Preparation of Electrophilic Trifluromethylthio Reagents from Nucleophilic Tetramethylammonium Trifluoromethylthiolate

Article abstract of DOI:10.1002/adsc.201601298

A straightforward synthetic entry to the principal classes of electrophilic trifluoromethylthiolating agents is presented. It draws on inexpensive, shelf-stable tetramethylammonium trifluoromethylthiolate (Me₄N–SCF₃) as the SCF₃source in the place of stoichiometric coinage metal-SCF₃complexes. (Figure presented.).

Full text of DOI:10.1002/adsc.201601298

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DOI: 10.1002/adsc.201601298
Preparation of Electrophilic Trifluromethylthio Reagents from
Nucleophilic Tetramethylammonium Trifluoromethylthiolate
Szabolcs Kovꢀcs,a Bilguun Bayarmagnai,a and Lukas J. Goossenb,*
a
FB Chemie-Organische Chemie, Technische Universitꢁt Kaiserslautern, Erwin-Schrçdinger-Straße, Geb. 54, 67663
Kaiserslautern, Germany
b
Fakultꢁt fꢂr Chemie und Biochemie, Ruhr-Universitꢁt Bochum, Universitꢁtsstraße 150, 44801 Bochum, Germany
E-mail: lukas.goossen@rub.de
Received: November 24, 2016; Revised: December 15, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601298.
Abstract: A straightforward synthetic entry to the
principal classes of electrophilic trifluoromethyl-
ACHTUNGTRENNUNGthiolating agents is presented. It draws on inexpen-
sive, shelf-stable tetramethylammonium trifluoro-
methylthiolate (Me4N–SCF3) as the SCF3 source in
the place of stoichiometric coinage metal-SCF3
complexes.
a single step.[8] Examples are nucleophilic trifluorome-
thylthiolations of vinyl and aryl halides mediated by
copper,[9] palladium,[10] or nickel,[11] as well as Sand-
meyer trifluoromethylthiolations.[12] The key advant-
age of a nucleophilic approach is that inexpensive
SCF3 sources may be used, such as the commercially
available, inexpensive Me4N–SCF3, which is generated
from Me4N–F, elemental sulfur and Ruppert–Prakash
reagent (TMS–CF3). The latter is sustainably accessi-
ble from the waste product fluoroform.[13] Alternative-
ly, SCF3 may be constructed in situ from SCN and
TMS–CF3.[12a,b,14] The drawback of nucleophilic tri-
fluoromethylthiolations is that they are based on pre-
functionalized substrates.
Keywords: C–H functionalization; fluorine; re-
agents; sulfur; synthetic methods; trifluorome-
thylthiolation
In comparison, electrophilic methods, either metal-
Fluorine-containing residues have become central free reactions[15] or catalyzed, e.g., by Rh,[16] Pd,[17] or
functionalities in drug-like molecules, because they Fe,[18] allow the direct trifluoromethylthiolation of C–
modulate their metabolic stability, lipophilicity, bio- H bonds. Examples are trifluoromethylthiolations of
availability and structural configuration.[1] “Fluorine- sp-, sp2- and sp3-hybridized carbon centers such as ter-
scans”, i.e., the systematic introduction of groups such minal alkynes, hetero- or electron-rich arenes, and
[4]
as CF3,[2] C2F5,[3] SCF3 and OCF3,[5] have become arenes and alkyl chains with directing groups, e.g., 2-
a standard tool in drug discovery. Thus, methods for pyridyl or quinoline-8-yl (Scheme 1). These transfor-
the late-stage introduction of fluorinated substituents mations demonstrate the tremendous synthetic poten-
into functionalized molecules are highly sought after. tial of electrophilic trifluoromethylthiolations. Howev-
In the past decade, powerful fluoroalkylation methods er, their main disadvantages lie in the difficulty to
have been developed. The attention has recently shift-
ed towards fluoroalkyl thioethers, since the SCF3
group induces even higher lipophilicity (Hansch con-
stant 1.44 for SCF3 vs. 0.88 for CF3) and membrane
permeability.[6] This is the key factor driving the in-
creasing use of SCF3 groups or their derivatives as
key functionalities of pharmaceutical and agrochemi-
cal products, examples of which include toltrazuril, ti-
florex and fipronil (Figure 1).
Traditionally, SCF3 groups are introduced via halo-
gen–fluorine exchange reactions.[7] The harsh reaction
conditions confine such approaches to the construc-
tion of simple building blocks.
In recent years, synthetic approaches have been de-
vised that allow the introduction of the SCF3 group in Figure 1. SCF3-containing drugs and agrochemicals.
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synthetic entry to the required SCF3 reagents to be
a top priority, because this would decisively improve
the practical utility and environmental footprint of
the synthetic concept as a whole. Me4N–SCF3 seemed
to be an ideal source of SCF3, because it is an inex-
pensive, commercially available raw material that
may be sourced from fluoroform, and can easily be
stored and handled. This reagent was first synthesized
by Rçschenthaler[25] and Yagupolskii[26] and has suc-
cessfully been employed in trifluoromethylthiolations
of aryl halides and triflates,[27] vinyl iodides,[28] boronic
acids,[29] and diazo compounds.[12d,30] In principle, its
reaction with haloamides (HetN–X) should lead to
the desired HetN–SCF3 compounds. However, in con-
trast to silver-based SCF3 sources, this salt exchange
lacks the formation of AgX as central driving force
and is, thus, much harder to achieve.
Scheme 1. Opportunities and limitations of electrophilic tri-
fluoromethylthiolations.
After intricate reaction development, we found that
the salt exchange equilibrium can still be shifted to-
wards the desired product by performing the reaction
access suitable trifluoromethylthiolating reagents and in acetonitrile at room temperature. DMF and DCM
the associated cost (Figure 2). also gave quantitative conversion as determined by in
N-(Trifluoromethylthio)phthalimide 1, disclosed by situ 19F NMR. However, this translated to good isolat-
Munavalli et al., was originally prepared from potassi- ed yields only when using acetonitrile as the solvent.
um phthalimide with highly toxic and difficult-to- During work-up, its intermediate polarity kept Me4N–
handle trifluoromethylsulfenyl chloride (CF3SCl).[19] SCF3 in solution but led to near-quantitative precipi-
Alternative syntheses of 1 from N-halophthalimides tation of Me4NBr. This protocol was first optimized
are based on AgSCF3,[20] which, in turn, is obtained for the model reaction of Me4N–SCF3 and NBS, then
from toxic CS2 and a large excess of silver fluoride. applied to a range of amidic SCF3 reagents (Table 1).
Shenꢄs succinimide reagent 2, Shen, Lu, and Buch- The conversion of Me4N–SCF3 to the product was
waldꢄs trifluoromethanesulfenates 4,[21] as well as monitored by in situ 19F NMR spectroscopy using 1,4-
Shenꢄs SCF3-saccharin 5 and -dibenzenesulfonimide difluorobenzene as the internal standard, which indi-
6,[22] are prepared along the same lines. Billardꢄs ani- cated that the reaction was complete after 2 hours
lide 3 is synthesized from TMS–CF3, dimethylamino- with near quantitative formation of the target mole-
sulfur trifluoride (DAST) and aniline.[23] However, its cule. After filtration, the product solution was free of
comparatively lower reactivity (SCF3 cation donating by-products, and ready to use in electrophilic trifluor-
ability 59.7 vs. 33.0 kcalmolÀ1 for reagent 1) leads to omethylthiolations. Products 1, 2 and 5 were suffi-
a more limited applicability in C–H functionaliza- ciently stable for chromatographic purification, lead-
tion.[24]
ing to good isolated yields. Dibenzenesulfonimide 6
In view of the tremendous progress achieved in was found to be moisture-sensitive and could not be
electrophilic trifluoromethylthiolation technology, we isolated in the same way. The protocol is applicable
assessed the development of a sustainable, low-cost not only to HetN–Br, but also to their inexpensive N-
chloro analogues.
In order to ascertain the activity of the electrophilic
SCF3 reagents prepared by our method, we applied
the filtered solutions of each HetN–SCF3 reagent 1, 2,
5, and 6 generated in situ from their corresponding
halides to a set of benchmark trifluoromethylthiola-
tion reactions (Scheme 2).
Arylboronic acid 7 was trifluoromethylthiolated in
high isolated yields. All reagents performed similarly,
and the yields (80–93%) were comparable to those re-
ported in the literature (90%) with isolated reagents
(Scheme 2, equation I).[20a] C–H trifluoromethylthiola-
tion of indole (9) also proceeded in high yields (78–
90%), comparable to those previously reported
(94%), using the SCF3 reagent solutions (Scheme 2,
Figure 2. Electrophilic trifluoromethylthiolating reagents
(HetN–SCF3).
+
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Table 1. Preparation of electrophilic trifluoromethylthiolat-
ing reagents.[a]
HetN
X
Yield[b] [%]
Br
Cl
91
90
Br
Cl
87
85
Br
Cl
85
81
Cl
95[c]
[a]
Reaction conditions: 0.55 mmol of Me4N–SCF3 in 1 mL
of MeCN was slowly added to a solution of 0.5 mmol of
HetN-X in 1 mL of MeCN at room temperature for 2
hours.
Isolated yield after column chromatography.
Yield determined by 19F NMR using 1,4-difluorobenzene
as an internal standard.
Scheme 2. Benchmarking the trifluoromethylthiolations with
the electrophilic HetN–X reagents as crude solutions; yields
for the isolated HetN–X solids in parentheses.
[b]
[c]
In summary, an efficient method for the in situ gen-
equation II).[15a] The sulfonamide reagents 5 and 6 eration of electrophilic SCF3 reagents starting from
performed particularly well, giving near-quantitative the inexpensive, bench-stable nucleophilic reagent
yields even in the absence of added chloride, which is Me4N–SCF3 is described. The reagent solutions thus
routinely used in the standard protocols for amide re- obtained can directly be used in state-of-the-art elec-
agents 1 and 2. Palladium-catalyzed ortho C–H tri- trophilic trifluoromethylthiolations, which are current-
fluoromethylthiolation of 2-phenylpyridine was also ly limited by the multi-step preparation and difficult
successful with reagent solutions 1, 2 and 5, resulting isolation of the SCF3 reagents.
in 60–80% yields (literature: 63%), but no product
was formed using the dibenzenesulfonimide
6
(Scheme 2, equation III).[17a] 1,3-Dimethoxybenzene Experimental Section
(13) underwent C–H trifluoromethylthiolation only
with the sulfonamide reagents, with yields (5: 83%) General Procedure
and 6: 90%) similar to those reported in the literature
A 20-mL crimp-cap vessel was charged with N-halo(sulfon)i-
(86%) (Scheme 2, equation IV).[22a] The isolation and
purification of reagents 1 and 2 was straightforward,
but led to only marginally better yields. Isolation of
reagents 5 and 6 proved to be troublesome, but can
be avoided by using the in situ procedure described
above, and which often led to improved yields. Over-
all, these examples illustrate the non-overlapping ac-
tivity profiles of amide- and sulfonamide-based tri-
fluoromethylthiolation reagents. The benefit of the
unifying in situ protocol for their preparation is that it
allows easy selection of the most adequate reagent for
any given synthetic problem.
mide derivative (2 mmol), and MeCN (3 mL). Me4N–SCF3
(385 mg, 2.2 mmol, 1.1 equiv.) in MeCN (3 mL) was added
dropwise and the reaction mixture was stirred for 2 h at
room temperature. Diethyl ether was added and the result-
ing mixture was filtered through a short pad of celite (5 g).
The resulting solution was concentrated and purified by
flash chromatography (SiO2, cyclohexane/ethyl acetate gra-
dient). For further details of the synthesis and characteriza-
tion, see the Supporting Information.
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[14] a) M. Tordeux, C. Francese, C. Wakselman, J. Fluorine
Acknowledgements
Chem. 1989, 43, 27–34; b) T. Billard, S. Large, B. R.
Langlois, Tetrahedron Lett. 1997, 38, 65–68; c) S.
Potash, S. Rozen, J. Fluorine Chem. 2014, 168, 173–176;
d) K. Jouvin, C. Matheis, L. J. Goossen, Chem. Eur. J.
2015, 21, 14324–14327; e) B. Exner, B. Bayarmagnai, F.
Jia, L. J. Goossen, Chem. Eur. J. 2015, 21, 17220–17223;
f) B. Bayarmagnai, C. Matheis, K. Jouvin, L. J. Goos-
sen, Angew. Chem. 2015, 127, 5845–5848; Angew.
Chem. Int. Ed. 2015, 54, 5753–5756; g) C. Matheis, M.
Wang, T. Krause, L. Goossen, Synlett 2015, 26, 1628–
1632.
We thank the Heinrich-Bçll-Stiftung e.V. (scholarship to
B.B.) and the Cluster of Excellence RESOLV (EXC 1069)
funded by the Deutsche Forschungsgemeinschaft for financial
support.
References
[1] a) J. Wang, M. Sꢀnchez-Rosellꢅ, J. L. AceÇa, C. del Po-
zo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H.
Liu, Chem. Rev. 2014, 114, 2432–2506; b) P. Jeschke,
ChemBioChem 2004, 5, 570–589; c) W. K. Hagmann, J.
Med. Chem. 2008, 51, 4359–4369.
[2] a) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011,
111, 4475–4521; b) T. Furuya, A. S. Kamlet, T. Ritter,
Nature 2011, 473, 470–477; c) T. Liang, C. N. Neumann,
T. Ritter, Angew. Chem. 2013, 125, 8372–8423; Angew.
Chem. Int. Ed. 2013, 52, 8214–8264; d) T. Liu, Q. Shen,
Eur. J. Org. Chem. 2012, 2012, 6679–6687; e) X.-F. Wu,
H. Neumann, M. Beller, Chem. Asian J. 2012, 7, 1744–
1754; f) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev.
2015, 115, 683–730.
[15] a) R. Honeker, J. B. Ernst, F. Glorius, Chem. Eur. J.
2015, 21, 8047–8051; b) T. Bootwicha, X. Liu, R. Pluta,
I. Atodiresei, M. Rueping, Angew. Chem. 2013, 125,
13093–13097; Angew. Chem. Int. Ed. 2013, 52, 12856–
12859; c) M. Rueping, X. Liu, T. Bootwicha, R. Pluta,
C. Merkens, Chem. Commun. 2014, 50, 2508–2511; d) J.
Luo, Z. Zhu, Y. Liu, X. Zhao, Org. Lett. 2015, 17,
3620–3623; e) C. Xu, Q. Shen, Org. Lett. 2015, 17,
4561–4563; f) Q. Xiao, Q. He, J. Li, J. Wang, Org. Lett.
2015, 17, 6090–6093; g) K. Liao, F. Zhou, J.-S. Yu, W.-
M. Gao, J. Zhou, Chem. Commun. 2015, 51, 16255–
16258; h) J.-J. Wu, J. Xu, X. Zhao, Chem. Eur. J. 2016,
22, 15265–15269.
[16] a) Q. Wang, F. Xie, X. Li, J. Org. Chem. 2015, 80, 8361–
8366; b) P. Luo, Q. Ding, Y. Ping, J. Hu, Org Biomol
Chem. 2016, 14, 2924–2929.
[17] a) C. Xu, Q. Shen, Org. Lett. 2014, 16, 2046–2049;
b) H.-Y. Xiong, T. Besset, D. Cahard, X. Pannecoucke,
J. Org. Chem. 2015, 80, 4204–4212.
[18] a) Q. Wang, Z. Qi, F. Xie, X. Li, Adv. Synth. Catal.
2015, 357, 355–360; b) T. Yang, L. Lu, Q. Shen, Chem.
Commun 2015, 51, 5479–5481.
[19] S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J.
Berg, G. W. Wagner, H. D. Durst, Synth. Commun.
2000, 30, 2847–2854.
[20] a) R. Pluta, P. Nikolaienko, M. Rueping, Angew. Chem.
2014, 126, 1676–1679; Angew. Chem. Int. Ed. 2014, 53,
1650–1653; b) K. Kang, C. Xu, Q. Shen, Org. Chem.
Front. 2014, 1, 294.
[21] X. Shao, C. Xu, L. Lu, Q. Shen, J. Org. Chem. 2015, 80,
3012–3021.
[3] A. Lishchynskyi, V. V. Grushin, J. Am. Chem. Soc.
2013, 135, 12584–12587.
[4] F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem.
2014, 2014, 2415–2428.
[5] a) G. L. Trainor, J. Carbohydr. Chem. 1985, 4, 545–563;
b) K. N. Hojczyk, P. Feng, C. Zhan, M.-Y. Ngai, Angew.
Chem. 2014, 126, 14787–14791; Angew. Chem. Int. Ed.
2014, 53, 14559–14563.
[6] C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaita-
ni, E. J. Lien, J. Med. Chem. 1973, 16, 1207–1216.
[7] Scherer, Angew. Chem. 1939, 52, 457–459.
[8] S. Barata-Vallejo, S. Bonesi, A. Postigo, Org. Biomol.
Chem. 2016, 14, 7150–7182.
[9] a) Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D.
Kong, Y. Yuan, K.-W. Huang, Angew. Chem. 2013, 125,
1588–1592; Angew. Chem. Int. Ed. 2013, 52, 1548–1552;
b) X. Shao, X. Wang, T. Yang, L. Lu, Q. Shen, Angew.
Chem. 2013, 125, 3541–3544; Angew. Chem. Int. Ed.
2013, 52, 3457–3460; c) C. Chen, Y. Xie, L. Chu, R.-W.
Wang, X. Zhang, F.-L. Qing, Angew. Chem. 2012, 124,
2542–2545; Angew. Chem. Int. Ed. 2012, 51, 2492–2495;
d) L. D. Tran, I. Popov, O. Daugulis, J. Am. Chem. Soc.
2012, 134, 18237–18240.
[10] G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew.
Chem. 2011, 123, 7450–7452; Angew. Chem. Int. Ed.
2011, 50, 7312–7314.
[11] C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012, 134,
183–185.
[12] a) G. Danoun, B. Bayarmagnai, M. F. Gruenberg, L. J.
Goossen, Chem. Sci. 2014, 5, 1312; b) B. Bayarmagnai,
C. Matheis, E. Risto, L. J. Goossen, Adv. Synth. Catal.
2014, 356, 2343–2348; c) G. Danoun, B. Bayarmagnai,
M. Grꢂnberg, C. Matheis, E. Risto, L. Gooßen, Synthe-
sis 2014, 46, 2283–2286; d) C. Matheis, V. Wagner, L. J.
Goossen, Chem. Eur. J. 2016, 22, 79–82.
[22] a) C. Xu, B. Ma, Q. Shen, Angew. Chem. 2014, 126,
9470–9474; Angew. Chem. Int. Ed. 2014, 53, 9316–9320;
b) P. Zhang, M. Li, X.-S. Xue, C. Xu, Q. Zhao, Y. Liu,
H. Wang, Y. Guo, L. Lu, Q. Shen, J. Org. Chem. 2016,
81, 7486–7509; c) X. Liu, R. An, X. Zhang, J. Luo, X.
Zhao, Angew. Chem. 2016, 128, 5940–5944; Angew.
Chem. Int. Ed. 2016, 55, 5846–5850.
[23] A. Ferry, T. Billard, B. R. Langlois, E. Bacquꢆ, J. Org.
Chem. 2008, 73, 9362–9365.
[24] M. Li, J. Guo, X.-S. Xue, J.-P. Cheng, Org. Lett. 2016,
18, 264–267.
[25] P. Kirsch, G. V. Roeschenthaler, B. Bissky, A. Kolo-
meitsev, (Merck GmbH), German Patent DE-A1
10254597, 2003.
[26] W. Tyrra, D. Naumann, B. Hoge, Y. L. Yagupolskii, J.
Fluorine Chem. 2003, 119, 101–107.
[27] a) J. Xu, X. Mu, P. Chen, J. Ye, G. Liu, Org. Lett. 2014,
16, 3942–3945; b) G. Yin, I. Kalvet, U. Englert, F.
Schoenebeck, J. Am. Chem. Soc. 2015, 137, 4164–4172;
[13] G. K. S. Prakash, P. V. Jog, P. T. D. Batamack, G. A.
Olah, Science 2012, 338, 1324–1327.
Adv. Synth. Catal. 0000, 000, 0 – 0
4
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c) A. B. Dꢂrr, G. Yin, I. Kalvet, F. Napoly, F. Schoene-
beck, Chem. Sci. 2016, 7, 1076–1081; d) G. Yin, I.
Kalvet, F. Schoenebeck, Angew. Chem. 2015, 127,
6913–6917; Angew. Chem. Int. Ed. 2015, 54, 6809–6813.
[28] M. Rueping, N. Tolstoluzhsky, P. Nikolaienko, Chem.
Eur. J. 2013, 19, 14043–14046.
[29] C.-P. Zhang, D. A. Vicic, Chem.- Asian J. 2012, 7, 1756–
1758.
[30] C. Matheis, T. Krause, V. Bragoni, L. J. Goossen,
Chem. Eur. J. 2016, 22, 12270–12273.
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6 Preparation of Electrophilic Trifluromethylthio Reagents
from Nucleophilic Tetramethylammonium
Trifluoromethylthiolate
Adv. Synth. Catal. 2017, 359, 1 – 6
Szabolcs Kovꢀcs, Bilguun Bayarmagnai, Lukas J. Goossen*
Adv. Synth. Catal. 0000, 000, 0 – 0
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