Multicomponent synthesis of epoxy-tetrahydronaphthyridine and structural diversification by subsequent fragmentation

Article abstract of DOI:10.1016/j.tet.2005.09.017

Three-component reaction of an α-isocyanoacetamide 7, an homoallylamine 8 and an aldehyde 9 in methanol at room temperature provides oxa-bridged tricycle 4 in good to excellent yield as a mixture of two separable diastereoisomers. In this one-pot multicom

Full text of DOI:10.1016/j.tet.2005.09.017

Tetrahedron 61 (2005) 11511–11519
Multicomponent synthesis of epoxy-tetrahydronaphthyridine and
structural diversification by subsequent fragmentation
*
Aude Fayol and Jieping Zhu
Institut de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
Received 14 July 2005; revised 30 August 2005; accepted 2 September 2005
Available online 23 September 2005
Abstract—Three-component reaction of an a-isocyanoacetamide 7, an homoallylamine 8 and an aldehyde 9 in methanol at room
temperature provides oxa-bridged tricycle 4 in good to excellent yield as a mixture of two separable diastereoisomers. In this one-pot
multicomponent process, one C–N, one C–O and three C–C bonds are formed with concomitant creation of five asymmetric centers and three
rings. Fragmentation of epoxy-tetrahydronaphthyridine 4 affords differentially substituted 5,6,7,8-tetrahydro-1,7-naphthyridine (5, 6)
depending on the reaction conditions, providing thus additional structural diversity. A one-pot three-component synthesis of 5,6,7,8-
tetrahydro-1,7-naphthyridine (6) from 7, 8 and 9 is also documented.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Structurally, 5,6,7,8-tetrahydro-1,7-naphthyridine (2) can
be considered as the ring constrained analogue of 3;
consequently it would be interesting to develop a more
efficient and flexible route to 2 in order to fully exploit its
potential biological functions. Impelled by an interest in
providing a rapid construction of polyheterocyclic scaffolds,
we report herein a multicomponent reaction6,7 for the
synthesis of oxa-bridged tricyclic compound 4 and its
subsequent fragmentation to 5,6,7,8-tetrahydro-1,7-
naphthyridine (5, 6, Fig. 2).
1,7-Naphthyridine (1) is an important heterocycle that is
found in the structure of a great number of bioactive
compounds.1 On the other hand, the biological profile of the
5,6,7,8-tetrahydro-1,7-naphthyridine or 8-azatetrahydro-
isoquinoline (2, Fig. 1) is poorly defined and only a few
syntheses have been reported. Besides the partial reduction
of 1,7-naphthyridine,2 mainly two strategies have been
developed for the access to the bicyclic heterocycles (2).
One is the annulation of a piperidine ring onto a
functionalized pyridine3 and the other is the elaboration of
a pyridine ring from a preformed piperidine derivative.4
Both synthetic routes suffer from the linearity and the ability
to introduce significant molecular complexity in each step.
Figure 2. Polysubstituted epoxy-tetrahydronaphthyridine (4) and 5,6,7,8-
tetrahydro-1,7-naphthyridine (5, 6).
Figure 1. Structure of 1,7-naphthyridine (1), 5,6,7,8-tetrahydro-1,7-
naphthyridine (2) and 2-(3-pyridyl)ethylamine (3).
2. Results and discussion
The 2-(3-pyridyl)ethylamine (3) is known to bind to
members of the dopaminergic and cholinergic receptors.5
2.1. Reaction sequence design
Based on the unique reactivity of a-isocyanoacetamide 7, an
efficient three-component synthesis of 5-aminooxazole has
been developed in our laboratory.8 Taking advantage of the
chemical reactivity of 5-aminooxazole and by fine tuning
the structure of the starting materials, several new multi-
component reactions have subsequently been devised for
Keywords: Multicomponent reaction (MCR); Isonitrile; Isocyanoaceta-
mide; Heterocycle; Naphthyridine; High throughput synthesis; Diversity-
oriented synthesis.
*
Corresponding author. Tel.: C33 1 69 82 31 31; fax: C33 1 69 07 72 47;
e-mail: zhu@icsn.cnrs-gif.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.017

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A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
the syntheses of a number of polyheterocycles6h,9 and
macrocycles.10 As a continuation of our work in this field, a
three-component synthesis of 4, 5, and 6 from a-iso-
cyanoacetamide 7, homoallylamine 8 and aldehyde 9 was
envisaged according to the sequence of events shown in
Scheme 1. Thus, condensation of an amine 8 and an
aldehyde 9 should give the Schiff base 10, which would
react with isonitrile 7 to produce the nitrilium intermediate
11. This latter intermediate, after tautomerization would
cyclize to produce the oxazole 12. Intramolecular Diels–
Alder cycloaddition of 12 between oxazole and the
tethered dienophile would furnish the epoxy-tetrahydro-
naphthyridine 4,11 which under appropriate conditions,
would undergo fragmentation to provide 5,6,7,8-tetrahydro-
1,7-naphthyridine (5 or 6).
2.2. Three-component synthesis of the epoxy-tetra-
hydronaphthyridine 4. Using isocyanoacetamide 7a,
5-benzylamino pentanoate (8a), an heptanal (9a) as test
substrates (Scheme 2), we performed a survey of reaction
conditions; the results are summarized in Table 1. When the
reaction was carried out in methanol (MeOH) at room
temperature, the oxa-bridged tricyclic compound (4) was
isolated in 71% yield as a mixture of two separable
diastereomers (entry 1). The stereoselectivity was time-
dependant indicating the reversibility of the final cyclo-
addition process (entry 2). Addition of ammonium chloride
(entry 3) was detrimental to the reaction,12 while the
presence of camphorsulfonic acid (entry 4) or silica gel
(entry 5) lowered the product yield.13 Performing the
reaction at higher temperature under otherwise identical
conditions decreased the yield of the desired product
(entries 6, 7). The high substrate concentration is favorable
to the overall reaction sequence (entries 1 vs 8). Performing
the reaction in toluene at room temperature in the presence
of lithium bromide14 afforded 4a in only 26% yield (entry
9). Forcing the reaction conditions led to the formation of
compound 5a, resulting from the fragementation of 4a, in
moderate yield (entries 10, 11). Interestingly, dichloro-
methane turned out to be a good solvent producing 4a in
69% yield (entry 12). Overall, under optimized conditions
(MeOH, 0.4 M, room temperature), we were able to produce
Scheme 1. Sequence of event of three-component synthesis of compounds
4, 5 and 6, a working hypothesis.
Scheme 2. Three-component reaction of 7a, 8a and 9a.
Table 1. Three-component synthesis of 4a, a survey of reaction conditionsa
Entry
Solvent
Time (h)
T (8C)
Additive
4a (5a) (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOHf
MeOHg
Toluene
Toluenef
Tolueneg
CH2Cl2
20
3
20
20
20
5
25
25
25
25
—
—
71b
66c
—
33
55
55
51
44
26
NH4Cld
CSAe
d
25
SiO2
—
—
—
LiBr
—
—
—
Reflux
Reflux
25
25
80
8
15
20
20
20
15
9
10
11
12
0 (23)
0 (25)
69
Reflux
25
Abbreviations: LiBr, lithium bromide; NH4Cl, ammonium chloride, SiO2, silica gel.
a General conditions: mole ratio: 7a/8a/9aZ1/1.2/1.2, CZ0.4 M.
b Diastereomeric ratio 2/1.
c Diastereomeric ratio 1/1.
d 1.0 equiv.
e 0.1 equiv.
f
CZ0.2 M.
g CZ0.1 M.

A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
11513
4a in 71% yield from readily accessible starting materials.
Neither external reagent, nor heating was required to trigger
the reaction sequence and simply mixing three inputs
together, a highly ordered and complex reaction sequence
took place to afford 4a with the creation of five chemical
bonds and three rings. The coupling constant of 3.7 Hz
between protons Ha and Hb indicated their gauche
relationship in compound 4a. Since Ha has to be endo-
oriented for the inherent ring strain imposed by the
connecting bridge,15 the observed coupling constant
indicated an exo position of the Hb, hence, an endo position
of the methyl ester group. This mode of ring formation is
indicative of a concerted rather than a stepwise process,
since one could expect the presence of exo, exo dia-
stereomers if the latter mechanism was operating. The face
selectivity for the cycloaddition is controlled solely by the
substituent at Cc and is apparently inefficient in the present
case since the observed selectivity (drZ2/1) was low and
reflected the thermodynamic controlled process (entries 1 vs
2). It is noteworthy that the intramolecular Diels–Alder
reaction of 5-amino oxazole and the tethered dienophile
occurred at room temperature16–19 in the absence of any
promoters.
The scope of this novel domino 3CR/IMDA reaction was
examined using three amines, three aldehydes and five
isocyanoacetamides as inputs (Fig. 3). Tricyclic compounds
synthesized by this multicomponent process (MeOH, room
temperature) were listed in Figure 4. Most of these
heterocycles (4) were isolated with good to excellent
yield. However, when isobutyaldehyde 9c was used as
input, 4g was isolated in only 21% yield together with
Figure 4. Representative structure of epoxy-tetrahydronaphthyridine, drZ
2/1; aonly one diastereoisomer was isolated.
oxazole 12g (60%). Heating to reflux was required to
complete the reaction sequence when isonitriles 7d and 7e,
derived from phenylglycine, were used. The presence of
phenyl substituent at the C-4 position of the 5-aminooxazole
may reduce the electron density of the diene unit, decreasing
consequently its reactivity towards the electron-poor
dienophile. Curiously, the primary amine 8b did not
participate in this reaction, although we have previously
demonstrated that simpler primary amine is an efficient
reaction partner in the three-component synthesis of
oxazole.8
2.3. Fragmentation of epoxy-tetrahydronaphthyridine 4
and three component synthesis of 6. Using 4a as model
compound, conditions for performing the fragmentation of
bridged a-amino ether function (Scheme 3) were surveyed
Figure 3. Structure of the starting materials.

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A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
Scheme 3. Acid-mediated fragmentation of epoxy-tetrahydronaphthyridine
4a.
varying solvents (MeOH, toluene), acids (TFA, p-TsOH,
TMSCl, TMSOTf) and temperatures (room temperature, 0,
K30, K78 8C). The results are summarized in Table 2. As
is seen, the fragmentation pathway depended on the reaction
conditions and both compounds 5a and 6a can be prepared
by combination of a suitable acid and a solvent. While
TMSCl in MeOH promoted the formation of 5a (entry 4),
TMSOTf in MeOH afforded both 5a and 6a in yields of 27
and 28%, respectively (entry 3). Interestingly, in dichloro-
methane and in the presence of trifluoroacetic acid (TFA),
compound 5a was isolated in 68% yield (entry 2), while in
methanol and in the presence of p-toluenesulfonic acid, an
alternative fragmentation occurred leading to compound 6a
as the only isolable product in 65% yield (entry 5). Figure 5
summarized the 5,6,7,8-tetrahydro-1,7-naphthyridine (5, 6)
synthesized by applying these two conditions [aCH2Cl2,
Figure 5. Fragmentation of epoxy-tetrahydronaphthyridine to 5,6,7,8-
a
tetrahydro-1,7-naphthyridine; CH2Cl2, TFA, room temperature; bMeOH,
c
p-TsOH, room temperature; one-pot three-component synthesis.
b
TFA, room temperature; MeOH, p-TsOH, room tempera-
ture] to the respective epoxy-tetrahydronaphthyridine.
Fragmentation of 4b with a phenyl substituent at the C-2
position was found to be more difficult and 5b was isolated
in only moderate yield under both conditions.
Scheme 4. Mechanistic hypothesis for the formation of naphthyridine 6.
13 which, after tautomerization and ejection of methanol
would provide compound 6.
Table 2. Fragmentation of 4a, a survey of reaction conditions
Ent- Solvent
ry
T (8C)
Acid (equiv) 5a (6a)
(%)a
It is evident that conditions for the three-component
synthesis of oxa-bridged tricycle 4 and its subsequent
fragmentation to 6 are compatible. This consideration
prompted us to examine the one-pot synthesis of 6. In the
event, stirring a solution of isocyanoacetamide 7a, amine 8a
and aldehyde 9a at room temperature for 2 h followed by
addition of p-TsOH provided directly the 5,6,7,8-tetra-
hydro-1,7-naphthyridine 6a in 48% yield. Compounds 6f
and 6h were similarly prepared by this one-pot procedure in
yields of 54 and 56%, respectively (Fig. 5).
1
2
3
4
5
MeOH
CH2Cl2
MeOH
MeOH
MeOH
K78 to Room temperature TFA (7)
31
68
Room temperature
Room temperature
Room temperature
Room temperature
TFA (10)
TMSOTf (3) 28 (27)
TMSCl (1)
TsOH (5)
21
(65)
Abbreviations: TFA, trifluoroacetic acid; TMSOTf, trimethylsilyl trifluoro-
methanesulfonate; TMSCl, trimethylsilyl chloride; TsOHZpara-toluene-
sulfonic acid.
a Refers to isolated yield.
While the formation of 5 can be rationalized based on an
assumption that the fragmentation of amino ether was
assisted by the lone-pair electron of nitrogen, the
fragmentation of 4 leading to 6 (p-TsOH in MeOH) is
more intriguing. A possible reaction sequence that
accounted for the formation of 6 was advanced in Scheme 4.
The nucleophilic addition of methanol (or water) onto the
imine would trigger the fragmentation to afford the ketone
3. Conclusion
In conclusion, we have developed a novel three-component
synthesis of epoxy-tetrahydro naphthyridine (4) starting
from easily available isocyanoacetamide (7), homoallyl-
amine (8) and aldehyde (9). It is worthy noting that neither

A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
11515
external reagent nor heating (or cooling) was required to
promote this rather complex transformation that leads to the
formation of five chemical bonds and three rings.
JZ7.8, 6.8 Hz, 1H), 7.18–7.30 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 23.9, 26.0, 39.0, 46.6, 46.7, 57.2, 127.6,
127.6, 128.7, 129.4, 135.2, 159.3, 163.0; MS (IE) m/z 202
[MKNC]C, 242 [M]C.
The process is also atom economic and ecologically benign
since only molecular water was lost in this multicomponent
process. Subsequent studies revealed that compound 4 can
undergo two types of fragmentation leading to differently
substituted 5,6,7,8-tetrahydro-1,7-naphthyridines (5, 6)
depending on the choice of the acid and reaction medium.
Thus, from the same starting materials, three different
heterocycles are readily synthesized by simply modifying
the workup procedure. The operational simplicity and good
to excellent chemical yield made these novel heterocycle
syntheses highly attractive in diversity-oriented synthesis
program.20
4.1.4. Compound 7d. Mp 89–90 8C; IR (CHCl3) n 3499,
3011, 2926, 2863, 2146 (N^C), 1664, 1497, 1439, 1361,
1
1302, 1273, 1234, 1115, 1069, 1000, 958, 859 cmK1; H
NMR (300 MHz, CDCl3) d 3.33 (m, 4H), 3.62 (m, 4H), 5.55
(s, 1H), 7.41 (m, 5H); 13C NMR (CDCl3, 62.5 MHz) d 43.1,
46.2, 60.1, 65.7, 66.4, 126.2, 129.4, 131.9, 163.1; MS (IE)
m/z 230 [M]C.
4.2. General procedure for the three-component
synthesis of epoxy-tetrahydronaphthyridine (4)
A solution of homoallylamine (8, 1.2 equiv) and aldehyde
(9, 1.2 equiv) in dry MeOH (0.4 M) was stirred at room
temperature for 1 h. a-Isocyanoacetamide (7, 1.0 equiv)
was added. After being stirred at room temperature for
additional 20 h, the reaction mixture was diluted with water;
the volatile was removed under reduce pressure and the
aqueous phase was extracted with dichloromethane. The
combined organic extracts were washed with brine, dried
over Na2SO4 and the solvent was removed under reduced
pressure. Purification of the crude product by either
preparative TLC (silica gel, eluent heptane/AcOEt) or
flash chromatography (silica gel, eluent heptane/AcOEt)
afforded the title compound.
4. Experimental
4.1. General procedure for the synthesis of isonitrile
a-Substituted-a-isocyano acetamides were obtained by
dehydration of the corresponding N-formyl derivatives.9
Synthesis of 7a is typical: a stirred solution of morpholinyl
amide of N-formyl phenylalanine (10.0 mmol) and triethyl-
amine (50.0 mmol) in dry dichloromethane (50.0 mL) was
cooled to K20 to K30 8C. Phosphorus oxychloride
(15.0 mmol) was added dropwise and the reaction mixture
was stirred for 2 h at K20 to K30 8C. An aqueous solution
of sodium bicarbonate was introduced dropwise so that the
temperature of mixture was maintained at K20 to K30 8C.
The mixture was stirred for 0.5 h and raised to room
temperature. The aqueous layer was separated and extracted
with dichloromethane. The organic extracts were combined,
washed with brine and dried over anhydrous sodium sulfate
and evaporated under reduced pressure. The crude reaction
mixture was purified by flash column chromatography on
silica gel to provide the isocyanide 7a.
4.2.1. Compound 4a. Yield: 71%, drZ2/1. Major isomer.
Yellow oil; IR (CHCl3) n 2956, 2929, 2859, 1732, 1635,
1
1495, 1453, 1347, 1271, 1118 cmK1; H NMR (300 MHz,
CDCl3) d 0.85 (t, JZ6.5 Hz, 3H), 1.27 (m, 8H), 1.45–1.86
(m, 4H), 2.12 (m, 1H), 2.24 (td, JZ13.0, 1.6 Hz, 1H), 2.59–
2.65 (m, 2H), 2.81 (d, JZ5.3 Hz, 1H), 2.82 (m, 1H), 2.96–
3.04 (m, 2H), 3.34 (t, JZ5.3 Hz, 1H), 3.40 (d, JZ13.7 Hz,
1H), 3.62 (s, 2H), 3.67–3.75 (m, 4H), 3.70 (s, 3H), 3.97 (d,
JZ13.7 Hz, 1H), 7.22–7.39 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 14.1, 22.6, 25.9, 27.8, 28.4, 29.9, 31.8, 35.3, 44.5,
48.4 (2C), 49.6, 49.9, 52.1, 54.3, 63.1, 67.0 (2C), 98.3,
107.1, 126.7, 126.8, 128.4 (2C), 128.7, 128.9 (2C), 129.1
(2C), 129.7 (2C), 135.9, 170.8, 176.1; MS (EI) m/z 474
[MKC6H13]C, 528 [MKOMe]C, 559 [M]C, 560 [MC
H]C; MS (ESI) m/z 560 [MCH]C; HRMS m/z calcd for:
[C34H45N3O4CH]C 560.3488, m/z found: 560.3502. Minor
isomer. Yellow oil; IR (CHCl3) n 2956, 2930, 2859, 1729,
1656, 1495, 1443, 1330, 1262, 1174, 1116 cmK1; 1H NMR
(300 MHz, CDCl3) d 0.88 (m, 3H), 1.27–1.79 (m, 11H),
2.09 (m, 1H), 2.26 (m, 1H), 2.54–2.65 (m, 3H), 2.82–2.90
(m, 1H), 2.83 (d, JZ3.3 Hz, 1H), 2.97–3.06 (m, 3H), 3.53
(d, JZ15.7 Hz, 1H), 3.66–3.76 (m, 5H), 3.67 (s, 3H), 3.88
(m, 2H), 7.30 (m, 10H); MS (IE) m/z 474 [MKC6H13]C,
559 [M]C; MS (ESI) m/z 560 [MCH]C; HRMS m/z calcd
for: [C34H45N3O4CH ]C 560.3488, m/z found: 560.3495.
4.1.1. Compound 7a. (Yield: 95%; eluent: heptane/
EtOAcZ2:1); white solid, mp 79–81 8C; IR (CHCl3) n
2928, 2863, 2142, 1668, 1496, 1456, 1116 cmK1; 1H NMR
(250 MHz, CDCl3): d 3.13–3.78 (m, 10H), 4.55 (t, 1H, JZ
7.3 Hz), 7.22–7.40 (m, 5H); 13C NMR (CDCl3, 62.5 MHz):
d 39.1, 42.9, 46.2, 55.0, 65.9, 66.4, 127.7, 128.8 (2CH),
129.4 (2CH), 135.0, 159.8, 163.5; MS (EI): m/z 244. Anal.
Calcd for C14H16N2O3: C, 68.83; H, 6.60; N, 11.47. Found:
C, 68.71; H, 6.54; N, 11.47.
4.1.2. Compound 7b. Mp 75–78 8C; IR (CHCl3) n 2949,
2862, 2142 (N^C), 1659, 1453, 1271, 1137, 993 cmK1; 1H
NMR (300 MHz, CDCl3) d 0.81–1.66 (m, 6H), 3.15–3.68
(m, 6H), 4.56 (dd, JZ8.2, 6.3 Hz, 1H), 7.24–7.36 (m, 5H);
RMN 13C (CDCl3, 75 MHz) d 23.6, 24.8, 25.3, 38.6, 43.3,
46.4, 54.7, 128.2, 127.0, 127.8, 128.9, 129.3, 134.9, 158.6,
162.6; MS (IE) m/z 216 [MKNC]C, 242 [M]C.
4.2.2. Compound 4b. Yield: 88%, drZ2/1. Major isomer.
Yellow oil; IR (CHCl3) n 2956, 2928, 2859, 1736, 1722,
4.1.3. Compound 7c. Mp 85–87 8C; IR (CHCl3) n 3032,
3011, 2982, 2956, 2882, 2146 (N^C), 1659, 1440, 1343,
1601, 1571, 1494, 1452, 1436, 1366, 1302, 1271, 1119 cmK1
;
1H NMR (300 MHz, CDCl3) d 0.87 (m, 3H), 1.30 (m, 8H),
1.57–1.96 (m, 4H), 2.27–2.35 (m, 2H), 2.78–2.87 (m, 3H),
3.00 (d, JZ3.5 Hz, 1H), 3.17–3.24 (m, 2H), 3.33 (s, 3H),
3.46 (m, 1H), 3.48 (d, JZ13.8 Hz, 1H), 3.76 (m, 4H), 3.99
1232 cmK1; H NMR (300 MHz, CDCl3) d 1.70–1.87 (m,
1
4H), 2.95–3.03 (m, 1H), 3.11 (dd, JZ13.7, 7.8 Hz, 1H),
3.22 (dd, JZ13.7, 6.8 Hz, 1H), 3.32–3.49 (m, 3H), 4.34 (dd,

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A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
(d, JZ13.8 Hz, 1H), 7.26–7.44 (m, 8H), 8.14 (m, 2H); 13
C
13.4 Hz, 1H), 3.80 (s, 3H), 3.90 (d, JZ13.4 Hz, 1H), 7.12–
7.35 (m, 10H); MS (ESI) m/z 544 [MCH]C, 566 [MC
Na]C. Minor isomer. Yellow oil; IR (CHCl3) n 3000, 2955,
2931, 2874, 1728, 1614, 1495, 1454, 1437, 1341, 1264,
NMR (75 MHz, CDCl3) d 14.1, 22.7, 25.9, 27.8, 27.9, 29.8,
31.8, 43.8, 48.1, 49.5, 49.9, 51.7, 53.8, 53.9, 63.0, 66.9 (2C),
97.2, 107.3, 126.8, 127.0 (2C), 128.2 (2C), 128.3 (2C),
129.1 (2C), 131.0, 131.9, 139.6, 169.8, 170.0; MS (IE) m/z;
MS (ESI) m/z 546 [MCH]C; HRMS m/z calcd for:
[C33H43N3O4CH]C 546.3332, m/z found: 546.3305.
1
1174 cmK1; H NMR (300 MHz, CDCl3) d 0.94 (m, 3H),
1.07 (m, 1H), 1.27–1.49 (m, 8H), 1.65 (m, 1H), 1.76 (m,
2H), 1.83–2.04 (m, 3H), 2.41 (m, 1H), 2.64–2.73 (m, 1H),
3.07 (m, 1H), 3.18–3.32 (m, 4H), 3.31 (d, JZ13.4 Hz, 1H),
3.42 (m, 1H), 3.51 (s, 2H), 3.59 (m, 1H), 3.80 (s, 3H), 3.80
(d, JZ13.4 Hz, 1H), 4.02 (m, 1H), 7.17–7.38 (m, 10H); MS
(ESI) m/z 544 [MCH]C, 566 [MCNa]C.
1
Minor isomer. Yellow oil; H NMR (300 MHz, CDCl3) d
0.92 (m, 3H), 1.32 (m, 8H), 1.76 (m, 2H), 1.90 (m, 1H), 2.26
(m, 1H), 2.44 (m, 1H), 2.63 (m, 1H), 2.79–2.85 (m, 2H),
2.95 (m, 1H), 3.03 (d, JZ3.5 Hz, 1H), 3.14 (m, 1H), 3.17–
3.24 (m, 2H), 3.35 (s, 3H), 3.77–3.80 (m, 4H), 3.92 (d, JZ
13.4 Hz, 1H), 4.00 (d, JZ13.4 Hz, 1H), 7.24–7.44 (m, 8H),
8.12 (m, 2H); 13C NMR (75 MHz, CDCl3) d 14.1, 22.7,
22.8, 26.7, 27.2, 28.3, 29.2, 32.1, 40.5, 42.5, 48.3, 50.8,
51.8, 58.0, 58.7, 67.0 (2C), 98.0, 106.8, 126.7, 127.1 (2C),
128.0 (2C), 128.2 (2C), 129.1 (2C), 130.9, 132.0, 140.4,
170.3, 170.4; MS (ESI) m/z 546 [MCH]C; HRMS m/z calcd
for: [C33H43N3O4CH]C 546.3332, m/z found: 546.3323.
4.2.6. Compound 4f. Yield: 77%, drZ2/1. Major isomer.
Yellow oil; H NMR (300 MHz, CDCl3) d 1.71–1.58 (m,
1
1H), 1.87 (m, 1H), 2.02–2.20 (m, 4H), 2.28 (m, 1H), 2.60–
2.68 (m, 2H), 2.75–2.96 (m, 2H), 2.84 (d, JZ3.6 Hz, 1H),
2.98–3.05 (m, 2H), 3.44 (t, JZ5.3 Hz, 1H), 3.47 (d, JZ
13.8 Hz, 1H), 3.64 (s, 2H), 3.71 (s, 3H), 3.66–3.77 (m, 4H),
4.06 (d, JZ13.8 Hz, 1H), 7.18–7.43 (m, 15H); 13C NMR
(75 MHz, CDCl3) d 30.3 (2C), 30.9, 33.0, 36.5, 45.5, 49.5
(2C), 50.8, 53.2, 54.8, 63.6, 68.0 (2C), 99.3, 108.3, 126.5,
127.8, 129.2 (2C), 129.3 (2C), 129.3 (2C), 129.4 (2C), 129.5
(2C), 129.6 (2C), 129.9, 130.4, 136.9, 144.2, 171.7, 177.5;
MS (ESI) m/z 580 [MCH]C. Minor isomer. Yellow oil; IR
(CHCl3) n 3086, 3002, 2954, 2924, 2860, 1733, 1706, 1632,
4.2.3. Compound 4c. Yield: 50%, 1 diastereomer. Yellow
oil; IR (CHCl3) n 3023, 2937, 2858, 1728, 1602, 1453, 1438,
1
1275, 1254 cmK1; H NMR (300 MHz, CDCl3) d 0.87 (m,
3H), 1.27 (m, 8H), 1.54–1.84 (m, 9H), 2.09 (m, 1H), 2.23
(m, 2H), 2.60–2.64 (m, 2H), 2.80 (m, 1H), 2.87 (d, JZ
3.6 Hz, 1H), 2.94–3.01 (m, 2H), 3.32 (t, JZ5.3 Hz, 1H),
3.40 (d, JZ13.6 Hz, 1H), 3.64 (s, 2H), 3.69 (s, 3H), 3.97 (d,
JZ13.6 Hz, 1H), 7.23–7.40 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 14.2, 22.8, 24.7, 26.0, 26.2 (2C), 29.1, 29.8, 31.9,
35.3, 44.7, 49.2 (2C), 49.8, 51.5, 63.4, 98.0, 108.2, 126.5,
126.9, 128.4 (2C), 128.9 (2C), 129.1 (2C), 129.5, 129.9
(2C), 136.5, 171.2, 177.1; MS (ESI) m/z 558 [MCH]C, 580
[MCNa]C.
1602, 1495, 1454, 1364, 1270, 1118 cmK1 1H NMR
;
(300 MHz, CDCl3) d 1.70–1.83 (m, 2H), 2.02–2.13 (m,
1H), 2.25–2.32 (m, 1H), 2.35–2.47 (m, 1H), 2.59–2.93
(m, 6H), 2.85 (d, JZ3.2 Hz, 1H), 2.99–3.07 (m, 2H), 3.12
(m, 1H), 3.54 (d, JZ16.1 Hz, 1H), 3.69 (s, 3H), 3.64–3.78
(m, 5H), 3.88 (m, 2H), 7.16–7.40 (m, 15H); MS (ESI) m/z
580 [MCH]C.
4.2.7. Compound 4g. Yield: 21%, 1 diastereomer. Yellow
oil; IR (CHCl3) n 3021, 2964, 2859, 1735, 1722, 1494, 1451,
1369, 1302, 1271, 1118 cmK1; 1H NMR (300 MHz, CDCl3)
d 1.17 (d, JZ6.9 Hz, 3H), 1.21 (d, JZ6.9 Hz, 3H), 1.65 (m,
1H), 1.78 (m, 1H), 2.22–2.41 (m, 3H), 2.76–2.88 (m, 3H),
2.98 (d, JZ3.6 Hz, 1H), 3.18–3.22 (m, 2H), 3.33 (m, 1H),
3.34 (s, 3H), 3.42 (d, JZ13.8 Hz, 1H), 3.78 (m, 4H), 4.08
(d, JZ13.8 Hz, 1H), 7.26–7.44 (m, 8H), 8.11 (d, JZ8.1 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 19.7, 21.7, 27.8, 28.4,
29.3, 44.5, 48.1, 49.6, 49.7, 51.8, 54.8, 66.9, 68.0 (2C), 98.3,
107.0, 126.7, 126.9 (2C), 128.3 (2C), 128.5 (4C), 130.9,
132.0, 140.0, 167.6, 170.1; MS (ESI) m/z 504 [MCH]C,
526 [MCNa]C.
4.2.4. Compound 4d. Yield: 70%, drZ2/1. Major isomer.
Yellow oil; IR (CHCl3) n 3065, 3003, 2954, 2859, 1736,
1722, 1601, 1495, 1452, 1436, 1365, 1302, 1271, 1255,
1
1169, 1119 cmK1; H NMR (300 MHz, CDCl3) d 1.69 (td,
JZ12.6, 3.2 Hz, 1H), 1.85 (m, 1H), 2.07–2.28 (m, 2H),
2.30–2.40 (m, 3H), 2.79–2.93 (m, 3H), 2.98–3.08 (m, 1H),
3.03 (d, JZ3.5 Hz, 1H), 3.22 (m, 2H), 3.34 (s, 3H), 3.54 (m,
2H), 3.77 (m, 4H), 4.07 (d, JZ13.9 Hz, 1H), 7.09–7.37 (m,
13H), 8.06 (m, 2H); 13C NMR (75 MHz, CDCl3) d 27.9,
29.3, 29.8, 31.7, 43.8, 48.1, 49.6, 49.8, 51.8, 53.7, 53.8,
62.4, 66.93, 97.9, 107.4, 125.6, 126.9, 127.0 (2C), 128.3
(4C), 128.4 (4C), 128.8 (2C), 131.1, 131.7, 139.5, 143.1,
170.0. Minor isomer. Yellow oil; 1H NMR (300 MHz,
CDCl3) d 1.76 (m, 2H), 2.16 (m, 1H), 2.45 (m, 1H), 2.60 (m,
1H), 2.70 (m, 1H), 2.74–2.84 (m, 2H), 2.90–3.00 (m, 3H),
3.02 (d, JZ3.2 Hz, 1H), 3.18–3.24 (m, 3H), 3.32 (s, 3H),
3.77 (m, 4H), 3.96 (m, 2H), 7.24–7.43 (m, 13H), 8.11 (m,
2H); 13C NMR (75 MHz, CDCl3) d 26.5, 29.3, 30.5, 33.6,
40.6, 42.4, 48.3, 50.7, 51.8, 58.0, 58.7, 67.0 (2C), 97.7,
106.9, 125.5, 126.8, 127.0 (2C), 128.1 (2C), 128.2 (4C),
128.6 (2C), 129.1 (2C), 130.9, 131.9, 140.2, 143.2, 170.2.
4.2.8. Compound 4h. Yield: 60%, 1 diastereomer. Yellow
oil; IR (CHCl3) n 3003, 2943, 2860, 1726, 1604, 1495, 1453,
1437, 1365, 1266, 1252, 1176, 1127 cmK1 1H NMR
;
(300 MHz, CDCl3) d 1.58–1.72 (m, 6H), 1.89 (m, 1H),
1.96–2.21 (m, 3H), 2.32 (m, 1H), 2.65–2.73 (m, 3H), 2.75–
2.90 (m, 2H), 2.94 (d, JZ3.5 Hz, 1H), 2.93–3.05 (m, 3H),
3.42–3.48 (m, 2H), 3.69 (s, 2H), 3.73 (s, 3H), 4.03 (d, JZ
14.2 Hz, 1H), 7.13–7.44 (m, 13H), 7.60 (s, 1H); MS (ESI)
m/z 656 [79BrMCH]C, 658 [81BrMCH]C, 678 [79BrMC
Na]C, 680 [81BrMCNa]C; HRMS m/z calcd for: [C36H40-
BrN3O4CH]C 656.2488, 658.2467, m/z found: 656.2522,
658.2510.
4.2.5. Compound 4e. Yield: 52%, drZ3/2. Major isomer.
Yellow oil; IR (CHCl3) n 3065, 2954, 2873, 1722, 1605,
1
1453, 1368, 1341, 1262, 1171 cmK1; H NMR (300 MHz,
CDCl3) d 0.88 (m, 3H), 1.26–1.51 (m, 8H), 1.62–1.77 (m,
4H), 1.88–2.00 (m, 3H), 2.29 (m, 1H), 2.64–2.98 (m, 3H),
3.13 (m, 1H), 3.19 (d, JZ13.4 Hz, 1H), 3.16–3.34 (m, 2H),
3.39–3.54 (m, 3H), 3.61 (d, JZ13.4 Hz, 1H), 3.70 (d, JZ
4.2.9. Compound 4i. Yield: 92%, drZ2/1. Major isomer.
Yellow oil; IR (CHCl3) n 3066, 3036, 3021, 3014, 2954,
2860, 1729, 1657, 1641, 1632, 1602, 1495, 1453, 1438,

A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
11517
1
1271, 1170, 1117 cmK1; H NMR (300 MHz, CDCl3) d
4.3.2. Compound 5b. Yellow oil; yield: 30%; IR (CHCl3) n
3018, 2954, 2930, 2858, 1730, 1602, 1450, 1436, 1415,
1.51–1.65 (m, 2H), 1.83 (m, 1H), 1.90–2.16 (m, 3H), 2.27
(m, 1H), 2.56–2.63 (m, 2H), 2.66–2.91 (m, 2H), 2.80 (d, JZ
3.7 Hz, 1H), 2.93–3.00 (m, 2H), 3.38 (t, JZ5.4 Hz, 1H),
3.43 (d, JZ14.6 Hz, 1H), 3.58 (s, 2H), 3.63–3.72 (m, 4H),
3.67 (s, 3H), 3.95 (d, JZ14.6 Hz, 1H), 7.03–7.36 (m, 13H),
7.52 (s, 1H); MS (ESI) m/z 658 [79BrMCH]C, 660
[81BrMCH]C. Minor isomer. Yellow oil; IR (CHCl3) n
3064, 3043, 3036, 3011, 2953, 1728, 1602, 1453, 1438,
1
1224, 1208, 1112 cmK1; H NMR (300 MHz, CDCl3) d
0.79 (t, JZ6.7 Hz, 3H), 1.18 (m, 7H), 1.36 (m, 1H), 1.75–
1.82 (m, 2H), 2.34–2.42 (m, 1H), 2.64–2.86 (m, 2H), 2.75
(m, 4H), 3.05–3.13 (m, 1H), 3.45 (m, 4H), 3.62 (d, JZ
13.6 Hz, 1H), 3.65 (m, 1H), 3.77 (d, JZ13.6 Hz, 1H), 3.89
(s, 3H), 7.16–7.39 (m, 8H), 7.47–7.50 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 14.2, 21.6, 22.7, 26.1, 29.4, 31.9, 33.9,
42.3, 51.4 (2C), 52.5, 57.7, 63.5, 67.3 (2C), 125.6, 126.9,
128.11 (3C), 128.2 (2C), 128.8 (2C), 129.1 (2C), 139.3
(2C), 139.4, 140.1, 154.9, 155.3, 168.7; MS (ESI) m/z 528
[MCH]C.
1
1272, 1191, 1117 cmK1; H NMR (300 MHz, CDCl3) d
1.63–1.86 (m, 2H), 2.00–2.12 (m, 1H), 2.29 (m, 3H), 2.45
(m, 1H), 2.57–2.72 (m, 2H), 2.74–2.90 (m, 2H), 2.86 (d, JZ
3.7 Hz, 1H), 2.97–3.11 (m, 3H), 3.55 (d, JZ16.1 Hz, 1H),
3.69 (s, 3H), 3.65–3.78 (m, 5H), 3.85 (s, 2H), 7.15–7.39 (m,
13H), 7.56 (s, 1H); MS (ESI) m/z 658 [79BrMCH]C, 660
[81BrMCH]C.
4.3.3. Compound 5c. Yellow oil; yield: 50%; IR (CHCl3) n
2935, 2857, 1730, 1602, 1493, 1453, 1437, 1414, 1348,
1
1274, 1175, 1150 cmK1; H NMR (300 MHz, CDCl3) d
0.87 (t, JZ6.6 Hz, 3H), 1.22–1.60 (m, 14H), 1.76–2.02 (m,
2H), 2.45–2.73 (m, 3H), 2.84 (m, 4H), 3.09 (m, 1H), 3.59 (d,
JZ13.5 Hz, 1H), 3.67 (m, 1H), 3.90 (d, JZ13.5 Hz, 1H),
3.91 (s, 3H), 4.08 (d, JZ14.3 Hz, 1H), 4.33 (d, JZ14.3 Hz,
1H), 7.19–7.39 (m, 10H); 13C NMR (75 MHz, CDCl3) d
14.1, 22.4, 22.7, 24.2, 25.6, 26.8 (3C), 29.5, 31.9, 33.4, 39.9,
43.5, 52.2 (2C), 57.9, 63.9, 124.7, 125.7, 126.9, 128.0 (2C),
128.2 (2C), 128.7 (2C), 128.8 (2C), 139.1, 139.6, 140.4,
140.9, 154.3, 157.2, 168.9; MS (ESI) m/z 540 [MCH]C,
562 [MCNa]C.
4.2.10. Compound 12g. Yellow oil; yield: 60%; IR (CHCl3)
n 3065, 2964, 2924, 2859, 1719, 1657, 1640, 1602, 1496,
1448, 1438, 1373, 1272, 1177, 1116 cmK1 1H NMR
;
(300 MHz, CDCl3) d 0.80 (d, JZ6.5 Hz, 3H), 1.11 (d, JZ
6.5 Hz, 3H), 2.29–2.49 (m, 3H), 2.85 (m, 2H), 3.14 (t, JZ
5.6 Hz, 4H), 3.26 (d, JZ13.9 Hz, 1H), 3.35 (d, JZ10.8 Hz,
1H), 3.74 (s, 3H), 3.90 (d, JZ5.6 Hz, 4H), 4.02 (d, JZ
13.9 Hz, 1H), 5.84 (d, JZ15.5 Hz, 1H), 6.95 (m, 1H), 7.46–
7.27 (m, 8H), 8.01 (d, JZ8.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) d 20.2, 20.3, 28.5, 31.2, 49.1, 50.5 (2C), 51.4, 55.2,
64.7, 67.0 (2C), 121.8, 123.6, 126.0 (2C), 126.9, 127.0,
128.3 (2C), 128.4 (2C), 128.9 (2C), 132.0, 139.5, 147.8,
150.6, 156.0, 166.9; MS (ESI) m/z 504 [MCH]C, 526 [MC
Na]C.
4.3.4. Compound 5f. Yellow oil; yield: 77%; IR (CHCl3) n
3065, 3004, 1731, 1602, 1495, 1453, 1437, 1414, 1299,
1
1263, 1176, 1112 cmK1; H NMR (300 MHz, CDCl3) d
2.13–2.42 (m, 2H), 2.53–2.83 (m, 5H), 2.92 (m, 4H), 3.10–
3.19 (m, 1H), 3.62 (d, JZ13.6 Hz, 1H), 3.68 (m, 4H), 3.78
(t, JZ5.4 Hz, 1H), 3.94 (s, 3H), 3.98 (d, JZ13.6 Hz, 1H),
4.15 (d, JZ14.4 Hz, 1H), 4.35 (d, JZ14.4 Hz, 1H), 7.08–
7.03 (m, 15H); 13C NMR (75 MHz, CDCl3) d 22.8, 29.4,
31.9, 35.2, 40.3, 43.9, 51.3, 52.6, 58.1, 63.8, 67.9 (2C),
125.5, 125.6, 126.1, 127.2, 128.3 (2C), 128.4 (2C), 128.5
(2C), 128.6 (2C), 128.8 (2C), 128.9 (2C), 139.3, 139.4,
140.2, 143.2, 155.0, 157.5, 168.7; MS (ESI) m/z 562 [MC
H]C, 584 [MCNa]C, 600 [MCK]C; HRMS m/z calcd for:
[C36H39N3O3CH]C 562.3070, m/z found: 562.3076.
4.3. General procedure for the synthesis of tetrahydro-
naphthyridines (5)
To a solution of epoxy-naphthyridine 4 in dry CH2Cl2
(0.2 M), TFA (10.0 equiv) was added and the reaction
mixture was stirred at room temperature, the reaction was
monitored by TLC (typically 30–60 min). After completion
of the reaction, the mixture was diluted with saturated
aqueous NaHCO3 solution and extracted with dichloro-
methane. The combined organic extracts were washed with
brine, dried over Na2SO4 and the solvent was removed
under reduced pressure. Purification of crude product by
either preparative TLC (silica gel, eluent heptane/AcOEt) or
flash chromatography (silica gel, eluent heptane/AcOEt)
afforded the tetrahydronaphthyridines 5.
1
4.3.5. Compound 5h. Yellow oil; yield: 73%; H NMR
(300 MHz, CDCl3) d 2.12–2.41 (m, 2H), 2.55–2.82 (m, 5H),
2.94 (m, 4H), 3.16 (m, 1H), 3.63 (d, JZ13.9 Hz, 1H), 3.70
(m, 4H), 3.77 (m, 1H), 3.93 (s, 3H), 3.97 (d, JZ13.9 Hz,
1H), 4.16 (d, JZ14.4 Hz, 1H), 4.37 (d, JZ14.4 Hz, 1H),
7.10–7.41 (m, 12H), 7.44 (d, JZ8.0 Hz, 1H), 7.60 (s, 1H);
13C NMR (75 MHz, CDCl3) d 22.5, 29.3, 31.8, 35.1, 40.2,
43.8, 51.2, 52.5, 57.4, 63.6, 67.7 (2C), 122.5, 125.1, 125.5,
126.0, 127.3, 128.2 (2C), 128.3 (2C), 128.4 (2C), 128.7
(2C), 129.9, 130.1, 131.6, 139.3, 139.9 (2C), 141.8, 142.7,
154, 6, 157.5, 168.5; MS (ESI) m/z 640 [79BrMCH]C, 642
[81BrMCH]C; HRMS m/z calcd for: [C36H38BrN3O3C
H]C 640.2175, 642.2154, m/z found: 640.2217, 642.2212.
4.3.1. Compound 5a. Yellow oil; yield: 68%; IR (CHCl3) n
3017, 2955, 2858, 1731, 1453, 1437, 1415, 1263, 1235,
1
1112 cmK1; H NMR (300 MHz, CDCl3) d 0.88 (t, JZ
6.6 Hz, 3H), 1.23–1.28 (m, 7H), 1.41–1.48 (m, 1H), 1.79–
2.04 (m, 2H), 2.46–2.56 (m, 1H), 2.61–2.76 (m, 2H), 2.90
(m, 4H), 3.11 (m, 1H), 3.61 (d, JZ13.6 Hz, 1H), 3.64–3.71
(m, 5H), 3.91 (d, JZ13.6 Hz, 1H), 3.94 (s, 3H), 4.14 (d, JZ
14.4 Hz, 1H), 4.34 (d, JZ14.4 Hz, 1H), 7.19–7.39 (m,
10H); 13C NMR (75 MHz, CDCl3) d 14.3, 22.5, 22.9, 25.8,
29.6, 32.1, 33.6, 40.4, 43.5, 51.3, 52.5, 58.0, 64.0, 67.9 (2C),
125.3, 126.1, 127.1, 128.3 (2C), 128.4 (2C), 128.8 (2C),
128.9 (2C), 139.3, 139.6, 140.2, 155.7, 157.3, 168.8; MS
(EI) m/z 91 [CH2Ph]C, 455 [MKC4H8NO]C, 456 [MK
C6H13]C, 510 [MKOMe]C; MS (ESI) m/z 542 [MCH]C.
4.4. General procedure for the synthesis of tetrahydro-
naphthyridines (6)
To a solution of epoxy-naphthyridine 4 in dry MeOH
(0.4 M), TsOH (5.0 equiv) was added and the reaction
mixture was stirred at room temperature, the reaction was

11518
A. Fayol, J. Zhu / Tetrahedron 61 (2005) 11511–11519
monitored by TLC (typically 30–60 min). After completion
of the reaction, the mixture was diluted with saturated
aqueous NaHCO3 solution and extracted with dichloro-
methane. The combined organic extracts were washed with
brine, dried over Na2SO4 and the solvent was removed
under reduced pressure. Purification of crude product by
either preparative TLC (silica gel, eluent heptane/AcOEt) or
flash chromatography (silica gel, eluent heptane/AcOEt)
afforded the tetrahydronaphthyridine 6.
JZ13.7 Hz, 1H), 4.13 (d, JZ13.7 Hz, 1H), 4.35 (d, JZ
13.7 Hz, 1H), 7.09–7.46 (m, 13H), 7.62 (s, 1H), 10.84 (s,
1H); 13C NMR (75 MHz, CDCl3) d 26.4, 31.4, 35.2, 38.8,
45.1, 52.7, 57.6, 64.1, 116.7, 122.5, 125.4, 126.1, 127.3,
127.9, 128.1 (2C), 128.2 (2C), 128.5 (2C), 129.1 (2C),
129.9, 130.1, 131.7, 139.3, 142.0, 142.9, 147.7, 149.3,
152.4, 171.1; MS (ESI) m/z 551 [79BrMCH]C, 573
[81BrMCH]C; HRMS m/z calcd for: [C32H31BrN2O3C
H]C: 571.1596, m/z found: 571.1610.
4.5. Three-component synthesis of of tetrahydro-
naphthyridines (6)
Acknowledgements
A solution of homoallylamine (8, 1.2 equiv) and aldehyde
(9, 1.2 equiv) in dry MeOH (0.4 M) was stirred at room
temperature for 1 h. a-Isocyanoacetamide (7, 1.0 equiv)
was added. After being stirred at room temperature for 20 h,
TsOH (5 equiv) was added and the reaction mixture was
stirred at room temperature for additional 30–60 min. The
reaction mixture was diluted with saturated aqueous
NaHCO3 solution, and extracted with dichloromethane.
The combined organic extracts were washed with brine,
dried over Na2SO4 and the solvent was removed under
reduced pressure. Purification of crude product by either
preparative TLC (silica gel, eluent heptane/AcOEt) or flash
chromatography (silica gel, eluent heptane/AcOEt) afforded
the tetrahydronaphthyridine 6.
We thank CNRS for financial support. A doctoral fellowship
`
´
from the ‘Ministere de l’Enseignement Superieur et de la
Recherche’ to A.F. are gratefully acknowledged.
References and notes
1. (a) Lowe, P. A. In Katritzky, A. R., Rees, C. W., Eds.;
Comprehensive Heterocyclic Chemistry; Pergamon: Oxford,
1984; Vol. 2, pp 581–627. (b) Wozniak, M. Heterocycles
1982, 19, 363–405. (c) Paulder, W. W.; Kress, T. J. In
Katritzky, A. R., Boulton, A., Eds.; Advances in Heterocyclic
Chemistry; Academic Press: New York, 1970; Vol. 11,
pp 123–175.
4.5.1. Compound 6a. Yellow oil; yield: 65% (two-steps);
47% (one-pot three component); IR (CHCl3) n 2957, 2931,
2858, 1674, 1601, 1535, 1441, 1408, 1344, 1175 cmK1; 1H
NMR (300 MHz, CDCl3) d 0.88 (t, JZ6.6 Hz, 3H), 1.09–
1.30 (m, 7H), 1.46 (m, 1H), 1.83–2.10 (m, 2H), 2.50 (m,
1H), 2.83–3.08 (m, 3H), 3.51 (d, JZ13.5 Hz, 1H), 3.70 (t,
JZ4.9 Hz, 1H), 3.95 (s, 3H), 3.98 (d, JZ13.5 Hz, 1H), 4.11
(d, JZ13.6 Hz, 1H), 4.30 (d, JZ13.6 Hz, 1H), 7.17–7.40
(m, 10H), 10.75 (s, 1H); 13C NMR (75 MHz, CDCl3) d 14.1,
22.7, 25.1, 26.3, 29.6, 31.9, 33.4, 38.9, 44.6, 52.6, 58.1,
64.3, 116.8, 126.0, 126.9, 127.9, 128.1 (2C), 128.2 (2C),
128.8 (2C), 129.0 (2C), 139.3, 139.6, 148.6, 148.9, 152.2,
171.2; MS (EI) m/z 91 [CH2Ph]C, 387 [MKC6H13]C; MS
(ESI) m/z 473 [MCH]C; HRMS m/z calcd for:
[C30H36N2O3CH]C 473. 2804, m/z found: 473.2768.
2. (a) Sato, Y.; Iwashige, T.; Miyadera, T. Chem. Pharm. Bull.
1960, 8, 427–435. (b) Armarego, W. L. F. J. Chem. Soc. 1967,
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(m, 4H), 3.43 (d, JZ13.6 Hz, 1H), 3.71 (m, 1H), 3.86 (s,
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4.24 (d, JZ13.7 Hz, 1H), 6.97–7.36 (m, 15H), 10.7 (br s,
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45.1, 52.6, 58.2, 64.1, 116.8, 125.3, 126.0, 126.7, 128.0,
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