (DCE, entry 8) or MeCN (entry
9) in the presence of KI and NaHCO3, with acetone (entry 10), N,N-dimethylformamide (DMF,
entry 11), or ethanol (entry 12) as the solvent, product 3a was produced in lower yields than that
achieved in THF, and always was 1,4-dioxane 4 formed. The examination of other halogen sources
as catalysts revealed that the use of tetrabutylammonium iodide (TBAI, entry 13), I2 (entry 14),
KBr (entry 15), or tetrabutylammonium bromide (TBAB, entry 16) all gave product 3a in
relatively modest yields after prolonged reaction times. A halogen source, which might serve as a
halide-exchange agent to facilitate the nucleophilic displacement process,[58],[59] is essential, for in
the absence of it only trace amounts of 3a were yielded (entry 17). With reduced loading of
5

NaHCO3 (entry 18), KI (entry 19), or sodium sulfinate 2a (entry 20), compromised yields of
β-ketosulfone 3a were observed. At ambient temperature, the decomposition of the reaction
system was predominant and 3a could not be isolated (entry 21).
Having developed optimized reaction conditions for the synthesis of
1-phenyl-2-tosylethan-1-one 3a, we subsequently explored the scope of this transformation (Table
2), and the results revealed that the substitution patterns of both aryl groups exert significant
effects on the reaction rate. α-Chloro-β-hydroxy ketone 1b bearing a methyl at the ortho-position
of the aroyl moiety is less reactive, and it reacted with sodium 4-methylbenzenesulfinate 2a to
furnish the C–C cleavage product 3b in a good yield after a prolonged reaction time (entry 2),
whereas corresponding β-ketosulfones 3c,ef were produced rapidly from substrates 1c,e,f derived
from aromatic ketones with an electron-withdrawing substituent at the para- or meta-position
(entries 3, 5 and 6). 3-Chloro-4-methoxy product 3d was prepared as well in 71% yield after 12 h
from related 3,4-disubstituted chlorohydrin 1d (entry 4). Furthermore, 2-thenoyl substrate 1g was
also compatible with this transformation, delivering the desired product 3g in 77% yield (entry 7).
Then, we investigated the substituent effect of the other aryl ring. It proved that whereas
chlorohydrins 1h,i having a p- or o-tolyl group adjacent to the C–O bond of the hydroxyl group
reacted with sodium sulfinate 2a smoothly, affording the expected sulfone 3a in diminished yields
(entries 8 and 9), the use of substrates 1j-l bearing an electron-deficient aryl group all gave 3a in
excellent yields (entries 10-12). Other sulfinate salts 2 were also tested. With sodium
6

benzenesulfinate 2b as the nucleophile, phenyl sulfones 3h-j were synthesized in moderate to
excellent yields from either electron-rich or -deficient β-chlorohydrins (entries 13-17). Similar
substituent effects were observed, and substrates 1 bearing an electron-withdrawing group on
either aryl ring were favored. Sodium 4-chlorobenzenesulfinate 3c is further less nucleophilic,
reflected by the relatively modest yields of the sulfonylation products 3k-m (entries 18-22). It is
worthy of notice that MeSO2Na 2d is also a competent sulfonylating reagent in this
transformation, for its reaction with substrate 1a gave mesylation product 3n in 81% yield after 10
h (entry 23). Unfortunately, the attempt to achieve trifluoromethylation by using CF3SO2Na 2e
met with no success (entry 24), probably due to its low nucleophilicity. This β-ketosulfone
synthesis could easily be scaled up to a gram-scale without an apparent decrease in yield (note c,
entry 1), thus rendering it a highly practical methodology.
Interestingly, the chlorinated substrates are critical, because when the corresponding
bromohydrin 1m or iodohydrin 1n, which bears a better but less electron-withdrawing leaving
group, was used instead of chloride 1a, the title reaction did not occur (entries 25-26, Table 2). In
the case concerns bromide 1m, though the substrate was consumed, there was no noticeable
product generated. In the case of β-iodohydrin 1n, an unstable and thus inseparable product rather
than the desired β-ketosulfone 3a was furnished. Another interesting phenomenon is that this
reaction is aerobic, for great sluggishness was observed when the reaction was run in a sealed tube
(note c, entry 1, Table 1). What is more, the control experiment of radical inhibition using
7

2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) suggested that a radical pathway might not be
involved (note e, entry 6, Table 1).
In an effort to gain further insights into the mechanism of this tandem reaction, density
functional theory (DFT) calculations were performed using the GAUSSIAN09 program[60] at the
M062X[61]/def2TZVP[62] level to evaluate the dissociation energies of the Csp3–Csp3 bond in
α-chloro-β-hydroxy ketone 1a and its bromide and iodide counterparts 1m,n (Figure 1). The
solvation effect of THF was considered.[63] The results showed that the direct cleavage processes
of the very bond in these electrically neutral halides, either homolytic or heterolytic, are so
endergonic that they might be impossible to occur (Figure 1a). Considering that the reaction
proceeded under basic conditions, and that a radical mechanism might be ruled out, we
subsequently examined the related heterolytic bond dissociation energies of the anionic variants.
While the calculated Csp3–Csp3 bond energies of carbanions 1a,m,n–H are still too large (Figure
1b), probably due to instabilities of the species resulted from bond breaking, carbanions
1a,m,n–H' are unlikely to undergo the desired bond cleavage either according to geometry
optimization, for the elimination of the chloride ion is strongly favored (Figure 1c). Finally,
analyses of the oxyanion variants 1a,m,n–H'' revealed that their Csp3–Csp3 bond cleavage
processes, which give 2-haloacetophenones and benzaldehyde and are in accordance with the
retro-aldol mechanism, are even exothermic and thus might be easy to occur (Figure 1d). On the
other hand, the very bond cleavage of chloride 1a–H'' is more exothermic than that of the
8

corresponding bromide and iodide, which might rationalize the fact that β-chlorohydrins are
essential (entries 25-26, Table 2).
In order to verify the above intermediates suggested by computations, gas
chromatography-mass spectrometry (GC-MS) analyses were conducted (Scheme 1). Indeed,
significant amounts of benzaldehyde and 2-chloroacetophenone were detected in the crude
mixtures of reactions of 1a under standard conditions of only 1 h, with or without sulfinate salt 2a
(Scheme 1a). These results indicated that a retro-aldol cleavage process might occur first, followed
by the nucleophilic substitution by sulfinate salts 2. Interestingly, in the reaction of 1b which
required a much longer reaction time, benzaldehyde was not detected, probably due to its aerobic
oxidation (Scheme 1b). This could affect the chemical equilibrium and facilitate the retro-aldol
cleavage, explaining the phenomenon that air was needed (note c, entry 1, Table 1).
The tandem retro-aldol cleavage/nucleophilic displacement mechanism was further
confirmed by the reaction of 2-chloroacetophenone with sodium 4-methylbenzenesulfinate 2a,
which afforded the same sulfone product 3a in an excellent yield within 1 h (Scheme 2).
This Csp3–Csp3 bond cleavage protocol could be extended to other nucleophiles. For
example, exposure of 2-chloro-3-hydroxy-1,3-diphenylpropan-1-one 1a and pentane-2,4-dione to
30 mol% of KI and
2
equiv of NaHCO3 in THF at 50 °C furnished
3-acetyl-1-phenylpentane-1,4-dione 5 in 71% yield (Scheme 3).
Conclusion
9

In conclusion, a KI/NaHCO3 promoted unstrained Csp3–Csp3 bond cleavage protocol of
chlorohydrins was developed. This reaction is metal-free, selective and efficient, and provides
access to β-ketosulfones under mild conditions with broad substrate scope. The mechanism was
thoroughly investigated by a combination of experimental and DFT methods, which suggested that
a retro-aldol cleavage/nucleophilic substitution sequence might be involved.
Experimental
Unless stated otherwise, chemicals were all purchased from commercial sources and used
without treatment. Thin-layer chromatography (TLC) was carried out using silica-gel GF254
plates. Products were purified by column chromatography over 300-400 mesh silica gel under a
positive pressure of air. 1H NMR and 13C NMR spectra were recorded at 25 °C on a Bruker Ascend
400 spectrometer in CDCl3 using tetramethylsilane (TMS) as internal standard. High-resolution
mass spectra (HRMS) were obtained using a Bruker microTOF II Focus spectrometer (ESI).
GC-MS analyses were performed on an Agilent 7890A gas chromatograph interfaced to a 5975C
mass selective detector in electron impact ionization mode. Substrates 1 were synthesized from
α,β-unsaturated ketones.[47]
Optimization of all molecular geometries and vibrational analyses were calculated at the
M062X function[61] by using the Gaussian 09 program[60] with the def2TZVP basis set.[62] All
calculated structures were true minima (i.e., no imaginary frequencies). Solvent effect was
calculated using the solvent model density (SMD) approach.[63]
10

General procedure (taking the synthesis of 3a as an example)
To a stirred solution of 2-chloro-3-hydroxy-1,3-diphenylpropan-1-one 1a (78 mg, 0.3
mmol), sodium 4-methylbenzenesulfinate 2a (106 mg, 0.6 mmol), and KI (15 mg, 0.09 mmol) in
THF (3.0 mL) was added NaHCO3 (50 mg, 0.6 mmol), and the mixture open to the air was stirred
for 3.5 h at 50 °C. After 1a was consumed, as indicated by TLC, the reaction mixture was
quenched with water (20.0 mL), and extracted with CH2Cl2 three times. The residue obtained after
evaporation of the solvent was purified by column chromatography on silica gel (petroleum
ether–ethyl acetate = 24:1, v/v) to afford 1-phenyl-2-tosylethan-1-one 3a as a white solid (77 mg,
93% yield): mp 108-109 °C. 1H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3H), 4.72 (s, 2H), 7.33-7.35
(m, 2H), 7.46-7.51 (m, 2H), 7.62 (dddd, J = 1.2, 1.3, 7.0, 6.9 Hz, 1H), 7.77 (ddd, J = 1.9, 1.7, 8.3
13
Hz, 2H), 7.94-7.97 (m, 2H); C NMR (100 MHz, CDCl3) δ = 188.15, 145.40, 135.79, 135.76,
134.34, 129.85, 129.36, 128.86, 128.64, 63.62, 21.73; HRMS (ESI-TOF) Calcd for C15H15O3S +
([M + H] + ) 275.0736. Found 275.0733.
Funding
This work was supported by the Applied Basic Research Programs of Yunnan Science and
Technology Department (2014FD039), the General Projects of Yunnan Education Department
(2017ZZX093), the Open Project of Jilin Province Key Laboratory of Organic Functional
Molecular Design & Synthesis (130028747), and the Foundation for Innovative Scientific
Research Team of Kunming University (2015CXTD03).
11

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14

Table 1. Optimization of reaction conditionsa
entry
x
catalyst base
mol%) equiv)
solvent
T (°C)
t (h)
yield of yield of
3ab (%) b (%)
1
2
3
2
2
2
KI (30) Et3N (2) THF
KI (30) DBU (2) THF
50
50
50
3.5 (48)c 87 (40)c 0 (0)c
0.5
0.5
45
0
50
92
KI (30) t-BuOK
THF
(2)
4
5
2
2
KI (30) KOH (2) THF
50
50
0.5
4
traced
86
8
0
KI (30) Na2CO3
(2)
THF
6
2
KI (30) NaHCO3 THF
(2)
50
3.5 (4)e 93 (87)e
0
7
8
2
2
KI (30) none
THF
50
50
24
24
nr
KI (30) NaHCO3 DCE
0 (75)f
11
15

(2)
9
2
2
2
2
2
2
2
2
KI (30) NaHCO3 MeCN
(2)
50
24
24
12
2
trace
(16)f
28
10
11
12
13
14
15
16
KI (30) NaHCO3 acetone 50
(2)
31 (22)f 14
KI (30) NaHCO3 DMF
(2)
50
50
50
50
50
50
72
58
56
56
53
71
6
KI (30) NaHCO3 EtOH
(2)
34
16
11
12
20
TBAI
(30)
NaHCO3 THF
(2)
15
24
24
24
I2 (30)
NaHCO3 THF
(2)
KBr
(30)
NaHCO3 THF
(2)
TBAB
(30)
NaHCO3 THF
(2)
16

17
18
19
20
21
2
none
NaHCO3 THF
(2)
50
50
50
50
rt
12
11
4
traced
trace
2
KI (30) NaHCO3 THF
(1.5)
83
0
2
KI (20) NaHCO3 THF
(2)
88
0
1.5
2
KI (30) NaHCO3 THF
(2)
9
85
trace
KI (30) NaHCO3 THF
(2)
24
traced
(5)f
0
aReaction conditions: 1a (0.3 mmol), solvent (3.0 mL), open to the air.
bIsolated yields.
cThe reaction was run in a sealed tube.
dThough 1a was consumed, no noticeable product was formed.
eTEMPO (3.0 equiv) was additionally added.
fRecovery of 1a.
17

Table 2. Scopea
entry
R1
R2
X
R3
t (h)
3.5
12
3.5
12
3
yieldb (%)
1
2
3
1
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
93 (92)c
78
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
2
2-Me
H
1b
1c
1d
1e
1f
3
4-Cl
H
92
4
3-Cl-4-MeO
H
71
5
4-NO2
H
96
6
3-NO2
H
3
94
7
2-thienyl
H
24
10
9
77
1g
1h
1i
3g
3a
3a
3a
3a
8
H
H
H
H
4-Me
2-Me
4-Cl
3-Cl
56
9
72
10
11
8
93
1j
8
90
1k
18

12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
2-Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
4-MePh
Ph
10
4.5
12
10
12
4
91
68
49
75
62
93
46
40
62
53
66
81
0d
1l
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2d
2e
2a
2a
3a
3h
3h
3h
3i
H
1a
1h
1j
H
4-Me
4-Cl
H
Ph
H
Ph
2-Me
4-Cl
H
Ph
1b
1c
1a
1h
1j
H
Ph
3j
H
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Me
48
12
12
12
4
3k
3k
3k
3l
H
4-Me
4-Cl
H
H
2-Me
4-Cl
H
1b
1c
1a
1a
1m
1n
H
3m
3n
H
10
24
24
24
H
H
CF3
H
H
4-MePh
4-MePh
0d
3a
3a
H
H
0e
aReaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), KI (0.09 mmol), NaHCO3 (0.6 mmol), THF (3.0 mL), 50 °C, open to the air.
19

bIsolated yields.
cReaction was performed with 1 g of 1a.
dThough the substrate was consumed, no noticeable product was formed.
eOnly an unstable and thus inseparable product was formed.
20

Figure 1. Calculated bond dissociation energies at the SMD-THF-M062X/def2TZVP level.
21

Scheme 1. GC-MS experiments.
22

Scheme 2. Nucleophilic substitution of 2-chloroacetophenone.
23

Scheme 3. Protocol extension.
24