A synthetic approach to tetrasubstituted alkenes: Using β-carbonyl benzothiazol-2-yl sulfones as electrophiles

Article abstract of DOI:10.1002/ejoc.201301021

A novel olefination method based on the modified Julia olefination reaction was developed. The reactions of β-carbonyl benzothiazol-2-yl sulfones with a series of alkynyllithiums and TMSCN gave the corresponding β-alkoxy sulfone intermediates, which under

Full text of DOI:10.1002/ejoc.201301021

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301021
A Synthetic Approach to Tetrasubstituted Alkenes: Using β-Carbonyl
Benzothiazol-2-yl Sulfones as Electrophiles
Song Ou,[a] Chun-Ru Cao,[a] Min Jiang,[a] and Jin-Tao Liu*[a]
Keywords: Olefination / Alkenes / Rearrangement / Sulfur / Lithium
A novel olefination method based on the modified Julia ole-
fination reaction was developed. The reactions of β-carbonyl
benzothiazol-2-yl sulfones with a series of alkynyllithiums
and TMSCN gave the corresponding β-alkoxy sulfone inter-
mediates, which underwent facile Smiles rearrangement and
spontaneous elimination to yield tetrasubstituted enynes and
cyanoalkenes, respectively.
enes along the mechanism of the modified Julia olefination
reaction. In this case, the key β-alkoxy sulfone intermediate
would be formed in a new manner and it should be possible
to prepare various alkenes including tetrasubstituted olefins
by changing the structures of both the arylsulfones and the
nucleophiles. To realize this assumption, we synthesized a
series of β-carbonyl benzothiazol-2-yl (BT)-sulfones and in-
vestigated their reactions with various nucleophiles. The re-
sults are reported in this paper.
Introduction
The olefin structure is present in many biologically active
compounds. Many olefins are also key intermediates as
building blocks in the total syntheses of natural products.[1]
Over the past several decades, a variety of approaches to
the synthesis of olefins have been developed that have at-
tempted to address these stringent demands. The most gen-
erally applicable methods involve the direct olefination of
carbonyl compounds, such as the Wittig,[2] Wadsworth–
Emmons,[3] Peterson,[4] Horner,[5] Johnson,[6] and Julia–Ko-
cienski[7] reactions. In Julia–Kocienski olefination, the re-
ductive elimination of β-acyloxy sulfones is the alkene for-
mation step. This methodology has found pivotal use in the
synthesis of many natural products.
Tetrasubstituted olefins have found wide application in
the preparation of drugs,[8] biologically active compounds,[9]
and materials, and they have additionally been used in ca-
talysis[10] and synthetic chemistry,[11] but the efficient syn-
thesis of tetrasubstituted olefins remains a challenge. In a
typical modified Julia olefination reaction, the key β-alkoxy
sulfone intermediate is formed by the addition of a nucleo-
philic metalated sulfone to a carbonyl compound. We con-
ceived that if electron-deficient benzothiazolylsulfones 1
containing a carbonyl group located at the β position were
used as electrophiles (Scheme 1), the addition of nucleo-
philes to the carbonyl group would result in the formation
of β-alkoxy sulfones A, which have a structure similar to
that of the key intermediates in the Julia olefination reac-
tion. These sulfone intermediates could then undergo
Smiles rearrangement[7a–7e] and elimination to produce alk-
Scheme 1. The proposed olefination of β-carbonyl BT-sulfones.
Results and Discussion
First, we prepared 2-(benzothiazole-2-sulfonyl)-1-phenyl-
ethanone (1a) from the reaction of 2-mercaptobenzothi-
azole with α-bromoacetophenone followed by the oxidation
of the resulting thioether. Unfortunately, this β-carbonyl
sulfone underwent enolization upon the addition of the ba-
sic nucleophile, and the enolate thus formed could not react
further with the nucleophiles. To avoid the enolization, we
designed and synthesized a series of β-carbonyl benzothi-
azol-2-yl sulfones 1b–g without α-hydrogen, as shown in
Table 1.
[a] Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
E-mail: jtliu@sioc.ac.cn
http://www.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301021.
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A Synthetic Approach to Tetrasubstituted Alkenes
Table 1. Preparation of β-carbonyl BT-sulfones.
this deficiency could be overcome by adding 2,2Ј-bipyridine
(1.2 equiv.) as a ligand to stabilize and deactivate the alk-
ynyllithium (Table 2, entries 7, 10, 13, 16, and 20). For dif-
ferent R1 substituents including tolyl, phenyl, and naphthyl,
the reaction performed well. In the case of sulfone 1f, the
reaction gave alkenes 3q–s in high yields as mixtures of E
and Z isomers.[14] The reaction did not exhibit significant
stereoselectivity (1.27:1–1.92:1), which was attributed to the
similar steric and electronic properties of the methyl and
ethyl group. Unfortunately, the reaction of β-carbonyl BT-
sulfone 1g was unsuccessful and no desired product was
formed because of steric hindrance (Table 2, entry 22).
Entry S-1
R1
R2
H
R3
1
Yield [%][a]
1
2
3
4
5
6
7
S-1a
C6H5
p-MeOC6H4 Me
p-tolyl
C6H5
1-naphthyl
C6H5
H
1a 84
1b 89
1c 92
1d 91
1e 87
1f 84
1g 45
S-1b
S-1c
S-1d
S-1e
S-1f
S-1g
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
C6H5
C6H5
Table 2. The reaction of β-carbonyl sulfones with alkynyllithium.[a]
[a] Total yield of the isolated product over two steps. BTSH = 2-
mercaptobenzothiazole.
Having β-carbonyl BT-sulfones 1b–g in hand, we next
examined their reactions with a series of nucleophiles. How-
ever, oxygen and nitrogen nucleophiles, such as NaOMe,
NaOEt, KOtBu, and amines, failed to afford the olefin
products. To our delight, it was found that carbon nucleo-
philes attacked the β-carbonyl group of these sulfones.
Phenylmagnesium bromide reacted with 1b at room tem-
perature to afford the desired olefin in low yield (Ͻ30%)
alongside some unidentified side products. Therefore, some
carbon nucleophiles were screened and alkynyllithium rea-
gents were found to be a good choice. At –78 °C, phenyl-
ethynyllithium reacted with sulfone 1b readily in THF to
yield desired β-alkoxy sulfone A, which underwent the tan-
dem Smiles rearrangement and elimination to give desired
tetrasubstituted olefin 3a in 93% yield (Scheme 2).
Entry
1
R1
R3
R4
3
Yield [%]
(E/Z)[b]
1
1b p-MeOC6H4 Me C6H5
1b p-MeOC6H4 Me C6H5
1b p-MeOC6H4 Me CF3
1b p-MeOC6H4 Me Me3Si
1b p-MeOC6H4 Me n-C4H9
1b p-MeOC6H4 Me COOEt
1b p-MeOC6H4 Me COOEt
1c p-MeC6H4
1c p-MeC6H4
1c p-MeC6H4
1d C6H5
3a 93
2[c]
3
3a 92
3b 89
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3c 94
3d 89
3e 45
3e 87[d]
3f 91
Me C6H5
Me CF3
Me COOEt
Me C6H5
Me CF3
Me COOEt
Me C6H5
Me CF3
Me COOEt
Me Me3Si
Et
Et
Et
Et
3g 88
3h 84[d]
3i 91
1d C6H5
1d C6H5
3j 88
3k 82[d]
3l 92
1e 1-naphthyl
1e 1-naphthyl
1e 1-naphthyl
1e 1-naphthyl
1f C6H5
3m 89
3n 84[d]
3o 93
C6H5
CF3
COOEt
Me3Si
3p 92 (1.75:1)[e]
3q 89 (1.50:1)[e]
3r 83[d] (1.27:1)[e]
1f C6H5
1f C6H5
Scheme 2. Reaction of 1b with phenylethynyllithium.
1f C6H5
3s 94 (1.92:1)[e]
[f]
1g C6H5
C6H5 C6H5
3t
–
Optimization of the reaction conditions showed that
THF and toluene were the preferred solvents for this reac-
tion. Other solvents such as hexane and ethyl ether were
excluded owing to their poor solvency for the substrates.
[a] Results are shown for reactions performed by following the
Barbier procedure unless otherwise indicated. [b] Yield of isolated
product. [c] The premetalated method was used. [d] 2,2Ј-Bipyridine
(1.2 equiv.) was added. [e] The E/Z ratio was determined by 1H
Both typical operation methods, the Barbier procedure[12] NMR spectroscopy. [f] No desired product.
and the premetalated procedure,[13] gave almost the same
results.
Using this novel protocol, we further investigated the re-
Using the Barbier procedure, we examined the scope of action of β-carbonyl BT-sulfones with trimethylsilyl cyanide
β-carbonyl sulfones 1b–g and alkynyllithium 2. Both elec- to develop a mild method to synthesize cyanoalkenes.[15] It
tron-poor and electron-rich alkynyllithiums were evaluated, was found that the expected cyanoalkenes could be pro-
and the results are summarized in Table 2. This novel ole- duced under mild conditions. The use of tetrabutylammo-
fination procedure tolerated a broad range of functional nium fluoride (TBAF, 1.2 equiv.) as an additive could help
groups. The reactions of alkynyllithiums bearing aryl, tri- to release the cyanide anion and reduce the reaction time.
fluoromethyl, silyl, and alkyl substituents proceeded well to However, inorganic reagents such as KCN and NaCN
give the corresponding conjugated enynes in good to excel- failed to initiate this transformation. Further examination
lent yields under the optimized reaction conditions. The of solvent effects revealed that CH3CN was the best solvent
presence of the COOEt group in the nucleophiles lowered for this transformation.
the yield of the enyne as a result of the high reactivity of
We examined the scope of β-carbonyl BT-sulfones 1b–g
this group to the alkynyllithium (Table 2, entry 6). However, with TMSCN (3.0 equiv.) in the presence of TBAF
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S. Ou, C.-R. Cao, M. Jiang, J.-T. Liu
SHORT COMMUNICATION
THF (10 mL) was added nBuLi (0.4 mL, 2.5 m in hexane) at
–78 °C. The mixture was stirred at –78 °C for 30 min, and then a
solution of β-carbonyl sulfone 1b (375 mg, 1.0 mmol) in THF
(2 mL) was added dropwise. The resulting mixture was stirred at
–78 °C for 1 h and then warmed to room temperature and
quenched with saturated aqueous NH4Cl solution. The aqueous
layer was extracted with ethyl ether (10 mL ϫ3). The combined
organic layer was washed with H2O (10 mL ϫ3) and dried with
anhydrous Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (petroleum ether)
to give 3a as a colorless oil (243 mg, 93%).
(1.2 equiv.) in CH3CN, and the results are shown in Table 3.
If R3 was an alkyl group, the reactions worked well and
afforded corresponding cyanoalkenes 4a–e in good yields
(77–87%; Table 3, entries 1–5). The reaction of β-carbonyl
BT-sulfone 1g, in which R3 = phenyl, failed to produce alk-
ene 4f under the same reaction conditions (Table 3, entry 6).
On the basis of the above experimental results, the new ole-
fination method we proposed in Scheme 1 may have success
with some other nucleophiles to afford the corresponding
tetrasubstituted alkenes.
Procedure for the Reaction of TMSCN with β-Carbonyl BT-Sulf-
ones: TBAF (296 mg, 1.2 mmol) was added to a solution of β-carb-
onyl BT-sulfone 1b (375 mg, 1 mmol) and TMSCN (297 mg,
3.0 mmol) in CH3CN (10 mL). The mixture was stirred at room
temperature overnight. After removal of solvent under reduced
pressure, the residue was purified by column chromatography on
silica gel (petroleum ether) to give 4a as a colorless oil (162 mg,
87%).
Table 3. The reaction of β-carbonyl sulfones with TMSCN.[a]
Supporting Information (see footnote on the first page of this arti-
cle): General information, general procedure for olefination, char-
1
acterization data, and copies of the H NMR and 13C NMR spec-
tra.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) for financial support (grant number 21172243).
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In conclusion, we have developed a novel olefination
method based on the mechanism of the modified Julia ole-
fination reaction, in which a new route to give access to key
β-alkoxy sulfone intermediate A was introduced. In com-
parison with the traditional Julia olefination reaction, this
new synthetic approach can add diversity to the olefin
products by varying the structures of both the sulfones and
the nucleophiles and is especially useful for the synthesis of
tetrasubstituted olefins.
Experimental Section
Procedure for the Reaction of Alkynyllithiums with β-Carbonyl BT-
Sulfones: To a solution of phenyl ethyne (110 mg, 1.1 mmol) in
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A Synthetic Approach to Tetrasubstituted Alkenes
[9]
[12] Typical Barbier procedure: Lithium diisopropylamide (LDA;
1.1 mL, 1.0 m in THF/hexane = 1:1) was added to a solution
of β-carbonyl sulfone 1 (1.0 mmol) and phenyl ethyne (110 mg,
1.1 mmol) in THF (12 mL) at –78 °C. The resulting mixture
was stirred at –78 °C for 1 h.
[13] Typical premetalated procedure: nBuLi (0.4 mL, 2.5 m in hex-
ane) was added to a solution of phenyl ethyne (110 mg,
1.1 mmol) in THF (10 mL) at –78 °C. The mixture was stirred
at –78 °C for 30 min and then a solution of β-carbonyl sulfone
1 (1.0 mmol) in THF (2 mL) was added dropwise. The resulting
mixture was stirred at –78 °C for 1 h.
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Received: July 10, 2013
Published Online: September 9, 2013
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