Iron/copper co-catalyzed highly selective arylation of sulfinamides with aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2019.151167

In the present study, an inexpensive but efficient Iron(III) and Copper(II) co-catalyst without ligands catalyzed arylation of sulfinamides with aryl iodide was primarily reported. In brief, in the presence of Fe(NO₃)₃·9H₂O, CuO and K₃PO₄, the highly selective C–N cross coupling of several sulfinamides and aryl iodides was achieved in high chemical yield, while the aryl chlorides and bromides could not yield coupling products. It is noteworthy that through the arylation of chiral tert-butanesulfinamide with aryl iodides, N-aryl tert-butanesulfinamides are provided without racemization, even in gram-scale. The possible mechanism was that This oxidative addition process between copper catalyst and aryl-iodides might be significantly accelerated by active Fe(III) species. Moreover, using this synthetic method, a facile and efficient access was developed for the derivatives of N-phenyl sulfinamides, which might help to develop new drug molecules and material chemicals.

Full text of DOI:10.1016/j.tetlet.2019.151167

Tetrahedron Letters 60 (2019) 151167
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron/copper co-catalyzed highly selective arylation of sulfinamides with
aryl iodides
b,
Shuanglin Qin a,b,1, Yunhao Luo b,1, Yue Sun b, Le Tian b, Shende Jiang a, Jun yan c, , Guang Yang
⇑
⇑
a School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, People’s Republic of China
b The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Key Laboratory for Medical Data Analysis and Statistical Research of Tianjin,
Tianjin 300071, People’s Republic of China
c School of Chemistry and Chemical Engineering, Central South University, Changsha 410083, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2019
Revised 11 September 2019
Accepted 17 September 2019
Available online 18 September 2019
In the present study, an inexpensive but efficient Iron(III) and Copper(II) co-catalyst without ligands cat-
alyzed arylation of sulfinamides with aryl iodide was primarily reported. In brief, in the presence of Fe
(NO3)3Á9H2O, CuO and K3PO4, the highly selective C–N cross coupling of several sulfinamides and aryl
iodides was achieved in high chemical yield, while the aryl chlorides and bromides could not yield cou-
pling products. It is noteworthy that through the arylation of chiral tert-butanesulfinamide with aryl
iodides, N-aryl tert-butanesulfinamides are provided without racemization, even in gram-scale. The pos-
sible mechanism was that This oxidative addition process between copper catalyst and aryl-iodides
might be significantly accelerated by active Fe(III) species. Moreover, using this synthetic method, a facile
and efficient access was developed for the derivatives of N-phenyl sulfinamides, which might help to
develop new drug molecules and material chemicals.
Keywords:
Iron/copper co-catalyzed
Sulfinamides
C–N bond formation
Cross coupling
Ó 2019 Elsevier Ltd. All rights reserved.
Gram-scale synthesis
Sulfinamides are a crucial class of organic compounds in mod-
ern organic chemistry [1]. Enantiomer-pure sulfinamides and their
derivatives have been widely employed in the synthesis of chiral
drugs and natural products [1]; it has also been used as chiral
ligands in catalytically asymmetric reactions [2]. Moreover, Sulfi-
namides are good precursors for the synthesis of sulfonamides,
which are found in many drug molecules [2]. Recently, synthetic
methodologies have been developed for transition metals cat-
alyzed formation of chiral C–C bonds, using sulfinamides as chiral
directing groups [3]. There were few facile methods developed for
direct formation of C–N bond between various sulfiniamides and
aryl halides. The arylations of sulfinamide derivatives from thiony-
lanilines, sulfinylazides, sulfonyl chlorides and methyl sulfonates
with Grignard reagents and amines have been investigated in sev-
eral papers [4]. Recently, Zeng group and Cai & Guo Group have
formulated the cross-coupling strategies to generate racemic and
chiral sulfinamides, using Pd and Cu catalysts, respectively [5].
Inspired by the pioneer Fe-catalyzed cross-coupling reactions [6],
especially Taillefer’s report [7], an extremely simple Iron(III)-
Copper(II) bimetallic catalytic system was demonstrated in this
study for N-arylation of sulfinamides with aryl iodides (Scheme 1).
A racemic tert-butanesulfinamide Rac-1 and 1-chloro-4-iodo-
benzene 2a were taken as model substrates for the initial investi-
gation. Taillefer’s optimized conditions were first employed for
the test. The desired product 3a was isolated with 36% yield
(Table 1, entry 1). As shown in entry 2, the reaction did not occur
when Cu(acac)2 replaced CuO. Note that the reactions led to clean
conversion when they were catalyzed by inorganic iron(III) salts
(e.g. FeCl3Á6H2O and Fe(NO3)3Á9H2O), and the isolated yields
⇑
Corresponding authors.
E-mail addresses: yanjun@csu.edu.cn (J. yan), Guang.yang@nankai.edu.cn
(G. Yang).
Scheme 1. Overview.
1
Shuanglin Qin and Yunhao Luo are contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2019.151167
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
S. Qin et al. / Tetrahedron Letters 60 (2019) 151167
Table 1
the method exhibits a good tolerance of functional group. For
Optimization of reaction conditions.
instance, substrates 2 bearing electron-withdrawing or electron-
donating at different positions of the aryl ring reacted efficiently
to generate the corresponding products 3b-3p of 79–93% yield
(table 2). Even for the secondary sulfinamides substrates, the
cross-coupling reactions could work excellently with high yield
under the optimized conditions (products 3t and 3u, table 2). In
the meantime, as shown in table 3, various patterns of substituted
sulfinamides could also couple with aryl iodides to generate the
products of good to excellent yield.
Based on these good results, enantiomeric pure (R)-tert-butane-
sulfinamide R-1 has been adopted as the coupling precursor
(as shown in table 4). High ee values of all coupling products were
used, which reveals no significant epimerization under the
optimized conditions. Moreover, gram-scale synthesis of chiral
N-aryl-tert-butanesulfinamides with excellent yield and enan-
tiomeric selectivity was also verified (Scheme 2).
To gain insights into the reaction mechanism, first, using excess
TEMPO was found to have no significant inhibiting effect on the
reaction, suggesting that the reaction did not undergo a radical
process (Entry 1, Table 5). It is noteworthy that all of the reactions
could occur smoothly and efficiently, when CuI and FeSO4Á7H2O
replaced CuO and Fe(NO3)3Á9H2O, respectively (Entry 2, 3 and 6,
Table 5). Bubbling air into the reaction could significantly stopped
the reaction (Entry 4, Table 5). Interestingly, as catalyzed by CuI
without Fe(NO3)3Á9H2O, the reaction was dramatically moderated.
62% of 3a was achieved over 60 h (Entry 5, Table 5). Using DMAc as
solvent instead of DMF, led to low yield (37%, Entry 7, Table 5). The
reaction did not occur when THF or DCE replaced DMF (Entry 8 and
9, Table 5). These results indicated that DMF played a crucial role in
the process of the reaction.
Entry
[Fe] cat.
(0.15 eqv.)
[Cu] cat.
(0.1 eqv.)
Bases
(2 eqv.)
Yieldb
1
2
3
4
5
6
7
8
9
10
Fe(acac)3
Fe(acac)3
FeCl3Á6H2O
CuO
Cu(acac)2
CuO
CuO
CuO
CuO
CuO
CuO
CuO
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOt-Bu
K3PO4
NaOH
36%
trace
79%
85%
83%
30%
93%
82%
NR
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2Oa
Fe(NO3)3Á9H2Oa
Fe(NO3)3Á9H2Oa
Fe(NO3)3Á9H2Oa
–
K3PO4
K3PO4
Fe(NO3)3Á9H2Oa
NR
a
0.1 eqv.
Isolated yield.
b
reached 79% and 85%, respectively (Entry 3 and entry 4). Reduction
of iron(III) catalyst loading to 0.1 eqv., the reaction was still effi-
cient (Entry 5). Besides, several common inorganic bases were
screened out for the reaction (entry 6, 7 and 8). The optimal result
was achieved from the addition of K3PO4, with the cross-coupling
product 3a of 93% yield (Entry 7). However, there was no reaction
without Fe(NO3)3Á9H2O or CuO catalysts (Entry 9 and 10).
With the optimized conditions in hand (Table 1, Entry 7), the
scope of substrates was further studied (Tables 2 and 3). As a
result, the cross-coupling did not have any effect on aryl bromides
and aryl chlorides. The products 3b, 3c, 3d, 3e and 3f might be vital
synthetic intermediates for further cross-coupling transformations
to fabricate more complicated compounds. All the coupling prod-
ucts could be isolated with good to excellent yield, suggesting that
However, the mechanism how iron interacts with copper cata-
lysts and how to accelerate the reaction is still unknown [7,8].
Based on the limited observations, the plausible mechanism is pro-
posed (Scheme 3) tentatively. Cu(II) might be firstly reduced by
DMF in high temperature to generate Cu(I) [9], which occurred
Table 2
Investigation of scope of aryl iodide.

S. Qin et al. / Tetrahedron Letters 60 (2019) 151167
3
Table 3
Cross-coupling reaction between more sulfiniamides with aryl iodides.
Table 4
Cross-coupling reaction between (R)-tert-butanesulfinamide with aryl iodides.
Entry
1c
Products
Yielda
91%
eeb
95%
2
90%
96%
3
93%
92%
99%
97%
4d
(continued on next page)

4
S. Qin et al. / Tetrahedron Letters 60 (2019) 151167
Table 4 (continued)
Entry
5
Products
Yielda
92%
eeb
99%
6d
93%
99%
a
Isolated yield.
ee values were measured by chiral HPLC.
The reaction was performed in gram-scale.
The absolute configuration of 8d and 8f were determined by X-ray crystallographic analysis (8d, CCDC 1900195; 8f, CCDC 1900194).
b
c
d
Scheme 2. Gram-scale coupling reaction to furnish chiral N-aryl-tert-butanesulfi-
namides 8a.
oxidative addition with PhI affording the Cu(III) species A. Fe(III) or
Fe(II) might play an essential role in stabilizing the deprotonated
sulfinamides. After the standard ligand exchange, followed by
reductive elimination, the cross-coupling product was finally
furnished.
Based on the excellent selectivity between sulfinamides and
aryl iodides, rather than aryl bromides, several derivatives of N-
phenyl sulfinamides could be effectively furnished by ‘‘a two-step
cross-coupling relay” (Scheme 4). To be specific, common interme-
diate 3d, obtained from arylation of tert-butanesulfinamide with p-
bromoiodobenzene, could directly deliver compounds 9 (Sono-
gashira), 10 (Suzuki), 11 (Buchwald-Hartwig) and 12 (Ullmann)
through transition metal catalyzed C–C or C–N cross-coupling
Scheme 3. Plausible Mechanism.
reactions. It would provide a quick method to furnish N-aryl sul-
fonamides (such as compound 13 and 14).
To sum up, in this study, a ligand-free Fe/Cu co-catalyzed C–N
cross coupling of sulfinamides with aryl iodides was developed.
Under the optimized conditions, Fe(NO3)3Á9H2O and CuO were
adopted as the co-catalytic system and K3PO4 as the base, and
the cross-coupling reaction took place efficiently and cost-eco-
nomically. Moreover, the chirality of (R)-tert-butanesulfinamides
could be retained in N-aryl tert-butanesulfinamides without
racemization under the optimized conditions. Besides, the gram-
scale synthesis was also easily performed with excellent yield
Table 5
Reactions for exploration of possible mechanism.
Entry
[Fe] cat.
[Cu] cat.
Additive
Solvent
Time
Yielda
1
2
3
4
5
6
7
8
9
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
FeSO4Á7H2O
CuO
CuI
CuO
CuO
CuI
TEMPOb
none
none
Air
none
none
none
none
none
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
THF
8 h
8 h
8 h
8 h
>60 h
8 h
8 h
8 h
8 h
62%
79%
95%
<5%
62%
76%
37%
NR
Fe(NO3)3Á9H2O
none
FeSO4Á7H2O
CuI
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
CuO
CuO
CuO
DCE
NR
a
b
c
Isolated yield.
2 equiv. of TEMPO was used.
DMAc = N,N-Dimethylacetamide.

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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151167.
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