Unexpected Role of p-Toluenesulfonylmethyl Isocyanide as a Sulfonylating Agent in Reactions with α-Bromocarbonyl Compounds

Article abstract of DOI:10.1021/acs.joc.6b00844

The reactions of p-toluenesulfonylmethyl isocyanide (TosMIC) with α-bromocarbonyl compounds leading efficiently to α-sulfonated ketones, esters, and amides were reported, in which an explicit new role of TosMIC as the sulfonylating agent was uncovered for the first time. Mechanistic study by control experiments and DFT calculations suggested that the reaction is initiated by Cu(OTf)₂-catalyzed hydration of TosMIC to form a formamide intermediate, which undergoes facile C-S bond cleavage under the mediation of a Cs₂CO₃ additive.

Full text of DOI:10.1021/acs.joc.6b00844

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Article
Unexpected Role of p-Toluenesulfonylmethyl Isocyanide (TosMIC) as a
Sulfonylating Agent in Reactions with alpha-Bromo Carbonyl Compounds
Jiajia Chen, Wei Guo, Zhenrong Wang, Lin Hu, Fan Chen, and Yuanzhi Xia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00844 • Publication Date (Web): 06 Jun 2016
Downloaded from http://pubs.acs.org on June 8, 2016
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Unexpected Role of pꢀToluenesulfonylmethyl Isocyanide (TosMIC) as a
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Sulfonylating Agent in Reactions with αꢀBromo Carbonyl Compounds
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Jiajia Chen,† Wei Guo,† Zhenrong Wang,† Lin Hu,‡ Fan Chen,*,† and Yuanzhi Xia*,†
†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
‡Department of Chemistry, Brandeis University, Massachusetts 02454ꢀ9110, United States
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ABSTRACT:
The reactions of pꢀtoluenesulfonylmethyl isocyanide (TosMIC) with αꢀbromo carbonyl compounds lead
efficiently to αꢀsulfonated ketones, esters, and amides were reported, in which an explicit new role of TosMIC as
the sulfonylating agent was uncovered for the first time. Mechanistic study by control experiments and DFT
calculations suggested that the reaction is initiated by Cu(OTf)2ꢀcatalyzed hydration of TosMIC to form a
formamide intermediate, which undergoes facile CꢀS bond cleavage under the mediation of Cs2CO3 additive.
1. INTRODUCTION
The pꢀtoluenesulfonylmethyl isocyanide (TosMIC) is a useful and versatile reagent in organic chemistry.1
Among different types of transformations, the αꢀacidity of TosMIC has been widely employed as results of strong
electronꢀwithdrawing effect of the two groups attached to this carbon (Scheme 1a). Thus, a variety of heterocycles,2
such as oxazolidines,3 oxazoles,4 indoles,5 pyrroles,6 thiazoles,7 triazoles8 etc., are readily accessible by
baseꢀinduced cycloadditions of TosMIC with different heteroatomꢀcontaining unsaturated functionalities. In these
reactions the 1,3ꢀdipolar character of TosMIC was exploited (Scheme 1b). In the absence of a dipolarphile, TosMIC
is a carbon nucleophile under basic conditions and undergoes substitution reactions readily with halides (Scheme
1c).9 Due to the facile cleavage of CꢀS bond, in most reactions the tosyl moiety of TosMIC substrate is finally
released into the reaction media as a leaving group,10 however, the using of TosMIC as a sulfonating agent is rare. 11
To search for new reactivity of TosMIC in organic transformations,12 in the current manuscript we reported a
new substitution reaction of TosMIC with αꢀbromo carbonyl compounds (1) in the presence of Cs2CO3. Instead of
working as a threeꢀatomꢀcomponent in cycloaddition reaction with the carbonyl functionality (Scheme 1b) or as a
carbon nucleophile in substitution with the bromide (Scheme 1c), we found that TosMIC is a sulfonylating agent to
afford αꢀsulfonated carbonyl compounds with the isocyanideꢀsubstituted methylene moiety being a leaving group
(Scheme 1d).
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Scheme 1. Different Roles of TosMIC in Organic Reactions
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2. RESULTS AND DISCUSSION
Our study started with condition optimization of the reaction between 2ꢀbromoꢀ1ꢀphenylpropanꢀ1ꢀone (1a)
and TosMIC (Table 1). First we carried out the reaction in toluene solution under catalystꢀfree conditions. When 1.5
equiv of Cs2CO3 was used as the base, αꢀsulfonation product 2a was obtained in 40% yield at room temperature
(entry 1). Slightly increased yield (44%) was achieved when carrying out the reaction at 50 °C (entry 2).
Interestingly, the yield of 2a could be increased to 52% with a slightly reduced amount of Cs2CO3 (entry 3). When
the reaction temperature was further elevated to 70 and 90 °C, the same yield (56%) was obtained (entries 4 and 5),
indicating the reaction temperature only has limited effect on the reaction efficiency. It was found that no better
yields could be obtained when other solvents such as DCE and acetonitrile were used (entries 6 and 7). However,
when 5 mol % Cu(OTf)2 was added as a catalyst, the yield of 2a was dramatically increased to 84% (entry 8), and
the yield could be further improved to 87% when the reaction was stirred for a longer time (entry 9). No catalytic
activity was found when other metal salts such as Pd(OAc)2 and AgOTf were used (entries 10 and 11). The yield
was only 70% when the Cuꢀcatalyzed reaction was run in dioxane solution (entry 12). Replacing Cs2CO3 with DBU
resulted in poor reactivity (entry 13). No reaction was observed when using 1.2 equiv Et3N (entry 14), K2CO3
(entry 15), or NaOtBu (entry 16) as the base source, and the using of CsOAc lead to a complex mixture (entry 17).
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Table 1. Screening of the Reaction Conditionsa
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Yield [%]b
Base [equiv]
[M]
Entry
Solvent
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1c
2d
3d
4
5e
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7c
8
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
DBU (1.2)
ꢀ
Toluene
Toluene
Toluene
Toluene
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DCE
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Acetonitrile
Toluene
Toluene
Toluene
Toluene
1,4ꢀDioxane
Toluene
Toluene
Toluene
Toluene
Toluene
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Cu(OTf)2
Cu(OTf)2
Pd(OAc)2
AgOTf
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
84
9f
87
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Et3N (1.2)
NR
Trace
Trace
Traceg
K2CO3 (1.2)
NaOtBu (1.2)
CsOAc (1.2)
a
Reaction conditions: 1a (0.3 mmol), TosMIC (0.9 mmol), catalyst (5 mol %), H2O (3 equiv), and anhydrous
solvent (2 mL) at 70 °C for 9 h. b Isolated yields. c At room temperature. d At 50 oC. e At 90 oC. f Reaction for 20 h.
g Complex mixture.
With the optimal reaction conditions in hand, the reaction scope for this Cu(OTf)2ꢀcatalyzed and
Cs2CO3ꢀpromoted sulfonylation of αꢀbromo ketones with TosMIC was then explored. As shown in Table 2, the
sulfonylation products could be afforded from a variety of αꢀbromo ketones. In comparison with 1a, when the alkyl
group (R2) attached to the α carbon is one carbon longer (1b), product 2b was obtained with a comparable yield of
89%. The alkyl group could be changed to a phenyl group (1c) to generate 2c in 79% yield. The electronic property
of the phenyl group attached directly to the carbonyl functionality does not have dramatic influence on the reaction
efficiency. For example, for reactions of electronꢀwithdrawing halide containing substrates, the corresponding
sulfonylation products 2dꢀ2g could be formed with yields around 80%. Interestingly, a higher yield of 90% of 2h
was obtained when both meta and para positions of the phenyl group are occupied with chloride atoms. When the
phenyl group is substituted with electronꢀdonating substituent at para and ortho positions, 2i and 2j were formed in
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Table 2. Scope of αꢀBromo Ketonesa
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5 mol % Cu(OTf)2
O
O
1.2 eq Cs2CO3
R2
R2
+
TsCH2NC
(TosMIC)
R1
R1
2 ml Toluene, 3 eq H2O
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O
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Ts
2a, 87%
Ts
Ts
2b, 89%
2c, 79%
O
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Br
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Ts
Ts
Ts
2f, 80%
O
Cl
2d, 80%
2e, 73%
O
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Cl
Ts
Ts
Ts
F
Cl
2g, 82%
2h, 90%
2i, 78%
O
OMe O
O
MeO
MeO
Ts
Ts
2j, 88%
Ts
2l, 62%b
2k, 83%
O
F
O
O
Cl
Ts
Ts
Br
Ts
2m, 78%
2n, 52%
2o, 80%
O
O
O
Ts
O
Ts
S
Ts
2r, 70%c
2p, 88%
2q, 85%
O
O
O
Ts
Ts
Ts
2s, 52%
2t, 54%
2u, 20%
a Reaction conditions: 1 (0.3 mmol), TosMIC (0.9 mmol), Cs2CO3 (1.2 equiv), Cu(OTf)2 (5 mol %), H2O (3 equiv),
and toluene (2 mL) at 70 °C for 20 h. b At 100 °C for 42 h. c In 2 mL 1,4ꢀdioxane for 12 h.
78 and 88% yields, respectively. When 3,4ꢀdimethoxylꢀsubstituted phenyl is contained, 83% yield of 2k was
obtained. As expected for substitution reactions, increasing the steric hindrance at the αꢀcarbon lowers the
efficiency of the reaction, and 2l was formed in a decreased yield of 62% when an isopropyl is attached to this
carbon. A chloride substitutent at the end of the alkyl chain does not disturb the reaction, and 2m was formed in 78%
yield. The phenyl group (R1) in the ketone substrate could be replaced with alkyl groups, thus 2n and 2o were
obtained in 52 and 80% yields, respectively. The lower efficiency for generation of 2n may be attributed to the
steric effect of the 2ꢀfluorophenyl group at the αꢀcarbon. The reactions of other aryl alkyl ketones were tested,
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which showed that good yields could be achieved in reactions affording products containing 1ꢀnaphthalenyl (2p),
2ꢀfuranyl (2q), and 2ꢀthiophenyl (2r) substituents. When tertiary bromides were used, substitution products 2s and
2t were obtained with moderate yields. The reaction of ketone with a primary bromide only afforded 2u in 20%
yield along with some unknown mixtures, indicating ketones with a primary bromide at the αꢀcarbon are too
reactive and thus are not compatible with the current conditions.
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Table 3. Reactions of αꢀBromo Esters and Amidesa
a Reaction conditions: 3 (0.3 mmol), TosMIC (0.9 mmol), Cs2CO3 (1.2 equiv), Cu(OTf)2 (5 mol %), H2O (3 equiv),
and toluene (2 mL) at 70 °C for 15 h. b In 2.0 mL dioxane for 9h.
After establishing the unique reactivity of TosMIC as a sulfonylating ageant in reactions with αꢀbromo ketones,
its reactions with other carbonyl compounds (3), such as esters and amides, were next studied (Table 3), and even
higher efficiency of the reactions was observed in several cases. In contrast to the relative lower reactivity of
αꢀphenyl substituted ketones (2c and 2n), the sulfonylation reactions of αꢀphenyl substituted esters gave rise to 4a
and 4b with yields around 90%. Substrates with αꢀphenyl groups of different electronic properties worked well
under the current condition, as good yields were obtained for reactions producing 4cꢀf. The obviously lower yield
of 4c than 4d suggested that the substrate is more reactive when the αꢀsubstituent is an electronꢀpoor aryl group.
The αꢀ1ꢀnaphthyl group containing substrates were compatible, generating 4g and 4h in 75% and 83% yields,
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respectively. These slightly decreased yields compared with 4a and 4b indicated that the reaction is marginally
influenced by steric effect of the 1ꢀnaphthyl group. When methyl 2ꢀbromohexanoate was used as a substrate, 4i was
obtained in 98% yield. High yields were also achieved with other ester derivatives with alkyl substituent at the
αꢀcarbon (4j and 4k). Interestingly, γꢀlactone could also be sulfonylated with TosMIC, albeit only moderate yield of
4l was obtained. The reaction could be applied to αꢀbromo amides, which lead to sulfonylation products 4m and 4n
in 70% and 90% yields, respectively.
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The reaction mechanism was next studied by control experiments. When the reaction of 1a and TosMIC was
run under conditions without water additive, only 24% of 2a was produced (Scheme 2a), demonstrating the
importance of water for realizing the reaction. It was assumed that the hydration of TosMIC to form intermediate A
may occur in the first step (Scheme 2b); however, when TosMIC was stirred under the standard condition, no A
was observed but only a small amount of dimerization product was found.13 Interestingly, if no Cu(OTf)2 and
Cs2CO3 were used in the reaction, hydration intermediate A could be isolated in 16% yield. Further investigation
indicated that a remarkably increased yield of A (81%) could be achieved when TosMIC was stirred in the absent
of Cs2CO3 (only 5 mol % Cu(OTf)2 and 1 equiv H2O were added). As expected, only trace amount of A was
observed if no water additive was used. The experiments in Scheme 2b clearly showed that the hydration of
TosMIC could occur in the reaction, but intermediate A is unstable in presence of Cs2CO3. Next, the reactions
between 1a and A were studied under different conditions (Scheme 2c). Under standard conditions, the reaction of
1a with A leads efficiently to 2a in 87%yield, confirming that A is an intermediate to the sulfonylation product. A
comparable yield of 85% was obtained if no Cu(OTf)2 catalyst was added, suggesting Cu(OTf)2 is not required for
the CꢀS bond cleavage and the substitution steps. Instead, the base additive was proved to be crucial for the
transformation from A, as no product was formed in the absence of Cs2CO3. Interestingly, water was found to have
some promoting effect on the formation of 2a from 1a and A, as notable decreasing of the yield to 53% was
observed when no water was added. In this case, an unexpected byproduct 5a was formed in 12% yield. The
structure of 5a suggests it may be resulted from Michael addition of product 2a to Nꢀmethyleneformamide, a
byꢀproduct generated from the CꢀS bond cleavage of A, under basic conditions. This assumption was supported by
the reaction between 2a and A under waterꢀfree condition (Scheme 2d), which gave rise to 5a in 28% yield.
Possibly, under standard conditions, the generated Nꢀmethyleneformamide was scavenged by facile reaction with
water, thus more product 2a was isolated.
Based on the above experiments, the plausible mechanism for the current transformation was outlined in
Scheme 3. In the first step, hydration of TosMIC to form A occurs under the catalysis of Lewis acidic Cu(OTf)2.
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Then, from formamide A, the CꢀS bond cleavage is mediated by Cs2CO3 to form celsium sulfinate and
Nꢀmethyleneformamide concurrently. The involvement of celsium sulfinate as an intermediate was supported by its
reaction with 1a without Cu(II) catalyst and water additive, which affords product 2a in 88% yield. Finally the
sulfonylation product 2 is generated by substitution of the αꢀbromo ketone 1 with sulfinate salt. Although reduced
yields were obtained in presence of radical scanvengers (given in SI), it is not unclear if the last step occurs via a
radical or ionic mechanism because decomposition of the bromide starting materials may occur when exposed to
radicals. 14
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Scheme 2. Experiments for Mechanistic Study
Scheme 3. Plausible Mechanism
H
Cu(OTf)2
Ts
N
TosMIC + H2O
Cs2CO3
CHO
A
(Isocyanide hydration)
1
p-MePhSO2Cs
2
N
CHO
(C-S bond cleavage)
(Substitution)
To better understand the details for the Cu(OTf)2ꢀcatalyzed isocyanide hydration and Cs2CO3ꢀmediated CꢀS
bond cleavage processes, DFT calculations15 at the M062X/6ꢀ31+G(d)/SDD level were performed (Scheme 4). For
the hydration step, the uncatalyzed reaction between TosMIC and a water cluster via TS1 requires an activation free
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energy of 30.4 kcal/mol (Scheme 4a). When the isocyanide moiety is σꢀcoordinated to Cu(OTf)2, the addition of
water occurs via TS2 with a reduced barrier of 28.5 kcal/mol (Scheme 4a), showing the hydration is catalyzed by
Lewis acidic Cu(II) salt. In experiments no αꢀsubstitution of TosMIC (or A) was observed, and consistently,
calculated reaction free energies in Scheme 4c showed that the deprotonation of the methylene in A by Cs2CO3 to
form A1 (Cꢀmetalation, 0.9 kcal/mol) was much less favorable thermodynamically than the deprotonation of the
amide moiety to form A2 (Nꢀmetalation, ꢀ14.7 kcal/mol). From A2, the CꢀS bond cleavage could be realized via
TSA2 with a very small activation barrier of 5.9 kcal/mol (Scheme 4d), in good agreement with the facile
decomposition of intermediate A in presence of Cs2CO3. In sharp contrast, the direct CꢀS bond cleavage from A
requires much higher activation energy of 35.8 kcal/mol (TSA, Scheme 4e). The geometric structure of TSA2
(given in SI) shows that the Cs atom has strong interactions with both the sulfinate and formamide moieties, thus
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facilitating the CꢀS bond cleavage.
Scheme 4. Computational Results15
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3. CONCLUSION
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In summary, we found a new type of reaction of TosMIC with a wide range of αꢀbromo carbonyl compounds
including ketones, esters, and amides, in which for the first time TosMIC acts implicitly as a sulfonylating agent.
Mechanistic studies by control experiments and DFT calculations suggested that the reaction is initiated by
Cu(OTf)2ꢀcatalyzed hydration of TosMIC to form a formamide intermediate, which undergoes facile CꢀS bond
cleavage under the mediation of Cs2CO3, and finally the in situ generated sulfinate salt is trapped by αꢀbromo
carbonyl compound to afford αꢀsulfonated ketones, esters, and amides. Novel transformations involving efficient
CꢀS bond cleavage/formation are ongoing in our laboratory.
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4. EXPERIMENTAL SECTION
General Information. All reactions were conducted under nitrogen atmosphere. Toluene and dioxane solvents
were distilled by standard procedures. TosMIC, 1a, 1n, 1u, 3i, and 3l were purchased from commercial available
resources and were used as received. All other αꢀbromo ketones were synthesized according to literature method.
Column chromatography was performed using 200−300 mesh silica with the proper solvent system according to
TLC analysis using UV light to visualize the reaction components. Nuclear magnetic resonance spectra were
recorded on a 500 MHz spectrometer (1H: 500 MHz, 13C: 125 MHz), using CDCl3 as the solvent with
tetramethylsilane (TMS) as an internal standard at room temperature. NMR data were reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, and brs = broad singlet), coupling constant in
Hz, and integration. Chemical shifts for 13C NMR spectra were recorded in parts per million from tetramethylsilane
using the central peak of deuterochloroform (77.0 ppm) as the internal standard. High resolution mass spectra were
recorded on an ESIꢀQꢀTOF mass spectrometer. Melting points were measured on X4 melting point apparatus.
Typical Procedure for the Preparation of 2-Bromo-1-phenylbutan-1-one 1b. To a 50 mL flask changed with a
magnetic stirring bar were added 1ꢀphenylbutanꢀ1ꢀone (3 mmol) and DCM solvent (5 mL). Br2 (mg, 3.3 mmol) was
first diluted in DCM (5 mL) and then transferred dropwisely to the ketone solution at room temperature. After the
reaction being stirred overnight, the mixture was poured into ethyl acetate (20 mL), which was washed with
saturated NaHCO3 (15 mL), saturated Na2S2O3 (15 mL), and brine (15 mL). The combined organic layers were
dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography
(petroleum ether/ethyl acetate) to afford 2b as a colorless liquid. All other αꢀbromoketones were prepared by
similar procedures except for 2o, which was prepared by reaction of heptanꢀ4ꢀone with NBS.
2-Bromo-1-phenylbutan-1-one (1b)16a:colorless liquid;1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.4 Hz, 2H),
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7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 5.08 (dd, J = 7.4, 6.7 Hz, 1H), 2.29–2.20 (m, J = 14.3, 7.2 Hz, 1H),
2.19–2.09 (m, J = 14.8, 7.4 Hz, 1H), 1.09 (t, J = 7.3 Hz, 3H).
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2-Bromo-1,2-diphenylethanone (1c)16b: white solid; H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.3 Hz, 2H),
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7.59–7.49 (m, 3H), 7.44 (t, J = 7.8 Hz, 2H), 7.40–7.28 (m, 3H), 6.38 (s, 1H).
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2-Bromo-1-(4-chlorophenyl)propan-1-one (1d)16c: white solid; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz,
2H), 7.47 (d, J = 8.7 Hz, 2H), 5.23 (q, J = 6.6 Hz, 1H), 1.90 (d, J = 6.6 Hz, 3H).
2-Bromo-1-(3-chlorophenyl)propan-1-one (1e)16c: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H),
7.89 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.0, 0.9 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 5.22 (q, J = 6.6 Hz, 1H).
2-Bromo-1-(2-bromophenyl)hexan-1-one (1f): faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0
Hz, 1H), 7.49 (dd, J = 7.6, 1.6 Hz, 1H), 7.41–7.36 (m, 1H), 7.35–7.29 (m, 1H), 5.09 (dd, J = 8.5, 5.7 Hz, 1H),
2.29–2.18 (m, 1H), 2.15–2.02 (m, 1H), 1.63–1.53 (m, 1H), 1.52–1.32 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz; CDCl3) δ 197.1, 139.7, 133.4, 131.9, 130.1, 127.4, 118.7, 52.0, 32.6, 29.4, 22.2, 13.8; HRMS (ESI)
calcd for C12H15Br2O+ ([M + H]+): 332.9484, found 332.9487.
2-Bromo-1-(2-fluorophenyl)propan-1-one (1g)16a: faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.90 (td, J =
7.7, 1.5 Hz, 1H), 7.55 (dd, J = 14.6, 7.7 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 10.8, 8.9 Hz, 1H), 5.30 (q, J
= 6.7 Hz, 1H), 1.90 (d, J = 6.6 Hz, 3H).
2-Bromo-1-(3,4-dichlorophenyl)butan-1-one (1h)16d: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J =
2.1 Hz, 1H), 7.84 (dd, J = 8.4, 2.1 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 4.95 (dd, J = 7.8, 6.3 Hz, 1H), 2.27–2.09 (m,
2H), 1.09 (t, J = 7.3 Hz, 3H).
2-Bromo-1-p-tolylpropan-1-one (1i)16e: white solid; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.29
(d, J = 8.0 Hz, 2H), 5.28 (q, J = 6.6 Hz, 1H), 2.43 (s, 3H), 1.90 (d, J = 6.6 Hz, 3H).
2-Bromo-1-(2-methoxyphenyl)butan-1-one (1j): colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 7.7,
1.6 Hz, 1H), 7.51–7.45 (m, 1H), 7.05–6.94 (m, 2H), 5.34 (dd, J = 7.9, 5.9 Hz, 1H), 3.91 (s, 3H), 2.29–2.18 (m, 1H),
2.08–1.98 (m, 1H), 1.08 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 196.3, 158.0, 133.9, 131.5, 126.3,
+
121.0, 111.6, 55.7, 55.6, 27.1, 12.2; HRMS (ESI) calcd for C11H13BrNaO2 ([M + Na]+): 278.9991, found
278.0004.
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2-Bromo-1-(3,4-dimethoxyphenyl)butan-1-one (1k)16f: white solid; H NMR (500 MHz, CDCl3) δ 7.65 (dd, J =
8.4, 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 7.5, 6.7 Hz, 1H), 3.97 (s, 3H),
3.95 (s, 3H), 2.23 (dq, J = 14.1, 7.1 Hz, 1H), 2.15 (dq, J = 14.6, 7.4 Hz, 1H), 1.08 (t, J = 7.3 Hz, 3H).
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2-Bromo-3-methyl-1-phenylbutan-1-one (1l)16a: white solid; H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 7.3 Hz,
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2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 4.94 (d, J = 8.6 Hz, 1H), 2.54–2.41 (m, 1H), 1.22 (d, J = 6.6
Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H).
2-Bromo-1-(4-bromophenyl)-4-chlorobutan-1-one (1m): white solid; m.p. 91–93 oC; 1H NMR (500 MHz, CDCl3)
δ 7.90 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 5.41 (dd, J = 8.1, 5.8 Hz, 1H), 3.90–3.70 (m, 2H), 2.56 (dd, J =
8.2, 5.2 Hz, 2H). 13C NMR (125 MHz; CDCl3) δ 191.5, 132.8, 132.2, 130.4, 129.3, 43.5, 42.3, 35.6; HRMS (ESI)
calcd for C10H10Br2ClO+ ([M + H]+): 338.8781, found 338.8783.
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3-Bromoheptan-4-one (1o)16g: colorless liquid; H NMR (500 MHz, CDCl3) δ 4.19 (dd, J = 8.0, 6.4 Hz, 1H),
2.72–2.57 (m, 2H), 2.09–2.01 (m, 1H), 2.00–1.90 (m, 1H), 1.69– 1.61 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.94 (t, J =
7.4 Hz, 3H).
2-Bromo-1-(naphthalen-1-yl)butan-1-one (1p): faint yellow solid; 1H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 8.6
Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.92–7.83 (m, 2H), 7.66–7.46 (m, 3H), 5.14 (dd, J = 7.5, 6.6 Hz, 1H), 2.39–2.28
(m, 1H), 2.22–2.12 (m, 1H), 1.13 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 196.6, 134.4, 134.0, 133.2,
130.8, 128.5, 128.2, 126.8, 125.6, 124.2, 53.2, 27.3, 12.2; HRMS (ESI) calcd for C14H14BrO+ ([M + H]+): 277.0223,
found 277.0222.
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2-Bromo-1-(furan-2-yl)butan-1-one (1q)16h: brown liquid; H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 1.0 Hz,
1H), 7.34 (d, J = 3.4 Hz, 1H), 6.60 (dd, J = 3.6, 1.7 Hz, 1H), 4.94 (dd, J = 7.7, 6.7 Hz, 1H), 2.26–2.16 (m, 1H),
2.15–2.05 (m, 1H), 1.07 (t, J = 7.3 Hz, 3H).
2-Bromo-1-(thiophen-2-yl)butan-1-one (1r)16i: faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J =
3.8, 0.9 Hz, 1H), 7.71 (dd, J = 4.9, 1.0 Hz, 1H), 7.17 (dd, J = 4.9, 3.9 Hz, 1H), 4.92 (dd, J = 7.6, 6.7 Hz, 1H),
2.29–2.19 (m, 1H), 2.18–2.07 (m, 1H), 1.08 (t, J = 7.3 Hz, 3H).
2-Bromo-2-methyl-1-phenylpropan-1-one (1s)16e: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.3
Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 2.03 (s, 6H).
(1-Bromocyclopentyl)(phenyl)methanone (1t)16j: white solid; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.5 Hz,
2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 2.58–2.38 (m, 4H), 2.07 (dd, J = 11.9, 5.1 Hz, 2H), 1.80 (t, J
= 7.2 Hz, 2H).
Typical Procedure for the Preparation of phenethyl 2-bromo-2-phenylacetate 3a. The phenethyl
2ꢀphenylacetate (9 mmol), AIBN (73.9 mg, 0.45 mmol ) and 20 mL CCl4 were placed in a 50 mL flask equipped
with a magnetic stir bar. After the reaction was stirred overnight at 70 oC, the precipitation was filtered and washed
with CCl4. Then the filtrate was evaporated under vacuum and the residue was purified by flash column
chromatography (petroleum ether/ethyl acetate) to afford the desired product 3a. Other αꢀbromo esters and amides
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were prepared from the corresponding ester and amide precursors by similar procedures.
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Phenethyl 2-bromo-2-phenylacetate (3a): white solid; m.p. 37 – 38 oC ; 1H NMR (500 MHz, CDCl3) δ 7.51–7.45
(m, 2H), 7.36–7.30 (m, 3H), 7.27–7.18 (m, 3H), 7.14 (d, J = 7.0 Hz, 2H), 5.32 (s, 1H), 4.38 (t, J = 7.0 Hz, 2H),
2.94 (t, J = 6.9 Hz, 2H); 13C NMR (125 MHz; CDCl3) δ 168.2, 137.2, 135.8, 129.2, 128.9, 128.8, 128.7, 128.6,
126.7, 66.8, 46.9, 34.8; HRMS (ESI) calcd for C16H16BrO2+ ([M + H]+): 319.0328, found 319.0327.
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Ethyl 2-bromo-2-phenylacetate (3b)16k: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.57–7.30 (m, 5H), 5.34
(s, 1H), 4.30–4.17 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).
Cyclohexyl 2-bromo-2-(4-methoxyphenyl)acetate (3c): faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J
= 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.32 (s, 1H), 4.92–4.73 (m, 1H), 3.80 (s, 3H), 1.90–1.75 (m, 2H),
1.76–1.64 (m, 2H), 1.55–1.40 (m, 3H), 1.39–1.22 (m, 3H); 13C NMR (125 MHz; CDCl3) δ 167.8, 160.2, 130.1,
128.1, 114.2, 74.7, 55.3, 47.3, 31.1, 25.3, 23.4, 23.4; HRMS (ESI) calcd for C15H19BrNaO3+ ([M + Na]+): 349.0410,
found 349.0413.
Cyclohexyl 2-bromo-2-(4-chlorophenyl)acetate (3d): faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.49 (d,
J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 5.28 (s, 1H), 4.87–4.80 (m, 1H), 1.89–1.75 (m, 2H), 1.75–1.62 (m, 2H),
1.55–1.40 (m, 3H), 1.40–1.24 (m, 3H); 13C NMR (125 MHz; CDCl3) δ 167.4, 135.2, 134.6, 130.1, 128.9, 75.1, 46.2,
31.1, 25.2, 23.4, 23.3; HRMS (ESI) calcd for C14H17BrClO2+ ([M + H]+): 331.0095, found 331.0103.
Ethyl 2-bromo-2-(4-methoxyphenyl)acetate (3e)16k: faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J
= 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.33 (s, 1H), 4.33–4.17 (m, 2H), 3.80 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).
Ethyl 2-bromo-2-(4-chlorophenyl)acetate (3f)16k: faint yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J =
8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.30 (s, 1H), 4.28–4.19 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).
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Benzyl 2-bromo-2-(naphthalen-1-yl)acetate (3g)16l: faint yellow solid; m.p. 42–43 C; H NMR (500 MHz,
CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 13.8, 8.2 Hz, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.59–7.46 (m, 2H),
7.41 (t, J = 7.7 Hz, 1H), 7.33–7.20 (m, 5H), 6.19 (s, 1H), 5.22 (q, J = 12.3 Hz, 2H); 13C NMR (125 MHz; CDCl3) δ
168.2, 134.9, 134.0, 131.5, 130.4,130.2, 129.1, 128.6, 128.5, 128.3,127.3, 126.9, 126.2, 125.4, 123.1, 68.3, 45.2;
HRMS (ESI) calcd for C19H15BrNaO2+ ([M + Na]+): 377.0148, found 377.0150.
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Ethyl 2-bromo-2-(naphthalen-1-yl)acetate (3h): faint yellow liquid; H NMR (500 MHz, CDCl3) δ 8.11 (d, J =
8.5 Hz, 1H), 7.86 (dd, J = 12.9, 8.2 Hz, 2H), 7.79 (d, J = 7.2 Hz, 1H), 7.61–7.57 (m, 1H), 7.51 (t, J = 7.1 Hz, 1H),
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7.47–7.42 (m, 1H), 6.15 (s, 1H), 4.30–4.21 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H).
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Phenethyl 2-bromohexanoate (3j): colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.33–7.27 (m, 2H), 7.26–7.20
(m, 3H), 4.39 (td, J = 7.0, 3.2 Hz, 2H), 4.18 (t, J = 7.4 Hz, 1H), 2.98 (t, J = 7.0 Hz, 2H), 2.08–1.87 (m, 2H),
1.44–1.22 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 169.8, 137.4, 128.9, 128.5, 126.7, 66.2,
46.1, 34.9, 34.7, 29.3, 22.0, 13.8; HRMS (ESI) calcd for C14H20BrO2+ ([M + H]+): 299.0641, found 299.0645.
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Benzyl 2-bromohexanoate (3k)16m: colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.42–7.30 (m, 5H), 5.20 (s,
2H), 4.25 (t, J = 7.4 Hz, 1H), 2.16–2.04 (m, 1H), 2.04–1.94 (m, 1H), 1.50–1.22 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H).
2-Bromo-N-methyl-N,2-diphenylacetamide (3m)16n: white solid; 1H NMR (500 MHz, CDCl3) δ 7.49–7.08 (m,
10H), 5.33 (s, 1H), 3.29 (s, 3H).
2-Bromo-N-methyl-N-phenylhexanamide (3n): colorless liquid; 1H NMR (500 MHz, CDCl3) δ 7.46 (t, J = 7.6 Hz,
2H), 7.40 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 4.08 (t, J = 7.4 Hz, 1H), 3.31 (s, 3H), 2.20–2.05 (m, 1H),
1.98–1.84 (m, 1H), 1.33–1.15 (m, 4H), 0.85 (t, J = 6.3 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 169.2, 143.0, 130.0,
128.5, 127.2, 44.2, 38.0, 35.1, 29.5, 22.1, 13.8; HRMS (ESI) calcd for C13H18BrNNaO+ ([M + Na]+): 306.0464,
found 306.0484.
Typical Procedure for Synthesis of 1-phenyl-2-tosylpropan-1-one 2a by Cu(OTf)2-Catalyzed Reaction between
TosMIC and 2-bromo-1-phenylpropan-1-one 1a. To a flameꢀdried Schlenk tube changed with a magnetic stirring
bar was added 1a (63.5 mg, 0.3 mmol), TosMIC (175.7 mg, 0.9 mmol), Cu(OTf)2 (5.4 mg, 0.015 mmol), Cs2CO3
(117.3 mg, 0.36 mmol), H2O (16.2 ꢁl, 0.9 mmol), and toluene (2 ml) under nitrogen atmosphere. The reaction
mixture was stirred at 70°C for 20 h. The mixture was quenched with saturated NH4Cl (15 ml) and then extracted
with ethyl acetate (15 ml x 3). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under
vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate or
cyclohexane/dichloromethane/ethylacetate) to afford product 2a (74.6 mg, 87% yield) as a white solid.
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1-phenyl-2-tosylpropan-1-one (2a). Obtained as a white solid (74.6 mg, 87%); m.p. 93–95 C; H NMR (500
MHz; CDCl3): δ 7.98 (d, J = 7.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 7.4 Hz, 1H) 7.49–7.46 (m, 2H) 7.31
(d, J = 8.2 Hz, 2H), 5.15 (q, J = 6.9 Hz, 1H) 2.43 (s, 3H) 1.56 (d, J = 6.9Hz, 3H); 13C NMR (125 MHz; CDCl3) δ
192.6, 145.3, 136.3, 134.0, 133.1, 129.8, 129.5, 129.2, 128.7, 65.1, 21.7, 13.2; HRMS (ESI) calcd for C16H17O3S+
( [M + H]+): 289.0893, found 289.0895.
1-phenyl-2-tosylbutan-1-one (2b). Obtained as a white solid (72.8 mg, 89%); m.p. 73–74 oC; 1H NMR (500 MHz,
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CDCl3) δ 7.97 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.29
(d, J = 8.2 Hz, 2H), 5.01 (dd, J = 10.8, 3.6 Hz, 1H), 2.41 (s, 3H), 2.20–2.18 (m, 1H), 2.09–2.00 (m, 1H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 192.8, 145.3, 137.5, 133.9, 133.6, 129.8, 129.5, 129.0, 128.7, 71.5,
22.0, 21.6, 11.5; HRMS (ESI) calcd for C17H19O3S+ ([M + H]+): 303.1049, found 303.1049.
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1,2-diphenyl-2-tosylethanone (2c). Obtained as a white solid (83.0 mg, 79%); m.p. 145–146 C; 1H NMR (500
MHz; CDCl3): δ 7.87 (d, J = 7.8 Hz, 2H), 7.54–7.25 (m, 10H), 7.19 (d, J = 8.0 Hz, 2H), 6.15 (s, 1H), 2.39 (s, 3H);
13C NMR (125 MHz; CDCl3) δ 190.8, 145.0, 136.1, 134.0, 133.9, 130.5, 130.3, 129.6, 129.1, 128.9, 128.8, 128.8,
128.7, 76.1, 21.7; HRMS (ESI) calcd for C21H19O3S+ ([M + H]+): 351.1049, found 351.1052.
1-(4-chlorophenyl)-2-tosylpropan-1-one (2d). Obtained as a white solid (76.5 mg, 80%); m.p. 126–127 C; 1H
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NMR (500 MHz; CDCl3): δ 7.93 (d, J = 8.4 Hz, 2H)，7.63 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.31 (d, J =
8.0 Hz, 2H) 5.10 (q, J = 6.9 Hz, 1H), 2.43 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 191.4,
145.5, 140.7, 134.7, 132.9, 130.6, 129.8, 129.6, 129.1, 65.2, 21.7, 13.1; HRMS (ESI) calcd for C16H16ClO3S+ ([M +
H]+): 323.0503, found 323.0506.
1-(3-chlorophenyl)-2-tosylpropan-1-one (2e). Obtained as a white solid (71.1 mg, 73%); m.p. 105 – 106 C;1H
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NMR (500 MHz, CDCl3) δ 7.90–7.84 (m, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.58–7.52 (m, 1H), 7.42 (t, J = 8.2 Hz, 1H),
7.31 (d, J = 8.1 Hz, 2H), 5.08 (q, J = 6.9 Hz, 1H), 2.43 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 191.5, 145.6, 137.8, 135.1, 133.8, 133.0, 130.0, 129.8, 129.6, 129.0, 127.3, 65.3, 21.7, 13.0; HRMS (ESI)
calcd for C16H16ClO3S+ ([M + H]+): 323.0503, found 323.0510.
1-(2-bromophenyl)-2-tosylhexan-1-one (2f). Obtained as a white solid (96.5 mg, 80%); m.p. 93–94 oC; 1H NMR
(500 MHz; CDCl3) δ 7.76–7.67 (m, 3H), 7.63 (d, J = 8.0 Hz, 1H), 7.45–7.30(m, 4H), 5.05 (dd, J = 10.0, 4.3 Hz,
1H), 2.45 (s, 3H), 2.09–1.98 (m, 2H), 1.41 – 1.24 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ
194.6, 145.3, 139.8, 134.4, 133.6, 132.8, 130.9, 129.8, 129.6, 127.5, 120.0, 73.4, 29.0, 28.3, 22.5, 21.7, 13.6;
HRMS (ESI) calcd for C19H22BrO3S+ ([M + H]+): 409.0468, found 409.0469.
1-(2-fluorophenyl)-2-tosylpropan-1-one (2g). Obtained as a white solid (75.5 mg, 82%); m.p. 83–84 oC; 1H NMR
(500 MHz; CDCl3) δ 7.77–7.74 (m, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.56–7.51 (m, 1H), 7.29 (dd, J = 8.1 Hz, 2H),
7.25–7.20 (m, 1H), 7.12–7.08 (m, 1H), 5.20 – 5.15 (m, 1H), 2.42 (s, 3H), 1.57 (d, J = 6.9 Hz); 13C NMR (125 MHz;
CDCl3) δ 191.1 (d, J = 3.8 Hz), 161.5 (d, J = 252.5 Hz), 145.2, 135.4 (d, J = 8.8 Hz), 133.8, 131.1 (d, J = 1.3 Hz),
129.6, 129.5, 125.7 (d, J = 11.3 Hz), 124.7 (d, J = 2.5 Hz), 116.7 (d, J = 23.8 Hz), 69.2 (d, J = 8.8 Hz), 21.6, 12.4;
HRMS (ESI) calcd for C16H16FO3S+ ([M + H]+): 307.0799, found 307.0796.
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1-(3,4-dichlorophenyl)-2-tosylbutan-1-one (2h). Obtained as a yellow solid (90.0 mg, 90%); m.p. 131–132 C;
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1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.65–7.55 (m, 3H), 7.32 (d,
J = 8.1 Hz, 2H), 4.87 (dd, J = 10.9, 3.5 Hz, 1H), 2.45 (s, 3H), 2.20–2.10 (m, 1H), 2.08–1.98 (m, 1H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 190.7, 145.7, 138.8, 136.9, 133.6, 133.2, 130.9, 130.8, 129.7, 129.6,
128.0, 71.9, 21.8, 21.7, 11.5; HRMS (ESI) calcd for C17H16Cl2O3SNa+ ([M + Na]+): 393.0089, found 393.0098.
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1-p-tolyl-2-tosylpropan-1-one (2i). Obtained as a white solid (70.6 mg, 78%); m.p. 104–105 C; H NMR (500
MHz; CDCl3): δ 7.88 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.31–7.26 (m , 4H), 5.13 (q, J = 6.6 Hz, 1H),
2.46–2.37 (m, 6H), 1.54 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 192.1, 145.3, 145.2, 133.9, 133.1,
129.8, 129.5, 129.4, 129.4, 64.9, 21.7, 21.7, 13.2; HRMS (ESI) calcd for C17H19O3S+ ([M + H]+): 303.1049, found
303.1049.
1-(2-methoxyphenyl)-2-tosylbutan-1-one (2j). Obtained as a white solid (84.3 mg, 88%); m.p. 106 – 107 C; 1H
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NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.57 (dd, J = 7.7, 1.8 Hz, 1H), 7.47–7.42 (m, 1H), 7.24 (d, J =
8.1 Hz, 2H), 6.99–6.93 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.47 (dd, J = 10.0, 4.3 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H),
2.15–2.03 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 194.5, 158.4, 144.8, 134.5, 134.5,
131.1, 129.5, 129.3, 128.3, 120.9, 111.8, 75.1, 55.6, 21.6, 21.6, 11.6; HRMS (ESI) calcd for C18H21O4S+ ([M + H]+):
333.1155, found 333.1142.
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1-(3,4-dimethoxyphenyl)-2-tosylbutan-1-one (2k). Obtained as a white solid (88.7 mg, 83%); m.p. 163–164 C;
1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 3H), 7.51 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.4 Hz,
1H), 4.94 (dd, J = 10.9, 3.5 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 2.44 (s, 3H), 2.20–2.10(m, 1H), 2.07–1.95 (m, 1H),
0.87 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 190.7, 154.3, 149.2, 145.2, 133.6, 130.7, 129.8, 129.4,
124.5, 110.6, 110.1, 71.1, 56.2, 56.0, 22.1, 21.7, 11.5; HRMS (ESI) calcd for C19H23O5S+ ([M + H]+): 363.1261,
found 363.1261.
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3-methyl-1-phenyl-2-tosylbutan-1-one (2l). Obtained as a white solid (58.4 mg, 62%); m.p. 81–82 C; H NMR
(500 MHz; CDCl3) δ 7.81 (d, J = 7.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 2H), 7.43–7.39 (m, 2H),
7.23 (d, 8.1 Hz, 2H), 4.87 (d, J = 9.1 Hz, 1H), 2.60–2.49 (m, 1H), 2.36 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H), 0.89 (d, J
= 6.6 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 193.9, 145.0, 137.8, 135.1, 133.6. 129.8, 129.4, 128.7, 128.6, 76.3,
29.6, 21.5, 21.4, 21.0; HRMS (ESI) calcd for C18H21O3S+ ([M + H]+): 317.1206, found 317.1207.
1-(4-bromophenyl)-4-chloro-2-tosylbutan-1-one (2m). Obtained as a white solid (97.2 mg, 78%); m.p. 145–146
oC; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.7 Hz, 2H), 7.60 (t, J = 8.5 Hz, 4H), 7.29 (d, J = 8.0 Hz, 2H), 5.35
(dd, J = 8.1, 5.8 Hz, 1H), 3.73–3.60 (m, 1H), 3.40–3.26 (m, 1H), 2.62–2.49 (m, 2H), 2.43 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 190.9, 145.9, 135.5, 133.2, 132.1, 130.6, 129.8, 129.8, 129.6, 67.4, 41.6, 30.5, 21.7; HRMS (ESI)
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calcd for C17H17BrClO3S+ ([M + H]+): 414.9765, found 414.9764.
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1-cyclopropyl-2-(2-fluorophenyl)-2-tosylethanone (2n). Obtained as a white solid (49.3 mg, 52%); m.p. 144–146
oC; 1H NMR (500 MHz; CDCl3) δ 7.64–7.61 (m, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.36–7.32 (m, 1H), 7.22 (d, J = 7.6
Hz, 2H), 7.16–7.13 (m, 1H), 7.00–6.95 (m, 1H), 5.86 (s, 1H), 2.41 (s, 3H), 2.19–2.18 (m, 1H), 1.25–0.94 (m, 4H);
13C NMR (125 MHz; CDCl3) δ 199.2, 160.9 (d, J = 248.8 Hz), 145.2, 134.6, 131.6 (d, J = 1.3 Hz), 131.2 (d, J = 8.8
Hz), 129.4, 129.3, 124.3 (d, J = 3.8 Hz), 116.2 (d, J = 13.8 Hz), 115.3 (d, J = 22.5 Hz), 71.5 (d, J = 1.3), 22.6, 21.6,
13.1, 13.1; HRMS (ESI) calcd for C18H18FO3S+ ([M + H]+): 333.0955, found 333.0971.
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3-tosylheptan-4-one (2o). Obtained as a white solid (62.3 mg, 80%); m.p. 64–65 oC; 1H NMR (500 MHz; CDCl3)
δ 7.65 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 4.05–3.96 (m, 1H), 2.88–2.77 (m, 1H), 2.62ꢀ2.50 (m, 1H), 2.45
(s, 3H), 1.98–1.79 (m, 2H), 1.61 (dt, J = 10.4, 6.9 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C
NMR (125 MHz; CDCl3) δ 202.4, 145.3, 133.6, 129.6, 129.4, 76.6, 47.0, 21.6, 20.8, 16.6, 13.4, 11.4; HRMS (ESI)
calcd for C14H21O3S+ ([M + H]+): 269.1206, found 269.1205.
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1-(naphthalen-1-yl)-2-tosylbutan-1-one (2p). Obtained as a white solid (93.1 mg, 88%); m.p. 129–131 C; H
NMR (500 MHz, CDCl3) δ 8.52 (d, J = 8.5 Hz, 1H), 8.04 (dd, J = 12.4, 7.8 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.69
(d, J = 8.2 Hz, 2H), 7.61–7.50 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 5.04 (dd, J = 10.8, 3.8 Hz, 1H), 2.39 (s, 3H),
2.29–2.10 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 195.2, 145.2, 135.8, 134.0, 134.0,
133.9, 130.1, 129.7, 129.5, 128.6, 128.5, 126.8, 125.5, 124.3, 74.8, 22.4, 21.6, 11.6; HRMS (ESI) calcd for
C21H21O3S+ ([M + H]+): 353.1206, found 353.1205.
1-(furan-2-yl)-2-tosylbutan-1-one (2q). Obtained as a yellow solid (73.7 mg, 85%); m.p. 116 – 117 oC; 1H NMR
(500 MHz; CDCl3) δ 7.71–7.59 (m, 3H), 7.34–7.28 (m, 3H), 6.60–6.53 (m, 1H), 4.82–4.74 (m, 1H), 2.42 (m, 3H),
2.18–2.08 (m, 1H), 2.07–1.97 (m, 1H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 180.3, 153.0, 147.9,
145.2, 133.8, 129.6, 129.5, 119.7, 113.0, 72.3, 21.6, 21.0, 11.4; HRMS (ESI) calcd for C15H17O4S+ ([M + H]+):
293.0842, found 293.0855.
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1-(thiophen-2-yl)-2-tosylbutan-1-one (2r). Obtained as a yellow solid (64.0 mg, 70%); m.p. 107–108 C; 1H
NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 3.9, 1.0 Hz, 1H), 7.73 (dd, J = 4.9, 1.0 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 7.16 (dd, J = 4.9, 3.9 Hz, 1H), 4.71 (dd, J = 11.0, 3.6 Hz, 1H), 2.42 (s, 3H), 2.20–2.11 (m,
1H), 2.03 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 184.6, 145.3, 144.8, 135.9, 134.3, 133.4,
129.8, 129.5, 128.6, 73.7, 21.7, 11.5; HRMS (ESI) calcd for C15H17O3S2+ ([M + H]+): 309.0614, found 309.0617.
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2-methyl-1-phenyl-2-tosylpropan-1-one (2s). Obtained as a faint yellow liquid (47.7 mg, 52%); H NMR (500
MHz, CDCl3) δ 7.93 (d, J = 7.5 Hz, 2H), 7.67 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H),
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7.31 (d, J = 7.7 Hz, 2H), 2.44 (s, 3H), 1.69 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 199.4, 145.2, 137.8, 132.3,
132.0, 130.5, 129.4, 128.9, 128.2, 73.3, 22.6, 21.7; HRMS (ESI) calcd for C17H19O3S+ ([M + H]+): 303.1049, found
303.1048.
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Phenyl(1-tosylcyclopentyl)methanone (2t). Obtained as a colorless liquid (52.9 mg, 54%); H NMR (500 MHz,
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CDCl3) δ 8.07 (d, J = 7.2 Hz, 2H), 7.61–7.51 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 2.72–2.64
(m, 2H), 2.49–2.39 (m, 5H), 1.91–1.80 (m, 2H), 1.59–1.48 (m, 2H); 13C NMR (125 MHz; CDCl3): 197.8, 145.1,
136.2, 133.0, 132.6, 130.3, 130.1, 129.3, 128.1, 84.3, 34.5, 26.0, 21.7; HRMS (ESI) calcd for C19H21O3S+ ([M +
H]+): 329.1206, found 329.1205.
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1-phenyl-2-tosylethanone (2u). Obtained as a white solid (16.6 mg, 20%); m.p. 98–99 C; 1H NMR (500 MHz,
CDCl3) δ 7.95 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.34
(d, J = 8.0 Hz, 2H), 4.72 (s, 2H), 2.44 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 188.2, 145.4, 135.8, 135.8, 134.4,
129.9, 129.4, 128.9, 128.6, 63.6, 21.7; HRMS (ESI) calcd for C15H15O3S+ ([M + H]+): 275.0736, found 275.0738.
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Phenethyl 2-phenyl-2-tosylacetate (4a). Obtained as a white solid (104.1 mg, 91%); m.p. 113 114 C; H NMR
(500 MHz, CDCl3) δ 7.48–7.08 (m, 14H), 5.06 (s, 1H), 4.44–4.27 (m, 2H), 2.90 (t, J = 7.1 Hz, 2H), 2.40 (s, 3H);
13C NMR (125 MHz; CDCl3) δ 164.9, 145.3, 137.1, 133.6, 130.3, 130.0, 129.6, 129.2, 128.9, 128.6, 128.5, 128.0,
126.7, 75.4, 66.8, 34.8, 21.7; HRMS (ESI) calcd for C23H23O4S+ ([M + H]+): 395.1312, found 395.1313.
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Ethyl 2-phenyl-2-tosylacetate (4b). Obtained as a white solid (84.7 mg, 89%); m.p. 111–112 C; H NMR (500
MHz; CDCl3): δ 7.48 (d, J = 8.1 Hz, 2H), 7.38–7.26 (m, 5H), 7.21 (d, J = 8.1 Hz, 2H), 5.08 (s, 1H), 4.21–4.18 (m,
2H), 2.41 (s, 3H), 1.23(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 164.9, 145.2, 133.6, 130.3, 130.0, 129.6,
129.2, 128.5, 128.1, 75.3, 62.4, 21.7, 13.9; HRMS (ESI) calcd for C17H19O4S+ ([M + H]+): 319.0999, found
319.1015.
Cyclohexyl 2-(4-methoxyphenyl)-2-tosylacetate (4c). Obtained as a faint yellow solid (94.4 mg, 80%); m.p.
104–105 oC; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.3 Hz,
2H), 6.82 (d, J = 8.8 Hz, 2H), 5.00 (s, 1H), 4.87–4.75 (m, 1H), 3.80 (s, 3H), 2.42 (s, 3H), 1.87–1.61 (m, 4H),
1.53–1.23 (m, 6H); 13C NMR (125 MHz; CDCl3) δ 164.6, 160.6, 145.0, 133.8, 131.6, 129.9, 129.1, 120.1, 113.9,
75.1, 75.0, 55.3, 31.2, 31.1, 25.2, 23.5, 23.4, 21.6; HRMS (ESI) calcd for C22H27O5S+ ([M + H]+): 403.1574, found
403.1570.
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Cyclohexyl 2-(4-chlorophenyl)-2-tosylacetate (4d). Obtained as a white solid (112.4 mg, 94%); m.p. 89–90 C;
1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.3 Hz, 2H), 7.34–7.23 (m, 6H), 5.02 (s, 1H), 4.86–4.79 (m, 1H), 2.43 (s,
3H), 1.85–1.74 (m, 2H), 1.73–1.63 (m, 2H), 1.53–1.24 (m, 6H); 13C NMR (125 MHz; CDCl3) δ 164.0, 145.4, 135.8,
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133.5, 131.6, 129.9, 129.3, 128.7, 126.8, 75.4, 74.8, 31.1, 31.1, 25.2, 23.4, 23.4, 21.7; HRMS (ESI) calcd for
C21H24ClO4S+ ([M + H]+): 407.1078, found 407.1080.
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Ethyl 2-(4-methoxyphenyl)-2-tosylacetate (4e). Obtained as a white solid (84.2 mg, 80%); m.p. 147–148 C; 1H
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NMR (500 MHz; CDCl3) δ 7.49 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 6.82 (d, J =
8.5 Hz, 2H), 5.03 (s, 1H), 4.27–4.09 (m, 2H), 3.79 (s, 3H), 2.41 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz; CDCl3) δ 165.1, 160.7, 145.1, 133.7, 131.6, 129.9, 129.2, 119.9, 114.0, 74.7, 62.3, 55.3, 21.6, 13.9; HRMS
(ESI) calcd for C18H21O5S+ ([M + H]+): 349.1104, found 349.1104.
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Ethyl 2-(4-chlorophenyl)-2-tosylacetate (4f). Obtained as a white solid (87.2 mg, 82%); m.p. 134–135 C; H
NMR (500 MHz; CDCl3) δ 7.50 (d, J = 8.2 Hz, 2H), 7.33–7.24 (m, 6H), 5.04 (s, 1H), 4.27–4.14 (m, 2H), 2.43 (s,
3H), 1.23 (t, J = 7.1, 3H); 13C NMR (125 MHz; CDCl3) δ 164.6, 145.5, 135.9, 133.3, 131.6, 129.9, 129.3, 128.8,
126.6, 62.6, 21.7, 13.9; HRMS (ESI) calcd for C17H18ClO4S+ ([M + H]+): 353.0609, found 353.0625.
Benzyl 2-(naphthalen-1-yl)-2-tosylacetate (4g). Obtained as a brown solid (95.7 mg, 75%); m.p. 135–136 oC; 1H
NMR (500 MHz, CDCl3) δ 7.97–7.75 (m, 4H), 7.46 (d, J = 7.1 Hz, 4H), 7.37 (t, J = 7.7 Hz, 1H), 7.29 (s, 3H), 7.23
(s, 2H), 7.09 (d, J = 7.7 Hz, 2H), 6.10 (s, 1H), 5.25–5.07 (m, 2H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
165.3, 145.2, 134.7, 133.8, 133.7, 132.0, 130.4, 130.0, 129.2, 129.0, 128.8, 128.6, 128.5, 128.4, 127.1, 125.9, 124.9,
123.8, 122.6, 69.3, 68.1, 21.6; HRMS (ESI) calcd for C26H23O4S+ ([M + H]+): 431.1312, found 431.1320.
Ethyl 2-(naphthalen-1-yl)-2-tosylacetate (4h). Obtained as a faint yellow solid (88.2 mg, 83%); m.p. 136–137 oC;
1H NMR (500 MHz; CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H) 7.88–7.82 (m, 2H), 7.75 (d, J = 7.1 Hz, 1H), 7.51–7.365 (m,
5H), 7.13 (d, J = 8.0 Hz, 2H), 6.07 (s, 1H), 4.26–4.21 (m, 1H), 4.19–4.12 (m, 1H), 2.35 (s, 3H), 1.20 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz; CDCl3) δ 165.4, 145.2, 133.8, 133.7, 132.0, 130.3, 130.1,129.1, 129.0, 128.6, 127.0,
125.9, 124.9, 124.1, 122.6, 69.4, 62.5, 21.6, 13.9; HRMS (ESI) calcd for C21H21O4S+ ([M + H]+): 369.1155, found
369.1156.
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Methyl 2-tosylhexanoate (4i). Obtained as a white solid (81.3 mg, 98%); m.p. 46–47 C; H NMR (500 MHz;
CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 3.92 (dd, J = 11.3, 3.8 Hz, 1H), 3.68 (s, 3H), 2.46 (s,
3H), 2.05–1.88 (m, 2H), 1.33–1.23(m, 4H), 0.87 (t, J = 7.0 MHz, 3H); 13C NMR (125 MHz; CDCl3) δ 166.6, 145.3,
134.2, 129.6, 129.3, 71.0, 52.8, 29.0, 26.6, 22.1, 21.7, 13.6; HRMS (ESI) calcd for C14H21O4S+ ([M + H]+):
285.1155, found 285.1156.
Phenethyl 2-tosylhexanoate (4j). Obtained as a white solid (94.1 mg, 88%); m.p. 35 – 36 oC; 1H NMR (500 MHz,
CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.35–7.26 (m, 4H), 7.25–7.20 (m, 1H), 7.15 (d, J = 7.5 Hz, 2H), 4.34–4.20 (m,
2H), 3.88 (dd, J = 11.3, 3.3 Hz, 1H), 2.85 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.03–1.94 (m, 1H), 1.93–1.82 (m, 1H),
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1.30–1.10 (m, 4H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.1, 145.3, 137.2, 134.3, 129.6,
129.4, 128.8, 128.5, 126.7, 71.1, 66.4, 34.7, 28.9, 26.6, 22.1, 21.7, 13.6; HRMS (ESI) calcd for C21H27O4S+ ([M +
H]+): 375.1625, found 375.1626.
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Benzyl 2-tosylhexanoate (4k). Obtained as a white solid (90.5 mg, 89%); m.p. 49–50 C; H NMR (500 MHz,
CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.33 (s, 3H), 7.25 (m, 4H), 5.08 (q, J = 12.2 Hz, 2H), 3.94 (dd, J = 11.2, 3.4 Hz,
1H), 2.41 (s, 3H), 2.10–2.01 (m, 1H), 2.00–1.91 (m, 1H), 1.34–1.17 (m, 4H), 0.83 (t, J = 6.6 Hz, 3H); 13C NMR
(125 MHz; CDCl3) δ 166.1, 145.2, 134.8, 134.2, 129.6, 129.3, 128.5, 70.9, 67.7, 28.9, 26.5, 22.1, 21.7, 13.6;
HRMS (ESI) calcd for C20H25O4S+ ([M + H]+): 361.1468, found 361.1476.
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3-tosyldihydrofuran-2(3H)-one (4l). Obtained as a white solid (30.4 mg, 52%); m.p. 74–75 C; H NMR (500
MHz; CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 4.51–4.36 (m, 2H), 4.04–4.01 (m, 1H) ,
3.05–2.70 ( m, 2H) , 2.47 (s,3H); 13C NMR (125 MHz; CDCl3) δ 168.3, 146.1, 133.7, 130.0, 129.4, 67.1, 63.6, 24.0,
21.8; HRMS (ESI) calcd for C11H13O4S+ ([M + H]+): 241.0529, found 241.0534.
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N-methyl-N,2-diphenyl-2-tosylacetamide (4m). Obtained as a white solid (76.3 mg, 67%); m.p. 150–151 C; 1H
NMR (500 MHz; CDCl3) δ 7.40–7.14 (m, 19H), 5.05 (s, 1H), 3.27 (s, 4H), 2.41 (s, 3H). 13C NMR (125 MHz;
CDCl3) δ 164.2, 144.8, 142.7, 133.7, 130.5, 130.3, 130.0, 129.3, 129.2, 128.7, 128.7, 128.4, 127.6, 72.6, 37.7, 21.7;
HRMS (ESI) calcd for C22H22NO3S+ ([M + H]+): 380.1315, found 380.1312.
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N-methyl-N-phenyl-2-tosylhexanamide (4n). Obtained as a white solid (96.6 mg, 90%); m.p. 110–112 C; H
NMR (500 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 2H), 7.51–7.27 (m, 7H), 4.00 (d, J = 11.1 Hz, 1H), 3.32 (s, 3H),
2.45 (s, 3H), 1.86–1.74 (m, 2H), 1.28–1.00 (m, 4H), 0.81 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz; CDCl3) δ 165.1,
144.9, 142.8, 134.3, 130.0, 129.2, 128.5, 66.7, 38.0, 28.8, 28.5, 22.3, 21.6, 13.6. HRMS (ESI) calcd for
C20H26NO3S+ ([M + H]+): 360.1628, found 360.1623.
N-(2-methyl-3-oxo-3-phenyl-2-tosylpropyl)formamide (5a). Obtained as a white solid (isolated yield: 28%); m.p.
148–150 oC;1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.94–7.90 (m, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.55 (t, J =
7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.32 (s, 1H), 4.02 (dd, J = 6.6, 3.3 Hz, 2H), 2.45 (s,
3H), 1.76 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 198.0, 161.4, 146.0, 137.3, 132.6, 131.8, 130.3, 129.7, 128.9,
128.4, 76.5, 41.3, 21.7, 17.4; HRMS (ESI) calcd for C18H20NO4S+ ([M + H]+): 346.1108, found 346.1121.
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N-(tosylmethyl)formamide (A). Obtained as a white solid (isolated yield: 81%); m.p. 107–108; H NMR (500
MHz, CDCl3) δ 8.06 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 6.0 Hz, 1H), 4.70 (d, J =
6.9 Hz, 2H), 2.42 (s, 3H); 13C NMR (125 MHz; CDCl3) δ 160.7, 145.7, 133.6, 130.1, 128.8, 58.9, 21.7.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
Computational details and results
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Copies of 1H and 13C NMR spectra for all new compounds
AUTHOR INFORMATION
Corresponding Authors
* xyz@wzu.edu.cn (Y.X.); fanchen@wzu.edu.cn (F.C.)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Zhejiang Provincial Natural Science Foundation (LY13B020007) and the National Natural Science
Foundation of China (21272178, 21372178, and 21572163) for financial support.
REFERENCES
(1) (a) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257. (b) Rostamnia, S. RSC Adv. 2015, 5, 97044. (c)
Dömling, A. Chem. Rev. 2006, 106, 17. (d) Hoppe, D. Angew. Chem. Int. Ed. 1974, 13, 789. (e) Tandon, V. K.; Rai,
S. Sulfur Rep. 2003, 24, 307. (f) Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57, 417. (g) Kaur, T.;
Wadhwa, P.; Sharma, A. RSC Adv. 2015, 5, 52769.
(2) (a) Lygin, A. V.; de Meijere, A. Angew. Chem. Int. Ed. 2010, 49, 9094. (b) Schöllkopf , U. Angew. Chem. Int. Ed.
1977, 16, 339.
(3) (a) Molander, G. A.; FeboꢀAyala, W.; JeanꢀGérard, L. Org. Lett. 2009, 11, 3830. (b) Sawamura, M.; Hamashima,
H.; Ito, Y. J. Org. Chem. 1990, 55, 5935. (c) Motoyama, Y.; Kawakami, H,; Shimozono, K.; Aoki, K.; Nishiyama,
H. Organometallics 2002, 21, 3408. (d) Motoyama, Y.; Shimozono, K.; Aoki, K.; Nishiyama, H. Organometallics
2002, 21, 1684.
(4) (a) Yugandar, S.; Acharya, A.; Ila, H. J. Org. Chem. 2013, 78, 3948. (b) Baumann, M.; Baxendale, I. R.; Ley, S.
V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231.
(5) (a) Zhang, X.; Feng, C.; Jiang, T.; Li, Y.; Pan, L.; Xu, X. Org. Lett. 2015, 17, 3576. (b) Wang, L.; Woods, K. W.;
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
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5
6
7
8
Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.ꢀH.; Marsh, K.; Warner, R.;
Lee, J. Y.; ZielinskiꢀMozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697. (c) Moskal,
J.; van Leusen, M. J. Org. Chem. 1986, 51, 4131.
9
(6) (a) Misra, N. C.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72, 1246. (b) Zhou, F.; Liu, J.; Ding, K.;
Liu, J.; Cai, Q. J. Org. Chem. 2011, 76, 5346. (c) Larionov, O. V.; de Meijere, A. Angew. Chem. Int. Ed. 2005, 44,
5664. (d) Yugandar, S.; Misra, N. C.; Parameshwarappa, G.; Panda, K.; Ila, H. Org. Lett. 2013, 15, 5250. (e) Liao,
J.ꢀY.; Shao, P.ꢀL.; Zhao, Y. J. Am. Chem. Soc. 2015, 137, 628.
10
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12
13
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55
56
57
58
59
60
(7) (a) PeterlinꢀMašič, L.; Jurca, A.; Marinko, P.; Jančar, A.; Kikelj, D. Tetrahedron 2002, 58, 1557. (b) Jacobi, P. A.;
Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327. (c) Oldenziel, O. H.; van
Leusen, A. M. Tetrahedron Lett. 1972, 13, 2777.
(8) Pierre, F.; Regan, C. F.; Chevrel, M.ꢀC.; SiddiquiꢀJain, A.; Macalino, D.; Streiner, N.; Drygin, D.; Haddach, M.;
O’Brien, S. E.; Rice, W. G.; Ryckman, D. M.; Bioorg. Med. Chem. Lett. 2012, 22, 3327.
(9) Crandall, J. K.; Pradat, C. J. Org. Chem. 1985, 50, 1327.
(10) (a) Minguez, J. M.; Vaquero, J. L.; GarcíaꢀNavio, J. L.; AlvarezꢀBuilla, J. Tetrahedron Lett. 1996, 37, 4263. (b)
Baeza, A.; Mendiola, J.; Burgos, C. J. Org. Chem. 2005, 70, 4879.
(11) (a) Liu, J.; Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 6204. (b) Bounar, H.; Liu, Z.; Zhang, L.; Guan, X.;
Yang, Z.; Liao, P.; Bi, X.; Li, X. Org. Biomol. Chem. 2015, 13, 8723. (c) Garima; Srivastava, V. P.; Yadav, L. D. S.
Tetrahedron Lett. 2011, 52, 4622.
(12) (a) Chen, BꢀC.; Bednarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.; Shen, Z.; Skoumbourdis, A. P.; Barrish, J.
C. Tetrahedron Lett. 2000, 41, 5453. (b) Mendiola, J.; Baeza, A.; AlvarezꢀBuilla, J.; Vaquero, J. J. J. Org. Chem.
2004, 69, 4974.
(13) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem. Int. Ed. 2013, 52, 6953.
(14) (a) Russell, G. A.; Ros, F. J. Am. Chem. Soc. 1985, 107, 2506. (b) Suryakiran, N.; Reddy, T. S.; Ashalatha, K.;
Lakshman, M.; Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 3853.
(15) See Supporting Information for computational details.
(16) (a) Lundin, P. M.; Esquivias, J.; Fu, G.C. Angew. Chem. Int. Ed. 2009, 48, 154. (b) Walter, M.; von Coburg,
Y.; Isensee, K.; Sander, K.; Ligneau, X.; Camelin, J.ꢀC. Stark, H. Bioorg. Med. Chem. Lett. 2010, 20, 5879. (c)
Blough, B. E.; Landavazo, A.; Partilla, J. S.; Baumann, M. H.; Decker, A. M.; Page, K. M.; Rothman, R. B. ACS
Med. Chem. Lett. 2014, 5, 623. (d) Carroll, F. I.; Blough, B. E.; Abraham, P.; Mills, A. C.; Holleman, J. A.;
Wolckenhauer, S. A.; Decker, A. M.; Landavazo, A.; McElroy, K. T.; Navarro, H. A.; Gatch, M. B.; Forster, M. J.
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J. Med. Chem. 2009, 52, 6768. (e) Lauriers, A. J.ꢀD.; Legault, C. Y. Org. Lett. 2016, 18, 108. (f) Conte, U.;
Ghislandi, V.; Caramella, C.; La Manna, A.; Pratesi, P. Farmaco Sci.1969, 24, 709. (g) Perez, D.; Greenspoon, N.;
Keinan, E. J. Org. Chem. 1987, 52, 5570. (h) Forbes, J. W.; Jungnickel, J. L. Appl. Spectrosc. 1965, 19, 124. (i)
Vol'kenshtein, Y. B.; Gol'dfarb, Y. L. Dokl. Akad. Nauk SSSR 1961, 138, 115. (j) Stevens, C. L.; Pillai, P. M.;
Taylor, K. G. J. Org. Chem. 1974, 39, 3158. (k) Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C. M.;
McKenzie, T. C.; Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell, F. M. J. Med. Chem. 1981, 24, 481. (l)
Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B. W.ꢀQ. Org. Lett. 2010, 12, 2052. (m) Mao, J.; Liu, F.; Wang, M.; Wu, L.;
Zheng, B.; Liu, S.; Zhong, J.; Bian, Q.; Walsh, P. J. J. Am. Chem. Soc. 2014, 136, 17662. (n) Li, D.; Yang, T.; Su,
H.; Yu, W. Adv. Synth. Catal. 2015, 357, 2529.
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