Isocyanide-Induced Activation of Copper Sulfate: Direct Access to Functionalized Heteroarene Sulfonic Esters

Article abstract of DOI:10.1002/anie.201612565

A novel and direct approach to alkyl/aryl heteroarene sulfonic esters using copper sulfate as the environmentally benign inorganic sulfonation reagent was first realized with the aid of isocyanide. A variety of heterocycles reacted to afford the corresponding sulfonic esters through C?H functionalization. In this transformation, the otherwise inert copper sulfate was unusually activated by an isocyanide and employed as the source of the sulfonic substituents in an unprecedented fashion. The findings suggest that an appropriate activator may liberate the chemical activities of some relatively inert inorganic salts for organic synthesis.

Full text of DOI:10.1002/anie.201612565

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612565
German Edition: DOI: 10.1002/ange.201612565
À
C H Activation
Isocyanide-Induced Activation of Copper Sulfate: Direct Access to
Functionalized Heteroarene Sulfonic Esters
Xiaohu Hong+, Qitao Tan+, Bingxin Liu, and Bin Xu*
Dedicated to Professor Shizheng Zhu on the occasion of his 70th birthday
Abstract: A novel and direct approach to alkyl/aryl hetero-
arene sulfonic esters using copper sulfate as the environ-
mentally benign inorganic sulfonation reagent was first
realized with the aid of isocyanide. A variety of heterocycles
in a stark contrast to other frequently used copper salts,
copper sulfate is employed at a limited level in organic
synthesis.[3] The principal uses of copper sulfate in organic
synthesis stem from the chemical properties of copper(II)
cation, and it is utilized as a dehydrating agent,[4] Lewis acid,[5]
oxidant,[6] or catalyst.[7] To our knowledge, the utilization of
the sulfate anion of copper sulfate has remained unexplored,
À
reacted to afford the corresponding sulfonic esters through C
H functionalization. In this transformation, the otherwise inert
copper sulfate was unusually activated by an isocyanide and
employed as the source of the sulfonic substituents in an
unprecedented fashion. The findings suggest that an appro-
priate activator may liberate the chemical activities of some
relatively inert inorganic salts for organic synthesis.
À
which is probably due to the robustness of the O S bond in
many sulfate moieties.[8] For example, copper(II) sulfate was
reported to decompose into copper(II) oxide and sulfur
trioxide at elevated temperature (> 6008C).[9] Therefore, to
utilize the sulfate anion in organic transformation, such as
À
C
opper salts, which are inexpensive and of low toxicity, have
sulfonation reaction, the cleavage of the inert O S bond is
necessary and challenging.
been widely used in organic reactions as catalysts or
mediators.[1] Recently, many copper salts have been fre-
Sulfonates are one of the most important classes in
surfactant industry as detergents and surface active agents.[10]
However, the traditional sulfonates are conventionally pre-
pared under harsh conditions by heating at elevated temper-
atures with corrosive or environmentally unfriendly oleum,
sulfur trioxide, or chlorosulfonic acid. Improved results could
be achieved using easily handling sulfur trioxide amine
complexes in sulfonation reactions.[11] Generally, the sulfonic
esters are accessible by several steps through tedious proce-
dures.[12] Thus, direct sulfonation using the sulfate anion of
copper sulfate will be remarkably different from traditional or
recently developed methods, which do not involve the
À
quently involved in C H bond functionalization for the
À
À
À
formation of C X, C O, and C N bonds by assembling their
anions to the substrates (Scheme 1).[2] Copper sulfate, known
as bluestone in its pentahydrate form, is abundant in nature
and has found vast practical uses including herbicide, wood
impregnation, and algae control in swimming pools. However,
[13]
À
cleavage of O S bonds.
Herein, we report an unprece-
dented sulfonation process employing copper sulfate as the
novel environmentally benign inorganic sulfonation reagent
to afford various heteroarene sulfonic esters in good yields
(Scheme 1). The significance of the given chemistry is
threefold: 1) It is the first direct transformation of safe and
low-cost copper sulfate to sulfonic esters, avoiding the
traditional use of corrosive hazards such as concentrated
sulfuric acid or chlorosulfonic acid; 2) the chemically inert
copper sulfate is activated unusually for the first time in the
presence of an isocyanide;[14] 3)the valuable mechanistic
insights could be expanded for promoting the discovery of
other new types of sulfonation reactions.
Isocyanides are not only important C1 synthons in organic
synthesis but also strong ligands towards transition met-
als.[14b,15] They could be generally activated as versatile
reactants for a variety of transformations when coordinated
to metals. Recently, we have successfully explored isocyanides
as crucial ligands to promote various copper-mediated trans-
formations.[2h,16] Inspired by these results, we started our
investigation by exploring the reaction of 1-phenyl-1H-indole
(1a) with copper sulfate in the presence of t-BuNC in 1,2-
À
Scheme 1. The utilities of copper salt anions in C H bond functional-
ization.
[*] Dr. X. Hong,[+] Prof. Dr. Q. Tan,[+] Prof. Dr. B. Liu, Prof. Dr. B. Xu
Department of Chemistry, Innovative Drug Research Center
School of Materials Science and Engineering
Shanghai University, Shanghai 200444 (China)
E-mail: xubin@shu.edu.cn
Homepage: http://www.xubin.shu.edu.cn
Prof. Dr. B. Xu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
and
Shanghai Key Laboratory of Green Chemistry and Chemical Pro-
cesses, Department of Chemistry
East China Normal University, Shanghai 200062 (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612565.
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dichloroethane at 1308C under a nitrogen atmosphere. After
an extensive screening of the ratios of the starting materials
(Supporting Information, Table S1), 1a/CuSO4/t-BuNC =
1:4:5 was found to be the best choice, affording the indolyl
sulfonic ester 2a in 86% yield (Table 1, entry 1).[17] Under
Table 1: Optimization of reaction conditions.[a]
Entry Change from standard conditions
Yield [%][b]
1
2
3
4
5
6
none
no t-BuNC
50 mol% t-BuNC
CuSO4·5H2O instead of CuSO4
Na2SO4 instead of CuSO4
8 mol% CuSO4, 10 mol% t-BuNC and 4.0 equiv of
Na2SO4 were used
86
–
trace
36
–
–
7
8
9
MgSO4 instead of CuSO4
MnSO4 instead of CuSO4
ZnSO4 instead of CuSO4
FeSO4·7H2O instead of CuSO4
XyNC instead of t-BuNC
PPh3 instead of t-BuNC
Xantphos instead of t-BuNC
bipyridine instead of t-BuNC
1,10-phen instead of t-BuNC
3.0 equiv of CuSO4
–
–
–
–
10
11
12
13
14
15
16
17
18
65
32 (83)
52
–
–
72 (95)
55 (62)
79
Scheme 2. Sulfonation scope of indoles. Reaction conditions:
1108C instead of 1308C
under air instead of N2 atmosphere
1 (0.4 mmol), CuSO4 (1.6 mmol), t-BuNC (2.0 mmol) in DCE (6.0 mL),
under nitrogen atmosphere, sealed tube, 20–36 h. Yields shown are of
the isolated products.
[a] Reaction conditions: 1a (0.2 mmol), CuSO4 (0.8 mmol), t-BuNC
(1.0 mmol) in DCE (3.0 mL), 1308C, under nitrogen atmosphere, sealed
tube, 20 h. DCE=1,2-dichloroethane, XyNC=2,6-dimethylphenylisoni-
trile. Xantphos=4,5-bis-di-phenylphosphanyl-9,9-dimethylxanthene.
[b] Isolated yield with the conversion of 1a shown in parentheses.
halides, -OMe or -CO2Me at the C5 or C6 position could also
undertake this reaction smoothly with moderate to good
yields (2k–2n). Primary and secondary alkyl, benzyl, allyl,
and pyridyl indoles could efficiently convert into the desired
sulfonation products in good yields (2o–2w). However, less
electron-rich N-acyl indoles (Ac, Ts, and Boc) did not give the
corresponding products. This newly established protocol was
not limited to indoles; azaindoles were also found to be
suitable substrates, affording products 2x and 2y in good
yields. The identity of 2m was determined by spectral analysis
and further confirmed by X-ray crystallographic analysis.[19]
Various alkyl halides were subsequently examined in the
sulfonation of N-(p-methoxyphenyl)indole (1c) using toluene
as solvent (Scheme 3). A wide range of primary alkyl
bromides could be employed in this reaction (3a–3 f).
Reaction using n-butyl chloride or n-butyl tosylate as
alkylating reagent afforded the corresponding 3c in dimin-
ished yield, while n-butyl iodide gave comparable yield to n-
butyl bromide. Secondary alkyl bromides, such as 2-bromo-
propane and 2-bromobutane, reacted with 1c to afford the
sulfonation products (3g and 3h) in 52% and 21% yield,
respectively, while tertiary alkyl bromides were not applicable
to the reaction. Notably, N-alkyl indoles and azaindole were
also found to be suitable substrates in the reaction (3i–3k).
For the efficient preparation of corresponding aryl
sulfonic esters, diaryliodonium salts were then selected as
otherwise identical conditions in the absence or using
catalytic amount of t-BuNC, none or just trace amount of
sulfonic ester 2a was observed (entries 2 and 3). If copper
sulfate pentahydrate was employed instead of the anhydrous
form, significant lower yield was obtained (entry 4). Interest-
ingly, among the sulfate salts screened (entries 5–10), only
copper sulfate could give the desired product in an appreci-
able yield indicating its unique role in this transformation.
XyNC and phosphine ligands[18] could also afford the desired
product, albeit in decreased yields (entries 11–13). Nitrogen-
containing ligands such as bipyridine or 1,10-phenanthroline,
however, could not afford the desired product (entries 14 and
15). Reducing the amount of copper sulfate, lowering the
reaction temperature, or performing the reaction under air
atmosphere caused somewhat lower yields (entries 16–18).
The scope of this reaction was next investigated, as shown
in Scheme 2. Substrates bearing electron-donating or elec-
tron-withdrawing groups at the N-phenyl rings underwent
sulfonation reaction smoothly (2a–2h), and functional groups
such as methyl, methoxyl, halide, and ester groups were all
tolerated. This sulfonation reaction also worked well with
substrates bearing methyl or phenyl group at the indole C2
position (2i and 2j). Furthermore, N-phenyl indoles having
2
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C2, or C5 position with different electronic properties,
affording the corresponding phenyl sulfonates in moderate
to good yields (4a–4h). N-Phenyl azaindole was also func-
tionalized in a similar manner (4i) and various symmetrical
diaryliodonium salts could be successfully employed to react
with N-phenyl indole (1a), affording indolyl C3 aryl sulfo-
nates in good yields (4j–4p). The identity of 4g was further
confirmed by X-ray crystallographic analysis.[19]
To further explore the generality and scope of this
approach, various heterocycles were investigated with slight
modifications to the standard reaction conditions (Scheme 5),
Scheme 3. Sulfonation scope of alkyl halides. Reaction conditions:
1 (0.4 mmol), CuSO4 (1.6 mmol), t-BuNC (2.0 mmol) in toluene/Alkyl-
Br (6.0 mL/1.0 mL), under nitrogen atmosphere, sealed tube, 20 h.
PMP=p-methoxyphenyl. Yields shown are of the isolated products.
the arylation reagent.[20] With the optimized reaction con-
ditions in hand (Supporting Information, Table S2, entry 15),
several substrates were investigated with diphenyliodonium
triflate or tetrafluoroborate as the arylation reagent at 1208C
(Scheme 4). This sulfonation reaction proceeded well with
functionalized indoles bearing various substitutions at the N1,
Scheme 5. Sulfonation scope of heterocycles. Reaction Conditions:
Reactions were conducted on 0.4 mmol scale, CuSO4 (1.6 mmol), t-
BuNC (2.0 mmol), 1308C, under nitrogen atmosphere, sealed tube,
20–48 h. Yields shown are of the isolated products. [a] DCE (6.0 mL).
[b] Yield based on 80% conversion. [c] n-Propyl bromide (1.0 mL) in
toluene (6.0 mL). [d] CuSO4 (1.2 mmol), t-BuNC (1.44 mmol), Ar2IX
(1.2 mmol) in CH3CN (6.0 mL), 1208C. [e] n-Propyl bromide (1.0 mL)
in CH3CN (6.0 mL).
due to the different electronic properties of each class of
heterocycles. To our delight, benzo[g]indole gave sulfonation
products 5a–5c in good yields, and 3,5-dimethyl-1-phenyl-
pyrazole could also be functionalized in a similar manner to
furnish 6a–6c in moderate yields. However, non-substituted
1-phenylpyrazole failed to react under the reaction conditions
which may be due to the electronic effects. Sulfonation of N-
phenyl pyrrole afforded 7a in 64% yield, while the reaction of
N-methyl carbazole with copper sulfate and n-propyl bromide
was sluggish under the standard condition. Intriguingly, when
changing the solvent from toluene to acetonitrile, the reaction
was improved and gave the n-propyl sulfonated product 8a in
72% yield. Furthermore, the phenyl sulfonic ester 8b could
be generated successfully in high yield from N-methyl
carbazole.
Scheme 4. Sulfonation scope of diaryliodonium salts. Reaction condi-
tions: 1 (0.4 mmol), CuSO4 (1.2 mmol), t-BuNC (1.44 mmol) and
Ar2IX (1.2 mmol) in CH3CN (6.0 mL), under nitrogen atmosphere,
sealed tube, 20 h. Yields shown are of the isolated products.
To gain insight into the possible pathway of this novel
sulfonation reaction, several control experiments were car-
ried out as shown in Scheme 6. Comparable yields could be
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electrophiles, such as alkyl halides or aryl iodonium salts, to
give the corresponding alkyl or aryl sulfonates, respectively.
In summary, we have developed a direct synthesis of
functionalized alkyl/aryl sulfonic esters using copper sulfate
as the novel sulfonating source through the activation effect
of tert-butyl isocyanide. Various heterocycles such as indoles,
azaindoles, pyrroles, pyrazoles, and carbazoles worked well to
afford the corresponding sulfonic esters smoothly. The given
approach represents the first example to use copper sulfate as
an environmentally benign inorganic sulfonation reagent and
provides a novel protocol for the activation of chemically
inert inorganic salts for application in organic synthesis. The
isocyanide is conceived to play a threefold role in the
activation of conventionally inert copper sulfate: 1) reducing
copper(II) to copper (I); 2) acting as a ligand; 3) facilitating
Scheme 6. Preliminary mechanistic studies.
À
the dissociation of the robust O S bond. Further research are
currently being investigated in our lab.
achieved
when
2,2,6,6-tetramethyl-piperidine-1-oxy
(TEMPO) or p-tert-butylphenol (PTBP) was used as radical
scavengers [Eq. (1)].[21] Moreover, when 1c was reacted with
a radical clock substrate 6-bromohex-1-ene, sulfonic ester 9 Experimental Section
1a (77.6 mg, 0.4 mmol), copper sulfate anhydrous (255.2 mg,
was obtained in 66% yield without observation of the
corresponding cyclization product [Eq. (2)]. These results
may rule out the possibility of radical pathways for this
transformation.[22] As isocyanides were well documented to
promote the transformation of CuII to CuI,[16b,23] we speculated
that the use of Cu2SO4 may also lead to the desired product.
To address this, N-phenyl indole 1a was treated with
relatively unstable Cu2SO4, which was freshly prepared from
Cu2O and (CH3)2SO4,[24] in the absence of t-BuNC in DCE
[Eq. (3)]. This reaction did afford the sulfonated product 2a,
albeit in only 9% yield [Eq. (3)]. The low yield may attribute
to the instability of Cu2SO4 at elevated temperature. Inter-
estingly, when the reaction was carried out in the presence of
t-BuNC, significantly improved yield was obtained, which
indicated that the isocyanide may play the second role, that is,
as a ligand.
1.6 mmol), and t-BuNC (166.0 mg, 2.0 mmol) in DCE (6.0 mL) were
added to a 35 mL sealed tube. The tube was sealed and the reaction
mixture was stirred at 1308C under nitrogen atmosphere. After 20 h,
the reaction mixture was diluted with water (10 mL) and extracted
with EtOAc (3 ꢀ 10 mL) and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The given residue
was purified by column chromatography (petroleum ether/EtOAc
5:1) to give the sulfonation product 2a (109.0 mg, 81%) as a yellow
solid.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21672136, 21272149 and 21302123) for financial sup-
port. The authors thank Prof. Hongmei Deng (Laboratory for
Microstructures, SHU) for NMR spectroscopic measure-
ments.
Although the detailed reaction mechanism remains to be
clarified, a plausible mechanism for this reaction was
proposed in Scheme 7. Copper sulfate was initially reduced
by t-BuNC to form the complex A, where the isocyanide also
acted as a ligand. The coordination of the isocyanide to
copper center may stabilize the CuI species and weaken the
Conflict of interest
The authors declare no conflict of interest.
À
O S bond thus activating the sulfate anion. The given
complex A reacted with electron-rich heteroarene substrate
to afford CuI heteroaryl sulfonic intermediate B via a Friedel–
Crafts-type SEAr reaction, which finally reacted with different
À
Keywords: C H activation · copper sulfate · heterocycles ·
isocyanide · sulfonation
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Manuscript received: December 27, 2016
Revised: February 12, 2017
Final Article published: && &&, &&&&
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Communications
À
C H Activation
X. Hong, Q. Tan, B. Liu,
B. Xu*
&&&& — &&&&
The magic of bluestone: A novel and
direct approach to alkyl/aryl heteroarene
sulfonic esters using copper sulfate as an
environmentally benign inorganic sulfo-
nation reagent was realized with the aid
of isocyanide. The otherwise chemically
inert copper sulfate was unusually acti-
vated by an isocyanide and employed as
the source of the sulfonic substituents in
an unprecedented fashion.
Isocyanide-Induced Activation of Copper
Sulfate: Direct Access to Functionalized
Heteroarene Sulfonic Esters
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!