Tandem Acyl Substitution/Michael Addition of Thioesters with Vinylmagnesium Bromide

Article abstract of DOI:10.1021/acs.orglett.9b00538

A tandem reaction of thioesters with vinylmagnesium bromide is reported. The initial acyl substitution provides an α,β-unsaturated ketone which further reacts with the liberated thiolate. This transition-metal-free synthesis of β-sulfanyl ketones takes place under mild reaction conditions, whereas the addition of a second Grignard molecule is almost completely suppressed. The carefully chosen parameters enabled the transformation of different substrates in moderate to good yields.

Full text of DOI:10.1021/acs.orglett.9b00538

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Acyl Substitution/Michael Addition of Thioesters with
Vinylmagnesium Bromide
†
†
‡
̈
Vera Hirschbeck, Marlene Boldl, Paul H. Gehrtz, and Ivana Fleischer*
Institute of Organic Chemistry, University of Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
̈ ̈
S
* Supporting Information
ABSTRACT: A tandem reaction of thioesters with vinyl-
magnesium bromide is reported. The initial acyl substitution
provides an α,β-unsaturated ketone which further reacts with
the liberated thiolate. This transition-metal-free synthesis of β-
sulfanyl ketones takes place under mild reaction conditions,
whereas the addition of a second Grignard molecule is almost
completely suppressed. The carefully chosen parameters
enabled the transformation of different substrates in moderate
to good yields.
hioesters are more reactive than alcohol-derived esters
Scheme 1. Transition-Metal-Catalyzed and -Free Synthesis
of Ketones from Thioesters
T
due to the poorer orbital overlap between the sulfur atom
and the carbonyl group. They can be synthesized by various
methods based on acylation chemistry1 or metal-catalyzed
transformations.2 Therefore, they are of great importance in
numerous synthetic applications,3 for example, in the synthesis
of ketones by a nucleophilic substitution with organometallic
reagents. In general, this transformation was intensively
investigated using various carboxylic acid derivatives.4 The
main issue is the control of chemoselectivity because a second
attack of the C-nucleophile to the desired ketone generates a
tertiary alcohol, which has to be avoided (overaddition).
Thioesters are less affected by this problem than oxoesters,
since they are more reactive than the resulting ketones, but the
overaddition can only be prevented by an inconvenient
controlled slow addition of the nucleophile.
Fortunately, transition-metal (TM) catalyzed cross-coupling
reactions can be used as an alternative. The oxidative addition
of the TM into the C(O)−S bond, followed by transmetalation
with an organometallic compound and reductive elimination,
enables the chemoselective formation of ketones (Scheme 1a).
In their pioneering works, Fukuyama, Liebeskind, and Strogl
reported a number of couplings employing different organo-
metallic compounds (based on Zn, B, Sn, and In) in
combination with a palladium catalyst.5 Nickel-catalyzed
versions were reported, as well.6 Moreover, the reaction of
thioester and Grignard reagent was shown by Marchese et al.7
The transformation was catalyzed by 4 mol % Fe(acac)3 and
conducted under mild reaction conditions (0 °C, 5−10 min)
in THF using aromatic and aliphatic Grignard reagents.
Since the employment of some transition metals is
expensive, uncatalyzed versions are always of considerable
interest (Scheme 1a). Anderson et al. reported the generation
of ketones from S-alkyl and S-aryl thioesters with
organocopper(I) complexes (e.g., (nBu)2CuLi) in good yields.8
By the application of 1.0 equiv of nBuMgBr, the tertiary alcohol
and the starting material were obtained in equal amounts,
n
whereas use of 1.5 equiv of BuMgBr·CuI led to the desired
ketone in >80% yield. A successful TM-free conversion of S-(2-
pyridyl)thioates (1) with Grignard reagent without the
formation of a tertiary alcohol was shown by Mukaiyama et
al.9 They argued that these substrates are able to form a six-
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00538
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
membered complex 2, with nitrogen being coordinated to the
magnesium ion. This complex reacts very slowly with a second
Grignard molecule in comparison to the starting material and
therefore enables a complete suppression of the side-product
formation. Thus, 2-pyridyl thioesters can be considered as
alternatives to Weinreb amides.4b
Table 1. Initial Optimizations
Herein, we report a transition metal free tandem reaction of
thioesters with vinylmagnesium bromide (3) under mild
reaction conditions (0 °C, 1 h) (Scheme 1b). An initial
nucleophilic substitution of the thioester with 3 generates the
Michael acceptor 4, followed by a nucleophilic addition of the
free thiolate to furnish β-sulfanyl ketones, which show unique
synthetic10 and also potential medicinal11 applications. We also
proposed the formation of a six-membered complex, which
enables a chemoselective formation of ketones, whereas
overaddition is almost completely suppressed. This reactivity
was also inadvertently observed by Chen et al. in the synthesis
of (+)-biotin.12 In the application of other Grignard reagents,
such as 1-propenyl- and isopropenylmagnesium bromide, no
selective ketone formation was observed, which emphasizes the
unique reactivity of 3 (see the Supporting Information for
details).13
entry temp (°C) time (h) 3 (equiv) additive conv (%) yield (%)
1
2
3
4
5
6
7
8
9
−78
−10
0
rt
0
0
0
0
0
1
1
1
1
1
1
1
1
1
2
4
3
3
3
3
1.2
2
3
3
3
0
89
97
100
70
88
92
99
96
100
99
0
73
75
51
48
64
66
65
74
64
65
b
EtSH
c
d
LiCl
10
11
0
0
3
3
a
Reaction conditions: 5a (163 mg, 1.02 mmol, 1.0 equiv), 3 (0.89 M
The first experiments were performed using thioester 5a and
vinylmagnesium bromide (3) in THF. At the beginning of this
project, we struggled with reproducibility problems. We came
to the conclusion that crystallization of 3 from the reaction
mixture, which can already take place below 25 °C, might be
the source of the problem. Since crystallization is strongly
influenced by purity and temperature, it is extremely important
to ensure the same conditions for each reaction. Therefore, the
batch of purchased vinylmagnesium bromide (different
purities), cooling system (different cooling capacity of Dewar
and crystallizing dish), and reaction flask (different wall
thickness and volume of the flask) might influence
crystallization and cannot be varied during the comparison of
different reaction parameters. Thus, every new batch of 3 was
applied in a test reaction in order to see if the yield has
changed. If crystallization is taking place, the problem can be
overcome by increasing the amount of solvent.
In the initial optimization using 5a as a test substrate,
different temperatures, reaction times, and equivalents of
Grignard reagents and additives were tested (Table 1). As
expected, no reaction was observed at −78 °C because
vinylmagnesium bromide crystallized instantly. On the other
hand, side reactions became more likely at room temperature,
resulting in a yield of only 51% (Table 1, entry 4). The best
result was observed at 0 °C (Table 1, entry 3), providing 6a in
75% yield with almost full conversion of thioester. Since a
lower amount of Grignard reagent might prevent a second
attack of vinylmagnesium bromide either to product 6a
yielding alcohol 8 or to the intermediate 4 (to give 7), 1.2
and 2.0 equiv of 3 were applied. However, the yields dropped
significantly (Table 1, entries 5 and 6). The combination of a
low concentration of the substrate (0.12 mol/L) and a large
excess of the Grignard reagent could facilitate the side reaction
(b) (Scheme 1), which might be avoided by the addition of
external EtSH (Table 1, entry 7). Interestingly, lower amounts
of the product were formed. Despite the small concentration of
free thiolate, the high selectivity for the nucleophilic addition
of EtSH instead of 3 to the Michael acceptor 4 is remarkable.
Therefore, we suggest the formation of chelate 10 via 1,4-
addition of intermediate 9, in which the thiol is not leaving the
in THF), THF (5 mL); yields and conversions were determined by
b
quant GC−FID using n-pentadecane as an internal standard. EtSH
c
d
(1.0 equiv). THF (1 mL). LiCl (0.2 equiv).
coordination sphere and is able to attack the Michael acceptor
rapidly (Figure 1).
Figure 1. 1,4-Addition and proposed intermediates.
Lowering the amount of solvent and thereby increasing the
substrate concentration leads to lower yield due to the partial
crystallization of 3, which was observed during the reaction
(Table 1, entry 8). LiCl might accelerate the nucleophilic
attack to 5a or 4 (Table 1, entry 9) or modulate the reactivity
of 3,14 but no effect was observed. Longer reaction time led to
decomposition (mainly overaddition) of the product under the
reaction conditions. The general difference between con-
version and yield can be explained by the formation of small
amounts of several different side products, which were
observed by GC−MS of the crude mixture but could not be
assigned.
Since the reaction time plays an important role, the reaction
progress was evaluated in order to find the optimum balance
between product formation and degradation (Figure 2).
Indeed, highest yield and full conversion were observed after
1 h. In the further course of the reaction, the side reactions
became prevalent. Interestingly, upon treatment of isolated 6a
with vinylmagnesium bromide (3.0 equiv) in THF at 0 °C for
1 h, 8 was generated in 83% yield (100% conversion). In the
reaction progress study, only 11% of the product reacted with
the remaining Grignard reagent. Therefore, it can be assumed
that chelate 10 is formed in the reaction mixture, which
impedes the attack of the second vinylmagnesium bromide
molecule. In conclusion, the best result was observed using 3.0
equiv of 3 at 0 °C for 1 h. Compound 6a was generated in a
B
DOI: 10.1021/acs.orglett.9b00538
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
demanding thioesters 5b, 5d, and 5e were less reactive,
generating a significantly lower yield. S-Phenyl-substituted
analogue led to a sluggish reaction and NMR yield of 14%.
Then the carbonyl substituent was varied. Disappointingly,
only traces of the product were observed for the α-substituted
5f, whereas β-substituted 5g provided 6g in 38% yield. The
long chain thioester 5h was also less reactive, furnishing 6h in
45% yield.
Furthermore, different aryl-substituted benzothioates (5i−
o) were tested. The unsubstituted 5i showed a yield of 65%,
whereas the electron-donating substituents present in 5j and
5k led to lower reactivity. Increasing the electron density at the
carbonyl center reduces the electrophilicity of thioester, and
therefore, the nucleophilic attack of 3 is slower. As expected,
the electron-deficient CF3 group in the para-position increased
the yield to 72% (6l). Chlorinated substrate 5m showed the
same reactivity as the unsubstituted one, which can be
explained by “chameleon-like” inductively electron-withdraw-
ing (−I) and electron-donating mesomeric (+M) effects. The
nitro group was not tolerated, which is not surprising since
reactions of nitroarenes with Grignard reagents are known in
the literature.15 In addition, substitution at the ortho-position
seems to be a limitation of the catalytic system, since no yield
was observed by using 5o. Moreover, 5p showed a similar
reactivity as 5i, with a yield of 64%, whereas 5q is more
compatible with 5a. Indole-substituted thioester 5r was
transformed in a yield of 27%, showing that a protection
step is not needed. The yield could not be increased by using 4
equivalents of 3. In most lower yielding reactions, the main
component of the crude reaction mixture was the unreacted
starting material and not one of the side products.
Figure 2. Reaction profile for the conversion of 5a with vinyl-
magnesium bromide (3). Reaction conditions: 5a (160 mg, 998 μmol,
1.0 equiv), 3 (0.52−0.89 M in THF, 3.0 equiv), THF (5 mL), 0
°C, 2 h. Yields were determined by quant GC−FID using n-
pentadecane as an internal standard.
yield of 75%, which is satisfactory for a two-step tandem
reaction.
With the optimized conditions in hand, the substrate
screening was performed beginning with the investigation of
the influence of the S-substituent (Scheme 2). The same yield
was observed by using 5c instead of the ethyl thioester 5a. The
transformation of 5a was also conducted on a 10 mmol scale
with the same result (75% yield). The sterically more
a
Scheme 2. Substrate Screening
The synthesized β-sulfanyl ketones can be used to generate
β-sulfonyl ketones in one oxidation step with mCPBA, which
was shown in an exemplary way by using 6a as a substrate
(Scheme 3). β-Sulfonyl ketones are important structural
Scheme 3. Synthesis of β-Sulfonyl Ketones 11 from β-
Sulfanyl Ketones 6a
motives in biologically active molecules16 and are also
common in organic synthesis.17 Their treatment with DBU
led to the elimination of the sulfonyl moiety and formation of
valuable vinyl ketone 13. Moreover, 6a was reduced to the
corresponding 3-thio-substituted alcohol 12.
In conclusion, a transition-metal-free two-step tandem
reaction of thioesters with vinylmagnesium bromide was
investigated. The likely formation of a chelate complex hinders
the attack of a second Grignard molecule and, hence, the
formation of a tertiary alcohol. Low temperature (0 °C) and
short reaction times (1 h) enabled the transformation of
various substrates in moderate to good yields. The obtained
a
Reaction conditions: 5a−r (1.0 mmol, 1.0 equiv), 3 (0.52−0.89 M in
b
THF, 3.0 equiv), THF (5 mL), 0 °C, 1 h. Isolated yields. Reaction at
10 mmol scale.
C
DOI: 10.1021/acs.orglett.9b00538
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siloxyallylmetallic species and their synthetic application. J. Am. Chem.
Soc. 1985, 107, 5495−5501. (d) Ryu, I.; Ikebe, M.; Sonoda, N.;
Yamato, S.-Y.; Yamamura, G.-H.; Komatsu, M. Chemistry of ketone
α,β-dianions. Acylation reactions of dianion cuprates by acid
chlorides. Tetrahedron Lett. 2002, 43, 1257−1259. (e) Murphy, J.
A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T.
A.; Hisler, K.; Dewis, M. L.; Carling, R. Direct Conversion of N-
Methoxy-N-methylamides (Weinreb Amides) to Ketones via a
Nonclassical Wittig Reaction. Org. Lett. 2005, 7, 1427−1429.
(f) Wang, X.-j.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.;
Senanayake, C. H. Addition of Grignard Reagents to Aryl Acid
Chlorides: An Efficient Synthesis of Aryl Ketones. Org. Lett. 2005, 7,
5593−5595. (g) Tsubouchi, A.; Onishi, K.; Takeda, T. Stereoselective
Preparation of 1-Siloxy-1-alkenylcopper Species by 1,2-Csp2-to-O
Silyl Migration of Acylsilanes. J. Am. Chem. Soc. 2006, 128, 14268−
14269. (h) Maloney, K. M.; Chung, J. Y. L. A General Procedure for
the Preparation of β-Ketophosphonates. J. Org. Chem. 2009, 74,
products can be used as building blocks for other synthetic
transformations, e.g., the generation of β-sulfonyl ketones.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00538.
Experimental procedures, analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ivana.fleischer@uni-tuebingen.de.
ORCID
̌
7574−7576. (i) Stefane, B. Selective Addition of Organolithium
Ivana Fleischer: 0000-0002-2609-6536
Present Address
‡(P.H.G.) Department of Organic Chemistry, Weizmann
Institute of Science, 234 Herzl St, Rehovot, Israel.
Author Contributions
†V.H. and M.B. contributed equally.
Notes
Reagents to BF2-Chelates of β-Ketoesters. Org. Lett. 2010, 12, 2900−
2903. (j) Genna, D. T.; Posner, G. H. Cyanocuprates Convert
Carboxylic Acids Directly into Ketones. Org. Lett. 2011, 13, 5358−
5361. (k) Liu, C.; Achtenhagen, M.; Szostak, M. Chemoselective
Ketone Synthesis by the Addition of Organometallics to N-
Acylazetidines. Org. Lett. 2016, 18, 2375−2378. (l) Meng, G.;
Szostak, M. N-Acyl-Glutarimides: Privileged Scaffolds in Amide N−C
Bond Cross-Coupling. Eur. J. Org. Chem. 2018, 2018, 2352−2365.
(m) Shi, S.; Nolan, S. P.; Szostak, M. Well-Defined Palladium(II)−
NHC Precatalysts for Cross-Coupling Reactions of Amides and Esters
by Selective N−C/O−C Cleavage. Acc. Chem. Res. 2018, 51, 2589−
2599.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Fonds der Chemischen Industrie (Liebig
Fellowship, I.F.; PhD fellowship, V.H., the University of
■
(5) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
A novel ketone synthesis by a palladium-catalyzed reaction of thiol
esters and organozinc reagents. Tetrahedron Lett. 1998, 39, 3189−
3192. (b) Liebeskind, L. S.; Srogl, J. Thiol Ester−Boronic Acid
Coupling. A Mechanistically Unprecedented and General Ketone
Synthesis. J. Am. Chem. Soc. 2000, 122, 11260−11261. (c) Wittenberg,
R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Ketone Synthesis under Neutral
Conditions. Cu(I) Diphenylphosphinate-Mediated, Palladium-Cata-
lyzed Coupling of Thiol Esters and Organostannanes. Org. Lett. 2003,
5, 3033−3035. (d) Fausett, B. W.; Liebeskind, L. S. Palladium-
Catalyzed Coupling of Thiol Esters with Aryl and Primary and
Secondary Alkyl Organoindium Reagents. J. Org. Chem. 2005, 70,
4851−4853.
(6) (a) Gehrtz, P. H.; Kathe, P.; Fleischer, I. Nickel-Catalyzed
Coupling of Arylzinc Halides with Thioesters. Chem. - Eur. J. 2018,
24, 8774−8778. (b) Shimizu, T.; Seki, M. A novel synthesis of
functionalized ketones via a nickel-catalyzed coupling reaction of zinc
reagents with thiolesters. Tetrahedron Lett. 2002, 43, 1039−1042.
(c) Wotal, A. C.; Weix, D. J. Synthesis of Functionalized Dialkyl
Ketones from Carboxylic Acid Derivatives and Alkyl Halides. Org.
Lett. 2012, 14, 1476−1479.
(7) Cardellicchio, C.; Fiandanese, V.; Marchese, G.; Ronzini, L. A
highly efficient synthetic route to ketones through sequential coupling
reactions of Grignard reagents with S-phenyl carbonochloridothioate
in the presence of nickel or iron catalysts. Tetrahedron Lett. 1985, 26,
3595−3598.
(8) Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. General
ketone synthesis. Reaction of organocopper reagents with S-alkyl and
S-aryl thioesters. J. Am. Chem. Soc. 1974, 96, 3654−3655.
(9) Mukaiyama, T.; Araki, M.; Takei, H. Reaction of S-(2-pyridyl)
thioates with Grignard reagents. Convenient method for the
preparation of ketones. J. Am. Chem. Soc. 1973, 95, 4763−4765.
(10) For selected examples, see: (a) Lauder, K.; Toscani, A.; Qi, Y.;
Lim, J.; Charnock, S. J.; Korah, K.; Castagnolo, D. Photo-biocatalytic
One-Pot Cascades for the Enantioselective Synthesis of 1,3-
Mercaptoalkanol Volatile Sulfur Compounds. Angew. Chem., Int. Ed.
2018, 57, 5803−5807. (b) Trost, B. M.; Keeley, D. E. New synthetic
methods. Secoalkylative approach to grandisol. J. Org. Chem. 1975, 40,
2013. (c) Cohen, T.; Mura, A. J.; Shull, D. W.; Fogel, E. R.; Ruffner,
Tu
Tubingen; Deutsche Forschungsgemeinchaft, ZUK63), and
̈
bingen (Institutional Strategy of the University of
̈
the University of Regensburg for financial support.
REFERENCES
■
(1) Kazemi, M.; Shiri, L. Thioesters synthesis: recent adventures in
the esterification of thiols. J. Sulfur Chem. 2015, 36, 613−623.
(2) For selected examples, see: (a) Lussem, B. J.; Gais, H.-J.
̈
Palladium-Catalyzed Enantioselective Allylic Alkylation of Thiocar-
boxylate Ions: Asymmetric Synthesis of Allylic Thioesters and
Memory Effect/Dynamic Kinetic Resolution of Allylic Esters. J. Org.
Chem. 2004, 69, 4041−4052. (b) Sawada, N.; Itoh, T.; Yasuda, N.
Efficient copper-catalyzed coupling of aryl iodides and thiobenzoic
acid. Tetrahedron Lett. 2006, 47, 6595−6597. (c) Cao, H.; McNamee,
L.; Alper, H. Palladium-Catalyzed Thiocarbonylation of Iodoarenes
with Thiols in Phosphonium Salt Ionic Liquids. J. Org. Chem. 2008,
73, 3530−3534. (d) Huang, Y.-T.; Lu, S.-Y.; Yi, C.-L.; Lee, C.-F. Iron-
Catalyzed Synthesis of Thioesters from Thiols and Aldehydes in
Water. J. Org. Chem. 2014, 79, 4561−4568. (e) Hirschbeck, V.;
Gehrtz, P. H.; Fleischer, I. Regioselective Thiocarbonylation of Vinyl
Arenes. J. Am. Chem. Soc. 2016, 138, 16794−16799.
(3) For reviews, see: (a) Hirschbeck, V.; Gehrtz, P. H.; Fleischer, I.
Metal-Catalyzed Synthesis and Use of Thioesters: Recent Develop-
ments. Chem. - Eur. J. 2018, 24, 7092−7107. (b) Pan, F.; Shi, Z.-J.
Recent Advances in Transition-Metal-Catalyzed C−S Activation:
From Thioester to (Hetero)aryl Thioether. ACS Catal. 2014, 4, 280−
288. (c) Wang, L.; He, W.; Yu, Z. Transition-metal mediated carbon−
sulfur bond activation and transformations. Chem. Soc. Rev. 2013, 42,
599−621.
(4) For selected examples, see: (a) Posner, G. H.; Whitten, C. E.;
McFarland, P. E. Organocopper chemistry. Halo-, cyano-, and
carbonyl-substituted ketones from the corresponding acyl chlorides
and organocopper reagents. J. Am. Chem. Soc. 1972, 94, 5106−5108.
(b) Nahm, S.; Weinreb, S. M. N-methoxy-N-methylamides as
effective acylating agents. Tetrahedron Lett. 1981, 22, 3815−3818.
(c) Enda, J.; Kuwajima, I. General method for generation of 3-
D
DOI: 10.1021/acs.orglett.9b00538
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
R. J.; Falck, J. R. Removal of sulfur groups from molecules by
copper(I). Preparation of sulfur-substituted 1,3-dienes for the Diels-
Alder reaction. J. Org. Chem. 1976, 41, 3218−3219. (d) Cherkauskas,
J. P.; Cohen, T. Carbonyl-protected β-lithio aldehydes and ketones via
reductive lithiation. A general preparative method for remarkably
versatile homoenolate equivalents. J. Org. Chem. 1992, 57, 6−8.
(11) Kumar, A.; Tripathi, V. D.; Kumar, P.; Gupta, L. P.; Akanksha;
Trivedi, R.; Bid, H.; Nayak, V. L.; Siddiqui, J. A.; Chakravarti, B.;
Saxena, R.; Dwivedi, A.; Siddiquee, M. I.; Siddiqui, U.; Konwar, R.;
Chattopadhyay, N. Design and synthesis of 1,3-biarylsulfanyl
derivatives as new anti-breast cancer agents. Bioorg. Med. Chem.
2011, 19, 5409−5419.
(12) Huang, J.; Xiong, F.; Wang, Z.-H.; Chen, F.-E. Unexpected
Ring Expansion of the (3aS,6aR)-γ-Thiolactone Moiety during the
Introduction of the (+)-Biotin Side Chain. Helv. Chim. Acta 2009, 92,
1445−1449.
(13) Zhu, M.; Liu, L.; Yu, H.-T.; Zhang, W.-X.; Xi, Z. Alkenyl
Magnesium Compounds: Generation and Synthetic Application.
Chem. - Eur. J. 2018, 24, 19122−19135.
(14) (a) Krasovskiy, A.; Knochel, P. A LiCl-Mediated Br/Mg
Exchange Reaction for the Preparation of Functionalized Aryl- and
Heteroarylmagnesium Compounds from Organic Bromides. Angew.
Chem., Int. Ed. 2004, 43, 3333−3336. (b) Krasovskiy, A.; Straub, B.
F.; Knochel, P. Highly Efficient Reagents for Br/Mg Exchange. Angew.
Chem., Int. Ed. 2006, 45, 159−162.
(15) (a) Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. Reactions of
nitroarenes with Grignard reagents. General method of synthesis of
alkyl-nitroso-substituted bicyclic aromatic systems. J. Chem. Soc.,
Perkin Trans. 1 1978, 1, 692−696. (b) Bartoli, G. Conjugate addition
of alkyl Grignard reagents to mononitroarenes. Acc. Chem. Res. 1984,
17, 109−115. (c) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
The reaction of vinyl grignard reagents with 2-substituted nitroarenes:
A new approach to the synthesis of 7-substituted indoles. Tetrahedron
Lett. 1989, 30, 2129−2132. (d) Bosco, M.; Dalpozzo, R.; Bartoli, G.;
Palmieri, G.; Petrini, M. Mechanistic studies on the reaction of nitro-
and nitrosoarenes with vinyl Grignard reagents. J. Chem. Soc., Perkin
Trans. 2 1991, 2, 657−663.
(16) Messinger, P.; Borchert-Bremer, R. γ-Oxosulfone als Aldehyd-
Dehydrogenase-Hemmer. Arch. Pharm. 1983, 316, 663−667.
(17) (a) Wan, X.; Meng, Q.; Zhang, H.; Sun, Y.; Fan, W.; Zhang, Z.
An Efficient Synthesis of Chiral β-Hydroxy Sulfones via Ru-Catalyzed
Enantioselective Hydrogenation in the Presence of Iodine. Org. Lett.
2007, 9, 5613−5616. (b) Liu, Y.; Qin, W.; Yan, H. Efficient
Enrichment of Chiral β-Sulfonyl Ketones through Asymmetric β-
Elimination. Synlett 2016, 27, 2756−2760. (c) Li, L.; Liu, Y.; Peng, Y.;
Yu, L.; Wu, X.; Yan, H. Kinetic Resolution of β-Sulfonyl Ketones
through Enantioselective β-Elimination using a Cation-Binding
Polyether Catalyst. Angew. Chem., Int. Ed. 2016, 55, 331−335. (d)
Hays, D.; Danielson, M.; Gerster, J.; Niwas, S.; Prince, R.; Kshirsagar,
T.; Heppne, P.; Moser, W.; Moseman, J.; Radmer, M.; Kavanagh, M.;
Strong, S.; Bonk, J. US Patent 20060100229, 2006.
E
DOI: 10.1021/acs.orglett.9b00538
Org. Lett. XXXX, XXX, XXX−XXX