Multi-component coupling synthesis of polycyclic pyrrole derivatives via Ir- and Rh-catalyzed cycloisomerizations with microwave heating

Article abstract of DOI:10.1016/j.tet.2007.07.105

CuBr₂-catalyzed three-component coupling of N-benzylallylamine, ethyl glyoxalate, and terminal alkynes afforded glycinate-tethered 1,6-enynes, which were further transformed into polycyclic pyrrole-2-carboxylates via iridium-catalyzed cycloisom

Full text of DOI:10.1016/j.tet.2007.07.105

Tetrahedron 63 (2007) 10149–10160
Multi-component coupling synthesis of polycyclic pyrrole
derivatives via Ir- and Rh-catalyzed cycloisomerizations
with microwave heating
*
Yoshihiko Yamamoto and Hiroki Hayashi
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received 10 June 2007; revised 26 July 2007; accepted 28 July 2007
Available online 3 August 2007
Abstract—CuBr2-catalyzed three-component coupling of N-benzylallylamine, ethyl glyoxalate, and terminal alkynes afforded glycinate-
tethered 1,6-enynes, which were further transformed into polycyclic pyrrole-2-carboxylates via iridium-catalyzed cycloisomerization/Diels–
Alder cycloaddition/dehydrogenation sequence under conventional and microwave heating conditions. The corresponding b-amino acid
analogues were obtained from the Ir-catalyzed reaction of enynes prepared from lithium amides of allylamines with methyl non-2-en-
4-ynoate. The Cu-catalyzed Mannich-type condensation was further extended to the synthesis of the glycinate-tethered dienyne and cyclo-
propylenyne, which were subjected to Rh-catalyzed cycloisomerizations to furnish bicyclic amino acids.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
different catalytic reactions for the substrate formation and
the subsequent cyclization into one sequential process is
highly desirable. Herein, we wish to report our effort to de-
velop sequential multi-component coupling processes, pro-
viding a rapid access to various polycyclic amino acids.5
The design and construction of novel a-amino acid struc-
tures has been an important subject in organic and bioor-
ganic chemistry.1 In particular, rigid a-amino acids with
constrained geometries have received great interest, because
they are capable of modifying the conformation of peptides.2
Thus, the rational introduction of unnatural a-amino acid
components into peptides enables the optimization of their
biological properties. In this regard, recent advances of the
transition-metal catalysis would make significant contribu-
tions toward the viable access to unique artificial a-amino
acids. In fact, Kotha and Undheim, have developed the tran-
sition-metal catalyzed approach to constrained a-amino
acids, where diynes, dienes, and enynes bearing a-amino
acid tethers were employed as synthetic precursors.3 We
also became interested in the utilization of the transition-
metal catalysis for the synthesis of biologically important
molecules, and have applied the ruthenium-catalyzed
[2+2+2] cycloaddition to the assembly of C-arylglycosides
and its conjugates with a-amino acids.4 In these previous
studies, a-amino-acid-tethered bifunctional substrates were
prepared by means of conventional nucleophilic substitution
and/or condensation reactions under acidic or basic condi-
tions, although a fully catalytic method that integrates two
Glycinate-tethered bifunctional molecules are fascinating
precursors for the synthesis of constrained cyclic a-amino
acids (Fig. 1). Kotha and co-workers synthesized glycinate-
tethered 1,7-enynes 1 from a protected glycine through
four-step operations. They subjected 1 to enyne metathesis
with Grubbs’ catalyst and the resultant dienes were
converted into constrained phenylalanine derivatives via
Diels–Alder cycloaddition and subsequent DDQ oxidation.6
Similar 1,7-diynes 2 were also prepared and subjected to
[2+2+2] cycloaddition with monoalkynes, leading directly
to similar constrained phenylalanine derivatives.6
TsN
EtO2C
TsN
EtO2C
R
R
1
2
P
N
H
R2
PN
EtO2C
R2
cat.
O
- H2O
EtO2C
H
H
Keywords: Copper catalyst; Iridium catalyst; Rhodium catalyst; Enynes;
Amino acids.
* Corresponding author. Tel./fax: +81 3 5734 3339; e-mail: omyy@apc.
titech.ac.jp
R1
3
R
Figure 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.105

10150
Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
Table 1. Mannich condensation of dibenzylamine, ethyl glyoxalate, and
On the other hand, the synthesis of glycinate-tethered 1,6-
enynes 3 has remained unexplored to date. This is probably
because of the difficulty of the synthesis of a-alkynylated
glycines. The parent ethynylglycine is known as antibiotic
FR-900130 (L-2-amino-3-butynoic acid), which was isolated
from a Streptomyces catenulae and characterized as an
N-acetylated form because of its instability.7 The chemical
synthesis of a-alkynylglycine derivatives has been rare. In
1977, Taub et al. and Metcalf et al. synthesized for the first
time a-ethynyl-3,4-dihydroxyphenylalanine via sequential
benzylation and acylation of the benzaldehyde imine of
3-(trimethylsilyl)propynylamine.8 a-Alkynylated glycinates
were also synthesized straightforwardly albeit in low to
moderate yields via addition of magnesium acetylides to
an a-imino ester generated in situ.9 Further, several research
groups have achieved the asymmetric synthesis of alkynyl-
glycinates by taking advantage of chiral auxiliaries, but the
previous reports required stoichiometric amounts of harmful
metal reagents and/or multi-step synthetic operations.10 In
terms of atom and step economy,11 a catalytic coupling pro-
tocol that minimizes chemical wastes as well as synthetic
operations is highly desirable. In this context, Chan and
co-workers recently developed the silver-catalyzed alkyny-
lation of a-imino esters under mild conditions, giving
N-PMP-protected alkynylglycines in high yields.12 We
also envisioned that a single-step assembly of unknown
enyne 3 would be realized using transition-metal catalyzed
Mannich-type condensation of commercially available ethyl
glyoxalate, terminal alkynes, and N-protected allylamines
only in a single operation (Fig. 1).
alkynesa
Run
R
CuX2
4, Isolated
yield (%)
1
2
3
4
5
Ph
Ph
CuBr2
CuBr2
CuCl2
CuBr2
CuBr2
4a, 89
4a, 85
4a, 79
4b, 81
Decomposition
Ph
nBu
Me3Si
a
All reactions were carried out with 10 mol % CuXn in dry benzene at room
temperature.
and more robust than CuBr. Under the optimal reaction con-
ditions, 1-hexyne and trimethylsilylacetylene similarly gave
rise to 4b (R¼nBu) or 4c (R¼TMS). The former was isolated
in 81% yield (run 4), but the latter was decomposed during
the chromatography on FlorisilÒ (run 5).
2.2. Synthesis of glycinate-tethered 1,6-enynes and their
cycloisomerization
Next, we carried out the synthesis of glycinate-tethered 1,6-
enyne 5a through the Cu-catalyzed three-component cou-
pling of N-benzylallylamine, ethyl glyoxalate, and 1-hexyne
(Scheme 2). Upon treatment with 10 mol % CuBr2 at room
temperature for 24 h, each 1 equiv of these components
gave rise to the desired enyne 5a in ca. 80% yield after filtra-
tion through a pad of FlorisilÒ. However, the purification of
the product with column chromatography on silica gel again
resulted in decomposition. Therefore, we decided to submit
the crude enyne directly to the transition-metal-catalyzed
cyclization reactions. The cycloisomerization of enynes is
known as a powerful method to obtain exocyclic 1,3-dienes,
which can be utilized as diene components of Diels–Alder
reaction.15 The crude enyne 5a was submitted to the reported
2. Results and discussion
2.1. Synthesis of alkynylglycinates via Mannich-type
three-component condensation
palladium-catalyzed
cycloisomerization
conditions
(5 mol % Pd2(dba)3, 10 mol % PPh3, 10 mol % AcOH, tolu-
ene reflux, 24 h)16 to result in the formation of an intractable
product mixture. Similarly, 5a failed to produce the ring-
closing enyne metathesis product,17 when it was heated
with the first generation Grubbs catalyst in refluxing toluene
for 24 h. These negative results are ascribed to the instability
of the a-alkynylglycinates. Then, we turned our attention to
the recently reported iridium catalyst system of Chatani and
co-workers.18 According to their report, crude 5a was treated
To this end, copper catalysis is considered to be the method
of choice, according to the recent excellent studies of
Knochel’s group.13 Thus, several copper salts were examined
as catalysts toward the reaction of each 1 equiv of ethyl
glyoxalate, dibenzylamine, and phenylacetylene in toluene
˚
containing molecular sieve 4 A at room temperature for
24 h (Scheme 1 and Table 1). The reaction proceeded in
the presence of 10 mol % CuBr, and the formation of the de-
sired alkynylglycinate 4a (R¼Ph) was confirmed by the 1H
NMR measurement of the crude product. Purification with
column chromatography on silica gel or alumina, however,
led to the decomposition of 4a to some other products.14
To avoid the decomposition, the crude materials were rap-
idly purified through a short column chromatography on Flo-
risilÒ to give 4a in 89% yield (Table 1, run 1). In a similar
manner, CuBr2 and CuCl2 gave 4a in 85 and 79% yields, re-
spectively (runs 2 and 3). In contrast, Cu(OAc)2 and CuI
proved to be ineffective. On the basis of these results, further
explorations were carried out with CuBr2, which is cheaper
Bn
N
BnN
EtO2C
H
10 mol% CuBr2
MS 4 Å
toluene, rt, 24 h
+
EtO2CCHO
+
n
Bu
n
5a
Bu
3 mol% [IrCl(cod)]2
BnN
12 mol% AcOH
toluene reflux, 24 h
n
EtO2C
Bu
6a
Me
Bn2NH
NBn2
BnN
+
EtO2CCHO
+
10 mol% CuXn
EtO2C
MS 4 Å
n
EtO2C
Bu
R
toluene, rt, 24 h
4
HC CR
7a 39%
Scheme 1.
Scheme 2.

Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
Table 2. Synthesis of polycyclic pyrrole-2-carboxylates 9a
10151
with 3 mol % [IrCl(cod)]2 and 12 mol % AcOH in refluxing
toluene for 24 h. As a result, 5a underwent clean cycloiso-
merization reaction, but the obtained product was the unex-
pected pyrrole-2-carboxylate 7a. The formation of 7a was
probably the consequence of the iridium-catalyzed isomeri-
zation of exocyclic diene 6a. Similar isomerization of exo-
cyclic dienes leading to pyrroles has been reported
previously.19
Run
Product
Method,b yield (%)
O
1
2
A, 62
B, 59
BnN
NPh
9a
n
EtO2C
O
O
Bu
3
4
A, 54
B, 29
BnN
NPh
9b
Encouraged by the above result, we attempted the Diels–
Alder trapping of putative exocyclic diene intermediate 6a
by carrying out the cycloisomerization of 5a in the presence
of a dienophile (Scheme 3). Surprisingly, such a one-pot,
domino cycloisomerization/Diels–Alder cycloaddition has
been less explored to date,20a,c,e,f while similar domino
processesinvolvingintramolecularHeckreaction20a–d orring-
closing enyne metathesis21 have been developed success-
fully. Without purification, freshly prepared 5a was directly
subjected to cycloisomerization in the presence of 1.1 equiv
N-phenylmaleimide in refluxing toluene for 7 h. Gratify-
ingly, a 1:1 cycloadduct of 5a with the maleimide was
formed, but the following structural analyses revealed that
the obtained product was fused pyrrole-2-carboxylate 9a.
In its 1H NMR spectrum, a singlet peak of the pyrrole proton
a to the nitrogen atom appeared at d 6.73 ppm. In addition,
the molecular ion peak M+ was observed at m/z 484 instead
of m/z 486 expected for Diels–Alder adduct 8a. Although
the detailed mechanism is unclear, 9a was presumably
formed by the dehydrogenative aromatization of 8a via
C–H activation onthe 3,4-dehydroprolinering with Irspecies.22
It is noteworthy that the yield of the cycloisomerization/
Diels–Alder reaction/dehydrogenative aromatization result-
ing in 9a (62%) was much higher than that of the cycloisome-
rization leading to 7a in the absence of the dienophile (39%).
EtO2C
O
O
Ph
BnN
NPh
9c
5
A, 41
EtO2C
O
OMe
O
6
7
A, 51
B, 47
BnN
NPh
9d
9e
9f
EtO2C
O
( )3
OMe
O
8
9
A, 62
B, 59
BnN
NPh
EtO2C
O
O
( )3
Cl
10
11
A, 74
B, 68
BnN
NPh
EtO2C
O
( )3
CO2Me
O
BnN
NPh
9g
12
A, 54
EtO2C
O
Fc
BnN
O
O
+
O
N
EtO2C
Ph
n
13
14
A, 52
B, 53
Bu
5a
1.1 equiv
BnN
O
9h
O
n
EtO2C
O
3 mol% [IrCl(cod)]2
12 mol% AcOH
toluene reflux, 24 h
Bu
BnN
NPh
O
O
n
EtO2C
O
Bu
8a
15
16
BnN
A, 35
B, 33
9i
O
EtO2C
( )3
- H2
BnN
NPh
CO2Me
a
Mannich couplings were carried out with each 1 equiv of N-benzylallyl-
amine, ethyl glyoxalate, and an alkyne in the presence of 10 mol %
˚
CuBr2 and MS 4 A in toluene at room temperature for 24 h. Cycloisome-
n
EtO2C
O
Bu
9a
Scheme 3.
rizations were carried out with crude enynes 5, 1.1 equiv of a dienophile in
the presence of 3 mol % [IrCl(cod)]2, 12 mol % AcOH in toluene.
Method A: toluene reflux for 24 h (7 h for runs 1 and 5). Method B:
microwave heating (150 ꢀC) for 0.5 h.
b
2.3. Scope and limitations of four-component coupling
synthesis of pyrrole-2-carboxylates
The generality of the present sequential four-component
coupling process was exemplified as summarized in Table
2. Although the use of phenylacetylene afforded the corre-
sponding enyne intermediate very cleanly, its cycloisomeri-
zation failed to complete within 10 h. To ensure complete
conversion of the enyne, the heating was continued for
24 h, resulting 9b in 54% (run 3). In striking contrast, trime-
thylsilylacetylene totally failed to give the corresponding
product. Similarly, 5-methoxy-1-pentyne, 5-chloro-1-
pentyne, and methyl 5-hexynoate gave rise to pyrrolecarbox-
ylates 9d, 9e, and 9f in 51–74% yields (runs 6, 8, and 10),
while the use of methyl propargyl ether resulted in the rather
lower yield (41%) of 9c (run 5). The reaction with ethynyl-
ferrocene afforded the corresponding adduct 9g in 54% yield
as crystals. Fortunately, recrystallization of the isolated 9g
gave a single crystal favorable for X-ray crystallography.
As shown by the ORTEP diagram in Figure 2, the central

10152
Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
role in the aromatization stage: the electron-withdrawing es-
BnN
EtO2C
N
O
O
H
ter functionality activates a-C–H bond to facilitate dehydro-
genation. To elucidate this, we prepared propanal-derived
enyne 10 and submitted it to cycloisomerization (Scheme
4). In the presence of the iridium catalyst, the toluene solu-
tion of isolated 10 and 1 equiv of N-phenylmaleimide were
heated in the microwave reactor at 150 ꢀC for 0.5 h. As ex-
pected, Diels–Alder adduct 1225 was obtained in 20% yield
along with pyrroles 11 and 13, while only 11 and 13 were ob-
tained in 22 and 49% yields under conventional heating con-
ditions. The reason for the formation of monocyclic pyrrole
11 even in the presence of the dienophile is not clear. The in-
termediacy of 12 in the formation of 13 was confirmed as
follows. Upon treatment with 3 mol % [IrCl(cod)]2 and
12 mol % AcOH in refluxing toluene for 3 h, the isolated
12 was converted into 13 in 76% yield. Interestingly, when
the same reaction was carried out in the presence of 1 equiv
of N-phenylmaleimide, 12 was totally consumed within
0.5 h to give 13 in a similar yield of 73%. In addition, N-phe-
nylsuccinimide, which was formed by the hydrogenation of
N-phenylmaleimide, was also detected by 1H NMR analysis
of the crude product mixture. These observations suggest
that the dienophiles were not essential for the aromatization
of the Diels–Alder adducts, but they facilitate the dehy-
drogenation as hydrogen acceptors. In fact, the cyclo-
isomerization of 10 was carried out with 3 equiv of
N-phenylmaleimide under microwave irradiation (150 ꢀC,
0.5 h) to afford 11 and 13 in 12 and 54% yields, respectively.
The use of a rhodium complex, [RhCl(cod)]2, in place of the
iridium precatalyst resulted in the no reaction.26 Other cata-
lytic conditions (2.5 mol % Pd2(dba)3/dppe/2AcOH, tolu-
ene, MW 150 ꢀC, 30 min;16 5 mol % Cp*RuCl(cod),
EtOH, room temperature, 13 h;27 5 mol % Cp*RuCl(cod),
AcOH, 65 ꢀC, 10 h27) also hardly converted 10 into the
cyclization products.
O
N
H
R
O
O
X
Fe
O
endo transition state
Figure 2.
cyclohexane ring has the all cis geometry as a result of the
endo-approach of the dienophile to the exocyclic diene inter-
mediate in the Diels–Alder transition state. In accord with
the H NMR and mass analyses, 9g has the pyrrole ring
that was formed by the dehydrogenation of the 3-pyrroline
moiety.
1
In addition to N-phenylmaleimide, maleic anhydride can be
used as a dienophile in the cycloisomerization step to afford
9h in 52% yield (run 13). On the other hand, the use of 1,4-
naphthoquinone led to the formation of 9i possessing both
pyrrole and naphthoquinone rings albeit in a lower yield of
35% (run 15). The formation of 9i is the consequence of
the two-fold dehydrogenation under the influence of the irid-
ium catalyst. The use of other allylamines and dienophiles
listed in Figure 3 resulted in the formation of intractable
products.
Bn
O
O
N
H
Ph
N
N
Ph
NPh
Bn
N
H
O
O
Figure 3.
With the advent of modern microwave reactors, the micro-
wave heating has become a powerful and reliable tool in or-
ganic synthesis.23 This is because microwave irradiation
often offers considerable rate acceleration as well as im-
proved product yields. Microwave activation has also proven
to be effective to the rapid assembly of heterocycles via
multi-component couplings.24 Thus, the cycloisomerization
of enyne 5a was carried out in a sealed vessel at 150 ꢀC for
0.5 h under microwave irradiation (Table 2, run 2). As a con-
sequence, 9a was obtained in a comparable yield of 59%. In
contrast, the sequential reaction starting from phenylacetyl-
ene resulted in a rather lower yield (29%) under the same
reaction conditions (run 4). This is presumably the result
of the extensive decomposition of the phenylacetylene-de-
rived enyne at 150 ꢀC. Then, other enynes bearing an alkyl
group on their alkyne terminals were subjected to micro-
wave-irradiated cycloisomerization to furnish the corre-
sponding adducts in similar yields with those under the
conventional heating conditions (runs 7, 9, 11, 14, and 16).
Bn
BnN
Et
10 61%
N
H
10 mol% CuBr2
+
MS 4Å
EtCHO
toluene, rt, 24h
n
Bu
+
n
Bu
O
3 mol% [IrCl(cod)]2
NPh
12 mol% AcOH
toluene
O
1 equiv
O
Me
BnN
Et
+
BnN
Et
NPh
n
n
O
Bu
Bu
12
11
O
MW150 °C, 0.5h
11 16%, 12 20%,13 46%.
Conventional reflux, 24h
11 22%, 13 49%.
+
BnN
Et
NPh
n
O
Bu
13
2.4. Impact of ester group on cyclization step: isolation
of Diels–Alder intermediate
Scheme 4.
2.5. Synthesis of b-amino-acid derivatives via Michael
Addition of lithium amides of allylamines to a conjugate
enynoate
As described above, the glycinate-tethered enynes were di-
rectly converted into the tricyclic pyrrole-2-carboxylates
via dehydrogenation of putative Diels–Alder adducts such
as 8a. The ethoxycarbonyl substituent on the 3-pyrroline
ring of these intermediates is considered to play an important
Davies and co-workers have achieved the asymmetric syn-
thesis of cyclic b-amino acids via conjugate addition of

Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
Me
10153
Me
a chiral lithium amide to 2,4-dienoates and subsequent ring-
closing metathesis of the resultant b-amino-acid-tethered
1,6-dienes.28 Inspired by their elegant work, we synthesized
the corresponding 1,6-enyne 16 by adapting the Michael ad-
dition of lithium amide 14 to methyl non-2-en-4-ynoate 15,
which was prepared according to the report by Takeuchi and
co-workers.29 The reaction of 14 and (E)-15 was executed at
ꢁ78 ꢀC in THF for 1 h to furnish the desired 16 albeit in
a low yield (Scheme 5). In striking contrast, the use of
(Z)-15 hardly afforded the Michael adduct. The obtained
enyne 16 was then allowed to react with N-phenylmaleimide
under the microwave heating conditions. To ensure the full
conversion of a Diels–Alder intermediate, an excess amount
(1.5 equiv) of the dienophile was used. Similarly with the
corresponding glycinate derivative 5a, the reaction reached
to completion within 0.5 h at 150 ꢀC to give rise to cycload-
duct 18 in 61% yield along with monocyclic pyrrole 17 (15%
yield).
Ar
MeO2C
N
Ar
N
THF
-78 °C, 1 h
Li
19 1.6 equiv
*
n
+
Bu
20 56%
MeO2C
(single diastereomer)
O
n
(E)-15
Bu
3 mol% [IrCl(cod)]2
12 mol% AcOH
toluene, MW 150 °C, 0.5 h
NPh
O
1.5 equiv
O
Me
Me
N
Ar
Me
*
N
NPh
+
Ar
*
*
n
n
O
Bu
MeO2C
Bu
MeO2C
22 54% (2 diastereomers)
21 21%
cat. conc.H2SO4 CH2Cl2/anisole
50 equiv CF3CO2H rt, 12 h
O
*
Bn
Bn
Ar = p-methoxyphenyl
N
Li
HN
MeO2C
NPh
N
THF
-78 °C, 2 h
*
MeO2C
16 33%
*
14 1.6 equiv
n
O
Bu
+
n
Bu
MeO2C
23 82% (single isomer)
n
O
(E)-15
Bu
Scheme 6.
NPh
3 mol% [IrCl(cod)]2
12 mol% AcOH
toluene, MW 150 °C, 0.5 h
O
2.6. Synthesis of other cyclic amino acids using rhodium-
catalyzed cycloisomerizations
1.5 equiv
O
We finally explored the rhodium-catalyzed intramolecular
[4+2] and [5+2] cycloadditions of glycinate-tethered di-
enyne 24 and cyclopropylenyne 27, which were readily
prepared by our copper-catalyzed Mannich route.31,32 The
Cu-catalyzed Mannich-type condensation of each 1 equiv
of N-benzylhexa-2,4-dienylamine, ethyl glyoxalate, and
1-hexyne gave rise to dienyne 24, which was directly sub-
jected to rhodium-catalyzed cycloaddition with microwave
heating at 120 ꢀC for 0.5 h (Scheme 7). Recently cationic
rhodium catalysts have been found effective for intramolec-
ular diene–alkyne cycloadditions.31 The cationic rhodium
catalyst system, 5 mol % RhCl(PPh3)3/AgOTf, however,
afforded cycloadduct 26 only in a low overall yield (28%).
Gratifyingly, the use of a neutral complex with the p-accept-
ing CO ligand, Rh(acac)(CO)2, under the same reaction
Me
BnN
MeO2C
+
BnN
NPh
O
n
n
Bu
Bu
MeO2C
17 15%
18 61%
Scheme 5.
Optically active derivative 20 was further prepared from chi-
ral amide 19 and subjected to microwave-assisted cycloiso-
merization (Scheme 6). Michael addition of 19 to (E)-15
1
gave 20 in 56% yield, and the H NMR analysis showed
that 20 was obtained as a single diastereomer.25 Under opti-
mal microwave heating conditions, 20 was allowed to react
with 1.5 equiv of N-phenylmaleimide to result in the forma-
tion of pyrroles 21 and 22 in 21 and 54% yields, respectively.
To our surprise, the 1H NMR analysis revealed that 22 was
obtained as two diastereomers with the ratio of a 1:1.7. Their
1H NMR spectra showed very similar spectral patterns with
that of 18. The p-methoxyphenylethyl group of 22 was re-
moved under acidic conditions in a mixed solvent of
CH2Cl2 and anisole at room temperature,30 affording N-un-
protected pyrrole 23 in 82% yield as a single stereoisomer.
At first, we suspected the epimerization of the benzylic ste-
reocenter on the chiral auxiliary under the cycloisomerization
conditions, but this possibility was ruled out by the following
experiment. No detectable change in the diastereomer ratio
was observed, when the partially separated higher polar
diastereomer of 22 (5.5:1) was treated with 5 mol % iridium
catalyst at 150 ꢀC for 30 min under microwave irradiation.
According to these results, we tentatively ascribed the dia-
stereomer formation to the racemization of enyne 20 or an
exocyclic diene intermediate prior to the diastereoselective
Diels–Alder cycloaddition.
Bn
N
H
Me
10 mol%
CuBr2
+
EtO2CCHO
+
MS 4 Å
toluene, rt, 24 h
n
Bu
5 mol%
Rh(acac)(CO)2
BnN
Me
EtO2C
toluene
MW 120 °C, 0.5 h
n
Bu
24
BnN
BnN
+
Me
Me
n
n
EtO2C
EtO2C
Bu
Bu
26
64% (2 steps) 36:64
25
Scheme 7.

10154
Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
conditions improved the product yields. Cyclohexadienes 25
and its olefin isomer 26 were obtained in 64% combined
yield with the ratio of 36:64.25
diene intermediates and subsequent dehydrogenative aroma-
tization. The corresponding b-amino acid analogues of the
tricyclic pyrrole-2-carboxylates were obtained from the
Ir-catalyzed reaction of enynes prepared from lithium
amides of allylamines with methyl non-2-en-4-ynoate. The
glycinate-tethered dienyne and cyclopropylenyne were sub-
jected to rhodium-catalyzed cycloadditions under micro-
wave irradiation to give the expected intramolecular [4+2]
and [5+2] cycloadducts in moderate yields.
Recently, Shibata and co-workers reported that several iri-
dium(I) complexes effectively catalyzed intramolecular
[4+2] cycloaddition of dienynes.33 With the expectation of
the direct formation of an aromatization product via sequen-
tial [4+2] cycloaddition/dehydrogenation, we carried out the
reaction of 24 under the cycloisomerization conditions
(1 mol % [IrCl(cod)]2, 4 mol % AcOH, toluene, MW
150 ꢀC, 30 min). Although 24 was completely consumed,
4. Experimental
4.1. General
1
none of the expected cycloadducts were detected by H
NMR analysis of crude reaction mixture. Next, Vaska’s com-
plex, IrCl(CO)(PPh3)2, was used as a precatalyst, because it
proved to be effective for the cycloaddition of dienynes.33 In
the presence of the 3 mol % catalyst, freshly prepared 24 was
heated in toluene at 120 ꢀC for 2 h with a microwave reactor,
resulting in a complex reaction mixture. Conventional heat-
ing conditions also proved to be ineffective for the Ir-cata-
lyzed [4+2] cycloaddition. Consequently, the neutral
rhodium catalyst is optimal for the present dienyne cycloiso-
merization.
Flash chromatography was performed with a silica gel col-
umn (Cica silica gel 60N) eluted with mixed solvents [hex-
ane/AcOEt]. TLC analyses were performed with Merck
1
TLC plate silica gel 60 F254. H and 13C NMR spectra
were measured on a Gemini 2000 NMR spectrometers as
1
CDCl3 solutions at 25 ꢀC. H NMR chemical shifts are
reported in terms of chemical shift (d, ppm) relative to the
singlet at 7.26 ppm for chloroform. Splitting patterns are
designated as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; quint, quinted; sext, sextet; sept, septet; m, multiplet.
Coupling constants are reported in hertz. 13C NMR spectra
were fully decoupled and are reported in terms of chemical
shift (d, ppm) relative to the triplet at d¼77.0 ppm for
CDCl3. Infrared spectra were recorded on a JASCO FT/IR-
230 spectrometer or a JASCO FT/IR-610 spectrometer.
Mass spectra were recorded on a JEOL JMS-T100CS mass
spectrometer as MeOH solutions. Elemental analyses were
performed with a Perkin–Elmer 2400II CHNS/O elemental
analyzer. Melting points were obtained by a Yamato Melting
Point Apparatus MP-12 and are uncorrected. Microwave
irradiation experiments were carried out with a single-
mode microwave reactor (CEM Discover LabMate). Closed
reaction vessels were used, and the temperature was moni-
tored by an on-line IR detector. Toluene was distilled from
In a similar manner, cyclopropylenyne 27 was prepared and
treated with 5 mol % Rh(acac)(CO)2 under the microwave
irradiation conditions to furnish seven-membered ring prod-
ucts 28 and 29 in 33% combined yield with the ratio of
55:45.25 Slight improvements in the yield and the selectivity
(46%, 63:37) were achieved when the cationic system,
5 mol % RhCl(PPh3)3/AgOTf, was applied to the same reac-
tion (Scheme 8).
Bn
N
H
10 mol% CuBr2
+
EtO2CCHO
MS 4 Å
toluene, rt, 24 h
+
n
Bu
5 mol% RhCl(PPh3)3
5 mol% AgOTf
BnN
. CuBr (Kishida, 99.9%) and ethyl glyoxalate (Fluka,
2
CaH2
50% toluene solution) were used without further purifica-
tion. [IrCl(cod)]2 was prepared according to the reported
procedures,34 and rhodium complexes are commercially
available.
EtO2C
toluene
MW 120 °C, 0.5 h
n
Bu
27
BnN
BnN
+
4.2. General procedure for Cu-catalyzed three-compo-
nent coupling: synthesis of alkynylglycinate 4b from
ethyl glyoxalate, dibenzylamine, and phenylacetylene
EtO2C
EtO2C
n
n
Bu
Bu
28
29
46% (2 steps) 63:37
˚
To a suspension of CuBr2 (22 mg, 0.1 mmol) and MS 4 A
Scheme 8.
(500 mg) in toluene (2 mL) were added ethyl glyoxalate so-
lution (ca. 50% in toluene, 0.20 mL), 1-hexyne (82 mg,
1.0 mmol), and dibenzylamine (197 mg, 1.0 mmol) in this
order at room temperature under Ar atmosphere. The solu-
tion was stirred at room temperature under Ar atmosphere
for 24 h. After filtration through a glass frit, the filtrate
was concentrated in vacuo. The residue was purified by short
column chromatography on FlorisilÒ eluted with ether to
give 4b (295 mg, 81%) as pale yellow oil. 1H NMR
(300 MHz, CDCl3): d 0.95 (t, J¼7.2 Hz, 3H), 1.29 (t,
J¼7.2 Hz, 3H), 1.42–1.62 (m, 4H), 2.31 (dt, J¼7.2,
2.4 Hz, 2H), 3.63 (d, J¼13.5 Hz, 2H), 3.79 (d, J¼13.5 Hz,
2H), 4.18 (q, J¼7.2 Hz, 1H), 4.19 (q, J¼7.2 Hz, 1H), 4.21
3. Conclusion
In conclusion, we successfully developed the straightfor-
ward approach to glycinate-tethered bifunctional molecules
via Cu-catalyzed Mannich-type condensation of N-benzyl-
allylamines, ethyl glyoxalate, and terminal alkynes. The re-
sultant glycinate-derivatives were directly used for the next
transition-metal-catalyzed carbocyclizations. The enynes
were subjected to the Ir-catalyzed cycloisomerization in
the presence of dienophiles to afford tricyclic pyrrole-2-car-
boxylates as a result of the Diels–Alder reaction of exocyclic

Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
10155
1
(t, J¼2.4 Hz, 1H), 7.21–7.34 (m, 6H), 7.41–7.44 (m, 4H);
13C NMR (75 MHz, CDCl3): d 13.63, 14.20, 18.51, 21.94,
30.88, 55.26, 55.63, 61.19, 72.48, 87.09, 126.88, 128.04,
128.92, 138.92, 169.23; IR (neat) 1742 cmꢁ1; MS (EI):
m/z (%): 363 (3) [M]+, 234 (2) [MꢁEt]+, 290 (100)
[MꢁCO2Et]+, 198 (30) [MꢁCO2Et–C6H5Me]+; EA calcd
(%) for C24H29NO2 (363.49): C 79.30, H 8.04, N 3.85;
found: C 79.25, H 8.09, N 3.84.
Compound 20: oil; H NMR (300 MHz, CDCl3): d 0.92 (t,
J¼7.5 Hz, 3H), 1.40 (d, J¼6.6 Hz, 3H), 1.38–1.52 (m,
4H), 2.19 (dt, J¼7.2, 2.1 Hz, 2H), 2.49 (dd, J¼14.4,
7.5 Hz, 1H), 2.56 (dd, J¼14.4, 8.1 Hz, 1H), 3.16 (dd,
J¼15.0, 7.2 Hz, 1H), 3.55 (s, 3H), 3.79 (s, 3H), 3.94 (q,
J¼6.6 Hz, 1H), 4.02 (tt, J¼8.1, 2.1 Hz, 1H), 5.03 (m, 1H),
5.14 (m, 1H), 5.78 (dddd, J¼17.2, 10.2, 7.2, 4.8 Hz, 1H),
6.82 (d, J¼9.0 Hz, 2H), 7.25 (d, J¼9.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d 13.4, 15.4, 18.3, 21.8, 30.9, 41.1,
46.9, 50.5, 51.4, 55.2, 57.3, 78.8, 85.5, 113.3, 116.0,
1
Compound 4a: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 1.31 (t, J¼7.2 Hz, 3H), 3.72 (d, J¼13.8 Hz, 2H), 3.89 (d,
J¼13.8 Hz, 2H), 4.22 (q, J¼7.2 Hz, 1H), 4.23 (q,
J¼7.2 Hz, 1H), 4.46 (s, 1H), 7.24–7.35 (m, 11H), 7.45–
7.54 (m, 4H); 13C NMR (75 MHz, CDCl3): d 14.3, 55.5,
56.2, 61.5, 82.1, 86.6, 122.6, 127.1, 128.1, 128.2, 128.3,
128.8, 131.9, 138.8, 168.7; IR (neat) 1741 cmꢁ1; MS (EI):
m/z (%): 383 (4) [M]+, 254 (0.8) [MꢁEt]+, 310 (100)
[MꢁCO2Et]+, 218 (35) [MꢁCO2Et–C6H5Me]+; EA calcd
(%) for C26H25NO2 (383.48): C 81.43, H 6.57, N 3.65;
found: C 81.56, H 6.52, N 3.57.
128.9, 136.9, 138.3, 158.5, 171.3; IR (neat) 1743 cmꢁ1
;
MS (ESI): calcd for C22H31NO3 (357.23): found m/z
380.19 [M+Na]+; EA calcd (%) for C22H31NO3 (357.49):
C 73.91, H 8.74, N 3.92; found: C 73.65, H 8.64, N 3.95.
4.4. Synthesis of pyrrole-2-carboxylate 7a from ethyl
glyoxalate, N-benzylallylamine, and 1-hexyne
˚
To a suspension of CuBr2 (22 mg, 0.1 mmol) and MS 4 A
(500 mg) in toluene (2 mL) was added ethyl glyoxalate solu-
tion (ca. 50% in toluene, 0.20 mL), 1-hexyne (82 mg,
1.0 mmol), and N-benzylallylamine (147 mg, 1.0 mmol) in
this order at room temperature under Ar atmosphere. The so-
lution was stirred at room temperature under Ar atmosphere
for 24 h. After filtration through a pad of FlorisilÒ, the fil-
trate was concentrated in vacuo. The residue was diluted
with degassed toluene (5 mL) and to this solution was added
[IrCl(cod)]2 (21 mg, 0.03 mmol) and AcOH (7 mL,
0.12 mmol). The solution was refluxed for 24 h under Ar.
After evaporation of the solvent, the residue was purified
by flash column chromatography on silica gel eluted with
hexane/AcOEt (35:1) to give 7a (123 mg, 39%) as pale yel-
1
Compound 10: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.93 (t, J¼7.2 Hz, 3H), 0.94 (t, J¼7.2 Hz, 3H), 1.40–
1.69 (m, 6H), 2.25 (t, J¼6.9, 2.1 Hz, 2H), 2.92 (dd,
J¼14.4, 7.8 Hz, 1H), 3.21 (ddt, J¼14.4, 4.5, 1.8 Hz, 1H),
3.32 (tt, J¼7.5, 1.8 Hz, 1H), 3.35 (d, J¼14.1 Hz, 1H), 3.81
(d, J¼14.1 Hz, 1H), 5.08 (m, 1H), 5.22 (m, 1H), 5.83
(dddd, J¼18.0, 9.0, 7.8, 4.5 Hz, 1H), 7.19–7.37 (m, 5H);
13C NMR (75 MHz, CDCl3): d 11.1, 13.5, 18.3, 21.8, 27.3,
31.3, 53.9, 54.1, 54.8, 78.1, 84.9, 116.6, 126.7, 128.2,
128.8, 137.3, 140.5; MS (ESI): calcd for C19H27N
(269.21): found m/z 270.21 [M+Na]+; EA calcd (%) for
C19H27N (269.42): C 84.70, H 10.10, N 5.20; found: C
84.81, H 9.93, N 5.25.
1
low oil. H NMR (300 MHz, CDCl3): d 0.90 (t, J¼7.2 Hz,
3H), 1.27 (t, J¼7.2 Hz, 3H), 1.31–1.52 (m, 6H), 2.00 (d,
J¼0.6 Hz, 3H), 2.70 (d, J¼7.5 Hz, 2H), 4.21 (q, J¼7.2 Hz,
2H), 6.60 (d, J¼0.6 Hz, 1H), 7.03–7.07 (m, 2H), 7.19–
7.31 (m, 3H); 13C NMR (75 MHz, CDCl3): d 9.92, 14.23,
14.35, 22.73, 26.12, 30.82, 32.21, 52.31, 59.39, 117.96,
118.63, 126.46, 126.87, 126.91, 128.32, 133.92, 138.94,
161.60; IR (neat) 1691 cmꢁ1; MS (EI): m/z (%): 313 (74)
[M]+, 256 (100) [MꢁBu]+, 184 (58) [MꢁCO2Et–
CH2]CHEt]+; EA calcd (%) for C22H27NO2 (313.43): C
76.64, H 8.68, N 4.47; found: C 76.74, H 8.64, N 4.40.
4.3. Synthesis of b-amino-acid-tethered enyne 16
To a solution of N-benzylallylamine (219 mg, 1.49 mmol) in
dry THF (3.5 mL) was added nBuLi (1.6 M in hexane,
0.9 mL, 1.44 mmol) at ꢁ78 ꢀC under Ar atmosphere. The
solution was stirred at this temperature for 1 h, and then
the solution was added to the solution of enynoate (E)-15
in dry THF (3.5 mL) at ꢁ78 ꢀC under Ar. After stirring an-
other 1 h, the reaction was quenched with satd NH4Cl
(20 mL), and the reaction mixture was extracted with Et2O
(20 mLꢂ3). The combined organic layer was washed with
brine (20 mL), dried with MgSO4, and concentrated in va-
cuo. The residue was purified by silica gel flash column
chromatography (hexane/AcOEt 30:1) to give 16 (92.1 mg,
4.5. General procedure for four-component coupling:
synthesis of tricyclic pyrrole-2-carboxylate 9a from
ethyl glyoxalate, N-benzylallylamine, 1-hexyne, and
N-phenylmaleimide
1
˚
To a suspension of CuBr2 (22 mg, 0.1 mmol) and MS 4 A
33%) as yellow oil. H NMR (300 MHz, CDCl3): d 0.94
(t, J¼7.2 Hz, 3H), 1.38–1.56 (m, 4H), 2.23 (dt, J¼6.6,
2.1 Hz, 2H), 2.57 (dd, J¼14.4, 6.6 Hz, 1H), 2.68 (dd,
J¼14.4, 9.0 Hz, 1H), 2.90 (dd, J¼14.1, 8.1 Hz, 1H), 3.20
(ddt, J¼14.1, 4.8, 2.0 Hz, 1H), 3.33 (d, J¼14.1 Hz, 1H),
3.65 (s, 3H), 3.80 (d, J¼14.1 Hz, 1H), 4.01 (ddt, J¼14.1,
9.0, 2.0 Hz, 1H), 5.08–5.24 (m, 2H), 5.78 (dddd, J¼17.6,
9.6, 8.4, 4.2 Hz, 1H), 7.20–7.30 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 13.4, 18.2, 21.8, 31.0, 39.8, 49.3,
51.4, 54.7, 76.0, 86.0, 117.2, 126.9, 128.2, 128.9, 136.6,
139.7, 171.3; IR (neat) 1745 cmꢁ1; MS (ESI): calcd for
C20H27NO2 (313.20): found m/z 336.18 [M+Na]+; EA calcd
(%) for C20H27NO2 (313.43): C 76.64, H 8.68, N 4.47;
found: C 76.33, H 9.08, N 4.37.
(500 mg) in toluene (2 mL) was added ethyl glyoxalate solu-
tion (ca. 50% in toluene, 0.20 mL), 1-hexyne (82 mg,
1.0 mmol), and N-benzylallylamine (147 mg, 1.0 mmol) in
this order at room temperature under Ar atmosphere. The so-
lution was stirred at room temperature under Ar atmosphere
for 24 h. After filtration through a pad of FlorisilÒ, the fil-
trate was concentrated in vacuo. The residue was diluted
with degassed toluene (5 mL) and to this solution was added
[IrCl(cod)]2 (21 mg, 0.03 mmol), AcOH (7 mL, 0.12 mmol),
and N-phenylmaleimide (200 mg, 1.1 mmol). The solution
was refluxed for 24 h under Ar. After evaporation of the sol-
vent, the residue was purified by flash column chromato-
graphy on silica gel eluted with hexane/AcOEt (40:1–5:1)

10156
Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
1
to give 9a (299 mg, 62%) as pale yellow oil. H NMR
(300 MHz, CDCl3): d 0.79 (t, J¼7.2 Hz, 3H), 1.05–1.30
(m, 5H), 1.32 (t, J¼7.2 Hz, 3H), 1.60–1.69 (m, 1H), 2.80
(ddd, J¼15.0, 8.0, 0.9 Hz, 1H), 3.18–3.40 (m, 3H), 4.13–
4.20 (m, 1H), 4.24 (dq, J¼10.8, 7.2 Hz, 1H), 4.32 (dq,
J¼10.8, 7.2 Hz, 1H), 5.54 (s, 2H), 6.73 (s, 1H), 7.09–7.12
(m, 2H), 7.23–7.63 (m, 8H); 13C NMR (75 MHz, CDCl3):
d (DEPT) 14.10 (CH3), 14.52 (CH3), 19.87 (CH2), 22.91
(CH2), 29.52 (CH2), 30.19 (CH2), 35.01 (CH), 39.88 (CH),
45.81 (CH), 52.44 (CH2), 59.84 (CH2), 117.62, 118.59,
124.86 (CH), 126.30 (CH), 126.66 (CH), 127.26 (CH),
128.45 (CH), 129.07 (CH), 131.53, 131.76, 138.33,
161.27, 177.36, 179.09; IR (CHCl3) 1709 cmꢁ1; MS (EI):
m/z (%): 484 (84) [M]+, 427 (74) [MꢁBu]+, 411 (100)
[MꢁCO2Et]+; EA calcd (%) for C30H32N2O4 (484.59): C
74.36, H 6.66, N 5.78; found: C 73.97, H 6.68, N 5.52.
126.2, 126.6, 127.1, 128.3, 128.3, 128.8, 131.1, 131.6,
138.1, 160.9, 177.0, 178.8; IR (CHCl3) 1710 cmꢁ1; MS
(EI): m/z (%): 500 (100) [M]+, 427 (97) [MꢁCO2Et]+, 395
(35) [MꢁCO2Et–HOMe]+; EA calcd (%) for C30H32N2O5
(500.59): C 71.98, H 6.44, N 5.60; found: C 72.05, H 6.44,
N 5.52.
1
Compound 9e: oil; H NMR (300 MHz, CDCl3): d 1.32 (t,
J¼7.2 Hz, 3H), 1.36–1.46 (m, 1H), 1.55–1.65 (m, 1H),
1.75–1.89 (m, 2H), 2.80 (ddd, J¼15.0, 9.0, 1.2 Hz, 1H),
3.20–3.38 (m, 3H), 3.42 (t, J¼6.6 Hz, 2H), 4.15–4.22 (m,
1H), 4.25 (dq, J¼10.8, 7.2 Hz, 1H), 4.31 (dq, J¼10.8,
3.6 Hz, 1 H), 5.52 (s, 2H), 6.74 (s, 1 H), 7.08–7.11 (m,
2H), 7.26–7.54 (m, 8H); 13C NMR (75 MHz, CDCl3):
d 14.5, 19.9, 27.7, 30.3, 34.3, 39.9, 45.0, 45.6, 52.6, 60.0,
117.7, 118.6, 125.1, 126.3, 126.7, 127.3, 128.5, 128.5,
129.1, 130.9, 131.7, 138.1, 161.0., 177.0, 178.8; IR
(CHCl3) 1709 cmꢁ1; MS (EI): m/z (%): 504 (45) [M]+,
458 (38) [MꢁHOEt]+, 427 (100) [MꢁC6H5]+, 381 (31)
[MꢁHOEt–C6H5]+; EA calcd (%) for C29H29ClN2O4
(505.00): C 68.97, H 5.79, N 5.55; found: C 69.13, H 5.74,
N 5.40.
The microwave heating was carried out as follows: to a dry
degassed toluene (5 mL) solution of the freshly prepared
enyne in a 6 mL reaction tube were added [IrCl(cod)]2
(20 mg, 0.03 mmol), AcOH (7 mL, 0.12 mmol), and N-phe-
nylmaleimide (200 mg, 1.1 mmol). The tube was sealed with
a Teflon cap and heated in a microwave reactor at 150 ꢀC for
0.5 h. The purification as above afforded 9a (287 mg, 59%).
Compound 9f: mp 57–59 ꢀC; 1H NMR (300 MHz, CDCl3):
d 1.32 (t, J¼7.2 Hz, 3H), 1.40–1.72 (m, 4H), 2.16–2.31 (m,
2H), 2.77 (ddd, J¼15.0, 9.0, 1.2 Hz, 1H), 3.18–3.40 (m, 3H),
3.60 (s, 3H), 4.15–4.22 (m, 1H), 4.24 (dq, J¼10.8, 7.2 Hz,
1H), 4.32 (dq, J¼10.8, 7.2 Hz, 1H), 5.49 (d, J¼15.3 Hz,
1H), 5.57 (d, J¼15.3 Hz, 1H), 6.73 (s, 1H), 7.10–7.13 (m,
2H), 7.27–7.53 (m, 8H); 13C NMR (75 MHz, CDCl3):
d 14.4, 19.8, 22.7, 29.7, 33.9, 34.6, 39.8, 45.6, 51.4, 52.4,
59.9, 117.6, 118.6, 124.9, 126.2, 126.7, 127.2, 128.4,
129.0, 130.9, 131.7, 138.2, 161.0, 173.3, 177.1, 178.8; IR
(CHCl3) 1711 cmꢁ1; MS (EI): m/z (%): 528 (100) [M]+,
455 (50) [MꢁCO2Et]+, 427 (38) [Mꢁ(CH2)3CO2Me]+; EA
calcd (%) for C31H32N2O6 (528.60): C 70.44, H 6.10, N
5.30; found: C 70.46, H 6.04, N 5.29.
1
Compound 9b: mp 201.0–201.6 ꢀC; H NMR (300 MHz,
CDCl3): d 1.21 (t, J¼7.2 Hz, 3H), 3.28–3.35 (m, 2H),
3.50–3.57 (m, 2H), 4.14 (q, J¼7.2 Hz, 2H), 5.33 (d,
J¼6.9 Hz, 1H), 5.45 (d, J¼12.6 Hz, 1H), 5.63 (d,
J¼12.6 Hz, 1H), 6.47–6.50 (m, 2H), 6.83 (s, 1H), 7.07–
7.35 (m, 13H); 13C NMR (75 MHz, CDCl3): d 14.3, 18.1,
38.4, 40.3, 45.8, 52.4, 59.9, 117.6, 117.7, 124.8, 126.3,
126.8, 126.0, 127.3, 128.3, 128.3, 128.5, 128.7, 129.0,
129.6, 131.3, 137.9, 138.9, 160.8, 176.4, 178.6; IR
(CHCl3) 1711 cmꢁ1; MS (EI): m/z (%): 504 (36) [M]+,
458 (100) [MꢁHOEt]+; EA calcd (%) for C32H28N2O4
(504.58): C 76.17, H 5.59, N 5.55; found: C 76.59, H 5.56,
N 5.42.
1
Compound 9g: mp 207.6–208.5 ꢀC; H NMR (300 MHz,
1
Compound 9c: mp 136.8–137.2 ꢀC; H NMR (300 MHz,
CDCl3): d 1.37 (t, J¼7.2 Hz, 3H), 3.08 (dd, J¼15.8,
8.7 Hz, 1H), 3.15 (dd, J¼15.8, 8.4 Hz, 1H), 3.26 (dd,
J¼9.0, 8.7 Hz, 1H), 3.34 (dd, J¼9.3, 5.4 Hz, 1H), 3.69–
3.70 (m, 1H), 3.97 (s, 5H), 4.03–4.06 (m, 1H), 4.07–4.09
(m, 1H), 4.18–4.20 (m, 1H), 4.30 (dq, J¼10.8, 7.2 Hz,
1H), 4.42 (dq, J¼10.8, 7.2 Hz, 1H), 5.24 (d, J¼5.4 Hz,
1H), 5.47 (d, J¼15.3 Hz, 1H), 5.71 (d, J¼15.3 Hz, 1H),
6.83 (s, 1H), 6.99–7.03 (m, 2H), 7.12–7.15 (m, 2H), 7.27–
7.41 (m, 6H); 13C NMR (75 MHz, CDCl3): d 14.4, 19.4,
34.7, 39.2, 48.3, 52.9, 60.1, 67.3, 67.4, 67.8, 68.5, 69.1,
87.7, 117.6, 118.7, 125.0, 126.2, 126.5, 127.2, 128.1,
128.4, 128.6, 131.5, 131.9, 138.5, 161.1, 176.4, 178.5; IR
(CHCl3) 1708 cmꢁ1; MS (EI): m/z (%): 612 (100) [M]+,
547 (2) [MꢁCp]+, 501 (17) [MꢁCO2Et–CpH]+; EA calcd
(%) for C36H32FeN2O4 (612.50): C 70.59, H 5.27, N 4.57;
found: C 70.58, H 5.15, N 4.61.
CDCl3): d 1.29 (t, J¼7.2 Hz, 3H), 2.92–3.00 (m, 1H), 3.09
(dd, J¼15.0, 9.0 Hz, 1H), 3.18 (s, 3H), 3.29–3.42 (m, 2H),
3.52 (dd, J¼9.6, 3.0 Hz, 1H), 3.81 (dd, J¼9.6, 3.9 Hz,
1H), 4.22 (dq, J¼10.5, 7.2 Hz, 1H), 4.27 (dd, J¼7.2,
3.6 Hz, 1H), 4.31 (dq, J¼10.5, 7.2 Hz, 1H), 5.40 (d,
J¼15.0 Hz, 1H), 5.63 (d, J¼15.0 Hz, 1H), 6.71 (s, 1H),
7.13–7.17 (m, 2H), 7.27–7.52 (m, 8H); 13C NMR
(75 MHz, CDCl3): d 14.5, 20.2, 34.4, 40.2, 42.3, 52.4,
58.7, 59.9, 74.9, 117.4, 119.5, 124.4, 126.3, 127.0, 127.3,
128.2, 128.5, 128.9, 130.2, 132.2, 138.1, 160.9, 177.3,
179.2; IR (CHCl3) 1707 cmꢁ1; MS (EI): m/z (%): 472 (46)
[M]+, 440 (14) [MꢁHOMe]+, 427 (100) [MꢁOEt]+; EA
calcd (%) for C28H28N2O5 (472.53): C 71.17, H 5.97, N
5.93; found: C 71.46, H 5.86, N 5.79.
1
Compound 9d: oil; H NMR (300 MHz, CDCl3): d 1.32 (t,
1
J¼7.2 Hz, 3H), 1.36–1.78 (m, 4H), 2.80 (ddd, J¼15.0, 9.0,
1.5 Hz, 1H), 3.17–3.37 (m, 5H), 3.23 (s, 3H), 4.13–4.21
(m, 1H), 4.24 (dq, J¼10.8, 7.2 Hz, 1H), 4.30 (dq, J¼10.8,
7.2 Hz, 1H), 5.49 (d, J¼15.3 Hz, 1H), 5.54 (d, J¼15.3 Hz,
1H), 6.72 (s, 1H), 7.09–7.13 (m, 2H), 7.27–7.53 (m, 8H);
13C NMR (75 MHz, CDCl3): d 14.4, 19.7, 26.7, 27.3, 34.6,
39.7, 45.6, 52.3, 58.2, 59.7, 72.3, 117.6, 118.3, 124.8,
Compound 9h: oil; H NMR (300 MHz, CDCl3): d 0.79 (t,
J¼7.2 Hz, 3H), 1.00–1.28 (m, 5H), 1.31 (t, J¼7.2 Hz, 3H),
1.52–1.63 (m, 1H), 2.80 (ddd, J¼15.6, 9.0, 1.2 Hz, 1H),
3.16 (dd, J¼15.6, 9.6 Hz, 1H), 3.35–3.52 (m, 2H), 4.04–
4.11 (m, 1H), 4.23 (dq, J¼10.8, 7.2 Hz, 1H), 4.30 (dq,
J¼10.8, 7.2 Hz, 1H), 5.47 (d, J¼15.0 Hz, 1H), 5.56
(d, J¼15.0 Hz, 1H), 6.70 (s, 1H), 7.06–7.09 (m, 2H),

Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
10157
7.27–7.34 (m, 3H); 13C NMR (75 MHz, CDCl3): d 14.1,
14.5, 19.4, 22.7, 29.5, 30.6, 34.6, 39.7, 46.6, 52.5, 60.0,
116.4, 118.8, 124.9, 126.7, 127.4, 128.5, 130.2, 138.1,
161.1, 172.1, 174.2; IR (CHCl3) 1779, 1693 cmꢁ1; MS
(EI): m/z (%): 409 (56) [M]+, 353 (100) [MꢁCH2]CHEt]+,
336 (39) [MꢁCO2Et]+; EA calcd (%) for C24H27NO5
(409.47): C 70.40, H 6.65, N 3.42; found: C 70.74, H 6.67,
N 3.31.
1709 cmꢁ1; MS (ESI): calcd for C29H32N2O2 (440.25):
found m/z 463.19 [M+Na]+; EA calcd (%) for C29H32N2O2
(440.58): C 79.06, H 7.32, N 6.36; found: C 79.11, H 7.38,
N 6.25.
1
Compound 17: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.89 (t, J¼6.9 Hz, 3H), 1.26–1.50 (m, 6H), 2.03 (d,
J¼0.9 Hz, 3H), 2.38 (t, J¼7.5 Hz, 2H), 3.46 (s, 2H), 3.56
(s, 3H), 5.03 (s, 2H), 6.40 (s, 1H), 6.99 (d, J¼6.9 Hz, 2H),
7.20–7.33 (m, 3H); 13C NMR (75 MHz, CDCl3): d 10.2,
13.9, 22.5, 24.7, 30.4, 30.8, 31.8, 50.4, 51.8, 116.9, 119.6,
121.1, 122.6, 126.6, 127.3, 128.7, 138.7, 171.4; IR
(CHCl3) 1739 cmꢁ1; MS (ESI): calcd for C20H27NO2
(313.20): found m/z 336.18 [M+Na]+; EA calcd (%) for
C20H27NO2 (313.43): C 76.64, H 8.68, N 4.47; found: C
76.57, H 8.74, N 4.48.
1
Compound 9i: mp 109.4–110.0 ꢀC; H NMR (300 MHz,
CDCl3): d 1.39 (t, J¼7.2 Hz, 3H), 1.35–1.45 (m, 2H),
1.75–2.02 (m, 2H), 2.16 (t, J¼7.5 Hz, 2H), 3.45 (dd,
J¼22.5, 3.0 Hz, 1H), 3.55 (s, 3H), 4.03 (dd, J¼22.5,
2.1 Hz, 1H), 4.30 (dq, J¼7.2, 3.6 Hz, 1H), 4.32 (dq,
J¼7.2, 3.6 Hz, 1H), 4.95–5.01 (m, 1H), 5.48 (d,
J¼15.3 Hz, 1H), 5.65 (d, J¼15.3 Hz, 1H), 6.80 (s, 1H),
7.07–7.10 (m, 2H), 7.21–7.33 (m, 3H), 7.69–7.75 (m, 2H),
8.09–8.16 (m, 2H); 13C NMR (75 MHz, CDCl3): d 14.5,
21.0, 21.9, 33.3, 34.2, 36.0, 51.4, 52.6, 59.9, 116.7, 117.2,
124.7, 126.1, 126.4, 126.6, 127.3, 128.5, 129.9, 131.9,
132.2, 138.3, 144.1, 146.8, 161.0, 173.5, 183.7, 184.3; IR
(CHCl3) 1731, 1689, 1660 cmꢁ1; MS (EI): m/z (%): 511
(26) [M]+, 480 (5) [MꢁOMe]+, 466 (2) [MꢁOEt]+, 438
(6) [MꢁCO2Et]+, 410 (100) [Mꢁ(CH2)3CO2Me]+; EA calcd
(%) for C31H29NO6 (511.57): C 72.78, H 5.71, N 2.74;
found: C 72.92, H 5.63, N 2.63.
1
Compound 18: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.83 (t, J¼6.9 Hz, 3H), 1.13–1.45 (m, 5H), 1.74 (m, 1H),
2.91 (dd, J¼15.0, 7.2 Hz, 1H), 3.13 (dd, J¼15.0, 8.4 Hz,
1H), 3.24–3.43 (m, 3H), 3.50 (d, J¼6.9 Hz, 2H), 3.57 (s,
3H), 5.04 (d, J¼16.5 Hz, 1H), 5.10 (d, J¼16.5 Hz, 1H),
6.52 (s, 1H), 6.98 (dd, J¼6.0, 2.1 Hz, 2H), 7.23–7.51 (m,
8H); 13C NMR (75 MHz, CDCl3): d 13.9, 20.7, 22.6, 29.8,
29.9, 30.3, 34.9, 40.7, 45.7, 50.6, 51.9, 116.6, 117.9,
120.5, 121.3, 126.5, 126.6, 127.6, 128.6, 128.8, 129.2,
132.2, 138.2, 171.0, 178.0, 179.7; IR (CHCl3) 1737,
1709 cmꢁ1; MS (ESI): calcd for C30H32N2O4 (484.24):
found m/z 507.20 [M+Na]+; EA calcd (%) for C30H32N2O4
(484.59): C 74.36, H 6.66, N 5.78; found: C 74.48, H 6.73,
N 5.58.
1
Compound 11: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.90 (t, J¼6.6 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 1.31–
1.51 (m, 6H), 2.02 (d, J¼0.6 Hz, 3H), 2.36 (t, J¼7.5 Hz,
2H), 2.47 (q, J¼7.5 Hz, 2H), 4.95 (s, 2H), 6.30 (s, 1H),
7.00 (d, J¼6.9 Hz, 2H), 7.20–7.32 (m, 3H); 13C NMR
(75 MHz, CDCl3): d 10.2, 14.0, 15.3, 17.5, 22.5, 24.8,
31.5, 32.0, 49.9, 116.8, 117.8, 119.6, 126.6, 127.2, 128.7,
131.0, 139.4; MS (ESI): calcd for C19H27N (269.21): found
m/z 270.21 [M+Na]+; EA calcd (%) for C19H27N (269.42): C
84.70, H 10.10, N 5.20; found: C 84.58, H 10.45, N 5.34.
1
Compound 21: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.88 (t, J¼6.9 Hz, 3H), 1.25–1.48 (m, 6H), 1.71 (d,
J¼6.9 Hz, 3H), 2.03 (d, J¼0.9 Hz, 3H), 2.36 (tt, J¼7.5,
3.9 Hz, 2H), 3.38 (d, J¼16.2 Hz, 1H), 3.51 (d, J¼16.2 Hz,
1H), 3.56 (s, 3H), 3.77 (s, 3H), 5.29 (q, J¼6.9 Hz, 1H),
6.52 (s, 1H), 6.81 (d, J¼9.0 Hz, 2H), 6.92 (d, J¼9.0 Hz,
2H); 13C NMR (75 MHz, CDCl3): d 10.4, 14.0, 22.4, 22.5,
24.7, 30.5, 30.8, 31.8, 51.8, 54.0, 55.2, 113.9, 115.4,
116.6, 121.1, 122.3, 127.1, 136.2, 158.7, 171.6; IR
(CHCl3) 1738 cmꢁ1; MS (ESI): calcd for C22H31NO3
(357.23): found m/z 380.19 [M+Na]+; EA calcd (%) for
C22H31NO3 (357.49): C 73.91, H 8.74, N 3.92; found: C
73.99, H 8.73, N 3.85.
1
Compound 12: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.87 (t, J¼6.6 Hz, 3H), 0.90 (t, J¼7.2 Hz, 3H), 1.18–
1.32 (m, 5H), 1.53 (m, 1H), 1.58–1.70 (m, 2H), 2.50–2.57
(m, 2H), 2.88 (m, 1H), 3.16 (dd, J¼9.9, 6.6 Hz, 1H), 3.22
(m, 1H), 3.32 (dt, J¼9.9, 7.2 Hz, 1H), 3.53 (d, J¼13.2 Hz,
1H), 3.51–3.58 (m, 1H), 3.71 (m, 1H), 4.06 (d, J¼13.2 Hz,
1H), 7.22–7.51 (m, 10 H); 13C NMR (75 MHz, CDCl3):
d 9.0, 13.8, 20.3, 22.7, 24.2, 29.7, 30.1, 34.1, 38.8, 44.8,
59.2, 61.9, 73.1, 126.4, 126.9, 128.4, 128.5, 128.7, 129.3,
132.0, 132.2, 138.5, 140.3, 177.8, 179.5; IR (CHCl3)
1712 cmꢁ1; MS (ESI): calcd for C29H34N2O2 (442.26):
found m/z 443.42 [M+H]+; EA calcd (%) for C29H34N2O2
(442.59): C 78.70, H 7.74, N 6.33; found: C 79.06, H 7.71,
N 6.00.
1
Compound 22: mp 185.6–186.2 ꢀC; H NMR (300 MHz,
CDCl3, 25 ꢀC): (more polar isomer) d 0.83 (t, J¼6.9 Hz,
3H), 1.15–1.41 (m, 5H), 1.71 (m, 1H), 1.75 (d, J¼6.6 Hz,
3H), 2.88 (dd, J¼15.0, 7.8 Hz, 1H), 3.13 (dd, J¼15.0,
9.0 Hz, 1H), 3.20–3.38 (m, 3H), 3.45 (d, J¼17.0 Hz, 1 H),
3.55 (s, 3H), 3.57 (d, J¼17.0 Hz, 1H), 3.78 (s, 3H), 5.31
(q, J¼6.6 Hz, 1H), 6.63 (s, 1H), 6.83 (d, J¼8.7 Hz, 2H),
6.95 (d, J¼8.7 Hz, 2H), 7.23–7.51 (m, 5H); (less polar iso-
mer) d 0.81 (t, J¼7.2 Hz, 3H), 1.05–1.45 (m, 6H), 1.74 (d,
J¼6.9 Hz, 3H), 2.93 (dd, J¼14.2, 6.3 Hz, 1H), 3.13 (dd,
J¼14.2, 8.4 Hz, 1H), 3.25–3.40 (m, 3H), 3.37 (d, J¼
17.1 Hz, 1H), 3.58 (d, J¼17.1 Hz, 1H), 3.60 (s, 3H), 3.77
(s, 3H), 5.31 (q, J¼6.9 Hz, 1H), 6.66 (s, 1H), 6.78 (d,
J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 7.22–7.50 (m,
5H); 13C NMR (75 MHz, CDCl3): (more polar isomer)
d 14.0, 20.7, 22.5, 22.6, 29.9, 30.0, 30.3, 34.9, 40.7, 46.0,
51.9, 54.3, 55.2, 113.8, 114.0, 116.2, 120.5, 120.8, 126.6,
1
Compound 13: oil; H NMR (300 MHz, CDCl3, 25 ꢀC):
d 0.85 (t, J¼7.2 Hz, 3H), 1.06 (t, J¼7.2 Hz, 3H), 1.20–
1.45 (m, 5H), 1.74 (m, 1H), 2.41–2.62 (m, 2H), 2.90 (dd,
J¼14.4, 7.2 Hz, 1H), 3.13 (dd, J¼14.4, 8.7 Hz, 1H), 3.27–
3.42 (m, 3H), 4.98 (d, J¼16.5 Hz, 1H), 5.04 (d,
J¼16.5 Hz, 1H), 6.42 (s, 1H), 6.98 (d, J¼6.0 Hz, 2H),
7.24–7.50 (m, 8H); 13C NMR (75 MHz, CDCl3): d 13.9,
15.3, 17.5, 20.8, 22.6, 29.9, 30.1, 34.9, 40.8, 46.2, 50.1,
116.2, 116.5, 118.3, 126.4, 126.6, 127.4, 128.6, 128.8,
129.2, 130.4, 132.2, 138.9, 178.3, 179.8; IR (CHCl3)

10158
Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
127.2, 128.6, 129.2, 132.2, 135.5, 158.9, 171.2, 178.1,
179.8; (less polar isomer) d 13.9, 20.9, 22.4, 22.5, 29.7,
29.8, 30.4, 34.8, 40.7, 45.6, 51.9, 54.2, 55.1, 113.8, 114.0,
116.3, 120.5, 120.9, 126.6, 126.8, 128.5, 129.1, 132.2,
135.7, 158.9, 171.2, 179.0, 179.7; IR (CHCl3) 1736,
1709 cmꢁ1; MS (ESI): calcd for C32H36N2O5 (528.26):
found m/z 551.21 [M+Na]+; EA calcd (%) for C32H36N2O5
(528.64): C 72.70, H 6.86, N 5.30; found: C 72.52, H 7.01,
N 5.33.
(ESI): calcd for C23H31NO2 (353.24): found m/z 376.22
[M+Na]+. This compound was not suitable for elemental
analysis because of ready aromatization under air. EA calcd
(%) for C23H31NO2 (353.50): C 78.15, H 8.84, N 3.96;
found: C 77.64, H 9.38, N 3.93.
Further elution with hexane/AcOEt (30:1) to give 26
(71.4 mg, 41%) as pale yellow oil. H NMR (300 MHz,
1
CDCl3): d 0.87 (t, J¼7.2 Hz, 3H), 1.11 (d, J¼7.2 Hz, 3H),
1.14 (t, J¼7.2 Hz, 3H), 1.27 (sext, J¼7.2 Hz, 2H), 1.33–
1.47 (m, 2H), 1.98–2.20 (m, 3H), 2.87 (m, 1H), 3.26–3.35
(m, 2H), 3.83 (s, 2H), 3.91 (s, 1H), 3.98 (dq, J¼7.2,
1.5 Hz, 1H), 5.56 (dt, J¼9.9, 2.1 Hz, 1H), 5.67 (dt, J¼9.6,
2.1 Hz, 1H), 7.21–7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 13.8, 14.0, 19.3, 22.9, 29.7, 29.9, 32.0, 40.1,
58.3, 59.7, 60.6, 67.4, 123.4, 127.2, 128.3, 129.3, 131.8,
133.0, 133.5, 138.6, 173.6; IR (CHCl3) 1728 cmꢁ1;MS
(ESI): calcd for C23H31NO2 (353.24): found m/z 376.22
[M+Na]+; EA calcd (%) for C23H31NO2 (353.50): C 78.15,
H 8.84, N 3.96; found: C 77.89, H 9.07, N 3.99.
4.6. Procedure for removal of chiral auxiliary of 22
To a solution of 22 (12.3 mg, 0.023 mmol) in CH2Cl2
(1 mL)/anisole (0.4 mL) were added CF3CO2H (0.1 mL)
and concd H2SO4 (1 drop) at room temperature. After stir-
ring for 12 h, the reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with 5% Na2CO3 (5 mL).
The aqueous solution was dried with Na2SO4, concentrated
in vacuo, and purified by flash column chromatography on
silica gel eluted with hexane/AcOEt (5:1) to give 23
(7.5 mg, 82%) as pale yellow oil. 1H NMR (300 MHz,
CDCl3, 25 ꢀC): d 0.84 (t, J¼7.5 Hz, 3H), 1.11–1.40 (m,
5H), 1.73 (m, 1H), 2.88 (dd, J¼15.0, 7.5 Hz, 1H), 3.16
(dd, J¼15.0, 8.4 Hz, 1H), 3.23–3.41 (m, 3H), 3.60 (d,
J¼17.1 Hz, 1H), 3.66 (d, J¼17.1 Hz, 1H), 3.71 (s, 3H),
6.60 (d, J¼1.8 Hz, 1H), 7.21–7.25 (m, 2H), 7.36–7.50 (m,
3H), 8.44 (br s, 1H); 13C NMR (75 MHz, CDCl3): d 13.9,
20.7, 22.5, 30.0, 31.2, 34.5, 40.7, 45.8, 52.1, 113.1, 117.5,
118.7, 119.4, 126.6, 128.6, 129.3, 132.2, 171.6, 178.0,
179.6; IR (CHCl3) 3100–3700, 1736, 1710 cmꢁ1; MS
(ESI): calcd for C23H26N2O4 (394.19): found m/z 417.17
[M+Na]+; EA calcd (%) for C23H26N2O4 (394.46): C
70.03, H 6.64, N 7.10; found: C 70.21, H 6.42, N 7.13.
4.8. Synthesis of cyclopropylenyne 27 and its
Rh-catalyzed cycloisomerization
˚
To a suspension of CuBr2 (11 mg, 0.05 mmol) and MS 4 A
(254 mg) in toluene (0.6 mL) was added ethyl glyoxalate so-
lution (ca. 50% in toluene, 0.10 mL), 1-hexyne (41 mg,
0.5 mmol), and N-benzyl-3-cyclopropylallylamine (93.9 mg,
0.5 mmol) in this order at room temperature under Ar at-
mosphere. The solution was stirred at room temperature
under Ar atmosphere for 24 h. After filtration through
a pad of FlorisilÒ, the filtrate was concentrated in vacuo.
To a dry degassed toluene (5 mL) solution of the obtained
cyclopropylenyne 27 in a 6 mL reaction tube were added
RhCl(PPh3)3 (23.2 mg, 0.025 mmol) and AgOTf (6.6 mg,
0.025 mmol). The tube was sealed with a Teflon cap
and heated in a microwave reactor at 120 ꢀC for 0.5 h. Af-
ter evaporation of the solvent, the residue was purified by
flash column chromatography on silica gel eluted with
hexane/AcOEt (100:1) to give a 1.7:1 mixture of 28 and
29 (81.4 mg, 46%) as pale yellow oil. Compound 28:
1H NMR (300 MHz, CDCl3): d 0.88 (t, J¼7.2 Hz, 3H),
1.25 (t, J¼7.5 Hz, 3H), 1.17–1.46 (m, 4H), 1.92–2.24
(m, 4H), 2.68 (m, 1H), 2.97 (t, J¼8.4 Hz, 1H), 3.22 (t,
J¼8.4 Hz, 1H), 3.67 (d, J¼12.9 Hz, 1H), 3.82 (m, 1H),
3.84 (d, J¼12.9 Hz, 1H), 4.10 (dq, J¼10.5, 7.5 Hz, 1H),
4.20 (dq, J¼10.5, 7.5 Hz, 1H), 4.28 (s, 1H), 5.35–5.41
(m, 1H), 5.47–5.56 (m, 1H), 7.22–7.32 (m, 5H); 13C
NMR (75 MHz, CDCl3): d 13.9, 14.2, 22.7, 26.7, 30.0,
30.2, 35.3, 39.6, 55.2, 58.3, 60.0, 66.9, 127.1, 128.3,
128.8, 128.9, 129.3, 136.6, 138.2, 138.9, 172.5; IR
(CHCl3) 1727 cmꢁ1; MS (ESI): calcd for C23H31NO2
(353.24): found m/z 376.22 [M+Na]+; EA calcd (%) for
C23H31NO2 (353.50): C 78.15, H 8.84, N 3.96; found: C
78.02, H 9.21, N 3.72. Compound 29: 1H NMR
(300 MHz, CDCl3): d 0.88 (t, J¼7.2 Hz, 3H), 1.25 (t,
J¼7.5 Hz, 3H), 1.20–1.43 (m, 4H), 1.92–2.26 (m, 5H),
2.49 (dd, J¼8.4, 6.0 Hz, 1H), 2.64 (m, 1H), 3.33 (t,
J¼8.4 Hz, 1H), 3.73 (s, 2H), 3.84 (m, 1H), 4.11 (q,
J¼7.5 Hz, 2H), 4.17 (s, 1H), 5.38–5.43 (m, 1H), 5.52–
5.60 (m, 1H), 7.21–7.35 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 13.9, 14.1, 22.8, 26.3, 29.7, 30.4, 35.0, 40.5,
56.8, 59.7, 60.3, 68.7, 127.1, 128.2, 129.0, 129.9, 131.9,
4.7. Synthesis of dienyne 24 and its Rh-catalyzed
cycloisomerization
˚
To a suspension of CuBr2 (11 mg, 0.05 mmol) and MS 4 A
(252 mg) in toluene (0.6 mL) were added ethyl glyoxalate
solution (ca. 50% in toluene, 0.10 mL), 1-hexyne (41 mg,
0.5 mmol), and N-benzylpenta-2,4-dienylamine (92.6 mg,
0.5 mmol) in this order at room temperature under Ar atmo-
sphere. The solution was stirred at room temperature under
Ar atmosphere for 24 h. After filtration through a pad of Flo-
risilÒ, the filtrate was concentrated in vacuo. To a dry de-
gassed toluene (5 mL) solution of the obtained dienyne 24
in a 6 mL reaction tube was added Rh(acac)(CO)2 (6.3 mg,
0.024 mmol). The tube was sealed with a Teflon cap and
heated in a microwave reactor at 120 ꢀC for 0.5 h. After
evaporation of the solvent, the residue was purified by flash
column chromatography on silica gel eluted with hexane/
AcOEt (50:1) to give 25 (41.2 mg, 23%) as pale yellow
oil. 1H NMR (300 MHz, CDCl3): d 0.89 (t, J¼7.2 Hz, 3H),
1.13 (d, J¼7.5 Hz, 3H), 1.23 (t, J¼7.5 Hz, 3H), 1.20–1.47
(m, 4H), 1.95–2.14 (m, 2H), 2.75 (dd, J¼11.0, 7.2 Hz,
1H), 2.72–2.86 (m, 1H), 3.05 (dd, J¼14.1, 6.9 Hz, 1H),
3.05–3.13 (m, 1H), 3.65 (d, J¼13.5 Hz, 1H), 3.87 (d,
J¼13.5 Hz, 1H), 4.14 (q, J¼7.2 Hz, 2H), 4.43 (s, 1H),
5.57 (ddd, J¼9.6, 3.0, 1.8 Hz, 1H), 5.74 (ddd, J¼9.6, 2.4,
1.8 Hz, 1H), 7.23–7.35 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 13.9, 14.3, 19.1, 22.5, 29.8, 30.0, 32.9, 40.9,
54.9, 55.0, 59.9, 66.1, 124.8, 127.1, 128.3, 128.7, 133.8,
133.9, 134.2, 139.2, 172.8; IR (CHCl3) 1730 cmꢁ1; MS

Y. Yamamoto, H. Hayashi / Tetrahedron 63 (2007) 10149–10160
10159
136.1, 137.5, 138.5, 173.0; IR (CHCl3) 1726 cmꢁ1; MS
(ESI): calcd for C23H31NO2 (353.24): found m/z 376.22
[M+Na]+; EA calcd (%) for C23H31NO2 (353.50): C
78.15, H 8.84, N 3.96; found: C 77.89, H 9.32, N 3.76.
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4.9. Crystallographic structural determination of 9g
A single crystal was mounted on a quartz fiber, and diffrac-
tion data were collected at 173 K on a Brucker SMART
APEX CCD diffractometer with graphite-monochromated
˚
Mo Ka radiation (l¼0.71073 A). An absorption correction
was made using SADABS. The structure was solved by di-
rect methods and refined by full-matrix least squares on F2
by using SHELXTL.35 All non-hydrogen atoms were refined
with anisotropic displacement parameters. All hydrogen
atoms were placed in calculated positions. The supplemen-
tary crystallographic data for this paper [CCDC 269756]
can also be obtained free of charge via www.ccdc.cam.ac.
uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
Acknowledgements
12. Ji, J.-X.; Au-Yeung, T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C.
Adv. Synth. Catal. 2004, 346, 42–44.
This research was partially supported by the MEXT, Grant-
in-Aid for Young Scientists (A) (17685008), and Scientific
Research on Priority Area ‘Creation of Biologically Func-
tional Molecules’ (18032036). We thank Prof. T. Ikariya
and S. Kuwata for use of the ESI mass and FT/IR spectro-
meters, and Prof. K. Tomooka for use of the NMR spectrom-
eter. We also thank Prof. H. Suzuki, T. Takao, and M. Oishi
for elemental analyses.
13. (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763–5766; (b)
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14. 1H NMR analysis of crude mixture revealed the formation
of dibenzylamine and ethyl 4-phenyl-2-oxobut-3-enonate
(Rambaud, M.; Bakasse, M.; Duguay, G.; Willieras, J.
Synthesis 1988, 564–566 ).
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