Tosvinyl and besvinyl as protecting groups of imides, azinones, nucleosides, sultams, and lactams. Catalytic conjugate additions to tosylacetylene

Article abstract of DOI:10.1021/jo501647w

The use of the 2-(4-methylphenylsulfonyl)-ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsvprotected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et₃N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)- or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.

Full text of DOI:10.1021/jo501647w

Article
pubs.acs.org/joc
Tosvinyl and Besvinyl as Protecting Groups of Imides, Azinones,
Nucleosides, Sultams, and Lactams. Catalytic Conjugate Additions to
Tosylacetylene
Elena Petit, Lluís Bosch, Joan Font, Laura Mola, Anna M. Costa,* and Jaume Vilarrasa*
̀
Departament de Química Organica, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: The use of the 2-(4-methylphenylsulfonyl)-
ethenyl (tosvinyl, Tsv) group for the protection of the NH
group of a series of imides, azinones (including AZT),
inosines, and cyclic sulfonamides has been examined. The Tsv-
protected derivatives are obtained in excellent yields by
conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone).
The stereochemistry of the double bond can be controlled at
will: with only 1 mol % of Et3N or with catalytic amounts of
NaH, the Z stereoisomers are generated almost exclusively,
while the E isomers are obtained using a stoichiometric
amount of DMAP. Analogous phenylsulfonylvinyl-protected
groups (with the besvinyl or Bsv group instead of Tsv) are
obtained stereospecifically by reaction with (Z)- or (E)-
bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in
the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition−elimination
mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.
quantitatively, and selectively either Z-vinyl or E-vinyl sulfone
derivatives as desired. The stability of these 2-(4-tolylsulfonyl)-
ethenyl groups (2-tosylvinyl, tosvinyl, Tsv),3 and appropriate
conditions for their removal should be then evaluated.
INTRODUCTION
■
Due to the strong electron-withdrawing character of the
sulfonyl group, 1-alkynyl and 1-alkenyl sulfones can participate
as acceptors in Michael-type additions and in [4 + 2]-, [3 + 2]-,
and [2 + 2]-cycloadditions. Consequently, they have many
synthetic applications.1 We were interested in the conjugate
additions of nucleophiles to ethynyl sulfones, in comparison
with those to other electron-deficient triple bonds.2 In this
regard, we planned to take advantage of the reactivity of
commercially available 1-(ethynylsulfonyl)-4-methylbenzene
(ethynyl p-tolyl sulfone, Ts−CCH), commonly called
tosylacetylene, to develop a procedure for the protection of
heterocyclic compounds with activated NH groups. As shown
in Scheme 1, this would require a conjugate addition (aza-
Michael addition) under very mild conditions to afford quickly,
The reaction of tosylacetylene with thiols was examined
exhaustively by the research group of Plumet and Arjona,4 with
whom some of us collaborated to develop a chemoselective
protection scheme for thiol groups.4b,5 O-Nucleophiles and
amines also react with tosylacetylene,1c and there are also a few
examples of the addition of the CONH groups of heterocyclic
compounds to alkynyl sulfones.6 However, despite the scarcity
of good methods for the protection of these moieties,3 and
even though it is a functionality that very often requires
protection during the synthesis of drugs, the use of the Tsv
group has not been studied in detail.6b,7 In this connection, we
have comparatively evaluated, for the first time, the protection
with Tsv of several relatively acidic NH groups (see Figure 1):
carboximides 1a and 1b; the special imide moiety of a
pyrimidine nucleoside (O-Ac-AZT, 1c); the particular amide
groups of 2-pyridone (1d), 2-hydroxyquinazoline (quinazolone
1e), and inosine 1f; cyclic sulfonamides (sultams 1g and 1h);
an N-acylsultam (saccharin, 1i). Less acidic NH-containing
substrates such as lactams 1j and 1k and a cyclic carbamate
(oxazolidinone 1l, Figure 1) were also included in the set. It
was crucial that Tsv could be introduced with Z or E
Scheme 1. Tosylacetylene as a Reagent for the Protection of
CONHCO and Related Groups
Received: July 21, 2014
Published: August 27, 2014
© 2014 American Chemical Society
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Table 1. Screening of the Reaction Conditions for the
a
Addition of Succinimide (1a) to Tosylacetylene
base or catalyst
(equiv)
T
(°C)
time
(h)
conv
(%)
yield
(%)
2a/3a (Z/
b
entry
E)
1
20
20
0
24
0
2
Et3N (0.1)
0.2
0.2
0.2
0.2
0.2
0.3
<0.2
<0.2
0.5
0.2
0.2
48
100
100
100
100
100
100
100
100
100
100
100
100
100
100
87
91
92
95
94
92
97
97
92
92
90
90
88
84
86:14
88:12
3
Et3N (0.1)
Figure 1. Set of compounds studied.
c
4
Et3N (0.01)
DIPEA (0.1)
DIPEA (0.05)
DIPEA (0.01)
NaH (0.2)
0
>99:1
c
5
20
20
0
>99:1
c
6
>99:1
configuration as desired, to avoid the formation of mixtures of
stereoisomers that would complicate the characterization of the
protected products. In several cases, the preparation of
derivatives with a 2-(benzenesulfonyl)ethenyl or 2-besylvinyl
substructure (PhSO2CHCH, besvinyl, Bsv) was also studied
for the sake of comparison. We believe that this study expands
the scope of the use of Tsv and related groups in organic
synthesis, which is currently somewhat limited.
c
7
>99:1
c
8
20
20
20
20
20
50
20
50
>99:1
c
9
NaH (0.05)
DMAP (0.1)
DMAP (0.5)
DMAP (1.0)
DMAP (1.0)
DABCO (0.2)
DABCO (1.0)
>99:1
10
11
12
13
14
15
93:7
74:26
55:45
c
<1:99
0.2
48
70:30
c
<1:99
RESULTS AND DISCUSSION
■
a
Standard conditions: 1a and tosylacetylene (1.2 equiv) were
dissolved in CH3CN (0.1 M) under N2, and the base was added at
0 °C; stirring was maintained at the temperature shown above, for the
time indicated. The isolated yields of isomers E+Z are given. E/Z
The great reactivity of electron-deficient triple bonds, linked to
strong EWGs such as SO2Ar, with nucleophiles should facilitate
the attachment of Tsv to the nitrogen of amides and imides,
which are poorly nucleophilic unless they are converted into
their more reactive anions. Several bases and catalysts are
reported for similar reactions.2,4,6 To identify the best
conditions for the stereoselective introduction of Tsv, we
started by studying the reaction of succinimide (1a), with a
relatively acidic NH group, with tosylacetylene, promoted by
Et3N, DIPEA (a basic but poorly nucleophilic tertiary amine),
NaH, DMAP, and DABCO (the last two less basic than a
standard tertiary amine but highly nucleophilic). The results of
this preliminary screening are shown in Table 1.
b
c
1
ratios were determined by H NMR (400 MHz). The minor isomer
1
was not detected by H NMR (400 MHz).
The NMR signals of the products proved to be diagnostic.
This is an advantage of this kind of protecting group (with a
double bond), as the introduction and removal can be easily
followed by NMR spectroscopy. For the sake of comparison we
allowed 1a to react with (Z)-1,2-bis(phenylsulfonyl)ethene and
with (E)-1,2-bis(phenylsulfonyl)ethene, both commercially
available.10 As summarized in Scheme 2, adduct Z (4a) was
Succinimide, 1a, does not react with tosylacetylene alone at
rt (entry 1), as expected, but the reaction is strongly accelerated
by the presence of a small amount of a base. All the basic
catalysts tested afford complete conversion in less than 30 min,
even at 0 °C and with only a trace of the base. The Z
stereoisomer 2a is always the major product, although the
degree of selectivity changes depending on the base and
conditions. The results obtained using Et3N or DIPEA are
similar although the reactions with the latter (compare entry 5
to 2) are slightly more Z-selective. To obtain 2a exclusively,
with Et3N, it is necessary to work with only a trace of the base
at 0 °C (entry 4). Catalytic amounts of NaH (entries 8 and 9)
also afford 2a with complete stereoselectivity, instantaneously.
Finally, we examined two bases of well-known nucleophilicity,
DMAP and DABCO,8 which gave mixtures of stereoisomers
(entries 10−12 and 14). However, on prolonged heating with
DMAP or DABCO the more stable E isomer (3a) became the
major compound (entries 13 and 15); the yields obtained with
DABCO were slightly lower than with DMAP.9 Heating in the
presence of Et3N caused a much slower isomerization. Thus, it
appears that adducts generated under kinetic control (basic
medium)5 isomerize to the thermodynamically favored E
isomers in the presence of the more nucleophilic bases (slowly
at rt, quantitatively after prolonged heating).
Scheme 2. Reaction of 1a with 1,2-Bis(sulfonyl)ethenes
formed with the former reagent and adduct E (5a) with the
latter, with an excellent stereospecificity.10 By analogy to the
Tsv group,3 we call these 2-(phenylsulfonyl)ethenyl substitu-
ents (Z)- and (E)-besvinyl groups, or simply Z-Bsv and E-Bsv,
as they contain benzenesulfonylvinyl moieties. The NMR
spectra of 4a and 5a correlated perfectly with those of 2a and
3a, respectively, as anticipated.11
Having established suitable conditions for the selective
preparation of either the Z- or E-protected succinimides, we
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a
extended the study to other compounds containing similar,
relatively acidic NH, such as compounds 1b−i shown in Figure
1. The results obtained in the preparation of Z derivatives, 2,
are shown in Table 2. In all cases, the yields were excellent.
Table 3. Preparation of E-Tsv-Protected Compounds 3b−h
a
Table 2. Preparation of Z-Tsv-Protected Compounds 2b−i
b
entry substrate
base
T (°C) time (h) yield (%)
3, E/Z
1
2
3
4
5
6
7
1b
1c
1d
1e
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
50
50
20
50
20
50
50
48
48
24
48
48
48
48
98
80
96
84
90
82
97
3b, >99:1
3c, >99:1
3d, >99:1
3e, >99:1
3f, >99:1
3g, >99:1
3h, >99:1
c
1f
T
time
(h)
yield
(%)
2/3 (Z/
b
entry substrate base (equiv)
(°C)
E)
1g
1h
c
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1d
1e
1e
Et3N (0.01)
Et3N (0.03)
Et3N (0.01)
DIPEA (0.01)
Et3N (0.01)
NaH (0.2)
0
0.2
0.3
0.6
1.0
0.1
0.5
0.5
1.0
2.5
1.6
89
85
92
89
92
87
86
87
96
>99:1
c
a
0
>99:1
Standard conditions: 1a−h and tosylacetylene (1.2 equiv) were
0
98:2
93:7
dissolved in CH3CN (0.1 M) under N2, and DMAP (1.0 equiv) was
then added. Stirring at the temperatures shown in the table was
0
b
maintained for the time indicated. E/Z ratios determined by 1H
c
20
20
10
−5
20
20
>99:1
c
c
NMR. CH3CN/CH2Cl2 (1:1) was used as the solvent.
>99:1
d
1f
Et3N (0.03)
Et3N (0.03)
Et3N (0.03)
NaH (0.2)
95:5
c
equiv of DABCO instead of 1 equiv of DMAP, the yields of 3
were lower (in the 60−88% range, data not shown in Table 3).9
Again, the behavior of saccharin was special. Mixing
equivalent amounts of saccharin (1i) and DMAP in CH3CN
caused immediate precipitation of the 4-(dimethylamino)-
pyridinium salt of saccharin, which dissolved as soon as
tosylacetylene was added. After a few minutes another salt
precipitated, which was identified as 6.15 This probably results
from conjugate addition of DMAP to tosylacetylene followed
by protonation of the resulting anion by saccharin (Scheme 3).
1g
1h
1i
>99:1
98:2
e
c
90
>99:1
a
Standard conditions: 1b−i and tosylacetylene (1.2 equiv) were
dissolved in CH3CN (0.1 M) under N2, and the corresponding base
was slowly added at 0 °C. Stirring at the temperature shown in the
table was maintained for the time indicated. The isolated yields of
b
1
isomers E+Z are given. E/Z ratios were determined by H NMR.
The minor isomer was not detected by H NMR. CH3CN/CH2Cl2
(1:1) was used as the solvent. Conversion was complete, but the
product partially decomposed when purification was attempted by
column chromatography.
c
d
1
e
Scheme 3. Formation of Salt 6 and Isomerization of 2i to 3i
Experiments carried out in 1:1 CH2Cl2/CH3CN or in THF,
although not included in Table 2 for the sake of simplicity, gave
similar or only slightly lower results, respectively. The E
isomers were rarely detected; they were only noted in the cases
of pyridone (1d), inosine (1f), and naphthosultam (1h), but as
very minor products. Saccharin (1i), with a highly acidic NH
(pKa = 1.6 in H2O,12a pKa = 4 in DMSO12b), with a poorly
nucleophilic anion, reacts very slowly, even in the presence of
stoichiometric amounts of DIPEA or Et3N; however, Z-Tsv-
protected saccharin 2i can be prepared by using NaH (entry
10). It is uncommon for an N-acylsulfonamide moiety
embedded in a drug to require protection, but we included
this compound in the set to check the capacity of “sodium
saccharine” to behave as a nucleophile against triple bonds
activated by an electron-withdrawing group.13
Isomerization of Z isomers, once isolated, to E isomers could
be accomplished by nucleophilic catalysis. For example,
isomerization of (Z)-2b to (E)-3b was complete by addition
of a stoichiometric amount of DMAP and heating at 50 °C for
48 h. With substoichiometric amounts of DMAP or DABCO,
the isomerization was incomplete.14
We could obtain directly the E stereoisomers as indicated in
the case of 1a, that is, by reaction of the substrate with 100 mol
% of DMAP for many hours (Table 3). In fact, to achieve
complete formation of the E isomer, heating was necessary in
most of the cases, but not always (entries 3 and 5). With 1
The isolation of this salt is consistent with the role of DMAP as
a nucleophilic catalyst or promoter. Compound 6 remained
unaltered when heated in CH3CN for 1 day. Nevertheless, 3i
was isolated in 90% yield by treatment of its Z stereoisomer, 2i,
prepared as reported in Table 2, with a catalytic amount of
DMAP at rt.
The less acidic lactams 1j and 1k and oxazolidinone 1l do
not react with H−CC−Ts under the conditions optimized
for the Z-Tsv and E-Tsv derivatives.16 As an alternative, we
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could examine their synthetic equivalents X−CHCH−SO2Ar
(X = halogen or other good leaving groups).17 In practice, we
have used 1,2-bis(phenylsulfonyl)ethenes (PhSO2−CHCH−
SO2Ph) for the protection of 1j−l (as Bsv derivatives, see
Scheme 2), by means of the known stereospecific Ad−E
reaction6b,7,10 of nucleophiles to these activated alkenes. Our
results are summarized in Scheme 4. Thus, by reaction with
Table 4. Removal of the Tsv and Bsv Groups with
Nucleophiles
Scheme 4. Preparation of 4j−l and 5j−l
a
b
entry
substrate
method
T (°C)
time (h)
1a−i yield (%)
1
2a
2a
3a
4a
5a
2b
3b
2c
2c
3c
2d
2d
3d
2e
2e
3e
2f
A
A
A
A
A
A
A
A
C
C
A
C
C
A
C
C
B
A
A
50
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
0.25
15
15
15
15
0.25
0.25
0.5
2
98
97
82
90
92
95
82
97
96
97
97
95
90
85
75
91
91
90
70
2
3
4
5
6
7
8
(Z)-1,2-bis(phenylsulfonyl)ethene, the lithium salts of 1j−l
afforded Z-Bsv-protected compounds 4j−l with high selectivity,
whereas with the sodium salts (generated from NaH or
NaHMDS, either in substoichiometric or stoichiometric
amounts) we obtained a mixture of Z-Bsv and E-Bsv
derivatives. On the other hand, by reaction with (E)-1,2-
bis(phenylsulfonyl)ethene, the sodium salts of 1j−l, in the
presence of an excess of 15-crown-5, gave exclusively the
desired E-Bsv derivatives.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
2
0.5
0.5
0.5
0.5
1
1
0.5
0.5
2
The stabilities of the CON−Tsv, CON−Bsv, SO2N−Tsv,
and SO2N−Bsv bonds were examined in basic and acidic
media. (1) Removal of the TBDPS group of 4k was
accomplished with TBAF at rt in excellent yield with partial
Z to E isomerization of the Bsv group; meanwhile, use of TBAF
buffered with HOAc cleaved the silyl ether while hardly
affecting the Tsv group (no isomerization). (2) Compound 5k
could be α-benzylated in good yield (LiHMDS, THF, −78 °C,
benzyl bromide, rt), the Bsv group remaining intact. (3) The
acetyl group of 2c could be removed quantitatively by
treatment with 1% NaOMe in MeOH, while the Z
configuration of the Tsv group was maintained; however,
these reaction conditions could not be applied to 2f, which
suffered secondary reactions. (4) When treated with 10%
TsOH·H2O in MeOH at rt, the acetyl groups of inosine 3f were
slowly cleaved but the Tsv group remained unaltered; also,
compounds 2b, 2g, and 5l were recovered intact after treatment
with these reagents even on heating at 55 °C for 48 h. From
these experiments, we can conclude that the Tsv group is not
sensitive to acid media or to non-nucleophilic bases.
3f
0
2g
2g
3g
2h
2h
2i
20
55
55
20
20
20
20
20
55
55
55
55
20
55
c
d
C
48
48
2
91
c
e
C
86
f
A
95
88
89
70
90
81
77
70
c
C
2
B
0.5
0.5
1
c
2i
C
c
3i
C
4j
D
D
D
D
5.5
5.5
24
20
18
4.5
5j
4k
5k
4l
e
76
c
e
C
88
c
5l
C
94
a
Method A: dodecanethiol (1.5 equiv), NaH (3.0 equiv), CH3CN.
Method B: sodium dodecanethiolate (1.2 equiv), CH3CN. Method C:
pyrrolidine (2.0 equiv), CH3CN. Method D: pyrrolidine (4.0 equiv),
NaH (0.3 equiv), CH3CN. Isolated yields after removal of reagent
b
excess and separation from Nu−CHCH−EWG by flash column
c
Several deprotection procedures, based on an addition−
elimination mechanism, were examined. A selection of the most
relevant results is shown in Table 4. The most general method
was the use of dodecanethiol and an excess of sodium hydride
(method A). The deprotected compounds were isolated in
chromatography. Conversions were complete. With 4.0 equiv of
d
e
pyrrolidine. Brsm yields (92% conversion). Brsm yields (90%
f
conversion). THF as the solvent instead of CH3CN.
predominated. Nevertheless, sodium dodecanethiolate alone,
without additional NaH (method B), was enough in some cases
(Table 4, entries 17 and 24). Lactams 4j and 4k and
oxazolidinone 4l isomerized to the corresponding E isomers
5j−l and did not react further when treated with sodium
dodecanethiolate (by method A or B); this result was not
excellent yields, as well as coproducts CH3(CH2)11SCH
3
CHTs or CH3(CH2)11SCHCHBs (only isomers E, JHH
=
14.6 Hz). The excess of NaH (relative to the thiol) was
necessary, otherwise the initial intermediates from conjugate
addition of the nucleophile (N,S-acetals, thiohemiaminals)18
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solvent resonance as the internal standard (CHCl3 impurity in CDCl3,
δ 7.26 ppm; CD3SOCHD2 in DMSO-d6, δ 2.50 ppm). Data are
reported in the following order: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants in hertz, integration; the aromatic protons of Ts
groups (AA′XX′ systems) usually appear as doublets (br d in the
expanded spectra). 13C NMR spectra were recorded in CDCl3 or
DMSO on the above-mentioned spectrometers (100.6 MHz for 13C)
with complete proton decoupling. Chemical shifts are reported in ppm
with the solvent as the internal standard (CDCl3, δ 77.2 ppm; DMSO-
d6, δ 39.5 ppm). Where necessary, 2D NMR experiments (HSQC and
NOESY) were carried out to assist in structure elucidation and signal
assignments. All the IR spectra were recorded on a FT-IR instrument
equipped with an ATR accessory; only the relevant bands are reported,
in cm−1. All the high-resolution mass spectra (HRMS) were obtained
by the electrospray ionization (ESI+, TOF) technique.
General Procedure for the Addition of Imides, Azinones,
Nucleosides, and Sultams to Tosylacetylene, To Obtain 2. Et3N
(as a 0.1 M solution in CH3CN) or NaH was slowly added at 0 °C to a
solution of the corresponding substrate and tosylacetylene (ethynyl 4-
methylphenyl sulfone, 1.2 equiv) under a N2 atmosphere. The reaction
was stirred at the temperature indicated in Table 1 (entries 2−9) and
Table 2 until TLC analysis indicated complete consumption of the
substrate. The solvent was removed under reduced pressure, and the
residue was dissolved in CH2Cl2, washed with 0.5 M HCl and brine,
dried over anhyd MgSO4, filtered, and concentrated. Purification by
flash column chromatography on silica gel afforded stereopure alkenes
2.
unexpected, bearing in mind that the dodecanethiolate ion
might be a better leaving group than the anions of 1j−l.
We also explored the performance of pyrrolidine (method
C) in this transformation, with satisfactory results, except for
some particular cases, viz., we noted that pyrrolidine attacked
the carbonyl carbon of Tsv-protected imides 2a, 2b, 3a, 3b, and
3f rather than undergoing the desired conjugate addition. The
deprotection of camphorsultam derivatives 2g and 3g was very
slow, due to steric hindrance, but camphorsultam could be
isolated in good yield by increasing the amount of pyrrolidine
and the temperature (see entries 20 and 21). Lactams 4j, 4k, 5j,
and 5k could be deprotected in good yields by the combined
use of pyrrolidine (4.0 equiv) and NaH (0.3 equiv) (method D,
entries 27−30); in all other cases, stable aminal intermediates
predominated and could be isolated.19 Geometrical isomers 4l
and 5l show a remarkable difference in reactivity when treated
with pyrrolidine (entries 31 and 32). Whereas 4l (Z isomer)
reacted smoothly at rt and furnished 1l in excellent yield, its E
isomer 5l did not react. Only after heating the reaction mixture
to 55 °C did we achieve complete conversion of 5l to 1l. In
general, we observed that Z-Tsv and Z-Bsv were removed more
readily than their thermodynamically more stable E isomers, as
was to be expected.
The N-Tsv- and N-Bsv-protected compounds may be
transformed to the corresponding N-vinyl derivatives, via
cleavage of the C−SO2 bonds under reductive conditions.20
Also, the Tsv- and Bsv-containing compounds can be
hydrogenated (H2 balloon, Pd/C) within minutes to give
quantitatively the corresponding 2-tosylethyl (tosethyl, Tse6b)
and 2-(benzenesulfonyl)ethyl (besethyl, Bse) derivatives, as we
checked with compounds 3a, 3e, and 5l.
Compound 2a (>99:1 Z/E, 78 mg, 92%, with 0.01 equiv of Et3N),
N-[(Z)-2-(4-methylphenylsulfonyl)ethenyl]succinimide. White solid;
mp 171−172 °C; Rf = 0.34 (hexanes/EtOAc, 20:80); 1H NMR
(CDCl3) δ 2.45 (s, 3H), 2.88 (s, 4H), 6.43 (d, J = 9.0, 1H), 6.55 (d, J
= 9.0, 1H), 7.36 (d, J = 8.4, 2H), 7.82 (d, J = 8.4, 2H); 13C NMR
(CDCl3) δ 21.8, 28.9, 126.2, 128.3, 130.0, 130.1, 136.9, 145.4, 174.5;
IR 1780, 1714, 1613; HRMS m/z calcd for C13H14NO4S+ [M + H]+
280.0638, found 280.0632.
CONCLUSIONS
2b (>99:1 Z/E, 110 mg, 89%, with 0.01 equiv of Et3N), N-[(Z)-2-
■
(4-methylphenylsulfonyl)ethenyl]phthalimide. White solid; mp
A series of heterocyclic compounds containing CONHCO,
CONHCHCH, CONHCHN, and SO2NH moieties react
with tosylacetylene to furnish N-2-tosylethenyl adducts
(tosvinyl or Tsv derivatives) with Z configuration in the
presence of Et3N or NaH as catalysts. Isomeric E adducts can
be produced by using DMAP in stoichiometric amounts. Thus,
the Z-Tsv or E-Tsv protecting groups can be introduced at will.
Analogous derivatives and analogous protected lactams and
oxazolidinones, with 2-(benzenesulfonyl)ethenyl substituents
(called here Z-besvinyl or Z-Bsv, and E-besvinyl or E-Bsv), can
also be stereoselectively obtained by reaction with Z- or E-1,2-
bis(phenylsulfonyl)ethene, respectively. The Tsv and Bsv
groups are stable in acid media and non-nucleophilic bases
and can be removed efficiently via an addition−elimination
mechanism by treatment with good nucleophiles such as
sodium dodecanethiolate or pyrrolidine, depending on the case.
1
173−175 °C; Rf = 0.55 (CH2Cl2/MeOH, 99:1); H NMR (CDCl3,
400 MHz) δ 2.43 (s, 3H), 6.42 (d, J = 9.2, 1H), 6.76 (d, J = 9.2, 1H),
7.35 (d, J = 8.2, 2H), 7.80 (m, AA′ subsystem, 2H), 7.86 (d, J = 8.2,
2H), 7.96 (m, BB′, 2H); 13C NMR (CDCl3) δ 21.8, 124.4, 124.9,
127.9, 128.3, 130.0, 132.1, 134.9, 137.5, 145.1, 165.4; IR 1786, 1721,
1590; HRMS m/z calcd for C17H14NO4S+ [M + H]+ 328.0638, found
328.0634.
2c (>99:1 Z/E, 81 mg, 85%, with 0.03 equiv of Et3N), 5′-O-acetyl-
3′-azido-3′-deoxy-3-[(Z)-2-(4-methylphenylsulfonyl)-ethenyl]-
thymidine. Foam; Rf = 0.12 (CH2Cl2/MeOH, 99:1); 1H NMR
(CDCl3) δ 1.97 (br d, J = 1.2, 3H), 2.13 (s, 3H), 2.43 (s, 3H), 2.44−
2.61 (m, 2H), 4.11 (dt, J = 5.5, J = 4.0, 1H), 4.21 (dt, J = 7.3, J = 6.0,
1H), 4.35 (dd, J = 12.3, J = 3.7, 1H), 4.39 (dd, J = 12.3, J = 4.4, 1H),
6.09 (t, J = 6.0, 1H), 6.48 (d, J = 8.8, 1H), 6.71 (d, J = 8.8, 1H), 7.32
(q, J = 1.2, 1H), 7.33 (d, J = 8.2, 2H), 7.78 (d, J = 8.2, 2H); 13C NMR
(CDCl3) δ 12.7, 20.5, 21.3, 37.3, 60.2, 63.1, 81.7, 86.3, 109.5, 127.7,
129.6, 130.4, 134.6, 136.4, 144.8, 148.8, 161.9, 170.0; IR 2103, 1739,
1715, 1662; HRMS m/z calcd for C21H24N5O7S+ [M + H]+ 490.1391,
found 490.1387.
EXPERIMENTAL SECTION
■
2d (98:2 Z/E, 64 mg, 92%, with 0.01 equiv of Et3N). Data for
chromatographically pure N-[(Z)-2-(4-methylphenyl-sulfonyl)-
ethenyl]-2-pyridone. White solid; mp 110−112 °C; Rf = 0.40
General Information. Unless specified otherwise, all starting
materials and reagents were obtained from commercial suppliers and
used without further purification. All reactions were conducted in
oven-dried glassware, under dry nitrogen, with anhydrous solvents,
which were dried and distilled before use according to standard
procedures. Solvents used for isolation of products and chromatog-
raphy were glass distilled. Analytical thin-layer chromatography (TLC)
was performed on 0.25 mm silica gel plates (F254); retention factors
(Rf) are approximate. Flash column chromatography was performed
on silica gel 60 (35−70 μm). Yields were determined after purification
of the desired compound by column chromatography on silica gel.
1
(CH2Cl2/MeOH, 98:2); H NMR (CDCl3) δ 2.41 (s, 3H), 6.24 (td
J = 6.8, 1.2, 1H), 6.34 (d, J = 9.5, 1H), 6.47 (br d, J = 9.4, 1H), 7.30 (d,
J = 8.2, 2H), 7.33−7.39 (m, 1H), 7.35 (d, J = 9.5, 1H), 7.71−7.76 (m,
1H), 7.73 (d, J = 8.2, 2H); 13C NMR (CDCl3) δ 21.8, 105.8, 120.8,
125.7, 127.8, 130.1, 135.4, 136.9, 138.4, 141.5, 145.5, 161.6; IR 1671,
1619; HRMS m/z calcd for C14H14NO3S+ [M + H]+ 276.0689, found
276.0690.
2e (>99:1 Z/E, 163 mg, 92%, with 0.01 equiv of Et3N), 1-[(Z)-2-(4-
methylphenylsulfonyl)ethenyl]-2-quinoxalinone. White solid; mp
1
1
Melting points are uncorrected. H NMR spectra were recorded on
170−172 °C; Rf = 0.58 (CH2Cl2/EtOAc, 1:1); H NMR (CDCl3) δ
400 MHz spectrometers. Chemical shifts are reported in ppm with the
2.40 (s, 3H), 6.79 (d, J = 8.8, 1H), 6.89 (d, J = 8.8, 1H), 7.19 (dd, J =
8830
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The Journal of Organic Chemistry
Article
8.4, J = 1.1, 1H), 7.23 (d, J = 8.2, 2H), 7.39 (ddd, J = 8.0, J = 7.5, J =
1.1, 1H), 7.55 (ddd, J = 8.4, J = 7.5, J = 1.5, 1H), 7.65 (d, J = 8.2, 2H),
7.87 (dd, J = 8.0, J = 1.5, 1H), 8.18 (s, 1H); 13C NMR (CDCl3) δ 21.8,
114.9, 124.8, 128.5, 129.1, 129.9, 130.6, 131.3, 131.9, 133.0, 135.3,
135.7, 145.8, 149.9, 153.3; IR 1678, 1607; HRMS m/z calcd for
C17H15N2O3S+ [M + H]+ 327.0798, found 327.0800.
= 8.2, 2H), 7.52 (d, J = 14.3, 1H), 7.79−7.85 (m, 4H), 7.92−7.98 (m,
3H); 13C NMR (CDCl3) δ 21.8, 119.0, 124.6, 127.8, 128.8, 130.1,
131.3, 135.6, 138.2, 144.5, 165.1; IR 1796, 1723, 1622; HRMS m/z
calcd for C17H14NO4S+ [M + H]+ 328.0638, found 328.0635.
3c (>99:1 E/Z, 93 mg, 80%), 5′-O-acetyl-3′-azido-3′-deoxy-3-[(E)-
2-(4-methylphenylsulfonyl)ethenyl]thymidine. White solid; mp 98−
1
100 °C; Rf = 0.30 (CH2Cl2/MeOH, 99:1); H NMR (CDCl3) δ 1.94
2f (95:5 Z/E, 50 mg, 86%, with 0.03 equiv of Et3N). Data for
chromatographically pure 2′,3′,5′-tri-O-acetyl-1-[(Z)-2-(4-
methylphenylsulfonyl)ethenyl]inosine. White solid; mp 96−98 °C;
(s, 3H), 2.12 (s, 3H), 2.34−2.39 (m, 1H), 2.42 (s, 3H), 2.46−2.57 (m,
1H), 4.06−4.09 (m, 1H), 4.18−4.22 (m, 1H), 4.32 (dd, J = 12.4, J =
3.6, 1H), 4.38 (dd, J = 12.4, J = 4.4, 1H), 6.05 (t, J = 6.1, 1H), 7.31 (m,
3H), 7.71 (d, J = 14.3, 1H), 7.78 (d, J = 8.0, 2H), 8.37 (d, J = 14.3,
1H); 13C NMR (CDCl3) δ 13.5, 20.9, 21.7, 37.9, 60.4, 63.2, 82.3, 87.0,
110.1, 123.3, 127.8, 130.0, 131.8, 134.2, 138.1, 144.5, 149.1, 161.6,
170.3; IR 2109, 1739, 1718, 1651; HRMS m/z calcd for
C21H24N5O7S+ [M + H]+ 490.1391, found 490.1387.
1
Rf = 0.45 (CH2Cl2/MeOH, 95:5); H NMR (CDCl3) δ 2.11 (s, 3H),
2.16 (s, 6H), 2.39 (s, 3H), 4.36−4.49 (m, 3H), 5.57 (t, J = 5.0, 1H),
5.81 (t, J = 5.4, 1H), 6.16 (d, J = 5.4, 1H), 6.56 (d, J = 9.2, 1H), 7.29
(d, J = 8.2, 2H), 7.36 (d, J = 9.2, 1H), 7.72 (d, J = 8.2, 2H), 7.96 (s,
1H), 8.31 (s, 1H); 13C NMR (CDCl3) δ 20.5, 20.6, 20.9, 21.8, 63.1,
70.6, 73.5, 80.6, 86.8, 122.7, 125.2, 127.9, 130.2, 135.0, 137.2, 139.4,
145.2, 145.3, 146.1, 155.1, 169.4, 169.7, 170.4; IR 1742, 1704, 1631;
HRMS m/z calcd for C25H27N4O10S+ [M + H]+ 575.1442, found
575.1447.
3d (>99:1 E/Z, 83 mg, 96%), N-[(E)-2-(4-methylphenylsulfonyl)-
ethenyl]-2-pyridone. White solid; mp 195−196 °C; Rf = 0.63
1
(CH2Cl2/MeOH, 98:2); H NMR (CDCl3) δ 2.44 (s, 3H), 6.23 (br
2g (>99:1 Z/E, 64 mg, 87%, with 0.03 equiv of Et3N), (S)-N-[(Z)-2-
(4-methylphenylsulfonyl)ethenyl]-2,10-camphorsultam. White
solid; mp 131−133 °C; Rf = 0.54 (CH2Cl2/MeOH, 99.5:0.5); 1H
NMR (CDCl3) δ 0.91 (s, 3H), 0.94 (s, 3H), 1.41−1.46 (m, 1H),
1.53−1.59 (m, 1H), 1.90−1.97 (m, 3H), 2.25 (dd, J = 13.7, J = 8.0,
1H), 2.36−2.42 (m, 1H), 2.44 (s, 3H), 3.31 (d, J = 13.8, 1H), 3.36 (d,
J = 13.8, 1H), 4.38 (dd, J = 7.9, J = 4.8, 1H), 5.45 (d, J = 9.8, 1H), 6.54
(d, J = 9.8, 1H), 7.33 (d, J = 8.4, 2H), 7.79 (d, J = 8.4, 2H); 13C NMR
(CDCl3) δ 20.1, 20.2, 21.8, 27.0, 31.9, 35.0, 44.4, 48.3, 50.0, 52.7, 68.1,
111.7, 126.3, 127.5, 130.0, 139.6, 144.5; IR 1608; HRMS m/z calcd for
t, J = 6.8, 1H), 6.58 (br d, J = 9.1, 1H), 7.06 (d, J = 14.1, 1H), 7.28−
7.37 (m, 4H), 7.82 (d, J = 8.3, 2H), 8.22 (d, J = 14.1, 1H); 13C NMR
(CDCl3) δ 21.8, 108.0, 120.1, 122.9, 127.9, 130.2, 133.0, 137.3, 137.8,
140.0, 144.8, 161.3; IR 1682, 1625; HRMS m/z calcd for
C14H14NO3S+ [M + H]+ 276.0689, found 276.0690.
3e (>99:1 E/Z, 86 mg, 84%), 1-[(E)-2-(4-methylphenylsulfonyl)-
ethenyl]-2-quinoxalinone. White solid; mp 168−170 °C; Rf = 0.66
(CH2Cl2/EtOAc, 1:1); 1H NMR (CDCl3) δ 2.44 (s, 3H), 7.36 (d, J =
8.2, 2H), 7.47 (ddd, J = 8.1, J = 7.2, J = 1.3, 1H), 7.59 (dd, J = 8.6, J =
1.4, 1H), 7.65 (ddd, J = 8.6, J = 7.2, J = 1.6, 1H), 7.84 (d, J = 8.4, 2H),
7.88 (d, J = 13.7, 1H), 8.07 (d, J = 13.7, 1H), 8.21 (s, 1H); 13C NMR
(CDCl3) δ 21.8, 114.4, 125.9, 127.2, 127.9, 130.3, 130.7, 131.3, 131.4,
131.8, 133.4, 137.4, 145.0, 150.3, 154.0; IR 1681, 1612; HRMS m/z
calcd for C17H15N2O3S+ [M + H]+ 327.0798, found 327.0802.
3f (>99:1 E/Z, 52 mg, 90%), 2′,3′,5′-tri-O-acetyl-1-[(E)-2-(4-
methylphenylsulfonyl)ethenyl]inosine. White solid; mp 108−109 °C;
+
C19H26NO4S2 [M + H]+ 396.1298, found 396.1293.
2h (98:2 Z/E, 153 mg, 96%, with 0.03 equiv of Et3N). Data for
chromatographically pure N-[(Z)-2-(4-methylphenylsulfonyl)-
ethenyl]-1,8-naphthosultam. White solid; mp 188−190 °C; Rf =
1
0.24 (CH2Cl2); H NMR (CDCl3) δ 2.38 (s, 3H), 6.65 (d, J = 8.6,
1H), 6.82 (d, J = 8.6, 1H), 7.17 (dd, J = 6.9, J = 1.1, 1H), 7.27 (d, J =
8.3, 2H), 7.59−7.68 (m, 2H), 7.77 (dd, J = 8.1, J = 7.2, 1H), 7.85 (d, J
= 8.3, 2H), 7.97 (d, J = 7.2, 1H), 8.13 (d, J = 8.1, 1H); 13C NMR
(CDCl3) δ 21.8, 108.4, 120.2, 120.2, 120.6, 127.8, 128.1, 128.4, 129.5,
129.5, 130.0, 130.9, 131.8, 132.1, 135.7, 137.2, 145.3; IR 1615; HRMS
1
Rf = 0.51 (CH2Cl2/MeOH, 95:5); H NMR (CDCl3) δ 2.09 (s, 3H),
2.12 (s, 3H), 2.14 (s, 3H), 2.44 (s, 3H), 4.35 (dd, J = 12.3, J = 4.6,
1H), 4.39−4.47 (m, 2H), 5.54 (t, J = 5.2, 1H), 5.81 (t, J = 5.4, 1H),
6.08 (d, J = 5.2, 1H), 7.36 (d, J = 8.2, 2H), 7.42 (d, J = 14.1, 1H), 7.82
(d, J = 8.2, 2H), 7.95 (s, 1H), 8.10 (s, 1H), 8.14 (d, J = 14.1, 1H); 13C
NMR (CDCl3) δ 20.5, 20.7, 20.9, 21.8, 63.0, 70.6, 73.6, 80.6, 86.5,
124.5, 127.9, 128.9, 130.3, 132.6, 136.2, 138.5, 145.9, 147.5, 147.6,
155.3, 169.4, 169.7, 170.4; IR 1748, 1712; HRMS m/z calcd for
C25H27N4O10S+ [M + H]+ 575.1442, found 575.1447.
+
m/z calcd for C19H16NO4S2 [M + H]+ 386.0515, found 386.0526.
2i (>99:1 Z/E, 103 mg, 90%, with 0.2 equiv of NaH), N-[(Z)-2-(4-
methylphenylsulfonyl)ethenyl]saccharin. White solid; mp 168−170
1
°C; Rf = 0.55 (hexanes:EtOAc, 1:1); H NMR (DMSO-d6) δ 2.41 (s,
3H), 6.91 (d, J = 8.4, 1H), 7.36 (d, J = 8.4, 1H), 7.48 (d, J = 8.3, 2H),
7.80 (d, J = 8.3, 2H), 8.08 (td, J = 7.5, J = 0.6, 1H), 8.14 (td, J = 7.6, J
= 1.0, 1H), 8.23 (d, J = 7.5, 1H), 8.43 (d, J = 7.4, 1H); 13C NMR
(DMSO-d6) δ 21.1, 122.0, 122.0, 125.9, 126.1, 127.9, 130.0, 135.1,
135.8, 136.4, 136.5, 136.6, 145.1, 156.4; IR 1753, 1618; HRMS (ESI+)
3g (>99:1 E/Z, 580 mg, 82%), (S)-N-[(E)-2-(4-
methylphenylsulfonyl)ethenyl]-2,10-camphorsultam. White solid;
mp 97−98 °C; Rf = 0.68 (CH2Cl2/MeOH, 99.5:0.5); 1H NMR
(CDCl3) δ 0.95 (s, 3H), 1.02 (s, 3H), 1.31 (t, J = 8.3, 1H), 1.43 (t, J =
9.1, 1H), 1.81 (dd, J = 12.9, J = 7.9, 1H), 1.90−1.95 (m, 3H), 2.07−
2.15 (m, 1H), 2.41 (s, 3H), 3.31 (d, J = 13.9, 1H), 3.36 (d, J = 13.8,
1H), 3.48 (dd, J = 7.8, J = 4.8, 1H), 5.70 (d, J = 13.6, 1H), 7.30 (d, J =
8.2, 2H), 7.51 (d, J = 13.6, 1H), 7.74 (d, J = 8.2, 2H); 13C NMR
(CDCl3) δ 20.0, 20.4, 21.7, 26.8, 32.3, 35.9, 44.7, 48.1, 50.3, 50.7, 64.5,
110.7, 127.4, 130.0, 134.8, 139.0, 144.0; IR 1609; HRMS m/z calcd for
+
m/z calcd for C16H14NO5S2 [M + H]+ 364.0308, found 364.0314.
Purification by column chromatography was not necessary (and it is
not recommended, because of partial decomposition).
General Procedure for the Addition of Imides, Azinones,
Nucleosides, and Sultams to Tosylacetylene, To Obtain 3.
Tosylacetylene (1.2 equiv) and the corresponding substrate were
dissolved in CH3CN (0.1 M) under a N2 atmosphere. DMAP was then
added, and the reaction was stirred at 20 °C or 50 °C (see Table 3)
until TLC analysis indicated complete disappearance of the Z isomer
(usually 1 or 2 days). The solvent was removed under reduced
pressure, and the residue was dissolved in CH2Cl2. The organic layer
was washed with 0.5 M aqueous HCl and brine, dried over anhyd
MgSO4, filtered, and concentrated. Purification by flash column
chromatography on silica gel afforded pure 3.
+
C19H26NO4S2 [M + H]+ 396.1298, found 396.1293.
3h (>99:1 E/Z, 56 mg, 97%), N-[(E)-2-(4-methylphenylsulfonyl)-
ethenyl]-1,8-naphthosultam. White solid; mp 181−183 °C; Rf = 0.30
1
(CH2Cl2); H NMR (CDCl3) δ 2.44 (s, 3H), 6.72 (d, J = 13.9, 1H),
7.18 (m, 1H), 7.35 (d, J = 8.4, 2H), 7.66−7.68 (m, 2H), 7.80−7.86
(m, 1H), 7.84 (d, J = 8.4, 2H), 7.90 (d, J = 13.9, 1H), 8.02 (d, J = 7.3,
1H), 8.18 (d, J = 8.4, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 21.8,
105.6, 112.5, 118.8, 120.5, 121.4, 127.6, 128.6, 128.9, 129.5, 130.1,
130.6, 131.0, 132.3, 132.5, 138.5, 144.4; IR 1622; HRMS m/z calcd for
3a (>99:1 E/Z, 1.36 g, 90%), 1-N-[(E)-2-(4-methylphenylsulfonyl)-
ethenyl]succinimide. White solid; mp 192−194 °C; Rf = 0.51
+
C19H16NO4S2 [M + H]+ 386.0515, found 386.0525.
1
(hexanes/EtOAc, 20:80); H NMR (CDCl3) δ 2.43 (s, 3H), 2.83 (s,
N-[(E)-2-(4-Methylphenylsulfonyl)ethenyl]saccharin, 3i. A solu-
tion of DMAP (4 mg, 0.03 mmol) and 2i (228 mg, 0.627 mmol) in
CH3CN (6.3 mL) was stirred overnight at rt. The solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography (hexanes:EtOAc, 1:1) to afford 3i (205 mg,
90%, >99:1 E/Z) as a White solid: mp 208−209 °C; Rf = 0.54
(hexanes/EtOAc, 1:1); 1H NMR (CDCl3) δ 2.45 (s, 3H), 6.93 (d, J =
4H), 7.33 (d, J = 8.2, 2H), 7.58 (d, J = 14.2, 1H), 7.78 (d, J = 14.2,
1H), 7.78 (d, J = 8.2, 2H); 13C NMR (CDCl3) δ 21.8, 27.9, 121.1,
127.8, 128.5, 130.1, 137.7, 144.7, 174.1; IR 1731, 1622; HRMS m/z
calcd for C13H14NO4S+ [M + H]+ 280.0638, found 280.0632.
3b (>99:1 E/Z, 1.47 g, 98%), N-[(E)-2-(4-methylphenylsulfonyl)-
ethenyl]phthalimide. White solid; mp 186−187 °C; Rf = 0.77
(CH2Cl2/MeOH, 99:1); 1H NMR (CDCl3) δ 2.43 (s, 3H), 7.34 (d, J
8831
dx.doi.org/10.1021/jo501647w | J. Org. Chem. 2014, 79, 8826−8834

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14.3, 1H), 7.36 (d, J = 8.0, 2H), 7.83 (d, J = 8.0, 2H), 7.92−8.00 (m,
4H), 8.17 (d, J = 7.3, 1H); 13C NMR (CDCl3) δ 21.8, 118.0, 121.6,
126.0, 126.5, 127.0, 127.9, 130.2, 135.4, 136.3, 137.3, 137.6, 144.9,
156.2; IR 1739, 1623; HRMS m/z calcd for C16H14NO5S2+ [M + H]+
364.0308, found 364.0304.
General Procedure for the Preparation of 4. LiHMDS (1.5
equiv, 1.0 M in THF) was added dropwise to a solution of the
substrate in THF (0.1 M) under a N2 atmosphere at 0 °C. (Z)-1,2-
Bis(phenylsulfonyl)ethene (1.5 equiv) was then slowly added, and the
reaction was stirred until TLC analysis indicated complete
consumption of the starting material (a few minutes). The reaction
mixture was diluted with H2O and extracted with EtOAc. The
combined organic layers were washed with brine, dried over anhyd
MgSO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel.
4a (93:7 Z:E, 97 mg, 95%). Data for chromatographically pure 1-
[(Z)-2-(phenylsulfonyl)ethenyl]succinimide, 4a. White solid; mp
118−120 °C; Rf = 0.48 (hexanes/EtOAc, 20:80); 1H NMR
(CDCl3) δ 2.88 (s, 4H), 6.44 (d, J = 9.0, 1H), 6.58 (d, J = 9.0,
1H), 7.54−7.59 (m, 2H), 7.63−7.70 (m, 1H), 7.92−7.97 (m, 2H); 13C
NMR (CDCl3) δ 28.9, 126.6, 128.2, 129.4, 129.7, 134.3, 139.8, 174.5;
IR 1730, 1637; HRMS (ESI+) m/z calcd for C12H12NO4S+ [M + H]+
266.0482, found 266.0486.
4j (94:6 Z/E, 155 mg, 95%). Data for chromatographically pure
1-[(Z)-2-(phenylsulfonyl)ethenyl]-2-pyrrolidinone. White solid; mp
116−118 °C; Rf = 0.52 (CH2Cl2/MeOH, 99:1); 1H NMR (CDCl3) δ
2.08−2.18 (m, 2H), 2.50 (t, J = 8.1, 2H), 4.22 (t, J = 7.3, 2H), 5.58 (d,
J = 10.7, 1H), 7.19 (d, J = 10.7, 1H), 7.53−7.59 (m, 2H), 7.61−7.66
(m, 1H), 7.91−7.96 (m, 2H); 13C NMR (CDCl3) δ 18.3, 29.9, 48.9,
108.2, 126.9, 129.3, 130.8, 133.3, 142.6, 175.8; IR 1721, 1603; HRMS
(ESI+) m/z calcd for C12H14NO3S+ [M + H]+: 252.0689, found:
252.0691.
129.5, 133.7, 140.7, 173.9; IR 1715, 1621, 1365, 1132; HRMS (ESI+)
m/z calcd for C12H12NO4S+ [M + H]+ 266.0482, found 266.0485.
5j (>99:1 E/Z, 570 mg, 91%), 1-[(E)-2-(phenylsulfonyl)ethenyl]-2-
pyrrolidinone. White solid; mp 143−145 °C; Rf = 0.39 (CH2Cl2/
1
MeOH, 99:1); H NMR (CDCl3) δ 2.09−2.17 (m, 2H), 2.52 (t, J =
8.2, 2H), 3.47 (t, J = 7.3, 2H), 5.72 (d, J = 13.7, 1H), 7.46−7.52 (m,
2H), 7.54−7.59 (m, 1H), 7.84−7.87 (m, 2H), 8.05 (d, J = 13.7, 1H);
13C NMR (CDCl3) δ 17.5, 30.8, 45.2, 110.2, 127.2, 129.3, 133.1, 136.2,
142.0, 174.4; IR 1727, 1610; HRMS (ESI+) m/z calcd for
C12H14NO3S+ [M + H]+: 252.0689, found: 252.0693.
5k (>99:1 E/Z, 133 mg, 90%), 5-tert-butyldiphenylsilyloxymethyl-
N-[(E)-2-(phenylsulfonyl)ethenyl]-2-pyrrolidinone. White solid; mp
1
164−165 °C; Rf = 0.73 (CH2Cl2/EtOAc, 1:1); H NMR (CDCl3) δ
0.99 (s, 9H), 2.16−2.22 (m, 2H), 2.41−2.50 (m, 1H), 2.74 (dt, J =
17.9, J = 10.3, 1H), 3.57 (dd, J = 10.9, J = 2.9, 1H), 3.76 (dd, J = 10.9, J
= 4.2, 1H), 3.84−3.91 (m, 1H), 5.75 (d, J = 14.0, 1H), 7.33−7.39 (m,
4H), 7.40−7.45 (m, 2H), 7.47−7.52 (m, 4H), 7.53−7.59 (m, 3H),
7.78−7.81 (m, 2H), 7.99 (d, J = 14.0, 1H); 13C NMR (CDCl3) δ 19.2,
22.0, 26.8, 30.5, 58.5, 62.8, 110.4, 127.2, 128.1, 128.1, 129.2, 129.9,
130.2, 130.3, 132.1, 132.7, 132.9, 135.5, 135.5, 135.6, 142.2, 175.1; IR
1730, 1612; HRMS m/z calcd for C29H34NO4SSi+ [M + H]+:
520.1972, found 520.1976.
5l (>99:1 E/Z, 170 mg, 96%), (S)-4-benzyl-3-[(E)-2-
(phenylsulfonyl)ethenyl]-1,3-oxazolidin-2-one. White solid; mp
1
162−163 °C; Rf = 0.63 (CH2Cl2/MeOH, 99:1); H NMR (CDCl3)
δ 2.83 (dd, J = 14.0, J = 7.9, 1H), 3.09 (dd, J = 14.0, J = 4.1, 1H),
4.23−4.30 (m, 2H), 4.31−4.36 (m, 1H), 5.93 (d, J = 13.9, 1H), 7.10
(d, J = 8.1, 2H), 7.20−7.30 (m, 3H), 7.52−7.57 (m, 2H), 7.59−7.64
(m, 1H), 7.82 (d, J = 13.9, 1H), 7.89 (d, J = 8.1, 2H); 13C NMR
(CDCl3) δ 37.2, 55.7, 67.4, 110.7, 127.4, 127.9, 129.3, 129.3, 129.4,
133.3, 134.1, 136.6, 141.8, 154.2; IR 1749, 1614; HRMS m/z calcd for
C18H18NO4S+ [M + H]+: 344.0951, found: 344.0954.
4k (90:10 Z/E, 109 mg, 90%). Data for chromatographically pure
5-tert-butyldiphenylsilyloxymethyl-N-[(Z)-2-(phenylsulfonyl)-
ethenyl]-2-pyrrolidinone. White solid; mp 160−162 °C; Rf = 0.80
Removal of the Tsv Group. Method A. A suspension of
dodecanethiol (1.5 equiv) and NaH (3.0 equiv) in CH3CN was added
to a solution of the protected substrate in anhyd CH3CN (0.1 M). The
resulting mixture was stirred at the temperature shown in Table 4 until
TLC indicated complete consumption of the starting material. The
reaction was quenched with water, neutralized with 0.5 M aqueous
HCl, and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel.
Removal of the Tsv Group. Method B. A suspension of sodium
1-dodecanethiolate (1.2 equiv) in CH3CN was added to a solution of
the protected substrate in anhyd CH3CN (0.1 M). TLC indicated
complete consumption of the starting material after stirring at 0 °C or
rt for a few minutes (see Table 4). The reaction was quenched with
water, neutralized with 0.5 M aqueous HCl, and extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried
over MgSO4, filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel.
Removal of the Tsv and Bsv Groups. Method C. Pyrrolidine
(2.0 equiv) was added to a solution of the protected substrate in anhyd
CH3CN (0.1 M), and the mixture was stirred at rt or 55 °C (see Table
4) until TLC indicated complete consumption of the starting material.
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel.
Removal of the Tsv and Bsv Groups. Method D. Pyrrolidine
(2.0 equiv) and NaH (0.3 equiv) were added to a solution of the
protected substrate in anhyd CH3CN (0.1 M). The mixture was stirred
at 55 °C until TLC indicated complete consumption of the starting
material. The solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography on silica gel.
1
(CH2Cl2/EtOAc, 1:1); H NMR (CDCl3) δ 1.00 (s, 9H), 2.09−2.33
(m, 2H), 2.45 (ddd, J = 17.9, J = 10.2, J = 2.1, 1H), 2.80 (dt, J = 17.9, J
= 10.2, 1H), 3.58 (dd, J = 11.4, J = 1.9, 1H), 3.87 (dd, J = 11.4, J = 2.2,
1H), 5.09 (br d, J = 8.9, 1H), 5.40 (d, J = 10.8, 1H), 6.98 (d, J = 10.8,
1H), 7.31−7.36 (m, 2H), 7.37−7.47 (m, 6H), 7.48−7.52 (m, 3H),
7.54−7.57 (m, 2H), 7.72−7.76 (m, 2H); 13C NMR (CDCl3) δ 19.1,
21.5, 26.9, 30.2, 59.8, 64.3, 109.3, 126.9, 127.8, 127.9, 129.2, 130.0,
130.0, 132.6, 132.9, 133.3, 135.7, 135.8, 141.9, 176.6; IR 1713, 1605;
HRMS m/z calcd for C29H34NO4SSi+ [M + H]+: 520.1972, found
520.1976.
4l (94:6 Z/E, 139 mg, 90%). Data for chromatographically pure
(S)-4-benzyl-3-[(Z)-2-(phenylsulfonyl)ethenyl]-1,3-oxazolidin-2-one.
1
White solid; mp 119−121 °C; Rf = 0.76 (CH2Cl2/MeOH, 99:1); H
NMR (CDCl3) δ 2.64 (dd, J = 13.3, J = 10.3, 1H), 3.58 (dd, J = 13.3, J
= 3.4, 1H), 4.21−4.23 (m, 2H), 5.50 (m, 1H), 5.61 (d, J = 10.8, 1H),
7.02 (d, J = 10.8, 1H), 7.23−7.27 (m, 1H), 7.29−7.37 (m, 4H), 7.52−
7.58 (m, 2H), 7.60−7.66 (m, 1H), 7.94−7.98 (m, 2H); 13C NMR
(CDCl3) δ 36.4, 57.4, 66.2, 109.3, 127.1, 127.3, 128.9, 129.4, 129.8,
130.0, 133.7, 135.0, 141.6, 155.6; IR 1762, 1617; HRMS m/z calcd for
C18H18NO4S+ [M + H]+: 344.0951, found 344.0954.
General Procedure for the Preparation of 5. NaH (1.1 equiv)
and 15-crown-5 (1.5 equiv) were added to a solution of the substrate
in THF (0.1 M) under a N2 atmosphere at 0 °C. (E)-1,2-
Bis(phenylsulfonyl)ethene (which is rather insoluble in most solvents,
1.3 equiv) was then added in portions, and the reaction was stirred at
rt until TLC analysis indicated complete consumption of the starting
material (around 4 h). The reaction mixture was diluted with H2O and
extracted with CH2Cl2. The combined organic fractions were washed
with brine, dried over anhyd MgSO4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel.
5a (>99:1 E/Z, 99 mg, 97%), 1-[(E)-2-(phenylsulfonyl)ethenyl]-
succinimide, 5a. White solid; mp 186−187 °C; Rf = 0.32 (hexanes/
EtOAc, 20:80); 1H NMR (CDCl3) δ 2.83 (s, 4H), 7.52−7.57 (m, 2H),
7.59 (d, J = 14.2, 1H), 7.60−7.65 (m, 1H), 7.82 (d, J = 14.2, 1H),
7.90−7.93 (m, 2H); 13C NMR (CDCl3) δ 27.9, 121.0, 127.8, 128.9,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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The Journal of Organic Chemistry
Article
DIPEA), see: (a) Mayr, H.; Lakhdar, S.; Maji, B.; Ofial, A. R. Beilstein J.
Org. Chem. 2012, 8, 1458−1478. (b) De Rycke, N.; Couty, F.; David,
O. R. P. Chem.Eur. J. 2011, 17, 12852−12871. (c) Baidya, M.; Mayr,
H. Chem. Commun. 2008, 1792−1794. (d) Aggarwal, V. K.; Emme, I.;
Fulford, S. Y. J. Org. Chem. 2003, 68, 692−700.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: amcosta@ub.edu.
*E-mail: jvilarrasa@ub.edu.
(9) We attribute this fact to the higher tendency of DABCO to be
involved in the concomitant formation of a tosylacetylene dimer (Ts−
Notes
The authors declare no competing financial interest.
3
CC−CHCH−Ts, δ 6.72 and 6.93, J = 15.4 Hz, which we have
confirmed by blank experiments with Ts−CCH and catalytic
amounts of DABCO) and subsequent additions, including polymer-
ization, which also makes the separation of the desired product more
difficult. There is only one precedent of a similar dimerization:
(a) Sardari, S.; Khalaj, V.; Khomeini, M. M.; Azerang, P. U.S. Patent
2013 8,569,361B1. By contrast, dimerizations of propynoate esters are
much better known: (b) Ramachandran, P. V.; Rudd, M. T.; Reddy,
M. V. R. Tetrahedron Lett. 2005, 46, 2547−2549 and references cited
therein. (c) Reference 2 (and ref 10 cited therein).
ACKNOWLEDGMENTS
■
Grants CTQ2009-13590 (Spanish Government, Madrid),
2009SGR825 (AGAUR), and CTQ2012-39230 are acknowl-
edged. David de Vicente carried out preliminary experiments
during his Masters Thesis. L.M. holds a UB studentship.
REFERENCES
■
(1) For reviews, see: (a) Back, T. G.; Clary, K.-N.; Gao, D. Chem.
Rev. 2010, 110, 4498−4553. (b) Zhu, Q.; Lu, Y. Austral. J. Chem. 2009,
62, 951−955. (c) Back, T. G. Tetrahedron 2001, 57, 5263−5301. For
reviews of organocatalytic conjugate additions (with sections on vinyl
sulfones), see: (d) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun.
(10) (Z)-Bis(phenylsulfonyl)ethene (purchased from TCI Europe)
was nearly a 98:2 Z/E mixture by 1H NMR. Isomer E (also purchased
from TCI Europe) was >99% pure. There are precedents of
stereospecific reactions of these two reagents with nucleophiles. See:
(a) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006−4014. (5-
iodomethyl-2-pyrrolidinone). For reaction with 1,3-oxazolidine-2-
thiones or a derivative of 1,3-oxazine-2-thione, see: (b) Girniene, J.;
́
2007, 3123−3135. (e) Almasi, D.; Alonso, D. A.; Najera, C.
Tetrahedron: Asymmetry 2007, 18, 299−365. For pioneering additions
of amines to conjugate acetylenic sulfones, see: (f) Truce, W. E.;
Brady, D. G. J. Org. Chem. 1966, 31, 3543−3550. (g) Stirling, C. J. M.
J. Chem. Soc. 1964, 5863−5869.
̌
Tardy, S.; Tatibouet, A.; Sackus, A.; Rollin, P. Tetrahedron Lett. 2004,
̈
45, 6443−6446. (c) Tardy, S.; Tatibouet, A.; Rollin, P.; Dujardin, G.
̈
Synlett. 2006, 45, 1425−1427. (d) Leconte, N.; Silva, S.; Tatibouet, A.;
Rauter, A. P.; Rollin, P. Synlett 2006, 301−305.
̈
(2) For the conjugate additions of CONHCO and CONH groups to
methyl propynoate (methyl propiolate), see: Mola, L.; Font, J.; Bosch,
L.; Caner, J.; Costa, A. M.; Etxebarría-Jardí, G.; Pineda, O.; de Vicente,
D.; Vilarrasa, J. J. Org. Chem. 2013, 78, 5832−5842 and references
cited therein..
(3) The tosvinyl group was abbreviated as Tsv in: Wuts, P. G. M.;
Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; Wiley:
Hoboken, 2007; p 899.
(4) (a) Arjona, O.; Iradier, F.; Medel, R.; Plumet, J. J. Org. Chem.
1999, 64, 6090−6093. (b) Arjona, O.; Medel, R.; Rojas, J. K.; Costa, A.
M.; Vilarrasa, J. Tetrahedron Lett. 2003, 44, 6369−6372. (c) Medel, R.;
Monterde, M. I.; Plumet, J.; Rojas, J. K. J. Org. Chem. 2005, 70, 735−
738. Also see: (d) Medel, R.; Plumet, J. Synthesis 2006, 1339−1342.
(5) The updated summary is that thiols, at rt, with only a trace
amount of Et3N afford almost exclusively Z-Tsv-protected compounds,
whereas sodium thiolates give rise almost exclusively to E-Tsv
derivatives. In general, conjugate additions to tosylacetylene afford
the kinetically controlled cis products (isomers Z) via trans addition,
whereas isomerization via addition−elimination can lead to the
thermodynamically more stable E isomers.
(11) Similarly, we prepared stereopure samples of Z-Bsv and E-Bsv
derivatives of 1f (that is, compounds 4f and 5f), to confirm that the
procedure is general and can be applied to nucleosides. Results not
included for simplicity’s sake.
(12) (a) Bell, R. P.; Higginson, W. C. E. Proc. R. Soc. A 1949, 197,
141−159. (b) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456−463.
(13) Reactions of saccharine with dimethyl acetylenedicarboxylate
and related triple bonds have been reported: (a) Yavari, I.; Alizadeh,
A.; Anary-Abbasinejad, M. Tetrahedron Lett. 2002, 43, 9449−9452.
(b) Maghsoodlou, M. T.; Heydari, R.; Habibi-Khorassani, S. M.;
Hazeri, N.; Lashkari, M.; Rostamizadeh, M.; Sajadikhah, S. S. Synth.
Commun. 2011, 41, 569−578. (c) Shajari, N.; Ramazani, A. Asian J.
Chem. 2007, 19, 1581−1583.
(14) For example, heating 2b with 0.5 equiv of DMAP, in CH3CN at
50 °C for 48 h, gave a 10:90 mixture of 2b and 3b.
1
(15) Spectral data for 6: H NMR (DMSO-d6, 400 MHz) δ 2.41 (s,
3H), 3.29 (s, 6H), 7.16 (d, J = 7.4, 2H), 7.50 (d, J = 7.9, 2H), 7.54−
7.59 (m, 3H), 7.60−7.66 (m, 1H), 7.75 (d, J = 13.8, 1H), 7.83 (d, J =
7.9, 2H), 8.15 (d, J = 13.8, 1H), 8.54 (d, J = 7.5, 2H); 13C NMR
(DMSO-d6, 100.6 MHz) δ 21.1, 40.6, 108.1, 119.1, 119.9, 122.4, 127.3,
130.2, 130.9, 131.5, 134.9, 137.3, 139.4, 140.9, 144.8, 145.3, 156.7,
167.8; HRMS (ESI+) m/z calcd for C16H19N2O2S+ [M]+ 303.1162,
found: 303.1165.
(6) Additions to tosylacetylene: (a) Back, T. G.; Parvez, M.; Wulff, J.
E. J. Org. Chem. 2003, 68, 2223−2233 (amides). (b) Dransfield, P. J.;
Dilley, A. S.; Wang, S.; Romo, D. Tetrahedron 2006, 62, 5223−5247
(protection of a cyclic urea, viz., imidazol-2-one). (c) Gao, D.; Parvez,
M.; Back, T. G. Chem.Eur. J. 2010, 16, 14281−14284 (amides).
(d) Gao, D.; Back, T. G. Chem.Eur. J. 2012, 18, 14828−14840
(amides). (e) Khong, S.; Kwon, O. J. Org. Chem. 2012, 77, 8257−8267
(sulfonamides). For additions to other sulfonylacetylenes: (f) Hase-
gawa, K.; Hirooka, S.; Kawahara, H.; Nakayama, A.; Ishikawa, K.;
Takeda, N.; Mukai, H. Bull. Chem. Soc. Jpn. 1978, 51, 1805−1810
(intramolecular Michael addition of ureas). (g) Xiang, J.; Jiang, W.;
Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1997, 119, 4123−4129
(phthalimide + phenylethynyl trifluoromethyl sulfone). (h) Back, T.
G.; Wulff, J. E. Chem. Commun. 2002, 1710−1711 (amides to alkynyl
p-tolyl sulfones). For additions followed by rearrangements, see:
(i) Weston, M. H.; Parvez, M.; Back, T. G. J. Org. Chem. 2010, 75,
5402−5405. (j) Tayama, E.; Igarashi, T.; Iwamoto, H.; Hasegawa, E.
Org. Biomol. Chem. 2012, 10, 339−345 and references therein.
(7) Dransfield, P. J.; Wang, S.; Dilley, A.; Romo, D. Org. Lett. 2005, 7,
1679−1682.
(16) Tertiary amines and the DMAP/tosylacetylene adducts are not
basic enough to significantly deprotonate lactam CONH groups, so
the conjugate addition reactions do not progress. When the lactam
anions are generated with strong bases and tosylacetylene is added,
proton exchanges occur to give the starting lactams (no reaction) and
tosylacetylide, Ts−CC−, which polymerizes (also see ref 9).
(17) We carried out one experiment of this type. We treated the
sodium salt of butyrolactam (1j) with 6 (E-DMAP+CHCHTs
Sacc−; see Scheme 3) in CH3CN at 25 °C. The reaction was complete
in less than 30 min. Compound 3j was isolated in ≥90% yield.
1
(18) The N,S-acetals (thiohemiaminals) were detected by H NMR
of the crude reaction mixtures. Characteristic signals (for the
thiohemiaminal derived from 3b and dodecanethiol, CDCl3, 400
MHz): δ 3.56 (dd, J = 14.9, J = 2.6, 1H), 4.67 (dd, J = 14.9, J = 11.7,
1H), 5.71 (dd, J = 11.7, J = 2.6, 1H).
(19) Isolation and characterization of the aminal (addition product)
from 4j and pyrrolidine as follows. Pyrrolidine (67 μL, 0.81 mmol)
was added to a solution of 4j (51 mg, 0.20 mmol) in CH3CN (2 mL).
(8) For reviews and relevant works on the relative nucleophilicity of
neutral nitrogen bases (DABCO > DMAP ≫ Et3N ≫ DIPEA) and on
their basicities in aqueous media (DABCO < DMAP < Et3N <
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After the reaction was stirred for 4.5 h at rt, TLC indicated that the
starting material had disappeared to give a less polar product. The
solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (CH2Cl2/
MeOH 99:1) to give the corresponding aminal, 7 (61 mg, 0.19 mmol,
1
92%): oil; Rf = 0.20 (CH2Cl2/MeOH 99:1); H NMR (CDCl3, 400
MHz) δ 1.59−1.71 (m, 4H), 1.71−1.81 (m, 1H), 1.82−1.92 (m, 1H),
2.19−2.29 (m, 2H), 2.39−2.46 (m, 2H), 2.48−2.54 (m, 2H), 3.27−
3.36 (m, 2H), 3.48 (dd, J = 14.8, J = 3.3, 1H), 3.66 (dd, J = 14.8, J =
9.9, 1H), 4.89 (dd, J = 9.9, J = 3.3, 1H), 7.52−7.58 (m, 2H), 7.61−7.67
(m, 1H), 7.89−7.93 (m, 2H); 13C NMR (CDCl3, 100.6 MHz) δ 18.4,
23.5, 31.4, 44.5, 49.8, 55.6, 65.4, 128.4, 129.3, 134.0, 139.2, 176.0;
HRMS (ESI+) m/z calcd for C16H23N2O3S+ [M + H]+ 323.1424,
found: 323.1464.
(20) (a) Review: Alonso, D. A.; Naj
367−656. Also see: (b) Cabianca, E.; Cher
de Lucchi, O. Synlett 2001, 1962−1964. (c) Cabianca, E.; Cher
Rollin, P.; Tatibouet, A.; de Lucchi, O. Tetrahedron Lett. 2002, 43,
́
era, C. Org. React. 2008, 72,
y, F.; Rollin, P.; Cossu, S.;
y, F.;
́
́
̈
585−587. (d) Chery, F.; Desroses, M.; Tatibouet, A.; de Lucchi, O.;
̈
Rollin, P. Tetrahedron 2003, 59, 4563−4572. (e) Chery, F.; Pillard, C.;
Tatibouet, A.; de Lucchi, O.; Rollin, P. Tetrahedron 2006, 62, 5141−
̈
5151.
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