European Journal of Organic Chemistry
10.1002/ejoc.201800095
COMMUNICATION
The additional presence of a halogen on the thioanisol core did
not alter the outcome (18). Running the reaction at higher
temperatures (-40 or 0 °C) would suggest a considerably
increased stability of those α-sulfur substituted methyllithiums.
The procedure is also amenable for furnishing interesting
scaffolds such as β-oxo thioacetals 20-21 via the formation of
organic phase was dried over Na
The resulting crude compounds were purified through flash
column chromatography.
2
SO
4
and concentrated in vacuo.
General Procedure for the lithiation via deprotonation.
The thioether derivative (2.0 equiv) was added to a solution of
DABCO (2 equiv) at 0 °C (or, alternatively at -78 °C for
compounds 18, 20 and 21) in THF (1 M concentration) under
Argon atmosphere. Then n-butyllithium (1.8 equiv) was added
dropwise and, the mixture stirred for 1.5 hours at the same
temperature (-40 °C for compounds 20 and 21). A 0.5 M solution
of the Weinreb amide (1.0 equiv) in dry THF was added and, the
mixture was stirred at 0 °C for 1.5 hours (-78 °C for 6 hours and
then rt for 12 hours for compounds 20 and 21). After quenching
methoxy(phenylthio)methyllithium.[29]
Finally,
1,3-dithiane
underwent the lithiation-Weinreb amide trapping sequence thus,
yielding the cyclic α,α-dithioketone 22.
with aqueous NH
Extraction with Et
organic phase over Na
4
Cl, the reaction mixture was allowed to reach rt.
O (x 3), washing with brine and drying the
SO afforded crude (previous
2
2
4
a
concentration in vacuo) which was purified through flash column
chromatography.
Acknowledgements
The authors thank the University of Vienna for generous support,
MSc L. Urtis and MSc F. Patanè for experimental assistance and
MSc. D. Dobusch for HRMS analyses. R. S. acknowledges the
OEAD for a predoctoral Ernst Mach grant.
Scheme 3. Synthesis of α-arylthiomethyl ketones and α-thioacetal-like
methylketones.
Keywords: Homologation • Lithiation • Weinreb amides • Sulfur
•
Ketones
Conclusions
References
In summary, we have disclosed a reliable and direct access to
variously substituted β-thiomethyl ketones through the addition of
α-sulfur methyllithium reagents to Weinreb amides. By properly
selecting the conditions for forming the carbanions (the Yus’
arene-catalyzed Li-metal mediated lithiation or the organolithium-
mediated deprotonation), it is possible to chemoselectively
modulate the access to the targets. Uniformly high yields and the
fully transfer of stereochemical information from the starting
Weinreb amide to the final compounds make this simple tactic
particularly suitable for further applications in organic synthesis.
[
1] a) T. Kondo, T.-a. Mitsudo, Chem. Rev. 2000, 100, 3205-3220; b) P. Chauhan, S.
Mahajan, D. Enders, Chem. Rev. 2014, 114, 8807-8864.
2] S. Chitra, N. Paul, S. Muthusubramanian, P. Manisankar, P. Yogeeswari, D. Sriram,
Eur. J. Med. Chem. 2011, 46, 4897-4903.
3] a) A. Kumar, S. Sharma, V. D. Tripathi, S. Srivastava, Tetrahedron 2010, 66, 9445-
9449; b) S. Kramer, T. Skrydstrup, Angew. Chem. Int. Ed. 2012, 51, 4681-4684.
[
[
[
[
4] B. M. Trost, Chem. Rev. 1978, 78, 363-382.
5] a) B. C. Ranu, R. Jana, Adv. Synth. Catal. 2005, 347, 1811-1818; b) C. B. Reese, H. P.
Sanders, J. Chem. Soc., Perkin Trans. 1 1982, 2719-2724; c) B. C. Ranu, T. Mandal, J. Org.
Chem. 2004, 69, 5793-5795.
[
[
1
[
6] B. M. Trost, T. N. Salzmann, K. Hiroi, J. Am. Chem. Soc. 1976, 98, 4887-4902.
7] S. E. Denmark, S. Rossi, M. P. Webster, H. Wang, J. Am. Chem. Soc. 2014, 136,
3016-13028.
8] L.-H. Zou, D. L. Priebbenow, L. Wang, J. Mottweiler, C. Bolm, Adv. Synth. Catal. 2013,
55, 2558-2563.
9] a) T. Ye, M. A. McKervey, Chem. Rev. 1994, 94, 1091-1160; b) G. Maas, Angew. Chem.
3
[
Experimental Section
Int. Ed. 2009, 48, 8186-8195; c) M. Regitz, G. Maas, Diazo Compounds - Properties and
Synthesis, Academic Press, Orlando, 1986; d) Y. Zhang, J. Wang, Chem. Commun. 2009,
0
, 5350-5361.
General Procedure for the lithiation with Li metal.
[
[
10] R. M. P. Dias, A. C. B. Burtoloso, Org. Lett. 2016, 18, 3034-3037.
11] a) S. Biswas, R. A. Watile, J. S. M. Samec, Chem. Eur. J. 2014, 20, 2159-2163; b) A.
Lithium metal (7.0 equiv, 25% dispersion in mineral oil) was
placed in a Schlenk tube under Argon, washed with dry THF for 3
times and suspended in the same solvent (1 M concentration).
DTBB (5 mol %) was added and, the mixture was stirred until the
appearance of the dark green colour. This suspension was cooled
down to -78 °C and then, ClCH SCH (2.0 equiv) was added
2 3
dropwise. A 1.0 M solution of the Weinreb amide (1.0 equiv) in dry
THF was introduced and, the mixture was kept under stirring at -
Cadu, R. A. Watile, S. Biswas, A. Orthaber, P. J. R. Sjöberg, J. S. M. Samec, Org. Lett.
2014, 16, 5556-5559.
[12] a) B. V. Varun, K. Gadde, K. R. Prabhu, Org. Biomol. Chem. 2016, 14, 7665-7670; b)
X.-B. Xu, Z.-H. Lin, Y. Liu, J. Guo, Y. He, Org. Biomol. Chem. 2017, 15, 2716-2720; c) H.
Wang, G. Wang, Q. Lu, C.-W. Chiang, P. Peng, J. Zhou, A. Lei, Chem. Eur. J. 2016, 22,
14489-14493; d) A. F. Vaquer, A. Frongia, F. Secci, E. Tuveri, RSC Adv. 2015, 5, 96695-
96704; e) N. Devi, R. Rahaman, K. Sarma, T. Khan, P. Barman, Eur. J. Org. Chem. 2017,
2017, 1520-1525; f) J. M. Hatcher, M. C. Kohler, D. M. Coltart, Org. Lett. 2011, 13, 3810-
3813.
7
8 °C for 3 hours and then, quenched with aqueous NH
Subsequently, the reaction mixture was allowed to reach rt and
extracted three times with Et O, washed with brine, and the
4
Cl.
[13] a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815-3818; b) S.
Balasubramaniam, I. S. Aidhen, Synthesis 2008, 3707-3738; c) V. Pace, W. Holzer, B.
2
This article is protected by copyright. All rights reserved.