1,2-Bis(arylthio)arene synthesis: Via aryne intermediates

Article abstract of DOI:10.1039/c9cc03863a

Lithium 1,1-diadamantylamide (LDAM) base-promoted insertion of arynes into disulfide S-S bonds is described. After generation of arynes from readily available aryl halides and triflates, reactions with diaryl and diisopropyl disulfides afford the insertion products in moderate to excellent yields. Use of 1-cyclohexenyl triflate gave an excellent yield of 1,2-bis(phenylthio)cyclohexene.

Full text of DOI:10.1039/c9cc03863a

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1,2-Bis(arylthio)arene synthesis via aryne
intermediates†
Cite this:DOI: 10.1039/c9cc03863a
Milad Mesgar, Justin Nguyen-Le and Olafs Daugulis
*
Received 18th May 2019,
Accepted 11th July 2019
DOI: 10.1039/c9cc03863a
rsc.li/chemcomm
Lithium 1,1-diadamantylamide (LDAM) base-promoted insertion of
We have reported the preparation, characterization, and use
arynes into disulfide S–S bonds is described. After generation of of bulky lithium 1,1-diadamantyl amide in base-promoted
arynes from readily available aryl halides and triflates, reactions insertion of arynes into Si–P, Si–S, Si–N, and C–C bonds.4
with diaryl and diisopropyl disulfides afford the insertion products Arynes were generated from aryl triflates and halides.5 Reac-
in moderate to excellent yields. Use of 1-cyclohexenyl triflate gave tions possess high functional group compatibility, with cyano,
an excellent yield of 1,2-bis(phenylthio)cyclohexene.
trifluoromethyl, vinyl, methoxy, chloro, fluoro, and even formyl
moieties tolerated. The bulkiness of LDAM suppresses aryne
With few exceptions, 1,2-bis(arylthio)arenes are prepared from reactions with base. We speculated that similar conditions
1,2-dihaloarenes via nucleophilic aromatic substitution or could be used for base-promoted aryne generation and insertion
transition-metal catalyzed or promoted pathways.1 Three into S–S bonds. The optimization of the reaction conditions is
papers report aryne reactions with disulfides that result in presented in Table 1. If 2-naphthyl triflate 1 is reacted with
the formation of 1,2-bis(arylthio)arenes.2 In 1986, Nakayama diphenyl disulfide 2 and LDAM base 3 in THF solvent, low yields
disclosed the use of diphenyliodonium-2-carboxylate and dia- of 4 were obtained (entries 1 and 2). The yields were somewhat
zotized anthranilic acid as aryne precursors in reaction with variable, and unreacted aryl triflate was observed in a crude
diaryl disulfides. 1,2-Bis(arylthio)arenes were isolated in 8–30% reaction mixture. Better results were obtained in diethyl ether/
yields.2a More recently, Raminelli disclosed one example of 1,2- cyclohexane mixed solvent (entries 3 and 4). Use of a diethyl
bis(phenylthio)benzene synthesis by treatment of diphenyl ether/THF mixture was successful as well (entries 5–9). The best
disulfide with o-(trimethylsilyl)phenyl triflate in the presence results were obtained at 0 1C by employing a triflate/disulfide/
of CsF at room temperature.2b We have reported that arynes LDAM ratio of 1/1.2/1.5, affording 80% NMR and 71% isolated
generated from silyl aryl triflates or halides react with bis-
(trifluoromethyl)disulfide to afford 1,2-bis-trifluoromethyl-
thioarenes.2c However, in line with previous observations, the
Table 1 Optimization conditionsa
method is not compatible with diaryl disulfides providing low
yields of products. Transition-metal catalyzed pathways leading to
1,2-bis(arylthio)arenes may require relatively harsh reaction con-
ditions and use of 1,2-dihaloarenes, which have limited commer-
cial availability. o-(Trimethylsilyl)aryl triflate starting materials
for aryne reactions are even less available. Synthesis of 1,2-
bis(arylthio)arenes from readily available aryl halides and aryl
triflates would allow easy structural modifications and access to
a more diverse set of ligands for transition metal catalysis and
other applications.3 We report here a base-promoted, efficient
synthesis of 1,2-bis(arylthio)arenes from aryl halides and triflates
by employing lithium 1,1-diadamantylamide (LDAM) base.
Entry
1/2/3
Solvent
T, 1C, t, h
Yield,b
%
1
2
3
4
5
6
7
8
9
1/1/1.2
1/1/1.2
1/1.2/2
1/1.2/1.2
1/2/2
1/1/1.2
1/1.2/1.2
1/1.2/1.5
1/1.2/2
THF
THF
0, 38
25, 38
0, 47
0, 47
0, 24
25, 38
0, 47
0, 47
0, 47
35
25
74
69
70
20
72
Et2O/C6H12 (1/1)
Et2O/C6H12 (1/1)
Et2O/THF (49/1)
Et2O/THF (49/1)
Et2O/THF (49/1)
Et2O/THF (49/1)
Et2O/THF (49/1)
80 (71c)
78
a
b
Department of Chemistry, University of Houston, Houston, TX, 77204-5003, USA.
E-mail: olafs@uh.edu
Aryne precursor 1 (0.25 mmol), solvent (1.5 mL). Yields determined
c
by GC analysis, n-decane internal standard. Isolated yield. LDAM =
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc03863a
lithium 1,1-diadamantylamide (3).
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yields of 4 (entry 8). The room-temperature reaction gave a 20% acceptable to excellent yields of 1,2-bis(arylthio)arenes were
NMR yield (entry 6). An increased amount of 3 did not improve obtained (entries 2 and 3). 1-Naphthyl and 2-naphthyl triflates
the yield (entry 9).
afford products in 61 and 71% yields, respectively (entries 4 and 5).
The reaction scope with respect to aryl triflates is presented Notably, 2-naphthyl triflate gives one isomer of bis(phenylthio)-
in Table 2. Reaction of phenyl triflate with diphenyl disulfide naphthalene, showing selective formation of one isomer of
gives the product in 91% isolated yield (entry 1). Methyl- and naphthalyne. Phenyl, alkyl, and silyl substituents are tolerated
methoxy-substituted aryl triflates are reactive as well, and as well (entries 6–8). Several reactions were performed with
substituted diaryl disulfides. Bis(4-t-butylphenyl)disulfide and
bis(4-tolyl)disulfide react with silyl- and methyl-substituted aryl
triflates giving products in good yields (entries 9–12). Interest-
Table 2 Reaction scope with respect to aryl triflatesa
ingly, dimethylsulfamate can be employed as a leaving group
(entry 13). The advantage of sulfamate relative to triflate is its
lower cost.
Estrone-derived aryl triflate 5 was converted to bis(arylthio)
Entry
1
Aryne precursor
Product
Yield, %
91
derivative 5a in 72% yield, showing relevance of the methodology
to the modification of biologically active compounds (Scheme 1).
One isomer of the product was obtained, demonstrating regio-
selective formation of an aryne intermediate. Additionally,
we performed reaction of a BINOL-derived triflate 6 with bis(4-
methylphenyl)disulphide, and product 6a was isolated in 59% yield.
The reaction scope with respect to disulfides is shown in
Table 3. The reaction conditions are similar to the ones used in
Table 2. The aryne generated from 4-methoxy-1-naphthyl tri-
flate was reacted with a selection of disulfides. 4-Methoxy-1,2-
bis(phenylthio)naphthalene was synthesized in 89% isolated
yield (entry 1). When bis(4-methylphenyl) and bis(4-tert-
butylphenyl)disulfides were employed, products were isolated
in 88% and 95% yields (entries 2 and 3). A chloro substituent
on the disulfide is compatible with reaction conditions and the
product was isolated in 72% yield (entry 4). Three isomeric
dimethoxyphenyl disulfides were reacted with 4-methoxy-1-
naphthyl triflate in the presence of base to afford the products
in 68%, 64%, and 62% isolated yields, respectively (entries 5–7).
Heterocycles are compatible with the reaction conditions as
well. 4-Methoxy-1,2-bis(5-methyl-2-thienylthio)naphthalene was
synthesized in 58% isolated yield (entry 8).
2
3
84
56
4
61
5
6
7
8
71
68
82
91
Aryl halides are often cheaper or more readily available than
aryl triflates. Unfortunately, use of an aryl chloride as the aryne
source gave only a modest yield of the product (Scheme 2, 8). If
aryl bromide was employed, the yield was increased to 65%.
Trimethoxyphenyl bromide is reactive as well, and 11 was isolated
in 78% yield. Aryl bromide possessing an electron-withdrawing
trifluoromethyl substituent afforded 13 in 72% yield.
9b
94
68
10c
11b
12c
94
499
13
55
a
Reaction conditions: aryne precursor (0.25 mmol), ArSSAr (0.3 mmol),
LDAM (0.5 mmol), Et2O/THF (49/1), 47 h, 0 1C. Yields are isolated yields.
b
c
Bis(4-tert-butylphenyl)disulfide was used. Di(p-tolyl)disulfide was
Scheme 1 Bis(arylthiolation) of estrone and BINOL derivatives.
used. Please see the ESI for details.
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Table 3 Reaction scope with respect to ArSSAra
Entry
1
(ArS)2
(PhS)2
Product
Yield, %
89
2
3
4
5
6
7
(4-MeC6H4S)2
(4-tBuC6H4S)2
(4-ClC6H4S)2
88
95
72
68
64
62
Scheme 2 Aryl halides as aryne precursors.
(4-MeOC6H4S)2
(3-MeOC6H4S)2
(2-MeOC6H4S)2
Scheme 3 Reactions of cyclohexyne, 8-quinolyne, and diisopropyl
disulfide.
8
58
The performance of LiTMP and LDAM bases in aryne reac-
tions with diaryl disulfide was studied (Scheme 4). Identical
conditions were used for comparison. Bromide 12 was reacted
with bis(p-tolyl)disulfide in the presence of LiTMP or LDAM.
The crude NMR yields were measured by using a benzotrifluoride
internal standard. Reaction promoted by LiTMP afforded 42%
NMR yield of 13, while use of LDAM gave 77% NMR and 72%
isolated yield of 13.
a
Reaction conditions: aryne precursor (0.25 mmol), ArSSAr (0.3 mmol),
LDAM (0.5 mmol), Et2O/THF (19/1), 47 h, 0 1C. Yields are isolated yields.
Please see the ESI for details.
Some reactions involving cyclohexyne and quinolyne, as well
as diisopropyl disulfide were also investigated (Scheme 3).6 We were
pleased that the reaction of 1-cyclohexenyl triflate with diphenyl
disulfide was successful. Under the conditions employed previously,
1,2-bis(4,40-t-butylphenylthio)cyclo-hexene 15 was synthesized
in 94% isolated yield. Reactions with 1-cyclopentenyl and
1-cycloheptenyl triflates were not successful. 8-Quinolinyl triflate
reacts with diphenyl disulfide to afford the product 17 in 29%
isolated yield. Additionally, dialkyl disulfides, such as diisopropyl
disulfides, are reactive as well and 19 was isolated in 56% yield.
Scheme 4 Base comparison.
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In summary, a general method for the synthesis of 1,2-bis-
(arylthio)arenes is described. Arynes generated from aryl triflates
and aryl halides by treatment with bulky 1,1-diadamantylamide
base react with diaryl disulfides to afford 1,2-bis(arylthio)arenes.
Use of 1-cyclohexenyl triflate gave an excellent yield of 1,2-
bis(phenylthio)cyclohexene.
´
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We are grateful to the Welch Foundation (Chair E-0044) and
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Conflicts of interest
There are no conflicts to declare.
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