4-Cyanobenzenesulfonamides: Amine Synthesis and Protecting Strategy To Compliment the Nosyl Group

Article abstract of DOI:10.1021/acs.joc.7b00608

4-Cyanobenzenesulfonamides of secondary amines were found to cleave to the parent amine cleanly under the action of thiol and base. This feature readily lends itself to the use of this motif as an amine protecting/activating group within a broader context of amine synthesis. The crystalline sulfonamides could be further elaborated by alkylation and arylation similarly to nitrobenzenesulfonamides. The sulfonamides could withstand conditions that functionalize nitroarenes, such as reductions and vicarious nucleophilic substitution reactions.

Full text of DOI:10.1021/acs.joc.7b00608

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Featured Article
4-Cyanobenzenesulfonamides: An Amine Synthesis
and Protecting Strategy to Compliment the Nosyl Group
Michael A. Schmidt, Ryjul W. Stokes, Merrill L. Davies, and Frederick Roberts
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00608 • Publication Date (Web): 14 Apr 2017
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4ꢀCyanobenzenesulfonamides: An Amine Synthesis and Protecting Strategy to Compliment the Nosyl
Group
Michael A. Schmidt1*, Ryjul W. Stokes1, Merrill L. Davies2, Frederick Roberts2.
1Chemical & Synthetic Development, Technologies Group
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2Chemical & Synthetic Development, Special Analytical Support
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BristolꢀMyers Squibb, 1 Squibb Dr, New Brunswick NJ, 08903
Abstract:
4ꢀCyanobenzenesulfonamides of secondary amines were found to cleave to the parent amine
cleanly under the action of thiol and base. This feature readily lends itself to the use of this motif as an
amine protecting/activating group within a broader context of amine synthesis. The crystalline
sulfonamides could be further elaborated by alkylation and arylation similarly to
nitrobenzenesulfonamides. The sulfonamides could withstand conditions that functionalize nitroarenes,
such as reductions and vicarious nucleophilic substitution reactions.
Introduction
In the course of a recent project, we desired a synthetic strategy with stable, predominately
crystalline intermediates. This feature could allow for efficient, large scale purification of compounds via
crystallization rather than tedious chromatography and also allow for easy handling, transport and storage
of intermediates in the synthetic route. A pꢀtoluenesulfonamide derivative met these criteria, however
proved too stable to be easily cleaved, jeopardizing more sensitive functional groups.1 Many derivatives
with easily cleavable sulfonamide groups (e.g. SES, 9ꢀanthracenylsulfonyl) were oils and/or unstable to
downstream chemistry and oftentimes the corresponding sulfonyl chloride was expensive and/or not
readily available. The easily cleavable nosyl group, pioneered by Fukuyama2, was not strategic, as there
was nitroꢀspecific chemistry in the sequence. Screening a wide variety of readily available, potentially
easily removable sulfonamides, we found both 2ꢀ and 4ꢀcyanobenzenesulfonamides (abbreviated herein
as 2ꢀCs and 4ꢀCs respectively) could be cleaved with thiolate anions, similarly to the nosyl group. We
chose to focus more on the 4ꢀCs over the 2ꢀCs as the compounds were on average, more crystalline.
Herein we describe the applicability of 4ꢀcyanobenzenesulfonamides in complex amine synthesis and as a
protecting group.
Results and Discussion
A convenient source of the 4ꢀCs group is the commercially available sulfonyl chloride. We found
however, that certain commercial lots contained significant amounts (up to 13 weight percent by
quantitative NMR analysis) of insoluble, NMR and HPLCꢀsilent solids, likely stemming from the reagent
preparation.3 To remedy this, we developed a purification protocol to improve the quality of the reagent.
The crude sulfonyl chloride is stirred in warm toluene, filtered warm to remove insoluble impurities and
then the solvent is removed. A further recrystallization, if desired, from toluene and hexane affords 4ꢀ
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CsCl as sandy, light beige crystals (m.p. 108–109 °C). The sulfonic acid was never detected in large
amounts by HPLC analysis, and what little was detected remains mostly in the filter cake during the
initial filtration. However the uncertainty in the ionization state of this impurity in the commercial lot
(e.g. free acid or an unknown salt form) led us to examine a more general solution to remove it using an
aqueous wash. We found it is possible to wash the impurities away with a 1 M, pH=7 aqueous sodium
phosphate buffer without any significant reaction with the sulfonyl chloride.
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A variety of amines were sulfonylated under two mild, general conditions (Table 1). The choice
of the condition depended on the amine (aryl or alkyl). For anilines, the optimal conditions were 2,6ꢀ
lutidine as a base and dichloromethane as the solvent. In the case of pꢀbromoaniline we found the use of
stronger bases such as triethylamine could lead to double sulfonylation owing to the acidity of the product
2.4 This disulfonylated compound did not act as a Csꢀ transfer reagent, even after addition of DMAP (10
mol%). The deactivated Nꢀmethyl nitroaniline required pyridine as a base and 1,2ꢀdichloroethane at 60°C
for 24 h to reach completion to form 3. Upon aqueous work up, many sulfonylated anilines precipitated
from the organic layer. Exchanging the solvent for tetrahydrofuran before water addition solubilized the
products and allowed for a much easier aqueous work up. Interestingly, performing the sulfonylation of
the anilines in tetrahydrofuran was prohibitively slow. For most primary and secondary alkyl amines, the
sulfonamide is synthesized cleanly with triethylamine in tetrahydrofuran. These reaction were run at
approximately 0ꢀ5 °C to mitigate the exotherm of the reaction. In the case of the serine amino acid
derivative leading to product 9, we found the inverse, dropwise addition of the trimethylamine last
minimized the selfꢀoligomerization of the free amino ester, observed to minor extent (~5%) otherwise.
Table 1. Sulfonylation of Amines with 4ꢀCsCl.
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The resulting sulfonamides were capable of being further functionalized under conditions
comparable to nitrobenzenesulfonamides (Table 2).2 For example, the sulfonamides could be alkylated
under Mitsunobu conditions (Table 2, Entries 1ꢀ3). The optimal conditions were triphenylphosphine
(1.25 to 2.00 equiv.) with DEAD or DIAD (1.25 to 2.00 equiv.). With ADDP, the competing side
reaction to form product 2,5ꢀdipiperdinꢀ1ꢀylꢀ1,3,4ꢀoxadiazole was observed in significant amounts.
Sulfonamide 4 could be converted to PMB derivative 10 with predominant inversion (96.8 to 3.2 e.r.) and
the serine derivative could be converted to the highly crystalline aziridine 11. Interestingly, in the case of
the aryl sulfonamide 2 the stabilized ylide 2ꢀ(triphenylꢀλ5ꢀphosphanylidene)acetonitrile could function as
a dehydrating agent (1.50 equiv., 90 °C, 2 h) in a similar fashion to the work of Tsunoda.5 This particular
ylide reagent worked well only for the aryl sulfonamide; the alkyl sulfonamides (e.g. 5) are likely not
acidic enough to participate as efficiently.4 Standard alkylation conditions (2.00 equiv. electrophile, 2.00
equiv. potassium carbonate, 5.00 mL/g DMF) could also be used to propargylate the indoyl sulfonamide 7
(Table 2, Entry 4) or alkylate the sulfonamide 8 (Table 2, Entry 5) without epimerization (99.9 to 0.1 e.r.).
Arylation of the sulfonamides can be achieved using a direct SNAr of 5 with the appropriately activated 1ꢀ
fluoroꢀ2ꢀnitrobenzene (1.50 equiv.) with potassium carbonate (2.00 equiv.) in DMF at 100 °C (Table 2,
Entry 6). Additionally, arylation can also be achieved by a ChanꢀEvansꢀLam coupling6, as exemplified
by 15 (Table 2, Entry 7).
Table 2. Derivatization of 4ꢀCyanobezenesulfonamides
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The cleavage of a secondary sulfonamide occurred analogously to the nosyl group and was
initially observed using 10.0 equivalents of 1ꢀdodecanethiol and 9.5 equivalents of cesium carbonate in
dimethylsulfoxide at room temperature.7 While this reaction was clean and rapid, we sought to identify
an alternative base and solvent pair that would be more economical and practical to use. To that end we
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screened a variety of additional solvents (methanol, toluene, acetonitrile, tetrahydrofuran and
dimethylformamide) and bases (cesium carbonate, potassium carbonate, potassium hydroxide,
trimethylamine, Hunig’s base and DBU). From this screen we identified that base strength and base
solubility were important parameters that affected the rate of the deprotection, with the stronger, soluble
base DBU being optimal. Subtle solvent effects also impacted the rate. While the cleavage of 1 in
toluene took nearly 24 h, the reaction was complete in 11 h in fluorobenzene, 7 h in trifluorotoluene and 3
h in nitrobenzene. Ultimately, DMF provided the fastest rate, and allowed the reduction of the thiol to
5.00 equivalents and the DBU to 4.75 equivalents. Heating the reactions to 50 or 60 °C generally
provided more byproducts. Other mercaptans were not effective, such 2ꢀmercaptoacetic acid (multiple
byproducts) and pꢀthiocresol (no reaction). Commercial, HPLC grade DMF was used which had a typical
water content of 47ꢀ370 ppm by Karl Fischer titration. To test the tolerability of the reaction towards
water, the deprotection of 12 was studied with varying levels of water in the DMF solvent. DMF with a
water content of 360 ppm, 0.1622 wt% and 0.7557 wt% had near identical rate and purity profile. There
was a slight depression in rate at the highest level of water. As expected, the combination of the thiol
and base in DMF was sensitive to air, and if present would lead to oxidative dimerization of the thiol to
the disulfide which would precipitate from solution. A control experiment revealed that sparging a
solution of the thiol in DMF with nitrogen for a minimum of 20 min prior to the introduction of the base
eliminated the oxidation.8 Thus the optimium protocol for deprotection was sparging a solution of the
substrate and dodecanethiol (5.00 equiv.) in DMF (10 mL/g) for 20 min followed by the addition of DBU
(4.75 equiv.) and stirring under nitrogen. For small scale experiments (<1 mL reaction volume),
transferring a sparged stock solution of the thiol in DMF into a purged vessel containing the substrate
prior to DBU introduction was effective. A variety of substrates were deprotected under this protocol
(Table 3) with good yields. During the deprotection of the tryptamine sulfonamide derivative 13, we
isolated a small amount (~5%) of the Markovnikov hydrothiolationꢀadduct. The rates of deprotection
appeared to correlate with the electronics of the nitrogen of the sulfonamide, with electronꢀpoor substrates
reacting, on average, faster. As a whole, the deprotection of the Cs group is slower than the Ns group,
potentially due to a smaller concentration of the productive JacksonꢀMeisenheimer complex.9
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Table 3. Deprotection of the Sulfonamide Group
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We next preliminarily examined the scope and limitations of a 4ꢀCs strategy (Figure 1).
Unfortunately, primary sulfonamides (e.g. 2 and 4) were not deprotected to any major extent under the
current reaction conditions. A possible explanation is that the smaller concentration of the Jacksonꢀ
Meisenheimer complex (relative to a nosyl deprotection) is further stymied by the likely deprotonation of
the sulfonamide to form the relatively electonꢀrich sulfonamide anion.4 To explore this hypothesis,
treatment of sulfonamide 4 with Boc2O and 10 mol% DMAP in dichloromethane afforded the Bocꢀ
protected sulfonamide 22 which after solvent concentration, was used directly in the 4ꢀCs deprotection
affording the carbamate 23 in 93% overall yield (Figure 1, Equation 1). Addition of Boc2O (or TFAA),
1ꢀdodecanethiol and DBU at once to 4 did not lead to 22 or 23, additionally, the use of SꢀBoc
dodecanethiol10 and DMAP was not successful. We next examined the stability of the 4ꢀCs group to a
variety of reaction conditions (Figure 1, Equations 2 and 3) that could be incompatible with a nosyl
group. Gratifyingly, nitro sulfonamide 3 could be functionalized selectively at the nitro group under
certain cases without attack at the nitrile of the sulfonamide. For example, the nitro group in 3 was
reduced to an amino group, 24 with zinc and isobutyric acid in 90% yield. In addition, 3 could be
functionalized using a vicarious nucleophilic substitution reaction with chloromethyl phenylsulfone in
good yield (92%).11 Treatment of 1 with 3.00 equivalents 10 M aqueous sodium hydroxide in
tetrahydrofuran at 50 °C for 24 h afforded no reaction, as did treatment of 1 with 3.00 equivalents of
hydrazine in tetrahydrofuran at 50 °C for 24 h. Interestingly, treatment of 1 with 3.00 equivalents of 50
wt% aqueous hydroxylamine (Figure 1, Equation 4) at 50 °C for 5 h had completely converted 1 to two
products identified by LCMS as the amidoxime 26 (hydroxylamine addition) and the primary amide 27
(water addition) in approximately 60:40 ratio. The high level of the hydrolysis product may be explained
by Oꢀattack of hydroxylamine, potentially though the tautomer, ammonia oxide, followed by hydrolysis
of this activated imidate, a mode of reactivity proposed for hydroxylamineꢀmediated ester hydrolysis.12
A
sulfonamide 29 (Figure 1, Equation 5), prepared either from the sulfonylation of alanine derivative 28
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(97% yield) to give the corresponding sulfonamide 30 (not shown), then alkylation (97% yield, 99.5 to
0.5 e.r.), or through the Mitsunobu reaction of 4 with tertꢀbutyl Dꢀlactate (86% yield, 99.8 to 0.2 e.r.) was
found to undergo the deprotection to 31 in 80% yield, however we isolated 11% of a tertiary amine
product 32, resulting from the migration of the sulfonamide aryl group to the αꢀcarbon of the amino acid.
The rearrangement is known in the case of the nosyl group and other electron deficient sulfonamides of
amino esters (including 4ꢀCs).13 The resulting two products 31 and 32 however, were found to have low
enantiopurity (~60 to 40 e.r. for 31 and racemic for 32). A control deprotection experiment8 without
addition of thiol revealed that DBU is competent in racemizing 29 within 2 h, however with cesium
carbonate, the rate is much slower (91 to 9 e.r. after 24 h). Replacing the DBU with cesium carbonate in
the deprotection of 29 however, afforded both 31 and 32 in similar yields (80% and 6% respectively) but
only slightly better enantiopurity (~69 to 31 e.r. for 31 and 57 to 43 e.r. for 32, the absolute
stereochemistry was not determined, assigned to R by analogy to reference 13), indicating the possibility
that the thiolate anion is additionally responsible for the erosion. Replacing 1ꢀdodecanethiol with tertꢀ
dodecanethiol afforded predominately 32 (73.2 to 26.8 e.r. crude) and only a trace of 31. The use of the
polysulfide, sodium tetrasulfide was ineffective (trace product).
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Figure 1 Additional Reactions with Sulfonamides
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In conclusion we’ve explored the use of a 4ꢀcyanobenzenesulfonyl group to protect amines and
enable further nitrogen functionalization in a manner analogous to the nosyl group.
4ꢀ
cyanobenzenesulfonamides could be alkylated with alkyl halides or through a Mitsunobu reaction with
inversion. Additionally, the sulfonamides can be arylated through a direct SNAr of an appropriately
activated arene or with arylboronic acids through a ChanꢀEvansꢀLam coupling. We have shown that,
while the deprotection of the 4ꢀCs group is slower than the nosyl group, it can be removed efficiently with
dodecanethiol and DBU. The thiol was air sensitive under the deprotection conditions, however a
nitrogen sparge can effectively halt the oxidation.
We’ve demonstrated that the 4ꢀ
cyanobenzenesulfonamide group can survive nitroꢀspecific functional group manipulations such as a zinc
reduction and a vicarious nucleophilic substitution reaction. Lastly, a brief examination of the stability of
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the sulfonamide nitrile group to nucleophiles reveals stability towards hydrazine and hydroxide, however
a vulnerability towards hydroxylamine. Additionally, amino acid derivatives can undergo rearrangement
and partial racemization during the deprotection. The sum of these observations hold promise for the 4ꢀ
Cs group in synthetic strategies that contain nitroꢀ specific chemistry where a nosyl group may be
unsuitable.
Experimental Section
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General Experimental
All reactions were performed in round bottomed flasks or 1 dram screwꢀcap, pressure relief vials.
Stainless steel syringes were used to transfer liquids. All starting materials and reagents were corrected
for potency. Flash column chromatography was performed using silica gel (20ꢀ40 µm silica). Organic
solution were concentrated on a rotary evaporator at ~20 torr at 23ꢀ35 °C.
Analytical thin layer
chromatography was performed on TLC silica gel 60 F254 glass backed 2.5 x 7.5 cm plates and the
products were observed under ultraviolet light (254 nm). Melting points were determined with a capillary
melting point apparatus and are uncorrected. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded with a 400 MHz spectrometer and are recorded in parts per million from internal
tetramethylsilane on the δ scale and are referenced from the residual protium in the NMR solvent (CHCl3:
δ 7.27, C2D5HSO: δ 2.50). Data is reported as follows: chemical shift [multiplicity (app = apparent, s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants(s) in Hertz, integration].
Carbon nuclear magnetic resonance (13C NMR) spectra were recorded with a 400 MHz spectrophotometer
and are recorded in parts per million from internal tetramethylsilane on the δ scale and are referenced
from the carbon resonances in the NMR solvent (CHCl3: δ 77.0, C2D5HSO: δ 39.5). Data is reported as
follows: chemical shift.
Purification of 4-Cyanobenzenesulfonyl Chloride:
To commercial 4ꢀcyanobenzenesulfonyl chloride was added toluene (10.8 mL/g) and the mixture
was heated to an internal temperature of 50 °C, stirred for 5 min, then filtered at this temperature. The
solids, if present, were discarded and the supernatant can be analyzed by HPLC for the presence of the
sulfonic acid. If present, the cooled toluene stream can be washed with a pH 7 aqueous sodium phosphate
buffer (1.0 M, 10 mL/g), then dried over sodium sulfate, and filtered. If the sulfonic acid is not present,
the wash can be omitted. In either case, the toluene is then concentrated in vacuo to afford beige solids.
These solids are typically of good enough quality for use. If desired, these solids can be dissolved in
toluene (1.00 mL/g) at an internal temperature of 70 °C. Once dissolved, the solution is cooled to room
temperature with stirring. Upon reaching room temperature, hexanes (4.00 mL/g) is added slowly over 1
h and the slurry is aged for an additional 1 h. The crystals are isolated by filtration and the cake is washed
with hexanes (1.00 mL/g) then dried at room temperature in a vacuum oven with a light nitrogen sweep to
constant weight to afford the sulfonyl chloride as granular, light beige crystals. Typical recoveries are
approximately around 90% of theoretical.
(toluene/hexanes): 108ꢀ109 °C. H NMR (CDCl3, 400 MHz): δ 8.19 (app d, J=8.8 Hz, 2H), 7.95 (app d,
J=8.7 Hz, 2H).
Rf (15% ethyl acetate in hexanes): 0.46. M.p.
1
4-Cyano-N-(4-methoxyphenyl)-N-methylbenzenesulfonamide (1):
To a round bottomed flask was added 4ꢀmethoxyꢀNꢀmethylaniline hydrochloride (5.00 g, 28.2
mmol, 1.00 equiv.), dichloromethane (100 mL) and 2,6ꢀlutidine (7.26 mL, 62.1 mmol, 2.20 equiv.). 4ꢀ
Cyanobenzenesulfonyl chloride (5.81 g, 28.8 mmol, 1.02 equiv.) was added and the pale yellow solution
was stirred for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between
tetrahydrofuran (100 mL) and water (50 mL). The layers were separated and the aqueous layer was
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extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL),
dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark solid. The solids were
slurried in boiling isopropanol (200 mL) for 5 minutes, then allowed to cool to room temperature over 15
h. The solvent was reduced by 50% in vacuo then the crystals were isolated by filtration. The cake was
washed with a 50 volume% hexanes in isopropanol solution (2 x 25 mL), then dried in a vacuum oven at
50 °C, with a light nitrogen sweep to constant weight to afford the product as bone colored crystals (7.76
g, 91%).
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Rf (30% ethyl acetate in hexanes): 0.46. M.p. (isopropanol): 158ꢀ162 °C. 1H NMR (DMSOꢀd6, 400
MHz): δ 8.08 (app d, J=8.6 Hz, 2H), 7.67 (app d, J=8.6 Hz, 2H), 7.00 (app d, J=9.1 Hz, 2H), 6.89 (app d,
J=9.1 Hz, 2H), 3.74 (s, 3H), 3.13 (s, 3H). 13C NMR (DMSOꢀd6, 100.6 MHz): δ 158.5, 140.1, 133.4,
133.0, 128.2, 128.0, 117.6, 115.5, 114.2, 55.3, 38.5. IR (KBr) (cmꢀ1): 2231 (m), 1356 (s), 1247 (s), 1174
(s), 1024 (m). HRMS (ESI) (m/z): calc’d for C17H17O5N2S [M+OAc]–: 361.08527, found 361.08487.
N-(4-Bromophenyl)-4-cyanobenzenesulfonamide (2):
To a round bottomed flask was added 4ꢀbromoaniline (5.00 g, 28.2 mmol, 1.00 equiv.),
dichloromethane (100 mL) and 2,6ꢀlutidine (3.61 mL, 31.0 mmol, 1.10 equiv.). 4ꢀCyanobenzenesulfonyl
chloride (5.81 g, 28.8 mmol, 1.02 equiv.) was added and the pale yellow solution was stirred for 5 h. The
solvent was evaporated in vacuo and the residue was partitioned between tetrahydrofuran (100 mL) and
water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL), then the combined
organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in
vacuo to afford a dark yellow solid. The solids were dissolved in boiling isopropanol (200 mL), then
allowed to cool to room temperature over 4 h. The solvent was reduced by 50% in vacuo then the crystals
were isolated by filtration. The cake was washed with isopropanol (2 x 20 mL), then dried in a vacuum
oven at 50 °C, with a light nitrogen sweep to constant weight to afford the product as bone colored
crystals (8.05 g, 85%). Rf (15% ethyl acetate in hexanes): 0.35. M.p. (isopropanol): 205ꢀ206 °C. 1H
NMR (DMSOꢀd6, 400 MHz): δ 10.71 (s, 1H), 8.05 (app d, J=8.6 Hz, 2H), 7.90 (app d, J=8.6 Hz, 2H),
7.44 (app d, J=8.8 Hz, 2H), 7.04 (app d, J=8.8 Hz, 2H). 13C NMR (DMSOꢀd6, 100.6 MHz): δ 143.1,
136.4, 133.6, 132.2, 127.4, 122.4, 117.5, 117.0, 115.6. IR (KBr) (cmꢀ1): 3246 (br s), 2241 (m), 1331 (s),
1164 (s), 914 (m). HRMS (ESI) (m/z): calc’d for C13H8O2N2BrS [MꢀH]–: 334.94844, found 334.94815.
4-Cyano-N-methyl-N-(4-nitrophenyl)benzenesulfonamide (3):
To a round bottomed flask was added NꢀmethylꢀNꢀ4ꢀnitroaniline (5.00 g, 31.9 mmol, 1.00
equiv.), 1,2ꢀdichloroethane (50 mL) and pyridine (2.84 mL, 35.1 mmol, 1.10 equiv.).
4ꢀ
Cyanobenzenesulfonyl chloride (6.56 g, 32.5 mmol, 1.02 equiv.) was added and the mixture was heated
to an internal temperature of 60 °C and stirred for 24 h. The yellow solution was cooled to room
temperature and the solvent was removed in vacuo. The solids were dissolved in a mixture of
tetrahydrofuran (100 mL) and water (50 mL) with heating. After cooling, the aqueous layer was
separated and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with
brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The
solid was briefly (5 min) slurried in refluxing isopropanol (200 mL) and allowed to cool to room
temperature over 15 h affording a light colored solid with a yellow supernatant. The solvent was reduced
by 50% in vacuo and the solids were isolated by filtration. The dense cake was carefully suspended in a
solution of 50 volume% isopropanol in hexanes (20 mL) and deliquored and this process was repeated
twice more. The solids were dried in a vacuum oven at 50 °C, with a light nitrogen sweep to constant
weight to afford the product as bone colored solids (9.23 g, 91%). Rf (30% ethyl acetate in hexanes):
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0.31. M.p. (isopropanol): 165ꢀ166 °C. H NMR (DMSOꢀd6, 400 MHz): δ 8.22 (app d, J=9.4 Hz, 2H),
8.08 (app d, J=8.6 Hz, 2H), 7.75 (app d, J=8.6 Hz, 2H), 7.48 (app d, J=9.1 Hz, 2H), 3.25 (s, 3H). 13C
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NMR (DMSOꢀd6, 100.6 MHz): δ 146.3, 145.5, 139.5, 133.7, 128.1, 126.2, 124.4, 117.5, 116.1, 37.6. IR
(KBr) (cmꢀ1): 2238 (m), 1519 (s), 1361 (s), 1173 (s), 878 (m). HRMS (ESI) (m/z): calc’d for
C16H14O6N3S [M+AcO]–: 376.05978, found 376.05879.
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4-Cyano-N-(4-methoxybenzyl)benzenesulfonamide (4):
To a roundꢀbottomed flask was added 4ꢀmethoxybenzylamine (5.00 g, 35.4 mmol, 1.00 equiv.),
tetrahydrofuran (100 mL) and triethylamine (5.48 mL, 38.9 mmol, 1.10 equiv.). The solution was cooled
to an internal temperature of 3 °C with an iceꢀwater bath and 4ꢀcyanobenzenesulfonyl chloride (7.28 g,
36.1 mmol, 1.02 equiv.) was added in portions, maintaining the internal temperature below 15 °C (~30
min). The mixture was allowed to warm to room temperature and was stirred for 1 h. The slurry was
washed with water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The
combined organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to afford an orange solid. The crude was dissolved in
boiling isopropanol (100 mL), then allowed to cool with stirring for 15 h. The light beige crystals were
isolated by filtration and dried in a vacuum oven at 50 °C with a light nitrogen sweep to constant weight
(9.95 g, 93%). Rf (45% ethyl acetate in hexanes): 0.53. M.p. (isopropanol): 132.5ꢀ133 °C. 1H NMR
(DMSOꢀd6, 400 MHz): δ 8.39 (br t, J=6.2 Hz, 1H), 8.02 (app d, J=8.6 Hz, 2H), 7.88 (app d, J=8.1 Hz,
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2H), 7.09 (app d, J=8.8 Hz, 2H), 6.79 (app d, J=8.6 Hz, 2H), 3.97 (d, J=6.3 Hz, 2H), 3.70 (s, 3H). C
NMR (DMSOꢀd6, 100.6 Hz): δ 158.5, 145.1, 133.2, 129.1, 128.9, 127.2, 117.8, 114.6, 113.6, 55.1, 45.7.
IR (KBr) (cmꢀ1): 3244 (br s), 2233 (m), 1513 (s), 1343 (s), 884 (m). HRMS (ESI) (m/z): calc’d for
C15H18O3N3S [M+NH4]+: 320.10634, found 320.10733.
(–)-4-Cyano-N-(((1R,2S,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)benzenesulfonamide (5):
To a roundꢀbottomed flask was added (–)ꢀcisꢀmyrtanylamine (5.00 g, 32.0 mmol, 1.00 equiv.), 2ꢀ
methyltetrahydrofuran (100 mL) and triethylamine (4.95 mL, 35.2 mmol, 1.10 equiv.). The solution was
cooled to an internal temperature of 5 °C with an iceꢀwater bath and 4ꢀcyanobenzenesulfonyl chloride
(6.58 g, 32.6 mmol, 1.02 equiv.) was added in portions, maintaining the internal temperature below 15 °C
(~10 min). The mixture was allowed to warm to room temperature and was stirred for 1.5 h. The slurry
was washed with a 1 N aqueous solution of hydrochloric acid (100 mL), then a saturated, aqueous
solution of brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in
vacuo to afford a tan oil. The oil was purified by flash column chromatography over silica gel (25% ethyl
acetate in hexanes) to afford the product as a thick oil that crystallized upon standing (9.87 g, 97%). Rf
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(25% ethyl acetate in hexanes): 0.50. M.p. (ethyl acetate/hexane): 87ꢀ90 °C. H NMR (DMSOꢀd6, 400
MHz): δ 8.09 (app d, J=8.6 Hz, 2H), 7.91ꢀ7.94 (m, 3H), 2.72ꢀ2.76 (m, 2H), 2.24ꢀ2.30 (m, 1H), 2.02ꢀ2.10
(m, 1H), 1.75ꢀ1.88 (m, 5H), 1.29ꢀ1.37 (m, 1H), 1.08 (s, 3H), 0.85 (s, 3H), 0.78 (d, J=9.6 Hz, 1H). 13C
NMR (DMSOꢀd6, 100.6 MHz): δ 144.9, 133.4, 127.2, 117.8, 114.7, 47.8, 42.4, 40.7, 40.5, 38.1, 32.4,
27.6, 25.5, 22.7, 19.0. [α]D20: –14.24 ° (c = 8.17 mg/mL, chloroform). IR (KBr) (cmꢀ1): 3271 (br s), 2240
(m), 1343 (s), 1161 (s), 841 (m). HRMS (ESI) (m/z): calc’d for C17H21O2N2S [MꢀH]–: 317.13183, found
317.13126.
4-Cyano-N-(2-(pyridin-2-yl)ethyl)benzenesulfonamide (6):
To a roundꢀbottomed flask was added the amine (5.00 g, 38.9 mmol, 1.00 equiv.), tetrahydrofuran
(100 ml) and trimethylamine (6.02 mL, 42.8 mmol, 1.10 equiv.). The solution was cooled to an internal
temperature of 2.3 °C with an iceꢀwater bath and 4ꢀcyanobenzenesulfonyl chloride (8.00 g, 39.7 mmol,
1.02 equiv.) was added in portions, maintaining an internal temperature below 5 °C (~45 min). The
mixture was allowed to warm to room temperature and was stirred for 1 h. The slurry was washed with
water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined
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organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a red solid. The crude was slurried in boiling
isopropanol (150 mL) for 5 min, then was allowed to cool to room temperature and stir for 16 h. The
solvent was reduced by 50% then the crystals were isolated by filtration. The cake was washed with a 50
volume% hexanes in isopropanol solution (2 x 25 mL), then dried in a vacuum oven at 50 °C, with a light
nitrogen sweep to constant weight to afford the product as bone colored crystals (9.56 g, 86%). Rf (2.5%
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methanol in dichloromethane): 0.34. M.p. (isopropanol): 146ꢀ148 °C. H NMR (DMSOꢀd6, 400 MHz): δ
8.42 (ddd, J=4.8, 1.8, 1.0 Hz, 1H), 8.04ꢀ8.07 (m, 3H), 7.92 (app, d, J=8.6 Hz, 2H), 7.66 (td, J=7.6, 1.9
Hz, 1H), 7.17ꢀ7.21 (m, 2H), 3.18 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.3 Hz, 2H). 13C NMR (DMSOꢀd6, 100.6
Hz): δ 158.0, 149.0, 144.6, 136.4, 133.4, 127.2, 123.3, 121.6, 117.8, 114.8, 42.2, 37.3. IR (KBr) (cmꢀ1):
3017 (br m), 2232 (m), 1599 (m), 1321 (s), 1158 (s), 923 (m). HRMS (ESI) (m/z): calc’d for
C14H14O2N3S [M+H]+: 288.08012, found 288.08096.
N-(2-(1H-Indol-3-yl)ethyl)-4-cyanobenzenesulfonamide (7):
To a roundꢀbottomed flask was added tryptamine (5.00 g, 30.6 mmol, 1.00 equiv.),
tetrahydrofuran (100 ml) and trimethylamine (4.74 mL, 33.6 mmol, 1.10 equiv.). The solution was
cooled to an internal temperature of 2.5 °C with an iceꢀwater bath and 4ꢀcyanobenzenesulfonyl chloride
(6.29 g, 31.2 mmol, 1.02 equiv.) was added in portions, maintaining an internal temperature below 10 °C
(~10 min). The mixture was allowed to warm to room temperature and was stirred for 1 h. The slurry
was washed with water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The
combined organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to afford a red solid. The crude was dissolved in
boiling toluene (750 mL) whereupon a dark residue separated. The solution was decanted away from the
dark residue while hot, then was allowed to cool to room temperature and stir for 16 h. The beige crystals
were isolated by filtration and dried in a vacuum oven at 50 °C, with a light nitrogen sweep to constant
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weight (9.29 g, 93%). Rf (45% ethyl acetate in hexanes): 0.40. M.p. (toluene): 153ꢀ155 °C. H NMR
(DMSOꢀd6, 400 MHz): δ 10.80 (br s, 1H), 8.05 (t, J=5.7 Hz, 1H), 7.95 (app, d, J=8.6 Hz, 2H), 7.87 (app
d, J=8.8 Hz, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.04 (td, J=7.5,
1.1 Hz, 1H), 6.94 (td, J=7.4, 0.8 Hz, 1H), 3.05ꢀ3.10 (m, 2H), 2.79 (t, J=7.5 Hz, 2H). 13C NMR (DMSOꢀ
d6, 100.6 Hz): δ 144.7, 136.1, 133.2, 127.0, 126.9, 123.1, 120.1, 118.3, 118.0, 117.8, 114.6, 111.4, 110.7,
43.4, 25.4. IR (KBr) (cmꢀ1): 3400 (br s), 3262 (br s), 2239 (m), 1318 (s), 1155 (s), 846 (m). HRMS (ESI)
(m/z): calc’d for C17H14O2N3S [MꢀH]–: 324.08012, found 324.07953.
(–)-(S)-4-Cyano-N-(1-phenylethyl)benzenesulfonamide (8):
To a roundꢀbottomed flask was added the amine (5.00 g, 41.3 mmol, 1.00 equiv.), tetrahydrofuran
(100 ml) and trimethylamine (6.33 mL, 45.4 mmol, 1.10 equiv.). The solution was cooled to an internal
temperature of 0.4 °C with an iceꢀwater bath and 4ꢀcyanobenzenesulfonyl chloride (8.66 g, 42.1 mmol,
1.02 equiv.) was added in portions, maintaining an internal temperature below 5 °C (~30 min). The
mixture was allowed to warm to room temperature and was stirred for 1 h. The slurry was washed with
water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined
organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford an orange solid. The crude was dissolved in boiling
isopropanol (75 mL), then was allowed to cool to room temperature and stir for 1 h. The solvent was
reduced by 66% then the crystals were isolated by filtration. The cake was washed with isopropanol (2 x
10 mL), then dried in a vacuum oven at 50 °C, with a light nitrogen sweep to constant weight to afford the
product as white crystals (10.81 g, 92%). The product was found to have a chiral purity of 99.9 to 0.1 e.r.
by chiral HPLC analysis. Sample prep: 2.0 mg/mL in acetonitrile. Column: Phenomenex Lux Celluloseꢀ
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3 (3 µm, 4.6 x 150 mm). Column temperature: 30 °C. Detector wavelength: 254 nm. Injection volume:
4 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05 volume% trifluoroacetic acid in methanol:water
(20:80 volume%). Mobile phase “B”: 0.05 volume% trifluoroacetic acid in methanol:acetonitrile (20:80
volume%). Gradient: t=0 min: 0% “B”, t=24 min: 100% “B”, t=24 min: 100% “B”. 8: 13.26 min, ent-8:
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14.11 min. Rf (25% ethyl acetate in hexanes): 0.29. M.p. (isopropanol): 149ꢀ150 °C. H NMR (DMSOꢀ
d6, 400 MHz): δ 8.54 (d, J=8.3 Hz, 1H), 7.88 (app d, J=8.3 Hz, 2H), 7.73 (app d, J=8.6 Hz, 2H), 7.09ꢀ
7.16 (m, 5H), 4.41 (dq, J=8.3, 6.9 Hz, 1H), 1.26 (d, J=6.8 Hz, 3H). 13C NMR (DMSOꢀd6, 100.6 Hz): δ
145.5, 142.6, 132.9, 128.1, 127.1, 126.8, 126.0, 117.8, 114.2, 53.2, 23.6. [α]D20: –38.71 ° (c = 2.97
mg/mL, methanol). IR (KBr) (cmꢀ1): 3246 (m), 2235 (m), 1436 (m), 1334 (s), 1163 (s), 648 (m). HRMS
(ESI) (m/z): calc’d for C15H13O2N2S [MꢀH]–: 285.06922, found 285.06992.
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(+)-Benzyl (4-Cyanophenylsulfonyl)-L-serinate (9):
A mixture of Lꢀserine benzyl ester benzenesulfonate salt (5.00 g, 13.9 mmol, 1.00 equiv.) and 4ꢀ
cyanobenzensulfonyl chloride (2.84 g, 14.1 mmol, 1.02 equiv.) in tetrahydrofuran (100 mL) was cooled to
an internal temperature of 2.0 °C with an iceꢀwater bath and triethylamine (4.29 mL, 30.5 mmol, 2.20
equiv.) was added dropwise over 15 min, maintaining an internal temperature below 5.0 °C. The slurry
was warmed to room temperature and stirred for 1 h. The reaction mixture was poured into water (50
mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and
the combined organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to afford a tan oil. The residue was purified by flash
column chromatography over silica gel (0 to 5% methanol in dichloromethane gradient) to afford the
product as a white solid (4.11 g, 82%). The product was found to have a chiral purity of 99.8 to 0.2 e.r.
by chiral HPLC analysis. Sample prep: 2.0 mg/mL in isopropanol. Column: Chiralpak IG (5 µm, 4.6 x
150 mm). Column temperature: 30 °C. Detector wavelength: 254 nm. Injection volume: 5 µL. Flow
rate: 1.0 mL/min. Mobile phase “A”: heptane. Mobile phase “B”: 50:50 volume% methanol in ethanol.
Gradient: t=0 min: 5% “B”, t=25 min: 50% “B”, t=30 min: 50% “B”. 9: 17.84 min, ent-9: 19.60 min. Rf
(2.5% methanol in dichloromethane): 0.30. M.p. (methanol/dichloromethane): 123ꢀ124 °C. 1H NMR
(DMSOꢀd6, 400 MHz): δ 8.71 (d, J=8.8 Hz, 1H), 7.97 (app d, J=8.6 Hz, 2H), 7.92 (app d, J=8.6 Hz, 2H),
7.31ꢀ7.38 (m, 3H), 7.23ꢀ7.25 (m, 2H), 5.15 (t, J=5.7 Hz, 1H), 4.96 (d, J=12.6 Hz, 1H), 4.92 (d, J=12.9
Hz, 1H), 4.03 (dt, J=8.8, 5.6 Hz, 1H), 3.53ꢀ3.63 (m, 2H). 13C NMR (DMSOꢀd6, 100.6 Hz): δ 169.6,
145.2, 135.6, 133.1, 128.4, 128.0, 127.7, 127.2, 117.8, 114.8, 66.1, 62.0, 58.1. [α]D20: +44.93 ° (c = 8.17
mg/mL, chloroform). IR (KBr) (cmꢀ1): 3503 (br s), 3163 (br s), 2237 (m), 1744 (s), 1316 (s), 1164 (s),
839 (m). HRMS (ESI) (m/z): calc’d for C17H15O5N2S [MꢀH]–: 359.06962, found 359.06888.
(–)-(S)-4-Cyano-N-(4-methoxybenzyl)-N-(1-phenylethyl)benzenesulfonamide (10) (Via Mitsunobu
Reaction):
A solution of PMB sulfonamide 4 (1.00 g, 3.31 mmol, 1.00 equiv.), (R)ꢀ1ꢀphenylethanol (800 µL,
6.61 mmol, 2.00 equiv.) and triphenylphosphine (1.75 g, 6.61 mmol, 2.00 equiv.) in dichloromethane
(10.0 mL) was cooled to an internal temperature of 1.4 °C with an iceꢀwater bath and a solution of diethyl
azodicarboxylate (40 wt% in toluene, 3.01 mL, 6.61 mmol, 2.00 equiv.) was added slowly, maintaining
the internal temperature below 5 °C (90 min). The mixture was warmed to room temperature and stirred
for 1 h. The reaction mixture was purified directly by flash column chromatography twice (100%
dichloromethane for the first column, then 0 to 30% ethyl acetate in hexanes gradient for the second
column) to afford the product as a thick, clear gel that slowly crystallized (1.00 g, 74%). The product was
found to have a chiral purity of 96.8 to 3.2 e.r. by chiral HPLC analysis. Sample prep: 2.0 mg/mL in
acetonitrile. Column: Phenomenex Lux Celluloseꢀ1 (3µm, 4.6 x 150 mm). Column temperature: 30 °C.
Detector wavelength: 254 nm. Injection volume: 4 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05
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volume% trifluoroacetic acid in methanol:water (20:80 volume%). Mobile phase “B”: 0.05 volume%
trifluoroacetic acid in methanol:acetonitrile (20:80 volume%). Gradient: t=0 min: 0% “B”, t=20 min:
100% “B”, t=24 min: 100% “B”. ent-10: 18.08 min, 10: 18.96 min. Rf (25% ethyl acetate in hexanes):
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0.34. M.p. (ethyl acetate/hexanes): 85ꢀ86 °C. H NMR (DMSOꢀd6, 400 MHz): δ 7.99 (app d, J=8.6 Hz,
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2H), 7.86 (app d, J=8.6 Hz, 2H), 7.21ꢀ7.24 (m, 3H), 7.10ꢀ7.14 (m, 2H), 6.94 (app d, J=8.8 Hz, 2H), 6.72
(app d, J=8.6 Hz, 2H), 5.18 (q, J=7.0 Hz, 1H), 4.35 (d, J=15.7 Hz, 1H), 4.17 (d, J=15.7 Hz, 1H), 3.70 (s,
3H), 1.34 (d, J=7.1 Hz, 3H). 13C NMR (DMSOꢀd6, 100.6 Hz): δ 158.4, 144.8, 139.2, 133.2, 129.3, 129.1,
128.2, 127.62, 127.60, 127.4, 117.7, 114.8, 113.4, 56.3, 55.0, 47.2, 17.9. [α]D20: –56.89 ° (c = 7.11
mg/mL, chloroform). IR (KBr) (cmꢀ1): 2231 (m), 1615 (m), 1513 (s), 1359 (s), 834 (s). HRMS (ESI)
(m/z): calc’d for C23H22O3N2S [M+NH4]+: 424.16894, found 424.16919.
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(–)-Benzyl (S)-1-(4-cyanophenylsulfonyl)aziridine-2-carboxylate (11):
A suspension of the sulfonamide (+)-9 (1.00 g, 2.78 mmol, 1.00 equiv.) and triphenylphosphine
(919 mg, 3.47 mmol, 1.25 equiv.) was cooled to an internal temperature of 3.5 °C with an iceꢀwater bath
and a solution of diethyl azodicarboxylate (40 wt% in toluene, 1.58 mL, 3.47 mmol, 1.25 equiv.) was
added slowly, maintaining the internal temperature below 5 °C (30 min). The mixture was stirred for an
additional 1 h and became homogeneous then purified directly by flash column chromatography over
silica gel (15 to 30% ethyl acetate in hexanes) to afford the product as a white crystalline solid (659 mg,
69%). Rf (25% ethyl acetate in hexanes): 0.34. M.p. (ethyl acetate/hexane): 121ꢀ122 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.08 (app d, J=8.6 Hz, 2H), 7.82 (app d, J=8.8 Hz, 2H), 7.37ꢀ7.39 (m, 3H), 7.29ꢀ
7.30 (m, 2H), 5.18 (d, J=12.1 Hz, 1H), 5.14 (d, J=12.1 Hz, 1H), 3.44 (dd, J=7.1, 4.3 Hz, 1H), 2.89 (d,
J=7.1 Hz, 1H), 2.69 (d, J=4.3 Hz, 1H). 13C NMR (CDCl3, 100.6 MHz): δ 165.9, 141.2, 134.4, 132.9,
128.7, 128.6, 128.5, 128.3, 117.6, 116.9, 67.7, 36.4, 32.2. [α]D20: –28.37 ° (c = 13.06 mg/mL,
chloroform). IR (KBr) (cmꢀ1): 2232 (m), 1751 (s), 1331 (s), 1200 (s), 1164 (s). HRMS (ESI) (m/z):
calc’d for C19H17O6N2S [M+AcO]–: 401.08018, found 401.07941.
N-(4-Bromophenyl)-4-cyano-N-(3-phenylpropyl)benzenesulfonamide (12):
To the sulfonamide 2 (1.00 g, 2.97 mmol, 1.00 equiv.) and 3ꢀphenylꢀ1ꢀpropanol (721 µL, 5.19
mmol, 1.75 equiv.) in toluene (10 mL) was added triphenylphosphoranylideneacetonitrile (1.34 g, 4.45
mmol, 1.50 equiv.) and the mixture was heated in a 90 °C bath for 2 h, cooled to room temperature and
concentrated in vacuo. The residue was purified directly by flash column chromatography over silica gel
(100% dichloromethane) to afford the product as a thick oil that crystallized upon standing (1.30 g, 96%).
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Rf (15% ethyl acetate in hexanes): 0.30. M.p. (dichloromethane): 110ꢀ111 °C. H NMR (DMSOꢀd6, 400
MHz): δ 8.08 (app d, J=8.6 Hz, 2H), 7.72 (app d, J=8.6 Hz, 2H), 7.58 (app d, J=8.8 Hz, 2H), 7.24 (app t,
J=7.3 Hz, 2H), 7.15 (app t, J=7.3 Hz, 1H), 7.11 (app d, J=8.1 Hz, 2H), 7.06 (app d, J=8.6 Hz, 2H), 3.60
(app t, J=6.8 Hz, 2H), 2.57 (app t, J=7.7 Hz, 2H), 1.54ꢀ1.62 (m, 2H). 13C NMR (DMSOꢀd6, 100.6 MHz):
δ 141.1, 141.0, 137.3, 133.5, 132.3, 130.6, 128.3, 128.2, 128.0, 125.9, 121.4, 117.6, 115.6, 49.6, 31.7,
29.5. IR (KBr) (cmꢀ1): 2234 (m), 1488 (m), 1353 (s), 1163 (s), 1039 (m). HRMS (ESI) (m/z): calc’d for
C24H22O4N2BrS [M+AcO]–: 513.04782, found 513.04682.
N-(2-(1H-Indol-3-yl)ethyl)-4-cyano-N-(prop-2-yn-1-yl)benzenesulfonamide (13):
To a vigorously stirring suspension of sulfonamide 7 (1.00 g, 3.07 mmol, 1.00 equiv.) and
potassium carbonate (858 mg, 6.15 mmol, 2.00 equiv.) in dimethylformamide (Water content by Karl
Fischer titration: 99.9062 ppm, 5.00 mL) was added a solution of propargyl bromide (80 wt% in toluene,
685 µL, 6.15 mmol, 2.00 equiv.). The slurry was heated to an internal temperature of 100 °C under
nitrogen and was stirred for 15 h. The mixture was cooled to room temperature and partitioned between
water (10 mL) and ethyl acetate (10 mL). The layers were split and the aqueous layer was extracted with
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ethyl acetate (2 x 5 mL). The combined organic layers were washed with a saturated, aqueous solution of
brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark oil. The
crude was purified by flash chromatography over silica gel (0 to 25% ethyl acetate in hexanes gradient) to
afford a gel that was sonicated in methyl tertꢀbutyl ether (5 mL) for 5 min to produce a solid. The solid
was concentrated in vacuo and dried in a vacuum oven at 50 °C, with a light nitrogen sweep to constant
weight to afford the product as a fine, light yellow solid that entrained 5 mol% methyl tertꢀbutyl ether
(corrected mass: 810 mg, 72%). Rf (25% ethyl acetate in hexanes): 0.25. M.p. (methyl tertꢀbutyl ether):
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J=8.8 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.07 (app td,
J=7.5, 1.1 Hz, 1H), 6.97 (app td, J=7.0, 1.0 Hz, 1H), 4.27 (d, J=2.3 Hz, 2H), 3.45 (dd, J=8.7, 6.7 Hz, 2H),
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3.19 (t, J=2.4 Hz, 1H), 2.98 (dd, J=7.1, 6.5 Hz, 2H). C NMR (DMSOꢀd6, 100.6 Hz): δ 142.6, 136.2,
133.2, 127.9, 126.9, 123.2, 121.0, 118.4, 118.0, 117.7, 115.3, 111.5, 110.2, 77.0, 76.6, 47.1, 36.3, 23.7.
IR (KBr) (cmꢀ1): 3440 (br s), 3266 (s), 2233 (m), 1352 (s), 1163 (s). HRMS (ESI) (m/z): calc’d for
C20H18O2N3S [M+H]+: 364.11142, found 364.11264.
(–)-(S)-4-Cyano-N-(4-methoxybenzyl)-N-(1-phenylethyl)benzenesulfonamide (10) (Via Alkylation):
To a vigorously stirring suspension of sulfonamide 8 (99.9 to 0.1 e.r., 1.00 g, 3.49 mmol, 1.00
equiv.) and potassium carbonate (975 mg, 6.98 mmol, 2.00 equiv.) in dimethylformamide (Water content
by Karl Fischer titration: 73.4642 ppm, 5.00 mL) was added paraꢀmethoxybenzyl chloride (966 µL, 6.98
mmol, 2.00 equiv.). The slurry was heated to an internal temperature of 60 °C under nitrogen and was
stirred for 6 h. The mixture was cooled to room temperature and partitioned between water (10 mL) and
ethyl acetate (10 mL). The layers were split and the aqueous layer was extracted with ethyl acetate (2 x 5
mL). The combined organic layers were washed with a saturated, aqueous solution of brine (5 mL), dried
over sodium sulfate, filtered and concentrated in vacuo to afford a clear oil. The crude residue was
purified by flash chromatography over silica gel (0 to 30% ethyl acetate in hexanes gradient) to afford the
product as a thick gel that slowly solidified (1.35 g, 95%). The product was found to have a chiral purity
of 99.9 to 0.1 e.r. by chiral HPLC analysis. [α]D20: –59.37 ° (c = 7.11 mg/mL, chloroform). For
characterization data and chiral method, see above.
(–)-4-Cyano-N-(((1R,2S,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-N-(2-
nitrophenyl)benzenesulfonamide (14):
To a vigorously stirring suspension of sulfonamide 5 (1.00 g, 3.14 mmol, 1.00 equiv.) and
potassium carbonate (877 mg, 6.28 mmol, 2.00 equiv.) in dimethylformamide (Water content by Karl
Fischer titration: 75.2330 ppm, 5.00 mL) was added 1ꢀfluoroꢀ2ꢀnitrobenzene (500 µL, 4.71 mmol, 1.50
equiv.). The slurry was heated to an internal temperature of 100 °C under nitrogen and was stirred for 8.5
h. The mixture was cooled to room temperature and partitioned between water (20 mL) and ethyl acetate
(25 mL). The layers were split and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The
combined organic layers were washed with a saturated, aqueous solution of brine (10 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to afford a dark residue. The crude was purified by
flash chromatography over silica gel (75 to 100% dichloromethane in hexanes gradient) to afford a gel
that was sonicated in hexanes (5 mL) for 5 min to produce the product as a fine, light yellow powder
(1.34 g, 97%).
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Rf (25% ethyl acetate in hexanes): 0.44. M.p. (dichloromethane/hexane): 167ꢀ170 °C. H NMR (DMSOꢀ
d6, 400 MHz) (1:1 mixture of rotamers by NOESY analysis14, reported as observed): δ 8.09 (d, J=7.6 Hz,
2H), 8.03 (dd, J=7.7, 1.6 Hz, 0.5H), 8.00 (dd, J=7.8, 1.5 Hz, 0.5H), 7.60ꢀ7.68 (m, 4H), 7.24 (d, J=7.6 Hz,
0.5H), 7.21 (d, J=7.8 Hz, 0.5H), 3.77 (dd, J=13.3, 3.4 Hz, 0.5H), 3.74 (dd, J=12.8, 2.2 Hz, 0.5H), 3.49
(dd, J=13.5, 5.4 Hz, 0.5H), 3.40 (dd, J=13.8, 5.2 Hz, 0.5H), 2.27ꢀ2.32 (m, 0.5H), 2.18ꢀ2.24 (m, 1H), 2.10
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(br m, 1H) 1.62ꢀ1.96 (m, 5H), 1.22ꢀ1.34 (m, 0.5H), 1.16 (s, 1.5H), 1.05 (s, 1.5H), 0.99 (s, 1.5H), 0.98 (s,
1.5H), 0.77 (app t, J=8.7 Hz, 1H). 13C NMR (DMSOꢀd6, 100.6 MHz) (mixture of rotamers, reported as
observed): δ 148.9, 148.6, 140.8, 140.7, 133.7, 133.6, 131.2, 131.1, 129.7, 129.6, 129.2, 128.2, 128.1,
125.8, 125.6, 117.5, 115.9, 56.1, 56.0, 43.7, 42.1, 40.4, 38.8, 38.0, 37.9, 32.3, 32.0, 27.6, 27.3, 25.5, 25.3,
22.8, 22.6, 19.0, 18.8. [α]D20: –43.55 ° (c = 10.0 mg/mL, chloroform). IR (KBr) (cmꢀ1): 2917 (m), 2236
(m), 1528 (s), 1349 (s), 1171 (s). HRMS (ESI) (m/z): calc’d for C23H26O4N3S [M+H]+: 440.16385, found
440.16440.
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4-Cyano-N-(naphthalen-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzenesulfonamide (15):
To a mixture of the sulfonamide 6 (1.00 g, 3.48 mmol, 1.00 equiv.), copper (II) acetate (5.22
mmol, 1.50 equiv.) and 2ꢀnaphthylboronic acid (1.89 g, 10.44 mmol, 3.00 equiv.) was added
dichloromethane (20 mL) and the solvent line was marked on the flask with a marker, then the slurry was
stirred for 5 min. Pyridine (853 µL, 10.44 mmol, 3.00 equiv.) was added and the majority of the solids
dissolved, turning into a green colored solution. The mixture was stirred open to air for 24 h.
Occasionally, the agitation was suspended, and the dichloromethane solvent was recharged back to the
marked line. The slurry was then passed through a plug of silica gel (1.5” height, 1” diameter). The pad
was flushed with dichloromethane containing ammonia15 (2 x 25 ml) and the orange filtrate was
concentrated in vacuo. The residue was purified by flash column chromatography over silica gel twice (0
to 2.5% methanol in dichloromethane for the first column, then 25 to 50% ethyl acetate in hexanes for the
second column) to afford the product as a white solid (1.03 g, 72%). Rf (35% ethyl acetate in hexanes)
0.29. M.p. (ethyl acetate/hexane): 147ꢀ150 °C. 1H NMR (DMSOꢀd6, 400 MHz): δ 8.41ꢀ8.43 (m, 1H),
8.04 (app d, J=8.6 Hz, 2H), 7.87ꢀ7.95 (m, 3H), 7.72 (d, J=8.6 Hz, 2H), 7.63ꢀ7.67 (m, 2H), 7.52ꢀ7.59 (m,
2H), 7.15ꢀ7.20 (m, 3H), 4.09 (t, J=7.3 Hz, 2H), 2.86 (t, J=7.3 Hz, 2H). 13C NMR (DMSOꢀd6, 100.6 Hz):
δ 157.6, 149.0, 141.6, 136.4, 135.5, 133.4, 132.9, 132.2, 128.9, 128.02, 127.99, 127.6, 127.5, 126.9,
126.7, 126.2, 123.4, 121.7, 117.7, 115.5, 50.2, 36.5. IR (KBr) (cmꢀ1): 3056 (w), 2234 (m), 1594 (m),
1354 (s), 1160 (s). HRMS (ESI) (m/z): calc’d for C24H20O2N3S [M+H]+: 414.12707, found 414.12781.
4-Methoxy-N-methylaniline (16):
A solution of sulfonamide 1 (500 mg, 1.65 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (1.98 mL,
8.27 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 328.544 ppm,
5.00 mL) was sparged with nitrogen for 20 min before adding DBU (1.18 mL, 7.85 mmol, 4.75 equiv.).
The solution becomes yellow and was stirred for 12 h under nitrogen. The reaction mixture was then
poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The
residue was purified by flash column chromatography over silica gel (0 to 50% ethyl acetate in hexanes
gradient) to afford the product as a light yellow solid (221 mg, 97%). The spectral data matched a
literature report.16 1H NMR (DMSOꢀd6, 400 MHz): δ 6.72 (app d, J=9.1 Hz, 2H), 6.48 (app d, J=8.8 Hz,
2H), 5.15 (br d, J=3.8 Hz, 1H), 3.63 (s, 3H), 2.61 (d, J=4.8 Hz, 3H).
4-Bromo-N-(3-phenylpropyl)aniline (17):
A solution of the sulfonamide 12 (200 mg, 0.439 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (526
µL, 2.19 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 360.054
ppm, 2.00 mL) was sparged with nitrogen for 20 min before adding DBU (314 µL, 2.09 mmol, 4.75
equiv.). The solution becomes yellow and was stirred for 6 h under nitrogen. The reaction mixture was
then poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The
residue was purified by flash column chromatography over silica gel (0 to 10% ethyl acetate in hexane
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gradient) to afford the product as a light yellow oil (119 mg, 94%). The spectral data matched a literature
report.17 1H NMR (CDCl3, 400 MHz): δ 7.31 (app t, J=7.2 Hz, 2H), 7.20ꢀ7.27 (m, 5H), 6.45 (app d, J=8.8
Hz, 2H), 3.65 (br s, 1H), 3.12 (t, J=7.1 Hz, 2H), 2.74 (t, J=7.6 Hz, 2H), 1.96 (quintet, J=7.3 Hz, 2H).
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(+)-N-(((1R,2S,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-2-nitroaniline (18):
A solution of sulfonamide 14, 200 mg, 0.455 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (545 µL,
2.28 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 321.480 ppm,
2.00 mL) was sparged with nitrogen for 20 min before adding DBU (325 µL, 2.16 mmol, 4.75 equiv.).
The solution becomes orange and was stirred for 1 h under nitrogen. The reaction mixture was poured
into a pH=7 aqueous, sodium phosphate buffer (0.5 M, 10 mL) and extracted with ethyl acetate (3 x 10
mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to
afford a yellow oil. The residue was purified by flash column chromatography over silica gel twice (0 to
5% ethyl acetate in hexanes gradient) to afford the product as a thick orange oil that slowly solidified (115
mg, 92%). Rf (5% ethyl acetate in hexanes) 0.40. M.p. (ethyl acetate/hexane): 55ꢀ56 °C. 1H NMR
(DMSOꢀd6, 400 MHz): δ 8.20 (br t, J=5.3 Hz, 1H), 8.05 (dd, J=8.6, 1.5 Hz, 1H), 7.52 (ddd, J=8.5, 7.0,
1.1 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.67 (ddd, J=8.5, 7.0, 1.3 Hz, 1H) 3.29ꢀ3.38 (m, 2H), 2.32ꢀ2.38 (m,
2H), 1.83ꢀ2.00 (m, 5H), 1.54ꢀ1.63 (m, 1H), 1.18 (s, 3H), 1.06 (s, 3H), 0.89 (d, J=9.6 Hz, 1H). 13C NMR
(DMSOꢀd6, 100.6 Hz): δ 145.2, 136.6, 130.8, 126.2, 115.0, 114.5, 47.8, 43.3, 40.8, 39.8, 38.3, 32.8, 27.8,
25.6, 22.9, 19.3. [α]D20: +7.71 ° (c = 6.35 mg/mL, chloroform). IR (thin film) (cmꢀ1): 3380 (br m), 1619
(s), 1574 (m), 1513 (s), 1264 (s). HRMS (ESI) (m/z): calc’d for C16H23O2N2 [M+H]+: 275.17540, found
275.17636.
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N-(2-(1H-Indol-3-yl)ethyl)prop-2-yn-1-amine (19):
A solution of sulfonamide 13 (200 mg, 0.550 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (659 µL,
2.75 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 348.983 ppm,
2.00 mL) was sparged with nitrogen for 20 min before adding DBU (393 µL, 2.61 mmol, 4.75 equiv.).
The solution becomes yellow and was stirred for 13.5 h under nitrogen. The reaction mixture was then
poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The
residue was purified by flash column chromatography over silica gel (0 to 100% ethyl acetate in
dichloromethane gradient) to afford the product as a light yellow solid (99.8 mg, 91%). Rf (100% ethyl
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acetate) 0.27. M.p. (ethyl acetate/dichloromethane): 53ꢀ54 °C. H NMR (DMSOꢀd6, 400 MHz): δ 10.78
(br s), 7.51 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.96
(t, J=7.3 Hz, 1H), 3.35 (d, J=2.3 Hz, 2H), 3.02 (t, J=2.4 Hz, 1H), 2.78ꢀ2.87 (m, 4H), 1.88 (br s, 1H). 13C
NMR (DMSOꢀd6, 100.6 Hz): δ 136.2, 127.3, 122.5, 120.8, 118.3, 118.1, 112.5, 111.3, 83.2, 73.4, 48.8,
37.3, 25.2. IR (KBr) (cmꢀ1): 3304 (s), 2831 (s), 1452 (s), 1096 (m), 744 (s). HRMS (ESI) (m/z): calc’d
for C13H15N2 [M+H]+: 199.12298, found 199.12344.
N-(2-(pyridin-2-yl)ethyl)naphthalen-2-amine (20):
A solution of sulfonamide 15 (200 mg, 0.484 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (579 µL,
2.42 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 160.938 ppm,
2.00 mL) was sparged with nitrogen for 20 min before adding DBU (345 µL, 2.30 mmol, 4.75 equiv.).
The solution becomes yellow and was stirred for 15 h under nitrogen. The reaction mixture was then
poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The
residue was purified by flash column chromatography over silica gel (25 to 75% ethyl acetate in hexanes
gradient) to afford the product as a light tan solid (117.1 mg, 98%). Rf (75% ethyl acetate in hexanes)
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0.51, M.p. (ethyl acetate/hexane): 72ꢀ73 °C, H NMR (DMSOꢀd6, 400 MHz): δ 8.53 (d, J=4.8 Hz, 1H),
7.72 (td, J=7.6, 1.6 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.56ꢀ7.59 (m, 2H), 7.35 (d, J=7.6 Hz, 1H), 7.29 (t,
J=7.4 Hz, 1H), 7.23 (app t, J=6.2 Hz, 1H), 7.09 (t, J=7.1 Hz, 1H), 6.96 (dd, J=8.8, 2.0 Hz, 1H), 6.76 (s,
1H), 6.02 (br t, J=5.4 Hz, 1H), 3.48 (q, J=7.0 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H). 13C NMR (DMSOꢀd6,
100.6 Hz): δ 159.5, 149.1, 146.6, 136.4, 135.2, 128.3, 127.4, 126.4, 125.9, 125.4, 123.2, 121.5, 121.0,
118.3, 102.3, 42.8, 36.9. IR (KBr) (cmꢀ1): 3306 (m), 2836 (m), 1630 (s), 1225 (m), 829 (s). HRMS (ESI)
(m/z): calc’d for C17H17N2 [M+H]+: 249.13863, found 249.13922.
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(–)-(S)-N-(4-Methoxybenzyl)-1-phenylethan-1-amine (21):
A solution of sulfonamide 10 (200 mg, 0.492 mmol, 1.00 equiv.) and 1ꢀdodecanethiol (601 µL,
2.46 mmol, 5.00 equiv.) in dimethylformamide (Water content by Karl Fischer titration: 75.1916 ppm,
2.00 mL) was sparged with nitrogen for 20 min before adding DBU (356 µL, 2.34 mmol, 4.75 equiv.).
The solution becomes yellow and was stirred for 22 h under nitrogen. The reaction mixture was then
poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers
were washed with a saturated, aqueous solution of brine (10 mL), dried over sodium sulfate, filtered and
concentrated in vacuo to afford a light yellow oil. The residue was purified by flash column
chromatography over silica gel (0 to 100% ethyl acetate in hexanes gradient) to afford the product as a
clear oil (110.6 mg, 98%). The spectral data matched a literature report.18 The product was found to have
a chiral purity of >99.9 to 0.1 e.r. by chiral HPLC analysis. Sample prep: 4.0 mg/mL in isopropanol.
Column: Phenomenex Lux Celluloseꢀ3 (3µm, 4.6 x 150 mm). Column temperature: 30 °C. Detector
wavelength: 230 nm. Injection volume: 10 µL. Flow rate: 1.2 mL/min. Mobile phase “A”: 0.05
volume% diethylamine in heptane. Mobile phase “B”: 0.05 volume% diethylamine in ethanol. Gradient:
t=0 min: 3% “B”, t=2 min: 3% “B”, t=20 min: 20% “B”, t=24 min: 20% “B”. 21: 5.61 min, ent-21: 6.27
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min. H NMR (CDCl3, 400 MHz): δ 7.35ꢀ7.37 (m, 4H), 7.25ꢀ7.29 (m, 1H), 7.21 (app d, J=8.6 Hz, 2H),
6.86 (app d, J=8.6 Hz, 2H), 3.79ꢀ3.83 (m, 4H), 3.60 (d, J=12.9 Hz, 1H), 3.54 (d, J=12.9 Hz, 1H), 1.57 (br
s, 1H), 1.37 (d, J=6.6 Hz, 3H). [α]D20: –47.87 ° (c = 8.0 mg/mL, chloroform).
tert-Butyl (4-Methoxybenzyl)carbamate (23):
To a solution of sulfonamide 4 (1.00 g, 3.31 mmol, 1.00 equiv.) and 4ꢀN,Nꢀ
dimethylaminopyridine (40.8 mg, 0.33 mmol, 0.10 equiv.) in dichloromethane (7.50 mL) was added diꢀ
tertꢀbutyl dicarbonate (893 mg, 3.97 mmol, 1.20 equiv.) and the solution was stirred. Moderate offꢀ
gassing was observed and the reaction reached completion (Rf 22 (30% ethyl acetate in hexanes): 0.50)
after 1 h. The solution was concentrated in vacuo, then the clear syrup was dissolved in
dimethylformamide (Water content by Karl Fischer titration: 369.286 ppm, 10.00 mL) and 1ꢀ
dodecanethiol (3.96 mL, 16.5 mmol, 5.00 equiv.) was added. The mixture was sparged with nitrogen for
20 min before adding DBU (2.36 mL, 15.7 mmol, 4.75 equiv.). The light orange solution was stirred for
2 h, poured into water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. The residue
was purified flash column chromatography over silica gel (0 to 30% ethyl acetate in hexanes gradient) to
afford the desired product 23 as a clear oil that slowly solidified (733 mg, 93%). The spectral data
matched a literature report.19 1H NMR (CDCl3, 400 MHz): δ 7.21 (d, J=8.3 Hz, 2H), 6.87 (app d, J=8.6
Hz, 2H), 4.78 (br s, 1H), 4.25 (br d, J=5.3 Hz, 2H), 3.80 (s, 3H), 1.47 (s, 9H).
N-(4-aminophenyl)-4-cyano-N-methylbenzenesulfonamide (24):
To a suspension of the sulfonamide 3 (1.00 g, 3.15 mmol, 1.00 equiv.) and washed zinc20 (2.06 g,
31.52 mmol, 10.00 equiv.) in dichloromethane (20.0 mL) was slowly added isobutyric acid (2.92 mL,
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31.52 mmol, 10.00 equiv.) at a rate such that the internal temperature did not exceed 30 °C (~15 min),
using an iceꢀwater bath to regulate the temperature. Upon complete addition, the slurry was stirred for 30
min, then the solids were filtered and washed with dichloromethane (2 x 10 mL). The combined
dichloromethane streams were added into a saturated aqueous solution of sodium bicarbonate (75 mL).
The layers were split and the aqueous layer was extracted with dichloromethane (2 x 25 mL). The
combined organic layers were washed with water (25 mL), then a saturated, aqueous solution of brine (25
mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow foam. The residue
was purified by flash column chromatography over silica gel (25 to 50% ethyl acetate in hexanes) to
afford the product as off white crystals (810 mg, 90%). Rf (50% ethyl acetate in hexanes) 0.38. M.p.
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(ethyl acetate/hexane): 165ꢀ166 °C. H NMR (DMSOꢀd6, 400 MHz): δ 8.07 (app d, J=8.6 Hz, 2H), 7.67
(app d, J=8.6 Hz, 2H), 6.67 (app d, J=8.8 Hz, 2H), 6.45 (app d, J=8.8 Hz, 2H), 5.27 (br s, 2H), 3.07 (s,
3H). 13C NMR (DMSOꢀd6, 100.6 Hz): δ 148.4, 140.5, 113.2, 128.3, 128.2, 127.6, 117.7, 115.4, 113.7,
38.6. IR (KBr) (cmꢀ1): 3457 (br m), 3368 (br m), 2241 (m), 1647 (s), 1514 (s). HRMS (ESI) (m/z): calc’d
for C14H14O2N3S [M+H]+: 288.08012, found 288.08126.
4-Cyano-N-methyl-N-(4-nitro-3-((phenylsulfonyl)methyl)phenyl)benzenesulfonamide (25):
To an oven dried flask was added the sulfonamide 3 (1.00 g, 3.15 mmol, 1.00 equiv.) and
chloromethyl phenyl sulfone (774 mg, 3.94 mmol, 1.25 equiv.). Tetrahydrofuran (15.0 mL, Water
content by Karl Fischer titration: 33.4481 ppm) was added and the mixture was stirred under nitrogen
until a homogeneous solution forms (approximately 2ꢀ3 min.). The solution was cooled to an internal
temperature of ꢀ50 °C with a dry iceꢀacetone bath and a solution of potassium tertꢀbutoxide in
tetrahydrofuran (1.0 M, 7.88 mL, 7.88 mmol, 2.50 equiv.) was added dropwise, maintaining the internal
temperature at ꢀ50 °C (approximately 10 min). Immediately upon addition of the base, an intense violet
color develops. After addition, the deep violet solution is stirred at an internal temperature of ꢀ50 °C for
1.5 h, then a solution of acetic acid (542 µL, 9.45 mmol, 3.00 equiv.) in tetrahydrofuran (5.00 mL) is
added dropwise, maintaining an internal temperature of ꢀ50 °C (approximately 5 min.), then the mixture
is allowed to warm to room temperature. At approximately ꢀ38 °C, the violet color disappears. The
reaction mixture was poured into a pH=7 aqueous, sodium phosphate buffer (1.0 M, 50 mL) and the
layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 mL), and the combined
organic layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium
sulfate, filtered and concentrated in vacuo to afford a tan gel. The residue was purified by flash column
chromatography over silica gel (0 to 5% ethyl acetate in dichloromethane) to afford the product as a white
powder (1.36 g, 92%).
Rf (5% ethyl acetate in dichloromethane) 0.48.
M.p. (ethyl
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acetate/dichloromethane): 170ꢀ172 °C. H NMR (DMSOꢀd6, 400 MHz): δ 8.10 (app d, J=8.6 Hz, 2H),
8.05 (d, J=8.8 Hz, 1H), 7.70ꢀ7.76 (m, 3H), 7.58ꢀ7.63 (m, 4H), 7.46 (dd, J=8.8, 2.5 Hz, 1H), 7.22 (d, J=2.5
Hz, 1H), 5.13 (s, 2H), 3.09 (s, 3H). 13C NMR (DMSOꢀd6, 100.6 MHz): δ 147.0, 144.3, 139.4, 137.6,
134.3, 133.7, 130.6, 129.5, 128.0, 127.9, 126.6, 126.5, 124.0, 117.5, 116.2, 56.9, 37.4. IR (KBr) (cmꢀ1):
2238 (m), 1521 (s), 1364 (s), 1183 (s), 1153 (s). HRMS (ESI) (m/z): calc’d for C21H21O6N4S [M+NH4]+:
489.08970, found 489.09079.
(+)-tert-Butyl (4-Cyanophenylsulfonyl)-L-alaninate (30):
A mixture of Lꢀalanine tertꢀbutyl ester hydrochloride (5.00 g, 27.0 mmol, 1.00 equiv.) in
tetrahydrofuran (100 mL) was cooled to an internal temperature of 4.5 °C with an iceꢀwater bath and
triethylamine (8.35 mL, 59.3 mmol, 2.20 equiv.) was added. The slurry was cooled to an internal
temperature of 2.2 °C and 4ꢀcyanobenzensulfonyl chloride (5.66 g, 27.5 mmol, 1.02 equiv.) was added in
portions over 30 min, maintaining an internal temperature below 5.0 °C. The slurry was warmed to room
temperature and stirred for 1 h. The reaction mixture was poured into water (50 mL) and the layers were
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separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic
layers were washed with a saturated, aqueous solution of brine (50 mL), dried over sodium sulfate,
filtered and concentrated in vacuo to afford a tan oil. The residue was purified by flash column
chromatography over silica gel (5 to 40% ethyl acetate in hexanes gradient) to afford the product as a
thick oil that crystallized upon standing (8.15 g, 97%). The product was found to have a chiral purity of
99.9 to 0.1 e.r. by chiral HPLC analysis. Sample prep: 2.0 mg/mL in isopropanol. Column: Chiralpak
AZꢀ3R (3 µm, 4.6 x 150 mm). Column temperature: 30 °C. Detector wavelength: 254 nm. Injection
volume: 10 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05 volume% trifluoroacetic acid in
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acetonitrile:water (5:95 volume%).
Mobile phase “B”: 0.05 volume% trifluoroacetic acid in
acetonitrile:water (95:5 volume%). Gradient: t=0 min: 0% “B”, t=25 min: 100% “B”, t=30 min: 100%
“B”. 30: 14.17 min, ent-30: 15.76 min. Rf (30% ethyl acetate in hexanes): 0.46. M.p. (ethyl
1
acetate/hexanes): 88ꢀ89 °C. H NMR (DMSOꢀd6, 400 MHz): δ 8.57 (d, J=8.8 Hz, 1H), 8.07 (app d, J=8.8
Hz, 2H), 7.94 (app d, J=8.6 Hz, 2H), 3.81 (dq, J=8.6, 7.3 Hz, 1H), 1.24 (s, 9H), 1.18 (d, J=7.3 Hz, 3H).
20
13C NMR (DMSOꢀd6, 100.6 Hz): δ 170.5, 145.4, 133.2, 127.3, 117.7, 114.7, 80.9, 51.8, 27.3, 18.5. [α]D
:
+27.12 ° (c = 8.61 mg/mL, dichloroethane). IR (KBr) (cmꢀ1): 3270 (br s), 2233 (m), 1723 (s), 1316 (s),
1120 (s), 838 (m). HRMS (ESI) (m/z): calc’d for C14H17O4N2S [MꢀH]–: 309.09035, found 309.08994.
(–)-tert-Butyl N-(4-Cyanophenylsulfonyl)-N-(4-methoxybenzyl)-L-alaninate (29) (Via Mitsunobu
Reaction):
A solution of PMB sulfonamide 4 (1.00 g, 3.31 mmol, 1.00 equiv.), (+)ꢀtertꢀbutyl Dꢀlactate (732
mg, 4.96 mmol, 1.50 equiv.) and triphenylphosphine (1.30 g, 4.96 mmol, 1.50 equiv.) in dichloromethane
(10.0 mL) was cooled to an internal temperature of 1.1 °C with an iceꢀwater bath and a solution of diethyl
azodicarboxylate (40 wt% in toluene, 2.26 mL, 4.96 mmol, 1.50 equiv.) was added slowly, maintaining
the internal temperature below 5 °C (30 min). The mixture was warmed to room temperature and stirred
for 2 h. The reaction mixture was purified directly by flash column chromatography (0 to 25% ethyl
acetate in hexanes gradient) to afford the product as a thick, clear gel (1.22 g, 86%). The gel will slowly
crystallize (~1 mo). Alternatively, the gel can be dissolved with heating in a 1:2 v/v solution of
tetrahydrofuran in hexanes (9 mL), upon concentration the product was observed to crystallize. The
product was found to have a chiral purity of 99.8 to 0.2 e.r. by chiral HPLC analysis after
chromatography, before crystallization. Sample prep: 2.0 mg/mL in isopropanol. Column: Phenomenex
Lux Celluloseꢀ3 (3µm, 4.6 x 150 mm). Column temperature: 25 °C. Detector wavelength: 254 nm.
Injection volume: 5 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.05 volume% trifluoroacetic acid in
acetonitrile:water (5:95 volume%).
acetonitrile:water (95:5 volume%). Gradient: t=0 min: 0% “B”, t=25 min: 100% “B”, t=30 min: 100%
“B”. 29: 17.61 min, ent-29: 18.47 min. Rf (20% ethyl acetate in hexanes): 0.33. M.p.
Mobile phase “B”: 0.05 volume% trifluoroacetic acid in
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(tetrahydrofuran/hexanes): 92ꢀ95 °C. H NMR (DMSOꢀd6, 400 MHz): δ 8.06 (app d, J=8.6 Hz, 2H), 7.98
(app d, J=8.6 Hz, 2H), 7.21 (app d, J=8.8 Hz, 2H), 6.86 (app d, J=8.8 Hz, 2H), 4.59 (d, J=16.2 Hz, 1H),
4.52 (q, J=7.3 Hz, 1H), 4.22 (d, J=16.2 Hz, 1H), 3.73 (s, 3H), 1.24 (s, 9H), 1.16 (d, J=7.3 Hz, 3H). 13C
NMR (DMSOꢀd6, 100.6 Hz): δ 169.2, 158.6, 144.1, 133.3, 129.2, 129.1, 127.8, 117.6, 115.1, 113.6, 81.3,
56.0, 55.0, 48.6, 27.3, 16.8. [α]D20: –41.58 ° (c = 8.58 mg/mL, chloroform). IR (thin film) (cmꢀ1): 2235
(m), 1736 (s), 1515 (m), 1341 (m), 1148 (s). HRMS (ESI) (m/z): calc’d for C22H26O5N2NaS [M+Na]+:
453.14546, found 453.14651.
(–)-tert-Butyl N-(4-Cyanophenylsulfonyl)-N-(4-methoxybenzyl)-L-alaninate (29) (Via Alkylation):
To a vigorously stirring suspension of sulfonamide 30 (99.9 to 0.1 e.r., 1.00 g, 3.22 mmol, 1.00
equiv.) and potassium carbonate (899 mg, 6.44 mmol, 2.00 equiv.) in dimethylformamide (Water content
by Karl Fischer titration: 44.6623 ppm, 5.00 mL) was added paraꢀmethoxybenzyl chloride (892 µL, 6.44
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mmol, 2.00 equiv.). The slurry was heated to an internal temperature of 60 °C under nitrogen and was
stirred for 4.5 h. The mixture was cooled to room temperature and partitioned between water (10 mL)
and ethyl acetate (10 mL). The layers were split and the aqueous layer was extracted with ethyl acetate (2
x 5 mL). The combined organic layers were washed with a saturated, aqueous solution of brine (5 mL),
dried over sodium sulfate, filtered and concentrated in vacuo to afford a clear oil. The crude residue was
purified by flash chromatography over silica gel (0 to 25% ethyl acetate in hexanes gradient) to afford the
product as a thick gel that slowly solidified (1.34 g, 97%). The product was found to have a chiral purity
of 99.5 to 0.5 e.r. by chiral HPLC analysis. For characterization data and chiral method, see above.
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tert-Butyl N-(4-Methoxybenzyl)alaninate (31):
A solution of sulfonamide (29 from the Mitsunobu reaction, 200 mg, 0.465 mmol, 1.00 equiv.)
and 1ꢀdodecanethiol (1.11 mL, 4.65 mmol, 10.00 equiv.) in dimethylformamide (Water content by Karl
Fischer titration: 46.4896 ppm, 2.00 mL) was sparged with nitrogen for 20 min before adding DBU (349
µL, 2.32 mmol, 5.00 equiv.). The solution becomes a light yellow and was stirred for 23 h under
nitrogen. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (3 x
10 mL). The combined organic layers were washed with a saturated aqueous solution of brine (10 mL),
dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified
flash column chromatography over silica gel (0 to 50% ethyl acetate in hexanes gradient) to afford the
desired product 31 as a clear oil (98.1 mg, 80%). The product21 was found to have a chiral purity of
approximately 60 to 40 e.r. by chiral HPLC analysis. Sample prep: 4.0 mg/mL in methanol. Column:
Chiralpak IDꢀ3 (3µm, 4.6 x 150 mm). Column temperature: 40 °C. Detector wavelength: 220 nm.
Injection volume: 5 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.01 M ammonium acetate in
acetonitrile:water (5:95 volume%). Mobile phase “B”: 0.01 M ammonium acetate in acetonitrile:water
(95:5 volume%). Gradient: t=0 min: 0% “B”, t=20 min: 50% “B”, t=24 min: 50% “B”. (S)-31: 17.89
min, (R)-31: 18.35 min. Rf (50% ethyl acetate in hexanes): 0.54. 1H NMR (DMSOꢀd6, 400 MHz): δ
7.20 (app d, J=8.6 Hz, 2H), 6.86 (app d, J=8.6 Hz, 2H), 3.72 (s, 3H), 3.64 (d, J=12.9 Hz, 1H), 3.50 (d,
J=12.9 Hz, 1H), 3.07 (q, J=6.7 Hz, 1H), 2.18 (br s, 1H), 1.42 (s, 9H), 1.14 (d, J=6.8 Hz, 3H). 13C NMR
(DMSOꢀd6, 100.6 Hz): δ 174.5, 158.1, 132.2, 129.1, 113.5, 79.9, 55.9, 55.0, 50.2, 27.7, 18.9. IR21 (KBr)
(cmꢀ1): 2933 (br s), 2272 (m), 1744 (s), 1519 (s), 1255 (s), 815 (m). HRMS (ESI) (m/z): calc’d for
C15H24O3N [M+H]+: 266.17507, found 266.17599.
tert-Butyl 2-(4-Cyanophenyl)-2-((4-methoxybenzyl)amino)propanoate (32):
The arylated product 32 was also isolated as a white solid (18.2 mg, 11%). The product was
found to be racemic by chiral HPLC analysis. Sample prep: 2.0 mg/mL in methanol. Column: Chiralpak
IG (5µm, 4.6 x 150 mm). Column temperature: 30 °C. Detector wavelength: 220 nm. Injection volume:
10 µL. Flow rate: 1.0 mL/min. Mobile phase “A”: 0.01 M ammonium acetate in acetonitrile:water (5:95
volume%). Mobile phase “B”: 0.01 M ammonium acetate in acetonitrile:water (95:5 volume%).
Gradient: t=0 min: 0% “B”, t=30 min: 100% “B”, t=37 min: 100% “B”. Ent-1-32: 23.31 min, Ent-2-32:
1
24.28 min. Rf (50% ethyl acetate in hexanes): 0.90. M.p. (ethyl acetate/hexanes): 70ꢀ73 °C. H NMR
(DMSOꢀd6, 400 MHz): δ 7.83 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 6.88 (d,
J=8.6 Hz, 2H), 3.73 (s, 3H), 3.54 (dd, J=12.5, 8.0 Hz, 1H), 3.43 (dd, J=12.6, 6.3 Hz, 1H), 2.70 (br t,
J=7.2 Hz, 1H), 1.55 (s, 3H), 1.40 (s, 9H). 13C NMR (DMSOꢀd6, 100.6 Hz): δ 172.7, 158.2, 149.3, 132.6,
132.2, 129.0, 127.0, 118.7, 113.6, 110.0, 81.2, 65.6, 55.0, 46.8, 27.5, 24.8. IR (Thin Film) (cmꢀ1): 3337
(br w), 2229 (m), 1725 (s), 1514 (s), 1250 (s). HRMS (ESI) (m/z): calc’d for C22H27O3N2 [M+H]+:
367.20162, found 367.20245.
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Associated Content:
Supporting Information
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Supporting information is available free of charge
Quality assessment of commercial 4ꢀcyanobenzenesulfonyl chloride
Air oxidation studies of 1ꢀdodecanethiol
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Racemization study of 29
Copies of chiral HPLC, 1H NMR and 13C NMR spectra
Acknowledgements:
We would like to thank Dr. Robert Waltermire and Dr. David Kronenthal for supporting the
BristolꢀMyers Squibb Undergraduate Summer Internship for R.W.S. We would like to thank Dr. Adrian
Ortiz for reviewing the manuscript. We’d like to thank Gottfried Wenke for pKa determinations, Larisa
Zueva and Tianhong Zhang for IR and OR determinations and Jon Marshall for HRMS support. We are
grateful to Dr. Sloan Ayers for assistance in obtaining a NOESY spectra.
Author Information:
Corresponding Author
*Eꢀmail: Michael.Schmidt@bms.com
Notes
The authors declare no competing financial interests.
1
a) Kocieński, P. J. Protecting Groups, Georg Thieme Verlag: Stuttgart, New York, 1994. b) Wuts, P. G. M.;
Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, 2004.
See also c) Searles, S.; Nukina, S. Chem. Rev. 1959, 59, 1077.
2 Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. See also references cited within.
3 From a modified Sandmeyer reaction: a) Mansfeld, M.; Pařík, Ludwig, M. Collect. Czech. Chem. Commun. 2004,
69, 1479. b) Hogan, P. J.; Cox, B. G. Org. Process Res. Dev. 2009, 13, 875. c) MaletꢀSanz, L.; Madrzak, J.; Ley, S.
V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324. From a metalꢀhalogen exchange/SO2 trap/Oxidative
chlorination: d) Hamada, T.; Yonemitsu, O. Synthesis, 1986, 852. e) Pandya, R.; Murashima, T.; Tedeschi, L.;
Barrett, A. G. M. J. Org. Chem. 2003, 68, 8274. From the reaction of pꢀsulfonaminobenzoic acid with PCl5: f)
Ishifuku, K.; Sakurai, H.; Okamoto, H.; Satoh, S. Yakugaku Zasshi 1949, 69, 417. g) Trave, R. Farmaco, 1960, 15,
474. From oxidative chlorination of 4ꢀ(methylthio)benzonitrile: h) Karino, H.; Goda, H.; Sakamoto, J.; Yoshida, K.;
Nishiguchi, H. Patent WO 9633167 1996.
4 The aqueous pKa of 2 was measured to be 7.0, similar to the 4ꢀnitrobenzenesulfonamide of pꢀbromoaniline which
was measured to be 6.9. The alkyl sulfonamide 5 was measured to be 10.9.
a) Tsunoda, T.; Ozaki, F.; Itô, S. Tetrahedron Lett. 1994, 35, 5081. b) Tsunoda, T.; Nagaku, M.; Nagino, C.;
5
Kawamura, Y.; Ozaki, F.; Hioki, H.; Itô, S. Tetrahedron Lett. 1995, 36, 2531. c) Tsunoda, T.; Yamamoto, H.; Goda,
K.; Itô, S. Tetrahedron Lett. 1996, 37, 2457. d) Tsunoda, T.; Nagino, C.; Oguri, M.; Itô, S. Tetrahedron Lett. 1997,
37, 2459.
6 a) Chan, D. M. T.; Monaco, K. L.; Wang, R.ꢀp.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. b) Evans, D. A.;
Katz, J. L.; West, T. R. Tetrahedron Lett, 1998, 39, 2937. c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941.
7
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4ꢀDodecylthiobenzonitrile was isolated as a byꢀproduct and the structure was confirmed by comparison of the H
NMR spectrum with a literature report. Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 2357.
8 Please see the Supporting Information for details.
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9 a) Terrier, F. Chem. Rev. 1982, 82, 77. b) Artamkina, G. A.; Egorov, M. P.; Beletskaya, I. P. Chem. Rev. 1982, 82,
427. See also reference 2.
10 Temperini, A.; Annesi, D.; Testaferri, L.; Tiecco, M. Tetrahedron Lett. 2010, 51, 5368.
11 Mąkosza, M. Synthesis 2011, 15, 2341.
12 a) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4581. b) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4585. c) Silva,
C. M.; Dias, I. C.; Pliego, J. R. Org. Biomol. Chem. 2015, 13, 6217.
13 a) Wilson, M. W.; AultꢀJustus, S. E.; Hodges, J. C.; Rubin, J. R. Tetrahedron, 1999, 55, 1647. b) Lupi, V.; Penso,
M.; Foschi, F.; Gassa, F.; Mihali, V.; Tagliabue, A. Chem. Commun. 2009, 5012. c) Foschi, F.; Landini, D.; Lupi,
V.; Mihali, V.; Penso, M.; Pilati, T.; Tagliabue, A. Chem. Eur. J. 2010, 16, 10667.
14 Hu, D. X.; Grice, P.; Ley, S. V. J. Org. Chem. 2012, 77, 5198.
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15 A 28ꢀ30 wt% aqueous solution of ammonium hydroxide was extracted with an equal volume of dichloromethane.
The dichloromethane layer was dried over sodium sulfate then filtered with gentle suction.
16 Jiao, J.; Zhang, X.ꢀR.; Chang, N.ꢀH.; Wang, J.; Wei, J.ꢀF.; Shi, X.ꢀY.; Chen, Z.ꢀG. J. Org. Chem. 2011, 76, 1180.
17 Li, H.; Achard, M.; Bruneau, C.; Sortais, J.ꢀB.; Darcel, C. RSC Adv., 2014, 4, 25892.
18 Pan, H.ꢀJ.; Zhang, Y.; Shan, C.; Yu, Z.; Lan, Y.; Zhao, Y. Angew. Chem. Int. Ed. 2016, 55, 9615.
19 Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956.
20
The zinc was washed according to Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 6th
Ed.; Elsevier: Oxford, 2009; p 503..
Crude zinc powder was slurried with an aqueous solution of 2 wt%
hydrochloric acid (2.5 mL/g Zn) for 1 min then filtered; this process was repeated once more. The zinc was then
washed with water (3 x 0.85 mL/g Zn), then ethanol (2 x 1.67 mL/g Zn), then methyl tertꢀbutyl ether (1.67 mL/g
Zn). Between each wash, the solids were collected by filtration and slurried in the subsequent wash for ~0.5ꢀ1 min.
The lumpy grey powder was crushed and dried in vacuo to constant weight prior to use.
21
The chiral data and IR spectrum were obtained on the HCl salt as solutions of the freebase appeared to degrade
over time. The amine was dissolved in MTBE (10 ml/g) and 1.0 equiv of HCl (4 M HCl in dioxane) was added.
The slurry was stirred for 15 min, then the solvents were concentrated in vacuo. The white powder was suspended
in MTBE (5 ml/g) and filtered.
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