Glyoxalate-derived aldimines in cycloaddition reactions with olefins

Article abstract of DOI:10.1002/ejoc.201100395

The reaction of aldimine 1a, derived from ethyl glyoxalate, with activated dienophiles, such as styrene and indene, gave the tetrahydro-1,5-naphthyridine derivatives 3 with regio- and stereoselective control of three stereocenters through a [4+2] cycloaddition process via endo transition states. However, when aldimine 1a was used in the reaction with strained olefins, such as norbornene or dicyclopentadiene, the corresponding [4+2] and [2+2] cycloadducts were obtained, through exclusive exo π-facial stereoselective cycloaddition. The addition of a second strained C=C bond in the olefin, such as norbornadiene, increased the multifunctional character of the olefin and a mixture of the corresponding exo [4+2] 11a and exo [2+2] 12a cycloadducts, as well as the corresponding HOMO cycloadduct 13a, was obtained. Reaction between norbornadiene and aldimines derived from p-nitro- and o,p-dinitroanilines and ethyl glyoxalate gave exo [4+2] cycloadducts 11b,c, HOMO cycloadducts 13b,c and α-amino γ-lactones 15b,c. A mechanistic explanation for the formation of the new products is suggested. Glyoxalate-derived aldimines react with styrene and indene to give endo [4+2] cycloadducts and with strained olefins to afford both exo [4+2] and [2+2] cycloadducts. The reaction with norbornadiene gives a mixture of exo [4+2] and [2+2] cycloadducts and the HOMO [2+2+2] cycloadduct, while the reaction of aldimines derived from nitroanilines with norbornadiene gives exo [4+2] and HOMO [2+2+2] cycloadducts and α-amino γ-lactones.

Full text of DOI:10.1002/ejoc.201100395

FULL PAPER
DOI: 10.1002/ejoc.201100395
Glyoxalate-Derived Aldimines in Cycloaddition Reactions with Olefins
Francisco Palacios,*[a] Concepción Alonso,[a] María Fuertes,[a] Jose M. Ezpeleta,[b] and
Gloria Rubiales[a]
Keywords: Cycloaddition / Nitrogen heterocycles / Strained molecules / Aldimines
The reaction of aldimine 1a, derived from ethyl glyoxalate,
with activated dienophiles, such as styrene and indene, gave
the tetrahydro-1,5-naphthyridine derivatives 3 with regio-
and stereoselective control of three stereocenters through a
[4+2] cycloaddition process via endo transition states. How-
ever, when aldimine 1a was used in the reaction with
strained olefins, such as norbornene or dicyclopentadiene,
the corresponding [4+2] and [2+2] cycloadducts were ob-
olefin, such as norbornadiene, increased the multifunctional
character of the olefin and a mixture of the corresponding
exo [4+2] 11a and exo [2+2] 12a cycloadducts, as well as the
corresponding HOMO cycloadduct 13a, was obtained. Reac-
tion between norbornadiene and aldimines derived from p-
nitro- and o,p-dinitroanilines and ethyl glyoxalate gave exo
[4+2] cycloadducts 11b,c, HOMO cycloadducts 13b,c and α-
amino γ-lactones 15b,c. A mechanistic explanation for the
tained, through exclusive exo π-facial stereoselective cyclo- formation of the new products is suggested.
addition. The addition of a second strained C=C bond in the
gested. The use of Lewis acids in these reactions minimizes
Introduction
competitive side reactions, thereby allowing good to excel-
lent yields and high regio- and diastereoselectivities in the
preparation of nitrogen-containing heterocycles.
Nitrogen-containing heterocycles are important com-
pounds widely employed in the fields of biochemistry, phar-
maceutics and materials science.[1] Consequently, reactions,
including hetero-Diels–Alder reactions of azadienes,[2] have
attracted special interest because of their utility in the syn-
thesis of nitrogen-containing heterocycles, both chemo- and
stereoselectively. In this context, the Povarov reaction[3,4]
represents an excellent method in which aldimines derived
from aromatic amines and aldehydes react with electron-
rich alkenes in the presence of a Lewis acid catalyst to give
1,2,3,4-tetrahydroquinoline derivatives. This process has
found applications in total synthesis, for example, in the
synthesis of (Ϯ)-martinelline, (Ϯ)-martinellic acid, luotonin
A and camptothecin.[5]
Herein, we describe our results when N-(3-pyridyl)-
aldimine derived from glyoxalate 1a reacts as a heterodiene
in aza-Diels–Alder reactions (ADAR) with simple and
strained olefins to obtain a new family of functionalized
polycyclic heterocyclic compounds derived from α-amino
esters, such as polycyclic 1,5-naphthyridine derivatives con-
taining a carboxy group in position 6. The presence of a
carboxylate group not only increases the reactivity of the
aldimine (heterodiene), but also opens a new entry to the
preparation of polycyclic heterocycles derived from α-
amino esters. Some methods has been described for the
preparation of polycyclic 1,5-naphthyridine compounds[12]
and they are present in the skeleton of a wide number of
biologically active derivatives.[13] In addition, the introduc-
tion of a carboxylate group in position 6 of an 1,5-naphth-
yridine ring system has an important application for brain
microdialysis studies due to the effect of these compounds
on dopamine and serotonine concentrations.[14] Further-
more, the use of strained olefins, such as norbornene or
norbornadiene, gives access to new polycyclic derivatives
containing four, five and six-membered heterocycles.
We have been involved in the chemistry of 1-[6] and 2-
azadienes,[7] as well as in the development of new methods
for the preparation of three-,[8] five-,[9] and six-membered[10]
nitrogen-containing heterocycles. Recently, we reported a
combined theoretical and experimental study[11] of a Pova-
rov-type cycloaddition reaction, in which a double Lewis
acid activated asynchronous concerted process was sug-
[a] Departamento de Química Orgánica I, Facultad de Farmacia
and Centro de Investigación y de Estudios Avanzados “Lucio
Lascaray” (Lascaray Research Hub), Universidad del País
Vasco,
Apartado 450, 01080 Vitoria, Spain
Results and Discussion
Fax: +34-945-013049
E-mail: francisco.palacios@.ehu.es
Reactions between ethyl glyoxalate derived 1a and dieno-
philes such as styrene (2a) and indene (2b) were performed
at room temperature in the presence of BF3·Et2O (1 equiv.)
and corresponding bi- and tetracyclic endo 1,2,3,4-tetra-
[b] Departamento de Física Aplicada, Facultad de Farmacia,
Universidad del País Vasco,
Apartado 450, 01080 Vitoria, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100395.
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Glyoxalate-Derived Aldimines in Cycloaddition Reactions
hydro-1,5-naphthyridines (3a,b) were selectively obtained excess of catalyst was needed to accelerate the reaction by
(Scheme 1 and Table 1, entries 1 and 2). Regioselective coordination of the catalyst BF3·Et2O with the imine nitro-
1,2,3,4-tetrahydro-1,7-naphthyridine (3Ј) formation was not gen atom.
observed in a similar way to that previously reported.[11]
The structures of compounds 3 were assigned on the ba-
The use of a slight excess of BF3·Et2O (1.2 equiv.) decreased sis of 1D and 2D NMR spectroscopy, including 1D
the reaction time required to carry out the process (see NOESY, HMQC and HMBC experiments, and mass spec-
1
Table 1, entries 1 and 2). These results may be explained trometric data. The H NMR spectrum of compound 3b
given that, when 1 equiv. of Lewis acid was used, it coordi- showed one doublet at δ = 4.66 ppm with a coupling con-
nated preferentially with the pyridine nitrogen atom and an stant of 3JHH = 8.8 Hz corresponding to the proton 11b-H,
one doublet at δ = 4.22 ppm with coupling constant of 3JHH
= 3.5 Hz corresponding to the proton 6-H, one multiplet at
δ = 3.68–3.63 ppm corresponding to the proton 6a-H, and
two double doublets at δ = 3.17 ppm (with coupling con-
3
2
stants of JHH = 9.9 and JHH = 15.5 Hz) and at δ =
3
2
2.90 ppm (with coupling constants of JHH = 8.4 and JHH
= 15.5 Hz) corresponding to the protons of the methylene
group. An HMBC study of compound 3b showed, among
others, two cross-signals between 11b-H and aromatic car-
bon atoms of pyridine and phenyl rings, which confirmed
the regiochemistry of the process. In the 1D NOESY spec-
trum of compound 3b, the selective saturation of the doub-
let at δ = 4.66 ppm (Figure 1) corresponding to proton 11b-
H afforded a positive NOESY with protons 6-H at δ =
4.22 ppm (1.69%) and 6a-H at δ = 3.68–3.63 ppm (3.53%).
This observation together with the coupling constants ob-
served in the 1H NMR spectrum of compound 3b is consis-
tent with the relative cis configuration of all these protons.
As far as we know, these compounds 3 represent the first
examples of bi- (3a) and tetracyclic (3b) 1,5-naphthyridines
derived from α-amino esters.
Scheme 1. Cycloaddition reactions of 1a with 2a,b in the presence
of BF3·Et2O.
Table 1. Experimental reaction conditions and compounds ob-
tained from the reactions of aldimines 1 with alkenes 2.
Figure 1. Relative configuration assigned by NOESY 1D of com-
pound 3b.
The formation of polycyclic compounds 3 could be ex-
plained by a [4+2] cycloaddition reaction of double-acti-
vated imine 1a with dienophiles 2a,b via endo cycloadducts
4 followed by prototropic tautomerization under the reac-
tion conditions (Scheme 1).
However, different behaviour was observed for 1a in cy-
cloaddition reactions with strained olefins. Thus, reaction
between 1a and norbornene (2c; Scheme 2, X–X = CH2–
CH2) was performed at room temperature in the presence
of 1.2 equiv. of BF3·Et2O and polycyclic compounds 6a and
8a were regioselectively obtained (Scheme 2, and Table 1,
entry 3).
The structure of exo compound 6a was assigned on the
basis of mass spectrometric data and 1D NMR spec-
troscopy, including 1D NOESY, which indicated the anti
configuration of hydrogen atoms of the 6 and 6a positions.
[a] In the presence of 1 equiv. of BF3·Et2O. [b] In the presence of
1.2 equiv. of BF3·Et2O. [c] Ͼ99% consumption of starting materials
and percentage of compounds observed (NMR spectroscopic
analysis of the crude reaction mixture). [d] Yield of isolated com-
pounds when 1.2 equiv. of BF3·Et2O were used. [e] In the presence
of 0.2 equiv. of BF3·Et2O. [f] Not isolated, only observed in the
crude reaction mixture. [g] Yield of isolated compounds when
0.2 equiv. of BF3·Et2O were used.
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FULL PAPER
explain not only the formation of [4+2] intermediate 5 to
give cycloadduct 6, but also the formation of a [2+2] inter-
mediate 7 to give the four-membered adduct 8 (Scheme 3).
This approximation of norbornene (2c) to heterodiene has
been suggested previously[4c] by an asynchronous concerted
pathway for the formation of [4+2] adducts, although in
this case, when aromatic aldimines were used, only the for-
mation of [4+2] cycloadducts was reported.
Scheme 2. Cycloaddition reactions of 1a with 2c,d in the presence
of BF3·Et2O.
The structure of new compound 8a was assigned on the
basis of 1D and 2D NMR spectroscopy, including 1D
NOESY, HMQC and HMBC experiments, and mass spec-
Scheme 3. Proposed mechanism pathways for the formation of ad-
ducts 6, and 8 from the reaction of 1a with 2c or 2d.
1
trometric data. The H NMR spectrum of compound 8a
showed four singlets at δ = 4.00, 3.62, 2.58 and 2.35 ppm
Many discussions have appeared concerning the mecha-
corresponding to the protons 4-H, 2-H, 1-H and 5-H, nism of ADAR, suggesting a concerted mechanism[4c] as
respectively, one doublet at δ = 2.18 ppm with a coupling well as a stepwise mechanism.[16] In fact, more than one
3
constant of JHH = 5.1 Hz corresponding to the proton 6- mechanism can be proposed for the formation of these
H, and signals for four aromatic protons corresponding to compounds. Thus, the exo-facial approximation of 2c (X–
the pyridine ring, indicating that this ring was not involved X = CH2–CH2) to 1a (Scheme 3, approach from 9) with
in the formation of this adduct.
Similarly, the reaction of α-imino ester 1a with dicyclo- bonds could lead to the [4+2] intermediate 5 and then the
pentadiene[15] 2d [Scheme 2, X–X = CH(CH2–CH=CH)- corresponding cycloadduct
(Scheme 3, pathway i),
CH] at room temperature in the presence of BF3·Et2O gave whereas the exo approximation with the formation of
a mixture of corresponding polycyclic compounds 6b and iminic–Cnorbornene and Niminic–Cnorbornene bonds could lead
the formation of Ciminic–Cnorbornene and Cpyridinic–Cnorbornene
6
C
8b (Scheme 2 and Table 1, entry 4). When 1.2 equiv. of to the [2+2] intermediate 7 and the heterocycle 8 (Scheme 3,
BF3·Et2O were used the reaction time decreased (Table 1, pathway ii). However, as observed previously, for the reac-
entry 4). It is noteworthy that no reports have been found tion between aryl imines and acyclic and cyclic 1,3-
for this kind of reactivity when aldimines were used. There- dienes,[16b] a stepwise reaction mechanism through ionic in-
fore, as far as we know, four-membered ring containing termediates 10 (Scheme 3, pathways iii and iv) cannot be
compounds 8 obtained by [2+2] cycloaddition reactions of discarded.
aldimines are described and obtained here for the first time
and new compounds 6 represent the first examples of tetra- Diels–Alder reagent, for example, norbornadiene (2e). It is
(6a) and pentacyclic (6b) ring-fused 1,5-naphthyridines. well known that 2e presents a second strained carbon–car-
The process was also extended to an “amphoteric”
The formation of obtained polycyclic compounds 6 and bon double bond and could behave as a “dienophile”, giv-
8 could be explained either by a concerted process or by a ing [4+2] cycloadducts, by acting as an olefin (2π–reagent)
stepwise mechanism. Based on the stereochemistry of iso- in [2+2] cycloaddition reactions or as a “diene”, giving the
lated compounds 6 and 8, a mechanism with exclusive exo- corresponding HOMO adduct.[17] In our case, aldimine 1a
π-facial stereoselectivity (Scheme 3, approach from 9) could reacted with 2e at room temperature in the presence of
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Glyoxalate-Derived Aldimines in Cycloaddition Reactions
Scheme 4. Cycloaddition reactions of 1a with 2e in the presence of BF3·Et2O.
1.2 equiv. of BF3·Et2O and a polyfunctional behaviour of
2e was observed to give a mixture of the corresponding exo
[4+2] cycloadduct 11a, the exo [2+2] cycloadduct 12a and
HOMO cycloadduct 13a (Scheme 4, Table 1, entry 5) after
quantitative conversion of starting materials, as observed
by NMR spectroscopic analysis (15/65/20 for compounds
11a, 12a and 13a, respectively).
The structures of compounds 11a and 12a were assigned
on the basis of 1D and 2D NMR spectroscopy and mass
spectrometric data and are consistent with previous adducts
Figure 2. Relative configuration assigned by the 1D NOESY spec-
trum of compound 13a.
6 and 8 reported before (see the Supporting Information
and Experimental Section). The 1H NMR spectrum of
compound 13a showed, among others, two doublets at δ =
2
1.62 and 1.75 ppm with coupling constants of JHH
=
11.0 Hz corresponding to the methylenic protons, one sing- could be explained, as in the case of 2c, by an exo stereose-
let at δ = 2.39 ppm corresponding to the proton 6-H, one lective [4+2] or [2+2] approach, respectively, between 1a
double doublet at δ = 2.63 ppm with coupling constants of and 2e (see Scheme 3, X–X = CH=CH, see above). On the
3JHH = 2.1 and 2.1 Hz corresponding to 1-H, one singlet at other hand, the formation of HOMO cycloadduct 13a
δ = 3.86 ppm corresponding to the proton 9-H and one could be explained by a [2+2+2] cycloaddition reaction, by
double doublet at δ = 4.12 ppm with coupling constants of means of homodienophilic endo-facial selective approach of
3JHH = 2.1 and 3JHH = 2.2 Hz corresponding to the proton 2e to the imine (see 14 in Scheme 4) with exo adduct forma-
7-H. An HMBC study of compound 13a showed, among tion.[19]
others, cross-signals between 9-H and 1–C, 9-H and 6–C,
Taking into account the behaviour observed, we thought
1-H and 7–C, 7-H and 1–C, which are in accordance with that aldimines derived from anilines with electron-with-
the proposed structure for compound 13a (see the Support- drawing groups and ethyl glyoxalate could also behave in
ing Information). In the 1D NOESY spectrum of com- the same way as those derived from pyridines. In this way,
pound 13a, the selective saturation singlet at δ = 3.86 ppm we studied the reaction between 2e and aldimines derived
corresponding to the proton 9-H (Figure 2) afforded a posi- from p-nitro and o,p-dinitroanilines and ethyl glyoxalate
tive NOESY with protons 1-H at δ = 2.63 ppm (1.24%) and 1b,c (Scheme 5). When aldimine 1b (R = H) reacted with
2-H at δ = 1.21–1.24 ppm (1.00%) and with two pyridinic 2e at room temperature in the presence of 0.2 equiv. of
protons at δ = 8.06 and 6.90 ppm. All of these observations BF3·Et2O, a mixture of exo [4+2] cycloadduct 11b and
are consistent with the relative configuration shown in Fig- HOMO cycloadduct 13b, as the major compound, was ob-
ure 2.
tained (Table 1, entry 6). Traces of lactone 15b were ob-
The stereoselectivity observed for cycloadducts 11a and served in the crude reaction mixture and [2+2] cycloadduct
12a is in accordance with our previous observation[18] when was not observed. On the other hand, when 1c (R = NO2)
1,2-diaza-1,3-butadiene reacted with a strained olefin, such was used, the formation of exo-[4+2] cycloadduct 11c,
as 2e, to give only the exo-tricyclic pyridazine derivative. HOMO cycloadduct 13c and α-amino-γ-lactone 15c was
The formation of the heterocyclic compounds 11a and 12a observed (Scheme 5 and Table 1, entry 7).
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F. Palacios, C. Alonso, M. Fuertes, J. M. Ezpeleta, G. Rubiales
FULL PAPER
this is the first mechanistic approximation reported for the
formation of these γ-lactones and the first example applied
to cyclic olefins.
Conclusions
The [4+2] cycloaddition reaction, via endo transition
states, of aldimine 1a derived from ethyl glyoxalate with 2a
and 2b gives tetrahydro-1,5-naphthyridine derivatives 3 with
regio- and stereoselective control of three stereocenters.
However, when aldimine 1a was used in the reaction with
strained olefins, such as 2c or 2d, both the corresponding
exo [4+2] and [2+2] cycloadducts were obtained through
exo-π-facial stereoselective addition. In a similar way, reac-
tion with an “amphoteric” norbornadiene gave a mixture
of corresponding exo [4+2] 11a, and [2+2] cycloadducts 12a
generated by exo-facial approach of the olefin to the imine,
and also the HOMO ([2+2+2]) cycloadduct 13a, the forma-
tion of which can be explained by endo-facial approach of
the olefin to the imine. The reaction between 2e and ald-
imines derived from p-nitro and o,p-dinitroanilines and
ethyl glyoxalate gave exo [4+2] cycloadducts 11, HOMO
cycloadducts 13 and α-amino-γ-lactones 15.
Scheme 5. Cycloaddition reactions of imines 1b,c with 2e in the
presence of BF3·Et2O.
Experimental Section
General: Solvents for extraction and chromatography were of tech-
nical grade. All solvents used in reactions were freshly distilled from
appropriate drying agents before use. All other reagents were dis-
tilled as necessary. All reactions were performed under dry nitro-
gen. TLC was performed on silica gel plates and visualization was
accomplished by UV light or KMnO4 staining. 1H, 13C, and 2D
NMR spectra were recorded with a Varian Unity Plus 300 and
Bruker Avance 400 spectrometer by using CDCl3. High-resolution
mass spectra were obtained by chemical ionization (CI) with an
Agilent Jet Stream spectrometer with a LC/Q-TOF (Micromass)
analyzer (serial number: US93620455). IR spectra were recorded
with a Nicolet iS10 spectrometer.
The structures of compounds 11b,c and 13b,c were as-
signed on the basis of NMR spectroscopic and mass spec-
trometric data. The structure of 15c was confirmed unam-
biguously by X-ray crystallography (Figure 3).
General Procedure for the Preparation of Imines 1: A solution of
the amine (2 mmol) and aldehyde (2 mmol) in CHCl3 (15 mL) with
molecular sieves was stirred at the appropriate temperature until
TLC indicated the disappearance of the starting materials. The mo-
lecular sieves were removed by filtration under dry nitrogen, and
the resulting solution was used without purification in subsequent
reactions because the reaction product was unstable during distil-
lation and/or chromatography.
Figure 3. ORTEP view of molecular structure of compound 15c.
Ellipsoids are drawn at the 50% probability level.
As previously discussed, the formation of HOMO cy-
cloadducts 13b,c could be explained by a [2+2+2] cycload-
dition reaction and the formation of compounds 11 can be
explained by an exo π-facial approach (see Scheme 5), af-
fording corresponding exo cycloadducts. Moreover, in our
case, an exo π-facial approach in a stepwise mechanism in-
volving a Bürgi–Dunitz approach[20] (Scheme 5, approach
from 16) with 2e orientated to the less hindered side of 1,
may lead to ionic intermediates 17 favoured by the electron-
withdrawing effect of the nitro group and could explain the
formation of lactones 15. Although one example of γ-lac-
Ethyl 2-(Pyridine-3-ylimino)acetate (1a): 3-Aminopiridine (2 mmol,
0.19 g) and ethyl glyoxalate stabilized in toluene (2 mmol, 0.41 mL)
were stirred at room temperature for 24 h. 1H NMR
3
(400 MHz,CDCl3) of crude reaction mixture: δ = 1.28 (t, JHH
=
3
3
2
7.1, JHH = 7.2 Hz, 3 H), 4.25 (dq, JHH = 7.2, JHH = 1.1 Hz, 2
H), 5.14 (s, 1 H), 7.05 (m, 2 H) 8.03 (dd, 3JHH = 4.4, 4JHH = 1.5 Hz,
1 H), 8.12 (d, JHH = 2.5 Hz, 1 H) ppm. 13C NMR (100 MHz,
4
CDCl3) of crude reaction mixture: δ = 15.0, 62.1, 81.5, 120.4, 123.7,
137.0, 140.6, 140.8, 168.5 ppm.
Ethyl 2-(4-Nitrophenylimino)acetate (1b): 4-Nitroaniline (2 mmol,
tones from imines and acyclic olefins has been described,[21] 0.28 g) and ethyl glyoxalate stabilized in toluene (2 mmol, 0.41 mL)
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Glyoxalate-Derived Aldimines in Cycloaddition Reactions
were stirred at reflux for 24 h. 1H NMR (400 MHz,CDCl3) of
CDCl3): δ = 14.3, 21.0, 32.1, 42.5, 48.6, 61.5, 121.8, 124.3, 126.5,
crude reaction mixture: δ = 1.28–1.33 (m, 3 H), 4.25–4.32 (m, 2
126.6, 127.2, 139.6, 140.4, 141.9, 144.1, 144.9, 171.3 ppm. IR: ν
˜
max
3
4
H), 6.74 (dd, JHH = 7.0, JHH = 2.0 Hz, 2 H), 7.20 (s, 1 H), 8.07
= 3259.10, 3069.13, 2974.14, 1710.82, 1223.22 cm–1. HRMS (CI):
calcd. for C18H18N2O2 [M]+ 294.1368; found 294.1376.
3
4
(dd, JHH = 7.0, JHH = 2.0 Hz, 2 H) ppm.
Ethyl 2-(2,4-Dinitrophenylimino)acetate (1c): 2,4-Dinitroaniline
(2 mmol, 0.37 g) and ethyl glyoxalate stabilized in toluene (2 mmol,
0.41 mL) were stirred at reflux for 24 h. 1H NMR
(400 MHz,CDCl3) of crude reaction mixture: δ = 1.31–1.35 (m, 3
H), 4.31–4.33 (m, 2 H), 6.83 (d, 3JHH = 9.2 Hz, 1 H), 8.15 (d, 3JHH
= 9.2 Hz, 1 H), 9.05 (s, 1 H) ppm.
Ethyl 5,6,6a,7,8,9,10,10a-Octahydro-7,10-methylenebenzo[c][1,5]-
naphthyridine-6-carboxylate (6a) and Ethyl 3-(pyridin-3-yl)-3-aza-
tricyclo[4.2.1.02,5]nonane-4-carboxylate (8a): The general procedure
was carried out by using freshly distilled norbornene (2c; 2 mmol,
0.19 g), imine 1a and BF3·Et2O (2.4 mmol, 0.43 mL). The mixture
was stirred at room temperature for 12 h (99% consumption of
the starting materials by NMR spectroscopic analysis of the crude
reaction mixture). Compounds 6a and 8a were observed as a mix-
ture 3:1. Purification by flash column chromatography on silica gel
using a gradient elution of 30 to 50% ethyl acetate in hexane af-
forded 6a (0.30 g, 55%) and 8a (0.08 g, 15%) as yellow oils.
General Procedure for the Reaction between Aldimines 1 and Olefins
2: Olefin 2 (2 mmol) and BF3·Et2O were added to a solution of the
previously prepared aldimine 1 (2 mmol) in CHCl3 (15 mL). The
mixture was stirred at the appropriate temperature until TLC and
1H NMR spectroscopy indicated the disappearance of 1. The reac-
tion mixture was diluted with dichloromethane (20 mL), washed
with a 2 m aqueous solution of NaOH (20 mL) and water (20 mL),
extracted with dichloromethane (2ϫ20 mL) and dried (MgSO4).
Removal of the solvent under vacuum afforded an oil that was
purified by silica gel flash column chromatography (eluent: hexane/
AcOEt) to afford the product 3.
6a: Rf = 0.50 (50:50 hexane/EtOAc). 1H NMR (400 MHz, CDCl3):
2
δ = 0.96 (d, JHH = 10.1 Hz, 1 H), 1.11–1.60 (m, 6 H), 2.28 (d,
3
3JHH = 2.3 Hz, 1 H), 2.36–2.44 (m, 1 H), 2.67 (d, JHH = 3.8 Hz,
3
3
1 H), 2.74 (d, JHH = 9.0 Hz, 1 H), 3.55 (d, JHH = 5.6 Hz 1 H),
6.80–6.85 (m, 2 H), 7.93 (dd, 3JHH = 4.1, 4JHH = 2.1 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.9, 28.5, 29.9, 34.0, 42.7, 44.4,
45.8, 45.9, 57.4, 61.0, 121.2, 122.0, 139.5, 140.8, 147.2, 172.6 ppm.
Ethyl 4-Phenyl-1,2,3,4-tetrahydro-1,5-naphthyridine-2-carboxylate
(3a): The general procedure was carried out by using freshly dis-
tilled styrene (2a; 2 mmol, 0.21 mL) and imine 1a. When 2 mmol
(0.36 mL) of BF3·Et2O was used, the mixture was stirred at room
temperature for 24 h (99% consumption of the starting materials
by NMR spectroscopic analysis of the crude reaction mixture).
When 2.4 mmol (0.43 mL) of BF3·Et2O was used, the mixture was
stirred at room temperature for 5 h (99% consumption of the start-
ing materials by NMR spectroscopic analysis of the crude reaction
mixture). Purification by flash column chromatography on silica
gel using a gradient elution of 30 to 50% ethyl acetate in hexane
afforded 3a as an orange oil (0.34 g, 60%). Rf = 0.35 (50:50 hexane/
EtOAc). 1H NMR (400 MHz, CDCl3): δ = 1.08–1.13 (m, 3 H), 2.23
(ddd, 2JHH = 13.3, 3JHH = 9.8, 3JHH = 6.3 Hz, 1 H), 2.6 (ddd, 2JHH
IR: ν
= 3321.41, 2925.53, 2854.08, 1735.58, 1457.10 cm–1.
˜
max
HRMS (CI): calcd. for C16H20N2O2 [M]+ 272.1525; found
272.1531.
8a: Rf = 0.24 (50:50 hexane/EtOAc). 1H NMR (400 MHz, CDCl3):
δ = 1.10–1.65 (m, 6 H), 2.20 (d, 3JHH = 5.1 Hz, 1 H), 2.35 (s, 1 H),
2.58 (s, 1 H), 3.62 (s, 1 H), 4.00 (s, 1 H), 4.13–4.25 (m, 2 H), 6.76–
6.80 (m, 1 H), 7.02–7.07 (m, 1 H), 7.92–7.97 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2, 19.8, 31.0, 31.7, 39.3, 43.6, 51.7,
60.8, 61.3, 63.5, 121.1, 123.5, 137.0, 139.4, 142.5, 172.7 ppm. IR:
ν
= 2956.37, 2872.72, 1744.06, 1583.49, 1487.65 cm–1. HRMS
˜
max
(CI): calcd. for C16H20N2O2 [M]+ 272.1525; found 272.1532.
Ethyl 6,6a,7,7a,8,10a,11,11a-Octahydro-7,11-methylene-5H-indeno-
[5,6-c][1,5]naphthyridine-6-carboxylate (6ba and 6bb) and Ethyl
1-(Pyridine-3-yl)-2,2a,3,3a,4,6a,7,7a-octahydro-3,7-methylene-1H-
indeno[5,6-b]azete-2-carboxylate (8ba and 8bb): The general pro-
cedure was carried out by using dicyclopentadiene (2d; 2 mmol,
0.27 mL) and imine 1a. When 2 mmol (0.36 mL) of BF3·Et2O was
used, the mixture was stirred at room temperature for 48 h (99%
consumption of the starting materials by NMR spectroscopic
analysis of the crude reaction mixture). When 2.4 mmol (0.43 mL)
of BF3·Et2O was used, the mixture was stirred at room temperature
for 21 h (99% consumption of the starting materials by NMR spec-
troscopic analysis of the crude reaction mixture). Purification by
flash column chromatography on silica gel using a gradient elution
of 30–50% ethyl acetate in hexane afforded 6b as a black oil (0.40 g,
65%) as a diastereomeric mixture 50:50 of compounds 6b (a and
b) and 8b as a black oil (0.09 g, 14%) as a diastereomeric mixture
50:50 of compounds 8b (a and b).
3
3
= 13.2, JHH = 9.5, JHH = 3.6 Hz, 1 H), 3.85–4.00 (m, 2 H), 4.1
3
3
3
3
(dd, JHH = 9.4, JHH = 6.0 Hz, 1 H), 4.3 (dd, JHH = 9.8, JHH
3.9 Hz, 1 H), 4.4 (s, NH), 6.8 (dd, JHH = 8.0, JHH = 2.0 Hz, 1
=
3
3
3
3
H), 6.9 (dd, JHH = 8.1, JHH = 4.2 Hz, 1 H), 7.04–7.25 (m, 10 H,
Har), 7.85 (d, JHH = 4.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
3
CDCl3): δ = 13.9, 34.7, 45.7, 53.0, 61.4, 121.3, 122.4, 126.4, 128.4,
128.6, 139.3, 139.8, 143.5, 143.8, 172.2 ppm. IR: ν
= 3376.25,
˜
max
2974.14, 2926.65, 1726.65, 1457.52, 1254.88 cm–1. HRMS (CI):
calcd. for C17H18N2O2 [M]+ 282.1368; found 282.1370.
Ethyl 6,6a,7,11b-Tetrahydro-5H-indeno[2,1-c][1,5]naphthyridine-6-
carboxylate (3b): The general procedure was carried out by using
freshly distilled indene (2b; 2 mmol, 0.24 mL) and imine 1a. When
2 mmol (0.36 mL) of BF3·Et2O were used, the mixture was stirred
at room temperature for 4 h (99% consumption of the starting ma-
terials by NMR spectroscopic analysis of the crude reaction mix-
ture). When 2.4 mmol (0.43 mL) of BF3·Et2O were used, the mix-
ture was stirred at room temperature for 3 h (99% consumption of
the starting materials by NMR spectroscopic analysis of the crude
reaction mixture). Purification by flash column chromatography on
silica gel using a gradient elution of 30 to 50% ethyl acetate in
hexane afforded 3b as an orange solid (0.40 g, 68%); m.p. 131.4–
6b: Rf = 0.43 (50:50 hexane/EtOAc). 1H NMR (400 MHz, CDCl3):
2
δ = 1.10–1.20 (m, 6 H, for a and b), 1.22 (d, JHH = 10.0 Hz, 1 H,
2
2
a), 1.27 (d, JHH = 10.5 Hz, 1 H, b), 1.53 (d, JHH = 10.8 Hz, 1 H,
2
3
a), 1.65 (d, JHH = 10.4 Hz, 1 H, b), 2.20 (d, JHH = 4.5 Hz, 1 H,
a), 2.23–2.32 (m, 4 H, a and b), 2.33–2.38 (m, 1 H, b), 2.39–2.61
132.2 °C. 1H NMR (400 MHz, CDCl3): δ = 1.31–1.35 (m, 3 H), (m, 4 H, a and b), 2.61–2.69 (m, 1 H, b), 2.75 (d, JHH = 9.0 Hz,
3
2
3
2
3
2.90 (dd, JHH = 15.5, JHH = 8.4 Hz, 1 H), 3.17 (dd, JHH = 15.5,
1 H, a), 2.74–2.78 (m, 1 H, b), 2.90 (d, JHH = 3.9 Hz, 1 H, b),
3JHH = 9.9 Hz, 1 H), 3.63–3.68 (m, 1 H), 4.22 (d, JHH = 3.5 Hz, 3.06–3.15 (m, 2 H, a and b), 3.39–3.43 (m, 2 H, a and b), 4.00–4.15
1 H), 4.24–4.40 (m, 3 H), 4.66 (d, JHH = 8.8 Hz, 1 H), 6.84–6.92
3
3
(m, 4 H, a and b), 5.50–5.55 (m, 1 H, b), 5.60–5.70 (m, 1 H for b,
3
(m, 2 H), 7.15–7.21 (m, 3 H), 7.75 (d, JHH = 7.8 Hz, 1 H), 8.02 2 H for a), 6.73–6.82 (m, 4H a and b), 7.92–7.96 (m, 2 H a and b)
(dd, JHH = 4.1, JHH = 2.0 Hz, 1 H) ppm. 13C NMR (75 MHz,
ppm. 13C NMR (75 MHz, CDCl3) for 6b (a): δ = 14.1, 32.2, 37.0,
3
4
Eur. J. Org. Chem. 2011, 4318–4326
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4323

F. Palacios, C. Alonso, M. Fuertes, J. M. Ezpeleta, G. Rubiales
FULL PAPER
38.2, 41.2, 42.6, 47.4, 47.4, 52.6, 57.9, 61.2, 121.3, 122.2, 131.0,
132.5, 139.4, 141.4, 148.2, 172.7 ppm. 13C NMR (75 MHz, CDCl3):
for 6b (b): δ = 14.0, 32.3, 37.1, 38.6, 41.7, 42.2, 45.4, 48.2, 53.3,
2
1.41 (m, 1 H) 1.49–1.53 (m, 1 H), 1.62 (d, JHH = 11.0 Hz, 1 H),
2
3
1.75 (d, JHH = 11.0 Hz, 1 H), 2.39 (s, 1 H), 2.63 (dd, JHH = 2.1,
3JHH = 2.1 Hz, 1 H), 3.86 (s, 1 H), 4.12 (dd, JHH = 2.1, JHH
57.2, 61.2, 121.3, 122.1, 131.5, 132.0, 139.6, 141.2, 147.8, 2.2 Hz, 1 H), 4.20–4.28 (m, 2 H), 6.90 (ddd, JHH = 8.5, JHH
=
=
3
3
3
4
4
3
3
172.6 ppm. IR: νmax = 3255.94, 2951.98, 1745.65, 1584.17, 1492.35,
3.0, JHH = 1.3 Hz, 1 H), 7.11 (dd, JHH = 8.4, JHH = 4.6 Hz, 1
˜
3
4
4
1337.20 cm–1. HRMS (CI): calcd. for C19H22N2O2 [M]+ 310.1681;
found 310.1684.
H), 8.00 (dd, JHH = 4.6, JHH = 1.0 Hz, 1 H), 8.06 (d, JHH =
3.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.6, 14.1,
14.7, 14.9, 29.6, 38.8, 47.9, 61.1, 63.2, 65.6, 119.6, 123.4, 135.7,
8b: Rf = 0.09 (50:50 hexane/EtOAc). 1H NMR (400 MHz, CDCl3):
δ = 1.21–1.33 (m, 10 H, a and b), 1.97–2.97 (m, 14 H, a and b),
4.05–4.09 (m, 2 H, a and b), 4.13–4.30 (m, 4 H, a and b), 5.40–5.43
(m, 1 H for a), 5.54–5.59 (m, 1 H for b), 5.69–5.71 (m, 1 H for b),
5.72–5.75 (m, 1 H for a), 6.80–6.84 (m, 2 H a and b), 7.08–7.12 (m,
2 H, a and b), 7.94–7.95 (m, 2 H, a and b), 7.98–8.00 (m, 2 H, a
and b) ppm. 13C NMR (75 MHz, CDCl3) for 8b (a) 14.20, 32.50,
35.18, 39.18, 41.82, 47.84, 52.05, 58.28, 59.44, 61.39, 63.04, 121.50,
123.70, 130.46, 131.91, 132.41, 132.56, 132.77, 172.74 ppm. 13C
NMR (75 MHz, CDCl3) ppm: for 8b (b): δ = 14.20, 32.83, 38.08,
44.82, 46.95, 47.04, 47.15, 50.00, 59.32, 61.43, 63.06, 121.45,
123.70, 131.91, 132.41, 136.38, 138.84, 142.68, 172.63 ppm. IR:
138.7, 144.4 172.3 ppm. IR: ν
= 2983.35, 2871.39, 1740.03,
˜
max
1583.88 cm–1. HRMS (CI): calcd. for C16H18N2O2 [M]+ 270.1368;
found 270.1371.
Ethyl 7,10-Methylene-2-nitro-5,6,6a,7,10,10a-hexahydrophen-
anthridine-6-carboxylate (11b), Ethyl 8-(4-Nitrophenyl)-8-azatetra-
cyclo[4.3.0.02,4.03,7]nonane-9-carboxylate (13b) and 4,7-Methylene-
3-(4-nitrophenylamino)-3a,4,7,7a-tetrahydrobenzofuran-2(3H)-one
(15b): The general procedure was carried out by using freshly dis-
tilled norbornadiene (2e; 2 mmol, 0.20 mL), imine 1d and
BF3·Et2O (0.4 mmol, 0.07 mL) at room temperature for 48 h (99%
consumption of the starting materials by NMR spectroscopic
analysis of the crude reaction mixture). Compounds 11b, 13b and
15b were observed as a 3:6:1 mixture. Purification by flash column
chromatography on silica gel using a gradient elution of 10 to 50%
ethyl acetate in hexane afforded 11b (0.11 g, 17%) as a brown oil
and 13b (0.28 g, 45%) as a yellow oil. Compound 15b was not
isolated because it was unstable during distillation and/or
chromatography.
ν
= 2939.62, 1743.03, 1583.14, 1487.92, 1184.45, 706.81 cm–1.
˜
max
HRMS (CI): calcd. for C19H22N2O2 [M]+ 310.1681; found
310.1685.
Ethyl 5,6,6a,7,8,9,10,10a-Octahydro-7,10-methylenebenzo[c][1,5]-
naphthyridine-6-carboxylate (11a), Ethyl 3-(Pyridin-3-yl)-3-aza-
tricyclo[4.2.1.02,5]non-7-ene-4-carboxylate (12a) and Ethyl 8-(Pyr-
idin-3-yl)-8-azatetracyclo[4.3.0.02,4.03,7]nonane-9-carboxylate (13a):
The general procedure was carried out as described in the main
text by using freshly distilled norbornadiene (2e; 2 mmol, 0.20 mL),
imine 1a and BF3·Et2O (2.4 mmol, 0.43 mL) at room temperature
for 5 h (99% consumption of the starting materials by NMR spec-
troscopic analysis of the crude reaction mixture). Compounds 11a,
12a and 13a were observed as a 1:3:1 mixture. Purification by flash
column chromatography on silica gel using a gradient elution of 20
to 50% ethyl acetate in hexane afforded 11a (0.07 g, 12%) as a
brown oil, 12a (0.33 g, 54%) as a brown oil and 13a (0.10 g, 16%)
as a black oil.
11b: Rf = 0.68 (50:50 hexane/EtOAc). 1H NMR (400 MHz,
3
2
CDCl3): δ = 1.18 (t, JHH = 7.2 Hz, 3 H), 1.25 (d, JHH = 9.0 Hz,
2
3
3
1 H), 1.53 (d, JHH = 9.0 Hz, 1 H), 2.25 (dd, JHH = 7.2, JHH
7.0 Hz, 1 H), 2.56 (d, JHH = 8.7 Hz, 1 H), 2.91 (s, 1 H), 2.96 (s, 1
H), 3.69 (d, JHH = 7.2, JHH = 5.5 Hz, 1 H), 4.11 (q, JHH
=
3
3
3
3
=
3
7.2 Hz, 2 H), 4.79 (s, NH), 6.24 (s, 2 H), 6.60 (d, JHH = 8.9 Hz, 1
H), 7.83 (d, JHH = 8.9 Hz, 1 H), 8.03 (s, 1 H) ppm. 13C NMR
3
(75 MHz, CDCl3): δ = 14.1, 38.3, 41.8, 43.6, 48.2, 51.7, 58.7, 61.7,
114.64, 123.16, 125.35, 126.58, 137.27, 138.1, 139.9, 150.7,
172.2 ppm. IR:
ν
= 3363.59, 2967.81, 1723.48, 1593.67,
˜
max
1311.87 cm–1. HRMS (CI): calcd. for C17H18N2O4 [M]+ 314.1267;
found 314.1271.
11a: Rf = 0.38 (50:50 hexane/EtOAc). 1H NMR (400 MHz,
CDCl3): δ = 1.24–1.30 (m, 3 H), 1.31 (d, 2JHH = 9.0 Hz, 1 H), 1.62
2
3
3
(d, JHH = 9.0 Hz, 1 H), 2.40 (dd, JHH = 7.2, JHH = 7.8 Hz, 1
13b: Rf = 0.75 (50:50 hexane/EtOAc). 1H NMR (400 MHz,
CDCl3): δ = 1.19–1.27 (m, 4 H), 1.38–1.42 (m, 1 H), 1.44–1.49 (m,
1 H), 1.60 (d, 2JHH = 11.3 Hz, 1 H), 1.70 (d, 2JHH = 11.4 Hz, 1 H),
3
H), 2.68 (d, JHH = 9.0 Hz, 1 H), 3.00 (s, 1 H), 3.40 (s, 1 H), 3.69
3
3
(dd, JHH = 6.0, JHH = 1.6 Hz, 1 H), 4.11 (s, NH), 4.17–4.22 (m,
2 H), 6.30–6.35 (m, 2 H), 6.95–6.96 (m, 2 H), 8.07 (dd, 3JHH = 6.2,
4JHH = 2.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1,
41.3, 42.5, 43.6, 48.0, 49.8, 59.2, 61.4, 121.4, 121.8, 137.6, 138.0,
3
3
2.36 (s, 1 H), 2.61 (dd, JHH = 2.1, JHH = 2.1 Hz, 1 H), 3.96 (s, 1
3
H), 4.16 (s, 1 H), 4.18–4.22 (m, 2 H), 6.45 (d, JHH = 9.3 Hz, 2 H),
8.03 (d, JHH = 9.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
3
140.6, 140.6, 148.0, 172.8 ppm. IR: ν
= 3354.09, 2970.98,
˜
max
= 14.5, 15.1, 15.4, 30.2, 39.1, 48.5, 61.8, 64.2, 65.4, 111.9, 126.4,
1729.82, 1584.17 cm–1. HRMS (CI): calcd. for C16H18N2O2 [M]+
138.4, 153.0, 171.7 ppm. IR: ν
= 2977.46, 1740.03, 1595.67,
˜
max
270.13683; found 270.13627.
1318.72 cm–1. HRMS (CI): calcd. for C17H18N2O4 [M]+ 314.1267;
12a: Rf = 0.28 (50:50 hexane/EtOAc). 1H NMR (400 MHz,
CDCl3): δ = 1.24–1.31 (m, 3 H), 1.45–1.54 (m, 2 H), 2.53 (dd, 3JHH
found 314.1273.
Ethyl 7,10-Methylene-2,4-dinitro-5,6,6a,7,10,10a-hexahydrophen-
anthridine-6-carboxylate (11c), Ethyl 8-(2,4-Dinitrophenyl)-8-aza-
tetracyclo[4.3.0.02,4.03,7]nonane-9-carboxylate (13c) and 3-(2,4-Di-
nitrophenylamino)-4,7-methylene-3a,4,7,7a-tetrahydrobenzofuran-
2(3H)-one (15c): The general procedure was carried out by using
freshly distilled norbornadiene (2e; 2 mmol, 0.20 mL), imine 1e and
BF3·Et2O (0.4 mmol, 0.07 mL) at reflux for 48 h (99% consump-
tion of the starting materials by NMR spectroscopic analysis of
the crude reaction mixture). Compounds 11c, 13c and 15c were
3
= 4.6, JHH = 3.5 Hz, 1 H), 3.00 (s, 1 H), 3.39 (s, 1 H), 4.05 (d,
3
3JHH = 3.2 Hz, 1 H), 4.12 (d, JHH = 5.6 Hz, 1 H), 4.22–4.28 (m,
3
3
3
2 H), 6.02 (dd, JHH = 5.7, JHH = 3.2 Hz, 1 H), 6.21 (dd, JHH
=
3
3
3
5.7, JHH = 3.0 Hz, 1 H), 6.87 (dd, JHH = 8.3, JHH = 2.7 Hz, 1
3
3
3
H), 7.19 (dd, JHH = 8.4, JHH = 4.8 Hz, 1 H), 7.96 (d, JHH
=
2.7 Hz, 1 H), 8.00 (d, JHH = 4.8 Hz, 1 H) ppm. 13C NMR
3
(75 MHz, CDCl3): δ = 14.2, 39.2, 40.4, 42.6, 42.8, 61.2, 61.5, 64.2,
118.8, 124.0, 132.0, 136.5, 137.9, 142.1, 171.4 ppm. IR: ν
=
˜
max
2986.81, 1723.48, 1590.50, 1489.18, 1185.22 cm–1. HRMS (CI):
calcd. for C16H18N2O2 [M]+ 270.1368; found 270.1368.
observed as
a 1:2:1 mixture. Purification by flash column
chromatography on silica gel using a gradient elution of 10 to 50%
13a: Rf = 0.16 (50:50 hexane/EtOAc). 1H NMR (400 MHz, ethyl acetate in hexane afforded 11c (0.11 g, 15%), 13c (0.32 g,
3
CDCl3): δ = 1.21–1.25 (m, 1 H)1.32 (t, JHH = 7.1 Hz, 3 H), 1.38– 45%) and 15c (0.12 g, 18%) as yellow solids.
4324
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4318–4326

Glyoxalate-Derived Aldimines in Cycloaddition Reactions
1
2000, 287, 1964–1969; d) S. J. Teague, A. M. Davis, P. D. Lee-
son, T. Oprea, Angew. Chem. Int. Ed. 1999, 38, 3743–3748; e)
R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown,
T. A. Keating, Acc. Chem. Res. 1996, 29, 123–131.
For recent contributions on azadienes, see: a) M. Presset, Y.
Coquerel, J. Rodriguez, Org. Lett. 2010, 12, 4212–4215; b) K.
Nagaiah, A. Venkatesham, R. R. Srinivasa, V. Saddanapu, J. S.
Yadav, S. J. Basha, A. V. S. Sarma, B. Sridhar, A. Addlagatta,
Bioorg. Med. Chem. Lett. 2010, 20, 3259–3264; c) J. E. Mullins,
J. L. G. Etoga, M. Gajewski, J. I. DeGraw, C. M. Thompson,
M. Charles, Tetrahedron Lett. 2009, 50, 2298–2300; d) B. Gro-
enendaal, E. Ruijter, R. V. A. Orru, Chem. Commun. 2008,
5474–5489; e) K. G. R. Masschelein, C. V. Stevens, Tetrahedron
Lett. 2008, 49, 4336–4338.
For review see: a) P. J. Tambade, Y. P. Patil, B. M. Bhanage,
Curr. Org. Chem. 2009, 13, 1805–1819; b) V. V. Kouznetsov,
Tetrahedron 2009, 65, 2721–2750; c) L. S. Povarov, Russ. Chem.
Rev. 1967, 36, 656–670.
For recent contributions, see: a) H. Xu, S. J. Zuend, Y. Woll,
M. G. Tao, E. N. Jacobsen, Science 2010, 327, 986–990; b) K.
De, J. Legros, B. Crousse, S. Chandrasekaran, D. Bonnet-
Delpon, Org. Biomol. Chem. 2010, 9, 347–350; c) C. D. Smith,
J. I. Gavrilyuk, A. J. Lough, R. A. Batey, J. Org. Chem. 2010,
75, 702–715.
11c: M.p. 162.7–163.8 °C. H NMR (400 MHz, CDCl3): δ = 1.23
2
3
3
(d, JHH = 9.3 Hz, 1 H), 1.35 (t, JHH = 7.2, JHH = 7.1 Hz, 3 H),
1.48 (d, JHH = 9.4 Hz, 1 H), 2.51–2.54 (m, 1 H), 2.60 (d, JHH
2
3
=
3
1.1 Hz 1 H), 2.73 (s, 1 H), 3.02 (d, JHH = 8.9 Hz, 1 H), 4.23 (d,
[2]
3JHH = 5.4 Hz, 1 H), 4.30–4.41 (m, 2 H), 6.28 (dd, JHH = 5.6,
3
3JHH = 2.9 Hz, 1 H), 6.33 (dd, JHH = 5.6, JHH = 3.1 Hz, 1 H),
3
3
8.17 (d, 4JHH = 1.7 Hz, 1 H), 8.67 (s, NH), 8.92 (d, JHH = 2.7 Hz,
4
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.5, 40.6, 42.8, 44.3,
45.3, 56.1, 56.8, 62.5, 121.5, 129.6, 132.1, 132.6, 137.4, 137.9, 140.6,
147.2, 169.9 ppm. IR: ν
= 3366.36, 2977.46, 1742.98, 1619.24,
˜
max
1589.77, 1333.45 cm–1. HRMS (CI): calcd. for C17H17N3O6 [M]+
359.1117; found 359.1123.
1
[3]
[4]
13c: M.p. 159.5–160.7 °C. H NMR (400 MHz, CDCl3): δ = 1.13–
3
3
1.68 (m, 7 H), 2.36 (s, 1 H), 2.58 (dd, JHH = 2.1, JHH = 2.1 Hz,
1 H), 3.92 (dd, JHH = 2.3, JHH = 2.3 Hz, 1 H), 4.11–4.20 (m, 3
3
3
3
3
4
H), 6.63 (d, JHH = 9.5 Hz, 1 H), 8.05 (dd, JHH = 9.5, JHH
=
2.7 Hz, 1 H), 8.40 (d, JHH = 2.7 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1, 14.6, 15.3, 15.9, 29.5, 38.6, 47.5, 61.9,
65.9, 66.8, 116.3, 123.2, 127.2, 135.5, 136.0, 144.6, 170.0 ppm. IR:
4
ν
= 2974.51, 1740.03, 1607.45, 1527.90, 1321.67 cm–1. HRMS
˜
max
(CI): calcd. for C17H17N3O6 [M]+ 359.1117; found 359.1123.
[5]
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Zinder, J. Org. Chem. 2004, 69, 7171–7182; b) H. Rapoport,
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1
15c: M.p. 197.8–198.9 °C. H NMR (400 MHz, CDCl3): δ = 1.56
2
2
(d, JHH = 10.3 Hz, 1 H), 1.88 (d, JHH = 10.4 Hz, 1 H), 2.39–2.42
(m, 1 H), 3.08 (s, 1 H), 3.22 (s, 1 H), 4.18 (dd, JHH = 6.6, JHH
3
3
=
3
3
3.8 Hz, 1 H), 6.14 (dd, JHH = 5.8, JHH = 3.2 Hz, 1 H), 6.35 (dd,
3JHH = 5.8, JHH = 3.0 Hz, 1 H), 7.22 (d, JHH = 8.9 Hz, 1 H),
3
3
[6]
[7]
3
3
3
8.36 (dd, JHH = 9.3, JHH = 2.6 Hz, 1 H), 8.72 (d, JHH = 6.1 Hz,
1 H, NH), 9.16 (d, JHH = 2.6 H, 1 H) ppm. 13C NMR (75 MHz,
3
CDCl3): δ = 42.3, 45.7, 46.0, 46.6, 56.1, 82.7, 114.9, 123.9, 130.4,
131.5, 133.8, 137.6, 139.7, 147.0, 174.8 ppm. IR: ν
= 3342.98,
˜
max
2982.42, 1772.48, 1616.11, 1592.26, 1337.74 cm–1. HRMS (CI):
calcd. for C15H13N3O6 [M]+ 331.0804; found 331.0804.
CCDC-817516-contains the supplementary crystallographic
data for compound 15c. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H NMR and 13C NMR spectra of compounds 3a,
1
3b, 6a, 6b, 8a, 8b, 11a, 11b, 11c, 12a, 13a, 13b, 13c and 15c,
NOESY-1D experiments for compounds: 3b, 6a, 12a and 13a,
HMQC experiments for compounds: 3b, 6b, 8a, 12a, 13a and 13b.
HMBC experiments for compounds: 8a, 13a and 13b and TOCSY
experiment for compound 6b are available free of charge via the
internet.
[10]
Acknowledgments
Financial support from the Universidad del País Vasco/Euskal
Herriko Unibertsitatea (UPV/EHU) (grant number GIU 09/56),
GV/EJ (IT-422-10) and the Spanish Ministerio de Ciencia e Innov-
ación (MICINN) (Madrid DGI, grant number CTQ2009-12156) is
gratefully acknowledged. M. F. thanks UPV/EHU for a formation
contract. UPV/EHU-SGIker technical support (MICINN, GV/EJ,
European Social Fund) is also gratefully acknowledged.
[11]
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www.eurjoc.org
4325

F. Palacios, C. Alonso, M. Fuertes, J. M. Ezpeleta, G. Rubiales
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Received: March 22, 2011
Published Online: June 9, 2011
4326
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4318–4326