Nucleophilicity Parameters of Arylsulfonyl-Substituted Halomethyl Anions

Article abstract of DOI:10.1021/acs.joc.6b02844

The rates of the reactions of the arylsulfonyl-substituted carbanions carrying α-chloro and α-bromo substituents (1a-e) with quinone methides 2a-g and benzylidenemalonates 2h and 2i in DMSO were determined photometrically at 20 °C. The reactions were perf

Full text of DOI:10.1021/acs.joc.6b02844

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Article
Nucleophilicity parameters of arylsulfonyl substituted halomethyl anions
Zhen Li, Quan Chen, Peter Mayer, and Herbert Mayr
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02844 • Publication Date (Web): 20 Jan 2017
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Nucleophilicity parameters of arylsulfonyl substituted halomethyl anions
Zhen Li,§ Quan Chen,§ Peter Mayer, and Herbert Mayr*
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Department Chemie, LudwigꢀMaximiliansꢀUniversität München, Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
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*
Eꢀmail: Herbert.Mayr@cup.uniꢀmuenchen.de
Abstract
The rates of the reactions of the arylsulfonyl substituted carbanions carrying αꢀchloro and αꢀbromo substituents 1a−e with quinone
methides 2a−g and benzylidenemalonates 2h−i in DMSO were determined photometrically at 20 °C. The reactions were carried out under
pseudoꢀfirstꢀorder conditions, and the secondꢀorder rate constants were obtained as the slopes of the plots of the pseudoꢀfirstꢀorder rate
constants versus the concentrations of the reactants used in excess. The secondꢀorder rate constants correlate linearly with the parameters
E of the reference electrophiles according to the linear freeꢀenergy relationship log k2(20 °C) = sN(N + E), which allowed to derive the
nucleophileꢀspecific parameters N and sN of the carbanions 1a−e. The resulting nucleophilicity parameters in the range 23 < N < 29 reveals
the title compounds to be among the most reactive nucleophiles, so far integrated in our comprehensive nucleophilicity scale.
Introduction
Carbanions bearing leaving groups at the αꢀposition are useful reagents in organic synthesis. They are widely used in Darzens
condensations,1 cyclopropanations,2 and vicarious nucleophilic substitutions.3 Knowledge of the nucleophilic reactivities of these carbanions
would be a valuable tool for designing their use in synthesis. In numerous previous investigations, we had found that the rates of the reactions
of nucleophiles with carbocations and acceptorꢀsubstituted ethylenes can be predicted by eq 1, which characterizes electrophiles by one
parameter, the electrophilicity E, and nucleophiles by two solventꢀdependent parameters, the nucleophilicity parameter N and the
susceptibility parameter sN.4
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log k2(20 °C) = sN(N + E) (1)
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More than 1000 nucleophiles and 270 electrophiles have so far been characterized on the basis of this linear freeꢀenergy relationship.5
We now report on the application of this method to characterize the nucleophilicities of arylsulfonyl substituted carbanions carrying αꢀchloro
and αꢀbromo substituents 1a−e (Scheme 1). Quinone methides 2a−g and benzylidenemalonates 2h−i (Table 1) were used as reference
electrophiles for these investigations.
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SCHEME 1. ClꢀStabilized Carbanions 1a−d, and BrꢀStabilized Carbanion 1e
TABLE 1. Quinone Methides 2a−g and Diethyl Benzylidenemalonates 2h−i.
Results and Discussion
Product studies. As representative examples for the reactions of carbanions 1 with quinone methides 2a−g, we have investigated the
corresponding reactions with 2c. Treatment of 1aꢀH with 1 equivalent of tꢀBuOK in DMF at ꢀ50 °C and subsequent addition of 0.5 equivalent of
2c gave a phenolate which was treated with 2% aqueous HCl after 5 min at ꢀ50 °C to yield 75% of 3aꢀH as a mixture of two diastereomers.
The reaction of 1d with 2c proceeded analogously (Scheme 2).
SCHEME 2. Synthesis of Michael Adducts 3ꢀH by the Reactions of Carbanions 1 with Quinone Methide 2c at ꢀ50 °C
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When the reactions of 1a−c and of 1e with 2c were carried out in DMSO at 20 °C and quenched with 2% aqueous HCl after 10 min,
mixtures of 4ꢀH and 5aꢀH were obtained, while 1d gave a complex mixture of products (Scheme 3). Because of the high melting point of
DMSO, low temperature studies were not possible as in DMF (see above).
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SCHEME 3. Reaction of Carbanion 1 with Quinone Methide 2c at 20 °C
The structure of 4aꢀH was confirmed by single crystal Xꢀray crystallography (Figure 1). Treatment of isolated 4aꢀH with tꢀBuOK led to
formation of 5aꢀH (Scheme 4). In order to investigate whether the weaker Brønsted base 1aꢀK which may be the effective base under the
conditions of Scheme 3 can also affect this elimination, 4aꢀH was also treated with 1aꢀK. As shown in Scheme 4, this reaction proceeded
slowly, and after 10 min a similar amount of 5aꢀH was obtained as in the reaction of 1a with 2c described in Scheme 3.
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FIGURE 1. ORTEPꢀdrawing of the crystal structure of 4aꢀH.
(The ellipsoid probability level is 50%)
SCHEME 4. Transformation of 4aꢀH into 5aꢀH.
OMe
PhO2S
1) Base (2eq), DMSO, 20 °C
2) 2% HCl(aq)
tꢀBu
HO
tꢀBu
OMe
tꢀBu
tꢀBu
OH
5aꢀHa
Base
4aꢀH
10 min
tꢀBuOK
10%
30 h
90%
1aꢀK
10 min
60 h
6%
90%
a Yield of isolated product.
These observations suggest the reaction mechanism described in Scheme 5. Michael addition of the carbanion 1a to the electrophilic
double bond of the quinone methide 2c yields the phenolate anion 3a. This intermediate was trapped by protonation with 2% aqueous HCl,
when the reaction was carried out in DMF at ꢀ50 °C (Scheme 2). At 20 °C, intramolecular cyclization may lead to the formation of spirodienone
A, which undergoes spontaneous ring opening with formation of the mesomerically stabilized zwitterion B. As an alternative to this mechanism
suggested by Groszek,7 phenoxideꢀmigration with substitution of Cl− gives B directly through a transition state resembling A. Deprotonation
yields the phenolate 4a (4aꢀH was isolated, Scheme 3 and Figure 1), which is selectively formed as the (E)ꢀdiastereomer, probably because of
attractive intramolecular πꢀπ interaction of the two aryl rings in the intermediate zwitterion B, as previously suggested by Groszek.7 Slow
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−
elimination of PhSO2 from 4a yields the alkynyl substituted phenol 5aꢀH. The formation of Michael adducts of type 3ꢀH and of the rearranged
elimination products 4ꢀH from the reaction of tolylsulfonyl chloromethyl anion 1 (R = Me) with quinone methides has previously been reported
by Groszek and coworkers.7
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SCHEME 5. Plausible Mechanism for the Reaction of 1a with 2c
The NaOH induced reaction of 1aꢀH with benzylidenemalonate 2h in DMSO gave the Michael adduct 6aꢀH, as previously reported for the
corresponding reaction in DMF.8 The reaction of 1bꢀH with 2h proceeded analogously (Scheme 6).
SCHEME 6. Reaction of Benzylidenemalonate 2h with Carbanions 1
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Kinetic investigations. All kinetic investigations were performed in DMSO solution at 20°C and monitored photometrically by following the
disappearance of the colored quinone methides or benzylidenemalonates. Generally a high excess of the carbanions over the electrophiles
was used to achieve firstꢀorder kinetics. As reported earlier,9 the carbanions 1a−e disproportionate slowly at room temperature. For that
reason, the doubleꢀmixing mode of stopped flow UVꢀVis spectrometers was used to generate solutions of the carbanions 1a−e by mixing the
CH acids (1a−e)ꢀH with tBuOK. After a userꢀdefined delay period (1 − 30s), the solutions of carbanions were combined with the electrophiles
2a−i.
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Figure 2 illustrates the decay of the absorption of 2c (λmax = 393 nm) in DMSO at 20 °C after addition of 20 equivalents of 1a
(pseudoꢀfirstꢀorder conditions). The absorbance decreases to about 15% of its initial value within 50 ms and then shows a very slow increase.
Separate UVꢀVis measurements showed that the residual absorbance after 50 ms is due to the generation of 4a, which has an absorption
maximum at 504 nm. The subsequent slow increase (insert of Figure 2) is due to the formation of 5a by elimination of PhSO2H from 4a.
Depending on the excess of base used for these experiments, the alkyne is either formed as the anion 5a or its conjugate acid 5aꢀH. While an
analogous behavior was observed for all other reactions of 1 with the quinone methides 2a−g, the corresponding reactions with the
benzylidenemalonates 2h,i showed only the fast decay of the absorption band of 2h,i.
The firstꢀorder rate constants kobs were obtained by leastꢀsquares fitting of the exponential function A = A0 exp(ꢀkobst) + C to the observed
timeꢀdependent absorbances A of the quinone methides 2a−g (in the initial period) and of the benzylidenemalonates 2h,i. According to eq 2
and eq 3, the pseudoꢀfirstꢀorder rate constant kobs should be proportional to the concentration of the carbanions 1. As shown for the reaction of
1a with 2c in Figure 3, kobs correlates linearly with the concentrations of the carbanions 1, and the negative intercept may be due to partial
decomposition of the carbanions 1. Though the intercept is small and negligible in most of these correlations (SI), in few cases even small
positive intercepts were observed. The secondꢀorder rate constants k2 listed in Table 2 correspond to the slopes of the kobs versus [1]
correlations. The experimental secondꢀorder rate constant k2 for the reaction of 1a with 2h (149 Mꢀ1 sꢀ1) is close to that (200 Mꢀ1 sꢀ1)
extrapolated for this reaction in DMF at 20 °C from the measured rate constant at ꢀ40 °C.8
ꢀd[2]/dt = k2[1][2]
(2)
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for [1]0 >> [2]0
⇒
kobs = k2[1]0
(3)
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FIGURE 2. Monoexponential decay of the absorbance A (at 393 nm) during the first 200 ms of the reaction of 1a (1.00 x 10ꢀ3 mol Lꢀ1) with 2c (5.00 x 10ꢀ5 mol Lꢀ1) in DMSO at
20 °C. Inset: slow increase of the absorbance at 393 nm at 20 °C between 0.05 and 500 s.
200
180
kobs = 145840[1a] ꢀ 43.02
R² = 0.9946
160
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↑
100
k
obs/sꢀ1
80
60
40
20
0
0
0.0005
0.001
0.0015
0.002
[1a]/M
→
FIGURE 3. Correlation of kobs for reaction of 1a with 2c versus the concentration of 1a.
In order to determine the nucleophileꢀspecific parameters N and sN of the carbanions 1a−e according to eq 1, the secondꢀorder rate
constants (log k2) of their reactions with electrophiles 2 (see Table 2) were plotted against the previously reported electrophilicity parameters E
of 2a−i (Table 1). Figure 4 and Figure S1 (SI) show that log k2 for these reactions correlate linearly with E as required by eq 1 and thus allow
the calculation of the nucleophileꢀspecific parameters N and sN listed in Table 2. The similarities of the slopes of the correlations for the
carbanions 1b−d (Figure 4 and Figure S1), which are numerically expressed by the sN parameters in Table 2, imply that the relative
nucleophilicities of the carbanions 1b−d depend only slightly on the electrophilicities of the reaction partners. The Hammett correlation for the
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reactions of carbanions 1a−d with benzylidenemalonate 2h is of moderate quality and gives rise to the Hammett reaction constant ρ = ꢀ1.50
(Figure 5). Since the substituted aryl ring is separated from the nucleophilic reaction center by the sulfonyl group, the Hammett reaction
constant ρ has a small negative value.
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TABLE 2. SecondꢀOrder Rate Constants (k2) for the Reactions of Carbanions 1aꢀe with Quinone Methides 2a−g and Benzylidenemalonates 2h−i in DMSO at 20°C
a
Carbanion
Electrophile
k2 (Mꢀ1 Sꢀ1)
N, sN
1.46 × 105
3.35 × 104
2.65 × 104
3.92 × 104
1.49 × 102
1.08 × 105
8.87 × 104
2.01 × 104
4.90 × 101
2.85 × 101
1.77 × 104
9.19× 103
5.65 × 104
2.21 × 104
6.89 × 104
2.90 × 104
2.00 × 104
2.78 × 105
7.11 × 104
1.17 × 104
4.90 × 103
28.27, 0.42
1a
2c
2d
2e
2g
2h
2b
2c
2d
2h
2i
1b
26.90, 0.45
1c
2d
2e
2f
25.59, 0.51
2g
2a
2b
2c
2a
2c
2d
2e
1d
1e
24.88, 0.49
23.90, 0.62
a The nucleophileꢀspecific parameters N and sN were derived from the intercepts (on the abscissa) and the slopes of the correlations between log k2 (this table) and the
electrophilicity parameters E from Table 1. For details see text.
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FIGURE 4. Correlation of log k2 for the reactions of the carbanions 1a and 1c−e with the quinone methides 2a−g and benzylidenemalonates 2h−i versus the electrophilicity
parameters E of the corresponding electrophiles. For the sake of clarity, the correlation line for 1b is only shown in the SI.
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FIGURE 5. Correlation of log k2 of the reactions of carbanions 1a−d with benzylidenemalonate 2h versus the Hammett σp values for R. a log k2 calculated by eq 1 with E from
Table 1.
Figure 6 compares the reactivities of 1a−e with that of the previously characterized phenylsulfonyl substituted benzyl anion 1f. As the sN
values for these carbanions differ slightly, their relative nucleophilic reactivities depend somewhat on the electrophilicity of the reaction partner.
The reactivities of the arylsulfonyl substituted halomethyl anions 1a−e towards 2c differ by less than a factor of 7. The chloroꢀsubstituted
carbanion 1a is two times more reactive than the corresponding bromoꢀderivative 1e. The similar nucleophilic reactivities of the phenylsulfonyl
substituted carbanions 1a and 1f show that αꢀchloro and αꢀphenyl substitution has a similar effect on nucleophilic reactivities as on the
corresponding basicities in DMSO (1aꢀH : pKa = 23.8,10 1fꢀH: pKa = 23.4311).
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log k2 towards 2c
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O
O
S
Ph
5.5
5.1
4.7
4.3
5.41a
1f
O
S
O
Cl
Br
O
5.16
4.85
O
S
Cl
Cl
1a
4.95
O
S
O
Cl
4.83a
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1b
1e
O
O
S
O
S
O
NC
1c
Cl
4.30
1d
O2N
FIGURE 6. Comparison of log k2 for the reactions of carbanions 1aꢀf with electrophile 2c in DMSO at 20 °C. a log k2 (2c) calculated by eq 1 with E from Table 1. N and sN
values of 1f from ref 12d.
Conclusion
FIGURE 7. Comparison of nucleophilicity parameters N ( in DMSO at 20 °C) of 1a and 1d with other classes of nucleophiles. a N and sN values of 1g and 1j were taken from
ref 12a, of 1h and 1i from ref 12b, of 1k from ref 12c, of 1l, 1m and 1n from ref 12d, of 1o from ref 12e, of 1p from ref 4b.
The rate constants for the reactions of the Clꢀ, Brꢀsubstituted carbanions 1a−e with the selected reference electrophiles (quinone
methides and diethyl benzylidenemalonates) in DMSO follow the linear freeꢀenergy relationship eq 1. For that reason, it is possible to include
these compounds in our comprehensive nucleophilicity scale and to compare their reactivities with those of other nucleophiles (Figure 7). As
they contain halogens in αꢀposition, which can be nucleophilically substituted, carbanions 1 show carbenoid character and yield epoxides1,
aziridines1c,13 and cyclopropanes2 by reaction with carbonyl compounds, imines, and Michael acceptors, respectively. In this aspect they
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resemble the behavior of sulfur and nitrogen ylides, some representatives of which are also shown on the left side of Figure 7. Though the
relative reactivities of these nucleophiles depend somewhat on the electrophilicity of the reaction partner due to the different values of sN, the
ranking based on N in Figure 7 gives a rough orientation. Thus, one can see that the arylsulfonyl substituted chloromethyl anions are stronger
nucleophiles than semistabilized sulfur ylides, and therefore, can be used for the synthesis of epoxides from nonꢀactivated ketones. The high
nucleophilic reactivities of 1a−e combined with the high nucleofugality of chloride and bromide, also explains their versatile applications in
vicarious nucleophilic substitutions.3
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Experimental Section
Chloromethyl aryl sulfones (1a−d)ꢀH and bromomethyl phenyl sulfone 1eꢀH. Chloromethyl phenyl sulfone 1aꢀH (>97%) and
bromomethyl phenyl sulfone 1eꢀH (98%) are commercially available compounds. Compounds (1b−d)ꢀH were prepared by chlorination of the
corresponding 4ꢀsubstituted thioanisoles14, and subsequent mꢀCPBA oxidation15 following literature procedures.14,15 1bꢀH is a known
compound fully characterized already.16 For the reason of simplicity, the 1H NMR signals of AA’BB’ꢀspin systems of pꢀdisubstituted aromatic
rings of all compounds described below were treated as doublets. NMR signal assignments were based on additional 2DꢀNMR experiments
(COSY, HSQC, HMBC).
Chloromethyl 4ꢀnitrophenyl sulfone (1dꢀH) (General procedure 1). 4ꢀNitrothioanisole (3.50 g, 20.7 mmol) was treated with
Nꢀchlorosuccinimide (3.18 g, 23.8 mmol) in dry carbon tetrachloride (21 mL) at 35 °C for 24 h. Succinimide precipitated and was removed by
filtration. After evaporation of the solvent the residue was dissolved in 65 mL of DCM, cooled in an iceꢀwater bath with stirring, and 77%
mꢀchloroperoxybenzoic acid (11.0 g, 49.1 mmol) was added in portions within 5 min. The mixture was stirred at 0 °C for 40 min and 5 h at
room temperature. After addition of ether, the solution was washed with water, 10% aqueous NaOH, an aqueous solution of
Na2S2O3ꢀNaIꢀNaOH, and a saturated aqueous solution of NaCl. The organic extract was dried over MgSO4, and the solvent was removed
using a rotary evaporator. The residue was recrystallized from EtOAc and pentane to give a yellow solid 1dꢀH (3.42 g, 14.5 mmol, 70%), mp
138−143 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.50 (d, J = 8.8 Hz, 2 H, Hꢀ3 and Hꢀ5), 8.23 (d, J = 8.9 Hz, 2 H, Hꢀ2 and Hꢀ6), 5.50 (s, 2 H, Hꢀ1).
13C NMR (101 MHz, DMSOꢀd6) δ 151.1 (Cꢀ4), 141.2 (Cꢀ7), 130.6 (Cꢀ2 and Cꢀ6), 124.6 (Cꢀ3 and Cꢀ5), 57.1 (Cꢀ1). HRMS (EI) m/z: [M+—] calcd
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for C7H6ClNO4S 234.9701, found 234.9702. IR (ATR) v (cmꢀ1) = 2942, 1607, 1531, 1475, 1401, 1334, 1236, 1209, 1155, 1131, 1083, 1011,
873, 854, 796, 755, 723, 679.
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Chloromethyl 4ꢀcyanophenyl sulfone (1cꢀH). General procedure 1 was applied to 4ꢀcyanothioanisole (1.49 g, 10.0 mmol),
Nꢀchlorosuccinimide (1.40 g, 10.5 mmol) and 77% mꢀchloroperoxybenzoic acid (5.31 g, 23.7 mmol). 1cꢀH was obtained as a white solid (1.62
g, 7.53 mmol, 75%) mp 133−138 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.21 (d, J = 8.7 Hz, 2 H, Hꢀ2 and Hꢀ7), 8.13 (d, J = 8.7 Hz, 2 H, Hꢀ3 and
Hꢀ6), 5.46 (s, 2 H, Hꢀ1). 13C NMR (101 MHz, DMSOꢀd6) δ 139.9 (Cꢀ8), 133.5 (Cꢀ2 and Cꢀ7), 129.6 (Cꢀ3 and Cꢀ6), 117.4 (Cꢀ5), 117.1 (Cꢀ4), 57.0
(Cꢀ1). HRMS (EI) m/z: [M+—] calcd for C8H6ClNO2S 214.9802, found 214.9796. IR (ATR) v (cmꢀ1) = 3019, 2240, 1387, 1327, 1293, 1146, 1081,
1015, 850, 841, 794, 778, 732, 693.
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Reaction of carbanion 1a with quinone methide 2c in DMF at ꢀ50 °C (General procedure 2). To a solution of tꢀBuOK (112 mg, 1.00
mmol) in anhydrous DMF (5 mL) at ꢀ50 °C was added a solution of 1aꢀH (190 mg, 1.00 mmol) in anhydrous DMF (5 mL) and successively a
solution of 2c (162 mg, 0.500 mmol) in anhydrous DMF (5 mL). After 5 min, 100 mL of 2% aqueous HCl was added and the mixture was
extracted with CHCl3. The organic phase was washed by water three times to remove remaining DMF, dried with anhydrous MgSO4 and
filtered. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give a pale yellow
liquid: 2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ(2ꢀchloroꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(phenylsulfonyl)ethyl)phenol (3aꢀH), ~ 1.3:1 mixture of diastereomers. (193 mg,
0.375 mmol, 75%). Diastereomer A:1H NMR (599 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 2 H, Hꢀ15 x 2), 7.57 (t, J = 7.3 Hz, 1 H, Hꢀ17), 7.43 (dd, J
= 7.2, 7.2 Hz, 2 H, Hꢀ16 x 2), 7.33 (d, J = 8.2 Hz, 2 H, Hꢀ4 x 2), 7.12 (s, 2 H, Hꢀ8 x 2), 6.81 (d, J = 8.0 Hz, 2 H, Hꢀ5 x 2), 5.41 – 5.38 (m, 1 H, Hꢀ1,
overlap with B), 5.14 (s, 1 H, OH), 5.06 (d, J = 4.7 Hz, 1 H, Hꢀ2), 3.78 (s, 3 H, Hꢀ7 x 3), 1.39 (s, 18 H, Hꢀ11 x 18). 13C NMR (151 MHz, CDCl3) δ
158.8 (Cꢀ6), 153.0 (Cꢀ12), 137.1 (Cꢀ14), 136.0 (Cꢀ9 x 2), 134.0 (Cꢀ17), 131.0 (Cꢀ3), 130.9 (Cꢀ13), 130.8 (Cꢀ4 x 2), 129.7 (Cꢀ15 x 2), 128.8
(Cꢀ16 x 2), 125.0 (Cꢀ8 x 2), 113.6 (Cꢀ5 x 2), 79.4 (Cꢀ1), 55.3 (Cꢀ7), 50.6 (Cꢀ2), 34.4 (Cꢀ10 x 2), 30.3 (Cꢀ11 x 6). Diastereomer B: 1H NMR (599
MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 2 H, Hꢀ15 x 2), 7.54 (t, J = 7.1 Hz, 1 H, Hꢀ17), 7.38 (dd, J = 7.4, 7.4 Hz, 2 H, Hꢀ16 x 2), 7.25 (d, J = 9.3 Hz,
2 H, Hꢀ4 x 2), 7.15 (s, 2 H, Hꢀ8 x 2), 6.81 (d, J = 8.0 Hz, 2 H, Hꢀ5 x 2), 5.41 – 5.38 (m, 1 H, Hꢀ1, overlap with A), 5.12 (s, 1 H, OH), 4.97 (d, J =
5.3 Hz, 1 H, Hꢀ2), 3.77 (s, 3 H, Hꢀ7 x 3), 1.38 (s, 18 H, Hꢀ11 x 18). 13C NMR (151 MHz, CDCl3) δ 158.7 (Cꢀ6), 153.1 (Cꢀ12), 136.6 (Cꢀ14), 135.5
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(Cꢀ9 x 2), 133.9 (Cꢀ17), 132.4 (Cꢀ3), 130.0 (Cꢀ15 x 2), 129.4 (Cꢀ4 x 2), 128.8 (Cꢀ13), 128.5 (Cꢀ16 x 2), 126.4 (Cꢀ8 x 2), 114.1 (Cꢀ5 x 2), 79.8
(Cꢀ1), 55.3 (Cꢀ7), 51.2 (Cꢀ2), 34.4 (Cꢀ10 x 2), 30.4 (Cꢀ11 x 6). HRMS (EI) m/z: [M+—] calcd for C29H35ClO4S 514.1939, found 514.1948. IR (ATR)
v (cmꢀ1) = 3634, 2956, 1610, 1511, 1435, 1361, 1322, 1309, 1250, 1212, 1179, 1150, 1135, 1081, 1032, 887, 836, 810, 685, 667.
(E)ꢀ2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀ((4ꢀnitrophenyl)sulfonyl)vinyl)phenol (3dꢀH): General procedure 2 was applied to
1dꢀH (235 mg, 1.00 mmol), 2c (162 mg, 0.500 mmol) and tꢀBuOK (112 mg, 1.00 mmol). 3dꢀH was obtained as a pale yellow liquid and a
mixture of diastereomers. (199 mg, 0.355 mmol, 71%, dr ~ 1.1:1). Diastereomer A: 1H NMR (599 MHz, CDCl3) δ 8.20 (d, J = 9.0 Hz, 2 H, Hꢀ16
x 2), 7.84 (d, J = 9.0 Hz, 2 H, Hꢀ15 x 2), 7.29 (d, J = 8.8 Hz, 2 H, Hꢀ4 x 2), 7.08 (s, 2 H, Hꢀ8 x 2), 6.78 (d, J = 8.9 Hz, 2 H, Hꢀ5 x 2), 5.42 (d, J =
5.5 Hz, 1 H, Hꢀ1), 5.16 (s, 1 H, OH), 5.01 (d, J = 5.5 Hz, 1 H, Hꢀ2), 3.77 (s, 3 H, Hꢀ7 x 3), 1.37 (s, 18 H, Hꢀ11 x 18). 13C NMR (151 MHz, CDCl3)
δ 159.19 (Cꢀ6), 153.35 (Cꢀ12), 150.77 (Cꢀ17), 142.55 (Cꢀ14), 136.28 (Cꢀ9 x 2), 131.16 (Cꢀ15 x 2), 130.80 (Cꢀ4 x 2), 130.42 (Cꢀ3), 130.07
(Cꢀ13), 125.06 (Cꢀ8 x 2), 123.67 (Cꢀ16 x 2), 113.83 (Cꢀ5 x 2), 79.77 (Cꢀ1), 55.38 (Cꢀ7), 50.92 (Cꢀ2), 34.51 (Cꢀ10 x 2), 30.39 (Cꢀ11 x 6).
Diastereomer B: 1H NMR (599 MHz, CDCl3) δ 8.14 (d, J = 9.1 Hz, 2 H, Hꢀ16 x 2), 7.75 (d, J = 9.0 Hz, 2 H, Hꢀ15 x 2), 7.20 (d, J = 8.9, 2 H, Hꢀ4
x 2), 7.12 (s, 2 H, Hꢀ8 x 2), 6.79 (d, J = 8.8 Hz, 2 H, Hꢀ5 x 2), 5.45 (d, J = 6.0 Hz, 1 H, Hꢀ1), 5.15 (s, 1 H, OH), 4.93 (d, J = 5.9 Hz, 1 H, Hꢀ2),
3.75 (s, 3 H, Hꢀ7 x 3), 1.34 (s, 18 H, Hꢀ11 x 18). 13C NMR (151 MHz, CDCl3) δ 159.06 (Cꢀ6), 153.55 (Cꢀ12), 150.67 (Cꢀ17), 142.15 (Cꢀ14),
135.88 (Cꢀ9 x 2), 131.53 (Cꢀ15 x 2), 131.48 (Cꢀ3), 129.45 (Cꢀ4 x 2), 128.19 (Cꢀ13), 126.45 (Cꢀ8 x 2), 123.39 (Cꢀ16 x 2), 114.28 (Cꢀ5 x 2), 80.29
(Cꢀ1), 55.34 (Cꢀ7), 51.38 (Cꢀ2), 34.41 (Cꢀ10 x 2), 30.32 (Cꢀ11 x 6). HRMS (EI) m/z: [M+—] calcd for C29H34ClNO6S 559.1790, found 559.1795.
IR (ATR) v (cmꢀ1) = 3631, 2956, 1608, 1531, 1511, 1434, 1346, 1309, 1251, 1179, 1150, 1080, 1032, 908, 853, 752, 681.
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Reaction of carbanion 1a with quinone methide 2c in DMSO at 20 °C (General procedure 3). To a solution of 1a (190 mg, 1.00 mmol)
in anhydrous DMSO (5 mL) was added a solution of tꢀBuOK (112 mg, 1.00 mmol) in anhydrous DMSO (5 mL) at room temperature. After 2
min, a solution of 2c (162 mg, 0.500 mmol) in anhydrous DMSO (10 mL) was added to the resulting solution. The completion of the reaction
was checked by TLC and quenched by 100 mL 2% aqueous HCl followed with CHCl3 extraction. The organic extract was washed by water
three times to remove remaining DMSO, dried with anhydrous MgSO4 and filtered. The solvent was evaporated under reduced pressure and
the crude product was purified by column chromatography to obtain white solid 4aꢀH (167 mg, 0.351 mmol, 70%) and byproduct colorless
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(E)ꢀ2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀ(phenylsulfonyl)vinyl)phenol (4aꢀH): white solid, mp 147−152 °C. 1H NMR (599 MHz,
CDCl3) δ 7.84 (s, 1 H, Hꢀ1), 7.66 – 7.57 (m, 2 H, Hꢀ15 x 2), 7.50 (t, J = 7.4 Hz, 1 H, Hꢀ17), 7.37 (dd, J = 8.5, 7.1 Hz, 2 H, Hꢀ16 x 2), 7.05 (d, J =
8.9 Hz, 2 H, Hꢀ3 x 2), 6.71 (s, 2 H, Hꢀ9 x 2), 6.69 (d, J = 9.0 Hz, 2 H, Hꢀ4 x 2), 5.31 (s, 1 H, OH), 3.75 (s, 3 H, Hꢀ6 x 3), 1.28 (s, 18 H, Hꢀ13 x 18).
13C NMR (151 MHz, CDCl3) δ 161.03 (Cꢀ5), 154.60 (Cꢀ11), 139.54 (Cꢀ14), 139.47 (Cꢀ7), 136.62 (Cꢀ1), 136.55 (Cꢀ10 x 2), 132.83 (Cꢀ17),
132.35 (Cꢀ3 X 2), 128.83 (Cꢀ15 x 2), 128.58 (Cꢀ16 x 2), 127.71 (Cꢀ9 x 2), 125.96 (Cꢀ2), 122.10 (Cꢀ8), 113.96 (Cꢀ4 x 2), 55.41 (Cꢀ6), 34.39
(Cꢀ12 x 2), 30.33 (Cꢀ13 x 6). HRMS (EI) m/z: [M+—] calcd for C29H34O4S 478.2172, found 478.2172. IR (ATR) v (cmꢀ1) = 3552, 2949, 1606, 1513,
1444, 1419, 1376, 1305, 1282, 1256, 1236, 1177, 1147, 1110, 1036, 1023, 981, 895, 840, 804, 765, 751, 714, 689, 666.
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2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ((4ꢀmethoxyphenyl)ethynyl)phenol (5aꢀH): colorless liquid. 1H NMR (599 MHz, CDCl3) δ 7.46 (d, J = 8.7 Hz, 2 H,
Hꢀ4 x 2), 7.34 (s, 2 H, Hꢀ9 x 2), 6.86 (d, J = 8.7 Hz, 2 H, Hꢀ3 x 2), 5.35 (s, 1 H, OH), 3.82 (s, 3 H, Hꢀ1 x 3), 1.45 (s, 18 H, Hꢀ12 x 18). 13C NMR
(151 MHz, CDCl3) δ 159.4 (Cꢀ2), 154.3 (Cꢀ13), 136.2 (Cꢀ10 x 2), 133.0 (Cꢀ4 x 2), 128.6 (Cꢀ9 x 2), 116.1 (Cꢀ5), 114.5 (Cꢀ8), 114.1 (Cꢀ3 x 2),
89.3 (Cꢀ7), 87.0 (Cꢀ6), 55.4 (Cꢀ1), 34.5 (Cꢀ11 x 2), 30.4 (Cꢀ12 x 6). HRMS (EI) m/z: [M+—] calcd for C23H28O2 336.2084, found 336.2081. IR
(ATR) v (cmꢀ1) = 3625, 2956, 1606, 1509, 1433, 1287, 1174,1152，1119, 1105, 1031, 885, 830, 806, 774, 757.
(E)ꢀ2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ(1ꢀ((4ꢀchlorophenyl)sulfonyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)vinyl)phenol (4bꢀH). General procedure 3 was applied to
1bꢀH (225 mg, 1.00 mmol), 2c (162 mg, 0.500 mmol) and tꢀBuOK (112 mg, 1.00 mmol). 4bꢀH was obtained as a pale yellow liquid (156 mg,
0.305 mmol, 61%) 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1 H, Hꢀ1), 7.52 (d, J = 8.6 Hz, 2 H, Hꢀ15 x 2), 7.34 (d, J = 8.5 Hz, 2 H, Hꢀ16 x 2), 7.06
(d, J = 8.8 Hz, 2 H, Hꢀ3 x 2), 6.72 (s, 2 H, Hꢀ9 x 2), 6.70 (d, J = 8.8 Hz, 2 H, Hꢀ4 x 2), 5.34 (s, 1 H, OH), 3.76 (s, 3 H, Hꢀ6 x 3), 1.30 (s, 18 H,
Hꢀ13 x 18). 13C NMR (101 MHz, CDCl3) δ 161.19 (Cꢀ5), 154.72 (Cꢀ11), 139.52 (Cꢀ17), 139.21 (Cꢀ7), 138.03 (Cꢀ14), 136.82 (Cꢀ1), 136.76 (Cꢀ10
x 2), 132.42 (Cꢀ3 x 2), 130.29 (Cꢀ15 x 2), 128.80 (Cꢀ16 x 2), 127.76 (Cꢀ9 x 2), 125.78 (Cꢀ2), 121.88 (Cꢀ8), 114.02 (Cꢀ4 x 2), 55.43 (Cꢀ6), 34.42
(Cꢀ12 x 2), 30.33 (Cꢀ13 x 6). HRMS (EI) m/z: [M+—] calcd for C29H33ClO4S 512.1783, found 512.1792. IR (ATR) v (cmꢀ1) = 3628, 2955, 1601,
1510, 1474, 1436, 1375, 1303, 1253, 1176, 1145, 1029, 982, 828, 765, 706, 669.
(E)ꢀ2,6ꢀDiꢀtertꢀbutylꢀ4ꢀ(1ꢀ((4ꢀcyanophenyl)sulfonyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)vinyl)phenol (4cꢀH): General procedure 3 was applied to
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1cꢀH (215 mg, 1.00 mmol), 2c (162 mg, 0.500 mmol) and tꢀBuOK (112 mg, 1.00 mmol). 4cꢀH was obtained as a yellow solid (111 mg, 0.220
mmol, 44%) mp 135−140 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1 H, Hꢀ1)), 7.71 (d, J = 8.1 Hz, 2 H, Hꢀ15 x 2), 7.66 (d, J = 8.2 Hz, 2 H, Hꢀ16
x 2), 7.06 (d, J = 8.4 Hz, 2 H, Hꢀ3 x 2), 6.74 (s, 2 H, Hꢀ9 x 2), 6.71 (d, J = 8.4 Hz, 2 H, Hꢀ4 x 2), 5.38 (s, 1 H, OH), 3.77 (s, 3 H, Hꢀ6 x 3), 1.30 (s,
18 H, Hꢀ13 x 18). 13C NMR (101 MHz, CDCl3) δ 161.5 (Cꢀ5), 154.9 (Cꢀ11), 144.1 (Cꢀ14), 138.2 (Cꢀ1 and Cꢀ7 ), 137.0 (Cꢀ10 x 2), 132.6 (Cꢀ3 x
2), 132.2 (Cꢀ16 x 2), 129.4 (Cꢀ15 x 2), 127.8 (Cꢀ9 x 2), 125.5 (Cꢀ2), 121.4 (Cꢀ8), 117.4 (Cꢀ18), 116.4 (Cꢀ17), 114.1 (Cꢀ4 x 2), 55.5 (Cꢀ6), 34.4
(Cꢀ12 x 2), 30.4 (Cꢀ13 x 6). HRMS (EI) m/z: [M+—] calcd for C30H33NO4S 503.2125, found 503.2124. IR (ATR) v (cmꢀ1) = 3598, 2956, 2232,
1664, 1603, 1511, 1436, 1422, 1358, 1310, 1174, 1120, 1081, 1033, 978, 892, 826, 755, 670.
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Reaction of carbanion 1 with benzylidenemalonate 2h (General procedure 4). To a solution of 1a (98.0 mg, 0.516 mmol) and 2h (100
mg, 0.344 mmol) in anhydrous DMSO (5 mL) was added anhydrous NaOH (20.6 mg, 0.515 mmol). The resulting solution was stirred for 2h at
room temperature and then quenched by saturated NH4Cl solution followed with CHCl3 extraction. The organic extract was washed by water
three times to remove remaining DMSO, dried with anhydrous MgSO4 and filtered. The solvent was evaporated under reduced pressure and
the
residue
was
purified
by
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chromatography
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yellow
liquid
diethyl
2ꢀ(2ꢀchloroꢀ1ꢀ(4ꢀ(dimethylamino)phenyl)ꢀ2ꢀ(phenylsulfonyl)ethyl)malonate (6aꢀH) (119 mg, 0.248 mmol, 72%, dr ~ 5:1). The major
diastereomer could be isolated in pure form and its full characterization is as same as literature reported.7
Diethyl 2ꢀ(2ꢀchloroꢀ2ꢀ((4ꢀchlorophenyl)sulfonyl)ꢀ1ꢀ(4ꢀ(dimethylamino)phenyl)ethyl)malonate (6bꢀH). General procedure 4 was
applied to 1bꢀH (117 mg, 0.520 mmol), 2h (100 mg, 0.344 mmol) and NaOH (20.6 mg, 0.515 mmol). 6bꢀH was obtained as a pale yellow liquid
(123 mg, 0.238 mmol, 70%, dr ~ 2:1), minor diastereomer decomposed during purification. Major diastereomer:1H NMR (599 MHz, CDCl3) δ
7.60 (d, J = 8.7 Hz, 2 H, Hꢀ16 x 2), 7.36 (d, J = 8.6 Hz, 2 H, Hꢀ17 x 2), 7.16 (d, J = 8.8 Hz, 2 H, Hꢀ11 x 2), 6.49 (d, J = 8.3 Hz, 2 H, Hꢀ12 x 2),
5.66 (d, J = 7.3 Hz, 1 H, Hꢀ1), 4.44 (d, J = 8.6 Hz, 1 H, Hꢀ3), 4.18 – 4.09 (m, 3 H, Hꢀ2 and Hꢀ8 x 2), 4.01 (q, J = 7.1 Hz, 2 H, Hꢀ5 x 2), 2.91 (s, 6
H, Hꢀ14 x 6), 1.21 (t, J = 7.2 Hz, 3 H, Hꢀ9 x 3), 1.08 (t, J = 7.1 Hz, 3 H, Hꢀ6 x 3). 13C NMR (151 MHz, CDCl3) δ 168.0 (Cꢀ7), 167.6 (Cꢀ4), 150.4
(Cꢀ13), 140.5 (Cꢀ18), 136.4 (Cꢀ15), 131.1 (Cꢀ11 x 2), 130.6 (Cꢀ16 x 2), 129.3 (Cꢀ17 x 2), 121.5 (Cꢀ10), 112.0 (Cꢀ12 x 2), 76.5 (Cꢀ1), 62.0 (Cꢀ8),
61.7 (Cꢀ5), 55.4 (Cꢀ3), 47.4 (Cꢀ2), 40.5 (Cꢀ14 x 2), 14.1 (Cꢀ9), 13.9 (Cꢀ6). HRMS (EI) m/z: [M+—] calcd for C23H27Cl2NO6S 515.0931, found
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515.0925. IR (ATR) v (cmꢀ1) = 2981, 2929, 1728, 1613, 1523, 1475, 1445, 1394, 1332, 1279, 1256, 1089, 1012, 947, 819, 751, 666.
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Associated Content
Supporting Information
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Details of the kinetic experiments, correlation line (log k2 against E) for 1b, NMR spectra of all characterized compounds, and crystallographic
data. This material is available free of charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
* Eꢀmail: Herbert.Mayr@cup.uniꢀmuenchen.de
Author Contributions
§Z.L. and Q.C contributed equally to this work.
Notes
The authors declare no competing financial interest.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749, project B1) and the China Scholarship Council (fellowship to Z.L.) for financial
support. We are grateful to Nathalie Hampel for preparing quinone methides and benzylidenemalonates. Furthermore, we thank Dr. Armin R.
Ofial and Dr. Guillaume Berionni for helpful discussions.
References
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