Synthesis of enamides from aldehydes and amides

Article abstract of DOI:10.1016/j.tet.2004.05.082

A range of double unsaturated amides (15, 19, and 21), obtained by cross-coupling reactions was reacted with aldehydes to hemiaminals. Heating the hemiaminals in the presence of Ac₂O and pyridine affected clean conversion to the corresponding enamides, such as 42, 45, and 47. Alternatively, N,S-acetals were prepared which were oxidized to the sulfones. Treatment with base also gave the enamides, favoring the cis-isomer. However, this method is less general. Application of these methods led to the natural products lansiumamide-A (30_cis), lansiumamide-I (31) and lansiumamide-B (32).

Full text of DOI:10.1016/j.tet.2004.05.082

Tetrahedron 60 (2004) 6665–6677
Synthesis of enamides from aldehydes and amides
*
Alexander Bayer and Martin E. Maier
¨
¨
¨
¨
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
Received 9 February 2004; revised 28 April 2004; accepted 24 May 2004
Available online 19 June 2004
Abstract—A range of double unsaturated amides (15, 19, and 21), obtained by cross-coupling reactions was reacted with aldehydes to
hemiaminals. Heating the hemiaminals in the presence of Ac2O and pyridine affected clean conversion to the corresponding enamides, such
as 42, 45, and 47. Alternatively, N,S-acetals were prepared which were oxidized to the sulfones. Treatment with base also gave the enamides,
favoring the cis-isomer. However, this method is less general. Application of these methods led to the natural products lansiumamide-A
(30_cis), lansiumamide-I (31) and lansiumamide-B (32).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A number of natural products are known that contain an
acylated enamine (¼enamide) as a key structural feature
(Fig. 1). These enamides may be further distinguished
whether the carboxylic acid part is saturated or unsaturated.
Protonation of the enamide would lead to a highly
electrophilic acyliminium ion1 which could be involved in
the mode of action of such compounds. Depicted is the
proteasome inhibitor TMC-95A (1),2 the cytotoxic alkaloid
Figure 1. Some natural products that contain an enamide subunit.
Keywords: Enamides; Cross-coupling; N,S-Acetals; Benzolactones.
*
Corresponding author. Tel.: þ49-7071-29-75247; fax: þ49-7071-29-
5137; e-mail address: martin.e.maier@uni-tuebingen.de
Figure 2. Representative benzolactone enamides and analogs 7 and 8.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.082

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A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
chondriamide A (2),3 and the antifungal and cytotoxic
compound crocacin A (3).4
Probably, the most interesting compounds of this class are
the recently discovered benzolactone enamides.5 Some
important benzolactone enamides are apicularen A,6
salicylihalamide A7 and oximidine II (Fig. 2).8 These
compounds have been found to be potent inhibitors of
human cancer cells. It seems that the mode of action is
due to the selective inhibition of mammalian vacuolar
V-ATPases.9 The comparison of the three compounds 5, 7
and 8 clearly demonstrates that the enamide is related to
the biological activity.10 Besides the enamides, there are
also existing hydrated enamides. One example is the
macrolide (2)-zampanolide (9) which contains such a
rather uncommon N-acyl hemiaminal side chain.11 Usually,
aminals and hemiaminals are unstable, however, acylation
confers some hydrolytic stability, possibly due to the
presence of a hydrogen bond.12
While the synthesis of the macrocyclic core of the more
complex enamides represents a challenge for itself, the
establishment of the enamide functionality can be a
bottleneck in a synthesis endeavor. So far, five different
strategies have been described in the context of enamide
natural products: (a) trapping of isocyanates that were
generated by Curtius rearrangement with vinyl metal
species.13 (b) Cross-coupling of a vinyl iodide with an
(unsaturated) amide in the presence of a copper carboxyl-
ate.14 (c) Base-induced elimination of an amide from a
bisacylated aminal.15 (d) Peterson-type elimination of an
acylated amino alcohol with the trialkylsilyl group next to
the nitrogen.16 (e) Rearrangement–hydrolysis of a-silyl-
allyl amides.17
Scheme 1. Synthesis of the (Z,Z)-heptadienamide 15.
The N-acyl hemiaminal can be synthesized by oxidative
decarboxylation from a suitable N-acyl-a-amino acid,12a by
acylation of a protected hemiaminal18 or in a direct fashion
by reaction of an aldehyde with an amide anion.19 In this
paper we present our own studies towards the synthesis of
unsaturated enamides. In the course of this work, we
discovered a practical method for the conversion of
N-acylated hemiaminals to enamides.
Scheme 2. Synthesis of the (Z,Z)-heptadienamide 15 from the heptenyna-
mide 19.
2. Results
2.1. Syntheses of unsaturated amides
Several of the carboxylic acids present in the natural
enamides are highly unsaturated. The presence of cis double
bonds complicates the synthesis and makes these carboxylic
acid derivatives prone to isomerization. In order to prepare
the (Z,Z)-di-unsaturated amide 15 or its ester 14, we
compared the direct diene synthesis, the reduction of the
enyne 18, and the reduction of the diyne 21 (Schemes 1–3).
First, the Z-iodoacrylate 11 was prepared by addition of
hydrogen iodide to the triple bond.20 The direct synthesis
began with pentenoic acid 12 that was converted in two
steps to the Z-bromide 13.21 Metallation to the vinyllithium
intermediate, transmetalation with ZnCl2, followed by
cross-coupling reaction with Z-3-iodoacrylic ester (11)
provided the (Z,Z)-configurated ester 14 in good yield.
Scheme 3. Synthesis of the (Z,Z)-heptadienamide 15 from the heptadiy-
namide 21.
However, under these conditions, isomerization of the
double bond next to the carboxyl group occurred (2Z,4Z/
2E,4Z¼64:36). Moreover, the subsequent aminolysis of the
ester to the amide 15 proceeded in low yield (36%).
A variation of the Fu¨rstner strategy22 started with the
cross-coupling reaction of butynylzinc [prepared from

A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
6667
1-bromo-1-butyne (17)23] with the 3-iodoacrylic ester 11.
While the Lindlar reduction of the enyne 18 provided the
Z,Z-dienoate 14 in high yield, the aminolysis gave the amide
15 only in moderate yield.
Changing the order of events improved the overall yield
(Scheme 2). Thus, aminolysis of the ester 18 gave the
heptenynamide 19 in excellent yield. A selective hydro-
genation under Lindlar conditions then furnished the
Z,Z-configurated amide 15. In order to prevent over-
reduction the consumption of hydrogen has to be carefully
monitored. The X-ray structure analysis revealed that the
amide group of 15 is rotated slightly out of plane of the
diene system.24
A third route to the amide 15 also started with the alkynyl
bromide 17 available by base induced elimination of
HBr from 1,2-dibromobutane (Scheme 3). A diethyl
ether solution of the volatile bromide 17 was coupled in
the presence of CuCl with the alkyne25 20 (Cadiot–
Chodkiewicz–Coupling) providing the diyne 21 in good
yield. A Lindlar hydrogenation also led to the (Z,Z)-amide
15. Like with the other Lindlar reduction, over-reduction
can occur, resulting in formation of Z-configurated
1,2-unsaturated amide 22.
2.2. Formation of enamides from aldehydes and amides
A simple strategy towards enamides would involve the
elimination of water from a N-acylhemiaminal. Initially, we
thought a better leaving group might facilitate the
elimination and prevent the hydrolysis. Using the cinnama-
mide 24 and 2-phenylacetaldehyde (23) as model com-
pounds, various conditions for affecting the desired
transformation were screened (Scheme 4). For example,
treatment of the amide 24 with aldehyde 23 in the presence
of trimethylsilyl triflate gave the bisacylated aminal 25 with
no trace of the hemiaminal 29. Stirring of the aminal
derivative 25 with thiophenol in CHCl3 at 60 8C provided
the thioaminal 26. The chloroform solvent dissolves the
starting material and provides the trace of acid that is
necessary to replace one of the amides from the bisacylated
aminal. Heating, treatment with acid or base did not give
any of the enamide 30 from the hemithioaminal 26.
Therefore, the sulfide 26 was oxidized to the corresponding
sulfone 27 with mCPBA.
Scheme 4. Synthesis of the enamides 30–32 from the sulfone 27 and the
hemiaminal 29.
enamides 30_trans and 30_cis could be converted to the
corresponding N-methyl derivative by deprotonation with
NaH and alkylation with methyl iodide. Compound 31
corresponds to the natural product lansiumamide-I, whereas
the Z-isomer 32 is called lansiumamide B.26 The enamide
30_cis is the natural product lansiumamide A.
An alternative route to the sulfide 26 utilized addition of the
aluminum carboximidoate 28, generated from the amide 24
and diisobutylaluminium hydride,19 to the aldehyde 23
providing the hemiaminal 29 in reasonable yield. Treatment
of this compound with thiophenol in dichloromethane
provided the sulfide 26 as well.
A similar sequence of reactions was utilized to produce the
enamides 38_trans and 38_cis (Scheme 5). In this case, the
cinnamamide 24 ((2E)-3-phenylacrylamide) was reacted
with 3-phenylpropanal (33). Thus, 24 and 33 in presence of
TMSOTf yielded the bisacylated aminal 34 in 79% yield.
Replacement of one amide group with thiophenol led to the
N,S-acetal 35 which served as precursor to the sulfone 36.
Elimination of phenylsulfinic acid under the action of DBU
led to the predominant formation of the cis-isomer 38_cis
(trans/cis ratio¼26:74). The difference can be attributed to
the formation of a conjugated system (influence of the
phenyl group) in the case of 30_trans and 30_cis.
Elimination studies were carried out on the sulfone 27 and
the hemiaminal 29. Thus, stirring a solution of the sulfone
27 in THF in the presence of DBU affected clean
elimination affording the (E)-and (Z)-enamide 30_trans
and 30_cis in good yield (E/Z¼65:35). Alternatively,
formation of the enamide could be affected by refluxing
the hemiaminal 29 in a solution of THF containing acetic
anhydride (15 equiv.) and pyridine (30 equiv.). In this case
however, the E/Z changed slightly to 71:29. Each of the two
The combination of the amide 24 and the aldehyde 33 was
also done with the aza-aldol reaction, resulting in the

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A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
Figure 3. Possible mechanism for the formation of the enamides.
Scheme 5. Synthesis of the enamides 38 from the sulfone 36 and the
hemiaminal 37.
hemiaminal 37. Again, the method using acetic anhydride in
the presence of pyridine gave an excellent yield for the
enamides 38_trans and 38_cis. Remarkably, the isomer
ratio changed under these conditions leading predominantly
to the trans isomer 38_trans. The X-ray structure of this
isomer is shown in Scheme 5.24
Scheme 6. Synthesis of the enamides 42 from the sulfone 41 and the
hemiaminal 39.
view to incorporate them into some benzolactone enamides
(Scheme 6). Thus, the enynamide 19 was converted to the
corresponding aluminiumiminoate and then added to
phenylpropanal 33 resulting in the hemiaminal 39 in good
yield. Treatment with thiophenol in chloroform provided the
N,S-acetal 40. This transacetalization was accompanied by
some isomerization of the double bond. Oxidation of the
sulfide 40 led to the sulfone 41. Elimination of the sulfinic
acid under basic conditions furnished the enamides 42 as a
cis/trans mixture (trans/cis¼25:75). In this case, the route
via the bisaminal and the sulfone was not successful. While
the diaminal from amide 19 and the aldehyde 33 could be
prepared (19% yield) replacement of one amide with a
thiophenol led to a mixture of compounds.
With substrate 37 another set of conditions was tried for the
elimination. Thus, treatment of the hemiaminal 37 with
mesyl chloride, DBU in CH2Cl2 did indeed give the
enamides 38_trans and 38_cis, but only in low yield. The
dominant formation of the cis isomer (trans/cis
ratio¼33:77) points to a similar mechanism for the
elimination step.
Regarding the mechanism of elimination we propose that
the enamide formation via the sulfone and the mesylate
proceeds through an acylimine intermediate, which subse-
quently undergoes tautomerization (Fig. 3). The different
ratios with the Ac2O/pyridine method and the fact that the
elimination needs heating supports a concerted Tschugaew
mechanism.
If the aza-aldol reaction was applied to the diynamide 21,
the corresponding hemiaminal 44 was obtained in lower
yield (Scheme 7). In this case, as a substantial amount of the
trans amide 43 was formed due to reduction of the first triple
bond by DIBAL. After chromatographic separation of the
two compounds, water elimination from 44 provided the
Having established two methods for the formation of the
enamide from an aldehyde and an amide, we next employed
the double unsaturated amides that were prepared with a

A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
6669
Table 1 summarizes the results of the enamide forming
reactions. With exception of the lansiumamide cases
(Scheme 4, enamide 30) it can be outlined that the base-
induced elimination of the sulfones and the mesylates leads
preferentially to the cis isomers whereas the thermal
elimination (Ac2O, pyridine, reflux) produces the trans
enamides as major products.
3. Summary
In summary, we described efficient routes to several double
unsaturated amides using cross-coupling methods. Via the
corresponding aluminium anions, the amides were reacted
with aldehydes such as 3-phenylpropanal. Conversion of the
resulting hemiaminals to the enamides was affected by
simply heating the hemiaminal in the presence of acetic
anhydride and pyridine. Due to some reduction of the triple
bond by DIBAL, the hemiaminal formation was less
efficient in the case of the diynamide 21. In some cases,
the enamide was formed from the bisacylated aminals which
were obtained from the unsaturated amide and an aldehyde.
Replacement of one amide group by thiophenol, oxidation
to the sulfone and base-induced elimination also can provide
the enamide structure. However, we found this method to be
less general and it also involves more steps. Both of the
methods provide the enamides as cis/trans mixtures. While,
the dehydration of the hemiaminals usually gives the trans-
isomer as the major product, the elimination of the sulfinic
acid favors the cis-isomer. With these methods the natural
products lansiumamide were synthesized. The dehydration
procedure has great potential for application toward the
synthesis of natural benzolactone enamides, such as
apicularen A. Studies along these lines are currently
underway in our laboratory.
Scheme 7. Synthesis of the enamides 45_trans and 45_cis containing a
diynamide.
enamides 45, with the trans isomer being the major
diastereomer (trans/cis¼63:37). With the diynamide 21
and aldehyde 33 the bisacylated aminal could be obtained
(76%), but the subsequent reaction with thiophenol did not
give the desired N,S-acetal.
Finally, this direct synthesis of an enamide was performed
with the Z,Z-dienamide 15 and the aldehyde 33. As it turned
out, both steps proceeded with good efficiency. Thus,
reaction of the aluminum anion of the amide 15 with
aldehyde 33 gave the hemiaminal 46 in 84% yield. The
subsequent dehydration under the action of acetic anhydride
and pyridine furnished the enamides 47_trans and 47_cis in
high yield. Again, the trans isomer 47_trans was slightly
favored over the corresponding cis isomer (trans/cis¼
69:31) (Scheme 8).
4. Experimental
4.1. General
1H and 13C NMR: Bruker Avance 400, spectra were
recorded at 295 K either in CDCl3, C6D6, DMSO-d6,
THF-d8, acetone-d6 or DMF-d7; chemical shifts are
calibrated to the residual proton and carbon resonance of
the solvent: CDCl3 (dH 7.25, dC 77.0 ppm), C6D6 (dH 7.16,
dC 128.0 ppm), DMSO-d6 (dH 2.49, dC 39.5 ppm), THF-d8
(dH 1.73, 3.58, dC 25.3, 67.4 ppm), acetone-d6 (dH 2.04, dC
29.8, 206.7 ppm), or DMF-d7 (dH 2.74, 2.91, 8.01, dC 30.1,
35.2, 162.7 ppm). Melting points: Bu¨chi Melting Point
B-540, uncorrected. IR: Jasco FT/IR-430. EI-MS: Finnigan
Triple-Stage-Quadrupol (TSQ-70). HRMS (FT-ICR):
Bruker Daltonic APEX 2 with electron spray ionization
(ESI). Flash chromatography: J. T. Baker silica gel
43–60 mm. Thin-layer chromatography Machery-Nagel
Polygram Sil G/UV254. Solvents were distilled prior to
use; petroleum ether with a boiling range of 40–60 8C was
used. Reactions were generally run under an argon
atmosphere. Compounds 16 (1,2-dibromobutane) and 24
(cinnamamide) were obtained from commercial sources.
The preparation of 14 from 18, and 15 from 14 was
performed according to the literature.22 Compounds 11,20
13,21 and 2025 were prepared according to the literature.
Scheme 8. Synthesis of the enamides 47_trans and 47_cis containing a Z,Z-
dienamide.
Table 1. Comparison of isolated yields and trans/cis-ratios
Entry Enamide
DBU, THF,
reflux
MsCl, DBU,
CH2Cl2, reflux
Ac2O, py, THF,
reflux
Yield trans/cis Yield trans/cis Yield trans/cis
(%)
(%)
(%)
1
2
3
4
5
30
38
42
45
47
92
86
71
—
—
65:35
26:74
25:75
—
—
23
29
—
—
—
92
95
75
25
83
71:29
69:31
70:30
63:37
69:31
33:77
35:65
—
—
—

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A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
General procedure 1 for aza-aldol-reaction. To a well
stirred solution of the amide (1 equiv.) in dry THF
(4 mL/mmol) was added DIBAL (1.0 M in hexane,
1.15 equiv.) dropwise at 0 8C. After the mixture was stirred
for 30 min at 0 8C, the aldehyde (1.5 equiv.) was added. The
resulting solution was stirred overnight at 0 8C, before it was
diluted with ethyl acetate (10 mL/mmol) and quenched with
water (10 mL/mmol) at 0 8C. After separation of the layers,
the aqueous layer was extracted with ethyl acetate (2£
10 mL/mmol). The combined organic layers were washed
with brine (2 mL/mmol), dried over MgSO4, filtered, and
concentrated in vacuo.
portions at 210 8C m-chloroperbenzoicacid (mCPBA)
(2.2 equiv.), which was purified by washing three times
with pH 7 buffer and drying in vacuo prior to use. The
mixture was allowed to warm to 0 8C within 30 min. The
resulting suspension was diluted with CH2Cl2, filtered,
washed with CH2Cl2, and concentrated in vacuo.
General procedure 7 for coupling of an amide with an
aldehyde to give a diacylated aminal. To a well stirred
suspension of cinnamamide (2 equiv.) in dry CH2Cl2
(1 mL/mmol) was added the aldehyde (1.1 equiv.) and
trimethylsilyltrifluoromethane sulfonate (0.025 equiv.). The
mixture was vigorously stirred overnight at room tempera-
ture, diluted with toluene (1 mL/mmol), and filtered. The
precipitate was washed several times with toluene
(0.05 mL/mmol) and dried under reduced pressure to yield
the pure product.
General procedure 2 for elimination-reaction by inter-
mediate acetylation. To a stirred solution of the hydroxy-
amide (1 equiv.) in dry THF (15 mL/mmol) was added dry
pyridine (30 equiv.) and dry acetic anhydride (15 equiv.).
After refluxing the mixture for 3 days, it was cooled to room
temperature, and diluted with ethyl acetate (200 mL/mmol)
and water (100 mL/mmol). The layers were separated,
and the organic layer was washed with saturated NH4Cl
solution (3£75 mL/mmol), water (75 mL/mmol) and brine
(25 mL/mmol), dried over MgSO4, filtered, and concen-
trated in vacuo.
General procedure 8 for substitution of an amide from a
diamide with thiophenol. To a well stirred suspension of the
diamide (1 equiv.) in CHCl3 (25 mL/mmol) was added
thiophenol (1 equiv.). The mixture was heated under reflux
overnight, and concentrated in vacuo.
General procedure 9 for aminolysis. To a stirred solution of
the methyl ester (1 equiv.) in methanol (0.65 mL/mmol)
was added a 25% solution of ammonia in water
(17 mL/mmol). After vigorously stirring at room tempera-
ture for four days, the mixture was extracted with ethyl
acetate (5£17 mL/mmol). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
General procedure 3 for elimination-reaction by inter-
mediate mesylation. To a well stirred solution of the
hydroxyamide (1 equiv.) in dry CH2Cl2 (10 mL/mmol) was
added dry 1,8-diazabicyclo-[5.4.0]-undec-7-en (DBU)
(1.2 equiv.) at 0 8C. After the mixture was stirred for
10 min at 0 8C, mesylchloride (1.1 equiv.) was added. The
solution was stirred for another 15 min at 0 8C, before
additionally dry DBU (1.2 equiv.) was added at 0 8C. The
mixture was allowed to reach room temperature, and stirred
overnight. After quenching the reaction by addition of
water (10 mL/mmol), the layers were separated, and the
aqueous layer was extracted with dichloromethane (2£
10 mL/mmol). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo.
4.1.1. (2Z,4Z)-Hepta-2,4-dienoic methyl ester (14). To a
stirred suspension of lithium (0.017 g, 2.5 mmol, 5.0 equiv.)
in dry diethyl ether (2 mL) was slowly added a solution
of (1Z)-1-bromobut-1-ene21 (13) (0.17 g, 1.3 mmol,
2.5 equiv.) in dry diethyl ether (1 mL) within 1 h at 0 8C.
The resulting reaction mixture was stirred for additional
30 min at room temperature, before the remaining unreacted
lithium was removed. The mixture was again cooled to
0 8C, and a solution of zinc chloride (0.19 g, 1.4 mmol,
2.8 equiv.) in dry THF (2 mL) was added. After stirring for
20 min at 0 8C, a solution of Z-3-iodoacrylic methylester
(11) (0.11 g, 0.50 mmol, 1 equiv.) and bis(acetonitrile)
palladium(II) chloride (0.013 g, 0.050 mmol, 0.10 equiv.)
in dry THF (3 mL) was added at 0 8C. The reaction mixture
was allowed to reach room temperature, and stirred
overnight. After quenching the reaction by addition of
water (25 mL), the layers were separated, and the aqueous
layer was extracted with diethyl ether (3£20 mL). The
combined organic layers were washed with brine (5 mL),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the crude product by flash chromatography
(petroleum ether/diethyl ether, 25:1) gave 0.049 g (70%) of
14 as a colorless oil (2Z,4Z/2E,4Z¼64:36). Data for the
major product: TLC (petroleum ether/diethyl ether, 25:1):
Rf¼0.39; 1H NMR (CDCl3): d 1.02 (t, J¼7.6 Hz, 3H, CH3),
2.27 (dtd, J¼15.2, 7.6, 1.3 Hz, 2H, CH2), 3.72 (s, 3H,
OCH3), 5.67 (d, J¼11.6 Hz, 1H, CH), 5.86–5.94 (m, 1H,
CH), 6.93 (dd, J¼11.9, 11.6 Hz, 1H, CH), 7.18–7.23 (m,
1H, CH); 13C NMR (CDCl3): d 13.9 (C-7), 20.8 (C-6), 51.1
(OCH3), 116.9 (C-2), 123.7 (C-4), 139.0 (C-5), 143.3 (C-3),
167.0 (CO); IR (film): 2967, 2938, 2875, 1720, 1631, 1592,
General procedure 4 for methylation of enamides. To a well
stirred solution of the enamide (1 equiv.) in dry THF
(12.5 mL/mmol) was slowly added sodium hydride
(1.05 equiv.) at 0 8C. After the mixture was stirred for 1 h
at 0 8C, methyl iodide (1.1 equiv.) was added. The mixture
was allowed to reach room temperature, and stirred
overnight. After quenching the reaction by addition of
water (60 mL/mmol), the layers were separated, and the
aqueous layer was extracted with diethyl ether (2£
60 mL/mmol). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo.
General procedure 5 for substitution of hydroxyamide with
thiophenol. To a well stirred solution of the hydroxyamide
(1 equiv.) in dry CH2Cl2 (10 mL/mmol) and dry THF
(2 mL/mmol) was added thiophenol (1.2 equiv.). After
stirring overnight at room temperature, silica gel was
added to the reaction mixture, followed by concentration in
vacuo.
General procedure 6 for oxidation of phenylthioamide with
mCPBA. To a well stirred solution of phenylthioamide
(1 equiv.) in dry CH2Cl2 (15 mL/mmol) was added in small

A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
6671
1444, 1365, 1289, 1231, 1195, 1175, 1132 cm21; MS (EI),
m/z (%): 140 (24) [M]þ, 111 (100), 109 (16), 81 (32), 79
(34), 55 (8), 53 (11), 41 (9), 39 (8); HRMS (EI): [M]þ calcd
for C8H12O2 140.083721, found 140.086261.
1332, 1230, 1134 cm21; MS (EI), m/z (%): 127 (40) [M]þ,
112 (37), 98 (100), 81 (80), 69 (40), 59 (58), 55 (76), 44
(67), 41 (72); HRMS (EI): [M]þ calcd for C7H13NO
127.099705, found 127.100488.
4.1.2. (2Z,4Z)-Hepta-2,4-dienamide (15). (a) From diyna-
mide 21. To a stirred suspension of commercially available
Lindlar catalyst (0.005 g, 0.30 mol%) and quinoline
(0.024 mL, 0.12 mmol, 12 mol%) in methanol (5 mL),
was added diynamide 21 (0.061 g, 0.50 mmol, 1 equiv.)
and the resulting suspension was vigorously stirred under an
atmosphere of H2 (approximately 1 atm). The consumption
of H2 was carefully monitored and the reaction stopped after
175 min, when a decrease in the consumption of H2 was
noticed. The mixture was filtered through a pad of Celite,
washed with methanol (3£5 mL), and concentrated in
vacuo. Purification of the crude product by flash chroma-
tography (petroleum ether/ethyl acetate, 3:2) gave 0.050 g
(80%) of 15 as colorless crystals.
4.1.3. 1-Bromobut-1-yne (17). In a round-bottomed flask
connected with a cold trap, which was cooled to 260 8C, a
well stirred suspension of potassium tert-butanolate (11.2 g,
0.10 mol, 2.0 equiv.) and [18]-crown-6 (0.026 g, 0.10 mmol,
0.0020 equiv.) in dry diethyl ether (50 mL) was slowly
treated with 1,2-dibromobutane (16) (6.1 mL, 50 mmol,
1.0 equiv.). After the reflux from the exothermic reaction
ceases, the mixture was heated at 40 8C under reflux of the
cold trap for 2 h. While the mixture was cooling down to
room temperature, in a second flask, bromine (3.86 mL,
75 mmol, 1.5 equiv.) was slowly added to a solution of
potassium hydroxide (11.2 g, 0.20 mol, 4 equiv.) in water
(50 mL) at 25 8C. This solution was added to the reaction
mixture of but-1-yne, and the resulting mixture was
vigorously stirred at 25 8C for 7 h. After separation of the
phases, the aqueous layer was extracted with diethyl ether
(3£50 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo (up to 700 mbar
at 40 8C) to yield 4.34 g (61%) of a colorless, 75 M solution
of 1-bromobut-1-yne (17) in diethyl ether (concentration
was estimated from the NMR integration). 1H NMR
(CDCl3): d 1.13 (t, J¼7.6 Hz, 3H, CH3), 2.20 (q, J¼
7.6 Hz, 2H, CH2); 13C NMR (CDCl3): d 13.4 (C-4), 13.4
(C-3), 37.1 (C-1), 81.6 (C-2); IR (film): 3272, 3062, 3034,
2925, 1722, 1683, 1628, 1532, 1448, 1344, 1308, 1209,
1146, 1081 cm21; MS (EI), m/z (%): 134 (95) [M, 81Br]þ,
132 (100) [M, 79Br]þ, 119 (48) [M2CH3, 81Br]þ, 117 (53)
[M2CH3, 79Br]þ, 53 (29); HRMS (EI): [M]þ calcd for
C4H5Br 131.95746, found 131.95807.
(b) From (2Z)-hept-2-en-4-ynamide (19). To a stirred
suspension of commercially available Lindlar catalyst
(0.010 g, 1.2 mol%) and quinoline (0.015 mL,
0.075 mmol, 15 mol%) in methanol (5 mL), was added
(2Z)-hept-2-en-4-ynamide (19) (0.062 g, 0.50 mmol,
1 equiv.) and the resulting suspension was vigorously
stirred under an atmosphere of H2 (approximately 1 atm).
The consumption of H2 was carefully monitored and the
reaction stopped, when a decrease in the consumption of H2
was noticed. The mixture was filtered through a pad of
Celite, washed with methanol (3 £ 5 mL), and concentrated
in vacuo. Purification of the crude product by flash
chromatography (petroleum ether/ethyl acetate, 1:3) gave
0.050 g (80%) of 15 as colorless crystals.
(c) From (Z,Z)-configurated ester 14. (2Z,4Z)-Hepta-2,4-
dienoic methyl ester (14) (0.18 g, 1.3 mmol) was converted
to 15 according to general procedure 9. Purification of the
crude product by flash chromatography (petroleum ether/
ethyl acetate, 1:1) gave 0.058 g (36%) of 15 as colorless
crystals.
4.1.4. (2Z)-Hept-2-en-4-ynamide (19). (2Z)-Hept-2-en-4-
ynoic methyl ester (18) (0.207 g, 1.50 mmol) was converted
to amide 19 according to general procedure 9. Purification
of the crude product by flash chromatography (petroleum
ether/ethyl acetate, 1:3) gave 0.175 g (95%) of 19 as a
colorless solid, mp 48 8C. TLC (petroleum ether/ethyl
1
acetate, 1:3): Rf¼0.33; H NMR (CDCl3): d 1.20 (t, J¼
Data for amide 15. Mp 82 8C; TLC (petroleum ether/ethyl
1
7.6 Hz, 3H, CH3), 2.44 (qd, J¼7.6, 2.0 Hz, 2H, CH2), 6.02
(d, J¼12.1 Hz, 1H, CH), 6.07 (td, J¼12.1, 2.0 Hz, 1H, CH),
6.20 (s, br, 1H, NH2), 7.17 (s, br, 1H, NH2); 13C NMR
(CDCl3): d 13.3 (C-7), 13.5 (C-6), 76.4 (C-4), 105.3 (C-5),
117.7 (C-3), 132.4 (C-2), 167.2 (CO); IR (film): 3355, 3194,
2981, 2942, 2881, 2279, 2210, 1665, 1606, 1435, 1324,
1238, 1061 cm21; MS (EI), m/z (%): 123 (25) [M]þ, 122
(100) [M2H]þ, 108 (18), 95 (30), 82 (68), 77 (36), 54 (29),
39 (26); HRMS (EI): [M2H]þ calcd for C7H8NO
122.06059, found 122.05986.
acetate, 1:1): Rf¼0.41; H NMR (CDCl3): d 1.02 (t, J¼
7.6 Hz, 3H, CH3), 2.25 (dtd, J¼15.2, 7.6, 1.5 Hz, 2H, CH2),
5.39–5.74 (s, br, 2H, NH2), 5.64 (d, J¼11.5 Hz, 1H, CH),
5.81–5.87 (m, 1H, CH), 6.81 (dd, J¼11.9, 11.5 Hz, 1H,
CH), 7.17–7.23 (m, 1H, CH); 13C NMR (CDCl3): d 14.0
(C-7), 20.7 (C-6), 119.1 (C-2), 123.6 (C-4), 136.4 (C-3),
142.1 (C-5), 168.5 (CO); IR (film): 3396, 3196, 3009, 2967,
2934, 1651, 1606, 1455, 1369, 1326, 1299, 1263, 851 cm21
;
MS (EI), m/z (%): 125 (6) [M]þ, 109 (5), 96 (100), 81 (22),
79 (28), 67 (14), 53 (12), 41 (12), 39 (14); HRMS (EI): [M]þ
calcd for C7H11NO 125.084064, found 125.085354.
4.1.5. Hepta-2,4-diynamide (21). To a well stirred suspen-
sion of hydroxylamine hydrochloride (0.34 g, 5.0 mmol,
0.73 equiv.), copper(I) chloride (0.062 g, 0.63 mol,
0.093 equiv.) and propylamine (0.96 mL, 12 mmol,
1.7 equiv.) in dry methanol (25 mL) was added propiol-
amide (20) (0.47 g, 6.8 mmol, 1 equiv.) at 30 8C. After the
further addition of dry methanol (10 mL), a 75 M solution of
1-bromobut-1-yne (17) in diethyl ether diluted with dry
methanol (15 mL) was added dropwise at 30 8C. After the
mixture was stirred overnight at 30 8C, methanol was partly
Data for amide 22. Mp 70 8C; TLC (petroleum ether/ethyl
acetate, 1:3): Rf¼0.48; 1H NMR (CDCl3): d 0.88 (t,
J¼7.1 Hz, 3H, CH3), 1.28–1.43 (m, 4H, CH2), 2.59–2.65
(m, 2H, CH2), 5.49 (s, br, 1H, NH2), 5.72 (dt, J¼11.6,
1.5 Hz, 1H, CH), 5.76 (s, br, 1H, NH2), 5.99–6.06 (m, 1H,
CH); 13C NMR (CDCl3): d 13.9 (C-7), 22.3 (C-6), 28.4
(C-5), 31.4 (C-4), 121.2 (C-2), 147.1 (C-3), 168.6 (CO); IR
(KBr): 3381, 3195, 2951, 2924, 2860, 1670, 1617, 1438,

6672
A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
evaporated. The resulting suspension was diluted with water
(100 mL) and extracted with a 1:1 mixture of diethyl ether
and ethyl acetate (4£100 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the crude product by flash chromatography
(petroleum ether/ethyl acetate, 1:1) gave 0.70 g (86%) of 21
as colorless leaflets, mp 149 8C. TLC (petroleum ether/
ethyl acetate, 1:1): Rf¼0.49; 1H NMR (acetone-d6): d
1.15 (t, J¼7.6 Hz, 3H, CH3), 2.39 (q, J¼7.6 Hz, 2H, CH2),
6.99 (s, br, 1H, NH2), 7.44 (s, br, 1H, NH2); 13C NMR
(acetone-d6): d 13.1 (C-6), 13.2 (C-7), 63.5 (C-4), 69.3
(C-3), 69.6 (C-2), 88.0 (C-5), 153.7 (CO); IR (KBr): 3316,
3274, 3205, 2988, 2942, 2769, 2406, 2248, 2158, 1652,
1608, 1457, 1389, 1312, 1200, 1130, 1063 cm21; MS (EI),
m/z (%): 121 (93) [M]þ, 105 (100), 93 (40), 77 (64), 51 (47);
HRMS (EI): [M]þ calcd for C7H7NO 121.05276, found
121.05473.
4.1.8. (2E)-3-Phenyl-N-[2-phenyl-1-(phenylsulfonyl)-
ethyl]acrylamide (27). Phenylthioamide 26 (1.43 g,
3.97 mmol) was converted to phenylsulfonylamide 27
according to general procedure 6. Purification of the
reaction mixture by flash chromatography (petroleum
ether/ethyl acetate, 3:1) gave 0.991 g (64%) of 27 as
colorless oil. TLC (petroleum ether/ethyl acetate, 3:1):
1
Rf¼0.30; H NMR (CDCl3): d 3.20 (dd, J¼14.6, 10.9 Hz,
1H, CH2Ph), 3.70 (dd, J¼14.6, 3.8 Hz, 1H, CH2Ph), 5.73
(ddd, J¼10.9, 10.4, 3.8 Hz, 1H, CHSO2Ph), 6.22 (d, J¼
15.7 Hz, 1H, CH), 6.48 (d, br, J¼10.4 Hz, 1H, NH), 7.18–
7.64 (m, 13H, CHar), 7.29 (d, J¼15.7 Hz, 1H, CH),0 7.95–
8.01 (m, 2H, CHar); 13C NMR (CDCl3): d 32.7 (C-2 ), 69.6
(C-10), 118.5 (C-2), 127.3 (CHar), 127.9 (CHar), 127.9
(CHar), 128.8 (CHar), 128.8 (CHar), 128.8 (CHar), 128.8
(CHar), 129.2 (CHar), 129.2 (CHar), 129.2 (CHar), 129.2
(CHar), 129.2 (CHar), 129.2 (CHar), 130.2 (CHar), 134.1
(Car), 134.3 (CHar), 134.5 (Car), 136.5 (Car), 142.8 (C-3),
164.8 (CO); IR (film): 3272, 3062, 3034, 2925, 1722, 1683,
4.1.6. 1,1-Dicinnamido-2-phenylethane (25). Conversion
of phenylacetaldehyde (23) (5.05 mL, 55.0 mmol) accord-
ing to general procedure 7 gave 16.4 g (83%) of diamide 25
as a colorless solid, mp 181 8C. TLC (petroleum ether/ethyl
1628, 1532, 1448, 1344, 1308, 1209, 1146, 1081 cm21
;
HRMS (ESI): [MþNa]þ calcd for C23H21NNaO3S
414.11344, found 414.11377.
1
acetate, 1:1): Rf¼0.53; H NMR (DMF-d7): d 3.13–3.15
(m, 2H, CH2Ph), 5.92–5.99 (m, 1H, CH), 6.74 (d, J¼
15.7 Hz, 2H, CH), 7.10–7.56 (m, 15H, CHar), 7.49 (d, J¼
15.7 Hz, 2H, CH), 8.54 (d, br, J¼7.6 Hz, 2H, NH); 130C
NMR (DMF-d7): d 41.1 (C-2), 58.9 (C-1), 122.7 (C-2 ),
127.0 (CHar), 128.3 (CHar), 128.3 (CHar), 128.9 (CHar),
128.9 (CHar), 129.6 (CHar), 129.6 (CHar), 130.0 (CHar),
130.0 (CHar), 130.2 (CHar), 135.9 (Car), 138.6 (Car), 140.1
(C-30), 165.3 (CO); IR (KBr): 3376, 3283, 3175, 3029, 1662,
4.1.9. (2E)-N-(1-Hydroxy-2-phenylethyl)-3-phenylacryl-
amide (29). Cinnamamide (24) (0.294 g, 2.00 mmol) was
converted to hydroxyamide 29 according to general
procedure 1 by treatment with phenylacetaldehyde (23).
Purification of the crude reaction mixture by flash
chromatography (dichloromethane/acetone, 5:1) gave
0.117 g (40%) of unreacted amide and 0.307 g (58%) of
29 as a colorless solid, mp 111 8C. TLC (petroleum ether/
ethyl acetate, 1:1): Rf¼0.45; 1H NMR (THF-d8): d
2.84–2.94 (m, 2H, CH2Ph), 5.16 (d, J¼4.0 Hz, 1H, OH),
5.62–5.68 (m, 1H, CHOH), 6.50 (d, J¼15.7 Hz, 1H, CH),
7.11–7.51 (m, 10H, CHar), 7.54 (d, J¼15.7 Hz, 1H, CH),
7.630(d, br, J¼7.8 Hz, 1H, NH); 13C NMR (THF-d8): d 43.5
(C-2 ), 75.3 (C-10), 122.7 (C-2), 126.8 (CHar), 128.4 (CHar),
128.7 (CHar), 129.5 (CHar), 130.0 (CHar), 130.5 (CHar),
136.5 (Car), 138.9 (C-3), 140.6 (Car), 165.3 (CO); IR (KBr):
3347, 3279, 3060, 3029, 2934, 2914, 1652, 1597, 1539,
1451, 1227, 1079, 1055 cm21; HRMS (ESI): [MþNa]þ
calcd for C17H17NNaO2 290.11515, found 290.11525.
1630, 1562, 1512, 1449, 1399, 1350, 1234, 1206, 975 cm21
;
HRMS (ESI): [MþNa]þ calcd for C26H24N2NaO2
419.17300, found 419.17275.
4.1.7. (2E)-3-Phenyl-N-[2-phenyl-1-(phenylthio)ethyl]-
acrylamide (26). (a) From diamide 25. Diamide 25
(3.97 g, 10.0 mmol) was converted to phenylthioamide 26
according to general procedure 8. Purification of the
reaction mixture by flash chromatography (petroleum
ether/ethyl acetate, 3:1) gave 1.12 g (28%) of unreacted
starting material 25 and 1.13 g (31%) of 26 as a colorless
solid.
4.1.10. (2E)-3-Phenyl-N-[(E/Z)-2-phenylvinyl]acryl-
amide (30). (a) From sulfone 27. A solution of phenyl-
sulfonylamide 27 (0.059 g, 0.15 mmol, 1 equiv.) and dry
DBU (0.024 mL, 0.16 mmol, 1.05 equiv.) in dry THF
(5.0 mL) was stirred at room temperature overnight. The
mixture was diluted with water (15 mL), and extracted with
diethyl ether (3£15 mL). The combined organic layers were
washed with brine (3 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash
chromatography (petroleum ether/ethyl acetate, 4:1) gave
0.034 g (92%) of 30 as yellow crystals (E/Z¼65:35).
(b) From hydroxyamide 29. Hydroxyamide 29 (0.067 g,
0.25 mmol) was converted to phenylthioamide 26 according
to general procedure 5. Purification of the crude product by
flash chromatography (petroleum ether/ethyl acetate, 3:1)
gave 0.060 g (67%) of 26 as a colorless solid, mp 98 8C.
TLC (petroleum ether/ethyl acetate, 3:1): Rf¼0.45; 1H
NMR (THF-d8): d 3.06–3.18 (m, 2H, CH2Ph), 5.84–5.89
(m, 1H, CHSPh), 6.42 (d, J¼15.7 Hz, 1H, CH), 7.13–7.50
(m, 15H, CHar), 7.44 (d, J¼15.7 Hz, 1H, CH), 7.720 (d, br,
J¼9.1 Hz, 1H, NH); 13C NMR (THF-d8): d 42.9 (C-2 ), 58.2
(C-10), 121.9 (C-2), 127.3 (CHar), 127.5 (CHar), 128.4
(CHar), 128.4 (CHar), 128.9 (CHar), 128.9 (CHar), 129.5
(CHar), 129.5 (CHar), 129.5 (CHar), 129.5 (CHar), 130.0
(CHar), 130.2 (CHar), 130.2 (CHar), 132.2 (CHar), 132.2
(CHar), 135.5 (Car), 136.4 (Car), 138.4 (Car), 141.0 (C-3),
165.0 (CO); IR (KBr): 3242, 3059, 3026, 2920, 2750, 1949,
1880, 1652, 1620, 1548, 1495, 1483, 1449, 1439, 1348,
1284, 1215 cm21; HRMS (ESI): [MþNa]þ calcd for
C23H21NNaOS 382.12361, found 382.12370.
(b) From hydroxyamide 29. Hydroxyamide 29 (0.027 g,
0.10 mmol) was converted to enamide 30 according to
general procedure 2. Purification of the crude product by
flash chromatography (petroleum ether/ethyl acetate, 3:1)
gave 0.023 g (92%) of 30 as yellow crystals (E/Z¼71:29).
Compound 30_trans. Mp 210 8C; TLC (petroleum ether/
1
ethyl acetate, 2:1): Rf¼0.54; H NMR (DMSO-d6): d 6.24

A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
6673
(d, J¼14.7 Hz, 1H, CH), 6.71 (d, J¼15.9 Hz, 1H, CH),
7.13–7.58 (m, 10H, CHar), 7.60 (m, 1H, CH), 7.61 (m, 1H,
CH), 10.48 (d, br, J¼10.1 Hz, 1H, NH); 13C NMR (DMSO-
d6): d 112.2 (C-20), 120.9 (C-2), 123.7 (C-10), 125.2 (CHar),
125.2 (CHar), 126.2 (CHar), 127.8 (CHar), 127.8 (CHar),
128.7 (CHar), 128.7 (CHar), 129.0 (CHar), 129.0 (CHar),
129.9 (CHar), 134.6 (Car), 136.5 (Car), 140.6 (C-3), 162.6
(CO); IR (KBr): 3220, 3027, 1951, 1883, 1805, 1745, 1637,
3025, 1658, 1637, 1614, 1495, 1449, 1362, 1176, 1111,
1085 cm21; MS (EI), m/z (%): 263 (5) [M]þ, 207 (5), 172
(5), 131 (26), 103 (27), 84 (100); HRMS (EI): [M]þ calcd
for C18H17NO 263.13101, found 263.13218.
4.1.13. 1,1-Dicinnamido-3-phenylpropane (34). Conver-
sion of phenylpropanal (33) (7.83 mL, 59.2 mmol) accord-
ing to general procedure 7 gave 17.5 g (79%) of diamide 34
as a colorless solid, mp 176 8C. TLC (petroleum ether/ethyl
1608, 1518, 1486, 1450, 1345, 1243, 1195 cm21
.
1
acetate, 1:1): Rf¼0.35; H NMR (DMSO-d6): d 2.01–2.07
Compound 30_cis. Mp 124 8C; TLC (petroleum ether/ethyl
acetate, 2:1): Rf¼0.70; 1H NMR (CDCl3): d 5.83 (d,
J¼9.8 Hz, 1H, CH), 6.37 (d, J¼15.4 Hz, 1H, CH), 7.13 (dd,
J¼11.1, 9.8 Hz, 1H, CH), 7.25–7.52 (m, 10H, CHar), 7.73
(d, J¼15.4 Hz, 1H, CH), 7.74 (d, br0, J¼11.1 Hz, 1H, NH);
13C NMR (CDCl3): d 110.6 (C-2 ), 119.4 (C-2), 122.3
(C-10), 127.0 (CHar), 128.0 (CHar), 128.0 (CHar), 128.0
(CHar), 128.0 (CHar), 128.9 (CHar), 128.9 (CHar), 129.2
(CHar), 129.2 (CHar), 130.2 (CHar), 134.5 (Car), 135.8 (Car),
143.1 (C-3), 163.1 (CO); IR (KBr): 3241, 3052, 3023, 1952,
1899, 1661, 1644, 1625, 1512, 1488, 1451, 1337, 1256,
1205, 1190 cm21; MS (EI), m/z (%): 249 (28) [M]þ, 207
(14), 149 (28), 131 (100), 119 (84), 103 (84), 77 (49);
HRMS (EI): [M]þ calcd for C17H15NO 249.11536, found
249.11360.
(m, 2H, CH2), 2.63 (dd, J¼8.1, 7.6 Hz, 2H, CH2Ph), 5.53–
5.61 (m, 1H, CH), 6.70 (d, J¼15.9 Hz, 2H, CH), 6.95–7.57
(m, 15H, CHar), 7.46 (d, J¼15.9 Hz, 2H, CH), 8.51 (d,
J¼7.6 Hz, 2H, NH); 13C NMR (DMSO-d6): d 31.1 (C-3),
35.7 (C-2), 55.9 (C-1), 122.0 (C-20), 125.8 (CHar), 127.5
(CHar), 127.5 (CHar), 128.3 (CHar), 128.3 (CHar), 128.3
(CHar), 128.3 (CHar), 129.0 (CHar), 129.0 (CHar), 129.5
(CHar), 134.9 (Car), 139.2 (C-30), 141.2 (Car), 164.3 (CO);
IR (KBr): 3282, 3115, 3024, 2952, 2918, 2858, 1659, 1628,
1562, 1519, 1448, 1349, 1209, 1090, 971 cm21; HRMS
(ESI): [MþNa]þ calcd for C27H26N2NaO2 433.18865,
found 433.18870.
4.1.14. (2E)-3-Phenyl-N-[3-phenyl-1-(phenylthio)propyl]-
acrylamide (35). (a) From diamide 34. Diamide 34 (0.31 g,
0.75 mmol) was converted to phenylthioamide 35 according
to general procedure 8. Purification of the reaction mixture
by flash chromatography (petroleum ether/ethyl acetate,
3:1) gave 0.19 g (67%) of 35 as a colorless solid.
4.1.11. (2E)-N-Methyl-3-phenyl-N-[(E)-2-phenylvinyl]-
acrylamide (31). Enamide 30_trans (0.040 g, 0.16 mmol)
was converted to N-methyl-enamide 31 according to general
procedure 4. Purification of the crude product by flash
chromatography (petroleum ether/ethyl acetate, 4:1) gave
0.037 g (88%) of 31 as yellow crystals, mp 118 8C. TLC
(petroleum ether/ethyl acetate, 4:1): Rf¼0.38; 1H NMR
(250 MHz, 356 K, DMSO-d6): d 3.03 (s, 3H, CH3), 6.18
(d, J¼14.7 Hz, 1H, CH), 7.14–7.47 (m, 8H, CHar), 7.37
(d, J¼15.3 Hz, 1H, CH), 7.62 (d, J¼15.3 Hz, 1H, CH),
(b) From hydroxyamide 37. Hydroxyamide 37 (0.070 g,
0.25 mmol) was converted to phenylthioamide 35 according
to general procedure 5. Purification of the crude product by
flash chromatography (petroleum ether/ethyl acetate, 3:1)
gave 0.081 g (87%) of 35 as a colorless solid, mp 108 8C.
TLC (petroleum ether/ethyl acetate, 3:1): Rf¼0.47; 1H
NMR (CDCl3): d 2.07–2.22 (m, 2H, CH2), 2.76–2.96 (m,
2H, CH2Ph), 5.59–5.65 (m, 1H, CHSPh), 5.82 (d, br,
J¼9.6 Hz, 1H, NH), 6.24 (d, J¼15.4 Hz, 1H, CH), 7.18–
7.50 (m, 15H, CHar), 7.54 (d, J¼15.4 Hz, 1H, CH); 13C
NMR (CDCl3): d 32.6 (C-30), 37.7 (C-20), 56.5 (C-10), 119.8
(C-2), 126.1 (CHar), 127.7 (CHar), 127.8 (CHar), 127.8
(CHar), 128.4 (CHar), 128.4 (CHar), 128.5 (CHar), 128.5
(CHar), 128.8 (CHar), 128.8 (CHar), 129.0 (CHar), 129.0
(CHar), 129.9 (CHar), 132.5 (CHar), 132.5 (CHar), 132.5
(Car), 134.5 (Car), 140.7 (Car), 141.9 (C-3), 164.8 (CO); IR
(KBr): 3284, 3026, 2918, 2855, 1650, 1615, 1525, 1449,
1348, 1220, 1026, 975 cm21; HRMS (ESI): [MþNa]þ calcd
for C24H23NNaOS 396.13926, found 396.13914.
7.72–7.76 (m, 2H, CHar), 7.93 (d, J¼14.7 Hz, 1H, CH); 13
C
NMR (62.9 MHz, 356 K, DMSO-d6): d 30.9 (CH3), 111.1
(C-20), 117.9 (C-2), 125.2 (CHar), 125.2 (CHar), 125.7
(CHar), 127.7 (CHar), 127.7 (CHar), 128.1 (CHar), 128.1
(CHar), 128.1 (CHar), 128.3 (CHar), 128.3 (CHar), 129.3
(C-10), 134.6 (Car), 136.5 (Car), 142.6 (C-3), 164.6 (CO); IR
(KBr): 3080, 3028, 1653, 1636, 1608, 1448, 1386, 1344,
1295, 1226, 1116, 978, 965 cm21; MS (EI), m/z (%): 263
(19) [M]þ, 172 (7), 160 (18), 131 (100), 103 (60), 77 (37);
HRMS (EI): [M]þ calcd for C18H17NO 263.131005, found
263.136118.
4.1.12. (2E)-N-Methyl-3-phenyl-N-[(Z)-2-phenylvinyl]-
acrylamide (32). Hydroxyamide 30_cis (0.040 g,
0.16 mmol) was converted to N-methyl-enamide 32 accord-
ing to general procedure 4. Purification of the crude product
by flash chromatography (petroleum ether/ethyl acetate,
4:1) gave 0.034 g (81%) of 32 as yellow crystals, mp 74 8C.
TLC (petroleum ether/ethyl acetate, 4:1): Rf¼0.36; 1H
NMR (CDCl3): d 3.02 (s, 3H, CH3), 6.17 (d, J¼8.6 Hz, 1H,
CH), 6.43 (d, J¼8.6 Hz, 1H, CH), 6.86 (d, J¼15.4 Hz, 1H,
CH), 7.14–7.39 (m, 10H, CHar), 7.56 (d, J¼15.4 Hz, 1H,
CH); 13C NMR (CDCl3): d 34.6 (CH3), 118.3 (C-2), 125.0
(C-20), 127.9 (CHar), 127.9 (CHar), 128.1 (CHar), 128.6
(C-10), 128.6 (CHar), 128.6 (CHar), 128.6 (CHar), 128.7
(CHar), 128.7 (CHar), 128.8 (CHar), 129.7 (CHar), 134.4
(Car), 135.2 (Car), 142.7 (C-3), 166.4 (CO); IR (KBr): 3060,
4.1.15. (2E)-3-Phenyl-N-[3-phenyl-1-(phenylsulfonyl)-
propyl]acrylamide (36). Phenylthioamide 35 (1.51 g,
4.03 mmol) was converted to phenylsulfonylamide 36
according to general procedure 6. Purification of the
reaction mixture by flash chromatography (petroleum
ether/ethyl acetate, 2:1) gave 1.48 g (91%) of 36 as a
colorless solid, mp 62 8C. TLC (petroleum ether/ethyl
acetate, 2:1): Rf¼0.34; 1H NMR (CDCl3): d 2.13–2.24
(m, 1H, CH2), 2.60–2.69 (m, 1H, CH2), 2.73–2.86 (m, 2H,
CH2Ph), 5.59–5.65 (m, 1H, CHSO2Ph), 6.26 (d, J¼
15.7 Hz, 1H, CH), 6.32 (d, br, J¼10.4 Hz, 1H, NH),
7.15–7.62 (m, 11H, CHar), 7.48 (d, J¼15.7 Hz, 1H, CH),
7.86–8.08 (m, 4H, CHar); 13C NMR (CDCl3): d 28.5 (C-20),

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A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
31.5 (C-30), 69.0 (C-10), 118.7 (C-2), 126.4 (CHar), 127.9
(CHar), 127.9 (CHar), 128.4 (CHar), 128.4 (CHar), 128.6
(CHar), 128.6 (CHar), 128.8 (CHar), 128.8 (CHar), 129.0
(CHar), 129.0 (CHar), 129.1 (CHar), 129.1 (CHar), 130.1
(CHar), 134.2 (CHar), 134.2 (Car), 136.4 (Car), 139.8 (Car),
142.8 (C-3), 165.3 (CO); IR (KBr): 3285, 3060, 3029, 2932,
2858, 1726, 1661, 1631, 1531, 1447, 1344, 1307, 1207,
1145, 1082, 975 cm21; HRMS (ESI): [MþNa]þ calcd for
C24H23NNaO3S 428.12909, found 428.12923.
(CHar), 129.9 (CHar), 134.5 (Car), 140.4 (Car), 142.4 (C-3),
163.0 (CO); IR (KBr): 3263, 3188, 3064, 3027, 2904, 1650,
1625, 1527, 1346, 1223, 950 cm21
.
Compound 38_cis. Mp 118 8C; TLC (petroleum ether/ethyl
1
acetate, 2:1): Rf¼0.65; H NMR (CDCl3): d 3.46 (d, J¼
7.3 Hz, 2H, CH2Ph), 5.05 (dt, J¼8.3, 7.3 Hz, 1H, CH), 6.31
(d, J¼15.4 Hz, 1H, CH), 7.01 (dd, J¼8.3, 10.6 Hz, 1H, CH),
7.15 (d, br, J¼10.6 Hz, 1H, NH), 7.25–7.48 (m, 10H, CHar),
7.620 (d, J¼15.4 Hz, 1H, CH); 13C NMR (CDCl3): d 32.2
(C-3 ), 109.6 (C-20), 119.7 (C-2), 122.4 (C-10), 126.5 (CHar),
127.9 (CHar), 127.9 (CHar), 128.3 (CHar), 128.3 (CHar),
128.7 (CHar), 128.7 (CHar), 128.8 (CHar), 128.8 (CHar),
130.0 (CHar), 134.5 (Car), 139.5 (Car), 142.5 (C-3), 163.0
(CO); IR (KBr): 3272, 3192, 3058, 3026, 2897, 1650, 1618,
1516, 1340, 1255, 1210, 980 cm21; MS (EI), m/z (%): 263
(52) [M]þ, 172 (80), 131 (100), 103 (75), 77 (61); HRMS
(EI): [M]þ calcd for C18H17NO 263.131005, found
263.132184.
4.1.16. (2E)-N-(1-Hydroxy-3-phenylpropyl)-3-phenyl-
acrylamide (37). Cinnamamide 24 (1.47 g, 10.0 mmol)
was converted to hydroxyamide 37 according to general
procedure 1 by treatment with 3-phenylpropanal. Purifi-
cation of the crude product by flash chromatography
(petroleum ether/ethyl acetate, 3:2) gave 2.70 g (96%) of
37 as a colorless solid, mp 114 8C. TLC (petroleum ether/
ethyl acetate, 1:1): Rf¼0.52; 1H NMR (DMSO-d6): d 1.74–
1.89 (m, 2H, CH2), 2.56–2.68 (m, 2H, CH2Ph), 5.24–5.31
(m, 1H, CHOH), 5.75 (d, J¼4.8 Hz, 1H, OH), 6.66 (d,
J¼15.9 Hz, 1H, CH), 7.15–7.56 (m, 10H, CHar), 7.41 (d,
J¼15.9 Hz, 1H, CH), 8.47 (d,0 J¼8.6 Hz, 1H, NH); 130C
NMR (DMSO-d6): d 30.9 (C-3 ), 38.0 (C-20), 72.0 (C-1 ),
122.4 (C-2), 125.7 (CHar), 127.5 (CHar), 128.3 (CHar), 128.3
(CHar), 128.9 (CHar), 129.5 (CHar), 134.9 (Car), 139.1 (C-3),
141.7 (Car), 164.2 (CO); IR (KBr): 3283, 3063, 3025,
2959, 2921, 2856, 1656, 1626, 1537, 1455, 1360, 1328,
1221, 1042 cm21; HRMS (ESI): [MþNa]þ calcd for
C18H19NNaO2 304.13080, found 304.13083.
4.1.18. (2Z)-N-(1-Hydroxy-3-phenylpropyl)hept-2-en-4-
ynamide (39). Amide 19 (0.123 g, 1.00 mmol) was
converted to hydroxyamide 39 according to general
procedure 1 by treatment with 3-phenylpropanal (33).
Purification of the crude product by flash chromatography
(petroleum ether/ethyl acetate, 1:1) gave 0.213 g (83%) of
39 as a colorless solid, mp 80 8C. TLC (petroleum ether/
1
ethyl acetate, 1:1): Rf¼0.37; H NMR (C6D6): d 0.77 (t,
J¼7.3 Hz, 3H, CH3), 1.77–2.02 (m, 2H, CH2), 1.87 (qd,
J¼7.3, 2.2 Hz, 2H, CH2), 2.64–2.80 (m, 2H, CH2Ph), 4.60
(s, br, 1H, OH), 5.55 (dt, J¼12.1, 2.2 Hz, 1H, CH), 5.62 (m,
1H, CHOH), 5.93 (d, J¼12.1 Hz, 1H, CH), 7.02–7.13 (m,
5H, CHar), 7.66 (d, br, J¼6.8 Hz, 1H, NH); 13C NMR
(C6D6): d 13.1 (C-7), 13.3 (C-6), 31.4 (C-30), 37.7 (C-20),
74.3 (C-10), 77.0 (C-4), 104.7 (C-5), 116.8 (C-3), 126.2
(CHar), 127.9 (CHar), 128.1 (CHar), 128.7 (CHar), 128.7
(CHar), 133.3 (C-2), 141.7 (Car), 165.3 (CO); IR (KBr):
3262, 3178, 3060, 2972, 2213, 1656, 1608, 1543, 1318,
1278, 1226, 1174 cm21; HRMS (ESI): [MþNa]þ calcd for
C16H19NNaO2 280.13080, found 280.13070.
4.1.17. (2E)-3-Phenyl-N-[(1E/Z)-3-phenylprop-1-enyl]-
acrylamide (38). (a) From sulfone 36. A solution of
phenylsulfonylamide 36 (0.125 g, 0.308 mmol, 1 equiv.)
and dry DBU (0.0487 mL, 0.323 mmol, 1.05 equiv.) in dry
THF (7.5 mL) was heated under reflux for 4 h. The mixture
was allowed to reach room temperature, diluted with water
(25 mL), and extracted with diethyl ether (3£25 mL). The
combined organic layers were washed with brine (5 mL),
dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash chromatography
(petroleum ether/ethyl acetate, 4:1) gave 0.070 g (86%) of
38 as colorless crystals (E/Z¼26:74).
4.1.19. (2E/Z)-N-[3-Phenyl-1-(phenylthio)propyl]hept-2-
en-4-ynamide (40). Hydroxyamide 39 (0.028 g,
0.11 mmol) was converted to phenylthioamide 40 according
to general procedure 5. Purification of the reaction mixture
by flash chromatography (petroleum ether/ethyl acetate,
4:1) gave 0.035 g (91%) of 40 as a colorless solid (E/
Z¼20:80).
(b) From hydroxyamide 37. Hydroxamide 37 (0.056 g,
0.20 mmol) was converted to enamide 38 according to
general procedure 2. Purification of the crude product by
flash chromatography (petroleum ether/ethyl acetate, 3:1)
gave 0.050 g (95%) of 38 as colorless crystals (E/Z¼69:31).
Conversion of hydroxyamide 37 (0.051 g, 0.18 mmol) to
enamide 38 was also performed according to general
procedure 3. Purification by flash chromatography (petro-
leum ether/ethyl acetate, 3:1) gave 0.011 g (23%) of 38 as
colorless crystals (E/Z¼33:67).
Compound 40_trans. Mp 111 8C; TLC (petroleum ether/
1
ethyl acetate, 4:1): Rf¼0.52; H NMR (THF-d8): d 1.13 (t,
J¼7.6 Hz, 3H, CH3), 1.93–2.12 (m, 2H, CH2), 2.34 (td,
J¼7.6, 2.3 Hz, 2H, CH2), 2.73 (dd, J¼8.1, 7.8 Hz, 2H,
CH2Ph), 5.52–5.58 (m, 1H, CHSPh), 6.13 (d, J¼15.4 Hz,
1H, CH), 6.58 (dt, J¼15.4, 2.3 Hz, 1H, CH), 7.10–7.25 (m,
8H, CHar), 7.38–7.40 (m, 2H, CHar), 7.78 (d, br, J¼9.4 Hz,
1H, NH); 13C NMR (THF-d8): d 13.8 (C-7), 14.0 (C-6), 33.5
(C-3(0), 38.9 (C-20), 56.9 (C-10), 78.5 (C-4), 99.5 (C-5),
122.2 (C-3), 126.7 (CHar), 127.7 (CHar), 129.1 (CHar), 129.1
(CHar), 129.2 (CHar), 129.2 (CHar), 129.5 (CHar), 129.5
(CHar), 132.7 (CHar), 132.7 (CHar), 132.9 (C-2), 134.9 (Car),
142.2 (Car), 164.3 (CO); IR (KBr): 3292, 3056, 2920, 2845,
2215, 1644, 1615, 1530, 1483, 1455, 1317, 1274, 1216,
Compound 38_trans. Mp 132 8C; TLC (petroleum ether/
1
ethyl acetate, 2:1): Rf¼0.58; H NMR (CDCl3): d 3.44 (d,
J¼7.3 Hz, 2H, CH2Ph), 5.41 (dt, J¼13.9, 7.3 Hz, 1H, CH),
6.43 (d, J¼15.4 Hz, 1H, CH), 7.08 (dd, J¼13.9, 10.9 Hz,
1H, CH), 7.23–7.55 (m, 10H, CHar), 7.25 (d, br, J¼10.9 Hz,
1H, NH), 7.75 (d, J¼15.4 Hz, 1H, CH); 13C NMR (CDCl3):
d 36.2 (C-30), 112.7 (C-20), 119.8 (C-2), 123.7 (C-10), 126.2
(CHar), 127.9 (CHar), 127.9 (CHar), 128.4 (CHar), 128.4
(CHar), 128.4 (CHar), 128.4 (CHar), 128.8 (CHar), 128.8

A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
6675
1197, 1166, 1079, 1025 cm21; HRMS (ESI): [MþNa]þ
gave 0.018 g (75%) of 42 as colorless crystals (E/Z¼70:30).
Conversion of hydroxyamide 39 (0.025 g, 0.097 mmol) to
enamide 42 was also performed according to general
procedure 3. Purification by flash chromatography (petro-
leum ether/ethyl acetate, 3:1) gave 5.0 mg (42%) of amide 19
and 6.7 mg (29%) of 42 as colorless crystals (E/Z¼35:65).
calcd for C22H23NNaOS 372.13926, found 372.13937.
Compound 40_cis. Mp 74 8C; TLC (petroleum ether/ethyl
1
acetate, 4:1): Rf¼0.43; H NMR (THF-d8): d 1.12 (t, J¼
7.6 Hz, 3H, CH3), 1.98–2.15 (m, 2H, CH2), 2.34 (td, J¼7.6,
0.8 Hz, 2H, CH2), 2.34 (dd, J¼8.1, 7.8 Hz, 2H, CH2Ph),
5.51–5.57 (m, 1H, CHSPh), 5.95 (m, 2H, 2£CH), 7.10–
7.27 (m, 8H, CHar), 7.41–7.43 (m, 2H, CHar), 7.69 (d, br,
J¼9.4Hz, 1H, NH); 13C NMR (THF-d8): d 13.6 (C-7), 13.8
(C-6), 33.2 (C-30), 38.8 (C-20), 56.7 (C-10), 77.5 (C-4), 103.3
(C-5), 117.4 (C-3), 126.5 (CHar), 127.6 (CHar), 128.9
(CHar), 128.9 (CHar), 129.0 (CHar), 129.0 (CHar), 129.4
(CHar), 129.4 (CHar), 132.7 (CHar), 132.7 (CHar), 132.9 (C-
2), 134.6 (Car), 141.9 (Car), 163.7 (CO); IR (KBr): 3227,
3056, 3028, 2979, 2207, 1652, 1606, 1537, 1455, 1317,
1286, 1263, 1227, 1152, 1087, 1040 cm21; HRMS (ESI):
[MþNa]þ calcd for C22H23NNaOS 372.13926, found
372.13904.
Compound 42_trans. Mp 89 8C; TLC (petroleum ether/ethyl
acetate, 2:1): Rf¼0.55; 1H NMR (C6D6): d 0.71 (t, J¼
7.3 Hz, 3H, CH3), 1.79 (qd, J¼7.3 Hz, 2.0 Hz, 2H, CH2),
3.12 (d, J¼7.3 Hz, 2H, CH2Ph), 5.08 (dt, J¼14.2, 7.3 Hz,
1H, CH), 5.50 (dt, J¼12.1, 2.0 Hz, 1H, CH), 5.93 (d,
J¼12.1 Hz, 1H, CH), 7.02–7.14 (m, 5H, CHar), 7.29 (dd,
J¼14.2, 10.6 Hz, 1H, CH), 8.51 (d, br, J¼10.6 Hz, 1H,
NH); 13C NMR (C6D6): d 13.2 (C-7), 13.2 (C-6), 36.5
(C-30), 77.0 (C-4), 104.6 (C-5), 111.5 (C-20), 116.4 (C-3),
124.2 (C-10), 126.3 (CHar), 127.9 (CHar), 128.1 (CHar),
128.3 (CHar), 128.7 (CHar), 133.2 (C-2), 141.0 (Car), 161.3
(CO); IR (KBr): 3234, 3032, 2976, 2205, 1645, 1603, 1526,
1300, 1275, 1226, 1081 cm21
.
4.1.20. (2Z)-N-[3-Phenyl-1-(phenylsulfonyl)propyl]hept-
2-en-4-ynamide (41). Phenylthioamide 40 (0.017 g,
0.049 mmol) was converted to phenylsulfonylamide 41
according to general procedure 6, with additional stirring of
the reaction mixture at 0 8C for 2 h before workup.
Purification of the reaction mixture by flash chroma-
tography (petroleum ether/ethyl acetate, 2:1) gave 0.018 g
(96%) of 41 as colorless crystals, mp 52 8C. TLC (petroleum
Compound 42_cis. Mp 73 8C; TLC (petroleum ether/ethyl
acetate, 2:1): Rf¼0.63; 1H NMR (C6D6): d 0.66 (t, J¼
7.3 Hz, 3H, CH3), 1.74 (dq, J¼7.3, 2.0 Hz, 2H, CH2), 3.16
(d, J¼7.6 Hz, 2H, CH2Ph), 4.75 (dt, J¼8.7, 7.6 Hz, 1H,
CH), 5.52 (dt, J¼12.1, 2.0 Hz, 1H, CH), 5.99 (d, J¼12.1 Hz,
1H, CH), 6.96–7.12 (m, 5H, CHar), 7.36 (dd, J¼8.7, 7.9 Hz,
1H, CH), 9.01 (d, br, J¼7.9 Hz, 1H, NH); 13C NMR (C6D6):
d 13.1 (C-7), 13.4 (C-6), 32.7 (C-30), 770.1 (C-4), 105.1
(C-5), 109.0 (C-20), 116.1 (C-3), 122.8 (C-1 ), 126.5 (CHar),
127.9 (CHar), 128.1 (CHar), 128.3 (CHar), 128.8 (CHar),
133.4 (C-2), 139.8 (Car), 161.5 (CO); IR (KBr): 3265, 3027,
2205, 1651, 1607, 1523, 1265, 1218, 1113 cm21; MS (EI),
m/z (%): 239 (13) [M]þ, 224 (17) [M2CH3]þ, 210 (15)
[M2Et]þ, 148 (46), 132 (53), 122 (100), 107 (56), 91 (98),
77 (64); HRMS (EI): [M]þ calcd for C16H17NO
239.131005, found 239.133176.
1
ether/ethyl acetate, 2:1): Rf¼0.35; H NMR (THF-d8): d
1.20 (t, J¼7.6 Hz, 3H, CH3), 2.00–2.11 (m, 1H, CH2), 2.46
(td, J¼7.6, 2.2 Hz, 2H, CH2), 2.49–2.56 (m, 1H, CH2),
2.64–2.72 (m, 1H, CH2Ph), 2.76–2.83 (m, 1H, CH2Ph),
5.28–5.34 (m, 1H, CHSO2Ph), 5.84 (d, J¼11.6, 1H, CH),
5.99 (dt, J¼11.6, 2.2, 1H, CH), 7.12–7.25 (m, 5H, CHar),
7.47–7.62 (m, 3H, CHar), 7.85–7.86 (m, 2H, CHar), 7.98 (d,
br, J¼10.4 Hz, 1H, NH); 13C NMR (THF-d8): d 13.7 (C-7),
14.1 (C-6), 29.8 (C-20), 32.3 (C-30), 69.1 (C-10), 77.5 (C-4),
104.9 (C-5), 118.7 (C-3), 126.9 (CHar), 129.2 (CHar), 129.2
(CHar), 129.2 (CHar), 129.2 (CHar), 129.6 (CHar), 129.6
(CHar), 130.1 (CHar), 130.1 (CHar), 132.0 (C-2), 134.4
(CHar), 138.8 (Car), 141.6 (Car), 163.8 (CO); IR (KBr):
3295, 3063, 3025, 2977, 2935, 2207, 1660, 1608, 1525,
1449, 1322, 1305, 1214, 1149, 1084 cm21; HRMS (ESI):
[MþNa]þ calcd for C22H23NNaO3S 404.12909, found
404.12926.
4.1.22. N-(1-Hydroxy-3-phenylpropyl)hepta-2,4-diyna-
mide (44). Amide 21 (0.12 g, 1.0 mmol) was converted to
hydroxyamide 44 according to general procedure 1 by
treatment with 3-phenylpropanal (33). Purification of the
reaction mixture by flash chromatography (petroleum ether/
ethyl acetate, 3:2) gave 0.069 g (27%) of 43 as a yellow oil
and 0.089 g (35%) of 44 as a colorless oil.
4.1.21. (2Z)-N-[(1E/Z)-3-Phenylprop-1-enyl]hept-2-en-4-
ynamide (42). (a) From sulfone 41. A solution of
phenylsulfonylamide 41 (9.2 mg, 0.024 mmol, 1 equiv.)
and dry DBU (3.8 mL, 0.025 mmol, 1.05 equiv.) in dry THF
(2.0 mL) was heated under reflux overnight. The mixture
was cooled to room temperature, and diluted with water
(2 mL) and ethyl acetate (10 mL). The organic layer was
washed with saturated NH4Cl solution (3 mL), water (3 mL)
and brine (2 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash
chromatography (petroleum ether/ethyl acetate, 2:1) gave
4.1 mg (71%) of 42 as colorless crystals (E/Z¼25:75).
Data for 43. TLC (petroleum ether/ethyl acetate, 1:1):
Rf¼0.59; 1H NMR (CDCl3): d 1.17 (t, J¼7.6 Hz, 3H, CH3),
1.86–2.07 (m, 2H, CH2), 2.37 (qd, J¼7.6, 2.1 Hz, 2H,
CH2), 2.68–2.86 (m, 2H, CH2Ph), 3.75 (s, br, 1H, OH),
5.36–5.41 (m, 1H, CHOH), 5.94 (d, br, J¼5.8 Hz, 1H, NH),
6.01 (d, J¼15.4 Hz, 1H, CH), 6.68 (dt, J¼15.4, 2.1 Hz, 1H,
CH), 7.16–7.31 (m, 5H, CHar); 13C NMR (CDCl3): d 13.4
(C-7), 13.4 (C-6), 30.9 (C-30), 36.3 (C-20), 74.4 (C-10), 77.2
(C-4), 101.2 (C-5), 123.9 (C-3), 126.2 (CHar), 128.4 (CHar),
128.4 (CHar), 128.6 (CHar), 128.6 (CHar), 130.5 (C-2), 140.8
(Car), 165.9 (CO); IR (film): 3227, 2977, 2958, 2885, 2243,
2214, 1655, 1614, 1534, 1456, 1367, 1314, 1192, 1121,
1068, 1037 cm21; HRMS (ESI): [MþNa]þ calcd for
C16H19NNaO2 280.13080, found 280.13083.
(b) From hydroxyamide 39. Hydroxyamide 39 (0.026 g,
0.10 mmol) was converted to enamide 42 according to
general procedure 2. Purification of the crude product by
flash chromatography (petroleum ether/ethyl acetate, 3:1)
Data for 44. TLC (petroleum ether/ethyl acetate, 1:1):
Rf¼0.66; 1H NMR (THF-d8): d 1.15 (t, J¼7.6 Hz, 3H, CH3),

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A. Bayer, M. E. Maier / Tetrahedron 60 (2004) 6665–6677
1.75–1.90 (m, 2H, CH2), 2.35 (q, J¼7.6 Hz, 2H, CH2),
2.60–2.74 (m, 2H, CH2Ph), 5.22 (d, br, J¼4.1 Hz, 1H, OH),
5.27–5.33 (m, 1H, CHOH), 7.09–7.23 (m, 5H, CHar), 8.27
(d, br, J¼7.8 Hz, 1H, NH)0; 13C NMR (THF-d8): d 13.3
(C-7), 13.4 (C-6), 32.2 (C-2 ), 38.7 (C-30), 63.9 (C-4), 68.8
(C-2), 70.1 (C-3), 73.7 (C-10), 87.3 (C-5), 126.5 (CHar),
129.0 (CHar), 129.0 (CHar), 129.1 (CHar), 129.1 (CHar),
142.8 (Car), 151.9 (CO); IR (film): 3272, 3028, 2984, 2940,
2243, 2152, 1635, 1532, 1497, 1455, 1281, 1192, 1094,
J¼8.3 Hz, 1H, NH);0 13C NMR (DMSO-d6): d 14.0 (C-7),
19.9 (C-6), 30.9 (C-3 ), 37.9 (C-20), 71.5 (C-10), 121.5 (C-2),
124.2 (C-4), 125.7 (CHar), 128.3 (CHar), 128.3 (CHar), 128.3
(CHar), 128.3 (CHar), 134.5 (C-3), 139.9 (C-5), 141.7 (Car),
165.1 (CO); IR (KBr): 3299, 2928, 2871, 1660, 1532, 1455,
1255, 1217, 1097, 1067 cm21; HRMS (ESI): [2MþNa]þ
calcd for C32H42N2NaO4 541.30368, found 541.30358.
4.1.25. (2Z,4Z)-N-[(1E/Z)-3-Phenylprop-1-enyl]hepta-
2,4-dienamide (47). Hydroxyamide 46 (0.026 g, 0.10 mmol)
was converted to enamide 47 according to general
procedure 2. Purification of the crude product by flash
chromatography (petroleum ether/ethyl acetate, 5:1) gave
0.020 g (83%) of 47 as a colorless solid (E/Z¼69:31).
1042 cm21
;
C16H17NNaO2 278.11515, found 278.11512.
HRMS (ESI): [MþNa]þ calcd for
4.1.23. N-[(1E/Z)-3-Phenylprop-1-enyl]hepta-2,4-diyna-
mide (45). Hydroxyamide 44 (0.026 g, 0.10 mmol) was
converted to the enamides 45 according to general
procedure 2. Purification of the crude product by flash
chromatography (petroleum ether/ethyl acetate, 3:1) gave
6.0 mg (25%) of 45 as a colorless solid (E/Z¼63:37).
Compound 47_trans. Mp 104 8C; TLC (petroleum ether/
1
ethyl acetate, 4:1): Rf¼0.60; H NMR (C6D6): d 0.79 (t,
J¼7.6 Hz, 3H, CH3), 1.99 (dq, J¼7.6, 7.8 Hz, 2H, CH2),
3.08 (d, J¼7.3 Hz, 2H, CH2Ph), 4.82 (dt, J¼14.2, 7.3 Hz,
1H, CH), 5.03 (d, J¼11.4 Hz, 1H, CH), 5.63 (dt, J¼11.1,
7.8 Hz, 1H, CH), 6.19 (d, br, J¼8.6 Hz, 1H, NH), 6.63 (dd,
J¼11.9, 11.4 Hz, 1H, CH), 7.03–7.16 (m, 5H, CHar), 7.18
(m, 1H, CH), 8.00 (dd, J¼11.9, 11.1 Hz, 1H,0CH); 13C NMR
(C6D6): d 14.0 (C-7), 20.8 (C-6), 36.5 (C-3 ), 111.3 (C-20),
119.8 (C-2), 124.2 (C-10), 124.9 (C-4), 126.3 (CHar), 127.9
(CHar), 128.1 (CHar), 128.7 (CHar), 128.7 (CHar), 136.7
(C-3), 141.2 (Car), 141.6 (C-5), 162.7 (CO); IR (KBr): 3247,
3183, 3028, 2665, 2871, 1639, 1542, 1455, 1367, 1296,
Compound 45_trans. Mp 115 8C; TLC (petroleum ether/
1
ethyl acetate, 3:1): Rf¼0.53; H NMR (CDCl3): d 1.18 (t,
J¼7.6 Hz, 3H, CH3), 2.34 (d, J¼7.6 Hz, 2H, CH2), 3.35 (d,
J¼7.3 Hz, 2H, CH2Ph), 5.35 (dt, J¼14.1, 7.3 Hz, 1H, CH),
6.83 (ddt, J¼14.1, 10.9, 1.4 Hz, 1H, CH), 7.15–7.30 (m,
5H, CHar), 7.16 (d, br, J¼10.9 Hz, 1H, NH); 13C NMR
(CDCl3): d 12.8 (C-7), 13.2 (C-6), 36.1 (C-30), 63.0 (C-4),
67.50 (C-2), 77.2 (C-3), 88.6 (C-5), 113.8 (C-20), 122.5
(C-1 ), 126.4 (CHar), 128.4 (CHar), 128.4 (CHar), 128.5
(CHar), 128.5 (CHar), 139.8 (Car), 148.9 (CO); IR (KBr):
3233, 3183, 2925, 2854, 2241, 2152, 1624, 1458, 1375,
1243, 1221, 951 cm21
.
1291, 1246 cm21
.
Compound 47_cis. Mp 104 8C; TLC (petroleum ether/ethyl
acetate, 4:1): Rf¼0.70; 1H NMR (C6D6): d 0.77 (t, J¼
7.6 Hz, 3H, CH3), 1.97 (dq, J¼7.6, 7.8 Hz, 2H, CH2), 2.94
(d, J¼7.3 Hz, 2H, CH2Ph), 4.69 (dt, J¼8.6, 7.3 Hz, 1H,
CH), 4.98 (d, J¼11.4 Hz, 1H, CH), 5.62 (dt, J¼11.1, 7.8 Hz,
1H, CH), 6.52 (d, br, J¼8.6 Hz, 1H, NH), 6.58 (dd, J¼11.9,
11.4 Hz, 1H, CH), 6.96–7.13 (m, 5H, CHar), 7.23 (m, 1H,
CH), 7.94 (dd, J¼11.9, 11.1 Hz, 1H, CH); 13C NMR
(C6D6): d 14.0 (C-7), 20.8 (C-6), 32.1 (C-30), 108.2 (C-20),
119.6 (C-2), 122.9 (C-10), 124.8 (C-4), 126.5 (CHar), 128.3
(CHar), 128.3 (CHar), 128.5 (CHar), 128.9 (CHar), 137.0
(C-3), 141.1 (Car), 141.8 (C-5), 162.7 (CO); IR (KBr): 3340,
3065, 3027, 2966, 2929, 1647, 1590, 1500, 1454, 1370,
1262, 1208 cm21; MS (EI), m/z (%): 241 (13) [M]þ, 212
(25) [M2Et]þ, 150 (20), 132 (37), 124 (42), 96 (41), 91
(100), 81 (32); HRMS (EI): [M]þ calcd for C16H19NO
241.146655, found 241.148525.
Compound 45_cis. Mp 82 8C; TLC (petroleum ether/ethyl
1
acetate, 3:1) Rf¼0.59; H NMR (CDCl3): d 1.19 (t, J¼
7.6 Hz, 3H, CH3), 2.35 (d, J¼7.6 Hz, 2H, CH2), 3.38 (d,
J¼7.3 Hz, 2H, CH2Ph), 5.04 (dt, J¼8.6, 7.3 Hz, 1H, CH),
6.84 (ddt, J¼10.9, 8.6, 1.5 Hz, 1H, CH), 7.15–7.34 (m, 5H,
CHar), 7.19 (d, br, J¼10.9 Hz, 1H, NH); 13C NMR (CDCl3):
d 12.8 (C-7), 13.2 (C-6), 32.0 (C-30),063.0 (C-4), 67.5 (C-2),
77.2 (C-3), 88.8 (C-5), 111.0 (C-2 ), 121.0 (C-10), 126.6
(CHar), 128.2 (CHar), 128.2 (CHar), 128.8 (CHar), 128.8
(CHar), 138.9 (Car), 149.1 (CO); IR (KBr): 3259, 3170,
2922, 2851, 2242, 2153, 1621, 1520, 1454, 1378, 1282,
1246, 1187 cm21; MS (EI), m/z (%): 237 (24) [M]þ, 236
(100) [M2H]þ, 222 (56) [M2CH3]þ, 208 (34) [M2Et]þ,
146 (52), 130 (20), 105 (100), 91 (30), 77 (69), 51 (22);
HRMS (EI): [M2H]þ calcd for C16H14NO 236.107530,
found 236.112115.
4.1.24. (2Z,4Z)-N-(1-Hydroxy-3-phenylpropyl)hepta-2,4-
dienamide (46). Amide 15 (0.063 g, 0.50 mmol) was
converted to hydroxyamide 46 according to general
procedure 1 by treatment with 3-phenylpropanal (33).
Purification of the crude product by flash chromatography
(petroleum ether/ethyl acetate, 3:2) gave 0.11 g (84%) of 46
as colorless crystals, mp 97 8C. TLC (petroleum ether/ethyl
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(grant Ma 1012/10-1) and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank A. Nagele
for the measurement of the X-ray structures and
G. Nicholson for the ESI-HRMS.
¨
1
acetate, 1:1): Rf¼0.51; H NMR (DMSO-d6): d 0.95 (t,
J¼7.3 Hz, 3H, CH3), 1.67–1.83 (m, 2H, CH2), 2.18–2.25
(m, 2H, CH2), 2.54–2.62 (m, 2H, CH2Ph), 5.14–5.20 (m,
1H, CHOH), 5.64 (d, J¼4.8 Hz, 1H, OH), 5.72 (m, 1H, CH),
5.74 (d, J¼11.4 Hz, 1H, CH), 6.75 (dd, J¼11.6, 11.4 Hz,
1H, CH), 7.14–7.19 (m, 3H, CHar), 7.25–7.28 (m, 2H,
CHar), 7.35 (dd, J¼11.6, 11.1 Hz, 1H, CH), 8.37 (d, br,
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