Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents

Article abstract of DOI:10.1002/anie.201805859

The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, s_N), using the linear free-energy relationship log k₂=s_N(N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido-derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X?SCF₃ bonds (Tt⁺DA), the cumol-derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O?S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis.

Full text of DOI:10.1002/anie.201805859

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Accepted Article
Title: Exploration of the Synthetic Potential of Electrophilic
Trifluoromethylthiolating and Difluoromethylthiolating Reagents
Authors: Xiao-Song Xue, Jingjing Zhang, Jin-Dong Yang, Hanliang
Zheng, Herbert Mayr, and Jin-Pei Cheng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805859
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10.1002/anie.201805859
Angewandte Chemie International Edition
COMMUNICATION
Exploration of the Synthetic Potential of Electrophilic
Trifluoromethylthiolating and Difluoromethylthiolating Reagents
Jingjing Zhang,+ Jin-Dong Yang,+ Hanliang Zheng, Xiao-Song Xue*, Herbert Mayr*, Jin-Pei Cheng
Abstract: Electrophilicity parameters (E) of some popular
trifluoromethylthiolating and difluoromethylthiolating reagents were
determined by following the kinetics of their reactions with a series of
enamines and carbanions with known nucleophilicity parameters (N,
sN), using the linear free-energy relationship log k2 = sN(N + E). The
electrophilic reactivities of these reagents cover a range of 17 orders
of magnitude, with Shen and Lu’s reagent 1a being the most reactive
and Billard’s reagent 1h the least reactive electrophile. While the
observed electrophilic reactivities (E) of the amido-derived
trifluoromethylthiolating reagents correlate well with the calculated
Gibbs energies of the heterolytic cleavage of the X-SCF3 bonds
(Tt+DA), the cumol-derived reagents 1f and 1g are more reactive
than expected from the thermodynamics of the O-S cleavage. The E
parameters of tri(di)fluoromethylthiolating reagents derived in this
work provide an ordering principle for their use in synthesis.
are solvent-dependent nucleophile-specific parameters, and E is
an electrophile-specific parameter. Since its introduction in
1994,[7] eq. (1) has widely been applied for characterizing the
electrophilic reactivities of carbocations, Michael acceptors,
imines, quinones, and other π-systems.[8]
log k2(20 °C) = sN(N + E)
(1)
We now report on the determination of the electrophilicities
of various SCF3 and SCF2H reagents 1a-i by investigating the
kinetics of their reactions with enamines (2a-b) or carbanions
(2c-g), whose N and sN parameters are listed in Table 1.
Table 1. Enamines and carbanions used as reference nucleophiles in this
work.[9]
Nucleophile[a]
N (sN)[b]
λmax [nm]
2a
8.78 (0.83)
306
X = NO2
X = CN
X = H
2b-NO2
2b-CN
2b-H
10.42 (0.82)
10.63 (0.84)
11.66 (0.82)
11.99 (0.84)
14.94 (0.96)
465
375
317
296
538
Recently, there has been growing interest in trifluoromethylthio (-
SCF3) and difluoromethylthio (-SCF2H) groups. Due to their
unique properties, such as high lipophilicity and strong electron-
withdrawing ability, they may strongly improve the
pharmacokinetic properties of lead compounds.[1] Consequently,
a number of shelf-stable electrophilic trifluoromethylthiolating[2,3,4]
and difluoromethylthiolating reagents[5] that allow efficient
incorporation of these groups under mild conditions have been
developed by several groups, such as the teams of Billard,[3c-e, g]
Shen and Lu,[3f, h-i, m, 5] and Shibata[6]. One notable question has
remained open, however. That is, can the synthetic potential of
these synthetically important reagents be predicted?
X = OMe
2b-OMe
2c
X = NO2
2d-NO2
2d-COMe
2d-CN
13.91 (0.76)
16.03 (0.86)
16.55 (0.78)
17.19 (0.56)
17.46 (0.65)
17.52 (0.74)
19.67 (0.68)
20.00 (0.71)
22.60 (0.57)
360
340
328
325
370
327
539
550
375
X = COMe
X = CN
X = SO2Ph
X = COPh
X = CO2Et
X = CN
2d-SO2Ph
2d-COPh
2d-CO2Et
2e-CN
X = CO2Et
2e-CO2Et
2f
2g
27.54 (0.57)
340
[a] The potassium salts (2c-d)-K were isolated while (2e-g) were generated in
DMSO solution by treatment of their conjugate acids with KOtBu. [b]
Nucleophile-specific reactivity parameters N and sN of enamines are in CH3CN
at 20 °C , and carbanions are in DMSO at 20 °C .
The reactions of the fluoromethylating reagents 1 with the
nucleophiles 2 gave the tri(di)fluoromethylthiolated products in
71–91% yield after aqueous workup (Scheme 1 and Table 3, see
SI for details). Since analogous reactions can be expected for
the combination of 1 with other nucleophiles, product studies
have not been performed for all reactions that have been studied
Figure 1. Popular electrophilic SCF3 and SCF2H reagents.
We herein report on the quantification of the electrophilicities
of some popular tri(di)fluoromethylthiolating reagents (Fig. 1)
utilizing the linear free energy relationship (1), where sN and N
kinetically.
The kinetics of the reactions of 1a-i with enamines 2a-b or
carbanions 2c-g were studied in CH3CN or DMSO solution at
20 °C by following the disappearance of the UV/Vis absorptions
H. Zheng, Prof. Dr. X. -S. Xue, Prof. Dr. J.-P. Cheng
State Key Laboratory of Elemento-organic Chemistry, College of
Chemistry, Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin), Nankai University, Tianjin 300071, China.
E-mail: xuexs@nankai.edu.cn
J. Zhang, Dr. J. Yang, Prof. Dr. J.-P. Cheng
Center of Basic Molecular Science, Department of Chemistry,
Tsinghua University, Beijing 100084, China.
of the reference nucleophiles
2 under pseudo-first-order
conditions ([1]0/[2]0 > 10). The first-order rate constants kobs (s-1)
were derived by least-squares fitting of the exponential function
Abs = Abs0·exp(-kobst) + C to the observed time-dependent
absorbances. Plots of kobs versus the concentrations of the
nucleophiles gave straight lines as shown for one example in Fig.
2 and for all other reactions in the SI. The slopes of these plots
correspond to the second-order rate constants k2 (M-1 s-1) which
are summarized in Table 2.
Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, 81377 München (Germany)
E-mail: herbert.mayr@cup.uni-muenchen.de.
[+]These authors contributed equally to this work.
Supporting information for this article is given via a link at the end
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10.1002/anie.201805859
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Second-order rate constants k2 for the reactions of reagents 1 with
reference nucleophiles 2 in CH3CN or DMSO at 20 °C
Electrophile[a]
Nucleophile
k2exp [M-1 s-1]
k2calcd [M-1 s-1]
1.81 × 102
3.91 × 104
3.76 × 103
6.90 × 103
9.58 × 104
8.11 × 101
1.77 × 104
1.70 × 103
3.06 × 103
4.25 × 104
3.25 × 101
7.93 × 102
3.42 × 103
4.09 × 103
8.94 × 102
3.99 × 103
1.39 × 104
1.06 × 101
1.93 × 102
9.64 × 102
1.29 × 103
4.68 × 103
2.28
k2exp/k2calcd
0.90
1.07
1.39
1.11
0.71
0.79
1.11
1.42
1.35
0.61
0.25
0.06
3.39
3.64
2.21
0.47
1.99
0.19
0.07
3.40
2.70
3.29
0.31
0.03
3.28
2.39
3.94
0.53
0.42
2a
(1.62 ± 0.09) × 102
(4.17 ± 0.41) × 104
(5.23 ± 0.22) × 103
(7.63 ± 0.19) × 103
(6.78 ± 0.35) × 104
(6.38 ± 0.66) × 101
(1.96 ± 0.21) × 104
(2.42 ± 0.06) × 103
(4.13 ± 0.08) × 103
(2.61 ± 0.08) × 104
8.06 ± 0.17
2b-H
2b-NO2
2b-CN
2b-OMe
2a
E = -6.06
2b-H
Scheme 1. Reactions of SCF3/SCF2H reagents with enamines and carbanions.
[a] Yields of isolated products after purification by column chromatography.
2b-NO2
2b-CN
2b-OMe
2d-NO2
2c
Plots of (log k2)/sN vs N for the reactions of 1a,b with the
enamines 2a,b were linear with slopes close to 1.0, showing that
these reactions follow eq. 1 (Figure 3a), thus providing the E
parameters for 1a,b. Much poorer correlations were found for
the analogous reactions of 1c-i with carbanions as illustrated by
Figure 3b. Approximate E parameters for 1c-i were, therefore,
obtained by enforcing a unity slope in the (logk2)/sN vs N
correlations (Fig. 3b). Comparison of the experimental rate
constants k2exp with thosecalculated by eq. (1) from the E values
in Table 2 and N and sN from Table 1 shows agreement within a
factor of 30 (right column of Table 2), i. e., within the tolerance
limit of eq. (1). Because of the significant scatter in these plots,
we did not attempt to improve the correlations by including an
electrophile-specific sensitivity parameter sE.[10] It has to be
E = -6.48
(4.62 ± 0.15) × 101
(1.16 ± 0.05) × 104
(1.49 ± 0.10) × 104
(1.98 ± 0.11) × 103
(1.89 ± 0.09) × 103
(2.77 ± 0.18) × 104
2.03 ± 0.08
2d-COMe
2d-CN
2d-SO2Ph
2d-COPh
2d-CO2Et
2d-NO2
2c
E = -11.92
(1.26 ± 0.05) × 101
(3.28 ± 0.03) × 103
(3.48 ± 0.04) × 103
(1.54 ± 0.02) × 104
0.71 ± 0.03
2d-COMe
2d-CN
2d-CO2Et
2d-NO2
2c
E = -12.56
E = -13.44
exp
calcd
admitted, however, that the comparison of k2
and k2
in
Table 2 may not be representative, because all reaction series in
Table 2 refer to reactions with either enamines or carbanions. If
there were electrophiles which can be studied with both classes
of nucleophiles, larger deviations can be expected.
0.94 ± 0.04
2.75 × 101
1.69 × 102
2.67 × 102
1.05 × 103
1.03 × 104
2.65 × 104
2d-COMe
2d-CN
2d-CO2Et
2e-CN
(5.54 ± 0.30) × 102
(6.38 ± 0.30) × 102
(4.14 ± 0.14) × 103
(5.41 ± 0.12) × 103
(1.11 ± 0.07) × 104
2e-CO2Et
2f
(3.16 ± 0.06) × 105
1.08 × 105
2.93
E = -13.77
2d-CO2Et
2e-CN
2e-CO2Et
2f
(2.63 ± 0.13) × 102
(4.45 ± 0.43) × 102
(1.88 ± 0.09) × 103
(3.56 ± 0.13) × 105
1.66 × 102
3.18 × 103
7.78 × 103
4.03 × 104
1.58
0.14
0.24
8.83
E
= -14.52
Figure 2. Monoexponential decay of the absorbance Abs (at 390 nm) with time
for the reaction of 2b-CN (5.62 × 10-5 M) with 1a (2.55 × 10-3 M) in CH3CN at
20 ℃. Inset: Correlation of kobs with the concentrations of 1a.
2g
(2.56 ± 0.17) × 102[b]
identical
-
E = -23.32
2d-NO2
2c
(1.76 ± 0.04) × 101
(1.19 ± 0.03) × 102
(1.53 ± 0.05) × 104
(1.36 ± 0.13) × 104
(1.51 ± 0.11) × 104
(5.46 ± 0.37) × 104
3.61 × 101
9.05 × 102
3.86 × 103
4.55 × 103
4.37 × 103
2.05 × 105
0.49
0.13
3.96
2.99
3.46
0.27
2d-COMe
2d-CN
2d-COPh
2e-CN
E = -11.86
[a] Electrophilicity parameters E were derived according to Equation (1), and
1a and 1b were measured in CH3CN, other reagents were measured in
DMSO. [b] Only one k2exp value was used for the determination of E.
Figure 3. Plots of (log k2)/sN for the reactions of enamines 2a-b with 1a (a)
and carbanions 2c-d with 1d (b) against the nucleophilicity parameters N (see
the SI for other reagents).
reagent 1e (E: -13.44)[3g]. The electrophilicities of Shen and Lu’s
first- (1g)[3f] and second- (1f)[3i] generation O-SCF3 reagents are
very close to each other, in line with Shen and Lu’s report that
cumyl trifluoromethanesulfenates with or without substituent at
the aromatic ring show similar reactivity toward a variety of
nucleophiles.[3i] Billard’s first generation reagent 1h[3c] (E: -
23.32), is by far the least electrophilic reagent studied, but can
efficiently be activated by Brønsted and Lewis acids. [1c,1j] Shen
and Lu’s difluoromethylthiolating reagent 1i[5] (E: -11.86) is only
slightly more electrophilic than its SCF3 analog 1c, suggesting
The graphical presentation of the E parameters in the right
part of Fig. 4 indicates the ranking 1a,b >> 1c,d,e > 1f,g >> 1h,
in agreement with previous qualitative observations. Shen and
Lu’s reagent 1a[3k] (E: -6.06), is the most electrophilic SCF3
reagent of this series, slightly more reactive than Shen’s N-
trifluoromethyl-thiosaccharin 1b[3h] (E: -6.48). The electrophilicity
of Haas’ reagent 1d (E: -12.56)[3a] is similar to those of
Munavalli’s 1c (E: -11.92)[3b] and Billard’s second generation
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10.1002/anie.201805859
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COMMUNICATION
that replacement of one F by H might also have little effect on
the electrophilicities of the other SCF3 reagents listed in Fig. 4.
Table 3. Reactions of SCF3 reagents with pyrroles, indoles, enamines and
carbanions in CH3CN.[a]
Nucleophile
N
1b[e]
1d[f]
1g[f]
1h[f]
Product
[i]
5.55[b]
100%
0
0
-
[i]
5.75[b]
100%
0
0
-
[i]
6.91[c]
10.67[c]
11.99[c]
100%
100%
0
0
0
-
[i]
55%
60%[g]
-
85%[k]
44%[g]
76%[g]
0
14.91[c]
16.03[d]
55%[g,h]
81%[g]
82%[k]
0
0
[j]
[j]
+
+
[j]
[j]
17.52[d]
19.67[d]
+
72%[k]
+
0
0
[j]
[j]
+
+
83%[k]
[a] Yields were determined by 1H NMR using CH2Br2 as the internal standard.
[b] Measured in CH2Cl2. [c] Measured in CH3CN. [d] Measured in DMSO. [e]
Reaction conditions: SCF3 reagent (0.2 mmol), nucleophiles (0.2 mmol),
CH3CN (1 mL), 20 °C , 3 h. [f] Reaction conditions: SCF3 reagents (0.2 mmol),
nucleophiles (0.2 mmol), CH3CN (1 mL), 20 °C ,
8 h. [g] Yields were
determined by 1H NMR after hydrolysis. [h] With some not identified side
products. [i] Not tested, because 1h did not even react with stronger
nucleophiles. [j] Reaction expected, but not tested. [k] Isolated yields.
the limitations of eq. (1): Since eq. (1) is calibrated for reactions
in which only one new σ-bond is formed in the rate-limiting step,
it is not applicable to reactions with bridging electrophiles. The
suggested intermediacy of episulfonium ions from 1a and
styrenes[3k] is thus supported by the fact that these reactions
proceed faster than calculated by eq. (1). Nucleophilic
assistance by the solvent DMF through stabilizing the
developing positive charge at the benzylic carbon may also
accelerate the electrophilic attack of 1a at CC-double bonds in
this solvent. Surprisingly, 1b did not react with 3-aryl-substituted
furans in DMF at 90 °C, but good yields were obtained when
NaCl was present.[11]
Figure 4. Predicting the scope of non-catalyzed reactions of SCF3/SCF2H
reagents 1a-i with carbon-centered nucleophiles. – N parameters from. Ref. 8.
How can synthetic chemists make use of the E parameters
determined in this work? The left part of Fig. 4 lists carbon-
centered nucleophiles with increasing reactivities from top to
bottom. Both scales are arranged in a way, that systems at the
same level (E + N = -3) should react with a rate constant of 10-3
M-1s-1 (from eq (1) for sN = 1.0 at 20 °C), which corresponds to a
half reaction time of somewhat more than 1 h for 0.2 M
solutions. Thus, one can expect that at room temperature the
Whereas the electrophilicity of 1d is not sufficient for attack
at the indoles depicted in Fig. 4, Table 3 shows its reaction with
2,4-dimethylpyrrole as well as with enamines and carbanions,
which are positioned lower in Fig. 4. In line with these findings,
agent 1c, which is slightly more electrophilic than 1d, has
previously been reported to trifluoromethylthiolate enamines at
room temperature.[3b]
tri(di)fluoromethylthiolating agents
1
should react with
nucleophiles on the same level or located lower in Fig. 4.
In order to examine this prediction, we have selected a
representative electrophile from each of the four groups and
determined the yields of their reactions with typical nucleophiles
at 20 °C. Table 3 shows that 1b was the only reagent which
underwent non-catalyzed reactions with the indoles listed in Fig.
4. In agreement with this observation, Shen, Lu, and co-workers
reported that in the absence of any additive, reagent 1a which
has a similar E value as 1b could trifluoromethylthiolate indoles
and pyrroles under mild conditions.[3k] The same paper stated,
however, that also styrene (N = 0.78) reacted with 1a at 20 °C
though styrene is above 1a in Fig. 4, and eq. (1) predicts a rate
constant of 10-5 M-1s-1, which corresponds to a half reaction time
of 2 days at the given conditions. This example indicates one of
Lu and Shen’s reagent 1g, which did not react with 2,4-
dimethylpyrrole under the conditions of Table 3, was found to
react with enamines, including those which are only slightly
more nucleophilic than 2,4-dimethylpyrrole.
Whereas 1d and 1g reacted smoothly with the stabilized
carbanions shown in Table 3, Fig.
4 indicates that the
electrophilicity of 1h is so low that it does not even react with
carbanions of N < 20. In order to determine its electrophilicity we
investigated its reaction with 2g, the anion derived from ethyl
phenylacetate, which is so nucleophilic (N = 27.54) that it did not
even fit in Fig.4. The nitrogen of 1h is rather basic, however, that
it can easily be activated by Brønsted and Lewis acids to form
reagents which even react with ordinary alkenes[3d] and
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10.1002/anie.201805859
Angewandte Chemie International Edition
COMMUNICATION
moderately activated arenes.[4] Since PhNHSCF3 (1h’) can be
expected not to differ too much in reactivity from its methylated
analog 1h, its failure to undergo non-catalyzed reactions with
allylsilanes is also in line with Fig. 4. The reaction proceeds with
good yields, however, when 1h’ is activated by acetyl chloride.[12]
Please note that Fig. 4 includes only carbon nucleophiles.
Since the N and sN parameters have been derived from
reactions with C-electrophiles, and E parameters have been
derived from reactions with C-nucleophiles, eq. (1) can only be
applied to reactions where at least one of the reaction centers is
carbon. One can assume, however, that the relative reactivities
of electrophiles 1a-i also hold with respect to other types of
nucleophiles, and Cahard and coworkers have recently shown
that allylic alcohols react with the highly electrophilic 1b in the
presence of base to give trifluoromethyl sulfoxides after [2,3]-
sigmatropic rearrangement.[13]
We are grateful to the financial support from Natural Science
Foundation of China (Grant Nos. 21772098, 21390400, 21602116),
the State Key Laboratory on Elemento-organic Chemistry, the
Fundamental Research Funds for the Central Universities, and
Tsinghua University Initiative Scientific Research Program (Grant
Nos. 20131080083, 20141081295).
Keywords: trifluoromethylthiolating reagent •
difluoromethylthiolating reagent• linear free-energy relationships
• electrophilicity • structure–reactivity relationships
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electrophilic reactivities
E of N-SCF3 reagents with their
calculated Tt+DA parameters[15] was observed, however (Fig. 5a).
The positive deviation of 1f,g from this so-called
Bell−Evans−Polanyi correlation line[16] for N-SCF3 reagents
indicates that O-SCF3 compounds react via lower intrinsic
barriers, in line with Hoz’ rule[17] that in nucleophilic substitutions,
the intrinsic barriers are the lower, the further right nucleophiles
and nucleofuges are in the periodic table. The even better
correlation between the electrophilic reactivities E and the pKa
values of the corresponding X-H acids in water is probably due
to the fact that the lower intrinsic barriers for the reactions of the
O-SCF3 reagents are compensated by a larger difference
between O-H and O-S bond energies than between N-H and N-
S bond energies (Fig. 5b). These correlations allow a quick
estimation of electrophilic reactivities for new reagents from
thermodynamic data.
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nucleophilicity parameters N, sN,
http://www.cup.lmu.de/oc/mayr/DBintro.html.
E
and
see
Figure 5. Plots of measured electrophilicities E against (a) the corresponding
Tt+DA values taken from ref.15 (not including 1f and 1g), and (b) experimental
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pKa values of corresponding X-H acids (in water)[18]
.
In summary, the second-order rate constants of 1a-i with
enamines and carbanions have been used to derive the
empirical electrophilicity parameters E of the most common
tri(di)fluoromethylthiolating reagents. The rule of thumb that
uncatalyzed reactions of the tri(di)fluoromethylthiolating reagents
1a-i will take place with those nucleophiles positioned below
themselves in Fig. 4 (i.e., when E + N > -3) has been
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[16] M. G. Evans, M. Polanyi, Trans. Faraday Soc. 1938, 34, 11-24.
[17] S. Hoz, H. Basch, J. L.Wolk, T. Hoz, E. Rozental, J. Am. Chem. Soc.
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demonstrated to be
a good guide for the design of
tri(di)fluoromethylthiolating reactions by the product studies in
Table 3 and many examples reported in the literature.
Acknowledgements
[18] Internet
Bond-energy
Databank
(iBonD)
Home
Page.
http://ibond.chem.tsinghua.edu.cn or http://ibond.nankai.edu.cn.
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10.1002/anie.201805859
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Jingjing Zhang,+ Jin-Dong
Yang,+ Hanliang Zheng, Xiao-
Song Xue*, Herbert Mayr*, Jin-
Pei Cheng
Page No. – Page No.
Exploration of the Synthetic Potential of
Electrophilic Trifluoromethylthiolating and
Difluoromethylthiolating Reagents
Electrophilicities (E) of some popular trifluoromethylthiolating and difluoromethylthiolating reagents were investigated by following the kinetics
of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, sN) using the linear free-energy
relationship log k2 = sN(N + E). The electrophilicity parameters for these reagents thus derived cover a reactivity range of 17 orders of
magnitude. The definition of the E parameters of tri(di)fluoromethylthiolating reagents offers an expeditious means of predicting
unprecedented reactions.
This article is protected by copyright. All rights reserved.