Efficient preparations of novel ynamides and allenamides

Article abstract of DOI:10.1016/S0040-4020(00)01014-0

Practical syntheses of a series of novel ynamides and allenamides are described here. While a base-induced isomerization protocol of propargyl amides leads to an array of chiral and achiral allenamides, ynamides are prepared from enamides via bromination followed by base-induced elimination of the Z-bromoenamides. These ynamides and allenamides possess improved thermal stability compared to ynamines and allenamines. They can be isolated, purified, and handled with ease, and thus, should be synthetically more useful than traditional ynamines and allenamines.

Full text of DOI:10.1016/S0040-4020(00)01014-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 459±466
Ef®cient preparations of novel ynamides and allenamides
²
Lin-Li Wei, Jason A. Mulder, Hui Xiong, Craig A. Zi®csak, Christopher J. Douglas
*
and Richard P. Hsung
Department of Chemistry, The University of Minnesota, 207 Pleasant Street S.E., Minneapolis, MN 55455, USA
Received 12 September 2000; accepted 25 October 2000
AbstractÐPractical syntheses of a series of novel ynamides and allenamides are described here. While a base-induced isomerization
protocol of propargyl amides leads to an array of chiral and achiral allenamides, ynamides are prepared from enamides via bromination
followed by base-induced elimination of the Z-bromoenamides. These ynamides and allenamides possess improved thermal stability
compared to ynamines and allenamines. They can be isolated, puri®ed, and handled with ease, and thus, should be synthetically more
useful than traditional ynamines and allenamines. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have been exploring reactivities of some electron-
de®cient variants of ynamines and allenamines, or simply
ynamides and allenamides, in which the nitrogen atom is
substituted with an electron-withdrawing group.4,5 Our
designs would speci®cally feature either an imidazolidinone
or oxazolidinone moiety, thereby also providing a practical
entry to chiral ynamides and allenamides (Fig. 2).4,5 The
electron-withdrawing group serves to diminish the elec-
tron-donating ability of the nitrogen atom, thereby offering
superior stability to the traditional ynamines and allen-
amines.
Alkynes and allenes are extremely versatile functional
groups in organic synthesis leading to a diverse array of
synthetic methods. Two important subgroups would be
those nitrogen atom substituted alkynes and allenes or
ynamines1 and allenamines, respectively.2 The electron-
donating ability of the nitrogen atom renders them even
more synthetically useful than alkynes and allenes because
of the electronic bias imposed by the heteroatom, allowing
regioselective transformation of these organic synthons
(Fig. 1). While the synthetic signi®cance of ynamines in
organic chemistry was ®rmly established by the work of
many organic chemists more than ®fteen years ago,1 the
synthetic scope of allenamines has remained very limited.2,3
However, there have been relatively few synthetic appli-
cations using either ynamines or allenamines in recent
decades. This lack of attention is in part attributed to the
dif®culty in preparation and handling of ynamines and
allenamines due to their high reactivity and sensitivity
toward hydrolysis and polymerization.
Although preparations of some electron-de®cient
ynamines6,7 and allenamines8,9 as well as improved thermal
stability of electron-de®cient ynamines have been docu-
mented,6 it was not until recently that reactivities of elec-
tron-de®cient ynamines and allenamines were explored in
transition metal-mediated processes,10,11 while examples of
palladium catalyzed cross-couplings,12 cyclizations,13 and
[212] cycloaddition reactions14 using allenamides have
also appeared in literature. Speci®cally, stereoselective
Figure 1.
Keywords: ynamides; allenamides; bromination.
* Corresponding author. Tel.: 11-612-625-3045; fax: 11-612-626-7541; e-mail: hsung@chem.umn.edu
UMN undergraduate research participant: 1998±1999.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01014-0

460
L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
Figure 2.
Scheme 1.
reactions using our ynamides4 and allenamides5 for
constructions of heterocycles and other useful organic
building blocks have been investigated. Our studies along
with recent literature reports demonstrate the synthetic
potential of ynamides and allenamides as well as a renewed
interest. Given their synthetic potential, we disclose here the
details for preparations of our ynamides and allenamides.
cleanly using 20 mol% KOH in DMSO. Both the allena-
mide 2 and ynamide 3 are stable crystalline solids (Scheme
1).
The synthetic sequence for preparation of 3 represents a
practical approach for the synthesis of ynamides of our
interest. Toward this goal, a series of propargylated amides
shown as 5 were prepared from corresponding lactams,
2-oxazolidinone, or N-methyl-2-imidazolidinone shown as
4 (Scheme 2). However, subsequent isomerization of
propargyl amides 5 using t-BuOK in anhydrous THF at
ambient temperature provided only the allenamides 6. A
variety of achiral allenamides 8±13 were obtained in good
overall yields. These allenamides clearly possess much
improved thermal stability than allenamines. They can
survive either silica gel or basic alumina column chroma-
tography, and are not readily polymerized even at tempera-
tures greater than 808C which is well beyond the
temperature limit for thermal polymerization of allen-
amines.2,3f,5 These improvements suggest the loss of ability
of the nitrogen atom in donating toward the allene moiety
2. Results and discussions
Although there is a diverse array of known methods that
give useful preparations of ynamines,15 a base-induced
isomerization protocol appears to be the most ef®cient and
has worked well for the synthesis of various ynamines. In
addition, in a related study,4 the known vinylogous ynamide
3 was prepared in 80% overall yield from acridone using
conditions similar to those reported by Katritzky.16 It was
found that isomerization of the propargylated acridone 1
could be arrested at the vinylogous allenamide 2, but by
extending the reaction time, isomerization of 2 led to 3
Scheme 2.
Scheme 3.

L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
461
Scheme 4.
due to a more delocalized nitrogen lone pair, thereby lead-
ing to reduced reactivity and greater stability.
formation of 22 presumably is a result of t-BuOK attacking
the oxazolidinone ring in 19 leading to the chloroketene
imine intermediate 21 instead of deprotonating the vinyl
proton. The nitrogen atom served as an excellent leaving
group because of its electron de®ciency due to the electro-
negative chlorine atoms.
On the other hand, attempts to effect the reaction by using
different bases (KOH, or NaHCO3), different solvents
(DMSO, THF, CH3CN, or DMF), and different reaction
temperatures (rt to 708C) and durations (12 h to 8 days)
failed to provide the ynamides 7. Finally, isomerization of
the propargylated phthalamide 14 failed to give either the
corresponding allenamide 15 or ynamide 16 under a variety
of conditions (Scheme 3), and in most cases, the starting
material 14 was recovered.
Viehe has also reported similar products resulting from base
treatment of mono-chloroenamides,6 and more signi®cantly,
Viehe found that mono-bromoenamides are better substrates
for base-induced eliminations, leading to the ®rst reported
electron-de®cient ynamines.6 We decided to follow this
approach and prepared chiral enamides 23 and 24 via
p-TsOH catalyzed condensations of corresponding chiral
oxazolidinones and aldehydes.20 However, unlike those
reported by Viehe,6 brominations of 23 and 24 were not
trivial. Standard bromination conditions such as Br2 and
Et3N at a variety of temperatures and solvents led to desired
bromoenamides 25 or 26 in 5±10% yields at the best.
Intriguingly, 60±80% of the starting enamide 23 or 24
was consistently recovered under these conditions, thereby
suggesting a reversible bromine addition that was occurring
in this process. Another possibility would be that enamides
23 and 24 are simply less reactive toward standard bromi-
nation conditions and more drastic conditions were needed.
Chiral allenamides could also be readily prepared using this
base-induced isomerization protocol. As shown in Scheme
4, a variety of chiral allenamides 18a±e were obtained in
high yields over two steps starting from Close's chiral
imidazolidinone 17a,17 Evans' oxazolidinone auxiliaries
17b±d,18 or Sibi's dibenzylidene substituted oxazolidinone
17e.19 It is noteworthy that isomerizations of chiral propar-
gyl amides 17a±e using 20 mol% of t-BuOK in anhydrous
THF provided chiral allenamides 18a±e in much higher
yields than those achiral examples described in Scheme 2.
This could be attributed to the fact that these chiral allen-
amides are even more stable than the achiral ones, and given
such an improved stability and ease of experimental
handling, they can be obtained in gram quantities using
conditions described here.
After exploring a variety of conditions, it was found that by
either re¯uxing 23 with Br2 in 1,2-dichloroethane (Method
A in Scheme 6), or re¯uxing 24 with NBS in 1,2-dichloro-
ethane (Method B), the desired bromoenamides 25 and 26
could be prepared in 67 and 85% yields, respectively. Both
bromoenamides 25 and 26 were isolated as a mixture of E
and Z isomers. The Method A provided 25 with an E/Z ratio
of 1:8, and the Method B provided 26 with an E/Z ratio of
1.5:1, and the E and Z con®gurations of 25 and 26 were
determined using nOe experiments.21 More interestingly,
the Method A appears to work well for enamides where R
is an alkyl substituent, while the Method B only works well
for enamides where R is an aromatic substituent.
Having established that the base-induced isomerization
serves as a practical entry to allenamides but not ynamides,
we began exploring other approaches that may present simi-
lar ef®ciency for synthesis of our ynamides. Because the
literature indicated that dichloroenamides may be converted
to electron-de®cient ynamines using alkyl lithium
reagents,7a the dichloroenamide 19 was prepared from
oxazolidinone and trichloroethylene. The Z stereochemistry
in 19 was assigned based on those examples reported in
literature.7a However, we failed to isolate any desired
ynamide 20 when 19 was treated with either n-BuLi or
t-BuLi (Scheme 5).
Subsequent treatment of 25-Z and 26-Z with 1±2 equiv. of
t-BuOK in THF at room temperature provided the desired
ynamides 27 and 28 in 70 and 36% yields, respectively.
Again, unlike those conditions reported by Viehe,6
When switching to t-BuOK, the carbonate 22 was isolated in
54% yield after stirring at room temperature for 1 h. The
Scheme 5.

462
L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
Scheme 6.
t-BuOK must be added carefully as a solution in THF to the
solution of the enamides 25-Z or 26-Z in THF at 08C before
warming up to room temperature. Severe decomposition
occurred when t-BuOK was added as a solid and/or at
room temperature. The bromoenamides 25-E and 26-E
appeared to be resilient toward t-BuOK induced elimi-
nation. The desired ynamides 27 and 28 were not found
even after re¯uxing 25-E and 26-E with t-BuOK in
THF for 24 h, and the starting materials were
completely recovered. Following the same reaction proto-
col, ynamides 29±32 were prepared in yields ranging from
40±88%.
using t-BuOK led to the ynamide 34 in 50% yield. The
signi®cance of achieving this preparation is that the chiral
ynamide 34 is the ®rst chiral equivalent and electron-
de®cient variant of Ficini's N,N-diethyl-1-amino-1-
propyne.1 Hence, the ynamide 34 should be useful for
preparation of other functionalized chiral ynamides using
similar methods as employed for Ficini's ynamine.1,15
We have described here ef®cient and practical syntheses of
novel ynamides and allenamides. Given the synthetic poten-
tial of these organic synthons as demonstrated in recent
literature and on-going effort from our4,5 as well as other
laboratories,10±14 these preparations should help facilitate
further interests from the synthetic community.
Although this particular sequence for preparations of
ynamides still suffers from the lack of ability to eliminate
the E-bromoenamides, the overall sequence offers a very
short and practical entry to a diverse array of achiral and
chiral ynamides. All these ynamides are very stable
thermally and are relatively more stable than those allen-
amides described above. The ynamide 31 is the least stable
among all the new ynamides prepared here, and thus, it
appears that ynamides are thermodynamically more stable
than allenamides. However, the isomerization protocol
described in Scheme 2, presumably a thermodynamically
driven process, is evidently arrested at the allenamide
stage (see intermediate 6). The reason is not fully clear at
this point except that the deprotonation±protonation process
during the isomerization of 6 to the ynamide 7 must be very
slow, perhaps owing to potential decreasing in the acidity of
the proton alpha to the nitrogen atom.
3. Experimental
3.1. General procedure for preparation of N-allenyl
imidazolidinones/oxazolidinones
3.1.1. Preparation of N-propargyl imidazolidinones and
oxazolidinones. To a homogeneous solution of imidazo-
lidinone/oxazolidinone (5.0 mmol) in anhydrous THF
(30 mL) was added NaH (60 wt% in mineral oil,
1.2 equiv.) in small portions (Caution). The resulting
suspension was stirred for 30 min at room temperature
before the addition of propargyl bromide (2 equiv.). The
precipitation of sodium salt did not affect the reaction.
The mixture was stirred at rt for 16±24 h, after which the
mixture was concentrated and redissolved into ether (,20±
50 mL) and ®ltered through a small bed of celite. The
solvent was concentrated under reduced pressure, and the
residue was puri®ed by ¯ash silica gel column chroma-
tography23 (gradient solvent system: 0±20% EtOAc in
hexane) to provide the desired propargyl products in high
yields (.90%).
Finally, as shown in Scheme 7, the enamide 3322 could also
be subjected to the Method A for bromination to provide the
corresponding bromoenamide in 70% yield with a E/Z ratio
of 1:2. A subsequent elimination of the Z-bromoenamide
3.1.2. Preparation of allenamides. To a homogeneous
solution of the propargyl product prepared above
(5.0 mmol) in anhydrous THF (5.0 mL) was added freshly
made t-BuOK/t-BuOH (200 mg, 20 mol%) under nitrogen.
The reaction mixture was stirred at rt for 16±24 h. The
reaction progress was monitored by TLC (25 or 50%
Scheme 7.

L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
463
1
EtOAc in hexane) or H NMR. After removing the solvent
2H, Jˆ6.3 Hz), 3.64 (t, 2H, Jˆ6.0 Hz), 5.34 (d, 2H,
Jˆ6.3 Hz), 7.49 (t, 1H, Jˆ6.3 Hz); 13C NMR (300 MHz,
CDCl3) d 23.9, 26.0, 28.3, 28.8, 33.9, 44.4, 86.2, 97.3,
172.7, 202.0; IR (neat) cm21 3046m, 2926s, 2858s,
1958w, 1644s, 874s; MS (EI): m/e (% relative intensity)
165 (100) M1, 136 (30), 122 (28), 108 (30); m/e calcd for
C10H15NO 165.1154, measured 165.1158.
under reduced pressure, the crude mixture was redissolved
in ether (,20±50 mL) and ®ltered through a small bed of
celite or basic Al2O3 (25% EtOAc in hexane as eluent). The
solvent was removed under reduced pressure to provide
pure allenamides in high yields (.90%). For all allenamides
except 10 and 18a, further puri®cation can be achieved by
¯ash silica gel column chromatography (gradient solvent
system: 0±50% EtOAc in hexane). The allenamides 10
and 18a could not survive on silica gel (especially in the
case of the allenamide 10, and thus, the Rf value could not
even be determined), and puri®cation may be achieved by
simple ®ltration.
3.1.9. Allenamide 18a. Rfˆ0.45 (50% EtOAc in hexane,
mostly decomposed); mp 113±1158C; [a]2D0ˆ296.9 (c
1
0.13, CHCl3); H NMR (300 MHz, CDCl3) d 0.74 (d, 3H,
Jˆ 6.6 Hz), 2.77 (s, 3H), 3.84 (dq, 1H, Jˆ6.6, 8.7 Hz), 4.68
(d, 1H, Jˆ8.7 Hz), 4.75 (dd, 1H, Jˆ6.3, 9.0 Hz), 5.04 (dd,
1H, Jˆ6.3, 9.0 Hz), 6.96 (t, 1H, Jˆ6.3 Hz), 7.06±7.31 (m,
5H); 13C NMR (75 MHz, CDCl3) d 15.0, 28.8, 55.6, 60.9,
86.7, 96.4, 127.9, 128.2, 128.6, 136.1, 157.9, 202.4 (missing
2 signals due to overlap); IR (neat) cm21 3052s, 2924s,
1961m, 1709s, 1456s, 1401s, 880m; MS (EI) for
C14H16N2O: m/e (% relative intensity) 228 (77) M1, 111
(70), 227 (72), 170 (29), 118 (77), 117 (100); m/e calcd
for C14H16N2O 228.1262, measured 228.1241.
3.1.3. Compound 8. Please see Ref. 8a for literature prece-
dent. Rfˆ0.29 (33% EtOAc in hexane); oil; 1H NMR
(300 MHz, CDCl3) d 2.09 (quint, 2H, Jˆ7.8 Hz), 2.47 (t,
2H, Jˆ 8.1 Hz), 3.41 (t, 2H, Jˆ7.5 Hz), 5.37 (d, 2H,
Jˆ6.6 Hz), 7.08 (t, 1H, Jˆ6.6 Hz); 13C NMR (75 MHz,
CDCl3) d 17.3, 31.0, 45.6, 86.5, 95.6, 172.8, 202.5; IR
(neat) cm21 3031m, 2977m, 1959w, 1692s, 882m; MS
(EI): m/e (% relative intensity) 123 (95) M1, 95 (100), 68
(40); m/e calcd for C7H9NO 123.0684, measured 123.0686.
3.1.10. Allenamide 18b. Rfˆ0.57 (50% EtOAc in hexane,
mostly decomposed); oil; [a]2D0ˆ2156.4 (c 0.225, CHCl3);
1H NMR (300 MHz, CDCl3) d 4.10 (dd, 1H, Jˆ6.0, 8.7 Hz),
4.64 (t, 1H, Jˆ6.0 Hz), 4.78±4.84 (m, 2H), 5.10 (dd, 1H,
Jˆ6.3, 9.6 Hz), 6.73 (t, 1H, Jˆ6.3 Hz), 7.16±7.33 (m, 5H);
13C NMR (75 MHz, CDCl3) d 59.0, 70.6, 87.7, 95.6, 126.5,
128.7, 129.0, 138.4, 155.5, 201.9 (missing 2 signals due
to overlap); IR (neat) cm1 3063m, 3035s, 2979s, 1963w,
1767s, 1494s, 1462s, 1216s, 966m, 911s, 881s; MS
(EI) for C12H11N1O2: m/e (% relative intensity) 201
(15) M1, 200 (14), 156 (100), 129 (17), 115 (19), 104
(45); m/e calcd for C12H11NO2 201.0790, measured
201.0784.
3.1.4. Compound 9. Rfˆ0.42 (50% EtOAc in hexane); mp
1
42±458C; H NMR (300 MHz, CDCl3) d 3.62 (t, 2H, Jˆ
8.1 Hz), 4.44 (t, 2H, Jˆ8.1 Hz), 5.46 (d, 2H, Jˆ6.3 Hz),
6.90 (t, 1H, Jˆ6.3 Hz); 13C NMR (75 MHz, CDCl3) d
42.9, 62.3, 87.7, 96.6, 155.2, 201.3; IR (neat) cm21
3287m, 2923m, 1977m, 1731s, 1434s; MS (EI): m/e (%
relative intensity) 125 (100) M1, 98 (20), 80 (40); m/e
calcd for C6H7NO2 125.0477, measured 125.0475.
1
3.1.5. Compound 10. Oil; H NMR (300 MHz, CDCl3) d
2.84 (s, 3H), 3.41 (m, 4H), 5.39 (d, 2H, Jˆ6.3 Hz), 7.03 (t,
1H, Jˆ 6.3 Hz); 13C NMR (75 MHz, CDCl3) d 30.8, 40.5,
44.3, 87.0, 97.9, 157.2, 201.3; IR (neat) cm21 3032m,
2942s, 2883s, 1958m, 1693s, 885s; MS (EI): m/e (% relative
intensity) 138 (100) M1, 110 (15), 80 (17); m/e calcd for
C7H10N2O 138.0793, measured 138.0797.
3.1.11. Allenamide 18c. Rfˆ0.66 (50% EtOAc in hexane);
mp 108±1128C; [a]D20ˆ260.7 (c 0.30, CHCl3); H NMR
1
(300 MHz, CDCl3) d 4.85 (dd, 1H, Jˆ6.3, 10.0 Hz), 5.13
(d, 1H, Jˆ8.1 Hz), 5.17 (dd, 1H, Jˆ6.3, 10.0 Hz), 5.92 (d,
1H, Jˆ8.1 Hz), 6.80±6.84 (m, 2H), 6.93 (t, 1H, Jˆ6.3 Hz),
6.96±7.09 (m, 8H); 13C NMR (75 MHz, CDCl3) d 64.0,
80.3, 87.6, 95.8, 126.2, 127.3, 127.9, 128.05, 128.09,
128.14, 133.9, 134.0, 155.2, 202.2 (missing 4 signals due
to overlap); IR (neat) cm21 3036m, 2982w, 1961w, 1754s,
1456s, 1396s, 1266s, 1032s, 885m; MS (EI) for
C18H15N1O2: m/e (% relative intensity) 277 (2) M1, 233
(100), 179 (51), 165 (36), 115 (46); m/e calcd for
C18H15NO2 277.1103, measured 277.1097.
3.1.6. Compound 11. Rfˆ0.43 (33% EtOAc in hexane); oil;
1H NMR (300 MHz, CDCl3) d 1.75±1.90 (m, 4H), 2.46 (t,
2H, Jˆ6.3 Hz), 3.31 (t, 2H, Jˆ6.0 Hz), 5.37 (d, 2H,
Jˆ6.3 Hz), 7.61 (t, 1H, Jˆ6.3 Hz); 13C NMR (75 MHz,
CDCl3) d 20.8, 22.4, 32.6, 45.8, 86.8, 98.7, 167.8, 202.0;
IR (neat) cm21 3047s, 2946s, 1956w, 1650s, 873s; MS (EI):
m/e (% relative intensity) 137 (100) M1, 108 (22), 95 (40),
80 (35); m/e calcd for C8H11NO 137.0841, measured
137.0844.
3.1.12. Allenamide 18d. Rfˆ0.59 (50% EtOAc in hexane);
1
3.1.7. Compound 12. Rfˆ0.54 (50% EtOAc in hexane); oil;
1H NMR (300 MHz, CDCl3) d 1.50±1.86 (m, 6H), 2.59 (t,
2H, Jˆ5.4 Hz), 3.48 (t, 2H, Jˆ4.8 Hz), 5.37 (d, 2H,
Jˆ6.6 Hz), 7.44 (t, 1H, Jˆ6.6 Hz); 13C NMR (75 MHz,
CDCl3) d 23.2, 27.4, 29.4, 36.9, 45.7, 87.2, 99.2, 173.5,
201.3; IR (neat) cm21 3043m, 2928s, 2857s, 1959w,
1642s, 876s; MS (EI): m/e (% relative intensity) 151 (100)
M1, 122 (17), 108 (30), 80 (31); m/e calcd for C9H13NO
151.0997, measured 151.1000.
oil; [a]2D0ˆ222.7 (c 0.15, CHCl3); H NMR (300 MHz,
CDCl3) d 2.74 (dd, 1H, Jˆ8.7, 14.0 Hz), 3.23 (dd, 1H, Jˆ
3.0, 14.0 Hz), 4.05±4.25 (m, 3H), 5.51 (dd, 1H, Jˆ6.3,
9.9 Hz), 5.57 (dd, 1H, Jˆ6.3, 9.9 Hz), 6.90 (t, 1H, Jˆ
6.3 Hz), 7.15±7.35 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 37.1, 55.6, 66.7, 88.0, 96.0, 127.3, 128.9, 129.3, 135.4,
154.97, 201.6 (missing 2 signals due to overlap); IR (neat)
cm21 3062m, 3030s, 1961m, 1760s, 1496s, 1456s, 1233s,
1067s, 863s, 800m; MS (EI) for C13H13N1O2: m/e (%
relative intensity) 215 (60) M1, 170 (32), 124 (100), 117
(38), 91 (58); m/e calcd for C13H13NO2 215.0946, measured
215.0942.
3.1.8. Compound 13. Rfˆ0.56 (50% EtOAc in hexane); oil;
1H NMR (300 MHz, CDCl3) d 1.40±1.90 (m, 8H), 2.573 (t,

464
L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
3.1.13. Allenamide 18e. Rfˆ0.64 (50% EtOAc in hexane);
thick foam; [a]D20ˆ2318.3 (c 0.12, CHCl3); 1H NMR
(300 MHz, CDCl3) d 4.39 (dd, 1H, Jˆ3.6, 8.7 Hz), 4.49
(dd, 1H, Jˆ8.7, 8.7 Hz), 4.64 (ddd, 1H, Jˆ3.6, 3.9,
8.7 Hz), 4.72 (d, 1H, Jˆ3.9 Hz), 5.36 (dd, 1H, Jˆ6.6,
10.2 Hz), 5.43 (dd, 1H, Jˆ6.6, 10.2 Hz), 6.86 (t, 1H,
Jˆ6.6 Hz), 7.07±7.38 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 49.3, 57.2, 64.9, 88.2, 96.1, 127.2, 127.7, 128.5,
128.7, 128.9, 129. 2, 138.0, 139.7, 155.0, 201.4 (missing 4
signals due to overlap); IR (neat) cm21 3055m, 3031m,
2924m, 1960w, 1757s, 1458s, 1266s, 889m; MS (EI) for
C19H17N1O2: m/e (% relative intensity) 291 (53) M1, 167
(61), 165 (39), 152 (25), 124 (100), 115 (14); m/e calcd for
C19H17NO2 291.1259, measured 291.1260.
(gradient solvent system: 0±25% EtOAc in hexane) to
provide a separable E/Z mixture of vinyl bromides.
3.2.2. Method B: To a homogeneous solution of enamide
(1.0 mmol) in anhydrous dichloroethane (25 mL) was added
NBS in one shot. The resulting mixture was re¯uxed for 1 h
under nitrogen. After which, the solution was concentrated
under reduced pressure, and the residue puri®ed by ¯ash
silica gel column chromatography (gradient solvent system:
0±20% EtOAc in hexane) to provide a separable E/Z
mixture of vinyl bromides.
3.2.3. Preparation of ynamides 27±32, 34. To a homo-
geneous solution of vinyl bromide (1.0 mmol) at 2108C
in anhydrous THF (50 mL) was added t-BuOK (1.5±
3.0 equiv.) in THF dropwise over 10 min under nitrogen.
The resulting mixture was warmed to room temperature
and stirred for 3 h. After which, the mixture was ®ltered
through celite and concentrated under reduced pressure,
3.1.14. Synthesis of dichloroenamide 19. To a stirred solu-
tion of 2-oxazolidinone (4.44 g, 50 mmol) in 120 mL DMF
was added sodium hydride (2.25 g, 56 mmol) at room
temperature. After 1 h, trichloroethylene (18 mL,
200 mmol) was added and the reaction was stirred for
24 h. Removal of DMF and residual trichloroethylene in
vacuo provided a residue that was partitioned between
CH2Cl2 and H2O. Separation and extraction of the aqueous
layer with CH2Cl2 (3£80 mL), drying of the combined
organic layers (Na2SO4), and evaporation of solvent
provided a brown oil. Column chromatography (hexane/
ethyl acetate) afforded 19 (5.52 g, 61%) as a white solid.
Rfˆ0.68 (5% MeOH in Et2O); mp 65±668C; 1H NMR
(300 MHz, CDCl3) d 3.80 (dd, 2H, Jˆ7.1, 8.6 Hz), 4.45
(dd, 2H, Jˆ7.1, 8.6 Hz), 6.31 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 44.1, 63.0, 116.8, 127.1, 153.9; IR (neat) cm21
3091m, 2988w, 2911w, 1767s, 1623m, 1480m, 1399s; MS
(EI): m/e (% relative intensity) 181 (21) M1,146 (29), 137
(17), 122 (17), 102 (100), 75 (36); m/e calcd for
C5H5NO235Cl37Cl, 182.9668, measured 182.9670.
³
and the residue was puri®ed by ¯ash silica gel chromato-
graphy (gradient solvent system: 0±25% EtOAc in hexane)
to provide the desired ynamides in good to high yields.
3.2.4. Ynamide 27. Rfˆ0.34 (25% EtOAc in hexane); oil;
[a]2D0ˆ144.4 (c 0.54, CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 0.83 (t, 3H, Jˆ7.2 Hz), 0.90 (m, 6H), 1.18±1.36 (m, 4H),
1.40±1.52 (m, 2H), 2.13 (m, 1H), 2.24 (t, 2H, Jˆ 7.2 Hz),
3.85 (ddd, 1H, Jˆ3.9, 5.7, 9.0 Hz), 4.05 (dd, 1H, Jˆ5.7,
9.0 Hz), 4.29 (t, 1H, Jˆ9.0 Hz); 13C NMR (75 MHz,
CDCl3) d 13.9, 15.0, 17.1, 18.4, 22.1, 28.4, 28.9, 31.0,
61.7, 64.5, 69.3, 72.2, 156.7; IR (neat) cm21 2930m,
2264m, 1771s, 1413m, 1198m, 1113m; MS (EI) for
C13H21NO2: m/e (% relative intensity) 222 (5) M2H1179
(100), 167 (61), 94 (46), 70 (48), 55 (52); m/e calcd for
C13H21NO21H 224.1651, measured 224.1655.
3.1.15. Synthesis of compound 22. To a stirred solution of
19 (110.7 mg, 0.61 mmol) in 10 mL THF was added
t-BuOK (141.7 mg, 1.26 mmol). The mixture turned
immediately to a dark brown, and after 1 h, THF was
removed in vacuo. The residue was taken up in CH2Cl2
and ®ltered through a short column of celite to afford 22
(97 mg, 54%) as a dark oil. Rfˆ0.06 (25% EtOAc in
3.2.5. Ynamide 28. Rfˆ0.20 (25% EtOAc in hexane); mp
86±888C; [a]D20ˆ141.9 (c 0.525, CH2Cl2); 1H NMR
(500 MHz, CDCl3) d 0.95 (m, 6H), 2.20 (m, 1H), 3.97
(ddd, 1H, Jˆ3.9, 5.7, 9.0 Hz), 4.11 (dd, 1H, Jˆ5.7,
9.0 Hz), 4.35 (t, 1H, Jˆ9.0 Hz), 7.18±7.26 (m, 3H), 7.32±
7.39 (m, 2H); 13C NMR (75 MHz, CDCl3) d 15.3, 17.2,
29.3, 62.1, 64.9, 72.3, 78.5, 122.4, 128.1, 128.3, 131.5,
156.0 (missing 2 signals due to overlap); IR (neat) cm21
2965w, 2254m, 1764s, 1412m, 1204m, 1089m; MS (EI)
for C14H15NO2: m/e (% relative intensity) 229 (97) M1,
228 (100), 207 (14), 169 (24), 142 (56), 115 (42); m/e
calcd for C14H15NO2 229.1103, measured 229.1105.
1
hexane); oil; H NMR (300 MHz, CDCl3) d 1.46 (s, 9H),
1.49 (s, 9H), 3.57 (t, 2H, Jˆ6.0 Hz), 3.89 (s, 2H), 4.25 (t,
2H, Jˆ6.0 Hz); 13C NMR (75 MHz, CDCl3) d 27.6, 27.9,
35.9, 47.5, 66.9, 80.0, 81.9, 153.5, 157.7 (missing 4 signals
due to overlap); IR (neat) cm21 2976m, 1741s, 1675s,
1367m, 1275s, 1254s; MS (EI): m/e (% relative intensity)
181 (8) M112H-2t-Bu, 164 (11), 119 (50), 106 (11), 57
(100).
3.2.6. Ynamide 29. Rfˆ0.20 (25% EtOAc in hexane); mp
97±988C; [a]D20ˆ2117.7 (c 0.62, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 3.03 (m, 1H), 3.15 (m, 1H), 4.18 (m,
1H), 4.37 (d, 2H, Jˆ4.5 Hz), 7.23±7.48 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 37.9, 58.4, 67.4, 73.2, 77.9, 122.1,
127.5, 128.2, 128.3, 129.0, 129.3, 131.6, 134.1, 155.4
(missing 4 signals due to overlap); IR (neat) cm21 2928w,
2255m, 1773s, 1411m, 1210m, 1086m; MS (EI) for
C18H15NO2: m/e (% relative intensity) 277 (90) M1, 232
(14), 186 (42), 142 (100), 115 (79), 91 (48); Anal. Calcd
3.2. General procedure for preparation of ynamides
3.2.1. Enamide bromination. Method A: To a homo-
geneous solution of enamide (1.0 mmol) in anhydrous 1,2-
dichloroethane (20 mL) at 2408C was added Br2
(1.5 equiv.) in 1,2-dichloroethane (5 mL) dropwise over
10 minutes under nitrogen. The resulting solution was
warmed to room temperature for 30 min before being
subjected to re¯ux for 12 h. After which, the solution was
concentrated under reduced pressure, and the residue was
puri®ed by ¯ash silica gel column chromatography
³
Due to moderate decomposition ynamide 34 was puri®ed utilizing a
basic alumina column.

L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
465
for: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.75; H, 5.60; N,
4.90.
ment of Chemistry Lando/NSF Program for Summer
Research Fellowships.
3.2.7. Ynamide 30. Rfˆ0.33 (25% EtOAc in hexane); oil;
[a]2D0ˆ2108.0 (c 0.565, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 0.91 (t, 3H, Jˆ7.2 Hz), 1.20±1.50 (m, 4H),
1.52±1.62 (m, 2H), 2.36 (t, 2H, Jˆ7.2 Hz), 2.93 (m, 1H),
3.21 (m, 1H), 4.09 (dd, 1H, Jˆ5.4, 8.1 Hz), 4.15±4.30 (m,
1H), 4.30 (t, 1H, Jˆ8.1 Hz), 7.18±7.24 (m, 2H), 7.27±7.38
(m, 3H); 13C NMR (75 MHz, CDCl3) d 13.9, 18.4, 22.1,
28.5, 31.0, 37.7, 58.2, 67.1, 68.9, 73.4, 127.3, 128.9,
129.3, 134.3, 156.1 (missing 2 signals due to overlap); IR
(neat) cm21 2930m, 2266w, 1774s, 1412m, 1186m, 1115m;
MS (EI) for C17H21NO2: m/e (% relative intensity) 271 (5)
M1, 180 (100), 117 (70), 91 (58), 80 (21), 54 (21); Anal.
Calcd for: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.38; H,
7.67; N, 5.16.
References
1. For reviews on chemistry of ynamines see (a) Ficini, J.
Tetrahedron 1976, 32, 1448. (b) Himbert, G. In Methoden
Der Organischen Chemie (Houben-Weyl); Kropf, H.,
Schaumann, E., Eds.; Georg Thieme: Stuttgart, 1993;
pp 3267±3443.
2. For reviews see: (a) Saalfrank, R. W.; Lurz, C. J. In Methoden
Der Organischen Chemie (Houben-Weyl); Kropf, H.,
Schaumann, E., Eds.; Georg Thieme: Stuttgart, 1993; p 3093.
(b) Schuster, H. E.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley: New York, 1984.
3. For the few speci®c examples see: (a) Nijs, R.; Verkruijsse,
H. D.; Harder, S.; van der Kerk, A. C. H. T. M.; Brandsma, L.
3.2.8. Ynamide 31. Rfˆ0.19 (25% EtOAc in hexane); mp
186±1888C; [a]D20ˆ2263.0 (c 0.54, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 0.80 (d, 3H, Jˆ6.6 Hz), 2.86 (s,
3H), 3.95 (m, 1H), 5.05 (d, 1H, Jˆ8.7 Hz), 7.16±7.40 (m,
10H); 13C NMR (75 MHz, CDCl3) d 14.8, 28.9, 55.7, 64.1,
71.4, 81.5, 123.3, 127.1, 127.7, 127.9, 128.5, 131.2, 134.6,
156.1 (missing 4 signals due to overlap); IR (neat) cm21
2932w, 2238m, 1712s, 1428m, 1405m, 1289w, 1170m;
MS (EI) for C19H18N2O: m/e (% relative intensity) 290
(100) M1, 232 (52), 204 (30), 128 (19), 115 (21); m/e
calcd for C19H18N2O 290.1419, measured 290.1419.
Â
Synth. Commun. 1991, 21, 653. (b) Broggini, G.; Bruche, L.;
Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1990, 533.
(c) DeJong, R. L. P.; Brandsma, L. J. Organomet. Chem.
1986, 316, C21. (d) Klop, W.; Klusener, P. A. A.; Brandsma,
L. Recl. J. R. Neth. Chem. Soc. 1984, 103, 27 and 85. (e) Klop,
W.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1983, 988.
(f) Verkruijsse, H. D.; Bos, H. J. T.; de Noten, L. J.; Brandsma,
L. Recl. J. R. Neth. Chem. Soc. 1981, 100, 244.
4. Hsung, R. P.; Zi®csak, C. A.; Wei, L.-L.; Douglas, C. J.;
Xiong, H.; Mulder, J. A. Org. Lett. 1999, 1, 1237.
5. (a) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.;
Nkansah, N. T. Org. Lett. 1999, 1, 2145. (b) Wei, L.-L.;
Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron Lett.
1999, 40, 6903. (c) Xiong, H.; Hsung, R. P.; Wei, L.-L.;
Berry, C. R.; Mulder, J. A.; Stockwell, B. Org. Lett. 2000,
2, 2869.
3.2.9. Ynamide 32. Rfˆ0.17 (25% EtOAc in hexane); oil;
1H NMR (300 MHz, CDCl3) d 0.89 (t, 3H, Jˆ7.2 Hz),
1.20±1.42 (m, 6H), 1.50 (tt, 2H, Jˆ7.5, 7.5 Hz), 2.08 (tt,
2H, Jˆ7.5, 7.5 Hz), 2.33 (t, 2H, Jˆ7.2 Hz), 2.42 (t, 2H,
Jˆ8.4 Hz), 3.65 (t, 2H, Jˆ7.2 Hz); 13C NMR (75 MHz,
CDCl3) d 14.0, 18.5, 18.6, 22.5, 28.5, 28.8, 29.5, 31.3,
50.0, 71.5, 72.6, 176.0; IR (neat) cm21 2928m, 2260m,
1718s, 1397m, 1297m, 1218m; MS (EI) for C12H19NO:
m/e (% relative intensity) 193 (7) M1, 178 (21), 164 (51),
150 (44), 136 (40), 124 (100), 96 (57), 86 (85), 80 (47), 67
(39); m/e calcd for C12H19NO 193.1467, measured
193.1469.
6. For the ®rst examples of ynamides see: (a) Janousek, Z.;
Collard, J.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1972,
11, 917. (b) Gof®n, E.; Legrand, Y.; Viehe, H. G. J. Chem.
Res., Synopsis 1977, 105.
7. For other recent examples see: (a) Joshi, R. V.; Xu, Z.-Q.;
Ksebati, M. B.; Kessel, D.; Corbett, T. H.; Drach, J. C.;
Zemlicka, J. J. Chem. Soc., Perkin Trans. 1 1994, 1089.
(b) Novikov, M. S.; Khlebnikov, A. F.; Kostikov, R. R.
J. Org. Chem. USSR 1991, 27, 1576. (c) Tikhomirov, D. A.;
Eremeev, A. V. Chem. Heterocycl. Comp. 1987, 23, 1141.
(d) Balsamo, A.; Macchia, B.; Macchia, F.; Rossello, A.
Tetrahedron Lett. 1985, 26, 4141.
3.2.10. Ynamide 34. Rfˆ0.40 (33% EtOAc in hexane); oil;
[a]2D0ˆ2124.1 (c 0.395, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 1.81 (s, 3H), 4.19 (dd, 1H, Jˆ6.9, 9.0 Hz), 4.70
(t, 1H, Jˆ8.7 Hz), 5.00 (dd, 1H, Jˆ7.2, 8.7 Hz), 7.32±7.35
(m, 2H), 7.40±7.45 (m, 3H); 13C NMR (75 MHz, CDCl3) d
29.7, 62.0, 67.9, 68.3, 70.7, 126.8, 129.3, 129.4, 136.5,
156.6 (missing 2 signals due to overlap); IR (neat) cm21
2918m, 2270w, 1771s, 1409m, 1188m, 1040m; MS (EI)
for C12H11NO2: m/e (% relative intensity) 201 (100) M1,
156 (63), 142 (52), 103 (44), 91 (51), 66 (83); m/e calcd
for C12H11NO2 201.0790, measured 201.0794.
8. For the ®rst examples of allenamides see: (a) Dickinson, W. B.;
Lang, P. C. Tetrahedron Lett. 1967, 3035. (b) Overman, L. E.;
Marlowe, C. K.; Clizbe, L. A. Tetrahedron Lett. 1979, 599.
Â
9. For hetero-aromatic systems based allenamides see: (a) Radl,
Â
Â
S.; Kovarova, L. Collect. Czech. Chem. Commun. 1991, 56,
2413. (b) Reisch, J.; Salehi-Artimani, R. A. J. Heterocycl.
Chem. 1989, 26, 1803. (c) Mahamoud, A.; Galy, J. P.;
Vincent, E. J. Synthesis 1981, 917. (c) Jones, B. C. N. M.;
Silverton, J. V.; Simons, C.; Megati, S.; Nishimura, H.;
Maeda, Y.; Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1995,
38, 1397.
Acknowledgements
R. P. H. thanks the American Cancer Society for an insti-
tutional grant [IRG-58-001-40-IRG-26]. R. P. H. also
thanks R. W. Johnson Pharmaceutical Institute for a
generous grant from the Focused Giving Program.
C. J. D. thanks Pharmacia-Upjohn and UMN Depart-
10. Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037.
È
11. (a) Witulski, B.; Gobmann, M. J. Chem. Soc., Chem. Commun.
1999, 1879. (b) Witulski, B.; Stengel, T. Angew. Chem., Int.
Ed. Engl. 1998, 37, 489. (c) Witulski, B.; Stengel, T. Angew.
Chem., Int. Ed. Engl. 1998, 38, 2426.

466
L.-L. Wei et al. / Tetrahedron 57 (2001) 459±466
12. Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, N. Tetrahedron
Lett. 1998, 39, 435 (and references cited therein).
13. (a) Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.;
Nakamura, O. Tetrahedron 1996, 52, 6581. (b) Farina, V.;
Kant, J. Tetrahedron Lett. 1992, 33, 3559 and 3563.
14. Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru,
Y. J. Am. Chem. Soc. 1997, 119, 10869 (and references cited
therein).
15. (a) Collard-Motte, J.; Janousek, Z. Top. Curr. Chem. 1986,
130, 89. (b) Viehe, H. G. Chemistry of Acetylenes, Ynamines;
Marcel Dekker: New York, 1969.
16. Katritzky, A. R.; Ramer, W. H. J. Org. Chem. 1985, 50, 852.
17. Close, W. J. J. Org. Chem. 1950, 15, 1131.
18. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77.
19. (a) Sibi, M. P.; Deshpande, P. K.; Ji, J. G. Tetrahedron Lett.
1995, 36, 8965. (b) Sibi, M. P.; Ji, J. G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 190. (c) Sibi, M. P.; Porter, N. A. Acc. Chem.
Res. 1999, 32, 163.
Scheme 8.
1
26 were accomplished by H NMR correlations. The vinyl
protons in Z isomers are consistently and distinctly more
down®eld shifted than those of E isomers (Scheme 8).
22. Kwon, T. W.; Keusenkothen, P. F.; Smith, M. B. J. Org.
Chem. 1992, 57, 6169.
20. Zezza, C. A.; Smith, M. B. Synth. Commun. 1987, 17, 729.
21. For assigning E and Z con®gurations of 25 and 26, nOe experi-
ments were carried out using the following E- and Z-bromo-
enamides which were prepared from the enamide 33.
Subsequent assignments of E and Z con®gurations of 25 and
23. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.