Nucleophilic halo-michael addition under lewis-base activation

Article abstract of DOI:10.1039/c9cc07068k

A simple and general conjugate nucleophilic halogenation is presented. The THTO/halosilane combination has shown the ability to act as a nucleophilic halide source in the conjugate addition to a variety of Michael acceptors. In addition, a straightforward diastereoselective halogen installation using α,β-unsaturated acyloxazolidinones as platforms has been developed.

Full text of DOI:10.1039/c9cc07068k

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Nucleophilic halo-Michael addition under
Lewis-base activation†
Cite this: Chem. Commun., 2019,
55, 12936
Vıctor Laina-Martın, ‡a Ignacio Perez,‡a Jose A. Fernandez-Salas *a and
´
´
´
´
ab
Received 10th September 2019,
Accepted 2nd October 2019
Jose Aleman
*
´
´
DOI: 10.1039/c9cc07068k
rsc.li/chemcomm
A simple and general conjugate nucleophilic halogenation is presented.
The THTO/halosilane combination has shown the ability to act as a
nucleophilic halide source in the conjugate addition to a variety of
Michael acceptors. In addition, a straightforward diastereoselective
halogen installation using a,b-unsaturated acyloxazolidinones as
platforms has been developed.
Organic halides stand as the foundation upon which organic
chemistry has been built over the decades. Indeed, aryl halides are
among the most important building blocks, used on a daily basis,
especially as starting materials for a range of metal-mediated cross-
coupling reactions.1 Alkyl halides are among the most versatile
compounds in organic synthesis, commonly used in alkylation
reactions,2 radical cascades,3 and alkyl cross-coupling chemistry.4
Scheme 1 Previous works (A and B) and present work (C).
Moreover, the reactive nature of alkyl halides has also been exploited additions as the Michael reaction remains a key transformation
in medicinal chemistry and chemical biology,5 as well as in natural in organic chemistry since it represents a powerful tool for the
product synthesis.6 Chiral organohalides have attracted the attention rapid installation of molecular complexity.12 Nevertheless, only
of organic chemists over the years as they are an interesting class few methodologies describe the direct nucleophilic addition
of synthetic intermediates. This interest has led to a variety of of halides to electron-deficient alkenes. In this sense, the
synthetic methods focused on the asymmetric installation of these formation of b-halo-adducts using highly reactive Lewis acids
functionalities.7 Electrophilic halogenating processes, such as such as AlCl3, ZrCl4 or BBr3 as halogen source have been the
a-halogenation of carbonyls8 or halogenation of olefins,7b,9 main approach, but only described for ketones.13 However, the
have been the method of choice for this challenging objective b-haloketones under these drastic conditions suffer spontaneous
(Scheme 1, eqn (A)). Moreover, the stereoselective nucleophilic dehydrohalogenation. In order to avoid the use of these strong
halogenation has been underdeveloped; ring-opening of meso Lewis acids, halosilanes have been used in the synthesis of
epoxides10 and SN2 displacement7a,11 have been the preferred b-haloketones.14 It should be highlighted that only ketones have
strategies for this purpose (Scheme 1, eqn (B)).
been reported to be reactive under such systems.
In this regard, a,b-unsaturated carbonyl compounds have
In spite of these particular achievements, the corresponding
traditionally been the platform of choice for milliard of nucleophilic conjugate nucleophilic halogenation still stands as an outstanding
challenge in asymmetric synthesis, probably due to the low nucleo-
philicity of halides and the instability of the corresponding
a
´
´
Organic Chemistry Department, Modulo 1, Universidad Autonoma de Madrid,
28049 Madrid, Spain. E-mail: j.fernandez@uam.es, jose.aleman@uam.es;
Web: http://www.uam.es/jose.aleman
enantioenriched b-substituted adducts. In this regard, the con-
jugate chlorination to chiral acryloylureas and a,b-unsaturated
imides, using very reactive Lewis acids (TiCl4 and the in situ
generated BCl2OR), has been described.15,16 However, the corres-
ponding chloroderivatives were obtained with low-moderate
diastereoselectivities and very limited scope probably affected
by the nature of the highly reactive halogenating reagent.
b Institute for Advanced Research in Chemical Sciences (IAdChem),
´
Universidad Autonoma de Madrid, 28049 Madrid, Spain
† Electronic supplementary information (ESI) available. CCDC 1952333 (4e). For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc07068k
‡ These authors contributed equally.
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Therefore, we believe there is still great room for improvement in conjugate addition to the Michael acceptor (entries 4–8), being
the challenging nucleophilic b-halogenation of a,b-unsaturated tetrahydrothiophene S-oxide (THTO) the one that showed better
carbonyl compounds.
performance. Remarkably, in presence of THTO the reaction
Herein, we describe a stereoselective installation of chlorine showed good reactivity and high diastereoselectivity (entry 8). We
and bromine in a conjugate fashion to a,b-unsaturated acylox- then examined different chlorosilyl derivatives as chloride source
azolidinones, promoted by a sulfoxide, which is able to activate (entries 9–12). Only PhSiCl3 presented a similar reactivity when
the organosilane used as halide source (Scheme 1, eqn (C)). compared with AllylSiCl3 (entry 11 vs. 8). When performed with a
In addition, the reaction has been expanded to the conjugate higher quantity of the silyl nucleophile, full conversion to the
1,4-bromination of different Michael acceptors using a bromosilyl desired b-chloro-adduct was obtained although this led to a slight
derivative which implies, to the best of our knowledge, the first erosion in the diastereoselectivity (entry 13). We then decided to
methodology described in the literature for that purpose. The mild modify the structure of the chiral inductor and a bulkier group
reaction conditions of the proposed halogenation give access to (tBu) was installed in the oxazolidinone. After optimizing the
b-chlorinated and b-brominated compounds in good yields.
amount of the organosilane and the concentration required to
We began our investigations by studying the reaction of reach full conversion, 1b led to the desired b-chlorocarbonyl adduct
a,b-unsaturated oxazolidinone bearing an iso-propyl group (1a) with excellent yield and diastereoselectivity (entry 14).
as model substrate with different chlorosilane derivatives in the
Once the reaction conditions had been optimised (entry 14,
presence of various promoters (Table 1 and see ESI† for all the Table 1), we studied the scope of the reaction considering the
details). At first, we performed a preliminary reaction with chlorination of differently substituted a,b-unsaturated acylox-
commercially available allyltrichlorosilane (AllylSiCl3) as chloride azolidinones (Table 2). The reaction proceeded smoothly
source in absence of a promoter in dichloromethane and the employing the corresponding Michael acceptors bearing aliphatic
reaction did not take place (entry 1). In order to increase the chains. High yields and diastereoselectivities of the desired
conversion, we considered enhancing the reactivity of the electro- b-chloroderivatives were obtained in all cases (3b–e). Unfortunately,
phile by using a Lewis acid such as Yb(OTf)3. However, although the aromatic analogues were not suitable for the chloride conjugate
the desired b-chloroderivative was obtained in moderate yield, the addition. Thus, we envisioned that using the bromosilyl-analogue –
diastereoselectivity observed was practically null (entry 2). Different which is more electrophilic and generates a more nucleophilic
solvents were then studied (see ESI†). Hexafluorobenzene (HFB) halide – would potentially promote the conjugate addition solving
displayed the best performance, showing an increased stereo- the reactivity issues that the chlorination presented. Therefore, we
selectivity (entry 3). We then considered to use a nucleophilic
activator to trigger the halide addition.10,14d Among the Lewis bases
tested, only the sulfoxides17 showed the ability to promote the
Table
2
Scope of the diastereoselective conjugate halogenation of
a,b-unsaturated acyloxazolidinones
Table 1 Optimization of the conjugate nucleophilic diastereoselective
halogenation of a,b-unsaturated oxazolidinonesa
Entry R1
R23SiCl
Promoter
Solvent Conv.b
d.r.c
1
2
3
4
5
6
7
8
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
AllylSiCl3
AllylSiCl3e
AllylSiCl3
AllylSiCl3
AllylSiCl3
AllylSiCl3
AllylSiCl3
AllylSiCl3
TMSCl
—
DCM
o10
57
50
n.r.
n.r.
n.r.
21
48
10
n.r.
47
25
—
d
Yb(OTf)3d DCM
60 : 40
87 : 13
—
—
—
85 : 15
87 : 13
—
Yb(OTf)3
Ph3PO
Phenol
PPh3
HFB
HFB
HFB
HFB
HFB
HFB
HFB
HFB
HFB
HFB
HFB
HFBg
DMSO
THTO
THTO
9
10
11
12
13
14
TMS-SiMe2Cl THTO
—
PhSiCl3
SiCl4
AllylSiCl3 f
THTO
THTO
THTO
THTO
86 : 14
86 : 14
80 : 20
e
100
tBu AllylSiCl3
94 (82) 96 : 4
a
Standard conditions: 0.1 mmol of 1, 0.1 mmol of silane and 0.1 mmol of
promoter in 1.2 mL of solvent were used. b The conversion was determined
by H-NMR. c The diastereoisomeric ratio (d.r.) was measured by H-NMR.
Reaction conditions: to a solution of 1 (0.1 mmol) in HFB (2.5 mL),
1
1
a
d
f
e
20 mol% was used. 3 equivalents of silane and THTO were used. THTO (0.4 mmol) and allylSiCl3 (0.4 mmol) were sequentially added at
g
b
4 equivalents of silane and THTO were used. 2.5 mL of solvent were r.t. To a solution of 1 (0.1 mmol) in HFB (2.5 mL), THTO (0.4 mmol)
used.
and PhSiBr3 (0.4 mmol) were sequentially added at r.t.
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tested tribromo(phenyl)silane (PhSiBr3) in the conjugate addition
in the presence of THTO, and after small optimization (see ESI†),
we were able to obtain the corresponding bromo-Michael adduct 4a
in excellent yield and diastereoselectivity. A bulkier carbon chain
substituent such as iso-propyl was very well tolerated, reaching the
desired product (4b) with excellent diastereoselectivities. To our
delight, the nucleophilic bromination of the Michael acceptor
bearing a phenyl ring proceeded efficiently (4c). We then studied
the stereoelectronic nature of the aromatic ring. The electron-
withdrawing NO2 group as well as different halogens allocated in
para and ortho position of the aromatic ring led to the desired
b-bromoderivatives with very good results in both yield and
diastereoselectivity (4d–g). Electron-rich aromatic ring enabled
efficient access to the corresponding b-bromo-acyl oxazolidinone
(4h). More electron-rich systems (1l) were not tolerated and the
reaction did not take place. Gratifyingly, the a-disubstituted
acyloxazolidinone was very well tolerated and the bromo-adduct
was obtained with excellent diastereoselectivity (4i).
The absolute configuration of product 4e was unequivocally
assigned as R by X-ray diffraction (see ESI†).18 The same stereo-
chemical outcome was assumed for the rest of compounds 3 and 4.
As mentioned above, despite the interest of organohalides,
not many methods have been developed for the nucleophilic
1,4-halogenation, especially considering a general system able
to halogenate a variety of Michael acceptors (Table 3). At first, we
wanted to test the generality of our method and a,b-unsaturated
esters and amides – known to be less reactive in conjugate
additions – were submitted to our optimised reaction conditions.
Satisfyingly, acyclic and cyclic esters and amides showed to be
reactive under the optimised reaction conditions and the desired
brominated adducts were obtained with good yields (7c and 7e–h).
In addition, to further demonstrate the applicability and the
gentleness of the method, hydrolysable cyano group was proven
to be tolerated, and both aromatic and aliphatic a,b-unsaturated
nitriles led to the desired b-bromoderivatives with excellent yields
(7a and 7b). More reactive Michael acceptors were also shown to be
compatible (7d). In addition, for the case of 8a and 8b, the
dibrominated products were obtained as major product, showing
the dual activity of the active species formed in situ.
Scheme 2 Derivatisation of b-halo-acyloxazolidinones.
As stated before, organic halides are powerful and versatile
building blocks in organic chemistry due to their inherent and wide
reactivity. In order to liberate the enantiopure haloderivative, the
chiral auxiliary was removed under different reaction conditions
(Scheme 2). Facile acyloxazolidinone cleavage in presence of LiOH
and H2O2 efficiently led to the carboxylic acid, compound with a
great potential to be further derivatised (Scheme 2, left). NaBH4
reduction gave rise to the desired enantiomerically pure primary
alcohol bearing the chiral bromine in synthetically useful yields
(Scheme 2, right).
In order to explain the b-halogenation using the silane/sulfoxide
system, a mechanistic proposal is depicted in Scheme 3. The
combination of an organohalosilyl derivative with a sulfoxide leads
to the corresponding halosulfonium salt that has been widely used
in organic synthesis, mainly as electrophilic halogen source.19,20
This strategy has been followed in an attempt to avoid the use of
hazardous and difficult to handle elemental halogen. Remarkably,
it has never been utilised in a Michael-type process. At first, we
propose the THTO activation by the halosilane derivative forms the
halosulfonium halide (identified by 1H-NMR),20,21 which would
then interact with the carbonyl group through the electrophilic
sulfur atom. Very reactive intermediate I would then undergo the
nucleophilic conjugate addition, giving rise to intermediate II.
Intramolecular protonation of this species leads to the desired
halogenated product, releasing 3,4-dihydro-2H-thiophen-1-ium salt
that could potentially form 2,3-dihydrothiophene. Another mole-
cule of the active bromosulfonium bromide would then be capable
to dibrominate the CQC of the formed heterocycle, giving rise to
2,3-dichlorothiophane (isolated and characterised), and release
tetrahydrothiophene (identified in the crude NMR).21
In conclusion, we have described an efficient, straight-
forward and facile methodology to install chloride and bromide
through a Michael addition under mild reaction conditions.
The sulfoxide/halosilane system is able to introduce halides in
Table 3 Scope of the nucleophilic b-bromination of Michael acceptorsa
a
Reaction conditions: to a solution of 1 (0.1 mmol) in DCM (2.5 mL),
THTO (0.4 mmol) and tribromo(phenyl)silane (0.4 mmol) were sequentially
added at r.t. b The methyl ester gets hydrolised to the carboxylic acid 7c
(R = H) during the bromination process.
Scheme 3 Proposed reaction mechanism for the b halogenation.
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Synthesis, 2010, 2679; (i) S. Bertelsen, N. Halland, S. Bachmann,
M. Marigo, A. Braunton and K.-A. Jørgensen, Chem. Commun., 2005,
4821.
9 For selected reviews, see: (a) S. E. Denmark, W. E. Kuester and
M. T. Burk, Angew. Chem., Int. Ed., 2012, 51, 10938; (b) G. Chen and
S. Ma, Angew. Chem., Int. Ed., 2010, 49, 8306.
10 (a) C. E. Carret and G. C. Fu, J. Org. Chem., 1997, 62, 4534;
(b) S. E. Denmark, P. A. Barsanti, K.-T. Wong and R. A. Stavenger,
J. Org. Chem., 1998, 63, 2428; (c) A. V. Malkov, M. R. Gordon,
S. Stoncius, J. Hussain and P. Kocovsky, Org. Lett., 2009, 11, 5390;
(d) G. Sabitha, R. S. Babu, M. Rajkumar, Ch. S. Reddy and
J. S. Yadav, Tetrahedron Lett., 2001, 42, 3955.
11 For a recent example, see: D. Canestrari, S. Lancianesi, E. Badiola,
C. Strinna, H. Ibrahim and M. F. A. Adamo, Org. Lett., 2017, 19, 918.
12 (a) G. H. Posner, in Organic Reactions, ed. W. G. Dauben, John Wiley &
Sons, Inc., New York, NY, USA, 1972, pp. 1–114; (b) B. H. Lipshutz and
S. Sengupta, in Organic Reactions, ed. L. A. Paquette, John Wiley &
Sons, Inc., New York, NY, USA, 1992, pp. 135–631; (c) T. Jerphagnon,
M. G. Pizzuti, A. J. Minnaard and B. L. Feringa, Chem. Soc. Rev., 2009,
a nucleophilic manner to different Michael acceptors. Moreover,
the system has been extended and an efficient and straightforward
diastereoselective version using a,b-unsaturated acyloxazolidinones
as platforms has been developed. Finally, in order to explain the
unexpected nucleophilic behaviour of the sulfonium halide formed
in situ, a mechanism has been proposed.
We are grateful to the Spanish Government (CTQ2015-
64561-R and RTI2018-095038-B-I00), ‘‘Comunidad de Madrid’’
and European Structural Funds (S2018/NMT-4367). J. A. F.-S.
thanks the Spanish Government for a Juan de la Cierva and
´
Ramon y Cajal contracts. V. L.-M. thanks the Universidad
´
Autonoma de Madrid for a predoctoral fellowship (FPI-UAM).
´
I. P. thanks CONACYT-Mexico for a postdoctoral fellowship.
¨
`
38, 1039; (d) A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and
Conflicts of interest
´
M. Dieguez, Chem. Rev., 2008, 108, 2796; (e) B. E. Rossiter and
N. M. Swingle, Chem. Rev., 1992, 92, 771.
There are no conflicts to declare.
13 (a) S. Roscales, A. Rincon, E. Buxaderas and A. G. Csaky, Tetrahedron
Lett., 2012, 53, 4721; (b) R. D. Bach and J. M. Domagala, J. Org. Chem.,
1984, 49, 4181; (c) Y. Itoh, R. Kitaguchi, M. Naito and Y. Hashimoto,
Bioorg. Med. Chem., 2011, 19, 6768; (d) C. Napolitano, A. Natoni,
C. Santocanale, L. Evensen, J. B. Lorens and P. V. Murphy, Bioorg.
Med. Chem. Lett., 2011, 21, 1167; (e) C. Napolitano, P. McArdle and
P. V. Murphy, J. Org. Chem., 2010, 75, 7404; ( f ) E. A. Couladouros,
A. P. Mihou and E. A. Bouzas, Org. Lett., 2004, 6, 977; (g) A. S.-Y. Lee,
S.-H. Wang and Y.-T. Chang, J. Chin. Chem. Soc., 2014, 61, 364.
Notes and references
1 (a) C.-C.-C. Johansson Seechurn, M.-O. Kitching, T.-J. Colacot and
V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062; (b) Metal Catalyzed
Cross-Coupling Reactions and More, ed. A. De Meijere, S. Brase and
M. Oestreich, Wiley-VCH, Weinheim, 2014, vol. 3; (c) Cross-Coupling
Reactions, Workbench, ed. G. A. Molander, M. Larhed and J. Wolfe,
Science of Synthesis Series, Thieme Chemistry, Stuttgart, 2013; 14 (a) R. D. Miller and D. R. Mckean, Tetrahedron Lett., 1979, 2304; (b) G. Gil,
(d) Cross Coupling Reactions in Organic Synthesis Themed Issue,
Chem. Soc. Rev., 2011, 40, 4877.
2 F.-A. Carey and R.-J. Sundberg, Advanced Organic Chemistry, Part B:
Tetrahedron Lett., 1984, 25, 3805; (c) C. Le Roux, H. Gaspard-Iloughmane
and J. Dubac, J. Org. Chem., 1994, 59, 2238; (d) T. A. Salama and
S. S. Elmorsy, Chin. Chem. Lett., 2011, 22, 1171.
Reaction and Synthesis, Springer, New York, NY, USA, 5th edn, 2007, 15 (a) K. Kishikawa, A. Furusawa, S. Kohmoto, M. Yamamoto and
p. 217.
K. Yamada, J. Org. Chem., 1993, 58, 7296; (b) K. Kishikawa,
M. Yamamoto, S. Kohmoto and K. Yamada, Chem. Lett., 1990, 1123.
16 (a) G. Cardillo, E. Di Martino, L. Gentilucei, C. Tomasini and
L. Tomasoni, Tetrahedron: Asymmetry, 1995, 6, 1957; (b) G. Cardillo,
A. De Simone, L. Gentilucci and C. Tomasini, J. Chem. Soc., Chem.
Commun., 1994, 735.
3 K.-C. Nicolaou, D.-J. Edmonds and P.-G. Bulger, Angew. Chem., Int. Ed.,
2006, 45, 7134.
4 N. Kambe, T. Iwasaki and J. Terao, Chem. Soc. Rev., 2011, 40, 4937.
´
5 B. Gal, C. Bucher and N. Z. Burns, Mar. Drugs, 2016, 14, 206.
6 W.-J. Chung and C.-D. Vanderwal, Angew. Chem., Int. Ed., 2016, 55, 4396.
7 For selected reviews, see: (a) W.-J. Chung and C.-D. Vanderwal, 17 (a) X. Ma, J. Yu, M. Jiang, M. Wang, L. Tang, M. Wei and Q. Zhou,
Angew. Chem., Int. Ed., 2016, 55, 4396; (b) A. Castellanos and S.-P.
Fletcher, Chem. – Eur. J., 2011, 17, 5766; (c) J.-A. Ma and D. Cahard,
Chem. Rev., 2004, 104, 6119.
Eur. J. Org. Chem., 2019, 4593; (b) S. Song, X. Sun, X. Li, Y. Yuan and
N. Jiao, Org. Lett., 2015, 17, 2886; (c) L.-H. Choudhury, T. Parvin and
A.-T. Khan, Tetrahedron, 2009, 65, 9513; (d) V.-P. Demertzidou,
S. Pappa, V. Sarli and A.-L. Zografos, J. Org. Chem., 2017, 82, 8710.
8 For selected reviews, see: (a) A.-N. French, S. Bissmire and T. Wirth,
Chem. Soc. Rev., 2004, 33, 354. For selected asymmetric a-halogenation, 18 See ESI† for X-ray structure. CCDC 1952333 (4e).
see: (b) H. Ibrahim and A. Togni, Chem. Commun., 2004, 1147; 19 Only one example describe the use of an halodimethylsulfonium
(c) M. Oestreich, Angew. Chem., Int. Ed., 2005, 44, 2324; (d) S. France,
A. Weatherwax and T. Lectka, Eur. J. Org. Chem., 2005, 475; (e) M. Marigo
and K.-A. Jørgensen, Chem. Commun., 2006, 2001; ( f ) V.-A. Brunet and
halide for the synthesis of a-haloketones through a nucleophilic of
an epoxide promoted by Et3N: G. A. Olah, Y. D. Vankar and
M. Arvanaghi, Tetrahedron Lett., 1979, 38, 3653.
D. O’Hagan, Angew. Chem., Int. Ed., 2008, 47, 1179; (g) M. Ueda, T. Kano 20 For a review, see: L. H. Choudhury, Synlett, 2006, 1619.
and K. Maruoka, Org. Biomol. Chem., 2009, 7, 2005; (h) K. Shibatomi, 21 G. E. Wilson Jr. and R. Albert, J. Org. Chem., 1973, 38, 2156.
This journal is ©The Royal Society of Chemistry 2019
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