The Synthesis of Alkyl and (Hetero)aryl Sulfonamides from Sulfamoyl Inner Salts

Article abstract of DOI:10.1021/acs.joc.5b01287

An approach to the synthesis of sulfonamides from sulfamoyl inner salts and organometallic species is presented. A range of sulfamoyl carbamates, amines, and metals are explored. Primary, secondary, and tertiary alkyl-, aryl-, and heteroaryllitihium and magnesium nucleophiles were successful. This approach yields bench-stable intermediates and avoids many of the functional group incompatibilities, regioselectivity issues, and high-energy reagents generally associated with the synthesis of sulfonamides. Additionally, the products may be purified by basic extraction or salt formation, avoiding chromatography.

Full text of DOI:10.1021/acs.joc.5b01287

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The Journal of Organic Chemistry
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The Synthesis of Alkyl and (Hetero)aryl Sulfonamides From Sul-
famoyl Inner Salts1
Joseph M. Young, Aisha G. Lee,† Ramalakshmi Y. Chandrasekaran, Joseph W. Tucker*
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Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road,
Groton, Connecticut 06340, United States
E-mail: joseph.tucker@pfizer.com
ABSTRACT: An approach to the synthesis of sulfonamides from sulfamoyl inner salts and organometallic species is presented. A
range of sulfamoyl carbamates, amines, and metals are explored. Primary, secondary, and tertiary alkyl-, aryl-, and heteroarylliti-
hium and magnesium nucleophiles were successful. This approach yields bench-stable intermediates and avoids many of the func-
tional group incompatibilities, regioselectivity issues, and high-energy reagents generally associated with the synthesis of sulfona-
mides. Additionally, the products may be purified by basic extraction or salt formation, avoiding chromatography.
Sulfonamides are an important functional group found throughout the pharmacopeia in therapeutic agents as diverse as sul-
fadimidine2 and tipranovir.3 They impart several attributes to molecules that make them attractive in drug discovery, including a
high total polar surface area (TPSA),4 which has been associated with improved outcomes in toxicology studies,5 a moderately
high pKa,6 and a distinct conformation7 that creates an approximately 90° turn in a molecule. Despite this utility, and an increas-
ing number of options for arylating and alkylating on the nitrogen,8-10 syntheses of primary sulfonamides still rely almost entirely
upon high-energy aminating reagents,11 Friedel-Crafts sulfaminations of electron rich benzene rings and olefins,12-13 oxidations of
sulfinamides, or the condensation of ammonia with sulfonyl halides, which themselves are synthesized using either strongly oxi-
dizing or chlorinating reagents14-16 and can be unstable.15 Recent advances in sulfinate synthesis have given rise to a number of
excellent publications addressing some of the liabilities of these approaches. For example, two recent publications by Shavnya17
and Willis18 provide efficient protocols for the coupling of an in situ generated sulfinate with an amine using a chlorinating or
brominating agent, removing the need for isolation of the sulfinate or sulfonyl chloride by providing the sulfonamide directly
from a multicomponent coupling. However, all of these advances still require a sulfur or nitrogen oxidation step, and we propose
that an alternative method which improves tolerance for electron rich (hetero)arenes, generates bench-stable products, and reduc-
es safety hazards would be extremely attractive.
The use of a readily purchased or synthesized organometallic species19-20 and a S(IV) or S(VI) source to directly form the C—
S(O)2 (NR2) bond would meet our desired criteria, but this disconnection is infrequently used for the synthesis of sulfonamides.
There are several examples of the synthesis of sulfinamides from S(IV) sources, including N-aryl aminosulfones21 or alkylsulfu-
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ramidous chlorides22 and esters,23 using a range of organometallics (Fig. 1). These sulfinamides may then be converted to sulfon-
amides via a subsequent oxidation reaction, typically with m-CPBA.24 While the yields of each step are generally excellent, this
remains an underutilized method of sulfonamide synthesis, which is likely due to two reasons. The first two protocols (eq. 1,2)
yield a limited set of 2° or 3° sulfinamides with nitrogen substituents that can be difficult to further modify. Meanwhile, alkyl-
sulfuramidous esters, generally generated in situ from thionyl chloride and an amino alcohol, have found widespread use for the
synthesis of highly hindered sulfonamides such as t-butyl and mesityl, but are rarely used to functionalize more reactive nucleo-
philes due to the competing formation of symmetric sulfoxides (eq. 3). Therefore, we sought a more general protocol involving a
suitable S(VI) reagent which could afford more easily diversifiable reaction products as well as obviating the need for subsequent
oxidative manipulations.
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Figure 1. Literature examples of organometallic sulfinamidation.
Interestingly, to the best of our knowledge, only three examples of this transformation using an S(VI) source are reported in the
literature (Fig. 2). Nishimura and co-workers opened an N-alkyl thiadiazolidinone 1,1-dioxide with methyl magnesium bromide
to form a methanesulfonamide (eq. 4),25 Lacôte and co-workers performed a radical-mediated coupling of chlorosulfonamides
with allyl stannanes (eq. 5),26 and Arnswald and co-workers utilized aryl stannanes in a Friedel-Crafts-like ipso substitution reac-
tion with chlorosulfonyl isocyanate (eq. 6).27
Figure 2. Examples of organometallic sulfonamidation.
This last example is related to a large, but rarely utilized, subset of chemistry using N-carbamoyl sulfamide inner salts. Typi-
cally used for dehydration or amination chemistry,28,29-ref these salts react with a range of soft carbon nucleophiles such as
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enamines (Scheme 1, eq. 7), to yield N-carbamoyl sulfonamides.30,31 However, we could find no examples of a reaction between
a sulfamide inner salt and a hard carbon nucleophile such as a Grignard reagent (eq. 8), and we were intrigued by this absence
from the literature.
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Scheme 1. Precedent (7) and proposed (8) reaction of C-nucleophiles with Burgess inner salts.
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We envisioned three possible products could result from addition of a single equivalent of phenylmagnesium bromide to I.
There was some concern that the Grignard reagent, a “hard” nucleophile, would preferentially add to the carbonyl of I or II, over
the “soft” sulfur center, and that this accounted for the dearth of literature in this area. Gratifyingly, however, phenylmagnesium
bromide added cleanly to commercial inner salt 1 (Table 1, entry 1), yielding the desired benzyl (phenylsulfonyl)carbamate in
56% yield after chromatography. Similar reactivity was observed with readily prepared inner salts 232 and 328 (Table 1, entries 2-
3).
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Table 1. Nucleophilic additions to sulfamoyl inner salts
entry
R’’-M
equiv. of
R’’-M
1.1
inner
yield
salt
1
1
2
3
4
5
6
7
8
9
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhLi
56%
60%
57%
NR
1.1
2
1.1
3
4.0
5
1.1
6
NR
1.1
4
NR
1.1
2
50%a
28%
NR
PhLi
1.1
3
t-BuMgBr
3.0
3
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12b
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AdMgBr
t-BuLi
3.0
1.0
3
3
2
2
3
3
NR
20%
NR
1
2
3
4
5
6
7
8
PhZnBr
0.66
1.5
3-MeC6H4MgBr
3-MeC6H4MgBr
3-
39%c
57%
53%
2.0
1.0
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MeOC6H4MgBr
3-
16d
17
1.1
4.0
3
3
64%c
50%
MeOC6H4MgBr
4-
MeOC6H4MgBr
4-MeSC6H4MgBr
2-MeC6H4MgBr
2-
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19
20
1.1
3.0
3.0
3
3
2
51%c
47%
21%c
MeOC6H4MgBr
2-
21
3.0
3
31%
MeOC6H4MgBr
2-MeC6H4MgBr
2-MeC6H4MgBr
BnMgBr
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23f
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1.2
1.2
1.0
3.0
4.0
2.0
3.0
1.0
1.0
1.0
2.0
3
3
3
3
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3
3
1
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3
3
NR
NR
31%
33%
27%
34%
17%c
49%
NR
C6H11MgBr
i-PrMgCl●LiCl
7
8
NR
4-CO2Me-
C6H4MgCl
NR
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General conditions: 0 °C, 0.15 M final concentration, 60-90 min. a Purified by salt formation followed by acidification. b 0-55 °C. c
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Isolated as an ammonium salt. d 1 g scale. e 2.5 equiv. BF3●OEt2. f 2.5 equiv. MgBr2●OEt2. NR: no reaction.
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Benzyl carbamoyl derivative 3 offered several advantages over 1 and 2, including indefinite stability at 5 °C, and reaction
products that were readily quantified by NMR (Fig. 3, eq. 9) and easily visualized during purification.33,34 Using 3 as the limiting
reagent, the balance of the material in the crude NMR spectrum from entry 3 was identified as O-benzyl carbamate B, arising
from unreacted 3 (0-10%, based on integration of PhCH2OC(O)NH2 peak), and products arising from addition to the carbamate
of the product, N-phenylsulfonyl benzamide C and phenylsulfonamide D (0-5% based on integration of PhCH2OH peak). Un-
surprisingly, C and D increased with addition of extra equivalents of nucleophile and increasing reaction times and temperatures.
Although unpurified mass recoveries ranged from 70-90% and >80% purity, the isolated yields were modest, and reflect issues
with chromatographically separating the desired material from side products on small scale in order to generate analytically pure
material. The desired product could generally be isolated from the observed by-products via extractive purification to improve
isolated yields, vide infra.
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Figure 3. Products observed.
Three additional inner salts were surveyed. The bench-stable DABCO (5)35 and DMAP (6)36 complexes did not yield the de-
sired products (entries 4-5). Complex 5 was insoluble under the standard reaction conditions, even with addition of two extra
equivalents of phenylmagnesium bromide, while 6 yielded only products arising from addition to the pyridine moiety.37 The ex-
tremely stable trifluoroethylcarbamoyl inner salt 438 also failed to react (entry 6). This result implies that the reaction likely pro-
ceeds through sulfonyl carbamate II. If the inner salt form I were the dominant electrophilic species, we expect 4 to be more re-
active due to greater anion stabilization and thus greater partial positive charge on the sulfur center.
Two additional metals were explored. Organolithiums reacted similarly to Grignards (entries 7-8) with one notable exception.
t-Butyllithium (entry 11) cleanly provide benzyl (t-butylsulfonyl) carbamate,39 while t-butyl and adamantyl Grignards14 (entries
9-10) yielded only O-benzyl carbamate.40 Aryl zincates proved not to be competent nucleophiles, even with prolonged reaction
times and warming (entry 12).41
A wide range of organometallics were successfully utilized. Simply substituted aryl Grignards added rapidly with only one
equivalent of nucleophile (entries 13-18), while more hindered o-substituted nucleophiles typically required longer reaction times
and additional equivalents of nucleophile for full consumption of the inner salt (entries 19-21). The addition of Lewis acids in an
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attempt to accelerate the reaction either by capturing the NEt3 or activating the electrophile resulted only in recovery of A (entries
22-23). Non-aryl nucleophiles were also viable. Primary alkyl Grignards added cleanly with only one equivalent of nucleophile,
(entry 24), while the more hindered secondary alkyl Grignards required additional time and reagent (entries 25-26). Heterocycles
7 and 8 both provided acceptable yields of pharmaceutically relevant sulfonamides (entries 27-28). Alkynes also proved to be
successful, although not with 3, (entries 29-31), yielding a primary ethynylsulfonamide precursor in 4 fewer steps than previous
syntheses.42 Finally, aryl Grignard reagents bearing electron withdrawing groups did not efficiently add to inner salt 3 (entry 32).
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One major concern with our established protocol was the lower-than-expected post-purification yields for many of the sub-
strates. Pre-purification mass-recovery was typically >80%, but poor resolution between A and the other reaction products on
silica gel meant that large portions were lost during chromatographic isolation of analytically pure material. The difference in
yields between entries 7 and 8 indicated that perhaps purification by salt formation would improve mass recovery. Although this
did work in the case of the 3-methoxyphenyl (entry 16 vs 15), the wide range in pKa’s and solubility of our products precluded
development of a standard protocol, and substrates such as entry 28 proved difficult to purify in this manner. Initial attempts
with direct purification of the magnesium amides generated in the reaction by liquid-liquid extraction yielded poor results as
well, as these salts were too soluble in organic solvents in the presence of THF to efficiently extract. Fortuitously however, a
protocol consisting of isolation of the protonated acid, extraction from Et2O with 1 N NaOH, acidification of the aqueous layer to
pH 1 with concentrated HCl, and then re-extraction of the product with EtOAc yielded material >95% pure by NMR and in sig-
nificantly better yields.
Table 2. Isolation of products in high purity via extractive purification
yield
equiv. of
R’’-M
previous
yield
entry
R’’-M
from
LLE
55%
1
2
3
t-BuLi
2-MeO
C6H4MgBr
9
1.0
2.0
2.0
20%
31%
17%
68%
51%
The sulfonyl carbamates generated with this method are useful in a range of chemistry. The t-butyl43 and benzyl44 carbamates
can be smoothly removed under mild, orthogonal conditions to afford primary sulfonamides. The low pKa45 of the products per-
mits smooth alkylation under Mitsunobu conditions46 to provide both useful intermediates46 and secondary sulfonamides after
carbamate removal.
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In conclusion, we have developed a broad method for the direct sulfonamidation of organolithium and organomagnesium nu-
cleophiles that avoids unstable intermediates and highly energetic reagents. The N-carbamoyl products generated are bench-
stable, useful in a wide variety of N-alkylation and N-arylation chemistries, and can be readily deprotected.
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EXPERIMENTAL SECTION
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General procedure A for the addition of alkyllithium and Grignard reagents to sulfamoyl inner salts: In an oven-dried,
nitrogen-purged round-bottomed flask equipped with magnetic stirbar and rubber septum, the inner salt (1.0 equiv) was dissolved
in THF sufficient to make the final concentration of the reaction 0.15 M. The mixture was cooled in an ice-water bath, and a so-
lution of the nucleophile (1-3 equiv) was added dropwise. After 60-90 min, the reaction was quenched with sufficient acid such
that the final pH was < 5 (or <1 if the calculated pKa <4). The mixture was extracted with EtOAc, dried, and concentrated. The
material was then purified by flash-column chromatography, by formation of an ammonium salt, or both sequentially.
General procedure B for the addition of alkyllithium and Grignard reagents to sulfamoyl inner salts: In an oven-dried,
nitrogen-purged round-bottomed flask equipped with magnetic stirbar and rubber septum, the inner salt (1.0 equiv) was dissolved
in THF sufficient to make the final concentration of the reaction 0.15 M. The mixture was cooled in an ice-water bath, and a so-
lution of the nucleophile (1-2 equiv) was added dropwise. After 90 min, the reaction was quenched with 5 equiv 1 N HCl. The
mixture was extracted with EtOAc, dried, and concentrated. The material was suspended in Et2O and extracted thrice with 1 N
NaOH. The combined aqueous layers were acidified to pH 1 with concentrated HCl and extracted with EtOAc. The combined
EtOAc layers were dried over Na2SO4, filtered and concentrated to provide the desired material.
Methyl (phenylsulfonyl)carbamate (Table 1, entry 1)47 Using the general procedure A, to 1 (213 mg, 0.894 mmol) in THF
(5.0 mL) was added PhMgCl in THF (0.49 mL, 0.98 mmol, 2.0 M). The reaction was stirred for 60 min and quenched with 1 N
HCl and worked-up as above. The material was loaded onto diatomaceous earth with DCM and purified on a 12 g silica ISCO
Gold cartridge (0-100% EtOAc in heptanes, 25 column volumes) to provide the title compound as a white solid (108 mg, 56%),
1
which was identical by H- and 13C-NMR to the published material. mp: 131-135 °C; 1H NMR (CDCl3, 400 MHz) δ 8.05-8.08
(m, 2H), 7.98 (bs, 1H), 7.67 (tt, J = 7.4, 1.6 Hz, 1H), 7.54-7.59 (m, 2H), 3.71 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 150.9,
138.3, 134.0, 129.0, 128.3, 53.7.
tert-Butyl (phenylsulfonyl)carbamate (Table 1, entry 2)48 Using the general procedure A, to 2 (200 mg, 0.713 mmol) and
THF (3.2 mL) was added PhMgCl in THF (0.39 mL, 0.79 mmol , 2.0 M). The reaction was stirred for 60 min and quenched with
1 N HCl and worked-up as above. The crude mixture was treated with 500 µL THF, 70 uL conc. NH4OH and 2 mL of Et2O and
the resulted slurry was stirred overnight. The ammonium salt of the desired material was collected by filtration the next day.
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These solids were re-dissolved in 10 mL of 0.1 N HCl and extracted 2x30 mL of DCM. The combined organic extract was dried
over Na2SO4, filtered, and concentrated to isolate 110 mg (60% yield) of desired as white crystalline solids. mp 116.4-120.2 °C;
1H NMR (CDCl3, 400 MHz) δ 8.12 (bs, 1H), 8.01-8.03 (m, 2H), 7.61-7.66 (m, 1H), 7.51-7.56 (m, 2H), 1.36 (s, 9H);
13C{1H}NMR (CDCl3, 100 MHz) δ 149.7, 139.2, 133.9, 129.1, 128.4, 84.5, 28.3; HRMS (ESI) m/z calculated for C11H15NNaO4S
[M+Na]+ 280.0614; found 280.0617.
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Benzyl (phenylsulfonyl)carbamate (Table 1, entry 3) Using the general procedure, to 3 (203. mg, 0.646 mmol) and THF
(3.9 mL) was added PhMgCl in THF (0.33 mL, 0.65 mmol, 2.0 M). The reaction was stirred for 60 min and quenched with
AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, concen-
trated, and then purified on a 12 g Redi-Sep Gold cartridge (0-100% EtOAc in heptanes, gradient over 25 CV, hold at 12% for 4
CV) to provide the title compound as a white solid (108 mg, 57.4%). mp 102.7-106.6 °C; 1H NMR (CDCl3, 400 MHz) δ 7.98-
8.04 (m, 3 H), 7.64 (tt, J = 7.8 ,1.2 Hz, 1H), 7.48-7.53 (m, 2H), 7.31-7.35 (m, 3H), 7.23-7.27 (m, 2H), 5.10 (s, 2H); 13C{1H}NMR
(CDCl3, 100 MHz) δ 150.4, 134.3, 133.9, 128.9, 128.7, 128.6, 128.4, 128.3, 68.6; HRMS (ESI) m/z calculated for C14H13NNaO4S
[M+Na]+ 314.0457, found 314.0456.
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Benzyl (tert-butylsulfonyl)carbamate (Table 1, entry 11) Using the general procedure A, to 3 (205 mg, 0.652 mmol) and
THF (3.9 mL) was added t-BuLi in pentane (0.42mL, 0.42 mmol, 1.7 M). The reaction was stirred for 90 min and quenched
with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, con-
centrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to provide the title
compound as a white solid. (36 mg, 20% yield). mp: 64-73 °C; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.39 (m, 5H) 7.29 (bs, 1H),
5.20 (s, 2H), 1.48 (s, 9H); 13C{1H}NMR (CDCl3, 100 MHz) δ 151.0, 134.6, 128.72, 128.66, 128.5, 68.7, 63.3, 24.3; HRMS (ESI)
m/z calculated for C12H17NNaO4S [M+Na]+ 294.0770 found 294.0768.
Benzyl (tert-butylsulfonyl)carbamate (Table 2, Entry 1) Using general procedure B, to 3 (672 mg, 2.14 mmol) and THF
(12.6 mL) was added t-BuLi in pentane (1.4 mL, 2.4 mmol, 1.7 M). The reaction was stirred for 90 min and worked up as de-
scribed to provide the product as a solid (339 mg, 58%).
Ammonium (tert-butoxycarbonyl)(m-tolylsulfonyl)amide (Table 1, entry 13) Using the general procedure A, to 2 (1.69
mL, 0.713 mmol, 0.42M) in benzene and THF (2.0 mL) was added m-MePhMgCl in THF (1.1 mL, 1.1 mmol, 1.0 M). The reac-
tion was stirred for 60 min and quenched with 1 N HCl and worked-up as above. The material was loaded onto diatomaceous
earth with DCM and purified on a 12 g silica ISCO Gold cartridge (0-100% EtOAc in heptanes, 25 column volumes) and the
peak at 10 column volumes was isolated to provide 135 mg of the free acid of the title compound as a white solid and containing
a 5% t-butylcarbamate impurity. This solid was was treated with 500 µL THF, 70 µL conc NH4OH and 2 mL of Et2O and the re-
sulted slurry was stirred overnight. The solids were collected via vacuum filtration, and the cake washed with Et2O, to provide
the title compound as a white solid (80 mg, 39%). mp: 131-135 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.51-7.53 (m, 2H), 7.31
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(t, J = 8.6 Hz, 1H), 7.26 (d, J = 6.8 Hz, 1H), 2.34 (s, 3H), 1.22 (s, 9H); 13C{1H}NMR (DMSO-d6, 100 MHz) δ 150.9, 138.3,
134.0, 129.0, 128.3, 53.7; HRMS (ESI) m/z calculated for C12H17NNaO4S [M+Na]+ 294.0770, found 294.0769.
1
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3
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Benzyl (m-tolylsulfonyl)carbamate (Table 1, entry 14) Using the general procedure A, to 3 (202 mg, 0.646 mmol) and THF
(3.3 mL) was added m-MePhMgCl in THF (1.2 mL, 1.2 mmol, 1.0 M). The reaction was stirred for 60 min and quenched with
AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, concen-
trated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to provide the title com-
pound as a clear oil. (112 mg, 57% yield). 1H NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 7.80 (m, 2H), 7.43-7.45 (m, 1H), 7.36-
7.40 (m, 1H), 7.32-7.34 (m, 3H), 7.24-7.27 (m, 2H), 5.10 (s, 2H), 2.39 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 150.4, 139.2,
138.2, 134.7, 134.3, 128.8, 128.7, 128.6, 128.5, 128.3, 125.4, 68.6, 21.2; HRMS (ESI) m/z calculated for C15H15NNaO4S
[M+Na]+ 328.0614, found 328.0615.
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Benzyl ((3-methoxyphenyl)sulfonyl)carbamate (Table 1, entry 15) Using the general procedure A, to 3 (199 mg, 0.633
mmol) and THF (3.6 mL) was added 3-MeOPhMgCl in THF (0.63 mL, 0.63 mmol, 1.0 M). The reaction was stirred for 60 min
and quenched with AcOH and worked-up as above. The layers were separated, and the aqueous layer extracted twice with 10
mL EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated, followed by azeotroping thrice
with heptanes to provide a clear oil. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, con-
centrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to provide the title
compound (108 mg, 53% yield). 1H NMR (CDCl3, 400 MHz) δ 7.82 (bs, 1H), 7.59 (m, 1H), 7.51 (t, J = 1.95 Hz, 1H), 7.32-7.43
(m, 4H), 7.25-7.27 (m, 2H) 7.16 (ddd, J = 8.2, 2.7, 0.8 Hz, 1H), 5.11 (s, 2H), 3.80 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ
159.67, 150.3, 139.5, 130.0, 128.7, 128.6, 128.3, 120.7, 120.4, 112.6, 68.7, 55.6; HRMS (ESI) m/z calculated for C15H15NNaO5S
[M+Na]+ 344.0563, found 344.0565.
Gram-scale synthesis of ammonium ((benzyloxy)carbonyl)((3-methoxyphenyl)sulfonyl)amide (Table 1, entry 16) An ov-
en dried round-bottomed flask was equipped with a dried stirbar, capped with a rubber septum, fitted with an electronic tempera-
ture probe, and purged with nitrogen gas. The flask was charged with 3 (1.05 g, 3.34 mmol) and THF (18.6 mL) and the solu-
tion was stirred until the inner salt had completely dissolved. The flask was placed in an ice-brine bath and then charged 3-
MeOPhMgCl in THF (3.7 mL, 3.7 mmol, 1.0 M), keeping the internal temperature < -5 °C. Upon completion of addition, ex-
changed the cooling bath with an ice-water bath. At 60 min, the reaction had reached 0.5 °C and was quenched by addition of 3
mL 1 N HCl. The mixture was diluted with 10 mL of water and the pH adjusted to 1 with concentrated HCl. The reaction was
diluted with 20 mL EtOAc. The layers were separated, and the aqueous layer extracted twice with 20 mL EtOAc. The combined
organic layers were dried over Na2SO4, filtered, and concentrated to provide a clear oil. The crude material was dissolved in 5
mL of iPA and 2 mL 7 N NH3 in MeOH. After 10 min, the volatiles were removed in vacuo to leave a gummy residue. The res-
idue was stirred in 5 mL of EtOAc until a precipitate began to form, and then 10 mL heptanes was added. After 2 h, the solid
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was collected by vacuum filtration and the cake washed with EtOAc and heptanes to afford the title compound as a tan solid (720
mg, 64%). m.p.: 90-95 °C, then decomposition. mp: 90-95 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.18-7.33 (m, 12H), 6.95-7.01
(m, 1H), 4.80 (s, 2H), 3.75 (s, 3H); 13C{1H}NMR (DMSO-d6, 100 MHz) δ 158.5, 157.9, 147.2, 138.4, 128.9, 128.1, 127.3, 127.1,
118.9, 115.6, 112.0, 64.8, 55.2; HRMS (ESI) m/z calculated for C15H15NNaO5S [M+Na]+ 344.0563, found 344.0567.
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Benzyl ((4-methoxyphenyl)sulfonyl)carbamate (Table 1, entry 17) Using the general procedure A, to 3 (200. mg, 0.636
mmol) and THF (1.7 mL) was added 4-MeOPhMgBr in 2-MeTHF (2.5 mL, 2.5 mmol, 2.0 M). The reaction was stirred for 90
min and quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diato-
maceous earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to
provide the title compound (102 mg, 49.9% yield) as a white solid. mp: 100-105 °C; 1H NMR (CDCl3, 400 MHz) δ 7.94 (m, 2H),
7.32-7.36 (m, 3H), 7.25-7.26 (m, 2H), 6.95 (m, 2H), 5.10 (s, 2H), 3.88 (s, 3H); 13C{1H}NMR (CDCl3, 100 MHz) δ 163.9, 150.4,
134.4, 130.7, 129.7, 128.7, 128.6, 128.4, 114.1, 68.5, 55.7; HRMS (ESI) m/z calculated for C15H15NNaO5S [M+Na]+ 344.0563,
found 344.0559.
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Ammonium ((benzyloxy)carbonyl)((4-(methylthio)phenyl)sulfonyl)amide (Table 1, entry 18) Using the general procedure
A, to 3 (206 mg, 0.655 mmol) and THF (3.0 mL) was added 4-MeSPhMgBr in THF (1.5 mL, 0.72 mmol, 0.5 M). The reaction
was stirred for 60 min and quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM,
charged with diatomaceous earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-100%
EtOAc in heptanes) to provide the free acid of the title compound a white solid containing O-benzyl carbamate. The material
was dissolved in 500 µL THF and 70 µ 28% aqueous NH4OH. After 10 min, 3 mL Et2O was added and the slurry stirred over-
night. The solids were collected via vacuum filtration and the cake washed with Et2O to provide the title compound as a white
solid (112 mg, 51%). mp: 123-135 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.63-7.66 (m, 2H), 7.21-7.32 (m, 7H), 7.08 (bs,
4H), 4.78 (s, 2H) (S-Me is under solvent peak); 13C{1H}NMR (DMSO-d6, 100 MHz) δ 167.07, 151.3, 150.6, 147.9, 137.8,
137.0,136.97, 136.8, 134.1, 74.6, 23.9; HRMS (ESI) m/z calculated for C15H15NNaO4S2 [M+Na]+ 360.0335, found 360.0335.
Benzyl (o-tolylsulfonyl)carbamate (Table 1, entry 19) Using the general procedure A, to 3 (200 mg, 0.636 mmol) and THF
(3.0 mL) was added o-MePhMgCl in THF (1.9 mL, 1.9 mmol, 1.0 M). The reaction was stirred for 90 min and quenched with
AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, concen-
trated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to provide the title com-
pound a clear oil containing an 8% O-Bn Carbamate impurity (95 mg, 47% yield adjusted for impurity). 1H NMR (CDCl3, 400
MHz) δ 8.10 (m, 1H), 7.52 (td, J = 7.4, 1.6 Hz, 1H), 7.45 (bs, 1H), 7.3-7.4 (m, 4H), 7.20-7.23 (m, 2H), 5.08 (s, 2H), 2.65 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz) δ 150.4, 137.7, 136.3, 134.3, 133.9, 132.5, 131.2, 128.6, 128.5, 128.3, 126.2, 68.6, 20.2;
HRMS (ESI) m/z calculated for C15H15NNaO4S [M+Na]+ 328.0614, found 328.0616.
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Ammonium (tert-butoxycarbonyl)((2-methoxyphenyl)sulfonyl)amide (Table 1, entry 20) Using the general procedure A,
to 2 (1.2 mL, 0.71 mmol, 0.61M) in benzene and THF (0.9 mL) was added 2-MeOPhMgBr in THF (2.2 mL, 2.1 mmol, 1.0 M).
The reaction was stirred for 90 min and quenched with 1 N HCl and worked-up as above. The material was dissolved in 0.5 mL
THF and 70 µL of 28% NH4OH was added. After 10 min, the mixture was concentrated under streaming nitrogen to dryness.
The resulting brown solid was pulped in 4 mL 3:1 heptane:EtOAc overnight. The solids were collected via vacuum filtration and
the cake washed with EtOAc to provide the title compound as a tan solid (46 mg, 21%). mp: 105-113 °C; 1H NMR (CD3OD,
400 MHz) δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.51 (m, 1H), 7.11 (d , J = 7.4 Hz, 1H), 7.02 (td, J = 7.8, 1.2 Hz, 1H), 3.91 (s, 3H),
1.29 (s, 9H); 13C{1H}NMR (CD3OD, 100 MHz) δ 158.5, 134.9, 131.9, 131.8, 120.8, 113.5, 80.6, 56.6, 28.6 (carbamate
RNC(O)OR below the noise); HRMS (ESI) m/z calculated for C12H17NNaO5S [M+Na]+ 310.0720, found 310.0718.
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Benzyl ((2-methoxyphenyl)sulfonyl)carbamate (Table 1, entry 21) Using the general procedure A, to 3 (200 mg, 0.636
mmol) and THF (1.7 mL) was added 2-MeOPhMgBr in THF (1.9 mL, 1.9 mmol, 1.0 M). The reaction was stirred for 90 min
and quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatoma-
ceous earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-100% EtOAc in heptanes).
The fractions that absorbed most strongly at 280 nm were concentrated to provide the title compound as a clear oil that solidified
upon standing(63 mg, 31% yield). 1H NMR (CDCl3, 400 MHz) δ 8.02 (d, J = 7.8 Hz, 1H), 7.78 (bs, 1H), 7.60 (t, J = 8.20 Hz,
1H), 7.32 (m, 3H), 7.19 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H), 3.92 (s, 3H); 13C{1H}NMR
(CDCl3, 100 MHz) δ 156.8, 150.47, 135.8, 134.6, 131.7, 128.5, 128.2, 125.8, 120.4, 112..2, 68.3, 56.3; HRMS (ESI) m/z calcu-
lated for C15H15NNaO5S [M+Na]+ 344.0563, found 344.0557.
Benzyl ((2-methoxyphenyl)sulfonyl)carbamate (Table 2, entry 2) Using general procedure B, to 3 (591 mg, 1.88 mmol) and
THF (5.0 mL) was added 2-methoxyphenylmagnesium bromide in THF (3.8 mL, 3.8 mmol, 1.0 M). The reaction was stirred for
90 min and worked up as described to provide the product as a solid (408 mg, 68%).
Benzyl (benzylsulfonyl)carbamate (Table 1, entry 24) Using the general procedure A, to 3 (200 mg, 0.636 mmol) and THF
(4.0 mL) was added BnMgCl in THF (0.32mL, 0.64 mmol, 2.0 M). The reaction was stirred for 60 min and quenched with
AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, concen-
trated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-100% EtOAc in heptanes). The fractions contain-
ing only a single CAM-staining spot were collected and concentrated to provide the title compound as a white solid (60 mg, 31%
yield). Mp: 106-109 °C; 1H NMR (CDCl3, 400 MHz) δ 7.35-7.46 (m, 6H), 7.29-7.33 (m, 2H), 7.23-7.26 (m, 2H), 6.91 (bs, 1H),
5.25 (s, 2H), 4.61 (s, 2H); ); 13C{1H}NMR (CDCl3, 100 MHz) δ 150.8, 134.4, 130.6, 129.2, 129.01, 128.99, 128.8, 128.7, 127.7,
68.9. 58.4; HRMS (ESI) m/z calculated for C15H15NNaO4S [M+Na]+ 328.0614, found 328.0614.
Benzyl (cyclohexylsulfonyl)carbamate (Table 1, entry 25) Using the general procedure A, to 3 (209 mg, 0.665 mmol) and
THF (2.28 mL) was added C6H11MgCl in THF/toluene (1.5 mL, 2.0 mmol, 1.3 M). The reaction was stirred for 90 min and
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quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous
earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0-60% EtOAc in heptanes) to pro-
vide the title compound (66 mg, 33% yield), containing a 5% O-benzyl carbamate impurity, as a clear oil . 1H NMR (CDCl3, 400
MHz) δ 7.53 (bs, 1H), 7.36-7.40 (m, 5H), 5.21 (s, 2H), 3.47 (tt, J = 12.1, 3.5 Hz, 1H), 2.14-2.19 (m, 2H), 1.87-1.92 (m, 2H),
1.68-1.73 (m, 1H), 1.58 (qd, J = 12.5, 3.1 Hz, 2H), 1.12-1.33 (m, 3H); ); 13C{1H}NMR (CDCl3, 100 MHz) δ 151.0, 134.5, 128.8,
128.7, 128.4, 68.7, 61.3, 25.8, 24.87, 24.85; HRMS (ESI) m/z calculated for C14H19NNaO4S [M+Na]+: 320.0927, found
320.0926.
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Benzyl (isopropylsulfonyl)carbamate (Table 1, entry 26) Using the general procedure A, to 3 (200.0 mg, 0.636 mmol) and
THF (2.3 mL) was added iPrMgCl●LiCl in THF (2.0 mL, 2.5 mmol, 1.3 M). The reaction was stirred for 2.75 h and quenched
with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous earth, con-
centrated, and then purified on a 12 g Redi-Sep Gold cartridge (see attachment) to provide the title compound as a white solid (45
mg, 27%). mp: 82-87 °C; 1H NMR (CDCl3, 400 MHz) δ 7.35-7.45 (m, 5H), 7.18 (bs, 1H), 5.22 (s, 2H), 3.77 (sept, J = 7.0 Hz,
1H), 1.43 (d, J = 7.0 Hz, 6H); 13C{1H}NMR (CDCl3, 100 MHz) δ 150.8, 134.4, 128.9, 128.8, 128.5, 68.83, 53.91, 16.1; HRMS
(ESI) m/z calculated for C11H15NNaO4S [M+Na]+ 280.0614, found 280.0612.
Benzyl ((2,4-dimethoxypyrimidin-5-yl)sulfonyl)carbamate (Table 1, entry 27) Using the general procedure A, to 3 (203.7
mg, 0.648 mmol) and THF (1.0 mL) was added 7 in THF (3.0 mL, 1.3 mmol, 0.65 M). The reaction was stirred for 90 min and
quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with diatomaceous
earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0% 2 CV, 0-30% 5 CV, 30% 5 CV,
30-100% 10 CV, EtOAc in heptanes) to provide the title compound a white solid, which was pulped in 1 mL EtOAc overnight to
provide the title compound as a white solid containing a 5% 2,4-dimethoxypyrimidine impurity (80 mg, 34% yield adjusted for
1
impurity). mp: 145-157 °C; H NMR (CDCl3, 400 MHz) δ 8.84 (s, 1H), 7.65 (bs, 1H), 7.34-7.37 (m, 3H,), 7.25-7.28 (m, 2H),
5.13 (s, 2H), 4.09 (m, 6H); 13C{1H}NMR (CDCl3, 100 MHz) δ 167.7, 167.0, 150.0, 134.3, 128.9, 128.7, 128.5, 113.4, 68.9, 56.0,
55.4; HRMS (ESI) m/z calculated for C14H15N3NaO6S [M+Na]+ 376.0574, found 376.0573.
Ammonium ((benzyloxy)carbonyl)((3-methylthiophen-2-yl)sulfonyl)amide (Table 1, entry 28) Using the general proce-
dure A, to 3 (207 mg, 0.658 mmol) and THF (2.8 mL) was added 8 in THF (1.5 mL, 2.0 mmol, 1.3 M). The reaction was stirred
for 90 min and quenched with AcOH and worked-up as above. The crude material was dissolved in 10 mL DCM, charged with
diatomaceous earth, concentrated, and then purified on a 12 g Redi-Sep Gold cartridge (gradient elution, 0% 2 CV, 0-30% 5 CV,
30% 5 CV, 30-100% 10 CV, EtOAc in heptanes). The fractions containing the peak at 10 CV was concentrated to provide the
free acid of the title compound a white solid containing O-benzyl carbamate (63 mg, 85% pure). The material was dissolved in 2
mL 7 N NH3in MeOH. After 20 min, the volatiles were removed, and the oil slurred in 3 mL 2:1 heptanes:EtOAc overnight. The
solids were collected via vacuum filtration and the cake washed with EtOAc to provide the title compound as a white solid (35
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1
mg, 17%). mp: 103.6-109.1 (decomposition); H NMR (CD3OD, 400 MHz) δ7.41 (d, J = 5.1 Hz, 1H), 7.21-7.30 (m, 5H), 6.86
(d, J= 4.7 Hz, 1H), 4.97 (s, 2H), 2.43 (s, 3H); 13C{1H}NMR (CD3OD, 100 MHz) δ 160.2, 141.5, 139.9, 138.9, 132.0, 129.4,
128.7, 67.6, 15.0; HRMS (ESI) m/z calculated for C13H13NNaO4S2 [M+Na]+ 334.0178, found 334.0176.
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Benzyl ((3-methylthiophen-2-yl)sulfonyl)carbamate (Table 2, Entry 3) Using general procedure B, to 3 (604 mg, 1.92
mmol) and THF (2.53 mL) was added (3-methylthiophen-2-yl)MgBr in THF (7.68 mL, 3.84 mmol, 0.5 M). The reaction was
stirred for 90 min and worked up as described to provide the product as an oil (304 mg, 51%). 1H NMR (CDCl3, 400 MHz) δ
8.33 (s, 1H), 7.50 (d, J = 4.7 Hz, 1H), 7.30-7.36 (m, 3H), 7.21-7.26 (m, 2H), 6.88 (d, J = 5.1 Hz, 1H), 5.12 (s, 2H), 2.48 (s, 3H);
13C{1H}NMR (CDCl3, 100 MHz) δ 150.4, 145.3, 134.2, 132.0, 131.9, 131.4, 128.6, 128.5. 128.3, 68.6, 14.9.Methyl ((phe-
nylethynyl)sulfonyl)carbamate (Table 1, entry 29) An oven dried round-bottomed flask was equipped with a dried stir bar,
capped with a rubber septum, and purged with nitrogen gas. The flask was charged with phenyl acetylene (540 mg, 5.20 mmol)
and THF (2.59 mL). The mixture was cooled to 0 °C and treated with n-BuLi (2.5 M in hexane, 2.1 mL, 5.2 mmol). The mixture
was allowed to warm to room temperature to afford a 1.1 M solution of (phenylethynyl)lithium. Then using the general proce-
dure A, to 1 (122 mg, 0.512 mmol) and THF (3.0 mL) was added the (phenylethynyl)lithium solution (0.44 mL, 0.51 mmol). The
reaction was stirred for 60 min and quenched with 1 N HCl and worked-up as above. The material was loaded onto diatomaceous
earth with DCM and purified on a 12 g silica ISCO Gold cartridge (0-100% EtOAc in heptanes, 20 column volumes) to provide
the title compound as a white solid (60 mg, 49%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1
H), 7.43 (t, J = 8.0 Hz, 2 H), 3.90 (s, 3 H); 13C{1H}NMR (CDCl3, 100 MHz) δ 150.2, 133.1, 132.0, 128.8, 117.3, 91.3, 82.1, 54.2;
this compound proved too unstable to obtain an HRMS.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: joseph.tucker@pfizer.com
Present Addresses
† Eastern Point Rd., Groton, CT 06340
Author Contributions
The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Drs. Christopher J. Helal and Brian T. O’Neill for helpful discussions, Mr. James Bradow for purification assistance, and Dr.
Anabella Villalobos for support.
ASSOCIATED CONTENT
Supporting Information
The supplementary information includes materials and instrumentation data with associated references and copies of 1H- and 13C{1H}NMR
spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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(1) A portion of this work was presented at the 248th ACS National Meeting & Exposition, San Francisco, CA, United States, August 10-14,
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which made it possible to visualize the product and the side-products with the same method. The t-butyl and methyl carbamates consistently
stained only in Bromocresol Green, which visualized neither the amide nor the O-alkyl carbamate side products.
(34) The primary advantage of 2, beyond orthogonal carbamate removal conditions, was that the products were more easily purified by salt for-
mation followed by crystallization. We were unable to find broadly applicable crystallization conditions for the benzyl or methyl sulfamoyl car-
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(39) Tertiary alkyl sulfonamides are typically synthesized in one of three ways: for an example of α-alkylation of a sulfonamide, see Li, J.; Smith,
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