Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions

Article abstract of DOI:10.1021/acs.joc.6b01421

An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This transformation does not require an exogenous acid, base, or transition metal catalyst; instead the addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields than more encumbered N-alkyl sulfonamides. The trichloroacetimidate alkylating agent must be a stable cation precursor for the substitution reaction to proceed under these conditions.

Full text of DOI:10.1021/acs.joc.6b01421

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Note
Alkylation of Sulfonamides with
Trichloroacetimidates Under Thermal Conditions
Daniel R Wallach, and John Daniel Chisholm
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01421 • Publication Date (Web): 03 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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Alkylation of Sulfonamides with
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Trichloroacetimidates Under Thermal Conditions
Daniel R. Wallach and John D. Chisholm*
Department of Chemistry, 1ꢀ014 Center for Science and Technology, Syracuse University,
Syracuse, NY 13244
jdchisho@syr.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal you are submitting your paper to)
NH
CCl3
O
R2
O
R2
S
O
HN
Ar
S
toluene
O
H2N
+
O
reflux, 18 h
Ar
R1
R1
Abstract
An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This
transformation does not require an exogenous acid, base, or transition metal catalyst, instead the
addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner
appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields
than more encumbered Nꢀalkyl sulfonamides. The trichloroacetimidate alkylating agent must be
a stable cation precursor for the substitution reaction to proceed under these conditions.
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The sulfonamide functional group has played an important role in the development of
numerous pharmaceuticals. While best known as antibiotics, sulfonamide scaffolds provide a
diverse range of biological activity including antitumor, antiviral, diuretic, antiꢀinflammatory and
antiꢀhypertensive properties.1 Summaries of the top selling pharmaceuticals clearly demonstrate
that sulfonamides are well represented in these valuable structures.2 Data on recently approved
pharmaceuticals indicate that sulfonamides continue to be popular in drug discovery,3 with
recent publications in the medicinal chemistry field corroborating that the investigation of
sulfonamideꢀcontaining structures is ongoing.4 Sulfonamides also have proven useful in
agricultural and insecticidal applications.5
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In addition, sulfonamides serve an important function in synthetic organic chemistry, as
they facilitate the introduction of nitrogen into organic molecules. The sulfonamide may then
serve as a protecting group for the nitrogen atom during further synthetic manipulation. The use
of sulfonamides as protecting groups in complex molecules was hindered by the harsh
conditions6 needed to remove the sulfonamide. The development of 2ꢀ(trimethylsilyl)ꢀ
ethanesulfonamide (SESꢀNH2) by Weinreb7 and the implementation of 2ꢀ and 4ꢀ
nitrobenzenesulfonamides by Fukuyama8 have resulted in a greatly increased use of
sulfonamides in organic synthesis, primarily because these sulfonamides are readily and reliably
removed under mild conditions. These developments have greatly popularized the use of
sulfonamides in complex molecule synthesis.
With the obvious value of sulfonamides in chemical and pharmaceutical research,
methods for their formation and elaboration have been heavily investigated. Classically
substituted sulfonamides may be formed from amines and sulfonyl chlorides,9 by direct
alkylation of sulfonamides with alkyl halides,10 or through reductive amination.11 The Mitsunobu
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reaction has also been employed to convert an alcohol into a sulfonamide.7b,8a,12 Given the high
level of interest in sulfonamides, it is perhaps unsurprising that new, more atomꢀeconomical
catalytic methods for their formation have continued to evolve. Many of these methods employ
transition metal catalysts, including the hydroaminations of alkenes,13 CꢀH activation methods,14
metal catalyzed additions to Nꢀsulfonyl imines,6b,15 alkylation via πꢀallyl metal complexes,16 and
alkylation of alcohols via borrowing hydrogen methods.17 Direct alkylation of benzylic and
allylic alcohols and ethers has also been explored,18 although these methods typically require the
use of strong Brønsted or Lewis acids and elevated temperatures.
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As part of our recent investigations into the use of trichloroacetimidates to alkylate
carboxylic acids, alcohols, thiols and anilines under mild conditions,19 we sought to determine if
sulfonamides could be similarly elaborated. Lewis acid promoted alkylation with
trichloroacetimidates has been widely utilized in the synthesis of ethers20 and carbohydrates.21
Trichloroacetimidate displacements produce only trichloroacetamide as a byproduct, which is
typically unreactive and may be removed by washing with aqueous NaOH solution.19d More
recently there have been several reports of additiveꢀfree trichloroacetimidate substitution
reactions, with only heating being necessary to effect the displacement of some
trichloroacetimidates with alcohols19c and thiols.19d Development of a new, catalystꢀfree method
to access substituted sulfonamides would provide an inexpensive method to access these
structures under mild conditions. Little is known about the reactivity of sulfonamides with
trichloroacetimidates, although recently Kuroda and coꢀworkers reported an intramolecular SN2'
substitution reaction of allylic imidates and sulfonamides catalyzed by a chiral phosphoric acid.22
To our knowledge this is the only example of a reaction between a trichloroacetimidate and a
sulfonamide in the literature.
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Initially, the reaction of pꢀtoluenesulfonamide 1 with 1ꢀphenethyl trichloroacetimidate 2
was studied (Table 1). Utilizing BF3•OEt2 as a catalyst in toluene, alkylation was rapid but only a
29% yield of the desired alkylation product 3 was realized. This poor yield was due to a
significant portion of imidate 2 rearranging to the corresponding trichloroacetamide 4 during the
alkylation. This rearrangement also complicated the isolation of the product 3, as the acetamide
possessed similar chromatographic motility. Brønsted acid catalysis had proven superior in our
study on the alkylation of anilines with trichloroacetimidates,19e and so these catalysts were
investigated next. Weak acids like PPTS gave a slower reaction resulting in a 50% yield, while
stronger acids like dinitrobenzenesulfonic acid (DNBSA) gave a more rapid alkylation in 71%
yield. While the reaction may be catalyzed with Brønsted or Lewis acids, given the acidity of the
sulfonamide functional group the transformation in principle may also occur without a catalyst
under thermal conditions as observed with alcohols and thiols.19c,19d
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Table 1. Addition of Toluenesulfonamide 1 to Phenethyl Trichloroacetimidate 2.
CH3
O
NH
CCl3
O
HN
CCl3
S
4
O
O
HN
Ph
O
Ph
S
+
1
2
3
H2N
O
Ph
H2NCOCCl3
5
entry equiv 2
1
2
conditions
1.2 BF3•OEt2 (10 mol %), rt, 18 h toluene
1.2 PPTS (10 mol %), rt, 18 h toluene
1.2 DNBSA (10 mol %), rt, 18 h toluene
solvent yield (%)
29
50
71
76
24
32
0
0
86
74
3
4
5
6
7
8
9
10
1.2
1.2
1.2
1.2
1.2
1.5
1.5
reflux, 18 h
reflux, 4 h
reflux, 8 h
86 °C, 18 h
reflux, 18 h
refluxa
toluene
toluene
toluene
toluene
THF
toluene
toluene
reflux, 18 h
aThe imidate added in 6 portions (one every 30 min) over 2.5 h, then the reaction mixture was refluxed for another
16 h.
Heating a mixture of sulfonamide 1 and imidate 2 in toluene to reflux for 18 hours (entry
4) resulted in a 76% yield of alkylated product. Shorter reaction times were not as effective, as
the reaction was incomplete and therefore provided more moderate yields. Attempts to perform
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the alkylation at lower temperatures in toluene (entry 7) and in lower boiling solvents like THF
(entry 8) provided only unreacted starting materials, so a temperature near refluxing toluene was
necessary for the alkylation to proceed. At this point it was noted that while pꢀ
toluenesulfonamide 1 was only slightly soluble in refluxing toluene, imidate 2 and the
trichloroacetamide byproduct 5 were completely soluble, which led to the hypothesis that as
trichloroacetamide 5 was formed it could compete with the sulfonamide 1 as a nucleophile,
leading to the undesired product 4. To combat this problem the imidate 2 was added to the
reaction mixture in portions which resulted in an increased yield of 86% (entry 9). Even though
1.5 equivalents of imidate was used this reaction, no increase in yield was noted with 1.5 equiv
of imidate without the portionwise addition (entry 10). As entry 9 provided the best yield, this
procedure was used henceforth.
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The scope of the reaction of with respect to sulfonamide was then investigated (Table 2).
A variety of different sulfonamides were found to undergo the alkylation reaction with imidate 2
in useful yields. Benzenesulfonamides substituted with electron donating groups provided
excellent yields alkylated sulfonamide products (entries 1ꢀ3). 2ꢀNitrobenzenesulfonamide 12
only provided a yield of 13% (entry 5), which was disappointing as Fukuyama has demonstrated
the utility of this sulfonamide for installing amines.8a This poor yield was attributed to the
particular insolubility of this sulfonamide in toluene. Use of other solvents (α,α,αꢀ
trifluorotoluene, DCE, acetonitrile) did not improve the yield of the transformation. After some
experimentation a solution was found, with a reaction catalyzed by BF3ˑOEt2 providing a 70%
yield when the imidate added over the course of one hour via syringe pump to the reaction
mixture.
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Table 2. Alkylation of Sulfonamides with Imidate 2.
NH
O
R2
O
R1
S
R2
toluene
R1
S
O
CCl3
2
N
+
O
N
reflux, 18 h
O
H
Ph
Ph
7
8
9
entry sulfonamide
product
yield (%)
86
O
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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49
50
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54
55
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58
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60
O
1
HN
O
S
H2N
1
O
3
Ph
OCH3
OCH3
O
S
O
2
3
4
5
75
74
HN
Ph
S
O
H2N
6
O
7
O
O
S
HN
Ph
S
O
H2N
8
9
O
Cl
Cl
O
O
S
S
85
HN
Ph
O
H2N
10
O
11
O
O
13 (70a)
S
S
HN
Ph
12
O
H2N
NO2
O
NO2
13
O
O
S
HN
S
O
6
7
8
79
76
53
O
H2N
14
15
Ph
O
O
S
S
HN
O
H2N
16
O
17
Ph
O
S
Si(CH3)3
O
S
O
Si(CH3)3
HN
Ph
O
H2N
18
19
O
9
O
20
O
98
S
O
21
S
N
O
N
O
H
Ph
O
N
O
S
O
10
11
27
0b
S
O
N
22
23
H
Ph
O
N
O
Bn
Ph
S
O
Bn
S
N
24
O
25
H
aYield for a modified procedure using 10 mol % BF3•OEt2 in toluene at room temperature with the imidate being
added as a refluxing solution of sulfonamide with a syringe pump over 1 hour. Starting sulfonamide 24 recovered
b
unchanged.
Alkyl sulfonamides were also well tolerated in the reaction with yields ranging from 70
to 79% (entries 6ꢀ8). The successful alkylation of 2ꢀ(trimethylsilyl)ꢀethanesulfonamide 18 is
particularly notable, as this sulfonamide can be removed to reveal the corresponding amine by
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treatment with fluoride. Sulfonamide 18 is often utilized to introduce a protected nitrogen into
complex molecules.7c The inexpensive carboxylic sulfonamide saccharin 20 reacted with
trichloroacetimidate 2 with excellent yield of 98% (entry 9). Saccharin has been used as a
replacement for phthalimide in the Gabriel synthesis,23 making this an inexpensive method to
incorporate nitrogen in organic substrates. Nitrogen substitution on the sulfonamide gave lower
yields, with Nꢀmethylbenzenesulfonamide 22 providing 27% of 23 (entry 10). Nꢀ
Benzylbenzenesulfonamide 24 failed to react (entry 11). The decreased reactivity of Nꢀ
substituted sulfonamides can be attributed to sterics, and explains why no dialkylation products
were observed.
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11
12
13
14
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16
17
18
19
20
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22
23
24
25
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32
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42
43
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45
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49
50
51
52
53
54
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56
57
58
59
60
To further probe the reaction scope the reactivity of differentially substituted
trichloroacetimidates with pꢀtoluenesulfonamide 1 was investigated (Table 3). Secondary
benzylic trichloroacetimidates were effective substrates, providing the Nꢀalkyl sulfonamides in
good yields. These reactions tolerated a sterically encumbering orthoꢀsubstituent on the aromatic
ring next to the reactive center (as seen in the formation of 33 and 35). The furanyl imidate 36
proved to be susceptible to hydrolysis and rearrangement to the corresponding acetamide, but
still provided a 44% yield of substitution product 37.
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Table 3. Addition of p-Toluenesulfonamide 1 to Different Trichloroacetimidates.
TsNH2
1
H
NH
toluene
R1
Ts
N
reflux, 18 h
Cl3C
O
R1
7
8
9
entry
1
imidate
product
yield (%)
86
NH
2
3
TsHN
Ph
Cl3C
NH
O
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TsHN
27
2
3
4
5
6
89
79
79
94
88
Cl3C
O
26
NH
Cl3C
O
TsHN
29
28
NH
Cl3C
O
TsHN
31
30
NH
TsHN
Cl3C
NH
O
33
32
O
O
O
TsHN
35
Cl3C
O
34
Br
O
Br
NH
O
O
7
8
44
89
TsHN
Cl3C
O
36
37
NH Ph
Ph
38
39
Ph
Cl3C
O
Ph
TsHN
Ph
NH Ph
Cl3C
O
TsHN
41
9
67
40
CO2Me
CO2Me
OMe
3
3
NH
TsHN
43
Cl3C
O
10
11
68
55
42
OMe
NH
TsHN
45
Cl3C
O
44
NH
46
47
51
TsHN
Ph
12
13
14
15
16
0
60
28
5
Cl3C
O
Ph
NH
48
49
Cl3C
O
TsHN
NH
50
TsHN
Cl3C
O
NH
52
TsHN 53
Cl3C
O
NH
54
0
55
TsHN
Cl3C
O
Diphenylmethyl imidate readily participated in the reaction to provide an 89% yield of
sulfonamide 39. This is notable as diphenylmethyl groups have been utilized as protecting
groups for sulfonamides.24 Other diarylmethyl imidates also provided synthetically useful yields
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in the alkylation reaction, providing 41 in 67% yield. A number of primary benzylic
trichloroacetimidates were also evaluated. Use of 4ꢀmethoxybenzyl trichloroacetimidate 42 or oꢀ
tolyl trichloroacetimidate 44 provided the alkylated products 43 and 45, but the yields were
lower than was observed for the secondary benzylic imidates. Benzyl trichloroacetimidate 46
was unreactive under these conditions. Secondary allylic trichloroacetimidates provided good
yields of alkylated products, as seen in the case of compound 49. Simple allyl
trichloroacetimidate 50 provided a much lower yield of the product. Methyl and tertꢀbutyl
trichloroacetimidate were also evaluated, but product was only observed in the methyl case
which gave low conversion.
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18
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20
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22
23
24
25
26
27
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30
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35
36
37
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43
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45
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49
50
51
52
53
54
55
56
57
58
59
60
As defined in Table 3, imidates that are precursors to stable carbocations provide higher
yields under these reaction conditions. This implies that the reaction proceeds through an SN1
pathway, where the imidate ionizes and then is trapped with the sulfonamide. To further test this
hypothesis the enantiopure imidate (R)ꢀ219e was subjected to the reaction conditions, providing
the sulfonamide 3 in 81% yield (Scheme 1), however the product was racemic. This result is
inconsistent with an SN2 pathway, and further supports an SN1 pathway as is commonly invoked
for trichloroacetimidate substitution reactions with benzylic substrates.
Scheme 1. Substitution with a Chiral Trichloroacetimidate.
NH
O
O
H
S
O
CCl3
S
N
H2N
1
O
O
Ph
2
toluene
reflux, 18 h
3 81%
50:50 R:S
Ph
>98:2 R:S
The new reaction was then applied to the synthesis of an interesting ketoprofen analog 58
(Scheme 2) discovered by Sakurai and coꢀworkers.25 Sulfonamide 58 showed a number of
interesting pharmacological properties such as LTD4 antagonistic activity, TXA2 antagonistic
activity, and TXA2 synthase inhibitory activity.25ꢀ26 The synthetic scheme used by Sakurai to
synthesize 58 involved the forming the azide, which was then reduced to the corresponding
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amine followed by transformation into the sulfonamide. Alternatively, sulfonamide 58 could be
synthesized via imidate 40, which avoids the use of the toxic sodium azide and eliminating the
need for azide reduction. Initially, alcohol 56 was synthesized following the procedure of
Sakurai and coworkers (Scheme 2).25 Formation of the corresponding imidate 40 proceeded in
near quantitative yield. Imidate 40 was displaced with 4ꢀchlorobenzenesulfonamide 10 to obtain
sulfonamide 57 in 88% yield. Sulfonamide 57 may be transformed to ketoprofen analog 58 via
saponification.25
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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58
59
60
Scheme 2. Synthesis of a Ketoprofen Analog.
NH
O
CCl3
OH
Cl3CCN
10 mol % DBU
Ph
Cl
Ph
CH2Cl2
56
40
99%
CO2Me
CO2Me
3
3
Cl
O
O
H
S
88% 57 R = Me
S
N
NaOH
(ref 23)
O
H2N
10
O
58 R = H
Ph
toluene
reflux, 18 h
CO2R
3
In summary, thermal conditions for the alkylation of sulfonamides with
trichloroacetimidates have been developed. Unsubstituted sulfonamides were found to undergo
alkylation well, but Nꢀsubstituted sulfonamides were not effectively alkylated. The
trichloroacetimidate alkylation partner must be a precursor to a stabilized carbocation, with the
preponderance of evidence supporting an SN1 reaction pathway in most cases. The formal
synthesis of a biologically active ketoprofen analog was accomplished using this new
substitution reaction.
Experimental Section
Representative Sulfonamide Substitution Procedure A: To a flame dried round bottom flask
under an atmosphere of argon was added pꢀtoluene sulfonamide 1 (0.13 g, 0.77 mmol) and
toluene (4 mL). Phenethyl imidate 219e (51 mg, 0.19 mmol) was added and the reaction mixture
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was heated to reflux. Phenethyl imidate 2 (0.05 g, 0.19 mmol) was added to the refluxing
reaction mixture every 30 minutes until 1.14 mmol (1.5 equiv) of phenethyl imidate was added.
After stirring at reflux overnight, the reaction mixture was allowed to cool to room temperature,
preadsorbed on silica gel and purified by silica gel chromatography (30% ethyl acetate/70%
hexanes) to give 0.180 g (86%) of substituted sulfonamide 3 as a white solid.
4-Methyl-N-(1-phenylethyl)benzenesulfonamide (3).27
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Prepared using procedure A (0.180 g, 86%) using the known imidate19e and purified using silica
gel chromatography (30% ethyl acetate/70% hexanes).
3. White solid (0.18 g, 86%); mp = 74ꢀ78 °C; TLC Rf = 0.43 (20% ethyl acetate/80% hexanes);
1H NMR (300 MHz, CDCl3) δ 7.61 (dt, J = 8.7, 2.1 Hz, 2H), 7.21ꢀ7.17 (m, 5H), 7.11ꢀ7.08 (m,
2H), 4.76 (d, J = 6.8 Hz, 1H), 4.47 (p, J = 6.9 Hz, 1H), 2.39 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 143.1, 142.0, 137.7, 129.4, 128.5, 127.5, 127.1, 126.1, 53.6, 23.5,
21.5. Chiral HPLC analysis: Chiralcel OD (heptane/iꢀPrOH = 90/10, 1.0 mL/min, 254 nm, 25
°C): t = 10.6, 12.8 min.
4-Methoxy-N-(1-phenylethyl)benzenesulfonamide (7).28
Prepared using procedure A (0.17 g, 75%) using the known imidate19e and purified by silica gel
chromatography (100% DCM).
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7. Waxy offꢀwhite solid (0.17 g, 75%); mp = 94ꢀ96 °C; TLC Rf = 0.25 (100% DCM); H NMR
(400 MHz, CDCl3) δ 7.65 (dt, J = 9.2, 2.8 Hz, 2H), 7.21ꢀ7.15 (m, 3H), 7.11ꢀ7.09 (m, 2H), 6.82
(dt, J = 9.6 , 2.8 Hz, 2H), 5.35 (d, J = 7.2 Hz, 1H), 4.43 (p, J = 7.2 Hz, 1H), 3.82 (s, 3H), 1.40 (d,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6, 142.2, 132.2, 129.2, 128.5, 127.4, 126.2,
114.0. 55.6, 53.7, 23.6.
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N-(1-Phenylethyl)benzenesulfonamide (9).29
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Prepared using procedure A (0.14 g, 72%) using the known imidate19e and purified using silica
gel chromatography (30% ethyl acetate/70% hexanes).
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9. White solid (0.14 g, 85%); mp = 87ꢀ91 °C; TLC Rf = 0.44 (30% ethyl acetate/70% hexanes);
1H NMR (400 MHz, CDCl3) δ 7.74ꢀ7.71 (m, 2H), 7.44 (td, J = 6.4, 1.2 Hz, 1H), 7.36ꢀ7.31 (m,
2H), 7.14ꢀ7.07 (m, 5H), 5.65 (d, J = 7.2 Hz, 1H), 4.48 (p, J = 6.8 Hz, 1H), 1.40 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 142.0, 140.7, 132.3, 128.8, 128.5, 127.4, 127.0, 126.1, 53.8,
23.6.
4-Chloro-N-(1-phenylethyl)benzenesulfonamide (11).30
Prepared using procedure A (0.19 g, 83%) using the known imidate19e and purified using silica
gel chromatography (10% ethyl acetate/90% hexanes).
11. White amorphous solid (0.15 g, 67%); mp = 71ꢀ75 °C; TLC Rf = 0.21 (10% ethyl
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acetate/90% hexanes); H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.8
Hz, 3H), 7.19ꢀ7.17 (m, 2H), 7.08ꢀ7.05 (m, 2H), 5.14 (d, J = 7.2 Hz, 1H), 4.50 (p, J = 6.8 Hz,
1H), 1.44 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.6, 139.2, 138.7, 129.0, 128.6,
128.5, 127.6, 126.1, 53.9, 23.6.
2-Nitro-N-(1-phenylethyl)benzenesulfonamide (13).31
2ꢀNitrobenzenesulfonamide (0.18 g, 0.87 mmol) and BF3•OEt2 (0.02 g, 0.09 mmol) were
suspended in DCM (4 mL). The suspension was heated to reflux. A 0.1 M solution of 1ꢀ
phenethyl trichloroacetimidate 219e (0.30 g, 1.13 mmol) in DCM was added to the suspension
using a syringe pump over the course of one hour. The reaction was refluxed for 18h. After
cooling to room temperature, the reaction was poured into saturated aq. NaHCO3 and extracted
with DCM (3x). The combined organic extracts were dried over Na2SO4, filtered and
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concentrated in vacuo. The residue was purified via silica gel chromatography (100% DCM)
providing 13 (0.18 g, 70%) as a white solid. The sulfonamide 13 was also prepared using
procedure A (0.04 g, 13%).
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13. White solid (0.18 g, 70%); mp = 89ꢀ91 °C; TLC Rf = 0.58 (100% DCM); H NMR (400
MHz, CDCl3) δ 7.71 (dd, J = 8.0, 1.2 Hz, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (td, J = 7.6,
1.2 Hz, 1H), 7.40 (td, J = 8.0, 1.6 Hz, 1H), 7.12ꢀ7.06 (m, 5H), 5.77 (d, J = 8.4 Hz, 1H), 4.69 (p, J
= 6.8 Hz, 1H), 1.52 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.3, 141.2, 134.5,
132.9, 132.5, 130.8, 128.5, 127.7, 126.1, 124.9, 55.0, 23.7.
N-(1-Phenylethyl)methanesulfonamide (15).31
Prepared using procedure A (0.12 g, 79%) using the known imidate19e and purified using silica
gel chromatography (30% ethyl acetate/70% hexanes).
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15. Yellow oil (0.12 g, 79%); TLC Rf = 0.35 (30% ethyl acetate/70% hexanes); H NMR (400
MHz, CDCl3) δ 7.39ꢀ7.26 (m, 5H), 5.16 (d, J = 7.2 Hz, 1H); 4.64 (p, J = 7.2 Hz, 1H), 2.61 (s,
13
3H), 1.53 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 142.4, 129.0, 128.0, 126.2, 53.8,
41.8, 24.0.
N-(1-Phenylethyl)ethanesulfonamide (17).32
Prepared using procedure A (0.15 g, 76%) using the known imidate19e and purified using silica
gel chromatography (100% DCM flushed with 30% ethyl acetate/70% hexanes).
17. White solid (0.15 g, 76%); mp = 89ꢀ91 °C; TLC Rf = 0.34 (30% ethyl acetate/70% hexanes);
1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.26 (m, 5H), 5.17 (br d, J = 7.1 Hz, 1H), 4.62 (p, J = 7.1
Hz, 1H), 2.76 (h, J = 7.4 Hz, 1H), 2.61 (h, J = 7.4 Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H), 1.17 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.8, 128.8, 127.9, 126.2, 53.7, 47.9, 24.2, 8.0.
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N-(1-Phenylethyl)-2-(trimethylsilyl)ethanesulfonamide (19).33
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Prepared using procedure A (0.13 g, 70%) using the known imidate19e and purified by silica gel
chromatography (30% ethyl acetate/80% hexanes).
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19. White crystals (0.13 g, 70%); mp = 61ꢀ64 °C; TLC Rf = 0.58 (20% ethyl acetate/80%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.27 (m, 5H), 4.73 (d, J = 6.9 Hz, 1H), 4.62 (p, J =
6.9 Hz, 1H), 2.61 (td, J = 14.0, 3.9 Hz, 1H), 2.47 (td, J = 13.9, 4.4 Hz, 1H), 1.54 (d, J = 6.9 Hz,
13
3H), 0.86 (td, J = 13.8, 4.0, 1H), 0.74 (td, J = 14.0, 4.3 Hz, 1H), ꢀ0.13 (s, 9H); C NMR (100
MHz, CDCl3) δ 143.0, 129.1, 128.2, 126.4, 53.9, 50.0, 24.3, 10.5, ꢀ2.0.
3-Oxo-N-(1-phenylethyl)benzo[d]isothiazole-2(3H)-sulfonamide 1,1-dioxide (21).34
Prepared using procedure A using the known imidate19e and purified by silica gel
chromatography (20% ethyl acetate/80% hexanes). The crude product was then taken up in ethyl
acetate (30 mL) and washed with 2M NaOH (5 x 20 mL). The organic layers were combined,
dried over sodium sulfate and concentrated in vacuo to provide 21 as a clear colorless oil (0.22 g,
98%).
21. Clear colorless oil (0.22 g, 98%); TLC Rf = 0.37 (20% ethyl acetate/80% hexanes); 1H NMR
(400 MHz, CDCl3) δ 7.98ꢀ7.95 (m, 1H), 7.90ꢀ7.88 (m, 1H), 7.82 (td, J = 7.4, 1.2 Hz, 1H), 7.77
(td, J = 7.2, 1.4 Hz, 1H), 7.60ꢀ7.57 (m, 2H), 7.36 (tt, J = 6.8, 1.2 Hz, 2H), 7.29 (tt, J = 6.2, 1.3
Hz, 1H), 5.45 (q, J = 7.3 Hz, 1H), 2.03 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
158.5, 138.6, 137.8, 134.6, 134.2, 128.5, 128.2, 127.7, 127.3, 125.0, 120.7, 53.0, 17.7.
4-Methyl-N-(1-phenylethyl)benzenesulfonamide (23).35
Prepared using procedure A (0.06 g, 27%) using the known imidate19e and purified using silica
gel chromatography (100% DCM).
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23. White powder (0.06 g, 27%); mp = 60ꢀ62 °C; TLC Rf = 0.52 (100% DCM); H NMR (400
MHz, CDCl3) δ 7.74 (dt, J = 8.4, 1.8 Hz, 2H), 7.32ꢀ7.24 (m, 7H), 5.29 (q, J = 7.0 Hz, 1H), 2.57
(s, 3H), 2.43 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.1, 139.9,
137.3, 129.7, 128.4, 127.5, 127.3, 127.1, 54.8, 28.4, 21.5, 15.2.
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1-(p-Tolyl)ethyl 2,2,2-trichloroacetimidate (26)
To a round bottom flask under argon was added 1ꢀ(pꢀtolyl)ethanol (0.51 g, 3.74 mmol),
trichloroacetonitrile (0.48 mL, 4.86 mmol) and DCM (7 mL). DBU (0.06 mL, 0.37 mmol) was
added and the reaction mixture was stirred at room temperature for 18 h. Triethylamine (1 mL)
was added to the reaction mixture and the solvent was removed in vacuo. Purification of the
residue by silica gel chromatography (1% triethylamine/9% ethyl acetate/90% hexanes) provided
imidate 26 as white crystals (0.81 g, 77%).
26. White crystals (0.81 g, 77%); mp = 41ꢀ42 °C; TLC Rf = 0.50 (10% ethyl acetate/90%
hexanes); IR (KBr) 3344, 2982, 2931, 2868, 1663, 1285 cmꢀ1; H NMR (400 MHz, CDCl3) δ
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8.27 (br s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 5.94 (q, J = 6.6 Hz, 1H), 2.34
(s, 3H), 1.63 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 138.4, 137.6, 129.2,
125.8, 91.8, 77.2, 22.2, 21.2. Anal. Calcd for C11H12Cl3NO: C, 47.09; H, 4.31; N,4.99. Found:
C,46.75; H, 4.05; N, 4.80.
4-Methyl-N-(1-(p-tolyl)ethyl)benzenesulfonamide (27).36
Prepared using procedure A (0.19 g, 89%) using imidate 26 and purified using silica gel
chromatography (30% ethyl acetate/70% hexanes).
27. White powder (0.19 g, 89%); mp = 118ꢀ119 °C; TLC Rf = 0.65 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.62 (dt, J = 8.3, 1.0 Hz, 2H), 7.17 (dd, J = 8.5, 0.6 Hz,
2H), 6.98 (app s, 4H), 5.04 (d, J = 7.0 Hz, 1H), 4.40 (p, J = 6.9 Hz, 1H), 2.38 (s, 3H), 2.27 (s,
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3H) 1.39 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 143.0, 139.1, 137.8, 137.1, 129.4,
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1,2,3,4-Tetrahydronaphthalen-1-yl 2,2,2-trichloroacetimidate (28)
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To a round bottom flask under argon was added 1,2,3,4ꢀtetrahydronaphthalenꢀ1ꢀol (1.00 g, 6.75
mmol), DBU (0.10 mL, 0.67 mmol) and DCM (23 mL). The reaction mixture was stirred at
room temperature for 15 minutes and then cooled to 0°C in an ice/water bath.
Trichloroacetonitrile (0.88 mL, 8.77 mmol) was added and the reaction mixture was warmed to
room temperature and stirred overnight. The solvent was then removed in vacuo. Triethylamine
(1 mL) was added and the residue was purified by silica gel chromatography (2%
triethylamine/10% ethyl acetate/88% hexanes) to provide 28 as a clear colorless oil (1.68 g,
94%).
28. Clear colorless oil (1.68 g, 94%); TLC Rf = dec. (10% ethyl acetate/90% hexanes); IR (thin
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film on KBr) 3341, 3064, 3024, 2940, 2869, 1657 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.39 (br
s, 1H), 7.39ꢀ7.37 (m, 1H), 7.27ꢀ7.14 (m, 3H), 6.10 (t, J = 4.8 Hz, 1H), 2.93ꢀ2.74 (m, 2H), 2.22ꢀ
1.96 (m, 3H), 1.89ꢀ1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.5, 138.1, 134.2, 129.6,
129.1, 128.3, 126.1, 92.1, 75.5, 29.1, 27.9, 19.1. Anal. Calcd for C12H12Cl3NO: C, 49.26; H,
4.13; N,4.75. Found: C,48.92; H, 4.44; N, 4.92.
4-Methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzenesulfonamide (29).37
Prepared using procedure A (0.18 g, 79%) using imidate 28 and purified using silica gel
chromatography (30% ethyl acetate/70% hexanes).
29. Beige solid (0.18 g, 79%); mp = 115ꢀ118 °C; TLC Rf = 0.62 (30% ethyl acetate/ 70%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.75 (td, J = 8.4, 1.9 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H),
7.05 (td, J = 7.3, 1.2 Hz, 1H), 7.00ꢀ6.94 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 4.67 (br d, J = 7.8 Hz,
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1H), 4.37 (p, J = 5.2 Hz, 1H), 2.71ꢀ2.54 (m, 2H), 2.38 (s, 3H), 1.79ꢀ1.71 (m, 3H), 1.66ꢀ1.62 (m,
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1H); C NMR (100 MHz, CDCl3) δ 143.4, 138.2, 137.6, 135.6, 129.8, 129.2, 128.8, 127.6,
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127.2, 126.3, 51.9, 30.8, 28.9, 21.6, 19.2.
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1-(Naphthalen-1-yl)ethyl 2,2,2-trichloroacetimidate (30).
To a round bottom flask under argon was added 1ꢀ(naphthalenꢀ1ꢀyl)ethanol (0.85 g, 4.92 mmol),
trichloroacetonitrile (0.59 mL, 5.90 mmol) and DCM (12 mL). DBU (0.08 mL, 0.49 mmol) was
added to the reaction mixture and the reaction mixture was stirred at room temperature for 18h.
Triethylamine (1 mL) was added to the reaction mixture and the reaction mixture was purified by
silica gel chromatography (2% triethylamine/8% ethyl acetate/90% hexanes) to provide 30 as a
clear colorless oil (1.32 g, 85%).
30. Clear colorless oil (1.32 g, 85%); TLC Rf = 0.80 (10% ethyl acetate/90% hexanes); IR (thin
film on KBr) 3339, 3052, 2983, 2933, 2870, 1661, 1598 cmꢀ1; H NMR (400 MHz, CDCl3) δ
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8.36 (br s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.89ꢀ7.87 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.71 (d, J =
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7.1 Hz, 1H), 7.56ꢀ7.47 (m, 3H), 6.74 (q, J = 6.6 Hz, 1H), 1.81 (d, J = 6.6 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 161.7, 137.1, 133.8, 130.2, 128.9, 128.5, 126.3, 125.7, 125.4, 123.2, 123.0,
91.8, 74.6, 21.34. Anal. Calcd for C14H12Cl3NO: C, 53.11; H, 3.82; N,4.42. Found: C,53.47; H,
3.62; N, 4.75.
4-Methyl-N-(1-(naphthalen-1-yl)ethyl)benzenesulfonamide (31).28
Prepared using procedure A (0.20 g, 79%) using imidate 30 and purified using silica gel
chromatography (30% ethyl acetate/70% hexanes).
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MHz, CDCl3) δ 7.89ꢀ7.87 (m, 1H), 7.80ꢀ7.78 (m, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.56 (dt, J = 8.3,
1.7 Hz, 2H), 7.47ꢀ7.40 (m, 2H), 7. 36 (dd, J = 7.2, 1.0 Hz, 1H), 7.31ꢀ7.27 (m, 1H), 7.04 (d, J =
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7.9 Hz, 2H), 5.28 (p, J = 6.8 Hz, 1H), 5.15 (d, J = 6.8 Hz, 1H), 2.31 (s, 3H), 1.58 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 143.1, 137.7, 137.5, 133.8, 130.1, 129.3, 128.8, 128.1,
127.1, 126.3, 125.6, 125.3, 123.4, 122.6, 49.8, 23.2, 21.4.
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1-(o-Tolyl)ethyl 2,2,2-trichloroacetimidate (32).
To a round bottom flask under argon was added 1ꢀ(oꢀtolyl)ethanol (1.08 g, 8.89 mmol),
trichloroacetonitrile (1.16 mL, 11.56 mmol) and DCM (17 mL). DBU (0.13 mL, 0.89 mmol) was
added and the reaction mixture was stirred at room temperature for 18 h. The solvent was then
removed in vacuo. Triethylamine (1 mL) was added and the residue was purified by silica gel
chromatography (1% triethylamine/9% ethyl acetate/90% hexanes) to provide S3 as white
crystals (1.82 g, 73%).
32. Clear colorless oil (1.82 g, 73%); TLC Rf = 0.68 (10% ethyl acetate/90% hexanes); IR (KBr)
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3342, 3025, 2980, 2931, 1662, 1288 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.27 (br s, 1H), 7.51ꢀ
7.48 (m, 1H), 7.25ꢀ7.14 (m, 3H), 6.14 (q, J = 6.5 Hz, 1H), 2.42 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 161.5, 139.7, 134.7, 130.3, 127.7, 126.3, 125.1, 91.8, 74.3, 21.0,
19.0. Anal. Calcd for C11H12Cl3NO: C, 47.09; H, 4.31; N,4.99. Found: C, 46.88; H, 4.06; N,
4.81.
4-Methyl-N-(1-(o-tolyl)ethyl)benzenesulfonamide (33).6b
Prepared using procedure A (0.21 g, 94%) using imidate 32 and purified using silica gel
chromatography (30% ethyl acetate/70% hexanes).
33. Offꢀwhite solid (0.31 g, 94%); mp = 87ꢀ89 °C; TLC Rf = 0.56 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.50 (dt, J = 8.3, 1.7 Hz, 2H), 7.06ꢀ7.01 (m, 3H), 6.95ꢀ
6.87 (m, 3H), 5.60 (d, J = 7.2 Hz, 1H), 4.62 (p, J = 6.9 Hz, 1H), 2.24 (s, 3H), 2.10 (s, 3H), 1.23
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(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.0, 140.5, 137.7, 134.3, 130.3, 129.4,
127.1, 127.0, 126.4, 125.5, 49.8, 23.1 21.5, 19.0.
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1-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethyl 2,2,2-trichloroacetimidate (34).
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To a round bottom flask under argon was added 1ꢀ(6ꢀbromobenzo[d][1,3]dioxolꢀ5ꢀyl)ethanol38
(2.90 g, 11.83 mmol), DBU (0.18 mL, 1.18 mmol) and DCM (39 mL). The reaction mixture was
stirred at room temperature for 15 min. and then cooled to 0°C in an ice/water bath.
Trichloroacetonitrile (1.53 mL, 15.38 mmol) was added to the reaction mixture and the reaction
mixture was warmed to room temperature and stirred overnight. The solvent was then removed
in vacuo. Triethylamine (1 mL) was added and the residue was purified by silica gel
chromatography (1% triethylamine/50% ethyl acetate/49% hexanes) to provide 34 as a clear
colorless oil (3.80 g, 83%).
34. Clear colorless oil (3.80 g, 83%); TLC Rf = 0.69 (30% ethyl acetate/70% hexanes); IR (thin
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film on KBr) 3339, 3080, 2983, 2930, 2897, 1667 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.37 (br
s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.17 (q, J = 6.4 Hz, 1H), 5.96 (q, J = 1.2 Hz, 2H), 1.58 (d, J =
13
6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 161.1, 147.81, 147.80, 134.2, 112.6, 112.0, 106.2,
101.8, 91.5, 76.3, 21.0. Anal. Calcd for C11H9BrCl3NO3: C, 33.92; H, 2.33; N,3.60. Found: C,
33.88; H, 2.49; N, 3.48.
N-(1-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethyl)-4-methylbenzenesulfonamide (35).
Prepared using procedure A (0.29 g, 88%) using imidate 34 and purified by silica gel
chromatography (30% ethyl acetate.70% hexanes).
35. Yellow powder (0.29 g, 88%); mp = 106 °C (dec); TLC Rf = 0.53 (30% ethyl acetate/70%
1
hexanes); IR (KBr) 3272, 2986, 1714, 1503, 1478, 1326 cmꢀ1; H NMR (400 MHz, CDCl3) δ
7.64 (dt, J = 8.5, 1.9 Hz, 2H), 7.18 (dd, J = 8.4, 0.5 Hz, 2H), 6.82 (s, 1H), 6.69 (s, 1H), 5.89 (dd,
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J = 6.9, 1.4 Hz, 2H), 5.46 (d, J = 6.6 Hz, 1H), 4.79 (p, J = 6.8 Hz, 1H), 2.38 (s, 3H), 1.32 (d, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.6, 147.4, 143.2, 137.0, 134.6, 129.4, 127.2,
112.37, 112.36, 107.4, 101.8, 52.9, 22.9, 21.5. Anal. Calcd for C16H16BrNO4S: C, 48.25; H, 4.05;
N, 3.52. Found: C, 48.07; H, 4.06; N, 3.30.
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1-(Furan-2-yl)pentyl 2,2,2-trichloroacetimidate (36).
To a round bottom flask containing 1ꢀ(furanꢀ2ꢀyl)pentanꢀ1ꢀol39 (0.52 g, 3.37 mmol) dissolved in
DCM (33 mL) was added trichloroacetonitrile (0.58 g, 4.04 mmol) and DBU (0.05 g, 0.34
mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was then
removed in vacuo. Triethylamine (1 mL) was added and the residue was purified by silica gel
chromatography (1% triethylamine/19% ethyl acetate/80% hexanes) to provide 36 as a yellow oil
(0.32 g, 33%).
36. Yellow oil (0.32 g, 33%); TLC Rf = 0.62 (20% ethyl acetate/80% hexanes); IR (KBr) 3346,
2960, 2873, 1656, 1501 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.40 (dd, J = 1.8, 0.8
Hz, 1H), 6.39 (d, J = 3.12 Hz, 1H), 6.34 (dd, J = 3.2, 1.8 Hz, 1H), 5.96 (t, J = 6.6 Hz, 1H), 2.18ꢀ
2.08 (m, 1H), 2.07ꢀ1.98 (m, 1H), 1.47ꢀ1.26 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.0, 152.3, 142.4, 110.2, 108.5, 91.7, 73.9, 32.4, 27.4, 22.3, 13.9. Anal. Calcd
for C11H14Cl3NO2: C, 44.25; H, 4.73; N, 4.69. Found: C, 44.49; H, 4.45; N, 4.79.
N-(1-(Furan-2-yl)pentyl)-4-methylbenzenesulfonamide (37).40
Prepared using procedure A (0.09 g, 44%) with imidate 37 and purified using silica gel
chromatography (20% ethyl acetate/80% hexanes).
37. Reddish solid (0.09 g, 44%); mp = 54ꢀ56 °C; TLC Rf = 0.38 (20% ethyl acetate.80%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.61 (dt, J = 8.5, 1.9Hz, 2H), 7.18 (dd, J = 8.5, 0.6 Hz,
2H), 7.12 (dd, J = 1.8, 0.8 Hz, 1H), 6.09 (dd, J = 3.2, 1.8 Hz, 1H), 5.89 (d, J = 3.2 Hz, 1H), 5.1
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(d, J = 8.7 Hz, 1H),4.38 (q, J = 7.3 Hz, 1H), 2.37 (s, 3H). 1.78ꢀ1.73 (m, 2H), 1.28ꢀ1.20 (m, 3H),
1.18ꢀ1.11 (m, 1H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 153.2, 142.9, 141.7,
137.8, 129.3, 127.0, 109.9, 106.7, 51.7, 34.7, 27.7, 22.1, 21.4, 13.8.
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N-Benzhydryl-4-methylbenzenesulfonamide (39).41
Prepared using procedure A (0.23 g, 89%) using the known imidate42 and purified using silica
gel chromatography (20% ethyl acetate/80% hexanes).
39. White powder (0.23 g, 89%); mp = 122ꢀ124 °C; TLC Rf = 0.42 (20% ethyl acetate/80%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.56 (dt, J = 8.5, 2.0 Hz, 2H), 7.23ꢀ7.19 (m, 6H), 7.15ꢀ
13
7.08 (m, 6H), 5.56 (d, J = 6.8 Hz, 1H), 5.01 (d, J = 6.8 Hz, 1H), 2.38 (s, 3H); C NMR (100
MHz, CDCl3) δ 143.2, 140.6, 137.4, 129.4, 128.5, 127.5, 127.4, 127.2, 61.4, 21.5.
Methyl 4-(4-(phenyl(2,2,2-trichloro-1-iminoethoxy)methyl)phenyl)butanoate (40).
To a round bottom flask containing alcohol 5625 (0.0 9 g, 0.31 mmol) was added DCM (1 mL)
followed by trichloroacetonitrile (0.06 g, 0.38 mmol) and DBU (0.01 g, 0.03 mmol). The
reaction mixture was stirred at room temperature for 4 hours. The solvent was then removed in
vacuo. Triethylamine (1 mL) was added to the residue and the reaction mixture was purified by
silica gel chromatography (1% triethylamine/29% ethyl acetate/70% hexanes) to provide 40 as a
pale yellow oil (0.130 g, 99%).
40. Pale yellow oil (0.13 g, 99%); TLC Rf = 0.22 (30% ethyl acetate/70% hexanes); IR (KBr)
1
3651, 3279, 1731, 1495 cmꢀ1; H NMR (400 MHz CDCl3) δ 8.40 (br s, 1H), 7.43ꢀ7.41 (m, 2H),
7.35ꢀ7.33 (m, 4H), 7.29ꢀ7.28 (m, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 3.63 (s, 3H), 2.62 (t,
J = 7.4 Hz, 2H), 2.32 (t, J = 7.4 Hz, 2H), 1.93 (p, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 173.8, 161.4, 141.2, 139.9, 137.5, 128.6, 128.5, 128.0, 127.1, 126.9, 91.7, 81.3, 51.5, 34.8, 34.4
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26.3. Anal. Calcd for C20H20Cl3NO3: C, 56.03; H, 4.70; N, 3.27. Found: C, 56.28; H, 4.90; N,
3.28.
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Methyl 4-(4-((4-methylphenylsulfonamido)(phenyl)methyl)phenyl)butanoate (41).
Prepared following procedure A (0.23 g, 67%) with imidate 40 and purified using silica gel
chromatography (30% ethyl acetate/70% hexanes) followed by a second purification using silica
gel chromatography (100% DCM).
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41. Clear colorless oil (0.23 g, 67%); TLC Rf = 0.45 (30% ethyl acetate/70% hexanes); IR (thin
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film on KBr) 3328, 3227, 3062, 2950, 2864, 1731, 1599 cmꢀ1; H NMR (400 MHz, CDCl3) δ
7.55 (dt, J = 6.6, 1.6 Hz, 2H), 7.20ꢀ7.17 (m, 3H), 7.12ꢀ7.09 (m, 4H), 7.00 (d, J = 1.6 Hz, 4H),
5.53 (d, J = 6.9 Hz, 1H), 5.32 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H), 2.56 (t, J = 7.4 Hz, 2H), 2.36 (s,
13
3H), 2.29 (t, J = 7.4 Hz, 2H), 1.88 (p, J = 7.6 Hz, 2H); C NMR (100 MHz, CDCl3) δ 174.0,
143.0, 140.8, 140.7, 138.3, 137.4, 129.3, 128.6, 128.5, 127.44, 127.40, 127.3, 127.2, 61.1, 51.7,
34.6, 33.3, 26.4, 21.4. Anal. Calcd for C25H27NO4S: C, 68.62; H, 6.22; N, 3.20. Found: C, 68.52;
H, 6.44; N, 3.59.
N-(4-Methoxybenzyl)-4-methylbenzenesulfonamide (43).43
Prepared using procedure A (0.17 g, 75%) using the commercially available imidate and purified
using silica gel chromatography (100% DCM) followed by recrystallization from methanol.
43. White solid (0.17 g, 75%); mp = 122ꢀ123 °C; TLC Rf = 0.61 (40% acetone/60% hexanes); 1H
NMR (300 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.10 (d J = 8.7 Hz,
2H), 6.79 (d, J = 8.7 Hz, 2H), 4.59 (t, J = 5.8 Hz, 1H), 4.05 (d, J = 6.0 Hz, 2H), 3.78 (s, 3H),
2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 143.5, 136.9, 129.7, 128.3, 129.3, 127.2,
114.1, 55.3, 46.8, 21.5.
4-Methyl-N-(2-methylbenzyl)benzenesulfonamide (45).44
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Prepared using procedure A (0.12 g, 55%) using the known imidate45 and purified using silica
gel chromatography (30% ethyl acetate/70% hexanes).
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45. White solid (0.12 g, 55%); mp = 107ꢀ109 °C; TLC Rf = 0.31 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.76 (dt, J = 8.5, 2.0 Hz, 2H), 7.31 (dd, J = 8.5, 0.6 Hz,
2H), 7.20ꢀ7.10 (m, 4H), 4.45 (t, J = 5.8 Hz, 1H), 4.09 (d, J = 6.0 Hz, 2H), 2.44 (s, 3H), 2.24 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 143.6, 136.7, 136.6, 133.9, 130.6, 129.7, 128.9, 128.3,
127.2, 126.2, 45.4, 21.6, 18.8.
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N-(Cyclohex-2-en-1-yl)-4-methylbenzenesulfonamide (49).46
Prepared using procedure A (0.12 g, 60%) using the known imidate47 and purified using silica
gel chromatography (30% ethyl acetate/70% hexanes).
49. Colorless crystals (0.12 g, 60%); mp = 99ꢀ100 °C; TLC Rf = 0.45 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.77 (dt, J = 8.5, 2.0 Hz, 2H), 7.30 (dd, J = 8.5, 0.6 Hz,
2H). 5.79ꢀ5.74 (m, 1H), 5.37ꢀ5.32 (m, 1H), 4.44 (d, J = 8.6 Hz, 1H), 3.84ꢀ3.79 (m, 1H), 2.43 (s,
13
3H), 2.00ꢀ1.87 (m, 2H), 1.79ꢀ1.73 (m, 1H), 1.64ꢀ1.50 (m, 3H); C NMR (100 MHz, CDCl3) δ
143.2, 138.4, 131.5, 129.7, 127.1, 127.0, 49.0, 30.2, 24.5, 21.5, 19.3.
N-Allyl-4-methylbenzenesulfonamide (51).48
Prepared using procedure A (0.05 g, 28%) using the commercially available imidate and purified
using silica gel chromatography (30% ethyl acetate/ 70% hexanes).
51. Offꢀwhite solid (0.05 g, 28%); mp = 53ꢀ56 °C; TLC Rf = 0.42 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz CDCl3) δ 7.76 (dt, J = 8.5, 2.0 Hz, 2H), 7.31 (dd, J = 8.5, 0.6 Hz,
2H), 5.77ꢀ5.68 (m, 1H), 5.19ꢀ5.08 (m, 2H), 4.51 (t, J = 4.50 Hz, 1H), 3.59 (tt, J = 6.1, 1.5 Hz,
2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.5, 137.0, 133.0, 129.7, 127.2, 117.7, 45.8,
21.5.
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N,4-Dimethylbenzenesulfonamide (53).49
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Prepared using procedure A (0.010 g, 5%) using the commercially available imidate and purified
using silica gel chromatography (30% ethyl acetate/70% hexanes).
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53. Offꢀwhite solid (0.010 g, 5%); mp = 69ꢀ71 °C; TLC Rf = 0.33 (30% ethyl acetate/70%
hexanes); 1H NMR (400 MHz CDCl3) δ 7.68 (dt, J = 8.3Hz, 2H), 7.25 (dd, J = 8.4, 0.5 Hz, 2H),
13
4.22 (d, J = 4.7 Hz, 1H), 2.58 (d, J = 5.4 Hz, 3H), 2.37 (s, 3H); C NMR (100 MHz, CDCl3) δ
143.5, 135.8, 129.7, 127.3, 29.4, 21.5.
Methyl-4-(4-((4-chlorophenylsulfonamido)(phenyl)methyl)phenyl)butanoate (57).25
Prepared using procedure A (0.08 g, 88%) and purified using silica gel chromatography (30%
ethyl acetate/70% hexanes).
57. Clear colorless oil (0.08 g, 88%); TLC Rf = 0.40 (30% ethyl acetate/70% hexanes); IR (KBr)
3153, 2986, 2820, 1730, 1586 cmꢀ1; 1H NMR (400 MHz CDCl3) δ 7.53 (dt, J = 9.2, 2.5 Hz, 2H),
7.25ꢀ7.18 (m, 5H), 7.12ꢀ7.09 (m, 2H), 7.00 (br s, 4H), 5.58 (d, J = 7.6 Hz, 1H), 5.53 (d, J = 7.6
Hz, 1H), 3.65 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 2.30 (t, J = 7.4 Hz, 2H), 1.89 (p, J = 7.6 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 173.9, 141.1, 140.2, 139.0, 138.7, 137.7, 128.9, 128.7, 128.59,
128.57, 127.7, 127.4, 127.3, 61.3, 51.6, 34.6, 33.4, 26.4. Anal. Calcd for C24H24ClNO4S: C,
62.94; H, 5.28; N, 3.06. Found: C, 63.17; H, 5.35; N, 3.22.
1
Supporting Information Available: Copies of H NMR and 13C NMR spectra of new
compounds and chiral HPLC data for compounds 2 and 3. This material is available free of
charge via the Internet at http:// pubs.acs.org.
Author Information:
Corresponding Author
*Eꢀmail: jdchisho@syr.edu
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The authors declare no competing financial interest.
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Acknowledgements: Financial support was provided by the National Institute of General
Medical Sciences (R15ꢀGM116054). Acknowledgement is also made to the Donors of the
American Chemical Society Petroleum Research Fund for a New Directions award in support of
this research (54823ꢀND1). NMR spectra were obtained at Syracuse University using
instrumentation acquired with the assistance of the National Science Foundation (CHEꢀ
1229345).
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