Carbonyl olefination of diaryl ketones with heteroaryl sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2015.05.034

Heteroaryl sulfones are capable of converting the carbonyl functionalities to alkenyl motifs, which is well-known as Julia-Kocienski olefination reaction. However, their sulfoxide analogues have failed in such an olefination reaction for over twenty years

Full text of DOI:10.1016/j.tetlet.2015.05.034

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Carbonyl Olefination of Diaryl Ketones with Heteroaryl Sulfoxides
Bing Gao, Jingyu Hu, Yanchuan Zhao, Jinbo Hu
PII:
S0040-4039(15)00843-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.034
TETL 46306
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Tetrahedron Letters
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5 May 2015
7 May 2015
Please cite this article as: Gao, B., Hu, J., Zhao, Y., Hu, J., Carbonyl Olefination of Diaryl Ketones with Heteroaryl
Sulfoxides, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.034
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Carbonyl Olefination of Diaryl Ketones with
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Bing Gao, Jingyu Hu, Yanchuan Zhao, Jinbo Hu
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1
Tetrahedron Letters
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Carbonyl Olefination of Diaryl Ketones with Heteroaryl Sulfoxides
Bing Gaoa, Jingyu Hua, Yanchuan Zhaoa, Jinbo Hua,
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032,
China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Heteroaryl sulfones are capable of converting the carbonyl functionalities to alkenyl motifs,
which is well-known as Julia-Kocienski olefination reaction. However, their sulfoxide analogues
have failed in such an olefination reaction for over twenty years. In this manuscript, we
demonstrate that the heteroaryl sulfoxides-participated carbonyl olefination reaction can be
realized under certain conditions. Furthermore, a novel defluorinative olefination of diaryl
ketones has been achieved with 2-pyridyl sulfoxides.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sulfoxide
Fluorine
Olefination
The one-pot conversion of carbonyl compounds to alkenes
with heteroaryl sulfones is well-documented as the Julia-
Kocieski olefination,1,2 which has found broad application in
synthetic community due to its high efficacy, excellent functional
group compatibility, and controllable stereoselectivity.3,4 It is a
typical cascade process that involves three sequential steps: 1)
the nucleophilic addition of a sulfonyl carbanion to a carbonyl
group, 2) the ipso-substitution of the addition adduct at the
heteroaryl ring (also known as the Smiles rearrangement5), and 3)
the fragmentation of the resulting sulfinate salt to give an alkene.
A set of heteroaryl sulfones have been applied in this reaction,
among which 1,3-benzothiazol-2-yl (BT), 1-phenyl-1H-tetrazol-
5-yl (PT), 1-tert-butyl-1H-tetrazol-5-yl (TBT) sulfones are
frequently used as the most effective reagents (Fig 1).
Nevertheless, their sulfoxide analogues have never been
successfully applied in such a transformation since its first report
in 1991.1a A related report by Hild group demonstrated that the
in-situ formed addition adduct of a lithiated methyl 2-pyridyl
sulfoxide and benzaldehyde afforded disulfide rather than
alkene.6 Similar results were also observed in the reaction of -
hydroxysulfoxides of BT.7 Both groups ascribed the failure of the
olefination to the distinct reactivity of the sulfenate salt,8 as
compared to the sulfinate salt (in sulfones chemistry),9,10 and it
seems of special challenge to achieve the heteroaryl sulfoxides-
participated carbonyl olefination.
Mechanistic studies revealed that fluorine-substitution
significantly altered the reactivity of corresponding heteroaryl
sulfones.10b,10c This result prompted us to reassess the feasibility
of fluorinated heteroaryl sulfoxides in the Julia-Kocienski type
olefination reaction, and herein we disclose our results on this
topic. It is found that the 2-pyridyl sulfoxide derivatives, as well
as the BT sulfoxide, can indeed be used to accomplish carbonyl
olefinations under certain conditions. We have also discovered a
novel defluorinative olefination reaction of diaryl ketones with
fluorinated 2-pyridyl sulfoxides.
We recently found that difluoromethyl 2-pyridyl sulfone (2-
PySO2CF2H) was a more robust carbonyl gem-difluoroolefination
reagent than the BT, TBT, and PT analogues, despite the fact that
non-fluorinated 2-pyridyl sulfone derivatives were barely used in
reactions.10,11
Fig 1. Current status of heteroaryl sulfones and sulfoxides participated
conventional
Julia-Kocienski
olefination
reactions with carbonyl compounds.
———
 E-mail: jinbohu@sioc.ac.cn.

2
Tetrahedron
To examine the feasibility of each step in a typical Julia-
intriguingly, their nonfluorinated analogue 8 also reacted
smoothly, but to give a conventional Julia-Kocienski type
olefination product 9 (68% yield, eq 3), rather than the 2-
pyridinone substituted alkene. This was also in sharp contrast to
Hild group’s result that disulfide was obtained as major product.6
Addition adduct of 1 and aldehydes were also investigated, but
those reaction systems turned out quite complicated and gave
neither an alkene nor a disulfide.
Kocienski olefination reaction, a stepwise investigation was
carried out. Since the nucleophilic addition reaction between 2-
PySOCF2H (1) and benzophenone (2a) proceeded smoothly and
gave 3a in excellent yield,12 We next focused on examining the
ipso-substitution of 3a under various conditions. When it was
treated with DBU (Table 1, entry 2) in DMF at room
temperature, to our surprise, neither the gem-difluoroolefin 4a
nor a disulfide (Figure 1) was obtained. Instead, compound 5a
was detected as the sole fluorine-containing product according to
the 19F NMR spectrum, and it was later confirmed as a
monofluorinated alkene via X-ray crystallography analysis (see
supporting information). The use of other bases, such as
LiHMDS, KOtBu, and K2CO3, also gave 5a but in decreased
yields (entry 3-6). When KOH was used, a 4% yield of 4a was
detected along with 49% yield of 5a (entry 5). Further screening
of the reaction conditions revealed no improvement on the yield
of either 4a or 5a.
Table 1. The transformations of 3a under different reaction
conditions.a
Scheme 1. The controlled experiments to evaluate the fluorine-substitution
effects.
Considering that fluoroalkenes were electrophilic due to the
inducing effect of fluorine(s) and the electron-repulsion effect
between fluorine(s) and the double bond,14 we speculated product
5 (or 7) might result from the in-situ nucleophilic substitution of
2-pyridinone anion to 4 (or 11) under basic reaction conditions,15
both of which were the products of 2-PySO2CF2H-promoted
Julia-Kocienski olefination.10 To verify our hypothesis, gem-
difluoroalkene 4b (this compound was suitable for 19F NMR
spectrum monitoring) was treated with pyridine-2-ol (1.0 equiv)
and DBU (2.0 equiv) in DMF at room temperature for 10 h.
Monofluorinated alkene 5b was indeed isolated in 65% yield
along with its isomer 10 in 10% yield (Scheme 2, eq 1).
However, product 10 was not observed in the base-promoted
reactions of
a
b
The reaction was conducted on 0.15 mmol scale in 1.0 mL of solvent. 19F
NMR yield with PhCF3 as an internal standard. LiHMDS = Lithium
bis(trimethylsilyl)amide, DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. N.R =
no reaction.
The transformations of 3a under either neutral or acidic
o
conditions were investigated. When 3a was heated below 120 C
in different solvents, no conversion were observed. However,
after being heated to 150 oC for 4 hours in DMF, gem-
difluoroalkene 4a, instead of monofluoroalkene 5a, was obtained
in 51% yield. Acid additives (either Brønsted acid or Lewis acid,
entries 13-16) did not alter the reaction output but had subtle
impact on the yields. The results obtained under neutral/acidic
reaction conditions were in good accordance with that of the
gem-difluoroolefination of diaryl ketones with 2-PySO2CF2H.10b
However, the distinct results obtained under basic reaction
conditions, the monofluorinated alkenes, seemed quite confusing.
To probe the fluorine-substitution effects on the reactivity of
reagent 1,13 the following controlled experiments were carried
out as depicted in Scheme 1. The difluoromethylated addition
adduct 3b gave 5b in 46% yield under basic reaction conditions
(eq 1). Its monofluorinated analogue 6 was treated with identical
reaction conditions, and a nonfluorinated alkene 7 possessing
similar skeleton was isolated in 44% yield (eq 2). Most

3
Scheme 2. The controlled experiments for mechanistic study.
substituents on the aryl rings would slightly decrease the yield
of corresponding ketones (entry 8-9).
3b (Scheme 1, eq 1). Meanwhile, when 1.0 equivalent of 4b was
added to the reaction system of 3a, no cross-substituted product
5b was detected while 5a was isolated in 61% yield (Scheme 2,
eq 2). Accordingly, free 2-pyridinone anion seemed unlikely to
exist in current reaction system. Fluoroalkene 11 was also
subjected to the pyridine-2-ol/DBU/DMF reaction condition
(Scheme 2, eq 3), but no conversion was observed at room
temperature after 10 hours of standard reaction period. The
reaction proceeded slowly even at elevated temperature,
indicating that the in-situ nucleophilic substitution mechanism
seemed unlikely.
Table 2, Defluorinative olefination of diaryl ketones under
basic conditions.
On the basis of the controlled experiments, potential reaction
pathways of 2-pyridyl sulfoxide derivatives with carbonyl
compounds are postulated in Scheme 3. The reactions are
dominantly affected by the sulfenate salt intermediate (or sulfenic
acids, KI), which is highly unstable and its reactivity is extremely
sensitive to proximal substituents.8,16 The carbonyl olefination do
take place under the acidic reaction conditons with fluorinated
sulfoxides, and also under the basic reaction conditions with non-
fluorinated sulfoxides, when diaryl ketone substrates are
employed in both cases (Path A). For the fluorinated sulfoxides
under basic reaction conditions, Path B is proposed. The formal
oxidation state of sulphur in sulfenate is +2, and therefore it can
function as a nucleophile to induce -fluoride elimination.17 The
newly formed sulfine intermediate further undergoes
intramolecular reaction with the pyridyl functionality,18,19
followed by SO extrusion to give the final product. Path C is
unlikely responsible for the defluorinative olefination because 1)
the substitution isomer 10 is not observed under the base-
promoted reaction with 3b, 2) the free 2-pyridinone anions are
not captured, and 3) the nucleophilic substitution of
monofluorinated alkene with 2-pyridinone anions can hardly take
place at ambient temperature.
o
a 1 (3.0 mmol), 2 (2.0 equiv), KHMDS (2.0 equiv), DME (20 mL), -70 C, 1
h; then HCl (2M, 1 mL), -70 oC to rt. b 3 (1.0 mmol), DBU (2.0 equiv), DMF
c
(1.0 mL), rt, 10 h. 1 (0.5 mmol), LiHMDS (2.0 equiv), DMF (4.0 mL), -50
oC to rt. 58:42 dr. 68:32 (Z/E mixture). 50:50 dr. 96:4 (Z/E mixture).
d
e
f
g
h
i
j
k
l
52:48 dr. 48:52 (Z/E mixture). 48:52 dr. 76:24 (Z/E mixture). the
absolute configuration was not determined.
Heteroaryl sulfoxides of BT and PT were also examined. The
nucleophilic addition adduct of methyl 1,3-benzothiazol-2-yl
sulfoxide and 2b afforded olefin 4b in 60% yield with the
treatment of 2.0 equivalents of DBU in DMF, indicating a similar
substrates-effect as compared to the reported results.7 But its
difluorinated analogue failed to give the addition product with
diaryl ketone under current and modified reaction conditions, so
as it was with the PT analogues (Scheme 4).
Scheme 4. The generality of heteroaryl sulfoxides in carbonyl olefination
reactions.
In summary, we have evaluated the feasibility of heteroaryl
sulfoxides (especially 2-pyridyl sulfoxides) in the Julia-
Kocienski type olefination reactions. Our results disclose that
heteroaryl sulfoxides react with carbonyl compounds in tunable
pathways as compared to that of the sulfone analogues. Carbonyl
olefination can indeed be realized with both 2-pyridyl (2-Py)
sulfoxides and 1,3-benzothiazol-2-yl (BT) sulfoxide under
certain reaction conditions for the first time. Meanwhile,
fluorine-substitution can alter their reactivity of 2-pyridyl
sulfoxides to give a novel defluorinative olefination of diaryl
ketones. Results in this manuscript also provide helpful insights
in understanding the intrinsic difference of reactivity between
sulfones and sulfoxides.
Scheme 3. Plausible reaction pathways of 2-pyridyl sulfoxides with carbonyl
compounds.
Finally, diaryl ketones with different substituents were
examined under current base-promoted carbonyl defluorinative
olefination reaction conditions. As depicted in Table 2, the
monofluorinated olefination products were only obtained in
moderate yield due to uncontrollable side reactions of the
sulfenic intermediate.8,16,17 A one-pot Julia-Kocienski type
olefination procedure with substrate 2a was also carried out,
directly giving 5b in 27% yield (entry 2). Electron-withdrawing

4
Tetrahedron
Y. Mayumi, N. Zhao, S. Watanabe, M. Yokota and J. Ichikawa,
Angew. Chem., Int. Ed., 2013, 52, 7825; (e) P. J. Riss and F. I.
Aigbirhio, Chem. Commun., 2011, 47, 11873.
Acknowledgments
This work was supported by the National Basic Research Program of
China (2015CB931900, 2012CB215500), the National Natural
Science Foundation of China (21372246, 21421002), Shanghai
QMX program (13QH1402400) and the Chinese Academy of
Sciences.
16. S. Oae, Organic Sulfur Chemistry: Structure and Mechanism,
CRC, Florida, 1991.
17. (a) J. S. O'Donnell and A. L. Schwan, Tetrahedron Lett., 2003, 44,
6293; (b) A. L. Schwan, M. J. Verdu, S. P. Singh, J. S. O'Donnell
and A. N. Ahmadi, J. Org. Chem., 2009, 74, 6851; (c) S. P. Singh,
J. S. O'Donnell and A. L. Schwan, Org. Biomol. Chem., 2010, 8,
1712.
18. (a) H. Wasserma and W. Strehlow, Tetrahedron Lett., 1970, 795;
(b) E. Block, H. Bock, S. Mohmand, P. Rosmus and B. Solouki,
Angew. Chem., Int. Ed., 1976, 15, 383; (c) B. Zwanenburg, J.
Sulfur Chem., 2012, 34, 142.
19. The intramolecular nucleophilic attack of a pyridyl motif to an in-
situ generated sulfonyl iodide and subsequent fragmentation was
also observed in one of our previous works. Y. Zhao, B. Gao and
J. Hu, J. Am. Chem. Soc., 2012, 134, 5790.
References and notes
1. (a) J. B. Baudin, G. Hareau, S. A. Julia and O. Ruel, Tetrahedron
Lett., 1991, 32, 1175; (b) J. B. Baudin, G. Hareau, S. A. Julia and
O. Ruel, Bull. Soc. Chim. Fr., 1993, 130, 336; (c) J. B. Baudin, G.
Hareau, S. A. Julia, R. Lorne and O. Ruel, Bull. Soc. Chim. Fr.,
1993, 130, 856.
2. (a) P. R. Blakemore, W. J. Cole, P. J. Kocieński and A. Morley,
Synlett, 1998, 26; (b) P. J. Kocienski, A. Bell and P. R.
Blakemore, Synlett, 2000, 365.
3. (a) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 2563;
(b) C. Aïssa, Eur. J. Org. Chem., 2009, 1831; (c) R. Robiette and
J. Pospíšil, Eur. J. Org. Chem., 2013, 836.
4. For some applications of Julia-Kocienski olefination, see: (a) A.
Fettes and E. M. Carreira, J. Org. Chem., 2003, 68, 9274; (b) S. V.
Voitekhovich, P. N. Gaponik and G. I. Koldobskii, Russ. J. Org.
Chem., 2005, 41, 1565; (c) T. Takizawa, K. Watanabe, K. Narita,
T. Oguchi, H. Abe and T. Katoh, Chem. Commun., 2008, 1677;
(d) D. A. Evans, P. Nagorny, D. J. Reynolds and K. J. McRae,
Angew. Chem., Int. Ed., 2007, 46, 541; (e) H. Lei, J. Yan, J. Yu,
Y. Liu, Z. Wang, Z. Xu and T. Ye, Angew. Chem., Int. Ed., 2014,
53, 6533.
Supplementary Material
Electronic Supplementary Information (ESI) available:
Experimental details, characterization and copies of 1H, 19F
NMR, 13C NMR spectra and CCDC 1041858..
5. (a) L. A. Warren and S. Smiles, J. Chem. Soc., 1930, 1327; (b) J.
F. Burnett and R. E. Zahler, Chem. Rev., 1951, 49, 273; (c) T. N.
Gerasimova and E. F. Kolchina, J. Fluorine Chem., 1994, 66, 69;
(d) K. Plesniak, A. Zarecki and J. Wicha, in Sulfur-Mediated
Rearrangements II, ed. E. Schaumann, Springer, Berlin
Heidelberg, 2007, pp. 163-250.
6. M. Braun and W. Hild, Chem. Ber., 1986, 119, 2377.
7. N. Yamada, T. Koyasu, M. Sonami, M. Aoi, S. Tashiro, M. C.
Sheikh, Y. Ishida, W. Kawashima, T. Yoshimura and H. Morita,
Phosphorus, Sulfur Silicon Relat. Elem., 2010, 185, 1142.
8. Selected reviews on sulfenate (sulfenic acid) chemistry: (a) S.
Patai, The Chemistry of Sulphenic Acids and Their Derivatives.
Wiley, Chichester, 1990; (b) V. Gupta and K. S. Carroll, Biochim.
Biophys. Acta, 2014, 1840, 847.
9. Selected reviews on sulfinate (sulfinic acid) chemistry: (a) J. Aziz,
S. Messaoudi, M. Alami and A. Hamze, Org. Biomol. Chem.,
2014, 12, 9743; (b) C. Jacob, A. L. Holme and F. H. Fry, Org.
Biomol. Chem., 2004, 2, 1953; (c) W. E. Truce and A. M. Murphy,
Chem. Rev., 1951, 48, 69.
10. (a) Y. Zhao, W. Huang, L. Zhu and J. Hu, Org. Lett., 2010, 12,
1444; (b) B. Gao, Y. Zhao, M. Hu, C. Ni and J. Hu, Chem. Eur. J.,
2014, 20, 7803; (c) B. Gao, Y. Zhao, J. Hu and J. Hu, Org. Chem.
Front., 2015, 2, 163; (d) Y. Zhao, F. Jiang, J. Hu, J. Am. Chem.
Soc., 2015, DOI: 10.1021/jacs.5b02112.
11. For the synthesis of fluoroalkenes via Julia-Kocienski olefination,
see: (a) A. K. Ghosh and B. Zajc, Org. Lett., 2006, 8, 1553; (b) C.
Calata, J.-M. Catel, E. Pfund and T. Lequeux, Tetrahedron, 2009,
65, 3967; (c) L. Zhu, C. Ni, Y. Zhao and J. Hu, Tetrahedron,
2010, 66, 5089; (d) R. Kumar, P. Pradhan and B. Zajc, Chem.
Commun., 2011, 47, 3891; (e) D. O. Ayeni, S. K. Mandal and B.
Zajc, Tetrahedron Lett., 2013, 54, 6008;
12. See the supporting information for reaction condition
optimization.
13. (a) C. Ni, Y. Li and J. Hu, J. Org. Chem., 2006, 71, 6829; (b) C.
Ni, L. Zhang and J. Hu, J. Org. Chem., 2008, 73, 5699; (c) C. Ni
and J. Hu, Synlett, 2011, 70; (d) W. Zhang, C. Ni and J. Hu, Top.
Curr. Chem., 2012, 308, 25; (e) C. Ni, M. Hu and J. Hu, Chem.
Rev., 2015, 115, 765.
14. (a) K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford,
2006; (b) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications, 2nd Ed., Wiley-VCH, Weinheim, 2013.
15. For some applications of fluoroolefins on the basis of their
electrophilic properties, see: (a) B. Gao, Y. Zhao and J. Hu,
Angew. Chem., Int. Ed., 2015, 54, 638; (b) B. Gao, Y. Zhao, C. Ni
and J. Hu, Org. Lett., 2014, 16, 102; (c) Y. Xiong, X. Zhang, T.
Huang and S. Cao, J. Org. Chem., 2014, 79, 6395; (d) K. Fuchibe,

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The first example of sulfoxide-mediated one-pot carbonyl olefination reaction is described.
De-fluorinative olefination was observed.
Add new mechanistic insights into the Julia-Kocienski olefination reaction.