From furans to anilines: Toward one-pot two-step amination/Diels-Alder sequences

Article abstract of DOI:10.1021/jo7024916

(Chemical Equation Presented) Selective metal-free amination and Diels-Alder reactions are described in the furan series, leading to polysubstituted anilines or to stable oxabicyclic adducts in high yield. Interestingly, anilines are conveniently prepared through a novel one-pot, two-step amination/Diels-Alder procedure from commercially available 5-bromo-2-furaldehyde.

Full text of DOI:10.1021/jo7024916

From Furans to Anilines: Toward One-Pot Two-Step Amination/
Diels-Alder Sequences
Raouf Medimagh,† Sylvain Marque,*,† Damien Prim,*,† Saber Chatti,‡ and He´di Zarrouk‡
Institut LaVoisier de Versailles (ILV) UMR CNRS 8180, UniVersite´ de
Versailles-Saint-Quentin-en-YVelines, 45 AVenue des Etats-Unis, 78 035 Versailles, Cedex, France, and
Laboratoire de Chimie Verte, Institut National de Recherche et d’Analyse Physico-chimique (INRAP), Poˆle
Technologique de Sidi Thabet, 2020 Sidi Thabet, Tunisia
prim@chimie.uVsq.fr; sylVain.marque@chimie.uVsq.fr
ReceiVed NoVember 20, 2007
Selective metal-free amination and Diels-Alder reactions are described in the furan series, leading to
polysubstituted anilines or to stable oxabicyclic adducts in high yield. Interestingly, anilines are
conveniently prepared through a novel one-pot, two-step amination/Diels-Alder procedure from
commercially available 5-bromo-2-furaldehyde.
Introduction
its reactivity5 and extended the scope of this reaction. Indeed,
molecular orbital (MO) and FMO calculations concluded in an
increase of HOMO energy levels.2 For instance, a combination
of amino and ester groups led to a clear increase of HOMO
energy levels rising from -9.3 eV for furan to -8.8 eV for
5-aminofuran-2-carboxylate methyl ester. The latter break-
through has been elegantly examplified by Padwa and others
in the syntheses of complex polycyclic molecules or advanced
intermediates.2,6-15 Among the latter, 2-aminofurans revealed
especially useful partners in the preparation of cyclohexadienes
derivatives and polysubstituted anilines through bi-(inter)-
molecular processes. In this context, cycloadditions of substi-
tuted 2-amino furanes, bearing an additional NO2 or CN group,
The past decades have witnessed the versatility of furan
derivatives as building block in total synthesis of natural
products and pharmaceuticals.1,2 Among the most significant
examples in the furan chemistry, Diels-Alder cycloadditions
using this heterocycle as the 4π diene are of particular interest.
This pericyclic process is one of the most employed strategies
for the construction of six-membered rings. Although general
experimental conditions as temperature, solvent, concentration
of substrates obviously influence the reaction course, yields and
selectivities are strongly depending on the substitution pattern
of the furan ring. An overview of the recent literature clearly
sets suitable combinations of substituents at the furan heterocycle
and shows the structural diversity of transient or stable adducts
obtained through cycloadditions of furans. If furan itself is able
to undergo [4 + 2] cycloaddition reactions,1,3,4 it has been shown
that the introduction of both electron-donating groups and/or
electron-withdrawing groups at position 2 of the furan enhanced
(5) Potts, K. T.; Walsh, E. B. J. Org. Chem. 1988, 53, 1199-1202.
(6) Dean, F. AdV. Heterocycl. Chem. 1982, 31, 237-334.
(7) Jung, M. E.; Truc, V. C. Tetrahedron Lett. 1988, 29, 6059-6062.
(8) Schlessinger, R. H.; Bergstorm, C. P. J. Org. Chem. 1995, 60, 16-
17.
(9) Schlessinger, R. H.; Bergstorm, C. P. Tetrahedron Lett. 1996, 37,
2133-2136.
(10) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998, 63,
5304-5305.
† Universite´ de Versailles-Saint-Quentin-en-Yvelines.
‡ Institut National de Recherche et d’Analyse Physico-chimique (INRAP).
(1) Kappe, O. C.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179-14233.
(11) Padwa, A.; Kappe, O. C.; Reger, T. S. J. Org. Chem. 1996, 61,
4888-4889.
(12) Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J. Org. Chem.
1999, 64, 4617-4626.
(2) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem.
1997, 62, 4088-4096.
(13) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. J. Org.
Chem. 2003, 68, 2609-2617.
(3) Ouellette, R. J.; Rosenblum, A.; Booth, G. J. Org. Chem. 1968, 33,
4302-4303.
(14) Gustafsson, J.; Sterner, O. J. Org. Chem. 1994, 59, 3994-3997.
(15) Cochran, J. E.; Wu, T.; Padwa, A. Tetrahedron Lett. 1996, 37,
2903-2906.
(4) Kienzle, F. HelV. Chim. Acta 1975, 58, 1180-1183.
10.1021/jo7024916 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
J. Org. Chem. 2008, 73, 2191-2197
2191

Medimagh et al.
FIGURE 1. Direct access to anilines.
FIGURE 3. Shielding observed for H-3 and H-4 protons of 5-ami-
nofuranes.
FIGURE 2. Access to cyclohexadienes and anilines.
with various dienophiles allowed direct access to anilines with
good overall yields (Figure 1).2,16,17
Interestingly, 2-amino furanes, bearing mild electron-
withdrawing groups, selectively afforded cyclohexadiene deriva-
tives. In a further step and after Lewis acid treatment, the later
may transform into the corresponding anilines or phenols (Figure
2).15,18
FIGURE 4. From furan to aniline: one-pot, two-step access.
SCHEME 1. Amination of 5-Bromo-2-furaldehyded
These Diels-Alder reactions are assumed to proceed through
the formation of 7-oxabicyclo[2.2.1] adducts. However, such
intermediates are usually not observed. In most cases, rearo-
matization into the aniline derivatives spontaneously results from
either dehydration or a rearrangement of the cycloadduct, even
when using DMAD as the dienophile.
Although the Diels-Alder reaction starting from 2-amino
furanes offer competitive access to such anilines and/or key
intermediates, this strategy suffers from the lack of convenient
preparation methods to such reactive heterocycles. The prepara-
tion of 2-amino furanes is only scarcely reported and mainly
requires several steps such as dinitration of furane and subse-
quent displacement of one nitro group by an amine,2 preparation
of nitrofuroate followed by Pd-catalyzed reduction,15 interven-
tion by iron carbene complexes,16 or cyclopropenone ring
opening in the presence of carbonyl metals.17
a Amination was carried out in a mixture of dioxane:water 90:10.
b Amination was carried out with only 1.1 equiv of amine and 5 equiv of
NEt3. c By comparison with proton chemical shifts in 5-bromo-2-furaldehyde
(see Figure 3). d Reaction conditions: 2:1 equiv of amine and 3 equiv of
triethylamine were added to 5-bromofuran-2-carboxaldehyde refluxing in
water.
Recently, we reported on the metal-free amination of bro-
moheterocycles bearing carboxaldehydes, in aqueous medium.19-21
This procedure allowed the formation of aminoheterocycles,
including furanes, in high yields from commercially available
starting material. A typical example is depicted in Figure 3.
The 1H NMR spectra of compounds 1 and 2 are noteworthy
to observe the influence by the introduction of the amino
substituent on the chemical shifts of the residual protons of the
furan ring (Figure 3). Indeed, the proton H-3 and H-4 of 1
resonate at δ ) 7.17 and 6.54 ppm, respectively. In compound
2, they resonate at δ ) 7.08 and 5.22 ppm, respectively. No
significant shielding for H-3 was observed whereas the large
shielding ∆δ ) -1.32 observed for H-4 is in good agreement
with a decrease of the aromatic character and concomitant
increase of the diene character of 2-aminofurans. Thus, we
anticipated that this novel amine-carboxaldehyde combination
onto a furan ring would be effective as dienic partner in Diels-
Alder reactions and would afford new aniline derivatives. In
addition, we wondered if a one-pot, two-step amination/
cycloaddition sequence starting from bromofuraldehyde would
also allow the formation of anilines (Figure 4).
We report herein on the realization of this concept.
Results and Discussion
Amination Reaction. First, we prepared a new set of
aminofuraldehydes by metal-free amination in aqueous media.19
Secondary cyclic, acyclic and aromatic amines were tested and
the corresponding targets were isolated in good yields (Scheme
1). In general, the amination reactions were carried out in water
using 2 equiv of the reacting amine and an additional 3 equiv
of triethylamine.
(16) Semmelhack, M. F.; Park, J. Organometallics 1986, 5, 2550-2552.
(17) Chatani, N.; Hanafusa, T. J. Org. Chem. 1987, 52, 4408-4409.
(18) Boyd, G. V.; Heatherington, K. J. Chem. Soc., Perkin Trans. 1 1973,
2523-2531.
(19) Prim, D.; Kirsch, G. Tetrahedron 1999, 55, 6511-6526.
(20) Prim, D.; Kirsch, G.; Nicoud, J.-F. Synlett 1998, 383-384.
(21) Migianu, E.; Prim, D.; Kirsch, G. Synlett 2000, 459-462.
2192 J. Org. Chem., Vol. 73, No. 6, 2008

One-Pot Two-Step Amination/Diels-Alder Sequences
SCHEME 2. Selective Diels-Alder Reactions
TABLE 1. Optimization of the One-pot Processa
morpholine
(equiv)
NEt3
(equiv)
dienophile
(equiv)
time
(h)b
yield
(%)
entry
1
2
3
4
5
3
2
2
2
2
4
2
2
2
2
3
3
1
4
4
18
18
18
18
24
25
54
26
79
98
a Reaction conditions: 5-bromofuran-2-carboxaldehyde, morpholine,
NEt3 in refluxing 1,4-dioxane/water 9:1 during 4 h, then MgSO4 followed
by N-phenylmaleimide. b The indicated reaction time refers to the Diels-
Alder step.
Moving from N-phenylmaleimide and maleic anhydride to
DMAD led to unexpected products. In constrast to the literature
data we were able to isolate the oxabicycle 5a in 70% yield.
Moreover, the latter exhibit high stability, can be exposed to
air, and stored at room temperature without degradation.
Gratifyingly, four novel oxabicyclic structures 5a-d could be
isolated after cycloadditions using the parent amino furans 2a-d
under identical reaction conditions. Plausibly, the less marked
donor-attractor system (amine-carboxaldehyde) by comparison
with other combination described in the literature15 (involving
ester and nitro groups) may avoid the rearomatization process
and keep the oxabridge safe.
If the amination reaction afforded the morpholino- and
piperidino-furan in 79% and 80%, respectively, within 20 min,
6- and 10-h reaction courses were required to ensure completion
when using N-methylallylamine and N-methyl p-anisidine
(entries 3 and 4). In the latter cases, optimization of reaction
conditions and increase of additional base to 5 equiv had no
beneficial effect on isolated yields. In addition, attempts to use
organic solvents such as toluene or dioxane instead of water
led to a decrease of amination rates and are in full agreement
with previous data.19,20 However, the use of dioxane /water
mixture revealed beneficial in increasing the solubility of
reactants and decreasing amount of side products. Indeed, as
already established,19 the presence of water avoided the forma-
tion of an aminal intermediate and thus increased both amination
rates and yields.
It is worth noting that proton H-3 and H-4 in compounds
2a-d show similar characteristic chemical shifts (Scheme 1).
In all cases, introduction of the amino group only poorly affected
the chemical shifts of H-3 in aminofurans 2a-d. In contrast,
strong shielding ranging from -1.29 to -1.38 ppm were
observed for H-4, indicating a similar influence of the amino
substituent on the electronic distribution into the furan diene,
regardless of its cyclic, acyclic or aromatic structure.
Diels-Alder Reaction. Having various 5-aminofuraldehydes
in hand, we next examined their behavior in Diels-Alder
reactions. Cycloadditions were tested with three different
dienophiles: N-phenylmaleimide, maleic anhydride and dim-
ethylacetylene dicarboxylate (DMAD). To evaluate the dienic
potential of furans bearing an original donor-acceptor sub-
stituent combination (amine-aldehyde), morpholino furaldehyde
2a was chosen as the model compound. In a first set of reactions
furan 2a reacted with N-phenylmaleimide in water. Disappoint-
ingly, poor results or degradation byproducts have been
obtained. The same reaction with either N-phenylmaleimide or
maleic anhydride in toluene or dioxane at 70 °C afforded the
expected anilines in 70% and 30% yields, respectively (Scheme
2). Although these cycloadditions are assumed to proceed
through the oxabicycles 3, the latter were not observed.
Spontaneous ring opening followed by dehydration accounted
for rearomatization and formation of anilines 4a and 4b. The
modest yield obtained in case of 4a, was partly attributed to an
enhanced sensitivity of the anhydride toward hydrolysis and
water.
Toward One-Pot Amination/Diels-Alder Process. Encour-
aged by the results obtained in the above amination and
cycloaddition reactions, we started to examine combination of
both reactions in a one-pot sequence using 1, morpholine and
N-phenylmaleimide as starting material. The major point was
to determine suitable conditions for both reactions. If water was
the adequate solvent for the amination reaction, the cycloaddition
required toluene or dioxane to proceed without side reactions.
Thus, due to the high boiling point and water-miscible character,
1,4-dioxane was chosen as common solvent for both reactions.
In a first experiment under one-pot conditions, 3 equiv of
morpholine, 4 equiv of triethylamine and 3 equiv of dienophile
were reacted with furane 1. Only traces of aniline 4b could be
1
detected in H NMR of the crude material in dioxane. Thus,
we started optimization of several parameters such as solvent,
dienophile/diene and morpholine/triethylamine ratios.
The same reaction was then realized using dioxane/water
combination in various ratios and monitored by TLC. Complete
disappearance of the starting furan 1 was observed in 4 h using
a 9/1 dioxane/water ratio. Subsequent addition of the dienophile
led to various results depending on the presence of an additive.
Indeed, only the presence of MgSO4 as dehydration agent
allowed us to isolate aniline 4b in 25% yield (Table 1, entry
1). In addition, both morpholine/Et3N and 2a/dienophile ratios
were essential to the obtention of anilines. As indicated in Table
1, when the reaction was carried out with 2 equiv of morpholine
and Et3N, a substancial increase of aniline yields was observed
(entry 2), most likely due to the absence or minimization of
nucleophilic addition of residual amines at the dienophile.22
Moreover, dramatic influence of dienophile amounts over the
reaction rates is shown in entries 3 and 4. Reducing the amount
of dienophile to 1 equiv led to poor results (entry 3). In contrast,
the use of 4 equiv afforded the expected aniline 4b in a good
(22) In addition to expected anilines, side products rising from Michael
addition type of residual secondary amines on the dienophile were also
obtained. Data collected are in full agreement with the structure of the side
product. See experimental part for a full characterization of the compound
6.
J. Org. Chem, Vol. 73, No. 6, 2008 2193

Medimagh et al.
SCHEME 3. Anilines 4 through One-Pot Process
overall 79% yield (entry 4). Finally, the best result was obtained
with 2 equiv of morpholine, 2 equiv of Et3N, 4 equiv of
dienophile and increasing reaction time to 24 h. In these
conditions aniline 4b was isolated in nearly quantitative yield
(entry 5).
Next, other amines were checked in the one-pot amination/
Diels-Alder sequence (Scheme 3). Gratifyingly, several new
anilines, substituted by valuable carbonyl groups, were prepared
in overall satisfactory yields according to the aforementioned
procedure. The same conditions (Table 1, entry 2) were used
to appreciate at best the reactivity of secondary amines and not
to hide their nucleophilic features.
Results depicted in Scheme 3 deserve some comments. First,
our results corroborate the general nucleophilic reactivity order
established in recent Mayr’s group calculations.23 Increase of
the nitrogen atom donating ability in the starting amine and
aminofuran led to a clear enhancement of both amination and
Diels-Alder reactions. Classical synchronous as well as asyn-
chronous Diels-Alder mechanisms may account for the results
we observed in these series. It is also worth noting that increase
of ring strain from six- to three-membered cyclic amine resulted
in a sharp decrease of the amination and/or Diels-Alder
efficiency. Indeed, pyrrolidine-based aniline 4g was isolated with
a modest 27% and degradation took place with azetidine and
aziridine derivatives. Second, this procedure tolerates function-
alized amines as exemplified in structures 4h-j, which were
obtained in yields ranging from 62% to 96%. The use of
unprotected bis-amines such as piperazine and homopiperazine
led to unexpected results. No traces of dimeric compounds
resulting from a double amination/Diels-Alder sequence could
be isolated. In contrast, the mono amination/Diels-Alder
sequence followed by Michael addition between the residual
free nitrogen atom and N-phenylmaleimide afforded 4k and 4l
in 22% and 26% yields, respectively. Third, purification of
furans, especially when substituted by polar and functionalized
amino groups, is a tedious task, due in part to their well-known
instability. The one-pot amination/Diels-Alder sequence not
only avoids dull purification of the intermediates but also allows
a more easy purification of the less polar anilines.
Conclusion
In conclusion, we have developed a novel amination/Diels-
Alder reaction sequence from furans to anilines. This one-pot,
two-step procedure allowed the easy preparation of polysub-
stituted anilines. In addition, we also highlighted the first
selective synthesis of stable oxabicyclic structures in Diels-
Alder reactions involving aminofuraldehydes as dienophiles.
Experimental Section
General. Unless otherwise noted, all starting materials were
obtained from commercial suppliers and used without purification.
Petroleum ether was distilled under argon. Toluene and 1,4-dioxane
were used without distillation. All reactions were carried out under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator and the residue was
purified by silica gel chromatography using an ethyl acetate/
petroleum ether mixture as the eluent unless specified otherwise.
NMR spectra were recorded on a 300 and 200 MHz Brucker
spectrometer. Chemical shifts were reported in ppm relative to the
residual solvent peak (7.26 ppm for CHCl3, 2.05 ppm for acetone)
for 1H spectra and (77.00 ppm for CDCl3, 206.00 ppm for acetone-
d6) for 13C spectra. Melting points were measured on a Bu¨chi
Melting-Point B-545 and were uncorrected. High-resolution mass
spectroscopy data were recorded on a Autospec Ultima (Waters/
Micromass) device with a resolution of 5000 RP at 5%. Impact
electronic and chemical ionization spectroscopies were recorded
on a HP5989 B device of Hewlett-Packard; for electrospray mass
(23) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679-
3688.
2194 J. Org. Chem., Vol. 73, No. 6, 2008

One-Pot Two-Step Amination/Diels-Alder Sequences
spectroscopy an add-on 59 987 A was used; Branford source-type;
4 µL/min. Infrared spectra were recorded on a FT IR spectrometer
Nicolet Impact 400 D of Nicolet Instruments in KBr for liquid and
solid compounds. TLC was carried out on Silica Gel 60 F254 (0.5
mm thickness).
General Procedure for Amination. In a 25 mL round-bottom
flask were mixed 1 g of 5-bromo-2-furaldehyde (5.71 mmol), 2.38
mL of triethylamine (17.13 mmol, 3 equiv) and 1055 µL of
morpholine (12 mmol, 2 equiv) in 4 mL of water. The mixture
was heated at reflux for 20 min. The medium was allowed to cool
down at room temperature then extracted with 3 × 10 mL of CH2-
Cl2. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (petroleum ether/EtOAc 7:3) to give 818
mg of 5-morpholino-2-furancarboxaldehyde 2a as brown crystals
(79%).19
128.4 (CH), 129.2 (2CH), 131.2 (C), 133.5 (HCdCCHO), 135.2
(C), 153.1 (C), 166.1 (CON), 166.7 (CON), 188.2 (CHO). EI-MS
m/z (rel int): 336 (20), 318 (40), 306 (35), 293 (45), 250 (25), 167
(40), 149 (80), 57 (100). ESI-MS MeOH m/z (rel int): 695.3 (15,
2M + Na+), 393.5 (50), 391.3 (55, M + MeOH + Na+), 367.3
(20), 359.3 (100). HR-MS m/z calcd for C19H16N2O4 336.1110,
found 336.1110 ( 0.0001.
Aniline 4a. Following the procedure of cycloaddition, 50 mg of
2a (0.27 mmol) and 79.4 mg of maleic anhydride (0.81 mmol, 3
equiv) were mixed in toluene. After reaction, then concentration
in vaccum, the crude was purified by silica gel chromatography
(petroleum ether/EtOAc 7:3) to give a yellow solid (30%). Mp
187.5-189 °C. IR (KBr, ν, cm-1): 2963.0, 2925.6, 2852.4, 1827.3,
1766.1, 1684.0, 1671.9, 1616.9, 1547.8, 1435.9, 1261.4, 1240.0,
1214.8, 1111.7, 1052.8, 1019.7, 984.9, 918.6, 901.7, 801.4, 747.9.
1H NMR (CDCl3, 300 MHz): δ 3.56-3.59 (m, 4H, NCH2), 3.93-
3.96 (m, 4H, OCH2), 7.23 (d, 3J ) 9.1 Hz, 1H, HCdCN), 8.22 (d,
1H, 3J ) 8.9 Hz, HCdCCHO), 10.78 (s, 1H). 13C NMR (acetone-
d6, 75 MHz): δ 51.5 (2C, NCH2), 66.9 (2C, OCH2), 115.7 (C),
123.8 (HCdCN), 126.0 (C), 134.5 (HCdCCHO), 135.9 (C), 154.2
(C), 165.8 (COO), 166.6 (COO), 186.7 (CHO). ESI-MS MeOH
m/z (rel int): 316.2 (15, M + MeOH + Na+), 338.2 (10, M +
MeONa + Na+). HR-MS m/z calcd for C13H11NO5 261.0637, found
261.0637 ( 0.0001.
5-Piperidino-2-furancarboxaldehyde 2b. Following the general
procedure for amination, 5-bromo-2-furaldehyde led to brown
crystals (80%) after flash chromatography (petroleum ether/EtOAc
7:3).19
5-(N-Allyl-N-methyl)amino-2-furancarboxaldehyde 2c. Fol-
lowing the general procedure for amination, 5-bromo-2-furaldehyde
led to a purple oil (78%) after flash chromatography (petroleum
ether/EtOAc 6:4). IR (KBr, ν, cm-1): 3125.6, 3080.9, 2932.6,
2808.2, 1650.3, 1584.8, 1542.3, 1423.1, 1403.2, 1334.5, 1300.3,
1036.5, 1008.5, 919.8, 890.6, 775.6. 1H NMR (CDCl3, 300 MHz):
Cycloadduct 5a. Following the procedure of cycloaddition, 50
mg of 2a (0.27 mmol) and 100 µL of dimethylacethylene dicar-
boxylate (0.81 mmol, 3 equiv) were mixed in toluene. After
reaction, then concentration in vaccum, the crude was purified by
extraction with cold petroleum ether. The combined organic phase
was concentrated under reduced pressure and afforded the pure
cycloadduct (70%). Mp 198.2-199.5 °C. IR (KBr, ν, cm-1):
2979.2, 2958.5, 2860.6, 2830.3, 1735.5, 1683.3, 1583.2, 1474.5,
1441.2, 1340.1, 1318.9, 1248.9, 1187.2, 1150.8, 1112.8, 984.8,
3
δ 3.01 (s, 3H, NCH3), 3.96 (d, J ) 5.7 Hz, 2H, NCH2CHCH2),
5.16-5.24 (m, 3H, NCH2CHCH2 + HCdCN), 5.68-5.88 (m, 1H,
3
NCH2CHCH2), 7.19 (d, J ) 3.3 Hz, 1H, HCdCCHO), 8.95 (s,
1H, CHO). 13C NMR (CDCl3, 75 MHz): δ 35.3 (NCH3), 52.9
(NCH2CHdCH2), 86.2 (HCdCNMeCH2CHCH2), 118.0 (NCH2-
CHdCH2), 131.5 (NCH2CHdCH2), 131.7 (C, HCdCNMeCH2-
CHCH2), 144.0 (HCdCCHO), 163.3 (C, HCdCCHO), 170.5
(CHO). HR-MS m/z calcd for C9H11NO2 165.0790, found 165.0791
( 0.0001
1
864.9, 728.5. H NMR (acetone-d6, 300 MHz): δ 2.81-2.85 (m,
4H, NCH2), 3.64-3.67 (m, 4H, OCH2), 3.87 (s, 3H, CO2Me), 3.92
3
3
(s, 3H, CO2Me), 7.06 (d, J ) 9.1 Hz, 1H, HC-CN), 7.61 (d, J
) 8.9 Hz, 1H, HC-CCHO), 10.75 (s, 1H, CHO). 13C NMR
(acetone-d6, 75 MHz): δ 52.2 (NC-CCO2CH3), 53.2 (HOCC-
CCO2CH3), 54.1 (2C, NCH2), 67.8 (2C, OCH2), 110.1 (C), 119.9
(HC-CN), 131.1 (HC-CCHO), 135.7 (C), 143.1 (C, CdC), 159.5
(C, CdC), 168.3 (NC-CCO2CH3), 169.7 (HOCC-CCO2CH3),
190.5 (CHO). HR-MS m/z calcd for C15H17NO7 323.1005, found
323.1005 ( 0.0001.
5-(4-N-Methoxyphenyl-N-methylamino)-2-furancarboxalde-
hyde 2d. Following the general procedure for amination, 5-bromo-
2-furaldehyde led to a yellow solid (48%) after flash chromatog-
raphy (petroleum ether/EtOAc 65:35). Mp 70.1-70.8 °C. IR (KBr,
ν, cm-1): 3138.9, 2914.1, 2821.0, 1646.1, 1589.7, 1563.6, 1536.4,
1506.7, 1401.7, 1342.5, 1303.5, 1240.3, 1167.8, 1026.5, 752.3,
1
720.5, 560.7, 529.9. H NMR (CDCl3, 300 MHz): δ 3.44 (s, 3H,
3
NCH3), 3.81 (s, 3H, OCH3), 5.22 (d, J ) 3.8 Hz, 1H, HCdCN),
3
6.90 (d, J ) 8.9 Hz, 2H, Ph), 7.19-7.26 (m, 3H, Ph + HCd
Cycloadduct 5b. Following the procedure of cycloaddition, 50
mg of 2b (0.27 mmol) and 100 µL of dimethylacethylene
dicarboxylate (0.81 mmol, 3 equiv) led to a brown oil (70%). Mp
61.8-63.8 °C. IR (KBr, ν, cm-1): 2918.5, 2849.1, 1740.2, 1727.8,
1679.8, 1466.4, 1441.7, 1335.9, 1242.2, 1212.1, 1015.2. 1H NMR
(acetone-d6, 300 MHz): δ 1.50-1.59 (m, 6H, NCH2CH2CH2),
2.76-2.86 (m, 4H, NCH2), 3.85 (s, 3H, CO2Me), 3.92 (s, 3H, CO2-
CCHO), 9.02 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz): δ 38.7
(NCH3), 55.5 (OCH3), 88.4 (HCdCNPhOCH3), 114.8 (CH, NCd
CH-HCdCOMe), 125.9 (CH, NCdCH-HCdCOMe), 131.2
(HCdCCHO), 136.6 (C, HCdCNPhOCH3), 144.5 (C), 157.9 (C,
HCdCCHO), 162.9 (C), 171.1 (CHO). CI-MS NH3 m/z (rel int):
463 (10, 2M + H+), 249 (1, M + NH4+), 232 (100, MH+).
General Procedure for Cycloaddition. A mixture of 50 mg of
amino furaldehyde (0.27 mmol) and 0.81 mmol (3 equiv) of
dienophile was strirred in toluene (2 mL) and heated at 70 °C for
18 h. The solution was concentrated at reduced pressure, and then
the residue was purified.
3
3
Me), 7.02 (d, J ) 8.9 Hz, 1H, HC-CN), 7.55 (d, J ) 9.1 Hz,
1H, HC-CCHO), 10.72 (s, 1H, CHO). 13C NMR (acetone-d6, 75
MHz): δ 24.6 (NCH2CH2CH2), 27.3 (2C, NCH2CH2CH2), 52.1
(NC-CCO2CH3), 53.1 (HOCC-CCO2CH3), 55.2 (2C, NCH2),
109.9 (C), 119.8 (HC-CN), 131.2 (HC-CCHO), 135.5 (C), 144.7
(NCCdC), 159.3 (OHCCCdC), 168.4 (NC-CCO2CH3), 169.9
(HOCC-CCO2CH3), 190.4 (CHO). CI-MS CH4 m/z (rel int): 294
(100, (M - CO)H+), 322 (42, MH+). HR-MS m/z calcd for C16H19-
NO6 321.1212, found 321.1218 ( 0.0001.
Following the procedure for cycloaddition, 50 mg of 2a (0.27
mmol) and 140.3 mg of N-phenylmaleimide (0.81 mmol, 3 equiv)
were mixed in toluene. After reaction, then concentration in vaccum,
the crude was purified by silica gel chromatography (petroleum
ether/EtOAc 1:1) to afford aniline 4b as yellow crystals (79%).
Mp 232.4-233.6 °C. TLC: Rf ) 0.31 (cyclohexane/EtOAc 6:4).
IR (KBr, ν, cm-1): 2969.3, 2867.8, 1707.0, 1685.6, 1610.4, 1495.2,
1400.6, 1381.5, 1242.3, 1201.5, 1165.3, 1117.3, 992.9, 762.5, 692.3.
1H NMR (300 MHz, CDCl3): δ 3.51 (t, 3J ) 4.6 Hz, 4H, NCH2),
Cycloadduct 5c. Following the procedure of cycloaddition, 50
mg of 2c (0.27 mmol) and 100 µL of dimethylacethylene dicar-
boxylate (0.81 mmol, 3 equiv) afforded a colorless solid (62%).
IR (KBr, ν, cm-1): 3129.1, 2931.3, 2808.6, 1650.1, 1585.8, 1542.7,
1
1403.7, 1334.3, 1300.8, 1036.7, 1008.5, 775.6. H NMR (CDCl3,
3
3
5
3.93 (t, J ) 4.6 Hz, 4H, OCH2) 7.21 (d, J ) 13.2 Hz, J ) 0.7
Hz, 1H, HCdCN), 7.39-7.42 (m, 3H, Ph), 7.48-7.54 (m, 2H, Ph),
300 MHz): δ 2.57 (s, 3H, NMe), 3.40 (d, 3J ) 6.2 Hz, 2H, NCH2-
CHCH2), 3.88 (s, 3H, CO2Me), 3.90 (s, 3H, CO2Me), 5.04-5.16
(m, 2H, NCH2CHCH2), 5.68-5.82 (m, 1H, NCH2CHCH2), 7.01
3
5
8.17 (d, J ) 13.2 Hz, 1H, HCdCCHO), 10.96 (d, J ) 0.7 Hz,
1H, CHO). 13C NMR (75 MHz, CDCl3): δ 51.4 (2C, NCH2), 66.7
(2C, OCH2), 116.0 (C), 122.3 (HCdCN), 126.1 (C), 126.9 (2CH),
3
3
(d, J ) 9 Hz, 1H, HC-CN), 7.40 (d, J ) 9.1 Hz, 1H, HC-
CCHO), 10.90 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz): δ 43.0
J. Org. Chem, Vol. 73, No. 6, 2008 2195

Medimagh et al.
3
5
(NCH3), 52.2 (NC-CCO2CH3), 52.9 (HOCC-CCO2CH3), 61.0
(NCH2CHdCH2), 108.8 (C), 117.1 (NCH2CHdCH2), 119.5 (HC-
CN), 131.0 (HC-CCHO), 134.2 (C), 135.4 (NCH2CHdCH2), 142.8
(C, CdC), 159.1 (C, CdC), 168.6 (NC-CCO2CH3), 169.2
(HOCC-CCO2CH3), 188.9 (CHO). ESI-MS CH3CN m/z (rel int):
280.2 (100, (M - CO)H+), 302.2 (60, (M + Na+) - CO), 330.2
(50, M + Na+), 346.2 (20, M + K+), 581.4 (30, 2(M - CO) +
Na+), 637.1 (10, 2M + Na+). HR-MS m/z calcd for C15H17NO6
307.1056, found 307.1056 ( 0.0001.
Hz, 4H, NCH2), 7.12 (dd, J ) 9.2 Hz, J ) 0.8 Hz, 1H, HCd
CN), 7.24-7.46 (m, 5H, Ph), 8.00 (dd, 3J ) 9.1 Hz, 4J ) 1.1 Hz,
1H, HCdCCHO), 10.89 (d, J ) 0.8 Hz, 1H, CHO). 13C NMR
5
(75 MHz, CDCl3): δ 13.0 (2C, NCH2CH3), 46.9 (2C, NCH2), 112.5
(C), 121.6 (HCdCN), 124.0 (C), 127.0 (2CH), 128.2 (CH), 129.1
(2CH), 131.6 (C), 132.5 (HCdCCHO), 136.2 (C), 151.4 (C), 166.4
(CON), 166.9 (CON), 188.5 (CHO), EI-MS m/z (rel int): 322 (60),
307 (45), 293 (100), 279 (25), 265 (10), 249 (15), 77 (20). CI-MS
NH3 m/z (rel int): 323 (100, MH+).
Cycloadduct 5d. Following the procedure of cycloaddition, 50
mg of 2d (0.27 mmol) and 100 µL of dimethylacethylene
dicarboxylate (0.81 mmol, 3 equiv) afforded a solid (45%). IR (KBr,
ν, cm-1): 3141.1, 3004.6, 2951.4, 2928.5, 1728.1, 1681.5, 1512.0,
Aniline Homopiperidine 4e. Yellow crystals, 94% yield, mp
160.4-161.5 °C. TLC: Rf ) 0.13 (cyclohexane/EtOAc 9:1). IR
(KBr, ν, cm-1): 2944.6, 2929.2, 2852.8, 1701.3, 1671.4, 1611.5,
1
1539.9, 1504.9, 1423.2, 1378.4, 1257.1, 1162.2, 765.5. H NMR
1
1444.7, 1323.4, 1241.9, 1203.2, 1035.4, 1013.2, 818.9, 804.2. H
(300 MHz, CDCl3): δ 1.59-1.63 (m, 4H, NCH2CH2CH2), 1.86-
3
NMR (CDCl3, 300 MHz): δ 3.07 (s, 3H, NCH3), 3.75 (m, 6H,
OCH3+ CO2Me), 3.94 (s, 3H, CO2Me), 6.59 (d, 3J ) 9.2 Hz, 1H,
Ph), 6.76 (d, 3J ) 9.2 Hz, 1H, Ph), 7.06 (d, 3J ) 8.9 Hz, 2H, HC-
1.90 (m, 4H, NCH2CH2), 3.80 (t, J ) 5.8 Hz, 4H, NCH2), 7.15
3
(d, J ) 9.2 Hz, 1H, HCdCN), 7.40-7.48 (m, 3H, Ph), 7.50-
3
7.54 (m, 2H, Ph), 8.05 (d, J ) 9.2 Hz, 1H, HCdCCHO), 10.96
4
CN), 7.25-7.27 (m, 2H, Ph + HC-CCHO), 11.06 (d, J ) 0.4
(s, 1H, CHO). 13C NMR (75 MHz, CDCl3): δ 27.5 (2C, NCH2-
CH2CH2), 28.0 (2C, NCH2CH2), 53.5 (2C, NCH2), 110.8 (C), 120.8
(HCdCN), 123.5 (C), 127.0 (2CH), 128.2 (CH), 129.1 (2CH), 131.6
(C), 132.1 (HCdCCHO), 136.4 (C), 152.0 (C), 166.4 (CON), 167.0
(CON), 188.5 (CHO). EI-MS m/z (rel int): 348 (100), 305 (80),
277 (50), 255 (25). CI-MS CH4 m/z (rel int): 389 (10, MC3H5+),
377 (25, MC2H5+), 349 (100, MH+). ESI-MS m/z (rel int): 719.4
(50, 2M + Na+), 371.3 (100, M + Na+). HR-MS m/z calcd for
C21H20N2O3 348.1473, found 348.1475 ( 0.0001.
Hz, 1H, CHO). 13C NMR (CDCl3, 75 MHz): δ 41.1 (NCH3), 52.3
(NC-CCO2CH3), 53.4 (HOCC-CCO2CH3), 55.6 (OCH3), 110.7
(C), 114.8 (2C, NCCHdCHCOMe), 116.9 (2C, NCCHdCHCOMe),
117.6 (C), 121.3 (HC-CNPhOMe), 137.1 (HC-CCHO), 140.6 (C),
145.1 (HC-CNPhOMe), 153.7 (CCHO), 160.5 (C), 168.0 (NC-
CCO2CH3), 169.7 (HOCC-CCO2CH3), 190.9 (CHO). ESI-MS
CH3CN m/z (rel int): 368.2 (80, (M + Na+) - CO), 384.2 (100,
(M + K+) - CO), 412.1 (25, M + K+), 713.3 (70, 2(M - CO) +
Na+). HR-MS m/z calcd for C19H19NO7 373.1162, found 373.1161
( 0.0001.
Aniline (Dihomo)piperidine 4f. Yellow crystals, 89% yield, mp
117.7-122.9 °C. TLC: Rf ) 0.30 (cyclohexane/EtOAc 9:1). IR
(KBr, ν, cm-1): 2952.5, 2929.0, 2852.7, 1754.9, 1705.7, 1669.4,
1611.2, 1534.6, 1517.5, 1500.9, 1455.5, 1425.1, 1381.7, 1343.7,
1268.9, 1209.2, 1173.9, 1118.6, 820.9, 762.3, 749.6, 691.9. 1H NMR
(300 MHz, CDCl3): δ 1.40-1.65 (m, 6H, NCH2CH2CH2CH2),
General Procedure for One-Pot Process. In a 25 mL round-
bottom flask was dissolved 63.7 mg of 5-bromo-2-furaldehyde (0.35
mmol) in 2.0 mL of 1,4-dioxane and 0.2 mL of water. 0.07 mL of
morpholine (0.78 mmol, 2 equiv) and 0.10 mL of triethylamine
(0.72 mmol, 2 equiv) were added then the resulting solution was
stirred with an oversized magnetic bar during 4 h at reflux. The
mixture was allowed to cool down at room temperature, then 2 g
of magnesium sulfate were added, and 253.7 mg of N-phenylma-
leimide (1.43 mmol, 4 equiv). The mixture was refluxed for 24 h,
then the medium was allowed to cool down at room temperature
and the solvent was removed under vaccum. The residue purified
by flash-chromatography with a gradient of cyclohexane/EtOAc
70:30 to 60:40 as eluent led to 116.6 mg of rearomatized
cycloadduct 4b (0.347 mmol, 98%) as yellow crystals.
3
1.72-1.83 (m, 4H, NCH2CH2), 3.82 (t, J ) 5.9 Hz, 4H, NCH2),
7.05 (d, 3J ) 9.4 Hz, 1H, HCdCN), 7.30-7.36 (m, 3H, Ph), 7.39-
3
7.46 (m, 2H, Ph), 7.98 (d, J ) 9.3 Hz, 1H, HCdCCHO), 10.90
(s, 1H, CHO). 13C NMR (75 MHz, CDCl3): δ 24.5 (2C, NCH2-
CH2CH2), 26.6 (CH2), 26.4 (2C, NCH2CH2), 54.2 (2C, NCH2),
110.6 (C), 120.8 (HCdCN), 123.5 (C), 127.2 (2CH), 128.3 (CH),
129.2 (2CH), 131.7 (C), 132.4 (HCdCCHO), 136.6 (C), 150.9 (C),
166.5 (CON), 167.0 (CON), 188.6 (CHO). ESI-MS m/z (rel int):
385.3 (20, M + Na+), 287.3 (100). HR-MS m/z calcd for
C22H22N2O3 362.1630, found 362.1630 ( 0.0001.
Other rearomatized cycloadducts (4c-4l) were obtained by this
one-pot procedure with 2 equiv of secondary amine, 2 equiv of
triethylamine, 3 equiv of N-phenylmaleimide. The reaction time
was always of 4 h for the amination step, then 18 h for the Diels-
Alder.
Aniline Pyrollidine 4g. Yellow crystals, 27% yield, mp 224.4-
225.5 °C. TLC: Rf ) 0.60 (cyclohexane/EtOAc 6:4), 0.29
(petroleum ether/EtOAc 8:2). IR (KBr, ν, cm-1): 2962.3, 2922.1,
2874.0, 1702.1, 1680.6, 1612.3, 1545.5, 1503.4, 1427.3, 1376.8,
1
1361.3, 1254.9, 1196.7, 1155.4, 1116.2, 763.4, 689.5, 624.4. H
Aniline Piperidine 4c. Yellow crystals, 58% yield, mp 198.2-
199.5 °C. TLC: Rf ) 0.72 (cyclohexane/EtOAc 6:4), 0.21 (cyclo-
hexane/EtOAc 9:1). IR (KBr, ν, cm-1): 2928.4, 2848.9, 1705.0,
1684.6, 1610.3, 1502.1, 1378.4, 1242.9, 1186.1, 1129.0, 1114.2,
761.6, 690.4. 1H NMR (300 MHz, CDCl3): δ 1.65-1.72 (m, 2H,
NMR (300 MHz, CDCl3): δ 2.01-2.06 (m, 4H, NCH2CH2), 3.73
3
3
(t, J ) 6.5 Hz, 4H, NCH2) 6.96 (d, J ) 9.2 Hz, 1H, HCdCN),
7.37-7.42 (m, 3H, Ph), 7.48-7.53 (m, 2H, Ph), 8.04 (d, 3J ) 8.7
Hz, 1H, HCdCCHO), 10.94 (s, 1H, CHO). 13C NMR (75 MHz,
CDCl3): δ 25.7 (2C, NCH2CH2), 52.4 (2C, NCH2), 110.0 (C), 119.8
(HCdCN), 123.1 (C), 126.9 (2CH), 128.1 (CH), 129.0 (2CH), 131.6
(C), 132.3 (HCdCCHO), 136.0 (C), 149.1 (C), 166.4 (CON), 167.0
(CON), 188.4 (CHO). EI-MS m/z (rel int): 320 (100), 291 (40),
264 (40), 263(40), 235 (50), 223 (20), 160 (25), 144 (20), 77 (25).
CI-MS NH3 m/z (rel int): 321 (100, MH+). HR-MS m/z calcd for
C19H16N2O3 320.1161, found 320.1160 ( 0.0001.
3
NCH2CH2CH2), 1.77-1.84 (m, 4H, NCH2CH2), 3.49 (t, J ) 5.3
3
Hz, 4H, NCH2), 7.20 (d, J ) 8.9 Hz, 1H, HCdCN), 7.39-7.43
3
(m, 3H, Ph), 7.48-7.54 (m, 2H, Ph), 8.11 (d, J ) 9.1 Hz, 1H,
HCdCCHO), 10.95 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3):
δ 23.8 (NCH2CH2CH2), 25.90 (2C, NCH2CH2), 52.6 (2C, NCH2),
114.9 (C), 122.5 (HCdCN), 125.0 (C), 126.9 (2CH), 128.2 (CH),
129.1 (2CH), 131.5 (C), 133.0 (HCdCCHO), 135.5 (C), 153.5 (C),
166.1 (CON), 166.9 (CON), 188.3 (CHO). EI-MS m/z (rel int):
334 (100), 305 (45), 277 (50), 250 (45), 241 (25), 213 (25), 185
(25), 167 (25), 158 (25), 84 (50), 77 (50). CI-MS NH3 m/z (rel
int): 335 (100, MH+). HR-MS m/z calcd for C20H18N2O3 334.1317,
found 334.1318 ( 0.0001.
Aniline Hydroxyethoxypiperazine 4h. Yellow oil, 77% yield.
TLC: Rf ) 0.14 (EtOAc: MeOH 9:1). IR (KBr, ν, cm-1): 3369.3,
2945.2, 2828.1, 1731.5, 1707.9, 1610.5, 1499.7, 1454.8, 1379.9,
1
1296.9, 1237.6, 1139.5. H NMR (300 MHz, CDCl3): δ 2.65 (t,
3J ) 5.3 Hz, 2H, NCH2), 2.70-2.80 (m, 4H, NCH2), 3.50-3.55
(m, 4H, OCH2), 3.60-3.63 (m, 2H, OCH2), 3.67-3.70 (m, 4H,
OCH2), 3.79 (br, 1H, OH), 7.17 (d, 3J ) 8.9 Hz, 1H, NCH), 7.37-
Aniline Diethylamine 4d. Yellow oil, 36% yield. TLC: Rf )
0.53 (petroleum ether/EtOAc 8:2). IR (KBr, ν, cm-1): 2970.4,
2931.0, 2875.8, 1696.4, 1675.8, 1610.0, 1543.8, 1504.2, 1424.6,
1404.4, 1396.6, 1258.6, 1153.9, 741.3, 694.3. 1H NMR (300 MHz,
CDCl3): δ 1.30 (t, 3J ) 7.0 Hz, 6H, NCH2CH3), 3.66 (t, 3J ) 7.1
3
7.41 (m, 3H, Ph), 7.47-7.50 (m, 2H, Ph), 8.11 (dd, J ) 8.9 Hz,
4J ) 1.7 Hz, 1H, HCdCCHO), 10.92 (s, 1H, CHO). 13C NMR (75
MHz, CDCl3): δ 50.7 (2NCH2), 53.0 (2NCH2), 57.6 (OCH2), 61.8
(OCH2), 67.4 (OCH2), 72.3 (OCH2), 115.7 (C), 122.5 (HCdCN),
2196 J. Org. Chem., Vol. 73, No. 6, 2008

One-Pot Two-Step Amination/Diels-Alder Sequences
125.7 (C), 126.8 (2CH), 128.3 (CH), 129.1 (2CH), 131.2 (C), 133.3
(HCdCCHO), 135.1 (C), 152.9 (C), 166.0 (CON), 166.7 (CON),
188.1 (CHO). EI-MS m/z (rel int): 423 (10), 380 (25), 349 (30),
348 (100), 305 (20). CI-MS CH4 m/z (rel int): 452 (15, MC2H5+),
424 (100, MH+), 348 (15). ESI-MS, MeOH m/z (rel int): 478.2
(95, M + MeOH + Na+), 456.2 (75, M + MeOH+), 446.1 (100,
M + Na+), 424.1 (50, MH+). HR-MS m/z calcd for C23H25N3O5
423.1794, found 423.1793 ( 0.0001.
(4CH), 131.3 (C), 131.4 (C), 132.5 (HCdCCHO), 136.0 (C), 152.0
(C), 166.3 (CON), 166.8 (CON), 173.8 (CON), 175.3 (CON), 188.3
(CHO). EI-MS m/z (rel int): 522 (5), 448 (20), 434 (25), 402 (20),
205 (25), 173 (80), 146 (40), 119 (35), 113 (50), 103 (35), 93 (100).
CI-MS CH4 m/z (rel int): 523 (2, MH+), 350 (25), 206 (100), 174
(95). ESI-MS, MeOH m/z (rel int): 1099.8 (10, 2M + MeOH +
Na+), 1067.6 (15, 2M + Na+), 598.3 (40), 591.4 (60), 577.4 (60,
M + MeOH + Na+), 545.3 (100, M + Na+), 413.3 (30). HR-MS
m/z calcd for C30H26N4O5 522.1903, found 522.1901 ( 0.0001.
Aniline Allylpiperazine 4i. Yellow crystals, 91% yield, mp
97.3-98.8 °C. IR (KBr, ν, cm-1): 3069.4, 2874.1, 2815.1, 1764.2,
1710.6, 1680.7, 1609.5, 1552.9, 1501.0, 1445.4, 1382.2, 1336.0,
1237.2, 1196.5, 1173.8, 1119.0, 1004.2, 921.1, 762.2, 747.6, 691.3.
1H NMR (300 MHz, CDCl3): δ 2.60 (t, 3J ) 4.7 Hz, 4H, NCH2),
2.98 (d, 3J ) 6.5 Hz, 4H, NCH2CHCH2), 3.47 (t, 3J ) 4.7 Hz, 4H,
NCH2), 5.08-5.17 (m, 2H, NCH2CHCH2), 5.72-5.85 (m, 1H,
Aniline Piperazine 4l. Yellow oil, 22% yield. TLC: Rf ) 0.13
(cyclohexane/EtOAc 4:6). IR (KBr, ν, cm-1): 2925.1, 2850.9,
1711.5, 1609.8, 1499.9, 1444.0, 1382.3, 1240.5, 1172.7. 1H NMR
(300 MHz, CDCl3): δ 2.78-2.86 (m, 2H, NCH2+H2CCON),
2.92-2.99 (m, 1H, H2CCON), 3.05-3.08 (m, 2H, NCH2), 3.52-
3
3.95 (m, 4H, NCH2), 3.97-4.00 (m, 1H, NCH), 7.14 (d, J ) 8.9
3
NCH2CHCH2), 7.10 (d, J ) 9.1 Hz, 1H, HCdCN), 7.29-7.34
Hz, 1H, HCdCN), 7.19-7.21 (m, 2H, Ph), 7.32-7.48 (m, 8H, Ph),
3
3
4
(m, 3H, Ph), 7.39-7.44 (m, 2H, Ph), 8.03 (d, J ) 8.9 Hz, 1H,
8.10 (dd, J ) 8.9 Hz, J ) 1.5 Hz, 1H, HCdCCHO), 10.90 (s,
1H, CHO). 13C NMR (75 MHz, CDCl3): δ 31.3 (CH2CON), 49.1
(2C, NCH2), 51.1 (2C, NCH2), 62.4 (CHCON), 115.9 (C), 122.6
(HCdCN), 126.0 (C), 126.4 (2CH), 126.9 (2CH), 128.4 (CH), 128.8
(CH), 129.2 (4CH), 131.2 (C), 131.3 (C), 133.5 (HCdCCHO),
135.2 (C), 152.8 (C), 166.1 (CON), 166.7 (CON), 173.7 (CON),
174.6 (CON), 188.2 (CHO). EI-MS m/z (rel int): 508 (40), 334
(25), 305 (50), 293 (30), 229 (100), 173 (75), 119 (50). CI-MS
CH4 m/z (rel int): 524 (50), 391 (50), 279 (30), 261 (60), 206 (75),
183 (100). ESI-MS, MeOH m/z (rel int): 584.3 (40), 577.4 (50),
563.3 (75, M + MeOH + Na+), 531.2 (100, M + Na+), 413.3
(25), 172.1 (80). HR-MS m/z calcd for C29H24N4O5 508.1747, found
508.1743 ( 0.0001.
HCdCCHO), 10.85 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3):
δ 50.9 (2C, NCH2), 52.6 (2C, NCH2), 61.3 (NCH2CHCH2), 115.3
(C), 118.6 (NCH2CHCH2), 122.4 (HCdCN), 125.5 (C), 126.8
(2CH), 128.2 (CH), 128.9 (CH), 129.0 (CH), 131.2 (C), 133.2
(NCH2CHCH2), 134.2 (HCdCCHO), 135.1 (C), 152.9 (C), 165.9
(CON), 166.7 (CON), 188.0 (CHO). EI-MS m/z (rel int): 375 (20),
334 (10), 306 (20), 279 (15), 96 (100). CI-MS NH3 m/z (rel int):
376 (100, MH+). ESI-MS, MeOH m/z (rel int): 537.4 (25), 451.3
(50), 441.4 (30), 430.3 (60, M + MeOH + Na+), 408.4 (100, M +
MeOH + H+), 398.3 (100, M + Na+), 376.4 (100, MH+). HR-MS
m/z calcd for C22H21N3O3 375.1583, found 375.1583 ( 0.0001.
Aniline N-Methylallylamine 4j. Yellow solid, 62% yield, mp
75.2-80.2 °C. TLC: Rf ) 0.78 (pentane/EtOAc 6:4). IR (KBr, ν,
cm-1): 3070.3, 2964.7, 2874.1, 1747.8, 1705.3, 1680.4, 1609.9,
1550.3, 1502.8, 1402.5, 1374.6, 1248.2, 1200.3, 1174.1, 1143.0,
Michael Allylpiperazine 6. Yellow oil. IR (KBr, ν, cm-1):
3076.6, 2943.0, 2810.3, 1708.1, 1609.8, 1499.3, 1455.9, 1390.0,
1375.3, 1296.4, 1203.9, 1161.1, 1130.9, 1008.1, 758.3, 705.8, 697.3.
1H NMR (300 MHz, CDCl3): δ 2.47 (m, 3H), 2.56-2.64 (m, 3H),
2.80-2.96 (m, 6H), 3.88 (dd, 3J ) 8.7 Hz, 3J ) 5.1 Hz, 1H,
HCCONPh), 5.08-5.16 (m, 2H, NCH2CHCH2), 5.71-5.85 (m, 1H,
NCH2CHCH2), 7.17-7.20 (m, 2H, Ph), 7.31-7.42 (m, 3H, Ph).
13C NMR (75 MHz, CDCl3): δ 31.4 (H2CCONPh), 48.9 (NCH2-
CH2N), 52.7 (2C, NCH2CH2N), 61.4 (NCH2CHCH2), 62.3 (HC-
CONPh), 118.3 (NCH2CHCH2), 126.4 (2CH), 128.6 (CH), 129.1
(2CH), 131.4 (C), 134.5 (NCH2CHCH2), 174.0 (CON), 174.8
(CON). EI-MS m/z (rel int): 299 (15), 272 (20), 211 (100), 170
(30), 125 (50). CI-MS NH3 m/z (rel int): 300 (100, MH+). ESI-
MS m/z (rel int): 322.4 (30, M + Na+), 300.3 (100, MH+). HR-
MS m/z calcd for C17H21N3O2 299.1634, found 299.1633 ( 0.0001.
1
1115.9, 917.1, 826.6, 764.1, 691.8, 624.5. H NMR (300 MHz,
3
CDCl3): δ 3.06 (s, 3H, NMe), 4.05 (d, J ) 5.6 Hz, 2H, NCH2-
CHCH2), 5.08-5.21 (m, 2H, NCH2CHCH2), 5.81-5.94 (m, 1H,
3
NCH2CHCH2), 7.02 (d, J ) 9.1 Hz, 1H, HCdCN), 7.11-7.45
(m, 5H, Ph), 7.96 (d, 3J ) 9.1 Hz, 1H, HCdCCHO), 10.85 (s, 1H,
CHO). 13C NMR (75 MHz, CDCl3): δ 40.3 (NCH3), 58.2 (NCH2-
CHCH2), 118.4 (NCH2CHCH2), 121.6 (HCdCN), 124.2 (C), 125.9
(CH), 126.8 (CH), 127.8 (CH), 128.1 (CH), 129.0 (2CH), 132.4
(C), 132.8 (NCH2CHCH2), 134.0 (HCdCCHO), 135.6 (C), 152.4
(C), 166.0 (CON), 166.8 (CON), 188.1 (CHO). ESI-MS, MeOH
m/z (rel int): 375.2 (25, M + MeOH + Na+), 359.4 (15, M + K+),
343.2 (100, M + Na+). HR-MS m/z calcd for C19H16N2O3 320.1161,
found 320.1160 ( 0.0001.
Aniline Homopiperazine 4k. Yellow solid, 26% yield, mp
116.4-119.4 °C. TLC: Rf ) 0.22 (cyclohexane/EtOAc 3:7). IR
(KBr, ν, cm-1): 2928.7, 2852.0, 1709.0, 1671.9, 1609.2, 1543.9,
1499.7, 1455.5, 1419.0, 1379.3, 1194.0, 1165.9, 1119.4, 1070.2,
762.5, 694.0. 1H NMR (300 MHz, CDCl3): δ 2.09-2.11 (m, 2H,
NCH2CH2CH2N), 2.72 (dd, J ) 18.7 Hz, J ) 5.2 Hz, 1H, H2-
CCON), 2.78-2.90 (m, 1H, H2CCON), 3.01-3.13 (m, 3H, NCH2-
CH2CH2N+ NCH2CH2N), 3.19-3.26 (m, 1H, NCH2CH2N), 3.80
Acknowledgment. The authors are grateful to CNRS for a
grant (R.M.) and to the Universite´ de Versailles-Saint-Quentin-
en-Yvelines for financial and material support. The authors have
highly appreciated the helpful discussions with Vincent Stein-
meltz (ILV) in the mass spectrocopy elucidation of several
structures. We are also grateful to Dr. Sami Barrek & Chaouki
Belgacem (INRAP) for the high-resolution mass spectrospy
determinations.
2
3
3
3
(t, J ) 5.7 Hz, 2H, NCH2CH2CH2N), 3.93 (t, J ) 4.5 Hz, 1H,
NCH2CH2N), 4.08 (dd, 3J ) 9.2 Hz, 3J ) 5.1 Hz, 1H, NCH), 7.14
3
(d, J ) 9.2 Hz, 1H, HCdCN), 7.23-7.25 (m, 1H, Ph), 7.38-
Supporting Information Available: 1H and 13C NMR spectral
characterization data for compounds 2c, 2d, 4a-l, 5a-d, and 6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
3
7.54 (m, 9H, Ph), 8.07 (d, J ) 9.2 Hz, 1H, HCdCCHO), 10.96
(s, 1H, CHO). 13C NMR (75 MHz, CDCl3): δ 28.4 (NCH2CH2-
CH2N), 32.8 (CH2CON), 52.0 (NCH2), 52.1 (NCH2), 52.9 (NCH2),
54.4 (NCH2), 63.6 (CHCON), 117.7 (C), 120.8 (HCdCN), 124.1
(C), 126.3 (2CH), 127.0 (2CH), 128.2 (CH), 128.8 (CH), 129.1
JO7024916
J. Org. Chem, Vol. 73, No. 6, 2008 2197