Nucleophile-catalyzed additions to activated triple bonds. protection of lactams, imides, and nucleosides with MocVinyl and related groups

Article abstract of DOI:10.1021/jo4006409

Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or

Full text of DOI:10.1021/jo4006409

Featured Article
pubs.acs.org/joc
Nucleophile-Catalyzed Additions to Activated Triple Bonds.
Protection of Lactams, Imides, and Nucleosides with MocVinyl and
Related Groups
Laura Mola, Joan Font, Lluís Bosch, Joaquim Caner, Anna M. Costa,* Gorka Etxebarría-Jardí,
Oriol Pineda, David de Vicente, and Jaume Vilarrasa*
̀
Departament de Química Organica, Facultat de Química, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-
one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the
electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-
butyn-2-one, N-propynoylmorpholine, or N-methoxy-N-methylpropynamide
in the presence of many potential catalysts were examined. DABCO and,
second, DMAP appeared to be the best (highest reaction rates and E/Z
ratios), while RuCl3, RuClCp*(PPh3)2, AuCl, AuCl(PPh3), CuI, and
Cu2(OTf)2 were incapable of catalyzing such additions. The groups
incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we
name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties. Deprotections
were accomplished via exchange with good nucleophiles: the 1-dodecanethiolate anion turned out to be the most general and
efficient reagent, but in some particular cases other nucleophiles also worked (e.g., MocVinyl-inosines can be cleaved with
succinimide anion). Some structural and mechanistic details have been accounted for with the help of DFT and MP2
calculations.
Scheme 1. General Protection−Reaction(s)−Deprotection
Sequence for Heterocyclic CONH Groups
INTRODUCTION
■
The protection of the amide groups of the open-chain
carboxamides RCONHR′ is seldom needed in the total
synthesis of polyfunctional molecules since, from the point of
view of the retrosynthetic analysis, the robust amide bond is a
strategic bond that can be disconnected as soon as desired (that
is, it can be formed as late as desired). On the other hand, cyclic
amides (lactams, including unsaturated lactams such as 2-
pyridone), imides, cyclic carbamates (e.g., oxazolidin-2-ones),
and cyclic ureas (e.g., imidazolin-2-one and pyrimidin-2-one
derivatives), when embedded in alkaloids or in synthetic drugs,
as well as uracil, thymine, and their corresponding nucleosides,
very often do require protection of their reactive CONH
moiety. In fact, almost all of the examples found in Greene’s
book1 involve one or another of these types of heterocyclic
compounds.2 A representative sequence is shown in Scheme 1
with Boc as the PG, where (i) a cyclic CONH group is
converted into CONBoc, (ii) the desired reactions are carried
out (e.g., formation of a C−C bond at position α through
alkylation in a basic medium and/or a Pd-catalyzed C−C or
C−heteroatom coupling at a more remote position), and (iii)
the Boc group is finally removed by treatment with a Lewis acid
or with TFA. Other PGs have been used,1 but the example in
Scheme 1 is the most common.
(c); MorVinyl or Morv (d); and WeinVinyl or Weiv (e).
MocVinyl stands for 2-(methoxycarbonyl)ethen-1-yl, that is, a
methoxycarbonylvinyl group. BocVinyl stands for the analogous
tert-butoxycarbonylvinyl group. AcVinyl represents 3-oxo-1-
buten-1-yl (or simply acetylvinyl). MorVinyl is the 2-(4-
morpholinylcarbonyl)ethen-1-yl group, a 4-morpholinylcarbo-
nylvinyl substituent. Finally, WeinVinyl represents 2-(N-
methoxy-N-methylaminocarbonyl)ethen-1-yl, the group from
the Weinreb amide of the corresponding propenoic or acrylic
acid. Bioconjugation (ligation) of amides, imides, or related
compounds with electron-deficient alkynes would be another
potential application of the chemistry described here, although
it is outside the scope of the present work.
Here, we report an alternative set of electron-withdrawing
PGs for these heterocyclic CONH and CONHCO moieties
(see Scheme 1): MocVinyl or, if preferred for the sake of
simplification, Mov (a); BocVinyl or Bov (b); AcVinyl or Acv
Received: April 10, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
These groups can be introduced by the addition of the
CONH groups of lactams, imides, etc. to the triple bonds of
HCCCOOMe (methyl propynoate, or methyl propiolate,
which is a cheap, commercially available reagent), HC
CCOOt-Bu (tert-butyl propynoate), HCCCOMe (3-butyn-
2-one), HCCCON(CH2CH2)2O (N-propynoylmorpholine),
or HCCCON(OMe)Me (N-methoxy-N-methylpropyna-
mide). The advantages are that their presence can clearly be
observed via NMR spectroscopy (double bond) and their
removal can be generally effected via an addition−elimination
mechanism (exchange reactions), as explained below. In
principle, we did not consider acetylvinyl (Acv) a real or
practical group, due to the reactivity of its CO carbon atom.
Moreover, the MorVinyl and WeinVinyl groups, because of the
feasibility of their conversion into CHCHCOR and CH
CHCHO groups by reaction with organolithium or organo-
magnesium compounds and with DIBALH, respectively,3,4 may
have applications other than the simple role of protecting
groups. Nevertheless, these last three groups were included to
compare the reactivity of lactams, imides, and related
heterocyclic compounds with diverse electron-poor alkynes.
There are precedents of the addition of cyclic CONH groups
to activated terminal triple bonds,5 but the EWGs of the
adducts were not specifically conceived as PGs. On the other
hand, some applications have been found for the DMAP-
catalyzed additions to methyl propynoate.6,7 Here we provide a
generalization and update of these concepts that includes
unpublished work performed in our laboratory over the past
decade in connection with several Master and Ph.D. theses.
Table 1. Catalyzed Additions of 2-Pyrrolidinone (1) and
Succinimide (2) to Methyl Propynoate
a
base or
catalyst
(equiv)
sub-
entry strate
T
(°C)
time conv
adduct,
yield (%)
b
(h)
(%)
E/Z
1
2
3
4
5
1
1
1
1
1
70
20
20
20
20
15
15
2
0
50
DIPEA (1.0)
Et3N (1.0)
1a, 45
1a, 82
60:40
95:5
93:7
99:1
100
100
100
c
DMAP (0.5)
1
1a, 52
DABCO
0.2
1a, 98
d
(0.2)
6
2
2
2
2
2
2
2
2
70
20
20
20
20
20
20
20
4
0
20
7
NaH (0.2)
1
2a, 20
2a, 90
2a, 95
2a, 95
2a, 85
2a, 86
2a, 97
65:35
75:25
90:10
92:8
8
DIPEA (0.5)
Et3N (0.5)
4
100
100
100
100
100
100
9
0.5
0.8
0.3
0.2
0.2
10
11
12
13
DMAP (0.1)
DMAP (0.5)
DMAP (1.0)
97:3
97:3
DABCO
97:3
d
(0.2)
a
Standard conditions: 1 or 2 and the catalyst were dissolved in
CH3CN (0.1 M) under N2, and the activated triple bond (1.2 equiv)
was slowly added via syringe; stirring was maintained for the time
b
indicated; the isolated yields of isomers E + Z are given. E/Z ratios
c
were determined by 1H NMR. Dark (presumably polymeric) material
d
was also formed. In fact, 20 mol %, as only one of the N atoms is
RESULTS AND DISCUSSION
■
active.
We first studied the reaction of 2-pyrrolidinone (butyrolactam,
1) and of succinimide (2,5-pyrrolidinedione, 2), chosen as the
most simple examples of a cyclic amide and a CONHCO
substructure, respectively, with methyl propynoate (series a).
Without a base, neither 1 nor 2 reacted at rt or even on heating
to 70 °C (see Table 1, entries 1 and 6). A set of trisubstituted
nitrogen bases were examined as catalysts, ranging from the
toluene (2, which is only partially soluble, 20 mol % of
DABCO, 45 min, 90:10 E/Z).
It is worth noting that the methyl propynoate dimer (see
Scheme 2)10 was never a major product in the preceding
Scheme 2. Dimerization of Methyl Propynoate vs Formation
of 1a and 2a
i
quite basic but scarcely nucleophilic Pr2EtN (DIPEA) to the
moderately basic but highly nucleophilic 4-(dimethylamino)-
pyridine (DMAP) and to the less basic but most nucleophilic of
the set, 1,4-diazabicyclooctane (DABCO).8 The main products
were E/Z mixtures of the desired 1a and 2a, respectively, in
which the E isomer predominated. However, with 1 (with the
less acidic CONH group), the reactions were slower than with
2 (and than with all the other compounds studied here, see
below). In practice, in the case of 1 we had to add
stoichiometric or relatively large amounts of DIPEA, Et3N, or
DMAP (entries 2−4); otherwise, the conversions were too low
(results not included for the sake of simplicity). With large
amounts of DMAP, the percentage of dark, highly polar
byproducts increased more than the yield of 1a. DABCO (entry
5)9 appeared to be the most appropriate catalyst for the
conjugate addition of 1 to methyl propynoate. In the case of 2
(compare entries 7−13), the greater the nucleophilicity of the
additive (from DIPEA to DABCO) or the larger the amount of
DMAP, the faster the reaction rates and the higher the E/Z
ratios of 2a obtained. Other additives tested, Me3P, DBU, and
NHC,9 were less selective than DABCO and DMAP. The effect
of the solvents was not examined systematically, but we had
noted in preliminary experiments that the reactions were
slightly more rapid in polar solvents, such as CH3CN or DMF,
than in THF (2, 20 mol % of DABCO, 30 min, 95:5 E/Z) or
experiments. We detected this dimer by its characteristic NMR
spectra in some cases, but only as a minor compound. Since it is
well-known that DABCO and other catalysts favor its
formation,10 in fact, we confirmed by H NMR spectroscopy
1
that a 1:2 mixture of DABCO and HCCCOOMe in CD3CN
at rt, without adding any lactam or imide, immediately gave
such a dimer almost quantitatively, it may be deduced that in
the presence of a lactam- or imide-containing molecule, the first
adduct (Scheme 2) may react either with HCCCOOMe or
with the CONH/CONHCO group. The relative acidities of the
methyne proton of the triple bond (pKa ≈ 18.8) and the
amide/imide proton may be then crucial. As CONH/
CONHCO protons are more acidic (in water but, presumably,
B
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
a
Table 2. DABCO- and DMAP-Catalyzed Additions of 3−11 to Methyl Propynoate
entry
substrate
catalyst (equiv)
solvent
temp (°C)
time (h)
adduct, yield (%)
E/Z
1
3
4
DABCO (0.2)
DMAP (0.5)
DABCO (0.2)
DMAP (0.5)
DMAP (1.0)
DABCO (0.2)
DMAP (0.5)
DMAP (1.0)
DABCO (0.2)
DABCO (0.05)
DMAP (0.1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
20
20
20
20
20
20
20
20
20
0
0.2
1.0
0.2
0.8
0.2
0.2
0.3
0.2
0.2
0.7
1.0
72
3a, 95
4a, 97
4a, 88
5a, 99
5a, 99
5a, 97
6a, 96
6a, 99
>99:1
97:3
2
3
4
96:4
4
5
93:7
4
5
98:2
6
5
95:5
7
6
95:5
8
6
97:3
b
9
6
6a, 72
93:7
c
10
11
12
13
14
15
16
17
18
19
20
6
6a, 84
95:5
d
7
mixture
mixture
mixture
mixture
mixture
mixture
mixture
mixture
mixture
mixture
20
20
20
20
20
20
20
20
20
20
7a, 93
8a, 20
8a, 90
8a, 85
8a, 92
9a, 90
9a, 96
9a, 97
10a, 90
11a, 85
>99:1
80:20
86:14
91:9
8
8
DMAP (0.1)
DMAP (0.3)
DMAP (1.0)
DMAP (0.3)
DMAP (0.5)
DABCO (0.2)
DMAP (0.3)
DMAP (0.3)
4.0
1.2
0.1
1.0
0.5
0.5
1.0
1.2
8
8
>99:1
91:9
9
9
96:4
9
>99:1
91:9
10
11
90:10
a
Standard conditions: 3−9 and the catalyst were dissolved in CH3CN or CH3CN/CH2Cl2 (1:1) (see table), under N2, and methyl propynoate (1.2
equiv) was added via syringe; stirring was maintained at the temperature indicated. Most conversions are quantitative, unless otherwise mentioned;
b
c
the isolated yields of isomers E + Z are given. 20% of the (E)-O-substituted isomer was formed (3J = 12.2 Hz). 5% of the O-substituted isomer was
d
formed. Mixture of CH3CN and CH2Cl2 (1:1 v/v) in which protected nucleosides showed enhanced solubility.
in other polar solvents as well), the lactam/imide anions will
predominate over MeOOCCC−, so the dimer will be formed
in minor amounts and mainly at the end of the reaction, from
the remaining methyl propynoate.
not work at all either. Strong bases gave rise to non-
stereoselective additions (1.1 equiv of NaH in CH3CN, full
conversion, 60:40 E/Z of 2a). The best catalyst, of those
studied by us, was not a transition metal ion, a Lewis acid, or an
electrophile in general, but a good nucleophile (much less basic
than any trialkylamine), namely DABCO (Table 1).9
We also examined whether other transition-metal cations or
complexes with high affinity for triple bonds, such as
RuClCp*(PPh3 )2 , AuCl, AuCl(PPh3 ), CuI, and
Cu2(OTf)2·toluene, were capable or not of catalyzing the
conjugate additions of 1 and 2 (as well as that of oxazolidinone
3, see below) to methyl propynoate in the absence of bases.
The desired adducts were never observed in either CH3CN or
toluene.12 Some of these soft cations may generate acetylides13
(MCCCOOMe) and/or vinylidene complexes, but the
polarity of these intermediates does not seem appropriate for
nucleophile additions.
Compound 1a had previously been obtained as a 40:1 E/Z
mixture by a Ru(III)-catalyzed reaction between 2-pyrrolidi-
none (1) and methyl propynoate (in toluene at 100 °C for 15
h).11 Since, in addition to 3% of RuCl3·xH2O, 9% of DMAP,
9% of Bu3P, 15 mol % of K2CO3, and water or methanol were
added to the reaction flask,11 competition could have occurred
between Ru-, nucleophile-, and base-catalyzed processes. In our
experiments in toluene at 100 °C, RuCl3 did not cause the
conjugate addition in the absence of DMAP and Bu3P; on the
other hand, 15 mol % of K2CO3 alone gave a conversion of
70%, and 9 mol % of DMAP alone gave a conversion of 50%. In
short, RuCl3 is not an appropriate catalyst for the conjugate
additions of lactams to electron-poor alkynes.
As anticipated, 10 mol % of RuCl3·hydrate failed to bring
about the reaction of succinimide (2) with methyl propynoate
in refluxing CH3CN. Lewis acids such as BF3 or Sc(OTf)3 did
Once the conditions for the addition of a lactam and an
imide to electron-poor triple bonds were optimized, we
subjected a set of related substrates to these conditions. The
C
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
results are summarized in Table 2. Lactam 3, phthalimide (4),
Evans’ oxazolidinone 5 (taken as an example of a cyclic
carbamate), and 2-pyridone (6) were converted into the
expected addition products with excellent stereoselectivities
(Table 2, entries 1−10). In general, the greater the amount of
DMAP, the better the E selectivity obtained. The DABCO-
catalyzed processes also delivered products very quickly, in
excellent yields and with high stereoselectivities, with the
advantage that ≤0.2 equiv of the catalyst was required. With the
special case of 6 (2-pyridone/2-hydroxypyridine equilibrium),
DABCO gave also rise to minor O-alkylation products (entry
9); this can be remedied by carrying out the reaction with
smaller amounts of DABCO and at 0 °C (entry 10).
Thymidine derivative 7 (5′-O-Ac AZT) and inosine
derivatives 8−11 also yielded the expected products with
excellent conversions. In the case of 7, the E isomer was
obtained exclusively, with only 0.1 equiv of DMAP (entry 11).
For the inosine derivatives it was necessary to operate with at
least 1.0 equiv of DMAP to obtain E exclusively (entry 15).
Alternatively, 0.2 equiv of DABCO gave perfect diastereose-
lectivity (entry 18).
In short, the protecting group (E)-MocVinyl can quickly be
introduced at rt (or below) in the presence of ≤20 mol % of
DABCO or of substoichiometric amounts of DMAP. The
minor Z isomers that in some cases are formed concomitantly
do not interfere. This would not be the case if nearly equimolar
Z/E mixtures were always formed or if some substrates
produced Z isomers and others E isomers. As explained below,
there is no need for chromatographic separation or a
postreaction isomerization with further DABCO or DMAP,14
as the major E- and minor Z-stereoisomers can be removed
together later.
B3LYP/6-31+G(d)] with nearly identical results. In the case
of (E)-6a, where the calculations (Supporting Information)
suggest that its conformer (E)-6a′ has practically identical
energy, we have drawn both species (and the chemical shifts are
probably means of values for both conformers). The same is
true of the case (E)-7a/(E)-7a′, for which the calculations were
carried out with models (N-Me derivative), and in the case of
8a (where the calculated N-Me derivative is a model of 8a−
11a). The larger than usual chemical shifts of the olefin protons
of the MocVinyl groups, due to the well-known anisotropy of
the lactam or imide CO groups in close vicinity to some of
these protons, are worthy of note.
The conjugate or Michael-type addition reactions worked
equally well (see Table 3) with other electron-deficient triple
bonds such as tert-butyl propynoate (series b, entries 1−5), 3-
butyn-2-one (series c, entries 6−12), N-propynoylmorpholine
(series d, examples of entries 13−17), or N-methoxy-N-
methylpropynamide (series e, entries 18−20). For propyna-
mides d and e the reactions were slower but feasible; heating
was sometimes necessary, as anticipated assuming that the
CON(CH2CH2)2O and CON(OMe)Me groups (entries 13−
20) are weaker EWGs than ester or carbonyl groups. In general,
the tendency of series b−e to give mainly stereoisomers E is
similar to that noted for series a.
As most reactions in Tables 1−3 were very rapid, while the
resulting E/Z mixtures were not quickly converted into
stereopure E isomers or equilibrated by stirring them for a
few hours with DMAP, the E/Z ratios are not a consequence of
the final isomerization of the adducts in the reaction flasks.
They seem to have a kinetic origin or depend on the relative
stabilities of preceding reaction intermediates. In fact,
nucleophilic catalysts such as DABCO and DMAP (weaker
bases than trialkylamines, as is known) are the most efficient.
Thus, the main mechanism may involve allenolate zwitterions
as intermediates (see Scheme 3, which complements Scheme 2,
The NMR data for the addition products proved to be
diagnostic, as anticipated (Figure 1). This is an advantage of
Scheme 3. Mechanistic Proposal
Figure 1. Representative NMR data in CDCl3.
this PG, since its introduction and removal can be simply
evaluated by 1H NMR. Figure 1 shows representative
parameters for the double bond of a selection of MocVinyl
groups (see the Experimental Section and the Supporting
Information for data of other compounds). The δH values of
and the Supporting Information for DFT and MP2//DFT
calculations of the two minima located; in these minimum
energy structures the CCC bond angles of the allene moieties
are not linear, which can be explained by the partial negative
charge, due to the resonance, on the allene central carbon
atom). These intermediates take protons from the CONH- or
CONHCO-containing substrates. After the addition of the
lactam or imide anion, a small rotation around the C(sp3)−
3
the CH doublets of the major E isomers (with standard JHH
values) are clearly larger than those of the corresponding Z
isomers. Only the most stable conformers are depicted in
Figure 1. These are the lowest energy conformers predicted at
three different levels of theory [B3LYP/6-31+G(d), MP2/6-
31+G(d)//B3LYP/6-31+G(d), and MP2/6-311+G(d,p)//
D
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
a
Table 3. Representative Reactions of Lactams, Imides, and Related Compounds with Other Electron-Deficient Alkynes
entry
starting compds
catalyst (equiv)
solvent
temper. (°C)
time (h)
adduct, yield (%)
E/Z
1
1 + b
3 + b
4 + b
6 + b
10 + b
1 + c
5 + c
8 + c
8 + c
9 + c
10 + c
11 + c
2 + d
6 + d
6 + d
6 + d
7 + d
6 + e
7 + e
8 + e
DABCO (0.2)
DABCO (0.2)
DMAP (0.2)
DABCO (0.2)
DMAP (0.3)
DABCO (0.2)
DABCO (0.2)
CH3CN
CH3CN
CH3CN
CH3CN
20
20
20
20
20
20
20
20
20
20
20
20
20
80
20
20
80
80
80
80
0.2
0.2
0.3
0.2
0.8
0.8
0.2
24
2
1b, 98
3b, 90
4b, 96
6b, 92
10b, 91
99:1
>99:1
>99:1
93:7
2
3
4
b
5
mixture
CH3CN
CH3CN
mixture
mixture
mixture
mixture
mixture
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
mixture
94:6
c
6
1c, 75
>99:1
>99:1
c
7
5c, 75
8
8c, 20
8c, 93
9c, 97
10c, 97
11c, 90
2d, 92
6d, 88
6d, 85
9
DMAP (0.1)
DMAP (0.1)
DMAP (0.1)
DMAP (0.1)
DABCO (0.2)
DMAP (0.1)
DMAP (1.0)
DABCO (0.2)
DMAP (0.1)
DMAP (0.1)
DMAP (0.1)
DABCO (0.2)
>99:1
93:7
10
11
12
13
14
15
16
17
18
19
20
1
1
91:9
1
97:3
2.5
7
93:7
>99:1
>99:1
91:9
24
4
c
6d, 80
3
7d, 95
6e, 85
7e, 90
8e, 80
>99:1
>99:1
>99:1
91:9
7
12
6
a
Standard conditions: 1−11 and the catalyst were dissolved in the corresponding solvent (0.1 M) under N2; the activated triple bond (1.2 equiv)
was added via syringe and stirring was maintained for the time indicated; conversions were quantitative unless otherwise is mentioned; the isolated
b
yields of isomers E+Z are given. Mixture of CH3CN and CH2Cl2 (1:1, v/v) in which these protected nucleosides showed enhanced solubility at rt.
c
Plus 10−15% of O-substituted product of configuration E and other byproducts.
C(sp2) bond (principle of minimum motion) would place Nu
in the appropriate stereoelectronic arrangement for a
nucleofuge, so its elimination occurs with retention of
configuration (Scheme 3, right side).15 This mechanistic
proposal does not exclude the possibility that, with strong
bases in very polar media, a substantial percentage of the
products could arise from the direct addition of imide-like
anions to the electron-deficient triple bonds.
that these acidic conditions are incapable of cleaving the Boc
group).
The last task was to examine the deprotection procedures.
For the cleavage of the bond between the amide- or imide-like
N atom and MocVinyl and related groups, we tested several
nucleophiles that could remove the protecting group via an
addition−elimination (AE) mechanism. Most experiments were
carried out on series a (MocVinyl derivatives), for the sake of
simplicity, but we obtained similar results with representative
members of the other series. The most general reagent was 1-
dodecanethiol (no stench) plus NaH in THF (Table 4), as this
thiolate was effective with many substrates under mild
conditions, and no trace of the E or Z isomers of the starting
material remained. The major coproduct was
CH3(CH2)11SCHCHCOOMe, usually in 90:10 to 95:5 E/
Z ratios (when thiolate excesses were used, sometimes we also
detected the double addition product, (RS)2CHCH2COOMe).
On the other hand, simple lactam derivatives 1a and 3a
underwent nucleophilic attack at the CO carbon atom rather
than at Cβ under these conditions; as it was mandatory to use
another procedure, we subjected them to a standard hydro-
genation and elimination protocol.17 Simple imide derivatives
2a and 4a gave stable adducts (N,S-acetals, or hemithioaminal
intermediates) at rt, and unfortunately, mixtures of products
arising from the attack at the CO and at Cβ on heating. Thus,
we also applied the classical hydrogenation/elimination
protocol17 to imides 2a and 4a in very good yields. For 4a
(which turned out to be quite robust against strong bases) we
developed another procedure, described in Supporting
Information; it is based on the isolation of the primary adduct
The stability of MocVinyl, BocVinyl, MorVinyl, and
WeinVinyl against non-nucleophilic strong bases (required for
the detachment of α protons to the CO group of the lactam,
imide, and related groups) as well as against acidic media was
examined in several examples: (i) 1a was treated with LiHMDS
in THF at −78 °C and benzyl bromide was added to give the
corresponding Cα-alkylated derivative in good yield, without
detaching the MocVinyl group; (ii) removal of the TBS group
of 8a was carried out with TBAF/AcOH at 0 °C without
affecting the MocVinyl, BocVinyl, and MorVinyl groups,
respectively;16 (iii) MocVinyl groups of 1a−8a did survive
after treatment with MeOH and 10 mol % of TsOH·H2O
(overnight at rt, which cleaved acetoxy groups by trans-
esterification and silyl ethers by trans-silylation). BocVinyl
derivative 10b was stable during overnight treatment with
AcOH/H2O/THF; by adding a few drops of 2 M HCl the TBS
group was removed but nothing else. MorVinyl derivative 7d
and WeinVinyl 7e were stable in MeOH/TsOH at rt; on
heating for 24 h, deacetylation occurred (transesterification)
but the N-MorVinyl and N-WeinVinyl bonds were stable. In
short, Mov, Bov, Morv, and Weinv are not sensitive to bases,
provided that they are non-nucleophilic, and to acids (provided
E
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
or bases cannot be recommended. It has been demonstrated
that the MocVinyl group (Mov, series a) can advantageously be
used as a protecting group for lactams, imides, oxazolidinones,
nucleosides, and, in general, any kind of natural product
containing heterocyclic CONH- or CONHCO-related moi-
eties. It is quickly introduced at rt (or below) and easily
detected chromatographically, and by NMR, it is stable against
acids in general and can be removed by a standard procedure
(catalytic hydrogenation followed by treatment with base) or
with a thiolate ion via an AE mechanism; depending on the EW
features of the substrates, we have used alternative nucleophiles
(either pyrrolidine or the succinimide ion). As anticipated, the
BocVinyl group (Bov, series b), the analogous morpholine
amide (MorVinyl, Morv, series d), and the analogous Weinreb
amide (WeinVinyl, Weinv, series e) can similarly be added and
removed, but not so quickly; the last groups have been less
exhaustively studied because of the well-known role of Weinreb
and morpholine amides as surrogates for aldehydes and ketones
(so the removal of MorVinyl and WeinVinyl may lack practical
interest). We hope that MocVinyl and some of its partners will
have applications in stepwise syntheses of complex natural
products and medicinal drugs containing heterocyclic sub-
structures such as those examined here.
Table 4. Deprotection of MocVinyl and Related Groups
a
starting
reagent, :Nu or
NuH (equiv)
temp time yield
entry compd
solvent
THF
(°C)
(h)
(%)
1
2
3
5a
5c
6a
C12H25SH (2),
NaH (4)
50
5
85
90
83
C12H25SH/NaH
(2)
THF
THF
20
20
0.3
1
C12H25SH/NaH
(1.2)
4
5
6a
6e
pyrrolidine (4)
CH3CN
THF
20
20
2
2
95
92
C12H25SH/NaH
(3)
6
7a
C12H25SH/NaH
(1.2)
THF
20
2
96
7
8
7a
7d
pyrrolidine (4)
CH3CN
THF
20
20
2
2
92
92
C12H25SH/NaH
(2)
9
8a
8a
C12H25SH/NaH
(1.2)
THF
20
60
20
20
20
2
4
96
91
85
85
97
b
10
11
12
13
succinimide (2),
NaH (1.2)
CH3CN
b
10a
10b
11a
succinimide (2),
NaH (1.2)
DMF
24
2
EXPERIMENTAL SECTION
■
C12H25SH/NaH
(1.2)
THF
THF
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 or argon atmosphere with
anhydrous solvents, which were dried and distilled before use
according to standard procedures. Solvents used for isolation of
products and chromatography 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. Melting points have been
obtained with a Gallenkamp apparatus. 1H NMR spectra were
recorded in CDCl3 on 400 MHz spectrometers. Chemical shifts are
reported in ppm with the solvent resonance as the internal standard
(CDCl3, δ 7.26 ppm). Data are reported as usual: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin =
quintet, br s = broad singlet, m = multiplet), coupling constants (in
Hz), integration. 13C NMR spectra were recorded in CDCl3 on the
above-mentioned spectrometers (100.6 MHz for 13C) with complete
proton decoupling. Chemical shifts are reported in ppm (CDCl3, δ
77.0 ppm). Where necessary, 2D NMR experiments (HSQC and
NOESY, mainly) were carried out to assist in structure elucidation and
signal assignments. IR spectra were obtained as thin films on NaCl
plates or KBr discs. Only the more relevant frequencies (cm−1) are
reported. HRMS were obtained by using ESI-TOF techniques.
General Procedure for the Nucleophile-Catalyzed Addition
of Lactams, Imides, and Related Compounds to Electron-Poor
Alkynes. The substrate and either DMAP or DABCO were dissolved
in CH3CN or CH3CN/CH2Cl2 (0.1 M) under a N2 atmosphere. The
electron-poor alkyne (esters of propynoic acid, 3-butyn-2-one, amides
of propynoic acid) (1.2 equiv) was then slowly added via syringe, and
the reaction was stirred until TLC analysis indicated complete
consumption of the substrate. The solvent was removed under
reduced pressure, and the residue was purified by flash column
chromatography on silica gel.
C12H25SH/NaH
(1.2)
1
a
Isolated yields after removal of reagent excess and Nu-CHCH-
EWG by column chromatography. Conversions were complete.
b
Results were similar with potassium phthalimide in CH3CN at 60 °C.
(N,S-acetal) followed by the decomposition of this N,S-acetal
by addition of LiHMDS at 0 °C.
The deprotection of the MocVinyl group with an excess of
pyrrolidine in acetonitrile was also examined. With lactams 1a
and 3a, as well as with oxazolidinone 5a, pyrrolidine did not
react, even on heating, whereas imides (2a and 4a) were
partially attacked at their CO groups. Pyrrolidine was successful
with 6a (entry 4) and 7a (entry 7), but inosines (purine
nucleosides) gave both deprotection and attack at C2. For a
satisfactory deprotection of inosines, we developed an
alternative method to that of the 1-dodecanethiolate ion
explained in the preceding paragraph, that is, we deprotected
them with succinimide anion, by means of an exchange reaction
(for representative examples, see entries 10 and 11 of Table 4).
CONCLUSIONS
■
A variety of heterocyclic compounds containing CONH and
CONHCO groups react rapidly, fully, and stereoselectively, at
rt, with methyl propynoate18 and other compounds containing
electron-poor triple bonds, to afford N-substituted Michael-like
E-configuration adducts under nucleophilic catalysis, whereas
transition-metal catalysts and strong bases did not work or gave
nearly equimolar E/Z mixtures, respectively. The best catalyst is
DABCO and second DMAP. However, no method or reagent
is perfect. DABCO sometimes shows the handicap that with the
most reactive substrates it gives rise to a small percentage of O-
substituted adducts, although these can be isomerized to the
more stable N-MocVinyl isomers on heating (in the presence of
DABCO itself). DMAP has to be added in larger amounts than
DABCO to achieve the same performance. Other nucleophiles
1a (99:1 E:Z, 100 mg, 98%) was obtained using 0.2 equiv of
DABCO. 1-[(E)-2-(Methoxycarbonyl)vinyl]-2-pyrrolidinone, (E)-
1
1a: white solid; mp 77−79 °C; Rf = 0.67 (CH2Cl2/MeOH, 96:4); H
NMR (CDCl3, 400 MHz) δ 2.15−2.24 (m, 2H), 2.56 (t, J = 8.2, 2H),
3.57 (t, J = 7.3, 2H), 3.74 (s, 3 H), 5.21 (d, J = 14.2, 1H), 8.10 (d, J =
14.2, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 17.3, 30.8, 44.8, 51.3,
F
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
100.1, 137.3, 167.5, 174.2; IR (ATR) ν 2946, 1725, 1710, 1626;
100.6 MHz) δ 13.5, 20.8, 37.9, 51.8, 60.3, 63.1, 82.1, 86.7, 110.1, 113.7,
133.7, 134.4, 149.2, 161.8, 167.6, 170.2. Also see ref.21
+
HRMS (ESI+) m/z calcd for C8H12NO3 [M + H]+ 170.0812, found
170.0813. NMR data agree with those reported.11,19 1-[(Z)-2-
(Methoxycarbonyl)vinyl]-2-pyrrolidinone, (Z)-1a: oil; Rf = 0.74
(E)-8a (220 mg, 92%) was obtained using 1.0 equiv of DMAP.
2′,3′,5′-Tri-O-acetyl-1-[(E)-2-(methoxycarbonyl)vinyl]inosine,
1
1
(CH2Cl2/MeOH, 96:4); H NMR (CDCl3, 400 MHz) δ 2.07 (m,
(E)-8a: foam; Rf = 0.59 (CH2Cl2/MeOH, 90:10); H NMR (CDCl3,
2H), 2.48 (t, J = 8.1, 2H), 3.69 (s, 3H), 3.94−4.00 (m, 2H), 5.15 (d, J
= 10.6, 1H), 7.11 (d, J = 10.6, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
18.5, 30.2, 48.5, 51.2, 98.6, 133.9, 167.8, 176.0; IR (ATR) ν 2945,
400 MHz) δ 2.11 (s, 3H), 2.13 (s, 3H), 2.15 (s, 3H), 3.83 (s, 3H),
4.35−4.55 (m, 3H), 5.57 (t, J = 5.1, 1H), 5.86 (t, J = 5.3, 1H), 6.11 (d,
J = 5.1, 1H), 6.40 (d, J = 14.7, 1H), 7.89 (s, 1H), 8.24 (s, 1H), 8.40 (d,
J = 14.7, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 20.3, 20.5, 20.7, 52.1,
62.9, 70.3, 73.3, 80.3, 86.6, 111.3, 125.0, 136.9, 139.0, 143.6, 146.3,
154.6, 165.6, 169.2, 169.5, 170.2; IR (ATR) ν 3101, 1714, 1651, 1544;
+
1716, 1626; HRMS (ESI+) m/z calcd for C8H12NO3 [M + H]+
170.0812, found 170.0807.
2a (97:3 E:Z, 90 mg, 97%) was obtained using 0.2 equiv of
DABCO. N-[(E)-2-(Methoxycarbonyl)vinyl]succinimide, (E)-2a:
+
HRMS (ESI+) m/z calcd for C20H23N4O10 [M + H]+ 479.1409,
1
found 479.1406.
white solid; mp 81−83 °C; Rf = 0.62 (CH2Cl2/MeOH, 97:3); H
(E)-9a (60 mg, 97%) was obtained using 0.2 equiv of DABCO. 5′-
NMR (CDCl3, 400 MHz) δ 2.83 (s, 4H), 3.79 (s, 3H), 7.01 (d, J =
14.8, 1H), 7.76 (d, J = 14.8, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
27.7, 51.8, 110.3, 131.0, 167.1, 174.3; IR (ATR) ν 1723, 1643. NMR
data agree with those published.5f,20 N-[(Z)-2-(Methoxycarbonyl)-
O-Acetyl-2′,3′-di-O-isopropylidene-1-[(E)-2-(methoxycarbonyl)-
1
vinyl]inosine, (E)-9a: foam; Rf = 0.51 (CH2Cl2/MeOH, 90:10); H
NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.64 (s, 3H), 2.04 (s, 3H),
3.84 (s, 3H), 4.24 (dd, J = 12.0, J = 5.6, 1H), 4.16 (dd, J = 12.0, J = 4.2,
1H), 4.50−4.53 (m, 1H), 4.93 (dd, J = 3.5, J = 6.3, 1H), 5.22 (dd, J =
6.3, J = 2.4, 1H), 6.10 (d, J = 2.4, 1H), 6.38 (d, J = 14.7, 1H), 7.91 (s,
1H), 8.22 (s, 1H), 8.41 (d, J = 14.8, 1H); 13C NMR (CDCl3, 100.6
MHz) δ 20.6, 25.3, 27.1, 52.1, 63.9, 81.3, 84.6, 84.8, 90.9, 111.2, 114.9,
124.9, 136.9, 139.2, 143.5, 145.9, 154.6, 170.3, 170.2; HRMS (ESI+)
1
vinyl]succinimide, (Z)-2a: oil; Rf = 0.50 (CH2Cl2/MeOH 98:2); H
NMR (CDCl3, 400 MHz) δ 2.82 (s, 4H), 3.73 (s, 3H), 6.00 (d, J = 9.4,
1H), 6.53 (d, J = 9.4, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 28.4,
51.8, 118.0, 127.1, 164.6, 174.0; IR (ATR) ν 2930, 1732, 1641. NMR
data agree with those reported.5f
(E)-3a (59 mg, 95%) was obtained using 0.2 equiv of DABCO. (S)-
5-tert-Butyldiphenylsilyloxymethyl-N-[(E)-2-(methoxycarbonyl)-
vinyl]-2-pyrrolidinone, (E)-3a: white solid; mp 108−110 °C; Rf =
0.62 (CH2Cl2/MeOH, 97:3); 1H NMR (CDCl3, 400 MHz) δ 1.04 (s,
9H), 2.19−2.27 (m, 2H), 2.46 (m, 1H), 2.78 (dt, J = 17.7, J = 10.3,
1H), 3.66 (dd, J = 10.8, J = 2.6, 1H), 3.73 (s, 3H), 3.87 (dd, J = 10.8, J
= 3.9, 1H), 3.95−4.00 (m, 1H), 5.06 (d, J = 14.6, 1H), 7.33−7.49 (m,
6H), 7.56 (m, 2H), 7.63 (m, 2H), 8.01 (d, 1H, J = 14.6); 13C NMR
(CDCl3, 100.6 MHz) δ 19.1, 21.9, 26.7, 30.6, 51.3, 57.7, 62.3, 100.0,
127.8, 130.0, 132.1, 132.7, 135.5, 135.6, 136.6, 167.5, 174.8; HRMS
(ESI+) m/z calcd for C25H32NO4Si [M + H]+ 438.2095, found
438.2091.
+
m/z calcd for C19H23N4O8 [M + H]+ 435.1510, found 435.1507.
10a (91:9 E:Z, 108 mg, 90%) was obtained using 0.3 equiv of
DMAP. 5′-O-tert-Butyldimethylsilyl-2′,3′-di-O-isopropylidene-1-
[(E)-2-(methoxycarbonyl)vinyl]inosine, (E)-10a: foam; Rf = 0.69
1
(CH2Cl2/MeOH, 90:10); H NMR (CDCl3, 400 MHz) δ 0.05 (s,
3H), 0.06 (s, 3H), 0.86 (s, 9H) 1.40 (s, 3H), 1.64 (s, 3H), 3.81 (dd, J
= 3.3, J = 1.5, 1H), 3.83 (s, 3H), 3.90 (dd, J = 11.4, J = 3.0, 1H), 4.46−
4.48 (m, 1H), 4.90 (dd, J = 6.1, J = 2.2, 1H), 5.03 (dd, J = 6.1, J = 2.8,
1H), 6.14 (d, J = 2.8, 1H), 6.34 (d, J = 14.7, 1H), 8.10 (s, 1H), 8.22 (s,
1H), 8.45 (d, 1H, J = 14.7); 13C NMR (CDCl3, 100.6 MHz) δ −5.6,
−5.5, 18.3, 25.3, 25.8, 27.2, 52.0, 63.5, 81.2, 85.7, 87.1, 91.6, 110.8,
114.2, 124.5, 137.1, 139.8, 143.4, 146.0, 154.7, 165.4; IR (ATR): ν
2952, 1713, 1649, 1575; HRMS (ESI+) m/z calcd for C23H35N4O7Si+
[M + H]+ 507.2270, found 507.2266.
11a (90:10 E:Z, 84 mg, 85%) was obtained using 0.5 equiv of
DMAP. 3′,5′-Di-O-acetyl-2′-deoxy-1-[(E)-2-(methoxycarbonyl)-
vinyl]inosine, (E)-11a: foam; Rf = 0.54 (CH2Cl2/MeOH, 90:10);
1H NMR (CDCl3, 400 MHz) δ 2.10 (s, 3H), 2.15 (s, 6H), 2.64 (ddd, J
= 14.2, J = 6.1, J = 2.8, 1H), 2.86 (ddd, J = 14.2, J = 7.7, J = 6.6, 1H),
3.84 (s, 3H), 4.30−4.40 (m, 3H), 5.40−5.44 (m, 1H), 6.36 (dd, J =
6.3, J = 7.7, 1H), 6.39 (d, J = 14.7, 1H), 7.98 (s, 1H), 8.20 (s, 1H),
8.42 (d, J = 14.7, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 20.7, 20.8,
37.9, 52.1, 74.2, 63.6, 82.7, 84.7, 111.1, 124.7, 136.9, 138.6, 143.4,
146.2, 154.6, 165.7, 170.2, 170.3; IR (ATR) ν 2949, 1712, 1650;
HRMS (ESI+) m/z calcd for C18H21N4O8 [M + H]+ 421.1354, found
421.1356.
4a (96:4 E:Z, 69 mg, 88%) was obtained using 0.5 equiv of DMAP.
N-[(E)-2-(Methoxycarbonyl)vinyl]phthalimide, (E)-4a: white solid;
mp 126−128 °C; Rf = 0.50 (CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ
3.81 (s, 3H), 7.00 (d, J = 14.8, 1H), 7.82 (m, 2H), 7.95 (d, J = 14.8,
1H), 7.95 (m, 2H); 13C NMR (CDCl3, 100.6 MHz) δ 51.7, 108.2,
124.2, 131.1, 135.2, 165.4, 167.5; HRMS (ESI+) m/z calcd for
+
C12H10NO4 [M + H]+ 232.0604, found 232.0612. NMR data agree
with those reported.5f
5a (97:3 E:Z, 260 mg, 99%) was obtained using 0.5 equiv of DMAP.
(S)-4-Benzyl-3-[(E)-2-(methoxycarbonyl)vinyl]-1,3-oxazolidin-2-
one, (E)-5a: white solid; mp 80−82 °C; Rf = 0.62 (CH2Cl2/MeOH,
97:3); 1H NMR (CDCl3, 400 MHz) δ 2.81−2.86 (m, 1H), 3.20 (dd, J
= 13.8, J = 2.4, 1H), 3.77 (s, 3H), 4.25−4.33 (m, 3H), 5.43 (d, J =
14.4, 1H), 7.16−7.18 (m, 2H), 7.30−7.37 (m, 3H), 7.93 (d, J = 14.4,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 35.9, 51.5, 54.7, 66.7, 100.0,
127.6, 129.0, 129.2, 134.2, 137.6, 154.2, 167.0; IR (ATR) ν 2946,
1766, 1701, 1633; HRMS (ESI+) calcd for C14H16NO4 [M + H]+
262.1074, found 262.1081. NMR data agree with those reported.20
6a (97:3 E:Z, 177 mg, 99%) was obtained using 1.0 equiv of DMAP.
1-[(E)-2-(Methoxycarbonyl)vinyl]-2-pyridone, (E)-6a: orange solid;
mp = 114−116 °C; Rf = 0.55 (CH2Cl2/MeOH, 97:3); 1H NMR
(CDCl3, 400 MHz) δ 3.81 (s, 3H), 6.13 (d, J = 14.7, 1H), 6.25 (m,
1H), 6.61 (d, J = 9.3, 1H), 7.33 (ddd, J = 9.3, J = 6.5, J = 2.0, 1H), 7.43
(dd, J = 7.2, J = 1.7, 1H), 8.51 (d, J = 14.7, 1H); 13C NMR (CDCl3,
100.6 MHz) δ 51.8, 107.5, 108.2, 122.4, 131.3, 138.8, 140.0, 160.8,
166.2; IR (ATR) ν 2949, 1726, 1701, 1626; HRMS (ESI+) m/z calcd
1b (99:1 E:Z, 122 mg, 98%) was obtained using 0.2 equiv of
DABCO. 1-[(E)-2-(tert-Butoxycarbonyl)vinyl]-2-pyrrolidinone,
1
(E)-1b: mp 61−62 °C; Rf = 0.57 (CH2Cl2/MeOH, 95:5); H NMR
δ 1.41 (s, 9H), 2.10 (quin, J = 7.8, 2H), 2.46 (t, J = 8.2, 2H), 3.47 (t, J
= 7.2, 2H), 5.06 (d, J = 14.2, 1H), 7.91 (d, J = 14.2, 1H); 13C NMR δ
17.3, 28.1, 30.9, 44.9, 80.1, 102.6, 136.3, 166.4, 174.0. NMR data agree
with those already reported.22
(E)-3b (61 mg, 90%) was obtained using 0.2 equiv of DABCO. 1-
[(E)-2-(tert-Butoxycarbonyl)vinyl]-(S)-5-tert-butyldiphenylsilyloxy-
methyl-2-pyrrolidinone, (E)-3b: white solid; mp 134−136 °C; Rf =
1
0.80 (CH2Cl2/MeOH, 95:5); H NMR δ 1.03 (s, 9H), 1.49 (s, 9H),
+
for C9H10NO3 [M + H]+ 180.0655, found 180.0660.
2.16−2.25 (m, 2H), 2.40−2.47 (m, 1H), 2.76 (dt, J = 17.7, J = 10.2,
1H), 3.64 (dd, J = 10.8, J = 2.7, 1H), 3.85 (dd, J = 10.8, J = 3.9, 1H),
3.94−3.98 (m, 1H), 5.01 (d, J = 14.6, 1H), 7.34−7.47 (m, 6H), 7.54−
7.56 (m, 2H), 7.62−7.64 (m, 2H), 7.92 (d, J = 14.6, 1H); 13C NMR δ
19.0, 21.9, 26.7, 28.3, 30.6, 57.7, 62.4, 80.0, 102.4, 127.8, 127.9, 130.0,
132.1, 132.7, 135.5, 135.6, 166.4, 174.7; IR (ATR) ν 3067, 2999, 2886,
(E)-7a (183 mg, 93%) was obtained using 0.1 equiv of DMAP. 5′-
O-Acetyl-3′-azido-3′-deoxy-1-[(E)-2-(methoxycarbonyl)vinyl]-
thymidine, (E)-7a: white solid; mp 77−78 °C; Rf = 0.7 (CH2Cl2/
EtOAc, 1:1); Rf = 0.4 (CH2Cl2/MeOH, 98:2); 1H NMR (CDCl3, 400
MHz) δ 1.97 (d, J = 1.2, 3H), 2.14 (s, 3H), 2.39 (ddd, J = 13.8, J = 7.6,
J = 5.5, 1H), 2.54 (ddd, J = 13.8, J = 6.7, J = 5.7, 1H), 3.79 (s, 3H),
4.10 (dt, J = 5.6, J = 4.1, 1H), 4.20 (dt, J = 7.6, J = 5.7, 1H), 4.36 (ddd,
J = 20.0, J = 12.3, J = 4.1, 2H), 6.10 (t, J = 6.1, 1H), 7.06 (d, J = 14.8,
1H), 7.29 (q, J = 1.2, 1H), 8.26 (d, J = 14.8, 1H); 13C NMR (CDCl3,
+
2858, 1681; HRMS (ESI+) m/z calcd for C56H74N2NaO8Si2 [2M +
Na]+ 981.4876, found 981.4872.
(E)-4b (89 mg, 96%) was obtained using 0.2 equiv of DMAP. N-
[(E)-2-(tert-Butoxycarbonyl)vinyl]phthalimide, (E)-4b: white solid;
G
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
mp 124−126 °C; Rf = 0.71 (hexanes/EtOAc, 20:80); 1H NMR δ 1.53
(s, 9H), 6.89 (d, J = 14.7, 1H), 7.80−7.86 (m, 3H), 7.93−7.95 (m,
2H); 13C NMR δ 28.2, 80.8, 110.7, 124.1, 130.1, 131.4, 135.4, 165.5,
85.8, 87.2, 91.8, 114.3, 118.0, 119.5, 136.2, 139.0, 154.8, 196.8; HRMS
(ESI+) m/z calcd for C23H35N4O6Si+ [M + H]+ 491.2320, found
491.2318.
+
166.3; HRMS (ESI+) m/z calcd for C15H15NNaO4 [M + Na]+
11c (97:3 E:Z, 90 mg, 90%) was obtained using 0.1 equiv of DMAP.
3′,5′-Di-O-acetyl-2′-deoxy-1-[(E)-2-(3-oxo-1-butenyl)vinyl]inosine,
296.0893, found 296.0901.
1
6b (93:7 E:Z, 107 mg, 92%) was obtained using 0.2 equiv of
DABCO. 1-[(E)-2-(tert-Butoxycarbonyl)vinyl]-2-pyridone, (E)-6b:
mp 68−69 °C; Rf = 0.50 (CH2Cl2/MeOH, 96:4); 1H NMR δ 1.52 (s,
9H), 6.05 (d, J = 14.7, 1H), 6.25 (ddd, J = 7.2, J = 6.5, J = 1.2, 1H),
6.59 (dd, J = 9.2, J = 1.2, 1H), 7.34 (ddd, J = 9.3, J = 6.5, J = 1.9, 1H),
7.46 (dd, J = 7.2, J = 1.9, 1H), 8.38 (d, J = 14.7, 1H); 13C NMR δ 28.0,
81.1, 107.3, 110.9, 122.2, 131.6, 137.8, 139.9, 160.9, 164.9; HRMS
(E)-11c: foam; Rf = 0.56 (CH2Cl2/MeOH, 90:10); H NMR δ 2.10
(s, 3H), 2.15 (s, 3H), 2.44 (s, 3H), 2.65 (ddd, J = 6.1, J = 4.2, J = 2.8,
1H), 2.83 (ddd, J = 14.2, J = 7.7, J = 6.5, 1H), 4.31−4.41 (m, 3H),
5.40−5.44 (m, 1H), 6.36 (dd, J = 7.7, J = 6.2, 1H), 6.61 (d, J = 15.1,
1H), 8.00 (s, 1H), 8.23 (s, 1H), 8.33 (d, J = 15.1, 1H); 13C NMR δ
20.7, 20.8, 37.8, 63.5, 74.1, 82.7, 84.6, 119.5, 124.6, 135.9, 138.6, 143.3,
146.3, 154.7, 165.7, 170.1, 170.2, 196.6; HRMS (ESI+) m/z calcd for
+
C18H21N4O7 [M + H]+ 405.1405, found 405.1400.
+
(ESI+) m/z calcd for C12H16NO3 [M + H]+ 222.1125, found
N-Propynoylmorpholine was prepared according to ref 23: 1H
NMR δ 3.19 (s, 1H), 3.62−3.74 (m, 6H), 3.76−3.81 (m, 2H); 13C
NMR δ 41.8, 47.1, 66.3, 66.7, 75.0, 79.7, 151.8.
222.1123.
10b (94:6 E:Z, 118 mg, 91%) was obtained using 0.3 equiv of
DMAP. 1-[(E)-2-(tert-Butoxycarbonyl)vinyl]-5′-O-tert-butyldime-
thylsilyl-2′,3′-O-isopropylideneinosine, (E)-10b: foam; Rf = 0.43
2d (93:7 E:Z, 111 mg, 92%) was obtained using 0.2 equiv of
DABCO. N-[(E)-2-(4-Morpholino)carbonylvinyl]succinimide, (E)-
2d: orange solid; mp 146−148 °C; Rf = 0.64 (hexanes/EtOAc, 20:80);
1H NMR δ 2.82 (s, 4H), 3.70−3.74 (m, 8H), 7.50 (d, J = 14.1, 1H),
7.78 (d, J = 14.1, 1H); 13C NMR δ 27.7, 66.8, 109.0, 130.1, 164.9,
174.6; HRMS (ESI+) m/z calcd for C11H15N2O4+ [M + H]+ 239.1026,
found 239.1034.
1
(hexanes/EtOAc, 60:40); H NMR δ 0.05 (s, 3H), 0.06 (s, 3H), 0.86
(s, 9H), 1.41 (s, 3H), 1.54 (s, 9H), 1.64 (s, 3H), 3.80 (dd, J = 11.4, J =
3.4, 1H), 3.90 (dd, J = 11.4, J = 3.1, 1H), 4.47 (m, 1H), 4.90 (dd, J =
6.1, J = 2.2, 1H), 5.04 (dd, J = 6.1, J = 2.8, 1H), 6.13 (d, J = 2.7, 1H),
6.23 (d, J = 14.6, 1H), 8.09 (s, 1H), 8.19 (s, 1H), 8.30 (d, J = 14.7,
1H); 13C NMR δ −5.6, −5.5, 18.3, 25.3, 25.8, 27.2, 28.1, 63.5, 81.3,
81.7, 85.6, 87.1, 91.6, 113.7, 114.2, 124.5, 136.2, 138.8, 143.5, 146.1,
154.8, 164.4; HRMS (ESI+) m/z calcd for C26H41N4O7Si+ [M + H]+
549.2739, found 549.2738.
(E)-6d (105 mg, 85%) was obtained using 1.0 equiv of DMAP. 1-
[(E)-2-(4-Morpholino)carbonylvinyl]-2-pyridone, (E)-6d: amor-
1
phous; Rf = 0.41 (CH2Cl2/MeOH, 95:5); H NMR δ 3.65 (br s,
(E)-1c (68 mg, 75%) was obtained using 0.2 equiv of DABCO. 1-
[(E)-2-(3-Oxo-1-butenyl)vinyl]-2-pyrrolidinone, (E)-1c:19 oil; Rf =
0.48 (CH2Cl2/MeOH, 95:5); 1H NMR δ 2.16−2.27 (m, 2H), 2.29 (s,
3H), 2.58 (t, J = 8.2, 2H), 3.59 (t, J = 7.2, 2H), 5.54 (d, J = 14.7, 1H),
7.99 (d, J = 14.7, 1H); 13C NMR δ 17.4, 26.5, 31.0, 45.0, 111.4, 137.1,
174.6, 197.8.
8H), 6.20 (ddd, J = 7.1, J = 6.5, J = 1.4, 1H), 6.53 (dd, J = 9.3, J = 1.4,
1H), 7.07 (d, J = 13.9, 1H), 7.26 (ddd, J = 9.3, J = 6.5, J = 1.9, 1H),
7.36 (dd, J = 7.1, J = 1.9. 1H), 8.01 (d, J = 13.9, 1H); 13C NMR δ 42.5,
46.5, 66.8, 107.2, 110.0, 122.6, 134.3, 139.2, 139.4, 162.0, 164.8;
HRMS (ESI+) m/z calcd for C12H15N2O3+ [M + H]+ 235.1077, found
235.1079.
(E)-5c (57 mg, 75%) was obtained using 0.2 equiv of DABCO. (S)-
4-Benzyl-3-[(E)-2-(3-oxo-1-butenyl)vinyl]-1,3-oxazolidin-2-one,
(E)-5c: white solid; mp =108−110 °C; Rf = 0.59 (CH2Cl2/MeOH,
(E)-7d (172 mg, 95%) was obtained using 0.1 equiv of DMAP. 5′-
O-Acetyl-3′-azido-2′-deoxy-1-[(E)-2-morpholinocarbonylvinyl]-
thymidine,24 (E)-7d: white solid; mp 45−47 °C; Rf = 0.50 (CH2Cl2/
1
1
95:5); H NMR δ 2.31 (s, 3H), 2.77−2.87 (m, 1H), 3.21 (m, 1H),
MeOH, 95:5); H NMR δ 1.97 (d, J = 1.1, 3H), 2.14 (s, 3H), 2.38
4.26−4.37 (m, 3H), 5.75 (d, J = 14.9, 1H), 7.16−7.19 (m, 2H), 7.27−
7.39 (m, 3H), 7.80 (d, J = 14.9, 1H); 13C NMR δ 26.7, 36.2, 54.8, 66.9,
111.0, 127.7, 129.1, 129.2, 134.1, 137.3, 154.4, 196.9; IR 3448, 3072,
2963, 1766, 1626, 1416, 1211; HRMS (ESI+) m/z calcd for
(ddd, J = 14.0, J = 7.6, J = 5.6, 1H), 2.55 (ddd, J = 14.0, J = 6.6, J = 5.7,
1H), 3.60 (br s, 2H), 3.71 (br s, 6H), 4.10 (m, 1H), 4.21 (dt, J = 7.6, J
= 5.6, 1H), 4.34 (dd, J = 12.2, J = 3.8, 1H), 4.39 (dd, J = 12.2, J = 4.4,
1H), 6.12 (t, J = 6.1, 1H), 7.30 (q, J = 1.1, 1H), 7.56 (d, J = 14.2, 1H),
8.19 (d, J = 14.2, 1H); 13C NMR δ 13.4, 20.7, 37.8, 42.4 46.2, 60.3,
63.1, 66.8, 82.0, 86.5, 110.1, 112.8, 133.1, 133.4, 149.4, 162.1, 165.4,
170.1; HRMS (ESI+) m/z calcd for C19H25N6O7+ [M + H]+ 449.1779,
found 449.1780.
+
C14H16NO3 [M + H]+ 246.1125, found 246.1118.
(E)-8c (116 mg, 93%) was obtained using 0.1 equiv of DMAP.
2′,3′,5′-Tri-O-acetyl-1-[(E)-2-(3-oxo-1-butenyl)vinyl]inosine, (E)-
1
8c: foam; Rf = 0.57 (CH2Cl2/MeOH, 90:10); H NMR δ 2.11 (s,
3H), 2.14 (s, 3H), 2.15 (s, 3H), 2.43 (s, 3H), 4.34−4.48 (m, 3H), 5.56
(t, J = 5.1, 1H), 5.85 (t, J = 5.3, 1H), 6.10 (d, J = 5.1, 1H) 6.61 (d, J =
15.1, 1H), 7.98 (s, 1H), 8.24 (s, 1H), 8.31 (d, J = 15.2, 1H); 13C NMR
δ 20.3, 20.4, 20.7, 27.8, 62.9, 70.3, 73.3, 80.3, 86.6, 119.7, 124.8, 136.9,
139.0, 143.5, 146.4, 154.7, 169.2, 169.5, 170.2, 196.6; HRMS (ESI+)
N-Methoxy-N-methylpropynamide was prepared according to ref
23: H NMR δ 3.11 (s, 1H), 3.24 (br s, 3H), 3.78 (s, 3H).
1
(E)-6e (93 mg, 85%) was obtained using 0.1 equiv of DMAP. 1-
[(E)-2-(N-Methoxy-N-methylaminocarbonyl)vinyl]-2-pyridone,
(E)-6e: white solid; mp 110−111 °C; Rf = 0.40 (CH2Cl2/MeOH,
+
m/z calcd for C20H23N4O9 [M + H]+ 463.1460, found 463.1457.
1
95:5); H NMR δ 3.23 (s, 3H), 3.69 (s, 3H), 6.20 (ddd, J = 7.2, 6.6,
9c (93:7 E:Z, 101 mg, 97%) was obtained using 0.1 equiv of DMAP.
5′-O-Acetyl-2′,3′-O-isopropylidene-1-[(E)-2-(3-oxo-1-butenyl)-
vinyl]inosine, (E)-9c: white solid; mp 151−153 °C; Rf = 0.52
(CH2Cl2/MeOH, 90:10); 1H NMR δ 1.40 (s, 3H), 1.64 (s, 3H), 2.04
(s, 3H), 2.44 (s, 3H), 4.25 (dd, J = 12.0, J = 5.6, 1H), 4.35 (dd, J =
12.0, J = 4.2, 1H), 4.51−4.54 (m, 1H), 4.94 (dd, J = 6.3, J = 3.4, 1H),
5.22 (dd, J = 6.3, J = 2.4, 1H), 6.11 (d, J = 2.4, 1H), 6.61 (d, J = 15.1,
1H), 7.93 (s, 1H), 8.25 (s, 1H), 8.32 (d, J = 15.2, 1H); 13C NMR δ
20.7, 25.3, 27.1, 27.8, 63.9, 81.3, 84.6, 84.8, 91.0, 115.0, 119.6, 124.9,
135.9, 139.3, 140.0, 143.4, 154.7, 170.3, 196.6; HRMS (ESI+) m/z
1.3, 1H), 6.53 (dd, J = 9.0, J = 1.3, 1H), 6.84 (d, J = 14.4, 1H), 7.27
(ddd, J = 9.0, 6.6, 2.1, 1H), 7.44 (dd, J = 7.2, 1.9, 1H), 8.31 (d, J =
14.4, 1H); 13C NMR δ 32.3, 61.8, 107.1, 107.5, 122.3, 132.5, 138.6,
139.6, 161.2, 165.7; HRMS (ESI+) m/z calcd for C10H13N2O3+ [M +
H]+ 209.0921, found 209.0918.
(E)-7e (126 mg, 90%) was obtained using 0.1 equiv of DMAP. 5′-
O-Acetyl-3′-azido-3′-deoxy-3-[(E)-2-(N-methoxy-N-
methylaminocarbonylvinyl]thymidine,25 (E)-7e: white solid; mp
111−113 °C; Rf = 0.44 (CH2Cl2/MeOH, 95:5); 1H NMR δ 1.98 (d, J
= 1.2, 3H), 2.14 (s, 3H), 2.40 (ddd, J = 14.1, J = 7.6, J = 5.6, 1H) 1H),
2.53 (ddd, J = 14.1, J = 6.7, J = 5.6, 1H), 3.28 (s, 3H), 3.75 (s, 3H),
4.10 (dt, J = 5.6, J = 4.1, 1H), 4.21 (dt, J = 7.6, J = 5.6, 1H), 4.34 (dd, J
= 12.2, J = 3.8, 1H), 4.39 (dd, J = 12.2, J = 4.4, 1H), 6.14 (t, J = 6.2,
1H), 7.30 (q, J = 1.2, 1H), 7.60 (d, J = 14.6, 1H), 8.21 (d, J = 14.6,
1H); 13C NMR δ 13.5, 20.7, 32.5, 37.8, 60.3, 61.8, 63.1, 81.9, 86.5,
110.1, 112.1, 133.4, 133.4, 149.3, 162.0, 167.0, 170.1; HRMS (ESI+)
+
calcd for C19H23N4O7 [M + H]+ 419.1561, found 419.1555.
10c (91:9 E:Z, 95 mg, 97%) was obtained using 0.1 equiv of DMAP.
5′-O-tert-Butyldimethylsilyl-2′,3′-O-isopropylidene-1-[(E)-2-(3-
oxo-1-butenyl)vinyl]inosine, (E)-10c: foam; Rf = 0.56 (CH2Cl2/
1
MeOH, 90:10); H NMR δ 0.06 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H),
1.41 (s, 3H), 1.64 (s, 3H), 2.43 (s, 3H), 3.81 (dd, 1H, J = 11.4, J =
3.3), 3.91 (dd, 1H, J = 11.4, J = 3.0), 4.46−4.49 (m, 1H), 4.90 (dd, 1H,
J = 6.1, J = 2.2), 5.03 (dd, 1H, J = 6.1, J = 2.8), 6.14 (d, 1H, J = 2.8),
6.57 (d, 1H, J = 15.1), 8.11 (s, 1H), 8.24 (s, 1H), 8.35 (d, 1H, J =
15.1); 13C NMR δ −5.6, −5.4, 18.3, 25.3, 25.9, 27.2, 27.2, 63.6, 81.3,
+
m/z calcd for C17H23N6O7 [M + H]+ 423.1623, found 423.1619.
8e (91:9 E:Z, 53 mg, 80%) was obtained using 0.2 equiv of
DABCO. 2′,3′,5′-Tri-O-acetyl-1-[(E)-2-(N-methoxy-N-
methylaminocarbonyl)vinyl]inosine, (E)-8e: foam; Rf = 0.68
H
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
(hexanes/EtOAc, 20:80); H NMR δ 2.10 (s, 3H), 2.13 (s, 3H), 2.15
propynoate). This material is available free of charge via the
Internet at http://pubs.acs.org.
(s, 3H), 3.32 (s, 3H), 3.78 (s, 3H), 4.42−4.46 (m, 4H), 5.59 (t, J = 5.2,
1H), 5.89 (t, J = 5.2, 1H), 6.08 (d, J = 4.9, 1H), 7.18 (d, J = 14.3, 1H),
7.95 (s, 1H), 8.22−8.27 (m, 2H); 13C NMR δ 20.3, 20.5, 20.7, 62.1,
62.9, 70.3, 73.2, 80.2, 110.9, 125.1, 136.6, 137.6, 139.1, 144.8, 146.2,
155.1, 165.1, 169.3, 169.5, 170.3; HRMS (ESI+) m/z calcd for
AUTHOR INFORMATION
■
Corresponding Author
C21H26N5O10 [M + H]+ 508.1674, found 508.1682.
+
*E-mail: (A.M.C.) amcosta@ub.edu, (J.V.) jvilarrasa@ub.edu.
Removal of MocVinyl and Related Groups. To the protected
substrate (0.20 mmol) in anhyd THF (2 mL) was added a suspension
of sodium 1-dodecanethiolate in THF (2 mL). Depending on the ease
or difficulty of the deprotection (see Table 4), 0.24−0.40 mmol (1.2−
2.0 equiv) of 1-dodecanethiol plus 48 mg, 0.24−0.80 mmol (i.e., 1.2−
4.0 equiv) of NaH were used. After the mixture was stirred in a bath at
rt or 50 °C, for a few minutes up to 5 h, TLC indicated complete
consumption of the starting material. Quenching with water and
neutralization with 0.1 M HCl was followed by extraction with an
organic solvent (EtOAc or CH2Cl2 depending on the case, several
times, until all the organic products went to the organic phase). The
combined organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel.
Nucleoside 7a (79 mg, 0.20 mmol) was added to pyrrolidine (57
mg, 0.80 mmol) in CH3CN (2 mL), and the solution was stirred at rt
under N2 for 2 h (when TLC indicated the full disappearance of the
starting material). Evaporation under vacuum gave a residue that was
purified by flash column chromatography on silica gel, with CH2Cl2
and then CH2Cl2/EtOAc mixtures as the eluents. The less polar
methyl 3-(pyrrolidin-1-yl)propenoate was eluted first; afterward, the
desired product, 7, was isolated and dried (57 mg, 92%).
Nucleoside 8a (95 mg, 0.20 mmol) was added to a flask containing
sodium succinimide (from 40 mg, 0.40 mmol, of succinimide and 5.8
mg, 0.24 mmol, of NaH) in CH3CN (2 mL); DMF gave the same
result. The suspension was stirred at 60 °C (bath temperature) for 4 h
(when TLC indicated the full disappearance of 8a). After dilution with
water and several extractions with EtOAc, the combined extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
(with 95:5 CH2Cl2−MeOH, 2a was eluted first, and later 8, 72 mg,
91% yield).
Characterization of N,S-Acetals. Example. MocVinyl derivative
4a (100 mg, 0.43 mmol) in THF (4 mL) was added to a flask in which
1-dodecanethiol (174 mg, 0.86 mmol) and NaH (42 mg, 1.72 mmol)
were mixed at rt. After the mixture was stirred for 0.2 h, TLC indicated
that the starting material had disappeared to give a less polar product.
The reaction was quenched with aqueous HCl (0.5 M, 10 mL) and
diluted with CH2Cl2 (20 mL). The layers were separated. The aqueous
phase was re-extracted with CH2Cl2 (3 × 20 mL). The organic extracts
were dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (CH2Cl2) to
yield 4a·C12H26S (130 mg, 70%): oil; Rf = 0.73 (CH2Cl2); 1H NMR δ
0.86 (t, J = 6.9, 3H), 1.19−1.29 (m, 19H), 1.50−1.63 (m, 2H), 2.51−
2.58 (m, 1H), 2.63−2.70 (m, 1H), 3.15 (dd, J = 16.7, J = 6.2, 1H),
3.44 (dd, J = 16.7, J = 9.2, 1H), 3.63 (s, 3H), 5.69 (dd, J = 9.2, J = 6.2,
1H), 7.72 (m, 2H), 7.86 (m, 2H); 13C NMR δ 14.1, 28.7, 29.1, 29.3,
29.4, 29.42, 29.5, 29.59, 29.6, 31.9,51.1, 51.9, 123.5, 131.6, 134.2,
167.2, 170.1; HRMS (ESI+) m/z calcd for C24H36NO4S+ [M + H]+
434.2360, found 434.2357. Treatment of this adduct (217 mg, 0.5
mmol) with lithium hexamethyldisilylamide (LHMDS, 500 μL, 1 M in
THF, 0.5 mmol) at 0 °C for 15 min, followed by neutralization with
dilute HCl, evaporation to dryness under vacuum, and purification by
column chromatography, gave 4 (50 mg, 0.33 mmol, 61%).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Spanish Government contributed through Grant Nos.
CTQ-2006-15393 and CTQ-2009-13590, and the Generalitat
de Catalunya (Barcelona) provided a gift (2009SGR-00825).
L.M. currently has a doctorate studentship from the Universitat
̈
de Barcelona. Aida Riera participated in preliminary experi-
ments when she was an undergraduate student in our
department (2010).
REFERENCES
■
(1) Wutts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; Wiley: Hoboken, 2007; pp 894−916.
(2) For very recent, illustrative examples, see: (a) Alewi, B. A.;
Kurosu, M. Tetrahedron Lett. 2012, 53, 3758−3762. (b) Seo, J. H.; Liu,
P.; Weinreb, S. M. J. Org. Chem. 2010, 75, 2667−2680. (c) Benohoud,
M.; Leman, L.; Cardoso, S. H.; Retailleau, P.; Dauban, P.; Thierry, J.;
Dodd, R. H. J. Org. Chem. 2009, 74, 5331−5336. (d) Wang, J.; Liang,
Y.-L.; Qu, J. Chem. Commun. 2009, 5144−5146. (e) Dandepally, S. R.;
Williams, A. L. Tetrahedron Lett. 2009, 50, 1071−1074. (f) Reisman, S.
E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.;
Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130,
2087−2100. (g) Broch, S.; Anizon, F.; Moreau, P. Synthesis 2008,
2039−2044.
(3) For uses of morpholine amides, see: (a) Martín, R.; Romea, P.;
Tey, C.; Urpí, F.; Vilarrasa, J. Synlett 1997, 1414−1416. (b) Kurosu,
M.; Kishi, Y. Tetrahedron Lett. 1998, 39, 4793−4796. (c) Olivella, A.;
Rodríguez-Escrich, C.; Urpí, F.; Vilarrasa, J. J. Org. Chem. 2008, 73,
1578−1581 and references therein.
(4) For uses of Weinreb amides, see the following reviews:
(a) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707−3738.
(b) Adler, M.; Adler, S.; Boche, G. J. Phys. Org. Chem. 2005, 18, 193−
209. Weinreb amides of stabilized Wittig, Horner−Wadsworth−
Emmons, and Ando reagents afford higher selectivities than the
corresponding esters; see: (c) Ando, K.; Nagaya, S.; Tarumi, Y.
Tetrahedron Lett. 2009, 50, 5689−5691 and references therein.
(5) Michael-like conjugate additions to dialkyl acetylenedicarbox-
ylates (butynedioates) are not reviewed here. Pd-catalyzed couplings
of oxazolidin-2-ones with alkyl acrylates and Cu- and Pd-catalyzed
couplings with alkyl haloacrylates also lead to enamides but are not
considered here, either; for other approaches to enamides, see:
(a) Villa, M. V. J.; Targett, S. M.; Barnes, J. G.; Whittingham, W. G.;
Marquez, R. Org. Lett. 2007, 9, 1631−1633 and references cited
therein. For additions to triple bonds, see: (b) Fan, M.-J.; Li, G.-Q.;
Liang, Y.-M. Tetrahedron 2006, 62, 6782−6791 (phthalimide).
(c) Nishimura, T.; Wang, J.; Nagaosa, M.; Okamoto, K.; Shintani,
R.; Kwong, F.; Yu, W.; Chan, A. S. C.; Hayashi, T. J. Am. Chem. Soc.
2010, 132, 464−465 (phthalimide). (d) Lee, E.; Kim, S. K.; Kim, J. Y.;
Lim, J. Tetrahedron Lett. 2000, 41, 5915−5916 (azetidone and
oxazolidin-2-one, intramolecular radical cyclization). (e) Lee, E.; Kang,
T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C. K. Tetrahedron Lett.
1995, 36, 417−420 (carbamates and sulfonamides). (f) Ramazani, A.;
Kardan, M.; Noshiranzadeh, N. Synth. Commun. 2008, 38, 383−390
(K2HPO4, μW, succinimide and phthalimide, Z/E mixtures).
(g) Janey, J. M.; Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org.
Chem. 2000, 65, 9059−9068 (N-methylmorpholine, oxazolidinones).
(h) Ylioja, P. M.; Mosley, A. D.; Charlot, C. E.; Carbery, D. R.
Tetrahedron Lett. 2008, 49, 1111−1114. (i) Chatterjee, T.;
Chattopadhyay, S.; Mukhopadhyay, R.; Achari, B.; Chakraborty, S.;
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of the new compounds,
DFT and MP2 calculations of all possible conformations of 1a,
2a, 5a, and 6a and of models of 7a and 8a−11a, predicted
energies for selected exchange reactions, and predicted energies
for relevant initial intermediates (from DABCO and methyl
I
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Mukherjee, A. K. J. Chem. Res. 2005, 429−431 (2-methylquinazolin-4-
one). (j) Peshakova, L.; Kalcheva, V.; Madzhova, L. Izv. Khim. 1991,
24, 91−95; Chem. Abstr. 1992, 116, 173865 (thymine and uracil,
disubstituted compounds). (k) Lin, T. S.; Guo, J. Y.; Zhang, X. H.
Nucleosides Nucleotides 1990, 9, 923−935 (pyrimidine nucleosides,
anticancer agents) and references cited therein. (l) Scheiner, P.; Geer,
A.; Bucknor, A.-M.; Imbach, J.-L.; Schinazi, R. F. J. Med. Chem. 1989,
32, 73−76 (thymine, DBU). Conjugate additions of NH2 (over 75
journal articles), OH (over 200 papers), or SH (over 120 articles)
groups to activated terminal triple bonds are not considered here.
Men
2090−2098.
́
dez-Abt, G.; García-Tellado, F. Angew. Chem., Int. Ed. 2009, 48,
(11) (a) Goossen, L. J.; Arndt, M.; Blanchot, M.; Rudolphi, F.;
Menges, F.; Niedner-Schatteburg, G. Adv. Synth. Catal. 2008, 350,
2701−2707. (b) Goossen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem.,
Int. Ed. 2005, 44, 4042−4045.
(12) The reactions were run using 10 mol % of the transition-metal
salt or complex and 200 mol % of methyl propynoate in toluene at 100
°C. Under these conditions, oxazolidinone 3 did only react with
AuCl(PPh3), affording the α-addition product (that is, did react with
Ph3P that came from the partial decomposition of the gold
complex).10a,b
(13) This is the essence of the Sharpless “click” reactions among
azides and terminal triple bonds. For very recent reviews, see:
́
(a) Díez-Gonzalez, S. Cat. Sci. Technol 2011, 1, 166−178. (b) Hein, J.
E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302−1315.
(14) Compound (Z)-1a isomerized to its E isomer in refluxing
toluene, overnight, in the presence of DABCO (1 equiv). On the other
hand, nucleoside (Z)-8a isomerized to its isomer E much more easily,
since an 86:14 E/Z mixture (Table 2, entry 13) was converted to
>99:1 by simple treatment for 1 day with DMAP at rt. The O-
substituted derivatives (2-pyridyl-O-CHCH-COOMe, for example),
which were formed as impurities in some experiments, can be removed
by chromatography or, even better, can be rearranged to their major
N-MocVinyl isomers (to 6a, for example) with DABCO in refluxing
CH3CN for two days.
(6) Uridines: (a) Faja, M.; Ariza, X.; Gal
Tetrahedron Lett. 1995, 36, 3261−3264. (b) Costa, A. M.; Faja, M.;
Farras, J.; Vilarrasa, J. Tetrahedron Lett. 1998, 39, 1835−1838.
́
vez, C.; Vilarrasa, J.
̀
(c) Costa, A. M.; Vilarrasa, J. Tetrahedron Lett. 2000, 41, 3371−
3375. (d) Jin, S.; Miduturu, C. V.; McKinney, D. C.; Silverman, S. K. J.
Org. Chem. 2005, 70, 4284−4299. (e) Bonache, M.-C.; Quesada, E.;
Sheen, C.-W.; Balzarini, J.; Sluis-Cremer, N.; Per
Camarasa, M.-J.; San-Felix, A. Nucleos. Nucleot. Nucl. Acids 2008, 27,
351−357.
́ ́
ez-Perez, M. J.;
́
(7) Antimalarial agents from 6-membered lactams and several HC
C-EWG: (a) Katz, E.; Ma, J.; Kyle, D.; Ziffer, H. Bioorg. Med. Chem.
Lett. 1999, 9, 2969−2972. (b) Mekkonen, B.; Weiss, E.; Katz, E.; Ma,
J.; Ziffer, H.; Kyle, D. E. Bioorg. Med. Chem. 2000, 8, 1111−1116.
Identical cleavage of the C−N bond between the 3-oxo-1-propenyl
group and an indole ring: (c) Foettinger, A.; Melmer, M.; Leitner, A.;
Lindner, W. Bioconjugate Chem 2007, 18, 1678−1683.
(8) For some reviews and relevant works on the relative
nucleophilicity (DABCO > DBN ≥ DBU > DMAP ≫ Et3N ≫
DIPEA) and on the basicity in aqueous media (DABCO < DMAP <
Et3N < DIPEA < DBU ≤ DBN) of N-trisubstituted molecules, see:
(a) Mayr, H.; Lakhdar, S.; Maji, B.; Ofial, A. R. Beilst. 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.
(15) For related mechanisms involving haloacrylates, see: (a) Esteban,
J.; Costa, A. M.; Gomez, A.; Vilarrasa, J. Org. Lett. 2008, 10, 65−68.
́
(b) Kabir, M. S.; Namjoshi, O. A.; Verma, R.; Lorenz, M.;
Tiruveedhula, V. V. N. P. B.; Monte, A.; Bertz, S. H.; Schwabacher,
A. W.; Cook, J. M. J. Org. Chem. 2012, 77, 300−310.
(16) TBAF alone (Bu4N+F−·3H2O), due to the basicity of the
tetrabutylammonium alkoxide that is generated in the medium, causes
a N-to-O MocVinyl transfer (from the imide-like N to the O atom that
was deprotected) in some cases examined.
(9) The performance of DABCO can be attributed to its great
nucleophilicity (in spite of its low basicity: pKa = 8.7). 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU), which is almost as good a
nucleophile as DABCO (ref 8) and a stronger base, gave a 65:35 E/Z
ratio of 2a and polar byproducts; we did not systematically examine
DBU (or DBN) since it (they) may act both as a nucleophile and a
base. Quinuclidine could be more efficient than DABCO due to its
even higher nucleophilicity (ref 8) and stronger basicity (pKa = 11.3),
but it would also pose questions about the role played by each of these
two properties. Phosphanes were not systematically examined either,
as it is known that Ph3P may catalyze the α-addition (not the β-
addition) of several N-nucleophiles to electron-poor alkynes:
(a) Trost, B. M.; Dake, G. M. J. Am. Chem. Soc. 1997, 119, 7595−
7596. (b) Yavari, I.; Norouzi-Asari, H. Phosphorus, Sulfur Silicon 2002,
177, 87−92. We only examined Me3P (a good nucleophile but a
poorer base than Me3N, in fact with a pKa value almost identical to
DABCO), which in the case of 2 gave 2a as a 93:7 E/Z mixture (20
mol %, 15 min, full conversion); however, Me3P yielded around 60:40
E/Z mixtures of adducts when used as a catalyst in reactions of
thymidines and hypoxanthines with methyl propynoate, so we ruled it
out. With an N-heterocyclic carbene (NHC) such as the
imidazolylidene IPr (20 mol %, 20 min, full conversion), the product
was a 60/40 E/Z mixture; N-heterocyclic carbenes are strong bases.
(10) For recent illustrative examples of reactions that give this dimer
as a byproduct, see: (a) Chen, H.-G.; Lo, Y.-H.; Wu, F.-L.; Wang, H.-
Y.; Hsu, L.-S.; Hsiao, P.-I.; Liang, Y.-R.; Kuo, T.-S.; Huang, C.-C. Inorg.
Chem. Commun. 2010, 13, 956−968. (b) Barry, C. S.; Elsworth, J. D.;
Seden, P. T.; Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org.
(17) After the Pd-catalyzed hydrogenation of the conjugated double
bond (with a balloon of H2, which required less than 1 h for
completion), the purification of the crude product by treatment with a
strong base to produce an elimination reactionwe used 1.2 equiv of
LiHMDS in THF at 0 °Cimmediately furnished the deprotected
compounds. Many cleavages of RR′N-CH2CH2COOMe and RR′N-
CH2CH2CN (to give rise to RR′NH and CH2CH-EWG) can be
found in the chemical literature. For representative examples with
esters, see: (a) Robinson, R. S.; Dovey, M. C.; Gravestock, D. Eur. J.
Org. Chem. 2005, 505−511. (b) Denes, F.; Chemla, F.; Normant, J. F.
Synlett 2002, 919−922. For some classical examples with nitriles, see:
(c) Tyler, P. C.; Taylor, E. A.; Froehlich, R. F. G.; Schramm, V. L. J.
Am. Chem. Soc. 2007, 129, 6872−6879. (d) Liao, Y.; Bhattacharjee, S.;
Firestones, K. A.; Eichinger, B. E.; Paranji, R.; Anderson, C. A.;
Robinson, B. H.; Reid, P. J.; Dalton, L. R. J. Am. Chem. Soc. 2006, 128,
6847−6853. (e) Spychala, J. Synth. Commun. 2000, 30, 2497−2506.
(f) Lewis, A. F.; Revankar, G. R.; Hogan, M. E. J. Heterocycl. Chem.
1993, 30, 1309−1315. (g) Pursglove, L. A. J. Org. Chem. 1959, 24,
576−577. (h) Smith, N. L. J. Org. Chem. 1950, 15, 1125−1130.
(18) Ethyl propynoate (ethyl propiolate) has a similar price and is
also sold by many companies; it can be used in the same way, as an
alternative.
(19) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.
Tetrahedron Lett. 1992, 33, 6643−6646.
(20) Liu, Y.; Li, D.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50,
7333−7336.
(21) Other usual protecting groups for nucleosides were compatible
with the reaction conditions. For example, the 5′-O-TBS analogue of
7a could be similarly prepared in excellent yield. 3′-azido-5′-O-tert-
butyldimethylsilyl-1-[(E)-2-(methoxycarbonyl)vinyl]thymidine: oil; Rf
= 0.80 (CH2Cl2/EtOAc, 80:20); 1H NMR (CDCl3, 400 MHz) δ 0.14
(s, 6H), 0.93 (s, 9H), 1.96 (d, J = 1.2, 3H), 2.25 (m, 1H), 2.49 (m,
1H), 3.78 (s, 3H), 3.81 (m, 1H), 3.99 (m, 2H), 4.23 (td, J = 7.2, J =
4.3, 1H), 6.21 (t, J = 6.4, 1H), 7.07 (d, J = 14.8, 1H), 7.50 (d, J = 1.2,
Lett. 2006, 8, 3319−3322. (c) Tejedor, D.; Gonzal
́
ez-Cruz, D.; Santos-
Exposito, A.; Marrero-Tellado, J. J.; Armas, P.; García-Tellado, F.
́
Chem.Eur. J. 2005, 11, 3502−3510 and references cited therein.
(d) Matsuya, Y.; Hayashi, K.; Nemoto, H. J. Am. Chem. Soc. 2003, 125,
646−647 (and its ref 9). For acetylides from alkyl propynoates, see the
́
following review: (e) Tejedor, D.; Lopez-Tosco, S.; Cruz-Acosta, F.;
J
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1H), 8.28 (d, J = 14.8, 1H); 13C NMR (CDCl3, 100.6 MHz) δ −5.4,
−5.4, 13.4, 18.4, 25.9, 38.2, 51.7, 60.2, 62.8, 84.8, 85.7, 109.8, 113.5,
133.5, 134.6, 149.4, 161.9, 167.7; IR (ATR) ν 3085, 2952, 2110, 1750,
1711, 1667, 1633. For an application, see: Ariza, X.; Urpí, F.; Vilarrasa,
J. Tetrahedron Lett. 1999, 40, 7515−7517.
(22) Alonso, D. A.; Alonso, E.; Naj
Tetrahedron 1997, 53, 4835−4856.
(23) Delamarche, I.; Mosset, P. Tetrahedron Lett. 1993, 34, 2465−
2468.
́ ́
era, C.; Ramon, D. J.; Yus, M.
(24) These reactions are of general scope. For example, a 5′-O-TBS
group was also stable under the reaction conditions, as we have
similarly prepared the morpholine amide-containing 5′-OTBS-AZT
analogue of 7d (0.1 M in CH3CN, 0.1 equiv of DMAP, 1.5 equiv of N-
propynoylmorpholine, refluxing CH3CN for 4 h, 90% yield after
column chromatography): 1H NMR δ 0.12 (s, 6H), 0.91 (s, 9H), 1.94
(d, J = 1.1, 3H), 2.23 (dt, J = 13.7, J = 6.9, 1H), 2.47 (ddd, J = 13.7, J =
6.1, J = 4.4, 1H), 3.35−3.74 (m, 8H), 3.80 (dd, J = 11.4, J = 2.2, 1H),
3.92−4.00 (m, 2H), 4.21 (dt, J = 7.3, J = 4.2, 1H), 6.20 (t, J = 6.4, 1H),
7.49 (q, J = 1.1, 1H), 7.56 (d, J = 14.2, 1H), 8.20 (d, J = 14.2, 1H); 13C
NMR δ−5.5, −5.4, 13.4, 18.3, 25.9, 38.2, 42.4, 46.2, 60.3, 62.7, 66.8,
84.7, 85.6, 109.8, 112.5, 133.3, 149.5, 162.3, 165.5.
(25) The Weinreb amide-containing AZT derivative with a trityl
group, not included in Table 3 for the sake of simplification, was also
prepared without loss of 5′-O-Tr group, under similar conditions (0.1
M in CH3CN, 0.1 equiv of DMAP, 1.5 equiv of N-methoxy-N-
methylpropynamide, refluxing for 3 h, 91% yield after chromatog-
1
raphy): H NMR δ 2.39−2.48 (m, 1H), 2.49−2.58 (m, 1H), 3.25 (s,
3H), 3.44 (dd, J = 11.1, J = 2.9, 1H), 3.56 (dd, J = 11.1, J = 2.8, 1H),
3.71 (s, 3H), 3.95 (ddd, J = 5.9, J = 2.8, 1H), 4.34 (q, J = 6.8, 1H), 5.45
(d, J = 8.2, 1H), 6.18 (dd, J = 4.8, J = 6.4, 1H), 7.22−7.36 (m, 9H),
7.37−7.42 (m, 6H), 7.58 (d, J = 14.6, 1H), 7.87 (d, J = 8.2, 1H), 8.21
(d, J = 14.6, 1H); 13C NMR δ 32.4, 38.4, 59.0, 61.7, 61.9, 83.6, 85.7,
87.6, 101.3, 112.0, 127.4, 128.0, 128.4, 133.0, 137.8, 142.8, 149.4,
161.0, 166.8.
K
dx.doi.org/10.1021/jo4006409 | J. Org. Chem. XXXX, XXX, XXX−XXX