SNAAP sulfonimidate alkylating agent for acids, alcohols, and phenols 1

Article abstract of DOI:10.1055/s-0033-1339921

Stable, crystalline ethyl N-tert-butyl-4-nitrobenzenesulfonimidate has been prepared in high yield by direct O-ethylation of N-tert-butyl-4- nitrobenzenesulfonamide with iodoethane and silver(I) oxide in dichloromethane. This sulfonimidate directly ethylates various acids to esters; the stronger the acid, the faster it alkylates and in higher yield. It readily ethylates alcohols and phenols to ethers at room temperature in the presence of tetrafluoroboric acid catalyst without molecular rearrangements or racemization. We have defined these reactions as SNAAP alkylations: [substitution, nucleophilic of acids, alcohols and phenols]. The hard sulfonimidate alkylating agent is chemoselective, preferring oxygen > nitrogen > sulfur. The sulfonamide byproduct of alkylation is readily recycled to the sulfonimidate. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1339921

PAPER
▌3361
1
paper
SNAAP Sulfonimidate Alkylating Agent for Acids, Alcohols, and Phenols
SNAAP Sulfonimidate Alkylating Agent
Tom J. Maricich,* Matthew J. Allan, Brett S. Kislin, Andrea I-T. Chen, Fan-Chun Meng, Christine Bradford,
Nai-Chia Kuan, Jeremy Wood, Omonigho Aisagbonhi, Alethea Poste, Dustin Wride, Sylvia Kim, Therese Santos,
Michael Fimbres, Dianne Choi, Haydi Elia, Joseph Kaladjian, Ali Abou-Zahr, Arturo Mejia
Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Blvd, Long Beach, CA 90840, USA
Fax +1(562)9858557; E-mail: tom.maricich@csulb.edu
Received: 03.08.2013; Accepted after revision: 22.09.2013
roboric acid gives methyl ethers.9 The alkylation of alco-
Abstract: Stable, crystalline ethyl N-tert-butyl-4-nitrobenzenesul-
hols by oxonium salts10 requires reaction at room
fonimidate has been prepared in high yield by direct O-ethylation of
temperature for one week. Benzyl, allyl, and tert-butyl tri-
N-tert-butyl-4-nitrobenzenesulfonamide with iodoethane and sil-
ver(I) oxide in dichloromethane. This sulfonimidate directly ethyl-
chloroacetimidates have been shown to alkylate acids and
ates various acids to esters; the stronger the acid, the faster it alcohols under limited conditions11–16 without chemose-
lectivity.17
alkylates and in higher yield. It readily ethylates alcohols and phe-
nols to ethers at room temperature in the presence of tetrafluorobo-
ric acid catalyst without molecular rearrangements or racemization.
We have defined these reactions as SNAAP alkylations: [substitu-
tion, nucleophilic of acids, alcohols and phenols]. The hard sulfon-
imidate alkylating agent is chemoselective, preferring oxygen >
nitrogen > sulfur. The sulfonamide byproduct of alkylation is read-
ily recycled to the sulfonimidate.
There are limited previous reports of sulfonimidate reac-
tions with carboxylic acids and hydrochloric acid18,19 and
fluorosulfonic
acid;20
multistep
syntheses
of
sulfonimidates18,19 are tedious, often resulting in unstable
liquid products. As a result, alkylations by sulfonimidates
are, to the best of our knowledge, unexplored. The
N-alkylation of sulfonamides is well documented;21–24
however, no practical method for direct O-alkylation of
sulfonamides has been reported. Sulfonimidates, the
products of O-alkylation, have been prepared previously
by less direct, multistep methods (Scheme 1).18,19,20,25,26
Most of these methods required sulfinyl chloride25 and
sulfonimidoyl chloride precursors, which were combined
with alkoxides or alcohols and triethylamine in si-
tu.18,19,27,28 Reggelin and co-workers have reported29 ex-
tensively on chiral cyclic sulfonimidates prepared from
sulfonimidoyl chlorides.
Key words: mild alkylation, mild esterification, esters, ethers, sul-
fonimidate
There are a variety of methods for direct alkylation of car-
boxylic acids at oxygen, but many have limitations be-
cause of toxicity, thermal instability, reactivity with
moisture in air, multiple components, severe conditions,
or extended reaction times. A recent review by
Vorbruggen2 focused on the alkylation of carboxylic acids
and phenols with amide acetals. He noted that classical
procedures involving sterically hindered tetrahedral inter-
mediates limit the scope of those procedures. Additional-
ly, some direct alkylation methods, such as the toxic and
explosive diazoalkanes,3,4 also undergo side reactions
with aldehydes, ketones and α,β-unsaturated carbonyl
compounds.5 Amide acetals are effective alkylating
agents for many carboxylic acids and some acidic phe-
nols,2 but they are sensitive to water, alcohols, and
amines, and easily condense with active methylene
groups. Yoshino et al.6 reported an improved esterifica-
tion procedure for various carboxylic and phosphonic ac-
ids and other protic compounds with excess trialkyl
orthoacetates in ionic liquids at 80 °C. Raber et al.7 report-
ed the alkylation of carboxylic acids with trialkyloxonium
salts, but the literature is silent on the use of oxonium salts
to alkylate strong acids, such as methanesulfonic and tri-
fluoroacetic acids. Alkylation of alcohols directly, with-
out first having to convert them into alkoxides,8 is not
common. Acid-catalyzed methylation of alcohols by the
use of diazomethane and concentrated aqueous tetrafluo-
O
S
O
S
O
S
Cl2NMe
– Cl2
NaOEt or
R
OEt
R
Cl
R
Cl
EtOH, Et3N
NMe
NMe
Scheme 1 Sulfonimidates from sulfonimidoyl chlorides
In an earlier report,30 we presented evidence that N-alk-
oxybenzenesulfinamides could rearrange to alkyl sulfon-
imidates and alkylate alcohols in situ. Malacria et al.31
utilized this concept for their one-pot synthesis of sulfon-
imidates from sulfinamides, iodosobenzene, and primary
aliphatic alcohols. A more recent paper on this work32 in-
cludes asymmetric syntheses of sulfonimidates. Each of
these methods required sulfinyl chlorides or sulfinamides
derived from them, thus they were restricted to derivatives
compatible with chlorine and required several steps. Roy
showed that phenyl and 2,2,2-trifluoroethylsulfonimi-
dates could be prepared from various N-silylated sulfon-
amides.26 The sulfonimidoyl chloride intermediates were
prepared from sulfonamides with triphenylphosphine di-
chloride and triethylamine, then converted with the alco-
hol and triethylamine into sulfonimidates in 10–78%
yields. In many cases, the alkyl sulfonimidates reported
SYNTHESIS 2013, 45, 3361–3368
Advanced online publication: 07.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339921; Art ID: SS-2013-M0543-OP
© Georg Thieme Verlag Stuttgart · New York

3362
T. J. Maricich et al.
PAPER
O
O
O
O
O
OEt
I
S
S
S
Ag+
N–
t-Bu
I
Ag+
Nt-Bu
Ag2O
N–
2
t-Bu
O2N
O2N
O2N
– AgI
1
Scheme 2 Proposed mechanism for O-ethylation of sulfonamide
were unstable liquids at room temperature, with limited and nitrogen nucleophilic sites (Scheme 2). Consistent
stability in a freezer.20
with hard and soft acid and base theory (HSAB),36 the soft
silver(I) cation should reside at the softer nitrogen basic
site. Attack by nitrogen on the iodoethane may be sterical-
ly hindered both by the tightly complexed silver ion and
the N-tert-butyl group. O-Ethylation of the silver sulfon-
amide may be a concerted nucleophilic attack by oxygen
on the iodoethane carbon with loss of silver iodide. We
note that O-ethylation (kinetic path) is favored in dichlo-
romethane over N-ethylation (thermodynamic path) in
acetonitrile. Most likely, this is because dissociation of the
silver sulfonamide tight ion-pair may occur in polar sol-
vents like acetonitrile, and loss of the silver ion could de-
crease steric hindrance at nitrogen.
O-Alkylation of carboxylic amides gives imidates via
their silver salts and alkyl iodides.33–35 Control of reaction
variables alters the regiochemistry, favoring O- versus N-
alkylation. Challis and Iley20 applied this approach to sul-
fonamides, but only obtained N-alkylation in acetonitrile.
They concluded that: ‘O-alkyl sulphonimidates are un-
likely to be synthesized by direct O-substitution.’
We have successfully accomplished the preparation of
ethyl
N-tert-butyl-4-nitrobenzenesulfonimidate
(1)
(Equation 1) by silver oxide mediated O-ethylation of N-
tert-butyl-4-nitrobenzenesulfonamide (2). The best meth-
od we developed is a one-pot procedure involving anhy-
drous silver(I) oxide, iodoethane, and a sterically hindered
sulfonamide, such as 2, in anhydrous, refluxing dichloro-
methane. Stable, crystalline 1 has been prepared in ca.
90% yield by this method. N-Ethylation is a minor side re-
action. This method applies generally to other arenesul-
fonimidates, but these were not included here, because
they are unstable liquids at ambient temperature.
Stable, crystalline sulfonimidate 1 (Aldrich Cat. #L512311)
represents a special class of alkylating agent; reactions
with acids, alcohols and phenols are very simple, fast, and
safe. Isolation of the resulting products is very direct. We
have formulated the term SNAAP for the process, which
is an acronym for substitution, nucleophilic of acids, alco-
hols, and phenols.
O
O
OEt
O
O
HX
OEt
S
S
S
XEt
EtI, Ag2O
90%
Nt-Bu
Nt-Bu
NHt-Bu
pKa < 5
O2N
O2N
O2N
1
2
1
Equation 2 Sulfonimidate ethylation of acids
Equation 1 Direct sulfonamide to sulfonimidate synthesis
We have demonstrated the ethylation of a wide variety of
acids [pKa <5] (Equation 2) with 1 (Table 1) at ambient
temperature. The stronger the acid, the faster the ethyl-
ation reaction proceeds. Methanesulfonic acid (entry 1)
We have proposed a mechanism that begins with proton
abstraction by silver(I) oxide to produce an ambident sil-
ver sulfonamide tight ion-pair, which is capable of attack-
ing the iodoethane with competition between the oxygen
Table 1 Uncatalyzed Sulfonimidate Ethylation of Acids
Entry
Acid
pKa
Time
Product
Yield (%)
1
2
3
4
MeSO2OH
TFA
–1.9
0.0
15 min
<5 min
<5 min
<50 min
MeSO2OEt
CF3CO2Et
89a
100b
58a
Cl2CHCO2H
1.35
Cl2CHCO2Et
4-MeC6H4S(O)OH
1.99
2.2
4-MeC6H4S(O)OEt
74a
O
OEt
5
2.5 h
46a
NH
S
N
S
O
O
O
O
a Isolated yield.
b Yield was determined by NMR after removal of sulfonamide byproduct 2.
Synthesis 2013, 45, 3361–3368
© Georg Thieme Verlag Stuttgart · New York

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SNAAP Sulfonimidate Alkylating Agent
3363
O
O
O
S
O
S
O2N
N+
H
O2N
N
+
–O
R
HO
R
O
O
O
O
H
+
O2N
S
N
EtO
R
O
Scheme 3 Proposed mechanism of proton-promoted sulfonimidate ethylation of acids
O
O
OEt
S
O
H
O2N
N
+
+
O2N
S
N
••
HO
pKa1
R
EtO
R
O
O
pKa2
Scheme 4 Acid vs. sulfonamide pKa affects reactivity
gave ethyl methanesulfonate in high yield in less than 5 a higher concentration of the protonated sulfonimidate in-
minutes. 4-Toluenesulfinic acid (entry 4) gave exclusive- termediate. The best alkylation conversions (Scheme 4)
ly the hard product, ethyl 4-toluenesulfinate,37 by O-eth- were accomplished when pKa2 of the sulfonamide was
ylation. No soft, S-alkylation to give ethyl 4- higher than pKa1 of the acid being alkylated. This best ex-
methylphenyl sulfone was detected. Saccharin (entry 5) plains why salicylic (2.97) and mandelic (3.85) acids were
was O-ethylated directly by 1 in 2.5 hours to give 3-eth- ethylated on the carboxyl groups without affecting the hy-
oxy-1,2-benzthiazole 1,1-dioxide. The isolated product droxy groups. This may be because the pKa2 of the sulfon-
spectra are identical to the IR, NMR, and MS of authentic amide 2 is lower than the pKa1 of many alcohols and
samples. In each case, the sulfonamide byproduct 2 was phenols.38 Likewise, without acid catalysis, common al-
easily recovered and used to resynthesize the sulfonimi- cohols and phenols do not react with 1 for the same rea-
date 1. The proposed mechanism is shown in Scheme 3.
son. Ethylation of methanesulfonic acid with 1 is rapid
and nearly quantitative, because the acid pKa1 is much
lower than that of the sulfonamide (pKa1 << pKa2).38
Carboxylic acids with pKa values ranging from 2.85 to
4.29 required refluxing in tetrahydrofuran for two to five
days to obtain modest to good yields of the ethyl esters We have carried out the catalytic ethylation of aliphatic
(Table 2). Salicylic acid (entry 2) and mandelic acid (entry and aryl-substituted alcohols (Equation 3) in good to ex-
4) were chemoselective, alkylating only the acid. We at- cellent yields at room temperature, using tetrafluoroboric
tempted to accelerate sulfonimidate 1 esterification of acid dimethyl ether complex (10 mol%). Preliminary
benzoic acids (entries 1, 3, 5, and 6) using tetrafluoroboric small-scale reactions were easily followed by NMR spec-
acid dimethyl ether, but were unsuccessful; after one hour troscopy in carbon tetrachloride or deuterochloroform;
at room temperature, the sulfonimidate decomposed, with most were complete in less than 10 minutes at room tem-
no significant production of ethyl benzoates.
perature. In carbon tetrachloride, the byproduct sulfon-
amide 2 precipitated from solution as the reaction
progressed. Small aliphatic alcohols including primary,
As a general rule, uncatalyzed ethylation of strong acids
with lower pKa values occurs faster, probably because of
Table 2 Sulfonimidate Ethylation of Weaker Acids
Entry
Acid
pKa
Timea
Product
Yieldb (%)
1
2
3
4
5
6
7
2-BrC6H4CO2H
2-HOC6H4CO2H
3,4-Cl2C6H3CO2H
PhCH(OH)CO2H
4-BrC6H4CO2H
4-ClC6H4CO2H
PhCO2H
2.85
2.97
3.71
3.85
3.96
4.01
4.29
5 d
5 d
5 d
2 d
5 d
5 d
5 d
2-BrC6H4CO2Et
2-HOC6H4CO2Et
3,4-Cl2C6H3CO2Et
PhCH(OH)CO2Et
4-BrC6H4CO2Et
4-ClC6H4CO2Et
PhCO2Et
47
60c
71
95d
49
34
47
a In refluxing THF.
b Isolated yield.
c Crude yield.
d Excess acid (1.93 equiv).
© Georg Thieme Verlag Stuttgart · New York
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T. J. Maricich et al.
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OEt
S
O
S
ROH
H
ROEt
+
O2N
N
O2N
N
••
HBF4⋅OMe2
(10 mol%)
O
1
O
2
Equation 3 Sulfonimidate ethylation of alcohols
secondary, tertiary, allylic, and neopentyl were ethylated Likewise, alcohols containing phenyl groups gave only
(Table 3). These volatile ethers were identified by com- single, O-ethylation products (Table 4), which were iso-
parison with known NMR spectra after separation from 2. lated by flash chromatography or Kugelrohr distillation
No molecular rearrangements were observed in formation after precipitation and filtration of 2. These were identical
of the ethyl ethers. This is particularly notable; because to authentic ethyl ethers. Higher yields were usually ob-
many of these alcohols are prone to undergo acid-cata- tained by Kugelrohr distillation, which is our method of
lyzed rearrangements.10 Yields of these ethers (ranging choice for these liquids.
from 78 to 94%) were calculated from NMR spectra with
fluorobenzene as a quantitative, internal standard. Isola-
tion of ethers from solid alcohols was readily accom-
Table 4 Sulfonimidate Ethylation of Phenyl Alcohols Catalyzed by
Fluoroboric Acid–Dimethyl Ether Complex
plished on a gram scale. In the ethylation of (–)-
Entry Alcohol
Time
(min)
Product
Isolated
yield (%)
(1R,2S,5R)-menthol (Scheme 5), ethyl menthyl ether was
isolated in 72% yield without racemization. The optical
rotation, [α] –95.6 at 20.2 °C was consistent with the liter-
ature value of [α] –89.2 at 25 °C.39 Cholesterol was ethyl-
ated in 44% isolated yield by using 2.4 mol% of 48%
aqueous fluoroboric acid as catalyst.40
1
<5
62a, 62b
Ph
OEt
OEt
Ph
OH
OH
2
3
4
<15
<30
<30
55a, 85b
79b
Ph
Ph
Ph
Ph
OH
OH
OEt
OEt
70a
Table 3 Sulfonimidate Ethylation of Aliphatic Alcohols Catalyzed
by Fluoroboric Acid–Dimethyl Ether Complex
Ph
Ph
a Isolated by flash chromatography.
b Isolated by Kugelrohr distillation.
Entry
1
Alcohol
Product
Yielda (%)
81
Acid-catalyzed ethylation of phenols (Equation 4) gave
ethyl ethers. Catalyzed reactions proceeded faster and in
higher yields for phenols with electron-donating groups
compared with those having electron-withdrawing
groups. This suggests that the more electron-rich phenolic
oxygens are more nucleophilic in this ethylation reaction.
Purification of both alcohol and phenol ethers is easily ac-
complished by precipitation of the sulfonamide byproduct
2 with pentane, filtration, and treatment with sodium hy-
OH
OEt
2
80
OEt
OH
3
4
5
79
94
78
OH
OEt
OEt
OH
OEt
OH
Table 5 Sulfonimidate Ethylation of Electron-Rich Phenols Cata-
lyzed by Fluoroboric Acid–Dimethyl Ether Complex
a Yields were determined by NMR with an internal standard after re-
moval of sulfonamide byproduct 2.
Entry Phenol
Time (min) Products
Yield (%)
70a
1
2
3
4
5
PhOH
<30
<30
90
PhOEt
4-MeC6H4OH
4-t-BuC6H4OH
4-HOC6H4OH
4-MeC6H4OEt 87b
4-t-BuC6H4OEt 59b
4-EtOC6H4OEt 45c,d
HBF4⋅OMe2
+
1
72%
OH
OEt
<60
<60
4-EtOC6H4OH
4-EtOC6H4OEt 46c
C9H17
C9H17
OEt
OH
HBF4⋅H2O
68a
1 +
6
<30
44%
HO
EtO
a Isolated by flash chromatography.
b Isolated by Kugelrohr distillation.
c Crystallized solid.
Scheme 5 Sulfonimidate ethylation of menthol and cholesterol cat-
alyzed by fluoroboric acid
d From 2.2 equiv of 1.
Synthesis 2013, 45, 3361–3368
© Georg Thieme Verlag Stuttgart · New York

PAPER
SNAAP Sulfonimidate Alkylating Agent
3365
OEt
S
O
H
ArOH
O2N
N
O2N
S
N
+
ArOEt
••
HBF4⋅OMe2
(10 mol%)
O
1
O
2
Equation 4 Sulfonimidate ethylation of phenols
O
O
Me
BF4
Me
O2N
S
N
O2N
S
N+
H
–
O+
H
HO
R
••
O
O
1
Me
Me
H
O+
O
O
O+
H
–
Me
O
Me
BF4
H
R
O2N
S
N
R
O
2
Scheme 6 Proposed mechanism for catalyzed ethylation of alcohols and phenols
dride to remove residual sulfonamide, alcohols, or phe- azoalkane, trialkyloxonium tetrafluoroborate, and other
nols and any other protic substances. Final purification is alkylating agents.
accomplished by Kugelrohr distillation and/or flash chro-
Results from another stable, crystalline sulfonimidate re-
matography to give ethers identical to authentic samples
agent with a secondary, isopropyl alkylating group will be
(Table 5 and Table 6).
reported soon,1a along with electrophilic aromatic substi-
tutions by sulfonimidates and O-alkylations of amides.
Table 6 Sulfonimidate Ethylation of Electron-Deficient Phenols
Catalyzed by Fluoroboric Acid–Dimethyl Ether Complex
All reactions were carried out in oven-dried glassware. CH2Cl2 was
Entry Phenol
Time Products
(min)
Isolated
yield (%)
purified through an M Braun solvent purification system. Commer-
cially obtained Ag2O was finely ground, dried and stored in a dark-
ened vacuum oven for at least an hour before use. All other
commercially obtained chemicals were used as obtained, unless
noted otherwise. NMR spectra were recorded on a Bruker 500, 400,
or 300 MHz instrument in CDCl3 or CCl4. All of the alkylation
products are common esters or ethers; many of which are commer-
cially available and have spectra published in spectral data bases.
References are given for those that are less common. Copies of
spectra of the known products are provided in the Supporting Infor-
mation. Melting points are uncorrected. Flash chromatography was
accomplished with RediSepTM disposable columns by Isco, Inc.
Mass analyses were carried out at the University of California, Riv-
erside High Resolution Mass Spectrometry Facility, Riverside, CA,
USA.
1
2
3
4-BrC6H4OH
C6Cl5OH
<50 4-BrC6H5OEt
<60 C6Cl5OEt
54
32
59
2,4,6-Cl3C6H2OH <120 2,4,6-Cl3C6H2OEt
Based upon analogy to alkylations by amide acetals,2 a
mechanism for the catalyzed ethylation reactions is pro-
posed in Scheme 6. The protonated intermediate of the
product ether could catalyze the next alkylation reaction
by direct protonation of another sulfonimidate molecule.
A stable, crystalline 4-nitrobenzenesulfonimidate1 can be
prepared by a novel, direct O-ethylation of a sulfonamide
in high yield. This reagent readily ethylates acids to esters
without a catalyst, and alcohols and phenols to ethers with
fluoroboric acid catalyst. The stronger the acid, the faster
it alkylates and in higher yield. The more electron-rich an
alcohol or phenol is, the faster it is catalytically alkylated
by the sulfonimidate, and in higher yield. The sulfonimi-
date 1 is a hard alkylating agent, which prefers oxygen
over nitrogen and sulfur. Alkylation reactions occur with
a wide variety of labile acids, alcohols, and phenols to
give products without molecular or geometric rearrange-
ments, or racemization. Isolation of pure reaction prod-
ucts is easy and recycling of the byproduct sulfonamide 2
to the sulfonimidate reagent 1 is atom efficient and trivial.
Therefore, sulfonimidates are excellent alternatives to di-
N-tert-Butyl-4-nitrobenzenesulfonamide (2)
A previously filtered solution of 4-nitrobenzenesulfonyl chloride
(45 g, 204 mmol) in anhydrous CH2Cl2 (150 mL) was added slowly
(over a 1-h period) to an ice-cooled solution of t-BuNH2 (27.9 g,
40.0 mL, 381 mmol) in anhydrous CH2Cl2 (150 mL). After addition,
the mixture (containing white solids) was stirred overnight at r.t.
The precipitate was vacuum filtered; the orange filtrate was concen-
trated by rotary evaporation to give the crude product as a yellow
solid; crude yield: 51.31 g (98%); mp 98–105 °C; this material
could be recrystallized (MeOH–H2O, 100 mL:35 mL) to give light
yellow crystals; yield: 45.71 g (87%) mp 109–111 °C (Lit.41 108.5–
110 °C).
IR (KBr): 3274, 3107, 2989, 2877, 1612, 1538, 1358, 1172, 1091,
998, 855 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (s, 9 H), 5.23 (s, 1 H), 8.11
(d, J = 9.0 Hz, 2 H), 8.36 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CHCl3): δ = 30.1, 55.4, 124.3, 128.2, 149.2,
149.7.
© Georg Thieme Verlag Stuttgart · New York
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T. J. Maricich et al.
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Ethyl N-tert-Butyl-4-nitrobenzenesulfonimidate (1)
yield: 0.27 g (58%). IR and 1H NMR spectra were identical to pub-
lished spectra.
N-tert-Butyl-4-nitrobenzenesulfonamide (2, 5.7 g, 22 mmol) was
dissolved in anhydrous CH2Cl2 (30 mL) in a 250-mL aluminum-
foil-covered round-bottom flask with a condenser and drying tube.
Commercial Ag2O (5.11 g, 22 mmol) and molecular sieves (0.5 g)
(both of which had been finely ground and heated in vacuo in the
dark at 100 °C for at least 1 h) and EtI (12.3 g, 79 mmol) were added
to the mixture. This was refluxed with vigorous stirring overnight
[TLC (hexane–EtOAc, 3:1 + 1% Et3N) monitoring]. Additional EtI
(0.5 mL, 6.3 mmol) and anhydrous Ag2O (1.7 g, 7.1 mmol) were
added and the mixture was refluxed overnight again. If substantial
sulfonamide 2 remained after 2 d, then additional EtI, Ag2O, and
molecular sieves were added and the mixture was refluxed for a fur-
ther 1 d. Solids were removed by vacuum filtration with a fritted
funnel and Celite or glass filter paper. The filtrate was treated with
NaH (0.36 g, 15 mmol), which had been rinsed with hexane (3 ×).
The mixture was stirred overnight and vacuum filtered to remove
the sodium sulfonamide salt. The filtrate was concentrated by rotary
evaporation to give light yellow crystals; crude yield: 6.012 g
(95%); mp 51–53 °C). The yield may vary (85–95%) depending
upon the dryness of the materials and the quality of the Ag2O. Re-
crystallization was accomplished, if needed, by dissolving approxi-
mately one part sulfonimidate 1 in four parts MeOH (at r.t.) and
cooling overnight in a freezer (mp 53–55 °C). Successive concen-
trating of the filtrates and cooling in a freezer afforded additional
product.
Ethyl Methanesulfonate
Sulfonimidate 1 (0.546 g, 1.906 mmol, 1.1 equiv), dissolved in pen-
tane (ca. 100 mL), was treated with methanesulfonic acid (112.5 μL,
166.6 mg, 1.734 mmol) by syringe. The reaction was allowed to
take place for 15 min before concentration by rotary evaporation to
remove most of the pentane solvent. The liquid portion of the mix-
ture of solid byproduct 2 and pentane solution was pipetted through
a Pasteur pipet fitted with glass wool and a few centimeters of silica
gel. The filtrate was collected in a 25-mL round-bottom flask. An
additional few mL of pentane were used to rinse residual solids and
filtered through the same pipet. The resulting solution was concen-
trated and purified by Kugelrohr distillation to give ethyl methane-
1
sulfonate; yield: 192 mg (89%). H NMR spectra was identical to
the published spectrum.
Ethyl Trifluoroacetate
Sulfonimidate 1 (30 mg, 105 μmol, 1.1 equiv), dissolved in CCl4
(0.5 mL), was added to an NMR tube followed by TFA (7.1 μL,
10.9 mg, 95.2 μmol). The tube was shaken and analyzed by NMR
to observe that the reaction was complete. The mixture was filtered
through a Pasteur pipet fitted with glass wool and 2-cm of silica gel
to remove the byproduct sulfonamide 2. The filter was rinsed with
additional CCl4 (0.25 mL) into a separate NMR tube. CDCl3 (0.25
mL) and a drop of TMS were added for NMR analysis. Only ethyl
trifluoroacetate was observed.
IR (KBr): 3111, 2983, 1609, 1532, 1366, 1308, 1219, 1168, 1027,
906, 848, 765, 695 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.22 (t, J = 7 Hz, 3 H), 1.43 (s, 9
H), 3.92 (q, J = 7 Hz, 2 H), 8.13, (d, J = 9 Hz, 2 H), 8.31 (d, J = 9
Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 15.1, 33.1, 56.6, 66.3, 124.2,
129.1, 146.1, 150.1.
Ethyl 4-Toluenesulfinate
4-Toluenesulfinic acid (0.156 g, 1.00 mmol) was dissolved in a
minimal amount of CH2Cl2 (ca. 10 mL) and sulfonimidate 1 (0.315
g, 1.10 mmol, 1.1 equiv) was added to the solution. The mixture was
stirred at r.t. for less than 50 min and then CH2Cl2 was removed by
rotary evaporation. Pentane was added and solids were filtered. The
purity of the filtrate was determined by TLC (hexane–EtOAc, 6:1).
After Kugelrohr distillation and TLC analysis, the product was dis-
solved in pentane and treated with NaH (1 mmol) to remove protic
impurities. The solids were removed by filtration and pentane was
removed in vacuo to give the product; yield: 0.141 g (74%).
HRMS: m/z [M + H] calcd for C12H19N2O4S: 287.1060; found:
287.1068.
Anal. Calcd for C12H18N2O4S (286.35): C, 50.33; H, 6.34; N, 9.78.
Found: C, 50.79; H, 6.46; N, 9.71.
Ethylation of Strong Acids; General Procedure
Ethyl 2-Bromobenzoate; Typical Procedure for Ethylation of
Weaker Acids
The acid was added to a concentrated solution of sulfonimidate 1
(10% molar excess) dissolved in CH2Cl2. A mild exotherm was gen-
erally observed. Brief rotary evaporation to remove most of the sol-
vent was followed by addition of pentane to precipitate solid
byproduct 2 and residual 1. In some cases the reaction was run in
pentane or hexane. Vacuum filtration followed by rotary evapora-
tion of the pentane filtrate produced the crude ester product. Evalu-
ation of the expected product (whether solid or liquid) and of TLC
results helped to determine whether flash chromatography and/or
Kugelrohr (short path) distillation would be better for purification.
Most simple esters have the highest Rf values and lowest boiling
points among the residues remaining in the product, so purification
is usually straightforward.
Sulfonimidate 1 (0.859 g, 3.00 mmol) and 2-bromobenzoic acid
(0.601 g, 3.00 mmol) were refluxed in THF (25 mL) for 5 d. TLC
analysis (hexane–EtOAc, 6:1) showed that most of 1 had been con-
verted into the sulfonamide 2. The mixture was concentrated by ro-
tary evaporation and pentane (5 mL) was added. The pentane
solution was removed by pipet and treated with NaH to precipitate
any unreacted acid and residual 2. This solution was pipet filtered,
concentrated in vacuo and purified by Kugelrohr distillation; yield:
0.32 g (47%). IR and 1H NMR spectra were identical to published
spectra.
Ethyl 2-Hydroxy-2-phenylacetate
Sulfonimidate 1 (0.535 g, 1.87 mmol) and dl-mandelic acid (0.55 g,
3.61 mmol, 1.93 equiv) were refluxed in distilled THF (10 mL) for
2 d. TLC (hexane–EtOAc, 5:1) confirmed completion of the reac-
tion. The mixture was extracted with sat. NaHCO3 until the organic
layer showed no mandelic acid spot on TLC. The organic layer was
dried (anhyd MgSO4) and purified by flash chromatography (hex-
ane–EtOAc, 5:1). Fractions were collected and concentrated to give
the product; yield: 0.319 g (95%); mp 30–31 °C.
Ethyl 2,2-Dichloroacetate
Sulfonimidate 1 (0.859 g, 3.00 mmol) was dissolved in anhydrous
CH2Cl2 (1.5 mL) and added dropwise to a 25-mL round-bottom
flask containing dichloroacetic acid (250 μL, 0.375 g, 3 mmol). The
solution warmed up upon addition and imparted a fruity odor char-
acteristic of esters (TLC monitoring). Within 5 min, most of 1 ap-
peared to have reacted and a significant amount of the byproduct
sulfonamide 2 had been produced. The solution was concentrated
by rotary evaporation and pentane (5 mL) was added. The pentane
solution was pipetted out, leaving the undissolved sulfonamide
crystals behind. A small amount of NaH (0.1 g, 4 mmol) was added
to the pentane solution to precipitate salts of any unreacted acid and
residual 2. The solution was pipetted from the solids, concentrated,
and purified by Kugelrohr distillation to give ethyl dichloroacetate;
IR (KBr): 1733 (C=O), 3468 cm–1 (OH).
MS: m/z = 180 (base peak).
NMR-Scale Ethylation of Alcohols; General Procedure
Sulfonimidate 1 (30 mg, 0.105 mmol, 10 mol% excess) and alcohol
(0.97 mmol) were dissolved in CCl4 (0.5 mL) along with an internal
quantitative standard of PhF (2.3 μL, 0.024 mmol, 25 mol% of al-
Synthesis 2013, 45, 3361–3368
© Georg Thieme Verlag Stuttgart · New York

PAPER
SNAAP Sulfonimidate Alkylating Agent
3367
cohol) and added to an NMR tube. The alcohols studied were 2-
methylpropan-1-ol, butan-2-ol, 2-methylpropan-2-ol, but-3-en-2-
ol, and neopentyl alcohol. Spectra of each mixture were run before
addition of HBF4·OMe2 (1.0 μL, 9.7 μmol, 10 mol% of the alcohol
amount). The NMR tubes were capped and inverted several times
before recording the progress of each reaction. Reactions were fol-
lowed by observing the disappearance of the sulfonimidate 1 tert-
butyl peak at δ = 1.38 (in CCl4) and the appearance of the sulfon-
amide 2 tert-butyl peak at δ = 1.23. In each spectrum, a small singlet
appeared at δ = 3.2, which corresponds to Me2O from the catalyst.
Reactions with aliphatic alcohols were complete in less than 15 min.
Several molecular sieve pellets were added to each NMR tube to
neutralize the catalyst after completion of the reaction. Each prod-
uct was isolated, by pipetting the CCl4 solution from the precipitat-
ed sulfonamide 2. The samples were squeezed with a large pipet
bulb through a cotton-plugged Pasteur pipet containing silica gel
(ca. 3 cm). Each was rinsed with additional CCl4 (2 × 0.25 mL) into
an NMR tube for analysis. Excellent yields of the ethyl ethers of
each alcohol were observed. No evidence for molecular rearrange-
ments was seen.
trated by rotary evaporation to obtain the crude product. Kugelrohr
distillation gave pure product; yield: 389 mg (79%).
1-tert-Butyl-4-ethoxybenzene; Typical Procedure for Reactions
with Electron-Rich Phenols
Sulfonimidate 1 (1.030 g, 3.60 mmol) and 4-tert-butylphenol (0.450
g, 3.00 mmol) were dissolved in pentane (10 mL). The mixture was
magnetically stirred for at least 5 min before HBF4·OMe2 (31 μL,
0.3 mmol) was added. A light pink precipitate was observed within
5 s. After 90 min the reaction was complete, but TLC still showed
the presence of the phenol. After placing the plate in the I2 chamber,
2 new spots were observed. The new spots were assumed to be de-
rivatives of the phenols, possibly due to electrophilic aromatic sub-
stitution. After stirring overnight and filtering the precipitate, TLC
showed that multiple spots were still present. As a result, rinsed
NaH (171 mg, 4.41 mmol) suspended in pentane was added with an
eyedropper to react with the phenols. Bubbling occurred and the
tan-colored solution was stirred for ca. 10 min. The mixture was al-
lowed to settle for ca. 30 min. TLC showed multiple spots. Another
same amount of NaH was added and less bubbling occurred. The
mixture was left to sit overnight. The following day, TLC showed
only two faint spots rather than four or five. Sodium alkoxide salt
was then filtered out with a fritted funnel and the filtrate was trans-
ferred into a tared 25-mL round-bottom flask. The filtrate was con-
centrated by rotary evaporation and Kugelrohr distilled to obtain a
pure product; yield: 0.313 g (59%).
(1R,2S,5R)-2-Ethoxy-1-isopropyl-4-methylcyclohexane
(–)-(1R,2S,5R)-Menthol (1.000 g, 6.40 mmol, mp 42.5–43.7 °C)
and sulfonimidate 1 (2.017 g, 7.04 mmol) were dissolved in mag-
netically stirred, anhydrous CCl4 (20 mL) in a septum-capped 50-
mL round bottom flask with a drying tube. HBF4·OMe2 (66 μL, 0.64
mmol) was added [TLC (hexane–EtOAc, 4:1 + 1% Et3N) monitor-
ing]. After 4.5 h, the mixture was flash chromatographed (silica gel,
5 cm, 1-cm diameter column) to kill the catalyst and remove the sul-
fonamide byproduct 2. The reaction flask was rinsed with pentane
(3 × 5 mL) and flushed through the column. Solvent was removed
by rotary evaporation, followed by evacuation under high vacuum
to give the product; yield: 0.846 g (72%). The average optical rota-
tion for the product (three determinations) was [α]D –95.6 at
20.2 °C. The structure was confirmed by 1H NMR (400 MHz) and
GC/MS.
1-Bromo-4-ethoxybenzene; Typical Procedure for Reactions
with Electron-Deficient Phenols
Sulfonimidate 1 (299 mg, 1.04 mmol) and 4-bromophenol (129 mg,
0.746 mmol) were added to a magnetically stirred round-bottom
flask fitted with a septum. Anhydrous CH2Cl2 (ca. 2 mL) was added,
followed by HBF4·OMe2 catalyst (7.7 μL, 10 mol% of the amount
of phenol) [TLC (hexane–EtOAc, 4:1 + 1% Et3N) monitoring]. Af-
ter 50 min, when the reaction was complete (loss of TLC spot for 1),
the catalyst was quenched with several dry molecular sieve pellets.
Molecular sieves were filtered and rinsed with CH2Cl2, and the fil-
trate was concentrated by rotary evaporation. The concentrate was
dissolved in anhydrous CH2Cl2 (1 mL) and loaded onto a flash chro-
matography column (silica gel, 5 g, hexane); yield: 81 mg (54%).
(3β)-3-Ethoxycholest-5-ene
Sulfonimidate 1 (1.254 g, 4.38 mmol) and cholesterol (1.226 g, 3.17
mmol) were dissolved in anhydrous CH2Cl2 (10 mL) and treated
with 48% aq HBF4 catalyst (10.0 μL, 2.4 mol%) [TLC (hexane–
EtOAc, 4:1 + 1% Et3N) monitoring; aluminum-backed silica gel
plates were developed after elution by dipping in an acid developer
(5% H2SO4, 45% (95%) EtOH, and 50% anisaldehyde by volume)
with heating until blue cholesterol spots appeared against a peach
background]. The reaction was complete after 1 h, when the sulfon-
imidate and cholesterol spots disappeared. At that point, a few mg
of molecular sieves were added to the mixture to neutralize the acid.
After rotary evaporation, hexane (30 mL) was added to the concen-
trate and the mixture was stirred overnight. Solids were vacuum fil-
tered to give a clear filtrate, which was chromatographed (silica gel,
hexane–Et2O, 1:4). Clear fractions were concentrated by rotary
evaporation to give a white solid; yield: 0.573 g (44%); that was re-
crystallized (EtOH). The mixed melting point with commercial
Acknowledgment
We would like to thank U.S. Department of Education, McNair
Scholar (O.A.); Howard Hughes Medical Institute Scholar (A.P.);
CSULB President’s Scholar (C.B.); CSULB Women and Philan-
thropy Scholar (C.B.); CSULB Provost Scholars (N.-C.K., J.W.) for
student support; and Profs. Fred Wudl (UCSB) for method sugge-
stions, and Paul Buonora, Michael Schramm, and Gary Shankweiler
(CSULB) for manuscript review.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra of compounds 1 and 2 and of
1
(Sigma) product was not depressed (88–88.5 °C). H NMR spec-
trum of the synthetic product was identical to that of cholesteryl eth-
yl ether. Sulfonamide 2 was obtained (0.768 g, 68%) from the
reaction.
1H spectra of ethylation products reported in this study.SnouIfirp
m
tgoiraot
n
S
nuorm
gIifopitantr
References
3-Ethoxypropylbenzene; Typical Procedure
Sulfonimidate 1 (1030 mg, 3.60 mmol) and 3-phenylpropan-1-ol
(409 mg, 3.0 mmol) were dissolved in pentane (ca. 8 mL). The
clear, yellow solution was magnetically stirred for at least 5 min be-
fore HBF4·OMe2 catalyst (31 μL, 0.30 mmol) was added. Bubbling
occurred immediately and a white precipitate was observed. The
flask was warm to the touch. The reaction was complete in <30 min,
as observed by precipitation of 2, then left to stand overnight. The
next day, the precipitate appeared to be tan. The precipitate was fil-
tered by vacuum and rinsed with pentane. The filtrate was concen-
(1) This paper is a compilation of results previously presented in
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3361–3368

3368
T. J. Maricich et al.
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Synthesis 2013, 45, 3361–3368
© Georg Thieme Verlag Stuttgart · New York