Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: Scope and 15N NMR labeling experiments

Article abstract of DOI:10.1021/jo500553q

Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, ¹⁵N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use.

Full text of DOI:10.1021/jo500553q

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pubs.acs.org/joc
Synthesis of Sulfonyl Azides via Diazotransfer using an Imidazole-1-
15
sulfonyl Azide Salt: Scope and N NMR Labeling Experiments
Marc Y. Stevens, Rajiv T. Sawant, and Luke R. Odell*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, P.O. Box
574, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: Imidazole-1-sulfonyl azide hydrogen sulfate is
presented as an efficient reagent for the synthesis of sulfonyl
azides from primary sulfonamides. The described method is
experimentally simple and high-yielding and does not require
the addition of Cu salts. Furthermore, 15N NMR mechanistic
studies show the reaction proceeds via a diazo transfer
mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate
provides a considerable advantage over existing diazo transfer
reagents in terms of impact stability, cost, and ease of use.
varying yields. This was followed very recently15 by the
INTRODUCTION
■
synthesis of N,N′-disulfonylamidines from sulfonamides and
Sulfonyl azides have gained considerable interest over the past
acetylenes using nonafluorobutanesulfonyl azide (II) as the
decade as they provide a versatile starting point for the
diazo transfer reagent.16 Although II is shelf-stable and cost-
preparation of a diverse spectrum of organic compounds.1,2
efficient, it is a liquid at room temperature, whereas imidazole-
This is due to their remarkable ability to act as either three-
1-sulfonyl azide hydrogen sulfate17 (III) is easily prepared
nitrogen or one-nitrogen sources in copper-catalyzed azide−
from cheap starting materials in reproducible yields and is a
alkyne cycloaddition (CuAAC) reactions. Thus, sulfonyl
solid at room temperature. Moreover, the integrity of III can
azides can be selectively transformed into 1,2,3-triazoles via
readily be determined by appearance and 1H NMR and
a standard CuAAC process3,4 or alternatively into amidines,
melting point determination, whereas this is not possible with
amidates, or amides via a cycloaddition/isomerization process
II. In addition, a recent study17 investigating the explosive
to generate a highly reactive ketenimine intermediate.1 This
potential and shock sensitivity of various imidazole sulfonyl
azide salts showed III to be largely resistant to electrostatic
latter approach has recently been applied in the development
of one-pot synthesis of tetrasubstituted imidazoles,5
a
discharge and of low shock sensitivity (albeit not completely
insensitive). At the onset of our study, no similar investigation
has been carried out on II, leading us to select III for further
evaluation as a diazo transfer reagent. Although III (as its
hydrochloride salt18) has been employed in the functionaliza-
tion of aliphatic and aromatic amines,19−22 there is only one
reported example of this class of diazo transfer reagent being
used for the preparation of aryl sulfonyl azides in the
literature.14 Moreover, this example was reported without any
detailed experimental information, and accordingly, we wished
to expand the scope of this useful reaction.
phosphite-mediated synthesis of N-toluenesulfonylamidines,6
and a multicomponent cascade synthesis of substituted
iminocoumarins.7 Finally, sulfonyl azides have also been
employed as nitrene precursors in transition metal catalysis
C−H amidations and enantioselective enzymatic C−H
aminations.8
In the course of a parallel project, a key sulfonyl azide
precursor for 11C-labeling of an angiotensin II type 2 receptor
(AT2R) agonist was required.9 Traditionally, sulfonyl azides
have been prepared from the corresponding sulfonyl chloride
using sodium azide in acetonitrile, but this route is hampered
by the limited availability of starting materials and labile
reagents.10−13 Solvent choice is of utmost importance, as
sodium azide is known to form explosive diazidomethane in
the presence of polyhalomethanes, with sometimes explosive
results.12 To circumvent these issues, Fokin and co-workers
devised a method using widely available sulfonamides, which
are both air and moisture stable and unreactive to most
functional groups.14 This method employed trifluoromethane
sulfonyl azide (I, Figure 1), a diazo transfer reagent which is
shock-sensitive, costly, and lacking a standardized synthetic
procedure, must be prepared immediately prior to use in
RESULTS AND DISCUSSION
■
We began by identifying suitable conditions for the trans-
formation of an aryl sulfonamide to an aryl sulfonyl azide
using III. Although previous workers14,23 have reported the
use of a ternary solvent system, we sought to simplify the
synthetic protocol by replacing it with a binary or single
solvent system. This led us to choose the conditions of Stick
Received: March 8, 2014
© XXXX American Chemical Society
A
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Figure 1. Diazotransfer reagents previously used for the preparation of sulfonyl azides (I and II) and employed in this work (III).
et al. as a starting point.18 In a test reaction, III was added to
a mixture of p-toluenesulfonamide and inorganic base
(K2CO3) and allowed to stir for 18 h at ambient temperature
(entry 1, Table 1). This initial approach did not give any
detectable product by LC/MS analysis, leading us to
investigate i-PrOH as a solvent. Once again, no product was
observed, most likely due to solubility issues with the base.
Gratifyingly, the addition of H2O to the solvent system
proved helpful, with a marked increase in yield (entry 3).
Introduction of CuSO4 did not appear to affect the outcome
of the reaction (entry 4), and we therefore chose to continue
our studies using metal-free conditions. Comparable yields
were also achieved using both i-PrOH and THF in a 1:1 ratio
with H2O (entries 5 and 6). At this point, we suspected that 2
equiv of base might not be sufficient to ensure full conversion
to the desired sulfonylamide anion in the presence of the
diprotic salt 2. To our delight, increasing the number of
equivalents of base to 4 resulted in complete consumption of
1a, and the product 2a could be isolated in 86% yield (entry
7). Although switching the solvent system to i-PrOH/H2O
was even more beneficial (entry 8), the number of equivalents
of diazo transfer reagent could not be reduced without
concomitant reduction in yield (entry 9).
(2c). Sulfonamides bearing various halogen substitutents such
as bromide, chloride, and fluoride also performed well giving
good yields of the desired products (2b,i−k,n). Notably, the
reaction also tolerated a number of potentially reactive
substituents (see 2h,o,p), as well sterically hindered ortho-
substituted sulfonamides (2e,i,l). Increasing the scale to 1
mmol had no negative impact on the isolated yield, with 2l
and 2q giving 84 and 83%, respectively.
Table 2. Synthesis of Sulfonyl Azides 2 from Primary
Sulfonamides 1 Using Optimized Conditions (Isolated
Yields Shown)
Table 1. Optimization of the Reaction Conditions for the
Preparation of 2a from 1 Using Diazotransfer Reagent III
a
entry
base, equiv
solvent
MeOH
time (h)
yield (%)
b
1
K2CO3, 2
K2CO3, 2
K2CO3, 2
K2CO3, 2
K2CO3, 2
K2CO3, 2
K2CO3, 4
K2CO3, 4
18
18
18
18
18
18
18
18
2
3
i-PrOH
a
b
c
d
8 h reaction time. 66 h reaction time. 0.25 mmol scale. 1.1 mmol
scale.
c
c
MeOH/H2O
MeOH/H2O
29
32
33
45
86
90
b
4
c
5
6
7
8
THF/H2O
c
i-PrOH/H2O
To further explore the scope of the reaction, we applied our
c
MeOH/H2O
i-PrOH/H2O
i-PrOH/H2O
modified conditions to more complex aryl and heteroaryl
substrates (Table 3). Notably, the diuretics furosemide and
hydrochlorothiazide were transformed into their correspond-
ing sulfonyl azides in excellent yield, despite the presence of
ortho substituents and acidic functionalities (4b and 4k).
Electron-rich and electron-poor heterocyclic substrates
performed excellently (4a, 4c, 4e, 4j and 4m), whereas the
presence of a basic nitrogen ortho to the sulfonyl amide was
detrimental to the reaction, presumably by decreasing
nucleophilicity, and full conversion of starting material was
not achieved despite prolonged reaction times (4h and 4i).
Similarly, the antipsychotic sulpiride (3l) reacted sluggishly,
most likely due to interaction of the basic nitrogen with III.
Disappointingly, the reaction scope could not be extended to
alkyl sulfonamides, and only trace amounts of 4f were
detected by GC/MS analysis.24 Finally, cinnamic ester
c
c
d
9
K2CO3, 4
18
78
a
b
c
d
Isolated yield. 5 mol % of CuSO4 was added. 1/1 mixture. 1.3
equiv of diazo transfer reagent used. Typical procedure: A 2−5 mL
reaction vial was charged with sulfonamide (0.5 mmol), base (1−2
mmol), and solvent (6 mL). After 5 min of stirring, the diazo transfer
reagent (0.75 mmol) was added and the reaction stirred for 18 h.
Having identified suitable reaction conditions, we then
sought to explore the scope and limitations of the diazo
transfer reaction. As can be seen in Table 2, the reaction
displayed a wide substrate scope and gave the target sulfonyl
azides in good to excellent yields. Electron-rich sulfonamides
(2c−e,g,h,q) were found to be excellent substrates with full
conversion of starting material taking place in as little as 8 h
B
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weaker base (sodium acetate) gave only traces of the desired
product. Once generated, the nucleophile can attack either the
electrophilic sulfur center S1 or the terminal azide nitrogen of
III. Attack on sulfur (Scheme 1, path A) will expel an azide
anion, which can then displace the tosylamide group to give
the sulfonyl azide product. In path B, the nucleophile attacks
at the azide nitrogen generating a tetrazine intermediate,
which then collapses to give the sulfonyl azide product. In the
reaction of primary amines with p-toluenesulfonyl azide and
other diazo transfer reagents, the reaction is believed to
proceed via a diazo transfer pathway (path B), as evidenced
by the retention of configuration when using chiral amines.25
In contrast, the reaction mechanism for the synthesis of
sulfonyl azides from sulfonyl amides has not yet been
explored. Moreover, the achiral nature of the sulfonamide
group does not allow path A to be ruled out based on
retention or inversion of configuration. Accordingly we
decided to investigate the mechanism for the reaction using
15N isotopic labeling. To this end, we first prepared 15N
labeled tosyl amide 5 and subjected it to our standard
conditions. This resulted in the exclusive formation of a
product with m/z of +1, confirmed as the hitherto unreported
p-toluene sulfonyl azide-1-15N (6). These findings were in line
with previous work,26 confirming that diazo transfer (see
Scheme 1, path B), and not azidation (via attack on S1 of C)
had taken place. The efficiency of III as a diazo transfer
reagent may be, in part, due to the greater leaving group
ability of the electron-poor imidazole group.27 Furthermore,
imidazole-1-sulfonamide was not observed in any crude
reaction mixtures (LC/MS analysis) suggesting that it may
be hydrolytically labile under the basic conditions, thus
preventing diazo transfer from 6 to 7.
Table 3. Synthesis of Aryl and Heteroaryl Sulfonyl Azides 4
from Sulfonamides 3 (Isolated Yields Shown)
a
b
c
d
In order to determine the position of the label, we then
proceeded to reduce the product to the corresponding
sulfonamide, and NMR and ESI/MS analysis of all three
steps confirmed full conversion of the azide to the original
sulfonamide with no loss or scrambling of the 15N label, thus
confirming the position of the 15N label at N1 of the sulfonyl
azide. To the best of our knowledge, this is the first reported
synthesis of p-toluene sulfonyl azide-1-15N and this compound
should be useful for probing the mechanism of other sulfonyl
azide reactions as well as in the production of other 15N-
labeled compounds.
0.11 mmol scale. stirred for 48 h. 0.25 mmol scale. 1.00 mmol
scale.
derivative 3d and alkyne 3g were smoothly transformed into
4d and 4g under our metal-free reaction conditions, with no
traces of cycloaddition-derived byproducts being observed by
LC/MS analysis.
Two plausible mechanistic pathways for our reaction are
presented in Scheme 1. The first step is believed to be
generation of the nucleophilic sulfonamide anion. Conducting
the reaction in the absence of base or in the presence of a
Scheme 1. Proposed Reaction Pathway Based on 15N-Labeling Studies
C
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4-Methylbenzenesulfonyl azide (2a):29 colorless liquid (88 mg,
CONCLUSIONS
■
1
90%); H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 2H), 7.39
(d, J = 8.0 Hz, 2H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
146.5, 135.7, 130.6, 130.5, 127.7, 127.7, 22.0; IR (neat) cm−1 2126;
MS (EI) m/z 197.1.
In summary, we have expanded the scope of the diazo transfer
reaction using the stable and easy-to-handle imidazole-sulfonyl
azide salt III. The reaction was found to tolerate a wide range
of functional groups and afforded good to excellent yields of
the sulfonyl azide products without the addition of Cu salts.
Furthermore, the reaction was exemplified by the synthesis of
N1-labeled 15N labeled tosyl azide, and this compound was
used to elucidate the reaction mechanism. The reaction was
shown to proceed via a diazo transfer process following
nucleophilic attack at the terminal azide nitrogen in III. Work
is currently underway in our laboratory on extending this
reaction to alkyl sulfonamides.
4-Bromobenzesulfonyl azide (2b):14 white solid (101 mg, 77%);
1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 2H), 7.76 (dd, J
= 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 137.4, 133.0, 130.3,
128.9; IR (neat) cm−1 2126; MS (EI) m/z 260.9.
4-Methoxybenzenesulfonyl azide (2c):14 white solid (104 mg,
1
80%); H NMR (400 MHz, CDCl3) δ 7.95−7.79 (m, 2H), 7.15−
6.92 (m, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9,
130.2, 130.1, 115.2, 56.2; IR (neat) cm−1 2126; MS (EI) m/z 213.1.
3-Methylbenzenesulfonyl azide (2d):30 colorless liquid (62 mg,
1
63%); H NMR (400 MHz, CDCl3) δ 7.85−7.64 (m, 2H), 7.58−
7.41 (m, 2H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.5,
138.6, 135.9, 129.8, 128.0, 124.9, 21.7; IR (neat) cm−1 2125; MS
(EI) m/z 197.0.
EXPERIMENTAL SECTION
■
2-Methylbenzenesulfonyl azide (2e):31 colorless liquid (79 mg,
General Information. Analytical thin-layer chromatography was
performed on silica gel 60 F-254 plates and visualized with UV light.
Flash column chromatography was performed on a silica gel 60 (40−
1
80%); H NMR (400 MHz, CDCl3) δ 8.21−7.94 (m, 1H), 7.58 (td,
J = 7.6, 1.5 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 2.68 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 138.5, 136.8, 134.7, 133.1, 129.4, 126.5,
20.4; IR (neat) cm1 2123; MS (EI) m/z 197.1.
63 μm) and visualized with UV light. H and 13C NMR spectra were
1
recorded at 400 and 100 MHz respectively using CDCl3, MeOD,
CD3CN or DMSO-d6 as a solvent. 15N NMR spectra were recorded
at 40 MHz. Chemical shifts are referenced to TMS or HNO3 via
residual solvent signals. All reactions were performed in loosely
capped reaction vials designed for 2−6 mL reaction volumes, with
the exception of 4a−e, which were carried out in loosely capped 25
mL round-bottomed flasks. Compound 5 was prepared in an
Initiator single mode reactor producing controlled irradiation at 2450
MHz, and the temperature was monitored using the built-in online
IR sensor. LC/MS was performed on an instrument equipped with a
C18 column (50 × 3.0 mm, particle size 2.6 μm, pore size 100 Å).
Accurate mass values were determined on a mass spectrometer
equipped with an electrospray or electron-impact ion source and 7-T
hybrid ion trap (LTQ) or TOF detector, respectively. Flash column
chromatography was performed on silica gel 60 (40−63 μm). All
starting materials and reagents are commercially available and were
used as received, with the exception of isoquinoline-5-sulfonamide
(3e) and methyl (E)-3-(4-sulfamoylphenyl)acrylate (3d), the
syntheses of which are detailed in the Experimental Section of the
paper. Imidazole-1-azide hydrogen sulfate (III) was prepared by the
literature procedure, and spectral data for the isolated product were
in agreement with literature values.17
2-Naphthylbenzenesulfonyl azide (2f):14 stirred for 66 h; white
1
solid (75 mg, 65%); H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H),
8.03 (dd, J = 11.1, 8.4 Hz, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.89 (dd, J
= 8.7, 2.0 Hz, 1H), 7.77−7.60 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 136.0, 135.5, 132.2, 130.5, 130.3, 129.9, 129.9, 129.8,
128.5, 128.4, 122.1; IR (neat) cm−1 2119; MS (EI) m/z 233.9.
4-Hydroxybenzenesulfonyl azide (2h):14 colorless liquid (82 mg,
1
83%); H NMR (400 MHz, CDCl3) δ 8.03−7.54 (m, 2H), 7.14−
6.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.2, 130.5, 130.5,
129.6, 116.8; IR (neat) cm−1 2124; MS (EI) m/z 199.01.
2-Bromobenzenesulfonyl azide (2i):14 colorless liquid (106 mg,
1
81%); H NMR (400 MHz, CDCl3) δ 8.34−8.08 (m, 1H), 7.92−
7.71 (m, 1H), 7.60−7.47 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
138.5, 136.1, 135.7, 132.1, 128.2, 121.0; IR (neat) cm−1 2132; MS
(EI) m/z 262.9.
4-Chlorobenzenesulfonyl azide (2j):29 colorless liquid (80 mg,
1
74%); H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 2H), 7.59
(d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 141.7, 136.8,
130.0, 128.9; IR (neat) cm−1 2129; MS (EI) m/z 217.0
3-Chlorobenzenesulfonyl azide (2k):32 colorless liquid (72 mg,
66%); 1H NMR (400 MHz, CDCl3) δ 7.94 (t, J = 1.9 Hz, 1H),
7.90−7.78 (m, 1H), 7.76−7.63 (m, 1H), 7.57 (t, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 140.1, 136.1, 135.1, 131.1, 127.6,
125.7; IR (neat) cm−1 2127; MS (EI) m/z 217.1.
Caution! Sulfonyl azides are potentially explosive, and all reactions
should be carried out behind a blast shield. The authors recommend
the use of plastic spatulas for handling of solid material. Mother
liquors arising from the preparation of imidazole-1-sulfonyl azide
should be treated with excess sodium nitrite and thereafter 20%
H2SO4 to destroy azide species. Used silica gel should be treated in a
similar fashion to destroy residues of imidazole-1-sulfonyl azide.
2-(Trifluoromethyl)benzenesulfonyl azide (2l):33 white solid (95
1
mg, 75%); H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 7.5, 1.9 Hz,
1H), 7.97 (dd, J = 7.5, 1.7 Hz, 1H), 7.91−7.72 (m, 2H); 13C NMR
3
Imidazole-1-sulfonyl azide (prepared by the literature procedure18,28
is highly impact-sensitive and should be handled with great care.
)
(100 MHz, CDCl3) δ 137.0, 134.8, 132.8, 132.1, 128.8 (q, JCF = 6.1
4
Hz), 128.3, 123.3 (q, JCF = 274.0 Hz); IR (neat) cm−1 2133; MS
(EI) m/z 251.1.
General Procedure 1 for Preparation of Sulfonyl Azides
2a−p and 4f−m Exemplified by 4-tert-Butylbenzenesulfonyl
Azide (2g). To a vigorously stirred solution of sulfonamide (106
mg, 0.5 mmol) and K2CO3 (276 mg, 2 mmol) in 6 mL of solvent
(1:1 H2O/i-PrOH) in a reaction vial was added diazo transfer
reagent III (203 mg, 0.75 mmol). After being stirred for 18 h at
ambient temperature, the reaction mixture was diluted with 20 mL
saturated NaHCO3 and extracted with 2 × 50 mL EtOAc. The
combined organic phases were washed twice with brine and dried
over Na2SO4 and the volatiles evaporated in vacuo. The residue was
purified by silica gel chromatography (10% EtOAc in n-pentane
unless otherwise stated) to afford the title compound azide as a
4-(Trifluoromethyl)benzenesulfonyl azide (2m):34 white solid,
1
eluting in 6% EtOAc in pentane (65 mg, 52%); H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H); 13C
3
2
NMR (100 MHz, CDCl3) δ 141.8 (q, JCF = 1.4 Hz), 136.3 (q, JCF
3
4
= 33.4 Hz), 128.1, 126.89 (q, JCF = 3.7 Hz), 121.5 ppm (q, JCF
=
273.4 Hz); IR (neat) cm−1 2131; MS (EI) m/z 251.1.
4-Fluorobenzenesulfonyl azide (2n):34 colorless liquid (32 mg,
1
63%); H NMR (400 MHz, CDCl3) δ 8.27−7.69 (m, 2H), 7.39−
6.99 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.7 (d, JCF
=
1
4
3
258.7 Hz), 134.9 (d, JCF = 3.7 Hz), 130.5 (d, JCF = 9.9 Hz), 117.1
(d, JCF = 23.0 Hz); IR (neat) cm−1 2128; MS (EI) m/z 201.1.
2
4-Acetylbenzenesulfonyl azide (2o):35 colorless solid (85 mg,
1
white solid (84 mg, 71%): H NMR (400 MHz, CDCl3) δ 7.88 (d, J
1
= 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 159.0, 135.5, 127.4, 126.7, 35.5, 31.0; IR
(neat) cm−1 2127; MS (EI) calcd for C10H13N3O2S m/z 239.0728,
found m/z 239.0737.
76%); H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.6 Hz, 2H), 8.04
(d, J = 8.6 Hz, 2H), 2.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
196.3, 141.9, 141.6, 129.4, 127.8, 26.9; IR (neat) cm−1 2140; MS
(EI) m/z 225.1.
D
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4-Cyanobenzenesulfonyl azide (2p):36 white solid (71 mg, 68%);
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.5 Hz, 1H), 7.92 (d, J
= 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 142.6, 133.8, 128.4,
118.8, 117.0; IR (neat) cm−1 2129; MS (EI) m/z 208.0.
129.3, 126.1, 117.3; IR (neat) cm−1 2136; MS (ESI) calcd for
C9H7N4O2S m/z 235.0290 ([M + H+]), found m/z 235.0283.
4-Ethynylbenzenesulfonamide (4g): white solid, eluting in 50%
1
EtOAc in hexanes (103 mg, 76%); H NMR (400 MHz, CDCl3) δ
3-Methoxybenzenesulfonyl azide (2q):37 colorless liquid (185
mg, 83%); 1H NMR (400 MHz, CDCl3) δ 7.56−7.44 (m, 2H),
7.45−7.36 (m, 1H), 7.32−7.12 (m, 1H), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.5, 139.6, 121.6, 119.8, 112.2, 56.1; IR
(neat) cm−1 2128; MS (EI) m/z 213.1.
8.04−7.78 (m, 2H), 7.69 (d, J = 8.5 Hz, 2H), 3.35 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 138.4, 133.5, 130.4, 129.2, 82.6, 81.8; IR
(neat) cm−1 2131; MS (EI) calcd for C8H5N3O2S m/z 207.0108,
found m/z 207.0102.
4-Methylpyridine-2-sulfonyl azide (4h):30 stirred for 48 h;
colorless liquid, eluting in 20% EtOAc in hexanes (30 mg, 28%);
1H NMR (400 MHz, CDCl3) δ (d, J = 2.2 Hz, 1H), 7.91 (d, J = 8.1
Hz, 1H), 7.85−7.72 (m, 1H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.6, 151.4, 139.7, 138.8, 122.1, 19.1; IR (neat) cm−1
2132; MS (ESI) m/z 198.91.
Methyl (E)-3-(4-Sulfamoylphenyl)acrylate (3d). To a stirred
mixture of methyl (E)-3-(4-(N-(tert-butyl)sulfamoyl)phenyl)acrylate
(72 mg, 0.24 mmol) in anhydrous DCM (20 mL) at 0 °C under N2
atmosphere was added BCl3 (1 M, 2.66 mL, 2.66 mmol). The
reaction mixture was stirred for 1 h at ambient temperature and
monitored by TLC (25% EtOAc in n-pentane). Upon completion,
the reaction mixture was coevaporated with 3 × 10 mL CHCl3 and
the residue purified by silica gel chromatography (20−40% EtOAc in
n-pentane) to provide the title compound as a white solid (32 mg,
1-Methylimidazole-4-sulfonyl azide (4i):40 stirred for 48 h; white
1
solid (17 mg, 36%); H NMR (400 MHz, CDCl3) δ δ 7.61 (s, 1H),
7.57 (s, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.1,
139.3, 125.8, 34.6; IR (neat) cm−1 2133; MS (ESI) m/z 187.92.
5-(Pyridin-2-yl)thiophene-2-sulfonyl azide (4j): white solid,
eluting in 50% EtOAc in hexanes (66 mg, 77%); 1H NMR (400
MHz, CDCl3) δ 8.70−8.48 (m, 1H), 7.83−7.76 (m, 2H), 7.72 (d, J
= 7.7 Hz, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.36−7.27 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 155.3, 150.6, 150.4, 138.7, 137.5, 135.7,
124.5, 124.0, 119.7; IR (neat) cm−1 2135; MS (ESI) calcd for
C9H7N4O2S2 ([M + H+]) m/z 267.0010, found m/z 267.0007.
6-Chloro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-7-sulfonyl
azide 1,1-dioxide (4k): white solid, eluting in 50% EtOAc in hexanes
1
55%): H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.4 Hz, 2H),
7.87 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 16.1 Hz, 1H), 7.48 (s, 2H),
6.82 (dd, J = 16.1, 0.7 Hz, 1H), 3.78 (d, J = 0.8 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 167.3, 146.1, 143.7, 138.1, 129.7, 127.0,
121.3, 52.6; HRMS calcd for C10H10NO4S [M −] m/z 240.0331,
found m/z 240.0324.
Isoquinoline-5-sulfonamide (3e).38 Isoquinoline-5-sulfonic acid (2
g, 9.27 mmol) was dissolved in 40 mL of SOCl2 and refluxed for 8 h.
The resulting slurry was suspended in 20 mL of dichloromethane,
and 20 mL of NH4OH was added at 0 °C. After the mixture was
stirred for 18 h, the pH was adjusted to 7 by the addition of 1 M
HCl and the aqueous phase extracted with 2 × 100 mL EtOAc. The
combined organic phases were dried (Na2SO4) and concentrated in
vacuo, providing the title compound as a yellow solid (208 mg,
1
(245 mg, 76%); H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H),
7.06 (s, 1H), 4.86 (s, 2H); 13C NMR (100 MHz, methanol-d4) δ
148.7, 135.7, 128.8, 122.1, 119.3, 117.6, 54.6; IR (neat) cm−1 2237;
MS (ESI) calcd for C7H7ClN5O4S2 m/z 323.9628, found m/z
323.9624.
1
10%): H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.67 (d, J =
(S)-3-(((1-Ethylpyrrolidin-2-yl)methyl)carbamoyl)-4-methoxyben-
6.0 Hz, 1H), 8.51−8.24 (m, 3H), 7.83−7.78 (m, 1H), 7.77 (s, 2H);
13C NMR (100 MHz, DMSO-d6) 153.5, 144.5, 138.6, 132.9, 130.7,
130.4, 128.8, 126.6, 117.7; ESI (MS) m/z 208.78.
zenesulfonyl azide (4l): stirred for 48 h; colorless solid, eluting in
1
7% MeOH in dichloromethane (72 mg, 20%); H NMR (400 MHz,
CDCl3) δ 8.79 (d, J = 2.6 Hz, 1H), 8.29 (s, 1H), 8.01 (dd, J = 8.8,
2.6 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 4.07 (s, 3H), 3.74 (ddd, J =
13.9, 7.2, 3.0 Hz, 1H), 3.36 (dt, J = 14.0, 3.8 Hz, 1H), 3.31−3.18
(m, 1H), 2.93−2.80 (m, 1H), 2.74 (s, 1H), 2.35−2.21 (m, 2H), 1.92
(dt, J = 12.2, 8.2 Hz, 1H), 1.83−1.55 (m, 3H), 1.14 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ163.1, 161.8, 132.3, 131.9,
131.0, 123.5, 112.3, 62.3, 56.6, 53.7, 48.1, 41.3, 28.4, 23.0, 14.0; IR
(neat) cm−1 2130; MS (ESI) calcd for C15H22N5O4S ([M + H+]) m/
z 368.1393, found m/z 368.1392.
General Procedure II for Compounds 4a−e. As for
compounds 2a−q but with 12 mL of solvent.
6-Ethoxybenzo[d]thiazole-2-sulfonyl azide (4a): white solid (160
1
mg, 77%); H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.1 Hz, 1H),
7.36 (d, J = 2.5 Hz, 1H), 7.29−7.21 (m, 1H), 4.14 (q, J = 7.0 Hz,
2H), 1.49 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.7, 159.0, 146.4, 138.9, 126.5, 119.2, 103.8, 64.4, 14.6; IR (neat)
cm−1 2146; MS (ESI) calcd for C9H9N4O3S2 m/z 285.0116 ([M +
H+]), found m/z 285.0118.
6-Chloropyridine-3-sulfonyl azide (4m): white solid, eluting in
5-(Azidosulfonyl)-4-chloro-2-((furan-2-ylmethyl)amino)benzoic
1
50% EtOAc in hexanes (42 mg, 81%); H NMR (400 MHz, CDCl3)
acid (4b): tan solid, eluting in 20−80% EtOAc in hexanes (157 mg,
δ 9.22 (s, 1H), 8.79 (d, J = 5.3 Hz, 1H), 7.59 (d, J = 5.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 155.8, 151.5, 143.5, 133.9, 126.8; IR
(neat) cm−1 2143; MS (ESI) calcd for C5H4ClN4O2S ([M + H+])
m/z 218.9744, found m/z 218.9746.
1
82%); H NMR (400 MHz, DMSO-d6) δ 9.39−8.94 (m, 1H), 8.41
(s, 1H), 7.61 (dd, J = 1.9, 0.9 Hz, 1H), 7.22 (s, 1H), 6.54−6.15 (m,
2H), 4.63 (d, J = 5.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ
169.1, 155.1, 151.8, 143.8, 136.9, 136.7, 120.2, 115.2, 111.5, 108.8,
40.1; IR (neat) cm−1 2130; MS (ESI) calcd for C12H9ClN4O5S m/z
357.0060 ([M + H+]), found m/z 357.0061.
p-Toluenebenzenesulfonamide-15N (5).41 To a stirred sol-
ution of p-toluenesulfonyl chloride (325 mg, 1.7 mmol) in 5 mL of a
3:2 mixture of MeCN/THF were added 15NH4Cl (98 atom % 15N,
102 mg, 1.8 mmol) and Et3N (1178 μL, 8.5 mmol), and the mixture
was heated under microwave irradiation at 140 °C for 4 h. After
being cooled to room temperature, the volatiles were evaporated and
the residue taken up in satd NaHCO3 and extracted with 2 × 20 mL
EtOAc. The combined organic phases were dried over Na2SO4,
concentrated, and purified by silica gel chromatography (30% EtOAc
in hexanes), providing the title compound as a tan solid (186 mg,
4,5-Dichlorothiophene-2-sulfonyl azide (4c): white solid (90 mg,
1
70%); H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H); 13C NMR (100
MHz, CDCl3) δ135.9, 135.0, 133.6, 126.0; IR (neat) cm−1 2131; MS
(EI) calcd for C4HCl2N3O2S2 m/z 256.8887 ([M + H+], found m/z
256.8893.
Methyl (E)-3-(4-(azidosulfonyl)phenyl)acrylate (4d): white solid,
eluting in 20% EtOAc in hexanes (85 mg, 81%); 1H NMR (400
MHz, CDCl3) 7.96 (d, J = 8.4 Hz, 2H), 7.86−7.58 (m, 3H), 6.57 (d,
J = 16.1 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) 166.7,
142.1, 141.0, 139.5, 129.2, 128.4, 122.7, 52.4; IR (neat) cm−1 2129;
MS (ESI) calcd for C10H10N3O4S m/z 268.0392 ([M + H+]), found
m/z 268.0389.
1
63%): H NMR (400 MHz, DMSO-d6) δ 7.88−7.65 (m, 2H), 7.60−
7.31 (m, 3H), 7.21 (s, 1H), 2.41 (s, 3H); 13C NMR (400 MHz,
DMSO-d6) 141.4, 141.4, 129.3, 125.4, 20.9; 15N NMR (40 MHz,
CDCl3) −284.9; 15N/14N 98.9/1.1% as determined by MS (EI).
p-Toluenesulfonyl Azide-(15N)-1 (6). Prepared from 5 following
Isoquinoline 5-sulfonyl azide (4e):39 colorless liquid, eluting in
1
1
general procedure I: colorless liquid (60 mg, 60%); H NMR (400
50% EtOAc in hexanes (21 mg, 78%); H NMR (400 MHz, CDCl3)
MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H),
2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.2, 135.5, 135.5,
130.2, 127.5, 127.5, 21.7; 15N NMR (40 MHz. CDCl3) −280.2; IR
δ 9.40 (s, 1H), 8.77 (d, J = 6.0 Hz, 1H), 8.52 (dd, J = 7.4, 1.2 Hz,
1H), 8.32 (dd, J = 12.4, 7.2 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 153.6, 146.4, 136.0, 134.0, 133.4, 131.5,
E
dx.doi.org/10.1021/jo500553q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(neat) cm−1 2122; MS (EI) calcd for C7H7N215NO2S m/z 198.0229,
found 198.0228.
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Reduction of 6. To a methanolic solution of 6 (38 mg, 0.19
mmol) in a 2−5 mL reaction vial was added Pd/C (10% Pd, 3 mg,
0.03 mmol) and the mixture stirred under H2 atmosphere at ambient
temperature for 30 min. After filtration, the reaction mixture was
concentrated in vacuo and the crude material analyzed without
further purification. 15N/14N 98.6/1.4% as determined by MS (ESI).
(19) Johansson, H.; Pedersen, D. S. Eur. J. Org. Chem. 2012, 2012,
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra for all products and 15N spectra for 5 and
6. This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Other alkylsulfonamides tested were n-butylsulfonamide and
(1S)-10-camphorsulfonamide, none of which gave detectable
product.
(25) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. J.
Am. Chem. Soc. 2002, 124, 10773−10778.
AUTHOR INFORMATION
■
(26) Casewit, C.; Roberts, J. J. Am. Chem. Soc. 1980, 102, 2364−
2368.
Corresponding Author
*Phone: +46-18-4714297. Fax: +46-18-4714474. E-mail: luke.
odell@orgfarm.uu.se.
(27) Hanessian, S.; Vatel
10568.
̀
e, J.-M. Tetrahedron. 1996, 52, 10557−
(28) An alternative route to imidazole-1-sulfonyl azide is presented
in: Ye, H.; Liu, R.; Li, D.; Liu, Y.; Yuan, H.; Guo, W.; Zhou, L.; Cao,
X.; Tian, H.; Shen, J.; Wang, P. G. Org. Lett. 2013, 15, 18−21.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Adolf Gogoll for assistance with the 15N-
labeling studies, Dr. Vivek Konda for the kind gift of tert-butyl
3d, and Anna Skogh for critical review of the manuscript.
Financial support from the Knut and Alice Wallenberg
Foundation is gratefully acknowledged.
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823.
(33) Selander, N.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 2477−
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dx.doi.org/10.1021/jo500553q | J. Org. Chem. XXXX, XXX, XXX−XXX