Catalyst free annulative thioboration of unfunctionalized olefins

Article abstract of DOI:10.1039/c7cc06800j

A direct and catalyst-free annulative thioboration of unfunctionalized olefins has been developed. In the presence of BCl₃ as the sole boron source, the boryl group and thiol group are added to the C-C double bonds simultaneously. The boronic acids obtained can be protected to form synthetically ubiquitous pinacol boronate esters.

Full text of DOI:10.1039/c7cc06800j

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Catalyst Free Annulative Thioboration of Unfunctionalized Olefins
ZhantaoYang,ab Chun-Hua Yang,*a Shiqi Chen, a and Xixi Chen, a Litian Zhang, a Huijun Ren a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
direct and catalyst-free annulative thioboration of and vinyl sulfides in the absence of transition metal complexes
unfunctionalized olefins has been developed. In the presence of or additives, which demonstrated the ability of B–S σ bonds
BCl3 as the sole boron source, the boryl group and thiol group are from in-house synthesized reagents to add across Michael
added to the C-C double bonds simultaneously. The boronic acids acceptors through boron activation of the carbonyl oxygen.
S
obtained can be protected to form synthetically ubiquitous
pinacol boronate esters.
MeO
Me
OEt
OH
OH
O
S
Me
O
HO
HO
N
H
OH
O
HO
OH
O
Sulfides are key motifs in drug development1 and in many
organic materials,2 for example, antidiabetics,3 tazarotene,4
breynolide,5 anti-Alzheimer’s disease activity,6 antimicrobial
activity7(Figure 1). Many sulphur and nitrogen containing
heterocycles such as thiomorpholines display local anesthetic,8
anticonvulsant,9 antimycobacterial,10 anti-inflammatory,11 and
antidiabetic activities.12 Substituted thiomorpholines, in
particular, are useful scaffolds and property-enhancing
functional groups in drug discovery. Moreover, thiomorpholine
S
H
OH
OEt
antidiabetics
SGL T2 inhibitor
tazarotene
Breynolide
hypocholesterolemic
anti psoriasis and acne
MeO
F3
BnO
N
C
O
O
O
NO2
O
H2N
S
O
S
N NH
S
O
F
N
H
OH
MeO
OMe
t-Bu
anti-Alzheimer's disease
antimicrobial activity
S
nifurtimox
O
O
O
S
or its disulfoxide ring containing molecules such as sutezolid
A,13,
N
N
SMe
O
14
nifurtimox,15 thioridazine and artemisone B16 are
N
O
N
S
Me
•HCl
O
undergoing human clinical trials for the treatment of malaria,
chagas, psychoticism and tuberculosis, respectively (Figure 1).
Due to their enormous biological activities, significant efforts
have been made to develop new methods for C–S bond
formation. Thioboration, as a method for the construction of
C–S bond, has gotten more and more attention.
N
NH
O
O
sutezolid A
thioridazine
artemisone B
Figure
1 Selected examples of important compounds
containing C-S bonds
Recently, Blum and co-workers19 synthesized borylated
benzothiophenes via thioboration reaction (Scheme 1a).
Ingleson and co-workers20 described BCl3-induced annulative
thioboration of substituted alkynes (Scheme 1b). There are no
reports about thioboration of unfunctionalized alkenes.
Compared with alkynes, thioboration of unfunctionalized
olefins is more challenging due to the low electron cloud
density and low reactivity of olefins. We are interested in
developing new, straightforward procedures for the
thioboration of unfunctionalized olefins. Herein, we report our
recent results on the direct and catalyst-free intramolecular
thioboration of unfunctionalized C=C double bonds (Scheme
1c). Borylative cyclization of unsaturated C–C bonds proceeded
Thioboration, the simultaneous addition of sulfur and boron
across C–C π bonds, holds promise as an efficient route to
synthesize functionalized sulfides. In 1993, Miyaura and
Suzuki17 reported the first thioboration reaction of C–C π
systems. This method accomplished the addition of 9-
(alkylthio)-9-borabicyclo[3.3,1]nonanes (9-(RS)-9-BBN) to
terminal alkynes catalyzed by Pd(PPh3)4. In 2015, Bo,
Fernández and Westcott18 using ynones with PhSe-Bpin, PhS-
Bpin and BnS-Bpin, promoted the synthesis of vinyl selenides
a.College of Chemistry and Chemical Engineering, Anyang Normal University, 436
Xian’ge Road, Anyang 455000, P. R. China
successfully in the presence of proper boron source, such as
aminoboration,21-24
b.School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan
450001, P. R. China
oxyboration,25-27 thioboration.19,
20
†Electronic Supplementary Information (ESI) available: Experimental details
and full characterization of substrates and products. Crystallographic data for
compound 9a. See DOI: 10.1039/x0xx00000x.
Inspired by the literature studies, we proposed that annulative
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thioboration of unfunctionalized olefins may come true in the 3c
,
3d and 3e). As to the substrate 2-ethyl-2-methylpent-4-
presence of proper boron source.
ene-1-thiol (1f), an unseparated diastereoisomeric mixture (3f
,
dr=1:1) was obtained. When substrate 1j was subjected to the
same reaction, the thioboration product containing
octahydrobenzo[b]thiophene 3j (dr>10:1) was obtained in
good yield.
Table
1
Synthesis
of
tetrahydrothiophene
and
tetrahydrothiopyran via thioboration reactiona
Scheme 1 Previous thioboration reactions and this work.
We hypothesized that thioboration of methyl(pent-4-en-1-
yl)sulfane 1a’ would occur upon treatment with proper boron
source. Firstly, we choose BCl3 as the boron source. However,
no desired result was obtained. When the thiol group was
protected with an acetyl group, the thioboration product was
not detected as well. Then we removed all the protected
a
groups, to our delight, the substrate 1a was converted to the
Reactions conditions: (1) 0.2 mmol of substrate, 0.21 mmol
Na2CO3, 0.24 mmol of BCl3 and 2 mL of DCE under argon
atmosphere. (2) boronic acid (1 equiv.), pinacol (1.1 equiv.),
TEA (15 equiv.), CH2Cl2 (1 M).
thioboration product 2a sucessfully (Scheme 2). The
thioboration product 2a was obtained in good isolated yield.
When the disubstituted alkene (E)-6-phenylhex-5-ene-1-thiol
1k was subjected to the thioboration reaction, no desired
products was detected (Scheme 3).
Scheme 2 Thioboration of alkenes.
Encouraged by this result, we optimized the conditions for this
direct intramolecular thioboration reaction. When a base of
Na2CO3 was added to the reaction system of 1a and BCl3 in 1,2-
dichloroethane, the conversion of 2a was enhanced to 93%.
The thioboration reaction can proceed readily using 1.2 equiv.
BCl3 as boron source, Na2CO3 as base and 1,2-dichloroethane
(DCE) as the solvent. After complete consumption of the
starting material, the reaction mixture was carefully treated
with water, and the thioboration product was separated.
Esterification of thioboration product to the more air and
moisture stable pinacolboronic ester provided bench-stable
organoboron building blocks.
Scheme 3 Thioboration of disubstituted alkene.
We next turned our attention to the intramolecular
thioboration of substituted 2-allylbenzenethiol substrates
(Table 2). Reactions of substituted 2-allylbenzenethiol
substrates all proceeded readily. The desired thioboration
products 6a–c was isolated in moderate overall yields, and the
reaction was not overly sensitive to the electronic effect of
substituents on the benzene ring (Table 2).
Table 2 BCl3-induced thioboration reaction of alkenesa
Having optimized the reaction conditions, the substrate scope
of thioboration reaction was next examined. Thioboration
reactions of substituted 4-pentenyl-1-thiol and 5-hexenyl-1-
thiol substrates all proceeded readily (Table 1).
Substrates without substituents on the main chain (1a, 1g)
gave the corresponding thioboration products in good yields.
Substrates with small substituents such as, 2-phenyl (1b), 2,2-
diphenyl (1c), –(CH2)5– (1d, 1h), 2,2-dimethyl- (1e, 1i) or 2-
a
Reactions conditions: (1) 0.2 mmol of substrate, 0.21 mmol
ethyl-2-methyl (1f) on the mainchain, showed little effect on
the reaction, and normal thioboration products could be
isolated in satisfactory yields. The 2-phenylpent-4-ene-1-thiol
1b also underwent efficient conversion, giving the substituted
Na2CO3, 0.24 mmol of BCl3 and 2 mL of DCE under argon
atmosphere. (2) boronic acid (1 equiv.), pinacol (1.1 equiv.),
TEA (15 equiv.), CH2Cl2 (1 M).
Substituted thiomorpholines are useful scaffolds and property-
enhancing functional groups in drug discovery. Due to their
enormous biological activities, new methods for their efficient
and stereoselective synthesis are desirable. Herein we would
tetrahydrothiophene boronate
3b (an unseparated
diastereoisomeric mixture, dr=4:1) in 50% yield. The
thioboration reaction was not affected significantly by the
Thorpe–Ingold effect (compare the formation of products 3a
,
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like to describe a pathway for the synthesis of thiomorpholines 1a was subjected to the reaction, the thioboration product
from thioboration (Table 3). was obtained in good yield. These results indicated that the
Upon treatment with BCl3 (1.2 equiv), N-tethered thioalkenols thiol group was essential to the reaction. When a base of
underwent thioboration to provide thiomorpholine . When Na2CO3 was added to the reaction system of 1a and BCl3 in 1,2-
7
9
the substrate 7a was subjected to the thioboration reaction, a dichloroethane, the conversion of 2a was enhanced. This
single diastereomer (dr > 10:1) was isolated. The relative result possibly supports the assumption of the formation of
stereochemistry of the major diastereomer of thiomorpholine HCl during the reaction. Removal of HCl from the reaction
9a was assigned as 2,5-cis by X-ray crystallography (Supporting system should help to move the equilibrium to the right side
Information). The (S)-N-allyl-N-(1-mercapto-3-phenylpropan-2- and speed up the reaction.
yl)-4-methylbenzenesulfonamide 7b underwent efficient NMR spectroscopic experiments were also carried out to study
conversion, giving the substituted thiomorpholine 9b as a the interaction between BCl3 and the thiol group. 5-hexene-1-
single diastereomer (dr > 10:1) in 68% yield (Table 3). While thiol 1g was used as a model substrate. 1H NMR spectra
(R)-N-allyl-N-(1-mercapto-3-phenylpropan-2-yl)-4-
methylbenzene-sulfonamide 7c gave 9c as
showed that signals for thioboration products appeared after
single the addition of BCl3. 11B NMR was also carried out to study the
a
diastereomer (dr > 10:1) in 78% yield. The reaction proceeds interaction between BCl3 and the substrate. BCl3 showed a
with methyl substituted N-tethered thioalkenol 7d to give signal at 46.6 ppm. After the addition of the substrate 1g, the
substituted thiomorpholines in moderate yield. Gram-scale peak at 5.0 ppm took the place of the peak at 46.6 ppm. We
synthesis of 9c was also carried out to test the scalability of the reasoned that this change was due to the formation of LA···SH
method, and thioboration of 7c on 3.0 mmol scale afforded adduct intermediate.29
boronic ester 9c in 78% isolated yield.
Table 3 Synthesis of thiomorpholines via thioboration
reactiona
Scheme 5 Proposed thioboration reaction mechanism.
On the basis of previously reported results and these
preliminary studies, we propose a possible reaction pathway
for the intramolecular aminoboration reaction in Scheme 5.
When BCl3 is mixed with the substrate, it interacts with the
thiol to form an LA···SH adduct
reaction occurs via transition state
intermediate . The diastereoselectivity is rationalized by a
A
. Intramolecular thioboration
a
B
,
leading to the
Reactions conditions: (1) 0.2 mmol of substrate, 0.21 mmol
Na2CO3, 0.24 mmol of BCl3 and 2 mL of DCE under argon
C
atmosphere. (2) boronic acid (1 equiv.), pinacol (1.1 equiv.), chairlike transition state where the vicinal tosyl and benzyl
TEA (15 equiv.), CH2Cl2 (1 M).
substituents adopt pseudoaxial positions.30-33 Intermediate
C
then can be hydrolyzed to afford the final thioboration product
D
.
In conclusion, the first intramolecular thioboration of
unfunctionalized alkenes are reported. This scalable method
efficiently generates both the S-heterocycle and
a C–B
functional group handle in one synthetic step. These borylated
products are primed for downstream in situ functionalization
reactions or for isolation as bench-stable building blocks. The
good yields and mild reaction conditions make this
transformation an attractive method for the synthesis of a
variety of useful S-heterocyclic boronic acids and boronates.
Use of these new synthons in drug discovery should now be
facile. Research on intermolecular thioboration of
unfunctionalized olefins is in progress.
Scheme 4 Derivatization of thioboration products.
Finally, the synthetic versatility of these novel thioboration
products was explored (Scheme 4). Oxidation of (9c) with
sodium peroxoborate tetrahydrate gave (tetrahydro-2H-
thiopyran-2-yl)methanol
(
10c
)
in
86%
yield.
Organotrifluoroborates are valuable synthetic intermediates in
Suzuki cross-couplings.28 Treatment of alkylboronate 9c with
aqueous KHF2, afforded the corresponding trifluoroborate in a
high yield.
Conflicts of interest
Results in Scheme 2 showed that the thioboration products
was not detected when the substrate 1a’ and 1a’’ was
subjected to the reaction (Scheme 2). While the thiol substrate
There are no conflicts to declare.
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18. M. G. Civit, X. Sanz, C. M. Vogels, J. D. Webb, S. J. Geier, A.
Decken, C. Bo, S. A. Westcott and E. Fernandez, J. Org.
Chem., 2015, 80, 2148-2154.
19. D. J. Faizi, A. J. Davis, F. B. Meany and S. A. Blum, Angew.
Chem. Int. Ed., 2016, 55, 14286-14290.
20. A. J. Warner, A. Churn, J. S. McGough and M. J. Ingleson,
Angew. Chem. Int. Ed., 2017, 56, 354-358.
21. C.-H. Yang, Y.-S. Zhang, W.-W. Fan, G.-Q. Liu and Y.-M. Li,
Angew. Chem. Int. Ed., 2015, 54, 12636-12639.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (81703353), the China
Postdoctoral Science Foundation (2017M612421) and Henan
Province key laboratory of New Opto-Electronic functional
Materials (192109317007, 192109317008).
22. A. J. Warner, J. R. Lawson, V. Fasano and M. J. Ingleson,
Angew. Chem. Int. Ed., 2015, 54, 11245-11249.
Notes and references
23. E. Chong and S. A. Blum, J. Am. Chem. Soc., 2015, 137
10144-10147.
,
1. E. A. Ilardi, E. Vitaku and J. T. Njardarson, J. Med. Chem.,
2014, 57, 2832-2842.
24. T. Voss, C. Chen, G. Kehr, E. Nauha, G. Erker and D. W.
Stephan, Chem. Eur. J., 2010, 16, 3005-3008.
25. D. J. Faizi, A. Issaian, A. J. Davis and S. A. Blum, J. Am. Chem.
Soc., 2016, 138, 2126-2129.
26. K. N. Tu, J. J. Hirner and S. A. Blum, Org. Lett., 2016, 18, 480-
483.
2. D. A. Boyd, Angew. Chem. Int. Ed. , 2016, 55, 15486-15502.
3. H. Kakinuma, T. Oi, Y. Hashimoto-Tsuchiya, M. Arai, Y.
Kawakita, Y. Fukasawa, I. Iida, N. Hagima, H. Takeuchi,
Y. Chino, J. Asami, L. Okumura-Kitajima, F. Io, D.
Yamamoto, N. Miyata, T. Takahashi, S. Uchida and K.
Yamamoto, J. Med. Chem., 2010, 53, 3247-3261.
4. C. Madhu, S. Duff, V. Baumgarten, P. Rix, D. Small and D.
Tang-Liu, J. Pharm. Sci., 1997, 86, 972-974.
27. R. L. Melen, M. M. Hansmann, A. J. Lough, A. S. K. Hashmi
and D. W. Stephan, Chem. Eur. J., 2013, 19, 11928-
11938.
5. A. B. Smith, J. R. Empfield, R. A. Rivero, H. A. Vaccaro, J. J. W.
Duan and M. M. Sulikowski, J. Am. Chem. Soc., 1992,
114, 9419-9434.
6. H. Rueeger, R. Lueoend, O. Rogel, J.-M. Rondeau, H. Möbitz,
R. Machauer, L. Jacobson, M. Staufenbiel, S. Desrayaud
and U. Neumann, J. Med. Chem., 2012, 55, 3364-3386.
7. P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar and S.
Kabilan, Bioorg. Med. Chem. Lett., 2009, 19, 2981-2985.
28. L. Zhang, Z. Zuo, X. Leng and Z. Huang, Angew. Chem. Int. Ed.,
2014, 53, 2696-2700.
29. M. R. Smith, B. B. Singh and H. Gilman, Journal of
Organometallic Chemistry, 1973, 61, 1-6.
30. F. C. Sequeira and S. R. Chemler, Org. Lett., 2012, 14, 4482-
4485.
31. S. Toumieux, P. Compain, O. R. Martin and M. Selkti, Org.
Lett., 2006,
32. A. R. Modarresi-Alam, H. A. Amirazizi, H. Bagheri, H.-R.
8, 4493-4496.
8. L. A. Burrows and E. E. Reid, J. Am. Chem. Soc. , 1934, 56
,
1720-1724.
9. N. Edayadulla and P. Ramesh, Eur. J. Med. Chem., 2015, 106
44-49.
10. S. Indumathi, S. Perumal, D. Banerjee, P. Yogeeswari and D.
Sriram, Eur. J. Med. Chem., 2009, 44, 4978-4984.
11. P. Theodosis-Nobelos, M. Kourti, A. Gavalas and E. A. Rekka,
Bioorg. Med. Chem. Lett., 2016, 26, 910-913.
Bijanzadeh and E. Kleinpeter, J. Org. Chem., 2009, 74
4740-4746.
33. M.-E. Ragoussi, S. M. Walker, A. Piccanello, B. M. Kariuki, P.
N. Horton, N. Spencer and J. S. Snaith, J. Org. Chem.,
2010, 75, 7347-7357.
,
,
12.B. Han, J. L. Liu, Y. Huan, P. Li, Q. Wu, Z. Y. Lin, Z. F. Shen, D. L.
Yin and H. H. Huang, Chin. Chem. Lett., 2012, 23, 297-
300.
13. M. R. Barbachyn, D. K. Hutchinson, S. J. Brickner, M. H.
Cynamon, J. O. Kilburn, S. P. Klemens, S. E. Glickman, K.
C. Grega, S. K. Hendges, D. S. Toops, C. W. Ford and G.
E. Zurenko, J. Med. Chem., 1996, 39, 680-685.
14. B. Villemagne, C. Crauste, M. Flipo, A. R. Baulard, B. Déprez
and N. Willand, Eur. J. Med. Chem., 2012, 51, 1-16.
15. D. G. Arias, F. E. Herrera, A. S. Garay, D. Rodrigues, P. S.
Forastieri, L. E. Luna, M. D. L. M. Bürgi, C. Prieto, A. A.
Iglesias, R. M. Cravero and S. A. Guerrero, Eur. J. Med.
Chem., 2017, 125, 1088-1097.
16. R. K. Haynes, B. Fugmann, J. Stetter, K. Rieckmann, H.-D.
Heilmann, H.-W. Chan, M.-K. Cheung, W.-L. Lam, H.-N.
Wong, S. L. Croft, L. Vivas, L. Rattray, L. Stewart, W.
Peters, B. L. Robinson, M. D. Edstein, B. Kotecka, D. E.
Kyle, B. Beckermann, M. Gerisch, M. Radtke, G.
Schmuck, W. Steinke, U. Wollborn, K. Schmeer and A.
Römer, Angew. Chem. Int. Ed., 2006, 45, 2082-2088.
17. T. Ishiyama, K. Nishijima, N. Miyaura and A. Suzuki, J. Am.
Chem. Soc. , 1993, 115, 7219-7225.
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