Rapid Interception of CnF2n+1(O)SO. Radical with Copper-Based Carbene: A Novel Access to Perfluoroalkanesulfinate Ester

Article abstract of DOI:10.1002/chem.201805639

In this communication, an unprecedented interception of C_nF_2n+1(O)SO^. radical with a copper-based carbene has been established. Distinguished by wide substrate scopes and mild reaction conditions, this novel radical–carbene coupling reaction (RCC reaction) provides a fundamentally different and mechanistically interesting strategy for the synthesis of perfluoroalkanesulfinate esters.

Full text of DOI:10.1002/chem.201805639

DOI: 10.1002/chem.201805639
Communication
&
Radical Reactions
C
Rapid Interception of CnF2n+1(O)SO Radical with Copper-Based
Carbene: A Novel Access to Perfluoroalkanesulfinate Ester
Hanghang Wang, Haiyan Li, Yonggao Zheng, Pengcheng Lian, and Xiaobing Wan*[a]
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
Abstract: In this communication, an unprecedented inter-
C
ception of CnF2n+1(O)SO radical with a copper-based car-
bene has been established. Distinguished by wide sub-
strate scopes and mild reaction conditions, this novel radi-
cal–carbene coupling reaction (RCC reaction) provides a
fundamentally different and mechanistically interesting
strategy for the synthesis of perfluoroalkanesulfinate
esters.
Scheme 1. Synthetic use of Langlois reagent (CF3SO2Na).
Organofluorine compounds are widely used in agrochemistry,
medicine, and material sciences[1] since they often possess a
variety of remarkable physicochemical and biological proper-
ties,[2] such as solubility, lipophilicity as well as catabolic stabili-
ty.[2f,3] However, the utility of trifluoromethanesulfinate esters
has not been rigorously explored because of their synthetic in-
accessibility and instability. At a first glance, Langlois reagent
(CF3SO2Na), a commercially available, inexpensive, and stable
compound, appears to be a straightforward strategy for gener-
ating trifluoromethanesulfinate esters. In practice, however, the
strong propensity of CF3SO2Na to decompose with release of
SO2 has rendered it mostly a classic trifluoromethylation re-
agent for alkenes,[4] alkynes[5] and (hetero)arenes[6]
(Scheme 1a).
pling of a-aminoalkyl radicals and metal carbenes to generate
b-ester-g-amino ketones[9a,b] and indoles.[9c] We also developed
a RCC method that allowed the efficient preparation of isoxa-
zolines from Cu-based carbenes and nitroso radicals under
mild conditions.[9d] These results prompt us to speculate, as il-
C
lustrated in Scheme 1b, that the CF3(O)SO radical II, generated
by the single-electron oxidation of Langlois reagent, could be
rapidly intercepted by a highly active metal carbene prior to
its imminent decomposition (Scheme 1a) to form intermediate
III, which could then be further converted to various trifluoro-
methanesulfinate esters via protonolysis (Scheme 1b).
To test our hypothesis, we first performed a pilot coupling
reaction of a-diazoacetophenone 1a, which served as a car-
bene precursor, with CF3SO2Na 2a for the formation of trifluo-
romethanesulfinate ester 3a. Considering that the metal car-
bene plays a critical role in ensuring the successful capture of
Traditional trifluoromethanesulfinyl oxylation methods,
which are essentially ionic processes,[7] are often limited in sub-
strate scope, require hazardous reagents and harsh conditions,
and inevitably generate large amounts of toxic halide bypro-
ducts.[7b,d–g] To the best of our knowledge, there has not been
any published study on radical trifluoromethanesulfinyl oxyla-
tion reaction. Similar to radicals, metal carbenes are also highly
reactive and synthetically versatile species.[8] Radical–carbene
coupling (RCC) is considered a promising and mechanistically
interesting strategy for the synthesis of polyfunctionalized mol-
ecules considering that both of them have low concentrations
in the reaction system. Recently, we reported the direct cou-
C
CF3(O)SO radical, we screened a variety of transition-metal cat-
alysts containing Cu, Co, or Fe (for more details, see Support-
ing Information (SI), Table S1, entries 1–11). To our delight, run-
ning the coupling reaction at 608C for 1 h with Cu(OAc)2,
which is commercially available and inexpensive, led to the
best result and provided 3a, which was isolated in 75% yield
(Table 1, entry 1). Unsurprisingly, little product was formed
when no oxidant was used (Table 1, entry 5). However, product
3a was isolated in 38% yield even in the absence of Cu(OAc)2
C
(Table 1, entry 4), suggesting that CF3(O)SO could also be inter-
[a] H. Wang, H. Li, Y. Zheng, P. Lian, Prof. Dr. X. Wan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123 (P. R. China)
E-mail: wanxb@suda.edu.cn
cepted by the free carbene. Other oxidants, including di-tert-
butyl peroxide (DTBP), K2S2O8, H2O2, benzoperoxide (BPO), and
tert-butyl peroxybenzoate (TBPB), were all found to be signifi-
cantly less effective than TBHP in promoting the generation of
3a (for more details, see SI, Table S1, entries 14–19). Finally, we
evaluated several commonly used organic solvents, such as pe-
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201805639.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Solvent
Isolated yield [%]
1
2
3
4
5
6
7
8
Cu(OAc)2
Co(acac)2
FeSO4·7H2O
none
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TBHP
TBHP
TBHP
TBHP
none
DTBP
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
EA
EA
EA
EA
EA
EA
EA
PE
75
42
36
38
<5
<5
39
44
66
67
49
69
40
9
CHCl2CH2Cl
MeNO2
MeCN
DCE
CCl3CH3
10
11
12
13
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.6 mmol,
3.0 equiv), catalyst (0.02 mmol, 10 mol%), oxidant (1.0 mmol, 5.0 equiv),
and solvent (2.0 mL) for 1 h under air. EA=ethyl acetate, PE=petroleum
ether, DCE=1,2-dichloroethane, TBHP=tert-butyl hydroperoxide.
troleum ether (PE), CHCl2CH2Cl, MeNO2, MeCN, 1,2-dichloro-
ethane (DCE) and CCl3CH3. The results indicated that substitut-
ing ethyl acetate (EA) with any of these solvents would cause
the reaction efficiency to decrease slightly (Table 1, entries 8–
13).
With the optimal conditions in hand, we began to explore
the substrate scope of the reaction by first testing a series of
a-diazo ketones (Scheme 2). We found that both electron-do-
nating and electron-withdrawing groups were tolerated on the
benzene ring of 1a, affording the corresponding products 3a–
3s in moderate to good yields. Satisfyingly, halogens (F, Cl, and
Br) and hydroxyl were also well tolerated at the para- and
meta-positions, which opens possibilities for further chemical
modifications. It is noteworthy that the trifluoromethanesulfin-
yl oxylation of ortho-methyl aryldiazoketone into the desired
product 3r was not significantly affected by its apparent steric
hindrance (73% yield). The coupling reaction was shown to be
also compatible with aryl carbenes bearing a naphthalene or
thiophene moiety, as demonstrated by the synthesis of 3s and
3t in 52% and 63% yields, respectively. Moreover, alkyl-substi-
tuted a-diazo ketones were also suitable reactants for this
transformation (3u and 3v). Notably, the exact structure of tri-
fluoromethanesulfinate ester 3a was unambiguously deter-
mined by X-ray diffraction (Scheme 2).
Scheme 2. Scope of a-diazo ketones. Reaction conditions: 1 (0.2 mmol,
1.0 equiv), 2a (0.6 mmol, 3.0 equiv), Cu(OAc)2 (0.02 mmol, 10 mol%), TBHP
(1.0 mmol, 5.0 equiv, 70% in water), and EA (2.0 mL) for 1 h under air. Yields
of isolated products are given.
Next, we investigated whether we could expand the scope
of the coupling reaction to include diazo esters from phenols
and alcohols (Scheme 3). In all cases, the reactants were well
tolerated and converted to the corresponding a-trifluoro-
methanesulfinate ester products 3a’–3 f’ in moderate to good
yields. Notably, diazo esters carrying an acetyl (Ac) or tert-bu-
toxycarbonyl (Boc) protected amino group on the aromatic
ring could withstand the oxidation and furnish the desired
products 3e’ and 3 f’, albeit at slightly reduced yields of 41%
and 48%, respectively.
Scheme 3. Scope of diazo esters. Reaction conditions: 1’ (0.2 mmol,
1.0 equiv), 2a (0.6 mmol, 3.0 equiv), Cu(OAc)2 (0.02 mmol, 10 mol%), TBHP
(1.0 mmol, 5.0 equiv, 70% in water), and EA (2.0 mL) for 1 h under air. Yields
of isolated products are given.
To further enhance the utility of this methodology,
CnF2n+1SO2Na substrates of various lengths were also examined
(Scheme 4). As expected, all substrates could competently
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Scheme 4. Scope of CnF2n+1SO2Na. Reaction conditions: 1a (0.2 mmol,
1.0 equiv), 2 (0.6 mmol, 3.0 equiv), Cu(OAc)2 (0.02 mmol, 10 mol%), TBHP
(1.0 mmol, 5.0 equiv, 70% in water), and EA (2.0 mL) for 1 h under air. Yields
of isolated products are given.
Scheme 6. Proposed reaction mechanism.
copper-based carbene, followed by protonolysis process. We
are currently striving to achieve the construction of other fluo-
rine-containing compounds through RCC.
couple with 1a, enabling the preparation of a wide range of
agrochemically and/or pharmaceutically relevant a-perfluoroal-
kanesulfinate ketones (4a–4d) that could not be synthesized
by other methods.
Experimental Section
Subsequently, we conducted a series of mechanistic studies.
First, the inclusion of 1,1-diphenylethylene 6 in the coupling
reaction of 1a and 2a led to the identification and isolation of
two radical adducts 7 and 8 (the yields of 7 and 8 were based
upon 6), providing convincing evidence for the two key inter-
Diazo compounds (0.2 mmol), CnF2n+1SO2Na (0.6 mmol), and
Cu(OAc)2 (0.02 mmol) were added to a test tube charged with a
stirring bar. Ethyl acetate (2.0 mL) and TBHP (1.0 mmol, 70% in
water) were added using a syringe. The reaction mixture was
heated at 608C for 1 h, which was then quenched with saturated
Na2SO3 solution and extracted with ethyl acetate (3ꢁ3.0 mL). The
organic layers were combined and dried over anhydrous MgSO4.
Removal of the organic solvent followed by purification by flash
column chromatography (PE/EA) afforded the desired products.
C
C
mediates CF3(O)SO and CF3 (Scheme 5a). At the same time,
Acknowledgements
A Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions (PAPD), NSFC
(21572148, 21272165).
Conflict of interest
Scheme 5. Probe for the possible mechanism.
The authors declare no conflict of interest.
the desired product 3a can be also isolated in 60% yield (the
yield of 3a was based upon 1a). In addition, the generation of
3a was completely suppressed in the presence of the radical
inhibitor 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO,
Scheme 5b).[10] Altogether, these results indicated that
Keywords: carbenes · organic synthesis · radicals · radical
coupling · synthetic methods
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Based upon findings from the above experiments and litera-
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C
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Manuscript received: November 12, 2018
Revised manuscript received: December 3, 2018
Accepted manuscript online: December 12, 2018
Version of record online: && &&, 0000
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Communication
COMMUNICATION
&
Radical Reactions
H. Wang, H. Li, Y. Zheng, P. Lian, X. Wan*
&& – &&
C
Rapid Interception of CnF2n+1(O)SO
Radical with Copper-Based Carbene: A
Novel Access to
Perfluoroalkanesulfinate Ester
Better be quick! Through rapid inter-
action (RCC reaction) is distinguished by
wide substrate scopes, short reaction
time, mild reaction conditions, and op-
erational simplicity, leading to a variety
of perfluoroalkanesulfinate esters in sat-
isfactory yields.
C
ception of CnF2n+1(O)SO radical with a
copper-based carbene, a fundamentally
different and mechanistically interesting
synthetic strategy for perfluoroalkane-
sulfinate esters has been developed.
This novel radical–carbene coupling re-
Chem. Eur. J. 2019, 25, 1 – 5
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