Synthesis of bridged nicotinates having [n](2,5)pyridinophane skeletons (n=8-14)

Article abstract of DOI:10.1016/j.tet.2006.02.002

Synthesis of various bridged nicotinates 6 having [n](2,5)pyridinophane skeletons (n=8-14) was accomplished by the unique pyridine-formation reaction of methyl propiolate with a series of formyl-substituted (vinylimino)phosphoranes 5, which were prepared from the corresponding cycloalkanones 1 via Vilsmeier-Haack formylation giving chloro-substituted cycloalkenals 2, their thermal and photochemical transformation to formyl azirines 4, and the following ring-opening reactions with triphenylphosphine. The HPLC analysis of [11](2,5)pyridinophane derivatives, (S_p,S)-14 and (R_p,S)-14, showed that these diastereomers rapidly epimerize themselves at room temperature and that their planar-chirality was thermodynamically less stable as compared to the corresponding [11](2,5)cyclophane systems.

Full text of DOI:10.1016/j.tet.2006.02.002

Tetrahedron 62 (2006) 4128–4138
Synthesis of bridged nicotinates having [n](2,5)pyridinophane
skeletons (nZ8–14)
a, ,†
*
b
b
Shinsuke Yamada, Takayuki Ohhama, Akira Fusano,
a
b
Nobuhiro Kanomata,
Yoshiharu Ochiai, Jun Oikawa, Masahiro Yamaguchi and Fumio Sudo
b
b
b
a
Department of Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
b
Department of Industrial Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
Received 7 November 2005; revised 1 February 2006; accepted 2 February 2006
Available online 9 March 2006
Abstract—Synthesis of various bridged nicotinates 6 having [n](2,5)pyridinophane skeletons (nZ8–14) was accomplished by the unique
pyridine-formation reaction of methyl propiolate with a series of formyl-substituted (vinylimino)phosphoranes 5, which were prepared from
the corresponding cycloalkanones 1 via Vilsmeier–Haack formylation giving chloro-substituted cycloalkenals 2, their thermal and
photochemical transformation to formyl azirines 4, and the following ring-opening reactions with triphenylphosphine. The HPLC analysis of
[11](2,5)pyridinophane derivatives, (S ,S)-14 and (R ,S)-14, showed that these diastereomers rapidly epimerize themselves at room
p p
temperature and that their planar-chirality was thermodynamically less stable as compared to the corresponding [11](2,5)cyclophane
systems.
q 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
target molecules for studying their dynamic motions and the
correlation of the bridge lengths with synthetic efficiency. We
will report here the detailed results of the synthetic studies on
bridged nicotinates having [n](2,5)pyridinophane structures
(nZ8–14) incorporating various lengths of their oligomethy-
lene bridges.
(
various heteroaromatic compounds, and are particularly
Vinylimino)phosphoranes are versatile synthetic synthons of
1
2
useful for the syntheses of pyridine and pyridinophane
–6
7–9
derivatives. We have previously reported novel pyridine-
formation reactions of formyl-substituted (vinylimino)-
phosphoranes with acetylenic esters to give 2- and 2,5-sub-
2
stituted nicotinates, and their synthetic application to a
7
2. Results and discussion
bridged nicotinate having [10](2,5)pyridinophane structure.
1
Our recent studies revealed also that the bridged nicotinate
0
2.1. Synthetic strategy of bridged nicotinates
1
andbridgedbenzoate aresuchplanar-chiralsourcesthatthey
1
1
1,12
are readily accessible by crystallization-induced
or
Scheme 1 illustrates our retrosynthetic route for bridged
nicotinates having various lengths of oligomethylene chains,
13
adsorption-induced asymmetric transformation, and that
planar-chiral NADH models, derived from the bridged
nicotinate, exhibited one of the highest enantioselectivity in
biomimetic asymmetric reduction of pyruvate analogues
among a number of NADH-mimicking systems having been
7
1
4
reported so far. In the bridged nicoinate systems, the
decamethylene chains bridging para-positions of the pyridine
ringplayanextremelyimportantroleinshieldingeithersideof
two reactive faces and, therefore, the other nicotinates having
different sizes of oligomethylene chains became our next
Keywords: Planar-chirality; Pyridinophanes; Pyridine-formation reactions;
Aza-Wittig reactions; Cycloaddition.
*
Corresponding author. Tel.: C81 3 5286 3193; fax: C81 3 5286 3481;
e-mail: kanomata@waseda.jp
N.K. is a previous faculty member of Meiji University (1999–2005).
Scheme 1. Retrosynthetic analysis of bridged nicotinates having various
[n](2,5)cyclophane skeletons.
†
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.002

N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
4129
namely methyl [n](2,5)pyridinophane-3-carboxylates.
The final pyridine-formation is to be accomplished
by intramolecular aza-Wittig reactions of intermediates
A whose diene moieties should be derived from ring-
opening isomerizations of cyclobutene intermediates B. The
enamine-type [2C2] cycloaddition disassembles B into
methyl propiolate and (vinylimino)phosphorane deriva-
tives, the latter of which are transformed from halo-
substituted cycloalkenals being readily available by
Vilsmeier–Haack formylation of the corresponding
cycloalkanones.
chloroenals) were co-generated as well as the desired 2b–h
in the similar reaction conditions to those employed for 2a
(entry 2: see footnote). Eventually, we found even milder
reaction conditions working very well for the synthesis of
2b–h where the reactions with excess amounts of DMF and
POCl at 0 8C effected predominant formation of (Z)-2b–f in
3
good to moderate isolated yields (entries 2–7). For the
reactions giving compounds 2g,h, significant amounts of
(
E)-2g,h were generated as less reactive isomers in the
following steps as well as the desired (Z)-2g,h isolated in
moderate yields (entries 8 and 9). In case of compound 2e,
the formylation proceeded with high (Z)-selectivity and the
product was used for the next step without further
purification (entry 6).
2
.2. Preparation of (vinylimino)phosphoranes
The synthetic transformation to formyl-substituted (vinyl-
imino)phosphoranes 5a–h was achieved by the sequential
functionalization from cycloalkanones (1a–h) based on our
Then, we initially attempted the conversion of (Z)-2a–h thus
obtained into the corresponding 2-azidocycloalk-1-enecar-
baldehyde (3a–h), appropriate precursors for the subsequent
Staudinger reactions. But the formation of 3a was not
observed in the crude mixture produced by the reaction of
7
previously reported method giving 5d (Scheme 2).
Vilsmeyer–Haack formylation of cycloalkanones 1a–h
afforded the corresponding (Z)- and/or (E)-2-chloro-
cycloalk-1-enecarbaldehyde (2a–h) in good yields
2a with sodium azide and, instead, formylazirine 4a was
(
the formylation by using DMF and POCl with 1 equiv
Table 1). At the beginning of our study, we carried out
isolated exclusively in 83% yield (entry 1 in Table 2). On
the other hand, the reaction of the other chlorocycloalkenals
3
amount each at a high temperature and, indeed, the reaction
of cyclooctanone (1a) proceeded smoothly at 70 8C to afford
(Z)-2a exclusively in 84% yield (entry 1). However,
significant amounts of by-products (mostly b,g-unsaturated
2b–h afforded a mixture of (E)-3b–h and 4b–h, and none of
(
Z)-3b–h was isolated at room temperature. Thus, formation
of the azirines 4b–h was reasonably explained as a result of
releasing nitrogen out of less stable (Z)-3b–h. We have
therefore chosen the synthetic route to (vinylimino)-
phosphoranes 5a–h via azirine intermediates as well as
7
the transformation from 2d to 4d reported previously. After
the reaction of 2b–h with sodium azide was complete, the
crude mixtures containing (E)-3b–h were irradiated through
Pyrex filter (365 nm) to give the compounds 4b–h in
79–92% isolated yields (entries 2–8). The treatment with
triphenylphosphine in refluxing toluene effected the ring-
opening reaction of the azirine ring to give the desired
formyl-substituted (vinylimino)phosphoranes 5a–h in
7
5
6–99% yields (see Section 3.5). Except for compound
1
a, H NMR spectra of the other iminophosphoranes
exhibited two sorts of formyl protons corresponding to
E)- and (Z)-forms, the chemical shifts of which appeared at
(
d 9.84–9.93 and 10.57–10.71 ppm, respectively. The former
signals were unambiguously assigned to those of (E)-5b–h
whose signals at aliphatic regions were clearly informative
of their non-symmetric structures being attributed to
highly substituted trans-cycloalkenes with planar-chirality.
Scheme 2. Synthesis of formyl-substituted (vinylimino)phosphoranes 5a–h
from cycloalkanones 1a–h.
Table 1. Vilsmeier–Haack formylation of 1a–h
Table 2. Synthesis of formylazirines 4a–h
Entry
1
Conditions
T (8C) Time
Yield and ratio of 2
Crude E/Z Isolated
Entry
2
Conditions
Isolated
yield
(
h)
(%)
(%)
a
Method
Time (h)
4 (%)
1
2
3
4
a
b
b
c
d
e
f
g
h
70
75
0
0
0
K5
0
0
6
6
n/a
0/100
84 (Z)
75 (Z)
68 (Z)
90 (Z)
78 (Z)
a
85
b
0/100
17/83
3/97
18/82
6/94
22/78
44/56
48/52
1
2
3
a
b
c
d
e
f
A
B
B
B
A
A
A
A
19
5
4.5
5
3
3
3
3
83
79
85
84
80
82
82
92
48
24
48
48
48
48
72
Quant
99
95
91
98
b
c
5
4
c
n/a
6
7
8
9
5
6
7
8
52 (Z)
53 (Z)
50 (Z)
92
99
g
h
0
a
a
b,g-Unsaturated chloroenal (15%) was produced as a by-product as well
as 2b.
Previous work. See Ref. 7.
3 3
Method A: NaN 1.5 equiv, DMF, rt. Method B: NaN 1.25 equiv, LiCl
0.1 equiv, wet THF, rt. See Section 3 for details.
Obtained without photolysis.
Previous work. See Ref. 7.
b
c
b
c
Used in the following steps without further purification.

4
130
N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
Table 4. Synthesis of bridged nicotinates 6b–h
The compounds 5a–c, having an 11-membered ring or less,
exist as (Z)-form rich mixtures and, on the other hand, the
others exist as (E)-form rich mixtures to minimize their ring
strain. These compounds were produced as an inseparable
mixture and they were used in the following step without
further purification (Scheme 3).
a
b
Entry
5
n
Yield (Method A)
Yield (Method B)
6
(%)
7 (%)
6 (%)
7 (%)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
6
8
9
10
11
12
13
14
0
4
7
21
26
30
38
40
5
10
4
n/a
4
n/a
25
11
15
8
16
16
16
10
25
29
32
41
43
c
c
8
3
3
5
4
2
.3. Syntheses of bridged nicotinates
g
h
The reactions of the iminophosphoranes 5a–h with methyl
propiolate were thoroughly investigated for synthesizing
nicotinates 6a–h (Scheme 3). Table 3 indicates the reaction
conditions and yields of compound 6d, a representative
bridged nicotinates having a [10](2,5)pyridinophane skeleton,
as the results of our reinvestigation for seeking more efficient
synthetic protocol. Our previous one, where the compound 5d
reacts with 10 equiv amount of methyl propiolate in toluene at
a
Method A: reactions were performed with 10 equiv of methyl propiolate
in toluene at 140 8C for 12 h in autoclave.
Method B: reactions were performed with 5 equiv of methyl propiolate in
acetonitrile at 120 8C for 10 h in autoclave.
Previous work. See Ref. 7.
b
c
Table 4 tabulates the yields of bridged nicotinates 6b–h and
their isomers 7a–h obtained by the reactions of a series of
(vinylimino)phosphoranes 5a–h with methyl propiolate in
toluene and acetonitrile as solvent. These reactions also
proceeded well to result in the formation of methyl
[n](2,5)pyridinophane-3-carboxylates 6b–h having various
length of their oligomethylene chains (entries 1–3, 5–8). In
each case, the yield of 6b–h in acetonitrile was better than
that in toluene and unidentified by-products formed in these
reactions did not seriously disturb the isolation of 6 and 7.
Obviously, the yields of 6b–h increased as length of the
oligomethylene chain becomes longer. Though none of
[6](2,5)pyridinophane 6a was obtained from 5a (entry 1),
the compounds 6b,c were isolated even in relatively low
yields due to their higher strain as compared to 6d–h (entries
2 and 3). The reaction of 5e–h having a larger ring size
reacted with methyl propiolate more smoothly to result in
1
8
40 8Cfor12 h, gavethe desired6danditsisomer7din21and
% yield, respectively (See entry 4 of Method A in Table 4),
7
and we first examined the solvent effects. After running the
reactions of 5d with 5 equiv amount of methyl propiolate in
various solvents at 140 8C, we eventually found that
acetonitrile, an aprotic polar solvent, is more suitable for the
synthesis of 6d (entries 1–7). The reactions also work well
at 120 8C (entries 8–12), to give 6d with up to 25% yield
(
entry 9). The reactions with more or less amount of methyl
propiolate did not afford better results for the formation of 6d
entries 13 and 14). As a result, we were successful in reducing
(
the amount of methyl propiolate to 5 equiv, just a half
amount as compared to our original protocol, and in achieving
the milder reaction conditions at 120 8C for 10 h (See also
Section 3.6).
[
n](2,5)pyridinophane-3-carboxylate 6e–h (nZ11–14) in
moderate yields (entries 5–8). All the spectral data agree
with these proposed structures.
The postulated reaction pathways for the formation of 6b–h
and 7a–h are shown in Scheme 4. Enamine-type nucleo-
Scheme 3. Pyridinophane-formation reactions of formyl-substituted
(vinylimino)phosphoranes 5a–h with methyl propiolate.
1
5
philic addition of 5a–h occurs at the b-position of methyl
propiolate to form ionic intermediates 8a–h and the
following intramolecular addition onto C]N and C]O
produces cyclobutene intermediates B and 9, respectively.
The ring-opening reactions of B and 9 generate aldehydes A
a
Table 3. Reaction conditions and the yield of 6d
b
Entry
Conditions
Yield
MP
(equiv)
Solvent
T (8C)
Time (h) 6d (%)
c
1
2
3
4
5
5.0
5.0
5.0
5.0
5.0
Benzene
Toluene
Xylene
Chlorobenzene
1,1,2-Trichloro-
ethane
140
140
140
140
140
24
24
24
24
24
11
17
17
17
19
6
7
8
9
1
1
1
1
1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
1,4-Dioxane
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
140
140
120
120
120
120
120
120
120
24
24
12
10
8
6
4
10
8
12
22
21
25
24
22
19
17
16
d
d
d
d
d
d
d
0
1
2
3
4
10.0
a
b
c
d
All the reactions were carried out under 0.33 M solution of 5d.
Isolated yields unless otherwise specified.
Methyl propiolate.
Estimated by H NMR spectra.
1
Scheme 4. Postulated reaction pathways for the formation of 6 and 7.

N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
4131
and 10, which undergo intramolecular aza-Wittig reactions
to give 6b–h and 7a–h. The formation of 7a–h is also
explained by the following alternative pathway: [2C2]
cycloaddition of methyl propiolate onto N]P double bond
of 5a–h gives intermediates 11 and their subsequent ring-
opening to 12 and intramolecular Wittig reaction of 12
1
6
afford 7a–h. Formation of these ionic intermediates shown
in Scheme 4 seems to be suitable in an aprotic polar solvent
such as acetonitrile, leading to the higher yield of 6 and 7.
1
The H NMR spectra of parapyridinophanes6b,c (nZ8 and 9)
showed that some protons at oligomethylene bridges were
observed independently with unique chemical shifts and,
especially, one of them appeared at d K0.27 or K0.19 ppm
Scheme 5. Synthesis of [11](2,5)pyridinophane derivatives, (S ,S)-14 and
p
(R ,S)-14.
p
(
for 6b and 6c, respectively) as a distinctive up-field shift in
a shielding region above an aromatic ring. These findings
indicate that the compounds 6b,c have a stable planar-
chirality as well as [10](2,5)pyridinophane 6d that we
1
reported previously. As for [11](2,5)pyridinophane 6e, H
NMR spectrum exhibited that its rope-skipping mobility of
oligomethylene chain is apparently frozen in NMR time
scale according to the peak independency of its aliphatic
protons appearing at d 2.62, 2.68, 2.77, and 3.74 ppm
(
1H each, ArCH –) (Fig. 1a).
2
Figure 2. HPLC analyses of a diastereoisomeric mixture of (S
(R
p
p
,S)-14 and
,S)-14 at rt and 0 8C.
1
On the other hand, H NMR spectra of 6f–h (nZ12–14) are
much simpler than those of 6b–e and the proton pairs at each
methylene unit appear as equivalent signals [see signals
appearing at d 3.26 and 3.93 ppm (2H each, ArCH –) for 6f
2
in Fig. 1b] as well as Cs-symmetric isomers of the ortho-
bridged 7f–h. Consequently, undecamethylene or longer
bridges (nR11) are flexible enough to flip over their
pyridine rings and these molecules can hardly retain their
planar chirality at room temperature. These findings that we
have reported here provide a convenient route for the
syntheses of bridged nicotinates having [n](2,5)pyridino-
phane skeletons and unique dynamic behavior of these
novel ansa molecules.
1
Figure 1. H NMR spectra of bridged nicotinates 6e,f at rt: some
oligomethylene protons of (a) [11](2,5)pyridinophane 6e and
3. Experimental
(b) [12](2,5)pyridinophane 6f.
3.1. General
On the contrary, HPLC analysis of a diastereomeric mixture
of (S ,S)-14 and (R ,S)-14, derived from [11](2,5)pyridino-
p
p
NMR spectra were recorded on Bruker AVANCE600,
JEOL JNM-ECA500, JEOL Lambda500, JEOL JNM-A400,
JEOL JNM-AL300, or JEOL JNM-EX270 spectrometers.
Chemical shifts are reported in parts per million relative to
phane-3-carboxylic acid (13) (Scheme 5), showed an
inseparable single peak at room temperature, which
suggests their rapid dynamic interconversion via rope-
1
7
skipping isomerization in HPLC time scale (Fig. 2).
Indeed, at 0 8C, a typical plateau shape was observed in the
middle of coalescence peaks of the two diastereoisomers
1
Me Si for H NMR and to the central line of CDCl
4
(
3
13
77.0 ppm) for C NMR as internal standard. Unless
otherwise specified, NMR spectra were measured at
ambient temperature except for compound 14 (at 50 8C).
Mass spectra were recorded on Hitachi M-80, JEOL JMS-
SX102, or JEOL-HX110 spectrometers. Thin-layer chro-
matography was performed using Merck silica gel 60 F254
glass plates (Art. 5715, 0.5 mm thick) or Merck aluminum
oxide 60 F254 glass plates (Art. 5713, 0.25 mm thick). Flash
chromatography was performed using Silica gel FL60D
1
8
epimerizing themselves. This means that [11](2,5)pyridi-
nophane 6e also exists as a racemic equilibrium mixture
with rapid interconversion and its planar-chirality is not
stable enough to be resolved for the synthetic purposes. This
is in good contrast to the analogous [11](2,5)cyclophane
derivatives, which are reasonably stable against their
1
1
racemization or epimerization.

4132
N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
(
Fuji Silysia Chemical Ltd) unless otherwise specified.
mixture was stirred at room temperature for 30 min. The
mixture was cooled down to 0 8C and a solution of
cyclooctanone (2.52 g, 20.0 mmol) in CH Cl2 (5.0 ml)
2
Melting points were recorded on Yanagimoto apparatus and
are uncorrected. Cyclooctanone (1a), cyclodecanone (1b),
cylododecanone (1d), cyclotridecanone (1e), and cyclo-
pentadecanone (1g) are commercially available starting
materials and were used without further purification.
Cycloundecanone (1c) was prepared from cyclododecanone
was added dropwise at 0 8C. The reaction mixture was
heated at 70 8C for 6 h and, then, was poured into ice. The
organic layer was separated, the aqueous layer was
extracted with CH Cl , and the combined organic layer
2
2
1
9
according to the literature method.
was washed with small portions of water, brine and dried
over MgSO . After removal of solvent in vacuo, the residue
was distilled (64 8C, 0.3 mmHg) to give chloroaldehyde 2a
4
3.1.1. Cyclotetradecanone (1f). Cyclotetradecanone (1f)
was prepared from cyclopentadecanone (1g) according to
the similar method for the preparation of 1c.
1
(2.92 g, 16.9 mmol) in 84% yield: H NMR (500 MHz,
1
9
0 0
CDCl ) d 1.44–1.58 (m, 6H), 1.82 (m, 2H), 2.46 (AA XX ,
3
0
0
JAXCJAX
12.8 Hz, 2H), 10.17 (s, 1H). Compound 2a was reported
0
Z12.0 Hz, 2H), 2.76 (AA XX , JAXCJAX Z
0
To a solution of cyclopentadecanone (1g) (22.4 g,
00 mmol) in toluene (140 ml) and ether (15 ml) was
added dropwise bromine (10.0 ml, 200 mmol) and the
2
2
1
previously in literature.
mixture was stirred with a cooling bath at 20–25 8C for
3
vacuo, the residual toluene solution of dibromide was
treated with sodium methoxide (18.9 g, 350 mmol) in small
portions and the whole mixture was stirred at 20–25 8C for
3.2. General procedure for the synthesis of 2-chloro-
cycloalk-1-enecarbaldehyde (2b–h)
0 min. After removal of hydrogen bromide generated in
To a solution of DMF (4.6 ml, 60.1 mmol) in CH Cl
2
2
(10 ml) was added dropwise a solution of phosphorus
oxychloride (9.42 g, 61.4 mmol) in CH Cl (10 ml) with ice
3
0 min. After the reaction was complete, the mixture was
washed with water (1!50 ml), 5% hydrochloric acid (1!
50 ml) and brine (1!50 ml) and the aqueous layer was
2
2
cooling bath, and the mixture was stirred at room
temperature for 30 h. A solution of cycloalkanone 1b–h
1
extracted with ether (3!80 ml). The combined organic
layer was dried over sodium sulfate and, after removal of
solvent in vacuo, the residue was separated by flash
chromatography on silica gel (5% ether in hexane) to give
(20.1 mmol) in CH Cl (10 ml) was added dropwise at 0 8C,
and the mixture was stirred at 0 8C for 2 days. Cold water
2 2
was added and the mixture was extracted with CH Cl ,
2
2
washed with water and brine, and dried over Na SO . After
2
methyl cyclotetradec-1-encarboxylate (24.4 g, 96.7 mmol)
in 97% yield: H NMR (270 MHz, CDCl ) d 1.23–1.57 (m,
4
1
removal of solvent in vacuo, the residue gave the crude
products of 2-chlorocycloalk-1-enecarbaldehyde (2b–h).
3
0
0
2
0H), 2.31 (AA XX , JAXCJAX
0
Z11.2 Hz, 2H), 2.49 (m,
7
Compound 2d was reported previously in literature.
Reaction conditions and yields of 2a–h are summarized in
Table 1.
2H), 3.73 (s, 3H), 5.82 (t, JZ7.8 Hz, 1H). After the product
thus obtained was dissolved in sulfuric acid (73 ml) at 5 8C,
chloroform (61 ml) was added, sodium azide (9.23 g,
1
42 mmol) was added in portions at 40 8C, and the reaction
mixture was stirred at 35–40 8C for 1 h. The mixture was
poured into ice water (200 g each) and was extracted with
chloroform (3!100 ml). The combined organic layer was
washed with saturated aqueous sodium bicarbonate (2!
3.2.1. 2-Chlorocyclodec-1-enecarbaldehyde (2b). Com-
pound (Z)-2b. Oil; H NMR (500 MHz, CDCl ) d 1.23 (m,
1
3
2
H), 1.40–1.52 (m, 6H), 1.62 (m, 2H), 1.90 (br, 2H), 2.53 (t,
13
JZ6.5 Hz, 2H), 2.83 (br, 2H), 10.29 (s, 1H); C NMR
126 MHz, CDCl ) d 20.6, 20.8, 24.8, 25.0, 25.2, 25.5, 27.1,
2
00 ml) and dried over magnesium sulfate. After removal of
(
3
2
3
solvent in vacuo, the residue was purified by flash
chromatography on silica gel (2% ether in hexane) to give
cyclotetradecanone (1f) (13.7 g, 64.9 mmol) in 69% yield:
C
5.7, 135.5, 154.1, 192.4; MS (EI) m/z (%) 202 (1.1) [M C
C
], 200 (3.2) [M ], 165 (100); HRMS (EI) calcd for
2
0
35
C H
ClO 200.0968, found 200.0971.
1
11 17
H NMR (270 MHz, CDCl ) d 1.09–1.29 (m, 18H), 1.67
3
1
3
(
quint, JZ6.4 Hz, 4H), 2.44 (t, JZ6.4 Hz, 4H); C NMR
(
4
68 MHz, CDCl ) d 22.8, 24.3, 25.15, 25.20, 25.7, 26.0,
0.7, 212.2.
3.2.2. 2-Chlorocycloundec-1-enecarbaldehyde (2c). Com-
) d 1.23 (m,
3
3
1
pound (Z)-2c. Oil; H NMR (400 MHz, CDCl
2
H), 1.27–1.38 (m, 4H), 1.38–1.46 (m, 4H), 1.59 (m, 2H),
0
0
0
Z11.9 Hz, 2H),
3
5
.1.2. Cyclohexadecanone (1h). A solution of cyclohexadec-
-enone (11.8 g, 50.0 mmol) (commercially available from
1.86 (m, 2H), 2.47 (AA XX , JAXCJAX
0
0
2.77 (AA XX , JAXCJAX
C NMR (100 MHz, CDCl ) d 22.3, 23.2, 24.1, 25.2, 25.4,
0
Z12.2 Hz, 2H), 10.28 (s, 1H);
1
3
Tokyo Kasei Kogyo, TCI Japan) in ethanol (200 ml) was
stirred in the presence of Pd/C (5 wt%, 1.18 g) under
hydrogen atmosphere at room temperature for 2.5 h. After
the reaction was complete, the mixture was filtered through
Celite and the filtrate was concentrated in vacuo to give
3
25.7, 25.8, 32.3, 37.6, 125.5, 154.6, 192.8; MS (EI) m/z (%)
216 (1.8) [M C2], 214 (5.3) [M ], 67 (100). HRMS (EI)
C
C
3
19 ClO 214.1124, found 214.1119.
5
calcd for C12
H
2
1
1
Compound (E)-2c. Oil; H NMR (400 MHz, CDCl
cyclohexadecanone (1h) (11.8 g, 49.3 mmol, 99%) as a
white solid: H NMR (270 MHz, CDCl ) d 1.16–1.38 (m,
3
) d 0.98–
1
1.18 (m, 3H), 1.18–1.45 (m, 6H), 1.52 (m, 1H), 1.65–1.82
(m, 2H), 1.85–1.99 (m, 2H), 2.40–2.52 (m, 2H), 2.65 (ddd,
JZ13.7, 8.8, 3.9 Hz, 1H), 3.42 (ddd, JZ13.7, 11.7, 3.4 Hz,
3
2
2H), 1.64 (quint, JZ6.8 Hz, 4H), 2.41 (t, JZ6.8 Hz, 4H).
1
3
3.1.3. 2-Chlorocyclooct-1-enecarbaldehyde (2a). To a
solution of DMF (1.7 ml, 22.1 mmol) in CH Cl (5.0 ml)
1H), 10.15 (s, 1H); C NMR (100 MHz, CDCl
3
) d 23.4,
24.2, 25.07, 25.11, 25.4, 26.4 (2C), 27.0, 35.7, 140.6, 159.2,
2
2
3
H19 ClO 214.1124, found
5
was added dropwise a solution of phosphorous oxychloride
2.0 ml, 22.0 mmol) in 2.5 ml of CH Cl at 0 8C, and the
188.4. HRMS (EI) calcd for C12
214.1116.
(
2
2

N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
4133
3.2.3. 2-Chlorocyclotridec-1-enecarbaldehyde (2e). Com-
pound (Z)-2e. White solid; mp 38–39 8C (from MeOH); H
25.2, 26.07, 26.12, 26.27, 26.34, 26.7, 27.0, 27.3, 27.4, 27.5,
27.6, 28.2, 37.7, 135.8, 154.2, 192.2; MS (EI) m/z (%) 286
1
C
C
(2.2) [M C2], 284 (7.0) [M ], 55 (100). HRMS (EI) calcd
NMR (300 MHz, CDCl ) d 1.25–1.55 (m, 16H), 1.79 (m,
3
0
AA XX , JAXCJAX
0
35
2
(
H), 2.28 (AA XX , JAXCJAX
0
Z15.4 Hz, 2H), 2.60
for C H
17
ClO 284.1907, found 284.1911.
29
0
NMR (76 MHz, CDCl ) d 24.1, 24.30, 24.34, 24.5, 24.8,
0
13
0
Z16.1 Hz, 2H) 10.19 (s, 1H);
C
1
Compound (E)-2h. Oil; H NMR (400 MHz, CDCl ) d
3
3
2
5.0, 25.4, 25.78, 25.84, 26.3, 36.0, 136.2, 154.5, 191.8; MS
EI) m/z (%) 244 (23) [M C2], 242 (73) [M ], 207 (100);
1.15–1.40 (m, 20H), 1.46 (m, 2H), 1.73 (br s, 2H), 2.35–2.60
(br m, 3H), 3.40 (br, 1H), 10.04 (s, 1H); C NMR
(100 MHz, CDCl ) d 25.1, 25.2, 26.1, 26.25, 26.31, 26.56,
3
C
C
13
(
HRMS (EI) calcd for C H
2
Found: C, 69.01; H, 9.56.
3
5
ClO 242.1437, found
42.1443. Anal. Calcd for C H ClO: C, 69.26; H, 9.55.
1
4
23
25.62, 26.93, 26.97, 27.3, 27.4, 27.6, 28.2, 37.7, 135.8,
154.2, 192.1; MS (EI) m/z (%) 286 (9) [M C2], 284 (27)
1
4 23
C
C
M ], 249 (100). HRMS (EI) calcd for C H
35
[
284.1907, found 284.1902.
ClO
29
1
7
1
Compound (E)-2e. Obtained as a mixture with (Z)-2e: H
NMR (270 MHz, CDCl ) d 10.03 (s, 1H), and most aliphatic
3
signals are hidden behind those of (Z)-2e and are
unassigned.
3.3. Representative procedure for the synthesis
of formylazirine 4a,e–h (Method A)
3.2.4. 2-Chlorocyclotetradec-1-enecarbaldehyde (2f).
Compound (Z)-2f. White solid; mp 42–43 8C (from
A solution of (Z)-2a,e–h (4.61 mmol) and NaN (412 mg,
3
6.33 mmol) in 12.5 ml of DMF was stirred at room
temperature for 3 h. Water was added and the mixture was
extracted with ether. The combined ethereal layer was
1
MeOH); H NMR (400 MHz, CDCl ) d 1.20–1.61 (m,
3
0
H), 2.59 (AA XX , JAXCJAX
0
1
2
1
8H), 1.75 (m, 2H), 2.28 (AA XX , JAXCJAX
0
0
Z16.6 Hz,
0
H); C NMR (68 MHz, CDCl ) d 23.5, 24.0, 24.2, 24.9,
0
Z16.6 Hz, 2H), 10.22 (s,
washed with water and brine and dried over MgSO . The
4
1
3
filtrate was concentrated in vacuo and the residue was
dissolved in 25 ml of CHCl and was irradiated through
3
2
5.1, 25.3, 26.0, 26.4, 26.7, 27.1, 36.1, 136.1, 154.4, 192.1.
3
3
5
HRMS (EI) calcd for C H ClO 256.1594, found
25
Pyrex filter by using ultraviolet lamp (lmaxZ365 nm) for
8 h. After removal of solvent in vacuo, the residue was
chromatographed on silica gel by using CHCl –hexane (1/3)
3
1
5
2
Found: C, 69.78; H, 9.76.
56.1602. Anal. Calcd for C H ClO: C, 70.15; H, 9.81.
5 25
1
to give azirine 4a,e–h. See Table 2 for reaction conditions
and yields of 4a,e–h.
1
Compound (E)-2f. Oil; H NMR (270 MHz, CDCl ) d 0.98–
3
1
.51 (m, 17H), 1.51–1.75 (m, 2H), 1.85 (m, 1H), 2.43–2.55
(
(
m, 2H), 2.66 (dddd, JZ13.2, 7.3, 3.4, 1.5 Hz, 1H), 3.47
ddd, JZ14.4, 11.7, 3.6 Hz, 1H), 10.04 (d, JZ1.0 Hz, 1H);
3.3.1. 9-Azabicyclo[6.1.0]non-8-ene-1-carbaldehyde (4a).
Oil; bp 95–96 8C (0.3 mmHg); H NMR (500 MHz, CDCl )
1
3
C
C
MS (EI) m/z (%) 258 (12) [M C2], 256 (39) [M ] 221
(
d 1.02 (m, 1H), 1.36–1.50 (m, 3H), 1.53–1.74 (m, 4H), 2.00
(m, 1H), 2.47 (ddd, JZ15.8, 11.5, 2.1 Hz, 1H), 2.72 (ddd,
JZ15.0, 10.1, 5.1 Hz, 1H), 3.14 (ddd, JZ15.0, 6.4, 4.3 Hz,
3
5
100). HRMS (EI) calcd for C H
1
ClO 256.1594, found
5
25
2
56.1601.
.2.5. 2-Chlorocyclopentadec-1-enecarbaldehyde (2g).
Compound (Z)-2g. Oil; H NMR (500 MHz, CDCl ) d
1
3
1H), 8.80 (s, 1H); C NMR (126 MHz, CDCl ) d 19.6, 23.3,
24.9, 26.6, 27.8, 28.1, 48.8, 168.2, 200.8; MS (EI) m/z (%)
3
3
1
C
151 (4) [M ], 150 (19), 81 (100); HRMS (EI) calcd for
3
1
2
.25–1.42 (m, 18H), 1.50 (quint, JZ6.8 Hz, 2H), 1.72 (m,
C H13NO 151.0997, found 151.0996.
9
0
0
H), 2.28 (AA XX , JAXCJAX Z15.8 Hz, 2H), 2.58
0
0
0
13
(
AA XX , JAXCJAX
0
Z16.7 Hz, 2H), 10.20 (s, 1H);
C
NMR (76 MHz, CDCl ) d 25.2, 25.5, 25.9, 25.99, 26.02,
3.3.2. 14-Azabicyclo[11.1.0]tetradec-13-ene-1-carbalde-
hyde (4e). White solid; mp 62–63 8C (from hexane); H
1
3
2
1
6.2, 26.6, 26.7, 26.9, 27.0, 27.1, 27.4, 37.5, 135.7, 154.3,
91.9; MS (EI) m/z (%) 272 (15) [M C2], 270 (44) [M ],
NMR (400 MHz, CDCl ) d 1.14 (m, 1H), 1.19–1.52 (m, 16H),
3
C
C
1.74 (m, 1H), 2.00 (m, 1H), 2.35 (ddd, JZ14.6, 8.3, 6.3 Hz,
1H), 2.90 (ddd, JZ17.2, 6.9, 5.0 Hz, 1H), 3.02 (ddd, JZ17.2,
3
5
2
found 270.1754.
35 (100); HRMS (EI) calcd for C H
1
ClO 270.1750,
27
6
1
9.2, 4.5 Hz, 1H), 8.77 (s, 1H); C NMR (68 MHz, CDCl ) d
3
3
23.5, 23.7, 24.1, 24.4, 24.5, 25.7 (2C), 25.8, 27.0 (2C), 27.7,
49.0, 167.9, 200.9;MS(EI)m/z (%)221 (74)[M ], 192 (100);
1
Compound (E)-2g. Oil; H NMR (500 MHz, CDCl ) d 1.04–
C
3
1
.52 (m, 18H), 1.54–1.69 (m, 3H), 1.81 (m, 1H), 2.44 (ddd,
HRMS (EI) calcd for C H NO 221.1780, found 221.1789.
1
4 23
JZ12.4, 7.5, 3.8 Hz, 1H), 2.49 (ddd, JZ14.5, 4.7, 4.3 Hz,
Anal. Calcd for C H NO: C, 75.97; H, 10.47; N, 6.33.
1
4 23
1
H), 2.66 (ddd, JZ12.4, 9.4, 3.8 Hz, 1H), 3.44 (ddd, JZ
Found: C, 75.78; H, 10.67; N, 6.17.
1
4.5, 11.3, 3.4 Hz, 1H), 10.03 (s, 1H); C NMR (76 MHz,
3
1
CDCl ) d 25.6, 26.3, 26.6, 26.7, 26.8, 26.99, 27.04, 27.1,
27.48, 27.53, 27.6, 27.8, 34.6, 140.1, 158.9, 188.2; MS (EI)
m/z (%) 272 (18) [M C2], 270 (54) [M ], 235 (100);
3
3.3.3. 15-Azabicyclo[12.1.0]pentadec-14-ene-1-carbalde-
hyde (4f). Yellow solid; mp 38–39 8C (from hexane); H
NMR(400 MHz,CDCl )d1.20–1.59(m, 18H), 1.64–1.80(m,
3
2H), 1.98 (dtt, JZ12.7, 8.3, 6.3 Hz, 1H), 2.10 (ddd, JZ15.1,
8.3, 6.1 Hz, 1H), 2.87 (ddd, JZ17.1, 8.3, 5.4 Hz, 1H), 2.96
1
C
C
3
5
HRMS (EI) calcd for C H ClO 270.1750, found
27
1
6
2
70.1755.
.2.6. 2-Chlorocyclohexadec-1-enecarbaldehyde (2h).
Compound (Z)-2h. Oil; H NMR (400 MHz, CDCl ) d
1
3
(ddd, JZ17.1, 7.8, 5.4 Hz, 1H), 8.76 (s, 1H); C NMR
3
(68 MHz, CDCl ) d 23.4, 23.9, 25.3, 25.48, 25.54, 25.9, (2C),
26.1, 26.6, 27.19, 27.23, 27.5, 48.9, 168.0, 200.9; MS (EI) m/z
(%) 235 (100) [M ]. HRMS (EI) calcd for C H NO
3
1
3
0
0
C
1
JAX
.11–1.55 (m, 22H), 1.68 (m, 2H), 2.29 (AA XX , JAXC
15
25
0
0
0
Z15.1 Hz, 2H), 2.60 (AA XX , JAXCJAX
0
Z16.1 Hz,
235.1936, found 235.1935. Anal. Calcd for C H NO: C,
15 25
76.55; H, 10.71; N, 5.95. Found: C, 75.98; H, 10.76; N, 5.53.
1
3
2
H), 10.21 (s, 1H); C NMR (100 MHz, CDCl ) d 25.1,
3

4134
N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
C
MS (EI) m/z (%) 193 (16) [M ], 164 (100). HRMS (EI)
calcd for C H NO 193.1467, found 193.1462. Anal. Calcd
12 19
3.3.4. 16-Azabicyclo[13.1.0]hexadec-15-ene-1-carb-
aldehyde (4g). Oil; H NMR (400 MHz, CDCl ) d 1.15–
1
3
1
6
1
2
1
2
2
.42 (m, 19H), 1.51 (m, 1H), 1.66 (ddd, JZ15.1, 8.8,
.3 Hz, 1H), 1.75 (dt, JZ15.1, 7.3 Hz, 1H), 1.85 (dtt, JZ
5.1, 7.8, 6.4 Hz, 1H), 2.03 (ddd, JZ14.6, 9.3, 7.3 Hz, 1H),
.88 (dt, JZ16.1, 8.1 Hz, 1H), 2.91 (dt, JZ16.1, 8.1 Hz,
for C H NO: C, 74.57; H, 9.91; N, 7.25. Found: C, 74.31;
1
H, 10.00; N, 7.18.
2 19
3.5. General procedure for the synthesis
of iminophosphorane 5a–h
1
3
H), 8.75 (s, 1H); C NMR (68 MHz, CDCl ) d 23.4, 24.3,
5.77, 25.83, 25.91, 25.93, 26.0, 26.2, 26.5, 27.1, 27.4, 27.7,
7.8, 49.1, 167.8, 200.5; MS (EI) m/z (%) 249 (100) [M ];
3
C
A solution of azirine 4a–h (18.8 mmol) and PPh (5.03 g,
3
HRMS (EI) calcd for C H NO 249.2093, found 249.2092.
6 27
19.2 mmol) in toluene (20 ml) was heated at reflux for 3 h.
After the reaction mixture was concentrated in vacuo,
yellow solid precipitated in ether was filtered to give
iminophosphorane 5a–h. Compound 5d was reported
1
3.3.5. 17-Azabicyclo[14.1.0]heptadec-16-ene-1-carbalde-
hyde (4h). Yellow solid; mp 32–33 8C (from hexane); H
1
7
NMR (400 MHz, CDCl ) d 1.10–1.43 (m, 20H), 1.43–1.54
3
previously in literature.
(
m, 2H), 1.69 (ddd, JZ14.6, 9.0, 6.8 Hz, 1H), 1.76 (dt, JZ
1
2
2
2
2
4.6, 6.8 Hz, 1H), 1.91 (d!quint, JZ14.0, 7.2 Hz, 1H),
3.5.1. 2-(Triphenylphosphoranylideneamino)cyclooct-1-
enecarbaldehyde (5a). Yield 99%; Z-form only; mp 175–
.05 (ddd, JZ14.6, 8.0, 6.8 Hz, 1H), 2.88 (t, JZ6.8 Hz,
1
H), 8.76 (s, 1H); C NMR (100 MHz, CDCl ) d 23.6, 24.3,
3
1
176 8C (from toluene); H NMR (500 MHz, CDCl ) d 1.05
3
3
6.2, 26.3, 26.39, 26.42, 26.5, 26.9 (2C), 27.3, 27.6, 27.69,
7.74, 27.9, 48.9, 168.0, 200.7; MS (EI) m/z (%) 263 (100),
(m, 2H), 1.34–1.43 (m, 4H), 1.53 (m, 2H), 2.23 (t, JZ
6.7 Hz, 2H), 2.44 (t, JZ6.1 Hz, 2H), 7.48 (td, JH–H
7.3 Hz, JP–HZ3.1 Hz, 6H), 7.56 (ttd, JH–HZ7.3, 1.8 Hz,
JP–HZ1.2 Hz, 3H), 7.74 (ddd, JH–HZ7.3, 1.8 Hz, JP–HZ
Z
C
[
M ]. HRMS (EI) calcd for C H NO 263.2249, found
17 29
2
63.2249.
1
3
1
2.8 Hz, 6H), 10.69 (s, 1H); C NMR (76 MHz, CDCl ) d
3
3.4. Representative procedure for the synthesis
of formylazirine 4b–d (Method B)
23.4 (d, JP–CZ2.5 Hz), 26.1, 26.8, 28.6, 30.4, 35.5 (d,
JP–CZ8.7 Hz), 122.1 (d, JP–CZ17.4 Hz), 128.6 (d, JP–C
2.5 Hz, 6C), 131.0 (d, JP–CZ102.1 Hz, 3C), 132.0 (d,
Z
1
To a solution of (Z)-2b–d (10.0 mmol) in THF (20 ml) were
added NaN3 (812 mg, 12.5 mmol), LiCl (42.4 mg,
JP–CZ3.1 Hz, 3C), 132.2 (d, JP–CZ10.0 Hz, 6C), 171.9,
189.7; MS (EI) m/z (%) 413 (44) [M ], 262 (100); HRMS
C
1
.00 mmol), and 60 ml of H O, and the mixture was stirred
2
(EI) calcd for C H NOP 413.1908, found 413.1908. Anal.
27 28
at room temperature for 5 h. After white precipitate was
filtered off, the filtrate was concentrated in vacuo and the
residue was dissolved in ether (30 ml). The white solid was
precipitated again, filtered off, and washed several times
with ether. The filtrate was concentrated in vacuo to give a
crude mixture of the products containing trans-2-azido-
cycloalk-1-enecarbaldehyde 3b–d and formyl azirine 4b–d.
The mixture was dissolved in CHCl3 (40 ml) and was
irradiated through Pyrex filter by using ultraviolet lamp
Calcd for C H NOP: C, 78.43; H, 6.82; N, 3.39. Found: C,
2
78.21; H, 6.86; N, 3.31.
7 28
3.5.2. 2-(Triphenylphosphoranylideneamino)cyclodec-1-
enecarbaldehyde (5b). Yield 78%; E/ZZ25:75; mp 162–
1
164 8C (from toluene); H NMR (500 MHz, CDCl ) d 0.59
3
(m, 1H, E), 0.96 (m, 1H, E), 1.01–1.09 (m, 2H, E), 1.15 (m,
2H, Z), 1.28–1.43 (m, 8H, Z), 1.66 (m, 2H, Z), 1.80–1.94 (m,
2H, E), 2.27 (br, 2H, Z), 2.47 (t, JZ6.1 Hz, 2H, Z), 2.75–
(
monitored successfully with TLC on silica gel by using
CHCl –hexane (2/1) as a developer. After removal of
3
lmaxZ365 nm) for 8 h. The conversion of trans-azide was
2.85 (m, 2H, E), 3.20–3.27 (m, 1H, E), 7.46 (ddd, JH–HZ
7.9, 7.3 Hz, JP–HZ3.1 Hz, 6H, Z), 7.50 (ddd, JH–HZ7.9,
7.3 Hz, JP–HZ3.1 Hz, 6H, E), 7.55 (td, JH–HZ7.9 Hz,
solvent in vacuo, the residue was chromatographed on silica
gel by using ether–hexane (1/4) to give azirine 4b–d. See
Table 2 for reaction conditions and yields of 4b–d.
JP–HZ1.2 Hz, 3H, Z), 7.58 (td, JH–HZ7.9 Hz, JP–HZ
1.8 Hz, 3H, E), 7.71 (dd, JH–HZ7.3 Hz, JP–HZ12.2 Hz,
6H, Z), 7.78 (dd, JH–HZ7.3 Hz, JP–HZ12.2 Hz, 6H, E),
9.84 (s, 1H, E), 10.63 (s, 1H, Z) and the other signals of
7
Compound 4d was reported previously in literature.
1
3
E-form (7H) are hidden behind those of (Z)-form; C NMR
(76 MHz, CDCl ) d 21.4 (E), 22.0 (Z), 22.3 (Z), 23.0 (E),
3
.4.1. 11-Azabicyclo[8.1.0]undec-10-ene-1-carbaldehyde
4b). Oil; H NMR (500 MHz, CDCl ) d 1.20–1.68
3
1
(
(
(
23.1 (E), 23.4 (E), 24.9 (d, JP–CZ1.2 Hz, Z), 25.5 (E), 25.9
(E), 26.0 (Z), 26.37 (Z), 26.42 (Z), 26.6 (E), 26.8 (Z), 33.2 (d,
JP–CZ6.2 Hz, Z), 34.4 (d, JP–CZ9.3 Hz, E), 122.9 (d,
JP–CZ15.6 Hz, Z), 126.3 (d, JP–CZ21.9 Hz, E), 128.6 (d,
JP–CZ12.5 Hz, 6C, Z), 128.7 (d, JP–CZ10.6 Hz, 6C, E),
3
m, 10H), 1.71 (ddd, JZ15.4, 9.4, 2.1 Hz, 1H), 1.94
m, 2H), 2.38 (ddd, JZ15.4, 8.6, 2.1 Hz, 1H), 2.92 (ddd,
JZ16.7, 8.1, 4.3 Hz, 1H), 3.08 (ddd, JZ16.7, 7.7, 4.3 Hz,
1
H), 8.82 (s, 1H); C NMR (126 MHz, CDCl ) d 19.5, 22.4,
3
1
3
2
3.2, 23.8, 26.4, 26.5, 27.0, 28.4, 49.0, 169.4, 201.4; MS
EI) m/z (%) 179 (49) [M ], 150 (100); HRMS (EI) calcd
130.7, (d, JP–CZ101.5 Hz, 3C, E), 131.4 (d, JP–CZ
102.8 Hz, 3C, Z), 131.9 (d, JP–CZ2.5 Hz, 3C, Z), 132.2
(d, JP–CZ3.1 Hz, 3C, E), 132.3 (d, JP–CZ10.0 Hz, 6C, Z),
C
(
for C H NO 179.1310, found 139.1312.
1
1 17
1
32.5 (d, JP–CZ10.6 Hz, 6C, E), 170.9 (Z), 173.1 (E), 187.7
C
3
(
.4.2. 12-Azabicyclo[9.1.0]dodec-11-ene-1-carbaldehyde
4c). White solid; mp 43–44 8C (from hexane); H NMR
(E), 191.9 (Z); MS (EI) m/z (%) 441 (10) [M ], 262 (100);
HRMS (EI) calcd for C29 32NOP 441.2221, found
441.2227. Anal. Calcd for C29 32NOP: C, 78.29; H, 7.51;
1
H
H
(
400 MHz, CDCl ) d 1.12–1.52 (m, 12H), 1.57 (m, 1H),
3
1
1
8
2
.87 (m, 2H), 2.48 (dt, JZ14.6, 7.3 Hz, 1H), 2.95 (ddd, JZ
N, 3.26. Found: C, 78.50; H, 7.33; N, 3.12.
5.6, 6.8, 5.4 Hz, 1H), 3.10 (ddd, JZ15.6, 7.3, 5.4 Hz, 1H),
1
.80 (s, 1H); C NMR (100 MHz, CDCl ) d 22.72, 22.3,
3
3.5.3. 2-(Triphenylphosphoranylideneamino)cycloundec-
1-enecarbaldehyde (5c). Yield 80%; E/ZZ94:6; yellow
3
2.9, 23.1, 24.2, 25.3, 25.5, 27.7 (2C), 49.0, 169.2, 201.1;

N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
4135
1
solid; mp 171.9–172.4 8C (from toluene); H NMR
13
12.5 Hz, 6H, E), 9.85 (s, 1H, E), 10.71 (s, 1H, Z); C NMR
(
500 MHz, CDCl ) d 0.82 (m, 1H), 1.04 (m, 1H), 1.09–
3
(126 MHz, CDCl ) d 23.7 (Z), 23.9 (E), 24.13 (Z), 24.2 (E),
3
1
1
1
.36 (m, 8H), 1.46–1.67 (m, 3H), 1.77 (m, 1H), 2.17 (m,
H), 2.71 (ddd, JZ13.2, 9.8, 3.0 Hz, 1H), 2.79 (ddd, JZ
3.2, 7.5, 3.1 Hz, 1H), 3.13 (td, JZ12.4, 0.4 Hz, 1H), 7.49
24.3 (E), 24.76 (E), 24.81 (Z), 24.9 (Z), 25.0 (Z), 25.1 (Z),
25.4 (Z), 25.5 (E), 25.9 (E), 26.0 (Z), 26.4 (E), 26.91 (Z),
26.93 (E), 27.25 (Z), 27.33 (E), 27.6 (Z), 28.0 (E), 28.8 (E),
32.3 (d, JP–CZ7.2 Hz, E), 36.9 (d, JP–CZ8.3 Hz, Z), 122.8
(d, JP–CZ15.5 Hz, Z), 126.0 (d, JP–CZ19.7 Hz, E), 128.68
(d JP–CZ12.4 Hz, 6C, E), 128.70 (d, JP–CZ12.4 Hz, 6C, Z),
(
dddd, JH–HZ7.5, 7.0, 1.5 Hz, JP–HZ3.0 Hz, 6H), 7.57 (tq,
JH–HZ7.5, 1.5 Hz, JP–HZ1.5 Hz, 3H), 7.77 (dtd, JH–H
.0, 1.5 Hz, JP–HZ12.4 Hz, 6H), 9.93 (s, 1H) and most
Z
7
signals for (Z)-5c were overlapped with (E)-5c except
for d 1.39 (m, 4H), 2.26 (t, JZ6.8 Hz, 2H), 7.71 (dtd,
130.9 (d, JP–CZ102.4 Hz, 3C, E), 131.2 (d, JP–CZ
102.4 Hz, 3C, Z), 132.0 (d, JP–CZ3.1 Hz, 3C, Z), 132.1
(d, JP–CZ3.1 Hz, 3C, E), 132.36 (d, JP–CZ9.3 Hz, 6C, Z),
132.44 (d, JP–CZ10.3 Hz, 6C, E), 171.3 (Z), 171.8 (E),
188.3 (d, JP–CZ5.2 Hz, E), 191.3 (Z); MS (EI) m/z (%) 497
J
H–HZ7.1, 1.5 Hz, JP–HZ12.1 Hz, 6H) and 10.57 (s, 1H);
1
3
C NMR (100 MHz, CDCl ) d 23.55, 23.64, 24.3, 24.9,
6.55, 26.63 (2C), 26.9, 34.3 (d, JP–CZ8.6 Hz), 127.5 (d,
3
2
C
JP–CZ20.1 Hz) 128.7 (d, JP–CZ12.5 Hz, 6C), 131.2 (d,
JP–CZ102.6 Hz, 3C), 132.1 (d, JP–CZ2.9 Hz, 3C), 132.5 (d,
(9) [M ] 262 (100). HRMS (EI) calcd for C H NOP
497.2848, found 497.2850. Anal. Calcd for C H NOP: C,
33
40
33
40
JP–CZ10.5 Hz, 6C), 173.2, 188.4 (d, JP–CZ3.8 Hz); MS
79.64; H, 8.10; N, 2.81. Found: C, 79.83; H, 8.22; N, 2.69.
C
EI) m/z (%) 455 (15) [M ], 262 (100). HRMS (EI) calcd
(
for C H NOP 455.2378, found 455.2381.
30 34
3.5.7. 2-(Triphenylphosphoranylideneamino)cyclopenta-
dec-1-enecarbaldehyde (5g). Yield 85%; E/ZZ67:33; mp
1
173–176 8C (from toluene); H NMR (300 MHz, CDCl ) d
3.5.4. 2-(Triphenylphosphoranylideneamino)cyclo-
dodec-1-enecarbaldehyde (5d). Yield 91% (reported as
3
7
0.70 (m, 2H, Z), 0.87–1.65 (m, 22H for E and 19H for Z),
0
0
Z), 2.20 (AA XX , JAXCJAX
8
4% yield in our previous work); E/ZZ75:25.
1.78 (m, 1H, E), 2.06 (AA XX , JAXCJAX
0
0
Z17.3 Hz, 2H,
0
0
Z15.0 Hz, 2H, Z), 2.71 (ddd,
3
1
.5.5. 2-(Triphenylphosphoranylideneamino)cyclotridec-
-enecarbaldehyde (5e). Yield 88%; E/ZZ67:33; yellow
JZ12.8, 9.2, 3.7, 1H, E), 2.78 (ddd, JZ12.8, 5.9, 4.0 Hz,
1H, E), 3.04 (ddd, JZ13.4, 10.3, 3.3 Hz, 1H, E), 7.43–7.61
1
solid; mp 197–199 8C (from ether); H NMR (300 MHz,
CDCl ) d 0.75–0.93 (m, 1H for E and 2H for Z), 0.93–1.62
(m, 9H each, E and Z), 7.71 (dtd, JH–HZ7.0, 1.5 Hz, JP–H
12.5 Hz, 6H, Z), 7.75 (dddd, JH–HZ7.0, 1.7, 1.5 Hz, JP–H
Z
Z
3
1
3
(
(
m, 16H each, E and Z), 1.62–1.87 (m, 2H, E), 1.98
12.5 Hz, 6H, E), 9.85 (s, 1H, E), 10.67 (s, 1H, Z); C NMR
(76 MHz, CDCl ) d 23.9 (E), 24.5 (Z), 24.7 (Z), 24.8 (d,
JP–CZ1.2 Hz, Z), 24.9 (E), 25.7 (Z), 25.8 (Z), 26.1 (E),
0
0
0
0
AA XX , JAXCJAX
Z14.9 Hz, 2H, Z), 2.64 (ddd, JZ12.5, 10.6,
.2 Hz, 1H, E), 2.79 (ddd, JZ12.5, 6.3, 2.6 Hz, 1H, E), 3.05
ddd, JZ11.0, 10.7, 2.6 Hz, 1H, E), 7.43–7.53 (m, 6H each,
0
Z17.4 Hz, 2H, Z), 2.16 (br AA XX ,
3
JAXCJAX
2
(
0
26.17 (Z), 26.24 (Z), 26.46 (E), 26.51 (Z), 26.7 (E), 26.9 (E),
27.0 (E), 27.1 (Z), 27.21 (E), 27.25 (E), 27.9 (Z), 28.0 (E),
E and Z), 7.53–7.61 (m, 3H each, E and Z), 7.72 (dddd,
JH–HZ7.0, 2.0, 1.5 Hz, JP–HZ12.1 Hz, 6H, Z), 7.77 (dddd,
JH–HZ6.8, 2.0, 1.5 Hz, JP–HZ12.3 Hz, 6H, E), 9.85 (s, 1H,
28.3 (E), 28.9 (E), 31.9 (d, JP–CZ8.1 Hz, E), 37.1 (d, JP–C
7.5 Hz, Z), 122.5 (d, JP–CZ16.8 Hz, Z), 125.4 (d, JP–C
20.6 Hz, E), 128.5 (d, JP–CZ12.5 Hz, 6C each, E and Z),
130.4 (d, JP–CZ102.1 Hz, 3C, E), 130.9 (d, JP–C
Z
Z
1
3
E), 10.66 (s, 1H, Z); C NMR (126 MHz, CDCl ) d 22.0
Z
3
(
(
2
Z), 22.9 (E), 23.6 (E), 23.9 (Z), 24.0 (3C, Z), 24.1 (Z), 24.2
E), 24.7 (E), 25.2 (E), 25.3 (E), 25.5 (Z), 26.3, (Z), 26.7 (Z),
6.8 (E), 26.9 (Z), 27.1 (E), 27.4 (E), 28.1 (E), 32.7 (d,
101.5 Hz, 3C, Z), 131.8 (d, JP–CZ3.1 Hz, 3C, Z), 132.0
(d, JP–CZ2.5 Hz, 3C. E), 132.1 (d, JP–CZ10.0 Hz, 6C, Z),
132.2 (d, JP–CZ10.6 Hz, 6C, E), 171.4 (1C each, E and Z),
187.9 (d, JP–CZ3.7 Hz, E), 190.8 (Z) and two signals of
Z-form are overlapped; MS (EI) m/z (%) 511 (28) [M ],
262 (100); HRMS (EI) calcd for C34H42NOP 511.3004,
JP–CZ8.1 Hz, E), 35.4 (d, JP–CZ7.3 Hz, Z), 122.3
(
(
C
d, JP–CZ16.9 Hz, Z), 127.0 (d, JP–CZ20.1 Hz, E), 128.7
d, JP–CZ12.1 Hz, 6C, E), 128.8 (d, JP–CZ12.1 Hz, 6C, Z),
1
1
31.0 (d, JP–CZ102.3 Hz, 3C, E), 131.2 (d, JP–C
02.3 Hz, 3C, Z), 132.10 (d, JP–CZ3.2 Hz, 3C, Z), 132.13
Z
found 511.3004. Anal. Calcd for C34H42NOP: C, 79.81; H,
8.27; N, 2.74. Found: C, 79.57; H, 8.31; N, 2.73.
(
1
d, JP–CZ3.2 Hz, 3C, E), 132.5 (d, JP–CZ10.5 Hz, 6C, Z),
32.6 (d, JP–CZ10.5 Hz, 6C, E), 171.8 (Z), 172.3 (E), 188.3
3.5.8. 2-(Triphenylphosphoranylideneamino)cyclohexa-
dec-1-enecarbaldehyde (5h). Yield 85%; E/ZZ56:44;
white solid; mp 97–98 8C (from toluene); H NMR
(
[
d, JP–CZ4.0 Hz, E), 190.6 (Z); MS (EI) m/z (%) 483 (13.5)
C
M ], 262 (100); HRMS (EI) calcd for C H NOP
1
3
2 38
4
C, 79.47; H, 7.92; N, 2.90. Found: C, 79.15; H, 8.05; N,
83.2691, found 483.2689. Anal. Calcd for C H NOP:
(400 MHz, CDCl ) d 0.76 (m, 2H, Z), 0.85–0.98 (m, 1H
3
3
2
38
for E and 2H for Z), 1.12–1.44 (m, 22H for E and 18H for Z),
0 0
2
.88.
1.55–1.76 (m, 2H each, E and Z), 2.07 (AA XX , JAXC
0
0
0
JAX
Z17.1 Hz, 2H, Z), 2.21 (br AA XX , JAXCJAX Z
0
3
.5.6. 2-(Triphenylphosphoranylideneamino)cyclotetra-
16.6 Hz, 2H, Z), 2.65 (ddd, JZ12.7, 8.1, 5.1 Hz, 1H, E),
2.82 (ddd, JZ12.7, 6.7, 5.4 Hz, 1H, E), 3.07 (ddd, JZ13.0,
9.8, 5.6 Hz, 1H, E), 7.43–7.52 (m, 6H each, E and Z), 7.53–
7.61 (m, 3H each, E and Z), 7.68–7.79 (m, 6H each, E and
dec-1-enecarbaldehyde (5f). Yield 76%; E/ZZ68:32;
yellow solid; mp 171–173 8C (from toluene); H NMR
(500 MHz, CDCl ) d 0.77 (m, 2H, Z), 0.94–1.51 (m, 18H
3
each, E and Z), 1.53–1.70 (m, 2H, E), 1.79 (m, 1H, E), 2.07
1
1
3
Z), 9.85 (s, 1H, E), 10.70 (s, 1H, Z); C NMR (100 MHz,
CDCl ) d 24.2, 25.2, 25.4, 25.8, 26.1, 26.30, 26.32 (2C),
0
0
0
0
(
AA XX , JAXCJAX
JAXCJAX Z15.6 Hz, 2H, Z), 2.68 (ddd, JZ12.8, 8.1,
.3 Hz, 1H, E), 2.90 (ddd, JZ12.8, 8.8, 3.1 Hz, 1H, E),
.08 (m, 1H, E), 7.44–7.51 (m, 6H each, E and Z), 7.53–7.60
0
Z17.4 Hz, 2H, Z), 2.21 (AA XX ,
3
0
26.4, 26.6, 26.7, 26.8, 26.98, 27.01, 27.1, 27.4, 27.5 (2C),
27.7, 27.90, 27.93, 28.0, 28.4, 28.6, 29.3, 29.7, 32.9 (d,
3
3
JP–CZ8.3 Hz), 37.7 (d, JP–CZ8.3 Hz), 122.8 (d, JP–C
17.6 Hz), 125.8 (d, JP–CZ21.2 Hz), 128.7 (d, JP–C
Z
Z
(
m, 3H each, E and Z), 7.72 (ddd, JH–HZ8.2, 1.1 Hz, JP–H
Z
1
2.3 Hz, 6H, Z), 7.77 (ddd, JH–HZ8.3, 1.3 Hz, JP–H
Z
9.9 Hz), 130.9 (d, JP–CZ102.6 Hz), 131.3 (d,

4136
N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
JP–CZ102.6 Hz), 132.1, 132.2, 132.4 (d, JP–CZ9.9 Hz),
(m, 1H), 2.62 (ddd, JZ13.2, 8.4, 3.2 Hz, 1H), 2.68 (ddd, JZ
13.2, 8.0, 3.6 Hz, 1H), 2.77 (ddd, JZ12.5, 9.4, 3.6 Hz, 1H),
3.74 (ddd, JZ12.5, 8.6, 3.6 Hz, 1H), 3.93 (s, 3H), 7.97 (d,
1
32.5 (d, JP–CZ9.9 Hz), 171.3, 171.9, 188.1 (d, JP–CZ
C
.3 Hz), 191.4; MS (EI) m/z (%) 525 (28) [M ], 262 (100).
3
HRMS (EI) calcd for C H NOP 525.3161, found
1
3
JZ2.3 Hz, 1H), 8.49 (d, JZ2.3 Hz, 1H); C NMR
3
5
44
5
25.3154.
(68 MHz, CDCl ) d 25.3, 25.8, 26.4, 26.7, 27.2, 27.77,
27.82, 28.0, 28.5, 32.5, 36.0, 52.3, 125.3, 135.2, 138.6,
151.9, 161.3, 167.3; MS (EI) m/z (%) 289 (62) [M ], 230
3
C
3
.6. Reaction of 5 with methyl propiolate
(100); HRMS (EI) calcd for C H NO 289.2042, found
289.2055.
18 27 2
Method A. Representative procedure. A solution of
iminophosphorane 5g (4.06 g, 7.93 mmol) and methyl
propiolate (6.87 g, 81.7 mmol) in toluene (25 ml) was
heated at 140 8C in an autoclave reactor for 12 h. After
the mixture was concentrated in vacuo, the residue was
separated by flash chromatographed on silica gel (FL60D,
Fuji Silysia Chemical Ltd) by using ether–hexane (1/5) to
give nicotinates 6g (741 mg, 2.34 mmol) and 7g (70.8 mg,
3.6.4. Methyl [12](2,5)pyridinophane-3-carboxylate (6f).
Oil; H NMR (400 MHz, CDCl ) d 0.77–0.90 (m, 6H),
1
3
0.96–1.17 (m, 10H), 1.63 (m, 2H), 1.71 (quint, JZ6.6 Hz,
0
0
2H), 2.68 (AA XX , JAXCJAX
0
Z12.2 Hz, 2H), 3.26 (br,
2H), 3.93 (s, 3H), 7.94 (d, JZ2.2 Hz, 1H), 8.47 (d, JZ
1
2.2 Hz, 1H); C NMR (68 MHz, CDCl ) d 24.7, 25.7, 25.9,
3
3
0
.223 mmol) in 30 and 3% yields, respectively.
26.2, 26.8, 26.9, 27.36, 27.40, 28.6, 29.2, 31.7, 35.4, 52.1,
1
303 (52) [M ] 244 (100). HRMS (EI) calcd for C H NO
19 29 2
25.3, 134.7, 138.3, 151.9, 161.4, 167.4; MS (EI) m/z (%)
C
Method B. Representative procedure. A solution of
iminophosphorane 5d (4.70 g, 10.0 mmol) and methyl
propiolate (4.21 g, 50.0 mmol) in acetonitrile (30 ml) was
heated at 120 8C in an autoclave reactor for 10 h. After
removal of solvent and excess methyl propiolate in vacuo,
the residue was chromatographed on silica gel (silica gel
303.2198, found 303.2190.
3.6.5. Methyl [13](2,5)pyridinophane-3-carboxylate (6g).
Oil; H NMR (400 MHz, CDCl ) d 0.88 (m, 2H), 0.92–1.19
1
3
0
0
(m, 16H), 1.67 (m, 2H), 1.75 (m, 2H), 2.66 (AA XX , JAXC
0
0
0
6
0 N spherical, neutral, 40–50 mm, KANTO chemical Co.,
JAX
Z12.2 Hz, 2H), 3.24 (AA XX , JAXCJAX
0
Z12.2 Hz,
Inc.) by using acetone–toluene (1/19) to afford a crude
mixture of nicotinates 6d and 7d. The mixture was further
purified by flash chromatography on silica gel (FL60D, Fuji
Silysia Chemical Ltd) by using ether–hexane (1/5) to give
nicotinates 6d (688 mg, 2.50 mmol) and 7d (408 mg,
2H), 3.93 (s, 3H), 7.94 (d, JZ2.4 Hz, 1H), 8.48 (d, JZ
1
2.4 Hz, 1H); C NMR (68 MHz, CDCl ) d 25.8, 26.5, 26.6,
3
3
27.2, 27.3, 27.4, 27.7 (2C), 27.9, 28.6, 29.2, 31.8, 35.6, 52.2,
125.4, 134.6, 138.4, 153.1, 160.9, 167.6; MS (EI) m/z (%)
C
317 (100) [M ]; HRMS (EI) calcd for C H NO
2
2
0
31
1
.48 mmol) in 25 and 15% yields, respectively.
317.2355, found 317.2363.
Compounds 6d and 7d were reported previously in
literature. See Table 3 for reaction conditions and yields
of 6b–h and 7a–h.
3.6.6. Methyl [14](2,5)pyridinophane-3-carboxylate (6h).
Oil; H NMR (400 MHz, CDCl ) d 0.88–1.13 (m, 12H),
7
1
3
1.14–1.35 (m, 8H), 1.67 (m, 2H), 1.74 (m, 2H), 2.69
0
0
0 0
Z12.2 Hz, 2H), 3.24 (AA XX , JAXC
(
AA XX , JAXCJAX
0
3.6.1. Methyl [8](2,5)pyridinophane-3-carboxylate (6b).
Oil; H NMR (300 MHz, CDCl ) d K0.27 (m,1H), 0.14 (m,
JAX Z12.2 Hz, 2H), 3.92 (s, 3H), 7.93 (d, JZ2.2 Hz, 1H),
8.47 (d, JZ2.2 Hz, 1H); C NMR (100 MHz, CDCl ) d
0
1
13
3
3
1
2
1
1
3
1
2
1
H), 0.41–0.60 (m, 2H), 0.86–1.15 (m, 4H), 1.15–1.39 (m,
H), 1.58–1.83 (m, 2H), 2.66 (ddd, JZ13.0, 8.8, 4.8 Hz,
H), 2.73 (ddd, JZ12.7, 9.9, 4.7 Hz, 1H), 2.75 (ddd, JZ
3.0, 6.4, 4.8 Hz, 1H), 3.87 (ddd, JZ12.7, 6.2, 4.2 Hz, 1H),
.93 (s,3H), 8.02 (d, JZ1.8 Hz, 1H), 8.43 (d, JZ1.8 Hz,
25.0, 25.5, 26.3 (2C), 27.0, 27.3, 27.36, 27.44, 28.0 (2C),
28.5, 29.1, 31.4, 35.0, 52.2, 125.5, 134.2, 138.3, 152.0,
C
160.5, 167.6; MS (EI) m/z (%) 331 (100) [M ]. HRMS (EI)
calcd for C H NO 331.2511, found 331.2512.
2
1
33
2
1
3
H); C NMR (76 MHz, CDCl ) d 25.3, 25.4, 28.0, 28.7,
9.6, 30.6, 32.3, 36.6, 52.2, 124.8, 133.9, 138.5, 150.6,
63.0, 167.0; MS (EI) m/z (%) 247 (100) [M ]; HRMS (EI)
3.6.7. Methyl 5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-
3-carboxylate (7a). Oil; H NMR (500 MHz, CDCl ) d
3
1
3
C
1.33–1.43 (m 4H), 1.73 (m, 2H), 1.82 (m, 2H), 2.83
0
0
0 0
Z12.8 Hz, 2H), 3.03 (AA XX , JAXC
calcd for C H NO 247.1572, found 247.1579.
1
(AA XX , JAXCJAX
JAX Z12.5 Hz, 2H), 3.93 (s, 3H), 7.99 (d, JZ2.2 Hz, 1H),
0
5
21
2
0
1
3
3.6.2. Methyl [9](2,5)pyridinophane-3-carboxylate (6c).
Oil; H NMR (400 MHz, CDCl ) d K0.19 (m, 1H), 0.31 (m,
8.98 (d, JZ2.2 Hz, 1H); C NMR (76 MHz, CDCl ) d 25.8,
3
1
25.9, 30.5, 31.8, 32.0, 34.8, 52.2, 123.9, 136.1, 137.4, 148.3,
166.0, 166.3; MS (EI) m/z (%) 219 (100) [M ], 190 (98);
3
C
1H), 0.47 (m, 1H), 0.58–0.85 (m, 3H), 0.85–1.12 (m, 4H),
1.28–1.63 (m, 3H), 1.70 (m, 1H), 2.55 (ddd, JZ13.2, 8.2,
4.4 Hz, 1H), 2.76–2.85 (m, 2H), 3.79 (ddd, JZ12.2, 7.3,
4.4 Hz, 1H), 3.94 (s, 3H), 7.97 (d, JZ2.0 Hz, 1H), 8.50 (d,
HRMS (EI) calcd for C H NO 219.1259, found
17
1
3
2
219.1253.
1
3
JZ2.4 Hz, 1H); C NMR (100 MHz, CDCl ) d 22.7, 23.7,
2
3.6.8. Methyl 5,6,7,8,9,10,11,12-octahydrocyclodeca[b]-
pyridine-3-carboxylate (7b). White solid; mp 61–63 8C;
3
5.5, 27.4, 27.6, 28.6, 29.7, 32.3, 35.8, 52.3, 125.1, 134.4,
38.6, 151.9, 161.5, 167.3; MS (EI) m/z (%) 261 (100)
1
1
[
H NMR (500 MHz, CDCl ) d 1.06–1.17 (m, 4H), 1.46–
3
C
M ]. HRMS (EI) calcd for C H NO 261.1729, found
1
6
23
2
1.54 (m, 4H), 1.85 (tt, JZ6.4, 6.0 Hz, 2H), 2.00 (m, 2H),
2.91 (t, JZ6.4 Hz, 2H), 3.06 (m, 2H), 3.94 (s, 3H), 8.06 (d,
2
61.1728.
1
3
JZ1.8 Hz, 1H), 9.02 (d, JZ1.8 Hz, 1H); C NMR
3.6.3. Methyl [11](2,5)pyridinophane-3-carboxylate (6e).
Oil; H NMR (400 MHz, CDCl ) d 0.55–1.01 (m, 10H),
(68 MHz, CDCl ) d 20.5, 21.1, 26.1, 26.7, 28.3, 28.8,
29.1, 31.9, 52.2, 123.3, 135.5, 137.6, 147.8, 165.1, 166.1;
MS (EI) m/z (%) 247 (34) [M ], 204 (100); HRMS (EI)
3
1
3
C
1
.14 (m, 1H), 1.19–1.30 (m, 3H), 1.61–1.74 (m, 3H), 1.83

N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
4137
C
MS (EI) m/z (%) 331 (27) [M ], 165 (100). HRMS (EI)
calcd for C H NO 331.2511, found 331.2501.
calcd for C H NO 247.1572, found 247.1573. Anal.
1
5
21
2
Calcd for C H NO : C, 72.86; H, 8.56; N, 5.66. Found: C,
2
1
5
21
21 33
2
7
2.36; H, 8.56; N, 5.24.
3.7. Hydrolysis of [11](2,5)pyridinophane 6e
3.6.9. Methyl methyl 6,7,8,9,10,11,12,13-octahydrocy-
cloundeca[b]pyridine-3-carboxylate (7c). White solid;
A solution of 6e (170 mg, 0.587 mmol) in methanol–water
9/1, 8.0 ml) was stirred in the presence of lithium
1
mp 97–98 8C (from ethyl acetate–hexane); H NMR
(
hydroxide monohydrate (124 mg, 2.94 mmol) at room
temperature overnight. After removal of solvent in vacuo,
water was added and the solution was washed with ether.
The aqueous layer was acidified to pH 3 with hydrochloric
acid and extracted with chloroform. The organic layer was
dried over magnesium sulfate and was concentrated in
vacuo to give compound 13 (138 mg, 0.502 mmol) in 85%
yield.
(
400 MHz, CDCl ) d 1.09–1.28 (m, 6H), 1.30–1.42 (m,
3
H), 1.82 (m, 2H), 1.97 (m, 2H), 2.83 (t, JZ6.4 Hz, 2H),
4
2
1
.97 (t, JZ6.0 Hz, 2H), 3.94 (s, 3H), 8.06 (d JZ2.3 Hz,
1
3
H), 8.99 (d, JZ2.3 Hz, 1H); C NMR (100 MHz, CDCl3)
d 23.6, 23.7, 25.4, 26.26, 26.29, 27.5, 28.2, 29.3, 33.0, 52.2,
1
2
2
23.2, 136.3, 137.3, 147.6, 166.1, 166.3; MS (EI) m/z (%)
C
61 (29) [M ], 165 (100). HRMS (EI) calcd for C H NO
2
1
6
23
61.1729, found 261.1730.
3.7.1. [11](2,5)Pyridinophane-3-carboxylic acid (13).
White solid; mp 200–201 8C (from ethyl acetate);
3.6.10. Methyl 6,7,8,9,10,11,12,13,14,15-decahydrocyclo-
trideca[b]pyridine-3-carboxylate (7e). Oil; H NMR
1
1
H
NMR (400 MHz, CDCl ) d 0.51–1.04 (m, 10H), 1.10–1.35
3
(
1
2
300 MHz, CDCl ) d 1.20–1.58 (m, 14H), 1.71 (m, 2H),
3
0
0
(m, 4H), 1.46–1.95 (m, 4H), 2.59–2.77 (m, 2H), 2.83 (ddd,
JZ12.8, 8.7, 3.2 Hz, 1H), 3.91 (m, 1H), 4.14 (br s, 1H), 8.17
.81 (m, 2H), 2.65 (AA XX , JAXCJAX
.85 (AA XX , JAXCJ
0
Z16.9 Hz, 2H),
0
0
0
Z16.7 Hz, 2H), 3.93 (s, 3H), 8.01
AX
13
(d, JZ2.1 Hz, 1H), 8.55 (d, JZ2.1 Hz, 1H); C NMR
1
3
(
d, JZ2.0 Hz, 1H), 8.95 (d, JZ2.0 Hz, 1H); C NMR
(100 MHz, CDCl ) d 25.3, 25.6, 26.2, 26.5, 27.1, 27.7, 27.8,
3
(
76 MHz, CDCl ) d 23.9, 24.0, 24.66, 24.67, 26.2, 26.3,
3
27.9, 28.3, 32.4, 35.0, 126.8, 136.1, 140.3, 150.5, 161.1,
169.0; MS (EI) m/z (%) 275 (16) [M ], 230 (20), 69 (100).
2
1
6.4, 26.5, 27.5, 30.7, 33.9, 52.2, 123.7, 135.7, 138.1, 147.9,
65.5, 166.3; MS (EI) m/z (%) 289 (46) [M ], 165 (100);
C
C
HRMS (EI) calcd for C H NO 275.1885, found
1
7
25
2
HRMS (EI) calcd for C H NO 289.2042, found
1
8
27
2
275.1879. Anal. Calcd for C H NO : C, 74.14; H, 9.15;
17 25 2
2
89.2054.
N, 5.09. Found: C, 73.90; H, 9.19; N, 5.02.
.8. Synthesis of (S ,S)-14 and (R ,S)-14
3.6.11. Methyl 5,6,7,8,9,10,11,12,13,14,15,16-dodeca-
hydrocyclotetradeca[b]pyridine-3-carboxylate (7f).
3
p
p
White solid; mp 81–83 8C (from ethyl acetate–hexane);
H NMR (400 MHz, CDCl ) d 1.22–1.67 (m, 18H), 1.73 (m,
The compound 13 (207 mg, 0.754 mmol) was treated with
oxalyl chloride (132 ml, 1.51 mmol) in chloroform (1.5 ml)
and the mixture was stirred at room temperature for 1.5 h.
After solvent was removed in vacuo, the acid chloride thus
obtained was dissolved in chloroform (1.5 ml) and the
solution was added dropwise by syringe to a solution of (S)-
phenylalaninol (171 mg, 1.13 mmol) and triethylamine
1
3
0
0
2
(
H), 2.64 (AA XX , JAXCJAX
0
Z16.5 Hz, 2H), 2.82
0
0
AA XX , JAXCJAX
JZ2.3 Hz, 1H), 8.96 (d, JZ2.3 Hz, 1H); C NMR
100 MHz, CDCl ) d 23.9, 24.0, 24.9, 25.2, 25.35, 25.42,
0
Z16.9 Hz, 2H), 3.93 (s, 3H), 8.04 (d,
1
3
(
3
2
1
7.1, 27.5, 27.6, 29.2, 31.8, 34.4, 52.1, 123.5, 135.5, 138.1,
47.9, 165.1, 166.2; MS (EI) m/z (%) 303 (24) [M ] 165
C
(114 mg, 1.13 mmol) in chloroform (2.0 ml) at 0 8C. The
(
100). HRMS (EI) calcd for C H NO 303.2198, found
19 29 2
reaction mixture was then stirred at room temperature
overnight. After the reaction was complete, the mixture was
washed with saturated aqueous sodium bicarbonate, was
dried over magnesium sulfate, and was concentrated in
vacuo. The residue was then chromatographed on silica gel
by using ether to give an inseparable mixture of (S ,S)-14
p
and (R ,S)-14 (256 mg, 0.627 mmol) in 83% yield. HPLC
p
analyses, shown in Figure 2, were performed by using
SenshuPak PEGASIL Silica 120–5 column (4.6!250 mm)
and a UV detector (254 nm) with 20% acetonitrile in ethyl
acetate as an eluent (flow rate: 1.0 ml/min).
3
03.2208.
3.6.12. Methyl 6,7,8,9,10,11,12,13,14,15,16,17-dodecahy-
drocyclopentadeca[b]pyridine-3-carboxylate (7g). Oil;
1
H NMR (300 MHz, CDCl ) d 1.22–1.83 (m, 22H), 2.66
3
0
0
0 0
Z16.5 Hz, 2H), 2.84 (AA XX , JAXC
AX
(
AA XX , JAXCJ
0
0
JAX
Z16.5 Hz, 2H), 3.93 (s, 3H), 8.02 (d, JZ2.0 Hz, 1H),
1
3
8
2
3
.96 (d, JZ2.0 Hz, 1H); C NMR (76 MHz, CDCl ) d 25.4,
3
5.5, 25.9, 26.0, 26.6, 26.78, 26.83, 27.3, 27.4, 28.1, 29.3,
2.2, 35.2, 52.1, 123.6, 135.6, 137.9, 147.8, 165.3, 166.2;
C
MS (EI) m/z (%) 317 (75) [M ], 165 (100); HRMS (EI)
calcd for C H NO 317.2355, found 317.2359.
2
0
31
2
3.8.1. (S)-N-(1-Hydroxy-3-phenylpropan-2-yl)-(S)-
[
11](2,5)pyridinophane-3-carboxamide [(S ,S)-14 and
p
1
3
.6.13. Methyl 5,6,7,8,9,10,11,12,13,14,15,16,17,18-tetra-
decahydrocyclohexadeca[b]pyridine-3-carboxylate (7h).
(R ,S)-14]. Sticky oil; H NMR (400 MHz, CDCl ) d 0.60
p 3
(m, 2H), 0.67–1.10 (m, 18H), 1.10–1.28 (m, 8H), 1.48–1.79
(m, 8H), 2.43–2.55 (m, 2H), 2.59–2.68 (m, 3H), 2.73 (ddd,
JZ13.2, 8.4, 3.2 Hz, 1H), 2.87 (ddd, JZ12.8, 9.2, 3.2 Hz,
1H), 2.90–3.09 (m, 6H), 3.15 (ddd, JZ13.2, 9.2, 5.6 Hz,
1H), 3.71–3.75 (m, 2H), 3.80–3.84 (m, 2H), 4.37–4.46 (m,
1
White solid; mp 57–58 8C (from ethyl acetate); H NMR
(
400 MHz, CDCl ) d 1.25–1.39 (m, 12H), 1.39–1.52 (m,
3
0 0
8
JAX
H), 1.59 (m, 2H), 1.71 (m, 2H), 2.66 (AA XX , JAXC
0
0
0
Z16.0 Hz, 2H), 2.84 (AA XX , JAXCJAX Z16.5 Hz,
0
2
2
2
3
H), 3.93 (s, 3H), 8.04 (d, JZ2.3 Hz, 1H), 8.96 (d, JZ
2H), 6.00 (br, 1H), 6.08 (br, 1H), 7.25–7.38 (m, 12H), 8.39
1
.3 Hz, 1H); C NMR (100 MHz, CDCl ) d 25.7 (2C),
3
13
(d, JZ2.4 Hz, 2H); C NMR (151 MHz, CDCl , 50 8C) d
3
3
6.30, 26.33, 26.36, 26.44, 27.4 (2C), 27.8, 28.0, 28.9, 30.3,
2.2, 35.1, 52.1, 123.5, 135.5, 137.8, 147.9, 165.2, 166.2;
25.6 (2C), 26.0 (2C), 26.6 (2C), 26.8, 26.9, 27.27, 27.30,
27.47, 27.54, 27.965, 27.973, 27.99 (2C), 28.6 (2C), 32.56,

4138
N. Kanomata et al. / Tetrahedron 62 (2006) 4128–4138
3
1
1
1
2.58, 34.9, 35.1, 37.0, 37.1, 53.1, 53.3, 63.8, 64.3, 126.7,
7. Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122,
4563–4568. Kanomata, N.; Nakata, T. Angew. Chem., Int. Ed.
1997, 36, 1207–1211.
26.8, 128.7 (2C), 128.8 (2C), 129.2 (4C), 131.7, 131.9,
35.30 (2C), 135.32, 135.6, 137.6, 137.6, 150.49, 150.54,
57.4, 157.8, 169.0, 169.2; MS (FABC) m/z (%) 409 (100
8. Yamamoto, H.; Yuasa, M.; Nitta, M. Heterocycles 1999, 51,
2991–3000.
C
[MCH ]), 391 (21), 258 (34). HRMS (FABC) calcd for
C H N O [MCH ] 409.2855, found 409.2856. Anal.
Calcd for C H N O : C, 76.43; H, 8.88; N, 6.86. Found:
2
C, 76.56; H, 8.80; N, 6.35.
C
9. (a) Oikawa, T.; Kanomata, N.; Tada, M. J. Org. Chem. 1993,
58, 2046–2051. (b) Kanomata, N.; Nitta, M. J. Chem. Soc.,
Perkin Trans. 1 1990, 1119–1126. Kanomata, N.; Nitta, M.
Tetrahedron Lett. 1988, 29, 5957–5960.
2
6 37 2 2
6 36 2 2
1
1
0. Kanomata, N.; Maruyama, S.; Tomono, K.; Anada, S.
Tetrahedron Lett. 2003, 44, 3599–3603.
Acknowledgements
1. Ueda, T.; Kanomata, N.; Machida, H. Org. Lett. 2005, 7,
2365–2368.
This work was financially supported by JSPS Grant-in-Aid
for Scientific Research (B) (14350479) and by the Asahi
Glass Foundation, Japan. We thank Mr. Katsuhito Tomono,
Mr. Hironobu Kubota, and Mr. Narihito Ogawa (Meiji
University) for their technical assistance in obtaining some
experimental data.
12. Kanomata, N.; Ochiai, Y. Tetrahedron Lett. 2001, 42,
1045–1048.
13. Kanomata, N.; Oikawa, J. Tetrahedron Lett. 2003, 44,
3625–3628.
14. Review articles: (a) Kanomata, N. J. Synth. Org. Chem. Jpn.
(
Yuki Gosei Kagaku Kyokaishi) 1999, 57, 512–522. (b)
Dupas, G.; Levacher, V.; Bourguignon, J.; Qu e´ guiner, G.
Heterocycles 1994, 39, 405–429. (c) Burgess, V. A.; Davies,
S. G.; Skerlj, R. T. Tetrahedron: Asymmetry 1991, 2, 299–328.
5. Chinchilla, R.; B a¨ ckvall, J.-E. In The Chemistry of Enamines
Part 2; Rappoport, Z., Ed.; Wiley: Chichester, 1994;
pp 993–1048.
References and notes
1
1
1
. Review articles: (a) Arques, A.; Molina, P. Curr. Org. Chem.
2004, 8, 827–843. (b) Nitta, M. Rev. Heteroat. Chem. 1993, 9,
6. [2C2] Cycloaddition/ring-opening reactions were reported
between acetylenic esters and (vinylimino)phosphoranes: (a)
Wamhoff, H.; Haffmanns, G. Chem. Ber. 1984, 117, 585–621.
8
7–121.
2
. Kanomata, N.; Nakata, T. Heterocycles 1998, 48, 2551–2558.
. (a) Bonini, C.; D’Auria, M.; Funicello, M.; Romaniello, G.
Tetrahedron 2002, 58, 3507–3512. (b) Alvarez-Sarandes, R.;
Peinador, C.; Quintela, J. M. Tetrahedron 2001, 57,
3
(
b) Brown, G. W. J. Chem. Soc. (C) 1967, 2018–2021. (c)
Brown, G. W.; Cookson, R. C.; Stevens, I. D. R. Tetrahedron
Lett. 1964, 104, 1263–1266.
5
413–5420. (c) Jouanisson, A.; Couquelet, J.; Teulade, J.-C.;
1
7. The analytical HPLC conditions employed here are the same
as those effective for clean base-line separation of the
corresponding [10](2,5)pyridinophane analogues having the
identical chiral auxiliary of (S)-phenylananinol. See Section 3
for the details.
Chavignon, O.; Chabard, J.-L.; Dauphin, G. J. Heterocycl.
Chem. 1996, 33, 1247–1249.
. (a) Molina, P.; Pastor, A.; Vilaplana, M. J. J. Org. Chem.
4
1996, 61, 8094–8098. (b) Molina, P.; Pastor, A.; Vilaplana,
M. J. Tetrahedron Lett. 1995, 36, 8283–8286. (c) Molina, P.;
Pastor, A.; Vilaplana, M. J.; Foces-Foces, C. Tetrahedron 1995,
18. Schurig, V.; Buerkle, W. J. Am. Chem. Soc. 1982, 104,
7573–7580.
5
1, 1265–1276. Molina, P.; Aller, E.; Lopez-Lazaro, A.;
Alajarin, M.; Lorenzo, A. Tetrahedron Lett. 1994, 35,
817–3820.
. (a) Kanomata, N.; Kawaji, H.; Nitta, M. J. Org. Chem.
992, 57, 618–625. (b) Bohn, T.; Kramer, W.; Neidlein, R.;
Suschitzky, H. J. Chem. Soc., Perkin Trans. 1 1994,
47–951.
19. Wohllebe, J.; Garbisch, E. W., Jr. Org. Synth. 1977, 56,
107–111. Garbisch, E. W., Jr.; Wohllebe, J. J. Org. Chem.
1968, 33, 2157–2158.
3
5
6
1
20. Porter, N. A.; Chang, V. H.-T.; Magnin, D. R.; Wright, B. T.
J. Am. Chem. Soc. 1988, 110, 3554–3560.
9
21. Ruedi, G.; Oberli, M. A.; Nagel, M.; Hansen, H.-J. Org. Lett.
2004, 6, 3179–3181.
. (a) Nitta, M.; Ohnuma, M.; Iino, Y. J. Chem. Soc., Perkin
Trans. 1 1991, 1115–1118. (b) Iino, Y.; Nitta, M. Bull. Chem.
Soc. Jpn. 1988, 61, 2235–2237. (c) Kobayashi, T.; Iino, Y.;
Nitta, M. Nippon Kagaku Kaishi 1987, 1237–1243.
Kobayashi, T.; Nitta, M. Chem. Lett. 1986, 1549–1552.
22. (a) Ziegenbein, W.; Lang, W. Chem. Ber. 1960, 93,
2743–2749. (b) Kawamoto, H.; Nakashima, H.; Kato, T.;
Arai, S.; Kamata, K.; Iwasawa, Y. Tetrahedron 2001, 57,
981–986.