L-proline-promoted CuI-catalyzed C-S bond formation between aryl iodides and thiols

Article abstract of DOI:10.1080/00397910600977533

An improved, mild procedure for the CuI-catalyzed coupling reactions of aryl iodides with aliphatic and aromatic thiols, using L-proline as the ligand, is reported. This procedure is noteworthy given its high generality and exceptional level of functional group toleration. Copyright Taylor & Francis Group, LLC.

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L ‐Proline‐Promoted CuI‐Catalyzed C‐S Bond
Formation between Aryl Iodides and Thiols
Hui Zhang a , Weiguo Cao a b & Dawei Ma c
a Department of Chemistry, Shanghai University, Shanghai, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Science, Shanghai, China
c State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
Shanghai, China
Version of record first published: 25 Jul 2007.
To cite this article: Hui Zhang , Weiguo Cao & Dawei Ma (2007): L ‐Proline‐Promoted CuI‐Catalyzed C‐S Bond
Formation between Aryl Iodides and Thiols, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:1, 25-35
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Synthetic Communicationsw, 37: 25–35, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600977533
L-Proline-Promoted CuI-Catalyzed
C-S Bond Formation between Aryl
Iodides and Thiols
Hui Zhang
Department of Chemistry, Shanghai University, Shanghai, China
Weiguo Cao
Department of Chemistry, Shanghai University, Shanghai, China and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Science, Shanghai, China
Dawei Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
Shanghai, China
Abstract: An improved, mild procedure for the CuI-catalyzed coupling reactions of
aryl iodides with aliphatic and aromatic thiols, using L-proline as the ligand, is
reported. This procedure is noteworthy given its high generality and exceptional
level of functional group toleration.
Keywords: aryl sulfide, L-proline, copper iodide, cross-coupling
INTRODUCTION
Methods for the formation of aryl–sulfur bonds are indispensable tools in
synthetic chemistry. Their importance stems from the prevalence of aryl–
sulfur bonds in many molecules that are of biological, pharmaceutical, and
material interest.[1] However, only a few studies have been reported so far
Received in USA May 12, 2006
Address correspondence to Hui Zhang, Department of Chemistry, Shanghai Univer-
sity, Shanghai 200444, China. E-mail: yehao7171@163.com
25

26
H. Zhang, W. Cao, and D. Ma
for the formation of aryl–sulfur bonds using either Pd or Ni catalysts.[2,3]
Alternatively, one can use Cu catalysts to mediate the C-S bond formation.
This approach is attractive from an industrial perspective because Cu is
much less expensive and toxic than Pd and Ni.[4]
The traditional Cu-mediated coupling between thiols and aryl halides
requires the use of copper salts in greater than stoichiometric amounts, polar
solvents such as hexamethyl phosphoric acid triamide (HMPA), and high
temperatures (around 2008C).[5] Recently, Bates et al. reported an improved
protocol for the coupling between aryl iodides and thiols using 10 mol% CuI
and 10 mol% neocuproine, with NaOtBu as the base, in toluene at 1108C.[6]
Kong and Buchwald also reported an efficient Cu-catalyzed C-S coupling
reaction between aryl iodides and thiols using 5 mol% CuI and 2 equivalents of
HOCH2CH2OH as ligand.[7] Wu and He then reported that microwave heating
could enhance the CuI-catalyzed C-S couplings.[8] Naus et al. successfully
utilized the CuI catalysts for the arylation of 1-thiosugars.[9]
Our recent results on amino acid–promoted CuI-catalyzed C-N and C-O
coupling chemistry[10] suggest to us that by choosing a suitable amino acid as
ligand, our catalytic system might be used for C-S couplings and would be
tolerant of a wide variety of functional groups. At the same time, Deng
et al. reported their protocol for the coupling reaction of aryl iodides with
thiols, using 20 mol% N-methylglycine, 5 mol% CuI, and 2.5 equiv. KOH
in dioxane at 100–1208C.[11] However, the scope of functional groups is
somewhat limited by their use of a strong base and high temperature
(.1008C). Thus, we describe our method as an improvement on their
protocol. Under our mild conditions (20 mol% L-proline, 10 mol% CuI, 2
equiv. K2CO3 or K3PO4 as the mild base, in 1,2-dimethoxy ethane (DME)
or DMF at 808C), various functionalized aryl iodides coupled smoothly
with thiols to give satisfying results.
RESULTS AND DISCUSSION
In the first stage of the study, 4-methoxy-1-iodobenzene and thiophenol were
used as the prototypical substrate combination for preliminary optimization of
the reaction conditions (Table 1). Copper(I) complexes generally gave
superior results compared to copper(II) sources in terms of conversion and
yield of the desired product. A variety of these were efficient, but we chose
to focus on the use of CuI because of its stability in air. Among different
solvents, we found that DME was the solvent of the choice (Table 1,
entry 2). Both K2CO3 and K3PO4 were found to be effective bases for this
coupling reaction, but K2CO3 was better because of its higher yield of the
product. Compared to N,N-dimethylglycine, L-proline was the better ligand
(Table 1, entries 5, 6). Also, by lifting the temperature from 708C to 808C
and increasing the reaction time to 40 h, almost all the starting material was
converted into the desired product (Table 1, entry 8).

C-S Bond Formation between Aryl Iodides and Thiols
27
Table 1. CuI-catalyzed coupling reaction of thiophenol and 4-methoxy-1-iodoben-
zene under various conditionsa
T
Time
(h)
Yield
(%)b
Entry
Solvent
DMF
DME
Base
Ligand
L-proline
L-proline
(8C)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
70
70
70
70
70
70
70
80
24
24
24
24
24
24
24
40
48
67
40
57
55
28
15
99
Dioxane
L-proline
L-proline
Isopropanol K2CO3
DME
DME
DME
DME
K3PO4
K3PO4
L-proline
N,N-dimethylglycine
Cs2CO3 L-proline
K2CO3 L-proline
aGeneral conditions: CuI 10 mol%, 20 mol% ligand, 3 ml solvent, 2 mmol aryl
iodide, 1.2 equiv. PhSH, 2 equiv. base, under high purity nitrogen.
bIsolated yield.
Thus, the optimized reaction conditions were 10 mol% CuI, 2 equiv.
K2CO3, and 20 mol% L-proline in dry DME at 808C under high-purity
nitrogen. In the first part of this study, these reaction conditions were applied
to the coupling of various functionalized aryl iodides and thiophenol counter-
parts (Table 2). As can be seen, the reaction proceeds well with aryl iodides
carrying either electron-donating (e.g., OCH3) or electron-withdrawing
groups (e.g., CF3). The yields are mostly excellent. However, the bromo
group in o-bromoiodobenzene does not show any significant coupling
(Table 2, entry1); therefore, the present condition is not sufficient for the C-S
coupling reactions using aryl bromides as reactants. Morever, when this
procedure was applied to the coupling reactions of aryl iodides with alkyl
thiols, the coupling products were obtained in low yields (Table 2, entry 11).
Because alkyl thiol is generally less ionized than arenethiol under the
same basic condition, and the degree of ionization of the nucleophile in
solvent plays an important role in this type of coupling reaction,[10,12] we
choose the stronger base K3PO4 and the polar solvent DMF to replace
K2CO3 and DME in the procedure. To our delight, aryl iodides could be
coupled successfully with alkyl thiols in good yield under this improved
condition (Table 3). This second portion of our work involved the application
of our protocol to the combination of ortho-substituted aryl and of heteroaryl
iodide substrates (Table 3, entries 6, 7). As can be seen from the result in
entry 5, an alkanethiol with an electron-drawing ester group can only be
coupled in moderate yield. This demonstrates that the protocol is not
applied well with electron-deficient thiols.

28
H. Zhang, W. Cao, and D. Ma
Table 2. CuI-catalyzed carbon-sulfur bond formation of arenethiolsa
Aryl
iodides
Yield
(%)b
Entry
1
ArSH
Products
92
2
3
96
92
4
5
98
94
6
7
85
99
8
9
92
98
(continued)

C-S Bond Formation between Aryl Iodides and Thiols
29
Table 2. Continued
Aryl
iodides
Yield
(%)b
Entry
10
ArSH
Products
80
11
33
aReaction conditions: ArI 2 mmol, ArSH 1.2 equiv., CuI 10 mol%, K2CO3 2 equiv.,
L-proline 20 mol%, in DME at 808C under high purity nitrogen.
bIsolated yield.
CONCLUSION
An improved mild procedure has been found for the CuI-catalyzed coupling
reactions of aryl iodides with aliphatic and aromatic thiols with amino acid
as the ligand. This method is particularly noteworthy given its high generality,
exceptional level of functional group toleration, and satisfying yield of the
coupling product.
EXPERIMENTAL
General Considerations
All reactions were carried out in resealable tubes and run under an atmosphere
of high-purity nitrogen. DME and DMF were freshly distilled from CaH2.
K3PO4 was purchased from Fluka and used without further purification. It is
important that the base is powdered and free flowing, and the same is true
for K2CO3. Aryl iodides, amino acids, and thiols were purchased from com-
mercial sources and used without further purification. Copper(I) iodide was
used after washing with THF. Flash-column chromatography was performed
1
using silica gel H (10–40 m). H NMR and 13C NMR was recorded on
a 400-MHz instrument with chemical shifts reported relative to TMS. New
compounds were characterized by 1H NMR, 13C NMR, mass spectrum
(MS), and high resolution mass spectrum (HRMS). Compounds described
1
in the literature were characterized by comparing their H NMR to the pre-
viously reported data. All yields reported represent an average of at least
two independent runs; the purity of the products was confirmed by 1H NMR.

30
H. Zhang, W. Cao, and D. Ma
Table 3. CuI-catalyzed carbon–sulfur bond formation of alkylthiolsa
Aryl
iodides
Yield
(%)b
Entry
1
R2SH
Product
99
2
3
98
97
4
5
99
40
6
7
8
89
98
83
9
95
99
10
aReaction conditions: ArI 2 mmol, R2SH 1.2 equiv., CuI 10 mol%, K3PO4 2 equiv.,
L-proline 20 mol%, in DMF at 808C under high purity nitrogen.
bIsolated yield.

C-S Bond Formation between Aryl Iodides and Thiols
31
General Procedure for the Coupling Reaction of Aryl Iodides with
Thiols Catalyzed by CuI and L-proline
A screw-capped tube was charged with 10 mol% CuI, 20 mol% amino acid,
2 equiv. K2CO3 for arenethiol or K3PO4 for alkylthiol, 2 mmol aryl iodide
(if solid), and 1.1 equiv thiol (if solid); evacuated; and backfilled with
high-purity nitrogen (three cycles). Thiol (1.1 equiv.) (if liquid), 3 ml of
DME for arenethiol or DMF for alkylthiol, and 2 mmol of aryl iodide (if
liquid) were added by syringe at room temperature under nitrogen. The
sealed tube was put into the oil bath, which was preheated to 808C, and the
reaction mixture was stirred at the same temperature for 40 h. The cooled
mixture was partitioned between 10 ml of sat. NaCl aq. and 20 ml of
EtOAc. The organic layer was separated, and the aqueous layer was
extracted with 10 ml EtOAc each time until thin-layer chromatography
(TLC) showed no trace of the product left in the aqueous layer. The
combined organic layers were concentrated. Purification of the residue by
flash chromatography on silica gel (3 ꢀ 15 cm, petroleum ether/ethyl
acetate) gave the desired product.
Data
1
(2-Bromo-phenyl)-phenyl sulfide (Table 2, entry 1). Clear oil. H NMR
(400 MHz, CDCl3) d 7.55–7.57 (m, 1H), 7.34–7.47 (m, 5H), 7.12–7.16
(m, 1H), 7.01–7.05 (m, 1H), 6.91–6.94 (m, 1H); MS (EI) m/z 264 (Mþ)
(69), 266 [(M þ 2)þ] (69), 265, 186, 185, 184, 152, 92.
1
(3-Trifluromethyl-phenyl)-phenyl sulfide (Table 2, entry 2). Clear oil. H
NMR (400 MHz, CDCl3) d 7.52 (s, 1H), 7.26–7.50 (m, 8H); MS (EI) m/z
254 (Mþ), 255, 185, 184, 84, 77, 51.
(3,5-Dimethyl-phenyl)-phenyl sulfide (Table 2, entry 3). Clear oil. 1H NMR
(400 MHz, CDCl3) d 7.14–7.30 (m, 5H), 6.98 (s, 2H), 6.84 (d, J ¼ 0.9 Hz,
1H), 2.22 (s, 6H); MS (EI) m/z 214 (Mþ), 215, 199, 198, 184, 165, 77, 51.
(4-Amino-phenyl)-phenyl sulfide (Table 2, entry 4). Pale yellow solid. Mp:
1
94–968C. (lit.[13] mp: 95.88C) H NMR (400 MHz, CDCl3) d 7.07–7.32
(m, 7H), 6.65–6.69 (m, 2H), 3.80 (br s, 2H); MS (ESI) m/z 202 (M þ H)þ.
1-(4-Phenylsulfanyl-phenyl)-ethanone (Table 2, entry 5). Yellow solid.
1
Mp: 67–698C. (lit.[14] mp: 65.8–66.58C). H NMR (400 MHz, CDCl3) d
7.80–7.83 (m, 2H), 7.48–7.51 (m, 2H), 7.39–7.42 (m, 3H), 7.20–7.22
(m, 2H), 2.55 (s, 3H); MS (EI) m/z 228 (Mþ), 229, 214, 213, 185, 184,
152, 43.

32
H. Zhang, W. Cao, and D. Ma
1-Methoxy-4-(3,5-dimethylphenylsulfanyl)-benzene (Table 2, entry 6).
1
Oil. H NMR (400 MHz, CDCl3) d 7.37–7.39 (m, 2H), 6.85–6.88 (m, 2H),
6.81 (s, 2H), 6.77 (s, 1H), 3.80 (s, 3H), 2.22 (s, 6H); 13C NMR (100 MHz,
CDCl3,) d 159.7, 138.7, 137.9, 135.1, 128.0, 126.3, 124.9, 115.0, 55.4, 21.3;
MS (EI) m/z 244 (Mþ), 245, 229, 186, 86, 84, 77, 47; HRMS (ESI) for
C15H17OS [(M þ H)þ] found 245.0995, requires 245.0983.
1-Methoxy-4-phenylsulfanyl-benzene (Table 2, entry 7). Clear oil. 1H
NMR (400 MHz, CDCl3) d 7.41 (d, J ¼ 8.7 Hz, 2H), 7.10–7.24 (m, 5H),
6.89 (d, J ¼ 8.7 Hz, 2H), 3.81 (s, 3H); MS (EI) m/z 216 (Mþ), 217, 201,
171, 129, 77, 51, 45.
Diphenylsulfide (Table 2, entry 8). Clear oil. 1H NMR (400 MHz, CDCl3) d
7.30–7.35 (m, 4H), 7.26–7.29 (m, 4H), 7.21–7.25 (m, 2H); MS (EI) m/z 186
(Mþ), 185, 154, 109, 77, 65, 51, 39.
1-Methoxy-4-(3-trifluromethylphenylsulfanyl)-benzene (Table 2, entry 9).
Clear oil. 1H NMR (400 MHz, CDCl3) d 7.44 (d, J ¼ 8.7 Hz, 2H), 7.23–7.37
(m, 4H), 6.93 (d, J ¼ 8.7 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.5, 141.0, 136.3, 131.5, 131.2, 130.4, 129.3, 123.91, 123.87, 122.40,
122.23, 122.19, 115.4, 55.5; MS (EI) m/z 284 (Mþ), 286, 285, 270, 269,
241, 172, 171; HRMS (EI) for C14H11F3OS [(M þ H)þ] found 284.0490,
requires 284.0483.
1-Methoxy-4-p-tolylsulfanyl-benzene (Table 2, entry 10). Clear oil. 1H
NMR (400 MHz, CDCl3) d 7.35 (d, J ¼ 9.1 Hz, 2H), 7.12 (d, J ¼ 8.2 Hz,
2H), 7.04 (d, J ¼ 8.2 Hz, 2H), 6.85 (d, J ¼ 9.1 Hz, 2H), 3.78 (s, 3H), 2.28
(s, 3H); MS (EI) m/z 230 (Mþ), 231, 232, 216, 215, 200, 172, 171.
Butylsulfanyl-3-trifluoromethyl-benzene (Table 3, entry 1). Clear oil.
1H NMR (400 MHz, CDCl3) d 7.53 (s, 1H), 7.24–7.46 (m, 3H), 2.95
(t, J ¼ 7.3 Hz, 2H), 1.61–1.68 (m, 2H), 1.41–1.51 (m, 2H), 0.93
(t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 234 (Mþ), 235, 191, 178, 57, 45,
41, 39.
Butylsulfanyl-3,5-dimethyl-benzene (Table 3, entry 2). Clear oil. 1H NMR
(400 MHz, CDCl3) d 6.94 (s, 2H), 6.79 (s, 1H), 2.90 (t, J ¼ 7.3 Hz, 3H), 2.28
(s, 6H), 1.59–1.65 (m, 2H), 1.42–1.48 (m, 2H), 0.92 (t, J ¼ 7.3 Hz, 3H); MS
(EI) m/z 194 (Mþ), 196, 195, 151, 138, 105, 91, 41.
4-Butylsulfanyl-aniline (Table 3, entry 3). Yellow oil. 1H NMR
(400 MHz, CDCl3) d 7.22–7.23 (m, 2H), 6.60–6.62 (m, 2H), 3.68 (br s,
2H), 2.76 (t, J ¼ 7.3 Hz, 2H), 1.51–1.58 (m, 2H), 1.37–1.43 (m, 2H),
0.88 (t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 181 (Mþ), 183, 182, 138, 125,
124, 94, 80.

C-S Bond Formation between Aryl Iodides and Thiols
33
1-(4-Butylsulfanyl-phenyl)-ethanone (Table 3, entry 4). Clear oil. 1H
NMR (400 MHz, CDCl3) d 7.85 (d, J ¼ 8.7 Hz, 2H), 7.30 (d, J ¼ 8.7 Hz,
2H), 2.99 (t, J ¼ 7.3 Hz, 2H), 2.57 (s, 3H), 1.65–1.71 (m, 2H),
1.45–1.51 (m, 2H), 0.95 (t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 208 (Mþ),
209, 193, 152, 137, 109, 43, 41.
(4-Acetyl-phenylsulfanyl)-acetic acid methyl ester (Table 3, entry 5). Clear
oil. 1H NMR (400 MHz, CDCl3) d 7.88 (d, J ¼ 8.3 Hz, 2H), 7.38
(d, J ¼ 8.3 Hz, 2H), 3.75 (s, 5H), 2.59 (s, 3H); MS (EI) m/z 224 (Mþ), 225,
210, 209, 165, 123, 45, 43.
3-Butylsulfanyl-pyridine (Table 3, entry 6). Yellow oil. 1H NMR
(400 MHz, CDCl3) d 8.57 (s, 1H), 8.41 (br s, 1H), 7.62–7.64 (m, 1H),
7.19–7.22 (m, 1H), 2.93 (t, J ¼ 7.3 Hz, 2H), 1.59–1.69 (m, 2H), 1.40–1.50
(m, 2H), 0.92 (t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 167 (Mþ), 168, 124, 111,
78, 67, 57, 41.
1
Butyl-o-tolyl sulfide (Table 3, entry 7). Clear oil. H NMR (400 MHz,
CDCl3) d 7.25 (d, J ¼ 7.3 Hz, 1H), 7.12–7.16 (m, 2H), 7.04–7.08 (m, 1H),
2.89 (t, J ¼ 7.3 Hz, 2H), 2.36 (s, 3H), 1.61–1.69 (m, 2H), 1.43–1.49
(m, 2H), 0.93 (t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 180 (Mþ), 137, 124, 123,
91, 57, 45, 41.
1-(4-Benzylsulfanyl-phenyl)-ethanone (Table 3, entry 8). White solid. Mp:
1
113–1158C. (lit.[15] 113.9–115.38C). H NMR (400 MHz, CDCl3) d 7.83
(d, J ¼ 8.7 Hz, 2H), 7.26–7.38 (m, 7H), 4.22 (s, 2H), 2.56 (s, 3H); MS (EI)
m/z 242 (Mþ), 243, 108, 92, 91, 65, 45, 43.
1-Butylsulfanyl-4-methoxy-benzene (Table 3, entry 9). Clear oil. 1H
NMR (400 MHz, CDCl3) d 7.33 (d, J ¼ 8.7 Hz, 2H), 6.84 (d, J ¼ 8.7 Hz,
2H), 3.79 (s, 3H), 2.82 (t, J ¼ 7.3 Hz, 2H), 1.53–1.58 (m, 2H),
1.39–1.44 (m, 2H), 0.90 (t, J ¼ 7.3 Hz, 3H); MS (EI) m/z 196 (Mþ),
197, 153, 140, 139, 125, 57, 41.
1-(4-Cyclohexylmercapto-phenyl)-ethanone (Table 3, entry 10). Pale
yellow crystals. Mp: 66–688C. (lit.[16] mp: 67.5–688C). 1H NMR
(400 MHz, CDCl3) d 7.85 (d, J ¼ 7.8 Hz, 2H), 7.35 (d, J ¼ 7.8 Hz, 2H),
3.28–3.33 (m, 1H), 2.56 (s, 3H), 2.02–2.05 (m, 2H), 1.78–1.82 (m, 2H),
1.25–1.45 (m, 6H); MS (ESI) m/z 235 (Mþ).
ACKNOWLEDGMENT
We thank the foundation of Shanghai Municipal Commission of Education for
financial support under Grant no. 05AX12.

34
H. Zhang, W. Cao, and D. Ma
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