Chemo-controlled cross-coupling of Di(hetero)aryl disulfides with grignard reagents: C-C vs. C-S bond formation

Article abstract of DOI:10.1002/adsc.201400980

A general protocol for the chemoselectivity-controlled C-C and C-S coupling reactions of di(hetero)aryl disulfides with Grignard reagents catalyzed by ferrocene and palladium acetate has been developed. Ferrocene favored the formation of C-S coupled products at low temperature, whereas C-C bond couplings were favored when palladium acetate was used. All the reactions proceeded with excellent chemoselectivity and in good yields under mild conditions, and a library of molecules with pyridine and pyrimidine scaffolds was produced.

Full text of DOI:10.1002/adsc.201400980

UPDATES
DOI: 10.1002/adsc.201400980
Chemo-Controlled Cross-Coupling of Di(hetero)aryl Disulfides
À
À
with Grignard Reagents: C C vs. C S Bond Formation
Bao-Xin Du,a Zheng-Jun Quan,a,* Yu-Xia Da,a Zhang Zhang,a
and Xi-Cun Wanga,*
a
Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China. Gansu Key Laboratory of
Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu
730070, Peopleꢀs Republic of China
E-mail: quanzhengjun@hotmail.com or wangxicun@nwnu.edu.cn
Received: October 13, 2014; Revised: January 26, 2015; Published online: March 24, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400980.
Abstract: A general protocol for the chemoselectiv-
a variety of aromatic moieties and sulfur-containing
reagents.[4,5] Several papers dealing with the reactions
of alkenyl, vinyl, and aryl sulfides with Grignard re-
agents, mediated by Ni or Pd catalysts, and leading to
alkenes and biaryl compounds, have been publish-
ed.[5f,6] Since the pioneering work of Liebeskind, in
which Pd/Cu(I) carboxylate was employed as a cata-
lyst to achieve copper-mediated desulfurative cou-
pling of organosulfur compounds, these compounds
have attracted considerable interest as alternative
candidates for organohalide reagents among synthetic
organic chemists in the past decade.[7] Recently, some
examples of Rh- or Pd-catalyzed cross-coupling reac-
tions of aryl methyl sulfides with organoboron or or-
ganozinc compounds were reported. In these elegant
methods, the cross-coupling reaction was rationalized
À
À
ity-controlled C C and C S coupling reactions of
di(hetero)aryl disulfides with Grignard reagents cat-
alyzed by ferrocene and palladium acetate has been
À
developed. Ferrocene favored the formation of C S
À
coupled products at low temperature, whereas C C
bond couplings were favored when palladium ace-
tate was used. All the reactions proceeded with ex-
cellent chemoselectivity and in good yields under
mild conditions, and a library of molecules with pyr-
idine and pyrimidine scaffolds was produced.
À
Keywords: catalysis; cross-coupling; C S bond
cleavage; di(hetero)aryl disulfides; Grignard re-
agents
À
À
by a C S cleavage pathway to construct the new C C
bond.[8,9]
It is well known that disulfides (R2S2) are an impor-
À
À
Transition metal-catalyzed C C and C heteroatom tant class of organosulfur reagents for the construc-
À
cross-coupling reactions, as versatile and effective tion of C S bonds, and various nucleophilic reagents
methods in organic synthesis,[1,2] play a significant role have been employed to react with disulfides to con-
À
À
in materials chemistry and medicinal chemistry. Gen- struct C S bonds through S S bond cleavage
erally, such procedures involve the coupling of an ac- (Scheme 1, path a).[10–15] However, examples of the
tivated electrophilic substrate with a nucleophile coupling between disulfides and Grignard reagents
through a transition metal-mediated cross-coupling remain limited. In 1997, Rieke reported one example
reaction. In the past decades, great efforts have been of
a cross-coupling between 3-thienylmagnesium
devoted to extending this reaction to different elec- iodide and alkyl disulfides, affording 3-alkylthiothio-
trophiles. However, in most cases, the electrophiles phenes in moderate yield.[11a] Then, Glass and co-
were confined to aryl and alkenyl halides due to their workers used meta-terphenyl Grignard reagents to
higher reactivity towards transition metal catalysis.[3] react with MeSSO2Me or PhSSPh, synthesizing un-
Therefore, the development of new types of electro- symmetrical diaryl sulfides.[11b] There are no reports
philes is still in high demand.[3a]
on the utilization of an iron-catalyzed reaction of di-
Currently, organosulfur compounds, present in sulfides with Grignard reagents to realize the con-
À
many biologically active compounds, are widely used struction of a C C bond, although one paper from
as building blocks in organic synthesis and receive Itami et al. described the C C cross-coupling reaction
À
considerable attention. Some methods for the con- of alkenyl sulfides with Grignard reagents using
struction of C S bonds have been developed using Fe(acac)3 as a catalyst.[16] Our group recently devel-
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Chemo-Controlled Cross-Coupling of Di(hetero)aryl Disulfides
homocoupling) (entry 2). Similar to Fe(acac)3, ferro-
cene gave both 3aa and 4aa, and higher temperatures
À
and longer times improved the yield of the C C cou-
pling product (entries 3–5). It was discovered that fer-
rocene at a lower temperature (À208C) produced the
most promising results, providing 3aa in 74% yield in
a shorter time (entries 6 and 7). Lowering the temper-
ature (entry 8) or raising the equivalents of 2a
(1a:2a=1:4.8) (entry 9) did not provide better results.
Use of an excess of Grignard reagent decreased the
À
selectivity, resulting in a slightly lower yield of the C
S coupling product (entry 9 compared with entry 7).
With respect to its outstanding performance and
lower price, ferrocene was chosen as a better catalyst
À
for the C S coupling reaction (entry 7), although
Pd(OAc)2 was also an efficient catalyst favoring 3aa
(entry 10).
À
With the best reaction conditions for C S bond for-
mation established, C C bond formation was consid-
À
À
À
Scheme 1. Strategy for the construction of C C and C S
bonds through the coupling of disulfides.
ered. From the results in Table 1, higher temperatures
À
favored C C bond formation, but the yield was poor
(Table 1, entry 5). To reverse the selectivity, with the
À
oped the palladium- and copper-catalyzed desulfura- purpose of highly selective formation of the C C cou-
tive cross-coupling reactions of amines, arylboronic pling product 4aa, different Pd catalysts were then
acids and alkynes with disulfides as electrophiles to screened. The use of PdCl2 with a molar ratio of
[17]
À
À
À
generate C C and C N bonds (Scheme 1, path b).
1a:2a=1:2.4 gave the C S coupled 3aa as the major
It was logical to question whether disulfides could product (entry 11). However, an alteration of the
also serve as electrophilic partners in reactions with molar ratio to 1:4.8 resulted in the formation of 4aa
Grignard reagents to achieve the selective formation in 57% yield with 79:21 selectivity (entry 12). When
À
À
of C C and C S bonds.
Pd(OAc)2, Pd(PPh3)4, or PdCl2(dppf)2 was employed
Herein, we report our work on the reaction of di- as the catalyst (entries 13–16), the selectivity was re-
(hetero)aryl disulfides with Grignard reagents, which versed. A good yield (73%) and selectivity (97:3)
À
À
has resulted in the construction of C S and C C were obtained at 08C to room temperature for 2 h
bonds under Fe- and Pd-catalyzed conditions, respec- (entry 13). The yield of 4aa decreased at higher tem-
tively.
peratures, with the formation of the homocoupled
Interestingly, the reaction catalyzed by an Fe cata- product of 2a (entry 17). Then, solvent screening was
À
lyst readily gives the C S bond formation product, performed, and 1,4-dioxane was better than THF
whereas the Pd catalyst favors C C bond formation (entry 18). Finally, a trial of the reaction in the ab-
À
(Scheme 1, path c). Such a catalyst-based control of sence of a catalyst and ligand was performed, and 3aa
the chemoselectivity would provide a highly selective was obtained as the only product in 35% yield
entry into different products from the same sub- (entry 19).
À
strates. Control of selectivity – the same substrates
Then, the generality of this C S cross-coupling was
are applied for different products – remains one of investigated under the optimized Fe-catalyzed condi-
the most important challenges in organic chemistry.[18] tions (Table 1, entry 7). In general, a variety of di(he-
Among the methods that have been employed, con- tero)aryl disulfides smoothly reacted with different
À
trol of selectivity by catalysts has been proven to be Grignard reagents (RMgBr), leading to the C S
very beneficial.[19]
cross-coupling products (Scheme 2). Both electron-
Initially, our studies were focused on the selectivity rich magnesium bromides, such as methyl and 2-me-
À
À
of C C and C S couplings. The reaction of 1a with thoxyphenyl, and electron-poor magnesium bromides,
an excess amount of PhMgBr (2a) was used as such as 4-chlorophenyl, underwent C S cross-cou-
À
À
a model reaction to test the possibility of selective C
C and C S coupling. First, Fe catalysts were applied, Thienyl and 1-naphthyl groups could also be tolerated
and the use of Fe(acac)3 resulted in both C C and C
S coupling products 4aa and 3aa in 8% and 48% sulfides (1) with various Grignard reagents (2), in-
plings to deliver the products 3ab–3ah in good yields.
À
À
À
in this reaction. Similarly, a series of diheteroaryl di-
yield, respectively (entry 1), while FeCl3 gave 3aa as cluding ethyl-, butyl-, hexyl-, heptyl-, and nonylmag-
À
the sole product in 42% yield with formation of the nesium bromides, selectively generated C S coupled
homocoupling product of the Grignard reagent (GR products 3ai–3am in 71–79% yield. The use of
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Bao-Xin Du et al.
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst/Ligand
1a:2a[c]
Temp. [8C]
Time
Yield [%][b]
3aa 4aa
Selectivity
3aa:4aa
1
2
3
4
5
6
7
8
Fe(acac)3/–
FeCl3/–
ferrocene/–
ferrocene/–
ferrocene/–
fe(acac)3/–
ferrocene/–
ferrocene/–
1:4.8
1:4.8
1:4.8
1:4.8
1:4.8
1:2.4
1:2.4
1:2.4
1:4.8
1:2.4
1:2.4
1:4.8
1:4.8
1:4.8
1:4.8
1:4.8
1:4.8
1:4.8
1:2.4
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–65
À20
4 h
4 h
4 h
4
8
86:14
95:5
82:18
76:24
67:33
93:7
97:3
42
55
51
48
63
74
65
70
71
66
15
<2
<2
5
<2
12
16
24
<5
<2
<2
10
8
24 h
24 h
2 h
0.5 h
0.5 h
0.5 h
0.5 h
4 h
4 h
4 h
2 h
2 h
À20
À40
97:3
9
ferrocene/–
Pd(OAc)2/DPE-Phos
PdCl2/PPh3
À20
88:12
89:11
90:10
21:79
3:97
3:97
7:93
10
11
12
13
14
15
16
17
18d
19
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–r.t.
0–r.t.
65
7
PdCl2/PPh3
57
73
73
62
65
41
78
–
Pd(OAc)2/DPE-Phos
Pd(OAc)2/DPE-Phos
Pd(PPh3)4
PdCl2(dppf)2
Pd(OAc)2/DPE-Phos
Pd(OAc)2/DPE-Phos
–
2 h
4 h
2 h
2 h
<5
<2
<2
35
7:93
5:95
2:98
–
0–r.t.
r.t.
[a]
Conditions: 0.2 mmol 1a, 2a (1.0M in THF), catalyst (5 mol%), in 3 mL THF, under N2 atmosphere, unless otherwise
noted.
[b]
[c]
[d]
Isolated yield based on disulfide 1a (2 mmol).
Molar ratio of 1a to 2a.
The reaction was carried out in 2 mL THF and 1 mL 1,4-dioxane.
À
branched isopropylmagnesium bromide and the more the C S coupled products 3gh and 3ha were obtained
reactive benzylmagnesium bromide did not decrease as unique products, showing a lower activity in this
the efficiency of the reaction, giving the desired 3an– process. This reactivity of disulfides was also observed
3ao in good yields. Notably, 1,2-di(pyridin-2-yl) disul- in a previous study.[17b]
fide and aryl disulfides also resulted in 71–77% yields
After the tests with symmetrical diheteroaryl disul-
of 3fa–3ha.
fides, an unsymmetrical disulfide (1i) substrate was
Next, the optimized Pd-catalyzed conditions were examined. When the reaction of 1i with 2a was per-
À
À
explored to test the generality of the C C coupling formed under the C C coupling conditions, a mixture
(Scheme 3). Different diheteroaryl disulfides (1) of 4aa (70%), 4fa (8%), and the C S coupling prod-
À
could be well tolerated in this process, leading to the uct 3fa (48%) was obtained (Scheme 4).
desired products 4. Different Grignard reagents with
both aromatic and aliphatic groups gave the expected pled product 3aa can further react with 2a under the
products 4aa–4ca in good yields, whereas the 1,2-di- standard C C coupling conditions. The C C coupling
(pyridin-2-yl) disulfide reacted with phenyl- and hex- product 4aa was isolated in 71% yield together with
ylmagnesium bromide smoothly at 658C for 6 h, yield- the homocoupling product 2a (Scheme 5). This result
ing the desired products 4fa and 4fk in lower yields. implied that the C S coupled product 3 might be an
Compared with the tested nitrogen-containing dihe- important intermediate for the C C coupling product.
À
In addition to the disulfide employed, the C S cou-
À
À
À
À
teroaryl disulfides, aryl disulfides showed much lower
The control experiments used iodobenzene instead
reactivity. For example, the reaction of 1,2-diphenyl of the Grignard reagent to compare the reactivity of
disulfide and 1,2-bis(4-nitrophenyl) disulfide with ar-
ylmagnesium bromides did not result in any C C cou- (Scheme 6). The reaction of disulfide 1a with iodo-
pled product under similar reaction conditions, but benzene was performed under the C S (Path a) and
a Grignard reagent with a halogen substituent
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Chemo-Controlled Cross-Coupling of Di(hetero)aryl Disulfides
À
Scheme 2. Scope of the ferrocene-catalyzed C S cross-coupling of di(hetero)aryl disulfides and Grignard reagents.
À
Scheme 3. Scope of the Pd-catalyzed C C cross-coupling reaction between diheteroaryl disulfides 1a–1f and Grignard re-
agents 2.
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UPDATES
Bao-Xin Du et al.
acterized and it has been proven that they are the
most active catalysts for the cross-coupling. However,
it remains largely unknown if and how low-valent or-
ganoiron species react with Grignard reagents in solu-
tion.[20] Alternatively, a mechanism based on addition/
elimination was also proposed.[16] Recently, Neto pro-
posed that the cation [Fe(C5H5)]+ (m/z=121), formed
as a consequence of ferrocene decomposition, might
be a stronger Lewis acid and capable of catalyzing the
Biginelli reaction.[21] However, the cation [Fe(C5H5)]+
(m/z=121) was not detected by ESI-MS in the reac-
tion of 1a with 2a at room temperature. We surmised
that a similar addition/elimination mechanism might
Scheme 4. Selective cross-coupling of unsymmetrical disul-
fide 1i.
À
be possible in the ferrocene-catalyzed C S coupling
reaction. Finally, we have to stress that the exact
mechanism is yet to be established with more experi-
mental and theoretical studies.
In conclusion, we have developed simple and effi-
cient ferrocene- and Pd(OAc)2-catalyzed cross-cou-
plings of di(hetero)aryl disulfides with Grignard re-
À
À
agents, providing C S and C C bonds with excellent
chemoselectivity under mild conditions. Unlike the
previous reports, Grignard regents were used as nu-
Scheme 5. Identifying the components of the cross-coupling
reaction.
À
cleophiles, giving a high selectivity between C C and
C S bond formation and producing a library of mole-
À
cules with pyrimidine and pyridine scaffolds in good
isolated yields. The selectivity with different metal
catalysts may be worthy of investigation. Further
studies, including synthetic applications of this reac-
tion and the effects of the catalyst on the selectivity,
are being carried out in this group.
Experimental Section
General Procedure for the Synthesis of Thioethers 3
(3aa–3gh)
Under a nitrogen atmosphere, 1 (0.2 mmol, 109 mg) and fer-
rocene (5 mol%, 1.9 mg) were added to a Schlenk tube. The
tube was stoppered and degassed with nitrogen three times.
Distilled THF (3 mL) was added by syringe and the mixture
was stirred for 15 min. Then, the Grignard reagent 2
(0.48 mmol, 2.4 equiv., 1.0M solution in THF) was added
under nitrogen using a syringe. The reaction mixture was al-
lowed to stir for approximately 0.5 h at À208C and the reac-
tion was monitored by TLC analysis. Then, 2 mL water were
added to the mixture to quench the reaction, the organic
components were extracted with ethyl acetate and the re-
sulting extract was evaporated under vacuum and further
purified by column chromatography on silica gel with petro-
leum ether/ethanol (30:1) to give the corresponding prod-
ucts 3.
Scheme 6. Reactivity of iodobenzene in the cross-coupling
with disulfide 1a.
À
C C (Path b) coupling conditions. Unfortunately, no
desired product 3aa was obtained, and the starting
materials were recovered. When the reaction that was
catalyzed by Pd(OAc)2 in the presence of DPE-Phos
À
was heated at 1008C for 10 h, only a 20% yield of C
S coupled product 3aa was obtained without forming
À
the C C coupled product 4aa (Path c). These results
revealed that disulfides are favored over aryl halides
À
À
in the C C/C S cross-coupling reactions.
General Procedure for the Desulfurative Coupling
Process (4aa–4fk)
Generally, the mechanism of iron(III or II)-cata-
lyzed cross-coupling of aryl halides with Grignard re-
agents has been studied thoroughly. Low-valent iron
Under
a nitrogen atmosphere, 1 (0.2 mmol, 109 mg),
species (low-valent iron complexes) have been char- Pd(OAc)2 (5 mol%, 2.4 mg), and DPE-Phos (6 mol%,
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UPDATES
Chemo-Controlled Cross-Coupling of Di(hetero)aryl Disulfides
6.6 mg) were added to a Schlenk tube. The tube was stop-
pered and degassed with nitrogen three times. Then, 2
(1 mmol) and the solvent (THF/dioxane, 3 mL) were added
by syringe, and the mixture was stirred for 15 min. Next, the
mixture was cooled to 08C and the Grignard reagent 2
(0.96 mmol, 4.8 equiv., 1.0M solution in THF) was added
under nitrogen using a syringe at a low flow rate. Then, the
reaction mixture was allowed to stir for approximately 2 h
at room temperature, and the reaction was monitored by
TLC analysis. Then, 2 mL of water were added to the mix-
ture to quench the reaction, the organic components were
extracted with ethyl acetate, the resulting extract was evapo-
rated under vacuum and the residue further purified by
column chromatography on silica gel with petroleum ether/
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À
ethanol (45:1) to give the corresponding C C coupling
products.
Acknowledgements
Financial support was provided by the NSFC (Nos.
21362031, 21362032), the NSF of Gansu Province (No.
1308RJZA299), and Gansu Provincial Department of Fi-
nance.
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Adv. Synth. Catal. 2015, 357, 1270 – 1276